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7b9bd6b7763313c6526b2c23ba1486e269e2d076	cdc	None	In 1977, the national injury rate for workers in rendering plants was reported to be almost twice that reported for the manufacturing industries sector. The need to assess and identify the underlying causes of this high rate and provide recommendations to reduce the incidence of these injuries prompted the National Institute for Occupational Safety and Health (NIOSH) to survey rendering plants and assess the occupational hazards of the rendering process. This document critically reviews the scientific and technical information concerning mechanical injury, physical agents (eg, noise, heat), and biological and chemical agents in the rendering workplace. Chapter III of this document, entitled Health and Safety Guidelines, is provided so individuals immediately responsible for hazard control in their specific workplace will have a basis on which to formulate their own occupational safety and health program. Employer knowledge of and adherence to these guidelines will reduce adverse effects on worker safety and health. This document is also intended for use by unions, industrial trade associations, and scientific and technical investigators to further their own objectives in providing for a safer workplace. Furthermore, it is intended to assist the Occupational Safety and Health Administration, US Department of Labor, in its standards development and compliance activities. Contributions to this document by NIOSH staff, other Federal agencies or departments, the review consultants, the National Renderers Association, and The United Food and Commercial Workers are gratefully acknowledged. The views and conclusions expressed in this document, together with the recommendations, are those of NIOSH. They are not necessarily those of the consultants, the reviewers selected by professional societies, or other Federal agencies. However, all comments, whether or not incorporated, have been carefully considered. konaia d. uoene, r.a.# Infections resulting from organisms associated with animal material occur occasionally. Workers may also be exposed to chemicals generally associated with cleanup or maintenance activities. Under certain conditions, hazardous gases can be generated by anaerobic reactions during the holding of accumulated organic raw materials. Rendering facilities are of two types, those directly associated with meatpacking and poultry slaughtering and dressing operations (onsite) and those that are independent of these operations. There are approximately 3,000 workers associated with onsite rendering facilities and about 9,000 workers associated with independent rendering facilities in the United States. Rendering processes are classified according to whether inedible or edible products are produced. The major inedible fat products are grease and inedible tallow; major inedible protein meal products are meat meal and meat-and-bone meal. Edible products include lard, edible tallow, and certain proteinaceous tissues. Based on information from the available literature, reviewer comments, and plant site visits, NIOSH recommends guidelines for engineering controls and work practices to reduce the number of injuries and illnesses in rendering plants. Recommendations for training, posting, personal protective equipment programs, medical surveillance, and maintenance of relevant records are also included. # Background and Scope of Document The rendering of animal materials was one of the first recycling industries. It began about 150 years ago, and grew as the meat products industry grew. Many new uses were found for products derived from materials such as grease, hair, blood, feathers, hides, and bones . Products from rendering operations are either inedible or edible; inedible products include inedible tallow and grease and various protein meals such as blood meal, feather meal, meat meal, bone meal, and meat-and-bone meal. Edible products include lard, edible tallow, and protein tissue . Rendering performed at meatpacking or poultry dressing plants is referred to as onsite, or captive, rendering. Onsite Tenderers produce almost all of the edible lard and edible tallows made. Rendering not performed at meatpacking or poultry dressing plants is referred to as offsite, or independent, rendering. According to the Census of Manufactures, the independent rendering industry accounted for 69% of the inedible tallow and grease in 1977 . This Census reported that 500 establishments were classified under Animal and Marine Fats and Oils (SIC code 2077); about 450 of these rendered animal materials. The number of workers at onsite rendering facilities (SIC codes 2011 and 2016) was estimated to be about 3,000 (A Phifer, written communication, June 1978). The National Renderers Association has estimated that half of the 9,000 workers employed by independent rendering plants are involved in plant operations and maintenance (WH Prokup, written communication, February 1981). Table 1-1 summarizes production figures for the rendering industry . This document concerns occupational exposure in the manufacture of rendered animal products, particularly the handling and processing of raw materials at the rendering plant as well as maintenance, cleanup, and repair work. The collection of raw materials from butcher shops, supermarkets, restaurants, farms, and meatpacking plants is not a part of the rendering production process, and is not discussed here. The guidelines in Chapter III apply to both onsite and independent rendering. # Inedible Rendering Raw materials for independent inedible rendering come from a variety of sources, including butcher shops, restaurants, grocery stores, feedlots, and meatpacking plants . The raw materials are usually bones and bone fragments, offal, blood, feathers, other cut-up materials, and barrels of restaurant grease. This material, usually delivered in barrels or by a dump truck, is weighed, evaluated for potential endproducts, and dumped into receiving pits or bins. The trucks and barrels are hosed out and the washings are emptied into an adjacent pit and drained into an onsite waste-treatment system. Separated solids are recycled into the receiving pits. Some independent rendering plants also process dead stock. Plants without mechanized pre-breakers and crushers that can process whole dead animals must have the carcasses cut up with axes or knives by plant personnel. This is done either with the animal lying on the floor or hanging from an overhead rail. Adapted from reference 3 The raw material in the receiving pit is then crushed or ground to the size necessary for cooking or moisture evaporation , To limit the production of odor and to maintain product quality of the tallow or grease and protein meal, raw material is usually processed promptly. Size reduction operations use equipment such as pre-breakers, shredders, grinders, and hashers. Following the size reduction step the raw material is sent on to cookers which can either be a batch or continuous type . Figure 1-1 is a generalized flow diagram of this process. Figure 1-1 also shows ancillary processes which are discussed later. Onsite rendering operations in meatpacking and poultry dressing plants usually receive raw materials directly from the k ill floor. If the rendering operation is in a separate building on the same premises, the raw material is moved by pump or truck to the cookers. At this point the onsite and offsite rendering processes are similar . # (a) Batch Cooker Processing Moisture is evaporated and fats are released from the raw material by heating it under controlled conditions . A quantity of material is cooked in batch cookers to a specified moisture or temperature, and then the load is discharged. Figure 1-2 is a generalized diagram of a batch cooking system . Dry-batch rendering is the method most commonly used for inedible products. In this method, moisture is separated from the raw material by evaporation. Heat for evaporation is provided by steam in a jacket around the cooker, reaching process temperatures of 116-138 C (241-280 F). The areas around the process equipment are often hot; insulating process equipment and steam and condensate piping will result in a cooler environment. The water removed from the raw material in the cooking or evaporation step must be condensed and discharged into a sewer according to guidelines of local sewer ordinances for a city sewer or the Clean Water Act Amendments of 1977 for a navigable stream . Vapor is condensed primarily by contact or by surface condensers located just outside the plant or on the roof. Noncondensable vapor from the condenser, which gives off highly intense odors, can be controlled by venting to a scrubber or directly to the boiler that generates the plant's steam. After the moisture is removed, the liquid fat must be separated from the protein solids. In batch cooking, the initial separation is accomplished with a rectangular percolation pan that contains a perforated screen 6 -inches above a sloped bottom. This configuration allows the fluid tallow to drain and be separated from the protein solids. The protein solids s till containing about 25% tallow are conveyed to the screw press, which completes the separation. Solid protein material discharged from the screw press is known as cracklings. The cracklings are normally screened and ground with a hammer mill to produce meat-and-bone meal. These products are usually stored outside the plant in silos. Workers occasionally enter these silos for maintenance and repair work. Each rendering plant has a facility for loading trucks, railroad cars, or barges to move the rendered materials to the user. Solids can be top-loaded or end-loaded with flingers (conveyors that throw material horizontally) into covered trailers or boxcars. Stored grease and tallow are liquefied and then pumped into tank trailers or rail tankcars. # (b) Continuous Cooker Processing Continuous cooking systems for inedible rendering are increasingly common . The receiving, grinding, pressing, and storing operations are similar to those discussed for batch cooking. Continuous systems evaporate water and separate fats by steadily moving the material through the cookers. Advantages of the continuous system over the batch process include improved quality control of the product, better confinement of odor and fat-particle aerosols within the equipment, and a smaller space requirement. Although use of batch cookers has steadily decreased, they may never be entirely replaced by continuous systems; small rendering plants often cannot afford continuous systems. Continuous systems are highly automated and can be operated with fewer workers, but also require a greater maintenance effort because failure of any part can shut down an entire system. The instrumentation and controls for a continuous system are usually centralized at a panel that may be enclosed in a booth. Currently, the two most widely used continuous systems in inedible rendering are the Anderson C-G (Carver-Greenfield) system and the Duke system, shown in Figures 1-3 and 1-4, respectively . The Anderson C-G system first uses a fluidizing tank in which recycled fat is used to heat and slurry the raw material. Then the slurry is pumped to a disintegrator for further grinding and for breakdown of cellular structure to release fats. The resulting charge is then pumped to the evaporator, where moisture is removed under vacuum. In the Duke system, the cooker resembles a batch cooker, but differs in that material is continuously charged at one end, driven slowly through the horizontal cooker, and steadily discharged at the other end. Other systems, in limited use, are the Strataflow, the Pfaudler Low Temperature Centrifuge, and the Norwegian Stord-Bartz Rotadisc. Rendering operations that process a large volume of material are mechanically aided by screw conveyors, pumps, front-end loaders, and other equipment . Pressure vessels and systems, such as feather hydrolyzers, cooker steam jackets, filte r presses, and condensate returns, are also used. Other operations use boilers to generate steam or hot water and usually have some sort of system to recover the water vapor produced in the cooking process. For odor control, scrubbers or incinerators are used for cookers, dryers, and other process equipment. # Edible Rendering Edible rendering usually takes place as an adjunct to slaughtering and dressing processes, where edible raw material is readily available. It has been estimated that less than 2% of independent processers render edible material . A typical edible rendering process consists of a multistage centrifuge system that mechanically separates water from fat, in contrast to a cooking process in inedible rendering. In the edible processes, production volume and temperatures are usually much lower and sanitation requirements more stringent than in the inedible processes. Batch processes, which are becoming obsolete, are either "wet-batch" or "dry-batch" . In dry-batch low-temperature rendering, the charge is melted in a conventional cooker at a temperature that does not evaporate the moisture in the raw material. The fats are separated from the solids and water by screening or centrifuging. Remaining water entrained in the hot fat is then removed in a second centrifuge. The separated water, called tank water, can be further evaporated to a thick material known as stick, which can be used as tankage for inedible rendering. The solids can be sent to inedible rendering or used in edible meat meals. In wet-batch rendering, now essentially outdated, the material is heated by direct injection of steam. Three materials result: water, fat, and suspended solids (protein tissue). The fat is decanted and the water and solids are separated by filtration or centrifugation. Currently, edible material is most commonly rendered in continuous, wet systems in which low temperature and centrifugation are used to separate fats from water and solids (protein tissue) . Raw materials are cut finely and heated, which fluidizes them. The fluid mass passes into a centrifuge to separate the fat (and water) from the solids. The resulting solids can be used as food fillers or as pet food. The fat and water mixture goes to a second centrifuge for further separation. The final fat is low in acid and faintly colored. Water goes to the water treatment system, and sludge goes to inedible rendering. Process temperatures are about 49 C (120 F) for edible lard and 68 C (155 F) for edible tallow. # Ancillary Operations Ancillary operations performed in some rendering plants include the producing of blood meal and feather meal, the reclaiming of grease, the boning of dead stock for pet food, and the processing of hides. Blood from the k ill floor is coagulated and centrifuged, dried, and sold as a protein source for use in animal feed. Figure 1-5 is a flow scheme for the process. Blood received from the sticking area of a slaughtering plant is preheated and coagulated by steam injection in the continuous process. Solids are separated from liquids by centrifuge, and then dried and ground. In continuous systems, a gas-fired direct-heat dryer (ring dryer) or a rotary steam tube can be used to dry the blood. In batch processes, coagulation and moisture removal are performed in the batch cooker by drying. Blood meal is valued as animal feed because of its high lysine content. A batch process is less desirable than a continuous one because it results in a lower lysine content of the blood meal. Poultry feathers and hog hair are also processed in many plants (Figure 1-6) . The hair and feathers are hydrolyzed by cooking under pressure, dried in a steam tube or a ring dryer commonly at temperatures of 100 C (212 F), and then blended for use in animal feeds; feather or hair material may also be ground. Feather and hair meals are used as protein sources in animal feed. The growth of the restaurant business has made the reclaiming of restaurant grease an important part of the rendering industry (F Ward, written communication, December 1978). This reclaimed grease is used as stabilized animal fat for animal feed. A brief outline of this process is shown in Figure 1-7. Restaurant grease is delivered to rendering plants in large drums by bucket trucks or other types of barrel trucks. Drums weighing as much as 204 kg (450 lbs) are unloaded by hand or with mechanical aids, such as hand trucks or hoists. These drums are not only heavy, but many times have rough, sharp edges. The distance these drums are lifted, pushed, and pulled from the unloading dock to the hot room varies considerably from plant to plant. Steam, infrared radiation, or electric heaters are used to melt the grease while s till in the barrels, which are drained through metal screens and cleaned. The grease is then filtered or screened to remove coarse solids, heated to remove water (water may also be removed by settling), and further filtered or centrifuged to remove the fine solids. The resulting yellow grease is blended with antioxidants and stabilizers, and stored or shipped out for animal feed as stabilized animal fat. Some rendering plants supply pet food establishments with red meat. Good quality carcasses are placed on a rail where they are skinned and gutted. The meat is kept in a cooler and inspected until it is boned and sold the next day. At some rendering plants this accounts for about 10% of their total tonnage. Many rendering plants that handle a large number of dead stock find it economically favorable to remove the hides from dead carcasses for curing. These carcasses are skinned while hanging from a rail or lying on the floor. The carcass is usually taken by conveyor or cable to the pre-breaker, and the hide is trimmed, cleaned, and then cured in brine raceway vats. # Chemicals Used During Rendering Plant Operations Rendering plants use chemicals in several operations: cleaning, grease or fat processing, treating waste water, controlling odors, water cooling, and boiler operation [1,4). A partial list of the more common chemicals is given in Table 1-2. # II. OCCUPATIONAL HAZARDS Occupational hazards in rendering plants can be divided into three categories: those resulting in mechanical injury, those resulting from physical agents, and those resulting from exposure to, or contact with, biologic and chemical agents. # Hazards Resulting in Mechanical Injury According to the Bureau of Labor Statistics, the injury and illness incidence rate for the Animal and Marine Fats and Oils Industry (SIC code 2077) in 1977 was 25.0 cases/100 full-time workers (see Table II-l) . Injury and illness rates in these establishments averaged approximately 1.9 times as much and lost workday cases about 2.7 times as much than their respective rates for the manufacturing industries sector between 1972 and 1977. Although the number of lost-workday cases per 100 full-time workers was higher in animal and marine fats and oils establishments than comparable rates for the manufacturing industries sector, the average number of lost workdays per lost-workday case in these same establishments was lower. Table II-2 shows injury and illness rates for workers in animal and marine fats and oils establishments for 1972-1977. In each of these years, injuries accounted for approximately 96-98% of all reported cases. The BLS has also recently developed the Supplemental Data System, which has as its source of data the first report of injury or illness submitted by employers and insurance carriers to worker compensation agencies of various states . The source, type of accident, and nature of injury are described for compensable cases in 1977 for animal and marine fats and oils establishments in five states (Tables II-3, II-4, and II-5) . (States with 50 or more total cases a year were selected to establish more reliably the leading causes of injury.) Cross-tabulation of source of injury and accident type, nature of injury with part of body affected, nature and source of injury, and nature of injury and accident type has been provided by these states . These tables allow a more detailed analysis of the accident circumstances. Since the definition of a compensable case differs slightly from state to state, only general conclusions can be made concerning the sources, types of accidents, and natures of injuries in this industry. However, the summary data can help identify the areas in which engineering controls and safety activities need to be intensified and help pinpoint problems that must be solved. # (a) Walking-Working Surfaces In rendering plants, walking-working surfaces were listed as the source of about 14% of the compensable injuries in the five states (Table Adapted from references 7-11 II-3) , with falls being the most common type of accident resulting from this source (Table 11- 4). The major factor in this type of accident is the amount of friction between the shoe sole and the working surface. Shoe/working surface friction is affected by floor conditions, floor surface material, and shoe sole composition. *NA = Not available Because of rounding and fatality cases there may be a difference between the total and the sum of the rates for lost workday cases and nonfatal cases without lost workdays. # Adapted from references 7-11 Grease buildup is the major contributor to unsafe walking and working surfaces. The extent of the hazard depends upon the specific rendering process being employed and the extent to which fat and grease particles are confined within the equipment. While continuous rendering systems are able to confine the fat and grease particles, batch cooker operations are not, especially when the animal material is dumped from the cooker to the perc pan. In this situation exhaust ventilation is needed to pick up and remove the airborne fat particles and water vapor before they settle. NIOSH observed that in plants with grease buildup, the second level floor surface where the fat and grease particles settled was more slippery than the first level floor surface . Injuries from falls were usually sprains and strains, but there were also contusions, fractures, and lacerations (Table II-5 A review of the 1979 First Reports of injury or illness from the five selected states indicated that many slips and falls occurred when workers unloaded grease barrels or dead stock from trucks . Spillage from these barrels during their movement to the hot room caused the smooth metal surfaces of the trucks and the loading dock to become slippery. Secure lids for these barrels would minimize the grease buildup from the spillage. Sometimes grease was dumped onto the floor of the hot room before it was melted; when this occurred the boots of workers spread the grease and, therefore, the hazard to other areas. The hide processing area was also identified by these reports as another location in rendering plants where there is an increased risk of slips and falls. Workers there lift hides and heavy bags of salt for the curing process. Good housekeeping will also help minimize the hazards presented by spilled or settled materials that characterize the work environment in some rendering plants. Employer adherence to the general regulations for walking and working surfaces, listed in 29 CFR 1910.22, will reduce hazards by providing for clean, dry, orderly, and sanitary surfaces in addition to sufficiently safe clearances in aisleways where mechanical equipment is used. These aisleways should be kept clear and dry. Spillage can be minimized by ensuring that scrap carts, conveyors, and containers are not overloaded. Leaking pumps, pipes, and valves should be repaired promptly. When spills occur, the bulk of the fat and other solids may be removed with a shovel, and then the floor should be cleaned with water. As an alternative, absorbents can be used to absorb the grease and fat, and then swept up and discarded. Cleansers should be used to remove any remaining fat and grease. Subsequently, any remaining water or liquid should be mopped up and the surface dried as completely as possible. The type of floor surface can contribute to unsafe walking and working conditions. Independent rendering plants visited by NIOSH usually used smooth metal floors at the grease barrel unloading dock. While these floors provide the strength to resist damage from 204-kg (450-lb) barrels, they offer little slip resistance . Much use is made of metal plates, of either solid, expanded, or serrated metal, as flooring, stairs, loading dock areas, walkways, and catwalks. The walking-working surface of the solid plate can be finished in a raised pattern to increase its slip-resistance. However, at one rendering plant where an abrasive material was incorporated onto the steel floor to provide more traction, the grease barrels destroyed the finish after only a few days. If the slip-resistant surfaces are vulnerable to barrel abuse, then conveyors or other automatic barrel movers should be considered. At another plant, the plant manager was thinking of installing tracks so he could roll the barrels from the trucks to the hot room, thus avoiding damage to the floor surface . One type of solid rolled steel flooring has impregnated aluminum oxide particles. As the surface wears down, particles of the aluminum oxide are continually exposed to the walking-working surface. This type of plate material may be used as a structural component or laid down over existing flooring of all types . Concrete surfaces, especially those with broom finishes, provide traction in other areas of the plant until they are worn smooth. Concrete floors have marginal wear resistance. Brick floor surfaces present a reasonably slip-resistant surface. Floor brick with a cast-abrasive surface is even better . BLS data and the First Reports suggest that stairs in some rendering plants are particularly hazardous, involving 14 of the 55 working surface cases reported by four of the five states. At the independent rendering plants visited by NIOSH, the stairs always seemed hazardous to climb because they were slippery. At one plant, however, the stairs were made of corrugated metal that provided better traction . The type of footwear worn by workers can contribute to slips and falls. Shoe-working surface friction is affected by the shoe sole and heel composition and contact area . Most neoprene sole and heel materials provide a high degree of slip resistance and are resistant to leaking. Since most areas of (independent) rendering plants present some hazard of slips and falls, workers should be required to wear rubber or neoprene boots, preferably with safety toes. The material from which boot soles are constructed is more important than the sole pattern. A highly slip-resistant material with very little pattern is the safest type of footwear, as it provides greater contact with the floor surface . Adherence to regulations for covers and guardrails will protect workers from the various hazards associated with open pits, tanks, bins, and vats (29 CFR 1910.23). In independent rendering plants, the raw-materials receiving pit is often more than 4 feet (1.2 m) deep and is routinely equipped with conveyors or augers at the bottom to move the material into the grinding system. Raw material is dumped into the pits from dump trucks, flatbed trucks, barrels, and wheelbarrows. Standard guarding is necessary protection at these openings; however, special modifications of a toeboard on the charging side of the opening may be appropriate so it will not interfere with cleanup of raw materials spilled during the charging operation. (b) Boxes, Barrels, Containers, and Dead Stock In the five selected states, about 13% of the injuries listed were attributed to work with boxes, barrels, and other containers. Another 4% could be attributed to animal products such as carcasses, bones, and hides. Approximately 16% of all accidents were listed as overexertion (Table II-4 ), which most frequently involves lifting, pulling, or throwing of objects. The most common injury involved sprains and strains, frequently to the back . Rendering plants that process restaurant grease will handle many heavy barrels, and plants that process hides and pet food will handle more dead stock than other plants. Many plants do not handle any dead stock, but plants in the west and midwest process more dead stock than those in other parts of the country. In plants that process hides, lifting, pulling, and throwing injuries involving hides and heavy bags of salt are problems. A work practice guide for manual lifting has been developed by NIOSH , This guide makes recommendations for controlling various hazards related to unaided symmetric (two-handed) lifting of an object of known weight and size. Quantitative recommendations regarding the safe load weight, size, location, and frequency of handling are presented. In addition to recommendations for the selection and training of workers who must manually handle materials, the guide presents some engineering and administrative controls. The guide will help employers determine which lifting tasks being performed in their plants are unacceptable without engineering controls (above a maximum permissible limit (MPL)); unacceptable without administrative or engineering controls (between the action level (AL) and the MPL) and which are acceptable (below the action level). More detailed information on the maximum permissible limits and action levels can be found in the NIOSH work practice guide for manual lifting , Employers should ensure that hazardous pushing, pulling, and lifting tasks not covered by the NIOSH guide are either performed with the aid of some mechanical device, such as a hoist, or redesigned so that they can be performed safely. While a hoist will reduce the physical hazards associated with manual pushing, pulling, and lifting, it could introduce new physical hazards unless operational guidelines are developed and followed. In some rendering plants, workers clean up under perc pans held up by hoists. Inspection of hoists and their ceiling connections for possible corrosion should be performed frequently. Employers should also consider the use of jacks or posts as safety supports for perc pans. At one rendering plant visited by NIOSH, workers responsible for unloading grease barrels were aided by a conveyor that moved the grease barrels from the unloading dock to the hot room. After the grease was melted the barrels were automatically turned upside down and emptied. This greatly reduced the manual pushing, pulling, and lifting performed at this plant . NIOSH visited two other rendering plants that handled barrels of restaurant grease. At one of these, workers used hand trucks to move the barrels; at the other plant, because the hoist was inoperative, the workers moved the barrels manually. Minimizing the distance required to move the barrels will also reduce the amount of pushing, pulling, and lifting . Any worker involved in lifting, pushing, or pulling should be required to wear safety-toe footwear. Since these jobs are usually performed on slippery surfaces, the safety footwear should have soles made of slip-resistant material. Safety-toe footwear of the proper type is effective in reducing material handling injuries as well as slips and falls. Recommendations for safety-toe footwear are presented in ANSI Z41. 1-1967. The lids of barrels and other containers are often rough, and cuts and lacerations may result from handling them if gloves are not worn. Workers should be required to wear gloves when handling barrels and other containers. (c) Hand Tools Hand tools were listed as the source of about 12% of the compensable injuries in rendering plants in the five states (Table II-3). Renderers use knives and axes, as well as maintenance tools such as wrenches, hammers, and small hand-held power tools including d rills, welding torches, and small saws. Cuts and lacerations, most frequently of the fingers and hands, are caused often by hand tools. The most frequent hand tool accidents in many rendering plants involve knives. In some rendering plants knives are used to skin, gut, and bone carcasses and trim hides. Skinners of dead stock have often injured fingers, hands, arms, thighs, knees, legs, and feet . According to the 1979 First Reports, hide trimmers had similar accidents. These rendering plants should have a knife safety program that includes the use of personal protective equipment and training. The First Reports cited above indicate that when a worker was cutting a carcass every part of his body was vulnerable to knife wounds. The use of personal protective equipment should, therefore, be as extensive as possible. Other frequent causes of hand tool injuries result from cleavers, axes, and large knives used to reduce the animal carcasses to a size that is amenable to the rendering plant's equipment. Protective equipment including mesh gloves, arm protectors, and abdominal protectors should be used by workers cutting up the carcasses. Knives used in this task should have maximally guarded handles, designed to prevent the hand from slipping onto the blade. Hand tool-related injuries during maintenance operations can be reduced by the use of personal protective equipment such as safety shoes and gloves and by training workers in the proper use of tools. General industry standards for the use of hand tools are listed in 29 CFR 191029 CFR .241-1910. Hand saws and other powered tools must be properly grounded, insulated, or enclosed because of the wet conditions that often exist during their use. Powered equipment that uses a constant pressure switch must be chosen, when available, in order to shut off the power when the operator releases the pressure. To protect the eyes from flying particles when grinding, cutting, or sawing, workers should wear appropriate eye protection, such as face shields, safety glasses with side shields, goggles, or a combination. (d) Powered Industrial Trucks Vehicles were reported to be involved in about 9% of the injuries (Table II-3). All vehicles used in the industry were included, such as raw material pickup trucks, forklift trucks, and front-end loaders. Vehicle-related accidents occur both in the collection of raw material from butcher shops, restaurants, and meatpacking plants (activities not included in the scope of this document), and in the rendering plants themselves. Adherence to the regulations for powered industrial trucks listed in 29 CFR 1910.178 will reduce these injuries. They require safety training of operators, installation of mirrors at blind corners, inspection of vehicles prior to use, and the use of only properly maintained equipment. (e) Metal Items Metal items such as shafts, discs, and pulleys were involved in about 11% of all compensable injuries in the selected states (Table II-3); most injuries were cuts, lacerations, and contusions . Metal-item-related injuries occurred primarily in the handling of these objects during maintenance in tight quarters and around hot equipment in an uncomfortable (hot and humid) environment. These injuries can be prevented by the use of protective equipment such as safety shoes, gloves, and head protection (hard hats) and the training of workers in proper materials handling techniques. # (f) Machines and Conveyors Machines such as grinders, cookers, presses, and centrifuges were the source of about 1% of the compensable injuries (Table II-3). These machines are a relatively minor source of compensable injuries in the rendering process. Adherence to the general regulations for machine guarding listed in 29 CFR 1910 Subpart 0 will continue to protect the operator and other workers from the moving parts of machines. Rendering plants use screw conveyors (augers) to move material through the process. To prevent workers from coming into contact with moving parts, conveyors should be provided with covers that are either bolted on or electrically interlocked, which ensures that the conveyor will not be operated without proper guards in place. Where screw conveyors cannot be fully enclosed (receiving points and some points of discharge), they should be hooded or guarded by location or other suitable barrier. Start and stop controls should be located and guarded to prevent accidental operation, and a sufficient number of controls should be provided throughout the process area to stop the conveyors in an emergency. Plant machines and conveyors require maintenance, inspection, cleaning, adjusting, and servicing. Work that requires entrance into, or close contact with, machines or conveyors should not begin until 1ockout/tagout procedures are followed. NIOSH is preparing a document on controlling maintenance hazards that result from the presence of energy . The recommendations of this document are applicable to industries that use hazardous levels of energy for machines or processes and where maintenance activities could bring workers close to resulting hazards. In these instances, maintenance should only be performed after the energy is eliminated or controlled in accordance with the recommendations. The employer should be aware of the Federal regulations (29 CFR 1910.179) for the operation of cranes used to repair rendering equipment. Regulations also exist (29 CFR 1910.184) for the selection and inspection of chains used for hoisting. Workers should never attempt to unkink a chain that is under stress. (g) Hot Objects Steam and hot water, fat products, and process equipment such as cookers and ring dryers are sources of burns in rendering plants. Burns were reported in about 8% of the compensable cases (Table II-5 ). Steam and hot water are frequently used in some rendering plants to hose down equipment and greasy, slippery areas. In some First Reports, workers burned their legs and feet while using steam or hot water to clean their boots . Some workers using cold water-steam mix hoses for hot water operations have been exposed to steam when they mix too much steam with water. Other workers have been burned by steam and hot water because they lost control of hoses during cleanup operations. Steam and hot water lines should be marked and insulated. Hose used for cold water-steam mixes should be approved for use with steam. Cold water-steam mixes for obtaining hot water can be used only if suitable thermostatically-controlled mixing units are used. Mixing units need to withstand temperatures of 180 F (82 C) at a pressure of 150 psi. To discourage workers from using a hose with water temperatures ranging from 140 to 180 F (60 to 82 C) to wash personal equipment, equipment wash-off stations should be established in the plant. Water temperatures at these stations should be no higher than 120 F (49 C). To eliminate accidents occurring when workers lose control of a hose, steam and hot water hoses should be equipped with pressure-activated nozzles. These nozzles automatically shut off the steam or water when the worker lets go of the nozzle. To prevent hoses from rupturing, frequent inspections should be made to assess the condition of the hose. Mixing valves should also be inspected frequently. # (h) Repetitive Body Motion When an injury is due to a worker's repetitive motion rather than to what he is doing with an object, bodily motion should be designated as the source of the injury. Research has shown that cumulative trauma disorders of the hand and wrist are a common problem for workers who perform repetitive manual work. In recent years, tendonitis and tenosynovitis have become significant occupational diseases in some industries. In rendering plants, some operations with knives and shovels are repetitive. In Nebraska, bodily motion was listed as the source of 8% of all rendering injuries. Sprains and strains are the most frequent type of injury resulting from bodily motion . There are reports of tenosynovitis in workers who skinned dead stock. # Hazards from Physical Agents (a) Noise Workers may be exposed to high noise levels in some rendering plants because boilers, pre-breakers, crushers, disintegrators, and grinding mills can generate noise exceeding 90 dBA (Table II -6 ). In 1976, an OSHA inspection of an independent plant found that an operator at a control panel of the inedible rendering operation was exposed to a time-weighted average noise level of 91 dBA during an 8.5-hour exposure. The control panel in this plant was between two cookers, with a hogger (bone crusher) overhead. Unsuccessful attempts to reduce the noise level included installing rubber pads under motor mounts, maintenance of bearings, installing a curtain to reduce the impact of ground bones on the side of the bin, and separating the metal parts of processing equipment with sound-deadening materials. The successful solution was to install a control booth. The booth is used by the operator to monitor the machinery control panel and to do paperwork. With the doors of the booth closed, readings of 72 to 75 dBA were obtained at times of highest noise generation. Noise levels in this plant are typical for a plant with similar equipment and equipment layout (D Mackenzie, written communication, January 1979). During NIOSH visits to two independent rendering plants with Duke rendering systems, noise measurements were made. The control panel in one plant was in front of two cookers and closely surrounded by the rest of the process equipment, except for the hammer mill which was in an adjacent room. Noise levels of 91 dBA and 96 dBA were recorded at the control panel and hammer mill, respectively. At the other plant where the hammer mill was completely isolated in a separate room, 81 dBA was measured at the control panel. A different layout of process equipment at this plant was also a factor in the lower noise measurements. Noise measurements taken 6 feet (2m) in front of hammer mills at four rendering plants visited by NIOSH ranged from 94 to 106 dBA. These levels contributed to background noise levels at work stations in the plant. Information has been obtained concerning noise levels near process equipment (Anderson IBEC continuous system) at two rendering plants (A Phifer, written communication, June 1978). The data are presented in Table II-6. With the exception of one location, the reported area noise levels equaled or exceeded 90 dBA. In the boiler area, measurements of 97 and 98 dBA were recorded. The extent of worker exposure to noise at these levels was not recorded. Except for the boiler room, similar noise levels were obtained on a NIOSH plant site visit at another rendering plant with an Anderson system. Noise level measurements taken at cookers and expellers (presses) were usually greater than 85 dBA, but they always included background noise . Engineering controls and preventive maintenance are important elements of noise control. Proper maintenance of bearings, drive gears, rollers, and other moving parts is important in minimizing noise generation. Some noisy equipment may be enclosed and insulated. At some rendering plants visited by NIOSH, the layout of the process equipment, including the complete isolation of the grinding mills in a separate room, provided a work environment without exposure to high noise levels. Mufflers may be used on steam or compressed-air exhausts. Soundproof booths or enclosed control rooms may also be provided for operators in a noisy environment. If noise levels or exposure periods cannot be reduced, warning signs should be posted in the exposure area, and workers in the area should wear hearing protection, such as ear muffs, rubber or foam earplugs, or fiber plugs. Various NIOSH publications contain information necessary for an effective noise control program , Noise control should be considered when purchasing new equipment. # (b) Fire Industry professionals have cited fire as a common danger in rendering plants. The fire hazard rating of rendering plants is high, according to Best's Loss Control Engineering Manual , which provides data on the insured loss (fire, workmen's compensation, product liability) of a broad cross-section of industry. Best's rating system is based on the average experience of insurance companies encompassing 90-98% of the premiums written. Batch rendering operations received a rating of 8 on a scale of 0 to 10, with 10 representing the greatest hazard of fires. Older batch plants are more susceptible because they were constructed with wood or other combustible materials. Continuous rendering operations were considered less hazardous, but no numerical ratings were given. Continuous systems are usually installed in new buildings constructed of steel and concrete block or other noncombustible materials (W Prokop, written communication, June 1978). A leading cause of industrial fires is defective electrical equipment and wiring . Specific problems at rendering plants include improperly grounded equipment, frayed and bared wires, wet material around electrical outlets, and loose and corroded conduit connections. Electrical equipment and wiring should be installed and maintained in accordance with the latest National Electrical Codes. Because of the corrosive nature of the chemicals used and given off in rendering plants, all electrical equipment and wiring should be periodically inspected and tested to detect deficiencies and ensure continued satisfactory performance. Automatic sprinkler or foaming systems can be used effectively for fires in rendering plants, but they must be properly located for maximum efficiency. Welding and thermal cutting pose a potential fire hazard in confined spaces and rendering plant areas in which grease and other combustible materials have accumulated (A Phifer, written communication, June 1978) . They should be performed under maximum fire-safe working conditions. Grease or other combustible deposits must be removed from the working surface, and sparks should be contained. Fire extinguishing equipment suitable to the plant area should be available in adequate quantities within easy reach (A Phifer, written communication, June 1978). Excessive heat generated by friction is another major source of fires. Such excessive heat may result from inadequate lubrication, misaligned bearings, and improperly adjusted belt-driven machinery. A program of preventive maintenance that includes frequent inspections can minimize the risk of fires from these sources. Spontaneous ignition may also occur in rendering plants, particularly in the perc pans of the batch cooker systems if rendered material, heated to temperatures above 120 C (250 F), is held in the pan for a prolonged period (eg, overnight) . Fires of this type reportedly can be avoided if the material is processed within 8 to 12 hours after the fat is drained (W Prokop, written communication, December 1979). Fat mists from cookers may coat the entire inside of a rendering plant. Although fats do not have a low flashpoint, they can be ignited by open flames used carelessly or by uncontrolled heating. If exhaust ventilation is used to prevent the settling of released fat aerosols, the exhaust ductwork must also be kept clean. Exhaust fans should be equipped for automatic shutoff in the event of fire. Proper operation and maintenance of boilers and other pressure vessels are essential to their safe use. Boilers must be operated in strict conformance with local codes. At a minimum, all pressure vessels should be equipped with rupture discs and vents to prevent explosion. (c) Heat Some rendering plant workers (especially those working above hot process equipment) are exposed to hot and humid work environments, particularly during the summer . Such exposure may result in heat stroke, heat exhaustion, heat cramps, heat rash, and heat fatigue. A worker's ability to do his job is affected by working in hot environments. Heat tends to promote accidents due to the slipperiness of sweaty palms, dizziness, or the fogging of safety glasses. Since the frequency of accidents in general appears to be higher in hot environments, it is important to ensure that thermal stress does not make rendering jobs more dangerous . Much heat is created in rendering plants by equipment such as cookers and dryers. Energy conservation efforts that insulate hot equipment and steam and condensate piping will help reduce the heat load in rendering plants. Local exhaust systems at heat sources and general plant ventilation systems can also remove heat and humidity from the work areas (A Phifer, written communication, June 1978) and increase air c irculation. If heat stress is suspected, various means can be used to alleviate it. These means seek to reduce heat storage by the body, either by limiting input heat load, limiting metabolic heat load, or limiting exposure duration. In practice this can be radiant heat shielding, forced air movement, clothing designed to minimize heat absorption and maximize evaporative cooling, and worker rest schedules designed to prevent body temperatures from increasing over the work shift , Intake air, cooled by water-heat exchange, was directed at job stations for workers operating cookers at one plant visited by NIOSH . A NIOSH criteria document on hot environments recommended that newly exposed workers be acclimatized and that exposure time be short. A joint OSHA/NIOSH pamphlet, Hot Environments, is available to give employers and workers an overview of the health hazards of work in hot environments and to alert them to the precautions needed to avoid excessive heat stress . Hazards from Biologic and Chemical Agents (a) Acute Toxicants, Including Asphyxiants The anaerobic decomposition of biologic material can produce gases that may accumulate in drains, sewers, tanks, and other confined or enclosed spaces. Fatalities reported by two rendering facilities resulted from an apparent accumulation of toxic gases in confined spaces , Since this has not been widely recognized as a hazard in the rendering industry, these episodes are discussed here in detail. In 1975, workers died at a rendering plant where they were exposed to gases thought to be the result of decomposition of animal material , Six men were asphyxiated when a clogged drain was opened, presumably releasing lethal quantities of gaseous products into a confined space. The animal materials had been delivered by truck, weighed, and dumped into a large holding pit for materials to be rendered , After the trucks were unloaded, they were washed out, the drainage entering another pit (for waste collection) below the scales. This pit normally drained into a third, adjoining pit by gravity through a 6-inch drain pipe. However, the drain pipe was thought to have been clogged for 2 to 7 days . A maintenance man descended into the third pit to open the clogged drain, spending approximately 20 minutes in the pit with no apparent ill effects . Later, he reentered the third pit to shut off a sump pump but collapsed while attempting to climb out. Five men attempting to rescue him also died after entering the pit. None wore respiratory protection of any kind. Medical and autopsy findings showed signs of general hypoxia (stated as anoxia ) with acute edema of the brain and lungs. Four of the six victims had severe respiratory irritation, and one had a greenish discoloration of the viscera. Lung samples from five of the victims were analyzed by gas chromatograph for entrapped hydrogen sulfide; four lung samples from persons who had died from nonindustrial causes were analyzed as controls. Hydrogen sulfide was identified in all samples from the victims and in none from the controls. In addition, coins and keys in the pockets of some victims were darkened, and an analysis of them was positive for sulfur. Sludge samples collected from the bottom of the pit were refrigerated on the night of the accident and tested qualitatively for hydrogen sulfide the next morning with lead acetate. The tests were positive . On the day following the accident, lead acetate paper exposed 3 feet (0.9 m) above the sludge was positive for hydrogen sulfide. The toxicology department at Ohio State University collected a 40-liter air sample from the pit on the day after the accident, using a cadmium chloride solution in a midget impinger . Approximately 15 ppm of hydrogen sulfide was found in the sample. Samples collected in Saran bags by NIOSH personnel 2 days after the accident showed traces of hydrogen sulfide (2-3 ppm), but were negative for methane, combustible gases, oxygen deficiency, and oxides of nitrogen. The investigators interpreted the evidence as indicating that the deaths were probably caused by exposure to gases produced by decomposition of sulfur-containing organic material . On the basis of the medical and environmental findings (symptomatology, pathologic findings, qualitative identification of gases in air and sludge) and of the operational circumstances and history of this episode, hydrogen sulfide alone or a combination of carbon dioxide, methane, and hydrogen sulfide was believed to be the most likely cause . A similar episode was reported recently . Two workers died in June 1980 at a rendering facility of a poultry processing plant where they were exposed to an oxygen-deficient environment or to gases that were thought to have resulted from decomposition of animal material. The two men were asphyxiated when they climbed to the bottom of a 15-foot (meat) overflow holding tank (#2) that possibly contained lethal quantities of gaseous products. This overflow tank (#2) was filled with chicken parts (head, feet, and viscera) whenever the cooker and another overflow tank (#1) were full. The material placed in the overflow tanks was usually processed within 14 hours. Although the inside of overflow tank #1 was cleaned out at least three times per week, the inside of overflow tank #2, because of its location, was not cleaned out regularly. To give it a clean appearance, however, the outside was cleaned regularly. The men were requested to enter the tank (#2) to remove roofing material that had fallen into the tank the day before. Both men collapsed and died while inside the tank, neither man wearing respiratory protection of any kind. No autopsies were performed. At high temperatures, the sulfur-containing amino acids in the poultry offal remaining in the overflow tank could have degraded and produced hydrogen sulfide. The roofing material clogged a drain at the bottom of the tank, allowing buildup of any gases that may have formed , The evidence indicates that the deaths could have been caused by hydrogen sulfide exposure produced by decomposition of sulfur-containing organic material. Details of the toxicologic effects of occupational exposure to hydrogen sulfide and carbon dioxide, and recommendations for workplace exposure limits are given in the respective NIOSH criteria documents . Recommendations for entering, working in, and exiting from, confined spaces are given in the NIOSH criteria document Working in Confined Spaces , Adherence to these recommendations will protect health and significantly reduce accidental injury and death associated with entering, working in, and exiting from confined spaces. It will also make the worker cognizant of the hazards associated with his work area and the safe work practices necessary to deal with these hazards. (b) Infect ious Diseases Although infectious diseases have not been a major hazard in rendering plants in the United States, a few cases of brucellosis, psittacosis, Q-fever and anthrax have been reported. The agents for these diseases are introduced into the rendering environment by infected animal carcasses, but the rendered product is expected to be free of the disease agents because of the high temperature involved in the process. If infection with a zoonotic agent does occur, early diagnosis and treatment will tend to limit the duration and severity of the disease. Brucellosis is a zoonotic disease transmitted by direct contact with diseased animals (cattle, swine, sheep, goats, horses, and reindeer), by conjunctival exposure, airborne droplet exposure, and ingestion of contaminated material. Brucellosis is characterized by malaise, chills, sweating, body aches, headache, loss of appetite, weight loss, and a fever of 101-104 F (38-40 C). Brucellosis has a fatality rate of 2%, and death is rare in persons with antibiotic treatment. Untreated cases may become chronic . In the last 3 years for which data are available, independent rendering plant workers constituted 1.1% (3 of 271) of the brucellosis cases in the United States in 1976 Psittacosis is an infectious disease transmitted by direct contact with infected birds (eg, turkeys and pigeons) or the inhalation of dust from their droppings. This disease is characterized by an abrupt onset of shaking, chills, fever, headache, backache, photophobia, and loss of appetite . Complications may result, but recovery is the usual outcome. Fatality is rare. In 1961 and 1973, Langmuir reported on 26 cases of psittacosis among 38 workers (68.4%) of an independent rendering plant in Portland, Oregon, during the winter of 1955-1956. Infected turkeys had been chopped into small pieces and blown through a large duct into a vat for steam-pressure cooking. The disease occurred in workers in all job categories in the rendering plant except the truck drivers. The author suggested that the disease was transmitted by the infective aerosol produced by the chopping and blowing of the infected material. Q-fever is a zoonotic disease transmitted by direct contact with infected animals (eg, cattle, sheep, goats) or the inhalation of dust from their droppings. This disease is characterized by chilly sensations, retrobulbar headache, weakness, malaise, and severe sweating , Pneumonitis occurs in most cases, with mild cough and chest pains. The fatality rate of untreated patients is less than 1%, and, for patients treated with antibiotics, it is negligible. In 1947, Topping et al reported an outbreak of Q-fever among workers in a cattle and hog meatpacking plant in which rendering was also performed. Of 97 workers, 31 (32%) had Q-fever, including 3 of the 4 workers in the lard and tankage areas associated with the rendering process. These workers also assisted in the slaughtering process; therefore, the area of the plant where the infection was acquired could not be established. Three of five workers in the hide-curing area also developed the disease. The remaining cases occurred in the slaughtering and dressing, boning, and sausage areas. The authors concluded that handling the tissues of freshly slaughtered animals in a meatpacking plant can carry a high risk of Q-fever infection. Anthrax is a zoonotic disease transmitted by the inhalation of spores shed by infected animals (eg, cattle, sheep, horses, and pigs) or by direct contact with the animal. This disease is characterized by headache, nausea, vomiting, and fever . Untreated cutaneous anthrax has a fatality rate of 5-20%; with effective antibiotic therapy, however, there are essentially no deaths. The first case of human anthrax since 1955 was recorded in September 1980 in Colorado. It occurred in a 30-year-old man who had worked with animal carcasses. The man had assisted in skinning animal carcasses at a local rendering plant from August 26-31, during which time he was scratched on the arm by an animal hoof. A lesion and swelling developed; B anthracis was isolated from a wound culture. Surveillance of other workers at this plant has yielded no other cases in humans . Other zoonoses, such as leptospirosis, could presumably occur in rendering plant workers; however, no cases of this disease have been reported in the United States. Several measures can reduce the risk of transmitting these infectious diseases in rendering plants. These include frequent washing of the hands, the provision of separate eating areas, and provision of ventilation control to isolate airflows from raw material or processing areas into final product areas. Wounds should be thoroughly cleaned and receive prompt first aid. Since minor cuts are relatively common in the rendering industry, tetanus immunizations should always be current. Work areas in rendering plants should have conveniently located handwashing facilities with bowls large enough to minimize splashing. These areas should be supplied with hot and cold running water and should be directly connected to the drainage system. Smoking and eating in work areas of edible-rendering plants is prohibited by the US Department of Agriculture. (c) Chemical Irritants Affecting the Skin, Eyes, and Mucous Membranes Chemicals are used in rendering plants mostly for cleaning, to process animal material, treat waste water, and control odors, and in cooling towers and boilers (Table 1-1). However, workers are usually only exposed to the chemicals used for cleaning, deodorizing, and water treatment. Generally, these chemicals are alkalies or oxidizing agents and may cause chemical burns or irritation. Inhalation of these agents may result in lung irritation and injury. Skin contact may result in dermatitis. Injuries from mixing, storing, and applying these chemicals can be prevented if workers are trained to use personal protective equipment and the proper methods of handling chemicals. Full-face shields over chemical splash-type goggles, rubber gloves, rubber boots, rubber aprons, or rubber suits are examples of equipment that may be required. Where workers do their jobs in the presence of vapors or dust, there must be adequate ventilation. This may include a combination of general air ventilation and local exhaust ventilation. Respirators must be available for emergency protection where toxic vapors may be generated from some of the chemicals used in rendering plants (eg, chlorine). If a job requires a respirator, the employer must ensure that the worker is thoroughly trained in its use. Workers should be capable of and responsible for testing for leakage, proper fit, and proper operation of respirators. If chlorine or other toxic chemicals are used in a rendering facility, special engineering controls and work practices may be necessary. Details concerning safe work practices and engineering controls are presented in the chlorine criteria document . The employer should ensure that all compounds are used only in proper concentrations and in ways suitable for their intended purposes. Procedures must be established for mixing chemicals as recommended by the manufacturer or as developed by qualified plant personnel. In addition, employers should be familiar with all chemicals used, including their physical properties and any associated hazards. They must ensure that chemicals are kept in designated storage areas and that their use is accompanied by proper recordkeeping. Containers of chemicals should be tightly sealed and stored in a dry place. All chemical containers must be labeled. 1-1, hydrazine may be used as an oxygen scavenger in boiler systems. Hydrazine deserves special attention because it may be absorbed through the skin, is toxic, and is judged by NIOSH to be a potential human carcinogen. A recommended standard, including work practices, is presented in the hydrazine criteria document . Because other oxygen-scavenging chemicals may be used to remove oxygen, the use of hydrazine is unnecessary in rendering boiler systems (W Prokop, written communication, March 1979). # As indicated in Table # (d) Allergens Rendering plant workers are exposed to a variety of animal danders, including those of the hair, skin, feathers, and other animal materials. Exposure to airborne animal-dander particles may result in asthma, inflammation of the nasal mucosa, and conjunctivitis. A scratch by a part of a carcass can cause a pruritic wheal and flare response (urticaria) at the site of contact. No data are available to assess the effects of worker exposure to allergens in rendering operations. # III. HEALTH AND SAFETY GUIDELINES NIOSH has formulated these guidelines as a result of this study. These recommendations apply to workers who render animal materials, which includes the use of heat or mechanical means to reduce fat-containing tissues, bones, and whole carcasses, the reclaiming of grease, and the production of blood and feather meal. These recommendations also apply where dead stock is skinned, gutted, and boned and hides are trimmed and processed. They are not intended for workers who reduce marine raw materials because of differences in the process, raw material, and finished product. # Engineering Controls Engineering controls are the preferred approach to minimize the hazards from lifting, pushing, and pulling large and heavy containers and carcasses, excessive noise, wet and slippery surfaces, grease and fat buildup, unguarded process equipment, dust exposure, and potential toxic gas buildup in confined spaces. NIOSH recommends engineering controls to minimize the following hazards in rendering plants. # (a) Lifting A program should be instituted to identify hazardous lifting jobs. (1) All manual lifting jobs should be classified according to the criteria set forth in NIOSH's Work Practice Guide for Manual Lifting. (2) Manual lifting tasks classified between the action level (AL) and the maximum permissible level (MPL) require either administrative or engineering controls; lifting tasks above the MPL require engineering controls such as cranes and hoists . # (b) Pushing and Pulling A program should be instituted to identify hazardous pushing and pulling jobs. (1) Engineering controls such as hoists, conveyors, hand trucks, and automatic barrel decanters should be considered when frequent pushing or pulling is a part of any job. (2) If mechanical conveying devices are not available to minimize hazardous pushing and pulling, the layout of work stations in the plant should be planned to minimize the distance objects have to be transported. For example, drums should be unloaded as close as possible to processing operations. # (c) Noise The employer should be aware of the Federal regulation (29 CFR 1910.95) that protects workers against the effects of noise exposure. (1) To reduce noise exposure, techniques such as preventive maintenance, using proper operating speed, choosing appropriate equipment locations, and simple machine treatments (eg, vibration isolation or control) should be considered first. (2) Other forms of noise control, such as shields and barriers, should be considered when these other measures are inadequate. (3) NIOSH's Industrial Noise Control Manual, the United Auto Workers' Noise Control (Workers' Manual), OSHA's Noise Control Manual, and other similar publications should be consulted . # (d) Heat and Air Contaminants A program should be instituted to periodically identify any heat, humidity, or air contaminant problems in the plant. (1) Ventilation systems are recommended for controlling these problems. (2) Ventilation control of fat and grease emissions is recommended when the buildup of these materials makes walking and working surfaces hazardous. (3) Ventilation control of fat and grease emissions is recommended when the buildup of these materials in the plant creates a fire hazard. (4) Local exhaust ventilation is recommended when general ventilation does not adequately control these hazards. (5) Ventilation and/or air-conditioned enclosures should be provided in areas considered to be hot environments. (6) Ventilation systems should be designed to prevent air movement from raw material or processing areas to final product areas. (7) Ventilation systems should be subjected to regular cleaning and preventive maintenance to ensure their continued effectiveness. (e) Machines and Conveyors Guarding of machinery and power transmission equipment in a rendering plant should provide the maximum degree of protection to the workers. (1) Machines and power transmission equipment can be guarded with barriers, or be isolated. (2) Screw conveyors should be fully covered or guarded so that neither workers nor their clothing can contact moving parts. (3) Federal regulations (29 CFR 1910.219) exist which require mechanical power-transmission equipment (shafts, gears, pulleys, etc) within 7 feet (2.1 m) or less of the floor or of work platforms be covered or guarded. (f) Working in Confined Spaces Ventilation, as described in the NIOSH criteria document Working in Confined Spaces , is recommended for all confined space work. Installation of a ventilation system (eg, fans) for a confined space, where outside air is introduced and stagnant air is exhausted, will help prevent accumulation of any toxic gases. # (g) Walking-Working Surfaces Walking-working surfaces should receive attention to minimize the number of accidents involving them. (1) Walking-working surfaces should be slip-resistant. (2) Worn walking-working surfaces that have lost their slip-resistant characteristics should be replaced or refinished. # Work Practices (a) Walking-Working Surfaces Injuries caused by unsafe working surfaces can be reduced by minimizing the accumulation of grease or fat on floors, and by following the guidelines below: (1) Working surfaces, such as floors, platforms, and stairs, shall be kept clean and orderly. Federal regulation 29 CFR 1910.22 requires aisleways and passageways be kept clear, dry, and in good repair. (2) All elevated platforms, pits, and stairways should be guarded. Pits receiving raw material should be guarded on all sides. If necessary, guards may be removable on not more than two sides. The employer should be aware of the Federal regulations (29 CFR 1910(29 CFR .23-1910) that exist for the guarding of floor and wall openings, holes, and stairs. # (b) Hand-Held Equipment The use of hand-held equipment can be hazardous in rendering tasks . Compliance with the following recommendations will reduce the number of injuries associated with hand-held equipment. (1) Personal protective equipment such as mesh gloves, abdominal protectors, and arm guards should be worn by workers for hide removal and any carcass cutting operations. (2) The employer should be aware of the Federal regulations (29 CFR 1910(29 CFR .241-1910) that protect the worker against the hazards of hand and portable powered tools. Subsections of 29 CFR 1910.243 entitled "(a) Portable powered tools" and "(b) Pneumatic powered tools and hoses" are specifically relevant to rendering processes. (3) Employers should ensure that knives with hand guards are used in all carcass cutting and hide removal procedures. (4) Employers should ensure that workers using knives are provided with scabbards and are instructed in their proper use. (5) Employers should ensure that electric hand tools are properly grounded when in use. (6) Employers should ensure that all hand-held electrical tools with pressure switches (deadman controls) are considered for use. Frequent laundering of soiled work clothing is a generally accepted practice demonstrated to be effective in industries that are associated with the use of chemicals or other agents that may irritate skin or be toxic through dermal absorption. The harmful effects of these agents can be exacerbated by prolonged contact. Soiled work clothing should be laundered frequently, and the employer should ensure that clean work clothing is worn daily. # (e) Materials Handling and Storage Accidents involving powered industrial trucks have been recorded , and many of them could have been prevented by the following. The employer should be aware of the provisions of 29 CFR 191029 CFR .176-1910, which protects the worker against the hazards associated with materials handling and storage. Sections 176, 178, and 184, which address materials handling, powered industrial trucks, and slings, are especially relevant to rendering plants. (2) Employers should prohibit operators of front-end loaders or forklift trucks from raising or lowering the loader or forks while the vehicle is in motion in the plant. (3) Workers should operate forklifts with their load raised only enough to clear the driving surface. (f) Maintenance Many problems occurring in rendering plants could be prevented by adhering to the following recommendations. (1) A regular preventive maintenance program should be established to avoid fires and excessive noise generation that results from inadequate lubrication, misaligned bearings, and improperly adjusted belt-driven machinery. (2) All equipment, including valves, fittings, and connections, should be checked regularly for tightness and kept in good working condition. Inspections should be made immediately after new connections are made and after material is introduced. (3) Leaking steam lines should be repaired promptly. (4) Whenever maintenance work is to be performed, standardized safety procedures should be followed. These procedures should include adherence to NIOSH's recommendations for hazard control during maintenance , the use of protective equipment, and the proper selection and use of hand tools. (5) Maintenance work in a confined space should adhere to the recommendations of the NIOSH criteria document, Working in Confined Spaces . # (g) Entry into Confined Spaces When cleaning, maintenance, and repair of rendering equipment require entry into a confined space, the recommendations in the NIOSH criteria document should be adhered to. These recommendations include the following , (1) The employer shall designate in writing a person qualified by education or specialized training to anticipate, recognize, and evaluate worker exposure to hazardous substances or other unsafe conditions in a confined space. This person shall be authorized to specify necessary controls and protective actions to ensure worker safety. (2) Entry into a confined space shall be by permit only. The permit shall be an authorization and approval in writing that specifies the location and type of work to be performed. It should also certify that all existing hazards have been evaluated by the qualified person and that necessary protective measures have been taken to ensure the safety of each worker. (3) The designation of a confined space shall be based on the existing or potential hazards associated with it. (4) Entry into a confined space shall be prohibited until the atmosphere has been initially tested from the outside and found to be safe. The tests to be performed should include those for oxygen deficiency, flammability, and, if appropriate, toxic materials. (5) The entry permit shall include a list of protective equipment necessary for work in the confined space, as determined by the qualified person. (6) All workers associated with confined space entry shall be trained in the use of the appropriate personal protective equipment. (7) The need for respiratory protection shall be determined by the qualified person based on conditions and test results of the confined space and on the work to be performed. (h) Waste Disposal Local, state, and Federal regulations recognize the need for proper waste disposal in maintaining community health. Waste material should be disposed of in a manner not hazardous to plant personnel, and these disposal methods should conform to applicable local, state, and Federal regulations. (i) Sanitation and Personal Hygiene Some biological agents and chemical substances found in rendering plants can harm exposed workers. Adherence to the following guidelines will minimize these exposures. (2) Workers should be instructed by their employer to wash their hands with soap and water as frequently as practicable. As a minimum, workers should be encouraged to wash their hands during all workbreaks, before eating, and before and after using toilet facilities. # Posting Workers should be apprised of hazards in rendering facilities and of methods to protect themselves. Although all who work in rendering facilities should receive such training prior to placement, signs serve as important reminders. Signs are also an initial warning to workers not familiar with the facility, such as contractors, delivery people, and others. (a) Signs should be printed in English and in the predominant language of non-English-reading workers. Workers unable to read these signs should in some manner receive all necessary information regarding hazardous areas and should be informed of the instructions printed on these signs. Companies with superior safety performances have safety evaluation programs that anticipate and manage potential hazards. These companies have a strong management commitment to safety, are characterized by a safety program integrated into the larger management system, and they deal with safety as an intrinsic part of plant operations . Training should be repeated at least annually to reinforce established safe work practices and to update worker knowledge of changes in work practices, personal protective equipment, and process modifications. The employer should: (a) Ensure that workers can perform their assigned tasks safely before allowing them to participate in a rendering operation without direct supervision. (d) Ensure that workers are informed both orally and in writing of the safety rules established at their rendering facility. Those rules should provide safe standard operating procedures for all activities performed in the plant. Workers should also be informed orally of the hazards of each rendering operation. (e) Ensure that all new workers are trained in at least these five subjects. (1) The specific job function of the worker. (2) The general hazards of the rendering plants, including potential sources of mechanical injury and effects of excessive heat and noise, chemicals, decomposition gases, and infectious agents. (3) The proper use and maintenance of protective equipment, including respirators, when applicable. (4) Correct housekeeping practices. (5) Emergency procedures for fires, chemical leaks, electrical malfunctions, and evacuation of disabled workers. (f) Ensure that selected workers on each shift also receive training in first-aid procedures, firefighting, chemical leaks, and entry into confined spaces. # Industrial Safety and Health Surveys and Monitoring To ensure that workers are not exposed to hazardous conditions, the workplace should be surveyed periodically. Industrial safety and health surveys should be conducted according to the following guidelines. (c) If it has been determined that exposure to hazardous conditions exists, the employer should institute a program of personal monitoring to identify and measure, or to permit calculation of, the exposure of each worker. Source and area monitoring might be used to supplement personal monitoring. (1) In all personal monitoring, samples representative of exposure in the breathing zone of the worker should be collected. All noise measurements should be made with the sound-level meter or noise dosimeter in a location closely approximating the noise levels at the worker's head during normal operations. (2) If a worker is found to be exposed to hazardous agents exceeding recommended limits, his or her exposure should be measured frequently, control measures should be initiated, and the worker should be notified of the exposure and control measures. Accelerated monitoring should be considered until results indicate that the control measures are effective and that the worker's exposure no longer exceeds the recommended occupational exposure limit. Routine monitoring may then be resumed. (d) Some occupational hazards in the rendering process, primarily those related to safety, cannot be monitored as discussed above. When such hazards are identified in the industrial safety and health survey, the employer should notify workers of the hazardous condition, post the area, and initiate corrective action. Increasingly frequent safety surveys should be considered until the hazardous condition is corrected. # Recordkeeping Accurate recordkeeping of surveys, medical examinations, and other pertinent material will enable the employer to assess the efficiency of the plant's control program. (a) These records should be kept for at least 5 years after termination of employment. (b) Records should include: identification of the worker being monitored; duties and job locations within the worksite, times and dates of sampling and analytical methods used, and available evidence of their precision and accuracy; the number, duration, and analytical results of samples taken; and personal protective equipment used by the worker. Records of safety surveys should clearly identify and describe any hazardous condition and state the corrective action taken. Because rendering operations involve potential hazards to safety and health, proper training and education of workers is vital. A comprehensive, well-organized training program enables the employer to educate new workers in safe work practices and techniques from the beginning of their employment. Such training helps to establish a positive employer-worker relationship by demonstrating the employer's concern for, and commitment to, safe work practices. Training Methods, Need and Frequency, Evaluation, and Objectives (a) Methods Workers can be trained most effectively while on the job. Qualified personnel explain and demonstrate part of the task, and then the worker is allowed to do it. As the worker develops proficiency, other work segments may be added. Each new step requires close supervision until the worker is judged competent to perform his tasks proficiently and safely. # (b) Need and Frequency The employer must ensure that all workers can perform their intended tasks safely before allowing them to work in rendering operations without immediate supervision. The need and frequency for additional training will vary depending on the individual, the complexity of the task, and the nature of the operation's hazard. First-line supervisors may be the best judges of when and in what areas workers need additional training, because they can observe the workers frequently and be familiar with their work habits and performance. These supervisors are also likely to be best able to suggest how worker accidents might be minimized, since they usually have first-hand knowledge of the circumstances. # (c) Evaluation Evaluations of worker safety performance should be conducted by first-line supervisors who are best able to discern whether workers adhere to established work practices and safely perform their particular tasks. Written tests or check sheets may be used in conjunction with training and evaluating procedures. The success of the training program depends on participation and positive motivation by management. (d) Goals Specific goals should be established for each problem area in operations for which training is offered, including the following: The worker should know that a leading cause of accidents in rendering operations are unsafe walking-working surfaces. Workers should know that the frequency of slips and falls can be reduced by using proper floor materials and footwear. Workers should be aware of special hazards associated with unguarded pits and elevated work stations in rendering operations. (2) In the training program, the worker should be warned that hand tools are a major source of injury in rendering operations, especially where whole carcasses are cut with knives or axes, and in many maintenance operations. The worker should understand the purposes of the protective devices available, which, if used properly, will minimize or eliminate injuries. The worker should know how to properly select and fit mesh gloves, arm guards, and protective aprons. They should understand that properly used mechanical aids to lift or transport objects can help reduce the incidence of injury. If manual lifting is necessary, a job analysis should be performed before any lifting is done. The worker should be fully aware that the use of these techniques will minimize the chances of strains, sprains, and other injuries. (3) Workers should be given safety orientation, in which potential hazards in the rendering facility are pointed out, eg, hot process equipment, electrical equipment, confined spaces, and chemical storage areas. The worker should know the hazards associated with each chemical he uses and the proper procedures for handling such materials. He should also know the signs and symptoms associated with illnesses that might result from contact with infectious agents in his rendering operation, and know how these diseases can be transmitted. This is synonymous with continuous cooking. The raw material is fed continuously to the cooking device, and the cooked material discharges essentially at a constant rate. Horizontal, steam-jackated cylinder equipped with a mechanical agitator. The batch cooker follows a repetitive cycle: it is charged with the proper amount of raw material, dehydrates this material and finally discharges the cooked material. Solid protein material discharged from screw press after removal of liquid fat. Machine containing blades or knives which reduce raw material to a relatively uniform size. Fat taken from edible parts of the animal. Inedible tallow or grease. Protein product also known as hydrolyzed poultry feathers. A fat product with a tite r less than 40.0 degrees centigrade. Dry rendered protein product from mammal tissues with 4.4% or less phosphorus. All material from the animal's body cavity used for inedible rendering. Machine for removal of solids from liquids where a filte r cloth mounted on a series of leaves or plates is capable of accumulating a solid cake as pressure is applied continuously. All material from animal and poultry sources used for inedible rendering. The process of releasing fat by dehydrating raw material in a batch cooker or continuous rendering system with no direct addition of steam or water. A waste fat material obtained primarily from fast food restaurants. Machine used to separate fat from tankage continuously by applying the required pressure with a rotating screw. Fat obtained from the inedible body tissues of cattle and sheep. Animal fat product with a tite r of 40.0 degrees centigrade or higher. Fat obtained from the edible parts of cattle and sheep. Cooked material remaining after the liquid fat is drained and separated. An analytical measurement used to indicate the hardness or softness of fats. It is expressed in degrees centigrade. Pollution control device for contacting air exhausted from rendering plant with a water solution containing deodorizing chemicals. A disease that can be transmitted from animals to man. 58	In 1977, the national injury rate for workers in rendering plants was reported to be almost twice that reported for the manufacturing industries sector. The need to assess and identify the underlying causes of this high rate and provide recommendations to reduce the incidence of these injuries prompted the National Institute for Occupational Safety and Health (NIOSH) to survey rendering plants and assess the occupational hazards of the rendering process. This document critically reviews the scientific and technical information concerning mechanical injury, physical agents (eg, noise, heat), and biological and chemical agents in the rendering workplace. Chapter III of this document, entitled Health and Safety Guidelines, is provided so individuals immediately responsible for hazard control in their specific workplace will have a basis on which to formulate their own occupational safety and health program. Employer knowledge of and adherence to these guidelines will reduce adverse effects on worker safety and health. This document is also intended for use by unions, industrial trade associations, and scientific and technical investigators to further their own objectives in providing for a safer workplace. Furthermore, it is intended to assist the Occupational Safety and Health Administration, US Department of Labor, in its standards development and compliance activities. Contributions to this document by NIOSH staff, other Federal agencies or departments, the review consultants, the National Renderers Association, and The United Food and Commercial Workers are gratefully acknowledged. The views and conclusions expressed in this document, together with the recommendations, are those of NIOSH. They are not necessarily those of the consultants, the reviewers selected by professional societies, or other Federal agencies. However, all comments, whether or not incorporated, have been carefully considered. konaia d. uoene, r.a.# Infections resulting from organisms associated with animal material occur occasionally. Workers may also be exposed to chemicals generally associated with cleanup or maintenance activities. Under certain conditions, hazardous gases can be generated by anaerobic reactions during the holding of accumulated organic raw materials. Rendering facilities are of two types, those directly associated with meatpacking and poultry slaughtering and dressing operations (onsite) and those that are independent of these operations. There are approximately 3,000 workers associated with onsite rendering facilities and about 9,000 workers associated with independent rendering facilities in the United States. Rendering processes are classified according to whether inedible or edible products are produced. The major inedible fat products are grease and inedible tallow; major inedible protein meal products are meat meal and meat-and-bone meal. Edible products include lard, edible tallow, and certain proteinaceous tissues. Based on information from the available literature, reviewer comments, and plant site visits, NIOSH recommends guidelines for engineering controls and work practices to reduce the number of injuries and illnesses in rendering plants. Recommendations for training, posting, personal protective equipment programs, medical surveillance, and maintenance of relevant records are also included. # Background and Scope of Document The rendering of animal materials was one of the first recycling industries. It began about 150 years ago, and grew as the meat products industry grew. Many new uses were found for products derived from materials such as grease, hair, blood, feathers, hides, and bones [1]. Products from rendering operations are either inedible or edible; inedible products include inedible tallow and grease and various protein meals such as blood meal, feather meal, meat meal, bone meal, and meat-and-bone meal. Edible products include lard, edible tallow, and protein tissue [1 ]. Rendering performed at meatpacking or poultry dressing plants is referred to as onsite, or captive, rendering. Onsite Tenderers produce almost all of the edible lard and edible tallows made. Rendering not performed at meatpacking or poultry dressing plants is referred to as offsite, or independent, rendering. According to the Census of Manufactures, the independent rendering industry accounted for 69% of the inedible tallow and grease in 1977 [2]. This Census reported that 500 establishments were classified under Animal and Marine Fats and Oils (SIC code 2077); about 450 of these rendered animal materials. The number of workers at onsite rendering facilities (SIC codes 2011 and 2016) was estimated to be about 3,000 (A Phifer, written communication, June 1978). The National Renderers Association has estimated that half of the 9,000 workers employed by independent rendering plants are involved in plant operations and maintenance (WH Prokup, written communication, February 1981). Table 1-1 summarizes production figures for the rendering industry [3]. This document concerns occupational exposure in the manufacture of rendered animal products, particularly the handling and processing of raw materials at the rendering plant as well as maintenance, cleanup, and repair work. The collection of raw materials from butcher shops, supermarkets, restaurants, farms, and meatpacking plants is not a part of the rendering production process, and is not discussed here. The guidelines in Chapter III apply to both onsite and independent rendering. # Inedible Rendering Raw materials for independent inedible rendering come from a variety of sources, including butcher shops, restaurants, grocery stores, feedlots, and meatpacking plants [4]. The raw materials are usually bones and bone fragments, offal, blood, feathers, other cut-up materials, and barrels of restaurant grease. This material, usually delivered in barrels or by a dump truck, is weighed, evaluated for potential endproducts, and dumped into receiving pits or bins. The trucks and barrels are hosed out and the washings are emptied into an adjacent pit and drained into an onsite waste-treatment system. Separated solids are recycled into the receiving pits. Some independent rendering plants also process dead stock. Plants without mechanized pre-breakers and crushers that can process whole dead animals must have the carcasses cut up with axes or knives by plant personnel. This is done either with the animal lying on the floor or hanging from an overhead rail. Adapted from reference 3 The raw material in the receiving pit is then crushed or ground to the size necessary for cooking or moisture evaporation [4], To limit the production of odor and to maintain product quality of the tallow or grease and protein meal, raw material is usually processed promptly. Size reduction operations use equipment such as pre-breakers, shredders, grinders, and hashers. Following the size reduction step the raw material is sent on to cookers which can either be a batch or continuous type [4]. Figure 1-1 is a generalized flow diagram of this process. Figure 1-1 also shows ancillary processes which are discussed later. Onsite rendering operations in meatpacking and poultry dressing plants usually receive raw materials directly from the k ill floor. If the rendering operation is in a separate building on the same premises, the raw material is moved by pump or truck to the cookers. At this point the onsite and offsite rendering processes are similar [1]. # (a) Batch Cooker Processing Moisture is evaporated and fats are released from the raw material by heating it under controlled conditions [1,4]. A quantity of material is cooked in batch cookers to a specified moisture or temperature, and then the load is discharged. Figure 1-2 is a generalized diagram of a batch cooking system [4]. Dry-batch rendering is the method most commonly used for inedible products. In this method, moisture is separated from the raw material by evaporation. Heat for evaporation is provided by steam in a jacket around the cooker, reaching process temperatures of 116-138 C (241-280 F). The areas around the process equipment are often hot; insulating process equipment and steam and condensate piping will result in a cooler environment. The water removed from the raw material in the cooking or evaporation step must be condensed and discharged into a sewer according to guidelines of local sewer ordinances for a city sewer or the Clean Water Act Amendments of 1977 for a navigable stream [5]. Vapor is condensed primarily by contact or by surface condensers located just outside the plant or on the roof. Noncondensable vapor from the condenser, which gives off highly intense odors, can be controlled by venting to a scrubber or directly to the boiler that generates the plant's steam. After the moisture is removed, the liquid fat must be separated from the protein solids. In batch cooking, the initial separation is accomplished with a rectangular percolation pan that contains a perforated screen 6 -inches above a sloped bottom. This configuration allows the fluid tallow to drain and be separated from the protein solids. The protein solids s till containing about 25% tallow are conveyed to the screw press, which completes the separation. Solid protein material discharged from the screw press is known as cracklings. The cracklings are normally screened and ground with a hammer mill to produce meat-and-bone meal. These products are usually stored outside the plant in silos. Workers occasionally enter these silos for maintenance and repair work. Each rendering plant has a facility for loading trucks, railroad cars, or barges to move the rendered materials to the user. Solids can be top-loaded or end-loaded with flingers (conveyors that throw material horizontally) into covered trailers or boxcars. Stored grease and tallow are liquefied and then pumped into tank trailers or rail tankcars. # (b) Continuous Cooker Processing Continuous cooking systems for inedible rendering are increasingly common [1]. The receiving, grinding, pressing, and storing operations are similar to those discussed for batch cooking. Continuous systems evaporate water and separate fats by steadily moving the material through the cookers. Advantages of the continuous system over the batch process include improved quality control of the product, better confinement of odor and fat-particle aerosols within the equipment, and a smaller space requirement. Although use of batch cookers has steadily decreased, they may never be entirely replaced by continuous systems; small rendering plants often cannot afford continuous systems. Continuous systems are highly automated and can be operated with fewer workers, but also require a greater maintenance effort because failure of any part can shut down an entire system. The instrumentation and controls for a continuous system are usually centralized at a panel that may be enclosed in a booth. Currently, the two most widely used continuous systems in inedible rendering are the Anderson C-G (Carver-Greenfield) system and the Duke system, shown in Figures 1-3 and 1-4, respectively [4]. The Anderson C-G system first uses a fluidizing tank in which recycled fat is used to heat and slurry the raw material. Then the slurry is pumped to a disintegrator for further grinding and for breakdown of cellular structure to release fats. The resulting charge is then pumped to the evaporator, where moisture is removed under vacuum. In the Duke system, the cooker resembles a batch cooker, but differs in that material is continuously charged at one end, driven slowly through the horizontal cooker, and steadily discharged at the other end. Other systems, in limited use, are the Strataflow, the Pfaudler Low Temperature Centrifuge, and the Norwegian Stord-Bartz Rotadisc. Rendering operations that process a large volume of material are mechanically aided by screw conveyors, pumps, front-end loaders, and other equipment [4]. Pressure vessels and systems, such as feather hydrolyzers, cooker steam jackets, filte r presses, and condensate returns, are also used. Other operations use boilers to generate steam or hot water and usually have some sort of system to recover the water vapor produced in the cooking process. For odor control, scrubbers or incinerators are used for cookers, dryers, and other process equipment. # Edible Rendering Edible rendering usually takes place as an adjunct to slaughtering and dressing processes, where edible raw material is readily available. It has been estimated that less than 2% of independent processers render edible material [6]. A typical edible rendering process consists of a multistage centrifuge system that mechanically separates water from fat, in contrast to a cooking process in inedible rendering. In the edible processes, production volume and temperatures are usually much lower and sanitation requirements more stringent than in the inedible processes. Batch processes, which are becoming obsolete, are either "wet-batch" or "dry-batch" [1]. In dry-batch low-temperature rendering, the charge is melted in a conventional cooker at a temperature that does not evaporate the moisture in the raw material. The fats are separated from the solids and water by screening or centrifuging. Remaining water entrained in the hot fat is then removed in a second centrifuge. The separated water, called tank water, can be further evaporated to a thick material known as stick, which can be used as tankage for inedible rendering. The solids can be sent to inedible rendering or used in edible meat meals. In wet-batch rendering, now essentially outdated, the material is heated by direct injection of steam. Three materials result: water, fat, and suspended solids (protein tissue). The fat is decanted and the water and solids are separated by filtration or centrifugation. Currently, edible material is most commonly rendered in continuous, wet systems in which low temperature and centrifugation are used to separate fats from water and solids (protein tissue) [1]. Raw materials are cut finely and heated, which fluidizes them. The fluid mass passes into a centrifuge to separate the fat (and water) from the solids. The resulting solids can be used as food fillers or as pet food. The fat and water mixture goes to a second centrifuge for further separation. The final fat is low in acid and faintly colored. Water goes to the water treatment system, and sludge goes to inedible rendering. Process temperatures are about 49 C (120 F) for edible lard and 68 C (155 F) for edible tallow. # Ancillary Operations Ancillary operations performed in some rendering plants include the producing of blood meal and feather meal, the reclaiming of grease, the boning of dead stock for pet food, and the processing of hides. Blood from the k ill floor is coagulated and centrifuged, dried, and sold as a protein source for use in animal feed. Figure 1-5 is a flow scheme for the process. Blood received from the sticking area of a slaughtering plant is preheated and coagulated by steam injection in the continuous process. Solids are separated from liquids by centrifuge, and then dried and ground. In continuous systems, a gas-fired direct-heat dryer (ring dryer) or a rotary steam tube can be used to dry the blood. In batch processes, coagulation and moisture removal are performed in the batch cooker by drying. Blood meal is valued as animal feed because of its high lysine content. A batch process is less desirable than a continuous one because it results in a lower lysine content of the blood meal. Poultry feathers and hog hair are also processed in many plants (Figure 1-6) [4]. The hair and feathers are hydrolyzed by cooking under pressure, dried in a steam tube or a ring dryer commonly at temperatures of 100 C (212 F), and then blended for use in animal feeds; feather or hair material may also be ground. Feather and hair meals are used as protein sources in animal feed. The growth of the restaurant business has made the reclaiming of restaurant grease an important part of the rendering industry (F Ward, written communication, December 1978). This reclaimed grease is used as stabilized animal fat for animal feed. A brief outline of this process is shown in Figure 1-7. Restaurant grease is delivered to rendering plants in large drums by bucket trucks or other types of barrel trucks. Drums weighing as much as 204 kg (450 lbs) are unloaded by hand or with mechanical aids, such as hand trucks or hoists. These drums are not only heavy, but many times have rough, sharp edges. The distance these drums are lifted, pushed, and pulled from the unloading dock to the hot room varies considerably from plant to plant. Steam, infrared radiation, or electric heaters are used to melt the grease while s till in the barrels, which are drained through metal screens and cleaned. The grease is then filtered or screened to remove coarse solids, heated to remove water (water may also be removed by settling), and further filtered or centrifuged to remove the fine solids. The resulting yellow grease is blended with antioxidants and stabilizers, and stored or shipped out for animal feed as stabilized animal fat. Some rendering plants supply pet food establishments with red meat. Good quality carcasses are placed on a rail where they are skinned and gutted. The meat is kept in a cooler and inspected until it is boned and sold the next day. At some rendering plants this accounts for about 10% of their total tonnage. Many rendering plants that handle a large number of dead stock find it economically favorable to remove the hides from dead carcasses for curing. These carcasses are skinned while hanging from a rail or lying on the floor. The carcass is usually taken by conveyor or cable to the pre-breaker, and the hide is trimmed, cleaned, and then cured in brine raceway vats. # Chemicals Used During Rendering Plant Operations Rendering plants use chemicals in several operations: cleaning, grease or fat processing, treating waste water, controlling odors, water cooling, and boiler operation [1,4). A partial list of the more common chemicals is given in Table 1-2. # II. OCCUPATIONAL HAZARDS Occupational hazards in rendering plants can be divided into three categories: those resulting in mechanical injury, those resulting from physical agents, and those resulting from exposure to, or contact with, biologic and chemical agents. # Hazards Resulting in Mechanical Injury According to the Bureau of Labor Statistics, the injury and illness incidence rate for the Animal and Marine Fats and Oils Industry (SIC code 2077) in 1977 was 25.0 cases/100 full-time workers (see Table II-l) [7]. Injury and illness rates in these establishments averaged approximately 1.9 times as much and lost workday cases about 2.7 times as much than their respective rates for the manufacturing industries sector between 1972 and 1977. Although the number of lost-workday cases per 100 full-time workers was higher in animal and marine fats and oils establishments than comparable rates for the manufacturing industries sector, the average number of lost workdays per lost-workday case in these same establishments was lower. Table II-2 shows injury and illness rates for workers in animal and marine fats and oils establishments for 1972-1977. In each of these years, injuries accounted for approximately 96-98% of all reported cases. The BLS has also recently developed the Supplemental Data System, which has as its source of data the first report of injury or illness submitted by employers and insurance carriers to worker compensation agencies of various states [12]. The source, type of accident, and nature of injury are described for compensable cases in 1977 for animal and marine fats and oils establishments in five states (Tables II-3, II-4, and II-5) [13]. (States with 50 or more total cases a year were selected to establish more reliably the leading causes of injury.) Cross-tabulation of source of injury and accident type, nature of injury with part of body affected, nature and source of injury, and nature of injury and accident type has been provided by these states [14]. These tables allow a more detailed analysis of the accident circumstances. Since the definition of a compensable case differs slightly from state to state, only general conclusions can be made concerning the sources, types of accidents, and natures of injuries in this industry. However, the summary data can help identify the areas in which engineering controls and safety activities need to be intensified and help pinpoint problems that must be solved. # (a) Walking-Working Surfaces In rendering plants, walking-working surfaces were listed as the source of about 14% of the compensable injuries in the five states (Table Adapted from references 7-11 II-3) , with falls being the most common type of accident resulting from this source (Table 11- 4). The major factor in this type of accident is the amount of friction between the shoe sole and the working surface. Shoe/working surface friction is affected by floor conditions, floor surface material, and shoe sole composition. NA = Not available *Because of rounding and fatality cases there may be a difference between the total and the sum of the rates for lost workday cases and nonfatal cases without lost workdays. # Adapted from references 7-11 Grease buildup is the major contributor to unsafe walking and working surfaces. The extent of the hazard depends upon the specific rendering process being employed and the extent to which fat and grease particles are confined within the equipment. While continuous rendering systems are able to confine the fat and grease particles, batch cooker operations are not, especially when the animal material is dumped from the cooker to the perc pan. In this situation exhaust ventilation is needed to pick up and remove the airborne fat particles and water vapor before they settle. NIOSH observed that in plants with grease buildup, the second level floor surface where the fat and grease particles settled was more slippery than the first level floor surface [15]. Injuries from falls were usually sprains and strains, but there were also contusions, fractures, and lacerations (Table II-5 A review of the 1979 First Reports of injury or illness from the five selected states indicated that many slips and falls occurred when workers unloaded grease barrels or dead stock from trucks [16]. Spillage from these barrels during their movement to the hot room caused the smooth metal surfaces of the trucks and the loading dock to become slippery. Secure lids for these barrels would minimize the grease buildup from the spillage. Sometimes grease was dumped onto the floor of the hot room before it was melted; when this occurred the boots of workers spread the grease and, therefore, the hazard to other areas. The hide processing area was also identified by these reports as another location in rendering plants where there is an increased risk of slips and falls. Workers there lift hides and heavy bags of salt for the curing process. Good housekeeping will also help minimize the hazards presented by spilled or settled materials that characterize the work environment in some rendering plants. Employer adherence to the general regulations for walking and working surfaces, listed in 29 CFR 1910.22, will reduce hazards by providing for clean, dry, orderly, and sanitary surfaces in addition to sufficiently safe clearances in aisleways where mechanical equipment is used. These aisleways should be kept clear and dry. Spillage can be minimized by ensuring that scrap carts, conveyors, and containers are not overloaded. Leaking pumps, pipes, and valves should be repaired promptly. When spills occur, the bulk of the fat and other solids may be removed with a shovel, and then the floor should be cleaned with water. As an alternative, absorbents can be used to absorb the grease and fat, and then swept up and discarded. Cleansers should be used to remove any remaining fat and grease. Subsequently, any remaining water or liquid should be mopped up and the surface dried as completely as possible. The type of floor surface can contribute to unsafe walking and working conditions. Independent rendering plants visited by NIOSH usually used smooth metal floors at the grease barrel unloading dock. While these floors provide the strength to resist damage from 204-kg (450-lb) barrels, they offer little slip resistance [15]. Much use is made of metal plates, of either solid, expanded, or serrated metal, as flooring, stairs, loading dock areas, walkways, and catwalks. The walking-working surface of the solid plate can be finished in a raised pattern to increase its slip-resistance. However, at one rendering plant where an abrasive material was incorporated onto the steel floor to provide more traction, the grease barrels destroyed the finish after only a few days. If the slip-resistant surfaces are vulnerable to barrel abuse, then conveyors or other automatic barrel movers should be considered. At another plant, the plant manager was thinking of installing tracks so he could roll the barrels from the trucks to the hot room, thus avoiding damage to the floor surface [15]. One type of solid rolled steel flooring has impregnated aluminum oxide particles. As the surface wears down, particles of the aluminum oxide are continually exposed to the walking-working surface. This type of plate material may be used as a structural component or laid down over existing flooring of all types [17]. Concrete surfaces, especially those with broom finishes, provide traction in other areas of the plant until they are worn smooth. Concrete floors have marginal wear resistance. Brick floor surfaces present a reasonably slip-resistant surface. Floor brick with a cast-abrasive surface is even better [18]. BLS data and the First Reports suggest that stairs in some rendering plants are particularly hazardous, involving 14 of the 55 working surface cases reported by four of the five states. At the independent rendering plants visited by NIOSH, the stairs always seemed hazardous to climb because they were slippery. At one plant, however, the stairs were made of corrugated metal that provided better traction [15]. The type of footwear worn by workers can contribute to slips and falls. Shoe-working surface friction is affected by the shoe sole and heel composition and contact area [17]. Most neoprene sole and heel materials provide a high degree of slip resistance and are resistant to leaking. Since most areas of (independent) rendering plants present some hazard of slips and falls, workers should be required to wear rubber or neoprene boots, preferably with safety toes. The material from which boot soles are constructed is more important than the sole pattern. A highly slip-resistant material with very little pattern is the safest type of footwear, as it provides greater contact with the floor surface [18]. Adherence to regulations for covers and guardrails will protect workers from the various hazards associated with open pits, tanks, bins, and vats (29 CFR 1910.23). In independent rendering plants, the raw-materials receiving pit is often more than 4 feet (1.2 m) deep and is routinely equipped with conveyors or augers at the bottom to move the material into the grinding system. Raw material is dumped into the pits from dump trucks, flatbed trucks, barrels, and wheelbarrows. Standard guarding is necessary protection at these openings; however, special modifications of a toeboard on the charging side of the opening may be appropriate so it will not interfere with cleanup of raw materials spilled during the charging operation. (b) Boxes, Barrels, Containers, and Dead Stock In the five selected states, about 13% of the injuries listed were attributed to work with boxes, barrels, and other containers. Another 4% could be attributed to animal products such as carcasses, bones, and hides. Approximately 16% of all accidents were listed as overexertion (Table II-4 ), which most frequently involves lifting, pulling, or throwing of objects. The most common injury involved sprains and strains, frequently to the back [14]. Rendering plants that process restaurant grease will handle many heavy barrels, and plants that process hides and pet food will handle more dead stock than other plants. Many plants do not handle any dead stock, but plants in the west and midwest process more dead stock than those in other parts of the country. In plants that process hides, lifting, pulling, and throwing injuries involving hides and heavy bags of salt are problems. A work practice guide for manual lifting has been developed by NIOSH [19], This guide makes recommendations for controlling various hazards related to unaided symmetric (two-handed) lifting of an object of known weight and size. Quantitative recommendations regarding the safe load weight, size, location, and frequency of handling are presented. In addition to recommendations for the selection and training of workers who must manually handle materials, the guide presents some engineering and administrative controls. The guide will help employers determine which lifting tasks being performed in their plants are unacceptable without engineering controls (above a maximum permissible limit (MPL)); unacceptable without administrative or engineering controls (between the action level (AL) and the MPL) and which are acceptable (below the action level). More detailed information on the maximum permissible limits and action levels can be found in the NIOSH work practice guide for manual lifting [19], Employers should ensure that hazardous pushing, pulling, and lifting tasks not covered by the NIOSH guide are either performed with the aid of some mechanical device, such as a hoist, or redesigned so that they can be performed safely. While a hoist will reduce the physical hazards associated with manual pushing, pulling, and lifting, it could introduce new physical hazards unless operational guidelines are developed and followed. In some rendering plants, workers clean up under perc pans held up by hoists. Inspection of hoists and their ceiling connections for possible corrosion should be performed frequently. Employers should also consider the use of jacks or posts as safety supports for perc pans. At one rendering plant visited by NIOSH, workers responsible for unloading grease barrels were aided by a conveyor that moved the grease barrels from the unloading dock to the hot room. After the grease was melted the barrels were automatically turned upside down and emptied. This greatly reduced the manual pushing, pulling, and lifting performed at this plant [15]. NIOSH visited two other rendering plants that handled barrels of restaurant grease. At one of these, workers used hand trucks to move the barrels; at the other plant, because the hoist was inoperative, the workers moved the barrels manually. Minimizing the distance required to move the barrels will also reduce the amount of pushing, pulling, and lifting [15]. Any worker involved in lifting, pushing, or pulling should be required to wear safety-toe footwear. Since these jobs are usually performed on slippery surfaces, the safety footwear should have soles made of slip-resistant material. Safety-toe footwear of the proper type is effective in reducing material handling injuries as well as slips and falls. Recommendations for safety-toe footwear are presented in ANSI Z41. 1-1967. The lids of barrels and other containers are often rough, and cuts and lacerations may result from handling them if gloves are not worn. Workers should be required to wear gloves when handling barrels and other containers. (c) Hand Tools Hand tools were listed as the source of about 12% of the compensable injuries in rendering plants in the five states (Table II-3). Renderers use knives and axes, as well as maintenance tools such as wrenches, hammers, and small hand-held power tools including d rills, welding torches, and small saws. Cuts and lacerations, most frequently of the fingers and hands, are caused often by hand tools. The most frequent hand tool accidents in many rendering plants involve knives. In some rendering plants knives are used to skin, gut, and bone carcasses and trim hides. Skinners of dead stock have often injured fingers, hands, arms, thighs, knees, legs, and feet [16]. According to the 1979 First Reports, hide trimmers had similar accidents. These rendering plants should have a knife safety program that includes the use of personal protective equipment and training. The First Reports cited above indicate that when a worker was cutting a carcass every part of his body was vulnerable to knife wounds. The use of personal protective equipment should, therefore, be as extensive as possible. Other frequent causes of hand tool injuries result from cleavers, axes, and large knives used to reduce the animal carcasses to a size that is amenable to the rendering plant's equipment. Protective equipment including mesh gloves, arm protectors, and abdominal protectors should be used by workers cutting up the carcasses. Knives used in this task should have maximally guarded handles, designed to prevent the hand from slipping onto the blade. Hand tool-related injuries during maintenance operations can be reduced by the use of personal protective equipment such as safety shoes and gloves and by training workers in the proper use of tools. General industry standards for the use of hand tools are listed in 29 CFR 191029 CFR .241-1910. Hand saws and other powered tools must be properly grounded, insulated, or enclosed because of the wet conditions that often exist during their use. Powered equipment that uses a constant pressure switch must be chosen, when available, in order to shut off the power when the operator releases the pressure. To protect the eyes from flying particles when grinding, cutting, or sawing, workers should wear appropriate eye protection, such as face shields, safety glasses with side shields, goggles, or a combination. (d) Powered Industrial Trucks Vehicles were reported to be involved in about 9% of the injuries (Table II-3). All vehicles used in the industry were included, such as raw material pickup trucks, forklift trucks, and front-end loaders. Vehicle-related accidents occur both in the collection of raw material from butcher shops, restaurants, and meatpacking plants (activities not included in the scope of this document), and in the rendering plants themselves. Adherence to the regulations for powered industrial trucks listed in 29 CFR 1910.178 will reduce these injuries. They require safety training of operators, installation of mirrors at blind corners, inspection of vehicles prior to use, and the use of only properly maintained equipment. (e) Metal Items Metal items such as shafts, discs, and pulleys were involved in about 11% of all compensable injuries in the selected states (Table II-3); most injuries were cuts, lacerations, and contusions [14]. Metal-item-related injuries occurred primarily in the handling of these objects during maintenance in tight quarters and around hot equipment in an uncomfortable (hot and humid) environment. These injuries can be prevented by the use of protective equipment such as safety shoes, gloves, and head protection (hard hats) and the training of workers in proper materials handling techniques. # (f) Machines and Conveyors Machines such as grinders, cookers, presses, and centrifuges were the source of about 1% of the compensable injuries (Table II-3). These machines are a relatively minor source of compensable injuries in the rendering process. Adherence to the general regulations for machine guarding listed in 29 CFR 1910 Subpart 0 will continue to protect the operator and other workers from the moving parts of machines. Rendering plants use screw conveyors (augers) to move material through the process. To prevent workers from coming into contact with moving parts, conveyors should be provided with covers that are either bolted on or electrically interlocked, which ensures that the conveyor will not be operated without proper guards in place. Where screw conveyors cannot be fully enclosed (receiving points and some points of discharge), they should be hooded or guarded by location or other suitable barrier. Start and stop controls should be located and guarded to prevent accidental operation, and a sufficient number of controls should be provided throughout the process area to stop the conveyors in an emergency. Plant machines and conveyors require maintenance, inspection, cleaning, adjusting, and servicing. Work that requires entrance into, or close contact with, machines or conveyors should not begin until 1ockout/tagout procedures are followed. NIOSH is preparing a document on controlling maintenance hazards that result from the presence of energy [20]. The recommendations of this document are applicable to industries that use hazardous levels of energy for machines or processes and where maintenance activities could bring workers close to resulting hazards. In these instances, maintenance should only be performed after the energy is eliminated or controlled in accordance with the recommendations. The employer should be aware of the Federal regulations (29 CFR 1910.179) for the operation of cranes used to repair rendering equipment. Regulations also exist (29 CFR 1910.184) for the selection and inspection of chains used for hoisting. Workers should never attempt to unkink a chain that is under stress. (g) Hot Objects Steam and hot water, fat products, and process equipment such as cookers and ring dryers are sources of burns in rendering plants. Burns were reported in about 8% of the compensable cases (Table II-5 ). Steam and hot water are frequently used in some rendering plants to hose down equipment and greasy, slippery areas. In some First Reports, workers burned their legs and feet while using steam or hot water to clean their boots [16]. Some workers using cold water-steam mix hoses for hot water operations have been exposed to steam when they mix too much steam with water. Other workers have been burned by steam and hot water because they lost control of hoses during cleanup operations. Steam and hot water lines should be marked and insulated. Hose used for cold water-steam mixes should be approved for use with steam. Cold water-steam mixes for obtaining hot water can be used only if suitable thermostatically-controlled mixing units are used. Mixing units need to withstand temperatures of 180 F (82 C) at a pressure of 150 psi. To discourage workers from using a hose with water temperatures ranging from 140 to 180 F (60 to 82 C) to wash personal equipment, equipment wash-off stations should be established in the plant. Water temperatures at these stations should be no higher than 120 F (49 C). To eliminate accidents occurring when workers lose control of a hose, steam and hot water hoses should be equipped with pressure-activated nozzles. These nozzles automatically shut off the steam or water when the worker lets go of the nozzle. To prevent hoses from rupturing, frequent inspections should be made to assess the condition of the hose. Mixing valves should also be inspected frequently. # (h) Repetitive Body Motion When an injury is due to a worker's repetitive motion rather than to what he is doing with an object, bodily motion should be designated as the source of the injury. Research has shown that cumulative trauma disorders of the hand and wrist are a common problem for workers who perform repetitive manual work. In recent years, tendonitis and tenosynovitis have become significant occupational diseases in some industries. In rendering plants, some operations with knives and shovels are repetitive. In Nebraska, bodily motion was listed as the source of 8% of all rendering injuries. Sprains and strains are the most frequent type of injury resulting from bodily motion [14]. There are reports [16] of tenosynovitis in workers who skinned dead stock. # Hazards from Physical Agents (a) Noise Workers may be exposed to high noise levels in some rendering plants because boilers, pre-breakers, crushers, disintegrators, and grinding mills can generate noise exceeding 90 dBA (Table II -6 ). In 1976, an OSHA inspection of an independent plant found that an operator at a control panel of the inedible rendering operation was exposed to a time-weighted average noise level of 91 dBA during an 8.5-hour exposure. The control panel in this plant was between two cookers, with a hogger (bone crusher) overhead. Unsuccessful attempts to reduce the noise level included installing rubber pads under motor mounts, maintenance of bearings, installing a curtain to reduce the impact of ground bones on the side of the bin, and separating the metal parts of processing equipment with sound-deadening materials. The successful solution was to install a control booth. The booth is used by the operator to monitor the machinery control panel and to do paperwork. With the doors of the booth closed, readings of 72 to 75 dBA were obtained at times of highest noise generation. Noise levels in this plant are typical for a plant with similar equipment and equipment layout (D Mackenzie, written communication, January 1979). During NIOSH visits [15] to two independent rendering plants with Duke rendering systems, noise measurements were made. The control panel in one plant was in front of two cookers and closely surrounded by the rest of the process equipment, except for the hammer mill which was in an adjacent room. Noise levels of 91 dBA and 96 dBA were recorded at the control panel and hammer mill, respectively. At the other plant where the hammer mill was completely isolated in a separate room, 81 dBA was measured at the control panel. A different layout of process equipment at this plant was also a factor in the lower noise measurements. Noise measurements taken 6 feet (2m) in front of hammer mills at four rendering plants visited by NIOSH ranged from 94 to 106 dBA. These levels contributed to background noise levels at work stations in the plant. Information has been obtained concerning noise levels near process equipment (Anderson IBEC continuous system) at two rendering plants (A Phifer, written communication, June 1978). The data are presented in Table II-6. With the exception of one location, the reported area noise levels equaled or exceeded 90 dBA. In the boiler area, measurements of 97 and 98 dBA were recorded. The extent of worker exposure to noise at these levels was not recorded. Except for the boiler room, similar noise levels were obtained on a NIOSH plant site visit at another rendering plant with an Anderson system. Noise level measurements taken at cookers and expellers (presses) were usually greater than 85 dBA, but they always included background noise [15]. Engineering controls and preventive maintenance are important elements of noise control. Proper maintenance of bearings, drive gears, rollers, and other moving parts is important in minimizing noise generation. Some noisy equipment may be enclosed and insulated. At some rendering plants visited by NIOSH, the layout of the process equipment, including the complete isolation of the grinding mills in a separate room, provided a work environment without exposure to high noise levels. Mufflers may be used on steam or compressed-air exhausts. Soundproof booths or enclosed control rooms may also be provided for operators in a noisy environment. If noise levels or exposure periods cannot be reduced, warning signs should be posted in the exposure area, and workers in the area should wear hearing protection, such as ear muffs, rubber or foam earplugs, or fiber plugs. Various NIOSH publications contain information necessary for an effective noise control program [21][22][23], Noise control should be considered when purchasing new equipment. # (b) Fire Industry professionals have cited fire as a common danger in rendering plants. The fire hazard rating of rendering plants is high, according to Best's Loss Control Engineering Manual [24], which provides data on the insured loss (fire, workmen's compensation, product liability) of a broad cross-section of industry. Best's rating system is based on the average experience of insurance companies encompassing 90-98% of the premiums written. Batch rendering operations received a rating of 8 on a scale of 0 to 10, with 10 representing the greatest hazard of fires. Older batch plants are more susceptible because they were constructed with wood or other combustible materials. Continuous rendering operations were considered less hazardous, but no numerical ratings were given. Continuous systems are usually installed in new buildings constructed of steel and concrete block or other noncombustible materials (W Prokop, written communication, June 1978). A leading cause of industrial fires is defective electrical equipment and wiring [25]. Specific problems at rendering plants include improperly grounded equipment, frayed and bared wires, wet material around electrical outlets, and loose and corroded conduit connections. Electrical equipment and wiring should be installed and maintained in accordance with the latest National Electrical Codes. Because of the corrosive nature of the chemicals used and given off in rendering plants, all electrical equipment and wiring should be periodically inspected and tested to detect deficiencies and ensure continued satisfactory performance. Automatic sprinkler or foaming systems can be used effectively for fires in rendering plants, but they must be properly located for maximum efficiency. Welding and thermal cutting pose a potential fire hazard in confined spaces and rendering plant areas in which grease and other combustible materials have accumulated (A Phifer, written communication, June 1978) [16]. They should be performed under maximum fire-safe working conditions. Grease or other combustible deposits must be removed from the working surface, and sparks should be contained. Fire extinguishing equipment suitable to the plant area should be available in adequate quantities within easy reach (A Phifer, written communication, June 1978). Excessive heat generated by friction is another major source of fires. Such excessive heat may result from inadequate lubrication, misaligned bearings, and improperly adjusted belt-driven machinery. A program of preventive maintenance that includes frequent inspections can minimize the risk of fires from these sources. Spontaneous ignition may also occur in rendering plants, particularly in the perc pans of the batch cooker systems if rendered material, heated to temperatures above 120 C (250 F), is held in the pan for a prolonged period (eg, overnight) [26]. Fires of this type reportedly can be avoided if the material is processed within 8 to 12 hours after the fat is drained (W Prokop, written communication, December 1979). Fat mists from cookers may coat the entire inside of a rendering plant. Although fats do not have a low flashpoint, they can be ignited by open flames used carelessly or by uncontrolled heating. If exhaust ventilation is used to prevent the settling of released fat aerosols, the exhaust ductwork must also be kept clean. Exhaust fans should be equipped for automatic shutoff in the event of fire. Proper operation and maintenance of boilers and other pressure vessels are essential to their safe use. Boilers must be operated in strict conformance with local codes. At a minimum, all pressure vessels should be equipped with rupture discs and vents to prevent explosion. (c) Heat Some rendering plant workers (especially those working above hot process equipment) are exposed to hot and humid work environments, particularly during the summer [15,24]. Such exposure may result in heat stroke, heat exhaustion, heat cramps, heat rash, and heat fatigue. A worker's ability to do his job is affected by working in hot environments. Heat tends to promote accidents due to the slipperiness of sweaty palms, dizziness, or the fogging of safety glasses. Since the frequency of accidents in general appears to be higher in hot environments, it is important to ensure that thermal stress does not make rendering jobs more dangerous [27]. Much heat is created in rendering plants by equipment such as cookers and dryers. Energy conservation efforts that insulate hot equipment and steam and condensate piping will help reduce the heat load in rendering plants. Local exhaust systems at heat sources and general plant ventilation systems can also remove heat and humidity from the work areas (A Phifer, written communication, June 1978) and increase air c irculation. If heat stress is suspected, various means can be used to alleviate it. These means seek to reduce heat storage by the body, either by limiting input heat load, limiting metabolic heat load, or limiting exposure duration. In practice this can be radiant heat shielding, forced air movement, clothing designed to minimize heat absorption and maximize evaporative cooling, and worker rest schedules designed to prevent body temperatures from increasing over the work shift [28], Intake air, cooled by water-heat exchange, was directed at job stations for workers operating cookers at one plant visited by NIOSH [15]. A NIOSH criteria document on hot environments [28] recommended that newly exposed workers be acclimatized and that exposure time be short. A joint OSHA/NIOSH pamphlet, Hot Environments, is available to give employers and workers an overview of the health hazards of work in hot environments and to alert them to the precautions needed to avoid excessive heat stress [27]. Hazards from Biologic and Chemical Agents (a) Acute Toxicants, Including Asphyxiants The anaerobic decomposition of biologic material can produce gases that may accumulate in drains, sewers, tanks, and other confined or enclosed spaces. Fatalities reported by two rendering facilities resulted from an apparent accumulation of toxic gases in confined spaces [29,30], Since this has not been widely recognized as a hazard in the rendering industry, these episodes are discussed here in detail. In 1975, workers died at a rendering plant where they were exposed to gases thought to be the result of decomposition of animal material [29.31], Six men were asphyxiated when a clogged drain was opened, presumably releasing lethal quantities of gaseous products into a confined space. The animal materials had been delivered by truck, weighed, and dumped into a large holding pit for materials to be rendered [29,31], After the trucks were unloaded, they were washed out, the drainage entering another pit (for waste collection) below the scales. This pit normally drained into a third, adjoining pit by gravity through a 6-inch drain pipe. However, the drain pipe was thought to have been clogged for 2 to 7 days [29.31]. A maintenance man descended into the third pit to open the clogged drain, spending approximately 20 minutes in the pit with no apparent ill effects [31]. Later, he reentered the third pit to shut off a sump pump but collapsed while attempting to climb out. Five men attempting to rescue him also died after entering the pit. None wore respiratory protection of any kind. Medical and autopsy findings showed signs of general hypoxia (stated as anoxia [29]) with acute edema of the brain and lungs. Four of the six victims had severe respiratory irritation, and one had a greenish discoloration of the viscera. Lung samples from five of the victims were analyzed by gas chromatograph for entrapped hydrogen sulfide; four lung samples from persons who had died from nonindustrial causes were analyzed as controls. Hydrogen sulfide was identified in all samples from the victims and in none from the controls. In addition, coins and keys in the pockets of some victims were darkened, and an analysis of them was positive for sulfur. Sludge samples collected from the bottom of the pit were refrigerated on the night of the accident and tested qualitatively for hydrogen sulfide the next morning with lead acetate. The tests were positive [31]. On the day following the accident, lead acetate paper exposed 3 feet (0.9 m) above the sludge was positive for hydrogen sulfide. The toxicology department at Ohio State University collected a 40-liter air sample from the pit on the day after the accident, using a cadmium chloride solution in a midget impinger [31]. Approximately 15 ppm of hydrogen sulfide was found in the sample. Samples collected in Saran bags by NIOSH personnel 2 days after the accident showed traces of hydrogen sulfide (2-3 ppm), but were negative for methane, combustible gases, oxygen deficiency, and oxides of nitrogen. The investigators interpreted the evidence as indicating that the deaths were probably caused by exposure to gases produced by decomposition of sulfur-containing organic material [29]. On the basis of the medical and environmental findings (symptomatology, pathologic findings, qualitative identification of gases in air and sludge) and of the operational circumstances and history of this episode, hydrogen sulfide alone or a combination of carbon dioxide, methane, and hydrogen sulfide was believed to be the most likely cause [29]. A similar episode was reported recently [30]. Two workers died in June 1980 at a rendering facility of a poultry processing plant where they were exposed to an oxygen-deficient environment or to gases that were thought to have resulted from decomposition of animal material. The two men were asphyxiated when they climbed to the bottom of a 15-foot (meat) overflow holding tank (#2) that possibly contained lethal quantities of gaseous products. This overflow tank (#2) was filled with chicken parts (head, feet, and viscera) whenever the cooker and another overflow tank (#1) were full. The material placed in the overflow tanks was usually processed within 14 hours. Although the inside of overflow tank #1 was cleaned out at least three times per week, the inside of overflow tank #2, because of its location, was not cleaned out regularly. To give it a clean appearance, however, the outside was cleaned regularly. The men were requested to enter the tank (#2) to remove roofing material that had fallen into the tank the day before. Both men collapsed and died while inside the tank, neither man wearing respiratory protection of any kind. No autopsies were performed. At high temperatures, the sulfur-containing amino acids in the poultry offal remaining in the overflow tank could have degraded and produced hydrogen sulfide. The roofing material clogged a drain at the bottom of the tank, allowing buildup of any gases that may have formed [30], The evidence indicates that the deaths could have been caused by hydrogen sulfide exposure produced by decomposition of sulfur-containing organic material. Details of the toxicologic effects of occupational exposure to hydrogen sulfide and carbon dioxide, and recommendations for workplace exposure limits are given in the respective NIOSH criteria documents [32,33]. Recommendations for entering, working in, and exiting from, confined spaces are given in the NIOSH criteria document Working in Confined Spaces [34], Adherence to these recommendations will protect health and significantly reduce accidental injury and death associated with entering, working in, and exiting from confined spaces. It will also make the worker cognizant of the hazards associated with his work area and the safe work practices necessary to deal with these hazards. (b) Infect ious Diseases Although infectious diseases have not been a major hazard in rendering plants in the United States, a few cases of brucellosis, psittacosis, Q-fever and anthrax have been reported. The agents for these diseases are introduced into the rendering environment by infected animal carcasses, but the rendered product is expected to be free of the disease agents because of the high temperature involved in the process. If infection with a zoonotic agent does occur, early diagnosis and treatment will tend to limit the duration and severity of the disease. Brucellosis is a zoonotic disease transmitted by direct contact with diseased animals (cattle, swine, sheep, goats, horses, and reindeer), by conjunctival exposure, airborne droplet exposure, and ingestion of contaminated material. Brucellosis is characterized by malaise, chills, sweating, body aches, headache, loss of appetite, weight loss, and a fever of 101-104 F (38-40 C). Brucellosis has a fatality rate of 2%, and death is rare in persons with antibiotic treatment. Untreated cases may become chronic [35][36][37]. In the last 3 years for which data are available, independent rendering plant workers constituted 1.1% (3 of 271) of the brucellosis cases in the United States in 1976 [38] Psittacosis is an infectious disease transmitted by direct contact with infected birds (eg, turkeys and pigeons) or the inhalation of dust from their droppings. This disease is characterized by an abrupt onset of shaking, chills, fever, headache, backache, photophobia, and loss of appetite [33][34][35]. Complications may result, but recovery is the usual outcome. Fatality is rare. In 1961 and 1973, Langmuir [39,40] reported on 26 cases of psittacosis among 38 workers (68.4%) of an independent rendering plant in Portland, Oregon, during the winter of 1955-1956. Infected turkeys had been chopped into small pieces and blown through a large duct into a vat for steam-pressure cooking. The disease occurred in workers in all job categories in the rendering plant except the truck drivers. The author [40] suggested that the disease was transmitted by the infective aerosol produced by the chopping and blowing of the infected material. Q-fever is a zoonotic disease transmitted by direct contact with infected animals (eg, cattle, sheep, goats) or the inhalation of dust from their droppings. This disease is characterized by chilly sensations, retrobulbar headache, weakness, malaise, and severe sweating [35,36], Pneumonitis occurs in most cases, with mild cough and chest pains. The fatality rate of untreated patients is less than 1%, and, for patients treated with antibiotics, it is negligible. In 1947, Topping et al [41] reported an outbreak of Q-fever among workers in a cattle and hog meatpacking plant in which rendering was also performed. Of 97 workers, 31 (32%) had Q-fever, including 3 of the 4 workers in the lard and tankage areas associated with the rendering process. These workers also assisted in the slaughtering process; therefore, the area of the plant where the infection was acquired could not be established. Three of five workers in the hide-curing area also developed the disease. The remaining cases occurred in the slaughtering and dressing, boning, and sausage areas. The authors concluded that handling the tissues of freshly slaughtered animals in a meatpacking plant can carry a high risk of Q-fever infection. Anthrax is a zoonotic disease transmitted by the inhalation of spores shed by infected animals (eg, cattle, sheep, horses, and pigs) or by direct contact with the animal. This disease is characterized by headache, nausea, vomiting, and fever [35,37]. Untreated cutaneous anthrax has a fatality rate of 5-20%; with effective antibiotic therapy, however, there are essentially no deaths. The first case of human anthrax since 1955 was recorded in September 1980 in Colorado. It occurred in a 30-year-old man who had worked with animal carcasses. The man had assisted in skinning animal carcasses at a local rendering plant from August 26-31, during which time he was scratched on the arm by an animal hoof. A lesion and swelling developed; B anthracis was isolated from a wound culture. Surveillance of other workers at this plant has yielded no other cases in humans [42]. Other zoonoses, such as leptospirosis, could presumably occur in rendering plant workers; however, no cases of this disease have been reported in the United States. Several measures can reduce the risk of transmitting these infectious diseases in rendering plants. These include frequent washing of the hands, the provision of separate eating areas, and provision of ventilation control to isolate airflows from raw material or processing areas into final product areas. Wounds should be thoroughly cleaned and receive prompt first aid. Since minor cuts are relatively common in the rendering industry, tetanus immunizations should always be current. Work areas in rendering plants should have conveniently located handwashing facilities with bowls large enough to minimize splashing. These areas should be supplied with hot and cold running water and should be directly connected to the drainage system. Smoking and eating in work areas of edible-rendering plants is prohibited by the US Department of Agriculture. (c) Chemical Irritants Affecting the Skin, Eyes, and Mucous Membranes Chemicals are used in rendering plants mostly for cleaning, to process animal material, treat waste water, and control odors, and in cooling towers and boilers (Table 1-1). However, workers are usually only exposed to the chemicals used for cleaning, deodorizing, and water treatment. Generally, these chemicals are alkalies or oxidizing agents and may cause chemical burns or irritation. Inhalation of these agents may result in lung irritation and injury. Skin contact may result in dermatitis. Injuries from mixing, storing, and applying these chemicals can be prevented if workers are trained to use personal protective equipment and the proper methods of handling chemicals. Full-face shields over chemical splash-type goggles, rubber gloves, rubber boots, rubber aprons, or rubber suits are examples of equipment that may be required. Where workers do their jobs in the presence of vapors or dust, there must be adequate ventilation. This may include a combination of general air ventilation and local exhaust ventilation. Respirators must be available for emergency protection where toxic vapors may be generated from some of the chemicals used in rendering plants (eg, chlorine). If a job requires a respirator, the employer must ensure that the worker is thoroughly trained in its use. Workers should be capable of and responsible for testing for leakage, proper fit, and proper operation of respirators. If chlorine or other toxic chemicals are used in a rendering facility, special engineering controls and work practices may be necessary. Details concerning safe work practices and engineering controls are presented in the chlorine criteria document [43]. The employer should ensure that all compounds are used only in proper concentrations and in ways suitable for their intended purposes. Procedures must be established for mixing chemicals as recommended by the manufacturer or as developed by qualified plant personnel. In addition, employers should be familiar with all chemicals used, including their physical properties and any associated hazards. They must ensure that chemicals are kept in designated storage areas and that their use is accompanied by proper recordkeeping. Containers of chemicals should be tightly sealed and stored in a dry place. All chemical containers must be labeled. 1-1, hydrazine may be used as an oxygen scavenger in boiler systems. Hydrazine deserves special attention because it may be absorbed through the skin, is toxic, and is judged by NIOSH to be a potential human carcinogen. A recommended standard, including work practices, is presented in the hydrazine criteria document [44]. Because other oxygen-scavenging chemicals may be used to remove oxygen, the use of hydrazine is unnecessary in rendering boiler systems (W Prokop, written communication, March 1979). # As indicated in Table # (d) Allergens Rendering plant workers are exposed to a variety of animal danders, including those of the hair, skin, feathers, and other animal materials. Exposure to airborne animal-dander particles may result in asthma, inflammation of the nasal mucosa, and conjunctivitis. A scratch by a part of a carcass can cause a pruritic wheal and flare response (urticaria) at the site of contact. No data are available to assess the effects of worker exposure to allergens in rendering operations. # III. HEALTH AND SAFETY GUIDELINES NIOSH has formulated these guidelines as a result of this study. These recommendations apply to workers who render animal materials, which includes the use of heat or mechanical means to reduce fat-containing tissues, bones, and whole carcasses, the reclaiming of grease, and the production of blood and feather meal. These recommendations also apply where dead stock is skinned, gutted, and boned and hides are trimmed and processed. They are not intended for workers who reduce marine raw materials because of differences in the process, raw material, and finished product. # Engineering Controls Engineering controls are the preferred approach to minimize the hazards from lifting, pushing, and pulling large and heavy containers and carcasses, excessive noise, wet and slippery surfaces, grease and fat buildup, unguarded process equipment, dust exposure, and potential toxic gas buildup in confined spaces. NIOSH recommends engineering controls to minimize the following hazards in rendering plants. # (a) Lifting A program should be instituted to identify hazardous lifting jobs. (1) All manual lifting jobs should be classified according to the criteria set forth in NIOSH's Work Practice Guide for Manual Lifting. (2) Manual lifting tasks classified between the action level (AL) and the maximum permissible level (MPL) require either administrative or engineering controls; lifting tasks above the MPL require engineering controls such as cranes and hoists [19]. # (b) Pushing and Pulling A program should be instituted to identify hazardous pushing and pulling jobs. (1) Engineering controls such as hoists, conveyors, hand trucks, and automatic barrel decanters should be considered when frequent pushing or pulling is a part of any job. (2) If mechanical conveying devices are not available to minimize hazardous pushing and pulling, the layout of work stations in the plant should be planned to minimize the distance objects have to be transported. For example, drums should be unloaded as close as possible to processing operations. # (c) Noise The employer should be aware of the Federal regulation (29 CFR 1910.95) that protects workers against the effects of noise exposure. (1) To reduce noise exposure, techniques such as preventive maintenance, using proper operating speed, choosing appropriate equipment locations, and simple machine treatments (eg, vibration isolation or control) should be considered first. (2) Other forms of noise control, such as shields and barriers, should be considered when these other measures are inadequate. (3) NIOSH's Industrial Noise Control Manual, the United Auto Workers' Noise Control (Workers' Manual), OSHA's Noise Control Manual, and other similar publications should be consulted [21,45,46]. # (d) Heat and Air Contaminants A program should be instituted to periodically identify any heat, humidity, or air contaminant problems in the plant. (1) Ventilation systems are recommended for controlling these problems. (2) Ventilation control of fat and grease emissions is recommended when the buildup of these materials makes walking and working surfaces hazardous. (3) Ventilation control of fat and grease emissions is recommended when the buildup of these materials in the plant creates a fire hazard. (4) Local exhaust ventilation is recommended when general ventilation does not adequately control these hazards. (5) Ventilation and/or air-conditioned enclosures should be provided in areas considered to be hot environments. (6) Ventilation systems should be designed to prevent air movement from raw material or processing areas to final product areas. (7) Ventilation systems should be subjected to regular cleaning and preventive maintenance to ensure their continued effectiveness. (e) Machines and Conveyors Guarding of machinery and power transmission equipment in a rendering plant should provide the maximum degree of protection to the workers. (1) Machines and power transmission equipment can be guarded with barriers, or be isolated. (2) Screw conveyors should be fully covered or guarded so that neither workers nor their clothing can contact moving parts. (3) Federal regulations (29 CFR 1910.219) exist which require mechanical power-transmission equipment (shafts, gears, pulleys, etc) within 7 feet (2.1 m) or less of the floor or of work platforms be covered or guarded. (f) Working in Confined Spaces Ventilation, as described in the NIOSH criteria document Working in Confined Spaces [34], is recommended for all confined space work. Installation of a ventilation system (eg, fans) for a confined space, where outside air is introduced and stagnant air is exhausted, will help prevent accumulation of any toxic gases. # (g) Walking-Working Surfaces Walking-working surfaces should receive attention to minimize the number of accidents involving them. (1) Walking-working surfaces should be slip-resistant. (2) Worn walking-working surfaces that have lost their slip-resistant characteristics should be replaced or refinished. # Work Practices (a) Walking-Working Surfaces Injuries caused by unsafe working surfaces can be reduced by minimizing the accumulation of grease or fat on floors, and by following the guidelines below: (1) Working surfaces, such as floors, platforms, and stairs, shall be kept clean and orderly. Federal regulation 29 CFR 1910.22 requires aisleways and passageways be kept clear, dry, and in good repair. (2) All elevated platforms, pits, and stairways should be guarded. Pits receiving raw material should be guarded on all sides. If necessary, guards may be removable on not more than two sides. The employer should be aware of the Federal regulations (29 CFR 1910(29 CFR .23-1910) that exist for the guarding of floor and wall openings, holes, and stairs. # (b) Hand-Held Equipment The use of hand-held equipment can be hazardous in rendering tasks [13]. Compliance with the following recommendations will reduce the number of injuries associated with hand-held equipment. (1) Personal protective equipment such as mesh gloves, abdominal protectors, and arm guards should be worn by workers for hide removal and any carcass cutting operations. (2) The employer should be aware of the Federal regulations (29 CFR 1910(29 CFR .241-1910) that protect the worker against the hazards of hand and portable powered tools. Subsections of 29 CFR 1910.243 entitled "(a) Portable powered tools" and "(b) Pneumatic powered tools and hoses" are specifically relevant to rendering processes. (3) Employers should ensure that knives with hand guards are used in all carcass cutting and hide removal procedures. (4) Employers should ensure that workers using knives are provided with scabbards and are instructed in their proper use. (5) Employers should ensure that electric hand tools are properly grounded when in use. (6) Employers should ensure that all hand-held electrical tools with pressure switches (deadman controls) are considered for use. Frequent laundering of soiled work clothing is a generally accepted practice demonstrated to be effective in industries that are associated with the use of chemicals or other agents that may irritate skin or be toxic through dermal absorption. The harmful effects of these agents can be exacerbated by prolonged contact. Soiled work clothing should be laundered frequently, and the employer should ensure that clean work clothing is worn daily. # (e) Materials Handling and Storage Accidents involving powered industrial trucks have been recorded [13], and many of them could have been prevented by the following. (1) The employer should be aware of the provisions of 29 CFR 191029 CFR .176-1910, which protects the worker against the hazards associated with materials handling and storage. Sections 176, 178, and 184, which address materials handling, powered industrial trucks, and slings, are especially relevant to rendering plants. (2) Employers should prohibit operators of front-end loaders or forklift trucks from raising or lowering the loader or forks while the vehicle is in motion in the plant. (3) Workers should operate forklifts with their load raised only enough to clear the driving surface. (f) Maintenance Many problems occurring in rendering plants could be prevented by adhering to the following recommendations. (1) A regular preventive maintenance program should be established to avoid fires and excessive noise generation that results from inadequate lubrication, misaligned bearings, and improperly adjusted belt-driven machinery. (2) All equipment, including valves, fittings, and connections, should be checked regularly for tightness and kept in good working condition. Inspections should be made immediately after new connections are made and after material is introduced. (3) Leaking steam lines should be repaired promptly. (4) Whenever maintenance work is to be performed, standardized safety procedures should be followed. These procedures should include adherence to NIOSH's recommendations for hazard control during maintenance [20], the use of protective equipment, and the proper selection and use of hand tools. (5) Maintenance work in a confined space should adhere to the recommendations of the NIOSH criteria document, Working in Confined Spaces [34]. # (g) Entry into Confined Spaces When cleaning, maintenance, and repair of rendering equipment require entry into a confined space, the recommendations in the NIOSH criteria document should be adhered to. These recommendations include the following [34], (1) The employer shall designate in writing a person qualified by education or specialized training to anticipate, recognize, and evaluate worker exposure to hazardous substances or other unsafe conditions in a confined space. This person shall be authorized to specify necessary controls and protective actions to ensure worker safety. (2) Entry into a confined space shall be by permit only. The permit shall be an authorization and approval in writing that specifies the location and type of work to be performed. It should also certify that all existing hazards have been evaluated by the qualified person and that necessary protective measures have been taken to ensure the safety of each worker. (3) The designation of a confined space shall be based on the existing or potential hazards associated with it. (4) Entry into a confined space shall be prohibited until the atmosphere has been initially tested from the outside and found to be safe. The tests to be performed should include those for oxygen deficiency, flammability, and, if appropriate, toxic materials. (5) The entry permit shall include a list of protective equipment necessary for work in the confined space, as determined by the qualified person. (6) All workers associated with confined space entry shall be trained in the use of the appropriate personal protective equipment. (7) The need for respiratory protection shall be determined by the qualified person based on conditions and test results of the confined space and on the work to be performed. (h) Waste Disposal Local, state, and Federal regulations recognize the need for proper waste disposal in maintaining community health. Waste material should be disposed of in a manner not hazardous to plant personnel, and these disposal methods should conform to applicable local, state, and Federal regulations. (i) Sanitation and Personal Hygiene Some biological agents and chemical substances found in rendering plants can harm exposed workers. Adherence to the following guidelines will minimize these exposures. (2) Workers should be instructed by their employer to wash their hands with soap and water as frequently as practicable. As a minimum, workers should be encouraged to wash their hands during all workbreaks, before eating, and before and after using toilet facilities. # Posting Workers should be apprised of hazards in rendering facilities and of methods to protect themselves. Although all who work in rendering facilities should receive such training prior to placement, signs serve as important reminders. Signs are also an initial warning to workers not familiar with the facility, such as contractors, delivery people, and others. (a) Signs should be printed in English and in the predominant language of non-English-reading workers. Workers unable to read these signs should in some manner receive all necessary information regarding hazardous areas and should be informed of the instructions printed on these signs. Companies with superior safety performances have safety evaluation programs that anticipate and manage potential hazards. These companies have a strong management commitment to safety, are characterized by a safety program integrated into the larger management system, and they deal with safety as an intrinsic part of plant operations [47]. Training should be repeated at least annually to reinforce established safe work practices and to update worker knowledge of changes in work practices, personal protective equipment, and process modifications. The employer should: (a) Ensure that workers can perform their assigned tasks safely before allowing them to participate in a rendering operation without direct supervision. (d) Ensure that workers are informed both orally and in writing of the safety rules established at their rendering facility. Those rules should provide safe standard operating procedures for all activities performed in the plant. Workers should also be informed orally of the hazards of each rendering operation. (e) Ensure that all new workers are trained in at least these five subjects. (1) The specific job function of the worker. (2) The general hazards of the rendering plants, including potential sources of mechanical injury and effects of excessive heat and noise, chemicals, decomposition gases, and infectious agents. (3) The proper use and maintenance of protective equipment, including respirators, when applicable. (4) Correct housekeeping practices. (5) Emergency procedures for fires, chemical leaks, electrical malfunctions, and evacuation of disabled workers. (f) Ensure that selected workers on each shift also receive training in first-aid procedures, firefighting, chemical leaks, and entry into confined spaces. # Industrial Safety and Health Surveys and Monitoring To ensure that workers are not exposed to hazardous conditions, the workplace should be surveyed periodically. Industrial safety and health surveys should be conducted according to the following guidelines. (c) If it has been determined that exposure to hazardous conditions exists, the employer should institute a program of personal monitoring to identify and measure, or to permit calculation of, the exposure of each worker. Source and area monitoring might be used to supplement personal monitoring. (1) In all personal monitoring, samples representative of exposure in the breathing zone of the worker should be collected. All noise measurements should be made with the sound-level meter or noise dosimeter in a location closely approximating the noise levels at the worker's head during normal operations. (2) If a worker is found to be exposed to hazardous agents exceeding recommended limits, his or her exposure should be measured frequently, control measures should be initiated, and the worker should be notified of the exposure and control measures. Accelerated monitoring should be considered until results indicate that the control measures are effective and that the worker's exposure no longer exceeds the recommended occupational exposure limit. Routine monitoring may then be resumed. (d) Some occupational hazards in the rendering process, primarily those related to safety, cannot be monitored as discussed above. When such hazards are identified in the industrial safety and health survey, the employer should notify workers of the hazardous condition, post the area, and initiate corrective action. Increasingly frequent safety surveys should be considered until the hazardous condition is corrected. # Recordkeeping Accurate recordkeeping of surveys, medical examinations, and other pertinent material will enable the employer to assess the efficiency of the plant's control program. (a) These records should be kept for at least 5 years after termination of employment. (b) Records should include: identification of the worker being monitored; duties and job locations within the worksite, times and dates of sampling and analytical methods used, and available evidence of their precision and accuracy; the number, duration, and analytical results of samples taken; and personal protective equipment used by the worker. Records of safety surveys should clearly identify and describe any hazardous condition and state the corrective action taken. Because rendering operations involve potential hazards to safety and health, proper training and education of workers is vital. A comprehensive, well-organized training program enables the employer to educate new workers in safe work practices and techniques from the beginning of their employment. Such training helps to establish a positive employer-worker relationship by demonstrating the employer's concern for, and commitment to, safe work practices. Training Methods, Need and Frequency, Evaluation, and Objectives (a) Methods Workers can be trained most effectively while on the job. Qualified personnel explain and demonstrate part of the task, and then the worker is allowed to do it. As the worker develops proficiency, other work segments may be added. Each new step requires close supervision until the worker is judged competent to perform his tasks proficiently and safely. # (b) Need and Frequency The employer must ensure that all workers can perform their intended tasks safely before allowing them to work in rendering operations without immediate supervision. The need and frequency for additional training will vary depending on the individual, the complexity of the task, and the nature of the operation's hazard. First-line supervisors may be the best judges of when and in what areas workers need additional training, because they can observe the workers frequently and be familiar with their work habits and performance. These supervisors are also likely to be best able to suggest how worker accidents might be minimized, since they usually have first-hand knowledge of the circumstances. # (c) Evaluation Evaluations of worker safety performance should be conducted by first-line supervisors who are best able to discern whether workers adhere to established work practices and safely perform their particular tasks. Written tests or check sheets may be used in conjunction with training and evaluating procedures. The success of the training program depends on participation and positive motivation by management. (d) Goals Specific goals should be established for each problem area in operations for which training is offered, including the following: (1) The worker should know that a leading cause of accidents in rendering operations are unsafe walking-working surfaces. Workers should know that the frequency of slips and falls can be reduced by using proper floor materials and footwear. Workers should be aware of special hazards associated with unguarded pits and elevated work stations in rendering operations. (2) In the training program, the worker should be warned that hand tools are a major source of injury in rendering operations, especially where whole carcasses are cut with knives or axes, and in many maintenance operations. The worker should understand the purposes of the protective devices available, which, if used properly, will minimize or eliminate injuries. The worker should know how to properly select and fit mesh gloves, arm guards, and protective aprons. They should understand that properly used mechanical aids to lift or transport objects can help reduce the incidence of injury. If manual lifting is necessary, a job analysis should be performed before any lifting is done. The worker should be fully aware that the use of these techniques will minimize the chances of strains, sprains, and other injuries. (3) Workers should be given safety orientation, in which potential hazards in the rendering facility are pointed out, eg, hot process equipment, electrical equipment, confined spaces, and chemical storage areas. The worker should know the hazards associated with each chemical he uses and the proper procedures for handling such materials. He should also know the signs and symptoms associated with illnesses that might result from contact with infectious agents in his rendering operation, and know how these diseases can be transmitted. This is synonymous with continuous cooking. The raw material is fed continuously to the cooking device, and the cooked material discharges essentially at a constant rate. Horizontal, steam-jackated cylinder equipped with a mechanical agitator. The batch cooker follows a repetitive cycle: it is charged with the proper amount of raw material, dehydrates this material and finally discharges the cooked material. Solid protein material discharged from screw press after removal of liquid fat. Machine containing blades or knives which reduce raw material to a relatively uniform size. Fat taken from edible parts of the animal. Inedible tallow or grease. Protein product also known as hydrolyzed poultry feathers. A fat product with a tite r less than 40.0 degrees centigrade. Dry rendered protein product from mammal tissues with 4.4% or less phosphorus. All material from the animal's body cavity used for inedible rendering. Machine for removal of solids from liquids where a filte r cloth mounted on a series of leaves or plates is capable of accumulating a solid cake as pressure is applied continuously. All material from animal and poultry sources used for inedible rendering. The process of releasing fat by dehydrating raw material in a batch cooker or continuous rendering system with no direct addition of steam or water. A waste fat material obtained primarily from fast food restaurants. Machine used to separate fat from tankage continuously by applying the required pressure with a rotating screw. Fat obtained from the inedible body tissues of cattle and sheep. Animal fat product with a tite r of 40.0 degrees centigrade or higher. Fat obtained from the edible parts of cattle and sheep. Cooked material remaining after the liquid fat is drained and separated. An analytical measurement used to indicate the hardness or softness of fats. It is expressed in degrees centigrade. Pollution control device for contacting air exhausted from rendering plant with a water solution containing deodorizing chemicals. A disease that can be transmitted from animals to man. 58 # ACKNOWLEDGEMENTS The Division of Criteria Documentation and Standards Development, NIOSH, had primary responsibility for the development of this document and guidelines for the rendering of animal material. Martin N. Erlichman and Michael C.R. Alavanja, Dr. P.H., of this Division served as criteria managers. # Medical Preplacement medical examinations should be made available to all workers engaged in rendering processes so as to identify existing conditions that might predispose a worker to injury or illness. Subsequent periodic medical examinations provide for the reassessment of health and physical fitness in relation to possible job stress or hazards. Tetanus vaccination and boosters, unless current, are recommended because of the risk of cuts and puncture wounds. The medical surveillance program should include the following. (a) Preplacement Examinations These examinations should include at least: (1) A request that the employer provide pertinent information to the responsible physician, such as an estimate of the worker's potential exposure (including any available workplace sampling results), and a description of any protective devices or equipment the worker may be required to use. (2) Comprehensive medical and work histories with special emphasis on allergies and the musculoskeletal system. (3) Physical and job fitness examinations giving particular attention to the skin, eyes, back, and respiratory system. (4) A tetanus vaccination that subsequently should be made available on an appropriate routine schedule. (5) A judgment of the worker's ability to use negative-and positive-pressure respirators. (6) Baseline audiograms when exposures to noise are judged to possibly exceed Federal limits. (7) A written statement specifying any limitations that should be placed on the worker's job function (prepared following completion of the examination by the examiner). # (b) Periodic Examinations These examinations should be made available at least every 3 years, and include at least: (1) Reassessment of health and job fitness. (3) Listing of any limitations that should be placed on the worker's job function. # DEPARTMENT OF HEALTH AND HUMAN SERVICES P U B L IC H EA LT H S E R V IC E C E N T E R S F O R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E FOR O C C U P A T IO N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R	None	None
700bfe9ab30221c590cfd46193418462964f2d7d	cdc	None	# BACKGROUND Introduction The Centers for Disease Control and Prevention (CDC) Healthy Homes and Lead Poisoning Prevention Branch (HHLPPB) recognizes the need to address housing related issues, including lead exposure, in a more comprehensive manner. The HHLPPB also recognizes a need to provide guidance to an increasing number of state, tribal, territorial, and local Childhood Lead Poisoning Prevention Programs (CLPPPs) as they expand into Healthy Homes programs. This guidance seeks to assist CLPPPs-and other agencies involved in health or housing issues-in developing a comprehensive Healthy Homes program. # Overview of Health and Housing: Context for Transition Florence Nightingale once said that "The connection between the health and the dwelling of the population is one of the most important that exists." Although it is clear that the health of the family depends on having homes that are safe and free from hazards, much work remains to clarify these connections. Some 38 million US homes have lead-based paint hazards that can lead to childhood lead poisoning. 1 In addition, injuries, respiratory diseases such as asthma, and quality of life issues have been linked to the conditions present in approximately 6 million housing units nationwide. 2,3 Homes with moderate or severe physical problems place residents at increased risk for fire, electrical injuries, falls, rodent bites, and other illnesses or injuries. 2,4 Additional issues of concern include exposure to pesticide residues, indoor toxicants, tobacco smoke, and combustion gases. The burning of oil, gas, and kerosene can release a variety of combustion products, such as carbon monoxide. With proper education, home maintenance equipment, or testing, many of these home-related issues can be reduced or eliminated. # Healthy Homes and Lead Poisoning Prevention Healthy People 2020 is a national health agenda that envisions a society in which all people live long and healthy lives. A Healthy Homes program addresses Goal Two of that agenda: achieve health equity and eliminate health disparities. Healthy Homes also addresses eight proposed Healthy People 2020 Environmental Health objectives: - Reduction of the proportion of occupied housing units that have moderate or severe physical problems, - Reduce blood lead levels in children, - Reduce indoor allergen levels, - Increase the proportion of persons living in homes at risk that have an operating radon mitigation system, - Increase the number of new homes constructed with radon-reducing features, especially in high-radon-potential areas, - Increase the proportion of persons living in pre-1978 housing that has been tested for the presence of lead-based paint hazards, - Decrease the number of U.S. homes that have lead-based paint or related hazards, and - Increase the number of Territories, Tribes, States, and the District of Columbia that monitor diseases or conditions that can be caused by exposure to environmental hazards. 5 The Surgeon General' s Call to Action to Promote Healthy Homes outlines a comprehensive and coordinated Healthy Homes approach. This approach seeks to reduce disparities in the availability of healthy, safe, affordable, accessible, and environmentally friendly homes. The Call to Action declares, "A healthy home should be sited, designed, built, renovated, and maintained in ways that support the health of residents." Healthy home features include - How the home is constructed, designed, and maintained; - Physical characteristics; - Presence of safety devices; - Quality of indoor air and water; - Presence or absence of certain chemicals; - Individual resident behavior; and - Community characteristics. Presidential Executive Order 12898 for Environmental Justice addresses health and housing disparities among minority, low-income, and tribal populations. 6 The Order refers to the right of all persons to live in a healthy home and in an environment free of hazards. Environmental Justice supports the Healthy People 2020 national agenda by promoting a healthy quality of life and elimination of health/housing inequities for disparate populations. Institutionalizing environmental justice and implementing recommendations from the Surgeon General' s Call to Action are essential steps in eliminating health and housing disparities. # CDC' s Healthy Homes Initiative CDC' s Healthy Homes Initiative is a coordinated, comprehensive, and holistic approach to preventing diseases and injuries that result from housing-related hazards and deficiencies. 9 The Healthy Homes Initiative seeks to - Broaden the scope of single-issue public health programs-such as childhood lead poisoning prevention and asthma programs-to address multiple housing deficiencies that affect health and safety. - Build capacity and competency among environmental public health practitioners, public health nurses, housing specialists, managers, and others who work in the community to develop and manage comprehensive and effective Healthy Homes programs. - Promote, develop, and implement cross-disciplinary activities at the federal, state, tribal, territorial, and community levels to address the problem of unhealthy and unsafe homes through surveillance, research, and comprehensive prevention programs. - Facilitate the collection of local data and monitor progress toward reducing or eliminating housing deficiencies and hazards. - Promote research to determine causal relations between substandard housing and adverse health effects. - Develop guidelines to assess, reduce, and eliminate health and safety risks. - Identify and implement low-cost, reliable, and practical methods to reduce health and safety risks in substandard housing. # ASSESSMENT An essential first step to developing a successful Healthy Homes program is a comprehensive needs assessment. Established programs can also benefit from such an assessment to assist with focusing program goals and efforts. A needs assessment involves collecting and analyzing data to understand community demographics, to identify the health/housing needs of the community, and to examine program/partner capabilities. When developing a Healthy Homes program, the comprehensive needs assessment should at a minimum address - Community Analysis. Examine data to determine community demographics and health/housing issues. - Training and Education. Identify training needs for staff and partners to build a sustainable program. - Policy. Review housing, sanitation, and habitation statues or codes, and enforcement authorities within the jurisdiction of the program. - Program Experience. Examine organizational capacity and assess personnel knowledge, skills, and experience. - Partnerships. Examine effectiveness of existing partnerships, identify new partners for collaborative efforts, and develop a monitoring process when making referrals. - Program Evaluation. Evaluate performance by examining the processes and effects of current activities on the overall goals and objectives of your program. - Surveillance. Determine efficacy of surveillance efforts in conducting an ongoing, systematic examination of community needs. Use information collected for the needs assessment to develop a strategic plan. This plan will serve as a roadmap to assist programs in - Addressing weaknesses identified in the needs assessment, - Prioritizing the most relevant issues, and - Implementing an effective healthy homes program. # ASSESSMENT COMPONENTS # Community Analysis When developing a Healthy Homes program, managers and staff should understand their communities' demographics, health issues, and housing needs. Whenever possible, programs should use available data to identify health and housing hazards within the community; this may also require using data from partner organizations. After a review of the findings, programs may identify geographic areas and populations within the community to target for intervention. Further data collection may involve engaging the community by holding community meetings or using focus groups to understand health and housing needs from a different perspective. - Essentials for Healthy Homes Practitioners. For health and housing professionals seeking a solid understanding of Healthy Homes programs and principles. The course helps prepare students for the Healthy Homes Specialist Credential exam. # Training and Education - Launching a Healthy Homes Initiative. For health and housing professionals, policymakers, and advocates seeking to develop a Healthy Homes initiative in their community. - Building Healthy Homes. For designers, architects, and contractors seeking to understand building science and construction methods involving Healthy Homes. - Pediatric Environmental Home Assessment (online training). For nurses and other practitioners who do home visits and who seek to better assess their client' s homes for healthy home problems and make referrals for assistance. - Community Health Workers. For persons who work as health advocates in their communities. Those who complete this course will train Community Health Workers to 1) provide one-on-one and large-group education on Healthy Homes topics, 2) provide general advice about specific Healthy Homes problems, and 3) recommend Healthy Homes approaches for families, property owners, and other community members. The CDC Healthy Homes/Lead Poisoning Prevention Training Center offers four training tracks for new program personnel. These tracks provide instruction about lead poisoning prevention and healthy homes activities. They also provide core subject overviews as well as specialized training in Program Management, Data Management and Surveillance, Case Management, and Primary Prevention. 11 Specific issues within a community may require additional training (e.g., Integrated Pest Management, Radon, Asthma). Programs may not have the capacity to train staff and address all health/housing-related hazards within the community. To address those concerns, programs may need to identify and use community/national resources. # Policy With regard to state and local laws that address Healthy Homes issues, programs should identify gaps in regulations, ordinances, and program enforcement policies. Housing codes (i.e., codes for property maintenance, sanitation, and habitation) should be identified along with the appropriate agency that has enforcement authority. Programs should discuss with appropriate officials (e.g., legal counsel) how to use these authorities effectively to address health hazards in homes. As a part of the strategic plan, the program should develop an approach to address gaps/inconsistencies identified in current laws, regulations, codes, and policies. State and local health departments should consult with their general counsel' s office concerning rules and restrictions pertinent to lobbying activities. 12 # Program Experience The needs assessment should be used to evaluate agency resources, past performance, infrastructure, and management in regard to their goals. Programs should also assess the knowledge, skills, and experience of personnel in planning, managing, or conducting activities associated with housing or health-related programs. The Healthy Homes Specialist Credential should be considered when assessing program experience. Other programs that have transitioned to Healthy Homes have identified a need for access to social service agencies. 13 As a program plans to address Healthy Homes issues, it should also develop a mechanism to address social services issues. # Partnerships Programs should develop partnerships based on issues identified by the community analysis. First, programs should identify issues they can address successfully with existing resources. Then, programs should identify organizations within the community through which they can address other issues of concern. Programs should also engage faith-based and neighborhood organizations; such partnerships are critical to addressing community needs. Faith-based and neighborhood organizations are also essential to addressing health and environmental disparities found in low-income, vulnerable, and other underserved populations. A number of executive orders and policy statements mandate federal agencies to address environmental justice and faith-based community organizations in a more comprehensive manner. 6,8 Programs should survey the community and identify partners that can address their needs. # When developing partnerships, programs should employ concepts such as - Determine what all organizations-including yours-can contribute and gain through the collaboration. - Ensure that representatives have the expertise and organizational support to participate in the partnership. - Identify a common interest or value upon which to build the partnership, keeping in mind that values and interests may differ substantially. - Select partners that have the decision-making authority to move the partnership forward. - Establish through a formal process (e.g., Memorandum of Understanding or Agreement) the roles and responsibilities of program and partner. An organizational chart is helpful when depicting the relationship between these entities. There are a number of partners that programs may consider when developing a Healthy Homes program. Partnerships may include # Referral Process Referrals are an integral component of most Healthy Homes programs. HHLPPB' s experience has indicated that referrals to and from partners are difficult to track and follow through to resolution. Without ensuring follow up, a program has no way to measure impact, gauge effectiveness of interventions, or ensure cases have been adequately addressed. A program should specifically address how to track referrals and, for each Healthy Homes issue, ensure follow up. Programs should develop a comprehensive plan that describes how to identify, address, and resolve housing issues. Throughout the process, communication between program and partners is critical to ensure timely resolution of issues and documentation of activities. When developing an approach to addressing healthy homes issues, programs should consider three elements: - Identify the Issue. Determine the various mechanisms through which an issue will be identified. For example, when conducting home visits, will the program provide inspections to identify issues or receive referrals from other agencies that might also identify issues? - Address the Issue. Determine how issues will be addressed once they are identified. For example, will the program address all issues or will they make a referral to a partner agency to address some issues? How will the program determine if an issue has been addressed, particularly when making a referral? - Resolve the Issue. Determine what measures will be implemented to determine if an issue has been resolved. Will the program document results in a database once the issue has been resolved or when it is determined that an issue cannot be resolved? Will the program incorporate measures to reassess the issue and determine why it was not resolved? A flowchart similar to Figure 1 will help clarify the process of the program and its partners. Programs should develop a similar flowchart of their processes, including referrals, for each healthy housing issue. # Follow-up Care When determining if an issue has been resolved, programs should examine whether issues associated with either the house or the child have been addressed. Programs should be proactive in their approach for ensuring that properties identified with hazards are remediated. If a child moves before issues related to the house are resolved, programs should have a mechanism in place which allows continuous monitoring of the property; including enforcement actions. Programs should also provide direct case management (e.g. lead, asthma) or work in conjunction with other programs. All events associated with each element should be documented in the surveillance system. For some diseases and conditions, programs will follow both the child and the house over time. Children with lead poisoning or asthma, for example, require long term case management, as well as, ongoing assessment of housing hazards. In other cases, programs may only follow the house. For example, if the program provides/installs smoke alarms or other safety devices, an inventory of addresses where alarms have been installed should be created allowing programs to determine if an increase in safety devices leads to a decrease in specific injuries over time. # Surveillance Programs may need to obtain a new-or modify an existing-surveillance system capable of tracking housing variables. HHLPPB has developed the new Web-based Healthy Housing and Lead Poisoning Surveillance System (HHLPSS) that has the capacity to track lead and housing variables. HHLPPB provides this software at no cost to programs. However, to install and operate HHLPSS, programs must have specific hardware and software in place. This may require the purchase of new computer servers and supporting software. Programs should contact HHLPPB for more information on how to obtain or transition to HHLPSS. # Program Evaluation Evaluation is essential for effective public health programming and allows for continuous quality improvement. Dedication of time and funding to an evaluation component is important when developing a Healthy Homes program. An evaluation determines how well an activity fares compared with another option, plan, or period. It identifies expected outcomes of the program and develops mechanisms for evaluation design, data collection, and analysis. Public health officials can use the evaluation process to assess program effectiveness and make informed decisions. Evaluations are developed to focus on different aspects of a program: process, outcomes, and impact of the intervention. Each type of evaluation has its place in gathering evidence to assess or monitor whether a program reaches the intended population and meets its goals. Program evaluation answers two questions: - Are we doing things right? That is, are program activities implemented and functioning as planned? (Process evaluation); and - Are we doing the right things? That is, are program activities having the intended effect? (Outcome/impact evaluation) Reliance on the four standards of utility, feasibility, propriety, and accuracy will assist in the development of an evaluation methodology and will maximize the final evaluation tool' s utility. Essential components of a good evaluation process also include developing SMART Objectives -Specific, Measurable, Achievable, Relevant, and Time-bound. Logic models are useful when designing an evaluation framework. They demonstrate how activities included in the work plan relate to goals and objectives. Developing logic models in a collaborative manner builds a shared understanding of the program among stakeholders and provides user feedback. Evaluation measures or indicators can be developed from logic models by examining the relationships between the goals, objectives, and activities. These models can also be used for project planning or management and as a communication tool to relate the specifics to the big picture. A number of resources exist for program evaluation. # HEALTHY HOMES STRATEGIC PLAN The Healthy Homes strategic plan is a document whose development is based on issues identified during the needs assessment process. It should include goals, measurable objectives, and a timeline for addressing issues. The strategic plan should also incorporate the activities already underway. When developing goals and objectives for the strategic plan, the program should address four primary questions: - Who is the target audience for the intervention? - What are the anticipated barriers for implementing the intervention? - How will the identified barriers be addressed? - What are the expected outcomes? Programs should then develop activities that meet the intended goals and objectives. These include plans that - Define roles and responsibilities for accomplishing the objectives. - Evaluate the individual/community/institutional health impact of each strategy. - Communicate information in a clear and timely manner. - Develop an approach to strengthen / develop collaborations with other programs. # BEST PRACTICES Programs developing a Healthy Homes initiative are encouraged to undertake those interventions with proven efficacy. 4,13 In 2009, the National Center for Healthy Housing reviewed interventions pertinent to Healthy Homes. 4 # SUMMARY A Healthy Homes approach looks at a number of topics in a more holistic manner. While researchers and investigators have covered some topics extensively, others remain relatively unstudied. A rigorous needs assessment will allow a program to identify community issues and program strengths/weaknesses to develop a strategic plan. This plan will help guide a program and its partners to efficiently address community issues. As a program moves to implement community interventions, it should consider the results of previous research to help make such initiatives successful. Programs are also encouraged to communicate with each other and refer to other sources of guidance such as reports compiled by various health departments. 13 Development of a Healthy Homes program is an ongoing process that will need time, resources, and strong collaborative efforts to succeed. CDC' s HHLPPB remains committed to improving the health of people through healthy homes. # Contact Information # CDC/NCEH/HHLPPB 4770 Buford Highway, Mail Stop F-60 Atlanta, Georgia 30341 770-488-3300 - [email protected]	# BACKGROUND Introduction The Centers for Disease Control and Prevention (CDC) Healthy Homes and Lead Poisoning Prevention Branch (HHLPPB) recognizes the need to address housing related issues, including lead exposure, in a more comprehensive manner. The HHLPPB also recognizes a need to provide guidance to an increasing number of state, tribal, territorial, and local Childhood Lead Poisoning Prevention Programs (CLPPPs) as they expand into Healthy Homes programs. This guidance seeks to assist CLPPPs-and other agencies involved in health or housing issues-in developing a comprehensive Healthy Homes program. # Overview of Health and Housing: Context for Transition Florence Nightingale once said that "The connection between the health and the dwelling of the population is one of the most important that exists." Although it is clear that the health of the family depends on having homes that are safe and free from hazards, much work remains to clarify these connections. Some 38 million US homes have lead-based paint hazards that can lead to childhood lead poisoning. 1 In addition, injuries, respiratory diseases such as asthma, and quality of life issues have been linked to the conditions present in approximately 6 million housing units nationwide. 2,3 Homes with moderate or severe physical problems place residents at increased risk for fire, electrical injuries, falls, rodent bites, and other illnesses or injuries. 2,4 Additional issues of concern include exposure to pesticide residues, indoor toxicants, tobacco smoke, and combustion gases. The burning of oil, gas, and kerosene can release a variety of combustion products, such as carbon monoxide. With proper education, home maintenance equipment, or testing, many of these home-related issues can be reduced or eliminated. # Healthy Homes and Lead Poisoning Prevention Healthy People 2020 is a national health agenda that envisions a society in which all people live long and healthy lives. A Healthy Homes program addresses Goal Two of that agenda: achieve health equity and eliminate health disparities. Healthy Homes also addresses eight proposed Healthy People 2020 Environmental Health objectives: • Reduction of the proportion of occupied housing units that have moderate or severe physical problems, • Reduce blood lead levels in children, • Reduce indoor allergen levels, • Increase the proportion of persons living in homes at risk that have an operating radon mitigation system, • Increase the number of new homes constructed with radon-reducing features, especially in high-radon-potential areas, • Increase the proportion of persons living in pre-1978 housing that has been tested for the presence of lead-based paint hazards, • Decrease the number of U.S. homes that have lead-based paint or related hazards, and • Increase the number of Territories, Tribes, States, and the District of Columbia that monitor diseases or conditions that can be caused by exposure to environmental hazards. 5 The Surgeon General' s Call to Action to Promote Healthy Homes outlines a comprehensive and coordinated Healthy Homes approach. This approach seeks to reduce disparities in the availability of healthy, safe, affordable, accessible, and environmentally friendly homes. The Call to Action declares, "A healthy home should be sited, designed, built, renovated, and maintained in ways that support the health of residents." Healthy home features include • How the home is constructed, designed, and maintained; • Physical characteristics; • Presence of safety devices; • Quality of indoor air and water; • Presence or absence of certain chemicals; • Individual resident behavior; and • Community characteristics. [6][7][8] Presidential Executive Order 12898 for Environmental Justice addresses health and housing disparities among minority, low-income, and tribal populations. 6 The Order refers to the right of all persons to live in a healthy home and in an environment free of hazards. Environmental Justice supports the Healthy People 2020 national agenda by promoting a healthy quality of life and elimination of health/housing inequities for disparate populations. Institutionalizing environmental justice and implementing recommendations from the Surgeon General' s Call to Action are essential steps in eliminating health and housing disparities. # CDC' s Healthy Homes Initiative CDC' s Healthy Homes Initiative is a coordinated, comprehensive, and holistic approach to preventing diseases and injuries that result from housing-related hazards and deficiencies. 9 The Healthy Homes Initiative seeks to • Broaden the scope of single-issue public health programs-such as childhood lead poisoning prevention and asthma programs-to address multiple housing deficiencies that affect health and safety. • Build capacity and competency among environmental public health practitioners, public health nurses, housing specialists, managers, and others who work in the community to develop and manage comprehensive and effective Healthy Homes programs. • Promote, develop, and implement cross-disciplinary activities at the federal, state, tribal, territorial, and community levels to address the problem of unhealthy and unsafe homes through surveillance, research, and comprehensive prevention programs. • Facilitate the collection of local data and monitor progress toward reducing or eliminating housing deficiencies and hazards. • Promote research to determine causal relations between substandard housing and adverse health effects. • Develop guidelines to assess, reduce, and eliminate health and safety risks. • Identify and implement low-cost, reliable, and practical methods to reduce health and safety risks in substandard housing. # ASSESSMENT An essential first step to developing a successful Healthy Homes program is a comprehensive needs assessment. Established programs can also benefit from such an assessment to assist with focusing program goals and efforts. A needs assessment involves collecting and analyzing data to understand community demographics, to identify the health/housing needs of the community, and to examine program/partner capabilities. When developing a Healthy Homes program, the comprehensive needs assessment should at a minimum address • Community Analysis. Examine data to determine community demographics and health/housing issues. • Training and Education. Identify training needs for staff and partners to build a sustainable program. • Policy. Review housing, sanitation, and habitation statues or codes, and enforcement authorities within the jurisdiction of the program. • Program Experience. Examine organizational capacity and assess personnel knowledge, skills, and experience. • Partnerships. Examine effectiveness of existing partnerships, identify new partners for collaborative efforts, and develop a monitoring process when making referrals. • Program Evaluation. Evaluate performance by examining the processes and effects of current activities on the overall goals and objectives of your program. • Surveillance. Determine efficacy of surveillance efforts in conducting an ongoing, systematic examination of community needs. Use information collected for the needs assessment to develop a strategic plan. This plan will serve as a roadmap to assist programs in • Addressing weaknesses identified in the needs assessment, • Prioritizing the most relevant issues, and • Implementing an effective healthy homes program. # ASSESSMENT COMPONENTS # Community Analysis When developing a Healthy Homes program, managers and staff should understand their communities' demographics, health issues, and housing needs. Whenever possible, programs should use available data to identify health and housing hazards within the community; this may also require using data from partner organizations. After a review of the findings, programs may identify geographic areas and populations within the community to target for intervention. Further data collection may involve engaging the community by holding community meetings or using focus groups to understand health and housing needs from a different perspective. • Essentials for Healthy Homes Practitioners. For health and housing professionals seeking a solid understanding of Healthy Homes programs and principles. The course helps prepare students for the Healthy Homes Specialist Credential exam. # Training and Education • Launching a Healthy Homes Initiative. For health and housing professionals, policymakers, and advocates seeking to develop a Healthy Homes initiative in their community. • Building Healthy Homes. For designers, architects, and contractors seeking to understand building science and construction methods involving Healthy Homes. • Pediatric Environmental Home Assessment (online training). For nurses and other practitioners who do home visits and who seek to better assess their client' s homes for healthy home problems and make referrals for assistance. • Community Health Workers. For persons who work as health advocates in their communities. Those who complete this course will train Community Health Workers to 1) provide one-on-one and large-group education on Healthy Homes topics, 2) provide general advice about specific Healthy Homes problems, and 3) recommend Healthy Homes approaches for families, property owners, and other community members. The CDC Healthy Homes/Lead Poisoning Prevention Training Center offers four training tracks for new program personnel. These tracks provide instruction about lead poisoning prevention and healthy homes activities. They also provide core subject overviews as well as specialized training in Program Management, Data Management and Surveillance, Case Management, and Primary Prevention. 11 Specific issues within a community may require additional training (e.g., Integrated Pest Management, Radon, Asthma). Programs may not have the capacity to train staff and address all health/housing-related hazards within the community. To address those concerns, programs may need to identify and use community/national resources. # Policy With regard to state and local laws that address Healthy Homes issues, programs should identify gaps in regulations, ordinances, and program enforcement policies. Housing codes (i.e., codes for property maintenance, sanitation, and habitation) should be identified along with the appropriate agency that has enforcement authority. Programs should discuss with appropriate officials (e.g., legal counsel) how to use these authorities effectively to address health hazards in homes. As a part of the strategic plan, the program should develop an approach to address gaps/inconsistencies identified in current laws, regulations, codes, and policies. State and local health departments should consult with their general counsel' s office concerning rules and restrictions pertinent to lobbying activities. 12 # Program Experience The needs assessment should be used to evaluate agency resources, past performance, infrastructure, and management in regard to their goals. Programs should also assess the knowledge, skills, and experience of personnel in planning, managing, or conducting activities associated with housing or health-related programs. The Healthy Homes Specialist Credential should be considered when assessing program experience. Other programs that have transitioned to Healthy Homes have identified a need for access to social service agencies. 13 As a program plans to address Healthy Homes issues, it should also develop a mechanism to address social services issues. # Partnerships Programs should develop partnerships based on issues identified by the community analysis. First, programs should identify issues they can address successfully with existing resources. Then, programs should identify organizations within the community through which they can address other issues of concern. Programs should also engage faith-based and neighborhood organizations; such partnerships are critical to addressing community needs. Faith-based and neighborhood organizations are also essential to addressing health and environmental disparities found in low-income, vulnerable, and other underserved populations. A number of executive orders and policy statements mandate federal agencies to address environmental justice and faith-based community organizations in a more comprehensive manner. 6,8 Programs should survey the community and identify partners that can address their needs. # When developing partnerships, programs should employ concepts such as • Determine what all organizations-including yours-can contribute and gain through the collaboration. • Ensure that representatives have the expertise and organizational support to participate in the partnership. • Identify a common interest or value upon which to build the partnership, keeping in mind that values and interests may differ substantially. • Select partners that have the decision-making authority to move the partnership forward. • Establish through a formal process (e.g., Memorandum of Understanding or Agreement) the roles and responsibilities of program and partner. An organizational chart is helpful when depicting the relationship between these entities. There are a number of partners that programs may consider when developing a Healthy Homes program. Partnerships may include # Referral Process Referrals are an integral component of most Healthy Homes programs. HHLPPB' s experience has indicated that referrals to and from partners are difficult to track and follow through to resolution. Without ensuring follow up, a program has no way to measure impact, gauge effectiveness of interventions, or ensure cases have been adequately addressed. A program should specifically address how to track referrals and, for each Healthy Homes issue, ensure follow up. Programs should develop a comprehensive plan that describes how to identify, address, and resolve housing issues. Throughout the process, communication between program and partners is critical to ensure timely resolution of issues and documentation of activities. When developing an approach to addressing healthy homes issues, programs should consider three elements: • Identify the Issue. Determine the various mechanisms through which an issue will be identified. For example, when conducting home visits, will the program provide inspections to identify issues or receive referrals from other agencies that might also identify issues? • Address the Issue. Determine how issues will be addressed once they are identified. For example, will the program address all issues or will they make a referral to a partner agency to address some issues? How will the program determine if an issue has been addressed, particularly when making a referral? • Resolve the Issue. Determine what measures will be implemented to determine if an issue has been resolved. Will the program document results in a database once the issue has been resolved or when it is determined that an issue cannot be resolved? Will the program incorporate measures to reassess the issue and determine why it was not resolved? A flowchart similar to Figure 1 will help clarify the process of the program and its partners. Programs should develop a similar flowchart of their processes, including referrals, for each healthy housing issue. # Follow-up Care When determining if an issue has been resolved, programs should examine whether issues associated with either the house or the child have been addressed. Programs should be proactive in their approach for ensuring that properties identified with hazards are remediated. If a child moves before issues related to the house are resolved, programs should have a mechanism in place which allows continuous monitoring of the property; including enforcement actions. Programs should also provide direct case management (e.g. lead, asthma) or work in conjunction with other programs. All events associated with each element should be documented in the surveillance system. For some diseases and conditions, programs will follow both the child and the house over time. Children with lead poisoning or asthma, for example, require long term case management, as well as, ongoing assessment of housing hazards. In other cases, programs may only follow the house. For example, if the program provides/installs smoke alarms or other safety devices, an inventory of addresses where alarms have been installed should be created allowing programs to determine if an increase in safety devices leads to a decrease in specific injuries over time. # Surveillance Programs may need to obtain a new-or modify an existing-surveillance system capable of tracking housing variables. HHLPPB has developed the new Web-based Healthy Housing and Lead Poisoning Surveillance System (HHLPSS) that has the capacity to track lead and housing variables. HHLPPB provides this software at no cost to programs. However, to install and operate HHLPSS, programs must have specific hardware and software in place. This may require the purchase of new computer servers and supporting software. Programs should contact HHLPPB for more information on how to obtain or transition to HHLPSS. # Program Evaluation Evaluation is essential for effective public health programming and allows for continuous quality improvement. Dedication of time and funding to an evaluation component is important when developing a Healthy Homes program. An evaluation determines how well an activity fares compared with another option, plan, or period. It identifies expected outcomes of the program and develops mechanisms for evaluation design, data collection, and analysis. Public health officials can use the evaluation process to assess program effectiveness and make informed decisions. Evaluations are developed to focus on different aspects of a program: process, outcomes, and impact of the intervention. Each type of evaluation has its place in gathering evidence to assess or monitor whether a program reaches the intended population and meets its goals. Program evaluation answers two questions: • Are we doing things right? That is, are program activities implemented and functioning as planned? (Process evaluation); and • Are we doing the right things? That is, are program activities having the intended effect? (Outcome/impact evaluation) Reliance on the four standards of utility, feasibility, propriety, and accuracy will assist in the development of an evaluation methodology and will maximize the final evaluation tool' s utility. Essential components of a good evaluation process also include developing SMART Objectives -Specific, Measurable, Achievable, Relevant, and Time-bound. Logic models are useful when designing an evaluation framework. They demonstrate how activities included in the work plan relate to goals and objectives. Developing logic models in a collaborative manner builds a shared understanding of the program among stakeholders and provides user feedback. Evaluation measures or indicators can be developed from logic models by examining the relationships between the goals, objectives, and activities. These models can also be used for project planning or management and as a communication tool to relate the specifics to the big picture. A number of resources exist for program evaluation. [14][15][16][17][18][19][20][21][22][23][24] # HEALTHY HOMES STRATEGIC PLAN The Healthy Homes strategic plan is a document whose development is based on issues identified during the needs assessment process. It should include goals, measurable objectives, and a timeline for addressing issues. The strategic plan should also incorporate the activities already underway. When developing goals and objectives for the strategic plan, the program should address four primary questions: • Who is the target audience for the intervention? • What are the anticipated barriers for implementing the intervention? • How will the identified barriers be addressed? • What are the expected outcomes? Programs should then develop activities that meet the intended goals and objectives. These include plans that • Define roles and responsibilities for accomplishing the objectives. • Evaluate the individual/community/institutional health impact of each strategy. • Communicate information in a clear and timely manner. • Develop an approach to strengthen / develop collaborations with other programs. # BEST PRACTICES Programs developing a Healthy Homes initiative are encouraged to undertake those interventions with proven efficacy. 4,13 In 2009, the National Center for Healthy Housing reviewed interventions pertinent to Healthy Homes. 4 # SUMMARY A Healthy Homes approach looks at a number of topics in a more holistic manner. While researchers and investigators have covered some topics extensively, others remain relatively unstudied. A rigorous needs assessment will allow a program to identify community issues and program strengths/weaknesses to develop a strategic plan. This plan will help guide a program and its partners to efficiently address community issues. As a program moves to implement community interventions, it should consider the results of previous research to help make such initiatives successful. Programs are also encouraged to communicate with each other and refer to other sources of guidance such as reports compiled by various health departments. 13 Development of a Healthy Homes program is an ongoing process that will need time, resources, and strong collaborative efforts to succeed. CDC' s HHLPPB remains committed to improving the health of people through healthy homes. # Contact Information # CDC/NCEH/HHLPPB 4770 Buford Highway, Mail Stop F-60 Atlanta, Georgia 30341 770-488-3300 • [email protected] http://www.cdc.gov/healthyhomes	None	None
950ec388e63fa9f12ee936578d8881896eba5249	cdc	None	Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), simple, low-risk tests can be waived and performed with no routine regulatory oversight in physicians' offices and various other locations. Since CLIA was implemented, waived testing has steadily increased in the United States. Surveys conducted during 1999Surveys conducted during -2004 by the Centers for Medicare & Medicaid Services and studies funded by CDC during 1999-2003 evaluated testing practices in sites holding a CLIA Certificate of Waiver (CW). Although study findings indicate CW sites generally take measures to perform testing correctly, they raise quality concerns about practices that could lead to errors in testing and poor patient outcomes. These issues are probably caused, in part, by high personnel turnover rates, lack of understanding about good laboratory practices, and inadequate training. This report summarizes study findings and provides recommendations developed by the Clinical Laboratory Improvement Advisory Committee for conducting quality waived testing. These recommendations include considerations before introducing waived testing, such as management responsibility for testing, regulatory requirements, safety, physical and environmental requirements, benefits and costs, staffing, and documentation. They also cover good laboratory practices for the three phases of testing: 1) before testing (test ordering and specimen collection), 2) during testing (control testing, test performance, and result interpretation and recording), and 3) after testing (result reporting, documentation, confirmatory testing, and biohazard waste disposal). They are intended to be used by those who would benefit from improving their knowledge of good laboratory practices. Continued monitoring of waived testing, with a focus on personnel education and training, is needed to improve practices and enhance patient safety as waived testing continues to increase. devices that are waived from most federal oversight requirements (and are thus designated as waived tests), including requirements for personnel qualifications and training, quality control (QC) (unless specified as required in the test system instructions), proficiency testing (PT), and routine quality assessment. Advances in technology have made tests simpler, contributing to this shift in testing. In the past, tests such as prothrombin time, cholesterol, and glucose either used complex manual methodologies or were performed using sizable instrumentation suitable for use by highly trained personnel in traditional clinical laboratory settings. Many tests can now be performed using compact or hand held devices by personnel with limited experience and training. These advances have enabled more testing to be performed in emergency departments, hospital rooms, and physicians' offices and in nontraditional testing sites such as community counseling centers, pharmacies, nursing homes, ambulances, and health fairs. Since the 1992 inception of the program implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA), the numbers of waived tests and the sites that perform them have# Introduction Laboratory testing plays a critical role in health assessment, health care, and ultimately, the public's health. Test results contribute to diagnosis and prognosis of disease, monitoring of treatment and health status, and population screening for disease. Laboratory testing affects persons in every life stage, and almost everyone will experience having one or more laboratory tests conducted during their lifetime. An estimated 7-10 billion laboratory tests are performed each year in the United States (1,2), and laboratory test results influence approximately 70% of medical decisions (2)(3)(4). Increasingly, these decisions are based on simple tests performed at the point-of-care using # Scope of Waived Testing Sites performing only waived tests comprise 58% (105,138) of the approximately 180,000 laboratory testing sites in the United States (Table 1, Figure 1). Waived testing performed in these sites is often wellness testing, screening tests, or other critical testing that introduces a large population of persons into the health-care setting. Although the testing performed in CW sites accounts for 65 years and certain disabled persons, covers diagnostic laboratory testing. Payment data for 2004, provided by CMS, indicated that of the $3,494,840,086 spent on reimbursed laboratory testing for that year, $128,169,398 (3.7%) was for waived tests. The volume of Medicare Part B reimbursed waived laboratory testing in 2004 represented 8% of the total reimbursed testing volume for that year, a 57% increase over the volume in 2000 (Table 1). # Patient Safety Concerns Related to Waived Testing Efforts to reduce medical errors, improve health-care quality, and increase patient safety have been gaining national attention. A report issued in 1999 by the Institute of Medicine (IOM) presented a national agenda to address these issues and recommended strategies for change that included the implementation of safe practices at the health-care delivery level (7). As described in the IOM report, errors most often occur when multiple contributing factors converge, and preventing errors and improving patient safety require a systems approach. Five years after this seminal report, small but consequential changes have occurred that have shifted the focus to improving systems, engaging stakeholders, and motivating health-care providers to adopt new safe practices (8). Although by law waived tests should have insignificant risk for erroneous results, these tests are not completely error-proof and are not always used in settings that employ a systems approach to quality and patient safety. Errors can occur anywhere in the testing process, particularly when the manufacturer's instructions are not followed and when testing personnel are not familiar with all aspects of the test system and how testing is integrated into the facility's workflow. Although data have not been systematically collected on patient outcomes with waived testing, adverse events can occur (9). Some waived tests have potential for serious health impacts if performed incorrectly. For example, results from waived tests can be used to adjust medication dosages, such as prothrombin time testing in patients undergoing anticoagulant therapy and glucose monitoring in diabetics. In addition, erroneous results from diagnostic tests, such as those for human immunodeficiency virus (HIV) antibody, can have unintended consequences. The lack of oversight and requirements for personnel qualifications and training for an increasingly large number of CW sites is a concern and could contribute to errors and patient harm. During 1999-2001, CMS conducted on-site surveys of a representative sample of CW sites in 10 states to assess the quality of testing in these sites. These pilot surveys identified quality issues that could result in medical errors (10). Contributing factors included inadequate training in good laboratory practices and high turnover rates of testing personnel. As a result, during 2002-2004, CMS conducted nationwide on-site surveys of CW facilities to collect additional data that would provide an assessment of testing, promote good laboratory practices and encourage improvement through educational outreach, and make recommendations on the basis of cumulative survey findings. The data collected from these surveys, along with data on waived testing practices gathered through CDC-funded studies conducted during 1999-2003 by the state health departments of Arkansas, New York, and Washington (collectively referred to as the Laboratory Medicine Sentinel Monitoring Network ), support the initial CMS findings of gaps in good laboratory practices in these sites (11)(12)(13)(14)(15)(16). In addition, a 2001 report issued by the HHS Office of Inspector General (OIG), following their investigation of CLIA certification and enrollment processes, identified the lack of routine on-site visits to CW sites by surveyors representing state agencies and private sector accreditation organizations as presenting vulnerabilities in these sites. The OIG report indicated that approximately half of the state respondents reported problems related to quality issues with the waived laboratories in their states (e.g., failure to follow manufacturers' instructions or failure to identify incorrect results and performing unauthorized testing) (17). The concerns noted by states were similar to those identified in the CMS pilot studies. # CLIAC Response An initial CMS report of its 2002-2003 survey findings, presented to CLIAC in 2004, supported earlier concerns about the quality of testing practices and the need for education and training of testing personnel in CW sites. In response, the committee recommended publication of the 2002-2004 CMS data in conjunction with other data pertinent to waived testing performance along with recommendations for good laboratory practices for waived testing sites. This information would then be available to provide guidance to physicians, nurses, and other health-care providers in CW facilities. As a result, a workgroup was appointed to consider practices associated with the waived testing process and their impact on the quality of waived testing. This workgroup was comprised of key stakeholders in waived testing (i.e., CLIAC members; physicians; nurses; laboratorians; manufacturers; distributors; and representatives from CDC, CMS, and FDA). In its evaluations, the workgroup considered existing practice guidelines from professional organizations, waived testing recommendations from CMS, personal and professional experience, and publications related to waived testing. The workgroup's findings were presented to CLIAC for its deliberations at the February 2005 meeting, at which time CLIAC provided recommendations to HHS concerning good laboratory practices for waived testing sites. CLIAC supported publication of the recommendations, along with the data from the studies of CW sites, and suggested the publication could serve as a comprehensive source document that could be used to develop additional educational tools appropriate for specific target audiences. (11). The New York Sentinel Network (NYSN) consisted of approximately 600 limited service laboratories (facilities other than physician office laboratories that perform only waived tests and PPMP). NYSN collected its data through on-site surveys during which waived testing practices were assessed by surveyor observation and record reviews (11). # Surveys of Waived Testing Sites Methods # Survey Findings Demographics CMS surveyed 4,214 CW sites during April 15, 2002-November 12, 2004. This included 897 sites in 2002, 1,575 sites in 2003, and 1,742 sites in 2004. Of the CW facility types surveyed, POLs compose the largest percentage (47%), followed by skilled nursing facilities (14%) (Table 2). The CW sites surveyed estimated performing a broad range of annual test volumes (Figure 2). Of the facilities surveyed by 3). This correlates with data for the top five waived tests identified through the LMSMN, especially for POLs (11). Although not among the most commonly performed, waived tests are available for certain infectious diseases of public health significance and were reportedly performed by CW sites in the CMS surveys (influenza, 46 sites; HIV, four; and Lyme disease, one). # Personnel and Training Under CLIA, no education or training is required for the director or testing personnel in CW sites. The educational background and qualifications for directors and testing per-sonnel at CW sites were collected as part of the CMS surveys and by LMSMN (PNWSN and NYSN). The CMS surveys indicated that in 69% of CW sites, physicians served as directors, followed by nurses (17%) (Table 3). Similarly, 59% of the PNWSN CW site directors were physicians, with the remaining 41% having other backgrounds or degrees (12). For CW testing personnel, according to the CMS data, the top four categories were nurses (46%), medical assistants (25%), physicians (9%), and high school graduates (7%) (Table 3). NYSN reported that registered nurses (RNs) and licensed practical nurses (LPNs) served as testing personnel in 84% of the limited service laboratories they surveyed (13). Trained laboratorians (i.e., medical technologists and medical laboratory technicians) accounted for 2% of laboratory directors and testing personnel in the CW sites surveyed by CMS and a smaller percentage in the limited service laboratories surveyed by the NYSN (13). CMS surveys indicated that 43% of CW sites experienced a change in testing personnel during the preceding 12 months. Among the top categories of testing personnel in the PNWSN, turnover rates were highest for medical assistants (17%), followed by LPNs (13%), RNs (9%), and physicians (2%) (14). Although the majority of CW sites in the CMS surveys (90%) reported that new personnel were trained, fewer sites (85%) evaluated staff to ensure competency. Data identifying who provided training were not submitted for all sites in the surveys. However, according to the CW sites that provided this information for 2003-2004 (Table 4), nurses most frequently provided waived test training (33%), followed by the manufacturer or sales representatives (15%). Findings from a PNWSN study indicated that the highest percentage of personnel were initially trained by another employee (25%) or trained themselves by using instructions provided with the waived test system (17%) (15). Another PNWSN study indicated that most training (77%) took place in a day or less (14). Comments from this study reflected the thinking that training is not always necessary or that minimal time should be spent on training because persons have been trained in school or on other jobs. The time spent on training was not captured as part of the CMS surveys. # Testing Practices The CMS surveys indicated that the majority of the CW sites were aware of and followed some practices for ensuring the accuracy and reliability of their testing. However, lapses in quality were identified at certain sites, some of which could result in patient harm. In some instances, CW sites were determined to be performing testing Of the CW facilities CMS surveyed, 12% did not have the most recent instructions for the waived test systems they were using, and 21% of the sites reported they did not routinely check the product insert or instructions for changes to the information (Table 5). On the basis of manufacturer's instructions, 21% of the CW sites did not perform QC testing as specified, and 18% of the sites did not use correct terminology or units of measure when reporting results. Among other quality deficiencies identified were failure to adhere to proper expiration dates for the test system, reagents, or control materials (6%) and failure to adhere to the storage conditions as described in the product insert (3%). Six percent of CW sites did not perform follow-up confirmatory tests as specified in the instructions for certain waived tests (e.g., group A streptococcal antigen), and 5% did not perform function checks or calibration checks to ensure the test system was operating correctly. Findings from the LMSMN studies were similar to the CMS findings for these quality deficiencies (11). Although not usually specified in the product insert (and therefore not a CLIA requirement), proper documentation and recordkeeping of patient and testing information are also important elements of good laboratory practices. CMS surveys indicated that 45% of CW sites did not document the name, lot number, and expiration dates for tests performed; 35% did not maintain logs with records of their QC testing; 31% did not maintain a log or record of tests performed; and 9% did not require a requisition or test orders documented in a patient chart before performing a test (Table 5). NYSN observed similar findings but noted increased compliance with state requirements for documentation/recordkeeping when laboratories had formal affiliations with New York Statelicensed laboratories (11). # Discussion The findings from the CMS surveys and LMSMN studies indicated that the majority of CW testing sites performed testing correctly and provided reliable service. However, in CW sites, most directors and testing personnel did not have formal laboratory training or testing experience, there was a high turnover of personnel, and lapses in following manufacturers' instructions and instituting practices to ensure the quality of the testing were noted. The survey findings indicated that 485 (12%) of the 4,214 CW sites surveyed did not have the cur-rent manufacturers' instructions available, and 701 (21%) of the 3,317 sites surveyed during 2003-2004 did not check to be sure there had been no changes to the instructions. Test system instructions can change over time and CW sites sometimes switch test systems that could have different instructions. CMS survey results also indicated that, in varying proportions, when CW sites had the current instructions, they did not follow critical steps in the testing process (e.g., performing QC testing, reporting results correctly, adhering to expiration dates and appropriate storage requirements, and performing test system function checks or calibration checks). This is a concern because the only CLIA requirement for performing waived testing is to follow the manufacturer's instructions. Neglecting to follow instructions could cause inaccurate test results that could lead to incorrect diagnoses, inappropriate or unnecessary medical treatment, and poor patient outcomes. CMS surveys indicated that certain CW sites (5%) were performing testing more complex than waived testing without taking required measures to ensure quality. In certain CW sites, nonwaived microscopic examinations were being performed by personnel who lacked the education and training needed to develop the interpretive and judgment skills necessary to accurately perform these procedures. In addition, measures such as QC, PT, adequate documentation, and monitoring are required to ensure the accuracy and reliability of nonwaived test results. Although direct microscopic examinations can be conducted by a physician or midlevel health-care practitioner as part of a patient examination, testing must be conducted under a CLIA PPMP certificate. The quality issues identified through these surveys might have been caused, in part, by high turnover rates of testing personnel in CW sites, inadequate training with respect to waived testing, and lack of understanding of good laboratory practices, including the importance of following all aspects of the manufacturers' instructions. Although the study results indicated that most testing personnel were trained, they were often trained for minimum periods by persons who did not have formal education or training in clinical laboratory testing and who might not have understood the importance of measures to ensure quality testing. Certain testing personnel also were self-trained. In addition, when testing personnel were not evaluated to determine their competency level following training or on an ongoing basis, no assessment was conducted to determine whether the training was effective. The data demonstrate a need for educational information among CW site directors and testing personnel about the importance of following manufacturers' instructions, adhering to expiration dates, performing QC testing, and proper documentation and recordkeeping. One of the recommendations in the 2001 OIG report was that CMS should provide educational outreach to directors of waived and PPMP laboratories about the CLIA requirements (17). The findings in the 2002-2004 CMS surveys are subject to at least three limitations, and caution should be used in extrapolating the survey data to make generalizations about waived testing. First, the CMS surveys were not intended to be a scientific study of a random sample of CW sites. Waived testing data were collected by CMS to provide an assessment of testing practices, promote good laboratory practices, and encourage improvement through educational outreach. Although surveyors attempted to include a wide variety of CW sites in the sample, the sites were self-selected by surveyors and selection was based, to some degree, on convenience to the surveyors and willingness of the sites to participate in the voluntary surveys. However, few sites refused to participate in the surveys. Overall, the sites represent a nationwide sample and the distribution of CW facility types is similar to the distribution of CW facility types in the United States (Table 2). In addition, the 2002-2004 CMS survey findings resulted in the same general conclusions as the earlier CMS pilot studies, which were conducted on a random sample of laboratories (10). Second, the CMS data were collected and entered into the database by a large number of persons, introducing variability. Although training was provided before the surveys were conducted, the intent of the survey questions was subject to individual interpretation. Because the phrasing of some questions differed slightly from 2002 to 2003-2004, in certain cases, the meanings of the questions also changed. Finally, the CMS surveys did not assess the frequency of erroneous test results in CW sites or whether lapses in following manufacturers' instructions directly affected test results or patient outcomes. Similar limitations to these were identified in the LMSMN studies (11). The findings of the CMS and LMSMN studies are strikingly similar. Even though the majority of CW sites meet the CLIA requirement to follow manufacturers' instructions for test performance, and many sites follow additional good laboratory practices, over the years these studies have demonstrated that a persistent percentage of CW sites do not meet minimal requirements and are not aware of recommended practices to help ensure quality testing. Because surveying all CW sites is not feasible, the proposed actions to improve and promote quality testing in CW sites emphasize the importance of education and training for CW site directors and testing personnel. To provide a guide that can be adapted for use, either in part or as a whole, by persons or facilities considering the initiation of waived testing and personnel performing waived testing, CLIAC provided recommendations for good laboratory practices. By implementing these recommendations, CW sites could improve quality, reduce testing errors, and enhance patient safety. # Recommended Good Laboratory Practices Overview These recommendations are intended to promote the use of good laboratory practices by physicians, nurses, and other providers of waived testing in a variety of CW sites. They were developed on the basis of recommendations and other resources that provided additional information for promoting patient safety and the quality of CLIAC waived testing in laboratories or nontraditional testing sites (18)(19)(20)(21)(22). These recommendations address decisions that need to be made and steps to be taken as a facility begins offering waived testing or adds a new waived test. They also address developing procedures and training CW personnel and describe recommended practices for each phase of the total testing process, or path of workflow, including the important steps or activities before, during, and after testing. The activities that occur in each of these phases are critical to providing quality testing (Table 6). # Considerations Before Introducing Waived Testing or Offering a New Waived Test Forethought, planning, and preparation are critical to initiating high-quality waived testing in any type of setting. This section describes factors to consider before opening a waived testing site or offering an additional waived test. Questions to address include the following: - Management responsibility for testing. Who will be responsible and accountable for testing oversight at the CW site, and does this person have the appropriate training for making decisions on testing? - Regulatory requirements. What federal, state, and local regulations apply to testing, and is the site adequately prepared to comply with all regulations? # Management Responsibility Each testing site should identify at least one person responsible for testing oversight and decision-making, later referred to as the CW site director. In POLs, this might be a physician or someone in a senior management position who has the appropriate background and knowledge to make decisions about laboratory testing. Ideally, the person signing the CW application (CMS Form 116) is responsible for management of the testing operations. The management staff should demonstrate a commitment to the quality of testing service by complying with applicable regulatory requirements and promoting good laboratory practices. # Regulatory Requirements CLIA certification. Each site offering only waived testing that is not included under any other type of CLIA certificate must obtain a CLIA CW before testing patient specimens. Certain sites offering waived testing can be certified as part of a larger health-care organization that holds a CLIA Certificate of Compliance or Certificate of Accreditation. In addition, certain public health testing sites offering only waived testing can be included under a limited public health or mobile testing exception. A valid CLIA certificate is required for Medicare reimbursement. To apply for a CLIA certificate, CMS Form 116 (http:// www.cms.hhs.gov/clia/cliaapp.asp) must be completed and sent to the state agency for the state in which the testing site is located. This form asks for specific information, including the type of testing site (laboratory type), hours of operation, estimated total annual volume of waived testing, and the total number of persons involved in performing waived testing. The form must be signed by the facility owner or the facility director. Specific state agencies and contacts are available at . The state agency will process the application and send an invoice for the registration fee. If additional assistance is required, contact the appropriate CMS regional office (/ clia/ro-map.asp). CLIA requirements that apply to testing sites operating under a CW include the following: - (23). Regulatory requirements for all OSHA standards, including specific information for medical and dental offices (24), are available at http:// www.osha.gov and by telephone, 800-321-6742. The OSHA Bloodborne Pathogens Standard applies to sites where workers have potential occupational exposure to blood and infectious materials (25). The requirements for compliance with this standard include, but are not limited to: - A written plan for exposure control, including postexposure evaluation and follow-up for the employee in the event of an "exposure incident;" CDC and the Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS) have also published information about biosafety and precautions for preventing transmission of bloodborne pathogens in the workplace (26)(27)(28)(29)(30). Privacy and confidentiality requirements. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) established federal privacy standards to protect patients' medical records and other health information provided to health plans, doctors, hospitals, and other health-care providers. Under HIPAA, CW sites are required to establish policies and procedures to protect the confidentiality of health information about their patients, including patient identification, test results, and all records of testing. These medical records and other individually identifiable health information must be protected, whether on paper, in computers, or communicated orally. In addition, CW sites should be aware that applicable state laws that provide more stringent privacy protections for patients supersede HIPAA. Additional information on HIPAA is available at . # Physical Requirements for Testing Testing should be performed in a separate designated area where adequate space to safely conduct testing and maintain patient privacy is available. In addition, some tests have specific environmental requirements described in the manufacturer's product insert that need to be met to ensure reliable test results. Meeting these environmental conditions can be challenging in nontraditional settings (e.g., health fairs) or community outreach venues (e.g., shopping malls, meeting rooms, parks, parking lots, mobile vans, and buses). Factors to consider include: - and be able to be adequately disinfected; work space should be adequate in size for patient confidentiality, ease of specimen collection, test performance, and storage of supplies and records. # Benefit and Cost Considerations Evaluating the benefits of a particular test. Evaluate the test system, its intended use, performance characteristics, and the population to be tested when assessing whether to introduce waived testing or a new waived test. Information for this evaluation can be obtained from the test manufacturer's product insert (Table 7) or by speaking with the manufacturer's technical representatives. Specific considerations include: - Intended use -Be aware of the intended medical use for which FDA approved the test system as explained in the product insert. This section describes what is being measured by the test, the type of specimen for which it is approved, and whether it is a quantitative or qualitative measurement. - Performance characteristics -Assess the information on performance provided by the test manufacturer or published data. Review data that includes the test's accuracy, precision, sensitivity, specificity, and interferences. - Patient population -Consider the population that will be tested before offering a test. Some tests have not been evaluated for use in specific age groups (e.g., pediatric populations). The predictive value for certain types of test results in a specific patient population depends on the test's sensitivity, specificity, and the prevalence of the condition in the population. For example, when testing for a certain condition or disease in a low-prevalence population, the predictive value of a positive result will be low compared with the predictive value of a negative result. Refer to the product insert for limitations for use in particular patient populations. - Need for supplemental testing or patient follow up -Some waived tests provide preliminary results as part of a multitest series (e.g., rapid HIV testing) or results that must be considered in conjunction with other medical information. These test results might require additional testing before a definitive test result is obtained, and patients might need posttest counseling about the meaning of the test result. Assess the potential need for additional time, documentation, and staffing and a mechanism to refer additional testing to another laboratory when offering such tests. # Developing Procedures and Training Personnel After the decision is made to offer waived testing, it is good practice to develop written policies and procedures so that responsibilities and testing instructions are clearly described for the testing personnel and facility director. The testing procedures form the basis of training for testing personnel. These procedures should be derived from the manufacturer's instructions and should be in a language understandable to testing personnel. # Written Test Procedures To comply with CLIA requirements and provide accurate testing, CW sites must adhere to the manufacturer's current testing instructions. These instructions, as outlined in the product insert, include directions for specimen collection and handling, control procedures, test and reagent preparation, and instructions for test performance, interpretation, and reporting (Table 7). In addition, certain manufacturers provide quick reference instructions formatted as cards or small signs containing essential steps in conducting a test. Quick reference instructions should be clearly posted where testing is per-MMWR November 11, 2005 Explains what the test detects and a short history of the methodology, including the disease process or health condition being detected or monitored. Might include the response to disease (e.g., development of IgM antibodies), the symptoms and their severity, and the disease prevalence. Includes literature citations as applicable. States the methodology used in the test. Details the technical aspects (chemical, physical, physiologic, or biologic reactions) of the test, and explains how the components of the test system interact with the patient specimen to detect or measure a specific substance. Alerts the user of practices or conditions that might affect the test and warns of potential hazards (e.g., handling infectious specimens or toxic reagents). Frequent precautions include directions to not mix components from different lot numbers, to not use products past expiration dates, and the need for safe disposal of biohazardous waste. Might address conditions for specimen acceptability. Specifies conditions for storing reagents and test systems to protect their stability. Includes recommended temperature ranges and, as applicable, physical requirements (e.g., protection from humidity and light). Also addresses the stability of reagents and test systems when opened or after reconstitution and/or mixing. Describes indicators of reagent deterioration. Lists the reagents and materials supplied in the test system kit and the concentration and major ingredients used to make the reagents. Lists materials needed to perform the test but not provided in the test system kit. Details the procedures for specimen collection, handling, storage, and stability, including, as applicable, instructions for performing a fingerstick, appropriate anticoagulant or swab type, and directions for specimen preparation. Might address conditions for specimen acceptability. Provides step-by-step instructions for performing the test and frequently includes visual aids (e.g., pictures or graphs). Critical information (e.g., the order of reagent addition, timing of test steps, mixing and temperature requirements, and reading of the test results) is included. Describes conditions that might influence the test results or for which the test is not designed. Limitations could include: - possible interferences from medical conditions, drugs, or other substances. - warning that the test is not approved for use with alternate specimen types or in alternate populations (e.g., pediatric). - indications of the need for additional testing that might be more specific or more sensitive. - warning that the test does not differentiate between active infection and carrier states. - statement that the test result should be considered in the context of clinical signs and symptoms, patient history, and other test results. Describes the test result the user should expect (positive/negative or within/outside of a reference interval). Explains, as applicable, how results can vary depending on disease prevalence and the season of the year. Might include a brief description of studies conducted to derive this information. Details the results of studies conducted to evaluate test performance. Included are data used to determine accuracy, precision, sensitivity, specificity, and reproducibility of the test and results of cross-reactivity studies with interfering substances. - Product inserts vary in format, but the majority contain the information described above. Some information might appear in different sections than listed above because of format variations between manufacturers. Certificate of Waiver site directors and testing personnel should read this information for a complete understanding of each test. # Intended use Summary Test principle Precautions Storage/Stability Reagents and materials supplied # Materials required but not provided # Specimen collection and preparation Test procedure # Interpretation of results # Quality control (QC) Limitations Expected values Performance characteristics formed. The specific test system name should be on the quick reference instructions to avoid confusion. A comprehensive procedure manual is a valuable resource for CW sites. Although product inserts can be used as test procedures, these instructions will typically need to be supplemented with testing information that is unique to the CW site's operations and workflow (31). A procedure manual can also include examples of forms used (e.g., charts to record daily test kit storage temperatures, infectious disease reporting forms, or logs for recording control testing and test results) and check lists for personnel training. New testing procedures should be reviewed and signed by the CW site director before incorporating them into the procedure manual. The manual should be updated as tests or other aspects of the testing service change and should be reviewed by the director whenever changes are made. When procedures are no longer used, they should be removed from the manual and retained with a notation of the dates during which they were in service. When writing procedures for each CW site, it might be helpful to: - Use a template with standard component headings to facilitate writing a new procedure and promote ease of use when performing testing; - List all materials needed and how to prepare them before testing; - Include instructions for patient preparation and specimen collection; - Highlight key steps in the procedure (e.g., test incubation time); - List test limitations; - Describe actions to take when the test does not perform as expected; - Integrate control procedures with the steps for performing patient testing to assure control testing is performed; - Include established reference intervals and critical values for the test; and - Describe how to record and report results and how to handle critical values. # Personnel Training Trained and competent testing personnel are essential to good quality testing and patient care. Data from CDC and CMS surveys demonstrate that waived testing sites are subject to a high rate of personnel turnover. Personnel should be trained and competent in each test they will perform before reporting patient results (32,33 # Competency Assessment To ensure testing procedures are performed consistently and accurately, periodic evaluation of competency is recommended, with retraining, as needed, on the basis of results of the competency assessment (32). Assessment activities should be conducted in a positive manner with an emphasis on education and promoting good testing practices. Competency can be evaluated by methods such as observation, evaluating adequacy of documentation, or the introduction of mock specimens by testing control materials or previously tested patient specimens. External quality assessment or evaluation programs, such as voluntary PT programs, are another resource for assessment. # Additional Measures to Help Testing Staff Ensure Reliable Results The CW site director or person overseeing testing should promote quality testing and encourage staff to ask questions and seek help when they have concerns. Recommendations include: - Identifying a resource person or expert (e.g., a consultant or manufacturer's technical representative), available either off-site or on-site, to answer questions and be of assistance. - Posting telephone numbers for manufacturers' technical assistance representatives. - Designating an appropriately trained person, who understands the responsibilities and impact of changing from one test system to another, to discuss new products with sales representatives. Uninformed personnel might mistakenly use a promotional test kit, provided by a distributor or manufacturer's representative, for patient testing without realizing the consequences of test substitution. # Recommended Practices Before Testing Preparations before performing patient testing are a critical element in producing quality results. Paying attention to test orders, properly identifying and preparing the patient, collecting a good quality specimen, and setting up the test system and testing area all contribute to reliable test results. # Test Orders, Patient Identification, and Preparation Before collecting the specimen, confirm the test(s) ordered and the patient's identification and verify that pretest instructions or information, as applicable, have been provided. This includes: - Test orders -CW sites performing various waived tests should routinely confirm that the written test order is correct. If there is a question, check with the ordering clinician. Standing orders for certain tests might apply, but they should be documented. - Patient identification -Identify the patient before collecting the specimen. Because names can be similar and lead to confusion, use birth dates, middle initials, identification numbers, or other means to ensure the specimen is collected from the correct patient. - Pretest instructions -Some tests require special preparation on the patient's part (e.g., a fasting state for glucose testing). Provide the patient with pretest instructions, when appropriate, and when special preparation is needed, verify that patients received instructions before testing. To determine if patients followed the instructions, ask them to explain how they prepared for the test. - Pretest information -Discuss factors, test limitations, or medical indications that can affect test results with the patient, as appropriate, and provide pertinent information such as pamphlets supplied by the test manufacturer, when specified in the product insert. # Specimen Collection and Handling The product insert provides details on proper collection, handling, and storage of patient specimens. Collect waived test specimens exactly as described in the test system instructions, using the appropriate collection device and method to obtain a quality specimen (33)(34)(35)(36). Improperly collected, stored, or compromised specimens should not be tested. Specimens and, in some cases, test devices need to be appropriately labeled to prevent mix-up. Waived test specimens. Waived tests are approved for use only with direct, unprocessed specimens that do not require operator manipulation (Table 8). Specimens that are processed or manipulated by the user (e.g., serum or plasma) require centrifugation, dilution, extraction, or other preparation steps that require special training or instrumentation and are not appropriate for waived tests. Sometimes, tests can be performed using both processed and unprocessed specimen types, but are waived only for the unprocessed specimens, in which case the product insert should identify the appropriate specimen for the waived test. For example, a single product insert might include instructions for performing a waived test using unprocessed whole blood and for performing the same test using plasma, which would not be waived. Other examples include group A streptococcal antigen testing, which is waived only when performed on a throat swab and not when performed on a microbiology culture, and visual color comparison tests for hCG (pregnancy tests) using urine that are waived, whereas serum or plasma hCG tests are not waived. Specimen collection. The person collecting the patient specimen or giving the collection instructions should have a thorough understanding of the specimen type, proper collection method (including the need to wear gloves or other PPE as appropriate), and handling to assure a quality specimen (33)(34)(35)(36). Directions for specimen collection, handling, and storage are included in the product insert and must be followed explicitly. For example, instructions might specify one drop of capillary blood or include precautions to use the second drop of blood from a fingerstick rather than the first. When gloves are worn during specimen collection, they should be removed and discarded in an appropriate waste receptacle before contact with another patient. Hand hygiene should be performed between patients. Collection devices. Manufacturers might provide or specify specimen collection devices. These devices, whether supplied with the test system or specified in the product insert, are integral to the test system and should be used to ensure the correct specimen type and volume to provide reliable results. Containers and collection devices might have additives that affect the specimen or are part of the test and should not be substituted or altered. For example, throat swab collection kits used with group A streptococcal antigen tests might look the same; however, they might be made from a variety of fibers or contain different materials that could interfere with the test or affect organism viability. Whole blood capillary tubes (e.g., used for cholesterol, hemoglobin A 1 C, or Helicobacter pylori testing) can have additives or hold different specimen volumes which affect test reactions and results. Fingerstick and venipuncture collection devices are for onetime use only. Never reuse needles, syringes, or lancets. To avoid transmission of hepatitis B virus, hepatitis C virus, HIV, and other bloodborne pathogens, appropriately discard sharps, lancets, and platforms for spring-loaded lancets and disinfect instruments contaminated by blood (9,28). Specimen labeling. Labeling procedures should meet the needs of the testing site and should be adequate to prevent specimen mix-up. To prevent errors, always label specimens with pertinent information (e.g., unique patient name or other unique identifier). Depending on workflow, specimen labeling also might include the date and time of collection and identification of the collector. For waived tests in which the specimen is applied directly to the test device (e.g., throat swabs for group A streptococcal antigen), the test strip, cassette, or other device should be labeled with the patient identification before collecting the specimen, especially if more than one test is being performed at the same time. # Preparing the Testing Area, Test Materials, and Equipment Preparing the testing area and materials (e.g., kits, reagents, control materials, and equipment) before testing patient specimens is essential to maintaining efficient workflow and good quality testing (Table 9). Before beginning the test, read and understand the test instructions specified in the product insert and included in the CW site's procedures. Verify that the instructions are current for the test in use and that no changes have been made. Do not use product inserts that are out of date for the test system currently in use. When opening a new kit, check for notifications in the external labeling or special notices that might be included with product inserts or packaging. Additional considerations for good testing practices are: - Abide by expiration dates and discard expired reagents and test kits as soon as the expiration date elapses. - When preparing to perform testing, allow time for any refrigerated items, including reagents or patient specimens, to reach room temperature before testing, if specified in the product insert. # Recommended Practices During Testing When the testing area is prepared and the specimen has been collected, the process continues to the testing phase. Important activities during this phase include QC testing, test performance, result interpretation and recording. # Quality Control Testing Performing QC testing procedures provides assurance that the test performs as expected and alerts the user when problems occur. QC testing is designed to detect problems that might arise because of operator error, reagent or test kit deterioration, instrument malfunction, or improper environmental conditions. Test procedures should describe the type of Replenish supplies (e.g., specimen collection, biohazard waste containers, and forms) # Test system and reagents Check the product insert and exterior labeling on kits and reagents for changes Check and record expiration dates (Do not use expired reagents or kits) Check and record lot numbers for test kits, test devices and controls (Do not mix reagents from different products or lot numbers. If new lot, set up quality control as needed and refer to product insert for any changes in control ranges) Visually inspect reagents or vials for damage, discoloration, or contamination Prepare reagents according to instructions (If opening new reagents, write the date opened on the outside of the vial or test kit) # Inspect equipment and electrical connections for integrity If the test system incorporates internal calibration steps that need to be checked before testing, conduct the calibration check or set the test system as specified by the manufacturer- - Portable equipment, if moved, might be subject to inaccurate results. To verify proper test system functioning, perform control testing or calibration check procedures even if not specified by the manufacturer after moving the equipment. # MMWR November 11, 2005 controls to be used, how to perform QC testing (including QC testing frequency), and actions to be taken when QC results are unacceptable. Types of controls. Two types of controls typically found in waived tests are: - Internal, procedural, or built-in controls -evaluate whether certain aspects of the test system are working properly. They are designed to verify that the test system is working as expected, that sufficient specimen was added and, for unitized test devices, whether it migrated through the test strip properly. Certain test systems might have electronic internal controls to monitor electronic functions. - External controls -mimic patient specimens and monitor the testing process, from specimen application to result interpretation, to assure proper test performance. They might be provided as liquid or other materials similar to patient specimens and might be included with the test system or purchased separately. Frequency of control testing. For certain test systems, the product insert describes the minimum conditions or recommended frequencies for testing internal and/or external controls. Each site should determine the appropriate control testing frequency for each test system and the frequency should not be less than specified in the product insert. When determining the frequency for running external controls, consider the robustness of the test, stability of the environment, and skills and knowledge of the testing personnel. At a minimum, external controls should be tested with each new shipment of utilized test devices, when testing a new lot number, and by each new operator before conducting testing. Controls should be tested either before or concurrent with patient specimens by the same personnel who routinely perform patient testing. Corrective action when control testing fails. If controls do not perform as expected, patient testing should not be performed or results reported until the problem is identified and corrected. The product insert should provide information on procedures for handling unexpected control results, identifying sources of error (including interfering substances), and manufacturer contact information for technical assistance. This information might be incorporated into the facility's procedures or posted for quick reference. The test site should have telephone numbers or other contact information readily available (e.g., numbers for manufacturers' technical assistance, the facility's director, consultant, or public health departments). Documentation. Documenting and monitoring control testing results provides an indication that the test was properly performed by the operator and the test system (reagents, instruments, or any components) performed as expected. Records of control results should be periodically reviewed to detect shifts or changes in performance over time. # Performing the Test The following points are important to remember when performing the test: - Follow the steps in the test procedure in the exact order described in the product insert. - Test controls at the frequency determined by the CW site. - Pay attention to timing for waived tests, particularly unitized test devices that must be read during specific time intervals. Incorrect timing of these types of tests can give erroneous test results. Insufficient timing can result in false negative or invalid results because the specimen might not react completely with test system reagents. Time intervals longer than those specified in the product insert can result in false positive, false negative, or invalid results because of exaggerated color development, fading of reaction products, or migration beyond a visible range. Therefore, it is important to have a system established to read results during the correct timeframe, especially if conducting more than one test at a time. Suggestions for helping to ensure correct timing of tests include using timers that beep until turned off, using timers that can easily be worn or attached to clothing, using multiple timers when performing more than one test at a time, and maintaining extra timers and batteries. # Test Results Interpretation When the test is complete, interpret the results according to instructions in the product insert (including the quick reference guide). Test results are of the following two types: - Quantitative -Tests that provide numerical results generated by the test device or instrument. Numerical results are values corresponding to the concentration of the specific substance being measured. The value includes specific measurement units (e.g., such as a glucose result of 100 mg/dL). No interpretation is necessary to read the result. - Qualitative -Tests that detect whether a particular substance, condition, or microbiological organism is present or absent. Results are interpreted as positive/reactive, negative/nonreactive, or invalid. Invalid results might indicate a problem with the specimen or the test system. Diagrams, color photographs, and color-comparison charts are often part of the product insert and quick references and serve as guides for interpretation. # Resolving Problems If a discrepancy is identified between the patient's test results and the clinical information or if the results are invalid or otherwise compromised, testing should be repeated. Results should not be reported until the problem is resolved. Follow the steps in the product insert to resolve problems with test results. Unitized test system instructions usually suggest repeating the test with a new device and referring to QC or trouble-shooting procedures. If repeat testing does not resolve the problem, contact the manufacturer or product technical representative. Quantitative results can be obtained that are beyond the measuring range of the instrument or test device. Each site should have documentation of quantitative test measuring ranges and a procedure for handling test results that are beyond the reportable ranges, either low or high. # Recording Results Record test results according to the site's policy. Results can be recorded directly in a patient's chart, in log books, or on a separate report form. Records or logs of test results should have enough detail so the test site can retrieve information. Quantitative results should be recorded using the units of measurement of the test system. Qualitative test results should be recorded using interpretive words or abbreviations such as positive, negative, reactive or R, or nonreactive or NR instead of symbols like plus and minus (+, -) to help avoid clerical errors because a negative (-) sign can easily be changed to a positive (+) sign. If a test result is not acceptable or requires repeat testing (e.g., out of range or invalid), record the initial result, noting it was unacceptable, take steps necessary to resolve the problem, then record the correct result. Good laboratory practices include recording what happens, whether acceptable or not, and what is done to correct problems encountered during testing. # Recommended Practices After Testing After-testing activities include issuing test reports, supplemental or confirmatory testing, public health disease reporting (if required), testing area cleanup, biohazard waste disposal, and documentation of testing activities. # Test Reports After the completion of the test, results are documented and reported. Patient reports should be legible and reported in a timely manner to the appropriate person. Reports should meet the needs of the testing site and should be appropriately standardized so reports generated on-site are easily distinguishable from referral laboratory reports. Verbal reports of test results should be documented and followed by a written report. Waived testing sites, such as point-of-care sites or physicians' offices, might accurately and legibly record results directly in the patient's record as a matter of practice. If results are not recorded directly in a patient's chart, they should be recorded in a written report format that includes all information needed to correctly identify and interpret the results as determined by the testing site (Table 10). Critical values are test results necessary for patient evaluation or treatment that require immediate notification to the clinician. Each site should define the critical values, if appropriate, for the tests in use and ensure that testing personnel are aware of these values and the procedure for alerting the clinician. Procedures should be in place to ensure documentation of critical values and timely notification of the proper medical personnel. # Supplemental or Confirmatory Testing The product insert should explain when supplemental testing is needed to confirm a waived test result or when the test is to be used as part of a multitest algorithm. A confirmatory test could be a different waived test (performed at the testing site or another CW site) or a nonwaived test performed by a CLIA-certified referral laboratory (37) (Table 11). When nonwaived confirmatory testing is needed, the patient can be sent to another facility for specimen collection and testing, or the specimen can be collected at the CW site and sent to a referral laboratory. The CW site should have written policies to ensure confirmatory and supplemental testing is performed when needed. For each waived test that requires additional testing, the CW site should document the processes and procedures necessary to manage referral or confirmatory testing. When a CW site collects specimens for referral, procedures should include the following: - ments for confirmatory or supplemental tests for infectious diseases (e.g., HIV). Maintaining records of referred testing is important for patient care and follow-up. Logs and other records should have sufficient information to track and retrieve the test results and reports, such as: - Information linking the referred specimen to patient identification, - The name and contact information for the referral laboratory, - The test name and date referred, - Complete test results and the date received, and - The date the final report is issued. # Public Health Reporting Federal and state public health agencies require testing facilities to report confirmed positive results for certain infectious diseases (e.g., HIV, influenza, and Lyme disease) (38,39). Testing facilities should confer with local public health agencies for the most current information on required reporting procedures since diseases identified for reporting can change over time, and state requirements might vary. # Biohazard Waste Disposal Dispose of the biohazardous waste generated in specimen collection and testing according to site procedures that need to be in compliance with local ordinances, state, and federal OSHA regulations as previously discussed. # Documents and Records Documentation is essential to assure quality waived testing. Proper documentation is necessary for monitoring and assessing test performance, identifying and resolving problems that could affect patient testing, retrieving and verifying information, and maintaining adequate patient and personnel records. Log books or electronic systems can be used for maintaining and tracking information. In some cases, records might be part of the patient's medical chart. Testing records should be maintained in chronological order to facilitate retrieval of information if needed. In addition, control records should be kept in the order in which they were completed so they can easily be compared with test records if there are questions about testing performed within a specific time period. The person responsible for testing oversight and decision-making should review records periodically. State regulations or other governmental agencies might require CW sites to retain documents and records for a specific length of time. Aspects of testing for which records or documentation are recommended include: # Quality Assessment Good laboratory practices can be expanded to include assessment activities to evaluate and improve the quality of CW site testing. Assessment activities can be either internal or external, depending on the needs, resources, and practices of the site. # Internal Assessment Objective internal assessment offers flexible, low-cost options for evaluating quality such as self-conducted inspections, supervisory review of documented problems that occur in the different phases of the testing process, review of QC documentation, and testing and reporting procedures. Test performance can be assessed, if specimens are suitable, by exchanging specimens with another testing facility using the same test method(s) and comparing the results. Results from these assessment activities should be documented and evaluated, noting any irregularities and the actions taken to resolve problems or improve processes or procedures. # External Assessment Because CW sites are not routinely inspected by CMS, voluntary inspections by peers or consultants can offer additional educational opportunities and feedback on current practices along with ideas for quality improvement. Voluntary external inspections evaluate the testing site practices and documentation systems, and a more narrowly focused assessment of test performance can be accomplished by participating in performance evaluation programs or subscribing to PT programs. These programs provide challenge samples to test as if they were patient specimens and the results are evaluated with respect to how close they are to the intended target values. Participation in these types of programs can be used to evaluate overall testing performance and as a training or educational tool for testing personnel. # Conclusion This report summarizes the findings of multiple surveys of sites performing waived testing throughout the United States. Although the surveys were conducted through several mechanisms, the findings lead to similar conclusions about lapses in quality in CW sites, and they highlight the need for additional education and training related to waived testing for CW site directors and testing personnel. The recommendations provided in this report are intended to serve as a guide to improve the quality of testing in CW sites and enhance patient safety. They can be disseminated by a variety of individuals and organizations and adapted for use in different settings where waived testing is conducted. Continued surveillance and monitoring of waived testing performance is needed to determine the effectiveness of these recommendations on protecting and improving the public's health. # Terms and Abbreviations Used in this Report true or target value; freedom from error; the accuracy of results can be measured by comparing them to results accepted as correct (e.g., standard methods), or by comparing them with those from another laboratory that uses a comparable method a substance or constituent for which a laboratory conducts testing a protein formed in the body in response to a foreign substance (e.g., bacteria, viruses or chemical toxins) and that interacts with the foreign substance to weaken or neutralize it any substance that, when introduced into the body, causes the development of an immune response, such as antibody production Arkansas Sentinel Network a biological agent that has the capacity to produce deleterious effects on humans, such as microorganisms and toxins waste containing pathogens with sufficient virulence and quantity so that exposure to the waste by a susceptible host could result in an infectious disease the application of combinations of laboratory practice and procedure, laboratory facilities, and safety equipment when working with potentially infectious microorganisms to prevent infection microorganisms that, when present in human blood, can cause disease in humans. These pathogens include, but are not limited to, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) the process of testing and adjusting an instrument or test system to provide a known relationship between the value of the substance being measured by the test and the test system's measurement response. A calibration check is a mechanism to be sure the test system has remained stable and the results remain accurate a process of separating blood or other body fluid cells from liquid components using a device (centrifuge) containing compartments that spin rapidly around a central axis reproducibility; the measure of the closeness of the results obtained when analyzing the same sample more than once; the measure of agreement between replicate measurements of the same material a handbook that contains test methods and other information needed to perform testing written product information usually supplied by the manufacturer with each test kit or test system containing instructions and critical details for performing the test; also referred to as package insert proficiency testing; an external quality assessment program in which samples are periodically sent to testing sites for analysis a test that detects whether a particular analyte, constituent, or condition is present or absent a group of activities to monitor and evaluate the CW site's entire testing process to help ensure that test results are reliable, improve the testing process, and promote good quality testing practices quality control; the procedures used to detect and correct errors that occur because of test system failure, adverse environmental conditions and variance in operator performance, as well as the monitoring of the accuracy and precision of the test performance over time a test that measures the concentration or amount of an analyte in a specimen, whose results are expressed numerically cards or small signs containing diagrams or flow charts with essential steps for conducting a test that are often included with waived test systems a result that indicates the presence of the constituent that the test is designed to detect a substance that produces a chemical or biological reaction with a patient specimen that allows detection or measurement of the analyte for which the test is designed the range of test values expected for a designated population of persons (e.g., 95% of persons presumed to be healthy ) a laboratory that receives specimens from CW sites to perform additional testing, often for followup confirmatory testing; the majority of referral laboratories perform nonwaived testing the span of test result values for which the instrument or test device can accurately measure the lowest concentration of an analyte that can reliably be detected or measured by a test system the cell-free liquid remaining after whole blood has clotted or coagulated the ability of a test to detect a particular substance or constituent without interference or false reactions by other substances an approach used in healt-care settings to reduce the risk for transmission of microorganisms from both recognized and unrecognized sources of infection in a wide variety of human sources. The nature of medical procedures and testing in these settings requires expansion of Universal Precautions to include feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus, even when no visible blood is evident. the state health agency or other appropriate state or local agency that has an agreement under Section 1864 of the Social Security Act and is used by CMS to perform surveys and inspections the instructions and all of the instrumentation, reagents, and supplies needed to perform a test and generate results series of activities or path of workflow for performing testing that can be divided into three major phases; before testing, during testing, and after testing a self-contained test device to which a specimen is added directly and in which all steps of the testing process occur. A unitized device is used for a single test and must be discarded after testing. an approach to controlling infection. According to the concept of Universal Precautions, all human blood and certain human body fluids are treated as if known to be infectious for HIV, hepatitis B virus, hepatitis C virus, and other bloodborne pathogens. a test system, assay, or examination that has been cleared by the FDA for home use, or HHS has determined meets the CLIA criteria of being a simple test with an insignificant risk for an erroneous result blood containing all its cellular components that has not undergone centrifugation or had the plasma removed # INSTRUCTIONS ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 3.0 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training. CDC will award 0.3 continuing education units to participants who successfully complete this activity. Continuing Nursing Education (CNE). This activity for 3.4 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation.	Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), simple, low-risk tests can be waived and performed with no routine regulatory oversight in physicians' offices and various other locations. Since CLIA was implemented, waived testing has steadily increased in the United States. Surveys conducted during 1999Surveys conducted during -2004 by the Centers for Medicare & Medicaid Services and studies funded by CDC during 1999-2003 evaluated testing practices in sites holding a CLIA Certificate of Waiver (CW). Although study findings indicate CW sites generally take measures to perform testing correctly, they raise quality concerns about practices that could lead to errors in testing and poor patient outcomes. These issues are probably caused, in part, by high personnel turnover rates, lack of understanding about good laboratory practices, and inadequate training. This report summarizes study findings and provides recommendations developed by the Clinical Laboratory Improvement Advisory Committee for conducting quality waived testing. These recommendations include considerations before introducing waived testing, such as management responsibility for testing, regulatory requirements, safety, physical and environmental requirements, benefits and costs, staffing, and documentation. They also cover good laboratory practices for the three phases of testing: 1) before testing (test ordering and specimen collection), 2) during testing (control testing, test performance, and result interpretation and recording), and 3) after testing (result reporting, documentation, confirmatory testing, and biohazard waste disposal). They are intended to be used by those who would benefit from improving their knowledge of good laboratory practices. Continued monitoring of waived testing, with a focus on personnel education and training, is needed to improve practices and enhance patient safety as waived testing continues to increase. devices that are waived from most federal oversight requirements (and are thus designated as waived tests), including requirements for personnel qualifications and training, quality control (QC) (unless specified as required in the test system instructions), proficiency testing (PT), and routine quality assessment. Advances in technology have made tests simpler, contributing to this shift in testing. In the past, tests such as prothrombin time, cholesterol, and glucose either used complex manual methodologies or were performed using sizable instrumentation suitable for use by highly trained personnel in traditional clinical laboratory settings. Many tests can now be performed using compact or hand held devices by personnel with limited experience and training. These advances have enabled more testing to be performed in emergency departments, hospital rooms, and physicians' offices and in nontraditional testing sites such as community counseling centers, pharmacies, nursing homes, ambulances, and health fairs. Since the 1992 inception of the program implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA), the numbers of waived tests and the sites that perform them have# Introduction Laboratory testing plays a critical role in health assessment, health care, and ultimately, the public's health. Test results contribute to diagnosis and prognosis of disease, monitoring of treatment and health status, and population screening for disease. Laboratory testing affects persons in every life stage, and almost everyone will experience having one or more laboratory tests conducted during their lifetime. An estimated 7-10 billion laboratory tests are performed each year in the United States (1,2), and laboratory test results influence approximately 70% of medical decisions (2)(3)(4). Increasingly, these decisions are based on simple tests performed at the point-of-care using # Scope of Waived Testing Sites performing only waived tests comprise 58% (105,138) of the approximately 180,000 laboratory testing sites in the United States (Table 1, Figure 1). Waived testing performed in these sites is often wellness testing, screening tests, or other critical testing that introduces a large population of persons into the health-care setting. Although the testing performed in CW sites accounts for <10% of the total U.S. testing volume, this percentage has been increasing each year since the CLIA program began (Table 1). Most testing is not waived and is typically performed in hospital or reference laboratories (Certificate of Compliance and Certificate of Accreditation), which comprise 20% of the total number of testing sites (Figure 1). The remaining testing sites (22%) have PPMP certificates, meaning that in addition to waived tests, direct microscopic examinations of certain specimens can be performed as part of the patient's examination by that patient's physician or midlevel health-care practitioner. An increasing shift toward waived testing has resulted in a corresponding increase in health-care expenditures for this testing. Medicare Part B, the federal medical insurance program for persons aged >65 years and certain disabled persons, covers diagnostic laboratory testing. Payment data for 2004, provided by CMS, indicated that of the $3,494,840,086 spent on reimbursed laboratory testing for that year, $128,169,398 (3.7%) was for waived tests. The volume of Medicare Part B reimbursed waived laboratory testing in 2004 represented 8% of the total reimbursed testing volume for that year, a 57% increase over the volume in 2000 (Table 1). # Patient Safety Concerns Related to Waived Testing Efforts to reduce medical errors, improve health-care quality, and increase patient safety have been gaining national attention. A report issued in 1999 by the Institute of Medicine (IOM) presented a national agenda to address these issues and recommended strategies for change that included the implementation of safe practices at the health-care delivery level (7). As described in the IOM report, errors most often occur when multiple contributing factors converge, and preventing errors and improving patient safety require a systems approach. Five years after this seminal report, small but consequential changes have occurred that have shifted the focus to improving systems, engaging stakeholders, and motivating health-care providers to adopt new safe practices (8). Although by law waived tests should have insignificant risk for erroneous results, these tests are not completely error-proof and are not always used in settings that employ a systems approach to quality and patient safety. Errors can occur anywhere in the testing process, particularly when the manufacturer's instructions are not followed and when testing personnel are not familiar with all aspects of the test system and how testing is integrated into the facility's workflow. Although data have not been systematically collected on patient outcomes with waived testing, adverse events can occur (9). Some waived tests have potential for serious health impacts if performed incorrectly. For example, results from waived tests can be used to adjust medication dosages, such as prothrombin time testing in patients undergoing anticoagulant therapy and glucose monitoring in diabetics. In addition, erroneous results from diagnostic tests, such as those for human immunodeficiency virus (HIV) antibody, can have unintended consequences. The lack of oversight and requirements for personnel qualifications and training for an increasingly large number of CW sites is a concern and could contribute to errors and patient harm. During 1999-2001, CMS conducted on-site surveys of a representative sample of CW sites in 10 states to assess the quality of testing in these sites. These pilot surveys identified quality issues that could result in medical errors (10). Contributing factors included inadequate training in good laboratory practices and high turnover rates of testing personnel. As a result, during 2002-2004, CMS conducted nationwide on-site surveys of CW facilities to collect additional data that would provide an assessment of testing, promote good laboratory practices and encourage improvement through educational outreach, and make recommendations on the basis of cumulative survey findings. The data collected from these surveys, along with data on waived testing practices gathered through CDC-funded studies conducted during 1999-2003 by the state health departments of Arkansas, New York, and Washington (collectively referred to as the Laboratory Medicine Sentinel Monitoring Network [LMSMN]), support the initial CMS findings of gaps in good laboratory practices in these sites (11)(12)(13)(14)(15)(16). In addition, a 2001 report issued by the HHS Office of Inspector General (OIG), following their investigation of CLIA certification and enrollment processes, identified the lack of routine on-site visits to CW sites by surveyors representing state agencies and private sector accreditation organizations as presenting vulnerabilities in these sites. The OIG report indicated that approximately half of the state respondents reported problems related to quality issues with the waived laboratories in their states (e.g., failure to follow manufacturers' instructions or failure to identify incorrect results and performing unauthorized testing) (17). The concerns noted by states were similar to those identified in the CMS pilot studies. # CLIAC Response An initial CMS report of its 2002-2003 survey findings, presented to CLIAC in 2004, supported earlier concerns about the quality of testing practices and the need for education and training of testing personnel in CW sites. In response, the committee recommended publication of the 2002-2004 CMS data in conjunction with other data pertinent to waived testing performance along with recommendations for good laboratory practices for waived testing sites. This information would then be available to provide guidance to physicians, nurses, and other health-care providers in CW facilities. As a result, a workgroup was appointed to consider practices associated with the waived testing process and their impact on the quality of waived testing. This workgroup was comprised of key stakeholders in waived testing (i.e., CLIAC members; physicians; nurses; laboratorians; manufacturers; distributors; and representatives from CDC, CMS, and FDA). In its evaluations, the workgroup considered existing practice guidelines from professional organizations, waived testing recommendations from CMS, personal and professional experience, and publications related to waived testing. The workgroup's findings were presented to CLIAC for its deliberations at the February 2005 meeting, at which time CLIAC provided recommendations to HHS concerning good laboratory practices for waived testing sites. CLIAC supported publication of the recommendations, along with the data from the studies of CW sites, and suggested the publication could serve as a comprehensive source document that could be used to develop additional educational tools appropriate for specific target audiences. (11). The New York Sentinel Network (NYSN) consisted of approximately 600 limited service laboratories (facilities other than physician office laboratories [POLs] that perform only waived tests and PPMP). NYSN collected its data through on-site surveys during which waived testing practices were assessed by surveyor observation and record reviews (11). # Surveys of Waived Testing Sites Methods # Survey Findings Demographics CMS surveyed 4,214 CW sites during April 15, 2002-November 12, 2004. This included 897 sites in 2002, 1,575 sites in 2003, and 1,742 sites in 2004. Of the CW facility types surveyed, POLs compose the largest percentage (47%), followed by skilled nursing facilities (14%) (Table 2). The CW sites surveyed estimated performing a broad range of annual test volumes (Figure 2). Of the facilities surveyed by 3). This correlates with data for the top five waived tests identified through the LMSMN, especially for POLs (11). Although not among the most commonly performed, waived tests are available for certain infectious diseases of public health significance and were reportedly performed by CW sites in the CMS surveys (influenza, 46 sites; HIV, four; and Lyme disease, one). # Personnel and Training Under CLIA, no education or training is required for the director or testing personnel in CW sites. The educational background and qualifications for directors and testing per-sonnel at CW sites were collected as part of the CMS surveys and by LMSMN (PNWSN and NYSN). The CMS surveys indicated that in 69% of CW sites, physicians served as directors, followed by nurses (17%) (Table 3). Similarly, 59% of the PNWSN CW site directors were physicians, with the remaining 41% having other backgrounds or degrees (12). For CW testing personnel, according to the CMS data, the top four categories were nurses (46%), medical assistants (25%), physicians (9%), and high school graduates (7%) (Table 3). NYSN reported that registered nurses (RNs) and licensed practical nurses (LPNs) served as testing personnel in 84% of the limited service laboratories they surveyed (13). Trained laboratorians (i.e., medical technologists and medical laboratory technicians) accounted for 2% of laboratory directors and testing personnel in the CW sites surveyed by CMS and a smaller percentage in the limited service laboratories surveyed by the NYSN (13). CMS surveys indicated that 43% of CW sites experienced a change in testing personnel during the preceding 12 months. Among the top categories of testing personnel in the PNWSN, turnover rates were highest for medical assistants (17%), followed by LPNs (13%), RNs (9%), and physicians (2%) (14). Although the majority of CW sites in the CMS surveys (90%) reported that new personnel were trained, fewer sites (85%) evaluated staff to ensure competency. Data identifying who provided training were not submitted for all sites in the surveys. However, according to the CW sites that provided this information for 2003-2004 (Table 4), nurses most frequently provided waived test training (33%), followed by the manufacturer or sales representatives (15%). Findings from a PNWSN study indicated that the highest percentage of personnel were initially trained by another employee (25%) or trained themselves by using instructions provided with the waived test system (17%) (15). Another PNWSN study indicated that most training (77%) took place in a day or less (14). Comments from this study reflected the thinking that training is not always necessary or that minimal time should be spent on training because persons have been trained in school or on other jobs. The time spent on training was not captured as part of the CMS surveys. # Testing Practices The CMS surveys indicated that the majority of the CW sites were aware of and followed some practices for ensuring the accuracy and reliability of their testing. However, lapses in quality were identified at certain sites, some of which could result in patient harm. In some instances, CW sites were determined to be performing testing Of the CW facilities CMS surveyed, 12% did not have the most recent instructions for the waived test systems they were using, and 21% of the sites reported they did not routinely check the product insert or instructions for changes to the information (Table 5). On the basis of manufacturer's instructions, 21% of the CW sites did not perform QC testing as specified, and 18% of the sites did not use correct terminology or units of measure when reporting results. Among other quality deficiencies identified were failure to adhere to proper expiration dates for the test system, reagents, or control materials (6%) and failure to adhere to the storage conditions as described in the product insert (3%). Six percent of CW sites did not perform follow-up confirmatory tests as specified in the instructions for certain waived tests (e.g., group A streptococcal antigen), and 5% did not perform function checks or calibration checks to ensure the test system was operating correctly. Findings from the LMSMN studies were similar to the CMS findings for these quality deficiencies (11). Although not usually specified in the product insert (and therefore not a CLIA requirement), proper documentation and recordkeeping of patient and testing information are also important elements of good laboratory practices. CMS surveys indicated that 45% of CW sites did not document the name, lot number, and expiration dates for tests performed; 35% did not maintain logs with records of their QC testing; 31% did not maintain a log or record of tests performed; and 9% did not require a requisition or test orders documented in a patient chart before performing a test (Table 5). NYSN observed similar findings but noted increased compliance with state requirements for documentation/recordkeeping when laboratories had formal affiliations with New York Statelicensed laboratories (11). # Discussion The findings from the CMS surveys and LMSMN studies indicated that the majority of CW testing sites performed testing correctly and provided reliable service. However, in CW sites, most directors and testing personnel did not have formal laboratory training or testing experience, there was a high turnover of personnel, and lapses in following manufacturers' instructions and instituting practices to ensure the quality of the testing were noted. The survey findings indicated that 485 (12%) of the 4,214 CW sites surveyed did not have the cur-rent manufacturers' instructions available, and 701 (21%) of the 3,317 sites surveyed during 2003-2004 did not check to be sure there had been no changes to the instructions. Test system instructions can change over time and CW sites sometimes switch test systems that could have different instructions. CMS survey results also indicated that, in varying proportions, when CW sites had the current instructions, they did not follow critical steps in the testing process (e.g., performing QC testing, reporting results correctly, adhering to expiration dates and appropriate storage requirements, and performing test system function checks or calibration checks). This is a concern because the only CLIA requirement for performing waived testing is to follow the manufacturer's instructions. Neglecting to follow instructions could cause inaccurate test results that could lead to incorrect diagnoses, inappropriate or unnecessary medical treatment, and poor patient outcomes. CMS surveys indicated that certain CW sites (5%) were performing testing more complex than waived testing without taking required measures to ensure quality. In certain CW sites, nonwaived microscopic examinations were being performed by personnel who lacked the education and training needed to develop the interpretive and judgment skills necessary to accurately perform these procedures. In addition, measures such as QC, PT, adequate documentation, and monitoring are required to ensure the accuracy and reliability of nonwaived test results. Although direct microscopic examinations can be conducted by a physician or midlevel health-care practitioner as part of a patient examination, testing must be conducted under a CLIA PPMP certificate. The quality issues identified through these surveys might have been caused, in part, by high turnover rates of testing personnel in CW sites, inadequate training with respect to waived testing, and lack of understanding of good laboratory practices, including the importance of following all aspects of the manufacturers' instructions. Although the study results indicated that most testing personnel were trained, they were often trained for minimum periods by persons who did not have formal education or training in clinical laboratory testing and who might not have understood the importance of measures to ensure quality testing. Certain testing personnel also were self-trained. In addition, when testing personnel were not evaluated to determine their competency level following training or on an ongoing basis, no assessment was conducted to determine whether the training was effective. The data demonstrate a need for educational information among CW site directors and testing personnel about the importance of following manufacturers' instructions, adhering to expiration dates, performing QC testing, and proper documentation and recordkeeping. One of the recommendations in the 2001 OIG report was that CMS should provide educational outreach to directors of waived and PPMP laboratories about the CLIA requirements (17). The findings in the 2002-2004 CMS surveys are subject to at least three limitations, and caution should be used in extrapolating the survey data to make generalizations about waived testing. First, the CMS surveys were not intended to be a scientific study of a random sample of CW sites. Waived testing data were collected by CMS to provide an assessment of testing practices, promote good laboratory practices, and encourage improvement through educational outreach. Although surveyors attempted to include a wide variety of CW sites in the sample, the sites were self-selected by surveyors and selection was based, to some degree, on convenience to the surveyors and willingness of the sites to participate in the voluntary surveys. However, few sites refused to participate in the surveys. Overall, the sites represent a nationwide sample and the distribution of CW facility types is similar to the distribution of CW facility types in the United States (Table 2). In addition, the 2002-2004 CMS survey findings resulted in the same general conclusions as the earlier CMS pilot studies, which were conducted on a random sample of laboratories (10). Second, the CMS data were collected and entered into the database by a large number of persons, introducing variability. Although training was provided before the surveys were conducted, the intent of the survey questions was subject to individual interpretation. Because the phrasing of some questions differed slightly from 2002 to 2003-2004, in certain cases, the meanings of the questions also changed. Finally, the CMS surveys did not assess the frequency of erroneous test results in CW sites or whether lapses in following manufacturers' instructions directly affected test results or patient outcomes. Similar limitations to these were identified in the LMSMN studies (11). The findings of the CMS and LMSMN studies are strikingly similar. Even though the majority of CW sites meet the CLIA requirement to follow manufacturers' instructions for test performance, and many sites follow additional good laboratory practices, over the years these studies have demonstrated that a persistent percentage of CW sites do not meet minimal requirements and are not aware of recommended practices to help ensure quality testing. Because surveying all CW sites is not feasible, the proposed actions to improve and promote quality testing in CW sites emphasize the importance of education and training for CW site directors and testing personnel. To provide a guide that can be adapted for use, either in part or as a whole, by persons or facilities considering the initiation of waived testing and personnel performing waived testing, CLIAC provided recommendations for good laboratory practices. By implementing these recommendations, CW sites could improve quality, reduce testing errors, and enhance patient safety. # Recommended Good Laboratory Practices Overview These recommendations are intended to promote the use of good laboratory practices by physicians, nurses, and other providers of waived testing in a variety of CW sites. They were developed on the basis of recommendations and other resources that provided additional information for promoting patient safety and the quality of CLIAC waived testing in laboratories or nontraditional testing sites (18)(19)(20)(21)(22). These recommendations address decisions that need to be made and steps to be taken as a facility begins offering waived testing or adds a new waived test. They also address developing procedures and training CW personnel and describe recommended practices for each phase of the total testing process, or path of workflow, including the important steps or activities before, during, and after testing. The activities that occur in each of these phases are critical to providing quality testing (Table 6). # Considerations Before Introducing Waived Testing or Offering a New Waived Test Forethought, planning, and preparation are critical to initiating high-quality waived testing in any type of setting. This section describes factors to consider before opening a waived testing site or offering an additional waived test. Questions to address include the following: • Management responsibility for testing. Who will be responsible and accountable for testing oversight at the CW site, and does this person have the appropriate training for making decisions on testing? • Regulatory requirements. What federal, state, and local regulations apply to testing, and is the site adequately prepared to comply with all regulations? # Management Responsibility Each testing site should identify at least one person responsible for testing oversight and decision-making, later referred to as the CW site director. In POLs, this might be a physician or someone in a senior management position who has the appropriate background and knowledge to make decisions about laboratory testing. Ideally, the person signing the CW application (CMS Form 116) is responsible for management of the testing operations. The management staff should demonstrate a commitment to the quality of testing service by complying with applicable regulatory requirements and promoting good laboratory practices. # Regulatory Requirements CLIA certification. Each site offering only waived testing that is not included under any other type of CLIA certificate must obtain a CLIA CW before testing patient specimens. Certain sites offering waived testing can be certified as part of a larger health-care organization that holds a CLIA Certificate of Compliance or Certificate of Accreditation. In addition, certain public health testing sites offering only waived testing can be included under a limited public health or mobile testing exception. A valid CLIA certificate is required for Medicare reimbursement. To apply for a CLIA certificate, CMS Form 116 (http:// www.cms.hhs.gov/clia/cliaapp.asp) must be completed and sent to the state agency for the state in which the testing site is located. This form asks for specific information, including the type of testing site (laboratory type), hours of operation, estimated total annual volume of waived testing, and the total number of persons involved in performing waived testing. The form must be signed by the facility owner or the facility director. Specific state agencies and contacts are available at http://www.cms.hhs.gov/clia/ssa-map.asp. The state agency will process the application and send an invoice for the registration fee. If additional assistance is required, contact the appropriate CMS regional office (http://www.cms.hhs.gov/ clia/ro-map.asp). CLIA requirements that apply to testing sites operating under a CW include the following: • (23). Regulatory requirements for all OSHA standards, including specific information for medical and dental offices (24), are available at http:// www.osha.gov and by telephone, 800-321-6742. The OSHA Bloodborne Pathogens Standard applies to sites where workers have potential occupational exposure to blood and infectious materials (25). The requirements for compliance with this standard include, but are not limited to: • A written plan for exposure control, including postexposure evaluation and follow-up for the employee in the event of an "exposure incident;" CDC and the Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS) have also published information about biosafety and precautions for preventing transmission of bloodborne pathogens in the workplace (26)(27)(28)(29)(30). Privacy and confidentiality requirements. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) established federal privacy standards to protect patients' medical records and other health information provided to health plans, doctors, hospitals, and other health-care providers. Under HIPAA, CW sites are required to establish policies and procedures to protect the confidentiality of health information about their patients, including patient identification, test results, and all records of testing. These medical records and other individually identifiable health information must be protected, whether on paper, in computers, or communicated orally. In addition, CW sites should be aware that applicable state laws that provide more stringent privacy protections for patients supersede HIPAA. Additional information on HIPAA is available at http://www.hhs.gov/ocr/hipaa. # Physical Requirements for Testing Testing should be performed in a separate designated area where adequate space to safely conduct testing and maintain patient privacy is available. In addition, some tests have specific environmental requirements described in the manufacturer's product insert that need to be met to ensure reliable test results. Meeting these environmental conditions can be challenging in nontraditional settings (e.g., health fairs) or community outreach venues (e.g., shopping malls, meeting rooms, parks, parking lots, mobile vans, and buses). Factors to consider include: • and be able to be adequately disinfected; work space should be adequate in size for patient confidentiality, ease of specimen collection, test performance, and storage of supplies and records. # Benefit and Cost Considerations Evaluating the benefits of a particular test. Evaluate the test system, its intended use, performance characteristics, and the population to be tested when assessing whether to introduce waived testing or a new waived test. Information for this evaluation can be obtained from the test manufacturer's product insert (Table 7) or by speaking with the manufacturer's technical representatives. Specific considerations include: • Intended use -Be aware of the intended medical use for which FDA approved the test system as explained in the product insert. This section describes what is being measured by the test, the type of specimen for which it is approved, and whether it is a quantitative or qualitative measurement. • Performance characteristics -Assess the information on performance provided by the test manufacturer or published data. Review data that includes the test's accuracy, precision, sensitivity, specificity, and interferences. • Patient population -Consider the population that will be tested before offering a test. Some tests have not been evaluated for use in specific age groups (e.g., pediatric populations). The predictive value for certain types of test results in a specific patient population depends on the test's sensitivity, specificity, and the prevalence of the condition in the population. For example, when testing for a certain condition or disease in a low-prevalence population, the predictive value of a positive result will be low compared with the predictive value of a negative result. Refer to the product insert for limitations for use in particular patient populations. • Need for supplemental testing or patient follow up -Some waived tests provide preliminary results as part of a multitest series (e.g., rapid HIV testing) or results that must be considered in conjunction with other medical information. These test results might require additional testing before a definitive test result is obtained, and patients might need posttest counseling about the meaning of the test result. Assess the potential need for additional time, documentation, and staffing and a mechanism to refer additional testing to another laboratory when offering such tests. # Developing Procedures and Training Personnel After the decision is made to offer waived testing, it is good practice to develop written policies and procedures so that responsibilities and testing instructions are clearly described for the testing personnel and facility director. The testing procedures form the basis of training for testing personnel. These procedures should be derived from the manufacturer's instructions and should be in a language understandable to testing personnel. # Written Test Procedures To comply with CLIA requirements and provide accurate testing, CW sites must adhere to the manufacturer's current testing instructions. These instructions, as outlined in the product insert, include directions for specimen collection and handling, control procedures, test and reagent preparation, and instructions for test performance, interpretation, and reporting (Table 7). In addition, certain manufacturers provide quick reference instructions formatted as cards or small signs containing essential steps in conducting a test. Quick reference instructions should be clearly posted where testing is per-MMWR November 11, 2005 Explains what the test detects and a short history of the methodology, including the disease process or health condition being detected or monitored. Might include the response to disease (e.g., development of IgM antibodies), the symptoms and their severity, and the disease prevalence. Includes literature citations as applicable. States the methodology used in the test. Details the technical aspects (chemical, physical, physiologic, or biologic reactions) of the test, and explains how the components of the test system interact with the patient specimen to detect or measure a specific substance. Alerts the user of practices or conditions that might affect the test and warns of potential hazards (e.g., handling infectious specimens or toxic reagents). Frequent precautions include directions to not mix components from different lot numbers, to not use products past expiration dates, and the need for safe disposal of biohazardous waste. Might address conditions for specimen acceptability. Specifies conditions for storing reagents and test systems to protect their stability. Includes recommended temperature ranges and, as applicable, physical requirements (e.g., protection from humidity and light). Also addresses the stability of reagents and test systems when opened or after reconstitution and/or mixing. Describes indicators of reagent deterioration. Lists the reagents and materials supplied in the test system kit and the concentration and major ingredients used to make the reagents. Lists materials needed to perform the test but not provided in the test system kit. Details the procedures for specimen collection, handling, storage, and stability, including, as applicable, instructions for performing a fingerstick, appropriate anticoagulant or swab type, and directions for specimen preparation. Might address conditions for specimen acceptability. Provides step-by-step instructions for performing the test and frequently includes visual aids (e.g., pictures or graphs). Critical information (e.g., the order of reagent addition, timing of test steps, mixing and temperature requirements, and reading of the test results) is included. Describes conditions that might influence the test results or for which the test is not designed. Limitations could include: • possible interferences from medical conditions, drugs, or other substances. • warning that the test is not approved for use with alternate specimen types or in alternate populations (e.g., pediatric). • indications of the need for additional testing that might be more specific or more sensitive. • warning that the test does not differentiate between active infection and carrier states. • statement that the test result should be considered in the context of clinical signs and symptoms, patient history, and other test results. Describes the test result the user should expect (positive/negative or within/outside of a reference interval). Explains, as applicable, how results can vary depending on disease prevalence and the season of the year. Might include a brief description of studies conducted to derive this information. Details the results of studies conducted to evaluate test performance. Included are data used to determine accuracy, precision, sensitivity, specificity, and reproducibility of the test and results of cross-reactivity studies with interfering substances. * Product inserts vary in format, but the majority contain the information described above. Some information might appear in different sections than listed above because of format variations between manufacturers. Certificate of Waiver site directors and testing personnel should read this information for a complete understanding of each test. # Intended use Summary Test principle Precautions Storage/Stability Reagents and materials supplied # Materials required but not provided # Specimen collection and preparation Test procedure # Interpretation of results # Quality control (QC) Limitations Expected values Performance characteristics formed. The specific test system name should be on the quick reference instructions to avoid confusion. A comprehensive procedure manual is a valuable resource for CW sites. Although product inserts can be used as test procedures, these instructions will typically need to be supplemented with testing information that is unique to the CW site's operations and workflow (31). A procedure manual can also include examples of forms used (e.g., charts to record daily test kit storage temperatures, infectious disease reporting forms, or logs for recording control testing and test results) and check lists for personnel training. New testing procedures should be reviewed and signed by the CW site director before incorporating them into the procedure manual. The manual should be updated as tests or other aspects of the testing service change and should be reviewed by the director whenever changes are made. When procedures are no longer used, they should be removed from the manual and retained with a notation of the dates during which they were in service. When writing procedures for each CW site, it might be helpful to: • Use a template with standard component headings to facilitate writing a new procedure and promote ease of use when performing testing; • List all materials needed and how to prepare them before testing; • Include instructions for patient preparation and specimen collection; • Highlight key steps in the procedure (e.g., test incubation time); • List test limitations; • Describe actions to take when the test does not perform as expected; • Integrate control procedures with the steps for performing patient testing to assure control testing is performed; • Include established reference intervals and critical values for the test; and • Describe how to record and report results and how to handle critical values. # Personnel Training Trained and competent testing personnel are essential to good quality testing and patient care. Data from CDC and CMS surveys demonstrate that waived testing sites are subject to a high rate of personnel turnover. Personnel should be trained and competent in each test they will perform before reporting patient results (32,33 # Competency Assessment To ensure testing procedures are performed consistently and accurately, periodic evaluation of competency is recommended, with retraining, as needed, on the basis of results of the competency assessment (32). Assessment activities should be conducted in a positive manner with an emphasis on education and promoting good testing practices. Competency can be evaluated by methods such as observation, evaluating adequacy of documentation, or the introduction of mock specimens by testing control materials or previously tested patient specimens. External quality assessment or evaluation programs, such as voluntary PT programs, are another resource for assessment. # Additional Measures to Help Testing Staff Ensure Reliable Results The CW site director or person overseeing testing should promote quality testing and encourage staff to ask questions and seek help when they have concerns. Recommendations include: • Identifying a resource person or expert (e.g., a consultant or manufacturer's technical representative), available either off-site or on-site, to answer questions and be of assistance. • Posting telephone numbers for manufacturers' technical assistance representatives. • Designating an appropriately trained person, who understands the responsibilities and impact of changing from one test system to another, to discuss new products with sales representatives. Uninformed personnel might mistakenly use a promotional test kit, provided by a distributor or manufacturer's representative, for patient testing without realizing the consequences of test substitution. # Recommended Practices Before Testing Preparations before performing patient testing are a critical element in producing quality results. Paying attention to test orders, properly identifying and preparing the patient, collecting a good quality specimen, and setting up the test system and testing area all contribute to reliable test results. # Test Orders, Patient Identification, and Preparation Before collecting the specimen, confirm the test(s) ordered and the patient's identification and verify that pretest instructions or information, as applicable, have been provided. This includes: • Test orders -CW sites performing various waived tests should routinely confirm that the written test order is correct. If there is a question, check with the ordering clinician. Standing orders for certain tests might apply, but they should be documented. • Patient identification -Identify the patient before collecting the specimen. Because names can be similar and lead to confusion, use birth dates, middle initials, identification numbers, or other means to ensure the specimen is collected from the correct patient. • Pretest instructions -Some tests require special preparation on the patient's part (e.g., a fasting state for glucose testing). Provide the patient with pretest instructions, when appropriate, and when special preparation is needed, verify that patients received instructions before testing. To determine if patients followed the instructions, ask them to explain how they prepared for the test. • Pretest information -Discuss factors, test limitations, or medical indications that can affect test results with the patient, as appropriate, and provide pertinent information such as pamphlets supplied by the test manufacturer, when specified in the product insert. # Specimen Collection and Handling The product insert provides details on proper collection, handling, and storage of patient specimens. Collect waived test specimens exactly as described in the test system instructions, using the appropriate collection device and method to obtain a quality specimen (33)(34)(35)(36). Improperly collected, stored, or compromised specimens should not be tested. Specimens and, in some cases, test devices need to be appropriately labeled to prevent mix-up. Waived test specimens. Waived tests are approved for use only with direct, unprocessed specimens that do not require operator manipulation (Table 8). Specimens that are processed or manipulated by the user (e.g., serum or plasma) require centrifugation, dilution, extraction, or other preparation steps that require special training or instrumentation and are not appropriate for waived tests. Sometimes, tests can be performed using both processed and unprocessed specimen types, but are waived only for the unprocessed specimens, in which case the product insert should identify the appropriate specimen for the waived test. For example, a single product insert might include instructions for performing a waived test using unprocessed whole blood and for performing the same test using plasma, which would not be waived. Other examples include group A streptococcal antigen testing, which is waived only when performed on a throat swab and not when performed on a microbiology culture, and visual color comparison tests for hCG (pregnancy tests) using urine that are waived, whereas serum or plasma hCG tests are not waived. Specimen collection. The person collecting the patient specimen or giving the collection instructions should have a thorough understanding of the specimen type, proper collection method (including the need to wear gloves or other PPE as appropriate), and handling to assure a quality specimen (33)(34)(35)(36). Directions for specimen collection, handling, and storage are included in the product insert and must be followed explicitly. For example, instructions might specify one drop of capillary blood or include precautions to use the second drop of blood from a fingerstick rather than the first. When gloves are worn during specimen collection, they should be removed and discarded in an appropriate waste receptacle before contact with another patient. Hand hygiene should be performed between patients. Collection devices. Manufacturers might provide or specify specimen collection devices. These devices, whether supplied with the test system or specified in the product insert, are integral to the test system and should be used to ensure the correct specimen type and volume to provide reliable results. Containers and collection devices might have additives that affect the specimen or are part of the test and should not be substituted or altered. For example, throat swab collection kits used with group A streptococcal antigen tests might look the same; however, they might be made from a variety of fibers or contain different materials that could interfere with the test or affect organism viability. Whole blood capillary tubes (e.g., used for cholesterol, hemoglobin A 1 C, or Helicobacter pylori testing) can have additives or hold different specimen volumes which affect test reactions and results. Fingerstick and venipuncture collection devices are for onetime use only. Never reuse needles, syringes, or lancets. To avoid transmission of hepatitis B virus, hepatitis C virus, HIV, and other bloodborne pathogens, appropriately discard sharps, lancets, and platforms for spring-loaded lancets and disinfect instruments contaminated by blood (9,28). Specimen labeling. Labeling procedures should meet the needs of the testing site and should be adequate to prevent specimen mix-up. To prevent errors, always label specimens with pertinent information (e.g., unique patient name or other unique identifier). Depending on workflow, specimen labeling also might include the date and time of collection and identification of the collector. For waived tests in which the specimen is applied directly to the test device (e.g., throat swabs for group A streptococcal antigen), the test strip, cassette, or other device should be labeled with the patient identification before collecting the specimen, especially if more than one test is being performed at the same time. # Preparing the Testing Area, Test Materials, and Equipment Preparing the testing area and materials (e.g., kits, reagents, control materials, and equipment) before testing patient specimens is essential to maintaining efficient workflow and good quality testing (Table 9). Before beginning the test, read and understand the test instructions specified in the product insert and included in the CW site's procedures. Verify that the instructions are current for the test in use and that no changes have been made. Do not use product inserts that are out of date for the test system currently in use. When opening a new kit, check for notifications in the external labeling or special notices that might be included with product inserts or packaging. Additional considerations for good testing practices are: • Abide by expiration dates and discard expired reagents and test kits as soon as the expiration date elapses. • When preparing to perform testing, allow time for any refrigerated items, including reagents or patient specimens, to reach room temperature before testing, if specified in the product insert. # Recommended Practices During Testing When the testing area is prepared and the specimen has been collected, the process continues to the testing phase. Important activities during this phase include QC testing, test performance, result interpretation and recording. # Quality Control Testing Performing QC testing procedures provides assurance that the test performs as expected and alerts the user when problems occur. QC testing is designed to detect problems that might arise because of operator error, reagent or test kit deterioration, instrument malfunction, or improper environmental conditions. Test procedures should describe the type of Replenish supplies (e.g., specimen collection, biohazard waste containers, and forms) # Test system and reagents Check the product insert and exterior labeling on kits and reagents for changes Check and record expiration dates (Do not use expired reagents or kits) Check and record lot numbers for test kits, test devices and controls (Do not mix reagents from different products or lot numbers. If new lot, set up quality control as needed and refer to product insert for any changes in control ranges) Visually inspect reagents or vials for damage, discoloration, or contamination Prepare reagents according to instructions (If opening new reagents, write the date opened on the outside of the vial or test kit) # Inspect equipment and electrical connections for integrity If the test system incorporates internal calibration steps that need to be checked before testing, conduct the calibration check or set the test system as specified by the manufacturer* * Portable equipment, if moved, might be subject to inaccurate results. To verify proper test system functioning, perform control testing or calibration check procedures even if not specified by the manufacturer after moving the equipment. # MMWR November 11, 2005 controls to be used, how to perform QC testing (including QC testing frequency), and actions to be taken when QC results are unacceptable. Types of controls. Two types of controls typically found in waived tests are: • Internal, procedural, or built-in controls -evaluate whether certain aspects of the test system are working properly. They are designed to verify that the test system is working as expected, that sufficient specimen was added and, for unitized test devices, whether it migrated through the test strip properly. Certain test systems might have electronic internal controls to monitor electronic functions. • External controls -mimic patient specimens and monitor the testing process, from specimen application to result interpretation, to assure proper test performance. They might be provided as liquid or other materials similar to patient specimens and might be included with the test system or purchased separately. Frequency of control testing. For certain test systems, the product insert describes the minimum conditions or recommended frequencies for testing internal and/or external controls. Each site should determine the appropriate control testing frequency for each test system and the frequency should not be less than specified in the product insert. When determining the frequency for running external controls, consider the robustness of the test, stability of the environment, and skills and knowledge of the testing personnel. At a minimum, external controls should be tested with each new shipment of utilized test devices, when testing a new lot number, and by each new operator before conducting testing. Controls should be tested either before or concurrent with patient specimens by the same personnel who routinely perform patient testing. Corrective action when control testing fails. If controls do not perform as expected, patient testing should not be performed or results reported until the problem is identified and corrected. The product insert should provide information on procedures for handling unexpected control results, identifying sources of error (including interfering substances), and manufacturer contact information for technical assistance. This information might be incorporated into the facility's procedures or posted for quick reference. The test site should have telephone numbers or other contact information readily available (e.g., numbers for manufacturers' technical assistance, the facility's director, consultant, or public health departments). Documentation. Documenting and monitoring control testing results provides an indication that the test was properly performed by the operator and the test system (reagents, instruments, or any components) performed as expected. Records of control results should be periodically reviewed to detect shifts or changes in performance over time. # Performing the Test The following points are important to remember when performing the test: • Follow the steps in the test procedure in the exact order described in the product insert. • Test controls at the frequency determined by the CW site. • Pay attention to timing for waived tests, particularly unitized test devices that must be read during specific time intervals. Incorrect timing of these types of tests can give erroneous test results. Insufficient timing can result in false negative or invalid results because the specimen might not react completely with test system reagents. Time intervals longer than those specified in the product insert can result in false positive, false negative, or invalid results because of exaggerated color development, fading of reaction products, or migration beyond a visible range. Therefore, it is important to have a system established to read results during the correct timeframe, especially if conducting more than one test at a time. Suggestions for helping to ensure correct timing of tests include using timers that beep until turned off, using timers that can easily be worn or attached to clothing, using multiple timers when performing more than one test at a time, and maintaining extra timers and batteries. # Test Results Interpretation When the test is complete, interpret the results according to instructions in the product insert (including the quick reference guide). Test results are of the following two types: • Quantitative -Tests that provide numerical results generated by the test device or instrument. Numerical results are values corresponding to the concentration of the specific substance being measured. The value includes specific measurement units (e.g., such as a glucose result of 100 mg/dL). No interpretation is necessary to read the result. • Qualitative -Tests that detect whether a particular substance, condition, or microbiological organism is present or absent. Results are interpreted as positive/reactive, negative/nonreactive, or invalid. Invalid results might indicate a problem with the specimen or the test system. Diagrams, color photographs, and color-comparison charts are often part of the product insert and quick references and serve as guides for interpretation. # Resolving Problems If a discrepancy is identified between the patient's test results and the clinical information or if the results are invalid or otherwise compromised, testing should be repeated. Results should not be reported until the problem is resolved. Follow the steps in the product insert to resolve problems with test results. Unitized test system instructions usually suggest repeating the test with a new device and referring to QC or trouble-shooting procedures. If repeat testing does not resolve the problem, contact the manufacturer or product technical representative. Quantitative results can be obtained that are beyond the measuring range of the instrument or test device. Each site should have documentation of quantitative test measuring ranges and a procedure for handling test results that are beyond the reportable ranges, either low or high. # Recording Results Record test results according to the site's policy. Results can be recorded directly in a patient's chart, in log books, or on a separate report form. Records or logs of test results should have enough detail so the test site can retrieve information. Quantitative results should be recorded using the units of measurement of the test system. Qualitative test results should be recorded using interpretive words or abbreviations such as positive, negative, reactive or R, or nonreactive or NR instead of symbols like plus and minus (+, -) to help avoid clerical errors because a negative (-) sign can easily be changed to a positive (+) sign. If a test result is not acceptable or requires repeat testing (e.g., out of range or invalid), record the initial result, noting it was unacceptable, take steps necessary to resolve the problem, then record the correct result. Good laboratory practices include recording what happens, whether acceptable or not, and what is done to correct problems encountered during testing. # Recommended Practices After Testing After-testing activities include issuing test reports, supplemental or confirmatory testing, public health disease reporting (if required), testing area cleanup, biohazard waste disposal, and documentation of testing activities. # Test Reports After the completion of the test, results are documented and reported. Patient reports should be legible and reported in a timely manner to the appropriate person. Reports should meet the needs of the testing site and should be appropriately standardized so reports generated on-site are easily distinguishable from referral laboratory reports. Verbal reports of test results should be documented and followed by a written report. Waived testing sites, such as point-of-care sites or physicians' offices, might accurately and legibly record results directly in the patient's record as a matter of practice. If results are not recorded directly in a patient's chart, they should be recorded in a written report format that includes all information needed to correctly identify and interpret the results as determined by the testing site (Table 10). Critical values are test results necessary for patient evaluation or treatment that require immediate notification to the clinician. Each site should define the critical values, if appropriate, for the tests in use and ensure that testing personnel are aware of these values and the procedure for alerting the clinician. Procedures should be in place to ensure documentation of critical values and timely notification of the proper medical personnel. # Supplemental or Confirmatory Testing The product insert should explain when supplemental testing is needed to confirm a waived test result or when the test is to be used as part of a multitest algorithm. A confirmatory test could be a different waived test (performed at the testing site or another CW site) or a nonwaived test performed by a CLIA-certified referral laboratory (37) (Table 11). When nonwaived confirmatory testing is needed, the patient can be sent to another facility for specimen collection and testing, or the specimen can be collected at the CW site and sent to a referral laboratory. The CW site should have written policies to ensure confirmatory and supplemental testing is performed when needed. For each waived test that requires additional testing, the CW site should document the processes and procedures necessary to manage referral or confirmatory testing. When a CW site collects specimens for referral, procedures should include the following: • ments for confirmatory or supplemental tests for infectious diseases (e.g., HIV). Maintaining records of referred testing is important for patient care and follow-up. Logs and other records should have sufficient information to track and retrieve the test results and reports, such as: • Information linking the referred specimen to patient identification, • The name and contact information for the referral laboratory, • The test name and date referred, • Complete test results and the date received, and • The date the final report is issued. # Public Health Reporting Federal and state public health agencies require testing facilities to report confirmed positive results for certain infectious diseases (e.g., HIV, influenza, and Lyme disease) (38,39). Testing facilities should confer with local public health agencies for the most current information on required reporting procedures since diseases identified for reporting can change over time, and state requirements might vary. # Biohazard Waste Disposal Dispose of the biohazardous waste generated in specimen collection and testing according to site procedures that need to be in compliance with local ordinances, state, and federal OSHA regulations as previously discussed. # Documents and Records Documentation is essential to assure quality waived testing. Proper documentation is necessary for monitoring and assessing test performance, identifying and resolving problems that could affect patient testing, retrieving and verifying information, and maintaining adequate patient and personnel records. Log books or electronic systems can be used for maintaining and tracking information. In some cases, records might be part of the patient's medical chart. Testing records should be maintained in chronological order to facilitate retrieval of information if needed. In addition, control records should be kept in the order in which they were completed so they can easily be compared with test records if there are questions about testing performed within a specific time period. The person responsible for testing oversight and decision-making should review records periodically. State regulations or other governmental agencies might require CW sites to retain documents and records for a specific length of time. Aspects of testing for which records or documentation are recommended include: • # Quality Assessment Good laboratory practices can be expanded to include assessment activities to evaluate and improve the quality of CW site testing. Assessment activities can be either internal or external, depending on the needs, resources, and practices of the site. # Internal Assessment Objective internal assessment offers flexible, low-cost options for evaluating quality such as self-conducted inspections, supervisory review of documented problems that occur in the different phases of the testing process, review of QC documentation, and testing and reporting procedures. Test performance can be assessed, if specimens are suitable, by exchanging specimens with another testing facility using the same test method(s) and comparing the results. Results from these assessment activities should be documented and evaluated, noting any irregularities and the actions taken to resolve problems or improve processes or procedures. # External Assessment Because CW sites are not routinely inspected by CMS, voluntary inspections by peers or consultants can offer additional educational opportunities and feedback on current practices along with ideas for quality improvement. Voluntary external inspections evaluate the testing site practices and documentation systems, and a more narrowly focused assessment of test performance can be accomplished by participating in performance evaluation programs or subscribing to PT programs. These programs provide challenge samples to test as if they were patient specimens and the results are evaluated with respect to how close they are to the intended target values. Participation in these types of programs can be used to evaluate overall testing performance and as a training or educational tool for testing personnel. # Conclusion This report summarizes the findings of multiple surveys of sites performing waived testing throughout the United States. Although the surveys were conducted through several mechanisms, the findings lead to similar conclusions about lapses in quality in CW sites, and they highlight the need for additional education and training related to waived testing for CW site directors and testing personnel. The recommendations provided in this report are intended to serve as a guide to improve the quality of testing in CW sites and enhance patient safety. They can be disseminated by a variety of individuals and organizations and adapted for use in different settings where waived testing is conducted. Continued surveillance and monitoring of waived testing performance is needed to determine the effectiveness of these recommendations on protecting and improving the public's health. # Terms and Abbreviations Used in this Report true or target value; freedom from error; the accuracy of results can be measured by comparing them to results accepted as correct (e.g., standard methods), or by comparing them with those from another laboratory that uses a comparable method a substance or constituent for which a laboratory conducts testing a protein formed in the body in response to a foreign substance (e.g., bacteria, viruses or chemical toxins) and that interacts with the foreign substance to weaken or neutralize it any substance that, when introduced into the body, causes the development of an immune response, such as antibody production Arkansas Sentinel Network a biological agent that has the capacity to produce deleterious effects on humans, such as microorganisms and toxins waste containing pathogens with sufficient virulence and quantity so that exposure to the waste by a susceptible host could result in an infectious disease the application of combinations of laboratory practice and procedure, laboratory facilities, and safety equipment when working with potentially infectious microorganisms to prevent infection microorganisms that, when present in human blood, can cause disease in humans. These pathogens include, but are not limited to, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) the process of testing and adjusting an instrument or test system to provide a known relationship between the value of the substance being measured by the test and the test system's measurement response. A calibration check is a mechanism to be sure the test system has remained stable and the results remain accurate a process of separating blood or other body fluid cells from liquid components using a device (centrifuge) containing compartments that spin rapidly around a central axis reproducibility; the measure of the closeness of the results obtained when analyzing the same sample more than once; the measure of agreement between replicate measurements of the same material a handbook that contains test methods and other information needed to perform testing written product information usually supplied by the manufacturer with each test kit or test system containing instructions and critical details for performing the test; also referred to as package insert proficiency testing; an external quality assessment program in which samples are periodically sent to testing sites for analysis a test that detects whether a particular analyte, constituent, or condition is present or absent a group of activities to monitor and evaluate the CW site's entire testing process to help ensure that test results are reliable, improve the testing process, and promote good quality testing practices quality control; the procedures used to detect and correct errors that occur because of test system failure, adverse environmental conditions and variance in operator performance, as well as the monitoring of the accuracy and precision of the test performance over time a test that measures the concentration or amount of an analyte in a specimen, whose results are expressed numerically cards or small signs containing diagrams or flow charts with essential steps for conducting a test that are often included with waived test systems a result that indicates the presence of the constituent that the test is designed to detect a substance that produces a chemical or biological reaction with a patient specimen that allows detection or measurement of the analyte for which the test is designed the range of test values expected for a designated population of persons (e.g., 95% of persons presumed to be healthy [or normal]) a laboratory that receives specimens from CW sites to perform additional testing, often for followup confirmatory testing; the majority of referral laboratories perform nonwaived testing the span of test result values for which the instrument or test device can accurately measure the lowest concentration of an analyte that can reliably be detected or measured by a test system the cell-free liquid remaining after whole blood has clotted or coagulated the ability of a test to detect a particular substance or constituent without interference or false reactions by other substances an approach used in healt-care settings to reduce the risk for transmission of microorganisms from both recognized and unrecognized sources of infection in a wide variety of human sources. The nature of medical procedures and testing in these settings requires expansion of Universal Precautions to include feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus, even when no visible blood is evident. the state health agency or other appropriate state or local agency that has an agreement under Section 1864 of the Social Security Act and is used by CMS to perform surveys and inspections the instructions and all of the instrumentation, reagents, and supplies needed to perform a test and generate results series of activities or path of workflow for performing testing that can be divided into three major phases; before testing, during testing, and after testing a self-contained test device to which a specimen is added directly and in which all steps of the testing process occur. A unitized device is used for a single test and must be discarded after testing. an approach to controlling infection. According to the concept of Universal Precautions, all human blood and certain human body fluids are treated as if known to be infectious for HIV, hepatitis B virus, hepatitis C virus, and other bloodborne pathogens. a test system, assay, or examination that has been cleared by the FDA for home use, or HHS has determined meets the CLIA criteria of being a simple test with an insignificant risk for an erroneous result blood containing all its cellular components that has not undergone centrifugation or had the plasma removed # INSTRUCTIONS ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 3.0 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training. CDC will award 0.3 continuing education units to participants who successfully complete this activity. Continuing Nursing Education (CNE). This activity for 3.4 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # Acknowledgments The preparers acknowledge the contributions and assistance provided by John Hancock, James # Goal and Objectives This MMWR highlights quality issues identified in study findings of testing sites holding a Clinical Laboratory Improvement Amendments of 1988 (CLIA) Certificate of Waiver (CW). The goal of this report is to provide recommendations for good laboratory practices to improve the quality of waived testing and enhance patient care and safety. Upon completion of this educational activity, the reader should be able to describe 1) the quality issues reported in the study findings; 2) the requirements for obtaining a CW; 3) management's considerations before introducing waived testing; 4) the good laboratory practice recommendations for the three phases of testing; and 5) resources for personnel training and quality assessment. To receive continuing education credit, please answer all of the following questions. # Before performing a waived test, one should… A. confirm the test order is correct. B. collect test specimens exactly as described in the test system instructions. C. prepare the testing area and materials. D. confirm patient identity to ensure specimen collection from the correct patient. E. B, C and D. F. all of the above. # With unitized test use devices, external controls should be tested…	None	None
3dcb159faa743fc603b3028800c3ca194cdc7cbf	cdc	None	OBJECTIVE -To synthesize the cost-effectiveness (CE) of interventions to prevent and control diabetes, its complications, and comorbidities.We conducted a systematic review of literature on the CE of diabetes interventions recommended by the American Diabetes Association (ADA) and published between January 1985 and May 2008. We categorized the strength of evidence about the CE of an intervention as strong, supportive, or uncertain. CEs were classified as cost saving (more health benefit at a lower cost), very cost-effective# T he cost of diabetes in the U.S. in 2007 was $174 billion (1). Many interventions can reduce the burden of this disease. However, health care resources are limited; thus, interventions for diabetes prevention/control should be prioritized. We wanted to compare the effectiveness and costs of various interventions to find those that were the most effective for the least expense. Costeffective analysis is a useful tool for this purpose. Such analyses consist of compiling incremental cost-effectiveness ratios (ICERs), which are calculated as a ratio of the difference in costs to the difference in effectiveness between the intervention being evaluated and the comparison intervention. With the same health outcome indicator, ICERs of interventions are comparable. Therefore, these ICERs can make it easier to decide how to allocate resources. Although many cost-effectiveness (CE) analyses of diabetes interventions have been published, their qualities and conclusions vary. A systematic review, which appraises individual studies and summarizes results, would aid policy makers and clinicians in prioritizing interventions to prevent or treat diabetes and its complications. Few investigators have conducted systematic reviews of the CE of diabetes interventions (2)(3)(4)(5). The systematic review presented here, following the Cochrane Collaboration's protocol (6), includes all English language studies available from 1985 to May 2008. The interventions included only those recommended by the 2008 American Diabetes Association (ADA) Standards of Medical Care in Diabetes (7). # RESEARCH DESIGN AND METHODS # Study selection and protocols for review We searched the Medical Literature Analysis and Retrieval System Online (MED-LINE), Excerpta Medica (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Sociological Abstracts (Soc Abs), Web of Science (WOS), and Cochrane databases to identify relevant studies. We created a search strategy involving medical subject headings. The key words-and what each indicated-were: - Indicating diabetes: 26 key words indicating the disease of diabetes, such as "type 1 diabetes," "type 2 diabetes," "impaired glucose tolerance," and "insulin resistance"; - Indicating costs: ("cost or expenditure") OR ("costs and cost analysis") OR ("health care costs") OR ("cost of illness"); - Indicating effectiveness: ("benefit") OR ("life years") OR ("quality-adjusted life years") OR ("disability adjusted life years"); - Indicating CE analysis: OR ("cost-benefit analysis") OR ("cost-effectiveness analysis") OR ("cost-utility analysis") OR ("economic evaluation"). Database searches were based on matches in all four keyword categories. Reference lists of all the included articles were screened for additional citations, and Diabetes Care was reviewed manually, issue by issue, as the journal was expected to be highly relevant. Criteria for inclusion in the review were 1) original CE analysis; 2) intervention directed toward patients with type 1, type 2, or gestational diabetes mellitus (GDM) and recommended in the 2008 ADA standards for medical care (7); 3) outcomes were measured as life years gained (LYGs) or quality-adjusted life years gained (QALYs); and 4) publication in the English language occurred between January 1985 and May 2008 (2). To ensure that only studies with acceptable quality were included, we limited the analysis to studies considered good or excellent according to a 13-item qualityassessment tool based on the British Medical Journal authors' guide for economic studies (8). To make ICERs comparable across the studies, all costs are expressed as 2007 U.S. dollars with adjustment from other currencies, as needed, using the Federal Reserve Bank's annual foreign exchange rates (9) and from other cost years using the Consumer Price Index (10). If a study did not mention the year used in cost calculations, we assumed cost was as of one year before publication. ICERs were expressed as dollars per QALY or dollars per LYG and were rounded to the nearest hundred dollars per QALY or LYG. # Classification of cost-effectiveness of interventions Interventions were classified based on the level of CE by convention as described in the literature (2,11,12)-cost saving (an intervention generates a better health outcome and costs less than the comparison intervention) or cost neutral (ICER ϭ 0); very cost-effective (0 Ͻ ICER Յ $25,000 per QALY or LYG); cost-effective ($25,000 Ͻ ICER Յ $50,000 per QALY or LYG); marginally cost-effective ($50,000 Ͻ ICER Յ $100,000 per QALY or LYG); or not cost-effective (Ͼ$100,000 per QALY or LYG)-and whether evidence for the intervention's CE was strong, supportive, or uncertain as described below. There were two grades of evidence included in the "strong" group. Grade 1 was defined as 1) CE of the intervention was evaluated by two or more studies; 2) study quality was rated good or excellent; 3) effectiveness of interventions based on well-conducted, randomized clinical trials with adequate power and generalizable results or meta-analysis or a validated simulation model; 4) effectiveness of interventions rated as level A (clear evidence from well-conducted, generalizable, randomized controlled trials that were adequately powered; compelling nonexperimental evidence, i.e., the all or none rule developed by the Centre for Evidence-Based Medicine at the University of Oxford, U.K.) or level B (supportive evidence from wellconducted cohort studies or supportive evidence from a well-conducted casecontrol study) according to the 2008 ADA standards of medical care (7); and 5) similar ICERs reported across the studies. Grade 2 was defined as the same as Grade 1 except that the CE was based on only one study and the study was rated as excellent. We called the level of evidence "supportive" if only one study, rated lower than excellent, evaluated the CE of the intervention or if the effectiveness of the intervention was supported by either level C evidence (supportive evidence from poorly controlled or uncontrolled studies, or conflicting evidence with the weight of evidence supporting the recommendation) or expert consensus (level E) in ADA recommendations (7). The term "uncertain" was used to describe interventions with inconsistent evidence about CE across studies. # Reporting the results of the systematic review We reported the study results in two ways: 1) summarizing the key features and results for each included study; and 2) synthesizing the CE of the interventions based on the classification criteria described above. For the summary, we grouped interventions based on their intended purposes: a) preventing type 2 diabetes among high-risk persons; b) screening for undiagnosed type 2 diabetes and GDM; c) management of diabetes and risk factors for complications; d) screening for and early treatment of complications; and e) treatment of complications and comorbidities. We considered cases where the same intervention was applied to different populations or was compared with different interventions as different specific interventions and reported the ICERs separately. This was because both incremental costs and effectiveness of an intervention, and thus the ICERs, varied if the population and/or comparison group differed. If the CE of an intervention was evaluated from different study perspectives, we report the ICERs separately. We presented the ICERs in subgroups if their ICERs differed substantially from basecase analysis, and original studies reported the ICERs this way. If the study reported the ICERs only for population subgroups, we provided a range and, when available, trend of the ICERs. Finally, if a study used both LYGs and QALYs as study outcome measures, we reported the ICER in both costs per LYG and QALY. In reporting the synthesized results, we applied the following rules: 1) We used the median ICER to represent the CE of an intervention if the intervention was evaluated by more than one study. 2) We reported the ICERs from the longer analytical time horizon if the intervention was evaluated from both short-and longterm perspectives. This was appropriate since many of the benefits of most diabetes prevention and control interventions would come from preventing diabetic complications, which occur later in life. 3) We chose the health care system as our primary study perspective for the purpose of cross-study and cross-intervention comparisons. This study perspective included all the medical costs incurred no matter who paid. 4) If the ICERs of an intervention differed substantially between the U.S. and other developed countries (mainly European countries, Australia, and Canada), we reported the summary results separately by labeling the ICER for the U.S. or for the other countries. 5) If the trial on which the CE of an intervention was based was conducted in a mixed population with type 1 or type 2 diabetes, we assumed the CE was the same for both types of diabetes. RESULTS -The search yielded 9,461 abstracts. After reviewing the abstracts and subsequent reference tracking, we narrowed the focus to 197 possible original CE studies. Further review of the full text resulted in 56 CE studies that met our inclusion criteria. Figure 1 depicts the data abstraction process. Table 1 shows the detailed description of the CE studies that we included according to intervention type . We first grouped similar interventions together, then arranged them chronologically and by the first author's last name. Some studies that evaluated multiple interventions appear in more than one category. The information used to describe each study included the intervention being evaluated; comparison intervention, population, and country setting; data sources for the effectiveness of the intervention; study methods; quality of the study; analytical time horizon; discount rate (a rate that is used to convert future costs and benefits into their present values); and ICER. Thirty-nine of the 56 studies took a long-term analytical time horizon, such as 20 -30 years or lifetime. Nearly all of the studies with the long-term horizon used simulation modeling. Only one study was conducted in a developing country (Thailand) (57). There were 48 excellent studies and 8 good studies. Only three studies took perspectives other than the health care system. The interventions evaluated in these CE studies covered a wide range: lifestyle and medication therapy to prevent type 2 diabetes among high-risk individuals (eight studies); screening for undiagnosed type 2 diabetes or GDM (three studies); intensive glycemic control (12 studies); self-monitoring of blood glucose (one study); intensive hypertension control (four studies); statin therapy for cholesterol control (five studies); smoking cessation (one study); diabetic health education program (two studies); diabetes by grouping similar interventions together, then follow the year and alphabetical order of the first author's last name; the numbers in the parenthesis are the reference number. †The study was rated as "excellent" quality unless otherwise indicated. §The study was rated as "good" quality. The study is based on simulation modeling unless otherwise indicated. Within trial or within epidemiological study. ‡The study was done from the perspective of the health system unless otherwise indicated. ‡ ‡The study was done from the societal perspective. #The study done from the perspective of the health plan. † †The study was done from the federal budget perspective. † † †Third party payer perspective. # Cost-effectiveness of diabetes interventions # Cost-effectiveness of diabetes interventions disease management program (two studies); screening to prevent diabetic retinopathy (five studies); optimal foot care to prevent foot ulcer and amputation (two studies); ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to prevent diabetic end-stage renal diseases (ESRD) (15 studies); comprehensive interventions using a combination of several of the above secondary prevention interventions (two studies); and interventions treating diabetic retinopathy and foot ulcers (two studies). The classification of the interventions based on their level of CE and strength of evidence is presented in Table 2. For each intervention, we also described the number of studies that evaluated the CE of this intervention, its comparison intervention, and the study population in which the intervention was implemented. We reported the median and range of the IC-ERs across the studies. Twenty-six interventions were classified as supported by strong evidence concerning their CE (Table 2). Among these, six interventions were cost saving, eight were very cost-effective, six were costeffective, two were marginally costeffective, and four were not cost-effective. These interventions consisted of primary prevention, screening for undiagnosed type 2 diabetes, diabetic risk factor control, early prevention of diabetes complications, and treatment of diabetes complications. The six cost-saving interventions with strong evidence were 1) ACEI therapy for intensive hypertension control, as in the UK Prospective Diabetes Study (UKPDS), in persons with type 2 diabetes compared with standard hypertension control; 2) ACEI or ARB therapy to prevent ESRD for type 2 diabetes compared with no ACEI or ARB therapy; 3) early irbesartan therapy at the stage of microalbuminuria to prevent ESRD in people with type 2 diabetes compared with treatment at the stage of macroalbuminuria; 4) comprehensive foot care to prevent ulcers in mixed population with either type 1 or type 2 diabetes compared with usual care; 5) multi-component interventions for diabetic risk factor control and early detection of complications compared with conventional insulin therapy for persons with type 1 diabetes; and 6) multicomponent interventions for diabetic risk factor control and early detection of complications compared with standard glycemic control for persons with type 2 diabetes. Of the eight very cost-effective interventions with strong evidence, six were for persons with type 2 diabetes, one for persons with type 1 diabetes, and one for a mixed population with type 1 or type 2 diabetes. Interventions for type 2 diabetes included: 1) primary prevention through intensive lifestyle modification; 2) universal opportunistic screening for undiagnosed type 2 diabetes in African Americans between 45 and 54 years old; 3) intensive glycemic control as implemented in UKPDS; 4) statin therapy for secondary prevention of cardiovascular disease; 5) smoking cessation; and 6) annual screening for diabetic retinopathy and early treatment of it. The intervention for type 1 diabetes was annual screening for diabetic retinopathy and treating the positive cases. The intervention for mixed population of type 1 and type 2 diabetes was immediate vitrectomy to treat diabetic retinopathy compared with deferral of vitrectomy. The six cost-effective interventions with strong evidence were 1) one-time opportunistic targeted screening for undiagnosed type 2 diabetes in hypertensive persons aged 45 years and older compared with no screening; 2) intensive insulin treatment for persons with type 1 diabetes compared with conventional glycemic control; 3) UKPDS-like intensive glycemic control applied to the U.S. health care system among adults younger than age 54 years with type 2 diabetes compared with conventional glycemic control; 4) intensive glycemic control by a Diabetes Prevention Program (DPP) type of intensive lifestyle intervention in persons with newly diagnosed type 2 diabetes compared with conventional glycemic control; 5) statin therapy for primary prevention of cardiovascular disease in persons with type 2 diabetes compared with no statin therapy; 6) multi-component interventions including insulin therapy, ACEI therapy, and screening for retinopathy in persons with type 1 diabetes compared with intensive insulin therapy. The two marginally cost-effective interventions with strong evidence were 1) intensive glycemic control for all U.S. residents with type 2 diabetes diagnosed at age 25 years and older compared with usual care; and 2) screening for diabetic retinopathy every two years compared with screening every three years in persons with type 2 diabetes. The four interventions with strong evidence of not being cost-effective were 1) one-time universal opportunistic screening for undiagnosed type 2 diabetes among those aged 45 years and older compared with no screening; 2) universal screening for type 2 diabetes compared with targeted screening; 3) intensive glycemic control in the U.S. setting for patients diagnosed with diabetes at older ages (55-94 years of age) compared with usual care; and 4) annual screening for retinopathy compared with screening every two years. All these studies were for type 2 diabetes. There were 18 specific interventions for which their CEs were based only on "supportive" evidence. Among them, 15 were each supported by one CE study, 13 were supported by level C or level E evidence, and five were supported by level A or B evidence as defined in the 2008 ADA standards of medical care in diabetes (7). For those interventions with level A or B evidence, the CE of each intervention was evaluated by one study with a quality of being "good." In terms of the level of the CE, 10 of the 18 specific interventions based on "supportive" evidence were cost-saving, including 1) screening using the sequential method (50-g glucose challenge test followed by 100-g glucose tolerance test ) for GDM in 30-year-old pregnant women between 24 -28 weeks' gestation compared with no screening; 2) screening for GDM using the 100-g GTT method compared with no screening; 3) the sequential method compared with 75-g GTT screening for GDM; 4) 100-g GTT compared with 75-g GTT screening for GDM; 5) diabetes self-management education for persons with type 1 diabetes compared with no education; 6) fullreimbursement policy for ACEI for patients with type 1 diabetes compared with patients paying out-of-pocket; 7) fullreimbursement policy for ACEI for patients with type 2 diabetes compared with patients paying out-of-pocket; 8) screening using a mobile camera at a remote area and processing data in a reading center compared with a retina specialist's visit in a mixed population of type 1 and type 2 diabetes; 9) screening for diabetic nephropathy and ensuing ACEI or ARB therapy in persons with type 1 diabetes compared with no screening; and 10) intensified foot ulcer treatment in a mixed population with type 1 or type 2 diabetes compared with standard treatment. Seven of the 18 specific interventions were very cost-effective: 1) primary prevention of type 2 diabetes in women with GDM history through intensive lifestyle ‡, the study for within trial and the results from health plan perspective are not used for determining the cost-effectiveness of the intervention. §, get this number by taking the median for women in one study (conservative, women Ͼ men) as the results for that study, then take the median of the three study. , 50-g GTT ϩ 100-g GTT. ¶, the evidence was very weak: there was an over 40% probability that the intervention would cost more than $50,000/QALY in a long-term. intervention compared with usual care; 2) universal opportunistic screening for type 2 diabetes in African Americans aged 25-44 years compared with no screening; 3) 100-g GTT compared with the sequential screening method for detecting GDM in 30-year-old pregnant women between 24 -28 weeks' gestation; 4) diabetes self-management education for persons with type 2 diabetes compared with no education; 5) disease management programs using specialist nurse-led clinics to treat and control hypertension or hyperlipidemia in patients with type 2 diabetes in a city in England or a culturally sensitive case-management training program to control diabetes and its risk factors in a Latino population with both type 1 and type 2 diabetes in a U.S. county compared with usual care only; 6) selfmonitoring of blood glucose (SMBG) three times per day compared with no SMBG in type 2 noninsulin users; and 7) SMBG once per day compared with no SMBG in type 2 noninsulin users. One of the 18 specific interventions was costeffective, i.e., the use of metformin to prevent type 2 diabetes in obese persons with impaired glucose tolerance compared with standard lifestyle intervention. No interventions in the "supportive" evidence category were "marginally costeffective" or "not cost-effective." Current evidence is uncertain on how the CE of screening for undiagnosed type 2 diabetes would change with the age of those screened. Two studies evaluated the CE of screening for undiagnosed type 2 diabetes; one study reported that costeffectiveness ratios (CERs) increased with initial screening age (16) while the other reported that they decreased with screening age (35). CONCLUSIONS -Our systematic review showed that, with few exceptions, ADA-recommended interventions for preventing or treating diabetes and its complications were cost saving, very costeffective, or cost-effective (i.e., with an ICER of less than $50,000 per QALY or LYG), although the strength of evidence varied. Generally, interventions that cost less than $50,000 per QALY are considered an efficient use of resources and worth recommending (11). Interventions with strong evidence for being cost saving, very cost-effective, or cost-effective should be considered for implementation. Interventions with supportive evidence for being cost saving, very costeffective, or cost-effective should be adopted if extra resources are available or if similar interventions with strong evidence are unavailable or infeasible in a specific setting. The one intervention recommended by the ADA that was shown as not CE was screening for type 2 diabetes of all U.S. residents aged 45 years and older. When considering allocating resources efficiently, universal screening for undiagnosed diabetes should be undertaken with great caution. The high CE ratio for universal screening for undiagnosed type 2 diabetes was primarily attributable to the small gain in health benefit. For example, screening everyone aged 45 years and older gained only 0.003 QALY per eligible person compared with no screening. However the additional costs associated with screening and early treatments were relatively large ($564 per person). Although detecting and treating diabetes earlier can prevent future diabetes-related complications and their associated medical costs, such savings are relatively small ($57 per person). Combining the health benefit and costs would yield an ICER of more than $1 million per QALY (35). An alternative to broad screening is to focus on screening persons with additional risk factors, such as hypertension. Such targeted screening is shown to be costeffective when compared with no screening or universal screening. Intensive glycemic control for all U.S. residents with type 2 diabetes diagnosed at age 25 years and older is marginally CE. However the cost-effectiveness of this intervention varies by age at the time of the diabetes diagnosis. The intervention is cost-effective in persons diagnosed at 25-54 years of age. However, intensive glycemic control for those diagnosed with diabetes at 55 years of age and older is not cost-effective. In fact, this result is consistent with the ADA's recommendation of less stringent A1C goals for patients with limited life expectancies. The ADA recommended annual eye screening for diabetic retinopathy. This recommended intervention is very costeffective compared with no screening in persons with type 2 diabetes. If considering the efficient allocation of resources, however, screening every other year might be a better alternative. Screening annually leads to a small health benefit but results in a moderate additional cost. For example, Vijan et al. (69) showed that, compared with a 2-year screening, annual screening among persons at moderate risk (65 years old with A1C level 9%) resulted in an increase of 2-3 days of sight at a cost of $540 -690 per person. However the ADA also stated in its recommendation that "less frequent exams (every 2-3 years) may be considered following one or more normal eye exams." For the interventions with uncertain CE (including optimal age of starting screening for type 2 diabetes), following the current treatment guidelines may be the best option until more evidence on their CE is available. The CEs of 43 ADA-recommended interventions were evaluated. Of these, 25 were in the "strong" evidence category. This number would probably have been larger if we had used less stringent criteria to define evidence as being strong. For example, evidence on the CE of using metformin to prevent type 2 diabetes among high-risk individuals was considered "supportive" in our current classification even though the efficacy of the intervention was shown by wellconducted multi-center large clinical trials in different country settings (71,72), and its CE was evaluated by "excellent" CE studies (25,34). This intervention was considered to have supportive evidence because it ranked lower in the ADA recommendations (7). Among all the interventions considered, evidence for the CE of primary prevention through intensive lifestyle modification was the strongest regarding the quantity and quality of the CE studies and efficacy data. Several well-conducted clinical trials have shown the efficacy of intensive lifestyle modification in preventing diabetes in different country settings, such as the U.S. DPP (71), Finnish Diabetes Prevention Study (73), China Da Qing Diabetes Prevention Study (74), and Indian DPP (72). Eight cost-effectiveness studies (seven of them rated as excellent quality) have been conducted by different groups in different countries based on data from these well-conducted clinical trials (15,25,34,36,41,50,59,66). The results from these studies consistently showed that intensive lifestyle modification in persons with impaired glucose tolerance was cost saving or very cost-effective in the long run (15,25,34,36,41,50,59). Even in a shortterm and one-on-one consulting setting, the intervention remained cost-effective (66). The intervention would be more cost-effective than existing studies show if the cost of the lifestyle intervention could be reduced. This might be achieved by changing the setting in which the inter- # Cost-effectiveness of diabetes interventions vention is provided. Only one study found a DPP-like intervention to be marginally cost-effective (25). Even in this study, however, the intervention would have been very cost-effective (23) if done in the type of group environment that is most likely in a real-world setting. A group-based, DPP-style lifestyle intervention partnership with the YMCA costs $275 to $325 per participant in the first year compared with $1,400 in the oneon-one setting of the DPP trial (75). Preventing diabetes, in particular by lifestyle modification, is not only effective but also a very efficient use of health care resources. The CE of an intervention can vary by country setting. For example, intensive glycemic control (with a goal A1C level of 7%) in type 2 diabetic patients diagnosed at 25 years of age and older was marginally cost-effective in the U.S. but very cost-effective in other developed countries. Although the efficacy data of all studies of intensive glycemic control in type 2 diabetic patients were based on the same UKPDS data, the cost data were based on how residents of the different countries used health services and the cost of those services. The incremental cost of intensive glycemic control was much higher in the U.S. than in the U.K. because of different practice patterns. Patients outside the U.S. did not receive diabetes disease management services and had less frequent self-testing and physician office visits than their U.S. counterparts at the time these studies were conducted. If using the health services as described in the UKPDS setting but with the U.S. cost of these services, the CE of the intensive glycemic control in the U.S. would resemble that of other developed countries. Future economic evaluation of diabetes interventions should consider the following. First, more studies are needed to evaluate the CE of interventions that fell in the "supportive" evidence category. For studies with weaker efficacy data, further efficacy studies are needed. Second, there are also 38 interventions recommended by the ADA but they have not been evaluated for their CE or the studies did not meet the inclusion criteria for our review (list is available upon request from the authors). The CE of these interventions should be assessed. Third, more CE studies are needed that address interventions in real-world settings. For example, few studies considered attrition rate, noncompliance, and dropout rates in evaluat-ing CE. Fourth, more studies are needed to evaluate the CE of public policy changes. Only two studies evaluated public insurance reimbursement of ACEI therapy and both found this intervention to be cost saving. Finally, the CE of multiple interventions needs to be evaluated. In most real-world settings, patients receive multiple interventions simultaneously. Nearly all previous studies only evaluated the CE of a single intervention. This review's conclusions should be used with caution. First, our conclusions are based on available information up to May 2008. More studies have been published since then. In addition, data on both the effectiveness and cost of an intervention could have changed since the time the original study was conducted. Using the newly available data could change our current conclusion. For example, in our review, we concluded that the CE of optimal age to start screening for type 2 diabetes was uncertain. A recently published CE study on age at initiation of screening for type 2 diabetes, released after our analysis was complete, might change that conclusion (76). Another example is the large decrease in costs for metformin, statins, and ACEIs. Studies that evaluate CE using current costs might look more favorably on interventions that include statins and ACEIs than those reported here. Reevaluating the costs and benefits of these interventions, using current-day costs, is beyond the scope of this study. Second, when using the results and conclusions of our review, readers need to be certain that terms are understood correctly. For example, "intensive insulin treatment" in our review meant "multiple insulin injection" or "insulin infusion." Developments in medical technology might make continuous glucose monitoring systems, which record blood glucose levels throughout the day and night, more common. Drugs such as TZD Byetta and Gliptin, not available at the time covered by this review, are increasingly used to achieve intensive glycemic control. The CE of treatment with these and other new devices and drugs are unknown. New CE analyses are needed for these new interventions. Third, not everyone will necessarily agree with our classification criteria. Different classification criteria might have changed some conclusions. Fourth, most of the CE studies are based on simulation modeling. Although good-quality simulation modeling can provide information at a much lower cost than clinical trials, models are based on assumptions and represent a simplification of-and therefore might depart from-reality. Fifth, these CE studies use different methods, which could account for some differences in CERs. If the results from different models were consistent, we would have more confidence in the conclusion on the CE of the intervention. Sixth, we used the same threshold for the classification of the CE of interventions regardless of whether the ICERs were expressed as dollars per LYG or dollars per QALY, although they are different measures. The studies that reported costs per LYG did not incorporate the impact of the intervention on quality of life into the analysis. If they did, the cost per QALY could be higher, lower, or the same depending on the relative magnitude of the health benefit of the intervention on quality of life. Seventh, the interpretation of the CE of an intervention must include consideration of variables such as study population, comparison interventions, and country setting. Lastly, our recommendations are based on the CE of the interventions and not their efficacy; therefore, these recommendations are not necessarily the same as the ADA recommendations. The importance of CE in decision making should not be overstated. CE is only one aspect to consider. CE analysis does not address the distribution of costs and the benefits of an intervention, societal or personal willingness to pay, social and legal aspects, or ethical issues associated with each intervention. All these aspects are important in formulating public policy. The good news is that our study shows that a majority of the recommended diabetes interventions provide both health benefits and good use of health care resources.	OBJECTIVE -To synthesize the cost-effectiveness (CE) of interventions to prevent and control diabetes, its complications, and comorbidities.We conducted a systematic review of literature on the CE of diabetes interventions recommended by the American Diabetes Association (ADA) and published between January 1985 and May 2008. We categorized the strength of evidence about the CE of an intervention as strong, supportive, or uncertain. CEs were classified as cost saving (more health benefit at a lower cost), very cost-effective# T he cost of diabetes in the U.S. in 2007 was $174 billion (1). Many interventions can reduce the burden of this disease. However, health care resources are limited; thus, interventions for diabetes prevention/control should be prioritized. We wanted to compare the effectiveness and costs of various interventions to find those that were the most effective for the least expense. Costeffective analysis is a useful tool for this purpose. Such analyses consist of compiling incremental cost-effectiveness ratios (ICERs), which are calculated as a ratio of the difference in costs to the difference in effectiveness between the intervention being evaluated and the comparison intervention. With the same health outcome indicator, ICERs of interventions are comparable. Therefore, these ICERs can make it easier to decide how to allocate resources. Although many cost-effectiveness (CE) analyses of diabetes interventions have been published, their qualities and conclusions vary. A systematic review, which appraises individual studies and summarizes results, would aid policy makers and clinicians in prioritizing interventions to prevent or treat diabetes and its complications. Few investigators have conducted systematic reviews of the CE of diabetes interventions (2)(3)(4)(5). The systematic review presented here, following the Cochrane Collaboration's protocol (6), includes all English language studies available from 1985 to May 2008. The interventions included only those recommended by the 2008 American Diabetes Association (ADA) Standards of Medical Care in Diabetes (7). # RESEARCH DESIGN AND METHODS # Study selection and protocols for review We searched the Medical Literature Analysis and Retrieval System Online (MED-LINE), Excerpta Medica (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Sociological Abstracts (Soc Abs), Web of Science (WOS), and Cochrane databases to identify relevant studies. We created a search strategy involving medical subject headings. The key words-and what each indicated-were: • Indicating diabetes: 26 key words indicating the disease of diabetes, such as "type 1 diabetes," "type 2 diabetes," "impaired glucose tolerance," and "insulin resistance"; • Indicating costs: ("cost or expenditure") OR ("costs and cost analysis") OR ("health care costs") OR ("cost of illness"); • Indicating effectiveness: ("benefit") OR ("life years") OR ("quality-adjusted life years") OR ("disability adjusted life years"); • Indicating CE analysis: [(key words for costs) AND (keywords for effectiveness)] OR ("cost-benefit analysis") OR ("cost-effectiveness analysis") OR ("cost-utility analysis") OR ("economic evaluation"). Database searches were based on matches in all four keyword categories. Reference lists of all the included articles were screened for additional citations, and Diabetes Care was reviewed manually, issue by issue, as the journal was expected to be highly relevant. Criteria for inclusion in the review were 1) original CE analysis; 2) intervention directed toward patients with type 1, type 2, or gestational diabetes mellitus (GDM) and recommended in the 2008 ADA standards for medical care (7); 3) outcomes were measured as life years gained (LYGs) or quality-adjusted life years gained (QALYs); and 4) publication in the English language occurred between January 1985 and May 2008 (2). To ensure that only studies with acceptable quality were included, we limited the analysis to studies considered good or excellent according to a 13-item qualityassessment tool based on the British Medical Journal authors' guide for economic studies (8). To make ICERs comparable across the studies, all costs are expressed as 2007 U.S. dollars with adjustment from other currencies, as needed, using the Federal Reserve Bank's annual foreign exchange rates (9) and from other cost years using the Consumer Price Index (10). If a study did not mention the year used in cost calculations, we assumed cost was as of one year before publication. ICERs were expressed as dollars per QALY or dollars per LYG and were rounded to the nearest hundred dollars per QALY or LYG. # Classification of cost-effectiveness of interventions Interventions were classified based on the level of CE by convention as described in the literature (2,11,12)-cost saving (an intervention generates a better health outcome and costs less than the comparison intervention) or cost neutral (ICER ϭ 0); very cost-effective (0 Ͻ ICER Յ $25,000 per QALY or LYG); cost-effective ($25,000 Ͻ ICER Յ $50,000 per QALY or LYG); marginally cost-effective ($50,000 Ͻ ICER Յ $100,000 per QALY or LYG); or not cost-effective (Ͼ$100,000 per QALY or LYG)-and whether evidence for the intervention's CE was strong, supportive, or uncertain as described below. There were two grades of evidence included in the "strong" group. Grade 1 was defined as 1) CE of the intervention was evaluated by two or more studies; 2) study quality was rated good or excellent; 3) effectiveness of interventions based on well-conducted, randomized clinical trials with adequate power and generalizable results or meta-analysis or a validated simulation model; 4) effectiveness of interventions rated as level A (clear evidence from well-conducted, generalizable, randomized controlled trials that were adequately powered; compelling nonexperimental evidence, i.e., the all or none rule developed by the Centre for Evidence-Based Medicine at the University of Oxford, U.K.) or level B (supportive evidence from wellconducted cohort studies or supportive evidence from a well-conducted casecontrol study) according to the 2008 ADA standards of medical care (7); and 5) similar ICERs reported across the studies. Grade 2 was defined as the same as Grade 1 except that the CE was based on only one study and the study was rated as excellent. We called the level of evidence "supportive" if only one study, rated lower than excellent, evaluated the CE of the intervention or if the effectiveness of the intervention was supported by either level C evidence (supportive evidence from poorly controlled or uncontrolled studies, or conflicting evidence with the weight of evidence supporting the recommendation) or expert consensus (level E) in ADA recommendations (7). The term "uncertain" was used to describe interventions with inconsistent evidence about CE across studies. # Reporting the results of the systematic review We reported the study results in two ways: 1) summarizing the key features and results for each included study; and 2) synthesizing the CE of the interventions based on the classification criteria described above. For the summary, we grouped interventions based on their intended purposes: a) preventing type 2 diabetes among high-risk persons; b) screening for undiagnosed type 2 diabetes and GDM; c) management of diabetes and risk factors for complications; d) screening for and early treatment of complications; and e) treatment of complications and comorbidities. We considered cases where the same intervention was applied to different populations or was compared with different interventions as different specific interventions and reported the ICERs separately. This was because both incremental costs and effectiveness of an intervention, and thus the ICERs, varied if the population and/or comparison group differed. If the CE of an intervention was evaluated from different study perspectives, we report the ICERs separately. We presented the ICERs in subgroups if their ICERs differed substantially from basecase analysis, and original studies reported the ICERs this way. If the study reported the ICERs only for population subgroups, we provided a range and, when available, trend of the ICERs. Finally, if a study used both LYGs and QALYs as study outcome measures, we reported the ICER in both costs per LYG and QALY. In reporting the synthesized results, we applied the following rules: 1) We used the median ICER to represent the CE of an intervention if the intervention was evaluated by more than one study. 2) We reported the ICERs from the longer analytical time horizon if the intervention was evaluated from both short-and longterm perspectives. This was appropriate since many of the benefits of most diabetes prevention and control interventions would come from preventing diabetic complications, which occur later in life. 3) We chose the health care system as our primary study perspective for the purpose of cross-study and cross-intervention comparisons. This study perspective included all the medical costs incurred no matter who paid. 4) If the ICERs of an intervention differed substantially between the U.S. and other developed countries (mainly European countries, Australia, and Canada), we reported the summary results separately by labeling the ICER for the U.S. or for the other countries. 5) If the trial on which the CE of an intervention was based was conducted in a mixed population with type 1 or type 2 diabetes, we assumed the CE was the same for both types of diabetes. RESULTS -The search yielded 9,461 abstracts. After reviewing the abstracts and subsequent reference tracking, we narrowed the focus to 197 possible original CE studies. Further review of the full text resulted in 56 CE studies that met our inclusion criteria. Figure 1 depicts the data abstraction process. Table 1 shows the detailed description of the CE studies that we included according to intervention type . We first grouped similar interventions together, then arranged them chronologically and by the first author's last name. Some studies that evaluated multiple interventions appear in more than one category. The information used to describe each study included the intervention being evaluated; comparison intervention, population, and country setting; data sources for the effectiveness of the intervention; study methods; quality of the study; analytical time horizon; discount rate (a rate that is used to convert future costs and benefits into their present values); and ICER. Thirty-nine of the 56 studies took a long-term analytical time horizon, such as 20 -30 years or lifetime. Nearly all of the studies with the long-term horizon used simulation modeling. Only one study was conducted in a developing country (Thailand) (57). There were 48 excellent studies and 8 good studies. Only three studies took perspectives other than the health care system. The interventions evaluated in these CE studies covered a wide range: lifestyle and medication therapy to prevent type 2 diabetes among high-risk individuals (eight studies); screening for undiagnosed type 2 diabetes or GDM (three studies); intensive glycemic control (12 studies); self-monitoring of blood glucose (one study); intensive hypertension control (four studies); statin therapy for cholesterol control (five studies); smoking cessation (one study); diabetic health education program (two studies); diabetes by grouping similar interventions together, then follow the year and alphabetical order of the first author's last name; the numbers in the parenthesis are the reference number. †The study was rated as "excellent" quality unless otherwise indicated. §The study was rated as "good" quality. The study is based on simulation modeling unless otherwise indicated. **Within trial or within epidemiological study. ‡The study was done from the perspective of the health system unless otherwise indicated. ‡ ‡The study was done from the societal perspective. #The study done from the perspective of the health plan. † †The study was done from the federal budget perspective. † † †Third party payer perspective. # Cost-effectiveness of diabetes interventions # Cost-effectiveness of diabetes interventions disease management program (two studies); screening to prevent diabetic retinopathy (five studies); optimal foot care to prevent foot ulcer and amputation (two studies); ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to prevent diabetic end-stage renal diseases (ESRD) (15 studies); comprehensive interventions using a combination of several of the above secondary prevention interventions (two studies); and interventions treating diabetic retinopathy and foot ulcers (two studies). The classification of the interventions based on their level of CE and strength of evidence is presented in Table 2. For each intervention, we also described the number of studies that evaluated the CE of this intervention, its comparison intervention, and the study population in which the intervention was implemented. We reported the median and range of the IC-ERs across the studies. Twenty-six interventions were classified as supported by strong evidence concerning their CE (Table 2). Among these, six interventions were cost saving, eight were very cost-effective, six were costeffective, two were marginally costeffective, and four were not cost-effective. These interventions consisted of primary prevention, screening for undiagnosed type 2 diabetes, diabetic risk factor control, early prevention of diabetes complications, and treatment of diabetes complications. The six cost-saving interventions with strong evidence were 1) ACEI therapy for intensive hypertension control, as in the UK Prospective Diabetes Study (UKPDS), in persons with type 2 diabetes compared with standard hypertension control; 2) ACEI or ARB therapy to prevent ESRD for type 2 diabetes compared with no ACEI or ARB therapy; 3) early irbesartan therapy at the stage of microalbuminuria to prevent ESRD in people with type 2 diabetes compared with treatment at the stage of macroalbuminuria; 4) comprehensive foot care to prevent ulcers in mixed population with either type 1 or type 2 diabetes compared with usual care; 5) multi-component interventions for diabetic risk factor control and early detection of complications compared with conventional insulin therapy for persons with type 1 diabetes; and 6) multicomponent interventions for diabetic risk factor control and early detection of complications compared with standard glycemic control for persons with type 2 diabetes. Of the eight very cost-effective interventions with strong evidence, six were for persons with type 2 diabetes, one for persons with type 1 diabetes, and one for a mixed population with type 1 or type 2 diabetes. Interventions for type 2 diabetes included: 1) primary prevention through intensive lifestyle modification; 2) universal opportunistic screening for undiagnosed type 2 diabetes in African Americans between 45 and 54 years old; 3) intensive glycemic control as implemented in UKPDS; 4) statin therapy for secondary prevention of cardiovascular disease; 5) smoking cessation; and 6) annual screening for diabetic retinopathy and early treatment of it. The intervention for type 1 diabetes was annual screening for diabetic retinopathy and treating the positive cases. The intervention for mixed population of type 1 and type 2 diabetes was immediate vitrectomy to treat diabetic retinopathy compared with deferral of vitrectomy. The six cost-effective interventions with strong evidence were 1) one-time opportunistic targeted screening for undiagnosed type 2 diabetes in hypertensive persons aged 45 years and older compared with no screening; 2) intensive insulin treatment for persons with type 1 diabetes compared with conventional glycemic control; 3) UKPDS-like intensive glycemic control applied to the U.S. health care system among adults younger than age 54 years with type 2 diabetes compared with conventional glycemic control; 4) intensive glycemic control by a Diabetes Prevention Program (DPP) type of intensive lifestyle intervention in persons with newly diagnosed type 2 diabetes compared with conventional glycemic control; 5) statin therapy for primary prevention of cardiovascular disease in persons with type 2 diabetes compared with no statin therapy; 6) multi-component interventions including insulin therapy, ACEI therapy, and screening for retinopathy in persons with type 1 diabetes compared with intensive insulin therapy. The two marginally cost-effective interventions with strong evidence were 1) intensive glycemic control for all U.S. residents with type 2 diabetes diagnosed at age 25 years and older compared with usual care; and 2) screening for diabetic retinopathy every two years compared with screening every three years in persons with type 2 diabetes. The four interventions with strong evidence of not being cost-effective were 1) one-time universal opportunistic screening for undiagnosed type 2 diabetes among those aged 45 years and older compared with no screening; 2) universal screening for type 2 diabetes compared with targeted screening; 3) intensive glycemic control in the U.S. setting for patients diagnosed with diabetes at older ages (55-94 years of age) compared with usual care; and 4) annual screening for retinopathy compared with screening every two years. All these studies were for type 2 diabetes. There were 18 specific interventions for which their CEs were based only on "supportive" evidence. Among them, 15 were each supported by one CE study, 13 were supported by level C or level E evidence, and five were supported by level A or B evidence as defined in the 2008 ADA standards of medical care in diabetes (7). For those interventions with level A or B evidence, the CE of each intervention was evaluated by one study with a quality of being "good." In terms of the level of the CE, 10 of the 18 specific interventions based on "supportive" evidence were cost-saving, including 1) screening using the sequential method (50-g glucose challenge test followed by 100-g glucose tolerance test [GTT]) for GDM in 30-year-old pregnant women between 24 -28 weeks' gestation compared with no screening; 2) screening for GDM using the 100-g GTT method compared with no screening; 3) the sequential method compared with 75-g GTT screening for GDM; 4) 100-g GTT compared with 75-g GTT screening for GDM; 5) diabetes self-management education for persons with type 1 diabetes compared with no education; 6) fullreimbursement policy for ACEI for patients with type 1 diabetes compared with patients paying out-of-pocket; 7) fullreimbursement policy for ACEI for patients with type 2 diabetes compared with patients paying out-of-pocket; 8) screening using a mobile camera at a remote area and processing data in a reading center compared with a retina specialist's visit in a mixed population of type 1 and type 2 diabetes; 9) screening for diabetic nephropathy and ensuing ACEI or ARB therapy in persons with type 1 diabetes compared with no screening; and 10) intensified foot ulcer treatment in a mixed population with type 1 or type 2 diabetes compared with standard treatment. Seven of the 18 specific interventions were very cost-effective: 1) primary prevention of type 2 diabetes in women with GDM history through intensive lifestyle ‡, the study for within trial and the results from health plan perspective are not used for determining the cost-effectiveness of the intervention. §, get this number by taking the median for women in one study (conservative, women Ͼ men) as the results for that study, then take the median of the three study. , 50-g GTT ϩ 100-g GTT. ¶, the evidence was very weak: there was an over 40% probability that the intervention would cost more than $50,000/QALY in a long-term. intervention compared with usual care; 2) universal opportunistic screening for type 2 diabetes in African Americans aged 25-44 years compared with no screening; 3) 100-g GTT compared with the sequential screening method for detecting GDM in 30-year-old pregnant women between 24 -28 weeks' gestation; 4) diabetes self-management education for persons with type 2 diabetes compared with no education; 5) disease management programs using specialist nurse-led clinics to treat and control hypertension or hyperlipidemia in patients with type 2 diabetes in a city in England or a culturally sensitive case-management training program to control diabetes and its risk factors in a Latino population with both type 1 and type 2 diabetes in a U.S. county compared with usual care only; 6) selfmonitoring of blood glucose (SMBG) three times per day compared with no SMBG in type 2 noninsulin users; and 7) SMBG once per day compared with no SMBG in type 2 noninsulin users. One of the 18 specific interventions was costeffective, i.e., the use of metformin to prevent type 2 diabetes in obese persons with impaired glucose tolerance compared with standard lifestyle intervention. No interventions in the "supportive" evidence category were "marginally costeffective" or "not cost-effective." Current evidence is uncertain on how the CE of screening for undiagnosed type 2 diabetes would change with the age of those screened. Two studies evaluated the CE of screening for undiagnosed type 2 diabetes; one study reported that costeffectiveness ratios (CERs) increased with initial screening age (16) while the other reported that they decreased with screening age (35). CONCLUSIONS -Our systematic review showed that, with few exceptions, ADA-recommended interventions for preventing or treating diabetes and its complications were cost saving, very costeffective, or cost-effective (i.e., with an ICER of less than $50,000 per QALY or LYG), although the strength of evidence varied. Generally, interventions that cost less than $50,000 per QALY are considered an efficient use of resources and worth recommending (11). Interventions with strong evidence for being cost saving, very cost-effective, or cost-effective should be considered for implementation. Interventions with supportive evidence for being cost saving, very costeffective, or cost-effective should be adopted if extra resources are available or if similar interventions with strong evidence are unavailable or infeasible in a specific setting. The one intervention recommended by the ADA that was shown as not CE was screening for type 2 diabetes of all U.S. residents aged 45 years and older. When considering allocating resources efficiently, universal screening for undiagnosed diabetes should be undertaken with great caution. The high CE ratio for universal screening for undiagnosed type 2 diabetes was primarily attributable to the small gain in health benefit. For example, screening everyone aged 45 years and older gained only 0.003 QALY per eligible person compared with no screening. However the additional costs associated with screening and early treatments were relatively large ($564 per person). Although detecting and treating diabetes earlier can prevent future diabetes-related complications and their associated medical costs, such savings are relatively small ($57 per person). Combining the health benefit and costs would yield an ICER of more than $1 million per QALY (35). An alternative to broad screening is to focus on screening persons with additional risk factors, such as hypertension. Such targeted screening is shown to be costeffective when compared with no screening or universal screening. Intensive glycemic control for all U.S. residents with type 2 diabetes diagnosed at age 25 years and older is marginally CE. However the cost-effectiveness of this intervention varies by age at the time of the diabetes diagnosis. The intervention is cost-effective in persons diagnosed at 25-54 years of age. However, intensive glycemic control for those diagnosed with diabetes at 55 years of age and older is not cost-effective. In fact, this result is consistent with the ADA's recommendation of less stringent A1C goals for patients with limited life expectancies. The ADA recommended annual eye screening for diabetic retinopathy. This recommended intervention is very costeffective compared with no screening in persons with type 2 diabetes. If considering the efficient allocation of resources, however, screening every other year might be a better alternative. Screening annually leads to a small health benefit but results in a moderate additional cost. For example, Vijan et al. (69) showed that, compared with a 2-year screening, annual screening among persons at moderate risk (65 years old with A1C level 9%) resulted in an increase of 2-3 days of sight at a cost of $540 -690 per person. However the ADA also stated in its recommendation that "less frequent exams (every 2-3 years) may be considered following one or more normal eye exams." For the interventions with uncertain CE (including optimal age of starting screening for type 2 diabetes), following the current treatment guidelines may be the best option until more evidence on their CE is available. The CEs of 43 ADA-recommended interventions were evaluated. Of these, 25 were in the "strong" evidence category. This number would probably have been larger if we had used less stringent criteria to define evidence as being strong. For example, evidence on the CE of using metformin to prevent type 2 diabetes among high-risk individuals was considered "supportive" in our current classification even though the efficacy of the intervention was shown by wellconducted multi-center large clinical trials in different country settings (71,72), and its CE was evaluated by "excellent" CE studies (25,34). This intervention was considered to have supportive evidence because it ranked lower in the ADA recommendations (7). Among all the interventions considered, evidence for the CE of primary prevention through intensive lifestyle modification was the strongest regarding the quantity and quality of the CE studies and efficacy data. Several well-conducted clinical trials have shown the efficacy of intensive lifestyle modification in preventing diabetes in different country settings, such as the U.S. DPP (71), Finnish Diabetes Prevention Study (73), China Da Qing Diabetes Prevention Study (74), and Indian DPP (72). Eight cost-effectiveness studies (seven of them rated as excellent quality) have been conducted by different groups in different countries based on data from these well-conducted clinical trials (15,25,34,36,41,50,59,66). The results from these studies consistently showed that intensive lifestyle modification in persons with impaired glucose tolerance was cost saving or very cost-effective in the long run (15,25,34,36,41,50,59). Even in a shortterm and one-on-one consulting setting, the intervention remained cost-effective (66). The intervention would be more cost-effective than existing studies show if the cost of the lifestyle intervention could be reduced. This might be achieved by changing the setting in which the inter- # Cost-effectiveness of diabetes interventions vention is provided. Only one study found a DPP-like intervention to be marginally cost-effective (25). Even in this study, however, the intervention would have been very cost-effective (23) if done in the type of group environment that is most likely in a real-world setting. A group-based, DPP-style lifestyle intervention partnership with the YMCA costs $275 to $325 per participant in the first year compared with $1,400 in the oneon-one setting of the DPP trial (75). Preventing diabetes, in particular by lifestyle modification, is not only effective but also a very efficient use of health care resources. The CE of an intervention can vary by country setting. For example, intensive glycemic control (with a goal A1C level of 7%) in type 2 diabetic patients diagnosed at 25 years of age and older was marginally cost-effective in the U.S. but very cost-effective in other developed countries. Although the efficacy data of all studies of intensive glycemic control in type 2 diabetic patients were based on the same UKPDS data, the cost data were based on how residents of the different countries used health services and the cost of those services. The incremental cost of intensive glycemic control was much higher in the U.S. than in the U.K. because of different practice patterns. Patients outside the U.S. did not receive diabetes disease management services and had less frequent self-testing and physician office visits than their U.S. counterparts at the time these studies were conducted. If using the health services as described in the UKPDS setting but with the U.S. cost of these services, the CE of the intensive glycemic control in the U.S. would resemble that of other developed countries. Future economic evaluation of diabetes interventions should consider the following. First, more studies are needed to evaluate the CE of interventions that fell in the "supportive" evidence category. For studies with weaker efficacy data, further efficacy studies are needed. Second, there are also 38 interventions recommended by the ADA but they have not been evaluated for their CE or the studies did not meet the inclusion criteria for our review (list is available upon request from the authors). The CE of these interventions should be assessed. Third, more CE studies are needed that address interventions in real-world settings. For example, few studies considered attrition rate, noncompliance, and dropout rates in evaluat-ing CE. Fourth, more studies are needed to evaluate the CE of public policy changes. Only two studies evaluated public insurance reimbursement of ACEI therapy and both found this intervention to be cost saving. Finally, the CE of multiple interventions needs to be evaluated. In most real-world settings, patients receive multiple interventions simultaneously. Nearly all previous studies only evaluated the CE of a single intervention. This review's conclusions should be used with caution. First, our conclusions are based on available information up to May 2008. More studies have been published since then. In addition, data on both the effectiveness and cost of an intervention could have changed since the time the original study was conducted. Using the newly available data could change our current conclusion. For example, in our review, we concluded that the CE of optimal age to start screening for type 2 diabetes was uncertain. A recently published CE study on age at initiation of screening for type 2 diabetes, released after our analysis was complete, might change that conclusion (76). Another example is the large decrease in costs for metformin, statins, and ACEIs. Studies that evaluate CE using current costs might look more favorably on interventions that include statins and ACEIs than those reported here. Reevaluating the costs and benefits of these interventions, using current-day costs, is beyond the scope of this study. Second, when using the results and conclusions of our review, readers need to be certain that terms are understood correctly. For example, "intensive insulin treatment" in our review meant "multiple insulin injection" or "insulin infusion." Developments in medical technology might make continuous glucose monitoring systems, which record blood glucose levels throughout the day and night, more common. Drugs such as TZD Byetta and Gliptin, not available at the time covered by this review, are increasingly used to achieve intensive glycemic control. The CE of treatment with these and other new devices and drugs are unknown. New CE analyses are needed for these new interventions. Third, not everyone will necessarily agree with our classification criteria. Different classification criteria might have changed some conclusions. Fourth, most of the CE studies are based on simulation modeling. Although good-quality simulation modeling can provide information at a much lower cost than clinical trials, models are based on assumptions and represent a simplification of-and therefore might depart from-reality. Fifth, these CE studies use different methods, which could account for some differences in CERs. If the results from different models were consistent, we would have more confidence in the conclusion on the CE of the intervention. Sixth, we used the same threshold for the classification of the CE of interventions regardless of whether the ICERs were expressed as dollars per LYG or dollars per QALY, although they are different measures. The studies that reported costs per LYG did not incorporate the impact of the intervention on quality of life into the analysis. If they did, the cost per QALY could be higher, lower, or the same depending on the relative magnitude of the health benefit of the intervention on quality of life. Seventh, the interpretation of the CE of an intervention must include consideration of variables such as study population, comparison interventions, and country setting. Lastly, our recommendations are based on the CE of the interventions and not their efficacy; therefore, these recommendations are not necessarily the same as the ADA recommendations. The importance of CE in decision making should not be overstated. CE is only one aspect to consider. CE analysis does not address the distribution of costs and the benefits of an intervention, societal or personal willingness to pay, social and legal aspects, or ethical issues associated with each intervention. All these aspects are important in formulating public policy. The good news is that our study shows that a majority of the recommended diabetes interventions provide both health benefits and good use of health care resources. # Acknowledgments -T h e a u t h o r s c o nducted this project as part of their jobs as employees of the Centers for Disease Control and Prevention (CDC). The CDC is a federal agency in the U.S. government. The authors have no financial interest in this project. Parts of this study were presented at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5-9 June 2009, and at the Division of Diabetes Translation 2007 Annual Conference, Atlanta, Georgia, April 30 -May 3, 2007. We thank Drs. Sue Kirkman, Richard Khan, William H. Herman, John Anderson, Susan Braithwaite, Dan Lorber, and Vivian Fonseca for reviewing the earlier version of this manuscript and providing valuable comments. We also thank Elizabeth Lee Greene for her invaluable editorial assistance.	None	None
b1ed055483bb371adbbea210fff3ce03bd4747f6	cdc	None	depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Because of the high morbidity and mortality associated with health-care-associated pneumonia, several guidelines for its prevention and control have been published. The first CDC Guideline for Prevention of Nosocomial Pneumonia was published in 1981 and addressed the main infection-control problems related to hospital-acquired pneumonia at the time: the use of large-volume nebulizers that were attached to mechanical ventilators and improper reprocessing (i.e., cleaning and disinfection or sterilization) of respiratory-care equipment. The document also covered the prevention and control of hospital-acquired influenza and respiratory syncytial virus (RSV) infection. In 1994, the Healthcare Infection Control Practices Advisory Committee (HICPAC) (then known as the Hospital Infection Control Practices Advisory Committee) revised and expanded the CDC Guideline for Prevention of Nosocomial Pneumonia to include Legionnaires disease and pulmonary aspergillosis (1). HICPAC advises the secretary of Health and Human Services and the directors of CDC about the prevention and control of health-care-associated infections and related adverse events. The 1994 guideline addressed concerns related to preventing ventilator-associated pneumonia (VAP) (e.g., the role of stress-ulcer prophylaxis in the causation of pneumonia and the contentious roles of selective gastrointestinal decontamination and periodic changes of ventilator tubings in the prevention of the infection). The report also presented major changes in the recommendations to prevent and control hospital-acquired pneumonia caused by Legionnella spp. and aspergilli. In recent years, demand has increased for guidance on preventing and controlling pneumonia and other lower respiratory tract infections in health-care settings other than the acute-care hospital, probably resulting in part from the progressive shift in the burden and focus of health care in the United States away from inpatient care in the acute-care hospital and towards outpatient and long-term care in other health-care settings. In response to this demand, HICPAC revised the guideline to cover these other settings. However, infection-control data about the acute-care hospital setting are more abundant and well-analyzed; in comparison, data are limited from long-term care, ambulatory, and psychiatric facilities and other health-care settings. This report consists of Parts II and III of a three-part document (2) and contains the consensus HICPAC recommendations for the prevention of the following infections: bacterial pneumonia, Legionnaires disease, pertussis, invasive pulmonary aspergillosis (IPA), lower respiratory tract infections caused by RSV, parainfluenza and adenoviruses, and influenza. Part III provides suggested performance indicators to assist infection-control personnel in monitoring the implementation of the guideline recommendations in their facilities. Part I of the guideline provides the background for the recommendations and includes a discussion of the epidemiology, diagnosis, pathogenesis, modes of transmission, and prevention and control of the infections (3). Part I can be an important resource for educating health-care personnel. Because education of health-care personnel is the cornerstone of an effective infection-control program, health-care agencies should give high priority to continuing infection-control education programs for their staff members. HICPAC recommendations address such issues as education of health-care personnel about the prevention and control of health-care-associated pneumonia and other lower respiratory tract infections, surveillance and reporting of diagnosed cases of infections, prevention of person-to-person transmission of each disease, and reduction of host risk for infection. Lower respiratory tract infection caused by Mycobacterium tuberculosis is not addressed in this document; however, it is covered in a separate publication (3). The document was prepared by CDC; reviewed by experts in infection control, intensive-care medicine, pulmonology, respiratory therapy, anesthesiology, internal medicine, and pediatrics; and approved by HICPAC. The recommendations are endorsed by the American College of Chest Physicians, American Healthcare Association, Association for Professionals of Infection Control and Epidemiology, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, and Society of Critical Care Medicine. # Key Terms Used In the Guideline Protective environment (PE) is a specialized patient-care area, usually in a hospital, with a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of high-efficiency particulate air (HEPA) filtration, high numbers (>12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients who have received allogeneic hemopoietic stem-cell transplant (HSCT). Immunocompromised patients are those patients whose immune mechanisms are deficient because of immunologic disorders (e.g., human immunodeficiency virus infection, congenital immune deficiency syndrome, and chronic diseases ), or immunosuppressive therapy (e.g., radiation, cytotoxic chemotherapy, anti-rejection medication, and steroids). Immunocompromised patients who are identified as patients at high risk have the greatest risk for infection and include persons with severe neutropenia (i.e., an absolute neutrophil count of <500 cells/mL) for prolonged periods of time, recipients of allogeneic HSCT, and those who receive the most intensive chemotherapy (e.g., patients with childhood acute myelogenous leukemia). # Abbreviations Used In the Guideline ACIP # Categorization of Recommendations In this document, each recommendation is categorized on the basis of existing scientific evidence, theoretical rationale, applicability, and potential economic impact. In addition, a new category accommodates recommendations that are made on the basis of existing national or state health regulations. The following categorization scheme is applied in this guideline: Category IA. Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. Category IB. Strongly recommended for implementation and supported by certain clinical or epidemiologic studies and by strong theoretical rationale. Category IC. Required for implementation, as mandated by federal or state regulation or standard. Category II. Suggested for implementation and supported by suggestive clinical or epidemiologic studies or by strong theoretical rationale. No recommendation; unresolved issue. Practices for which insufficient evidence or no consensus exists about efficacy. # Prevention of Health-Care-Associated Bacterial Pneumonia # I. Staff Education and Involvement in Infection Prevention Educate health-care workers about the epidemiology of, and infection-control procedures for, preventing healthcare-associated bacterial pneumonia to ensure worker competency according to the worker's level of responsibility in the health-care setting, and involve the workers in the implementation of interventions to prevent healthcare-associated pneumonia by using performanceimprovement tools and techniques (IA) (4-11). # II. Infection and Microbiologic Surveillance A. Conduct surveillance for bacterial pneumonia in intensive care unit (ICU) patients who are at high risk for health-care-related bacterial pneumonia (e.g., patients with mechanically assisted ventilation or selected postoperative patients) to determine trends and help identify outbreaks and other potential infection-control problems (12,13). The use of the new National Nosocomial Infection Surveillance (NNIS) system's surveillance definition of pneumonia is recommended (14). Include data on the causative microorganisms and their antimicrobial susceptibility patterns (15). Express data as rates (e.g., number of infected patients or infections per 100 ICU days or per 1,000 ventilator days) to facilitate intrahospital comparisons and trend determination (12,16,17). Link monitored rates and prevention efforts and return data to appropriate health-care personnel (IB) (18). B. In the absence of specific clinical, epidemiologic, or infection-control objectives, do not routinely perform surveillance cultures of patients or of equipment or devices used for respiratory therapy, pulmonaryfunction testing, or delivery of inhalation anesthesia (II) (19)(20)(21)(22). # III. Prevention of Transmission of Microorganisms # Prevention and Control of Health-Care-Associated Influenza # I. Staff Education Provide health-care personnel continuing education or access to continuing education about the epidemiology, modes of transmission, diagnosis, and means of preventing the spread of influenza, in accordance with their level of responsibility in preventing health-care-associated influenza (II) (109,(387)(388)(389). # II. Surveillance A. Establish mechanisms by which facility personnel are promptly alerted about increased influenza activity in the community (II). B. Establish protocols for intensifying efforts to promptly diagnose cases of facility-acquired influenza 1. Determine the threshold incidence or prevalence of influenza or influenza-like illness in the facility at which laboratory testing of patients with influenza-like illness is to be undertaken and outbreak control measures are to be initiated (II) (390). 2. Arrange for laboratory tests to be available to clinicians for prompt diagnosis of influenza, especially during November-April (II) (391)(392)(393)(394). # III. Modifying Host Risk for Infection # Severe Acute Respiratory Syndrome Updated information about prevention and control of severe acute respiratory syndrome in health-care facilities is available in a separate publication (433). # Part III: Performance Indicators To assist infection-control personnel in assessing personnel adherence to the recommendations, the following performance measures are suggested: 1. Monitor rates of VAP; can use established benchmarks and definitions of pneumonia (e.g., NNIS definitions and rates) (14). Provide feedback to the staff about the facility's VAP rates and reminders about the need for personnel to adhere to infection-control practices that reduce the incidence of VAP. 2. Establish a SOP for influenza vaccination and monitor the percentage of eligible patients in acute-care settings or patients or residents in long-term-care settings who receive the vaccine. 3. Before and during the influenza season, monitor and record the number of eligible health-care personnel who receive the influenza vaccine and determine the desired unit-and facility-specific vaccination rates as recommended by ACIP. 4. Monitor the number of cases of health-care-associated RSV infections by geographic location within the facility and give prompt feedback to appropriate staff members to improve adherence to recommended infectioncontrol precautions. 5. Periodically review clinicians' use of laboratory diagnostic tests (both culture of appropriate respiratory specimen and the urine antigen test) for legionellosis, especially in patients who are at high risk for acquiring the disease (e.g., patients who are immunosuppressed, including recipients of HSCT or solid-organ transplant, or patients receiving systemic steroids; patients aged >65 years; or patients who have chronic underlying disease such as diabetes mellitus, congestive heart failure, and COPD). Provide feedback on the use of these tests to clinicians. 6. During construction or renovation activities in the facility, monitor personnel adherence to infection-control measures (e.g., use of barriers, maintenance of negative room pressure) that are aimed at minimizing dust dispersion in patient-care areas. Review all cases of healthcare-associated aspergillosis to determine the presence of remediable environmental risks. 7. Periodically monitor the frequency of diagnostic testing for pertussis and the time interval between suspicion of the infection and initiation of isolation precautions for patients in whom pertussis is suspected. know what matters.	depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Because of the high morbidity and mortality associated with health-care-associated pneumonia, several guidelines for its prevention and control have been published. The first CDC Guideline for Prevention of Nosocomial Pneumonia was published in 1981 and addressed the main infection-control problems related to hospital-acquired pneumonia at the time: the use of large-volume nebulizers that were attached to mechanical ventilators and improper reprocessing (i.e., cleaning and disinfection or sterilization) of respiratory-care equipment. The document also covered the prevention and control of hospital-acquired influenza and respiratory syncytial virus (RSV) infection. In 1994, the Healthcare Infection Control Practices Advisory Committee (HICPAC) (then known as the Hospital Infection Control Practices Advisory Committee) revised and expanded the CDC Guideline for Prevention of Nosocomial Pneumonia to include Legionnaires disease and pulmonary aspergillosis (1). HICPAC advises the secretary of Health and Human Services and the directors of CDC about the prevention and control of health-care-associated infections and related adverse events. The 1994 guideline addressed concerns related to preventing ventilator-associated pneumonia (VAP) (e.g., the role of stress-ulcer prophylaxis in the causation of pneumonia and the contentious roles of selective gastrointestinal decontamination and periodic changes of ventilator tubings in the prevention of the infection). The report also presented major changes in the recommendations to prevent and control hospital-acquired pneumonia caused by Legionnella spp. and aspergilli. In recent years, demand has increased for guidance on preventing and controlling pneumonia and other lower respiratory tract infections in health-care settings other than the acute-care hospital, probably resulting in part from the progressive shift in the burden and focus of health care in the United States away from inpatient care in the acute-care hospital and towards outpatient and long-term care in other health-care settings. In response to this demand, HICPAC revised the guideline to cover these other settings. However, infection-control data about the acute-care hospital setting are more abundant and well-analyzed; in comparison, data are limited from long-term care, ambulatory, and psychiatric facilities and other health-care settings. This report consists of Parts II and III of a three-part document (2) and contains the consensus HICPAC recommendations for the prevention of the following infections: bacterial pneumonia, Legionnaires disease, pertussis, invasive pulmonary aspergillosis (IPA), lower respiratory tract infections caused by RSV, parainfluenza and adenoviruses, and influenza. Part III provides suggested performance indicators to assist infection-control personnel in monitoring the implementation of the guideline recommendations in their facilities. Part I of the guideline provides the background for the recommendations and includes a discussion of the epidemiology, diagnosis, pathogenesis, modes of transmission, and prevention and control of the infections (3). Part I can be an important resource for educating health-care personnel. Because education of health-care personnel is the cornerstone of an effective infection-control program, health-care agencies should give high priority to continuing infection-control education programs for their staff members. HICPAC recommendations address such issues as education of health-care personnel about the prevention and control of health-care-associated pneumonia and other lower respiratory tract infections, surveillance and reporting of diagnosed cases of infections, prevention of person-to-person transmission of each disease, and reduction of host risk for infection. Lower respiratory tract infection caused by Mycobacterium tuberculosis is not addressed in this document; however, it is covered in a separate publication (3). The document was prepared by CDC; reviewed by experts in infection control, intensive-care medicine, pulmonology, respiratory therapy, anesthesiology, internal medicine, and pediatrics; and approved by HICPAC. The recommendations are endorsed by the American College of Chest Physicians, American Healthcare Association, Association for Professionals of Infection Control and Epidemiology, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, and Society of Critical Care Medicine. # Key Terms Used In the Guideline Protective environment (PE) is a specialized patient-care area, usually in a hospital, with a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of high-efficiency particulate air (HEPA) filtration, high numbers (>12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients who have received allogeneic hemopoietic stem-cell transplant (HSCT). Immunocompromised patients are those patients whose immune mechanisms are deficient because of immunologic disorders (e.g., human immunodeficiency virus [HIV] infection, congenital immune deficiency syndrome, and chronic diseases [(diabetes mellitus, cancer, emphysema, or cardiac failure]), or immunosuppressive therapy (e.g., radiation, cytotoxic chemotherapy, anti-rejection medication, and steroids). Immunocompromised patients who are identified as patients at high risk have the greatest risk for infection and include persons with severe neutropenia (i.e., an absolute neutrophil count [ANC] of <500 cells/mL) for prolonged periods of time, recipients of allogeneic HSCT, and those who receive the most intensive chemotherapy (e.g., patients with childhood acute myelogenous leukemia). # Abbreviations Used In the Guideline ACIP # Categorization of Recommendations In this document, each recommendation is categorized on the basis of existing scientific evidence, theoretical rationale, applicability, and potential economic impact. In addition, a new category accommodates recommendations that are made on the basis of existing national or state health regulations. The following categorization scheme is applied in this guideline: Category IA. Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. Category IB. Strongly recommended for implementation and supported by certain clinical or epidemiologic studies and by strong theoretical rationale. Category IC. Required for implementation, as mandated by federal or state regulation or standard. Category II. Suggested for implementation and supported by suggestive clinical or epidemiologic studies or by strong theoretical rationale. No recommendation; unresolved issue. Practices for which insufficient evidence or no consensus exists about efficacy. # Prevention of Health-Care-Associated Bacterial Pneumonia # I. Staff Education and Involvement in Infection Prevention Educate health-care workers about the epidemiology of, and infection-control procedures for, preventing healthcare-associated bacterial pneumonia to ensure worker competency according to the worker's level of responsibility in the health-care setting, and involve the workers in the implementation of interventions to prevent healthcare-associated pneumonia by using performanceimprovement tools and techniques (IA) (4-11). # II. Infection and Microbiologic Surveillance A. Conduct surveillance for bacterial pneumonia in intensive care unit (ICU) patients who are at high risk for health-care-related bacterial pneumonia (e.g., patients with mechanically assisted ventilation or selected postoperative patients) to determine trends and help identify outbreaks and other potential infection-control problems (12,13). The use of the new National Nosocomial Infection Surveillance (NNIS) system's surveillance definition of pneumonia is recommended (14). Include data on the causative microorganisms and their antimicrobial susceptibility patterns (15). Express data as rates (e.g., number of infected patients or infections per 100 ICU days or per 1,000 ventilator days) to facilitate intrahospital comparisons and trend determination (12,16,17). Link monitored rates and prevention efforts and return data to appropriate health-care personnel (IB) (18). B. In the absence of specific clinical, epidemiologic, or infection-control objectives, do not routinely perform surveillance cultures of patients or of equipment or devices used for respiratory therapy, pulmonaryfunction testing, or delivery of inhalation anesthesia (II) (19)(20)(21)(22). # III. Prevention of Transmission of Microorganisms # Prevention and Control of Health-Care-Associated Influenza # I. Staff Education Provide health-care personnel continuing education or access to continuing education about the epidemiology, modes of transmission, diagnosis, and means of preventing the spread of influenza, in accordance with their level of responsibility in preventing health-care-associated influenza (II) (109,(387)(388)(389). # II. Surveillance A. Establish mechanisms by which facility personnel are promptly alerted about increased influenza activity in the community (II). B. Establish protocols for intensifying efforts to promptly diagnose cases of facility-acquired influenza 1. Determine the threshold incidence or prevalence of influenza or influenza-like illness in the facility at which laboratory testing of patients with influenza-like illness is to be undertaken and outbreak control measures are to be initiated (II) (390). 2. Arrange for laboratory tests to be available to clinicians for prompt diagnosis of influenza, especially during November-April (II) (391)(392)(393)(394). # III. Modifying Host Risk for Infection # Severe Acute Respiratory Syndrome Updated information about prevention and control of severe acute respiratory syndrome in health-care facilities is available in a separate publication (433). # Part III: Performance Indicators To assist infection-control personnel in assessing personnel adherence to the recommendations, the following performance measures are suggested: 1. Monitor rates of VAP; can use established benchmarks and definitions of pneumonia (e.g., NNIS definitions and rates) (14). Provide feedback to the staff about the facility's VAP rates and reminders about the need for personnel to adhere to infection-control practices that reduce the incidence of VAP. 2. Establish a SOP for influenza vaccination and monitor the percentage of eligible patients in acute-care settings or patients or residents in long-term-care settings who receive the vaccine. 3. Before and during the influenza season, monitor and record the number of eligible health-care personnel who receive the influenza vaccine and determine the desired unit-and facility-specific vaccination rates as recommended by ACIP. 4. Monitor the number of cases of health-care-associated RSV infections by geographic location within the facility and give prompt feedback to appropriate staff members to improve adherence to recommended infectioncontrol precautions. 5. Periodically review clinicians' use of laboratory diagnostic tests (both culture of appropriate respiratory specimen and the urine antigen test) for legionellosis, especially in patients who are at high risk for acquiring the disease (e.g., patients who are immunosuppressed, including recipients of HSCT or solid-organ transplant, or patients receiving systemic steroids; patients aged >65 years; or patients who have chronic underlying disease such as diabetes mellitus, congestive heart failure, and COPD). Provide feedback on the use of these tests to clinicians. 6. During construction or renovation activities in the facility, monitor personnel adherence to infection-control measures (e.g., use of barriers, maintenance of negative room pressure) that are aimed at minimizing dust dispersion in patient-care areas. Review all cases of healthcare-associated aspergillosis to determine the presence of remediable environmental risks. 7. Periodically monitor the frequency of diagnostic testing for pertussis and the time interval between suspicion of the infection and initiation of isolation precautions for patients in whom pertussis is suspected. know what matters.	None	None
14197c4721fe2f39376f7103980bc8604a424cf2	cdc	None	On October 16, 2009, the Food and Drug Administration licensed quadrivalent human papillomavirus vaccine (HPV4; Gardasil, Merck & Co. Inc.) for use in males aged 9 through 26 years for prevention of genital warts caused by human papillomavirus (HPV) types 6 and 11. HPV4 had been licensed previously for use in females aged 9 through 26 years for prevention of HPV 6, 11, 16, and 18-related outcomes (i.e., vaginal, vulvar, and cervical precancers and cancers and genital warts). The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years (1). On October 21, 2009, ACIP provided guidance that HPV4 may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts; ACIP does not recommend HPV4 for routine use among males. This report presents the ACIP policy statement and summarizes background data. Issues reviewed by ACIP included efficacy, immunogenicity, and safety of the HPV4 vaccine in males, epidemiology of HPV and burden of HPV-associated diseases and cancers in males, costeffectiveness of male vaccination, and programmatic considerations.# HPV types 6 and 11 cause approximately 90% of genital warts and most cases of recurrent respiratory papillomatosis. Approximately 500,000 cases of genital warts are estimated to occur each year in the United States among sexually active men and women (2,3). Direct medical costs related to genital warts are estimated at $200 million per year (2,3); in addition, genital warts can have an adverse impact on quality of life (4). HPV-associated cancers in males include certain anal, penile, and oropharyngeal and oral cavity cancers caused primarily by HPV 16. HPV4 has high efficacy for prevention of genital warts. The phase III efficacy study enrolled 4,065 males aged 16 through 26 years. Participants were enrolled from North America, South America, Europe, Australia, and Asia. The efficacy for prevention of genital warts related to HPV types 6, 11, 16, or 18 among males who received all 3 vaccine doses and were seronegative at day 1, and DNA negative day 1 through month 7 to the respective HPV type (per protocol population) was 89.4%; the efficacy for HPV 6 or 11-related genital warts alone was approximately the same (Table) (5). The efficacy for prevention of HPV 6, 11, 16, or 18-related genital warts among males who received at least 1 vaccine dose and regardless of baseline DNA or serology (intent to treat population), was 67.2%, and the efficacy for prevention of genital warts related to any HPV type was 62.1% (Table) (5). No evidence of efficacy was observed among males who were infected with the respective HPV type at baseline. The median duration of follow-up at the time of the study's interim analysis was approximately 2.3 years. Data on immunogenicity in males are available from the phase III trial conducted among males aged 16 through 26 years, and from bridging immunogenicity studies conducted among males aged 9 through 15 years (5). Seroconversion rates were high for all four HPV types (HPV 6, 11, 16, or 18) targeted by HPV4, and postvaccination antibody titers were significantly higher in males aged 9 through 15 years compared with males aged 16 through 26 years (5). As observed previously with females, in the clinical trials for males, the most common adverse events were injection-site reactions, most of which were mild or moderate in intensity (5). Headache and fever were the most commonly reported systemic adverse reactions in both treatment groups (5). Postlicensure data in females indicate that HPV4 adverse events are similar to adverse events reported following administration of other vaccines to adolescents (6). Mathematical modeling suggests that adding male HPV vaccination to a female-only HPV vaccination program is not the most cost-effective vaccination strategy for reducing the overall burden of HPV-associated conditions in males and females when vaccination coverage of females is high (>80%) (7). When coverage of females is less than 80%, male vaccination might be cost-effective, although results vary substantially across models (7). Because the health burden is greater in females than males, and numerous models have shown vaccination of adolescent girls to be a cost-effective use of public health resources, improving coverage in females aged 11 and 12 years could potentially be a more effective and cost-effective strategy than adding male vaccination. Men who have sex with men (MSM) are particularly at risk for conditions associated with HPV types 6, 11, 16, and 18; diseases and cancers that have a higher incidence among MSM include anal intraepithelial neoplasias, anal cancers, and genital warts (8,9). HPV4 has high efficacy for prevention of anal intraepithelial neoplasias in MSM ( 10); however, this information was not available before the October 2009 ACIP meeting and has not yet been reviewed by FDA. # Vaccine Guidance The 3-dose series of HPV4 may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. HPV4 would be most effective when given before exposure to HPV through sexual contact. # Administration, Special Situations, Precautions, and Contraindications HPV4 is administered in a 3-dose schedule. The second dose is administered 1 to 2 months after the first dose, and the third dose is administered 6 months after the first dose. The minimum interval between the first and second dose of vaccine is 4 weeks, and the minimum interval between the second and third dose is 12 weeks. The minimum interval between the first and third dose is 24 weeks. Doses received after a dosing interval that is shorter than recommended should be readministered. If the HPV vaccine schedule is interrupted, the vaccine series does not need to be restarted. Coadministration of a different inactivated or live vaccine, either simultaneously or at any time before or after HPV4 is permitted because HPV4 is not a live vaccine. HPV4 can be administered to persons who are immunosuppressed (from disease or medications). However, the immune response and vaccine efficacy might be less than that in immunocompetent persons. Syncope can occur after vaccination and has been observed among adolescents and young adults. To avoid serious injury related to a syncopal episode, vaccine providers should consider observing patients for 15 minutes after they are vaccinated. HPV4 is contraindicated for persons with a history of immediate hypersensitivity to any vaccine component. HPV4 is a recombinant vaccine produced in Saccharomyces cerevisiae (baker's yeast) and is contraindicated for persons with a history of immediate hypersensitivity to yeast.	On October 16, 2009, the Food and Drug Administration licensed quadrivalent human papillomavirus vaccine (HPV4; Gardasil, Merck & Co. Inc.) for use in males aged 9 through 26 years for prevention of genital warts caused by human papillomavirus (HPV) types 6 and 11. HPV4 had been licensed previously for use in females aged 9 through 26 years for prevention of HPV 6, 11, 16, and 18-related outcomes (i.e., vaginal, vulvar, and cervical precancers and cancers and genital warts). The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years (1). On October 21, 2009, ACIP provided guidance that HPV4 may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts; ACIP does not recommend HPV4 for routine use among males. This report presents the ACIP policy statement and summarizes background data. Issues reviewed by ACIP included efficacy, immunogenicity, and safety of the HPV4 vaccine in males, epidemiology of HPV and burden of HPV-associated diseases and cancers in males, costeffectiveness of male vaccination, and programmatic considerations.# HPV types 6 and 11 cause approximately 90% of genital warts and most cases of recurrent respiratory papillomatosis. Approximately 500,000 cases of genital warts are estimated to occur each year in the United States among sexually active men and women (2,3). Direct medical costs related to genital warts are estimated at $200 million per year (2,3); in addition, genital warts can have an adverse impact on quality of life (4). HPV-associated cancers in males include certain anal, penile, and oropharyngeal and oral cavity cancers caused primarily by HPV 16. HPV4 has high efficacy for prevention of genital warts. The phase III efficacy study enrolled 4,065 males aged 16 through 26 years. Participants were enrolled from North America, South America, Europe, Australia, and Asia. The efficacy for prevention of genital warts related to HPV types 6, 11, 16, or 18 among males who received all 3 vaccine doses and were seronegative at day 1, and DNA negative day 1 through month 7 to the respective HPV type (per protocol population) was 89.4%; the efficacy for HPV 6 or 11-related genital warts alone was approximately the same (Table) (5). The efficacy for prevention of HPV 6, 11, 16, or 18-related genital warts among males who received at least 1 vaccine dose and regardless of baseline DNA or serology (intent to treat population), was 67.2%, and the efficacy for prevention of genital warts related to any HPV type was 62.1% (Table) (5). No evidence of efficacy was observed among males who were infected with the respective HPV type at baseline. The median duration of follow-up at the time of the study's interim analysis was approximately 2.3 years. Data on immunogenicity in males are available from the phase III trial conducted among males aged 16 through 26 years, and from bridging immunogenicity studies conducted among males aged 9 through 15 years (5). Seroconversion rates were high for all four HPV types (HPV 6, 11, 16, or 18) targeted by HPV4, and postvaccination antibody titers were significantly higher in males aged 9 through 15 years compared with males aged 16 through 26 years (5). As observed previously with females, in the clinical trials for males, the most common adverse events were injection-site reactions, most of which were mild or moderate in intensity (5). Headache and fever were the most commonly reported systemic adverse reactions in both treatment groups (5). Postlicensure data in females indicate that HPV4 adverse events are similar to adverse events reported following administration of other vaccines to adolescents (6). Mathematical modeling suggests that adding male HPV vaccination to a female-only HPV vaccination program is not the most cost-effective vaccination strategy for reducing the overall burden of HPV-associated conditions in males and females when vaccination coverage of females is high (>80%) (7). When coverage of females is less than 80%, male vaccination might be cost-effective, although results vary substantially across models (7). Because the health burden is greater in females than males, and numerous models have shown vaccination of adolescent girls to be a cost-effective use of public health resources, improving coverage in females aged 11 and 12 years could potentially be a more effective and cost-effective strategy than adding male vaccination. Men who have sex with men (MSM) are particularly at risk for conditions associated with HPV types 6, 11, 16, and 18; diseases and cancers that have a higher incidence among MSM include anal intraepithelial neoplasias, anal cancers, and genital warts (8,9). HPV4 has high efficacy for prevention of anal intraepithelial neoplasias in MSM ( 10); however, this information was not available before the October 2009 ACIP meeting and has not yet been reviewed by FDA. # Vaccine Guidance The 3-dose series of HPV4 may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. HPV4 would be most effective when given before exposure to HPV through sexual contact. # Administration, Special Situations, Precautions, and Contraindications HPV4 is administered in a 3-dose schedule. The second dose is administered 1 to 2 months after the first dose, and the third dose is administered 6 months after the first dose. The minimum interval between the first and second dose of vaccine is 4 weeks, and the minimum interval between the second and third dose is 12 weeks. The minimum interval between the first and third dose is 24 weeks. Doses received after a dosing interval that is shorter than recommended should be readministered. If the HPV vaccine schedule is interrupted, the vaccine series does not need to be restarted. Coadministration of a different inactivated or live vaccine, either simultaneously or at any time before or after HPV4 is permitted because HPV4 is not a live vaccine. HPV4 can be administered to persons who are immunosuppressed (from disease or medications). However, the immune response and vaccine efficacy might be less than that in immunocompetent persons. Syncope can occur after vaccination and has been observed among adolescents and young adults. To avoid serious injury related to a syncopal episode, vaccine providers should consider observing patients for 15 minutes after they are vaccinated. HPV4 is contraindicated for persons with a history of immediate hypersensitivity to any vaccine component. HPV4 is a recombinant vaccine produced in Saccharomyces cerevisiae (baker's yeast) and is contraindicated for persons with a history of immediate hypersensitivity to yeast.	None	None
0b7cbdb66da327f32576cb950aee5d1e9286e059	cdc	None	Spina bifida and anencephaly are common and serious birth defects. Avail able evidence indicates that 0.4 mg (400 \y.g) per day of folic acid, one of the B vitamins, will reduce the number of cases of neural tube defects (NTDs). In order to reduce the frequency of NTDs and their resulting disability, the United States Public Health Service- recommends that: All women of childbearing age in the United States who are capable of becoming pregnant should consume 0.4 mg of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs. Because the effects of higher intakes are not well known but include complicating the diagnosis of vitamin B12 deficiency, care should be taken to keep total folate consumption at <1 mg per day, except under the supervision of a physician. Women who have had a prior NTD-affected pregnancy are at high risk of having a subsequent affected pregnancy. When these women are planning to become pregnant, they should consult their physicians for advice.# INTRODUCTION Each year in the United States about 2,500 infants are born with the neural tube defects (NTDs) spina bifida and anencephaly. In addition, an unknown number of fetuses affected by these birth defects are aborted. All infants with anencephaly die shortly after birth, whereas the majority of babies born with spina bifida grow to adulthood with, in severe cases, paralysis and varying degrees of bowel and bladder incontinence. The evidence that consumption of folic acid, one of the B vitamins, before conception and during early pregnancy (the periconceptional period) can reduce the number of NTDs has been accumulating for several years. Published data are available from randomized controlled trials (1,2), nonrandomized intervention trials (3,4), and observational studies (5-8) (Tables 1 and 2, Figure 1). One of the most rigorously conducted studies was the randomized controlled trial sponsored by the British Medical Research Council (MRC) (2). The study showed that high-dose folic acid supplements (4.0 mg per day) used by women who had a prior NTD-affected pregnancy reduced the risk of having a subsequent NTD-affected pregnancy by 70%. Preliminary results from the Hungarian randomized controlled trial of multivitamin/mineral supplementation (including 0.8 mg of folic acid) among women who had not had a prior NTD-affected pregnancy were reported in 1989 (9). This trial was stopped in May 1992 on the advice of an ad hoc scientific advisory committee because of evidence of an NTD-protective effect of the multivitamin/mineral prepa ration relative to the study placebo preparation (Czeizel AE: personal communication, May 1992). Three of four published observational studies showed a lowered risk of NTDs for women who have not had a prior NTD-affected pregnancy and who consumed 0.4-0.8 mg (400-800 \|xg) of folic acid daily from multivitamin supplements (Tables 1 and 2, Figure 1). In summary, the data available indicate that folic acid can help avert NTDs when given at high-dose levels (i.e., 4.0 mg per day). The results of the British MRC study showed that the addition of other vitamins to 4.0 mg of folic acid confers no extra benefit in averting NTDs. Based on a synthesis of information from several studies, including those which used multivitamins containing folic acid at a daily dose level of s=0.4 mg, it was inferred that folic acid alone at levels of 0.4 mg per day will reduce the risk of NTDs. The protective effect found in the studies of lower-dose folic acid, measured by the reduction in NTD incidence, ranged from none to substantial (Tables 1 and 2, Figure 1); a reasonable estimate of the expected reduction in the United States is 50%. Thus there appear to be excellent prospects for substantially reducing the number of NTDs among U.S. women who have not had a prior NTD-affected pregnancy through the use of folic acid at intakes of approximately 0.4 mg daily. # RECOMMENDATIONS Available evidence indicates that 0.4 mg (400 \|xg) per day of folic acid, one of the Women who have had a prior NTD-affected pregnancy are at high risk of having a subsequent affected pregnancy. When these women are planning to become pregnant, they should consult their physicians for advice. # COMMENT The possibility for reducing by 50% the number of cases of spina bifida and other NTDs in the United States through daily consumption of 0.4 mg of folic acid presents an important opportunity in public health. Efforts are now being made by the PHS to assure that all women capable of becoming pregnant consume 0.4 mg of folic acid daily to achieve this goal. There are three potential approaches for the delivery of folic acid to the general population in the dosage recommended: a) improvement of dietary habits, b) fortification of the U.S. food supply, and c) use of dietary supplements. The Food and Drug Administration (FDA) will have to determine which approaches will best achieve the goal of increasing folic acid intake while ensuring that potential risks created by overfortification of food with folic acid, and thus overconsumption of this substance, are not reached. This process will require rulemaking and will include substantial efforts to involve the obstetrics community, other medical groups, the scientific community, consumers, industry, and other PHS agencies in a search for the best way to accomplish this goal. While this process is under way, and before the FDA issues final regulations on food fortification and permissible health claims on food labeling, further food fortification with folic acid would be inappropriate, and no health claims should be made. Folate intake 3=0.4 mg per day can be obtained from the diet through careful selection of foods. Folate is a generic term for food compounds that have the biologic activity of folic acid; in general, folates obtained from foods are not as well absorbed as is folic acid. Although the average consumption of dietary folate by women in the United States has been estimated to be about 0.2 mg per day (10), women who select foods consistent with the U.S. Dietary Guidelines for Americans and the U.S. Dietary Pyramid are likely to consume diets containing 5=0.4 mg of folate daily. Use of currently available fortified foods, such as some breakfast cereals, can also provide important sources of folic acid. Folic acid supplement pills containing 0.4 mg of folic acid also are available, as are multivitamin preparations containing folic acid. About 20% of U.S. women now consume multivitamin preparations, which generally contain 0.4 mg of folic acid (77). Supplements for pregnant women generally contain up to 0.8 mg of folic acid. Given these alternative routes for obtaining adequate amounts of folic acid, it is recommended that women be advised of the options available to them to obtain daily intakes of 0.4 mg of folic acid and be encouraged to meet this goal. The research that serves as the basis for this recommendation generally focused on the use of supplements from at least 1 month before conception through early pregnancy, the periconceptional period. Development of the defect in the neural tube occurs within the first month after conception, before most women are aware of their pregnancy. Because >50% of pregnancies in the United States are unplanned (12), it would be prudent for women to consume 0.4 mg of folic acid daily on a regular, continuous basis as long as they are capable of becoming pregnant. Because supplements containing folic acid at the 0.4 -mg level are widely available, this dosage has been the focus of the available observational research studies. It is possible that lower doses of folic acid may reduce the risk for NTDs, but further research would be needed to learn the minimum effective dose. At this time, FDA allows food to be labeled according to the level of nutrients in the food relative to the U.S. Recommended Daily Allowances (USRDAs). Consumption of folic acid at USRDA-level doses (0.4 mg for nonpregnant women) is considered a safe and desirable practice. Over the years, RDAs have ranged from 0.18 to 0.4 mg of folic acid for women of childbearing age. RDAs for pregnant women have ranged from 0.4 to 0.8 mg per day. Folic acid is a water-soluble vitamin, and any excess consumed is rapidly excreted in the urine. The effects of higher doses are not well known, although they include complicating the diagnosis of vitamin B12 deficiency in certain people (13). Irreversible neurologic damage may occur if B12 deficiency is not diagnosed and treated. Therefore, women should be careful to keep their total daily folate consump tion at <1 mg per day. Women may wish to consult their physicians or other health-care providers (nutritionists, dietitians) about how to best obtain the recom mended amount of folic acid, while avoiding excessive consumption. Caution should also be taken to prevent excessive use of multivitamin supplements or fortified foods containing vitamin A, since excess vitamin A may cause birth defects. Further research will be needed to identify any unknown adverse effects. It is expected that consumption of adequate folic acid will avert some, but not all, NTDs. The underlying causes of NTDs are not known. Thus it is not known what proportion of NTDs will be averted by adequate folic acid consumption. From the available evidence, CDC estimates that there is the potential for averting 50% of cases that now occur. However, until further research is done, no firm estimate of this proportion will be available. Moreover, further research will be needed to identify the causes of NTDs that are not averted by folic acid intake. The current recommendation is directed to all U.S. women, including women who have had a previous NTD-affected pregnancy. In August 1991, CDC issued a guideline (14) for women who have had a prior pregnancy affected by NTDs and who are planning to start a new pregnancy. The guideline called for the consumption of a 4.0mg daily dose of folic acid, from at least 1 month before conception through the first 3 months of pregnancy. The guideline did not specifically address the issue of folic acid consumption among these women during the times when they are not planning to become pregnant. Women who have had an NTD-affected pregnancy should consume 0.4 mg of folic acid per day, unless they are planning a pregnancy. When these women are planning to become pregnant, they can follow the August 1991 guideline and consult their physicians about the desirability of using 4.0 mg of folic acid per day. Because 4.0 mg of folic acid per day is a very high dose, there may be risks associated with these levels. Although it appears that a lower dose, such as 0.4 mg, may have as great a beneficial effect as 4.0 mg, women who are at very high risk of having an NTD-affected pregnancy may choose to follow the August 1991 guideline a) because it is based on data from the most rigorous study directly pertinent to their risk of NTDs, and b) because their risk of having an NTD-affected pregnancy may outweigh any risk that may occur as the result of the use of 4.0 mg of folic acid. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and is available on a paid subscription basis from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 783-3238. The data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the succeeding Friday. Inquiries about the MMWR Series, including material to be considered for publication, should be directed to: Editor, MMWR Series, Mailstop C-08, Centers for Disease Control, Atlanta, GA 30333; telephone (404) 332-4555.	Spina bifida and anencephaly are common and serious birth defects. Avail able evidence indicates that 0.4 mg (400 \y.g) per day of folic acid, one of the B vitamins, will reduce the number of cases of neural tube defects (NTDs). In order to reduce the frequency of NTDs and their resulting disability, the United States Public Health Service* recommends that: All women of childbearing age in the United States who are capable of becoming pregnant should consume 0.4 mg of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs. Because the effects of higher intakes are not well known but include complicating the diagnosis of vitamin B12 deficiency, care should be taken to keep total folate consumption at <1 mg per day, except under the supervision of a physician. Women who have had a prior NTD-affected pregnancy are at high risk of having a subsequent affected pregnancy. When these women are planning to become pregnant, they should consult their physicians for advice.# INTRODUCTION Each year in the United States about 2,500 infants are born with the neural tube defects (NTDs) spina bifida and anencephaly. In addition, an unknown number of fetuses affected by these birth defects are aborted. All infants with anencephaly die shortly after birth, whereas the majority of babies born with spina bifida grow to adulthood with, in severe cases, paralysis and varying degrees of bowel and bladder incontinence. The evidence that consumption of folic acid, one of the B vitamins, before conception and during early pregnancy (the periconceptional period) can reduce the number of NTDs has been accumulating for several years. Published data are available from randomized controlled trials (1,2), nonrandomized intervention trials (3,4), and observational studies (5-8) (Tables 1 and 2, Figure 1). One of the most rigorously conducted studies was the randomized controlled trial sponsored by the British Medical Research Council (MRC) (2). The study showed that high-dose folic acid supplements (4.0 mg per day) used by women who had a prior NTD-affected pregnancy reduced the risk of having a subsequent NTD-affected pregnancy by 70%. Preliminary results from the Hungarian randomized controlled trial of multivitamin/mineral supplementation (including 0.8 mg of folic acid) among women who had not had a prior NTD-affected pregnancy were reported in 1989 (9). This trial was stopped in May 1992 on the advice of an ad hoc scientific advisory committee because of evidence of an NTD-protective effect of the multivitamin/mineral prepa ration relative to the study placebo preparation (Czeizel AE: personal communication, May 1992). Three of four published observational studies showed a lowered risk of NTDs for women who have not had a prior NTD-affected pregnancy and who consumed 0.4-0.8 mg (400-800 \|xg) of folic acid daily from multivitamin supplements (Tables 1 and 2, Figure 1). In summary, the data available indicate that folic acid can help avert NTDs when given at high-dose levels (i.e., 4.0 mg per day). The results of the British MRC study showed that the addition of other vitamins to 4.0 mg of folic acid confers no extra benefit in averting NTDs. Based on a synthesis of information from several studies, including those which used multivitamins containing folic acid at a daily dose level of s=0.4 mg, it was inferred that folic acid alone at levels of 0.4 mg per day will reduce the risk of NTDs. The protective effect found in the studies of lower-dose folic acid, measured by the reduction in NTD incidence, ranged from none to substantial (Tables 1 and 2, Figure 1); a reasonable estimate of the expected reduction in the United States is 50%. Thus there appear to be excellent prospects for substantially reducing the number of NTDs among U.S. women who have not had a prior NTD-affected pregnancy through the use of folic acid at intakes of approximately 0.4 mg daily. # RECOMMENDATIONS Available evidence indicates that 0.4 mg (400 \|xg) per day of folic acid, one of the Women who have had a prior NTD-affected pregnancy are at high risk of having a subsequent affected pregnancy. When these women are planning to become pregnant, they should consult their physicians for advice. # COMMENT The possibility for reducing by 50% the number of cases of spina bifida and other NTDs in the United States through daily consumption of 0.4 mg of folic acid presents an important opportunity in public health. Efforts are now being made by the PHS to assure that all women capable of becoming pregnant consume 0.4 mg of folic acid daily to achieve this goal. There are three potential approaches for the delivery of folic acid to the general population in the dosage recommended: a) improvement of dietary habits, b) fortification of the U.S. food supply, and c) use of dietary supplements. The Food and Drug Administration (FDA) will have to determine which approaches will best achieve the goal of increasing folic acid intake while ensuring that potential risks created by overfortification of food with folic acid, and thus overconsumption of this substance, are not reached. This process will require rulemaking and will include substantial efforts to involve the obstetrics community, other medical groups, the scientific community, consumers, industry, and other PHS agencies in a search for the best way to accomplish this goal. While this process is under way, and before the FDA issues final regulations on food fortification and permissible health claims on food labeling, further food fortification with folic acid would be inappropriate, and no health claims should be made. Folate intake 3=0.4 mg per day can be obtained from the diet through careful selection of foods. Folate is a generic term for food compounds that have the biologic activity of folic acid; in general, folates obtained from foods are not as well absorbed as is folic acid. Although the average consumption of dietary folate by women in the United States has been estimated to be about 0.2 mg per day (10), women who select foods consistent with the U.S. Dietary Guidelines for Americans and the U.S. Dietary Pyramid are likely to consume diets containing 5=0.4 mg of folate daily. Use of currently available fortified foods, such as some breakfast cereals, can also provide important sources of folic acid. Folic acid supplement pills containing 0.4 mg of folic acid also are available, as are multivitamin preparations containing folic acid. About 20% of U.S. women now consume multivitamin preparations, which generally contain 0.4 mg of folic acid (77). Supplements for pregnant women generally contain up to 0.8 mg of folic acid. Given these alternative routes for obtaining adequate amounts of folic acid, it is recommended that women be advised of the options available to them to obtain daily intakes of 0.4 mg of folic acid and be encouraged to meet this goal. The research that serves as the basis for this recommendation generally focused on the use of supplements from at least 1 month before conception through early pregnancy, the periconceptional period. Development of the defect in the neural tube occurs within the first month after conception, before most women are aware of their pregnancy. Because >50% of pregnancies in the United States are unplanned (12), it would be prudent for women to consume 0.4 mg of folic acid daily on a regular, continuous basis as long as they are capable of becoming pregnant. Because supplements containing folic acid at the 0.4 -mg level are widely available, this dosage has been the focus of the available observational research studies. It is possible that lower doses of folic acid may reduce the risk for NTDs, but further research would be needed to learn the minimum effective dose. At this time, FDA allows food to be labeled according to the level of nutrients in the food relative to the U.S. Recommended Daily Allowances (USRDAs). Consumption of folic acid at USRDA-level doses (0.4 mg for nonpregnant women) is considered a safe and desirable practice. Over the years, RDAs have ranged from 0.18 to 0.4 mg of folic acid for women of childbearing age. RDAs for pregnant women have ranged from 0.4 to 0.8 mg per day. Folic acid is a water-soluble vitamin, and any excess consumed is rapidly excreted in the urine. The effects of higher doses are not well known, although they include complicating the diagnosis of vitamin B12 deficiency in certain people (13). Irreversible neurologic damage may occur if B12 deficiency is not diagnosed and treated. Therefore, women should be careful to keep their total daily folate consump tion at <1 mg per day. Women may wish to consult their physicians or other health-care providers (nutritionists, dietitians) about how to best obtain the recom mended amount of folic acid, while avoiding excessive consumption. Caution should also be taken to prevent excessive use of multivitamin supplements or fortified foods containing vitamin A, since excess vitamin A may cause birth defects. Further research will be needed to identify any unknown adverse effects. It is expected that consumption of adequate folic acid will avert some, but not all, NTDs. The underlying causes of NTDs are not known. Thus it is not known what proportion of NTDs will be averted by adequate folic acid consumption. From the available evidence, CDC estimates that there is the potential for averting 50% of cases that now occur. However, until further research is done, no firm estimate of this proportion will be available. Moreover, further research will be needed to identify the causes of NTDs that are not averted by folic acid intake. The current recommendation is directed to all U.S. women, including women who have had a previous NTD-affected pregnancy. In August 1991, CDC issued a guideline (14) for women who have had a prior pregnancy affected by NTDs and who are planning to start a new pregnancy. The guideline called for the consumption of a 4.0mg daily dose of folic acid, from at least 1 month before conception through the first 3 months of pregnancy. The guideline did not specifically address the issue of folic acid consumption among these women during the times when they are not planning to become pregnant. Women who have had an NTD-affected pregnancy should consume 0.4 mg of folic acid per day, unless they are planning a pregnancy. When these women are planning to become pregnant, they can follow the August 1991 guideline and consult their physicians about the desirability of using 4.0 mg of folic acid per day. Because 4.0 mg of folic acid per day is a very high dose, there may be risks associated with these levels. Although it appears that a lower dose, such as 0.4 mg, may have as great a beneficial effect as 4.0 mg, women who are at very high risk of having an NTD-affected pregnancy may choose to follow the August 1991 guideline a) because it is based on data from the most rigorous study directly pertinent to their risk of NTDs, and b) because their risk of having an NTD-affected pregnancy may outweigh any risk that may occur as the result of the use of 4.0 mg of folic acid. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and is available on a paid subscription basis from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 783-3238. The data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the succeeding Friday. Inquiries about the MMWR Series, including material to be considered for publication, should be directed to: Editor, MMWR Series, Mailstop C-08, Centers for Disease Control, Atlanta, GA 30333; telephone (404) 332-4555.	None	None
fa4463070a66ca04f3afe2e08a46f4204f49d836	cdc	None	Brown MJ, McLaine P, Dixon S, Simon P. A randomized community-based trial of home visiting to reduce blood lead levels in children. Pediatrics. In press 2005. Moel DI, Sachs HK, Drayton MA. Slow and natural reduction in blood lead level after chelation therapy for lead poisoning in childhood.# Table of Contents Preface This is the fifth revision of Preventing Lead Poisoning in Young Children by the Centers for Disease Control and Prevention (CDC). As with the previous statements, the recommendations presented here are based on scientific evidence and practical considerations. This revision accompanies a companion document, A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels <10 µg/dL in Children, developed by Advisory Committee on Lead Poisoning Prevention which reviews the scientific evidence for adverse effects in children at blood lead levels below 10 µg/dL. The data demonstrating that no "safe" threshold for blood lead levels (BLLs) in young children has been identified highlights the importance of preventing childhood exposures to lead. It confirms the need for a systematic and society wide effort to control or eliminate lead hazards in children's environments before they are exposed. This emphasis on primary prevention, although not entirely new, is highlighted here and is clearly the foremost action supported by the data presented in A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels <10 µg/dL in Children. Although there is evidence of adverse health effects in children with blood lead levels below 10 µg/dL, CDC has not changed its level of concern, which remains at levels >10 µg/dL. We believe it critical to focus available resources where the potential adverse effects remain the greatest. If no threshold level exists for adverse health effects, setting a new BLL of concern somewhere below 10 µg/dL would be based on an arbitrary decision. In addition, the feasibility and effectiveness of individual interventions to further reduce BLLs below 10 µg/dL has not been demonstrated. CDC is conducting several activities to focus efforts on preventing lead exposures to children. First, beginning in 2003, CDC required state and local health departments receiving funding for lead poisoning prevention activities to develop and implement strategic childhood lead poisoning elimination plans. Second, CDC and its federal partners, the Department of Housing and Urban Development and the Environmental Protection Agency, launched new initiatives to control leadbased paint hazards in the highest risk housing, addressing where successive cases of lead poisoning have been identified. Third, CDC and other federal agencies are developing a systematic and coordinated response to identify and eliminate nonpaint sources of exposure (e.g., lead jewelry, food and traditional medicines, and cosmetics). CDC continues to monitor progress toward the Healthy People 2010 objective of eliminating elevated BLLs in children at the national level through the National Health and Nutritional Examination Survey and at the state and local levels through the blood lead surveillance system. These complementary data provide ix essential information for the rational distribution of resources to communities with the highest risk for lead exposure. I wish to thank both current and former members of the Advisory Committee on Childhood Lead Poisoning Prevention and consultants who developed the documents in this statement and acknowledge their contribution to the health of the nation's children. The Committee considered a number of controversial issues, examined the existing data and reviewed the report of the work group. This 2005 statement represents agreement of 12 of the 13 Advisory Committee members serving on the committee as of October 2004. Thomas Sinks, Ph.D. # INTRODUCTION The U.S. Department of Health and Human Services has established an ambitious goal of eliminating elevated blood lead levels (BLLs) in children by 2010, a qualitatively different goal from earlier goals that focused on reducing the BLL considered toxic by various target amounts. 1 Recent research on lead's health effects at low levels, which suggests societal benefits from preventing even low level lead exposure in childhood, underscores the importance of this public health goal. This revised statement describes the public health implications of research findings regarding adverse health effects at low BLLs summarized in the accompanying review, and focuses on the Centers for Disease Control and Prevention's blood lead "level of concern." This statement aims to guide public health practice and policy development and review necessary steps to ensure progress toward meeting the 2010 goal. # PREVENTING CHILDHOOD LEAD POISONING IN THE UNITED STATES The reduction of BLLs in the United States during 1970-1999, primarily because of implementation of federal and state regulations to control lead exposure, was one of the most significant public health successes of the last half of the 20th century. 2 Nonetheless, some populations and geographic areas remain at disproportionately high risk for lead exposure. Specific strategies that target screening to high-risk children are essential to identify children with BLLs >10 µg/dL. Once identified, children with elevated BLLs should receive follow-up services as recommended in Managing Elevated Blood Lead Levels Among Young Children. 6 However, preventing elevated BLLs is the preferred course of action. A compelling body of evidence points to the limited effectiveness of waiting until children's BLLs are elevated before intervening with medical treatments, environmental remediation, or parental education. Data indicate that in many cases it takes years to reduce children's BLLs once levels are elevated whether the initial blood lead elevation is very high or moderate. The most common high-dose sources of lead exposure for U. S. children are lead-based paint and lead-contaminated house dust and soil. Recent studies have identified methods to reduce common household lead hazards safely. 16 Thus, a multitiered approach that includes secondary prevention through case identification and management of elevated BLLs is needed to eliminate childhood lead poisoning. However, because no level of lead in a child's blood can be specified as safe, primary prevention must serve as the foundation of the effort. # CDC'S BLOOD LEAD LEVEL OF CONCERN The adverse health effects associated with elevated BLLs have been widely studied and documented. Previously, CDC responded to the accumulated evidence of adverse effects associated with lead exposures by lowering the BLL of concern. Between 1960 and 1990 the blood lead level for individual intervention in children was lowered from 60 µg/dL to 25 µg/dL. In 1991 the CDC recommended lowering the level for individual intervention to 15 µg/dL and implementing communitywide primary lead poisoning prevention activities in areas where many children have BLLs >10 µg/dL. 17 Some activities, such as taking an environmental history, educating parents about lead, and conducting follow-up blood lead monitoring were suggested for children with BLLs of >10 µg/dL. 7 However, this level, which was originally intended to trigger communitywide prevention activities, has been misinterpreted frequently as a definitive toxicologic threshold. As the accompanying review of recent studies indicates, additional evidence exits of adverse health effects in children at BLLs <10 µg/dL. The available data are based on a sample of fewer than 200 children whose BLLs were never above 10 µg/dL and questions remain about the size of the effect. At this time there are valid reasons not to lower the level of concern established in 1991 including the following: - No effective clinical or public health interventions have been identified that reliably and consistently lower BLLs that already are 10 µg/dL, 18 so preventive lead hazard control measures need not be deferred pending further research findings or consensus. - No one threshold for adverse effects has been demonstrated. Thus the process for establishing a lower level of concern would be arbitrary and no particular BLL cutoff can be defended on the basis of the existing data. In addition, establishing a lower level of concern may provide a false sense of safety about the well being of children whose BLLs are below the threshold. - The adverse health effects associated with elevated BLLs are subtle. Individual variation in response to exposure and other influences on developmental status, make isolating the effect of lead or predicting the overall magnitude of potential adverse health effects exceedingly difficult. - Establishing a level of concern substantially <10 µg/dL probably would be accompanied by a sharp increase in misclassification of children as having an elevated BLL. The uncertainty associated with laboratory testing is too great to ensure that a single blood lead test reliably classifies individual children at levels <10 µg/dL. This misclassification could confuse both parents and clinicians and expenditure of resources on testing that does not aid decision making. - Efforts to identify and provide services to children with BLLs <10 µg/dL may deflect needed resources from children with higher BLLs who are likely to benefit most from individualized interventions. - Efforts to eliminate lead exposures through primary prevention have the greatest potential for success. Reducing exposures will benefit all children, regardless of their current BLL. # RESPONDING TO DATA ON ADVERSE HEALTH EFFECTS AT BLOOD LEAD LEVELS <10 µg/dL FROM A PUBLIC HEALTH PERSPECTIVE Since 1991, CDC has emphasized the need to make primary prevention of lead poisoning, through interventions that control or eliminate lead hazards before children are exposed, a high priority for health, housing, and environmental agencies at the state, local, and federal levels. Federal and state policies and programs, largely as the result of Title X of the 1992 Housing and Community Development Act (Public Law 102-550), increasingly have focused on the need for primary prevention using strategies known to effectively reduce residential lead hazards. 21 Research findings also indicate that primary prevention would be expected to benefit all children at high risk because communities with the largest percentages of children with BLLs >20 µg/dL also have the largest percentage of children with BLLs that are lower but still above the national average of approximately 2 µg/dL. 18 These data underscore the importance of targeting efforts to communities where risk for exposure is highest and provide a strong rationale for primary prevention efforts. The strategies described below will effectively direct efforts to achieve the Healthy People 2010 objective to eliminate lead poisoning in young children and can be expected to reduce lead exposure for all children. 1 Primary Prevention CDC's Advisory Committee on Childhood Lead Poisoning Prevention recently issued updated recommendations calling for the nation to focus on primary prevention of childhood lead poisoning. 22 Because the 2010 health objective of eliminating childhood lead poisoning can be achieved only through primary prevention, 22 this document provides important guidance to state and local agencies regarding the implementation of primary prevention activities. Given that the most important measure of a successful primary prevention strategy is elimination of lead exposure sources for young children, we focus here on the two main exposure sources for children in the United States: lead in housing and non-essential uses of lead in other products. Lead in Housing-Because lead-based paint is the most important source of lead exposure for young children, the first essential element of primary prevention is implementation of strategies to control lead paint-contaminated house dust and soil and poorly maintained lead paint in housing. After 10 or more years of widespread blood lead testing and data collection by CDC-supported state and local agencies, the specific addresses of housing units at which children repeatedly have been identified with elevated BLLs are known to local officials. Two examples are: - In Detroit, 657 addresses accounted for nearly 1,500 children with BLLs >20 µg/dL during the last 10 years because the sources of lead were never controlled completely when the initial case occurred. These housing units also probably were the source of lead exposure for several thousand Detroit children with BLLs >10 µg/dL. 26 - In Louisville, Kentucky, 35% of children identified with elevated BLLs during the last 5 years resided in 79 housing units; these units represent <0.3% of all housing units in the community. 27 These experiences are repeated in high-risk communities across the country. The infrastructure needed to identify high-risk housing and to prevent and control lead hazards in such housing is largely in place. Established firms certified in lead hazard evaluation and control now exist in most communities, as do other skilled trades people trained in lead-safe work practices necessary during routine maintenance and painting. Systematic identification and reduction of residential lead sources, particularly in old, poorly maintained housing where children with elevated BLLs are known to have lived, combined with periodic monitoring of housing conditions to detect new deterioration and resultant lead hazards will prevent lead exposure to children in the future and break the cycle of repeated cases of elevated BLLs. Other steps critical to success in controlling lead hazards in housing and preventing lead exposure in the future are 1) enforcement of lead safety and housing code requirements to ensure good property maintenance; 2) widespread adoption of leadsafe work practices to control, contain, and clean up lead dust during painting and remodeling projects; and 3) periodic monitoring of housing conditions to detect new deterioration and resultant lead hazard. Nonessential Uses of Lead-Because areas of the United States report that as many as 35% of children identified with elevated BLLs have been exposed to items decorated or made with lead, in some cases resulting in life-threatening BLLs, 28 the second crucial element of a primary prevention strategy is identification and restriction or elimination of nonessential uses of lead, particularly in both imported and domestically manufactured toys, eating and drinking utensils, cosmetics, and traditional medicines. This effort requires identifying communities where cultural practices and traditional medicines may put children at risk and incorporating lead poisoning prevention activities into health and community services that reach families at high risk for lead exposure from nonpaint sources. 7 The 2010 health objective cannot be achieved without a more systematic approach that, at a minimum, allows identification of lead-contaminated items and prohibits their sale before children are exposed. Ultimately, all nonessential uses of lead should be eliminated. # RECOMMENDATIONS # Changes in the Focus of CDC-Funded Programs To achieve these goals, CDC is focusing on eliminating childhood lead poisoning by preferentially funding programs to provide lead-related services for communities and populations with large numbers of children at high risk for lead exposure. The cooperative agreements with 42 state and local health departments funded for emphasize the importance of primary prevention and require funded state and local programs to work aggressively to develop and implement the necessary partnerships, programs and activities. CDC requires its state and local partners to undertake a strategic planning process, which includes gathering input from housing professionals, pediatric health-care providers, advocacy groups, parents of children with elevated BLLs, and others interested in preventing lead poisoning in children. These strategic plans, developed by local partners to respond to local conditions, drive primary prevention activities for the 3-year grant cycle. Progress toward eliminating childhood lead poisoning can be measured only by ongoing surveillance of BLLs in childhood populations where the risk for exposure is high, as well as continued monitoring of population-based BLLs through the National Health and Nutrition Examination Survey. 29 CDC's role in supporting state and local efforts and providing technical assistance to improve data management and reporting is essential to these activities. # Recommendations to Federal, State, and Local Government Agencies Achieving the Healthy People 2010 objective to eliminate childhood lead poisoning requires collaboration by many different federal, state and local agencies. Many of the roles and responsibilities for federal partners in the elimination effort are detailed in the report of the President's Task Force on Environmental Health Risks and Safety Risks in Children. 29 However, all levels of government share responsibility for primary prevention of childhood lead poisoning. Government agencies have the ability, through legislative and enforcement actions to spearhead prevention efforts and articulate clear public health goals and strategic priorities at the federal, state, and local government levels. # Federal agencies should: 1. Support and disseminate information about, and adequately fund, programs and interventions that will lead to full implementation of primary prevention. 2. Expand financial resources for permanent measures to control or eliminate residential lead hazards. 3. Monitor and enforce regulations controlling lead content of various environmental media, including air, water, and soil. 4. Identify populations in which the risk for exposure to nonpaint sources of lead is high, and develop strategies to minimize the risk. 5. Develop and implement regulatory and voluntary strategies to control nonessential uses of lead, particularly in items that are easily accessible to young children, such as toys, jewelry, eating and drinking utensils, traditional remedies, and cosmetics. 6. Evaluate the effectiveness of primary prevention activities in reducing lead exposure and eliminating childhood lead poisoning, particularly in areas where the risk for lead poisoning is substantially higher than for the general U. S. childhood population. 7. Develop new mathematical models of lead exposure or modify existing models, e.g., the Integrated Exposure Uptake and BioKinetic (IEUBK) Model for lead in children, currently used to establish thresholds for lead exposure in consumer products and areas with pervasive lead contamination. The exposure modeling should predict the magnitude of the increase in BLLs in a child as a result of exposure to a specific lead source rather than the probability of a BLLs >10 µg/dL. # State and local agencies should: 1. Update or establish and enforce regulatory requirements for lead safe housing that link lead safety to the housing and/or sanitary code. 2 Require that properties that have undergone lead paint abatement or substantial renovation to lead painted surfaces meet the EPA dust clearance testing prior to re-occupancy. Require dust testing in all cases where public health agencies have ordered paint repair, particularly in the homes of children already identified with elevated BLLs. 3 Promote broad use of lead-safe work practices for routine painting and maintenance projects in older homes, and make training in such practices widely available at low or no cost to painters, remodelers, landlords, and maintenance workers. 4. Establish formal agreements among health, social services, housing, and legal agencies to increase the sharing of data, educational information, violations, and success stories. 5. Provide information to caregivers about temporary measures that can reduce lead exposure as described in Managing Elevated Blood Lead Levels Among Young Children, 6 as well as information and referral for permanent abatement services. Recommendations to Health-Care Providers and Community-Based Health and Social Service Agencies CDC recommends that health care providers continue their traditional role of providing anticipatory guidance as part of routine well-child care, assessing risk for exposure to lead, conducting blood lead screening in children, and treating children identified with elevated BLLs. In addition health-care and social service providers are urged to expand their roles. They should keep abreast of research data that clarify the relationship between lead exposure and neurocognitive development in children. They also can strongly advocate for children and foster lead exposure prevention by helping facilitate implementation of the specific strategic plans to eliminate childhood lead poisoning in their local and state communities. Health-care and social service providers are highly effective child advocates, and their active participation in the process provides the expertise and leadership needed to reach this goal. Health-care and social service providers should: 1. Provide culturally appropriate education to all pregnant women and to families with young children about the principal sources of lead and ways to reduce exposure. 2. Target outreach, education, and screening programs to populations with the greatest risk for lead exposure. 3. Become aware of, and actively support, lead poisoning elimination efforts in the community. 4. Express concern to federal, state, and local policy and decision makers that children live in a lead safe environment and actively support legislation and regulatory initiatives. Advocate for lead-safe, affordable housing by supporting appropriate legislation. 5. Become aware of and comply with lead screening policies issued by Medicaid or state and local health departments. 6. Ensure training of staff members engaged in housing renovation or rehabilitation in lead-safe work practices. # CONCLUSION The Healthy People 2010 objective to eliminate BLLs >10 µg/dL in children is within our grasp. Research to further characterize and isolate the harmful effects of lead associated with various BLLs will help answer remaining questions and further refine the public health response. However, the approach needed is clear: identify and address existing lead hazards before children are exposed, otherwise hundreds of thousands of children will be placed at risk needlessly. The overall reduction of lead in the environment will benefit all children. 6 # List of Tables # EXECUTIVE SUMMARYÊ In March 2002, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) established a work group (WG) to review the available evidence of possible health effects of blood lead levels (BLLs) of below 10 micrograms per deciliter (µg/dL), the level of concern currently established by CDC. The WG was charged with designing and following a rigorous protocol to review studies of the health effects of lead exposure at very low BLLs. The workgroup intended to focus on studies of the effects of peak BLLs at <10 µg/dL in children never known to have a BLL exceeding 10 µg/dL. However, there are relatively few such studies and the workgroup decided to review the larger number of studies that could indirectly support or refute the existence of a threshold near 10 µg/dL. Although the workgroup members were the primary authors of this report, the ACCLPP reviewed the document and it was revised based on their comments. The majority of ACCLPP members accepted the findings of the report, with two members dissenting. # Methods The following criteria were used for selecting relevant studies to review: - BLLs were measured using graphite furnace atomic absorption spectrometry (GFAAS) or anodic stripping voltammetry (ASV); - the study was published in English; - for studies in which IQ or General Cognitive Index (GCI) was a measured outcome, an assessment of the association between BLLs in children and IQ or GCI was included; and - for studies in which IQ or GCI was not a measured outcome, an assessment of the association between BLLs in children and a specified health outcome was included. For each relevant study, a structured abstraction was performed that captured the following: - study location and sample size; - age at which BLL and cognitive or health outcome was measured; - the distribution of BLLs (mean or other measure of central tendency and variance) and percentage of participants with BLL <10 µg/dL; iii - crude and adjusted regression coefficients relating BLLs to outcome; - other measures of association (e.g., correlation coefficients); and - model type and covariates included in adjusted models. When reviewing the evidence, including indirect evidence from IQ studies, the workgroup considered both alternate explanations for study findings and potential effect of residual confounding. # Conclusions The main conclusions reached by the WG are summarized as follows. 1. Does available evidence support a negative association between measured BLLs <10 µg/dL and children's health? - The overall weight of available evidence supports an inverse (negative) association between BLLs <10 µg/dL and the cognitive function of children. - A steeper slope in the dose-response curve was observed at lower rather than higher BLLs. - The available evidence has important limitations, including the small number of directly relevant cohort studies and the inherent limitations of cross-sectional studies (i.e., the lack of data regarding both BLLs earlier in life and key covariates). - For health endpoints other than cognitive function (i.e., other neurologic functions, stature, sexual maturation, and dental caries), consistent associations exist between BLLs <10 µg/dL and poorer health indicators. # Are the observed associations likely to represent causal effects of lead on health? - Though not definitive, the available evidence supports the conclusion that the observed associations between BLLs <10 µg/dL and cognitive function are caused, at least in part, by lead toxicity. - The strength and shape of the causal relationship are uncertain because of limitations of the available evidence. - The health effects of lead are uncertain in individual children who have BLLs measured at a single point in time. Thus, scientific evidence does not provide a basis for classifying individual children with BLLs <10 µg/dL as "lead poisoned," as the term is used in the clinical setting. - The greatest source of uncertainty in evidence concerning the relationship between BLLs <10 µg/dL and children's cognitive function is the potential for residual confounding, especially by socioeconomic factors. - The available data for health endpoints other than cognitive function, taken mostly from cross-sectional studies, are limited; therefore, firm conclusions concerning causation can not be made. # Future Research Needs The WG identified the following research needs to address gaps in the existing base of evidence and to allow for more definite conclusions about the strength and shape of the causal relationship. - Prospective observational studies designed to minimize the chance of residual confounding. - Randomized trials to test interventions designed to reduce BLLs <10 µg/dL and assess the impact on children's cognitive development. # Background # Charge to the Work Group In March 2002, the Advisory Committee on Childhood Lead Poisoning Prevention agreed to establish a work group (WG) to review evidence of possible health effects of lead at blood lead levels less than 10 micrograms per deciliter (µg/dL), currently the threshold for defining an elevated blood lead level according to CDC guidelines (CDC 1991). The work group was charged as follows: "In October 1991, the Centers for Disease Control and Prevention issued Preventing Lead Poisoning in Young Children. This document heralded a change in the definition of the level for intervention for children with elevated blood lead levels (EBLLs) from a lead level of 25 µg/dL to 10 µg/dL. The report explained that this change was due to new data that indicated significant adverse effects of lead exposure in children at levels once thought to be unassociated with adverse effects. The 1991 document identified a goal to reduce children's blood lead levels below 10 µg/dL. Interventions for individual children were recommended at levels of 15 µg/dL and above. Research findings published and disseminated since October 1991 suggest that adverse effects from lead exposure and toxicity occur at blood lead levels below 10 µg/dL. Some studies suggest that some effects may be greater at blood lead levels (BLLs) below 10 µg/dL than at higher BLLs. Such research findings raise concerns about the inability to control lead exposure with conventional methods and lend credence to the importance of primary prevention measures to prevent lead exposure to children. The work group will be convened by the Advisory Committee on Childhood Lead Poisoning Prevention to review the existing evidence for adverse effects of lead exposure and toxicity on children at very low blood lead levels and to focus on effects at levels of 10 µg/dL and below. Rigorous criteria will be established for the literature review. The work group will then create, in conjunction with the committee, a summary of the evidence for publication." # Scientific and Public Health Context for the WG Review Prior reviews that compiled the extensive evidence from in vitro, animal, and human studies established lead as a multi-organ toxicant, including studies showing health effects at BLLs near 10 µg/dL (ATSDR 1999;WHO 1995;USEPA 1986). The published studies include a large body of literature establishing that lead is a developmental toxicant and that harmful effects of lead on children's development can occur without clinical signs, symptoms, or abnormal routine laboratory tests. In addition, a growing number of studies suggest that BLLs prevalent in the general population are associated with adverse health effects in adults and in the offspring of pregnant women. Finally, in more recent years, bone-lead levels measured by x-ray fluorescence have been used in epidemiologic studies as a measure of cumulative lead exposure. Although these were not considered in this review, a number of studies showing inverse relations of bone-lead level to health in general population samples (e.g., Cheng et al. 2001) add further evidence that cumulative lead exposure may be harmful to health at typical background exposure levels for the population in the United States. The observation that available epidemiologic evidence does not demonstrate a threshold below which no effect of lead is possible is not new. A review prepared for a 1986 workshop on lead exposure and child development stated, "There is little evidence for a threshold or no-effect level below which the lead/IQ association is not found. IQ deficits have been reported in studies where the mean lead level is 13 µg/dL (Yule et al. 1981) and similar deficits in the Danish study where the primary measure was tooth lead, but BLLs are lower at around 7 µg/dL." (Smith 1989) A review, meta-regression, and reanalysis of existing data (Schwartz 1994) reached essentially the same conclusion. Available data did not suggest a threshold below which no association between BLLs and intelligence in young children was evident. Recent studies (Canfield et al. 2003;Lanphear et al. 2000;Moss et al. 1999;Wu et al. 2003) provided more direct evidence of an association between BLLs and adverse health effects in the domains of cognitive function, neurologic function, growth, dental caries, and onset of puberty at levels well below 10 µg/dL. Thus, a reexamination of this issue is in order. As evidence from experimental animal studies and human epidemiologic studies has grown, CDC has lowered the BLL considered elevated for the purpose of interpreting clinical test results of an individual child (Table 1). CDC guidelines also have provided criteria for identifying children who have more severe manifestations of lead toxicity and/or a higher risk of lead-related sequellae. For example, CDC's 1975 and 1978 guidelines defined clinical "lead poisoning" on the basis of BLLs, symptoms, and/or levels of erythrocyte protoporphyrin (EP) or other indicators of lead-related biochemical derangements. CDC's 1985 guidelines used the terms "lead toxicity" and "lead poisoning" interchangeably to refer to BLLs >25 µg/dL with EP >35 µg/dL. However, the guidelines acknowledged that "lead poisoning" is generally understood for clinical purposes to refer to episodic, acute, symptomatic illness from lead toxicity. CDC's 1985 guidance also cautioned that blood lead thresholds established to guide follow-up and treatment for individual children "should not be interpreted as implying that a safe level of blood lead has been established." In 1991, CDC guidelines more directly acknowledged the difficulty in assigning terms to specific ranges of BLLs given the different settings in which BLLs are interpreted and given that manifestations of lead toxicity occur along a continuum: "It is not possible to select a single number to define lead poisoning for the various purposes of all of these groups " (CDC 1991). These guidelines also noted, "Some studies have suggested harmful effects at even lower levels ." In addition to these changes in criteria used to evaluate blood lead test results for individual children, recent analyses by the U.S. Department of Housing and Urban Development (HUD 1999) and the U.S. Environmental Protection Agency (USEPA 2000) to support the development of regulations governing lead exposure have assumed that the relation of increasing blood lead to decrements in children's IQ extends to BLLs <10 µg/dL. As BLLs considered elevated have fallen, measures to reduce or remove lead from a number of sources, including gasoline, soldered food and beverage containers, paint, drinking water, and industrial emissions have resulted in a dramatic decline in BLLs in the United States since the mid-1970s (Pirkle et al. 1994). The Second National Health and Nutrition Examination Survey (NHANES II) conducted from 1976 to 1980 demonstrated that, among U.S. children ages 6 months through 2 years, 84% of white children and more than 99% of black children had BLLs >10 µg/dL, and the median BLLs were 14 and 19 µg/dL, respectively (Mahaffey et al. 1982). A decline in BLLs during the course of that survey was noted, paralleling the falling consumption of leaded gasoline (Annest et al. 1983). A continued decline in BLLs was evident in subsequent NHANES surveys (Pirkle et al. 1994;NCEH 2003) and in clinical blood-lead test data compiled by state and local health agencies (Hayes et al. 1994;CDC 2003). Nationally, it is estimated that by 1999-2000, the prevalence of BLLs >10 µg/dL among children 1 to 5 years of age had fallen to 2.2% and the median level to 2.2 µg/dL (NCEH 2003). Although these reductions in lead exposure represent great progress, scientific advances have shed light on harmful effects of lead at levels of exposure once thought safe. In addition, industrial activity has widely dispersed lead in the environment from naturally occurring deposits. As a result, even at the lower exposure levels that prevail today, typical body burdens of lead are likely to be much higher than those present in pre-industrial humans, which by one estimate corresponded to a BLL of 0.016 µg/dL (Smith et al. 1992). Therefore, the potential for additional subclinical adverse effects of lead from currently prevailing exposures deserves careful study. Finally, although falling BLLs have benefited all demographic groups (Pirkle et al. 1994), stark demographic and geographic disparities continue to reflect the historic pattern; the risk of elevated BLLs in communities where poverty and older (i.e., that built before 1950) housing are prevalent remains several fold higher than the national average (Lanphear et al. 1998). # Review Methods # Scope and Approach Given the charge to the work group and the scientific and public health context, the WG did not attempt a comprehensive review of all evidence relating lead exposure to health. Instead, the WG set out to answer the following questions: 1. Does available evidence support negative associations between health indicators and children's blood lead levels measured <10 µg/dL? Ê 2. Are the observed associations likely to represent a causal effect of lead on health? To address these questions, the WG established criteria (see Methods) for published studies that would address the first question. In addition, the work group identified issues relevant to making causal inference from any observed associations. Identifying such issues is an essential step in interpreting evidence relevant to the WG charge. Human studies to assess potential health effects of environmental toxicants, such as lead, are usually observational in design (i.e., the health status of participants is related to some measure of exposure, dose, or body burden that varies on the basis of environmental factors and not experimental manipulations by the investigator). For ethical reasons, the limited number of human experimental studies that have evaluated causal relations between toxicant exposures and health usually have involved attempts to reduce exposure or body burden and assess the impact on health status. Such studies of lead-exposed children are rare, and to date none have focused on children with BLLs <10 µg/dL. Observational studies have inherent limitations-not specific to studies of lead toxicity-with the potential to produce biased results. Biases from observational studies can obscure true causal effects of toxicant exposures or produce associations between toxicant exposures and health status when no causal relation is present. Thus, statistical associations from individual observational studies or multiple studies subject to similar biases cannot establish causal relationships; additional, non-statistical criteria may be used to evaluate such evidence. Although causal criteria have been stated in various ways, the Surgeon General's Report on Smoking and Health (U.S. Public Health Service 1964) provides a useful set of criteria. They include: - The consistency of the association. Is a similar association observed across studies with varying methods and populations? - The strength of the association. The strength of an association is the extent to which the risk of a disease or a measure of health status varies in relation to exposure and can be expressed, for example, as a relative risk or regression coefficient. It is distinguished from the statistical significance of an association that reflects both the strength of the association and the sample size. An additional criterion, specificity of the association, is closely related to strength of the association and is considered less important in the context of multifactorial health conditions. - The temporal relationship of associated variables. Does the hypothesized causal exposure occur before the health outcome associated with it? - Coherence of the association. Is the observed association consistent with other relevant facts including, for example, experimental animal studies and the descriptive epidemiology of the health condition under study? The application of these criteria does not provide a clear demarcation for concluding definitive proof of causation versus inadequate evidence. Rather, the more the available evidence meets these criteria, the greater the confidence in causal inference about an association. Consistent with these criteria, the WG identified several issues specifically relevant to inferring causality from associations (or the lack of associations) of BLLs to health measures observed in studies of lowlevel lead exposure. These potential biases are not unique to studies of children with BLLs <10 µg/dL (e.g., Smith 1989). However, the larger number of human and experimental animal studies (including primate studies) and the nature of observed health effects associated with higher BLLs have conclusively demonstrated the adverse health effects of lead. However, far fewer studies of possible health effects of BLLs <10 µg/dL have been conducted, and the relative importance of some sources of bias may be greater at these lower levels. Therefore, the work group considered several issues in interpreting the findings of available studies (see Discussion). At the time of the WG's review, a consortium of investigators from several longitudinal studies of lead exposure and cognitive function in children were conducting a reanalysis of data pooled from these studies. These studies included serial measures of blood lead level, cognitive function, and a large number of potential confounders, thus providing stronger evidence than is available from cross-sectional studies. A focus of the pooled reanalysis involved studying the shape of the association between postnatal lead exposure at low levels and measured IQ (B. Lanphear, personal communication, 2003). The WG reviewed published reports from individual cohort studies from which data were pooled, but the final results of this pooled reanalysis were not available for inclusion in the WG report. Because of the nature of its charge, the WG did not develop policy recommendations or address questions relevant to such recommendations. Such policy decisions and questions will, if appropriate, be considered by the full ACCLPP after reviewing the findings of this report. # Criteria for Relevant Studies The WG initially considered, then rejected, limiting its review to studies for which published results provide direct comparisons between children with varying BLLs <10 µg/dL. Such a review would include a relatively small number of studies. Instead, the group decided that the larger number of studies that have included IQ as an outcome could, collectively, indirectly support or refute the existence a threshold near 10 µg/dL for the blood lead-IQ association. The rationale for this approach is based on that used in a review and metaregression reported by Schwartz (1994) and outlined in the following paragraphs. Suppose that, hypothetically, a threshold exists near 10 µg/dL, above which mean IQ decreases linearly with increasing blood lead, with a slope equal to x and below which mean IQ is not associated with blood lead 1 (see Figure 1-Hypothesized "true" relation A). In studies of children who have BLLs <10 µg/dL, estimated slopes would be, in the absence of sampling error, equal to 0. For studies in which all children have BLLs above the threshold, the estimated slope would be, again ignoring sampling error, equal to x. For studies in which some children have blood lead above and others below the threshold, estimated slopes will vary between 0 and x as shown in Figure 1. Thus, if regression coefficients estimating the IQ-blood lead slope are less negative (approaching 0) in populations with lower mean BLLs than in populations with higher mean levels, a threshold near 10 would be suggested. The absence of such a trend or an increase in slopes with decreasing mean blood lead level of the population studied would provide evidence against such a threshold and instead support "true" relations B and C, respectively. This ideal hypothetical case presumes that effect sizes from the studies compared are based on models that correctly specify the form of the BLL-IQ relation and that factors that might modify the relation do not vary across studies. Because of this approach, studies that assessed the association between blood lead and measured IQ were included in this review, even if the published results did not examine blood lead-IQ associations limited to BLLs <10 µg/dL (as was true in most cases). An additional reason for considering studies that measured IQ was the relationship of IQ to other outcomes of policy and public health importance including educational success and earnings potential (Grosse et al. 2002). Because the McCarthy Scales of Children's Ability (MSCA) General Cognitive Index (GCI) was used in a number of studies to measure cognitive function in preschool children and because GCI and IQ scores have similar distributions, studies using GCI as an outcome were also included in this review. The following criteria were used to select relevant studies to review for this report: 1. Blood lead levels were measured using graphite furnace atomic absorption spectrophotometry (GFAAS) or anodic stripping voltametry. 2. The study was published in English. # In addition, For studies in which IQ or GCI was a measured outcome, the study analyses included an assessment of the association between BLLs measured in children and IQ or GCI. For studies in which IQ or GCI was not a measured outcome, the study analyses included an assessment of the association between BLLs <10 µg/dL measured in children and a health outcome. The assessment could either be formal (e.g., non-linear modeling, linear modeling restricted to populations with all or at least 95% of children having BLLs <10 µg/dL, statistical comparison of two or more subgroups with BLLs <10 µg/dL) or informal (e.g., graphical display of results permitting visual assessment of blood lead-outcome relation in the range <10 µg/dL). # Literature Search To identify potentially relevant articles, a comprehensive report published by the Agency for Toxic Substances and Disease Registry (ATSDR 1999) was reviewed first to identify cited articles that related to low-level lead exposure in children. The list of potentially relevant citations identified in the ATSDR report was supplemented by three computerized literature searches, using Dialog ® to search Medline, Toxfile, and other bibliographic databases. Search terms (see Appendix A) were chosen to identify articles reporting on blood lead measurements and one or more domains of health related to lead exposure including neurodevelopment, cognitive function, intelligence, behavior, growth or stature, hearing, renal function, blood pressure, heme synthesis, hematopoiesis, and Vitamin D metabolism. The first search spanned articles published from 1995 through 2002 and indexed as of September 2002, the month and year that the initial search was performed. The second search was performed in April 2003 and spanned the period 2002 through the search date. A third search, spanning the years 1990 through 1996, was performed when a relevant article not cited in the ATSDR toxicological profile was identified by one of the work group members. In addition, potentially relevant articles were identified by work group members and through citations in articles identified previously. Abstracts were reviewed initially. If they were ambiguous or if they suggested the article was relevant, full articles were checked for relevance. Articles deemed relevant were abstracted for this report. Appendix A summarizes the number of possibly relevant references identified, full articles checked for relevance, and relevant articles abstracted and considered in the review. # Structured Abstracts For each relevant study, a structured study abstraction was performed that captured the following information: the study location, sample size, age at which blood lead was measured, age at which the outcome was measured, available information about the blood lead distribution (including mean or other measure of central tendency, variance, and percent of participants with BLLs <10 µg/dL), the crude and adjusted regression coefficients relating blood lead to outcome (if available), the type of model fit (linear, log linear, or other), and the covariates included in the adjusted model. If regression coefficients were not available, other measures of association reported (e.g., correlation coefficients) were noted. Because some studies fit multiple blood lead-outcome models (e.g., cohort studies with blood lead and IQ measured at multiple ages), relevant information about each model estimated was abstracted. For IQ studies, covariates measured and not included in adjusted models were recorded when available. # Review of Cohort Study Methods Among relevant published results were those from cohort studies specifically designed and conducted to study the relation of BLLs to children's cognitive function and other health outcomes. Because these studies had the strongest and best-documented study designs for this review, methods used for blood lead measurement and neuropsychological assessment were summarized for these studies. This information was collected from published studies; in some cases, the studies were supplemented by information provided through correspondence with the investigators. # Results # Studies Relating Postnatal Lead Exposure to IQ or General Cognitive Index Studies in which IQ or GCI were measured as an outcome and other criteria were met included 23 published reports from 16 separate study populations. Results from these studies are summarized in Table 2 (full scale IQ and GCI), Table 3 (performance IQ), and Table 4 (verbal IQ). Within each table, results are grouped according to the age at blood-lead measurement and age at outcome measurement; each grouping displays results sorted according to the measure of central tendency of the blood-lead distribution. Because some studies used linear models (BLLs were untransformed) and some used log-linear models (BLLs were log transformed), estimated regression coefficients were, when possible, used to calculate the estimated change in IQ or GCI corresponding to a blood lead increase from 5 to 15 µg/dL to allow for comparisons across studies. Covariates included in adjusted models are grouped into several broad domains that were addressed in most of the published studies. Among studies that provided results for the size and direction of the associations between BLLs and Full Scale IQ or GCI, regardless of statistical significance, a majority revealed that both crude and adjusted associations were consistent with an adverse effect-IQ decreases with increasing levels of blood lead. In most cases, covariate adjustment attenuated, but did not eliminate, these estimated associations. Findings for performance and verbal IQ were similar, with some studies showing stronger associations of lead with performance IQ and others with verbal IQ. Notable exceptions to this pattern, however, were found. Results from the Cleveland cohort (Ernhart et al. 1987(Ernhart et al. , 1988(Ernhart et al. , 1989) indicated a crude inverse association between blood lead and IQ but no association with covariate adjustment. In the Cincinnati and Boston cohort studies, BLLs measured at or below 12 months of age showed no association or a slightly positive association with covariateadjusted IQ (Dietrich et al. 1993;Bellinger et al. 1992). Though published results from a cohort study in Costa Rica (Wolf et al. 1994) did not provide the size and direction of the estimated blood lead-IQ slope, unpublished results provided to the WG did show covariate-adjusted IQ increasing with BLL (B. Lozoff, personal communication 2003). The estimated BLL-IQ association in the Kosovo cohort was strengthened substantially with covariate adjustment (Wasserman et al. 1997). No trend toward attenuation of the association between blood lead and IQ (or GCI) across studies with decreasing average BLLs is evident (Figures 2 and 3). In one of these studies, analyses were presented that provide more direct information concerning the association between BLL and cognitive function at BLLs <10 µg/dL. The steepest estimates of blood lead-IQ slope from the Rochester (Canfield et al. 2003) studies were based on analyses restricted to children whose measured BLL never exceeded 10 µg/dL. The estimated slope was substantially larger than those estimated from the entire study population (9.2 versus 5.3 IQ point reduction in covariate adjusted IQ for BLL increase from 5 to 15 µg/dL). Canfield and his colleagues ( 2004) also reported a non-linear model supporting a steeper blood lead-IQ slope at lower levels. Though published as a letter to the editor, rather than in a peer-reviewed article (and therefore not included in the structured review), similar findings were reported for a reanalysis of the Boston cohort: a steeper BLL-IQ slope in the population of children whose measured BLLs never exceeded 10 µg/dL, compared with the entire study population (Bellinger et al. 2003). Most of the published studies included at least one measure of socio-economic status. All of the published results from cohort studies were adjusted for Home Observation for Measurement Environment (HOME) score and birth weight; all except the Costa Rica cohort were adjusted for a measure of maternal intelligence. A reanalysis of the data from the Costa Rica cohort with adjustment for maternal IQ was consistent with the original finding of a non-significant positive blood lead-IQ slope (B. Lozoff, personal communication, 2003). Prenatal exposure to maternal smoking was adjusted in the majority of studies, whereas only in the Port Pirie cohort was a measure of postnatal environmental tobacco smoke exposure included. Iron deficiency anemia was included as a covariate in results from the Costa Rica study, which found no association of lead and IQ; the inverse blood lead-IQ associations in the Rochester study (Canfield et al. 2003) and the Karachi study (Rahman et al. 2002) were adjusted for serum transferrin saturation and hemoglobin, respectively. In addition, in the Kosovo study (Wasserman et al. 1997), alternative models were fit with adjustment for hemoglobin, resulting in no appreciable change in the lead coefficient. Not all studies reported regression coefficients that could be used to estimate the change in IQ associated with a BLL change of 5 to 15 µg/dL, and the overall pattern of results summarized above and in Figures 2 and 3 might have been altered had regression coefficients been available from all studies. For example, a member of the WG provided results of reanalysis of the data from the Costa Rica cohort, which showed no evidence of an inverse relation of BLL to IQ with adjustment for maternal IQ and other covariates used in the published result (Wolff et al. 1994;B. Lozoff, personal communication, 2003). # Studies of Health Endpoints Other than IQ and CGI More stringent criteria were required for inclusion of studies in this review if they assessed health endpoints other than general intelligence as measured by IQ or GCI. These studies are summarized in Table 5 and are described in the following paragraphs. Lanphear et al. (2000) analyzed data on BLLs on performance on standardized tests of cognitive function of 4,853 children age 6 through 16 years who were evaluated as part of the NHANES III survey, a multiphasic health interview and examination survey of a stratified probability sample of the U.S. population, carried out from 1988 through 1994. In this population, with a geometric mean BLL of 1.9 µg/dL and 98% of children having BLLs <10 µg/dL, significant inverse relations were found between BLLs and scores on the Wide Ranging Achievement Test (WRAT) arithmetic and reading scores and on the WISC-R block design and digit span subscales. The relationships were strengthened (the slopes became more negative) as analyses were progressively restricted to children with lower BLLs. Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While the results they present are largely consistent with the findings of Lanphear et al., they provided a critique of the validity of the NHANES III data for evaluating leadrelated impacts on neuropsychological development in children. Their critique did not provide results that could be summarized in the structured abstract format used in this report, so a discussion of the Stone et al. critique is found in Appendix B. # Cognitive Function # Other Neurobehavioral Measures and Visual Function Three reports (Altman et al. 1998;Walkowiak et al. 1998;Winneke et al. 1994) describe the relation of blood lead to several neurobehavioral measures and to visual function assessed in 384 school children 5 to 7 years of age in three cities in Eastern Germany. Blood lead levels were generally low, with a geometric mean of 4.25 µg/dL and 95% of children having BLLs <10 µg/dL. Walkowiak et al. (1998) reported a significant negative association between BLLs and WISC vocabulary subscale scores. Continuous performance test false positive and false negative responses increased with increasing BLLs. Other measures inversely related to BLL included performance on a pattern comparison test, finger tapping speed (Winneke et al. 1994), and visual evoked potential interpeak latency (Altman et al. 1998). Mendelsohn and colleagues (1999) found a 6 point deficit in the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development for children aged 12 to 36 months with BLLs 10-24 µg/dL compared with children who had BLLs <10 µg/dL. A scatterplot of covariate-adjusted MDI versus blood lead suggests the association continues at BLLs <10 µg/dL. # Neurotransmitter Metabolite Levels Among children ages 8 through 12 years with mean BLL of 3.95 µg/dL, a direct relation of blood lead (PbB) to higher urinary homovanillic acid, a neurotransmitter metabolite, was found for the subset of children with BLLs >5 µg/dL (Alvarez Leite et al. 2002). # Growth Two studies examined the relation of BLLs <10 µg/dL to somatic growth. Ballew et al. (1999), using the NHANES III data, found that BLLs were inversely related to height and to head circumference among children 1 to 7 years of age. A birth cohort of children in Mexico had BLLs and head circumference assessed every 6 months from 6 to 48 months of age, during which time the median BLL varied from 7 to 10 µg/dL (Rothenberg et al. 1999). Most postnatal blood lead measures were inversely correlated with covariate adjusted head circumference, with the strongest relation found between blood lead at age 12 months and head circumference at 36 months. Kafourou and colleagues (1997) reported a significant negative association between BLL and covariate-adjusted head circumference and height in a population of children with a median BLL of 9.8 µg/dL, with a scatterplot suggesting the relation extends to BLLs <10 µg/dL. # Sexual Maturation Two studies, both based on analyses of the NHANES III data, found an association between BLLs <10 µg/dL and later puberty in girls. Selevan et al. (2003) found that BLLs of 3 µg/dL, compared with 1 µg/dL, were associated with significant delays in breast and pubic hair development in African American and Mexican girls. The trend was similar, but not significant, for non-Hispanic white girls. Age at menarche was also delayed in relation to higher BLLs, but the association was only significant for African-American girls. Wu et al. (2003) reported similar findings for girls in the NHANES III population but did not stratify the analysis by racial/ ethnic group. Compared with BLLs 2.0 µg/dL and below, BLLs of 2.1-4.9 µg/dL were associated with significantly lower odds of attaining Tanner 2 stage pubic hair and menarche; whereas no overall association with breast development was noted. # Dental Caries In the NHANES III population, the odds of having dental caries, comparing children ages 5-17 years in the middle tertile of the BLL distribution (range of BLLs 1.7-4.1 µg/dL) with those in the lowest tertile, was significantly elevated (odds ratio=1.36, 95% confidence interval 1.01-1.83) (Moss et al. 1999). Gemmel et al. (2002) evaluated the association between BLLs and caries in 6-10 year old children from urban communities in eastern Massachusetts (mean BLL=2.9 µg/dL) and a rural community (mean BLL=1.7 µg/dL) in Maine. They found a significant direct relation of BLL to caries in the former, but not the latter population in which a non-significant decrease in caries' frequency was observed with increasing blood lead. In the urban population, the trend of increasing caries with PbB level was evident comparing children with BLLs of 1, 2, and 3 µg/dL. # Blood pressure and renal function Among 66-month-old children in Kosovo, a graph depicting adjusted mean systolic and diastolic blood pressure versus BLL showed no consistent trend across 4 groups of children (approximately 28 per group) with BLLs spanning a range from approximately 5 to 10 µg/dL (Factor Litvak et al. 1996). In a population of 12-to 15-year-old children living near a lead smelter and a control group, urinary retinal binding protein (U-RBP) was found to be significantly associated with BLL in a stepwise regression. When urinary RBP excretion was examined by BLL tertiles, significantly lower U-RBP was seen in the group with BLL < 8.64 µg/dL compared with BLLs 8.64-12.3 µg/dL. Roels et al. (1987) studied the relations of PbB to heme synthesis biomarkers and reported no evident threshold for inhibition of aminolevulinic acid dehydratase synthesis at PbB as low as 8-10 µg/dL, while the threshold for increasing erythrocyte protoporphyrin levels was evident in the range of 15-20 µg/dL, consistent with other studies, including two meeting criteria for inclusion in this report (Rabinowitz et al. 1986;Hammond et al. 1985). # Heme synthesis biomarkers # Discussion Question 1: Does available evidence support an inverse association between children's blood lead levels <10 µg/dL and children's health? The weight of available evidence, both indirect and direct, clearly favors an inverse association between these BLLs and cognitive function among children. The indirect evidence comes from the great majority of studies that have examined BLLs in relation to standardized measures of overall cognitive function; these studies reveal an inverse relationship and no trend toward weaker associations in populations with lower BLL distributions. More direct evidence of such an association comes from a recent analysis of data from a cohort designed from the start to study the relation of blood lead to child development (Canfield et al. 2003). This study demonstrated that the inverse relation between BLL and cognitive function exists and is stronger at BLLs <10 µg/dL compared with higher BLLs; it also does not show a threshold within the range of routinely measured BLLs below which no association was present. A recent letter to the editor described a reanalysis of the Boston cohort data (Bellinger et al. 2003) with findings consistent with Canfield et al (2003). Several recent analyses of data from the NHANES III and other populations also provide direct evidence of associations that imply adverse impacts of lead on indicators of children's neurocognitive development, stature, head circumference, dental caries, and sexual maturation in girls, occurring at measured BLLs <10 µg/dL. Though the number of studies providing direct evidence of associations at BLLs <10 µg/dL is limited and most are cross-sectional, they provide supporting evidence of an association in the context of the much larger number of studies that relate slightly higher levels of lead in blood to impairments of children's health. # Question 2: Are the observed associations likely to be causal? Though the weight of evidence favors an association between children's BLLs <10 µg/dL and health and, indeed, suggests that such relationships become steeper as BLLs decrease, the WG considered a number of concerns that must be addressed in judging whether such associations are likely to be causal. The work group concluded that collectively, these concerns and limitations of the available evidence preclude definitive conclusions about causation and leave considerable uncertainty concerning the magnitude and form of causal relations that may underlie these associations. At the same time, available evidence does not refute the interpretation that these associations are, at least in part, causal. These issues are discussed individually in the following text, followed by overall conclusions. # Biologic Plausibility Evidence from experimental animal and in vitro studies, which are not subject to confounding influences of concern in human observational studies, can establish causation and identify mechanisms that might be operative in humans assuming a suitable animal model. Thus, evidence from experimental animal and in vitro studies can help to assess potential dose-response relationships and thresholds within the context of any uncertainty added due to interspecies extrapolation. Therefore, an important consideration in judging whether associations between BLLs <10 µg/dL and health outcomes are likely to represent causal relationships is whether such relationships are biologically plausible on the basis of experimental animal and in vitro studies. These studies can also help to assess potential doseresponse relationships and thresholds, but extrapolation from in vitro and animal models to human health risk adds additional uncertainty. Lead is the most extensively studied environmental neurotoxicant. Animal and in vitro studies have provided abundant information concerning biochemical and physiologic changes caused by lead. Along with clinical and epidemiologic data, this evidence has clearly established that lead is toxic to the developing and mature nervous system. These data have been extensively reviewed elsewhere (USEPA 1986;ATSDR 1999;WHO 1995;Davis et al. 1990) and are not exhaustively reviewed here. Rather, this discussion highlights evidence concerning potential mechanisms of lead toxicity and data from animal studies that are relevant to the biologic plausibility of the toxicity of lead, especially to the developing nervous systems of children exposed at BLLs <10 µg/dL. Although the precise mechanisms of action and their relative importance in different manifestations of lead toxicity are not known definitively, in vitro studies demonstrate that lead can interfere with fundamental biochemical processes. At the most basic level, many of the proposed mechanisms of lead toxicity involve binding to proteins and/or interference with calcium dependent processes (Goldstein 1993). For some of the adverse health effects of lead (e.g., anemia), the lead-associated biochemical changes that contribute to the effect in humans are well understood. Lead interferes with heme synthesis in part by binding to sulfhydryl groups in the enzyme amino levulinic acid dehydratase (ALAD) (ATSDR 1999), which is especially sensitive to inhibition by lead (less than 0.5 micromoles per liter in vitro) (Kusell et al. 1978;Dresner et al. 1982). This inhibition causes delta amino levulinic acid, a potential neurotoxic agent, to accumulate. Lead also inhibits ferrochelatase, an enzyme catalyzing the incorporation of iron into protoporphyrin to form heme. This inhibition also may involve lead binding to protein sulfhydryl groups. Although anemia and accumulation of protoporphyrin IX in erythrocytes are the most obvious consequence of impaired heme synthesis, this pathway could play a role in lead-related impairment of cellular function throughout the body (USEPA 1986). By interfering with heme synthesis and perhaps by inducing enzymes that inactivate heme, lead can decrease the levels of heme in body tissues (Fowler et al. 1980). A reduction in the body heme pool may impair heme-dependent biochemical processes, such as cellular respiration, energy production, and the function of the cytochrome p-450 monooxygenase system involved in detoxification of xenobiotics and in transformation of endogenous compounds such as vitamin D precursors (USEPA 1986). For other more complex health effects of lead, such as impaired neurocognitive development and behavioral change, a number of plausible mechanisms have been demonstrated in animal and in vitro systems. Lead's impact on one or more biochemical systems needed for normal brain development and function could account for the neurobehavioral effects observed at low levels of exposure. Especially sensitive to lead in vitro is the activation of protein kinase C (PKC), a calcium dependent enzyme. Lead binds more avidly to PKC than its physiologic ligand, calcium, causing activation at picomolar concentrations in vitro. (Markovac and Goldstein 1988). The interactions between lead exposure and PKC activity in the brain are complex; chronic lead exposure may reduce activity of PKC associated with cell membranes while increasing cytosolic PKC activity. Lead effects on PKC activity have been proposed to mediate potential impacts of lead on cell growth and differentiation, including that of neural cells (Deng and Poretz 2002), the bloodbrain barrier, and long-term potentiation (a process related to memory) (Hussain et al. 2000). Lead also interferes with calcium-dependent control of neurotransmitter release at presynaptic nerve terminals; it may thereby interfere with signaling between neurons and possibly with development of neural networks. In both animal and in vitro studies, lead has been demonstrated to interfere with neurotransmitter systems, including interfering with dopamine binding and the inhibition of N-methyl-D-aspartate (NMDA) receptor activity. The large body of evidence from animal studies of lead exposure and neurodevelopment supports a causal effect that is persistent following exposure early in life and that generally parallels human studies in terms of the domains of function that are impaired (WHO 1995). Concerning blood lead-effect relationships, direct cross-species comparisons of BLLs cannot be made (Davis et al. 1990), and most animal studies demonstrating lead-related developmental neurotoxicity involved doses that produced BLLs well above 10 µg/dL. However, available studies provide strong evidence of adverse effects in animals with BLLs near 10 µg/dL. It should be noted that BLLs cited in animal studies generally involve mean levels achieved in experimental groups with individual animals varying, sometimes substantially, around that mean. Non-human primates experimentally exposed to lead early in life demonstrate dose related impairments in learning and behavior (Bushnell and Bowman 1979;Rice 1985;Levin and Boman 1986). One study, involving monkeys dosed during the first 200 days of life with 100 µg/kg/day lead or 50 µg/kg/day lead resulting in average peak BLLs of 25 and 15 µg/dL respectively, showed deficits relative to control monkeys (dose=0µg/kg/day lead; average peak BLL=3 µg/dL) at age 3 years on "discrimination reversal" tasks (the animals are taught to respond to a cue and then the cue is changed and the ability to learn the new cue, with and without irrelevant cues, is measured). At the time of testing, mean BLLs in the exposed groups had fallen to 13 and 11 µg/dL, respectively. Both exposure groups showed deficits, but deficits in the lower exposed group were evident only with more complex tasks (e.g., including irrelevant cues) (Rice 1985). The same monkeys showed persistent impairments at 9 to 10 years of age (Gilbert and Rice 1987). Experimental studies in rats have demonstrated behavioral effects at mean BLLs of 10-20 µg/dL (Cory-Slechta et al. 1985;Brockel and Cory-Slechta 1998). There is uncertainty about the relationship of the tissue or cellular levels of lead linked to physiologic changes in animal and in vitro studies to the corresponding human blood lead level required to produce such levels at target sites. Although most (90 to 99%) lead in whole blood is in red cells, plasma lead level likely better reflects lead transferred from bone stores and available for transfer to target tissues (Cake et al. 1996). Because red cells have limited capacity to accumulate lead, the relation of blood lead to plasma or serum lead is non-linear with serum lead increasing more rapidly at higher BLLs (Leggett 1993). In subjects with a mean BLL of 11.9 µg/dL, plasma lead levels ranged from 0.3 to 0.7% of whole BLLs (Hernandez-Avila et al. 1998). The relation of plasma serum levels in intact animals to tissue levels measured in in vitro models is probably more complex. It is also uncertain whether in vitro studies demonstrating possible mechanisms for low-level lead toxicity reflect mechanisms operative in the intact animal. For example, Zhao et al. (1998) found that lead interfered with PKC in choroid plexus endothelial cells in a dose dependent fashion over the concentration range of 0.1-10 micromolar. However, no effect on choroid plexus PKC activity was seen in an in vivo model. # Conclusions: The fundamental nature of biochemical and physiologic changes linked to lead in in vitro and experimental animal studies illustrates potential mechanisms for lead toxicity that might be operative in humans at very low exposure levels. Experimental animal studies support the biologic plausibility of adverse health effects of lead in children at BLLs near 10 µg/dL. However, definite conclusions concerning the relationship of health status of children and BLLs <10 µg/dL cannot be drawn from these studies because of limitations of extrapolating from in vitro systems to intact animals and from animals to humans and because of the limited amount of data available from studies of animals dosed to produce a range of BLLs less than 10 µg/dL. Data from primates, which can most readily be extrapolated to humans, are especially limited. On the other hand, given the uncertainty in extrapolating across species, the fact that animal test systems cannot match the complexity of learning tasks faced by young children, and the relatively small relative difference in BLLs shown to be harmful in animals and those at issue in children, adverse health effects in children at BLLs <10 µg/dL are biologically plausible. # Blood Lead Measurement The precision and accuracy of blood-lead measurements performed in an epidemiologic study impacts observed results. If BLLs are systematically over or underestimated, biases in estimated blood lead response relationships and/or no effect thresholds will result. All blood lead measurements involve some random error, which, if a true association between blood lead and health exists, will tend to bias estimates of the relation toward the null (i.e., no effect) value. The quality of blood lead measurements varies between laboratories, between different analytical technologies, and between different specimen collection techniques. In addition, laboratory performance for blood lead has improved markedly over the last three decades and continues to improve as new analytical technologies are developed. Each of these factors becomes important in assessing the quality of blood-lead measurements used in published studies. In this section, specimen collection and laboratory factors that can affect blood-lead precision and accuracy are considered. The widespread industrial use and dispersal of lead, particularly during the last century, has ensured that it is a ubiquitous contaminant. Therefore, to prevent false-positive results, stringent procedures are necessary to reduce environmental contamination of blood collection devices and supplies. Consequently, venous blood collected using evacuated tubes and needles certified as "lead-free" is considered the most appropriate specimen for blood lead measurements (NCCLS 2001). However, collection of venous blood from pediatric subjects is sometimes difficult; thus, capillary blood from a finger puncture is used widely for screening purposes. Published studies have compared the quality of blood lead results for capillary and venous specimens drawn simultaneously (Schlenker et al. 1994;Schonfeld et al. 1994;Parsons et al. 1997). With stringent precautions, particularly rigorous hand washing, contamination errors can be held to <4% (Parsons et al. 1997). Therefore, although venous blood is preferable for epidemiologic studies of environmental lead exposure, use of capillary blood is acceptable if collected by staff specially trained in the technique using devices certified as "lead-free." Data should be provided showing an acceptably low rate of contamination errors and low mean bias in the capillary BLLs as collected using the study protocol. Currently, three analytical approaches to blood lead measurement are used: atomic absorption spectrometry (AAS); anodic stripping voltammetry (ASV), and inductively coupled plasma mass spectrometry (ICP-MS). A thorough discussion of these analytical techniques is beyond the scope of this report; however, a comprehensive assessment has been published by the National Committee for Clinical Laboratory Standards (NCCLS 2001). Briefly, the older flame atomization AAS methods, which include MIBK-extraction and Delves cup, are less precise, with a detection limit near 5 µg/dL for Delves cup (Parsons and Slavin. 1993). Thus, they are not well suited for examining relationships between BLLs <10 µg/ dL and health. The electrothermal atomization techniques based on the graphite furnace (ETAAS) are more precise and more sensitive and, therefore, have better detection limits, typically around 1.0 µg/dL. A direct comparison between ASV and ETAAS techniques (Bannon et al. 2001) shows that the latter has better precision and better accuracy. Nonetheless, when operated in experienced hands and with a stringent quality assurance/quality control (QA/QC) program that includes calibration standards traceable to the mole via isotope dilution mass spectrometry (ID-MS), ASV can deliver blood-lead measurements with accuracy and precision sufficient to examine health effects at BLLs <10 µg/dL (Roda et al. 1988). In order to assess the accuracy and precision of blood-lead measurements made for research purposes, investigators should provide information on the laboratory's performance in measuring external quality control samples and on the between-run standard deviation for routine quality control samples that span the relevant blood lead range for a given study. # Conclusions: The key considerations relevant to judging the accuracy and precision of blood lead measurements in published studies include the type and quality of blood specimen collected, analytical methodology used by the laboratory, and internal and external QA/QC procedures in place. For the purpose of studying the relationship between BLLs <10 µg/dL and health endpoints venous samples are preferred and capillary samples are acceptable with evidence of a rigorous protocol to control contamination errors. Acceptable analytic methods include electrothermal AAS, ASV, and ICP-MS. Information on laboratory performance (i.e., accuracy and precision) from external and internal quality control data should be provided. To be included in this review, studies were required to have employed suitable measurement methods. In addition, venous samples were used for most postnatal blood lead measurements in the relevant cohort studies (Table 6) and others cited in this report. Given this and the blood lead quality control procedures reported in the most informative studies, it is highly unlikely that systematic errors in measurement in the relevant studies were sufficient to bias the observed blood lead distributions enough that associations observed <10 µg/dL were attributable to BLLs above that threshold. Random variation in BLLs and random error in BLL measurement would make it difficult to collect sufficient data to identify a threshold, if one were to exist. # Blood Lead Age Trend, Tracking, and Inference Concerning Blood Lead -Effect Relations in Children Age-related changes in children's BLLs and within-child correlation of blood lead measured at different ages may influence observed associations between BLL and health at a given age. In addition, the biologic impact of lead in children is likely determined not only to the BLL measured at any one time but, also, the ages at which a given level occurs and the duration of exposure. Under most exposure scenarios, children's BLLs show a characteristic age trend. A newborn's BLL will largely reflect the BLL of its mother. Because adult women tend to have lower BLLs than young children, umbilical cord BLLs are generally lower than BLLs during childhood. During the latter half of the first year of life, however, children's BLLs begin to increase as the infant becomes more active, mobile, and exposed to ambient lead. The onset of ambulation during this period is likely to be important, as are play patterns that bring the child into contact with environmental media such as lead-contaminated dust and soils. Other factors that affect exposure include the increased hand-to-mouth activity of children, including the practice of eating "in place," i.e., in play areas. Physiologic factors, such as more efficient absorption of ingested lead in children compared with adults, and their greater food and air intake on a body weight basis might also contribute to the early postnatal rise in BLL. The mean BLL within a study sample generally peaks during 18 to 36 months of age, and slowly declines over the next few years. This blood lead profile is seen among economically disadvantaged urban minority children (Dietrich et al. 2001) and among children living near lead smelters (Figure 4) (Tong et al. 1996). In cohorts with extremely high exposures, the blood lead decline might be very gradual (e.g., Wasserman et al. 1997). In the Cincinnati Study, the same general profile was evident in each of four strata defined by average lifetime BLL, suggesting that it is, to some extent, independent of the overall level of exposure. This blood lead profile has not been observed in all study cohorts, however. In the Boston Study, for example, mean BLL varied minimally, from 6.2 to 7.6 µg/dL, from birth through 5 years of age (Rabinowitz et al. 1984;Bellinger et al. 1991). One implication of the typical profile is that maximum level is often associated with age, constituting an obstacle to an effort to identify age-specific vulnerability to lead toxicity. Compounding this challenge is that, under many exposure scenarios (particularly those involving higher exposures), intra-individual stability of BLL tends to be substantial. That is, BLL tends to "track," so that if, at time 1, child A has a higher BLL than child B, child A is likely to have a higher BLL than child B at time 2 as well. Thus, children's rank ordering tends to be similar over time even though, in absolute value, BLL rises and falls over the course of childhood. Again, however, the degree of intra-individual stability varies from cohort to cohort. In the Boston Study cohort, for instance, the extent was limited; this stability is likely attributable to the generally low BLLs of the study population (Rabinowitz et al. 1984). A BLL measured after 36 months of age will, on average, be lower than the BLL that would have been measured if a child's blood been sampled sometime during the 18 to 36 month period. Suppose, however, that the critical period with regard to producing an adverse health outcome is the 18 to 36 month period, and that, in a study conducted post-36 months, an inverse association is noted between concurrent BLL and a health endpoint. If the concurrent BLL is the only index of lead exposure history available, basing a dose-effect assessment on it will, to the extent that the natural history of BLLs in the study cohort follows the canonical form illustrated above, result in an underestimate of the BLL responsible for any adverse health effects noted at the time of or subsequent to blood sampling. In other words, one will conclude that adverse health effects occur at lower BLLs than is the case. For instance, assume that the inverse association shown in Figure 5 holds between IQ and concurrent blood lead in a cross-sectional study of 6 year olds. If, however, the BLL of each child was, on average, 5 µg/dL greater at age 2 than at age 6, and age 2 is the time of greatest toxicologic significance (i.e., it is age at which lead exposure produced the IQ deficit observed at age 6), then the dose-effect relationship that underlies the association seen at age 6 would be more accurately described as in Figure 6. This dataset would thus not be informative with respect to the functional form of the dose-effect relationship at levels below 10 µg/dL insofar as (hypothetically) all children had a BLL greater than 10 µg/dL at age 2. Other uncertainties apply to interpreting blood lead-health associations (or lack of associations) observed at any point in time. First, the relation of age to vulnerability to lead toxicity is not well understood. Is BLL during the age period 18 to 36 months more toxicologically critical than a measure of cumulative lifetime exposure, such as the area under the curve or some other exposure index? Also, it is possible that the critical age varies with dose, health endpoint, or sociodemographic factors. Available studies do not provide consistent answers to these questions. For example, in the Boston cohort, blood lead at age 24 months was most strongly related to IQ at age 10 years (Bellinger et al. 1992), whereas in the Port Pirie Cohort, the lifetime average BLL through age 5 years was most predictive of IQ at age 11 to 13 years. If 18 to 36 months is the critical age of exposure, theoretically, it is possible to "adjust" an observed blood lead distribution measured at age 6 by some function to reflect the downward trend in BLL with age and estimate the blood lead distribution at a different age, (e.g., age 2 years). However, a "one size fits all" adjustment likely is not appropriate for all children. Moreover, the appropriate adjustment is likely to be study-site-specific (i.e., depend on the key exposure sources and pathways of a particular study cohort). It would be possible to get a general sense of how accurately past peak exposure can be estimated for children in cross-sectional studies by using data collected in prospective studies in which blood lead was measured frequently during the period spanning birth to school-age. Examining the distribution of the differences between BLLs measured at ages 18 to 36 months and at age 6 would suggest the amount of exposure misclassification that would result from applying a constant adjustment factor. # Conclusions: Because of age trends in blood lead and the tendency of BLLs to "track" within individual children, inferences drawn from cross-sectional associations between blood lead and health at a given age should be interpreted cautiously because of the influence of likely higher BLLs occurring earlier in life. It may be possible to apply data on age trends and within-subject correlation of blood lead to estimate, from an observed blood lead-health association, the approximate relation to BLLs at an earlier age. However, because age trends and the extent of "tracking" of blood lead levels vary from one population to another, it is not possible to estimate with confidence the distribution of blood lead levels earlier in life for any given population whose blood lead levels were only measured at one point in time. If the only relevant studies available are based on cross-sectional data (e.g., data from NHANES III), age trends and "tracking" of BLLs would represent a substantial challenge to inferring a causal link between BLLs <10 µg/dL and adverse health impacts. However, recently published results from two cohort studies (Canfield et al. 2003;Bellinger et al. 2003) showed inverse associations between BLLs measured early in life (6 to 24 months and 24 months, etc.) and IQ measured at older ages among children whose measured BLLs did not exceed 10 µg/dL. Therefore, associations observed in cross-sectional studies cited in this report likely do not exclusively result from the impact of higher BLLs experienced earlier in life. # Quality of Neurobehavioral Assessments As with blood lead (exposure) measurements, the accuracy, precision, and consistency of neurobehavioral assessments can influence observed blood leadoutcome relations. In order to judge whether the data from a study should be considered in characterizing the functional form of the dose-effect relationship at BLLs <10 µg/dL, one would like to have access to the following information about the conduct of the neurobehavioral assessments: - Assurance that examiners were blinded to all aspects of children's lead exposure histories. - The assessment setting. Assessments can be standardized when carried out in a hospital, neighborhood health center, or community center, but may be difficult to standardize in a participant's home. - Essentials of the process by which an examiner was trained, including the criterion used to certify an examiner (e.g., percent agreement on an item-byitem basis with some gold standard, average difference in scores assigned compared with gold standard, correlation with gold standard in terms of scores assigned). - The plan implemented for supervision of test administration over the course of data collection (e.g., periodic observation of test sessions, live or by videotape). - The plan implemented for supervision of test scoring over the course of data collection (e.g., double scoring of a sample of protocols). - The number of neurobehavioral examiners used over the course of data collection. - If more than one assessor was used, whether the data analysis plan included evaluation of an "assessor" effect (i.e., as a main effect and as a modifier of lead's association with endpoints). While some have argued that neurobehavioral examiners should have professional qualifications (e.g., Kaufman 2001 cites the need for a clinician with graduate-level training in psychometrics, neuropsychology, etc.), the Practice Committee of the American Academy of Clinical Neuropsychology supports the widespread practice of using non-doctoral level personnel, with appropriate training and supervision by a doctoral-level psychologist, in the administration and scoring of clinical neuropsychological evaluations (Brandt et al. 1999). Assuming examiners are blinded regarding BLLs, most problems with quality of neurobehavioral assessment would be expected to mask or underestimate true associations rather than create spurious ones. It is possible, for example, that use of non-professional examiners might introduce noise into the data, masking an association between toxicant exposure and performance. In one study of methylmercury (MeHg) exposure (Grandjean et al. 1997), MeHg was inversely associated with children's scores on the Similarities subtest of the WISC-III among children tested by the supervising doctoral-level study examiner. Assuming that blinding was preserved, use of non-professional examiners likely would not introduce a positive bias in effect estimates. Measurement quality problems causing bias of associations away from the null, without loss of blinding, are theoretically possible. For example, if one examiner consistently yields lower scores than another and that examiner, without knowledge of BLLs, is assigned to assessments of a segment of the study population at higher risk for lead exposure, a spurious inverse association could be created between lead level and neuropsychological test scores. # Conclusions: The key considerations in judging the quality of neurobehavioral assessments in the research setting are the blinding of examiners to leadexposure history, the training and supervision of examiners, and the setting for examinations. If examiners are truly blinded, other data quality problems generally will bias estimated relationships between blood lead and outcomes toward the null. Therefore, given that examiners were blinded to BLLs in cohort studies demonstrating associations (Table 6) and the NHANES III survey, errors in measurement of neuropsychological function likely did not contribute to observed associations with BLLs <10 µg/dL. # Potential Confounding Factors # Social Factors Socioeconomic factors influence both lead exposure and many health outcomes, including intellectual development, growth, and a number of chronic conditions, creating the potential for social factors to confound associations between children's lead exposure and health in observational studies. Because cognitive function as reflected in measured intelligence is strongly associated with socioeconomic status (SES) and because cognitive function in children is the most studied health endpoint in studies of lead-exposed children, this discussion is focused on possible SES confounding of associations between BLL and measured intelligence. The potential for reported subtle effects of lead on IQ and related measures of intellect to be attributable to confounding by socioeconomic factors warrants serious consideration . Key relations required for confounding to occur are almost certainly present-SES has been shown to be related to BLLs, presumably because the neighborhoods and homes in which families of lower income reside are associated with higher levels of lead in soil and residences. Socioeconomic status also is clearly related to measures of intelligence, whether through parental stimulation, nutrition, or resources available in the home. With an inverse relationship between socioeconomic factors and lead levels (i.e., higher SES predictive of lower lead levels) and a positive relationship between socioeconomic factors and measures of intelligence (higher SES predictive of higher intelligence test scores), failure to adjust for the confounding effect of socioeconomic factors will result in confounding that overstates the harmful effect of lead on IQ because the socioeconomic effect will be mixed with any true effect of lead exposure. In addition, confounding by social factors may be a concern for some other lead-associated health measures with social gradients such as height (Silventoinen 2003). Data presented from most of the key studies included in this review strongly suggest that substantial confounding by socioeconomic factors occurs. Even with adjustment for crude measures (e.g., parental education and household income ) (Lanphear et al. 2000), the apparent lead effect on cognitive function is greatly reduced. Such a pattern in which adjustment for a crude proxy results in a substantial decrement in the magnitude of association would suggest that "residual confounding" may be present in the adjusted estimate of effect. If residual confounding is indeed present, then tighter control for confounding with more refined measures of the social environment may further attenuate or eliminate the apparent effect (Savitz et al. 1989). The following factors complicate this scenario: 1. Socioeconomic status is a very elusive construct to fully capture; it is far more complex than is reflected in parental education or income. Socioeconomic status includes many aspects of economic means and associated lifestyle, so that adjustment for operational measures, such as education or income, will always be incomplete. Adjustment for an imperfect proxy measure of a confounder results in residual confounding (Greenland et al. 1985;Savitz et al. 1989). 2. Long-term lead exposure is imperfectly reflected in a current blood lead measure or to some extent, even from a series of blood lead measures (see Blood Lead Tracking) . Whatever physiologic effect lead might produce, available evidence suggests that the impact is chronic and cumulative. Beyond what is reflected in a blood-lead measure, SES may be indicative of historical exposure; thus, the observed effect of socioeconomic status would partly reflect an effect of lead exposure above and beyond the blood-lead measure. The nature and magnitude of these associations is less clear when focusing on BLLs <10 µg/dL. Measures of social advantage, including income and parental education, are associated with BLLs <10 µg/dL (e.g., Lanphear et al. 2000). However, the relative importance of different aspects of socioeconomic status and the pathways by which they affect lead exposure are not entirely clear. The association between lower income and deterioration of paint in older housing contributes to variation in BLLs, even BLLs <10 µg/dL. The increase in geometric mean blood lead associated with living in an older home is greater for children from low-income families than for those from middle income families (Pirkle et al. 1998). Nonetheless, with the elimination of lead in gasoline and the continued decline in the proportion of homes with leaded paint (Jacobs et al. 2002), the relative importance of lead exposure sources possibly is changing. It is also possible that the association of social factors with lead exposure is different for populations with BLLs <10 µg/dL than for those above that level. Several strategies have been applied to address the role of socioeconomic factors and isolate a non-specific effect of socioeconomic factors on IQ from an effect of lead exposure. First, populations can be sought or even constructed in which blood lead is not closely associated with SES as demonstrated most clearly in the Boston cohort (Bellinger et al. 1987). In that population, all in a relatively low blood lead range for that time and the great majority of relatively advantaged SES, there was a weak positive gradient between socioeconomic status and lead. The Kosovo cohort (Wasserman et al. 1997) also departed from the usual trend in that the more SES advantaged of the two communities studied was the site of a lead smelter. As a result, adjustment for social and other covariates actually strengthened the inverse relation of blood lead to IQ in that population. etc., and not adjust for the aspects that primarily serve as a proxy for lead exposure, such as age of housing and neighborhood. One example among published research of refining and decomposing the construct of socioeconomic status has been the use of the HOME scales to adjust for stimulation provided by caregivers. Use of HOME scales has in some cases further attenuated but not eliminated apparent lead-IQ associations. A third approach to examine the possibility of confounding of the blood lead-IQ relation at low levels would be to conduct a formal statistical assessment of the extent to which the strength of the observed association across studies varies in relation to control for relevant confounders, using meta-regression, as was applied by Schwartz (1994). This approach could be refined to assess possible residual confounding. One challenge in performing such an analysis using published summary data is the difficulty in operationalizing measures of the tightness of SES adjustment while controlling for other aspects of study design that might influence blood lead-IQ slopes. An alternative approach is discussed later in this report (see Research Needs). # Conclusions: On the basis of available evidence the observed associations between blood lead below 10 µg/dL and cognitive function likely do not entirely result from confounding. This conclusion is supported by the following evidence: - The studies showing the strongest relationship (Canfield et al. 2003;Bellinger et al. 2003) at low levels employed the HOME scale for adjustment, which is the best available measure for assessing the impact of the home environment on child development. - Two cohorts, Kosovo and Boston, in which strong associations were found between blood lead and IQ, were characterized by a direct, rather than inverse, correlation of blood lead with social advantage. - Associations of children's blood lead close to 10 µg/dL and intelligence have been seen in diverse geographic and social settings. - Animal data have demonstrated effects of lead at BLLs near 10 µg/dL. On the other hand, the ability to detect confounding by omitted covariates by comparisons across studies is limited because, for most covariates of potential interest, the number of relevant studies in one group being compared is limited. In other words, for a given covariate, either few studies included it (e.g., postnatal ETS exposure) or few excluded it (e.g., SES). At this point, the case for residual confounding by social environment is speculative, but available studies relating blood lead to cognitive function in children cannot entirely exclude the possibility that observed associations are at least partly influenced by it. Such a possibility does increase uncertainty about the actual strength and shape of blood lead relationships at BLLs less than 10 µg/dL. # Iron Status Nutritional factors, such as iron and zinc intake, that might be correlated with lead uptake and might influence children's health, could confound associations between BLLs and health from observational studies. The potential for iron deficiency to confound the association between blood lead and neurodevelopmental status has been of most concern and is the focus of this discussion. The likelihood of such bias is dependent upon the extent to which iron status was controlled in a given study and the prevalence of iron deficiency in a study population. Iron deficiency may impair neurodevelopment in a manner similar to low-level lead exposure and the populations at increased risk for iron deficiency and lead toxicity may overlap (Lozoff et al. 1991;Wasserman et al. 1999). However, the association between iron deficiency and blood lead is not consistent across populations (CDC 2002). Therefore, the potential for iron to confound an association of blood lead with neurodevelopmental status will vary across populations, depending on both the prevalence of iron deficiency and its association with blood lead level. For research purposes adequate assessment of iron status entails determination of hemoglobin or hematocrit and at least two other measures of iron status. Generally accepted definitions of iron deficiency and iron deficiency anemia depend on age-and sex-specific normal ranges. The iron status measures most commonly used are mean corpuscular volume (MCV), free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP), transferrin saturation, ferritin, and, more recently, transferrin receptor. The standard for defining iron deficiency is values indicating iron deficiency on at least two of these measures and/or response to iron therapy with an increase in hemoglobin to at least 10 g/L. The utility of ferritin in young infants is under debate, making it important that functional measures, such as MCV or ZPP be obtained. There are limitations of each measure (e.g., ferritin goes up with infection, MCV is down in hemoglobinopathies, etc.). Although iron deficiency with low hemoglobin has been associated with later impairment of cognitive function (Grantham-McGregor et al. 2001), it is not certain which measure(s) of iron status are most strongly related to neurodevelopmental outcomes. In studies of children with higher BLLs, controlling for hemoglobin is problematic because lead toxicity can reduce hemoglobin in the normal range or cause frank anemia. This is less of a concern in studies of children with BLLs <10 µg/dL, a range in which no meaningful impact on hemoglobin levels has been observed. Conclusions: Measurement of iron deficiency has been absent or suboptimal in most of the studies reviewed. Two studies in which iron status was controlled for using transferrin saturation (Canfield et al. 2003) and serum ferritin (Lanphear et al. 2000) found strong inverse relationships between blood lead and cognitive function, whereas a third study that controlled for the presence of iron-deficiency anemia found the opposite (Wolf et al. 1994). Furthermore, iron-deficiency anemia is the measure of iron status most clearly linked to impaired cognitive function; therefore, it seems unlikely that the prevalence of iron deficiency anemia could be high enough in the populations showing the strongest inverse relations of blood lead to cognitive function (Canfield et al. 2003;Bellinger et al. 2003;Lanphear et al. 2000) to entirely explain these associations. In the NHANES III data used by Lanphear et al. (2000), the prevalence of iron deficiency ranged from 1% to 9%, depending on the age and sex group (CDC 2002). Finally, in Kosovo, following treatment of iron-deficient children with iron supplements, no association of earlier hemoglobin levels with IQ at age 4 (Wassserman et al. 1994) or age 7 (Wasserman et al. 1997) was found. Thus, iron deficiency likely does not completely explain the inverse associations between BLLs <10 µg/dL and cognitive function. # Tobacco Blood lead levels in children have been associated with exposure to environmental tobacco smoke (assessed by caregiver report or by urinary cotinine levels) in both general population surveys (Stromberg et al. 2003;Mathee et al. 2002;Lanphear et al. 2000;Mannino et al. 2003) and in studies of children living near lead smelters (Willers et al. 1988;Baghurst et al. 1992;Baghurst et al. 1999). The explanation for this association is not entirely clear; possibilities include enhancement of lead uptake by environmental tobacco smoke (ETS), exposure to lead in ETS itself, and differences in cleaning practices or child supervision between households with and without smokers. Maternal smoking during pregnancy has been associated with behavioral problems and impaired cognitive development in children; fetal hypoxia is one possible contributing mechanism (Habek et al. 2000). Evidence for an effect of prenatal or postnatal ETS exposure on neurodevelopment is less clear (Eskenazi et al. 1999). As with studies of lead and neurodevelopment, social factors may confound, at least in part, the association between maternal smoking and neurodevelopment (Baghurst et al. 1992). A child's prenatal exposure to maternal smoking or pre-or postnatal exposure to ETS could, if these are causally related to impaired neurodevelopment or other adverse health outcomes, confound the observed associations of lead and health. In addition, if a relationship between postnatal ETS and neurodevelopment is established, lead exposure could be a mediating factor. # Conclusions: Of the studies reviewed, most did not assess prenatal or postnatal ETS as a possible confounding factor. Those that assessed tobacco at all controlled for maternal smoking during pregnancy. However, the two exceptions, Lanphear et al. (2000) in which serum cotinine measurements were used to control for ETS and a study based on the Port Pirie cohort (Tong et al. 1996;Baghurst et al. 1992) which reported postnatal parental smoking, provide no evidence that confounding by tobacco exposure accounts for the associations observed between blood lead and adverse health effects. Limitations in available studies leave some uncertainty as to what contribution, if any, ETS might make to observed associations between BLL and health. # Causal Direction Inference of causation from observational epidemiologic studies is sometimes complicated by the possibility that the health outcome under study could be a cause of the exposure or causally related to a third factor which itself is a cause of the exposure under study. Two factors that influence blood lead levels-mouthing behavior and calcium balance-are relevant to assessing causal direction in studies of the health effects of lead at low levels. # Mouthing behavior An important pathway of lead uptake by young children is ingestion of leadcontaminated dust (Charney et al. 1980;Bornschein et al. 1985), presumably through mouthing of hands, surfaces, and objects on which the dust is deposited. Although mouthing behavior is difficult to measure, children with more reported mouthing behavior have higher BLLs in relation to environmental lead exposure (Lanphear et al. 1998;Bellinger et al. 1986;Baghurst et al. 1999). Pica (purposeful ingestion of non-food items) can be a consequence of impaired neurodevelopment and can predispose one to lead ingestion (Cohen et al. 1976;McElvaine et al. 1992;Shannon et al. 1996), but the relation of variation in "normal" age-appropriate mouthing behavior to neurodevelopment is uncertain. However, in groups of children, average measured or caregiver reported mouthing has been shown to diminish with age (Juberg et al. 2001;Tulve et al. 2002). Nonetheless, it is unclear whether, at the individual level, more frequent mouthing behavior is a marker (independent of its effect on lead ingestion) for delayed neurodevelopment. If such behavior is a marker, then an association between blood lead level and impaired neurodevelopment would result, and failure to adjust for mouthing behavior would result in an overestimate of the blood-lead effect. On the other hand, if measured mouthing behavior is associated with cumulative lead exposure above and beyond that reflected in measured BLLs, then controlling for mouthing behavior could amount to over control, underestimating the true effect of lead on neurodevelopmental measures. # Conclusions: At this point, no direct evidence supports reverse causation by mouthing behavior, and this hypothesis remains speculative. Arguing against this possibility, Tong et al. (1996) reported that an early measure of neurocognitive development, the Bailey MDI, was not predictive of later BLLs. # Calcium balance Calcium balance changes in relation to growth during childhood and during the rapid expansion of bone mass during puberty and the pubertal growth spurt (Bronner et al. 1998;van Coeverden et al. 2002;Bailey et al. 2000); estradiol may influence bone mineral deposition in pubertal girls (Cadogan et al. 1998). It is possible that effect of skeletal growth and puberty on calcium balance could cause lower BLLs (Thane et al. 2002), just as the opposite changes in calcium balance during menopause appear to cause an increase in blood lead (Hernandez-Avila et al. 2000;Garrido Latorre et al. 2003). It should be noted that the average age at menarche among U.S. adolescents dropped by approximately 2.5 months between the periods 1963-1970 and 1988-94 and that this trend was accounted for in part by a rising prevalence of obesity (Anderson et al. 2003). Average BLLs were likely falling substantially during this same period. # Conclusions: Because human studies linking blood lead at levels <10 µg/dL to delayed puberty and smaller stature are, with one exception, cross-sectional and evidence is limited on this topic, reverse causation via changes in calcium balance cannot be ruled out as accounting for at least some of the observed associations. While the parallel secular trends in decreasing age at menarche and decreasing BLLs could be explained in part to a causal effect of lead delaying age at menarche, it is also possible that other secular trends (e.g. increasing obesity rates) have caused the trend toward earlier menarche. # Overall Conclusions Question 1: Does available evidence support an inverse association between children's blood lead levels <10 µg/dL and children's health? Because of the large number of studies that have assessed cognitive function as an outcome, the review and conclusions by the WG primarily focus on this health domain. The consensus of the WG is that the overall weight of available evidence supports an inverse association between BLLs <10 µg/dL and the cognitive function of children. The evidence for such an association is bolstered by the consistency across both cross-sectional and longitudinal studies in varied settings with blood lead distributions overlapping 10 µg/dL and by the lack of any trend towards a weaker association in studies with lower population mean BLLs. More recent studies and analyses best suited to examining this association (Canfield et al. 2003;Bellinger et al. 2003) have added to, rather than refuted, evidence for such an association noted in prior CDC guidance (1991). In reaching this conclusion, the WG is mindful of limitations in the available evidence base. Relatively few studies have directly examined the association between BLLs 10 µg/dL that was not measured. Such misclassification could produce an apparent inverse association between BLLs <10 µg/dL and health status even if a threshold existed at 10 µg/dL. Such misclassification, however, could not account for the observed BLL-IQ relation in the Canfield (2003) study, in which a steeper slope was observed at BLLs <5 µg/dL than at levels 5-10 µg/dL. For health endpoints other than cognitive function, including other neurologic functions, stature, sexual maturation, and dental caries, available data are more limited and less replication of findings exists across studies. Nonetheless, the available data from these studies are consistent with associations between higher BLLs and poorer health indicators for values <10 µg/dL . # Question 2: Are the observed associations likely to be causal? The work group concluded that, while available evidence does not permit a definitive causal interpretation of the observed associations between higher BLLs and adverse health indicators for values <10µg/dL, the weight of available evidence favors, and does not refute, the interpretation that these associations are, at least in part, causal. The WG also concluded that the limitations of the available evidence, including likely residual confounding by social environment, leave uncertainty about the absolute strength and shape of the causal relation at the population level. Even greater uncertainty attends the use of associations observed in the relevant population studies for interpretation of BLLs measured in individual children at a single point in time. Thus, the WG does not believe that the individual children can be classified as "lead poisoned," as the term is used in the clinical setting, on the basis of the associations observed in studies reviewed for this report. The basis of the overall WG conclusions is discussed below and is followed by a summary of the important limitations in the available evidence. The WG explored other possible explanations (aside from causation) for these associations and concluded that none are likely to fully explain the observed data. The context of evidence from animal, in vitro, and human studies of adult populations, also supports the consensus of the WG conclusion that the observed associations most likely represent, at least in part, causal adverse impacts of lead on children's cognitive function at BLLs <10 µg/dL. The greatest source of uncertainty in interpreting the relationship between BLLs <10 µg/dL and cognitive function is the potential for residual confounding by social factors. The conditions for residual confounding appear to be present: BLLs are strongly influenced by SES, SES is clearly related to measured cognitive function, and social factors that could influence BLL and cognitive function are difficult to measure precisely. Other sources of potential bias are, individually, less concerning than social confounding, but collectively they add to the overall uncertainty about the absolute strength and shape of the relation of BLL to impaired cognitive function. These include, random error in blood lead measurement and in a single BLL as a measure of chronic exposure, possible influence of factors that have not been fully addressed in published studies, including blood lead tracking and age trend, which limits cross-sectional studies in particular, tobacco smoke exposure, iron deficiency, and mouthing behavior. Error in measuring lead exposure would bias observed associations towards the null, while failure to adjust for the other factors noted would most likely bias observed associations away from the null. The recently reported trend of asymptotically increasing slopes of lead-associated decrements in cognitive test scores at lower BLLs (Bellinger et al. 2003;Canfield et al. 2003;Lanphear et al. 2000) would be expected if residual confounding were operative as illustrated in Figure 7. The graph on the left depicts a comparison of two groups of children who live in a high exposure setting. They differ, on average, with respect to aspects of the home and social environment that are not captured in measured covariates. This results in one group ingesting and absorbing twice as much lead and having, after adjustment for measured covariates, a mean IQ 1 point lower than the children raised in a more favorable environment. Assuming a roughly linear relation of lead intake to blood lead, the result is that one group has a mean blood lead twice as high, corresponding to a 10 µg/dL difference in blood lead and an estimated blood lead-IQ slope attributable to residual confounding of 0.1 IQ points per µg/dL. The figure on the right depicts the same hypothetical two populations living in a low exposure setting. The same imperfectly measured differences in social environment contribute to the equivalent covariate-adjusted difference in mean IQ, but in this case, although one group ingests twice as much contaminated dust as before, lower levels of lead contamination result in the two children having a blood lead difference of only 1 µg/dL in blood lead level. The result is an estimated blood lead-IQ slope attributable to residual confounding of 1.0 IQ points per µg/dL. In addition, a convincing and directly relevant biologic mechanism for such a dose response relation has yet to be demonstrated. Though this hypothetical example cannot demonstrate that residual confounding underlies the steep blood lead-IQ slopes observed at low levels, it does support the need for caution in interpreting the absolute value of the estimated effect sizes. The available data for these other health endpoints, taken mostly from crosssectional studies, are more limited and firm conclusions concerning causation cannot be made at this time. # Research Needs # Resolving residual confounding through observational studies It may be somewhat easier to identify study populations with BLLs <10 µg/dL in which socioeconomic factors are not associated with exposure as compared to populations with more widely varying blood lead levels within many low SES children, but few high SES children, may have blood lead levels above 20 or 30 µg/dL. Configuring a cohort similar to the one in Boston or assembling one from the pieces of others already studied could be helpful in isolating socioeconomic and lead effects from one another. Another formal statistical approach that could be applied to pooled data across multiple studies is the application of a hierarchical modeling approach as proposed by Schwartz et al. (2003, in press). # Controlled intervention trials While experimental designs can establish causation with greater confidence than observational studies, intentionally exposing some children to higher BLLs in a randomized controlled design would be unethical. However, randomized trials in which interventions are tested for their ability to reduce BLLs <10 µg/dL or prevent their increase provide an opportunity to support or refute a causal relationship between BLLs <10 µg/dL and adverse health outcomes. Studies testing such interventions should measure covariates relevant to assessing health effects, allowing a test of the causal hypothesis should they be successful at sufficiently reducing BLLs. # Animal and in vitro studies to explore mechanisms and dose-response relations While the overall evidence from animal or in vitro models supports the biologic plausibility of adverse effects of lead at BLLs <10 µg/dL, the WG is unaware of directly relevant animal or in vitro studies that demonstrate a steeper slope for adverse effects of lead exposure at lower BLLs than observed at higher levels. Demonstrating such a relationship in experimental studies and identifying possible mechanisms would increase confidence in a causal interpretation of the observed blood lead-response relationship in studies such as Canfield et al. (2003). # Notes: Figures 2 and 3 Selected estimates of change in outcome (Full Scale IQ or McCarthy General Cognitive Index (GCI) derived from regression coefficients and listed in Table 2 and the corresponding mean BLLs of the study population are displayed in Figures 2 and 3. Figure 2 contains results from studies where the BLLs were measured at ages 4 years. Figure 3 contains the results when both the BLLs and outcome measures were measured at ages >4 years. Both the crude (open dot) and adjusted (solid dot) coefficients are displayed in the figures when both are available. (The Kosovo and European Multicenter Study papers did not provide the crude coefficient). Although multiple models for a single study population may have been fit to results from differing ages within the defined age categories, only the regression coefficients for the highest age at which blood lead was measured (per study population) are included in the figures. (The highest outcome measure age was used as a tiebreaker when necessary.) Also, when models for both a concurrent blood lead measure and a lifetime average blood lead measure existed for the highest age at which blood lead was measured (Port Pirie and Rochester), the concurrent results were included. For the study that provided multiple models for the same highest-age blood lead versus outcome measure (Lavrion, Greece), the results from the model that included the most covariates were included. Any studies not providing both a regression coefficient and blood lead mean were excluded. Three-letter abbreviations for each study population, defined in the legends below, were used on the plots. (6,7,34) specimens for 6-, 12-, 18, and 24-month specimens were collected in capillary tubes by trained technicians. Blood samples were assayed in duplicate or triplicate. The analytical system was calibrated with aqueous standards of known lead concentrations. Each batch of samples was accompanied by a blood sample of known lead concentrations to quantify intralaboratory reliability. Several standardized blood samples with lead concentrations also were included after they became available in 1982 from CDC. (Rabinowitz, et al., 1985) 57-month venous blood samples were obtained. Lead was measured in duplicate by GFAAS. An aliquot of a standardized blood sample provided by the National Bureau of Standards was included in each batch of samples. (Bellinger, et al., 1991) Cincinnati Samples were measured by venipuncture, heel stick, and finger stick for infants and were analyzed by (13) ASV. Blood samples were obtained using either venipuncture or heel stick. Approximately 72% of all samples are venipuncture. For heel stick, two capillary tubes were filled for duplicate PbB determination. If venipuncture was possible, pediatric vacutainer tubes were filled, one for PbB determination and a second for serum iron and total iron binding capacity (TIBC) analyses. The sample was aliquoted and duplicate analyses performed according to a predetermined protocol using ASV. The laboratory participates in both the CDC and PA State Blood Lead and Protoporphyrin Programs. A series of bench-top QC samples and blind QC samples were analyzed with each run. (Bornschein et al., 1985) Cleveland Samples were measured by venous and were analyzed by GFAAS. Blood samples were collected in (14,15,16) heparinized plastic syringes which had been determined to be free of trace metals. The concentration of lead in whole blood samples was determined by GFAAS. All samples were run in duplicate. The within-run (same day) reproducibility was evaluated for a sample of adult whole blood. The obtained values were 55.2 ug/dl, 1.34, and 2.4%, respectively, for the mean, SD, and coefficient of variation. Regular assessment of accuracy and precision using CDC samples of bovine blood were conducted and found to be within the certified range. Two inter-laboratory reviews were conducted for further determination of accuracy. Blood-lead levels were not adjusted for hematocrit. (Ernhart, et al., 1985) Costa Rica Samples were measured by venous and were analyzed by GFAAS. Venipuncture samples were taken (41) and red blood cells were promptly separated and frozen for future analysis in the U.S. The frozen red cells were analyzed using GFAAS in a laboratory that participates in CDC's Maternal and Child Health Resources Development Proficiency Testing Program for Blood Lead. Quality control was monitored through certified controls obtained from the National Bureau of Standards. Red cell lead values were converted to whole blood-lead levels using the formula of Rosen et al.(1974). (Rothenberg, et al., 1994) MDI was administered at 6-month intervals beginning at 6 months of age, by examiners blind to the infants' lead levels. (Bellinger, et al., 1985) For WISC-R , most children were tested in a single session, 2 were seen in a second session to complete testing, and 7 were tested in their homes by parental request. Psychologists were blind to all aspects of child's developmental and lead exposure histories. For WISC-R, one experienced psychometrician performed all the assessments. Children were tested at a pediatric clinic. The examiner was blind to the exposure levels of the child. For MDI, all assessments took place in a prenatal and child welfare clinic. Psychometric tests were administered at an inner-city health clinic by the study leader or trained assistant with whom inter-tester reliability had been previously established. Testers were blind to children's blood-lead levels. WPPSI, MDI, and Stanford Binet IQ tests were conducted by well-trained examiners blind to all risk and background information. Home testing was used to control attrition, to minimize bias in attrition, and to facilitate administration of the HOME Inventory. Inter-observer agreement was checked through observation and duplicate scoring by a supervisor for approximately one out of every 26 examinations. Agreement was maintained at r=.99. Answer sheets were checked for possible irregularities by the supervisor within a few days of each administration. Spanish versions of Bayley MDI and WPPSI were used in the assessment. A single tester, trained by one of the primary investigators and the most senior research psychologist in the country, administered the assessments. The tester was blind to the children's iron status and never knew the blood-lead levels (these were performed in the U.S.). (Lozoff, personal communication) Three Yugoslavian psychologists scored the WISC-R and the McCarthy GCI independently. All interviews and assessment instruments were translated and administered in the two dominant languages of the region, Serbo-Croatian and Albanian. Training and reliability visits occurred. The average interclass correlation for 96 tests over study period was calculated. Four trained psychologists blind to children's lead levels administered the McCarthy GCI. As there were no norms for the McCarthy scale in the Mexican population, the U.S. norms were used to calculate GCI, with a Spanish translation of the test. Interexaminer reliability was assessed by calculating the correlation in GCI scores assigned by two of the psychologists with the scores of a third psychologist whom they observed applying the test in all possible combinations with 10 subjects for each combination. Mean observer-examiner correlation was .99. Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While the results they present are largely consistent with the findings of Lanphear et al. (2000), they provided a critique of the validity of the NHANES III data for evaluating lead-related impacts on neuropsychological development in children. Because their critique cuts across on neuropyschological measurements performed in the survey, the main points of their paper are summarized in this appendix, as follows. - Stone et al. note that the weighted mean values for the four measures used by Lanphear et al. are below the predicted mean based on standardization data for these tests collected in the early 1970s for the WISC-R) and early 1980s for the WRAT. Stone et al. argue that the mean values should be higher than predicted by the standardization means because of secular improvements in cognitive test scores. One possible reason cited for the discrepancy is that NHANES tests were not administered by a psychologist. It is unclear, however, if the population sample used in the standardization data was equally representative of the U.S. population at that time or if changes in the population composition since then would lead to an increase or decrease in overall mean test performance. More importantly, it is unclear how a bias in mean score, even if real, and the use of non-psychologists for testing could produce associations between BLLs and test scores, given that examiners could not have known the BLLs of participants. If nonpsychologists produced less precise test results than psychologists would have, the expected impact on regression coefficients would be a bias toward the null. - The age-adjusted scores used in NHANES are correlated with age, and they should not be. Stone et al. show that age is negatively correlated with arithmetic, block design, and digit span and positively correlated with reading. However, since BLLs decrease with age across the age range studied, the negative correlations would tend to produce a trend towards higher scores with increasing blood lead for those tests, the opposite of the findings of Stone et al. whether interviews were in Spanish, and several other factors, were not included in analyses. However, two problems are evident in alternative "two stage" analysis provided by Stone et al. First, it uses predicted rather than residual blood lead level as an independent variable in a model relating blood lead to test scores. This amounts to testing the relation to test scores of a linear combination of covariates, many included in the model with test score as the outcome. In addition at least one variable -having to repeat a grade -is included as a covariate, possibly result serious over control as B-3 discussed earlier. Lead associated cognitive and behavioral effects have, not surprisingly, been associated with an increased risk of failure to complete high school. Thus, controlling for failure to complete a grade could amount to controlling for an effect of, rather than a confounder of the lead effect. As a whole, the Stone et al. critique of the NHANES III data do not provide a convincing argument that the findings reported by Lanphear et al. (2000) result from problems with the sample or testing methods. However, the WG did consider the limitations of the Lanphear et al. study, including its cross-sectional design and limited data on potential confounders. This study was weighed in the overall context of other relevant studies, including the more persuasive cohort studies, which are largely consistent with the associations Lanphear et al. report. # B-4 The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry R-14 # APPENDIX A: LITERATURE REVIEW AND CLASSIFICATION UPDATE A-1 The literature review began with the Agency for Toxic Substances and Disease Registry's Toxicological Profile for Lead (ATSDR Tox Profile), published July 1999. The Health Effects chapter was thoroughly read and all articles relating to low blood lead levels in children were chosen, regardless of whether they demonstrated significant results. New literature searches were then performed by Battelle's Technical Information Center. The year 1995 was chosen as the cutoff date for the new searches because the WG felt that, before this time, research rarely focused on BLLs <10 µg/dL, and that most relevant articles before 1995 were cited in the ATSDR Toxicological Profile. Searches were performed on a variety of databases using DIALOG and a set of keywords. This literature search was first run for the years 1995-2002. In spring, 2003, the search was rerun for the years 2002-2003 to determine the relevance of recently published articles. Also at this time, the search was rerun for the years 1990-1996 for relevant articles that were not cited in the ATSDR Toxicological Profile. Titles and abstracts from each literature search were reviewed, and relevant articles were ordered for further review. Additional articles were identified while reviewing the selected articles and were added to the list of references, as were several articles recommended by workgroup members. The table below provides a summary of all the articles obtained from the various sources. This table shows when the search was performed, the years covered in the search, the number of articles found in the literature search, the number of articles ordered after the titles and abstracts had been reviewed, and the number of articles that were relevant for abstraction. 2 through 6. # Summary of Literature Review Results # Date of Search # Reference Number First Author Publication Date Journal Title Altmann, L.	Brown MJ, McLaine P, Dixon S, Simon P. A randomized community-based trial of home visiting to reduce blood lead levels in children. Pediatrics. In press 2005. Moel DI, Sachs HK, Drayton MA. Slow and natural reduction in blood lead level after chelation therapy for lead poisoning in childhood.# Table of Contents Preface This is the fifth revision of Preventing Lead Poisoning in Young Children by the Centers for Disease Control and Prevention (CDC). As with the previous statements, the recommendations presented here are based on scientific evidence and practical considerations. This revision accompanies a companion document, A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels <10 µg/dL in Children, developed by Advisory Committee on Lead Poisoning Prevention which reviews the scientific evidence for adverse effects in children at blood lead levels below 10 µg/dL. The data demonstrating that no "safe" threshold for blood lead levels (BLLs) in young children has been identified highlights the importance of preventing childhood exposures to lead. It confirms the need for a systematic and society wide effort to control or eliminate lead hazards in children's environments before they are exposed. This emphasis on primary prevention, although not entirely new, is highlighted here and is clearly the foremost action supported by the data presented in A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels <10 µg/dL in Children. Although there is evidence of adverse health effects in children with blood lead levels below 10 µg/dL, CDC has not changed its level of concern, which remains at levels >10 µg/dL. We believe it critical to focus available resources where the potential adverse effects remain the greatest. If no threshold level exists for adverse health effects, setting a new BLL of concern somewhere below 10 µg/dL would be based on an arbitrary decision. In addition, the feasibility and effectiveness of individual interventions to further reduce BLLs below 10 µg/dL has not been demonstrated. CDC is conducting several activities to focus efforts on preventing lead exposures to children. First, beginning in 2003, CDC required state and local health departments receiving funding for lead poisoning prevention activities to develop and implement strategic childhood lead poisoning elimination plans. Second, CDC and its federal partners, the Department of Housing and Urban Development and the Environmental Protection Agency, launched new initiatives to control leadbased paint hazards in the highest risk housing, addressing where successive cases of lead poisoning have been identified. Third, CDC and other federal agencies are developing a systematic and coordinated response to identify and eliminate nonpaint sources of exposure (e.g., lead jewelry, food and traditional medicines, and cosmetics). CDC continues to monitor progress toward the Healthy People 2010 objective of eliminating elevated BLLs in children at the national level through the National Health and Nutritional Examination Survey and at the state and local levels through the blood lead surveillance system. These complementary data provide ix essential information for the rational distribution of resources to communities with the highest risk for lead exposure. I wish to thank both current and former members of the Advisory Committee on Childhood Lead Poisoning Prevention and consultants who developed the documents in this statement and acknowledge their contribution to the health of the nation's children. The Committee considered a number of controversial issues, examined the existing data and reviewed the report of the work group. This 2005 statement represents agreement of 12 of the 13 Advisory Committee members serving on the committee as of October [19][20]2004. Thomas Sinks, Ph.D. # INTRODUCTION The U.S. Department of Health and Human Services has established an ambitious goal of eliminating elevated blood lead levels (BLLs) in children by 2010, a qualitatively different goal from earlier goals that focused on reducing the BLL considered toxic by various target amounts. 1 Recent research on lead's health effects at low levels, which suggests societal benefits from preventing even low level lead exposure in childhood, underscores the importance of this public health goal. This revised statement describes the public health implications of research findings regarding adverse health effects at low BLLs summarized in the accompanying review, and focuses on the Centers for Disease Control and Prevention's blood lead "level of concern." This statement aims to guide public health practice and policy development and review necessary steps to ensure progress toward meeting the 2010 goal. # PREVENTING CHILDHOOD LEAD POISONING IN THE UNITED STATES The reduction of BLLs in the United States during 1970-1999, primarily because of implementation of federal and state regulations to control lead exposure, was one of the most significant public health successes of the last half of the 20th century. 2 Nonetheless, some populations and geographic areas remain at disproportionately high risk for lead exposure. [3][4][5] Specific strategies that target screening to high-risk children are essential to identify children with BLLs >10 µg/dL. Once identified, children with elevated BLLs should receive follow-up services as recommended in Managing Elevated Blood Lead Levels Among Young Children. 6 However, preventing elevated BLLs is the preferred course of action. A compelling body of evidence points to the limited effectiveness of waiting until children's BLLs are elevated before intervening with medical treatments, environmental remediation, or parental education. [7][8][9][10][11][12] Data indicate that in many cases it takes years to reduce children's BLLs once levels are elevated whether the initial blood lead elevation is very high or moderate. [13][14][15] The most common high-dose sources of lead exposure for U. S. children are lead-based paint and lead-contaminated house dust and soil. Recent studies have identified methods to reduce common household lead hazards safely. 16 Thus, a multitiered approach that includes secondary prevention through case identification and management of elevated BLLs is needed to eliminate childhood lead poisoning. However, because no level of lead in a child's blood can be specified as safe, primary prevention must serve as the foundation of the effort. # 1 # CDC'S BLOOD LEAD LEVEL OF CONCERN The adverse health effects associated with elevated BLLs have been widely studied and documented. Previously, CDC responded to the accumulated evidence of adverse effects associated with lead exposures by lowering the BLL of concern. Between 1960 and 1990 the blood lead level for individual intervention in children was lowered from 60 µg/dL to 25 µg/dL. In 1991 the CDC recommended lowering the level for individual intervention to 15 µg/dL and implementing communitywide primary lead poisoning prevention activities in areas where many children have BLLs >10 µg/dL. 17 Some activities, such as taking an environmental history, educating parents about lead, and conducting follow-up blood lead monitoring were suggested for children with BLLs of >10 µg/dL. 7 However, this level, which was originally intended to trigger communitywide prevention activities, has been misinterpreted frequently as a definitive toxicologic threshold. As the accompanying review of recent studies indicates, additional evidence exits of adverse health effects in children at BLLs <10 µg/dL. The available data are based on a sample of fewer than 200 children whose BLLs were never above 10 µg/dL and questions remain about the size of the effect. At this time there are valid reasons not to lower the level of concern established in 1991 including the following: • No effective clinical or public health interventions have been identified that reliably and consistently lower BLLs that already are <10 µg/dL. Nonetheless, the sources of lead exposure and the population-based interventions that can be expected to reduce lead exposure are similar in children with BLLs <10 µg/ dL and >10 µg/dL, 18 so preventive lead hazard control measures need not be deferred pending further research findings or consensus. • No one threshold for adverse effects has been demonstrated. Thus the process for establishing a lower level of concern would be arbitrary and no particular BLL cutoff can be defended on the basis of the existing data. In addition, establishing a lower level of concern may provide a false sense of safety about the well being of children whose BLLs are below the threshold. • The adverse health effects associated with elevated BLLs are subtle. Individual variation in response to exposure and other influences on developmental status, make isolating the effect of lead or predicting the overall magnitude of potential adverse health effects exceedingly difficult. • Establishing a level of concern substantially <10 µg/dL probably would be accompanied by a sharp increase in misclassification of children as having an elevated BLL. The uncertainty associated with laboratory testing is too great to ensure that a single blood lead test reliably classifies individual children at levels <10 µg/dL. This misclassification could confuse both parents and clinicians and expenditure of resources on testing that does not aid decision making. • Efforts to identify and provide services to children with BLLs <10 µg/dL may deflect needed resources from children with higher BLLs who are likely to benefit most from individualized interventions. • Efforts to eliminate lead exposures through primary prevention have the greatest potential for success. Reducing exposures will benefit all children, regardless of their current BLL. # RESPONDING TO DATA ON ADVERSE HEALTH EFFECTS AT BLOOD LEAD LEVELS <10 µg/dL FROM A PUBLIC HEALTH PERSPECTIVE Since 1991, CDC has emphasized the need to make primary prevention of lead poisoning, through interventions that control or eliminate lead hazards before children are exposed, a high priority for health, housing, and environmental agencies at the state, local, and federal levels. [18][19][20] Federal and state policies and programs, largely as the result of Title X of the 1992 Housing and Community Development Act (Public Law 102-550), increasingly have focused on the need for primary prevention using strategies known to effectively reduce residential lead hazards. 21 Research findings also indicate that primary prevention would be expected to benefit all children at high risk because communities with the largest percentages of children with BLLs >20 µg/dL also have the largest percentage of children with BLLs that are lower but still above the national average of approximately 2 µg/dL. 18 These data underscore the importance of targeting efforts to communities where risk for exposure is highest and provide a strong rationale for primary prevention efforts. The strategies described below will effectively direct efforts to achieve the Healthy People 2010 objective to eliminate lead poisoning in young children and can be expected to reduce lead exposure for all children. 1 Primary Prevention CDC's Advisory Committee on Childhood Lead Poisoning Prevention recently issued updated recommendations calling for the nation to focus on primary prevention of childhood lead poisoning. 22 Because the 2010 health objective of eliminating childhood lead poisoning can be achieved only through primary prevention, 22 this document provides important guidance to state and local agencies regarding the implementation of primary prevention activities. Given that the most important measure of a successful primary prevention strategy is elimination of lead exposure sources for young children, we focus here on the two main exposure sources for children in the United States: lead in housing and non-essential uses of lead in other products. Lead in Housing-Because lead-based paint is the most important source of lead exposure for young children, the first essential element of primary prevention is implementation of strategies to control lead paint-contaminated house dust and soil and poorly maintained lead paint in housing. [23][24][25] After 10 or more years of widespread blood lead testing and data collection by CDC-supported state and local agencies, the specific addresses of housing units at which children repeatedly have been identified with elevated BLLs are known to local officials. Two examples are: • In Detroit, 657 addresses accounted for nearly 1,500 children with BLLs >20 µg/dL during the last 10 years because the sources of lead were never controlled completely when the initial case occurred. These housing units also probably were the source of lead exposure for several thousand Detroit children with BLLs >10 µg/dL. 26 • In Louisville, Kentucky, 35% of children identified with elevated BLLs during the last 5 years resided in 79 housing units; these units represent <0.3% of all housing units in the community. 27 These experiences are repeated in high-risk communities across the country. The infrastructure needed to identify high-risk housing and to prevent and control lead hazards in such housing is largely in place. Established firms certified in lead hazard evaluation and control now exist in most communities, as do other skilled trades people trained in lead-safe work practices necessary during routine maintenance and painting. Systematic identification and reduction of residential lead sources, particularly in old, poorly maintained housing where children with elevated BLLs are known to have lived, combined with periodic monitoring of housing conditions to detect new deterioration and resultant lead hazards will prevent lead exposure to children in the future and break the cycle of repeated cases of elevated BLLs. Other steps critical to success in controlling lead hazards in housing and preventing lead exposure in the future are 1) enforcement of lead safety and housing code requirements to ensure good property maintenance; 2) widespread adoption of leadsafe work practices to control, contain, and clean up lead dust during painting and remodeling projects; and 3) periodic monitoring of housing conditions to detect new deterioration and resultant lead hazard. Nonessential Uses of Lead-Because areas of the United States report that as many as 35% of children identified with elevated BLLs have been exposed to items decorated or made with lead, in some cases resulting in life-threatening BLLs, 28 the second crucial element of a primary prevention strategy is identification and restriction or elimination of nonessential uses of lead, particularly in both imported and domestically manufactured toys, eating and drinking utensils, cosmetics, and traditional medicines. This effort requires identifying communities where cultural practices and traditional medicines may put children at risk and incorporating lead poisoning prevention activities into health and community services that reach families at high risk for lead exposure from nonpaint sources. 7 The 2010 health objective cannot be achieved without a more systematic approach that, at a minimum, allows identification of lead-contaminated items and prohibits their sale before children are exposed. Ultimately, all nonessential uses of lead should be eliminated. # RECOMMENDATIONS # Changes in the Focus of CDC-Funded Programs To achieve these goals, CDC is focusing on eliminating childhood lead poisoning by preferentially funding programs to provide lead-related services for communities and populations with large numbers of children at high risk for lead exposure. The cooperative agreements with 42 state and local health departments funded for [2003][2004][2005][2006] emphasize the importance of primary prevention and require funded state and local programs to work aggressively to develop and implement the necessary partnerships, programs and activities. CDC requires its state and local partners to undertake a strategic planning process, which includes gathering input from housing professionals, pediatric health-care providers, advocacy groups, parents of children with elevated BLLs, and others interested in preventing lead poisoning in children. These strategic plans, developed by local partners to respond to local conditions, drive primary prevention activities for the 3-year grant cycle. Progress toward eliminating childhood lead poisoning can be measured only by ongoing surveillance of BLLs in childhood populations where the risk for exposure is high, as well as continued monitoring of population-based BLLs through the National Health and Nutrition Examination Survey. 29 CDC's role in supporting state and local efforts and providing technical assistance to improve data management and reporting is essential to these activities. # Recommendations to Federal, State, and Local Government Agencies Achieving the Healthy People 2010 objective to eliminate childhood lead poisoning requires collaboration by many different federal, state and local agencies. Many of the roles and responsibilities for federal partners in the elimination effort are detailed in the report of the President's Task Force on Environmental Health Risks and Safety Risks in Children. 29 However, all levels of government share responsibility for primary prevention of childhood lead poisoning. Government agencies have the ability, through legislative and enforcement actions to spearhead prevention efforts and articulate clear public health goals and strategic priorities at the federal, state, and local government levels. # Federal agencies should: 1. Support and disseminate information about, and adequately fund, programs and interventions that will lead to full implementation of primary prevention. 2. Expand financial resources for permanent measures to control or eliminate residential lead hazards. 3. Monitor and enforce regulations controlling lead content of various environmental media, including air, water, and soil. 4. Identify populations in which the risk for exposure to nonpaint sources of lead is high, and develop strategies to minimize the risk. 5. Develop and implement regulatory and voluntary strategies to control nonessential uses of lead, particularly in items that are easily accessible to young children, such as toys, jewelry, eating and drinking utensils, traditional remedies, and cosmetics. 6. Evaluate the effectiveness of primary prevention activities in reducing lead exposure and eliminating childhood lead poisoning, particularly in areas where the risk for lead poisoning is substantially higher than for the general U. S. childhood population. 7. Develop new mathematical models of lead exposure or modify existing models, e.g., the Integrated Exposure Uptake and BioKinetic (IEUBK) Model for lead in children, currently used to establish thresholds for lead exposure in consumer products and areas with pervasive lead contamination. The exposure modeling should predict the magnitude of the increase in BLLs in a child as a result of exposure to a specific lead source rather than the probability of a BLLs >10 µg/dL. # State and local agencies should: 1. Update or establish and enforce regulatory requirements for lead safe housing that link lead safety to the housing and/or sanitary code. 2 Require that properties that have undergone lead paint abatement or substantial renovation to lead painted surfaces meet the EPA dust clearance testing prior to re-occupancy. Require dust testing in all cases where public health agencies have ordered paint repair, particularly in the homes of children already identified with elevated BLLs. 3 Promote broad use of lead-safe work practices for routine painting and maintenance projects in older homes, and make training in such practices widely available at low or no cost to painters, remodelers, landlords, and maintenance workers. 4. Establish formal agreements among health, social services, housing, and legal agencies to increase the sharing of data, educational information, violations, and success stories. 5. Provide information to caregivers about temporary measures that can reduce lead exposure as described in Managing Elevated Blood Lead Levels Among Young Children, 6 as well as information and referral for permanent abatement services. Recommendations to Health-Care Providers and Community-Based Health and Social Service Agencies CDC recommends that health care providers continue their traditional role of providing anticipatory guidance as part of routine well-child care, assessing risk for exposure to lead, conducting blood lead screening in children, and treating children identified with elevated BLLs. In addition health-care and social service providers are urged to expand their roles. They should keep abreast of research data that clarify the relationship between lead exposure and neurocognitive development in children. They also can strongly advocate for children and foster lead exposure prevention by helping facilitate implementation of the specific strategic plans to eliminate childhood lead poisoning in their local and state communities. Health-care and social service providers are highly effective child advocates, and their active participation in the process provides the expertise and leadership needed to reach this goal. Health-care and social service providers should: 1. Provide culturally appropriate education to all pregnant women and to families with young children about the principal sources of lead and ways to reduce exposure. 2. Target outreach, education, and screening programs to populations with the greatest risk for lead exposure. 3. Become aware of, and actively support, lead poisoning elimination efforts in the community. 4. Express concern to federal, state, and local policy and decision makers that children live in a lead safe environment and actively support legislation and regulatory initiatives. Advocate for lead-safe, affordable housing by supporting appropriate legislation. 5. Become aware of and comply with lead screening policies issued by Medicaid or state and local health departments. 6. Ensure training of staff members engaged in housing renovation or rehabilitation in lead-safe work practices. # CONCLUSION The Healthy People 2010 objective to eliminate BLLs >10 µg/dL in children is within our grasp. Research to further characterize and isolate the harmful effects of lead associated with various BLLs will help answer remaining questions and further refine the public health response. However, the approach needed is clear: identify and address existing lead hazards before children are exposed, otherwise hundreds of thousands of children will be placed at risk needlessly. The overall reduction of lead in the environment will benefit all children. 6 # List of Tables # EXECUTIVE SUMMARYÊ In March 2002, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) established a work group (WG) to review the available evidence of possible health effects of blood lead levels (BLLs) of below 10 micrograms per deciliter (µg/dL), the level of concern currently established by CDC. The WG was charged with designing and following a rigorous protocol to review studies of the health effects of lead exposure at very low BLLs. The workgroup intended to focus on studies of the effects of peak BLLs at <10 µg/dL in children never known to have a BLL exceeding 10 µg/dL. However, there are relatively few such studies and the workgroup decided to review the larger number of studies that could indirectly support or refute the existence of a threshold near 10 µg/dL. Although the workgroup members were the primary authors of this report, the ACCLPP reviewed the document and it was revised based on their comments. The majority of ACCLPP members accepted the findings of the report, with two members dissenting. # Methods The following criteria were used for selecting relevant studies to review: • BLLs were measured using graphite furnace atomic absorption spectrometry (GFAAS) or anodic stripping voltammetry (ASV); • the study was published in English; • for studies in which IQ or General Cognitive Index (GCI) was a measured outcome, an assessment of the association between BLLs in children and IQ or GCI was included; and • for studies in which IQ or GCI was not a measured outcome, an assessment of the association between BLLs in children and a specified health outcome was included. For each relevant study, a structured abstraction was performed that captured the following: • study location and sample size; • age at which BLL and cognitive or health outcome was measured; • the distribution of BLLs (mean or other measure of central tendency and variance) and percentage of participants with BLL <10 µg/dL; iii • crude and adjusted regression coefficients relating BLLs to outcome; • other measures of association (e.g., correlation coefficients); and • model type and covariates included in adjusted models. When reviewing the evidence, including indirect evidence from IQ studies, the workgroup considered both alternate explanations for study findings and potential effect of residual confounding. # Conclusions The main conclusions reached by the WG are summarized as follows. 1. Does available evidence support a negative association between measured BLLs <10 µg/dL and children's health? • The overall weight of available evidence supports an inverse (negative) association between BLLs <10 µg/dL and the cognitive function of children. • A steeper slope in the dose-response curve was observed at lower rather than higher BLLs. • The available evidence has important limitations, including the small number of directly relevant cohort studies and the inherent limitations of cross-sectional studies (i.e., the lack of data regarding both BLLs earlier in life and key covariates). • For health endpoints other than cognitive function (i.e., other neurologic functions, stature, sexual maturation, and dental caries), consistent associations exist between BLLs <10 µg/dL and poorer health indicators. # Are the observed associations likely to represent causal effects of lead on health? • Though not definitive, the available evidence supports the conclusion that the observed associations between BLLs <10 µg/dL and cognitive function are caused, at least in part, by lead toxicity. • The strength and shape of the causal relationship are uncertain because of limitations of the available evidence. • The health effects of lead are uncertain in individual children who have BLLs measured at a single point in time. Thus, scientific evidence does not provide a basis for classifying individual children with BLLs <10 µg/dL as "lead poisoned," as the term is used in the clinical setting. • The greatest source of uncertainty in evidence concerning the relationship between BLLs <10 µg/dL and children's cognitive function is the potential for residual confounding, especially by socioeconomic factors. • The available data for health endpoints other than cognitive function, taken mostly from cross-sectional studies, are limited; therefore, firm conclusions concerning causation can not be made. # Future Research Needs The WG identified the following research needs to address gaps in the existing base of evidence and to allow for more definite conclusions about the strength and shape of the causal relationship. • Prospective observational studies designed to minimize the chance of residual confounding. • Randomized trials to test interventions designed to reduce BLLs <10 µg/dL and assess the impact on children's cognitive development. # Background # Charge to the Work Group In March 2002, the Advisory Committee on Childhood Lead Poisoning Prevention agreed to establish a work group (WG) to review evidence of possible health effects of lead at blood lead levels less than 10 micrograms per deciliter (µg/dL), currently the threshold for defining an elevated blood lead level according to CDC guidelines (CDC 1991). The work group was charged as follows: "In October 1991, the Centers for Disease Control and Prevention issued Preventing Lead Poisoning in Young Children. This document heralded a change in the definition of the level for intervention for children with elevated blood lead levels (EBLLs) from a lead level of 25 µg/dL to 10 µg/dL. The report explained that this change was due to new data that indicated significant adverse effects of lead exposure in children at levels once thought to be unassociated with adverse effects. The 1991 document identified a goal to reduce children's blood lead levels below 10 µg/dL. Interventions for individual children were recommended at levels of 15 µg/dL and above. Research findings published and disseminated since October 1991 suggest that adverse effects from lead exposure and toxicity occur at blood lead levels below 10 µg/dL. Some studies suggest that some effects may be greater at blood lead levels (BLLs) below 10 µg/dL than at higher BLLs. Such research findings raise concerns about the inability to control lead exposure with conventional methods and lend credence to the importance of primary prevention measures to prevent lead exposure to children. The work group will be convened by the Advisory Committee on Childhood Lead Poisoning Prevention to review the existing evidence for adverse effects of lead exposure and toxicity on children at very low blood lead levels and to focus on effects at levels of 10 µg/dL and below. Rigorous criteria will be established for the literature review. The work group will then create, in conjunction with the committee, a summary of the evidence for publication." # Scientific and Public Health Context for the WG Review Prior reviews that compiled the extensive evidence from in vitro, animal, and human studies established lead as a multi-organ toxicant, including studies showing health effects at BLLs near 10 µg/dL (ATSDR 1999;WHO 1995;USEPA 1986). The published studies include a large body of literature establishing that lead is a developmental toxicant and that harmful effects of lead on children's development can occur without clinical signs, symptoms, or abnormal routine laboratory tests. In addition, a growing number of studies suggest that BLLs prevalent in the general population are associated with adverse health effects in adults and in the offspring of pregnant women. Finally, in more recent years, bone-lead levels measured by x-ray fluorescence have been used in epidemiologic studies as a measure of cumulative lead exposure. Although these were not considered in this review, a number of studies showing inverse relations of bone-lead level to health in general population samples (e.g., Cheng et al. 2001) add further evidence that cumulative lead exposure may be harmful to health at typical background exposure levels for the population in the United States. The observation that available epidemiologic evidence does not demonstrate a threshold below which no effect of lead is possible is not new. A review prepared for a 1986 workshop on lead exposure and child development stated, "There is little evidence for a threshold or no-effect level below which the lead/IQ association is not found. IQ deficits have been reported in studies where the mean lead level is 13 µg/dL (Yule et al. 1981) and similar deficits in the Danish study where the primary measure was tooth lead, but BLLs are lower at around 7 µg/dL." (Smith 1989) A review, meta-regression, and reanalysis of existing data (Schwartz 1994) reached essentially the same conclusion. Available data did not suggest a threshold below which no association between BLLs and intelligence in young children was evident. Recent studies (Canfield et al. 2003;Lanphear et al. 2000;Moss et al. 1999;Wu et al. 2003) provided more direct evidence of an association between BLLs and adverse health effects in the domains of cognitive function, neurologic function, growth, dental caries, and onset of puberty at levels well below 10 µg/dL. Thus, a reexamination of this issue is in order. As evidence from experimental animal studies and human epidemiologic studies has grown, CDC has lowered the BLL considered elevated for the purpose of interpreting clinical test results of an individual child (Table 1). CDC guidelines also have provided criteria for identifying children who have more severe manifestations of lead toxicity and/or a higher risk of lead-related sequellae. For example, CDC's 1975 and 1978 guidelines defined clinical "lead poisoning" on the basis of BLLs, symptoms, and/or levels of erythrocyte protoporphyrin (EP) or other indicators of lead-related biochemical derangements. CDC's 1985 guidelines used the terms "lead toxicity" and "lead poisoning" interchangeably to refer to BLLs >25 µg/dL with EP >35 µg/dL. However, the guidelines acknowledged that "lead poisoning" is generally understood for clinical purposes to refer to episodic, acute, symptomatic illness from lead toxicity. CDC's 1985 guidance also cautioned that blood lead thresholds established to guide follow-up and treatment for individual children "should not be interpreted as implying that a safe level of blood lead has been established." In 1991, CDC guidelines more directly acknowledged the difficulty in assigning terms to specific ranges of BLLs given the different settings in which BLLs are interpreted and given that manifestations of lead toxicity occur along a continuum: "It is not possible to select a single number to define lead poisoning for the various purposes of all of these groups [e.g. clinicians, public health officials, and policy makers]" (CDC 1991). These guidelines also noted, "Some [epidemiologic] studies have suggested harmful effects at even lower levels [than a BLL of 10 µg/dL]." In addition to these changes in criteria used to evaluate blood lead test results for individual children, recent analyses by the U.S. Department of Housing and Urban Development (HUD 1999) and the U.S. Environmental Protection Agency (USEPA 2000) to support the development of regulations governing lead exposure have assumed that the relation of increasing blood lead to decrements in children's IQ extends to BLLs <10 µg/dL. As BLLs considered elevated have fallen, measures to reduce or remove lead from a number of sources, including gasoline, soldered food and beverage containers, paint, drinking water, and industrial emissions have resulted in a dramatic decline in BLLs in the United States since the mid-1970s (Pirkle et al. 1994). The Second National Health and Nutrition Examination Survey (NHANES II) conducted from 1976 to 1980 demonstrated that, among U.S. children ages 6 months through 2 years, 84% of white children and more than 99% of black children had BLLs >10 µg/dL, and the median BLLs were 14 and 19 µg/dL, respectively (Mahaffey et al. 1982). A decline in BLLs during the course of that survey was noted, paralleling the falling consumption of leaded gasoline (Annest et al. 1983). A continued decline in BLLs was evident in subsequent NHANES surveys (Pirkle et al. 1994;NCEH 2003) and in clinical blood-lead test data compiled by state and local health agencies (Hayes et al. 1994;CDC 2003). Nationally, it is estimated that by 1999-2000, the prevalence of BLLs >10 µg/dL among children 1 to 5 years of age had fallen to 2.2% and the median level to 2.2 µg/dL (NCEH 2003). Although these reductions in lead exposure represent great progress, scientific advances have shed light on harmful effects of lead at levels of exposure once thought safe. In addition, industrial activity has widely dispersed lead in the environment from naturally occurring deposits. As a result, even at the lower exposure levels that prevail today, typical body burdens of lead are likely to be much higher than those present in pre-industrial humans, which by one estimate corresponded to a BLL of 0.016 µg/dL (Smith et al. 1992). Therefore, the potential for additional subclinical adverse effects of lead from currently prevailing exposures deserves careful study. Finally, although falling BLLs have benefited all demographic groups (Pirkle et al. 1994), stark demographic and geographic disparities continue to reflect the historic pattern; the risk of elevated BLLs in communities where poverty and older (i.e., that built before 1950) housing are prevalent remains several fold higher than the national average (Lanphear et al. 1998). # Review Methods # Scope and Approach Given the charge to the work group and the scientific and public health context, the WG did not attempt a comprehensive review of all evidence relating lead exposure to health. Instead, the WG set out to answer the following questions: 1. Does available evidence support negative associations between health indicators and children's blood lead levels measured <10 µg/dL? Ê 2. Are the observed associations likely to represent a causal effect of lead on health? To address these questions, the WG established criteria (see Methods) for published studies that would address the first question. In addition, the work group identified issues relevant to making causal inference from any observed associations. Identifying such issues is an essential step in interpreting evidence relevant to the WG charge. Human studies to assess potential health effects of environmental toxicants, such as lead, are usually observational in design (i.e., the health status of participants is related to some measure of exposure, dose, or body burden that varies on the basis of environmental factors and not experimental manipulations by the investigator). For ethical reasons, the limited number of human experimental studies that have evaluated causal relations between toxicant exposures and health usually have involved attempts to reduce exposure or body burden and assess the impact on health status. Such studies of lead-exposed children are rare, and to date none have focused on children with BLLs <10 µg/dL. Observational studies have inherent limitations-not specific to studies of lead toxicity-with the potential to produce biased results. Biases from observational studies can obscure true causal effects of toxicant exposures or produce associations between toxicant exposures and health status when no causal relation is present. Thus, statistical associations from individual observational studies or multiple studies subject to similar biases cannot establish causal relationships; additional, non-statistical criteria may be used to evaluate such evidence. Although causal criteria have been stated in various ways, the Surgeon General's Report on Smoking and Health (U.S. Public Health Service 1964) provides a useful set of criteria. They include: • The consistency of the association. Is a similar association observed across studies with varying methods and populations? • The strength of the association. The strength of an association is the extent to which the risk of a disease or a measure of health status varies in relation to exposure and can be expressed, for example, as a relative risk or regression coefficient. It is distinguished from the statistical significance of an association that reflects both the strength of the association and the sample size. An additional criterion, specificity of the association, is closely related to strength of the association and is considered less important in the context of multifactorial health conditions. • The temporal relationship of associated variables. Does the hypothesized causal exposure occur before the health outcome associated with it? • Coherence of the association. Is the observed association consistent with other relevant facts including, for example, experimental animal studies and the descriptive epidemiology of the health condition under study? The application of these criteria does not provide a clear demarcation for concluding definitive proof of causation versus inadequate evidence. Rather, the more the available evidence meets these criteria, the greater the confidence in causal inference about an association. Consistent with these criteria, the WG identified several issues specifically relevant to inferring causality from associations (or the lack of associations) of BLLs to health measures observed in studies of lowlevel lead exposure. These potential biases are not unique to studies of children with BLLs <10 µg/dL (e.g., Smith 1989). However, the larger number of human and experimental animal studies (including primate studies) and the nature of observed health effects associated with higher BLLs have conclusively demonstrated the adverse health effects of lead. However, far fewer studies of possible health effects of BLLs <10 µg/dL have been conducted, and the relative importance of some sources of bias may be greater at these lower levels. Therefore, the work group considered several issues in interpreting the findings of available studies (see Discussion). At the time of the WG's review, a consortium of investigators from several longitudinal studies of lead exposure and cognitive function in children were conducting a reanalysis of data pooled from these studies. These studies included serial measures of blood lead level, cognitive function, and a large number of potential confounders, thus providing stronger evidence than is available from cross-sectional studies. A focus of the pooled reanalysis involved studying the shape of the association between postnatal lead exposure at low levels and measured IQ (B. Lanphear, personal communication, 2003). The WG reviewed published reports from individual cohort studies from which data were pooled, but the final results of this pooled reanalysis were not available for inclusion in the WG report. [Note: Results of the pooled renanlysis were published (Lanphear et al 2005) after the WG finished its review.] Because of the nature of its charge, the WG did not develop policy recommendations or address questions relevant to such recommendations. Such policy decisions and questions will, if appropriate, be considered by the full ACCLPP after reviewing the findings of this report. # ____________________ # Criteria for Relevant Studies The WG initially considered, then rejected, limiting its review to studies for which published results provide direct comparisons between children with varying BLLs <10 µg/dL. Such a review would include a relatively small number of studies. Instead, the group decided that the larger number of studies that have included IQ as an outcome could, collectively, indirectly support or refute the existence a threshold near 10 µg/dL for the blood lead-IQ association. The rationale for this approach is based on that used in a review and metaregression reported by Schwartz (1994) and outlined in the following paragraphs. Suppose that, hypothetically, a threshold exists near 10 µg/dL, above which mean IQ decreases linearly with increasing blood lead, with a slope equal to x and below which mean IQ is not associated with blood lead 1 (see Figure 1-Hypothesized "true" relation A). In studies of children who have BLLs <10 µg/dL, estimated slopes would be, in the absence of sampling error, equal to 0. For studies in which all children have BLLs above the threshold, the estimated slope would be, again ignoring sampling error, equal to x. For studies in which some children have blood lead above and others below the threshold, estimated slopes will vary between 0 and x as shown in Figure 1. Thus, if regression coefficients estimating the IQ-blood lead slope are less negative (approaching 0) in populations with lower mean BLLs than in populations with higher mean levels, a threshold near 10 would be suggested. The absence of such a trend or an increase in slopes with decreasing mean blood lead level of the population studied would provide evidence against such a threshold and instead support "true" relations B and C, respectively. This ideal hypothetical case presumes that effect sizes from the studies compared are based on models that correctly specify the form of the BLL-IQ relation and that factors that might modify the relation do not vary across studies. Because of this approach, studies that assessed the association between blood lead and measured IQ were included in this review, even if the published results did not examine blood lead-IQ associations limited to BLLs <10 µg/dL (as was true in most cases). An additional reason for considering studies that measured IQ was the relationship of IQ to other outcomes of policy and public health importance including educational success and earnings potential (Grosse et al. 2002). Because the McCarthy Scales of Children's Ability (MSCA) General Cognitive Index (GCI) was used in a number of studies to measure cognitive function in preschool children and because GCI and IQ scores have similar distributions, studies using GCI as an outcome were also included in this review. The following criteria were used to select relevant studies to review for this report: 1. Blood lead levels were measured using graphite furnace atomic absorption spectrophotometry (GFAAS) or anodic stripping voltametry. 2. The study was published in English. # In addition, For studies in which IQ or GCI was a measured outcome, the study analyses included an assessment of the association between BLLs measured in children and IQ or GCI. For studies in which IQ or GCI was not a measured outcome, the study analyses included an assessment of the association between BLLs <10 µg/dL measured in children and a health outcome. The assessment could either be formal (e.g., non-linear modeling, linear modeling restricted to populations with all or at least 95% of children having BLLs <10 µg/dL, statistical comparison of two or more subgroups with BLLs <10 µg/dL) or informal (e.g., graphical display of results permitting visual assessment of blood lead-outcome relation in the range <10 µg/dL). # Literature Search To identify potentially relevant articles, a comprehensive report published by the Agency for Toxic Substances and Disease Registry (ATSDR 1999) was reviewed first to identify cited articles that related to low-level lead exposure in children. The list of potentially relevant citations identified in the ATSDR report was supplemented by three computerized literature searches, using Dialog ® to search Medline, Toxfile, and other bibliographic databases. Search terms (see Appendix A) were chosen to identify articles reporting on blood lead measurements and one or more domains of health related to lead exposure including neurodevelopment, cognitive function, intelligence, behavior, growth or stature, hearing, renal function, blood pressure, heme synthesis, hematopoiesis, and Vitamin D metabolism. The first search spanned articles published from 1995 through 2002 and indexed as of September 2002, the month and year that the initial search was performed. The second search was performed in April 2003 and spanned the period 2002 through the search date. A third search, spanning the years 1990 through 1996, was performed when a relevant article not cited in the ATSDR toxicological profile was identified by one of the work group members. In addition, potentially relevant articles were identified by work group members and through citations in articles identified previously. Abstracts were reviewed initially. If they were ambiguous or if they suggested the article was relevant, full articles were checked for relevance. Articles deemed relevant were abstracted for this report. Appendix A summarizes the number of possibly relevant references identified, full articles checked for relevance, and relevant articles abstracted and considered in the review. # Structured Abstracts For each relevant study, a structured study abstraction was performed that captured the following information: the study location, sample size, age at which blood lead was measured, age at which the outcome was measured, available information about the blood lead distribution (including mean or other measure of central tendency, variance, and percent of participants with BLLs <10 µg/dL), the crude and adjusted regression coefficients relating blood lead to outcome (if available), the type of model fit (linear, log linear, or other), and the covariates included in the adjusted model. If regression coefficients were not available, other measures of association reported (e.g., correlation coefficients) were noted. Because some studies fit multiple blood lead-outcome models (e.g., cohort studies with blood lead and IQ measured at multiple ages), relevant information about each model estimated was abstracted. For IQ studies, covariates measured and not included in adjusted models were recorded when available. # Review of Cohort Study Methods Among relevant published results were those from cohort studies specifically designed and conducted to study the relation of BLLs to children's cognitive function and other health outcomes. Because these studies had the strongest and best-documented study designs for this review, methods used for blood lead measurement and neuropsychological assessment were summarized for these studies. This information was collected from published studies; in some cases, the studies were supplemented by information provided through correspondence with the investigators. # Results # Studies Relating Postnatal Lead Exposure to IQ or General Cognitive Index Studies in which IQ or GCI were measured as an outcome and other criteria were met included 23 published reports from 16 separate study populations. Results from these studies are summarized in Table 2 (full scale IQ and GCI), Table 3 (performance IQ), and Table 4 (verbal IQ). Within each table, results are grouped according to the age at blood-lead measurement and age at outcome measurement; each grouping displays results sorted according to the measure of central tendency of the blood-lead distribution. Because some studies used linear models (BLLs were untransformed) and some used log-linear models (BLLs were log transformed), estimated regression coefficients were, when possible, used to calculate the estimated change in IQ or GCI corresponding to a blood lead increase from 5 to 15 µg/dL to allow for comparisons across studies. Covariates included in adjusted models are grouped into several broad domains that were addressed in most of the published studies. Among studies that provided results for the size and direction of the associations between BLLs and Full Scale IQ or GCI, regardless of statistical significance, a majority revealed that both crude and adjusted associations were consistent with an adverse effect-IQ decreases with increasing levels of blood lead. In most cases, covariate adjustment attenuated, but did not eliminate, these estimated associations. Findings for performance and verbal IQ were similar, with some studies showing stronger associations of lead with performance IQ and others with verbal IQ. Notable exceptions to this pattern, however, were found. Results from the Cleveland cohort (Ernhart et al. 1987(Ernhart et al. , 1988(Ernhart et al. , 1989) indicated a crude inverse association between blood lead and IQ but no association with covariate adjustment. In the Cincinnati and Boston cohort studies, BLLs measured at or below 12 months of age showed no association or a slightly positive association with covariateadjusted IQ (Dietrich et al. 1993;Bellinger et al. 1992). Though published results from a cohort study in Costa Rica (Wolf et al. 1994) did not provide the size and direction of the estimated blood lead-IQ slope, unpublished results provided to the WG did show covariate-adjusted IQ increasing with BLL (B. Lozoff, personal communication 2003). The estimated BLL-IQ association in the Kosovo cohort was strengthened substantially with covariate adjustment (Wasserman et al. 1997). No trend toward attenuation of the association between blood lead and IQ (or GCI) across studies with decreasing average BLLs is evident (Figures 2 and 3). In one of these studies, analyses were presented that provide more direct information concerning the association between BLL and cognitive function at BLLs <10 µg/dL. The steepest estimates of blood lead-IQ slope from the Rochester (Canfield et al. 2003) studies were based on analyses restricted to children whose measured BLL never exceeded 10 µg/dL. The estimated slope was substantially larger than those estimated from the entire study population (9.2 versus 5.3 IQ point reduction in covariate adjusted IQ for BLL increase from 5 to 15 µg/dL). Canfield and his colleagues ( 2004) also reported a non-linear model supporting a steeper blood lead-IQ slope at lower levels. Though published as a letter to the editor, rather than in a peer-reviewed article (and therefore not included in the structured review), similar findings were reported for a reanalysis of the Boston cohort: a steeper BLL-IQ slope in the population of children whose measured BLLs never exceeded 10 µg/dL, compared with the entire study population (Bellinger et al. 2003). Most of the published studies included at least one measure of socio-economic status. All of the published results from cohort studies were adjusted for Home Observation for Measurement Environment (HOME) score and birth weight; all except the Costa Rica cohort were adjusted for a measure of maternal intelligence. A reanalysis of the data from the Costa Rica cohort with adjustment for maternal IQ was consistent with the original finding of a non-significant positive blood lead-IQ slope (B. Lozoff, personal communication, 2003). Prenatal exposure to maternal smoking was adjusted in the majority of studies, whereas only in the Port Pirie cohort was a measure of postnatal environmental tobacco smoke exposure included. Iron deficiency anemia was included as a covariate in results from the Costa Rica study, which found no association of lead and IQ; the inverse blood lead-IQ associations in the Rochester study (Canfield et al. 2003) and the Karachi study (Rahman et al. 2002) were adjusted for serum transferrin saturation and hemoglobin, respectively. In addition, in the Kosovo study (Wasserman et al. 1997), alternative models were fit with adjustment for hemoglobin, resulting in no appreciable change in the lead coefficient. Not all studies reported regression coefficients that could be used to estimate the change in IQ associated with a BLL change of 5 to 15 µg/dL, and the overall pattern of results summarized above and in Figures 2 and 3 might have been altered had regression coefficients been available from all studies. For example, a member of the WG provided results of reanalysis of the data from the Costa Rica cohort, which showed no evidence of an inverse relation of BLL to IQ with adjustment for maternal IQ and other covariates used in the published result (Wolff et al. 1994;B. Lozoff, personal communication, 2003). # Studies of Health Endpoints Other than IQ and CGI More stringent criteria were required for inclusion of studies in this review if they assessed health endpoints other than general intelligence as measured by IQ or GCI. These studies are summarized in Table 5 and are described in the following paragraphs. Lanphear et al. (2000) analyzed data on BLLs on performance on standardized tests of cognitive function of 4,853 children age 6 through 16 years who were evaluated as part of the NHANES III survey, a multiphasic health interview and examination survey of a stratified probability sample of the U.S. population, carried out from 1988 through 1994. In this population, with a geometric mean BLL of 1.9 µg/dL and 98% of children having BLLs <10 µg/dL, significant inverse relations were found between BLLs and scores on the Wide Ranging Achievement Test (WRAT) arithmetic and reading scores and on the WISC-R block design and digit span subscales. The relationships were strengthened (the slopes became more negative) as analyses were progressively restricted to children with lower BLLs. Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While the results they present are largely consistent with the findings of Lanphear et al., they provided a critique of the validity of the NHANES III data for evaluating leadrelated impacts on neuropsychological development in children. Their critique did not provide results that could be summarized in the structured abstract format used in this report, so a discussion of the Stone et al. critique is found in Appendix B. # Cognitive Function # Other Neurobehavioral Measures and Visual Function Three reports (Altman et al. 1998;Walkowiak et al. 1998;Winneke et al. 1994) describe the relation of blood lead to several neurobehavioral measures and to visual function assessed in 384 school children 5 to 7 years of age in three cities in Eastern Germany. Blood lead levels were generally low, with a geometric mean of 4.25 µg/dL and 95% of children having BLLs <10 µg/dL. Walkowiak et al. (1998) reported a significant negative association between BLLs and WISC vocabulary subscale scores. Continuous performance test false positive and false negative responses increased with increasing BLLs. Other measures inversely related to BLL included performance on a pattern comparison test, finger tapping speed (Winneke et al. 1994), and visual evoked potential interpeak latency (Altman et al. 1998). Mendelsohn and colleagues (1999) found a 6 point deficit in the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development for children aged 12 to 36 months with BLLs 10-24 µg/dL compared with children who had BLLs <10 µg/dL. A scatterplot of covariate-adjusted MDI versus blood lead suggests the association continues at BLLs <10 µg/dL. # Neurotransmitter Metabolite Levels Among children ages 8 through 12 years with mean BLL of 3.95 µg/dL, a direct relation of blood lead (PbB) to higher urinary homovanillic acid, a neurotransmitter metabolite, was found for the subset of children with BLLs >5 µg/dL (Alvarez Leite et al. 2002). # Growth Two studies examined the relation of BLLs <10 µg/dL to somatic growth. Ballew et al. (1999), using the NHANES III data, found that BLLs were inversely related to height and to head circumference among children 1 to 7 years of age. A birth cohort of children in Mexico had BLLs and head circumference assessed every 6 months from 6 to 48 months of age, during which time the median BLL varied from 7 to 10 µg/dL (Rothenberg et al. 1999). Most postnatal blood lead measures were inversely correlated with covariate adjusted head circumference, with the strongest relation found between blood lead at age 12 months and head circumference at 36 months. Kafourou and colleagues (1997) reported a significant negative association between BLL and covariate-adjusted head circumference and height in a population of children with a median BLL of 9.8 µg/dL, with a scatterplot suggesting the relation extends to BLLs <10 µg/dL. # Sexual Maturation Two studies, both based on analyses of the NHANES III data, found an association between BLLs <10 µg/dL and later puberty in girls. Selevan et al. (2003) found that BLLs of 3 µg/dL, compared with 1 µg/dL, were associated with significant delays in breast and pubic hair development in African American and Mexican girls. The trend was similar, but not significant, for non-Hispanic white girls. Age at menarche was also delayed in relation to higher BLLs, but the association was only significant for African-American girls. Wu et al. (2003) reported similar findings for girls in the NHANES III population but did not stratify the analysis by racial/ ethnic group. Compared with BLLs 2.0 µg/dL and below, BLLs of 2.1-4.9 µg/dL were associated with significantly lower odds of attaining Tanner 2 stage pubic hair and menarche; whereas no overall association with breast development was noted. # Dental Caries In the NHANES III population, the odds of having dental caries, comparing children ages 5-17 years in the middle tertile of the BLL distribution (range of BLLs 1.7-4.1 µg/dL) with those in the lowest tertile, was significantly elevated (odds ratio=1.36, 95% confidence interval 1.01-1.83) (Moss et al. 1999). Gemmel et al. (2002) evaluated the association between BLLs and caries in 6-10 year old children from urban communities in eastern Massachusetts (mean BLL=2.9 µg/dL) and a rural community (mean BLL=1.7 µg/dL) in Maine. They found a significant direct relation of BLL to caries in the former, but not the latter population in which a non-significant decrease in caries' frequency was observed with increasing blood lead. In the urban population, the trend of increasing caries with PbB level was evident comparing children with BLLs of 1, 2, and 3 µg/dL. # Blood pressure and renal function Among 66-month-old children in Kosovo, a graph depicting adjusted mean systolic and diastolic blood pressure versus BLL showed no consistent trend across 4 groups of children (approximately 28 per group) with BLLs spanning a range from approximately 5 to 10 µg/dL (Factor Litvak et al. 1996). In a population of 12-to 15-year-old children living near a lead smelter and a control group, urinary retinal binding protein (U-RBP) was found to be significantly associated with BLL in a stepwise regression. When urinary RBP excretion was examined by BLL tertiles, significantly lower U-RBP was seen in the group with BLL < 8.64 µg/dL compared with BLLs 8.64-12.3 µg/dL. Roels et al. (1987) studied the relations of PbB to heme synthesis biomarkers and reported no evident threshold for inhibition of aminolevulinic acid dehydratase synthesis at PbB as low as 8-10 µg/dL, while the threshold for increasing erythrocyte protoporphyrin levels was evident in the range of 15-20 µg/dL, consistent with other studies, including two meeting criteria for inclusion in this report (Rabinowitz et al. 1986;Hammond et al. 1985). # Heme synthesis biomarkers # Discussion Question 1: Does available evidence support an inverse association between children's blood lead levels <10 µg/dL and children's health? The weight of available evidence, both indirect and direct, clearly favors an inverse association between these BLLs and cognitive function among children. The indirect evidence comes from the great majority of studies that have examined BLLs in relation to standardized measures of overall cognitive function; these studies reveal an inverse relationship and no trend toward weaker associations in populations with lower BLL distributions. More direct evidence of such an association comes from a recent analysis of data from a cohort designed from the start to study the relation of blood lead to child development (Canfield et al. 2003). This study demonstrated that the inverse relation between BLL and cognitive function exists and is stronger at BLLs <10 µg/dL compared with higher BLLs; it also does not show a threshold within the range of routinely measured BLLs below which no association was present. A recent letter to the editor described a reanalysis of the Boston cohort data (Bellinger et al. 2003) with findings consistent with Canfield et al (2003). Several recent analyses of data from the NHANES III and other populations also provide direct evidence of associations that imply adverse impacts of lead on indicators of children's neurocognitive development, stature, head circumference, dental caries, and sexual maturation in girls, occurring at measured BLLs <10 µg/dL. Though the number of studies providing direct evidence of associations at BLLs <10 µg/dL is limited and most are cross-sectional, they provide supporting evidence of an association in the context of the much larger number of studies that relate slightly higher levels of lead in blood to impairments of children's health. # Question 2: Are the observed associations likely to be causal? Though the weight of evidence favors an association between children's BLLs <10 µg/dL and health and, indeed, suggests that such relationships become steeper as BLLs decrease, the WG considered a number of concerns that must be addressed in judging whether such associations are likely to be causal. The work group concluded that collectively, these concerns and limitations of the available evidence preclude definitive conclusions about causation and leave considerable uncertainty concerning the magnitude and form of causal relations that may underlie these associations. At the same time, available evidence does not refute the interpretation that these associations are, at least in part, causal. These issues are discussed individually in the following text, followed by overall conclusions. # Biologic Plausibility Evidence from experimental animal and in vitro studies, which are not subject to confounding influences of concern in human observational studies, can establish causation and identify mechanisms that might be operative in humans assuming a suitable animal model. Thus, evidence from experimental animal and in vitro studies can help to assess potential dose-response relationships and thresholds within the context of any uncertainty added due to interspecies extrapolation. Therefore, an important consideration in judging whether associations between BLLs <10 µg/dL and health outcomes are likely to represent causal relationships is whether such relationships are biologically plausible on the basis of experimental animal and in vitro studies. These studies can also help to assess potential doseresponse relationships and thresholds, but extrapolation from in vitro and animal models to human health risk adds additional uncertainty. Lead is the most extensively studied environmental neurotoxicant. Animal and in vitro studies have provided abundant information concerning biochemical and physiologic changes caused by lead. Along with clinical and epidemiologic data, this evidence has clearly established that lead is toxic to the developing and mature nervous system. These data have been extensively reviewed elsewhere (USEPA 1986;ATSDR 1999;WHO 1995;Davis et al. 1990) and are not exhaustively reviewed here. Rather, this discussion highlights evidence concerning potential mechanisms of lead toxicity and data from animal studies that are relevant to the biologic plausibility of the toxicity of lead, especially to the developing nervous systems of children exposed at BLLs <10 µg/dL. Although the precise mechanisms of action and their relative importance in different manifestations of lead toxicity are not known definitively, in vitro studies demonstrate that lead can interfere with fundamental biochemical processes. At the most basic level, many of the proposed mechanisms of lead toxicity involve binding to proteins and/or interference with calcium dependent processes (Goldstein 1993). For some of the adverse health effects of lead (e.g., anemia), the lead-associated biochemical changes that contribute to the effect in humans are well understood. Lead interferes with heme synthesis in part by binding to sulfhydryl groups in the enzyme amino levulinic acid dehydratase (ALAD) (ATSDR 1999), which is especially sensitive to inhibition by lead (less than 0.5 micromoles per liter in vitro) (Kusell et al. 1978;Dresner et al. 1982). This inhibition causes delta amino levulinic acid, a potential neurotoxic agent, to accumulate. Lead also inhibits ferrochelatase, an enzyme catalyzing the incorporation of iron into protoporphyrin to form heme. This inhibition also may involve lead binding to protein sulfhydryl groups. Although anemia and accumulation of protoporphyrin IX in erythrocytes are the most obvious consequence of impaired heme synthesis, this pathway could play a role in lead-related impairment of cellular function throughout the body (USEPA 1986). By interfering with heme synthesis and perhaps by inducing enzymes that inactivate heme, lead can decrease the levels of heme in body tissues (Fowler et al. 1980). A reduction in the body heme pool may impair heme-dependent biochemical processes, such as cellular respiration, energy production, and the function of the cytochrome p-450 monooxygenase system involved in detoxification of xenobiotics and in transformation of endogenous compounds such as vitamin D precursors (USEPA 1986). For other more complex health effects of lead, such as impaired neurocognitive development and behavioral change, a number of plausible mechanisms have been demonstrated in animal and in vitro systems. Lead's impact on one or more biochemical systems needed for normal brain development and function could account for the neurobehavioral effects observed at low levels of exposure. Especially sensitive to lead in vitro is the activation of protein kinase C (PKC), a calcium dependent enzyme. Lead binds more avidly to PKC than its physiologic ligand, calcium, causing activation at picomolar concentrations in vitro. (Markovac and Goldstein 1988). The interactions between lead exposure and PKC activity in the brain are complex; chronic lead exposure may reduce activity of PKC associated with cell membranes while increasing cytosolic PKC activity. Lead effects on PKC activity have been proposed to mediate potential impacts of lead on cell growth and differentiation, including that of neural cells (Deng and Poretz 2002), the bloodbrain barrier, and long-term potentiation (a process related to memory) (Hussain et al. 2000). Lead also interferes with calcium-dependent control of neurotransmitter release at presynaptic nerve terminals; it may thereby interfere with signaling between neurons and possibly with development of neural networks. In both animal and in vitro studies, lead has been demonstrated to interfere with neurotransmitter systems, including interfering with dopamine binding and the inhibition of N-methyl-D-aspartate (NMDA) receptor activity. The large body of evidence from animal studies of lead exposure and neurodevelopment supports a causal effect that is persistent following exposure early in life and that generally parallels human studies in terms of the domains of function that are impaired (WHO 1995). Concerning blood lead-effect relationships, direct cross-species comparisons of BLLs cannot be made (Davis et al. 1990), and most animal studies demonstrating lead-related developmental neurotoxicity involved doses that produced BLLs well above 10 µg/dL. However, available studies provide strong evidence of adverse effects in animals with BLLs near 10 µg/dL. It should be noted that BLLs cited in animal studies generally involve mean levels achieved in experimental groups with individual animals varying, sometimes substantially, around that mean. Non-human primates experimentally exposed to lead early in life demonstrate dose related impairments in learning and behavior (Bushnell and Bowman 1979;Rice 1985;Levin and Boman 1986). One study, involving monkeys dosed during the first 200 days of life with 100 µg/kg/day lead or 50 µg/kg/day lead resulting in average peak BLLs of 25 and 15 µg/dL respectively, showed deficits relative to control monkeys (dose=0µg/kg/day lead; average peak BLL=3 µg/dL) at age 3 years on "discrimination reversal" tasks (the animals are taught to respond to a cue and then the cue is changed and the ability to learn the new cue, with and without irrelevant cues, is measured). At the time of testing, mean BLLs in the exposed groups had fallen to 13 and 11 µg/dL, respectively. Both exposure groups showed deficits, but deficits in the lower exposed group were evident only with more complex tasks (e.g., including irrelevant cues) (Rice 1985). The same monkeys showed persistent impairments at 9 to 10 years of age (Gilbert and Rice 1987). Experimental studies in rats have demonstrated behavioral effects at mean BLLs of 10-20 µg/dL (Cory-Slechta et al. 1985;Brockel and Cory-Slechta 1998). There is uncertainty about the relationship of the tissue or cellular levels of lead linked to physiologic changes in animal and in vitro studies to the corresponding human blood lead level required to produce such levels at target sites. Although most (90 to 99%) lead in whole blood is in red cells, plasma lead level likely better reflects lead transferred from bone stores and available for transfer to target tissues (Cake et al. 1996). Because red cells have limited capacity to accumulate lead, the relation of blood lead to plasma or serum lead is non-linear with serum lead increasing more rapidly at higher BLLs (Leggett 1993). In subjects with a mean BLL of 11.9 µg/dL, plasma lead levels ranged from 0.3 to 0.7% of whole BLLs (Hernandez-Avila et al. 1998). The relation of plasma serum levels in intact animals to tissue levels measured in in vitro models is probably more complex. It is also uncertain whether in vitro studies demonstrating possible mechanisms for low-level lead toxicity reflect mechanisms operative in the intact animal. For example, Zhao et al. (1998) found that lead interfered with PKC in choroid plexus endothelial cells in a dose dependent fashion over the concentration range of 0.1-10 micromolar. However, no effect on choroid plexus PKC activity was seen in an in vivo model. # Conclusions: The fundamental nature of biochemical and physiologic changes linked to lead in in vitro and experimental animal studies illustrates potential mechanisms for lead toxicity that might be operative in humans at very low exposure levels. Experimental animal studies support the biologic plausibility of adverse health effects of lead in children at BLLs near 10 µg/dL. However, definite conclusions concerning the relationship of health status of children and BLLs <10 µg/dL cannot be drawn from these studies because of limitations of extrapolating from in vitro systems to intact animals and from animals to humans and because of the limited amount of data available from studies of animals dosed to produce a range of BLLs less than 10 µg/dL. Data from primates, which can most readily be extrapolated to humans, are especially limited. On the other hand, given the uncertainty in extrapolating across species, the fact that animal test systems cannot match the complexity of learning tasks faced by young children, and the relatively small relative difference in BLLs shown to be harmful in animals and those at issue in children, adverse health effects in children at BLLs <10 µg/dL are biologically plausible. # Blood Lead Measurement The precision and accuracy of blood-lead measurements performed in an epidemiologic study impacts observed results. If BLLs are systematically over or underestimated, biases in estimated blood lead response relationships and/or no effect thresholds will result. All blood lead measurements involve some random error, which, if a true association between blood lead and health exists, will tend to bias estimates of the relation toward the null (i.e., no effect) value. The quality of blood lead measurements varies between laboratories, between different analytical technologies, and between different specimen collection techniques. In addition, laboratory performance for blood lead has improved markedly over the last three decades and continues to improve as new analytical technologies are developed. Each of these factors becomes important in assessing the quality of blood-lead measurements used in published studies. In this section, specimen collection and laboratory factors that can affect blood-lead precision and accuracy are considered. The widespread industrial use and dispersal of lead, particularly during the last century, has ensured that it is a ubiquitous contaminant. Therefore, to prevent false-positive results, stringent procedures are necessary to reduce environmental contamination of blood collection devices and supplies. Consequently, venous blood collected using evacuated tubes and needles certified as "lead-free" is considered the most appropriate specimen for blood lead measurements (NCCLS 2001). However, collection of venous blood from pediatric subjects is sometimes difficult; thus, capillary blood from a finger puncture is used widely for screening purposes. Published studies have compared the quality of blood lead results for capillary and venous specimens drawn simultaneously (Schlenker et al. 1994;Schonfeld et al. 1994;Parsons et al. 1997). With stringent precautions, particularly rigorous hand washing, contamination errors can be held to <4% (Parsons et al. 1997). Therefore, although venous blood is preferable for epidemiologic studies of environmental lead exposure, use of capillary blood is acceptable if collected by staff specially trained in the technique using devices certified as "lead-free." Data should be provided showing an acceptably low rate of contamination errors and low mean bias in the capillary BLLs as collected using the study protocol. Currently, three analytical approaches to blood lead measurement are used: atomic absorption spectrometry (AAS); anodic stripping voltammetry (ASV), and inductively coupled plasma mass spectrometry (ICP-MS). A thorough discussion of these analytical techniques is beyond the scope of this report; however, a comprehensive assessment has been published by the National Committee for Clinical Laboratory Standards (NCCLS 2001). Briefly, the older flame atomization AAS methods, which include MIBK-extraction and Delves cup, are less precise, with a detection limit near 5 µg/dL for Delves cup (Parsons and Slavin. 1993). Thus, they are not well suited for examining relationships between BLLs <10 µg/ dL and health. The electrothermal atomization techniques based on the graphite furnace (ETAAS) are more precise and more sensitive and, therefore, have better detection limits, typically around 1.0 µg/dL. A direct comparison between ASV and ETAAS techniques (Bannon et al. 2001) shows that the latter has better precision and better accuracy. Nonetheless, when operated in experienced hands and with a stringent quality assurance/quality control (QA/QC) program that includes calibration standards traceable to the mole via isotope dilution mass spectrometry (ID-MS), ASV can deliver blood-lead measurements with accuracy and precision sufficient to examine health effects at BLLs <10 µg/dL (Roda et al. 1988). In order to assess the accuracy and precision of blood-lead measurements made for research purposes, investigators should provide information on the laboratory's performance in measuring external quality control samples and on the between-run standard deviation for routine quality control samples that span the relevant blood lead range for a given study. # Conclusions: The key considerations relevant to judging the accuracy and precision of blood lead measurements in published studies include the type and quality of blood specimen collected, analytical methodology used by the laboratory, and internal and external QA/QC procedures in place. For the purpose of studying the relationship between BLLs <10 µg/dL and health endpoints venous samples are preferred and capillary samples are acceptable with evidence of a rigorous protocol to control contamination errors. Acceptable analytic methods include electrothermal AAS, ASV, and ICP-MS. Information on laboratory performance (i.e., accuracy and precision) from external and internal quality control data should be provided. To be included in this review, studies were required to have employed suitable measurement methods. In addition, venous samples were used for most postnatal blood lead measurements in the relevant cohort studies (Table 6) and others cited in this report. Given this and the blood lead quality control procedures reported in the most informative studies, it is highly unlikely that systematic errors in measurement in the relevant studies were sufficient to bias the observed blood lead distributions enough that associations observed <10 µg/dL were attributable to BLLs above that threshold. Random variation in BLLs and random error in BLL measurement would make it difficult to collect sufficient data to identify a threshold, if one were to exist. # Blood Lead Age Trend, Tracking, and Inference Concerning Blood Lead -Effect Relations in Children Age-related changes in children's BLLs and within-child correlation of blood lead measured at different ages may influence observed associations between BLL and health at a given age. In addition, the biologic impact of lead in children is likely determined not only to the BLL measured at any one time but, also, the ages at which a given level occurs and the duration of exposure. Under most exposure scenarios, children's BLLs show a characteristic age trend. A newborn's BLL will largely reflect the BLL of its mother. Because adult women tend to have lower BLLs than young children, umbilical cord BLLs are generally lower than BLLs during childhood. During the latter half of the first year of life, however, children's BLLs begin to increase as the infant becomes more active, mobile, and exposed to ambient lead. The onset of ambulation during this period is likely to be important, as are play patterns that bring the child into contact with environmental media such as lead-contaminated dust and soils. Other factors that affect exposure include the increased hand-to-mouth activity of children, including the practice of eating "in place," i.e., in play areas. Physiologic factors, such as more efficient absorption of ingested lead in children compared with adults, and their greater food and air intake on a body weight basis might also contribute to the early postnatal rise in BLL. The mean BLL within a study sample generally peaks during 18 to 36 months of age, and slowly declines over the next few years. This blood lead profile is seen among economically disadvantaged urban minority children (Dietrich et al. 2001) and among children living near lead smelters (Figure 4) (Tong et al. 1996). In cohorts with extremely high exposures, the blood lead decline might be very gradual (e.g., Wasserman et al. 1997). In the Cincinnati Study, the same general profile was evident in each of four strata defined by average lifetime BLL, suggesting that it is, to some extent, independent of the overall level of exposure. This blood lead profile has not been observed in all study cohorts, however. In the Boston Study, for example, mean BLL varied minimally, from 6.2 to 7.6 µg/dL, from birth through 5 years of age (Rabinowitz et al. 1984;Bellinger et al. 1991). One implication of the typical profile is that maximum level is often associated with age, constituting an obstacle to an effort to identify age-specific vulnerability to lead toxicity. Compounding this challenge is that, under many exposure scenarios (particularly those involving higher exposures), intra-individual stability of BLL tends to be substantial. That is, BLL tends to "track," so that if, at time 1, child A has a higher BLL than child B, child A is likely to have a higher BLL than child B at time 2 as well. Thus, children's rank ordering tends to be similar over time even though, in absolute value, BLL rises and falls over the course of childhood. Again, however, the degree of intra-individual stability varies from cohort to cohort. In the Boston Study cohort, for instance, the extent was limited; this stability is likely attributable to the generally low BLLs of the study population (Rabinowitz et al. 1984). A BLL measured after 36 months of age will, on average, be lower than the BLL that would have been measured if a child's blood been sampled sometime during the 18 to 36 month period. Suppose, however, that the critical period with regard to producing an adverse health outcome is the 18 to 36 month period, and that, in a study conducted post-36 months, an inverse association is noted between concurrent BLL and a health endpoint. If the concurrent BLL is the only index of lead exposure history available, basing a dose-effect assessment on it will, to the extent that the natural history of BLLs in the study cohort follows the canonical form illustrated above, result in an underestimate of the BLL responsible for any adverse health effects noted at the time of or subsequent to blood sampling. In other words, one will conclude that adverse health effects occur at lower BLLs than is the case. For instance, assume that the inverse association shown in Figure 5 holds between IQ and concurrent blood lead in a cross-sectional study of 6 year olds. If, however, the BLL of each child was, on average, 5 µg/dL greater at age 2 than at age 6, and age 2 is the time of greatest toxicologic significance (i.e., it is age at which lead exposure produced the IQ deficit observed at age 6), then the dose-effect relationship that underlies the association seen at age 6 would be more accurately described as in Figure 6. This dataset would thus not be informative with respect to the functional form of the dose-effect relationship at levels below 10 µg/dL insofar as (hypothetically) all children had a BLL greater than 10 µg/dL at age 2. Other uncertainties apply to interpreting blood lead-health associations (or lack of associations) observed at any point in time. First, the relation of age to vulnerability to lead toxicity is not well understood. Is BLL during the age period 18 to 36 months more toxicologically critical than a measure of cumulative lifetime exposure, such as the area under the curve or some other exposure index? Also, it is possible that the critical age varies with dose, health endpoint, or sociodemographic factors. Available studies do not provide consistent answers to these questions. For example, in the Boston cohort, blood lead at age 24 months was most strongly related to IQ at age 10 years (Bellinger et al. 1992), whereas in the Port Pirie Cohort, the lifetime average BLL through age 5 years was most predictive of IQ at age 11 to 13 years. If 18 to 36 months is the critical age of exposure, theoretically, it is possible to "adjust" an observed blood lead distribution measured at age 6 by some function to reflect the downward trend in BLL with age and estimate the blood lead distribution at a different age, (e.g., age 2 years). However, a "one size fits all" adjustment likely is not appropriate for all children. Moreover, the appropriate adjustment is likely to be study-site-specific (i.e., depend on the key exposure sources and pathways of a particular study cohort). It would be possible to get a general sense of how accurately past peak exposure can be estimated for children in cross-sectional studies by using data collected in prospective studies in which blood lead was measured frequently during the period spanning birth to school-age. Examining the distribution of the differences between BLLs measured at ages 18 to 36 months and at age 6 would suggest the amount of exposure misclassification that would result from applying a constant adjustment factor. # Conclusions: Because of age trends in blood lead and the tendency of BLLs to "track" within individual children, inferences drawn from cross-sectional associations between blood lead and health at a given age should be interpreted cautiously because of the influence of likely higher BLLs occurring earlier in life. It may be possible to apply data on age trends and within-subject correlation of blood lead to estimate, from an observed blood lead-health association, the approximate relation to BLLs at an earlier age. However, because age trends and the extent of "tracking" of blood lead levels vary from one population to another, it is not possible to estimate with confidence the distribution of blood lead levels earlier in life for any given population whose blood lead levels were only measured at one point in time. If the only relevant studies available are based on cross-sectional data (e.g., data from NHANES III), age trends and "tracking" of BLLs would represent a substantial challenge to inferring a causal link between BLLs <10 µg/dL and adverse health impacts. However, recently published results from two cohort studies (Canfield et al. 2003;Bellinger et al. 2003) showed inverse associations between BLLs measured early in life (6 to 24 months and 24 months, etc.) and IQ measured at older ages among children whose measured BLLs did not exceed 10 µg/dL. Therefore, associations observed in cross-sectional studies cited in this report likely do not exclusively result from the impact of higher BLLs experienced earlier in life. # Quality of Neurobehavioral Assessments As with blood lead (exposure) measurements, the accuracy, precision, and consistency of neurobehavioral assessments can influence observed blood leadoutcome relations. In order to judge whether the data from a study should be considered in characterizing the functional form of the dose-effect relationship at BLLs <10 µg/dL, one would like to have access to the following information about the conduct of the neurobehavioral assessments: • Assurance that examiners were blinded to all aspects of children's lead exposure histories. • The assessment setting. Assessments can be standardized when carried out in a hospital, neighborhood health center, or community center, but may be difficult to standardize in a participant's home. • Essentials of the process by which an examiner was trained, including the criterion used to certify an examiner (e.g., percent agreement on an item-byitem basis with some gold standard, average difference in scores assigned compared with gold standard, correlation with gold standard in terms of scores assigned). • The plan implemented for supervision of test administration over the course of data collection (e.g., periodic observation of test sessions, live or by videotape). • The plan implemented for supervision of test scoring over the course of data collection (e.g., double scoring of a sample of protocols). • The number of neurobehavioral examiners used over the course of data collection. • If more than one assessor was used, whether the data analysis plan included evaluation of an "assessor" effect (i.e., as a main effect and as a modifier of lead's association with endpoints). While some have argued that neurobehavioral examiners should have professional qualifications (e.g., Kaufman 2001 cites the need for a clinician with graduate-level training in psychometrics, neuropsychology, etc.), the Practice Committee of the American Academy of Clinical Neuropsychology supports the widespread practice of using non-doctoral level personnel, with appropriate training and supervision by a doctoral-level psychologist, in the administration and scoring of clinical neuropsychological evaluations (Brandt et al. 1999). Assuming examiners are blinded regarding BLLs, most problems with quality of neurobehavioral assessment would be expected to mask or underestimate true associations rather than create spurious ones. It is possible, for example, that use of non-professional examiners might introduce noise into the data, masking an association between toxicant exposure and performance. In one study of methylmercury (MeHg) exposure (Grandjean et al. 1997), MeHg was inversely associated with children's scores on the Similarities subtest of the WISC-III among children tested by the supervising doctoral-level study examiner. Assuming that blinding was preserved, use of non-professional examiners likely would not introduce a positive bias in effect estimates. Measurement quality problems causing bias of associations away from the null, without loss of blinding, are theoretically possible. For example, if one examiner consistently yields lower scores than another and that examiner, without knowledge of BLLs, is assigned to assessments of a segment of the study population at higher risk for lead exposure, a spurious inverse association could be created between lead level and neuropsychological test scores. # Conclusions: The key considerations in judging the quality of neurobehavioral assessments in the research setting are the blinding of examiners to leadexposure history, the training and supervision of examiners, and the setting for examinations. If examiners are truly blinded, other data quality problems generally will bias estimated relationships between blood lead and outcomes toward the null. Therefore, given that examiners were blinded to BLLs in cohort studies demonstrating associations (Table 6) and the NHANES III survey, errors in measurement of neuropsychological function likely did not contribute to observed associations with BLLs <10 µg/dL. # Potential Confounding Factors # Social Factors Socioeconomic factors influence both lead exposure and many health outcomes, including intellectual development, growth, and a number of chronic conditions, creating the potential for social factors to confound associations between children's lead exposure and health in observational studies. Because cognitive function as reflected in measured intelligence is strongly associated with socioeconomic status (SES) and because cognitive function in children is the most studied health endpoint in studies of lead-exposed children, this discussion is focused on possible SES confounding of associations between BLL and measured intelligence. The potential for reported subtle effects of lead on IQ and related measures of intellect to be attributable to confounding by socioeconomic factors warrants serious consideration . Key relations required for confounding to occur are almost certainly present-SES has been shown to be related to BLLs, presumably because the neighborhoods and homes in which families of lower income reside are associated with higher levels of lead in soil and residences. Socioeconomic status also is clearly related to measures of intelligence, whether through parental stimulation, nutrition, or resources available in the home. With an inverse relationship between socioeconomic factors and lead levels (i.e., higher SES predictive of lower lead levels) and a positive relationship between socioeconomic factors and measures of intelligence (higher SES predictive of higher intelligence test scores), failure to adjust for the confounding effect of socioeconomic factors will result in confounding that overstates the harmful effect of lead on IQ because the socioeconomic effect will be mixed with any true effect of lead exposure. In addition, confounding by social factors may be a concern for some other lead-associated health measures with social gradients such as height (Silventoinen 2003). Data presented from most of the key studies included in this review strongly suggest that substantial confounding by socioeconomic factors occurs. Even with adjustment for crude measures (e.g., parental education and household income ) (Lanphear et al. 2000), the apparent lead effect on cognitive function is greatly reduced. Such a pattern in which adjustment for a crude proxy results in a substantial decrement in the magnitude of association would suggest that "residual confounding" may be present in the adjusted estimate of effect. If residual confounding is indeed present, then tighter control for confounding with more refined measures of the social environment may further attenuate or eliminate the apparent effect (Savitz et al. 1989). The following factors complicate this scenario: 1. Socioeconomic status is a very elusive construct to fully capture; it is far more complex than is reflected in parental education or income. Socioeconomic status includes many aspects of economic means and associated lifestyle, so that adjustment for operational measures, such as education or income, will always be incomplete. Adjustment for an imperfect proxy measure of a confounder results in residual confounding (Greenland et al. 1985;Savitz et al. 1989). 2. Long-term lead exposure is imperfectly reflected in a current blood lead measure or to some extent, even from a series of blood lead measures (see Blood Lead Tracking) . Whatever physiologic effect lead might produce, available evidence suggests that the impact is chronic and cumulative. Beyond what is reflected in a blood-lead measure, SES may be indicative of historical exposure; thus, the observed effect of socioeconomic status would partly reflect an effect of lead exposure above and beyond the blood-lead measure. The nature and magnitude of these associations is less clear when focusing on BLLs <10 µg/dL. Measures of social advantage, including income and parental education, are associated with BLLs <10 µg/dL (e.g., Lanphear et al. 2000). However, the relative importance of different aspects of socioeconomic status and the pathways by which they affect lead exposure are not entirely clear. The association between lower income and deterioration of paint in older housing contributes to variation in BLLs, even BLLs <10 µg/dL. The increase in geometric mean blood lead associated with living in an older home is greater for children from low-income families than for those from middle income families (Pirkle et al. 1998). Nonetheless, with the elimination of lead in gasoline and the continued decline in the proportion of homes with leaded paint (Jacobs et al. 2002), the relative importance of lead exposure sources possibly is changing. It is also possible that the association of social factors with lead exposure is different for populations with BLLs <10 µg/dL than for those above that level. Several strategies have been applied to address the role of socioeconomic factors and isolate a non-specific effect of socioeconomic factors on IQ from an effect of lead exposure. First, populations can be sought or even constructed in which blood lead is not closely associated with SES as demonstrated most clearly in the Boston cohort (Bellinger et al. 1987). In that population, all in a relatively low blood lead range for that time and the great majority of relatively advantaged SES, there was a weak positive gradient between socioeconomic status and lead. The Kosovo cohort (Wasserman et al. 1997) also departed from the usual trend in that the more SES advantaged of the two communities studied was the site of a lead smelter. As a result, adjustment for social and other covariates actually strengthened the inverse relation of blood lead to IQ in that population. etc., and not adjust for the aspects that primarily serve as a proxy for lead exposure, such as age of housing and neighborhood. One example among published research of refining and decomposing the construct of socioeconomic status has been the use of the HOME scales to adjust for stimulation provided by caregivers. Use of HOME scales has in some cases further attenuated but not eliminated apparent lead-IQ associations. A third approach to examine the possibility of confounding of the blood lead-IQ relation at low levels would be to conduct a formal statistical assessment of the extent to which the strength of the observed association across studies varies in relation to control for relevant confounders, using meta-regression, as was applied by Schwartz (1994). This approach could be refined to assess possible residual confounding. One challenge in performing such an analysis using published summary data is the difficulty in operationalizing measures of the tightness of SES adjustment while controlling for other aspects of study design that might influence blood lead-IQ slopes. An alternative approach is discussed later in this report (see Research Needs). # Conclusions: On the basis of available evidence the observed associations between blood lead below 10 µg/dL and cognitive function likely do not entirely result from confounding. This conclusion is supported by the following evidence: • The studies showing the strongest relationship (Canfield et al. 2003;Bellinger et al. 2003) at low levels employed the HOME scale for adjustment, which is the best available measure for assessing the impact of the home environment on child development. • Two cohorts, Kosovo and Boston, in which strong associations were found between blood lead and IQ, were characterized by a direct, rather than inverse, correlation of blood lead with social advantage. • Associations of children's blood lead close to 10 µg/dL and intelligence have been seen in diverse geographic and social settings. • Animal data have demonstrated effects of lead at BLLs near 10 µg/dL. On the other hand, the ability to detect confounding by omitted covariates by comparisons across studies is limited because, for most covariates of potential interest, the number of relevant studies in one group being compared is limited. In other words, for a given covariate, either few studies included it (e.g., postnatal ETS exposure) or few excluded it (e.g., SES). At this point, the case for residual confounding by social environment is speculative, but available studies relating blood lead to cognitive function in children cannot entirely exclude the possibility that observed associations are at least partly influenced by it. Such a possibility does increase uncertainty about the actual strength and shape of blood lead relationships at BLLs less than 10 µg/dL. # Iron Status Nutritional factors, such as iron and zinc intake, that might be correlated with lead uptake and might influence children's health, could confound associations between BLLs and health from observational studies. The potential for iron deficiency to confound the association between blood lead and neurodevelopmental status has been of most concern and is the focus of this discussion. The likelihood of such bias is dependent upon the extent to which iron status was controlled in a given study and the prevalence of iron deficiency in a study population. Iron deficiency may impair neurodevelopment in a manner similar to low-level lead exposure and the populations at increased risk for iron deficiency and lead toxicity may overlap (Lozoff et al. 1991;Wasserman et al. 1999). However, the association between iron deficiency and blood lead is not consistent across populations (CDC 2002). Therefore, the potential for iron to confound an association of blood lead with neurodevelopmental status will vary across populations, depending on both the prevalence of iron deficiency and its association with blood lead level. For research purposes adequate assessment of iron status entails determination of hemoglobin or hematocrit and at least two other measures of iron status. Generally accepted definitions of iron deficiency and iron deficiency anemia depend on age-and sex-specific normal ranges. The iron status measures most commonly used are mean corpuscular volume (MCV), free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP), transferrin saturation, ferritin, and, more recently, transferrin receptor. The standard for defining iron deficiency is values indicating iron deficiency on at least two of these measures and/or response to iron therapy with an increase in hemoglobin to at least 10 g/L. The utility of ferritin in young infants is under debate, making it important that functional measures, such as MCV or ZPP be obtained. There are limitations of each measure (e.g., ferritin goes up with infection, MCV is down in hemoglobinopathies, etc.). Although iron deficiency with low hemoglobin has been associated with later impairment of cognitive function (Grantham-McGregor et al. 2001), it is not certain which measure(s) of iron status are most strongly related to neurodevelopmental outcomes. In studies of children with higher BLLs, controlling for hemoglobin is problematic because lead toxicity can reduce hemoglobin in the normal range or cause frank anemia. This is less of a concern in studies of children with BLLs <10 µg/dL, a range in which no meaningful impact on hemoglobin levels has been observed. Conclusions: Measurement of iron deficiency has been absent or suboptimal in most of the studies reviewed. Two studies in which iron status was controlled for using transferrin saturation (Canfield et al. 2003) and serum ferritin (Lanphear et al. 2000) found strong inverse relationships between blood lead and cognitive function, whereas a third study that controlled for the presence of iron-deficiency anemia found the opposite (Wolf et al. 1994). Furthermore, iron-deficiency anemia is the measure of iron status most clearly linked to impaired cognitive function; therefore, it seems unlikely that the prevalence of iron deficiency anemia could be high enough in the populations showing the strongest inverse relations of blood lead to cognitive function (Canfield et al. 2003;Bellinger et al. 2003;Lanphear et al. 2000) to entirely explain these associations. In the NHANES III data used by Lanphear et al. (2000), the prevalence of iron deficiency ranged from 1% to 9%, depending on the age and sex group (CDC 2002). Finally, in Kosovo, following treatment of iron-deficient children with iron supplements, no association of earlier hemoglobin levels with IQ at age 4 (Wassserman et al. 1994) or age 7 (Wasserman et al. 1997) was found. Thus, iron deficiency likely does not completely explain the inverse associations between BLLs <10 µg/dL and cognitive function. # Tobacco Blood lead levels in children have been associated with exposure to environmental tobacco smoke (assessed by caregiver report or by urinary cotinine levels) in both general population surveys (Stromberg et al. 2003;Mathee et al. 2002;Lanphear et al. 2000;Mannino et al. 2003) and in studies of children living near lead smelters (Willers et al. 1988;Baghurst et al. 1992;Baghurst et al. 1999). The explanation for this association is not entirely clear; possibilities include enhancement of lead uptake by environmental tobacco smoke (ETS), exposure to lead in ETS itself, and differences in cleaning practices or child supervision between households with and without smokers. Maternal smoking during pregnancy has been associated with behavioral problems and impaired cognitive development in children; fetal hypoxia is one possible contributing mechanism (Habek et al. 2000). Evidence for an effect of prenatal or postnatal ETS exposure on neurodevelopment is less clear (Eskenazi et al. 1999). As with studies of lead and neurodevelopment, social factors may confound, at least in part, the association between maternal smoking and neurodevelopment (Baghurst et al. 1992). A child's prenatal exposure to maternal smoking or pre-or postnatal exposure to ETS could, if these are causally related to impaired neurodevelopment or other adverse health outcomes, confound the observed associations of lead and health. In addition, if a relationship between postnatal ETS and neurodevelopment is established, lead exposure could be a mediating factor. # Conclusions: Of the studies reviewed, most did not assess prenatal or postnatal ETS as a possible confounding factor. Those that assessed tobacco at all controlled for maternal smoking during pregnancy. However, the two exceptions, Lanphear et al. (2000) in which serum cotinine measurements were used to control for ETS and a study based on the Port Pirie cohort (Tong et al. 1996;Baghurst et al. 1992) which reported postnatal parental smoking, provide no evidence that confounding by tobacco exposure accounts for the associations observed between blood lead and adverse health effects. Limitations in available studies leave some uncertainty as to what contribution, if any, ETS might make to observed associations between BLL and health. # Causal Direction Inference of causation from observational epidemiologic studies is sometimes complicated by the possibility that the health outcome under study could be a cause of the exposure or causally related to a third factor which itself is a cause of the exposure under study. Two factors that influence blood lead levels-mouthing behavior and calcium balance-are relevant to assessing causal direction in studies of the health effects of lead at low levels. # Mouthing behavior An important pathway of lead uptake by young children is ingestion of leadcontaminated dust (Charney et al. 1980;Bornschein et al. 1985), presumably through mouthing of hands, surfaces, and objects on which the dust is deposited. Although mouthing behavior is difficult to measure, children with more reported mouthing behavior have higher BLLs in relation to environmental lead exposure (Lanphear et al. 1998;Bellinger et al. 1986;Baghurst et al. 1999). Pica (purposeful ingestion of non-food items) can be a consequence of impaired neurodevelopment and can predispose one to lead ingestion (Cohen et al. 1976;McElvaine et al. 1992;Shannon et al. 1996), but the relation of variation in "normal" age-appropriate mouthing behavior to neurodevelopment is uncertain. However, in groups of children, average measured or caregiver reported mouthing has been shown to diminish with age (Juberg et al. 2001;Tulve et al. 2002). Nonetheless, it is unclear whether, at the individual level, more frequent mouthing behavior is a marker (independent of its effect on lead ingestion) for delayed neurodevelopment. If such behavior is a marker, then an association between blood lead level and impaired neurodevelopment would result, and failure to adjust for mouthing behavior would result in an overestimate of the blood-lead effect. On the other hand, if measured mouthing behavior is associated with cumulative lead exposure above and beyond that reflected in measured BLLs, then controlling for mouthing behavior could amount to over control, underestimating the true effect of lead on neurodevelopmental measures. # Conclusions: At this point, no direct evidence supports reverse causation by mouthing behavior, and this hypothesis remains speculative. Arguing against this possibility, Tong et al. (1996) reported that an early measure of neurocognitive development, the Bailey MDI, was not predictive of later BLLs. # Calcium balance Calcium balance changes in relation to growth during childhood and during the rapid expansion of bone mass during puberty and the pubertal growth spurt (Bronner et al. 1998;van Coeverden et al. 2002;Bailey et al. 2000); estradiol may influence bone mineral deposition in pubertal girls (Cadogan et al. 1998). It is possible that effect of skeletal growth and puberty on calcium balance could cause lower BLLs (Thane et al. 2002), just as the opposite changes in calcium balance during menopause appear to cause an increase in blood lead (Hernandez-Avila et al. 2000;Garrido Latorre et al. 2003). It should be noted that the average age at menarche among U.S. adolescents dropped by approximately 2.5 months between the periods 1963-1970 and 1988-94 and that this trend was accounted for in part by a rising prevalence of obesity (Anderson et al. 2003). Average BLLs were likely falling substantially during this same period. # Conclusions: Because human studies linking blood lead at levels <10 µg/dL to delayed puberty and smaller stature are, with one exception, cross-sectional and evidence is limited on this topic, reverse causation via changes in calcium balance cannot be ruled out as accounting for at least some of the observed associations. While the parallel secular trends in decreasing age at menarche and decreasing BLLs could be explained in part to a causal effect of lead delaying age at menarche, it is also possible that other secular trends (e.g. increasing obesity rates) have caused the trend toward earlier menarche. # Overall Conclusions Question 1: Does available evidence support an inverse association between children's blood lead levels <10 µg/dL and children's health? Because of the large number of studies that have assessed cognitive function as an outcome, the review and conclusions by the WG primarily focus on this health domain. The consensus of the WG is that the overall weight of available evidence supports an inverse association between BLLs <10 µg/dL and the cognitive function of children. The evidence for such an association is bolstered by the consistency across both cross-sectional and longitudinal studies in varied settings with blood lead distributions overlapping 10 µg/dL and by the lack of any trend towards a weaker association in studies with lower population mean BLLs. More recent studies and analyses best suited to examining this association (Canfield et al. 2003;Bellinger et al. 2003) have added to, rather than refuted, evidence for such an association noted in prior CDC guidance (1991). In reaching this conclusion, the WG is mindful of limitations in the available evidence base. Relatively few studies have directly examined the association between BLLs <10 µg/dL and health status among children and many of those that have are cross sectional studies in which data are unavailable on BLLs earlier in life and key covariates. The WG concluded that findings from numerous published studies relating BLL to cognitive function, while not limited to children with BLLs <10 µg/dL, collectively were not consistent with a threshold for the BLL-cognitive function association at 10 µg/dL. This indirect evidence, however, is less persuasive than cohort studies and analyses that directly assess the relationship between BLL and health <10 µg/dL. These directly relevant studies analyzed data for children whose measured BLLs did not exceed 10 µg/dL (to the investigator's knowledge). Likely included in these analyses were some children who, because of random variation in BLL or age trends, did at some time have a BLL >10 µg/dL that was not measured. Such misclassification could produce an apparent inverse association between BLLs <10 µg/dL and health status even if a threshold existed at 10 µg/dL. Such misclassification, however, could not account for the observed BLL-IQ relation in the Canfield (2003) study, in which a steeper slope was observed at BLLs <5 µg/dL than at levels 5-10 µg/dL. For health endpoints other than cognitive function, including other neurologic functions, stature, sexual maturation, and dental caries, available data are more limited and less replication of findings exists across studies. Nonetheless, the available data from these studies are consistent with associations between higher BLLs and poorer health indicators for values <10 µg/dL . # Question 2: Are the observed associations likely to be causal? The work group concluded that, while available evidence does not permit a definitive causal interpretation of the observed associations between higher BLLs and adverse health indicators for values <10µg/dL, the weight of available evidence favors, and does not refute, the interpretation that these associations are, at least in part, causal. The WG also concluded that the limitations of the available evidence, including likely residual confounding by social environment, leave uncertainty about the absolute strength and shape of the causal relation at the population level. Even greater uncertainty attends the use of associations observed in the relevant population studies for interpretation of BLLs measured in individual children at a single point in time. Thus, the WG does not believe that the individual children can be classified as "lead poisoned," as the term is used in the clinical setting, on the basis of the associations observed in studies reviewed for this report. The basis of the overall WG conclusions is discussed below and is followed by a summary of the important limitations in the available evidence. The WG explored other possible explanations (aside from causation) for these associations and concluded that none are likely to fully explain the observed data. The context of evidence from animal, in vitro, and human studies of adult populations, also supports the consensus of the WG conclusion that the observed associations most likely represent, at least in part, causal adverse impacts of lead on children's cognitive function at BLLs <10 µg/dL. The greatest source of uncertainty in interpreting the relationship between BLLs <10 µg/dL and cognitive function is the potential for residual confounding by social factors. The conditions for residual confounding appear to be present: BLLs are strongly influenced by SES, SES is clearly related to measured cognitive function, and social factors that could influence BLL and cognitive function are difficult to measure precisely. Other sources of potential bias are, individually, less concerning than social confounding, but collectively they add to the overall uncertainty about the absolute strength and shape of the relation of BLL to impaired cognitive function. These include, random error in blood lead measurement and in a single BLL as a measure of chronic exposure, possible influence of factors that have not been fully addressed in published studies, including blood lead tracking and age trend, which limits cross-sectional studies in particular, tobacco smoke exposure, iron deficiency, and mouthing behavior. Error in measuring lead exposure would bias observed associations towards the null, while failure to adjust for the other factors noted would most likely bias observed associations away from the null. The recently reported trend of asymptotically increasing slopes of lead-associated decrements in cognitive test scores at lower BLLs (Bellinger et al. 2003;Canfield et al. 2003;Lanphear et al. 2000) would be expected if residual confounding were operative as illustrated in Figure 7. The graph on the left depicts a comparison of two groups of children who live in a high exposure setting. They differ, on average, with respect to aspects of the home and social environment that are not captured in measured covariates. This results in one group ingesting and absorbing twice as much lead and having, after adjustment for measured covariates, a mean IQ 1 point lower than the children raised in a more favorable environment. Assuming a roughly linear relation of lead intake to blood lead, the result is that one group has a mean blood lead twice as high, corresponding to a 10 µg/dL difference in blood lead and an estimated blood lead-IQ slope attributable to residual confounding of 0.1 IQ points per µg/dL. The figure on the right depicts the same hypothetical two populations living in a low exposure setting. The same imperfectly measured differences in social environment contribute to the equivalent covariate-adjusted difference in mean IQ, but in this case, although one group ingests twice as much contaminated dust as before, lower levels of lead contamination result in the two children having a blood lead difference of only 1 µg/dL in blood lead level. The result is an estimated blood lead-IQ slope attributable to residual confounding of 1.0 IQ points per µg/dL. In addition, a convincing and directly relevant biologic mechanism for such a dose response relation has yet to be demonstrated. Though this hypothetical example cannot demonstrate that residual confounding underlies the steep blood lead-IQ slopes observed at low levels, it does support the need for caution in interpreting the absolute value of the estimated effect sizes. The available data for these other health endpoints, taken mostly from crosssectional studies, are more limited and firm conclusions concerning causation cannot be made at this time. # Research Needs # Resolving residual confounding through observational studies It may be somewhat easier to identify study populations with BLLs <10 µg/dL in which socioeconomic factors are not associated with exposure as compared to populations with more widely varying blood lead levels within many low SES children, but few high SES children, may have blood lead levels above 20 or 30 µg/dL. Configuring a cohort similar to the one in Boston or assembling one from the pieces of others already studied could be helpful in isolating socioeconomic and lead effects from one another. Another formal statistical approach that could be applied to pooled data across multiple studies is the application of a hierarchical modeling approach as proposed by Schwartz et al. (2003, in press). # Controlled intervention trials While experimental designs can establish causation with greater confidence than observational studies, intentionally exposing some children to higher BLLs in a randomized controlled design would be unethical. However, randomized trials in which interventions are tested for their ability to reduce BLLs <10 µg/dL or prevent their increase provide an opportunity to support or refute a causal relationship between BLLs <10 µg/dL and adverse health outcomes. Studies testing such interventions should measure covariates relevant to assessing health effects, allowing a test of the causal hypothesis should they be successful at sufficiently reducing BLLs. # Animal and in vitro studies to explore mechanisms and dose-response relations While the overall evidence from animal or in vitro models supports the biologic plausibility of adverse effects of lead at BLLs <10 µg/dL, the WG is unaware of directly relevant animal or in vitro studies that demonstrate a steeper slope for adverse effects of lead exposure at lower BLLs than observed at higher levels. Demonstrating such a relationship in experimental studies and identifying possible mechanisms would increase confidence in a causal interpretation of the observed blood lead-response relationship in studies such as Canfield et al. (2003). # Notes: Figures 2 and 3 Selected estimates of change in outcome (Full Scale IQ or McCarthy General Cognitive Index (GCI) derived from regression coefficients and listed in Table 2 and the corresponding mean BLLs of the study population are displayed in Figures 2 and 3. Figure 2 contains results from studies where the BLLs were measured at ages <2 years, and outcome measures were measured at ages >4 years. Figure 3 contains the results when both the BLLs and outcome measures were measured at ages >4 years. Both the crude (open dot) and adjusted (solid dot) coefficients are displayed in the figures when both are available. (The Kosovo and European Multicenter Study papers did not provide the crude coefficient). Although multiple models for a single study population may have been fit to results from differing ages within the defined age categories, only the regression coefficients for the highest age at which blood lead was measured (per study population) are included in the figures. (The highest outcome measure age was used as a tiebreaker when necessary.) Also, when models for both a concurrent blood lead measure and a lifetime average blood lead measure existed for the highest age at which blood lead was measured (Port Pirie and Rochester), the concurrent results were included. For the study that provided multiple models for the same highest-age blood lead versus outcome measure (Lavrion, Greece), the results from the model that included the most covariates were included. Any studies not providing both a regression coefficient and blood lead mean were excluded. Three-letter abbreviations for each study population, defined in the legends below, were used on the plots. (6,7,34) specimens for 6-, 12-, 18, and 24-month specimens were collected in capillary tubes by trained technicians. Blood samples were assayed in duplicate or triplicate. The analytical system was calibrated with aqueous standards of known lead concentrations. Each batch of samples was accompanied by a blood sample of known lead concentrations to quantify intralaboratory reliability. Several standardized blood samples with lead concentrations also were included after they became available in 1982 from CDC. (Rabinowitz, et al., 1985) 57-month venous blood samples were obtained. Lead was measured in duplicate by GFAAS. An aliquot of a standardized blood sample provided by the National Bureau of Standards was included in each batch of samples. (Bellinger, et al., 1991) Cincinnati Samples were measured by venipuncture, heel stick, and finger stick for infants and were analyzed by (13) ASV. Blood samples were obtained using either venipuncture or heel stick. Approximately 72% of all samples are venipuncture. For heel stick, two capillary tubes were filled for duplicate PbB determination. If venipuncture was possible, pediatric vacutainer tubes were filled, one for PbB determination and a second for serum iron and total iron binding capacity (TIBC) analyses. The sample was aliquoted and duplicate analyses performed according to a predetermined protocol using ASV. The laboratory participates in both the CDC and PA State Blood Lead and Protoporphyrin Programs. A series of bench-top QC samples and blind QC samples were analyzed with each run. (Bornschein et al., 1985) Cleveland Samples were measured by venous and were analyzed by GFAAS. Blood samples were collected in (14,15,16) heparinized plastic syringes which had been determined to be free of trace metals. The concentration of lead in whole blood samples was determined by GFAAS. All samples were run in duplicate. The within-run (same day) reproducibility was evaluated for a sample of adult whole blood. The obtained values were 55.2 ug/dl, 1.34, and 2.4%, respectively, for the mean, SD, and coefficient of variation. Regular assessment of accuracy and precision using CDC samples of bovine blood were conducted and found to be within the certified range. Two inter-laboratory reviews were conducted for further determination of accuracy. Blood-lead levels were not adjusted for hematocrit. (Ernhart, et al., 1985) Costa Rica Samples were measured by venous and were analyzed by GFAAS. Venipuncture samples were taken (41) and red blood cells were promptly separated and frozen for future analysis in the U.S. The frozen red cells were analyzed using GFAAS in a laboratory that participates in CDC's Maternal and Child Health Resources Development Proficiency Testing Program for Blood Lead. Quality control was monitored through certified controls obtained from the National Bureau of Standards. Red cell lead values were converted to whole blood-lead levels using the formula of Rosen et al.(1974). (Rothenberg, et al., 1994) MDI was administered at 6-month intervals beginning at 6 months of age, by examiners blind to the infants' lead levels. (Bellinger, et al., 1985) For WISC-R , most children were tested in a single session, 2 were seen in a second session to complete testing, and 7 were tested in their homes by parental request. Psychologists were blind to all aspects of child's developmental and lead exposure histories. For WISC-R, one experienced psychometrician performed all the assessments. Children were tested at a pediatric clinic. The examiner was blind to the exposure levels of the child. For MDI, all assessments took place in a prenatal and child welfare clinic. Psychometric tests were administered at an inner-city health clinic by the study leader or trained assistant with whom inter-tester reliability had been previously established. Testers were blind to children's blood-lead levels. WPPSI, MDI, and Stanford Binet IQ tests were conducted by well-trained examiners blind to all risk and background information. Home testing was used to control attrition, to minimize bias in attrition, and to facilitate administration of the HOME Inventory. Inter-observer agreement was checked through observation and duplicate scoring by a supervisor for approximately one out of every 26 examinations. Agreement was maintained at r=.99. Answer sheets were checked for possible irregularities by the supervisor within a few days of each administration. Spanish versions of Bayley MDI and WPPSI were used in the assessment. A single tester, trained by one of the primary investigators and the most senior research psychologist in the country, administered the assessments. The tester was blind to the children's iron status and never knew the blood-lead levels (these were performed in the U.S.). (Lozoff, personal communication) Three Yugoslavian psychologists scored the WISC-R and the McCarthy GCI independently. All interviews and assessment instruments were translated and administered in the two dominant languages of the region, Serbo-Croatian and Albanian. Training and reliability visits occurred. The average interclass correlation for 96 tests over study period was calculated. Four trained psychologists blind to children's lead levels administered the McCarthy GCI. As there were no norms for the McCarthy scale in the Mexican population, the U.S. norms were used to calculate GCI, with a Spanish translation of the test. Interexaminer reliability was assessed by calculating the correlation in GCI scores assigned by two of the psychologists with the scores of a third psychologist whom they observed applying the test in all possible combinations with 10 subjects for each combination. Mean observer-examiner correlation was .99. Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While the results they present are largely consistent with the findings of Lanphear et al. (2000), they provided a critique of the validity of the NHANES III data for evaluating lead-related impacts on neuropsychological development in children. Because their critique cuts across on neuropyschological measurements performed in the survey, the main points of their paper are summarized in this appendix, as follows. • Stone et al. note that the weighted mean values for the four measures used by Lanphear et al. are below the predicted mean based on standardization data for these tests collected in the early 1970s for the WISC-R) and early 1980s for the WRAT. Stone et al. argue that the mean values should be higher than predicted by the standardization means because of secular improvements in cognitive test scores. One possible reason cited for the discrepancy is that NHANES tests were not administered by a psychologist. It is unclear, however, if the population sample used in the standardization data was equally representative of the U.S. population at that time or if changes in the population composition since then would lead to an increase or decrease in overall mean test performance. More importantly, it is unclear how a bias in mean score, even if real, and the use of non-psychologists for testing could produce associations between BLLs and test scores, given that examiners could not have known the BLLs of participants. If nonpsychologists produced less precise test results than psychologists would have, the expected impact on regression coefficients would be a bias toward the null. • The age-adjusted scores used in NHANES are correlated with age, and they should not be. Stone et al. show that age is negatively correlated with arithmetic, block design, and digit span and positively correlated with reading. However, since BLLs decrease with age across the age range studied, the negative correlations would tend to produce a trend towards higher scores with increasing blood lead for those tests, the opposite of the findings of Stone et al. whether interviews were in Spanish, and several other factors, were not included in analyses. However, two problems are evident in alternative "two stage" analysis provided by Stone et al. First, it uses predicted rather than residual blood lead level as an independent variable in a model relating blood lead to test scores. This amounts to testing the relation to test scores of a linear combination of covariates, many included in the model with test score as the outcome. In addition at least one variable -having to repeat a grade -is included as a covariate, possibly result serious over control as B-3 discussed earlier. Lead associated cognitive and behavioral effects have, not surprisingly, been associated with an increased risk of failure to complete high school. Thus, controlling for failure to complete a grade could amount to controlling for an effect of, rather than a confounder of the lead effect. As a whole, the Stone et al. critique of the NHANES III data do not provide a convincing argument that the findings reported by Lanphear et al. (2000) result from problems with the sample or testing methods. However, the WG did consider the limitations of the Lanphear et al. study, including its cross-sectional design and limited data on potential confounders. This study was weighed in the overall context of other relevant studies, including the more persuasive cohort studies, which are largely consistent with the associations Lanphear et al. report. # B-4 The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry R-14 # APPENDIX A: LITERATURE REVIEW AND CLASSIFICATION UPDATE A-1 The literature review began with the Agency for Toxic Substances and Disease Registry's Toxicological Profile for Lead (ATSDR Tox Profile), published July 1999. The Health Effects chapter was thoroughly read and all articles relating to low blood lead levels in children were chosen, regardless of whether they demonstrated significant results. New literature searches were then performed by Battelle's Technical Information Center. The year 1995 was chosen as the cutoff date for the new searches because the WG felt that, before this time, research rarely focused on BLLs <10 µg/dL, and that most relevant articles before 1995 were cited in the ATSDR Toxicological Profile. Searches were performed on a variety of databases using DIALOG and a set of keywords. This literature search was first run for the years 1995-2002. In spring, 2003, the search was rerun for the years 2002-2003 to determine the relevance of recently published articles. Also at this time, the search was rerun for the years 1990-1996 for relevant articles that were not cited in the ATSDR Toxicological Profile. Titles and abstracts from each literature search were reviewed, and relevant articles were ordered for further review. Additional articles were identified while reviewing the selected articles and were added to the list of references, as were several articles recommended by workgroup members. The table below provides a summary of all the articles obtained from the various sources. This table shows when the search was performed, the years covered in the search, the number of articles found in the literature search, the number of articles ordered after the titles and abstracts had been reviewed, and the number of articles that were relevant for abstraction. 2 through 6. # Summary of Literature Review Results # Date of Search # Reference Number First Author Publication Date Journal Title Altmann, L.	None	None
6f5bacb5f640dd689037c405a41a925d9cc3b144	cdc	None	Today, B. anthracis is considered one of the most serious biowarfare or bioterrorism agents because of the ability of the spores to persist in the environment, the ability of the aerosolized spores to readily cause infection via respiratory (inhalation) exposure, and the high mortality of resulting inhalation anthrax (7-9). CDC has classified anthrax as a category A biological warfare agent (10), meaning it has great potential to adversely affect public health. The lethality of aerosolized B. anthracis spores was demonstrated in 1979 when an unintentional release of B. anthracis spores from a military microbiology facility in the former Soviet Union resulted in 64 deaths (11). The cases of anthrax that occurred after B. anthracis spores were distributed through the U.S. mail in 2001 further underscored the potential dangers of this organism as a bioterrorism threat (12)(13)(14)(15). Vaccines against anthrax were first developed as early as 1880 and used in livestock ( 16).# Introduction Anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis (1,2). The disease most commonly occurs in wild and domestic mammals (e.g., cattle, sheep, goats, camels, antelope, and other herbivores) (3). Anthrax occurs in humans when they are exposed to infected animals or tissue from infected animals or when they are directly exposed to B. anthracis spores (4)(5)(6). Depending on the route of exposure, anthrax can occur in three forms: cutaneous, gastrointestinal, or inhalation. # Background B. anthracis is a facultatively anaerobic, gram-positive, encapsulated, spore-forming, nonmotile rod. The infectious form of B. anthracis that is predominantly found in the environment is the spore, which is approximately 1 µm × 2 µm; anthrax is contracted from these spores, which are highly resistant to heat, cold, drought, UV light, and gamma radiation. B. anthracis has three major virulence factors: an antiphagocytic capsule and two exotoxins, referred to as lethal toxin and edema toxin. These toxins are responsible for the primary clinical manifestations of hemorrhage, edema, necrosis, and death. Disease is categorized according to the route of human exposure to B. anthracis spores: cutaneous, gastrointestinal, or inhalation. The precise infectious dose of B. anthracis in humans by the various routes is not known; inhalation anthrax can develop in susceptible hosts after exposure to a relatively small number of spores (28,29). Based on data from studies of nonhuman primates, the lethal dose has been estimated to range from 2,500 to 760,000 spores (11,30). The majority of human anthrax cases worldwide are naturally occurring (i.e., not a result of bioterrorism). The case-fatality rate for anthrax ranges from <1% (for cutaneous anthrax treated with appropriate antimicrobial agents) to 86%-89% (during the 1979 outbreak in the former Soviet Union and in the United States during the 20th century, respectively) (6,11,31,32). # naturally occurring Anthrax Throughout much of the 20th century, anthrax in humans was grouped into two categories: agricultural or industrial (6,33). B. anthracis spores can remain viable and infective in soil for decades, during which time they serve as a potential source of infection for grazing livestock that might become infected when they ingest or inhale the spores. B. anthracis spores in soil generally do not pose a direct infection risk for humans, who are typically infected by B. anthracis spores through contact with contaminated animal products or an infected animal (28). Agricultural cases of anthrax occur among persons who have direct contact with infected sick or dying animals or who handle infected carcasses or tissues. Persons at risk for acquiring anthrax through agricultural exposure might include ranchers, veterinarians, slaughterhouse or abattoir workers, and butchers. Industrial cases of anthrax result from the cutaneous inoculation or inhalation of particles containing B. anthracis spores generated during the cleaning and industrial processing of contaminated hides, hair, or wool from infected animals. Workers in wool and mohair processing facilities were historically at risk for contracting both inhalation and cutaneous anthrax, which made the disease a substantial health hazard in the wool industry in the 19th century and throughout the first half of the 20th century (4,34). Industrial processing of animal hair or hides accounted for 153 (65%) of 236 anthrax cases reported to CDC during 1955-1999 (35); commercial products made from animal hair or hides accounted for an additional five (2%) cases. Of these 158 cases, the majority (94%) were cutaneous anthrax; 10 (6%) cases were inhalation anthrax. Naturally occurring anthrax cases also have occurred outside of agricultural and industrial settings as a result of contact with products from anthrax-infected animals. Such products include anthrax-contaminated bristle shaving brushes, animal skins, animal hair or yarn, and bone meal (31,(36)(37)(38)(39)(40)(41). During 2006-2008, three inhalation cases (in the United Kingdom, United States, and Scotland) and two cutaneous cases (in the United States) were associated with drums made from imported contaminated hides (36,39,(42)(43)(44). Estimating the worldwide incidence of naturally occurring human anthrax is difficult because reporting of anthrax cases is unreliable in many settings (28). However, anthrax is most commonly observed in agricultural regions with inadequate control programs for anthrax in livestock. Anthrax outbreaks affecting domestic animals in these regions lead to direct or indirect human infection. Enzootic and endemic regions include South America, Central America, southern and eastern Europe, Asia, Africa, the Caribbean, and the Middle East (28). The largest recent epidemic of human anthrax occurred in Zimbabwe during 1978-1980 and involved 9,445 cases, including 141 (1.5%) deaths (5). The incidence of anthrax in animals in the United States has decreased since the middle of the 20th century, from 25 states reporting animal outbreaks in 1951 to eight states reporting outbreaks for the 10-year period from 1997 to 2006 (45,46) Outbreaks among both domestic animals and wildlife continue to be reported from the Great Plains states from Texas to North Dakota and in western states, including California, Montana, Nevada, and New Mexico (45). Cases that occur sporadically in both domestic livestock and free-ranging wildlife might not be recognized. Anthrax is a nationally notifiable disease (information available at ). In the 21st century, naturally occurring cases of anthrax in the United States have occurred sporadically, with two or fewer cases reported each year. Of the 242 naturally occurring human anthrax cases reported to CDC during 1955-2007, 232 (96%) were cutaneous, 10 (4%) were inhalation, and none were gastrointestinal (CDC, unpublished data, 2010). The only reported case of gastrointestinal anthrax in the United States occurred in 1941 (47) and resulted from an industrial exposure, not from contaminated food. Although gastrointestinal exposure to anthrax has been documented in the United States, no confirmed cases of anthrax resulted from the exposures (48). In 2010, CDC received a report of a woman with severe gastrointestinal symptoms after exposure to B. anthracis spores (CDC, unpublished data, 2010). # Bioterrorism-Related Anthrax In 2001, 22 confirmed or suspected human cases of anthrax occurred in the eastern United States (referred to as the bioterrorism events of 2001 in this report) when B. anthracis spores were sent through the mail in powder-containing envelopes to news media companies and U.S. congressional leaders (14,15,49). Eleven of the 22 cases were inhalation anthrax, and 11 were cutaneous; 20 of the cases occurred in mail handlers or persons exposed to buildings where contaminated mail was processed or received (15). Five persons with inhalation anthrax died. The source of exposure was unknown in two of the fatal cases (50,51); however, cross-contaminated mail was considered a possible source. B. anthracis has been a focus of offensive and defensive biological warfare research programs worldwide (10). Anthrax was used against livestock and draft animals as a bioweapon by Germany during World War I; during World War II, Japan conducted weapon field trials with anthrax in Manchuria. Numerous countries, including the United States, the United Kingdom, the former Soviet Union, and Iraq, conducted anthrax weapons research at various times during World War II, the Cold War, and the decades that followed (52,53). In 1979, at least 96 persons were infected and 64 persons died during an anthrax outbreak in the Soviet city of Sverdlosk after anthrax was unintentionally released from a military microbiologic facility believed to be a biowarfare facility (11). In 1993, a religious cult, Aum Shinrikyo, unsuccessfully attempted to use B. anthracis as a weapon near Tokyo, Japan (54). In 2008, the Department of Homeland Security issued a statement indicating that anthrax poses a threat sufficient to affect U.S. national security (55). WHO experts have estimated that 50 kg of B. anthracis spores released upwind of a population center of 500,000 persons could result in 95,000 deaths and 125,000 hospitalizations (56), and a release of 100 kg of spores upwind of the Washington, DC, metropolitan area would result in an estimated 130,000 to 3 million deaths (57). An intentionally dispersed strain of B. anthracis might have different characteristics from a naturally occurring strain. Intentionally dispersed strains might demonstrate antimicrobial resistance or increased dispersion capabilities. Primary aerosolization (dispersion of particles in air resulting from the initial release) and secondary aerosolization (resulting from agitation of the settled particles from the primary release) are important considerations in bioterrorist acts (58)(59)(60)(61)(62)(63)(64). The magnitude of risk for inhalation anthrax from secondary aerosolization of B. anthracis spores is uncertain. The bioterrorism events of 2001 prompted extensive biodefense research, as well as the creation and implementation of bioterrorism preparedness plans. Since 2001, in addition to increasing the number of public health mechanisms by which drugs and vaccines are distributed and dispensed or administered (i.e., EUA), emergency response and preparedness measures have focused on improving the effectiveness and timeliness of distributing and dispensing antimicrobials and vaccine for PEP. Efforts also have been made to improve the availability and timely distribution and administration of AVA in postevent settings. Because AVA is not licensed for postexposure use, the vaccine may be made available under an IND protocol or possibly under an EUA in an emergency (19)(20)(21)(22). # Pathogenesis and Disease B. anthracis enters the host in the form of spores (65) at the epidermis (cutaneous anthrax), the gastrointestinal epithelium (gastrointestinal anthrax), or the lung mucosa (inhalation anthrax). It is unknown whether B. anthracis has an active invasive process, and the symptoms and incubation period vary depending on the route of exposure to the spores. In general, symptoms of any form of anthrax usually begin within 7 days of exposure (1). Most naturally occurring B. anthracis bacteria are sensitive to a wide range of antimicrobial agents. Before initiating antimicrobial treatment, appropriate specimens should be obtained for isolation of the organism by culture. In practice, B. anthracis is readily identifiable using a range of standard microbiological tests, including Gram stain, cell and colony morphology, sensitivity of the gamma phage of McCloy, and production of the γ-linked poly-d-glutamic acid (γDGA) capsule in blood or under culture in 20% carbon dioxide. Most cutaneous and gastrointestinal infections occur at the site of preexisting lesions (66). Inhalation anthrax occurs after inhalation of aerosolized particles containing viable B. anthracis spores and their deposition at the alveolar epithelial surface (6,66). Inhalation anthrax is not pneumonia; in this form of disease, the mediastinal lymph nodes are usually the nidus of bacterial proliferation. Spores also can germinate at the pulmonary epithelial surface, and lung tissue might be infected as a consequence of fulminant systemic bacterial proliferation from other portals of entry (67). Regardless of the route of exposure, vegetative B. anthracis can spread through the blood stream, causing systemic disease (i.e., systemic anthrax) that results in hypotensive shock and sudden death (65). Systemic anthrax is typically fatal unless diagnosed and treated promptly (11). Anthrax meningitis can occur secondary to any of the three forms of anthrax. Although meningitis can occur without any other clinical signs and symptoms of anthrax, the condition is most often associated with inhalation anthrax. The pathogenicity and proliferation of B. anthracis in the host are primarily a result of the combined actions of the γDGA capsule and the two protein exotoxins, edema toxin (a complex composed of protective antigen and edema factor) and lethal toxin (a complex of PA and lethal factor) (68). Production of the capsule and toxins parallels the germination and outgrowth of B. anthracis spores (69). The capsule is considered to be antiphagocytotic, and the exotoxins disarm the innate and acquired immune responses (70)(71)(72). Edema toxin increases host intracellular cyclic adenosine monophospate (cAMP) levels, resulting in cytokine modulation, upregulation of the anthrax toxin receptor, and disruption of interstitial fluid balance (73,74). Lethal toxin inactivates members of the mitogenactivated protein kinase kinase (MAPKK) family, causing an imbalance in the production or release of a range of cytokines (75,76). In cases of cutaneous anthrax and those in which the nidus of infection remains localized, the combined effects of the toxins are tissue edema and local tissue necrosis. In cases of systemic anthrax secondary to any form of initial disease, the toxins cause hemorrhagic tissue and organ necrosis, hypoxic insult, and edema. In cases of inhalation anthrax, the edema is most prominent in the pleura, whereas in gastrointestinal anthrax, the fluid accumulation is most prominent as ascites (77,78). # Cutaneous Anthrax More than 95% of all naturally occurring B. anthracis infections worldwide are cutaneous. This form of anthrax is associated with handling infected animals or contaminated items such as meat, wool, hides, leather, or hair products from infected animals (79). Cutaneous anthrax has characteristic signs and symptoms and is recognizable if the physician is familiar with the disease. The majority of cutaneous anthrax lesions develop in exposed areas such as the face, neck, arms, and hands. The lesion begins as a small, often pruritic papule that quickly enlarges and develops a central vesicle or bulla, which ruptures or erodes, leaving an underlying necrotic ulcer. A characteristic firmly adherent, black eschar develops over the surface of the ulcer. The lesion is usually painless. Satellite vesicles and ulcers might also form (80). Edematous swelling of the surrounding tissues occurs, often with regional lymphadenopathy and lymphangitis. Systemic signs and symptoms, including fever, malaise, and headache, might accompany the cutaneous lesion (1). Historically, case-fatality rates for cutaneous anthrax have been as high as 20% without appropriate treatment but <1% with appropriate antimicrobial therapy (6). Because the progression of the disease is mediated by toxins, the lesions progress through the various stages once they have appeared, even with antimicrobial therapy. Discharge from cutaneous lesions might be infectious; however, the risk for personto-person transmission of cutaneous anthrax is very low (81). Differential diagnoses for a blackened eschar or other lesion include staphylococcal or streptococcal cellulitis or lymphadenitis, eczema, and herpes simplex or varicella zoster. In addition, depending on the epidemiologic history or route of exposure, parapoxvirus infection (orf virus and pseudocowpox virus) should be considered, because they are the most common parapoxviruses in U.S. food animals such as cattle, sheep, and goats. The differential diagnoses also include brown recluse spider bite, rickettsial pox, ecthyma gangrenosum, ulceroglandular tularemia, plague, typhus, glanders, erysipelas, cat-scratch disease, rat-bite fever, aspergillosis, mucormycosis, vaccinia, cutaneous leishmaniasis, cutaneous tuberculosis, and leprosy (80,82). The incubation period for cutaneous disease is reported to be 5-7 days (range: 1-12 days) (83). However, during the 1979 Sverdlovsk outbreak, cutaneous cases reportedly developed up to 13 days after the aerosol release of spores (11), and an outbreak in Algeria was reported with a median incubation period of 19 days (84). # Gastrointestinal Anthrax Gastrointestinal anthrax typically occurs after eating raw or undercooked contaminated meat, although spores consumed through any route, including spores that are inhaled and subsequently swallowed, can result in gastrointestinal anthrax. In the United States, no cases of gastrointestinal anthrax have been reported since 1941 (47). Although gastrointestinal anthrax could occur as a result of bioterrorist activity, no bioterrorismassociated cases have been reported. Gastrointestinal anthrax can occur in two forms: 1) intestinal or abdominal or 2) oropharyngeal. Data from human cases and outbreaks are limited, although clinical disease likely ranges from asymptomatic to fatal (85). The primary site of infection is the gastrointestinal epithelium. Infection might be associated with preexisting lesions in the alimentary tract, which might play a role in the development of oropharyngeal lesions. However, studies in mice demonstrated infection in the Peyer patches of the small intestine after intragastric deposition of spores (67). The intestinal form develops when spores infect the gastrointestinal tract epithelium after consumption of undercooked, contaminated meat. Signs and symptoms range from subclinical gastrointestinal disturbances to clinical illness with nausea and vomiting, fever, anorexia, and abdominal pain and tenderness and can progress to hematemesis and bloody diarrhea. Abdominal distension with voluminous, hemorrhagic ascites might be present (85,86). The disease might progress to septicemia and toxemia, cyanosis, shock, and death (86)(87)(88). Extensive edema of infected intestinal segments and mesentery can develop, and lesions might become necrotic and ulcerated. Infection of the mesenteric lymph nodes accompanied by lymphadenopathy might develop (86). An eschar might develop on the wall of the terminal ileum or cecum (86,89), and the upper gastrointestinal tract is occasionally affected (85,(90)(91)(92). The oropharyngeal form occurs after infection of the oropharyngeal epithelium and is characterized by lesions at the base of the tongue or tonsils, with sore throat, dysphagia, fever, and regional lymphadenopathy. Edematous lesions develop, which progress to necrotic ulcers covered with a pseudomembrane. Edema and swelling develop in the oropharynx and neck, accompanied by cervical lymphadenopathy, pharyngitis, and fever (85,88). The differential diagnoses of hemorrhagic gastroenteritis or oropharyngeal lesions suspected to be gastrointestinal anthrax should include the following (28): food poisoning, acute appendicitis, ruptured viscus, diverticulitis, dysentery, parapharyngeal abscess, malignancy, hemorrhagic gastroenteritis from other infectious causes, necrotizing clostridial enteritis, streptococcal pharyngitis, Vincent angina, Ludwig angina, and diseases causing acute cervical lymphadenitis, acute gastritis, or acute abdomen. Organisms may be isolated from vomitus or feces, from swabs of oropharyngeal lesions, or from blood or ascites fluid (79,88). The incubation period for gastrointestinal disease is estimated to be 1-6 days; the case-fatality ratio is unknown but is estimated to range from 25% to 60% (1,88). # Inhalation Anthrax Inhalation anthrax is a systemic infection caused by inhalation of B. anthracis spores. The mediastinal lymph nodes are most often the nidus of bacterial proliferation. Inhalation anthrax has historically accounted for 5% of all anthrax cases in the United States (31). This form of the disease results from the inhalation of aerosolized B. anthracis spore-containing particles that are ≤5 microns (66). Spore-containing aerosols can be generated through industrial processing or work with spore-contaminated animal products such as wool, hair, or hides; by laboratory procedures such as vortexing of cultures; or as a result of the intentional release of aerosolized spores. Inhaled spores lodge in the alveolar recesses and can become dormant, remaining dormant for weeks to months They are subsequently taken up by alveolar macrophages and then germinate (93)(94)(95), leading to substantial variability in the incubation period. Early studies of inhalation anthrax demonstrated that inhaled spores are phagocytosed by macrophages in the lungs and transported to the pulmonary-associated lymph nodes, where germination and vegetative growth occur, followed by bacteremia and dissemination to the rest of the body (94)(95)(96). Once taken up by alveolar macrophages, some spores are transported to the pulmonary-associated lymph nodes, where they continue to germinate, multiply, and release toxins (69,(97)(98)(99)(100), resulting in hemorrhagic necrosis of the thoracic lymph nodes that drain the lungs, or a hemorrhagic mediastinitis. Animal models also have demonstrated rapid phagocytosis of B. anthracis spores by interstitial dendritic cells, followed by dendritic cell migration to the thoracic lymph nodes (100). Exposure to aerosolized spores also has resulted in infection of nasal-associated lymphoid tissues in <24 hours, followed by subsequent spread to mandibular lymph nodes (67). Necrotizing pneumonitis occasionally develops (12,101,102). Initial signs and symptoms of inhalation anthrax are nonspecific and might include sore throat, mild fever, and muscle aches; these symptoms might initially be mistaken for an upper respiratory infection (79,103). Approximately 2-3 days later, infected patients generally become progressively ill as respiratory symptoms develop, including severe dyspnea and hypoxemia, and the disease progresses with development of hypotension, diaphoresis, worsening dyspnea, shock, cyanosis, and stridor (104). Chest radiography often reveals the characteristic widened mediastinum (12,79). Antimicrobial agents are effective against germinating and vegetative B. anthracis, but dormant spores are refractory to antimicrobials. Studies in nonhuman primates receiving antimicrobials suggest that inhaled B. anthracis spores can persist for up to 100 days in a dormant state at the alveolar surface epithelium (95). Inhalation anthrax has developed up to 58 days after experimental aerosol exposure in primates that received postexposure antimicrobial prophylaxis for the first 30 days after aerosol exposure (93). Reported incubation periods for inhalation anthrax in humans range from 1 to 43 days (11,31). Disease development can be prevented as long as the administered antimicrobial agent is maintained at levels sufficient to kill germinating B. anthracis organisms while dormant spores are cleared from the host. Cessation of antimicrobial treatment before clearance of the spores might allow residual spores to germinate and cause infection; therefore, the onset of inhalation anthrax might appear to be delayed (11,93,95,102,105,106). This late germination has not been observed in persons who have had a cutaneous or gastrointestinal exposure. Studies in animals suggest that incubation periods might decrease when the inoculum quantity increases (95,107,108). Similarly, in one reported human case, in a patient aged 51 years who was a previously healthy office worker in a textile mill (31), epidemiologic and exposure data suggested that the incubation period was as short as 1 day. The textile mill processed imported goat hair and previously had reported workers with cutaneous anthrax; however, no inhalation cases had been reported. The affected office worker had rarely entered the mill but developed inhalation anthrax in 1961, 1 day after visiting a dusty carding room in the mill. Subsequent investigation determined that both the goat hair being processed and the mill itself were widely contaminated with B. anthracis. In the 1979 Sverdlosk outbreak of inhalation anthrax, cases were reported 2-43 days after the initial release (11). Although the exact date of exposure in the Sverdlosk outbreak was not confirmed, the modal incubation period was reported as 9-10 days (11,65), which is slightly longer than the estimated incubation periods of 2-6 days in the few reported outbreaks of inhalation anthrax (11,106). The Sverdlosk data are limited regarding use of antimicrobials and vaccine; the number of people who received an intervention and the effectiveness of the intervention are unknown. Therefore, estimations of the incubation period during this outbreak are difficult to calculate (109). During the U.S. bioterrorism events of 2001, the median incubation period for six of the first 10 cases was 4 days (range: 4-6 days) (12). A review of all the 2001 inhalation cases indicates that the estimated incubation period was 4.5 days (15), a period consistent with previous reports (1). Case-fatality ratios of 86% and 89% were reported after the 1979 Sverdlosk outbreak in the former Soviet Union and in the United States during in the 20th century, respectively (11,31,32). During the bioterrorism events of 2001, the casefatality ratio for patients with inhalation anthrax treated in intensive care units was 45% (five of 11 cases) (15). # Bacteremic Dissemination and Meningitis After infection at the primary cutaneous, gastrointestinal, or inhalation site, lymphatic and hematogenous proliferation of anthrax bacilli can result in dissemination to other organs and organ systems (i.e., systemic anthrax). Massive septicemia with 10 7 to 10 8 bacteria per milliliter of blood and toxemia can develop, systemic effects including high fever and shock develop quickly, and death usually follows rapidly (65). Laboratory animal and nonhuman primate model studies demonstrate hematogenous spread to abdominal organs and the central nervous system (107,(110)(111)(112) with systemic inflammation, increased vascular permeability, and disseminated intravascular coagulation (113). Autopsy findings among decedents of the 1979 Sverdlosk outbreak and the bioterrorism events of 2001 included hepatic congestion, congestive necrosis of the spleen, and submucosal gastrointestinal lesions (101,114). Anthrax meningitis has been reported with all three clinical forms of anthrax and likely results from hematogenous spread across the blood-brain barrier, generally presenting as hemorrhagic meningitis. Anthrax meningitis is characterized by a fulminant, rapidly progressive clinical course; even with aggressive therapy, cases are usually fatal (115,116). The likelihood of the development of clinical or subclinical meningitis in patients with severe systemic B. anthracis infections is high. In rare cases, anthrax meningitis has been reported without any other associated primary (i.e., cutaneous, gastrointestinal, or inhalation) manifestation of anthrax (115,116). A review of 82 cases of inhalation anthrax that occurred during 1900-2005 included 70 fatal cases. Among the 70 patients who died, 11 of 61 patients for whom data were available had signs of meningeal involvement, compared with none of 12 patients who survived; 44 of the 70 patients who died developed meningoencephalitis during the course of their disease, compared with none of the 12 patients who survived. Development of meningoencephalitis during the course of disease was found to be significantly associated with death (p = 0.003) (104). Studies in nonhuman primates have demonstrated meningeal involvement in 33%-77% of experimental inhalation anthrax cases (93,108,110,112). # Control and Prevention Human anthrax is best controlled through prevention, including preexposure vaccination for persons at high risk for encountering aerosolized B. anthracis spores, reduction of animal illness by vaccination of livestock at risk for anthrax, and environmental controls to decrease exposure to contaminated animal products, such as imported hair and skins. After a person is exposed to aerosolized B. anthracis spores, a combination of antimicrobials and vaccine provides the best available protection. # Reduction of Risk for Exposure The incidence of naturally occurring human anthrax in the United States is greatly reduced through vaccinating and preventing infection in livestock, improving industrial hygiene, and decreasing the use of contaminated raw imported materials. Effective animal disease control programs have reduced the incidence of animal anthrax, and therefore human anthrax, worldwide. Since the initiation of annual vaccination of livestock in endemic regions in 1957, naturally occurring human cases in the United States have decreased from 38 cases in 1956 to fewer than two cases annually during 1980-2008. Anthrax in livestock can be controlled through vaccination programs, rapid detection and reporting of cases, and proper disposal of dead animals with suspected or confirmed anthrax, preferably by incineration (28,45). In countries where anthrax is common and vaccination coverage among livestock is low, humans should avoid contact with livestock and products from animals that have not been inspected and found to be healthy before and after slaughter (1,3). In addition, consumption of meat from animals that experienced sudden, unexplained death or meat of uncertain origin should be avoided (1,5). Restrictions on the importation of hides and wools from countries in which anthrax is enzootic can reduce the number of U.S. cases.- Methods for sterilizing or inactivating spores on contaminated materials include steam sterilization or ethylene oxide gas sterilization, boiling or using dry heat, or treating with formaldehyde, glutaraldehyde, or hypochlorite for specified periods of time and exposure concentrations; air drying does not destroy B. anthracis spores (28,(117)(118)(119). Industrial exposure and infection have been controlled through improvements in industry hygiene standards, mechanization of animal processing, and strict importation guidelines. Although these improvements have reduced the risk among employees working with animals and animal products, the risk has not been completely eliminated (120,121). Precautions to minimize exposure when working with potentially contaminated animal hides have been published (36,43) and should be followed. # Vaccination Vaccine Development The first effective anthrax vaccines using live, attenuated cultures of B. anthracis were demonstrated in 1880 by William S. Greenfield and in 1881 by Louis Pasteur (16,122). Pasteur's vaccine required a primary inoculation of B. anthracis that had been incubated at 42 º -43 º C for 15-20 days (type I vaccine) followed by a second inoculation (type II vaccine) of less attenuated B. anthracis that had been incubated at 42 º -43 º C for 10-12 days. This duplex vaccine was used widely until approximately 1935, when the procedure was modified to exclude the type I vaccine and reduce the virulence of the type II vaccine by the addition of 1%-10% saponin. Although effective, the virulence of heat-attenuated vaccines varied. In 1939, Max Sterne developed a live, attenuated spore vaccine from an avirulent, noncapsulated variant of B. anthracis (123,124). The Sterne-type vaccines replaced the Pasteur heat-attenuated formulations as the veterinary vaccines of choice. The veterinary vaccine that is currently used in the United States is based on the B. anthracis Sterne 34F 2 strain and is produced using a deep culture technique at approximately 10 5 doses per liter. Receipt of a single dose provides the animal with effective immunity for at least 1 year; revaccination is recommended to ensure protection for >1 year (105). The feasibility of using acellular vaccines against B. anthracis was first suggested by investigators who discovered that injections of sterilized edema fluid from anthrax lesions provided protection in laboratory animals (125,126). This discovery led to the exploration of the use of artificially cultivated B. anthracis filtrates as vaccines (127)(128)(129)(130)(131) and thereby to the human anthrax vaccines currently licensed and used in the United States and Europe. The first such U.S. product was developed in 1954 as a cell-free filtrate from an aerobic culture of the Vollum strain of B. anthracis, precipitated with aluminum potassium sulfate (alum), and evaluated for potency (132,133). This vaccine provided protection in monkeys, caused minimal reactivity and short-term adverse events in humans, and was used in the original efficacy study of human vaccination against anthrax in the United States (17). In the 1960s, the vaccine manufacturing process in the United States was modified, leading to changes in the B. anthracis strain used (from the Vollum strain to V770-NP1-R) and a switch to a microaerophilic culture method. These alterations optimized the production of a stable and immunogenic formulation of vaccine antigen and increased the production scale. Subsequently, the Michigan Department of Public Health (MDPH), under a contract with DoD, pursued premarket approval of the vaccine (128,134,135). The formulation for which MDPH sought premarket approval became AVA; the vaccine was licensed by NIH in 1970 and reapproved for licensure by FDA in 1985 (136). The safety and immunogenicity of the three generations of anthrax vaccine have been evaluated, and the resulting data support the FDA licensure of AVA (135). AVA is now marketed as BioThrax (Emergent BioSolutions, Lansing, Michigan) and is licensed for use in persons aged 18-65 years who are at high risk for exposure. AVA is not licensed for use in children (i.e., persons aged <18 years) or pregnant women (137). # AVA AVA is the only licensed human anthrax vaccine in the United States. AVA was originally licensed for SC administration as a series of 6 priming doses (0, 2, and 4 weeks and 6, 12, and 18 months) followed by annual booster doses. AVA is a sterile, milky-white suspension prepared from cell-free filtrates of microaerophilic cultures of a toxigenic, nonencapsulated strain of B. anthracis V770-NP1-R. The production cultures are grown in a chemically defined protein-free medium consisting of a mixture of amino acids, vitamins, inorganic salts, and sugars. Each 0.5-mL dose contains proteins from the sterile filtrate culture fluid (released during the growth period), including the protein PA (83 kDa), and contains no dead or live bacteria. The final product is formulated to contain 1.2 mg/mL aluminum, added as aluminum hydroxide in 0.85% sodium chloride, and 25 µg/mL benzethonium chloride and 100 µg/mL formaldehyde, added as preservatives (137). # Route of Administration and Immunogenicity Numerous studies have demonstrated the immunogenicity of AVA in humans and animals. However, a serologic correlate of protection has not been fully defined. Several studies have demonstrated seroconversion (fourfold rise in anti-PA immunoglobulin G titers) rates of 85%-100% among adults receiving 2 and 3 doses of SC or IM AVA (138)(139)(140)(141), indicating a strong, long-lasting immune response to the vaccine. Additional data have demonstrated statistically significant increases in anti-PA IgG levels among those with a prolonged interval between the first and second doses of AVA when compared with persons receiving AVA as originally licensed (142). In December 2008, FDA approved a BLA supplement submitted by Emergent BioSolutions for use of AVA in a pre-event or preexposure setting. The current licensed schedule consists of 5 0.5-ml IM injections (at 0 and 4 weeks and 6, 12, and 18 months) and 0.5-ml booster injections at 1-year intervals after the 18-month dose. Although ACIP now recommends 5 doses of AVA administered IM for pre-event or preexposure prophylaxis, persons with medical contraindications to IM administration (e.g., persons with coagulation disorders) may continue to receive the vaccine by SC administration (25). However, when administering AVA as a component of PEP, the vaccine should only be administered with 3 doses by the SC route under an IND or EUA. A randomized study of 173 participants compared the first 3 AVA doses of the originally licensed schedule (SC injections at 0, 2, and 4 weeks) with alternate regimens (SC or IM injections at 0 and 4 weeks and SC or IM injections at 0 and 2 weeks). The antibody concentrations for the group that followed the originally licensed schedule were comparable to those from the groups receiving injections at 0-4 weeks. In addition, the groups that received AVA 4 weeks apart had peak anti-PA IgG concentrations that were approximately threefold higher than those for the groups that received AVA 2 weeks apart (143). This study suggested that increasing the interval between the first AVA doses might lead to an immune response comparable to that of the originally licensed schedule, with fewer doses required to achieve that response. However, the results of the study could not be used to support a change in the use of the vaccine because of the small sample size. In 2000, the U.S. Congress funded the CDC-sponsored AVRP clinical trial, a large, phase 4, double-blind, randomized, placebo-controlled study to assess the immune response to a reduced-dose schedule and a change in the route of administration from SC to IM (140). The AVRP clinical trial enrolled 1,564 civilian participants in five U.S. sites during May 2002-March 2004. Fifty-one percent of the participants were women, and 49% were men; ages ranged from 18-61 years and were evenly distributed among study groups. Approximately 75% of participants were white, 15% were black, and 10% were categorized as other. Participants were randomly assigned one of the following six vaccination schedules, with vaccinations administered over 42 months: 1) the originally licensed schedule of 8 SC doses (4 doses for the reported interim analysis); 2) 8 IM doses (4 IM doses for the reported interim analysis); 3-5) 7, 5, or 4 IM doses (3 IM doses through month 6, with the three groups combined into one group for purposes of the interim analysis); and 6) placebo (140). As of February 2009, when ACIP voted on the revised recommendations, data were available for review through dose 4. In 2005, CDC submitted data to FDA from the interim analysis of the first 1,005 enrolled participants who, at the time of the analysis, had received 4 doses of AVA by the SC route or the IM route or 3 doses by the IM route. Emergent BioSolutions subsequently filed a supplemental BLA. The primary outcome measures of this analysis were noninferiority of the anti-PA IgG geometric mean concentration (GMC), the geometric mean titer (GMT), and the proportion of responders with a fourfold increase in titer at week 8 (4 weeks after the week 4 dose) and month 7 (4 weeks after the month 6 dose) (140). At week 8, antibody responses were significantly higher in women than men in the 4-IM and 3-IM groups but not in the 4-SC group. By month 7, no significant differences between men and women had been detected in any of the groups analyzed. Antibody levels also were significantly higher in whites compared with blacks at week 8 (p<0.05), but by month 7, they were equivalent. Serological noninferiority analyses of antibody responses (anti-PA IgG GMC) demonstrated the noninferiority of both the 3-IM regimen and the 4-IM regimen to the originally licensed schedule at month 7 (Figure ). CDC is analyzing animal data and designing bridging studies to correlate nonhuman primate immune responses to AVA with survival from inhalation anthrax. Bridging of these data to human immune responses to AVA will provide additional information regarding immune correlates of protection against anthrax in nonhuman primates and serological markers of protection in vaccinated humans. # Efficacy Evidence for the efficacy of AVA comes from several studies in animals (including in nonhuman primates) and from a controlled vaccine trial in humans (17), observational data in humans (135,136), and immunogenicity data for humans and other mammals (129,130,139,141,144). A recent review provided support for the efficacy of AVA for persons aged 18-65 years (145); no data are available regarding the efficacy of anthrax vaccine for persons aged 65 years. The protective efficacy of the alum-precipitated vaccine (the original form of the PA filtrate vaccine) and AVA (adsorbed to aluminum hydroxide) has been demonstrated in several animal models using different routes of administration (127)(128)(129)132,144,(146)(147)(148)(149)(150)(151). The Rhesus macaque (Macaca mulatta) is considered a suitable model of inhalation anthrax in humans (108,152), and AVA has been shown to be protective against an aerosol challenge in macaques using B. anthracis strains of high virulence (132,149,(153)(154)(155). Initial evidence for efficacy in humans came from the Brachman study, a placebo-controlled, single-blind, clinical trial among workers in four northeastern U.S. mills that processed raw, imported goat hair (17). The study was conducted during 1955-1959 using the alum-precipitated vaccine, the precursor to the currently licensed AVA. A total of 1,249 workers were included: 379 received the full series of anthrax vaccine, 414 received placebo, 116 received an incomplete series of injections (with either vaccine or placebo), and 340 received no treatment (observational group). Before vaccination, the yearly average number of human cutaneous and inhalation anthrax cases among employees in these mills was 1.2 cases per 100 employees. During the study, 26 anthrax cases (five inhalation and 21 cutaneous) were reported from the four mills. All five inhalation cases (four of which were fatal) occurred in participants who had not received vaccine; two had received placebo, and three had been in the observational group. Twenty of the 21 cutaneous cases occurred among participants who had not been fully vaccinated. Fifteen of the 21 had received placebo injections, three had received no injections (observational group), and three had received some doses of anthrax vaccine. Among the three cases that occurred in vaccinated persons, one occurred just before administration of the scheduled third dose, one occurred 13 months after completion of the scheduled 6 doses (but before any booster doses were received), and one occurred just before receipt of the first booster dose. The efficacy analysis in this study included all cases of anthrax, regardless of the route of exposure or manifestation of the disease, providing a combined efficacy of 92.5% based on person-time of occupational exposure (17). During 1962-1974, CDC collected surveillance data, independently of the Brachman clinical study, on cases of anthrax in mill workers or persons living near mills in the United States (135,136). Vaccinated persons received either AVA or the earlier formulation used in the original 1950s clinical trial (17). No cases of inhalation anthrax were identified in any of the workers. Twenty-seven cases of cutaneous anthrax were identified by CDC, 24 of which were in unvaccinated persons. In vaccinated persons, one case occurred after receiving 1 dose of anthrax vaccine, and two cases occurred after receiving 2 doses of anthrax vaccine. No documented cases of anthrax were reported for persons who had received at least 3 of the recommended 6 doses of anthrax vaccine. A civilian advisory panel reviewed the CDC surveillance data and determined the vaccine to be effective (136). In March 2002, a committee appointed by the Institute of Medicine (IOM) released a comprehensive review of the most current safety and efficacy data available for AVA (152). The committee found human efficacy data to be limited to the Brachman study (17) and the CDC surveillance data (135,136) but concluded that the combination of human data and animal data demonstrated that AVA effectively protects humans from anthrax, including inhalation anthrax (152). The committee also determined that the mechanism of action of AVA protects humans from various B. anthracis strains and that a naturally occurring or bioengineered strain probably could not overcome AVA and cause anthrax (152). The duration of AVA protection in humans after the initial priming series is unknown. Persons are considered protected from anthrax for as long as they continue receiving AVA according to the licensed schedule. A 2002 study of military personnel who had received 1, 2, or 3 priming doses during the early 1990s, followed by 1 dose 18-24 months later, demonstrated that 99.3% of participants had measurable anamnestic responses (143). Data from animal studies suggest that the duration of protection after 2 doses might be 1-2 years and that 3 IM doses of AVA provide significant levels of protection in rhesus macaques for up to 4 years (140,144,149,155). Persisting, detectable PA-specific memory B cells in the blood might be useful markers for duration of immunity because of their ability to proliferate and differentiate rapidly into anti-PA antibody-secreting plasma cells. In a study of patients with clinical anthrax, peak anti-PA IgG levels after infection correlated with the number of PA-specific memory B cells in circulation up to at least 1 year after infection (156). Circulating PA-specific memory B cells also were detectable in AVA vaccine recipients. These data suggest that both survivors of inhalation anthrax and vaccine recipients develop long-term protective immunity to anthrax; quantitative analysis of PA-specific IgG B cell memory might be a useful predictor of the duration of protection against anthrax (156). # Safety At least eight reviews (9,135,136,145,152,(157)(158)(159) and 35 other publications include evaluations of AVA safety. # Prelicensure Adverse Event Surveillance Local Reactions. In prelicensure evaluations, 6,985 persons received 16,435 SC doses: 9,893 initial series doses and 6,542 annual boosters (160). Severe local reactions (defined as edema or induration of >120 mm) occurred after 1% of vaccinations. Moderate local reactions (defined as edema and induration of 30-120 mm) occurred after 3% of vaccinations. Mild local reactions (defined as erythema, edema, and induration of <30 mm) occurred after 20% of vaccinations. In a study of the alum-precipitated precursor to AVA, moderate local reactions were documented in 4% of vaccine recipients and mild reactions in 30% of recipients (17). Systemic Reactions. In prelicensure evaluations, systemic reactions (i.e., fever, chills, body aches, or nausea) occurred in <0.06% (in four of approximately 7,000) of vaccine recipients (160). In the study of the alum-precipitated precursor to AVA, systemic reactions occurred in 0.2% of vaccine recipients (17). # Postlicensure Adverse Event Surveillance During January 1, 1998-December 31, 2008, nearly 12.4 million doses of AVA were distributed for DoD and domestic licensed use (AT Waytes, Emergent BioSolutions, personal communication, November 5, 2009); 8.4 million of these doses were administered to approximately 2.1 million military personnel during March 1, 1998-December 31, 2008 (P Garman, Military Vaccine Agency, personal communication, November 5, 2009). Less than 1% of all AVA doses were distributed to nonmilitary sources (AT Waytes, Emergent BioSolutions, personal communication, November 5, 2009). The Vaccine Adverse Event Reporting System (VAERS) has been used extensively to monitor adverse events that occur after vaccination with AVA. VAERS (161-163), a U.S. national passive surveillance system for reporting adverse events that occur after administration of U.S. licensed vaccines, plays an important role in the identification of adverse events that warrant further investigation. Although VAERS data are useful for detecting rare adverse events and assessing reporting trends, they cannot be used to assess incidence rates or causality. Reports can be submitted voluntarily by anyone, including health-care providers, patients, manufacturers, or family members; therefore, reports might vary in quality and completeness, often lack detail, and might include inaccurate information. Because VAERS is a passive surveillance system, actual rates for adverse events cannot be calculated because the number of doses administered is unknown. Underreporting is another important limitation, as is differential reporting (e.g., increased reporting rates for specific vaccines or specific adverse events), which often occurs for more serious and unexpected events, events occurring soon after vaccination, events surrounded by publicity, and reports related to litigation proceedings (163,164). Hypotheses generated by VAERS must be confirmed by epidemiological studies (163). During January 1, 1998-December 31, 2008, VAERS received 6,015 nonduplicate reports from U.S. sources of adverse events after receipt of AVA, either alone or concurrently with other vaccines (CDC, unpublished data, 2010). Of these, 600 (9.9%) were categorized as serious events (i.e., events resulting in death, hospitalization, or permanent disability) (165). Approximately 74% of all reported adverse events that occurred after administration of AVA were in persons aged <40 years. Twenty-six percent occurred in women and 72% in men; sex was not specified in 2% of the reports. The majority (75%) received AVA alone, and 25% received the vaccine concurrently with other vaccines. Eighty three percent of AVA reports were documented as being administered or funded by the military (CDC, unpublished data, 2010). Adverse events reported to VAERS are coded using terms from the Medical Dictionary for Regulatory Activities (MedDRA) (166). Approximately 800 different MedDRA terms were reported in conjunction with AVA during 1998-2008. The 10 most common adverse events that occurred after AVA administration (either alone or concurrently with other vaccines) were arthralgia (n = 1,036, 17.2%), headache (n = 981, 16.3%), pruritis (n = 878, 14.6%), pain (824, 13.7%), injection-site erythema (n = 753, 12.5%), fever (n = 655, 10.9%), erythema (626, 10.4%), pain at the injection site (613, 10.2%), rash (606, 10.1%), and myalgia (583, 9.7%) (172). As of December 31, 2008, VAERS had received 25 reports of death among AVA recipients. Causes of death included a spectrum of cardiovascular disorders, unintentional or intentional injuries, malignancies, and chronic illnesses (CDC, unpublished data, 2010). Death reports have been summarized elsewhere (27,167,168). Reports to VAERS after AVA administration have been reviewed by several expert groups (157,158,167,168). In 2003, IOM (169) recommended that CDC partner with DoD to follow up on signals generated by reviews of VAERS and DoD data, using the DoD Defense Medical Surveillance System (DMSS), a relational surveillance database containing data from military recipients of AVA and other vaccines (170). Short-Term Adverse Events. Data on the safety of AVA are only available for persons aged 18-65 years; no information is available on the safety of this vaccine in children or older adults (>65 years). Much of the published data comes from the routine DoD anthrax vaccination program. Several studies, including clinical trials and uncontrolled observational studies, have examined immediate or short-term adverse events (e.g., hours to days) that occurred after receipt of AVA (171)(172)(173)(174)(175)(176)(177). The majority of these events have been limited to local reactions (e.g., erythema, swelling, pain or tenderness, itching, and nodules) or mild, self-limited systemic symptoms (e.g., fever, chills, myalgia, arthralgia, and malaise). After a comprehensive review, the IOM committee (152) found no evidence that AVA recipients had a higher risk than the general population for life-threatening or permanently disabling adverse events immediately after receiving AVA and that rates and types of immediate or short-term reactions were comparable to those for other vaccines regularly administered to adults (152). After the bioterrorism events of 2001, 1,727 persons participated in the CDC Anthrax Vaccine and Antimicrobial Availability program and received either AVA and antimicrobials or only antimicrobials (178). Among the enrollees, 199 participants opted to receive AVA and antimicrobials. Local and systemic adverse event profiles for AVA recipients compared with those for persons who received only antimicrobials indicated that a higher proportion of persons who received AVA reported adverse events than did persons who received only antimicrobials. The most commonly reported adverse events among vaccine recipients were discomfort at the injection site (70.9%), erythema (45.2%), induration (58.8%), and swelling (39.7%). Participants who received AVA by the SC route in the AVRP clinical trial reported warmth, tenderness, erythema, induration, and nodule development more frequently than participants who received AVA by the IM route. Although fatigue and headache were the most commonly reported systemic adverse events among clinical trial participants, they were reported by <11% of participants. Women reported significantly more injection-site and systemic adverse events than men (140). Several reviews have noted that women report a higher proportion of certain adverse events after AVA than men (152,157,167,168); this phenomenon has been documented with other vaccines as well (179). A comprehensive review of VAERS AVA data in 2004 demonstrated that women were 3 times more likely than men to have or report an adverse event. Women were not more likely to be hospitalized than men because of adverse events, although women accounted for a greater proportion of reported injection-site adverse events and moderate or extensive injection-site inflammation (157). A study of female AVRP clinical trial participants to assess the effect of progesterone levels on adverse events and immune response is ongoing; final data will be available in late 2010. Long-Term (Chronic) Adverse Events. DoD has published several studies of long-term health effects among vaccinated and unvaccinated military personnel (180)(181)(182)(183)(184). Additional studies have assessed the long-term health of vaccinated researchers and fertility parameters for vaccinated males (185,186). None of the studies found that the risk for adverse health effects or chronic diseases (e.g., cancer or infertility) was higher after anthrax vaccination. These studies of long-term health effects support the IOM finding (152) that no convincing evidence exists to indicate that the risk for developing long-term adverse health effects is higher among anthrax vaccine recipients. As with all vaccines, the possibility for rare adverse reactions does exist with AVA. The Vaccine Analytic Unit (VAU) (170), which was developed to implement the IOM recommendations (169), is a collaborative CDC and DoD project with FDA participation. Using data from DMSS, VAU can analyze vaccine safety data for all vaccines administered to active-duty and reserve service personnel. In a matched case-control study, VAU investigators found no significant associations between optic neuritis and previous receipt of AVA, smallpox, hepatitis B, or influenza vaccines (187). In addition, VAU found no association between concurrent receipt of multiple vaccinations and hospitalization risk among U.S. military personnel (188). Studies to address additional topics (e.g., Stevens Johnson syndrome/toxic epidermal necrolysis, type 1 diabetes mellitus, atrial fibrillation, and diffuse connective tissue diseases) are ongoing. # Effect of Route of Administration on Adverse Events A small randomized study on the effects of route of administration on adverse events found that systemic adverse events were uncommon and similar for IM and SC groups. All local reactions (i.e., tenderness, erythema, warmth, induration, and subcutaneous nodules) were significantly more common after SC injection than after IM injection. Women who received IM injections 4 weeks apart reported fewer of certain local adverse events than did women who received SC injections 2 weeks apart (143). The AVRP clinical trial demonstrated that the proportion of injection-site adverse events was lower in the group receiving 4 IM injections than in the group receiving 4 SC injections, especially among women, who experienced a significant decrease in the occurrence of warmth, tenderness, itching, erythema, induration, edema, and nodules. In addition, the duration of injection-site adverse events in the 4-IM group was shorter than that experienced by the 4-SC group. Persons in the 4-IM group also experienced significantly fewer moderate and severe injection-site adverse events (7.0%) than persons in the 4-SC group (10.2%, p = 0.04). Analog pain scale scores used to assess pain immediately after injection were significantly lower in the 4-IM group compared with the 4-SC group (p<0.01). In all study groups, women were almost twice as likely as men to experience an injection-site adverse event (OR = 1.93, p<0.01); however, the absolute differences between women and men for warmth, itching, erythema, induration, and nodules were largest in the 4-SC group. Route of administration was not associated with the occurrence of systemic adverse events, and the differences between men and women in regards to systemic adverse events were generally consistent across all study groups (including the placebo group) (140). # Effect of Vaccination on Pregnancy and Breastfeeding A paucity of data exists regarding the use of AVA during pregnancy; however, in general, the use of inactivated vaccines is considered safe during pregnancy (189)(190)(191)(192)(193). Some evidence indicates that nonspecific stimulation of the maternal immune system might decrease the risk for birth defects (194,195). Potential benefits gained from the use of AVA during pregnancy might outweigh the risk in certain situations. DoD policy is to exempt pregnant military women from anthrax vaccination; however, some women were inadvertently vaccinated with AVA while pregnant, as reported in a recent study that evaluated approximately 115,000 live births to military women (196). The study suggested that infants born to women who received anthrax vaccine in their first trimester of pregnancy had slightly higher odds of experiencing birth defects than infants born to never-vaccinated women (OR = 1.20, 95% confidence interval = 1.02-1.42) or to women vaccinated only after pregnancy (OR = 1.02, CI = 1.01-1.43). When infants born to women vaccinated during their first trimester were compared with infants born to women vaccinated outside the first trimester, no statistical association with birth defects was found (OR = 1.18, CI = 1.00-1.41). Of the 10 specific defects assessed in this study, only atrial septal defect (ASD) demonstrated a significant increase among infants born to women vaccinated during the first trimester. These findings were limited, partly because the code for ASD (per the International Classification of Diseases, Ninth Revision, Clinical Modification ) is the same as the code for patent foramen ovale, a common finding in preterm infants. When preterm infants with ASD as the only reported birth defect were excluded from analyses, the association between ASD and vaccination in the first trimester was no longer statistically significant. In addition, late recognition of pregnancy, a moderate risk factor for many birth defects, including ASD, might explain the number of women vaccinated during their first trimester. After review of these data and discussions with the authors of this study, ACIP concluded that AVA is safe to administer during pregnancy but recommended that pregnant women defer vaccination unless exposure to anthrax poses an immediate risk for disease (27). Another study of 385 women who had received at least 1 dose of AVA before becoming pregnant (197) found no evidence of miscarriage, infertility, or other reproductive problems among vaccinated women. In addition, the study did not support the hypothesis that AVA administration resulted in decreased pregnancy rates among those vaccinated before pregnancy. No data have been collected on the use of AVA among breastfeeding women. Therefore, whether anti-anthrax antibodies are transferred through milk from mother to infant is unknown; however, data from similar vaccines indicate that this might occur (198). No biological reason suggests that breastfeeding women or breastfed children have an increased risk for adverse events after the mother receives anthrax vaccine. Administration of other inactivated vaccines during breastfeeding is not medically contraindicated (199). # Vaccination of Children AVA use in children has not been studied, and the vaccine is not licensed for use in this population. A 2004 review demonstrated that children aged <18 months experienced more local erythema and induration after receipt of vaccines containing an aluminum hydroxide adjuvant than after receipt of nonadjuvanted vaccines. Erythema and induration were not reported in children aged 10-18 years, although these older children experienced local pain lasting up to 14 days after administration of vaccines with aluminum hydroxide adjuvants (200). The concentration of aluminum per dose of AVA is similar to that in the diptheria/tetanus/pertussis (DTaP) vaccine and is less than that in the combined DTaP/polio/hepatitis B vaccine (201). Because AVA contains aluminum hydroxide, local adverse events are likely to be similar to those described in adults administered AVA and in children administered other vaccines with similar aluminum hydroxide concentrations; ACIP concluded that no evidence suggests that the risk for serious adverse events after receipt of anthrax vaccine is higher in children. The morbidity of inhalation anthrax should be considered when children have been exposed to aerosolized B. anthracis spores. # PEP for Previously Unvaccinated Persons Vaccination as a Component of PEP Studies have demonstrated not only the persistence of spores in nonhuman primates up to 100 days after inhalation exposure (95) but also the potential for long-term spore survival and development of inhalation anthrax after discontinuation of postexposure antimicrobial agents (93,95). Because disease can develop long after exposure to spores, animal studies have examined the use of postexposure vaccination in combination with antimicrobial agents. Although the precise correlation between the immune response to vaccination and protection against disease has not been completely defined, several studies (93,95,102) have documented that 2-and 3-dose schedules of vaccination, combined with antimicrobial therapy, prevent development of disease in animals. Although the point at which a person develops immunity against anthrax after the first vaccination is unknown, available data indicate that the antibody response to the vaccination administered at week 26 (month 6) is characteristic of a strong anamnestic response, in turn indicating that the vaccine schedule of day 0, week 2, and week 4 effectively primes the immune system against PA. The available data on human responses to AVA indicate that use of the 3-dose SC regimen (with doses at 0, 2, and 4 weeks) for PEP results in rapid anti-PA antibody production at high levels (140,143) and is therefore an additional benefit to the approved antimicrobial therapies. Therefore, ACIP previously recommended that 3 doses of AVA (SC at day 0, week 2, and week 4) be administered in conjunction with antimicrobial therapy to previously unvaccinated persons who have been exposed to aerosolized B. anthracis spores (23,24). As described, the AVRP clinical trial (140) demonstrated that a vaccination schedule of doses administered at 0 and 4 weeks via the IM route elicited a lower antibody response at week 8 than did a schedule of doses administered at weeks 0, 2, and 4 via the SC or IM route (Figure). Because the clinical signifi-cance of the lower immune response to a schedule of doses administered at 0 and 4 weeks is not known, and sex-related differences in antibody levels exist, adherence to a schedule that produces rapid development of high antibody levels is particularly beneficial in a postexposure setting. Therefore, in June 2009, FDA recommended retaining the current PEP protocol (3-dose SC series administered at 0, 2, and 4 weeks in conjunction with antimicrobial therapy for a minimum of 60 days) until additional data are available (J Clifford, FDA, personal communication, June 24, 2009). After natural, occupational, or bioterrorism-related exposure to aerosolized B. anthracis spores, the combination of AVA and antimicrobials is more effective than use of antimicrobials only. Vaccination as a component of PEP is beneficial when antimicrobial PEP is discontinued too soon after exposure. Poor adherence to the prescribed regimen, which has been as low as 42%, minimizes the effectiveness of postexposure antimicrobial therapy (202). The bioterrorism events of 2001 also suggested that persons might be exposed to larger amounts of B. anthracis spores than those studied in animal models. A possible consequence would be prolonged spore clearance, with increased levels of residual spores at the alveolar surface epithelium and therefore an increased potential for infection when antimicrobial prophylaxis is discontinued after 60 days (202). Because of the potential for short incubation periods with inhalation anthrax, especially when the inhaled dose might be large, and the rapid progression and associated high morbidity and mortality, antimicrobial PEP should be initiated as soon as possible after inhalation exposure to aerosolized B. anthracis spores. Vaccination also should be initiated as quickly as possible but will likely occur several days after antimicrobial agent initiation for logistical reasons. To maximize the benefits of vaccine, the first dose should be initiated within 10 days of exposure. Antimicrobial use should continue until the immune response to the priming series has developed, which is expected to be 10-14 days after administration of the third dose of vaccine. PEP recommendations for inhalation exposure to aerosolized B. anthracis spores differ from those for a naturally occurring cutaneous or gastrointestinal exposure. Because AVA is not licensed for postexposure use, administration of AVA as a component of PEP is available under an IND application (IND #10061, held by CDC) and may be made available under an EUA (19)(20)(21)(22). † The PEP regimen included in the IND protocol includes children aged 0-17 years. IND protocols require detailed records to be kept; written, informed consent from all participants; data collection; reports to FDA; and follow-up of patients. The IND mecha-nism is generally suited to clinical practice and is not easily used during an emergency. The Project BioShield Act of 2004 authorizes the FDA commissioner to issue an EUA during an emergency under certain circumstances (21). Under an EUA, medical countermeasures to diagnose, treat, or prevent serious or life-threatening diseases for which no adequate, approved, and available product exists can be disseminated quickly for the protection and safety of the U.S. population. The issuance of an EUA enables large-scale use of a medical countermeasure (203) such as AVA as a component of PEP. AVA has been used extensively, including after the bioterrorism events of 2001, with a good safety profile; therefore, on the basis of a review of existing data and expert opinion, ACIP expects that future use of AVA as a component of PEP is likely to have a good safety profile. # Antimicrobial Agents as a Component of PEP Because limited data are available, the optimal duration of antimicrobial therapy in combination PEP is uncertain. Antimicrobial therapy for 60 days, without vaccine, might prevent inhalation anthrax; however, antimicrobial agents without vaccine might not protect persons from late spore germination. Using the limited available data, FDA licensed a 60-day course of antimicrobials for postexposure use; a shorter course (<60 days) of antimicrobial therapy, even when combined with a 3-dose AVA series, is not approved for use by FDA. In 2006, an expert panel (204) discussed whether, based on the limited evidence (102,139), the duration of antimicrobial use could be shortened with concurrent receipt of AVA. The panel determined that the available data were too limited to support a regimen of <60 days. Oral ciprofloxacin, oral doxycycline, and parenteral (IM) penicillin G procaine have been shown to be effective for PEP use in a nonhuman primate model (93) and are FDA approved for a 60-day course for inhalation anthrax (postexposure) in all age groups (205,206). Ciprofloxacin and doxycycline are equivalent first-line antimicrobial agents for PEP, because they are equally effective and have similar susceptibility profiles among naturally occurring B. anthracis isolates (93,207). In addition, both have similar safety profiles, with a low rate of anaphylactic reactions (208,209). Selection of PEP agents should involve consideration of the potential for antimicrobial resistance. Both naturally occurring constitutive and inducible β-lactamase production can be present in B. anthracis isolates (207,(210)(211)(212). Because induction of resistance has been previously reported in the nonhuman primate model ( 213), there are concerns that an insufficient dosage could induce penicillin resistance in humans (49,214,215). For these reasons, oral penicillins are not considered first-line antimicrobial agents for PEP but may be considered after the antimicrobial susceptibility profile of the organism is known. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole (207,216,217). Although oral amoxicillin is an alternative to the first-line PEP agents when antimicrobial susceptibility profiles demonstrate appropriate sensitivity (minimum inhibitory concentration ≤0.125 µg/mL), amoxicillin has not been studied for the prophylaxis or treatment of anthrax, and no safety or efficacy data are available for this indication. Amoxicillin is not FDA approved for use as a component of PEP and therefore should only be administered under an IND or possibly under an EUA to certain patient groups (e.g., children or pregnant or nursing women) during a declared emergency provided the criteria for issuance have been met. Because oral amoxicillin has better pharmacokinetics than equivalent doses of oral penicillin V, oral amoxicillin may be used with a less frequent dosing interval, potentially improving adherence to therapy (218)(219)(220)(221)(222). Compared with oral penicillin, oral amoxicillin has greater pulmonary penetration and is able to maintain a higher concentration above MIC in the target tissues (e.g., pulmonary-associated lymph nodes, tissues, and secretions) for a greater portion of the dosing interval (223)(224)(225)(226)(227). Oral amoxicillin at dosages approved for other indications (i.e., 500 mg/kg every 8 hours for adults; 45 mg/kg/day orally in 3 divided doses for children weighing <40 kg) should prevent postexposure inhalation anthrax if the B. anthracis strain in question has an amoxicillin MIC <0.125 µg/mL (225)(226)(227). Amoxicillin-clavulinic acid combinations may be considered for PEP. Because potassium clavulanate does not have a significant impact on the pharmacokinetics of oral amoxicillin, the dosage is based on the amoxicillin component (228). Levofloxacin been shown to be effective for PEP use in a nonhuman primate model (229) and is FDA approved for inhalation anthrax (postexposure) in patients aged >6 months (230). Short-term (up to 28 days) safety data exist, but extended-use (up to 60 days) data are limited (231). Therefore, levofloxacin is recommended as a second-line PEP antimicrobial agent to be reserved for instances in which tolerance issues or drug resistance patterns indicate its use. Dosing information for recommended antimicrobial agents for PEP is provided (Table 1). For patients unable to tolerate FDA-approved antimicrobial agents, clinicians may consider clindamycin, chloramphenicol, erythromycin, vancomycin, or other fluoroquinolones for PEP, based on in vitro susceptibility results. Administration of these agents would be considered off-label use (i.e., for other than the FDA-approved use) and might require an IND or EUA. # Adverse Events Associated with Antimicrobial PEP Adverse events associated with the long-term use of antimicrobial PEP include gastrointestinal upset and other conditions that are expected when normal body flora are disrupted by antimicrobial use (232). Any antimicrobial agent can have undesirable side effects, including allergic reactions. Patients should be urged to inform public health authorities and their health-care providers of any adverse events that occur. Longterm fluoroquinolone use has been associated with tendinitis and tendon tears (233). During the bioterrorism events of 2001, approximately 10,000 persons were recommended to receive a 60-day regimen of antimicrobial prophylaxis (doxycycline, ciprofloxacin, or amoxicillin) for suspected or confirmed exposure to B. anthracis spores. Adverse events that were commonly reported by patients were not serious and included diarrhea, stomach pain, nausea, vomiting, headache, dizziness, and fatigue (202,234). No serious adverse events were found to be definitely related to the use of prescribed antimicrobials (202,234). Adverse events associated with ciprofloxacin or doxycycline were not substantially different enough for one therapy to be recommended instead of the other (178,202). Among persons who began the 60-day PEP regimen, 21%-41% continued the regimen as prescribed (202). Adverse events were a commonly cited reason for discontinuation of antimicrobial PEP; 73 (78%) of the 93 persons in the Washington, DC, postal center who stopped taking antimicrobial PEP cited adverse events as a reason for nonadherence (235). Perceived risk for exposure to aerosolized B. anthracis was a statistically significant predictor of adherence to PEP (235), and according to one study, perceived risk was a stronger predictor of adherence than actual adverse events (202). # Antimicrobial Considerations for Pregnant or Breastfeeding Women Based on limited human clinical information, use of therapeutic doses of ciprofloxacin during pregnancy is unlikely to have a substantial teratogenic risk; however, the actual teratogenic risk from ciprofloxacin use during pregnancy is unknown (13,236). Even with these limited data, ciprofloxacin is recommended as the first-line antimicrobial agent of choice for PEP for asymptomatic pregnant or lactating women because of the severity of inhalation anthrax (237). Treatment should be changed to amoxicillin if the strain of B. anthracis is found to be sufficiently susceptible to penicillin (237). Potential risks associated with the use of tetracycline antimicrobials during pregnancy include dental staining of the fetal primary teeth and possible depressed fetal bone growth and dental enamel defects. Hepatic necrosis has been reported in pregnant women using tetracyclines, although such reports are rare (13). Tetracyclines should be used cautiously in asymptomatic pregnant women and only if contraindications to the use of other appropriate antimicrobial agents exist. Penicillins are generally considered to be safe during pregnancy and are not associated with an increased risk for fetal malformation (238). The American Academy of Pediatrics considers ciprofloxacin and tetracyclines (including doxycycline) to be appropriate for breastfeeding women because the amount of drug absorbed by infants is small; however, little is known about the safety of long-term use (239). Because of the severity of inhalation anthrax, ciprofloxacin and doxycycline are considered the firstline antimicrobial agents of choice for PEP (237) as indicated for adults in these recommendations. Because amoxicillin is known to be safe for infants, this antimicrobial is an option for PEP for breastfeeding mothers when the appropriate conditions described have been met and when the mother has no contraindications to amoxicillin. If an infant is exposed to B. anthracis and is receiving PEP, the antimicrobial regimen of the breastfeeding mother should be the same as that of the child, when possible, to minimize infant exposure to multiple drugs. If the drug used by the mother is contraindicated in her infant, the mother should express and discard her breast milk while being treated. Breastfeeding may resume after the mother completes the course of antimicrobial therapy (204,240,241). # Antimicrobial Considerations for Children Although antimicrobials such as ciprofloxacin or doxycycline are typically not administered to children, the severity of anthrax is sufficient that treatment with these antimicrobials is warranted and recommended for children who have been exposed to aerosolized B. anthracis spores. Amoxicillin is preferred for antimicrobial PEP in children when susceptibility testing indicates that the B. anthracis isolate involved is susceptible to penicillins (i.e., MIC ≤0.125 µg/mL for amoxicillin). In these instances, a transition from ciprofloxacin or doxycycline to amoxicillin is recommended for completion of the 60-day PEP antimicrobial regimen (Table 1). - Antimicrobials should continue for 14 days after administration of the third dose of vaccine. † AVA used for PEP must be administered subcutaneously. § Levofloxacin is a second-line antimicrobial agent for PEP for persons aged ≥6 mos with medical issues (e.g., tolerance or resistance to ciprofloxacin) that indicate its use. Children: 16 mg/kg/day divided every 12 hrs; each dose should not exceed 250 mg. Adults: 500 mg every 24 hrs. Safety data on extended use of levofloxacin in any population for >28 days are limited; therefore, levofloxacin PEP should only be used when the benefit outweighs the risk. ¶ The antimicrobial of choice for initial prophylactic therapy among pregnant women is ciprofloxacin. Doxycycline should be used with caution in asymptomatic pregnant women and only when other appropriate antimicrobial drugs are contraindicated. Although tetracyclines are not recommended during pregnancy, their use might be indicated for life-threatening illness. If susceptibility testing demonstrates an amoxicillin MIC ≤0.125 µg/mL, oral amoxicillin should be used to complete therapy. † † Use of tetracyclines and fluoroquinolones in children can have adverse effects. These effects must be weighed carefully against the risk for developing life-threatening disease. If exposure to B. anthracis is confirmed, children may be treated initially with ciprofloxacin or doxycycline as prophylaxis. However, amoxicillin is preferred for antimicrobial PEP in children when susceptibility testing indicates that the B. anthracis isolate is susceptible to penicillins. § § Each ciprofloxacin dose should not exceed 500 mg, or 1 g/day. ¶ ¶ In 1991, the American Academy of Pediatrics (AAP) amended the recommendation to allow treatment of young children with tetracyclines for serious infections such as Rocky Mountain spotted fever for which doxycycline might be indicated. Doxycycline is preferred for its twice daily dosage and low incidence of gastrointestinal side effects. * Because of the lack of data on amoxicillin dosages for treating anthrax (and the associated high mortality rate), AAP recommends a higher dosage of 80 mg/kg/day, divided into 3 daily doses; each dose should not exceed 500 mg. If this higher dosage of amoxicillin is used, recipients should be carefully monitored for side effects from long-term treatment. # Antimicrobial Considerations for other Populations For other specific populations, such as older adults or patients with certain underlying medical conditions (i.e., diabetes or renal failure), standard medical practice should be followed. Additional antimicrobial agents that are not FDA approved for treatment or prevention of anthrax but that may be considered include clindamycin, chloramphenicol, rifampin, vancomycin, and other fluoroquinolones. Health-care providers should consult with public health officials when choosing alternative antimicrobial agents and should consider the antimicrobial susceptibility of the associated strains of B. anthracis. # Risk for Exposure to B. anthracis Anthrax exposure is categorized as non-bioterrorism related (i.e., naturally occurring) or bioterrorism related (i.e., intentional). Although naturally occurring anthrax decreased substantially in the United States beginning in 1957 after the initiation of animal vaccination with the Sterne vaccine, persons in certain occupations remain at higher risk for naturally occurring anthrax exposure. In contrast, the risk for bioterrorism-related anthrax is difficult to predict. # General Public Members of the general public, including pregnant or breastfeeding women, are not at risk for exposure to naturally occurring anthrax but might be exposed through a bioterrorism event that would be time limited, sporadic, and most likely geographically limited, as well as difficult to predict, detect, or prevent (9). The target population for a bioterrorism-related release of B. anthracis cannot be predicted, and the risk for exposure cannot be reliably calculated. Once a bioterrorism event occurs, exposure and risk for disease development at the individual level are difficult to identify. No data suggest that the risk for developing anthrax is greater for pregnant women who have been exposed to B. anthracis than for nonpregnant women who have been exposed. Among children, naturally occurring cases and one confirmed case resulting from exposure during the 2001 bioterrorism events have been reported (43,(242)(243)(244). Data are limited regarding the risk for developing anthrax in children after exposure; however, the risk is assumed to be similar to the risk for adults. Like the general public, medical personnel are not at risk for exposure to naturally occurring anthrax but might be exposed through a bioterrorism event. In general, the risk for acquiring anthrax when caring for infected or contaminated patients is thought to be negligible because no person-to-person transmission or secondary cases of anthrax among medical personnel have been documented. Medical personnel are recommended to routinely follow infection control measures to minimize risk for known nosocomial infections (245). # Populations at Risk for occupational Exposure Persons who repeatedly enter potentially contaminated areas should use appropriate personal protective equipment (PPE), which is defined in this report as consisting of a powered airpurifying respirator with full-facepiece and high-efficiency particulate air (HEPA) filters, disposable protective clothing with integral hood and booties, and disposable gloves (246). However, despite the use of appropriate PPE, exposures during repeated encounters with contaminated areas might occur because PPE is not 100% effective, individual work practices might lead to exposure, breaches in PPE and environmental controls might occur, and some breaches might not be detected (247,248). # Persons Handling Animals or Animal Products Improvements in industrial hygiene standards, mechanization of animal processing, animal disease control, and strict importation guidelines have reduced the risk for exposure to anthrax among manufacturing employees working with animals and animal products such as imported animal hides, furs, bone meal, wool, animal hair, or bristles (6,31). § Nevertheless, slaughterhouse workers, butchers (249), and wool and mohair processors might still be at risk for exposure to B. anthracis spores if the industry standards are not upheld. Inhalation and cutaneous anthrax are occupational hazards primarily for workers who process hides, hair (especially from goats), bone and bone products, and wool (31,39,43) and for veterinary, agriculture, and wildlife workers who handle infected animals (48). Domestic exposure to B. anthracis spores might occur during contact with contaminated bone-meal fertilizer (40) or wool yarn (250), while making or playing contaminated goat-skin drums (37,38,44), and during contact with other domestic products (31,41). Occupational exposure to B. anthracis through contact with animals, whether in an agricultural or industrial setting, remains a risk when contact with animals with suspected or confirmed anthrax occurs. However, such human cases are rare (251), and cutaneous anthrax is the primary risk. Exposure to B. anthracis spores in soil is not considered a substantial risk for human inhalation anthrax because spores are bound to heavy soil particles (28). § Sanitary control of animal byproducts (except casings), and hay and straw, offered for entry into the United States, 9 C.F.R. Pt. 95. # Persons Working in Laboratories Multiple types of laboratories might work with B. anthracis, including academic (research), military, veterinary, food-testing, and public health laboratories. Direct and indirect contact with contaminated objects, accidental parenteral inoculation, and generation of aerosolized particles are all potential risks for infection. Certain activities increase the risk for exposure, such as working with large volumes and high concentrations of the organism or performing activities that might result in aerosolization, such as vortexing and centrifugation (252). In 2006, the Association of Public Health Laboratories website provided guidance to address sample transport, receipt, and screening of unknown environmental samples (253). # Persons Working in Postal Facilities The distribution of letters laden with anthrax spores through the U.S. Postal Service (USPS) in 2001 established the mail as a feasible route of exposure. In the event of another attack through the mail, the risk for exposure to aerosolized B. anthracis spores is presumed to be high among staff members in a USPS processing and distribution center who work with mechanical processing equipment that might generate aerosol particles. In response, USPS implemented environmental monitoring to rapidly identify the presence of B. anthracis in these centers. Detection of B. anthracis using these validated USPS monitors would identify a likely exposure (D Sosin, CDC, personal communication, October 2, 2008) and allow prompt initiation of antimicrobial PEP while laboratory verification is being performed. # Military Personnel The personnel who have been determined by DoD to be at risk for exposure to B. anthracis spores include military personnel being deployed to areas designated by DoD as posing a high risk for anthrax exposure, other select military units with unique missions, civilians deemed to be essential emergency personnel in designated locations, and contractors assigned to higher risk areas who are performing mission-essential services (254,255). # Persons Involved in Emergency Response Activities Environmental Investigators and Remediation Workers Conducting remediation of B. anthracis-contaminated areas can pose a risk for exposure to B. anthracis spores. Repeated occupational exposures might occur during environmental investigation or remediation efforts after identification of anthrax cases, regardless of whether the event is bioterrorism related. However, certain features of a bioterrorism event might result in higher risk for exposure during remediation activities. The characteristics of an intentionally dispersed strain of B. anthracis (e.g., antimicrobial resistance or dispersion capabilities) might differ from those of a naturally occurring strain. The level of environmental contamination resulting from intentionally dispersed strains, and therefore the potential for exposure at lower infective doses, might be significantly greater than the level of contamination that would result from naturally occurring strains. Because animal studies indicate that the incubation period for inhalation anthrax might be inversely related to the dose of B. anthracis spores (95,107,108), exposure to higher levels of spores may result in more rapid disease onset, with limited time for initiating PEP. # Emergency and other Responders Persons involved in emergency response activities might include persons who work in police departments, fire departments, hazardous material units, and the National Guard, as well as other government responders. These persons might perform site investigations, respond to suspicious substance reports (also known as white powder incidents), and perform other related activities such as evacuation procedures or other activities critical to the maintenance of infrastructure. The risk for potential exposures associated with responder activities varies depending on the situation. Although the risk for exposure to aerosolized B. anthracis spores is likely low, secondary aerosolization of previously settled spores might occur during the performance of certain activities (63). Because the location and dissemination of the organism as a result of a bioterrorism attack cannot be predicted, the risk for exposure to aerosolized B. anthracis spores in association with emergency response activities cannot be quantified. # Recommended Uses of Anthrax Vaccine AVA may be used 1) via the licensed schedule to prevent infection by priming the immune system before exposure to B. anthracis (pre-event or preexposure vaccination) and 2) after exposure to aerosolized B. anthracis spores under an IND or possibly under an EUA (PEP vaccination) (Tables 2 and 3). Recommendations for the use of AVA differ for pre-event or preexposure vaccination and postexposure vaccination. For pre-event or preexposure vaccination, ACIP recommends 5 IM doses administered at day 0, week 4, and months 6, 12, and 18, followed by annual boosters. To elicit the most substantial and rapid immune response possible among previously unvaccinated persons in a postexposure setting, PEP vaccination should be administered as a 3-dose SC series (at 0, 2, and 4 weeks) in conjunction with a 60-day course of appropriate antimicrobial agents. # Pre-event and Preexposure Vaccination By priming the immune system before exposure to B. anthracis spores, pre-event and preexposure vaccination might provide more protection than antimicrobial agents alone to persons at risk for occupational exposure to B. anthracis, including protection for persons exposed to large inocula, protection if the public health infrastructure cannot ensure immediate availability or timely delivery of postevent antimicrobial agents, and potential benefits if bioengineered strains were released, limiting antimicrobial PEP effectiveness. The potential benefits from pre-event and preexposure vaccination should be weighed against the resource requirements to implement and maintain the vaccination schedule, as well as the potential adverse events associated with vaccination. Decisions for pre-event vaccination should be made based on a calculated risk assessment. In the absence of such an assessment, vaccination may be considered based on an estimated/presumed risk-benefit assessment. Depending on the occupational activities of the vaccine recipient, pre-event or preexposure vaccination might not eliminate the need for appropriate personal protective equipment. # General Public Because the location and timing of a bioterrorism attack cannot be predicted, the risk-benefit profile for pre-event vaccination for the general public is low, and pre-event vaccination is not recommended. Preventing the morbidity and mortality associated with a deliberate release of B. anthracis depends on public vigilance, early detection and diagnosis, appropriate treatment, and rapid administration of PEP. # Special Populations # Pregnant and Breastfeeding Women In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of pregnant women is not recommended and should be deferred until after pregnancy. Breastfeeding is neither a precaution nor a contraindication to vaccination, and vaccination does not need to be deferred in a pre-event setting if the occupation of the breastfeeding mother poses a risk for exposure to B. anthracis. # Children In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of children is not recommended. # Medical Personnel Pre-event vaccination is not recommended for medical personnel. If exposed to aerosolized B. anthracis spores during a bioterrorism event, they should receive PEP in accordance with ACIP recommendations. # Populations at Risk for occupational Exposure Persons Handling Animals or Animal Products Routine preexposure vaccination for persons who handle animals or animal products is recommended only for persons for whom previously discussed standards and restrictions are insufficient to prevent exposure to B. anthracis spores. Preexposure vaccination is not recommended for persons who routinely have contact with animal hide drums or animal hides; other preventive measures are available. Routine vaccination of U.S. veterinarians and animal husbandry technicians is not recommended because of the low incidence of animal anthrax cases in the United States. However, vaccination might be recommended for veterinarians and other persons considered to be at high risk for anthrax exposure if they handle potentially infected animals in research settings or in areas with a high incidence of enzootic anthrax cases. # Laboratorians Preexposure vaccination is recommended for laboratorians at risk for repeated exposure to fully virulent B. anthracis spores, such as those who 1) work with high concentrations of spores with potential for aerosol production; 2) handle environmental samples that might contain powders and are associated with anthrax investigations; 3) routinely work with pure cultures of B. anthracis; 4) frequently work in spore-contaminated areas after a bioterrorism attack; or 5) work in other settings where repeated exposures to B. anthracis aerosols may occur. # MMWR July 23, 2010 # Persons Working in Postal Processing Facilities Because of biodetection systems in postal processing centers, contamination of mail with B. anthracis spores is likely to be detected rapidly, allowing postexposure therapy to be initiated immediately. Therefore, persons who work in these facilities are not recommended to receive pre-event vaccination. # Military Personnel Military personnel determined by DoD to have a calculable risk for exposure to aerosolized B. anthracis spores are recommended to receive preexposure vaccination. DoD has exclusionary criteria for employees, including an exclusion for pre-event vaccination of pregnant women (256,257). # Environmental Investigators and Remediation Workers Vaccination is recommended for persons who, as part of their occupation, might repeatedly enter areas contaminated with B. anthracis spores. # Emergency and other Responders Emergency and other responders are not recommended to receive routine pre-event anthrax vaccination because of the lack of a calculable risk assessment. However, responder units engaged in response activities that might lead to exposure to aerosolized B. anthracis spores may offer their workers voluntary pre-event vaccination. The vaccination program should be carried out under the direction of a comprehensive occupational health and safety program. # Delayed Doses Available data on AVA dosages suggest that increasing the interval between doses does not decrease the ultimate serologic response achieved or adversely affect the safety profile. Therefore, as with other vaccines, interruption of the vaccination schedule does not require restarting the entire series or the addition of extra doses (199). # PEP PEP should be used for previously unvaccinated persons after exposure to aerosolized B. anthracis spores, whether the exposure is naturally occurring, occupationally related, or intentional. To elicit the most substantial and rapid immune response possible for previously unvaccinated persons in a postexposure setting, vaccination should be administered as recommended in conjunction with appropriate antimicrobial agents (Tables 1 and 2). # PEP After Inhalation Exposure General Adult Population ACIP recommends a postexposure regimen of 60 days of appropriate antimicrobial prophylaxis combined with 3 SC doses of AVA (administered at 0, 2, and 4 weeks postexposure) as the most effective protection against inhalation anthrax for previously unvaccinated persons aged ≥18 years who have been exposed to aerosolized B. anthracis spores. After exposure to aerosolized B. anthracis spores, antimicrobial therapy should be initiated as soon as possible. Ideally, the first dose of vaccine should be administered within 10 days. Because AVA is not licensed for postexposure use, the vaccine will likely be made available either through an IND or an EUA during a public health emergency. In general, the peak serologic response to anthrax vaccine occurs 10-14 days after the third dose. To ensure continued protection, persons for whom vaccination has been delayed should extend antimicrobial use to 14 days after the third dose, even though this practice might result in use of antimicrobials for >60 days. Antimicrobials should not be used for <60 days in previously unvaccinated persons who have been exposed to aerosolized B. anthracis spores. # Pregnant Women In a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores, pregnancy is neither a precaution nor a contraindication to PEP. Pregnant women at risk for inhalation anthrax should receive AVA and 60 days of antimicrobial therapy as described. # Breastfeeding Women In a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores, breastfeeding remains neither a precaution nor a contraindication to PEP. Breastfeeding women at risk for inhalation anthrax should receive AVA and 60 days of antimicrobial therapy as described. # Children The use of AVA in children is not contraindicated in a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores. During such an event, public health authorities will determine whether, under the existing IND protocol, to offer vaccine to children aged 0-17 years. Under this IND protocol, 3 doses of vaccine would be administered in conjunction with 60 days of appropriate antimicrobial therapy. # PEP After Repeated occupational Exposures The combination of pre-event vaccine and appropriate PPE effectively protects fully vaccinated persons who work in occupations that might result in repeated exposure to aerosolized B. anthracis spores (Table 4). Antimicrobial PEP is not needed for fully vaccinated workers who wear appropriate PPE while working in environments contaminated with B. anthracis spores unless the PPE is disrupted. However, fully vaccinated workers who prefer additional protection may consider antimicrobial PEP under the direction of their occupational health program A 30-day course of antimicrobial PEP is recommended for partially vaccinated workers (Table 4), fully vaccinated workers who do not wear PPE, and fully vaccinated workers whose PPE has been disrupted; these workers should continue with their licensed vaccination regimen. ¶ Because respiratory protection can be disrupted in numerous ways (e.g., a face-seal leak in a respirator or not wearing personal protective equipment when entering an area presumed to be uncontaminated that is later determined to be contaminated) and such disruptions are not always detected, the threshold for assuming such a disruption has occurred should be extremely low. Fully vaccinated workers have completed the 5-dose IM series and have received all annual booster doses indicated by the licensed vaccination schedule. A 60-day course of antimicrobial PEP is recommended for previously unvaccinated workers. These workers also should begin receiving AVA as soon as possible using the PEP schedule of 3 SC doses. # PEP After naturally occurring Cutaneous or Gastrointestinal Exposure Vaccination is not recommended after cutaneous or gastrointestinal exposures that pose no risk for inhalation exposure. When a naturally occurring cutaneous exposure occurs, appropriate medical and public health personnel should be notified, and affected persons should be monitored for development of a spot, pimple, or boil-like lesion, especially in the exposed areas. For persons who experience a naturally occurring gastrointestinal exposure, such those who eat meat from an undercooked carcass of an anthrax-infected animal, antimicrobial PEP for 7-14 days may be considered. # Contraindication and Precautions for Use of AVA The following contraindication and precautions are relevant for both preexposure and postexposure settings (137). # Contraindication Although anaphylaxis after anthrax vaccination is extremely rare and no anaphylaxis deaths associated with AVA have been reported (CDC, unpublished data, 2010), an anaphylactic reaction can be life-threatening. Therefore, AVA is contraindicated for persons who have experienced an anaphylactic reaction after a previous dose of AVA or any of the vaccine components. # Precautions # Latex allergy: Because the vaccine vial stopper contains dry, natural rubber, caution should be used when administering the vaccine to persons with a latex allergy (137). Epinephrine solution (1:1000) should be available for immediate use in the event that an anaphylactic reaction occurs. # History of anthrax disease: A history of anthrax disease might increase the potential for severe local adverse reactions after AVA administration (137). # Impaired immune response: Patients with an impaired immune response might not be adequately immunized after administration of AVA (137). Moderate or severe acute illness: In a standard preexposure vaccination program, vaccination of persons with moderate or severe acute illness should be postponed until after recovery (137). In a postevent setting, the risks of administering vaccine to a person who has been exposed to anthrax but has moderate or severe acute illness should be weighed against the benefits of vaccination. Vaccine may be administered to persons who have a mild illness with or without a low-grade fever. # Reporting Adverse Events Adverse events that occur after administration of anthrax vaccine should be reported to VAERS, regardless of whether the reporter considers the vaccine to be the cause of the event. Information about VAERS and how to report vaccine adverse events is available at . Adverse events that occur after administration of antimicrobial agents should be reported to the FDA MedWatch program at . # Current and Future Research Research priorities for future studies on the currently licensed anthrax vaccine should include immunogenicity; additional evaluations of the dosing schedule (including the maximum time between boosters); additional long-term human safety studies; the number of vaccine doses required for PEP; the optimal duration of antimicrobial use in postexposure settings; antimicrobial susceptibility and treatment studies; optimal alternative antimicrobial agents for children, older adults (aged >65 years), and pregnant women; and the safety of anthrax vaccine in clinical toxicology studies among pregnant animals. Future research should include the groups for whom AVA is currently licensed, as well as children, older adults, and pregnant women. These research questions also should be addressed as new potential anthrax vaccines are identified and considered for use in humans. # Research on AVA and Future Anthrax Vaccines: Immunogenicity, Schedule, and Route Research is ongoing to address priority topics, including identification of quantitative immune correlates of protection in relevant animal species and defining the quantitative relationship between the vaccine-elicited immune response in these animal species and humans. Completion of the ongoing AVRP clinical trial should provide a definitive clinical evaluation of the effects of reducing the number of AVA doses (140). Information regarding the efficacy and safety of AVA in children and older adults also is needed, as is additional information regarding the safety and efficacy of AVA when used during pregnancy. Future research should include trials to obtain this information and to develop dosage recommendations for children. In addition, research to further develop both the recombinant PA (rPA) vaccines and the next generation of anthrax vaccines should continue. # Postexposure Prophylaxis Studies in animals indicate that the combination of antimicrobials and vaccination is very effective for preventing systemic B. anthracis infection. When using a combined approach the immune system benefits from the acute-phase antimicrobial protection provided against germinating spores and vegetative cells of B. anthracis while gaining enough time to complete immunological priming and establish anamnestic capability (i.e., immunological memory) (93). The effectiveness of vaccination might allow the antimicrobial course to be shortened from the recommended 60 days to as few as 14 days (102). Definitive, pivotal human studies to evaluate the magnitude and duration of the human immune response to anthrax vaccines when combined with antimicrobials have not been conducted. Additional research is needed to determine the optimal duration of antimicrobial administration in conjunction with the optimal doses of vaccine. # Long-term Safety of AVA The FDA final order for use of AVA emphasizes the need to continue postmarketing safety studies (135), and the IOM reports document the need for additional long-term follow-up of vaccine recipients (152,169). VAU continues to conduct research to address these issues through a combination of studies, including continued screening of the VAERS database for identification of potential long-term adverse events, hypothesis testing research studies using the DMSS database (170), and assessments of new safety signals identified from VAERS or other sources. # Alternative Anthrax Vaccines The rPA vaccines contain the purified protein of an avirulent, non-spore-forming strain of B. anthracis (258). Although recent phase 1 dose-escalation studies comparing rPA with AVA for reactogenicity, immunogenicity, and dosing range of rPA have been conducted (258,259), problems with vaccine formulation have delayed the start of phase 3 trials. One formulation demonstrated that immune responses of participants receiving rPA with adjuvant were not statistically significantly different from the responses of those receiving AVA (258). Evidence indicates that rPA candidate vaccines might cause fewer local adverse events than AVA administered subcutaneously (259). However, licensure of new anthrax vaccine will likely not occur for several years.	Today, B. anthracis is considered one of the most serious biowarfare or bioterrorism agents because of the ability of the spores to persist in the environment, the ability of the aerosolized spores to readily cause infection via respiratory (inhalation) exposure, and the high mortality of resulting inhalation anthrax (7-9). CDC has classified anthrax as a category A biological warfare agent (10), meaning it has great potential to adversely affect public health. The lethality of aerosolized B. anthracis spores was demonstrated in 1979 when an unintentional release of B. anthracis spores from a military microbiology facility in the former Soviet Union resulted in 64 deaths (11). The cases of anthrax that occurred after B. anthracis spores were distributed through the U.S. mail in 2001 further underscored the potential dangers of this organism as a bioterrorism threat (12)(13)(14)(15). Vaccines against anthrax were first developed as early as 1880 and used in livestock ( 16).# Introduction Anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis (1,2). The disease most commonly occurs in wild and domestic mammals (e.g., cattle, sheep, goats, camels, antelope, and other herbivores) (3). Anthrax occurs in humans when they are exposed to infected animals or tissue from infected animals or when they are directly exposed to B. anthracis spores (4)(5)(6). Depending on the route of exposure, anthrax can occur in three forms: cutaneous, gastrointestinal, or inhalation. # Background B. anthracis is a facultatively anaerobic, gram-positive, encapsulated, spore-forming, nonmotile rod. The infectious form of B. anthracis that is predominantly found in the environment is the spore, which is approximately 1 µm × 2 µm; anthrax is contracted from these spores, which are highly resistant to heat, cold, drought, UV light, and gamma radiation. B. anthracis has three major virulence factors: an antiphagocytic capsule and two exotoxins, referred to as lethal toxin and edema toxin. These toxins are responsible for the primary clinical manifestations of hemorrhage, edema, necrosis, and death. Disease is categorized according to the route of human exposure to B. anthracis spores: cutaneous, gastrointestinal, or inhalation. The precise infectious dose of B. anthracis in humans by the various routes is not known; inhalation anthrax can develop in susceptible hosts after exposure to a relatively small number of spores (28,29). Based on data from studies of nonhuman primates, the lethal dose has been estimated to range from 2,500 to 760,000 spores (11,30). The majority of human anthrax cases worldwide are naturally occurring (i.e., not a result of bioterrorism). The case-fatality rate for anthrax ranges from <1% (for cutaneous anthrax treated with appropriate antimicrobial agents) to 86%-89% (during the 1979 outbreak in the former Soviet Union and in the United States during the 20th century, respectively) (6,11,31,32). # naturally occurring Anthrax Throughout much of the 20th century, anthrax in humans was grouped into two categories: agricultural or industrial (6,33). B. anthracis spores can remain viable and infective in soil for decades, during which time they serve as a potential source of infection for grazing livestock that might become infected when they ingest or inhale the spores. B. anthracis spores in soil generally do not pose a direct infection risk for humans, who are typically infected by B. anthracis spores through contact with contaminated animal products or an infected animal (28). Agricultural cases of anthrax occur among persons who have direct contact with infected sick or dying animals or who handle infected carcasses or tissues. Persons at risk for acquiring anthrax through agricultural exposure might include ranchers, veterinarians, slaughterhouse or abattoir workers, and butchers. Industrial cases of anthrax result from the cutaneous inoculation or inhalation of particles containing B. anthracis spores generated during the cleaning and industrial processing of contaminated hides, hair, or wool from infected animals. Workers in wool and mohair processing facilities were historically at risk for contracting both inhalation and cutaneous anthrax, which made the disease a substantial health hazard in the wool industry in the 19th century and throughout the first half of the 20th century (4,34). Industrial processing of animal hair or hides accounted for 153 (65%) of 236 anthrax cases reported to CDC during 1955-1999 (35); commercial products made from animal hair or hides accounted for an additional five (2%) cases. Of these 158 cases, the majority (94%) were cutaneous anthrax; 10 (6%) cases were inhalation anthrax. Naturally occurring anthrax cases also have occurred outside of agricultural and industrial settings as a result of contact with products from anthrax-infected animals. Such products include anthrax-contaminated bristle shaving brushes, animal skins, animal hair or yarn, and bone meal (31,(36)(37)(38)(39)(40)(41). During 2006-2008, three inhalation cases (in the United Kingdom, United States, and Scotland) and two cutaneous cases (in the United States) were associated with drums made from imported contaminated hides (36,39,(42)(43)(44). Estimating the worldwide incidence of naturally occurring human anthrax is difficult because reporting of anthrax cases is unreliable in many settings (28). However, anthrax is most commonly observed in agricultural regions with inadequate control programs for anthrax in livestock. Anthrax outbreaks affecting domestic animals in these regions lead to direct or indirect human infection. Enzootic and endemic regions include South America, Central America, southern and eastern Europe, Asia, Africa, the Caribbean, and the Middle East (28). The largest recent epidemic of human anthrax occurred in Zimbabwe during 1978-1980 and involved 9,445 cases, including 141 (1.5%) deaths (5). The incidence of anthrax in animals in the United States has decreased since the middle of the 20th century, from 25 states reporting animal outbreaks in 1951 to eight states reporting outbreaks for the 10-year period from 1997 to 2006 (45,46) Outbreaks among both domestic animals and wildlife continue to be reported from the Great Plains states from Texas to North Dakota and in western states, including California, Montana, Nevada, and New Mexico (45). Cases that occur sporadically in both domestic livestock and free-ranging wildlife might not be recognized. Anthrax is a nationally notifiable disease (information available at http://www.cdc.gov/ncphi/disss/nndss/nndsshis.htm). In the 21st century, naturally occurring cases of anthrax in the United States have occurred sporadically, with two or fewer cases reported each year. Of the 242 naturally occurring human anthrax cases reported to CDC during 1955-2007, 232 (96%) were cutaneous, 10 (4%) were inhalation, and none were gastrointestinal (CDC, unpublished data, 2010). The only reported case of gastrointestinal anthrax in the United States occurred in 1941 (47) and resulted from an industrial exposure, not from contaminated food. Although gastrointestinal exposure to anthrax has been documented in the United States, no confirmed cases of anthrax resulted from the exposures (48). In 2010, CDC received a report of a woman with severe gastrointestinal symptoms after exposure to B. anthracis spores (CDC, unpublished data, 2010). # Bioterrorism-Related Anthrax In 2001, 22 confirmed or suspected human cases of anthrax occurred in the eastern United States (referred to as the bioterrorism events of 2001 in this report) when B. anthracis spores were sent through the mail in powder-containing envelopes to news media companies and U.S. congressional leaders (14,15,49). Eleven of the 22 cases were inhalation anthrax, and 11 were cutaneous; 20 of the cases occurred in mail handlers or persons exposed to buildings where contaminated mail was processed or received (15). Five persons with inhalation anthrax died. The source of exposure was unknown in two of the fatal cases (50,51); however, cross-contaminated mail was considered a possible source. B. anthracis has been a focus of offensive and defensive biological warfare research programs worldwide (10). Anthrax was used against livestock and draft animals as a bioweapon by Germany during World War I; during World War II, Japan conducted weapon field trials with anthrax in Manchuria. Numerous countries, including the United States, the United Kingdom, the former Soviet Union, and Iraq, conducted anthrax weapons research at various times during World War II, the Cold War, and the decades that followed (52,53). In 1979, at least 96 persons were infected and 64 persons died during an anthrax outbreak in the Soviet city of Sverdlosk after anthrax was unintentionally released from a military microbiologic facility believed to be a biowarfare facility (11). In 1993, a religious cult, Aum Shinrikyo, unsuccessfully attempted to use B. anthracis as a weapon near Tokyo, Japan (54). In 2008, the Department of Homeland Security issued a statement indicating that anthrax poses a threat sufficient to affect U.S. national security (55). WHO experts have estimated that 50 kg of B. anthracis spores released upwind of a population center of 500,000 persons could result in 95,000 deaths and 125,000 hospitalizations (56), and a release of 100 kg of spores upwind of the Washington, DC, metropolitan area would result in an estimated 130,000 to 3 million deaths (57). An intentionally dispersed strain of B. anthracis might have different characteristics from a naturally occurring strain. Intentionally dispersed strains might demonstrate antimicrobial resistance or increased dispersion capabilities. Primary aerosolization (dispersion of particles in air resulting from the initial release) and secondary aerosolization (resulting from agitation of the settled particles from the primary release) are important considerations in bioterrorist acts (58)(59)(60)(61)(62)(63)(64). The magnitude of risk for inhalation anthrax from secondary aerosolization of B. anthracis spores is uncertain. The bioterrorism events of 2001 prompted extensive biodefense research, as well as the creation and implementation of bioterrorism preparedness plans. Since 2001, in addition to increasing the number of public health mechanisms by which drugs and vaccines are distributed and dispensed or administered (i.e., EUA), emergency response and preparedness measures have focused on improving the effectiveness and timeliness of distributing and dispensing antimicrobials and vaccine for PEP. Efforts also have been made to improve the availability and timely distribution and administration of AVA in postevent settings. Because AVA is not licensed for postexposure use, the vaccine may be made available under an IND protocol or possibly under an EUA in an emergency (19)(20)(21)(22). # Pathogenesis and Disease B. anthracis enters the host in the form of spores (65) at the epidermis (cutaneous anthrax), the gastrointestinal epithelium (gastrointestinal anthrax), or the lung mucosa (inhalation anthrax). It is unknown whether B. anthracis has an active invasive process, and the symptoms and incubation period vary depending on the route of exposure to the spores. In general, symptoms of any form of anthrax usually begin within 7 days of exposure (1). Most naturally occurring B. anthracis bacteria are sensitive to a wide range of antimicrobial agents. Before initiating antimicrobial treatment, appropriate specimens should be obtained for isolation of the organism by culture. In practice, B. anthracis is readily identifiable using a range of standard microbiological tests, including Gram stain, cell and colony morphology, sensitivity of the gamma phage of McCloy, and production of the γ-linked poly-d-glutamic acid (γDGA) capsule in blood or under culture in 20% carbon dioxide. Most cutaneous and gastrointestinal infections occur at the site of preexisting lesions (66). Inhalation anthrax occurs after inhalation of aerosolized particles containing viable B. anthracis spores and their deposition at the alveolar epithelial surface (6,66). Inhalation anthrax is not pneumonia; in this form of disease, the mediastinal lymph nodes are usually the nidus of bacterial proliferation. Spores also can germinate at the pulmonary epithelial surface, and lung tissue might be infected as a consequence of fulminant systemic bacterial proliferation from other portals of entry (67). Regardless of the route of exposure, vegetative B. anthracis can spread through the blood stream, causing systemic disease (i.e., systemic anthrax) that results in hypotensive shock and sudden death (65). Systemic anthrax is typically fatal unless diagnosed and treated promptly (11). Anthrax meningitis can occur secondary to any of the three forms of anthrax. Although meningitis can occur without any other clinical signs and symptoms of anthrax, the condition is most often associated with inhalation anthrax. The pathogenicity and proliferation of B. anthracis in the host are primarily a result of the combined actions of the γDGA capsule and the two protein exotoxins, edema toxin (a complex composed of protective antigen [PA] and edema factor) and lethal toxin (a complex of PA and lethal factor) (68). Production of the capsule and toxins parallels the germination and outgrowth of B. anthracis spores (69). The capsule is considered to be antiphagocytotic, and the exotoxins disarm the innate and acquired immune responses (70)(71)(72). Edema toxin increases host intracellular cyclic adenosine monophospate (cAMP) levels, resulting in cytokine modulation, upregulation of the anthrax toxin receptor, and disruption of interstitial fluid balance (73,74). Lethal toxin inactivates members of the mitogenactivated protein kinase kinase (MAPKK) family, causing an imbalance in the production or release of a range of cytokines (75,76). In cases of cutaneous anthrax and those in which the nidus of infection remains localized, the combined effects of the toxins are tissue edema and local tissue necrosis. In cases of systemic anthrax secondary to any form of initial disease, the toxins cause hemorrhagic tissue and organ necrosis, hypoxic insult, and edema. In cases of inhalation anthrax, the edema is most prominent in the pleura, whereas in gastrointestinal anthrax, the fluid accumulation is most prominent as ascites (77,78). # Cutaneous Anthrax More than 95% of all naturally occurring B. anthracis infections worldwide are cutaneous. This form of anthrax is associated with handling infected animals or contaminated items such as meat, wool, hides, leather, or hair products from infected animals (79). Cutaneous anthrax has characteristic signs and symptoms and is recognizable if the physician is familiar with the disease. The majority of cutaneous anthrax lesions develop in exposed areas such as the face, neck, arms, and hands. The lesion begins as a small, often pruritic papule that quickly enlarges and develops a central vesicle or bulla, which ruptures or erodes, leaving an underlying necrotic ulcer. A characteristic firmly adherent, black eschar develops over the surface of the ulcer. The lesion is usually painless. Satellite vesicles and ulcers might also form (80). Edematous swelling of the surrounding tissues occurs, often with regional lymphadenopathy and lymphangitis. Systemic signs and symptoms, including fever, malaise, and headache, might accompany the cutaneous lesion (1). Historically, case-fatality rates for cutaneous anthrax have been as high as 20% without appropriate treatment but <1% with appropriate antimicrobial therapy (6). Because the progression of the disease is mediated by toxins, the lesions progress through the various stages once they have appeared, even with antimicrobial therapy. Discharge from cutaneous lesions might be infectious; however, the risk for personto-person transmission of cutaneous anthrax is very low (81). Differential diagnoses for a blackened eschar or other lesion include staphylococcal or streptococcal cellulitis or lymphadenitis, eczema, and herpes simplex or varicella zoster. In addition, depending on the epidemiologic history or route of exposure, parapoxvirus infection (orf virus and pseudocowpox virus) should be considered, because they are the most common parapoxviruses in U.S. food animals such as cattle, sheep, and goats. The differential diagnoses also include brown recluse spider bite, rickettsial pox, ecthyma gangrenosum, ulceroglandular tularemia, plague, typhus, glanders, erysipelas, cat-scratch disease, rat-bite fever, aspergillosis, mucormycosis, vaccinia, cutaneous leishmaniasis, cutaneous tuberculosis, and leprosy (80,82). The incubation period for cutaneous disease is reported to be 5-7 days (range: 1-12 days) (83). However, during the 1979 Sverdlovsk outbreak, cutaneous cases reportedly developed up to 13 days after the aerosol release of spores (11), and an outbreak in Algeria was reported with a median incubation period of 19 days (84). # Gastrointestinal Anthrax Gastrointestinal anthrax typically occurs after eating raw or undercooked contaminated meat, although spores consumed through any route, including spores that are inhaled and subsequently swallowed, can result in gastrointestinal anthrax. In the United States, no cases of gastrointestinal anthrax have been reported since 1941 (47). Although gastrointestinal anthrax could occur as a result of bioterrorist activity, no bioterrorismassociated cases have been reported. Gastrointestinal anthrax can occur in two forms: 1) intestinal or abdominal or 2) oropharyngeal. Data from human cases and outbreaks are limited, although clinical disease likely ranges from asymptomatic to fatal (85). The primary site of infection is the gastrointestinal epithelium. Infection might be associated with preexisting lesions in the alimentary tract, which might play a role in the development of oropharyngeal lesions. However, studies in mice demonstrated infection in the Peyer patches of the small intestine after intragastric deposition of spores (67). The intestinal form develops when spores infect the gastrointestinal tract epithelium after consumption of undercooked, contaminated meat. Signs and symptoms range from subclinical gastrointestinal disturbances to clinical illness with nausea and vomiting, fever, anorexia, and abdominal pain and tenderness and can progress to hematemesis and bloody diarrhea. Abdominal distension with voluminous, hemorrhagic ascites might be present (85,86). The disease might progress to septicemia and toxemia, cyanosis, shock, and death (86)(87)(88). Extensive edema of infected intestinal segments and mesentery can develop, and lesions might become necrotic and ulcerated. Infection of the mesenteric lymph nodes accompanied by lymphadenopathy might develop (86). An eschar might develop on the wall of the terminal ileum or cecum (86,89), and the upper gastrointestinal tract is occasionally affected (85,(90)(91)(92). The oropharyngeal form occurs after infection of the oropharyngeal epithelium and is characterized by lesions at the base of the tongue or tonsils, with sore throat, dysphagia, fever, and regional lymphadenopathy. Edematous lesions develop, which progress to necrotic ulcers covered with a pseudomembrane. Edema and swelling develop in the oropharynx and neck, accompanied by cervical lymphadenopathy, pharyngitis, and fever (85,88). The differential diagnoses of hemorrhagic gastroenteritis or oropharyngeal lesions suspected to be gastrointestinal anthrax should include the following (28): food poisoning, acute appendicitis, ruptured viscus, diverticulitis, dysentery, parapharyngeal abscess, malignancy, hemorrhagic gastroenteritis from other infectious causes, necrotizing clostridial enteritis, streptococcal pharyngitis, Vincent angina, Ludwig angina, and diseases causing acute cervical lymphadenitis, acute gastritis, or acute abdomen. Organisms may be isolated from vomitus or feces, from swabs of oropharyngeal lesions, or from blood or ascites fluid (79,88). The incubation period for gastrointestinal disease is estimated to be 1-6 days; the case-fatality ratio is unknown but is estimated to range from 25% to 60% (1,88). # Inhalation Anthrax Inhalation anthrax is a systemic infection caused by inhalation of B. anthracis spores. The mediastinal lymph nodes are most often the nidus of bacterial proliferation. Inhalation anthrax has historically accounted for 5% of all anthrax cases in the United States (31). This form of the disease results from the inhalation of aerosolized B. anthracis spore-containing particles that are ≤5 microns (66). Spore-containing aerosols can be generated through industrial processing or work with spore-contaminated animal products such as wool, hair, or hides; by laboratory procedures such as vortexing of cultures; or as a result of the intentional release of aerosolized spores. Inhaled spores lodge in the alveolar recesses and can become dormant, remaining dormant for weeks to months They are subsequently taken up by alveolar macrophages and then germinate (93)(94)(95), leading to substantial variability in the incubation period. Early studies of inhalation anthrax demonstrated that inhaled spores are phagocytosed by macrophages in the lungs and transported to the pulmonary-associated lymph nodes, where germination and vegetative growth occur, followed by bacteremia and dissemination to the rest of the body (94)(95)(96). Once taken up by alveolar macrophages, some spores are transported to the pulmonary-associated lymph nodes, where they continue to germinate, multiply, and release toxins (69,(97)(98)(99)(100), resulting in hemorrhagic necrosis of the thoracic lymph nodes that drain the lungs, or a hemorrhagic mediastinitis. Animal models also have demonstrated rapid phagocytosis of B. anthracis spores by interstitial dendritic cells, followed by dendritic cell migration to the thoracic lymph nodes (100). Exposure to aerosolized spores also has resulted in infection of nasal-associated lymphoid tissues in <24 hours, followed by subsequent spread to mandibular lymph nodes (67). Necrotizing pneumonitis occasionally develops (12,101,102). Initial signs and symptoms of inhalation anthrax are nonspecific and might include sore throat, mild fever, and muscle aches; these symptoms might initially be mistaken for an upper respiratory infection (79,103). Approximately 2-3 days later, infected patients generally become progressively ill as respiratory symptoms develop, including severe dyspnea and hypoxemia, and the disease progresses with development of hypotension, diaphoresis, worsening dyspnea, shock, cyanosis, and stridor (104). Chest radiography often reveals the characteristic widened mediastinum (12,79). Antimicrobial agents are effective against germinating and vegetative B. anthracis, but dormant spores are refractory to antimicrobials. Studies in nonhuman primates receiving antimicrobials suggest that inhaled B. anthracis spores can persist for up to 100 days in a dormant state at the alveolar surface epithelium (95). Inhalation anthrax has developed up to 58 days after experimental aerosol exposure in primates that received postexposure antimicrobial prophylaxis for the first 30 days after aerosol exposure (93). Reported incubation periods for inhalation anthrax in humans range from 1 to 43 days (11,31). Disease development can be prevented as long as the administered antimicrobial agent is maintained at levels sufficient to kill germinating B. anthracis organisms while dormant spores are cleared from the host. Cessation of antimicrobial treatment before clearance of the spores might allow residual spores to germinate and cause infection; therefore, the onset of inhalation anthrax might appear to be delayed (11,93,95,102,105,106). This late germination has not been observed in persons who have had a cutaneous or gastrointestinal exposure. Studies in animals suggest that incubation periods might decrease when the inoculum quantity increases (95,107,108). Similarly, in one reported human case, in a patient aged 51 years who was a previously healthy office worker in a textile mill (31), epidemiologic and exposure data suggested that the incubation period was as short as 1 day. The textile mill processed imported goat hair and previously had reported workers with cutaneous anthrax; however, no inhalation cases had been reported. The affected office worker had rarely entered the mill but developed inhalation anthrax in 1961, 1 day after visiting a dusty carding room in the mill. Subsequent investigation determined that both the goat hair being processed and the mill itself were widely contaminated with B. anthracis. In the 1979 Sverdlosk outbreak of inhalation anthrax, cases were reported 2-43 days after the initial release (11). Although the exact date of exposure in the Sverdlosk outbreak was not confirmed, the modal incubation period was reported as 9-10 days (11,65), which is slightly longer than the estimated incubation periods of 2-6 days in the few reported outbreaks of inhalation anthrax (11,106). The Sverdlosk data are limited regarding use of antimicrobials and vaccine; the number of people who received an intervention and the effectiveness of the intervention are unknown. Therefore, estimations of the incubation period during this outbreak are difficult to calculate (109). During the U.S. bioterrorism events of 2001, the median incubation period for six of the first 10 cases was 4 days (range: 4-6 days) (12). A review of all the 2001 inhalation cases indicates that the estimated incubation period was 4.5 days (15), a period consistent with previous reports (1). Case-fatality ratios of 86% and 89% were reported after the 1979 Sverdlosk outbreak in the former Soviet Union and in the United States during in the 20th century, respectively (11,31,32). During the bioterrorism events of 2001, the casefatality ratio for patients with inhalation anthrax treated in intensive care units was 45% (five of 11 cases) (15). # Bacteremic Dissemination and Meningitis After infection at the primary cutaneous, gastrointestinal, or inhalation site, lymphatic and hematogenous proliferation of anthrax bacilli can result in dissemination to other organs and organ systems (i.e., systemic anthrax). Massive septicemia with 10 7 to 10 8 bacteria per milliliter of blood and toxemia can develop, systemic effects including high fever and shock develop quickly, and death usually follows rapidly (65). Laboratory animal and nonhuman primate model studies demonstrate hematogenous spread to abdominal organs and the central nervous system (107,(110)(111)(112) with systemic inflammation, increased vascular permeability, and disseminated intravascular coagulation (113). Autopsy findings among decedents of the 1979 Sverdlosk outbreak and the bioterrorism events of 2001 included hepatic congestion, congestive necrosis of the spleen, and submucosal gastrointestinal lesions (101,114). Anthrax meningitis has been reported with all three clinical forms of anthrax and likely results from hematogenous spread across the blood-brain barrier, generally presenting as hemorrhagic meningitis. Anthrax meningitis is characterized by a fulminant, rapidly progressive clinical course; even with aggressive therapy, cases are usually fatal (115,116). The likelihood of the development of clinical or subclinical meningitis in patients with severe systemic B. anthracis infections is high. In rare cases, anthrax meningitis has been reported without any other associated primary (i.e., cutaneous, gastrointestinal, or inhalation) manifestation of anthrax (115,116). A review of 82 cases of inhalation anthrax that occurred during 1900-2005 included 70 fatal cases. Among the 70 patients who died, 11 of 61 patients for whom data were available had signs of meningeal involvement, compared with none of 12 patients who survived; 44 of the 70 patients who died developed meningoencephalitis during the course of their disease, compared with none of the 12 patients who survived. Development of meningoencephalitis during the course of disease was found to be significantly associated with death (p = 0.003) (104). Studies in nonhuman primates have demonstrated meningeal involvement in 33%-77% of experimental inhalation anthrax cases (93,108,110,112). # Control and Prevention Human anthrax is best controlled through prevention, including preexposure vaccination for persons at high risk for encountering aerosolized B. anthracis spores, reduction of animal illness by vaccination of livestock at risk for anthrax, and environmental controls to decrease exposure to contaminated animal products, such as imported hair and skins. After a person is exposed to aerosolized B. anthracis spores, a combination of antimicrobials and vaccine provides the best available protection. # Reduction of Risk for Exposure The incidence of naturally occurring human anthrax in the United States is greatly reduced through vaccinating and preventing infection in livestock, improving industrial hygiene, and decreasing the use of contaminated raw imported materials. Effective animal disease control programs have reduced the incidence of animal anthrax, and therefore human anthrax, worldwide. Since the initiation of annual vaccination of livestock in endemic regions in 1957, naturally occurring human cases in the United States have decreased from 38 cases in 1956 to fewer than two cases annually during 1980-2008. Anthrax in livestock can be controlled through vaccination programs, rapid detection and reporting of cases, and proper disposal of dead animals with suspected or confirmed anthrax, preferably by incineration (28,45). In countries where anthrax is common and vaccination coverage among livestock is low, humans should avoid contact with livestock and products from animals that have not been inspected and found to be healthy before and after slaughter (1,3). In addition, consumption of meat from animals that experienced sudden, unexplained death or meat of uncertain origin should be avoided (1,5). Restrictions on the importation of hides and wools from countries in which anthrax is enzootic can reduce the number of U.S. cases.* Methods for sterilizing or inactivating spores on contaminated materials include steam sterilization or ethylene oxide gas sterilization, boiling or using dry heat, or treating with formaldehyde, glutaraldehyde, or hypochlorite for specified periods of time and exposure concentrations; air drying does not destroy B. anthracis spores (28,(117)(118)(119). Industrial exposure and infection have been controlled through improvements in industry hygiene standards, mechanization of animal processing, and strict importation guidelines. Although these improvements have reduced the risk among employees working with animals and animal products, the risk has not been completely eliminated (120,121). Precautions to minimize exposure when working with potentially contaminated animal hides have been published (36,43) and should be followed. # Vaccination Vaccine Development The first effective anthrax vaccines using live, attenuated cultures of B. anthracis were demonstrated in 1880 by William S. Greenfield and in 1881 by Louis Pasteur (16,122). Pasteur's vaccine required a primary inoculation of B. anthracis that had been incubated at 42 º -43 º C for 15-20 days (type I vaccine) followed by a second inoculation (type II vaccine) of less attenuated B. anthracis that had been incubated at 42 º -43 º C for 10-12 days. This duplex vaccine was used widely until approximately 1935, when the procedure was modified to exclude the type I vaccine and reduce the virulence of the type II vaccine by the addition of 1%-10% saponin. Although effective, the virulence of heat-attenuated vaccines varied. In 1939, Max Sterne developed a live, attenuated spore vaccine from an avirulent, noncapsulated variant of B. anthracis (123,124). The Sterne-type vaccines replaced the Pasteur heat-attenuated formulations as the veterinary vaccines of choice. The veterinary vaccine that is currently used in the United States is based on the B. anthracis Sterne 34F 2 strain and is produced using a deep culture technique at approximately 10 5 doses per liter. Receipt of a single dose provides the animal with effective immunity for at least 1 year; revaccination is recommended to ensure protection for >1 year (105). The feasibility of using acellular vaccines against B. anthracis was first suggested by investigators who discovered that injections of sterilized edema fluid from anthrax lesions provided protection in laboratory animals (125,126). This discovery led to the exploration of the use of artificially cultivated B. anthracis filtrates as vaccines (127)(128)(129)(130)(131) and thereby to the human anthrax vaccines currently licensed and used in the United States and Europe. The first such U.S. product was developed in 1954 as a cell-free filtrate from an aerobic culture of the Vollum strain of B. anthracis, precipitated with aluminum potassium sulfate (alum), and evaluated for potency (132,133). This vaccine provided protection in monkeys, caused minimal reactivity and short-term adverse events in humans, and was used in the original efficacy study of human vaccination against anthrax in the United States (17). In the 1960s, the vaccine manufacturing process in the United States was modified, leading to changes in the B. anthracis strain used (from the Vollum strain to V770-NP1-R) and a switch to a microaerophilic culture method. These alterations optimized the production of a stable and immunogenic formulation of vaccine antigen and increased the production scale. Subsequently, the Michigan Department of Public Health (MDPH), under a contract with DoD, pursued premarket approval of the vaccine (128,134,135). The formulation for which MDPH sought premarket approval became AVA; the vaccine was licensed by NIH in 1970 and reapproved for licensure by FDA in 1985 (136). The safety and immunogenicity of the three generations of anthrax vaccine have been evaluated, and the resulting data support the FDA licensure of AVA (135). AVA is now marketed as BioThrax (Emergent BioSolutions, Lansing, Michigan) and is licensed for use in persons aged 18-65 years who are at high risk for exposure. AVA is not licensed for use in children (i.e., persons aged <18 years) or pregnant women (137). # AVA AVA is the only licensed human anthrax vaccine in the United States. AVA was originally licensed for SC administration as a series of 6 priming doses (0, 2, and 4 weeks and 6, 12, and 18 months) followed by annual booster doses. AVA is a sterile, milky-white suspension prepared from cell-free filtrates of microaerophilic cultures of a toxigenic, nonencapsulated strain of B. anthracis V770-NP1-R. The production cultures are grown in a chemically defined protein-free medium consisting of a mixture of amino acids, vitamins, inorganic salts, and sugars. Each 0.5-mL dose contains proteins from the sterile filtrate culture fluid (released during the growth period), including the protein PA (83 kDa), and contains no dead or live bacteria. The final product is formulated to contain 1.2 mg/mL aluminum, added as aluminum hydroxide in 0.85% sodium chloride, and 25 µg/mL benzethonium chloride and 100 µg/mL formaldehyde, added as preservatives (137). # Route of Administration and Immunogenicity Numerous studies have demonstrated the immunogenicity of AVA in humans and animals. However, a serologic correlate of protection has not been fully defined. Several studies have demonstrated seroconversion (fourfold rise in anti-PA immunoglobulin G [IgG] titers) rates of 85%-100% among adults receiving 2 and 3 doses of SC or IM AVA (138)(139)(140)(141), indicating a strong, long-lasting immune response to the vaccine. Additional data have demonstrated statistically significant increases in anti-PA IgG levels among those with a prolonged interval between the first and second doses of AVA when compared with persons receiving AVA as originally licensed (142). In December 2008, FDA approved a BLA supplement submitted by Emergent BioSolutions for use of AVA in a pre-event or preexposure setting. The current licensed schedule consists of 5 0.5-ml IM injections (at 0 and 4 weeks and 6, 12, and 18 months) and 0.5-ml booster injections at 1-year intervals after the 18-month dose. Although ACIP now recommends 5 doses of AVA administered IM for pre-event or preexposure prophylaxis, persons with medical contraindications to IM administration (e.g., persons with coagulation disorders) may continue to receive the vaccine by SC administration (25). However, when administering AVA as a component of PEP, the vaccine should only be administered with 3 doses by the SC route under an IND or EUA. A randomized study of 173 participants compared the first 3 AVA doses of the originally licensed schedule (SC injections at 0, 2, and 4 weeks) with alternate regimens (SC or IM injections at 0 and 4 weeks and SC or IM injections at 0 and 2 weeks). The antibody concentrations for the group that followed the originally licensed schedule were comparable to those from the groups receiving injections at 0-4 weeks. In addition, the groups that received AVA 4 weeks apart had peak anti-PA IgG concentrations that were approximately threefold higher than those for the groups that received AVA 2 weeks apart (143). This study suggested that increasing the interval between the first AVA doses might lead to an immune response comparable to that of the originally licensed schedule, with fewer doses required to achieve that response. However, the results of the study could not be used to support a change in the use of the vaccine because of the small sample size. In 2000, the U.S. Congress funded the CDC-sponsored AVRP clinical trial, a large, phase 4, double-blind, randomized, placebo-controlled study to assess the immune response to a reduced-dose schedule and a change in the route of administration from SC to IM (140). The AVRP clinical trial enrolled 1,564 civilian participants in five U.S. sites during May 2002-March 2004. Fifty-one percent of the participants were women, and 49% were men; ages ranged from 18-61 years and were evenly distributed among study groups. Approximately 75% of participants were white, 15% were black, and 10% were categorized as other. Participants were randomly assigned one of the following six vaccination schedules, with vaccinations administered over 42 months: 1) the originally licensed schedule of 8 SC doses (4 doses for the reported interim analysis); 2) 8 IM doses (4 IM doses for the reported interim analysis); 3-5) 7, 5, or 4 IM doses (3 IM doses through month 6, with the three groups combined into one group for purposes of the interim analysis); and 6) placebo (140). As of February 2009, when ACIP voted on the revised recommendations, data were available for review through dose 4. In 2005, CDC submitted data to FDA from the interim analysis of the first 1,005 enrolled participants who, at the time of the analysis, had received 4 doses of AVA by the SC route or the IM route or 3 doses by the IM route. Emergent BioSolutions subsequently filed a supplemental BLA. The primary outcome measures of this analysis were noninferiority of the anti-PA IgG geometric mean concentration (GMC), the geometric mean titer (GMT), and the proportion of responders with a fourfold increase in titer at week 8 (4 weeks after the week 4 dose) and month 7 (4 weeks after the month 6 dose) (140). At week 8, antibody responses were significantly higher in women than men in the 4-IM and 3-IM groups but not in the 4-SC group. By month 7, no significant differences between men and women had been detected in any of the groups analyzed. Antibody levels also were significantly higher in whites compared with blacks at week 8 (p<0.05), but by month 7, they were equivalent. Serological noninferiority analyses of antibody responses (anti-PA IgG GMC) demonstrated the noninferiority of both the 3-IM regimen and the 4-IM regimen to the originally licensed schedule at month 7 (Figure ). CDC is analyzing animal data and designing bridging studies to correlate nonhuman primate immune responses to AVA with survival from inhalation anthrax. Bridging of these data to human immune responses to AVA will provide additional information regarding immune correlates of protection against anthrax in nonhuman primates and serological markers of protection in vaccinated humans. # Efficacy Evidence for the efficacy of AVA comes from several studies in animals (including in nonhuman primates) and from a controlled vaccine trial in humans (17), observational data in humans (135,136), and immunogenicity data for humans and other mammals (129,130,139,141,144). A recent review provided support for the efficacy of AVA for persons aged 18-65 years (145); no data are available regarding the efficacy of anthrax vaccine for persons aged <18 years and >65 years. The protective efficacy of the alum-precipitated vaccine (the original form of the PA filtrate vaccine) and AVA (adsorbed to aluminum hydroxide) has been demonstrated in several animal models using different routes of administration (127)(128)(129)132,144,(146)(147)(148)(149)(150)(151). The Rhesus macaque (Macaca mulatta) is considered a suitable model of inhalation anthrax in humans (108,152), and AVA has been shown to be protective against an aerosol challenge in macaques using B. anthracis strains of high virulence (132,149,(153)(154)(155). Initial evidence for efficacy in humans came from the Brachman study, a placebo-controlled, single-blind, clinical trial among workers in four northeastern U.S. mills that processed raw, imported goat hair (17). The study was conducted during 1955-1959 using the alum-precipitated vaccine, the precursor to the currently licensed AVA. A total of 1,249 workers were included: 379 received the full series of anthrax vaccine, 414 received placebo, 116 received an incomplete series of injections (with either vaccine or placebo), and 340 received no treatment (observational group). Before vaccination, the yearly average number of human cutaneous and inhalation anthrax cases among employees in these mills was 1.2 cases per 100 employees. During the study, 26 anthrax cases (five inhalation and 21 cutaneous) were reported from the four mills. All five inhalation cases (four of which were fatal) occurred in participants who had not received vaccine; two had received placebo, and three had been in the observational group. Twenty of the 21 cutaneous cases occurred among participants who had not been fully vaccinated. Fifteen of the 21 had received placebo injections, three had received no injections (observational group), and three had received some doses of anthrax vaccine. Among the three cases that occurred in vaccinated persons, one occurred just before administration of the scheduled third dose, one occurred 13 months after completion of the scheduled 6 doses (but before any booster doses were received), and one occurred just before receipt of the first booster dose. The efficacy analysis in this study included all cases of anthrax, regardless of the route of exposure or manifestation of the disease, providing a combined efficacy of 92.5% based on person-time of occupational exposure (17). During 1962-1974, CDC collected surveillance data, independently of the Brachman clinical study, on cases of anthrax in mill workers or persons living near mills in the United States (135,136). Vaccinated persons received either AVA or the earlier formulation used in the original 1950s clinical trial (17). No cases of inhalation anthrax were identified in any of the workers. Twenty-seven cases of cutaneous anthrax were identified by CDC, 24 of which were in unvaccinated persons. In vaccinated persons, one case occurred after receiving 1 dose of anthrax vaccine, and two cases occurred after receiving 2 doses of anthrax vaccine. No documented cases of anthrax were reported for persons who had received at least 3 of the recommended 6 doses of anthrax vaccine. A civilian advisory panel reviewed the CDC surveillance data and determined the vaccine to be effective (136). In March 2002, a committee appointed by the Institute of Medicine (IOM) released a comprehensive review of the most current safety and efficacy data available for AVA (152). The committee found human efficacy data to be limited to the Brachman study (17) and the CDC surveillance data (135,136) but concluded that the combination of human data and animal data demonstrated that AVA effectively protects humans from anthrax, including inhalation anthrax (152). The committee also determined that the mechanism of action of AVA protects humans from various B. anthracis strains and that a naturally occurring or bioengineered strain probably could not overcome AVA and cause anthrax (152). The duration of AVA protection in humans after the initial priming series is unknown. Persons are considered protected from anthrax for as long as they continue receiving AVA according to the licensed schedule. A 2002 study of military personnel who had received 1, 2, or 3 priming doses during the early 1990s, followed by 1 dose 18-24 months later, demonstrated that 99.3% of participants had measurable anamnestic responses (143). Data from animal studies suggest that the duration of protection after 2 doses might be 1-2 years and that 3 IM doses of AVA provide significant levels of protection in rhesus macaques for up to 4 years (140,144,149,155). Persisting, detectable PA-specific memory B cells in the blood might be useful markers for duration of immunity because of their ability to proliferate and differentiate rapidly into anti-PA antibody-secreting plasma cells. In a study of patients with clinical anthrax, peak anti-PA IgG levels after infection correlated with the number of PA-specific memory B cells in circulation up to at least 1 year after infection (156). Circulating PA-specific memory B cells also were detectable in AVA vaccine recipients. These data suggest that both survivors of inhalation anthrax and vaccine recipients develop long-term protective immunity to anthrax; quantitative analysis of PA-specific IgG B cell memory might be a useful predictor of the duration of protection against anthrax (156). # Safety At least eight reviews (9,135,136,145,152,(157)(158)(159) and 35 other publications include evaluations of AVA safety. # Prelicensure Adverse Event Surveillance Local Reactions. In prelicensure evaluations, 6,985 persons received 16,435 SC doses: 9,893 initial series doses and 6,542 annual boosters (160). Severe local reactions (defined as edema or induration of >120 mm) occurred after 1% of vaccinations. Moderate local reactions (defined as edema and induration of 30-120 mm) occurred after 3% of vaccinations. Mild local reactions (defined as erythema, edema, and induration of <30 mm) occurred after 20% of vaccinations. In a study of the alum-precipitated precursor to AVA, moderate local reactions were documented in 4% of vaccine recipients and mild reactions in 30% of recipients (17). Systemic Reactions. In prelicensure evaluations, systemic reactions (i.e., fever, chills, body aches, or nausea) occurred in <0.06% (in four of approximately 7,000) of vaccine recipients (160). In the study of the alum-precipitated precursor to AVA, systemic reactions occurred in 0.2% of vaccine recipients (17). # Postlicensure Adverse Event Surveillance During January 1, 1998-December 31, 2008, nearly 12.4 million doses of AVA were distributed for DoD and domestic licensed use (AT Waytes, Emergent BioSolutions, personal communication, November 5, 2009); 8.4 million of these doses were administered to approximately 2.1 million military personnel during March 1, 1998-December 31, 2008 (P Garman, Military Vaccine Agency, personal communication, November 5, 2009). Less than 1% of all AVA doses were distributed to nonmilitary sources (AT Waytes, Emergent BioSolutions, personal communication, November 5, 2009). The Vaccine Adverse Event Reporting System (VAERS) has been used extensively to monitor adverse events that occur after vaccination with AVA. VAERS (161-163), a U.S. national passive surveillance system for reporting adverse events that occur after administration of U.S. licensed vaccines, plays an important role in the identification of adverse events that warrant further investigation. Although VAERS data are useful for detecting rare adverse events and assessing reporting trends, they cannot be used to assess incidence rates or causality. Reports can be submitted voluntarily by anyone, including health-care providers, patients, manufacturers, or family members; therefore, reports might vary in quality and completeness, often lack detail, and might include inaccurate information. Because VAERS is a passive surveillance system, actual rates for adverse events cannot be calculated because the number of doses administered is unknown. Underreporting is another important limitation, as is differential reporting (e.g., increased reporting rates for specific vaccines or specific adverse events), which often occurs for more serious and unexpected events, events occurring soon after vaccination, events surrounded by publicity, and reports related to litigation proceedings (163,164). Hypotheses generated by VAERS must be confirmed by epidemiological studies (163). During January 1, 1998-December 31, 2008, VAERS received 6,015 nonduplicate reports from U.S. sources of adverse events after receipt of AVA, either alone or concurrently with other vaccines (CDC, unpublished data, 2010). Of these, 600 (9.9%) were categorized as serious events (i.e., events resulting in death, hospitalization, or permanent disability) (165). Approximately 74% of all reported adverse events that occurred after administration of AVA were in persons aged <40 years. Twenty-six percent occurred in women and 72% in men; sex was not specified in 2% of the reports. The majority (75%) received AVA alone, and 25% received the vaccine concurrently with other vaccines. Eighty three percent of AVA reports were documented as being administered or funded by the military (CDC, unpublished data, 2010). Adverse events reported to VAERS are coded using terms from the Medical Dictionary for Regulatory Activities (MedDRA) (166). Approximately 800 different MedDRA terms were reported in conjunction with AVA during 1998-2008. The 10 most common adverse events that occurred after AVA administration (either alone or concurrently with other vaccines) were arthralgia (n = 1,036, 17.2%), headache (n = 981, 16.3%), pruritis (n = 878, 14.6%), pain (824, 13.7%), injection-site erythema (n = 753, 12.5%), fever (n = 655, 10.9%), erythema (626, 10.4%), pain at the injection site (613, 10.2%), rash (606, 10.1%), and myalgia (583, 9.7%) (172). As of December 31, 2008, VAERS had received 25 reports of death among AVA recipients. Causes of death included a spectrum of cardiovascular disorders, unintentional or intentional injuries, malignancies, and chronic illnesses (CDC, unpublished data, 2010). Death reports have been summarized elsewhere (27,167,168). Reports to VAERS after AVA administration have been reviewed by several expert groups (157,158,167,168). In 2003, IOM (169) recommended that CDC partner with DoD to follow up on signals generated by reviews of VAERS and DoD data, using the DoD Defense Medical Surveillance System (DMSS), a relational surveillance database containing data from military recipients of AVA and other vaccines (170). Short-Term Adverse Events. Data on the safety of AVA are only available for persons aged 18-65 years; no information is available on the safety of this vaccine in children or older adults (>65 years). Much of the published data comes from the routine DoD anthrax vaccination program. Several studies, including clinical trials and uncontrolled observational studies, have examined immediate or short-term adverse events (e.g., hours to days) that occurred after receipt of AVA (171)(172)(173)(174)(175)(176)(177). The majority of these events have been limited to local reactions (e.g., erythema, swelling, pain or tenderness, itching, and nodules) or mild, self-limited systemic symptoms (e.g., fever, chills, myalgia, arthralgia, and malaise). After a comprehensive review, the IOM committee (152) found no evidence that AVA recipients had a higher risk than the general population for life-threatening or permanently disabling adverse events immediately after receiving AVA and that rates and types of immediate or short-term reactions were comparable to those for other vaccines regularly administered to adults (152). After the bioterrorism events of 2001, 1,727 persons participated in the CDC Anthrax Vaccine and Antimicrobial Availability program and received either AVA and antimicrobials or only antimicrobials (178). Among the enrollees, 199 participants opted to receive AVA and antimicrobials. Local and systemic adverse event profiles for AVA recipients compared with those for persons who received only antimicrobials indicated that a higher proportion of persons who received AVA reported adverse events than did persons who received only antimicrobials. The most commonly reported adverse events among vaccine recipients were discomfort at the injection site (70.9%), erythema (45.2%), induration (58.8%), and swelling (39.7%). Participants who received AVA by the SC route in the AVRP clinical trial reported warmth, tenderness, erythema, induration, and nodule development more frequently than participants who received AVA by the IM route. Although fatigue and headache were the most commonly reported systemic adverse events among clinical trial participants, they were reported by <11% of participants. Women reported significantly more injection-site and systemic adverse events than men (140). Several reviews have noted that women report a higher proportion of certain adverse events after AVA than men (152,157,167,168); this phenomenon has been documented with other vaccines as well (179). A comprehensive review of VAERS AVA data in 2004 demonstrated that women were 3 times more likely than men to have or report an adverse event. Women were not more likely to be hospitalized than men because of adverse events, although women accounted for a greater proportion of reported injection-site adverse events and moderate or extensive injection-site inflammation (157). A study of female AVRP clinical trial participants to assess the effect of progesterone levels on adverse events and immune response is ongoing; final data will be available in late 2010. Long-Term (Chronic) Adverse Events. DoD has published several studies of long-term health effects among vaccinated and unvaccinated military personnel (180)(181)(182)(183)(184). Additional studies have assessed the long-term health of vaccinated researchers and fertility parameters for vaccinated males (185,186). None of the studies found that the risk for adverse health effects or chronic diseases (e.g., cancer or infertility) was higher after anthrax vaccination. These studies of long-term health effects support the IOM finding (152) that no convincing evidence exists to indicate that the risk for developing long-term adverse health effects is higher among anthrax vaccine recipients. As with all vaccines, the possibility for rare adverse reactions does exist with AVA. The Vaccine Analytic Unit (VAU) (170), which was developed to implement the IOM recommendations (169), is a collaborative CDC and DoD project with FDA participation. Using data from DMSS, VAU can analyze vaccine safety data for all vaccines administered to active-duty and reserve service personnel. In a matched case-control study, VAU investigators found no significant associations between optic neuritis and previous receipt of AVA, smallpox, hepatitis B, or influenza vaccines (187). In addition, VAU found no association between concurrent receipt of multiple vaccinations and hospitalization risk among U.S. military personnel (188). Studies to address additional topics (e.g., Stevens Johnson syndrome/toxic epidermal necrolysis, type 1 diabetes mellitus, atrial fibrillation, and diffuse connective tissue diseases) are ongoing. # Effect of Route of Administration on Adverse Events A small randomized study on the effects of route of administration on adverse events found that systemic adverse events were uncommon and similar for IM and SC groups. All local reactions (i.e., tenderness, erythema, warmth, induration, and subcutaneous nodules) were significantly more common after SC injection than after IM injection. Women who received IM injections 4 weeks apart reported fewer of certain local adverse events than did women who received SC injections 2 weeks apart (143). The AVRP clinical trial demonstrated that the proportion of injection-site adverse events was lower in the group receiving 4 IM injections than in the group receiving 4 SC injections, especially among women, who experienced a significant decrease in the occurrence of warmth, tenderness, itching, erythema, induration, edema, and nodules. In addition, the duration of injection-site adverse events in the 4-IM group was shorter than that experienced by the 4-SC group. Persons in the 4-IM group also experienced significantly fewer moderate and severe injection-site adverse events (7.0%) than persons in the 4-SC group (10.2%, p = 0.04). Analog pain scale scores used to assess pain immediately after injection were significantly lower in the 4-IM group compared with the 4-SC group (p<0.01). In all study groups, women were almost twice as likely as men to experience an injection-site adverse event (OR = 1.93, p<0.01); however, the absolute differences between women and men for warmth, itching, erythema, induration, and nodules were largest in the 4-SC group. Route of administration was not associated with the occurrence of systemic adverse events, and the differences between men and women in regards to systemic adverse events were generally consistent across all study groups (including the placebo group) (140). # Effect of Vaccination on Pregnancy and Breastfeeding A paucity of data exists regarding the use of AVA during pregnancy; however, in general, the use of inactivated vaccines is considered safe during pregnancy (189)(190)(191)(192)(193). Some evidence indicates that nonspecific stimulation of the maternal immune system might decrease the risk for birth defects (194,195). Potential benefits gained from the use of AVA during pregnancy might outweigh the risk in certain situations. DoD policy is to exempt pregnant military women from anthrax vaccination; however, some women were inadvertently vaccinated with AVA while pregnant, as reported in a recent study that evaluated approximately 115,000 live births to military women (196). The study suggested that infants born to women who received anthrax vaccine in their first trimester of pregnancy had slightly higher odds of experiencing birth defects than infants born to never-vaccinated women (OR = 1.20, 95% confidence interval [CI] = 1.02-1.42) or to women vaccinated only after pregnancy (OR = 1.02, CI = 1.01-1.43). When infants born to women vaccinated during their first trimester were compared with infants born to women vaccinated outside the first trimester, no statistical association with birth defects was found (OR = 1.18, CI = 1.00-1.41). Of the 10 specific defects assessed in this study, only atrial septal defect (ASD) demonstrated a significant increase among infants born to women vaccinated during the first trimester. These findings were limited, partly because the code for ASD (per the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]) is the same as the code for patent foramen ovale, a common finding in preterm infants. When preterm infants with ASD as the only reported birth defect were excluded from analyses, the association between ASD and vaccination in the first trimester was no longer statistically significant. In addition, late recognition of pregnancy, a moderate risk factor for many birth defects, including ASD, might explain the number of women vaccinated during their first trimester. After review of these data and discussions with the authors of this study, ACIP concluded that AVA is safe to administer during pregnancy but recommended that pregnant women defer vaccination unless exposure to anthrax poses an immediate risk for disease (27). Another study of 385 women who had received at least 1 dose of AVA before becoming pregnant (197) found no evidence of miscarriage, infertility, or other reproductive problems among vaccinated women. In addition, the study did not support the hypothesis that AVA administration resulted in decreased pregnancy rates among those vaccinated before pregnancy. No data have been collected on the use of AVA among breastfeeding women. Therefore, whether anti-anthrax antibodies are transferred through milk from mother to infant is unknown; however, data from similar vaccines indicate that this might occur (198). No biological reason suggests that breastfeeding women or breastfed children have an increased risk for adverse events after the mother receives anthrax vaccine. Administration of other inactivated vaccines during breastfeeding is not medically contraindicated (199). # Vaccination of Children AVA use in children has not been studied, and the vaccine is not licensed for use in this population. A 2004 review demonstrated that children aged <18 months experienced more local erythema and induration after receipt of vaccines containing an aluminum hydroxide adjuvant than after receipt of nonadjuvanted vaccines. Erythema and induration were not reported in children aged 10-18 years, although these older children experienced local pain lasting up to 14 days after administration of vaccines with aluminum hydroxide adjuvants (200). The concentration of aluminum per dose of AVA is similar to that in the diptheria/tetanus/pertussis (DTaP) vaccine and is less than that in the combined DTaP/polio/hepatitis B vaccine (201). Because AVA contains aluminum hydroxide, local adverse events are likely to be similar to those described in adults administered AVA and in children administered other vaccines with similar aluminum hydroxide concentrations; ACIP concluded that no evidence suggests that the risk for serious adverse events after receipt of anthrax vaccine is higher in children. The morbidity of inhalation anthrax should be considered when children have been exposed to aerosolized B. anthracis spores. # PEP for Previously Unvaccinated Persons Vaccination as a Component of PEP Studies have demonstrated not only the persistence of spores in nonhuman primates up to 100 days after inhalation exposure (95) but also the potential for long-term spore survival and development of inhalation anthrax after discontinuation of postexposure antimicrobial agents (93,95). Because disease can develop long after exposure to spores, animal studies have examined the use of postexposure vaccination in combination with antimicrobial agents. Although the precise correlation between the immune response to vaccination and protection against disease has not been completely defined, several studies (93,95,102) have documented that 2-and 3-dose schedules of vaccination, combined with antimicrobial therapy, prevent development of disease in animals. Although the point at which a person develops immunity against anthrax after the first vaccination is unknown, available data indicate that the antibody response to the vaccination administered at week 26 (month 6) is characteristic of a strong anamnestic response, in turn indicating that the vaccine schedule of day 0, week 2, and week 4 effectively primes the immune system against PA. The available data on human responses to AVA indicate that use of the 3-dose SC regimen (with doses at 0, 2, and 4 weeks) for PEP results in rapid anti-PA antibody production at high levels (140,143) and is therefore an additional benefit to the approved antimicrobial therapies. Therefore, ACIP previously recommended that 3 doses of AVA (SC at day 0, week 2, and week 4) be administered in conjunction with antimicrobial therapy to previously unvaccinated persons who have been exposed to aerosolized B. anthracis spores (23,24). As described, the AVRP clinical trial (140) demonstrated that a vaccination schedule of doses administered at 0 and 4 weeks via the IM route elicited a lower antibody response at week 8 than did a schedule of doses administered at weeks 0, 2, and 4 via the SC or IM route (Figure). Because the clinical signifi-cance of the lower immune response to a schedule of doses administered at 0 and 4 weeks is not known, and sex-related differences in antibody levels exist, adherence to a schedule that produces rapid development of high antibody levels is particularly beneficial in a postexposure setting. Therefore, in June 2009, FDA recommended retaining the current PEP protocol (3-dose SC series administered at 0, 2, and 4 weeks in conjunction with antimicrobial therapy for a minimum of 60 days) until additional data are available (J Clifford, FDA, personal communication, June 24, 2009). After natural, occupational, or bioterrorism-related exposure to aerosolized B. anthracis spores, the combination of AVA and antimicrobials is more effective than use of antimicrobials only. Vaccination as a component of PEP is beneficial when antimicrobial PEP is discontinued too soon after exposure. Poor adherence to the prescribed regimen, which has been as low as 42%, minimizes the effectiveness of postexposure antimicrobial therapy (202). The bioterrorism events of 2001 also suggested that persons might be exposed to larger amounts of B. anthracis spores than those studied in animal models. A possible consequence would be prolonged spore clearance, with increased levels of residual spores at the alveolar surface epithelium and therefore an increased potential for infection when antimicrobial prophylaxis is discontinued after 60 days (202). Because of the potential for short incubation periods with inhalation anthrax, especially when the inhaled dose might be large, and the rapid progression and associated high morbidity and mortality, antimicrobial PEP should be initiated as soon as possible after inhalation exposure to aerosolized B. anthracis spores. Vaccination also should be initiated as quickly as possible but will likely occur several days after antimicrobial agent initiation for logistical reasons. To maximize the benefits of vaccine, the first dose should be initiated within 10 days of exposure. Antimicrobial use should continue until the immune response to the priming series has developed, which is expected to be 10-14 days after administration of the third dose of vaccine. PEP recommendations for inhalation exposure to aerosolized B. anthracis spores differ from those for a naturally occurring cutaneous or gastrointestinal exposure. Because AVA is not licensed for postexposure use, administration of AVA as a component of PEP is available under an IND application (IND #10061, held by CDC) and may be made available under an EUA (19)(20)(21)(22). † The PEP regimen included in the IND protocol includes children aged 0-17 years. IND protocols require detailed records to be kept; written, informed consent from all participants; data collection; reports to FDA; and follow-up of patients. The IND mecha-nism is generally suited to clinical practice and is not easily used during an emergency. The Project BioShield Act of 2004 authorizes the FDA commissioner to issue an EUA during an emergency under certain circumstances (21). Under an EUA, medical countermeasures to diagnose, treat, or prevent serious or life-threatening diseases for which no adequate, approved, and available product exists can be disseminated quickly for the protection and safety of the U.S. population. The issuance of an EUA enables large-scale use of a medical countermeasure (203) such as AVA as a component of PEP. AVA has been used extensively, including after the bioterrorism events of 2001, with a good safety profile; therefore, on the basis of a review of existing data and expert opinion, ACIP expects that future use of AVA as a component of PEP is likely to have a good safety profile. # Antimicrobial Agents as a Component of PEP Because limited data are available, the optimal duration of antimicrobial therapy in combination PEP is uncertain. Antimicrobial therapy for 60 days, without vaccine, might prevent inhalation anthrax; however, antimicrobial agents without vaccine might not protect persons from late spore germination. Using the limited available data, FDA licensed a 60-day course of antimicrobials for postexposure use; a shorter course (<60 days) of antimicrobial therapy, even when combined with a 3-dose AVA series, is not approved for use by FDA. In 2006, an expert panel (204) discussed whether, based on the limited evidence (102,139), the duration of antimicrobial use could be shortened with concurrent receipt of AVA. The panel determined that the available data were too limited to support a regimen of <60 days. Oral ciprofloxacin, oral doxycycline, and parenteral (IM) penicillin G procaine have been shown to be effective for PEP use in a nonhuman primate model (93) and are FDA approved for a 60-day course for inhalation anthrax (postexposure) in all age groups (205,206). Ciprofloxacin and doxycycline are equivalent first-line antimicrobial agents for PEP, because they are equally effective and have similar susceptibility profiles among naturally occurring B. anthracis isolates (93,207). In addition, both have similar safety profiles, with a low rate of anaphylactic reactions (208,209). Selection of PEP agents should involve consideration of the potential for antimicrobial resistance. Both naturally occurring constitutive and inducible β-lactamase production can be present in B. anthracis isolates (207,(210)(211)(212). Because induction of resistance has been previously reported in the nonhuman primate model ( 213), there are concerns that an insufficient dosage could induce penicillin resistance in humans (49,214,215). For these reasons, oral penicillins are not considered first-line antimicrobial agents for PEP but may be considered after the antimicrobial susceptibility profile of the organism is known. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole (207,216,217). Although oral amoxicillin is an alternative to the first-line PEP agents when antimicrobial susceptibility profiles demonstrate appropriate sensitivity (minimum inhibitory concentration [MIC] ≤0.125 µg/mL), amoxicillin has not been studied for the prophylaxis or treatment of anthrax, and no safety or efficacy data are available for this indication. Amoxicillin is not FDA approved for use as a component of PEP and therefore should only be administered under an IND or possibly under an EUA to certain patient groups (e.g., children or pregnant or nursing women) during a declared emergency provided the criteria for issuance have been met. Because oral amoxicillin has better pharmacokinetics than equivalent doses of oral penicillin V, oral amoxicillin may be used with a less frequent dosing interval, potentially improving adherence to therapy (218)(219)(220)(221)(222). Compared with oral penicillin, oral amoxicillin has greater pulmonary penetration and is able to maintain a higher concentration above MIC in the target tissues (e.g., pulmonary-associated lymph nodes, tissues, and secretions) for a greater portion of the dosing interval (223)(224)(225)(226)(227). Oral amoxicillin at dosages approved for other indications (i.e., 500 mg/kg every 8 hours for adults; 45 mg/kg/day orally in 3 divided doses for children weighing <40 kg) should prevent postexposure inhalation anthrax if the B. anthracis strain in question has an amoxicillin MIC <0.125 µg/mL (225)(226)(227). Amoxicillin-clavulinic acid combinations may be considered for PEP. Because potassium clavulanate does not have a significant impact on the pharmacokinetics of oral amoxicillin, the dosage is based on the amoxicillin component (228). Levofloxacin been shown to be effective for PEP use in a nonhuman primate model (229) and is FDA approved for inhalation anthrax (postexposure) in patients aged >6 months (230). Short-term (up to 28 days) safety data exist, but extended-use (up to 60 days) data are limited (231). Therefore, levofloxacin is recommended as a second-line PEP antimicrobial agent to be reserved for instances in which tolerance issues or drug resistance patterns indicate its use. Dosing information for recommended antimicrobial agents for PEP is provided (Table 1). For patients unable to tolerate FDA-approved antimicrobial agents, clinicians may consider clindamycin, chloramphenicol, erythromycin, vancomycin, or other fluoroquinolones for PEP, based on in vitro susceptibility results. Administration of these agents would be considered off-label use (i.e., for other than the FDA-approved use) and might require an IND or EUA. # Adverse Events Associated with Antimicrobial PEP Adverse events associated with the long-term use of antimicrobial PEP include gastrointestinal upset and other conditions that are expected when normal body flora are disrupted by antimicrobial use (232). Any antimicrobial agent can have undesirable side effects, including allergic reactions. Patients should be urged to inform public health authorities and their health-care providers of any adverse events that occur. Longterm fluoroquinolone use has been associated with tendinitis and tendon tears (233). During the bioterrorism events of 2001, approximately 10,000 persons were recommended to receive a 60-day regimen of antimicrobial prophylaxis (doxycycline, ciprofloxacin, or amoxicillin) for suspected or confirmed exposure to B. anthracis spores. Adverse events that were commonly reported by patients were not serious and included diarrhea, stomach pain, nausea, vomiting, headache, dizziness, and fatigue (202,234). No serious adverse events were found to be definitely related to the use of prescribed antimicrobials (202,234). Adverse events associated with ciprofloxacin or doxycycline were not substantially different enough for one therapy to be recommended instead of the other (178,202). Among persons who began the 60-day PEP regimen, 21%-41% continued the regimen as prescribed (202). Adverse events were a commonly cited reason for discontinuation of antimicrobial PEP; 73 (78%) of the 93 persons in the Washington, DC, postal center who stopped taking antimicrobial PEP cited adverse events as a reason for nonadherence (235). Perceived risk for exposure to aerosolized B. anthracis was a statistically significant predictor of adherence to PEP (235), and according to one study, perceived risk was a stronger predictor of adherence than actual adverse events (202). # Antimicrobial Considerations for Pregnant or Breastfeeding Women Based on limited human clinical information, use of therapeutic doses of ciprofloxacin during pregnancy is unlikely to have a substantial teratogenic risk; however, the actual teratogenic risk from ciprofloxacin use during pregnancy is unknown (13,236). Even with these limited data, ciprofloxacin is recommended as the first-line antimicrobial agent of choice for PEP for asymptomatic pregnant or lactating women because of the severity of inhalation anthrax (237). Treatment should be changed to amoxicillin if the strain of B. anthracis is found to be sufficiently susceptible to penicillin (237). Potential risks associated with the use of tetracycline antimicrobials during pregnancy include dental staining of the fetal primary teeth and possible depressed fetal bone growth and dental enamel defects. Hepatic necrosis has been reported in pregnant women using tetracyclines, although such reports are rare (13). Tetracyclines should be used cautiously in asymptomatic pregnant women and only if contraindications to the use of other appropriate antimicrobial agents exist. Penicillins are generally considered to be safe during pregnancy and are not associated with an increased risk for fetal malformation (238). The American Academy of Pediatrics considers ciprofloxacin and tetracyclines (including doxycycline) to be appropriate for breastfeeding women because the amount of drug absorbed by infants is small; however, little is known about the safety of long-term use (239). Because of the severity of inhalation anthrax, ciprofloxacin and doxycycline are considered the firstline antimicrobial agents of choice for PEP (237) as indicated for adults in these recommendations. Because amoxicillin is known to be safe for infants, this antimicrobial is an option for PEP for breastfeeding mothers when the appropriate conditions described have been met and when the mother has no contraindications to amoxicillin. If an infant is exposed to B. anthracis and is receiving PEP, the antimicrobial regimen of the breastfeeding mother should be the same as that of the child, when possible, to minimize infant exposure to multiple drugs. If the drug used by the mother is contraindicated in her infant, the mother should express and discard her breast milk while being treated. Breastfeeding may resume after the mother completes the course of antimicrobial therapy (204,240,241). # Antimicrobial Considerations for Children Although antimicrobials such as ciprofloxacin or doxycycline are typically not administered to children, the severity of anthrax is sufficient that treatment with these antimicrobials is warranted and recommended for children who have been exposed to aerosolized B. anthracis spores. Amoxicillin is preferred for antimicrobial PEP in children when susceptibility testing indicates that the B. anthracis isolate involved is susceptible to penicillins (i.e., MIC ≤0.125 µg/mL for amoxicillin). In these instances, a transition from ciprofloxacin or doxycycline to amoxicillin is recommended for completion of the 60-day PEP antimicrobial regimen (Table 1). * Antimicrobials should continue for 14 days after administration of the third dose of vaccine. † AVA used for PEP must be administered subcutaneously. § Levofloxacin is a second-line antimicrobial agent for PEP for persons aged ≥6 mos with medical issues (e.g., tolerance or resistance to ciprofloxacin) that indicate its use. Children: 16 mg/kg/day divided every 12 hrs; each dose should not exceed 250 mg. Adults: 500 mg every 24 hrs. Safety data on extended use of levofloxacin in any population for >28 days are limited; therefore, levofloxacin PEP should only be used when the benefit outweighs the risk. ¶ The antimicrobial of choice for initial prophylactic therapy among pregnant women is ciprofloxacin. Doxycycline should be used with caution in asymptomatic pregnant women and only when other appropriate antimicrobial drugs are contraindicated. Although tetracyclines are not recommended during pregnancy, their use might be indicated for life-threatening illness. If susceptibility testing demonstrates an amoxicillin MIC ≤0.125 µg/mL, oral amoxicillin should be used to complete therapy. † † Use of tetracyclines and fluoroquinolones in children can have adverse effects. These effects must be weighed carefully against the risk for developing life-threatening disease. If exposure to B. anthracis is confirmed, children may be treated initially with ciprofloxacin or doxycycline as prophylaxis. However, amoxicillin is preferred for antimicrobial PEP in children when susceptibility testing indicates that the B. anthracis isolate is susceptible to penicillins. § § Each ciprofloxacin dose should not exceed 500 mg, or 1 g/day. ¶ ¶ In 1991, the American Academy of Pediatrics (AAP) amended the recommendation to allow treatment of young children with tetracyclines for serious infections such as Rocky Mountain spotted fever for which doxycycline might be indicated. Doxycycline is preferred for its twice daily dosage and low incidence of gastrointestinal side effects. * Because of the lack of data on amoxicillin dosages for treating anthrax (and the associated high mortality rate), AAP recommends a higher dosage of 80 mg/kg/day, divided into 3 daily doses; each dose should not exceed 500 mg. If this higher dosage of amoxicillin is used, recipients should be carefully monitored for side effects from long-term treatment. # Antimicrobial Considerations for other Populations For other specific populations, such as older adults or patients with certain underlying medical conditions (i.e., diabetes or renal failure), standard medical practice should be followed. Additional antimicrobial agents that are not FDA approved for treatment or prevention of anthrax but that may be considered include clindamycin, chloramphenicol, rifampin, vancomycin, and other fluoroquinolones. Health-care providers should consult with public health officials when choosing alternative antimicrobial agents and should consider the antimicrobial susceptibility of the associated strains of B. anthracis. # Risk for Exposure to B. anthracis Anthrax exposure is categorized as non-bioterrorism related (i.e., naturally occurring) or bioterrorism related (i.e., intentional). Although naturally occurring anthrax decreased substantially in the United States beginning in 1957 after the initiation of animal vaccination with the Sterne vaccine, persons in certain occupations remain at higher risk for naturally occurring anthrax exposure. In contrast, the risk for bioterrorism-related anthrax is difficult to predict. # General Public Members of the general public, including pregnant or breastfeeding women, are not at risk for exposure to naturally occurring anthrax but might be exposed through a bioterrorism event that would be time limited, sporadic, and most likely geographically limited, as well as difficult to predict, detect, or prevent (9). The target population for a bioterrorism-related release of B. anthracis cannot be predicted, and the risk for exposure cannot be reliably calculated. Once a bioterrorism event occurs, exposure and risk for disease development at the individual level are difficult to identify. No data suggest that the risk for developing anthrax is greater for pregnant women who have been exposed to B. anthracis than for nonpregnant women who have been exposed. Among children, naturally occurring cases and one confirmed case resulting from exposure during the 2001 bioterrorism events have been reported (43,(242)(243)(244). Data are limited regarding the risk for developing anthrax in children after exposure; however, the risk is assumed to be similar to the risk for adults. Like the general public, medical personnel are not at risk for exposure to naturally occurring anthrax but might be exposed through a bioterrorism event. In general, the risk for acquiring anthrax when caring for infected or contaminated patients is thought to be negligible because no person-to-person transmission or secondary cases of anthrax among medical personnel have been documented. Medical personnel are recommended to routinely follow infection control measures to minimize risk for known nosocomial infections (245). # Populations at Risk for occupational Exposure Persons who repeatedly enter potentially contaminated areas should use appropriate personal protective equipment (PPE), which is defined in this report as consisting of a powered airpurifying respirator with full-facepiece and high-efficiency particulate air (HEPA) filters, disposable protective clothing with integral hood and booties, and disposable gloves (246). However, despite the use of appropriate PPE, exposures during repeated encounters with contaminated areas might occur because PPE is not 100% effective, individual work practices might lead to exposure, breaches in PPE and environmental controls might occur, and some breaches might not be detected (247,248). # Persons Handling Animals or Animal Products Improvements in industrial hygiene standards, mechanization of animal processing, animal disease control, and strict importation guidelines have reduced the risk for exposure to anthrax among manufacturing employees working with animals and animal products such as imported animal hides, furs, bone meal, wool, animal hair, or bristles (6,31). § Nevertheless, slaughterhouse workers, butchers (249), and wool and mohair processors might still be at risk for exposure to B. anthracis spores if the industry standards are not upheld. Inhalation and cutaneous anthrax are occupational hazards primarily for workers who process hides, hair (especially from goats), bone and bone products, and wool (31,39,43) and for veterinary, agriculture, and wildlife workers who handle infected animals (48). Domestic exposure to B. anthracis spores might occur during contact with contaminated bone-meal fertilizer (40) or wool yarn (250), while making or playing contaminated goat-skin drums (37,38,44), and during contact with other domestic products (31,41). Occupational exposure to B. anthracis through contact with animals, whether in an agricultural or industrial setting, remains a risk when contact with animals with suspected or confirmed anthrax occurs. However, such human cases are rare (251), and cutaneous anthrax is the primary risk. Exposure to B. anthracis spores in soil is not considered a substantial risk for human inhalation anthrax because spores are bound to heavy soil particles (28). § Sanitary control of animal byproducts (except casings), and hay and straw, offered for entry into the United States, 9 C.F.R. Pt. 95. # Persons Working in Laboratories Multiple types of laboratories might work with B. anthracis, including academic (research), military, veterinary, food-testing, and public health laboratories. Direct and indirect contact with contaminated objects, accidental parenteral inoculation, and generation of aerosolized particles are all potential risks for infection. Certain activities increase the risk for exposure, such as working with large volumes and high concentrations of the organism or performing activities that might result in aerosolization, such as vortexing and centrifugation (252). In 2006, the Association of Public Health Laboratories website provided guidance to address sample transport, receipt, and screening of unknown environmental samples (253). # Persons Working in Postal Facilities The distribution of letters laden with anthrax spores through the U.S. Postal Service (USPS) in 2001 established the mail as a feasible route of exposure. In the event of another attack through the mail, the risk for exposure to aerosolized B. anthracis spores is presumed to be high among staff members in a USPS processing and distribution center who work with mechanical processing equipment that might generate aerosol particles. In response, USPS implemented environmental monitoring to rapidly identify the presence of B. anthracis in these centers. Detection of B. anthracis using these validated USPS monitors would identify a likely exposure (D Sosin, CDC, personal communication, October 2, 2008) and allow prompt initiation of antimicrobial PEP while laboratory verification is being performed. # Military Personnel The personnel who have been determined by DoD to be at risk for exposure to B. anthracis spores include military personnel being deployed to areas designated by DoD as posing a high risk for anthrax exposure, other select military units with unique missions, civilians deemed to be essential emergency personnel in designated locations, and contractors assigned to higher risk areas who are performing mission-essential services (254,255). # Persons Involved in Emergency Response Activities Environmental Investigators and Remediation Workers Conducting remediation of B. anthracis-contaminated areas can pose a risk for exposure to B. anthracis spores. Repeated occupational exposures might occur during environmental investigation or remediation efforts after identification of anthrax cases, regardless of whether the event is bioterrorism related. However, certain features of a bioterrorism event might result in higher risk for exposure during remediation activities. The characteristics of an intentionally dispersed strain of B. anthracis (e.g., antimicrobial resistance or dispersion capabilities) might differ from those of a naturally occurring strain. The level of environmental contamination resulting from intentionally dispersed strains, and therefore the potential for exposure at lower infective doses, might be significantly greater than the level of contamination that would result from naturally occurring strains. Because animal studies indicate that the incubation period for inhalation anthrax might be inversely related to the dose of B. anthracis spores (95,107,108), exposure to higher levels of spores may result in more rapid disease onset, with limited time for initiating PEP. # Emergency and other Responders Persons involved in emergency response activities might include persons who work in police departments, fire departments, hazardous material units, and the National Guard, as well as other government responders. These persons might perform site investigations, respond to suspicious substance reports (also known as white powder incidents), and perform other related activities such as evacuation procedures or other activities critical to the maintenance of infrastructure. The risk for potential exposures associated with responder activities varies depending on the situation. Although the risk for exposure to aerosolized B. anthracis spores is likely low, secondary aerosolization of previously settled spores might occur during the performance of certain activities (63). Because the location and dissemination of the organism as a result of a bioterrorism attack cannot be predicted, the risk for exposure to aerosolized B. anthracis spores in association with emergency response activities cannot be quantified. # Recommended Uses of Anthrax Vaccine AVA may be used 1) via the licensed schedule to prevent infection by priming the immune system before exposure to B. anthracis (pre-event or preexposure vaccination) and 2) after exposure to aerosolized B. anthracis spores under an IND or possibly under an EUA (PEP vaccination) (Tables 2 and 3). Recommendations for the use of AVA differ for pre-event or preexposure vaccination and postexposure vaccination. For pre-event or preexposure vaccination, ACIP recommends 5 IM doses administered at day 0, week 4, and months 6, 12, and 18, followed by annual boosters. To elicit the most substantial and rapid immune response possible among previously unvaccinated persons in a postexposure setting, PEP vaccination should be administered as a 3-dose SC series (at 0, 2, and 4 weeks) in conjunction with a 60-day course of appropriate antimicrobial agents. # Pre-event and Preexposure Vaccination By priming the immune system before exposure to B. anthracis spores, pre-event and preexposure vaccination might provide more protection than antimicrobial agents alone to persons at risk for occupational exposure to B. anthracis, including protection for persons exposed to large inocula, protection if the public health infrastructure cannot ensure immediate availability or timely delivery of postevent antimicrobial agents, and potential benefits if bioengineered strains were released, limiting antimicrobial PEP effectiveness. The potential benefits from pre-event and preexposure vaccination should be weighed against the resource requirements to implement and maintain the vaccination schedule, as well as the potential adverse events associated with vaccination. Decisions for pre-event vaccination should be made based on a calculated risk assessment. In the absence of such an assessment, vaccination may be considered based on an estimated/presumed risk-benefit assessment. Depending on the occupational activities of the vaccine recipient, pre-event or preexposure vaccination might not eliminate the need for appropriate personal protective equipment. # General Public Because the location and timing of a bioterrorism attack cannot be predicted, the risk-benefit profile for pre-event vaccination for the general public is low, and pre-event vaccination is not recommended. Preventing the morbidity and mortality associated with a deliberate release of B. anthracis depends on public vigilance, early detection and diagnosis, appropriate treatment, and rapid administration of PEP. # Special Populations # Pregnant and Breastfeeding Women In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of pregnant women is not recommended and should be deferred until after pregnancy. Breastfeeding is neither a precaution nor a contraindication to vaccination, and vaccination does not need to be deferred in a pre-event setting if the occupation of the breastfeeding mother poses a risk for exposure to B. anthracis. # Children In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of children is not recommended. # Medical Personnel Pre-event vaccination is not recommended for medical personnel. If exposed to aerosolized B. anthracis spores during a bioterrorism event, they should receive PEP in accordance with ACIP recommendations. # Populations at Risk for occupational Exposure Persons Handling Animals or Animal Products Routine preexposure vaccination for persons who handle animals or animal products is recommended only for persons for whom previously discussed standards and restrictions are insufficient to prevent exposure to B. anthracis spores. Preexposure vaccination is not recommended for persons who routinely have contact with animal hide drums or animal hides; other preventive measures are available. Routine vaccination of U.S. veterinarians and animal husbandry technicians is not recommended because of the low incidence of animal anthrax cases in the United States. However, vaccination might be recommended for veterinarians and other persons considered to be at high risk for anthrax exposure if they handle potentially infected animals in research settings or in areas with a high incidence of enzootic anthrax cases. # Laboratorians Preexposure vaccination is recommended for laboratorians at risk for repeated exposure to fully virulent B. anthracis spores, such as those who 1) work with high concentrations of spores with potential for aerosol production; 2) handle environmental samples that might contain powders and are associated with anthrax investigations; 3) routinely work with pure cultures of B. anthracis; 4) frequently work in spore-contaminated areas after a bioterrorism attack; or 5) work in other settings where repeated exposures to B. anthracis aerosols may occur. # MMWR July 23, 2010 # Persons Working in Postal Processing Facilities Because of biodetection systems in postal processing centers, contamination of mail with B. anthracis spores is likely to be detected rapidly, allowing postexposure therapy to be initiated immediately. Therefore, persons who work in these facilities are not recommended to receive pre-event vaccination. # Military Personnel Military personnel determined by DoD to have a calculable risk for exposure to aerosolized B. anthracis spores are recommended to receive preexposure vaccination. DoD has exclusionary criteria for employees, including an exclusion for pre-event vaccination of pregnant women (256,257). # Environmental Investigators and Remediation Workers Vaccination is recommended for persons who, as part of their occupation, might repeatedly enter areas contaminated with B. anthracis spores. # Emergency and other Responders Emergency and other responders are not recommended to receive routine pre-event anthrax vaccination because of the lack of a calculable risk assessment. However, responder units engaged in response activities that might lead to exposure to aerosolized B. anthracis spores may offer their workers voluntary pre-event vaccination. The vaccination program should be carried out under the direction of a comprehensive occupational health and safety program. # Delayed Doses Available data on AVA dosages suggest that increasing the interval between doses does not decrease the ultimate serologic response achieved or adversely affect the safety profile. Therefore, as with other vaccines, interruption of the vaccination schedule does not require restarting the entire series or the addition of extra doses (199). # PEP PEP should be used for previously unvaccinated persons after exposure to aerosolized B. anthracis spores, whether the exposure is naturally occurring, occupationally related, or intentional. To elicit the most substantial and rapid immune response possible for previously unvaccinated persons in a postexposure setting, vaccination should be administered as recommended in conjunction with appropriate antimicrobial agents (Tables 1 and 2). # PEP After Inhalation Exposure General Adult Population ACIP recommends a postexposure regimen of 60 days of appropriate antimicrobial prophylaxis combined with 3 SC doses of AVA (administered at 0, 2, and 4 weeks postexposure) as the most effective protection against inhalation anthrax for previously unvaccinated persons aged ≥18 years who have been exposed to aerosolized B. anthracis spores. After exposure to aerosolized B. anthracis spores, antimicrobial therapy should be initiated as soon as possible. Ideally, the first dose of vaccine should be administered within 10 days. Because AVA is not licensed for postexposure use, the vaccine will likely be made available either through an IND or an EUA during a public health emergency. In general, the peak serologic response to anthrax vaccine occurs 10-14 days after the third dose. To ensure continued protection, persons for whom vaccination has been delayed should extend antimicrobial use to 14 days after the third dose, even though this practice might result in use of antimicrobials for >60 days. Antimicrobials should not be used for <60 days in previously unvaccinated persons who have been exposed to aerosolized B. anthracis spores. # Pregnant Women In a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores, pregnancy is neither a precaution nor a contraindication to PEP. Pregnant women at risk for inhalation anthrax should receive AVA and 60 days of antimicrobial therapy as described. # Breastfeeding Women In a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores, breastfeeding remains neither a precaution nor a contraindication to PEP. Breastfeeding women at risk for inhalation anthrax should receive AVA and 60 days of antimicrobial therapy as described. # Children The use of AVA in children is not contraindicated in a postevent setting that poses a high risk for exposure to aerosolized B. anthracis spores. During such an event, public health authorities will determine whether, under the existing IND protocol, to offer vaccine to children aged 0-17 years. Under this IND protocol, 3 doses of vaccine would be administered in conjunction with 60 days of appropriate antimicrobial therapy. # PEP After Repeated occupational Exposures The combination of pre-event vaccine and appropriate PPE effectively protects fully vaccinated persons who work in occupations that might result in repeated exposure to aerosolized B. anthracis spores (Table 4). Antimicrobial PEP is not needed for fully vaccinated workers who wear appropriate PPE while working in environments contaminated with B. anthracis spores unless the PPE is disrupted. However, fully vaccinated workers who prefer additional protection may consider antimicrobial PEP under the direction of their occupational health program A 30-day course of antimicrobial PEP is recommended for partially vaccinated workers (Table 4), fully vaccinated workers who do not wear PPE, and fully vaccinated workers whose PPE has been disrupted; these workers should continue with their licensed vaccination regimen. ¶ Because respiratory protection can be disrupted in numerous ways (e.g., a face-seal leak in a respirator or not wearing personal protective equipment when entering an area presumed to be uncontaminated that is later determined to be contaminated) and such disruptions are not always detected, the threshold for assuming such a disruption has occurred should be extremely low. ** Fully vaccinated workers have completed the 5-dose IM series and have received all annual booster doses indicated by the licensed vaccination schedule. A 60-day course of antimicrobial PEP is recommended for previously unvaccinated workers. These workers also should begin receiving AVA as soon as possible using the PEP schedule of 3 SC doses. # PEP After naturally occurring Cutaneous or Gastrointestinal Exposure Vaccination is not recommended after cutaneous or gastrointestinal exposures that pose no risk for inhalation exposure. When a naturally occurring cutaneous exposure occurs, appropriate medical and public health personnel should be notified, and affected persons should be monitored for development of a spot, pimple, or boil-like lesion, especially in the exposed areas. For persons who experience a naturally occurring gastrointestinal exposure, such those who eat meat from an undercooked carcass of an anthrax-infected animal, antimicrobial PEP for 7-14 days may be considered. # Contraindication and Precautions for Use of AVA The following contraindication and precautions are relevant for both preexposure and postexposure settings (137). # Contraindication Although anaphylaxis after anthrax vaccination is extremely rare and no anaphylaxis deaths associated with AVA have been reported (CDC, unpublished data, 2010), an anaphylactic reaction can be life-threatening. Therefore, AVA is contraindicated for persons who have experienced an anaphylactic reaction after a previous dose of AVA or any of the vaccine components. # Precautions # Latex allergy: • Because the vaccine vial stopper contains dry, natural rubber, caution should be used when administering the vaccine to persons with a latex allergy (137). Epinephrine solution (1:1000) should be available for immediate use in the event that an anaphylactic reaction occurs. # History of anthrax disease: • A history of anthrax disease might increase the potential for severe local adverse reactions after AVA administration (137). # Impaired immune response: • Patients with an impaired immune response might not be adequately immunized after administration of AVA (137). Moderate or severe acute illness: • In a standard preexposure vaccination program, vaccination of persons with moderate or severe acute illness should be postponed until after recovery (137). In a postevent setting, the risks of administering vaccine to a person who has been exposed to anthrax but has moderate or severe acute illness should be weighed against the benefits of vaccination. Vaccine may be administered to persons who have a mild illness with or without a low-grade fever. # Reporting Adverse Events Adverse events that occur after administration of anthrax vaccine should be reported to VAERS, regardless of whether the reporter considers the vaccine to be the cause of the event. Information about VAERS and how to report vaccine adverse events is available at http://vaers.hhs.gov. Adverse events that occur after administration of antimicrobial agents should be reported to the FDA MedWatch program at http://www.fda.gov/medwatch. # Current and Future Research Research priorities for future studies on the currently licensed anthrax vaccine should include immunogenicity; additional evaluations of the dosing schedule (including the maximum time between boosters); additional long-term human safety studies; the number of vaccine doses required for PEP; the optimal duration of antimicrobial use in postexposure settings; antimicrobial susceptibility and treatment studies; optimal alternative antimicrobial agents for children, older adults (aged >65 years), and pregnant women; and the safety of anthrax vaccine in clinical toxicology studies among pregnant animals. Future research should include the groups for whom AVA is currently licensed, as well as children, older adults, and pregnant women. These research questions also should be addressed as new potential anthrax vaccines are identified and considered for use in humans. # Research on AVA and Future Anthrax Vaccines: Immunogenicity, Schedule, and Route Research is ongoing to address priority topics, including identification of quantitative immune correlates of protection in relevant animal species and defining the quantitative relationship between the vaccine-elicited immune response in these animal species and humans. Completion of the ongoing AVRP clinical trial should provide a definitive clinical evaluation of the effects of reducing the number of AVA doses (140). Information regarding the efficacy and safety of AVA in children and older adults also is needed, as is additional information regarding the safety and efficacy of AVA when used during pregnancy. Future research should include trials to obtain this information and to develop dosage recommendations for children. In addition, research to further develop both the recombinant PA (rPA) vaccines and the next generation of anthrax vaccines should continue. # Postexposure Prophylaxis Studies in animals indicate that the combination of antimicrobials and vaccination is very effective for preventing systemic B. anthracis infection. When using a combined approach the immune system benefits from the acute-phase antimicrobial protection provided against germinating spores and vegetative cells of B. anthracis while gaining enough time to complete immunological priming and establish anamnestic capability (i.e., immunological memory) (93). The effectiveness of vaccination might allow the antimicrobial course to be shortened from the recommended 60 days to as few as 14 days (102). Definitive, pivotal human studies to evaluate the magnitude and duration of the human immune response to anthrax vaccines when combined with antimicrobials have not been conducted. Additional research is needed to determine the optimal duration of antimicrobial administration in conjunction with the optimal doses of vaccine. # Long-term Safety of AVA The FDA final order for use of AVA emphasizes the need to continue postmarketing safety studies (135), and the IOM reports document the need for additional long-term follow-up of vaccine recipients (152,169). VAU continues to conduct research to address these issues through a combination of studies, including continued screening of the VAERS database for identification of potential long-term adverse events, hypothesis testing research studies using the DMSS database (170), and assessments of new safety signals identified from VAERS or other sources. # Alternative Anthrax Vaccines The rPA vaccines contain the purified protein of an avirulent, non-spore-forming strain of B. anthracis (258). Although recent phase 1 dose-escalation studies comparing rPA with AVA for reactogenicity, immunogenicity, and dosing range of rPA have been conducted (258,259), problems with vaccine formulation have delayed the start of phase 3 trials. One formulation demonstrated that immune responses of participants receiving rPA with adjuvant were not statistically significantly different from the responses of those receiving AVA (258). Evidence indicates that rPA candidate vaccines might cause fewer local adverse events than AVA administered subcutaneously (259). However, licensure of new anthrax vaccine will likely not occur for several years.	None	None
2308c46f6e09075189720fbd8a62a9beecce2931	cdc	None	INSIDE: Continuing Education Examination depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Improving preconception health can result in improved reproductive health outcomes, with potential for reducing societal costs as well (1)(2)(3)(4). Preconception care aims to promote the health of women of reproductive age before conception and thereby improve pregnancy-related outcomes (5)(6)(7). Therefore, the goals of the 10 recommendations in this report are to improve a woman's health before conception, whether before a first or a subsequent pregnancy. The recommendations are 1) individual responsibility across the lifespan, 2) consumer awareness, 3) preventive visits 4) interventions for identified risks, 5) interconception care, 6) prepregnancy checkup, 7) health insurance coverage for women with low incomes, 8) public health programs and strategies, 9) research, and 10) monitoring improvements. Since 1996, progress in the United States to improve pregnancy outcomes, including low birthweight, premature birth, and infant mortality has slowed, in part, because of inconsistent delivery and implementation of interventions before pregnancy to detect, treat, and help women modify behaviors, health conditions, and risk factors that contribute to adverse maternal and infant outcomes (8). This report discusses several interventions that, if implemented before pregnancy, can improve pregnancy outcomes for women and infants. However, millions of women and couples do not receive such interventions and services (8). Childbearing is a common experience among women in the United States. In 2000, an estimated 62 million U.S. women were of childbearing age (aged 15-44 years), distributed in approximately equal segments across the age groups of 15-24, 25-34, and 35-44 years (9). By age 25 years, approximately half of all women in the United States have experienced at least one birth, and approximately 85% of all women in the United States have given birth by age 44 years. In 2003, the fertility rate was 66 live births per 1,000 women aged 15-44 years, with highest rates among women aged 25-29 years (114 per 1,000) and lowest rates among women aged >44 years (0.5 per 1,000). A similar age pattern has been observed within racial/ethnic populations, although women aged <25 years who are non-Hispanic black and Native American had higher fertility rates than non-Hispanic whites and Asian/ Pacific Islanders. Hispanic women have the highest fertility rates overall and within each age group (10). In a 2004 survey of women aged 18-44 years, 84% had a health-care visit during the previous year, and slightly more than half (55%) of women of reproductive age obtained preventive health services in any given year, which are opportunities to deliver preconception care (11). Because approximately one third to half of women have more than one primary care provider (i.e., generally a family physician or internal medicine physician and an obstetrician/ gynecologist) (12), all providers who routinely treat women for well-woman examinations or other routine visits play an important role in improving preconception health. However, only approximately one of six obstetrician/gynecologists or family physicians had provided preconception care to the majority of the women for whom they provided prenatal care (13). Another study reported that mothers frequently interacted with pediatricians after the birth of one child and before conception of another, which affords another opportunity to promote preconception health care (14). Community health centers and other Federally Qualified Health Centers (FQHC), including primary care and prenatal care, deliver services to approximately 4.5 million women of childbearing age each year (15). These centers can be used to provide preconception care to women with low incomes (income <200% of the federal poverty level) and with no health insurance. This report provides recommendations to improve both preconception health and preconception health care. Several of the medical conditions, personal behaviors, psychosocial risks, and environmental exposures associated with negative pregnancy outcomes can be identified and modified before conception through clinical interventions. For certain conditions, opportunities for preventive interventions occur only before conception. Establishing preconception health screening as part of routine care for women of reproductive age has been discussed in previously published reports (2,5,6,7,13,14). However better health care alone will not achieve optimal improvements in women's preconception health and reproductive outcomes. Health promotion activities to modify personal knowledge and attitudes and behaviors related to reproductive risk factors and the use of a reproductive life plan for women and couples also have been proposed (16,17). A reproductive health plan reflects a person's intentions regarding the number and timing of pregnancies in the context of their personal values and life goals. This health plan might increase the number of planned pregnancies and encourage persons to address risk behaviors before conception, reducing the risk for adverse outcomes for both the mother and the infant. The recommendations should be used by consumers, clinical care providers, public health professionals, researchers, policy makers, and others concerned with the health of women, children, and families. Federal, state, and local public health agencies can play a vital role in translating these recommendations into projects, educational materials, and programs designed to improve preconception health. Primary care providers serving women of reproductive age, including obstetrician/gynecologists, family physicians, nurse midwives, nurse practitioners, and others working in various clinical settings, have an equally critical role to play in implementing these recommendations. CDC developed these recommendations by 1) reviewing published research; 2) convening the CDC/ASTDR Preconception Care Work Group, representing 22 programs; 3) evaluating presentations of best and emerging practice models at the National Summit on Preconception Care in 2005; and 4) convening the Select Panel on Preconception Care (SPPC), comprised of subject matter specialists on obstetrics and gynecology, nursing, public health, midwifery, epidemiology, dentistry, family practice, pediatrics, and other disciplines. Various databases (e.g., PubMed ® ) were searched to iden-tify published studies for review. Search parameters included preconception care, birth outcomes, reproductive health, and women's health. The reports were reviewed by the SPPC of specialists. These recommendations reflect the research, professional opinion, practice in medicine, public health, and related fields, which are sufficient to guide changes in program, practice, and policy. SPPC reviewed evidence to determine the effectiveness of certain interventions of preconception care (e.g., folic acid to prevent neural tube defects and cessation of alcohol use) and identified missed opportunities for dissemination of preconception information. Implementation of these effective interventions can contribute to the health of thousands of women each year. These recommendations are a strategic plan to improve preconception health through clinical care, individual behavior change, community-based public health programs, and social marketing campaigns to change consumer knowledge and attitudes and practices. In addition, they are designed to increase research knowledge related to preconception health and care and to improve reproductive health outcomes for all women and couples. Policy changes at the local, state, and federal levels will be necessary to support several of these recommendations. These policies will address changes in access, payment, and types of services available. Four goals were established for achieving these recommendations: 1) improve the knowledge and attitudes and behaviors of men and women related to preconception health; 2) assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health; 3) reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children; and 4) reduce the disparities in adverse pregnancy outcomes. # Preconception Health and Care Preconception care is recognized as a critical component of health care for women of reproductive age (1)(2)(3)(4)(5)7,16,17,(19)(20)(21)(22)(23)(24)(25). The main goal of preconception care is to provide health promotion, screening, and interventions for women of reproductive age to reduce risk factors that might affect future pregnancies (7,16,(22)(23)(24)(25). Preconception care is part of a larger health-care model that results in healthier women, infants, and families (7,16,(26)(27)(28)(29). A substantial number of definitions for preconception care have been used (2)(3)(4)(5)16,19,(30)(31)(32)(33). On the basis of previous guidelines and recommendations, SPPC developed a refined definition for preconception care. Preconception care is de-fined as a set of interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through prevention and management. Certain steps should be taken before conception or early in pregnancy to have a maximal effect on health outcomes. Preconception care is more than a single visit to a health-care provider and less than all well-woman care, as defined by including the full scope of preventive and primary care services for women before a first pregnancy or between pregnancies (i.e., commonly known as interconception care). Improving preconception health and pregnancy outcomes will require more than effective clinical care for women. Changes in the knowledge and attitudes and behaviors related to reproductive health among both men and women need to be made to improve preconception health. Despite several health promotion campaigns aimed at reducing smoking, misuse of alcohol, intimate partner violence, obesity, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), reduction of vaccine-preventable diseases, and exposure to occupational hazards, the majority of U.S. adults are not aware of how these and other health and lifestyle factors influence reproductive health and childbearing (34,35). Preconception health promotion, therefore, should focus on a general awareness among men and women regarding reproductive health and risks to childbearing (26). # Healthy People 2000/2010 Objectives for Improving Preconception Health and Guidelines for Preconception Care A Healthy People 2000 objective (objective 14.3) is for 60% of primary care physicians to provide age-appropriate preconception care (36). This objective was deleted from Healthy People 2010 because it was not being measured. Although no specific objective for preconception exists, several of those specified in Healthy People 2010 are relevant to preconception health (37,38). The Institute of Medicine, several national committees, and a substantial number of professional organizations have established guidelines and recommendations regarding the importance and content of preconception health care (1,3,4,(30)(31)(32)(33). The primary objective of these reports is to improve the health of women, children, and families. The previously issued evidence-based guidelines for preconception care have been summarized and are the foundation for the recommendations developed by SPPC. The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) have classified the main components of preconception care into four categories of interventions: physical assessment, risk screening, vaccinations, and counseling. Eight areas of risk screening are 1) reproductive awareness; 2) environmental toxins and teratogens; 3) nutrition and folic acid; 4) genetics; 5) substance use, including tobacco and alcohol; 6) medical conditions and medications; 7) infectious diseases and vaccination; and 8) psychosocial concerns (e.g., depression or violence) (3,24,(26)(27)(28)(29)(30)(31)33). Preconception care should be an essential part of primary and preventive care, rather than an isolated visit (4,5,(21)(22)(23)(24)(25)(26)32,39,40). Whereas a prepregnancy planning visit in the months before conception has been recommended (3,19,31), improving preconception health will require changes in the process of care, including the types of screening and riskreduction interventions offered to women of childbearing age. Guidelines for Perinatal Care, jointly issued by AAP and ACOG, has recommended that all health encounters during a woman's reproductive years, particularly those that are a part of preconception care, should include counseling on appropriate medical care and behavior to optimize pregnancy outcomes (41). Recommendations from these organizations are analogous to the risk screening recommended by the American Heart Association for cardiovascular disease (42). Several national organizations have recommended the routine delivery of preconception care. For example, the March of Dimes has recommended that the key physician/primary care provider and the obstetrician/gynecologist take advantage of every health encounter to provide preconception care and risk reduction before and between conceptions, the time when health encounters can improve health status (39). # Preconception Risks Associated with Adverse Pregnancy Outcomes Risk factors for adverse outcomes among women and infants occur during the preconception period and are characterized by the need to start, and sometimes finish, intervention(s) before conception occurs. In a systematic review, researchers (43) discussed published reports that identified a list of risk factors for which preconception care (i.e., risk assessment, health promotion, and interventions) can be effective. Women of childbearing age suffer from various chronic conditions and are exposed to (or consume) substances that can have an adverse effect on pregnancy outcomes, leading to pregnancy loss, infant death, birth defects, or other complications for mothers and infants. For example, in 2002, approximately 6% of adult women aged 18-44 years had asthma, 50% were overweight or obese, 3% had cardiac disease, 3% were hypertensive, 9% had diabetes, and 1% had thyroid disorder (44). Dental caries and other oral diseases also are common (>80% of women aged 20-39 years) and associated with complications for women and infants. In addition to having chronic diseases, a substantial proportion of women who become pregnant engage in high-risk behaviors and contribute to adverse pregnancy outcomes. In 2003, a total of 11% of pregnant women smoked during pregnancy, a risk factor for low birthweight (10), and 10% of pregnant women and 55% of women at risk for getting pregnant (i.e., those not using contraception or using ineffective contraceptive methods or using effective contraceptive methods inconsistently) consumed alcohol, a risk for fetal alcohol syndrome (45). Certain women also continued to engage in high-risk sexual behavior, potentially exposing themselves to sexually transmitted diseases (STDs), including HIV (46). Although a smaller proportion of women used illicit drugs, this high-risk behavior has been associated with adverse outcomes. These behaviors often co-occur, therefore, compounding the risk for adverse outcomes for certain groups. Immunization for adults and infants is critical for preventing infectious diseases (e.g., influenza and pertussis). Data from the Pregnancy Risk Assessment and Monitoring System (PRAMS) in four states (i.e., Maine, Michigan, Oklahoma, and West Virginia) indicated that 38% of mothers who planned pregnancies and an additional 30% who did not plan pregnancies had one or more indications for preconception counseling, including use of tobacco or alcohol, being underweight, or delayed initiation of prenatal care (47). In Minnesota and Washington, data from a telephone survey of women revealed that pregnancy intention was associated with health behaviors before pregnancy that might influence pregnancy outcome, with the most marked differences in smoking and vitamin use (48). Preconception health care is critical because several risk behaviors and exposures affect fetal development and subsequent outcomes. The greatest effect occurs early in pregnancy, often before women enter prenatal care or even know that they are pregnant (4,(23)(24)(25)49). For example, for optimal effect on reducing the risk for neural tube defects, folic acid supplementation should start at least 3 months before conception (50)(51)(52). During the first weeks (before 52 days' gestation) of pregnancy, exposure to alcohol, tobacco, and other drugs; lack of essential vitamins (e.g., folic acid); and workplace hazards can adversely affect fetal development and results in pregnancy complications and poor outcomes for both the mother and infant (45,(53)(54)(55)(56)(57)(58). This evidence demonstrates the potential impact of preconception care on the health of women and their infants. Social determinants of women's health also play a role in pregnancy outcomes. The health status of minority women with low incomes contributes to persistent, and sometimes increasing, disparities in birth outcomes. In one study, the reduced overall health status (including poorer physical and emotional health) of women with low income during the month before pregnancy was associated with an increased risk for preterm labor (59). Socioeconomic status directly and indirectly influences three major determinants of health: healthcare access, environmental exposure, and health behavior (60,61). Racial inequalities in access to effective treatment also influence these determinants of pregnancy outcomes for women and infants (62)(63)(64). The following selected preconception risk factors for adverse pregnancy outcomes and evidence for the effectiveness of preconception care have been used to develop clinical practice guidelines (e.g., AAP and ACOG). - (105)(106)(107)(108)(109). Appropriate weight loss and nutritional intake before pregnancy reduces these risks. - Oral anticoagulant. Warfarin, which is used for the control of blood clotting, has been demonstrated to be a teratogen. To avoid exposure to warfarin during early pregnancy, medications can be changed to a nonteratogenic anticoagulant before the onset of pregnancy (110-112). - STD. Chlamydia trachomatis and Neisseria gonorrhoeae have been strongly associated with ectopic pregnancy, infertility, and chronic pelvic pain. STDs during pregnancy might result in fetal death or substantial physical and developmental disabilities, including mental retardation and blindness (113,114). Early screening and treatment prevents these adverse outcomes. - Smoking. Preterm birth, low birthweight, and other adverse perinatal outcomes associated with maternal smoking in pregnancy can be prevented if women stop smoking before or during early pregnancy. Because only 20% of women successfully control tobacco dependence during pregnancy, cessation of smoking is recommended before pregnancy (115)(116)(117)(118). Several providers and maternal and child health researchers have recommended that health risks and behaviors be addressed during any encounter with the health-care system because approximately half of pregnancies in the United States are unintended (20,22,27,119,120). One clinical trial has indicated that provision of preconception care can increase pregnancy planning and intention (121). This finding is vital because studies have consistently demonstrated that planned pregnancies typically have improved outcomes for both women and infants. # Preconception Prevention and Intervention Since 1987, several reviews of published reports have assessed the evidence and documented the effectiveness for specific preconception interventions (2,5,33,43). A systematic review of 21 research trials published during the 1990s have strengthened the evidence base for preconception care in particular areas (e.g., folic acid deficiency, maternal PKU, and oral anticoagulant; 43). The effectiveness of several interventions that address the risk factors for adverse outcomes (19,33,43) have been documented, including folic acid supplementation (51,52,(122)(123)(124)(125); appropriate management of hyperglycemia (126)(127)(128)(129)(130)(131); rubella, influenza, and hepatitis vaccination; low phenylalanine diet (132)(133)(134); and provision of antiretroviral medications to reduce the risk for mother-to-child HIV transmission (97). Interventions for smoking and alcohol cessation (135)(136)(137)(138)(139) have been demonstrated to be effective in certain populations; however, they have been less effective with persons at highest risk (e.g., injection-drug users and polysubstance users). A list of core interventions exist that are part of preconception care services. These interventions are risk-specific; providers can screen and provide appropriate interventions for persons who need them. However, the best evidence for the effectiveness of these specific components of preconception care has been documented when the focus of delivery was on a single risk behavior and accompanying intervention, rather than delivery of multiple interventions. Because of the direct links between a mother's oral health and her offspring's risk for dental caries, dental interventions can reduce the risk for prematurity and low birthweight (140)(141)(142)(143). Evidence supporting interventions to reduce motherto-child transmission of cariogenic bacteria supports recommendations for the appropriate use of fluorides and dietary control to reduce maternal salivary reservoirs of cariogenic bacteria, particularly for women who have experienced high rates of dental caries (140). Interventions that address multiple pregnancy-related risk behaviors simultaneously have not been systematically evaluated and are less commonly delivered. The U.S. Preventive Services Task Force (USPSTF) evaluated the effectiveness of interventions related to smoking, alcohol misuse, and obesity, based on studies of interventions delivered in primary care settings that were not complicated by the additional delivery of multiple components of preconception care (69,70,(144)(145)(146)(147). These effective methods for intervention (e.g., the Five As ) for smoking cessation and brief counseling interventions to reduce alcohol misuse, as identified by USPSTF, provide models for the delivery of multiple interventions that can be adapted and tested (69,70). One study has reported the effectiveness of comprehensive preconception care; however, the findings have limited applicability for the implementation of preconception health-care services in the United States because the study was conducted in Hungary (147). One priority for preconception care activities is to ensure that evidence-based interventions are implemented to further improve infant and maternal pregnancy outcomes among women living with chronic conditions. Clinical practice guidelines (CPGs) for preconception care for specific maternal chronic health conditions have been developed by several national health professional groups (25)(26)(27)(28). For example, the American Diabetes Association has developed CPGs that should be followed before pregnancy for women with diabetes (81). The American Association of Clinical Endocrinologists has developed CPGs for women with hypothyroidism who are attempting to conceive (100). CPGs have also been developed for women being treated with teratogenic medications to guide the transition to safer medications. CPGs for women considering pregnancy and who are using antiepileptic drugs or oral anticoagulants have been developed by the American Academy of Neurology ( 77) and the American Heart Association/American College of Cardiologists (78), respectively. Whereas the evidence supporting specific interventions and the importance of intervening before pregnancy are definitive, limited evidence is available to determine effective methods for delivering preconception care and improving preconception health. Only a limited number of studies regarding effectiveness of interventions have been tested for increasing preconception screening, counseling, and intervention in primary care settings (121,148,149). In one randomized clinical trial, preconception risk factors were identified among women who sought care at a hospital primary care clinic for a pregnancy test. In this trial, an average of nine risk factors per woman was identified at the time of a negative pregnancy test. However, notifying women and their clinicians of identified preconception risks did not improve intervention rates (148). In another study in which didactic lectures and chart cues were used, significant increases occurred in risk screening for medical risk factors (15%-44%), medications (10%-30%), domestic violence (10%-57%), and nutrition (9%-50%) among nonpregnant women who attended an innercity hospital gynecologic clinic. However, intervention rates and provider attitudes toward preconception care did not change substantially (149). A prospective study of the effect of preconception health promotion on intendedness of pregnancy revealed that women in a family planning clinic who had received the intervention (22%) during routine visits were more likely to report intended pregnancies than those patients in the same clinic who were not exposed to the intervention (15) (121). A limited number of studies have assessed the best methods for integrating interventions to achieve maximum impact and optimize the use of limited resources. As with other types of preventive care services, time constraints limit physicians' ability to deliver health promotion interventions (144). Preconception care interventions can potentially be integrated into a limited number of model visits to focus on specific content at different visits, as is done for well-child care (150). Integrated and coordinated care services might also provide additional support to improve health outcomes. For example, an evaluation of the quality of care in the National Centers of Excellence in Women's Health indicated that women served in these centers, compared with community samples, received more clinical preventive services and had higher satisfaction levels (151). Another approach (e.g., self-management) to integrated service of delivery has been illustrated in CDC's recommendations in Strategies for Reducing Morbidity and Mortality from Diabetes Through Health-Care System Interventions and Diabetes Self-Management Education in Community Settings: A Report on Recommendations of the Task Force on Community Preventive Services (152). HIV intervention efforts also have suggested that integrated interventions address substance use and reduce sexual risk behaviors simultaneously. The purpose of preconception care is to deliver risk screening, health promotion, and effective interventions as a part of routine health care. In the United States, this approach is the standard used to achieve prevention of vaccine-preventable disease, heart disease, diabetes, and other chronic conditions. This approach is similar to well-child care, prenatal care, and adult wellness care in which studies have demonstrated the effectiveness of individual components rather than the effectiveness of combined interventions. However, effectiveness depends on ongoing monitoring of health status with interventions. Preconception care should be tailored to meet the needs of the individual woman. Because preconception care needs to be provided across the lifespan and not during only one visit, certain recommendations will be more relevant to women at different life stages and with varying levels of risk. Health promotion, risk screening, and interventions are different for a young woman who has never experienced pregnancy than for a woman aged 35 years who has had three children. Women with chronic diseases, previous pregnancy complications, or behavioral risk factors might need more intensive interventions. Such variations also place constraints on how interventions can and should be integrated. # Context and Frame Work for Recommendations The recommendations are designed to promote optimal health throughout the lifespan for women, children, and families by using both clinical care and population-focused public health strategies. In this report, the approach to promoting preconception health is not a single clinical visit but a process of care and interventions designed to address the needs of women during the different stages of reproductive life. SPPC has encouraged the use of a broad definition of prenatal care that includes ongoing preconception interventions, the addition of a prepregnancy visit, multiple postpartum visits, and the currently recommended prenatal care visits. Preconception care offers health services that allow women to maintain optimal health for themselves, choose the number and spacing of their pregnancies and, when desired, prepare for a healthy baby. Interventions and health care that occur before and between pregnancies are included in this report. This review identified areas for which further research is needed (43). Increasing evidence-based research of clinical and public health interventions by using both qualitative and quantitative methods is essential to the fulfillment of these recommendations. Each of the 10 recommendations has specific action steps that can be implemented in the next 2-5 years. Increasing access to and use of preconception care will not occur immediately; diffusion of innovation theory demonstrates how slowly concepts and best practices are typically disseminated (153,154). The action steps recommend revision of professional standards of care, modification of provider behaviors, development of effective health promotion messages, changes in consumer behavior, and adjustments to payment mechanisms. In addition, the recommendations emphasize individual behavior and responsibility for improving preconception health and identify specific evidence-based strategies for modifying individual knowledge and attitudes and behaviors across the lifespan. The recommendations promote changes in clinical care, public health programs at the federal, state, and local levels, and other community-based programs. For example, quality improvement strategies, commonly used today in clinical practice, might be used to modify provider knowledge and attitudes and behaviors. In addition to participation among traditional partners in public health interventions, improving preconception health will require increased involvement from partners in various sectors (e.g., education, housing, urban planning, and environmental health). These partners should be included as part of the comprehensive solution to improve women's health and the health of families. Approaches to improve surveillance, performance monitoring, and results accountability have been recom-mended along with strategies to integrate care, develop complementary approaches, and reduce duplication of activities among different professional and programmatic stakeholders. The risk and the burden of disease is unequally distributed, and a small number of women experience the majority of the pregnancy-related morbidity and mortality, which suggests that a two-step approach to implementing interventions would be beneficial. The first step would target women at highest risk (whether the risks are biologic or social) to reduce morbidity and mortality. The second step would aim to improve preconception health for all women of reproductive age, regardless of risk status. The recommendations emphasize targeting interventions for groups of women with known risks and conditions (e.g., those with previous poor pregnancy outcomes or chronic conditions). Culturally and linguistically appropriate systems of care are needed to ensure maximal use and impact of preconception health-care services. By increasing the acceptability, effectiveness, and impact of the health-care system through these changes, persons involved in improving preconception health care have the opportunity to address and reduce health disparities. The recommendations are a starting point to make comprehensive preconception care a standard of care in the United States and to provide a more universal, comprehensive, evidence-based model of preconception care. The recommendations will promote the development and practice of preconception care that will be flexible to meet persons' changing reproductive care needs and address risks throughout their lifespan. # How the Recommendations were Developed The recommendations were developed through the collaborative efforts of CDC and external partners to 1) target life stages in reproductive-aged women; 2) encourage special interest groups to collaborate to achieve common goals; 3) encourage scientific and public health collaboration; and 4) address health impact, public health systems, efficiency, and effectiveness. During 2003, a review of studies published regarding maternal and child health and preconception care was conducted by CDC to assess preconception care. The CDC work group also discussed opportunities for collaboration across programs. Several CDC programs in the work group had previously identified specific interventions with scientific evidence which, if delivered before conception, would promote preconception health and improve pregnancy-related outcomes. These programs recognized the need to integrate these interventions with similar services to improve coverage, effectiveness, access, efficiency, and ultimately maternal and infant pregnancy outcomes. The need for preconception health promotion and care was identified as a critical public health topic by CDC and partners. As a result, a broader working group of national organizations involved in preconception health issues were established (Appendix). In November 2004, the CDC work group and representatives of 16 external organizations discussed the evidence supporting preconception care to determine the steps that can be taken to develop national recommendations. The consensus of the participants was that a larger meeting on preconception care and an interdisciplinary panel of specialists should be convened in 2005. A steering committee and planning committee were established (including representatives from CDC and external partners) to plan for a national summit and to bring together a group of specialists with experience in data, practice, and policy issues related to preconception health. In June 2005, a national summit on preconception care was convened to gather information concerning promising practice models. The summit agenda was developed based on 68 submitted abstracts and reflected various preconception project models, finance approaches, and research questions (CDC, unpublished data, 2005). In conjunction with the summit, CDC convened SPPC, which included various subject matter specialists and representatives from national organizations concerned about the health of women, infants, and families. A Delphi technique was used to identify subject matter specialists to serve on SPPC. SPPC discussed recommendations regarding clinical practice, public health/community programs, research/data, and policy/finance. Initial recommendations were sent to the CDC work group, panel members, and additional subject matter specialists from academic and professional backgrounds for comment and review. Reviewers shared their comments in writing or as part of a series of conference calls convened by the SPPC steering committee. # Recommendations to Improve Preconception Health Ten recommendations were developed for improving preconception health through changes in consumer knowledge, clinical practice, public health programs, health-care financing, and data and research activities. Each recommendation has specific action steps. If each action step is implemented, benefits might be observed within 2-5 years, which would help achieve the Healthy People 2010 objectives to improve maternal and child health outcomes. The recommendations are aimed at achieving four goals, based on personal health outcomes. Goal 1. Improve the knowledge and attitudes and behaviors of men and women related to preconception health. Goal 2. Assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health. Goal 3. Reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children. Goal 4. Reduce the disparities in adverse pregnancy outcomes. The recommendations are a strategic plan for improving the health of women, their children, and their families and are based on existing knowledge and evidence-based practice. Improving preconception health among the estimated 62 million women of childbearing age (9) will require a multistrategy, action-oriented initiative. The recommendations, which are not prioritized, should be used by consumers, public health and clinical providers, researchers, and policy makers. Therefore, the recommendations should be implemented simultaneously. In the action steps, persons, public health and clinical providers, communities, governments (i.e., local, state, and federal), and professional organizations all have roles. Finally, these recommendations are designed to reduce disparities in maternal and infant health by improving the preconception health of women and men. # Recommendations Recommendation 1. Individual Responsibility Across the Lifespan. Each woman, man, and couple should be encouraged to have a reproductive life plan. The target population for preconception health promotion is women, from menarche to menopause, who are capable of having children, even if they do not intend to conceive. To reach such a broad group, a lifespan perspective is needed (3,17,20), which is commonly used in efforts to reduce chronic diseases, particularly cardiovascular disease. For example, persons are encouraged to consider the role of genetic and dietary factors in determining their risk for high cholesterol and to modify their behaviors according to cumulative individual risks (e.g., changes in diet, exercise, or medications) (155). Similarly, a lifespan approach can be used to focus in-dividual attention on reproductive health to reduce unintended pregnancies, age-related infertility, fetal exposures to teratogens, and to improve women's health and pregnancy outcomes (20). Certain researchers, providers, and health-care advocates have suggested developing a reproductive health life plan for young women and couples as they enter their reproductive years. However, reproductive health life plans have not been systematically implemented and evaluated (23,26,29,33). Implementing such a reproductive health life plan will require a change in provision of health services and health promotion (Box 1). Recommendation 2. Consumer Awareness. Increase public awareness of the importance of preconception health behaviors and preconception care services by using information and tools appropriate across various ages; literacy, including health literacy; and cultural/linguistic contexts. Consumers should be more involved in improving preconception care services. Knowledge and attitudes and behaviors related to reproductive health are influenced by childhood experiences and prevailing social norms among adults. Certain U.S. adults are not aware of the factors that influence reproductive health and childbearing (34,35). The preconception guidelines from Canada state that preconception care is 1) physical preparation for pregnancy and parenting and 2) the social, psychological, and spiritual components of pregnancy. The factors that influence attitudes regarding preconception care include a person's age and life stage, their childbearing history, and their life priorities (156). Activities specifically designed to improve school general health education are an essential step in improving reproductive awareness. Efforts to inform adults regarding the risks and opportunities to improve their health are equally important. Several health promotion campaigns provide opportunities to change adult knowledge and attitudes and behaviors, - Develop, evaluate, and disseminate age-appropriate educational curricula and modules for use in school health education programs. - Integrate reproductive health messages into existing health promotion campaigns (e.g., campaigns to reduce obesity and smoking). - Conduct consumer-focused research to identify terms that the public understands and to develop messages for promoting preconception health and reproductive awareness. - Design and conduct social marketing campaigns necessary to develop messages for promoting preconception health knowledge and attitudes, and behaviors among men and women of childbearing age. - Engage media partners to assist in depicting positive role models for lifestyles that promote reproductive health (e.g., delaying initiation of sexual activity, abstaining from unprotected sexual intercourse, and avoiding use of alcohol and drugs). # Box 2. Recommendation 2 preconception health action steps including campaigns designed to reduce tobacco use, promote responsible use of alcohol, and encourage healthy diet and optimal weight. Campaigns can include messages concerning reproductive health and childbearing. Such campaigns typically focus on the effect of adverse behaviors on children and do not include parallel messages regarding the potential impact on childbearing. New social marketing and health promotion campaigns that focus on how to prepare for childbearing and parenting can influence the behavior of men and women. For example, folic acid intake has been promoted among women of childbearing age (123). Similar to efforts to reduce teenage childbearing or increase use of prenatal care, the media can play a vital role in promoting reproductive awareness (157). Success in improving preconception health will require changes in public attitudes and has been achieved in other areas (e.g., attitudes changed during the previous 10 years regarding tobacco use, infant sleep position, or vaccinations for infants and toddlers instead of preschoolers) (158). A critical tool for stimulating these changes is social marketing, which is designed to influence the voluntary behavior of targeted audiences to improve their well-being (159,160). Consumer-friendly tools can help women self-assess risks, make plans, and take actions that will improve their health and that of their children. More consumer-focused research is needed to determine which messages and tools might be effective to encourage reproductive life planning. The SPPC members have suggested that such research explore which terms the public best understands, what messages might increase demand for services, and how touch-screen kiosks or other technology might be used to promote knowledge of preconception health topics (Box 2). Recommendation 3. Preventive Visits. As a part of primary care visits, provide risk assessment and educational and health promotion counseling to all women of childbearing age to reduce reproductive risks and improve pregnancy outcomes. Integration of preconception components into primary care can better serve women across their lifespan and at various levels of risk. Primary care integrates various health promotion, prevention, and acute care services to address the majority of personal health-care needs and common health problems in a community setting. Primary care also might include screening for and ongoing management of chronic conditions in a primary care setting. Elements of preconception care can be integrated into every primary care visit. Professional guidelines for clinicians (i.e., obstetrician/gynecologists, family practice physicians, certified nurse midwives, and nurse practitioners) who provide the majority of primary care to women in the United States should include routine risk assessment through screening (14,24,28,29,33). Different guidelines recommend eight to 10 specific areas for preconception risk assessment, including: 1) reproductive history; 2) environmental hazards and toxins; 3) medications that are known teratogens; 4) nutrition, folic acid intake, and weight management; 5) genetic conditions and family history; 6) substance use, including tobacco and alcohol; 7) chronic diseases (e.g., diabetes, hypertension, and oral health); 8) infectious diseases and vaccinations; 9) family planning; and 10) social and mental health concerns (e.g., depression, social support, domestic violence, and housing) (5)(6)(7)30,31,33,40,41). In addition to risk assessment or screening, professional guidelines include health promotion education and counseling related to reproductive health risks. Such activities should routinely include promotion of healthy behaviors; discussion of child spacing, family planning, and unintended pregnancy prevention; counseling concerning healthy diet, folic acid supplementation, and optimal weight; immunization for infectious disease; information regarding the importance of early prenatal care; and counseling concerning the availability of social and financial support programs. For women with identified risks, additional counseling, testing, and brief interventions (e.g., for smoking, alcohol, or changes in prescription medications) can be conducted in the primary care setting (68)(69)(70)(116)(117)(118) (e.g., a limited number of model visits), as is done for wellchild care. Clinical practice can be influenced by evidence-based guidelines, but additional strategies are needed to promote widespread adoption of professional guidelines (25,(30)(31)(32)(33)(151)(152)(153)(154). In the recommended action steps (Box 3), additional activities should be provided to support changes in primary care provider knowledge and attitudes and practices. Consolidation of existing guidelines, better tools, and use of quality improvement techniques have fostered changes in knowledge and practices (161)(162)(163)(164). For example, the Bright Futures Program has consolidated guidelines for child health, and the Bright Futures for Women's Health and Wellness offers models and opportunities for links to preconception care (165). Community health centers and other FQHC can be a key point of dissemination for strategies to improve preconception health. FQHC are a critical source of primary care for millions of women with low incomes and no insurance. Perinatal care for 332,000 women account for one of every 10 U.S. births (166). Among FQHC, the Health Disparities Collaboratives (HDC) Initiative is designed to improve the quality of primary care delivered, and approximately 600 FQHCs have participated (167). The HDC model relies on partnerships among community clinics, federal agencies, and national organizations. HDC started with a chronic disease care model for quality improvement, and a primary healthcare model integrated with the perinatal care collaboratives and other efforts has been developed. # Recommendation 4. Interventions for Identified Risks. Increase the proportion of women who receive interventions as follow-up to preconception risk screening, focusing on high priority interventions (i.e., those with evidence of effectiveness and greatest potential impact). Timely preconception interventions for certain conditions can substantially improve maternal health and birth outcomes (4,43). Separating childbearing from the management of chronic health problems and infectious diseases places women, their future pregnancies, and their future children at unnecessary risk (7,20,24,149). Conditions and risk factors have been identified for which the following exist 1) evidence of potential harm to mother or baby, 2) high prevalence of adverse pregnancy outcome or effective interventions for reducing adverse pregnancy outcomes, and 3) one or more effective interventions that have been evaluated. Certain women and men need additional counseling and interventions. For example, women who have conditions treated with medications that are known teratogens (e.g., anticonvulsant or anticoagulant medications and isotretinoins) might need to change prescriptions. Women with medical conditions associated with increased risks for morbidity and mortality to mother and fetus (e.g., diabetes, hypertension, heart disease, rubella sero-negativity, thrombophilias, dental disease, or obesity) need to control these conditions. Women with behaviors associated with increased health risks for the fetus (e.g., smoking and alcohol and illicit drug use) also need targeted interventions. Another group with specific counseling needs includes prospective parents with a family history of inherited (i.e., genetic) disorders. The preparers of this report analyzed the National Ambulatory Medical Care Survey (168) and demonstrated that diabetes affects approximately 1.85 million (21 per 1,000) women in the United States aged 18-44 years, and that preconceptional diabetes management has the potential to reduce the risk for pregnancy loss and congenital malformation for approximately 113,000 births per year. Anti-epileptic/ - Increase health provider (including primary and specialty care providers) awareness concerning the importance of ongoing care for chronic conditions and intervention for identified risk factors. (168). Women with chronic medical conditions and their specialty providers should take advantage of every opportunity to discuss preconception health and risks. These conditions and risk factors affect substantial proportions of the approximately 4 million pregnancies that occur in the United States each year. Studies of preconception care have indicated that providers do not routinely provide interventions for identified preconception risks (23,147,148,164,169). Dissemination of professional guidelines and evidence-based interventions are two vital ways to encourage changes in practice. However, quality improvement tools and techniques offer increased potential, particularly for specific interventions for women with identified conditions (162,170). Research has increasingly indicated that providers and health-care organizations are more likely to engage in evidence-based or best clinical practices, after participation in quality improvement projects (e.g., rapid improvement cycles using the plan/do/study/act approach, collaborative groups, or the model of improvement process that involves an aim/change/measure cycle) (162,170). Incorporation of preconception care modules into the curricula of medical graduate, postgraduate, and continuing medical education might be another method of disseminating messages regarding the importance and content of preconception care for women (Box 4). Recommendation 5. Interconception Care. Use the interconception period to provide additional intensive interventions to women who have had a previous pregnancy that ended in an adverse outcome (i.e., infant death, fetal loss, birth defects, low birthweight, or preterm birth). Experiencing an adverse outcome in a previous pregnancy is an important predictor of future reproductive risk (171)(172)(173). However, many women with adverse pregnancy outcomes do not receive targeted interventions to reduce risks during future pregnancies. Each year, approximately 28,000 infants die during the first year of life (171). Approximately 12% of all births are preterm (i.e., <37 weeks' gestation) (10), and an estimated 3% of infants are born with birth defects (174). Whereas a preterm birth is identified on birth certificates and a woman's primary care provider typically knows this information, professional guidelines do not include systematic follow-up and intervention for women with this critical predictor of risk. Postpartum visits are an opportunity to link women to interventions designed to reduce risks to them and their future chil-dren, and promising strategies focus on the postpartum period (170). The Health Employer Data and Information Set (HEDIS), used by public and private health plans, has measures for postpartum visits. HEDIS data indicate that 80% of women with private (i.e., commercial) insurance coverage and 55% of those covered by Medicaid receive postpartum checkups. However, for the majority of health plans, strategies to encourage compliance or address low rates of return for postpartum care have not been implemented (44). Measures for monitoring postpartum visits also are used by a limited number of state Title V Maternal Child Health Block Grant agencies (175). Data collected during postpartum visits typically have not been used to guide health-care system planning. Approaches to interconception care, which are part of preconception care, have been proposed (176,177), and certain approaches have been tested. For example, in the Interpregnancy Care Program of Grady Memorial Hospital in Atlanta, Georgia, researchers have been studying the effectiveness of interconception care in improving subsequent reproductive outcomes for women who have delivered a baby born at very low birthweight (<1,500 grams). This model focuses on reducing identified medical, dental, and psychosocial risks and assisting women in developing and - Consolidate existing professional guidelines to develop the recommended content and approach for such a visit. - Modify third party payer rules to permit payment for one prepregnancy visit per pregnancy, including development of billing and payment mechanisms. - Educate women and couples regarding the value and availability of prepregnancy planning visits. # Box 6. Recommendation 6 preconception health action steps achieving their reproductive goals for the future. During the pilot phase, the program identified and treated various medical conditions and reported substantial positive impact on the length of birth intervals (177). The federal Healthy Start program requires that a grantee follow a woman and her child for 2 years postpartum, providing interconception care. In addition, certain Healthy Start grantees provide more in-depth interconception services to women at high risk to reduce future adverse pregnancy outcomes (175). Across the United States, Healthy Start grantees (e.g., the Magnolia Project in northeastern Florida) are providing intensive postpartum case management for women at high risk for adverse pregnancy outcomes (178)(179). Opportunities are available to identify, refer, and serve women at high risk in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) nutrition sites, family planning clinics, and home visiting programs (175). Federal and state agencies can support such efforts with funding for demonstration, evaluation, and replication projects (Box 5). Recommendation 6. Prepregnancy Checkup. Offer, as a component of maternity care, one prepregnancy visit for couples and persons planning pregnancy. SPPC encourages the use of a broad definition of maternity care that includes the addition of a prepregnancy visit and the recommended prenatal and postpartum visits. The addition of this prepregnancy visit is an essential step toward improving pregnancy outcomes, particularly for those planning pregnancy. The Institute of Medicine Panel on Preventing Low Birthweight, the U.S. Public Health Service Expert Panel on the Content of Prenatal Care, and the national Committee on Perinatal Health have recommended that women have a prepregnancy visit (i.e., sometimes called a preconception visit) in the months before conception (1,3,4). Such visits would include preconception care content, providing women an opportunity to benefit from risk assessment, health promotion, and specific interventions related to circumstances when couples are trying to conceive. Adoption of the prepregnancy visit as a standard of care also can help to reinforce the importance of pregnancy planning and preparedness among women and men (Box 6). # Recommendation 7. Health Insurance Coverage for Women with Low Incomes. Increase public and private health insurance coverage for women with low incomes to improve access to preventive women's health and preconception and interconception care. Affordability of care is a major concern for multiple women (11,180,181), and improved access to preconception care is needed. Approximately 17 million women do not have health insurance, and they are more likely to postpone or forgo care (180). During 2003, one third of women with low incomes, half of women with disabilities, and 18% of all nonelderly (aged <65 years) women did not have health insurance (180). Younger women aged 18-34 years were more likely than older women not to have health insurance during 2003. Reflecting their income and employment status patterns (i.e., more likely to have incomes <200% of poverty level and less likely to be employed in jobs that offer health insurance), non-Hispanic white, Asian, and non-Hispanic black women were more likely than non-Hispanic white women not to have health insurance (11,180,181 # Box 7. Recommendation 7 preconception health action steps Medicaid is the primary mechanism for extending health coverage to women with low incomes and who do not have health insurance. During 2003, a total of 12% of all women of childbearing age and 37% of women with low incomes in that age group relied on Medicaid for health-care coverage (181,182). Medicaid has been demonstrated to be effective in improving access to health care for women with low incomes (179). Because nearly two thirds (63%) of women covered by Medicaid are of childbearing age, the program's performance is related to preconception care access and to the outcomes of pregnancy (183). Many women with low incomes, however, do not qualify for Medicaid because they do not have children aged <18 years or do not have documentation of legal residence in the United States. As states seek to expand Medicaid coverage to persons with low incomes and adults who do not have health insurance, women of childbearing age should receive priority for qualifying for Medicaid coverage. Since 1995, a total of 22 states have used their federal waiver authority to expand family planning services to women who do not otherwise qualify for Medicaid, known as family planning waivers. Certain states offer coverage to women who lose coverage after the birth of a baby or starting a job, whereas other states offer family planning coverage based on the income status of men and women (182). An evaluation of these family planning waiver projects prepared for the federal Center for Medicare and Medicaid Services indicated that the projects resulted in substantial savings to both the federal and state governments (184). Increased potential savings and prevention, however, can result if states provided coverage for more comprehensive risk screening, health promotion, and interventions, resulting in higher levels of preconception wellness (Box 7). # Recommendation 8. Public Health Programs and Strategies. Integrate components of preconception health into existing local public health and related programs, including emphasis on interconception interventions for women with previous adverse outcomes. Public health programs serve millions of women each year. Preconception interventions can be incorporated into these programs to target women at highest risk. Title X family planning programs provide approximately 4.6 million women with family planning education and contraceptives and pregnancy tests. However, a limited number of programs offer more comprehensive risk screening, reproductive health promotion, and reproductive life planning (185). Each year, WIC provides nutrition screening and counseling, supplemental food, and referrals to health services for approximately 8 million women during pregnancy and the postpartum period (186). These services provide an opportunity to promote preconception health and refer women at risk to clinicians. Federal and state public health programs funded by the Title V Maternal and Child Health Services Block Grant and CDC can give greater priority to preconception health and offer support for demonstration projects and evaluations of prevention programs. Whereas federally funded Healthy Start projects are required to have interconception health activities, these projects, located in communities with high infant mortality, provide opportunities to offer more systematic preconception screening, health promotion, and interventions. Publicly funded programs that offer screening and related services for STDs and HIV/AIDS also might provide risk assessment and health promotion interventions. Title X, WIC, Title V, Healthy Start, and other public health programs also provide a setting to test and evaluate new approaches to improve preconception health (44,187). Strategies to promote dialogue and action among community members for a geographically defined community or a community of professionals can help advance these recommendations and action steps (Box 8). Local task force groups that involve consumer, community leaders, and health professionals can help implement preconception strategies that are similar to strategies used previously for other topics (e.g., adolescent pregnancy prevention and childhood vaccinations). Functioning parallel to clinical practice collaboratives, public health practice collaboratives that link local public health programs can promote development and dissemination of community-based best practices. Recommendation 9. Research. Increase the evidence base and promote the use of the evidence to improve preconception health. At the state and local levels, PRAMS, Perinatal Periods of Risk, Fetal-Infant Mortality Review, and youth risk behavior surveys provide additional opportunities for the data collection, analysis, and interpretation that comprise public health surveillance (190,(192)(193)(194). The Maternal and Child Health Bureau, in cooperation with states, operates the Title V data and information system, which provides an opportunity to strengthen public health surveillance and performance monitoring. A review of stateselected performance measures and priority needs for 2006-2010 indicated that a limited number of states are monitoring trends for access to components of preconception and interconception care, access to primary care for women of childbearing age, unintended pregnancy, and other related topics (175). Since 1990, indicators and monitoring systems have been used not only to assess programs at the population level but also to measure the quality of health-care services. HEDIS is an example of a set of measures commonly used by purchasers of health-care coverage, including state Medicaid agencies and employers. HEDIS includes indicators on prenatal and postpartum care and family planning (195). New HEDIS measures are needed to monitor access to, use of, and outcomes of preconception care services as well as improved maternal and infant health. The recommendations in this report can be used as a frame work for developing or modifying # Box 9. Recommendation 9 preconception health action steps Additional evidence is needed regarding the effectiveness of interventions, the value of better service integration, and the potential cost benefit of preconception care for the general population and for women at high risk for poor pregnancy outcomes. Evaluations of preconception health programs and projects can help advance understanding of the potential impact of selected approaches. For certain clinical interventions (e.g., interventions to address multiple risk factors simultaneously or single risk factor interventions), randomized clinical trials are warranted, although not all preconception health interventions can be ethically tested in this manner. Economic studies, particularly of clinical intervention strategies, can support the case for wider dissemination of preconception care practices (188; Box 9). # Recommendation 10. Monitoring Improvements. Maximize public health surveillance and related research mechanisms to monitor preconception health. Community health data are used systematically to conduct public health surveillance to evaluate and improve health, health programs, and health policy (187). Surveillance includes monitoring the frequency of conditions, risk factors, services, and outcomes. CDC and other public health agencies conduct surveillance and maintain data collection and surveillance systems, and the field of maternal and child health benefits from several of these systems. For example, PRAMS, the Behavioral Risk Factor Surveillance System, and the National Survey of Family Growth (NSFG) can be modified to provide more data concerning preconception health (189- # Conclusion The 10 recommendations for improving preconception care services and the health of women and infants were developed through a process of consultation with a select panel of specialists from the relevant disciplines. Implementation of the recommendations will help achieve the SPPC vision of preconception health and pregnancy outcomes in which 1) women and men of childbearing age have high reproductive awareness (i.e., understand risk factors related to childbearing); 2) women and men have a reproductive life plan (e.g., whether or when they want to have children and how they will maintain their reproductive health); 3) pregnancies are intended and planned; 4) women and men of childbearing age have health-care coverage; 5) women of childbearing age are screened before pregnancy for risks related to the outcomes of pregnancy; and 6) women with a previous adverse preg-nancy outcome (e.g., infant death, very low birthweight or preterm birth) have access to interconception care aimed at reducing their risks. Improving preconception health will require changes in the knowledge and attitudes and behaviors of persons, families, communities, and institutions (e.g., government and healthcare settings). The purpose of preconception care is to improve the health of each woman before any pregnancy and thereby affect the future health of the woman, her child, and her family. The recommendations and specific action steps were developed as a result of SPPC meeting and implementation of CDC's preconception health programs. The frame work has incorporated both an ecological model and a lifespan perspective on health and recognized the unique contributions and challenges encountered by women, their families, communities, and institutions. Improving the health of women can increase the quality of health for families and the community. Several preconception care interventions have reduced risk and improved health outcomes. By increasing support for provision of preconception care, policy makers have the opportunity to promote broad-based programs and services aimed at improving the health of women, children, and families. The recommendations present a conceptual frame work for innovative service delivery models so that women are afforded the benefit of risk-appropriate preconception services during every encounter with the health-care system. - Apply public health surveillance strategies to monitor selected preconception health indicators (e.g., folic acid supplementation, smoking cessation, alcohol misuse, diabetes, and obesity). - Expand data systems and surveys (e.g., the Pregnancy Risk Assessment and Monitoring System and the National Survey of Family Growth) to monitor individual experiences related to preconception care. - Use geographic information system techniques to target preconception health programs and interventions to areas where high rates of poor health outcomes exist for women of reproductive age and their infants. - Use analytic tools (e.g., Perinatal Periods of Risk) to measure and monitor the proportion of risk attributable to the health of women before pregnancy. - Include preconception, interconception, and health status measures in population-based performance monitoring systems (e.g., in national and state Title V programs). - Include a measure of the delivery of preconception care services in the Healthy People 2020 objectives. - Develop and implement indicator quality improvement measures for all aspects of preconception care. For example, use the Health Employer Data and Information Set measures to monitor the percentage of women who complete preconception care and postpartum visits or pay for performance measures. # CDC/ATSDR Preconception Care Work Group Agency for Toxic Substances and Disease Registry: Robert H. Johnson, MD, Division of Health Education and Promotion. # Appendix # Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. You must complete and return the response form electronically or by mail by April 21, 2009, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1. 75 # Goals and Objectives This report provides an updated review of the evidence for interventions to improve the health of women before pregnancy. The goal of this report is to present 10 recommendations to improve preconception care, focusing on specific activities at the individual, clinical, public health, community, and research levels. Upon completion of this educational activity, the reader should be able to 1) describe the need for preconception health for families, 2) define preconception care, 3) list the 10 recommendations for improving preconception care, 4) list specific action steps for each recommendation, 5) describe the interventions for improving preconception health that are supported by professional guidelines, 6) describe the responsibilities of persons concerned with preconception health, and 7) describe areas of preconception health care that need further research. To receive continuing education credit, please answer all of the following questions.	INSIDE: Continuing Education Examination depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Improving preconception health can result in improved reproductive health outcomes, with potential for reducing societal costs as well (1)(2)(3)(4). Preconception care aims to promote the health of women of reproductive age before conception and thereby improve pregnancy-related outcomes (5)(6)(7). Therefore, the goals of the 10 recommendations in this report are to improve a woman's health before conception, whether before a first or a subsequent pregnancy. The recommendations are 1) individual responsibility across the lifespan, 2) consumer awareness, 3) preventive visits 4) interventions for identified risks, 5) interconception care, 6) prepregnancy checkup, 7) health insurance coverage for women with low incomes, 8) public health programs and strategies, 9) research, and 10) monitoring improvements. Since 1996, progress in the United States to improve pregnancy outcomes, including low birthweight, premature birth, and infant mortality has slowed, in part, because of inconsistent delivery and implementation of interventions before pregnancy to detect, treat, and help women modify behaviors, health conditions, and risk factors that contribute to adverse maternal and infant outcomes (8). This report discusses several interventions that, if implemented before pregnancy, can improve pregnancy outcomes for women and infants. However, millions of women and couples do not receive such interventions and services (8). Childbearing is a common experience among women in the United States. In 2000, an estimated 62 million U.S. women were of childbearing age (aged 15-44 years), distributed in approximately equal segments across the age groups of 15-24, 25-34, and 35-44 years (9). By age 25 years, approximately half of all women in the United States have experienced at least one birth, and approximately 85% of all women in the United States have given birth by age 44 years. In 2003, the fertility rate was 66 live births per 1,000 women aged 15-44 years, with highest rates among women aged 25-29 years (114 per 1,000) and lowest rates among women aged >44 years (0.5 per 1,000). A similar age pattern has been observed within racial/ethnic populations, although women aged <25 years who are non-Hispanic black and Native American had higher fertility rates than non-Hispanic whites and Asian/ Pacific Islanders. Hispanic women have the highest fertility rates overall and within each age group (10). In a 2004 survey of women aged 18-44 years, 84% had a health-care visit during the previous year, and slightly more than half (55%) of women of reproductive age obtained preventive health services in any given year, which are opportunities to deliver preconception care (11). Because approximately one third to half of women have more than one primary care provider (i.e., generally a family physician or internal medicine physician and an obstetrician/ gynecologist) (12), all providers who routinely treat women for well-woman examinations or other routine visits play an important role in improving preconception health. However, only approximately one of six obstetrician/gynecologists or family physicians had provided preconception care to the majority of the women for whom they provided prenatal care (13). Another study reported that mothers frequently interacted with pediatricians after the birth of one child and before conception of another, which affords another opportunity to promote preconception health care (14). Community health centers and other Federally Qualified Health Centers (FQHC), including primary care and prenatal care, deliver services to approximately 4.5 million women of childbearing age each year (15). These centers can be used to provide preconception care to women with low incomes (income <200% of the federal poverty level) and with no health insurance. This report provides recommendations to improve both preconception health and preconception health care. Several of the medical conditions, personal behaviors, psychosocial risks, and environmental exposures associated with negative pregnancy outcomes can be identified and modified before conception through clinical interventions. For certain conditions, opportunities for preventive interventions occur only before conception. Establishing preconception health screening as part of routine care for women of reproductive age has been discussed in previously published reports (2,5,6,7,13,14). However better health care alone will not achieve optimal improvements in women's preconception health and reproductive outcomes. Health promotion activities to modify personal knowledge and attitudes and behaviors related to reproductive risk factors and the use of a reproductive life plan for women and couples also have been proposed (16,17). A reproductive health plan reflects a person's intentions regarding the number and timing of pregnancies in the context of their personal values and life goals. This health plan might increase the number of planned pregnancies and encourage persons to address risk behaviors before conception, reducing the risk for adverse outcomes for both the mother and the infant. The recommendations should be used by consumers, clinical care providers, public health professionals, researchers, policy makers, and others concerned with the health of women, children, and families. Federal, state, and local public health agencies can play a vital role in translating these recommendations into projects, educational materials, and programs designed to improve preconception health. Primary care providers serving women of reproductive age, including obstetrician/gynecologists, family physicians, nurse midwives, nurse practitioners, and others working in various clinical settings, have an equally critical role to play in implementing these recommendations. CDC developed these recommendations by 1) reviewing published research; 2) convening the CDC/ASTDR Preconception Care Work Group, representing 22 programs; 3) evaluating presentations of best and emerging practice models at the National Summit on Preconception Care in 2005; and 4) convening the Select Panel on Preconception Care (SPPC), comprised of subject matter specialists on obstetrics and gynecology, nursing, public health, midwifery, epidemiology, dentistry, family practice, pediatrics, and other disciplines. Various databases (e.g., PubMed ® [18]) were searched to iden-tify published studies for review. Search parameters included preconception care, birth outcomes, reproductive health, and women's health. The reports were reviewed by the SPPC of specialists. These recommendations reflect the research, professional opinion, practice in medicine, public health, and related fields, which are sufficient to guide changes in program, practice, and policy. SPPC reviewed evidence to determine the effectiveness of certain interventions of preconception care (e.g., folic acid to prevent neural tube defects and cessation of alcohol use) and identified missed opportunities for dissemination of preconception information. Implementation of these effective interventions can contribute to the health of thousands of women each year. These recommendations are a strategic plan to improve preconception health through clinical care, individual behavior change, community-based public health programs, and social marketing campaigns to change consumer knowledge and attitudes and practices. In addition, they are designed to increase research knowledge related to preconception health and care and to improve reproductive health outcomes for all women and couples. Policy changes at the local, state, and federal levels will be necessary to support several of these recommendations. These policies will address changes in access, payment, and types of services available. Four goals were established for achieving these recommendations: 1) improve the knowledge and attitudes and behaviors of men and women related to preconception health; 2) assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health; 3) reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children; and 4) reduce the disparities in adverse pregnancy outcomes. # Preconception Health and Care Preconception care is recognized as a critical component of health care for women of reproductive age (1)(2)(3)(4)(5)7,16,17,(19)(20)(21)(22)(23)(24)(25). The main goal of preconception care is to provide health promotion, screening, and interventions for women of reproductive age to reduce risk factors that might affect future pregnancies (7,16,(22)(23)(24)(25). Preconception care is part of a larger health-care model that results in healthier women, infants, and families (7,16,(26)(27)(28)(29). A substantial number of definitions for preconception care have been used (2)(3)(4)(5)16,19,(30)(31)(32)(33). On the basis of previous guidelines and recommendations, SPPC developed a refined definition for preconception care. Preconception care is de-fined as a set of interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through prevention and management. Certain steps should be taken before conception or early in pregnancy to have a maximal effect on health outcomes. Preconception care is more than a single visit to a health-care provider and less than all well-woman care, as defined by including the full scope of preventive and primary care services for women before a first pregnancy or between pregnancies (i.e., commonly known as interconception care). Improving preconception health and pregnancy outcomes will require more than effective clinical care for women. Changes in the knowledge and attitudes and behaviors related to reproductive health among both men and women need to be made to improve preconception health. Despite several health promotion campaigns aimed at reducing smoking, misuse of alcohol, intimate partner violence, obesity, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), reduction of vaccine-preventable diseases, and exposure to occupational hazards, the majority of U.S. adults are not aware of how these and other health and lifestyle factors influence reproductive health and childbearing (34,35). Preconception health promotion, therefore, should focus on a general awareness among men and women regarding reproductive health and risks to childbearing (26). # Healthy People 2000/2010 Objectives for Improving Preconception Health and Guidelines for Preconception Care A Healthy People 2000 objective (objective 14.3) is for 60% of primary care physicians to provide age-appropriate preconception care (36). This objective was deleted from Healthy People 2010 because it was not being measured. Although no specific objective for preconception exists, several of those specified in Healthy People 2010 are relevant to preconception health (37,38). The Institute of Medicine, several national committees, and a substantial number of professional organizations have established guidelines and recommendations regarding the importance and content of preconception health care (1,3,4,(30)(31)(32)(33). The primary objective of these reports is to improve the health of women, children, and families. The previously issued evidence-based guidelines for preconception care have been summarized and are the foundation for the recommendations developed by SPPC. The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) have classified the main components of preconception care into four categories of interventions: physical assessment, risk screening, vaccinations, and counseling. Eight areas of risk screening are 1) reproductive awareness; 2) environmental toxins and teratogens; 3) nutrition and folic acid; 4) genetics; 5) substance use, including tobacco and alcohol; 6) medical conditions and medications; 7) infectious diseases and vaccination; and 8) psychosocial concerns (e.g., depression or violence) (3,24,(26)(27)(28)(29)(30)(31)33). Preconception care should be an essential part of primary and preventive care, rather than an isolated visit (4,5,(21)(22)(23)(24)(25)(26)32,39,40). Whereas a prepregnancy planning visit in the months before conception has been recommended (3,19,31), improving preconception health will require changes in the process of care, including the types of screening and riskreduction interventions offered to women of childbearing age. Guidelines for Perinatal Care, jointly issued by AAP and ACOG, has recommended that all health encounters during a woman's reproductive years, particularly those that are a part of preconception care, should include counseling on appropriate medical care and behavior to optimize pregnancy outcomes (41). Recommendations from these organizations are analogous to the risk screening recommended by the American Heart Association for cardiovascular disease (42). Several national organizations have recommended the routine delivery of preconception care. For example, the March of Dimes has recommended that the key physician/primary care provider and the obstetrician/gynecologist take advantage of every health encounter to provide preconception care and risk reduction before and between conceptions, the time when health encounters can improve health status (39). # Preconception Risks Associated with Adverse Pregnancy Outcomes Risk factors for adverse outcomes among women and infants occur during the preconception period and are characterized by the need to start, and sometimes finish, intervention(s) before conception occurs. In a systematic review, researchers (43) discussed published reports that identified a list of risk factors for which preconception care (i.e., risk assessment, health promotion, and interventions) can be effective. Women of childbearing age suffer from various chronic conditions and are exposed to (or consume) substances that can have an adverse effect on pregnancy outcomes, leading to pregnancy loss, infant death, birth defects, or other complications for mothers and infants. For example, in 2002, approximately 6% of adult women aged 18-44 years had asthma, 50% were overweight or obese, 3% had cardiac disease, 3% were hypertensive, 9% had diabetes, and 1% had thyroid disorder (44). Dental caries and other oral diseases also are common (>80% of women aged 20-39 years) and associated with complications for women and infants. In addition to having chronic diseases, a substantial proportion of women who become pregnant engage in high-risk behaviors and contribute to adverse pregnancy outcomes. In 2003, a total of 11% of pregnant women smoked during pregnancy, a risk factor for low birthweight (10), and 10% of pregnant women and 55% of women at risk for getting pregnant (i.e., those not using contraception or using ineffective contraceptive methods or using effective contraceptive methods inconsistently) consumed alcohol, a risk for fetal alcohol syndrome (45). Certain women also continued to engage in high-risk sexual behavior, potentially exposing themselves to sexually transmitted diseases (STDs), including HIV (46). Although a smaller proportion of women used illicit drugs, this high-risk behavior has been associated with adverse outcomes. These behaviors often co-occur, therefore, compounding the risk for adverse outcomes for certain groups. Immunization for adults and infants is critical for preventing infectious diseases (e.g., influenza and pertussis). Data from the Pregnancy Risk Assessment and Monitoring System (PRAMS) in four states (i.e., Maine, Michigan, Oklahoma, and West Virginia) indicated that 38% of mothers who planned pregnancies and an additional 30% who did not plan pregnancies had one or more indications for preconception counseling, including use of tobacco or alcohol, being underweight, or delayed initiation of prenatal care (47). In Minnesota and Washington, data from a telephone survey of women revealed that pregnancy intention was associated with health behaviors before pregnancy that might influence pregnancy outcome, with the most marked differences in smoking and vitamin use (48). Preconception health care is critical because several risk behaviors and exposures affect fetal development and subsequent outcomes. The greatest effect occurs early in pregnancy, often before women enter prenatal care or even know that they are pregnant (4,(23)(24)(25)49). For example, for optimal effect on reducing the risk for neural tube defects, folic acid supplementation should start at least 3 months before conception (50)(51)(52). During the first weeks (before 52 days' gestation) of pregnancy, exposure to alcohol, tobacco, and other drugs; lack of essential vitamins (e.g., folic acid); and workplace hazards can adversely affect fetal development and results in pregnancy complications and poor outcomes for both the mother and infant (45,(53)(54)(55)(56)(57)(58). This evidence demonstrates the potential impact of preconception care on the health of women and their infants. Social determinants of women's health also play a role in pregnancy outcomes. The health status of minority women with low incomes contributes to persistent, and sometimes increasing, disparities in birth outcomes. In one study, the reduced overall health status (including poorer physical and emotional health) of women with low income during the month before pregnancy was associated with an increased risk for preterm labor (59). Socioeconomic status directly and indirectly influences three major determinants of health: healthcare access, environmental exposure, and health behavior (60,61). Racial inequalities in access to effective treatment also influence these determinants of pregnancy outcomes for women and infants (62)(63)(64). The following selected preconception risk factors for adverse pregnancy outcomes and evidence for the effectiveness of preconception care have been used to develop clinical practice guidelines (e.g., AAP and ACOG). • (105)(106)(107)(108)(109). Appropriate weight loss and nutritional intake before pregnancy reduces these risks. • Oral anticoagulant. Warfarin, which is used for the control of blood clotting, has been demonstrated to be a teratogen. To avoid exposure to warfarin during early pregnancy, medications can be changed to a nonteratogenic anticoagulant before the onset of pregnancy (110-112). • STD. Chlamydia trachomatis and Neisseria gonorrhoeae have been strongly associated with ectopic pregnancy, infertility, and chronic pelvic pain. STDs during pregnancy might result in fetal death or substantial physical and developmental disabilities, including mental retardation and blindness (113,114). Early screening and treatment prevents these adverse outcomes. • Smoking. Preterm birth, low birthweight, and other adverse perinatal outcomes associated with maternal smoking in pregnancy can be prevented if women stop smoking before or during early pregnancy. Because only 20% of women successfully control tobacco dependence during pregnancy, cessation of smoking is recommended before pregnancy (115)(116)(117)(118). Several providers and maternal and child health researchers have recommended that health risks and behaviors be addressed during any encounter with the health-care system because approximately half of pregnancies in the United States are unintended (20,22,27,119,120). One clinical trial has indicated that provision of preconception care can increase pregnancy planning and intention (121). This finding is vital because studies have consistently demonstrated that planned pregnancies typically have improved outcomes for both women and infants. # Preconception Prevention and Intervention Since 1987, several reviews of published reports have assessed the evidence and documented the effectiveness for specific preconception interventions (2,5,33,43). A systematic review of 21 research trials published during the 1990s have strengthened the evidence base for preconception care in particular areas (e.g., folic acid deficiency, maternal PKU, and oral anticoagulant; 43). The effectiveness of several interventions that address the risk factors for adverse outcomes (19,33,43) have been documented, including folic acid supplementation (51,52,(122)(123)(124)(125); appropriate management of hyperglycemia (126)(127)(128)(129)(130)(131); rubella, influenza, and hepatitis vaccination; low phenylalanine diet (132)(133)(134); and provision of antiretroviral medications to reduce the risk for mother-to-child HIV transmission (97). Interventions for smoking and alcohol cessation (135)(136)(137)(138)(139) have been demonstrated to be effective in certain populations; however, they have been less effective with persons at highest risk (e.g., injection-drug users and polysubstance users). A list of core interventions exist that are part of preconception care services. These interventions are risk-specific; providers can screen and provide appropriate interventions for persons who need them. However, the best evidence for the effectiveness of these specific components of preconception care has been documented when the focus of delivery was on a single risk behavior and accompanying intervention, rather than delivery of multiple interventions. Because of the direct links between a mother's oral health and her offspring's risk for dental caries, dental interventions can reduce the risk for prematurity and low birthweight (140)(141)(142)(143). Evidence supporting interventions to reduce motherto-child transmission of cariogenic bacteria supports recommendations for the appropriate use of fluorides and dietary control to reduce maternal salivary reservoirs of cariogenic bacteria, particularly for women who have experienced high rates of dental caries (140). Interventions that address multiple pregnancy-related risk behaviors simultaneously have not been systematically evaluated and are less commonly delivered. The U.S. Preventive Services Task Force (USPSTF) evaluated the effectiveness of interventions related to smoking, alcohol misuse, and obesity, based on studies of interventions delivered in primary care settings that were not complicated by the additional delivery of multiple components of preconception care (69,70,(144)(145)(146)(147). These effective methods for intervention (e.g., the Five As [Ask, Advise, Assess, Assist, and Arrange]) for smoking cessation and brief counseling interventions to reduce alcohol misuse, as identified by USPSTF, provide models for the delivery of multiple interventions that can be adapted and tested (69,70). One study has reported the effectiveness of comprehensive preconception care; however, the findings have limited applicability for the implementation of preconception health-care services in the United States because the study was conducted in Hungary (147). One priority for preconception care activities is to ensure that evidence-based interventions are implemented to further improve infant and maternal pregnancy outcomes among women living with chronic conditions. Clinical practice guidelines (CPGs) for preconception care for specific maternal chronic health conditions have been developed by several national health professional groups (25)(26)(27)(28). For example, the American Diabetes Association has developed CPGs that should be followed before pregnancy for women with diabetes (81). The American Association of Clinical Endocrinologists has developed CPGs for women with hypothyroidism who are attempting to conceive (100). CPGs have also been developed for women being treated with teratogenic medications to guide the transition to safer medications. CPGs for women considering pregnancy and who are using antiepileptic drugs or oral anticoagulants have been developed by the American Academy of Neurology ( 77) and the American Heart Association/American College of Cardiologists (78), respectively. Whereas the evidence supporting specific interventions and the importance of intervening before pregnancy are definitive, limited evidence is available to determine effective methods for delivering preconception care and improving preconception health. Only a limited number of studies regarding effectiveness of interventions have been tested for increasing preconception screening, counseling, and intervention in primary care settings (121,148,149). In one randomized clinical trial, preconception risk factors were identified among women who sought care at a hospital primary care clinic for a pregnancy test. In this trial, an average of nine risk factors per woman was identified at the time of a negative pregnancy test. However, notifying women and their clinicians of identified preconception risks did not improve intervention rates (148). In another study in which didactic lectures and chart cues were used, significant increases occurred in risk screening for medical risk factors (15%-44%), medications (10%-30%), domestic violence (10%-57%), and nutrition (9%-50%) among nonpregnant women who attended an innercity hospital gynecologic clinic. However, intervention rates and provider attitudes toward preconception care did not change substantially (149). A prospective study of the effect of preconception health promotion on intendedness of pregnancy revealed that women in a family planning clinic who had received the intervention (22%) during routine visits were more likely to report intended pregnancies than those patients in the same clinic who were not exposed to the intervention (15) (121). A limited number of studies have assessed the best methods for integrating interventions to achieve maximum impact and optimize the use of limited resources. As with other types of preventive care services, time constraints limit physicians' ability to deliver health promotion interventions (144). Preconception care interventions can potentially be integrated into a limited number of model visits to focus on specific content at different visits, as is done for well-child care (150). Integrated and coordinated care services might also provide additional support to improve health outcomes. For example, an evaluation of the quality of care in the National Centers of Excellence in Women's Health indicated that women served in these centers, compared with community samples, received more clinical preventive services and had higher satisfaction levels (151). Another approach (e.g., self-management) to integrated service of delivery has been illustrated in CDC's recommendations in Strategies for Reducing Morbidity and Mortality from Diabetes Through Health-Care System Interventions and Diabetes Self-Management Education in Community Settings: A Report on Recommendations of the Task Force on Community Preventive Services (152). HIV intervention efforts also have suggested that integrated interventions address substance use and reduce sexual risk behaviors simultaneously. The purpose of preconception care is to deliver risk screening, health promotion, and effective interventions as a part of routine health care. In the United States, this approach is the standard used to achieve prevention of vaccine-preventable disease, heart disease, diabetes, and other chronic conditions. This approach is similar to well-child care, prenatal care, and adult wellness care in which studies have demonstrated the effectiveness of individual components rather than the effectiveness of combined interventions. However, effectiveness depends on ongoing monitoring of health status with interventions. Preconception care should be tailored to meet the needs of the individual woman. Because preconception care needs to be provided across the lifespan and not during only one visit, certain recommendations will be more relevant to women at different life stages and with varying levels of risk. Health promotion, risk screening, and interventions are different for a young woman who has never experienced pregnancy than for a woman aged 35 years who has had three children. Women with chronic diseases, previous pregnancy complications, or behavioral risk factors might need more intensive interventions. Such variations also place constraints on how interventions can and should be integrated. # Context and Frame Work for Recommendations The recommendations are designed to promote optimal health throughout the lifespan for women, children, and families by using both clinical care and population-focused public health strategies. In this report, the approach to promoting preconception health is not a single clinical visit but a process of care and interventions designed to address the needs of women during the different stages of reproductive life. SPPC has encouraged the use of a broad definition of prenatal care that includes ongoing preconception interventions, the addition of a prepregnancy visit, multiple postpartum visits, and the currently recommended prenatal care visits. Preconception care offers health services that allow women to maintain optimal health for themselves, choose the number and spacing of their pregnancies and, when desired, prepare for a healthy baby. Interventions and health care that occur before and between pregnancies are included in this report. This review identified areas for which further research is needed (43). Increasing evidence-based research of clinical and public health interventions by using both qualitative and quantitative methods is essential to the fulfillment of these recommendations. Each of the 10 recommendations has specific action steps that can be implemented in the next 2-5 years. Increasing access to and use of preconception care will not occur immediately; diffusion of innovation theory demonstrates how slowly concepts and best practices are typically disseminated (153,154). The action steps recommend revision of professional standards of care, modification of provider behaviors, development of effective health promotion messages, changes in consumer behavior, and adjustments to payment mechanisms. In addition, the recommendations emphasize individual behavior and responsibility for improving preconception health and identify specific evidence-based strategies for modifying individual knowledge and attitudes and behaviors across the lifespan. The recommendations promote changes in clinical care, public health programs at the federal, state, and local levels, and other community-based programs. For example, quality improvement strategies, commonly used today in clinical practice, might be used to modify provider knowledge and attitudes and behaviors. In addition to participation among traditional partners in public health interventions, improving preconception health will require increased involvement from partners in various sectors (e.g., education, housing, urban planning, and environmental health). These partners should be included as part of the comprehensive solution to improve women's health and the health of families. Approaches to improve surveillance, performance monitoring, and results accountability have been recom-mended along with strategies to integrate care, develop complementary approaches, and reduce duplication of activities among different professional and programmatic stakeholders. The risk and the burden of disease is unequally distributed, and a small number of women experience the majority of the pregnancy-related morbidity and mortality, which suggests that a two-step approach to implementing interventions would be beneficial. The first step would target women at highest risk (whether the risks are biologic or social) to reduce morbidity and mortality. The second step would aim to improve preconception health for all women of reproductive age, regardless of risk status. The recommendations emphasize targeting interventions for groups of women with known risks and conditions (e.g., those with previous poor pregnancy outcomes or chronic conditions). Culturally and linguistically appropriate systems of care are needed to ensure maximal use and impact of preconception health-care services. By increasing the acceptability, effectiveness, and impact of the health-care system through these changes, persons involved in improving preconception health care have the opportunity to address and reduce health disparities. The recommendations are a starting point to make comprehensive preconception care a standard of care in the United States and to provide a more universal, comprehensive, evidence-based model of preconception care. The recommendations will promote the development and practice of preconception care that will be flexible to meet persons' changing reproductive care needs and address risks throughout their lifespan. # How the Recommendations were Developed The recommendations were developed through the collaborative efforts of CDC and external partners to 1) target life stages in reproductive-aged women; 2) encourage special interest groups to collaborate to achieve common goals; 3) encourage scientific and public health collaboration; and 4) address health impact, public health systems, efficiency, and effectiveness. During 2003, a review of studies published regarding maternal and child health and preconception care was conducted by CDC to assess preconception care. The CDC work group also discussed opportunities for collaboration across programs. Several CDC programs in the work group had previously identified specific interventions with scientific evidence which, if delivered before conception, would promote preconception health and improve pregnancy-related outcomes. These programs recognized the need to integrate these interventions with similar services to improve coverage, effectiveness, access, efficiency, and ultimately maternal and infant pregnancy outcomes. The need for preconception health promotion and care was identified as a critical public health topic by CDC and partners. As a result, a broader working group of national organizations involved in preconception health issues were established (Appendix). In November 2004, the CDC work group and representatives of 16 external organizations discussed the evidence supporting preconception care to determine the steps that can be taken to develop national recommendations. The consensus of the participants was that a larger meeting on preconception care and an interdisciplinary panel of specialists should be convened in 2005. A steering committee and planning committee were established (including representatives from CDC and external partners) to plan for a national summit and to bring together a group of specialists with experience in data, practice, and policy issues related to preconception health. In June 2005, a national summit on preconception care was convened to gather information concerning promising practice models. The summit agenda was developed based on 68 submitted abstracts and reflected various preconception project models, finance approaches, and research questions (CDC, unpublished data, 2005). In conjunction with the summit, CDC convened SPPC, which included various subject matter specialists and representatives from national organizations concerned about the health of women, infants, and families. A Delphi technique was used to identify subject matter specialists to serve on SPPC. SPPC discussed recommendations regarding clinical practice, public health/community programs, research/data, and policy/finance. Initial recommendations were sent to the CDC work group, panel members, and additional subject matter specialists from academic and professional backgrounds for comment and review. Reviewers shared their comments in writing or as part of a series of conference calls convened by the SPPC steering committee. # Recommendations to Improve Preconception Health Ten recommendations were developed for improving preconception health through changes in consumer knowledge, clinical practice, public health programs, health-care financing, and data and research activities. Each recommendation has specific action steps. If each action step is implemented, benefits might be observed within 2-5 years, which would help achieve the Healthy People 2010 objectives to improve maternal and child health outcomes. The recommendations are aimed at achieving four goals, based on personal health outcomes. Goal 1. Improve the knowledge and attitudes and behaviors of men and women related to preconception health. Goal 2. Assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health. Goal 3. Reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children. Goal 4. Reduce the disparities in adverse pregnancy outcomes. The recommendations are a strategic plan for improving the health of women, their children, and their families and are based on existing knowledge and evidence-based practice. Improving preconception health among the estimated 62 million women of childbearing age (9) will require a multistrategy, action-oriented initiative. The recommendations, which are not prioritized, should be used by consumers, public health and clinical providers, researchers, and policy makers. Therefore, the recommendations should be implemented simultaneously. In the action steps, persons, public health and clinical providers, communities, governments (i.e., local, state, and federal), and professional organizations all have roles. Finally, these recommendations are designed to reduce disparities in maternal and infant health by improving the preconception health of women and men. # Recommendations Recommendation 1. Individual Responsibility Across the Lifespan. Each woman, man, and couple should be encouraged to have a reproductive life plan. The target population for preconception health promotion is women, from menarche to menopause, who are capable of having children, even if they do not intend to conceive. To reach such a broad group, a lifespan perspective is needed (3,17,20), which is commonly used in efforts to reduce chronic diseases, particularly cardiovascular disease. For example, persons are encouraged to consider the role of genetic and dietary factors in determining their risk for high cholesterol and to modify their behaviors according to cumulative individual risks (e.g., changes in diet, exercise, or medications) (155). Similarly, a lifespan approach can be used to focus in-dividual attention on reproductive health to reduce unintended pregnancies, age-related infertility, fetal exposures to teratogens, and to improve women's health and pregnancy outcomes (20). Certain researchers, providers, and health-care advocates have suggested developing a reproductive health life plan for young women and couples as they enter their reproductive years. However, reproductive health life plans have not been systematically implemented and evaluated (23,26,29,33). Implementing such a reproductive health life plan will require a change in provision of health services and health promotion (Box 1). Recommendation 2. Consumer Awareness. Increase public awareness of the importance of preconception health behaviors and preconception care services by using information and tools appropriate across various ages; literacy, including health literacy; and cultural/linguistic contexts. Consumers should be more involved in improving preconception care services. Knowledge and attitudes and behaviors related to reproductive health are influenced by childhood experiences and prevailing social norms among adults. Certain U.S. adults are not aware of the factors that influence reproductive health and childbearing (34,35). The preconception guidelines from Canada state that preconception care is 1) physical preparation for pregnancy and parenting and 2) the social, psychological, and spiritual components of pregnancy. The factors that influence attitudes regarding preconception care include a person's age and life stage, their childbearing history, and their life priorities (156). Activities specifically designed to improve school general health education are an essential step in improving reproductive awareness. Efforts to inform adults regarding the risks and opportunities to improve their health are equally important. Several health promotion campaigns provide opportunities to change adult knowledge and attitudes and behaviors, • Develop, evaluate, and disseminate age-appropriate educational curricula and modules for use in school health education programs. • Integrate reproductive health messages into existing health promotion campaigns (e.g., campaigns to reduce obesity and smoking). • Conduct consumer-focused research to identify terms that the public understands and to develop messages for promoting preconception health and reproductive awareness. • Design and conduct social marketing campaigns necessary to develop messages for promoting preconception health knowledge and attitudes, and behaviors among men and women of childbearing age. • Engage media partners to assist in depicting positive role models for lifestyles that promote reproductive health (e.g., delaying initiation of sexual activity, abstaining from unprotected sexual intercourse, and avoiding use of alcohol and drugs). # Box 2. Recommendation 2 preconception health action steps including campaigns designed to reduce tobacco use, promote responsible use of alcohol, and encourage healthy diet and optimal weight. Campaigns can include messages concerning reproductive health and childbearing. Such campaigns typically focus on the effect of adverse behaviors on children and do not include parallel messages regarding the potential impact on childbearing. New social marketing and health promotion campaigns that focus on how to prepare for childbearing and parenting can influence the behavior of men and women. For example, folic acid intake has been promoted among women of childbearing age (123). Similar to efforts to reduce teenage childbearing or increase use of prenatal care, the media can play a vital role in promoting reproductive awareness (157). Success in improving preconception health will require changes in public attitudes and has been achieved in other areas (e.g., attitudes changed during the previous 10 years regarding tobacco use, infant sleep position, or vaccinations for infants and toddlers instead of preschoolers) (158). A critical tool for stimulating these changes is social marketing, which is designed to influence the voluntary behavior of targeted audiences to improve their well-being (159,160). Consumer-friendly tools can help women self-assess risks, make plans, and take actions that will improve their health and that of their children. More consumer-focused research is needed to determine which messages and tools might be effective to encourage reproductive life planning. The SPPC members have suggested that such research explore which terms the public best understands, what messages might increase demand for services, and how touch-screen kiosks or other technology might be used to promote knowledge of preconception health topics (Box 2). Recommendation 3. Preventive Visits. As a part of primary care visits, provide risk assessment and educational and health promotion counseling to all women of childbearing age to reduce reproductive risks and improve pregnancy outcomes. Integration of preconception components into primary care can better serve women across their lifespan and at various levels of risk. Primary care integrates various health promotion, prevention, and acute care services to address the majority of personal health-care needs and common health problems in a community setting. Primary care also might include screening for and ongoing management of chronic conditions in a primary care setting. Elements of preconception care can be integrated into every primary care visit. Professional guidelines for clinicians (i.e., obstetrician/gynecologists, family practice physicians, certified nurse midwives, and nurse practitioners) who provide the majority of primary care to women in the United States should include routine risk assessment through screening (14,24,28,29,33). Different guidelines recommend eight to 10 specific areas for preconception risk assessment, including: 1) reproductive history; 2) environmental hazards and toxins; 3) medications that are known teratogens; 4) nutrition, folic acid intake, and weight management; 5) genetic conditions and family history; 6) substance use, including tobacco and alcohol; 7) chronic diseases (e.g., diabetes, hypertension, and oral health); 8) infectious diseases and vaccinations; 9) family planning; and 10) social and mental health concerns (e.g., depression, social support, domestic violence, and housing) (5)(6)(7)30,31,33,40,41). In addition to risk assessment or screening, professional guidelines include health promotion education and counseling related to reproductive health risks. Such activities should routinely include promotion of healthy behaviors; discussion of child spacing, family planning, and unintended pregnancy prevention; counseling concerning healthy diet, folic acid supplementation, and optimal weight; immunization for infectious disease; information regarding the importance of early prenatal care; and counseling concerning the availability of social and financial support programs. For women with identified risks, additional counseling, testing, and brief interventions (e.g., for smoking, alcohol, or changes in prescription medications) can be conducted in the primary care setting (68)(69)(70)(116)(117)(118) (e.g., a limited number of model visits), as is done for wellchild care. Clinical practice can be influenced by evidence-based guidelines, but additional strategies are needed to promote widespread adoption of professional guidelines (25,(30)(31)(32)(33)(151)(152)(153)(154). In the recommended action steps (Box 3), additional activities should be provided to support changes in primary care provider knowledge and attitudes and practices. Consolidation of existing guidelines, better tools, and use of quality improvement techniques have fostered changes in knowledge and practices (161)(162)(163)(164). For example, the Bright Futures Program has consolidated guidelines for child health, and the Bright Futures for Women's Health and Wellness offers models and opportunities for links to preconception care (165). Community health centers and other FQHC can be a key point of dissemination for strategies to improve preconception health. FQHC are a critical source of primary care for millions of women with low incomes and no insurance. Perinatal care for 332,000 women account for one of every 10 U.S. births (166). Among FQHC, the Health Disparities Collaboratives (HDC) Initiative is designed to improve the quality of primary care delivered, and approximately 600 FQHCs have participated (167). The HDC model relies on partnerships among community clinics, federal agencies, and national organizations. HDC started with a chronic disease care model for quality improvement, and a primary healthcare model integrated with the perinatal care collaboratives and other efforts has been developed. # Recommendation 4. Interventions for Identified Risks. Increase the proportion of women who receive interventions as follow-up to preconception risk screening, focusing on high priority interventions (i.e., those with evidence of effectiveness and greatest potential impact). Timely preconception interventions for certain conditions can substantially improve maternal health and birth outcomes (4,43). Separating childbearing from the management of chronic health problems and infectious diseases places women, their future pregnancies, and their future children at unnecessary risk (7,20,24,149). Conditions and risk factors have been identified for which the following exist 1) evidence of potential harm to mother or baby, 2) high prevalence of adverse pregnancy outcome or effective interventions for reducing adverse pregnancy outcomes, and 3) one or more effective interventions that have been evaluated. Certain women and men need additional counseling and interventions. For example, women who have conditions treated with medications that are known teratogens (e.g., anticonvulsant or anticoagulant medications and isotretinoins) might need to change prescriptions. Women with medical conditions associated with increased risks for morbidity and mortality to mother and fetus (e.g., diabetes, hypertension, heart disease, rubella sero-negativity, thrombophilias, dental disease, or obesity) need to control these conditions. Women with behaviors associated with increased health risks for the fetus (e.g., smoking and alcohol and illicit drug use) also need targeted interventions. Another group with specific counseling needs includes prospective parents with a family history of inherited (i.e., genetic) disorders. The preparers of this report analyzed the National Ambulatory Medical Care Survey (168) and demonstrated that diabetes affects approximately 1.85 million (21 per 1,000) women in the United States aged 18-44 years, and that preconceptional diabetes management has the potential to reduce the risk for pregnancy loss and congenital malformation for approximately 113,000 births per year. Anti-epileptic/ • Increase health provider (including primary and specialty care providers) awareness concerning the importance of ongoing care for chronic conditions and intervention for identified risk factors. (168). Women with chronic medical conditions and their specialty providers should take advantage of every opportunity to discuss preconception health and risks. These conditions and risk factors affect substantial proportions of the approximately 4 million pregnancies that occur in the United States each year. Studies of preconception care have indicated that providers do not routinely provide interventions for identified preconception risks (23,147,148,164,169). Dissemination of professional guidelines and evidence-based interventions are two vital ways to encourage changes in practice. However, quality improvement tools and techniques offer increased potential, particularly for specific interventions for women with identified conditions (162,170). Research has increasingly indicated that providers and health-care organizations are more likely to engage in evidence-based or best clinical practices, after participation in quality improvement projects (e.g., rapid improvement cycles using the plan/do/study/act approach, collaborative groups, or the model of improvement process that involves an aim/change/measure cycle) (162,170). Incorporation of preconception care modules into the curricula of medical graduate, postgraduate, and continuing medical education might be another method of disseminating messages regarding the importance and content of preconception care for women (Box 4). Recommendation 5. Interconception Care. Use the interconception period to provide additional intensive interventions to women who have had a previous pregnancy that ended in an adverse outcome (i.e., infant death, fetal loss, birth defects, low birthweight, or preterm birth). Experiencing an adverse outcome in a previous pregnancy is an important predictor of future reproductive risk (171)(172)(173). However, many women with adverse pregnancy outcomes do not receive targeted interventions to reduce risks during future pregnancies. Each year, approximately 28,000 infants die during the first year of life (171). Approximately 12% of all births are preterm (i.e., <37 weeks' gestation) (10), and an estimated 3% of infants are born with birth defects (174). Whereas a preterm birth is identified on birth certificates and a woman's primary care provider typically knows this information, professional guidelines do not include systematic follow-up and intervention for women with this critical predictor of risk. Postpartum visits are an opportunity to link women to interventions designed to reduce risks to them and their future chil-dren, and promising strategies focus on the postpartum period (170). The Health Employer Data and Information Set (HEDIS), used by public and private health plans, has measures for postpartum visits. HEDIS data indicate that 80% of women with private (i.e., commercial) insurance coverage and 55% of those covered by Medicaid receive postpartum checkups. However, for the majority of health plans, strategies to encourage compliance or address low rates of return for postpartum care have not been implemented (44). Measures for monitoring postpartum visits also are used by a limited number of state Title V Maternal Child Health Block Grant agencies (175). Data collected during postpartum visits typically have not been used to guide health-care system planning. Approaches to interconception care, which are part of preconception care, have been proposed (176,177), and certain approaches have been tested. For example, in the Interpregnancy Care Program of Grady Memorial Hospital in Atlanta, Georgia, researchers have been studying the effectiveness of interconception care in improving subsequent reproductive outcomes for women who have delivered a baby born at very low birthweight (<1,500 grams). This model focuses on reducing identified medical, dental, and psychosocial risks and assisting women in developing and • Consolidate existing professional guidelines to develop the recommended content and approach for such a visit. • Modify third party payer rules to permit payment for one prepregnancy visit per pregnancy, including development of billing and payment mechanisms. • Educate women and couples regarding the value and availability of prepregnancy planning visits. # Box 6. Recommendation 6 preconception health action steps achieving their reproductive goals for the future. During the pilot phase, the program identified and treated various medical conditions and reported substantial positive impact on the length of birth intervals (177). The federal Healthy Start program requires that a grantee follow a woman and her child for 2 years postpartum, providing interconception care. In addition, certain Healthy Start grantees provide more in-depth interconception services to women at high risk to reduce future adverse pregnancy outcomes (175). Across the United States, Healthy Start grantees (e.g., the Magnolia Project in northeastern Florida) are providing intensive postpartum case management for women at high risk for adverse pregnancy outcomes (178)(179). Opportunities are available to identify, refer, and serve women at high risk in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) nutrition sites, family planning clinics, and home visiting programs (175). Federal and state agencies can support such efforts with funding for demonstration, evaluation, and replication projects (Box 5). Recommendation 6. Prepregnancy Checkup. Offer, as a component of maternity care, one prepregnancy visit for couples and persons planning pregnancy. SPPC encourages the use of a broad definition of maternity care that includes the addition of a prepregnancy visit and the recommended prenatal and postpartum visits. The addition of this prepregnancy visit is an essential step toward improving pregnancy outcomes, particularly for those planning pregnancy. The Institute of Medicine Panel on Preventing Low Birthweight, the U.S. Public Health Service Expert Panel on the Content of Prenatal Care, and the national Committee on Perinatal Health have recommended that women have a prepregnancy visit (i.e., sometimes called a preconception visit) in the months before conception (1,3,4). Such visits would include preconception care content, providing women an opportunity to benefit from risk assessment, health promotion, and specific interventions related to circumstances when couples are trying to conceive. Adoption of the prepregnancy visit as a standard of care also can help to reinforce the importance of pregnancy planning and preparedness among women and men (Box 6). # Recommendation 7. Health Insurance Coverage for Women with Low Incomes. Increase public and private health insurance coverage for women with low incomes to improve access to preventive women's health and preconception and interconception care. Affordability of care is a major concern for multiple women (11,180,181), and improved access to preconception care is needed. Approximately 17 million women do not have health insurance, and they are more likely to postpone or forgo care (180). During 2003, one third of women with low incomes, half of women with disabilities, and 18% of all nonelderly (aged <65 years) women did not have health insurance (180). Younger women aged 18-34 years were more likely than older women not to have health insurance during 2003. Reflecting their income and employment status patterns (i.e., more likely to have incomes <200% of poverty level and less likely to be employed in jobs that offer health insurance), non-Hispanic white, Asian, and non-Hispanic black women were more likely than non-Hispanic white women not to have health insurance (11,180,181 # Box 7. Recommendation 7 preconception health action steps Medicaid is the primary mechanism for extending health coverage to women with low incomes and who do not have health insurance. During 2003, a total of 12% of all women of childbearing age and 37% of women with low incomes in that age group relied on Medicaid for health-care coverage (181,182). Medicaid has been demonstrated to be effective in improving access to health care for women with low incomes (179). Because nearly two thirds (63%) of women covered by Medicaid are of childbearing age, the program's performance is related to preconception care access and to the outcomes of pregnancy (183). Many women with low incomes, however, do not qualify for Medicaid because they do not have children aged <18 years or do not have documentation of legal residence in the United States. As states seek to expand Medicaid coverage to persons with low incomes and adults who do not have health insurance, women of childbearing age should receive priority for qualifying for Medicaid coverage. Since 1995, a total of 22 states have used their federal waiver authority to expand family planning services to women who do not otherwise qualify for Medicaid, known as family planning waivers. Certain states offer coverage to women who lose coverage after the birth of a baby or starting a job, whereas other states offer family planning coverage based on the income status of men and women (182). An evaluation of these family planning waiver projects prepared for the federal Center for Medicare and Medicaid Services indicated that the projects resulted in substantial savings to both the federal and state governments (184). Increased potential savings and prevention, however, can result if states provided coverage for more comprehensive risk screening, health promotion, and interventions, resulting in higher levels of preconception wellness (Box 7). # Recommendation 8. Public Health Programs and Strategies. Integrate components of preconception health into existing local public health and related programs, including emphasis on interconception interventions for women with previous adverse outcomes. Public health programs serve millions of women each year. Preconception interventions can be incorporated into these programs to target women at highest risk. Title X family planning programs provide approximately 4.6 million women with family planning education and contraceptives and pregnancy tests. However, a limited number of programs offer more comprehensive risk screening, reproductive health promotion, and reproductive life planning (185). Each year, WIC provides nutrition screening and counseling, supplemental food, and referrals to health services for approximately 8 million women during pregnancy and the postpartum period (186). These services provide an opportunity to promote preconception health and refer women at risk to clinicians. Federal and state public health programs funded by the Title V Maternal and Child Health Services Block Grant and CDC can give greater priority to preconception health and offer support for demonstration projects and evaluations of prevention programs. Whereas federally funded Healthy Start projects are required to have interconception health activities, these projects, located in communities with high infant mortality, provide opportunities to offer more systematic preconception screening, health promotion, and interventions. Publicly funded programs that offer screening and related services for STDs and HIV/AIDS also might provide risk assessment and health promotion interventions. Title X, WIC, Title V, Healthy Start, and other public health programs also provide a setting to test and evaluate new approaches to improve preconception health (44,187). Strategies to promote dialogue and action among community members for a geographically defined community or a community of professionals can help advance these recommendations and action steps (Box 8). Local task force groups that involve consumer, community leaders, and health professionals can help implement preconception strategies that are similar to strategies used previously for other topics (e.g., adolescent pregnancy prevention and childhood vaccinations). Functioning parallel to clinical practice collaboratives, public health practice collaboratives that link local public health programs can promote development and dissemination of community-based best practices. Recommendation 9. Research. Increase the evidence base and promote the use of the evidence to improve preconception health. # 191). At the state and local levels, PRAMS, Perinatal Periods of Risk, Fetal-Infant Mortality Review, and youth risk behavior surveys provide additional opportunities for the data collection, analysis, and interpretation that comprise public health surveillance (190,(192)(193)(194). The Maternal and Child Health Bureau, in cooperation with states, operates the Title V data and information system, which provides an opportunity to strengthen public health surveillance and performance monitoring. A review of stateselected performance measures and priority needs for 2006-2010 indicated that a limited number of states are monitoring trends for access to components of preconception and interconception care, access to primary care for women of childbearing age, unintended pregnancy, and other related topics (175). Since 1990, indicators and monitoring systems have been used not only to assess programs at the population level but also to measure the quality of health-care services. HEDIS is an example of a set of measures commonly used by purchasers of health-care coverage, including state Medicaid agencies and employers. HEDIS includes indicators on prenatal and postpartum care and family planning (195). New HEDIS measures are needed to monitor access to, use of, and outcomes of preconception care services as well as improved maternal and infant health. The recommendations in this report can be used as a frame work for developing or modifying # Box 9. Recommendation 9 preconception health action steps Additional evidence is needed regarding the effectiveness of interventions, the value of better service integration, and the potential cost benefit of preconception care for the general population and for women at high risk for poor pregnancy outcomes. Evaluations of preconception health programs and projects can help advance understanding of the potential impact of selected approaches. For certain clinical interventions (e.g., interventions to address multiple risk factors simultaneously or single risk factor interventions), randomized clinical trials are warranted, although not all preconception health interventions can be ethically tested in this manner. Economic studies, particularly of clinical intervention strategies, can support the case for wider dissemination of preconception care practices (188; Box 9). # Recommendation 10. Monitoring Improvements. Maximize public health surveillance and related research mechanisms to monitor preconception health. Community health data are used systematically to conduct public health surveillance to evaluate and improve health, health programs, and health policy (187). Surveillance includes monitoring the frequency of conditions, risk factors, services, and outcomes. CDC and other public health agencies conduct surveillance and maintain data collection and surveillance systems, and the field of maternal and child health benefits from several of these systems. For example, PRAMS, the Behavioral Risk Factor Surveillance System, and the National Survey of Family Growth (NSFG) can be modified to provide more data concerning preconception health (189- # Conclusion The 10 recommendations for improving preconception care services and the health of women and infants were developed through a process of consultation with a select panel of specialists from the relevant disciplines. Implementation of the recommendations will help achieve the SPPC vision of preconception health and pregnancy outcomes in which 1) women and men of childbearing age have high reproductive awareness (i.e., understand risk factors related to childbearing); 2) women and men have a reproductive life plan (e.g., whether or when they want to have children and how they will maintain their reproductive health); 3) pregnancies are intended and planned; 4) women and men of childbearing age have health-care coverage; 5) women of childbearing age are screened before pregnancy for risks related to the outcomes of pregnancy; and 6) women with a previous adverse preg-nancy outcome (e.g., infant death, very low birthweight or preterm birth) have access to interconception care aimed at reducing their risks. Improving preconception health will require changes in the knowledge and attitudes and behaviors of persons, families, communities, and institutions (e.g., government and healthcare settings). The purpose of preconception care is to improve the health of each woman before any pregnancy and thereby affect the future health of the woman, her child, and her family. The recommendations and specific action steps were developed as a result of SPPC meeting and implementation of CDC's preconception health programs. The frame work has incorporated both an ecological model and a lifespan perspective on health and recognized the unique contributions and challenges encountered by women, their families, communities, and institutions. Improving the health of women can increase the quality of health for families and the community. Several preconception care interventions have reduced risk and improved health outcomes. By increasing support for provision of preconception care, policy makers have the opportunity to promote broad-based programs and services aimed at improving the health of women, children, and families. The recommendations present a conceptual frame work for innovative service delivery models so that women are afforded the benefit of risk-appropriate preconception services during every encounter with the health-care system. • Apply public health surveillance strategies to monitor selected preconception health indicators (e.g., folic acid supplementation, smoking cessation, alcohol misuse, diabetes, and obesity). • Expand data systems and surveys (e.g., the Pregnancy Risk Assessment and Monitoring System and the National Survey of Family Growth) to monitor individual experiences related to preconception care. • Use geographic information system techniques to target preconception health programs and interventions to areas where high rates of poor health outcomes exist for women of reproductive age and their infants. • Use analytic tools (e.g., Perinatal Periods of Risk) to measure and monitor the proportion of risk attributable to the health of women before pregnancy. • Include preconception, interconception, and health status measures in population-based performance monitoring systems (e.g., in national and state Title V programs). • Include a measure of the delivery of preconception care services in the Healthy People 2020 objectives. • Develop and implement indicator quality improvement measures for all aspects of preconception care. For example, use the Health Employer Data and Information Set measures to monitor the percentage of women who complete preconception care and postpartum visits or pay for performance measures. # CDC/ATSDR Preconception Care Work Group Agency for Toxic Substances and Disease Registry: Robert H. Johnson, MD, Division of Health Education and Promotion. # Appendix # Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. You must complete and return the response form electronically or by mail by April 21, 2009, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1. 75 # Goals and Objectives This report provides an updated review of the evidence for interventions to improve the health of women before pregnancy. The goal of this report is to present 10 recommendations to improve preconception care, focusing on specific activities at the individual, clinical, public health, community, and research levels. Upon completion of this educational activity, the reader should be able to 1) describe the need for preconception health for families, 2) define preconception care, 3) list the 10 recommendations for improving preconception care, 4) list specific action steps for each recommendation, 5) describe the interventions for improving preconception health that are supported by professional guidelines, 6) describe the responsibilities of persons concerned with preconception health, and 7) describe areas of preconception health care that need further research. To receive continuing education credit, please answer all of the following questions.	None	None
2140e688764555774e6f35cca0b1afc9a407b7b8	cdc	None	This report provides updated information concerning the potential adverse events associated with vaccination for hepatitis B, poliomyelitis, measles, mumps, diphtheria, tetanus, and pertussis. This information incorporates findings from a series of recent literature reviews, conducted by an expert committee at the Institute of Medicine (IOM), of all evidence regarding the possible adverse consequences of vaccines administered to children. This report contains modifications to the previously published recommendations of the Advisory Committee on Immunization Practices (ACIP) and is based on an ACIP review of the IOM findings and new research on vaccine safety. In addition, this report incorporates information contained in the "Recommendations of the Advisory Committee on Immunization Practices: Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence" (MMWR 1993;42) and the "General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)" (MMWR 1994;43). Major changes to the previous recommendations are highlighted within the text, and specific information concerning the following vaccines and the possible adverse events associated with their administration are included: hepatitis B vaccine and anaphylaxis; measles vaccine and a) thrombocytopenia and b) possible risk for death resulting from anaphylaxis or disseminated disease in immunocompromised persons; diphtheria and tetanus toxoids and pertussis vaccine (DTP) and chronic encephalopathy; and tetanus-toxoid-containing vaccines and a) Guillain-Barré syndrome, b) brachial neuritis, and c) possible risk for death resulting from anaphylaxis. These modifications will be incorporated into more comprehensive ACIP recommendations for each vaccine when such statements are revised. Also included in this report are interim recommendations concerning the use of measles and mumps vaccines in a) persons who are infected with human immunodeficiency virus and b) persons who are allergic to eggs; ACIP is still evaluating these recommendations. In this publication, the terms "side effects" and "adverse reactions" are used interchangeably to denote the undesirable secondary effects resulting from vaccination.# INTRODUCTION Immunization has enabled the global eradication of smallpox (1 ), the elimination of poliomyelitis from the Western hemisphere (2 ), and major reductions in the incidence of other vaccine-preventable diseases in the United States (Table 1). However, although immunization has successfully reduced the incidence of vaccine-preventable diseases, vaccination can cause both minor and, rarely, serious side effects. Public awareness of and controversy about vaccine safety has increased, primarily because increases in vaccine coverage resulted in an increased number of adverse events that occurred after vaccination. Such adverse events include both true reactions to vaccine and events coincidental to, but not caused by, vaccination. Despite concerns about vaccine safety, vaccination is safer than accepting the risks for the diseases these vaccines prevent. Unless a disease has been eradicated (e.g., smallpox), failure to vaccinate increases the risks to both the individual and society. In response to concerns about vaccine safety, the National Childhood Vaccine Injury Act of 1986 established a no-fault compensation process for persons possibly injured by selected vaccines (3 ). The Act also mandated that the Institute of Medicine- (IOM) review scientific and other evidence regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review all available information on these vaccine adverse events; such information included epidemiologic studies, case series, individual case reports, and testimonials. To derive their conclusions, the IOM committee members created five categories of causality to describe the relationships between the vaccines and specific adverse events. The first IOM review examined certain events occurring after administration of pertussis and rubella vaccines (Table 2) (4 ). The second IOM review examined events occurring after administration of all other vaccines usually administered during childhood (i.e., diphtheria and tetanus toxoids and measles, mumps, hepatitis B, Haemophilus influenzae type b , and poliovirus vaccines) (Table 3) (5 ). Two other IOM committees have met since the findings of the second review were published. These two committees have published An independent research organization chartered by the National Academy of Sciences. (4 ), an independent research organization chartered by the National Academy of Sciences. The National Childhood Vaccine Injury Act of 1986 mandated that IOM review scientific and other evidence (e.g., epidemiologic studies, case series, individual case reports, and testimonials) regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review and summarize all available information; this committee created five categories of causality to describe the relationships between the vaccines and specific adverse events. ¶ IOM reviewed this adverse event again in 1994 (5 ). Defined in the controlled studies that were reviewed as encephalopathy, encephalitis, or encephalomyelitis. # TABLE 2. Summarized conclusions of evidence regarding the possible association between specific adverse effects and receipt of diphtheria and tetanus toxoids and pertussis vaccine (DTP)- and RA 27/3 measles-mumps-rubella (MMR) † vaccine, by determination of causality - their findings concerning both the diphtheria and tetanus toxoids and pertussis vaccine (DTP) and chronic nervous system dysfunction (Figure 1) (6 ) and research strategies for vaccine-associated adverse events (7 ). The Advisory Committee on Immunization Practices (ACIP) recently reviewed the findings of the IOM committees and modified the previously published ACIP recommendations to ensure consistency with IOM conclusions. These recommendations, which are included in this report, update all previously published ACIP recommendations pertaining to the precautions, contraindications, side effects, and adverse reactions- associated with specific vaccines. ACIP accepted the IOM conclusions for MMWR September 6, 1996 (5 ), an independent research organization chartered by the National Academy of Sciences. The National Childhood Vaccine Injury Act of 1986 mandated that IOM review scientific and other evidence (e.g., epidemiologic studies, case series, individual case reports, and testimonials) regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review and summarize all available information; this committee created five categories of causality to describe the relationships between the vaccines and specific adverse events. † DT=diphtheria and tetanus toxoids for pediatric use; Td=diphtheria and tetanus toxoids for adult use. § If the data derived from studies of a monovalent preparation, then the causal relationship also extended to multivalent preparations. If the data derived exclusively from studies of the measles-mumps-rubella (MMR) vaccine, the vaccine is specified parenthetically in italics. In the absence of data concerning the monovalent preparation, the causal relationship determined for the multivalent preparations did not extend to the monovalent components. ¶ For some adverse events, the IOM committee was charged with assessing the causal relationship between the adverse event and only oral poliovirus vaccine (OPV) (i.e., for poliomyelitis) or only inactivated poliovirus vaccine (IPV) (i.e., for anaphylaxis and thrombocytopenia). If the conclusions for the two vaccines differed for the other adverse events, the vaccine to which the adverse event applied is specified parenthetically in italics. The evidence used to establish a causal relationship for anaphylaxis applies to MMR vaccine. The evidence regarding monovalent measles vaccine favored acceptance of a causal relationship, but this evidence was less convincing than that for MMR vaccine because of either incomplete documentation of symptoms or the possible attenuation of symptoms by medical intervention. † † This table lists weight-of-evidence determinations only for deaths that were classified as sudden infant death syndrome (SIDS) and deaths that were a consequence of vaccine-strain viral infection. However, if the evidence favored the acceptance of (or established) a causal relationship between a vaccine and a possibly fatal adverse event, then the evidence also favored the acceptance of (or established) a causal relationship between the vaccine and death from the adverse event. Direct evidence regarding death in association with a vaccine-associated adverse event was limited to a) Td and Guillain-Barré syndrome, b) tetanus toxoid and anaphylaxis, and c) OPV and poliomyelitis. § § The evidence derived from studies of DT. If the evidence favored rejection of a causal relationship between DT and encephalopathy, then the evidence also favored rejection of a causal relationship between Td and tetanus toxoid and encephalopathy. ¶ ¶ Infantile spasms and SIDS occur only in an age group that is administered DT but not Td or tetanus toxoid. * The evidence derived primarily from studies of DTP, although the evidence also favored rejection of a causal relationship between DT and SIDS. † † † The evidence derived from studies of tetanus toxoid. If the evidence favored acceptance of (or established) a causal relationship between tetanus toxoid and an adverse event, then the evidence also favored acceptance of (or established) a causal relationship between DT and Td and the adverse event. § § § This conclusion differs from the information contained in the ACIP recommendations because of new information that became available after IOM published this table. ¶ ¶ ¶ Deaths occurred primarily among persons known to be immunocompromised. almost all vaccine adverse events; the few exceptions generally occurred because new information that was available to ACIP had not been available when the IOM committees published their recommendations. These exceptions included a) oral poliovirus vaccine (OPV) and Guillain-Barré syndrome (GBS), b) tetanus-toxoidcontaining vaccines and GBS, and c) DTP and chronic nervous system dysfunction. In addition, this report incorporates information contained in the "Recommendations of the Advisory Committee on Immunization Practices: Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence" (MMWR 1993;42) and the "General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)" (MMWR 1994;43). To facilitate recognition of the new recommendations in this report, all major changes that are being made to the previously published ACIP statements are highlighted within the text. These changes include information on the following vaccines and the possible adverse events associated with their administration: - Hepatitis B vaccine and anaphylaxis; - Measles vaccine and a) thrombocytopenia and b) possible risk for death resulting from anaphylaxis or disseminated disease in immunocompromised persons; - DTP and chronic encephalopathy; and - Tetanus-toxoid-containing vaccines and a) GBS, b) brachial neuritis, and c) possible risk for death resulting from anaphylaxis. The modifications contained in this report, and possibly other changes as new information becomes available, will be incorporated into more comprehensive ACIP recommendations for each vaccine when such statements are revised. # HEPATITIS B VACCINE The following recommendations concerning adverse events associated with hepatitis B vaccination update those applicable sections in "Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination-Recommendations of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1991;40). # Vaccine Side Effects and Adverse Reactions Hepatitis B vaccines are safe to administer to adults and children. More than an estimated 10 million adults and 2 million infants and children have been vaccinated in the United States, and at least 12 million children have been vaccinated worldwide. # Vaccine-Associated Side Effects Pain at the injection site (3%-29%) and a temperature greater than 37.7 C (1%-6%) have been among the most frequently reported side effects among adults and children receiving vaccine (8)(9)(10)(11)(12). In placebo-controlled studies, these side effects were reported no more frequently among vaccinees than among persons receiving a placebo (11,12 ). Among children receiving both hepatitis B vaccine and DTP, these mild side effects have been observed no more frequently than among children receiving only DTP. The recommendation to begin hepatitis B vaccination soon after birth has raised the concern that a substantial number of infants will require an extensive medical evaluation for elevated temperatures secondary to hepatitis B vaccination. Several population-based studies to evaluate this possibility are in progress. # Adverse Events In the United States, surveillance of adverse reactions indicated a possible association between GBS and receipt of the first dose of plasma-derived hepatitis B vaccine (CDC, unpublished data; 13 ). However, an estimated 2.5 million adults received one or more doses of recombinant hepatitis B vaccine during 1986-1990, and available data concerning these vaccinees do not indicate an association between receipt of recombinant vaccine and GBS (CDC, unpublished data). Based on reports to the Vaccine Adverse Events Reporting System (VAERS), the estimated incidence rate of anaphylaxis among vaccine recipients is low (i.e., approximately one event per 600,000 vaccine doses distributed). Two of these adverse events occurred in children (CDC, unpublished data). In addition, only one case of anaphylaxis occurred among 100,763 children ages 10-11 years who had been vaccinated with recombinant vaccine in British Columbia (D. Scheifele, unpublished data), and no adverse events were reported among 166,757 children who had been vaccinated with plasma-derived vaccine in New Zealand (5 ). Although none of the persons who developed anaphylaxis died, this adverse event can be fatal; in addition, hepatitis B vaccine can-in rare instances-cause a life-threatening hypersensitivity reaction in some persons (5 ). Therefore, subsequent vaccination with hepatitis B vaccine is contraindicated for persons who have previously had an anaphylactic response to a dose of this vaccine. Large-scale hepatitis B immunization programs for infants in Alaska, New Zealand, and Taiwan have not established an association between vaccination and the occurrence of other severe adverse events, including seizures and GBS (B. McMahon and A. Milne, unpublished data; 14 ). However, systematic surveillance for adverse reactions in these populations has been limited, and only a minimal number of children have received recombinant vaccine. Any presumed risk for adverse events that might be causally associated with hepatitis B vaccination must be balanced with the expected risk for hepatitis B virus (HBV)-related liver disease. Currently, an estimated 2,000-5,000 persons in each U.S. birth cohort will die as a result of HBV-related liver disease because of the 5% lifetime risk for HBV infection. As hepatitis B vaccine is introduced for routine vaccination of infants, surveillance for vaccine-associated adverse events will continue to be an important part of the program despite the current record of safety. Any adverse event suspected to be associated with hepatitis B vaccination should be reported to VAERS. VAERS forms can be obtained by calling (800) 822-7967. # POLIOMYELITIS PREVENTION The following recommendations concerning adverse events associated with poliomyelitis vaccination update those applicable sections in "Poliomyelitis Prevention: Recommendation of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1982;31:22-6,31-4) and "Poliomyelitis Prevention: Enhanced-Potency Inactivated Poliomyelitis Vaccine-Supplementary Statement" (MMWR 1987;36:795-8). # Precautions and Contraindications Pregnancy Although no conclusive evidence documents the adverse effects of OPV or inactivated poliovirus vaccine (IPV) in pregnant women and their developing fetuses, vaccination of pregnant women should be avoided. However, if immediate protection against poliomyelitis is necessary, OPV or IPV can be given. # Immunodeficiency Persons who have congenitally acquired immune-deficiency diseases (e.g., combined immunodeficiency, hypogammaglobulinemia, and agammaglobulinemia) should not be given OPV because of their substantially increased risk for vaccineassociated disease. Furthermore, persons who have altered immune status resulting from acquired conditions (e.g., human immunodeficiency virus infection, leukemia, lymphoma, or generalized malignancy) or who have immune systems compromised by therapy (e.g., treatment with corticosteroids, alkylating drugs, antimetabolites, or radiation) should not receive OPV because of the theoretical risk for paralytic disease. IPV-and not OPV-should be used to vaccinate immunodeficient persons and their household contacts. Many immunosuppressed persons are already immune to polioviruses because of previous vaccination or exposure to wild-type virus when they were immunocompetent. Although such persons should not receive OPV, their risk for paralytic disease may be less than that of persons who have congenitally acquired immunodeficiency. Although a protective immune response to IPV in the immunodeficient patient cannot be ensured, the vaccine is safe and some protection may result from its administration. If a household contact of an immunodeficient person is vaccinated inadvertently with OPV, the OPV recipient should avoid close physical contact with the immunodeficient person for approximately 4-6 weeks after vaccination (i.e., during the period of maximum excretion of vaccine virus). If such contact cannot be avoided, rigorous hygiene and hand washing after contact with feces (e.g., after diaper changing) and avoidance of contact with saliva (e.g., by not sharing eating utensils or food) should be practiced. These practices are an acceptable, but probably less effective, alternative than refraining from contact. Because immunodeficiency is possible in other children born to a family in which one child is immunodeficient, OPV should not be administered to a member of such a household until the immune status of the recipient and other children in the family is documented. # Adverse Reactions OPV In rare instances, administration of OPV has been associated with paralytic poliomyelitis in healthy recipients and their contacts. Very rarely, OPV has caused fatal paralytic poliomyelitis in immunocompromised persons (5 ). Other than efforts for identifying persons with immune-deficiency conditions, no procedures are currently available to identify persons likely to experience such adverse reactions. Although the risk of vaccine-associated paralysis is extremely small for vaccinees and their susceptible, close, personal contacts, they should be informed of this risk. Available data do not indicate a measurable increased risk for GBS after receipt of OPV. Initial reports (at the time of IOM review) of two studies conducted in Finland suggested that OPV might cause GBS. These studies identified an apparent increased incidence of GBS that was temporally associated with mass OPV vaccination of children and adults who had previously received IPV (15,16 ). Since the IOM review, a reanalysis of the data derived from the studies conducted in Finland and an analysis of an observational study conducted in the United States have not demonstrated a causal relationship between OPV and GBS in infants (17 ). Because OPV contains trace amounts of streptomycin, bacitracin, and neomycin, its use is contraindicated in persons who have previously had an anaphylactic reaction to OPV or to these antibiotics. # IPV No serious side effects of currently available IPV have been documented. Since IPV contains trace amounts of streptomycin and neomycin, there is a possibility of hypersensitivity reactions in individuals sensitive to these antibiotics. # MEASLES PREVENTION The following recommendations concerning adverse events associated with measles vaccination update those applicable sections in "Measles Prevention: Recommendations of the Immunization Practices Advisory Committee" (MMWR 1989; 38), and they apply regardless of whether the vaccine is administered as a single antigen or as a component of measles-rubella (MR) or measles-mumps-rubella (MMR) vaccine. Information concerning adverse events associated with the mumps component of MMR vaccine is reviewed later in this document (see Mumps Prevention), and information concerning the rubella component is located in the previously published ACIP statement for rubella (18 ). # Side Effects and Adverse Reactions More than 240 million doses of measles vaccine were distributed in the United States from 1963 through 1993. The vaccine has an excellent record of safety. From 5% to 15% of vaccinees may develop a temperature of ≥103 F (≥39.4 C) beginning 5-12 days after vaccination and usually lasting several days (19 ). Most persons with fever are otherwise asymptomatic. Transient rashes have been reported for approximately 5% of vaccinees. Central nervous system (CNS) conditions, including encephalitis and encephalopathy, have been reported with a frequency of less than one per million doses administered. The incidence of encephalitis or encephalopathy after measles vaccination of healthy children is lower than the observed incidence of encephalitis of unknown etiology. This finding suggests that the reported severe neurologic disorders temporally associated with measles vaccination were not caused by the vaccine. These adverse events should be anticipated only in susceptible vaccinees and do not appear to be age-related. After revaccination, most reactions should be expected to occur only among the small proportion of persons who failed to respond to the first dose. # Personal and Family History of Convulsions As with the administration of any agent that can produce fever, some children may have a febrile seizure. Although children with a personal or family history of seizures are at increased risk for developing idiopathic epilepsy, febrile seizures following vaccinations do not in themselves increase the probability of subsequent epilepsy or other neurologic disorders. Most convulsions following measles vaccination are simple febrile seizures, and they affect children without known risk factors. An increased risk of these convulsions may occur among children with a prior history of convulsions or those with a history of convulsions in first-degree family members (i.e., siblings or parents) (20 ). Although the precise risk cannot be determined, it appears to be low. In developing vaccination recommendations for these children, ACIP considered a number of factors, including risks from measles disease, the large proportion (5%-7%) of children with a personal or family history of convulsions, and the fact that convulsions following measles vaccine are uncommon. Studies conducted to date have not established an association between MMR vaccination and the development of a residual seizure disorder (5 ). ACIP concluded that the benefits of vaccinating these children greatly outweigh the risks. They should be vaccinated just as children without such histories. Because the period for developing vaccine-induced fever occurs approximately 5-12 days after vaccination, prevention of febrile seizures is difficult. Prophylaxis with antipyretics has been suggested as one alternative, but these agents may not be effective if given after the onset of fever. To be effective, such agents would have to be initiated before the expected onset of fever and continued for 5-7 days. However, parents should be alert to the occurrence of fever after vaccination and should treat their children appropriately. Children who are being treated with anticonvulsants should continue to take them after measles vaccination. Because protective levels of most currently available anticonvulsant drugs (e.g., phenobarbital) are not achieved for some time after therapy is initiated, prophylactic use of these drugs does not seem feasible. The parents of children who have either a personal or family history of seizures should be advised of the small increased risk of seizures following measles vaccination. In particular, they should be told in advance what to do in the unlikely event that a seizure occurs. The permanent medical record should document that the small risk of postimmunization seizures and the benefits of vaccination have been discussed. # Subacute Sclerosing Panencephalitis (SSPE) Measles vaccine significantly reduces the likelihood of developing SSPE, as evidenced by the near elimination of SSPE cases after widespread measles vaccination began. SSPE has been reported rarely in children who do not have a history of natural measles infection but who have received measles vaccine. The available evidence suggests that at least some of these children may have had an unidentified measles infection before vaccination and that the SSPE probably resulted from the natural measles infection. The administration of live measles vaccine does not increase the risk for SSPE, regardless of whether the vaccinee has had measles infection or has previously received live measles vaccine (5,21 ). # Thrombocytopenia Surveillance of adverse reactions in the United States and other countries indicates that MMR vaccine can, in rare circumstances, cause clinically apparent thrombocytopenia within the 2 months after vaccination. In prospective studies, the reported incidence of clinically apparent thrombocytopenia after MMR vaccination ranged from one case per 30,000 vaccinated children in Finland (22 ) and Great Britain (23 ) to one case per 40,000 in Sweden, with a temporal clustering of cases occurring 2-3 weeks after vaccination (24 ). With passive surveillance, the reported incidence was approximately one case per 100,000 vaccine doses distributed in Canada and France (25 ), and approximately one case per 1 million doses distributed in the United States (26 ). The clinical course of these cases was usually transient and benign, although hemorrhage occurred rarely (26 ). Furthermore, the risk for thrombocytopenia during rubella or measles infection is much greater than the risk after vaccination. Of 30,000 schoolchildren in one Pennsylvania county who had been infected with rubella during the 1963-64 measles epidemic, 10 children developed thrombocytopenic purpura (incidence: one case per 3,000 children) (27 ). Based on case reports, the risk for thrombocytopenia may be higher for persons who previously have had idiopathic thrombocytopenic purpura, particularly for those who had thrombocytopenic purpura after an earlier dose of MMR vaccine (5,28,29 ). # Revaccination Risks There is no evidence of an increased risk for adverse reactions after administration of live measles vaccine to persons who are already immune to measles as a result of either previous vaccination or natural disease. # Precautions and Contraindications Pregnancy Live measles vaccine, when given as a component of MR or MMR, should not be given to women known to be pregnant or who are considering becoming pregnant within the next 3 months. Women who are given monovalent measles vaccine should not become pregnant for at least 30 days after vaccination. This precaution is based on the theoretical risk of fetal infection, although no evidence substantiates this theoretical risk. Considering the importance of protecting adolescents and young adults against measles, asking women if they are pregnant, excluding those who are, and explaining the theoretical risks to the others before vaccination are sufficient precautions. # Febrile Illness The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the cause of the illness and the severity of symptoms. Minor illnesses, such as a mild upper-respiratory infection with or without low-grade fever, are not contraindications for vaccination. For persons whose compliance with medical care cannot be assured, every opportunity should be taken to provide appropriate vaccinations. Children with moderate or severe febrile illnesses can be vaccinated as soon as they have recovered from the acute phase of the illness. This wait avoids superimposing adverse effects of vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine. Performing routine physical examinations or measuring temperatures are not prerequisites for vaccinating infants and children who appear to be in good health. Asking the parent or guardian if the child is ill, postponing vaccination for children with moderate or severe febrile illnesses, and vaccinating those without contraindications are appropriate procedures in childhood immunization programs. # Allergic Reactions Hypersensitivity reactions rarely occur after the administration of MMR or any of its component vaccines. Most of these reactions are minor and consist of a wheal and flare or urticaria at the injection site. Immediate, anaphylactic reactions to MMR or its component vaccines are extremely rare. Although >70 million doses of MMR vaccine have been distributed in the United States since VAERS was implemented in 1990, only 33 cases of anaphylactic reactions that occurred after MMR vaccination have been reported. Furthermore, only 11 of these cases a) occurred immediately after vaccination and b) occurred in persons who had symptoms consistent with anaphylaxis (CDC, unpublished data). In the past, persons who had a history of anaphylactic reactions (i.e., hives, swelling of the mouth or throat, difficulty breathing, hypotension, and shock) following egg ingestion were considered to be at increased risk for serious reactions after receipt of measles-containing vaccines, which are produced in chick embryo fibroblasts. Protocols requiring caution were developed for skin testing and vaccinating persons who had had anaphylactic reactions after egg ingestion (30)(31)(32)(33)(34). However, the predictive value of such skin testing and the need for special protocols when vaccinating egg-allergic persons with measles-containing vaccines is uncertain. The results of recent studies suggest that anaphylactic reactions to measles-containing vaccines are not associated with hypersensitivity to egg antigens but with some other component of the vaccines. The risk for serious allergic reaction to these vaccines in egg-allergic patients is extremely low, and skin testing is not necessarily predictive of vaccine hypersensitivity (35)(36)(37). Therefore, ACIP is re-evaluating whether skin testing and the use of special protocols are routinely necessary when administering MMR or other measles-containing vaccines to persons who have a history of anaphylactic-like reactions after egg ingestion. MMR and its component vaccines contain hydrolyzed gelatin as a stabilizer. The literature contains a single case report of a person with an anaphylactic sensitivity to gelatin who had an anaphylactic reaction after receipt of the MMR vaccine licensed in the United States (38 ). Similar cases have occurred in Japan (39 ). Therefore, ACIP is currently considering recommendations for vaccination of persons who have had an anaphylactic reaction to gelatin or gelatin-containing products. In the meantime, such persons should be vaccinated with MMR and its component vaccines with extreme caution. MMR vaccine and its component vaccines contain trace amounts of neomycin. Although the amount present is less than that usually used for a skin test to determine hypersensitivity, persons who have experienced anaphylactic reactions to neomycin should not be given these vaccines. Most often, neomycin allergy is manifested by contact dermatitis rather than anaphylaxis. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine. Live measles virus vaccine does not contain penicillin. # Thrombocytopenia Children who have a history of thrombocytopenic purpura or thrombocytopenia may be at increased risk for developing clinically significant thrombocytopenia after MMR vaccination. The decision to vaccinate should depend on the benefits of immunity to measles, mumps, and rubella and the risks for recurrence or exacerbation of thrombocytopenia after vaccination or during natural infections with measles or rubella. The benefits of immunization are usually greater than the potential risks, and administration of MMR vaccine is justified-particularly with regard to the even greater risk for thrombocytopenia after measles or rubella disease. However, avoiding a subsequent dose might be prudent if the previous episode of thrombocytopenia occurred in close temporal proximity to (i.e., within 6 weeks after) the previous vaccination. Serologic evidence of measles immunity in such persons may be sought in lieu of MMR vaccination. # Recent Administration of Immune Globulins Previous recommendations, based on data from persons who received low doses of immune globulin preparations, stated that MMR and its individual component vaccines could be administered as early as 6 weeks to 3 months after administration of immune globulins (40,41 ). However, recent evidence suggests that high doses of immune globulins can inhibit the immune response to measles vaccine for more than 3 months (42,43 ). Administration of immune globulins also can inhibit the response to rubella vaccine (42 ). The effect of immune globulin preparations on the response to mumps vaccine is unknown, but commercial immune globulin preparations contain antibodies to these viruses. Blood (e.g., whole blood, packed red blood cells, and plasma) and other antibodycontaining blood products (e.g., immune globulin; specific immune globulins; and immune globulin, intravenous ) can diminish the immune response to MMR or its individual component vaccines. Therefore, after an immune globulin preparation is received, these vaccines should not be administered before the recommended interval (Tables 4 and 5). However, the postpartum vaccination of rubella-susceptible women with the rubella or MMR vaccine should not be delayed because anti-Rho(D) IG (human) or any other blood product was received during the last trimester of pregnancy or at delivery. These women should be vaccinated immediately after delivery and, if possible, tested at least 3 months later to ensure immunity to rubella and, if necessary, to measles. If administration of an immune globulin preparation becomes necessary because of imminent exposure to disease, MMR or its component vaccines can be administered simultaneously with the immune globulin preparation, although vaccineinduced immunity might be compromised. The vaccine should be administered at a site remote from that chosen for the immune globulin inoculation. Unless serologic testing indicates that specific antibodies have been produced, vaccination should be repeated after the recommended interval (Tables 4 and 5). If administration of an immune globulin preparation becomes necessary after MMR or its individual component vaccines have been administered, interference can occur. Usually, vaccine virus replication and stimulation of immunity will occur 1-2 weeks after vaccination. Thus, if the interval between administration of any of these vaccines and subsequent administration of an immune globulin preparation is , whole blood, packed red cells, plasma, and platelet products). † The duration of interference of immune globulin preparations with the immune response to the measles component of the MMR, measles-rubella, and monovalent measles vaccine is dose-related (Table 5). This table is not intended for determining the correct indications and dosage for the use of immune globulin preparations. Unvaccinated persons may not be fully protected against measles during the entire suggested time interval, and additional doses of immune globulin and/or measles vaccine may be indicated after measles exposure. The concentration of measles antibody in a particular immune globulin preparation can vary by lot. The rate of antibody clearance after receipt of an immune globulin preparation also can vary. The recommended time intervals are extrapolated from an estimated half-life of 30 days for passively acquired antibody and an observed interference with the immune response to measles vaccine for 5 months after a dose of 80 mg IgG/kg (42 ). † Assumes a serum IgG concentration of 16 mg/mL. § Measles vaccination is recommended for most HIV-infected children who do not have evidence of severe immunosuppression, but it is contraindicated for patients who have congenital disorders of the immune system. ¶ Formerly referred to as idiopathic thrombocytopenic purpura. # TABLE 5. Suggested intervals between administration of immune globulin preparations for various indications and vaccines containing live measles virus <14 days, vaccination should be repeated after the recommended interval (Tables 4 and 5), unless serologic testing indicates that antibodies were produced. # Altered Immunocompetence Non-HIV-Infected Persons. Replication of vaccine viruses can be enhanced in persons with immune-deficiency diseases and in persons with immunosuppression, as occurs with leukemia, lymphoma, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids. Evidence based on case reports has linked measles vaccine and measles infection to subsequent death in some severely immunocompromised children. Of the >200 million doses of measles vaccine administered in the United States, fewer than five such deaths have been reported (5 ). Patients who have such conditions or are undergoing such therapies (excluding most HIV-infected patients) should not be given live measles virus vaccine. Patients with leukemia in remission who have not received chemotherapy for at least 3 months may receive live-virus vaccines. The exact amount of systemically absorbed corticosteroids and the duration of administration needed to suppress the immune system of an otherwise healthy child are not well defined. Most experts agree that steroid therapy usually does not contraindicate administration of live virus vaccine when it is short term (i.e., <2 weeks); low to moderate dose; long-term, alternate-day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administered topically (skin or eyes), by aerosol, or by intraarticular, bursal, or tendon injection (44 ). Although of recent theoretical concern, no evidence of increased severe reactions to live vaccines has been reported among persons receiving steroid therapy by aerosol, and such therapy is not in itself a reason to delay vaccination. The immunosuppressive effects of steroid treatment vary, but many clinicians consider a dose equivalent to either 2 mg/kg of body weight or a total of 20 mg per day of prednisone as sufficiently immunosuppressive to raise concern about the safety of vaccination with live virus vaccines (44 ). Corticosteroids used in greater than physiologic doses also can reduce the immune response to vaccines. Physicians should wait at least 3 months after discontinuation of therapy before administering a live-virus vaccine to patients who have received high systemically absorbed doses of corticosteroids for ≥2 weeks. HIV-Infected Persons. Because of the increased risk for severe complications associated with measles infection and the absence of serious adverse events after measles vaccination among HIV-infected persons (41,45 ), ACIP has recommended that MMR vaccine be administered to all asymptomatic HIV-infected persons and that MMR vaccine be considered for administration to all symptomatic HIV-infected persons who would otherwise be eligible for measles vaccine-even though the immune response may be attenuated in such persons (41,44,45 ). There is a theoretical risk for an increase (probably transient) in HIV viral load following MMR vaccination because such effects have been observed with other vaccines (46,47 ). Because of the recently reported case of pneumonitis in a measles vaccinee who had an advanced case of acquired immunodeficiency syndrome (AIDS) (48 ) and because of other evidence indicating a diminished antibody response to measles vaccination among severely immunocompromised persons (49 ), ACIP is re-evaluating the recommendations for vaccination of severely immunocompromised HIV-infected persons. In the interim, it may be prudent to withhold MMR or other measlescontaining vaccines from HIV-infected persons with evidence of severe immunosuppression, defined as either a) CD4+ T-lymphocyte counts <750 for children ages <12 months, <500 for children ages 1-5 years, or <200 for persons ages ≥6 years; or b) CD4+ T-lymphocytes constituting <15% of total lymphocytes for children ages <13 years or <14% for persons ages ≥13 years (50,51 ). ACIP continues to recommend MMR for HIV-infected persons without evidence of measles immunity (47 ) who are not severely immunocompromised (50,51 ). Severely immunocompromised and other symptomatic HIV-infected patients who are exposed to measles should receive immune globulin (IG), regardless of prior vaccination status (44 ). In addition, health-care providers should weigh the risks and benefits of measles vaccination or IG prophylaxis for severely immunocompromised HIV-infected patients who are at risk for measles exposure because of outbreaks or international travel. Because the immunologic response to both live and killed antigen vaccines may decrease as HIV disease progresses (44,52 ), vaccination early in the course of HIV infection may be more likely to induce an immune response. Therefore, HIV-infected infants without severe immunosuppression should routinely receive MMR as soon as possible upon reaching their first birthday. Evaluation and testing of asymptomatic persons to identify HIV infection are not necessary before deciding to administer MMR or other measles-containing vaccine (44 ). # Management of Patients with Contraindications to Measles Vaccine If immediate protection against measles is required for persons with contraindications to measles vaccination, passive immunization with IG, 0.25 mL/kg (0.11 mL/lb) of body weight (maximum dose=15 mL), should be given as soon as possible after known exposure. Exposed symptomatic HIV-infected and other immunocompromised persons should receive IG regardless of their previous vaccination status; however, IG in usual doses may not be effective in such patients. For immunocompromised persons, the recommended dose is 0.5 mL/kg of body weight if IG is administered intramuscularly (maximum dose=15 mL). This corresponds to a dose of protein of approximately 82.5 mg/kg (maximum dose=2,475 mg). Intramuscular IG may not be needed if a patient with HIV infection is receiving 100-400 mg/kg IGIV at regular intervals and the last dose was given within 3 weeks of exposure to measles. Because the amounts of protein administered are similar, high-dose IGIV may be as effective as IG given intramuscularly. However, no data are available concerning the effectiveness of IGIV in preventing measles. # Simultaneous Administration of Vaccines In general, simultaneous administration of the most widely used live and inactivated vaccines does not impair antibody responses or increase rates of adverse reactions (53 ). The administration of MMR vaccine yields results similar to the administration of individual measles, mumps, and rubella vaccines at different sites or at different times. Vaccines recommended for administration at 12-15 months of age can be administered at either one or two visits. There are equivalent antibody responses and no clinically significant increases in the frequency of adverse events when DTP, MMR, and OPV (or IPV) vaccines and H. influenzae type b conjugate vaccine (HbCV) are administered either simultaneously at different sites or at separate times. If a child might not be brought back for future vaccinations, all vaccines (including DTP , OPV , MMR, varicella, HbCV, and hepatitis B vaccines) may be administered simultaneously, as appropriate to the child's age and previous vaccination status. # MUMPS PREVENTION The following recommendations concerning adverse events associated with mumps vaccination update those applicable sections in "Mumps Prevention" (MMWR 1989;38:388-92,397-400), and they apply regardless of whether the vaccine is administered as a single antigen or as a component of MR or MMR vaccine. Information concerning adverse events associated with the measles component of MMR vaccine is reviewed earlier in this document (see Measles Prevention), and information concerning the rubella component is located in the previously published ACIP statement for rubella (18 ). # Adverse Effects of Vaccine Use In field trials before licensure, illnesses did not occur more often in vaccinees than in unvaccinated controls (54 ). Reports of illnesses following mumps vaccination have mainly been episodes of parotitis and low-grade fever. Allergic reactions including rash, pruritus, and purpura have been temporally associated with mumps vaccination but are uncommon and usually mild and of brief duration. The reported occurrence of encephalitis within 30 days of receipt of a mumps-containing vaccine (0.4 per million doses) is not greater than the observed background incidence rate of CNS dysfunction in the normal population. Aseptic meningitis has been epidemiologically associated with receipt of the vaccine containing the Urabe strain of mumps virus, but not with the vaccine containing the Jeryl Lynn strain, the latter of which is used in vaccine distributed in the United States (5 ). During 1988-1992, 15 sentinel surveillance laboratories in the United Kingdom identified 13 aseptic meningitis cases that had occurred within 15-35 days after vaccination with the Urabe strain (i.e., 91 cases per 1 million doses distributed) (55 ). No vaccine-associated aseptic meningitis cases have been reported since 1992, when only the Jeryl Lynn strain has been used (23 ). Febrile seizures also have been infrequently reported. However, no evidence suggests that mumps vaccine causes residual seizure disorder (5 ). Although sensorineural deafness following mumps vaccination has been reported rarely, the data are inadequate to distinguish vaccine from nonvaccine causation. No association has been established between mumps vaccination and pancreatic damage or subsequent development of diabetes mellitus (5 ). # Contraindications to Vaccine Use Pregnancy Although mumps vaccine virus has been shown to infect the placenta and fetus (56), there is no evidence that it causes congenital malformations in humans. However, because of the theoretical risk of fetal damage, it is prudent to avoid giving live virus vaccine to pregnant women. Live mumps vaccine, when combined with rubella vaccine, should not be administered to women known to be pregnant or who are considering becoming pregnant within the next 3 months. Women vaccinated with monovalent mumps vaccine should avoid becoming pregnant for 30 days after the vaccination. Routine precautions for vaccinating postpubertal women include asking if they are or may be pregnant, excluding those who say they are, and explaining the theoretical risk to those who plan to receive the vaccine. Vaccination during pregnancy should not be considered an indication for termination of pregnancy. However, the final decision about interruption of pregnancy must rest with the individual patient and her physician. # Severe Febrile Illness Vaccine administration should not be postponed because of minor or intercurrent febrile illnesses, such as mild upper respiratory infections. However, vaccination of persons with severe febrile illnesses should generally be deferred until they have recovered from the acute phase of the illness. # Allergic Reactions Hypersensitivity reactions rarely occur after the administration of MMR or any of its component vaccines. Most of these reactions are minor and consist of a wheal and flare or urticaria at the injection site. Immediate, anaphylactic reactions to MMR or its component vaccines are extremely rare. Although >70 million doses of MMR vaccine have been distributed in the United States since VAERS was implemented in 1990, only 33 cases of anaphylactic reactions that occurred after MMR vaccination have been reported. Furthermore, only 11 of these cases a) occurred immediately after vaccination and b) occurred in persons who had symptoms consistent with anaphylaxis (CDC, unpublished data). In the past, persons who had a history of anaphylactic reactions (i.e., hives, swelling of the mouth or throat, difficulty breathing, hypotension, and shock) following egg ingestion were considered to be at increased risk for serious reactions after receipt of mumps-containing vaccines, which are produced in chick embryo fibroblasts. Protocols requiring caution were developed for skin testing and vaccinating persons who had had anaphylactic reactions after egg ingestion (30)(31)(32)(33)(34). However, the predictive value of such skin testing and the need for special protocols when vaccinating egg-allergic persons with mumps-containing vaccines is uncertain. The results of recent studies suggest that anaphylactic reactions to mumps-containing vaccines are not associated with hypersensitivity to egg antigens but with some other component of the vaccines. The risk for serious allergic reaction to these vaccines in egg-allergic patients is extremely low, and skin testing is not necessarily predictive of vaccine hypersensitivity (35)(36)(37). Therefore, ACIP is re-evaluating whether skin testing and the use of special protocols are routinely necessary when administering mumps-containing vaccines to persons who have a history of anaphylactic-like reactions after egg ingestion. MMR and its component vaccines contain hydrolyzed gelatin as a stabilizer. The literature contains a single case report of a person with an anaphylactic sensitivity to gelatin who had an anaphylactic reaction after receipt of the MMR vaccine licensed in the United States (38 ). Similar cases have occurred in Japan (39 ). Therefore, ACIP is currently considering recommendations for vaccination of persons who have had an anaphylactic reaction to gelatin or gelatin-containing products. In the meantime, such persons should be vaccinated with MMR or other mumps vaccines with extreme caution. Since mumps vaccine contains trace amounts of neomycin (25 µg), persons who have experienced anaphylactic reactions to topically or systemically administered neomycin should not receive mumps vaccine. Most often, neomycin allergy is manifested as a contact dermatitis, which is a delayed-type (cell-mediated) immune response, rather than anaphylaxis. In such persons, the adverse reaction, if any, to 25 µg of neomycin in the vaccine would be an erythematous, pruritic nodule or papule at the site of injection after 48-96 hours. A history of contact dermatitis to neomycin is not a contraindication to receiving mumps vaccine. Live mumps virus vaccine does not contain penicillin. # Recent Injection of Immune Globulin The effect of immune globulin preparations on the response to mumps vaccine is unknown, but commercial immune globulin preparations contain mumps antibodies. Therefore, monovalent mumps or rubella-mumps vaccine should be given at least 2 weeks before the administration of an immune globulin preparation or deferred until approximately 3 months after the administration of an immune globulin preparation. For suggested time intervals between administration of immune globulin preparations and vaccines containing live measles virus, refer to Table 5. # Altered Immunocompetence In theory, replication of the mumps vaccine virus may be potentiated in patients with immune deficiency diseases and by the suppressed immune responses that occur with leukemia, lymphoma, or generalized malignancy or with therapy with corticosteroids, alkylating drugs, antimetabolites, or radiation. In general, patients with such conditions should not be given live mumps virus vaccine. Because vaccinated persons do not transmit mumps vaccine virus, the risk of mumps exposure for those patients may be reduced by vaccinating their close susceptible contacts. An exception to these general recommendations is in persons infected with HIV; asymptomatic HIV-infected children should receive MMR as soon as possible upon reaching their first birthday (44 ), and MMR vaccine should be considered for all symptomatic HIV-infected children who do not have evidence of severe immunosuppression (see Measles Prevention, Altered Immunocompetence). Patients with leukemia in remission whose chemotherapy has been terminated for at least 3 months may also receive live mumps virus vaccine. Most experts agree that steroid therapy usually does not contraindicate administration of live virus vaccine when it is short term (i.e., <2 weeks); low to moderate dose; long-term, alternate-day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administered topically (skin or eyes), by aerosol, or by intraarticular, bursal, or tendon injection (44 ). However, mumps vaccine should be avoided if systemic immunosuppressive levels are reached by prolonged, extensive, topical application. # DTP The following recommendations concerning adverse events associated with DTP vaccination update those applicable sections in "Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures-Recommendations of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1991;40). # Side Effects and Adverse Reactions Following DTP Vaccination Local reactions (generally erythema and induration with or without tenderness) are common after the administration of vaccines containing diphtheria, tetanus, or pertussis antigens. Occasionally, a nodule may be palpable at the injection site of adsorbed products for several weeks. Sterile abscesses at the injection site have been reported rarely (6-10 events per million doses of DTP). Mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia occur frequently. These reactions are substantially more common following the administration of DTP than of DT, but they are self-limited and can be safely managed with symptomatic treatment. Acetaminophen is frequently given by physicians to lessen fever and irritability associated with DTP vaccination, and it may be useful in preventing seizures among febrile-convulsion-prone children. However, fever that does not begin until ≥24 hours after vaccination or persists for more than 24 hours after vaccination should not be assumed to be due to DTP vaccination. These new or persistent fevers should be evaluated for other causes so that treatment is not delayed for serious conditions such as otitis media or meningitis. Moderate-to-severe systemic events include high fever (i.e., temperature of ≥40.5 C ); persistent, inconsolable crying lasting ≥3 hours; collapse (hypotonic-hyporesponsive episode); or short-lived convulsions (usually febrile). These events occur infrequently. These events appear to be without sequelae (57)(58)(59). Other more severe neurologic events, such as a prolonged convulsion or encephalopathy, although rare, have been reported in temporal association with DTP administration. Approximate rates for the occurrence of adverse events following receipt of DTP (regardless of dose number in the series or age of the child) are shown in Table 6 (60,61 ). The frequencies of local reactions and fever are substantially higher with increasing numbers of doses of DTP, while other mild-to-moderate systemic reactions (e.g., fretfulness, vomiting) are substantially less frequent (59)(60)(61). Concern about the possible role of pertussis vaccine in causing neurologic reactions has been present since the earliest days of vaccine use. Rare but serious acute neurologic illnesses, including encephalitis/encephalopathy and prolonged convulsions, have been anecdotally reported following receipt of whole-cell pertussis vaccine given as DTP (62,63 ). Whether pertussis vaccine causes or is only coincidentally related to such illnesses or reveals an inevitable event has been difficult to determine conclusively for the following reasons: a) serious acute neurologic illnesses often occur or become manifest among children during the first year of life irrespective of vaccination; b) there is no specific clinical sign, pathologic finding, or laboratory test which can determine whether the illness is caused by the DTP; c) it may be difficult to determine with certainty whether infants <6 months of age are neurologically normal, which complicates assessment of whether vaccinees were already neurologically impaired before receiving DTP; and d) because these events are exceedingly rare, appropriately designed large studies are needed to address the question. Despite these methodologic difficulties, the National Childhood Encephalopathy Study (NCES) and other controlled epidemiologic studies have provided evidence that DTP can cause acute encephalopathy (64)(65)(66)(67)(68). This adverse event occurs rarely, with an estimated risk of zero to 10.5 episodes per million DTP vaccinations (68 ). A detailed follow-up of the NCES indicated that children who had had a serious acute neurologic illness after DTP administration were significantly more likely than children in the control group to have chronic nervous system dysfunction 10 years later. These children with chronic nervous system dysfunction were more likely than children in the control group to have received DTP within 7 days of onset of the original serious acute neurologic illness (i.e., 12 of 367 children vs. six of 723 children) (69 ). After reviewing the follow-up data, IOM concluded that the NCES provided evidence of an association between DTP and chronic nervous system dysfunction in children who had had a serious acute neurologic illness after vaccination with DTP. The committee proposed three possible explanations for this association. First, the acute neurologic illness and subsequent chronic nervous system dysfunction might have been caused by DTP. Second, DTP might trigger an acute neurologic illness and subsequent chronic nervous system dysfunction in children who have underlying brain or metabolic abnormalities. Such children might experience similar chronic dysfunction in the absence of DTP vaccination if other stimuli (e.g., fever or infection) are present. Third, DTP might cause an acute neurologic illness in children who have underlying brain or metabolic abnormalities that would inevitably have led to chronic TABLE 6. Adverse events- occurring within 48 hours after vaccination with diphtheria and tetanus toxoids and pertussis vaccine (DTP) nervous system dysfunction even if the acute neurologic illness had not developed (6 ) . IOM concluded that the NCES data do not support one explanation over another. According to IOM, the balance of evidence was consistent with a causal relationship between DTP and some forms of chronic nervous system disorders in children who had developed an acute neurologic disorder after receiving DTP. However, IOM also concluded that the results were insufficient to determine whether DTP increases the overall risk for chronic nervous system dysfunction in children. A subcommittee of the National Vaccine Advisory Committee (NVAC) also reviewed the study and concluded that the results were insufficient to determine whether DTP administration before the acute neurologic event influenced the potential for neurologic dysfunction 10 years later (Ad hoc Subcommittee of the NVAC, unpublished data, 1994). ACIP concurs with this evaluation. Although the NCES examined and reported risk for the 7 days after DTP vaccination, the increased risk for serious acute neurologic illness occurred primarily during the first 3 days after DTP administration (64 ). Thus, if an association between DTP and chronic encephalopathy exists, the risk is primarily in the first 3 days after DTP vaccination. Among a subset of children who were participating in the NCES and who had infantile spasms, both DTP and DT vaccination appeared either to precipitate early manifestations of the condition or to lead to its identification by parents (70 ). IOM reviewed this and other studies and concluded that neither vaccine causes the illness (71,72 ). Sudden infant death syndrome (SIDS) is listed on death certificates as the cause of death for 5,000-6,000 infants (ages 0-364 days) each year in the United States. Because the peak incidence of SIDS for infants occurs at 2-4 months of age, many instances of a close temporal relation between SIDS and receipt of DTP are to be expected by simple chance. Only one methodologically rigorous study has suggested that DTP vaccination might cause SIDS (73 ). A total of four deaths were reported within 3 days of DTP vaccination, compared with 1.36 expected deaths. However, these deaths were unusual in that three of the four occurred within a 13-month interval during the 12-year study. These four children also tended to be vaccinated at older ages than their controls, suggesting that they might have had other unrecognized risk factors for SIDS independent of vaccination. In contrast, DTP vaccination was not associated with SIDS in several larger studies performed in the past decade (62,(74)(75)(76). In addition, none of three studies that examined unexpected deaths among infants not classified as SIDS found an association with DTP vaccination (73,75,76 ). IOM reviewed these studies and concluded that the available information does not establish a causal relationship between DTP and SIDS (4 ). IOM concluded recently that no available evidence indicates that DTP might cause transverse myelitis, other more subtle neurologic disorders (e.g., hyperactivity, learning disorders, and infantile autism), and progressive degenerative conditions of the CNS (4 ). Furthermore, one study indicated that children who received pertussis vaccine exhibited fewer school problems than those who did not, even after adjustment for socioeconomic status (77 ). Recent data suggest that infants and young children who have ever had convulsions (febrile or afebrile) or who have immediate family members with such histories are more likely to have seizures following DTP vaccination than those without such histories (78,79 ). For those with a family history of seizures, the increased risks of seizures occurring within 3 days of receipt of DTP or 4-28 days following receipt of DTP are identical, suggesting that these histories are nonspecific risk factors and are unrelated to DTP vaccination (79 ). Rarely, immediate anaphylactic reactions (i.e., swelling of the mouth, breathing difficulty, hypotension, or shock) have been reported after receipt of preparations containing diphtheria, tetanus, and/or pertussis antigens. However, no deaths caused by anaphylaxis following DTP vaccination have been reported to CDC since the inception of vaccine-adverse-events reporting in 1978, a period during which more than 80 million doses of publicly purchased DTP vaccine were administered. While substantial underreporting exists in this passive surveillance system, the severity of anaphylaxis and its immediacy following vaccination suggest that such events are likely to be reported. Although no causal relation to any specific component of DTP has been established, the occurrence of true anaphylaxis usually contraindicates further doses of any one of these components. Rashes that are macular, papular, petechial, or urticarial and appear hours or days after a dose of DTP are frequently antigen-antibody reactions of little consequence or are due to other causes, such as viral illnesses, and are unlikely to recur following subsequent injections (80,81 ). In addition, there is no evidence for a causal relation between DTP vaccination and hemolytic anemia or thrombocytopenic purpura. # Precautions and Contraindications # General Considerations The decision to administer or delay DTP vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Although a moderate or severe febrile illness is sufficient reason to postpone vaccination, minor illnesses such as mild upper-respiratory infections with or without low-grade fever are not contraindications. If ongoing medical care cannot be assured, taking every opportunity to provide appropriate vaccinations is particularly important. Children with moderate or severe illnesses with or without fever can receive DTP as soon as they have recovered. Waiting a short period before administering DTP avoids superimposing the adverse effects of the vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to vaccination. Routine physical examinations or temperature measurements are not prerequisites for vaccinating infants and children who appear to be in good health. Appropriate immunization practice includes asking the parent or guardian if the child is ill, postponing DTP vaccination for those with moderate or severe acute illnesses, and vaccinating those without contraindications or precautionary circumstances. When an infant or child returns for the next dose of DTP, the parent should always be questioned about any adverse events that might have occurred following the previous dose. A history of prematurity generally is not a reason to defer vaccination (82)(83)(84). Preterm infants should be vaccinated according to their chronological age from birth. Immunosuppressive therapies-including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) -may reduce the immune response to vaccines. Short-term (<2-week) corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive. Although no specific studies with pertussis vaccine are available, if immunosuppressive therapy will be discontinued shortly, it is reasonable to defer vaccination until the patient has been off therapy for 1 month; otherwise, the patient should be vaccinated while still on therapy (85 ). # Special Considerations for Preparations Containing Pertussis Vaccine Precautions and contraindications guidelines that were previously published regarding the use of pertussis vaccine were based on three assumptions about the risks for adverse events associated with pertussis vaccination: a) that the vaccine on rare occasions caused acute encephalopathy resulting in permanent brain damage; b) that pertussis vaccine aggravated preexisting CNS disease; and c) that certain nonencephalitic reactions are predictive of more severe reactions with subsequent doses (86 ). In addition, children from whom pertussis vaccine was withheld were thought to be well protected by herd immunity, a belief that is no longer valid. The current revised ACIP recommendations reflect better understanding of the risks associated not only with pertussis vaccine but also with pertussis disease. # Contraindications If any of the following events occur in temporal relationship to the administration of DTP, further vaccination with DTP is contraindicated (Table 7): 1. An immediate anaphylactic reaction. The rarity of such reactions to DTP is such that they have not been adequately studied. Because of uncertainty as to which component of the vaccine might be responsible, no further vaccination with any of the three antigens in DTP should be carried out. Alternatively, because of the importance of tetanus vaccination, such individuals may be referred for evaluation by an allergist and desensitized to tetanus toxoid if a specific allergy can be demonstrated (87,88 ). 2. Encephalopathy (not due to another identifiable cause). This is defined as an acute, severe CNS disorder occurring within 7 days following vaccination and generally consisting of major alterations in consciousness, unresponsiveness, generalized or focal seizures that persist more than a few hours, with failure to recover within 24 hours. Even though causation by DTP cannot be established, no subsequent doses of pertussis vaccine should be given. It # TABLE 7. Contraindications and precautions to subsequent vaccination with diphtheria and tetanus toxoids and pertussis vaccine (DTP) Classification/Response to DTP vaccination # Contraindications - An immediate anaphylactic reaction. - Encephalopathy occurring within 7 days after vaccination. # Precautions - Fever ≥105 F (≥40.5 C) that is not attributed to another identifiable cause occurring within 48 hours after vaccination. - Collapse or shock-like state (i.e., a hypotonic-hyporesponsive episdode) occurring within 48 hours after vaccination. - Persistent, inconsolable crying lasting ≥3 hours and occurring within 48 hours after vaccination. - Convulsions with or without fever occurring within 3 days after vaccination. may be desirable to delay for months before administering the balance of the doses of DT necessary to complete the primary schedule. Such a delay allows time for clarification of the child's neurologic status. # Precautions If any of the following events occur in temporal relation to receipt of DTP, the decision to give subsequent doses of vaccine containing the pertussis component should be carefully considered (Table 7). Although these events were considered absolute contraindications in previous ACIP recommendations, there may be circumstances, such as a high incidence of pertussis, in which the potential benefits outweigh possible risks, particularly because these events are not associated with permanent sequelae (86 ). The following events were previously considered contraindications and are now considered precautions: 1. Temperature of ≥40.5 C (≥105 F) within 48 hours not due to another identifiable cause. Such a temperature is considered a precaution because of the likelihood that fever following a subsequent dose of DTP also will be high. has a seizure following the first or second dose of DTP, it is desirable to delay subsequent doses until the child's neurologic status is better defined. By the end of the first year of life, the presence of an underlying neurologic disorder has usually been determined and appropriate treatment instituted. DT vaccine should not be administered before a decision has been made about whether to restart the DTP series. Regardless of which vaccine is given, it is prudent also to administer acetaminophen, 15 mg/kg of body weight, at the time of vaccination and every 4 hours subsequently for 24 hours (92,93 ). # Vaccination of infants and young children who have underlying neurologic disorders Infants and children with recognized, possible, or potential underlying neurologic conditions present a unique problem. They seem to be at increased risk for the appearance of manifestations of the underlying neurologic disorder within 2-3 days after vaccination. However, more prolonged manifestations or increased progression of the disorder or exacerbation of the disorder as a result of DTP vaccination have not been recognized (94 ). In addition, most neurologic conditions in infancy and young childhood are associated with evolving, changing neurological findings. Functional abnormalities are often unmasked by progressive neurologic development. Thus, confusion over the interpretation of progressive neurologic signs may arise when DTP vaccination or any other therapeutic or preventive measure is carried out. Protection against diphtheria, tetanus, and pertussis is as important for children with neurologic disabilities as for other children. Such protection may be even more important for neurologically disabled children. They often receive custodial care or attend special schools where the risk of pertussis is greater because DTP vaccination is avoided for fear of adverse reactions. Also, if pertussis affects a neurologically disabled child who has difficulty in handling secretions and in cooperating with symptomatic care, it may aggravate preexisting neurologic problems because of anoxia, intracerebral hemorrhages, and other manifestations of the disease. Whether and when to administer DTP to children with proven or suspected underlying neurologic disorders must be decided on an individual basis. Important considerations include the current local incidence of pertussis, the near absence of diphtheria in the United States, and the low risk of infection with Clostridium tetani. On the basis of these considerations and the nature of the child's disorder, the following approaches are recommended: # Vaccination of infants and young children who have a family history of convulsion or other CNS disorder A family history of convulsions or other CNS disorder is not a contraindication to pertussis vaccination (95 ). Acetaminophen should be given at the time of DTP vaccination and every 4 hours for 24 hours to reduce the possibility of postvaccination fever (92,93 ). # Preparations Containing Diphtheria Toxoid and Tetanus Toxoid The only contraindication to tetanus and diphtheria toxoids is a history of a neurologic or severe hypersensitivity reaction following a previous dose. Vaccination with tetanus and diphtheria toxoids is not known to be associated with an increased risk of convulsions. Local side effects alone do not preclude continued use. If an anaphylactic reaction to a previous dose of tetanus toxoid is suspected, intradermal skin testing with appropriately diluted tetanus toxoid may be useful before a decision is made to discontinue tetanus toxoid vaccination (86 ). In one study, 94 of 95 persons with histories of anaphylactic symptoms following a previous dose of tetanus toxoid were nonreactive following intradermal testing and tolerated further tetanus toxoid challenge without incident (86 ). One person had erythema and induration immediately following skin testing, but tolerated a full IM dose without adverse effects. Mild, nonspecific skin-test reactivity to tetanus toxoid, particularly if used undiluted, appears to be fairly common. Most vaccinees develop inconsequential cutaneous delayed hypersensitivity to the toxoid. Although very rare, severe hypersensitivity reactions may occur after receipt of tetanus-toxoid-containing vaccines; these reactions can be life-threatening (5 ). Persons who experienced Arthus-type hypersensitivity reactions or a temperature of >103 F (>39.4 C) following a prior dose of tetanus toxoid usually have high serum tetanus antitoxin levels and should not be given even emergency doses of Td more frequently than every 10 years, even if they have a wound that is neither clean nor minor. If a contraindication to using tetanus-toxoid-containing preparations exists for a person who has not completed a primary series of tetanus toxoid immunization and that person has a wound that is neither clean nor minor, only passive immunization should be given using tetanus IG (TIG). On the basis of a) a report of a 42-year-old man who had GBS on three separate occasions after receipt of tetanus toxoid and b) evidence that a vaccine-induced immunologic response can cause GBS, IOM concluded that tetanus-toxoid-containing vaccines can trigger the onset of GBS in adults. GBS can be a life-threatening disease. Persons who have a history of GBS associated with a particular vaccine may be at increased risk for recurrent GBS after subsequent doses of that vaccine (5 ). However, in a study in which an estimated 1.2 million doses of tetanus-containing toxoid were administered to persons >18 years of age, two cases of GBS were expected by chance alone during the 6 weeks after vaccination, and only one case was reported (CDC, unpublished data). This finding suggests that the risk for GBS after administration of tetanus toxoid is extremely low. No increased risk for GBS has been observed with the use of DTP in children. In a study of 0.7 million children of preschool-ages who were vaccinated with DTP during a 7-year period, three cases of GBS were expected by chance alone during the 6 weeks after vaccination, and only two cases were reported (17 ). Because tetanus vaccination has been associated rarely with recurrence of GBS, the decision to administer additional doses of tetanus-toxoid-containing vaccine to persons who have had GBS within 6 weeks after receiving tetanus toxoid should be based on the benefits of subsequent vaccination and the risk for recurrence of GBS. For example, vaccination is usually justified for children whose primary immunization schedules are incomplete (i.e., fewer than three doses have been received); but routine booster vaccination probably is not indicated for adults who have received three or more doses. Vaccination with tetanus-toxoid-containing vaccines has been associated with brachial neuritis in adult vaccinees, with a relative risk of 5-10 in comparison with the population-based background incidence and a 1-month attributable incidence of approximately one-half to one case per 100,000 recipients of tetanus toxoid (5 ). Although no evidence exists that tetanus and diphtheria toxoids are teratogenic, waiting until the second trimester of pregnancy to administer Td is a reasonable precaution for minimizing any concern about the theoretical possibility of such reactions. # Misconceptions Concerning Contraindications to DTP Some health-care providers inappropriately consider certain conditions or circumstances as contraindications to DTP vaccination. These include the following: 1. Soreness, redness, or swelling at the DTP vaccination site or temperature of <40.5 C (<105 F). 2. Mild, acute illness with low-grade fever or mild diarrheal illness affecting an otherwise healthy child. 3. Current antimicrobial therapy or the convalescent phase of an acute illness. 4. Recent exposure to an infectious disease. 5. Prematurity. The appropriate age for initiating vaccination among the prematurely born infant is the usual chronological age from birth (82)(83)(84). Full doses (0.5 mL) of vaccine should be used. 6. History of allergies or relatives with allergies. 7. Family history of convulsions. 8. Family history of SIDS. 9. Family history of an adverse event following DTP vaccination. # Event Frequency of event †	This report provides updated information concerning the potential adverse events associated with vaccination for hepatitis B, poliomyelitis, measles, mumps, diphtheria, tetanus, and pertussis. This information incorporates findings from a series of recent literature reviews, conducted by an expert committee at the Institute of Medicine (IOM), of all evidence regarding the possible adverse consequences of vaccines administered to children. This report contains modifications to the previously published recommendations of the Advisory Committee on Immunization Practices (ACIP) and is based on an ACIP review of the IOM findings and new research on vaccine safety. In addition, this report incorporates information contained in the "Recommendations of the Advisory Committee on Immunization Practices: Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence" (MMWR 1993;42[No. RR-4]) and the "General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)" (MMWR 1994;43[No. RR-1]). Major changes to the previous recommendations are highlighted within the text, and specific information concerning the following vaccines and the possible adverse events associated with their administration are included: hepatitis B vaccine and anaphylaxis; measles vaccine and a) thrombocytopenia and b) possible risk for death resulting from anaphylaxis or disseminated disease in immunocompromised persons; diphtheria and tetanus toxoids and pertussis vaccine (DTP) and chronic encephalopathy; and tetanus-toxoid-containing vaccines and a) Guillain-Barré syndrome, b) brachial neuritis, and c) possible risk for death resulting from anaphylaxis. These modifications will be incorporated into more comprehensive ACIP recommendations for each vaccine when such statements are revised. Also included in this report are interim recommendations concerning the use of measles and mumps vaccines in a) persons who are infected with human immunodeficiency virus and b) persons who are allergic to eggs; ACIP is still evaluating these recommendations. In this publication, the terms "side effects" and "adverse reactions" are used interchangeably to denote the undesirable secondary effects resulting from vaccination.# INTRODUCTION Immunization has enabled the global eradication of smallpox (1 ), the elimination of poliomyelitis from the Western hemisphere (2 ), and major reductions in the incidence of other vaccine-preventable diseases in the United States (Table 1). However, although immunization has successfully reduced the incidence of vaccine-preventable diseases, vaccination can cause both minor and, rarely, serious side effects. Public awareness of and controversy about vaccine safety has increased, primarily because increases in vaccine coverage resulted in an increased number of adverse events that occurred after vaccination. Such adverse events include both true reactions to vaccine and events coincidental to, but not caused by, vaccination. Despite concerns about vaccine safety, vaccination is safer than accepting the risks for the diseases these vaccines prevent. Unless a disease has been eradicated (e.g., smallpox), failure to vaccinate increases the risks to both the individual and society. In response to concerns about vaccine safety, the National Childhood Vaccine Injury Act of 1986 established a no-fault compensation process for persons possibly injured by selected vaccines (3 ). The Act also mandated that the Institute of Medicine (IOM) review scientific and other evidence regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review all available information on these vaccine adverse events; such information included epidemiologic studies, case series, individual case reports, and testimonials. To derive their conclusions, the IOM committee members created five categories of causality to describe the relationships between the vaccines and specific adverse events. The first IOM review examined certain events occurring after administration of pertussis and rubella vaccines (Table 2) (4 ). The second IOM review examined events occurring after administration of all other vaccines usually administered during childhood (i.e., diphtheria and tetanus toxoids and measles, mumps, hepatitis B, Haemophilus influenzae type b [Hib], and poliovirus vaccines) (Table 3) (5 ). Two other IOM committees have met since the findings of the second review were published. These two committees have published An independent research organization chartered by the National Academy of Sciences. (4 ), an independent research organization chartered by the National Academy of Sciences. The National Childhood Vaccine Injury Act of 1986 mandated that IOM review scientific and other evidence (e.g., epidemiologic studies, case series, individual case reports, and testimonials) regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review and summarize all available information; this committee created five categories of causality to describe the relationships between the vaccines and specific adverse events. ¶ IOM reviewed this adverse event again in 1994 (5 ). * Defined in the controlled studies that were reviewed as encephalopathy, encephalitis, or encephalomyelitis. # TABLE 2. Summarized conclusions of evidence regarding the possible association between specific adverse effects and receipt of diphtheria and tetanus toxoids and pertussis vaccine (DTP)* and RA 27/3 measles-mumps-rubella (MMR) † vaccine, by determination of causality - their findings concerning both the diphtheria and tetanus toxoids and pertussis vaccine (DTP) and chronic nervous system dysfunction (Figure 1) (6 ) and research strategies for vaccine-associated adverse events (7 ). The Advisory Committee on Immunization Practices (ACIP) recently reviewed the findings of the IOM committees and modified the previously published ACIP recommendations to ensure consistency with IOM conclusions. These recommendations, which are included in this report, update all previously published ACIP recommendations pertaining to the precautions, contraindications, side effects, and adverse reactions* associated with specific vaccines. ACIP accepted the IOM conclusions for MMWR September 6, 1996 (5 ), an independent research organization chartered by the National Academy of Sciences. The National Childhood Vaccine Injury Act of 1986 mandated that IOM review scientific and other evidence (e.g., epidemiologic studies, case series, individual case reports, and testimonials) regarding the possible adverse consequences of vaccines administered to children. IOM constituted an expert committee to review and summarize all available information; this committee created five categories of causality to describe the relationships between the vaccines and specific adverse events. † DT=diphtheria and tetanus toxoids for pediatric use; Td=diphtheria and tetanus toxoids for adult use. § If the data derived from studies of a monovalent preparation, then the causal relationship also extended to multivalent preparations. If the data derived exclusively from studies of the measles-mumps-rubella (MMR) vaccine, the vaccine is specified parenthetically in italics. In the absence of data concerning the monovalent preparation, the causal relationship determined for the multivalent preparations did not extend to the monovalent components. ¶ For some adverse events, the IOM committee was charged with assessing the causal relationship between the adverse event and only oral poliovirus vaccine (OPV) (i.e., for poliomyelitis) or only inactivated poliovirus vaccine (IPV) (i.e., for anaphylaxis and thrombocytopenia). If the conclusions for the two vaccines differed for the other adverse events, the vaccine to which the adverse event applied is specified parenthetically in italics. The evidence used to establish a causal relationship for anaphylaxis applies to MMR vaccine. The evidence regarding monovalent measles vaccine favored acceptance of a causal relationship, but this evidence was less convincing than that for MMR vaccine because of either incomplete documentation of symptoms or the possible attenuation of symptoms by medical intervention. † † This table lists weight-of-evidence determinations only for deaths that were classified as sudden infant death syndrome (SIDS) and deaths that were a consequence of vaccine-strain viral infection. However, if the evidence favored the acceptance of (or established) a causal relationship between a vaccine and a possibly fatal adverse event, then the evidence also favored the acceptance of (or established) a causal relationship between the vaccine and death from the adverse event. Direct evidence regarding death in association with a vaccine-associated adverse event was limited to a) Td and Guillain-Barré syndrome, b) tetanus toxoid and anaphylaxis, and c) OPV and poliomyelitis. § § The evidence derived from studies of DT. If the evidence favored rejection of a causal relationship between DT and encephalopathy, then the evidence also favored rejection of a causal relationship between Td and tetanus toxoid and encephalopathy. ¶ ¶ Infantile spasms and SIDS occur only in an age group that is administered DT but not Td or tetanus toxoid. * The evidence derived primarily from studies of DTP, although the evidence also favored rejection of a causal relationship between DT and SIDS. † † † The evidence derived from studies of tetanus toxoid. If the evidence favored acceptance of (or established) a causal relationship between tetanus toxoid and an adverse event, then the evidence also favored acceptance of (or established) a causal relationship between DT and Td and the adverse event. § § § This conclusion differs from the information contained in the ACIP recommendations because of new information that became available after IOM published this table. ¶ ¶ ¶ Deaths occurred primarily among persons known to be immunocompromised. almost all vaccine adverse events; the few exceptions generally occurred because new information that was available to ACIP had not been available when the IOM committees published their recommendations. These exceptions included a) oral poliovirus vaccine (OPV) and Guillain-Barré syndrome (GBS), b) tetanus-toxoidcontaining vaccines and GBS, and c) DTP and chronic nervous system dysfunction. In addition, this report incorporates information contained in the "Recommendations of the Advisory Committee on Immunization Practices: Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence" (MMWR 1993;42[No. RR-4]) and the "General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)" (MMWR 1994;43[No. RR-1]). To facilitate recognition of the new recommendations in this report, all major changes that are being made to the previously published ACIP statements are highlighted within the text. These changes include information on the following vaccines and the possible adverse events associated with their administration: • Hepatitis B vaccine and anaphylaxis; • Measles vaccine and a) thrombocytopenia and b) possible risk for death resulting from anaphylaxis or disseminated disease in immunocompromised persons; • DTP and chronic encephalopathy; and • Tetanus-toxoid-containing vaccines and a) GBS, b) brachial neuritis, and c) possible risk for death resulting from anaphylaxis. The modifications contained in this report, and possibly other changes as new information becomes available, will be incorporated into more comprehensive ACIP recommendations for each vaccine when such statements are revised. # HEPATITIS B VACCINE The following recommendations concerning adverse events associated with hepatitis B vaccination update those applicable sections in "Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States Through Universal Childhood Vaccination-Recommendations of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1991;40[No. RR-13]). # Vaccine Side Effects and Adverse Reactions Hepatitis B vaccines are safe to administer to adults and children. More than an estimated 10 million adults and 2 million infants and children have been vaccinated in the United States, and at least 12 million children have been vaccinated worldwide. # Vaccine-Associated Side Effects Pain at the injection site (3%-29%) and a temperature greater than 37.7 C (1%-6%) have been among the most frequently reported side effects among adults and children receiving vaccine (8)(9)(10)(11)(12). In placebo-controlled studies, these side effects were reported no more frequently among vaccinees than among persons receiving a placebo (11,12 ). Among children receiving both hepatitis B vaccine and DTP, these mild side effects have been observed no more frequently than among children receiving only DTP. The recommendation to begin hepatitis B vaccination soon after birth has raised the concern that a substantial number of infants will require an extensive medical evaluation for elevated temperatures secondary to hepatitis B vaccination. Several population-based studies to evaluate this possibility are in progress. # Adverse Events In the United States, surveillance of adverse reactions indicated a possible association between GBS and receipt of the first dose of plasma-derived hepatitis B vaccine (CDC, unpublished data; 13 ). However, an estimated 2.5 million adults received one or more doses of recombinant hepatitis B vaccine during 1986-1990, and available data concerning these vaccinees do not indicate an association between receipt of recombinant vaccine and GBS (CDC, unpublished data). Based on reports to the Vaccine Adverse Events Reporting System (VAERS), the estimated incidence rate of anaphylaxis among vaccine recipients is low (i.e., approximately one event per 600,000 vaccine doses distributed). Two of these adverse events occurred in children (CDC, unpublished data). In addition, only one case of anaphylaxis occurred among 100,763 children ages 10-11 years who had been vaccinated with recombinant vaccine in British Columbia (D. Scheifele, unpublished data), and no adverse events were reported among 166,757 children who had been vaccinated with plasma-derived vaccine in New Zealand (5 ). Although none of the persons who developed anaphylaxis died, this adverse event can be fatal; in addition, hepatitis B vaccine can-in rare instances-cause a life-threatening hypersensitivity reaction in some persons (5 ). Therefore, subsequent vaccination with hepatitis B vaccine is contraindicated for persons who have previously had an anaphylactic response to a dose of this vaccine. Large-scale hepatitis B immunization programs for infants in Alaska, New Zealand, and Taiwan have not established an association between vaccination and the occurrence of other severe adverse events, including seizures and GBS (B. McMahon and A. Milne, unpublished data; 14 ). However, systematic surveillance for adverse reactions in these populations has been limited, and only a minimal number of children have received recombinant vaccine. Any presumed risk for adverse events that might be causally associated with hepatitis B vaccination must be balanced with the expected risk for hepatitis B virus (HBV)-related liver disease. Currently, an estimated 2,000-5,000 persons in each U.S. birth cohort will die as a result of HBV-related liver disease because of the 5% lifetime risk for HBV infection. As hepatitis B vaccine is introduced for routine vaccination of infants, surveillance for vaccine-associated adverse events will continue to be an important part of the program despite the current record of safety. Any adverse event suspected to be associated with hepatitis B vaccination should be reported to VAERS. VAERS forms can be obtained by calling (800) 822-7967. # POLIOMYELITIS PREVENTION The following recommendations concerning adverse events associated with poliomyelitis vaccination update those applicable sections in "Poliomyelitis Prevention: Recommendation of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1982;31:22-6,31-4) and "Poliomyelitis Prevention: Enhanced-Potency Inactivated Poliomyelitis Vaccine-Supplementary Statement" (MMWR 1987;36:795-8). # Precautions and Contraindications Pregnancy Although no conclusive evidence documents the adverse effects of OPV or inactivated poliovirus vaccine (IPV) in pregnant women and their developing fetuses, vaccination of pregnant women should be avoided. However, if immediate protection against poliomyelitis is necessary, OPV or IPV can be given. # Immunodeficiency Persons who have congenitally acquired immune-deficiency diseases (e.g., combined immunodeficiency, hypogammaglobulinemia, and agammaglobulinemia) should not be given OPV because of their substantially increased risk for vaccineassociated disease. Furthermore, persons who have altered immune status resulting from acquired conditions (e.g., human immunodeficiency virus [HIV] infection, leukemia, lymphoma, or generalized malignancy) or who have immune systems compromised by therapy (e.g., treatment with corticosteroids, alkylating drugs, antimetabolites, or radiation) should not receive OPV because of the theoretical risk for paralytic disease. IPV-and not OPV-should be used to vaccinate immunodeficient persons and their household contacts. Many immunosuppressed persons are already immune to polioviruses because of previous vaccination or exposure to wild-type virus when they were immunocompetent. Although such persons should not receive OPV, their risk for paralytic disease may be less than that of persons who have congenitally acquired immunodeficiency. Although a protective immune response to IPV in the immunodeficient patient cannot be ensured, the vaccine is safe and some protection may result from its administration. If a household contact of an immunodeficient person is vaccinated inadvertently with OPV, the OPV recipient should avoid close physical contact with the immunodeficient person for approximately 4-6 weeks after vaccination (i.e., during the period of maximum excretion of vaccine virus). If such contact cannot be avoided, rigorous hygiene and hand washing after contact with feces (e.g., after diaper changing) and avoidance of contact with saliva (e.g., by not sharing eating utensils or food) should be practiced. These practices are an acceptable, but probably less effective, alternative than refraining from contact. Because immunodeficiency is possible in other children born to a family in which one child is immunodeficient, OPV should not be administered to a member of such a household until the immune status of the recipient and other children in the family is documented. # Adverse Reactions OPV In rare instances, administration of OPV has been associated with paralytic poliomyelitis in healthy recipients and their contacts. Very rarely, OPV has caused fatal paralytic poliomyelitis in immunocompromised persons (5 ). Other than efforts for identifying persons with immune-deficiency conditions, no procedures are currently available to identify persons likely to experience such adverse reactions. Although the risk of vaccine-associated paralysis is extremely small for vaccinees and their susceptible, close, personal contacts, they should be informed of this risk. Available data do not indicate a measurable increased risk for GBS after receipt of OPV. Initial reports (at the time of IOM review) of two studies conducted in Finland suggested that OPV might cause GBS. These studies identified an apparent increased incidence of GBS that was temporally associated with mass OPV vaccination of children and adults who had previously received IPV (15,16 ). Since the IOM review, a reanalysis of the data derived from the studies conducted in Finland and an analysis of an observational study conducted in the United States have not demonstrated a causal relationship between OPV and GBS in infants (17 ). Because OPV contains trace amounts of streptomycin, bacitracin, and neomycin, its use is contraindicated in persons who have previously had an anaphylactic reaction to OPV or to these antibiotics. # IPV No serious side effects of currently available IPV have been documented. Since IPV contains trace amounts of streptomycin and neomycin, there is a possibility of hypersensitivity reactions in individuals sensitive to these antibiotics. # MEASLES PREVENTION The following recommendations concerning adverse events associated with measles vaccination update those applicable sections in "Measles Prevention: Recommendations of the Immunization Practices Advisory Committee" (MMWR 1989; 38[No. S-9]), and they apply regardless of whether the vaccine is administered as a single antigen or as a component of measles-rubella (MR) or measles-mumps-rubella (MMR) vaccine. Information concerning adverse events associated with the mumps component of MMR vaccine is reviewed later in this document (see Mumps Prevention), and information concerning the rubella component is located in the previously published ACIP statement for rubella (18 ). # Side Effects and Adverse Reactions More than 240 million doses of measles vaccine were distributed in the United States from 1963 through 1993. The vaccine has an excellent record of safety. From 5% to 15% of vaccinees may develop a temperature of ≥103 F (≥39.4 C) beginning 5-12 days after vaccination and usually lasting several days (19 ). Most persons with fever are otherwise asymptomatic. Transient rashes have been reported for approximately 5% of vaccinees. Central nervous system (CNS) conditions, including encephalitis and encephalopathy, have been reported with a frequency of less than one per million doses administered. The incidence of encephalitis or encephalopathy after measles vaccination of healthy children is lower than the observed incidence of encephalitis of unknown etiology. This finding suggests that the reported severe neurologic disorders temporally associated with measles vaccination were not caused by the vaccine. These adverse events should be anticipated only in susceptible vaccinees and do not appear to be age-related. After revaccination, most reactions should be expected to occur only among the small proportion of persons who failed to respond to the first dose. # Personal and Family History of Convulsions As with the administration of any agent that can produce fever, some children may have a febrile seizure. Although children with a personal or family history of seizures are at increased risk for developing idiopathic epilepsy, febrile seizures following vaccinations do not in themselves increase the probability of subsequent epilepsy or other neurologic disorders. Most convulsions following measles vaccination are simple febrile seizures, and they affect children without known risk factors. An increased risk of these convulsions may occur among children with a prior history of convulsions or those with a history of convulsions in first-degree family members (i.e., siblings or parents) (20 ). Although the precise risk cannot be determined, it appears to be low. In developing vaccination recommendations for these children, ACIP considered a number of factors, including risks from measles disease, the large proportion (5%-7%) of children with a personal or family history of convulsions, and the fact that convulsions following measles vaccine are uncommon. Studies conducted to date have not established an association between MMR vaccination and the development of a residual seizure disorder (5 ). ACIP concluded that the benefits of vaccinating these children greatly outweigh the risks. They should be vaccinated just as children without such histories. Because the period for developing vaccine-induced fever occurs approximately 5-12 days after vaccination, prevention of febrile seizures is difficult. Prophylaxis with antipyretics has been suggested as one alternative, but these agents may not be effective if given after the onset of fever. To be effective, such agents would have to be initiated before the expected onset of fever and continued for 5-7 days. However, parents should be alert to the occurrence of fever after vaccination and should treat their children appropriately. Children who are being treated with anticonvulsants should continue to take them after measles vaccination. Because protective levels of most currently available anticonvulsant drugs (e.g., phenobarbital) are not achieved for some time after therapy is initiated, prophylactic use of these drugs does not seem feasible. The parents of children who have either a personal or family history of seizures should be advised of the small increased risk of seizures following measles vaccination. In particular, they should be told in advance what to do in the unlikely event that a seizure occurs. The permanent medical record should document that the small risk of postimmunization seizures and the benefits of vaccination have been discussed. # Subacute Sclerosing Panencephalitis (SSPE) Measles vaccine significantly reduces the likelihood of developing SSPE, as evidenced by the near elimination of SSPE cases after widespread measles vaccination began. SSPE has been reported rarely in children who do not have a history of natural measles infection but who have received measles vaccine. The available evidence suggests that at least some of these children may have had an unidentified measles infection before vaccination and that the SSPE probably resulted from the natural measles infection. The administration of live measles vaccine does not increase the risk for SSPE, regardless of whether the vaccinee has had measles infection or has previously received live measles vaccine (5,21 ). # Thrombocytopenia Surveillance of adverse reactions in the United States and other countries indicates that MMR vaccine can, in rare circumstances, cause clinically apparent thrombocytopenia within the 2 months after vaccination. In prospective studies, the reported incidence of clinically apparent thrombocytopenia after MMR vaccination ranged from one case per 30,000 vaccinated children in Finland (22 ) and Great Britain (23 ) to one case per 40,000 in Sweden, with a temporal clustering of cases occurring 2-3 weeks after vaccination (24 ). With passive surveillance, the reported incidence was approximately one case per 100,000 vaccine doses distributed in Canada and France (25 ), and approximately one case per 1 million doses distributed in the United States (26 ). The clinical course of these cases was usually transient and benign, although hemorrhage occurred rarely (26 ). Furthermore, the risk for thrombocytopenia during rubella or measles infection is much greater than the risk after vaccination. Of 30,000 schoolchildren in one Pennsylvania county who had been infected with rubella during the 1963-64 measles epidemic, 10 children developed thrombocytopenic purpura (incidence: one case per 3,000 children) (27 ). Based on case reports, the risk for thrombocytopenia may be higher for persons who previously have had idiopathic thrombocytopenic purpura, particularly for those who had thrombocytopenic purpura after an earlier dose of MMR vaccine (5,28,29 ). # Revaccination Risks There is no evidence of an increased risk for adverse reactions after administration of live measles vaccine to persons who are already immune to measles as a result of either previous vaccination or natural disease. # Precautions and Contraindications Pregnancy Live measles vaccine, when given as a component of MR or MMR, should not be given to women known to be pregnant or who are considering becoming pregnant within the next 3 months. Women who are given monovalent measles vaccine should not become pregnant for at least 30 days after vaccination. This precaution is based on the theoretical risk of fetal infection, although no evidence substantiates this theoretical risk. Considering the importance of protecting adolescents and young adults against measles, asking women if they are pregnant, excluding those who are, and explaining the theoretical risks to the others before vaccination are sufficient precautions. # Febrile Illness The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the cause of the illness and the severity of symptoms. Minor illnesses, such as a mild upper-respiratory infection with or without low-grade fever, are not contraindications for vaccination. For persons whose compliance with medical care cannot be assured, every opportunity should be taken to provide appropriate vaccinations. Children with moderate or severe febrile illnesses can be vaccinated as soon as they have recovered from the acute phase of the illness. This wait avoids superimposing adverse effects of vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine. Performing routine physical examinations or measuring temperatures are not prerequisites for vaccinating infants and children who appear to be in good health. Asking the parent or guardian if the child is ill, postponing vaccination for children with moderate or severe febrile illnesses, and vaccinating those without contraindications are appropriate procedures in childhood immunization programs. # Allergic Reactions Hypersensitivity reactions rarely occur after the administration of MMR or any of its component vaccines. Most of these reactions are minor and consist of a wheal and flare or urticaria at the injection site. Immediate, anaphylactic reactions to MMR or its component vaccines are extremely rare. Although >70 million doses of MMR vaccine have been distributed in the United States since VAERS was implemented in 1990, only 33 cases of anaphylactic reactions that occurred after MMR vaccination have been reported. Furthermore, only 11 of these cases a) occurred immediately after vaccination and b) occurred in persons who had symptoms consistent with anaphylaxis (CDC, unpublished data). In the past, persons who had a history of anaphylactic reactions (i.e., hives, swelling of the mouth or throat, difficulty breathing, hypotension, and shock) following egg ingestion were considered to be at increased risk for serious reactions after receipt of measles-containing vaccines, which are produced in chick embryo fibroblasts. Protocols requiring caution were developed for skin testing and vaccinating persons who had had anaphylactic reactions after egg ingestion (30)(31)(32)(33)(34). However, the predictive value of such skin testing and the need for special protocols when vaccinating egg-allergic persons with measles-containing vaccines is uncertain. The results of recent studies suggest that anaphylactic reactions to measles-containing vaccines are not associated with hypersensitivity to egg antigens but with some other component of the vaccines. The risk for serious allergic reaction to these vaccines in egg-allergic patients is extremely low, and skin testing is not necessarily predictive of vaccine hypersensitivity (35)(36)(37). Therefore, ACIP is re-evaluating whether skin testing and the use of special protocols are routinely necessary when administering MMR or other measles-containing vaccines to persons who have a history of anaphylactic-like reactions after egg ingestion. MMR and its component vaccines contain hydrolyzed gelatin as a stabilizer. The literature contains a single case report of a person with an anaphylactic sensitivity to gelatin who had an anaphylactic reaction after receipt of the MMR vaccine licensed in the United States (38 ). Similar cases have occurred in Japan (39 ). Therefore, ACIP is currently considering recommendations for vaccination of persons who have had an anaphylactic reaction to gelatin or gelatin-containing products. In the meantime, such persons should be vaccinated with MMR and its component vaccines with extreme caution. MMR vaccine and its component vaccines contain trace amounts of neomycin. Although the amount present is less than that usually used for a skin test to determine hypersensitivity, persons who have experienced anaphylactic reactions to neomycin should not be given these vaccines. Most often, neomycin allergy is manifested by contact dermatitis rather than anaphylaxis. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine. Live measles virus vaccine does not contain penicillin. # Thrombocytopenia Children who have a history of thrombocytopenic purpura or thrombocytopenia may be at increased risk for developing clinically significant thrombocytopenia after MMR vaccination. The decision to vaccinate should depend on the benefits of immunity to measles, mumps, and rubella and the risks for recurrence or exacerbation of thrombocytopenia after vaccination or during natural infections with measles or rubella. The benefits of immunization are usually greater than the potential risks, and administration of MMR vaccine is justified-particularly with regard to the even greater risk for thrombocytopenia after measles or rubella disease. However, avoiding a subsequent dose might be prudent if the previous episode of thrombocytopenia occurred in close temporal proximity to (i.e., within 6 weeks after) the previous vaccination. Serologic evidence of measles immunity in such persons may be sought in lieu of MMR vaccination. # Recent Administration of Immune Globulins Previous recommendations, based on data from persons who received low doses of immune globulin preparations, stated that MMR and its individual component vaccines could be administered as early as 6 weeks to 3 months after administration of immune globulins (40,41 ). However, recent evidence suggests that high doses of immune globulins can inhibit the immune response to measles vaccine for more than 3 months (42,43 ). Administration of immune globulins also can inhibit the response to rubella vaccine (42 ). The effect of immune globulin preparations on the response to mumps vaccine is unknown, but commercial immune globulin preparations contain antibodies to these viruses. Blood (e.g., whole blood, packed red blood cells, and plasma) and other antibodycontaining blood products (e.g., immune globulin; specific immune globulins; and immune globulin, intravenous [IGIV]) can diminish the immune response to MMR or its individual component vaccines. Therefore, after an immune globulin preparation is received, these vaccines should not be administered before the recommended interval (Tables 4 and 5). However, the postpartum vaccination of rubella-susceptible women with the rubella or MMR vaccine should not be delayed because anti-Rho(D) IG (human) or any other blood product was received during the last trimester of pregnancy or at delivery. These women should be vaccinated immediately after delivery and, if possible, tested at least 3 months later to ensure immunity to rubella and, if necessary, to measles. If administration of an immune globulin preparation becomes necessary because of imminent exposure to disease, MMR or its component vaccines can be administered simultaneously with the immune globulin preparation, although vaccineinduced immunity might be compromised. The vaccine should be administered at a site remote from that chosen for the immune globulin inoculation. Unless serologic testing indicates that specific antibodies have been produced, vaccination should be repeated after the recommended interval (Tables 4 and 5). If administration of an immune globulin preparation becomes necessary after MMR or its individual component vaccines have been administered, interference can occur. Usually, vaccine virus replication and stimulation of immunity will occur 1-2 weeks after vaccination. Thus, if the interval between administration of any of these vaccines and subsequent administration of an immune globulin preparation is , whole blood, packed red cells, plasma, and platelet products). † The duration of interference of immune globulin preparations with the immune response to the measles component of the MMR, measles-rubella, and monovalent measles vaccine is dose-related (Table 5). This table is not intended for determining the correct indications and dosage for the use of immune globulin preparations. Unvaccinated persons may not be fully protected against measles during the entire suggested time interval, and additional doses of immune globulin and/or measles vaccine may be indicated after measles exposure. The concentration of measles antibody in a particular immune globulin preparation can vary by lot. The rate of antibody clearance after receipt of an immune globulin preparation also can vary. The recommended time intervals are extrapolated from an estimated half-life of 30 days for passively acquired antibody and an observed interference with the immune response to measles vaccine for 5 months after a dose of 80 mg IgG/kg (42 ). † Assumes a serum IgG concentration of 16 mg/mL. § Measles vaccination is recommended for most HIV-infected children who do not have evidence of severe immunosuppression, but it is contraindicated for patients who have congenital disorders of the immune system. ¶ Formerly referred to as idiopathic thrombocytopenic purpura. # TABLE 5. Suggested intervals between administration of immune globulin preparations for various indications and vaccines containing live measles virus <14 days, vaccination should be repeated after the recommended interval (Tables 4 and 5), unless serologic testing indicates that antibodies were produced. # Altered Immunocompetence Non-HIV-Infected Persons. Replication of vaccine viruses can be enhanced in persons with immune-deficiency diseases and in persons with immunosuppression, as occurs with leukemia, lymphoma, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids. Evidence based on case reports has linked measles vaccine and measles infection to subsequent death in some severely immunocompromised children. Of the >200 million doses of measles vaccine administered in the United States, fewer than five such deaths have been reported (5 ). Patients who have such conditions or are undergoing such therapies (excluding most HIV-infected patients) should not be given live measles virus vaccine. Patients with leukemia in remission who have not received chemotherapy for at least 3 months may receive live-virus vaccines. The exact amount of systemically absorbed corticosteroids and the duration of administration needed to suppress the immune system of an otherwise healthy child are not well defined. Most experts agree that steroid therapy usually does not contraindicate administration of live virus vaccine when it is short term (i.e., <2 weeks); low to moderate dose; long-term, alternate-day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administered topically (skin or eyes), by aerosol, or by intraarticular, bursal, or tendon injection (44 ). Although of recent theoretical concern, no evidence of increased severe reactions to live vaccines has been reported among persons receiving steroid therapy by aerosol, and such therapy is not in itself a reason to delay vaccination. The immunosuppressive effects of steroid treatment vary, but many clinicians consider a dose equivalent to either 2 mg/kg of body weight or a total of 20 mg per day of prednisone as sufficiently immunosuppressive to raise concern about the safety of vaccination with live virus vaccines (44 ). Corticosteroids used in greater than physiologic doses also can reduce the immune response to vaccines. Physicians should wait at least 3 months after discontinuation of therapy before administering a live-virus vaccine to patients who have received high systemically absorbed doses of corticosteroids for ≥2 weeks. HIV-Infected Persons. Because of the increased risk for severe complications associated with measles infection and the absence of serious adverse events after measles vaccination among HIV-infected persons (41,45 ), ACIP has recommended that MMR vaccine be administered to all asymptomatic HIV-infected persons and that MMR vaccine be considered for administration to all symptomatic HIV-infected persons who would otherwise be eligible for measles vaccine-even though the immune response may be attenuated in such persons (41,44,45 ). There is a theoretical risk for an increase (probably transient) in HIV viral load following MMR vaccination because such effects have been observed with other vaccines (46,47 ). Because of the recently reported case of pneumonitis in a measles vaccinee who had an advanced case of acquired immunodeficiency syndrome (AIDS) (48 ) and because of other evidence indicating a diminished antibody response to measles vaccination among severely immunocompromised persons (49 ), ACIP is re-evaluating the recommendations for vaccination of severely immunocompromised HIV-infected persons. In the interim, it may be prudent to withhold MMR or other measlescontaining vaccines from HIV-infected persons with evidence of severe immunosuppression, defined as either a) CD4+ T-lymphocyte counts <750 for children ages <12 months, <500 for children ages 1-5 years, or <200 for persons ages ≥6 years; or b) CD4+ T-lymphocytes constituting <15% of total lymphocytes for children ages <13 years or <14% for persons ages ≥13 years (50,51 ). ACIP continues to recommend MMR for HIV-infected persons without evidence of measles immunity (47 ) who are not severely immunocompromised (50,51 ). Severely immunocompromised and other symptomatic HIV-infected patients who are exposed to measles should receive immune globulin (IG), regardless of prior vaccination status (44 ). In addition, health-care providers should weigh the risks and benefits of measles vaccination or IG prophylaxis for severely immunocompromised HIV-infected patients who are at risk for measles exposure because of outbreaks or international travel. Because the immunologic response to both live and killed antigen vaccines may decrease as HIV disease progresses (44,52 ), vaccination early in the course of HIV infection may be more likely to induce an immune response. Therefore, HIV-infected infants without severe immunosuppression should routinely receive MMR as soon as possible upon reaching their first birthday. Evaluation and testing of asymptomatic persons to identify HIV infection are not necessary before deciding to administer MMR or other measles-containing vaccine (44 ). # Management of Patients with Contraindications to Measles Vaccine If immediate protection against measles is required for persons with contraindications to measles vaccination, passive immunization with IG, 0.25 mL/kg (0.11 mL/lb) of body weight (maximum dose=15 mL), should be given as soon as possible after known exposure. Exposed symptomatic HIV-infected and other immunocompromised persons should receive IG regardless of their previous vaccination status; however, IG in usual doses may not be effective in such patients. For immunocompromised persons, the recommended dose is 0.5 mL/kg of body weight if IG is administered intramuscularly (maximum dose=15 mL). This corresponds to a dose of protein of approximately 82.5 mg/kg (maximum dose=2,475 mg). Intramuscular IG may not be needed if a patient with HIV infection is receiving 100-400 mg/kg IGIV at regular intervals and the last dose was given within 3 weeks of exposure to measles. Because the amounts of protein administered are similar, high-dose IGIV may be as effective as IG given intramuscularly. However, no data are available concerning the effectiveness of IGIV in preventing measles. # Simultaneous Administration of Vaccines In general, simultaneous administration of the most widely used live and inactivated vaccines does not impair antibody responses or increase rates of adverse reactions (53 ). The administration of MMR vaccine yields results similar to the administration of individual measles, mumps, and rubella vaccines at different sites or at different times. Vaccines recommended for administration at 12-15 months of age can be administered at either one or two visits. There are equivalent antibody responses and no clinically significant increases in the frequency of adverse events when DTP, MMR, and OPV (or IPV) vaccines and H. influenzae type b conjugate vaccine (HbCV) are administered either simultaneously at different sites or at separate times. If a child might not be brought back for future vaccinations, all vaccines (including DTP [or DTaP], OPV [or IPV], MMR, varicella, HbCV, and hepatitis B vaccines) may be administered simultaneously, as appropriate to the child's age and previous vaccination status. # MUMPS PREVENTION The following recommendations concerning adverse events associated with mumps vaccination update those applicable sections in "Mumps Prevention" (MMWR 1989;38:388-92,397-400), and they apply regardless of whether the vaccine is administered as a single antigen or as a component of MR or MMR vaccine. Information concerning adverse events associated with the measles component of MMR vaccine is reviewed earlier in this document (see Measles Prevention), and information concerning the rubella component is located in the previously published ACIP statement for rubella (18 ). # Adverse Effects of Vaccine Use In field trials before licensure, illnesses did not occur more often in vaccinees than in unvaccinated controls (54 ). Reports of illnesses following mumps vaccination have mainly been episodes of parotitis and low-grade fever. Allergic reactions including rash, pruritus, and purpura have been temporally associated with mumps vaccination but are uncommon and usually mild and of brief duration. The reported occurrence of encephalitis within 30 days of receipt of a mumps-containing vaccine (0.4 per million doses) is not greater than the observed background incidence rate of CNS dysfunction in the normal population. Aseptic meningitis has been epidemiologically associated with receipt of the vaccine containing the Urabe strain of mumps virus, but not with the vaccine containing the Jeryl Lynn strain, the latter of which is used in vaccine distributed in the United States (5 ). During 1988-1992, 15 sentinel surveillance laboratories in the United Kingdom identified 13 aseptic meningitis cases that had occurred within 15-35 days after vaccination with the Urabe strain (i.e., 91 cases per 1 million doses distributed) (55 ). No vaccine-associated aseptic meningitis cases have been reported since 1992, when only the Jeryl Lynn strain has been used (23 ). Febrile seizures also have been infrequently reported. However, no evidence suggests that mumps vaccine causes residual seizure disorder (5 ). Although sensorineural deafness following mumps vaccination has been reported rarely, the data are inadequate to distinguish vaccine from nonvaccine causation. No association has been established between mumps vaccination and pancreatic damage or subsequent development of diabetes mellitus (5 ). # Contraindications to Vaccine Use Pregnancy Although mumps vaccine virus has been shown to infect the placenta and fetus (56), there is no evidence that it causes congenital malformations in humans. However, because of the theoretical risk of fetal damage, it is prudent to avoid giving live virus vaccine to pregnant women. Live mumps vaccine, when combined with rubella vaccine, should not be administered to women known to be pregnant or who are considering becoming pregnant within the next 3 months. Women vaccinated with monovalent mumps vaccine should avoid becoming pregnant for 30 days after the vaccination. Routine precautions for vaccinating postpubertal women include asking if they are or may be pregnant, excluding those who say they are, and explaining the theoretical risk to those who plan to receive the vaccine. Vaccination during pregnancy should not be considered an indication for termination of pregnancy. However, the final decision about interruption of pregnancy must rest with the individual patient and her physician. # Severe Febrile Illness Vaccine administration should not be postponed because of minor or intercurrent febrile illnesses, such as mild upper respiratory infections. However, vaccination of persons with severe febrile illnesses should generally be deferred until they have recovered from the acute phase of the illness. # Allergic Reactions Hypersensitivity reactions rarely occur after the administration of MMR or any of its component vaccines. Most of these reactions are minor and consist of a wheal and flare or urticaria at the injection site. Immediate, anaphylactic reactions to MMR or its component vaccines are extremely rare. Although >70 million doses of MMR vaccine have been distributed in the United States since VAERS was implemented in 1990, only 33 cases of anaphylactic reactions that occurred after MMR vaccination have been reported. Furthermore, only 11 of these cases a) occurred immediately after vaccination and b) occurred in persons who had symptoms consistent with anaphylaxis (CDC, unpublished data). In the past, persons who had a history of anaphylactic reactions (i.e., hives, swelling of the mouth or throat, difficulty breathing, hypotension, and shock) following egg ingestion were considered to be at increased risk for serious reactions after receipt of mumps-containing vaccines, which are produced in chick embryo fibroblasts. Protocols requiring caution were developed for skin testing and vaccinating persons who had had anaphylactic reactions after egg ingestion (30)(31)(32)(33)(34). However, the predictive value of such skin testing and the need for special protocols when vaccinating egg-allergic persons with mumps-containing vaccines is uncertain. The results of recent studies suggest that anaphylactic reactions to mumps-containing vaccines are not associated with hypersensitivity to egg antigens but with some other component of the vaccines. The risk for serious allergic reaction to these vaccines in egg-allergic patients is extremely low, and skin testing is not necessarily predictive of vaccine hypersensitivity (35)(36)(37). Therefore, ACIP is re-evaluating whether skin testing and the use of special protocols are routinely necessary when administering mumps-containing vaccines to persons who have a history of anaphylactic-like reactions after egg ingestion. MMR and its component vaccines contain hydrolyzed gelatin as a stabilizer. The literature contains a single case report of a person with an anaphylactic sensitivity to gelatin who had an anaphylactic reaction after receipt of the MMR vaccine licensed in the United States (38 ). Similar cases have occurred in Japan (39 ). Therefore, ACIP is currently considering recommendations for vaccination of persons who have had an anaphylactic reaction to gelatin or gelatin-containing products. In the meantime, such persons should be vaccinated with MMR or other mumps vaccines with extreme caution. Since mumps vaccine contains trace amounts of neomycin (25 µg), persons who have experienced anaphylactic reactions to topically or systemically administered neomycin should not receive mumps vaccine. Most often, neomycin allergy is manifested as a contact dermatitis, which is a delayed-type (cell-mediated) immune response, rather than anaphylaxis. In such persons, the adverse reaction, if any, to 25 µg of neomycin in the vaccine would be an erythematous, pruritic nodule or papule at the site of injection after 48-96 hours. A history of contact dermatitis to neomycin is not a contraindication to receiving mumps vaccine. Live mumps virus vaccine does not contain penicillin. # Recent Injection of Immune Globulin The effect of immune globulin preparations on the response to mumps vaccine is unknown, but commercial immune globulin preparations contain mumps antibodies. Therefore, monovalent mumps or rubella-mumps vaccine should be given at least 2 weeks before the administration of an immune globulin preparation or deferred until approximately 3 months after the administration of an immune globulin preparation. For suggested time intervals between administration of immune globulin preparations and vaccines containing live measles virus, refer to Table 5. # Altered Immunocompetence In theory, replication of the mumps vaccine virus may be potentiated in patients with immune deficiency diseases and by the suppressed immune responses that occur with leukemia, lymphoma, or generalized malignancy or with therapy with corticosteroids, alkylating drugs, antimetabolites, or radiation. In general, patients with such conditions should not be given live mumps virus vaccine. Because vaccinated persons do not transmit mumps vaccine virus, the risk of mumps exposure for those patients may be reduced by vaccinating their close susceptible contacts. An exception to these general recommendations is in persons infected with HIV; asymptomatic HIV-infected children should receive MMR as soon as possible upon reaching their first birthday (44 ), and MMR vaccine should be considered for all symptomatic HIV-infected children who do not have evidence of severe immunosuppression (see Measles Prevention, Altered Immunocompetence). Patients with leukemia in remission whose chemotherapy has been terminated for at least 3 months may also receive live mumps virus vaccine. Most experts agree that steroid therapy usually does not contraindicate administration of live virus vaccine when it is short term (i.e., <2 weeks); low to moderate dose; long-term, alternate-day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administered topically (skin or eyes), by aerosol, or by intraarticular, bursal, or tendon injection (44 ). However, mumps vaccine should be avoided if systemic immunosuppressive levels are reached by prolonged, extensive, topical application. # DTP The following recommendations concerning adverse events associated with DTP vaccination update those applicable sections in "Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures-Recommendations of the Immunization Practices Advisory Committee (ACIP)" (MMWR 1991;40[No. RR-10]). # Side Effects and Adverse Reactions Following DTP Vaccination Local reactions (generally erythema and induration with or without tenderness) are common after the administration of vaccines containing diphtheria, tetanus, or pertussis antigens. Occasionally, a nodule may be palpable at the injection site of adsorbed products for several weeks. Sterile abscesses at the injection site have been reported rarely (6-10 events per million doses of DTP). Mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia occur frequently. These reactions are substantially more common following the administration of DTP than of DT, but they are self-limited and can be safely managed with symptomatic treatment. Acetaminophen is frequently given by physicians to lessen fever and irritability associated with DTP vaccination, and it may be useful in preventing seizures among febrile-convulsion-prone children. However, fever that does not begin until ≥24 hours after vaccination or persists for more than 24 hours after vaccination should not be assumed to be due to DTP vaccination. These new or persistent fevers should be evaluated for other causes so that treatment is not delayed for serious conditions such as otitis media or meningitis. Moderate-to-severe systemic events include high fever (i.e., temperature of ≥40.5 C [≥105 F]); persistent, inconsolable crying lasting ≥3 hours; collapse (hypotonic-hyporesponsive episode); or short-lived convulsions (usually febrile). These events occur infrequently. These events appear to be without sequelae (57)(58)(59). Other more severe neurologic events, such as a prolonged convulsion or encephalopathy, although rare, have been reported in temporal association with DTP administration. Approximate rates for the occurrence of adverse events following receipt of DTP (regardless of dose number in the series or age of the child) are shown in Table 6 (60,61 ). The frequencies of local reactions and fever are substantially higher with increasing numbers of doses of DTP, while other mild-to-moderate systemic reactions (e.g., fretfulness, vomiting) are substantially less frequent (59)(60)(61). Concern about the possible role of pertussis vaccine in causing neurologic reactions has been present since the earliest days of vaccine use. Rare but serious acute neurologic illnesses, including encephalitis/encephalopathy and prolonged convulsions, have been anecdotally reported following receipt of whole-cell pertussis vaccine given as DTP (62,63 ). Whether pertussis vaccine causes or is only coincidentally related to such illnesses or reveals an inevitable event has been difficult to determine conclusively for the following reasons: a) serious acute neurologic illnesses often occur or become manifest among children during the first year of life irrespective of vaccination; b) there is no specific clinical sign, pathologic finding, or laboratory test which can determine whether the illness is caused by the DTP; c) it may be difficult to determine with certainty whether infants <6 months of age are neurologically normal, which complicates assessment of whether vaccinees were already neurologically impaired before receiving DTP; and d) because these events are exceedingly rare, appropriately designed large studies are needed to address the question. Despite these methodologic difficulties, the National Childhood Encephalopathy Study (NCES) and other controlled epidemiologic studies have provided evidence that DTP can cause acute encephalopathy (64)(65)(66)(67)(68). This adverse event occurs rarely, with an estimated risk of zero to 10.5 episodes per million DTP vaccinations (68 ). A detailed follow-up of the NCES indicated that children who had had a serious acute neurologic illness after DTP administration were significantly more likely than children in the control group to have chronic nervous system dysfunction 10 years later. These children with chronic nervous system dysfunction were more likely than children in the control group to have received DTP within 7 days of onset of the original serious acute neurologic illness (i.e., 12 [3.3%] of 367 children vs. six [0.8%] of 723 children) (69 ). After reviewing the follow-up data, IOM concluded that the NCES provided evidence of an association between DTP and chronic nervous system dysfunction in children who had had a serious acute neurologic illness after vaccination with DTP. The committee proposed three possible explanations for this association. First, the acute neurologic illness and subsequent chronic nervous system dysfunction might have been caused by DTP. Second, DTP might trigger an acute neurologic illness and subsequent chronic nervous system dysfunction in children who have underlying brain or metabolic abnormalities. Such children might experience similar chronic dysfunction in the absence of DTP vaccination if other stimuli (e.g., fever or infection) are present. Third, DTP might cause an acute neurologic illness in children who have underlying brain or metabolic abnormalities that would inevitably have led to chronic TABLE 6. Adverse events* occurring within 48 hours after vaccination with diphtheria and tetanus toxoids and pertussis vaccine (DTP) nervous system dysfunction even if the acute neurologic illness had not developed (6 ) . IOM concluded that the NCES data do not support one explanation over another. According to IOM, the balance of evidence was consistent with a causal relationship between DTP and some forms of chronic nervous system disorders in children who had developed an acute neurologic disorder after receiving DTP. However, IOM also concluded that the results were insufficient to determine whether DTP increases the overall risk for chronic nervous system dysfunction in children. A subcommittee of the National Vaccine Advisory Committee (NVAC) also reviewed the study and concluded that the results were insufficient to determine whether DTP administration before the acute neurologic event influenced the potential for neurologic dysfunction 10 years later (Ad hoc Subcommittee of the NVAC, unpublished data, 1994). ACIP concurs with this evaluation. Although the NCES examined and reported risk for the 7 days after DTP vaccination, the increased risk for serious acute neurologic illness occurred primarily during the first 3 days after DTP administration (64 ). Thus, if an association between DTP and chronic encephalopathy exists, the risk is primarily in the first 3 days after DTP vaccination. Among a subset of children who were participating in the NCES and who had infantile spasms, both DTP and DT vaccination appeared either to precipitate early manifestations of the condition or to lead to its identification by parents (70 ). IOM reviewed this and other studies and concluded that neither vaccine causes the illness (71,72 ). Sudden infant death syndrome (SIDS) is listed on death certificates as the cause of death for 5,000-6,000 infants (ages 0-364 days) each year in the United States. Because the peak incidence of SIDS for infants occurs at 2-4 months of age, many instances of a close temporal relation between SIDS and receipt of DTP are to be expected by simple chance. Only one methodologically rigorous study has suggested that DTP vaccination might cause SIDS (73 ). A total of four deaths were reported within 3 days of DTP vaccination, compared with 1.36 expected deaths. However, these deaths were unusual in that three of the four occurred within a 13-month interval during the 12-year study. These four children also tended to be vaccinated at older ages than their controls, suggesting that they might have had other unrecognized risk factors for SIDS independent of vaccination. In contrast, DTP vaccination was not associated with SIDS in several larger studies performed in the past decade (62,(74)(75)(76). In addition, none of three studies that examined unexpected deaths among infants not classified as SIDS found an association with DTP vaccination (73,75,76 ). IOM reviewed these studies and concluded that the available information does not establish a causal relationship between DTP and SIDS (4 ). IOM concluded recently that no available evidence indicates that DTP might cause transverse myelitis, other more subtle neurologic disorders (e.g., hyperactivity, learning disorders, and infantile autism), and progressive degenerative conditions of the CNS (4 ). Furthermore, one study indicated that children who received pertussis vaccine exhibited fewer school problems than those who did not, even after adjustment for socioeconomic status (77 ). Recent data suggest that infants and young children who have ever had convulsions (febrile or afebrile) or who have immediate family members with such histories are more likely to have seizures following DTP vaccination than those without such histories (78,79 ). For those with a family history of seizures, the increased risks of seizures occurring within 3 days of receipt of DTP or 4-28 days following receipt of DTP are identical, suggesting that these histories are nonspecific risk factors and are unrelated to DTP vaccination (79 ). Rarely, immediate anaphylactic reactions (i.e., swelling of the mouth, breathing difficulty, hypotension, or shock) have been reported after receipt of preparations containing diphtheria, tetanus, and/or pertussis antigens. However, no deaths caused by anaphylaxis following DTP vaccination have been reported to CDC since the inception of vaccine-adverse-events reporting in 1978, a period during which more than 80 million doses of publicly purchased DTP vaccine were administered. While substantial underreporting exists in this passive surveillance system, the severity of anaphylaxis and its immediacy following vaccination suggest that such events are likely to be reported. Although no causal relation to any specific component of DTP has been established, the occurrence of true anaphylaxis usually contraindicates further doses of any one of these components. Rashes that are macular, papular, petechial, or urticarial and appear hours or days after a dose of DTP are frequently antigen-antibody reactions of little consequence or are due to other causes, such as viral illnesses, and are unlikely to recur following subsequent injections (80,81 ). In addition, there is no evidence for a causal relation between DTP vaccination and hemolytic anemia or thrombocytopenic purpura. # Precautions and Contraindications # General Considerations The decision to administer or delay DTP vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Although a moderate or severe febrile illness is sufficient reason to postpone vaccination, minor illnesses such as mild upper-respiratory infections with or without low-grade fever are not contraindications. If ongoing medical care cannot be assured, taking every opportunity to provide appropriate vaccinations is particularly important. Children with moderate or severe illnesses with or without fever can receive DTP as soon as they have recovered. Waiting a short period before administering DTP avoids superimposing the adverse effects of the vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to vaccination. Routine physical examinations or temperature measurements are not prerequisites for vaccinating infants and children who appear to be in good health. Appropriate immunization practice includes asking the parent or guardian if the child is ill, postponing DTP vaccination for those with moderate or severe acute illnesses, and vaccinating those without contraindications or precautionary circumstances. When an infant or child returns for the next dose of DTP, the parent should always be questioned about any adverse events that might have occurred following the previous dose. A history of prematurity generally is not a reason to defer vaccination (82)(83)(84). Preterm infants should be vaccinated according to their chronological age from birth. Immunosuppressive therapies-including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) -may reduce the immune response to vaccines. Short-term (<2-week) corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive. Although no specific studies with pertussis vaccine are available, if immunosuppressive therapy will be discontinued shortly, it is reasonable to defer vaccination until the patient has been off therapy for 1 month; otherwise, the patient should be vaccinated while still on therapy (85 ). # Special Considerations for Preparations Containing Pertussis Vaccine Precautions and contraindications guidelines that were previously published regarding the use of pertussis vaccine were based on three assumptions about the risks for adverse events associated with pertussis vaccination: a) that the vaccine on rare occasions caused acute encephalopathy resulting in permanent brain damage; b) that pertussis vaccine aggravated preexisting CNS disease; and c) that certain nonencephalitic reactions are predictive of more severe reactions with subsequent doses (86 ). In addition, children from whom pertussis vaccine was withheld were thought to be well protected by herd immunity, a belief that is no longer valid. The current revised ACIP recommendations reflect better understanding of the risks associated not only with pertussis vaccine but also with pertussis disease. # Contraindications If any of the following events occur in temporal relationship to the administration of DTP, further vaccination with DTP is contraindicated (Table 7): 1. An immediate anaphylactic reaction. The rarity of such reactions to DTP is such that they have not been adequately studied. Because of uncertainty as to which component of the vaccine might be responsible, no further vaccination with any of the three antigens in DTP should be carried out. Alternatively, because of the importance of tetanus vaccination, such individuals may be referred for evaluation by an allergist and desensitized to tetanus toxoid if a specific allergy can be demonstrated (87,88 ). 2. Encephalopathy (not due to another identifiable cause). This is defined as an acute, severe CNS disorder occurring within 7 days following vaccination and generally consisting of major alterations in consciousness, unresponsiveness, generalized or focal seizures that persist more than a few hours, with failure to recover within 24 hours. Even though causation by DTP cannot be established, no subsequent doses of pertussis vaccine should be given. It # TABLE 7. Contraindications and precautions to subsequent vaccination with diphtheria and tetanus toxoids and pertussis vaccine (DTP) Classification/Response to DTP vaccination # Contraindications • An immediate anaphylactic reaction. • Encephalopathy occurring within 7 days after vaccination. # Precautions • Fever ≥105 F (≥40.5 C) that is not attributed to another identifiable cause occurring within 48 hours after vaccination. • Collapse or shock-like state (i.e., a hypotonic-hyporesponsive episdode) occurring within 48 hours after vaccination. • Persistent, inconsolable crying lasting ≥3 hours and occurring within 48 hours after vaccination. • Convulsions with or without fever occurring within 3 days after vaccination. may be desirable to delay for months before administering the balance of the doses of DT necessary to complete the primary schedule. Such a delay allows time for clarification of the child's neurologic status. # Precautions If any of the following events occur in temporal relation to receipt of DTP, the decision to give subsequent doses of vaccine containing the pertussis component should be carefully considered (Table 7). Although these events were considered absolute contraindications in previous ACIP recommendations, there may be circumstances, such as a high incidence of pertussis, in which the potential benefits outweigh possible risks, particularly because these events are not associated with permanent sequelae (86 ). The following events were previously considered contraindications and are now considered precautions: 1. Temperature of ≥40.5 C (≥105 F) within 48 hours not due to another identifiable cause. Such a temperature is considered a precaution because of the likelihood that fever following a subsequent dose of DTP also will be high. has a seizure following the first or second dose of DTP, it is desirable to delay subsequent doses until the child's neurologic status is better defined. By the end of the first year of life, the presence of an underlying neurologic disorder has usually been determined and appropriate treatment instituted. DT vaccine should not be administered before a decision has been made about whether to restart the DTP series. Regardless of which vaccine is given, it is prudent also to administer acetaminophen, 15 mg/kg of body weight, at the time of vaccination and every 4 hours subsequently for 24 hours (92,93 ). # Vaccination of infants and young children who have underlying neurologic disorders Infants and children with recognized, possible, or potential underlying neurologic conditions present a unique problem. They seem to be at increased risk for the appearance of manifestations of the underlying neurologic disorder within 2-3 days after vaccination. However, more prolonged manifestations or increased progression of the disorder or exacerbation of the disorder as a result of DTP vaccination have not been recognized (94 ). In addition, most neurologic conditions in infancy and young childhood are associated with evolving, changing neurological findings. Functional abnormalities are often unmasked by progressive neurologic development. Thus, confusion over the interpretation of progressive neurologic signs may arise when DTP vaccination or any other therapeutic or preventive measure is carried out. Protection against diphtheria, tetanus, and pertussis is as important for children with neurologic disabilities as for other children. Such protection may be even more important for neurologically disabled children. They often receive custodial care or attend special schools where the risk of pertussis is greater because DTP vaccination is avoided for fear of adverse reactions. Also, if pertussis affects a neurologically disabled child who has difficulty in handling secretions and in cooperating with symptomatic care, it may aggravate preexisting neurologic problems because of anoxia, intracerebral hemorrhages, and other manifestations of the disease. Whether and when to administer DTP to children with proven or suspected underlying neurologic disorders must be decided on an individual basis. Important considerations include the current local incidence of pertussis, the near absence of diphtheria in the United States, and the low risk of infection with Clostridium tetani. On the basis of these considerations and the nature of the child's disorder, the following approaches are recommended: 1. # Vaccination of infants and young children who have a family history of convulsion or other CNS disorder A family history of convulsions or other CNS disorder is not a contraindication to pertussis vaccination (95 ). Acetaminophen should be given at the time of DTP vaccination and every 4 hours for 24 hours to reduce the possibility of postvaccination fever (92,93 ). # Preparations Containing Diphtheria Toxoid and Tetanus Toxoid The only contraindication to tetanus and diphtheria toxoids is a history of a neurologic or severe hypersensitivity reaction following a previous dose. Vaccination with tetanus and diphtheria toxoids is not known to be associated with an increased risk of convulsions. Local side effects alone do not preclude continued use. If an anaphylactic reaction to a previous dose of tetanus toxoid is suspected, intradermal skin testing with appropriately diluted tetanus toxoid may be useful before a decision is made to discontinue tetanus toxoid vaccination (86 ). In one study, 94 of 95 persons with histories of anaphylactic symptoms following a previous dose of tetanus toxoid were nonreactive following intradermal testing and tolerated further tetanus toxoid challenge without incident (86 ). One person had erythema and induration immediately following skin testing, but tolerated a full IM dose without adverse effects. Mild, nonspecific skin-test reactivity to tetanus toxoid, particularly if used undiluted, appears to be fairly common. Most vaccinees develop inconsequential cutaneous delayed hypersensitivity to the toxoid. Although very rare, severe hypersensitivity reactions may occur after receipt of tetanus-toxoid-containing vaccines; these reactions can be life-threatening (5 ). Persons who experienced Arthus-type hypersensitivity reactions or a temperature of >103 F (>39.4 C) following a prior dose of tetanus toxoid usually have high serum tetanus antitoxin levels and should not be given even emergency doses of Td more frequently than every 10 years, even if they have a wound that is neither clean nor minor. If a contraindication to using tetanus-toxoid-containing preparations exists for a person who has not completed a primary series of tetanus toxoid immunization and that person has a wound that is neither clean nor minor, only passive immunization should be given using tetanus IG (TIG). On the basis of a) a report of a 42-year-old man who had GBS on three separate occasions after receipt of tetanus toxoid and b) evidence that a vaccine-induced immunologic response can cause GBS, IOM concluded that tetanus-toxoid-containing vaccines can trigger the onset of GBS in adults. GBS can be a life-threatening disease. Persons who have a history of GBS associated with a particular vaccine may be at increased risk for recurrent GBS after subsequent doses of that vaccine (5 ). However, in a study in which an estimated 1.2 million doses of tetanus-containing toxoid were administered to persons >18 years of age, two cases of GBS were expected by chance alone during the 6 weeks after vaccination, and only one case was reported (CDC, unpublished data). This finding suggests that the risk for GBS after administration of tetanus toxoid is extremely low. No increased risk for GBS has been observed with the use of DTP in children. In a study of 0.7 million children of preschool-ages who were vaccinated with DTP during a 7-year period, three cases of GBS were expected by chance alone during the 6 weeks after vaccination, and only two cases were reported (17 ). Because tetanus vaccination has been associated rarely with recurrence of GBS, the decision to administer additional doses of tetanus-toxoid-containing vaccine to persons who have had GBS within 6 weeks after receiving tetanus toxoid should be based on the benefits of subsequent vaccination and the risk for recurrence of GBS. For example, vaccination is usually justified for children whose primary immunization schedules are incomplete (i.e., fewer than three doses have been received); but routine booster vaccination probably is not indicated for adults who have received three or more doses. Vaccination with tetanus-toxoid-containing vaccines has been associated with brachial neuritis in adult vaccinees, with a relative risk of 5-10 in comparison with the population-based background incidence and a 1-month attributable incidence of approximately one-half to one case per 100,000 recipients of tetanus toxoid (5 ). Although no evidence exists that tetanus and diphtheria toxoids are teratogenic, waiting until the second trimester of pregnancy to administer Td is a reasonable precaution for minimizing any concern about the theoretical possibility of such reactions. # Misconceptions Concerning Contraindications to DTP Some health-care providers inappropriately consider certain conditions or circumstances as contraindications to DTP vaccination. These include the following: 1. Soreness, redness, or swelling at the DTP vaccination site or temperature of <40.5 C (<105 F). 2. Mild, acute illness with low-grade fever or mild diarrheal illness affecting an otherwise healthy child. 3. Current antimicrobial therapy or the convalescent phase of an acute illness. 4. Recent exposure to an infectious disease. 5. Prematurity. The appropriate age for initiating vaccination among the prematurely born infant is the usual chronological age from birth (82)(83)(84). Full doses (0.5 mL) of vaccine should be used. 6. History of allergies or relatives with allergies. 7. Family history of convulsions. 8. Family history of SIDS. 9. Family history of an adverse event following DTP vaccination. # Event Frequency of event †	None	None
20c29b9d8002cb30bbf4166f5642aed537ac9377	cdc	None	Reproduced with permission. Urban yellow fever is transmitted from person to person through the bite of an infected Aedes aegypti mosquito. In recent years, reinfestations of Ae. aegypti have occurred in countries throughout the world, contributing to the threat of epidemic yellow fever reemergence in new locations and highlighting the importance of vaccination programs for prevention.# Introduction Yellow fever occurs only in Africa and South America. The World Health Organization (WHO) estimates that a total of 200,000 cases of yellow fever occur each year (1). The clinical spectrum of yellow fever ranges from subclinical infection to overwhelming pansystemic disease (2). Yellow fever has an abrupt onset after an incubation period of 3-6 days, and usually includes fever, prostration, headache, photophobia, lumbosacral pain, extremity pain (including the knee joints), epigastric pain, anorexia, and vomiting. The illness might progress to liver and renal failure, and hemorrhagic symptoms and signs caused by thrombocytopenia and abnormal clotting and coagulation can occur. The fatality rate of severe yellow fever is approximately 20%. Definitive diagnosis is made by viral culture of blood or tissue specimens or by identification of yellow fever virus antigen or nucleic acid in tissues (including liver) using immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA) antigen capture, or polymerase chain reaction tests (3). Although antibodies are not always present during the first week of illness, detection of yellow fever-specific immunoglobulin M (IgM) antibody by capture ELISA with confirmation of >4-fold rise in neutralizing antibody titers between acute-and convalescent-phase serum samples is also diagnostic. Treatment for yellow fever consists of providing general supportive care and varies, depending on which organ systems are involved. No effective specific antiviral therapy for yellow fever has been identified. Two forms of yellow fever, urban and jungle, are epidemiologically distinguishable. Clinically and etiologically they are identical (4,5). Urban yellow fever is an epidemic viral disease of humans transmitted from infected to susceptible persons by Aedes aegypti mosquitoes, which breed in domestic and peridomestic containers (e.g., water jars, barrels, drums, tires, or tin cans) and thus in close association with humans. In areas where Ae. aegypti has been eliminated or suppressed, urban yellow fever has disappeared. In the mid-1900s, eradication of Ae. aegypti in multiple countries, notably Panama, Brazil, Ecuador, Peru, Bolivia, Paraguay, Uruguay, and Argentina, led to the disappearance of urban yellow fever. The last documented Ae. aegypti-borne yellow fever epidemic in the western hemisphere occurred in Trinidad in 1954. However, in recent years, reinfestation of countries that had previously eradicated Ae. aegypti has occurred (5). Ae. aegypti mosquitoes are strongly suspected as having played a role in transmission in outbreaks occurring in Bolivia in 1989Bolivia in , 1990Bolivia in , and 1998. Other countries remain infested, including areas of Venezuela and the Guianas, which include enzootic areas for jungle yellow fever. In Africa, yellow fever epidemics caused by transmission by Ae. aegypti continue to occur and involve human populations both in towns and in rural villages (8,9). Jungle yellow fever is primarily an enzootic viral disease transmitted among nonhuman primate hosts by different mosquito vectors, but endemic and epidemic jungle yellow fever can occur. It is observed only in forest-savannah zones of tropical Africa and in forested areas of South America but, in the past, occasionally extended into parts of Central America; it is enzootic in the jungles on the island of Trinidad. In South America, approximately 500 human cases are reported annually, primarily among men with occupational exposures in forested areas; however, the disease is believed to be substantially underreported (10). In Africa, epidemics involving treehole-breeding mosquito vectors affect thousands of persons at intermittent intervals, but only a limited number of cases are officially reported. Sometimes the disease is not detected in an area for years but then will reappear. Delineation of affected areas depends on surveillance for animal reservoirs and vectors, accurate diagnosis, and prompt reporting of all human cases. The jungle yellow fever cycle might be active but unrecognized in forested areas of countries within the yellow fever-endemic zone (Figure ). Urban yellow fever can be prevented by vaccinating human populations at risk for infection or by suppressing populations of Ae. aegypti mosquitoes so that they no longer perpetuate infection. Jungle yellow fever can most effectively be prevented by vaccination of human populations at risk for exposure. # Yellow Fever Vaccine Yellow fever vaccine is a live, attenuated virus preparation made from the 17D yellow fever virus strain (11). Historically, the 17D vaccine has been considered to be one of the safest and most effective live virus vaccines ever developed (2,12). The virus is grown in chick embryos inoculated with a seed virus of a fixed passage level. The 17D yellow fever vaccine virus family is the foundation for both the 17D-204 lineage and 17DD lineage. Vaccine type 17D-204 is used in both the United States and Australia, whereas vaccine type 17DD is used in Brazil. The two vaccine types share 99.9% sequence homology (13). The 17D-204 strain YF-VAX ® (manufactured by Aventis, Swiftwater, Pennsylvania) vaccine is a freeze-dried supernatant of centrifuged embryo homogenate, packaged in 1-dose and 5-dose vials for domestic use. The vaccine should be stored at temperatures of 2 º C-8 º C (35 º F-46 º F) until it is reconstituted by the addition of diluent (sterile, physiologic saline) supplied by the manufacturer. Multidose vials of reconstituted vaccine should be held at 2 º C-8 º C (35 º F-46 º F); unused vaccine should be discarded within 1 hour after reconstitution. # Vaccine Use Persons Living or Traveling in Endemic Areas Persons aged >9 months who are traveling to or living in areas of South America and Africa where yellow fever infection is officially reported should be vaccinated. These areas are listed in the "Bi-Weekly Summary of Countries with Areas Infected with Quarantinable Diseases," available at state and local health departments. Information concerning known or probable infected areas is also available from WHO (http:// www.who.int), the Pan American Health Organization, the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC, or at http:// www.cdc.gov/travel. Vaccination is also recommended for travel to countries that do not officially report the disease but that lie in the yellow fever-endemic zone (see shaded areas in the figure). In recent years, fatal cases of yellow fever have occurred among unvaccinated tourists from the United States and Europe who visited rural areas within the yellow fever-endemic zone (3,(14)(15)(16)(17)(18). Because of incomplete surveillance, the actual areas of yellow fever virus activity might exceed the infected zones officially reported by individual ministries of health. The manufacturer and the Food and Drug Administration (FDA) recommend that vaccination of infants aged 3 years (including two fatal cases in persons aged 3 and 53 years). Because recent experience in use of the vaccine among children aged <6 months is limited and because age-specific vaccine administration records are not available, calculation of age-specific rates of yellow fever vaccine-associated encephalitis is impossible. In unusual circumstances, physicians considering vaccinating infants aged <9 months or pregnant women should contact the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC for advice (see Precautions and Contraindications). Despite the lack of such information, ACIP and WHO recognize that situations occur in which vaccination of an infant aged <9 months might be considered. One such situation is the unavoidable exposure of children aged 6-8 months to an environment where an increased likelihood of becoming infected with the yellow fever virus exists (e.g., a setting of endemic or epidemic yellow fever) (1). Because of the risk for encephalitis, in no instance should infants aged <6 months receive yellow fever vaccine. Because the seroconversion rate after vaccination of pregnant women might be markedly reduced compared with that of other healthy women, serologic tests to determine if a specific yellow fever immune response exists should be considered. To discuss the need for serologic testing, the appropriate state health department or the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC should be contacted (see Precautions and Contraindications). # Laboratory Personnel Laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of the 17D vaccine strain by direct or indirect contact or by aerosols should also be vaccinated. # Requirements for Vaccination Before International Travel For purposes of international travel, yellow fever vaccines produced by different manufacturers worldwide must be approved by WHO and administered at an approved yellow fever vaccination center. In addition to CDC's Division of Global Migration and Quarantine, state and territorial health departments have the authority to designate nonfederal vaccination centers; these centers can be identified by contacting state or local health departments. Vaccinees should receive an International Certificate of Vaccination that has been completed, signed, and validated with the center's stamp when the vaccine is administered. Vaccination for international travel might be required under circumstances other than those specified in this report. Certain countries in Africa require evidence of vaccination from all entering travelers. Other countries might waive the requirements for travelers coming from areas where no evidence exists of substantial risk for yellow fever and who are staying <2 weeks. Because requirements might change, all travelers should seek up-to-date information from health departments, CDC, and WHO. Travel agencies, international airlines, or shipping lines also should have up-to-date information. Certain countries require persons, even if only in transit, to have valid International Certificates of Vaccination if they have been in countries either known or thought to have yellow fever virus. Such requirements might be enforced strictly, including for persons traveling from Africa or South America to Asia. Travelers should consult CDC's travel information website at (19) to determine requirements and regulations for vaccination. # Primary Vaccination For persons of all ages for whom vaccination is indicated, a single subcutaneous injection of 0.5 mL of reconstituted vaccine is used. # Booster Doses The International Health Regulations require revaccination at intervals of 10 years. Revaccination can boost antibody titer; however, evidence from multiple studies (20-23) demonstrates that yellow fever vaccine immunity persists for 30-35 years and probably for life. # Safety General Events Reactions to 17D yellow fever vaccine are typically mild. After vaccination, vaccinees have reported mild headaches, myalgia, low-grade fevers, or other minor symptoms for 5-10 days. In clinical trials, where symptoms are actively elicited, incidence of mild adverse events has been <25% (24,25). Approximately 1% of vaccinees curtail regular activities. Immediate hypersensitivity reactions, characterized by rash, urticaria, or asthma, are uncommon (i.e., an estimated incidence of 1/130,000-250,000) and occur principally among persons with histories of allergies to egg or other substances (26). Gelatin is used as a stabilizer in different vaccines, including yellow fever vaccine. Gelatin has been implicated as a cause of allergic reaction related to other vaccines and, therefore, might also do the same regarding yellow fever vaccine (27)(28)(29). Vaccine strain viremia after primary vaccination with yellow fever vaccine frequently occurs among healthy persons, but is usually waning or absent after the first week (2,30). # Yellow Fever Vaccine-Associated Neurotropic Disease Historically, yellow fever vaccine-associated neurotropic disease (formerly known as postvaccinal encephalitis) among children has been the most common serious adverse event associated with yellow fever vaccines. Worldwide, only 23 cases of encephalitis temporally associated with or confirmed to be caused by 17D vaccine have been reported in the scientific literature since the introduction of the 17D seed lot system in 1945 (2,(31)(32)(33); of these, 16 have occurred among children aged <9 months. The other seven cases occurred among persons aged 3-76 years. Only three of these cases of encephalitis were associated with vaccinations in the United States; one occurred in 1959 (in a person aged 10 weeks); the second in 1965 (in a person aged 3 years); and one in 1998 (in a person aged 76 years). One of the three cases was fatal, and 17D virus was isolated from the brain of this patient (33). Since 1965, only one case of yellow fever vaccine-associated encephalitis in the United States has been reported in the scientific literature. The case occurred in a male aged 76 years who suffered both yellow fever vaccine-associated neurotropic disease and yellow fever vaccine-associated viscerotropic disease (31). The most recent case of possible yellow fever vaccine-associated neurotropic disease was reported in 2002 from Thailand and involved a man aged 53 years who had unrecognized human immunodeficiency virus (HIV) infection (32). Recently, four reports have been made to the Vaccine Adverse Event Reporting System (VAERS) of encephalitis among adult recipients of yellow fever vaccine (persons aged 16, 36, 41, and 71 years) with onset of illness 4-23 days after vaccination. The occurrence of vaccine-associated neurotropic disease does not appear to be confined to infants but does appear to be limited. The risk for vaccine-associated neurotropic disease has been estimated as <1/8,000,000 persons (2). # Yellow Fever Vaccine-Associated Viscerotropic Disease Recently, a new serious adverse reaction syndrome has been described among recipients of different yellow fever vaccines. This syndrome was previously reported as febrile multiple organ system failure, and is now called yellow fever vaccineassociated viscerotropic disease. In July 2001, the first seven case reports of this syndrome appeared in the scientific literature. These cases occurred during 1996-2001 and described patients with severe multiple organ system failure; 6 of the 7 patients died (31,(34)(35)(36). Subsequently, retrospective and prospective case finding has identified three additional suspected cases (37)(38)(39). These additional cases demonstrate that this serious adverse reaction probably occurs as a clinical spectrum of disease severity, from moderate illness with focal organ dysfunction to severe disease with overt multiple organ system failure and death. These 10 cases demonstrate the viscerotropic potential of 17D vaccine virus among certain persons. A phase III nonplacebo controlled clinical trial was recently completed that compared safety and reactogenicity among 1,440 healthy volunteers randomized to receive either one of two 17D-204 vaccines, ARILVAX™ (manufactured by Evans Vaccines Speke, Liverpool, United Kingdom) or YF-VAX ® (Aventis Pasteur Inc., Swiftwater, Pennsylvania) (24). Adverse events were actively monitored for 30 days. Although no placebo group was included, which limits the interpretation of results, 3%-4% of vaccine recipients in both arms of the study experienced mild elevation of hepatic transaminases within the first 10 days after vaccination; all enzyme elevations returned to normal by day 30 postvaccination. Finally, mounting evidence exists that persons are most at risk for yellow fever vaccine-associated viscerotropic disease after their first vaccination. All cases reported thus far have occurred among such persons. In addition, clinical studies have demonstrated that mild adverse events after yellow fever vaccination are less common among previously immunized persons (24) and that vaccine viremia is not detectable among those receiving booster doses (30). Vaccine-Associated Viscerotropic Disease Among U.S. Citizens. During 1996-1998, four U.S. citizens (aged 63, 67, 76, and 79 years) became ill 2-5 days after receiving YF-VAX (17D-204 vaccine) (31). All four persons required intensive care after they experienced fever, hypotension, respiratory failure, elevated hepatocellular enzymes, hyperbilirubinemia, lymphocytopenia, and thrombocytopenia; three of the four also experienced renal failure, which required hemodialysis. Three of the four died. Blood was available for viral isolation from two of the four patients. Vaccine-type yellow fever virus was isolated from the blood of both of these patients 7-8 days after vaccination. Cerebrospinal fluid was also available from one of the two patients. Virus was isolated from this specimen, which was obtained when the patient experienced encephalitis (31). Minimal periportal inflammation without hepatocellular necrosis was observed in the liver specimen from the only U.S. patient who underwent a liver biopsy 28 days after illness onset; IHC revealed limited numbers of Kupffer cells containing yellow fever virus antigen. In the United States, safety-monitoring data were available for an estimated 1.55 million vaccine doses of YF-VAX (17D-204) vaccine distributed to civilian vaccination centers in the United States during 1990-1998 (40). During this period, four cases of yellow fever vaccine-associated viscerotropic disease were reported to VAERS, providing an estimated reported incidence of 2.5/1,000,000 (or 1/400,000) doses distributed. YF-VAX was also administered to approximately 9 million military personnel during the same period of observation (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998). This estimated incidence based on VAERS might be low because of limitations (e.g., underreporting of cases and imprecise information regarding the number of doses actually administered, including to nonimmune primary vaccinees who appear to be the major, if not only, risk group) (41). Vaccine-Associated Viscerotropic Disease Among Persons Outside the United States. In addition to the cases reported in the United States, in 2001, one Australian citizen (aged 56 years) became ill after receiving a 17D-204 yellow fever vaccination (34), and in 1999 and 2000, two Brazilian citizens (aged 5 and 22 years) became ill 3-4 days after receiving 17DD vaccine (35). Strain 17DD is different from strain 17D-204, which is used in both the United States and Australia, but the two viruses are derived from a common ancestor (17D virus) and are closely related (13). In the Brazilian and Australian cases, histopathologic changes in the liver included midzonal necrosis, microvesicular fatty change, and Councilman bodies, which are characteristic of wild-type yellow fever. Yellow fever antigen was identified by IHC in areas of midzonal necrosis in liver specimens from the two 17DD recipients, and flavivirus-like particles consistent with yellow fever virus were identified by electron microscopy in areas of midzonal necrosis in a liver specimen from the 17D-204 recipient. Yellow fever vaccine virus (17DD or 17D-204) was isolated from blood and autopsy material (i.e., brain, liver, kidney, spleen, lung, skeletal muscle, or skin) from each of these three persons, all of whom died 8-11 days after vaccination. In Brazil, an estimated 23 million vaccine doses were distributed in vaccination campaigns during the 15-month period in which the two reported cases occurred 6 months apart (42). Thus, a crude estimate of occurrence for this serious adverse event in Brazil might be 0.09/1,000,000 doses distributed. However, certain limitations to this estimate exist. First, the number of doses administered during a vaccination campaign substantially overestimates the true number of persons vaccinated since certain persons receive multiple vaccinations. Second, experience in Brazil indicates that approximately half of vaccinees are already immune to yellow fever and thus, theoretically, would not be at risk for this adverse event. And finally, the numerator is only derived from published case studies, not from formal surveillance systems and therefore probably underestimates the true number of cases of this adverse event. Because mutational changes associated with a reversion to virulence were not detected in the genomes of 17DD vaccine viruses recovered from patients and because these viruses had a vaccine-type phenotype among experimental animals, Brazilian authorities assume that the occurrences are caused by undefined host factors (43). Additional Case Reports. Three additional cases of severe adverse events after yellow fever vaccination have been reported in the scientific literature (37)(38)(39). These cases occurred among persons aged 45, 50, and 71 years, and the patients required hospitalization for illness, which was characterized by fever and elevated liver enzymes (37-39) and renal abnormalities (37,38). All three persons recovered from their illness. Yellow fever virus was isolated from the blood of the one person tested (38). Vaccine strain viremia after primary vaccination with yellow fever vaccine frequently occurs among healthy persons, but is usually waning or absent after the first week (2,30). Two persons were tested for antibodies to yellow fever virus; one of these patients had unusually high levels of yellow fever antibodies (39), and the antibody levels of the other person were described as having increased during the 3 days after administration (38). Summary of Case Reports. In the cases from Brazil and Australia, a causal association between yellow fever vaccineassociated viscerotropic disease and vaccination with 17DD or 17D-204 yellow fever vaccine is supported by histopathologic studies, isolation of genetically stable vaccine-type virus from multiple tissues other than blood, and the temporal relationship between vaccination and illness onset. Thus, both the 17DD and 17D-204 yellow fever vaccines must be considered as a possible, but rare, cause of yellow fever vaccineassociated viscerotropic disease that is similar to fulminant yellow fever caused by wild-type yellow fever virus. Accurately measuring the incidence of this rare vaccine-associated viscerotropic disease is impossible because adequate prospective data are unavailable; however, crude estimates of the reported frequency range from 0.09 (in Brazil) to 2.5 (in the United States) per 1,000,000 doses distributed. The real incidence might be higher (41). Because of a lack of tissue specimens from the majority of the U.S. cases of yellow fever vaccine-associated viscerotropic disease, no definitive laboratory support for a causal relationship exists for these cases. However, the recent receipt of yellow fever vaccination and the similarity of the clinical symptoms among all four U.S. cases indicate that yellow fever vaccine is a probable cause of the disease in these cases. Whether and in what way underlying host factors (genetic or acquired) or preexisting clinical conditions might have contributed to the course or outcome of yellow fever vaccine-associated viscerotropic disease is unknown. Because of recent reports of yellow fever deaths among unvaccinated travelers to areas endemic for yellow fever and of these reports of vaccine-associated viscerotropic disease, physicians should be careful to administer yellow fever vaccine only to persons truly at risk for exposure to yellow fever. Additional surveillance to better monitor and quantify yellow fever vaccine-specific adverse outcomes should also be established. Studies are being conducted to clarify the cause and risk factors for these rare adverse events associated with the 17D yellow fever vaccines. # Precautions and Contraindications Age Infants aged <6 months are likely to be more susceptible to the serious adverse reaction of yellow fever vaccine-associated neurotropic disease (also known as postvaccinal encephalitis) than older children, and vaccination of infants aged <6 months is contraindicated. The risk for this complication appears agerelated. The manufacturer and FDA recommend that vaccination of infants aged <9 months be avoided because of the risk for encephalitis, and that travel of such persons to countries in yellow fever-endemic zones or to countries experiencing an epidemic should be postponed or avoided, whenever possible. In unusual circumstances, physicians considering vaccinating infants aged <9 months who are traveling to endemic areas should contact the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC for advice. A recent analysis of adverse events passively reported to VAERS during 1990-1998 indicates that persons aged >65 years might be at increased risk for systemic adverse events after vaccination, compared with younger persons (40). Travelers aged >65 years should discuss with their physicians the risks and benefits of vaccination in the context of their destination-specific risk for exposure to yellow fever virus. Nevertheless, yellow fever remains a key cause of illness and death in South America and sub-Saharan Africa where potential yellow fever transmission zones have expanded to urban areas with substantial populations of susceptible humans and the Ae. aegypti vector mosquito. In addition, unvaccinated U.S. travelers to South America have contracted fatal yellow fever (3,(14)(15)(16)(17)(18). Consequently, despite these rare adverse events, yellow fever vaccination of travelers to high-risk areas should be encouraged as a key prevention strategy. # Pregnancy The safety of yellow fever vaccination during pregnancy has not been established, and the vaccine should be administered only if travel to an endemic area is unavoidable and if an increased risk for exposure exists. On the basis of clinical evaluation of a total of 81 infants in two different studies who were born to mothers vaccinated during pregnancy, infection of the fetus with YF17D apparently occurs at a low rate (i.e., 1 of 81) and has not been associated with congenital anomalies (2,44,45). In a recent case-control study of women vaccinated with YF 17D during early pregnancy, the relative risk for spontaneous abortion was 2.3, but the difference was not statistically significant (95% confidence interval = 0.65-8.03) (46). Information from limited clinical trials in Africa and Europe indicates that the risk from vaccination for pregnant women who cannot avoid mosquito exposure in yellow fever-endemic areas is outweighed by the risk for yellow fever infection (44). If international travel requirements are the only reason to vaccinate a pregnant woman, rather than an increased risk for infection, efforts should be made to obtain a waiver letter from the traveler's physician (Appendix). Pregnant women who must travel to areas where the risk for yellow fever infection is high should be vaccinated and, despite the apparent safety of this vaccine, infants born to these women should be monitored closely for evidence of congenital infection and other possible adverse effects resulting from yellow fever vaccination. If vaccination of a pregnant woman is deemed necessary, serologic testing to document an immune response to the vaccine can be considered, because the seroconversion rate for pregnant women in a developing nation has been reported to be substantially lower than that observed for other healthy adults and children (45). To discuss the need for serologic testing, the appropriate state health department or the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC should be contacted. # Nursing Mothers Whether this vaccine is excreted in human milk is unknown. No reports exist of adverse events or transmission of the 17D vaccine viruses from nursing mother to infant. However, as a precautionary measure, vaccination of nursing mothers should be avoided because of the theoretical risk for the transmission of 17D virus to the breast-fed infant. When travel of nursing mothers to high-risk yellow fever-endemic areas cannot be avoided or postponed, such persons can be vaccinated. # Altered Immune Status Infection with yellow fever vaccine virus poses a theoretical risk for encephalitis to 1) patients with acquired immunodeficiency syndrome (AIDS); 2) patients who are infected with HIV and have other manifestations of HIV infection (32); 3) patients with leukemia, lymphoma, generalized malignancy; or 4) those whose immunologic responses are suppressed by corticosteroids, alkylating drugs, antimetabolites, or radiation. Such patients should not be vaccinated. If travel to a yellow fever-infected zone is necessary, patients should be advised of the risks posed by such travel, instructed in methods for avoiding vector mosquitoes, and supplied with vaccination waiver letters by their physicians (Appendix). Low-dose (i.e., 20-mg prednisone or equivalent/day), short-term (i.e., <2 weeks) systemic corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be sufficiently immunosuppressive to constitute an increased hazard to recipients of yellow fever vaccine. Persons who are HIV-infected but do not have AIDS or other symptomatic manifestations of HIV infection, who have established laboratory verification of adequate immune system function, and who cannot avoid potential exposure to yellow fever virus should be offered the choice of vaccination. Despite the theoretical risk for neuroinvasion and encephalitis, clinical or epidemiologic studies to evaluate the risk for yellow fever vaccination among such recipients have not been reported. If international travel requirements are the only reason to vaccinate an asymptomatic HIV-infected person, rather than an increased risk for infection, efforts should be made to obtain a waiver letter from the traveler's physician (Appendix). Asymptomatic HIV-infected persons who must travel to areas where the risk for yellow fever infection is high should be offered the choice of vaccination and monitored closely for possible adverse effects. Data regarding seroconversion rates after yellow fever vaccination among asymptomatic HIV-infected persons are limited, but they do indicate that the seroconversion rates among such persons is reduced. One month after receiving a 17D yellow fever vaccination, only 70% of 33 HIV-infected adults with CD4 + T lymphocyte cell counts >200/mm 3 developed neutralizing antibody (47). Yellow fever vaccine typically induces seroconversion among >90% of healthy adults. Among HIV-infected infants simultaneously vaccinated with a 17D yellow fever and measles vaccines, only 3 of 18 developed neutralizing antibody, compared with 74% of 57 HIV-seronegative infants who simultaneously received the two vaccines (48). Because vaccination of asymptomatic HIV-infected persons might be less effective than that for persons not infected with HIV, measurement of their neutralizing antibody response to vaccination should be considered before travel. # Hypersensitivity Yellow fever vaccine is produced in chick embryos and should not be administered to persons hypersensitive to eggs; typically, persons who are able to eat eggs or egg products can receive the vaccine. If international travel regulations are the only reason to vaccinate a patient hypersensitive to eggs, efforts should be made to obtain a waiver (Appendix). If vaccination of a person with a questionable history of egg hypersensitivity is considered essential because of a high risk for exposure, an intradermal test dose can be administered under close medical supervision. Specific directions for skin testing are located in the package insert (49). # Simultaneous Administration of Other Vaccines Determination of whether to administer yellow fever vaccine and other immunobiologics simultaneously should be made on the basis of convenience to the traveler in completing the desired vaccinations before travel and on information regarding possible interference. The following discussion should help guide these decisions. Limited clinical studies have demonstrated that the serologic response to yellow fever vaccine is not inhibited by the administration of certain other vaccines concurrently or at intervals of a 1 day-1 month (50). Measles, smallpox, and yellow fever vaccines have been administered in combination (51,52); Bacillus Calmette-Guérin (BCG) and yellow fever vaccines have been administered simultaneously without interference. Yellow fever vaccine can be administered concurrently with hepatitis A or hepatitis B vaccines (53,54). In addition, yellow fever vaccine has been administered concurrently with the typhoid fever vaccine, Typhim Vi ® (manufactured by Aventis Pasteur, Inc., Swiftwater, Pennsylvania) and the meningococcal vaccine, Menomune ® (Aventis Pasteur, Inc., Swiftwater, Pennsylvania), with no reported evidence of an effect on the immune response to any of the three vaccines individually and no unusual safety problems (55). No data exist regarding possible interference between yellow fever and rabies or Japanese encephalitis vaccines. In a prospective study of persons administered yellow fever vaccine and an intramuscular dose of commercially available immune globulin, no alteration of the immunologic response to yellow fever vaccine was detected when compared with controls (56). Although chloroquine inhibits replication of yellow fever virus in vitro, it does not adversely affect antibody responses to yellow fever vaccine among humans receiving antimalaria prophylaxis (57). # Surveillance and Research Priorities Yellow fever vaccine has been considered to be one of the safest vaccines. The frequency of the adverse events reported in these recommendations is low enough that, given the relatively limited numbers of yellow fever vaccine doses administered in the United States, sporadic cases of severe adverse events that occurred earlier might not have been appreciated or investigated. Unfortunately, yellow fever vaccine has been used most widely during outbreaks and in areas where surveillance for vaccine-associated adverse events has been difficult and might have been masked by wild-type yellow fever infections. The YF17D-associated adverse event reports, combined with the growing momentum for mass vaccination in the wake of increased yellow fever activity, underscore the importance of further investigations to define and quantify YF17D vaccine risks and to characterize their pathogenesis. Accordingly, the following activities are recommended: - Enhanced surveillance for systemic adverse events after yellow fever vaccination should be introduced at U.S.certified yellow fever vaccination centers and in settings where yellow fever vaccine is administered in other countries. The majority of yellow fever vaccine administered in the United States is done through the vaccination of U.S. military personnel and their dependents. The vaccine safety profile among U.S. military personnel might not be representative of the U.S. population at large; however, this population might still serve as an excellent source of additional information in quantifying the risk for adverse events through both retrospective and prospective studies. Accordingly, the U.S. military should be encouraged to share information regarding its yellow fever vaccination program, including annual number of doses administered and substantial adverse events that might be related to yellow fever vaccine. - Although neurovirulence assays among primates were required to qualify yellow fever vaccine in different production stages, certain patients described in a recent report exhibited viscerotropic (e.g., hepatic, renal, or cardiac) abnormalities that might not have been detected earlier. # Appendix Waiver Letters from Physicians A physician's letter stating the contraindication to vaccination has been acceptable to certain governments outside the United States. Ideally, the letter should be written on letterhead stationary and bear the stamp used by health department and official vaccination centers to validate the International Certificate of Vaccination. When planning to use a waiver letter, the traveler should also obtain specific and authoritative advice from the embassy or consulate of the country or countries she or he plans to visit. Waivers of requirements obtained from embassies or consulates should be documented by appropriate letters and retained for presentation with the International Health Certificate. # Recommendations and Reports # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.2 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # The objectives are relevant to the goal of this report. A	Reproduced with permission. Urban yellow fever is transmitted from person to person through the bite of an infected Aedes aegypti mosquito. In recent years, reinfestations of Ae. aegypti have occurred in countries throughout the world, contributing to the threat of epidemic yellow fever reemergence in new locations and highlighting the importance of vaccination programs for prevention.# Introduction Yellow fever occurs only in Africa and South America. The World Health Organization (WHO) estimates that a total of 200,000 cases of yellow fever occur each year (1). The clinical spectrum of yellow fever ranges from subclinical infection to overwhelming pansystemic disease (2). Yellow fever has an abrupt onset after an incubation period of 3-6 days, and usually includes fever, prostration, headache, photophobia, lumbosacral pain, extremity pain (including the knee joints), epigastric pain, anorexia, and vomiting. The illness might progress to liver and renal failure, and hemorrhagic symptoms and signs caused by thrombocytopenia and abnormal clotting and coagulation can occur. The fatality rate of severe yellow fever is approximately 20%. Definitive diagnosis is made by viral culture of blood or tissue specimens or by identification of yellow fever virus antigen or nucleic acid in tissues (including liver) using immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA) antigen capture, or polymerase chain reaction tests (3). Although antibodies are not always present during the first week of illness, detection of yellow fever-specific immunoglobulin M (IgM) antibody by capture ELISA with confirmation of >4-fold rise in neutralizing antibody titers between acute-and convalescent-phase serum samples is also diagnostic. Treatment for yellow fever consists of providing general supportive care and varies, depending on which organ systems are involved. No effective specific antiviral therapy for yellow fever has been identified. Two forms of yellow fever, urban and jungle, are epidemiologically distinguishable. Clinically and etiologically they are identical (4,5). Urban yellow fever is an epidemic viral disease of humans transmitted from infected to susceptible persons by Aedes aegypti mosquitoes, which breed in domestic and peridomestic containers (e.g., water jars, barrels, drums, tires, or tin cans) and thus in close association with humans. In areas where Ae. aegypti has been eliminated or suppressed, urban yellow fever has disappeared. In the mid-1900s, eradication of Ae. aegypti in multiple countries, notably Panama, Brazil, Ecuador, Peru, Bolivia, Paraguay, Uruguay, and Argentina, led to the disappearance of urban yellow fever. The last documented Ae. aegypti-borne yellow fever epidemic in the western hemisphere occurred in Trinidad in 1954. However, in recent years, reinfestation of countries that had previously eradicated Ae. aegypti has occurred (5). Ae. aegypti mosquitoes are strongly suspected as having played a role in transmission in outbreaks occurring in Bolivia in 1989Bolivia in , 1990Bolivia in , and 1998. Other countries remain infested, including areas of Venezuela and the Guianas, which include enzootic areas for jungle yellow fever. In Africa, yellow fever epidemics caused by transmission by Ae. aegypti continue to occur and involve human populations both in towns and in rural villages (8,9). Jungle yellow fever is primarily an enzootic viral disease transmitted among nonhuman primate hosts by different mosquito vectors, but endemic and epidemic jungle yellow fever can occur. It is observed only in forest-savannah zones of tropical Africa and in forested areas of South America but, in the past, occasionally extended into parts of Central America; it is enzootic in the jungles on the island of Trinidad. In South America, approximately 500 human cases are reported annually, primarily among men with occupational exposures in forested areas; however, the disease is believed to be substantially underreported (10). In Africa, epidemics involving treehole-breeding mosquito vectors affect thousands of persons at intermittent intervals, but only a limited number of cases are officially reported. Sometimes the disease is not detected in an area for years but then will reappear. Delineation of affected areas depends on surveillance for animal reservoirs and vectors, accurate diagnosis, and prompt reporting of all human cases. The jungle yellow fever cycle might be active but unrecognized in forested areas of countries within the yellow fever-endemic zone (Figure ). Urban yellow fever can be prevented by vaccinating human populations at risk for infection or by suppressing populations of Ae. aegypti mosquitoes so that they no longer perpetuate infection. Jungle yellow fever can most effectively be prevented by vaccination of human populations at risk for exposure. # Yellow Fever Vaccine Yellow fever vaccine is a live, attenuated virus preparation made from the 17D yellow fever virus strain (11). Historically, the 17D vaccine has been considered to be one of the safest and most effective live virus vaccines ever developed (2,12). The virus is grown in chick embryos inoculated with a seed virus of a fixed passage level. The 17D yellow fever vaccine virus family is the foundation for both the 17D-204 lineage and 17DD lineage. Vaccine type 17D-204 is used in both the United States and Australia, whereas vaccine type 17DD is used in Brazil. The two vaccine types share 99.9% sequence homology (13). The 17D-204 strain YF-VAX ® (manufactured by Aventis, Swiftwater, Pennsylvania) vaccine is a freeze-dried supernatant of centrifuged embryo homogenate, packaged in 1-dose and 5-dose vials for domestic use. The vaccine should be stored at temperatures of 2 º C-8 º C (35 º F-46 º F) until it is reconstituted by the addition of diluent (sterile, physiologic saline) supplied by the manufacturer. Multidose vials of reconstituted vaccine should be held at 2 º C-8 º C (35 º F-46 º F); unused vaccine should be discarded within 1 hour after reconstitution. # Vaccine Use Persons Living or Traveling in Endemic Areas Persons aged >9 months who are traveling to or living in areas of South America and Africa where yellow fever infection is officially reported should be vaccinated. These areas are listed in the "Bi-Weekly Summary of Countries with Areas Infected with Quarantinable Diseases," available at state and local health departments. Information concerning known or probable infected areas is also available from WHO (http:// www.who.int), the Pan American Health Organization, the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC, or at http:// www.cdc.gov/travel. Vaccination is also recommended for travel to countries that do not officially report the disease but that lie in the yellow fever-endemic zone (see shaded areas in the figure). In recent years, fatal cases of yellow fever have occurred among unvaccinated tourists from the United States and Europe who visited rural areas within the yellow fever-endemic zone (3,(14)(15)(16)(17)(18). Because of incomplete surveillance, the actual areas of yellow fever virus activity might exceed the infected zones officially reported by individual ministries of health. The manufacturer and the Food and Drug Administration (FDA) recommend that vaccination of infants aged <9 months be avoided because of the risk for encephalitis, and that travel of such persons to countries in yellow fever-endemic zones or to countries experiencing an epidemic be postponed or avoided, whenever possible. Using yellow fever vaccine among infants aged <9 months has not been formally evaluated. Since 1945, among the reported cases of vaccine-associated encephalitis, only two cases have been reported of children aged 6 and 7 months developing encephalitis after yellow fever vaccination. In comparison, 14 such cases have occurred among children aged <4 months and seven cases among persons aged >3 years (including two fatal cases in persons aged 3 and 53 years). Because recent experience in use of the vaccine among children aged <6 months is limited and because age-specific vaccine administration records are not available, calculation of age-specific rates of yellow fever vaccine-associated encephalitis is impossible. In unusual circumstances, physicians considering vaccinating infants aged <9 months or pregnant women should contact the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC for advice (see Precautions and Contraindications). Despite the lack of such information, ACIP and WHO recognize that situations occur in which vaccination of an infant aged <9 months might be considered. One such situation is the unavoidable exposure of children aged 6-8 months to an environment where an increased likelihood of becoming infected with the yellow fever virus exists (e.g., a setting of endemic or epidemic yellow fever) (1). Because of the risk for encephalitis, in no instance should infants aged <6 months receive yellow fever vaccine. Because the seroconversion rate after vaccination of pregnant women might be markedly reduced compared with that of other healthy women, serologic tests to determine if a specific yellow fever immune response exists should be considered. To discuss the need for serologic testing, the appropriate state health department or the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC should be contacted (see Precautions and Contraindications). # Laboratory Personnel Laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of the 17D vaccine strain by direct or indirect contact or by aerosols should also be vaccinated. # Requirements for Vaccination Before International Travel For purposes of international travel, yellow fever vaccines produced by different manufacturers worldwide must be approved by WHO and administered at an approved yellow fever vaccination center. In addition to CDC's Division of Global Migration and Quarantine, state and territorial health departments have the authority to designate nonfederal vaccination centers; these centers can be identified by contacting state or local health departments. Vaccinees should receive an International Certificate of Vaccination that has been completed, signed, and validated with the center's stamp when the vaccine is administered. Vaccination for international travel might be required under circumstances other than those specified in this report. Certain countries in Africa require evidence of vaccination from all entering travelers. Other countries might waive the requirements for travelers coming from areas where no evidence exists of substantial risk for yellow fever and who are staying <2 weeks. Because requirements might change, all travelers should seek up-to-date information from health departments, CDC, and WHO. Travel agencies, international airlines, or shipping lines also should have up-to-date information. Certain countries require persons, even if only in transit, to have valid International Certificates of Vaccination if they have been in countries either known or thought to have yellow fever virus. Such requirements might be enforced strictly, including for persons traveling from Africa or South America to Asia. Travelers should consult CDC's travel information website at http://www.cdc.gov/travel (19) to determine requirements and regulations for vaccination. # Primary Vaccination For persons of all ages for whom vaccination is indicated, a single subcutaneous injection of 0.5 mL of reconstituted vaccine is used. # Booster Doses The International Health Regulations require revaccination at intervals of 10 years. Revaccination can boost antibody titer; however, evidence from multiple studies (20-23) demonstrates that yellow fever vaccine immunity persists for 30-35 years and probably for life. # Safety General Events Reactions to 17D yellow fever vaccine are typically mild. After vaccination, vaccinees have reported mild headaches, myalgia, low-grade fevers, or other minor symptoms for 5-10 days. In clinical trials, where symptoms are actively elicited, incidence of mild adverse events has been <25% (24,25). Approximately 1% of vaccinees curtail regular activities. Immediate hypersensitivity reactions, characterized by rash, urticaria, or asthma, are uncommon (i.e., an estimated incidence of 1/130,000-250,000) and occur principally among persons with histories of allergies to egg or other substances (26). Gelatin is used as a stabilizer in different vaccines, including yellow fever vaccine. Gelatin has been implicated as a cause of allergic reaction related to other vaccines and, therefore, might also do the same regarding yellow fever vaccine (27)(28)(29). Vaccine strain viremia after primary vaccination with yellow fever vaccine frequently occurs among healthy persons, but is usually waning or absent after the first week (2,30). # Yellow Fever Vaccine-Associated Neurotropic Disease Historically, yellow fever vaccine-associated neurotropic disease (formerly known as postvaccinal encephalitis) among children has been the most common serious adverse event associated with yellow fever vaccines. Worldwide, only 23 cases of encephalitis temporally associated with or confirmed to be caused by 17D vaccine have been reported in the scientific literature since the introduction of the 17D seed lot system in 1945 (2,(31)(32)(33); of these, 16 have occurred among children aged <9 months. The other seven cases occurred among persons aged 3-76 years. Only three of these cases of encephalitis were associated with vaccinations in the United States; one occurred in 1959 (in a person aged 10 weeks); the second in 1965 (in a person aged 3 years); and one in 1998 (in a person aged 76 years). One of the three cases was fatal, and 17D virus was isolated from the brain of this patient (33). Since 1965, only one case of yellow fever vaccine-associated encephalitis in the United States has been reported in the scientific literature. The case occurred in a male aged 76 years who suffered both yellow fever vaccine-associated neurotropic disease and yellow fever vaccine-associated viscerotropic disease (31). The most recent case of possible yellow fever vaccine-associated neurotropic disease was reported in 2002 from Thailand and involved a man aged 53 years who had unrecognized human immunodeficiency virus (HIV) infection (32). Recently, four reports have been made to the Vaccine Adverse Event Reporting System (VAERS) of encephalitis among adult recipients of yellow fever vaccine (persons aged 16, 36, 41, and 71 years) with onset of illness 4-23 days after vaccination. The occurrence of vaccine-associated neurotropic disease does not appear to be confined to infants but does appear to be limited. The risk for vaccine-associated neurotropic disease has been estimated as <1/8,000,000 persons (2). # Yellow Fever Vaccine-Associated Viscerotropic Disease Recently, a new serious adverse reaction syndrome has been described among recipients of different yellow fever vaccines. This syndrome was previously reported as febrile multiple organ system failure, and is now called yellow fever vaccineassociated viscerotropic disease. In July 2001, the first seven case reports of this syndrome appeared in the scientific literature. These cases occurred during 1996-2001 and described patients with severe multiple organ system failure; 6 of the 7 patients died (31,(34)(35)(36). Subsequently, retrospective and prospective case finding has identified three additional suspected cases (37)(38)(39). These additional cases demonstrate that this serious adverse reaction probably occurs as a clinical spectrum of disease severity, from moderate illness with focal organ dysfunction to severe disease with overt multiple organ system failure and death. These 10 cases demonstrate the viscerotropic potential of 17D vaccine virus among certain persons. A phase III nonplacebo controlled clinical trial was recently completed that compared safety and reactogenicity among 1,440 healthy volunteers randomized to receive either one of two 17D-204 vaccines, ARILVAX™ (manufactured by Evans Vaccines Speke, Liverpool, United Kingdom) or YF-VAX ® (Aventis Pasteur Inc., Swiftwater, Pennsylvania) (24). Adverse events were actively monitored for 30 days. Although no placebo group was included, which limits the interpretation of results, 3%-4% of vaccine recipients in both arms of the study experienced mild elevation of hepatic transaminases within the first 10 days after vaccination; all enzyme elevations returned to normal by day 30 postvaccination. Finally, mounting evidence exists that persons are most at risk for yellow fever vaccine-associated viscerotropic disease after their first vaccination. All cases reported thus far have occurred among such persons. In addition, clinical studies have demonstrated that mild adverse events after yellow fever vaccination are less common among previously immunized persons (24) and that vaccine viremia is not detectable among those receiving booster doses (30). Vaccine-Associated Viscerotropic Disease Among U.S. Citizens. During 1996-1998, four U.S. citizens (aged 63, 67, 76, and 79 years) became ill 2-5 days after receiving YF-VAX (17D-204 vaccine) (31). All four persons required intensive care after they experienced fever, hypotension, respiratory failure, elevated hepatocellular enzymes, hyperbilirubinemia, lymphocytopenia, and thrombocytopenia; three of the four also experienced renal failure, which required hemodialysis. Three of the four died. Blood was available for viral isolation from two of the four patients. Vaccine-type yellow fever virus was isolated from the blood of both of these patients 7-8 days after vaccination. Cerebrospinal fluid was also available from one of the two patients. Virus was isolated from this specimen, which was obtained when the patient experienced encephalitis (31). Minimal periportal inflammation without hepatocellular necrosis was observed in the liver specimen from the only U.S. patient who underwent a liver biopsy 28 days after illness onset; IHC revealed limited numbers of Kupffer cells containing yellow fever virus antigen. In the United States, safety-monitoring data were available for an estimated 1.55 million vaccine doses of YF-VAX (17D-204) vaccine distributed to civilian vaccination centers in the United States during 1990-1998 (40). During this period, four cases of yellow fever vaccine-associated viscerotropic disease were reported to VAERS, providing an estimated reported incidence of 2.5/1,000,000 (or 1/400,000) doses distributed. YF-VAX was also administered to approximately 9 million military personnel during the same period of observation (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998). This estimated incidence based on VAERS might be low because of limitations (e.g., underreporting of cases and imprecise information regarding the number of doses actually administered, including to nonimmune primary vaccinees who appear to be the major, if not only, risk group) (41). Vaccine-Associated Viscerotropic Disease Among Persons Outside the United States. In addition to the cases reported in the United States, in 2001, one Australian citizen (aged 56 years) became ill after receiving a 17D-204 yellow fever vaccination (34), and in 1999 and 2000, two Brazilian citizens (aged 5 and 22 years) became ill 3-4 days after receiving 17DD vaccine (35). Strain 17DD is different from strain 17D-204, which is used in both the United States and Australia, but the two viruses are derived from a common ancestor (17D virus) and are closely related (13). In the Brazilian and Australian cases, histopathologic changes in the liver included midzonal necrosis, microvesicular fatty change, and Councilman bodies, which are characteristic of wild-type yellow fever. Yellow fever antigen was identified by IHC in areas of midzonal necrosis in liver specimens from the two 17DD recipients, and flavivirus-like particles consistent with yellow fever virus were identified by electron microscopy in areas of midzonal necrosis in a liver specimen from the 17D-204 recipient. Yellow fever vaccine virus (17DD or 17D-204) was isolated from blood and autopsy material (i.e., brain, liver, kidney, spleen, lung, skeletal muscle, or skin) from each of these three persons, all of whom died 8-11 days after vaccination. In Brazil, an estimated 23 million vaccine doses were distributed in vaccination campaigns during the 15-month period in which the two reported cases occurred 6 months apart (42). Thus, a crude estimate of occurrence for this serious adverse event in Brazil might be 0.09/1,000,000 doses distributed. However, certain limitations to this estimate exist. First, the number of doses administered during a vaccination campaign substantially overestimates the true number of persons vaccinated since certain persons receive multiple vaccinations. Second, experience in Brazil indicates that approximately half of vaccinees are already immune to yellow fever and thus, theoretically, would not be at risk for this adverse event. And finally, the numerator is only derived from published case studies, not from formal surveillance systems and therefore probably underestimates the true number of cases of this adverse event. Because mutational changes associated with a reversion to virulence were not detected in the genomes of 17DD vaccine viruses recovered from patients and because these viruses had a vaccine-type phenotype among experimental animals, Brazilian authorities assume that the occurrences are caused by undefined host factors (43). Additional Case Reports. Three additional cases of severe adverse events after yellow fever vaccination have been reported in the scientific literature (37)(38)(39). These cases occurred among persons aged 45, 50, and 71 years, and the patients required hospitalization for illness, which was characterized by fever and elevated liver enzymes (37-39) and renal abnormalities (37,38). All three persons recovered from their illness. Yellow fever virus was isolated from the blood of the one person tested (38). Vaccine strain viremia after primary vaccination with yellow fever vaccine frequently occurs among healthy persons, but is usually waning or absent after the first week (2,30). Two persons were tested for antibodies to yellow fever virus; one of these patients had unusually high levels of yellow fever antibodies (39), and the antibody levels of the other person were described as having increased during the 3 days after administration (38). Summary of Case Reports. In the cases from Brazil and Australia, a causal association between yellow fever vaccineassociated viscerotropic disease and vaccination with 17DD or 17D-204 yellow fever vaccine is supported by histopathologic studies, isolation of genetically stable vaccine-type virus from multiple tissues other than blood, and the temporal relationship between vaccination and illness onset. Thus, both the 17DD and 17D-204 yellow fever vaccines must be considered as a possible, but rare, cause of yellow fever vaccineassociated viscerotropic disease that is similar to fulminant yellow fever caused by wild-type yellow fever virus. Accurately measuring the incidence of this rare vaccine-associated viscerotropic disease is impossible because adequate prospective data are unavailable; however, crude estimates of the reported frequency range from 0.09 (in Brazil) to 2.5 (in the United States) per 1,000,000 doses distributed. The real incidence might be higher (41). Because of a lack of tissue specimens from the majority of the U.S. cases of yellow fever vaccine-associated viscerotropic disease, no definitive laboratory support for a causal relationship exists for these cases. However, the recent receipt of yellow fever vaccination and the similarity of the clinical symptoms among all four U.S. cases indicate that yellow fever vaccine is a probable cause of the disease in these cases. Whether and in what way underlying host factors (genetic or acquired) or preexisting clinical conditions might have contributed to the course or outcome of yellow fever vaccine-associated viscerotropic disease is unknown. Because of recent reports of yellow fever deaths among unvaccinated travelers to areas endemic for yellow fever and of these reports of vaccine-associated viscerotropic disease, physicians should be careful to administer yellow fever vaccine only to persons truly at risk for exposure to yellow fever. Additional surveillance to better monitor and quantify yellow fever vaccine-specific adverse outcomes should also be established. Studies are being conducted to clarify the cause and risk factors for these rare adverse events associated with the 17D yellow fever vaccines. # Precautions and Contraindications Age Infants aged <6 months are likely to be more susceptible to the serious adverse reaction of yellow fever vaccine-associated neurotropic disease (also known as postvaccinal encephalitis) than older children, and vaccination of infants aged <6 months is contraindicated. The risk for this complication appears agerelated. The manufacturer and FDA recommend that vaccination of infants aged <9 months be avoided because of the risk for encephalitis, and that travel of such persons to countries in yellow fever-endemic zones or to countries experiencing an epidemic should be postponed or avoided, whenever possible. In unusual circumstances, physicians considering vaccinating infants aged <9 months who are traveling to endemic areas should contact the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC for advice. A recent analysis of adverse events passively reported to VAERS during 1990-1998 indicates that persons aged >65 years might be at increased risk for systemic adverse events after vaccination, compared with younger persons (40). Travelers aged >65 years should discuss with their physicians the risks and benefits of vaccination in the context of their destination-specific risk for exposure to yellow fever virus. Nevertheless, yellow fever remains a key cause of illness and death in South America and sub-Saharan Africa where potential yellow fever transmission zones have expanded to urban areas with substantial populations of susceptible humans and the Ae. aegypti vector mosquito. In addition, unvaccinated U.S. travelers to South America have contracted fatal yellow fever (3,(14)(15)(16)(17)(18). Consequently, despite these rare adverse events, yellow fever vaccination of travelers to high-risk areas should be encouraged as a key prevention strategy. # Pregnancy The safety of yellow fever vaccination during pregnancy has not been established, and the vaccine should be administered only if travel to an endemic area is unavoidable and if an increased risk for exposure exists. On the basis of clinical evaluation of a total of 81 infants in two different studies who were born to mothers vaccinated during pregnancy, infection of the fetus with YF17D apparently occurs at a low rate (i.e., 1 of 81) and has not been associated with congenital anomalies (2,44,45). In a recent case-control study of women vaccinated with YF 17D during early pregnancy, the relative risk for spontaneous abortion was 2.3, but the difference was not statistically significant (95% confidence interval = 0.65-8.03) (46). Information from limited clinical trials in Africa and Europe indicates that the risk from vaccination for pregnant women who cannot avoid mosquito exposure in yellow fever-endemic areas is outweighed by the risk for yellow fever infection (44). If international travel requirements are the only reason to vaccinate a pregnant woman, rather than an increased risk for infection, efforts should be made to obtain a waiver letter from the traveler's physician (Appendix). Pregnant women who must travel to areas where the risk for yellow fever infection is high should be vaccinated and, despite the apparent safety of this vaccine, infants born to these women should be monitored closely for evidence of congenital infection and other possible adverse effects resulting from yellow fever vaccination. If vaccination of a pregnant woman is deemed necessary, serologic testing to document an immune response to the vaccine can be considered, because the seroconversion rate for pregnant women in a developing nation has been reported to be substantially lower than that observed for other healthy adults and children (45). To discuss the need for serologic testing, the appropriate state health department or the Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) or the Division of Global Migration and Quarantine (telephone: 404-498-1600) at CDC should be contacted. # Nursing Mothers Whether this vaccine is excreted in human milk is unknown. No reports exist of adverse events or transmission of the 17D vaccine viruses from nursing mother to infant. However, as a precautionary measure, vaccination of nursing mothers should be avoided because of the theoretical risk for the transmission of 17D virus to the breast-fed infant. When travel of nursing mothers to high-risk yellow fever-endemic areas cannot be avoided or postponed, such persons can be vaccinated. # Altered Immune Status Infection with yellow fever vaccine virus poses a theoretical risk for encephalitis to 1) patients with acquired immunodeficiency syndrome (AIDS); 2) patients who are infected with HIV and have other manifestations of HIV infection (32); 3) patients with leukemia, lymphoma, generalized malignancy; or 4) those whose immunologic responses are suppressed by corticosteroids, alkylating drugs, antimetabolites, or radiation. Such patients should not be vaccinated. If travel to a yellow fever-infected zone is necessary, patients should be advised of the risks posed by such travel, instructed in methods for avoiding vector mosquitoes, and supplied with vaccination waiver letters by their physicians (Appendix). Low-dose (i.e., 20-mg prednisone or equivalent/day), short-term (i.e., <2 weeks) systemic corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be sufficiently immunosuppressive to constitute an increased hazard to recipients of yellow fever vaccine. Persons who are HIV-infected but do not have AIDS or other symptomatic manifestations of HIV infection, who have established laboratory verification of adequate immune system function, and who cannot avoid potential exposure to yellow fever virus should be offered the choice of vaccination. Despite the theoretical risk for neuroinvasion and encephalitis, clinical or epidemiologic studies to evaluate the risk for yellow fever vaccination among such recipients have not been reported. If international travel requirements are the only reason to vaccinate an asymptomatic HIV-infected person, rather than an increased risk for infection, efforts should be made to obtain a waiver letter from the traveler's physician (Appendix). Asymptomatic HIV-infected persons who must travel to areas where the risk for yellow fever infection is high should be offered the choice of vaccination and monitored closely for possible adverse effects. Data regarding seroconversion rates after yellow fever vaccination among asymptomatic HIV-infected persons are limited, but they do indicate that the seroconversion rates among such persons is reduced. One month after receiving a 17D yellow fever vaccination, only 70% of 33 HIV-infected adults with CD4 + T lymphocyte cell counts >200/mm 3 developed neutralizing antibody (47). Yellow fever vaccine typically induces seroconversion among >90% of healthy adults. Among HIV-infected infants simultaneously vaccinated with a 17D yellow fever and measles vaccines, only 3 of 18 developed neutralizing antibody, compared with 74% of 57 HIV-seronegative infants who simultaneously received the two vaccines (48). Because vaccination of asymptomatic HIV-infected persons might be less effective than that for persons not infected with HIV, measurement of their neutralizing antibody response to vaccination should be considered before travel. # Hypersensitivity Yellow fever vaccine is produced in chick embryos and should not be administered to persons hypersensitive to eggs; typically, persons who are able to eat eggs or egg products can receive the vaccine. If international travel regulations are the only reason to vaccinate a patient hypersensitive to eggs, efforts should be made to obtain a waiver (Appendix). If vaccination of a person with a questionable history of egg hypersensitivity is considered essential because of a high risk for exposure, an intradermal test dose can be administered under close medical supervision. Specific directions for skin testing are located in the package insert (49). # Simultaneous Administration of Other Vaccines Determination of whether to administer yellow fever vaccine and other immunobiologics simultaneously should be made on the basis of convenience to the traveler in completing the desired vaccinations before travel and on information regarding possible interference. The following discussion should help guide these decisions. Limited clinical studies have demonstrated that the serologic response to yellow fever vaccine is not inhibited by the administration of certain other vaccines concurrently or at intervals of a 1 day-1 month (50). Measles, smallpox, and yellow fever vaccines have been administered in combination (51,52); Bacillus Calmette-Guérin (BCG) and yellow fever vaccines have been administered simultaneously without interference. Yellow fever vaccine can be administered concurrently with hepatitis A or hepatitis B vaccines (53,54). In addition, yellow fever vaccine has been administered concurrently with the typhoid fever vaccine, Typhim Vi ® (manufactured by Aventis Pasteur, Inc., Swiftwater, Pennsylvania) and the meningococcal vaccine, Menomune ® (Aventis Pasteur, Inc., Swiftwater, Pennsylvania), with no reported evidence of an effect on the immune response to any of the three vaccines individually and no unusual safety problems (55). No data exist regarding possible interference between yellow fever and rabies or Japanese encephalitis vaccines. In a prospective study of persons administered yellow fever vaccine and an intramuscular dose of commercially available immune globulin, no alteration of the immunologic response to yellow fever vaccine was detected when compared with controls (56). Although chloroquine inhibits replication of yellow fever virus in vitro, it does not adversely affect antibody responses to yellow fever vaccine among humans receiving antimalaria prophylaxis (57). # Surveillance and Research Priorities Yellow fever vaccine has been considered to be one of the safest vaccines. The frequency of the adverse events reported in these recommendations is low enough that, given the relatively limited numbers of yellow fever vaccine doses administered in the United States, sporadic cases of severe adverse events that occurred earlier might not have been appreciated or investigated. Unfortunately, yellow fever vaccine has been used most widely during outbreaks and in areas where surveillance for vaccine-associated adverse events has been difficult and might have been masked by wild-type yellow fever infections. The YF17D-associated adverse event reports, combined with the growing momentum for mass vaccination in the wake of increased yellow fever activity, underscore the importance of further investigations to define and quantify YF17D vaccine risks and to characterize their pathogenesis. Accordingly, the following activities are recommended: • Enhanced surveillance for systemic adverse events after yellow fever vaccination should be introduced at U.S.certified yellow fever vaccination centers and in settings where yellow fever vaccine is administered in other countries. The majority of yellow fever vaccine administered in the United States is done through the vaccination of U.S. military personnel and their dependents. The vaccine safety profile among U.S. military personnel might not be representative of the U.S. population at large; however, this population might still serve as an excellent source of additional information in quantifying the risk for adverse events through both retrospective and prospective studies. Accordingly, the U.S. military should be encouraged to share information regarding its yellow fever vaccination program, including annual number of doses administered and substantial adverse events that might be related to yellow fever vaccine. • Although neurovirulence assays among primates were required to qualify yellow fever vaccine in different production stages, certain patients described in a recent report exhibited viscerotropic (e.g., hepatic, renal, or cardiac) abnormalities that might not have been detected earlier. # Appendix Waiver Letters from Physicians A physician's letter stating the contraindication to vaccination has been acceptable to certain governments outside the United States. Ideally, the letter should be written on letterhead stationary and bear the stamp used by health department and official vaccination centers to validate the International Certificate of Vaccination. When planning to use a waiver letter, the traveler should also obtain specific and authoritative advice from the embassy or consulate of the country or countries she or he plans to visit. Waivers of requirements obtained from embassies or consulates should be documented by appropriate letters and retained for presentation with the International Health Certificate. # Recommendations and Reports # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.2 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # The objectives are relevant to the goal of this report. A	None	None
840a764198cb296a01b11b6509eb286f28d0462a	cdc	None	These recommendations of the Advisory Committee on Immunization Practices (ACIP) update the previous recommendations on human rabies prevention (CDC. Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices. MMWR 1999;48 ) and reflect the status of rabies and antirabies biologics in the United States. This statement 1) provides updated information on human and animal rabies epidemiology; 2) summarizes the evidence regarding the effectiveness/efficacy, immunogenicity, and safety of rabies biologics; 3) presents new information on the cost-effectiveness of rabies postexposure prophylaxis; 4) presents recommendations for rabies postexposure and pre-exposure prophylaxis; and 5) presents information regarding treatment considerations for human rabies patients. These recommendations involve no substantial changes to the recommended approach for rabies postexposure or pre-exposure prophylaxis. ACIP recommends that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive rabies immunization with human rabies immune globulin (HRIG) and vaccination with a cell culture rabies vaccine. For persons who have never been vaccinated against rabies, postexposure antirabies vaccination should always include administration of both passive antibody (HRIG) and vaccine (human diploid cell vaccine or purified chick embryo cell vaccine ). Persons who have ever previously received complete vaccination regimens (pre-exposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have previously had a documented rabies virus neutralizing antibody titer should receive only 2 doses of vaccine: one on day 0 (as soon as the exposure is recognized and administration of vaccine can be arranged) and the second on day 3. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virus neutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies. A regimen of 5 1-mL doses of HDCV or PCECV should be administered intramuscularly to previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon as possible after exposure (day 0). Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. Rabies pre-exposure vaccination should include three 1.0-mL injections of HDCV or PCECV administered intramuscularly (one injection per day on days 0, 7, and 21 or 28). Modifications were made to the language of the guidelines to clarify the recommendations and better specify the situations in which rabies post-and pre-exposure prophylaxis should be administered. No new rabies biologics are presented, and no changes were made to the vaccination schedules. However, rabies vaccine adsorbed (RVA, Bioport Corporation) is no longer available for rabies postexposure or pre-exposure prophylaxis, and intradermal pre-exposure prophylaxis is no longer recommended because it is not available in the United States. MMWR May 23, 10. Which of the following statements about rabies are true? (Indicate all that are true.) A. Human rabies is a fatal disease <50% of the time. B. During the previous 2 decades, the majority of indigenous human rabies cases in the United States have been associated with canine variants of the rabies virus. C. U.S. citizens traveling abroad can be at serious risk for exposure to avian rabies. D. Although human rabies cases in the United States are rare, exposure to rabid or potentially rabid animals remains a relatively common event. E. Postexposure prophylaxis is effective after the onset of clinical illness in the majority of cases. 11. Which best describes your professional activities? A. Physician. B. Nurse. C. Health educator. D. Veterinarian. E. Other. Vol. 57 / No. RR-3 Recommendations and Reports CE-3 Detach or photocopy.# Introduction Rabies is a zoonotic disease caused by RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus (1)(2)(3)(4). Virus is typically present in the saliva of clinically ill mammals and is transmitted through a bite. After entering the central nervous system of the next host, the virus causes an acute, progressive encephalomyelitis that is almost always fatal. The incubation period in humans is usually several weeks to months, but ranges from days to years. As a result of improved canine vaccination programs and stray animal control, a marked decrease in domestic animal rabies cases in the United States occurred after World War II. This decline led to a substantial decrease in indigenously acquired rabies among humans (5). In 1946, a total of 8,384 indigenous rabies cases were reported among dogs and 33 cases in humans. In 2006, a total of 79 cases of rabies were reported in domestic dogs, none of which was attributed to enzootic dog-to-dog transmission, and three cases were reported in humans (6). The infectious sources of the 79 cases in dogs were wildlife reservoirs or dogs that were translocated from localities where canine rabies virus variants still circulate. None of the 2006 human rabies cases was acquired from indigenous domestic animals (6). Thus, the likelihood of human exposure to a rabid domestic animal in the United States has decreased substantially. However, one of the three human rabies cases diagnosed in 2006 was associated with a dog bite that occurred in the Philippines, where canine rabies is enzootic. The risk for reintroduction from abroad remains (7). International travelers to areas where canine rabies remains enzootic are at risk for exposure to rabies from domestic and feral dogs. Unlike the situation in developing countries, wild animals are the most important potential source of infection for both humans and domestic animals in the United States. Most reported cases of rabies occur among carnivores, primarily raccoons, skunks, and foxes and various species of bats. Rabies among insectivorous bats occurs throughout the continental United States. Hawaii remains consistently rabiesfree. For the past several decades, the majority of naturally acquired, indigenous human rabies cases in the United States have resulted from variants of rabies viruses associated with insectivorous bats (5). The lone human case reported in the United States during 2005 and two of the three human rabies cases in 2006 were attributed to bat exposures (6,8). During 2004, two of the eight human rabies cases resulted from bat exposures. One of these rabies patients recovered and remains the only rabies patient to have survived without the administration of rabies vaccination (9). Rabies was not immediately recognized as the cause of death in the other 2004 patient, and organs and a vascular graft from this patient were transplanted into four persons, resulting in clinical rabies and death in all of the recipients (10). Approximately 16,000-39,000 persons come in contact with potentially rabid animals and receive rabies postexposure prophylaxis each year (11). To appropriately manage potential human exposures to rabies, the risk for infection must be accurately assessed. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Prophylaxis is occasionally complicated by adverse reactions, but these reactions are rarely severe (12)(13)(14)(15)(16). For these recommendations, data on the safety and efficacy of active and passive rabies vaccination were derived from both human and animal studies. Because controlled human trials cannot be performed, studies describing extensive field experience and immunogenicity studies from certain areas of the world were reviewed. These studies indicated that postexposure prophylaxis combining wound treatment, local infiltration of rabies immune globulin (RIG), and vaccination is uniformly effective when appropriately administered (17)(18)(19)(20)(21)(22). However, rabies has occasionally developed among humans when key elements of the rabies postexposure prophylaxis regimens were omitted or incorrectly administered. Timely and appropriate human pre-exposure and postexposure prophylaxis will prevent human rabies; however, the number of persons receiving prophylaxis can be reduced if other basic public health and veterinary programs are working to prevent and control rabies. Practical and accurate health education about rabies, domestic animal vaccination and responsible pet care, modern stray animal control, and prompt diagnosis can minimize unnecessary animal exposures, alleviate inherent natural risks after exposure, and prevent many circumstances that result in the need for rabies prophylaxis. # Methods The Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup first met in July 2005 to review previous ACIP recommendations on the prevention of human rabies (published in 1999) and to outline a plan for updating and revising the recommendations to provide clearer, more specific guidance for the administration of rabies preexposure and postexposure prophylaxis. The workgroup held monthly teleconferences to discuss their review of published and unpublished data on rabies and related biologic products. Data on the effectiveness, efficacy, immunogenicity, and safety of rabies biologics in both human and animal studies were reviewed using a systematic, evidence-based approach. Randomized trials or well-conducted cohort studies with untreated comparison groups would provide the best evidence of the direct effectiveness of rabies pre-exposure and postexposure prophylaxis to prevent rabies-associated death. However, because of the almost universal fatality among untreated persons infected with rabies virus, no such controlled studies exist. However, studies describing final health outcomes among persons exposed to the rabies virus do exist, including studies using formulations of rabies biologics, timing of vaccine doses, and routes of administration that are not recommended for use in the United States. These and other studies were identified by reviewing the PubMed database and relevant bibliographies and by consulting subjectmatter experts. The literature review did not identify any studies of the direct effectiveness of rabies pre-exposure vaccination in preventing human rabies cases. Such studies would be difficult to conduct because rabies pre-exposure vaccination is intended to simplify the postexposure prophylaxis that is required after a recognized rabies exposure. Rabies preexposure vaccination also might afford immunity against an unrecognized rabies exposure, an outcome that would be difficult to measure in controlled studies. However, rabies cases have occurred among those who received rabies pre-exposure prophylaxis and did not receive rabies postexposure prophylaxis (23), indicating that pre-exposure prophylaxis in humans is not universally effective without postexposure prophylaxis. Because of the paucity of formal studies on the effectiveness of rabies pre-exposure vaccination in humans, the literature was searched for studies that reported clinical outcomes among animals that received pre-exposure rabies prophylaxis with cell culture rabies vaccine and were subsequently challenged with rabies virus. Evaluation of the effectiveness of antirabies biologics in experimental animal models has been essential to developing successful rabies prevention approaches for exposed humans. Animal studies investigating the effectiveness of both pre-exposure and posteexposure rabies prophylaxis were reviewed and were used to make inferences about the direct effectiveness of licensed rabies biologics in preventing human rabies. Data regarding the immunogenicity of rabies biologics also were reviewed. Assessing protective immunity against rabies is complex. Virus neutralizing antibodies are believed to have a primary role in preventing rabies virus infection. However, antibody titers alone do not always directly correlate with absolute protection because of other important immunologic factors. Nonetheless, the ability of a vaccine to elicit rabies virus neutralizing antibodies in animals and humans and the demonstration of protection in animals is generally viewed as a reasonable surrogate of protection for inferential extension to humans (24). Although a definitive "protective" titer cannot be described for all hosts under all exposure scenarios, two working definitions of adequate rabies virus neutralizing antibody reference values have been developed to define an appropriate, intact adaptive host response to vaccination. The literature review included studies in humans that measured rabies virus neutralizing antibody in response to rabies postexposure prophylaxis consisting of human rabies immune globulin (HRIG) and 5 intramuscular (IM) doses of cell culture rabies vaccine and the recommended pre-exposure prophylaxis regimen of 3 IM doses of cell culture vaccine. The outcomes of interest for these studies were antibody titers of 0.5 IU/mL (used by the World Health Organization as an indicator of an adequate adaptive immune response) (25) or complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT) (used by ACIP as an indicator of an adequate adaptive immune response) (26). The literature also was searched for evidence regarding the safety of the licensed rabies biologics available for use in the United States in both pre-exposure and postexposure situations. ACIP's charter requires the committee to consider the costs and benefits of potential recommendations when they are deliberating recommendations for vaccine use in the United States. Few studies exist on the cost-effectiveness of rabies prophylaxis in various potential exposure scenarios. A challenge in conducting such studies is the lack of data on the probability of rabies transmission under different exposure scenarios, except when the involved animal tests positive for rabies. To provide information on the cost-effectiveness of rabies postexposure prophylaxis, a new analysis was conducted to estimate the cost-effectiveness of rabies postexposure prophylaxis in various potential exposure scenarios. A Delphi methodology was used to estimate the risk for transmission of rabies to a human in each of the scenarios, and this information was used in the cost-effectiveness calculations. The rabies workgroup reviewed the previous ACIP recommendations on the prevention of human rabies and deliberated on the available evidence. When definitive research evidence was lacking, the recommendations incorporated expert opinion of the workgroup members. and external review process to update and clarify wording in the document. # Rabies Biologics Three cell culture rabies vaccines are licensed in the United States: human diploid cell vaccine (HDCV, Imovax ® Rabies, sanofi pasteur), purified chick embryo cell vaccine (PCECV, RabAvert ® , Novartis Vaccines and Diagnostics), and rabies vaccine adsorbed (RVA, Bioport Corporation). Only HDCV and PCECV are available for use in the United States (Table 1). For each of the available vaccines, the potency of 1 dose is greater than or equal to the WHO-recommended standard of 2.5 international units (IU) per 1.0 mL of vaccine (27). A full 1.0-mL IM dose is used for both pre-exposure and postexposure prophylaxis regimens. Rabies vaccines induce an active immune response that includes the production of virus neutralizing antibodies. The active antibody response requires approximately 7-10 days to develop, and detectable rabies virus neutralizing antibodies generally persist for several years. A vaccination series is initiated and completed usually with one vaccine product. No clinical trials were identified that document a change in efficacy or the frequency of adverse reactions when the series is initiated with one vaccine product and completed with another. The passive administration of RIG is intended to provide an immediate supply of virus neutralizing antibodies to bridge the gap until the production of active immunity in response to vaccine administration. Use of RIG provides a rapid, passive immunity that persists for a short time (half-life of approximately 21 days) (28). Two antirabies immune globulin (IgG) formulations prepared from hyperimmunized human donors are licensed and available for use in the United States: HyperRab ™ S/D (Talecris Biotherapeutics) and Imogam ® Rabies-HT (sanofi pasteur). In all postexposure prophylaxis regimens, except for persons previously vaccinated, HRIG should be administered concurrently with the first dose of vaccine. # Vaccines Licensed for Use in the United States Human Diploid Cell Vaccine HDCV is prepared from the Pitman-Moore strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration, and inactivated with betapropiolactone (22). HDCV is formulated for IM administration in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0 mL just before administration. One dose of reconstituted vaccine contains <150 µg neomycin sulfate, <100 mg albumin, and 20 µg of phenol red indicator. It contains no preservative or stabilizer. # Purified Chick Embryo Cell Vaccine PCECV became available in the United States in 1997. The vaccine is prepared from the fixed rabies virus strain Flury LEP grown in primary cultures of chicken fibroblasts (29). The virus is inactivated with betapropiolactone and further processed by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0 mL just before administration. One dose of reconsti- † For postexposure prophylaxis, the vaccine is administered on days 0, 3, 7, 14 and 28 in patients who have not been previously vaccinated and on days 0 and 3 in patients who have been previously vaccinated. For pre-exposure prophylaxis, the vaccine is administered on days 0, 7 and 21 or 28. § As much of the product as is anatomically feasible should be infiltrated into and around the wound. Any remaining product should be administered intramuscularly in the deltoid or quadriceps (at a location other than that used for vaccine inoculation to minimize potential interference). tuted vaccine contains <12 mg polygeline, <0.3 mg human serum albumin, 1 mg potassium glutamate, and 0.3 mg sodium EDTA. No preservatives are added. # Rabies Immune Globulins Licensed for Use in the United States The two HRIG products, HyperRab ™ S/D and Imogam ® Rabies-HT, are IgG preparations concentrated by cold ethanol fractionation from plasma of hyperimmunized human donors. The HyperRab ™ S/D is formulated through the treatment of the immune globulin fraction with 0.3% tri-n-butyl phosphate (a solvent to inactivate potential adventitious viruses) and 0.2% sodium cholate (a detergent to inactivate potential adventitious viruses) and the application of heat (30°C for 6 hours). After ultrafiltration, the final product is a 15%-18% protein solution in glycine. The Imogam ® Rabies-HT is prepared from the cold ethanol fraction of pooled venous plasma of donors, stabilized with glycine, and subjected to a heat-treatment process (58°C-60°C for 10 hours) to inactivate potential adventitious viruses, with the final formulation consisting of 10%-18% protein. Both HRIGs are standardized at an average potency value of 150 IU per mL, and supplied in 2-mL (300 IU) vials for pediatric use and 10-mL (1,500 IU) vials for adult use. The recommended dose is 20 IU/kg (0.133 mL/kg) body weight. Both HRIG preparations are considered equally efficacious when used as described in these recommendations. These products are made from the plasma of hyperimmunized human donors that, in theory, might contain infectious agents. Nevertheless, the risk that such products will transmit an infectious agent has been reduced substantially by screening plasma donors for previous exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. No transmission of adventitious agents has been documented after administration of HRIGs licensed in the United States. # Effectiveness and Immunogenicity of Rabies Biologics # Effectiveness of Rabies Postexposure Prophylaxis: Human Studies A literature search identified 11 studies regarding the direct effectiveness of varying regimens of rabies postexposure prophylaxis in preventing rabies-associated deaths (18,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). An additional eight studies were identified from reviews of bibliographies or consultations with subject matter experts (19,(40)(41)(42)(43)(44)(45)(46). Three large retrospective cohort studies were identified that describe differences in rabies mortality between rabies-exposed persons (persons who were exposed to proven or suspected rabid animals) who were vaccinated with older formulations of rabies vaccine compared with similarly exposed persons who were not administered prophylaxis (41,44,46). In one 1923 study of 2,174 persons bitten by "presumably rabid" dogs in India, 2.9% of persons vaccinated with 1% Semple nerve tissue rabies vaccine (NTV) subcutaneously for 14 days died from rabies compared with 6.2% of unvaccinated persons (41). Another study of persons bitten by assumed infective rabid animals (i.e., one or more other persons bitten by the same animal died from rabies) during 1946-1951 indicated that 8.3% of persons "completely treated" with 5% Semple rabies vaccine, 23.1% of "incompletely treated", and 43.2% of unvaccinated persons died from rabies (46). A third study in Thailand in 1987 documented no deaths among 723 persons bitten by dogs (661 of these persons were bitten by confirmed rabid dogs) who received one of three rabies vaccines: Semple vaccine (n = 427), HDCV (n = 257), or duck embryo vaccine (n = 39) (44). However, 45% (nine of 20) of unvaccinated persons who were bitten by confirmed rabid dogs died from rabies. All of the persons who died were severely bitten on the face, neck, or arms. All unvaccinated persons who survived after having been bitten by confirmed rabid dogs were bitten either on the legs or feet. Although these studies describe outcomes of persons receiving older formulations of rabies vaccines that are not used in the United States, they demonstrate that a majority of persons bitten by known rabid dogs did not acquire rabies and provide historical evidence of a substantial protective effect of rabies vaccination after rabies exposure. The effectiveness of cell culture rabies vaccine plus rabies IgG in preventing human deaths after rabies exposure has been demonstrated in certain studies (18,19,(30)(31)(32)39,45). One prospective study described 10 children (aged <12 years) and 32 adults who had been administered HRIG (Hyperrab ® , Cutter Laboratories, Berkeley, CA, USA) and 5 IM doses of HDCV (L'Institut Merieux, Lyons, France) after exposure to suspected or confirmed rabid animals (brain-tissue positive by fluorescent antibody testing) (30). All exposed persons remained rabies-free during 5 years of observation. Another study investigated outcomes for 90 persons with high-risk exposures (bites or direct exposure to saliva from animals shown to be rabid by fluorescent antibody tests or bites from wild carnivores or bats that were not available for testing) who were treated with HRIG and 5 IM doses of HDCV (Wyeth Laboratories, Radnor, PA) (18). All patients, including 21 who were bitten by proven rabid animals (brain tissue (39,45). Several studies also have demonstrated the effectiveness of intradermal (ID) administration of cell culture rabies vaccine with or without RIG (of human or equine origin) in preventing rabies among exposed humans (33)(34)(35)37). Two studies demonstrated the role of RIG administration in conjunction with vaccine in rabies postexposure prophylaxis (42,43). The first described quantitative serologic outcomes in 29 persons severely bitten by a rabid wolf and demonstrated the importance of rabies antiserum administration in the establishment of an early, passive, rabies virus neutralizing antibody level in patients and protection against rabies (40,43). Among five patients treated with 2 doses of rabies antiserum and NTV for 21 days, all had detectable levels of rabies virus neutralizing antibody during the first 5 days and all survived. Among seven patients treated with 1 dose of antiserum in addition to NTV, all had detectable antibody during the first 5 days, but four of six had low antibody titers by day 21. One of the seven failed to develop more than a very low antibody level beyond day 7 and eventually died from rabies. Among the five persons treated with NTV without antiserum, none had detectable antibody levels before day 19, and three died from rabies. In the second study, none of 27 persons severely wounded by rabid animals in China who were treated with purified hamster kidney cell (PHKC) rabies vaccine plus horse-origin rabies immune serum died from rabies (42). In contrast, all three severely wounded persons treated with PHKC alone died. # Effectiveness of Rabies Postexposure Prophylaxis: Animal Studies During the preceding four decades, results of experimental studies using various animal species have supported the use of cell culture-based vaccines for protection against rabies after infections. For example, a postexposure prophylaxis experiment conducted in 1971 in rhesus monkeys using an experimental purified, concentrated tissue-culture vaccine alone, or in combination with homologous antirabies serum, demonstrated that a single administration of tissue-culture vaccine after exposure to rabies virus provided substantial (seven of eight animals) protection against the development of rabies. In addition to demonstrating that homologous or heterologous antirabies serum alone resulted in poor protection from rabies (63%-88% mortality), the experimental data suggested that highly concentrated, purified tissue-culture vaccine might be effective for postexposure prophylaxis in humans (47). A study in 1981 documented limited protection against a lethal rabies virus challenge in goats who received ERA vaccine with or without antirabies goat serum (48). In cattle, another livestock species, the superiority of tissue culture vaccine over brain-origin vaccine was demonstrated (49). Similarly, in sheep, vaccine alone provided limited protection, but vaccine in combination with polyclonal IgG provided the best outcome (50). A 1989 evaluation of postexposure prophylaxis administered to dogs demonstrated similar findings. The combination of serum and vaccine provided nearly complete protection compared with animals receiving vaccine only and nontreated controls (51). Previous animal postexposure research focused primarily on interventions against traditional rabies viruses. However, new causative agents of rabies continue to emerge, as demonstrated by the recent description of four novel lyssaviruses from bats in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV) (52,53). The combined effect of RIG and vaccine after exposure to these four new isolates was investigated in a Syrian hamster model, using commercially available human products or an experimental mAb (54). Conventional rabies postexposure prophylaxis provided little or no protection against all four new bat viruses. In general, protection was inversely related to the genetic distance between the new isolates and traditional rabies viruses, which demonstrated the usefulness of this animal model in estimating the potential impact of these new lyssaviruses on human and domestic animal health. # Immunogenicity of Rabies Postexposure Prophylaxis To assess the ability of rabies postexposure prophylaxis to elicit rabies virus neutralizing antibodies in humans, studies were reviewed that documented antibody responses to rabies postexposure prophylaxis. Four studies of antibody responses to rabies postexposure prophylaxis with 5 IM doses of HDCV with or without HRIG were identified (30,(55)(56)(57). Because no studies were identified that examined antibody responses to postexposure or simulated postexposure prophylaxis with 5 IM doses of the licensed PCECV vaccine (RabAvert ® ) plus HRIG, a study reporting antibody responses to 6 IM doses of another PCECV formulation (Rabipur ® , Novartis Vaccines and Diagnostics) administered with or without HRIG was reviewed (36). In a randomized trial, all persons receiving HRIG and 5 IM doses of HDCV (Imovax ® Rabies) developed rabies virus antibody titers >0.5 IU/mL lasting up to 42 days after prophylaxis initiation (56). In a 1999 case-series, among 40 persons with diverse histories of exposure to animals suspected of having rabies, all persons who received 5 IM doses of HDCV with or without HRIG seroconverted or had increases in baseline serum antibody titers after the fifth vaccine dose (geometric mean titer = 6.22 IU/mL) (57). Furthermore, a significantly higher mean antibody titer was observed in the group that received HDCV and HRIG (GMT = 12.3 IU/mL; standard error = 2.9) than in the group that received HDCV alone (GMT = 8.5 IU/mL; SE = 1.6; p=0.0043). In a randomized, modified double-blind, multicenter, simulated postexposure trial, 242 healthy adult volunteers were administered HRIG (Imogam ® Rabies-HT) and 5 IM doses of either HDCV (Imovax ® Rabies) or a chromatographically purified Vero-cell rabies vaccine (CPRV) (55). All participants had rabies virus neutralizing antibody titers >0.5 IU/mL by day 14 and maintained this level through day 42. Participants receiving HDCV had higher GMTs on days 14 and 42 than did participants receiving CPRV. In the prospective study comparing rabies neutralizing antibodies in the serum of children compared with adults following postexposure prophylaxis, all 25 adults and eight children tested on day 14 had rabies virus neutralizing antibody concentrations >0.5 IU/mL (30). In addition, no differences in antibody titer were observed between adults and children, and all persons remained alive during the 5 years of follow-up. # Effectiveness of Rabies Pre-Exposure Prophylaxis: Animal Studies Because no studies exist on the effectiveness of rabies preexposure prophylaxis in preventing rabies deaths in humans, literature was reviewed on the effectiveness of pre-exposure vaccination in animal models. The effectiveness of rabies vaccine has been appreciated for most of the 20 th century on the basis of animal experiments. Commercial rabies vaccines are licensed for certain domestic species, all of which entail the direct demonstration of efficacy after the administration of a single pre-exposure dose, and observed protection from rabies virus challenge for a minimum duration of 1-4 years after vaccination of captive animals. In addition, rabies preexposure vaccine research varies typically either by modification of standard regimens of vaccination or the relative antigenic value or potency of vaccine administration to ani-mals. For example, at least five studies involved animals challenged with rabies viruses (challenge standard virus or street rabies virus isolates) and other lyssaviruses (European bat lyssavirus 1, EBL2, Australian bat lyssavirus , and WCBV, IRKV, ARAV, KHUV) after primary vaccination with PCECV (58) or HDCV (54,(58)(59)(60)(61)(62). Two of seven studies reported seroconversion in mice and humans. Complete protection of animals from rabies virus infection was observed in all experiments that used PCECV or HDCV IM for primary vaccination except in one group that had been challenged by CVS through the intracranial route and experienced 5% mortality (59). Evaluation of crossprotection of HDCV against WCBV, ARAV, IRKV, KHUV, and ABL through IM challenge showed 44%, 55%, 67%, 89% and 79% survival, respectively (54). These studies demonstrated the usefulness of commercial human vaccines when administered to animals, with resulting protection dependent on the relative degree of phylogenetic relatedness between the rabies vaccine strain and the particular lyssavirus isolate. # Immunogenicity of Rabies Pre-Exposure Prophylaxis: Human Studies Thirteen studies were identified that provide evidence of the effectiveness of pre-exposure rabies vaccination in eliciting an adaptive host immune response in humans. The outcomes of interest for these studies (29,(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74) include the two working definitions of adequate rabies virus neutralizing antibody reference values that have been developed to define an appropriate, intact adaptive host response to vaccination: antibody titers of 0.5 IU/mL or complete virus neutralization at a 1:5 serum dilution by RFFIT (26). Multiple studies comparing different pre-exposure prophylaxis regimens provide evidence that vaccination with 3 IM doses of cell culture rabies vaccine (the recommended preexposure regimen) result in neutralizing antibody titers >0.5 IU/mL by days 14 (70,71), 21 (63,74), 28 (64,69,72), or 49 (67,68,75) after primary vaccination. One study in 1987 documented antibody responses in 177 healthy student volunteers aged 18-24 years following primary vaccination with either PCECV (Behringwerke) or HDCV (Behringwerke) (71). On day 14 after vaccination (first dose administered on day 0), no significant difference in GMT was observed between participants who received 3 IM doses of PCECV on days 0, 7, and 21 (GMT = 5.9 IU/mL) compared with persons who received 3 IM doses of HDCV (GMT = 4.4 IU/mL). On day 42, the GMT of the HDCV group was significantly higher than that of the PCECV group (13.7 IU/mL versus 8.4 IU/mL; p<0.025). Another study documented similar antibody responses to primary vaccination with HDCV in healthy veterinary students (64). The GMT of persons receiving 3 IM doses of HDCV on days 0, 7, and 28 was 10.2 IU/mL (range: 0.7-51.4) on day 28 and 37.7 IU/mL (range: 5.4-278.0) on day 42. Another study documented even higher GMTs among 78 volunteers in a randomized trial studying differences between primary vaccination with PCECV (Behringwerke) and HDCV (L'Institut Merieux) administered IM or ID on days 0, 7, and 28 (29). The day 28 GMT among persons receiving HDCV IM (GMT = 239 RFFIT titer/mL; range: 56-800) was significantly higher than the GMT among persons receiving PCECV IM (GMT = 138 RFFIT titer/mL; range: 45-280). On days 50 and 92, no significant difference in GMT was observed between the two groups in which vaccine was administered IM, and the GMTs of the IM groups were significantly higher than the ID groups. Another study also observed higher antibody titers on days 49 and 90 and 26 months after primary vaccination with HDCV (Imovax ® Rabies) when the vaccine was administered IM compared with ID on days 0, 7, and 28 (68). A randomized trial was conducted to determine the equivalence and interchangeability of PCECV (RabAvert ® ) and HDCV (Imovax ® Rabies) administered IM on days 0, 7, and 28 for rabies pre-exposure prophylaxis to 165 healthy, rabies vaccine naïve veterinary students (66). No significant difference in GMT was observed among the HDCV and PCECV groups on days 28 and 42. Although the 3-dose rabies pre-exposure prophylaxis series has been the standard regimen recommended by WHO (17) and ACIP (26), a 2-dose pre-exposure series has been used previously in some countries (76). One study compared antibody responses in persons receiving 2 (days 0 and 28) versus 3 (days 0, 7, and 28) IM doses of either HDCV (Pasteur Merieux Connaught, Lyon, France) or purified Vero cell rabies vaccine (PVRV) (Pasteur Merieux Connaught) and indicated that the cohort seroconversion rate decreased more rapidly among persons receiving 2 doses compared with those receiving 3 doses (p<0.001), indicating superior longer term immunogenicity when 3 vaccine doses were administered (73). In addition to the rapidity of the immune response resulting from rabies pre-exposure vaccination, another important consideration is the length of duration or persistence of the immune response. One study reported rapid declines in GMT at 4 months after initial vaccination among persons receiving 3-dose primary vaccination with HDCV (L'Institut Merieux) or PVRV (L'Institut Merieux) on days 0, 7, and 21 followed by stabilization of the antibody level through 21 months (63). Another study observed persistent GMTs among persons receiving 3-dose (days 0, 7, and 28) primary vaccination with PCECV (Behringwerke) and HDCV (L'Institut Merieux) IM on day 365 (PCECV GMT = 189 RFFIT titer/mL; range: 53-1400; HDCV GMT = 101 RFFIT titer/mL; range: 11-1400) and day 756 (PCECV GMT = 168 RFFIT titer/ mL; range: 50-3600; HDCV GMT = 92 RFFIT titer/mL; range: 11-480) after initial vaccination (29). On day 387 post vaccination, another study indicated that the GMT among persons receiving PCECV (RabAvert ® ) IM on days 0, 7, and 28 (GMT = 2.9 IU/mL) was significantly higher than the GMT in the HDCV (Imovax ® Rabies) group (GMT = 1.5 IU/mL; p0.5 IU/mL on days 387, as did 95.7% of persons vaccinated with HDCV. Another study indicated that all persons receiving PCECV (Behringwerke) IM on days 0, 7, and 21 maintained antibody titers >0.5 IU/mL 2 years after primary vaccination (71). In summary, rabies virus neutralizing antibody titers >0.5 IU/mL were observed in all persons at 180 days and 96.8% at 365 days after initial vaccination (72), 94% of persons at 21 months after initial vaccination ( 63), and all persons tested at 26 months after primary vaccination (77). An important use of rabies pre-exposure prophylaxis is to prime the immune response to enable a rapid anamnestic response to postexposure booster vaccination and simplify the postexposure prophylaxis requirements for previously vaccinated persons. One study observed antibody responses to 1or 2-dose (days 0 and 3) IM booster vaccinations with PCECV (RabAvert ® ) in persons who had received primary vaccination with either PCECV IM or HDCV IM 1 year earlier (66). All participants who had initially received PCECV primary vaccination and 66 of 69 (96%) who had initially received HDCV primary vaccination had titers >0.5 IU/mL before booster vaccination. No significant differences in GMT were observed between 1-and 2-dose booster groups on days 3 (2-dose GMT = 2.07 IU/mL; 1-dose GMT = 2.87 IU/ mL), seven (2-dose GMT = 51.67 IU/mL; 1-dose GMT = 51.23 IU/mL) and 365 (2-dose GMT = 30.60 IU/mL; 1-dose GMT = 26.10 IU/mL) (66). However, a significantly higher GMT was observed on day 21 for persons receiving 2-dose boosters (GMT = 151.63 IU/mL) compared with 1-dose boosters (GMT = 120.91 IU/mL). All persons tested at day 365 post-booster dose in both 1-and 2-dose booster groups had rabies virus neutralizing antibody titers >0.5 IU/mL regardless of whether PCECV or HDCV was used for primary vaccination. Another study documented rapid antibody responses to a single booster dose of HDCV (Imovax ® Rabies) or CPRV (Pasteur Merieux Connaught), with all persons in both groups exhibiting antibody titers >0.5 IU/mL on days 7 and 14 post-booster dose (72). # Safety of Rabies Biologics Eight studies regarding the safety of rabies biologics used in postexposure or simulated postexposure settings (36,(55)(56)(57)(78)(79)(80)(81) and eight studies of safety in pre-exposure settings were identified (63)(64)(65)68,71,72,82). Three identified studies investigated reports of adverse events in both postexposure and pre-exposure settings (14,83,84). Reviews of relevant bibliographies identified one additional study examining the safety of PCECV when used without HRIG for postexposure prophylaxis in children (85). # HDCV Studies of the use of HDCV reported local reactions (e.g., pain at the injection site, redness, swelling, and induration) among 60.0%-89.5% of recipients (63)(64)(65)68,72). Local reactions were more common than systemic reactions. Most local reactions were mild and resolved spontaneously within a few days. Local pain at the injection site was the most frequently reported adverse reaction occurring in 21%-77% of vaccinees (24,63,68,71,72,80). Mild systemic reactions (e.g., fever, headache, dizziness, and gastrointestinal symptoms) were reported in 6.8%-55.6% of recipients (63,64,68,72). Systemic hypersensitivity reactions have been reported in up to 6% of persons receiving booster vaccination with HDCV following primary rabies prophylaxis, 3% occurring within 1 day of receiving boosters, and 3% occurring 6-14 days after boosters (82). In one study, hypersensitivity reactions (e.g., urticaria, pruritic rash, and angioedema) were reported in 5.6% (11 of 99) of schoolchildren aged 5-13 years following pre-exposure prophylaxis with IM HDCV (72). Angioedema was observed in 1.2% of these school children after booster doses of HDCV 1 year after primary vaccination with HDCV. In 46 months of surveillance for adverse events following HDCV administration during 1980-1984, CDC received reports of 108 systemic allergic reactions (ranging from hives to anaphylaxis) following HDCV (11 per 10,000 vaccinees) (14). These included nine cases of presumed Type I immediate hypersensitivity (one of 10,000), 87 cases of presumed Type III hypersensitivity (nine of 10,000), and 12 cases of hypersensitivity of indeterminate type. All nine of the presumed immediate hypersensitivity reactions occurred during either primary pre-exposure or postexposure vaccination. Most (93%) of the Type III hypersensitivity reactions were observed following booster vaccination. Systemic allergic reactions have been associated with the presence of betapropiolactone-altered human albumin in HDCV and the development of immunoglobulin E (IgE) antibodies to this allergen (82,86). No deaths resulting from these reactions were reported. In four studies investigating the safety of rabies postexposure prophylaxis with both HRIG and HDCV, no serious adverse events were observed (55)(56)(57)78). Local reactions were common, and pain at the injection site was reported by 7%-92% of participants (55)(56)(57). Studies of the frequency of systemic adverse reactions following rabies vaccination are limited by small sample sizes. Systemic adverse reactions were not observed in any of the participants in one study with a relatively small sample size (78). In two other studies in which adverse events were collected using patient self-monitoring forms and investigator interviews at each visit, systemic reactions were reported by 76%-100% of participants (55,56). However, none of these reported systemic adverse events was considered to be serious. Rare, individual case reports of neurologic adverse events following rabies vaccination have been reported, but in none of the cases has causality been established. Four cases of neurologic illness resembling Guillain-Barré syndrome occurring after treatment with HDCV were identified (13,(87)(88)(89). One case of acute neurologic syndrome involving seizure activity was reported following the administration of HDCV and HRIG (90). Other central and peripheral nervous system disorders have been temporally associated with HDCV vaccine (91). # PCECV In studies of PCECV use, local reactions (e.g., pain at the injection site, redness, swelling, and induration) were reported among 11%-57% of recipients (29,79,84). Local pain at the injection site, the most common local reaction, was reported in 2%-23% of vaccinees (29,71,79,81,83,85). Systemic reactions were less common and have been reported in 0-31% of vaccine recipients (79,83,84). One study investigated adverse events among 271 children in India who received rabies postexposure prophylaxis with PCECV IM without HRIG following bites from suspected or confirmed rabid dogs (85). Overall, 7% of the children experienced mild to moderate clinical reactions. The most frequently reported reaction was local pain after the first or second dose (4%). Another study documented clinical reactions in 29 persons administered 6 IM doses of PCECV with (n = four) or without HRIG following bites by suspected rabid stray dogs. No serious adverse events were observed during the course of or after prophylaxis (36). Another case report documented one case of neurologic illness resembling Guillain-Barré syndrome after vaccination with PCECV in India (92). A retrospective review of adverse events following administration of PCECV was conducted using data from the United # HRIG In a clinical trial involving 16 volunteers in each group, participants receiving HRIG plus placebo (administered to mimic vaccine) commonly reported local reactions (100% in conventionally produced HRIG group, 75% in heat-treated HRIG group), including pain/tenderness (100% conventional HRIG, 50% heat-treated HRIG), erythema (63% conventional, 25% heat-treated), and induration (50% conventional, 31% heat-treated) (56). Systemic reactions were reported in 75% of participants in the conventional HRIG group and 81% in the heat-treated group. Headache was the most commonly reported systemic reaction (50% conventional, 69% heat-treated). The majority of the reported local and systemic reactions were mild, and no significant differences were observed in the frequency of adverse events between treatment groups. No serious adverse events, including immediate hypersensitivity reactions or immune-complex-like disease, were reported. # Cost-Effectiveness of Rabies Postexposure Prophylaxis ACIP's charter requires the committee, when deliberating recommendations for vaccine use in the United States, to consider the cost and benefits of potential recommendations. Cost-effectiveness studies combine different types of data (e.g., epidemiologic, clinical, cost, and vaccine effectiveness), and the results from such studies allow public health officials, medical practitioners, and the public to make more informed decisions when evaluating the risk for disease against the cost of the vaccine, including vaccine-related side effects. CDC analyzed the cost-effectiveness of rabies postexposure prophylaxis for each of eight contact (risk of transmission) scenarios, with the outcome being the net cost (in dollars) per life saved (in 2004 dollars). The perspective was societal, which means that all costs and all benefits were included, regardless of who pays and who benefits. For each risk-oftransmission scenario, three cost-effectiveness ratios were calculated: average, most, and least cost-effective. Average cost-effective ratios were calculated using median transmission risk values (Table 2) and average cost of postexposure prophylaxis. Most cost-effective ratios were calculated using greatest (largest) transmission risk values and least cost of postexposure prophylaxis. Least cost-effective ratios were calculated using lowest transmission risk and greatest cost of postexposure prophylaxis. The analysis assumed that the direct medical costs associated with postexposure prophylaxis included 1 dose of HRIG ($326-$1,434), 5 doses of HDCV ($113-$679 each), hospital charges ($289-$624), and physician charges ($295-$641) (95). Indirect costs included travel, lost wages, alternative medicine, and other costs ($161-$2,161) (96). A societal perspective requires the valuation of the loss of productivity to society caused by premature death. Therefore, human life lost was valued using the average present value, in 2004 dollars, of expected future lifetime earnings and housekeeping services ($1,109,920) (97). All costs were adjusted to 2004 dollars using the medical care price index. The study also assumed that rabies postexposure prophylaxis, when administered according to these recommendations, was essentially 100% effective in preventing a clinical case of human rabies. The probabilities of rabies transmission to a human following possible contact with different species of potentially rabid animals was assessed by a panel of experts using the Delphi methodology, except for "animal tests positive for rabies" when probabilities were obtained from a previous study (98) (Table 2). Under all three cost-effectiveness scenarios, the analysis determined that it is always cost saving to administer postexposure prophylaxis if a patient is bitten by a rabid animal that has tested positive for rabies or if a patient is bitten by a reservoir or vector species (e.g. skunk, raccoon, bat, or fox bite in the United States or dog bite in countries with dog variant rabies), even if the animal is not available for testing. For all other transmission risk situations, the average net cost effectiveness ratio was always a net cost per life saved (range: $2.9 million per life saved following a bite from an untested cat to $4 billion per life saved following a lick from an untested dog). The wide range of probabilities of risk for trans-mission for the bat bite scenario resulted in the widest range of cost-effectiveness ratios (Table 2). Until more precise estimates of risk for transmission are obtained, these estimates illustrate the difficulty clinicians and public health officials will continue to encounter in unequivocally determining the cost-effectiveness of providing PEP. # Rabies Postexposure Prophylaxis # Rationale for Prophylaxis ACIP (26) and WHO (25) recommend that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive vaccination with HRIG and vaccination with cell culture rabies vaccines. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency. Because rabies biologics are valuable resources that are periodically in short supply, a risk assessment weighing potential adverse consequences associated with administering postexposure prophylaxis along with their severity and likelihood versus the actual risk for the person acquiring rabies should be conducted in each situation involving a possible rabies exposure. Because the balance of benefit and harm will differ among exposed persons on the basis of the risk for infection, recommendations regarding rabies postexposure prophylaxis are dependent upon associated risks including 1) type of exposure, 2) epidemiology of animal rabies in the area where the contact occurred and species of animal involved, and 3) circumstances of the exposure incident. The reliability of this information should be assessed for each incident. The decision of whether to initiate rabies postexposure prophylaxis also depends on the availability of the exposing animal for observation or rabies testing (Table 3). Because the epidemiology and pathogenesis of rabies are complex, these recommendations cannot be specific for every possible circumstance. Clinicians should seek assistance from local or state public health officials for evaluating exposures or determining the need for postexposure management in situations that are not routine. State and local officials have access to CDC rabies experts for particularly rare situations or difficult decisions. ($162 million-$8.4 billion) - Contact with a potentially rabid animal does not necessarily constitute an exposure. A bite exposure is defined as "any penetration of the skin by teeth." A nonbite exposure is defined as "contamination of open wounds, abrasions (including scratches) or mucous membranes with saliva or other potentially infectious material (e.g., neural tissue)." † Probabilities of rabies transmission to a human were obtained from a panel of experts, except for "animal tests positive for rabies" when probabilities obtained from a previous study. § Estimates of the direct medical costs of rabies postexposure prophylaxis (PEP) were converted into 2004 dollars using the medical care price index. The cost-effectiveness of PEP under each contact scenario is calculated using the median probability of becoming clinically ill with rabies and the average cost of PEP. The most cost-effective ratio is calculated using the minimum cost of PEP and the maximum probability of becoming clinically ill with rabies. The least cost-effective ratio is calculated using the maximum cost of PEP and the minimum probability of becoming clinically ill with rabies. ¶ Animals not available for testing. The skunk bite data are considered applicable to bites from other rabies reservoir species (e.g., bats, raccoons, and foxes in the United States and dog bites occurring in countries with dog variant rabies). No recognized bite or saliva exposure. # MMWR May 23, # Types of Exposure When an exposure has occurred, the likelihood of rabies infection varies with the nature and extent of that exposure. Under most circumstances, two categories of exposure (bite and nonbite) should be considered. The most dangerous and common route of rabies exposure is from the bite of a rabid mammal. An exposure to rabies also might occur when the virus, from saliva or other potentially infectious material (e.g., neural tissue), is introduced into fresh, open cuts in skin or onto mucous membranes (nonbite exposure). Indirect contact and activities (e.g., petting or handling an animal, contact with blood, urine or feces, and contact of saliva with intact skin) do not constitute exposures; therefore, postexposure prophylaxis should not be administered in these situations. Exposures to bats deserve special assessment because bats can pose a greater risk for infecting humans under certain circumstances that might be considered inconsequential from a human perspective (i.e., a minor bite or lesion). Human-to-human transmission occurs almost exclusively as a result of organ or tissue transplantation. Clinicians should contact local or state public health officials for assistance in determining the likelihood of a rabies exposure in a specific situation. Bite exposures. Any penetration of the skin by teeth constitutes a bite exposure. All bites, regardless of body site or evidence of gross trauma, represent a potential risk. The risk for transmission varies in part with the species of biting animal, the anatomic site of the bite, and the severity of the wound (98). Although risk for transmission might increase with wound severity, rabies transmission also occurs from bites by some animals (e.g., bats) that inflict rather minor injury compared with larger-bodied carnivores, resulting in lesions that are difficult to detect under certain circumstances (8,(99)(100)(101)(102)(103). Nonbite exposures. Nonbite exposures from animals very rarely cause rabies. However, occasional reports of nonbite transmission suggest that such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis (104). The nonbite exposures of highest risk appear to be among surgical recipients of corneas, solid organs, and vascular tissue transplanted from patients who died of rabies and persons exposed to large amounts of aerosolized rabies virus. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies have been attributed to possible airborne exposures in caves containing millions of free-tailed bats (Tadarida brasiliensis) in the Southwest. However, alternative infection routes can not be discounted (105)(106)(107)(108)(109). Similar airborne incidents have not occurred in approximately 25 years, probably because of elevated awareness of such risks resulting in increased use of appropriate preventive measures. The contamination of open wounds or abrasions (including scratches) or mucous membranes with saliva or other potentially infectious material (e.g., neural tissue) from a rabid animal also constitutes a nonbite exposure. Rabies virus is inactivated by desiccation, ultraviolet irradiation, and other factors and does not persist in the environment. In general, if the suspect material is dry, the virus can be considered noninfectious. Nonbite exposures other than organ or tissue trans- Livestock, small rodents (rabbits and Consider individually Consult public health officials. Bites from hares), large rodents (woodchucks squirrels, hamsters, guinea pigs, gerbils, and beavers), and other mammals chipmunks, rats, mice, other small rodents, rabbits, and hares almost never require antirabies postexposure prophylaxis. - During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. † Postexposure prophylaxis should be initiated as soon as possible following exposure to such wildlife unless the animal is available for testing and public health authorities are facilitating expeditious laboratory testing or it is already known that brain material from the animal has tested negative. Other factors that might influence the urgency of decision-making regarding initiation of postexposure prophylaxis before diagnostic results are known include the species of the animal, the general appearance and behavior of the animal, whether the encounter was provoked by the presence of a human, and the severity and location of bites. Discontinue vaccine if appropriate laboratory diagnostic test (i.e., the direct fluorescent antibody test) is negative. § The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. plants have almost never been proven to cause rabies, and postexposure prophylaxis is not indicated unless the nonbite exposure met the definition of saliva or other potentially infectious material being introduced into fresh, open cuts in skin or onto mucous membranes. Bat Exposures. The most common rabies virus variants responsible for human rabies in the United States are batrelated; therefore, any potential exposure to a bat requires a thorough evaluation. If possible, bats involved in potential human exposures should be safely collected and submitted for rabies diagnosis. Most submitted bats (approximately 94%) (110) will not be rabid and such timely diagnostic assessments rule out the need for large investments in risk assessments and unnecessary prophylaxis. The risk for rabies resulting from an encounter with a bat might be difficult to determine because of the limited injury inflicted by a bat bite (compared with more obvious wounds caused by the bite of terrestrial carnivores), an inaccurate recall of a bat encounter that might have occurred several weeks or months earlier, and evidence that some bat-related rabies viruses might be more likely to result in infection after inoculation into superficial epidermal layers (111). For these reasons, any direct contact between a human and a bat should be evaluated for an exposure. If the person can be reasonably certain a bite, scratch, or mucous membrane exposure did not occur, or if the bat is available for testing and is negative for presence of rabies virus, postexposure prophylaxis is not necessary. Other situations that might qualify as exposures include finding a bat in the same room as a person who might be unaware that a bite or direct contact had occurred (e.g., a deeply sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person). These situations should not be considered exposures if rabies is ruled out by diagnostic testing of the bat, or circumstances suggest it is unlikely that an exposure took place. Other household members who did not have direct contact with the bat or were awake and aware when in the same room as the bat should not be considered as having been exposed to rabies. Circumstances that make it less likely that an undetected exposure occurred include the observation of bats roosting or flying in a room open to the outdoors, the observation of bats outdoors or in a setting where bats might normally be present, or situations in which the use of protective covers (e.g., mosquito netting) would reasonably be expected to preclude unnoticed contact. Because of the complexity of some of these situations, consultation with state and local health departments should always be sought. If necessary, further guidance can be sought from CDC and experts in bat ecology. During 1990-2007, a total of 34 naturally acquired batassociated human cases of rabies was reported in the United States. In six cases, a bite was reported; in two cases, contact with a bat and a probable bite were reported; in 15 cases, physical contact was reported (e.g., the removal of a bat from the home or workplace or the presence of a bat in the room where the person had been sleeping), but no bite was documented; and in 11 cases, no bat encounter was reported. In these cases, an unreported or undetected bat bite remains the most plausible hypothesis because the genetic sequences of the human rabies viruses closely matched those of specific species of bats. Clustering of human cases associated with bat exposures has never been reported in the United States (e.g., within the same household or among a group of campers where bats were observed during their activities) (8,101,110). Human-to-Human Exposures. Human-to-human transmission can occur in the same way as animal-to-human transmission (i.e., the virus is introduced into fresh open cuts in skin or onto mucous membranes from saliva or other potentially infectious material such as neural tissue). Organ and tissue transplantation resulting in rabies transmission has occurred among 16 transplant recipients from corneas (n = eight), solid organs (n = seven), and vascular tissue (n = one). Each of the donors died of an illness compatible with or proven to be rabies (10,(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123). The 16 cases occurred in five countries: the United States (five cases: one corneal transplant transmission, three solid organ transmissions, and one vascular graft transmission), Germany (four cases), Thailand (two cases), India (two cases), Iran (two cases), and France (one case). No documented laboratory-diagnosed cases of human-tohuman rabies transmission have been documented from a bite or nonbite exposure other than the transplant cases (124). At least two cases of human-to-human rabies transmission in Ethiopia have been suggested, but rabies as the cause of death was not confirmed by laboratory testing (125). The reported route of exposure in both cases was direct salivary contact from another human (i.e., a bite and a kiss). Routine delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless the health-care worker is reasonably certain that he or she was bitten by the patient or that his or her mucous membranes or nonintact skin was exposed directly to potentially infectious saliva or neural tissue. Adherence to standard precautions for all hospitalized patients as outlined by the Hospital Infection Control Practices Advisory Committee will minimize the need for postexposure prophylaxis in such situations (126). Staff should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning (25). # MMWR May 23, # Animal Rabies Epidemiology Bats. Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important wildlife reservoirs for variants of rabies virus transmitted to humans (5,101,102,110). Transmission of rabies virus can occur from minor, seemingly underappreciated or unrecognized bites from bats (8,(99)(100)(101)(102)(103). Laboratory data support a hypothesis that bat rabies virus variants associated with silver-haired bats (Lasionycteris noctivagans) and eastern pipistrelles (Pipistrellus subflavus) have biologic characteristics that might allow a higher likelihood of infection after superficial inoculation, such as into cells of epidermal origin (127). Human and domestic animal contact with bats should be minimized, and bats should never be handled by untrained and unvaccinated persons or be kept as pets (128). Wild Terrestrial Carnivores. Raccoons, skunks, and foxes are the terrestrial carnivores most often infected with rabies in the United States (5). Suggestive clinical signs of rabies among wildlife cannot be interpreted reliably. All bites by such wildlife should be considered possible exposures to rabies virus. Postexposure prophylaxis should be initiated as soon as possible following exposure to such wildlife, unless the animal is available for diagnosis and public health authorities are facilitating expeditious laboratory testing, or if the brain tissue from the animal has already tested negative. Wild terrestrial carnivores that are available for diagnostic testing should be euthanized as soon as possible (without unnecessary damage to the head), and the brain should be submitted for rabies diagnosis (129,130). If the results of testing are negative by immunofluorescence, human rabies postexposure prophylaxis is not necessary. Other factors that might influence the urgency of decision-making regarding the initiation of postexposure prophylaxis before diagnostic results are known include the species of the animal, the general appearance and behavior of the animal, whether the encounter was provoked by the presence of a human, and the severity and location of bites. Other Wild Animals. Rodents are not reservoirs of rabies virus. Small rodents (e.g., squirrels, chipmunks, rats, mice, hamsters, guinea pigs, and gerbils) and lagomorphs (including rabbits and hares) are rarely infected with rabies and have not been known to transmit rabies to humans (131,132). During 1990-1996, in areas of the country where raccoon rabies was enzootic, woodchucks accounted for 93% of the 371 cases of rabies among rodents reported to CDC (5,133,134). In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate postexposure prophylaxis (135). The offspring of wild animals crossbred to domestic dogs and cats (wild animal hybrids) are considered wild animals by the National Association of State and Public Health Veterinarians and CSTE. Because the period of rabies virus shedding in wild animal hybrids is unknown, when such animals bite humans euthanasia and rabies testing of the hybrid animal is the safest course of action. Vaccination should be discontinued if diagnostic tests of the involved animal are negative for rabies infection. However, because wolves and dogs have very similar genetic makeup and many animals that are advertised as "wolf-dogs" might actually be dogs, each wolf hybrid bite situation should be evaluated individually, taking into account the likelihood that it is a hybrid, the severity of the wound, and the assessment by the bite victim and his or her health-care provider. State or local health departments should be consulted before a decision is made to euthanize and test an animal. Wild animals and wild animal hybrids should not be kept as pets (128) or be publicly accessible. Humans who work with wild animals maintained in United States Department of Agriculture-licensed research facilities or accredited zoological parks should be educated on preventing bites and should receive rabies pre-exposure vaccinations. Rabies exposures of these animal handlers might require booster postexposure vaccinations in lieu of euthanasia and testing of the animal depending on employment requirements. Domestic Dogs, Cats, and Ferrets. The likelihood of rabies in a domestic animal varies regionally, and the need for postexposure prophylaxis also varies on the basis of regional epidemiology. The number of reported cases of rabies in domestic dogs has decreased substantially in the United States, primarily because of improved canine vaccination and stray animal control programs (5). In the continental United States, rabies among dogs has been reported sporadically along the United States-Mexico border and in areas of the United States with enzootic wildlife rabies (5). During 2000-2006, more cats than dogs were reported rabid in the United States (6). The majority of these cases were associated with the epizootic of rabies among raccoons in the eastern United States. The large number of rabid cats compared with other domestic animals might be attributed to a lower vaccination rate among cats because of less stringent cat vaccination laws; fewer confinement or leash laws; and the nocturnal activity patterns of cats placing them at greater risk for exposure to infected raccoons, skunks, foxes, and bats. In certain developing countries, dogs remain the major reservoir and vector of rabies and represent an increased risk for rabies exposure in such countries (136). A healthy domestic dog, cat, or ferret that bites a person should be confined and observed for 10 days (128,137,138). Those that remain alive and healthy 10 days after a bite would not have been shedding rabies virus in their saliva and would not have been infectious at the time of the bite (25). All domestic dogs, cats, and ferrets kept as pets should be vaccinated against rabies. Even if they are not, such animals might still be confined and observed for 10 days after a bite to reliably determine the risk for rabies exposure for the person who was bitten. Any illness in the animal during the confinement period before release should be evaluated by a veterinarian and reported immediately to the local public health department. If signs suggestive of rabies develop, postexposure prophylaxis of the bite victim should be initiated. The animal should be euthanized and its head removed and shipped, under refrigeration, for examination by a qualified laboratory. If the biting animal is stray or unwanted, it should either be confined and observed for 10 days or euthanized immediately and submitted for rabies diagnosis (128). Other Domestic Animals. In all instances of exposure to other domestic animal species, local or state health department should be consulted before a decision is made to euthanize and test the animal or initiate postexposure prophylaxis (128). # Circumstances of Biting Incident and Vaccination Status of Exposing Animal An unprovoked attack by an animal might be more likely than a provoked attack to indicate that the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked. Other factors to consider when evaluating a potential rabies exposure include the epidemiology of rabies in the area, the biting animal's history and health status (e.g., abnormal behavior and signs of illness), and the potential for the animal to be exposed to rabies (e.g., presence of an unexplained wound or history of exposure to a rabid animal). A dog, cat, or ferret with a history of continuously current vaccination (i.e., no substantial gaps in vaccination coverage) is unlikely to become infected with rabies (128,137,(139)(140)(141). Even after an initial rabies vaccination, young or naïve animals remain at risk for rabies because of the potential exposures preceding vaccination or before adequate induction of immunity during the 28 days after primary vaccination (128). # Treatment of Wounds and Vaccination The essential components of rabies postexposure prophylaxis are wound treatment and, for previously unvaccinated persons, the administration of both HRIG and vaccine (Table 4) (142). Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Incubation periods of more than 1 year have been reported in humans (143). Therefore, when a documented or likely exposure has occurred, postexposure prophylaxis should be administered regardless should be infiltrated around the wound(s) and any remaining volume should be administered intramuscularly (IM) at an anatomical site distant from vaccine administration. Also, RIG should not be administered in the same syringe as vaccine. Because RIG might partially suppress active production of antibody, no more than the recommended dose should be given. # Vaccine Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid area § ), one each on days 0 ¶ , 3, 7, 14, and 28. # Previously vaccinated † Wound cleansing All postexposure prophylaxis should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidine-iodine solution should be used to irrigate the wounds. RIG RIG should not be administered. Vaccine HDCV or PCECV 1.0 mL, IM (deltoid area § ), one each on days 0 ¶ and 3. - These regimens are applicable for all age groups, including children. † Any person with a history of a complete pre-exposure or postexposure vaccination regimen with HDCV, PCECV, or rabies vaccine adsorbed, or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination. § The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh can be used. Vaccine should never be administered in the gluteal area. ¶ Day 0 is the day the first dose of vaccine is administered. -f the length of the delay, provided that compatible clinical signs of rabies are not present in the exposed person. The administration of postexposure prophylaxis to a clinically rabid human patient has demonstrated consistent ineffectiveness (25). In 1977, WHO recommended a regimen of RIG and 6 doses of HDCV over a 90-day period. This recommendation was based on studies in Germany and Iran (19,21). When used in this manner, the vaccine was safe and effective in persons bitten by animals proven to be rabid and induced an adequate antibody response in all recipients (19). Studies conducted in the United States by CDC have documented that a regimen of 1 dose of HRIG and 5 doses of HDCV over a 28-day period was safe and induced an adequate antibody response in all recipients (18). Clinical trials with PCECV have demonstrated immunogenicity equivalent to that of HDCV (144). Cell culture vaccines have been used effectively with HRIG or RIG of equine origin (ERIG) worldwide to prevent rabies in persons bitten by various rabid animals (18,19). Worldwide, WHO estimates that postexposure prophylaxis is initiated on 10-12 million persons annually (144). An estimated 16,000-39,000 persons in the United States receive a full postexposure course each year (11). Although postexposure prophylaxis has not always been properly administered in the United States, no failures have been documented since current biologics have been licensed. # Treatment of Wounds Regardless of the risk for rabies, the optimal medical treatment of animal bite wounds includes the recognition and treatment of serious injury (e.g., nerve or tendon laceration), avoidance or management of infection (both local and systemic), and approaches that will yield the best possible cosmetic results (145). For many types of bite wounds, immediate gentle irrigation with water or a dilute water povidone-iodine solution markedly decrease the risk for bacterial infection (146). Care should be taken not to damage skin or tissues. Wound cleansing is especially important in rabies prevention because thorough wound cleansing alone without other postexposure prophylaxis markedly reduce the likelihood of rabies in animal studies (147,148). Consideration should be given to the need for a booster dose of tetanus vaccine (149,150). Decisions regarding the use of antibiotic prophylaxis (151) and primary wound closure (152) should be individualized on the basis of the exposing animal species, size and location of the wound(s), and time interval since the bite. Suturing should be avoided, when possible. # Vaccination Postexposure antirabies vaccination should always include administration of both passive antibody and vaccine, with the exception of persons who have ever previously received complete vaccination regimens (pre-exposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have previously had a documented rabies virus neutralizing antibody titer. These persons should receive only vaccine (i.e., postexposure for a person previously vaccinated). The combination of HRIG and vaccine is recommended for both bite and nonbite exposures reported by persons who have never been previously vaccinated for rabies, regardless of the interval between exposure and initiation of prophylaxis. If postexposure prophylaxis has been initiated and appropriate laboratory diagnostic testing (i.e., the direct fluorescent antibody test) indicates that the exposing animal was not rabid, postexposure prophylaxis can be discontinued. Rabies IgG Use. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virusneutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies. If HRIG was not administered when vaccination was begun (i.e., day 0), it can be administered up to and including day 7 of the postexposure prophylaxis series (153). Beyond the seventh day, HRIG is not indicated because an antibody response to cell culture vaccine is presumed to have occurred. Because HRIG can partially suppress active production of antibody, the dose administered should not exceed the recommended dose (154). The recommended dose of HRIG is 20 IU/kg (0.133 mL/kg) body weight. This formula is applicable to all age groups, including children. If anatomically feasible, the full dose of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume should be injected IM at a site distant from vaccine administration. This recommendation for HRIG administration is based on reports of rare failures of postexposure prophylaxis when less than the full amount of HRIG was infiltrated at the exposure sites (155). HRIG should never be administered in the same syringe or in the same anatomical site as the first vaccine dose. However, subsequent doses of vaccine in the 5-dose series can be administered in the same anatomic location where the HRIG dose was administered, if this is the preferable site for vaccine administration (i.e., deltoid for adults or anterolateral thigh for infants and small children). Vaccine Use. Two rabies vaccines are available for use in the United States (Table 1); either can be administered in conjunction with HRIG at the beginning of postexposure pro-phylaxis. A regimen of one-mL doses of HDCV or PCECV should be administered IM to previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon as possible after exposure. This date is then considered day 0 of the postexposure prophylaxis series. Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. For adults, the vaccination should always be administered IM in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for HDCV or PCECV injections because administration of HDCV in this area results in lower neutralizing antibody titers (156). # Deviations from Recommended Postexposure Vaccination Schedules Every attempt should be made to adhere to the recommended vaccination schedules. Once vaccination is initiated, delays of a few days for individual doses are unimportant, but the effect of longer lapses of weeks or more is unknown (157). Most interruptions in the vaccine schedule do not require reinitiation of the entire series (158). For most minor deviations from the schedule, vaccination can be resumed as though the patient were on schedule. For example, if a patient misses the dose scheduled for day 7 and presents for vaccination on day 10, the day 7 dose should be administered that day and the schedule resumed, maintaining the same interval between doses. In this scenario, the remaining doses would be administered on days 17 and 31. When substantial deviations from the schedule occur, immune status should be assessed by performing serologic testing 7-14 days after administration of the final dose in the series. # Postexposure Prophylaxis Outside the United States Persons exposed to rabies outside the United States in countries where rabies is enzootic might receive postexposure prophylaxis with regimens or biologics that are not used in the United States, including purified vero cell rabies vaccine (Verorab ™ , Imovax -Rabies vero ™ , TRC Verorab ™ ), purified duck embryo vaccine (Lyssavac N ™ ), and different formulations of PCECV (Rabipur ® ) or HDCV (Rabivac ™ ). This information is provided to familiarize physicians with some of the regimens used more widely abroad. These regimens have not been submitted for approval by the U.S. Food and Drug Administration (FDA) for use in the United States (37,74,(159)(160)(161)(162)(163)(164)(165)(166)(167)(168). If postexposure prophylaxis is initiated outside the United States using one of these regimens or vaccines of nerve tissue origin, additional prophylaxis might be necessary when the patient presents for care in the United States. State or local health departments should be contacted for specific advice in such cases. Rabies virus neutralizing antibody titers from specimens collected 1-2 weeks after preexposure or postexposure prophylaxis would be considered adequate if complete neutralization of challenge virus at a 1:5 serum dilution by RFFIT occurs. Purified ERIG or fractions of ERIG have been used in developing countries where HRIG might not have been available. The incidence of adverse reactions after ERIG administration has been low (0.8%-6.0%), and most of those that occurred were minor (169)(170)(171). In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither HRIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis (172). Although no postexposure prophylaxis failures have occurred in the United States since cell culture vaccines and HRIG have been routinely used, failures have occurred abroad when less than potent biologics were used, if some deviation was made from the recommended postexposure prophylaxis protocol, or when less than the recommended amount of RIG was administered (155,(173)(174)(175). Specifically, patients who contracted rabies after postexposure prophylaxis might not have had adequate local wound cleansing, might not have received rabies vaccine injections in the deltoid area (i.e., vaccine was administered in the gluteal area), or might not have received appropriate infiltration of RIG around the wound site. Substantial delays between exposure and initiation of prophylaxis are of concern, especially with severe wounds to the face and head, which might provide access to the central nervous system through rapid viral neurotropism. # Rabies Pre-Exposure Prophylaxis Pre-exposure rabies prophylaxis is administered for several reasons. First, although pre-exposure vaccination does not eliminate the need for additional medical evaluation after a rabies exposure, it simplifies management by eliminating the need for RIG and decreasing the number of doses of vaccine needed. This is particularly important for persons at high risk for being exposed to rabies in areas where modern immunizing products might not be available or where cruder, less safe biologics might be used, placing the exposed person at increased risk for adverse events. Second, pre-exposure prophylaxis might offer partial immunity to persons whose postexposure prophylaxis is delayed. Finally, pre-exposure prophylaxis might provide some protection to persons at risk for unrecognized exposures to rabies. Pre-exposure vaccination should be offered to persons in high-risk groups, such as veterinarians and their staff, animal handlers, rabies researchers, and certain laboratory workers. Pre-exposure vaccination also should be considered for persons whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies. In addition, some international travelers might be candidates for pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care, including rabies vaccine and immune globulin, might be limited. Routine pre-exposure prophylaxis for the general U.S. population or routine travelers to areas where rabies is not enzootic is not recommended (176,177). # Primary Vaccination Three 1.0-mL injections of HDCV or PCECV should be administered IM (deltoid area), one injection per day on days 0, 7, and 21 or 28 (Table 5). The immunogenicity of IM primary vaccination with PCECV and HDCV has been reviewed. Vaccine preparations for ID administration are no longer available in the United States. # Pre-Exposure Booster Doses of Vaccine Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category ) (178) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies virus neutralizing antibody every 6 months. An IM booster dose (Table 5) of vaccine should be administered if the serum titer falls to maintain a serum titer corresponding to a value of at least complete neutralization at a 1:5 serum dilution by the RFFIT. The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), cavers, veterinarians and staff, and animalcontrol and wildlife officers in areas where animal rabies is enzootic. The frequent-risk category also includes persons who frequently handle bats, regardless of location in the United States or throughout the world, because of the existence of lyssaviruses on all continents except Antarctica. Persons in the frequent-risk group should have a serum sample tested for rabies virus neutralizing antibody every 2 years. If the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and terrestrial animal-control and wildlife officers working in areas where rabies is uncommon to rare (infrequent exposure group) and certain at-risk international travelers who have completed a full pre-exposure vaccination series with licensed vaccines and according to schedule do not require routine serologic verification of detectable antibody titers or routine pre-exposure booster doses of vaccine. If they are exposed to rabies in the future, they are considered immunologically primed against rabies and simply require postexposure prophylaxis for a person previously vaccinated (i.e., days 0 and 3 vaccination). # Postexposure Prophylaxis for Previously Vaccinated Persons If a person is exposed to rabies, local wound care remains an important part of postexposure prophylaxis, even for previously vaccinated persons. Previously vaccinated persons are those who have received one of the recommended pre-exposure or postexposure regimens of HDCV, PCECV, or RVA or those who received another vaccine and had a documented rabies virus neutralizing antibody titer. These persons should receive 2 IM doses (1.0 mL each in the deltoid) of vaccine, one immediately and one 3 days later. Administration of RIG is unnecessary and should not be administered to previously vaccinated persons because the administration of passive antibody might inhibit the relative strength or rapidity of an expected anamnestic response (77). For previously vaccinated persons who are exposed to rabies, determining the rabies virus neutralizing antibody titer for decision-making about prophylaxis is inappropriate for at least three reasons. First, several days will be required to collect the serum and determine the test result. Second, no "protective" titer is known. Finally, although rabies virus neutralizing antibodies are important components, other immune effectors also are operative in disease prevention. # Vaccination and Serologic Testing # Post-Vaccination Serologic Testing In CDC studies, all healthy persons tested 2-4 weeks after completion of pre-exposure and postexposure rabies prophylaxis in accordance with ACIP guidelines demonstrated an adequate antibody response to rabies (18,73,179,180). Therefore, no testing of patients completing pre-exposure or postexposure prophylaxis is necessary to document seroconversion unless the person is immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone pre-exposure vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When that is not possible, immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their virus neutralizing antibody titers checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public health officials. When titers are obtained, specimens collected 1-2 weeks after pre-exposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. Antibody titers might decline over time since the last vaccination. Small differences (i.e., within one dilution of sera) in the reported values of rabies virus neutralizing antibody titer (most properly reported according to a standard as IU/mL) might occur among laboratories that provide antibody determination using the recommended RFFIT. Rabies antibody titer determination tests that are not approved by FDA are not appropriate for use as a substitute for RFFIT in suspect human rabies antemortem testing because discrepant results between such tests and measures of actual virus neutralizing activity by RFFIT have been observed (181). # Serologic Response and Pre-Exposure Booster Doses of Vaccine Although virus neutralizing antibody levels might not definitively determine a person's susceptibility or protection from a rabies virus exposure, titers in persons at risk for exposure are used to monitor the relative rabies immune status over time (182). To ensure the presence of a primed immune response over time among persons at higher than normal risk for exposure, titers should be checked periodically, with booster doses administered only as needed. Two years after primary pre-exposure vaccination, a complete neutralization of challenge virus at a dilution of 1:5 (by the RFFIT) was observed among 93%-98% of persons who received the 3-dose pre-exposure series intramuscularly and 83%-95% of persons who received the 3-dose series intradermally (68). If the titer falls below the minimum acceptable antibody level of complete neutralization at a serum dilution of 1:5, a single pre-exposure booster dose of vaccine is recommended for persons at continuous or frequent risk for exposure to rabies (Table 6). # Management and Reporting of Adverse Reactions to Rabies Biologics Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. Usually, such reactions can be successfully managed with anti-inflammatory, antihistaminic, and antipyretic agents. When a person with a history of hypersensitivity to rabies vaccine must be revaccinated, empiric intervention such as pretreatment with antihistamines might be considered. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination (184). Although serious systemic, anaphylactic, or neuroparalytic reactions are rare during and after the administration of rabies vaccines, such reactions pose a serious dilemma for the patient and the attending physician (14). A patient's risk for acquiring rabies must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious adverse reactions for persons receiving rabies vaccines can be sought from the state or local health department or CDC. All clinically significant adverse events occurring following administration of rabies vaccine should be reported to VAERS, even if causal relation to vaccination is not certain. Although VAERS is subject to limitations common to passive surveillance systems, including underreporting and reporting bias, it is a valuable tool for characterizing the safety profile of vaccines and identifying risk factors for rare serious adverse reactions to vaccines (94). VAERS reporting forms and information are available at or by telephone (800-822-7967). Web-based reporting is available and health-care providers are encouraged to report electronically at Entryintro.htm. Clinically significant adverse events following HRIG administration should be reported to the Food and Drug Administration's MedWatch. Reports can be submitted electronically to . # Precautions and Contraindications Immunosuppression Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination (185,186). For persons with immunosuppression, pre-exposure prophylaxis should be administered with the awareness that the immune response might be inadequate. Patients who are immunosuppressed by disease or medications should postpone pre-exposure vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should have their virus neutralizing antibody titers checked after completing the pre-exposure series. A patient who fails to seroconvert after the third dose should be managed in consultation with their physician and appropriate public health officials. No cases of rabies postexposure prophylaxis failure have been documented among persons immunosuppressed because of human immunodeficiency virus infection. Immunosuppressive agents should not be administered during postexposure prophylaxis unless essential for the treatment of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, one or more serum samples should be tested for rabies virus neutralizing antibody to ensure that an acceptable antibody response has developed. If no acceptable antibody response is detected, the patient should be managed in consultation with their physician and appropriate public health officials. # Pregnancy Because of the potential consequences of inadequately managed rabies exposure, pregnancy is not considered a contraindication to postexposure prophylaxis. Certain studies have indicated no increased incidence of abortion, premature births, or fetal abnormalities associated with rabies vaccination (187)(188)(189). If the risk for exposure to rabies is substantial, pre-exposure prophylaxis also might be indicated during pregnancy. Rabies exposure or the diagnosis of rabies in the mother should not be regarded as reasons to terminate the pregnancy (157). # Allergies Persons who have a history of serious hypersensitivity to components of rabies vaccine or to other vaccines with components that are also present in rabies vaccine should be revaccinated with caution (184). # Indigent Patient Programs Both rabies vaccine manufacturers have patient assistant programs that provide medications to uninsured or underinsured patients. Sanofi pasteur's Indigent Patient Program (providing Imogam ® Rabies-HT and Imovax ® Rabies) is administered through the National Organization for Rare Disorders. Information is available by telephone (877-798-8716) or e-mail ([email protected]). Information on Novartis Pharmaceuticals Patient Assistance Program for RabAvert ® is available at . novartis.com/patients/drug-pricing/assistance-programs.shtml. # Treatment of Human Rabies Rabies is associated with the highest case fatality rate of any infectious disease. No proven effective medical treatment is recognized after the development of clinical signs. Combined with intensive care, experimental measures have included administration of vidarabine, multisite ID vaccination with cell-culture vaccines, human leukocyte interferon, RIG by the intravenous and intrathecal routes, antithymocyte globulin, inosine pranobex, ribavirin, ketamine, and high doses of steroids (190)(191)(192)(193)(194)(195)(196)(197). Initiation of rabies vaccination after onset of clinical symptoms in patients with confirmed rabies diagnoses is not recommended and might be detrimental. Survival has been well documented for only six patients. In five of these cases, the persons had received rabies vaccination before the onset of disease (198)(199)(200)(201)(202). Only one patient has recovered from rabies without the institution of rabies vaccination (9,203). Despite these successes, rabies is not considered curable. Treatment of clinical rabies remains an extreme challenge. Rapid antemortem diagnosis is a priority. When a definitive diagnosis is obtained, primary health considerations should focus, at a minimum, on comfort care and adequate sedation of the patient in an appropriate medical facility. Sedation is often necessary because patients might become extremely agitated, especially in the presence of stimuli such as loud noises, air currents, and the sight or sound of running water, particularly during the acute neurologic phase of the disease (25). Beyond the overt clinical situation associated with progressive encephalitis, during fluctuating periods of lucidity, patient stress might be compounded by the psychological trauma resulting from a sense of personal isolation and hopelessness from the prognosis. As new potential treatments become available, medical staff at specialized tertiary care hospitals might consider institution of an aggressive approach to experimental therapies, especially in confirmed cases in young healthy persons at an early stage of clinical disease, after in depth discussions and informed consent by the patient, family or legal representatives (http:// www.mcw.edu/display/router.asp?DocID=11655). Parties authorized to give permission for such treatment also should be aware of the high probability for treatment failure, the anticipated expenses, and that in the rare instances of patient survival, the recovery might be associated with a variety of neurologic deficits requiring a lengthy period of rehabilitation (204). Continued efforts focusing on the elimination of exposure to sources of virus and the institution of appropriate and timely prophylaxis after exposure occurs remain the most effective public health measures to prevent human rabies. # Precautions for Safe Clinical Management of Human Rabies Patients Human rabies patients do not pose any greater infection risk to health-care personnel than do patients with more common bacterial and viral infections (25). Medical staff should adhere to standard precautions as outlined by the Hospital Infection Control Practices Advisory Committee (126). Staff should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning (25). Postexposure prophylaxis is indicated only when the patient has bitten another person or when the patient's saliva or other potentially infectious material such as neural tissue has contaminated an open wound or mucous membrane. depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices # Appendix Abbreviations Used in This Report # Goal and Objectives This report provides recommendations for preventing rabies among humans. These recommendations were developed by CDC staff members and the Rabies Working Group of the Advisory Committee on Immunization Practices. The goal of this report is to guide clinical practice and policy development related to appropriate management of persons at risk for rabies. Upon completion of this educational activity, the reader should be able to1) describe groups for whom rabies pre-exposure prophylaxis are indicated, 2) describe groups for whom rabies serologic testing are indicated, 3) describe groups for whom booster dosing are indicated, 4) describe some of the common rabies reservoirs in the United States, and 5) describe the essential elements of rabies postexposure prophylaxis. To receive continuing education credits, please answer all of the following questions. # Which of the following lists of potential exposure types by animals are correctly ordered from the likely greatest risk for rabies virus infection to the least risk for infection? A. Raccoon scratches are greater than licks to the skin, which are greater than bites. B. Dog licks to the skin are greater than scratches, which are greater than bites. C. Skunk scratches are greater than bites, which are greater than licks to the skin. D. Bat licks to the skin are greater than scratches, which are greater than bites. E. None of the above.	These recommendations of the Advisory Committee on Immunization Practices (ACIP) update the previous recommendations on human rabies prevention (CDC. Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices. MMWR 1999;48 [No. RR-1]) and reflect the status of rabies and antirabies biologics in the United States. This statement 1) provides updated information on human and animal rabies epidemiology; 2) summarizes the evidence regarding the effectiveness/efficacy, immunogenicity, and safety of rabies biologics; 3) presents new information on the cost-effectiveness of rabies postexposure prophylaxis; 4) presents recommendations for rabies postexposure and pre-exposure prophylaxis; and 5) presents information regarding treatment considerations for human rabies patients. These recommendations involve no substantial changes to the recommended approach for rabies postexposure or pre-exposure prophylaxis. ACIP recommends that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive rabies immunization with human rabies immune globulin (HRIG) and vaccination with a cell culture rabies vaccine. For persons who have never been vaccinated against rabies, postexposure antirabies vaccination should always include administration of both passive antibody (HRIG) and vaccine (human diploid cell vaccine [HDCV] or purified chick embryo cell vaccine [PCECV]). Persons who have ever previously received complete vaccination regimens (pre-exposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have previously had a documented rabies virus neutralizing antibody titer should receive only 2 doses of vaccine: one on day 0 (as soon as the exposure is recognized and administration of vaccine can be arranged) and the second on day 3. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virus neutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies. A regimen of 5 1-mL doses of HDCV or PCECV should be administered intramuscularly to previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon as possible after exposure (day 0). Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. Rabies pre-exposure vaccination should include three 1.0-mL injections of HDCV or PCECV administered intramuscularly (one injection per day on days 0, 7, and 21 or 28). Modifications were made to the language of the guidelines to clarify the recommendations and better specify the situations in which rabies post-and pre-exposure prophylaxis should be administered. No new rabies biologics are presented, and no changes were made to the vaccination schedules. However, rabies vaccine adsorbed (RVA, Bioport Corporation) is no longer available for rabies postexposure or pre-exposure prophylaxis, and intradermal pre-exposure prophylaxis is no longer recommended because it is not available in the United States. MMWR May 23, 10. Which of the following statements about rabies are true? (Indicate all that are true.) A. Human rabies is a fatal disease <50% of the time. B. During the previous 2 decades, the majority of indigenous human rabies cases in the United States have been associated with canine variants of the rabies virus. C. U.S. citizens traveling abroad can be at serious risk for exposure to avian rabies. D. Although human rabies cases in the United States are rare, exposure to rabid or potentially rabid animals remains a relatively common event. E. Postexposure prophylaxis is effective after the onset of clinical illness in the majority of cases. 11. Which best describes your professional activities? A. Physician. B. Nurse. C. Health educator. D. Veterinarian. E. Other. Vol. 57 / No. RR-3 Recommendations and Reports CE-3 Detach or photocopy.# Introduction Rabies is a zoonotic disease caused by RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus (1)(2)(3)(4). Virus is typically present in the saliva of clinically ill mammals and is transmitted through a bite. After entering the central nervous system of the next host, the virus causes an acute, progressive encephalomyelitis that is almost always fatal. The incubation period in humans is usually several weeks to months, but ranges from days to years. As a result of improved canine vaccination programs and stray animal control, a marked decrease in domestic animal rabies cases in the United States occurred after World War II. This decline led to a substantial decrease in indigenously acquired rabies among humans (5). In 1946, a total of 8,384 indigenous rabies cases were reported among dogs and 33 cases in humans. In 2006, a total of 79 cases of rabies were reported in domestic dogs, none of which was attributed to enzootic dog-to-dog transmission, and three cases were reported in humans (6). The infectious sources of the 79 cases in dogs were wildlife reservoirs or dogs that were translocated from localities where canine rabies virus variants still circulate. None of the 2006 human rabies cases was acquired from indigenous domestic animals (6). Thus, the likelihood of human exposure to a rabid domestic animal in the United States has decreased substantially. However, one of the three human rabies cases diagnosed in 2006 was associated with a dog bite that occurred in the Philippines, where canine rabies is enzootic. The risk for reintroduction from abroad remains (7). International travelers to areas where canine rabies remains enzootic are at risk for exposure to rabies from domestic and feral dogs. Unlike the situation in developing countries, wild animals are the most important potential source of infection for both humans and domestic animals in the United States. Most reported cases of rabies occur among carnivores, primarily raccoons, skunks, and foxes and various species of bats. Rabies among insectivorous bats occurs throughout the continental United States. Hawaii remains consistently rabiesfree. For the past several decades, the majority of naturally acquired, indigenous human rabies cases in the United States have resulted from variants of rabies viruses associated with insectivorous bats (5). The lone human case reported in the United States during 2005 and two of the three human rabies cases in 2006 were attributed to bat exposures (6,8). During 2004, two of the eight human rabies cases resulted from bat exposures. One of these rabies patients recovered and remains the only rabies patient to have survived without the administration of rabies vaccination (9). Rabies was not immediately recognized as the cause of death in the other 2004 patient, and organs and a vascular graft from this patient were transplanted into four persons, resulting in clinical rabies and death in all of the recipients (10). Approximately 16,000-39,000 persons come in contact with potentially rabid animals and receive rabies postexposure prophylaxis each year (11). To appropriately manage potential human exposures to rabies, the risk for infection must be accurately assessed. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Prophylaxis is occasionally complicated by adverse reactions, but these reactions are rarely severe (12)(13)(14)(15)(16). For these recommendations, data on the safety and efficacy of active and passive rabies vaccination were derived from both human and animal studies. Because controlled human trials cannot be performed, studies describing extensive field experience and immunogenicity studies from certain areas of the world were reviewed. These studies indicated that postexposure prophylaxis combining wound treatment, local infiltration of rabies immune globulin (RIG), and vaccination is uniformly effective when appropriately administered (17)(18)(19)(20)(21)(22). However, rabies has occasionally developed among humans when key elements of the rabies postexposure prophylaxis regimens were omitted or incorrectly administered. Timely and appropriate human pre-exposure and postexposure prophylaxis will prevent human rabies; however, the number of persons receiving prophylaxis can be reduced if other basic public health and veterinary programs are working to prevent and control rabies. Practical and accurate health education about rabies, domestic animal vaccination and responsible pet care, modern stray animal control, and prompt diagnosis can minimize unnecessary animal exposures, alleviate inherent natural risks after exposure, and prevent many circumstances that result in the need for rabies prophylaxis. # Methods The Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup first met in July 2005 to review previous ACIP recommendations on the prevention of human rabies (published in 1999) and to outline a plan for updating and revising the recommendations to provide clearer, more specific guidance for the administration of rabies preexposure and postexposure prophylaxis. The workgroup held monthly teleconferences to discuss their review of published and unpublished data on rabies and related biologic products. Data on the effectiveness, efficacy, immunogenicity, and safety of rabies biologics in both human and animal studies were reviewed using a systematic, evidence-based approach. Randomized trials or well-conducted cohort studies with untreated comparison groups would provide the best evidence of the direct effectiveness of rabies pre-exposure and postexposure prophylaxis to prevent rabies-associated death. However, because of the almost universal fatality among untreated persons infected with rabies virus, no such controlled studies exist. However, studies describing final health outcomes among persons exposed to the rabies virus do exist, including studies using formulations of rabies biologics, timing of vaccine doses, and routes of administration that are not recommended for use in the United States. These and other studies were identified by reviewing the PubMed database and relevant bibliographies and by consulting subjectmatter experts. The literature review did not identify any studies of the direct effectiveness of rabies pre-exposure vaccination in preventing human rabies cases. Such studies would be difficult to conduct because rabies pre-exposure vaccination is intended to simplify the postexposure prophylaxis that is required after a recognized rabies exposure. Rabies preexposure vaccination also might afford immunity against an unrecognized rabies exposure, an outcome that would be difficult to measure in controlled studies. However, rabies cases have occurred among those who received rabies pre-exposure prophylaxis and did not receive rabies postexposure prophylaxis (23), indicating that pre-exposure prophylaxis in humans is not universally effective without postexposure prophylaxis. Because of the paucity of formal studies on the effectiveness of rabies pre-exposure vaccination in humans, the literature was searched for studies that reported clinical outcomes among animals that received pre-exposure rabies prophylaxis with cell culture rabies vaccine and were subsequently challenged with rabies virus. Evaluation of the effectiveness of antirabies biologics in experimental animal models has been essential to developing successful rabies prevention approaches for exposed humans. Animal studies investigating the effectiveness of both pre-exposure and posteexposure rabies prophylaxis were reviewed and were used to make inferences about the direct effectiveness of licensed rabies biologics in preventing human rabies. Data regarding the immunogenicity of rabies biologics also were reviewed. Assessing protective immunity against rabies is complex. Virus neutralizing antibodies are believed to have a primary role in preventing rabies virus infection. However, antibody titers alone do not always directly correlate with absolute protection because of other important immunologic factors. Nonetheless, the ability of a vaccine to elicit rabies virus neutralizing antibodies in animals and humans and the demonstration of protection in animals is generally viewed as a reasonable surrogate of protection for inferential extension to humans (24). Although a definitive "protective" titer cannot be described for all hosts under all exposure scenarios, two working definitions of adequate rabies virus neutralizing antibody reference values have been developed to define an appropriate, intact adaptive host response to vaccination. The literature review included studies in humans that measured rabies virus neutralizing antibody in response to rabies postexposure prophylaxis consisting of human rabies immune globulin (HRIG) and 5 intramuscular (IM) doses of cell culture rabies vaccine and the recommended pre-exposure prophylaxis regimen of 3 IM doses of cell culture vaccine. The outcomes of interest for these studies were antibody titers of 0.5 IU/mL (used by the World Health Organization [WHO] as an indicator of an adequate adaptive immune response) (25) or complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT) (used by ACIP as an indicator of an adequate adaptive immune response) (26). The literature also was searched for evidence regarding the safety of the licensed rabies biologics available for use in the United States in both pre-exposure and postexposure situations. ACIP's charter requires the committee to consider the costs and benefits of potential recommendations when they are deliberating recommendations for vaccine use in the United States. Few studies exist on the cost-effectiveness of rabies prophylaxis in various potential exposure scenarios. A challenge in conducting such studies is the lack of data on the probability of rabies transmission under different exposure scenarios, except when the involved animal tests positive for rabies. To provide information on the cost-effectiveness of rabies postexposure prophylaxis, a new analysis was conducted to estimate the cost-effectiveness of rabies postexposure prophylaxis in various potential exposure scenarios. A Delphi methodology was used to estimate the risk for transmission of rabies to a human in each of the scenarios, and this information was used in the cost-effectiveness calculations. The rabies workgroup reviewed the previous ACIP recommendations on the prevention of human rabies and deliberated on the available evidence. When definitive research evidence was lacking, the recommendations incorporated expert opinion of the workgroup members. and external review process to update and clarify wording in the document. # Rabies Biologics Three cell culture rabies vaccines are licensed in the United States: human diploid cell vaccine (HDCV, Imovax ® Rabies, sanofi pasteur), purified chick embryo cell vaccine (PCECV, RabAvert ® , Novartis Vaccines and Diagnostics), and rabies vaccine adsorbed (RVA, Bioport Corporation). Only HDCV and PCECV are available for use in the United States (Table 1). For each of the available vaccines, the potency of 1 dose is greater than or equal to the WHO-recommended standard of 2.5 international units (IU) per 1.0 mL of vaccine (27). A full 1.0-mL IM dose is used for both pre-exposure and postexposure prophylaxis regimens. Rabies vaccines induce an active immune response that includes the production of virus neutralizing antibodies. The active antibody response requires approximately 7-10 days to develop, and detectable rabies virus neutralizing antibodies generally persist for several years. A vaccination series is initiated and completed usually with one vaccine product. No clinical trials were identified that document a change in efficacy or the frequency of adverse reactions when the series is initiated with one vaccine product and completed with another. The passive administration of RIG is intended to provide an immediate supply of virus neutralizing antibodies to bridge the gap until the production of active immunity in response to vaccine administration. Use of RIG provides a rapid, passive immunity that persists for a short time (half-life of approximately 21 days) (28). Two antirabies immune globulin (IgG) formulations prepared from hyperimmunized human donors are licensed and available for use in the United States: HyperRab ™ S/D (Talecris Biotherapeutics) and Imogam ® Rabies-HT (sanofi pasteur). In all postexposure prophylaxis regimens, except for persons previously vaccinated, HRIG should be administered concurrently with the first dose of vaccine. # Vaccines Licensed for Use in the United States Human Diploid Cell Vaccine HDCV is prepared from the Pitman-Moore strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration, and inactivated with betapropiolactone (22). HDCV is formulated for IM administration in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0 mL just before administration. One dose of reconstituted vaccine contains <150 µg neomycin sulfate, <100 mg albumin, and 20 µg of phenol red indicator. It contains no preservative or stabilizer. # Purified Chick Embryo Cell Vaccine PCECV became available in the United States in 1997. The vaccine is prepared from the fixed rabies virus strain Flury LEP grown in primary cultures of chicken fibroblasts (29). The virus is inactivated with betapropiolactone and further processed by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0 mL just before administration. One dose of reconsti- † For postexposure prophylaxis, the vaccine is administered on days 0, 3, 7, 14 and 28 in patients who have not been previously vaccinated and on days 0 and 3 in patients who have been previously vaccinated. For pre-exposure prophylaxis, the vaccine is administered on days 0, 7 and 21 or 28. § As much of the product as is anatomically feasible should be infiltrated into and around the wound. Any remaining product should be administered intramuscularly in the deltoid or quadriceps (at a location other than that used for vaccine inoculation to minimize potential interference). tuted vaccine contains <12 mg polygeline, <0.3 mg human serum albumin, 1 mg potassium glutamate, and 0.3 mg sodium EDTA. No preservatives are added. # Rabies Immune Globulins Licensed for Use in the United States The two HRIG products, HyperRab ™ S/D and Imogam ® Rabies-HT, are IgG preparations concentrated by cold ethanol fractionation from plasma of hyperimmunized human donors. The HyperRab ™ S/D is formulated through the treatment of the immune globulin fraction with 0.3% tri-n-butyl phosphate (a solvent to inactivate potential adventitious viruses) and 0.2% sodium cholate (a detergent to inactivate potential adventitious viruses) and the application of heat (30°C [86°F] for 6 hours). After ultrafiltration, the final product is a 15%-18% protein solution in glycine. The Imogam ® Rabies-HT is prepared from the cold ethanol fraction of pooled venous plasma of donors, stabilized with glycine, and subjected to a heat-treatment process (58°C-60°C [136°F-140°F] for 10 hours) to inactivate potential adventitious viruses, with the final formulation consisting of 10%-18% protein. Both HRIGs are standardized at an average potency value of 150 IU per mL, and supplied in 2-mL (300 IU) vials for pediatric use and 10-mL (1,500 IU) vials for adult use. The recommended dose is 20 IU/kg (0.133 mL/kg) body weight. Both HRIG preparations are considered equally efficacious when used as described in these recommendations. These products are made from the plasma of hyperimmunized human donors that, in theory, might contain infectious agents. Nevertheless, the risk that such products will transmit an infectious agent has been reduced substantially by screening plasma donors for previous exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. No transmission of adventitious agents has been documented after administration of HRIGs licensed in the United States. # Effectiveness and Immunogenicity of Rabies Biologics # Effectiveness of Rabies Postexposure Prophylaxis: Human Studies A literature search identified 11 studies regarding the direct effectiveness of varying regimens of rabies postexposure prophylaxis in preventing rabies-associated deaths (18,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). An additional eight studies were identified from reviews of bibliographies or consultations with subject matter experts (19,(40)(41)(42)(43)(44)(45)(46). Three large retrospective cohort studies were identified that describe differences in rabies mortality between rabies-exposed persons (persons who were exposed to proven or suspected rabid animals) who were vaccinated with older formulations of rabies vaccine compared with similarly exposed persons who were not administered prophylaxis (41,44,46). In one 1923 study of 2,174 persons bitten by "presumably rabid" dogs in India, 2.9% of persons vaccinated with 1% Semple nerve tissue rabies vaccine (NTV) subcutaneously for 14 days died from rabies compared with 6.2% of unvaccinated persons (41). Another study of persons bitten by assumed infective rabid animals (i.e., one or more other persons bitten by the same animal died from rabies) during 1946-1951 indicated that 8.3% of persons "completely treated" with 5% Semple rabies vaccine, 23.1% of "incompletely treated", and 43.2% of unvaccinated persons died from rabies (46). A third study in Thailand in 1987 documented no deaths among 723 persons bitten by dogs (661 of these persons were bitten by confirmed rabid dogs) who received one of three rabies vaccines: Semple vaccine (n = 427), HDCV (n = 257), or duck embryo vaccine (n = 39) (44). However, 45% (nine of 20) of unvaccinated persons who were bitten by confirmed rabid dogs died from rabies. All of the persons who died were severely bitten on the face, neck, or arms. All unvaccinated persons who survived after having been bitten by confirmed rabid dogs were bitten either on the legs or feet. Although these studies describe outcomes of persons receiving older formulations of rabies vaccines that are not used in the United States, they demonstrate that a majority of persons bitten by known rabid dogs did not acquire rabies and provide historical evidence of a substantial protective effect of rabies vaccination after rabies exposure. The effectiveness of cell culture rabies vaccine plus rabies IgG in preventing human deaths after rabies exposure has been demonstrated in certain studies (18,19,(30)(31)(32)39,45). One prospective study described 10 children (aged <12 years) and 32 adults who had been administered HRIG (Hyperrab ® , Cutter Laboratories, Berkeley, CA, USA) and 5 IM doses of HDCV (L'Institut Merieux, Lyons, France) after exposure to suspected or confirmed rabid animals (brain-tissue positive by fluorescent antibody testing) (30). All exposed persons remained rabies-free during 5 years of observation. Another study investigated outcomes for 90 persons with high-risk exposures (bites or direct exposure to saliva from animals shown to be rabid by fluorescent antibody tests or bites from wild carnivores or bats that were not available for testing) who were treated with HRIG and 5 IM doses of HDCV (Wyeth Laboratories, Radnor, PA) (18). All patients, including 21 who were bitten by proven rabid animals (brain tissue (39,45). Several studies also have demonstrated the effectiveness of intradermal (ID) administration of cell culture rabies vaccine with or without RIG (of human or equine origin) in preventing rabies among exposed humans (33)(34)(35)37). Two studies demonstrated the role of RIG administration in conjunction with vaccine in rabies postexposure prophylaxis (42,43). The first described quantitative serologic outcomes in 29 persons severely bitten by a rabid wolf and demonstrated the importance of rabies antiserum administration in the establishment of an early, passive, rabies virus neutralizing antibody level in patients and protection against rabies (40,43). Among five patients treated with 2 doses of rabies antiserum and NTV for 21 days, all had detectable levels of rabies virus neutralizing antibody during the first 5 days and all survived. Among seven patients treated with 1 dose of antiserum in addition to NTV, all had detectable antibody during the first 5 days, but four of six had low antibody titers by day 21. One of the seven failed to develop more than a very low antibody level beyond day 7 and eventually died from rabies. Among the five persons treated with NTV without antiserum, none had detectable antibody levels before day 19, and three died from rabies. In the second study, none of 27 persons severely wounded by rabid animals in China who were treated with purified hamster kidney cell (PHKC) rabies vaccine plus horse-origin rabies immune serum died from rabies (42). In contrast, all three severely wounded persons treated with PHKC alone died. # Effectiveness of Rabies Postexposure Prophylaxis: Animal Studies During the preceding four decades, results of experimental studies using various animal species have supported the use of cell culture-based vaccines for protection against rabies after infections. For example, a postexposure prophylaxis experiment conducted in 1971 in rhesus monkeys using an experimental purified, concentrated tissue-culture vaccine alone, or in combination with homologous antirabies serum, demonstrated that a single administration of tissue-culture vaccine after exposure to rabies virus provided substantial (seven of eight animals) protection against the development of rabies. In addition to demonstrating that homologous or heterologous antirabies serum alone resulted in poor protection from rabies (63%-88% mortality), the experimental data suggested that highly concentrated, purified tissue-culture vaccine might be effective for postexposure prophylaxis in humans (47). A study in 1981 documented limited protection against a lethal rabies virus challenge in goats who received ERA vaccine with or without antirabies goat serum (48). In cattle, another livestock species, the superiority of tissue culture vaccine over brain-origin vaccine was demonstrated (49). Similarly, in sheep, vaccine alone provided limited protection, but vaccine in combination with polyclonal IgG provided the best outcome (50). A 1989 evaluation of postexposure prophylaxis administered to dogs demonstrated similar findings. The combination of serum and vaccine provided nearly complete protection compared with animals receiving vaccine only and nontreated controls (51). Previous animal postexposure research focused primarily on interventions against traditional rabies viruses. However, new causative agents of rabies continue to emerge, as demonstrated by the recent description of four novel lyssaviruses from bats in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV) (52,53). The combined effect of RIG and vaccine after exposure to these four new isolates was investigated in a Syrian hamster model, using commercially available human products or an experimental mAb (54). Conventional rabies postexposure prophylaxis provided little or no protection against all four new bat viruses. In general, protection was inversely related to the genetic distance between the new isolates and traditional rabies viruses, which demonstrated the usefulness of this animal model in estimating the potential impact of these new lyssaviruses on human and domestic animal health. # Immunogenicity of Rabies Postexposure Prophylaxis To assess the ability of rabies postexposure prophylaxis to elicit rabies virus neutralizing antibodies in humans, studies were reviewed that documented antibody responses to rabies postexposure prophylaxis. Four studies of antibody responses to rabies postexposure prophylaxis with 5 IM doses of HDCV with or without HRIG were identified (30,(55)(56)(57). Because no studies were identified that examined antibody responses to postexposure or simulated postexposure prophylaxis with 5 IM doses of the licensed PCECV vaccine (RabAvert ® ) plus HRIG, a study reporting antibody responses to 6 IM doses of another PCECV formulation (Rabipur ® , Novartis Vaccines and Diagnostics) administered with or without HRIG was reviewed (36). In a randomized trial, all persons receiving HRIG and 5 IM doses of HDCV (Imovax ® Rabies) developed rabies virus antibody titers >0.5 IU/mL lasting up to 42 days after prophylaxis initiation (56). In a 1999 case-series, among 40 persons with diverse histories of exposure to animals suspected of having rabies, all persons who received 5 IM doses of HDCV with or without HRIG seroconverted or had increases in baseline serum antibody titers after the fifth vaccine dose (geometric mean titer [GMT] = 6.22 IU/mL) (57). Furthermore, a significantly higher mean antibody titer was observed in the group that received HDCV and HRIG (GMT = 12.3 IU/mL; standard error [SE] = 2.9) than in the group that received HDCV alone (GMT = 8.5 IU/mL; SE = 1.6; p=0.0043). In a randomized, modified double-blind, multicenter, simulated postexposure trial, 242 healthy adult volunteers were administered HRIG (Imogam ® Rabies-HT) and 5 IM doses of either HDCV (Imovax ® Rabies) or a chromatographically purified Vero-cell rabies vaccine (CPRV) (55). All participants had rabies virus neutralizing antibody titers >0.5 IU/mL by day 14 and maintained this level through day 42. Participants receiving HDCV had higher GMTs on days 14 and 42 than did participants receiving CPRV. In the prospective study comparing rabies neutralizing antibodies in the serum of children compared with adults following postexposure prophylaxis, all 25 adults and eight children tested on day 14 had rabies virus neutralizing antibody concentrations >0.5 IU/mL (30). In addition, no differences in antibody titer were observed between adults and children, and all persons remained alive during the 5 years of follow-up. # Effectiveness of Rabies Pre-Exposure Prophylaxis: Animal Studies Because no studies exist on the effectiveness of rabies preexposure prophylaxis in preventing rabies deaths in humans, literature was reviewed on the effectiveness of pre-exposure vaccination in animal models. The effectiveness of rabies vaccine has been appreciated for most of the 20 th century on the basis of animal experiments. Commercial rabies vaccines are licensed for certain domestic species, all of which entail the direct demonstration of efficacy after the administration of a single pre-exposure dose, and observed protection from rabies virus challenge for a minimum duration of 1-4 years after vaccination of captive animals. In addition, rabies preexposure vaccine research varies typically either by modification of standard regimens of vaccination or the relative antigenic value or potency of vaccine administration to ani-mals. For example, at least five studies involved animals challenged with rabies viruses (challenge standard virus [CVS] or street rabies virus isolates) and other lyssaviruses (European bat lyssavirus [EBL] 1, EBL2, Australian bat lyssavirus [ABL], and WCBV, IRKV, ARAV, KHUV) after primary vaccination with PCECV (58) or HDCV (54,(58)(59)(60)(61)(62). Two of seven studies reported seroconversion in mice and humans. Complete protection of animals from rabies virus infection was observed in all experiments that used PCECV or HDCV IM for primary vaccination except in one group that had been challenged by CVS through the intracranial route and experienced 5% mortality (59). Evaluation of crossprotection of HDCV against WCBV, ARAV, IRKV, KHUV, and ABL through IM challenge showed 44%, 55%, 67%, 89% and 79% survival, respectively (54). These studies demonstrated the usefulness of commercial human vaccines when administered to animals, with resulting protection dependent on the relative degree of phylogenetic relatedness between the rabies vaccine strain and the particular lyssavirus isolate. # Immunogenicity of Rabies Pre-Exposure Prophylaxis: Human Studies Thirteen studies were identified that provide evidence of the effectiveness of pre-exposure rabies vaccination in eliciting an adaptive host immune response in humans. The outcomes of interest for these studies (29,(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74) include the two working definitions of adequate rabies virus neutralizing antibody reference values that have been developed to define an appropriate, intact adaptive host response to vaccination: antibody titers of 0.5 IU/mL or complete virus neutralization at a 1:5 serum dilution by RFFIT (26). Multiple studies comparing different pre-exposure prophylaxis regimens provide evidence that vaccination with 3 IM doses of cell culture rabies vaccine (the recommended preexposure regimen) result in neutralizing antibody titers >0.5 IU/mL by days 14 (70,71), 21 (63,74), 28 (64,69,72), or 49 (67,68,75) after primary vaccination. One study in 1987 documented antibody responses in 177 healthy student volunteers aged 18-24 years following primary vaccination with either PCECV (Behringwerke) or HDCV (Behringwerke) (71). On day 14 after vaccination (first dose administered on day 0), no significant difference in GMT was observed between participants who received 3 IM doses of PCECV on days 0, 7, and 21 (GMT = 5.9 IU/mL) compared with persons who received 3 IM doses of HDCV (GMT = 4.4 IU/mL). On day 42, the GMT of the HDCV group was significantly higher than that of the PCECV group (13.7 IU/mL versus 8.4 IU/mL; p<0.025). Another study documented similar antibody responses to primary vaccination with HDCV in healthy veterinary students (64). The GMT of persons receiving 3 IM doses of HDCV on days 0, 7, and 28 was 10.2 IU/mL (range: 0.7-51.4) on day 28 and 37.7 IU/mL (range: 5.4-278.0) on day 42. Another study documented even higher GMTs among 78 volunteers in a randomized trial studying differences between primary vaccination with PCECV (Behringwerke) and HDCV (L'Institut Merieux) administered IM or ID on days 0, 7, and 28 (29). The day 28 GMT among persons receiving HDCV IM (GMT = 239 RFFIT titer/mL; range: 56-800) was significantly higher than the GMT among persons receiving PCECV IM (GMT = 138 RFFIT titer/mL; range: 45-280). On days 50 and 92, no significant difference in GMT was observed between the two groups in which vaccine was administered IM, and the GMTs of the IM groups were significantly higher than the ID groups. Another study also observed higher antibody titers on days 49 and 90 and 26 months after primary vaccination with HDCV (Imovax ® Rabies) when the vaccine was administered IM compared with ID on days 0, 7, and 28 (68). A randomized trial was conducted to determine the equivalence and interchangeability of PCECV (RabAvert ® ) and HDCV (Imovax ® Rabies) administered IM on days 0, 7, and 28 for rabies pre-exposure prophylaxis to 165 healthy, rabies vaccine naïve veterinary students (66). No significant difference in GMT was observed among the HDCV and PCECV groups on days 28 and 42. Although the 3-dose rabies pre-exposure prophylaxis series has been the standard regimen recommended by WHO (17) and ACIP (26), a 2-dose pre-exposure series has been used previously in some countries (76). One study compared antibody responses in persons receiving 2 (days 0 and 28) versus 3 (days 0, 7, and 28) IM doses of either HDCV (Pasteur Merieux Connaught, Lyon, France) or purified Vero cell rabies vaccine (PVRV) (Pasteur Merieux Connaught) and indicated that the cohort seroconversion rate decreased more rapidly among persons receiving 2 doses compared with those receiving 3 doses (p<0.001), indicating superior longer term immunogenicity when 3 vaccine doses were administered (73). In addition to the rapidity of the immune response resulting from rabies pre-exposure vaccination, another important consideration is the length of duration or persistence of the immune response. One study reported rapid declines in GMT at 4 months after initial vaccination among persons receiving 3-dose primary vaccination with HDCV (L'Institut Merieux) or PVRV (L'Institut Merieux) on days 0, 7, and 21 followed by stabilization of the antibody level through 21 months (63). Another study observed persistent GMTs among persons receiving 3-dose (days 0, 7, and 28) primary vaccination with PCECV (Behringwerke) and HDCV (L'Institut Merieux) IM on day 365 (PCECV GMT = 189 RFFIT titer/mL; range: 53-1400; HDCV GMT = 101 RFFIT titer/mL; range: 11-1400) and day 756 (PCECV GMT = 168 RFFIT titer/ mL; range: 50-3600; HDCV GMT = 92 RFFIT titer/mL; range: 11-480) after initial vaccination (29). On day 387 post vaccination, another study indicated that the GMT among persons receiving PCECV (RabAvert ® ) IM on days 0, 7, and 28 (GMT = 2.9 IU/mL) was significantly higher than the GMT in the HDCV (Imovax ® Rabies) group (GMT = 1.5 IU/mL; p<0.05) (66). All persons vaccinated with PCECV had antibody titers >0.5 IU/mL on days 387, as did 95.7% of persons vaccinated with HDCV. Another study indicated that all persons receiving PCECV (Behringwerke) IM on days 0, 7, and 21 maintained antibody titers >0.5 IU/mL 2 years after primary vaccination (71). In summary, rabies virus neutralizing antibody titers >0.5 IU/mL were observed in all persons at 180 days and 96.8% at 365 days after initial vaccination (72), 94% of persons at 21 months after initial vaccination ( 63), and all persons tested at 26 months after primary vaccination (77). An important use of rabies pre-exposure prophylaxis is to prime the immune response to enable a rapid anamnestic response to postexposure booster vaccination and simplify the postexposure prophylaxis requirements for previously vaccinated persons. One study observed antibody responses to 1or 2-dose (days 0 and 3) IM booster vaccinations with PCECV (RabAvert ® ) in persons who had received primary vaccination with either PCECV IM or HDCV IM 1 year earlier (66). All participants who had initially received PCECV primary vaccination and 66 of 69 (96%) who had initially received HDCV primary vaccination had titers >0.5 IU/mL before booster vaccination. No significant differences in GMT were observed between 1-and 2-dose booster groups on days 3 (2-dose GMT = 2.07 IU/mL; 1-dose GMT = 2.87 IU/ mL), seven (2-dose GMT = 51.67 IU/mL; 1-dose GMT = 51.23 IU/mL) and 365 (2-dose GMT = 30.60 IU/mL; 1-dose GMT = 26.10 IU/mL) (66). However, a significantly higher GMT was observed on day 21 for persons receiving 2-dose boosters (GMT = 151.63 IU/mL) compared with 1-dose boosters (GMT = 120.91 IU/mL). All persons tested at day 365 post-booster dose in both 1-and 2-dose booster groups had rabies virus neutralizing antibody titers >0.5 IU/mL regardless of whether PCECV or HDCV was used for primary vaccination. Another study documented rapid antibody responses to a single booster dose of HDCV (Imovax ® Rabies) or CPRV (Pasteur Merieux Connaught), with all persons in both groups exhibiting antibody titers >0.5 IU/mL on days 7 and 14 post-booster dose (72). # Safety of Rabies Biologics Eight studies regarding the safety of rabies biologics used in postexposure or simulated postexposure settings (36,(55)(56)(57)(78)(79)(80)(81) and eight studies of safety in pre-exposure settings were identified (63)(64)(65)68,71,72,82). Three identified studies investigated reports of adverse events in both postexposure and pre-exposure settings (14,83,84). Reviews of relevant bibliographies identified one additional study examining the safety of PCECV when used without HRIG for postexposure prophylaxis in children (85). # HDCV Studies of the use of HDCV reported local reactions (e.g., pain at the injection site, redness, swelling, and induration) among 60.0%-89.5% of recipients (63)(64)(65)68,72). Local reactions were more common than systemic reactions. Most local reactions were mild and resolved spontaneously within a few days. Local pain at the injection site was the most frequently reported adverse reaction occurring in 21%-77% of vaccinees (24,63,68,71,72,80). Mild systemic reactions (e.g., fever, headache, dizziness, and gastrointestinal symptoms) were reported in 6.8%-55.6% of recipients (63,64,68,72). Systemic hypersensitivity reactions have been reported in up to 6% of persons receiving booster vaccination with HDCV following primary rabies prophylaxis, 3% occurring within 1 day of receiving boosters, and 3% occurring 6-14 days after boosters (82). In one study, hypersensitivity reactions (e.g., urticaria, pruritic rash, and angioedema) were reported in 5.6% (11 of 99) of schoolchildren aged 5-13 years following pre-exposure prophylaxis with IM HDCV (72). Angioedema was observed in 1.2% of these school children after booster doses of HDCV 1 year after primary vaccination with HDCV. In 46 months of surveillance for adverse events following HDCV administration during 1980-1984, CDC received reports of 108 systemic allergic reactions (ranging from hives to anaphylaxis) following HDCV (11 per 10,000 vaccinees) (14). These included nine cases of presumed Type I immediate hypersensitivity (one of 10,000), 87 cases of presumed Type III hypersensitivity (nine of 10,000), and 12 cases of hypersensitivity of indeterminate type. All nine of the presumed immediate hypersensitivity reactions occurred during either primary pre-exposure or postexposure vaccination. Most (93%) of the Type III hypersensitivity reactions were observed following booster vaccination. Systemic allergic reactions have been associated with the presence of betapropiolactone-altered human albumin in HDCV and the development of immunoglobulin E (IgE) antibodies to this allergen (82,86). No deaths resulting from these reactions were reported. In four studies investigating the safety of rabies postexposure prophylaxis with both HRIG and HDCV, no serious adverse events were observed (55)(56)(57)78). Local reactions were common, and pain at the injection site was reported by 7%-92% of participants (55)(56)(57). Studies of the frequency of systemic adverse reactions following rabies vaccination are limited by small sample sizes. Systemic adverse reactions were not observed in any of the participants in one study with a relatively small sample size (78). In two other studies in which adverse events were collected using patient self-monitoring forms and investigator interviews at each visit, systemic reactions were reported by 76%-100% of participants (55,56). However, none of these reported systemic adverse events was considered to be serious. Rare, individual case reports of neurologic adverse events following rabies vaccination have been reported, but in none of the cases has causality been established. Four cases of neurologic illness resembling Guillain-Barré syndrome occurring after treatment with HDCV were identified (13,(87)(88)(89). One case of acute neurologic syndrome involving seizure activity was reported following the administration of HDCV and HRIG (90). Other central and peripheral nervous system disorders have been temporally associated with HDCV vaccine (91). # PCECV In studies of PCECV use, local reactions (e.g., pain at the injection site, redness, swelling, and induration) were reported among 11%-57% of recipients (29,79,84). Local pain at the injection site, the most common local reaction, was reported in 2%-23% of vaccinees (29,71,79,81,83,85). Systemic reactions were less common and have been reported in 0-31% of vaccine recipients (79,83,84). One study investigated adverse events among 271 children in India who received rabies postexposure prophylaxis with PCECV IM without HRIG following bites from suspected or confirmed rabid dogs (85). Overall, 7% of the children experienced mild to moderate clinical reactions. The most frequently reported reaction was local pain after the first or second dose (4%). Another study documented clinical reactions in 29 persons administered 6 IM doses of PCECV with (n = four) or without HRIG following bites by suspected rabid stray dogs. No serious adverse events were observed during the course of or after prophylaxis (36). Another case report documented one case of neurologic illness resembling Guillain-Barré syndrome after vaccination with PCECV in India (92). A retrospective review of adverse events following administration of PCECV was conducted using data from the United # HRIG In a clinical trial involving 16 volunteers in each group, participants receiving HRIG plus placebo (administered to mimic vaccine) commonly reported local reactions (100% in conventionally produced HRIG group, 75% in heat-treated HRIG group), including pain/tenderness (100% conventional HRIG, 50% heat-treated HRIG), erythema (63% conventional, 25% heat-treated), and induration (50% conventional, 31% heat-treated) (56). Systemic reactions were reported in 75% of participants in the conventional HRIG group and 81% in the heat-treated group. Headache was the most commonly reported systemic reaction (50% conventional, 69% heat-treated). The majority of the reported local and systemic reactions were mild, and no significant differences were observed in the frequency of adverse events between treatment groups. No serious adverse events, including immediate hypersensitivity reactions or immune-complex-like disease, were reported. # Cost-Effectiveness of Rabies Postexposure Prophylaxis ACIP's charter requires the committee, when deliberating recommendations for vaccine use in the United States, to consider the cost and benefits of potential recommendations. Cost-effectiveness studies combine different types of data (e.g., epidemiologic, clinical, cost, and vaccine effectiveness), and the results from such studies allow public health officials, medical practitioners, and the public to make more informed decisions when evaluating the risk for disease against the cost of the vaccine, including vaccine-related side effects. CDC analyzed the cost-effectiveness of rabies postexposure prophylaxis for each of eight contact (risk of transmission) scenarios, with the outcome being the net cost (in dollars) per life saved (in 2004 dollars). The perspective was societal, which means that all costs and all benefits were included, regardless of who pays and who benefits. For each risk-oftransmission scenario, three cost-effectiveness ratios were calculated: average, most, and least cost-effective. Average cost-effective ratios were calculated using median transmission risk values (Table 2) and average cost of postexposure prophylaxis. Most cost-effective ratios were calculated using greatest (largest) transmission risk values and least cost of postexposure prophylaxis. Least cost-effective ratios were calculated using lowest transmission risk and greatest cost of postexposure prophylaxis. The analysis assumed that the direct medical costs associated with postexposure prophylaxis included 1 dose of HRIG ($326-$1,434), 5 doses of HDCV ($113-$679 each), hospital charges ($289-$624), and physician charges ($295-$641) (95). Indirect costs included travel, lost wages, alternative medicine, and other costs ($161-$2,161) (96). A societal perspective requires the valuation of the loss of productivity to society caused by premature death. Therefore, human life lost was valued using the average present value, in 2004 dollars, of expected future lifetime earnings and housekeeping services ($1,109,920) (97). All costs were adjusted to 2004 dollars using the medical care price index. The study also assumed that rabies postexposure prophylaxis, when administered according to these recommendations, was essentially 100% effective in preventing a clinical case of human rabies. The probabilities of rabies transmission to a human following possible contact with different species of potentially rabid animals was assessed by a panel of experts using the Delphi methodology, except for "animal tests positive for rabies" when probabilities were obtained from a previous study (98) (Table 2). Under all three cost-effectiveness scenarios, the analysis determined that it is always cost saving to administer postexposure prophylaxis if a patient is bitten by a rabid animal that has tested positive for rabies or if a patient is bitten by a reservoir or vector species (e.g. skunk, raccoon, bat, or fox bite in the United States or dog bite in countries with dog variant rabies), even if the animal is not available for testing. For all other transmission risk situations, the average net cost effectiveness ratio was always a net cost per life saved (range: $2.9 million per life saved following a bite from an untested cat to $4 billion per life saved following a lick from an untested dog). The wide range of probabilities of risk for trans-mission for the bat bite scenario resulted in the widest range of cost-effectiveness ratios (Table 2). Until more precise estimates of risk for transmission are obtained, these estimates illustrate the difficulty clinicians and public health officials will continue to encounter in unequivocally determining the cost-effectiveness of providing PEP. # Rabies Postexposure Prophylaxis # Rationale for Prophylaxis ACIP (26) and WHO (25) recommend that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive vaccination with HRIG and vaccination with cell culture rabies vaccines. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency. Because rabies biologics are valuable resources that are periodically in short supply, a risk assessment weighing potential adverse consequences associated with administering postexposure prophylaxis along with their severity and likelihood versus the actual risk for the person acquiring rabies should be conducted in each situation involving a possible rabies exposure. Because the balance of benefit and harm will differ among exposed persons on the basis of the risk for infection, recommendations regarding rabies postexposure prophylaxis are dependent upon associated risks including 1) type of exposure, 2) epidemiology of animal rabies in the area where the contact occurred and species of animal involved, and 3) circumstances of the exposure incident. The reliability of this information should be assessed for each incident. The decision of whether to initiate rabies postexposure prophylaxis also depends on the availability of the exposing animal for observation or rabies testing (Table 3). Because the epidemiology and pathogenesis of rabies are complex, these recommendations cannot be specific for every possible circumstance. Clinicians should seek assistance from local or state public health officials for evaluating exposures or determining the need for postexposure management in situations that are not routine. State and local officials have access to CDC rabies experts for particularly rare situations or difficult decisions. ($162 million-$8.4 billion) * Contact with a potentially rabid animal does not necessarily constitute an exposure. A bite exposure is defined as "any penetration of the skin by teeth." A nonbite exposure is defined as "contamination of open wounds, abrasions (including scratches) or mucous membranes with saliva or other potentially infectious material (e.g., neural tissue)." † Probabilities of rabies transmission to a human were obtained from a panel of experts, except for "animal tests positive for rabies" when probabilities obtained from a previous study. § Estimates of the direct medical costs of rabies postexposure prophylaxis (PEP) were converted into 2004 dollars using the medical care price index. The cost-effectiveness of PEP under each contact scenario is calculated using the median probability of becoming clinically ill with rabies and the average cost of PEP. The most cost-effective ratio is calculated using the minimum cost of PEP and the maximum probability of becoming clinically ill with rabies. The least cost-effective ratio is calculated using the maximum cost of PEP and the minimum probability of becoming clinically ill with rabies. ¶ Animals not available for testing. The skunk bite data are considered applicable to bites from other rabies reservoir species (e.g., bats, raccoons, and foxes in the United States and dog bites occurring in countries with dog variant rabies). ** No recognized bite or saliva exposure. # MMWR May 23, # Types of Exposure When an exposure has occurred, the likelihood of rabies infection varies with the nature and extent of that exposure. Under most circumstances, two categories of exposure (bite and nonbite) should be considered. The most dangerous and common route of rabies exposure is from the bite of a rabid mammal. An exposure to rabies also might occur when the virus, from saliva or other potentially infectious material (e.g., neural tissue), is introduced into fresh, open cuts in skin or onto mucous membranes (nonbite exposure). Indirect contact and activities (e.g., petting or handling an animal, contact with blood, urine or feces, and contact of saliva with intact skin) do not constitute exposures; therefore, postexposure prophylaxis should not be administered in these situations. Exposures to bats deserve special assessment because bats can pose a greater risk for infecting humans under certain circumstances that might be considered inconsequential from a human perspective (i.e., a minor bite or lesion). Human-to-human transmission occurs almost exclusively as a result of organ or tissue transplantation. Clinicians should contact local or state public health officials for assistance in determining the likelihood of a rabies exposure in a specific situation. Bite exposures. Any penetration of the skin by teeth constitutes a bite exposure. All bites, regardless of body site or evidence of gross trauma, represent a potential risk. The risk for transmission varies in part with the species of biting animal, the anatomic site of the bite, and the severity of the wound (98). Although risk for transmission might increase with wound severity, rabies transmission also occurs from bites by some animals (e.g., bats) that inflict rather minor injury compared with larger-bodied carnivores, resulting in lesions that are difficult to detect under certain circumstances (8,(99)(100)(101)(102)(103). Nonbite exposures. Nonbite exposures from animals very rarely cause rabies. However, occasional reports of nonbite transmission suggest that such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis (104). The nonbite exposures of highest risk appear to be among surgical recipients of corneas, solid organs, and vascular tissue transplanted from patients who died of rabies and persons exposed to large amounts of aerosolized rabies virus. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies have been attributed to possible airborne exposures in caves containing millions of free-tailed bats (Tadarida brasiliensis) in the Southwest. However, alternative infection routes can not be discounted (105)(106)(107)(108)(109). Similar airborne incidents have not occurred in approximately 25 years, probably because of elevated awareness of such risks resulting in increased use of appropriate preventive measures. The contamination of open wounds or abrasions (including scratches) or mucous membranes with saliva or other potentially infectious material (e.g., neural tissue) from a rabid animal also constitutes a nonbite exposure. Rabies virus is inactivated by desiccation, ultraviolet irradiation, and other factors and does not persist in the environment. In general, if the suspect material is dry, the virus can be considered noninfectious. Nonbite exposures other than organ or tissue trans- Livestock, small rodents (rabbits and Consider individually Consult public health officials. Bites from hares), large rodents (woodchucks squirrels, hamsters, guinea pigs, gerbils, and beavers), and other mammals chipmunks, rats, mice, other small rodents, rabbits, and hares almost never require antirabies postexposure prophylaxis. * During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. † Postexposure prophylaxis should be initiated as soon as possible following exposure to such wildlife unless the animal is available for testing and public health authorities are facilitating expeditious laboratory testing or it is already known that brain material from the animal has tested negative. Other factors that might influence the urgency of decision-making regarding initiation of postexposure prophylaxis before diagnostic results are known include the species of the animal, the general appearance and behavior of the animal, whether the encounter was provoked by the presence of a human, and the severity and location of bites. Discontinue vaccine if appropriate laboratory diagnostic test (i.e., the direct fluorescent antibody test) is negative. § The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. plants have almost never been proven to cause rabies, and postexposure prophylaxis is not indicated unless the nonbite exposure met the definition of saliva or other potentially infectious material being introduced into fresh, open cuts in skin or onto mucous membranes. Bat Exposures. The most common rabies virus variants responsible for human rabies in the United States are batrelated; therefore, any potential exposure to a bat requires a thorough evaluation. If possible, bats involved in potential human exposures should be safely collected and submitted for rabies diagnosis. Most submitted bats (approximately 94%) (110) will not be rabid and such timely diagnostic assessments rule out the need for large investments in risk assessments and unnecessary prophylaxis. The risk for rabies resulting from an encounter with a bat might be difficult to determine because of the limited injury inflicted by a bat bite (compared with more obvious wounds caused by the bite of terrestrial carnivores), an inaccurate recall of a bat encounter that might have occurred several weeks or months earlier, and evidence that some bat-related rabies viruses might be more likely to result in infection after inoculation into superficial epidermal layers (111). For these reasons, any direct contact between a human and a bat should be evaluated for an exposure. If the person can be reasonably certain a bite, scratch, or mucous membrane exposure did not occur, or if the bat is available for testing and is negative for presence of rabies virus, postexposure prophylaxis is not necessary. Other situations that might qualify as exposures include finding a bat in the same room as a person who might be unaware that a bite or direct contact had occurred (e.g., a deeply sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person). These situations should not be considered exposures if rabies is ruled out by diagnostic testing of the bat, or circumstances suggest it is unlikely that an exposure took place. Other household members who did not have direct contact with the bat or were awake and aware when in the same room as the bat should not be considered as having been exposed to rabies. Circumstances that make it less likely that an undetected exposure occurred include the observation of bats roosting or flying in a room open to the outdoors, the observation of bats outdoors or in a setting where bats might normally be present, or situations in which the use of protective covers (e.g., mosquito netting) would reasonably be expected to preclude unnoticed contact. Because of the complexity of some of these situations, consultation with state and local health departments should always be sought. If necessary, further guidance can be sought from CDC and experts in bat ecology. During 1990-2007, a total of 34 naturally acquired batassociated human cases of rabies was reported in the United States. In six cases, a bite was reported; in two cases, contact with a bat and a probable bite were reported; in 15 cases, physical contact was reported (e.g., the removal of a bat from the home or workplace or the presence of a bat in the room where the person had been sleeping), but no bite was documented; and in 11 cases, no bat encounter was reported. In these cases, an unreported or undetected bat bite remains the most plausible hypothesis because the genetic sequences of the human rabies viruses closely matched those of specific species of bats. Clustering of human cases associated with bat exposures has never been reported in the United States (e.g., within the same household or among a group of campers where bats were observed during their activities) (8,101,110). Human-to-Human Exposures. Human-to-human transmission can occur in the same way as animal-to-human transmission (i.e., the virus is introduced into fresh open cuts in skin or onto mucous membranes from saliva or other potentially infectious material such as neural tissue). Organ and tissue transplantation resulting in rabies transmission has occurred among 16 transplant recipients from corneas (n = eight), solid organs (n = seven), and vascular tissue (n = one). Each of the donors died of an illness compatible with or proven to be rabies (10,(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123). The 16 cases occurred in five countries: the United States (five cases: one corneal transplant transmission, three solid organ transmissions, and one vascular graft transmission), Germany (four cases), Thailand (two cases), India (two cases), Iran (two cases), and France (one case). No documented laboratory-diagnosed cases of human-tohuman rabies transmission have been documented from a bite or nonbite exposure other than the transplant cases (124). At least two cases of human-to-human rabies transmission in Ethiopia have been suggested, but rabies as the cause of death was not confirmed by laboratory testing (125). The reported route of exposure in both cases was direct salivary contact from another human (i.e., a bite and a kiss). Routine delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless the health-care worker is reasonably certain that he or she was bitten by the patient or that his or her mucous membranes or nonintact skin was exposed directly to potentially infectious saliva or neural tissue. Adherence to standard precautions for all hospitalized patients as outlined by the Hospital Infection Control Practices Advisory Committee will minimize the need for postexposure prophylaxis in such situations (126). Staff should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning (25). # MMWR May 23, # Animal Rabies Epidemiology Bats. Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important wildlife reservoirs for variants of rabies virus transmitted to humans (5,101,102,110). Transmission of rabies virus can occur from minor, seemingly underappreciated or unrecognized bites from bats (8,(99)(100)(101)(102)(103). Laboratory data support a hypothesis that bat rabies virus variants associated with silver-haired bats (Lasionycteris noctivagans) and eastern pipistrelles (Pipistrellus subflavus) have biologic characteristics that might allow a higher likelihood of infection after superficial inoculation, such as into cells of epidermal origin (127). Human and domestic animal contact with bats should be minimized, and bats should never be handled by untrained and unvaccinated persons or be kept as pets (128). Wild Terrestrial Carnivores. Raccoons, skunks, and foxes are the terrestrial carnivores most often infected with rabies in the United States (5). Suggestive clinical signs of rabies among wildlife cannot be interpreted reliably. All bites by such wildlife should be considered possible exposures to rabies virus. Postexposure prophylaxis should be initiated as soon as possible following exposure to such wildlife, unless the animal is available for diagnosis and public health authorities are facilitating expeditious laboratory testing, or if the brain tissue from the animal has already tested negative. Wild terrestrial carnivores that are available for diagnostic testing should be euthanized as soon as possible (without unnecessary damage to the head), and the brain should be submitted for rabies diagnosis (129,130). If the results of testing are negative by immunofluorescence, human rabies postexposure prophylaxis is not necessary. Other factors that might influence the urgency of decision-making regarding the initiation of postexposure prophylaxis before diagnostic results are known include the species of the animal, the general appearance and behavior of the animal, whether the encounter was provoked by the presence of a human, and the severity and location of bites. Other Wild Animals. Rodents are not reservoirs of rabies virus. Small rodents (e.g., squirrels, chipmunks, rats, mice, hamsters, guinea pigs, and gerbils) and lagomorphs (including rabbits and hares) are rarely infected with rabies and have not been known to transmit rabies to humans (131,132). During 1990-1996, in areas of the country where raccoon rabies was enzootic, woodchucks accounted for 93% of the 371 cases of rabies among rodents reported to CDC (5,133,134). In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate postexposure prophylaxis (135). The offspring of wild animals crossbred to domestic dogs and cats (wild animal hybrids) are considered wild animals by the National Association of State and Public Health Veterinarians and CSTE. Because the period of rabies virus shedding in wild animal hybrids is unknown, when such animals bite humans euthanasia and rabies testing of the hybrid animal is the safest course of action. Vaccination should be discontinued if diagnostic tests of the involved animal are negative for rabies infection. However, because wolves and dogs have very similar genetic makeup and many animals that are advertised as "wolf-dogs" might actually be dogs, each wolf hybrid bite situation should be evaluated individually, taking into account the likelihood that it is a hybrid, the severity of the wound, and the assessment by the bite victim and his or her health-care provider. State or local health departments should be consulted before a decision is made to euthanize and test an animal. Wild animals and wild animal hybrids should not be kept as pets (128) or be publicly accessible. Humans who work with wild animals maintained in United States Department of Agriculture-licensed research facilities or accredited zoological parks should be educated on preventing bites and should receive rabies pre-exposure vaccinations. Rabies exposures of these animal handlers might require booster postexposure vaccinations in lieu of euthanasia and testing of the animal depending on employment requirements. Domestic Dogs, Cats, and Ferrets. The likelihood of rabies in a domestic animal varies regionally, and the need for postexposure prophylaxis also varies on the basis of regional epidemiology. The number of reported cases of rabies in domestic dogs has decreased substantially in the United States, primarily because of improved canine vaccination and stray animal control programs (5). In the continental United States, rabies among dogs has been reported sporadically along the United States-Mexico border and in areas of the United States with enzootic wildlife rabies (5). During 2000-2006, more cats than dogs were reported rabid in the United States (6). The majority of these cases were associated with the epizootic of rabies among raccoons in the eastern United States. The large number of rabid cats compared with other domestic animals might be attributed to a lower vaccination rate among cats because of less stringent cat vaccination laws; fewer confinement or leash laws; and the nocturnal activity patterns of cats placing them at greater risk for exposure to infected raccoons, skunks, foxes, and bats. In certain developing countries, dogs remain the major reservoir and vector of rabies and represent an increased risk for rabies exposure in such countries (136). A healthy domestic dog, cat, or ferret that bites a person should be confined and observed for 10 days (128,137,138). Those that remain alive and healthy 10 days after a bite would not have been shedding rabies virus in their saliva and would not have been infectious at the time of the bite (25). All domestic dogs, cats, and ferrets kept as pets should be vaccinated against rabies. Even if they are not, such animals might still be confined and observed for 10 days after a bite to reliably determine the risk for rabies exposure for the person who was bitten. Any illness in the animal during the confinement period before release should be evaluated by a veterinarian and reported immediately to the local public health department. If signs suggestive of rabies develop, postexposure prophylaxis of the bite victim should be initiated. The animal should be euthanized and its head removed and shipped, under refrigeration, for examination by a qualified laboratory. If the biting animal is stray or unwanted, it should either be confined and observed for 10 days or euthanized immediately and submitted for rabies diagnosis (128). Other Domestic Animals. In all instances of exposure to other domestic animal species, local or state health department should be consulted before a decision is made to euthanize and test the animal or initiate postexposure prophylaxis (128). # Circumstances of Biting Incident and Vaccination Status of Exposing Animal An unprovoked attack by an animal might be more likely than a provoked attack to indicate that the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked. Other factors to consider when evaluating a potential rabies exposure include the epidemiology of rabies in the area, the biting animal's history and health status (e.g., abnormal behavior and signs of illness), and the potential for the animal to be exposed to rabies (e.g., presence of an unexplained wound or history of exposure to a rabid animal). A dog, cat, or ferret with a history of continuously current vaccination (i.e., no substantial gaps in vaccination coverage) is unlikely to become infected with rabies (128,137,(139)(140)(141). Even after an initial rabies vaccination, young or naïve animals remain at risk for rabies because of the potential exposures preceding vaccination or before adequate induction of immunity during the 28 days after primary vaccination (128). # Treatment of Wounds and Vaccination The essential components of rabies postexposure prophylaxis are wound treatment and, for previously unvaccinated persons, the administration of both HRIG and vaccine (Table 4) (142). Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Incubation periods of more than 1 year have been reported in humans (143). Therefore, when a documented or likely exposure has occurred, postexposure prophylaxis should be administered regardless should be infiltrated around the wound(s) and any remaining volume should be administered intramuscularly (IM) at an anatomical site distant from vaccine administration. Also, RIG should not be administered in the same syringe as vaccine. Because RIG might partially suppress active production of antibody, no more than the recommended dose should be given. # Vaccine Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid area § ), one each on days 0 ¶ , 3, 7, 14, and 28. # Previously vaccinated † Wound cleansing All postexposure prophylaxis should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidine-iodine solution should be used to irrigate the wounds. RIG RIG should not be administered. Vaccine HDCV or PCECV 1.0 mL, IM (deltoid area § ), one each on days 0 ¶ and 3. * These regimens are applicable for all age groups, including children. † Any person with a history of a complete pre-exposure or postexposure vaccination regimen with HDCV, PCECV, or rabies vaccine adsorbed, or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination. § The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh can be used. Vaccine should never be administered in the gluteal area. ¶ Day 0 is the day the first dose of vaccine is administered. of the length of the delay, provided that compatible clinical signs of rabies are not present in the exposed person. The administration of postexposure prophylaxis to a clinically rabid human patient has demonstrated consistent ineffectiveness (25). In 1977, WHO recommended a regimen of RIG and 6 doses of HDCV over a 90-day period. This recommendation was based on studies in Germany and Iran (19,21). When used in this manner, the vaccine was safe and effective in persons bitten by animals proven to be rabid and induced an adequate antibody response in all recipients (19). Studies conducted in the United States by CDC have documented that a regimen of 1 dose of HRIG and 5 doses of HDCV over a 28-day period was safe and induced an adequate antibody response in all recipients (18). Clinical trials with PCECV have demonstrated immunogenicity equivalent to that of HDCV (144). Cell culture vaccines have been used effectively with HRIG or RIG of equine origin (ERIG) worldwide to prevent rabies in persons bitten by various rabid animals (18,19). Worldwide, WHO estimates that postexposure prophylaxis is initiated on 10-12 million persons annually (144). An estimated 16,000-39,000 persons in the United States receive a full postexposure course each year (11). Although postexposure prophylaxis has not always been properly administered in the United States, no failures have been documented since current biologics have been licensed. # Treatment of Wounds Regardless of the risk for rabies, the optimal medical treatment of animal bite wounds includes the recognition and treatment of serious injury (e.g., nerve or tendon laceration), avoidance or management of infection (both local and systemic), and approaches that will yield the best possible cosmetic results (145). For many types of bite wounds, immediate gentle irrigation with water or a dilute water povidone-iodine solution markedly decrease the risk for bacterial infection (146). Care should be taken not to damage skin or tissues. Wound cleansing is especially important in rabies prevention because thorough wound cleansing alone without other postexposure prophylaxis markedly reduce the likelihood of rabies in animal studies (147,148). Consideration should be given to the need for a booster dose of tetanus vaccine (149,150). Decisions regarding the use of antibiotic prophylaxis (151) and primary wound closure (152) should be individualized on the basis of the exposing animal species, size and location of the wound(s), and time interval since the bite. Suturing should be avoided, when possible. # Vaccination Postexposure antirabies vaccination should always include administration of both passive antibody and vaccine, with the exception of persons who have ever previously received complete vaccination regimens (pre-exposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have previously had a documented rabies virus neutralizing antibody titer. These persons should receive only vaccine (i.e., postexposure for a person previously vaccinated). The combination of HRIG and vaccine is recommended for both bite and nonbite exposures reported by persons who have never been previously vaccinated for rabies, regardless of the interval between exposure and initiation of prophylaxis. If postexposure prophylaxis has been initiated and appropriate laboratory diagnostic testing (i.e., the direct fluorescent antibody test) indicates that the exposing animal was not rabid, postexposure prophylaxis can be discontinued. Rabies IgG Use. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virusneutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies. If HRIG was not administered when vaccination was begun (i.e., day 0), it can be administered up to and including day 7 of the postexposure prophylaxis series (153). Beyond the seventh day, HRIG is not indicated because an antibody response to cell culture vaccine is presumed to have occurred. Because HRIG can partially suppress active production of antibody, the dose administered should not exceed the recommended dose (154). The recommended dose of HRIG is 20 IU/kg (0.133 mL/kg) body weight. This formula is applicable to all age groups, including children. If anatomically feasible, the full dose of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume should be injected IM at a site distant from vaccine administration. This recommendation for HRIG administration is based on reports of rare failures of postexposure prophylaxis when less than the full amount of HRIG was infiltrated at the exposure sites (155). HRIG should never be administered in the same syringe or in the same anatomical site as the first vaccine dose. However, subsequent doses of vaccine in the 5-dose series can be administered in the same anatomic location where the HRIG dose was administered, if this is the preferable site for vaccine administration (i.e., deltoid for adults or anterolateral thigh for infants and small children). Vaccine Use. Two rabies vaccines are available for use in the United States (Table 1); either can be administered in conjunction with HRIG at the beginning of postexposure pro-phylaxis. A regimen of one-mL doses of HDCV or PCECV should be administered IM to previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon as possible after exposure. This date is then considered day 0 of the postexposure prophylaxis series. Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. For adults, the vaccination should always be administered IM in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for HDCV or PCECV injections because administration of HDCV in this area results in lower neutralizing antibody titers (156). # Deviations from Recommended Postexposure Vaccination Schedules Every attempt should be made to adhere to the recommended vaccination schedules. Once vaccination is initiated, delays of a few days for individual doses are unimportant, but the effect of longer lapses of weeks or more is unknown (157). Most interruptions in the vaccine schedule do not require reinitiation of the entire series (158). For most minor deviations from the schedule, vaccination can be resumed as though the patient were on schedule. For example, if a patient misses the dose scheduled for day 7 and presents for vaccination on day 10, the day 7 dose should be administered that day and the schedule resumed, maintaining the same interval between doses. In this scenario, the remaining doses would be administered on days 17 and 31. When substantial deviations from the schedule occur, immune status should be assessed by performing serologic testing 7-14 days after administration of the final dose in the series. # Postexposure Prophylaxis Outside the United States Persons exposed to rabies outside the United States in countries where rabies is enzootic might receive postexposure prophylaxis with regimens or biologics that are not used in the United States, including purified vero cell rabies vaccine (Verorab ™ , Imovax -Rabies vero ™ , TRC Verorab ™ ), purified duck embryo vaccine (Lyssavac N ™ ), and different formulations of PCECV (Rabipur ® ) or HDCV (Rabivac ™ ). This information is provided to familiarize physicians with some of the regimens used more widely abroad. These regimens have not been submitted for approval by the U.S. Food and Drug Administration (FDA) for use in the United States (37,74,(159)(160)(161)(162)(163)(164)(165)(166)(167)(168). If postexposure prophylaxis is initiated outside the United States using one of these regimens or vaccines of nerve tissue origin, additional prophylaxis might be necessary when the patient presents for care in the United States. State or local health departments should be contacted for specific advice in such cases. Rabies virus neutralizing antibody titers from specimens collected 1-2 weeks after preexposure or postexposure prophylaxis would be considered adequate if complete neutralization of challenge virus at a 1:5 serum dilution by RFFIT occurs. Purified ERIG or fractions of ERIG have been used in developing countries where HRIG might not have been available. The incidence of adverse reactions after ERIG administration has been low (0.8%-6.0%), and most of those that occurred were minor (169)(170)(171). In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither HRIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis (172). Although no postexposure prophylaxis failures have occurred in the United States since cell culture vaccines and HRIG have been routinely used, failures have occurred abroad when less than potent biologics were used, if some deviation was made from the recommended postexposure prophylaxis protocol, or when less than the recommended amount of RIG was administered (155,(173)(174)(175). Specifically, patients who contracted rabies after postexposure prophylaxis might not have had adequate local wound cleansing, might not have received rabies vaccine injections in the deltoid area (i.e., vaccine was administered in the gluteal area), or might not have received appropriate infiltration of RIG around the wound site. Substantial delays between exposure and initiation of prophylaxis are of concern, especially with severe wounds to the face and head, which might provide access to the central nervous system through rapid viral neurotropism. # Rabies Pre-Exposure Prophylaxis Pre-exposure rabies prophylaxis is administered for several reasons. First, although pre-exposure vaccination does not eliminate the need for additional medical evaluation after a rabies exposure, it simplifies management by eliminating the need for RIG and decreasing the number of doses of vaccine needed. This is particularly important for persons at high risk for being exposed to rabies in areas where modern immunizing products might not be available or where cruder, less safe biologics might be used, placing the exposed person at increased risk for adverse events. Second, pre-exposure prophylaxis might offer partial immunity to persons whose postexposure prophylaxis is delayed. Finally, pre-exposure prophylaxis might provide some protection to persons at risk for unrecognized exposures to rabies. Pre-exposure vaccination should be offered to persons in high-risk groups, such as veterinarians and their staff, animal handlers, rabies researchers, and certain laboratory workers. Pre-exposure vaccination also should be considered for persons whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies. In addition, some international travelers might be candidates for pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care, including rabies vaccine and immune globulin, might be limited. Routine pre-exposure prophylaxis for the general U.S. population or routine travelers to areas where rabies is not enzootic is not recommended (176,177). # Primary Vaccination Three 1.0-mL injections of HDCV or PCECV should be administered IM (deltoid area), one injection per day on days 0, 7, and 21 or 28 (Table 5). The immunogenicity of IM primary vaccination with PCECV and HDCV has been reviewed. Vaccine preparations for ID administration are no longer available in the United States. # Pre-Exposure Booster Doses of Vaccine Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category [Table 6]) (178) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies virus neutralizing antibody every 6 months. An IM booster dose (Table 5) of vaccine should be administered if the serum titer falls to maintain a serum titer corresponding to a value of at least complete neutralization at a 1:5 serum dilution by the RFFIT. The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), cavers, veterinarians and staff, and animalcontrol and wildlife officers in areas where animal rabies is enzootic. The frequent-risk category also includes persons who frequently handle bats, regardless of location in the United States or throughout the world, because of the existence of lyssaviruses on all continents except Antarctica. Persons in the frequent-risk group should have a serum sample tested for rabies virus neutralizing antibody every 2 years. If the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and terrestrial animal-control and wildlife officers working in areas where rabies is uncommon to rare (infrequent exposure group) and certain at-risk international travelers who have completed a full pre-exposure vaccination series with licensed vaccines and according to schedule do not require routine serologic verification of detectable antibody titers or routine pre-exposure booster doses of vaccine. If they are exposed to rabies in the future, they are considered immunologically primed against rabies and simply require postexposure prophylaxis for a person previously vaccinated (i.e., days 0 and 3 vaccination). # Postexposure Prophylaxis for Previously Vaccinated Persons If a person is exposed to rabies, local wound care remains an important part of postexposure prophylaxis, even for previously vaccinated persons. Previously vaccinated persons are those who have received one of the recommended pre-exposure or postexposure regimens of HDCV, PCECV, or RVA or those who received another vaccine and had a documented rabies virus neutralizing antibody titer. These persons should receive 2 IM doses (1.0 mL each in the deltoid) of vaccine, one immediately and one 3 days later. Administration of RIG is unnecessary and should not be administered to previously vaccinated persons because the administration of passive antibody might inhibit the relative strength or rapidity of an expected anamnestic response (77). For previously vaccinated persons who are exposed to rabies, determining the rabies virus neutralizing antibody titer for decision-making about prophylaxis is inappropriate for at least three reasons. First, several days will be required to collect the serum and determine the test result. Second, no "protective" titer is known. Finally, although rabies virus neutralizing antibodies are important components, other immune effectors also are operative in disease prevention. # Vaccination and Serologic Testing # Post-Vaccination Serologic Testing In CDC studies, all healthy persons tested 2-4 weeks after completion of pre-exposure and postexposure rabies prophylaxis in accordance with ACIP guidelines demonstrated an adequate antibody response to rabies (18,73,179,180). Therefore, no testing of patients completing pre-exposure or postexposure prophylaxis is necessary to document seroconversion unless the person is immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone pre-exposure vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When that is not possible, immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their virus neutralizing antibody titers checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public health officials. When titers are obtained, specimens collected 1-2 weeks after pre-exposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. Antibody titers might decline over time since the last vaccination. Small differences (i.e., within one dilution of sera) in the reported values of rabies virus neutralizing antibody titer (most properly reported according to a standard as IU/mL) might occur among laboratories that provide antibody determination using the recommended RFFIT. Rabies antibody titer determination tests that are not approved by FDA are not appropriate for use as a substitute for RFFIT in suspect human rabies antemortem testing because discrepant results between such tests and measures of actual virus neutralizing activity by RFFIT have been observed (181). # Serologic Response and Pre-Exposure Booster Doses of Vaccine Although virus neutralizing antibody levels might not definitively determine a person's susceptibility or protection from a rabies virus exposure, titers in persons at risk for exposure are used to monitor the relative rabies immune status over time (182). To ensure the presence of a primed immune response over time among persons at higher than normal risk for exposure, titers should be checked periodically, with booster doses administered only as needed. Two years after primary pre-exposure vaccination, a complete neutralization of challenge virus at a dilution of 1:5 (by the RFFIT) was observed among 93%-98% of persons who received the 3-dose pre-exposure series intramuscularly and 83%-95% of persons who received the 3-dose series intradermally (68). If the titer falls below the minimum acceptable antibody level of complete neutralization at a serum dilution of 1:5, a single pre-exposure booster dose of vaccine is recommended for persons at continuous or frequent risk for exposure to rabies (Table 6). # Management and Reporting of Adverse Reactions to Rabies Biologics Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. Usually, such reactions can be successfully managed with anti-inflammatory, antihistaminic, and antipyretic agents. When a person with a history of hypersensitivity to rabies vaccine must be revaccinated, empiric intervention such as pretreatment with antihistamines might be considered. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination (184). Although serious systemic, anaphylactic, or neuroparalytic reactions are rare during and after the administration of rabies vaccines, such reactions pose a serious dilemma for the patient and the attending physician (14). A patient's risk for acquiring rabies must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious adverse reactions for persons receiving rabies vaccines can be sought from the state or local health department or CDC. All clinically significant adverse events occurring following administration of rabies vaccine should be reported to VAERS, even if causal relation to vaccination is not certain. Although VAERS is subject to limitations common to passive surveillance systems, including underreporting and reporting bias, it is a valuable tool for characterizing the safety profile of vaccines and identifying risk factors for rare serious adverse reactions to vaccines (94). VAERS reporting forms and information are available at http://www.vaers.hhs.gov or by telephone (800-822-7967). Web-based reporting is available and health-care providers are encouraged to report electronically at https://secure.vaers.org/VaersData Entryintro.htm. Clinically significant adverse events following HRIG administration should be reported to the Food and Drug Administration's MedWatch. Reports can be submitted electronically to http://www.fda.gov/MedWatch. # Precautions and Contraindications Immunosuppression Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination (185,186). For persons with immunosuppression, pre-exposure prophylaxis should be administered with the awareness that the immune response might be inadequate. Patients who are immunosuppressed by disease or medications should postpone pre-exposure vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should have their virus neutralizing antibody titers checked after completing the pre-exposure series. A patient who fails to seroconvert after the third dose should be managed in consultation with their physician and appropriate public health officials. No cases of rabies postexposure prophylaxis failure have been documented among persons immunosuppressed because of human immunodeficiency virus infection. Immunosuppressive agents should not be administered during postexposure prophylaxis unless essential for the treatment of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, one or more serum samples should be tested for rabies virus neutralizing antibody to ensure that an acceptable antibody response has developed. If no acceptable antibody response is detected, the patient should be managed in consultation with their physician and appropriate public health officials. # Pregnancy Because of the potential consequences of inadequately managed rabies exposure, pregnancy is not considered a contraindication to postexposure prophylaxis. Certain studies have indicated no increased incidence of abortion, premature births, or fetal abnormalities associated with rabies vaccination (187)(188)(189). If the risk for exposure to rabies is substantial, pre-exposure prophylaxis also might be indicated during pregnancy. Rabies exposure or the diagnosis of rabies in the mother should not be regarded as reasons to terminate the pregnancy (157). # Allergies Persons who have a history of serious hypersensitivity to components of rabies vaccine or to other vaccines with components that are also present in rabies vaccine should be revaccinated with caution (184). # Indigent Patient Programs Both rabies vaccine manufacturers have patient assistant programs that provide medications to uninsured or underinsured patients. Sanofi pasteur's Indigent Patient Program (providing Imogam ® Rabies-HT and Imovax ® Rabies) is administered through the National Organization for Rare Disorders. Information is available by telephone (877-798-8716) or e-mail ([email protected]). Information on Novartis Pharmaceuticals Patient Assistance Program for RabAvert ® is available at http://www.corporatecitizenship. novartis.com/patients/drug-pricing/assistance-programs.shtml. # Treatment of Human Rabies Rabies is associated with the highest case fatality rate of any infectious disease. No proven effective medical treatment is recognized after the development of clinical signs. Combined with intensive care, experimental measures have included administration of vidarabine, multisite ID vaccination with cell-culture vaccines, human leukocyte interferon, RIG by the intravenous and intrathecal routes, antithymocyte globulin, inosine pranobex, ribavirin, ketamine, and high doses of steroids (190)(191)(192)(193)(194)(195)(196)(197). Initiation of rabies vaccination after onset of clinical symptoms in patients with confirmed rabies diagnoses is not recommended and might be detrimental. Survival has been well documented for only six patients. In five of these cases, the persons had received rabies vaccination before the onset of disease (198)(199)(200)(201)(202). Only one patient has recovered from rabies without the institution of rabies vaccination (9,203). Despite these successes, rabies is not considered curable. Treatment of clinical rabies remains an extreme challenge. Rapid antemortem diagnosis is a priority. When a definitive diagnosis is obtained, primary health considerations should focus, at a minimum, on comfort care and adequate sedation of the patient in an appropriate medical facility. Sedation is often necessary because patients might become extremely agitated, especially in the presence of stimuli such as loud noises, air currents, and the sight or sound of running water, particularly during the acute neurologic phase of the disease (25). Beyond the overt clinical situation associated with progressive encephalitis, during fluctuating periods of lucidity, patient stress might be compounded by the psychological trauma resulting from a sense of personal isolation and hopelessness from the prognosis. As new potential treatments become available, medical staff at specialized tertiary care hospitals might consider institution of an aggressive approach to experimental therapies, especially in confirmed cases in young healthy persons at an early stage of clinical disease, after in depth discussions and informed consent by the patient, family or legal representatives (http:// www.mcw.edu/display/router.asp?DocID=11655). Parties authorized to give permission for such treatment also should be aware of the high probability for treatment failure, the anticipated expenses, and that in the rare instances of patient survival, the recovery might be associated with a variety of neurologic deficits requiring a lengthy period of rehabilitation (204). Continued efforts focusing on the elimination of exposure to sources of virus and the institution of appropriate and timely prophylaxis after exposure occurs remain the most effective public health measures to prevent human rabies. # Precautions for Safe Clinical Management of Human Rabies Patients Human rabies patients do not pose any greater infection risk to health-care personnel than do patients with more common bacterial and viral infections (25). Medical staff should adhere to standard precautions as outlined by the Hospital Infection Control Practices Advisory Committee (126). Staff should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning (25). Postexposure prophylaxis is indicated only when the patient has bitten another person or when the patient's saliva or other potentially infectious material such as neural tissue has contaminated an open wound or mucous membrane. depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices # Appendix Abbreviations Used in This Report # Goal and Objectives This report provides recommendations for preventing rabies among humans. These recommendations were developed by CDC staff members and the Rabies Working Group of the Advisory Committee on Immunization Practices. The goal of this report is to guide clinical practice and policy development related to appropriate management of persons at risk for rabies. Upon completion of this educational activity, the reader should be able to1) describe groups for whom rabies pre-exposure prophylaxis are indicated, 2) describe groups for whom rabies serologic testing are indicated, 3) describe groups for whom booster dosing are indicated, 4) describe some of the common rabies reservoirs in the United States, and 5) describe the essential elements of rabies postexposure prophylaxis. To receive continuing education credits, please answer all of the following questions. # Which of the following lists of potential exposure types by animals are correctly ordered from the likely greatest risk for rabies virus infection to the least risk for infection? A. Raccoon scratches are greater than licks to the skin, which are greater than bites. B. Dog licks to the skin are greater than scratches, which are greater than bites. C. Skunk scratches are greater than bites, which are greater than licks to the skin. D. Bat licks to the skin are greater than scratches, which are greater than bites. E. None of the above.	None	None
34398c447a5c1fa74e3a48dedb7bd54b64131711	cdc	None	The National Institute for Occupational Safety and Health (N IO SH ) recommends that employee exposure to dibromochloropropane in the workplace be controlled so that no worker will be exposed to dibromochloropropane in excess of 10 ppb (0.1 mg/cu m) in air. The N IO SH recommendations is to restrict exposure to very low levels that can still be reliably measured in the workplace. The recom mended exposure limit of 10 ppb is above the lowest level at which a reliable estimate of occupational ex posure to dibromochloropropane can be determined at this time. The recommended standard contains recommendations for medical surveillance, informing employees of hazards, sanitation, work practices, la beling and posting, personal protective clothing and equipment, monitoring and recordkeeping. The recommended standard is designed to pro tect the health and provide for the safety of em ployees for up to a 10-hour shift, 40-hour workweek, over a working lifetime. Compliance with all sec tions of the standard should, at the minimum, sub stantially reduce adverse effects of exposure to dibro mochloropropane in the workplace. The employer should regard the recommended workplace environ mental limit as the upper bondary for exposure and make every effort to keep the exposure as low as possible. The possible effects on the health of employees chronically exposed to DBCP may include sterility, diminished renal function, and degeneration and cir rhosis of the liver. In addition, ingestion of daily doses of DBCP by mice and rats has been found to result in the appearance of gastric cancers in both sexes of both species and in mammary cancers in female rats. Although an increased risk for cancer has not been seen with inhalation exposures, these results are not definitive, therefore the risk of cancer due to occupational exposure to DBCP remains a continuing concern. There are indications from in vitro experiments that mutagenic effects may occur also, but there has been no study yet of this possi bility with mammalian subjects. Employees should be told of these possible effects and informed that some 20-25 years of experience in the manufacture and formulation of DBCP has not yet called such effects in employees of the pesticide industry to the notice of physicians and epidemiologists. A more detailed review of the known health effects are given in Enclosure 1. The recommended standard is part of a continu ing series of recommendations developed by NIOSH in accordance with the Occupational Safety and Health Act of 1970. The recommended standard is being transmitted to the Department of Labor, September 2, 1977, for review and consideration in the prepara tion of an emergency temporary standard. If research by NIOSH results in the development of improved methods for sampling and analysis of dibromochloro propane in air from the occupational environment, information regarding the new methods will be for warded to the Department of Labor. # I. RECOMM ENDATIONS FOR A TEMPORARY EMERGENCY STANDARD FOR OCCUPATIONAL EXPOSURE TO DIBROMOCHLOROPROPANE The National Institute for Occupational Safety and Health (N IO SH ) recommends that employee exposure to dibromochloropropane (DBCP) in the workplace be controlled by adherence to the follow ing sections. The standard is designed to protect the health and provide for the safety of employees for up to a 10-hour work shift, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should, at the minimum, substantially reduce the effects of DBCP on the health of em ployees and provide for their safety. The employer should regard the recommended workplace environ mental limit as the upper boundary for exposure and make every effort to keep the exposure as low as possible. The criteria and standard will be subject to review and revision as necessary. The possible effects on the health of employees chronically exposed to DBCP may include sterility, diminished renal function, and degeneration and cirrhosis of the liver. In addition, ingestion of daily doses of DBCP by mice and rats has been found to result in the appearance of gastric cancers in both sexes of both species and in mammary cancers in female rats. Although an increased risk for cancer has not been seen with inhalation exposures, thescresults are not definitive, therefore the risk of cancer due to occupational exposure to DBCP remains a continuing concern. There are indications from in vitro experiments that mutagenic effects may occur also, but there has been no study yet of this possibility with mammalian subjects. Employees should be told of these possible effects and informed that some 20-25 years of experience in the manufacture and formula tion of DBCP has not yet called such effects in employees of the pesticide industry to the notice of physicians and epidemiologists. A more detailed re view of the known health effects are given in En closure 1. Sampling methods utilizing both charcoal and Florisil® tubes have been reported to NIOSH as acceptable for measurements at the recommended en vironmental limit. However, an evaluation of the suggested methods has not yet been completed by NIOSH. Such a laboratory evaluation should be completed in the first part of FY 78. "Occupational exposure to dibromochloropro pane" refers to any workplace situation in which DBCP is manufactured, formulated, or stored. All sections of the standard shall apply where there is occupational exposure to DBCP. Section 1 -Environmental (W orkplace Air) (a) Concentration Dibromochloropropane shall be controlled in the workplace so that no employee is exposed to airborne dibromochloropropane, at a concentration greater than 10 parts per billion (approximately 0.1 m g/cu m) determined as a time weighted average (T W A ) con centration for up to a 10-hour work shift, 40-hour workweek. (b) Sampling and Analytical Methods The environmental limit represents a concentra tion of dibromochloropropane measurable by reported sampling and analytical methods. Section 2 -Medical Medical surveillance shall be made available to employees as outlined below: (a) Comprehensive preplacement or initial med ical and work histories with emphasis on reproductive experience and menstrual history. (b) Comprehensive physical examination with emphasis on the genito-urinary tract including testicle size and consistency in males. (1 ) Semen analysis to include sperm count, motility and morphology. (2 ) Other tests, such as serum testosterone, serum follicle stimulating hormone (FSH ), and serum lutenizing hormone (L H ) may be carried out if, in the opinion of the responsible physician, they are indicated. In addition, screening tests of the renal and hepatic systems may be considered. (3) A judgment of the worker's ability to use positive pressure respirators. (c) Employees shall be counseled by the physi cian to ensure that each employee is aware that DBCP has been implicated in the production of effects on the reproductive system including sterility in male workers. In addition, they should be made aware that cancer has been produced in some animals. W hile the relevancy of these findings are not yet clearly de fined, they do indicate that both employees and employers should do everything possible to minimize exposure to DBCP. (d ) Periodic examinations containing the ele ments of the preplacement or initial examination shall be made available on at least an annual basis. (e) Examinations of current employees shall be made available as soon as practic?ble after the promulgation of a standard for DBCP. (f) Medical surveillance shall be made available to any worker suspected of having been exposed to DBCP. (g) Pertinent medical records shall be maintained for all employees subject to exposure to DBCP in the workplace. Such records shall be maintained for at least 30 years after termination of employment. These records shall be made available to the desig nated medical representatives of the Secretary of Health, Education, and W elfare, of the Secretary of Labor, of the employer, the employee, or former employee. # Section 3 -Labeling and Posting A label shall be placed on each shipping and storage container of dibromochloropropane and all areas where there is occupational exposure to dibromochloropropane shall be posted. All warning signs shall be printed both in English and in the predominant language of non-Englishreading workers. Illiterate workers and workers read ing languages other than those used on labels and posted signs shall be informed of the hazardous areas and shall be informed of the instructions printed on labels and signs. ( (1 ) Engineering controls shall be used wher ever needed to keep airborne dibromochloropropane concentrations below the recommended occupational exposure limit. Compliance with this limit may be achieved by the use of respirators under the following conditions only: (A ) During the time necessary to install or test the required engineering controls. (B ) For nonroutine operations, such as emergency maintenance or repair activities. (C ) During emergencies when air con centrations of dibromochloropropane may exceed the recommended occupational exposure limit. (2) W hen a respirator is permitted by para graph (a )( 1 ) of this section, it shall be selected and used pursuant to the following requirements: (A ) The employer shall ensure that no employee is exposed to dibromochloropropane be cause of improper respirator selection, fit, use, or maintenance. (B ) The employer shall establish and en force a respirator program meeting the requirements of 29 CFR 1910.134 as amended. (C ) The employer shall provide respira tors in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided when necessary. (D ) Respiratory protective devices de scribed in Table 1-1 shall be those approved under the provisions of 30 CFR 11. (E ) Respirators specified for use in higher concentrations of dibromochloropropane may be used in atmospheres of lower concentrations. (F ) The employer shall ensure that res pirators are adequately cleaned and maintained, and that employees are instructed and drilled, at least annually, in the proper use and testing for leakage of respirators assigned to them. (G ) Respirators shall be easily accessible and employees shall be informed of their location. (b ) Eye protection Eye protection shall be provided by the employer and used by the employees where eye contact with liquid dibromochloropropane is likely. Selection, use, and maintenance of eye protective equipment shall be in accordance with the provisions of the American National Standard Practice for Occupational and Ed ucational Eye and Face Protection, ANSI Z87. . Unless eye protection is afforded by a respirator hood or facepiece, protective goggles or a face shield (8-inch minimum) shall be worn at operations where there is danger of contact of the eyes with liquid dibromochloropropane be cause of spills or splashes. If there is danger of liquid dibromochloropropane striking the eyes from under neath or around the sides of the face shield, safety goggles shall be worn as added protection. (c) Protective Clothing Protective clothing shall be resistant to the pene tration and to the chemical action of dibromochloro propane. Additional protection, including gloves, bib-type aprons, boots, and overshoes, shall be pro vided for, and worn by, each employee during any operation that may cause direct contact with liquid dibromochloropropane. Supplied-air hoods or suits resistant to penetration by dibromochloropropane shall be worn when entering confined spaces, such as pits or storage tanks. In situations where heat stress is likely to occur, supplied-air suits, preferably cooled, are recommended. The employer shall ensure that all personal protective clothing is inspected regularly for defects and is maintained in a clean and satis factory condition by the employee. Section 5 -Informing Employees of Hazards from Dibromochloropropane (a) All new and present employees working where occupational exposure to dibromochloropro pane may occur shall be informed orally and in writ ing of the hazards, relevant signs and symptoms of exposure, appropriate emergency procedures, and proper conditions and precautions concerning safe use and handling of dibromochloropropane. This infor mation should be readily available to all employees involved in the manufacture, formulation, or storage of dibromochloropropane and shall be posted in prominent positions within the workplace. (b) All employees involved with the manufac ture, formulation, or storage of dibromochloropro pane shall be informed that it has been implicated in human reproductive abnormalities and has induced gastric cancers in animals following oral intubation. (c) Employers shall institute a continuing edu cation program to ensure that all employees have cur rent knowledge of job hazards, maintenance pro cedures, cleanup methods, emergency procedures, and evacuation procedures. This program shall include at least : Emergency procedures and drills. Instruction in handling spills and leaks. Decont? mination procedures. Location and use of firefighting equipment. First-aid procedures, equipment location, and use. Rescue procedures. Confined space entry procedures. Records of such training shall be kept for inspection by authorized personnel as required. This program shall be held for all employees with occupational exposure to dibromochloropropane at intervals not greater than quarterly, or whenever there is a process change. (d ) Information as required shall be recorded on the "Material Safety Data Sheet," or on a simi lar form approved by the Occupational Safety and Health Administration, U.S. Department of Labor. Section 6 -W ork Practices (a) Emergency Procedures For all work areas where emergencies may occur, the employer shall take all necessary steps to ensure that employees are instructed in and follow the pro cedures specified below and any others appropriate to the specific operation or process. (1 ) Procedures shall include at least pre arranged plans for re-entry into areas where dibromo chloropropane leaks or spills have occurred for clean up, decontamination, or maintenance purposes. (2) Evacuation alarm systems shall be pro vided by the employer. (3 ) Personal protective equipment and cloth ing as specified in Section 4 shall be used by trained personnel essential to emergency operations. (4) Nonessential employees shall be evacu ated from hazardous areas during emergencies. Per imeters of these areas shall be delineated, posted, and secured. The employees in adjacent areas shall be trained in evacuation procedures if these work areas become involved. (5) O n!/ personnel trained in the emer gency procedures and protected against the attendant hazards shall shut off sources of dibromochloropro pane, clean up spills, control and repair leaks, and fight fires in dibromochloropropane areas. (6) F.refighting procedures shall be estab lished for areas where flammable materials are used with dibromochloropropane. Chemical foam, carbon dioxide, or dry chemicals shall be used for fighting fires in areas where dibromochloropropane is present. Proper protective respirators and clothing shall be worn by all personnel in the hazard area until con centrations of airborne dibromocholorpropane have been demonstrated by monitoring to be below the recommended occupational exposure limit. (7 ) Showers, eyewash fountains, and wash room facilities shall be provided and so located as to be readily accessible to workers in all areas where skin or eye contact with liquid dibromochloropropane is likely. If liquid dibromochloropropane is splashed on the clothing or skin, contaminated clothing shall be promptly removed and the skin washed thoroughly with soap and water. If liquid dibromochloropropane gets into the eyes, they shall be irrigated immediately with copious quantities of running water. (8) Medical attention shall be provided promptly for any affected worker. Such exposures shall be reported to the immediate supervisor by the affected worker or by a fellow employee. (b) Control of Airborne Dibromochloropropane (1) Suitable engineering controls designed to limit exposure to dibromochloropropane to that prescribed in Section 1(a) shall be used. The use of completely enclosed processes is the recommended method of control for dibromochloropropane. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. W hen a local exhaust ventilation system is used, it shall be designed to prevent the accumulation or recirculation of ventilation control or process air in the work room, to maintain dibromochloropropane concentra tions below the limit of the recommended standard, and to remove dibromochloropropane from the breath ing zones of employees. Exhaust systems discharging into outside air must conform with applicable local, state, and federal air pollution regulations. Ventila tion systems shall be subjected to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic airflow measure ments at least every 3 months. Measurements of sys tem efficiency shall also be made immediately by personnel properly attired in specific protective equip ment when any change in production, process, or con trol might result in increased concentrations of air borne dibromochloropropane. Tempered makeup air shall be provided to work areas in which exhaus ventilation is operating. (c) Handling of Dibromochloropropane and General W ork Practices (1 ) W ritten operating instructions and emer gency medical procedures shall be formulated and posted where dibromochloropropane is handled or used. (2) Prompt medical attention shall be pro vided if there is known or suspected exposure to dibromochloropropane, whether or not symptoms are present. (3) The employer shall ensure that safety showers, eyewash fountains, and other emergency equipment is in proper working order through reg ularly scheduled inspections performed by qualified maintenance personnel. (4 ) Dibromochloropropane operating systems shall be inspected daily for signs of leaks by person nel attired in specified protective equipment. All equipment including valves, fittings, and connections shall be checked for tightness and good working order. All newly made connections shall be checked for Jeaks immediately after dibromochloropropane is introduced by trained personnel attired in prescribed personal protective equipment. (5 ) If there is a leak, the leak shall be cor rected immediately. W ork shall resume normally only after necessary repair or replacement has been completed, the area has been ventilated, and the concentration of dibromochloropropane has been de termined by monitoring to be below the recommended occupational exposure limit. (6 ) Transportation and use of dibromo chloropropane shall comply with all applicable local, state, apd federal regulations. Strict adherence to the pesticide container label requirements for appli cation and personal protection shall be followed. Additional standards for pesticide use by agricultural workers can be found in 40 CFR 170. (7 ) W hen dibromochloropropane containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control while moving. (8 ) Process valves and pumps shall be read ily accessible and should not be located in pits and congested areas. (9 ) Containers and systems shall be handled and opened with care. Approved protective equip ment as specified in Section 4 shall be worn whileopening, connecting, and disconnecting dibromo chloropropane containers and systems. Adequate ventilation shall be available to prevent exposure to dibromochloropropane when opening containers and systems. (10) Personnel shall work in teams when di bromochloropropane is first admitted to a system, while repairing leaks, or when entering a confined or enclosed space. (d ) W ork Areas (1) Dibromochloropropane Hazard Areas A hazard area shall be considered as any space workers may enter that has physical characteristics and sources of dibromochloropropane that could re sult in air concentrations exceeding the recommended limit. Exits shall be plainly marked and shall open outward. Emergency exit doors shall be conveniently located and shall open into areas which will remain free of contamination in an emergency. At least two separate means of exit shall be provided from each room or building in which dibromochloropropane is stored, handled, or used in quantities that could create a haza'rd. (2 ) Confined or Enclosed Spaces Entry into confined spaces, such as tanks, pits, process vessels, tank cars, sewers, or tunnels, where there may be limited egress shall be controlled by a permit system. Permits shall be signed by an author ized employer representative certifying that preven tive and protective measures have been followed. Confined spaces which have contained dibromo chloropropane shall be thoroughly ventilated to en sure an adequate supply of oxygen, tested for dibro mochloropropane and other contaminants, and inspected for compliance with these requirements prior to each entry. Adequate ventilation shall be maintained while workers are in the space. Leakage of dibromochloropropane into the confined space while work is in progress shall be prevented by dis connecting and blanking the dibromochloropropane supply lines. An individual entering confined spaces shall be furnished with appropriate personal protec tive equipment and protected by a lifeline harness tended by another worker outside the space, who shall also be equipped for entry with approved per sonal protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephone, radio, or other suitable means) shall be maintained by the standby person with the employee inside the confined or enclosed space. A third employee, equipped to proceed to the aid of the other two if necessary, shall have general surveillance of their activities. (e) Storage (1 ) Storage facilities shall be designed to contain spills completely within a surrounding dike and to prevent contamination of workroom air. (2 ) Storage of dibromochloropropane in the same area as reactive metals, such as aluminum or magnesium, or as liquid ammonia shall be pro hibited. (3 ) Storage containers shall be periodically inspected for leakage. (4 ) Ventilation switches and emergency res piratory equipment shall be located outside storage areas in readily accessible locations which will be free of dibromochloropropane in an emergency. (f) Spills, Leaks, and W aste Disposal (1 ) If dibromochloropropane leaks or is spilled, the following steps shall be taken: (A ) Evacuate all nonessential person nel from the area. (B ) Adequately ventilate the area of the spill or leak to prevent accumulation of the vapor. (C ) If in liquid form, collect spilled ma terial for reclamation or absorb in vermiculite, dry sand, earth, or similar nonreactive material. (D ) If in solid form, collect spilled ma terial in the most convenient and safe manner for reclamation or for disposal. (2 ) Personnel entering the spill or leak area shall be furnished with appropriate personal protec tive equipment. All other personnel shall be ex cluded from the area. (3 ) AH wastes and residues containing dibromochloropropane shall be collected in dibromochloropropane resistant containers and incinerated or buried in such a manner that no dibromochloropropane or toxic decomposition products are released to the environment. (b ) Appropriate locker rooms shall be available for changing into required protective clothing in ac cordance with 29 CFR 1910.141(e). Clothing con taminated with liquid dibromochloropropane shall be immediately removed and placed in a closed container in a well-ventilated area for later disposal or decon tamination. Employers shall require personnel who work with dibromochloropropane to shower before leaving the workplace at the end of a workday. (c) Employers shall ensure that employees who handle dibromochloropropane wash their hands thoroughly with soap and water before eating, smok ing, or using toilet facilities. (d ) The storage, dispensing, preparation, and consumption of food, beverages, or tobacco shall be prohibited in dibromochloropropane work areas. (e) The employer shall ensure that personnel who launder and clean clothing or equipment con taminated with dibromochloropropane are provided adequate personal protective equipment to prevent exposure and shall ensure that these employees are aware of the potential hazards of exposure to di bromochloropropane. Section 8 -M onitoring and Recordkeeping Requirements (a) Industrial hygiene surveys shall be made in any workplace where dibromochloropropane is han dled, processed, or stored. Records of these surveys, including the basis for concluding that environmental concentrations are below the recommended limit shall be maintained. Surveys shall be repeated every month or whenever a process change is made. (b ) W here exposure concentrations have not been determined, they shall be determined as soon as practicable after the promulgation of a standard based on these recommendations. (c) Requirements set forth below apply to work areas where there is occupational exposure to dibro mochloropropane. (1) An adequate number of samples shall be collected monthly for the evaluation of the work environment with respect to the occupational expo sure of the employees. (2) Environmental samples shall be taken when a new process is installed or process changes are made which may cause an increase in environ mental concentrations. Significantly increased pro duction, relocation of existing operations, interrup tion of normal maintenance schedules, or other func tion which may increase dibromochloropropane con centrations shall require resampling and analysis. (3 ) The minimum number of representative exposure determinations for an operation or process shall be based on variations in exposures and pro duction schedules and in accordance with the provi sions prescribed in Section 1 (b ). (4) If initial, periodic, or special evaluations indicate that the recommended limit is exceeded, cor rective engineering or other control measures shall be immediately instituted to ensure the safety of em ployees until a concentration below the occupational exposure limit is achieved. In such cases, sampling of each operation and work location shall be conducted until two consecutive employee exposure measure ments, taken at least 1 week apart, reveal that the employee is not exposed to dibromochloropropane above the recommended occupational exposure limit. Employers shall notify in writing, within 5 days, every employee who is found to be exposed to di bromochloropropane above the recommended environ mental limit. (d ) Employers or their successors shall maintain records which shall include sampling and analytical methods, types of respiratory protection used, con centrations found, and information concerning ex posure of employees to dibromochloropropane. Each employee shall have access to data on his or her own environmental exposures. Pertinent records of occu pational accidents and environmental exposures within the workplace shall be kept for at least 30 years after the worker's employment has ended. Rec ords of occupational exposures applicable to an em ployee should be included in that employee's medical records. The medical representatives of the Secre tary of Health, Education, and W elfare, of the Sec retary of Labor, of the employee or former employee, and of the employer shall have access to all such records. # I # APPENDIX I M ETH O D FOR SA M PLIN G D IBRO M O -CH LO RO PRO PA N E IN AIR The following method is based on detailed reports from two representatives of the Shell Development Company. These reports have been communicated only by telephone. The method has not been pub lished and has not been evaluated in NIOSH labora tories. The method has been tested by Shell with a number of field samples. Procedure 1. An air sample is collected on a tube of Florisil.® 2. If the samples cannot be analyzed immediately after collection, the samples should be stored at -200°C. The refrigerated samples may be stored for two weeks or less. 3. The l,2-dibromo-3-chloropropane is desorbed from the Florisil® with hexane. 4. Analysis is accomplished with a gas chromato graph equipped with an electron-capture detector. # Useful Range The method is applicable to air concentrations ranging from 1 to 100 parts per billion (0.01 to 1 m g/cu m ). # ATTACHMENT I LITERATURE REVIEW FOR DIBROMOCHLOROPROPANE Background: 1,2-dibrom o-3 -c h lo ro p ro p a n e (DBCP) has the formula CH.,Br-CHBr-CH2C l. It has a gram molecular weight of 236.36. An amber to brown liquid with a pungent odor, DBCP has a specific gravity of 2.09 at 14°C referred to water. It has an index of refraction of 1.553 at 14°C for the D-line of the emission spectrum of sodium. DBCP has a vapor pressure of less than 1 mm of Hg at 21°C and boils at 199°C under a pressure of 760 mm of Hg. It is miscible with aliphatic and aromatic hydrocarbons, isopropyl alcohol, 1,2-dichloropropane, tetrachloroethylene, 1,1,2-trichloroethane, and oils. The undiluted material has no flash nor fire point. Because DBCP has been diluted commonly with kero sene or other flammable solvents, the preparations available in the market place may have flash points in the vicinity of 35-36°C (Tagliabue closed cup). DBCP has been used in agriculture as a nematocide since 1955, being supplied for such use in the forms of liquid concentrate, emulsifiable concentrate, powder, granules, and solid material. Formulations of DBCP were registered for use as fumigant nematocides in 1964 on evidence that residues of the material as such would not remain on harvested raw agricultural commodities and that the only residue would consist of inorganic bromides. Newsome et al. (1977) reported, however, that substantial amounts of DBCP were found in radishes (up to 0.20 ppm) and carrots (up to 1.55 ppm in roots and 0.64 ppm in the tops) grown in soil treated with this fumigant. The estimated use of DBCP in the United States in recent years has ranged from 3.6 million pounds in 1971 to 12.3 million pounds in 1972 (USDA esti mates) . In 1971,' more than 59% of the DBCP used was applied in the Pacific Coast states (Andrilenas, 1974). The material is sold under such names as Nemagon, Fumazone, Nemafume, Nemaset, and Nematox. On August 5, 1977, the National Institute for Occupational Safety and Health (N IO SH ) was re quested by the Oil, Chemical and Atomic Workers (O CA W ) union to conduct a health hazard evalua tion at the Oxidental Chemical Company plant in Lathrop, California. This request was made when representatives of OCAW learned that a number of workers at this plant had abnormally low sperm counts. On August 9 and 10, NIOSH conducted a walk through inspection of the Lathrop plant and met with representatives from the company, the local union, and California OSHA. NIOSH staff also met with Dr. W horton, Univ. of Calif., Berkeley, who had consulted with the company and the union previ ously and who had conducted medical examinations of the affected employees. Medical examinations of a number of additional employees have subsequently been conducted by NIOSH staff in conjunction with Dr. Whorton. On August 12, the Occupational Safety and Health Administration in a telegram alerted approxi mately 80 manufacturers and formulators to the po tential hazard of worker exposure to DBCP. On August 23, a guideline document detailing suggested work practices was forwarded to these same affected companies. On August 19, the Director, NIOSH, wrote to the major manufacturers of DBCP requesting infor mation to fully evaluate the extent of the hazard posed by exposure to DBCP. Animal Toxicity. Torkelson et al. (1961) re ported that results of studies of the toxicity of DBCP for various species of animals by two different labora tories (A and B). Rakhmatulayev (1971) Rakhmatulayev listed the effects of lethal doses as being brief central excitation followed by depression, analgesia, uncoordinated activity of skeletal muscles, and paralysis of limbs. Torkelson et al. (1961) reported also that DBCP as a 1 r /c solution in propylene glycol or as undiluted liquid dropped into conjunctival sacs of rabbits' eyes produced slight irritation and pain of the conjunctivae and iris. These effects disappeared after 1-2 days. W ashing the eyes with water 30 seconds after contact with DBCP did not alter the conjunctival and iridial responses. Rakhmatulayev 350 316 Applications of 0.5 ml of DBCP to the shaven backs of 4 rabbits produced slight erythema in abraded areas of skin and no signs of irritation in intact skin (Torkelson et al., 1961). Repetition of such applications resulted in only a slight crustiness of the skin after 20 applications. The dermis and subcutaneous tissue at the site of application in one rabbit had extensive necrosis and infiltration with polymorphonuclear leucocytes upon microscopic ex amination. An unspecified number of other rabbits subjected to repeated, covered applications of a lO'/r solution of DBCP in the methylether of dipropylene glycol to their shaven bellies, the applications being renewed every 24 hours up to a total of 10 applica tions, had no lesions other than slight hyperemia and scaliness of the skin at the site of application. Per cutaneous LD50's for the rabbit were 1400 m g/kg when undiluted DBCP was applied for 24 hours and 500 m g/kg when DBCP was applied as a 10% solu tion in propylene glycol. Rats reported by Torkelson et al. (1961) to have been exposed to vaporized DBCP were observed to become apathetic, sluggish and ataxic but not to be completely narcotized. Clouding of the cornea or lens was seen with exposures to the higher concentra tions (up to about 400 ppm ). Laboratory A found that the LC50 fell from about 400 ppm with a 1-hour exposure to one of about 110 ppm for a 7-hour expo sure. Laboratory B did not estimate LC50's but ob tained mortalities in groups of rats that suggest a relationship between duration of exposure and LC50 fairly similar to that found by laboratory A within the range of durations of exposure used by the latter group. Laboratory B found that a concentration of about 290 ppm killed 2/12 rats at an exposure dura tion of 12 minutes, 3/12 rats at one of 30 minutes, and 3/12 rats at one of 60 minutes. These values suggest, but do not demonstrate, that the same straight line relationship between log concentration and duration of exposure found by Laboratory A for durations of 1 to 7 hours may not obtain with dura tions of exposure less than 1 hour. Fifty inhalation exposures lasting for 7 hours, 5 days/week, of male rats to a concentration of DBCP of 5 ppm killed 0/15 animals, one to 10 ppm killed 2/15, and one to 20 ppm killed 10/15. Even the lowest of these concentrations produced a decrease of 18.6% in the mean weight of the testes. This was not a statistically significant decrease. Ex posure to the next higher concentration (10 ppm) produced a statistically significant decrease (49.0% ) in the mean weight of the testes. Exposure to that concentration also resulted in a significant increase in the weight of the kidney (31.7% )-These studies were performed by Laboratory A (Torkelson et al., 1961). Laboratory B (Torkelson et al., 1961) exposed male and female rats to 50 7-hour exposures to 12 ppm of DBCP. These exposures resulted in the deaths of 8/20 male and of 10/20 female rats, de generative changes in the seminiferous tubules, reduc tion in the number of sperm cells, increase in the proportion of abnormal sperm cells, increase in the number of Sertoli cells in the males, significant in creases in the weights of the kidneys in both sexes with cloudy swelling of the epithelium of the proxi mal convoluted tubules and increased amounts of interstitial tissue in the kidneys of the males, and dilatation of the sinusoids and centrilobular conges tion in the livers of both sexes. Laboratory B (Torkelson et al., 1961) also gave to guinea pigs and rabbits 66 7-hour exposures to va porized DBCP in a concentration of 12 ppm. These exposures killed no animals but did result in statis tically significant decreases in the mean weights of the testes in both species. Two female monkeys exposed for 50 and 60 times, respectively, to 12 ppm of DBCP developed severe leukopenias and anemias. The concentrations of bromide in the sera of the ex posed rats, guinea pigs, and rabbits ranged between 6.7 and 12.8 m g/100 ml whereas those of the control animals of these 3 species ranged from 0 to 7.8 m g /100 ml. Torkelson et al. (1961) reported also the results from a 90-day feeding study with rats of both sexes. The concentrations of DBCP in the diet were 0, 5, 20, 50, 150, 450, and 1350 ppm. The kidneys of female rats fed diets with concentrations of 20 or more ppm of DBCP and the livers of those fed diets containing 450 or more ppm were significantly heavier than those of the controls. Only those males fed the diet includ ing 1350 ppm of DBCP had kidneys and livers sig nificantly heavier than those of the controls. These studies revealed that DBCP had two out standing toxic effects in subacute exposures: an antispermiogenic effect in the male and a nephrotoxic effect that occurred in both sexes of the rat, but espe cially in the female. Laboratory B was able to show that neither the adrenocorticotropic hormone (A C T H ), cortisone, nor testosterone altered bene ficially the effect of DBCP on the testes. Indeed, testosterone enhanced the atrophic effect of DBCP. The final bit of information in the paper by Torkelson et al. (1961) was that men given brief exposure to a concentration of 1.7 ppm of DBCP described a definite, not unpleasant, odor. The auth ors recommended that occupational exposure to DBCP be controlled to hold the airborne concentration of the nematocide below 1 ppm. Rakhmatulayev (1971) also reported results from a subacute (2l/2 months' duration) and a chronic (8 months' duration) experiment using rats and administering DBCP by mouth in doses of 17.5-70 m g7kg (subacute) and .0005-5 m g/kg (chronic). The most sensitive indicators of toxic activity by DBCP in these experiments were reductions in the weight of the testes and in duration of motility of spermatozoa, decreased avidity of leucocytes for en gulfing bacteria and decreased rate of positive con ditioning. These effects were present with the dose of 0.05 mg/kg, but not with that of 0.005 m g/kg, in the chronic exposure study. Faydysh (1973) performed another study of the effect of prolonged administration (5 months) of DBCP in oral doses of 0.05, 0.5, and 5.0 m g/kg. The two highest doses were observed to decrease both the activity of neutrophils in engulfing and digesting bacteria and the concentration of these cells in the blood. These results confirm the report of Rakhmatulayev (1971) mentioned just above. Because phagocytically-mediated immunity is one of the defensive mechanisms of the body against conditions related to proliferation of abnormal cells, these effects of DBCP may contribute to the carcinogenic activity of this compound in experimental animals. Faydysh et al. (1970) and Faydysh and Avkhimenko (1974) studied further the effects of DBCP on testicular function. In the first study, 10 male rats were given daily oral doses of 70 m g/kg of DBCP in sunflower seed oil. Ten other male rats were given corresponding volumes of the sunflower seed oil alone. Five of the rats given DBCP died between days 20 and 25 of the experiment; the other 5 lived through the 45 days of the experiment. At necropsy, all internal organs were pallid and the gastric mucosa was noted to have been thinned. Although the blood was not examined specifically, the authors' description of the general appearance of the internal organs and of the vascular system raises a suspicion that there was marked anemia. The major parenchymatous organs, particularly the liver and kidneys, and the testes had undergone pro nounced necrotic effects. The livers contained areas of cirrhosis replacing necrotised tissue and the spleens had areas of necrosis in both the white and the red pulps. The parenchyma destroyed in the testes also was replaced by scar tissue. Some regenerative ac tivity was visible in the parenchymatous organs. The second paper demonstrated that similar changes could be accomplished by a daily dose of 0.5 m g/kg given during a longer period of time. This suggests that DBCP exerts some relatively, or possibly completely, irreversible action that eventually accumulates to pro duce a deleterious effect on target organs. Reznik and Sprinchan (1975) studied the gona dotropic actions of DBCP in both male and female rats. Single oral doses of 100 m g/kg or daily doses of 10 mg/kg, administered for 4 to 5 months, were used. The single dose produced within one week a decrease in the sperm count in the semen from 4.9±0.2 m illion/m g to 2.6±0.3 million /mg. At the same time, there was a decrease in the duration of mortility of the spermatozoa from about 31 minutes to about 15 minutes. In the females, the estrus cycle was prolonged, both estrus and diestrus becoming longer. The repeated doses of DBCP eventually pro duced effects similar to those that followed the single large dose. By the fourth month of administration, the concentration of spermatozoa in the semen was 2.5±0.5 m illion/m g vs 4.9±0.3 m illion/m g in the controls and the duration of motility of the sperma tozoa Was 29 minutes whereas that of spermatozoa from,control rats was 51 minutes. During the first month of daily doses, 24% of the females developed atypical estrus cycles; by the fifth month, this figure rose to 70% . At the same time, the duration of the cycles increased; 57% of the females became acyclic by the fifth month. It is apparent, therefore, that an effect on sperm count in the male may not be the only effect on human fertility from occupational ex posure to DBCP and that the possibility of induction of sterility in female employees needs to be con sidered also. No experimental study of teratogenic or muta genic activities by DBCP in mammals has been found. Rosenkranz (1975) examined the effects of this sub stance on two strains of E. coli and on two of the tester strains of Salmonella typhimurium: TA 1530 and TA 1538. DBCP was mutagenic for the first of these tester strains but not for the second, indicating that it induces mutations of the base-substitution but not of the frame-shift type. The finding that DBCP inhibited growth of a strain of E. coli deficient in D NA polymerase to nearly 2.4x the extent of its in hibition of that of a strain with a normal complement of the polymerase indicates that its principal effect is on the DNA. These results are reminiscent of those of Vogel and Chandler (1974) in which they found that 1,2-dibromopropane was definitely mutagenic in Drosophila. As pointed out by these latter auth ors, the important property of vicinal 1,2-dibromides is that in solution they readily rearrange to form the very reactive bromonium ions. This ability would not be modified importantly by substitution of a chlorine atom on the third carbon of propane. The National Cancer Institute undertook in 1972 studies of the possible carcinogenicity of DBCP, as one of a group of halogenated compounds. As early as 14 weeks after the initiation of administration by stomach tube of daily doses of 24 m g/kg of DBCP dissolved in corn oil, 5 times per week, several female rats were found to have palpable mammary tumors (Olson et al., 1973). Female rats given daily doses of 12 m g/kg of DBCP had not developed mammary tumors. After the fourteenth week, the closes were increased to 30 and 15 m g/kg/day. These doses were continued up to a total duration of the experiment of 54 weeks. During this period, 7 males and 11 females of the 50 rats of each sex given each dose of DBCP used in the experiment died without tumors. Seventeen of the male rats and 33 of the females given the high dose developed squamous carcinomas of the forestomach and 12 of the females had adenocarcinomas of the breast. Five female rats given the low dose of DBCP developed mammary carcinomas and 4 males and 14 females developed gastric carcinomas. One male among the 20 rats of each sex used as vehicle controls developed a tumor that was not described more specifically. Groups of 50 male mice given 160 or 80 m g/kg/day of DBCP for 14 weeks, 200 or 100 m g/kg/day for the next 13 weeks, and 260 or 130 m g/kg/day for 25 weeks and numerically similar groups of female mice given 120 or 60 m g/kg/day for the first 14 weeks and thereafter given the same doses as the males developed 14 gastric carcinomas in males and 9 in females on the high dose, and 3 in each sex on the low dose of DBCP. N o mammary carcinomas developed in the female mice and no tumors of any sort developed in the vehicle controls (20 of each sex for each species). A report in abstract form (Powers et al., 1975) at a later stage of the same study (after 78 weeks) changed the results in a quantitative way only, the incidence of mammary adenocarcinoma in female rats increasing to 54% and that of squamous cell carcinoma of the stomach exceeding 60% in the rats and 90% in the mice. A draft of the final report of the contractor (Hazleton Laboratories America, 1977) to the N a tional Cancer Institute reveals that male B6C3F1 mice received 160 or 80 m g/kg/day of DBCP by gavage for 11 weeks, 200 or 100 m g/kg/day for 14 weeks and 260 or 130 m g/kg/day for 22 or 33 weeks, respectively. The time weighted average daily doses were 219 m g/kg for the high-dose group and 113 m g/kg for the low-dose group. The female mice of the same strain received 120 or 60 m g/kg/day during the first 11 weeks and thereafter received the same doses as the males. The time-weighted average doses for the females were 209 m g/kg and 109 m g/kg. Osborne-Mendel rats of the two sexes were given identical doses: 24 or 12 m g/kg for the first 9 weeks, 15 m g/kg for 60 weeks (males) or 64 weeks (fem ales), followed by a 5-week observation period for the males, for the low-dose group, and 30 m g/kg for 55 weeks for the high dose group. For both male and female rats, the time-weighted average daily doses, 5 days/week, were 15 m g/kg for the low dose group and 29 m g/kg for the high dose one. The preliminary estimates are that the growth of male mice decreased slightly after the first 8 weeks on the high dose and after 22 weeks on the low dose. The growth of the females may have decreased after 32 weeks on the high dose. Mortality among the male mice increased after 36 weeks on the high dose and after 38 weeks on the low dose; that among the females increased after 36 weeks on the high dose and after 43 weeks on the low dose. The incidences of gastric cancer in male mice were 93.5% on the low dose and 97.9% on the high dose. No other tumors were reported in the mice but toxic nephro pathy was found in 23.8% and 93.8% of male mice on the low and high doses, respectively. The similar preliminary estimates for rats are that the growth of the females decreased slightly after 9 weeks on either the low or the high dose. Mortality among the male rats increased after 47 weeks on the high dose and after 60 weeks on the low dose; that among female rats increased after 28 weeks on the high dose and after 31 weeks on the low dose. The incidences of gastric cancer were 76% on the low dose and 59% on the high dose. In the females, adenocarcinoma of the breast appeared in 48% of the rats on the low dose and 62% of those on the high dose. In both sexes of this species, there were appreciable occurrences of other malignant and be nign tumors (50% and 18% in males on the low and high doses, respectively, and 14% and 20% in the females on the low and high doses). The most common of these tumors were hemangiomas and hemangiosarcomas. Among the control rats, mammary carcinoma occurred in 10% of the female colony controls and in none of the vehicle controls. Hemangiomas or hemangiosarcomas occurred in about 5.3% of male colony control rats and 15% of the females; they appeared in 5.0% of female vehicle control rats and in none of the male ones. Cancer of the forestomach was found in no control rats or mice. Toxic nephropathy was found in 23-9% of male mice and 28% of female mice on the low dose and in 93.7% of male and female mice on the high dose of DBCP. Among fats, this type of lesion was found in 100% of both male and female rats on the low dose of DBCP and in 98% and 100% of the male and female rats, respectively, on the high dose of this compound. W ard and Habermann (1974), perhaps using some of the animals from the study just summarized, reported that the squamous cell carcinomas of the forestomach induced in mice and rats by gavage of DBCP directly into the stomach invaded the wall of the stomach and metastasized in peritoneal surfaces, especially in rats. The metastatic tumors frequently were associated with peritonitis and abscesses. On the basis of these studies with experimental animals, DBCP appears to have only slight irritative r effect on intact skin or serous surfaces of the body, but to be somewhat more irritative of respiratory mucous membranes. In two rodent species, it appears to be carcinogenic, affecting mammary tissue in the female rat and producing invasive gastric carcinomas after direct introduction into the stomachs of either sex of mice and rats. Malignant neoplasms have not been reported in rats exposed to vaporized DBCP in concentrations that killed 40 to 50% of the ex posed animals and that lasted for long enough to allow the appearance of mammary carcinomas in the exposed females if a time course similar to that fol lowing gavage obtained. The likelihood of induc tion of malignancies by occupational exposures to DBCP is difficult to predict from these studies, there fore. It seems possible that, if ingestion of DBCP can be avoided, there will be small, if any, prob ability that exposure to DBCP will induce cancer. On the other hand, no one can be certain at present that this is true. In addition, the undoubted activity of this nematocide in disturbing reproductivity physi ology, which has been demonstrated in the male employee but apparently has not been recognized ir. the female, an d . in producing renotoxic and hepatotoxic effects in rodents indicate that dedicated efforts to minimize exposure to this compound are necessary. There is no good quantitative basis for an occupa tional exposure limit, but the finding by Rakhmatulayev (1971) that repeated daily doses of 0.05 m g/kg of DBCP to male rats eventually produced decreases in the weight of the testes and in the phagocytic activity of the polymorphonuclear leucocytes indicate that the occupational exposure level should be set at a ceiling of 0.1 m g/cu m (O.Olppm). This figure is based on a daily ventilatory exchange of 18 cu m by a 70 kg man during a 10-hour work day. If all the DBCP inhaled were retained in the employee's body, this would yield a daily dose of 0.0257 m g/kg to the standard man. The draft report of a 90-day study of the inhala tion toxicity of DBCP (Hazelton Laboratories Amer ica, 1976) indicates that both rats and mice exposed for 6 hours a day, on 5 days in each of 13 weeks, to concentrations of this compound just above 1 ppm underwent slight, but definite, changes in the rate of growth and in pellation. These findings indicate that the ceiling recommended gives a probable margin of safety for man of close to 100. Comparison of the qualitative and quantitative actions of ethylene dibromide (See N IO SH 's Criteria Document for a review) and DBCP demonstrates that, although the two compounds are similar in their abilities to induce gastric cancers by gavage but ap parently not by other routes of administration, DBCP has actions that have not been reported for ethylene dibromide. Furthermore, it appears to be 10 to 20 times as potent as ethylene dibromide. # D E P A R T M E N T O F H E A L T H , E D U C A T I O N , A N D W E L F A R E PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R	# The National Institute for Occupational Safety and Health (N IO SH ) recommends that employee exposure to dibromochloropropane in the workplace be controlled so that no worker will be exposed to dibromochloropropane in excess of 10 ppb (0.1 mg/cu m) in air. The N IO SH recommendations is to restrict exposure to very low levels that can still be reliably measured in the workplace. The recom mended exposure limit of 10 ppb is above the lowest level at which a reliable estimate of occupational ex posure to dibromochloropropane can be determined at this time. The recommended standard contains recommendations for medical surveillance, informing employees of hazards, sanitation, work practices, la beling and posting, personal protective clothing and equipment, monitoring and recordkeeping. The recommended standard is designed to pro tect the health and provide for the safety of em ployees for up to a 10-hour shift, 40-hour workweek, over a working lifetime. Compliance with all sec tions of the standard should, at the minimum, sub stantially reduce adverse effects of exposure to dibro mochloropropane in the workplace. The employer should regard the recommended workplace environ mental limit as the upper bondary for exposure and make every effort to keep the exposure as low as possible. The possible effects on the health of employees chronically exposed to DBCP may include sterility, diminished renal function, and degeneration and cir rhosis of the liver. In addition, ingestion of daily doses of DBCP by mice and rats has been found to result in the appearance of gastric cancers in both sexes of both species and in mammary cancers in female rats. Although an increased risk for cancer has not been seen with inhalation exposures, these results are not definitive, therefore the risk of cancer due to occupational exposure to DBCP remains a continuing concern. There are indications from in vitro experiments that mutagenic effects may occur also, but there has been no study yet of this possi bility with mammalian subjects. Employees should be told of these possible effects and informed that some 20-25 years of experience in the manufacture and formulation of DBCP has not yet called such effects in employees of the pesticide industry to the notice of physicians and epidemiologists. A more detailed review of the known health effects are given in Enclosure 1. The recommended standard is part of a continu ing series of recommendations developed by NIOSH in accordance with the Occupational Safety and Health Act of 1970. The recommended standard is being transmitted to the Department of Labor, September 2, 1977, for review and consideration in the prepara tion of an emergency temporary standard. If research by NIOSH results in the development of improved methods for sampling and analysis of dibromochloro propane in air from the occupational environment, information regarding the new methods will be for warded to the Department of Labor. # I. RECOMM ENDATIONS FOR A TEMPORARY EMERGENCY STANDARD FOR OCCUPATIONAL EXPOSURE TO DIBROMOCHLOROPROPANE The National Institute for Occupational Safety and Health (N IO SH ) recommends that employee exposure to dibromochloropropane (DBCP) in the workplace be controlled by adherence to the follow ing sections. The standard is designed to protect the health and provide for the safety of employees for up to a 10-hour work shift, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should, at the minimum, substantially reduce the effects of DBCP on the health of em ployees and provide for their safety. The employer should regard the recommended workplace environ mental limit as the upper boundary for exposure and make every effort to keep the exposure as low as possible. The criteria and standard will be subject to review and revision as necessary. The possible effects on the health of employees chronically exposed to DBCP may include sterility, diminished renal function, and degeneration and cirrhosis of the liver. In addition, ingestion of daily doses of DBCP by mice and rats has been found to result in the appearance of gastric cancers in both sexes of both species and in mammary cancers in female rats. Although an increased risk for cancer has not been seen with inhalation exposures, thescresults are not definitive, therefore the risk of cancer due to occupational exposure to DBCP remains a continuing concern. There are indications from in vitro experiments that mutagenic effects may occur also, but there has been no study yet of this possibility with mammalian subjects. Employees should be told of these possible effects and informed that some 20-25 years of experience in the manufacture and formula tion of DBCP has not yet called such effects in employees of the pesticide industry to the notice of physicians and epidemiologists. A more detailed re view of the known health effects are given in En closure 1. Sampling methods utilizing both charcoal and Florisil® tubes have been reported to NIOSH as acceptable for measurements at the recommended en vironmental limit. However, an evaluation of the suggested methods has not yet been completed by NIOSH. Such a laboratory evaluation should be completed in the first part of FY 78. "Occupational exposure to dibromochloropro pane" refers to any workplace situation in which DBCP is manufactured, formulated, or stored. All sections of the standard shall apply where there is occupational exposure to DBCP. Section 1 -Environmental (W orkplace Air) (a) Concentration Dibromochloropropane shall be controlled in the workplace so that no employee is exposed to airborne dibromochloropropane, at a concentration greater than 10 parts per billion (approximately 0.1 m g/cu m) determined as a time weighted average (T W A ) con centration for up to a 10-hour work shift, 40-hour workweek. (b) Sampling and Analytical Methods The environmental limit represents a concentra tion of dibromochloropropane measurable by reported sampling and analytical methods. Section 2 -Medical Medical surveillance shall be made available to employees as outlined below: (a) Comprehensive preplacement or initial med ical and work histories with emphasis on reproductive experience and menstrual history. (b) Comprehensive physical examination with emphasis on the genito-urinary tract including testicle size and consistency in males. (1 ) Semen analysis to include sperm count, motility and morphology. (2 ) Other tests, such as serum testosterone, serum follicle stimulating hormone (FSH ), and serum lutenizing hormone (L H ) may be carried out if, in the opinion of the responsible physician, they are indicated. In addition, screening tests of the renal and hepatic systems may be considered. (3) A judgment of the worker's ability to use positive pressure respirators. (c) Employees shall be counseled by the physi cian to ensure that each employee is aware that DBCP has been implicated in the production of effects on the reproductive system including sterility in male workers. In addition, they should be made aware that cancer has been produced in some animals. W hile the relevancy of these findings are not yet clearly de fined, they do indicate that both employees and employers should do everything possible to minimize exposure to DBCP. (d ) Periodic examinations containing the ele ments of the preplacement or initial examination shall be made available on at least an annual basis. (e) Examinations of current employees shall be made available as soon as practic?ble after the promulgation of a standard for DBCP. (f) Medical surveillance shall be made available to any worker suspected of having been exposed to DBCP. (g) Pertinent medical records shall be maintained for all employees subject to exposure to DBCP in the workplace. Such records shall be maintained for at least 30 years after termination of employment. These records shall be made available to the desig nated medical representatives of the Secretary of Health, Education, and W elfare, of the Secretary of Labor, of the employer, the employee, or former employee. # Section 3 -Labeling and Posting A label shall be placed on each shipping and storage container of dibromochloropropane and all areas where there is occupational exposure to dibromochloropropane shall be posted. All warning signs shall be printed both in English and in the predominant language of non-Englishreading workers. Illiterate workers and workers read ing languages other than those used on labels and posted signs shall be informed of the hazardous areas and shall be informed of the instructions printed on labels and signs. ( (1 ) Engineering controls shall be used wher ever needed to keep airborne dibromochloropropane concentrations below the recommended occupational exposure limit. Compliance with this limit may be achieved by the use of respirators under the following conditions only: (A ) During the time necessary to install or test the required engineering controls. (B ) For nonroutine operations, such as emergency maintenance or repair activities. (C ) During emergencies when air con centrations of dibromochloropropane may exceed the recommended occupational exposure limit. (2) W hen a respirator is permitted by para graph (a )( 1 ) of this section, it shall be selected and used pursuant to the following requirements: (A ) The employer shall ensure that no employee is exposed to dibromochloropropane be cause of improper respirator selection, fit, use, or maintenance. (B ) The employer shall establish and en force a respirator program meeting the requirements of 29 CFR 1910.134 as amended. (C ) The employer shall provide respira tors in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided when necessary. (D ) Respiratory protective devices de scribed in Table 1-1 shall be those approved under the provisions of 30 CFR 11. (E ) Respirators specified for use in higher concentrations of dibromochloropropane may be used in atmospheres of lower concentrations. (F ) The employer shall ensure that res pirators are adequately cleaned and maintained, and that employees are instructed and drilled, at least annually, in the proper use and testing for leakage of respirators assigned to them. (G ) Respirators shall be easily accessible and employees shall be informed of their location. (b ) Eye protection Eye protection shall be provided by the employer and used by the employees where eye contact with liquid dibromochloropropane is likely. Selection, use, and maintenance of eye protective equipment shall be in accordance with the provisions of the American National Standard Practice for Occupational and Ed ucational Eye and Face Protection, ANSI Z87. . Unless eye protection is afforded by a respirator hood or facepiece, protective goggles [splash-proof safety goggles (cup-cover type dust and splash safety gog gles) which comply with 29 CFR 1910.133(a) (2 ) -( a ) ( 6 ) ] or a face shield (8-inch minimum) shall be worn at operations where there is danger of contact of the eyes with liquid dibromochloropropane be cause of spills or splashes. If there is danger of liquid dibromochloropropane striking the eyes from under neath or around the sides of the face shield, safety goggles shall be worn as added protection. (c) Protective Clothing Protective clothing shall be resistant to the pene tration and to the chemical action of dibromochloro propane. Additional protection, including gloves, bib-type aprons, boots, and overshoes, shall be pro vided for, and worn by, each employee during any operation that may cause direct contact with liquid dibromochloropropane. Supplied-air hoods or suits resistant to penetration by dibromochloropropane shall be worn when entering confined spaces, such as pits or storage tanks. In situations where heat stress is likely to occur, supplied-air suits, preferably cooled, are recommended. The employer shall ensure that all personal protective clothing is inspected regularly for defects and is maintained in a clean and satis factory condition by the employee. Section 5 -Informing Employees of Hazards from Dibromochloropropane (a) All new and present employees working where occupational exposure to dibromochloropro pane may occur shall be informed orally and in writ ing of the hazards, relevant signs and symptoms of exposure, appropriate emergency procedures, and proper conditions and precautions concerning safe use and handling of dibromochloropropane. This infor mation should be readily available to all employees involved in the manufacture, formulation, or storage of dibromochloropropane and shall be posted in prominent positions within the workplace. (b) All employees involved with the manufac ture, formulation, or storage of dibromochloropro pane shall be informed that it has been implicated in human reproductive abnormalities and has induced gastric cancers in animals following oral intubation. (c) Employers shall institute a continuing edu cation program to ensure that all employees have cur rent knowledge of job hazards, maintenance pro cedures, cleanup methods, emergency procedures, and evacuation procedures. This program shall include at least : Emergency procedures and drills. Instruction in handling spills and leaks. Decont? mination procedures. Location and use of firefighting equipment. First-aid procedures, equipment location, and use. Rescue procedures. Confined space entry procedures. Records of such training shall be kept for inspection by authorized personnel as required. This program shall be held for all employees with occupational exposure to dibromochloropropane at intervals not greater than quarterly, or whenever there is a process change. (d ) Information as required shall be recorded on the "Material Safety Data Sheet," or on a simi lar form approved by the Occupational Safety and Health Administration, U.S. Department of Labor. Section 6 -W ork Practices (a) Emergency Procedures For all work areas where emergencies may occur, the employer shall take all necessary steps to ensure that employees are instructed in and follow the pro cedures specified below and any others appropriate to the specific operation or process. (1 ) Procedures shall include at least pre arranged plans for re-entry into areas where dibromo chloropropane leaks or spills have occurred for clean up, decontamination, or maintenance purposes. (2) Evacuation alarm systems shall be pro vided by the employer. (3 ) Personal protective equipment and cloth ing as specified in Section 4 shall be used by trained personnel essential to emergency operations. (4) Nonessential employees shall be evacu ated from hazardous areas during emergencies. Per imeters of these areas shall be delineated, posted, and secured. The employees in adjacent areas shall be trained in evacuation procedures if these work areas become involved. (5) O n!/ personnel trained in the emer gency procedures and protected against the attendant hazards shall shut off sources of dibromochloropro pane, clean up spills, control and repair leaks, and fight fires in dibromochloropropane areas. (6) F.refighting procedures shall be estab lished for areas where flammable materials are used with dibromochloropropane. Chemical foam, carbon dioxide, or dry chemicals shall be used for fighting fires in areas where dibromochloropropane is present. Proper protective respirators and clothing shall be worn by all personnel in the hazard area until con centrations of airborne dibromocholorpropane have been demonstrated by monitoring to be below the recommended occupational exposure limit. (7 ) Showers, eyewash fountains, and wash room facilities shall be provided and so located as to be readily accessible to workers in all areas where skin or eye contact with liquid dibromochloropropane is likely. If liquid dibromochloropropane is splashed on the clothing or skin, contaminated clothing shall be promptly removed and the skin washed thoroughly with soap and water. If liquid dibromochloropropane gets into the eyes, they shall be irrigated immediately with copious quantities of running water. (8) Medical attention shall be provided promptly for any affected worker. Such exposures shall be reported to the immediate supervisor by the affected worker or by a fellow employee. (b) Control of Airborne Dibromochloropropane (1) Suitable engineering controls designed to limit exposure to dibromochloropropane to that prescribed in Section 1(a) shall be used. The use of completely enclosed processes is the recommended method of control for dibromochloropropane. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. W hen a local exhaust ventilation system is used, it shall be designed to prevent the accumulation or recirculation of ventilation control or process air in the work room, to maintain dibromochloropropane concentra tions below the limit of the recommended standard, and to remove dibromochloropropane from the breath ing zones of employees. Exhaust systems discharging into outside air must conform with applicable local, state, and federal air pollution regulations. Ventila tion systems shall be subjected to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic airflow measure ments at least every 3 months. Measurements of sys tem efficiency shall also be made immediately by personnel properly attired in specific protective equip ment when any change in production, process, or con trol might result in increased concentrations of air borne dibromochloropropane. Tempered makeup air shall be provided to work areas in which exhaus ventilation is operating. (c) Handling of Dibromochloropropane and General W ork Practices (1 ) W ritten operating instructions and emer gency medical procedures shall be formulated and posted where dibromochloropropane is handled or used. (2) Prompt medical attention shall be pro vided if there is known or suspected exposure to dibromochloropropane, whether or not symptoms are present. (3) The employer shall ensure that safety showers, eyewash fountains, and other emergency equipment is in proper working order through reg ularly scheduled inspections performed by qualified maintenance personnel. (4 ) Dibromochloropropane operating systems shall be inspected daily for signs of leaks by person nel attired in specified protective equipment. All equipment including valves, fittings, and connections shall be checked for tightness and good working order. All newly made connections shall be checked for Jeaks immediately after dibromochloropropane is introduced by trained personnel attired in prescribed personal protective equipment. (5 ) If there is a leak, the leak shall be cor rected immediately. W ork shall resume normally only after necessary repair or replacement has been completed, the area has been ventilated, and the concentration of dibromochloropropane has been de termined by monitoring to be below the recommended occupational exposure limit. (6 ) Transportation and use of dibromo chloropropane shall comply with all applicable local, state, apd federal regulations. Strict adherence to the pesticide container label requirements for appli cation and personal protection shall be followed. Additional standards for pesticide use by agricultural workers can be found in 40 CFR 170. (7 ) W hen dibromochloropropane containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control while moving. (8 ) Process valves and pumps shall be read ily accessible and should not be located in pits and congested areas. (9 ) Containers and systems shall be handled and opened with care. Approved protective equip ment as specified in Section 4 shall be worn whileopening, connecting, and disconnecting dibromo chloropropane containers and systems. Adequate ventilation shall be available to prevent exposure to dibromochloropropane when opening containers and systems. (10) Personnel shall work in teams when di bromochloropropane is first admitted to a system, while repairing leaks, or when entering a confined or enclosed space. (d ) W ork Areas (1) Dibromochloropropane Hazard Areas A hazard area shall be considered as any space workers may enter that has physical characteristics and sources of dibromochloropropane that could re sult in air concentrations exceeding the recommended limit. Exits shall be plainly marked and shall open outward. Emergency exit doors shall be conveniently located and shall open into areas which will remain free of contamination in an emergency. At least two separate means of exit shall be provided from each room or building in which dibromochloropropane is stored, handled, or used in quantities that could create a haza'rd. (2 ) Confined or Enclosed Spaces Entry into confined spaces, such as tanks, pits, process vessels, tank cars, sewers, or tunnels, where there may be limited egress shall be controlled by a permit system. Permits shall be signed by an author ized employer representative certifying that preven tive and protective measures have been followed. Confined spaces which have contained dibromo chloropropane shall be thoroughly ventilated to en sure an adequate supply of oxygen, tested for dibro mochloropropane and other contaminants, and inspected for compliance with these requirements prior to each entry. Adequate ventilation shall be maintained while workers are in the space. Leakage of dibromochloropropane into the confined space while work is in progress shall be prevented by dis connecting and blanking the dibromochloropropane supply lines. An individual entering confined spaces shall be furnished with appropriate personal protec tive equipment and protected by a lifeline harness tended by another worker outside the space, who shall also be equipped for entry with approved per sonal protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephone, radio, or other suitable means) shall be maintained by the standby person with the employee inside the confined or enclosed space. A third employee, equipped to proceed to the aid of the other two if necessary, shall have general surveillance of their activities. (e) Storage (1 ) Storage facilities shall be designed to contain spills completely within a surrounding dike and to prevent contamination of workroom air. (2 ) Storage of dibromochloropropane in the same area as reactive metals, such as aluminum or magnesium, or as liquid ammonia shall be pro hibited. (3 ) Storage containers shall be periodically inspected for leakage. (4 ) Ventilation switches and emergency res piratory equipment shall be located outside storage areas in readily accessible locations which will be free of dibromochloropropane in an emergency. (f) Spills, Leaks, and W aste Disposal (1 ) If dibromochloropropane leaks or is spilled, the following steps shall be taken: (A ) Evacuate all nonessential person nel from the area. (B ) Adequately ventilate the area of the spill or leak to prevent accumulation of the vapor. (C ) If in liquid form, collect spilled ma terial for reclamation or absorb in vermiculite, dry sand, earth, or similar nonreactive material. (D ) If in solid form, collect spilled ma terial in the most convenient and safe manner for reclamation or for disposal. (2 ) Personnel entering the spill or leak area shall be furnished with appropriate personal protec tive equipment. All other personnel shall be ex cluded from the area. (3 ) AH wastes and residues containing dibromochloropropane shall be collected in dibromochloropropane resistant containers and incinerated or buried in such a manner that no dibromochloropropane or toxic decomposition products are released to the environment. (b ) Appropriate locker rooms shall be available for changing into required protective clothing in ac cordance with 29 CFR 1910.141(e). Clothing con taminated with liquid dibromochloropropane shall be immediately removed and placed in a closed container in a well-ventilated area for later disposal or decon tamination. Employers shall require personnel who work with dibromochloropropane to shower before leaving the workplace at the end of a workday. (c) Employers shall ensure that employees who handle dibromochloropropane wash their hands thoroughly with soap and water before eating, smok ing, or using toilet facilities. (d ) The storage, dispensing, preparation, and consumption of food, beverages, or tobacco shall be prohibited in dibromochloropropane work areas. (e) The employer shall ensure that personnel who launder and clean clothing or equipment con taminated with dibromochloropropane are provided adequate personal protective equipment to prevent exposure and shall ensure that these employees are aware of the potential hazards of exposure to di bromochloropropane. Section 8 -M onitoring and Recordkeeping Requirements (a) Industrial hygiene surveys shall be made in any workplace where dibromochloropropane is han dled, processed, or stored. Records of these surveys, including the basis for concluding that environmental concentrations are below the recommended limit shall be maintained. Surveys shall be repeated every month or whenever a process change is made. (b ) W here exposure concentrations have not been determined, they shall be determined as soon as practicable after the promulgation of a standard based on these recommendations. (c) Requirements set forth below apply to work areas where there is occupational exposure to dibro mochloropropane. (1) An adequate number of samples shall be collected monthly for the evaluation of the work environment with respect to the occupational expo sure of the employees. (2) Environmental samples shall be taken when a new process is installed or process changes are made which may cause an increase in environ mental concentrations. Significantly increased pro duction, relocation of existing operations, interrup tion of normal maintenance schedules, or other func tion which may increase dibromochloropropane con centrations shall require resampling and analysis. (3 ) The minimum number of representative exposure determinations for an operation or process shall be based on variations in exposures and pro duction schedules and in accordance with the provi sions prescribed in Section 1 (b ). (4) If initial, periodic, or special evaluations indicate that the recommended limit is exceeded, cor rective engineering or other control measures shall be immediately instituted to ensure the safety of em ployees until a concentration below the occupational exposure limit is achieved. In such cases, sampling of each operation and work location shall be conducted until two consecutive employee exposure measure ments, taken at least 1 week apart, reveal that the employee is not exposed to dibromochloropropane above the recommended occupational exposure limit. Employers shall notify in writing, within 5 days, every employee who is found to be exposed to di bromochloropropane above the recommended environ mental limit. (d ) Employers or their successors shall maintain records which shall include sampling and analytical methods, types of respiratory protection used, con centrations found, and information concerning ex posure of employees to dibromochloropropane. Each employee shall have access to data on his or her own environmental exposures. Pertinent records of occu pational accidents and environmental exposures within the workplace shall be kept for at least 30 years after the worker's employment has ended. Rec ords of occupational exposures applicable to an em ployee should be included in that employee's medical records. The medical representatives of the Secre tary of Health, Education, and W elfare, of the Sec retary of Labor, of the employee or former employee, and of the employer shall have access to all such records. # I # APPENDIX I M ETH O D FOR SA M PLIN G D IBRO M O -CH LO RO PRO PA N E IN AIR The following method is based on detailed reports from two representatives of the Shell Development Company. These reports have been communicated only by telephone. The method has not been pub lished and has not been evaluated in NIOSH labora tories. The method has been tested by Shell with a number of field samples. Procedure 1. An air sample is collected on a tube of Florisil.® 2. If the samples cannot be analyzed immediately after collection, the samples should be stored at -200°C. The refrigerated samples may be stored for two weeks or less. 3. The l,2-dibromo-3-chloropropane is desorbed from the Florisil® with hexane. 4. Analysis is accomplished with a gas chromato graph equipped with an electron-capture detector. # Useful Range The method is applicable to air concentrations ranging from 1 to 100 parts per billion (0.01 to 1 m g/cu m ). # ATTACHMENT I LITERATURE REVIEW FOR DIBROMOCHLOROPROPANE Background: 1,2-dibrom o-3 -c h lo ro p ro p a n e (DBCP) has the formula CH.,Br-CHBr-CH2C l. It has a gram molecular weight of 236.36. An amber to brown liquid with a pungent odor, DBCP has a specific gravity of 2.09 at 14°C referred to water. It has an index of refraction of 1.553 at 14°C for the D-line of the emission spectrum of sodium. DBCP has a vapor pressure of less than 1 mm of Hg at 21°C and boils at 199°C under a pressure of 760 mm of Hg. It is miscible with aliphatic and aromatic hydrocarbons, isopropyl alcohol, 1,2-dichloropropane, tetrachloroethylene, 1,1,2-trichloroethane, and oils. The undiluted material has no flash nor fire point. Because DBCP has been diluted commonly with kero sene or other flammable solvents, the preparations available in the market place may have flash points in the vicinity of 35-36°C (Tagliabue closed cup). DBCP has been used in agriculture as a nematocide since 1955, being supplied for such use in the forms of liquid concentrate, emulsifiable concentrate, powder, granules, and solid material. Formulations of DBCP were registered for use as fumigant nematocides in 1964 on evidence that residues of the material as such would not remain on harvested raw agricultural commodities and that the only residue would consist of inorganic bromides. Newsome et al. (1977) reported, however, that substantial amounts of DBCP were found in radishes (up to 0.20 ppm) and carrots (up to 1.55 ppm in roots and 0.64 ppm in the tops) grown in soil treated with this fumigant. The estimated use of DBCP in the United States in recent years has ranged from 3.6 million pounds in 1971 to 12.3 million pounds in 1972 (USDA esti mates) . In 1971,' more than 59% of the DBCP used was applied in the Pacific Coast states (Andrilenas, 1974). The material is sold under such names as Nemagon, Fumazone, Nemafume, Nemaset, and Nematox. On August 5, 1977, the National Institute for Occupational Safety and Health (N IO SH ) was re quested by the Oil, Chemical and Atomic Workers (O CA W ) union to conduct a health hazard evalua tion at the Oxidental Chemical Company plant in Lathrop, California. This request was made when representatives of OCAW learned that a number of workers at this plant had abnormally low sperm counts. On August 9 and 10, NIOSH conducted a walk through inspection of the Lathrop plant and met with representatives from the company, the local union, and California OSHA. NIOSH staff also met with Dr. W horton, Univ. of Calif., Berkeley, who had consulted with the company and the union previ ously and who had conducted medical examinations of the affected employees. Medical examinations of a number of additional employees have subsequently been conducted by NIOSH staff in conjunction with Dr. Whorton. On August 12, the Occupational Safety and Health Administration in a telegram alerted approxi mately 80 manufacturers and formulators to the po tential hazard of worker exposure to DBCP. On August 23, a guideline document detailing suggested work practices was forwarded to these same affected companies. On August 19, the Director, NIOSH, wrote to the major manufacturers of DBCP requesting infor mation to fully evaluate the extent of the hazard posed by exposure to DBCP. Animal Toxicity. Torkelson et al. (1961) re ported that results of studies of the toxicity of DBCP for various species of animals by two different labora tories (A and B). Rakhmatulayev (1971) Rakhmatulayev listed the effects of lethal doses as being brief central excitation followed by depression, analgesia, uncoordinated activity of skeletal muscles, and paralysis of limbs. Torkelson et al. (1961) reported also that DBCP as a 1 r /c solution in propylene glycol or as undiluted liquid dropped into conjunctival sacs of rabbits' eyes produced slight irritation and pain of the conjunctivae and iris. These effects disappeared after 1-2 days. W ashing the eyes with water 30 seconds after contact with DBCP did not alter the conjunctival and iridial responses. # 9 Rakhmatulayev 350 316 Applications of 0.5 ml of DBCP to the shaven backs of 4 rabbits produced slight erythema in abraded areas of skin and no signs of irritation in intact skin (Torkelson et al., 1961). Repetition of such applications resulted in only a slight crustiness of the skin after 20 applications. The dermis and subcutaneous tissue at the site of application in one rabbit had extensive necrosis and infiltration with polymorphonuclear leucocytes upon microscopic ex amination. An unspecified number of other rabbits subjected to repeated, covered applications of a lO'/r solution of DBCP in the methylether of dipropylene glycol to their shaven bellies, the applications being renewed every 24 hours up to a total of 10 applica tions, had no lesions other than slight hyperemia and scaliness of the skin at the site of application. Per cutaneous LD50's for the rabbit were 1400 m g/kg when undiluted DBCP was applied for 24 hours and 500 m g/kg when DBCP was applied as a 10% solu tion in propylene glycol. Rats reported by Torkelson et al. (1961) to have been exposed to vaporized DBCP were observed to become apathetic, sluggish and ataxic but not to be completely narcotized. Clouding of the cornea or lens was seen with exposures to the higher concentra tions (up to about 400 ppm ). Laboratory A found that the LC50 fell from about 400 ppm with a 1-hour exposure to one of about 110 ppm for a 7-hour expo sure. Laboratory B did not estimate LC50's but ob tained mortalities in groups of rats that suggest a relationship between duration of exposure and LC50 fairly similar to that found by laboratory A within the range of durations of exposure used by the latter group. Laboratory B found that a concentration of about 290 ppm killed 2/12 rats at an exposure dura tion of 12 minutes, 3/12 rats at one of 30 minutes, and 3/12 rats at one of 60 minutes. These values suggest, but do not demonstrate, that the same straight line relationship between log concentration and duration of exposure found by Laboratory A for durations of 1 to 7 hours may not obtain with dura tions of exposure less than 1 hour. Fifty inhalation exposures lasting for 7 hours, 5 days/week, of male rats to a concentration of DBCP of 5 ppm killed 0/15 animals, one to 10 ppm killed 2/15, and one to 20 ppm killed 10/15. Even the lowest of these concentrations produced a decrease of 18.6% in the mean weight of the testes. This was not a statistically significant decrease. Ex posure to the next higher concentration (10 ppm) produced a statistically significant decrease (49.0% ) in the mean weight of the testes. Exposure to that concentration also resulted in a significant increase in the weight of the kidney (31.7% )-These studies were performed by Laboratory A (Torkelson et al., 1961). Laboratory B (Torkelson et al., 1961) exposed male and female rats to 50 7-hour exposures to 12 ppm of DBCP. These exposures resulted in the deaths of 8/20 male and of 10/20 female rats, de generative changes in the seminiferous tubules, reduc tion in the number of sperm cells, increase in the proportion of abnormal sperm cells, increase in the number of Sertoli cells in the males, significant in creases in the weights of the kidneys in both sexes with cloudy swelling of the epithelium of the proxi mal convoluted tubules and increased amounts of interstitial tissue in the kidneys of the males, and dilatation of the sinusoids and centrilobular conges tion in the livers of both sexes. Laboratory B (Torkelson et al., 1961) also gave to guinea pigs and rabbits 66 7-hour exposures to va porized DBCP in a concentration of 12 ppm. These exposures killed no animals but did result in statis tically significant decreases in the mean weights of the testes in both species. Two female monkeys exposed for 50 and 60 times, respectively, to 12 ppm of DBCP developed severe leukopenias and anemias. The concentrations of bromide in the sera of the ex posed rats, guinea pigs, and rabbits ranged between 6.7 and 12.8 m g/100 ml whereas those of the control animals of these 3 species ranged from 0 to 7.8 m g /100 ml. Torkelson et al. (1961) reported also the results from a 90-day feeding study with rats of both sexes. The concentrations of DBCP in the diet were 0, 5, 20, 50, 150, 450, and 1350 ppm. The kidneys of female rats fed diets with concentrations of 20 or more ppm of DBCP and the livers of those fed diets containing 450 or more ppm were significantly heavier than those of the controls. Only those males fed the diet includ ing 1350 ppm of DBCP had kidneys and livers sig nificantly heavier than those of the controls. These studies revealed that DBCP had two out standing toxic effects in subacute exposures: an antispermiogenic effect in the male and a nephrotoxic effect that occurred in both sexes of the rat, but espe cially in the female. Laboratory B was able to show that neither the adrenocorticotropic hormone (A C T H ), cortisone, nor testosterone altered bene ficially the effect of DBCP on the testes. Indeed, testosterone enhanced the atrophic effect of DBCP. The final bit of information in the paper by Torkelson et al. (1961) was that men given brief exposure to a concentration of 1.7 ppm of DBCP described a definite, not unpleasant, odor. The auth ors recommended that occupational exposure to DBCP be controlled to hold the airborne concentration of the nematocide below 1 ppm. Rakhmatulayev (1971) also reported results from a subacute (2l/2 months' duration) and a chronic (8 months' duration) experiment using rats and administering DBCP by mouth in doses of 17.5-70 m g7kg (subacute) and .0005-5 m g/kg (chronic). The most sensitive indicators of toxic activity by DBCP in these experiments were reductions in the weight of the testes and in duration of motility of spermatozoa, decreased avidity of leucocytes for en gulfing bacteria and decreased rate of positive con ditioning. These effects were present with the dose of 0.05 mg/kg, but not with that of 0.005 m g/kg, in the chronic exposure study. Faydysh (1973) performed another study of the effect of prolonged administration (5 months) of DBCP in oral doses of 0.05, 0.5, and 5.0 m g/kg. The two highest doses were observed to decrease both the activity of neutrophils in engulfing and digesting bacteria and the concentration of these cells in the blood. These results confirm the report of Rakhmatulayev (1971) mentioned just above. Because phagocytically-mediated immunity is one of the defensive mechanisms of the body against conditions related to proliferation of abnormal cells, these effects of DBCP may contribute to the carcinogenic activity of this compound in experimental animals. Faydysh et al. (1970) and Faydysh and Avkhimenko (1974) studied further the effects of DBCP on testicular function. In the first study, 10 male rats were given daily oral doses of 70 m g/kg of DBCP in sunflower seed oil. Ten other male rats were given corresponding volumes of the sunflower seed oil alone. Five of the rats given DBCP died between days 20 and 25 of the experiment; the other 5 lived through the 45 days of the experiment. At necropsy, all internal organs were pallid and the gastric mucosa was noted to have been thinned. Although the blood was not examined specifically, the authors' description of the general appearance of the internal organs and of the vascular system raises a suspicion that there was marked anemia. The major parenchymatous organs, particularly the liver and kidneys, and the testes had undergone pro nounced necrotic effects. The livers contained areas of cirrhosis replacing necrotised tissue and the spleens had areas of necrosis in both the white and the red pulps. The parenchyma destroyed in the testes also was replaced by scar tissue. Some regenerative ac tivity was visible in the parenchymatous organs. The second paper demonstrated that similar changes could be accomplished by a daily dose of 0.5 m g/kg given during a longer period of time. This suggests that DBCP exerts some relatively, or possibly completely, irreversible action that eventually accumulates to pro duce a deleterious effect on target organs. Reznik and Sprinchan (1975) studied the gona dotropic actions of DBCP in both male and female rats. Single oral doses of 100 m g/kg or daily doses of 10 mg/kg, administered for 4 to 5 months, were used. The single dose produced within one week a decrease in the sperm count in the semen from 4.9±0.2 m illion/m g to 2.6±0.3 million /mg. At the same time, there was a decrease in the duration of mortility of the spermatozoa from about 31 minutes to about 15 minutes. In the females, the estrus cycle was prolonged, both estrus and diestrus becoming longer. The repeated doses of DBCP eventually pro duced effects similar to those that followed the single large dose. By the fourth month of administration, the concentration of spermatozoa in the semen was 2.5±0.5 m illion/m g vs 4.9±0.3 m illion/m g in the controls and the duration of motility of the sperma tozoa Was 29 minutes whereas that of spermatozoa from,control rats was 51 minutes. During the first month of daily doses, 24% of the females developed atypical estrus cycles; by the fifth month, this figure rose to 70% . At the same time, the duration of the cycles increased; 57% of the females became acyclic by the fifth month. It is apparent, therefore, that an effect on sperm count in the male may not be the only effect on human fertility from occupational ex posure to DBCP and that the possibility of induction of sterility in female employees needs to be con sidered also. No experimental study of teratogenic or muta genic activities by DBCP in mammals has been found. Rosenkranz (1975) examined the effects of this sub stance on two strains of E. coli and on two of the tester strains of Salmonella typhimurium: TA 1530 and TA 1538. DBCP was mutagenic for the first of these tester strains but not for the second, indicating that it induces mutations of the base-substitution but not of the frame-shift type. The finding that DBCP inhibited growth of a strain of E. coli deficient in D NA polymerase to nearly 2.4x the extent of its in hibition of that of a strain with a normal complement of the polymerase indicates that its principal effect is on the DNA. These results are reminiscent of those of Vogel and Chandler (1974) in which they found that 1,2-dibromopropane was definitely mutagenic in Drosophila. As pointed out by these latter auth ors, the important property of vicinal 1,2-dibromides is that in solution they readily rearrange to form the very reactive bromonium ions. This ability would not be modified importantly by substitution of a chlorine atom on the third carbon of propane. The National Cancer Institute undertook in 1972 studies of the possible carcinogenicity of DBCP, as one of a group of halogenated compounds. As early as 14 weeks after the initiation of administration by stomach tube of daily doses of 24 m g/kg of DBCP dissolved in corn oil, 5 times per week, several female rats were found to have palpable mammary tumors (Olson et al., 1973). Female rats given daily doses of 12 m g/kg of DBCP had not developed mammary tumors. After the fourteenth week, the closes were increased to 30 and 15 m g/kg/day. These doses were continued up to a total duration of the experiment of 54 weeks. During this period, 7 males and 11 females of the 50 rats of each sex given each dose of DBCP used in the experiment died without tumors. Seventeen of the male rats and 33 of the females given the high dose developed squamous carcinomas of the forestomach and 12 of the females had adenocarcinomas of the breast. Five female rats given the low dose of DBCP developed mammary carcinomas and 4 males and 14 females developed gastric carcinomas. One male among the 20 rats of each sex used as vehicle controls developed a tumor that was not described more specifically. Groups of 50 male mice given 160 or 80 m g/kg/day of DBCP for 14 weeks, 200 or 100 m g/kg/day for the next 13 weeks, and 260 or 130 m g/kg/day for 25 weeks and numerically similar groups of female mice given 120 or 60 m g/kg/day for the first 14 weeks and thereafter given the same doses as the males developed 14 gastric carcinomas in males and 9 in females on the high dose, and 3 in each sex on the low dose of DBCP. N o mammary carcinomas developed in the female mice and no tumors of any sort developed in the vehicle controls (20 of each sex for each species). A report in abstract form (Powers et al., 1975) at a later stage of the same study (after 78 weeks) changed the results in a quantitative way only, the incidence of mammary adenocarcinoma in female rats increasing to 54% and that of squamous cell carcinoma of the stomach exceeding 60% in the rats and 90% in the mice. A draft of the final report of the contractor (Hazleton Laboratories America, 1977) to the N a tional Cancer Institute reveals that male B6C3F1 mice received 160 or 80 m g/kg/day of DBCP by gavage for 11 weeks, 200 or 100 m g/kg/day for 14 weeks and 260 or 130 m g/kg/day for 22 or 33 weeks, respectively. The time weighted average daily doses were 219 m g/kg for the high-dose group and 113 m g/kg for the low-dose group. The female mice of the same strain received 120 or 60 m g/kg/day during the first 11 weeks and thereafter received the same doses as the males. The time-weighted average doses for the females were 209 m g/kg and 109 m g/kg. Osborne-Mendel rats of the two sexes were given identical doses: 24 or 12 m g/kg for the first 9 weeks, 15 m g/kg for 60 weeks (males) or 64 weeks (fem ales), followed by a 5-week observation period for the males, for the low-dose group, and 30 m g/kg for 55 weeks for the high dose group. For both male and female rats, the time-weighted average daily doses, 5 days/week, were 15 m g/kg for the low dose group and 29 m g/kg for the high dose one. The preliminary estimates are that the growth of male mice decreased slightly after the first 8 weeks on the high dose and after 22 weeks on the low dose. The growth of the females may have decreased after 32 weeks on the high dose. Mortality among the male mice increased after 36 weeks on the high dose and after 38 weeks on the low dose; that among the females increased after 36 weeks on the high dose and after 43 weeks on the low dose. The incidences of gastric cancer in male mice were 93.5% on the low dose and 97.9% on the high dose. No other tumors were reported in the mice but toxic nephro pathy was found in 23.8% and 93.8% of male mice on the low and high doses, respectively. The similar preliminary estimates for rats are that the growth of the females decreased slightly after 9 weeks on either the low or the high dose. Mortality among the male rats increased after 47 weeks on the high dose and after 60 weeks on the low dose; that among female rats increased after 28 weeks on the high dose and after 31 weeks on the low dose. The incidences of gastric cancer were 76% on the low dose and 59% on the high dose. In the females, adenocarcinoma of the breast appeared in 48% of the rats on the low dose and 62% of those on the high dose. In both sexes of this species, there were appreciable occurrences of other malignant and be nign tumors (50% and 18% in males on the low and high doses, respectively, and 14% and 20% in the females on the low and high doses). The most common of these tumors were hemangiomas and hemangiosarcomas. Among the control rats, mammary carcinoma occurred in 10% of the female colony controls and in none of the vehicle controls. Hemangiomas or hemangiosarcomas occurred in about 5.3% of male colony control rats and 15% of the females; they appeared in 5.0% of female vehicle control rats and in none of the male ones. Cancer of the forestomach was found in no control rats or mice. Toxic nephropathy was found in 23-9% of male mice and 28% of female mice on the low dose and in 93.7% of male and female mice on the high dose of DBCP. Among fats, this type of lesion was found in 100% of both male and female rats on the low dose of DBCP and in 98% and 100% of the male and female rats, respectively, on the high dose of this compound. W ard and Habermann (1974), perhaps using some of the animals from the study just summarized, reported that the squamous cell carcinomas of the forestomach induced in mice and rats by gavage of DBCP directly into the stomach invaded the wall of the stomach and metastasized in peritoneal surfaces, especially in rats. The metastatic tumors frequently were associated with peritonitis and abscesses. On the basis of these studies with experimental animals, DBCP appears to have only slight irritative r effect on intact skin or serous surfaces of the body, but to be somewhat more irritative of respiratory mucous membranes. In two rodent species, it appears to be carcinogenic, affecting mammary tissue in the female rat and producing invasive gastric carcinomas after direct introduction into the stomachs of either sex of mice and rats. Malignant neoplasms have not been reported in rats exposed to vaporized DBCP in concentrations that killed 40 to 50% of the ex posed animals and that lasted for long enough to allow the appearance of mammary carcinomas in the exposed females if a time course similar to that fol lowing gavage obtained. The likelihood of induc tion of malignancies by occupational exposures to DBCP is difficult to predict from these studies, there fore. It seems possible that, if ingestion of DBCP can be avoided, there will be small, if any, prob ability that exposure to DBCP will induce cancer. On the other hand, no one can be certain at present that this is true. In addition, the undoubted activity of this nematocide in disturbing reproductivity physi ology, which has been demonstrated in the male employee but apparently has not been recognized ir. the female, an d . in producing renotoxic and hepatotoxic effects in rodents indicate that dedicated efforts to minimize exposure to this compound are necessary. There is no good quantitative basis for an occupa tional exposure limit, but the finding by Rakhmatulayev (1971) that repeated daily doses of 0.05 m g/kg of DBCP to male rats eventually produced decreases in the weight of the testes and in the phagocytic activity of the polymorphonuclear leucocytes indicate that the occupational exposure level should be set at a ceiling of 0.1 m g/cu m (O.Olppm). This figure is based on a daily ventilatory exchange of 18 cu m by a 70 kg man during a 10-hour work day. If all the DBCP inhaled were retained in the employee's body, this would yield a daily dose of 0.0257 m g/kg to the standard man. The draft report of a 90-day study of the inhala tion toxicity of DBCP (Hazelton Laboratories Amer ica, 1976) indicates that both rats and mice exposed for 6 hours a day, on 5 days in each of 13 weeks, to concentrations of this compound just above 1 ppm underwent slight, but definite, changes in the rate of growth and in pellation. These findings indicate that the ceiling recommended gives a probable margin of safety for man of close to 100. Comparison of the qualitative and quantitative actions of ethylene dibromide (See N IO SH 's Criteria Document for a review) and DBCP demonstrates that, although the two compounds are similar in their abilities to induce gastric cancers by gavage but ap parently not by other routes of administration, DBCP has actions that have not been reported for ethylene dibromide. Furthermore, it appears to be 10 to 20 times as potent as ethylene dibromide. # D E P A R T M E N T O F H E A L T H , E D U C A T I O N , A N D W E L F A R E PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R	None	None
b9cb760b77b9fa6b03010806fad2096e28181702	cdc	None	# Introduction Findings from several clinical trials have demonstrated safety 1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM), 2,3 men and women in heterosexual discordant couples, 4 and heterosexual men and women recruited as individuals 5 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) and emtricitabine (F). 3 In addition, one clinical trial among persons who inject drugs (PWID) (also called injection drug users 6 and one among men and women in heterosexual HIV-discordant couples 4 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone. The demonstrated efficacy of daily oral PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including persons in the drug treatment group and persons in the placebo group. In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada (F/TDF) "in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk." 7 In May 2018, the approval for F/TDF was extended to adolescents weighing at least 35 kg (77 lb) based on safety trials in adolescents 8 and young adults. 9 In June 2019, the US Preventive Services Task Force recommended PrEP for adults and adolescents at risk of HIV acquisition with an "A" rating (high certainty that the net benefit of the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection is substantial). 10 And in October 2019, based on a clinical trial conducted with 5,313 MSM and 74 transgender women, the FDA approved a PrEP indication for daily F/TAF for sexually active persons at risk of HIV acquisition. 3 Women at risk through receptive vaginal sex were excluded from the F/TAF approval, because no women (assigned female sex at birth) were included in the efficacy and safety PrEP trial. In 2020, results from a clinical trial conducted with MSM and transgender women 11 and another conducted African women 12 reported high efficacy and safety for bimonthly injections of cabotegravir (CAB) for PrEP. Submission of data for review by the FDA for approval of a PrEP indication is planned in 2021. On the basis of these trial results and FDA approvals, the U.S. Public Health Service published a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States in 2014 and updated it in 2017 and in 2020. . This supplement to the PHS PrEP Clinical Practice Guidelines is intended to provide additional information that may be useful to clinicians providing PrEP. As additional materials become available, this document will be updated. Many of the studies that informed these guidelines included small numbers of transgender women and none included transgender men, as a result, data specifically relevant for transgender and non-binary people are often limited or not available. Most sections of this supplement, therefore, use the terminology, 'women' and 'men' unless specifically referring to transgender women or men. We continue to advocate for greater inclusion of transgender and non-binary people in PrEP-related research and recommend gender-inclusive models of PrEP care to ensure that services encompass and address the needs of all persons who would benefit from its use.  Administered a gluteal IM injection of cabotegravir (600 mg in 3 ml)  A follow-up appointment date As the provider, I will: 1 An off-label use It has been explained to me that: - Taking a dose of PrEP medication every day will lower my risk of getting HIV infection. - This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. - This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. - It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). - My provider will test for HIV infection at least once every 3 months. Therefore, I will: - Try my best to take the medication my provider has prescribed every day. - Talk to my provider about any problems I have in taking the medication every day. - Not share the medication with any other person. - Attend all my scheduled appointments. - Call _________________ to reschedule any appointments I cannot attend. # Give one copy to patient Preexposure Prophylaxis for the Prevention of HIV Infection in the United States -2021 Update Clinical Providers' Supplement Page 10 of 53 Patient Section -"2-1-1" Dosing It has been explained to me that: - Taking the PrEP medication I have been prescribed (Truvada) both before and after I have sex every day can lower my risk of getting HIV infection. - I should take 2 pills in the 2-24 hours before I expect to have sex, then 1 pill a day later, and 1 pill two days later. - If I am having sex at least once a week, I should consider taking PrEP medication daily rather than before and after each time I have sex. - This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. - This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. - It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). - My provider will test for HIV infection at least once every 3 months. Therefore, I will: - Try my best to take the medication my provider has prescribed before and after each time I have sex. - Talk to my provider about any problems I have in taking the medication before and after each time I have sex. - Not share the medication with any other person. - Attend all my scheduled appointments. - Call _________________ to reschedule any appointments I cannot attend. # Patient Section -Cabotegravir Injections It has been explained to me that: - Receiving the PrEP injections (cabotegravir) every 8 weeks will lower my risk of getting HIV infection. - This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. - This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. - It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). - My provider will test for HIV infection at least once every 4 months. Therefore, I will: - Attend all my scheduled appointments. - Call _________________ to reschedule any appointments I cannot attend. - Talk to my provider if I want to stop taking PrEP injections so that I can stop safely # Give one copy to patient # Section 2 PrEP Information Sheet Pre-exposure Prophylaxis (PrEP) for HIV Prevention Frequently Asked Questions What is PrEP? "PrEP" stands for preexposure prophylaxis. The word "prophylaxis" (pronounced pro fil ak sis) means to prevent or control the spread of an infection or disease. The goal of PrEP is to prevent HIV infection from taking hold if you are exposed to the virus. This is done by taking a pill that contains 2 HIV medications every day or by getting an injection with 1 HIV medicine every 2 months. These are the same medicines used to stop the virus from growing in people who already have HIV infection. # Why take PrEP? Nearly 40,000 people get infected with HIV each year in the U.S. More of these infections are happening in some groups of people and some areas of the country than in others. # Is PrEP a vaccine? No. PrEP medication does not work the same way as a vaccine. When you take a vaccine, it trains the body's immune system to fight off infection for years. You will need to take a pill every day by mouth for PrEP medications to protect you from infection. PrEP does not work after you stop taking it. The medications that have been shown to be safe and to help block HIV infection are called "Truvada" (pronounced tru va duh) or "Descovy" (pronounced des koh vee). Truvada is a combination of 2 drugs (tenofovir disoproxil fumarate and emtricitabine). Descovy is a combination of 2 drugs (tenofovir alafenamide and emtricitabine). The drug in the injection is called cabotegravir (pronounced cab oh teh gruh veer) .These medicines work by blocking important pathways that the HIV virus uses to set up an infection. If you take either of these medications as PrEP daily, the presence of the medication in your bloodstream can often stop the HIV virus from establishing itself and spreading in your body. If you do not take the pills in the way you were instructed, there may not be enough medicine in your blood stream to stop the virus from establishing an infection in your body. # Should I consider taking daily PrEP? PrEP is not for everyone. You should consider PrEP if you are a man or woman who sometimes has sex without using a condom, especially if you have a sex partner who you know has HIV infection and does not have his/her virus under control with medication. You should also consider PrEP if you don't know whether your partner has HIV infection, but you know that your partner is at risk (for example, your partner injects drugs or is having sex with other people in addition to you) or if you have recently been told by a health care provider that you had a sexually transmitted infection. If your partner has HIV infection, PrEP may be an option to help protect you from getting HIV infection while you try to get pregnant, during pregnancy, or while breastfeeding. # How well does PrEP work? PrEP was tested in several large studies with men and women at high risk of being exposed to HIV while having sex or injecting drugs. All people in these studies ( 1) were tested at the beginning of the trial to be sure that they did not have HIV infection, (2) agreed to take an oral PrEP tablet daily or an injection every other month, (3) received intensive counseling on safersex and safe-injection behavior, (4) were tested regularly for sexually transmitted infections, and ( 5) were given a regular supply of condoms. In these studies, when people took PrEP daily (or missed only occasional doses) or had regular PrEP injections, the risk of getting HIV infection during sex dropped by 90% or more. When people who used PrEP in the community were assessed, the risk of getting HIV infection during sex dropped by up to 99%. People who take PrEP daily as prescribed rarely get HIV infection. More information on the details of these studies can be found at . # Is PrEP safe? The clinical trials also provided safety information on PrEP. Some people in the trials of oral PrEP medicines had early side effects such as an upset stomach or loss of appetite, but these side effects were mild and usually went away within the first month. Some people also had a mild headache. Many people in trials of PrEP injections had a reaction at the injection site like mild pain, redness, or swelling. These reactions were mild and lasted only a couple of days. No serious side effects were observed. You should tell your health care provider if these or other symptoms become severe or do not go away. # How can I start PrEP? If you think you may be at high risk for HIV, talk to your provider about PrEP. If you and your health care provider agree that PrEP might reduce your risk of getting HIV infection, you will need to come in for a general health physical, blood tests for HIV, and tests for other infections that you can get from sex partners. For oral PrEP, your blood will also be tested to see if your kidneys are functioning well. If these tests show that PrEP medicines are likely to be safe for you to take and that you might benefit from PrEP, your health care provider will give you the form of PrEP you decide on; either a prescription for an oral pill (Truvada or Descovy) or an injection with cabotegravir. Taking PrEP medicines will require you to follow-up regularly with your health care provider. You will receive counseling on sexual behaviors and blood tests for HIV infection and to see if your body is reacting well to Truvada, Descovy, or cabotegravir. You should take your oral medicine daily as prescribed or your injections every two months, and your health care provider will advise you about ways to help you take it regularly so that it stands the best chance to help you avoid HIV infection. Tell your health care provider if you are having trouble remembering to take your medicine, return for your injections, or if you want to stop PrEP. # Is daily Truvada my only choice for PrEP? If you are a man who has sex with men (MSM) or a transgender woman, there is a second option for taking daily PrEP. A large study of MSM showed that daily use of a second medication called Descovy, is just as safe and effective as Truvada. Since Descovy was not studied in persons assigned female sex at birth, it is unknown whether it is effective protection for vaginal sex. So, it should only be prescribed to MSM. An additional trial has shown that injections with cabotegravir every two months is highly effective HIV prevention. # Is taking medication every day my only choice for PrEP? Another large study with MSM showed that for men who have sex infrequently, Truvada can be highly protective when taken only before and after sex. Among men who could anticipate when they would have sex, they took two pills several hours before having sex on a given day, then one pill a day later, and a final pill the next day. Because of this schedule of pill taking, it's called "2-1-1" PrEP. This was only studied with Truvada taken by MSM, so 2-1-1 PrEP is NOT prescribed for women or with Descovy, because we do not know it will work well. An additional trial has shown that injections with cabotegravir every two months is highly effective HIV prevention. # If I take PrEP can I stop using condoms when I have sex? You should not stop using condoms because you are taking PrEP. If PrEP is taken daily, it offers a lot of protection against HIV infection, but not 100%. Condoms also offer a lot of protection against HIV infection if they are used correctly every time you have sex, but not 100%. PrEP medications don't give you any protection from other infections you can get during sex, but condoms do. So, you will get the most protection from HIV and other sexual infections if you consistently take PrEP medication and consistently use condoms during sex. # How long do I need to take PrEP? You should discuss this with your health care provider. There are several reasons that people stop taking PrEP. If your risk of getting HIV infections becomes low because of changes that occur in your life, you may want to stop taking PrEP. You can restart PrEP later if your life changes in ways that increase your risk. If you find you don't want to take a pill every day or often forget to take your pills, or don't want to continue PrEP injections, other ways of protecting yourself from HIV infection may work better for you. If you have side effects from the medication that are interfering with your life or if blood tests show that your body is reacting to PrEP in unsafe ways, your health care provider may stop prescribing PrEP for you. # Do I need to do anything special if I want to stop having PrEP injections? If you stop taking PrEP pills, the medication clears from your body within a couple of weeks. But when you stop receiving PrEP injections, the medication takes a year or more to completely leave your body (sometimes called the "tail" period). As the level of medication drops, protection drops and you can get HIV if you are exposed to it. If you have low levels of medication and get HIV, the virus can be less sensitive to the medication ('resistant") and this might effect which medications would treat your infection. For that reason, it is important to have effective protection against HIV during the months while the cabotegravir is gradually leaving your body. This may mean you need to take daily oral PrEP medication for several months. It is important to make a plan with your provider for protection during this period. # Section 3 Medication Information Sheets Truvada and Descovy Medication Information Sheet for Patients Brand name: Truvada (tru va duh), Descovy (des koh vee) Generic name: tenofovir disoproxil fumarate and emtricitabine, tenofovir alafenamide and emtricitabine # Why is this medication prescribed? - Truvada and Descovy are two of several medications that are currently used to treat human immunodeficiency virus (HIV) - Truvada and Descovy are now being also used to prevent HIV infection. - Truvada and Descovy are sometimes prescribed to some people who do not have HIV infection (for example, those who do not always use condoms or who have a sex partner that has HIV infection) to help reduce their chances of getting HIV infection. - When you take Truvada or Descovy to prevent HIV infection, health care providers refer to this use as "pre-exposure prophylaxis" or "PrEP." - Descovy is not prescribed for women (persons assigned female at birth). # How does PrEP medication help prevent HIV infection? - HIV is a virus that attacks your body's immune cells (the cells that work to fight infections). - Truvada and Descovy each contain a different form of tenofovir. They work against HIV in the same way so patients can take either medication (but not both). - The 2 medications that make up Truvada and Descovy (tenofovir and emtricitabine) block important pathways that viruses use to set up infection. - If you take Truvada or Descovy as PrEP daily, the presence of the medication in your bloodstream will usually stop the virus from establishing itself and slow the spread of HIV in your body. - PrEP with Truvada or Descovy does not work all the time so you should also use condoms during sex for the most protection from HIV and other sexually transmitted infections. How should this medicine be used? - You must take one tablet of Truvada or Descovy by mouth every day. - Follow the directions on your prescription label carefully and ask your health care provider or pharmacist to explain any part you do not understand. - Do not stop taking Truvada or Descovy without talking to your health care provider. When your supply of PrEP medicine starts to run low, contact your health care provider or pharmacist to get more. - You will be at higher risk of becoming infected with HIV if you often miss doses or stop taking PrEP medicine than if you take it every day. # What special precautions should I follow? Before taking Truvada or Descovy, you must do the following: - Tell your health care provider and pharmacist if you are allergic to tenofovir, emtricitabine, or any other medications. - Tell your health care provider and pharmacist about all prescription and nonprescription medications (e.g., over-the-counter pain medications, vitamins, nutritional supplements, protein powders, or herbal products), you are taking. Your health care provider may need to change the doses of your medications or monitor you carefully for side effects. - Tell your health care provider if you have or have ever had kidney disease. - Tell your health care provider if you become pregnant or if you are breastfeeding. # What special dietary instructions should I follow? - Continue your normal diet unless your health care provider tells you otherwise. # What should I do if I forget a dose? - Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. - Do not take a double dose to make up for a missed one. # What side effects can this medication cause? You may experience the following side effects while taking Truvada: - upset stomach - headache - vomiting - loss of appetite - a small weight gain - a change in the amount of some types of fats (lipids) in your blood These side effects usually fade during the first month of taking PrEP medication. Tell your health care provider if any of these symptoms are severe or do not go away. # What other information should I know? - Do not let anyone else take your medication. - Ask your pharmacist if you have any questions about refilling your prescription. - Write a list of all of your prescription and over-the-counter medicines, as well as any vitamins, minerals, or other dietary supplements that you take. - Bring your medication list with you each time you visit a health care provider or if you are admitted to a hospital. Keep it with you always in case of emergencies. # Cabotegravir Medication Information Sheet for Patients Brand name: cabotegravir (cab oh teh gruh veer) # Generic name: cabotegravir Why is this medication prescribed? - Cabotegravir is one of several medications that are currently used to treat human immunodeficiency virus (HIV) - Cabotegravir is now being also used to prevent HIV infection. - Cabotegravir injections are sometimes given to some people who do not have HIV infection (for example, those who do not always use condoms or who have a sex partner that has HIV) to help reduce their chances of getting HIV. - When you take cabotegravir to prevent HIV infection, healthcare providers refer to this use as "pre-exposure prophylaxis" or "PrEP." # How does PrEP medication help prevent HIV infection? - HIV is a virus that attacks your body's immune cells (the cells that work to fight infections). - Cabotegravir works against HIV by blocking important pathways that viruses use to set up infection. - If you take cabotegravir injections for PrEP, the presence of the medication in your bloodstream will usually stop the virus from establishing itself and slow the spread of HIV in your body. - PrEP with cabotegravir does not work all the time so you should also use condoms during sex for the most protection from HIV and other sexually transmitted infections. How should this medicine be used? - You will receive a cabotegravir injection into the buttock muscle in the back side of your hip. - Ask your health care provider or nurse to explain any part of PrEP use that you do not understand. - Do not stop taking cabotegravir injections without talking to your health care provider. - You will be at risk of getting HIV if you stop taking PrEP injections without starting another effective prevention method. # What special precautions should I follow? Before getting a cabotegravir injection, you must do the following: - Tell your health care provider and pharmacist about all prescription and nonprescription medications (e.g., vitamins, nutritional supplements, and herbal products), you are taking. Your health care provider may need this information to know if any of these medicines interact with the cabotegravir. - Tell your health care provider if you become pregnant or if you are breastfeeding. # What special dietary instructions should I follow? - Continue your normal diet unless your health care provider tells you otherwise. # What should I do if I forget my appointment for an injection? - If you miss an injection appointment, schedule another visit to continue injections. # What side effects can this medication cause? You may experience the following side effects at the site where you got your cabotegravir injection: - mild or moderate pain - redness - local swelling These side effects usually fade within a few days of your PrEP injection. Taking an over-thecounter pain medication and using a heating pad at the site of the injection for 15-20 minutes a couple of times each day may help reduce the reaction. Tell your health care provider if any of these symptoms are severe or do not go away. If you experience a serious side effect, you or your health care provider may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (at ) or by phone (1-800-332-1088). Lastly, when people have lots of virus in their body during acute HIV infection, they are more likely to pass the virus on to people they have sex with, especially since they may not know yet that they have HIV. For example, if your last HIV test result was negative and your partner also had a recent negative HIV test result, you might choose to have sex without a condom just at the time when it's very likely you could more easily pass the virus to others. The sooner you know you have become infected, the more careful you can be to protect others from getting HIV infection. # How is HIV treated? People who have HIV infection are treated with combinations of 2 or more medicines that fight HIV. Nearly all health care providers start people on treatment medications as soon as HIV tests show they have gotten the virus. Treatment also reduces the chances that a person with HIV infection will transmit the virus to his/her sex partners. When treatment is able to reduce the amount of HIV in your blood to a level too low to be measured (also called "undetectable"), there is effectively no risk of passing the virus to another person during sex. # What do I do if I suspect I might have acute HIV infection? First, contact your health care provider's office and arrange to be examined and have the right blood tests. Second, discuss with your health care provider whether to stop your PrEP medications or continue them until your test results are back. Third, be especially careful to use condoms and take other safer sex measures to protect your partner(s). # Section 5 Risk Reduction Counseling Assessing HIV and STI risk should be a part of every initial and follow-up PrEP visit. Based on the risks identified for a patient's potential exposure to HIV, you should encourage risk reduction by providing prevention counseling whether the patient will be prescribed PrEP or not. Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the patient's culture, language, sex and gender identity, sexual orientation, age, and developmental level. USPSTF recommends intensive behavioral counseling for all sexually active adolescents and for adults at increased risk for STIs and HIV. For patients being prescribed PrEP, they will be utilizing the most effective HIV risk reduction method available. Educating the patient on how to ensure PrEP is maximally effective and supporting adherence to PrEP should be prioritized. Following that, you should provide sciencebased information on other HIV and STI prevention methods such as condoms, reducing the number of sexual partners, knowing their partner's HIV status, understanding the benefits of an HIV partner being on treatment with an undetectable viral load, and strategies to reduce the effect of alcohol or drug use on sexual risk taking. The goal should be to provide the patient with the necessary information for them to decide which prevention strategies they consider achievable and valuable. Having a risk-reduction conversation can be challenging. The conversation often takes time and behavioral change in any patient can be slow. For PrEP patients who will be regularly monitored, you will have time to build a relationship with the patient during regular follow-up visits. These follow-up visits offer opportunities for an ongoing discussion of HIV risk including ways the patient could further reduce their risk. Critical to building a respectful relationship is to approach the conversation without judgement. The goal is to develop a risk reduction plan that meets the patient's needs while keeping their risk as low as possible. Some patients will not make the objectively safest choice or the choice that you believe is best. In these situations, you have to be prepared to accept and support the patient's decisions, and continue to provide non-judgmental, evidence-based information. # Section 6 MSM Risk Index Epidemiologic studies have identified a wide range or personal, relationship, partner, social, cultural, network, and community factors that may be associated with the presence of HIV infection. However, to provide PrEP or other intensive HIV prevention services, it is necessary to briefly and systematically screen for key information about those factors that are predictive of acquiring HIV infection. This section contains a tool that clinicians may use to quickly and systematically determine which MSM are at high risk of acquiring HIV infection and for whom PrEP may be indicated. If score is below 10, provide indicated standard HIV prevention services. # Section 7 PWID (IDU) Risk Index Epidemiologic studies have identified a wide range or personal, relationship, partner, social, cultural, network, and community factors that may be associated with the presence of HIV infection. However, to provide PrEP (or other intensive HIV prevention services), it is necessary to briefly and systematically screen for key information about those factors that are predictive of acquiring HIV infection. This section contains a tool that clinicians can use to quickly and systematically determine which persons who inject drugs (PWID) (also called injection drug users ) are at high risk for acquiring HIV infection and for whom PrEP may be indicated. Add the scores for age and methadone use to the Composite Injection Subscore to yield a Total Score _________ Total Score- - If the total score is 46 or greater, evaluate for PrEP or other intensive HIV prevention services for PWID. If score is 45 or less, provide indicated standard HIV prevention services for PWID. To identify active PWID in a clinician's practice, we recommend asking all their patients a routine question: "Have you ever injected drugs that were not prescribed for you by a physician?" If yes, ask, "When was the last time you injected any drugs?" Only complete PWID risk index if they have injected any nonprescription drug during the past 6 months. # Section 8 Management of Patients Who Acquire HIV While on PrEP Patients who are being prescribed PrEP might acquire HIV infection for several reasons. When HIV infection is detected at the first follow-up visit after PrEP initiation, it can indicate that the patient had undetected acute infection when PrEP was initiated. When infection is detected at later follow-up visits, as it most commonly occurs, it might be because patients have stopped taking PrEP, have been taking it infrequently, or have been stopping and restarting it without retesting for HIV infection before restarting. Rarely, despite high adherence to continuous daily dosing, patients taking PrEP have acquired HIV infection. Infection while taking PrEP as prescribed can occur because of exposure to a drug-resistant viral strain 15 or simply because, even with daily use, PrEP protection is high but not 100%. 16 In all cases, when an HIV test during a follow-up visit indicates possible infection in a PrEP patient, the following steps should be taken: - Counsel the patient about their HIV status and the resulting management plan: - If a single rapid antibody blood test was positive, explain the need to confirm presumptive HIVpositive status with laboratory testing. o If a rapid 4 th generation (antigen/antibody) blood test was positive, explain high likelihood of HIV infection that will need to be confirmed with additional laboratory testing. o If a positive HIV test was based on laboratory testing with confirmatory results already known, explain certainty of HIV diagnosis. o Ask about signs and symptoms of acute infection since last clinic visit as well as PrEP medication adherence history. - Conduct confirmatory HIV testing (if not completed already) and supplemental tests, if indicated: - If one or more rapid tests were positive, draw blood for confirmatory laboratory-based HIV testing with adequate blood for reflex HIV viral load testing if confirmed to be HIV infected. o If laboratory-based testing was positive, draw blood for HIV viral load, CD4 cell count, and HIV resistance testing. o For persons with confirmed HIV infection, conduct the following supplemental testing indicated for initiation of HIV treatment, including but not necessarily limited to the following: 32 Chemistry screen, ALT, AST, bilirubin, CBC with differential, urinalysis, and pregnancy test (in people of childbearing potential). Fasting lipid profile, glucose, and hemoglobin A1c are also indicated, on the day that seroconversion is detected, if possible. - Convert the PrEP regimen to an HIV treatment regimen recommended by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. 17 o It is not necessary to stop antiretrovirals entirely while waiting for additional laboratory test results. In the most likely event that the patient has HIV infection, immediate initiation of HIV treatment is indicated. Select from among the regimens recommended in the DHHS treatment guidelines. 17 If the patient is taking oral PrEP - Continue the prescription of Truvada (TDF 300 mg/FTC 200 mg) once daily, pending results of resistance tests. - Add a third medication according to criteria in the section on "Recommended Initial Regimens for Most People with HIV" in the DHHS treatment guidelines. 17 If the patient is receiving CAB injections: - Initiate a treatment regimen according to criteria in the section on "Recommended Initial Regimens for Most People with HIV" in the DHHS treatment guidelines. 17 Do not hold initiation of treatment while waiting fo results of resistance tests. Consultation with an HIV specialist may be obtained by calling the toll-free national PrEPline at 855-448-7737. In cases where a viral strain with significant resistance to tenofovir or cabotegravir is later identified, the regimen can then be optimized. In cases where HIV infection is not confirmed, the patient can be returned to a PrEP regimen.. o Ask if the patient had condomless sex or shared injection equipment during the past 72 hours, and if yes, offer nPEP for exposed partners. - Consult with and transfer care to an experienced HIV care provider, if necessary. o Clinicians can call the National Clinical Consultation Center toll-free at (800) 933-3413. - Discuss or complete insurance paperwork necessary for coverage of treatment medication. o Patients who are receiving medication through PrEP-specific medication assistance programs will need to switch to an HIV treatment assistance program. o Public or private insurance plans will generally not require additional paperwork but prior authorizations for PrEP may raise questions when switching to a prescription for a treatment regimen. - Schedule follow-up visits, including social services, if required. - Complete an HIV case report for the health department (completion of fields related to PrEP use at the time of seroconversion is highlighted in red below). # Section 9 Transition of Patients From Nonoccupational Postexposure Prophylaxis (nPEP) to Preexposure Prophylaxis (PrEP) Two types of patients may be considered candidates for PrEP use after a course of nonoccupational postexposure prophylaxis (nPEP): - Patients who request PrEP and also have had a possible sexual or injection drug-related HIV exposure in the prior 72 hours (i.e., are within the recommended window to start nPEP); or - Patients who request repeated courses of nPEP, particularly over a relatively recent period (e.g., more than twice during the past 6 months). If evaluation demonstrates nPEP is clinically indicated and that the patient is also eligible for PrEP (e.g., behavioral risk for repeated HIV exposure, recent bacterial STI diagnosis in a sexually active person), then these patients should both be provided a 28-day course of nPEP and be evaluated for transition to PrEP at the conclusion of their nPEP course. - Reinforce the critical nature of safer sexual or injection drug use strategies while pending PrEP initiation; - Obtain baseline testing per PrEP guidelines; and - Initiate PrEP, when possible. # Consultation Consultation with local or regional experts in nPEP and PrEP, or with the toll-free national PrEPline at 855-448-7737 or PEPline at 888-448-4911, can be sought for clinical scenarios requiring additional information or management options. # Section 12 Methods for Developing the PrEP Clinical Practice Guideline In 2009, in recognition of the lead time needed to develop clinical guidance for the safe and effective use of PrEP should clinical trials results support it, CDC initiated a formal guidelines development process to allow for early review of the relevant literature, discussion of potential guidelines content given scenarios of potential trial results, and gathering information and understanding the perspectives of experts and stakeholders. This process was designed to provide a basis for the rapid issuance of interim guidance, to be followed by Public Health Service guidelines as soon as the earliest trial findings indicated sufficient PrEP efficacy and safety to merit its implementation for HIV prevention through one or more routes of transmission. This guidelines development process was based on a review of experience with the development of other clinical and nonclinical guidelines at CDC, including guidelines for STD treatment and antiretroviral prevention of mother-to-child transmission following the ACTG 076 trial results. There were five basic components to the process for developing the 2014 PrEP guidelines: 1. An HHS Public Health Service (PHS) Working Group to develop interagency consensus on major points of implementation policy and provide agency review of guidelines. This working group included representatives from agencies that would formally clear PHS guidelines, including FDA, HRSA, NIH, HHS/OHAP, as well as agencies that may implement such guidance, including IHS and VA. The 2014 draft clinical practice guideline and clinical providers supplement were reviewed by CDC, FDA, NIH, HRSA, and HHS, and a series of webinars were held in 2012 and 2013 to obtain additional expert opinion and public engagement on draft recommendations for PrEP use. The draft guideline and supplement were then reviewed by a panel of 6 external peer reviewers who had not been involved in their development. At each step, revisions were made in response to reviewer and public comments received. For the 2021 update, the systematic review of published literature was updated through December 2020, additions to the evidence review tables were made; minor clarifying edits to the supporting text were made to enhance consistency with recently updated STD, nPEP, and perinatal guidelines sections relevant to PrEP; and updated references were added. For the 2021 update, changes to the graded recommendations were made to include adolescents, Descovy, and cabotegravir for PrEP (see "What's New" page in the 2021 guidelines). The updated guideline was then shared with a group of 4 external peer reviewers for comment and public comment on the changes was obtained. # Plans for Updates to the Guideline PrEP is a rapidly changing field of HIV prevention with several additional clinical trials and studies are now underway or planned. Updates to these guidelines are anticipated as studies provide new information on PrEP efficacy, HIV testing, drug levels, adherence, longer term clinical safety, and changes in HIV risk behaviors associated with PrEP medication use for HIV uninfected MSM, heterosexuals, injection drug use, pregnant women and their newborns; as well as information on the efficacy and safety of other antiretroviral medications, and other routes and schedules of medication delivery for PrEP. When significant new data become available that may affect patient safety or graded recommendations for PrEP use, an announcement with suggested revisions to the existing guidelines will be posted on the CDC web site for a 2-week public comment period. These comments will be reviewed and a determination made as to whether additional revisions to the guideline are indicated. Final updated guidelines will then be posted on the CDC web site. Adolescents. In addition to these standing work groups, technical expert panels were convened to inform guidelines for PrEP use in the following areas: Public health and clinical ethics; Monitoring and evaluation framework; Financing and reimbursement issues; Preconception and intrapartum use of PrEP; Public health legal and regulatory issues; and Issues relevant to benefits managers and insurers. 4. A series of stakeholder web/phone conferences were held to receive input on questions, concerns, and preferences from a variety of perspectives, including the perspectives of community-based organizations, state and local AIDS offices, professional associations, and others. 5. After the publication of the first efficacy trial results, a face-to-face consultation of external experts, partners, agencies, and other stakeholders was held to consider the recommendations for guidance made by the above groups and to discuss any additional ideas for inclusion in PrEP guidelines. The 2017 and 2021 updates to the guidelines and supplement were based on systematic literature reviews and the work of a CDC writing team. External Consultants: The working groups and expert panels listed here were convened by teleconference before trial results were available (2009-2010) and some were reconvened after each trial results for each population group were published. As technical experts, prevention partners, and key stakeholders, they were asked to assist in identifying relevant scientific/medical literature and share thoughts on topics that would inform the development of possible future guidelines for PrEP use in the US. They did not participate in the writing of these guidelines. No financial disclosures were sought. See Clinical Providers' Supplement section 14 for a description of the criteria use for constitution of the working groups and expert panels. Institutional associations listed for participants are those at the time of the group discussions and may have changed since. # Potential conflicts of interest: CDC and individual employees involved in the guideline development process are named in US government patents and patent applications related to methods for HIV prophylaxis. # None This process allowed wide input, transparency in discussing the many issues involved, time for the evolution of awareness of PrEP and ideas for its possible implementation, in addition to facilitating the development of a foundation for the eventual guidance. At the same time, it allowed for guidelines based on expert opinion, and recommendations deemed feasible by clinical providers and policymakers. OR antiretrovirus- OR anti-retrovirus- OR Truvada OR tenofovir OR emtricitabine OR (TDF ADJ5 FTC) OR Descovy OR cabotegravir)) - AND NOT animals - in the title, abstract, keyword heading word, subject heading fields Retrieved citations were provided in an Endnote reference file for deduplication. Then 2 scientists independently reviewed the citations and removed articles that were not published in English, did not contain data (e.g., editorials, reviews, news reports), or did not contain data about oral TDF/FTC or cabotegravir injections for PrEP. The next step was to screen citations to remove articles that did not contain new data about oral PrEP (data/analyses not previously published). For the 2021 update, year of publication, author, and titles were compared with the 2017Endnote library as necessary to identify already exiting entries. During this step, abstracts or full articles were read and publications were categorized into the following groups: # SYSTEMATIC LITERATURE REVIEW METHODS - New clinical trial results; - New human observational study results; - New survey, focus group, or other behavioral study results; - New cost analysis results (e.g., program cost, cost benefit analysis); - New modeling results (e.g., impact models); - New laboratory human study results (e.g., drug levels, resistance); or - None of the above. The coding by the two reviewers was then compared and discrepancies were reconciled. Citations with no new data about daily oral PrEP with TDF/FTC or cabotegravir injections were deleted from the updated Endnote 2020 library. Data from the clinical trial, human observational study, and laboratory human study results were added to the evidence tables. Study findings presented in the evidence tables were each assessed for quality of the study using GRADE criteria 18 (see guidelines Appendix 1, Table 8). Then all data supporting a specific recommendation were given a summary strength of evidence rating (across all studies relevant to that recommendation) using the same system as used for the DHHS antiretroviral treatment guidelines 17 (see PrEP clinical practice guidelines Appendix 1, Table 9). # DRAFT GUIDELINE WRITING AND REVIEW PRIOR TO PUBLICATION The draft was written to address guidelines standards for review of the strength of evidence (GRADE approach 18 ) as well as a format designed to promote guideline implementation (GLIA 19 ), dissemination (GEM 20 ), and adoption (AGREE 21 ).	# Introduction Findings from several clinical trials have demonstrated safety 1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM), 2,3 men and women in heterosexual discordant couples, 4 and heterosexual men and women recruited as individuals 5 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) and emtricitabine (F). 3 In addition, one clinical trial among persons who inject drugs (PWID) (also called injection drug users [IDU] 6 and one among men and women in heterosexual HIV-discordant couples 4 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone. The demonstrated efficacy of daily oral PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including persons in the drug treatment group and persons in the placebo group. In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada (F/TDF) "in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk." 7 In May 2018, the approval for F/TDF was extended to adolescents weighing at least 35 kg (77 lb) based on safety trials in adolescents 8 and young adults. 9 In June 2019, the US Preventive Services Task Force recommended PrEP for adults and adolescents at risk of HIV acquisition with an "A" rating (high certainty that the net benefit of the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection is substantial). 10 And in October 2019, based on a clinical trial conducted with 5,313 MSM and 74 transgender women, the FDA approved a PrEP indication for daily F/TAF for sexually active persons at risk of HIV acquisition. 3 Women at risk through receptive vaginal sex were excluded from the F/TAF approval, because no women (assigned female sex at birth) were included in the efficacy and safety PrEP trial. In 2020, results from a clinical trial conducted with MSM and transgender women 11 and another conducted African women 12 reported high efficacy and safety for bimonthly injections of cabotegravir (CAB) for PrEP. Submission of data for review by the FDA for approval of a PrEP indication is planned in 2021. On the basis of these trial results and FDA approvals, the U.S. Public Health Service published a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States in 2014 and updated it in 2017 and in 2020. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf. This supplement to the PHS PrEP Clinical Practice Guidelines is intended to provide additional information that may be useful to clinicians providing PrEP. As additional materials become available, this document will be updated. Many of the studies that informed these guidelines included small numbers of transgender women and none included transgender men, as a result, data specifically relevant for transgender and non-binary people are often limited or not available. Most sections of this supplement, therefore, use the terminology, 'women' and 'men' unless specifically referring to transgender women or men. We continue to advocate for greater inclusion of transgender and non-binary people in PrEP-related research and recommend gender-inclusive models of PrEP care to ensure that services encompass and address the needs of all persons who would benefit from its use.  Administered a gluteal IM injection of cabotegravir (600 mg in 3 ml)  A follow-up appointment date As the provider, I will: 1 An off-label use It has been explained to me that: • Taking a dose of PrEP medication every day will lower my risk of getting HIV infection. • This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. • This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. • It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). • My provider will test for HIV infection at least once every 3 months. Therefore, I will: • Try my best to take the medication my provider has prescribed every day. • Talk to my provider about any problems I have in taking the medication every day. • Not share the medication with any other person. • Attend all my scheduled appointments. • Call _________________ to reschedule any appointments I cannot attend. # Give one copy to patient Preexposure Prophylaxis for the Prevention of HIV Infection in the United States -2021 Update Clinical Providers' Supplement Page 10 of 53 Patient Section -"2-1-1" Dosing It has been explained to me that: • Taking the PrEP medication I have been prescribed (Truvada) both before and after I have sex every day can lower my risk of getting HIV infection. • I should take 2 pills in the 2-24 hours before I expect to have sex, then 1 pill a day later, and 1 pill two days later. • If I am having sex at least once a week, I should consider taking PrEP medication daily rather than before and after each time I have sex. • This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. • This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. • It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). • My provider will test for HIV infection at least once every 3 months. Therefore, I will: • Try my best to take the medication my provider has prescribed before and after each time I have sex. • Talk to my provider about any problems I have in taking the medication before and after each time I have sex. • Not share the medication with any other person. • Attend all my scheduled appointments. • Call _________________ to reschedule any appointments I cannot attend. # Patient Section -Cabotegravir Injections It has been explained to me that: • Receiving the PrEP injections (cabotegravir) every 8 weeks will lower my risk of getting HIV infection. • This medicine does not completely eliminate my risk of getting HIV infection and does not reduce my risk of getting a sexually transmitted infection, so using condoms during sex will provide additional protection. • This medicine may cause side effects, so I should contact my provider for advice by calling ________________ if I have any health problems. • It is important for my health to find out quickly if I get HIV infection while I'm taking this medication, so: o I will contact my provider right away if I have symptoms of possible HIV infection (fever with sore throat, rash, headache, or swollen glands). • My provider will test for HIV infection at least once every 4 months. Therefore, I will: • Attend all my scheduled appointments. • Call _________________ to reschedule any appointments I cannot attend. • Talk to my provider if I want to stop taking PrEP injections so that I can stop safely # Give one copy to patient # Section 2 PrEP Information Sheet Pre-exposure Prophylaxis (PrEP) for HIV Prevention Frequently Asked Questions What is PrEP? "PrEP" stands for preexposure prophylaxis. The word "prophylaxis" (pronounced pro fil ak sis) means to prevent or control the spread of an infection or disease. The goal of PrEP is to prevent HIV infection from taking hold if you are exposed to the virus. This is done by taking a pill that contains 2 HIV medications every day or by getting an injection with 1 HIV medicine every 2 months. These are the same medicines used to stop the virus from growing in people who already have HIV infection. # Why take PrEP? Nearly 40,000 people get infected with HIV each year in the U.S. More of these infections are happening in some groups of people and some areas of the country than in others. # Is PrEP a vaccine? No. PrEP medication does not work the same way as a vaccine. When you take a vaccine, it trains the body's immune system to fight off infection for years. You will need to take a pill every day by mouth for PrEP medications to protect you from infection. PrEP does not work after you stop taking it. The medications that have been shown to be safe and to help block HIV infection are called "Truvada" (pronounced tru va duh) or "Descovy" (pronounced des koh vee). Truvada is a combination of 2 drugs (tenofovir disoproxil fumarate and emtricitabine). Descovy is a combination of 2 drugs (tenofovir alafenamide and emtricitabine). The drug in the injection is called cabotegravir (pronounced cab oh teh gruh veer) .These medicines work by blocking important pathways that the HIV virus uses to set up an infection. If you take either of these medications as PrEP daily, the presence of the medication in your bloodstream can often stop the HIV virus from establishing itself and spreading in your body. If you do not take the pills in the way you were instructed, there may not be enough medicine in your blood stream to stop the virus from establishing an infection in your body. # Should I consider taking daily PrEP? PrEP is not for everyone. You should consider PrEP if you are a man or woman who sometimes has sex without using a condom, especially if you have a sex partner who you know has HIV infection and does not have his/her virus under control with medication. You should also consider PrEP if you don't know whether your partner has HIV infection, but you know that your partner is at risk (for example, your partner injects drugs or is having sex with other people in addition to you) or if you have recently been told by a health care provider that you had a sexually transmitted infection. If your partner has HIV infection, PrEP may be an option to help protect you from getting HIV infection while you try to get pregnant, during pregnancy, or while breastfeeding. # How well does PrEP work? PrEP was tested in several large studies with men and women at high risk of being exposed to HIV while having sex or injecting drugs. All people in these studies ( 1) were tested at the beginning of the trial to be sure that they did not have HIV infection, (2) agreed to take an oral PrEP tablet daily or an injection every other month, (3) received intensive counseling on safersex and safe-injection behavior, (4) were tested regularly for sexually transmitted infections, and ( 5) were given a regular supply of condoms. In these studies, when people took PrEP daily (or missed only occasional doses) or had regular PrEP injections, the risk of getting HIV infection during sex dropped by 90% or more. When people who used PrEP in the community were assessed, the risk of getting HIV infection during sex dropped by up to 99%. People who take PrEP daily as prescribed rarely get HIV infection. More information on the details of these studies can be found at http://www.cdc.gov/hiv/prep. # Is PrEP safe? The clinical trials also provided safety information on PrEP. Some people in the trials of oral PrEP medicines had early side effects such as an upset stomach or loss of appetite, but these side effects were mild and usually went away within the first month. Some people also had a mild headache. Many people in trials of PrEP injections had a reaction at the injection site like mild pain, redness, or swelling. These reactions were mild and lasted only a couple of days. No serious side effects were observed. You should tell your health care provider if these or other symptoms become severe or do not go away. # How can I start PrEP? If you think you may be at high risk for HIV, talk to your provider about PrEP. If you and your health care provider agree that PrEP might reduce your risk of getting HIV infection, you will need to come in for a general health physical, blood tests for HIV, and tests for other infections that you can get from sex partners. For oral PrEP, your blood will also be tested to see if your kidneys are functioning well. If these tests show that PrEP medicines are likely to be safe for you to take and that you might benefit from PrEP, your health care provider will give you the form of PrEP you decide on; either a prescription for an oral pill (Truvada or Descovy) or an injection with cabotegravir. Taking PrEP medicines will require you to follow-up regularly with your health care provider. You will receive counseling on sexual behaviors and blood tests for HIV infection and to see if your body is reacting well to Truvada, Descovy, or cabotegravir. You should take your oral medicine daily as prescribed or your injections every two months, and your health care provider will advise you about ways to help you take it regularly so that it stands the best chance to help you avoid HIV infection. Tell your health care provider if you are having trouble remembering to take your medicine, return for your injections, or if you want to stop PrEP. # Is daily Truvada my only choice for PrEP? If you are a man who has sex with men (MSM) or a transgender woman, there is a second option for taking daily PrEP. A large study of MSM showed that daily use of a second medication called Descovy, is just as safe and effective as Truvada. Since Descovy was not studied in persons assigned female sex at birth, it is unknown whether it is effective protection for vaginal sex. So, it should only be prescribed to MSM. An additional trial has shown that injections with cabotegravir every two months is highly effective HIV prevention. # Is taking medication every day my only choice for PrEP? Another large study with MSM showed that for men who have sex infrequently, Truvada can be highly protective when taken only before and after sex. Among men who could anticipate when they would have sex, they took two pills several hours before having sex on a given day, then one pill a day later, and a final pill the next day. Because of this schedule of pill taking, it's called "2-1-1" PrEP. This was only studied with Truvada taken by MSM, so 2-1-1 PrEP is NOT prescribed for women or with Descovy, because we do not know it will work well. An additional trial has shown that injections with cabotegravir every two months is highly effective HIV prevention. # If I take PrEP can I stop using condoms when I have sex? You should not stop using condoms because you are taking PrEP. If PrEP is taken daily, it offers a lot of protection against HIV infection, but not 100%. Condoms also offer a lot of protection against HIV infection if they are used correctly every time you have sex, but not 100%. PrEP medications don't give you any protection from other infections you can get during sex, but condoms do. So, you will get the most protection from HIV and other sexual infections if you consistently take PrEP medication and consistently use condoms during sex. # How long do I need to take PrEP? You should discuss this with your health care provider. There are several reasons that people stop taking PrEP. If your risk of getting HIV infections becomes low because of changes that occur in your life, you may want to stop taking PrEP. You can restart PrEP later if your life changes in ways that increase your risk. If you find you don't want to take a pill every day or often forget to take your pills, or don't want to continue PrEP injections, other ways of protecting yourself from HIV infection may work better for you. If you have side effects from the medication that are interfering with your life or if blood tests show that your body is reacting to PrEP in unsafe ways, your health care provider may stop prescribing PrEP for you. # Do I need to do anything special if I want to stop having PrEP injections? If you stop taking PrEP pills, the medication clears from your body within a couple of weeks. But when you stop receiving PrEP injections, the medication takes a year or more to completely leave your body (sometimes called the "tail" period). As the level of medication drops, protection drops and you can get HIV if you are exposed to it. If you have low levels of medication and get HIV, the virus can be less sensitive to the medication ('resistant") and this might effect which medications would treat your infection. For that reason, it is important to have effective protection against HIV during the months while the cabotegravir is gradually leaving your body. This may mean you need to take daily oral PrEP medication for several months. It is important to make a plan with your provider for protection during this period. # Section 3 Medication Information Sheets Truvada and Descovy Medication Information Sheet for Patients Brand name: Truvada (tru va duh), Descovy (des koh vee) Generic name: tenofovir disoproxil fumarate and emtricitabine, tenofovir alafenamide and emtricitabine # Why is this medication prescribed? • Truvada and Descovy are two of several medications that are currently used to treat human immunodeficiency virus (HIV) • Truvada and Descovy are now being also used to prevent HIV infection. • Truvada and Descovy are sometimes prescribed to some people who do not have HIV infection (for example, those who do not always use condoms or who have a sex partner that has HIV infection) to help reduce their chances of getting HIV infection. • When you take Truvada or Descovy to prevent HIV infection, health care providers refer to this use as "pre-exposure prophylaxis" or "PrEP." • Descovy is not prescribed for women (persons assigned female at birth). # How does PrEP medication help prevent HIV infection? • HIV is a virus that attacks your body's immune cells (the cells that work to fight infections). • Truvada and Descovy each contain a different form of tenofovir. They work against HIV in the same way so patients can take either medication (but not both). • The 2 medications that make up Truvada and Descovy (tenofovir and emtricitabine) block important pathways that viruses use to set up infection. • If you take Truvada or Descovy as PrEP daily, the presence of the medication in your bloodstream will usually stop the virus from establishing itself and slow the spread of HIV in your body. • PrEP with Truvada or Descovy does not work all the time so you should also use condoms during sex for the most protection from HIV and other sexually transmitted infections. How should this medicine be used? • You must take one tablet of Truvada or Descovy by mouth every day. • Follow the directions on your prescription label carefully and ask your health care provider or pharmacist to explain any part you do not understand. • Do not stop taking Truvada or Descovy without talking to your health care provider. When your supply of PrEP medicine starts to run low, contact your health care provider or pharmacist to get more. • You will be at higher risk of becoming infected with HIV if you often miss doses or stop taking PrEP medicine than if you take it every day. # What special precautions should I follow? Before taking Truvada or Descovy, you must do the following: • Tell your health care provider and pharmacist if you are allergic to tenofovir, emtricitabine, or any other medications. • Tell your health care provider and pharmacist about all prescription and nonprescription medications (e.g., over-the-counter pain medications, vitamins, nutritional supplements, protein powders, or herbal products), you are taking. Your health care provider may need to change the doses of your medications or monitor you carefully for side effects. • Tell your health care provider if you have or have ever had kidney disease. • Tell your health care provider if you become pregnant or if you are breastfeeding. # What special dietary instructions should I follow? • Continue your normal diet unless your health care provider tells you otherwise. # What should I do if I forget a dose? • Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. • Do not take a double dose to make up for a missed one. # What side effects can this medication cause? You may experience the following side effects while taking Truvada: • upset stomach • headache • vomiting • loss of appetite • a small weight gain • a change in the amount of some types of fats (lipids) in your blood These side effects usually fade during the first month of taking PrEP medication. Tell your health care provider if any of these symptoms are severe or do not go away. # What other information should I know? • Do not let anyone else take your medication. • Ask your pharmacist if you have any questions about refilling your prescription. • Write a list of all of your prescription and over-the-counter medicines, as well as any vitamins, minerals, or other dietary supplements that you take. • Bring your medication list with you each time you visit a health care provider or if you are admitted to a hospital. Keep it with you always in case of emergencies. # Cabotegravir Medication Information Sheet for Patients Brand name: cabotegravir (cab oh teh gruh veer) # Generic name: cabotegravir Why is this medication prescribed? • Cabotegravir is one of several medications that are currently used to treat human immunodeficiency virus (HIV) • Cabotegravir is now being also used to prevent HIV infection. • Cabotegravir injections are sometimes given to some people who do not have HIV infection (for example, those who do not always use condoms or who have a sex partner that has HIV) to help reduce their chances of getting HIV. • When you take cabotegravir to prevent HIV infection, healthcare providers refer to this use as "pre-exposure prophylaxis" or "PrEP." # How does PrEP medication help prevent HIV infection? • HIV is a virus that attacks your body's immune cells (the cells that work to fight infections). • Cabotegravir works against HIV by blocking important pathways that viruses use to set up infection. • If you take cabotegravir injections for PrEP, the presence of the medication in your bloodstream will usually stop the virus from establishing itself and slow the spread of HIV in your body. • PrEP with cabotegravir does not work all the time so you should also use condoms during sex for the most protection from HIV and other sexually transmitted infections. How should this medicine be used? • You will receive a cabotegravir injection into the buttock muscle in the back side of your hip. • Ask your health care provider or nurse to explain any part of PrEP use that you do not understand. • Do not stop taking cabotegravir injections without talking to your health care provider. • You will be at risk of getting HIV if you stop taking PrEP injections without starting another effective prevention method. # What special precautions should I follow? Before getting a cabotegravir injection, you must do the following: • Tell your health care provider and pharmacist about all prescription and nonprescription medications (e.g., vitamins, nutritional supplements, and herbal products), you are taking. Your health care provider may need this information to know if any of these medicines interact with the cabotegravir. • Tell your health care provider if you become pregnant or if you are breastfeeding. # What special dietary instructions should I follow? • Continue your normal diet unless your health care provider tells you otherwise. # What should I do if I forget my appointment for an injection? • If you miss an injection appointment, schedule another visit to continue injections. # What side effects can this medication cause? You may experience the following side effects at the site where you got your cabotegravir injection: • mild or moderate pain • redness • local swelling These side effects usually fade within a few days of your PrEP injection. Taking an over-thecounter pain medication and using a heating pad at the site of the injection for 15-20 minutes a couple of times each day may help reduce the reaction. Tell your health care provider if any of these symptoms are severe or do not go away. If you experience a serious side effect, you or your health care provider may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (at http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088). Lastly, when people have lots of virus in their body during acute HIV infection, they are more likely to pass the virus on to people they have sex with, especially since they may not know yet that they have HIV. For example, if your last HIV test result was negative and your partner also had a recent negative HIV test result, you might choose to have sex without a condom just at the time when it's very likely you could more easily pass the virus to others. The sooner you know you have become infected, the more careful you can be to protect others from getting HIV infection. # How is HIV treated? People who have HIV infection are treated with combinations of 2 or more medicines that fight HIV. Nearly all health care providers start people on treatment medications as soon as HIV tests show they have gotten the virus. Treatment also reduces the chances that a person with HIV infection will transmit the virus to his/her sex partners. When treatment is able to reduce the amount of HIV in your blood to a level too low to be measured (also called "undetectable"), there is effectively no risk of passing the virus to another person during sex. # What do I do if I suspect I might have acute HIV infection? First, contact your health care provider's office and arrange to be examined and have the right blood tests. Second, discuss with your health care provider whether to stop your PrEP medications or continue them until your test results are back. Third, be especially careful to use condoms and take other safer sex measures to protect your partner(s). # Section 5 Risk Reduction Counseling Assessing HIV and STI risk should be a part of every initial and follow-up PrEP visit. Based on the risks identified for a patient's potential exposure to HIV, you should encourage risk reduction by providing prevention counseling whether the patient will be prescribed PrEP or not. Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the patient's culture, language, sex and gender identity, sexual orientation, age, and developmental level. USPSTF recommends intensive behavioral counseling for all sexually active adolescents and for adults at increased risk for STIs and HIV. For patients being prescribed PrEP, they will be utilizing the most effective HIV risk reduction method available. Educating the patient on how to ensure PrEP is maximally effective and supporting adherence to PrEP should be prioritized. Following that, you should provide sciencebased information on other HIV and STI prevention methods such as condoms, reducing the number of sexual partners, knowing their partner's HIV status, understanding the benefits of an HIV partner being on treatment with an undetectable viral load, and strategies to reduce the effect of alcohol or drug use on sexual risk taking. The goal should be to provide the patient with the necessary information for them to decide which prevention strategies they consider achievable and valuable. Having a risk-reduction conversation can be challenging. The conversation often takes time and behavioral change in any patient can be slow. For PrEP patients who will be regularly monitored, you will have time to build a relationship with the patient during regular follow-up visits. These follow-up visits offer opportunities for an ongoing discussion of HIV risk including ways the patient could further reduce their risk. Critical to building a respectful relationship is to approach the conversation without judgement. The goal is to develop a risk reduction plan that meets the patient's needs while keeping their risk as low as possible. Some patients will not make the objectively safest choice or the choice that you believe is best. In these situations, you have to be prepared to accept and support the patient's decisions, and continue to provide non-judgmental, evidence-based information. # Section 6 MSM Risk Index Epidemiologic studies have identified a wide range or personal, relationship, partner, social, cultural, network, and community factors that may be associated with the presence of HIV infection. However, to provide PrEP or other intensive HIV prevention services, it is necessary to briefly and systematically screen for key information about those factors that are predictive of acquiring HIV infection. This section contains a tool that clinicians may use to quickly and systematically determine which MSM are at high risk of acquiring HIV infection and for whom PrEP may be indicated. If score is below 10, provide indicated standard HIV prevention services. # Section 7 PWID (IDU) Risk Index Epidemiologic studies have identified a wide range or personal, relationship, partner, social, cultural, network, and community factors that may be associated with the presence of HIV infection. However, to provide PrEP (or other intensive HIV prevention services), it is necessary to briefly and systematically screen for key information about those factors that are predictive of acquiring HIV infection. This section contains a tool that clinicians can use to quickly and systematically determine which persons who inject drugs (PWID) (also called injection drug users [IDU]) are at high risk for acquiring HIV infection and for whom PrEP may be indicated. # __________ Add the scores for age and methadone use to the Composite Injection Subscore to yield a Total Score _________ Total Score* * If the total score is 46 or greater, evaluate for PrEP or other intensive HIV prevention services for PWID. If score is 45 or less, provide indicated standard HIV prevention services for PWID. To identify active PWID in a clinician's practice, we recommend asking all their patients a routine question: "Have you ever injected drugs that were not prescribed for you by a physician?" If yes, ask, "When was the last time you injected any drugs?" Only complete PWID risk index if they have injected any nonprescription drug during the past 6 months. # Section 8 Management of Patients Who Acquire HIV While on PrEP Patients who are being prescribed PrEP might acquire HIV infection for several reasons. When HIV infection is detected at the first follow-up visit after PrEP initiation, it can indicate that the patient had undetected acute infection when PrEP was initiated. When infection is detected at later follow-up visits, as it most commonly occurs, it might be because patients have stopped taking PrEP, have been taking it infrequently, or have been stopping and restarting it without retesting for HIV infection before restarting. Rarely, despite high adherence to continuous daily dosing, patients taking PrEP have acquired HIV infection. Infection while taking PrEP as prescribed can occur because of exposure to a drug-resistant viral strain 15 or simply because, even with daily use, PrEP protection is high but not 100%. 16 In all cases, when an HIV test during a follow-up visit indicates possible infection in a PrEP patient, the following steps should be taken: • Counsel the patient about their HIV status and the resulting management plan: o If a single rapid antibody blood test was positive, explain the need to confirm presumptive HIVpositive status with laboratory testing. o If a rapid 4 th generation (antigen/antibody) blood test was positive, explain high likelihood of HIV infection that will need to be confirmed with additional laboratory testing. o If a positive HIV test was based on laboratory testing with confirmatory results already known, explain certainty of HIV diagnosis. o Ask about signs and symptoms of acute infection since last clinic visit as well as PrEP medication adherence history. • Conduct confirmatory HIV testing (if not completed already) and supplemental tests, if indicated: o If one or more rapid tests were positive, draw blood for confirmatory laboratory-based HIV testing with adequate blood for reflex HIV viral load testing if confirmed to be HIV infected. o If laboratory-based testing was positive, draw blood for HIV viral load, CD4 cell count, and HIV resistance testing. o For persons with confirmed HIV infection, conduct the following supplemental testing indicated for initiation of HIV treatment, including but not necessarily limited to the following: 32 ▪ Chemistry screen, ALT, AST, bilirubin, CBC with differential, urinalysis, and pregnancy test (in people of childbearing potential). ▪ Fasting lipid profile, glucose, and hemoglobin A1c are also indicated, on the day that seroconversion is detected, if possible. • Convert the PrEP regimen to an HIV treatment regimen recommended by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. 17 o It is not necessary to stop antiretrovirals entirely while waiting for additional laboratory test results. In the most likely event that the patient has HIV infection, immediate initiation of HIV treatment is indicated. Select from among the regimens recommended in the DHHS treatment guidelines. 17 ▪ If the patient is taking oral PrEP • Continue the prescription of Truvada (TDF 300 mg/FTC 200 mg) once daily, pending results of resistance tests. • Add a third medication according to criteria in the section on "Recommended Initial Regimens for Most People with HIV" in the DHHS treatment guidelines. 17 ▪ If the patient is receiving CAB injections: • Initiate a treatment regimen according to criteria in the section on "Recommended Initial Regimens for Most People with HIV" in the DHHS treatment guidelines. 17 Do not hold initiation of treatment while waiting fo results of resistance tests. Consultation with an HIV specialist may be obtained by calling the toll-free national PrEPline at 855-448-7737. In cases where a viral strain with significant resistance to tenofovir or cabotegravir is later identified, the regimen can then be optimized. In cases where HIV infection is not confirmed, the patient can be returned to a PrEP regimen.. o Ask if the patient had condomless sex or shared injection equipment during the past 72 hours, and if yes, offer nPEP for exposed partners. • Consult with and transfer care to an experienced HIV care provider, if necessary. o Clinicians can call the National Clinical Consultation Center toll-free at (800) 933-3413. • Discuss or complete insurance paperwork necessary for coverage of treatment medication. o Patients who are receiving medication through PrEP-specific medication assistance programs will need to switch to an HIV treatment assistance program. o Public or private insurance plans will generally not require additional paperwork but prior authorizations for PrEP may raise questions when switching to a prescription for a treatment regimen. • Schedule follow-up visits, including social services, if required. • Complete an HIV case report for the health department (completion of fields related to PrEP use at the time of seroconversion is highlighted in red below). # Section 9 Transition of Patients From Nonoccupational Postexposure Prophylaxis (nPEP) to Preexposure Prophylaxis (PrEP) Two types of patients may be considered candidates for PrEP use after a course of nonoccupational postexposure prophylaxis (nPEP): • Patients who request PrEP and also have had a possible sexual or injection drug-related HIV exposure in the prior 72 hours (i.e., are within the recommended window to start nPEP); or • Patients who request repeated courses of nPEP, particularly over a relatively recent period (e.g., more than twice during the past 6 months). If evaluation demonstrates nPEP is clinically indicated and that the patient is also eligible for PrEP (e.g., behavioral risk for repeated HIV exposure, recent bacterial STI diagnosis in a sexually active person), then these patients should both be provided a 28-day course of nPEP and be evaluated for transition to PrEP at the conclusion of their nPEP course. • Reinforce the critical nature of safer sexual or injection drug use strategies while pending PrEP initiation; • Obtain baseline testing per PrEP guidelines; and • Initiate PrEP, when possible. # Consultation Consultation with local or regional experts in nPEP and PrEP, or with the toll-free national PrEPline at 855-448-7737 or PEPline at 888-448-4911, can be sought for clinical scenarios requiring additional information or management options. # Section 12 Methods for Developing the PrEP Clinical Practice Guideline In 2009, in recognition of the lead time needed to develop clinical guidance for the safe and effective use of PrEP should clinical trials results support it, CDC initiated a formal guidelines development process to allow for early review of the relevant literature, discussion of potential guidelines content given scenarios of potential trial results, and gathering information and understanding the perspectives of experts and stakeholders. This process was designed to provide a basis for the rapid issuance of interim guidance, to be followed by Public Health Service guidelines as soon as the earliest trial findings indicated sufficient PrEP efficacy and safety to merit its implementation for HIV prevention through one or more routes of transmission. This guidelines development process was based on a review of experience with the development of other clinical and nonclinical guidelines at CDC, including guidelines for STD treatment and antiretroviral prevention of mother-to-child transmission following the ACTG 076 trial results. There were five basic components to the process for developing the 2014 PrEP guidelines: 1. An HHS Public Health Service (PHS) Working Group to develop interagency consensus on major points of implementation policy and provide agency review of guidelines. This working group included representatives from agencies that would formally clear PHS guidelines, including FDA, HRSA, NIH, HHS/OHAP, as well as agencies that may implement such guidance, including IHS and VA. The 2014 draft clinical practice guideline and clinical providers supplement were reviewed by CDC, FDA, NIH, HRSA, and HHS, and a series of webinars were held in 2012 and 2013 to obtain additional expert opinion and public engagement on draft recommendations for PrEP use. The draft guideline and supplement were then reviewed by a panel of 6 external peer reviewers who had not been involved in their development. At each step, revisions were made in response to reviewer and public comments received. For the 2021 update, the systematic review of published literature was updated through December 2020, additions to the evidence review tables were made; minor clarifying edits to the supporting text were made to enhance consistency with recently updated STD, nPEP, and perinatal guidelines sections relevant to PrEP; and updated references were added. For the 2021 update, changes to the graded recommendations were made to include adolescents, Descovy, and cabotegravir for PrEP (see "What's New" page in the 2021 guidelines). The updated guideline was then shared with a group of 4 external peer reviewers for comment and public comment on the changes was obtained. # Plans for Updates to the Guideline PrEP is a rapidly changing field of HIV prevention with several additional clinical trials and studies are now underway or planned. Updates to these guidelines are anticipated as studies provide new information on PrEP efficacy, HIV testing, drug levels, adherence, longer term clinical safety, and changes in HIV risk behaviors associated with PrEP medication use for HIV uninfected MSM, heterosexuals, injection drug use, pregnant women and their newborns; as well as information on the efficacy and safety of other antiretroviral medications, and other routes and schedules of medication delivery for PrEP. When significant new data become available that may affect patient safety or graded recommendations for PrEP use, an announcement with suggested revisions to the existing guidelines will be posted on the CDC web site for a 2-week public comment period. These comments will be reviewed and a determination made as to whether additional revisions to the guideline are indicated. Final updated guidelines will then be posted on the CDC web site. # ▪ Adolescents. In addition to these standing work groups, technical expert panels were convened to inform guidelines for PrEP use in the following areas: ▪ Public health and clinical ethics; ▪ Monitoring and evaluation framework; ▪ Financing and reimbursement issues; ▪ Preconception and intrapartum use of PrEP; ▪ Public health legal and regulatory issues; and ▪ Issues relevant to benefits managers and insurers. 4. A series of stakeholder web/phone conferences were held to receive input on questions, concerns, and preferences from a variety of perspectives, including the perspectives of community-based organizations, state and local AIDS offices, professional associations, and others. 5. After the publication of the first efficacy trial results, a face-to-face consultation of external experts, partners, agencies, and other stakeholders was held to consider the recommendations for guidance made by the above groups and to discuss any additional ideas for inclusion in PrEP guidelines. The 2017 and 2021 updates to the guidelines and supplement were based on systematic literature reviews and the work of a CDC writing team. External Consultants: The working groups and expert panels listed here were convened by teleconference before trial results were available (2009-2010) and some were reconvened after each trial results for each population group were published. As technical experts, prevention partners, and key stakeholders, they were asked to assist in identifying relevant scientific/medical literature and share thoughts on topics that would inform the development of possible future guidelines for PrEP use in the US. They did not participate in the writing of these guidelines. No financial disclosures were sought. See Clinical Providers' Supplement section 14 for a description of the criteria use for constitution of the working groups and expert panels. Institutional associations listed for participants are those at the time of the group discussions and may have changed since. # Potential conflicts of interest: CDC and individual employees involved in the guideline development process are named in US government patents and patent applications related to methods for HIV prophylaxis. . # None This process allowed wide input, transparency in discussing the many issues involved, time for the evolution of awareness of PrEP and ideas for its possible implementation, in addition to facilitating the development of a foundation for the eventual guidance. At the same time, it allowed for guidelines based on expert opinion, and recommendations deemed feasible by clinical providers and policymakers. OR antiretrovirus* OR anti-retrovirus* OR Truvada OR tenofovir OR emtricitabine OR (TDF ADJ5 FTC) OR Descovy OR cabotegravir)) • AND NOT animals • in the title, abstract, keyword heading word, subject heading fields Retrieved citations were provided in an Endnote reference file for deduplication. Then 2 scientists independently reviewed the citations and removed articles that were not published in English, did not contain data (e.g., editorials, reviews, news reports), or did not contain data about oral TDF/FTC or cabotegravir injections for PrEP. The next step was to screen citations to remove articles that did not contain new data about oral PrEP (data/analyses not previously published). For the 2021 update, year of publication, author, and titles were compared with the 2017Endnote library as necessary to identify already exiting entries. During this step, abstracts or full articles were read and publications were categorized into the following groups: # SYSTEMATIC LITERATURE REVIEW METHODS • New clinical trial results; • New human observational study results; • New survey, focus group, or other behavioral study results; • New cost analysis results (e.g., program cost, cost benefit analysis); • New modeling results (e.g., impact models); • New laboratory human study results (e.g., drug levels, resistance); or • None of the above. The coding by the two reviewers was then compared and discrepancies were reconciled. Citations with no new data about daily oral PrEP with TDF/FTC or cabotegravir injections were deleted from the updated Endnote 2020 library. Data from the clinical trial, human observational study, and laboratory human study results were added to the evidence tables. Study findings presented in the evidence tables were each assessed for quality of the study using GRADE criteria 18 (see guidelines Appendix 1, Table 8). Then all data supporting a specific recommendation were given a summary strength of evidence rating (across all studies relevant to that recommendation) using the same system as used for the DHHS antiretroviral treatment guidelines 17 (see PrEP clinical practice guidelines Appendix 1, Table 9). # DRAFT GUIDELINE WRITING AND REVIEW PRIOR TO PUBLICATION The draft was written to address guidelines standards for review of the strength of evidence (GRADE approach 18 ) as well as a format designed to promote guideline implementation (GLIA 19 ), dissemination (GEM 20 ), and adoption (AGREE 21 ).	None	None
f88e72cfe8da3f64d274eddfa57d3f83ad380d05	cdc	None	# i. Executive Summary This report contains 16 guidelines and six procedures for implementing the CDC/ATSDR Policy on Releasing and Sharing Data 9 pertaining to CDC's re-release of State-provided data. Section 1 contains the background and purpose for establishment of these guidelines and procedures. Section 2 describes the characteristics of CDC data systems that are considered in-scope for this report. The guidelines and procedures in this report have been specifically prepared to address the policies and practices that CDC programs establish for re-release of State-provided data that are not already covered by a written formal data re-release procedure at the time this report is finalized. The data re-release guidelines included in this report are described in detail in Sections 3 and 4. Section 3 includes two guidelines which pertain to the development of data agreements with State data providers. The first guideline in Section 3 requires CDC - programs to develop data agreements with State data providers, through collaboration and negotiation, in advance of receiving data from data providers. This guideline also acknowledges that in some CDC programs, States currently release data to CDC in the absence of explicit data agreements, and a process is necessary to develop these agreements even as data sharing continues. The second guideline in Section 3 lists suggested content of the CDC program data re-release plan and is based on the guidelines for protecting and releasing data that are described in Sections 4A through 4C. The nature of confidentiality protection, a suggested content element of the data re-release plan (see Guideline 2), is based on guidelines on existing confidentiality standards and procedures (see Section 4D). The guidelines in Section 4 are grouped in three main categories: 1) guidelines representing administrative requirements for all re-releases of State-provided data; 2) guidelines that apply to re-release of State-provided data as public-use data; and 3) guidelines that apply to the re-release of State-provided data as restricted-access data. Each guideline represents a "minimum standard" for CDC programs to address when developing their program-specific release plan for re-release of State-provided data. CDC programs may wish to adopt more stringent standards than the minimum standard. Most guidelines and procedures are accompanied by a best practices statement, reflecting applicable references, resources, or selected examples of practices by CDC programs or other Federal or State programs that appear to be consistent with the guidelines. The best practices statement is meant to be descriptive rather than prescriptive. In other words, it is being left to the discretion of each Center, Institute, or Office (CIO) and their respective programs to consider for themselves whether it is appropriate to implement the listed best practice element or implement another approach. Because CDC data systems vary widely with respect to their content and format, it is important that both the guidelines and best practices allow for flexibility within the context of the principles espoused by CDC policy. Section 5 contains descriptions of practices that support re-release of data. These descriptions are meant to help facilitate CDC's adoption of the guidelines and likely will merit more discussion and consideration within CDC. Section 6 includes the proposed deadline and steps for CDC's implementation of the guidelines and procedures and Section 7 includes recommendations for providing feedback to CSTE during CDC's implementation of the guidelines and procedures. While this document was developed for CDC data systems having specific characteristics (see Section 2), selected information in this document may be applicable for any CDC program that releases or shares data. However, this determination is left to the judgment of the CDC CIOs and their respective programs. # Background and Purpose States + have a long-standing history of voluntarily reporting individually identifiable data to CDC on incident conditions or diseases that are of public health importance 1 . Recent developments in telecommunications and computerization have greatly enhanced the ability to compile and share such public health data. While the electronic exchange and accumulation of data on individual cases promises public health benefits, it has the potential to threaten individual privacy. The challenge is to balance the need for data protection with another competing interest of public health-the need to share data collected in the interest of public health as broadly as possible, with appropriate protections, with public health practitioners and with researchers conducting studies that have the potential to benefit public health. If such a balance is not achieved, potential data providers may choose to withhold data to protect it 2 . The U.S. State and Territorial Health Agencies operate within the authority of statespecific laws and regulations that control the collection and protection of individually + Throughout this document, "States" should be understood to refer to both U.S. States and Territories. identifiable data. Therefore, States are ultimately responsible for confidentiality protections, regardless of whether the data reside temporarily with a data steward, such as CDC, or reside within their own agencies. Since the mid-1980s, the CDC and Council of State and Territorial Epidemiologists (CSTE) have been engaged in extensive discussions over issues related to re-release by CDC of data released by States to CDC. States wanted assurance that CDC programs would apply consistent principles and adhere to certain standards when releasing such data. Appendix A describes relevant events leading up to the establishment of the CDC-CSTE Intergovernmental Data Release Guidelines Working Group (DRGWG). CDC has a responsibility to ensure that CDC programs protect the confidentiality of the State-provided data they have been entrusted with, and inform CSTE and data providers how the confidentiality of this data is being protected. In addition, CDC and CSTE have a shared responsibility to develop feasible guidelines for CDC programs that are consistent with State laws, regulations, and policies protecting confidentiality and that reflect state-of-the-art or best practices 3,4,5,6 . The CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data are intended to: 1) complement existing Federal laws that govern data release and protect confidentiality (Appendices B1 and B2); 2) augment current CDC policies such as The CDC Staff Manual on Confidentiality 7 and the NCHS Staff Manual on Confidentiality 8 ; and 3) provide an implementation guide for the newly published CDC/ATSDR Policy on Releasing and Sharing Data 9 (www.cdc.gov/od/foia/policies/sharing.htm), with respect to the re-release of State-provided data. This report should be used by CDC programs when developing their program-specific data re-release procedures for State-provided data. This report describes guidelines (minimum standards) for the development of programspecific data release plans and procedures for re-release of State-provided data by CDC. These guidelines are consistent with and expand upon the requirements listed in the CDC/ATSDR Policy for Releasing and Sharing Data 9 . A key principle of this report is the need for CDC programs to develop data agreements with State data providers before the data are received by CDC. The report also recognizes that in some CDC programs, States currently release data to CDC in the absence of explicit data agreements, and a process is necessary to develop these agreements even as data sharing continues. To facilitate this process, CDC programs will develop data re-release plans based on accepted data release practices and procedures as well as scientifically acceptable principles for confidentiality protection. Prior to finalization, draft CDC programspecific data release plans will be shared with data providers for their input. Formal agreement for each data re-release plan will be obtained from the data providers through an opt-in or opt-out "statement of response" from the data providers. For data providers deciding to opt-out of the data release plan, further negotiation with the data providers will be needed to customize the plan to meet State requirements. Data collected by CDC, including data collected by States and provided to CDC, becomes Federal record once received by CDC, and is subject to Federal laws and rules governing data release and Federal records retention laws. These include, but are not limited to, the Freedom of Information Act (FOIA), the Privacy Act of 1974, Confidentiality Assurances and Certificates of Confidentiality (see Appendix B for further details). These laws, which are highlighted in Appendices B1 (Federal Laws and Rules Governing Data Release) and B2 (overview of selected Federal laws), may provide CDC with the ability to protect certain types of data from public re-disclosure; they also may require the retention and/or disclosure of data in some circumstances. Data use agreements must conform to the requirements of these laws when applicable. # What Type of Data do the CDC-ATSDR Data Release Guidelines and Procedures Apply to? The CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data contain information that may be applicable for any CDC program that releases or shares data; however, it has been prepared specifically to address the policies and practices CDC programs establish for State-provided data shared with CDC that are not already covered by a written formal data re-release procedure at the time this report is finalized. State-provided data are defined, in this report, as population-based data intended to represent a complete count of cases (or a statistical sample of all cases in a given population) that are collected by U.S. State and Territorial Health Agencies related to the health or exposure status of individual U.S. residents, which fall under State legal authority for collection and protection of privacy and confidentiality, and that are reported to CDC by State health departments. The Guidelines and Procedures also apply to unweighted microdata 10,11 (individual person records) from sample surveys administered by State Health Agencies which send CDC data containing personal identifiers or information about survey respondents that could potentially be used to identify survey respondents. Furthermore, these data release guidelines and procedures apply to State-provided surveillance and information data about events (such as a chemical spill or conflagration, etc.) only if data has been provided by the State in the format of individual person records associated with the event (see the glossary definition of "individually identifiable data," which mentions that both direct and indirect identifiers can potentially be used to establish individual identity). # Data from Indian Tribal nations that comes to CDC indirectly through State Health Agencies are covered by the guidelines and procedures in this report because these data are being directly reported to CDC under the authority of the State Health Agency. For CDC public health surveillance systems which are comprised of data from State Health Agencies and other data sources, such as the Vaccine Adverse Events Reporting System, one data release procedure should be developed and that procedure should not be in conflict with the data release guidelines for State-provided data. Although most of the guidelines are applicable for any data that are released or shared, data not specifically covered by the CDC-ATSDR Data Release Guidelines and Procedures for Re-Release of State-Provided Data include, but are not limited to, the following: - individually identifiable data that are not collected under U.S. State health agency authority, such as data that CDC collects directly, and data that are reported directly to CDC by Indian Tribal nations; - data collected specifically for research or an outbreak investigation; - data that are not individually identifiable or potentially identifiable; - data systems that use public-use data compiled from another data system considered to be the primary data system. # Agreements with Data Providers # A. Introduction This section and the next (Section 4) describe 16 guideline elements (the "Guidelines") that collectively constitute the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data. Each guideline represents a "minimum standard" for CDC programs to address when developing their program-specific data release procedures for re-release of State-provided data. CDC programs may wish to adopt more stringent standards than the minimum standard. The guidelines in Section 3 apply to all re-releases of State-provided data. The guidelines in Section 4 are grouped into three main categories: (1) guidelines representing administrative requirements that apply to all re-releases of State-provided data, (2) guidelines that apply to re-releases of Stateprovided data as public-use data, and (3) guidelines that apply to the re-release of Stateprovided data as restricted-access data. Best practices statements accompany most of the guidelines. The best practices statements reflect applicable references and resources or selected examples of practices by CDC programs or other Federal or State programs that appear to be consistent with the guidelines. On occasion, more than one best practices standard is shown because they may represent viable alternative options for specific CDC programs. The best practices statements differ from the guidelines, in that the best practices statements are not minimum standards, but rather a listing of approaches that may merit more discussion and consideration within CDC. The best practices statements are meant to be descriptive rather than prescriptive. In other words, it is being left to the discretion of each CDC program to consider for themselves whether it is appropriate to implement the listed best practices statements or implement another approach to meet the intent of the guideline. Because CDC data systems vary widely with respect to their content and format, it is important that both the guidelines and best practices allow for flexibility within the context of the principles espoused by the CDC policy. The guidelines that apply to the re-release of restricted-access data using Data Sharing Agreements (DSAs) (see Section 4C) do not apply to re-release of restricted-access data through CDC-controlled data centers or by licensing non-CDC researchers to use certain data. At the time this report was developed, only NCHS and one program within the National Immunization Program were re-releasing data through a research data center and no CDC programs were re-releasing data through licensing agreements. Hence, until CDC implements a process for instituting these alternative mechanisms for data rerelease more broadly within CDC, it is considered premature for this report to address the procedures needed for these alternative data re-release mechanisms. In the future, CDC and CSTE will need to develop additional implementation policies and procedures for data re-released through these mechanisms. For information about the NCHS Research Data Center, refer to www.cdc.gov/nchs/r&d/rdc.htm. Additional information about data centers 5,12 (controlled sites for accessing data) and data licensing 5,13 can be found elsewhere. The cross-reference table included below lists the guidelines (see Sections 3 and 4A-4C) and procedures for implementing confidentiality protection (see Section 4D) that apply to re-releases of microdata and tabular data (including pre-calculated tables) through online query systems or other formats. Data 9 and will be based upon accepted data release practices and procedures (see Section 4A-C for guidelines on protecting and releasing data and see Section 4D for a description of confidentiality protection standards and procedures). The data re-release plan will also describe the content and format of data to be released as either non-identifiable public-use data or identifiable/potentially identifiable restricted-access data (see also Guideline # Cross-Reference There may be some aspects of the data re-release plan that may need to be deferred until the data are reviewed by the CDC program. In this situation, a short-term (and most likely brief) data re-release plan could be drafted in collaboration with the State data providers prior to the time CDC receives the data and then a more comprehensive longerterm data re-release plan developed after the CDC program has reviewed the data. The short-term plan could simply remind the State data providers about any assurances and approvals that are in place to protect the data, if any, and inform them that no data, or very limited data, will be re-released before the longer-term plan is developed (see Figure 1 below for boilerplate language for a short-term data release plan and data agreement with data providers). The short-term initial data agreement with State data providers should specify the expected time the initial plan will remain in place as well as the number of months the CDC program anticipates it will take to complete the longer-term more comprehensive data re-release plan in collaboration with State data providers. CDC programs will solicit the State data provider's input and formal agreement with the proposed data re-release plan by asking the data providers for a formal "statement of response," which at a minimum should include the State's decision to either "opt-in" or "opt-out" of the plan or components of the plan (e.g., a State may want to include their data in a CDC program's re-release of public-use data, but not restricted-access data). The CDC program may want to customize the proposed data re-release plan for State data providers wishing to opt-out of the plan because it does not offer adequate protection for their State's data. For example, if feasible, the CDC program could withhold re-release of data below a specific sub-state geographic level for some States. While States have the option to refrain from providing data to CDC if the CDC plan provides less protection than State requirements, this should be a very rare occurrence that is only used as a last resort option by the State. The CDC program will review and, if necessary, update the data release plan periodically, and will notify States whenever a change in procedure is anticipated. The provisions of the data re-release plan will be consistent with all applicable Federal and State laws and regulations. The CDC program will be responsible for determining that the agreements with data providers meet the requirements of the Federal laws and regulations under which it operates (see Appendix B1 and B2 for a summary of the Federal laws that apply to CDC's re-release of data). Similarly, the State data providers will be responsible for determining that the data agreement is consistent with all State laws and regulations under which it operates. Any requests the receives for data submitted during this pilot test period will be referred back to the State data providers. The more comprehensive data re-release plan will address the need for CDC to re-release data when requests are made for data submitted outside the pilot test period. ►Best practices for Guideline 1: The NCHS and NAPHSIS have an agreed upon data re-release agreement for vital statistics data. The CDC AIDS Program asked States to select the level of sub-State geographic detail that specific variables in the AIDS Public Information Data Set (PIDS) could be tabulated for, by predefining a select group of options they could select from, such as health-district level; county-level; MSAs with 100,000 or more people; MSAs with 500,000 or more people, etc. This process enabled CDC to customize the AIDS data re-release procedure to meet the different requirements of individual States. # Guideline 2: Suggested Content of the Data Re-Release Plan The content of the data re-release plan will vary according to the needs of the CDC program and data providers. - For CDC and State and local public health employees, permission for use of restricted-access data sets will be limited to those employees having official programmatic duties warranting access to these data. - For other data requestors, permission for use of restricted-access data will be based upon a review of the stated purpose of the data request (the stated purpose of the data request should be consistent with the original purpose for data collection), an assessment of whether the requested data would be appropriate to use for the intended purpose, and the need for using restricted-access data versus another type of available data set (e.g., a PUDS). The CDC/ATSDR Policy on Releasing and Sharing Data states: "CDC strives to have data release policies that are fair to all users, regardless of their organizational affiliation." CDC programs should develop a procedure describing the criteria for determining who can access non-PUDS (i.e., restricted-access) data and the party or parties within CDC who are responsible for making these decisions. Procedures for releasing restrictedaccess data include authenticating the requestor's identity (see Guideline 10) and the use of data sharing agreements (DSA) (see Guidelines 11,13,14,15). ►Best practices for Guideline 5: The NCHS Policy on Micro-data Dissemination 14 (www.cdc.gov/nchs/about/policy/policy.htm) states: "No individual-at NCHS or elsewhere-may claim entitlement to obtain or access identifiable data collected by NCHS by virtue of his or her employment. Access to identifiable data is not determined solely by employment status, organizational affiliation, or financial commitment. More important are the need for identifiable data, the use to which the data will be put, and the requestor's role and responsibility with respect to the data collection activity. Since any access to identifiable data poses risk, access to such data will be carefully evaluated and tracked after access is granted." The CDC/NCHSTP assurance of confidentiality for HIV/AIDS data states "No CDC HIV/AIDS surveillance or research information that could be used to identify any individual or institution on whom a record is maintained, either directly or indirectly, will be made available to anyone for non-public health purposes. In particular, such information will not be disclosed to the public; to family members; to parties involved in civil, criminal, or administrative litigation, or for commercial purposes; to agencies of the Federal, State, or local government. Data will only be released to the public, to other components of CDC, or to agencies of the Federal, State, or local government for public health purposes in accordance with the policies for data release established by the Council of State and Territorial Epidemiologists." The 'minimum necessary' standard provision in the HIPAA Privacy Rule indicates that a "covered entity must make reasonable efforts to limit protected health information to the minimum necessary to accomplish the intended purpose of the use, disclosure, or request." Applying the intent of this standard to CDC data re-release procedures, only the minimum necessary data elements that can be justified by the data requestor to accomplish the proposed analysis should be re-released to data requestors, because additional variables may increase the disclosure risk potential of the data unnecessarily. Guideline 6: Include Disclaimer with Re-Release of Provisional Data 'Provisional' or 'preliminary' data are thought to be close to final but subject to change as additional records are added to the dataset or updated information is obtained. The exact definition of 'provisional' or 'preliminary' varies by data system. Because provisional data may be subject to substantial change, it may not be appropriate for these data to be used for all purposes for which finalized data are used. The CDC program will inform State data providers of their procedure for any proposed re-release of provisional public-use and restricted-access data and States, in turn, will indicate their agreement or disagreement with the re-release procedure via their "statement of response" (see Guideline 1). A "Provisional Data Disclaimer" should accompany provisional data rereleases. It should encourage the data user to consider the provisional nature of the data before using it for decisions. In addition, the disclaimer should describe how the data are reviewed to ensure accuracy, and when the data are considered finalized. ►Best practices for Guideline 6: Data quality review is considered complete upon mutual agreement by the State and CDC, once the maximum achievable quality has been attained. Explicit criteria for data finalization should be documented and include adequate time for corrections from data providers and for case investigation to establish final case classification. # Guideline 7: Maintain Log of Data Sets Re-Released The CDC program which re-releases State-provided data will maintain a log of data sets released. ►Best practices for Guideline 7: For PUDS data, the log of data sets released represents an inventory of the different PUDS data sets CDC has released. Ideally, such an inventory would be posted on the Internet, include a description of all State-provided PUDS public health surveillance data released by CDC, and be formatted so it can be queried by users. While the inventory is useful to inform interested parties as to the existence of these data sets, its primary function within CDC is to remind the CDC program that a potential exists for data users to combine related data sets in order to access more information than just a single data set would provide. Thus, the inventory should prompt CDC programs to perform disclosure risk assessment within the context of all previously released related data sets. Minimum data elements for the PUDS inventory could include the date the PUDS was first released, conditions or diseases included in the data set, variables and coding formats contained within the PUDS, and information on how to request the PUDS. If more than one PUDS data set is released by a single CDC program, the program should clarify how their PUDS data sets are different. For restricted-access data, the primary purpose of the log of releases is to be able to track the status and terms of each data sharing agreement (DSA). This log is for internal CDC use by the CDC program responsible for tracking compliance with the terms of the DSA. Ideally, such a log would be posted on the CDC Intranet. The log of releases for restricted-access data sets should be audited to assess whether the person or persons granted access to restricted-access data are complying with the terms of their DSA. Minimum elements for the restricted-access log may include name and affiliation of the person responsible for compliance with the terms of the DSA and information on how to contact them, names of all collaborators on the project (and information on how to contact them), the list of variables and coding formats released, the name of the conditions or diseases represented by the data, and a checklist of requirements the CDC program needs to verify as per the DSA (For example, if a pre-publication review of the report was required by the DSA, the date the data user sent the report to CDC for review and the date the review was completed and comments sent to the data user; or, the date the data set was returned to CDC or destroyed, etc.). # B. Re-release of State-Provided Data as Public-Use Data CDC's re-release of data as a PUDS does not require the use of a DSA. When PUDS are created by CDC programs, they should be made available to all interested users, without restrictions. # Guideline 8: Planning for Release of Public-Use Data Refer to the CDC/ATSDR Policy on Releasing and Sharing Data 9 for information about the release of data for public use. This Policy indicates "procedures for releasing publicuse data should be consistent with the CDC's Public Health Information Network's functions and specifications 15 ." The CDC/ATSDR Policy indicates each plan for release of public-use data should include the following: - A procedure to ensure that confidential information is not disclosed. - A procedure to ensure that data is released in a form that does not endanger national security or compromise law enforcement activities. - Analysis plans and other documentation required by the Office of Management and Budget regulation on data quality 16 . - Instructions for non-CDC users on the appropriate use of the data. - The date the data will be released, which should be as soon as possible after the data are collected, scrutinized for errors and validated. The release of these data should occur no more than one year after these activities are completed. - The formats in which the data will be released (e.g., ASCII). For each format, give specifications (e.g., variable definitions) and information on standards for transmission. The CDC/ATSDR Policy on Releasing and Sharing Data 9 also states CIOs may release data without restrictions for public use through the CDC Information Center or data may be shared through the CDC/ATSDR Scientific Data Repository and its data dissemination portal CDC WONDER (wonder.cdc.gov/welcome.html ). # Guideline 9: Include Disclosure Statement with PUDS At the time each PUDS is released or accessed, CDC programs will include a written statement about the following responsibilities users of public-use data have: - A statement informing PUDS users of their responsibility to maintain confidentiality, including (per the CDC/ATSDR Policy on Releasing and Sharing Data 9 ), "instructions that non-CDC data users must agree not to link data with other data sets….. … instructions to report to the CDC ADS any inadvertent discovery of the identity of any person and to make no use of that discovery." - A statement informing PUDS users of their responsibility not to imply or state, either in written or oral form, that interpretations based on the data are those of the original data sources (e.g., the U.S. States) or the CDC public health surveillance program that provided the data, unless the data user and data sources are formally collaborating on the proposed analysis. - A statement informing users of their responsibility to acknowledge, in all reports based on these data, the original source of the data (e.g., the States that provided the data to CDC) as well as the name of the CDC public health surveillance program that re-released the data. ►Best practices for Guideline 9: CDC NCHS requests that PUDS users agree to: - "Use the data in this dataset for statistical reporting and analysis only. ►Best practices for Guideline 10: Following are examples. - Written requests for access to State-provided data are required to be on letterhead stationery. - Oral or email requests from a known individual are considered as needing no further verification. An electronic authentication protocol can use one or more of the following methods. - Software access control: Password or challenge phrase; Digital certificate - Physical device: Hardware "token" (e.g., USB connection); Digital fob (auto-generated passnumber); SmartCard - Biometric scan The electronic process for identification-authentication can be linked to authorization "rights" which specify levels of access. # Guideline 11: All Requestors Wanting to Use Restricted-Access Data are Required to Sign a DSA The CDC program should confirm, via the "statement of response" (see Guideline 1) that the State granted permission for the data to be re-released as a restricted-access data file. In addition, prior to CDC's re-release of these data, all requestors must sign a DSA which governs the protection and use of these data. The CDC program which re-releases Stateprovided data will retain signed copies of the DSA. A DSA may be subsumed in a larger interagency Memorandum of Understanding (MOU). ►Best practices for Guideline 11: The 2002 modification to the HIPAA Privacy Rule permits release of a "limited data set" as long as a there is a written data use agreement. This HIPAA standard is consistent with the use of "restricted-access" data and DSAs described within the guidelines section of this report. # Guideline 12: Monitor User Compliance with DSAs The CDC program which re-releases State-provided data will monitor compliance with the terms of the DSA. ►Best practices for Guideline 12: A passive approach to compliance monitoring is acceptable, as long as the following criteria are met: - The data user is informed of the penalty for not complying with the terms of the DSA. (The intent of the penalty is to deter breaches in compliance.) - The data user is fully informed about their responsibilities in using the data. - The data steward institutes a process for logging compliance problems they become aware of. - The CDC program takes appropriate actions to resolve any identified problems and implements (if possible) procedures to avoid similar types of problems in the future. Examples of active compliance monitoring methods include: - Pre-publication review of reports, articles, graphs, maps, or tables. - Prior review of presentations based on the dataset. - Annual letters sent by data stewards to confirm whether the data requestor's use of the dataset has been completed and whether the data requestor has taken steps to either destroy or return the dataset. Pre-publication or pre-presentation review can include both privacy protection as well as accuracy of scientific inferences. Releasing and Sharing Data 9 for "special-use agreements," but also includes additional criteria: # C2. Development of Data Sharing Agreements for Restricted-Access Data - A description of the use to which the data will be put, and limitations on usage of data. The data requestor's description of their intended use of the data should provide evidence to the CDC program that there is a legitimate public health purpose that justifies the use of the data. The data user should also demonstrate their need for restricted-access data versus other available data, such as a PUDS. - Information on any laws pertaining to the DSA. - The names of every person who will have access to the data and specification of procedures for extending the provisions of the DSA to named collaborators (e.g., requiring signed confidentiality pledges, etc). - The name of the person primarily responsible for care of the released data and compliance with the terms of the agreement. - A list of mechanisms for preservation of confidentiality. These mechanisms should include both limitations on access (i.e., specified staff only) and technical security practices (such as encryption). - A list of restrictions on releasing analytic results. - A clearly stated prohibition on any attempt to link the dataset with any other dataset without prior CDC permission (see Guideline 14). - A clearly stated prohibition on the further release of data to other parties without prior CDC permission (see Guideline 15). Requests from legal authorities (such as under conditions of a declared public health emergency) or FOIA requests must be referred by the data user to the CDC data steward. - A stated requirement for the data user to notify the CDC ADS if any individual person represented in the dataset is inadvertently identified during approved usage. - A stated limitation of the right of access to data based on the role of an individual, with a stated requirement to return or destroy the dataset when the requestor changes positions in the agency or leaves the agency. - A stated requirement to return or destroy the dataset and all derived files when use is completed (the term "use" in this sense may include a specified plan for re-analyzing the data after the initial analysis is completed). - A statement informing users of their responsibility not to imply or state, either in written or oral form, that interpretations based on the data are those of the original data sources (for example, the U.S. States) or the CDC program that provided the data, unless the data user and data providers are formally collaborating on the proposed analysis. - A statement informing users of their responsibility to acknowledge, in all reports based on these data, the original source of the data (for example, the States that initially provided the data) as well as the name of the CDC program that re-released the data to the user (see best practices for an example). - A description of the penalty that may be imposed on the data user for breaching the terms of the DSA. - Provisions that govern emergency requests for identifiable or otherwise confidential data (See also Guideline 16). - For DSAs with CDC staff acting as a data user, the following are to be included in the DSA: - A statement indicating that if the CDC data user plans to publish a report that singles out specific States or Cities in the discussion section of the report, the Restricted-access data include identifiable or potentially identifiable data. The data set derived from linking a restricted-access data set to another data file may be even more individually identifiable than the original data. Thus, there is a need to ensure disclosure review takes into account the variables included after the linkage. The CDC program interested in re-releasing restricted-access data for a linked data analysis should obtain, or require the data requestor to obtain, written permission from the data providers (the States contributing the data) for the proposed linked analysis. Prior to seeking permission from the data providers, the data requestor should complete and sign the standard DSA (see Guidelines 11, 13) and, in addition, attach an addendum to the DSA which includes the following information, so the CDC program and data providers can determine whether to approve the data request: 1) source and description of the data file to which the restricted-access data will be linked; 2) written description of the variables and coding formats to be included in the final linked file; and 3) description of the data requestor's plan for conducting additional disclosure review to ensure that variables contributed in the linking process do not lead to re-identification of the individual described in the original data file. ►Best practices for Guideline 14: Examples of special procedures for linked analyses are: - "separation of duties", where no single individual is able to conduct all of the steps in the linkage process. - post-linkage de-identification. Standard de-identification methods should be used, such as numerator and denominator cell aggregation or suppression rules. GAO Report #GAO-01126SP titled "RECORD LINKAGE AND PRIVACY: Issues in Creating New Federal Research and Statistical Information 21 " may serve as a useful reference of techniques which can be employed to ensure privacy protection for data linkages. Linkage can be conducted inside a CDC-controlled data center. This guideline applies to "modified" data shared outside of such centers. Data shared outside CDC-controlled data centers are partially or substantially modified, as needed, in order to minimize the likelihood of breaches of confidentiality. # Other Parties Restricted-access data can be released further to other parties as de-identified data, in one of two ways: 1) by creating a de-identified data set (i.e., a PUDS) from the restrictedaccess data set and then disseminating data from the PUDS, or 2) by generating deidentified data directly from the restricted-access data set (where the restricted-access data file, by definition, includes identifiable or potentially identifiable data). If the requestor plans to release de-identified data generated directly from a restrictedaccess data file (situation #2 described above), a procedure must be implemented to ensure that the generated data have been de-identified appropriately. In this situation, the data requestor is required to submit an addendum to the standard DSA (See Guidelines 11, 13) describing the procedures that will be implemented to audit the results of the data generated for further release to other parties. If the requestor plans to release de-identified data that are generated from a de-identified data set created from the restricted-access data set (situation #1 described above), an addendum to the standard DSA is not required. ►Best practices for Guideline 15: If the requestor plans release via an online interactive query system which generates tables from restricted data, an automated algorithm for de-identification must act prior to release, and its results must be checked by an automated audit protocol. An automated audit protocol assesses disclosure risk against pre-determined thresholds. (See Procedure 4.) . However, the HIPAA Privacy Rule's "safe harbor" method of de-identification is deemed inadequate protection for public health agencies to use for de-identifying data sets because public health agencies collect many more demographic variables than do covered health entities. # C3. Emergency Requests for Data # D. Confidentiality Protection In addition, public health agencies are expected to have a much higher level of sophistication with regard to disclosure review than entities covered by HIPAA. Other useful materials on confidentiality protection have been developed and will be useful to those involved in data protection and re-release, including a book published in # B. Procedures for Implementing Confidentiality Protection The following is a list of procedures for confidentiality protection. One or more of these procedures may be appropriate for a given data system. It is not the intention of this report to imply that all these methods need to be used for each data system. CDC programs may wish to seek expert consultation on the issue of confidentiality protection and disclosure risk assessment and control before finalizing a data re-release plan (see Practice E (in Section 5 of this report). # Procedure 1. Limit Disclosure of Potential Identifiers The CDC programs that re-release State-provided data will delete, as necessary, all information judged to be of potential use in making individuals to whom they pertain "identifiable" (see "individually identifiable data" in Glossary). Particular attention will be devoted to information that can lead directly to an individual or their family, such as: - Name - Street address - Social Security Number - Medical record number - Telephone number Other information is extremely useful in narrowing the possibilities that information may refer to a particular individual. Those providing low-level geographic detail and precise timing of certain events are particularly important. # Geographic Information - Zip code (9-, 5-, and even 3-digit) - Census tract - City/town - County # Timing of events - Exact date of birth (year-month-day) - Exact date of event (year-month-day) - Month and year of birth (year-month) - Month and year of event (year-month) Information concerning location (e.g., geography) and timing of events, along with details concerning the following types of information can serve to reveal individual identity: - Occupation (e.g. 3-or higher digit codes) - Education (e.g. single years) - Race/ethnicity (e.g. Aleutian, Filipino v. Asian) - Income (as a continuous, un-topcoded variable) - Medical condition/diagnosis (e.g. detailed site specific cancers) and cause of death (e.g. 3-or higher digit ICD code) There could be other program-specific variables that may be used to help disclose individual identity. Prior to re-release, these items must be thoroughly reviewed for their potential for personal re-identification. It is not the intent of these guidelines to imply that all of these fields must always be deleted. Under appropriate conditions and with proper safeguards, such items may be released. It is not the intent of these guidelines to recommend a single strategy for the limitation of disclosure risk. It is recognized that both programmatic and statistical considerations may come into play in deciding appropriate protections for data release. For example, an alternative to field (variable) deletion is data value recoding (see Procedure 2). Prior re-releases of data should be considered in a cumulative fashion. As stated in the document Identifiability in Microdata Files 22 "Each of these files may be considered safe to release by themselves. However, there may be enough information in the two files combined to effect a re-identification." (HIPAA) 2001 Privacy Rule's safe harbor method of deidentification (which requires covered entities to remove all of a list of 18 enumerated identifiers and have no actual knowledge that the information that remains could be used alone or in combination to identify an individual who is a subject of the information) is deemed inadequate protection for pubic health agencies to use for de-identifying data sets because public health agencies collect many more demographic variables than do covered entities, according to the viewpoint of DRGWG representatives. In addition, public health agencies are expected to have a much higher level of sophistication with regard to disclosure review than covered entities. ►Best The HIPAA Privacy Rule de-identification standard that is consistent with this guideline requires "a person with appropriate knowledge and experience applying generally acceptable statistical and scientific principles and methods for rendering information not individually identifiable makes and documents a determination that there is a very small risk that the information could be used by others to identify a subject of the information" (45 CFR Part 164.514(b)(1)(i)). The HIPAA Privacy Rule was modified in 2002. The 2002 modification to the HIPAA Privacy Rule permits release of data that is not fully de-identified through a "limited data set," as long as the data are governed by a data use agreement which provides sufficient privacy and confidentiality protection for the data. For the limited data set, all direct identifiers must be removed from the data file. However, dates such as birth date, date of death, and dates of admission or discharge could be released in the data file, but only if this information is needed for the purpose of the release. In addition, the limited data set may include 5-digit zip code or any other geographic subdivisions, such as State, county, city, precinct and their equivalent geocodes, except for street address. The Privacy Rule clarifies standards for the creation of deidentified data sets and "limited data sets." The limited data set concept is consistent with the concept of "restricted-access" data that is discussed in this report. # Procedure 2. Aggregate Data Values The CDC programs which re-release State-provided data, either as "microdata" files (e.g., data files or records on an individual person) or as tabular data, will recode fields as needed in order to aggregate data values. Common methods include: - collapsing continuous/interval data (e.g., age; date of occurrence) into broad categories; - collapsing ordinal data (e.g., location geography) into broader categories; - grouping nominal data (e.g., diagnosis) into broad categories; - truncating variables (e.g., name). - top-coding or bottom-coding variables. ►Best practices for Procedure 2: Refer to the Federal Committee on Statistical Methodology's Statistical Working Paper #22: Report on Statistical Disclosure Limitation Methodology 11 for a description of common methods used to protect microdata and tabular data, available at www.fcsm.gov/workingpapers/wp22.html. # Procedure 3. Limit the Number of Records or the Number of Fields The CDC program which re-releases State-provided data as "microdata" files will consider the applicability of other methods to protect microdata releases from disclosure risk. Common methods include: - including data from only a sample of the full dataset; - limiting the number of variables in the released file. For example, consider (1) releasing only those variables essential to analysis; and (2) limiting the number of contextual or ecological variables--information that describes a geographic area, such as where a case-patient resides--because this type of information can lead to the identification of that area. ►Best practices for Procedure 3: Refer to the Federal Committee on Statistical Methodology's Statistical Working Paper #22: Report on Statistical Disclosure Limitation Methodology 11 for a description of common methods used to protect microdata, available at fcsm.gov/working-papers/wp22.html. # Procedure 4. Use Numerator Rules for Data Aggregation or Suppression The CDC program which re-releases State-provided data as tabular data or microdata will use numerator rules (cell size) to either - guide selection of groupings of aggregated data values; or, if aggregation is insufficient, - suppress release of certain cells in a table. There is no single numeric threshold for cell aggregation that is appropriate for all data in tabular or microdata format. Selection of an appropriate threshold level is guided by multiple factors, including: - sensitivity of the data (subject matter); - format of the data (e.g., whether the data are continuous or categorical); - level of detail in the data, especially the level of geographic detail; - likelihood that a specific record in a database may represent a unique person in a small population; - population or subgroup denominator size, as well as the numerator size. The CDC staff manual on confidentiality 7 generally advises a minimum numerator cell size of "3". Thus, numerator cell size counts of "1" or "2" are not generally advised, with some notable exceptions. The CDC staff manual on confidentiality 7 indicates the following exceptions to minimum numerator cell size rule of "3": a) "It has been a longstanding tradition in the field of morbidity or mortality statistics not to suppress small frequency cells in the tabulation and presentation of data. For example, it has been considered important to know that there were two deaths from rabies in Rio Arriba County, N. Mex., in a given year, or that there were only one infant death and two fetal deaths in Aitkin County, Minn. These types of exceptions to general CDC practices in other programs are followed because they have been accepted traditionally and because they rarely, if ever, reveal information about individuals that is not known socially." b) "Tables may show simple counts of numbers of persons, even though the number in a cell is only '1' or '2' provided the classifying data are not judged to be sensitive in the context of the table..." The Washington State guideline states: "If the count of cases or events in a cell is less than three, the data analyst needs to consider whether a breach of confidentiality is likely. A count of no events in the cell is clearly no threat to confidentiality, but a count of one or two events may be." (See www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm.) A rule which combines numerators and denominators will meet this standard, such as a rule that data are not released if the population is less than a certain size and the number of events in a cell is less than a certain size. For example, Missouri uses a complex combined rule 23 : "A table is not reported if a table cell subtracted from the number of total events of the same data file for the same characteristics yields a small number (less than 10 When primary cell suppression is used, it is generally accepted that 1) complementary cell suppression will need to be employed to avoid back-calculation by subtraction; and 2) if tabular data are suppressed using automated algorithms on a large number of related tables or via web-based interactive query systems generating tables directly from raw data, that procedures for postsuppression auditing should be employed. However, precise methods for automated suppression and auditing, that are easily implemented, still need to be developed. Therefore, at this time, it is not possible to implement this "best practice," but it should be considered for future implementation. # Procedure 5. Use Denominator Rules for Data Aggregation or Suppression The CDC programs which re-release State-provided data as tabular data or microdata will use denominator rules (population size) to either: - guide selection of groupings of aggregated data values; or, if aggregation is insufficient, - suppress release of certain cells in a table. ►Best practices for Procedure 5: A rule which combines numerators and denominators will meet this standard, such as a rule that addresses the relationship between the size of the numerator and the size of the denominator. An approach commonly used for microdata is that data are not released if the total population from which the data are drawn is less than a certain size, based on the premise of a size sufficiently large that no subcell of the variables contained in the data would be expected to be smaller than a certain size. In considering the population size in tabulated data, guidelines employed by the Washington State Department of Health state that "Generally, tabular data based on denominators greater than 300 persons per cell present minimal risk for individual identification. ... Caution should be exercised by the analyst if the population size is between 100 and 300, and extreme caution is warranted when the population is less than 100." (See www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm.) As indicated in Procedure 4 above, in the case of tabulated data Missouri focuses on the number of people in the population with the characteristic indicated in a given numerator. If the difference between the two is less than a minimum number, this information is not be published. On the other hand, in this scheme a very small cell number could be published if the denominator were large enough. (See www.cdc.gov/epo/dphsi/AI/confiles/day1/Land1.ppt). With regard to total population size, the statistical literature contains a great deal of discussion of appropriate minimal sizes and there is clearly variation depending upon information content and special considerations. The most general statement is found in the Federal Committee on Statistical Methodology's Statistical Policy Working Paper 2 where it is stated "Geographic information must be restricted beyond the point where an individual user could be familiar with a significant proportion of the universe, but whether that point comes at 25,000, 250,000 or 1 million will depend on the detail in the file and other restrictions imposed." (See www.fcsm.gov/working-papers/sw2.html p 28). The Federal Committee on Statistical Methodology's Confidentiality and Data Access Committee Checklist on Disclosure Potential of Proposed Data Releases 6 calls for "a minimum of 100,000 persons in the sampled area … provide rationale." (See fcsm.gov/committees/cdac/checklist_799.doc). The NCHS version of this checklist contains the following language: "Generally one has to balance the level of survey detail against the level of geography. The greater the amount of detail, the more risk is entailed for lower levels of geography. Similarly, with very high levels of geography, greater detail may be made available. General Rule: All geographic areas that are identified must have a minimum of 100,000 persons in the sampled area (according to latest Census or Census estimate). Caution: the figure of 100,000 is not without some risk. For certain target populations the members of which are be found infrequently in a population, a higher number may be desired." # Procedure 6. Refrain From Using Techniques that Distort Data for Privacy Protection The CDC programs which re-release State-provided data will refrain from distorting data (either altering data values or omitting records from the dataset) unless this approach is employed as a last resort and is absolutely necessary for the purpose of privacy protection. ►Best practices for Procedure 6: Examples of distorting data include adding statistical noise, data swapping, blanking and imputing for randomly selected records, and blurring data (replacing a reported value by an average value). Current methods of perturbative "statistical disclosure control" are not optimal because one cannot prospectively assess how the distortion of the data will affect the results of an analysis. This is a problem particularly if recommendations for public health action are made based on the analysis of distorted data. At the discretion of the CIO, when a data requestor plans to make public health recommendations based on analysis of altered data, the CDC program holding that data may offer to confirm the requestor's findings by performing a re-analysis on un-altered data. Alternatively, researchers should be provided the opportunity to obtain restricted-access data under a data sharing agreement, or conduct re-analysis themselves in a CDC-controlled research data center. See also Practice G which mentions that a new form of disclosure limitation, entitled "controlled tabular adjustment," is being researched; software is being developed to implement this new method. It was beyond the scope of this report to assess which data distortion methods minimize the magnitude of data distortion. # Practices to Support Re-Release of Data # B. Development of a Data Set Inventory to Facilitate Disclosure Risk Assessment Disclosure risk assessment is performed to estimate, either qualitatively or quantitatively, the probability that a data set poses a high or low risk of re-identification in terms of the information it contains about individuals and the status of their health. Since the risk of re-identification may be increased if a one data set can be linked to an another data set, CDC data stewards should be aware of the data sets other CDC components release that could have the potential for linkage with data sets their own programs release. To help facilitate this aspect of disclosure risk assessment, CDC should compile and regularly update an inventory of data sets that have already been released and that are eligible for release in the near future. The inventory should be posted on the CDC Intranet in a browsable (or queriable) format and should include, for each data set, the name of the CDC program releasing the data set, data steward contact information, and data set documentation (see the "Documentation" section of the CDC/ATSDR Policy on Releasing and Sharing Data 9 for recommended categories of information data set documentation should include), including the names of diseases or conditions about which the data are tabulated , and the variables and coding formats used. # C. Development of Instructions # D. Evaluations to Assess Whether a Breach of Confidentiality has # Occurred This report and the CDC/ATSDR Policy on Releasing and Sharing Data states that potential confidentiality breaches should be reported to the CDC ADS. This passive approach to ascertaining potential confidentiality breaches assumes that CDC will receive such reports. CDC should consider the feasibility of taking a more active approach to identifying confidentiality breaches. If feasible to do so, CDC may wish to itself develop or contract with others to develop standard criteria for CDC programs to use in conducting active approaches. # E. Consultation with Experts on Confidentiality Protection and # Disclosure Risk Assessment This report is not intended to be (and cannot be) a comprehensive resource on confidentiality protection or disclosure risk assessment and control. CDC programs may need to consult with experts on these issues as they develop program-specific data rerelease procedures that are consistent with guidelines and procedures in this report. CDC may wish to generally offer their programs the services of specified experts on these issues. In addition, CDC may wish to develop an interest group forum on confidentiality and data release patterned after the Confidentiality and Data Access Committee (CDAC). CDAC, an interest group of the Office of Management and Budget's Federal Committee on Statistical Methodology (fcsm.gov/committees/cdac/cdac.html ), was formed because staff members of statistical agencies who worked in the "confidentiality area" expressed a need to have a forum where they could communicate among themselves and exchange ideas. # F. Establish a CDC Intranet Site Where Materials Referenced in this # Report, from Various Websites, Are Archived This report cites various materials that are currently posted on the Internet pertaining to "training" issues, such as data release policies, confidentiality protection, or disclosure review assessment that would be useful to preserve for use with this report. To preserve the future availability of these materials, CDC should consider creating an Intranet site where these materials are archived. # G. Need for Continuing Discussions of Methods for Privacy Protection, # Disclosure Risk, and Other Issues The adoption of these guidelines should not deter CDC, CSTE, and others from future discussions of new methods for privacy protection and disclosure risk assessment and review. The guidelines and procedures are not "written in stone" and should be considered subject to change as new information and methods become available. For example, at the time this report was developed, the Working Group was not aware of any CDC programs using secondary (complementary) suppression based on methodologic principles, to avoid back-calculation (by subtraction) of the content of table cells that have undergone primary suppression. In addition, the Working Group was not aware of any algorithms being used by health agencies for automated suppression and auditing of one or more related tables. As noted in the best practices section for confidentiality protection Procedure #4 (see Section 4D, Procedure 4), precise and easy-to-implement methods for automated suppression and auditing of tables still need to be developed. Because use of web-based interactive query systems for data dissemination is increasing, future discussions should focus on the development and use of automated suppression and auditing methodologies for use by CDC programs. In 2002, the NCHS Office of Research and Methodology (ORM) sponsored the development of methodologic software for complementary cell suppression (and controlled rounding and controlled random perturbation) in two-way statistical tables of counts or magnitudes. CDC may wish to explore these automated methods for complementary cell suppression which are statistically-based in lieu of using ad-hoc or manual approaches. The NCHS ORM also noted that research is underway for a new form of disclosure limitation in tables called "controlled tabular adjustment," which is not limited by the dimensionality or complexity of tables. While Procedure 6 indicates CDC programs should refrain from using disclosure limitation techniques that distort data, it may be useful for CDC to assess or contract with others to assess which of the various perturbative statistical disclosure control methods minimize the magnitude of data distortion, for potential use by public health systems. Since CDC program data stewards will most likely be the primary staff responsible for writing program-specific procedures, under the direction of the CIO data-release review board or another oversight mechanism, CDC may wish to consider establishing a cross-CIO forum for data stewards to brainstorm and share suggestions for implementing the CDC-ATSDR Data Release Guidelines and Procedures for Re-Release of State-Provided Data. Various issues were raised during the review of this document that the DRGWG did not address, but that merit future discussion, including the following concerns and issues that were expressed: - CDC may fail to inform data users of potential weaknesses or peculiarities of the data when it releases the data, while the State may have provided such information to the user. - CDC may re-release data selectively so that wrong inferences would be drawn from it, while the State would have released a different dataset in response to the same request. - CDC may fail to inform the States of re-releases it has made of data that came from that State. - CDC may re-release data containing uncorrected errors, while the State may have released the same data with corrections. More generally, data rereleased by CDC may not be exactly the same as the corresponding dataset held by the State, and the user would not be informed of this possibility. - CDC collects and uses data from various State agencies other than State health agencies, such as labor departments, environmental departments, and agriculture departments. These other sources of data were not included within the scope of the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data because of the way the Data Release Guidelines Working Group was constituted. Future discussions within CDC should focus on whether the implementation guidelines for the CDC-ATSDR Policy for Releasing and Sharing Data in this report should also apply to data from State agencies other than State health agencies. - State-provided data that comes to CDC from other Federal agencies and not directly from State health agencies are not considered within the scope of the # CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data. Each request for this type of data may need to be handled differently, depending on the specifics of the situation, such as whether an MOU or other written agreement exists between the two Federal agencies or other statutory protections exist that define how external requests for data will be handled. In addition, for FOIA requests, an assessment may be needed to identify whether any FOIA exemptions may apply or whether the situation warrants a referral by the FOIA Officer to the Federal agency which was the source of the data being sent to CDC. Future discussions within CDC should focus on efficient processes for handling these types of data requests. # Implementation Steps # Proposed Deadline and Steps for CDC's Implementation of the # Guidelines and Procedures CDC and ATSDR programs having surveillance systems that fall within the scope of the CDC-ATSDR data release guidelines and procedures should examine their data re-release practices as of the effective date of the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data to see if they meet the minimum standards. If their procedures do not meet the minimum standards, CDC programs should have two years to revise their procedures to bring them into conformance, unless an appeal for an extension is requested from and granted by the CDC ADS. CDC CIOs should be responsible for ensuring that the guidelines and procedures are implemented either through the establishment of a CIO data-release review board (see the CDC/ATSDR Policy on Releasing and Sharing Data 9 ), which might report to the CIO ADS and might include the CIO Information Resources Manager and relevant data stewards, or CIOs might wish to implement the policy using an alternative oversight mechanism. The OPS Announcement that is distributed after the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data are cleared by CDC should indicate the guidelines apply to data shared between the States and CDC that are not already covered by a formal written data re-release procedure. CDC programs should examine their practices, as of the distribution date, to see if they meet the minimum standards in guidelines, and if not, to revise them to bring them into conformance with the minimum standard guidelines. CDC program data re-release procedures should be forwarded to the CDC ADS Office where an assessment of conformance with the CDC-ATSDR Data Release Guidelines and Procedures for Rerelease of State-Provided Data will be done. # Feedback to CSTE # Feedback to CSTE Regarding CDC's Implementation of the Guidelines CDC should advise CSTE on at least an annual basis during the implementation phase of these guidelines, on the status of completion of implementation. In addition, CDC should communicate with CSTE regularly regarding the results of evaluations conducted after the guidelines and procedures have been implemented by CDC programs, particularly if the results of the evaluations indicate that a revision of the guidelines is warranted. # DRGWG Members # CDC Members # CIO Primary Representative Alternate Representative importance of the work undertaken by the DRGWG and for allowing their staff to dedicate time and resources to this effort. # Glossary Audit trail: The maintenance of information, in a logbook or database, pertaining the request for and release and use of individually identifiable data. # Authentication: The process by which the identity of a person requesting access to individually identifiable data (restricted-access data) is verified. # Automated audit protocol: In terms of disclosure risk control, the use of linear programming to identify complementary cell suppressions for a primary cell suppression and to audit the proposed cell suppression pattern to see if it provides the required level of protection. Research seems to indicate that linear programming methodologies provide good but not optimal results. For this reason, it is not enough to just perform an automated audit for secondary cell suppression. The result of the algorithm needs to be checked to see if it is successful. # Bottom-coding: A technique used to mask microdata that involves creating categories for data values that are below a certain level. This method differs from aggregation, in that all data values below a certain threshold are grouped; other values in the field may or may not be grouped. See top-coding. Cell suppression: One of the most commonly used ways of protecting sensitive cells in tabular data. It is obvious that in a row with a suppressed sensitive cell, at least one additional cell must be suppressed, or the value in the sensitive cell could be calculated exactly by subtraction from the marginal total. The same is true for the column which contains a suppressed cell. For this reason, certain other cells must also be suppressed. The suppression of a sensitive cell is termed a primary cell suppression. Suppression of other cells to prevent one from calculating the value in the sensitive cell is termed complementary (or secondary) cell suppression. # Computational disclosure control: The process by which data values are aggregated to increase the granularity of specific variables, such as grouping age into age groups prior to data release. # Confidentiality: The treatment of information that an individual or institution has disclosed in a relationship of trust, with the expectation that it will not be divulged to others in ways that are inconsistent with the understanding of the original disclosure. It encompasses access to and disclosure of information in accordance with requirements of law and/or official policy 26 . Confidentiality breach: "An unauthorized release of identifiable or confidential data or information, which may result from a security failure, intentional inappropriate behavior, human error, or natural disaster. A breach of confidentiality may or may not result in harm to one or more individuals." (Source: Washington State Department of Health "Guidelines for Working With Small Numbers, Glossary" (accessible at www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm, accessed on April 11, 2002). Disclosure: In this report, disclosure refers to the unauthorized public disclosure of information about a person, about which data have been collected. A disclosure may occur as a result of a confidentiality breach. The definition of disclosure used in the HIPAA Privacy Rule is different from the definition in this report. For purposes of HIPAA, disclosure means the release, transfer, provision of access to, or divulging in any other manner of information outside the entity holding the information. # Disclosure (risk) assessment: A systematic review of a data file conducted to determine if any of the proposed contents present an unacceptable risk of individual disclosure. Disclosure risk assessment and control are usually conducted to prepare a public-use data set, and they can also be conducted when preparing a data set that is potentially linkable to another released data set. Disclosure (risk) control (also referred to as disclosure limitation or disclosure protection): The application of measures to reduce the possibility of identifying an individual through the characteristics available in a data file. Disclosure risk assessment and control are usually conducted in order to prepare a public-use data set, and they can also be conducted when preparing a data set that is potentially linkable to another released data set. Disclosure control includes steps taken to modify or suppress information that might identify an individual directly or indirectly before the data are made available to others for analysis (see page 3 of the Doyle book 3 ). Perturbative disclosure control methods distort (alter) the data before it is released while nonperturbative methods do not alter the data, but instead partially suppress or reduce the detail of the original data set (see page 112 of the Doyle book 3 ). Individually identifiable data: Data or information which can be used to establish individual identity, either directly, using items such as name, address, or unique identifying number, or indirectly by linking data about a case-individual with other information that uniquely identifies them. Microdata: A data file containing information in which each record provides information at the unit of data collection (e.g., individual persons, events, households, or establishments). Penalties: Penalties for a breach of confidentiality can range from imposing fines or a prison sentence to disciplinary action, barring an individual from receiving data in the future, or termination of employment or contract. Penalties can be established to differentiate willful from inadvertent disclosure and they can be tailored to the type of party responsible for the breach of confidentiality--an employee, contractor, or external data requestor. Population-based data: A complete count of cases occurring within a given population or a statistical sample of all cases occurring within a given population. # Predecisional exemption: The Freedom of Information Act's "predecisional" exception is explained in 5 U.S.C. § 552(b)(5) as "inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than an agency in litigation with the agency." The term "predecisional" has been traditionally defined by the courts as meaning "antecedent to the adoption of an agency policy." 27 # Privacy: The right of individuals to hold information about themselves in secret, free from the knowledge of others 28 . Privacy Manager: A person who develops and implements a data system's confidentiality policy and is responsible for clearing responses to data requests for a surveillance system. A data steward may act as a privacy manager. (See definition of Data steward in the glossary). Proprietary: Produced or collected in such a way that exclusive rights may apply. Provisional or preliminary data: These data are thought to be close to final but subject to change as additional records are added to the dataset or updated information is obtained. The exact definition of 'provisional' and 'preliminary' varies by data system (see Guideline 6). # Public health emergency: An occurrence or imminent threat of an adverse health event caused by epidemic of pandemic disease, infectious agent, biologic or chemical toxin, environmental disaster, or any agent that poses a real and substantial risk for a significant number of human fatalities or cases of permanent or long-term disability. Public-Use data: Data available to any requestor. Public-use data are sometimes referred to as "de-identified data" and include public-use data sets (PUDS), tables, or other data formats, with all individually identifiable data or information removed, and with the remaining fields modified or suppressed so as to reduce disclosure risk as much as reasonably possible and such that it is not possible to create any tables that violate the numerator or denominator cell size rules for a given surveillance system. Public-Use Data Set (PUDS): See public-use data. Re-release: For purposes of this report, CDC's re-release of data that the States initially provided to CDC through their data release procedures. Data can be re-released to data users who are internal or external to CDC in various formats, including CDC reports, publications, graphs, tables, maps, presentations, and data files. Restricted-access: Allowing the use of an Agency's microdata under controlled conditions. Restricted-access may mean allowing the use of an agency's data only to those who sign a formal data sharing agreement or permitting access to the data only at CDC-controlled research data centers, where CDC exercises direct supervision of the data use in order to protect confidentiality. # Security: The mechanisms (administrative, technical, physical) by which privacy and confidentiality policies are implemented in computer and telecommunication systems. # Top-coding: A technique used to mask microdata that involves creating categories for data values that exceed a certain level. This method differs from aggregation, in that all data values above a certain threshold are grouped; other values in a field may or may not be grouped. See bottom-coding. The Privacy Act of 1974 (5 U.S.C. 552a) prohibits agency disclosure of any record maintained in a Federal system of records when the primary method by which the data will be retrieved is by name, social security number, or other identifying particular, such as thumb print, except pursuant to a written request, or with the prior written consent of, the individual to whom the record pertains. The creation of a Federal system of records is announced in the Federal Register. While the Privacy Act is generally protective, it contains several exceptions to the Privacy Act which permit disclosure without a subject's consent, including disclosure of the record for a routine use. A routine use is a disclosure which is compatible with the purpose for which the record was collected, and which is included in the system notice. A complete list of exceptions is found within Title 5 U.S.C. 552(a) (see Appendix B2). # Appendices In addition to the Privacy Act of 1974, which contains criminal penalties for the unauthorized disclosure of protected information, the Trade Secrets Act (Table 1) makes it unlawful for any officer or employee of the United States or of any Federal department or agency to publish, divulge, disclose, or make known in any manner not authorized by law any information gained through the course of Federal employment that concerns or relates to "trade secrets, processes, operations, style of work, or apparatus, or to the identity, confidential statistical data, amount or source of any income, profits, or losses, or expenditures of any person, firm, partnership, corporation, or association…" Information acquired through the course of official duties, through an investigation or examination, or seen in a document, is covered by the Trade Secrets Act. Some types of data CDC receives from States may fall under this act, making the unauthorized disclosure potentially a criminal offense. Under the Trade Secrets Act (18 U.S.C. Section 1905), a person "…shall be fined not more than $1,000, or imprisoned not more than one year, or both; and shall be removed from office or employment." Under the Privacy Act of 1974, Subsection 552a(i) (1), a person who willfully discloses information to another person who is not entitled to receive it "…shall be guilty of a misdemeanor and fined not more than $5,000." The "Related Statutory Authorities" section of the Standards of Ethical Conduct for Employees of the Executive Branch (5 CFR 2635.902; see www.usoge.gov/pages/laws_regs_fedreg_stats/oge_regs/5cfr2635.html) cites the prohibition against disclosure of proprietary information and certain other information of a confidential nature which is contained in the Trade Secrets Act (18 U.S.C. Section 1905). (d). Data collected under a project with a 308(d) assurance of confidentiality may not be released in identifiable form without the consent of the individual or entity that supplied the information. CDC has historically been rigorous in its approval process for the discretionary use of this authority in order to prevent misuse of the protections as a mechanism for refusing to share data. forum, whether it is a Federal or State proceeding, whether the United States is a party, and the particular laws at issue. # Special Confidentiality The human subjects Common Rule (Table 1) applies to all applications and proposals for research involving human subjects to be conducted, supported, or subject to regulation by a Federal department or agency. One of the many requirements of the Common Rule includes the provision, when appropriate, for the privacy of subjects to be protected (45 CFR Part 46, Section 46.111). At the time this report was drafted, it was not possible to include a summary about how the Confidential Information Protection and Statistical Efficiency provisions of the E-Government Act of 2002 will impact CDC data systems. The Office of Management and Budget is expected to issue definitive guidance on this issue at a later date. # Introduction Under the Freedom of Information Act (FOIA) (Title 5 United States Code §552 or 5 USC 552), all Federal agency records are subject to disclosure unless covered (in whole or part) by one (or more) of nine exemptions. The Privacy Act applies only to records in "systems of records" , from which information is retrieved by an individual's name or other identifier. Such records are subject to release to individuals asking for their own records, to other requestors with the signed consent of the named individual, or to other requestors without a subject's consent under limited conditions specified in the Privacy Act. Definition -The term ''system of records'' means a group of any records under the control of any Federal agency from which information is retrieved by the name of the individual or by some identifying number, symbol, or other identifying particular assigned to the individual. # Freedom of Information Act (Title 5 USC 552) The Freedom of Information Act (FOIA) provides that, upon receiving a written request from any person, a Federal agency must release any requested agency record unless that record falls within one of the nine FOIA exemptions. FOIA applies to only Federal agencies, and covers only records in the possession and control of those agencies except in certain narrow instances involving grantee-held data. - Exemptions from FOIA (Title 5 USC 552b) 1. protects from disclosure national security information concerning national defense or foreign policy, provided that it has been properly classified pursuant to Executive Order 12,958. 2. related solely to the internal personnel rules and practices of an agency; (a) internal matters of a relatively trivial nature; (b) more substantial internal matters, the disclosure of which would risk circumvention of a legal requirement. 3. specifically exempted from disclosure by statute (other than section 552b of this title), provided that such statute: (a) requires that the matter be withheld from the public in such a manner as to leave no discretion on the issue; or (b) establishes particular criteria for withholding or refers to particular types of matters to be withheld; 4. trade secrets and commercial or financial information obtained from a person that is privileged or confidential; 5. inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than agency in litigation with the agency; 6. personnel and medical files and similar files the disclosure of which would constitute a clearly unwarranted invasion of personal privacy; 7. records or information compiled for law enforcement purposes, but only to the extent that the production of such law enforcement records or information: (a) could reasonably be expected to interfere with enforcement proceedings; (b) would deprive a person of a right to a fair trial or an impartial adjudication; (c) could reasonably be expected to constitute an unwarranted invasion of a person's privacy; (d) could reasonably be expected to disclose the identity of a confidential source, including a State, local or foreign agency or authority or any private institution which furnished information on a confidential basis, and, in the case of a record or information compiled by a criminal law enforcement authority in the course of a criminal investigation or by an agency conducting a lawful national security intelligence investigation, information furnished by a confidential source; (e) would disclose techniques and procedures for law enforcement investigations or prosecutions, or would disclose guidelines for law enforcement investigations or prosecutions if such disclosure could reasonably be expected to risk circumvention of the law; or (f) could reasonably be expected to endanger the life or physical safety of any individual; 8. contained in or related to examination, operating, or condition reports prepared by, on behalf of, or for the use of an agency responsible for the regulation or supervision of financial institutions; or 9. geological and geophysical information and data, including maps, concerning wells. Any reasonably segregable portion of a record shall be provided to any person requesting such record after deletion of the portions which are exempt under this subsection. The amount of information deleted shall be indicated on the released portion of the record, unless including that indication would harm an interest protected by the exemption in this subsection under which the deletion is made. If technically feasible, the amount of information deleted shall be indicated at the place in the record where such deletion is made. # Privacy Act (5 USC 552a) The Privacy Act applies to records maintained by a Federal agency in a system of records in which the primary method for data to be retrieved is by full names, social security numbers, or other identifying particulars. The Privacy Act states "No agency shall disclose any record which is contained in a system of records by any means of communication to any person, or to another agency, except pursuant to a written request by, or with the prior written consent of, the individual to whom the record pertains." The Act goes on to state the following exceptions, which are discretionary: # Disclosures Permitted by the Privacy Act The Privacy Act permits disclosure without a subject's consent in certain circumstances: 1. to those officers and employees of the agency which maintains the record who have a need for the record in the performance of their duties; 2. required under section 552 (FOIA) of this title; 3. for a routine use (disclosure of identifiable data outside the Department for a purpose compatible with the purpose for which the data were collected); 4. to the Bureau of the Census for purposes of planning or carrying out a census or survey or related activity; 5. to a recipient who has provided the agency with advance adequate written assurance that the record will be used solely as a statistical research or reporting record, and the record is to be transferred in a form that is not individually identifiable; 6. to the National Archives and Records Administration as a record which has sufficient historical or other value to warrant its continued preservation by the United States Government; 7. to another agency or to an instrumentality of any jurisdiction within or under the control of the United States for a civil or criminal law enforcement activity if the activity is authorized by law, and if the head of the agency or instrumentality has made a written request to the agency which maintains the record specifying the particular portion desired and the law enforcement activity for which the record is sought; 8. to a person pursuant to a showing of compelling circumstances affecting the health or safety of an individual if upon such disclosure notification is transmitted to the last known address of such individual; 9. to either House of Congress, or, to the extent of matter within its jurisdiction, any committee or subcommittee thereof, any joint committee of Congress or subcommittee of any such joint committee; 10. to the Comptroller General, or any of his authorized representatives, in the course of the performance of the duties of the General Accounting Office; 11. pursuant to the order of a court of competent jurisdiction; 12. to a consumer reporting agency in accordance with section 3711 f (Title 31 USC 3711f -Money and Finance: Collection and Compromise). The Privacy Act does not protect some records with identifiers: 1. Records of dead persons; Under the authority in Section 308(d) of the Public Health Service Act, CDC can provide confidentiality protection to a project when necessary to achieve the project's objectives, and when the respondents would not otherwise furnish valid sensitive information without that assurance. 308(d) protects information collected for a project from being used for any purpose other than the purpose for which is was collected unless the person or establishment from which the data were obtained has consented to such use. Confidentiality assurances protect against disclosures under a court order and provide protections that the Privacy Act does not. For example, the Privacy Act only protects individual participants, but confidentiality assurances can also protect institutions. Confidentiality protection granted by the CDC promises participants and institutions that their data will be shared only with those individuals and organizations listed in the consent form and/or the Assurance of Confidentiality Statement for the project. Projects that involve the collection of sensitive information frequently need confidentiality protection. Sensitive information includes (but is not limited to) data collection on sexual behaviors, drug uses, mental health status, or other information that if released could reasonably be damaging to an individual's financial standing, employability, or reputation. The full text of Section 308(d) of the Public Health Service Act follows: "No information, if an establishment or person supplying the information or described in it is identifiable, obtained in the course of activities undertaken or supported under section 304, 306, or 307 may be used for any purpose other than the purpose for which it was supplied unless such establishment or person has consented (as determined under regulations of the Secretary) to its use for such other purpose; and in the case of information obtained in the course of health statistical or epidemiological activities under section 304 or 306 , such information may not be published or released in other form if the particular establishment or person supplying the information or described in it is identifiable unless such establishment or person has consented (as determined under regulations of the Secretary) to its publication or release in other form." "The Secretary may authorize persons engaged in biomedical, behavioral, clinical, or other research (including research on mental health, including research on the use and effect of alcohol and other psychoactive drugs) to protect the privacy of individuals who are the subject of such research by withholding from all persons not connected with the conduct of such research the names or other identifying characteristics of such individuals. Persons so authorized to protect the privacy of such individuals may not be compelled in any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings to identify such individuals." Certificates # Applying for Confidentiality Protections Investigator(s) formally apply for confidentiality protections if they believe such protection is necessary to achieve the project objectives and to obtain valid information of a sensitive nature. Data release: Dissemination of data either in a public-use file or as a result of an ad hoc request which results in the data steward no longer controlling the use of the data. Data may be released in a variety of formats including, but not limited to, tables, microdata (person records), or online query systems. Data sharing: Granting certain individuals or organizations access to data that contain individually identifiable information with the understanding that individually identifiable or potentially identifiable data cannot be re-released further unless a special data sharing agreement governs the use and re-release of the data and is agreed upon by CDC and the data provider(s). # Data sharing agreement (DSA): A mechanism by which a data requestor and CDC program can define the terms of data access that can be granted to requestors. # Appendix B1. Federal Laws and Rules Governing Data Release CDC's practices and policies regarding data release are based on the framework of Federal Laws governing the maintenance and public disclosure of Federal records, the protection of key public priorities such as privacy, proprietary information, and national security, and obligations arising out of litigation or other compulsory processes. The purpose of this section is to provide an overview of the major Federal Laws that may affect the release of State data or that may compel disclosure of State data. The applicability and implications of these laws will vary depending on the nature of the data and other circumstances. These variations will not be analyzed in detail here. Questions by data stewards about the applicability of legal requirements should be directed to appropriate legal counsel. Data collected by CDC, including data collected by States and provided to CDC, generally become a Federal record once received by CDC, and are subject to Federal laws and rules governing data release and Federal records retention laws. These include but are not limited to, the Freedom of Information Act (FOIA), the Privacy Act of 1974, Confidentiality Assurances, and Certificates of Confidentiality. These legal authorities are highlighted in Appendix B2 (overview of selected Federal laws). Guidance on the application of the HIPAA Privacy Rule to public health is provided in a recently published Morbidity and Mortality Weekly Report supplement 29 (www.cdc.gov/mmwr/pdf/wk/mmsu5201.pdf). These Federal laws may provide CDC with the ability to protect certain types of data from public re-disclosure; they also may require the retention and/or disclosure of data in some circumstances. Data use agreements must conform to the requirements of these laws when applicable. Legal Proceedings. In some instances, data collected by CDC, including data collected by States and sent to CDC, may be implicated in some type of lawsuit or administrative proceeding. The disclosure of such data may be sought through voluntary disclosure or compulsory process. Generally, CDC uses available legal mechanisms to protect the confidentiality of identifiable data, and to protect other public interests described previously. Generally, CDC has been successful in such instances. However, it is important to keep in mind that the ability to protect confidential or identifiable information in litigation or other legal proceedings depends on a variety of factors such as whether the data has special confidentiality protection, the type of court or	# i. Executive Summary This report contains 16 guidelines and six procedures for implementing the CDC/ATSDR Policy on Releasing and Sharing Data 9 pertaining to CDC's re-release of State-provided data. Section 1 contains the background and purpose for establishment of these guidelines and procedures. Section 2 describes the characteristics of CDC data systems that are considered in-scope for this report. The guidelines and procedures in this report have been specifically prepared to address the policies and practices that CDC programs establish for re-release of State-provided data that are not already covered by a written formal data re-release procedure at the time this report is finalized. The data re-release guidelines included in this report are described in detail in Sections 3 and 4. Section 3 includes two guidelines which pertain to the development of data agreements with State data providers. The first guideline in Section 3 requires CDC * programs to develop data agreements with State data providers, through collaboration and negotiation, in advance of receiving data from data providers. This guideline also acknowledges that in some CDC programs, States currently release data to CDC in the absence of explicit data agreements, and a process is necessary to develop these agreements even as data sharing continues. The second guideline in Section 3 lists suggested content of the CDC program data re-release plan and is based on the guidelines for protecting and releasing data that are described in Sections 4A through 4C. The nature of confidentiality protection, a suggested content element of the data re-release plan (see Guideline 2), is based on guidelines on existing confidentiality standards and procedures (see Section 4D). The guidelines in Section 4 are grouped in three main categories: 1) guidelines representing administrative requirements for all re-releases of State-provided data; 2) guidelines that apply to re-release of State-provided data as public-use data; and 3) guidelines that apply to the re-release of State-provided data as restricted-access data. Each guideline represents a "minimum standard" for CDC programs to address when developing their program-specific release plan for re-release of State-provided data. CDC programs may wish to adopt more stringent standards than the minimum standard. Most guidelines and procedures are accompanied by a best practices statement, reflecting applicable references, resources, or selected examples of practices by CDC programs or other Federal or State programs that appear to be consistent with the guidelines. The best practices statement is meant to be descriptive rather than prescriptive. In other words, it is being left to the discretion of each Center, Institute, or Office (CIO) and their respective programs to consider for themselves whether it is appropriate to implement the listed best practice element or implement another approach. Because CDC data systems vary widely with respect to their content and format, it is important that both the guidelines and best practices allow for flexibility within the context of the principles espoused by CDC policy. Section 5 contains descriptions of practices that support re-release of data. These descriptions are meant to help facilitate CDC's adoption of the guidelines and likely will merit more discussion and consideration within CDC. Section 6 includes the proposed deadline and steps for CDC's implementation of the guidelines and procedures and Section 7 includes recommendations for providing feedback to CSTE during CDC's implementation of the guidelines and procedures. While this document was developed for CDC data systems having specific characteristics (see Section 2), selected information in this document may be applicable for any CDC program that releases or shares data. However, this determination is left to the judgment of the CDC CIOs and their respective programs. # Background and Purpose States + have a long-standing history of voluntarily reporting individually identifiable data to CDC on incident conditions or diseases that are of public health importance 1 . Recent developments in telecommunications and computerization have greatly enhanced the ability to compile and share such public health data. While the electronic exchange and accumulation of data on individual cases promises public health benefits, it has the potential to threaten individual privacy. The challenge is to balance the need for data protection with another competing interest of public health-the need to share data collected in the interest of public health as broadly as possible, with appropriate protections, with public health practitioners and with researchers conducting studies that have the potential to benefit public health. If such a balance is not achieved, potential data providers may choose to withhold data to protect it 2 . The U.S. State and Territorial Health Agencies operate within the authority of statespecific laws and regulations that control the collection and protection of individually + Throughout this document, "States" should be understood to refer to both U.S. States and Territories. identifiable data. Therefore, States are ultimately responsible for confidentiality protections, regardless of whether the data reside temporarily with a data steward, such as CDC, or reside within their own agencies. Since the mid-1980s, the CDC and Council of State and Territorial Epidemiologists (CSTE) have been engaged in extensive discussions over issues related to re-release by CDC of data released by States to CDC. States wanted assurance that CDC programs would apply consistent principles and adhere to certain standards when releasing such data. Appendix A describes relevant events leading up to the establishment of the CDC-CSTE Intergovernmental Data Release Guidelines Working Group (DRGWG). CDC has a responsibility to ensure that CDC programs protect the confidentiality of the State-provided data they have been entrusted with, and inform CSTE and data providers how the confidentiality of this data is being protected. In addition, CDC and CSTE have a shared responsibility to develop feasible guidelines for CDC programs that are consistent with State laws, regulations, and policies protecting confidentiality and that reflect state-of-the-art or best practices 3,4,5,6 . The CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data are intended to: 1) complement existing Federal laws that govern data release and protect confidentiality (Appendices B1 and B2); 2) augment current CDC policies such as The CDC Staff Manual on Confidentiality 7 and the NCHS Staff Manual on Confidentiality 8 ; and 3) provide an implementation guide for the newly published CDC/ATSDR Policy on Releasing and Sharing Data 9 (www.cdc.gov/od/foia/policies/sharing.htm), with respect to the re-release of State-provided data. This report should be used by CDC programs when developing their program-specific data re-release procedures for State-provided data. This report describes guidelines (minimum standards) for the development of programspecific data release plans and procedures for re-release of State-provided data by CDC. These guidelines are consistent with and expand upon the requirements listed in the CDC/ATSDR Policy for Releasing and Sharing Data 9 . A key principle of this report is the need for CDC programs to develop data agreements with State data providers before the data are received by CDC. The report also recognizes that in some CDC programs, States currently release data to CDC in the absence of explicit data agreements, and a process is necessary to develop these agreements even as data sharing continues. To facilitate this process, CDC programs will develop data re-release plans based on accepted data release practices and procedures as well as scientifically acceptable principles for confidentiality protection. Prior to finalization, draft CDC programspecific data release plans will be shared with data providers for their input. Formal agreement for each data re-release plan will be obtained from the data providers through an opt-in or opt-out "statement of response" from the data providers. For data providers deciding to opt-out of the data release plan, further negotiation with the data providers will be needed to customize the plan to meet State requirements. Data collected by CDC, including data collected by States and provided to CDC, becomes Federal record once received by CDC, and is subject to Federal laws and rules governing data release and Federal records retention laws. These include, but are not limited to, the Freedom of Information Act (FOIA), the Privacy Act of 1974, Confidentiality Assurances and Certificates of Confidentiality (see Appendix B for further details). These laws, which are highlighted in Appendices B1 (Federal Laws and Rules Governing Data Release) and B2 (overview of selected Federal laws), may provide CDC with the ability to protect certain types of data from public re-disclosure; they also may require the retention and/or disclosure of data in some circumstances. Data use agreements must conform to the requirements of these laws when applicable. # What Type of Data do the CDC-ATSDR Data Release Guidelines and Procedures Apply to? The CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data contain information that may be applicable for any CDC program that releases or shares data; however, it has been prepared specifically to address the policies and practices CDC programs establish for State-provided data shared with CDC that are not already covered by a written formal data re-release procedure at the time this report is finalized. State-provided data are defined, in this report, as population-based data intended to represent a complete count of cases (or a statistical sample of all cases in a given population) that are collected by U.S. State and Territorial Health Agencies related to the health or exposure status of individual U.S. residents, which fall under State legal authority for collection and protection of privacy and confidentiality, and that are reported to CDC by State health departments. The Guidelines and Procedures also apply to unweighted microdata 10,11 (individual person records) from sample surveys administered by State Health Agencies which send CDC data containing personal identifiers or information about survey respondents that could potentially be used to identify survey respondents. Furthermore, these data release guidelines and procedures apply to State-provided surveillance and information data about events (such as a chemical spill or conflagration, etc.) only if data has been provided by the State in the format of individual person records associated with the event (see the glossary definition of "individually identifiable data," which mentions that both direct and indirect identifiers can potentially be used to establish individual identity). # Data from Indian Tribal nations that comes to CDC indirectly through State Health Agencies are covered by the guidelines and procedures in this report because these data are being directly reported to CDC under the authority of the State Health Agency. For CDC public health surveillance systems which are comprised of data from State Health Agencies and other data sources, such as the Vaccine Adverse Events Reporting System, one data release procedure should be developed and that procedure should not be in conflict with the data release guidelines for State-provided data. Although most of the guidelines are applicable for any data that are released or shared, data not specifically covered by the CDC-ATSDR Data Release Guidelines and Procedures for Re-Release of State-Provided Data include, but are not limited to, the following: • individually identifiable data that are not collected under U.S. State health agency authority, such as data that CDC collects directly, and data that are reported directly to CDC by Indian Tribal nations; • data collected specifically for research or an outbreak investigation; • data that are not individually identifiable or potentially identifiable; • data systems that use public-use data compiled from another data system considered to be the primary data system. # Agreements with Data Providers # A. Introduction This section and the next (Section 4) describe 16 guideline elements (the "Guidelines") that collectively constitute the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data. Each guideline represents a "minimum standard" for CDC programs to address when developing their program-specific data release procedures for re-release of State-provided data. CDC programs may wish to adopt more stringent standards than the minimum standard. The guidelines in Section 3 apply to all re-releases of State-provided data. The guidelines in Section 4 are grouped into three main categories: (1) guidelines representing administrative requirements that apply to all re-releases of State-provided data, (2) guidelines that apply to re-releases of Stateprovided data as public-use data, and (3) guidelines that apply to the re-release of Stateprovided data as restricted-access data. Best practices statements accompany most of the guidelines. The best practices statements reflect applicable references and resources or selected examples of practices by CDC programs or other Federal or State programs that appear to be consistent with the guidelines. On occasion, more than one best practices standard is shown because they may represent viable alternative options for specific CDC programs. The best practices statements differ from the guidelines, in that the best practices statements are not minimum standards, but rather a listing of approaches that may merit more discussion and consideration within CDC. The best practices statements are meant to be descriptive rather than prescriptive. In other words, it is being left to the discretion of each CDC program to consider for themselves whether it is appropriate to implement the listed best practices statements or implement another approach to meet the intent of the guideline. Because CDC data systems vary widely with respect to their content and format, it is important that both the guidelines and best practices allow for flexibility within the context of the principles espoused by the CDC policy. The guidelines that apply to the re-release of restricted-access data using Data Sharing Agreements (DSAs) (see Section 4C) do not apply to re-release of restricted-access data through CDC-controlled data centers or by licensing non-CDC researchers to use certain data. At the time this report was developed, only NCHS and one program within the National Immunization Program were re-releasing data through a research data center and no CDC programs were re-releasing data through licensing agreements. Hence, until CDC implements a process for instituting these alternative mechanisms for data rerelease more broadly within CDC, it is considered premature for this report to address the procedures needed for these alternative data re-release mechanisms. In the future, CDC and CSTE will need to develop additional implementation policies and procedures for data re-released through these mechanisms. For information about the NCHS Research Data Center, refer to www.cdc.gov/nchs/r&d/rdc.htm. Additional information about data centers 5,12 (controlled sites for accessing data) and data licensing 5,13 can be found elsewhere. The cross-reference table included below lists the guidelines (see Sections 3 and 4A-4C) and procedures for implementing confidentiality protection (see Section 4D) that apply to re-releases of microdata and tabular data (including pre-calculated tables) through online query systems or other formats. Data 9 and will be based upon accepted data release practices and procedures (see Section 4A-C for guidelines on protecting and releasing data and see Section 4D for a description of confidentiality protection standards and procedures). The data re-release plan will also describe the content and format of data to be released as either non-identifiable public-use data or identifiable/potentially identifiable restricted-access data (see also Guideline # Cross-Reference # 2). There may be some aspects of the data re-release plan that may need to be deferred until the data are reviewed by the CDC program. In this situation, a short-term (and most likely brief) data re-release plan could be drafted in collaboration with the State data providers prior to the time CDC receives the data and then a more comprehensive longerterm data re-release plan developed after the CDC program has reviewed the data. The short-term plan could simply remind the State data providers about any assurances and approvals that are in place to protect the data, if any, and inform them that no data, or very limited data, will be re-released before the longer-term plan is developed (see Figure 1 below for boilerplate language for a short-term data release plan and data agreement with data providers). The short-term initial data agreement with State data providers should specify the expected time the initial plan will remain in place as well as the number of months the CDC program anticipates it will take to complete the longer-term more comprehensive data re-release plan in collaboration with State data providers. CDC programs will solicit the State data provider's input and formal agreement with the proposed data re-release plan by asking the data providers for a formal "statement of response," which at a minimum should include the State's decision to either "opt-in" or "opt-out" of the plan or components of the plan (e.g., a State may want to include their data in a CDC program's re-release of public-use data, but not restricted-access data). The CDC program may want to customize the proposed data re-release plan for State data providers wishing to opt-out of the plan because it does not offer adequate protection for their State's data. For example, if feasible, the CDC program could withhold re-release of data below a specific sub-state geographic level for some States. While States have the option to refrain from providing data to CDC if the CDC plan provides less protection than State requirements, this should be a very rare occurrence that is only used as a last resort option by the State. The CDC program will review and, if necessary, update the data release plan periodically, and will notify States whenever a change in procedure is anticipated. The provisions of the data re-release plan will be consistent with all applicable Federal and State laws and regulations. The CDC program will be responsible for determining that the agreements with data providers meet the requirements of the Federal laws and regulations under which it operates (see Appendix B1 and B2 for a summary of the Federal laws that apply to CDC's re-release of data). Similarly, the State data providers will be responsible for determining that the data agreement is consistent with all State laws and regulations under which it operates. Any requests the [insert name of the surveillance system] receives for data submitted during this pilot test period will be referred back to the State data providers. The more comprehensive data re-release plan will address the need for CDC to re-release data when requests are made for data submitted outside the pilot test period. ►Best practices for Guideline 1: The NCHS and NAPHSIS have an agreed upon data re-release agreement for vital statistics data. The CDC AIDS Program asked States to select the level of sub-State geographic detail that specific variables in the AIDS Public Information Data Set (PIDS) could be tabulated for, by predefining a select group of options they could select from, such as health-district level; county-level; MSAs with 100,000 or more people; MSAs with 500,000 or more people, etc. This process enabled CDC to customize the AIDS data re-release procedure to meet the different requirements of individual States. # Guideline 2: Suggested Content of the Data Re-Release Plan The content of the data re-release plan will vary according to the needs of the CDC program and data providers. • For CDC and State and local public health employees, permission for use of restricted-access data sets will be limited to those employees having official programmatic duties warranting access to these data. • For other data requestors, permission for use of restricted-access data will be based upon a review of the stated purpose of the data request (the stated purpose of the data request should be consistent with the original purpose for data collection), an assessment of whether the requested data would be appropriate to use for the intended purpose, and the need for using restricted-access data versus another type of available data set (e.g., a PUDS). The CDC/ATSDR Policy on Releasing and Sharing Data states: "CDC strives to have data release policies that are fair to all users, regardless of their organizational affiliation." CDC programs should develop a procedure describing the criteria for determining who can access non-PUDS (i.e., restricted-access) data and the party or parties within CDC who are responsible for making these decisions. Procedures for releasing restrictedaccess data include authenticating the requestor's identity (see Guideline 10) and the use of data sharing agreements (DSA) (see Guidelines 11,13,14,15). ►Best practices for Guideline 5: The NCHS Policy on Micro-data Dissemination 14 (www.cdc.gov/nchs/about/policy/policy.htm) states: "No individual-at NCHS or elsewhere-may claim entitlement to obtain or access identifiable data collected by NCHS by virtue of his or her employment. Access to identifiable data is not determined solely by employment status, organizational affiliation, or financial commitment. More important are the need for identifiable data, the use to which the data will be put, and the requestor's role and responsibility with respect to the data collection activity. Since any access to identifiable data poses risk, access to such data will be carefully evaluated and tracked after access is granted." The CDC/NCHSTP assurance of confidentiality for HIV/AIDS data states "No CDC HIV/AIDS surveillance or research information that could be used to identify any individual or institution on whom a record is maintained, either directly or indirectly, will be made available to anyone for non-public health purposes. In particular, such information will not be disclosed to the public; to family members; to parties involved in civil, criminal, or administrative litigation, or for commercial purposes; to agencies of the Federal, State, or local government. Data will only be released to the public, to other components of CDC, or to agencies of the Federal, State, or local government for public health purposes in accordance with the policies for data release established by the Council of State and Territorial Epidemiologists." The 'minimum necessary' standard provision in the HIPAA Privacy Rule indicates that a "covered entity must make reasonable efforts to limit protected health information to the minimum necessary to accomplish the intended purpose of the use, disclosure, or request." Applying the intent of this standard to CDC data re-release procedures, only the minimum necessary data elements that can be justified by the data requestor to accomplish the proposed analysis should be re-released to data requestors, because additional variables may increase the disclosure risk potential of the data unnecessarily. Guideline 6: Include Disclaimer with Re-Release of Provisional Data 'Provisional' or 'preliminary' data are thought to be close to final but subject to change as additional records are added to the dataset or updated information is obtained. The exact definition of 'provisional' or 'preliminary' varies by data system. Because provisional data may be subject to substantial change, it may not be appropriate for these data to be used for all purposes for which finalized data are used. The CDC program will inform State data providers of their procedure for any proposed re-release of provisional public-use and restricted-access data and States, in turn, will indicate their agreement or disagreement with the re-release procedure via their "statement of response" (see Guideline 1). A "Provisional Data Disclaimer" should accompany provisional data rereleases. It should encourage the data user to consider the provisional nature of the data before using it for decisions. In addition, the disclaimer should describe how the data are reviewed to ensure accuracy, and when the data are considered finalized. ►Best practices for Guideline 6: Data quality review is considered complete upon mutual agreement by the State and CDC, once the maximum achievable quality has been attained. Explicit criteria for data finalization should be documented and include adequate time for corrections from data providers and for case investigation to establish final case classification. # Guideline 7: Maintain Log of Data Sets Re-Released The CDC program which re-releases State-provided data will maintain a log of data sets released. ►Best practices for Guideline 7: For PUDS data, the log of data sets released represents an inventory of the different PUDS data sets CDC has released. Ideally, such an inventory would be posted on the Internet, include a description of all State-provided PUDS public health surveillance data released by CDC, and be formatted so it can be queried by users. While the inventory is useful to inform interested parties as to the existence of these data sets, its primary function within CDC is to remind the CDC program that a potential exists for data users to combine related data sets in order to access more information than just a single data set would provide. Thus, the inventory should prompt CDC programs to perform disclosure risk assessment within the context of all previously released related data sets. Minimum data elements for the PUDS inventory could include the date the PUDS was first released, conditions or diseases included in the data set, variables and coding formats contained within the PUDS, and information on how to request the PUDS. If more than one PUDS data set is released by a single CDC program, the program should clarify how their PUDS data sets are different. For restricted-access data, the primary purpose of the log of releases is to be able to track the status and terms of each data sharing agreement (DSA). This log is for internal CDC use by the CDC program responsible for tracking compliance with the terms of the DSA. Ideally, such a log would be posted on the CDC Intranet. The log of releases for restricted-access data sets should be audited to assess whether the person or persons granted access to restricted-access data are complying with the terms of their DSA. Minimum elements for the restricted-access log may include name and affiliation of the person responsible for compliance with the terms of the DSA and information on how to contact them, names of all collaborators on the project (and information on how to contact them), the list of variables and coding formats released, the name of the conditions or diseases represented by the data, and a checklist of requirements the CDC program needs to verify as per the DSA (For example, if a pre-publication review of the report was required by the DSA, the date the data user sent the report to CDC for review and the date the review was completed and comments sent to the data user; or, the date the data set was returned to CDC or destroyed, etc.). # B. Re-release of State-Provided Data as Public-Use Data CDC's re-release of data as a PUDS does not require the use of a DSA. When PUDS are created by CDC programs, they should be made available to all interested users, without restrictions. # Guideline 8: Planning for Release of Public-Use Data Refer to the CDC/ATSDR Policy on Releasing and Sharing Data 9 for information about the release of data for public use. This Policy indicates "procedures for releasing publicuse data should be consistent with the CDC's Public Health Information Network's functions and specifications 15 ." The CDC/ATSDR Policy indicates each plan for release of public-use data should include the following: • A procedure to ensure that confidential information is not disclosed. • A procedure to ensure that data is released in a form that does not endanger national security or compromise law enforcement activities. • Analysis plans and other documentation required by the Office of Management and Budget regulation on data quality 16 . • Instructions for non-CDC users on the appropriate use of the data. • The date the data will be released, which should be as soon as possible after the data are collected, scrutinized for errors and validated. The release of these data should occur no more than one year after these activities are completed. • The formats in which the data will be released (e.g., ASCII). For each format, give specifications (e.g., variable definitions) and information on standards for transmission. The CDC/ATSDR Policy on Releasing and Sharing Data 9 also states CIOs may release data without restrictions for public use through the CDC Information Center or data may be shared through the CDC/ATSDR Scientific Data Repository and its data dissemination portal CDC WONDER (wonder.cdc.gov/welcome.html ). # Guideline 9: Include Disclosure Statement with PUDS At the time each PUDS is released or accessed, CDC programs will include a written statement about the following responsibilities users of public-use data have: • A statement informing PUDS users of their responsibility to maintain confidentiality, including (per the CDC/ATSDR Policy on Releasing and Sharing Data 9 ), "instructions that non-CDC data users must agree not to link data with other data sets….. [and]… instructions to report to the CDC ADS any inadvertent discovery of the identity of any person and to make no use of that discovery." • A statement informing PUDS users of their responsibility not to imply or state, either in written or oral form, that interpretations based on the data are those of the original data sources (e.g., the U.S. States) or the CDC public health surveillance program that provided the data, unless the data user and data sources are formally collaborating on the proposed analysis. • A statement informing users of their responsibility to acknowledge, in all reports based on these data, the original source of the data (e.g., the States that provided the data to CDC) as well as the name of the CDC public health surveillance program that re-released the data. ►Best practices for Guideline 9: CDC NCHS requests that PUDS users agree to: • "Use the data in this dataset for statistical reporting and analysis only. ►Best practices for Guideline 10: Following are examples. • Written requests for access to State-provided data are required to be on letterhead stationery. • Oral or email requests from a known individual are considered as needing no further verification. An electronic authentication protocol can use one or more of the following methods. • Software access control: Password or challenge phrase; Digital certificate • Physical device: Hardware "token" (e.g., USB connection); Digital fob (auto-generated passnumber); SmartCard • Biometric scan The electronic process for identification-authentication can be linked to authorization "rights" which specify levels of access. # Guideline 11: All Requestors Wanting to Use Restricted-Access Data are Required to Sign a DSA The CDC program should confirm, via the "statement of response" (see Guideline 1) that the State granted permission for the data to be re-released as a restricted-access data file. In addition, prior to CDC's re-release of these data, all requestors must sign a DSA which governs the protection and use of these data. The CDC program which re-releases Stateprovided data will retain signed copies of the DSA. A DSA may be subsumed in a larger interagency Memorandum of Understanding (MOU). ►Best practices for Guideline 11: The 2002 modification to the HIPAA Privacy Rule permits release of a "limited data set" as long as a there is a written data use agreement. This HIPAA standard is consistent with the use of "restricted-access" data and DSAs described within the guidelines section of this report. # Guideline 12: Monitor User Compliance with DSAs The CDC program which re-releases State-provided data will monitor compliance with the terms of the DSA. ►Best practices for Guideline 12: A passive approach to compliance monitoring is acceptable, as long as the following criteria are met: • The data user is informed of the penalty for not complying with the terms of the DSA. (The intent of the penalty is to deter breaches in compliance.) • The data user is fully informed about their responsibilities in using the data. • The data steward institutes a process for logging compliance problems they become aware of. • The CDC program takes appropriate actions to resolve any identified problems and implements (if possible) procedures to avoid similar types of problems in the future. Examples of active compliance monitoring methods include: • Pre-publication review of reports, articles, graphs, maps, or tables. • Prior review of presentations based on the dataset. • Annual letters sent by data stewards to confirm whether the data requestor's use of the dataset has been completed and whether the data requestor has taken steps to either destroy or return the dataset. Pre-publication or pre-presentation review can include both privacy protection as well as accuracy of scientific inferences. Releasing and Sharing Data 9 for "special-use agreements," but also includes additional criteria: # C2. Development of Data Sharing Agreements for Restricted-Access Data • A description of the use to which the data will be put, and limitations on usage of data. The data requestor's description of their intended use of the data should provide evidence to the CDC program that there is a legitimate public health purpose that justifies the use of the data. The data user should also demonstrate their need for restricted-access data versus other available data, such as a PUDS. • Information on any laws pertaining to the DSA. • The names of every person who will have access to the data and specification of procedures for extending the provisions of the DSA to named collaborators (e.g., requiring signed confidentiality pledges, etc). • The name of the person primarily responsible for care of the released data and compliance with the terms of the agreement. • A list of mechanisms for preservation of confidentiality. These mechanisms should include both limitations on access (i.e., specified staff only) and technical security practices (such as encryption). • A list of restrictions on releasing analytic results. • A clearly stated prohibition on any attempt to link the dataset with any other dataset without prior CDC permission (see Guideline 14). • A clearly stated prohibition on the further release of data to other parties without prior CDC permission (see Guideline 15). Requests from legal authorities (such as under conditions of a declared public health emergency) or FOIA requests must be referred by the data user to the CDC data steward. • A stated requirement for the data user to notify the CDC ADS if any individual person represented in the dataset is inadvertently identified during approved usage. • A stated limitation of the right of access to data based on the role of an individual, with a stated requirement to return or destroy the dataset when the requestor changes positions in the agency or leaves the agency. • A stated requirement to return or destroy the dataset and all derived files when use is completed (the term "use" in this sense may include a specified plan for re-analyzing the data after the initial analysis is completed). • A statement informing users of their responsibility not to imply or state, either in written or oral form, that interpretations based on the data are those of the original data sources (for example, the U.S. States) or the CDC program that provided the data, unless the data user and data providers are formally collaborating on the proposed analysis. • A statement informing users of their responsibility to acknowledge, in all reports based on these data, the original source of the data (for example, the States that initially provided the data) as well as the name of the CDC program that re-released the data to the user (see best practices for an example). • A description of the penalty that may be imposed on the data user for breaching the terms of the DSA. • Provisions that govern emergency requests for identifiable or otherwise confidential data (See also Guideline 16). • For DSAs with CDC staff acting as a data user, the following are to be included in the DSA: o A statement indicating that if the CDC data user plans to publish a report that singles out specific States or Cities in the discussion section of the report, the Restricted-access data include identifiable or potentially identifiable data. The data set derived from linking a restricted-access data set to another data file may be even more individually identifiable than the original data. Thus, there is a need to ensure disclosure review takes into account the variables included after the linkage. The CDC program interested in re-releasing restricted-access data for a linked data analysis should obtain, or require the data requestor to obtain, written permission from the data providers (the States contributing the data) for the proposed linked analysis. Prior to seeking permission from the data providers, the data requestor should complete and sign the standard DSA (see Guidelines 11, 13) and, in addition, attach an addendum to the DSA which includes the following information, so the CDC program and data providers can determine whether to approve the data request: 1) source and description of the data file to which the restricted-access data will be linked; 2) written description of the variables and coding formats to be included in the final linked file; and 3) description of the data requestor's plan for conducting additional disclosure review to ensure that variables contributed in the linking process do not lead to re-identification of the individual described in the original data file. ►Best practices for Guideline 14: Examples of special procedures for linked analyses are: • "separation of duties", where no single individual is able to conduct all of the steps in the linkage process. • post-linkage de-identification. Standard de-identification methods should be used, such as numerator and denominator cell aggregation or suppression rules. GAO Report #GAO-01126SP titled "RECORD LINKAGE AND PRIVACY: Issues in Creating New Federal Research and Statistical Information 21 " may serve as a useful reference of techniques which can be employed to ensure privacy protection for data linkages. Linkage can be conducted inside a CDC-controlled data center. This guideline applies to "modified" data shared outside of such centers. Data shared outside CDC-controlled data centers are partially or substantially modified, as needed, in order to minimize the likelihood of breaches of confidentiality. # Other Parties Restricted-access data can be released further to other parties as de-identified data, in one of two ways: 1) by creating a de-identified data set (i.e., a PUDS) from the restrictedaccess data set and then disseminating data from the PUDS, or 2) by generating deidentified data directly from the restricted-access data set (where the restricted-access data file, by definition, includes identifiable or potentially identifiable data). If the requestor plans to release de-identified data generated directly from a restrictedaccess data file (situation #2 described above), a procedure must be implemented to ensure that the generated data have been de-identified appropriately. In this situation, the data requestor is required to submit an addendum to the standard DSA (See Guidelines 11, 13) describing the procedures that will be implemented to audit the results of the data generated for further release to other parties. If the requestor plans to release de-identified data that are generated from a de-identified data set created from the restricted-access data set (situation #1 described above), an addendum to the standard DSA is not required. ►Best practices for Guideline 15: If the requestor plans release via an online interactive query system which generates tables from restricted data, an automated algorithm for de-identification must act prior to release, and its results must be checked by an automated audit protocol. An automated audit protocol assesses disclosure risk against pre-determined thresholds. (See Procedure 4.) . However, the HIPAA Privacy Rule's "safe harbor" method of de-identification is deemed inadequate protection for public health agencies to use for de-identifying data sets because public health agencies collect many more demographic variables than do covered health entities. # C3. Emergency Requests for Data # D. Confidentiality Protection In addition, public health agencies are expected to have a much higher level of sophistication with regard to disclosure review than entities covered by HIPAA. Other useful materials on confidentiality protection have been developed and will be useful to those involved in data protection and re-release, including a book published in # B. Procedures for Implementing Confidentiality Protection The following is a list of procedures for confidentiality protection. One or more of these procedures may be appropriate for a given data system. It is not the intention of this report to imply that all these methods need to be used for each data system. CDC programs may wish to seek expert consultation on the issue of confidentiality protection and disclosure risk assessment and control before finalizing a data re-release plan (see Practice E (in Section 5 of this report). # Procedure 1. Limit Disclosure of Potential Identifiers The CDC programs that re-release State-provided data will delete, as necessary, all information judged to be of potential use in making individuals to whom they pertain "identifiable" (see "individually identifiable data" in Glossary). Particular attention will be devoted to information that can lead directly to an individual or their family, such as: • Name • Street address • Social Security Number • Medical record number • Telephone number Other information is extremely useful in narrowing the possibilities that information may refer to a particular individual. Those providing low-level geographic detail and precise timing of certain events are particularly important. # Geographic Information • Zip code (9-, 5-, and even 3-digit) • Census tract • City/town • County # Timing of events • Exact date of birth (year-month-day) • Exact date of event (year-month-day) • Month and year of birth (year-month) • Month and year of event (year-month) Information concerning location (e.g., geography) and timing of events, along with details concerning the following types of information can serve to reveal individual identity: • Occupation (e.g. 3-or higher digit codes) • Education (e.g. single years) • Race/ethnicity (e.g. Aleutian, Filipino v. Asian) • Income (as a continuous, un-topcoded variable) • Medical condition/diagnosis (e.g. detailed site specific cancers) and cause of death (e.g. 3-or higher digit ICD code) There could be other program-specific variables that may be used to help disclose individual identity. Prior to re-release, these items must be thoroughly reviewed for their potential for personal re-identification. It is not the intent of these guidelines to imply that all of these fields must always be deleted. Under appropriate conditions and with proper safeguards, such items may be released. It is not the intent of these guidelines to recommend a single strategy for the limitation of disclosure risk. It is recognized that both programmatic and statistical considerations may come into play in deciding appropriate protections for data release. For example, an alternative to field (variable) deletion is data value recoding (see Procedure 2). Prior re-releases of data should be considered in a cumulative fashion. As stated in the document Identifiability in Microdata Files 22 "Each of these files may be considered safe to release by themselves. However, there may be enough information in the two files combined to effect a re-identification." (HIPAA) 2001 Privacy Rule's safe harbor method of deidentification (which requires covered entities to remove all of a list of 18 enumerated identifiers and have no actual knowledge that the information that remains could be used alone or in combination to identify an individual who is a subject of the information) is deemed inadequate protection for pubic health agencies to use for de-identifying data sets because public health agencies collect many more demographic variables than do covered entities, according to the viewpoint of DRGWG representatives. In addition, public health agencies are expected to have a much higher level of sophistication with regard to disclosure review than covered entities. ►Best The HIPAA Privacy Rule de-identification standard that is consistent with this guideline requires "a person with appropriate knowledge and experience applying generally acceptable statistical and scientific principles and methods for rendering information not individually identifiable makes and documents a determination that there is a very small risk that the information could be used by others to identify a subject of the information" (45 CFR Part 164.514(b)(1)(i)). The HIPAA Privacy Rule was modified in 2002. The 2002 modification to the HIPAA Privacy Rule permits release of data that is not fully de-identified through a "limited data set," as long as the data are governed by a data use agreement which provides sufficient privacy and confidentiality protection for the data. For the limited data set, all direct identifiers must be removed from the data file. However, dates such as birth date, date of death, and dates of admission or discharge could be released in the data file, but only if this information is needed for the purpose of the release. In addition, the limited data set may include 5-digit zip code or any other geographic subdivisions, such as State, county, city, precinct and their equivalent geocodes, except for street address. The Privacy Rule clarifies standards for the creation of deidentified data sets and "limited data sets." The limited data set concept is consistent with the concept of "restricted-access" data that is discussed in this report. # Procedure 2. Aggregate Data Values The CDC programs which re-release State-provided data, either as "microdata" files (e.g., data files or records on an individual person) or as tabular data, will recode fields as needed in order to aggregate data values. Common methods include: • collapsing continuous/interval data (e.g., age; date of occurrence) into broad categories; • collapsing ordinal data (e.g., location geography) into broader categories; • grouping nominal data (e.g., diagnosis) into broad categories; • truncating variables (e.g., name). • top-coding or bottom-coding variables. ►Best practices for Procedure 2: Refer to the Federal Committee on Statistical Methodology's Statistical Working Paper #22: Report on Statistical Disclosure Limitation Methodology 11 for a description of common methods used to protect microdata and tabular data, available at www.fcsm.gov/workingpapers/wp22.html. # Procedure 3. Limit the Number of Records or the Number of Fields The CDC program which re-releases State-provided data as "microdata" files will consider the applicability of other methods to protect microdata releases from disclosure risk. Common methods include: • including data from only a sample of the full dataset; • limiting the number of variables in the released file. For example, consider (1) releasing only those variables essential to analysis; and (2) limiting the number of contextual or ecological variables--information that describes a geographic area, such as where a case-patient resides--because this type of information can lead to the identification of that area. ►Best practices for Procedure 3: Refer to the Federal Committee on Statistical Methodology's Statistical Working Paper #22: Report on Statistical Disclosure Limitation Methodology 11 for a description of common methods used to protect microdata, available at fcsm.gov/working-papers/wp22.html. # Procedure 4. Use Numerator Rules for Data Aggregation or Suppression The CDC program which re-releases State-provided data as tabular data or microdata will use numerator rules (cell size) to either • guide selection of groupings of aggregated data values; or, if aggregation is insufficient, • suppress release of certain cells in a table. There is no single numeric threshold for cell aggregation that is appropriate for all data in tabular or microdata format. Selection of an appropriate threshold level is guided by multiple factors, including: • sensitivity of the data (subject matter); • format of the data (e.g., whether the data are continuous or categorical); • level of detail in the data, especially the level of geographic detail; • likelihood that a specific record in a database may represent a unique person in a small population; • population or subgroup denominator size, as well as the numerator size. The CDC staff manual on confidentiality 7 generally advises a minimum numerator cell size of "3". Thus, numerator cell size counts of "1" or "2" are not generally advised, with some notable exceptions. The CDC staff manual on confidentiality 7 indicates the following exceptions to minimum numerator cell size rule of "3": a) "It has been a longstanding tradition in the field of morbidity or mortality [and vital] statistics not to suppress small frequency cells in the tabulation and presentation of data. For example, it has been considered important to know that there were two deaths from rabies in Rio Arriba County, N. Mex., in a given year, or that there were only one infant death and two fetal deaths in Aitkin County, Minn. These types of exceptions to general CDC practices in other programs are followed because they have been accepted traditionally and because they rarely, if ever, reveal information about individuals that is not known socially." b) "Tables may show simple counts of numbers of persons, even though the number in a cell is only '1' or '2' provided the classifying data are not judged to be sensitive in the context of the table..." The Washington State guideline states: "If the count of cases or events in a cell is less than three, the data analyst needs to consider whether a breach of confidentiality is likely. A count of no events in the cell is clearly no threat to confidentiality, but a count of one or two events may be." (See www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm.) A rule which combines numerators and denominators will meet this standard, such as a rule that data are not released if the population is less than a certain size and the number of events in a cell is less than a certain size. For example, Missouri uses a complex combined rule 23 : "A table is not reported if a table cell subtracted from the number of total events of the same data file for the same characteristics yields a small number (less than 10 When primary cell suppression is used, it is generally accepted that 1) complementary cell suppression will need to be employed to avoid back-calculation by subtraction; and 2) if tabular data are suppressed using automated algorithms on a large number of related tables or via web-based interactive query systems generating tables directly from raw data, that procedures for postsuppression auditing should be employed. However, precise methods for automated suppression and auditing, that are easily implemented, still need to be developed. Therefore, at this time, it is not possible to implement this "best practice," but it should be considered for future implementation. # Procedure 5. Use Denominator Rules for Data Aggregation or Suppression The CDC programs which re-release State-provided data as tabular data or microdata will use denominator rules (population size) to either: • guide selection of groupings of aggregated data values; or, if aggregation is insufficient, • suppress release of certain cells in a table. ►Best practices for Procedure 5: A rule which combines numerators and denominators will meet this standard, such as a rule that addresses the relationship between the size of the numerator and the size of the denominator. An approach commonly used for microdata is that data are not released if the total population from which the data are drawn is less than a certain size, based on the premise of a size sufficiently large that no subcell of the variables contained in the data would be expected to be smaller than a certain size. In considering the population size in tabulated data, guidelines employed by the Washington State Department of Health state that "Generally, tabular data based on denominators greater than 300 persons per cell present minimal risk for individual identification. ... Caution should be exercised by the analyst if the population size is between 100 and 300, and extreme caution is warranted when the population is less than 100." (See www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm.) As indicated in Procedure 4 above, in the case of tabulated data Missouri focuses on the number of people in the population with the characteristic indicated in a given numerator. If the difference between the two is less than a minimum number, this information is not be published. On the other hand, in this scheme a very small cell number could be published if the denominator were large enough. (See www.cdc.gov/epo/dphsi/AI/confiles/day1/Land1.ppt). With regard to total population size, the statistical literature contains a great deal of discussion of appropriate minimal sizes and there is clearly variation depending upon information content and special considerations. The most general statement is found in the Federal Committee on Statistical Methodology's Statistical Policy Working Paper 2 where it is stated "Geographic information must be restricted beyond the point where an individual user could be familiar with a significant proportion of the universe, but whether that point comes at 25,000, 250,000 or 1 million will depend on the detail in the file and other restrictions imposed." (See www.fcsm.gov/working-papers/sw2.html p 28). The Federal Committee on Statistical Methodology's Confidentiality and Data Access Committee Checklist on Disclosure Potential of Proposed Data Releases 6 calls for "a minimum of 100,000 persons in the sampled area … [else] provide rationale." (See fcsm.gov/committees/cdac/checklist_799.doc). The NCHS version of this checklist contains the following language: "Generally one has to balance the level of survey detail against the level of geography. The greater the amount of detail, the more risk is entailed for lower levels of geography. Similarly, with very high levels of geography, greater detail may be made available. General Rule: All geographic areas that are identified must have a minimum of 100,000 persons in the sampled area (according to latest Census or Census estimate). Caution: the figure of 100,000 is not without some risk. For certain target populations the members of which are be found infrequently in a population, a higher number may be desired." # Procedure 6. Refrain From Using Techniques that Distort Data for Privacy Protection The CDC programs which re-release State-provided data will refrain from distorting data (either altering data values or omitting records from the dataset) unless this approach is employed as a last resort and is absolutely necessary for the purpose of privacy protection. ►Best practices for Procedure 6: Examples of distorting data include adding statistical noise, data swapping, blanking and imputing for randomly selected records, and blurring data (replacing a reported value by an average value). Current methods of perturbative "statistical disclosure control" are not optimal because one cannot prospectively assess how the distortion of the data will affect the results of an analysis. This is a problem particularly if recommendations for public health action are made based on the analysis of distorted data. At the discretion of the CIO, when a data requestor plans to make public health recommendations based on analysis of altered data, the CDC program holding that data may offer to confirm the requestor's findings by performing a re-analysis on un-altered data. Alternatively, researchers should be provided the opportunity to obtain restricted-access data under a data sharing agreement, or conduct re-analysis themselves in a CDC-controlled research data center. See also Practice G which mentions that a new form of disclosure limitation, entitled "controlled tabular adjustment," is being researched; software is being developed to implement this new method. It was beyond the scope of this report to assess which data distortion methods minimize the magnitude of data distortion. # Practices to Support Re-Release of Data # B. Development of a Data Set Inventory to Facilitate Disclosure Risk Assessment Disclosure risk assessment is performed to estimate, either qualitatively or quantitatively, the probability that a data set poses a high or low risk of re-identification in terms of the information it contains about individuals and the status of their health. Since the risk of re-identification may be increased if a one data set can be linked to an another data set, CDC data stewards should be aware of the data sets other CDC components release that could have the potential for linkage with data sets their own programs release. To help facilitate this aspect of disclosure risk assessment, CDC should compile and regularly update an inventory of data sets that have already been released and that are eligible for release in the near future. The inventory should be posted on the CDC Intranet in a browsable (or queriable) format and should include, for each data set, the name of the CDC program releasing the data set, data steward contact information, and data set documentation (see the "Documentation" section of the CDC/ATSDR Policy on Releasing and Sharing Data 9 for recommended categories of information data set documentation should include), including the names of diseases or conditions about which the data are tabulated , and the variables and coding formats used. # C. Development of Instructions # D. Evaluations to Assess Whether a Breach of Confidentiality has # Occurred This report and the CDC/ATSDR Policy on Releasing and Sharing Data states that potential confidentiality breaches should be reported to the CDC ADS. This passive approach to ascertaining potential confidentiality breaches assumes that CDC will receive such reports. CDC should consider the feasibility of taking a more active approach to identifying confidentiality breaches. If feasible to do so, CDC may wish to itself develop or contract with others to develop standard criteria for CDC programs to use in conducting active approaches. # E. Consultation with Experts on Confidentiality Protection and # Disclosure Risk Assessment This report is not intended to be (and cannot be) a comprehensive resource on confidentiality protection or disclosure risk assessment and control. CDC programs may need to consult with experts on these issues as they develop program-specific data rerelease procedures that are consistent with guidelines and procedures in this report. CDC may wish to generally offer their programs the services of specified experts on these issues. In addition, CDC may wish to develop an interest group forum on confidentiality and data release patterned after the Confidentiality and Data Access Committee (CDAC). CDAC, an interest group of the Office of Management and Budget's Federal Committee on Statistical Methodology (fcsm.gov/committees/cdac/cdac.html ), was formed because staff members of statistical agencies who worked in the "confidentiality area" expressed a need to have a forum where they could communicate among themselves and exchange ideas. # F. Establish a CDC Intranet Site Where Materials Referenced in this # Report, from Various Websites, Are Archived This report cites various materials that are currently posted on the Internet pertaining to "training" issues, such as data release policies, confidentiality protection, or disclosure review assessment that would be useful to preserve for use with this report. To preserve the future availability of these materials, CDC should consider creating an Intranet site where these materials are archived. # G. Need for Continuing Discussions of Methods for Privacy Protection, # Disclosure Risk, and Other Issues The adoption of these guidelines should not deter CDC, CSTE, and others from future discussions of new methods for privacy protection and disclosure risk assessment and review. The guidelines and procedures are not "written in stone" and should be considered subject to change as new information and methods become available. For example, at the time this report was developed, the Working Group was not aware of any CDC programs using secondary (complementary) suppression based on methodologic principles, to avoid back-calculation (by subtraction) of the content of table cells that have undergone primary suppression. In addition, the Working Group was not aware of any algorithms being used by health agencies for automated suppression and auditing of one or more related tables. As noted in the best practices section for confidentiality protection Procedure #4 (see Section 4D, Procedure 4), precise and easy-to-implement methods for automated suppression and auditing of tables still need to be developed. Because use of web-based interactive query systems for data dissemination is increasing, future discussions should focus on the development and use of automated suppression and auditing methodologies for use by CDC programs. In 2002, the NCHS Office of Research and Methodology (ORM) sponsored the development of methodologic software for complementary cell suppression (and controlled rounding and controlled random perturbation) in two-way statistical tables of counts or magnitudes. CDC may wish to explore these automated methods for complementary cell suppression which are statistically-based in lieu of using ad-hoc or manual approaches. The NCHS ORM also noted that research is underway for a new form of disclosure limitation in tables called "controlled tabular adjustment," which is not limited by the dimensionality or complexity of tables. While Procedure 6 indicates CDC programs should refrain from using disclosure limitation techniques that distort data, it may be useful for CDC to assess or contract with others to assess which of the various perturbative statistical disclosure control methods minimize the magnitude of data distortion, for potential use by public health systems. Since CDC program data stewards will most likely be the primary staff responsible for writing program-specific procedures, under the direction of the CIO data-release review board or another oversight mechanism, CDC may wish to consider establishing a cross-CIO forum for data stewards to brainstorm and share suggestions for implementing the CDC-ATSDR Data Release Guidelines and Procedures for Re-Release of State-Provided Data. Various issues were raised during the review of this document that the DRGWG did not address, but that merit future discussion, including the following concerns and issues that were expressed: • CDC may fail to inform data users of potential weaknesses or peculiarities of the data when it releases the data, while the State may have provided such information to the user. • CDC may re-release data selectively so that wrong inferences would be drawn from it, while the State would have released a different dataset in response to the same request. • CDC may fail to inform the States of re-releases it has made of data that came from that State. • CDC may re-release data containing uncorrected errors, while the State may have released the same data with corrections. More generally, data rereleased by CDC may not be exactly the same as the corresponding dataset held by the State, and the user would not be informed of this possibility. • CDC collects and uses data from various State agencies other than State health agencies, such as labor departments, environmental departments, and agriculture departments. These other sources of data were not included within the scope of the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data because of the way the Data Release Guidelines Working Group was constituted. Future discussions within CDC should focus on whether the implementation guidelines for the CDC-ATSDR Policy for Releasing and Sharing Data in this report should also apply to data from State agencies other than State health agencies. • State-provided data that comes to CDC from other Federal agencies and not directly from State health agencies are not considered within the scope of the # CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data. Each request for this type of data may need to be handled differently, depending on the specifics of the situation, such as whether an MOU or other written agreement exists between the two Federal agencies or other statutory protections exist that define how external requests for data will be handled. In addition, for FOIA requests, an assessment may be needed to identify whether any FOIA exemptions may apply or whether the situation warrants a referral by the FOIA Officer to the Federal agency which was the source of the data being sent to CDC. Future discussions within CDC should focus on efficient processes for handling these types of data requests. # Implementation Steps # Proposed Deadline and Steps for CDC's Implementation of the # Guidelines and Procedures CDC and ATSDR programs having surveillance systems that fall within the scope of the CDC-ATSDR data release guidelines and procedures should examine their data re-release practices as of the effective date of the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data to see if they meet the minimum standards. If their procedures do not meet the minimum standards, CDC programs should have two years to revise their procedures to bring them into conformance, unless an appeal for an extension is requested from and granted by the CDC ADS. CDC CIOs should be responsible for ensuring that the guidelines and procedures are implemented either through the establishment of a CIO data-release review board (see the CDC/ATSDR Policy on Releasing and Sharing Data 9 ), which might report to the CIO ADS and might include the CIO Information Resources Manager and relevant data stewards, or CIOs might wish to implement the policy using an alternative oversight mechanism. The OPS Announcement that is distributed after the CDC-ATSDR Data Release Guidelines and Procedures for Re-release of State-Provided Data are cleared by CDC should indicate the guidelines apply to data shared between the States and CDC that are not already covered by a formal written data re-release procedure. CDC programs should examine their practices, as of the distribution date, to see if they meet the minimum standards in guidelines, and if not, to revise them to bring them into conformance with the minimum standard guidelines. CDC program data re-release procedures should be forwarded to the CDC ADS Office where an assessment of conformance with the CDC-ATSDR Data Release Guidelines and Procedures for Rerelease of State-Provided Data will be done. # Feedback to CSTE # Feedback to CSTE Regarding CDC's Implementation of the Guidelines CDC should advise CSTE on at least an annual basis during the implementation phase of these guidelines, on the status of completion of implementation. In addition, CDC should communicate with CSTE regularly regarding the results of evaluations conducted after the guidelines and procedures have been implemented by CDC programs, particularly if the results of the evaluations indicate that a revision of the guidelines is warranted. # DRGWG Members # CDC Members # CIO Primary Representative Alternate Representative importance of the work undertaken by the DRGWG and for allowing their staff to dedicate time and resources to this effort. # Glossary Audit trail: The maintenance of information, in a logbook or database, pertaining the request for and release and use of individually identifiable data. # Authentication: The process by which the identity of a person requesting access to individually identifiable data (restricted-access data) is verified. # Automated audit protocol: In terms of disclosure risk control, the use of linear programming to identify complementary cell suppressions for a primary cell suppression and to audit the proposed cell suppression pattern to see if it provides the required level of protection. Research seems to indicate that linear programming methodologies provide good but not optimal results. For this reason, it is not enough to just perform an automated audit for secondary cell suppression. The result of the algorithm needs to be checked to see if it is successful. # Bottom-coding: A technique used to mask microdata that involves creating categories for data values that are below a certain level. This method differs from aggregation, in that all data values below a certain threshold are grouped; other values in the field may or may not be grouped. See top-coding. Cell suppression: One of the most commonly used ways of protecting sensitive cells in tabular data. It is obvious that in a row with a suppressed sensitive cell, at least one additional cell must be suppressed, or the value in the sensitive cell could be calculated exactly by subtraction from the marginal total. The same is true for the column which contains a suppressed cell. For this reason, certain other cells must also be suppressed. The suppression of a sensitive cell is termed a primary cell suppression. Suppression of other cells to prevent one from calculating the value in the sensitive cell is termed complementary (or secondary) cell suppression. # Computational disclosure control: The process by which data values are aggregated to increase the granularity of specific variables, such as grouping age into age groups prior to data release. # Confidentiality: The treatment of information that an individual or institution has disclosed in a relationship of trust, with the expectation that it will not be divulged to others in ways that are inconsistent with the understanding of the original disclosure. It encompasses access to and disclosure of information in accordance with requirements of law and/or official policy 26 . Confidentiality breach: "An unauthorized release of identifiable or confidential data or information, which may result from a security failure, intentional inappropriate behavior, human error, or natural disaster. A breach of confidentiality may or may not result in harm to one or more individuals." (Source: Washington State Department of Health "Guidelines for Working With Small Numbers, Glossary" (accessible at www.doh.wa.gov/Data/Guidelines/SmallNumbers.htm, accessed on April 11, 2002). Disclosure: In this report, disclosure refers to the unauthorized public disclosure of information about a person, about which data have been collected. A disclosure may occur as a result of a confidentiality breach. The definition of disclosure used in the HIPAA Privacy Rule is different from the definition in this report. For purposes of HIPAA, disclosure means the release, transfer, provision of access to, or divulging in any other manner of information outside the entity holding the information. # Disclosure (risk) assessment: A systematic review of a data file conducted to determine if any of the proposed contents present an unacceptable risk of individual disclosure. Disclosure risk assessment and control are usually conducted to prepare a public-use data set, and they can also be conducted when preparing a data set that is potentially linkable to another released data set. Disclosure (risk) control (also referred to as disclosure limitation or disclosure protection): The application of measures to reduce the possibility of identifying an individual through the characteristics available in a data file. Disclosure risk assessment and control are usually conducted in order to prepare a public-use data set, and they can also be conducted when preparing a data set that is potentially linkable to another released data set. Disclosure control includes steps taken to modify or suppress information that might identify an individual directly or indirectly before the data are made available to others for analysis (see page 3 of the Doyle book 3 ). Perturbative disclosure control methods distort (alter) the data before it is released while nonperturbative methods do not alter the data, but instead partially suppress or reduce the detail of the original data set (see page 112 of the Doyle book 3 ). Individually identifiable data: Data or information which can be used to establish individual identity, either directly, using items such as name, address, or unique identifying number, or indirectly by linking data about a case-individual with other information that uniquely identifies them. Microdata: A data file containing information in which each record provides information at the unit of data collection (e.g., individual persons, events, households, or establishments). Penalties: Penalties for a breach of confidentiality can range from imposing fines or a prison sentence to disciplinary action, barring an individual from receiving data in the future, or termination of employment or contract. Penalties can be established to differentiate willful from inadvertent disclosure and they can be tailored to the type of party responsible for the breach of confidentiality--an employee, contractor, or external data requestor. Population-based data: A complete count of cases occurring within a given population or a statistical sample of all cases occurring within a given population. # Predecisional exemption: The Freedom of Information Act's "predecisional" exception is explained in 5 U.S.C. § 552(b)(5) as "inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than an agency in litigation with the agency." The term "predecisional" has been traditionally defined by the courts as meaning "antecedent to the adoption of an agency policy." 27 # Privacy: The right of individuals to hold information about themselves in secret, free from the knowledge of others 28 . Privacy Manager: A person who develops and implements a data system's confidentiality policy and is responsible for clearing responses to data requests for a surveillance system. A data steward may act as a privacy manager. (See definition of Data steward in the glossary). Proprietary: Produced or collected in such a way that exclusive rights may apply. Provisional or preliminary data: These data are thought to be close to final but subject to change as additional records are added to the dataset or updated information is obtained. The exact definition of 'provisional' and 'preliminary' varies by data system (see Guideline 6). # Public health emergency: An occurrence or imminent threat of an adverse health event caused by epidemic of pandemic disease, infectious agent, biologic or chemical toxin, environmental disaster, or any agent that poses a real and substantial risk for a significant number of human fatalities or cases of permanent or long-term disability. Public-Use data: Data available to any requestor. Public-use data are sometimes referred to as "de-identified data" and include public-use data sets (PUDS), tables, or other data formats, with all individually identifiable data or information removed, and with the remaining fields modified or suppressed so as to reduce disclosure risk as much as reasonably possible and such that it is not possible to create any tables that violate the numerator or denominator cell size rules for a given surveillance system. Public-Use Data Set (PUDS): See public-use data. Re-release: For purposes of this report, CDC's re-release of data that the States initially provided to CDC through their data release procedures. Data can be re-released to data users who are internal or external to CDC in various formats, including CDC reports, publications, graphs, tables, maps, presentations, and data files. Restricted-access: Allowing the use of an Agency's microdata under controlled conditions. Restricted-access may mean allowing the use of an agency's data only to those who sign a formal data sharing agreement or permitting access to the data only at CDC-controlled research data centers, where CDC exercises direct supervision of the data use in order to protect confidentiality. # Security: The mechanisms (administrative, technical, physical) by which privacy and confidentiality policies are implemented in computer and telecommunication systems. # Top-coding: A technique used to mask microdata that involves creating categories for data values that exceed a certain level. This method differs from aggregation, in that all data values above a certain threshold are grouped; other values in a field may or may not be grouped. See bottom-coding. The Privacy Act of 1974 (5 U.S.C. 552a) prohibits agency disclosure of any record maintained in a Federal system of records when the primary method by which the data will be retrieved is by name, social security number, or other identifying particular, such as thumb print, except pursuant to a written request, or with the prior written consent of, the individual to whom the record pertains. The creation of a Federal system of records is announced in the Federal Register. While the Privacy Act is generally protective, it contains several exceptions to the Privacy Act which permit disclosure without a subject's consent, including disclosure of the record for a routine use. A routine use is a disclosure which is compatible with the purpose for which the record was collected, and which is included in the system notice. A complete list of exceptions is found within Title 5 U.S.C. 552(a) (see Appendix B2). # Appendices In addition to the Privacy Act of 1974, which contains criminal penalties for the unauthorized disclosure of protected information, the Trade Secrets Act (Table 1) makes it unlawful for any officer or employee of the United States or of any Federal department or agency to publish, divulge, disclose, or make known in any manner not authorized by law any information gained through the course of Federal employment that concerns or relates to "trade secrets, processes, operations, style of work, or apparatus, or to the identity, confidential statistical data, amount or source of any income, profits, or losses, or expenditures of any person, firm, partnership, corporation, or association…" Information acquired through the course of official duties, through an investigation or examination, or seen in a document, is covered by the Trade Secrets Act. Some types of data CDC receives from States may fall under this act, making the unauthorized disclosure potentially a criminal offense. Under the Trade Secrets Act (18 U.S.C. Section 1905), a person "…shall be fined not more than $1,000, or imprisoned not more than one year, or both; and shall be removed from office or employment." Under the Privacy Act of 1974, Subsection 552a(i) (1), a person who willfully discloses information to another person who is not entitled to receive it "…shall be guilty of a misdemeanor and fined not more than $5,000." The "Related Statutory Authorities" section of the Standards of Ethical Conduct for Employees of the Executive Branch (5 CFR 2635.902; see www.usoge.gov/pages/laws_regs_fedreg_stats/oge_regs/5cfr2635.html) cites the prohibition against disclosure of proprietary information and certain other information of a confidential nature which is contained in the Trade Secrets Act (18 U.S.C. Section 1905). (d). Data collected under a project with a 308(d) assurance of confidentiality may not be released in identifiable form without the consent of the individual or entity that supplied the information. CDC has historically been rigorous in its approval process for the discretionary use of this authority in order to prevent misuse of the protections as a mechanism for refusing to share data. forum, whether it is a Federal or State proceeding, whether the United States is a party, and the particular laws at issue. # Special Confidentiality The human subjects Common Rule (Table 1) applies to all applications and proposals for research involving human subjects to be conducted, supported, or subject to regulation by a Federal department or agency. One of the many requirements of the Common Rule includes the provision, when appropriate, for the privacy of subjects to be protected (45 CFR Part 46, Section 46.111). At the time this report was drafted, it was not possible to include a summary about how the Confidential Information Protection and Statistical Efficiency provisions of the E-Government Act of 2002 will impact CDC data systems. The Office of Management and Budget is expected to issue definitive guidance on this issue at a later date. # Introduction Under the Freedom of Information Act (FOIA) (Title 5 United States Code §552 or 5 USC 552), all Federal agency records are subject to disclosure unless covered (in whole or part) by one (or more) of nine exemptions. The Privacy Act applies only to records in "systems of records" [defined in 5 USC §552a(a)( 5)], from which information is retrieved by an individual's name or other identifier. Such records are subject to release to individuals asking for their own records, to other requestors with the signed consent of the named individual, or to other requestors without a subject's consent under limited conditions specified in the Privacy Act. Definition -The term ''system of records'' means a group of any records under the control of any Federal agency from which information is retrieved by the name of the individual or by some identifying number, symbol, or other identifying particular assigned to the individual. # Freedom of Information Act (Title 5 USC 552) The Freedom of Information Act (FOIA) provides that, upon receiving a written request from any person, a Federal agency must release any requested agency record unless that record falls within one of the nine FOIA exemptions. FOIA applies to only Federal agencies, and covers only records in the possession and control of those agencies except in certain narrow instances involving grantee-held data. • Exemptions from FOIA (Title 5 USC 552b) 1. protects from disclosure national security information concerning national defense or foreign policy, provided that it has been properly classified pursuant to Executive Order 12,958. 2. related solely to the internal personnel rules and practices of an agency; (a) internal matters of a relatively trivial nature; (b) more substantial internal matters, the disclosure of which would risk circumvention of a legal requirement. 3. specifically exempted from disclosure by statute (other than section 552b of this title), provided that such statute: (a) requires that the matter be withheld from the public in such a manner as to leave no discretion on the issue; or (b) establishes particular criteria for withholding or refers to particular types of matters to be withheld; 4. trade secrets and commercial or financial information obtained from a person that is privileged or confidential; 5. inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than agency in litigation with the agency; 6. personnel and medical files and similar files the disclosure of which would constitute a clearly unwarranted invasion of personal privacy; 7. records or information compiled for law enforcement purposes, but only to the extent that the production of such law enforcement records or information: (a) could reasonably be expected to interfere with enforcement proceedings; (b) would deprive a person of a right to a fair trial or an impartial adjudication; (c) could reasonably be expected to constitute an unwarranted invasion of a person's privacy; (d) could reasonably be expected to disclose the identity of a confidential source, including a State, local or foreign agency or authority or any private institution which furnished information on a confidential basis, and, in the case of a record or information compiled by a criminal law enforcement authority in the course of a criminal investigation or by an agency conducting a lawful national security intelligence investigation, information furnished by a confidential source; (e) would disclose techniques and procedures for law enforcement investigations or prosecutions, or would disclose guidelines for law enforcement investigations or prosecutions if such disclosure could reasonably be expected to risk circumvention of the law; or (f) could reasonably be expected to endanger the life or physical safety of any individual; 8. contained in or related to examination, operating, or condition reports prepared by, on behalf of, or for the use of an agency responsible for the regulation or supervision of financial institutions; or 9. geological and geophysical information and data, including maps, concerning wells. Any reasonably segregable portion of a record shall be provided to any person requesting such record after deletion of the portions which are exempt under this subsection. The amount of information deleted shall be indicated on the released portion of the record, unless including that indication would harm an interest protected by the exemption in this subsection under which the deletion is made. If technically feasible, the amount of information deleted shall be indicated at the place in the record where such deletion is made. # Privacy Act (5 USC 552a) The Privacy Act applies to records maintained by a Federal agency in a system of records in which the primary method for data to be retrieved is by full names, social security numbers, or other identifying particulars. The Privacy Act states "No agency shall disclose any record which is contained in a system of records by any means of communication to any person, or to another agency, except pursuant to a written request by, or with the prior written consent of, the individual to whom the record pertains." The Act goes on to state the following exceptions, which are discretionary: # Disclosures Permitted by the Privacy Act The Privacy Act permits disclosure without a subject's consent in certain circumstances: 1. to those officers and employees of the agency which maintains the record who have a need for the record in the performance of their duties; 2. required under section 552 (FOIA) of this title; 3. for a routine use (disclosure of identifiable data outside the Department for a purpose compatible with the purpose for which the data were collected); 4. to the Bureau of the Census for purposes of planning or carrying out a census or survey or related activity; 5. to a recipient who has provided the agency with advance adequate written assurance that the record will be used solely as a statistical research or reporting record, and the record is to be transferred in a form that is not individually identifiable; 6. to the National Archives and Records Administration as a record which has sufficient historical or other value to warrant its continued preservation by the United States Government; 7. to another agency or to an instrumentality of any jurisdiction within or under the control of the United States for a civil or criminal law enforcement activity if the activity is authorized by law, and if the head of the agency or instrumentality has made a written request to the agency which maintains the record specifying the particular portion desired and the law enforcement activity for which the record is sought; 8. to a person pursuant to a showing of compelling circumstances affecting the health or safety of an individual if upon such disclosure notification is transmitted to the last known address of such individual; 9. to either House of Congress, or, to the extent of matter within its jurisdiction, any committee or subcommittee thereof, any joint committee of Congress or subcommittee of any such joint committee; 10. to the Comptroller General, or any of his authorized representatives, in the course of the performance of the duties of the General Accounting Office; 11. pursuant to the order of a court of competent jurisdiction; 12. to a consumer reporting agency in accordance with section 3711 f (Title 31 USC 3711f -Money and Finance: Collection and Compromise). # • The Privacy Act does not protect some records with identifiers: 1. Records of dead persons; Under the authority in Section 308(d) of the Public Health Service Act, CDC can provide confidentiality protection to a project when necessary to achieve the project's objectives, and when the respondents would not otherwise furnish valid sensitive information without that assurance. 308(d) protects information collected for a project from being used for any purpose other than the purpose for which is was collected unless the person or establishment from which the data were obtained has consented to such use. Confidentiality assurances protect against disclosures under a court order and provide protections that the Privacy Act does not. For example, the Privacy Act only protects individual participants, but confidentiality assurances can also protect institutions. Confidentiality protection granted by the CDC promises participants and institutions that their data will be shared only with those individuals and organizations listed in the consent form and/or the Assurance of Confidentiality Statement for the project. Projects that involve the collection of sensitive information frequently need confidentiality protection. Sensitive information includes (but is not limited to) data collection on sexual behaviors, drug uses, mental health status, or other information that if released could reasonably be damaging to an individual's financial standing, employability, or reputation. The full text of Section 308(d) of the Public Health Service Act follows: "No information, if an establishment or person supplying the information or described in it is identifiable, obtained in the course of activities undertaken or supported under section 304, 306, or 307 may be used for any purpose other than the purpose for which it was supplied unless such establishment or person has consented (as determined under regulations of the Secretary) to its use for such other purpose; and in the case of information obtained in the course of health statistical or epidemiological activities under section 304 or 306 , such information may not be published or released in other form if the particular establishment or person supplying the information or described in it is identifiable unless such establishment or person has consented (as determined under regulations of the Secretary) to its publication or release in other form." "The Secretary may authorize persons engaged in biomedical, behavioral, clinical, or other research (including research on mental health, including research on the use and effect of alcohol and other psychoactive drugs) to protect the privacy of individuals who are the subject of such research by withholding from all persons not connected with the conduct of such research the names or other identifying characteristics of such individuals. Persons so authorized to protect the privacy of such individuals may not be compelled in any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings to identify such individuals." Certificates # Applying for Confidentiality Protections Investigator(s) formally apply for confidentiality protections if they believe such protection is necessary to achieve the project objectives and to obtain valid information of a sensitive nature. # Data release: Dissemination of data either in a public-use file or as a result of an ad hoc request which results in the data steward no longer controlling the use of the data. Data may be released in a variety of formats including, but not limited to, tables, microdata (person records), or online query systems. Data sharing: Granting certain individuals or organizations access to data that contain individually identifiable information with the understanding that individually identifiable or potentially identifiable data cannot be re-released further unless a special data sharing agreement governs the use and re-release of the data and is agreed upon by CDC and the data provider(s). # Data sharing agreement (DSA): A mechanism by which a data requestor and CDC program can define the terms of data access that can be granted to requestors. # Appendix B1. Federal Laws and Rules Governing Data Release CDC's practices and policies regarding data release are based on the framework of Federal Laws governing the maintenance and public disclosure of Federal records, the protection of key public priorities such as privacy, proprietary information, and national security, and obligations arising out of litigation or other compulsory processes. The purpose of this section is to provide an overview of the major Federal Laws that may affect the release of State data or that may compel disclosure of State data. The applicability and implications of these laws will vary depending on the nature of the data and other circumstances. These variations will not be analyzed in detail here. Questions by data stewards about the applicability of legal requirements should be directed to appropriate legal counsel. Data collected by CDC, including data collected by States and provided to CDC, generally become a Federal record once received by CDC, and are subject to Federal laws and rules governing data release and Federal records retention laws. These include but are not limited to, the Freedom of Information Act (FOIA), the Privacy Act of 1974, Confidentiality Assurances, and Certificates of Confidentiality. These legal authorities are highlighted in Appendix B2 (overview of selected Federal laws). Guidance on the application of the HIPAA Privacy Rule to public health is provided in a recently published Morbidity and Mortality Weekly Report supplement 29 (www.cdc.gov/mmwr/pdf/wk/mmsu5201.pdf). These Federal laws may provide CDC with the ability to protect certain types of data from public re-disclosure; they also may require the retention and/or disclosure of data in some circumstances. Data use agreements must conform to the requirements of these laws when applicable. Legal Proceedings. In some instances, data collected by CDC, including data collected by States and sent to CDC, may be implicated in some type of lawsuit or administrative proceeding. The disclosure of such data may be sought through voluntary disclosure or compulsory process. Generally, CDC uses available legal mechanisms to protect the confidentiality of identifiable data, and to protect other public interests described previously. Generally, CDC has been successful in such instances. However, it is important to keep in mind that the ability to protect confidential or identifiable information in litigation or other legal proceedings depends on a variety of factors such as whether the data has special confidentiality protection, the type of court or	None	None
d4f6524012e9a4bd1893f961dd4cda04fe32fa34	cdc	None	Disseminates successful models as part of a coordi nated effort to educate and reach out to the public (Hamburg, 1998;Mercy et al., 1993). The chapters in this report are keyed to each of these components of the public health approach. Chapter 2 presents research describing the magnitude by the University of Michigan's Institute for Social Research (Johnston et al., 1995) - Youth Risk Behavior Surveillance Study sponsored by the Centers for Disease Control and Prevention in collaboration with Federal, state, and local part ners (Brener et al., 1999)No single study, however well designed, is sufficient to establish causation or, in intervention research, effi cacy or effectiveness. Findings must be replicated before gaining widespread acceptance by the scientif ic community. The strength of the evidence amassed for any scientific fact or conclusion is referred to as the level of evidence.# Message from Donna E. Shalala # Secretary o f Health and Human Services The first, most enduring responsibility of any society is to ensure the health and well-being of its children. It is a responsibility to which multiple programs of the Department of Health and Human Services are dedicated and an arena in which we can claim many remarkable successes in recent years. From new initiatives in child health insur ance and Head Start, to innovative approaches to child care, to the investment in medical research that has amelio rated and even eliminated the threat of many once lethal childhood diseases, we have focused directly and con structively on the needs of millions of children. Through programs designed to enhance the strength and resiliency of families and family members across the life span and through our investments in diverse community resources, we are also helping to enhance the lives and enrich the opportunities of millions more of our children. Although we can take rightful pride in our accomplishments on behalf of U.S. youths, we can and must do more. The world remains a threatening, often dangerous place for children and youths. And in our country today, the greatest threat to the lives of children and adolescents is not disease or starvation or abandonment, but the ter rible reality of violence. We certainly do not know all of the factors that have contributed to creating what many citizens-young and old alike-view as our culture of violence. It is clear, however, that as widespread as the propensity for and tol erance of violence is throughout our society-and despite efforts that, since 1994, have achieved dramatic declines in official records of violence on the part of young people-every citizen must assume a measure of responsibili ty for helping to reduce and prevent youth violence. Information is a powerful tool, and this Surgeon General's report is an authoritative source of information. In directing the Surgeon General to prepare a scholarly report that would summarize what research can tell us about the magnitude, causes, and prevention of youth violence, President Clinton sought a public health perspec tive on the problem to complement the extraordinary work and achievements in this area that continue to be real ized through the efforts of our criminal and juvenile justice systems. Over the past several months, the Department of Health and Human Services has worked with many hundreds of dedicated researchers, analysts, and policy makers whose interests and expertise lie outside the traditional domains of health and human services. What has become clear through our collaboration is that collectively we possess the tools and knowledge needed to throw safety lines to those young Americans who already have been swept up in the currents of violence and to strength en the protective barriers that exist in the form of family, peers, teachers, and the countless others whose lives are dedicated to the futures of our children. This Surgeon General's report seeks to focus on action steps that all Americans can take to help address the problem, and continue to build a legacy of health and safety for our young people and the Nation as a whole. # n ( # Foreword The opportunity for three Federal agencies, each with a distinct public health mission, to collaborate in developing the Surgeon General's report on youth violence has been an invigorating and rewarding intellectual challenge. We and our respective staffs were pleased to find that the importance that we collectively assign to the topic of youth violence transcended any impediments to a true, shared effort. Obstacles that one might have anticipated-for example, difficul ties in exchanging data and discussing concepts that emanate from many different scientific disciplines-proved to be surmountable. Indeed, many of the differences in perspective and scientific approach that distinguish the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Substance Abuse and Mental Health Services Administration (SAMHSA), when combined, afforded us a much fuller appreciation of the problem and much firmer grounds for optimism that the problem can be solved than is obvious from within the boundaries, or con fines, of a single organization. The mission of CDC is to promote health and quality of life by preventing and controlling disease, injury, and dis ability. The NIH, of which the National Institute of Mental Health (NIMH) is one component, is responsible for gener ating new knowledge that will lead to better health for everyone. SAMHSA is charged with improving the quality and availability of prevention, treatment, and rehabilitation services in order to reduce illness, death, disability, and cost to society resulting from substance abuse and mental illnesses. Common to each of the agencies is an interest in prevent ing problems before they have a chance to impair the health of individuals, families, communities, or society in its entire ty. Toward this end, CDC, NIH/NIMH, and SAMHSA each support major long-term research projects involving nation ally representative samples of our Nation's youth. These studies, which are introduced and described in the report that follows, are designed both to monitor the health status of young Americans and to identify factors that can be shown to carry some likelihood of risk for jeopardizing health-information that lends itself to mounting effective interventions. The designation of youth violence as a public health issue complements the more traditional status of the problem as a criminal justice concern. Here again, it has been satisfying for all of us in the public health sector to reach across professional and disciplinary boundaries to our colleagues in law, criminology, and justice and work to meld data that deepen our understanding of the patterns and nature of violence engaged in by young people throughout our country. What has emerged with startling clarity from an exhaustive review of the scientific literature and from analyses of key new data sources is that we as a Nation have made laudable progress in gaining an understanding of the magnitude of the problem. We have made great strides in identifying and quantifying factors that, in particular settings or combi nations, increase the probability that violence will occur. And we have developed an array of interventions of welldocumented effectiveness in helping young people whose lives are already marked by a propensity for violence as well as in preventing others from viewing violence as a solution to needs, wants, or problems. CDC, NIH/NIMH, and SAMHSA look forward to continuing collaborations, begun during the development of this report, that will extend further the abilities of policy makers, communities, families, and individuals to understand youth violence and how to prevent it. # Preface from the Surgeon General U.S. Public Health Service The immediate impetus for this Surgeon General's Report on Youth Violence was the Columbine High School tragedy that occurred in Colorado in April 1999, resulting in the deaths of 14 students, including 2 perpetrators, and a teacher. In the aftermath of that shocking event, both the Administration and Congress requested a report summa rizing what research has revealed to us about youth violence, its causes, and its prevention. Our review of the scientific literature supports the main conclusion of this report: that as a Nation, we possess knowledge and have translated that knowledge into programs that are unequivocally effective in preventing much serious youth violence. Lest this conclusion be considered understated or muted, it is important to realize that only a few years ago, substantial numbers of leading experts involved in the study and treatment of youth violence had come to a strikingly different conclusion. Many were convinced then that nothing could be done to stem a tide of serious youth violence that had erupted in the early 1980s. During the decade extending from 1983 to 1993, arrests of youths for serious violent offenses surged by 70 percent; more alarmingly, the number of young people who committed a homicide nearly tripled over the course of that deadly decade. In many quarters, dire predictions about trends in youth violence yielded to resignation; elsewhere, fear and concern prompted well-meaning officials and policy makers to grasp at any proposed solutions, often with little, if any, systematic attention to questions of the efficacy or effective ness of those approaches. Fortunately, the past two decades have also been distinguished by the sustained efforts of researchers, legislators, and citizens from all walks of life to understand and address the problem of youth violence. One seminal contribu tion to these efforts was an initiative taken by one of my predecessors, Surgeon General C. Everett Koop, to address violence as a public health issue; that is, to apply the science of public health to the treatment and prevention of vio lence. As evident throughout this report, that endorsement was key to encouraging multiple Federal, state, local, and private entities to invest wisely and consistently in research on many facets of youth violence and to translate the knowledge gained into an exciting variety of intervention programs. Although much remains to be learned, we can be heartened by our accomplishments to date. For one, our care ful analyses, together with those conducted by components of the justice system, have demonstrated the pervasive ness of youth violence in our society; no community is immune. In light of that evidence, it has been most encour aging to me to see that the citizens with whom I have interacted in hundreds of communities around the Nation want us to find answers that will help all of our youth. There is a powerful consensus that youth violence is, indeed, our Nation's problem, and not merely a problem of the cities, or of the isolated rural regions, or any single segment of our society. Equally encouraging have been our findings that intervention strategies exist today that can be tailored to the needs of youths at every stage of development, from young childhood to late adolescence. There is no justification for pessimism about reaching young people who already may be involved in serious violence. Another critical bit of information from our analyses of the research literature is that all intervention programs are not equally suited to all children and youths. A strategy that may be effective for one age may be ineffective for older or younger children. Certain hastily adopted and implemented strategies may be ineffective-and even deleterious-for all children and youth. Understanding that effectiveness varies underscored for us the importance of bridging the gap between science and practice. Only through rigorous research and thorough, repeated evaluations of programs as they operate in the real world will we be assured that we are using our resources wisely. In presenting this Surgeon General's report, I wish to acknowledge our indebtedness to the many scientists who have persisted in their work in this difficult, often murky area and whose results we have scrutinized and drawn on. We are also immensely grateful to the countless parents, police officers, teachers, juvenile advocates, health and human service workers, and people in every walk of life who recognize the inestimable value of our Nation's youth and the importance of peace, security, and comity in their lives. For millions of youths and their families, a period of life that should have been distinguished by good health and great promise was instead marred by injuries, disability, and death . This epidemic of violence not only left lasting scars on victims, perpetrators, and their families and friends, it also wounded communities and, in ways not yet fully understood, the country as a whole. Since 1993, the peak year of the epidemic, there have been some encouraging signs that youth vio lence is declining. Three important indicators of violent behavior-arrest records, victimization data, and hospital emergency room records-have shown significant downward trends nationally. These offi cial records reveal only a small part of the picture, however. A fourth key indicator of violence-confidential reports by youths themselves-reveals that the pro portion of young people who acknowledge having committed serious, potentially lethal acts of physical violence has remained level since the peak of the epi demic. In 1999, for instance, there were 104,000 arrests of persons under age 18 for robbery, forcible rape, aggravated assault, or homicide (Snyder, 2000); of those arrests, 1,400 were for homicides perpetrated by adolescents (Snyder, 2000) and, occasionally, even younger children ). Yet in any given year in the late 1990s, at least 10 times as many youths reported that they had engaged in some form of violent behavior that could have seriously injured or killed another person. The high prevalence of violent behavior reported by adolescents underscores the importance of this report at this time. Americans cannot afford to become complacent. Even though youth violence is less lethal today than it was in 1993, the percentage of adolescents involved in violent behavior remains alarmingly high. The epi demic of lethal violence that swept the United States was fueled in large part by easy access to weapons, notably firearms-and youths' self-reports of violence indicate that the potential for a resurgence of lethal violence exists. Yet viewing homicide as a barometer of all youth violence can be quite misleading. Similarly, judging the success of violence prevention efforts solely on the basis of reductions in homicides can be unwise. This report, the first Surgeon General's report on youth violence in the United States, summarizes an extensive body of research and seeks to clarify seem ingly contradictory trends, such as the discrepancies noted above between official records of youth vio lence and young people's self-reports of violent behaviors. It describes research identifying and clari fying the factors that increase the risk, or statistical probability, that a young person will become violent, as well as studies that have begun to identify devel opmental pathways that may lead a young person into a violent lifestyle. The report also explores the less well developed research area of factors that seem to protect youths from viewing violence as an accept able-or inevitable-way of approaching or respond ing to life events. Finally, the report reviews research on the effectiveness of specific strategies and pro grams designed to reduce and prevent youth violence. As these topics suggest, the key to preventing a great deal of violence is understanding where and when it occurs, determining what causes it, and scientifically documenting which of many strategies for prevention and intervention are truly effective. This state-of-thescience report summarizes progress toward those goals. The most important conclusion-of the report is that the United States is well past the "nothing works" era with respect to reducing and preventing youth vio lence. Less than 10 years ago, many observers pro jected an inexorably rising tide of violence; the recent, marked reductions in arrests of young perpetrators and in victimization reports appear to belie those dire pre dictions. We possess the knowledge and tools needed to reduce or even prevent much of the most serious youth violence. Scientists from many disciplines, working in a variety of settings with public and pri vate agencies, are generating needed information and putting it to use in designing, testing, and evaluating intervention programs. The most urgent need now is a national resolve to confront the problem of youth violence systematically, using research-based approaches, and to correct dam aging myths and stereotypes that interfere with the task at hand. This report is designed to help meet that need. The report makes it clear that after years of effort and massive expenditures of public and private resources, the search for solutions to the problem of youth violence remains an enormous challenge Sechrest et al., 1979). Some tra ditional as well as seemingly innovative approaches to reducing and preventing youth violence have failed to deliver on their promise, and successful approaches are often eclipsed by random violent events such as the recent school shootings that have occurred in com munities throughout the country. Youth violence is a high-visibility, high-priority concern in every sector of U.S. society. We have come to understand that young people in every community are involved in violence, whether the community is a small town or central city, a neatly groomed suburb, or an isolated rural region. Although male adolescents, particularly those from minority groups, are dispro portionately arrested for violent crimes, self-reports indicate that differences between minority and major ity populations and between male and female adoles cents may not be as large as arrest records indicate or conventional wisdom holds. Race/ethnicity, consid ered in isolation from other life circumstances, sheds little light on a given child's or adolescent's propensi-"^T~r engaging in violence. This chapter describes the scope and focus of the report and explains how the public health approach advances efforts to understand and. prevent youth violence. Common myths about youth violence are presented and debunked. Uncorrected, these myths lead to misguided public policies, inefficient use of public and private resources, and loss of traction in efforts to address the problem. Documentation for the facts that counter these myths appears in later chapters. This chapter also lays out the scientific basis of the report-that is, the standards of evidence that research studies had to meet in order to be included in the report and the sources of data cited throughout. Final sections of this chapter preview subsequent chapters and list the report's major conclusions. # Sc o p e , Fo c u s , a n d O v e r a r c h in g T h e m e s The mission of the Surgeon General is to protect and improve the public health of the Nation, and this report was developed within the responsibilities and spirit of that mission. The designation of youth vio lence as a public health concern is a recent develop ment. As discussed below in greater detail, public health offers an approach to youth violence that focuses on prevention rather than consequences. It provides a framework for research and intervention that draws on the insights and strategies of diverse disciplines. Tapping into a rich but often fragmented knowledge base about risk factors, preventive inter ventions, and public education, the public health per spective calls for examining and reconciling what are frequently contradictory conclusions about youth violence. Although the public health approach opens up a broad array of considerations, the focus of this initial report is the perpetration by juveniles of interpersonal physical assault that carries a significant risk of injury or death. As restrictive as it may at first appear, this focus draws on a wealth of research into individual, family, school, peer group, and community factors that are associated with serious violence in the second decade of life. This report defines serious violence as aggravated assault, robbery, rape, and homicide; here after, it refers simply to "violence" or "violent crime," thus avoiding repetitious use of the terms "serious vio lence" or "serious violent crime." The report views violence from a developmental perspective. It examines the interactions of youths' personal characteristics and the social contexts in which they live-as well as the timing of those inter actions-to understand why some young people become involved in violence and some do not. This perspective considers a range of risks over the life course, from prenatal factors to factors influencing whether patterns of violent behavior in adolescence will persist into adulthood. The developmental per spective has enabled scientists to identify two general onset trajectories of violence: one in which violent behaviors emerge before puberty, and one in which they appear after puberty. Of the two, the early-onset trajectory provides stronger evidence of a link between early childhood experiences and persistent, even lifelong involvement in violent behavior. The developmental perspective is important because it enables us to time interventions for the particular point or stage of life when they will have the greatest positive effect. The young people on whom this report focuses are principally children and adolescents from about age 10 through high school. Research reviewed in Chapter 4 shows that although risk factors for vio lence vary by stage of development, most youth vio lence emerges during the second decade of life. Appropriate interventions before and-as is increas ingly well documented-during this period have a good chance of redirecting violent young people toward healthy and constructive adult lives. The win dow of opportunity for effective interventions opens early and rarely, if ever, closes. # S e c o n d a r y A r e a s o f C o n c e r n Many legitimate concerns and issues that are indis putably associated with violence by young people are not addressed in depth in this first report. Behavioral patterns marked by aggressiveness, antisocial behav ior, verbal abuse, and externalizing (the acting out of feelings) are peripheral to the main focus of the report. These behaviors may include violent physical interactions, such as hitting, slapping, and fist-fight ing, that can have significant consequences but gen erally present little likelihood of serious injury or death. Therefore, such behaviors will be discussed only to the extent that they can be considered risk fac tors for violence. Research has shown that victims and offenders share many personal characteristics and that victim ization and perpetration of violent behavior are often entwined. Nonetheless, this report does not focus on victims of violence perpetrated by young offenders. Rather, it blends offender-based research with tradi tional public health concepts of prevention and inter vention in an effort to bridge the gap between crimi nology and the social and developmental sciences, on the one hand, and traditional public health approaches to youth violence, on the other. The report does not address violence against inti mate partners, except when such violence is committed by a young person. The plight of victims, many of whom are children and adolescents, is of the utmost importance, but a key element in helping victims of violence is understanding the perpetrators of violence. Particular categories of crime, such as dating violence and hate crimes (motivated by racist or homophobic attitudes, for example), are important manifestations of violence, including violence committed by youths, and they demand research and targeted interventions. The limited amount of research conducted in this area has focused on victims, so there is little scientific evidence about what distinguishes perpetrators of these specific types of crimes (see reviews by Bergman, 1992;Comstock, 1991;and D'Augelli & Dark, 1984). Self-directed violence-that is, self-inflicted injury and suicide-is not covered either. In collabo ration with other Federal health agencies, the Office of the Surgeon General developed a National Strategy for the Prevention of Suicide (U.S. Public Health Service, 1999). In directing national attention to suicide as a major, yet largely preventable public health problem, the Surgeon General is bringing together health professional organizations, educa tors, health care executives, and managed care clini-cal directors to discuss gaps in scientific knowledge that impede efforts to decrease the incidence of suicide among Americans of all ages. The vast majority of youth suicides occur in the context of mental disorders (Brent et al., 1988;Shaffer et al., 1996), a topic that was reviewed in depth in the Surgeon General's report on mental health (U.S. DHHS, 1999). Finally, the report does not propose public policy to reduce or prevent youth violence. The purpose of this report, like others from U.S. Surgeons General, is to review and describe existing knowledge in order to provide a basis for action at all levels of society. The last chapter identifies potential courses of action, including specific areas in which research is needed, but suggesting whether and how such action will lend itself to policy development is beyond the purview of this report. # Y o u t h V io l e n c e : T h e P u b l ic H e a l t h A p p r o a c h In October 1985, Surgeon General C. Everett Koop convened an unprecedented Workshop on Violence and Public Health (U.S. DHHS, 1986). The partici pants agreed strongly that it was time public health perspectives and expertise were brought to bear on questions of crime and violence. Throughout much of the last century, these questions had been domi nated by the social sciences and the criminal justice system. For the most part, health care efforts were restricted to the rehabilitation of convicted offenders (Sechrest et al., 1979;U.S. DHHS, 1986). Dissatisfaction with both the timing and the out comes of the "rehabilitation ideal" spurred the search - for a more effective role for health care in addressing violence. With its emphasis on prevention of disease or injury, the public health approach to violence offers an appealing alternative to an exclusive focus on rehabilitation. Primary prevention identifies behav ioral, environmental, and biological risk factors associated with violence and takes steps to educate individuals and communities and protect them from these risks. Central to education and protection is the iciple that health promotion is best learned, per-ERLC formed, and maintained when it is ingrained in indi viduals' and communities' daily routines and percep tions of what constitutes good health practices. Public health practitioners and advocates have taken the lead in encouraging alliances and networks among academic disciplines, professions, organiza tions, and communities to make health concerns per manent public priorities and part of personal practices. In that tradition, participants at the 1985 Surgeon General's conference emphasized the importance of convincing the public that violence should be treated as a public health problem. As Marvin Wolfgang, a distin guished leader in the field of criminology, told confer ees, "Our nation must feel as comfortable in controlling its violent behavioral urges and practices as it does in controlling bacterial, viral, and physical manifestations of morbidity and death" (U.S. DHHS, 1986). Just as the application of public health principles and strategies has reduced the number of traffic fatal ities and deaths attributed to tobacco use (CDC, 1999), the public health approach can help reduce the number of injuries and deaths caused by violence. Broader than the medical model, which is concerned with the diagnosis, treatment, and mechanisms of spe cific illnesses in individual patients, public health offers a practical, goal-oriented, and communitybased approach to promoting and maintaining health. To identify problems and develop solutions for entire population groups, the public health approach: - Defines the problem, using surveillance processes designed to gather data that establish the nature of the problem and the trends in its incidence and prevalence; - Identifies potential causes through epidemiological analyses that identify risk and protective factors associated with the problem; - Designs, develops, and evaluates the effectiveness and generalizability of interventions; and # Introduction -f the problem of violent behavior by young people. Chapter 3 explores how violence develops and emerges over time. Chapter 4 summarizes research on risk and protective factors for youth violence; Appendix 4-B elaborates on the effects of exposure to media violence (including violence in interactive media) as a risk factor for aggressive and violent behavior. Chapter 5 focuses on the design, evaluation, and refinement of numerous programs and strategies that seek to reduce or prevent youth violence; Appendix 5-B provides details on specific programs discussed in the chapter. Chapter 6 suggests future courses of action, including the necessary next steps in research. A glossary of technical and disciplinespecific terms follows. # M y t h s A b o u t Y o u t h V io l e n c e An important reason for making research findings widely available is to challenge false notions and mis conceptions about youth violence. Myths such as those listed below are intrinsically dangerous. Assumptions that a problem does not exist or failure to recognize the true nature of a problem can obscure the need for informed policy or for interventions. An example is the conventional wisdom in many circles that the epidemic of youth violence so evident in the early 1990s is over. Alternatively, myths may trigger public fears and lead to inappropriate or misguided policies that result in inefficient use of scarce public resources. An example is the current policy of waiving or transferring young offenders into adult criminal courts and prisons. # Myth: The epidemic o f violent behavior that marked the early 1990s is over, and young people-as well as the rest o f U.S. society-are much safer today. Fact: Although such key indicators of violence as arrest and victimization data clearly show significant reductions in violence since the peak of the epidemic in 1993, an equally important indicator warns against concluding that the problem is solved. Self-reports by youths reveal that involvement in some violent behav iors remains at 1993 levels (see Chapter 2). Myth: Most future offenders can be identified in early childhood. Fact: Exhibiting uncontrolled behavior or being diagnosed with conduct disorder as a young child does not predetermine violence in adolescence. A majority of young people who become violent during their ado lescent years were not highly aggressive or "out of control" in early childhood, and the majority of chil dren with mental and behavioral disorders do not become violent in adolescence (see Chapter 3). Myth: Child abuse and neglect inevitably lead to violent behavior later in life. Fact: Physical abuse and neglect are relatively weak predictors of violence, and sexual abuse does not predict violence. Most children who are abused or neglected will not become violent offenders during adolescence (see Chapter 4). Myth: African American and Hispanic youths are more likely to become involved in violence than other racial or ethnic groups. Fact: Data from confidential interviews with youths indicate that race and ethnicity have little bear ing on the overall proportion of racial and ethnic groups that engage in nonfatal violent behavior. However, there are racial and ethnic differences in homicide rates. There are also differences in the tim ing and continuity of violence over the life course, which account in part for the overrepresentation of these groups in U.S. jails and prisons (see Chapter 2). # Myth: A new violent breed o f young superpreda tors threatens the United States. Fact: There is no evidence that young people involved in violence during the peak years of the early 1990s were more frequent or more vicious offenders than youths in earlier years. The increased lethality . resulted from gun use, which has since decreased dra matically. There is no scientific evidence to document the claim of increased seriousness or callousness (see Chapter 3). # Myth: Getting tough with juvenile offenders by trying them in adult criminal courts reduces the like lihood that they will commit more crimes. Fact: Youths transferred to adult criminal court have significantly higher rates of reoffending and a greater likelihood of committing subsequent felonies than youths who remain in the juvenile justice system. They are also more likely to be victimized, physically and sexually (see Chapter 5). # Myth: Nothing works with respect to treating or preventing violent behavior. Fact: A number of prevention and intervention programs that meet very high scientific standards of effectiveness have been identified (see Chapter 5). Myth: In the 1990s, school violence affected mostly white students or students who attended sub urban or rural schools. Fact: African American and Hispanic males attending large inner-city schools that serve very poor neighborhoods faced-and still face-the greatest risk of becoming victims or perpetrators of a violent act at school. This is true despite recent shootings in suburban, middle-class, predominantly white schools (see Chapter 2). # Myth: Weapons-related injuries in schools have increased dramatically in the last 5 years. Fact: Weapons-related injuries have not changed significantly in the past 20 years. Compared to neigh borhoods and homes, schools are relatively safe places for young people (see Chapter 2). # Myth: Most violent youths will end up being arrested fo r a violent crime. Fact: Most youths involved in violent behavior will never be arrested for a violent crime (see Chapter 2). # So u r c e s o f D a ta a n d St a n d a r d s o f Ev id e n c e # Data Sources Several comprehensive scholarly reviews of various facets of youth violence were published in the 1990s. Professional organizations, Federal agencies, the National Academy of Sciences, and university-based researchers have invested immense energy in reviewing research on the occurrence and patterns of youth violence, its causes and consequences, interven tion strategies, and implications for society. Key contributions to this rich information base include: - NIMH Taking Stock o f Risk Factors fo r Child/Youth Externalizing Behavior Problems (Hann & Borek, - Serious and Violent Juvenile Offenders - The American Psychological Association's report Violence and Youth (APA, 1993) and Reason to Hope (Eron et al., 1994) - Preventing Crime: What Works, What Doesn't, What' s Promising. A Report to the United States Congress (Sherman et al., 1997) - The OJJDP national report Juvenile Offenders and Victims - The American Sociological Association's Social Causes o f Violence: Crafting a Science Agenda (Levine & Rosich, 1996) This report draws extensively-but not exclusive ly-on concepts, general information, and data con tained in these documents. The authors gratefully acknowledge the contributors to and publishers of these earlier studies. Whenever the report draws heav ily on one of these master sources, that fact is noted. Specific references to these documents are provided where appropriate. Contributors to and editors of this report have also consulted peer-reviewed journals, books, and govern ment reports and statistical compilations. Some infor mation not considered in prior reviews is contained in this report. When appropriate, the editors have drawn on dissertations and forthcoming work that they judged to be of high quality. During the development of this report, special data analyses were obtained from established surveys of U.S. adolescents. The key data sources for these analyses are the following: - The National Center for Juvenile Justice's up-todate information on juvenile arrests for violent crimes (Snyder, 2000) - The National Crime Victimization Survey (Rand et al., 1998) # Standards of Scientific Evidence for Multidisciplinary Research The public health approach relies on a multidiscipli nary, multijurisdictional knowledge base. Thus, in preparing this report, it was necessary to draw conclu sions from research in psychology (social, develop mental, clinical, and experimental), sociology, crimi nology, neuroscience, public health, epidemiology, communications, and education. Integrating findings and conclusions across disciplinary lines is never easy. The questions under study generally determine what approach scientists will take to designing and conduct ing research, and the approach often determines how investigators report their findings and conclusions. Even when scientific approaches are similar, investiga tors in different disciplines frequently employ different terminology to describe similar concepts. In striving to apply scientific standards consis tently across the many fields of research reviewed, this report has emphasized two criteria: appropriately rigorous methods of inquiry and sufficient data to sup port major conclusions. The need for rigor is obvious: The tools or strategies employed in research-like the conclusions reached-are only as good as the preci sion with which research questions are framed. But the quality of a given study depends on other factors as well, including: - General data collection design. Data may be obtained through four major types of study design: experimental, longitudinal, cross-sectional, and case study. This report relies primarily on experimental and longitudinal designs, with some use of cross sectional studies. (These three methods are described below.) - Sampling, or the selection of persons to be studied. Individuals in a study may be recruited or identi fied through probability or nonprobability sam pling, or they may be assigned to experimental or control groups by a random process, a precision or group-matching process, or some other means. This report refers to probability samples as repre sentative samples. - Validity and reliability of measures or instruments used in the research. - Appropriateness and level of control incorporated into the analysis of findings. Level of control refers to efforts to take into account other factors that might be influencing data or responses from subjects. - Appropriateness and significance of generalizations. As noted earlier, four of the chapters in this report-those concerned with magnitude, demograph ics, risk and protective factors, and intervention research and evaluation-mirror components of the public health approach to youth violence. Each of these areas involves research from different disci plines and scientific approaches; therefore, the types of research designs and forms of analysis presented differ somewhat from chapter to chapter. Experimental research is the preferred method for assessing cause and effect as well as for determining how effectively an intervention works. Many of the violence prevention programs reviewed in Chapter 5 meet the standard of rigorous experimental (or wellexecuted quasi-experimental) designs. In an experi mental study, researchers randomly assign an inter vention to one group of study participants, the experi mental group, and provide standard care or no inter vention to another group, the control group. A study with a randomly assigned control group enables researchers to conclude that observed changes in the experimental group would not have happened without the intervention and did not occur by chance. The dif-ference in outcome between the experimental and control groups, which in this case may be the reduc tion or elimination of violent behaviors, can then be attributed to the intervention. Ideally, researchers assign study participants to the experimental intervention or the control group at random. Randomization eliminates bias in the assign ment process and provides a way of determining the likelihood that the effects observed occurred by chance. In this report, most weight is given to true experimental studies. In some cases, true experiments may be too difficult or expensive to conduct, or they may pose unacceptable ethical problems. In such cases, carefully designed and executed quasi-experi mental studies are accepted as meeting the standard. Evidence from an experimental study is consid ered stronger when, in addition to analyzing the main effects of an intervention, researchers analyze the mediating effects. This analysis permits researchers to determine whether a change in the targeted risk or protective factor accounts for the observed change in violence-that is, did the intervention work because it changed the degree of risk? Without this information, researchers cannot explain the success of a program. Chapters 4 and 5 make use of meta-analyses. Meta-analysis describes a statistical method for eval uating the conclusions of numerous studies to deter mine the average size and consistency of the effect of a particular treatment or intervention strategy com mon to all of the studies. The technique makes the results of different studies comparable so that an over all effect can be identified. A meta-analysis deter mines whether there is consistent evidence that a treat ment has a statistically significant effect, and it esti mates the average size of that effect. Epidemiological research, reviewed in Chapters 2 and 3, focuses primarily on general population studies that use probability samples and cross-sectional or lon gitudinal designs (Kleinbaum et al., 1982;Lilienfeld & Lilienfeld, 1980;Rothman & Greenland, 1998). Probability samples let researchers generalize from their study to the entire population sampled. Cross-sec tional studies involve a single contact with participants for data collection at a given point in time. Multiple O cross-sectional studies involve several waves of data collection over time (annually, for example) but typi cally with different participants at each contact and therefore with no way to link a given person's respons es at one time with those at a later time. Prospective longitudinal and panel designs involve multiple con tacts with the same study participants over time. Responses at one data collection point can be linked to responses at a later point. Longitudinal studies are used for research on individual development or growth. Longitudinal designs are necessary to estimate the predictive effect of a given risk or protective factor on later violent behavior. Although cross-sectional designs are sometimes used, they cannot provide estimates of individual-level predictive effects. They can establish simultaneous relationships between risk factors and vio lence, but conclusions drawn from cross-sectional stud ies are not as strong as those drawn from longitudinal studies. In cross-sectional studies, cause and effect are unclear and reciprocal effects may inflate the estimates. Experimental studies are sometimes used to esti mate the effects of risk and protective factors, but this practice is rare because of ethical and cost considera tions. For example, it would be unthinkable to intro duce drug use to a group of adolescents to see whether drugs are a risk factor for violence. However, it would be ethical to conduct a predictive study that selects persons who are not violent and follows them over time. Those who began to use illicit substances would be compared with those who did not, to determine whether drug users are more likely to become involved in violent behaviors at some later date. If they were, then the results would indicate that drug use predicts violence or that drug use increases the probability of future violence. # Introduction This report does not rely on any single study for conclusions. Only findings that have been replicated in several studies, consistently and with no contrary results, are reported as part of the contemporary knowl edge base. When the report cites unreplicated studies that are of high quality, that have not been refuted by other evidence, and that point in a clear direction, the findings are described as tentative or suggestive. These findings may point to future research needs and direc tions, but the report takes a conservative approach to drawing conclusions from them. # O v e r v ie w o f t h e R e p o r t 's C h a p t e r s The Surgeon General's report on youth violence reviews a vast, multidisciplinary, and often controver sial research literature. Chapters 2 through 5 address, respectively, the extent and magnitude of youth vio lence; the developmental characteristics of, or paths to, youth violence; personal and environmental factors that may either place a child or adolescent at risk of violent behavior or protect a young person from suc cumbing to those risk factors; and violence interven tion and prevention programs. The final chapter in the report identifies areas of opportunity for future efforts to combat and prevent youth violence. This section provides a brief overview of each chapter, while the following section presents a sum mary of key conclusions drawn from each. Chapter 2 examines the magnitude of and trends in youth violence over the last two decades. It describes two different, but complementary ways of measuring violence-official reports and self-reports. Official arrest data offer an obvious means of deter mining the extent of youth violence. Indeed, a surge in arrests for violent crimes marked what is now recog nized as an epidemic of youth violence from 1983 to 1993. Arrests were driven largely by the rapid prolif eration of firearms use by adolescents engaging in violent acts and the likelihood that violent confronta tions would-as they did-produce serious or lethal injuries. Today, with fewer young people carrying weapons, including guns, to school and elsewhere than in the early 1990s, violent encounters are less likely to result in homicide and serious injury and therefore are less likely to draw the attention of police. By 1999, arrest rates for homicide, rape, and robbery had all dropped below 1983 rates. In contrast, arrest rates for aggravated assault remained higher than they were in 1983, having declined only 24 percent from the peak rates in 1994. Another way of measuring violence is on the basis of confidential reporting by youths themselves. Confidential surveys find that 10 to 15 percent of high school seniors report having committed an act of seri ous violence in recent years. These acts typically do not come to the attention of police; in part because they are less likely to involve firearms than in previ ous years. Over the past two decades, self-reported violence by high school seniors increased nearly 50 percent, a trend similar to that found in arrests for vio lent crimes. But this proportion has not declined in the years since 1993-it remains at peak levels. Chapter 2 considers how and to what extent arrest data and self report data vary, including variations by sex and race or ethnicity. In the aggregate, the best available evi dence from multiple sources indicates that youth vio lence is an ongoing national problem, albeit one that is largely hidden from public view. Chapter 3 examines routes that may lead a young person into violence. Viewed from a developmental perspective, violence stems from a complex interac tion of individuals with their environment at particu lar times in their lives. Longitudinal research has enabled investigators to describe the emergence of violence in terms of two, and possibly more, lifecourse trajectories. Chapter 3 discusses the earlyonset and late-onset emergence of violence, which occur before and after puberty, respectively. These trajectories offer insights into the likely course, severity, and duration of violence over the life course and have practical implications for the timing of intervention programs and strategies. The chapter reviews research on the co-occurrence of serious vio lence and other problems, including drug use and mental disorders. Finally, it underscores the impor tance-and the paucity-of research on factors asso ciated with the cessation of youth violence or its con tinuation into adulthood. Extensive research in recent decades has sought to identify various personal characteristics and environ mental conditions that either place children and ado lescents at risk of violent behavior or that seem to pro tect them from the effects of risk. Risk and protective factors, which are the focus of Chapter 4, can be found in every area of life. They exert different effects at dif ferent stages of development, they tend to appear in clusters, and they appear to gain strength in numbers. As the chapter notes, risk probabilities apply to groups, not to individuals. Although risk factors are not necessarily causes, a central aim of the public health approach to youth violence is to identify these predictors and determine when in the life course they typically come into play. Such information enables researchers to design preventive programs that can be put in place at just the right time to be most effective. The chapter examines risk from the perspectives of both childhood and adolescence and, within each of these developmental periods, considers risk factors occurring in the individual, family, school, peer group, and community domains. Childhood risk factors for violence in adolescence include involvement in serious (but not necessarily violent) criminal acts and sub stance use before puberty, being male, aggressiveness, low family socioeconomic status/poverty, and antiso cial parents-all either individual or family risk fac tors. The influence of family is largely supplanted in adolescence by peer influences, thus risk factors with the largest predictive effects in adolescence include weak social ties, ties to antisocial or delinquent peers, and belonging to a gang. Having committed serious (but not necessarily violent) criminal offenses is also an important risk factor in adolescence. Identifying and understanding how protective fac tors influence behavior is potentially as important to preventing and stopping violence as identifying and understanding risk factors. Several protective factors have been proposed, but to date only two have been found to buffer the risk of violence-an intolerant atti tude toward deviance and commitment to school. Protective factors warrant, and are beginning to receive, more research attention. Despite past contentions that "nothing works" to prevent youth violence, the evidence presented in Chapter 5 demonstrates that prevention efforts can be effective against both early-and late-onset violence in the general youth population, high-risk youths, and even youths who are already violent or seriously delin quent. The chapter highlights 27 specific programs that, based on existing data, help prevent youth vio lence. The most effective of these programs combine components known to prevent violence by themselves, particularly social skills training for youths and inter ventions that include parents or entire families. Chapter 5 also highlights important limitations in the current research on youth violence prevention. Little is known about the scientific effectiveness of hundreds of programs now being used in U.S. schools and communities. This situation is disconcerting, given that many well-intentioned youth violence pre vention programs have been found ineffective or harmful to youths. Even less is known about how to implement effective programs on a national scale without compromising their results. The information presented in Chapter 5 shows that youth violence prevention not only works, it can also be cost-effective. In a number of cases, the long term financial benefits of prevention are substantially greater than the costs of the programs themselves. These promising findings indicate that prevention plays an important role in providing a safe environ ment for youths. Finally, Chapter 6 presents several options for future action. First, the scientific base must continue to be expanded. Effective interventions exist, but only continued research can document those programs that meet a standard of effectiveness and those that do not-and should therefore be discarded. The chapter identifies the following courses of action: - Disseminate model programs with incentives that will ensure fidelity to original program design when taken to scale - Provide training and certification programs for intervention personnel - Improve public awareness of effective interventions - Convene youths and families, researchers, and pri vate and public organizations for a periodic youth violence summit - Improve Federal, state, and local strategies for reporting crime information and violent deaths # C h a p t e r C o n c l u s io n s Chapter 2 1. The decade between 1983 and 1993 was marked by an epidemic of increasingly lethal violence that was associated with a large rise in the use of firearms and involved primarily African American males. There was a modest rise in the proportion of young persons involved in other forms of seri ous violence. 2. Since 1994, a decline in homicide arrests has reflected primarily the decline in use of firearms. There is some evidence that the smaller decline in nonfatal serious violence is also attributable to declining firearm use. 3. By 1999, arrest rates for violent crimes-with the exception of aggravated assault-had fallen below 1983 levels. Arrest rates for aggravated assault remain almost 70 percent higher than they were in 1983, and this is the offense most fre quently captured in self-reports of violence. 4. Despite the present decline in gun use and in lethal violence, the self-reported proportion of young people involved in nonfatal violence has not declined from the peak years of the epidemic, nor has the proportion of students injured with a weapon at school declined. 5. The proportion of schools in which gangs are ' present continued to increase after 1994 and has only recently (1999) declined. However, evidence shows that the number of youths involved with gangs has not declined and remains near the peak levels of 1996. r 6. Although arrest statistics cannot readily track firearm use in specific serious crimes other than homicide, firearm use in violent crimes declined among persons of all ages between 1993 and 1998. 7. The steep rise and fall in arrest rates for homicide over the past two decades have been matched by similar, but less dramatic changes in some of the other indicators of violence, including arrest rates for all violent crimes and incident rates from vic tims' self-reports. This pattern is not matched by arrests for selected offenses, such as aggravated assault, or incident rates and prevalence rates from offenders' self-reports. 8. Young men-particularly those from minority groups-are disproportionately arrested for vio lent crimes. But self-reports indicate that differ ences between minority and majority populations and between young men and young women may not be as large as arrest records indicate or con ventional wisdom holds. Race/ethnicity, consid ered in isolation from other life circumstances, sheds little light on a given child's or adolescent's propensity for engaging in violence. 9. Schools nationwide are relatively safe. Compared to homes and neighborhoods, schools have fewer homicides and nonfatal injuries. Youths at greatest risk of being killed in school-associated violence are those from a racial or ethnic minority, senior high schools, and urban school districts. # Chapter 3 1. There are two general onset trajectories for youth violence-an early one, in which violence begins before puberty, and a late one, in which violence begins in adolescence. Youths who become vio lent before about age 13 generally commit more crimes, and more serious crimes, for a longer time. These young people exhibit a pattern of escalating violence through childhood, and they sometimes continue their violence into adulthood. 2. Most youth violence begins in adolescence and ends with the transition into adulthood. 3. Most highly aggressive children or children with behavioral disorders do not become serious vio lent offenders. 4. Surveys consistently find that about 30 to 40 per cent of male youths and 15 to 30 percent of female youths report having committed a serious violent offense by age 17. 5. Serious violence is part of a lifestyle that includes drugs, guns, precocious sex, and other risky behaviors. Youths involved in serious violence often commit many other types of crimes and exhibit other problem behaviors, presenting a serious challenge to intervention efforts. Successful interventions must confront not only the violent behavior of these young people, but also their lifestyles, which are teeming with risk. 6. The differences in patterns of serious violence by age of onset and the relatively constant rates of individual offending have important implications for prevention and intervention programs. Early childhood programs that target at-risk children and families are critical for preventing the onset of a chronic violent career, but programs must also be developed to combat late-onset violence. 7. The importance of late-on set violence prevention is not widely recognized or well understood. Substantial numbers of serious violent offenders emerge without warning signs in their childhood. A comprehensive community prevention strategy must address both onset patterns and ferret out their causes and risk factors. # Chapter 4 1. Risk and protective factors exist in every area of life-individual, family, school, peer group, and community. Individual characteristics interact in complex ways with people and conditions in the environment to produce violent behavior. O 2. Risk and protective factors vary in predictive power depending on when in the course of devel opment they occur. As children move from infan cy to early adulthood, some risk factors will become more important and others less important. Substance use, for example, is a much stronger risk factor at age 9 than it is at age 14. 3. The strongest risk factors during childhood are involvement in serious, but not necessarily violent criminal behavior, substance use, being male, physical aggression, low family socioeconomic status or poverty and antisocial parents-all indi vidual or family characteristics-or conditions. . During adolescence, the influence of family is largely supplanted by peer influences. The strongest risk factors are weak ties to convention al peers, ties to antisocial or delinquent peers, belonging to a gang, and involvement in other criminal acts. 5. Risk factors do not operate in isolation-the more risk factors a child or young person is exposed to, the greater the likelihood that he or she will become violent. Risk factors can be buffered by protective factors, however. An adolescent with an intolerant attitude toward deviance, for example, is unlikely to seek or be sought out by delinquent peers, a strong risk factor for violence at that age. 6. Given the strong evidence that risk factors predict the likelihood of future violence, they are useful for identifying vulnerable populations that may benefit from intervention efforts. Risk markers such as race or ethnicity are frequently confused with risk factors; risk markers have no causal rela tion to violence. 7. No single risk factor or combination of factors can predict violence with unerring accuracy. Most young people exposed to a single risk factor will not become involved in violent behavior; similar ly, many young people exposed to multiple risks will not become violent. By the same token, pro , tective factors cannot guarantee that a child exposed to risk will not become violent. # Introduction Chapter 5 1. A number of youth violence intervention and pre vention programs have demonstrated that they are effective; assertions that "nothing works" are false. 2. Most highly effective programs combine compo nents that address both individual risks and envi ronmental conditions, particularly building indi vidual skills and competencies, parent effective ness training, improving the social climate of the school, and changes in type and level of involve ment in peer groups. 3. Rigorous evaluation of programs is critical. While hundreds of prevention programs are being used in schools and communities throughout the coun try, little is known about the effects of most of them. 4. At the time this report was prepared, nearly half of the most thoroughly evaluated strategies for pre venting violence had been shown to be ineffec tive-and a few were known to harm participants. In schools, interventions that target change in the social context appear to be more effective, on average, than those that attempt to change indi vidual attitudes, skills, and risk behaviors. 6. Involvement with delinquent peers and gang membership are two of the most powerful predic tors of violence, yet few effective interventions have been developed to address these problems. 7. Program effectiveness depends as much on the quality of implementation as the type of interven tion. Many programs are ineffective not because their strategy is misguided, but because the quali ty of implementation is poor. # P r e p a r a t io n o f t h e R e p o r t To address the troubling presence of violence in the lives of U.S. youths, the Administration and Congress urged the Surgeon General to develop a report on youth violence, with particular focus on the scope of the prob lem, its causes, and how to prevent it. Surgeon General Dr. David Satcher requested three agencies, all compo nents of the Department of Health and Human Services, to share lead responsibility for preparing the report. The agencies are the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Substance Abuse and Mental Health Services Administration (SAMHSA). Under Dr. Satcher's guidance, these agencies established a Planning Board comprising individuals with expertise in diverse disciplines and professions involved in the study, treatment, and prevention of youth violence. The Planning Board also enlisted individuals representing various Federal departments, including particularly the Department of Justice (juve nile crime aspects of youth violence), the Department of Education (school safety issues), and the Department of Labor (the association between youth violence and youth employment, and out-of-school youth). Invaluable' assistance was obtained as well from individual citizens who have founded and oper ate nonprofit organizations designed to meet the needs of troubled and violent youths. Most important, young people themselves accepted invitations to become involved in the effort. All of these persons helped to plan the report and participated in its prepublication reviews. # Introduction Rand, M. R., Lynch, J. R, & Cantor, D. (1997). Criminal victimization, 1973 # H eadlines proclaim that the epidemic of youth violence that began in the early 1980s is over, but the reality behind this seemingly good news is far more complex and unsettling. Public health stud ies show that youth violence is an ongoing, startling ly pervasive problem. This chapter describes the magnitude of and trends in violent crime by young people, focusing on homicide, robbery, aggravated assault, and forcible rape (see Box 2-1 for defini tions). A later chapter (Chapter 4) seeks to explain why young people become involved in violence in the first place. # M e a s u r in g Y o u t h V io l e n c e Surveillance is the backbone of the public health approach to youth violence or any other public health problem. It reveals the magnitude of a problem, tracks the magnitude over time, and uses the information gained from such monitoring to help shape actions to prevent or combat the problem. Two approaches to measuring the magnitude of youth violence are commonly used. The first relies on official crime statistics compiled by law enforcement agencies, typically arrest reports. These statistics can not answer questions about how many young people commit violent crimes or how many violent crimes were committed, but they can answer questions about the number of crimes reported to the police, the vol ume and types of arrests, and how the volume changes over time. The second approach surveys young people and asks them in confidence about violent acts they have committed or have been victims of during a given period of time. Such reports can be obtained from the same group of people over a long period of time (a lon gitudinal survey) or from different groups of people at # Criminal Homicide-Murder and Non Negligent Manslaughter The willful (non-negligent) killing of one human being by another. # Robbery The taking or attempting to take anything of value from the care, custody, or control of a person or persons by force or threat of force or violence and/or putting the victim in fear. # Aggravated Assault An unlawful attack by one person upon another wherein the offender uses a weapon or displays it in a threatening manner, or the victim suffers obvious severe or aggravated bodily injury involving appar ent broken bones, loss of teeth, possible internal injury, severe laceration, or loss of consciousness. # Forcible Rape The carnal knowledge of a person, forcibly and/or against that person's will, or not forcibly or against the person's will where the victim is inca pable of giving consent because of his/her tempo rary or permanent mental or physical incapacity (or because of his/her youth). the same point in time (a cross-sectional survey). A prominent example of a repeated cross-sectional sur vey cited in this chapter is Monitoring the Future, a survey of high school seniors, that has been conducted annually since 1975. Reports from young people them selves offer the best way to measure violent behavior that never reaches the attention of the justice system. In fact, evidence in this chapter makes it unmistakably clear that most crimes by young people do not reach the attention of the justice system. Self-reports are well suited to answering such questions as: What proportion of youths are violent? What types of violent acts do they commit? Has the volume of violence changed over time? Are there dif ferences by sex and race/ethnicity? When during development does violence arise, and what forms does it take? How do children's patterns of violence evolve over time, and how long do they last? These questions relate to the magnitude of violent behavior and to its developmental pathways, and they are addressed in this chapter and the next. Both arrest reports and self-reports are reason ably valid and reliable ways of measuring the partic ular aspects of violence they were designed to meas ure (for general reviews see Blumstein et al., 1986;Hindelang et al., 1981;Huizinga & Elliott, 1986). Arrests appear to be more objective, but they are not a good general measure of violent behavior, for sev eral reasons. First, the majority of aggravated assaults, robberies, and rapes are never reported to the police; arrests are made in fewer than half of reported crimes Maguire and Pastore, 1999;; and most youths involved in violent crimes are never arrested for a violent crime . Thus, arrests seriously underestimate the volume of violent crime and fail to distinguish accurately between those who are and are not involved in violence. Second, arrest records do not accurately reflect the distribution of reported vio lent crimes; that is, the offenses for which youths are arrested are not representative of the crimes reported to police . Nonetheless, arrest records are the best measure of the justice system's response to observed or reported crime. Self-reports were designed specifically to over come the limitations of violence measures based on official records of criminal behavior. They provide a more direct measure of criminal behavior, but they too have their limitations. Youths may fail to report their violent behavior accurately, either deliberately or because of memory problems, and they may exaggerate their involvement, reporting rather trivial events in response to questions about serious forms of violence. Research reveals that exaggeration (overreporting) is a greater problem than underreporting for reports that cover the previous year , but sophisticated self-report measures can minimize these potential sources of error Huizinga & Elliott, 1986). The advantages of self reports are that they capture not only unreported offens es but also details not found in arrest records. In' addi tion, this measure of violent offending is not subject to any of the biases that might be involved in arrest processes.' The general conclusion from studies evalu ating the validity and reliability of self-reports is that they compare favorably with other standard, accepted social science indicators (Hindelang et al., 1981). Both types of measures contribute to our under standing of violence. The key to using them is to understand their relative strengths and limitations, determine where they reinforce each other and where they diverge or conflict, and then interpret the differ ences in findings, if possible (Brener et al., 1995;Hindelang et al., 1981;Huizinga & Elliott, 1986;. # T h e V io l e n c e Ep id e m ic Arrest rates of young people for homicide and other violent crimes skyrocketed from 1983 to 1993. In response to the dramatic increase in the number of Questions have been raised about potential racial/ethnic biases in both types o f measures. There is evidence that arrests o f whites, compared to those o f African Americans, are underrepresented in local arrest records and archives (Ceerken, 1994). Some studies find racial/ethnic bias in arrests and other justice system processing, w h ile others do not (for reviews, see Austin & Allen, 2000;Hawkins et al., 1998;Sampson & Lauritsen, 1997). Comparisons o f an individual's arrest and self-reported offenses reveal a greater discrepancy for African Americans than whites, w ith African American males self-reporting fewer o f the offenses found in their official records (Hindelang et al., 1981;Huizinga & Elliott, 1986). If one accepts the accuracy o f arrest records, this finding w ould indicate an underreporting on the part o f African American males, but there are reasons to question this assumption (see Elliott, 1982;Huizinga & Elliott, 1986). The question o f racial/ethnic bias in both asures remains controversial. murders committed by young people, Congress and many state legislatures passed new gun control laws, established boot camps, and began waiving children as young as 10 out of the juvenile justice system and into adult criminal courts. Then, starting in the mid-1990s, overall arrest rates began to decline, returning by 1999 to rates only slightly higher than those in 1983. Several important indicators were used to track youth violence during these years, but their findings did not always agree. Arrest rates, as noted above, pro vide strong evidence of both a violence epidemic between 1983 and 1993/1994 and a subsequent decline to 1999. Several other indicators of violence furnish similar, but not as robust evidence of a violence epi demic that later subsided. However, the decline in arrest rates is not uniform for all types of violent crime. Moreover, another key indicator-the volume of vio lent behavior, which is based on self-reports-does not show a decline in youth violence after 1993. As explained later, that indicator remained high and essen tially level from 1993 to 1998. This chapter answers the questions raised by these disparate findingsnamely, whether the epidemic of violence is really over and why leading indicators of youth violence do not agree. . A rise and subsequent decline in the use of firearms and other weapons by young people provides one potential explanation for the different trends in arrest records and self-reports. The violence epidemic was accompanied by an increase in weapons carrying and use. During this era, instant access to weapons, especially firearms, often turned an angry encounter into a seriously violent or lethal one, which, in turn, drew attention from the police in the form of an arrest. As weapons carrying declined, so too did arrest rates, perhaps because the violence was less injurious or lethal. But the amount of underlying violent behavior (on the basis of self-reports) did not change much-if anything, it appears to have increased in recent years. That undercurrent of violent behavior could reignite into a new epidemic if weapons carrying rises again. From a public health perspective, a resurgence of weapons carrying-and hence the potential for anoth er epidemic of violence-poses a grave threat. # A r r e s t s f o r V io l e n t C r im e s The Federal Bureau of Investigation (FBI) monitors arrests made by law enforcement agencies across the United States through the Uniform Crime Reporting (UCR) program. Since the 1930s, this program has compiled annual arrest information submitted volun tarily by thousands of city, county, and state police agencies. This information currently comes from police jurisdictions that represent only 68 percent of the population, so FBI figures represent projections of these data to the entire U.S. population . The UCR tabulates the number, rate, and certain features of arrests made by law enforcement agencies. Because some people are arrested more than once a year, the UCR cannot provide an accurate count of the number of people arrested or the proportion of the total population arrested (the prevalence). Nor can the UCR provide an accurate count of the number of crimes committed. A single arrest may account for a series of crimes, or a single crime may involve the arrest of more than one person. Young people tend to commit crimes in groups, so the number of youths arrested inflates the number of crimes committed . As noted earlier, arrest rates are also prone to certain types of error. Unless indicated otherwise, the figures on arrests were assembled by the FBI. # Arrest Rates and Trends As shown in Figure 2-1, overall arrest rates for vio lent crimes by youths between the ages of 10 and 17 rose sharply from 1983 to 1993/1994. Rates then declined until 1999, the most recent year for which figures are available. Figure 2-2, page 21, shows arrest rates for each of the four violent crimes considered in this report. In 1999, arrests of young people for all crimes totaled 2.4 million (Snyder, unpublished), with 104,000 arrests for violent crimes. Arrests for aggravated assault (69,600) and robbery (28,000) were the most frequent, with arrests for forcible rape (5,000) and murder (1,400) trailing significantly behind. In 1998, youths crimes, a share that has decreased slightly (16 percent) in recent years (Snyder, unpublished). Although the 1999 arrest rate for violent crimes was the lowest in this decade, it is still 15 percent higher than the 1983 rate (Snyder, unpublished). As seen in Figure 2-2, the 1999 rates for homicide, robbery, and rape are below the 1983 rates; however, arrests for aggravated assault are still nearly 70 percent higher than 1983 rates. The sheer magnitude of the increase in arrest rates between 1983 and 1993/1994 is striking. Overall, arrest rates of youths for violent offenses grew by about 70 percent. The increase in homicides commit ted by young people was particularly alarming. Both the rate of homicide arrests and the actual number of young people who were arrested for a homicide near ly tripled . This increase was consistent for adolescents at each age between 14 and 17 . The decade-long upsurge in homicides was tied to an increased use of firearms in the commission of crimes (Cherry et al., 1998;. Likewise, the downward trend in homicide arrests from 1993 to 1999 can be traced largely to a decline in firearm usage. The critical role of firearms in homicide and other violent crimes is supported by arrest, victim ization, hospitalization, and self-report data. Analysis of arrest data (Figure 2-3, page 22) shows an unequivocal upsurge in firearm usage by young people who committed homicide. In 1983, youths were equally likely to use firearms and other weapons, such as a knife or club, to kill someone. By 1994, 82 percent of homicides by young people were committed with firearms . Virtually all of the increase in firearm-related homi cides involved African American youths . The precipitous drop in homicides between 1994 and 1998 coincided with a decline in firearm usage, again mostly by African American youths . of firearm use. A large increase in the number of young people killed by firearms between 1987 and 1993 was followed by a decrease. More than 2,000 youths were homicide victims in 1993, the peak year . Most victims were male, and a disproportionately high percentage were African American males . The use of firearms in violent crimes other than homicide cannot readily be tracked in youth arrest sta tistics, but for Americans of all ages, firearm use in violent crimes increased from 1985 to 1992 and then declined from 1993 to 1998. Firearm use during rob beries increased 33 percent between 1985 and 1992; the decline in firearm use from 1993 to 1998 was nearly 20 percent for aggravated assaults but only 6 Firearm use can also be tracked indirectly, through victims treated in hospital emergency depart ments. Since 1992, injuries related to firearms have been monitored through an emergency department surveillance system.- 3 Although there are no data from this source to corroborate the growing pattern of firearm injuries before 1992, there are data to corrob orate the decline since then. Figure 2-A presents a spe cial analysis of emergency department surveillance data on youths age 10 to 19. It shows that the rate of firearms-related injuries among young people treated in hospital emergency departments dropped by almost 50. percent from 1993 to 1998. Data on male youths alone reveal a similarly dramatic drop. Youths are victim s in about 27 percent o f homicides comm itted by other youths . 3 The National Electronic Injury Surveillance System (NEISS); NEISS is operated by the U.S. Consumer Product Safety Commission. . A O On 1 or more of the 30 days preceding the survey. 95% confidence intervals for carried weapon = ± 1.3-2.3; for carried weapon at school = ± 0 .9-1.5; and for carried gun = ± 0 .8 -1 .3 . In the early 1990s, high school students began to report that they were increasingly less likely to carry guns anywhere and specifically less likely to carry them to school. Figure 2-5 illustrates these trends, as well as trends in general weapons carrying, based on data from the Youth Risk Behavior Survey (YRBS).4 Each trend shows a significant linear decrease, although the decline in weapons carrying in general leveled off in 1999 CDC, 2000a;Kann et al., 2000). Thus, there has been an upsurge and then a decline in the use of firearms and weapons over the past two decades. The easy availability of guns and the resulting rise in lethal violence was caused at least in part by the emerging crack cocaine markets in the mid-1980s and the recruitment of youths into these markets, where carrying guns became routine (Blumstein & Wallman, 2000). It also resulted from changes in the types of guns manufactured, with cheaper, larger caliber guns flooding the gun markets (Wintemute, 2000). The reasons for the decline are complex and not well understood, but they do involve changes in the car rying and use of guns in violent encounters (Blumstein & Wallman, 2000). The explanations most often given are a decline in youth involvement in the crack market and in gang involvement in crack distribution, police crackdowns on gun carrying and illegal gun purchases, longer sentences for violent crimes involving a gun, a strong economy, and expanded crime and violence pre vention programs. After reviewing these and other potential explanations for the drop in violence, Blumstein and Wallman (2000) concluded that no sin gle factor was responsible; rather, the decrease in vio lence resulted from the combination of many factors. # Comparing Arrests to Other Trends As noted above, the steep rise and fall in arrest rates over the past two decades has been matched to some extent by changes in leading indicators of violence. Figure 2-6 tracks the trends in four indicators: arrest rates for homicide only, arrest rates for all serious vio lent crimes, incident rates from victims' self-reports, and incident rates from offenders' self-reports. The incident rate is a measure of the volume of violence. It refers to the number of self-reported vio lent acts within a given-sized population-in this case, the number of violent acts per 1,000 young peo ple. In contrast, the prevalence rate indicates what proportion of that population is involved in one or more violent behaviors. Figure 2-6 compares arrest rates with self-reported incident rates (rather than with prevalence rates) because both measure the volume of violent events. Even though arrest and incident rates measure different events and have different absolute magnitudes, the degree of change in these rates over time can be compared. 0 # Arrests Versus Self-Reported Incidents The sharpest increases in Figure 2-6 are for the two arrest indicators. Homicide arrest rates were roughly 170 percent higher in 1993 than in 1983, and arrest rates for all serious violent crimes were 70 percent higher. The incident rates of serious violent crimes reported by victims and the rates of serious assault and robbery reported by offenders increased to a lesser extent, by about 50 percent. By 1999, arrest rates for homicide, robbery, and rape had dropped below their 1983 levels; by 1997, victim-reported incident rates had dropped back to roughly their 1983 levels. Arrests for aggravated assaults remained high, however-at almost 70 per cent above their 1983 level. Since the peak year of arrests for aggravated assault (1994), arrests for this violent crime have declined only 24 percent. Self-reported violent offending showed no decline at all. After rising by about 50 percent, the incident rate of self-reported serious assaults and robbery remained essentially level through 1998.. The leveling off of This self-reported incident rate appears to be much higher (e.g., almost 400 assaults w ith injury and robberies w ith a weapon were reported per 1,000 high school seniors in 1998) than the arrest rate for aggravated assault and robbery (about 350 arrests per 100,000 youth, see Figure 2-2), but the tw o are not strictly comparable: high school seniors (17-and 18-year-olds) have much higher arrest rates as a group than do 10-to 17-year-olds. The MTF prevalence estimates for both violent behavior and drug use have been confirm ed by other studies in which there is overlap in years and ages. For example, see and Menard and Elliott (1993). About 16,000 high school seniors at 130 schools participate, although only about 3,000 o f the students are asked questions about their v io lent behavior. Since the beginning o f the survey in 1975, the participation rate among schools has ranged from 60 to 80 percent, and the stu dent response rate has ranged from 77 to 86 percent (Kaufman et al.,199?' determining the extent of youth violence. They fur nish a window into violent behavior that never reach es the police. For example, the National Crime Victimization Survey reveals that the majority (58 percent) of serious violent crimes committed by youths are not reported to the police . A large fraction of the crimes that are reported never result in an arrest. Estimates indi cate that only 6 to 14 percent of chronic violent offenders are ever arrested for a serious violent crime (Dunford & Elliott, 1984;Elliott, 2000a;Huizinga et al., 1996;. The MTF gathers data about five acts of violence and from them compiles a violence index (see Figure 2-8 for the specific offenses included). This violence index is not the same as the UCR violent crime index, which aggregates the four types of arrests covered in this chapter. According to the MTF's vio lence index, about 3 out of 10 high school seniors reported having committed a violent act in the past year, an annual prevalence rate of about 30 percent. The M TF's violence index has been relatively stable for almost 20 years, in sharp contrast to the. dramat ic increase in arrests. ' Although the prevalence rate of self-reported vio lent behavior is relatively constant, it is still strikingly high, partly because high school seniors age 17 and 18 are at the peak ages of violent offending and partly because the violence index includes some less serious violent behaviors as well as some very serious ones. Because this report focuses on violent behavior carrying the potential for serious injury or death, Figure 2-8 also includes the prevalence rates of assault with injury and robbery with a weapon, the two most serious acts in the MTF violence index. An assault with injury could lead to an arrest for aggravated assault; likewise, a robbery with a weapon could lead to an arrest for armed robbery. Therefore, assault with injury and rob bery with a weapon may be used as proxy measures for aggravated assault and armed robbery, respectively. Over the past two decades, the MTF's prevalence rates for assault with injury ranged from 10 to 15 per cent (± 1.3 to 1.8). A small but significant increase took place between 1979 and 1998. About half of this increase occurred between 1983 and 1993, but rates remained fairly constant after 1993 (the increase from 1993 to 1998 shown in Figure 2-8 is not statistically significant). The prevalence of robbery with a weapon ranged from 2 to 5 percent (± 0.7 to 1.1) between 1983 and 1993 and remained constant thereafter. Thus, unlike arrest data, MTF data show no evidence of a downward trend in self-reported assaults or robberies after 1993. Prevalence rates of this magnitude-10 to 15 per cent of high school seniors8-for the most serious types of violence are confirmed by other self-report surveys described in Chapter 3. For example, an aver age prevalence rate of 9 percent (± 2.0) was reported for 17-year-olds between 1976 and 1982 in the National Youth Survey, whose measure of violence includes aggravated assault, robbery, gang fights, and rape. This rate is similar to the MTF's, but the National Youth Survey measure includes more serious violent offenses. Two general city surveys-the Denver Youth Survey and the Rochester Youth Development Survey, which use the same measure of violence as the National Youth Survey-report some what higher prevalence rates among 17-year-olds: 12 percent (± 1.6) and 14 percent (± 2.0), respectively.9 # International Prevalence Are U.S. youths unique in reporting a high prevalence of violent behavior? How do they compare to their European counterparts? The answers can be found by comparing the MTF findings with the International Self-Report Delinquency Study (Junger-Tas et al., 1994), a study of delinquent behavior conducted in several European countries. Like the MTF, this study relies on self-reported behavior. Of the countries included, only England/Wales, the Netherlands, Spain, and Italy used a probability sample that provided national estimates of violence comparable to the violence index used in the MTF survey. Self-reported serious violence # Year Sources: Rates for violence index: Johnston, 2000; rates for assault with injury and robbery with weapon: Maguire and Pastore, 1999. Entries above are 3-year running averages of the prevalence of each of the specified acts. The violence index is defined as the percent committing any of the specified following five acts, with no missing data allowed: hit an instructor or supervisor; gotten into serious fight in school or at work; taken part in a fight where a group of your friends were against another group; hurt somebody badly enough to need bandages or a doctor (assault with injury); used a knife or gun or some other thing (like a club) to get something from a person (robbery with a weapon). 95% confidence intervals for the violence index are all less than ± 2.5%; for assault, less than ± 2%; for robbery, less than ± 1.1%. among young people age 16 to 17 in these countries in 1992 or 1993 ranged from 16 to 26 percent (Table 2-1). These prevalence rates are lower than the U.S. rate of about 30 percent for the MTF's violence index. Thus, while the questions in the international study may be somewhat different, the findings show that while a higher proportion of U.S. youths commit vio lent acts, youth violence is not unique to the United States. A major difference between the United States and several other industrial countries is the ease of access to firearms. From 1990 to 1995, the United States had the highest rate of firearm-related deaths among youths in the industrialized world (CDC, 1997). The rate for children below age 15 was five times higher than that of 25 other countries combined. In summary, youth violence, although interna tional in scope, is greater in the United States, more likely to involve firearms, and more lethal in its con sequences. According to self-reports, both the preva lence and incidence (volume) of assault and robbery increased among U.S. high school seniors between 1983 and 1993. This finding is consistent with an epi demic of violence among U.S. youths, although self reports point to a more modest upsurge than arrest trends do. However, both self-reports and arrest rates for aggravated assault point to an ongoing problem of youth violence after the apparent end of the violence epidemic. Thus, the rise and fall in arrest rates for most violent offenses is set against more enduring rates of violent behavior. # D if f e r e n c e s b y S ex a n d Ra c e /Et h n ic i t y Self-reported violence and arrest rates for violent offenses can also be compared by sex and by race/ethnicity. Ratios based on these two sources of data show similar findings with respect to sex but remarkably different findings with respect to race/ethnicity-dif ferences that have yet to be fully explained. , 1983 to 1993 and 1993 to 1998. In gen eral, there was little change in those periods, with one exception. In 1983 and 1993, the ratios of male to female youths committing violent acts were 7.4 to 1 and 7.0 to 1, respectively. This means that for every violent act committed by female youths in these years, at least seven violent acts were committed by male youths. By 1998, this ratio had closed to 3.5 to 1, indicating that O l. -M liE S T C O P Y A V A ILA B LE females are closing the gap. The difference in preva lence rates changed little over the same period, but at a ratio of 2 to 1, it was much smaller to begin with. Taken together, the trends show that the proportions of males and females involved in violence (the. preva lence rate) have not changed but that the relative num ber of violent acts by males and females (the incident rate) has changed, with females committing more vio lent acts in 1998 than in earlier years. Differences by race are also presented in Table 2-2. The only available national comparisons for seri ous violence are for white and African American youths (see Chapter 3 for local longitudinal studies that include rates for Hispanic youths). Overall, inci dent rates are lower for white than African American youths over these years; the gaps are largest in 1993 and 1998, when approximately 1.5 violent acts were 49 ---------------" committed by African Americans for every 1 violent act b y whites. The racial gap appeared to increase somewhat during the violence epidemic and has remained higher through 1998. There are essentially no differences by race in the prevalence rates for seri ous self-reported violent behavior. # Differences in Arrest Rates Arrest rates differed widely by sex and by race/ethnicity between 1983 and 1998 (Table 2-3). Overall, the dif ference was greater by sex than by race/ethnicity and was most evident in regard to homicide arrests: In 1998, 11 times as many males were arrested as females. A sim ilar male-female gap was evident for robbery, but the gap for aggravated assault was considerably smaller. Trends in the male-female gap vary, depending on the crime for which youths are arrested. From 1983 to 1993, the male-female disparity in homicide arrests doubled: In other words, the violence epidemic was driven by arrests of males. During the same period, the male-female gap in arrests for both robbery and aggravated assault shrank. More recently, from 1993 to 1998, the male-female disparity in all three types of arrests has held constant or declined further. Differences in arrest rates by sex are similar in magnitude to differences in self-reported violent inci dents. Combining aggravated assault and robbery arrest data yields male:female ratios of 6.8 to 1, 5.7 to 1, and 4.3 to 1 for 1983, 1993, and 1998, respective ly.10 The ratios for self-reported incidents were 7.4 to 1, 7.0 to 1, and 3.5 to 1 (Table 2-2). Thus, both self report and arrest rates attest to a difference by sex in the volume of violence but also to a narrowing of that gap between 1983 and 1998-except for homicide arrests. Possible reasons for the male-female gap are discussed in Chapter 4. Self-reports and arrest rates provide different pic tures of violent offending by race. Self-reports, as noted above, reveal small differences between African American and white youths. Arrest records, on the other hand, reveal large differences, even though these gaps narrowed between 1993 and 1998 (Table 2-3). The narrowing of the gap was particularly noteworthy for homicide arrests: Whereas about nine African American youths were arrested for every white youth in 1993, only about five were arrested for each white youth in 1998. Even at 5 to 1, the ratio of African American to white youths arrested for homicide remains greater than that of Native American or Asian youths to white youths. Ratios cannot be calculated for Hispanic youths because data for this ethnic group are not broken out in the UCR or other systematic data collection sys tems (Soriano, 1998). A few regional and city studies suggest that homicide arrest rates for Hispanic males are substantially higher than those for non-Hispanic white males and that African American males typical ly have the highest rates (Prothrow-Stith & Weissman, 1991;Smith et al., 1988;Sommers & Baskin, 1992;Zahn, 1988). The difference between homicide arrests of Hispanic and non-Hispanic white youths is sub stantial in these studies, but it is not as great as the dif ference between African American and white youths. The existence of much larger racial and ethnic dif ferences in arrest rates than in self-reported violence is a matter of great concern. On the one hand, there is no reason to expect similar distributions, because these measures were designed to assess different aspects of violence. But if both measures are valid and reliable, the discrepancy suggests that the probability of being arrested for a violent offense varies with race/ethnici ty. Explanations for this discrepancy focus on selective reporting of offenses to the police, different patterns of police surveillance, racial/ethnic biases in self-report measures, and racial/ethnic bias on the part of police, victims, and witnesses. Some studies have explored these explanations, but their findings are not definitive (Austin & Allen, 2000;Blumstein et al., 1986;Hawkins et al., 1998;Sampson & Lauritsen, 1997). This complex issue will also be discussed in Chapter 3, which considers other dimension's of violent offending. Arrest ratios of Native American" to white youths are similar, except for the homicide ratio in 1998. Similarly, arrest rates of Asian Americans for homicide and robbery differ little from those of whites, but at least two whites are arrested on charges of rape or aggravated assault for every Asian American. Possible reasons for these differences have not been well studied. In sum, racial and ethnic differences in rates of violence are greater in arrest statistics than in self reports of violent behavior. The reasons are not well understood, with conflicting evidence from various studies. Self-reports and arrest records produce simi lar estimates of trends in violence by sex: Violent behavior still occurs more often among male than female youths, but the gap has been narrowing. # V io l e n c e a t Sc h o o l Recent shootings at schools have galvanized public concern about school safety, but studies described here find that schools nationwide are relatively safe. In contrast to public perceptions, schools have fewer homicides and nonfatal injuries than homes and neighborhoods. However, some students are at greater risk of being killed or injured at school than othersspecifically, senior high school students from racial or ethnic minorities who attend schools in urban districts (Kachur et al., 1996). # Homicides and Nonfatal Injuries Two nationwide studies of school homicides have been conducted by the Centers for Disease Control and Prevention in collaboration with the U.S. Departments " The 1998 arrest rate was atypically high for the 1993-1999 period. This rate was tw ice the rate for every other year over this period and ^-'"p e a rs to be an anomaly. -f Education and Justice. The first study covered a 2year period from July 1992 through June 1994 and identified 68 students who were killed on or near school grounds or at school-related events (Kachur et al., 1996). Most of the victims were male and were killed with a firearm. These homicides represent less than 1 percent of all youth homicides in the period studied, and the estimated incidence of school-associated vio lent death was 0.09 per 100,000 student-years.12 Those at greatest risk of being killed were from racial or eth nic minorities, from senior high schools, and from urban school districts. The homicide rate in urban schools, for example, was nine times greater than the rate in rural schools. Most offenders and victims alike were male, under age 20, and from a racial or ethnic minority. The most common motives were an interper sonal dispute or gang-related activities. The second study, using the same methodology, updated the figures through June 1999 (CDC, 2000a). It identified 177 students age 5 to 19 who were killed in this 5-year period; the vast majority of the homi cides (84 percent) involved firearms. School-associat ed homicides remained at less than 1 percent of all homicides among students, but the frequency of homi cides involving more than one victim increased. The three school years from August 1995 through June 1998 saw an average of five multiple-victim homi cides or homicide-suicides per year. An average of one such event occurred in each of the 3 years from August 1992 through July 1995. Thus, trends throughout the 1990s show that the number of school homicides has been declining. Yet within this overall trend, homicides involving more than one victim appear to have been increasing. In regard to nonfatal injuries at school, the National Crime Victimization Survey found in 1998 that the rate of serious violent crimes against youths age 12 to 18 was one-half as great when they were at school as when they were not. At school, the highest victimization rates were among male students and younger students (age 12 to 14) (Kaufman et al., 2000). The rate was highest in urban schools in 1992, but by 1998 the rates at urban, suburban, and rural schools were similar. Overall, cr Q between 1992 and 1998, the rate of serious violent crimes at school remained relatively stable at about 8 to 13 per 1,000 students (Kaufman et al., 2000). The stability of this trend is corroborated by the MTF survey, which asks high school seniors whether they have been victims of violence. The percentage of seniors reporting that they had been injured with a weapon at school remained stable at about 5 percent from 1976 to 1998 (Flanagan & Maguire, 1992;Maguire & Pastore, 1999) (Figure 2-9). The same vic timization rate is reported by the National Study of Delinquency Prevention in Schools for 1998 (Gottfredson et al., 2000). However, the MTF trend masks large fluctuations in victimization reported by African American students (Figure 2-9). From 1980 to 1998, between 4 (± 2.8) and 13 (± 3.6) percent of African American students reported having been injured with a weapon at school. # Weapons at School Recent findings regarding students carrying weapons (a gun, knife, or club, for example) at school are encouraging. In 1999, the Youth Risk Behavior Survey (YRBS) found that about 7 percent of all high school students reported carrying a weapon on school proper ty within the last 30 days (Kann et al., 2000) (Figure 2-5). In 1993, almost 12 percent of high school stu dents reported carrying a weapon at school in the last 30 days (Kann et al., 1995), a 42 percent decrease Kann et al., 2000). A somewhat less pronounced decline was apparent among high school seniors in the MTF survey (Kaufman et al., 1998). Both studies found the problem to be of rough ly the same magnitude: In 1995, about 6 to 8 percent of 12th graders reported carrying a weapon at school at least once during the past month. Evidence of an upsurge in the number of students carrying weapons at school before 1993 is less clear. The YRBS first asked this question in 1993, and the MTF did not ask until the 1990s. Nonetheless, smaller or less representative studies suggest a substantial increase in weapon carrying between the 1980s and the early 1990s (reviewed in Elliott et al., 1998). Entries are 3-year running averages of the percentage of 12th graders who reported that someone had injured them with a weapon at school during the past 12 months. Examples of weapons are knives, guns, and clubs. "At school" means inside or outside the school building or on a school bus. 95% confidence intervals for total sample and whites are less than ± 1.5%; for African Americans, less than ± 4.6%. # Perceptions of School Violence Although the overall risk of violence and injury at school has not changed substantially over the past 20 years, both students and their parents report being increasingly apprehensive about their schools. Studies reveal that, during the early 1990s, students grew more fearful about being attacked or harmed at school and that they were avoiding certain places within their schools (Kaufman et al., 1998). By 1999, these fears had subsided somewhat (Kaufman et al., 2000), but parents still say they are afraid for their children at school. A recent Gallup poll found that nearly half of the parents surveyed feared for their children's safety when they sent them off to school, whereas only 24 percent of parents reported this concern in 1977 (Gallup, 1999a). In May 1999, shortly after the shoot ings at Columbine High School in Littleton, Colorado, 74 percent of parents said that a school shooting was very likely or somewhat likely to happen in their com munity (Gallup, 1999b). O Public perceptions about school safety seem at odds with the evidence that the risk for serious violence at school has not changed substantially over the past 20 years. But several indicators of violence did increase during the epidemic-school fights, gangs, drug use, and students carrying weapons to school. While gangs and weapon carrying have declined recently, the rates of drug use and physical fighting are high and have not changed between 1991between and 1999between (Brenner et al., 1999). Today's school bullies are still more likely to be carry ing guns than those of the early 1980s, and the propor tion of students reporting that they felt too unsafe to go to school has not changed since the peak of the violence epidemic in the mid-1990s. These findings add to the concern that the violence epidemic is not yet over. # G a n g s a n d V io l e n c e Gang members, a relatively small proportion of the adolescent population, commit the majority of serious youth violence (see Spergel, 1990, for a review). In two major longitudinal studies in Denver and Rochester (discussed in more detail in Chapter 3), 14 to 30 percent of the youths surveyed were gang mem bers at some time during the study, and they account ed for 68 to 79 percent of the serious violence report ed . Similar findings have been reported in other studies using nonrandomized local samples (Battin et al., 1996;Fagan, 1990). In Rochester, 66 percent of chronic violent offenders were in gangs . A high proportion of gang members are also involved in drug sales and possessing/carrying a gun, two behaviors closely linked to serious violence. The 1999 National Youth Gang Survey (a national survey of law enforcement agencies) estimates that 46 percent of youth gang members are involved in street drug sales (Egley, 2000). In the Rochester study, 67 percent of youths reporting they owned/carried a gun for pro tection were gang members and 32 percent reported they sold drugs. Only 3 to 7 percent of non-gun own ers or sport gun owners were involved in drug selling. Further, 85 percent of youths who owned guns for pro tection were involved with peers who owned guns for protection . Rates of . violence are higher in schools where gangs are present. The rate of victimization in schools with gangs is 7.5 percent, compared to 2.7 percent in schools without gangs . Gangs are present not only in inner-city schools, but in many suburban and rural schools as well. Between 1989 and 1995, the proportion of students reporting gangs at their school increased from 15 percent to 28 percent . By 1999, how ever, that figure had dropped to 17 percent (Kaufman et al., 2000). A decline in the number of gangs in U.S. schools between 1996 and 1997 has also been report ed by law enforcement agencies (National Youth Gang Center, 1999). The National Youth Gang Survey reported more than 26,000 active youth gangs in schools and com munities in 1999, down 15 percent from 1996 (Egley, 2000). Yet the same survey reported more than 840,500 active gang members in 1999, a decline of less than 1 percent from the peak level in 1996. Thus, from this source, it appears that the number of youths actively involved in gangs remains very high. The racial/ethnic composition of gangs in 1999 was 47 percent Hispanic, 31 percent African American, 13 percent non-Hispanic white, and 7 per cent Asian. These rates have been relatively constant since 1990. In 1998, 92 percent of all gang members were male (National Youth Gang Center, 2000), although some evidence indicated that girls' involvement in gangs increased during the epidemic (Chesney-Lind et al., 1996;Chesney-Lind & Brown, 1999;. However, the National Youth Gang Survey reports a decline in female membership, with less than 2 percent of gangs nationwide reporting pre dominantly female membership. # C o n c l u s io n s The United States suffered an epidemic of violence in the decade from about 1983 to 1993. Arrest rates of young people for homicide and other violent crimes skyrocketed. Several other violence indicators con firmed an epidemic of violence during that period. There are three factors that appear to play a sig nificant role in this dramatic surge in lethal violence or injury: gangs, drugs, and guns. The combination of increased involvement in gangs, selling drugs on the street, and carrying guns for protection had lethal implications. And it was African American and Hispanic males who were disproportionately caught up in this set of circumstances. After 1993/1994, arrests and victims' reports of violence began to decline, returning in 1999 to rates only slightly higher than those in 1983. These declines come as welcome news. Yet several other leading indicators of violence remain high. Young people's self-reports of violence have not declined at all. Arrest rates for aggravated assault remain quite high. Some estimates of gang membership indicate that this prob lem remains close to levels at the peak of the epidem ic. Indeed, self-reported violent behavior is at least as high today as it was in 1993. Why has this important indicator of violence remained high while other indi cators have come down? A major reason is firearms usage. It is now clear that the violence epidemic was caused largely by an upsurge in the use of firearms by young people. Ready access to firearms during a violent confrontation often had grievous consequences. Youth violence became more lethal, resulting in dramatically higher rates of homicide and serious injury. This triggered reporting to and response from police, leading to higher rates of arrest. Although firearm usage may not cause vio lence, it clearly increases the severity of violence. Today's youth violence is less lethal, largely because of a decline in the use of firearms. Fewer young people today are carrying weapons, including guns, and fewer are taking them to school. Homicides at school are declining. Violent confrontations are less likely to result in killing or serious injury, and the police are less likely to be called in for an arrest. This is a heartening trend, but this is not the time for complacency. Violent behavior is just as prevalent today as it was during the violence epidemic. Some 10 to 15 percent of high school seniors reveal in confi dential surveys that they have committed at least one act of serious violence in the past year. This prevalence rate has been slowly yet steadily rising since 1980. There is also a difference by sex in the volume of violence. Male youths commit many more violent acts than female youths, according to both arrest records and self-reports. The existence of a racial difference between African American and white youths is more questionable. Arrest records indicate that many more African American than white youths commit violent crimes, whereas self-reports indicate much smaller racial differences in incident rates and nonexistent dif ferences in prevalence rates. The disparities between these two indicators of violence have not been satis factorily investigated, and more research on them is clearly warranted. Looking at all self-reported violent behavior, it is apparent that youth violence still poses a serious pub lic health problem. Should firearms once again become appealing and accessible to young people, the potential for a recurrence of the violence epidemic is quite real. The magnitude of serious violence occurring beneath the police radar should warn us that youth violence is ^'sistent problem demanding a focus on prevention. # M -st violence begins in the second decade of life. This chapter looks closely at childhood and adolescence as critical periods of development to trace how violence unfolds-its onset, duration, and t continuity into adulthood. It also examines violence in relation to other risky behaviors that emerge in adolescence. The dynamics of youth violence are best under stood from a developmental perspective, which recog nizes that patterns of behavior change over the life course. Adolescence is a time of tumultuous change and vulnerability, which can include an increase in the frequency and means of expression of violence and other risky behaviors. Understanding when and under what circumstances violent behavior typically occurs helps researchers craft interventions that target those critical points in development. Our understanding of developmental patterns de pends in large part on longitudinal studies, which track the same group of individuals over long periods of time, sometimes a decade or more. Four major longitu dinal studies are described in this chapter. They add new dimensions to the surveillance statistics presented in Chapter 2, and they provide essential background for Chapter 4, which deals with why young people become involved in violence. # Ea r l ya n d La t e -O n s e t T r a je c t o r ie s Longitudinal research has detected two prominent developmental trajectories for the emergence of youth violence, one characterized by an early onset of violence and one by a late onset. Children who com mit their first serious violent act before puberty are in the early-onset group, whereas youths who do not become violent until adolesence are in the late-onset group. While other developmental trajectories have been identified (D'Unger et al., 1998;, this report focuses on the early-and late-onset trajectories because they are recognized by most researchers, they debunk the myth that all seri ous violent offenders can be identified in early child hood, and they have strikingly different implications for prevention. In the early-onset trajectory, problem behavior that begins in early childhood gradually escalates to more violent behavior, culminating in serious violence before adolescence. A child's first serious violent act may have been officially recorded, or it may have been reported by the child to researchers in a confi dential survey. The early-onset group, in contrast to the late-onset group, is characterized by higher rates of offending and more serious offenses in adoles cence, as well as by greater persistence of violence from adolescence into adulthood (reviewed in Tolan &Gorman-Smith, 1998). The National Youth Survey shows that nearly 13 percent of male adolescents in the early-onset tra jectory engaged in violence for two or more years, compared to only 2.5 percent in the late-onset trajec tory (Tolan & Gorman-Smith, 1998). Between 20 and 45 percent of boys who are seri ous violent offenders by age 16 or 17 initiated their violence in childhood (D'Unger et al., 1998;Elliott et al., 1986;. A higher percentage of girls who were serious violent offenders by age 16 or 17 (45 to 69 percent) were violent in childhood (Elliott et al., 1986;. This means that most violent youths' begin their violent behavior during adolescence. However, the youths who commit most of the violent acts, who commit the most serious violent acts, and who continue their violent behavior beyond adolescence begin during childhood Moffitt, 1993;Tolan, 1987;Tolan & Gorman-Smith, 1998). The greater prevalence of late-onset youth vio lence refutes the myth that all serious violent offend ers can be identified in early childhood. In fact, the majority of young people who become violent show little or no evidence of childhood behavioral disor ders, high levels of aggression, or problem behav iors-all predictors of later violence. The implications of these findings for prevention are clear: Programs are needed to address both earlyand late-onset violence. Targeting prevention programs solely to younger children with problem behavior miss es over half of the children who will eventually become serious violent offenders, although universal prevention programs in childhood may be effective in preventing late-onset violence (see Chapters 4 and 6). # O n s e t a n d Pr e v a l e n c e o f S e r io u s V io l e n c e Much of what is known about the onset, prevalence, and other characteristics of serious violence during the adolescent years comes from four important longitu dinal surveys. The only nationally representative one is the National Youth Survey (NYS), an ongoing study of 1,725 youths age 11 to 17 in 1976, when the survey began (Elliott, 1994). These youths have been tracked by researchers for more than two decades and through nine waves, or points at which they were interviewed and/or their official records were sought to corrobo rate self-reported violence.2 The other three longitudinal studies cited here are city surveys sponsored by the U.S. Office of Juvenile Justice and Delinquency Prevention and the National Institutes of Health Thornberry et al., 1995).3 Beginning in 1988, three teams of researchers began to interview 4,500 youths age 7 to 15 in three cities-Denver, Pittsburgh, and Rochester (New York). These youths were monitored at different points from 1988 to 1994. Each sample disproportion ately represents youths at high risk of delinquency to ensure that it is large enough to draw valid conclu sions about delinquency and violence, but each also uses weighting procedures to yield locally representa tive estimates. The estimates presented here are based on weighted data. These four surveys define serious violence as aggravated assault, robbery, gang fights, or rape; an individual is labeled a serious violent offender if he or she reports committing any one or more of these offenses.4 Gang fights are included because follow-up information on these fights reveals that most of them involve injury serious enough to require medical attention (Elliott, 1994). Only the NYS reports the hazard rate for serious violence during the first two decades of life.5 The haz ard rate is the proportion of persons who initiate seri ous violence at a given age. Serious violence begins mostly between the ages of 12 and 20 (Figure 3-1). In fact, 85 percent of people who become involved in serious violence by age 27 report that their first act occurred between age 12 and 20. The onset of serious violence is negligible after age 23 and before age 10 (only 0.2 percent of arrests for serious violent crime in 1997 involved a child under age 10 ). The peak age of onset is 16, when about 5 percent of male adolescents report their first act of serious vio lence. The age of onset peaks somewhat later for The Developmental D ynam ics of Youth Violence somewhat by race/ethnicity. It is lower for white males (5 percent) than for African American males (8 percent) (Elliott, 2000a). A similar finding is reported in the Pittsburgh Youth Survey .6 No comparable hazard rates have been pub lished for female youths, but other studies have found that they are generally lower.7 Age-specific prevalence-that is, the proportion of youths at any given age who report having com mitted at least one serious violent act-is also greatest in the second decade of life. The NYS and the three city surveys find that, broadly speaking, age-specific prevalence among male youths ranges from about 8 to 20 percent between the ages of 12 and 20 (Figure 3-2). Among females, it ranges from 1 to 18 percent (Table 3-1). There is some variability across surveys, however. In general, the NYS has lower rates than the three city surveys, reflecting the difference between a national sample and local samples drawn from urban 1986, whereas the three city surveys cover the years 1986 or 1988 to 1994, the peak years of the violence epidemic (see Chapter 2). Nevertheless, the estimates for age 17 across these longitudinal surveys are in the same range as those for high school seniors in the Monitoring the Future survey (see Chapter 2). Another key difference between the national and city surveys is the maturation effect, or the age at which serious violence begins to decline sharply dur ing the transition to adulthood. The NYS shows a decline in age-specific prevalence starting in the late teen years and a steep drop-off by age 20. In contrast, the city surveys, which were begun more recently, do not show a decline in the late teen years , and they have not yet published data on prevalence in early adulthood. Therefore, it is too soon to tell whether or at what age more recent groups of youths will mature out of violence. It is possible that young people are staying violent longer. Some important differences in age-specific preva lence by sex have emerged from the data (Table 3-1). Female adolescents have lower rates of serious vio lence throughout the second decade. For the NYS and Denver surveys, rates at age 12 are about twice as high for boys as for girls. Between age 12 and 15 in Rochester, the rates are fairly similar. For all studies, the rates for females at age 17 are about one-quarter the rates for males. In addition, the peak age of seri ous violent offending occurs a few years earlier among females, and their maturation out of serious violence is both earlier and steeper than males'. Age-specific prevalence also varies by race/eth nicity (Table 3-1). The NYS finds a significant racial gap between ages and 17, when rates for African © .BEST COPY .AVAILABLE American youths are 36 to 50 percent higher than those for white youths. The city surveys show an even wider gap between African American and white youths . Rates among Hispanic youths, reported only for Denver and Rochester, are similar to or lower than those reported by African American youths in these cities. The prevalence reported by Hispanic youths ranges from 6 to 12 per cent in Denver and about 10 to 20 percent in Rochester. Possible reasons for developmental differ ences by sex, race, and ethnicity are discussed in Chapter 4. None of these comparisons takes into account the effects of poverty, education, housing, or other environmental conditions. # C u m u l a t iv e P r e v a l e n c e Figure 3-2. Prevalence of serious violence among male youths, by age: four longitudinal surveys youths, the NYS shows it rising to about 40 percent and then leveling off beyond age 22. In the city sur veys, it reaches more than 40 percent of male and 32 percent of female youths by age 17. Not only is the rise in cumulative prevalence by age 17 steeper in the city surveys, the magnitude is substantially higher. These differences between a nationally representa tive sample and city samples are to be expected. The timing of the surveys may also explain some of the dif ferences. For example, 17-year-olds in the NYS were interviewed at some point between 1976 and 1982, whereas 17-year-olds in the city surveys were inter viewed at some point between 1988 and 1994, the era during which the self-reported prevalence of serious youth violence increased somewhat (see Chapter 2). There is a pronounced difference in cumulative prevalence by sex. Among I7-year-olds, the Denver Cumulative prevalence refers to the proportion of youths at any particular age who have ever commit ted a serious violent offense.8 As a measure of vio lence, it tends to equalize rather than magnify differ ences across populations because it counts youths only once, regardless of when or how often they engaged in violent acts. The most striking feature of the cumulative preva lence is its sheer magnitude: About 30 to 40 percent of male and 16 to 32 percent of female youths have com mitted a serious violent offense by age 17 (Figure 3-3). Although these rates are only slightly higher than those found in international studies, they repre sent a more serious set of offenses (Junger-Tas et al., 1994). The cumulative prevalence of youth violence is generally consistent across the four surveys. For male Cum ulative prevalence is also known as lifetim e prevalence or ever-prevalence to a given age. Confidence intervals are as follows: NYS African American males = .45 (± 9.8); NYS white males = .38 (± 3.9); RYDS males = .40 (± 3.7); DYS males = .43 (± 3.6); PYS males = .44 (± 2.6); RYDS females = .32 (± 6.1); DYS females = .16 (± 2.8). survey found a cumulative prevalence of 16 percent for female youths and 43 percent for male youths, whereas the Rochester survey showed 32 percent and 40 percent, respectively. Data on cumulative preva lence for females are not available in the Pittsburgh survey or the NYS.9 On the other hand, there are few differences in cumulative prevalence by race over the teen years, according to the NYS. By age 23, white males had a cumulative prevalence of 38 percent and African American males had a cumulative prevalence of 45 percent, a difference that is not statistically significant (Figure 3-3). # Ra t e s o f O f f e n d in g a n d V io l e n t C a r e e r s Violent youths commit a remarkably high number of crimes (Tolan & Gorman-Smith, 1998). An analysis of NYS data shows that these young people (both male and female) averaged 15.6 rapes, robberies, aggravated assaults, or some combination of these crimes over a 16-year period (1976 to 1992) (Elliott, 2000b). W hat's more, they averaged just over six serious violent offenses each during the years in which they were active (Elliott, 2000b).10 This mean annual rate of offending is similar to rates reported in the three city surveys for males (about 5 to 9 seri ous violent offenses per year) but much higher than the rates for females (2 to 4.5 per year). It is noteworthy that the mean annual rate of indi vidual offending appears to be essentially unchanged over the past two decades. This finding is corroborat ed by a study of trends among juvenile offenders processed by a county court system in Arizona (Snyder, 1998) and by an analysis of both National Crime Victimization Survey data and arrest records (Snyder & Sickmund, 2000). Finally, the Monitoring the Future survey (see Chapter 2) found no significant changes in individual offending rates for robbery or assault with injury between 1983 and 1993." Career length has been variously defined as the number of years of active offending, the maximum number of consecutive years, or the span between the first and last year during which a young person meets the criteria for a serious violent offender (Blumstein et al., 1986). There are relatively few estimates of vio lent career lengths. In the NYS, the mean career length (number of years of active violent offending) was 2.6 years. The most frequent career length was 1 year (36.8 percent of serious violent offenders). Three-quarters of these serious violent youths had careers lasting 3 years or less, and 15 percent had careers of 5 years or more (Elliott, 2000b). Based on 5 years of data, the Denver survey reports that 42 per cent of serious violent youths were active for only 1 year, 22 percent for 2 years, and 31 percent for 3 or more years . The typical violent career comprises either a single year of continuous offending or a longer period of inter mittent offending. Relatively few violent careers are characterized by years of uninterrupted violence. In Denver, well over half of the careers that lasted three or more years had at least one year with no violent offend ing; three-quarters of those that spanned a 5-year period had an intermittent pattern of offending . Evidence that most careers lasting more than 1 year were characterized by intermittent offending also surfaced in the NYS (Elliott et al., 1986). This intermit tent pattern makes it difficult to identify serious violent offenders with cross-sectional studies or with longitudi nal studies that have long periods between data collec tion . In sum, these studies suggest that in most cases vio lent careers are relatively short and are characterized by intermittent offending. During active periods, however, most careers are marked by a high rate of violent offending-up to 10 offenses per year (Elliott et al., 1986;. # D e v e l o p m e n t a l Pa t h w a y T o V io l e n c e Violent youths do not usually begin their careers with a serious violent offense. While the developmental path way varies, depending on what types of behavior are monitored, studies generally agree that a violent career begins with relatively minor forms of antisocial or delinquent behavior. These acts later increase in fre quency, seriousness, and variety, often progressing to serious violent behavior (Elliott, 1994;Moffitt, 1993;Tolan & Gorman-Smith, 1998). Several complex pathways to serious violence have been proposed (Loeber, 1996;Elliott, 1994). The NYS suggests that violence escalates over time. Most serious violent youths who engage in multiple types of violent behavior begin with aggravated assault, then add a robbery, and finally a rape. (Rape appears to be the end point of the progression, although there were not enough homicides in the NYS sample to include homicide in the analysis.) Robbery precedes rape in over 70 percent of cases in which both acts have been reported, and about 15 percent of serious violent offenders in the NYS reported having committed a rape (Elliott, 1994(Elliott, , 2000a. This sequence must be considered tentative because it is based on a single study. When serious violence becomes part of a youth's repertoire of antisocial behavior, it does not substitute for less serious forms of violence; rather, it adds to them and escalates the overall frequency of violent acts. Thus, serious violent youths are high-frequency offend ers who are involved in many less serious as well as serious offenses. These youths account for a major share of all criminal behavior, a pattern that is explored more fully in the next section. 11 Calculations were done by the senior scientific editor Elliott on the basis o f M onitoring the Future prevalence and frequency data on aggra vated assault and robbery contained in the 1991 and 1998 Sourcebooks o f Criminal Justice Statistics (Flanagan & Maguire, 1992;Maguire & Pastore, 1999). Individual offending rates are based on estimated incident rates. For this calculation, frequencies associated w ith categorical scores were as follows: not at all = 0; once = 1; tw ice = 2; 3 or 4 times = 3.5; and 5 or more times = 5. Individual offending rates for robbery in both 1983 and 1993 were 1.8. Rates for assault w ith injury were 2.3 and 2.6 (not significant). The mean individual offending rate can remain relatively constant despite increases in prevalence and incident rates noted in Chapter 2. # C h r o n ic V io l e n t O f f e n d e r s A minority of serious violent youths are responsible for the overwhelming majority of serious violent crime, a finding supported by numerous self-report and arrest studies (Tolan & Gorman-Smith, 1998;Tracy & Kempf-Leonard, 1996). In the city surveys, chronic offenders, though representing less than 20 percent of all serious violent offenders; accounted for 75 to 80 per cent of self-reported violent crimes . NYS data yield similar findings: Chronic offenders (youths with three or more violent offenses) accounted for 76 percent of all felony assaults and 89 percent of all robberies reported by offenders in 1980 . Chronic violent youths may also account for a dis proportionate share of all youth crime. The NYS reveals that in 1980 these serious violent offenders accounted for 79 percent of all felony theft, 66 percent of all illegal services (primarily drug selling), and 50 percent of all self-reported crime . In the Philadelphia Birth Cohort Study, 15 percent of youthful offenders accounted for 74 percent of all offi cial crime (Tracy & Kempf-Leonard, 1996). As noted earlier, youths whose violence begins before puberty are more likely to become chronic vio lent offenders . In the Rochester survey, 39 percent of children who initiated violent behavior by age 9 eventually became chronic offenders, 30 percent of those who initiated violence between the ages of 10 and 12 became chronic offenders, and 23 percent of those who initiated violence after age 13 became chronic violent offenders. In Denver, 62 per cent of those initiating violence by age 9 and 48 percent of those initiating violence between 10 and 12 became chronic violent offenders. Looking at this another way, 55 percent of all chronic violent offenders in Denver came from the early-onset trajectory . While the late-onset trajectory involves a sub stantially larger group of youths, fewer than half of all chronic offenders come from this group. Although most chronic violent offenders in the three city surveys (62 to 77 percent) eventually had contact with the police for some offense (though not necessarily a violent offense), one-quarter to one-third 0 were never arrested . Among those who were arrested for some offense, the first con tact came well after they had begun their violent careers. Interventions by the justice system occur too late to prevent such youths from escalating from less serious offenses to serious violence. Fortunately, it appears that at least half of chronic violent offenders can be identified as being at risk in childhood. Research has found a powerful relationship between membership in a gang and chronic involve ment in serious violence (see review in . As noted earlier (see Chapter 2), gang members, a relatively small proportion of the adolescent popula tion, commit the majority of serious youth violence (see Spergel, 1990, andThomberry, 1998, for reviews). # S u p e r p r e d a t o r s ? Between 1983 and 1993, adolescents were committing homicide at dramatically higher rates than in previous years (see Chapter 2). Did those youths represent a new breed of frequent, vicious, remorseless killers? Did the character of violent youths change during that time-and is it still different today (Bennett et al., 1996)? The answer seems to be no, for several reasons. First, the increase in homicides was similar across all age groups (see Chapter 2). This suggests that it resulted from a relatively sudden change in the envi ronment that affected all youths rather than from a gradual change in the socialization process, which would have led to progressively more vicious youths with each succeeding age group. Second, the increase in homicides was highly specific to certain youthsnamely, African American males (Zimring, 1998); moreover, it did not take place among females (see Chapter 2). Third, during the violence epidemic, there was a decline in family members killed by youths . Fourth, a new breed of superpredators should have resulted in more burglaries, auto thefts, and lar cenies, but no such increases occurred . It should also have resulted in more homicides involving knives and other weapons, but this did not occur (Zimring, 1998). Fifth, there was no evidence that individual rates of serious violent crime changed during the epidemic. More youths were involved, but the average number of offenses committed by each did not change. Finally, there may be anecdotal evidence that today's youths show less remorse for their violence, but this has not been substantiated by research. In sum, the epidemic of violence from 1983 to 1993 does not seem to have resulted from a basic change in the offending rates and viciousness of young offenders. Rather, it resulted primarily from a relative ly sudden change in the social environment-the intro duction of guns into violent exchanges among youths. The violence epidemic was, in essence, the result of a change in the presence and type of weapon used, which increased the lethality of violent incidents (Wintemute, 2000). # C o -O c c u r r in g Pr o b l e m B e h a v io r s Serious violence is accompanied by a wide range of other problem behaviors, including property crimes, substance use, gun ownership, dropping out of school, early sexual activity, and reckless driving. The co occurrence of these problem behaviors has been borne out by numerous national - and local studies (see reviews in Elliott, 1993;Huizinga & Jakob-Chen, 1998;Tolan & Gorman-Smith, 1998). The overlap is greatest between serious violence and other forms of crime. In the three city surveys, 82 to 92 percent of chronic violent youths were involved in property crimes, 71 to 82 percent in public disorder crimes, and 26 to 45 percent in selling drugs . Very similar rates were found in the NYS . Rates of co-occur rence were much higher among serious violent youths than among less violent youths. Substance use and abuse are a central feature of a violent lifestyle (Dembo et al., 1991;Elliott, 1994;Johnson et al., 1991). In the Denver survey, for example, about 58 percent of serious vio lent offenders were alcohol users and 34 percent were marijuana users. The prevalence and frequen cy of use were much lower in youths who were not seriously violent (Huizinga & Jakob-Chen, 1998). The NYS indicates that 94 percent of serious violent youths in 1980 were using alcohol, 85 percent were using marijuana, and 55 percent were using several illicit drugs. Over half (55 percent) were abusing drugs-that is, they reported health or relationship - problems, or both, associated with their drug use . Similar findings regarding the overlap of sub stance use and serious violence hold for the Rochester study (Thornberry et al., 1995). Moreover, chronic violent youths in Rochester and violent youths in the NYS had higher rates of dropping out of school, gun ownership and use, teenage sexual activity and par enthood, tobacco use, driving under the influence of alcohol or drugs, and gang membership than nonseri ous offenders or nonoffenders (Elliott, 1993;Thornberry et al., 1995). In sum, these studies show that a sizable propor tion of serious violent youths have co-occurring problem behaviors-and at rates significantly higher than those of their less violent counterparts. However, by no means all serious violent youths or even all chronic violent youths have co-occurring problems. Moreover, not all youths with problem behaviors are seriously violent. The fact that serious violence and problem behaviors tend to occur together does not necessarily mean that one causes the other (see Chapter 4) (Elliott, 1993;. # Violence and Mental Health The relationship between violence and mental health has been studied more intensively in adults than in young people. An earlier U.S. Surgeon General's report on mental health, after weighing the evidence, empha sized that the contribution of mental disorders to over all violence in the United States is very small. In fact, public fear is out of proportion to the actual risk of vio lence, which contributes to the stigmatizing of people with severe mental disorders (Link et al., 1999). Even though the risk of violence is low overall, it is greatest for adults with serious mental disorders who also abuse substances (Steadman et al., 1998;Swanson, 1994). Although violence is relatively widespread among adolescents, few studies have been undertaken on the co-occurrence of violence and mental health problems or disorders among U.S. adolescents. Such popula tion-based studies are important because they avoid the bias inherent in surveying hospitalized patients or convicted offenders. Both the NYS and the Denver survey examine the co-occurrence of serious violence and mental health problems. In the NYS, 28 percent of serious offenders age 11 to 17 were classified as having men tal health problems, compared to 13 to 14 percent of nonserious delinquent youths and 9 percent of nonof fenders. Youths were classified as having mental health problems on the basis of their responses to questions about emotional problems, social isolation, and feelings of loneliness . (The questions were not designed to arrive at a diagnosis of a mental disorder.) Serious violent offenders were more likely than either nonserious offenders or nonoffenders to report having these types of mental health problems. In the Denver study, serious violent youths were found to have higher rates of psychological problems, based on parents' responses to the Child Behavior Checklist (Achenbach & Edelbrock, 1983). These problems included externalizing and internalizing behavior, depression, uncommunicativeness, obses sive-compulsive behavior, hyperactivity, social with drawal, and aggressiveness. The rates at which most of these problems occurred in serious offenders were no different from the rates at which they occurred in nonviolent delinquent youths; however, rates in non delinquent youths were lower. Thus, delinquent youths in general were more likely to have psycho logical problems than nondelinquent youths (Huizinga & Jakob-Chen, 1998). Two problems were linked directly to violent behavior-externalizing symptoms and aggressive behavior. Approximately half of all serious violent offenders display these problems, although the link with externalizing behaviors is statistically significant only for boys. In addition, parents of violent offenders report seeking help for mental health problems more often than parents of nondelinquent or nonviolent delinquent youths. These parents did not go to mental health professionals or school counselors; rather, they sought the advice of friends, relatives, and spiritual leaders (ministers, rabbis, or priests). A similar finding is reported in the Pittsburgh study (Stouthamer-Loeber & Thomas, 1992). The Denver study found no differences between the self-esteem of serious violent offenders and non violent offenders or nonoffenders (Huizinga & Jakob-Chen, 1998). In general, there is little evidence that low self-esteem causes violence or that violent offend ers have low self-esteem. On the contrary, the evi dence is more consistent with the position that high self-esteem and threats to high esteem lead to violence (Baumeister et al., 1996). This has important implica tions for treatment and intervention programs and the use of esteem-building activities in these programs. A population-based study in New Zealand found that in young adulthood (age 21), serious violent offenders are more likely than nonoffenders to exhib it substance dependence disorders, schizophreniaspectrum disorders,12 or both (Arseneault et al., 2000). These New Zealand findings are consistent with the studies of U.S. adults showing that the greatest risk of violence stems from the combination of serious men tal disorder and substance dependence. However, about 10 percent of serious violent offenders13 in the New Zealand study exhibited schizophrenia-spectrum disorders without substance dependence or other psy chiatric conditions. The researchers concluded that while the contribution of serious mental illness to vio lence in young adults remains small, it may be slight ly higher than it is in adults. One possible reason for the difference is that the overwhelming majority of young adults with mental disorders in the New The Developm ental Dynam ics of Youth Violence Zealand study had not been treated or hospitalized within the previous year. Another recent community-based study found a link between personality disorders (a group of severe mental disorders) and violence. Adolescents with personality disorders,14 as determined by diagnostic interviews, were more likely than other adolescents to commit vio lent acts such as assault with injury and robbery (Johnson et al., 2000). For example, about 36 percent of adolescents with personality disorders versus 16 percent without the disorders committed a violent act against others15 during adolescence. The relationship between personality disorders and violence remained after taking many factors into account, including co-occurring depression, anxiety, and substance disorders. Only a few adolescents (13 percent) with personality disorders had received mental health services during the previous year (Johnston, personal communication, 2000). Thus, there is some evidence of a relationship between serious mental disorders and violence in ado lescents or young adults in the general population. Young people with serious mental disorders may be at risk of becoming violent if they also abuse substances or if they have not received treatment for their mental disorder. More research .is needed to understand the relationship between serious youth violence and men tal illness. # O f f e n d in g a n d V ic t im iz a t io n Violent offenders are frequently victims of violence Lauritsen et al., 1991;Sampson & Lauritsen, 1990. Data from the NYS reveal that victimization is highest among African Americans, males, and frequent offenders (Lauritsen et al., 1991). In addition, youths who report abusing drugs and alcohol, hanging out with delin quent peers, and participating in social activities with little adult supervision are at greater risk of being vic tims of violence (Gottfredson, 1984;Lauritsen et al., 1991;Sampson & Lauritsen, 1990). A delinquent lifestyle greatly increases the likelihood of being a vic tim and appears to account for some of the disparities observed in offending and victimization by race/ethnicity and sex. The Denver survey shows that 42 per cent of serious violent offenders are also victims of violence (Huizinga & Jakob-Chen, 1998), with higher rates among male offenders than female offenders. There are many reasons for the overlap between offending and victimization. Perhaps the most com mon is that the offender is injured by the intended tar get-either during the offense or later, in retaliation. Another reason is that offenders tend to live in more violent environments or their lifestyles take them into high-risk environments. The predictive relationship between victimization and offending, as well as the relationship with early child abuse, is discussed in Chapter 4. # T r a n s it io n t o A d u l t h o o d The transition from adolescence to adulthood features a fairly abrupt discontinuation of serious violence, at least according to the NYS. Rates of onset and agespecific prevalence show dramatic declines, and the cumulative prevalence levels off, as discussed above. Only about 20 percent of serious violent offenders continue their violent careers into their twenties (Elliott, 1994). -While there are no differences by sex in the apparent termination of violent offending, there are significant differences by race. Twice as many African American as white youths continue their violent behavior into the adult years (Elliott, 1994). Preliminary analyses suggest that cessation of offend ing is related to having a stable job and a stable inti mate relationship. By 1992, the most recent year for which data are available, many people monitored by the NYS had reached their late twenties and early thirties. There is virtually no published information about what patterns of violence may have continued into their adult years. The more recent city surveys have published age-spe cific and cumulative prevalence findings only up to age 19, but these studies are still being conducted. Some evidence from these surveys (Figure 3-2) sug gests that violent careers are lasting longer, but addi tional waves of data are needed to verify this trend. Understanding the demographics and dynamics of how patterns of serious violence change with the tran sition into adulthood is critical to designing programs that enhance the termination of violence. # C o n c l u s io n s The prevalence of serious violence by age 17 is star tling. About 30 to 40 percent of male and 15 to 30 per cent of female youths report having committed a seri ous violent offense at some point in their lives. This cumulative prevalence is similar among African American and white males, in contrast to other meas ures of violence, which show racial disparities (see Chapter 2). Two general onset trajectories emerge from longi tudinal studies of youth violence-an early-onset tra jectory that begins before puberty and a late-onset one that begins in adolescence. Youths in the early-onset trajectory generally commit more crimes, and more serious crimes, for a longer time. These young people exhibit a pattern of escalating violence through child hood and adolescence, and frequently into adulthood. Most youths who become violent, however, begin in adolescence. Their late-onset offending is usually limited to a short period, peaking at about age 16 and dropping off dramatically by age 20. They typically show few signs in childhood that they will become violent later on, laying to rest the myth that all violent adolescents can be identified in childhood. The rate of individual offending appears to have remained virtually unchanged, both during and since the years of the violence epidemic, which began in 1983 and peaked in 1993. This finding, together with evidence that the epidemic was specific to gun-related violence, challenges the myth that the early 1990s produced a generation of superpredators who were - more vicious and who committed dramatically more crimes than earlier generations of young people. At the same time, the finding of a stable individual offending rate indicates that the violence epidemic has not altogether subsided. Serious violence is frequently part of a lifestyle that includes drugs, guns, precocious sex, and other risky behaviors. Youths involved in serious violence typically commit many other types of crimes and exhibit other problem behaviors, presenting a serious challenge to intervention efforts. Successful interven tions must confront not only the violent behavior of these young people, but also their lifestyles, which are teeming with risk. Prevention and intervention programs must also take into account the different patterns of violence typical of the early-and late-onset trajectories, as well as the relatively constant rates of individual offending. Early childhood programs that target at-risk children and families are critical for preventing the onset of a chronic violent career, but programs must also be developed to combat late-onset violence. The impor tance of late-onset violence prevention is neither widely recognized nor well understood. Substantial numbers of serious violent offenders emerge seeming ly without warning. A comprehensive community pre vention strategy must address both onset patterns and ferret out their respective causes and risk factors. But what do we know about why young people become involved in violence? Why do some youths get caught up in violence while others do not? There is no simple answer to these questions, but scientists have identified a number of things that put children and adolescents at risk of violent behavior and some things that seem to protect them from the effects of risk. # In t r o d u c t io n t o R is k a n d Pr o t e c t iv e Fa c t o r s The concepts of risk and protection are integral to public health. A risk factor is anything that increases the probability that a person will suffer harm. A pro tective factor is something that decreases the potential harmful effect of a risk factor. In the context of this report, risk factors increase the probability that a young person will become violent, while protective factors buffer the young person against those risks. The public health approach to youth violence involves identifying risk and protective factors, determining how they work, making the public aware of these findings, and designing programs to prevent or stop the violence. Risk factors for violence are not static. Their pre dictive value changes depending on when they occur in a young person's development, in what social con text, and under what circumstances. Risk factors may be found in the individual, the environment, or the individual's ability to respond to the demands or requirements of the environment. Some factors come into play during childhood or even earlier, whereas others do not appear until adolescence. Some involve the family, others the neighborhood, the school, or the peer group. Some become less important as a person matures, while others persist throughout the life span. To complicate the picture even further, some factors may constitute risks during one stage of development but not another. Finally, the factors that predict the onset of violence are not necessarily the same as those that predict the continuation or cessation of violence. Violence prevention and intervention efforts hinge on identifying risk and protective factors and determining when in the course of development they emerge. To be effective, such efforts must be appro priate to a youth's stage of development. A program that is effective in childhood may be ineffective in ' adolescence and vice versa. Moreover, the risk and protective factors targeted by violence prevention pro grams may be different from those targeted by inter vention programs, which are designed to prevent the reoccurrence of violence. This report groups risk and protective factors into five domains: individual, family, peer group, school, and community, which includes both the neighborhood and the larger society (Box 4-1). Factors do not always fit neatly into these areas, however. Broken homes are classified as a family risk factor, but the presence of many such families in a community can contribute to social disorganiza tion, an important community-level risk factor (Bursik & Grasmick, 1993;. # Risk Factors Risk factors are not necessarily causes. Researchers identify risk factors for youth violence by tracking the development of children and adolescents over the first two decades of life and measuring how frequently par ticular personal characteristics and social conditions at a given age are linked to violence at later stages of the life course. Evidence for these characteristics and social conditions must go beyond simple empirical relationships, however. To be considered risk factors, they must have both a theoretical rationale and a demonstrated ability to predict violence-essential conditions for a causal relationship (Earls, 1994;Kraemer et al., 1997;. The reason risk factors are not considered causes is that, in most cases, scientists lack experimental evidence that changing a risk factor produces changes in the onset or rate of violence. As used in this report, risk factors are personal characteristics or environmental conditions that pre dict the onset, continuity, or escalation of violence. The question of causality has practical implica tions for prevention efforts. Prevention depends large-erJ c copy available ly on risk factors being true causes of violence. In practical terms, research has amassed enough strong, consistent evidence for the risk factors discussed in this report to provide a basis for prevention programs, even though a strict cause-and-effect relationship has been established for relatively few of them. Most of the risk factors identified do not appear to have a strong biological basis. Instead, it is theorized, they result from social learning or the combination of social learning and biological processes. This means that violent youths who have violent parents are far more likely to have modeled their behavior on their parents' behavior-to have learned violent behavior from them-than simply to have inherited it from them. Likewise, society's differing expectations of boys and girls-expecting boys to be more aggres sive, for example-can result in learned behaviors that increase or decrease the risk of violence. The bulk of the research that has been done on risk factors identifies and measures their predictive value separately, without taking into account the influence of other risk factors. More important than any individual factor, however, is the accumulation of risk factors. Risk factors usually exist in clusters, not in isolation. Children who are abused or neglected, for example, tend to be in poor families with single par ents living in disadvantaged neighborhoods beset with violence, drug use, and crime. Studies of multiple risk factors have found that they have independent, addi tive effects-that is, the more risk factors a child is exposed to, the greater the likelihood that he or she will become violent. One study, for example, has found that a 10-year-old exposed to 6 or more risk fac tors is 10 times as likely to be violent by age 18 as a 10-year-old exposed to only one factor (Herrenkohl et al" 2000). Researchers have theorized that risk factors also interact with each other, but to date they have found little evidence of interaction. What evidence does exist suggests that interactions between or among fac tors produce only small effects, but work in this area is continuing. To date, much more research has been done on risk factors than protective factors, but that picture, too, is changing. # O # ERIC # Developmental Progression to Violence Scientific theory and research take two different approaches to how youth violence develops-one that focuses on the onset of violent behavior and its frequency, patterns, and continuity over the life course and one that focuses on the emergence of risk factors at different stages of the life course. Chapter 3 describes two developmental trajectories for the onset of violent behavior-one in which vio lence begins in childhood (before puberty) and con tinues into adolescence, and one in which violence begins in adolescence. In contrast, this chapter considers the timing of risk factors. It identifies the individual characteristics, experiences, and environmental conditions in child hood or adolescence that predict involvement in vio lent behavior in late adolescence-that is, age 15 to 18, the peak years of offending. Research shows that different risk factors may emerge in these two devel opmental periods and that the same risk factors may have different effect sizes, or predictive power, in these periods. The timing of risk factors and the onset of vio lence are connected. Only risk factors that emerge in early childhood can logically account for violence that begins before puberty. However, these early risk factors may or may not be implicated in violence that begins in adolescence. In fact, studies show that many youths with late-onset violence did not encounter the childhood risk factors responsible for early-onset violence. For these youths, risk factors for violence emerged in adolescence Moffitt et al., 1996;Simons et al., 1994). # Limitations of Risk Factors Risk factors are powerful tools for identifying and locating populations and individuals with a high potential for becoming violent, and they provide valu able targets for programs aimed at preventing or reducing violence. But there are important limitations to our knowledge about and use of risk factors. The following cautions are worth bearing in mind: - No single risk factor or set of risk factors is power ful enough to predict with certainty that youths will become violent. Poor performance in school is a risk factor, for example, but by no means will all young people who perform poorly in school become violent. Similarly, many youths are exposed to mul tiple risks yet avoid becoming involved in violence (Garmezy, 1985;Rutter, 1985;Werner & Smith, 1982. - Because public health research is based on observa tions and statistical probabilities in large popula tions, risk factors can be used to predict violence in groups with particular characteristics or environ mental conditions but not in individuals. - Given these two limitations, assessments designed to target individual youths for intervention pro grams must be used with great care. Most individual youths identified by existing risk factors for vio lence, even youths facing accumulated risks, never become violent (Farrington, 1997;Lipsey & Derzon, 1998). - Some risk factors are not amenable to change and therefore are not good targets for intervention (Earls, 1994;Hawkins et al., 1998a). Being bom male is an example. - Of the risk factors that are amenable to change, some are not realistic targets of preventive efforts. Eliminating poverty is not a realistic short-term goal, for example, but programs that counter some of the effects of poverty are. (Eliminating or reduc ing poverty should be a high-priority long-term goal, however.) - Some situations and conditions that influence the likelihood of violence or the form it takes may not be identified by longitudinal studies as risk factors (predictors) for violence. Situational factors such as bullying, taunting, and demeaning interactions can serve as catalysts for unplanned violence. The social context can influence the seriousness or form of violence-for example, the presence of a gun or a gathering crowd of peers that makes a youth feel he (or she) needs to protect his (or her) reputation. These may not be primary causes of violence, yet they are contributing factors and are important to understanding how a violent exchange unfolds. Such influences, although important, may not be identified in this report because of the way risk fac tors are defined. - Many studies of risk factors, particularly earlier ones, drew their samples from white boys and young men. The limited focus of these studies calls into question their predictive power for girls and women and for other racial or ethnic groups. Differences among cultures and their socialization and expectations of girls and boys may modify the influences of some risk factors in these groups. Nonetheless, most of the risk factors identified in this report do apply broadly to all young people. All children go through the same basic stages of human development-and prevention of youth violence is based on understanding when and how risk factors come into play at various stages of development. Moreover, there is some evidence that most risk fac-79 tors are equally valid predictors of delinquency and violence regardless of sex, race, or ethnicity (Rosay et al., 2000;Williams et al., 1999). Sophisticated studies that identify how cultural differences affect the inter play of the individual and his or her surroundings will make possible more effective prevention efforts. # Protective Factors There is some disagreement about exactly what pro tective factors are. They have been viewed both as the absence of risk and as something conceptually distinct from risk (Guerra, 1998;lessor et al., 1995;Wasserman & Miller, 1998). The former view typically places risk and protective factors on the opposite ends of a continuum. For example, good par ent-child relations might be considered a protective factor because it is the opposite of poor parent-child relations, a known risk factor. But a simple linear rela tionship of this sort (where the risk of violence decreases as parent-child relations improve) blurs the distinction between risk and protection, making them essentially the same thing.1 The view that protection is conceptually distinct from risk (the view used in this report) defines protec tive factors as characteristics or conditions that inter act with risk factors to reduce their influence on vio lent behavior (Garmezy, 1985;Rutter, 1985;. For example, low family socio economic status is a risk factor for violence, and a warm, supportive relationship with a parent may be a protective factor. The warm relationship does not improve the child's economic status, but it does buffer the child from some of the adverse effects of poverty. Protective factors may or may not have a direct effect on violence (compare lessor et al., 1995 and. Interest in protective factors emerged from research in the field of developmental psychopatholo gy. Investigators observed that children with exposure to multiple risk factors often escaped their impact. This led to a search for the characteristics or condi tions that might confer resilience-that is, factors that moderate or buffer the effects of risk (Davis, 1999;Garmezy, 1985;Rutter, 1987;Werner, 1989). Protective factors offer an explanation for why chil dren and adolescents who face the same degree of risk may be affected differently. The concept of protective factors is familiar in public health. Wearing seat belts, for example, reduces the risk of serious injury or death in a car crash. Identifying and measuring the effects of protective factors is a new area of violence research, and infor mation about these factors is limited. Because they buffer the effect of risk factors, protective factors are an important tool in violence prevention. Like risk factors, proposed protective factors are grouped into individual, family, school, peer group, and community categories. They may differ at various stages of development, they may interact, and they may exert cumulative effects (Catalano et al., 1998;Furstenberg et al., 1999;Garmezy, 1985;lessor et al., 1995;Rutter, 1979;Sameroff et al., 1993;. Just as risk factors do not necessarily cause an individual child or young person to become violent, protective factors do not guarantee that an individual child or young person will not become vio lent. They reduce the probability that groups of young people facing a risk factor or factors will become involved in violence. # A Note on Sources This chapter draws heavily on four important studies: Lipsey & Derzon's meta-analysis of 34 longitudinal studies on risk factors for violence (1998); Hawkins et al.'s study of malleable risk and protective factors drawn from 30 longitudinal studies, including some not included in the Lipsey & Derzon meta-analysis (Hawkins et al., 1998c); Paik and Comstock's meta analysis of 217 studies of exposure to media violence and its effects on aggression and violence (1994); and the National Institute of Mental Health's Taking Stock report (Hann & Borek, in press), an extensive review of research on risk factors for aggression and other behavior problems. . Additional risk factors and classes of risk factors have been added from other sources. For example, there is adequate evidence to establish harsh, lax, or inconsistent discipline as a separate risk factor, although Lipsey and Derzon include it in the poor par ent-child relations class. Academic failure, family con flict, and belonging to a gang are additional examples of risk factors not included in any of the meta-analyses. The measure of effect size used in these tables is a bivariate correlation (r), or simple correlation between two variables. All estimates of effect size are statistically significant and are based on multiple stud ies, with those for risk classes typically involving more studies than those for separate risk factors. The studies reviewed in Lipsey and Derzon, Paik and Comstock, and Hawkins et al. are not cited here; how ever, other studies that were used to establish a risk factor or that are included in estimates of effect size are cited.3 There is a rich and extensive body of research on risks for antisocial behavior, externalizing behavior, conduct disorder, and aggression (Hann & Borek, in press). Each of these terms defines a pattern or set of behaviors that includes aggressive or violent behavior, but most of the behaviors included are either non physical, nonviolent acts or relatively minor forms of physical aggression. Risk factors for antisocial behav ior may be quite different from those that predict vio lent behavior (robbery, aggravated assault, rape, and homicide). Since antisocial behavior does not present the potential for serious injury or death that violence does, this report relies on studies that identify risk fac tors for serious offenses generally and violent behav ior specifically, bearing in mind that the vast majority of serious offenders report having been involved in violent offenses. # Summary Risk and protective factors can be found in every area of a child or adolescent's life, they exert different effects at different stages of development, and they gain strength in numbers. The public health approach to the problem of youth violence seeks to identify risk and protective factors, determine when in the life course they typically occur and how they operate, and enable researchers to design preventive programs to be put in place at just the right time to be most effective. This chapter describes what is known about indi vidual, family, school, peer group, and community risk and protective factors that exert their effects in child hood and adolescence. It describes the power of early risk factors, which come into play before puberty, and late risk factors, which exert their influence after puberty, to predict the likelihood of youth violence. # R is k Fa c t o r s in C h i l d h o o d The first decade of life encompasses a vast period of human development. Infants form attachments to par ents or other loving adults and begin to become aware of themselves as separate beings. As toddlers, they begin to talk, to assert themselves, to explore the world around them, and to extend their emotional and social bonds to people other than their parents. The start of school is a milestone in children's con tinuing social and intellectual development. Other chil dren become more important in their lives, though still not as important as family members. They begin to empathize with others and hone their sense of right and wrong. As they progress through elementary school, children gain valuable reasoning and problem-solving skills as well as social skills. Exposure to or involvement in violence can disrupt normal development of both children and adolescents, with profound effects on their mental, physical, and emo tional health.4 In addition, exposure to violence affects children and adolescents differently at different stages of development (Marans & Adelman, 1997). Young children exposed to violence may have nightmares or be afraid to go to sleep, fear being left alone, or regress to earlier behavior, such as baby talk or bed-wetting. They may exhibit excessive irritability or excitability. Violence in the family, especially, may inhibit young children's ability to form trusting rela tionships and develop independence. Elementary school children who live in violent neighborhoods may also experience sleep distur bances and be less likely to explore their environ ment. In addition, they can become frightened, anx ious, depressed, and aggressive. They may have trou ble concentrating in school. Because they understand that violence is intentional, they may worry about what they could have done to prevent or stop it (Osofsky, 1999). Violence also affects parents. Adults living in vio lent households or neighborhoods may not be able to keep their children safe or to protect them from harmful influences. Some parents living in unsafe neighbor hoods do not let their children play outside. While this solution may safeguard children temporarily, it can also impede healthy development. Parents in these situations understandably feel helpless and hopeless. Those who have been traumatized by violence themselves may, like their children, become anxious, withdrawn, or depressed. Under such circumstances, parents cannot respond spontaneously and joyously to their children, making it difficult for children to develop strong, secure attachments to their parents. Forming a bond with a lov ing, responsive parent or other adult caregiver is an essential factor in healthy development (Furstenberg et al., 1999;Osofsky, 1999;. Children and families exposed to or involved in violence may want to seek professional advice in addressing their mental, physical, and emotional health concerns. # Risk Factors by Domain A few risk factors for youth violence occur before birth. Others come into play as the child develops in response to his or her family and surroundings. Thus, most of the risk factors that exert an effect before puberty are found in the individual and family domains rather than in the larger world, a situation that changes dramatically in adolescence. Childhood risk factors are listed by domain in Box 4-1; effect sizes are listed in # Individual The most powerful early risk factors for violence at age 15 to 18 are involvement in general offenses and sub stance use before age 12. General offenses include seri ous, but not necessarily violent acts, such as burglary, grand theft, extortion, and conviction for a felony. Children engaging in such crimes often come to the attention of the police and juvenile justice system. Numerous studies have documented the overlap between serious nonviolent and violent offenses in ado lescence, so early involvement in serious offenses car ries a substantial risk for violence later. Experimentation with drugs, alcohol, tobacco, or some combination of these substances is not particu larly unusual by age 18, but use of these substances by children under the age of 12 is. Not only are these substances harmful to health, they are illegal. Thus, use of these substances signals antisocial attitudes and early involvement in a delinquent lifestyle that often comes to include violent behavior in adoles cence . Two moderate risk factors emerge in childhood, being male and aggression. Boys (and young men) are far more likely than girls to be violent (see Chapter 2), yet some researchers have suggested that sex is a risk marker rather than a risk factor (Earls, 1994;Hawkins et al., 1998a;Kraemer et al., 1997). A risk marker is a characteristic or condition that is associated with known risk factors but exerts no causal influence of its own (Earls, 1994;.5 For example, many more boys than girls are hyperactive, a risk factor with a small effect size, so some of the predictive power of being male may actually be the influence of hyperactivity. Moreover, boys have tradi tionally been exposed to more violence than girls, and socially approved male role models are more aggres sive, suggesting that social learning plays a role in this risk factor. However, research indicates that being male confers risk even after accounting for other known risk factors. This suggests that being male is a risk factor rather than a risk marker, perhaps with some biological or biological-environmental interac tion as the causal mechanism. Many studies have found aggression-character ized as aggressive and disruptive behavior, verbal aggression, and aggression toward objects-to be a moderate risk factor among boys, although there is some evidence that physical aggressiveness is actual ly responsible for most of the observed effect . Additional research is needed to sort out the unique influence of each of these types of aggression. The remaining individual risk factors have rela tively small effect sizes. Various psychological condi tions, such as hyperactivity, impulsiveness, daring, and short attention span, pose a small risk for violence. A consistent individual predictor is hyperactivity/low attention, the central components of attentiondeficit/hyperactivity disorder (ADHD), a cognitive disorder that may be genetically influenced in some way (Hawkins et al., 1998a). ADHD is characterized by restlessness, excessive activity, and difficulty pay ing attention, traits that may also contribute to low aca demic performance, a risk factor in school. Hyperactivity is often found in combination with phys ical aggression, another risk factor. Some researchers question the independent effect of hyperactivity on later violence, suggesting that the effect is actually physical aggression (and perhaps low academic per formance) that was not controlled for in earlier studies of hyperactivity . There is little agreement about the mechanism linking hyperac tivity to violence. The effects of children's exposure to television and film violence have been studied extensively in regard to aggression, but there is relatively little research regard ing the effects on more serious forms of violent behav ior (for an extended discussion, see Appendix 4-B). Experimental studies have found that exposure to media violence has a small average effect size (.13) on serious forms of violence ; the average effect size in cross-sectional survey studies was very small (.06). Two frequently cited longitudinal studies have examined the effects that exposure to tele vision violence in childhood produces on violent behavior during adolescence or early adulthood. One, in which participants reported having punched, beat en, or choked someone as young adults, found a signif icant predictive effect for women (.22) but no signifi cant effect for men (Huesmann et al., submitted). The other study, in which teenage males reported being involved in a knife fight, car theft, mugging, gang fight, or similar delinquent behavior, found a statistically sig nificant predictive effect in only one of nine tests . Exposure to violence appears to have a weak predictive effect on relatively immediate violence in experimental studies, but there is little con sistent evidence to date for a long-term predictive effect. Little research has been done on violence in other media-video games, music videos, and the Internet. A recent meta-analysis by Anderson and Bushman (in press) reports that video game violence has a small average effect size (.19) on physical aggression in experim ental and cross-sectional studies. Theoretically, the influence of these interactive media might well be greater than that of television and films, which present a passive form of exposure, but there are no studies to date of the effects of exposure to these types of media violence and violent behavior. This is a different use o f the term "risk marker" than that proposed by Kraemer et al. (1997). They use risk marker to refer to a risk factor or cause (such as sex or race) that cannot, in practical terms, be changed by an intervention. This report focuses on its causal role rather than its am enability to change. Problem behavior, another risk factor with a small effect size, refers to relatively minor problem behav iors such as stealing, truancy, disobedience, and tem per tantrums. While not serious in themselves, antiso cial behaviors may set the stage for more serious non violent or violent behavior later. The medical or physical risk factor includes a number of conditions that as a group are somewhat predictive of violence. Prenatal and early postnatal complications, a more specific set of medical condi tions, have been found to have inconsistent effects across a number of studies (Hawkins et al., 1998c). These complications encompass a broad group of genetic conditions or physical injuries to the brain and nervous system that interfere with normal develop ment, including low birth weight, oxygen deprivation, and exposure to toxins such as lead, alcohol, or drugs (Hawkins et al., 1998b). Low resting heart rate, a con dition that has been studied primarily in boys, is asso ciated with fearlessness or stimulation seeking, both characteristics that may predispose them to aggression and violence (Raine et al., 1997;Hawkins et al., 1998c), but there is not enough evidence to establish this condition as a risk factor for violence. Some stud ies have even questioned its effects on aggression (Van HuIIe et al., 2000;Wadsworth, 1976;Kindlon et al., 1995). There is also no evidence that internalizing disorders-nervousness and withdrawal, anxiety, and worrying-are related to later violence (Hawkins et al., 1998c). Low IQ, or low intelligence, includes learning problems and poor language ability. This risk factor has a small effect size and is often accompanied by other risk factors with small effect sizes, such as hyperactivity/Iow attention and poor performance in school. Antisocial beliefs and attitudes, including dishon esty, rule-breaking, hostility to police, and a general ly favorable attitude toward violence, usually consti tute a risk factor in adolescence, not childhood (Hawkins et al., 1998c). Only dishonesty in child hood is predictive of later violence or delinquency, and its effect is small. # O # Family There are no known strong risk factors for youth vio lence in the family domain, but low socioeconomic status/poverty and having antisocial parents are moderate factors. Socioeconomic status generally refers to par ents' education and occupation as well as their income. Poorly educated parents may be unable to help their children with schoolwork, for example, and children living in poor neighborhoods generally have less access to recreational and cultural opportunities. In addition, many poor families live in violent neighborhoods, and exposure to violence can adversely affect both parents and children, as described above. Limited social and economic resources contribute to parental stress, child abuse and neglect, damaged parent-child relations, and family breakup-all risk factors with small effects in childhood. Studies suggest that antisocial parents-that is, violent, criminal parents-represent an environmental rather than a genetic risk factor (Moffitt, 1987). In other words, children learn violent behavior by observ ing their parents rather than by inheriting a propensity for violence. In fact, attachment to parents, a possible protective factor, can have the opposite effect if the parents are violent (Hawkins et al., 1998c). Among the early risk factors with small effect sizes on youth violence is poor parent-child relations. One specific risk factor in this class-harsh, lax, or inconsistent discipline-is also somewhat predictive of later violence (Hawkins et al., 1998c). Children need reasonable, consistent discipline to establish the boundaries of acceptable and unacceptable behavior. Children who are treated harshly may view rough treatment as acceptable, those who are given no guid ance may engage in whatever behavior gets them what they want, and children who receive mixed signals are completely at sea regarding appropriate behavior. Other family conditions, such as high stress, large size, and marital discord, also exert a small effect on later violence. Another childhood predictor with a small effect size is broken homes, a category that includes divorced, separated, or never-married parents and a child's separation from parents before age 16. Separation from parents also operates as a distinct risk factor, again with a small effect size. Abusive parenting in general and neglect in par ticular are predictors of later violence, but they have very small effect sizes. Neglect operates as a distinct risk factor, possibly because neglected children are less likely to be supervised or taught appropriate behavior. This is not to imply that child abuse and neglect do not cause serious problems in adolescence: Indeed, they have large effects on mental health prob lems, substance abuse, and poor school performance (Belsky & Vondra, 1987;Cicchetti & Toth, 1995;Dembo et al., 1992;Silverman et al., 1996;Smith & Thornberry, 1995). This finding is discussed in more detail below, in the section on unexpected findings and effects. # School The only early risk factor in the school domain is poor attitude toward and performance in school, and its effects are small. Numerous individual and family factors may contribute to poor performance, making it a fairly broad measure. For example, a child who is physically aggressive and is rejected by peers or who has difficulty concentrating or sitting still in class may understandably have difficulty performing aca demic tasks. Children who have been exposed to vio lence, as noted earlier, may also have trouble concen trating in school. # Peer Group Young children do not socialize extensively with other children and are not strongly influenced by peers. Peers become more important as children progress through elementary school, although school-age chil dren still look primarily to parents for cues on how to behave. Nonetheless, weak social ties to conventional peers and associating with antisocial peers both exert small effects in childhood. Children with weak social ties are those who attend few social activities and have low popularity with conventional peers. School-age children often reject physically aggressive children because of their inappropriate behavior (Hann & Borek, in press;. The combination of rejection and aggressiveness exacerbates behavior problems, mak ing it more difficult for aggressive children to form positive relationships with other children. Indeed, recent research indicates that children who are both aggressive and rejected show poorer adjustment in elementary school than children who are aggressive, rejected, or neither (Hann & Borek, in press). Being drawn to antisocial peers may introduce or reinforce antisocial attitudes and behavior in children. Indeed, aggressive children tend to seek each other out (Hann & Borek, in press). # Community Community risk factors, such as living in socially dis organized neighborhoods or neighborhoods with high rates of crime, violence, and drugs, are not powerful individual-level predictors in childhood because these external influences have less direct impact on children than on adolescents. They may well exert indirect influ ences through poor parenting practices, lack of family resources, and parent criminality or antisocial behavior. # Summary The most powerful early predictors of violence at age 15 to 18 are involvement in general offenses (serious, but not necessarily violent, criminal acts) and sub stance use. Moderate factors are being male, aggres siveness, low family socioeconomic status/poverty, and antisocial parents. # R is k Fa c t o r s in A d o l e s c e n c e Violence increases dramatically in the second decade of life, peaking during late adolescence at 12 to 20 percent of all young people and dropping off again sharply by the early twenties. Some of these youths followed the childhood-onset trajectory, becoming violent before puberty and escalating their rate of offending during adolescence. But over half of all vio lent youths begin their violent behavior in mid-to late adolescence. These youths gave little indication of problem behavior in childhood and did not have poor relations with their parents. There are numerous theories about why violence begins in adolescence, but a few themes run through most of them Pepler & Slaby, 1994). Developmentally, puberty is accompanied by major physical and emotional changes that alter a young person's relationships and patterns of interac tion with others. The transition into adolescence begins the move toward independence from parents and the need to establish one's own values, personal and sexual identity, and the skills and competencies needed to compete in adult society. Independence requires young people to renegotiate family rules and degree of supervision by parents, a process that can generate conflict and withdrawal from parents. At the same time, social networks expand, and relationships with peers and adults in new social contexts equal or exceed in importance the relationships with parents. The criteria for success and acceptance among peers and adults change. Adapting to all of these changes in relationships, social contexts, status, and performance criteria can generate great stress, feelings of rejection, and anger at perceived or real failure. Young people may be attracted to violent behavior as a way of asserting their independence of the adult world and its rules, as a way of gaining the attention and respect of peers, as a way of compensating for limited personal compe tencies, or as a response to restricted opportunities for success at school or in the community. Good rela tionships with parents during childhood will help in a successful transition to adolescence, but they do not guarantee it. Adolescents exposed to violence at home may experience some of the same emotions and difficulties as younger school-age children-for example, fear, guilt, anxiety, depression, and trouble concentrating in school. In addition, adolescents may feel more vulner able to violence from peers at school or gangs in their neighborhood and hopeless about their lives and their odds of surviving to adulthood. These young people may not experience the growing feelings of compe tence that are important at their stage of development. Ultimately, their exposure to violence may lead them to become violent themselves. Studies have shown that O adolescents exposed to violence are more likely to engage in violent acts, often as preemptive strikes in the face of a perceived threat (Fagan & Wilkinson, 1998;Singer et al., 1994Singer et al., , 1995. # Risk Factors by Domain Not surprisingly, different risk factors for violence assume importance in adolescence. Family factors lose predictive value relative to peer-oriented risk fac tors such as weak social ties to conventional peers, antisocial or delinquent friends, and membership in a gang (Table 4-1). Even involvement in general offenses, which had the largest effect size in child hood, has only a moderate effect size in adolescence. # Individual In early adolescence, involvement in general offens es-that is, illegal but not necessarily violent acts, including felonies-becomes a moderate risk factor for violence between the ages of 15 and 18. Its pre dictive power lessens from childhood, largely because teenagers are somewhat more likely than children to engage in illegal behavior. . Psychological conditions, notably , restlessness, difficulty concentrating, and risk taking,, have small effect sizes in adolescence. Restlessness and difficul ty .concentrating can affect performance in school, a risk factor whose importance increases slightly in ado lescence. Risk taking gains predictive power in early adolescence, particularly in combination with other factors. A reckless youth who sees violence as an acceptable means of expression, for example, is more likely to engage in violent behavior. Aggressiveness exerts a small effect on later vio lence among adolescent males, as does simply being male. While aggressiveness is unusual in children between the ages of about 6 and 10, it is not terribly unusual in adolescence. Similarly, physical violence and crimes against persons in early adolescence have a small effect on the likelihood of violence at ages 15 to 18. Antisocial attitudes and beliefs, including hostility toward police and a positive attitude toward violence, are more important predictors among adolescent boys than they are among children, but their effect sizes remain small. Antisocial behavior and low IQ continue to have small effect sizes in adolescence. Substance use, which was a strong predictor of later violence for children, poses a small risk of later violence for adolescents. The question as to whether drug use causes young people to become violent is complex and has been widely studied (see Miczek et al., 1994 for a review), but there is little compelling pharmacological evidence linking illicit drug use and violence. In one large study, youths reported that over 80 percent of the violent incidents they initiated had not been preceded by drug use, including alcohol use . Thus, the risk may lie more in the characteristics of the social settings in which drug use and violence are likely to occur than in any effect of drugs on behavior (Parker & Auerhahn, 1998;. The majority of violent adolescent offenders use alcohol and illicit drugs (see Chapter 3). Illicit drug use tends to begin after the onset of violence and to be associated with more frequent violent behavior and a longer criminal career . This find ing suggests that drug use may contribute to continued violence rather than to the onset of violence, but it is far from conclusive. Evidence shows that some vio lent behavior stems from robberies or other attempts to.get money to support a drug habit but also that this link is relatively rare. If any substance can be said to cause youth violence, that substance is alcohol (APA, 1993;Parker & Auerhahn, 1998); however, this causal link is inconclusive because adolescent drinking is dependent to a large degree on the situation and social context in which it takes place (for reviews, see Parker & Auerhahn, 1998;Pemanen, 1991;Roizen, 1993). # Family Parents' direct influence on behavior is largely eclipsed by peer influence during adolescence. Not surprisingly, therefore, most family risk factors dimin ish in importance, including the influence of antisocial parents and low socioeconomic status, the most pow erful early risk factors. There are no large or even mod erate risk factors in the family domain in adolescence. Poor parent-child relations continue to have a small effect size, but for adolescents this category includes inadequate supervision and monitoring of young people's activities and low parental involve ment, in addition to inappropriate discipline (Elliott et al., 1985;Hawkins et al., 1998a;Roitberg & Menard, 1995). Broken homes and parental abuse also exert small effects. Other adverse family conditions present a risk factor; for example, some studies have found that family conflict is a risk factor for violence among adolescent males. Although parents can and do influence their ado lescents' behavior, they do so largely indirectly. The kind of peers chosen by young people, for example, is related to the relationship they have with their parents Hill et al., 1999;Simons et al., 1994). # School There are no large or moderate risk factors for vio lence in the school domain, but poor attitude toward or performance in school-particularly if it leads to academic failure-is a slightly larger risk factor in early adolescence than in childhood. Research on school violence indicates that a cul ture of violence has arisen in some schools, adversely affecting not just students but teachers and adminis trators as well (Gottfredson et al., in press;Lorion, 1998). Students exposed to violence at school may react by staying home to avoid the threat or by taking weapons to school in order to defend themselves . For their part, teachers may bum out after years of dealing with discipline problems and threats of violence. Schools located in socially disorganized neighbor hoods are more likely to have a high rate of violence than schools in other neighborhoods (Laub & Lauritsen, 1998). At the same time, however, researchers emphasize that most of the violence to which young people are exposed takes place in their home neighborhood or the neighborhood surrounding the school, not in the school itself (Laub & Lauritsen, 1998). Individual schools, like individual students, do not necessarily reflect the characteristics of the sur rounding neighborhood. A stable, well-administered school in a violent neighborhood may function as a safe haven for students. Some gang activity takes place in schools, but school gangs are generally younger and less violent than street gangs, which form in neighborhoods (Laub & Lauritsen, 1998). Gangs in schools increased dra matically (by 87 percent) between 1989 and 1995 but have recently declined (see Chapter 3). The chances of becoming a victim of violence are more than two and one-half times as great in schools where gangs are reported, and these schools are disproportionately located in disadvantaged, disorganized neighborhoods (Met Life, 1993;. Peer groups complicate the picture further. They operate both in neighborhoods and in schools, but the concentration of young people in schools may intensi fy the influence of these groups. One large study of adolescent males found that some schools have domi nant peer groups that value academic achievement and disapprove of violence, while others have groups that approve of the use of violence (Felson et al., 1994). This study found that the risk of becoming involved in violence varied depending on the dominant peer cul ture in their school, regardless of their own views about the use of violence. # Peer Group Peer groups are all-im portant in adolescence. Adolescents who have weak social ties-that is, who are not involved in conventional social activities and are unpopular at school-are at high risk of becoming violent, as are adolescents with antisocial, delinquent peers. These two types of peer relationships often go together, since adolescents who are rejected by or unpopular with conventional peers may find accept ance only in antisocial or delinquent peer groups. Social isolation-having neither conventional nor antisocial friends-is not a risk factor for violence, however (Cairns & Cairns, 1991;Fergusson & Lynskey, 1996;. A third risk factor with a large effect size on violence is belonging to a gang. Gang mem bership increases the risk of violence above and O beyond the risk posed by having delinquent peers (Thornberry, 1998). These three peer group factors appear to have independent effects, they sometimes cluster together, and they are all powerful late predic tors of violence in adolescence. Researchers who have studied what causes young people to join gangs have found that the risk factors for gang membership are virtually the same as those for violence generally (Hill et al., 1999). The notion that gangs act as surrogate families for children who do not have close ties to their own fam ilies is not borne out by recent data (Hill et al., 1999), but gangs do strengthen young people's sense of belonging, their independence from parents, and their self-esteem. Estimates from law enforcement agencies indicate that gang members are overwhelm ingly male and the great majority (almost 80 percent) are African American or Hispanic . But surveys in which young peo ple identify themselves as gang members suggest that there are substantially larger proportions of white and female gang members. In a survey of near ly 6,000 8th graders in 1995, 25 percent of white stu dents and 38 percent of female students reported they were gang members (Esbensen & Osgood, 1997). Lacking comparisons within ethnic groups, it is difficult to tell whether ethnicity per se is a risk factor in gang membership. # Community Increasing involvement in the community is a healthy part of adolescent development, unless the communi ty itself poses a threat to health and safety. Social dis organization and the presence of crime and drugs in the neighborhood pose a small risk of violence when measured on an individual level, as they are in Table 4-1. As noted in the table, however, both of these risk factors have a substantially greater effect on the neighborhood level, where they measure the average rate of violent offending by youths living in the neigh borhood or community. Socially disorganized communities are character ized in part by economic and social flux, high turnover of residents, and a large proportion of disrupted or sin-gle-parent families, all of which lessen the likelihood that adults will be involved in informal networks of social control. As a result, there is generally little adult knowledge or supervision of the activities of teenagers and a high rate of crime. Moreover, in areas experienc ing economic decline, there are likely to be few neigh borhood businesses. In such an environment, it is hard for young people to avoid being drawn into violence. Not only are they on their own after school, they are exposed to violent adults and youth gangs, they have few part-time job opportunities, and their neighborhood is not likely to offer many after-school activities such as sports or youth groups (Bursik & Grasmick, 1993;Sampson et al., 1987). Social disorganization is also a risk factor for vio lence in rural areas. One study of rural communities found that poverty plays a less important role in pre dicting violence than residential instability, broken homes, and other indicators of social disorganization (Osgood & Chambers, 2000). In fact, very poor areas were not characterized by high residential instability or a large proportion of broken homes. In cities, how ever, the combination of poverty with instability and family disruption is predictive of violence (Bursik & Grasmick, 1993;. Adolescents who are exposed to violence in their neighborhood feel vulnerable and unable to control their lives. These feelings can lead to helplessness and hopelessness. Such young people may turn to violence as a way of asserting control over their surroundings. They may arm themselves or even join a gang for pro tection. Studies have shown that adolescents exposed to violence are more likely to engage in violent acts, often as preemptive strikes in the face of a perceived threat (Singer et al., 1994(Singer et al., , 1995. Neighborhood adults who are involved in crime pose a risk because young people may emulate them. Easily available drugs add to the risk of violence. As noted earlier, drug use is associated with both a higher rate of offending and a longer criminal career . More important, ready availability of drugs indicates that considerable drug trafficking is taking place in the neighborhood-and drug trafficking is dan gerous for buyer and seller alike. # Summary Violence peaks during the second decade of life. The youths who first became violent in childhood escalate their violence in adolescence, and a larger group of young people embarks on violence in adolescence. For some young people, violence represents a way of gain ing the respect of peers, enhancing their sense of self worth, or declaring their independence from adults. Violence drops off as adolescents enter adulthood and assume adult roles. Parents' direct influence on behavior is largely sup planted in adolescence by peer influences. Thus the most powerful peer predictors of violence in adoles cence are weak social ties to conventional peers, ties to antisocial, delinquent peers, and belonging to a gang. # Unexpected Findings and Effects This chapter does not identify a number of characteris tics and conditions frequently thought of as risk factors. Furthermore, some of the risk factors that have been identified may exhibit smaller effect sizes than expect ed. There are two reasons for this. First, this report relies on longitudinal studies, which identify risk fac tors and their effect sizes on the basis of their ability to predict future behavior. Much of this research involves identifying risks for aggression, externalizing behavior, or antisocial behavior-not risks for violence. While there is considerable overlap between the risk factors for aggression and those for violence, there are some important differences, particularly with respect to effect sizes (Hann & Borek, in press). Television violence, for example, has a very large effect on aggressive behavior but only a small effect on violence. Second, some stud ies that have been widely cited in the media involve cross-sectional and retrospective research designs, which are inappropriate for identifying factors that pre dict future violence. Conduct disorder has been linked to youth vio lence in numerous studies, but the cluster of symp toms used to determine this disorder includes physi cal aggressiveness, nonphysical aggressiveness, and antisocial attitudes and beliefs. For purposes of pre dicting violence, the critical question is: What com ponents of this disorder actually confer risk? There is some evidence that physical aggression accounts for most of the predictive power of conduct disorder and has a moderate to small effect size as a predictor of violence. Antisocial attitudes and beliefs also predict violence, but with an even smaller effect size. The three com ponents of conduct disorder generally cluster togeth er, which accounts for their having been combined into a single risk factor in earlier studies. Other childhood disorders such as attention-deficit/hyperactivity disorder, depressive and anxiety disorders, and their symptoms do not cause violent behavior, but their presence often signals serious behavioral and emotional problems that negatively affect fami ly, social, and academic functioning, domains of risk for violent behavior. Race has long been considered a risk factor for the onset of violence, and it is included as a risk fac tor in most studies using simple bivariate predictors of violence. The question is whether race predicts violence once other known risk factors are taken into account. Studies that have accounted for the effects of other known risk factors have typically found no significant effect of race on youth violence Roitberg & Menard, 1995). Thus, race appears to be a risk marker rather than a risk factor. Race is a proxy for other known risk factors-living in poor, single-parent families, doing poorly at school, and being exposed to neigh borhood disadvantage, gangs, violence, and crime. The evidence suggests that the link between race and violence is based largely on social and political dis tinctions rather than biological differences. Ethnicity has also been proposed as a risk factor, but it has not been studied extensively enough to include here. Young people from ethnic minorities may be subject to prejudice and thus to limited opportunity, and they may face unique stresses when their family culture conflicts with the dominant U.S. culture. At the same time, their ethnic culture may offer them strong support and guidance and thus function as a protective factor (APA, 1993). Child abuse is widely considered to be a powerful risk factor for youth violence. This belief is based on a number of early studies that suffered from serious methodological problems (see Dodge et al., 1990;Garbarino & Plantz, 1986;Howing et al., 1990;and Widom, 1989 for reviews). In more sophisticated, con trolled longitudinal studies, the effects are much small er (see Table 4-1), a finding that holds for both self report and official record studies. In addition, studies reporting on child abuse as a predictor of nonviolent delinquent behavior or less serious offenses find larger effect sizes than those cited here for violence or serious delinquency (Bolton et al., 1977;Widom, 1989Widom, ,1991Zingraff et al., 1993Zingraff et al., , 1994. Neither sexual abuse nor physical abuse is a significant predictor of youth violence when considered alone (Hawkins et al., 1998c). Sexual abuse has been linked to criminal behavior in adulthood (Widom & Ames, 1994), but not to violence in adolescence. Although the effect size of child abuse or neglect is small when a correlation measure is used (as in Table 4-1), the relative risk of violence among abused or neglected children can be substantial. Knowing that a child was abused does not help much in predicting future violence, however, since the vast majority of abused children do not become violent. For example, one longitudinal study showed that 5 percent of abused children were arrested for a violent crime by age 18, compared to 3 percent of nonabused children (Widom, 1991). The relative risk of arrest for violence is nearly twice as great in the abused group as in the nonabused group, yet the correlation for this relation ship is .07, a small effect size.6 In other words, even though the probability of later violence is substantial ly higher among abused than nonabused youths in this study, the correlation is small because the majority of all youths (95 percent of abused and 97 percent of nonabused youths) did not become violent. When the proportion of youths who become vio lent is greater, the relative risks appear to be lower. Thus, when subjects in the 1991 Widom study were tracked to age 30, the relative risk of violence dropped to 1.3 (Widom, 2000). In the one longitudi nal self-report study to date, which had relatively high proportions of abused children reporting vio lence, the relative risk of violence was 1.2 (Smith & Thornberry, 1995). In both of these cases, the corre lation was less than .10. Heredity does not seem to play a strong role in vio lence (see Cary, 1994 for a review). While there is some evidence supporting a genetic effect, the proposed mechanisms are very complex and nonspecific (Turbin, 2000). Neurotransmitters such as dopamine, serotonin, and GABA may play a role in aggression, but so far their mechanisms of action are unclear and there is insufficient evidence to consider them predictors of violence. In general, there are no known neurobiologi cal patterns that are precise and specific enough to be considered reliable risk factors for violent behavior . Drug trafficking in early adolescence predicts later violence (Hawkins et al., 1998c;Herrenkohl et al., 2000;Menard et al., in press;. This risk factor is not included here because only one study presents corre lations (or the data necessary to calculate them); there fore, average effect size could not be estimated. In the Menard et al. study, the correlation between selling marijuana and violence in adolescence was .33; for selling hard drugs, it was .27. In the Hawkins et al. study, the odds ratio for selling drugs at age 14 and violence at age 18 was 3.34; it was 4.55 for selling at age 16 and violence at age 18. Drug selling'thus appears to have at least a moderate effect size. # Pr o p o s e d Protective Factors in C h il d h o o d a n d A do lescence Research on resilience and the public health approach to the problem of youth violence have brought a new awareness of, and research on, pro tective factors-those aspects of the individual and his or her environment that buffer or moderate the effect of risk. Identifying and understanding how protective factors operate is potentially as important to violence prevention and intervention efforts as research on risk factors. To date, the evidence regarding protective factors against violence has not met the standards established for risk factors. Therefore, this report does not refer to protective factors, only to proposed protective factors (Table 4-2). There are several reasons for this: Not all studies define protective factors as buffering the effects of risk; most studies have looked for an effect on antisocial behavior in general, not on violence specifically; and those that have found buffering effects on violence have not been adequate ly replicated. This does not mean that protective fac tors do not exist, just that more research is needed to identify them.7 Most studies of protective factors do not specify when in the course of development these factors exert their buffering effects or how they change over the life course. Further study is needed to clarify these points; therefore, Table 4-2 does not show age of onset for the proposed protective factors listed. # A Note on Sources The authors of a 1995 longitudinal study on protective factors and their buffering effects on the risk of prob lem behavior in adolescence (lessor et al., 1995) recently reexamined their data to see whether they could find any buffering effect specifically on vio lence. They did find a buffering effect, but their results must be considered preliminary until they are replicat ed by others. Nonetheless, these findings are encour aging, since they indicate that several of the factors identified as protective against problem behavior also provided a buffering effect against violence. By implication, other studies that have demonstrated buffering effects on the risk of antisocial behavior or general delinquency (for example, Fergusson & Lynskey, 1996) may also contain evidence of potential protective factors against violence. The discussion of proposed protective factors in this report rests on the 7 There is a fairly extensive body o f research on protective factors in the field o f psychopathology (Carmezy, 1985;Rae-Crant et al., 1989;Rolf et al., 1993;Rutter, 1979Rutter, , 1985Rutter et al., 1979;Stattin et al., 1997;W erner andSmith, 1982, 1992). There are also a number o f studies focusing on delinquency that purport to identify protective factors (Brewer et al., 1995 reanalysis of the 1995 study data (Turbin, 2000), as well as on results from other studies, bearing in mind the caveats noted above. The 1995 lessor study grouped possible protective factors together and found that students who scored high on this index of protection were buffered from the effects of risk, compared to students who scored low on the index. The index was composed of seven psy chosocial protective factors: attitudinal intolerance of deviance, positive orientation to health, religiosity,, positive relations with adults, perceived consequences for misbehavior, friends as models for conventional behaviors, and high involvement in conventional activ ities. In an analysis of specific factors, however, only two-an intolerant attitude toward deviance and com mitment to school-had significant protective effects. The new findings show that the same two factors appear to exert a significant, though small, buffering effect on risk factors for violence. # Proposed Protective Factors by Domain One of the proposed protective factors shown to have a buffering effect on the risk of violence is an individ ual characteristic, and the other falls into the domain BEST COPY AVAILABLE of school; both are classed as having a small effect. No other factors in the individual, family, school, or peer group domains have been shown to exert signifi cant buffering effects on risk factors for violence, although they have been shown to moderate the risk of antisocial behavior or delinquency. No protective fac tors have been proposed yet in the community domain. # Individual An intolerant attitude toward deviance, including vio lent behavior, is the strongest proposed protective fac tor. It reflects a commitment to traditional values and norms as well as disapproval of activities that violate these norms. Young people whose attitudes are anti thetical to violence are unlikely to become involved in activities that could lead to violence or to associate with peers who are delinquent or violent. The four remaining individual factors have not yet been shown to moderate violence, although they may buffer risks for antisocial behavior or general delin quency. High IQ has been cited as a possible protec tive factor (Fergusson & Lynskey, 1996;Garmezy, 1985;Rutter, 1985;Werner & Smith, 1982). Children with above-average IQs may exhibit qualities, such as curiosity and creativity, that help them make the most of early educational, artistic, and cultural experiences. Above-average IQ can also help a child excel in school. High IQ may increase an adolescent's chances of benefiting from educational, creative, and cultural opportunities. For youths facing multiple risk factors, exposure to the wider world may open a window on alternative values and lifestyles. Being bom female has also been cited (Garmezy, 1985;Rutter, 1985;Wemer & Smith, 1982), but it is the opposite of being bom male, a risk factor, and as yet there is no evidence of a buffering effect. Being a girl entails less exposure to violence, less impulsive ness and daring, and being expected to behave less aggressively than boys. Some studies have proposed positive social ori entation as a protective factor (Garmezy, 1985;lessor et al., 1998;Rutter, 1985;Werner & Smith, 1982). Like commitment to school, a positive social orientation indicates that a young person has adopt ed traditional values and norms, a slightly different emphasis than intolerance of deviance. This pro posed factor appears to be the opposite of antisocial attitudes and beliefs, a late-onset risk factor that has a small effect size. Perceived sanctions for transgressions, a protec tive factor in the earlier lessor study (1995), refers to perceived peer disapproval of deviant behavior. The reanalysis of those original data reveals that this pro posed factor has no significant protective effect on risk of violence or problem behavior. # Family There is no doubt that an essential aspect of healthy child development is forming a secure attachment in infancy to a parent or other adult who senses and responds to a baby's needs (Bell & Fink, 2000). Likewise, researchers agree that having a loving adult who is interested in and supportive of a child or young person's ideas and activities helps that child or ado lescent develop the confidence and competence need ed to progress from one stage of development to the next. Good relations with an adult who supports con ventional behavior and disapproves of delinquent O behavior can provide invaluable guidance for young people. The question is whether these relationships moderate the effects of exposure to risk and thus fit the definition of a protective factor. A warm, supportive relationship with parents or other adults has been shown to protect against antiso cial behavior, but studies so far have not found a sig nificant buffering effect on the risk of violence (Hawkins et al., 1998c;Klein & Forehand, 2000;Rutter, 1979;Turbin, 2000;Wemer & Smith, 1992). It is uncertain whether family protective factors, like family risk factors, become less influential as young people progress through adolescence. Parental support and encouragement remain important, but even parents who have had a good relationship with thenchildren before puberty may affect their adolescents' behavior only indirectly-for example, through choice of friends . This indirect influence is not inconsequential, however; associating with peers who disapprove of violence may inhibit later violence in young people (Hawkins et al., 1998c), and parents' positive evaluation of peers has been found to reduce the risk of delinquency . Several studies have pointed to monitoring or supervision of activities as a protective factor against delinquency and antisocial behavior, but this is essen tially the opposite of failure to monitor, an adolescentonset risk factor with a small effect size. To date, no evidence of moderating effects on the risk of violence has been presented (Baldwin et al., 1990;Klein & Forehand, 2000;. # School Commitment to school is the second proposed protec tive factor that has been found to buffer the risk of youth violence. Young people who are committed to school have embraced the goals and values of an influential social institution. Such young people are unlikely to engage in violence, both because it is incompatible with their orientation and because it would jeopardize their achievement in school and their standing with adults (lessor et al., 1995;Turbin, 2000). This proposed factor is included because it appears to buffer the risk of violence, not because it is 93 the opposite of poor attitude toward or performance in school, a risk factor with small effect sizes in both childhood and adolescence. School can give adolescents who face multiple risk factors a place in which to excel socially and academi cally. Achievement in school and the approval of teach ers provide the recognition so important to adolescent development-recognition some adolescents do not receive from other sources. Encouragement from teachers can give young people the confidence to seek continued educational or job skills training. In addition, schools with peer groups that value academic achieve ment may lower students' risk of becoming involved in violence (Felson et al., 1994). Unfortunately, schools with a culture of violence may be unable to exert their very important protective function. Extracurricular activities in art, music, drama, school publications, and the like give adolescents an opportunity to participate in constructive group activities and achieve recognition for their efforts. Studies have found that recognition for or involve ment in conventional activities-whether family, school, extracurricular, religious, or community-is a protective factor against antisocial behavior (lessor et al., 1995;Rae-Grant et al., 1989). The reanalysis of the lessor data shows that involvement in family, volunteer, and school club activities other than sports has an insignificant effect on risk for violence (Turbin, 2000). # Peer Group Having friends who behave conventionally is a pro posed protective factor that seems to reduce the risk of delinquency, but there is no evidence of a true buffer ing effect on specific risk factors. Buffering effects on violence were not significant in the reanalysis of the lessor data (Turbin, 2000; see also . However, as noted earlier, researchers have found that associating with peers who disapprove of violence may inhibit violence in young people (Hawkins et al., 1998c;lessor et al., 1995). # O # Summary Although the body of research on protective factors is growing, very little work has been done specifically on protective factors that buffer the risk of violence. Some researchers have identified individual and environmen tal characteristics that can be considered candidates for protective factors. Lacking adequate scientific evidence of the nature, mechanism, size, and timing of these can didates' moderating effects, however, this report con siders all of them proposed protective factors. One recent reanalysis of earlier data has found two proposed protective factors that seem to buffer the risk of violence-an intolerant attitude toward deviance and commitment to school. These two fac tors appear to exert a statistically significant, though small, buffering effect on the risk of violence, but until these findings are replicated, they must be considered preliminary. Identifying and understanding how protective fac tors operate is as important to preventing and stopping violence as identifying and understanding risk factors. This area of the public health approach to youth vio lence cries out for more research. # C o n c l u s io n s Scientists have identified a number of personal char acteristics and environmental conditions that put chil dren and adolescents at risk of violent behavior and some that seem to protect them from the effects of risk. These risk and protective factors can be found in every area of life, they exert different effects at differ ent stages of development, they tend to appear in clus ters, and they appear to gain strength in numbers. The public health approach to youth violence involves identifying risk and protective factors, determining when in the life course they typically come into play, designing preventive programs that can be put in place at just the right time to be most effective, and making the public aware of these findings. Many years of research have yielded valuable insights into the risk factors involved in the onset and developmental course of violence. Less work has been done on protective factors, but that situation is changing. Some basic principles have emerged from these studies: Risk and protective factors exist in every area of life-individual, family, school, peer group, and community. Individual characteristics interact in complex ways with a child's or adolescent's envi ronment to produce violent behavior. Risk and protective factors vary in predictive power depending on when in the course of human devel opment they occur. As children move from infancy to early adulthood, some risk factors will become more important and others less important. Substance use, for example, is a far more powerful risk factor at age 9 than it is at age 14. Risk factors do not operate in isolation-the more risk factors a child or young person is exposed to, the greater the likelihood that he or she will become violent. Risk factors can be buffered by protective factors, however. An adolescent with an intolerant attitude toward violence is unlikely to engage in violence, even if he or she is associating with delin quent peers, a major risk factor for violence at that age. Risk factors increase the likelihood that a young person will become violent, but they may not actu ally cause a young person to become violent. Scientists view them as reliable predictors or even as probable causes of youth violence. They are use ful for identifying vulnerable populations that may be amenable to intervention efforts. Risk markers such as race or ethnicity are frequent ly confused with risk factors; risk markers have no causal relation to violence. No single risk factor or combination of factors can predict violence with unerring accuracy. Few young people exposed to a single risk factor will become involved in violent behavior; similarly, most young people exposed to multiple risks will not become violent. By the same token, protective factors cannot guarantee that a child exposed to risk will not become violent. Researchers have identified at least two onset tra jectories for youth violence: a childhood trajectory that begins before puberty and an adolescent one that begins after puberty. Violence peaks during the second decade of life. The small group of offenders who began their violent behavior in childhood commits more violent offenses, and the larger group of adolescent offenders begins to become involved in violence. - Early risk factors for violence in adolescence include involvement in serious (but not necessari ly violent) criminal acts and substance use before puberty, being male, aggressiveness, low family socioeconomic status/poverty, and antisocial par ents. All of these early risks stem from a child's individual characteristics and interaction with his or her family. The influence of family is largely supplanted in adolescence by peer influences; thus, risk factors with the largest predictive effects in adolescence include weak social ties to conven tional peers, ties to antisocial or delinquent peers, and belonging to a gang. Committing serious (but not necessarily violent) criminal offenses is also an important risk factor in adolescence. Drug selling is a risk factor, but its effect size has not been established. - Identifying and understanding how protective fac tors operate is potentially as important to preventing and stopping violence as identifying and under standing risk factors. Several protective factors have been proposed, but to date only two have been found to buffer the risk of violence-an intolerant attitude toward deviance and commitment to school. Protective factors warrant more research attention. Violence prevention and intervention efforts hinge on identifying risk and protective factors and determining when in the course of development they emerge. More research in these areas is needed, par ticularly concerning why violence stops or continues in childhood and adolescence.-Nonetheless, the research carried out to date provides a solid founda tion for programs aimed at reducing risk factors and promoting protective ones-and thereby preventing violence, the subject of Chapter 5. # R e f e r e n c e s A m erican Psychological A ssociation. (1993). Violence 1972). During this period, new media emerged-video games, cable television, music videos, and the Internet. As they gained popularity, these media, along with tele vision, prompted public concern and research attention. Recent surveys depict the abundance of (primari ly electronic) media in U.S. homes (Roberts et al., 1999;Woodard, 1998) and the extensive presence of violence within the media landscape (Wilson et al., 1997(Wilson et al., , 1998. They also show that the proliferation of new media has expanded the opportunities for chil dren to be exposed to media violence at home. Current psychological theory suggests that the interactive nature of many of these new media may affect chil dren's behavior more powerfully than passive media such as television. Research to test this assumption is not yet well developed, and accurate measurement is needed to determine how much violence children are actually exposed to through various media-and how patterns of exposure vary among American youths. In reading this discussion of research on the impact of media violence on America's youth, a few major points should be kept in mind: - First, research on the effects of media violence examines many kinds of outcomes in young people. Researchers have focused primarily on aggression, an outcome that psychologists define as any behav ior, physical or verbal, that is intended to harm another person. Physical aggression may range from less serious acts, such as pushing or shoving, to more serious physical contact and fighting, to very serious violent acts that carry a significant risk of injury or death, such as assault, robbery, rape, and homicide. Some studies have focused on how media violence affects aggressive thinking, including beliefs and attitudes. Other studies have focused on the effects of media violence on aggressive emotions-that is, on emotional reactions, such as anger, that are relat ed to aggressive behavior. In this discussion, the label "violence" is reserved for the most extreme end of the physical aggression spectrum. - Second, as noted in Chapter 4, the preponderance of evidence indicates that violent behavior seldom results from a single cause; rather, multiple factors converging over time contribute to such behavior. Accordingly, the influence of the mass media, how ever strong or weak, is best viewed as one of the many potential factors that help to shape behavior, including violent behavior. - Third, a developmental perspective is essential for understanding how media violence affects youth behavior and for framing any coherent public health response to it. Although this report focuses general ly on the violent behavior of adolescents, it is criti cal to understand how children are influenced by and respond to media violence, especially in order to recognize and help those who are particularly susceptible to adverse effects. Most youths who are aggressive and engage in some forms of antisocial behavior do not become violent teens and adults. However, it is well established that many violent adolescents and adults were highly aggressive and 1 0 4 8; even violent at younger ages, and the highly aggres sive child is at increased risk of growing up to be a more aggressive young adult . Because influences that promote aggressive behavior in some young children can contribute to increasingly aggressive and even violent behavior many years later, it is important to understand the early factors that may play a role in later outcomes. - Fourth, a growing body of research supports theo ries that explain how exposure to media violence would activate aggressive behaviors or attitudes in some children. Humans begin imitating other indi viduals at a very early age, and young children learn many motor and social skills by observing the behavior of others (Bandura, 1977). Social interac tions shape the scripts for behavior that children acquire, but observational learning is a powerful mechanism for acquiring social scripts throughout childhood (Huesmann, 1998). Most researchers agree that such observational learning is probably the major psychological process underlying the effects of media violence on aggressive behavior. This same process could explain how prosocial behavior depicted in the media might encourage positive behavior in children (Friedlander, 1993;Harold, 1986;Mares, 1996). # M e d ia V io l e n c e : Ex p o s u r e a n d C o n t e n t American children and youths spend, on average, more than 4 hours a day with television, computers, videotaped movies, and video games (Roberts et al., 1999;Woodard, 2000). But their exposure to media varies considerably, depending on their age, parental viewing habits, and family socioeconomic status (SES). Most systematic research on children's expo sure to violent media dates back to the 1970s, when most families did not have access to cable television, music videos, video games, or the Internet. As noted earlier, very few contemporary studies systematically document children's actual consumption of violent media; this is particularly true for the newer media. Several content analyses over the last 30 years have systematically examined violence on television (Gerbner et al., 1980;Potter et al., 1995;Signorielli, 1990). The largest and most recent of these was the National Television Violence Survey (NTVS)1 (Wilson et al., 1997(Wilson et al., , 1998, which examined the amount and content of violence2 on American televi sion for three consecutive years, as well as contextual variables that may make it more likely for aggression and violence to be accepted, learned, and imitated. Smith and Donnerstein (1998) report the following NTVS findings: - 61 percent of television programs contain some vio lence, and only 4 percent of television programs with violent content feature an "antiviolence" theme. - 44 percent of the violent interactions on television involve perpetrators who have some attractive qual ities worthy of emulation. - 43 percent of violent scenes involve humor either directed at the violence or used by characters involved with violence. - Nearly 75 percent of violent scenes on television feature no immediate punishment for or condemna tion of violence. - 40 percent of programs feature "bad" characters who are never or rarely punished for their aggres sive actions. The NTVS report notes that many television pro grams fail to depict the harmful consequences of vio lence. Specifically, it finds that of all violent behav ioral interactions on television, 58 percent depict no pain, 47 percent depict no harm, and 40 percent depict harm unrealistically. Of all violent scenes on televi- The NTVS random ly sampled programs from 6:00 a.m. to 11:00 p.m. on 23 broadcast and cable channels over a 20-week period from O ctober to June during the 1994 through 1997 view ing seasons. A sum o f 119 hours per channel, or 2,500 hours o f television programming was assessed each year. The NTVS defined violence as "overt depiction o f a credible threat o f physical force, or the actual use o f such force intended to physically harm an animate being or group o f beings." Content analyses o f television programs generally treat the program itself as the unit o f analysis and exclude advertisements."Violence also includes certain depictions o f physically harmful consequences against an animate being or group that occur as a result o f unseen violent means. Thus, there are three prim ary types o f violent depictions: credible threats, behavioral acts, and harmful consequences (Smith & Donnerstein, 1998, p. 170). sion, 86 percent feature no blood or gore. Only 16 per cent of violent programs feature the long-term, realis tic consequences of violence. # M a jo r B e h a v io r a l Effe c t s o f M e d ia V io l e n c e Because an exhaustive description of the research lit erature is not possible within this brief discussion, findings from meta-analyses are reported3 where available. In meta-analyses, the results of multiple studies are combined and compared systematically and an overall effect size computed. These analyses include findings from randomized experiments that look at aggression immediately after viewing vio lence, as well as cross-sectional surveys that provide a snapshot of the relationship between viewing violence and behavior at a fixed point in time. Also presented are findings from longitudinal studies that examine whether exposure to media violence affects violence and aggression over time. # Television and Film Violence Many anecdotal reports have described instances in which television and film violence led to immediate violent behavior in individual children, but scientific studies of this relationship draw a more complex and qualified picture. Most of the relevant research has focused on how watching dramatic violence on televi sion and film affects aggressive thoughts and emo tions, as well as aggressive behavior. Some important studies address violence as well. # Experimental Studies A substantial number of laboratory and field experi ments over the past half-century have examined whether children exposed to violent behavior on film or television behave more aggressively immediately afterwards (see reviews by Bushman & Huesmann, 2000;Comstock & Scharrer, 1999;Geen, 1990;Geen & Thomas, 1986;Huesmann et al., 1997). Many stud ies have also examined the immediate effect of media violence on aggressive thoughts or emotions (Rule & Ferguson, 1986), which have been shown to increase the risk of aggressive behavior (Dodge & Frame, 1982;Huesmann & Guerra, 1997). The most recent and comprehensive meta-analy sis of media violence was conducted by , who examined effect sizes from 217 empirical studies on media violence and aggres sive and violent behavior published between 1957 and 1990. The analysis indicates clearly that brief expo sure to violent dramatic presentations on television or in films causes short-term increases in the aggressive behavior of youths, including physically aggressive behavior. Across all the randomized experiments, the unweighted average effect size was large (r = .37).4 When only experiments examining physical aggres sion as the outcome were examined, the effect size was also large (r = .32). Although the experimental methods used in these studies enable researchers to test causality more read ily than other research methods as noted by Comstock and Paik (1991), the findings may not necessarily apply to all real-world settings. Because experiments are narrowly focused on testing specific causal hypotheses, they do not examine the effects of all fac tors that might be present in more realistic situations. This means that some real-world influences might actually lessen or even eliminate the aggressive reac tions observed in experiments. For example, while tel evision, film, and other media contain a variety of antisocial and other messages, most laboratory studies to date have exposed study participants primarily to violent materials. In addition, participants may react differently in the laboratory when they realize that their expressions of aggression will not be punished (Gunter, 1983). Any summary of these experimental results should also acknowledge the argument raised by some critics (such as Freedman, 1992) that many study participants provide the responses they believe the researcher wants. Despite these limitations, labo ratory experiments are important because they allow researchers to isolate the unique effect of exposure to violence on subsequent behavior. An important general finding from these experi mental studies is that not all youths seem to be affect ed equally by media violence. Effects seem to be strongest on youths who are predisposed to be aggres sive for some reason or who have been aroused or provoked (Berkowitz, 1993;Bushman, 1995;Geen & O'Neal, 1969). # Cross-Sectional Surveys Cross-sectional surveys over the past 40 years have generally focused on establishing a link between the current aggressiveness of children and the amount of television and film violence they watch regularly (see reviews by Bushman & Huesmann, 2000;Chaffee, 1972;Comstock & Scharrer, 1999;Eysenck & Nias, 1978;Huesmann & Miller, 1994). Paik and Comstock's meta-analysis (1994) indi cates that in cross-sectional surveys viewing media violence was positively correlated with various meas ures of aggression. They reported small to moderate effect sizes across all measures of aggression (r = .19) and for physical aggression alone (r = .20). For the outcome of most concern to this report-criminal vio lence against a person-the effect size was small (r = .06). These results suggest that the link between media violence and aggressive behavior found in laboratory studies may also hold for behaviors outside the labo ratory. However, cross-sectional surveys do not by themselves indicate whether media violence is caus ing aggression, whether aggressive youths are attract ed to media violence, or whether some other factor is predisposing some youths to watch more violence and behave more aggressively. # Longitudinal Studies Long-term studies in which exposure to media vio lence in early childhood is related to later aggression and violence (such as aggravated assault, robbery, rape, and homicide) can identify the enduring effects of media violence. In most such studies to date, how ever, aggression, not violence, has been the primary outcome measured. In the absence of a meta-analysis, the findings of three frequently cited longitudinal studies on the effects of media violence are discussed briefly below. Studies examining effects over shorter time periods (Singer et al., 1984) or with internation al samples (Huesmann & Eron, 1986) are not includ ed here. In a study begun in 1960 on a sample of 875 youths in New York State, Eron and colleagues found that for boys, but not for girls, exposure to media vio lence at age 8 was significantly related to aggressive behavior a decade later (r = .31, N = 211, p < .01) (Eron et al., 1972;Lefkowitz et al., 1977). At both times, peers assessed physical and verbal aggression. The longitudinal correlation remained above .25, even in separate analyses statistically controlling for factors such as the child's initial aggressiveness, the child's intelligence, family SES, parents' aggressiveness, and parents' punishment and nurturance of the child. examined the probability of initiating aggression after exposure to violence on television in 2,400 boys and girls age 7 to 12 from two midwestem cities who had been surveyed up to six times between 1970 and 1973. A sample of 800 teenage boys5 was studied at five times to identify the effect of violent television on aggression and vio lence. For the elementary school sample, the average cross-sectional correlation between exposure to media violence and personal aggression was small for boys (r = .17) and large for girls (r = .30). The researchers then attempted to predict aggressive behavior at one point in time from the extent to which children viewed television violence at an earlier time, while controlling for earlier aggressive characteris tics. They examined this prediction over 15 time intervals ranging from 5 months to 3 years apart. For elementary school boys, only 2 of the 15 predictions at different intervals were statistically significant. For girls, only three predictions were statistically signifi cant. In the teenage male sample, only one of eight correlations was significant. In only one of nine analyses using measures of violence (for example, knife fight, car theft, mugging, gang fight) were boys with greater exposure to television violence more likely to initiate violence 2 years later than those with less exposure. The third longitudinal study of media violence effects began in the late 1970s and spanned five coun tries (Huesmann et al., submitted;Huesmann et al., 1984;Huesmann & Eron, 1986). In each locale, sam ples of middle-class youths were examined three times between age 6 to 8 or age 8 to 11. Both physical and verbal aggression were assessed by peers. The correlations between aggression and overall viewing of television violence at a single point in time were small to moderate and often significant. In the United States, the 3-year average correlation was moderate for boys and for girls (r = .25 and r = .29, respective ly; p < .001). The predictive power of viewing televi sion violence for childhood aggression a year later varied substantially. In the United States, girls' view ing of television violence had a significant effect (P = .17, N = 89, p < .05) on their later aggression, even after accounting for early levels of aggression, SES, and scholastic achievement. For boys, television vio lence alone did not predict later aggression. When the investigators took into account both exposure to tele vision violence and identification with aggressive tel evision characters, they found a positive relation with aggressiveness (P = .19, N = 84, p < .05). A follow-up study of over 300 people in the U.S. sample 15 years later suggested that media violence has a delayed effect on aggression (Huesmann et al., submitted). There was a small to moderate longitudi nal correlation between childhood television viewing and a composite measure of young adult aggression (physical, verbal, and indirect aggression) for both men (r = .21, N = 153, p < .01) and women (r = .19, N = 176, p < .01). When the outcome was limited to physical aggression, the correlations were smaller (r = .17 and r = .15, respectively). Furthermore, women who had watched relatively more television violence as girls committed significantly more specific acts of violence as adults, such as "punching, beating, or choking another adult," than did the other women (17 percent versus 4 percent). There were no significant differences among the men. Other analyses showed th a t e ffe c ts rem ain ed s ig n ific a n t ev en w hen researchers controlled for parent education and chil dren's scholastic achievement (P = .19 for boys, P = .17 for girls, p < .05). In addition, aggressive behavior did not significantly increase boys' or girls' viewing of television violence (P = .08 for boys and P = .04 for girls; p = ns). In summary, these longitudinal studies show a small, but often statistically significant, long-term relationship between viewing television violence in childhood and later aggression, especially in late ado lescence and early adulthood. Some evidence suggests that more aggressive children watch more violence, but the evidence is stronger that watching media vio lence is a precursor of increased aggression. # Other Studies Other studies have explored the behavioral impact of introducing television in several countries (Centerwall, 1989a(Centerwall, , 1989b(Centerwall, , 1992Joy et al., 1986;Williams, 1986). These studies indicate that when tel evision was introduced, aggression and violence increased. The findings must be viewed with caution, however, because they do not take into account a range of other factors that may influence national crime rates and the amount of violence watched on television. Despite anecdotal reports of a "contagion of vio lence," relatively little systematic research has exam ined whether seeing or hearing about violence in news coverage encourages violent or aggressive behavior. On the whole, the limited data available support the notion of a contagion effect. This evidence is derived from studies examining how reports of a well-known person's suicide affect the likelihood of imitative sui cide (Phillips, 1979(Phillips, ,1982Simon, 1979;Stack, 1989). Other studies of the contagion effect (Berkowitz & Macaulay, 1971;Phillips, 1983) have been questioned because of their research methods and the ambiguity of their results (Baron & Reiss, 1985; see Phillips & Bollen, 1985 for a response). This area merits addi tional research. # Violence in Other Media # Internet Theoretically, the effects of exposure to media vio lence extend to Internet media as well. To date, how ever, no studies have been published regarding the effects of Web-based media violence on youth aggres sion and violence. # Music Videos A relatively small amount of research has focused on the impact of music videos with violent or antisocial themes (Baxter et al" 1985;Caplan, 1985;Hansen & Hansen, 1990;Johnson et al" 1995aJohnson et al" , 1995bRich et al" 1998). Randomized experiments indicate that exposure to violent or antisocial rap videos can increase aggres sive thinking, but no research has yet tested how such exposure directly affects physical aggression. # Youth Violence: A Report of the Surgeon General # Video Games The impact of video games containing violence has recently become a focus of research because children are theoretically more susceptible to behavioral influ ences when they are active participants than when they are observers. To date, violent video games have not been studied as extensively as violent television or movies. The number of studies investigating the impact of such games on youth aggression is small, there have been none on serious violence, and none has been longitudinal. A recent meta-analysis of these studies found that the overall effect size for both randomized and corre lational studies was small for physical aggression (r = .19) and m oderate for aggressive thinking (r = .27) (Anderson & Bushman, in press). In separate analyses, the effect sizes for both randomized and cross-sectional studies was small (r = .18 and .19, respectively). The impact of video games on violent behavior remains to be determined. # Potential Moderators of Behavioral Effects Research suggests that not all youths are affected in the same way by viewing media violence. Factors that appear to influence the effects of media violence on 0 aggressive or violent behavior include characteristics of the viewer (such as age, intelligence, aggressive ness, and whether the child perceives the media as realistic and identifies with aggressive characters) and his or her social environment (for example, parental influences), as well as aspects of media content (including characteristics of perpetrators, degree of realism and justification for violence, and depiction of consequences of violence). Evidence that these factors moderate the influence of media violence is limited, and it is more relevant to aggression than to violence. For example, studies of responses to violent television and films and violent video games have found that people who were initially more aggressive than other subjects were more affected in behavior, thoughts, and emotions (Anderson & Dill, 2000;Bushman, 1995;Bushman & Geen, 1990;Friedrich & Stein, 1973;Josephson, 1987). Research in this area clearly suggests that the impact of violent tel evision, film, and video games on aggression is moder ated by viewers' aggressive characteristics. Evidence that other individual, environmental, and content factors moderate the effects of exposure to media violence is less clear. Some studies suggest that these factors may buffer or enhance effects, but few have tested for such influences. Although limited in scope and depth, such studies provide clues to potential avenues for prevention efforts. For example, preliminary data point to the potentially vital role of parents in supervising their children's exposure to violent media and in helping them interpret it (Nathanson, 1999). # S u m m a r y o f M ajor Empirical Research Fin d in g s A substantial body of research now indicates that expo sure to media violence increases children's physically and verbally aggressive behavior in the short term (within hours to days of exposure). Media violence also increases aggressive attitudes and emotions, which are theoretically linked to aggressive and vio lent behavior. Findings from a smaller body of longi tudinal studies suggest a small but statistically signifi cant impact on aggression over many years. The evi dence for long-term effects on violence is inconsistent. Based on the findings of studies reported here, the average effect sizes of exposure to media violence on various measures of aggression range from small (r = .15) to quite large (r = .64). The evidence that exposure to media violence is a risk factor for violent behavior is more limited, with small average effect sizes of r = .06 in cross-sectional surveys, r = .13 in experimental studies , and r = .00 to .22 in longitudinal studies (Huesmann et al., submitted;. Taken together, findings to date suggest that media violence has a relatively small impact on violence. The effect on aggression is stronger, ranging from small to moderate. Although there is clear scientific evidence of a correlation between exposure to media violence and some violent behaviors, randomized experimentsthe research methodology best suited to determining causality-cannot ethically be used in studies of vio lent behavior. Thus, the causal links between media violence and behavior are more firmly established for aggressive behavior than for violent behavior. Longitudinal studies, which also provide some insights into this issue, have linked repeated exposure to media violence in the early, years with an increased likelihood of aggressive behavior in the teen and adult years. However, few of these studies have reported on violence as an outcome. Moreover, the violent behav iors that are the focus of this report (homicide, forcible rape, aggravated assault,, and robbery) occur infrequently and are subject to multiple influences. At present, it is extremely difficult to distinguish between the relatively small, long-term effects of media expo sure and those other influences. In sum, a diverse body of research provides strong evidence that exposure to violence in the media can increase children's aggressive behavior in the short term. Some studies suggest that long-term effects exist, and there are strong theoretical reasons why this is the case. But many questions remain regarding the short-and long-term effects of media violence, espe cially on violent behavior. # Preventive Efforts Efforts to reduce the presumed harmful effects of media violence on youths have taken various forms, including: - Attempting to reduce the amount of media violence and children's access to it (for example, calls for media self-regulation and violence ratings); - Encouraging and facilitating parental monitoring of children's access to media (for example, V-chip leg islation and advisory labels on music and video games); - Educating parents and children about the potential dangers of media violence (for example, media and empathy educational programs); and - Targeting children's views about violence to reduce the chances that they will imitate the violence they see (Corder-Bolz, 1980;Hicks, 1968;Huesmann et al., 1983;Linz et al., 1990;Nathanson, 1999). From a public health perspective, this preventive domain is largely uncharted territory. Few preventive efforts have been studied systematically. Furthermore, not enough research has been done to form a basis for the design of many experimental interventions. As noted in other parts of this report, an extensive body of scientific research undergirds our emerging knowledge about effective ways of preventing youth violence. Although many violence prevention programs address a complex array of risk and protective factors in the lives of young people, they have not yet addressed the role of the media. This gap needs to be filled. # Im plic a tio n s Research to date justifies sustained efforts to curb the adverse effects of media violence on youths. Although our knowledge is incomplete, it is sufficient to devel op a coherent public health approach to violence pre vention that builds upon what is known, even as more research is under way. Unlike earlier Federal research reports on media violence and youth (National Institute of Mental Health, 1982; U.S. Surgeon General's Scientific Advisory Committee on Television and Social Behavior, 1972), this discussion takes place within a broader examination of the caus es and prevention of youth violence. This context is vital. It permits media violence to be regarded as one of many complex influences on the behavior of America's children and young people. It also suggests that multilayered solutions are needed to address aggressive and violent behavior. A variety of media violence is present in the homes of young children, with considerable variation in the degree of parental supervision (Woodard, 1998). Regardless of government and other interested groups' attempts to limit the amount of violence reaching American families, families themselves play a critical role in guiding what reaches their children. Whether by adopting V-chip technology for home tel evision programming, by using Internet violence screening, or simply by monitoring closely children's use of televisions, computers, and video games, par ents can limit and shape their children's selection of, interaction with, and response to media violence. Community groups-including schools, faith-based organizations, and Parent Teacher Associations-can teach parents and children how to be more critical consumers of media. Federal agencies can be more active in encouraging needed research, in sharing research findings with the public, in encouraging increased interaction between violence prevention researchers and media researchers, and in creating networks for sharing solutions to social and public health problems. (Gallup, 1999). This per ception, combined with the increased lethality of youth violence in the early 1990s, has lent urgency to the search for effective violence prevention efforts. Hundreds of youth violence prevention programs are being used in schools and communities throughout the country, yet little is known about the actual effects of many of them (Gottfredson et al., 2000;Tolan & Guerra, 1994). Few such programs have been rigor ously evaluated, including many ongoing efforts (Elliott, 1998). The evaluations that have been done indicate that much of the money America spends on youth violence prevention is spent on ineffectivesometimes even harmful-programs and policies . At the same time, researchers know much more today about how to prevent youth violence than they did two decades ago, when some declared that "noth ing works" to prevent violence Sechrest et al., 1979). This is clearly no longer the case. Over the past few decades, social scientists have made great strides in uncovering the causes and corre lates of youth violence. Unfortunately, the news about effective programs has been slow to bring about change in school, com munity, and juvenile justice system prevention efforts, where precious resources continue to be spent on inef fective programs. Some experts believe that youth crime and violence rates could be "substantially" reduced simply by reallocating the money now spent on ineffective policies and programs to those that do work (Mendel, 2000, p. 1). The strategy of using prevention resources to their fullest potential presents many challenges. The first lies in identifying effective prevention approaches and programs. Differentiating between effective and inef fective ones can be a difficult chore for schools, com munities, and juvenile justice authorities. Numerous agencies and organizations have published recom mendations on "what works" in youth violence pre vention, but in many cases there is little consistency regarding the specific programs they recommend. The reason for this inconsistency is a lack of uniformly applied scientific standards for what works. # Pr o m o t in g H ealthy, N o n v io l e n t C h ildren This chapter identifies a set of standards based on sci entific consensus and applies those standards to the literature on youth violence prevention in order to identify with confidence general strategies and pro grams that work, that are promising, or that do not work to prevent youth violence. This information can be used by schools, communities, juvenile justice agencies, program funders, and others interested in youth violence prevention to aid their programming decisions. With this information in hand, it may be possible to fulfill the prediction that better use of existing prevention resources can substantially reduce the problem of youth violence. The first section of this chapter describes the methods used in this report to identify best practices in youth violence prevention. The second describes cur rently accepted scientific standards for determining program effectiveness. The third section applies those standards to the existing youth violence prevention lit erature and presents findings on best practices-what works, what is promising, and what does not work. The information in that section is based on currently available research and is not intended to be the final word on the subject. As more programs are evaluated, the standards outlined in this report can be used to identify additional programs and strategies that work in preventing youth violence. The fourth section, on cost-effectiveness, is intended to enhance the information provided in the best practices section by adding another dimension to the determination of what works. The conclusion dis cusses the need to take the next step in preventing youth violence by learning how to preserve the bene fits of successful prevention programs when imple menting them on a national scale. # M e t h o d s o f Identifying Best P ractices Identifying the best practices for preventing youth vio lence involves two approaches, each with its own lim itations. The first is meta-analysis, a rigorous statistical method of combining the results of several studies to obtain more reliable estimates of the effects of a gen eral type of treatment or intervention. This quantitative approach can be used to summarize program evalua tion evidence and draw overall conclusions about the strength and consistency of the influence, or effect size, that particular types of programs have on violent behavior. In the field of youth violence, meta-analysis has been used primarily for evaluations of interven tions with violent or delinquent youths. The second, less empirical approach is to review the evaluation research and identify the general strate gies that characterize effective programs. While such reviews are not quantitative, they are more easily con ducted than meta-analyses, and they offer useful information for generating hypotheses and drawing general conclusions about the effectiveness of various strategies for preventing youth violence. In identifying best practices, this report relies heav ily on recently published reviews and focuses mainly on strategies and programs with demonstrated effects on youth violence and on the major risk factors for youth violence. Strategies and programs are first classified as effective or ineffective. Effective strategies and pro grams are then further broken down into Model pro grams, which meet very high standards of demon strated effectiveness, and Promising programs, which meet a minimum standard. Finally, within Model and Promising categories, a distinction is made between strategies and programs that have demonstrated effects on violence and serious delinquency (Level 1) and those that have demonstrated effectiveness on known risk factors (Level 2). The decision to include serious delinquency along with violence as a criterion for Level 1 pro grams was based upon the major meta-analysis of program effectiveness (Lipsey & Wilson, 1998), which did not differentiate between those two out comes. Serious delinquency was a major risk factor for violence in both the early and late onset of risk (see Chapter 4). Level 2 Model programs are those that address any of the other risk factors with large effect sizes (substance use, weak social ties, antiso cial or delinquent peers, gang membership).1 For Promising strategies, Level 1 again refers to pro grams with demonstrated effects on violence and serious delinquency. Level 2 programs are those with demonstrated effects on any risk factor with an effect size of .10 or greater. No attempt was made to systematically search the literature for programs and strategies that affect small risk factors for youth violence, such as academic fail ure or anxiety and depressive disorders. Therefore, some effective programs or strategies that target small risk factors may not be included. However, such pro grams and strategies occasionally came to our atten tion; those that did were included if the risk factors they affected had an effect size of .10 or greater. Thus, risk factors such as child abuse and neglect, which have an effect size of less than .10, are not covered in this report.2 Also excluded are clinical trials of psy chotropic medications, which have proved effective in treating some affective disorders that are risk factors for youth violence but have not been shown in rigorous clinical studies to reduce youth violence specifically. A review of these interventions can be found in Mental Health: A Report o f the Surgeon General (1999). Several major reviews of youth violence preven tion and intervention programs have been published in the past decade. This chapter draws mainly upon the following:3 - Preventing Crime: What Works, What Doesn't, What' s Promising. A Report to the United States Congress (Sherman et al., 1997) - The Office of Juvenile Justice and Delinquency Prevention's A Sourcebook: Serious, Violent, and Chronic Juvenile Offenders (Howell et al., 1995) - The Office of Juvenile Justice and Delinquency Prevention's Guide fo r Implementing the Comprehensive Strategy for Serious, Violent, and Chronic Juvenile Offenders (Howell, 1995) - The Centers for Disease Control and Prevention's Best Practices o f Youth Violence Prevention: A Sourcebook for Community Action (Thornton et al., - The American Youth Policy Forum's Less Hype, More Help: Reducing Juvenile Crime, What Works-And What Doesn' t - The Center for the Study and Prevention of Violence's Blueprints fo r Violence Prevention - "School-Based Crime Prevention" (Gottfredson et al., in press) To improve readability, the reviews listed above are cited here and in the section below on scientific standards for effectiveness, but they are not referred to repeatedly in the section on best practices. Citations not listed above will be included where appropriate. Many reviews use either no explicit criteria or only minimal criteria for identifying the programs they rec ommend, making it difficult to draw clear conclusions about the effectiveness of individual violence preven tion strategies. This report limits its identification of effective programs to those meeting a minimum stan dard of study design similar to the maximum standard described in Sherman et al. (1997) and Gottfredson et al. (in press). In those two reports, a scientific methods score of 4 or 5 indicates that an evaluation used an experimental or quasi-experimental design. This report applied that design standard to the extent possible, given the limitations described above. This report also attempts to distinguish between absolute deterrent effects, in which an intervention is compared to no treatment, and marginal deterrent effects, in which the intervention or strategy is evalu ated against another treatment. Marginal deterrent effects are effects of the intervention over and above the effects of another treatment strategy and thus may underestimate the true effects of the intervention, com pared to receiving no treatment at all. In such cases, the nature of the comparison group is identified in the text. Both meta-analyses and reviews can be used to identify successful strategies, approaches, or types of programs used to prevent youth violence. However, this general approach has a critical limitation: Within any given category of programs, there may be specif ic programs that are effective and others that are not; moreover, programs may be effective for some popu lations but not others (males but not females, for example). The general effect size is an estimate of the average effect and thus may not characterize any par ticular program or its use for a particular population. Often the effects of individual programs within each general strategy vary widely. For this reason, it is necessary to take one more step in the identification of best practices-focusing specifically on individual programs that work. Identifying specific programs that work requires a clear set of standards for judging effectiveness. This chapter describes the scientific community's consen sus regarding standards and how this report applied those standards to the evaluation literature to place programs in one of three categories: Model (demon strates a high level of effectiveness), Promising (meets minimal standards of effectiveness), or Does Not Work (consistent evidence of no effects or harmful effects). Few existing violence prevention and intervention programs have met the qualifications of a Model pro gram. Many more have met the standards for a Promising program, and even more would probably meet these standards if evaluated appropriately. The fact that a program is not identified in this report as Promising or Model does not mean it is ineffective; in most cases it means only that it has not been rigorous ly evaluated. Those evaluated and found to be ineffec tive are identified as ineffective. While hundreds of programs are employed throughout the United States to prevent youth violence and treat young offenders, only those with a credible scientific evaluation are highlighted in this report. This shortfall underscores the need for a renewed focus on evaluation in the field of youth violence prevention. # Scientific St a n d a r d s for D eterm inin g Pro g r a m Effectiveness The scientific community agrees on three standards for evaluating effectiveness: rigorous experimental design, evidence of significant deterrent effects, and replication of these effects at multiple sites or in clini cal trials. For example, the level of evidence required to establish the effects of an agent or intervention in Mental Health: A Report of the Surgeon General (1999) was demonstration of the effects in random ized, controlled experimental studies that had been replicated. The U.S. Food and Drug Administration requires the same level of evidence before approving a new drug for use in humans. Unfortunately, this level of evidence has not been routinely required by agen cies that recommend or fund youth violence preven tion programs, though some organizations and most researchers are calling for establishment of meaningful 0 criteria for program effectiveness (Elliott, 1998;Mendel, 2000, p. 74). Most researchers want evalua tions to meet one or more of these three scientific stan dards for assessing effectiveness. Rigorous experimental design includes, at a mini mum, random assignment to treatment and control groups (Andrews, 1994;Center for Substance Abuse Prevention, 2000;Chamberlain & Mihalic, 1998;Howell et al., 1995;Lipsey, 1992a;Lonigan et al., 1998). A less stringent, but acceptable, study design is quasi-experimental, in which equivalent comparison and control groups are established but assignment of study participants to the groups is not random (Center for Substance Abuse Prevention, 2000; Howell et al., 1995;Lipsey, 1992b;Sherman et al., 1997;Tolan & Guerra, 1994). Well-designed studies should also have low rates of participant attrition, adequate measurement, and appropriate analyses (Andrews, 1994;Center for Substance Abuse Prevention, 2000;Chamberlain & Mihalic, 1998). High attrition can undermine the equivalence of experimental and control groups. It can also signal problems in program implementation. Adequate measurement implies that the study meas ures, including the outcome measure, are reliable and valid indicators of the intended outcomes and that they are applied with quality, consistency, and appro priate timing (Tolan & Guerra, 1994). In clinical trials, replication means conducting both efficacy and effectiveness trials (Lonigan et al., 1998). Efficacy trials test for benefits to participants in a con trolled, experimental setting, and effectiveness trials test for benefits in a natural, applied setting. In practice, this distinction is often blurred, but the principle of independent replication at multiple sites is well estab lished. Replication is an important element of program evaluation because it establishes that a program and its effects can be exported to new sites and implemented by new teams under different conditions. A program that is demonstrated to be effective at more than one site is likely to be effective at other sites as well. Statistical significance is based on the level of confidence with which one can conclude that a differ ence between two or more groups (generally a treat ment and a control group) results from the treatment delivered and not, for example, from the selection process or chance. A probability value of .05 is wide ly accepted as the threshold for statistical significance; a probability below this threshold (p < .05) indicates that a difference of this magnitude could happen by chance less than 5 percent of the time. High-quality evaluations of youth violence pre vention programs should be designed to demonstrate with this degree of confidence that a program is reduc ing the onset or prevalence of violent behavior or indi vidual rates of offending (Andrews, 1994;Tolan & Guerra, 1994). Since serious delinquency is strongly related to violence, reductions in serious criminal behavior (or index crimes) are also considered to be acceptable outcome measures for identifying effective violence prevention programs (Andrews, 1994;Elliott, 1998;Lipsey, 1992aLipsey, , 1992b. However, direct scientific evidence of a deterrent effect on violent behavior is certainly preferable. Prevention programs are designed to prevent or reduce violent behaviors by acting on risk and protec tive factors. Reducing risk is a less stringent standard than reducing violence, but reducing risk undoubtedly holds some promise of preventing violence. Thus, sig nificant changes in risk factors for violence are acceptable indications of program effectiveness Gottfredson et al., in press;Howell et al., 1995;Sherman et al., 1997). In addition, because most violence begins in adolescence, child hood interventions are concerned primarily with risk reduction. A less widely accepted but nevertheless important standard for demonstrating effectiveness is long-term sustainability of effects . Although this criterion may not be required to estab lish effectiveness in other disciplines, it is very impor tant in evaluating violence prevention programs because beneficial effects can diminish quickly after youths leave a treatment setting or program to return to their usual environment. Effective programs produce long-term changes in individual competencies, environmental conditions, and patterns of behavior. Thus, successful programs get youths off a violent life course trajectory. The sus tainability of effects is particularly difficult for early intervention programs, which can be implemented more than a decade before the peak age of onset for youth violence. Ideally, effects would be sustained though adolescence. On a practical level, programs in this report are considered to have demonstrated sus tainability if the effects of the intervention continue for at least a year after treatment or participation in the designed intervention, with no evidence of a subse quent loss of effect . Higher standards should be set for programs that are promoted and disseminated on a national level than for those being developed and implemented on a more restricted basis at the local level. Before a program is recommended and funded for national implementation, it is important to show clearly that it has a significant, sustained preventive or deterrent effect and that it can be expected to have positive results in a wide range of community settings (as long as it is implemented cor rectly and with the appropriate population). Programs that meet such high standards are designated Model programs. Those that do not quite meet these rigorous standards are recognized and encouraged as Promising, with the caution that they be carefully evaluated. Identifying ineffective programs is another ele ment of assessing best practices. It is as important to know which programs do not work-and should not be supported with limited prevention funds-as it is to know which do work. The same scientific stan dards are used in judging effectiveness and ineffec tiveness. Because it is generally unlikely that a highquality evaluation will be conducted on a program that shows little sign of effectiveness, only two spe cific programs have been designated Does Not Work in this report. Some general strategies identified as ineffective in this report may not actually be flawed; rather, their lack of effectiveness may result from poor program implementation or a poor match between program and target population. Alternatively, some approach es may appear ineffective when used in isolation because their effects are quite small and difficult to detect. These approaches should not be used alone, but they may be useful as components of more com prehensive strategies that have positive preventive effects. In other cases, however, a program or approach may be ineffective because the basic strate gy is flawed-that is, the method or approach used to change the targeted risk or protective factors does not have the intended effect. The following is a summary of the scientific stan dards for establishing the effects of a violence preven tion program. # Model - Rigorous experimental design (experimental or quasi-experimental) - Significant deterrent effects on: -Violence or serious delinquency (Level 1) -Any risk factor for violence with a large effect size (.30 or greater) (Level 2) - Replication with demonstrated effects - Sustainability of effects # Promising - Rigorous experimental design (experimental or quasi-experimental) - Significant deterrent effects on: -Violence or serious delinquency (Level 1) -Any risk factor for violence with an effect size of .10 or greater (Level 2) - Either replication or sustainability of effects # Does Not Work - Rigorous experimental design (experimental or quasi-experimental) - Significant evidence of null or negative effects on violence or known risk factors for violence - Replication, with the preponderance of evidence . suggesting that the program is ineffective or harmful Youth Violence: A Report of the Surgeon General Other standards have been proposed for youth violence prevention programs, particularly those intended for implementation on a national level. One of these is cost-effectiveness, a key consideration in program funding but not a scientific criterion for effectiveness. Unfortunately, there are no standardized cost criteria for violence prevention programs, so it is difficult to compare costs across programs (Elliott, 1998). Moreover, it is difficult to obtain reliable costbenefit estimates for individual programs. Despite these obstacles, some researchers have conducted extensive reviews of the costs and benefits of violence and delinquency prevention and in terv en tio n p ro gram s (G reenw ood, 1995;G reenw ood et al., 1998;K aroly et al., 1998;Washington State Institute for Public Policy, 1999). Their findings will be discussed in the cost-effectiveness section of this chapter. This is an important and growing area of research. Setting such stringent scientific standards auto matically limits the number and types of programs that will be identified as effective in this report. The spe cific programs that can meet these standards will be determined in part by the nature of the program-the design must lend itself to scientific evaluation-and in part by whether funding has been made available for program evaluation. For instance, early childhood individual change programs are overrepresented in the list of effective programs. This fact is probably a result of the relatively large amount of funding allocated to the study of these programs and the relative ease with which experimental evaluations can be carried out. On the other hand, programs promoting change in the social structure, community-level programs, and pro grams that focus on environmental change more gen erally (in schools, neighborhoods, peer groups, and so on) are probably underrepresented in this report. Evaluation of such programs and strategies is more dif ficult and costly; therefore, fewer rigorous evaluations of these programs have been done. Because of these limitations, the programs dis cussed in this report may not represent the overall bal ance of youth violence prevention programs currently being implemented in communities throughout the country. This shortcoming highlights the need for more research on program effectiveness and for the development of additional criteria and valid measures for assessing the effects of community-or schoolbased and environmental change programs. In addi tion, the imbalance should not be interpreted as an indication that such programs are less effective than programs that focus on individual change. Indeed, there is some evidence that school-based programs designed to change the social climate of the classroom or school are more effective than individual change programs (Gottfredson et al., in press). # St a t e g ie s a n d P r o g r a m s : M o d e l , P r o m is in g , a n d D o e s N o t W o r k It is important to reiterate that the specific programs and general strategies discussed in this report have been identified from recent reviews of the literature on youth violence prevention. Although this information is growing rapidly, youth violence prevention remains a young field, and only limited evaluation data are available for many strategies and programs. Therefore, the absence of a particular strategy or program from this section does not in any way imply that it is inef fective; rather, the information available is not suffi cient to justify any conclusions about its effectiveness. Model and Promising programs meet the scientif ic criteria for effectiveness outlined above within the populations in which they have been tested (as indi cated in the text). These programs are widely regard ed by the youth violence prevention community as effective. Appendix 5-A shows the consistency with which they have been recommended by various inde pendent groups of researchers as best practices in youth violence prevention. With only a few excep tions, each of the programs has already been identified as a best practice in two or more other reports on what works in youth violence prevention. This section is divided into prevention and inter vention efforts. True prevention, or primary preven tion, is defined in this report as lessening the likeli hood that youths in a treatment or intervention pro gram will initiate violent behavior, compared to youths in a control group. In some cases, the preven tion of risk factors for violent behavior is considered the outcome, and the reduced likelihood of youths' encountering this risk is the measure of effective ness. Therefore, prevention programs are designed to target youths who have not yet become involved in violence or encountered specific risk factors for vio lence. Prevention efforts include general strategies and programs that target general (universal) popula tions of youths. Intervention, on the other hand, is defined as reducing the risk of violence among youths who dis play one or more risk factors for violence (high-risk youths) or preventing further violence or the escalation of violence among youths who are already involved in violent behavior. These types of interventions are also known as secondary and tertiary prevention, respec tively. Thus, intervention includes programs that target high-risk (selected) populations of youths or already violent (indicated) youths. Although there is some overlap between prevention and intervention efforts, programs that are most effective in general populations of young people are not always effective in reducing further violence among seriously delinquent youths. The programs discussed below are listed in Appendix 5-B, along with more detailed information on each one. Specific results of the evaluations are found there; findings are described in general terms in this chapter. Box 5-1 summarizes effective and inef fective strategies, and Box 5-2 lists the programs dis cussed below by best practices category: Model, Promising, or Does Not Work. # Primary Prevention: General Populations of Young People All of the programs and strategies discussed in this section are primary prevention approaches to reduc ing youth violence-that is, they are implemented on a universal scale and aim to prevent the onset of youth violence and related risk factors. Some are designed to change individual risk factors, others tar get environmental risk factors, and a few are designed to change both. # Skill-and Competency-Building Programs Skills-oriented programs are among the most effective general strategies for reducing youth violence and risk factors for youth violence. In fact, two universal pro grams that take this approach have met the criteria for a Model program: Life Skills Training and the Midwestern Prevention Project. Life Skills Training (LST) is designed to prevent or reduce gateway drug use. The program targets stu dents in middle or junior high school, with initial implementation in grades 6 and 7 and booster sessions for the next 2 years. The curriculum has three major components: self-management skills, social skills, and information and skills related specifically to drug use. Teachers use a variety of techniques, including instruction, demonstration, feedback, reinforcement, and practice, to train students in these three core areas. Evaluations show that the program can cut tobacco, marijuana, and alcohol use. Moreover, long-term effects of participation in Life Skills Training include a lower risk of polydrug use, pack-a-day smoking, and inhalant, narcotic, and hallucinogen use. The Midwestern Prevention Project targets middle school students (grades 6 or 7). Its goal is to reduce the risk of gateway drug use associated with the transition from early adolescence to middle through late adoles-cence by training youths to avoid drug use and situa tions in which drugs are likely to be used. The program has five major components that are implemented in stepwise fashion over the course of approximately 4 years: mass media program, school program, parent education and organization, community organization, and local health policy. The mass media program spans the duration of the project, while the other components are introduced at a rate of approximately one per year. The school-based component forms the core of the pro gram. This project has demonstrated positive effects on a number of outcomes that are closely related to youth violence. For instance, it has been shown to reduce daily smoking and marijuana use and to lessen mari juana use, hard drug use, and smoking through age 23. In addition, the project has facilitated improvements in parent-child communication about drug use and in the development of prevention programs, activities, and services within communities. Two school-based programs that focus on teaching important social skills to students, Promoting Alternative Thinking Strategies and I Can Problem Solve, meet the criteria for a Promising program. The Promoting Alternative Thinking Strategies (PATHS) curriculum is taught to elementary school students at entrance through grade 5. Lessons targeting emotional competence (expression, understanding, and regula tion), self-control, social competence, positive peer rela tions, and interpersonal problem-solving skills are deliv ered three times a week in 20-to 30-minute sessions. Evaluations of PATHS show that this program has posi tive effects on several risk factors associated with vio lence, including aggressive behavior, anxiety and depression, conduct problems, and lack of self-control. The effectiveness of PATHS has been demonstrated for both regular-education and special-education students. I Can Problem Solve has been used effectively with students in nursery school, kindergarten, and grades 5 and 6. The main goal of this program, which is implemented in 12 small-group sessions over 3 months, is to train children to use problem-solving skills to find solutions to interpersonal problems. In evaluations, I Can Problem Solve has improved class room behavior and children's problem-solving skills for up to 4 years after the end of the intervention. Whereas this program is appropriate for all children, it has been most effective with children living in poor, urban areas. drug and alcohol use. Children who participate in LIFT exhibit less physical aggression on the play ground, better social skills, and, in the long term, less likelihood of associating with delinquent peers, using alcohol, or being arrested. # Behavior Management Programs Strategies that take a behavioral approach to youth violence can also have positive, consistent effects on violence, delinquency, and related risk factors. The behavioral approaches shown to be effective in pre venting youth violence on a universal scale are gener ally school-based and include behavior monitoring and reinforcement of attendance, academic progress and school behavior, and behavioral techniques for classroom management. Much of the evidence on the effectiveness of behavior monitoring and reinforcement comes from studies conducted by Bry and colleagues (Bry, 1982;Bry & George, 1979. These studies pro vide evidence' that interventions focusing on enhanc ing positive student behavior, attendance, and aca demic achievement through consistent rewards and monitoring can reduce substance use, self-reported criminal activity, and arrests, as well as enhance aca demic achievement in middle school students. In one study, for example, students exposed to this type of intervention were far less likely than students in a con trol group to have a delinquency record 5 years after the program. Behavioral techniques for classroom manage ment are a general strategy for changing the classroom environment. According to a review by O ' Leary and O'Leary (1977), the best strategies for promoting pos itive classroom behavior are establishing clear rules and directions, use of praise and approval, behavior modeling, token reinforcement, self-specification of contingencies, self-reinforcement, and behavior shap ing. Several strategies aimed at reducing negative stu dent behaviors are also effective: ignoring misbehav ior, reinforcing behavior that is incompatible with negative behavior, relaxation methods, and using disciplinary techniques such as soft reprimands, time outs, and point loss and fines in token economies. # 124'm The Seattle Social Development Project is an excellent example of a program that includes classroom behavior management among its core components. The goal of this Model program is to enhance elementary school students' bonds with school and their families while decreasing a number of early risk factors for vio lence. Like other Model programs in this report, the ini tiative includes both individual and environmental change approaches and multiple components known to improve the effectiveness of violence prevention efforts. In addition to classroom behavior management, the components include child skills training and parent training, discussed later in this section. Through these three components, which target prosocial behavior, interpersonal problem solving, academic success, and avoidance of drug use, the Seattle Social Development Project reduces the initia tion of alcohol, marijuana, and tobacco use by grade 6 and improves attachment and commitment to school. At age 18, youths who participated in the full 5-year version of this program have lower rates of violence, heavy drinking, and sexual activity (including multi ple sexual partners and pregnancy) and better aca demic performance than controls. The Seattle Social Development Project has been used effectively in both general populations of youths and high-risk children attending elementary and middle school. Classroom behavior management is also a core component of three Promising programs: the Bullying Prevention Program, the Good Behavior Game, and the School Transitional Environmental Program. The Bullying Prevention Program targets students in ele mentary, middle, and junior high school. It begins with an anonymous student questionnaire designed to assess bullying problems in individual schools. Using this information, parents and teachers implement school-, classroom-, and individual-level interven tions designed to address the bullying problems iden tified in the questionnaire, including individual work with students identified as bullies and victims. At the classroom level, teachers and students work together to establish and reinforce a set of rules about behavior and bullying, creating a positive, antibullying climate. This program has both individual change and environ mental change objectives. In elementary and junior high schools in Bergen, Norway, bullying problems were cut in half two years after the intervention. Antisocial behavior, including theft, vandalism, and truancy, also dropped during these years, and the social climate of the school improved. Replications have been conducted in England, Germany, and the United States, with similar effects. Like the Bullying Prevention Program, the Good Behavior Game uses classroom behavior manage ment as the primary means of reducing problem behaviors. The Good Behavior Game targets elemen tary school children and seeks to improve their psy chological well-being and decrease early aggressive or shy behavior. While both of these programs can reduce antisocial behavior, their effects on violence and delinquency have not yet been measured. This intervention has shown positive effects, as measured by teachers' reports of aggressive and shy behaviors in first-graders. Long-term evaluations show sustained decreases in aggression among boys rated most aggressive in first grade. Effects on vio lence and delinquency have not been measured. The third Promising primary intervention pro gram that makes use of classroom behavior manage ment is the School Transitional Environmental Program, or STEP. STEP is based on the Transitional Life Events model, which postulates that stressful life events, such as transitions between schools, place children at risk of maladaptive behav ior. The program's goals are to reduce the stress and disorganization often associated with changing schools by redefining the role of homeroom teachers. Behavior management is used to create an environ ment that promotes academic achievement and reduces school behavior problems and absenteeism. Participation in this program has been shown to reduce substance use and delinquency while improv ing academic achievement and school dropout rates. The STEP program has been most successful with students entering junior and senior high schools in urban, predominantly nonwhite communities. The program is also effective with students at high risk of behavioral problems. # Capacity-Building Programs Several other school-level environmental approaches are effective in reducing youth violence and related outcomes. For instance, those that focus on building a school's capacity to plan, implement, and sustain pos itive changes can significantly reduce student delin quency and drug use. One program in which students were empowered to address school safety problems resulted in significant reductions in fighting and teacher victimization. Program Development Education is an example of this approach to reducing youth violence. It is a structured organizational devel opment approach used to help organize, plan, initiate, and sustain school change. This approach has demon strated positive effects on delinquency rates lasting at least 2 years into the program. evidence is not yet strong enough to classify the Boys and Girls Clubs and the Big Brothers Big Sisters of America programs as Model or Promising, it is strong enough to conclude that the general strat egy of these and similar programs is effective at reducing youth violence and violence-related out comes. For instance, evaluations of Boys and Girls Clubs have shown reductions in vandalism, drug trafficking, and youth crime. An evaluation of a Canadian after-school program demonstrated large reductions in arrests. Although this general strategy is included with the primary prevention efforts, it can also be considered a secondary prevention strategy, since the specific youth development programs list ed above are usually implemented in high-risk neighborhoods. # Teaching Strategies Two other school-based primary prevention strategies are effective at reducing the risk of academic failure, a risk factor for youth violence: continuous progress program s and cooperative learning. Continuous progress programs are designed to allow students to proceed through a hierarchy of skills, advancing to the next level as each skill is mastered. This approach has shown consistent, positive effects on academic achievement in elementary school students in seven separate evaluations. Cooperative learning is another innovative envi ronmental change approach that can improve academ ic achievement in elementary school children. Quite different from continuous progress programs, cooper ative learning programs place students of various skill levels together in small groups, allowing students to help each other learn. Studies by Slavin (1989Slavin ( , 1990 show that this approach has positive effects on atti tudes toward school, race relations, attitudes toward mainstreamed special-education students, and aca demic achievement. # Community-Based Programs Community-based strategies can also affect youth violence at the universal level. One such strategy is positive youth development programs. While the # Ineffective Primary Prevention Programs # School-Based Programs Some educational approaches that target universal populations have shown a consistent lack of effect in scientific studies. Peer-led programs, including peer counseling, peer mediation, and peer leaders, are among them. In a 1987 review of these interventions, Gottfredson concluded that there is no evidence of a positive effect and that these strategies can actually harm high school students. Results of a meta-analysis confirmed this finding, adding that adult-led programs are as effective as, or more effective than, peer-led programs in reducing youth violence and related risk factors. Nonpromotion to succeeding grades is another educational approach that can have harmful effects. Studies of this approach demonstrate negative effects on student achievement, attendance, behavior, and attitudes toward school. One school-based universal prevention program meets the criteria for Does Not Work: Drug Abuse Resistance Education, or DARE. DARE is the most widely implemented youth drug prevention program in the United States. It receives substantial support from parents, teachers, police, and government fund ing agencies, and its popularity persists despite numerous well-designed evaluations and meta-analy ses that consistently show little or no deterrent effects on substance use. Overall, evidence on the effects of the traditional DARE curriculum, which is imple mented in grades 5 and 6, shows that children who participate are as likely to use drugs as those who do not participate. However, some positive effects have been demonstrated regarding attitudes toward police. Researchers have suggested several reasons for DARE's lack of effectiveness. The program is most commonly criticized for its limited use of social skills training and for being developmentally inappropriate. Specifically, DARE is implemented too early in child development: It is hard to teach children who have not gone through puberty how to deal with the peer pressure to use drugs that they,will encounter in middle school. Changes are being made at the national level in an attempt to improve the program's effectiveness. DARE developers have added social skills training sessions to the core curriculum and have developed a modified version of the curriculum that can be used in older student populations. These versions of DARE have not yet been evaluated.4 # Secondary Prevention: Children at High Risk of Violence Secondary prevention programs and strategies are implemented on a selected scale, for children at enhanced risk of youth violence, and are aimed at pre venting the onset and reducing the risk of violence. Programs that target the families of high-risk children are among the most effective in preventing violence. Several family-based strategies and programs are included in the discussion below. # Parent Training One effective approach involves training parents to use specific child management skills. A review by Dumas (1989) shows that parent training can lead to clear improvements in children's antisocial behavior (includ ing aggression) and family management practices. In individual studies with disruptive/aggressive/hyperactive boys and girls, parent training has resulted in reduced aggressive, antisocial, and delinquent behav iors; lower arrest rates (including arrests for assault); less overall delinquency; and academic improvement. The following five Promising youth violence preven tion programs include parent-training components. The Montreal Longitudinal Study, sometimes called the Preventive Treatment Program, is a 2-year intervention aimed at preventing delinquency among 7to 9-year-old boys from low-income families who have been identified as disruptive. The program has two major components: school-based social skills training (19 sessions) and parent training (17 sessions). The par ent-training sessions, provided every 2 weeks for the duration of the intervention, teach parents to read with their children, monitor and reinforce their children's behavior, use effective discipline, and manage family crises. A long-term follow-up of Canadian boys enrolled in this program found positive effects on academic achievement and avoidance of gang involvement, drug and alcohol use, and delinquency up to age 15. The Syracuse Family Development Research Program targets parents and children in impover ished families. It provides weekly home visitation with parent training by paraprofessional child devel opment trainers and 5-year individualized day care that includes child training on social and cognitive skills and child behavior management. The Perry Preschool Program provides early education to chil dren age 3 and 4 from families with low socioeco nomic status. The preschool lasts 2 years and is designed to offer high-quality early childhood educa tion and promote young children's intellectual, social, and physical development. In addition, this intervention provides weekly home visits by teachers and referrals for social services, when needed. Both of these programs have demonstrated long-term effects (up to age 19) on delinquency, academic achievement, and other school-related outcomes. In addition, the Perry Preschool Program has produced significant reductions in antisocial behavior, serious fights, police contacts, and school dropout rates. Parent training is one of a broad range of family services offered through Parent Child Development Center Programs, which target low-income families with children age 2 months to 3 years. The parent training component of this intervention targets moth ers as the primary caregivers and focuses on infant and child development, home management, and fami ly communication and interaction skills. The pro grams have positive effects on a variety of risk factors for youth violence, including child antisocial behavior and fighting and mother-child relationships. The Parent-Child Interaction Training program targets low-income parents with preschool children who have at least one behavioral or emotional prob lem. Parents enrolled in the program participate in a series of four to five small-group sessions in which they learn a variety of parenting skills such as man agement of child behavior. This intervention has been shown to improve family management practices and reduce children's antisocial behaviors, including aggression and anxiety. # Home Visitation Another effective family-based approach to prevent ing youth violence is home visitation, in which a nurse or other professional goes to the child's home and pro vides training, counseling, support, monitoring, or all of these services to first-time, low-income, or other wise at-risk mothers. This strategy is particularly effective when implemented before children develop behaviors that put them at risk of violence. Home visitation, with or without early childhood education programs, has shown significant long-term effects on violence, delinquency, and related risk fac tors in a number of studies. The degree of effect is dependent on several factors, including length (only long-term programs have demonstrated consistent effects), delivery (nurses appear to be the most effec tive home visitors, although some positive effects have been demonstrated with other types of visitors), and timing (the earlier these programs begin, the better). Prenatal and Infancy Home Visitation by Nurses is the only home visitation program that meets the cri teria for a Model youth violence prevention program. # O It also incorporates all of the characteristics associat ed with the most effective home visitation programs: It is delivered by nurses, it begins early (before the child's birth), and it is long-term, lasting from before birth to age 2. Home visits are scheduled at intervals from 1 week to 1 month throughout the 2-year inter vention. The program targets low-income, at-risk pregnant women bearing their first child. The goals are (1) to improve pregnancy outcomes and child care, health, and development, (2) to build a social support network around the family, and (3) to enhance moth ers' personal development, including educational achievement, participation in the workforce, and per sonal competency skills and self-efficacy. Prenatal and Infancy Home Visitation by Nurses has a number of long-term, positive effects on youth violence and related outcomes, including fewer arrests and less'alcohol use by youths at age 15 and lower rates of child abuse and neglect, compared to controls. While child abuse and neglect are not usually consid ered a violence outcome in this report, they are includ ed here because the intervention is designed for moth ers who are still youths themselves. # Multicontextual Programs Several Promising secondary youth violence preven tion programs address multiple contexts that affect a child's risk of future violence: home, school, and com munity. The Yale Child Welfare Project is a Promising program that uses in-home visitation and day care to deliver parent training and other family and child services. This intervention targets healthy, first-born infants of mothers with incomes below the poverty level who live in inner cities. The 30-month program includes weekly home visits (usually by a social worker), pediatric medical care, psychological services, and early education (day care) for children. Ten-year follow-up of families involved in the Yale Child Welfare Project shows that the program has pos itive effects on parent involvement in their children's education, academic achievement (less need for reme dial and supportive services), and antisocial behavior. Striving Together to Achieve Rewarding Tomorrows, CASASTART, formerly known as the Children At Risk (CAR) program, targets at-risk youths age 11 to 13 who live in severely distressed neighbor hoods. The intervention has eight core components; each targeting a different context that affects the risk of violence: community-enhanced policing/enhanced enforcement, case management for youth and families, criminal/juvenile justice intervention, family services, after-school and summer activities, educational services, mentoring, and incentives for participation. Evaluations of CASASTART demonstrate that it has positive effects on avoidance of gateway drug use, violent crime, and drug sales and that these effects are sustained up to 1 year after participation. The most comprehensive of these Promising mul ticontextual interventions is Families and Schools Together, or the FAST Track project. This interven tion combines several of the strategies identified in this chapter as effective: social skills training, parent training, home visitation, academic tutoring, and classroom behavior management techniques. The pro gram targets children identified as disruptive in kindergarten and aims to prevent severe, chronic con duct problems by increasing communication and strengthening bonds between the school, home, and child, thereby enhancing social, cognitive, and prob lem-solving skills and improving peer relationships. FAST Track has positive effects on several risk factors associated with youth violence, including academic achievement and parent-child relationships. Although initial evaluations did not show any effects of this program on children's antisocial behaviors, the long term follow-up studies now in progress should be able to determine whether FAST Track has a significant effect on this violence-related outcome. Another comprehensive Promising intervention, The Incredible Years Series, is a series of curricula for parents, teachers, and children aimed at promoting social competence and preventing, reducing, and treat ing conduct problems in at-risk children age 3 to 8 . In each of these three curricula, trained facilitators use videotapes to encourage problem solving and discus sion. # Academic Programs Several educational approaches are effective at improv ing academic achievement, a weak but nevertheless important risk factor for late-onset youth violence (see Chapter 4). An effective secondary prevention strategy for improving academic performance is compensatory education, which targets students at risk of academic failure. Compensatory education strategies (such as cross-age or adult tutoring) that involve pulling stu dents out of their regular classes to receive extra assis tance in reading and math can improve long-term aca demic performance for all students, regardless of their achievement level. Moreover, when older students tutor younger students, both groups show academic gains. A meta-analysis of peer and cross-age tutoring of elemen tary and middle school students showed substantial effect sizes for academic achievement in both tutors and those tutored (Cohen et al., 1982). In more recent years, the compensatory education approach has been expanded to include schoolwide interventions. Preventive Intervention is a 2-year, school-based behavioral reinforcement program that begins in grade 7 and targets students with low academic moti vation, family problems, or disciplinary problems. The intervention includes behavior monitoring and reinforcement in the classroom as well as enhanced communication (through regular classroom meetings and reports to parents) between teachers, students, and parents regarding behavior and attendance at school. Educational assistance is one of three major com ponents of the Quantum Opportunities Program, a community-based intervention that targets adoles cents from families receiving public assistance. Students who participate in this program are assigned to a peer group and a caring adult and receive up to 250 hours of educational services to enhance academ ic skills; activities targeting personal development, life skills, career planning, and other areas; and serv ice opportunities in the community. The intervention begins at grade 9 and continues through high school. Both of these programs have demonstrated posi tive effects on several aspects of academic achieve ment, and Preventive Intervention has been shown to reduce drug use and the risk of having a county court record 5 years after participation. # Moral-Reasoning, Problem-Solving, Thinking Skills As seen in some of the programs above, interventions that aim to improve youths' moral-reasoning, problem solving, and thinking skills are also effective approach es to reducing youth violence in high-risk populations. For instance, one moral-reasoning-based intervention implemented in "behavior-disordered" high school stu dents has demonstrated lasting positive effects by reducing police contacts and official school disciplinary actions (Arbuthnot & Gordon, 1986). Evidence of the effectiveness of social problem-solving interventions includes a study of children and young adolescents referred for treatment of antisocial behavior; these youths showed significantly lower aggression scores after treatment and lower rates of externalizing behav ior 1 year later (Kazdin et al., 1989). The evidence supporting thinking skills approaches is similar, with particularly impressive results from two interventions: Lochman's Anger Coping Intervention and Rotheram's social skills training intervention. Lochman (Lochman, 1992;Lochman et al., 1984) reports large reductions in dis ruptive-aggressive behavior immediately after the program and reductions in substance use 3 years later in high-risk, aggressive boys in grades 4 through 6 . Rotheram's studies (1982) demonstrate improvements in academic achievement and in aggressive problem solving responses-both risk factors for violent behavior. Researchers speculate that one reason for the effectiveness of social skills interventions is that they are often more comprehensive in scope than other types of cognitive-behavioral approaches to pre venting youth violence and related outcomes. # Ineffective Secondary Prevention Approaches Whereas the research presented above demon strates that a large number of approaches and pro e m s can have significant, positive effects on youth violence and violence-related risk factors, several popular prevention approaches used in high-risk pop ulations have been shown to be ineffective. These include gun buyback programs, firearm training, and mandatory gun ownership. Gun buyback programs, a particularly expen sive strategy, have consistently been shown to have no effect on gun violence, including firearm-related homicide and injury. This finding may appear coun terintuitive, given the fact that these programs do, in fact, take guns off the street. However, there is some evidence that most of the guns turned in are not func tional and that most persons turning in guns have other guns at home. Two less popular strategies, firearm training and mandatory gun ownership, have also demonstrated no significant effects on firearm-related crimes. These approaches were expected to deter gun violence by increasing the num ber of private citizens who were trained to use guns properly and who owned firearms for protection. Two community-based strategies for preventing youth violence, redirecting youth behavior and shifting peer group norms, have also shown a lack of effect in reducing youth violence. In fact, because both approaches tend to group high-risk youths together, they can actually increase the cohesiveness of delinquent peer groups and facilitate deviancy training (Dishion et al., 1994(Dishion et al., , 1995. Programs that aim to redirect high-risk youth toward conventional activities involve recreational, enrichment, and leisure activities, including the popular Midnight Basketball program. In general, programs that focus on shifting peer group norms have attempted to turn youth gangs into benign clubs. Instead, these programs have had no effect or have actually increased gang-related delinquent behavior. # Tertiary Prevention: Violent or Seriously Delinquent Youths Each of the programs and strategies highlighted in this section is implemented on an indicated scale, that is, for young people who have already demon strated violent or seriously delinquent behavior. The best information on general strategies that are effec tive dr ineffective in reducing the risk of further vio lence among these youths comes from meta-analy ses. The most rigorous and most frequently cited meta-analyses of violence prevention programs are those conducted by Lipsey and colleagues and by Andrews and colleagues (Lipsey, 1992a(Lipsey, , 1992bLipsey & Wilson, 1998;Andrews, 1994;Andrews et al., 1990). This section draws largely on these analy ses, which include interventions targeting youths involved in any delinquent behavior and those involved in serious delinquent behavior. To enhance readability, the meta-analyses are cited here rather than throughout the text. Effect sizes are a stan dardized mean difference, corrected for small sam ple size and method effects. This measure reflects the average difference (expressed in standard devi ation units) between the program group and com parison groups in regard to violence, substance abuse, and risk factors. Two major conclusions come from Lipsey's research. The first is that effective treatment can divert a significant proportion of delinquent and vio lent youths from future violence and crime. This finding contradicts the conclusions of scientists two decades ago who declared that nothing had been shown to prevent youth violence. The second major conclusion is that there is enormous variability in the effectiveness of different types of programs for seri ously delinquent youth. The most effective pro grams, on average, reduce the rate of subsequent offending by nearly half (46 percent), compared to controls, whereas the least effective programs actu ally increase the rate of subsequent offending by 18 percent, compared to controls. So, while some kinds of interventions substantially reduce youth violence and delinquency, others appear to be harmful (iatro genic), actually increasing involvement in these behaviors. # Behavioral and Skill Development Interventions Studies of male serious offenders demonstrate that treatment which includes a social perspective-taking/role-taking component can improve role-taking skills and reduce serious delinquent behavior for at - > .131 least 18 months after treatment (Chandler, 1993). This finding is consistent with results from the Lipsey (Table 5-1) and Andrews studies, which indicate that multimodal, behavioral, and skills-oriented inter ventions are more effective than counseling and other less-structured approaches (see also Gendreau & Ross, 1987). In fact, in most youth populations-uni versal, selected, or indicated-behavioral and skillsoriented strategies are among the most effective vio lence prevention approaches. # Family Clinical Interventions Although Lipsey reports only a small average effect size for reducing recidivism with family therapy (Table 5-1), the review literature indicates that specif ic strategies can be quite effective at preventing vio lence in delinquent youths and preventing further vio lence in already violent youths. One such approach is marital and family therapy by clinical staff. While marital and family therapy can include several differ ent strategies, a common thread is the focus on chang ing maladaptive or dysfunctional patterns of family interaction and communication, including negative parenting behaviors-all risk factors for youth vio lence. Marital and family therapy shows consistent, positive effects on family functioning, child behavior, family interactions, and delinquency (Tremblay & Craig, 1995). Long-term studies have demonstrated positive effects of family therapy by clinical staff last ing up to 9 years. Three Model tertiary youth violence prevention programs that use the family therapy approach are Functional Family Therapy, Multisystemic Therapy, and Multidimensional Treatment Foster Care. They are described below. Functional Family Therapy (FFT) is actually a secondary and tertiary prevention program, since it targets youths 11 to 18 years old at risk of or already demonstrating delinquency, violence, substance use, conduct disorder, oppositional defiant disorder, or disruptive behavior disorder. FFT is a multistep, pha sic intervention that includes 8 to 30 hours of direct services for youths and their families, depending upon individual needs. The phases of the interven- & Wilson, 1998, p. 318). t+ This calculation assumes a 50% recidivism rate in the absence of intervention. tion include engagement (to reduce the risk of early dropout), motivation (to change maladaptive beliefs and behaviors), assessment (to clarify interpersonal behavior and relationships), behavior change (including skills training for youths and parents), and generalization (in which individualized casework is used to ensure that new skills are applied to func tional family needs). These services are delivered in multiple settings by a wide range of interventionists, including supervised paraprofessionals, trained probation officers, mental health technicians, and mental health professionals with appropriate advanced degrees. The benefits of FFT include the effective treatment of conduct disor-0 -oppositional defiant disorder, disruptive behavior )T COPY AVAILABLE l 3 3 i 6 disorder, and alcohol and other drug abuse disorders; reductions in the need for more restrictive, costly serv ices and other social services; reductions in the inci dence of the original problem being addressed; and reductions in the proportion of youths who eventually enter the adult criminal justice system. In two trials, recidivism was found to be lower among participants than controls. Evidence of a diffusion effect was also found, with fewer siblings of participants acquiring a court record in the 2 to 3 years following treatment. Multisystemic Therapy (MST) is an intensive family-and community-based treatment that address es multiple determinants of antisocial behavior. This approach is implemented within a network of inter connected systems that includes one or more of the following contexts: individual, family, peer, school, and neighborhood. MST targets families with chil dren in the juvenile justice system who are violent, substance-abusing, or chronic offenders and at high risk of out-of-home placement. Four types of servic es are delivered through a home-based model: strate gic family therapy, structural family therapy, behav ioral parent training, and cognitive-behavioral thera py. While the intensity of services ultimately depends on individual youth and family needs, the average MST family receives 60 hours of direct services delivered over a period of 4 months. Program out comes in serious delinquents include reductions in long-term rates of rearrest, reductions in out-of-home placements, improvements in family functioning, and reductions in mental health problems among treated youths, compared to controls. Multidimensional Treatment Foster Care is a multisystemic (multicontextual) clinical intervention that targets teenagers with histories of chronic and severe criminal behavior as an alternative to incarcera tion, group or residential treatment, or hospitalization. Meta-analyses conducted by Lipsey and others demon strate that community-based treatment is more success ful than residential treatment for this population of youths. Multidimensional Treatment Foster Care implementers recruit, train, and supervise foster fami lies to offer youths treatment and intensive supervision at home, in school, and in the community. The program also provides parent training and other services to the biological families of treated youths, helping to improve family relationships and reduce delinquency when youths return to their homes. Youths who partici pate in this program also receive behavior management and skill-focused therapy and a community liaison who coordinates contacts among case managers and others involved with the youths. Evaluations indicate that Multidimensional Treatment Foster Care can reduce the number of days of incarceration, overall arrest rates, drug use, and program dropout rates in treated youths versus controls during the first 1 2 months after com pleting treatment; it can also speed the placement of youths in less restrictive, community settings. # Justice System Services Justice system approaches to preventing youth vio lence can be effective when they focus on providing services rather than instituting greater penalties. One promising justice system approach is wraparound services, in which comprehensive services are tai lored to individual youths, as opposed to trying to fit youths into predetermined or inflexible programs. Evaluations of Wraparound Milwaukee have shown reductions in recidivism and arrests during the year following participation. One juvenile justice system approach to prevent ing youth violence meets the standards described above for a Promising program: Intensive Protective Supervision Project. This intervention removes delin quent youths (status offenders) under the age of 16 from criminal justice institutions and provides them with proactive and extensive community supervision. This program has been shown to have greater deter rent effects on referrals to juvenile court than standard protective supervision does. # Ineffective Tertiary Programs and Strategies Several popular juvenile justice approaches to pre venting further criminal behavior in delinquent youths have been shown to be consistently ineffective: specifically, boot camps, residential programs, milieu treatment, behavioral token programs, and waivers to adult court. # Boot Camps Perhaps the most well known of these approaches, boot camps for delinquent youths are modeled after military basic training, with a primary focus on disci pline. Compared to traditional forms of incarceration, boot camps produced no significant effects on recidi vism in three out of four evaluations and trends toward increased recidivism in two. The fourth evalu ation showed significant harmful effects on youths, with a significant increase in recidivism. Boot camps typically focus very narrowly on phys ical discipline, a highly specific personal skill, rather than a broader range of skills and competencies, such as those addressed by effective programs. Boot camps are also a setting in which youths are exposed to other delinquent youths, who can act as models and positive ly reinforce delinquent behavior (Dishion et al., 1994). # Residential Programs Residential programs, interventions that take place in psychiatric or correctional institutions, also show little promise of reducing subsequent crime and vio lence in delinquent youths. While some residential programs appear to have positive effects on youths as long as they remain in the institutional setting, research demonstrates consistently that these effects diminish once young people leave. Evaluations of two residential programs showed that participating youths were actually more likely to be rearrested and to report they had committed serious offenses during follow up. In both studies, the comparison group consisted of youths assigned to regular training schools. Two general approaches that are popular in resi dential settings are milieu treatment and behavioral token programs. Both strategies aim to change the organizational structures of residential programs. The milieu treatment approach is characterized by resident involvement in decision making and day-to-day inter action for psychotherapeutic discussion. While this approach shows some positive effects when individual responsibility is stressed, the more common strategy of group decision making has shown no positive effect on recidivism after release. Moreover, Lipsey and Wilson's meta-analysis shows that milieu therapy is one of the least effective approaches to preventing recidivism in serious juvenile offenders (Table 5-1). In behavioral token programs, youths are reward ed for conforming to rules, exhibiting prosocial behav ior, and not exhibiting antisocial or violent behavior. Like some other residential approaches, behavioral token programs can have positive effects on targeted behaviors while youths are institutionalized. However, when this strategy is used alone, any such effects dis appear when youths leave the program. # Waivers to Adult Court Another popular justice system approach to deterring youth violence, waivers to adult court, can have par ticularly harmful effects on delinquent youths. The idea behind this approach, "adult time for adult crime," was widely accepted into practice in the 1990s, when youth violence escalated dramatically. Evaluations of these programs suggest that they increase future crim inal behavior rather than deter it, as advocates of this approach had hoped. Moreover, placing youths in adult criminal institutions exposes them to harm. Results from a series of reports indicate that young people placed in adult correctional institutions, compared to those placed in institutions designed for youths, are eight times as likely to commit suicide, five times as likely to be sexually assaulted, twice as likely to be beaten by staff, and 50 percent as likely to be attacked with a weapon (Bishop, 2000;Bishop & Frazier, 2000;Fagan et al., 1989;Flaherty, 1980). # Counseling Several counseling, therapy, and social work approach es to treating delinquent youths have also been shown to be ineffective in the review literature, a finding that is consistent with the results of Lipsey's meta-analyses (Table 5-1). One "mainstay" (Tolan & Guerra, 1994, p. 15) of the juvenile justice system's toolkit against youth violence, social casework, combines individual psy chotherapy or counseling with close supervision of youths and coordination of social services. Even when implemented carefully and comprehensively, programs that use this approach have failed to demonstrate any positive effects on recidivism. In fact, one long-term follow-up of delinquent youths treated in this setting shows several significant negative effects, including increases in alcoholism, unemployment, marital diffi culties, and premature death (McCord, 1978). Meta-analyses also demonstrate that individual counseling can be one of the least effective prevention approaches for delinquent youths. However, the effects of this strategy appear to depend largely on the popula tion. Though relatively ineffective for general delin quency and only marginally effective for institutional ized seriously delinquent youths, individual counseling emerged as one of the most effective intervention approaches for noninstitutionalized seriously delin quent youths in Lipsey's studies (Table 5-1). The rea son for this difference is unclear, but it illustrates the importance of program characteristics other than con tent, particularly the importance of matching the pro gram to the appropriate target population. A meta analysis by Andrews and colleagues (1990) confirms this finding, demonstrating that appropriate treatment can deter reoffending, whereas interventions that are poorly matched to the populations served can have no effect or a negative effect. # Shock Programs One tertiary youth violence prevention intervention meets the scientific criteria established above for Does Not Work: Scared Straight. Scared Straight is an example of a shock probation or parole program in which brief encounters with inmates describing the brutality of prison life or short-term incarceration in prisons or jails is expected to shock, or deter, youths from committing crimes. Numerous studies of Scared Straight have demonstrated that the program does not deter future criminal activities. In some studies, rear rest rates were similar between controls and youths who participated in Scared Straight. In others, youths exposed to Scared Straight actually had higher rates of rearrest than youths not involved in this intervention. Studies of other shock probation programs have shown similar effects. (For more information on Scared Straight and similar shock probation interventions, see Boudouris & Turnbull, 1985;Buckner & Chesney-Lind, 1983;Finckenauer, 1982;Lewis, 1983;Sherman et al" 1997;Vito, 1984;Vito & Allen, 1981.) # C o s t -E f f e c t iv e n e s s Violence costs the United States an estimated $425 billion in direct and indirect costs each year (Illinois Center for Violence Prevention, 1998). Of these costs, approximately $90 billion is spent on the criminal jus tice system, $65 billion on security, $5 billion on the treatment of victims, and $170 billion on lost produc tivity and quality of life. The annual costs to victims are approximately $178 billion (Illinois Center for Violence Prevention, 1998). The most logical way to reduce these costs is to prevent violence altogether. Preventing a single violent crime not only averts the costs of incarceration, it also prevents the short-and long-term costs to victims, including material losses and the costs associated with physical and psycholog ical trauma. Despite these facts, policy in the United States continues to focus on get-tough laws and incarceration for serious violent criminals, as opposed to prevention and intervention (Greenwood, 1995). Federal spend ing on school-based crime, violence, and drug preven tion programs is quite modest, compared to spending on crime and drug control strategies such as policing and prison construction (Gottfredson et al., in press). Not only are preventive approaches more beneficial than get-tough laws, some prevention and intervention strategies cost less over the long run than mandatory sentences and other get-tough approaches. In an effort to determine the cost-effectiveness of California's three-strikes-and-you're-out law, which mandates life sentences for repeat offenders, Greenwood (1995) compared that approach to the benefits and cost-effectiveness of a number of crime prevention strategies. He estimated that each serious crime-homicide, rape, robbery, assault, or residential burglary-prevented by the three-strikes law cost the criminal justice system in California an additional $16,000 over the amount spent prior to this legisla tion. Using this price as the standard for cost-effec tiveness, Greenwood calculated the costs per serious crime prevented of four prevention and intervention strategies: ( 1) early childhood intervention (perinatal home visitation continuing through the first 2 years, combined with 4 years of enriched day care programs) for high-risk families, (2 ) parent training for families with children who have shown aggressive behavior ("acted out") in school, (3) improved public school programs that target all youth, and (4) early interven tions for very young delinquents. The costs calculated for each of these interventions included only direct program costs, not such indirect benefits as the money saved by averting incarceration or preventing victim trauma and its medical and social consequences. Table 5-2 shows the benefits of the various pre vention and intervention programs with respect to the number of serious crimes each can be expected to pre- Source: Greenwood, 1995. 1 All estimates are based on 1992 crime figures and 1990 population figures. 2 Crime prevention numbers for first 5 years include child abuse. vent over the course of 30 years. The major disadvan tage of the prevention approach is clear-there is a time lag between implementation of programs and the appearance of effects. Because of this time lag, pro grams that are cost-effective in the long run do not appear so in the short run. In addition, long periods between an intervention and the high-risk period of a youth's life offer more opportunity for decay of a pro gram's effects (Greenwood et al., 1998). In the case of early childhood programs, it takes approximately 15 years before significant effects on youth violence can be appreciated, given the peak ages at which young people are involved in violence. Early intervention with delinquent youths that includes day treatment and home monitoring has a shorter lag time because the intervention is introduced later in life yet early in a violent career. Of the four approaches listed in Table 5-2, the most cost-effective in the long run is parent training, which costs only $392 to implement per serious crime averted after the program has been in effect 30 years. This is less than one-fortieth the estimated cost of preventing serious crime under the three-strikes law. Day treatment and monitoring for delinquent youths are also more cost-effective than mandatory sentencing, costing less than one-sixth as much as the three-strikes approach. The least cost-effective of the four are prenatal and early childhood intervention and school-based programs that target all students. However, early childhood interventions that include prenatal home visitation and enhanced day care can be expected to 5 These reductions in ch ild abuse were not considered in this analysis. 0 136 halve the incidence of child abuse among high-risk families (that is, low-income families headed by a sin gle mother).5 Moreover, early childhood intervention may improve educational achievement and reduce teen pregnancy rates. School-based programs have benefits other than prevention of violent crime, including higher educational achievement for all stu dents. In a later analysis, Greenwood et al. (1998) found that school-based prevention programs that tar geted disadvantaged youths specifically and included incentives (such as cash) for graduating from high school were almost 1 0 times as cost-effective as the three-strikes approach. In general, Greenwood's findings suggest that interventions targeting problem youths-either chil dren who act out or delinquent youths-are more costeffective than interventions that target general popula tions of youths. In addition, they confirm that preven tion is truly more cost-effective in the long run than incarceration. Costs aside, prevention may not have as great an effect on rates of violence as imposing longer manda tory sentences on repeat offenders. Other analyses demonstrate that the three-strikes law can reduce seri ous crime by 2 1 percent, whereas graduation incen tives only reduce it by approximately 15 percent, par ent training by 7 percent, early childhood intervention by 5 percent, and delinquent supervision by less than 2 percent (Greenwood et al., 1998). However, the four prevention and intervention strategies combined cost nearly $1.2 billion per year less to implement than the three-strikes strategy alone, and together they could prevent a substantial portion of the 80 percent of seri ous crimes that are not averted by mandatory sentenc ing (Greenwood et al., 1998). Graduation incentive programs could pay for themselves with the money they save by averting the eventual incarceration of many youths, and the other prevention and interven tion strategies could pay for up to 40 percent of their costs in the same manner. Studies of two targeted early childhood intervention programs, the Perry Preschool and the Elmira, New York, Prenatal and Infancy Home Visitation by Nurses, indicate that these programs can actually save the gov ernment up to three times their cost when delinquency prevention and other benefits are considered (Karoly et al., 1998). It is noteworthy that although the cost-effec tiveness data in Table 5-2 were calculated using crime and population statistics for California, they have national implications with respect to the relative costs and benefits of violence prevention and incarceration. Researchers at the Washington State Institute for Public Policy, who conducted a similar analysis (Aos et al., 1999), point out that the most effective programs are not always the most cost-effective. They note the importance of matching the intervention to the popula tion-a particular challenge for programmers, but one that has a critical effect on both the overall effective ness and the cost-effectiveness of an intervention. The results of the Washington study are summa rized in Table 5-3. While this table includes only the programs and approaches discussed in this report, the Washington study actually included many more programs and strategies, including some targeting adult offenders. All cost estimates in Table 5-3 were calculated using the same methodology so that pro grams can be compared. Although most costs are cal culated as direct, per-participant program costs, the costs of Multidimensional Treatment Foster Care are calculated relative to regular group home costs, and the costs of intensive supervision programs and boot camps are calculated relative to regular court proba tion costs. (Thus, the negative program cost of boot camps means that these programs cost less to imple ment than regular court probation programs.) This # E R I C -verall approach may not be the same one used by other researchers to calculate program costs, result ing in inconsistencies between costs in this table and those projected by individual program designers . Nevertheless, the Washington study offers some useful insights into the cost-effectiveness of youth violence prevention. Looking at the benefits to the criminal justice system alone (that is, benefits to the taxpayer), many early interventions and selected strategies come close to paying for themselves with the money they save; others actually achieve benefits that are greater than program costs. The Seattle Social Development Project, for instance, now saves $0.90 from reduced rates of crime for every tax dollar spent. Programs targeting at-risk or delinquent youths can be even more cost-effective. For example, taxpayers today can expect to save $14.07 in future criminal jus tice costs for every dollar spent on Multidimensional Treatment Foster Care. The same trend holds when considering the bene fits of youth crime prevention to both the criminal jus tice system and crime victims (personal and property losses)-the largest economic returns are achieved with interventions targeted at juvenile offenders, who are at greatest risk of future offending. The Model programs in this group return $ 1 1 to $ 2 2 for every dol lar invested. However, even programs aimed at nonof fenders can achieve significant cost benefits when future savings to potential crime victims (due to a reduction in the number of victims) and the taxpayer are combined. According to the Washington study, society gains at least $0.50 over program costs for each dollar spent on the Perry Preschool Program, Prenatal and Infancy Home Visitation by Nurses, the Seattle Social Development Project, and Big Brothers Big Sisters of America. In general, these analyses underestimate the bene fits of prevention programs because they fail to con sider many of the indirect benefits of preventing seri ous or violent offenses, such as increased work pro ductivity, increased taxes realized, reduced welfare assistance costs, and reduced victim medical costs. # C o n c l u s io n s Clearly, we are past the era in which some observers believed that "nothing works" to prevent youth vio lence. Numerous programs have demonstrated their effectiveness in reducing risk factors for serious vio lence. At the same time, there is a pressing need to eval uate more youth violence prevention programs. Of the hundreds of programs currently in use throughout the United States, only six met the criteria for a Model pro gram, and 21 met the criteria for a Promising program. Of the 266 school-based program modules reviewed by Gottfredson et al. (in press), all of which were formally evaluated against a control or comparison group, only 1 0 percent received the highest score for scientific rigor (the experimental design standard used here). For most O I RJCbeST copy available violence, crime, and drug prevention' programs now being implemented, there is simply no evidence regard ing effectiveness. Although well-designed program evaluations are expensive and time-consuming, they are the only way to determine the effectiveness of exist ing youth violence prevention programs. Nearly half of the most thoroughly evaluated strategies for preventing youth violence are ineffective, however, and a few are even harmful. It is in society's best interest to evaluate programs before exposing chil dren and adolescents to them-otherwise we run the risk of harming young people rather than helping them. The most effective youth violence prevention programs are targeted appropriately, address several age-appropriate risk and protective factors in differ- # G o i n g t o Sc a l e While identifying best practices in youth violence pre vention is critical to reducing the number of young people involved in and affected by violence, it is not the last step. The manner in which a program is imple mented can have an enormous impact on its effective ness-even the best programs are effective only when implemented with high quality and fidelity to the pro gram's design. In other words, using an effective strat egy is only part of what is required to achieve effec tive results. Details of program delivery, including characteristics of the youths receiving the interven tion, the setting in which they are treated, and the intensity or duration of the intervention, play impor tant roles in determining effectiveness. Programs must be delivered with design fidelity, to a specific popula tion of youths, within a specific context, and for a spe cific period of time. Unfortunately, very little is known about how to preserve a prevention program's positive effects when it is implemented on a wide-scale or national level. What research has been conducted indicates that effective implementation is at least as important to a program's success as the characteristics and content of the program itself (Petersilia, 1990;Lipsey, 1992aLipsey, , 1992b. $tudies of program implementation consis tently find that effectiveness depends on the following principles, according to a review by Petersilia (1990, p. 130): - The project addresses a pressing local problem. - The project has clearly articulated goals that reflect the needs and desires of the "customer." - The project has a receptive environment in both the parent organization and the larger system. - The organization has a leader who is committed to the objectives, values, and implications of the proj ect and who can devise practical strategies to moti vate and effect change. - The project has a director who shares the leader's ideas and values and uses them to guide the imple mentation process and ongoing operation of the project. - Practitioners make the project their own rather than being coerced into it; that is, they buy into it, partici pate in its development, and have incentives to maintain its integrity during the process of change. - The project has clear lines of authority: There is no ambiguity as to who is in charge. - The change and its implementation are not complex and sweeping. - The organization has secure administrators, low staff turnover, and plentiful resources. Gendreau et al. (1999) organize these same prin ciples into four categories: general organizational fac tors, program factors, change agent factors, and staffing activities. While they acknowledge the impor tance of a program's characteristics, such as its theo retical basis, they also stress that positive change and success are dependent on much more than the specif ic characteristics of a prevention program or interven tion. Characteristics of the implementer, the environ ment in which the program is implemented, and even the target population have a significant influence on overall program effects. Both the Petersilia and Gendreau et al. studies dis cuss characteristics of effective implementation with in a correctional setting. The Centers for Disease Control and Prevention's (CDC) Best Practices of Youth Violence Prevention (Thornton et al., 2000) and a recent review by Gottfredson et al. (2000) suggest that many of the same characteristics help determine the success of violence and delinquency prevention programs. In particular, the CDC study highlights the importance of training, monitoring, and supporting the staff who implement a program on the local level. An appropriate match between staff and the target population can also contribute to program success, particularly in parent-and family-based programs. Staff must be committed to the program, experienced with the general strategy being used, knowledgeable about the target community, and capable of managing group dynamics and overcoming resistance. Likewise, as noted by Petersilia, maintaining community involvement is a key element of program success. Finally, linking a youth violence prevention program to existing strategies and support agencies in the com munity or school can contribute to success (Thornton et al., 2 0 0 0 ). A similar group of implementation characteris tics affects the success of school-based delinquency prevention programs, according to Gottfredson and colleagues (2000). In a study of more than 1,200 schools throughout the United States, they found that extensive, high-quality training and supervision, as well as support for the program from the principal of the school, are key elements of success. Schools also appear to have greater success with standardized materials and methods, as well as programs that can be incorporated into the regular school program. Consistent with Petersilia's principles, local buy-in and initiation of school-based delinquency preven tion are important predictors of program success. Multiple sources of information, including the use of an expert to assist with training and implementation, also help to ensure positive results. Improvements in any or all of these factors should improve the quali ty of the overall prevention program-and its effects on youths. The CDC recommends monitoring the progress and quality of program implementation on a local level. This step can be particularly important when implementing Model programs. The proven effective ness of these programs in multiple, long-term studies makes them suitable for implementation on a wide, or even national, scale, but even Model programs are successful only when implemented with fidelity. While it is not always necessary to conduct expensive outcome evaluations of Model programs, given their demonstrated positive effects and ongoing national evaluations, it is critical to monitor the quality of implementation on the local level. Scientific research has established the effective ness of a number of prevention programs, and evalu ation studies are sure to identify more in the near future. Although the studies cited above offer valu able guidance, more research is needed on how to implement youth violence prevention programs with fidelity on a national scale, how to monitor program fidelity on this scale, and how to increase community and agency capacity for implementing these pro grams. In addition, large-scale program dissemina tion will affect the overall benefits of individual youth violence prevention programs. Addressing these issues will require a major investment of time and resources, but it is the essential next step in the continuing effort to find effective solutions to the problem of youth violence. Thornton et al., 2000. 4. Developmental Research and Program s, Inc., 2000. 5. Howell, 1995. The 1995 O J JD P report does not include the full complement of the office's recommendations regarding youth violence prevention. Sin ce 1995, the group has released several sm aller publications in which it specifically recommends other prevention strategies identified as effective in this report. - Evidence of effectiveness: Evaluations performed at the end of the 9th grade show that STEP students have fewer school absences, higher grade-point averages, more positive feelings about school, and a better self concept than controls. In long-term studies, STEP stu dents had lower dropout rates than controls (2 1 per cent versus 43 percent), higher grades, and fewer absences. In a replication of the program in middle and junior high schools, both STEP and control stu dents showed increases in substance use, delinquent acts, and depression, and decreases in academic per formance and self-confidence. However, these changes were significandy smaller among STEP stu dents than controls. Students who participated in STEP also had lower dropout rates than controls. Replication in students with lower risk profiles 1 year after participation in STEP confirmed these findings, showing lower rates of delinquency and higher self esteem, academic performance, and school attendance than controls. This program has not been evaluated in small or high-achieving schools. In past studies, the program has worked best in large schools. The major limitation to the evaluation research on this program is that the first study lacked pretest measures; howev er, the researchers reported no differences between treated students and controls with respect to atten dance and grades at baseline. - For further information: - Evidence of effectiveness: In a multi site, random ized evaluation, a follow-up through the expected time of graduation showed that treated youths were significantly less likely than controls to be arrested (0.17 versus 0.58 arrests per person), were more likely to graduate (63 versus 42 percent), were more likely to attend postsecondary schools (42 versus 16 percent), were less likely to be dropouts, were more likely to receive an honor or award, were less likely to become teen parents, and were more likely to be involved in community service, be hopeful about the future, and consider their lives a success. Follow-up for 2 years after graduation revealed per sistent, positive program effects. - For further information: (1989)(1990)(1991)(1992)(1993). Waltham, MA: Brandeis University Heller Graduate School Center for Human Resources. # 4J Chapter 6 A V ision for the Future I n the late 1990s, people in the United States were stunned by a series of tragic shootings at schools that were planned and carried out by youths. These shocking, widely reported events prompted the prepa ration of this Surgeon General's report on youth vio lence. Yet these shootings were not characteristic of youth violence nationally. Moreover, at the time of the shootings, youth violence in the United States appeared to be on a downward trend. Serious youth violence-that is, physical assault by a child or adolescent that carries a significant risk of injuring or killing another person-began to emerge as a social and public health problem of siz able proportions in the 1980s. Arrests of youths for index crimes (robbery, aggravated assault, rape, and homicide) peaked in 1993 after a decade of climbing rapidly, leading some observers to express doubt that anything could be done to halt the epidemic of youth violence. By 1999, after 6 years of sustained decline nationwide, arrests of youths for robbery, rape, and homicide began to resemble the pre-epidemic arrest rates of 1983. A striking exception to this trend was arrests for aggravated assault, which remained 70 per cent above 1983 rates. While arrest records and victimization reports indicated that youth violence was generally declining, other sources of information presented a different pic ture. In approaching youth violence as a public health problem, this report has looked beyond arrest and other criminal justice records to several national sur veys in which high school-age youths report in confi dence on their violent behavior. These self-reports reveal that the propensity for and actual involvement of youths in serious violence have not declined with arrest rates. Rather, they have remained at the peak rates of 1993, a troublesome finding. In January 2001, as this report goes to press, the first indications of a long-awaited downturn in self-reported violent behav ior are being countered by signs from the FBI's Uniform Crime Reports database that the decline in arrests of youths for violent crimes has bottomed out and, for some index crimes, has begun to climb again. Clearly, the dynamics and magnitude of youth violence remain fluid and complex. Nevertheless, research in the past several decades has developed a wealth of information about the causes of youth vio lence and how to prevent it. Numerous studies have identified and examined specific risk factors for vio lence-the personal and environmental features of young people's lives that increase the statistical prob ability of their engaging in violent behaviors. Research also has begun to identify protective factors that appear to buffer the effects of risk factors. While this information has been accumulating, researchers, youth service practitioners, and others have been designing, implementing, and evaluating a variety of programs and strategies to reduce or prevent the occurrence of youth violence. The best of these inter ventions target populations of young people identified as being particularly at risk of becoming involved in a violent lifestyle. Many effective intervention programs exist to reduce and prevent youth violence. The United States is well past the point where anyone can claim that "nothing works" to prevent youth violence or to mod ify the destructive life courses of youths who are either engaged in or appear to be headed for lifestyles characterized by violence. At the same time, however, many purported youth violence prevention programs used today are untested, and some are known to be ineffective or even deleterious to a child or adoles cent's healthy, safe development. The courses of action highlighted below are potential next steps. These are not formal policy rec ommendations. Instead, they represent a vision for the future built on information we possess today. They are intended for policy makers, service and treatment providers, people affiliated with the juvenile justice system, researchers, and most important, the people of the United States. This vision for the future is present ed with the hope that it will engage an expanding number of citizens in the challenge of redressing the problem of youth violence. # C o n t in u e t o B u il d t h e Sc ie n c e Ba s e Scientific research is an essential underpinning of the public health approach to the problem of youth vio lence. Years of extensive research have revealed the scope of the problem, and we are beginning to under stand how to intervene effectively to reduce and pre vent violence. Yet most violence prevention programs used in schools, communities, and the justice system today have not been subjected to systematic scientific evaluation, so their effectiveness-or lack of effec tiveness-is unknown. Given evidence that some well-intentioned prevention and intervention pro grams have proved to be harmful, it is imperative that all programs be scientifically evaluated. Research must also be prepared to address areas of emerging concern. One that has become increasingly clear is the need for studies to investigate intimate violence, or dating violence, among youths to identify patterns that predict continuation of such behaviors into adulthood and to design new types of interventions targeting this form of violent behavior. Another area of concern requiring research is the impact of violent interactive media, such as computer games, on serious violent behavior. This Surgeon General's report is issued at a time of unprecedented scientific opportunity in numerous disciplines-developmental psychology, sociology, criminology, epidemiology, neuroscience, and many other fields. No single research specialty holds the key to understanding, treating, and preventing vio lence. Rather, they must work together. One of the greatest challenges to researchers today is finding new ways to use the tools, strategies, and insights from these diverse fields of research to reveal the many fac tors that may lead a young person toward-or protect a young person from-involvement in violence. A related need is to invest in cross-level research designs that will enable researchers to examine individual, family, and community factors simultaneously. Research frequently examines questions and issues that crop up in the daily lives of millions of people-the relationship of media depictions of vio lence to violent behavior is a key example; the impact of strategies to discourage firearm use is another. Such familiarity often increases the likelihood that a person will hold strong opinions regarding the effect of television or popular music, or the presence and use of weapons, on violent behavior. Appropriately designed and conducted research offers a factual basis, rather than opinion, for proposing and debating social policy. It is therefore critical to devise ways of giving people with diverse interests (including par ents, teachers, and others) a voice in identifying urgent research questions and to inform them about the conclusions drawn from research. # A c c e l e r a t e t h e D e c l in e in G u n U se b y Y o u t h s in V io l e n t En c o u n t e r s The carrying and use of guns by youths in violent encounters have declined dramatically since 1993, the peak of the violence epidemic. To accelerate that decline, we must seek to understand more completely the reasons for it. Are youths' decisions not to carry or use guns in violent encounters related to any specific strategies put in place to discourage firearm use, or did the drop in firearm use result from other factors or conditions? Clearly, important questions remain about precisely what has happened in communities nationwide to reduce the frequency with which ado lescents carry guns. While some research has addressed these questions (Blumstein & Wallman, 2000), further studies are imperative-data document ing the continuing magnitude of violent behaviors suggest that a return to lethal violence is likely if ado lescents once again carry and use guns in violent encounters. # Fa c il it a t e t h e En t r y o f Y o u t h s in t o Effe c t iv e I n t e r v e n t io n P r o g r a m s Ra t h e r T h a n I n c a r c e r a t in g T h e m In the 1990s, faced with the epidemic of violence and largely unaware that research had found some vio lence prevention programs to be effective-as well as often buying into the "just desserts" philosophy-the only option some legislators saw was to lock up vio lent youths to protect society. New evidence makes a compelling case that intervention programs can be cost-effective and can reduce the likelihood that youths will become repeat offenders. Given this evi dence, it is in the country's interest to place as many violent youths as possible in these programs, thus cor recting the imbalance that now favors use of the crim inal justice system over effective intervention pro grams. Reclaiming youths from a violent lifestyle has clear advantages over warehousing them in prisons and training schools. Effective programs are not available in many communities. Special efforts must be undertaken to increase awareness of these programs, provide techni cal assistance and information about them, and devise incentives for states and communities to invest in test ed programs. At present, states and communities are squandering substantial amounts of money on untest ed programs or programs known to be ineffective. Policy makers must be encouraged to focus existing resources on programs that work; evidence of effec tiveness might be required, for example, as a condi tion of receiving Federal or local funding. An informed public is also critical in building support for effective alternatives to incarceration. # D is s e m in a t e M o d e l Pr o g r a m s w it h I n c e n t iv e s T h a t W il l En s u r e F id e l it y t o O r ig in a l P r o g r a m D e s ig n W h e n T a k e n t o Sc a l e Experience has shown repeatedly that intervention programs shown to be effective in their original sites do not yield uniform outcomes when replicated else where. Upon examination, program evaluators often find that subtle modifications have been introduced into the model program. Lack of a particular category of personnel in a given location, for example, may prompt a program director to substitute professionals or paraprofessionals without proper credentials. Faceto-face training sessions that initially encouraged interaction between a program originator and new staff may be supplanted by videotaped tutorials. The frequency of participants' contacts with a program may be lessened or program duration abbreviated. Legislators, agency administrators, and program directors should be encouraged to identify incentives for ensuring that the integrity of a model program is not compromised when it is replicated. # Pr o v id e T r a in in g a n d C e r t if ic a t io n Pr o g r a m s f o r I n t e r v e n t io n Pe r s o n n e l The major challenge in implementing effective inter vention programs on a national scale is guaranteeing a well-trained staff that understands the intervention and its limitations. Staff must be adequately trained to deliver a particular intervention in the specific settings for which it was designed. Yet because the supply of appropriately trained individuals who are available to work in the variety of settings in which violence pre vention programs operate is limited, operational entropy often sets in. Establishing formal training pro grams and university certification programs will help ensure the quality of interventions. # Im p r o v e P u b l ic A w a r e n e s s o f Ef f e c t iv e I n t e r v e n t io n s Identifying specific youth violence interventions as effective in this report will probably stimulate demand for these programs. Youth advocacy organizations have an opportunity to educate citizens on how to interact effectively with their local educational and juvenile justice systems, with appropriate sectors of the elected government, and with private organiza tions involved in youth violence prevention. Media campaigns and public service announce ments offer a means of increasing public awareness. News or documentary television programs featuring model programs have had a measurable impact both on the funding of the programs and on the volume of requests from sites throughout the country for infor-mation about the programs. The 1938 film Boys Town, with Spencer Tracy and Mickey Rooney, proved high ly beneficial to the reputation and funding opportuni ties available to Boys Town. Conceivably, featuring model youth violence prevention programs in popular films today could have an equivalent effect. The move to a public health focus on violence involves new players and new collaborative partnerships among criminologists, psychologists, psychiatrists, sociolo gists, neuroscientists, and others. Physicians and other general medical service providers have important roles to play, but they are not yet sufficiently involved. Preparation of the Surgeon General's report under scored the risks of disciplinary compartmentalization in the study of youth violence. There is no common place where information needed by all parties interested in the problem of youth violence can be exchanged. A rich literature on research and services appears in the specialty journals of various disciplines, in professional newsletters, in the mass media, and increasingly on the World Wide Web. Lack of interaction between academic research centers and the community-based agencies responsible for imple menting youth violence prevention programs or provid ing medical services to victims (many of whom are also perpetrators) can result in significant costs. A periodic, highly visible national summit that receives wide popular as well as specialized media coverage would offer a way of disseminating infor mation on new research findings, effective programs and strategies, best practices, and related information for diverse audiences. # Im p r o v e Fe d e r a l , Sta t e , a n d L o c a l St r a t e g ie s f o r R e p o r t in g C r im e I n f o r m a t io n a n d V io l e n t D e a t h s The proportion of law enforcement agencies nation wide that report arrests to the FBI's Uniform Crime Reports (UCR) program has been declining. In 1999, . O participating agencies represented only 63 percent of the U.S. population. The accuracy of national esti mates would be enhanced if this reporting rate were improved. In addition to expanding the participation rate, opportunities for improvement might entail: - Including arrest rates for all racial and ethnic groups. Hispanics in particular are not represented in systematic data collection systems. - Encouraging law enforcement agencies to partici pate in the National Incident-Based Reporting System. Developed by the UCR, the incident-based reporting system provides a much richer data set for tracking violent crime than the aggregated data available in the current UCR. Another potentially useful, innovative data set is the National Violent Death Reporting System proposed by the Centers for Disease Control and Prevention. This data set would help in monitoring the magnitude and char acteristics of youth violence on a timely basis so that programmatic and policy responses can be more effectively planned and evaluated. - Develop a standard set of questions for national self-report surveys (such as Monitoring the Future) that include serious violent offenses. Annual data from these surveys should be obtained from all adolescents age 11 through 17, not just high school seniors. At present, variation among surveys in the age of respondents, data obtained, and frequency of data collection severely limit any composite picture that might result. Data collection efforts must make use of the best methodology available and include follow-up questions on each reported violent event to determine weapon use, drug or alcohol involve ment at the time of the event, seriousness of injury, victim's relationship to offender, number of youths involved in the attack, and other details. Such data enable researchers to correct for the overreporting in the simple checklist used in most surveys. # C o n c l u s io n Youth Violence: A Report of the Surgeon General offers compelling testimony that the safety and well being of children and adolescents are issues of the utmost importance and urgency to individuals and lies organizations throughout the United States. The report has drawn on the expertise of countless persons in diverse private organizations; in local, state, and Federal government agencies; in schools; and most important, in families-all of whom are dedicating immense energy and caring to countering the most common threat to the lives of young Americans. Thanks to these efforts and to the insights and actions of young people themselves, it is clear today that youth violence is not an intractable problem; rather, it is a behavior that we can understand, treat, and pre vent. This final chapter has offered courses of action intended to help inform the decisions that we must make as we strive to ensure that every child has the opportunity to grow and mature safely, healthily, and happily. R e f e r e n c e Blumstein, A., & Wallman, J. (2000).. The crime drop in America. Cambridge, United Kingdom: Cambridge University Press. # G lossary Absolute deterrent effects. Effects that are demon strated when an intervention produces better out comes compared to no treatment. # Age of onset (of serious violence). The age at which an individual reports his or her first act of serious violence. Age-specific prevalence. The proportion of youths at any given age who report having committed at least one serious violent act in the past year. # Aggravated assault. An unlawful attack by one per son upon another wherein the offender uses a weapon or displays it in a threatening manner, or the victim suffers obvious severe or aggravated bodily injury involving apparent broken bones, loss of teeth, possible internal injury, severe laceration, or loss of consciousness. Along with homicide, rob bery, and rape, one of the four violent crimes cov ered in this report. # Aggression (aggressive behavior). Behavior, physical or verbal, that is intended to harm another person. # Antisocial attitudes. Favorable attitudes toward vio lence, dishonesty, and rule breaking with hostility toward authority. # Antisocial behaviors. Problem behaviors that range from relatively minor acts such as lying, stealing, truancy, disobedience, and temper tantrums to seri ous nonviolent or violent behavior such as burglary or aggravated assault. # Attention-deficit/hyperactivity disorder (ADHD). A cognitive disorder characterized by restlessness, excessive activity, and difficulty paying attention. # Career length. Variously defined as the number of years of active offending; or the maximum number of consecutive years of offending; or the span between the first and last year during which a youth meets the criteria for a serious violent offender. # Case study research. A type of study design involv ing multiple observations of a single individual over time. # Chronic offenders. Variously defined by some mini mum number of offenses; for example, youths with three or more serious violent offenses per year. # Contagion effect (of violence). Unproved notion that seeing or hearing about violence in news coverage encourages violent or aggressive behavior. # Control group. A group that receives standard care or no intervention in a research study, compared to the experimental, treatment, or intervention group. # Co-occurrence (of problem behaviors). The simul taneous display of violence and other problem behaviors (e.g., substance use, property crimes, gun ownership). Although these behaviors occur togeth er, it cannot be assumed that one behavior causes another. Conduct disorder. Childhood disorder marked by persistent acts of aggressive or antisocial behavior. Cross-sectional research. A type of study design, fre quently used in public opinion polls, surveys, and epidemiological research. It involves a single con tact with participants for data collection at a given point in time and thus does not permit researchers to estimate individual-level change, development, or predictive effects of a given risk or protective factor on later violent behavior. Cumulative prevalence (lifetime prevalence or ever-prevalence). The proportion of youths at any particular age who have ever committed a serious violent offense. Delinquent (antisocial) lifestyle. A pattern of con sciously chosen and sustained behaviors that include antisocial or illegal acts, typically involving property crimes, substance use, gun ownership, and promiscuity. Deterrent effects (absolute). See Absolute deter rent effects. # Deterrent effects (marginal). See Marginal deter rent effects. # Developmental perspective (on youth violence ). An approach to understanding youth violence that con siders the complex interaction of individuals with their environment at particular times in their lives; this approach recognizes that patterns of behavior change over the life course. Early-onset trajectory. A pattern of violent behavior that emerges before adolescence, defined in this report as about age 13. In this pathway, problem behaviors in childhood gradually escalate over time to more violent ones, culminating in serious vio lence before adolescence. This pattern is less preva lent than the late-onset trajectory and is character ized by higher offending rates, greater seriousness of adolescent offenses, and greater persistence of violence from adolescence into adulthood. Effect size. The predictive power of an individual or general type of risk or protective factor; or the size of the deterrent effect of an intervention compared to no treatment or a standard treatment. The meas ure used for risk factor effect sizes in this report is a simple correlation between two variables. For pro gram effectiveness, the effect size measure is the average difference (standardized) between the treat ment and control group means on the selected recidivism measure. # Effectiveness trials. Research that tests for benefits to participants in a natural or applied setting. # Efficacy trials. Research that tests for benefits to par ticipants in a controlled or experimental setting. Epidemiology. Study of the factors influencing the incidence, frequency, and distribution of healthrelated events in the population; identifying appro priate risk and protective factors for prevention and intervention programs. # Experimental research. A type of study design involving comparison of a group that receives an intervention (experimental or treatment group) and a group that receives standard care or no interven tion (control group) in which participants are ran domly assigned to one of these groups. This study design permits researchers to assess cause-andeffect relationships and can be used to determine intervention effectiveness. # Externalizing symptoms. A behavioral pattern charac terized by the acting out of psychological problems. Hazard rate. The proportion of individuals who initi ate a given behavior (e.g., serious violence) at a given age. Homicide. The willful (nonnegligent) killing of one human being by another; along with robbery, aggra vated assault, and rape, one of the four violent crimes covered in this report.* # Iatrogenic. In the context of youth violence, interven tions that are harmful or actually increase involve ment in violence. Incident rate. The number of self-reported violent acts within a given-sized population, a measure of the volume of violence; as used in this report, the number of violent acts per 1,000 young people. o Public health approach. A practical, goal-oriented, and community-based approach to promoting and sustaining health. This approach seeks to identify risk and protective factors, determine when in the life course they typically occur and how they operate, and enable researchers to design preventive programs that are effective in reducing risk and promoting protec tion. # Intervention. Quasi-experimental research. A type of study design with experimental and control groups but without random assignment to these groups. Groups are matched on selected characteristics, or differences are controlled in the analysis. The claim of group equivalence or comparability is not as strong with this design as in an experimental design. # Rape (forcible rape). The carnal knowledge of a per son, forcibly and/or against that person's will; or not forcibly or against the person's will where the vic tim is incapable of giving consent because of his or her temporary or permanent mental or physical incapacity (or because of his or her youth). Along with homicide, robbery, and aggravated assault, one of the four violent crimes covered in this report.* # Reliability (of research instruments or measures). The consistency of a measure; the measure yields the same result on different occasions or applica tions (when no real change has occurred). # Replication. Repeating an intervention or prevention program at multiple sites to determine if the results will be the same; establishes that a program can be effective at other sites when implemented by new teams under different conditions. # Risk factor. In the context of youth violence, personal characteristics or environmental conditions that increase the likelihood that a young person will become violent but that may not actually cause a per son to become violent. Risk factors are grouped into individual, family, school, peer group, and communi ty domains. The more risk factors a young person is exposed to, the greater the likelihood that he or she will become violent. # Risk marker. A personal characteristic or environ mental condition associated with known risk factors but having no causal relation to violence on its own. Robbery. The taking or attempting to take anything of value from the care, custody, or control of a person or persons by force or threat of force or violence and/or putting the victim in fear. Along with homi cide, aggravated assault, and rape, one of the four violent crimes covered in this report.* Sampling. The selection of persons to be studied in a research project. Schizophrenia-spectrum disorders. Broad category of disorders that includes individuals with symptoms such as serious distortions of reality (including hal lucinations and delusions), withdrawal from social interaction, and disorganization and fragmentation of perception, thought, and emotion, for which other plausible explanations could be ruled out. # Secondary prevention. In the context of this report, strategies and programs that reduce the risk of vio lence among youths who display one or more risk factors for violence (high-risk youths). Self-directed violence. Self-inflicted injury and sui cide; not the focus of this report. Self-report studies. Research that asks people in con fidence to describe their own behavior. In the con text of youth violence, surveys that ask young peo ple in confidence about violent acts they have com mitted or have been victims of during a given peri od of time. # Serious violent crime (serious violence or index crimes). As defined in this report, aggravated assault, robbery, rape, and homicide. ous and nonserious offenses. These youths account for a major share of all criminal behavior by persons under age 18. # Serious violent youths. # Socially disorganized community. A community characterized by high levels of poverty, unemploy ment, high turnover of residents, and a large pro portion of disrupted or single-parent families. Socioeconomic status. In reference to youths, their parents' education, occupation, and income. Statistical significance. The level of confidence with which one can conclude that a difference between two or more groups (generally a treatment and con trol group) is the result of the treatment delivered rather than the selection process or chance. A proba bility value of .05 is widely accepted as the threshold for statistical significance in the social and behav ioral sciences; a probability value below this thresh old (p < .05) indicates that a difference of this mag nitude could happen by chance less than 5 percent of the time. # Superpredators. A new breed of violent youths who commit more frequent and vicious violent crimes, without remorse, than in previous generations. Contrary to a recent myth, there is no evidence that this type of violent youths emerged in the 1990s. # Surveillance. A type of research that establishes the nature of a health problem, describes its incidence and prevalence trends, and monitors its magnitude over time. Public health specialists use this infor mation to determine appropriate prevention and intervention efforts. # Sustained effects. Changes in individual competencies and environmental conditions produced by effective programs that last at least a year beyond treatment or participation in the intervention. # Tertiary prevention. In the context of this report, strategies and programs that prevent further vio lence or the escalation of violence among youths already involved in violent behavior. # Uniform Crime Reporting (UCR) program. Operated by the FBI since the 1930s, the program monitors arrests made by law enforcement agencies across the United States and compiles annual arrest information. Validity (of research instruments or measures). Wraparound services. An approach that is designed to tailor social services to the individual. ,63,66,68 Aggression,reduction in,49,51,64,66,69,106,108,109,111,112,116,137,146,147,148 1, 5, 9, 11, 17, 18-26, 27, 29, 32-34, 43, 48, 49, 52, 153 , racial and ethnic, 18, 20-21, 27-30, 31, 34 at greatest risk of school homicide, 31 # Youth Risk Behavior Survey (YRBS # N______________________ _ ______________ # BEST COPY AVAILABLE Functional Family Therapy (FFT) - Contact information: James F. Alexander, Ph.D. University of Utah Department of Psychology, SBS 502 Salt Lake City, UT 84121 (801) 581-6538 - Evidence of effectiveness: In multiple clinical tri als, FFT achieved significant reductions in the pro portion of youths who reoffended (60 percent of treated youths were arrested after the program ver sus 93 percent of controls in one study and 11 per cent versus 67 percent in another) and the frequen cy of offending up to 2.5 years after participation in the intervention. Diffusion effects on the siblings of target youths have also been observed, with signifi cantly fewer siblings of FFT youths than control youths having juvenile court records 2.5 to 3.5 years after the program. - For further information: - . - Evidence of effectiveness: A randomized evalua tion of Multidimensional Treatment Foster Care compared to group care in boys only demonstrated the following results at a 1 2 -month follow-up: Treated boys spent significantly more days in their placements, were less likely to run away from their placements, and spent twice as many days living with their families or relatives. One year after leav ing treatment, treated boys had significantly larger decreases in arrest rates than controls, had signifi cantly fewer arrests overall, and were significantly more likely not to have been arrested at all during follow-up. Treated boys also reported significantly fewer criminal activities (general delinquency, index offenses, and felony assaults). In prior evalu-ations that included both boys and girls, Multidimensional Treatment Foster Care improved rates of program completion, reduced rates of incar ceration and number of days incarcerated during the first year after treatment, and resulted in a faster drop in rates of problem behavior for seriously impaired youths. -F o r further information: - Eddy, J. M., & Chamberlain, P. (2000). Family management and deviant peer association as mediators of the impact of treatment condition on youth antisocial behavior. Journal o f Consulting and Clinical Psychology, 5, 857-863. - Moore, K. J., Sprengelmeyer, P. G., & Chamberlain, P. (in press). Community-based treatment for adjudicated delinquents: The Oregon Social Learning Center's "Monitor" treatment foster care program. Residential Treatment for Children and Youth. - . show that participation in MST can have significant positive effects on behavior problems (including conduct problems, anxiety-withdrawal, immaturity, and socialized aggression), family relations, and self-reported offenses immediately after treatment. Fifty-nine weeks after referral, seriously delinquent youth who participated in MST had slightly more than half as many arrests as controls (mean = 0.87 versus 1.52), spent an average of 73 fewer days incarcerated in justice system facilities, and showed reductions in aggression with peers. After 2.4 years, MST youths were half as likely as control youths to have been rearrested. In Columbia, Missouri, MST improved family relations and arrest rates, including arrests for violent and substance-related crimes, and demonstrated a dose-response effect, with program completers demonstrating significantly more bene fits than dropouts. -For further information: delinquency initiation, improvements in family man agement practices and parent-child relationships, greater attachment and commitment to school, and less involvement with antisocial peers. Follow-up at age 18 shows that the Seattle Social Development Project significantly improves long-term attachment and commitment to school and school achievement and reduces rates of self-reported violent acts and heavy alcohol use. At follow-up, students who received the full intervention were also less likely than controls to be sexually active, to have had mul tiple sex partners, and to have been or have gotten someone pregnant (this difference was only mar ginally significant, at p = .057). Replications of this program have confirmed its benefits in both gen eral and high-risk populations of youths. -F o r further information: The Midwestern Prevention Project - For further information: - Evidence of effectiveness: No significant differ ences between treated and control boys were observed immediately after treatment, but 2 years later treated youths were involved in fewer fights, were half as likely to have serious school adjust ment problems, and were less likely to be involved in delinquent activities than those in the control group. Boys followed to age 12 (3 years after the intervention) had significantly lower rates of delin quency, fighting, serious difficulties in school, and placement in special-education classes, and they were rated as significantly more well adjusted in school than controls. Three years later, treated boys were less likely than untreated boys to report gang involvement, drunkenness, or drug use in the past year, delinquency, and having friends arrested by police. Because the effects of this intervention on girls are unknown, these benefits can be expected only when the intervention is implemented in boys. -For further information: (2000). Communities That Care® prevention strategies: A research guide to what works. Seattle, WA. Perry Preschool Program - For further information: - Berrueta-Clement, J. R., Schweinhart, L. J., Barnett, W. S., Epstein, A. S., & Weikart, D. P. (1984). - For further information: - Evidence of effectiveness: The most dramatic effects of the program were demonstrated in a 1 0year follow-up evaluation that showed reduced juvenile delinquency and improved school func tioning. Children in the program also demonstrated more positive self-ratings, higher educational goals, and increased self-efficacy. Benefits to par ents included greater encouragement of their chil dren's success and increased family unity. The existing evaluation research on this program is lim ited by several factors: The program has not been replicated; there was relatively high attrition of families in the initial studies that may have led to a positive bias in the follow-up results; and allocation to treatment and control groups was not random ized. This program is no longer deliverable-that is, no technical assistance is available to those who wish to implement it. - For further information: - For further information: - For further information: Good Behavior Game - For more information: - Evidence of effectiveness: In nursery school and kindergarten students, I Can Problem Solve signifi cantly reduced impulsive and inhibited classroom behavior and improved problem-solving skills at posttest and 1 year. A second study demonstrated sustained improvements in classroom behavior and problem solving 3 to 4 years after the end of the pro gram. In 5th-and 6th-graders, the program increased the use of positive and prosocial behav iors and improved peer relationships and problem solving skills. In general, it appears that the program is more effective in high-risk students than in stu dents from the general population. Prior studies of this intervention did not use a randomized study design and were limited by high attrition. - For further information: # Evidence of effectiveness: In a series of six ran domized trials, the parent program reduced conduct problems and improved parent-child relationships. In two randomized studies, the teacher program reduced peer aggression in the classroom, increased positive interactions with teachers and peers, and enhanced school readiness. Two randomized studies of the child program demonstrated reductions in conduct problems at home and school and improve ments in problem solving with peers. Program effects have been shown to persist for at least one year after treatment. - For further information: - Developmental Research and Programs, Inc. (2000). Communities That Care® prevention strategies: A research guide to what works. Seattle, WA. # Linking the Interests of Families and Teachers (LIFT) - - Evidence of effectiveness: In short-term evalua tions, LIFT decreased children's physical aggres sion on the playground (particularly children rated by their teachers as most aggressive at the start of the study), increased children's social skills, and decreased aversive behavior in mothers rated most aversive at baseline, relative to controls. Three years after participation in the program, lst-grade partici pants had fewer increases in attention-deficit disor der-related behaviors (inattentiveness, impulsivity, and hyperactivity) than controls. At follow-up, 5thgrade participants had fewer associations with delinquent peers, were less likely to initiate pat terned alcohol use, and were significantly less like ly than controls to have been arrested. - For further information: - - Evidence of effectiveness: Evaluations of this pro gram have demonstrated enhanced school achieve ment in grades 2 and 3; improved parenting skills at the end of the program, at (the child's) age 4, and in grades 2 and 3; and reduced aggressive behavior by children at ages 4 to 7 and 8 to 11. Unfortunately, the evaluations of these programs conducted to date have been limited by high attrition rates. - For further information: - Preventive Intervention - Evidence of effectiveness: Evaluations of this pro gram demonstrate both short-and long-term effec tiveness on violence-related risk factors, including higher grades and attendance at the end of the pro gram; significantly lower drug use, school-related problems, and unemployment after 1 year; signifi cantly fewer students with county court records at 5 years; and lower rates of reported criminal behavior at the 1.5 year follow-up (marginal significance, p < .075). Program effects on self-reported criminal behavior did not reach statistical significance, although the treatment and control groups did differ significantly with respect to the proportion of stu dents with a juvenile record. - For further information: - Bry, B. H. (1982). Reducing the incidence of adolescent problems through preventive inter vention: One-and five-year follow-up. American Journal of Community Psychology, 10, 265-276. - Bry, B. H., & George, F. E. (1980). The preven tive effects of early intervention on the atten dance and grades of urban adolescents. Professional Psychology, 11, 252-260. - Bry, B. H., & George, F. E. (1979) - Evidence of effectiveness: Evaluations of this intervention have demonstrated that PATHS improves self-control, understanding and recogni tion of emotions, the ability to tolerate frustration, the use of effective conflict-resolution strategies, thinking and planning skills, and conduct problems, such as aggression. In students with special needs, PATHS has also been shown to significantly reduce symptoms of anxiety, depression, and sadness and to reduce conduct problems. - For further information: - Greenberg, M. T., Kusche, C., & Mihalic, S. (1998) - Thornton, T. N., Craft, C. A., Dahlberg, L. L., Lynch, B. S., & Baer, K. (2000). - Evidence of effectiveness: An evaluation conduct ed 10 years after participation in the program showed that youths enrolled in the Yale Child Welfare Project missed significantly fewer days of school, required significantly fewer remedial and supportive school services, and were rated signifi cantly less negative and more socially well adjusted by their teachers compared to controls. Some pro gram effects on academic achievement showed sig nificant diffusion effects on siblings. However, the sample in this study was small, with only 14 of the original 17 pairs of matched treatment and control youths available for evaluation at follow-up. In addition, this study used a quasi-experimental design. This program is no longer deliverable-that is, no technical assistance is available to those who wish to implement it. - For further information: - Seitz, V., Rosenbaum, L. K., & Apfel, N. H. (1985). Effects of family support intervention: A ten-year follow-up. Child Development, 56, 376-391. Late-onset trajectory. A pattern of violent behavior that emerges in adolescence, defined in this report as about age 13. This pattern is more prevalent than the early-onset trajectory and is characterized by a shorter period of involvement, lower frequency of offending, and a lower likelihood of continuing into adulthood. Individuals who are characterized by this pattern typically give few external signs in child hood that they will become violent offenders. # Level of control. Efforts to take into account other factors that might influence the data or responses from participants in a research study; contributes to the quality of a given study. # Level of evidence. The strength of the evidence amassed for any scientific fact or conclusion. # Lifestyle. A pattern of consciously chosen, observable behaviors that a person engages in on a consistent and regular basis. Locally representative (probability) sample. In this report, the term representative sample is used to refer to a probability sample-a sample that is selected in such a way that its characteristics can be generalized to the population (e.g., city or county) from which it was drawn with a known degree of accuracy. The accuracy of generalizations from probability samples is given in the form of a confi dence interval. In this report, 95 percent confidence intervals (CIs) are reported, indicating an upper and lower bound for the population estimate that is accurate at least 95 percent of the time. Longitudinal research. Used in etiological (causal) and developmental research, a type of study design involving multiple contacts with the same study par ticipants over time; allows researchers to estimate how well a given risk or protective factor predicts later violent behavior for individuals or groups. Marginal deterrent effects. Effects that are demon strated when an intervention produces significantly better outcomes compared to another treatment; may underestimate the true effects of the interven tion compared to receiving no treatment at all. # Maturation effect. An effect associated with growing older or maturing, it may refer to changes in one's physical or social development. The term refers specifically to a sharp reduction in youth violence observed during the transition to adulthood, usually during the late teen years to age 20. Mediating-effects analysis. An analysis that permits researchers to determine whether a change in the targeted risk or protective factor accounts for an observed change in violence. # Meta-analysis. A rigorous statistical method of com bining the results of several studies to obtain more reliable estimates of the effects of a general type of treatment or intervention; can be used to summarize program evaluation and draw overall conclusions about the strength and consistency of the influence, or effect size, that particular types of programs have on violence. # Model program. A prevention program that meets the highest scientific standard for effectiveness, as evi denced in published evaluations; has a significant, sustained preventive or deterrent effect and has been replicated in different communities or settings. It has been shown to work and can be expected to have a positive result in a wide range of community . settings. # Monitoring the Future (MTF # National Electronic Injury Surveillance System (NEISS). Operated by the U.S. Consumer Product Safety Commission since 1992, the system monitors types of injuries treated in emergency departments, including those related to firearms. # National Television Violence Survey (NTVS). A recent content analysis of television programming examining its portrayal of violence. The study assessed a total of 2,500 hours of television pro gramming during the 1994 through 1997 viewing seasons. Physical aggressiveness. Relatively nonserious forms of violent behavior, often displayed in early child hood and continued into adolescence, including hit ting, biting, kicking, punching, or otherwise inten tionally hurting others. # National Youth Survey (NYS Population-based studies. Studies based on general population samples rather than selected or institu tional samples (e.g., prisoners, hospital patients, nursing home residents, expelled students). Findings O from these studies apply to general populations, whereas findings from studies of selected or institu tional samples apply specifically to persons in these settings or groups. Post-traumatic stress disorder (PTSD). Disorder in which a stressful experience is traumatic and pro duces severe, recurring symptoms. Prevalence rate. As used in this report, the proportion of youths involved in one or more violent behaviors during some specified time interval, for example, the past year, by age 18, or ever. # Primary prevention (true prevention). As defined in this report, strategies and programs that reduce the likelihood that youths will initiate violent behavior compared to youths in a control group; programs designed to target youths who have not yet become involved in violence or encountered specific risk fac tors for violence; identifies behavioral, environmen tal, and biological risk factors associated with vio lence and takes steps to educate individuals and com munities about and protect them from these risks. # Probability sample. A sample selected in such a way that its characteristics can be generalized to the pop ulation from which it was drawn with a known degree of accuracy. The level of accuracy for pro portions, means, and correlations is presented as a 95 percent confidence interval, which contains the true population value 95 percent of the time. See Locally representative sample. Promising program. Prevention programs in this cat egory meet two of the scientific standards for effec tiveness; they do not meet all of the rigorous stan dards of Model programs, but they are recognized and encouraged with the caution that they be care fully evaluated. Protective factor. As used in this report, personal characteristics or environmental conditions that reduce the potential harmful effect of a risk factor for violent behavior; characteristics that buffer or mod erate the effect of risk.	Disseminates successful models as part of a coordi nated effort to educate and reach out to the public (Hamburg, 1998;Mercy et al., 1993). The chapters in this report are keyed to each of these components of the public health approach. Chapter 2 presents research describing the magnitude by the University of Michigan's Institute for Social Research (Johnston et al., 1995) • Youth Risk Behavior Surveillance Study sponsored by the Centers for Disease Control and Prevention in collaboration with Federal, state, and local part ners (Brener et al., 1999)No single study, however well designed, is sufficient to establish causation or, in intervention research, effi cacy or effectiveness. Findings must be replicated before gaining widespread acceptance by the scientif ic community. The strength of the evidence amassed for any scientific fact or conclusion is referred to as the level of evidence.# Message from Donna E. Shalala # Secretary o f Health and Human Services The first, most enduring responsibility of any society is to ensure the health and well-being of its children. It is a responsibility to which multiple programs of the Department of Health and Human Services are dedicated and an arena in which we can claim many remarkable successes in recent years. From new initiatives in child health insur ance and Head Start, to innovative approaches to child care, to the investment in medical research that has amelio rated and even eliminated the threat of many once lethal childhood diseases, we have focused directly and con structively on the needs of millions of children. Through programs designed to enhance the strength and resiliency of families and family members across the life span and through our investments in diverse community resources, we are also helping to enhance the lives and enrich the opportunities of millions more of our children. Although we can take rightful pride in our accomplishments on behalf of U.S. youths, we can and must do more. The world remains a threatening, often dangerous place for children and youths. And in our country today, the greatest threat to the lives of children and adolescents is not disease or starvation or abandonment, but the ter rible reality of violence. We certainly do not know all of the factors that have contributed to creating what many citizens-young and old alike-view as our culture of violence. It is clear, however, that as widespread as the propensity for and tol erance of violence is throughout our society-and despite efforts that, since 1994, have achieved dramatic declines in official records of violence on the part of young people-every citizen must assume a measure of responsibili ty for helping to reduce and prevent youth violence. Information is a powerful tool, and this Surgeon General's report is an authoritative source of information. In directing the Surgeon General to prepare a scholarly report that would summarize what research can tell us about the magnitude, causes, and prevention of youth violence, President Clinton sought a public health perspec tive on the problem to complement the extraordinary work and achievements in this area that continue to be real ized through the efforts of our criminal and juvenile justice systems. Over the past several months, the Department of Health and Human Services has worked with many hundreds of dedicated researchers, analysts, and policy makers whose interests and expertise lie outside the traditional domains of health and human services. What has become clear through our collaboration is that collectively we possess the tools and knowledge needed to throw safety lines to those young Americans who already have been swept up in the currents of violence and to strength en the protective barriers that exist in the form of family, peers, teachers, and the countless others whose lives are dedicated to the futures of our children. This Surgeon General's report seeks to focus on action steps that all Americans can take to help address the problem, and continue to build a legacy of health and safety for our young people and the Nation as a whole. # n ( # Foreword The opportunity for three Federal agencies, each with a distinct public health mission, to collaborate in developing the Surgeon General's report on youth violence has been an invigorating and rewarding intellectual challenge. We and our respective staffs were pleased to find that the importance that we collectively assign to the topic of youth violence transcended any impediments to a true, shared effort. Obstacles that one might have anticipated-for example, difficul ties in exchanging data and discussing concepts that emanate from many different scientific disciplines-proved to be surmountable. Indeed, many of the differences in perspective and scientific approach that distinguish the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Substance Abuse and Mental Health Services Administration (SAMHSA), when combined, afforded us a much fuller appreciation of the problem and much firmer grounds for optimism that the problem can be solved than is obvious from within the boundaries, or con fines, of a single organization. The mission of CDC is to promote health and quality of life by preventing and controlling disease, injury, and dis ability. The NIH, of which the National Institute of Mental Health (NIMH) is one component, is responsible for gener ating new knowledge that will lead to better health for everyone. SAMHSA is charged with improving the quality and availability of prevention, treatment, and rehabilitation services in order to reduce illness, death, disability, and cost to society resulting from substance abuse and mental illnesses. Common to each of the agencies is an interest in prevent ing problems before they have a chance to impair the health of individuals, families, communities, or society in its entire ty. Toward this end, CDC, NIH/NIMH, and SAMHSA each support major long-term research projects involving nation ally representative samples of our Nation's youth. These studies, which are introduced and described in the report that follows, are designed both to monitor the health status of young Americans and to identify factors that can be shown to carry some likelihood of risk for jeopardizing health-information that lends itself to mounting effective interventions. The designation of youth violence as a public health issue complements the more traditional status of the problem as a criminal justice concern. Here again, it has been satisfying for all of us in the public health sector to reach across professional and disciplinary boundaries to our colleagues in law, criminology, and justice and work to meld data that deepen our understanding of the patterns and nature of violence engaged in by young people throughout our country. What has emerged with startling clarity from an exhaustive review of the scientific literature and from analyses of key new data sources is that we as a Nation have made laudable progress in gaining an understanding of the magnitude of the problem. We have made great strides in identifying and quantifying factors that, in particular settings or combi nations, increase the probability that violence will occur. And we have developed an array of interventions of welldocumented effectiveness in helping young people whose lives are already marked by a propensity for violence as well as in preventing others from viewing violence as a solution to needs, wants, or problems. CDC, NIH/NIMH, and SAMHSA look forward to continuing collaborations, begun during the development of this report, that will extend further the abilities of policy makers, communities, families, and individuals to understand youth violence and how to prevent it. # Preface from the Surgeon General U.S. Public Health Service The immediate impetus for this Surgeon General's Report on Youth Violence was the Columbine High School tragedy that occurred in Colorado in April 1999, resulting in the deaths of 14 students, including 2 perpetrators, and a teacher. In the aftermath of that shocking event, both the Administration and Congress requested a report summa rizing what research has revealed to us about youth violence, its causes, and its prevention. Our review of the scientific literature supports the main conclusion of this report: that as a Nation, we possess knowledge and have translated that knowledge into programs that are unequivocally effective in preventing much serious youth violence. Lest this conclusion be considered understated or muted, it is important to realize that only a few years ago, substantial numbers of leading experts involved in the study and treatment of youth violence had come to a strikingly different conclusion. Many were convinced then that nothing could be done to stem a tide of serious youth violence that had erupted in the early 1980s. During the decade extending from 1983 to 1993, arrests of youths for serious violent offenses surged by 70 percent; more alarmingly, the number of young people who committed a homicide nearly tripled over the course of that deadly decade. In many quarters, dire predictions about trends in youth violence yielded to resignation; elsewhere, fear and concern prompted well-meaning officials and policy makers to grasp at any proposed solutions, often with little, if any, systematic attention to questions of the efficacy or effective ness of those approaches. Fortunately, the past two decades have also been distinguished by the sustained efforts of researchers, legislators, and citizens from all walks of life to understand and address the problem of youth violence. One seminal contribu tion to these efforts was an initiative taken by one of my predecessors, Surgeon General C. Everett Koop, to address violence as a public health issue; that is, to apply the science of public health to the treatment and prevention of vio lence. As evident throughout this report, that endorsement was key to encouraging multiple Federal, state, local, and private entities to invest wisely and consistently in research on many facets of youth violence and to translate the knowledge gained into an exciting variety of intervention programs. Although much remains to be learned, we can be heartened by our accomplishments to date. For one, our care ful analyses, together with those conducted by components of the justice system, have demonstrated the pervasive ness of youth violence in our society; no community is immune. In light of that evidence, it has been most encour aging to me to see that the citizens with whom I have interacted in hundreds of communities around the Nation want us to find answers that will help all of our youth. There is a powerful consensus that youth violence is, indeed, our Nation's problem, and not merely a problem of the cities, or of the isolated rural regions, or any single segment of our society. Equally encouraging have been our findings that intervention strategies exist today that can be tailored to the needs of youths at every stage of development, from young childhood to late adolescence. There is no justification for pessimism about reaching young people who already may be involved in serious violence. Another critical bit of information from our analyses of the research literature is that all intervention programs are not equally suited to all children and youths. A strategy that may be effective for one age may be ineffective for older or younger children. Certain hastily adopted and implemented strategies may be ineffective-and even deleterious-for all children and youth. Understanding that effectiveness varies underscored for us the importance of bridging the gap between science and practice. Only through rigorous research and thorough, repeated evaluations of programs as they operate in the real world will we be assured that we are using our resources wisely. In presenting this Surgeon General's report, I wish to acknowledge our indebtedness to the many scientists who have persisted in their work in this difficult, often murky area and whose results we have scrutinized and drawn on. We are also immensely grateful to the countless parents, police officers, teachers, juvenile advocates, health and human service workers, and people in every walk of life who recognize the inestimable value of our Nation's youth and the importance of peace, security, and comity in their lives. For millions of youths and their families, a period of life that should have been distinguished by good health and great promise was instead marred by injuries, disability, and death . This epidemic of violence not only left lasting scars on victims, perpetrators, and their families and friends, it also wounded communities and, in ways not yet fully understood, the country as a whole. Since 1993, the peak year of the epidemic, there have been some encouraging signs that youth vio lence is declining. Three important indicators of violent behavior-arrest records, victimization data, and hospital emergency room records-have shown significant downward trends nationally. These offi cial records reveal only a small part of the picture, however. A fourth key indicator of violence-confidential reports by youths themselves-reveals that the pro portion of young people who acknowledge having committed serious, potentially lethal acts of physical violence has remained level since the peak of the epi demic. In 1999, for instance, there were 104,000 arrests of persons under age 18 for robbery, forcible rape, aggravated assault, or homicide (Snyder, 2000); of those arrests, 1,400 were for homicides perpetrated by adolescents (Snyder, 2000) and, occasionally, even younger children ). Yet in any given year in the late 1990s, at least 10 times as many youths reported that they had engaged in some form of violent behavior that could have seriously injured or killed another person. The high prevalence of violent behavior reported by adolescents underscores the importance of this report at this time. Americans cannot afford to become complacent. Even though youth violence is less lethal today than it was in 1993, the percentage of adolescents involved in violent behavior remains alarmingly high. The epi demic of lethal violence that swept the United States was fueled in large part by easy access to weapons, notably firearms-and youths' self-reports of violence indicate that the potential for a resurgence of lethal violence exists. Yet viewing homicide as a barometer of all youth violence can be quite misleading. Similarly, judging the success of violence prevention efforts solely on the basis of reductions in homicides can be unwise. This report, the first Surgeon General's report on youth violence in the United States, summarizes an extensive body of research and seeks to clarify seem ingly contradictory trends, such as the discrepancies noted above between official records of youth vio lence and young people's self-reports of violent behaviors. It describes research identifying and clari fying the factors that increase the risk, or statistical probability, that a young person will become violent, as well as studies that have begun to identify devel opmental pathways that may lead a young person into a violent lifestyle. The report also explores the less well developed research area of factors that seem to protect youths from viewing violence as an accept able-or inevitable-way of approaching or respond ing to life events. Finally, the report reviews research on the effectiveness of specific strategies and pro grams designed to reduce and prevent youth violence. As these topics suggest, the key to preventing a great deal of violence is understanding where and when it occurs, determining what causes it, and scientifically documenting which of many strategies for prevention and intervention are truly effective. This state-of-thescience report summarizes progress toward those goals. The most important conclusion-of the report is that the United States is well past the "nothing works" era with respect to reducing and preventing youth vio lence. Less than 10 years ago, many observers pro jected an inexorably rising tide of violence; the recent, marked reductions in arrests of young perpetrators and in victimization reports appear to belie those dire pre dictions. We possess the knowledge and tools needed to reduce or even prevent much of the most serious youth violence. Scientists from many disciplines, working in a variety of settings with public and pri vate agencies, are generating needed information and putting it to use in designing, testing, and evaluating intervention programs. The most urgent need now is a national resolve to confront the problem of youth violence systematically, using research-based approaches, and to correct dam aging myths and stereotypes that interfere with the task at hand. This report is designed to help meet that need. The report makes it clear that after years of effort and massive expenditures of public and private resources, the search for solutions to the problem of youth violence remains an enormous challenge Sechrest et al., 1979). Some tra ditional as well as seemingly innovative approaches to reducing and preventing youth violence have failed to deliver on their promise, and successful approaches are often eclipsed by random violent events such as the recent school shootings that have occurred in com munities throughout the country. Youth violence is a high-visibility, high-priority concern in every sector of U.S. society. We have come to understand that young people in every community are involved in violence, whether the community is a small town or central city, a neatly groomed suburb, or an isolated rural region. Although male adolescents, particularly those from minority groups, are dispro portionately arrested for violent crimes, self-reports indicate that differences between minority and major ity populations and between male and female adoles cents may not be as large as arrest records indicate or conventional wisdom holds. Race/ethnicity, consid ered in isolation from other life circumstances, sheds little light on a given child's or adolescent's propensi-"^T~r engaging in violence. This chapter describes the scope and focus of the report and explains how the public health approach advances efforts to understand and. prevent youth violence. Common myths about youth violence are presented and debunked. Uncorrected, these myths lead to misguided public policies, inefficient use of public and private resources, and loss of traction in efforts to address the problem. Documentation for the facts that counter these myths appears in later chapters. This chapter also lays out the scientific basis of the report-that is, the standards of evidence that research studies had to meet in order to be included in the report and the sources of data cited throughout. Final sections of this chapter preview subsequent chapters and list the report's major conclusions. # Sc o p e , Fo c u s , a n d O v e r a r c h in g T h e m e s The mission of the Surgeon General is to protect and improve the public health of the Nation, and this report was developed within the responsibilities and spirit of that mission. The designation of youth vio lence as a public health concern is a recent develop ment. As discussed below in greater detail, public health offers an approach to youth violence that focuses on prevention rather than consequences. It provides a framework for research and intervention that draws on the insights and strategies of diverse disciplines. Tapping into a rich but often fragmented knowledge base about risk factors, preventive inter ventions, and public education, the public health per spective calls for examining and reconciling what are frequently contradictory conclusions about youth violence. Although the public health approach opens up a broad array of considerations, the focus of this initial report is the perpetration by juveniles of interpersonal physical assault that carries a significant risk of injury or death. As restrictive as it may at first appear, this focus draws on a wealth of research into individual, family, school, peer group, and community factors that are associated with serious violence in the second decade of life. This report defines serious violence as aggravated assault, robbery, rape, and homicide; here after, it refers simply to "violence" or "violent crime," thus avoiding repetitious use of the terms "serious vio lence" or "serious violent crime." The report views violence from a developmental perspective. It examines the interactions of youths' personal characteristics and the social contexts in which they live-as well as the timing of those inter actions-to understand why some young people become involved in violence and some do not. This perspective considers a range of risks over the life course, from prenatal factors to factors influencing whether patterns of violent behavior in adolescence will persist into adulthood. The developmental per spective has enabled scientists to identify two general onset trajectories of violence: one in which violent behaviors emerge before puberty, and one in which they appear after puberty. Of the two, the early-onset trajectory provides stronger evidence of a link between early childhood experiences and persistent, even lifelong involvement in violent behavior. The developmental perspective is important because it enables us to time interventions for the particular point or stage of life when they will have the greatest positive effect. The young people on whom this report focuses are principally children and adolescents from about age 10 through high school. Research reviewed in Chapter 4 shows that although risk factors for vio lence vary by stage of development, most youth vio lence emerges during the second decade of life. Appropriate interventions before and-as is increas ingly well documented-during this period have a good chance of redirecting violent young people toward healthy and constructive adult lives. The win dow of opportunity for effective interventions opens early and rarely, if ever, closes. # S e c o n d a r y A r e a s o f C o n c e r n Many legitimate concerns and issues that are indis putably associated with violence by young people are not addressed in depth in this first report. Behavioral patterns marked by aggressiveness, antisocial behav ior, verbal abuse, and externalizing (the acting out of feelings) are peripheral to the main focus of the report. These behaviors may include violent physical interactions, such as hitting, slapping, and fist-fight ing, that can have significant consequences but gen erally present little likelihood of serious injury or death. Therefore, such behaviors will be discussed only to the extent that they can be considered risk fac tors for violence. Research has shown that victims and offenders share many personal characteristics and that victim ization and perpetration of violent behavior are often entwined. Nonetheless, this report does not focus on victims of violence perpetrated by young offenders. Rather, it blends offender-based research with tradi tional public health concepts of prevention and inter vention in an effort to bridge the gap between crimi nology and the social and developmental sciences, on the one hand, and traditional public health approaches to youth violence, on the other. The report does not address violence against inti mate partners, except when such violence is committed by a young person. The plight of victims, many of whom are children and adolescents, is of the utmost importance, but a key element in helping victims of violence is understanding the perpetrators of violence. Particular categories of crime, such as dating violence and hate crimes (motivated by racist or homophobic attitudes, for example), are important manifestations of violence, including violence committed by youths, and they demand research and targeted interventions. The limited amount of research conducted in this area has focused on victims, so there is little scientific evidence about what distinguishes perpetrators of these specific types of crimes (see reviews by Bergman, 1992;Comstock, 1991;and D'Augelli & Dark, 1984). Self-directed violence-that is, self-inflicted injury and suicide-is not covered either. In collabo ration with other Federal health agencies, the Office of the Surgeon General developed a National Strategy for the Prevention of Suicide (U.S. Public Health Service, 1999). In directing national attention to suicide as a major, yet largely preventable public health problem, the Surgeon General is bringing together health professional organizations, educa tors, health care executives, and managed care clini-cal directors to discuss gaps in scientific knowledge that impede efforts to decrease the incidence of suicide among Americans of all ages. The vast majority of youth suicides occur in the context of mental disorders (Brent et al., 1988;Shaffer et al., 1996), a topic that was reviewed in depth in the Surgeon General's report on mental health (U.S. DHHS, 1999). Finally, the report does not propose public policy to reduce or prevent youth violence. The purpose of this report, like others from U.S. Surgeons General, is to review and describe existing knowledge in order to provide a basis for action at all levels of society. The last chapter identifies potential courses of action, including specific areas in which research is needed, but suggesting whether and how such action will lend itself to policy development is beyond the purview of this report. # Y o u t h V io l e n c e : T h e P u b l ic H e a l t h A p p r o a c h In October 1985, Surgeon General C. Everett Koop convened an unprecedented Workshop on Violence and Public Health (U.S. DHHS, 1986). The partici pants agreed strongly that it was time public health perspectives and expertise were brought to bear on questions of crime and violence. Throughout much of the last century, these questions had been domi nated by the social sciences and the criminal justice system. For the most part, health care efforts were restricted to the rehabilitation of convicted offenders (Sechrest et al., 1979;U.S. DHHS, 1986). Dissatisfaction with both the timing and the out comes of the "rehabilitation ideal" spurred the search • for a more effective role for health care in addressing violence. With its emphasis on prevention of disease or injury, the public health approach to violence offers an appealing alternative to an exclusive focus on rehabilitation. Primary prevention identifies behav ioral, environmental, and biological risk factors associated with violence and takes steps to educate individuals and communities and protect them from these risks. Central to education and protection is the iciple that health promotion is best learned, per-ERLC formed, and maintained when it is ingrained in indi viduals' and communities' daily routines and percep tions of what constitutes good health practices. Public health practitioners and advocates have taken the lead in encouraging alliances and networks among academic disciplines, professions, organiza tions, and communities to make health concerns per manent public priorities and part of personal practices. In that tradition, participants at the 1985 Surgeon General's conference emphasized the importance of convincing the public that violence should be treated as a public health problem. As Marvin Wolfgang, a distin guished leader in the field of criminology, told confer ees, "Our nation must feel as comfortable in controlling its violent behavioral urges and practices as it does in controlling bacterial, viral, and physical manifestations of morbidity and death" (U.S. DHHS, 1986). Just as the application of public health principles and strategies has reduced the number of traffic fatal ities and deaths attributed to tobacco use (CDC, 1999), the public health approach can help reduce the number of injuries and deaths caused by violence. Broader than the medical model, which is concerned with the diagnosis, treatment, and mechanisms of spe cific illnesses in individual patients, public health offers a practical, goal-oriented, and communitybased approach to promoting and maintaining health. To identify problems and develop solutions for entire population groups, the public health approach: • Defines the problem, using surveillance processes designed to gather data that establish the nature of the problem and the trends in its incidence and prevalence; • Identifies potential causes through epidemiological analyses that identify risk and protective factors associated with the problem; • Designs, develops, and evaluates the effectiveness and generalizability of interventions; and # Introduction of the problem of violent behavior by young people. Chapter 3 explores how violence develops and emerges over time. Chapter 4 summarizes research on risk and protective factors for youth violence; Appendix 4-B elaborates on the effects of exposure to media violence (including violence in interactive media) as a risk factor for aggressive and violent behavior. Chapter 5 focuses on the design, evaluation, and refinement of numerous programs and strategies that seek to reduce or prevent youth violence; Appendix 5-B provides details on specific programs discussed in the chapter. Chapter 6 suggests future courses of action, including the necessary next steps in research. A glossary of technical and disciplinespecific terms follows. # M y t h s A b o u t Y o u t h V io l e n c e An important reason for making research findings widely available is to challenge false notions and mis conceptions about youth violence. Myths such as those listed below are intrinsically dangerous. Assumptions that a problem does not exist or failure to recognize the true nature of a problem can obscure the need for informed policy or for interventions. An example is the conventional wisdom in many circles that the epidemic of youth violence so evident in the early 1990s is over. Alternatively, myths may trigger public fears and lead to inappropriate or misguided policies that result in inefficient use of scarce public resources. An example is the current policy of waiving or transferring young offenders into adult criminal courts and prisons. # Myth: The epidemic o f violent behavior that marked the early 1990s is over, and young people-as well as the rest o f U.S. society-are much safer today. Fact: Although such key indicators of violence as arrest and victimization data clearly show significant reductions in violence since the peak of the epidemic in 1993, an equally important indicator warns against concluding that the problem is solved. Self-reports by youths reveal that involvement in some violent behav iors remains at 1993 levels (see Chapter 2). Myth: Most future offenders can be identified in early childhood. Fact: Exhibiting uncontrolled behavior or being diagnosed with conduct disorder as a young child does not predetermine violence in adolescence. A majority of young people who become violent during their ado lescent years were not highly aggressive or "out of control" in early childhood, and the majority of chil dren with mental and behavioral disorders do not become violent in adolescence (see Chapter 3). Myth: Child abuse and neglect inevitably lead to violent behavior later in life. Fact: Physical abuse and neglect are relatively weak predictors of violence, and sexual abuse does not predict violence. Most children who are abused or neglected will not become violent offenders during adolescence (see Chapter 4). Myth: African American and Hispanic youths are more likely to become involved in violence than other racial or ethnic groups. Fact: Data from confidential interviews with youths indicate that race and ethnicity have little bear ing on the overall proportion of racial and ethnic groups that engage in nonfatal violent behavior. However, there are racial and ethnic differences in homicide rates. There are also differences in the tim ing and continuity of violence over the life course, which account in part for the overrepresentation of these groups in U.S. jails and prisons (see Chapter 2). # Myth: A new violent breed o f young superpreda tors threatens the United States. Fact: There is no evidence that young people involved in violence during the peak years of the early 1990s were more frequent or more vicious offenders than youths in earlier years. The increased lethality . resulted from gun use, which has since decreased dra matically. There is no scientific evidence to document the claim of increased seriousness or callousness (see Chapter 3). # Myth: Getting tough with juvenile offenders by trying them in adult criminal courts reduces the like lihood that they will commit more crimes. Fact: Youths transferred to adult criminal court have significantly higher rates of reoffending and a greater likelihood of committing subsequent felonies than youths who remain in the juvenile justice system. They are also more likely to be victimized, physically and sexually (see Chapter 5). # Myth: Nothing works with respect to treating or preventing violent behavior. Fact: A number of prevention and intervention programs that meet very high scientific standards of effectiveness have been identified (see Chapter 5). Myth: In the 1990s, school violence affected mostly white students or students who attended sub urban or rural schools. Fact: African American and Hispanic males attending large inner-city schools that serve very poor neighborhoods faced-and still face-the greatest risk of becoming victims or perpetrators of a violent act at school. This is true despite recent shootings in suburban, middle-class, predominantly white schools (see Chapter 2). # Myth: Weapons-related injuries in schools have increased dramatically in the last 5 years. Fact: Weapons-related injuries have not changed significantly in the past 20 years. Compared to neigh borhoods and homes, schools are relatively safe places for young people (see Chapter 2). # Myth: Most violent youths will end up being arrested fo r a violent crime. Fact: Most youths involved in violent behavior will never be arrested for a violent crime (see Chapter 2). # So u r c e s o f D a ta a n d St a n d a r d s o f Ev id e n c e # Data Sources Several comprehensive scholarly reviews of various facets of youth violence were published in the 1990s. Professional organizations, Federal agencies, the National Academy of Sciences, and university-based researchers have invested immense energy in reviewing research on the occurrence and patterns of youth violence, its causes and consequences, interven tion strategies, and implications for society. Key contributions to this rich information base include: • NIMH Taking Stock o f Risk Factors fo r Child/Youth Externalizing Behavior Problems (Hann & Borek, • Serious and Violent Juvenile Offenders • The American Psychological Association's report Violence and Youth (APA, 1993) and Reason to Hope (Eron et al., 1994) • Preventing Crime: What Works, What Doesn't, What' s Promising. A Report to the United States Congress (Sherman et al., 1997) • The OJJDP national report Juvenile Offenders and Victims • The American Sociological Association's Social Causes o f Violence: Crafting a Science Agenda (Levine & Rosich, 1996) This report draws extensively-but not exclusive ly-on concepts, general information, and data con tained in these documents. The authors gratefully acknowledge the contributors to and publishers of these earlier studies. Whenever the report draws heav ily on one of these master sources, that fact is noted. Specific references to these documents are provided where appropriate. Contributors to and editors of this report have also consulted peer-reviewed journals, books, and govern ment reports and statistical compilations. Some infor mation not considered in prior reviews is contained in this report. When appropriate, the editors have drawn on dissertations and forthcoming work that they judged to be of high quality. During the development of this report, special data analyses were obtained from established surveys of U.S. adolescents. The key data sources for these analyses are the following: • The National Center for Juvenile Justice's up-todate information on juvenile arrests for violent crimes (Snyder, 2000) • The National Crime Victimization Survey (Rand et al., 1998) # Standards of Scientific Evidence for Multidisciplinary Research The public health approach relies on a multidiscipli nary, multijurisdictional knowledge base. Thus, in preparing this report, it was necessary to draw conclu sions from research in psychology (social, develop mental, clinical, and experimental), sociology, crimi nology, neuroscience, public health, epidemiology, communications, and education. Integrating findings and conclusions across disciplinary lines is never easy. The questions under study generally determine what approach scientists will take to designing and conduct ing research, and the approach often determines how investigators report their findings and conclusions. Even when scientific approaches are similar, investiga tors in different disciplines frequently employ different terminology to describe similar concepts. In striving to apply scientific standards consis tently across the many fields of research reviewed, this report has emphasized two criteria: appropriately rigorous methods of inquiry and sufficient data to sup port major conclusions. The need for rigor is obvious: The tools or strategies employed in research-like the conclusions reached-are only as good as the preci sion with which research questions are framed. But the quality of a given study depends on other factors as well, including: • General data collection design. Data may be obtained through four major types of study design: experimental, longitudinal, cross-sectional, and case study. This report relies primarily on experimental and longitudinal designs, with some use of cross sectional studies. (These three methods are described below.) • Sampling, or the selection of persons to be studied. Individuals in a study may be recruited or identi fied through probability or nonprobability sam pling, or they may be assigned to experimental or control groups by a random process, a precision or group-matching process, or some other means. This report refers to probability samples as repre sentative samples. • Validity and reliability of measures or instruments used in the research. • Appropriateness and level of control incorporated into the analysis of findings. Level of control refers to efforts to take into account other factors that might be influencing data or responses from subjects. • Appropriateness and significance of generalizations. As noted earlier, four of the chapters in this report-those concerned with magnitude, demograph ics, risk and protective factors, and intervention research and evaluation-mirror components of the public health approach to youth violence. Each of these areas involves research from different disci plines and scientific approaches; therefore, the types of research designs and forms of analysis presented differ somewhat from chapter to chapter. Experimental research is the preferred method for assessing cause and effect as well as for determining how effectively an intervention works. Many of the violence prevention programs reviewed in Chapter 5 meet the standard of rigorous experimental (or wellexecuted quasi-experimental) designs. In an experi mental study, researchers randomly assign an inter vention to one group of study participants, the experi mental group, and provide standard care or no inter vention to another group, the control group. A study with a randomly assigned control group enables researchers to conclude that observed changes in the experimental group would not have happened without the intervention and did not occur by chance. The dif-ference in outcome between the experimental and control groups, which in this case may be the reduc tion or elimination of violent behaviors, can then be attributed to the intervention. Ideally, researchers assign study participants to the experimental intervention or the control group at random. Randomization eliminates bias in the assign ment process and provides a way of determining the likelihood that the effects observed occurred by chance. In this report, most weight is given to true experimental studies. In some cases, true experiments may be too difficult or expensive to conduct, or they may pose unacceptable ethical problems. In such cases, carefully designed and executed quasi-experi mental studies are accepted as meeting the standard. Evidence from an experimental study is consid ered stronger when, in addition to analyzing the main effects of an intervention, researchers analyze the mediating effects. This analysis permits researchers to determine whether a change in the targeted risk or protective factor accounts for the observed change in violence-that is, did the intervention work because it changed the degree of risk? Without this information, researchers cannot explain the success of a program. Chapters 4 and 5 make use of meta-analyses. Meta-analysis describes a statistical method for eval uating the conclusions of numerous studies to deter mine the average size and consistency of the effect of a particular treatment or intervention strategy com mon to all of the studies. The technique makes the results of different studies comparable so that an over all effect can be identified. A meta-analysis deter mines whether there is consistent evidence that a treat ment has a statistically significant effect, and it esti mates the average size of that effect. Epidemiological research, reviewed in Chapters 2 and 3, focuses primarily on general population studies that use probability samples and cross-sectional or lon gitudinal designs (Kleinbaum et al., 1982;Lilienfeld & Lilienfeld, 1980;Rothman & Greenland, 1998). Probability samples let researchers generalize from their study to the entire population sampled. Cross-sec tional studies involve a single contact with participants for data collection at a given point in time. Multiple O cross-sectional studies involve several waves of data collection over time (annually, for example) but typi cally with different participants at each contact and therefore with no way to link a given person's respons es at one time with those at a later time. Prospective longitudinal and panel designs involve multiple con tacts with the same study participants over time. Responses at one data collection point can be linked to responses at a later point. Longitudinal studies are used for research on individual development or growth. Longitudinal designs are necessary to estimate the predictive effect of a given risk or protective factor on later violent behavior. Although cross-sectional designs are sometimes used, they cannot provide estimates of individual-level predictive effects. They can establish simultaneous relationships between risk factors and vio lence, but conclusions drawn from cross-sectional stud ies are not as strong as those drawn from longitudinal studies. In cross-sectional studies, cause and effect are unclear and reciprocal effects may inflate the estimates. Experimental studies are sometimes used to esti mate the effects of risk and protective factors, but this practice is rare because of ethical and cost considera tions. For example, it would be unthinkable to intro duce drug use to a group of adolescents to see whether drugs are a risk factor for violence. However, it would be ethical to conduct a predictive study that selects persons who are not violent and follows them over time. Those who began to use illicit substances would be compared with those who did not, to determine whether drug users are more likely to become involved in violent behaviors at some later date. If they were, then the results would indicate that drug use predicts violence or that drug use increases the probability of future violence. # Introduction This report does not rely on any single study for conclusions. Only findings that have been replicated in several studies, consistently and with no contrary results, are reported as part of the contemporary knowl edge base. When the report cites unreplicated studies that are of high quality, that have not been refuted by other evidence, and that point in a clear direction, the findings are described as tentative or suggestive. These findings may point to future research needs and direc tions, but the report takes a conservative approach to drawing conclusions from them. # O v e r v ie w o f t h e R e p o r t 's C h a p t e r s The Surgeon General's report on youth violence reviews a vast, multidisciplinary, and often controver sial research literature. Chapters 2 through 5 address, respectively, the extent and magnitude of youth vio lence; the developmental characteristics of, or paths to, youth violence; personal and environmental factors that may either place a child or adolescent at risk of violent behavior or protect a young person from suc cumbing to those risk factors; and violence interven tion and prevention programs. The final chapter in the report identifies areas of opportunity for future efforts to combat and prevent youth violence. This section provides a brief overview of each chapter, while the following section presents a sum mary of key conclusions drawn from each. Chapter 2 examines the magnitude of and trends in youth violence over the last two decades. It describes two different, but complementary ways of measuring violence-official reports and self-reports. Official arrest data offer an obvious means of deter mining the extent of youth violence. Indeed, a surge in arrests for violent crimes marked what is now recog nized as an epidemic of youth violence from 1983 to 1993. Arrests were driven largely by the rapid prolif eration of firearms use by adolescents engaging in violent acts and the likelihood that violent confronta tions would-as they did-produce serious or lethal injuries. Today, with fewer young people carrying weapons, including guns, to school and elsewhere than in the early 1990s, violent encounters are less likely to result in homicide and serious injury and therefore are less likely to draw the attention of police. By 1999, arrest rates for homicide, rape, and robbery had all dropped below 1983 rates. In contrast, arrest rates for aggravated assault remained higher than they were in 1983, having declined only 24 percent from the peak rates in 1994. Another way of measuring violence is on the basis of confidential reporting by youths themselves. Confidential surveys find that 10 to 15 percent of high school seniors report having committed an act of seri ous violence in recent years. These acts typically do not come to the attention of police; in part because they are less likely to involve firearms than in previ ous years. Over the past two decades, self-reported violence by high school seniors increased nearly 50 percent, a trend similar to that found in arrests for vio lent crimes. But this proportion has not declined in the years since 1993-it remains at peak levels. Chapter 2 considers how and to what extent arrest data and self report data vary, including variations by sex and race or ethnicity. In the aggregate, the best available evi dence from multiple sources indicates that youth vio lence is an ongoing national problem, albeit one that is largely hidden from public view. Chapter 3 examines routes that may lead a young person into violence. Viewed from a developmental perspective, violence stems from a complex interac tion of individuals with their environment at particu lar times in their lives. Longitudinal research has enabled investigators to describe the emergence of violence in terms of two, and possibly more, lifecourse trajectories. Chapter 3 discusses the earlyonset and late-onset emergence of violence, which occur before and after puberty, respectively. These trajectories offer insights into the likely course, severity, and duration of violence over the life course and have practical implications for the timing of intervention programs and strategies. The chapter reviews research on the co-occurrence of serious vio lence and other problems, including drug use and mental disorders. Finally, it underscores the impor tance-and the paucity-of research on factors asso ciated with the cessation of youth violence or its con tinuation into adulthood. Extensive research in recent decades has sought to identify various personal characteristics and environ mental conditions that either place children and ado lescents at risk of violent behavior or that seem to pro tect them from the effects of risk. Risk and protective factors, which are the focus of Chapter 4, can be found in every area of life. They exert different effects at dif ferent stages of development, they tend to appear in clusters, and they appear to gain strength in numbers. As the chapter notes, risk probabilities apply to groups, not to individuals. Although risk factors are not necessarily causes, a central aim of the public health approach to youth violence is to identify these predictors and determine when in the life course they typically come into play. Such information enables researchers to design preventive programs that can be put in place at just the right time to be most effective. The chapter examines risk from the perspectives of both childhood and adolescence and, within each of these developmental periods, considers risk factors occurring in the individual, family, school, peer group, and community domains. Childhood risk factors for violence in adolescence include involvement in serious (but not necessarily violent) criminal acts and sub stance use before puberty, being male, aggressiveness, low family socioeconomic status/poverty, and antiso cial parents-all either individual or family risk fac tors. The influence of family is largely supplanted in adolescence by peer influences, thus risk factors with the largest predictive effects in adolescence include weak social ties, ties to antisocial or delinquent peers, and belonging to a gang. Having committed serious (but not necessarily violent) criminal offenses is also an important risk factor in adolescence. Identifying and understanding how protective fac tors influence behavior is potentially as important to preventing and stopping violence as identifying and understanding risk factors. Several protective factors have been proposed, but to date only two have been found to buffer the risk of violence-an intolerant atti tude toward deviance and commitment to school. Protective factors warrant, and are beginning to receive, more research attention. Despite past contentions that "nothing works" to prevent youth violence, the evidence presented in Chapter 5 demonstrates that prevention efforts can be effective against both early-and late-onset violence in the general youth population, high-risk youths, and even youths who are already violent or seriously delin quent. The chapter highlights 27 specific programs that, based on existing data, help prevent youth vio lence. The most effective of these programs combine components known to prevent violence by themselves, particularly social skills training for youths and inter ventions that include parents or entire families. Chapter 5 also highlights important limitations in the current research on youth violence prevention. Little is known about the scientific effectiveness of hundreds of programs now being used in U.S. schools and communities. This situation is disconcerting, given that many well-intentioned youth violence pre vention programs have been found ineffective or harmful to youths. Even less is known about how to implement effective programs on a national scale without compromising their results. The information presented in Chapter 5 shows that youth violence prevention not only works, it can also be cost-effective. In a number of cases, the long term financial benefits of prevention are substantially greater than the costs of the programs themselves. These promising findings indicate that prevention plays an important role in providing a safe environ ment for youths. Finally, Chapter 6 presents several options for future action. First, the scientific base must continue to be expanded. Effective interventions exist, but only continued research can document those programs that meet a standard of effectiveness and those that do not-and should therefore be discarded. The chapter identifies the following courses of action: • Disseminate model programs with incentives that will ensure fidelity to original program design when taken to scale • Provide training and certification programs for intervention personnel • Improve public awareness of effective interventions • Convene youths and families, researchers, and pri vate and public organizations for a periodic youth violence summit • Improve Federal, state, and local strategies for reporting crime information and violent deaths # C h a p t e r C o n c l u s io n s Chapter 2 1. The decade between 1983 and 1993 was marked by an epidemic of increasingly lethal violence that was associated with a large rise in the use of firearms and involved primarily African American males. There was a modest rise in the proportion of young persons involved in other forms of seri ous violence. 2. Since 1994, a decline in homicide arrests has reflected primarily the decline in use of firearms. There is some evidence that the smaller decline in nonfatal serious violence is also attributable to declining firearm use. 3. By 1999, arrest rates for violent crimes-with the exception of aggravated assault-had fallen below 1983 levels. Arrest rates for aggravated assault remain almost 70 percent higher than they were in 1983, and this is the offense most fre quently captured in self-reports of violence. 4. Despite the present decline in gun use and in lethal violence, the self-reported proportion of young people involved in nonfatal violence has not declined from the peak years of the epidemic, nor has the proportion of students injured with a weapon at school declined. 5. The proportion of schools in which gangs are ' present continued to increase after 1994 and has only recently (1999) declined. However, evidence shows that the number of youths involved with gangs has not declined and remains near the peak levels of 1996. r 6. Although arrest statistics cannot readily track firearm use in specific serious crimes other than homicide, firearm use in violent crimes declined among persons of all ages between 1993 and 1998. 7. The steep rise and fall in arrest rates for homicide over the past two decades have been matched by similar, but less dramatic changes in some of the other indicators of violence, including arrest rates for all violent crimes and incident rates from vic tims' self-reports. This pattern is not matched by arrests for selected offenses, such as aggravated assault, or incident rates and prevalence rates from offenders' self-reports. 8. Young men-particularly those from minority groups-are disproportionately arrested for vio lent crimes. But self-reports indicate that differ ences between minority and majority populations and between young men and young women may not be as large as arrest records indicate or con ventional wisdom holds. Race/ethnicity, consid ered in isolation from other life circumstances, sheds little light on a given child's or adolescent's propensity for engaging in violence. 9. Schools nationwide are relatively safe. Compared to homes and neighborhoods, schools have fewer homicides and nonfatal injuries. Youths at greatest risk of being killed in school-associated violence are those from a racial or ethnic minority, senior high schools, and urban school districts. # Chapter 3 1. There are two general onset trajectories for youth violence-an early one, in which violence begins before puberty, and a late one, in which violence begins in adolescence. Youths who become vio lent before about age 13 generally commit more crimes, and more serious crimes, for a longer time. These young people exhibit a pattern of escalating violence through childhood, and they sometimes continue their violence into adulthood. 2. Most youth violence begins in adolescence and ends with the transition into adulthood. 3. Most highly aggressive children or children with behavioral disorders do not become serious vio lent offenders. 4. Surveys consistently find that about 30 to 40 per cent of male youths and 15 to 30 percent of female youths report having committed a serious violent offense by age 17. 5. Serious violence is part of a lifestyle that includes drugs, guns, precocious sex, and other risky behaviors. Youths involved in serious violence often commit many other types of crimes and exhibit other problem behaviors, presenting a serious challenge to intervention efforts. Successful interventions must confront not only the violent behavior of these young people, but also their lifestyles, which are teeming with risk. 6. The differences in patterns of serious violence by age of onset and the relatively constant rates of individual offending have important implications for prevention and intervention programs. Early childhood programs that target at-risk children and families are critical for preventing the onset of a chronic violent career, but programs must also be developed to combat late-onset violence. 7. The importance of late-on set violence prevention is not widely recognized or well understood. Substantial numbers of serious violent offenders emerge without warning signs in their childhood. A comprehensive community prevention strategy must address both onset patterns and ferret out their causes and risk factors. # Chapter 4 1. Risk and protective factors exist in every area of life-individual, family, school, peer group, and community. Individual characteristics interact in complex ways with people and conditions in the environment to produce violent behavior. O 2. Risk and protective factors vary in predictive power depending on when in the course of devel opment they occur. As children move from infan cy to early adulthood, some risk factors will become more important and others less important. Substance use, for example, is a much stronger risk factor at age 9 than it is at age 14. 3. The strongest risk factors during childhood are involvement in serious, but not necessarily violent criminal behavior, substance use, being male, physical aggression, low family socioeconomic status or poverty and antisocial parents-all indi vidual or family characteristics-or conditions. . # 4. During adolescence, the influence of family is largely supplanted by peer influences. The strongest risk factors are weak ties to convention al peers, ties to antisocial or delinquent peers, belonging to a gang, and involvement in other criminal acts. 5. Risk factors do not operate in isolation-the more risk factors a child or young person is exposed to, the greater the likelihood that he or she will become violent. Risk factors can be buffered by protective factors, however. An adolescent with an intolerant attitude toward deviance, for example, is unlikely to seek or be sought out by delinquent peers, a strong risk factor for violence at that age. 6. Given the strong evidence that risk factors predict the likelihood of future violence, they are useful for identifying vulnerable populations that may benefit from intervention efforts. Risk markers such as race or ethnicity are frequently confused with risk factors; risk markers have no causal rela tion to violence. 7. No single risk factor or combination of factors can predict violence with unerring accuracy. Most young people exposed to a single risk factor will not become involved in violent behavior; similar ly, many young people exposed to multiple risks will not become violent. By the same token, pro , tective factors cannot guarantee that a child exposed to risk will not become violent. # Introduction Chapter 5 1. A number of youth violence intervention and pre vention programs have demonstrated that they are effective; assertions that "nothing works" are false. 2. Most highly effective programs combine compo nents that address both individual risks and envi ronmental conditions, particularly building indi vidual skills and competencies, parent effective ness training, improving the social climate of the school, and changes in type and level of involve ment in peer groups. 3. Rigorous evaluation of programs is critical. While hundreds of prevention programs are being used in schools and communities throughout the coun try, little is known about the effects of most of them. 4. At the time this report was prepared, nearly half of the most thoroughly evaluated strategies for pre venting violence had been shown to be ineffec tive-and a few were known to harm participants. # 5. In schools, interventions that target change in the social context appear to be more effective, on average, than those that attempt to change indi vidual attitudes, skills, and risk behaviors. 6. Involvement with delinquent peers and gang membership are two of the most powerful predic tors of violence, yet few effective interventions have been developed to address these problems. 7. Program effectiveness depends as much on the quality of implementation as the type of interven tion. Many programs are ineffective not because their strategy is misguided, but because the quali ty of implementation is poor. # P r e p a r a t io n o f t h e R e p o r t To address the troubling presence of violence in the lives of U.S. youths, the Administration and Congress urged the Surgeon General to develop a report on youth violence, with particular focus on the scope of the prob lem, its causes, and how to prevent it. Surgeon General Dr. David Satcher requested three agencies, all compo nents of the Department of Health and Human Services, to share lead responsibility for preparing the report. The agencies are the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Substance Abuse and Mental Health Services Administration (SAMHSA). Under Dr. Satcher's guidance, these agencies established a Planning Board comprising individuals with expertise in diverse disciplines and professions involved in the study, treatment, and prevention of youth violence. The Planning Board also enlisted individuals representing various Federal departments, including particularly the Department of Justice (juve nile crime aspects of youth violence), the Department of Education (school safety issues), and the Department of Labor (the association between youth violence and youth employment, and out-of-school youth). Invaluable' assistance was obtained as well from individual citizens who have founded and oper ate nonprofit organizations designed to meet the needs of troubled and violent youths. Most important, young people themselves accepted invitations to become involved in the effort. All of these persons helped to plan the report and participated in its prepublication reviews. # Introduction Rand, M. R., Lynch, J. R, & Cantor, D. (1997). Criminal victimization, 1973 # H eadlines proclaim that the epidemic of youth violence that began in the early 1980s is over, but the reality behind this seemingly good news is far more complex and unsettling. Public health stud ies show that youth violence is an ongoing, startling ly pervasive problem. This chapter describes the magnitude of and trends in violent crime by young people, focusing on homicide, robbery, aggravated assault, and forcible rape (see Box 2-1 for defini tions). A later chapter (Chapter 4) seeks to explain why young people become involved in violence in the first place. # M e a s u r in g Y o u t h V io l e n c e Surveillance is the backbone of the public health approach to youth violence or any other public health problem. It reveals the magnitude of a problem, tracks the magnitude over time, and uses the information gained from such monitoring to help shape actions to prevent or combat the problem. Two approaches to measuring the magnitude of youth violence are commonly used. The first relies on official crime statistics compiled by law enforcement agencies, typically arrest reports. These statistics can not answer questions about how many young people commit violent crimes or how many violent crimes were committed, but they can answer questions about the number of crimes reported to the police, the vol ume and types of arrests, and how the volume changes over time. The second approach surveys young people and asks them in confidence about violent acts they have committed or have been victims of during a given period of time. Such reports can be obtained from the same group of people over a long period of time (a lon gitudinal survey) or from different groups of people at # Criminal Homicide-Murder and Non Negligent Manslaughter The willful (non-negligent) killing of one human being by another. # Robbery The taking or attempting to take anything of value from the care, custody, or control of a person or persons by force or threat of force or violence and/or putting the victim in fear. # Aggravated Assault An unlawful attack by one person upon another wherein the offender uses a weapon or displays it in a threatening manner, or the victim suffers obvious severe or aggravated bodily injury involving appar ent broken bones, loss of teeth, possible internal injury, severe laceration, or loss of consciousness. # Forcible Rape The carnal knowledge of a person, forcibly and/or against that person's will, or not forcibly or against the person's will where the victim is inca pable of giving consent because of his/her tempo rary or permanent mental or physical incapacity (or because of his/her youth). the same point in time (a cross-sectional survey). A prominent example of a repeated cross-sectional sur vey cited in this chapter is Monitoring the Future, a survey of high school seniors, that has been conducted annually since 1975. Reports from young people them selves offer the best way to measure violent behavior that never reaches the attention of the justice system. In fact, evidence in this chapter makes it unmistakably clear that most crimes by young people do not reach the attention of the justice system. Self-reports are well suited to answering such questions as: What proportion of youths are violent? What types of violent acts do they commit? Has the volume of violence changed over time? Are there dif ferences by sex and race/ethnicity? When during development does violence arise, and what forms does it take? How do children's patterns of violence evolve over time, and how long do they last? These questions relate to the magnitude of violent behavior and to its developmental pathways, and they are addressed in this chapter and the next. Both arrest reports and self-reports are reason ably valid and reliable ways of measuring the partic ular aspects of violence they were designed to meas ure (for general reviews see Blumstein et al., 1986;Hindelang et al., 1981;Huizinga & Elliott, 1986). Arrests appear to be more objective, but they are not a good general measure of violent behavior, for sev eral reasons. First, the majority of aggravated assaults, robberies, and rapes are never reported to the police; arrests are made in fewer than half of reported crimes Maguire and Pastore, 1999;; and most youths involved in violent crimes are never arrested for a violent crime . Thus, arrests seriously underestimate the volume of violent crime and fail to distinguish accurately between those who are and are not involved in violence. Second, arrest records do not accurately reflect the distribution of reported vio lent crimes; that is, the offenses for which youths are arrested are not representative of the crimes reported to police . Nonetheless, arrest records are the best measure of the justice system's response to observed or reported crime. Self-reports were designed specifically to over come the limitations of violence measures based on official records of criminal behavior. They provide a more direct measure of criminal behavior, but they too have their limitations. Youths may fail to report their violent behavior accurately, either deliberately or because of memory problems, and they may exaggerate their involvement, reporting rather trivial events in response to questions about serious forms of violence. Research reveals that exaggeration (overreporting) is a greater problem than underreporting for reports that cover the previous year , but sophisticated self-report measures can minimize these potential sources of error Huizinga & Elliott, 1986). The advantages of self reports are that they capture not only unreported offens es but also details not found in arrest records. In' addi tion, this measure of violent offending is not subject to any of the biases that might be involved in arrest processes.' The general conclusion from studies evalu ating the validity and reliability of self-reports is that they compare favorably with other standard, accepted social science indicators (Hindelang et al., 1981). Both types of measures contribute to our under standing of violence. The key to using them is to understand their relative strengths and limitations, determine where they reinforce each other and where they diverge or conflict, and then interpret the differ ences in findings, if possible (Brener et al., 1995;Hindelang et al., 1981;Huizinga & Elliott, 1986;. # T h e V io l e n c e Ep id e m ic Arrest rates of young people for homicide and other violent crimes skyrocketed from 1983 to 1993. In response to the dramatic increase in the number of Questions have been raised about potential racial/ethnic biases in both types o f measures. There is evidence that arrests o f whites, compared to those o f African Americans, are underrepresented in local arrest records and archives (Ceerken, 1994). Some studies find racial/ethnic bias in arrests and other justice system processing, w h ile others do not (for reviews, see Austin & Allen, 2000;Hawkins et al., 1998;Sampson & Lauritsen, 1997). Comparisons o f an individual's arrest and self-reported offenses reveal a greater discrepancy for African Americans than whites, w ith African American males self-reporting fewer o f the offenses found in their official records (Hindelang et al., 1981;Huizinga & Elliott, 1986). If one accepts the accuracy o f arrest records, this finding w ould indicate an underreporting on the part o f African American males, but there are reasons to question this assumption (see Elliott, 1982;Huizinga & Elliott, 1986). The question o f racial/ethnic bias in both asures remains controversial. murders committed by young people, Congress and many state legislatures passed new gun control laws, established boot camps, and began waiving children as young as 10 out of the juvenile justice system and into adult criminal courts. Then, starting in the mid-1990s, overall arrest rates began to decline, returning by 1999 to rates only slightly higher than those in 1983. Several important indicators were used to track youth violence during these years, but their findings did not always agree. Arrest rates, as noted above, pro vide strong evidence of both a violence epidemic between 1983 and 1993/1994 and a subsequent decline to 1999. Several other indicators of violence furnish similar, but not as robust evidence of a violence epi demic that later subsided. However, the decline in arrest rates is not uniform for all types of violent crime. Moreover, another key indicator-the volume of vio lent behavior, which is based on self-reports-does not show a decline in youth violence after 1993. As explained later, that indicator remained high and essen tially level from 1993 to 1998. This chapter answers the questions raised by these disparate findingsnamely, whether the epidemic of violence is really over and why leading indicators of youth violence do not agree. . A rise and subsequent decline in the use of firearms and other weapons by young people provides one potential explanation for the different trends in arrest records and self-reports. The violence epidemic was accompanied by an increase in weapons carrying and use. During this era, instant access to weapons, especially firearms, often turned an angry encounter into a seriously violent or lethal one, which, in turn, drew attention from the police in the form of an arrest. As weapons carrying declined, so too did arrest rates, perhaps because the violence was less injurious or lethal. But the amount of underlying violent behavior (on the basis of self-reports) did not change much-if anything, it appears to have increased in recent years. That undercurrent of violent behavior could reignite into a new epidemic if weapons carrying rises again. From a public health perspective, a resurgence of weapons carrying-and hence the potential for anoth er epidemic of violence-poses a grave threat. # A r r e s t s f o r V io l e n t C r im e s The Federal Bureau of Investigation (FBI) monitors arrests made by law enforcement agencies across the United States through the Uniform Crime Reporting (UCR) program. Since the 1930s, this program has compiled annual arrest information submitted volun tarily by thousands of city, county, and state police agencies. This information currently comes from police jurisdictions that represent only 68 percent of the population, so FBI figures represent projections of these data to the entire U.S. population . The UCR tabulates the number, rate, and certain features of arrests made by law enforcement agencies. Because some people are arrested more than once a year, the UCR cannot provide an accurate count of the number of people arrested or the proportion of the total population arrested (the prevalence). Nor can the UCR provide an accurate count of the number of crimes committed. A single arrest may account for a series of crimes, or a single crime may involve the arrest of more than one person. Young people tend to commit crimes in groups, so the number of youths arrested inflates the number of crimes committed . As noted earlier, arrest rates are also prone to certain types of error. Unless indicated otherwise, the figures on arrests were assembled by the FBI. # Arrest Rates and Trends As shown in Figure 2-1, overall arrest rates for vio lent crimes by youths between the ages of 10 and 17 rose sharply from 1983 to 1993/1994. Rates then declined until 1999, the most recent year for which figures are available. Figure 2-2, page 21, shows arrest rates for each of the four violent crimes considered in this report. In 1999, arrests of young people for all crimes totaled 2.4 million (Snyder, unpublished), with 104,000 arrests for violent crimes. Arrests for aggravated assault (69,600) and robbery (28,000) were the most frequent, with arrests for forcible rape (5,000) and murder (1,400) trailing significantly behind. In 1998, youths crimes, a share that has decreased slightly (16 percent) in recent years (Snyder, unpublished). Although the 1999 arrest rate for violent crimes was the lowest in this decade, it is still 15 percent higher than the 1983 rate (Snyder, unpublished). As seen in Figure 2-2, the 1999 rates for homicide, robbery, and rape are below the 1983 rates; however, arrests for aggravated assault are still nearly 70 percent higher than 1983 rates. The sheer magnitude of the increase in arrest rates between 1983 and 1993/1994 is striking. Overall, arrest rates of youths for violent offenses grew by about 70 percent. The increase in homicides commit ted by young people was particularly alarming. Both the rate of homicide arrests and the actual number of young people who were arrested for a homicide near ly tripled . This increase was consistent for adolescents at each age between 14 and 17 . The decade-long upsurge in homicides was tied to an increased use of firearms in the commission of crimes (Cherry et al., 1998;. Likewise, the downward trend in homicide arrests from 1993 to 1999 can be traced largely to a decline in firearm usage. The critical role of firearms in homicide and other violent crimes is supported by arrest, victim ization, hospitalization, and self-report data. Analysis of arrest data (Figure 2-3, page 22) shows an unequivocal upsurge in firearm usage by young people who committed homicide. In 1983, youths were equally likely to use firearms and other weapons, such as a knife or club, to kill someone. By 1994, 82 percent of homicides by young people were committed with firearms . Virtually all of the increase in firearm-related homi cides involved African American youths . The precipitous drop in homicides between 1994 and 1998 coincided with a decline in firearm usage, again mostly by African American youths . of firearm use. A large increase in the number of young people killed by firearms between 1987 and 1993 was followed by a decrease. More than 2,000 youths were homicide victims in 1993, the peak year . Most victims were male, and a disproportionately high percentage were African American males . The use of firearms in violent crimes other than homicide cannot readily be tracked in youth arrest sta tistics, but for Americans of all ages, firearm use in violent crimes increased from 1985 to 1992 and then declined from 1993 to 1998. Firearm use during rob beries increased 33 percent between 1985 and 1992; the decline in firearm use from 1993 to 1998 was nearly 20 percent for aggravated assaults but only 6 Firearm use can also be tracked indirectly, through victims treated in hospital emergency depart ments. Since 1992, injuries related to firearms have been monitored through an emergency department surveillance system.* 3 Although there are no data from this source to corroborate the growing pattern of firearm injuries before 1992, there are data to corrob orate the decline since then. Figure 2-A presents a spe cial analysis of emergency department surveillance data on youths age 10 to 19. It shows that the rate of firearms-related injuries among young people treated in hospital emergency departments dropped by almost 50. percent from 1993 to 1998. Data on male youths alone reveal a similarly dramatic drop. Youths are victim s in about 27 percent o f homicides comm itted by other youths . 3 The National Electronic Injury Surveillance System (NEISS); NEISS is operated by the U.S. Consumer Product Safety Commission. . A O On 1 or more of the 30 days preceding the survey. 95% confidence intervals for carried weapon = ± 1.3-2.3; for carried weapon at school = ± 0 .9-1.5; and for carried gun = ± 0 .8 -1 .3 . In the early 1990s, high school students began to report that they were increasingly less likely to carry guns anywhere and specifically less likely to carry them to school. Figure 2-5 illustrates these trends, as well as trends in general weapons carrying, based on data from the Youth Risk Behavior Survey (YRBS).4 Each trend shows a significant linear decrease, although the decline in weapons carrying in general leveled off in 1999 CDC, 2000a;Kann et al., 2000). Thus, there has been an upsurge and then a decline in the use of firearms and weapons over the past two decades. The easy availability of guns and the resulting rise in lethal violence was caused at least in part by the emerging crack cocaine markets in the mid-1980s and the recruitment of youths into these markets, where carrying guns became routine (Blumstein & Wallman, 2000). It also resulted from changes in the types of guns manufactured, with cheaper, larger caliber guns flooding the gun markets (Wintemute, 2000). The reasons for the decline are complex and not well understood, but they do involve changes in the car rying and use of guns in violent encounters (Blumstein & Wallman, 2000). The explanations most often given are a decline in youth involvement in the crack market and in gang involvement in crack distribution, police crackdowns on gun carrying and illegal gun purchases, longer sentences for violent crimes involving a gun, a strong economy, and expanded crime and violence pre vention programs. After reviewing these and other potential explanations for the drop in violence, Blumstein and Wallman (2000) concluded that no sin gle factor was responsible; rather, the decrease in vio lence resulted from the combination of many factors. # Comparing Arrests to Other Trends As noted above, the steep rise and fall in arrest rates over the past two decades has been matched to some extent by changes in leading indicators of violence. Figure 2-6 tracks the trends in four indicators: arrest rates for homicide only, arrest rates for all serious vio lent crimes, incident rates from victims' self-reports, and incident rates from offenders' self-reports. The incident rate is a measure of the volume of violence. It refers to the number of self-reported vio lent acts within a given-sized population-in this case, the number of violent acts per 1,000 young peo ple. In contrast, the prevalence rate indicates what proportion of that population is involved in one or more violent behaviors. Figure 2-6 compares arrest rates with self-reported incident rates (rather than with prevalence rates) because both measure the volume of violent events. Even though arrest and incident rates measure different events and have different absolute magnitudes, the degree of change in these rates over time can be compared. 0 # Arrests Versus Self-Reported Incidents The sharpest increases in Figure 2-6 are for the two arrest indicators. Homicide arrest rates were roughly 170 percent higher in 1993 than in 1983, and arrest rates for all serious violent crimes were 70 percent higher. The incident rates of serious violent crimes reported by victims and the rates of serious assault and robbery reported by offenders increased to a lesser extent, by about 50 percent. By 1999, arrest rates for homicide, robbery, and rape had dropped below their 1983 levels; by 1997, victim-reported incident rates had dropped back to roughly their 1983 levels. Arrests for aggravated assaults remained high, however-at almost 70 per cent above their 1983 level. Since the peak year of arrests for aggravated assault (1994), arrests for this violent crime have declined only 24 percent. Self-reported violent offending showed no decline at all. After rising by about 50 percent, the incident rate of self-reported serious assaults and robbery remained essentially level through 1998.. The leveling off of This self-reported incident rate appears to be much higher (e.g., almost 400 assaults w ith injury and robberies w ith a weapon were reported per 1,000 high school seniors in 1998) than the arrest rate for aggravated assault and robbery (about 350 arrests per 100,000 youth, see Figure 2-2), but the tw o are not strictly comparable: high school seniors (17-and 18-year-olds) have much higher arrest rates as a group than do 10-to 17-year-olds. The MTF prevalence estimates for both violent behavior and drug use have been confirm ed by other studies in which there is overlap in years and ages. For example, see and Menard and Elliott (1993). About 16,000 high school seniors at 130 schools participate, although only about 3,000 o f the students are asked questions about their v io lent behavior. Since the beginning o f the survey in 1975, the participation rate among schools has ranged from 60 to 80 percent, and the stu dent response rate has ranged from 77 to 86 percent (Kaufman et al.,199?' determining the extent of youth violence. They fur nish a window into violent behavior that never reach es the police. For example, the National Crime Victimization Survey reveals that the majority (58 percent) of serious violent crimes committed by youths are not reported to the police . A large fraction of the crimes that are reported never result in an arrest. Estimates indi cate that only 6 to 14 percent of chronic violent offenders are ever arrested for a serious violent crime (Dunford & Elliott, 1984;Elliott, 2000a;Huizinga et al., 1996;. The MTF gathers data about five acts of violence and from them compiles a violence index (see Figure 2-8 for the specific offenses included). This violence index is not the same as the UCR violent crime index, which aggregates the four types of arrests covered in this chapter. According to the MTF's vio lence index, about 3 out of 10 high school seniors reported having committed a violent act in the past year, an annual prevalence rate of about 30 percent. The M TF's violence index has been relatively stable for almost 20 years, in sharp contrast to the. dramat ic increase in arrests. ' Although the prevalence rate of self-reported vio lent behavior is relatively constant, it is still strikingly high, partly because high school seniors age 17 and 18 are at the peak ages of violent offending and partly because the violence index includes some less serious violent behaviors as well as some very serious ones. Because this report focuses on violent behavior carrying the potential for serious injury or death, Figure 2-8 also includes the prevalence rates of assault with injury and robbery with a weapon, the two most serious acts in the MTF violence index. An assault with injury could lead to an arrest for aggravated assault; likewise, a robbery with a weapon could lead to an arrest for armed robbery. Therefore, assault with injury and rob bery with a weapon may be used as proxy measures for aggravated assault and armed robbery, respectively. Over the past two decades, the MTF's prevalence rates for assault with injury ranged from 10 to 15 per cent (± 1.3 to 1.8). A small but significant increase took place between 1979 and 1998. About half of this increase occurred between 1983 and 1993, but rates remained fairly constant after 1993 (the increase from 1993 to 1998 shown in Figure 2-8 is not statistically significant). The prevalence of robbery with a weapon ranged from 2 to 5 percent (± 0.7 to 1.1) between 1983 and 1993 and remained constant thereafter. Thus, unlike arrest data, MTF data show no evidence of a downward trend in self-reported assaults or robberies after 1993. Prevalence rates of this magnitude-10 to 15 per cent of high school seniors8-for the most serious types of violence are confirmed by other self-report surveys described in Chapter 3. For example, an aver age prevalence rate of 9 percent (± 2.0) was reported for 17-year-olds between 1976 and 1982 in the National Youth Survey, whose measure of violence includes aggravated assault, robbery, gang fights, and rape. This rate is similar to the MTF's, but the National Youth Survey measure includes more serious violent offenses. Two general city surveys-the Denver Youth Survey and the Rochester Youth Development Survey, which use the same measure of violence as the National Youth Survey-report some what higher prevalence rates among 17-year-olds: 12 percent (± 1.6) and 14 percent (± 2.0), respectively.9 # International Prevalence Are U.S. youths unique in reporting a high prevalence of violent behavior? How do they compare to their European counterparts? The answers can be found by comparing the MTF findings with the International Self-Report Delinquency Study (Junger-Tas et al., 1994), a study of delinquent behavior conducted in several European countries. Like the MTF, this study relies on self-reported behavior. Of the countries included, only England/Wales, the Netherlands, Spain, and Italy used a probability sample that provided national estimates of violence comparable to the violence index used in the MTF survey. Self-reported serious violence # Year Sources: Rates for violence index: Johnston, 2000; rates for assault with injury and robbery with weapon: Maguire and Pastore, 1999. Entries above are 3-year running averages of the prevalence of each of the specified acts. The violence index is defined as the percent committing any of the specified following five acts, with no missing data allowed: hit an instructor or supervisor; gotten into serious fight in school or at work; taken part in a fight where a group of your friends were against another group; hurt somebody badly enough to need bandages or a doctor (assault with injury); used a knife or gun or some other thing (like a club) to get something from a person (robbery with a weapon). 95% confidence intervals for the violence index are all less than ± 2.5%; for assault, less than ± 2%; for robbery, less than ± 1.1%. among young people age 16 to 17 in these countries in 1992 or 1993 ranged from 16 to 26 percent (Table 2-1). These prevalence rates are lower than the U.S. rate of about 30 percent for the MTF's violence index. Thus, while the questions in the international study may be somewhat different, the findings show that while a higher proportion of U.S. youths commit vio lent acts, youth violence is not unique to the United States. A major difference between the United States and several other industrial countries is the ease of access to firearms. From 1990 to 1995, the United States had the highest rate of firearm-related deaths among youths in the industrialized world (CDC, 1997). The rate for children below age 15 was five times higher than that of 25 other countries combined. In summary, youth violence, although interna tional in scope, is greater in the United States, more likely to involve firearms, and more lethal in its con sequences. According to self-reports, both the preva lence and incidence (volume) of assault and robbery increased among U.S. high school seniors between 1983 and 1993. This finding is consistent with an epi demic of violence among U.S. youths, although self reports point to a more modest upsurge than arrest trends do. However, both self-reports and arrest rates for aggravated assault point to an ongoing problem of youth violence after the apparent end of the violence epidemic. Thus, the rise and fall in arrest rates for most violent offenses is set against more enduring rates of violent behavior. # D if f e r e n c e s b y S ex a n d Ra c e /Et h n ic i t y Self-reported violence and arrest rates for violent offenses can also be compared by sex and by race/ethnicity. Ratios based on these two sources of data show similar findings with respect to sex but remarkably different findings with respect to race/ethnicity-dif ferences that have yet to be fully explained. , 1983 to 1993 and 1993 to 1998. In gen eral, there was little change in those periods, with one exception. In 1983 and 1993, the ratios of male to female youths committing violent acts were 7.4 to 1 and 7.0 to 1, respectively. This means that for every violent act committed by female youths in these years, at least seven violent acts were committed by male youths. By 1998, this ratio had closed to 3.5 to 1, indicating that O l. -M liE S T C O P Y A V A ILA B LE females are closing the gap. The difference in preva lence rates changed little over the same period, but at a ratio of 2 to 1, it was much smaller to begin with. Taken together, the trends show that the proportions of males and females involved in violence (the. preva lence rate) have not changed but that the relative num ber of violent acts by males and females (the incident rate) has changed, with females committing more vio lent acts in 1998 than in earlier years. Differences by race are also presented in Table 2-2. The only available national comparisons for seri ous violence are for white and African American youths (see Chapter 3 for local longitudinal studies that include rates for Hispanic youths). Overall, inci dent rates are lower for white than African American youths over these years; the gaps are largest in 1993 and 1998, when approximately 1.5 violent acts were 49 ---------------" committed by African Americans for every 1 violent act b y whites. The racial gap appeared to increase somewhat during the violence epidemic and has remained higher through 1998. There are essentially no differences by race in the prevalence rates for seri ous self-reported violent behavior. ■ ■ ------------------------------------- # Differences in Arrest Rates Arrest rates differed widely by sex and by race/ethnicity between 1983 and 1998 (Table 2-3). Overall, the dif ference was greater by sex than by race/ethnicity and was most evident in regard to homicide arrests: In 1998, 11 times as many males were arrested as females. A sim ilar male-female gap was evident for robbery, but the gap for aggravated assault was considerably smaller. Trends in the male-female gap vary, depending on the crime for which youths are arrested. From 1983 to 1993, the male-female disparity in homicide arrests doubled: In other words, the violence epidemic was driven by arrests of males. During the same period, the male-female gap in arrests for both robbery and aggravated assault shrank. More recently, from 1993 to 1998, the male-female disparity in all three types of arrests has held constant or declined further. Differences in arrest rates by sex are similar in magnitude to differences in self-reported violent inci dents. Combining aggravated assault and robbery arrest data yields male:female ratios of 6.8 to 1, 5.7 to 1, and 4.3 to 1 for 1983, 1993, and 1998, respective ly.10 The ratios for self-reported incidents were 7.4 to 1, 7.0 to 1, and 3.5 to 1 (Table 2-2). Thus, both self report and arrest rates attest to a difference by sex in the volume of violence but also to a narrowing of that gap between 1983 and 1998-except for homicide arrests. Possible reasons for the male-female gap are discussed in Chapter 4. Self-reports and arrest rates provide different pic tures of violent offending by race. Self-reports, as noted above, reveal small differences between African American and white youths. Arrest records, on the other hand, reveal large differences, even though these gaps narrowed between 1993 and 1998 (Table 2-3). The narrowing of the gap was particularly noteworthy for homicide arrests: Whereas about nine African American youths were arrested for every white youth in 1993, only about five were arrested for each white youth in 1998. Even at 5 to 1, the ratio of African American to white youths arrested for homicide remains greater than that of Native American or Asian youths to white youths. Ratios cannot be calculated for Hispanic youths because data for this ethnic group are not broken out in the UCR or other systematic data collection sys tems (Soriano, 1998). A few regional and city studies suggest that homicide arrest rates for Hispanic males are substantially higher than those for non-Hispanic white males and that African American males typical ly have the highest rates (Prothrow-Stith & Weissman, 1991;Smith et al., 1988;Sommers & Baskin, 1992;Zahn, 1988). The difference between homicide arrests of Hispanic and non-Hispanic white youths is sub stantial in these studies, but it is not as great as the dif ference between African American and white youths. The existence of much larger racial and ethnic dif ferences in arrest rates than in self-reported violence is a matter of great concern. On the one hand, there is no reason to expect similar distributions, because these measures were designed to assess different aspects of violence. But if both measures are valid and reliable, the discrepancy suggests that the probability of being arrested for a violent offense varies with race/ethnici ty. Explanations for this discrepancy focus on selective reporting of offenses to the police, different patterns of police surveillance, racial/ethnic biases in self-report measures, and racial/ethnic bias on the part of police, victims, and witnesses. Some studies have explored these explanations, but their findings are not definitive (Austin & Allen, 2000;Blumstein et al., 1986;Hawkins et al., 1998;Sampson & Lauritsen, 1997). This complex issue will also be discussed in Chapter 3, which considers other dimension's of violent offending. Arrest ratios of Native American" to white youths are similar, except for the homicide ratio in 1998. Similarly, arrest rates of Asian Americans for homicide and robbery differ little from those of whites, but at least two whites are arrested on charges of rape or aggravated assault for every Asian American. Possible reasons for these differences have not been well studied. In sum, racial and ethnic differences in rates of violence are greater in arrest statistics than in self reports of violent behavior. The reasons are not well understood, with conflicting evidence from various studies. Self-reports and arrest records produce simi lar estimates of trends in violence by sex: Violent behavior still occurs more often among male than female youths, but the gap has been narrowing. # V io l e n c e a t Sc h o o l Recent shootings at schools have galvanized public concern about school safety, but studies described here find that schools nationwide are relatively safe. In contrast to public perceptions, schools have fewer homicides and nonfatal injuries than homes and neighborhoods. However, some students are at greater risk of being killed or injured at school than othersspecifically, senior high school students from racial or ethnic minorities who attend schools in urban districts (Kachur et al., 1996). # Homicides and Nonfatal Injuries Two nationwide studies of school homicides have been conducted by the Centers for Disease Control and Prevention in collaboration with the U.S. Departments " The 1998 arrest rate was atypically high for the 1993-1999 period. This rate was tw ice the rate for every other year over this period and ^-•'"p e a rs to be an anomaly. of Education and Justice. The first study covered a 2year period from July 1992 through June 1994 and identified 68 students who were killed on or near school grounds or at school-related events (Kachur et al., 1996). Most of the victims were male and were killed with a firearm. These homicides represent less than 1 percent of all youth homicides in the period studied, and the estimated incidence of school-associated vio lent death was 0.09 per 100,000 student-years.12 Those at greatest risk of being killed were from racial or eth nic minorities, from senior high schools, and from urban school districts. The homicide rate in urban schools, for example, was nine times greater than the rate in rural schools. Most offenders and victims alike were male, under age 20, and from a racial or ethnic minority. The most common motives were an interper sonal dispute or gang-related activities. The second study, using the same methodology, updated the figures through June 1999 (CDC, 2000a). It identified 177 students age 5 to 19 who were killed in this 5-year period; the vast majority of the homi cides (84 percent) involved firearms. School-associat ed homicides remained at less than 1 percent of all homicides among students, but the frequency of homi cides involving more than one victim increased. The three school years from August 1995 through June 1998 saw an average of five multiple-victim homi cides or homicide-suicides per year. An average of one such event occurred in each of the 3 years from August 1992 through July 1995. Thus, trends throughout the 1990s show that the number of school homicides has been declining. Yet within this overall trend, homicides involving more than one victim appear to have been increasing. In regard to nonfatal injuries at school, the National Crime Victimization Survey found in 1998 that the rate of serious violent crimes against youths age 12 to 18 was one-half as great when they were at school as when they were not. At school, the highest victimization rates were among male students and younger students (age 12 to 14) (Kaufman et al., 2000). The rate was highest in urban schools in 1992, but by 1998 the rates at urban, suburban, and rural schools were similar. Overall, cr Q between 1992 and 1998, the rate of serious violent crimes at school remained relatively stable at about 8 to 13 per 1,000 students (Kaufman et al., 2000). The stability of this trend is corroborated by the MTF survey, which asks high school seniors whether they have been victims of violence. The percentage of seniors reporting that they had been injured with a weapon at school remained stable at about 5 percent from 1976 to 1998 (Flanagan & Maguire, 1992;Maguire & Pastore, 1999) (Figure 2-9). The same vic timization rate is reported by the National Study of Delinquency Prevention in Schools for 1998 (Gottfredson et al., 2000). However, the MTF trend masks large fluctuations in victimization reported by African American students (Figure 2-9). From 1980 to 1998, between 4 (± 2.8) and 13 (± 3.6) percent of African American students reported having been injured with a weapon at school. # Weapons at School Recent findings regarding students carrying weapons (a gun, knife, or club, for example) at school are encouraging. In 1999, the Youth Risk Behavior Survey (YRBS) found that about 7 percent of all high school students reported carrying a weapon on school proper ty within the last 30 days (Kann et al., 2000) (Figure 2-5). In 1993, almost 12 percent of high school stu dents reported carrying a weapon at school in the last 30 days (Kann et al., 1995), a 42 percent decrease Kann et al., 2000). A somewhat less pronounced decline was apparent among high school seniors in the MTF survey (Kaufman et al., 1998). Both studies found the problem to be of rough ly the same magnitude: In 1995, about 6 to 8 percent of 12th graders reported carrying a weapon at school at least once during the past month. Evidence of an upsurge in the number of students carrying weapons at school before 1993 is less clear. The YRBS first asked this question in 1993, and the MTF did not ask until the 1990s. Nonetheless, smaller or less representative studies suggest a substantial increase in weapon carrying between the 1980s and the early 1990s (reviewed in Elliott et al., 1998). Entries are 3-year running averages of the percentage of 12th graders who reported that someone had injured them with a weapon at school during the past 12 months. Examples of weapons are knives, guns, and clubs. "At school" means inside or outside the school building or on a school bus. 95% confidence intervals for total sample and whites are less than ± 1.5%; for African Americans, less than ± 4.6%. # Perceptions of School Violence Although the overall risk of violence and injury at school has not changed substantially over the past 20 years, both students and their parents report being increasingly apprehensive about their schools. Studies reveal that, during the early 1990s, students grew more fearful about being attacked or harmed at school and that they were avoiding certain places within their schools (Kaufman et al., 1998). By 1999, these fears had subsided somewhat (Kaufman et al., 2000), but parents still say they are afraid for their children at school. A recent Gallup poll found that nearly half of the parents surveyed feared for their children's safety when they sent them off to school, whereas only 24 percent of parents reported this concern in 1977 (Gallup, 1999a). In May 1999, shortly after the shoot ings at Columbine High School in Littleton, Colorado, 74 percent of parents said that a school shooting was very likely or somewhat likely to happen in their com munity (Gallup, 1999b). O Public perceptions about school safety seem at odds with the evidence that the risk for serious violence at school has not changed substantially over the past 20 years. But several indicators of violence did increase during the epidemic-school fights, gangs, drug use, and students carrying weapons to school. While gangs and weapon carrying have declined recently, the rates of drug use and physical fighting are high and have not changed between 1991between and 1999between (Brenner et al., 1999). Today's school bullies are still more likely to be carry ing guns than those of the early 1980s, and the propor tion of students reporting that they felt too unsafe to go to school has not changed since the peak of the violence epidemic in the mid-1990s. These findings add to the concern that the violence epidemic is not yet over. # G a n g s a n d V io l e n c e Gang members, a relatively small proportion of the adolescent population, commit the majority of serious youth violence (see Spergel, 1990, for a review). In two major longitudinal studies in Denver and Rochester (discussed in more detail in Chapter 3), 14 to 30 percent of the youths surveyed were gang mem bers at some time during the study, and they account ed for 68 to 79 percent of the serious violence report ed . Similar findings have been reported in other studies using nonrandomized local samples (Battin et al., 1996;Fagan, 1990). In Rochester, 66 percent of chronic violent offenders were in gangs . A high proportion of gang members are also involved in drug sales and possessing/carrying a gun, two behaviors closely linked to serious violence. The 1999 National Youth Gang Survey (a national survey of law enforcement agencies) estimates that 46 percent of youth gang members are involved in street drug sales (Egley, 2000). In the Rochester study, 67 percent of youths reporting they owned/carried a gun for pro tection were gang members and 32 percent reported they sold drugs. Only 3 to 7 percent of non-gun own ers or sport gun owners were involved in drug selling. Further, 85 percent of youths who owned guns for pro tection were involved with peers who owned guns for protection . Rates of . violence are higher in schools where gangs are present. The rate of victimization in schools with gangs is 7.5 percent, compared to 2.7 percent in schools without gangs . Gangs are present not only in inner-city schools, but in many suburban and rural schools as well. Between 1989 and 1995, the proportion of students reporting gangs at their school increased from 15 percent to 28 percent . By 1999, how ever, that figure had dropped to 17 percent (Kaufman et al., 2000). A decline in the number of gangs in U.S. schools between 1996 and 1997 has also been report ed by law enforcement agencies (National Youth Gang Center, 1999). The National Youth Gang Survey reported more than 26,000 active youth gangs in schools and com munities in 1999, down 15 percent from 1996 (Egley, 2000). Yet the same survey reported more than 840,500 active gang members in 1999, a decline of less than 1 percent from the peak level in 1996. Thus, from this source, it appears that the number of youths actively involved in gangs remains very high. The racial/ethnic composition of gangs in 1999 was 47 percent Hispanic, 31 percent African American, 13 percent non-Hispanic white, and 7 per cent Asian. These rates have been relatively constant since 1990. In 1998, 92 percent of all gang members were male (National Youth Gang Center, 2000), although some evidence indicated that girls' involvement in gangs increased during the epidemic (Chesney-Lind et al., 1996;Chesney-Lind & Brown, 1999;. However, the National Youth Gang Survey reports a decline in female membership, with less than 2 percent of gangs nationwide reporting pre dominantly female membership. # C o n c l u s io n s The United States suffered an epidemic of violence in the decade from about 1983 to 1993. Arrest rates of young people for homicide and other violent crimes skyrocketed. Several other violence indicators con firmed an epidemic of violence during that period. There are three factors that appear to play a sig nificant role in this dramatic surge in lethal violence or injury: gangs, drugs, and guns. The combination of increased involvement in gangs, selling drugs on the street, and carrying guns for protection had lethal implications. And it was African American and Hispanic males who were disproportionately caught up in this set of circumstances. After 1993/1994, arrests and victims' reports of violence began to decline, returning in 1999 to rates only slightly higher than those in 1983. These declines come as welcome news. Yet several other leading indicators of violence remain high. Young people's self-reports of violence have not declined at all. Arrest rates for aggravated assault remain quite high. Some estimates of gang membership indicate that this prob lem remains close to levels at the peak of the epidem ic. Indeed, self-reported violent behavior is at least as high today as it was in 1993. Why has this important indicator of violence remained high while other indi cators have come down? A major reason is firearms usage. It is now clear that the violence epidemic was caused largely by an upsurge in the use of firearms by young people. Ready access to firearms during a violent confrontation often had grievous consequences. Youth violence became more lethal, resulting in dramatically higher rates of homicide and serious injury. This triggered reporting to and response from police, leading to higher rates of arrest. Although firearm usage may not cause vio lence, it clearly increases the severity of violence. Today's youth violence is less lethal, largely because of a decline in the use of firearms. Fewer young people today are carrying weapons, including guns, and fewer are taking them to school. Homicides at school are declining. Violent confrontations are less likely to result in killing or serious injury, and the police are less likely to be called in for an arrest. This is a heartening trend, but this is not the time for complacency. Violent behavior is just as prevalent today as it was during the violence epidemic. Some 10 to 15 percent of high school seniors reveal in confi dential surveys that they have committed at least one act of serious violence in the past year. This prevalence rate has been slowly yet steadily rising since 1980. There is also a difference by sex in the volume of violence. Male youths commit many more violent acts than female youths, according to both arrest records and self-reports. The existence of a racial difference between African American and white youths is more questionable. Arrest records indicate that many more African American than white youths commit violent crimes, whereas self-reports indicate much smaller racial differences in incident rates and nonexistent dif ferences in prevalence rates. The disparities between these two indicators of violence have not been satis factorily investigated, and more research on them is clearly warranted. Looking at all self-reported violent behavior, it is apparent that youth violence still poses a serious pub lic health problem. Should firearms once again become appealing and accessible to young people, the potential for a recurrence of the violence epidemic is quite real. The magnitude of serious violence occurring beneath the police radar should warn us that youth violence is •^'••sistent problem demanding a focus on prevention. # M ost violence begins in the second decade of life. This chapter looks closely at childhood and adolescence as critical periods of development to trace how violence unfolds-its onset, duration, and t continuity into adulthood. It also examines violence in relation to other risky behaviors that emerge in adolescence. The dynamics of youth violence are best under stood from a developmental perspective, which recog nizes that patterns of behavior change over the life course. Adolescence is a time of tumultuous change and vulnerability, which can include an increase in the frequency and means of expression of violence and other risky behaviors. Understanding when and under what circumstances violent behavior typically occurs helps researchers craft interventions that target those critical points in development. Our understanding of developmental patterns de pends in large part on longitudinal studies, which track the same group of individuals over long periods of time, sometimes a decade or more. Four major longitu dinal studies are described in this chapter. They add new dimensions to the surveillance statistics presented in Chapter 2, and they provide essential background for Chapter 4, which deals with why young people become involved in violence. # Ea r l ya n d La t e -O n s e t T r a je c t o r ie s Longitudinal research has detected two prominent developmental trajectories for the emergence of youth violence, one characterized by an early onset of violence and one by a late onset. Children who com mit their first serious violent act before puberty are in the early-onset group, whereas youths who do not become violent until adolesence are in the late-onset group. While other developmental trajectories have been identified (D'Unger et al., 1998;, this report focuses on the early-and late-onset trajectories because they are recognized by most researchers, they debunk the myth that all seri ous violent offenders can be identified in early child hood, and they have strikingly different implications for prevention. In the early-onset trajectory, problem behavior that begins in early childhood gradually escalates to more violent behavior, culminating in serious violence before adolescence. A child's first serious violent act may have been officially recorded, or it may have been reported by the child to researchers in a confi dential survey. The early-onset group, in contrast to the late-onset group, is characterized by higher rates of offending and more serious offenses in adoles cence, as well as by greater persistence of violence from adolescence into adulthood (reviewed in Tolan &Gorman-Smith, 1998). The National Youth Survey shows that nearly 13 percent of male adolescents in the early-onset tra jectory engaged in violence for two or more years, compared to only 2.5 percent in the late-onset trajec tory (Tolan & Gorman-Smith, 1998). Between 20 and 45 percent of boys who are seri ous violent offenders by age 16 or 17 initiated their violence in childhood (D'Unger et al., 1998;Elliott et al., 1986;. A higher percentage of girls who were serious violent offenders by age 16 or 17 (45 to 69 percent) were violent in childhood (Elliott et al., 1986;. This means that most violent youths' begin their violent behavior during adolescence. However, the youths who commit most of the violent acts, who commit the most serious violent acts, and who continue their violent behavior beyond adolescence begin during childhood Moffitt, 1993;Tolan, 1987;Tolan & Gorman-Smith, 1998). The greater prevalence of late-onset youth vio lence refutes the myth that all serious violent offend ers can be identified in early childhood. In fact, the majority of young people who become violent show little or no evidence of childhood behavioral disor ders, high levels of aggression, or problem behav iors-all predictors of later violence. The implications of these findings for prevention are clear: Programs are needed to address both earlyand late-onset violence. Targeting prevention programs solely to younger children with problem behavior miss es over half of the children who will eventually become serious violent offenders, although universal prevention programs in childhood may be effective in preventing late-onset violence (see Chapters 4 and 6). # O n s e t a n d Pr e v a l e n c e o f S e r io u s V io l e n c e Much of what is known about the onset, prevalence, and other characteristics of serious violence during the adolescent years comes from four important longitu dinal surveys. The only nationally representative one is the National Youth Survey (NYS), an ongoing study of 1,725 youths age 11 to 17 in 1976, when the survey began (Elliott, 1994). These youths have been tracked by researchers for more than two decades and through nine waves, or points at which they were interviewed and/or their official records were sought to corrobo rate self-reported violence.2 The other three longitudinal studies cited here are city surveys sponsored by the U.S. Office of Juvenile Justice and Delinquency Prevention and the National Institutes of Health Thornberry et al., 1995).3 Beginning in 1988, three teams of researchers began to interview 4,500 youths age 7 to 15 in three cities-Denver, Pittsburgh, and Rochester (New York). These youths were monitored at different points from 1988 to 1994. Each sample disproportion ately represents youths at high risk of delinquency to ensure that it is large enough to draw valid conclu sions about delinquency and violence, but each also uses weighting procedures to yield locally representa tive estimates. The estimates presented here are based on weighted data. These four surveys define serious violence as aggravated assault, robbery, gang fights, or rape; an individual is labeled a serious violent offender if he or she reports committing any one or more of these offenses.4 Gang fights are included because follow-up information on these fights reveals that most of them involve injury serious enough to require medical attention (Elliott, 1994). Only the NYS reports the hazard rate for serious violence during the first two decades of life.5 The haz ard rate is the proportion of persons who initiate seri ous violence at a given age. Serious violence begins mostly between the ages of 12 and 20 (Figure 3-1). In fact, 85 percent of people who become involved in serious violence by age 27 report that their first act occurred between age 12 and 20. The onset of serious violence is negligible after age 23 and before age 10 (only 0.2 percent of arrests for serious violent crime in 1997 involved a child under age 10 [ Maguire & Pastore, 1999]). The peak age of onset is 16, when about 5 percent of male adolescents report their first act of serious vio lence. The age of onset peaks somewhat later for The Developmental D ynam ics of Youth Violence somewhat by race/ethnicity. It is lower for white males (5 percent) than for African American males (8 percent) (Elliott, 2000a). A similar finding is reported in the Pittsburgh Youth Survey .6 No comparable hazard rates have been pub lished for female youths, but other studies have found that they are generally lower.7 Age-specific prevalence-that is, the proportion of youths at any given age who report having com mitted at least one serious violent act-is also greatest in the second decade of life. The NYS and the three city surveys find that, broadly speaking, age-specific prevalence among male youths ranges from about 8 to 20 percent between the ages of 12 and 20 (Figure 3-2). Among females, it ranges from 1 to 18 percent (Table 3-1). There is some variability across surveys, however. In general, the NYS has lower rates than the three city surveys, reflecting the difference between a national sample and local samples drawn from urban 1986, whereas the three city surveys cover the years 1986 or 1988 to 1994, the peak years of the violence epidemic (see Chapter 2). Nevertheless, the estimates for age 17 across these longitudinal surveys are in the same range as those for high school seniors in the Monitoring the Future survey (see Chapter 2). Another key difference between the national and city surveys is the maturation effect, or the age at which serious violence begins to decline sharply dur ing the transition to adulthood. The NYS shows a decline in age-specific prevalence starting in the late teen years and a steep drop-off by age 20. In contrast, the city surveys, which were begun more recently, do not show a decline in the late teen years , and they have not yet published data on prevalence in early adulthood. Therefore, it is too soon to tell whether or at what age more recent groups of youths will mature out of violence. It is possible that young people are staying violent longer. Some important differences in age-specific preva lence by sex have emerged from the data (Table 3-1). Female adolescents have lower rates of serious vio lence throughout the second decade. For the NYS and Denver surveys, rates at age 12 are about twice as high for boys as for girls. Between age 12 and 15 in Rochester, the rates are fairly similar. For all studies, the rates for females at age 17 are about one-quarter the rates for males. In addition, the peak age of seri ous violent offending occurs a few years earlier among females, and their maturation out of serious violence is both earlier and steeper than males'. Age-specific prevalence also varies by race/eth nicity (Table 3-1). The NYS finds a significant racial gap between ages and 17, when rates for African © .BEST COPY .AVAILABLE American youths are 36 to 50 percent higher than those for white youths. The city surveys show an even wider gap between African American and white youths . Rates among Hispanic youths, reported only for Denver and Rochester, are similar to or lower than those reported by African American youths in these cities. The prevalence reported by Hispanic youths ranges from 6 to 12 per cent in Denver and about 10 to 20 percent in Rochester. Possible reasons for developmental differ ences by sex, race, and ethnicity are discussed in Chapter 4. None of these comparisons takes into account the effects of poverty, education, housing, or other environmental conditions. # C u m u l a t iv e P r e v a l e n c e Figure 3-2. Prevalence of serious violence among male youths, by age: four longitudinal surveys youths, the NYS shows it rising to about 40 percent and then leveling off beyond age 22. In the city sur veys, it reaches more than 40 percent of male and 32 percent of female youths by age 17. Not only is the rise in cumulative prevalence by age 17 steeper in the city surveys, the magnitude is substantially higher. These differences between a nationally representa tive sample and city samples are to be expected. The timing of the surveys may also explain some of the dif ferences. For example, 17-year-olds in the NYS were interviewed at some point between 1976 and 1982, whereas 17-year-olds in the city surveys were inter viewed at some point between 1988 and 1994, the era during which the self-reported prevalence of serious youth violence increased somewhat (see Chapter 2). There is a pronounced difference in cumulative prevalence by sex. Among I7-year-olds, the Denver Cumulative prevalence refers to the proportion of youths at any particular age who have ever commit ted a serious violent offense.8 As a measure of vio lence, it tends to equalize rather than magnify differ ences across populations because it counts youths only once, regardless of when or how often they engaged in violent acts. The most striking feature of the cumulative preva lence is its sheer magnitude: About 30 to 40 percent of male and 16 to 32 percent of female youths have com mitted a serious violent offense by age 17 (Figure 3-3). Although these rates are only slightly higher than those found in international studies, they repre sent a more serious set of offenses (Junger-Tas et al., 1994). The cumulative prevalence of youth violence is generally consistent across the four surveys. For male Cum ulative prevalence is also known as lifetim e prevalence or ever-prevalence to a given age. Confidence intervals are as follows: NYS African American males = .45 (± 9.8); NYS white males = .38 (± 3.9); RYDS males = .40 (± 3.7); DYS males = .43 (± 3.6); PYS males = .44 (± 2.6); RYDS females = .32 (± 6.1); DYS females = .16 (± 2.8). # 64 survey found a cumulative prevalence of 16 percent for female youths and 43 percent for male youths, whereas the Rochester survey showed 32 percent and 40 percent, respectively. Data on cumulative preva lence for females are not available in the Pittsburgh survey or the NYS.9 On the other hand, there are few differences in cumulative prevalence by race over the teen years, according to the NYS. By age 23, white males had a cumulative prevalence of 38 percent and African American males had a cumulative prevalence of 45 percent, a difference that is not statistically significant (Figure 3-3). # Ra t e s o f O f f e n d in g a n d V io l e n t C a r e e r s Violent youths commit a remarkably high number of crimes (Tolan & Gorman-Smith, 1998). An analysis of NYS data shows that these young people (both male and female) averaged 15.6 rapes, robberies, aggravated assaults, or some combination of these crimes over a 16-year period (1976 to 1992) (Elliott, 2000b). W hat's more, they averaged just over six serious violent offenses each during the years in which they were active (Elliott, 2000b).10 This mean annual rate of offending is similar to rates reported in the three city surveys for males (about 5 to 9 seri ous violent offenses per year) but much higher than the rates for females (2 to 4.5 per year). It is noteworthy that the mean annual rate of indi vidual offending appears to be essentially unchanged over the past two decades. This finding is corroborat ed by a study of trends among juvenile offenders processed by a county court system in Arizona (Snyder, 1998) and by an analysis of both National Crime Victimization Survey data and arrest records (Snyder & Sickmund, 2000). Finally, the Monitoring the Future survey (see Chapter 2) found no significant changes in individual offending rates for robbery or assault with injury between 1983 and 1993." Career length has been variously defined as the number of years of active offending, the maximum number of consecutive years, or the span between the first and last year during which a young person meets the criteria for a serious violent offender (Blumstein et al., 1986). There are relatively few estimates of vio lent career lengths. In the NYS, the mean career length (number of years of active violent offending) was 2.6 years. The most frequent career length was 1 year (36.8 percent of serious violent offenders). Three-quarters of these serious violent youths had careers lasting 3 years or less, and 15 percent had careers of 5 years or more (Elliott, 2000b). Based on 5 years of data, the Denver survey reports that 42 per cent of serious violent youths were active for only 1 year, 22 percent for 2 years, and 31 percent for 3 or more years . The typical violent career comprises either a single year of continuous offending or a longer period of inter mittent offending. Relatively few violent careers are characterized by years of uninterrupted violence. In Denver, well over half of the careers that lasted three or more years had at least one year with no violent offend ing; three-quarters of those that spanned a 5-year period had an intermittent pattern of offending . Evidence that most careers lasting more than 1 year were characterized by intermittent offending also surfaced in the NYS (Elliott et al., 1986). This intermit tent pattern makes it difficult to identify serious violent offenders with cross-sectional studies or with longitudi nal studies that have long periods between data collec tion . In sum, these studies suggest that in most cases vio lent careers are relatively short and are characterized by intermittent offending. During active periods, however, most careers are marked by a high rate of violent offending-up to 10 offenses per year (Elliott et al., 1986;. # D e v e l o p m e n t a l Pa t h w a y T o V io l e n c e Violent youths do not usually begin their careers with a serious violent offense. While the developmental path way varies, depending on what types of behavior are monitored, studies generally agree that a violent career begins with relatively minor forms of antisocial or delinquent behavior. These acts later increase in fre quency, seriousness, and variety, often progressing to serious violent behavior (Elliott, 1994;Moffitt, 1993;Tolan & Gorman-Smith, 1998). Several complex pathways to serious violence have been proposed (Loeber, 1996;Elliott, 1994). The NYS suggests that violence escalates over time. Most serious violent youths who engage in multiple types of violent behavior begin with aggravated assault, then add a robbery, and finally a rape. (Rape appears to be the end point of the progression, although there were not enough homicides in the NYS sample to include homicide in the analysis.) Robbery precedes rape in over 70 percent of cases in which both acts have been reported, and about 15 percent of serious violent offenders in the NYS reported having committed a rape (Elliott, 1994(Elliott, , 2000a. This sequence must be considered tentative because it is based on a single study. When serious violence becomes part of a youth's repertoire of antisocial behavior, it does not substitute for less serious forms of violence; rather, it adds to them and escalates the overall frequency of violent acts. Thus, serious violent youths are high-frequency offend ers who are involved in many less serious as well as serious offenses. These youths account for a major share of all criminal behavior, a pattern that is explored more fully in the next section. 11 Calculations were done by the senior scientific editor Elliott on the basis o f M onitoring the Future prevalence and frequency data on aggra vated assault and robbery contained in the 1991 and 1998 Sourcebooks o f Criminal Justice Statistics (Flanagan & Maguire, 1992;Maguire & Pastore, 1999). Individual offending rates are based on estimated incident rates. For this calculation, frequencies associated w ith categorical scores were as follows: not at all = 0; once = 1; tw ice = 2; 3 or 4 times = 3.5; and 5 or more times = 5. Individual offending rates for robbery in both 1983 and 1993 were 1.8. Rates for assault w ith injury were 2.3 and 2.6 (not significant). The mean individual offending rate can remain relatively constant despite increases in prevalence and incident rates noted in Chapter 2. ■ ; :• 6 6 47 # C h r o n ic V io l e n t O f f e n d e r s A minority of serious violent youths are responsible for the overwhelming majority of serious violent crime, a finding supported by numerous self-report and arrest studies (Tolan & Gorman-Smith, 1998;Tracy & Kempf-Leonard, 1996). In the city surveys, chronic offenders, though representing less than 20 percent of all serious violent offenders; accounted for 75 to 80 per cent of self-reported violent crimes . NYS data yield similar findings: Chronic offenders (youths with three or more violent offenses) accounted for 76 percent of all felony assaults and 89 percent of all robberies reported by offenders in 1980 . Chronic violent youths may also account for a dis proportionate share of all youth crime. The NYS reveals that in 1980 these serious violent offenders accounted for 79 percent of all felony theft, 66 percent of all illegal services (primarily drug selling), and 50 percent of all self-reported crime . In the Philadelphia Birth Cohort Study, 15 percent of youthful offenders accounted for 74 percent of all offi cial crime (Tracy & Kempf-Leonard, 1996). As noted earlier, youths whose violence begins before puberty are more likely to become chronic vio lent offenders . In the Rochester survey, 39 percent of children who initiated violent behavior by age 9 eventually became chronic offenders, 30 percent of those who initiated violence between the ages of 10 and 12 became chronic offenders, and 23 percent of those who initiated violence after age 13 became chronic violent offenders. In Denver, 62 per cent of those initiating violence by age 9 and 48 percent of those initiating violence between 10 and 12 became chronic violent offenders. Looking at this another way, 55 percent of all chronic violent offenders in Denver came from the early-onset trajectory . While the late-onset trajectory involves a sub stantially larger group of youths, fewer than half of all chronic offenders come from this group. Although most chronic violent offenders in the three city surveys (62 to 77 percent) eventually had contact with the police for some offense (though not necessarily a violent offense), one-quarter to one-third 0 were never arrested . Among those who were arrested for some offense, the first con tact came well after they had begun their violent careers. Interventions by the justice system occur too late to prevent such youths from escalating from less serious offenses to serious violence. Fortunately, it appears that at least half of chronic violent offenders can be identified as being at risk in childhood. Research has found a powerful relationship between membership in a gang and chronic involve ment in serious violence (see review in . As noted earlier (see Chapter 2), gang members, a relatively small proportion of the adolescent popula tion, commit the majority of serious youth violence (see Spergel, 1990, andThomberry, 1998, for reviews). # S u p e r p r e d a t o r s ? Between 1983 and 1993, adolescents were committing homicide at dramatically higher rates than in previous years (see Chapter 2). Did those youths represent a new breed of frequent, vicious, remorseless killers? Did the character of violent youths change during that time-and is it still different today (Bennett et al., 1996)? The answer seems to be no, for several reasons. First, the increase in homicides was similar across all age groups (see Chapter 2). This suggests that it resulted from a relatively sudden change in the envi ronment that affected all youths rather than from a gradual change in the socialization process, which would have led to progressively more vicious youths with each succeeding age group. Second, the increase in homicides was highly specific to certain youthsnamely, African American males (Zimring, 1998); moreover, it did not take place among females (see Chapter 2). Third, during the violence epidemic, there was a decline in family members killed by youths . Fourth, a new breed of superpredators should have resulted in more burglaries, auto thefts, and lar cenies, but no such increases occurred . It should also have resulted in more homicides involving knives and other weapons, but this did not occur (Zimring, 1998). Fifth, there was no evidence that individual rates of serious violent crime changed during the epidemic. More youths were involved, but the average number of offenses committed by each did not change. Finally, there may be anecdotal evidence that today's youths show less remorse for their violence, but this has not been substantiated by research. In sum, the epidemic of violence from 1983 to 1993 does not seem to have resulted from a basic change in the offending rates and viciousness of young offenders. Rather, it resulted primarily from a relative ly sudden change in the social environment-the intro duction of guns into violent exchanges among youths. The violence epidemic was, in essence, the result of a change in the presence and type of weapon used, which increased the lethality of violent incidents (Wintemute, 2000). # C o -O c c u r r in g Pr o b l e m B e h a v io r s Serious violence is accompanied by a wide range of other problem behaviors, including property crimes, substance use, gun ownership, dropping out of school, early sexual activity, and reckless driving. The co occurrence of these problem behaviors has been borne out by numerous national • and local studies (see reviews in Elliott, 1993;Huizinga & Jakob-Chen, 1998;Tolan & Gorman-Smith, 1998). The overlap is greatest between serious violence and other forms of crime. In the three city surveys, 82 to 92 percent of chronic violent youths were involved in property crimes, 71 to 82 percent in public disorder crimes, and 26 to 45 percent in selling drugs . Very similar rates were found in the NYS . Rates of co-occur rence were much higher among serious violent youths than among less violent youths. Substance use and abuse are a central feature of a violent lifestyle (Dembo et al., 1991;Elliott, 1994;Johnson et al., 1991). In the Denver survey, for example, about 58 percent of serious vio lent offenders were alcohol users and 34 percent were marijuana users. The prevalence and frequen cy of use were much lower in youths who were not seriously violent (Huizinga & Jakob-Chen, 1998). The NYS indicates that 94 percent of serious violent youths in 1980 were using alcohol, 85 percent were using marijuana, and 55 percent were using several illicit drugs. Over half (55 percent) were abusing drugs-that is, they reported health or relationship • problems, or both, associated with their drug use . Similar findings regarding the overlap of sub stance use and serious violence hold for the Rochester study (Thornberry et al., 1995). Moreover, chronic violent youths in Rochester and violent youths in the NYS had higher rates of dropping out of school, gun ownership and use, teenage sexual activity and par enthood, tobacco use, driving under the influence of alcohol or drugs, and gang membership than nonseri ous offenders or nonoffenders (Elliott, 1993;Thornberry et al., 1995). In sum, these studies show that a sizable propor tion of serious violent youths have co-occurring problem behaviors-and at rates significantly higher than those of their less violent counterparts. However, by no means all serious violent youths or even all chronic violent youths have co-occurring problems. Moreover, not all youths with problem behaviors are seriously violent. The fact that serious violence and problem behaviors tend to occur together does not necessarily mean that one causes the other (see Chapter 4) (Elliott, 1993;. # Violence and Mental Health The relationship between violence and mental health has been studied more intensively in adults than in young people. An earlier U.S. Surgeon General's report on mental health, after weighing the evidence, empha sized that the contribution of mental disorders to over all violence in the United States is very small. In fact, public fear is out of proportion to the actual risk of vio lence, which contributes to the stigmatizing of people with severe mental disorders (Link et al., 1999). Even though the risk of violence is low overall, it is greatest for adults with serious mental disorders who also abuse substances (Steadman et al., 1998;Swanson, 1994). Although violence is relatively widespread among adolescents, few studies have been undertaken on the co-occurrence of violence and mental health problems or disorders among U.S. adolescents. Such popula tion-based studies are important because they avoid the bias inherent in surveying hospitalized patients or convicted offenders. Both the NYS and the Denver survey examine the co-occurrence of serious violence and mental health problems. In the NYS, 28 percent of serious offenders age 11 to 17 were classified as having men tal health problems, compared to 13 to 14 percent of nonserious delinquent youths and 9 percent of nonof fenders. Youths were classified as having mental health problems on the basis of their responses to questions about emotional problems, social isolation, and feelings of loneliness . (The questions were not designed to arrive at a diagnosis of a mental disorder.) Serious violent offenders were more likely than either nonserious offenders or nonoffenders to report having these types of mental health problems. In the Denver study, serious violent youths were found to have higher rates of psychological problems, based on parents' responses to the Child Behavior Checklist (Achenbach & Edelbrock, 1983). These problems included externalizing and internalizing behavior, depression, uncommunicativeness, obses sive-compulsive behavior, hyperactivity, social with drawal, and aggressiveness. The rates at which most of these problems occurred in serious offenders were no different from the rates at which they occurred in nonviolent delinquent youths; however, rates in non delinquent youths were lower. Thus, delinquent youths in general were more likely to have psycho logical problems than nondelinquent youths (Huizinga & Jakob-Chen, 1998). Two problems were linked directly to violent behavior-externalizing symptoms and aggressive behavior. Approximately half of all serious violent offenders display these problems, although the link with externalizing behaviors is statistically significant only for boys. In addition, parents of violent offenders report seeking help for mental health problems more often than parents of nondelinquent or nonviolent delinquent youths. These parents did not go to mental health professionals or school counselors; rather, they sought the advice of friends, relatives, and spiritual leaders (ministers, rabbis, or priests). A similar finding is reported in the Pittsburgh study (Stouthamer-Loeber & Thomas, 1992). The Denver study found no differences between the self-esteem of serious violent offenders and non violent offenders or nonoffenders (Huizinga & Jakob-Chen, 1998). In general, there is little evidence that low self-esteem causes violence or that violent offend ers have low self-esteem. On the contrary, the evi dence is more consistent with the position that high self-esteem and threats to high esteem lead to violence (Baumeister et al., 1996). This has important implica tions for treatment and intervention programs and the use of esteem-building activities in these programs. A population-based study in New Zealand found that in young adulthood (age 21), serious violent offenders are more likely than nonoffenders to exhib it substance dependence disorders, schizophreniaspectrum disorders,12 or both (Arseneault et al., 2000). These New Zealand findings are consistent with the studies of U.S. adults showing that the greatest risk of violence stems from the combination of serious men tal disorder and substance dependence. However, about 10 percent of serious violent offenders13 in the New Zealand study exhibited schizophrenia-spectrum disorders without substance dependence or other psy chiatric conditions. The researchers concluded that while the contribution of serious mental illness to vio lence in young adults remains small, it may be slight ly higher than it is in adults. One possible reason for the difference is that the overwhelming majority of young adults with mental disorders in the New The Developm ental Dynam ics of Youth Violence Zealand study had not been treated or hospitalized within the previous year. Another recent community-based study found a link between personality disorders (a group of severe mental disorders) and violence. Adolescents with personality disorders,14 as determined by diagnostic interviews, were more likely than other adolescents to commit vio lent acts such as assault with injury and robbery (Johnson et al., 2000). For example, about 36 percent of adolescents with personality disorders versus 16 percent without the disorders committed a violent act against others15 during adolescence. The relationship between personality disorders and violence remained after taking many factors into account, including co-occurring depression, anxiety, and substance disorders. Only a few adolescents (13 percent) with personality disorders had received mental health services during the previous year (Johnston, personal communication, 2000). Thus, there is some evidence of a relationship between serious mental disorders and violence in ado lescents or young adults in the general population. Young people with serious mental disorders may be at risk of becoming violent if they also abuse substances or if they have not received treatment for their mental disorder. More research .is needed to understand the relationship between serious youth violence and men tal illness. # O f f e n d in g a n d V ic t im iz a t io n Violent offenders are frequently victims of violence Lauritsen et al., 1991;Sampson & Lauritsen, 1990. Data from the NYS reveal that victimization is highest among African Americans, males, and frequent offenders (Lauritsen et al., 1991). In addition, youths who report abusing drugs and alcohol, hanging out with delin quent peers, and participating in social activities with little adult supervision are at greater risk of being vic tims of violence (Gottfredson, 1984;Lauritsen et al., 1991;Sampson & Lauritsen, 1990). A delinquent lifestyle greatly increases the likelihood of being a vic tim and appears to account for some of the disparities observed in offending and victimization by race/ethnicity and sex. The Denver survey shows that 42 per cent of serious violent offenders are also victims of violence (Huizinga & Jakob-Chen, 1998), with higher rates among male offenders than female offenders. There are many reasons for the overlap between offending and victimization. Perhaps the most com mon is that the offender is injured by the intended tar get-either during the offense or later, in retaliation. Another reason is that offenders tend to live in more violent environments or their lifestyles take them into high-risk environments. The predictive relationship between victimization and offending, as well as the relationship with early child abuse, is discussed in Chapter 4. # T r a n s it io n t o A d u l t h o o d The transition from adolescence to adulthood features a fairly abrupt discontinuation of serious violence, at least according to the NYS. Rates of onset and agespecific prevalence show dramatic declines, and the cumulative prevalence levels off, as discussed above. Only about 20 percent of serious violent offenders continue their violent careers into their twenties (Elliott, 1994). -While there are no differences by sex in the apparent termination of violent offending, there are significant differences by race. Twice as many African American as white youths continue their violent behavior into the adult years (Elliott, 1994). Preliminary analyses suggest that cessation of offend ing is related to having a stable job and a stable inti mate relationship. By 1992, the most recent year for which data are available, many people monitored by the NYS had reached their late twenties and early thirties. There is virtually no published information about what patterns of violence may have continued into their adult years. The more recent city surveys have published age-spe cific and cumulative prevalence findings only up to age 19, but these studies are still being conducted. Some evidence from these surveys (Figure 3-2) sug gests that violent careers are lasting longer, but addi tional waves of data are needed to verify this trend. Understanding the demographics and dynamics of how patterns of serious violence change with the tran sition into adulthood is critical to designing programs that enhance the termination of violence. # C o n c l u s io n s The prevalence of serious violence by age 17 is star tling. About 30 to 40 percent of male and 15 to 30 per cent of female youths report having committed a seri ous violent offense at some point in their lives. This cumulative prevalence is similar among African American and white males, in contrast to other meas ures of violence, which show racial disparities (see Chapter 2). Two general onset trajectories emerge from longi tudinal studies of youth violence-an early-onset tra jectory that begins before puberty and a late-onset one that begins in adolescence. Youths in the early-onset trajectory generally commit more crimes, and more serious crimes, for a longer time. These young people exhibit a pattern of escalating violence through child hood and adolescence, and frequently into adulthood. Most youths who become violent, however, begin in adolescence. Their late-onset offending is usually limited to a short period, peaking at about age 16 and dropping off dramatically by age 20. They typically show few signs in childhood that they will become violent later on, laying to rest the myth that all violent adolescents can be identified in childhood. The rate of individual offending appears to have remained virtually unchanged, both during and since the years of the violence epidemic, which began in 1983 and peaked in 1993. This finding, together with evidence that the epidemic was specific to gun-related violence, challenges the myth that the early 1990s produced a generation of superpredators who were • more vicious and who committed dramatically more crimes than earlier generations of young people. At the same time, the finding of a stable individual offending rate indicates that the violence epidemic has not altogether subsided. Serious violence is frequently part of a lifestyle that includes drugs, guns, precocious sex, and other risky behaviors. Youths involved in serious violence typically commit many other types of crimes and exhibit other problem behaviors, presenting a serious challenge to intervention efforts. Successful interven tions must confront not only the violent behavior of these young people, but also their lifestyles, which are teeming with risk. Prevention and intervention programs must also take into account the different patterns of violence typical of the early-and late-onset trajectories, as well as the relatively constant rates of individual offending. Early childhood programs that target at-risk children and families are critical for preventing the onset of a chronic violent career, but programs must also be developed to combat late-onset violence. The impor tance of late-onset violence prevention is neither widely recognized nor well understood. Substantial numbers of serious violent offenders emerge seeming ly without warning. A comprehensive community pre vention strategy must address both onset patterns and ferret out their respective causes and risk factors. But what do we know about why young people become involved in violence? Why do some youths get caught up in violence while others do not? There is no simple answer to these questions, but scientists have identified a number of things that put children and adolescents at risk of violent behavior and some things that seem to protect them from the effects of risk. # In t r o d u c t io n t o R is k a n d Pr o t e c t iv e Fa c t o r s The concepts of risk and protection are integral to public health. A risk factor is anything that increases the probability that a person will suffer harm. A pro tective factor is something that decreases the potential harmful effect of a risk factor. In the context of this report, risk factors increase the probability that a young person will become violent, while protective factors buffer the young person against those risks. The public health approach to youth violence involves identifying risk and protective factors, determining how they work, making the public aware of these findings, and designing programs to prevent or stop the violence. Risk factors for violence are not static. Their pre dictive value changes depending on when they occur in a young person's development, in what social con text, and under what circumstances. Risk factors may be found in the individual, the environment, or the individual's ability to respond to the demands or requirements of the environment. Some factors come into play during childhood or even earlier, whereas others do not appear until adolescence. Some involve the family, others the neighborhood, the school, or the peer group. Some become less important as a person matures, while others persist throughout the life span. To complicate the picture even further, some factors may constitute risks during one stage of development but not another. Finally, the factors that predict the onset of violence are not necessarily the same as those that predict the continuation or cessation of violence. Violence prevention and intervention efforts hinge on identifying risk and protective factors and determining when in the course of development they emerge. To be effective, such efforts must be appro priate to a youth's stage of development. A program that is effective in childhood may be ineffective in ' adolescence and vice versa. Moreover, the risk and protective factors targeted by violence prevention pro grams may be different from those targeted by inter vention programs, which are designed to prevent the reoccurrence of violence. This report groups risk and protective factors into five domains: individual, family, peer group, school, and community, which includes both the neighborhood and the larger society (Box 4-1). Factors do not always fit neatly into these areas, however. Broken homes are classified as a family risk factor, but the presence of many such families in a community can contribute to social disorganiza tion, an important community-level risk factor (Bursik & Grasmick, 1993;. # Risk Factors Risk factors are not necessarily causes. Researchers identify risk factors for youth violence by tracking the development of children and adolescents over the first two decades of life and measuring how frequently par ticular personal characteristics and social conditions at a given age are linked to violence at later stages of the life course. Evidence for these characteristics and social conditions must go beyond simple empirical relationships, however. To be considered risk factors, they must have both a theoretical rationale and a demonstrated ability to predict violence-essential conditions for a causal relationship (Earls, 1994;Kraemer et al., 1997;. The reason risk factors are not considered causes is that, in most cases, scientists lack experimental evidence that changing a risk factor produces changes in the onset or rate of violence. As used in this report, risk factors are personal characteristics or environmental conditions that pre dict the onset, continuity, or escalation of violence. The question of causality has practical implica tions for prevention efforts. Prevention depends large-erJ c copy available ly on risk factors being true causes of violence. In practical terms, research has amassed enough strong, consistent evidence for the risk factors discussed in this report to provide a basis for prevention programs, even though a strict cause-and-effect relationship has been established for relatively few of them. Most of the risk factors identified do not appear to have a strong biological basis. Instead, it is theorized, they result from social learning or the combination of social learning and biological processes. This means that violent youths who have violent parents are far more likely to have modeled their behavior on their parents' behavior-to have learned violent behavior from them-than simply to have inherited it from them. Likewise, society's differing expectations of boys and girls-expecting boys to be more aggres sive, for example-can result in learned behaviors that increase or decrease the risk of violence. The bulk of the research that has been done on risk factors identifies and measures their predictive value separately, without taking into account the influence of other risk factors. More important than any individual factor, however, is the accumulation of risk factors. Risk factors usually exist in clusters, not in isolation. Children who are abused or neglected, for example, tend to be in poor families with single par ents living in disadvantaged neighborhoods beset with violence, drug use, and crime. Studies of multiple risk factors have found that they have independent, addi tive effects-that is, the more risk factors a child is exposed to, the greater the likelihood that he or she will become violent. One study, for example, has found that a 10-year-old exposed to 6 or more risk fac tors is 10 times as likely to be violent by age 18 as a 10-year-old exposed to only one factor (Herrenkohl et al" 2000). Researchers have theorized that risk factors also interact with each other, but to date they have found little evidence of interaction. What evidence does exist suggests that interactions between or among fac tors produce only small effects, but work in this area is continuing. To date, much more research has been done on risk factors than protective factors, but that picture, too, is changing. # O # ERIC , 77 # Developmental Progression to Violence Scientific theory and research take two different approaches to how youth violence develops-one that focuses on the onset of violent behavior and its frequency, patterns, and continuity over the life course and one that focuses on the emergence of risk factors at different stages of the life course. Chapter 3 describes two developmental trajectories for the onset of violent behavior-one in which vio lence begins in childhood (before puberty) and con tinues into adolescence, and one in which violence begins in adolescence. In contrast, this chapter considers the timing of risk factors. It identifies the individual characteristics, experiences, and environmental conditions in child hood or adolescence that predict involvement in vio lent behavior in late adolescence-that is, age 15 to 18, the peak years of offending. Research shows that different risk factors may emerge in these two devel opmental periods and that the same risk factors may have different effect sizes, or predictive power, in these periods. The timing of risk factors and the onset of vio lence are connected. Only risk factors that emerge in early childhood can logically account for violence that begins before puberty. However, these early risk factors may or may not be implicated in violence that begins in adolescence. In fact, studies show that many youths with late-onset violence did not encounter the childhood risk factors responsible for early-onset violence. For these youths, risk factors for violence emerged in adolescence Moffitt et al., 1996;Simons et al., 1994). # Limitations of Risk Factors Risk factors are powerful tools for identifying and locating populations and individuals with a high potential for becoming violent, and they provide valu able targets for programs aimed at preventing or reducing violence. But there are important limitations to our knowledge about and use of risk factors. The following cautions are worth bearing in mind: • No single risk factor or set of risk factors is power ful enough to predict with certainty that youths will become violent. Poor performance in school is a risk factor, for example, but by no means will all young people who perform poorly in school become violent. Similarly, many youths are exposed to mul tiple risks yet avoid becoming involved in violence (Garmezy, 1985;Rutter, 1985;Werner & Smith, 1982. • Because public health research is based on observa tions and statistical probabilities in large popula tions, risk factors can be used to predict violence in groups with particular characteristics or environ mental conditions but not in individuals. • Given these two limitations, assessments designed to target individual youths for intervention pro grams must be used with great care. Most individual youths identified by existing risk factors for vio lence, even youths facing accumulated risks, never become violent (Farrington, 1997;Lipsey & Derzon, 1998). • Some risk factors are not amenable to change and therefore are not good targets for intervention (Earls, 1994;Hawkins et al., 1998a). Being bom male is an example. • Of the risk factors that are amenable to change, some are not realistic targets of preventive efforts. Eliminating poverty is not a realistic short-term goal, for example, but programs that counter some of the effects of poverty are. (Eliminating or reduc ing poverty should be a high-priority long-term goal, however.) • Some situations and conditions that influence the likelihood of violence or the form it takes may not be identified by longitudinal studies as risk factors (predictors) for violence. Situational factors such as bullying, taunting, and demeaning interactions can serve as catalysts for unplanned violence. The social context can influence the seriousness or form of violence-for example, the presence of a gun or a gathering crowd of peers that makes a youth feel he (or she) needs to protect his (or her) reputation. These may not be primary causes of violence, yet they are contributing factors and are important to understanding how a violent exchange unfolds. Such influences, although important, may not be identified in this report because of the way risk fac tors are defined. • Many studies of risk factors, particularly earlier ones, drew their samples from white boys and young men. The limited focus of these studies calls into question their predictive power for girls and women and for other racial or ethnic groups. Differences among cultures and their socialization and expectations of girls and boys may modify the influences of some risk factors in these groups. Nonetheless, most of the risk factors identified in this report do apply broadly to all young people. All children go through the same basic stages of human development-and prevention of youth violence is based on understanding when and how risk factors come into play at various stages of development. Moreover, there is some evidence that most risk fac-79 tors are equally valid predictors of delinquency and violence regardless of sex, race, or ethnicity (Rosay et al., 2000;Williams et al., 1999). Sophisticated studies that identify how cultural differences affect the inter play of the individual and his or her surroundings will make possible more effective prevention efforts. # Protective Factors There is some disagreement about exactly what pro tective factors are. They have been viewed both as the absence of risk and as something conceptually distinct from risk (Guerra, 1998;lessor et al., 1995;Wasserman & Miller, 1998). The former view typically places risk and protective factors on the opposite ends of a continuum. For example, good par ent-child relations might be considered a protective factor because it is the opposite of poor parent-child relations, a known risk factor. But a simple linear rela tionship of this sort (where the risk of violence decreases as parent-child relations improve) blurs the distinction between risk and protection, making them essentially the same thing.1 The view that protection is conceptually distinct from risk (the view used in this report) defines protec tive factors as characteristics or conditions that inter act with risk factors to reduce their influence on vio lent behavior (Garmezy, 1985;Rutter, 1985;. For example, low family socio economic status is a risk factor for violence, and a warm, supportive relationship with a parent may be a protective factor. The warm relationship does not improve the child's economic status, but it does buffer the child from some of the adverse effects of poverty. Protective factors may or may not have a direct effect on violence (compare lessor et al., 1995 and. Interest in protective factors emerged from research in the field of developmental psychopatholo gy. Investigators observed that children with exposure to multiple risk factors often escaped their impact. This led to a search for the characteristics or condi tions that might confer resilience-that is, factors that moderate or buffer the effects of risk (Davis, 1999;Garmezy, 1985;Rutter, 1987;Werner, 1989). Protective factors offer an explanation for why chil dren and adolescents who face the same degree of risk may be affected differently. The concept of protective factors is familiar in public health. Wearing seat belts, for example, reduces the risk of serious injury or death in a car crash. Identifying and measuring the effects of protective factors is a new area of violence research, and infor mation about these factors is limited. Because they buffer the effect of risk factors, protective factors are an important tool in violence prevention. Like risk factors, proposed protective factors are grouped into individual, family, school, peer group, and community categories. They may differ at various stages of development, they may interact, and they may exert cumulative effects (Catalano et al., 1998;Furstenberg et al., 1999;Garmezy, 1985;lessor et al., 1995;Rutter, 1979;Sameroff et al., 1993;. Just as risk factors do not necessarily cause an individual child or young person to become violent, protective factors do not guarantee that an individual child or young person will not become vio lent. They reduce the probability that groups of young people facing a risk factor or factors will become involved in violence. # A Note on Sources This chapter draws heavily on four important studies: Lipsey & Derzon's meta-analysis of 34 longitudinal studies on risk factors for violence (1998); Hawkins et al.'s study of malleable risk and protective factors drawn from 30 longitudinal studies, including some not included in the Lipsey & Derzon meta-analysis (Hawkins et al., 1998c); Paik and Comstock's meta analysis of 217 studies of exposure to media violence and its effects on aggression and violence (1994); and the National Institute of Mental Health's Taking Stock report (Hann & Borek, in press), an extensive review of research on risk factors for aggression and other behavior problems. . Additional risk factors and classes of risk factors have been added from other sources. For example, there is adequate evidence to establish harsh, lax, or inconsistent discipline as a separate risk factor, although Lipsey and Derzon include it in the poor par ent-child relations class. Academic failure, family con flict, and belonging to a gang are additional examples of risk factors not included in any of the meta-analyses. The measure of effect size used in these tables is a bivariate correlation (r), or simple correlation between two variables. All estimates of effect size are statistically significant and are based on multiple stud ies, with those for risk classes typically involving more studies than those for separate risk factors. The studies reviewed in Lipsey and Derzon, Paik and Comstock, and Hawkins et al. are not cited here; how ever, other studies that were used to establish a risk factor or that are included in estimates of effect size are cited.3 There is a rich and extensive body of research on risks for antisocial behavior, externalizing behavior, conduct disorder, and aggression (Hann & Borek, in press). Each of these terms defines a pattern or set of behaviors that includes aggressive or violent behavior, but most of the behaviors included are either non physical, nonviolent acts or relatively minor forms of physical aggression. Risk factors for antisocial behav ior may be quite different from those that predict vio lent behavior (robbery, aggravated assault, rape, and homicide). Since antisocial behavior does not present the potential for serious injury or death that violence does, this report relies on studies that identify risk fac tors for serious offenses generally and violent behav ior specifically, bearing in mind that the vast majority of serious offenders report having been involved in violent offenses. # Summary Risk and protective factors can be found in every area of a child or adolescent's life, they exert different effects at different stages of development, and they gain strength in numbers. The public health approach to the problem of youth violence seeks to identify risk and protective factors, determine when in the life course they typically occur and how they operate, and enable researchers to design preventive programs to be put in place at just the right time to be most effective. This chapter describes what is known about indi vidual, family, school, peer group, and community risk and protective factors that exert their effects in child hood and adolescence. It describes the power of early risk factors, which come into play before puberty, and late risk factors, which exert their influence after puberty, to predict the likelihood of youth violence. # R is k Fa c t o r s in C h i l d h o o d The first decade of life encompasses a vast period of human development. Infants form attachments to par ents or other loving adults and begin to become aware of themselves as separate beings. As toddlers, they begin to talk, to assert themselves, to explore the world around them, and to extend their emotional and social bonds to people other than their parents. The start of school is a milestone in children's con tinuing social and intellectual development. Other chil dren become more important in their lives, though still not as important as family members. They begin to empathize with others and hone their sense of right and wrong. As they progress through elementary school, children gain valuable reasoning and problem-solving skills as well as social skills. Exposure to or involvement in violence can disrupt normal development of both children and adolescents, with profound effects on their mental, physical, and emo tional health.4 In addition, exposure to violence affects children and adolescents differently at different stages of development (Marans & Adelman, 1997). Young children exposed to violence may have nightmares or be afraid to go to sleep, fear being left alone, or regress to earlier behavior, such as baby talk or bed-wetting. They may exhibit excessive irritability or excitability. Violence in the family, especially, may inhibit young children's ability to form trusting rela tionships and develop independence. Elementary school children who live in violent neighborhoods may also experience sleep distur bances and be less likely to explore their environ ment. In addition, they can become frightened, anx ious, depressed, and aggressive. They may have trou ble concentrating in school. Because they understand that violence is intentional, they may worry about what they could have done to prevent or stop it (Osofsky, 1999). Violence also affects parents. Adults living in vio lent households or neighborhoods may not be able to keep their children safe or to protect them from harmful influences. Some parents living in unsafe neighbor hoods do not let their children play outside. While this solution may safeguard children temporarily, it can also impede healthy development. Parents in these situations understandably feel helpless and hopeless. Those who have been traumatized by violence themselves may, like their children, become anxious, withdrawn, or depressed. Under such circumstances, parents cannot respond spontaneously and joyously to their children, making it difficult for children to develop strong, secure attachments to their parents. Forming a bond with a lov ing, responsive parent or other adult caregiver is an essential factor in healthy development (Furstenberg et al., 1999;Osofsky, 1999;. Children and families exposed to or involved in violence may want to seek professional advice in addressing their mental, physical, and emotional health concerns. # Risk Factors by Domain A few risk factors for youth violence occur before birth. Others come into play as the child develops in response to his or her family and surroundings. Thus, most of the risk factors that exert an effect before puberty are found in the individual and family domains rather than in the larger world, a situation that changes dramatically in adolescence. Childhood risk factors are listed by domain in Box 4-1; effect sizes are listed in # Individual The most powerful early risk factors for violence at age 15 to 18 are involvement in general offenses and sub stance use before age 12. General offenses include seri ous, but not necessarily violent acts, such as burglary, grand theft, extortion, and conviction for a felony. Children engaging in such crimes often come to the attention of the police and juvenile justice system. Numerous studies have documented the overlap between serious nonviolent and violent offenses in ado lescence, so early involvement in serious offenses car ries a substantial risk for violence later. Experimentation with drugs, alcohol, tobacco, or some combination of these substances is not particu larly unusual by age 18, but use of these substances by children under the age of 12 is. Not only are these substances harmful to health, they are illegal. Thus, use of these substances signals antisocial attitudes and early involvement in a delinquent lifestyle that often comes to include violent behavior in adoles cence . Two moderate risk factors emerge in childhood, being male and aggression. Boys (and young men) are far more likely than girls to be violent (see Chapter 2), yet some researchers have suggested that sex is a risk marker rather than a risk factor (Earls, 1994;Hawkins et al., 1998a;Kraemer et al., 1997). A risk marker is a characteristic or condition that is associated with known risk factors but exerts no causal influence of its own (Earls, 1994;.5 For example, many more boys than girls are hyperactive, a risk factor with a small effect size, so some of the predictive power of being male may actually be the influence of hyperactivity. Moreover, boys have tradi tionally been exposed to more violence than girls, and socially approved male role models are more aggres sive, suggesting that social learning plays a role in this risk factor. However, research indicates that being male confers risk even after accounting for other known risk factors. This suggests that being male is a risk factor rather than a risk marker, perhaps with some biological or biological-environmental interac tion as the causal mechanism. Many studies have found aggression-character ized as aggressive and disruptive behavior, verbal aggression, and aggression toward objects-to be a moderate risk factor among boys, although there is some evidence that physical aggressiveness is actual ly responsible for most of the observed effect . Additional research is needed to sort out the unique influence of each of these types of aggression. The remaining individual risk factors have rela tively small effect sizes. Various psychological condi tions, such as hyperactivity, impulsiveness, daring, and short attention span, pose a small risk for violence. A consistent individual predictor is hyperactivity/low attention, the central components of attentiondeficit/hyperactivity disorder (ADHD), a cognitive disorder that may be genetically influenced in some way (Hawkins et al., 1998a). ADHD is characterized by restlessness, excessive activity, and difficulty pay ing attention, traits that may also contribute to low aca demic performance, a risk factor in school. Hyperactivity is often found in combination with phys ical aggression, another risk factor. Some researchers question the independent effect of hyperactivity on later violence, suggesting that the effect is actually physical aggression (and perhaps low academic per formance) that was not controlled for in earlier studies of hyperactivity . There is little agreement about the mechanism linking hyperac tivity to violence. The effects of children's exposure to television and film violence have been studied extensively in regard to aggression, but there is relatively little research regard ing the effects on more serious forms of violent behav ior (for an extended discussion, see Appendix 4-B). Experimental studies have found that exposure to media violence has a small average effect size (.13) on serious forms of violence ; the average effect size in cross-sectional survey studies was very small (.06). Two frequently cited longitudinal studies have examined the effects that exposure to tele vision violence in childhood produces on violent behavior during adolescence or early adulthood. One, in which participants reported having punched, beat en, or choked someone as young adults, found a signif icant predictive effect for women (.22) but no signifi cant effect for men (Huesmann et al., submitted). The other study, in which teenage males reported being involved in a knife fight, car theft, mugging, gang fight, or similar delinquent behavior, found a statistically sig nificant predictive effect in only one of nine tests . Exposure to violence appears to have a weak predictive effect on relatively immediate violence in experimental studies, but there is little con sistent evidence to date for a long-term predictive effect. Little research has been done on violence in other media-video games, music videos, and the Internet. A recent meta-analysis by Anderson and Bushman (in press) reports that video game violence has a small average effect size (.19) on physical aggression in experim ental and cross-sectional studies. Theoretically, the influence of these interactive media might well be greater than that of television and films, which present a passive form of exposure, but there are no studies to date of the effects of exposure to these types of media violence and violent behavior. This is a different use o f the term "risk marker" than that proposed by Kraemer et al. (1997). They use risk marker to refer to a risk factor or cause (such as sex or race) that cannot, in practical terms, be changed by an intervention. This report focuses on its causal role rather than its am enability to change. Problem behavior, another risk factor with a small effect size, refers to relatively minor problem behav iors such as stealing, truancy, disobedience, and tem per tantrums. While not serious in themselves, antiso cial behaviors may set the stage for more serious non violent or violent behavior later. The medical or physical risk factor includes a number of conditions that as a group are somewhat predictive of violence. Prenatal and early postnatal complications, a more specific set of medical condi tions, have been found to have inconsistent effects across a number of studies (Hawkins et al., 1998c). These complications encompass a broad group of genetic conditions or physical injuries to the brain and nervous system that interfere with normal develop ment, including low birth weight, oxygen deprivation, and exposure to toxins such as lead, alcohol, or drugs (Hawkins et al., 1998b). Low resting heart rate, a con dition that has been studied primarily in boys, is asso ciated with fearlessness or stimulation seeking, both characteristics that may predispose them to aggression and violence (Raine et al., 1997;Hawkins et al., 1998c), but there is not enough evidence to establish this condition as a risk factor for violence. Some stud ies have even questioned its effects on aggression (Van HuIIe et al., 2000;Wadsworth, 1976;Kindlon et al., 1995). There is also no evidence that internalizing disorders-nervousness and withdrawal, anxiety, and worrying-are related to later violence (Hawkins et al., 1998c). Low IQ, or low intelligence, includes learning problems and poor language ability. This risk factor has a small effect size and is often accompanied by other risk factors with small effect sizes, such as hyperactivity/Iow attention and poor performance in school. Antisocial beliefs and attitudes, including dishon esty, rule-breaking, hostility to police, and a general ly favorable attitude toward violence, usually consti tute a risk factor in adolescence, not childhood (Hawkins et al., 1998c). Only dishonesty in child hood is predictive of later violence or delinquency, and its effect is small. # O # Family There are no known strong risk factors for youth vio lence in the family domain, but low socioeconomic status/poverty and having antisocial parents are moderate factors. Socioeconomic status generally refers to par ents' education and occupation as well as their income. Poorly educated parents may be unable to help their children with schoolwork, for example, and children living in poor neighborhoods generally have less access to recreational and cultural opportunities. In addition, many poor families live in violent neighborhoods, and exposure to violence can adversely affect both parents and children, as described above. Limited social and economic resources contribute to parental stress, child abuse and neglect, damaged parent-child relations, and family breakup-all risk factors with small effects in childhood. Studies suggest that antisocial parents-that is, violent, criminal parents-represent an environmental rather than a genetic risk factor (Moffitt, 1987). In other words, children learn violent behavior by observ ing their parents rather than by inheriting a propensity for violence. In fact, attachment to parents, a possible protective factor, can have the opposite effect if the parents are violent (Hawkins et al., 1998c). Among the early risk factors with small effect sizes on youth violence is poor parent-child relations. One specific risk factor in this class-harsh, lax, or inconsistent discipline-is also somewhat predictive of later violence (Hawkins et al., 1998c). Children need reasonable, consistent discipline to establish the boundaries of acceptable and unacceptable behavior. Children who are treated harshly may view rough treatment as acceptable, those who are given no guid ance may engage in whatever behavior gets them what they want, and children who receive mixed signals are completely at sea regarding appropriate behavior. Other family conditions, such as high stress, large size, and marital discord, also exert a small effect on later violence. Another childhood predictor with a small effect size is broken homes, a category that includes divorced, separated, or never-married parents and a child's separation from parents before age 16. Separation from parents also operates as a distinct risk factor, again with a small effect size. Abusive parenting in general and neglect in par ticular are predictors of later violence, but they have very small effect sizes. Neglect operates as a distinct risk factor, possibly because neglected children are less likely to be supervised or taught appropriate behavior. This is not to imply that child abuse and neglect do not cause serious problems in adolescence: Indeed, they have large effects on mental health prob lems, substance abuse, and poor school performance (Belsky & Vondra, 1987;Cicchetti & Toth, 1995;Dembo et al., 1992;Silverman et al., 1996;Smith & Thornberry, 1995). This finding is discussed in more detail below, in the section on unexpected findings and effects. # School The only early risk factor in the school domain is poor attitude toward and performance in school, and its effects are small. Numerous individual and family factors may contribute to poor performance, making it a fairly broad measure. For example, a child who is physically aggressive and is rejected by peers or who has difficulty concentrating or sitting still in class may understandably have difficulty performing aca demic tasks. Children who have been exposed to vio lence, as noted earlier, may also have trouble concen trating in school. # Peer Group Young children do not socialize extensively with other children and are not strongly influenced by peers. Peers become more important as children progress through elementary school, although school-age chil dren still look primarily to parents for cues on how to behave. Nonetheless, weak social ties to conventional peers and associating with antisocial peers both exert small effects in childhood. Children with weak social ties are those who attend few social activities and have low popularity with conventional peers. School-age children often reject physically aggressive children because of their inappropriate behavior (Hann & Borek, in press;. The combination of rejection and aggressiveness exacerbates behavior problems, mak ing it more difficult for aggressive children to form positive relationships with other children. Indeed, recent research indicates that children who are both aggressive and rejected show poorer adjustment in elementary school than children who are aggressive, rejected, or neither (Hann & Borek, in press). Being drawn to antisocial peers may introduce or reinforce antisocial attitudes and behavior in children. Indeed, aggressive children tend to seek each other out (Hann & Borek, in press). # Community Community risk factors, such as living in socially dis organized neighborhoods or neighborhoods with high rates of crime, violence, and drugs, are not powerful individual-level predictors in childhood because these external influences have less direct impact on children than on adolescents. They may well exert indirect influ ences through poor parenting practices, lack of family resources, and parent criminality or antisocial behavior. # Summary The most powerful early predictors of violence at age 15 to 18 are involvement in general offenses (serious, but not necessarily violent, criminal acts) and sub stance use. Moderate factors are being male, aggres siveness, low family socioeconomic status/poverty, and antisocial parents. # R is k Fa c t o r s in A d o l e s c e n c e Violence increases dramatically in the second decade of life, peaking during late adolescence at 12 to 20 percent of all young people and dropping off again sharply by the early twenties. Some of these youths followed the childhood-onset trajectory, becoming violent before puberty and escalating their rate of offending during adolescence. But over half of all vio lent youths begin their violent behavior in mid-to late adolescence. These youths gave little indication of problem behavior in childhood and did not have poor relations with their parents. There are numerous theories about why violence begins in adolescence, but a few themes run through most of them Pepler & Slaby, 1994). Developmentally, puberty is accompanied by major physical and emotional changes that alter a young person's relationships and patterns of interac tion with others. The transition into adolescence begins the move toward independence from parents and the need to establish one's own values, personal and sexual identity, and the skills and competencies needed to compete in adult society. Independence requires young people to renegotiate family rules and degree of supervision by parents, a process that can generate conflict and withdrawal from parents. At the same time, social networks expand, and relationships with peers and adults in new social contexts equal or exceed in importance the relationships with parents. The criteria for success and acceptance among peers and adults change. Adapting to all of these changes in relationships, social contexts, status, and performance criteria can generate great stress, feelings of rejection, and anger at perceived or real failure. Young people may be attracted to violent behavior as a way of asserting their independence of the adult world and its rules, as a way of gaining the attention and respect of peers, as a way of compensating for limited personal compe tencies, or as a response to restricted opportunities for success at school or in the community. Good rela tionships with parents during childhood will help in a successful transition to adolescence, but they do not guarantee it. Adolescents exposed to violence at home may experience some of the same emotions and difficulties as younger school-age children-for example, fear, guilt, anxiety, depression, and trouble concentrating in school. In addition, adolescents may feel more vulner able to violence from peers at school or gangs in their neighborhood and hopeless about their lives and their odds of surviving to adulthood. These young people may not experience the growing feelings of compe tence that are important at their stage of development. Ultimately, their exposure to violence may lead them to become violent themselves. Studies have shown that O adolescents exposed to violence are more likely to engage in violent acts, often as preemptive strikes in the face of a perceived threat (Fagan & Wilkinson, 1998;Singer et al., 1994Singer et al., , 1995. # Risk Factors by Domain Not surprisingly, different risk factors for violence assume importance in adolescence. Family factors lose predictive value relative to peer-oriented risk fac tors such as weak social ties to conventional peers, antisocial or delinquent friends, and membership in a gang (Table 4-1). Even involvement in general offenses, which had the largest effect size in child hood, has only a moderate effect size in adolescence. # Individual In early adolescence, involvement in general offens es-that is, illegal but not necessarily violent acts, including felonies-becomes a moderate risk factor for violence between the ages of 15 and 18. Its pre dictive power lessens from childhood, largely because teenagers are somewhat more likely than children to engage in illegal behavior. . Psychological conditions, notably , restlessness, difficulty concentrating, and risk taking,, have small effect sizes in adolescence. Restlessness and difficul ty .concentrating can affect performance in school, a risk factor whose importance increases slightly in ado lescence. Risk taking gains predictive power in early adolescence, particularly in combination with other factors. A reckless youth who sees violence as an acceptable means of expression, for example, is more likely to engage in violent behavior. Aggressiveness exerts a small effect on later vio lence among adolescent males, as does simply being male. While aggressiveness is unusual in children between the ages of about 6 and 10, it is not terribly unusual in adolescence. Similarly, physical violence and crimes against persons in early adolescence have a small effect on the likelihood of violence at ages 15 to 18. Antisocial attitudes and beliefs, including hostility toward police and a positive attitude toward violence, are more important predictors among adolescent boys than they are among children, but their effect sizes remain small. Antisocial behavior and low IQ continue to have small effect sizes in adolescence. Substance use, which was a strong predictor of later violence for children, poses a small risk of later violence for adolescents. The question as to whether drug use causes young people to become violent is complex and has been widely studied (see Miczek et al., 1994 for a review), but there is little compelling pharmacological evidence linking illicit drug use and violence. In one large study, youths reported that over 80 percent of the violent incidents they initiated had not been preceded by drug use, including alcohol use . Thus, the risk may lie more in the characteristics of the social settings in which drug use and violence are likely to occur than in any effect of drugs on behavior (Parker & Auerhahn, 1998;. The majority of violent adolescent offenders use alcohol and illicit drugs (see Chapter 3). Illicit drug use tends to begin after the onset of violence and to be associated with more frequent violent behavior and a longer criminal career . This find ing suggests that drug use may contribute to continued violence rather than to the onset of violence, but it is far from conclusive. Evidence shows that some vio lent behavior stems from robberies or other attempts to.get money to support a drug habit but also that this link is relatively rare. If any substance can be said to cause youth violence, that substance is alcohol (APA, 1993;Parker & Auerhahn, 1998); however, this causal link is inconclusive because adolescent drinking is dependent to a large degree on the situation and social context in which it takes place (for reviews, see Parker & Auerhahn, 1998;Pemanen, 1991;Roizen, 1993). # Family Parents' direct influence on behavior is largely eclipsed by peer influence during adolescence. Not surprisingly, therefore, most family risk factors dimin ish in importance, including the influence of antisocial parents and low socioeconomic status, the most pow erful early risk factors. There are no large or even mod erate risk factors in the family domain in adolescence. Poor parent-child relations continue to have a small effect size, but for adolescents this category includes inadequate supervision and monitoring of young people's activities and low parental involve ment, in addition to inappropriate discipline (Elliott et al., 1985;Hawkins et al., 1998a;Roitberg & Menard, 1995). Broken homes and parental abuse also exert small effects. Other adverse family conditions present a risk factor; for example, some studies have found that family conflict is a risk factor for violence among adolescent males. Although parents can and do influence their ado lescents' behavior, they do so largely indirectly. The kind of peers chosen by young people, for example, is related to the relationship they have with their parents Hill et al., 1999;Simons et al., 1994). # School There are no large or moderate risk factors for vio lence in the school domain, but poor attitude toward or performance in school-particularly if it leads to academic failure-is a slightly larger risk factor in early adolescence than in childhood. Research on school violence indicates that a cul ture of violence has arisen in some schools, adversely affecting not just students but teachers and adminis trators as well (Gottfredson et al., in press;Lorion, 1998). Students exposed to violence at school may react by staying home to avoid the threat or by taking weapons to school in order to defend themselves . For their part, teachers may bum out after years of dealing with discipline problems and threats of violence. Schools located in socially disorganized neighbor hoods are more likely to have a high rate of violence than schools in other neighborhoods (Laub & Lauritsen, 1998). At the same time, however, researchers emphasize that most of the violence to which young people are exposed takes place in their home neighborhood or the neighborhood surrounding the school, not in the school itself (Laub & Lauritsen, 1998). Individual schools, like individual students, do not necessarily reflect the characteristics of the sur rounding neighborhood. A stable, well-administered school in a violent neighborhood may function as a safe haven for students. Some gang activity takes place in schools, but school gangs are generally younger and less violent than street gangs, which form in neighborhoods (Laub & Lauritsen, 1998). Gangs in schools increased dra matically (by 87 percent) between 1989 and 1995 but have recently declined (see Chapter 3). The chances of becoming a victim of violence are more than two and one-half times as great in schools where gangs are reported, and these schools are disproportionately located in disadvantaged, disorganized neighborhoods (Met Life, 1993;. Peer groups complicate the picture further. They operate both in neighborhoods and in schools, but the concentration of young people in schools may intensi fy the influence of these groups. One large study of adolescent males found that some schools have domi nant peer groups that value academic achievement and disapprove of violence, while others have groups that approve of the use of violence (Felson et al., 1994). This study found that the risk of becoming involved in violence varied depending on the dominant peer cul ture in their school, regardless of their own views about the use of violence. # Peer Group Peer groups are all-im portant in adolescence. Adolescents who have weak social ties-that is, who are not involved in conventional social activities and are unpopular at school-are at high risk of becoming violent, as are adolescents with antisocial, delinquent peers. These two types of peer relationships often go together, since adolescents who are rejected by or unpopular with conventional peers may find accept ance only in antisocial or delinquent peer groups. Social isolation-having neither conventional nor antisocial friends-is not a risk factor for violence, however (Cairns & Cairns, 1991;Fergusson & Lynskey, 1996;. A third risk factor with a large effect size on violence is belonging to a gang. Gang mem bership increases the risk of violence above and O beyond the risk posed by having delinquent peers (Thornberry, 1998). These three peer group factors appear to have independent effects, they sometimes cluster together, and they are all powerful late predic tors of violence in adolescence. Researchers who have studied what causes young people to join gangs have found that the risk factors for gang membership are virtually the same as those for violence generally (Hill et al., 1999). The notion that gangs act as surrogate families for children who do not have close ties to their own fam ilies is not borne out by recent data (Hill et al., 1999), but gangs do strengthen young people's sense of belonging, their independence from parents, and their self-esteem. Estimates from law enforcement agencies indicate that gang members are overwhelm ingly male and the great majority (almost 80 percent) are African American or Hispanic . But surveys in which young peo ple identify themselves as gang members suggest that there are substantially larger proportions of white and female gang members. In a survey of near ly 6,000 8th graders in 1995, 25 percent of white stu dents and 38 percent of female students reported they were gang members (Esbensen & Osgood, 1997). Lacking comparisons within ethnic groups, it is difficult to tell whether ethnicity per se is a risk factor in gang membership. # Community Increasing involvement in the community is a healthy part of adolescent development, unless the communi ty itself poses a threat to health and safety. Social dis organization and the presence of crime and drugs in the neighborhood pose a small risk of violence when measured on an individual level, as they are in Table 4-1. As noted in the table, however, both of these risk factors have a substantially greater effect on the neighborhood level, where they measure the average rate of violent offending by youths living in the neigh borhood or community. Socially disorganized communities are character ized in part by economic and social flux, high turnover of residents, and a large proportion of disrupted or sin-gle-parent families, all of which lessen the likelihood that adults will be involved in informal networks of social control. As a result, there is generally little adult knowledge or supervision of the activities of teenagers and a high rate of crime. Moreover, in areas experienc ing economic decline, there are likely to be few neigh borhood businesses. In such an environment, it is hard for young people to avoid being drawn into violence. Not only are they on their own after school, they are exposed to violent adults and youth gangs, they have few part-time job opportunities, and their neighborhood is not likely to offer many after-school activities such as sports or youth groups (Bursik & Grasmick, 1993;Sampson et al., 1987). Social disorganization is also a risk factor for vio lence in rural areas. One study of rural communities found that poverty plays a less important role in pre dicting violence than residential instability, broken homes, and other indicators of social disorganization (Osgood & Chambers, 2000). In fact, very poor areas were not characterized by high residential instability or a large proportion of broken homes. In cities, how ever, the combination of poverty with instability and family disruption is predictive of violence (Bursik & Grasmick, 1993;. Adolescents who are exposed to violence in their neighborhood feel vulnerable and unable to control their lives. These feelings can lead to helplessness and hopelessness. Such young people may turn to violence as a way of asserting control over their surroundings. They may arm themselves or even join a gang for pro tection. Studies have shown that adolescents exposed to violence are more likely to engage in violent acts, often as preemptive strikes in the face of a perceived threat (Singer et al., 1994(Singer et al., , 1995. Neighborhood adults who are involved in crime pose a risk because young people may emulate them. Easily available drugs add to the risk of violence. As noted earlier, drug use is associated with both a higher rate of offending and a longer criminal career . More important, ready availability of drugs indicates that considerable drug trafficking is taking place in the neighborhood-and drug trafficking is dan gerous for buyer and seller alike. # Summary Violence peaks during the second decade of life. The youths who first became violent in childhood escalate their violence in adolescence, and a larger group of young people embarks on violence in adolescence. For some young people, violence represents a way of gain ing the respect of peers, enhancing their sense of self worth, or declaring their independence from adults. Violence drops off as adolescents enter adulthood and assume adult roles. Parents' direct influence on behavior is largely sup planted in adolescence by peer influences. Thus the most powerful peer predictors of violence in adoles cence are weak social ties to conventional peers, ties to antisocial, delinquent peers, and belonging to a gang. # Unexpected Findings and Effects This chapter does not identify a number of characteris tics and conditions frequently thought of as risk factors. Furthermore, some of the risk factors that have been identified may exhibit smaller effect sizes than expect ed. There are two reasons for this. First, this report relies on longitudinal studies, which identify risk fac tors and their effect sizes on the basis of their ability to predict future behavior. Much of this research involves identifying risks for aggression, externalizing behavior, or antisocial behavior-not risks for violence. While there is considerable overlap between the risk factors for aggression and those for violence, there are some important differences, particularly with respect to effect sizes (Hann & Borek, in press). Television violence, for example, has a very large effect on aggressive behavior but only a small effect on violence. Second, some stud ies that have been widely cited in the media involve cross-sectional and retrospective research designs, which are inappropriate for identifying factors that pre dict future violence. Conduct disorder has been linked to youth vio lence in numerous studies, but the cluster of symp toms used to determine this disorder includes physi cal aggressiveness, nonphysical aggressiveness, and antisocial attitudes and beliefs. For purposes of pre dicting violence, the critical question is: What com ponents of this disorder actually confer risk? There is some evidence that physical aggression accounts for most of the predictive power of conduct disorder and has a moderate to small effect size as a predictor of violence. Antisocial attitudes and beliefs also predict violence, but with an even smaller effect size. The three com ponents of conduct disorder generally cluster togeth er, which accounts for their having been combined into a single risk factor in earlier studies. Other childhood disorders such as attention-deficit/hyperactivity disorder, depressive and anxiety disorders, and their symptoms do not cause violent behavior, but their presence often signals serious behavioral and emotional problems that negatively affect fami ly, social, and academic functioning, domains of risk for violent behavior. Race has long been considered a risk factor for the onset of violence, and it is included as a risk fac tor in most studies using simple bivariate predictors of violence. The question is whether race predicts violence once other known risk factors are taken into account. Studies that have accounted for the effects of other known risk factors have typically found no significant effect of race on youth violence Roitberg & Menard, 1995). Thus, race appears to be a risk marker rather than a risk factor. Race is a proxy for other known risk factors-living in poor, single-parent families, doing poorly at school, and being exposed to neigh borhood disadvantage, gangs, violence, and crime. The evidence suggests that the link between race and violence is based largely on social and political dis tinctions rather than biological differences. Ethnicity has also been proposed as a risk factor, but it has not been studied extensively enough to include here. Young people from ethnic minorities may be subject to prejudice and thus to limited opportunity, and they may face unique stresses when their family culture conflicts with the dominant U.S. culture. At the same time, their ethnic culture may offer them strong support and guidance and thus function as a protective factor (APA, 1993). Child abuse is widely considered to be a powerful risk factor for youth violence. This belief is based on a number of early studies that suffered from serious methodological problems (see Dodge et al., 1990;Garbarino & Plantz, 1986;Howing et al., 1990;and Widom, 1989 for reviews). In more sophisticated, con trolled longitudinal studies, the effects are much small er (see Table 4-1), a finding that holds for both self report and official record studies. In addition, studies reporting on child abuse as a predictor of nonviolent delinquent behavior or less serious offenses find larger effect sizes than those cited here for violence or serious delinquency (Bolton et al., 1977;Widom, 1989Widom, ,1991Zingraff et al., 1993Zingraff et al., , 1994. Neither sexual abuse nor physical abuse is a significant predictor of youth violence when considered alone (Hawkins et al., 1998c). Sexual abuse has been linked to criminal behavior in adulthood (Widom & Ames, 1994), but not to violence in adolescence. Although the effect size of child abuse or neglect is small when a correlation measure is used (as in Table 4-1), the relative risk of violence among abused or neglected children can be substantial. Knowing that a child was abused does not help much in predicting future violence, however, since the vast majority of abused children do not become violent. For example, one longitudinal study showed that 5 percent of abused children were arrested for a violent crime by age 18, compared to 3 percent of nonabused children (Widom, 1991). The relative risk of arrest for violence is nearly twice as great in the abused group as in the nonabused group, yet the correlation for this relation ship is .07, a small effect size.6 In other words, even though the probability of later violence is substantial ly higher among abused than nonabused youths in this study, the correlation is small because the majority of all youths (95 percent of abused and 97 percent of nonabused youths) did not become violent. When the proportion of youths who become vio lent is greater, the relative risks appear to be lower. Thus, when subjects in the 1991 Widom study were tracked to age 30, the relative risk of violence dropped to 1.3 (Widom, 2000). In the one longitudi nal self-report study to date, which had relatively high proportions of abused children reporting vio lence, the relative risk of violence was 1.2 (Smith & Thornberry, 1995). In both of these cases, the corre lation was less than .10. Heredity does not seem to play a strong role in vio lence (see Cary, 1994 for a review). While there is some evidence supporting a genetic effect, the proposed mechanisms are very complex and nonspecific (Turbin, 2000). Neurotransmitters such as dopamine, serotonin, and GABA may play a role in aggression, but so far their mechanisms of action are unclear and there is insufficient evidence to consider them predictors of violence. In general, there are no known neurobiologi cal patterns that are precise and specific enough to be considered reliable risk factors for violent behavior . Drug trafficking in early adolescence predicts later violence (Hawkins et al., 1998c;Herrenkohl et al., 2000;Menard et al., in press;. This risk factor is not included here because only one study presents corre lations (or the data necessary to calculate them); there fore, average effect size could not be estimated. In the Menard et al. study, the correlation between selling marijuana and violence in adolescence was .33; for selling hard drugs, it was .27. In the Hawkins et al. study, the odds ratio for selling drugs at age 14 and violence at age 18 was 3.34; it was 4.55 for selling at age 16 and violence at age 18. Drug selling'thus appears to have at least a moderate effect size. # Pr o p o s e d Protective Factors in C h il d h o o d a n d A do lescence Research on resilience and the public health approach to the problem of youth violence have brought a new awareness of, and research on, pro tective factors-those aspects of the individual and his or her environment that buffer or moderate the effect of risk. Identifying and understanding how protective factors operate is potentially as important to violence prevention and intervention efforts as research on risk factors. To date, the evidence regarding protective factors against violence has not met the standards established for risk factors. Therefore, this report does not refer to protective factors, only to proposed protective factors (Table 4-2). There are several reasons for this: Not all studies define protective factors as buffering the effects of risk; most studies have looked for an effect on antisocial behavior in general, not on violence specifically; and those that have found buffering effects on violence have not been adequate ly replicated. This does not mean that protective fac tors do not exist, just that more research is needed to identify them.7 Most studies of protective factors do not specify when in the course of development these factors exert their buffering effects or how they change over the life course. Further study is needed to clarify these points; therefore, Table 4-2 does not show age of onset for the proposed protective factors listed. # A Note on Sources The authors of a 1995 longitudinal study on protective factors and their buffering effects on the risk of prob lem behavior in adolescence (lessor et al., 1995) recently reexamined their data to see whether they could find any buffering effect specifically on vio lence. They did find a buffering effect, but their results must be considered preliminary until they are replicat ed by others. Nonetheless, these findings are encour aging, since they indicate that several of the factors identified as protective against problem behavior also provided a buffering effect against violence. By implication, other studies that have demonstrated buffering effects on the risk of antisocial behavior or general delinquency (for example, Fergusson & Lynskey, 1996) may also contain evidence of potential protective factors against violence. The discussion of proposed protective factors in this report rests on the 7 There is a fairly extensive body o f research on protective factors in the field o f psychopathology (Carmezy, 1985;Rae-Crant et al., 1989;Rolf et al., 1993;Rutter, 1979Rutter, , 1985Rutter et al., 1979;Stattin et al., 1997;W erner andSmith, 1982, 1992). There are also a number o f studies focusing on delinquency that purport to identify protective factors (Brewer et al., 1995 reanalysis of the 1995 study data (Turbin, 2000), as well as on results from other studies, bearing in mind the caveats noted above. The 1995 lessor study grouped possible protective factors together and found that students who scored high on this index of protection were buffered from the effects of risk, compared to students who scored low on the index. The index was composed of seven psy chosocial protective factors: attitudinal intolerance of deviance, positive orientation to health, religiosity,, positive relations with adults, perceived consequences for misbehavior, friends as models for conventional behaviors, and high involvement in conventional activ ities. In an analysis of specific factors, however, only two-an intolerant attitude toward deviance and com mitment to school-had significant protective effects. The new findings show that the same two factors appear to exert a significant, though small, buffering effect on risk factors for violence. # Proposed Protective Factors by Domain One of the proposed protective factors shown to have a buffering effect on the risk of violence is an individ ual characteristic, and the other falls into the domain BEST COPY AVAILABLE of school; both are classed as having a small effect. No other factors in the individual, family, school, or peer group domains have been shown to exert signifi cant buffering effects on risk factors for violence, although they have been shown to moderate the risk of antisocial behavior or delinquency. No protective fac tors have been proposed yet in the community domain. # Individual An intolerant attitude toward deviance, including vio lent behavior, is the strongest proposed protective fac tor. It reflects a commitment to traditional values and norms as well as disapproval of activities that violate these norms. Young people whose attitudes are anti thetical to violence are unlikely to become involved in activities that could lead to violence or to associate with peers who are delinquent or violent. The four remaining individual factors have not yet been shown to moderate violence, although they may buffer risks for antisocial behavior or general delin quency. High IQ has been cited as a possible protec tive factor (Fergusson & Lynskey, 1996;Garmezy, 1985;Rutter, 1985;Werner & Smith, 1982). Children with above-average IQs may exhibit qualities, such as curiosity and creativity, that help them make the most of early educational, artistic, and cultural experiences. Above-average IQ can also help a child excel in school. High IQ may increase an adolescent's chances of benefiting from educational, creative, and cultural opportunities. For youths facing multiple risk factors, exposure to the wider world may open a window on alternative values and lifestyles. Being bom female has also been cited (Garmezy, 1985;Rutter, 1985;Wemer & Smith, 1982), but it is the opposite of being bom male, a risk factor, and as yet there is no evidence of a buffering effect. Being a girl entails less exposure to violence, less impulsive ness and daring, and being expected to behave less aggressively than boys. Some studies have proposed positive social ori entation as a protective factor (Garmezy, 1985;lessor et al., 1998;Rutter, 1985;Werner & Smith, 1982). Like commitment to school, a positive social orientation indicates that a young person has adopt ed traditional values and norms, a slightly different emphasis than intolerance of deviance. This pro posed factor appears to be the opposite of antisocial attitudes and beliefs, a late-onset risk factor that has a small effect size. Perceived sanctions for transgressions, a protec tive factor in the earlier lessor study (1995), refers to perceived peer disapproval of deviant behavior. The reanalysis of those original data reveals that this pro posed factor has no significant protective effect on risk of violence or problem behavior. # Family There is no doubt that an essential aspect of healthy child development is forming a secure attachment in infancy to a parent or other adult who senses and responds to a baby's needs (Bell & Fink, 2000). Likewise, researchers agree that having a loving adult who is interested in and supportive of a child or young person's ideas and activities helps that child or ado lescent develop the confidence and competence need ed to progress from one stage of development to the next. Good relations with an adult who supports con ventional behavior and disapproves of delinquent O behavior can provide invaluable guidance for young people. The question is whether these relationships moderate the effects of exposure to risk and thus fit the definition of a protective factor. A warm, supportive relationship with parents or other adults has been shown to protect against antiso cial behavior, but studies so far have not found a sig nificant buffering effect on the risk of violence (Hawkins et al., 1998c;Klein & Forehand, 2000;Rutter, 1979;Turbin, 2000;Wemer & Smith, 1992). It is uncertain whether family protective factors, like family risk factors, become less influential as young people progress through adolescence. Parental support and encouragement remain important, but even parents who have had a good relationship with thenchildren before puberty may affect their adolescents' behavior only indirectly-for example, through choice of friends . This indirect influence is not inconsequential, however; associating with peers who disapprove of violence may inhibit later violence in young people (Hawkins et al., 1998c), and parents' positive evaluation of peers has been found to reduce the risk of delinquency . Several studies have pointed to monitoring or supervision of activities as a protective factor against delinquency and antisocial behavior, but this is essen tially the opposite of failure to monitor, an adolescentonset risk factor with a small effect size. To date, no evidence of moderating effects on the risk of violence has been presented (Baldwin et al., 1990;Klein & Forehand, 2000;. # School Commitment to school is the second proposed protec tive factor that has been found to buffer the risk of youth violence. Young people who are committed to school have embraced the goals and values of an influential social institution. Such young people are unlikely to engage in violence, both because it is incompatible with their orientation and because it would jeopardize their achievement in school and their standing with adults (lessor et al., 1995;Turbin, 2000). This proposed factor is included because it appears to buffer the risk of violence, not because it is 93 the opposite of poor attitude toward or performance in school, a risk factor with small effect sizes in both childhood and adolescence. School can give adolescents who face multiple risk factors a place in which to excel socially and academi cally. Achievement in school and the approval of teach ers provide the recognition so important to adolescent development-recognition some adolescents do not receive from other sources. Encouragement from teachers can give young people the confidence to seek continued educational or job skills training. In addition, schools with peer groups that value academic achieve ment may lower students' risk of becoming involved in violence (Felson et al., 1994). Unfortunately, schools with a culture of violence may be unable to exert their very important protective function. Extracurricular activities in art, music, drama, school publications, and the like give adolescents an opportunity to participate in constructive group activities and achieve recognition for their efforts. Studies have found that recognition for or involve ment in conventional activities-whether family, school, extracurricular, religious, or community-is a protective factor against antisocial behavior (lessor et al., 1995;Rae-Grant et al., 1989). The reanalysis of the lessor data shows that involvement in family, volunteer, and school club activities other than sports has an insignificant effect on risk for violence (Turbin, 2000). # Peer Group Having friends who behave conventionally is a pro posed protective factor that seems to reduce the risk of delinquency, but there is no evidence of a true buffer ing effect on specific risk factors. Buffering effects on violence were not significant in the reanalysis of the lessor data (Turbin, 2000; see also . However, as noted earlier, researchers have found that associating with peers who disapprove of violence may inhibit violence in young people (Hawkins et al., 1998c;lessor et al., 1995). # O # Summary Although the body of research on protective factors is growing, very little work has been done specifically on protective factors that buffer the risk of violence. Some researchers have identified individual and environmen tal characteristics that can be considered candidates for protective factors. Lacking adequate scientific evidence of the nature, mechanism, size, and timing of these can didates' moderating effects, however, this report con siders all of them proposed protective factors. One recent reanalysis of earlier data has found two proposed protective factors that seem to buffer the risk of violence-an intolerant attitude toward deviance and commitment to school. These two fac tors appear to exert a statistically significant, though small, buffering effect on the risk of violence, but until these findings are replicated, they must be considered preliminary. Identifying and understanding how protective fac tors operate is as important to preventing and stopping violence as identifying and understanding risk factors. This area of the public health approach to youth vio lence cries out for more research. # C o n c l u s io n s Scientists have identified a number of personal char acteristics and environmental conditions that put chil dren and adolescents at risk of violent behavior and some that seem to protect them from the effects of risk. These risk and protective factors can be found in every area of life, they exert different effects at differ ent stages of development, they tend to appear in clus ters, and they appear to gain strength in numbers. The public health approach to youth violence involves identifying risk and protective factors, determining when in the life course they typically come into play, designing preventive programs that can be put in place at just the right time to be most effective, and making the public aware of these findings. Many years of research have yielded valuable insights into the risk factors involved in the onset and developmental course of violence. Less work has been done on protective factors, but that situation is changing. Some basic principles have emerged from these studies: Risk and protective factors exist in every area of life-individual, family, school, peer group, and community. Individual characteristics interact in complex ways with a child's or adolescent's envi ronment to produce violent behavior. Risk and protective factors vary in predictive power depending on when in the course of human devel opment they occur. As children move from infancy to early adulthood, some risk factors will become more important and others less important. Substance use, for example, is a far more powerful risk factor at age 9 than it is at age 14. Risk factors do not operate in isolation-the more risk factors a child or young person is exposed to, the greater the likelihood that he or she will become violent. Risk factors can be buffered by protective factors, however. An adolescent with an intolerant attitude toward violence is unlikely to engage in violence, even if he or she is associating with delin quent peers, a major risk factor for violence at that age. Risk factors increase the likelihood that a young person will become violent, but they may not actu ally cause a young person to become violent. Scientists view them as reliable predictors or even as probable causes of youth violence. They are use ful for identifying vulnerable populations that may be amenable to intervention efforts. Risk markers such as race or ethnicity are frequent ly confused with risk factors; risk markers have no causal relation to violence. No single risk factor or combination of factors can predict violence with unerring accuracy. Few young people exposed to a single risk factor will become involved in violent behavior; similarly, most young people exposed to multiple risks will not become violent. By the same token, protective factors cannot guarantee that a child exposed to risk will not become violent. Researchers have identified at least two onset tra jectories for youth violence: a childhood trajectory that begins before puberty and an adolescent one that begins after puberty. Violence peaks during the second decade of life. The small group of offenders who began their violent behavior in childhood commits more violent offenses, and the larger group of adolescent offenders begins to become involved in violence. • Early risk factors for violence in adolescence include involvement in serious (but not necessari ly violent) criminal acts and substance use before puberty, being male, aggressiveness, low family socioeconomic status/poverty, and antisocial par ents. All of these early risks stem from a child's individual characteristics and interaction with his or her family. The influence of family is largely supplanted in adolescence by peer influences; thus, risk factors with the largest predictive effects in adolescence include weak social ties to conven tional peers, ties to antisocial or delinquent peers, and belonging to a gang. Committing serious (but not necessarily violent) criminal offenses is also an important risk factor in adolescence. Drug selling is a risk factor, but its effect size has not been established. • Identifying and understanding how protective fac tors operate is potentially as important to preventing and stopping violence as identifying and under standing risk factors. Several protective factors have been proposed, but to date only two have been found to buffer the risk of violence-an intolerant attitude toward deviance and commitment to school. Protective factors warrant more research attention. Violence prevention and intervention efforts hinge on identifying risk and protective factors and determining when in the course of development they emerge. More research in these areas is needed, par ticularly concerning why violence stops or continues in childhood and adolescence.-Nonetheless, the research carried out to date provides a solid founda tion for programs aimed at reducing risk factors and promoting protective ones-and thereby preventing violence, the subject of Chapter 5. # R e f e r e n c e s A m erican Psychological A ssociation. (1993). Violence 1972). During this period, new media emerged-video games, cable television, music videos, and the Internet. As they gained popularity, these media, along with tele vision, prompted public concern and research attention. Recent surveys depict the abundance of (primari ly electronic) media in U.S. homes (Roberts et al., 1999;Woodard, 1998) and the extensive presence of violence within the media landscape (Wilson et al., 1997(Wilson et al., , 1998. They also show that the proliferation of new media has expanded the opportunities for chil dren to be exposed to media violence at home. Current psychological theory suggests that the interactive nature of many of these new media may affect chil dren's behavior more powerfully than passive media such as television. Research to test this assumption is not yet well developed, and accurate measurement is needed to determine how much violence children are actually exposed to through various media-and how patterns of exposure vary among American youths. In reading this discussion of research on the impact of media violence on America's youth, a few major points should be kept in mind: • First, research on the effects of media violence examines many kinds of outcomes in young people. Researchers have focused primarily on aggression, an outcome that psychologists define as any behav ior, physical or verbal, that is intended to harm another person. Physical aggression may range from less serious acts, such as pushing or shoving, to more serious physical contact and fighting, to very serious violent acts that carry a significant risk of injury or death, such as assault, robbery, rape, and homicide. Some studies have focused on how media violence affects aggressive thinking, including beliefs and attitudes. Other studies have focused on the effects of media violence on aggressive emotions-that is, on emotional reactions, such as anger, that are relat ed to aggressive behavior. In this discussion, the label "violence" is reserved for the most extreme end of the physical aggression spectrum. • Second, as noted in Chapter 4, the preponderance of evidence indicates that violent behavior seldom results from a single cause; rather, multiple factors converging over time contribute to such behavior. Accordingly, the influence of the mass media, how ever strong or weak, is best viewed as one of the many potential factors that help to shape behavior, including violent behavior. • Third, a developmental perspective is essential for understanding how media violence affects youth behavior and for framing any coherent public health response to it. Although this report focuses general ly on the violent behavior of adolescents, it is criti cal to understand how children are influenced by and respond to media violence, especially in order to recognize and help those who are particularly susceptible to adverse effects. Most youths who are aggressive and engage in some forms of antisocial behavior do not become violent teens and adults. However, it is well established that many violent adolescents and adults were highly aggressive and 1 0 4 8; even violent at younger ages, and the highly aggres sive child is at increased risk of growing up to be a more aggressive young adult . Because influences that promote aggressive behavior in some young children can contribute to increasingly aggressive and even violent behavior many years later, it is important to understand the early factors that may play a role in later outcomes. • Fourth, a growing body of research supports theo ries that explain how exposure to media violence would activate aggressive behaviors or attitudes in some children. Humans begin imitating other indi viduals at a very early age, and young children learn many motor and social skills by observing the behavior of others (Bandura, 1977). Social interac tions shape the scripts for behavior that children acquire, but observational learning is a powerful mechanism for acquiring social scripts throughout childhood (Huesmann, 1998). Most researchers agree that such observational learning is probably the major psychological process underlying the effects of media violence on aggressive behavior. This same process could explain how prosocial behavior depicted in the media might encourage positive behavior in children (Friedlander, 1993;Harold, 1986;Mares, 1996). # M e d ia V io l e n c e : Ex p o s u r e a n d C o n t e n t American children and youths spend, on average, more than 4 hours a day with television, computers, videotaped movies, and video games (Roberts et al., 1999;Woodard, 2000). But their exposure to media varies considerably, depending on their age, parental viewing habits, and family socioeconomic status (SES). Most systematic research on children's expo sure to violent media dates back to the 1970s, when most families did not have access to cable television, music videos, video games, or the Internet. As noted earlier, very few contemporary studies systematically document children's actual consumption of violent media; this is particularly true for the newer media. Several content analyses over the last 30 years have systematically examined violence on television (Gerbner et al., 1980;Potter et al., 1995;Signorielli, 1990). The largest and most recent of these was the National Television Violence Survey (NTVS)1 (Wilson et al., 1997(Wilson et al., , 1998, which examined the amount and content of violence2 on American televi sion for three consecutive years, as well as contextual variables that may make it more likely for aggression and violence to be accepted, learned, and imitated. Smith and Donnerstein (1998) report the following NTVS findings: • 61 percent of television programs contain some vio lence, and only 4 percent of television programs with violent content feature an "antiviolence" theme. • 44 percent of the violent interactions on television involve perpetrators who have some attractive qual ities worthy of emulation. • 43 percent of violent scenes involve humor either directed at the violence or used by characters involved with violence. • Nearly 75 percent of violent scenes on television feature no immediate punishment for or condemna tion of violence. • 40 percent of programs feature "bad" characters who are never or rarely punished for their aggres sive actions. The NTVS report notes that many television pro grams fail to depict the harmful consequences of vio lence. Specifically, it finds that of all violent behav ioral interactions on television, 58 percent depict no pain, 47 percent depict no harm, and 40 percent depict harm unrealistically. Of all violent scenes on televi- The NTVS random ly sampled programs from 6:00 a.m. to 11:00 p.m. on 23 broadcast and cable channels over a 20-week period from O ctober to June during the 1994 through 1997 view ing seasons. A sum o f 119 hours per channel, or 2,500 hours o f television programming was assessed each year. The NTVS defined violence as "overt depiction o f a credible threat o f physical force, or the actual use o f such force intended to physically harm an animate being or group o f beings." Content analyses o f television programs generally treat the program itself as the unit o f analysis and exclude advertisements."Violence also includes certain depictions o f physically harmful consequences against an animate being or group that occur as a result o f unseen violent means. Thus, there are three prim ary types o f violent depictions: credible threats, behavioral acts, and harmful consequences (Smith & Donnerstein, 1998, p. 170). sion, 86 percent feature no blood or gore. Only 16 per cent of violent programs feature the long-term, realis tic consequences of violence. # M a jo r B e h a v io r a l Effe c t s o f M e d ia V io l e n c e Because an exhaustive description of the research lit erature is not possible within this brief discussion, findings from meta-analyses are reported3 where available. In meta-analyses, the results of multiple studies are combined and compared systematically and an overall effect size computed. These analyses include findings from randomized experiments that look at aggression immediately after viewing vio lence, as well as cross-sectional surveys that provide a snapshot of the relationship between viewing violence and behavior at a fixed point in time. Also presented are findings from longitudinal studies that examine whether exposure to media violence affects violence and aggression over time. # Television and Film Violence Many anecdotal reports have described instances in which television and film violence led to immediate violent behavior in individual children, but scientific studies of this relationship draw a more complex and qualified picture. Most of the relevant research has focused on how watching dramatic violence on televi sion and film affects aggressive thoughts and emo tions, as well as aggressive behavior. Some important studies address violence as well. # Experimental Studies A substantial number of laboratory and field experi ments over the past half-century have examined whether children exposed to violent behavior on film or television behave more aggressively immediately afterwards (see reviews by Bushman & Huesmann, 2000;Comstock & Scharrer, 1999;Geen, 1990;Geen & Thomas, 1986;Huesmann et al., 1997). Many stud ies have also examined the immediate effect of media violence on aggressive thoughts or emotions (Rule & Ferguson, 1986), which have been shown to increase the risk of aggressive behavior (Dodge & Frame, 1982;Huesmann & Guerra, 1997). The most recent and comprehensive meta-analy sis of media violence was conducted by , who examined effect sizes from 217 empirical studies on media violence and aggres sive and violent behavior published between 1957 and 1990. The analysis indicates clearly that brief expo sure to violent dramatic presentations on television or in films causes short-term increases in the aggressive behavior of youths, including physically aggressive behavior. Across all the randomized experiments, the unweighted average effect size was large (r = .37).4 When only experiments examining physical aggres sion as the outcome were examined, the effect size was also large (r = .32). Although the experimental methods used in these studies enable researchers to test causality more read ily than other research methods as noted by Comstock and Paik (1991), the findings may not necessarily apply to all real-world settings. Because experiments are narrowly focused on testing specific causal hypotheses, they do not examine the effects of all fac tors that might be present in more realistic situations. This means that some real-world influences might actually lessen or even eliminate the aggressive reac tions observed in experiments. For example, while tel evision, film, and other media contain a variety of antisocial and other messages, most laboratory studies to date have exposed study participants primarily to violent materials. In addition, participants may react differently in the laboratory when they realize that their expressions of aggression will not be punished (Gunter, 1983). Any summary of these experimental results should also acknowledge the argument raised by some critics (such as Freedman, 1992) that many study participants provide the responses they believe the researcher wants. Despite these limitations, labo ratory experiments are important because they allow researchers to isolate the unique effect of exposure to violence on subsequent behavior. An important general finding from these experi mental studies is that not all youths seem to be affect ed equally by media violence. Effects seem to be strongest on youths who are predisposed to be aggres sive for some reason or who have been aroused or provoked (Berkowitz, 1993;Bushman, 1995;Geen & O'Neal, 1969). # Cross-Sectional Surveys Cross-sectional surveys over the past 40 years have generally focused on establishing a link between the current aggressiveness of children and the amount of television and film violence they watch regularly (see reviews by Bushman & Huesmann, 2000;Chaffee, 1972;Comstock & Scharrer, 1999;Eysenck & Nias, 1978;Huesmann & Miller, 1994). Paik and Comstock's meta-analysis (1994) indi cates that in cross-sectional surveys viewing media violence was positively correlated with various meas ures of aggression. They reported small to moderate effect sizes across all measures of aggression (r = .19) and for physical aggression alone (r = .20). For the outcome of most concern to this report-criminal vio lence against a person-the effect size was small (r = .06). These results suggest that the link between media violence and aggressive behavior found in laboratory studies may also hold for behaviors outside the labo ratory. However, cross-sectional surveys do not by themselves indicate whether media violence is caus ing aggression, whether aggressive youths are attract ed to media violence, or whether some other factor is predisposing some youths to watch more violence and behave more aggressively. # Longitudinal Studies Long-term studies in which exposure to media vio lence in early childhood is related to later aggression and violence (such as aggravated assault, robbery, rape, and homicide) can identify the enduring effects of media violence. In most such studies to date, how ever, aggression, not violence, has been the primary outcome measured. In the absence of a meta-analysis, the findings of three frequently cited longitudinal studies on the effects of media violence are discussed briefly below. Studies examining effects over shorter time periods (Singer et al., 1984) or with internation al samples (Huesmann & Eron, 1986) are not includ ed here. In a study begun in 1960 on a sample of 875 youths in New York State, Eron and colleagues found that for boys, but not for girls, exposure to media vio lence at age 8 was significantly related to aggressive behavior a decade later (r = .31, N = 211, p < .01) (Eron et al., 1972;Lefkowitz et al., 1977). At both times, peers assessed physical and verbal aggression. The longitudinal correlation remained above .25, even in separate analyses statistically controlling for factors such as the child's initial aggressiveness, the child's intelligence, family SES, parents' aggressiveness, and parents' punishment and nurturance of the child. examined the probability of initiating aggression after exposure to violence on television in 2,400 boys and girls age 7 to 12 from two midwestem cities who had been surveyed up to six times between 1970 and 1973. A sample of 800 teenage boys5 was studied at five times to identify the effect of violent television on aggression and vio lence. For the elementary school sample, the average cross-sectional correlation between exposure to media violence and personal aggression was small for boys (r = .17) and large for girls (r = .30). The researchers then attempted to predict aggressive behavior at one point in time from the extent to which children viewed television violence at an earlier time, while controlling for earlier aggressive characteris tics. They examined this prediction over 15 time intervals ranging from 5 months to 3 years apart. For elementary school boys, only 2 of the 15 predictions at different intervals were statistically significant. For girls, only three predictions were statistically signifi cant. In the teenage male sample, only one of eight correlations was significant. In only one of nine analyses using measures of violence (for example, knife fight, car theft, mugging, gang fight) were boys with greater exposure to television violence more likely to initiate violence 2 years later than those with less exposure. The third longitudinal study of media violence effects began in the late 1970s and spanned five coun tries (Huesmann et al., submitted;Huesmann et al., 1984;Huesmann & Eron, 1986). In each locale, sam ples of middle-class youths were examined three times between age 6 to 8 or age 8 to 11. Both physical and verbal aggression were assessed by peers. The correlations between aggression and overall viewing of television violence at a single point in time were small to moderate and often significant. In the United States, the 3-year average correlation was moderate for boys and for girls (r = .25 and r = .29, respective ly; p < .001). The predictive power of viewing televi sion violence for childhood aggression a year later varied substantially. In the United States, girls' view ing of television violence had a significant effect (P = .17, N = 89, p < .05) on their later aggression, even after accounting for early levels of aggression, SES, and scholastic achievement. For boys, television vio lence alone did not predict later aggression. When the investigators took into account both exposure to tele vision violence and identification with aggressive tel evision characters, they found a positive relation with aggressiveness (P = .19, N = 84, p < .05). A follow-up study of over 300 people in the U.S. sample 15 years later suggested that media violence has a delayed effect on aggression (Huesmann et al., submitted). There was a small to moderate longitudi nal correlation between childhood television viewing and a composite measure of young adult aggression (physical, verbal, and indirect aggression) for both men (r = .21, N = 153, p < .01) and women (r = .19, N = 176, p < .01). When the outcome was limited to physical aggression, the correlations were smaller (r = .17 and r = .15, respectively). Furthermore, women who had watched relatively more television violence as girls committed significantly more specific acts of violence as adults, such as "punching, beating, or choking another adult," than did the other women (17 percent versus 4 percent). There were no significant differences among the men. Other analyses showed th a t e ffe c ts rem ain ed s ig n ific a n t ev en w hen researchers controlled for parent education and chil dren's scholastic achievement (P = .19 for boys, P = .17 for girls, p < .05). In addition, aggressive behavior did not significantly increase boys' or girls' viewing of television violence (P = .08 for boys and P = .04 for girls; p = ns). In summary, these longitudinal studies show a small, but often statistically significant, long-term relationship between viewing television violence in childhood and later aggression, especially in late ado lescence and early adulthood. Some evidence suggests that more aggressive children watch more violence, but the evidence is stronger that watching media vio lence is a precursor of increased aggression. # Other Studies Other studies have explored the behavioral impact of introducing television in several countries (Centerwall, 1989a(Centerwall, , 1989b(Centerwall, , 1992Joy et al., 1986;Williams, 1986). These studies indicate that when tel evision was introduced, aggression and violence increased. The findings must be viewed with caution, however, because they do not take into account a range of other factors that may influence national crime rates and the amount of violence watched on television. Despite anecdotal reports of a "contagion of vio lence," relatively little systematic research has exam ined whether seeing or hearing about violence in news coverage encourages violent or aggressive behavior. On the whole, the limited data available support the notion of a contagion effect. This evidence is derived from studies examining how reports of a well-known person's suicide affect the likelihood of imitative sui cide (Phillips, 1979(Phillips, ,1982Simon, 1979;Stack, 1989). Other studies of the contagion effect (Berkowitz & Macaulay, 1971;Phillips, 1983) have been questioned because of their research methods and the ambiguity of their results (Baron & Reiss, 1985; see Phillips & Bollen, 1985 for a response). This area merits addi tional research. # 0 8 # Violence in Other Media # Internet Theoretically, the effects of exposure to media vio lence extend to Internet media as well. To date, how ever, no studies have been published regarding the effects of Web-based media violence on youth aggres sion and violence. # Music Videos A relatively small amount of research has focused on the impact of music videos with violent or antisocial themes (Baxter et al" 1985;Caplan, 1985;Hansen & Hansen, 1990;Johnson et al" 1995aJohnson et al" , 1995bRich et al" 1998). Randomized experiments indicate that exposure to violent or antisocial rap videos can increase aggres sive thinking, but no research has yet tested how such exposure directly affects physical aggression. # Youth Violence: A Report of the Surgeon General # Video Games The impact of video games containing violence has recently become a focus of research because children are theoretically more susceptible to behavioral influ ences when they are active participants than when they are observers. To date, violent video games have not been studied as extensively as violent television or movies. The number of studies investigating the impact of such games on youth aggression is small, there have been none on serious violence, and none has been longitudinal. A recent meta-analysis of these studies found that the overall effect size for both randomized and corre lational studies was small for physical aggression (r = .19) and m oderate for aggressive thinking (r = .27) (Anderson & Bushman, in press). In separate analyses, the effect sizes for both randomized and cross-sectional studies was small (r = .18 and .19, respectively). The impact of video games on violent behavior remains to be determined. # Potential Moderators of Behavioral Effects Research suggests that not all youths are affected in the same way by viewing media violence. Factors that appear to influence the effects of media violence on 0 aggressive or violent behavior include characteristics of the viewer (such as age, intelligence, aggressive ness, and whether the child perceives the media as realistic and identifies with aggressive characters) and his or her social environment (for example, parental influences), as well as aspects of media content (including characteristics of perpetrators, degree of realism and justification for violence, and depiction of consequences of violence). Evidence that these factors moderate the influence of media violence is limited, and it is more relevant to aggression than to violence. For example, studies of responses to violent television and films and violent video games have found that people who were initially more aggressive than other subjects were more affected in behavior, thoughts, and emotions (Anderson & Dill, 2000;Bushman, 1995;Bushman & Geen, 1990;Friedrich & Stein, 1973;Josephson, 1987). Research in this area clearly suggests that the impact of violent tel evision, film, and video games on aggression is moder ated by viewers' aggressive characteristics. Evidence that other individual, environmental, and content factors moderate the effects of exposure to media violence is less clear. Some studies suggest that these factors may buffer or enhance effects, but few have tested for such influences. Although limited in scope and depth, such studies provide clues to potential avenues for prevention efforts. For example, preliminary data point to the potentially vital role of parents in supervising their children's exposure to violent media and in helping them interpret it (Nathanson, 1999). # S u m m a r y o f M ajor Empirical Research Fin d in g s A substantial body of research now indicates that expo sure to media violence increases children's physically and verbally aggressive behavior in the short term (within hours to days of exposure). Media violence also increases aggressive attitudes and emotions, which are theoretically linked to aggressive and vio lent behavior. Findings from a smaller body of longi tudinal studies suggest a small but statistically signifi cant impact on aggression over many years. The evi dence for long-term effects on violence is inconsistent. # 0 9 Based on the findings of studies reported here, the average effect sizes of exposure to media violence on various measures of aggression range from small (r = .15) to quite large (r = .64). The evidence that exposure to media violence is a risk factor for violent behavior is more limited, with small average effect sizes of r = .06 in cross-sectional surveys, r = .13 in experimental studies , and r = .00 to .22 in longitudinal studies (Huesmann et al., submitted;. Taken together, findings to date suggest that media violence has a relatively small impact on violence. The effect on aggression is stronger, ranging from small to moderate. Although there is clear scientific evidence of a correlation between exposure to media violence and some violent behaviors, randomized experimentsthe research methodology best suited to determining causality-cannot ethically be used in studies of vio lent behavior. Thus, the causal links between media violence and behavior are more firmly established for aggressive behavior than for violent behavior. Longitudinal studies, which also provide some insights into this issue, have linked repeated exposure to media violence in the early, years with an increased likelihood of aggressive behavior in the teen and adult years. However, few of these studies have reported on violence as an outcome. Moreover, the violent behav iors that are the focus of this report (homicide, forcible rape, aggravated assault,, and robbery) occur infrequently and are subject to multiple influences. At present, it is extremely difficult to distinguish between the relatively small, long-term effects of media expo sure and those other influences. In sum, a diverse body of research provides strong evidence that exposure to violence in the media can increase children's aggressive behavior in the short term. Some studies suggest that long-term effects exist, and there are strong theoretical reasons why this is the case. But many questions remain regarding the short-and long-term effects of media violence, espe cially on violent behavior. # Preventive Efforts Efforts to reduce the presumed harmful effects of media violence on youths have taken various forms, including: • Attempting to reduce the amount of media violence and children's access to it (for example, calls for media self-regulation and violence ratings); • Encouraging and facilitating parental monitoring of children's access to media (for example, V-chip leg islation and advisory labels on music and video games); • Educating parents and children about the potential dangers of media violence (for example, media and empathy educational programs); and • Targeting children's views about violence to reduce the chances that they will imitate the violence they see (Corder-Bolz, 1980;Hicks, 1968;Huesmann et al., 1983;Linz et al., 1990;Nathanson, 1999). From a public health perspective, this preventive domain is largely uncharted territory. Few preventive efforts have been studied systematically. Furthermore, not enough research has been done to form a basis for the design of many experimental interventions. As noted in other parts of this report, an extensive body of scientific research undergirds our emerging knowledge about effective ways of preventing youth violence. Although many violence prevention programs address a complex array of risk and protective factors in the lives of young people, they have not yet addressed the role of the media. This gap needs to be filled. # Im plic a tio n s Research to date justifies sustained efforts to curb the adverse effects of media violence on youths. Although our knowledge is incomplete, it is sufficient to devel op a coherent public health approach to violence pre vention that builds upon what is known, even as more research is under way. Unlike earlier Federal research reports on media violence and youth (National Institute of Mental Health, 1982; U.S. Surgeon General's Scientific Advisory Committee on Television and Social Behavior, 1972), this discussion takes place within a broader examination of the caus es and prevention of youth violence. This context is vital. It permits media violence to be regarded as one of many complex influences on the behavior of America's children and young people. It also suggests that multilayered solutions are needed to address aggressive and violent behavior. A variety of media violence is present in the homes of young children, with considerable variation in the degree of parental supervision (Woodard, 1998). Regardless of government and other interested groups' attempts to limit the amount of violence reaching American families, families themselves play a critical role in guiding what reaches their children. Whether by adopting V-chip technology for home tel evision programming, by using Internet violence screening, or simply by monitoring closely children's use of televisions, computers, and video games, par ents can limit and shape their children's selection of, interaction with, and response to media violence. Community groups-including schools, faith-based organizations, and Parent Teacher Associations-can teach parents and children how to be more critical consumers of media. Federal agencies can be more active in encouraging needed research, in sharing research findings with the public, in encouraging increased interaction between violence prevention researchers and media researchers, and in creating networks for sharing solutions to social and public health problems. (Gallup, 1999). This per ception, combined with the increased lethality of youth violence in the early 1990s, has lent urgency to the search for effective violence prevention efforts. Hundreds of youth violence prevention programs are being used in schools and communities throughout the country, yet little is known about the actual effects of many of them (Gottfredson et al., 2000;Tolan & Guerra, 1994). Few such programs have been rigor ously evaluated, including many ongoing efforts (Elliott, 1998). The evaluations that have been done indicate that much of the money America spends on youth violence prevention is spent on ineffectivesometimes even harmful-programs and policies . At the same time, researchers know much more today about how to prevent youth violence than they did two decades ago, when some declared that "noth ing works" to prevent violence Sechrest et al., 1979). This is clearly no longer the case. Over the past few decades, social scientists have made great strides in uncovering the causes and corre lates of youth violence. Unfortunately, the news about effective programs has been slow to bring about change in school, com munity, and juvenile justice system prevention efforts, where precious resources continue to be spent on inef fective programs. Some experts believe that youth crime and violence rates could be "substantially" reduced simply by reallocating the money now spent on ineffective policies and programs to those that do work (Mendel, 2000, p. 1). The strategy of using prevention resources to their fullest potential presents many challenges. The first lies in identifying effective prevention approaches and programs. Differentiating between effective and inef fective ones can be a difficult chore for schools, com munities, and juvenile justice authorities. Numerous agencies and organizations have published recom mendations on "what works" in youth violence pre vention, but in many cases there is little consistency regarding the specific programs they recommend. The reason for this inconsistency is a lack of uniformly applied scientific standards for what works. # Pr o m o t in g H ealthy, N o n v io l e n t C h ildren This chapter identifies a set of standards based on sci entific consensus and applies those standards to the literature on youth violence prevention in order to identify with confidence general strategies and pro grams that work, that are promising, or that do not work to prevent youth violence. This information can be used by schools, communities, juvenile justice agencies, program funders, and others interested in youth violence prevention to aid their programming decisions. With this information in hand, it may be possible to fulfill the prediction that better use of existing prevention resources can substantially reduce the problem of youth violence. The first section of this chapter describes the methods used in this report to identify best practices in youth violence prevention. The second describes cur rently accepted scientific standards for determining program effectiveness. The third section applies those standards to the existing youth violence prevention lit erature and presents findings on best practices-what # 115 works, what is promising, and what does not work. The information in that section is based on currently available research and is not intended to be the final word on the subject. As more programs are evaluated, the standards outlined in this report can be used to identify additional programs and strategies that work in preventing youth violence. The fourth section, on cost-effectiveness, is intended to enhance the information provided in the best practices section by adding another dimension to the determination of what works. The conclusion dis cusses the need to take the next step in preventing youth violence by learning how to preserve the bene fits of successful prevention programs when imple menting them on a national scale. # M e t h o d s o f Identifying Best P ractices Identifying the best practices for preventing youth vio lence involves two approaches, each with its own lim itations. The first is meta-analysis, a rigorous statistical method of combining the results of several studies to obtain more reliable estimates of the effects of a gen eral type of treatment or intervention. This quantitative approach can be used to summarize program evalua tion evidence and draw overall conclusions about the strength and consistency of the influence, or effect size, that particular types of programs have on violent behavior. In the field of youth violence, meta-analysis has been used primarily for evaluations of interven tions with violent or delinquent youths. The second, less empirical approach is to review the evaluation research and identify the general strate gies that characterize effective programs. While such reviews are not quantitative, they are more easily con ducted than meta-analyses, and they offer useful information for generating hypotheses and drawing general conclusions about the effectiveness of various strategies for preventing youth violence. In identifying best practices, this report relies heav ily on recently published reviews and focuses mainly on strategies and programs with demonstrated effects on youth violence and on the major risk factors for youth violence. Strategies and programs are first classified as effective or ineffective. Effective strategies and pro grams are then further broken down into Model pro grams, which meet very high standards of demon strated effectiveness, and Promising programs, which meet a minimum standard. Finally, within Model and Promising categories, a distinction is made between strategies and programs that have demonstrated effects on violence and serious delinquency (Level 1) and those that have demonstrated effectiveness on known risk factors (Level 2). The decision to include serious delinquency along with violence as a criterion for Level 1 pro grams was based upon the major meta-analysis of program effectiveness (Lipsey & Wilson, 1998), which did not differentiate between those two out comes. Serious delinquency was a major risk factor for violence in both the early and late onset of risk (see Chapter 4). Level 2 Model programs are those that address any of the other risk factors with large effect sizes (substance use, weak social ties, antiso cial or delinquent peers, gang membership).1 For Promising strategies, Level 1 again refers to pro grams with demonstrated effects on violence and serious delinquency. Level 2 programs are those with demonstrated effects on any risk factor with an effect size of .10 or greater. No attempt was made to systematically search the literature for programs and strategies that affect small risk factors for youth violence, such as academic fail ure or anxiety and depressive disorders. Therefore, some effective programs or strategies that target small risk factors may not be included. However, such pro grams and strategies occasionally came to our atten tion; those that did were included if the risk factors they affected had an effect size of .10 or greater. Thus, risk factors such as child abuse and neglect, which have an effect size of less than .10, are not covered in this report.2 Also excluded are clinical trials of psy chotropic medications, which have proved effective in treating some affective disorders that are risk factors for youth violence but have not been shown in rigorous clinical studies to reduce youth violence specifically. A review of these interventions can be found in Mental Health: A Report o f the Surgeon General (1999). Several major reviews of youth violence preven tion and intervention programs have been published in the past decade. This chapter draws mainly upon the following:3 • Preventing Crime: What Works, What Doesn't, What' s Promising. A Report to the United States Congress (Sherman et al., 1997) • The Office of Juvenile Justice and Delinquency Prevention's A Sourcebook: Serious, Violent, and Chronic Juvenile Offenders (Howell et al., 1995) • The Office of Juvenile Justice and Delinquency Prevention's Guide fo r Implementing the Comprehensive Strategy for Serious, Violent, and Chronic Juvenile Offenders (Howell, 1995) • The Centers for Disease Control and Prevention's Best Practices o f Youth Violence Prevention: A Sourcebook for Community Action (Thornton et al., # 2000) • The American Youth Policy Forum's Less Hype, More Help: Reducing Juvenile Crime, What Works-And What Doesn' t • The Center for the Study and Prevention of Violence's Blueprints fo r Violence Prevention • "School-Based Crime Prevention" (Gottfredson et al., in press) To improve readability, the reviews listed above are cited here and in the section below on scientific standards for effectiveness, but they are not referred to repeatedly in the section on best practices. Citations not listed above will be included where appropriate. Many reviews use either no explicit criteria or only minimal criteria for identifying the programs they rec ommend, making it difficult to draw clear conclusions about the effectiveness of individual violence preven tion strategies. This report limits its identification of effective programs to those meeting a minimum stan dard of study design similar to the maximum standard described in Sherman et al. (1997) and Gottfredson et al. (in press). In those two reports, a scientific methods score of 4 or 5 indicates that an evaluation used an experimental or quasi-experimental design. This report applied that design standard to the extent possible, given the limitations described above. This report also attempts to distinguish between absolute deterrent effects, in which an intervention is compared to no treatment, and marginal deterrent effects, in which the intervention or strategy is evalu ated against another treatment. Marginal deterrent effects are effects of the intervention over and above the effects of another treatment strategy and thus may underestimate the true effects of the intervention, com pared to receiving no treatment at all. In such cases, the nature of the comparison group is identified in the text. Both meta-analyses and reviews can be used to identify successful strategies, approaches, or types of programs used to prevent youth violence. However, this general approach has a critical limitation: Within any given category of programs, there may be specif ic programs that are effective and others that are not; moreover, programs may be effective for some popu lations but not others (males but not females, for example). The general effect size is an estimate of the average effect and thus may not characterize any par ticular program or its use for a particular population. Often the effects of individual programs within each general strategy vary widely. For this reason, it is necessary to take one more step in the identification of best practices-focusing specifically on individual programs that work. Identifying specific programs that work requires a clear set of standards for judging effectiveness. This chapter describes the scientific community's consen sus regarding standards and how this report applied those standards to the evaluation literature to place programs in one of three categories: Model (demon strates a high level of effectiveness), Promising (meets minimal standards of effectiveness), or Does Not Work (consistent evidence of no effects or harmful effects). Few existing violence prevention and intervention programs have met the qualifications of a Model pro gram. Many more have met the standards for a Promising program, and even more would probably meet these standards if evaluated appropriately. The fact that a program is not identified in this report as Promising or Model does not mean it is ineffective; in most cases it means only that it has not been rigorous ly evaluated. Those evaluated and found to be ineffec tive are identified as ineffective. While hundreds of programs are employed throughout the United States to prevent youth violence and treat young offenders, only those with a credible scientific evaluation are highlighted in this report. This shortfall underscores the need for a renewed focus on evaluation in the field of youth violence prevention. # Scientific St a n d a r d s for D eterm inin g Pro g r a m Effectiveness The scientific community agrees on three standards for evaluating effectiveness: rigorous experimental design, evidence of significant deterrent effects, and replication of these effects at multiple sites or in clini cal trials. For example, the level of evidence required to establish the effects of an agent or intervention in Mental Health: A Report of the Surgeon General (1999) was demonstration of the effects in random ized, controlled experimental studies that had been replicated. The U.S. Food and Drug Administration requires the same level of evidence before approving a new drug for use in humans. Unfortunately, this level of evidence has not been routinely required by agen cies that recommend or fund youth violence preven tion programs, though some organizations and most researchers are calling for establishment of meaningful 0 criteria for program effectiveness (Elliott, 1998;Mendel, 2000, p. 74). Most researchers want evalua tions to meet one or more of these three scientific stan dards for assessing effectiveness. Rigorous experimental design includes, at a mini mum, random assignment to treatment and control groups (Andrews, 1994;Center for Substance Abuse Prevention, 2000;Chamberlain & Mihalic, 1998;Howell et al., 1995;Lipsey, 1992a;Lonigan et al., 1998). A less stringent, but acceptable, study design is quasi-experimental, in which equivalent comparison and control groups are established but assignment of study participants to the groups is not random (Center for Substance Abuse Prevention, 2000; Howell et al., 1995;Lipsey, 1992b;Sherman et al., 1997;Tolan & Guerra, 1994). Well-designed studies should also have low rates of participant attrition, adequate measurement, and appropriate analyses (Andrews, 1994;Center for Substance Abuse Prevention, 2000;Chamberlain & Mihalic, 1998). High attrition can undermine the equivalence of experimental and control groups. It can also signal problems in program implementation. Adequate measurement implies that the study meas ures, including the outcome measure, are reliable and valid indicators of the intended outcomes and that they are applied with quality, consistency, and appro priate timing (Tolan & Guerra, 1994). In clinical trials, replication means conducting both efficacy and effectiveness trials (Lonigan et al., 1998). Efficacy trials test for benefits to participants in a con trolled, experimental setting, and effectiveness trials test for benefits in a natural, applied setting. In practice, this distinction is often blurred, but the principle of independent replication at multiple sites is well estab lished. Replication is an important element of program evaluation because it establishes that a program and its effects can be exported to new sites and implemented by new teams under different conditions. A program that is demonstrated to be effective at more than one site is likely to be effective at other sites as well. Statistical significance is based on the level of confidence with which one can conclude that a differ ence between two or more groups (generally a treat ment and a control group) results from the treatment delivered and not, for example, from the selection process or chance. A probability value of .05 is wide ly accepted as the threshold for statistical significance; a probability below this threshold (p < .05) indicates that a difference of this magnitude could happen by chance less than 5 percent of the time. High-quality evaluations of youth violence pre vention programs should be designed to demonstrate with this degree of confidence that a program is reduc ing the onset or prevalence of violent behavior or indi vidual rates of offending (Andrews, 1994;Tolan & Guerra, 1994). Since serious delinquency is strongly related to violence, reductions in serious criminal behavior (or index crimes) are also considered to be acceptable outcome measures for identifying effective violence prevention programs (Andrews, 1994;Elliott, 1998;Lipsey, 1992aLipsey, , 1992b. However, direct scientific evidence of a deterrent effect on violent behavior is certainly preferable. Prevention programs are designed to prevent or reduce violent behaviors by acting on risk and protec tive factors. Reducing risk is a less stringent standard than reducing violence, but reducing risk undoubtedly holds some promise of preventing violence. Thus, sig nificant changes in risk factors for violence are acceptable indications of program effectiveness Gottfredson et al., in press;Howell et al., 1995;Sherman et al., 1997). In addition, because most violence begins in adolescence, child hood interventions are concerned primarily with risk reduction. A less widely accepted but nevertheless important standard for demonstrating effectiveness is long-term sustainability of effects . Although this criterion may not be required to estab lish effectiveness in other disciplines, it is very impor tant in evaluating violence prevention programs because beneficial effects can diminish quickly after youths leave a treatment setting or program to return to their usual environment. Effective programs produce long-term changes in individual competencies, environmental conditions, and patterns of behavior. Thus, successful programs get youths off a violent life course trajectory. The sus tainability of effects is particularly difficult for early intervention programs, which can be implemented more than a decade before the peak age of onset for youth violence. Ideally, effects would be sustained though adolescence. On a practical level, programs in this report are considered to have demonstrated sus tainability if the effects of the intervention continue for at least a year after treatment or participation in the designed intervention, with no evidence of a subse quent loss of effect . Higher standards should be set for programs that are promoted and disseminated on a national level than for those being developed and implemented on a more restricted basis at the local level. Before a program is recommended and funded for national implementation, it is important to show clearly that it has a significant, sustained preventive or deterrent effect and that it can be expected to have positive results in a wide range of community settings (as long as it is implemented cor rectly and with the appropriate population). Programs that meet such high standards are designated Model programs. Those that do not quite meet these rigorous standards are recognized and encouraged as Promising, with the caution that they be carefully evaluated. Identifying ineffective programs is another ele ment of assessing best practices. It is as important to know which programs do not work-and should not be supported with limited prevention funds-as it is to know which do work. The same scientific stan dards are used in judging effectiveness and ineffec tiveness. Because it is generally unlikely that a highquality evaluation will be conducted on a program that shows little sign of effectiveness, only two spe cific programs have been designated Does Not Work in this report. Some general strategies identified as ineffective in this report may not actually be flawed; rather, their lack of effectiveness may result from poor program implementation or a poor match between program and target population. Alternatively, some approach es may appear ineffective when used in isolation because their effects are quite small and difficult to detect. These approaches should not be used alone, but they may be useful as components of more com prehensive strategies that have positive preventive effects. In other cases, however, a program or approach may be ineffective because the basic strate gy is flawed-that is, the method or approach used to change the targeted risk or protective factors does not have the intended effect. The following is a summary of the scientific stan dards for establishing the effects of a violence preven tion program. # Model • Rigorous experimental design (experimental or quasi-experimental) • Significant deterrent effects on: -Violence or serious delinquency (Level 1) -Any risk factor for violence with a large effect size (.30 or greater) (Level 2) • Replication with demonstrated effects • Sustainability of effects # Promising • Rigorous experimental design (experimental or quasi-experimental) • Significant deterrent effects on: -Violence or serious delinquency (Level 1) -Any risk factor for violence with an effect size of .10 or greater (Level 2) • Either replication or sustainability of effects # Does Not Work • Rigorous experimental design (experimental or quasi-experimental) • Significant evidence of null or negative effects on violence or known risk factors for violence • Replication, with the preponderance of evidence . suggesting that the program is ineffective or harmful Youth Violence: A Report of the Surgeon General Other standards have been proposed for youth violence prevention programs, particularly those intended for implementation on a national level. One of these is cost-effectiveness, a key consideration in program funding but not a scientific criterion for effectiveness. Unfortunately, there are no standardized cost criteria for violence prevention programs, so it is difficult to compare costs across programs (Elliott, 1998). Moreover, it is difficult to obtain reliable costbenefit estimates for individual programs. Despite these obstacles, some researchers have conducted extensive reviews of the costs and benefits of violence and delinquency prevention and in terv en tio n p ro gram s (G reenw ood, 1995;G reenw ood et al., 1998;K aroly et al., 1998;Washington State Institute for Public Policy, 1999). Their findings will be discussed in the cost-effectiveness section of this chapter. This is an important and growing area of research. Setting such stringent scientific standards auto matically limits the number and types of programs that will be identified as effective in this report. The spe cific programs that can meet these standards will be determined in part by the nature of the program-the design must lend itself to scientific evaluation-and in part by whether funding has been made available for program evaluation. For instance, early childhood individual change programs are overrepresented in the list of effective programs. This fact is probably a result of the relatively large amount of funding allocated to the study of these programs and the relative ease with which experimental evaluations can be carried out. On the other hand, programs promoting change in the social structure, community-level programs, and pro grams that focus on environmental change more gen erally (in schools, neighborhoods, peer groups, and so on) are probably underrepresented in this report. Evaluation of such programs and strategies is more dif ficult and costly; therefore, fewer rigorous evaluations of these programs have been done. Because of these limitations, the programs dis cussed in this report may not represent the overall bal ance of youth violence prevention programs currently being implemented in communities throughout the country. This shortcoming highlights the need for more research on program effectiveness and for the development of additional criteria and valid measures for assessing the effects of community-or schoolbased and environmental change programs. In addi tion, the imbalance should not be interpreted as an indication that such programs are less effective than programs that focus on individual change. Indeed, there is some evidence that school-based programs designed to change the social climate of the classroom or school are more effective than individual change programs (Gottfredson et al., in press). # St a t e g ie s a n d P r o g r a m s : M o d e l , P r o m is in g , a n d D o e s N o t W o r k It is important to reiterate that the specific programs and general strategies discussed in this report have been identified from recent reviews of the literature on youth violence prevention. Although this information is growing rapidly, youth violence prevention remains a young field, and only limited evaluation data are available for many strategies and programs. Therefore, the absence of a particular strategy or program from this section does not in any way imply that it is inef fective; rather, the information available is not suffi cient to justify any conclusions about its effectiveness. Model and Promising programs meet the scientif ic criteria for effectiveness outlined above within the populations in which they have been tested (as indi cated in the text). These programs are widely regard ed by the youth violence prevention community as effective. Appendix 5-A shows the consistency with which they have been recommended by various inde pendent groups of researchers as best practices in youth violence prevention. With only a few excep tions, each of the programs has already been identified as a best practice in two or more other reports on what works in youth violence prevention. This section is divided into prevention and inter vention efforts. True prevention, or primary preven tion, is defined in this report as lessening the likeli hood that youths in a treatment or intervention pro gram will initiate violent behavior, compared to youths in a control group. In some cases, the preven tion of risk factors for violent behavior is considered the outcome, and the reduced likelihood of youths' encountering this risk is the measure of effective ness. Therefore, prevention programs are designed to target youths who have not yet become involved in violence or encountered specific risk factors for vio lence. Prevention efforts include general strategies and programs that target general (universal) popula tions of youths. Intervention, on the other hand, is defined as reducing the risk of violence among youths who dis play one or more risk factors for violence (high-risk youths) or preventing further violence or the escalation of violence among youths who are already involved in violent behavior. These types of interventions are also known as secondary and tertiary prevention, respec tively. Thus, intervention includes programs that target high-risk (selected) populations of youths or already violent (indicated) youths. Although there is some overlap between prevention and intervention efforts, programs that are most effective in general populations of young people are not always effective in reducing further violence among seriously delinquent youths. The programs discussed below are listed in Appendix 5-B, along with more detailed information on each one. Specific results of the evaluations are found there; findings are described in general terms in this chapter. Box 5-1 summarizes effective and inef fective strategies, and Box 5-2 lists the programs dis cussed below by best practices category: Model, Promising, or Does Not Work. # Primary Prevention: General Populations of Young People All of the programs and strategies discussed in this section are primary prevention approaches to reduc ing youth violence-that is, they are implemented on a universal scale and aim to prevent the onset of youth violence and related risk factors. Some are designed to change individual risk factors, others tar get environmental risk factors, and a few are designed to change both. # Skill-and Competency-Building Programs Skills-oriented programs are among the most effective general strategies for reducing youth violence and risk factors for youth violence. In fact, two universal pro grams that take this approach have met the criteria for a Model program: Life Skills Training and the Midwestern Prevention Project. Life Skills Training (LST) is designed to prevent or reduce gateway drug use. The program targets stu dents in middle or junior high school, with initial implementation in grades 6 and 7 and booster sessions for the next 2 years. The curriculum has three major components: self-management skills, social skills, and information and skills related specifically to drug use. Teachers use a variety of techniques, including instruction, demonstration, feedback, reinforcement, and practice, to train students in these three core areas. Evaluations show that the program can cut tobacco, marijuana, and alcohol use. Moreover, long-term effects of participation in Life Skills Training include a lower risk of polydrug use, pack-a-day smoking, and inhalant, narcotic, and hallucinogen use. The Midwestern Prevention Project targets middle school students (grades 6 or 7). Its goal is to reduce the risk of gateway drug use associated with the transition from early adolescence to middle through late adoles-cence by training youths to avoid drug use and situa tions in which drugs are likely to be used. The program has five major components that are implemented in stepwise fashion over the course of approximately 4 years: mass media program, school program, parent education and organization, community organization, and local health policy. The mass media program spans the duration of the project, while the other components are introduced at a rate of approximately one per year. The school-based component forms the core of the pro gram. This project has demonstrated positive effects on a number of outcomes that are closely related to youth violence. For instance, it has been shown to reduce daily smoking and marijuana use and to lessen mari juana use, hard drug use, and smoking through age 23. In addition, the project has facilitated improvements in parent-child communication about drug use and in the development of prevention programs, activities, and services within communities. Two school-based programs that focus on teaching important social skills to students, Promoting Alternative Thinking Strategies and I Can Problem Solve, meet the criteria for a Promising program. The Promoting Alternative Thinking Strategies (PATHS) curriculum is taught to elementary school students at entrance through grade 5. Lessons targeting emotional competence (expression, understanding, and regula tion), self-control, social competence, positive peer rela tions, and interpersonal problem-solving skills are deliv ered three times a week in 20-to 30-minute sessions. Evaluations of PATHS show that this program has posi tive effects on several risk factors associated with vio lence, including aggressive behavior, anxiety and depression, conduct problems, and lack of self-control. The effectiveness of PATHS has been demonstrated for both regular-education and special-education students. I Can Problem Solve has been used effectively with students in nursery school, kindergarten, and grades 5 and 6. The main goal of this program, which is implemented in 12 small-group sessions over 3 months, is to train children to use problem-solving skills to find solutions to interpersonal problems. In evaluations, I Can Problem Solve has improved class room behavior and children's problem-solving skills for up to 4 years after the end of the intervention. Whereas this program is appropriate for all children, it has been most effective with children living in poor, urban areas. drug and alcohol use. Children who participate in LIFT exhibit less physical aggression on the play ground, better social skills, and, in the long term, less likelihood of associating with delinquent peers, using alcohol, or being arrested. # Behavior Management Programs Strategies that take a behavioral approach to youth violence can also have positive, consistent effects on violence, delinquency, and related risk factors. The behavioral approaches shown to be effective in pre venting youth violence on a universal scale are gener ally school-based and include behavior monitoring and reinforcement of attendance, academic progress and school behavior, and behavioral techniques for classroom management. Much of the evidence on the effectiveness of behavior monitoring and reinforcement comes from studies conducted by Bry and colleagues (Bry, 1982;Bry & George, 1979. These studies pro vide evidence' that interventions focusing on enhanc ing positive student behavior, attendance, and aca demic achievement through consistent rewards and monitoring can reduce substance use, self-reported criminal activity, and arrests, as well as enhance aca demic achievement in middle school students. In one study, for example, students exposed to this type of intervention were far less likely than students in a con trol group to have a delinquency record 5 years after the program. Behavioral techniques for classroom manage ment are a general strategy for changing the classroom environment. According to a review by O ' Leary and O'Leary (1977), the best strategies for promoting pos itive classroom behavior are establishing clear rules and directions, use of praise and approval, behavior modeling, token reinforcement, self-specification of contingencies, self-reinforcement, and behavior shap ing. Several strategies aimed at reducing negative stu dent behaviors are also effective: ignoring misbehav ior, reinforcing behavior that is incompatible with negative behavior, relaxation methods, and using disciplinary techniques such as soft reprimands, time outs, and point loss and fines in token economies. # 124'm The Seattle Social Development Project is an excellent example of a program that includes classroom behavior management among its core components. The goal of this Model program is to enhance elementary school students' bonds with school and their families while decreasing a number of early risk factors for vio lence. Like other Model programs in this report, the ini tiative includes both individual and environmental change approaches and multiple components known to improve the effectiveness of violence prevention efforts. In addition to classroom behavior management, the components include child skills training and parent training, discussed later in this section. Through these three components, which target prosocial behavior, interpersonal problem solving, academic success, and avoidance of drug use, the Seattle Social Development Project reduces the initia tion of alcohol, marijuana, and tobacco use by grade 6 and improves attachment and commitment to school. At age 18, youths who participated in the full 5-year version of this program have lower rates of violence, heavy drinking, and sexual activity (including multi ple sexual partners and pregnancy) and better aca demic performance than controls. The Seattle Social Development Project has been used effectively in both general populations of youths and high-risk children attending elementary and middle school. Classroom behavior management is also a core component of three Promising programs: the Bullying Prevention Program, the Good Behavior Game, and the School Transitional Environmental Program. The Bullying Prevention Program targets students in ele mentary, middle, and junior high school. It begins with an anonymous student questionnaire designed to assess bullying problems in individual schools. Using this information, parents and teachers implement school-, classroom-, and individual-level interven tions designed to address the bullying problems iden tified in the questionnaire, including individual work with students identified as bullies and victims. At the classroom level, teachers and students work together to establish and reinforce a set of rules about behavior and bullying, creating a positive, antibullying climate. This program has both individual change and environ mental change objectives. # 2 5 In elementary and junior high schools in Bergen, Norway, bullying problems were cut in half two years after the intervention. Antisocial behavior, including theft, vandalism, and truancy, also dropped during these years, and the social climate of the school improved. Replications have been conducted in England, Germany, and the United States, with similar effects. Like the Bullying Prevention Program, the Good Behavior Game uses classroom behavior manage ment as the primary means of reducing problem behaviors. The Good Behavior Game targets elemen tary school children and seeks to improve their psy chological well-being and decrease early aggressive or shy behavior. While both of these programs can reduce antisocial behavior, their effects on violence and delinquency have not yet been measured. This intervention has shown positive effects, as measured by teachers' reports of aggressive and shy behaviors in first-graders. Long-term evaluations show sustained decreases in aggression among boys rated most aggressive in first grade. Effects on vio lence and delinquency have not been measured. The third Promising primary intervention pro gram that makes use of classroom behavior manage ment is the School Transitional Environmental Program, or STEP. STEP is based on the Transitional Life Events model, which postulates that stressful life events, such as transitions between schools, place children at risk of maladaptive behav ior. The program's goals are to reduce the stress and disorganization often associated with changing schools by redefining the role of homeroom teachers. Behavior management is used to create an environ ment that promotes academic achievement and reduces school behavior problems and absenteeism. Participation in this program has been shown to reduce substance use and delinquency while improv ing academic achievement and school dropout rates. The STEP program has been most successful with students entering junior and senior high schools in urban, predominantly nonwhite communities. The program is also effective with students at high risk of behavioral problems. # Capacity-Building Programs Several other school-level environmental approaches are effective in reducing youth violence and related outcomes. For instance, those that focus on building a school's capacity to plan, implement, and sustain pos itive changes can significantly reduce student delin quency and drug use. One program in which students were empowered to address school safety problems resulted in significant reductions in fighting and teacher victimization. Program Development Education is an example of this approach to reducing youth violence. It is a structured organizational devel opment approach used to help organize, plan, initiate, and sustain school change. This approach has demon strated positive effects on delinquency rates lasting at least 2 years into the program. evidence is not yet strong enough to classify the Boys and Girls Clubs and the Big Brothers Big Sisters of America programs as Model or Promising, it is strong enough to conclude that the general strat egy of these and similar programs is effective at reducing youth violence and violence-related out comes. For instance, evaluations of Boys and Girls Clubs have shown reductions in vandalism, drug trafficking, and youth crime. An evaluation of a Canadian after-school program demonstrated large reductions in arrests. Although this general strategy is included with the primary prevention efforts, it can also be considered a secondary prevention strategy, since the specific youth development programs list ed above are usually implemented in high-risk neighborhoods. # Teaching Strategies Two other school-based primary prevention strategies are effective at reducing the risk of academic failure, a risk factor for youth violence: continuous progress program s and cooperative learning. Continuous progress programs are designed to allow students to proceed through a hierarchy of skills, advancing to the next level as each skill is mastered. This approach has shown consistent, positive effects on academic achievement in elementary school students in seven separate evaluations. Cooperative learning is another innovative envi ronmental change approach that can improve academ ic achievement in elementary school children. Quite different from continuous progress programs, cooper ative learning programs place students of various skill levels together in small groups, allowing students to help each other learn. Studies by Slavin (1989Slavin ( , 1990 show that this approach has positive effects on atti tudes toward school, race relations, attitudes toward mainstreamed special-education students, and aca demic achievement. # Community-Based Programs Community-based strategies can also affect youth violence at the universal level. One such strategy is positive youth development programs. While the # Ineffective Primary Prevention Programs # School-Based Programs Some educational approaches that target universal populations have shown a consistent lack of effect in scientific studies. Peer-led programs, including peer counseling, peer mediation, and peer leaders, are among them. In a 1987 review of these interventions, Gottfredson concluded that there is no evidence of a positive effect and that these strategies can actually harm high school students. Results of a meta-analysis confirmed this finding, adding that adult-led programs are as effective as, or more effective than, peer-led programs in reducing youth violence and related risk factors. Nonpromotion to succeeding grades is another educational approach that can have harmful effects. Studies of this approach demonstrate negative effects on student achievement, attendance, behavior, and attitudes toward school. One school-based universal prevention program meets the criteria for Does Not Work: Drug Abuse Resistance Education, or DARE. DARE is the most widely implemented youth drug prevention program in the United States. It receives substantial support from parents, teachers, police, and government fund ing agencies, and its popularity persists despite numerous well-designed evaluations and meta-analy ses that consistently show little or no deterrent effects on substance use. Overall, evidence on the effects of the traditional DARE curriculum, which is imple mented in grades 5 and 6, shows that children who participate are as likely to use drugs as those who do not participate. However, some positive effects have been demonstrated regarding attitudes toward police. Researchers have suggested several reasons for DARE's lack of effectiveness. The program is most commonly criticized for its limited use of social skills training and for being developmentally inappropriate. Specifically, DARE is implemented too early in child development: It is hard to teach children who have not gone through puberty how to deal with the peer pressure to use drugs that they,will encounter in middle school. Changes are being made at the national level in an attempt to improve the program's effectiveness. DARE developers have added social skills training sessions to the core curriculum and have developed a modified version of the curriculum that can be used in older student populations. These versions of DARE have not yet been evaluated.4 # Secondary Prevention: Children at High Risk of Violence Secondary prevention programs and strategies are implemented on a selected scale, for children at enhanced risk of youth violence, and are aimed at pre venting the onset and reducing the risk of violence. Programs that target the families of high-risk children are among the most effective in preventing violence. Several family-based strategies and programs are included in the discussion below. # Parent Training One effective approach involves training parents to use specific child management skills. A review by Dumas (1989) shows that parent training can lead to clear improvements in children's antisocial behavior (includ ing aggression) and family management practices. In individual studies with disruptive/aggressive/hyperactive boys and girls, parent training has resulted in reduced aggressive, antisocial, and delinquent behav iors; lower arrest rates (including arrests for assault); less overall delinquency; and academic improvement. The following five Promising youth violence preven tion programs include parent-training components. The Montreal Longitudinal Study, sometimes called the Preventive Treatment Program, is a 2-year intervention aimed at preventing delinquency among 7to 9-year-old boys from low-income families who have been identified as disruptive. The program has two major components: school-based social skills training (19 sessions) and parent training (17 sessions). The par ent-training sessions, provided every 2 weeks for the duration of the intervention, teach parents to read with their children, monitor and reinforce their children's behavior, use effective discipline, and manage family crises. A long-term follow-up of Canadian boys enrolled in this program found positive effects on academic achievement and avoidance of gang involvement, drug and alcohol use, and delinquency up to age 15. The Syracuse Family Development Research Program targets parents and children in impover ished families. It provides weekly home visitation with parent training by paraprofessional child devel opment trainers and 5-year individualized day care that includes child training on social and cognitive skills and child behavior management. The Perry Preschool Program provides early education to chil dren age 3 and 4 from families with low socioeco nomic status. The preschool lasts 2 years and is designed to offer high-quality early childhood educa tion and promote young children's intellectual, social, and physical development. In addition, this intervention provides weekly home visits by teachers and referrals for social services, when needed. Both of these programs have demonstrated long-term effects (up to age 19) on delinquency, academic achievement, and other school-related outcomes. In addition, the Perry Preschool Program has produced significant reductions in antisocial behavior, serious fights, police contacts, and school dropout rates. Parent training is one of a broad range of family services offered through Parent Child Development Center Programs, which target low-income families with children age 2 months to 3 years. The parent training component of this intervention targets moth ers as the primary caregivers and focuses on infant and child development, home management, and fami ly communication and interaction skills. The pro grams have positive effects on a variety of risk factors for youth violence, including child antisocial behavior and fighting and mother-child relationships. The Parent-Child Interaction Training program targets low-income parents with preschool children who have at least one behavioral or emotional prob lem. Parents enrolled in the program participate in a series of four to five small-group sessions in which they learn a variety of parenting skills such as man agement of child behavior. This intervention has been shown to improve family management practices and reduce children's antisocial behaviors, including aggression and anxiety. # Home Visitation Another effective family-based approach to prevent ing youth violence is home visitation, in which a nurse or other professional goes to the child's home and pro vides training, counseling, support, monitoring, or all of these services to first-time, low-income, or other wise at-risk mothers. This strategy is particularly effective when implemented before children develop behaviors that put them at risk of violence. Home visitation, with or without early childhood education programs, has shown significant long-term effects on violence, delinquency, and related risk fac tors in a number of studies. The degree of effect is dependent on several factors, including length (only long-term programs have demonstrated consistent effects), delivery (nurses appear to be the most effec tive home visitors, although some positive effects have been demonstrated with other types of visitors), and timing (the earlier these programs begin, the better). Prenatal and Infancy Home Visitation by Nurses is the only home visitation program that meets the cri teria for a Model youth violence prevention program. # O It also incorporates all of the characteristics associat ed with the most effective home visitation programs: It is delivered by nurses, it begins early (before the child's birth), and it is long-term, lasting from before birth to age 2. Home visits are scheduled at intervals from 1 week to 1 month throughout the 2-year inter vention. The program targets low-income, at-risk pregnant women bearing their first child. The goals are (1) to improve pregnancy outcomes and child care, health, and development, (2) to build a social support network around the family, and (3) to enhance moth ers' personal development, including educational achievement, participation in the workforce, and per sonal competency skills and self-efficacy. Prenatal and Infancy Home Visitation by Nurses has a number of long-term, positive effects on youth violence and related outcomes, including fewer arrests and less'alcohol use by youths at age 15 and lower rates of child abuse and neglect, compared to controls. While child abuse and neglect are not usually consid ered a violence outcome in this report, they are includ ed here because the intervention is designed for moth ers who are still youths themselves. # Multicontextual Programs Several Promising secondary youth violence preven tion programs address multiple contexts that affect a child's risk of future violence: home, school, and com munity. The Yale Child Welfare Project is a Promising program that uses in-home visitation and day care to deliver parent training and other family and child services. This intervention targets healthy, first-born infants of mothers with incomes below the poverty level who live in inner cities. The 30-month program includes weekly home visits (usually by a social worker), pediatric medical care, psychological services, and early education (day care) for children. Ten-year follow-up of families involved in the Yale Child Welfare Project shows that the program has pos itive effects on parent involvement in their children's education, academic achievement (less need for reme dial and supportive services), and antisocial behavior. Striving Together to Achieve Rewarding Tomorrows, CASASTART, formerly known as the Children At Risk (CAR) program, targets at-risk youths age 11 to 13 who live in severely distressed neighbor hoods. The intervention has eight core components; each targeting a different context that affects the risk of violence: community-enhanced policing/enhanced enforcement, case management for youth and families, criminal/juvenile justice intervention, family services, after-school and summer activities, educational services, mentoring, and incentives for participation. Evaluations of CASASTART demonstrate that it has positive effects on avoidance of gateway drug use, violent crime, and drug sales and that these effects are sustained up to 1 year after participation. The most comprehensive of these Promising mul ticontextual interventions is Families and Schools Together, or the FAST Track project. This interven tion combines several of the strategies identified in this chapter as effective: social skills training, parent training, home visitation, academic tutoring, and classroom behavior management techniques. The pro gram targets children identified as disruptive in kindergarten and aims to prevent severe, chronic con duct problems by increasing communication and strengthening bonds between the school, home, and child, thereby enhancing social, cognitive, and prob lem-solving skills and improving peer relationships. FAST Track has positive effects on several risk factors associated with youth violence, including academic achievement and parent-child relationships. Although initial evaluations did not show any effects of this program on children's antisocial behaviors, the long term follow-up studies now in progress should be able to determine whether FAST Track has a significant effect on this violence-related outcome. Another comprehensive Promising intervention, The Incredible Years Series, is a series of curricula for parents, teachers, and children aimed at promoting social competence and preventing, reducing, and treat ing conduct problems in at-risk children age 3 to 8 . In each of these three curricula, trained facilitators use videotapes to encourage problem solving and discus sion. # Academic Programs Several educational approaches are effective at improv ing academic achievement, a weak but nevertheless important risk factor for late-onset youth violence (see Chapter 4). An effective secondary prevention strategy for improving academic performance is compensatory education, which targets students at risk of academic failure. Compensatory education strategies (such as cross-age or adult tutoring) that involve pulling stu dents out of their regular classes to receive extra assis tance in reading and math can improve long-term aca demic performance for all students, regardless of their achievement level. Moreover, when older students tutor younger students, both groups show academic gains. A meta-analysis of peer and cross-age tutoring of elemen tary and middle school students showed substantial effect sizes for academic achievement in both tutors and those tutored (Cohen et al., 1982). In more recent years, the compensatory education approach has been expanded to include schoolwide interventions. Preventive Intervention is a 2-year, school-based behavioral reinforcement program that begins in grade 7 and targets students with low academic moti vation, family problems, or disciplinary problems. The intervention includes behavior monitoring and reinforcement in the classroom as well as enhanced communication (through regular classroom meetings and reports to parents) between teachers, students, and parents regarding behavior and attendance at school. Educational assistance is one of three major com ponents of the Quantum Opportunities Program, a community-based intervention that targets adoles cents from families receiving public assistance. Students who participate in this program are assigned to a peer group and a caring adult and receive up to 250 hours of educational services to enhance academ ic skills; activities targeting personal development, life skills, career planning, and other areas; and serv ice opportunities in the community. The intervention begins at grade 9 and continues through high school. Both of these programs have demonstrated posi tive effects on several aspects of academic achieve ment, and Preventive Intervention has been shown to reduce drug use and the risk of having a county court record 5 years after participation. # Moral-Reasoning, Problem-Solving, Thinking Skills As seen in some of the programs above, interventions that aim to improve youths' moral-reasoning, problem solving, and thinking skills are also effective approach es to reducing youth violence in high-risk populations. For instance, one moral-reasoning-based intervention implemented in "behavior-disordered" high school stu dents has demonstrated lasting positive effects by reducing police contacts and official school disciplinary actions (Arbuthnot & Gordon, 1986). Evidence of the effectiveness of social problem-solving interventions includes a study of children and young adolescents referred for treatment of antisocial behavior; these youths showed significantly lower aggression scores after treatment and lower rates of externalizing behav ior 1 year later (Kazdin et al., 1989). The evidence supporting thinking skills approaches is similar, with particularly impressive results from two interventions: Lochman's Anger Coping Intervention and Rotheram's social skills training intervention. Lochman (Lochman, 1992;Lochman et al., 1984) reports large reductions in dis ruptive-aggressive behavior immediately after the program and reductions in substance use 3 years later in high-risk, aggressive boys in grades 4 through 6 . Rotheram's studies (1982) demonstrate improvements in academic achievement and in aggressive problem solving responses-both risk factors for violent behavior. Researchers speculate that one reason for the effectiveness of social skills interventions is that they are often more comprehensive in scope than other types of cognitive-behavioral approaches to pre venting youth violence and related outcomes. # Ineffective Secondary Prevention Approaches Whereas the research presented above demon strates that a large number of approaches and pro e m s can have significant, positive effects on youth violence and violence-related risk factors, several popular prevention approaches used in high-risk pop ulations have been shown to be ineffective. These include gun buyback programs, firearm training, and mandatory gun ownership. Gun buyback programs, a particularly expen sive strategy, have consistently been shown to have no effect on gun violence, including firearm-related homicide and injury. This finding may appear coun terintuitive, given the fact that these programs do, in fact, take guns off the street. However, there is some evidence that most of the guns turned in are not func tional and that most persons turning in guns have other guns at home. Two less popular strategies, firearm training and mandatory gun ownership, have also demonstrated no significant effects on firearm-related crimes. These approaches were expected to deter gun violence by increasing the num ber of private citizens who were trained to use guns properly and who owned firearms for protection. Two community-based strategies for preventing youth violence, redirecting youth behavior and shifting peer group norms, have also shown a lack of effect in reducing youth violence. In fact, because both approaches tend to group high-risk youths together, they can actually increase the cohesiveness of delinquent peer groups and facilitate deviancy training (Dishion et al., 1994(Dishion et al., , 1995. Programs that aim to redirect high-risk youth toward conventional activities involve recreational, enrichment, and leisure activities, including the popular Midnight Basketball program. In general, programs that focus on shifting peer group norms have attempted to turn youth gangs into benign clubs. Instead, these programs have had no effect or have actually increased gang-related delinquent behavior. # Tertiary Prevention: Violent or Seriously Delinquent Youths Each of the programs and strategies highlighted in this section is implemented on an indicated scale, that is, for young people who have already demon strated violent or seriously delinquent behavior. The best information on general strategies that are effec tive dr ineffective in reducing the risk of further vio lence among these youths comes from meta-analy ses. The most rigorous and most frequently cited meta-analyses of violence prevention programs are those conducted by Lipsey and colleagues and by Andrews and colleagues (Lipsey, 1992a(Lipsey, , 1992bLipsey & Wilson, 1998;Andrews, 1994;Andrews et al., 1990). This section draws largely on these analy ses, which include interventions targeting youths involved in any delinquent behavior and those involved in serious delinquent behavior. To enhance readability, the meta-analyses are cited here rather than throughout the text. Effect sizes are a stan dardized mean difference, corrected for small sam ple size and method effects. This measure reflects the average difference (expressed in standard devi ation units) between the program group and com parison groups in regard to violence, substance abuse, and risk factors. Two major conclusions come from Lipsey's research. The first is that effective treatment can divert a significant proportion of delinquent and vio lent youths from future violence and crime. This finding contradicts the conclusions of scientists two decades ago who declared that nothing had been shown to prevent youth violence. The second major conclusion is that there is enormous variability in the effectiveness of different types of programs for seri ously delinquent youth. The most effective pro grams, on average, reduce the rate of subsequent offending by nearly half (46 percent), compared to controls, whereas the least effective programs actu ally increase the rate of subsequent offending by 18 percent, compared to controls. So, while some kinds of interventions substantially reduce youth violence and delinquency, others appear to be harmful (iatro genic), actually increasing involvement in these behaviors. # Behavioral and Skill Development Interventions Studies of male serious offenders demonstrate that treatment which includes a social perspective-taking/role-taking component can improve role-taking skills and reduce serious delinquent behavior for at > .131 least 18 months after treatment (Chandler, 1993). This finding is consistent with results from the Lipsey (Table 5-1) and Andrews studies, which indicate that multimodal, behavioral, and skills-oriented inter ventions are more effective than counseling and other less-structured approaches (see also Gendreau & Ross, 1987). In fact, in most youth populations-uni versal, selected, or indicated-behavioral and skillsoriented strategies are among the most effective vio lence prevention approaches. # Family Clinical Interventions Although Lipsey reports only a small average effect size for reducing recidivism with family therapy (Table 5-1), the review literature indicates that specif ic strategies can be quite effective at preventing vio lence in delinquent youths and preventing further vio lence in already violent youths. One such approach is marital and family therapy by clinical staff. While marital and family therapy can include several differ ent strategies, a common thread is the focus on chang ing maladaptive or dysfunctional patterns of family interaction and communication, including negative parenting behaviors-all risk factors for youth vio lence. Marital and family therapy shows consistent, positive effects on family functioning, child behavior, family interactions, and delinquency (Tremblay & Craig, 1995). Long-term studies have demonstrated positive effects of family therapy by clinical staff last ing up to 9 years. Three Model tertiary youth violence prevention programs that use the family therapy approach are Functional Family Therapy, Multisystemic Therapy, and Multidimensional Treatment Foster Care. They are described below. Functional Family Therapy (FFT) is actually a secondary and tertiary prevention program, since it targets youths 11 to 18 years old at risk of or already demonstrating delinquency, violence, substance use, conduct disorder, oppositional defiant disorder, or disruptive behavior disorder. FFT is a multistep, pha sic intervention that includes 8 to 30 hours of direct services for youths and their families, depending upon individual needs. The phases of the interven- & Wilson, 1998, p. 318). t+ This calculation assumes a 50% recidivism rate in the absence of intervention. tion include engagement (to reduce the risk of early dropout), motivation (to change maladaptive beliefs and behaviors), assessment (to clarify interpersonal behavior and relationships), behavior change (including skills training for youths and parents), and generalization (in which individualized casework is used to ensure that new skills are applied to func tional family needs). These services are delivered in multiple settings by a wide range of interventionists, including supervised paraprofessionals, trained probation officers, mental health technicians, and mental health professionals with appropriate advanced degrees. The benefits of FFT include the effective treatment of conduct disor-0 -oppositional defiant disorder, disruptive behavior )T COPY AVAILABLE l 3 3 i 6 disorder, and alcohol and other drug abuse disorders; reductions in the need for more restrictive, costly serv ices and other social services; reductions in the inci dence of the original problem being addressed; and reductions in the proportion of youths who eventually enter the adult criminal justice system. In two trials, recidivism was found to be lower among participants than controls. Evidence of a diffusion effect was also found, with fewer siblings of participants acquiring a court record in the 2 to 3 years following treatment. Multisystemic Therapy (MST) is an intensive family-and community-based treatment that address es multiple determinants of antisocial behavior. This approach is implemented within a network of inter connected systems that includes one or more of the following contexts: individual, family, peer, school, and neighborhood. MST targets families with chil dren in the juvenile justice system who are violent, substance-abusing, or chronic offenders and at high risk of out-of-home placement. Four types of servic es are delivered through a home-based model: strate gic family therapy, structural family therapy, behav ioral parent training, and cognitive-behavioral thera py. While the intensity of services ultimately depends on individual youth and family needs, the average MST family receives 60 hours of direct services delivered over a period of 4 months. Program out comes in serious delinquents include reductions in long-term rates of rearrest, reductions in out-of-home placements, improvements in family functioning, and reductions in mental health problems among treated youths, compared to controls. Multidimensional Treatment Foster Care is a multisystemic (multicontextual) clinical intervention that targets teenagers with histories of chronic and severe criminal behavior as an alternative to incarcera tion, group or residential treatment, or hospitalization. Meta-analyses conducted by Lipsey and others demon strate that community-based treatment is more success ful than residential treatment for this population of youths. Multidimensional Treatment Foster Care implementers recruit, train, and supervise foster fami lies to offer youths treatment and intensive supervision at home, in school, and in the community. The program also provides parent training and other services to the biological families of treated youths, helping to improve family relationships and reduce delinquency when youths return to their homes. Youths who partici pate in this program also receive behavior management and skill-focused therapy and a community liaison who coordinates contacts among case managers and others involved with the youths. Evaluations indicate that Multidimensional Treatment Foster Care can reduce the number of days of incarceration, overall arrest rates, drug use, and program dropout rates in treated youths versus controls during the first 1 2 months after com pleting treatment; it can also speed the placement of youths in less restrictive, community settings. # Justice System Services Justice system approaches to preventing youth vio lence can be effective when they focus on providing services rather than instituting greater penalties. One promising justice system approach is wraparound services, in which comprehensive services are tai lored to individual youths, as opposed to trying to fit youths into predetermined or inflexible programs. Evaluations of Wraparound Milwaukee have shown reductions in recidivism and arrests during the year following participation. One juvenile justice system approach to prevent ing youth violence meets the standards described above for a Promising program: Intensive Protective Supervision Project. This intervention removes delin quent youths (status offenders) under the age of 16 from criminal justice institutions and provides them with proactive and extensive community supervision. This program has been shown to have greater deter rent effects on referrals to juvenile court than standard protective supervision does. # Ineffective Tertiary Programs and Strategies Several popular juvenile justice approaches to pre venting further criminal behavior in delinquent youths have been shown to be consistently ineffective: specifically, boot camps, residential programs, milieu treatment, behavioral token programs, and waivers to adult court. # Boot Camps Perhaps the most well known of these approaches, boot camps for delinquent youths are modeled after military basic training, with a primary focus on disci pline. Compared to traditional forms of incarceration, boot camps produced no significant effects on recidi vism in three out of four evaluations and trends toward increased recidivism in two. The fourth evalu ation showed significant harmful effects on youths, with a significant increase in recidivism. Boot camps typically focus very narrowly on phys ical discipline, a highly specific personal skill, rather than a broader range of skills and competencies, such as those addressed by effective programs. Boot camps are also a setting in which youths are exposed to other delinquent youths, who can act as models and positive ly reinforce delinquent behavior (Dishion et al., 1994). # Residential Programs Residential programs, interventions that take place in psychiatric or correctional institutions, also show little promise of reducing subsequent crime and vio lence in delinquent youths. While some residential programs appear to have positive effects on youths as long as they remain in the institutional setting, research demonstrates consistently that these effects diminish once young people leave. Evaluations of two residential programs showed that participating youths were actually more likely to be rearrested and to report they had committed serious offenses during follow up. In both studies, the comparison group consisted of youths assigned to regular training schools. Two general approaches that are popular in resi dential settings are milieu treatment and behavioral token programs. Both strategies aim to change the organizational structures of residential programs. The milieu treatment approach is characterized by resident involvement in decision making and day-to-day inter action for psychotherapeutic discussion. While this approach shows some positive effects when individual responsibility is stressed, the more common strategy of group decision making has shown no positive effect on recidivism after release. Moreover, Lipsey and Wilson's meta-analysis shows that milieu therapy is one of the least effective approaches to preventing recidivism in serious juvenile offenders (Table 5-1). In behavioral token programs, youths are reward ed for conforming to rules, exhibiting prosocial behav ior, and not exhibiting antisocial or violent behavior. Like some other residential approaches, behavioral token programs can have positive effects on targeted behaviors while youths are institutionalized. However, when this strategy is used alone, any such effects dis appear when youths leave the program. # Waivers to Adult Court Another popular justice system approach to deterring youth violence, waivers to adult court, can have par ticularly harmful effects on delinquent youths. The idea behind this approach, "adult time for adult crime," was widely accepted into practice in the 1990s, when youth violence escalated dramatically. Evaluations of these programs suggest that they increase future crim inal behavior rather than deter it, as advocates of this approach had hoped. Moreover, placing youths in adult criminal institutions exposes them to harm. Results from a series of reports indicate that young people placed in adult correctional institutions, compared to those placed in institutions designed for youths, are eight times as likely to commit suicide, five times as likely to be sexually assaulted, twice as likely to be beaten by staff, and 50 percent as likely to be attacked with a weapon (Bishop, 2000;Bishop & Frazier, 2000;Fagan et al., 1989;Flaherty, 1980). # Counseling Several counseling, therapy, and social work approach es to treating delinquent youths have also been shown to be ineffective in the review literature, a finding that is consistent with the results of Lipsey's meta-analyses (Table 5-1). One "mainstay" (Tolan & Guerra, 1994, p. 15) of the juvenile justice system's toolkit against youth violence, social casework, combines individual psy chotherapy or counseling with close supervision of youths and coordination of social services. Even when implemented carefully and comprehensively, programs that use this approach have failed to demonstrate any positive effects on recidivism. In fact, one long-term follow-up of delinquent youths treated in this setting shows several significant negative effects, including increases in alcoholism, unemployment, marital diffi culties, and premature death (McCord, 1978). Meta-analyses also demonstrate that individual counseling can be one of the least effective prevention approaches for delinquent youths. However, the effects of this strategy appear to depend largely on the popula tion. Though relatively ineffective for general delin quency and only marginally effective for institutional ized seriously delinquent youths, individual counseling emerged as one of the most effective intervention approaches for noninstitutionalized seriously delin quent youths in Lipsey's studies (Table 5-1). The rea son for this difference is unclear, but it illustrates the importance of program characteristics other than con tent, particularly the importance of matching the pro gram to the appropriate target population. A meta analysis by Andrews and colleagues (1990) confirms this finding, demonstrating that appropriate treatment can deter reoffending, whereas interventions that are poorly matched to the populations served can have no effect or a negative effect. # Shock Programs One tertiary youth violence prevention intervention meets the scientific criteria established above for Does Not Work: Scared Straight. Scared Straight is an example of a shock probation or parole program in which brief encounters with inmates describing the brutality of prison life or short-term incarceration in prisons or jails is expected to shock, or deter, youths from committing crimes. Numerous studies of Scared Straight have demonstrated that the program does not deter future criminal activities. In some studies, rear rest rates were similar between controls and youths who participated in Scared Straight. In others, youths exposed to Scared Straight actually had higher rates of rearrest than youths not involved in this intervention. Studies of other shock probation programs have shown similar effects. (For more information on Scared Straight and similar shock probation interventions, see Boudouris & Turnbull, 1985;Buckner & Chesney-Lind, 1983;Finckenauer, 1982;Lewis, 1983;Sherman et al" 1997;Vito, 1984;Vito & Allen, 1981.) # C o s t -E f f e c t iv e n e s s Violence costs the United States an estimated $425 billion in direct and indirect costs each year (Illinois Center for Violence Prevention, 1998). Of these costs, approximately $90 billion is spent on the criminal jus tice system, $65 billion on security, $5 billion on the treatment of victims, and $170 billion on lost produc tivity and quality of life. The annual costs to victims are approximately $178 billion (Illinois Center for Violence Prevention, 1998). The most logical way to reduce these costs is to prevent violence altogether. Preventing a single violent crime not only averts the costs of incarceration, it also prevents the short-and long-term costs to victims, including material losses and the costs associated with physical and psycholog ical trauma. Despite these facts, policy in the United States continues to focus on get-tough laws and incarceration for serious violent criminals, as opposed to prevention and intervention (Greenwood, 1995). Federal spend ing on school-based crime, violence, and drug preven tion programs is quite modest, compared to spending on crime and drug control strategies such as policing and prison construction (Gottfredson et al., in press). Not only are preventive approaches more beneficial than get-tough laws, some prevention and intervention strategies cost less over the long run than mandatory sentences and other get-tough approaches. In an effort to determine the cost-effectiveness of California's three-strikes-and-you're-out law, which mandates life sentences for repeat offenders, Greenwood (1995) compared that approach to the benefits and cost-effectiveness of a number of crime prevention strategies. He estimated that each serious crime-homicide, rape, robbery, assault, or residential burglary-prevented by the three-strikes law cost the criminal justice system in California an additional $16,000 over the amount spent prior to this legisla tion. Using this price as the standard for cost-effec tiveness, Greenwood calculated the costs per serious crime prevented of four prevention and intervention strategies: ( 1) early childhood intervention (perinatal home visitation continuing through the first 2 years, combined with 4 years of enriched day care programs) for high-risk families, (2 ) parent training for families with children who have shown aggressive behavior ("acted out") in school, (3) improved public school programs that target all youth, and (4) early interven tions for very young delinquents. The costs calculated for each of these interventions included only direct program costs, not such indirect benefits as the money saved by averting incarceration or preventing victim trauma and its medical and social consequences. Table 5-2 shows the benefits of the various pre vention and intervention programs with respect to the number of serious crimes each can be expected to pre- Source: Greenwood, 1995. 1 All estimates are based on 1992 crime figures and 1990 population figures. 2 Crime prevention numbers for first 5 years include child abuse. vent over the course of 30 years. The major disadvan tage of the prevention approach is clear-there is a time lag between implementation of programs and the appearance of effects. Because of this time lag, pro grams that are cost-effective in the long run do not appear so in the short run. In addition, long periods between an intervention and the high-risk period of a youth's life offer more opportunity for decay of a pro gram's effects (Greenwood et al., 1998). In the case of early childhood programs, it takes approximately 15 years before significant effects on youth violence can be appreciated, given the peak ages at which young people are involved in violence. Early intervention with delinquent youths that includes day treatment and home monitoring has a shorter lag time because the intervention is introduced later in life yet early in a violent career. Of the four approaches listed in Table 5-2, the most cost-effective in the long run is parent training, which costs only $392 to implement per serious crime averted after the program has been in effect 30 years. This is less than one-fortieth the estimated cost of preventing serious crime under the three-strikes law. Day treatment and monitoring for delinquent youths are also more cost-effective than mandatory sentencing, costing less than one-sixth as much as the three-strikes approach. The least cost-effective of the four are prenatal and early childhood intervention and school-based programs that target all students. However, early childhood interventions that include prenatal home visitation and enhanced day care can be expected to 5 These reductions in ch ild abuse were not considered in this analysis. 0 136 halve the incidence of child abuse among high-risk families (that is, low-income families headed by a sin gle mother).5 Moreover, early childhood intervention may improve educational achievement and reduce teen pregnancy rates. School-based programs have benefits other than prevention of violent crime, including higher educational achievement for all stu dents. In a later analysis, Greenwood et al. (1998) found that school-based prevention programs that tar geted disadvantaged youths specifically and included incentives (such as cash) for graduating from high school were almost 1 0 times as cost-effective as the three-strikes approach. In general, Greenwood's findings suggest that interventions targeting problem youths-either chil dren who act out or delinquent youths-are more costeffective than interventions that target general popula tions of youths. In addition, they confirm that preven tion is truly more cost-effective in the long run than incarceration. Costs aside, prevention may not have as great an effect on rates of violence as imposing longer manda tory sentences on repeat offenders. Other analyses demonstrate that the three-strikes law can reduce seri ous crime by 2 1 percent, whereas graduation incen tives only reduce it by approximately 15 percent, par ent training by 7 percent, early childhood intervention by 5 percent, and delinquent supervision by less than 2 percent (Greenwood et al., 1998). However, the four prevention and intervention strategies combined cost nearly $1.2 billion per year less to implement than the three-strikes strategy alone, and together they could prevent a substantial portion of the 80 percent of seri ous crimes that are not averted by mandatory sentenc ing (Greenwood et al., 1998). Graduation incentive programs could pay for themselves with the money they save by averting the eventual incarceration of many youths, and the other prevention and interven tion strategies could pay for up to 40 percent of their costs in the same manner. Studies of two targeted early childhood intervention programs, the Perry Preschool and the Elmira, New York, Prenatal and Infancy Home Visitation by Nurses, indicate that these programs can actually save the gov ernment up to three times their cost when delinquency prevention and other benefits are considered (Karoly et al., 1998). It is noteworthy that although the cost-effec tiveness data in Table 5-2 were calculated using crime and population statistics for California, they have national implications with respect to the relative costs and benefits of violence prevention and incarceration. Researchers at the Washington State Institute for Public Policy, who conducted a similar analysis (Aos et al., 1999), point out that the most effective programs are not always the most cost-effective. They note the importance of matching the intervention to the popula tion-a particular challenge for programmers, but one that has a critical effect on both the overall effective ness and the cost-effectiveness of an intervention. The results of the Washington study are summa rized in Table 5-3. While this table includes only the programs and approaches discussed in this report, the Washington study actually included many more programs and strategies, including some targeting adult offenders. All cost estimates in Table 5-3 were calculated using the same methodology so that pro grams can be compared. Although most costs are cal culated as direct, per-participant program costs, the costs of Multidimensional Treatment Foster Care are calculated relative to regular group home costs, and the costs of intensive supervision programs and boot camps are calculated relative to regular court proba tion costs. (Thus, the negative program cost of boot camps means that these programs cost less to imple ment than regular court probation programs.) This # E R I C overall approach may not be the same one used by other researchers to calculate program costs, result ing in inconsistencies between costs in this table and those projected by individual program designers . Nevertheless, the Washington study offers some useful insights into the cost-effectiveness of youth violence prevention. Looking at the benefits to the criminal justice system alone (that is, benefits to the taxpayer), many early interventions and selected strategies come close to paying for themselves with the money they save; others actually achieve benefits that are greater than program costs. The Seattle Social Development Project, for instance, now saves $0.90 from reduced rates of crime for every tax dollar spent. Programs targeting at-risk or delinquent youths can be even more cost-effective. For example, taxpayers today can expect to save $14.07 in future criminal jus tice costs for every dollar spent on Multidimensional Treatment Foster Care. The same trend holds when considering the bene fits of youth crime prevention to both the criminal jus tice system and crime victims (personal and property losses)-the largest economic returns are achieved with interventions targeted at juvenile offenders, who are at greatest risk of future offending. The Model programs in this group return $ 1 1 to $ 2 2 for every dol lar invested. However, even programs aimed at nonof fenders can achieve significant cost benefits when future savings to potential crime victims (due to a reduction in the number of victims) and the taxpayer are combined. According to the Washington study, society gains at least $0.50 over program costs for each dollar spent on the Perry Preschool Program, Prenatal and Infancy Home Visitation by Nurses, the Seattle Social Development Project, and Big Brothers Big Sisters of America. In general, these analyses underestimate the bene fits of prevention programs because they fail to con sider many of the indirect benefits of preventing seri ous or violent offenses, such as increased work pro ductivity, increased taxes realized, reduced welfare assistance costs, and reduced victim medical costs. # C o n c l u s io n s Clearly, we are past the era in which some observers believed that "nothing works" to prevent youth vio lence. Numerous programs have demonstrated their effectiveness in reducing risk factors for serious vio lence. At the same time, there is a pressing need to eval uate more youth violence prevention programs. Of the hundreds of programs currently in use throughout the United States, only six met the criteria for a Model pro gram, and 21 met the criteria for a Promising program. Of the 266 school-based program modules reviewed by Gottfredson et al. (in press), all of which were formally evaluated against a control or comparison group, only 1 0 percent received the highest score for scientific rigor (the experimental design standard used here). For most O I RJCbeST copy available violence, crime, and drug prevention' programs now being implemented, there is simply no evidence regard ing effectiveness. Although well-designed program evaluations are expensive and time-consuming, they are the only way to determine the effectiveness of exist ing youth violence prevention programs. Nearly half of the most thoroughly evaluated strategies for preventing youth violence are ineffective, however, and a few are even harmful. It is in society's best interest to evaluate programs before exposing chil dren and adolescents to them-otherwise we run the risk of harming young people rather than helping them. The most effective youth violence prevention programs are targeted appropriately, address several age-appropriate risk and protective factors in differ- # G o i n g t o Sc a l e While identifying best practices in youth violence pre vention is critical to reducing the number of young people involved in and affected by violence, it is not the last step. The manner in which a program is imple mented can have an enormous impact on its effective ness-even the best programs are effective only when implemented with high quality and fidelity to the pro gram's design. In other words, using an effective strat egy is only part of what is required to achieve effec tive results. Details of program delivery, including characteristics of the youths receiving the interven tion, the setting in which they are treated, and the intensity or duration of the intervention, play impor tant roles in determining effectiveness. Programs must be delivered with design fidelity, to a specific popula tion of youths, within a specific context, and for a spe cific period of time. Unfortunately, very little is known about how to preserve a prevention program's positive effects when it is implemented on a wide-scale or national level. What research has been conducted indicates that effective implementation is at least as important to a program's success as the characteristics and content of the program itself (Petersilia, 1990;Lipsey, 1992aLipsey, , 1992b. $tudies of program implementation consis tently find that effectiveness depends on the following principles, according to a review by Petersilia (1990, p. 130): • The project addresses a pressing local problem. • The project has clearly articulated goals that reflect the needs and desires of the "customer." • The project has a receptive environment in both the parent organization and the larger system. • The organization has a leader who is committed to the objectives, values, and implications of the proj ect and who can devise practical strategies to moti vate and effect change. • The project has a director who shares the leader's ideas and values and uses them to guide the imple mentation process and ongoing operation of the project. • Practitioners make the project their own rather than being coerced into it; that is, they buy into it, partici pate in its development, and have incentives to maintain its integrity during the process of change. • The project has clear lines of authority: There is no ambiguity as to who is in charge. • The change and its implementation are not complex and sweeping. • The organization has secure administrators, low staff turnover, and plentiful resources. Gendreau et al. (1999) organize these same prin ciples into four categories: general organizational fac tors, program factors, change agent factors, and staffing activities. While they acknowledge the impor tance of a program's characteristics, such as its theo retical basis, they also stress that positive change and success are dependent on much more than the specif ic characteristics of a prevention program or interven tion. Characteristics of the implementer, the environ ment in which the program is implemented, and even the target population have a significant influence on overall program effects. Both the Petersilia and Gendreau et al. studies dis cuss characteristics of effective implementation with in a correctional setting. The Centers for Disease Control and Prevention's (CDC) Best Practices of Youth Violence Prevention (Thornton et al., 2000) and a recent review by Gottfredson et al. (2000) suggest that many of the same characteristics help determine the success of violence and delinquency prevention programs. In particular, the CDC study highlights the importance of training, monitoring, and supporting the staff who implement a program on the local level. An appropriate match between staff and the target population can also contribute to program success, particularly in parent-and family-based programs. Staff must be committed to the program, experienced with the general strategy being used, knowledgeable about the target community, and capable of managing group dynamics and overcoming resistance. Likewise, as noted by Petersilia, maintaining community involvement is a key element of program success. Finally, linking a youth violence prevention program to existing strategies and support agencies in the com munity or school can contribute to success (Thornton et al., 2 0 0 0 ). A similar group of implementation characteris tics affects the success of school-based delinquency prevention programs, according to Gottfredson and colleagues (2000). In a study of more than 1,200 schools throughout the United States, they found that extensive, high-quality training and supervision, as well as support for the program from the principal of the school, are key elements of success. Schools also appear to have greater success with standardized materials and methods, as well as programs that can be incorporated into the regular school program. Consistent with Petersilia's principles, local buy-in and initiation of school-based delinquency preven tion are important predictors of program success. Multiple sources of information, including the use of an expert to assist with training and implementation, also help to ensure positive results. Improvements in any or all of these factors should improve the quali ty of the overall prevention program-and its effects on youths. The CDC recommends monitoring the progress and quality of program implementation on a local level. This step can be particularly important when implementing Model programs. The proven effective ness of these programs in multiple, long-term studies makes them suitable for implementation on a wide, or even national, scale, but even Model programs are successful only when implemented with fidelity. While it is not always necessary to conduct expensive outcome evaluations of Model programs, given their demonstrated positive effects and ongoing national evaluations, it is critical to monitor the quality of implementation on the local level. Scientific research has established the effective ness of a number of prevention programs, and evalu ation studies are sure to identify more in the near future. Although the studies cited above offer valu able guidance, more research is needed on how to implement youth violence prevention programs with fidelity on a national scale, how to monitor program fidelity on this scale, and how to increase community and agency capacity for implementing these pro grams. In addition, large-scale program dissemina tion will affect the overall benefits of individual youth violence prevention programs. Addressing these issues will require a major investment of time and resources, but it is the essential next step in the continuing effort to find effective solutions to the problem of youth violence. Thornton et al., 2000. 4. Developmental Research and Program s, Inc., 2000. 5. Howell, 1995. The 1995 O J JD P report does not include the full complement of the office's recommendations regarding youth violence prevention. Sin ce 1995, the group has released several sm aller publications in which it specifically recommends other prevention strategies identified as effective in this report. • Evidence of effectiveness: Evaluations performed at the end of the 9th grade show that STEP students have fewer school absences, higher grade-point averages, more positive feelings about school, and a better self concept than controls. In long-term studies, STEP stu dents had lower dropout rates than controls (2 1 per cent versus 43 percent), higher grades, and fewer absences. In a replication of the program in middle and junior high schools, both STEP and control stu dents showed increases in substance use, delinquent acts, and depression, and decreases in academic per formance and self-confidence. However, these changes were significandy smaller among STEP stu dents than controls. Students who participated in STEP also had lower dropout rates than controls. Replication in students with lower risk profiles 1 year after participation in STEP confirmed these findings, showing lower rates of delinquency and higher self esteem, academic performance, and school attendance than controls. This program has not been evaluated in small or high-achieving schools. In past studies, the program has worked best in large schools. The major limitation to the evaluation research on this program is that the first study lacked pretest measures; howev er, the researchers reported no differences between treated students and controls with respect to atten dance and grades at baseline. • For further information: • Evidence of effectiveness: In a multi site, random ized evaluation, a follow-up through the expected time of graduation showed that treated youths were significantly less likely than controls to be arrested (0.17 versus 0.58 arrests per person), were more likely to graduate (63 versus 42 percent), were more likely to attend postsecondary schools (42 versus 16 percent), were less likely to be dropouts, were more likely to receive an honor or award, were less likely to become teen parents, and were more likely to be involved in community service, be hopeful about the future, and consider their lives a success. Follow-up for 2 years after graduation revealed per sistent, positive program effects. • For further information: (1989)(1990)(1991)(1992)(1993). Waltham, MA: Brandeis University Heller Graduate School Center for Human Resources. # * 4J Chapter 6 A V ision for the Future I n the late 1990s, people in the United States were stunned by a series of tragic shootings at schools that were planned and carried out by youths. These shocking, widely reported events prompted the prepa ration of this Surgeon General's report on youth vio lence. Yet these shootings were not characteristic of youth violence nationally. Moreover, at the time of the shootings, youth violence in the United States appeared to be on a downward trend. Serious youth violence-that is, physical assault by a child or adolescent that carries a significant risk of injuring or killing another person-began to emerge as a social and public health problem of siz able proportions in the 1980s. Arrests of youths for index crimes (robbery, aggravated assault, rape, and homicide) peaked in 1993 after a decade of climbing rapidly, leading some observers to express doubt that anything could be done to halt the epidemic of youth violence. By 1999, after 6 years of sustained decline nationwide, arrests of youths for robbery, rape, and homicide began to resemble the pre-epidemic arrest rates of 1983. A striking exception to this trend was arrests for aggravated assault, which remained 70 per cent above 1983 rates. While arrest records and victimization reports indicated that youth violence was generally declining, other sources of information presented a different pic ture. In approaching youth violence as a public health problem, this report has looked beyond arrest and other criminal justice records to several national sur veys in which high school-age youths report in confi dence on their violent behavior. These self-reports reveal that the propensity for and actual involvement of youths in serious violence have not declined with arrest rates. Rather, they have remained at the peak rates of 1993, a troublesome finding. In January 2001, as this report goes to press, the first indications of a long-awaited downturn in self-reported violent behav ior are being countered by signs from the FBI's Uniform Crime Reports database that the decline in arrests of youths for violent crimes has bottomed out and, for some index crimes, has begun to climb again. Clearly, the dynamics and magnitude of youth violence remain fluid and complex. Nevertheless, research in the past several decades has developed a wealth of information about the causes of youth vio lence and how to prevent it. Numerous studies have identified and examined specific risk factors for vio lence-the personal and environmental features of young people's lives that increase the statistical prob ability of their engaging in violent behaviors. Research also has begun to identify protective factors that appear to buffer the effects of risk factors. While this information has been accumulating, researchers, youth service practitioners, and others have been designing, implementing, and evaluating a variety of programs and strategies to reduce or prevent the occurrence of youth violence. The best of these inter ventions target populations of young people identified as being particularly at risk of becoming involved in a violent lifestyle. Many effective intervention programs exist to reduce and prevent youth violence. The United States is well past the point where anyone can claim that "nothing works" to prevent youth violence or to mod ify the destructive life courses of youths who are either engaged in or appear to be headed for lifestyles characterized by violence. At the same time, however, many purported youth violence prevention programs used today are untested, and some are known to be ineffective or even deleterious to a child or adoles cent's healthy, safe development. The courses of action highlighted below are potential next steps. These are not formal policy rec ommendations. Instead, they represent a vision for the future built on information we possess today. They are intended for policy makers, service and treatment providers, people affiliated with the juvenile justice system, researchers, and most important, the people of the United States. This vision for the future is present ed with the hope that it will engage an expanding number of citizens in the challenge of redressing the problem of youth violence. # C o n t in u e t o B u il d t h e Sc ie n c e Ba s e Scientific research is an essential underpinning of the public health approach to the problem of youth vio lence. Years of extensive research have revealed the scope of the problem, and we are beginning to under stand how to intervene effectively to reduce and pre vent violence. Yet most violence prevention programs used in schools, communities, and the justice system today have not been subjected to systematic scientific evaluation, so their effectiveness-or lack of effec tiveness-is unknown. Given evidence that some well-intentioned prevention and intervention pro grams have proved to be harmful, it is imperative that all programs be scientifically evaluated. Research must also be prepared to address areas of emerging concern. One that has become increasingly clear is the need for studies to investigate intimate violence, or dating violence, among youths to identify patterns that predict continuation of such behaviors into adulthood and to design new types of interventions targeting this form of violent behavior. Another area of concern requiring research is the impact of violent interactive media, such as computer games, on serious violent behavior. This Surgeon General's report is issued at a time of unprecedented scientific opportunity in numerous disciplines-developmental psychology, sociology, criminology, epidemiology, neuroscience, and many other fields. No single research specialty holds the key to understanding, treating, and preventing vio lence. Rather, they must work together. One of the greatest challenges to researchers today is finding new ways to use the tools, strategies, and insights from these diverse fields of research to reveal the many fac tors that may lead a young person toward-or protect a young person from-involvement in violence. A related need is to invest in cross-level research designs that will enable researchers to examine individual, family, and community factors simultaneously. Research frequently examines questions and issues that crop up in the daily lives of millions of people-the relationship of media depictions of vio lence to violent behavior is a key example; the impact of strategies to discourage firearm use is another. Such familiarity often increases the likelihood that a person will hold strong opinions regarding the effect of television or popular music, or the presence and use of weapons, on violent behavior. Appropriately designed and conducted research offers a factual basis, rather than opinion, for proposing and debating social policy. It is therefore critical to devise ways of giving people with diverse interests (including par ents, teachers, and others) a voice in identifying urgent research questions and to inform them about the conclusions drawn from research. # A c c e l e r a t e t h e D e c l in e in G u n U se b y Y o u t h s in V io l e n t En c o u n t e r s The carrying and use of guns by youths in violent encounters have declined dramatically since 1993, the peak of the violence epidemic. To accelerate that decline, we must seek to understand more completely the reasons for it. Are youths' decisions not to carry or use guns in violent encounters related to any specific strategies put in place to discourage firearm use, or did the drop in firearm use result from other factors or conditions? Clearly, important questions remain about precisely what has happened in communities nationwide to reduce the frequency with which ado lescents carry guns. While some research has addressed these questions (Blumstein & Wallman, 2000), further studies are imperative-data document ing the continuing magnitude of violent behaviors suggest that a return to lethal violence is likely if ado lescents once again carry and use guns in violent encounters. # Fa c il it a t e t h e En t r y o f Y o u t h s in t o Effe c t iv e I n t e r v e n t io n P r o g r a m s Ra t h e r T h a n I n c a r c e r a t in g T h e m In the 1990s, faced with the epidemic of violence and largely unaware that research had found some vio lence prevention programs to be effective-as well as often buying into the "just desserts" philosophy-the only option some legislators saw was to lock up vio lent youths to protect society. New evidence makes a compelling case that intervention programs can be cost-effective and can reduce the likelihood that youths will become repeat offenders. Given this evi dence, it is in the country's interest to place as many violent youths as possible in these programs, thus cor recting the imbalance that now favors use of the crim inal justice system over effective intervention pro grams. Reclaiming youths from a violent lifestyle has clear advantages over warehousing them in prisons and training schools. Effective programs are not available in many communities. Special efforts must be undertaken to increase awareness of these programs, provide techni cal assistance and information about them, and devise incentives for states and communities to invest in test ed programs. At present, states and communities are squandering substantial amounts of money on untest ed programs or programs known to be ineffective. Policy makers must be encouraged to focus existing resources on programs that work; evidence of effec tiveness might be required, for example, as a condi tion of receiving Federal or local funding. An informed public is also critical in building support for effective alternatives to incarceration. # D is s e m in a t e M o d e l Pr o g r a m s w it h I n c e n t iv e s T h a t W il l En s u r e F id e l it y t o O r ig in a l P r o g r a m D e s ig n W h e n T a k e n t o Sc a l e Experience has shown repeatedly that intervention programs shown to be effective in their original sites do not yield uniform outcomes when replicated else where. Upon examination, program evaluators often find that subtle modifications have been introduced into the model program. Lack of a particular category of personnel in a given location, for example, may prompt a program director to substitute professionals or paraprofessionals without proper credentials. Faceto-face training sessions that initially encouraged interaction between a program originator and new staff may be supplanted by videotaped tutorials. The frequency of participants' contacts with a program may be lessened or program duration abbreviated. Legislators, agency administrators, and program directors should be encouraged to identify incentives for ensuring that the integrity of a model program is not compromised when it is replicated. # Pr o v id e T r a in in g a n d C e r t if ic a t io n Pr o g r a m s f o r I n t e r v e n t io n Pe r s o n n e l The major challenge in implementing effective inter vention programs on a national scale is guaranteeing a well-trained staff that understands the intervention and its limitations. Staff must be adequately trained to deliver a particular intervention in the specific settings for which it was designed. Yet because the supply of appropriately trained individuals who are available to work in the variety of settings in which violence pre vention programs operate is limited, operational entropy often sets in. Establishing formal training pro grams and university certification programs will help ensure the quality of interventions. # Im p r o v e P u b l ic A w a r e n e s s o f Ef f e c t iv e I n t e r v e n t io n s Identifying specific youth violence interventions as effective in this report will probably stimulate demand for these programs. Youth advocacy organizations have an opportunity to educate citizens on how to interact effectively with their local educational and juvenile justice systems, with appropriate sectors of the elected government, and with private organiza tions involved in youth violence prevention. Media campaigns and public service announce ments offer a means of increasing public awareness. News or documentary television programs featuring model programs have had a measurable impact both on the funding of the programs and on the volume of requests from sites throughout the country for infor-mation about the programs. The 1938 film Boys Town, with Spencer Tracy and Mickey Rooney, proved high ly beneficial to the reputation and funding opportuni ties available to Boys Town. Conceivably, featuring model youth violence prevention programs in popular films today could have an equivalent effect. The move to a public health focus on violence involves new players and new collaborative partnerships among criminologists, psychologists, psychiatrists, sociolo gists, neuroscientists, and others. Physicians and other general medical service providers have important roles to play, but they are not yet sufficiently involved. Preparation of the Surgeon General's report under scored the risks of disciplinary compartmentalization in the study of youth violence. There is no common place where information needed by all parties interested in the problem of youth violence can be exchanged. A rich literature on research and services appears in the specialty journals of various disciplines, in professional newsletters, in the mass media, and increasingly on the World Wide Web. Lack of interaction between academic research centers and the community-based agencies responsible for imple menting youth violence prevention programs or provid ing medical services to victims (many of whom are also perpetrators) can result in significant costs. A periodic, highly visible national summit that receives wide popular as well as specialized media coverage would offer a way of disseminating infor mation on new research findings, effective programs and strategies, best practices, and related information for diverse audiences. # Im p r o v e Fe d e r a l , Sta t e , a n d L o c a l St r a t e g ie s f o r R e p o r t in g C r im e I n f o r m a t io n a n d V io l e n t D e a t h s The proportion of law enforcement agencies nation wide that report arrests to the FBI's Uniform Crime Reports (UCR) program has been declining. In 1999, . O participating agencies represented only 63 percent of the U.S. population. The accuracy of national esti mates would be enhanced if this reporting rate were improved. In addition to expanding the participation rate, opportunities for improvement might entail: • Including arrest rates for all racial and ethnic groups. Hispanics in particular are not represented in systematic data collection systems. • Encouraging law enforcement agencies to partici pate in the National Incident-Based Reporting System. Developed by the UCR, the incident-based reporting system provides a much richer data set for tracking violent crime than the aggregated data available in the current UCR. Another potentially useful, innovative data set is the National Violent Death Reporting System proposed by the Centers for Disease Control and Prevention. This data set would help in monitoring the magnitude and char acteristics of youth violence on a timely basis so that programmatic and policy responses can be more effectively planned and evaluated. • Develop a standard set of questions for national self-report surveys (such as Monitoring the Future) that include serious violent offenses. Annual data from these surveys should be obtained from all adolescents age 11 through 17, not just high school seniors. At present, variation among surveys in the age of respondents, data obtained, and frequency of data collection severely limit any composite picture that might result. Data collection efforts must make use of the best methodology available and include follow-up questions on each reported violent event to determine weapon use, drug or alcohol involve ment at the time of the event, seriousness of injury, victim's relationship to offender, number of youths involved in the attack, and other details. Such data enable researchers to correct for the overreporting in the simple checklist used in most surveys. # C o n c l u s io n Youth Violence: A Report of the Surgeon General offers compelling testimony that the safety and well being of children and adolescents are issues of the utmost importance and urgency to individuals and lies organizations throughout the United States. The report has drawn on the expertise of countless persons in diverse private organizations; in local, state, and Federal government agencies; in schools; and most important, in families-all of whom are dedicating immense energy and caring to countering the most common threat to the lives of young Americans. Thanks to these efforts and to the insights and actions of young people themselves, it is clear today that youth violence is not an intractable problem; rather, it is a behavior that we can understand, treat, and pre vent. This final chapter has offered courses of action intended to help inform the decisions that we must make as we strive to ensure that every child has the opportunity to grow and mature safely, healthily, and happily. R e f e r e n c e Blumstein, A., & Wallman, J. (2000).. The crime drop in America. Cambridge, United Kingdom: Cambridge University Press. # G lossary Absolute deterrent effects. Effects that are demon strated when an intervention produces better out comes compared to no treatment. # Age of onset (of serious violence). The age at which an individual reports his or her first act of serious violence. Age-specific prevalence. The proportion of youths at any given age who report having committed at least one serious violent act in the past year. # Aggravated assault. An unlawful attack by one per son upon another wherein the offender uses a weapon or displays it in a threatening manner, or the victim suffers obvious severe or aggravated bodily injury involving apparent broken bones, loss of teeth, possible internal injury, severe laceration, or loss of consciousness. Along with homicide, rob bery, and rape, one of the four violent crimes cov ered in this report.* # Aggression (aggressive behavior). Behavior, physical or verbal, that is intended to harm another person. # Antisocial attitudes. Favorable attitudes toward vio lence, dishonesty, and rule breaking with hostility toward authority. # Antisocial behaviors. Problem behaviors that range from relatively minor acts such as lying, stealing, truancy, disobedience, and temper tantrums to seri ous nonviolent or violent behavior such as burglary or aggravated assault. # Attention-deficit/hyperactivity disorder (ADHD). A cognitive disorder characterized by restlessness, excessive activity, and difficulty paying attention. # Career length. Variously defined as the number of years of active offending; or the maximum number of consecutive years of offending; or the span between the first and last year during which a youth meets the criteria for a serious violent offender. # Case study research. A type of study design involv ing multiple observations of a single individual over time. # Chronic offenders. Variously defined by some mini mum number of offenses; for example, youths with three or more serious violent offenses per year. # Contagion effect (of violence). Unproved notion that seeing or hearing about violence in news coverage encourages violent or aggressive behavior. # Control group. A group that receives standard care or no intervention in a research study, compared to the experimental, treatment, or intervention group. # Co-occurrence (of problem behaviors). The simul taneous display of violence and other problem behaviors (e.g., substance use, property crimes, gun ownership). Although these behaviors occur togeth er, it cannot be assumed that one behavior causes another. Conduct disorder. Childhood disorder marked by persistent acts of aggressive or antisocial behavior. Cross-sectional research. A type of study design, fre quently used in public opinion polls, surveys, and epidemiological research. It involves a single con tact with participants for data collection at a given point in time and thus does not permit researchers to estimate individual-level change, development, or predictive effects of a given risk or protective factor on later violent behavior. Cumulative prevalence (lifetime prevalence or ever-prevalence). The proportion of youths at any particular age who have ever committed a serious violent offense. # 171 Delinquent (antisocial) lifestyle. A pattern of con sciously chosen and sustained behaviors that include antisocial or illegal acts, typically involving property crimes, substance use, gun ownership, and promiscuity. Deterrent effects (absolute). See Absolute deter rent effects. # Deterrent effects (marginal). See Marginal deter rent effects. # Developmental perspective (on youth violence ). An approach to understanding youth violence that con siders the complex interaction of individuals with their environment at particular times in their lives; this approach recognizes that patterns of behavior change over the life course. Early-onset trajectory. A pattern of violent behavior that emerges before adolescence, defined in this report as about age 13. In this pathway, problem behaviors in childhood gradually escalate over time to more violent ones, culminating in serious vio lence before adolescence. This pattern is less preva lent than the late-onset trajectory and is character ized by higher offending rates, greater seriousness of adolescent offenses, and greater persistence of violence from adolescence into adulthood. Effect size. The predictive power of an individual or general type of risk or protective factor; or the size of the deterrent effect of an intervention compared to no treatment or a standard treatment. The meas ure used for risk factor effect sizes in this report is a simple correlation between two variables. For pro gram effectiveness, the effect size measure is the average difference (standardized) between the treat ment and control group means on the selected recidivism measure. # Effectiveness trials. Research that tests for benefits to participants in a natural or applied setting. # Efficacy trials. Research that tests for benefits to par ticipants in a controlled or experimental setting. Epidemiology. Study of the factors influencing the incidence, frequency, and distribution of healthrelated events in the population; identifying appro priate risk and protective factors for prevention and intervention programs. # Experimental research. A type of study design involving comparison of a group that receives an intervention (experimental or treatment group) and a group that receives standard care or no interven tion (control group) in which participants are ran domly assigned to one of these groups. This study design permits researchers to assess cause-andeffect relationships and can be used to determine intervention effectiveness. # Externalizing symptoms. A behavioral pattern charac terized by the acting out of psychological problems. Hazard rate. The proportion of individuals who initi ate a given behavior (e.g., serious violence) at a given age. Homicide. The willful (nonnegligent) killing of one human being by another; along with robbery, aggra vated assault, and rape, one of the four violent crimes covered in this report.* # Iatrogenic. In the context of youth violence, interven tions that are harmful or actually increase involve ment in violence. Incident rate. The number of self-reported violent acts within a given-sized population, a measure of the volume of violence; as used in this report, the number of violent acts per 1,000 young people. o Public health approach. A practical, goal-oriented, and community-based approach to promoting and sustaining health. This approach seeks to identify risk and protective factors, determine when in the life course they typically occur and how they operate, and enable researchers to design preventive programs that are effective in reducing risk and promoting protec tion. # Intervention. Quasi-experimental research. A type of study design with experimental and control groups but without random assignment to these groups. Groups are matched on selected characteristics, or differences are controlled in the analysis. The claim of group equivalence or comparability is not as strong with this design as in an experimental design. # Rape (forcible rape). The carnal knowledge of a per son, forcibly and/or against that person's will; or not forcibly or against the person's will where the vic tim is incapable of giving consent because of his or her temporary or permanent mental or physical incapacity (or because of his or her youth). Along with homicide, robbery, and aggravated assault, one of the four violent crimes covered in this report.* # Reliability (of research instruments or measures). The consistency of a measure; the measure yields the same result on different occasions or applica tions (when no real change has occurred). # Replication. Repeating an intervention or prevention program at multiple sites to determine if the results will be the same; establishes that a program can be effective at other sites when implemented by new teams under different conditions. # Risk factor. In the context of youth violence, personal characteristics or environmental conditions that increase the likelihood that a young person will become violent but that may not actually cause a per son to become violent. Risk factors are grouped into individual, family, school, peer group, and communi ty domains. The more risk factors a young person is exposed to, the greater the likelihood that he or she will become violent. # Risk marker. A personal characteristic or environ mental condition associated with known risk factors but having no causal relation to violence on its own. Robbery. The taking or attempting to take anything of value from the care, custody, or control of a person or persons by force or threat of force or violence and/or putting the victim in fear. Along with homi cide, aggravated assault, and rape, one of the four violent crimes covered in this report.* Sampling. The selection of persons to be studied in a research project. Schizophrenia-spectrum disorders. Broad category of disorders that includes individuals with symptoms such as serious distortions of reality (including hal lucinations and delusions), withdrawal from social interaction, and disorganization and fragmentation of perception, thought, and emotion, for which other plausible explanations could be ruled out. # Secondary prevention. In the context of this report, strategies and programs that reduce the risk of vio lence among youths who display one or more risk factors for violence (high-risk youths). Self-directed violence. Self-inflicted injury and sui cide; not the focus of this report. Self-report studies. Research that asks people in con fidence to describe their own behavior. In the con text of youth violence, surveys that ask young peo ple in confidence about violent acts they have com mitted or have been victims of during a given peri od of time. # Serious violent crime (serious violence or index crimes). As defined in this report, aggravated assault, robbery, rape, and homicide. ous and nonserious offenses. These youths account for a major share of all criminal behavior by persons under age 18. # Serious violent youths. # Socially disorganized community. A community characterized by high levels of poverty, unemploy ment, high turnover of residents, and a large pro portion of disrupted or single-parent families. Socioeconomic status. In reference to youths, their parents' education, occupation, and income. Statistical significance. The level of confidence with which one can conclude that a difference between two or more groups (generally a treatment and con trol group) is the result of the treatment delivered rather than the selection process or chance. A proba bility value of .05 is widely accepted as the threshold for statistical significance in the social and behav ioral sciences; a probability value below this thresh old (p < .05) indicates that a difference of this mag nitude could happen by chance less than 5 percent of the time. # Superpredators. A new breed of violent youths who commit more frequent and vicious violent crimes, without remorse, than in previous generations. Contrary to a recent myth, there is no evidence that this type of violent youths emerged in the 1990s. # Surveillance. A type of research that establishes the nature of a health problem, describes its incidence and prevalence trends, and monitors its magnitude over time. Public health specialists use this infor mation to determine appropriate prevention and intervention efforts. # Sustained effects. Changes in individual competencies and environmental conditions produced by effective programs that last at least a year beyond treatment or participation in the intervention. # Tertiary prevention. In the context of this report, strategies and programs that prevent further vio lence or the escalation of violence among youths already involved in violent behavior. # Uniform Crime Reporting (UCR) program. Operated by the FBI since the 1930s, the program monitors arrests made by law enforcement agencies across the United States and compiles annual arrest information. Validity (of research instruments or measures). Wraparound services. An approach that is designed to tailor social services to the individual. ,63,66,68 Aggression,reduction in,[134][135][136]49,51,64,66,69,106,108,109,111,112,116,[135][136]137,146,147,148 1, 5, 9, 11, 17, 18-26, 27, 29, 32-34, 43, 48, 49, 52, 153 , racial and ethnic, 18, 20-21, 27-30, 31, 34 at greatest risk of school homicide, 31 # Youth Risk Behavior Survey (YRBS # N______________________ _ ______________ # BEST COPY AVAILABLE Functional Family Therapy (FFT) • Contact information: James F. Alexander, Ph.D. University of Utah Department of Psychology, SBS 502 Salt Lake City, UT 84121 (801) 581-6538 • Evidence of effectiveness: In multiple clinical tri als, FFT achieved significant reductions in the pro portion of youths who reoffended (60 percent of treated youths were arrested after the program ver sus 93 percent of controls in one study and 11 per cent versus 67 percent in another) and the frequen cy of offending up to 2.5 years after participation in the intervention. Diffusion effects on the siblings of target youths have also been observed, with signifi cantly fewer siblings of FFT youths than control youths having juvenile court records 2.5 to 3.5 years after the program. • For further information: • . • Evidence of effectiveness: A randomized evalua tion of Multidimensional Treatment Foster Care compared to group care in boys only demonstrated the following results at a 1 2 -month follow-up: Treated boys spent significantly more days in their placements, were less likely to run away from their placements, and spent twice as many days living with their families or relatives. One year after leav ing treatment, treated boys had significantly larger decreases in arrest rates than controls, had signifi cantly fewer arrests overall, and were significantly more likely not to have been arrested at all during follow-up. Treated boys also reported significantly fewer criminal activities (general delinquency, index offenses, and felony assaults). In prior evalu-ations that included both boys and girls, Multidimensional Treatment Foster Care improved rates of program completion, reduced rates of incar ceration and number of days incarcerated during the first year after treatment, and resulted in a faster drop in rates of problem behavior for seriously impaired youths. •F o r further information: • Eddy, J. M., & Chamberlain, P. (2000). Family management and deviant peer association as mediators of the impact of treatment condition on youth antisocial behavior. Journal o f Consulting and Clinical Psychology, 5, 857-863. • Moore, K. J., Sprengelmeyer, P. G., & Chamberlain, P. (in press). Community-based treatment for adjudicated delinquents: The Oregon Social Learning Center's "Monitor" treatment foster care program. Residential Treatment for Children and Youth. • . show that participation in MST can have significant positive effects on behavior problems (including conduct problems, anxiety-withdrawal, immaturity, and socialized aggression), family relations, and self-reported offenses immediately after treatment. Fifty-nine weeks after referral, seriously delinquent youth who participated in MST had slightly more than half as many arrests as controls (mean = 0.87 versus 1.52), spent an average of 73 fewer days incarcerated in justice system facilities, and showed reductions in aggression with peers. After 2.4 years, MST youths were half as likely as control youths to have been rearrested. In Columbia, Missouri, MST improved family relations and arrest rates, including arrests for violent and substance-related crimes, and demonstrated a dose-response effect, with program completers demonstrating significantly more bene fits than dropouts. •For further information: delinquency initiation, improvements in family man agement practices and parent-child relationships, greater attachment and commitment to school, and less involvement with antisocial peers. Follow-up at age 18 shows that the Seattle Social Development Project significantly improves long-term attachment and commitment to school and school achievement and reduces rates of self-reported violent acts and heavy alcohol use. At follow-up, students who received the full intervention were also less likely than controls to be sexually active, to have had mul tiple sex partners, and to have been or have gotten someone pregnant (this difference was only mar ginally significant, at p = .057). Replications of this program have confirmed its benefits in both gen eral and high-risk populations of youths. •F o r further information: # 151 The Midwestern Prevention Project • For further information: • Evidence of effectiveness: No significant differ ences between treated and control boys were observed immediately after treatment, but 2 years later treated youths were involved in fewer fights, were half as likely to have serious school adjust ment problems, and were less likely to be involved in delinquent activities than those in the control group. Boys followed to age 12 (3 years after the intervention) had significantly lower rates of delin quency, fighting, serious difficulties in school, and placement in special-education classes, and they were rated as significantly more well adjusted in school than controls. Three years later, treated boys were less likely than untreated boys to report gang involvement, drunkenness, or drug use in the past year, delinquency, and having friends arrested by police. Because the effects of this intervention on girls are unknown, these benefits can be expected only when the intervention is implemented in boys. •For further information: (2000). Communities That Care® prevention strategies: A research guide to what works. Seattle, WA. • # 153 Perry Preschool Program • For further information: • Berrueta-Clement, J. R., Schweinhart, L. J., Barnett, W. S., Epstein, A. S., & Weikart, D. P. (1984). • For further information: • Evidence of effectiveness: The most dramatic effects of the program were demonstrated in a 1 0year follow-up evaluation that showed reduced juvenile delinquency and improved school func tioning. Children in the program also demonstrated more positive self-ratings, higher educational goals, and increased self-efficacy. Benefits to par ents included greater encouragement of their chil dren's success and increased family unity. The existing evaluation research on this program is lim ited by several factors: The program has not been replicated; there was relatively high attrition of families in the initial studies that may have led to a positive bias in the follow-up results; and allocation to treatment and control groups was not random ized. This program is no longer deliverable-that is, no technical assistance is available to those who wish to implement it. • For further information: • For further information: • For further information: • # 157 Good Behavior Game • For more information: • Evidence of effectiveness: In nursery school and kindergarten students, I Can Problem Solve signifi cantly reduced impulsive and inhibited classroom behavior and improved problem-solving skills at posttest and 1 year. A second study demonstrated sustained improvements in classroom behavior and problem solving 3 to 4 years after the end of the pro gram. In 5th-and 6th-graders, the program increased the use of positive and prosocial behav iors and improved peer relationships and problem solving skills. In general, it appears that the program is more effective in high-risk students than in stu dents from the general population. Prior studies of this intervention did not use a randomized study design and were limited by high attrition. • For further information: # • Evidence of effectiveness: In a series of six ran domized trials, the parent program reduced conduct problems and improved parent-child relationships. In two randomized studies, the teacher program reduced peer aggression in the classroom, increased positive interactions with teachers and peers, and enhanced school readiness. Two randomized studies of the child program demonstrated reductions in conduct problems at home and school and improve ments in problem solving with peers. Program effects have been shown to persist for at least one year after treatment. • For further information: • Developmental Research and Programs, Inc. (2000). Communities That Care® prevention strategies: A research guide to what works. Seattle, WA. • . # Linking the Interests of Families and Teachers (LIFT) • • Evidence of effectiveness: In short-term evalua tions, LIFT decreased children's physical aggres sion on the playground (particularly children rated by their teachers as most aggressive at the start of the study), increased children's social skills, and decreased aversive behavior in mothers rated most aversive at baseline, relative to controls. Three years after participation in the program, lst-grade partici pants had fewer increases in attention-deficit disor der-related behaviors (inattentiveness, impulsivity, and hyperactivity) than controls. At follow-up, 5thgrade participants had fewer associations with delinquent peers, were less likely to initiate pat terned alcohol use, and were significantly less like ly than controls to have been arrested. • For further information: • • Evidence of effectiveness: Evaluations of this pro gram have demonstrated enhanced school achieve ment in grades 2 and 3; improved parenting skills at the end of the program, at (the child's) age 4, and in grades 2 and 3; and reduced aggressive behavior by children at ages 4 to 7 and 8 to 11. Unfortunately, the evaluations of these programs conducted to date have been limited by high attrition rates. • For further information: • Preventive Intervention • Evidence of effectiveness: Evaluations of this pro gram demonstrate both short-and long-term effec tiveness on violence-related risk factors, including higher grades and attendance at the end of the pro gram; significantly lower drug use, school-related problems, and unemployment after 1 year; signifi cantly fewer students with county court records at 5 years; and lower rates of reported criminal behavior at the 1.5 year follow-up (marginal significance, p < .075). Program effects on self-reported criminal behavior did not reach statistical significance, although the treatment and control groups did differ significantly with respect to the proportion of stu dents with a juvenile record. • For further information: • Bry, B. H. (1982). Reducing the incidence of adolescent problems through preventive inter vention: One-and five-year follow-up. American Journal of Community Psychology, 10, 265-276. • Bry, B. H., & George, F. E. (1980). The preven tive effects of early intervention on the atten dance and grades of urban adolescents. Professional Psychology, 11, 252-260. • Bry, B. H., & George, F. E. (1979) • Evidence of effectiveness: Evaluations of this intervention have demonstrated that PATHS improves self-control, understanding and recogni tion of emotions, the ability to tolerate frustration, the use of effective conflict-resolution strategies, thinking and planning skills, and conduct problems, such as aggression. In students with special needs, PATHS has also been shown to significantly reduce symptoms of anxiety, depression, and sadness and to reduce conduct problems. • For further information: • Greenberg, M. T., Kusche, C., & Mihalic, S. (1998) • Thornton, T. N., Craft, C. A., Dahlberg, L. L., Lynch, B. S., & Baer, K. (2000). • Evidence of effectiveness: An evaluation conduct ed 10 years after participation in the program showed that youths enrolled in the Yale Child Welfare Project missed significantly fewer days of school, required significantly fewer remedial and supportive school services, and were rated signifi cantly less negative and more socially well adjusted by their teachers compared to controls. Some pro gram effects on academic achievement showed sig nificant diffusion effects on siblings. However, the sample in this study was small, with only 14 of the original 17 pairs of matched treatment and control youths available for evaluation at follow-up. In addition, this study used a quasi-experimental design. This program is no longer deliverable-that is, no technical assistance is available to those who wish to implement it. • For further information: • Seitz, V., Rosenbaum, L. K., & Apfel, N. H. (1985). Effects of family support intervention: A ten-year follow-up. Child Development, 56, 376-391. # 165 Late-onset trajectory. A pattern of violent behavior that emerges in adolescence, defined in this report as about age 13. This pattern is more prevalent than the early-onset trajectory and is characterized by a shorter period of involvement, lower frequency of offending, and a lower likelihood of continuing into adulthood. Individuals who are characterized by this pattern typically give few external signs in child hood that they will become violent offenders. # Level of control. Efforts to take into account other factors that might influence the data or responses from participants in a research study; contributes to the quality of a given study. # Level of evidence. The strength of the evidence amassed for any scientific fact or conclusion. # Lifestyle. A pattern of consciously chosen, observable behaviors that a person engages in on a consistent and regular basis. Locally representative (probability) sample. In this report, the term representative sample is used to refer to a probability sample-a sample that is selected in such a way that its characteristics can be generalized to the population (e.g., city or county) from which it was drawn with a known degree of accuracy. The accuracy of generalizations from probability samples is given in the form of a confi dence interval. In this report, 95 percent confidence intervals (CIs) are reported, indicating an upper and lower bound for the population estimate that is accurate at least 95 percent of the time. Longitudinal research. Used in etiological (causal) and developmental research, a type of study design involving multiple contacts with the same study par ticipants over time; allows researchers to estimate how well a given risk or protective factor predicts later violent behavior for individuals or groups. Marginal deterrent effects. Effects that are demon strated when an intervention produces significantly better outcomes compared to another treatment; may underestimate the true effects of the interven tion compared to receiving no treatment at all. # Maturation effect. An effect associated with growing older or maturing, it may refer to changes in one's physical or social development. The term refers specifically to a sharp reduction in youth violence observed during the transition to adulthood, usually during the late teen years to age 20. Mediating-effects analysis. An analysis that permits researchers to determine whether a change in the targeted risk or protective factor accounts for an observed change in violence. # Meta-analysis. A rigorous statistical method of com bining the results of several studies to obtain more reliable estimates of the effects of a general type of treatment or intervention; can be used to summarize program evaluation and draw overall conclusions about the strength and consistency of the influence, or effect size, that particular types of programs have on violence. # Model program. A prevention program that meets the highest scientific standard for effectiveness, as evi denced in published evaluations; has a significant, sustained preventive or deterrent effect and has been replicated in different communities or settings. It has been shown to work and can be expected to have a positive result in a wide range of community . settings. # Monitoring the Future (MTF # National Electronic Injury Surveillance System (NEISS). Operated by the U.S. Consumer Product Safety Commission since 1992, the system monitors types of injuries treated in emergency departments, including those related to firearms. # National Television Violence Survey (NTVS). A recent content analysis of television programming examining its portrayal of violence. The study assessed a total of 2,500 hours of television pro gramming during the 1994 through 1997 viewing seasons. Physical aggressiveness. Relatively nonserious forms of violent behavior, often displayed in early child hood and continued into adolescence, including hit ting, biting, kicking, punching, or otherwise inten tionally hurting others. # National Youth Survey (NYS Population-based studies. Studies based on general population samples rather than selected or institu tional samples (e.g., prisoners, hospital patients, nursing home residents, expelled students). Findings O from these studies apply to general populations, whereas findings from studies of selected or institu tional samples apply specifically to persons in these settings or groups. Post-traumatic stress disorder (PTSD). Disorder in which a stressful experience is traumatic and pro duces severe, recurring symptoms. Prevalence rate. As used in this report, the proportion of youths involved in one or more violent behaviors during some specified time interval, for example, the past year, by age 18, or ever. # Primary prevention (true prevention). As defined in this report, strategies and programs that reduce the likelihood that youths will initiate violent behavior compared to youths in a control group; programs designed to target youths who have not yet become involved in violence or encountered specific risk fac tors for violence; identifies behavioral, environmen tal, and biological risk factors associated with vio lence and takes steps to educate individuals and com munities about and protect them from these risks. # Probability sample. A sample selected in such a way that its characteristics can be generalized to the pop ulation from which it was drawn with a known degree of accuracy. The level of accuracy for pro portions, means, and correlations is presented as a 95 percent confidence interval, which contains the true population value 95 percent of the time. See Locally representative sample. Promising program. Prevention programs in this cat egory meet two of the scientific standards for effec tiveness; they do not meet all of the rigorous stan dards of Model programs, but they are recognized and encouraged with the caution that they be care fully evaluated. Protective factor. As used in this report, personal characteristics or environmental conditions that reduce the potential harmful effect of a risk factor for violent behavior; characteristics that buffer or mod erate the effect of risk.	None	None
e7c469ffea0b3d426d0efdff8e5b15c47021ed55	cdc	None	The Advisory Committee on Immunization Practices (ACIP) annually reviews the recommended Adult Immunization Schedule to ensure that the schedule reflects current recommendations for the licensed vaccines. In October 2009, ACIP approved the Adult Immunization Schedule for 2010, which includes several changes. A bivalent human papillomavirus vaccine (HPV2) was licensed for use in females in October 2009. ACIP recommends vaccination of females with either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4). HPV4 was licensed for use in males in October 2009, and ACIP issued a permissive recommendation for use in males. Introductory sentences were added to the footnotes for measles, mumps, rubella, influenza, pneumococcal, hepatitis A, hepatitis B, and meningococcal vaccines. Clarifications were made to the footnotes for measles, mumps, rubella, influenza, hepatitis A, meningococcal, and Haemophilus influenza type b vaccines, and schedule information was added to the hepatitis B vaccine footnote.# The meningococcal vaccine footnote (#11) clarifies which vaccine formulations are preferred for adults aged ≤55 years and ≥56 years, and which vaccine formulation can be used for revaccination. New examples have been added to demonstrate who should and should not be considered for revaccination. The selected conditions for Haemophilus influenza type b (Hib) footnote (#13) clarifies which highrisk persons may receive 1 dose of Hib vaccine. The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians. Adults with uncertain or incomplete history of primary vaccination series with tetanus and diphtheria toxoid-containing vaccines should begin or complete a primary vaccination series. A primary series for adults is 3 doses of tetanus and diphtheria toxoid-containing vaccines; administer the first 2 doses at least 4 weeks apart and the third dose 6--12 months after the second; Tdap can substitute for any one of the doses of Td in the 3-dose primary series. The booster dose of tetanus and diphtheria toxoid-containing vaccine should be administered to adults who have completed a primary series and if the last vaccination was received ≥10 years previously. Tdap or Td vaccine may be used, as indicated. If a woman is pregnant and received the last Td vaccination ≥10 years previously, administer Td during the second or third trimester. If the woman received the last Td vaccination <10 years previously, administer Tdap during the immediate postpartum period. A dose of Tdap is recommended for postpartum women, close contacts of infants aged <12 months, and all healthcare personnel with direct patient contact if they have not previously received Tdap. An interval as short as 2 years from the last Td vaccination is suggested; shorter intervals can be used. Td may be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap can be administered instead of Td to a pregnant woman. Consult the ACIP statement for recommendations for giving Td as prophylaxis in wound management. # Human papillomavirus (HPV) vaccination HPV vaccination is recommended at age 11 or 12 years with catch-up vaccination at ages 13 through 26 years. Ideally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated consistent with age-based recommendations. Sexually active females who have not been infected with any of the four HPV vaccine types (types 6, 11, 16, 18, all of which HPV4 prevents) or any of the two HPV vaccine types (types 16 and 18, both of which HPV2 prevents) receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. HPV4 or HPV2 can be administered to persons with a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test, because these conditions are not evidence of prior infection with all vaccine HPV types. HPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. HPV4 would be most effective when administered before exposure to HPV through sexual contact. A complete series for either HPV4 or HPV2 consists of 3 doses. The second dose should be administered 1--2 months after the first dose; the third dose should be administered 6 months after the first dose. Although HPV vaccination is not specifically recommended for persons with the medical indications described in Figure 2, "Vaccines that might be indicated for adults based on medical and other indications," it may be administered to these persons because the HPV vaccine is not a live-virus vaccine. However, the immune response and vaccine efficacy might be less for persons with the medical indications described in Figure 2 than in persons who do not have the medical indications described or who are immunocompetent. Health-care personnel are not at increased risk because of occupational exposure and should be vaccinated consistent with age-based recommendations. # Varicella vaccination All adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine if not previously vaccinated or the second dose if they have received only 1 dose, unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of persons with immunocompromising conditions) or 2) are at high risk for exposure or transmission (e.g., teachers; child-care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or having an atypical case, a mild case, or both, healthcare providers should seek either an epidemiologic link with a typical varicella case or to a laboratory-confirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on diagnosis or verification of herpes zoster by a health-care provider; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Pregnant women should be assessed for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4--8 weeks after the first dose. # Herpes zoster vaccination A single dose of zoster vaccine is recommended for adults aged ≥60 years regardless of whether they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication. # Measles, mumps, rubella (MMR) vaccination Adults born before 1957 generally are considered immune to measles and mumps. Measles component: Adults born during or after 1957 should receive 1 or more doses of MMR vaccine unless they have 1) a medical contraindication; 2) documentation of vaccination with 1 or more doses of MMR vaccine; 3) laboratory evidence of immunity; or 4) documentation of physician-diagnosed measles. A second dose of MMR vaccine, administered 4 weeks after the first dose, is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) have been vaccinated previously with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963--1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Mumps component: Adults born during or after 1957 should receive 1 dose of MMR vaccine unless they have 1) a medical contraindication; 2) documentation of vaccination with 1 or more doses of MMR vaccine; 3) laboratory evidence of immunity; or 4) documentation of physician-diagnosed mumps. A second dose of MMR vaccine, administered 4 weeks after the first dose, is recommended for adults who 1) live in a community experiencing a mumps outbreak and are in an affected age group; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Health-care personnel born before 1957: For unvaccinated health-care personnel born before 1957 who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, health-care facilities should consider vaccinating personnel with 2 doses of MMR vaccine at the appropriate interval (for measles and mumps) and 1 dose of MMR vaccine (for rubella), respectively. During outbreaks, health-care facilities should recommend that unvaccinated health-care personnel born before 1957, who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, receive 2 doses of MMR vaccine during an outbreak of measles or mumps, and 1 dose during an outbreak of rubella. Complete information about evidence of immunity is available at . Unvaccinated persons who anticipate close personal contact (e.g., household contact or regular babysitting) with an international adoptee from a country of high or intermediate endemicity during the first 60 days after arrival of the adoptee in the United States should consider vaccination. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally ≥2 weeks before the arrival of the adoptee. Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6--12 months (Havrix), or 0 and 6--18 months (Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered on days 0, 7, and 21--30 followed by a booster dose at month 12 may be used. # Hepatitis B vaccination Vaccinate persons with any of the following indications and any person seeking protection from hepatitis B virus (HBV) infection. Behavioral: Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection-drug users; and men who have sex with men. Occupational: Health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids. Medical: Persons with end-stage renal disease, including patients receiving hemodialysis; persons with HIV infection; and persons with chronic liver disease. Other: Household contacts and sex partners of persons with chronic HBV infection; clients and staff members of institutions for persons with developmental disabilities; and international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at ). Hepatitis B vaccination is recommended for all adults in the following settings: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day-care facilities for persons with developmental disabilities. Administer or complete a 3-dose series of hepatitis B vaccine to those persons not previously vaccinated. The second dose should be administered 1 month after the first dose; the third dose should be administered at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered on days 0, 7, and 21--30 followed by a booster dose at month 12 may be used. Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 µg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 µg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. # Meningococcal vaccination Meningococcal vaccine should be administered to persons with the following indications. Medical: Adults with anatomic or functional asplenia, or persistent complement component deficiencies. Other: First-year college students living in dormitories; microbiologists routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season ), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. These schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults aged ≥19 years, as of January 1, 2009. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those that are used primarily for travelers or are issued during the year, consult the manufacturers' package inserts and the complete statements from	The Advisory Committee on Immunization Practices (ACIP) annually reviews the recommended Adult Immunization Schedule to ensure that the schedule reflects current recommendations for the licensed vaccines. In October 2009, ACIP approved the Adult Immunization Schedule for 2010, which includes several changes. A bivalent human papillomavirus vaccine (HPV2) was licensed for use in females in October 2009. ACIP recommends vaccination of females with either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4). HPV4 was licensed for use in males in October 2009, and ACIP issued a permissive recommendation for use in males. Introductory sentences were added to the footnotes for measles, mumps, rubella, influenza, pneumococcal, hepatitis A, hepatitis B, and meningococcal vaccines. Clarifications were made to the footnotes for measles, mumps, rubella, influenza, hepatitis A, meningococcal, and Haemophilus influenza type b vaccines, and schedule information was added to the hepatitis B vaccine footnote.# The meningococcal vaccine footnote (#11) clarifies which vaccine formulations are preferred for adults aged ≤55 years and ≥56 years, and which vaccine formulation can be used for revaccination. New examples have been added to demonstrate who should and should not be considered for revaccination. The selected conditions for Haemophilus influenza type b (Hib) footnote (#13) clarifies which highrisk persons may receive 1 dose of Hib vaccine. The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians. Adults with uncertain or incomplete history of primary vaccination series with tetanus and diphtheria toxoid-containing vaccines should begin or complete a primary vaccination series. A primary series for adults is 3 doses of tetanus and diphtheria toxoid-containing vaccines; administer the first 2 doses at least 4 weeks apart and the third dose 6--12 months after the second; Tdap can substitute for any one of the doses of Td in the 3-dose primary series. The booster dose of tetanus and diphtheria toxoid-containing vaccine should be administered to adults who have completed a primary series and if the last vaccination was received ≥10 years previously. Tdap or Td vaccine may be used, as indicated. If a woman is pregnant and received the last Td vaccination ≥10 years previously, administer Td during the second or third trimester. If the woman received the last Td vaccination <10 years previously, administer Tdap during the immediate postpartum period. A dose of Tdap is recommended for postpartum women, close contacts of infants aged <12 months, and all healthcare personnel with direct patient contact if they have not previously received Tdap. An interval as short as 2 years from the last Td vaccination is suggested; shorter intervals can be used. Td may be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap can be administered instead of Td to a pregnant woman. Consult the ACIP statement for recommendations for giving Td as prophylaxis in wound management. # Human papillomavirus (HPV) vaccination HPV vaccination is recommended at age 11 or 12 years with catch-up vaccination at ages 13 through 26 years. Ideally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated consistent with age-based recommendations. Sexually active females who have not been infected with any of the four HPV vaccine types (types 6, 11, 16, 18, all of which HPV4 prevents) or any of the two HPV vaccine types (types 16 and 18, both of which HPV2 prevents) receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. HPV4 or HPV2 can be administered to persons with a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test, because these conditions are not evidence of prior infection with all vaccine HPV types. HPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. HPV4 would be most effective when administered before exposure to HPV through sexual contact. A complete series for either HPV4 or HPV2 consists of 3 doses. The second dose should be administered 1--2 months after the first dose; the third dose should be administered 6 months after the first dose. Although HPV vaccination is not specifically recommended for persons with the medical indications described in Figure 2, "Vaccines that might be indicated for adults based on medical and other indications," it may be administered to these persons because the HPV vaccine is not a live-virus vaccine. However, the immune response and vaccine efficacy might be less for persons with the medical indications described in Figure 2 than in persons who do not have the medical indications described or who are immunocompetent. Health-care personnel are not at increased risk because of occupational exposure and should be vaccinated consistent with age-based recommendations. # Varicella vaccination All adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine if not previously vaccinated or the second dose if they have received only 1 dose, unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of persons with immunocompromising conditions) or 2) are at high risk for exposure or transmission (e.g., teachers; child-care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or having an atypical case, a mild case, or both, healthcare providers should seek either an epidemiologic link with a typical varicella case or to a laboratory-confirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on diagnosis or verification of herpes zoster by a health-care provider; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Pregnant women should be assessed for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4--8 weeks after the first dose. # Herpes zoster vaccination A single dose of zoster vaccine is recommended for adults aged ≥60 years regardless of whether they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication. # Measles, mumps, rubella (MMR) vaccination Adults born before 1957 generally are considered immune to measles and mumps. Measles component: Adults born during or after 1957 should receive 1 or more doses of MMR vaccine unless they have 1) a medical contraindication; 2) documentation of vaccination with 1 or more doses of MMR vaccine; 3) laboratory evidence of immunity; or 4) documentation of physician-diagnosed measles. A second dose of MMR vaccine, administered 4 weeks after the first dose, is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) have been vaccinated previously with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963--1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Mumps component: Adults born during or after 1957 should receive 1 dose of MMR vaccine unless they have 1) a medical contraindication; 2) documentation of vaccination with 1 or more doses of MMR vaccine; 3) laboratory evidence of immunity; or 4) documentation of physician-diagnosed mumps. A second dose of MMR vaccine, administered 4 weeks after the first dose, is recommended for adults who 1) live in a community experiencing a mumps outbreak and are in an affected age group; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Health-care personnel born before 1957: For unvaccinated health-care personnel born before 1957 who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, health-care facilities should consider vaccinating personnel with 2 doses of MMR vaccine at the appropriate interval (for measles and mumps) and 1 dose of MMR vaccine (for rubella), respectively. During outbreaks, health-care facilities should recommend that unvaccinated health-care personnel born before 1957, who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, receive 2 doses of MMR vaccine during an outbreak of measles or mumps, and 1 dose during an outbreak of rubella. Complete information about evidence of immunity is available at http://www.cdc.gov/vaccines/recs/provisional/default.htm. Unvaccinated persons who anticipate close personal contact (e.g., household contact or regular babysitting) with an international adoptee from a country of high or intermediate endemicity during the first 60 days after arrival of the adoptee in the United States should consider vaccination. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally ≥2 weeks before the arrival of the adoptee. Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6--12 months (Havrix), or 0 and 6--18 months (Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered on days 0, 7, and 21--30 followed by a booster dose at month 12 may be used. # Hepatitis B vaccination Vaccinate persons with any of the following indications and any person seeking protection from hepatitis B virus (HBV) infection. Behavioral: Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection-drug users; and men who have sex with men. Occupational: Health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids. Medical: Persons with end-stage renal disease, including patients receiving hemodialysis; persons with HIV infection; and persons with chronic liver disease. Other: Household contacts and sex partners of persons with chronic HBV infection; clients and staff members of institutions for persons with developmental disabilities; and international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at http://wwwn.cdc.gov/travel/contentdiseases.aspx). Hepatitis B vaccination is recommended for all adults in the following settings: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day-care facilities for persons with developmental disabilities. Administer or complete a 3-dose series of hepatitis B vaccine to those persons not previously vaccinated. The second dose should be administered 1 month after the first dose; the third dose should be administered at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule, administered on days 0, 7, and 21--30 followed by a booster dose at month 12 may be used. Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 µg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 µg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. # Meningococcal vaccination Meningococcal vaccine should be administered to persons with the following indications. Medical: Adults with anatomic or functional asplenia, or persistent complement component deficiencies. Other: First-year college students living in dormitories; microbiologists routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season [December through June]), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. These schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults aged ≥19 years, as of January 1, 2009. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those that are used primarily for travelers or are issued during the year, consult the manufacturers' package inserts and the complete statements from	None	None
3533dc64a4d91af123ce3e00ba0555d031e0067d	cdc	None	# I. RECOMMENDATIONS FOR A CHLOROFORM STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chloroform (CHC13) in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and safety of workers for up to a 10-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of chloroform on the health and safety of workers. The standard is measurable by techniques that are valid, reproducible, and available to industry and governmental agencies. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. "Exposure to chloroform" is defined as exposure above half the timeweighted average (TWA) environmental limit. Exposures at lower environmental concentrations will not require adherence to the following sections, except for Sections 4 (b) and (c) and Section 6 (d). # Section 1 -Environmental (Workplace Air) (a) Concentration Occupational exposure shall be controlled so that no worker will be exposed to chloroform in excess of 10 ppm (48.9 mg/cu m) determined as a time-weighted average exposure for up to a 10-hour workday, 40-hour workweek, or for any 10-minute period to more than 50 ppm (244 mg/cu m ) . # (b) Sampling and Analysis The procedure for sampling and analysis of workroom air for compli ance with the standard shall be as provided in Appendix I, or by any method shown to be equivalent or better in precision, sensitivity, accuracy, and specificity. Section 2 -Medical (a) Comprehensive preplacement medical examinations shall be made available to all workers subject to "exposure to chloroform" and yearly thereafter, unless a different frequency is indicated by professional medical judgment. (b) These examinations shall include, but shall not be limited to: (1) A comprehensive or interim medical and work history giving special attention to gastrointestinal symptoms and mental status. The worker's alcohol consumption should be reviewed. (2) A comprehensive medical examination, giving particular attention to cardiac rhythm, liver and kidney function. Liver function tests and urinalysis shall be performed. (3) An evaluation of the advisability of the worker's using negative-or positive-pressure respirators. Avoid breathing vapor. Avoid contact with skin. May generate toxic phosgene gas on contact with flame or very hot metal surface. This warning sign shall be printed both in English and in the pre dominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous conditions. All illiterate workers shall receive such training. If exposures to chloroform in the workroom exceed the recommended standard, and a variance permitting the use of respiratory controls has been granted, the following shall be added to the sign: No worker allowed to enter area without proper respiratory protection. # Section 4 -Personal Protective Equipment and Clothing When the limit of exposure to chloroform prescribed in subsection (a) of Section 1 cannot be met through application of available engineering controls in the design of equipment, systems, or operating procedures, an employer must utilize, as provided in subsection (a) of this Section, a program of respiratory protection to effect the required protection of every worker exposed. # (a) Respiratory Protection Appropriate respirators shall be provided and used when a variance has been granted to allow respirators as a means of control of exposure to routine operations and while the application is pending. Administrative controls can be used to reduce exposure. Respirators shall also be provided and used for nonroutine operations (occasional brief exposures above the standard and for emergencies); however, for these instances a variance is not required but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: (1) For the purpose of determining the type of r tor to be used, the employer shall measure the atmospheric concentration of chloroform in the workplace when the initial application for variance is made and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the chloroform concentration. This requirement shall not apply when only atmosphere-supplying positive pressure respirators are used. The respirator and cartridge or canister used shall be of the appropriate class, as determined on the basis of exposure to chloroform. The employer shall ensure that no worker is being exposed to chloroform in excess of the standard because of improper respirator selection, fit, use, or maintenance. The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided. (5) Respiratory protective devices described in Table I-1 shall be those approved under provisions of 30 CFR 11. (6) Respirators specified for use in higher concentra tions of chloroform are permitted in atmospheres of lower concentrations. (7) Chemical cartridges and canisters shall not be used for periods of time in excess of those indicated in Table 1-1. Employees shall be given instruction on the use of respirators assigned to them, cleaning of the respirators, and how to test for leakage. (9) Wherever bulk chloroform is handled, emergency and escape-type respirators shall be made readily available for each worker. Continuous contact must be maintained with employees working in enclosed spaces where chloroform concentration may become excessive. # (b) Protective Clothing In any operation where the worker may come into direct contact with liquid chloroform, protective clothing shall be worn. The clothing must be both impervious and resistant (such as neoprene or polyvinyl chloride) to chloroform. Bib-type aprons should be at least knee length, gloves should be lined to absorb perspiration, and boots or overshoes shall be provided when necessary. Impervious supplied air hoods or suits should be worn when entering areas with limited egress such as pits or tanks. All protective clothing should be well aired and inspected for physical defects prior to reuse. 1) Full face gas mask, chest or back mounted type, with industrial size organic vapor canister. Maximum service life of 2 hours. 2) Type C supplied air respirator, demand type (negative pressure), with full facepiece. 1) Type C supplied air respirator, con tinuous flow or pressure-demand type (positive pressure) with full face piece, hood or helmet. 1) Self-contained breathing apparatus with positive pressure in full facepiece. 2) Combination supplied air respirator pressure-demand type, with auxiliary self-contained air supply. 1) Self-contained breathing apparatus with positive pressure in facepiece. 2) Combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply. 1) Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure). 2) Full-face gas mask, front or back mount type with industrial size organic vapor canister. 3) Mouthpiece respirator with escape type organic vapor canister (escape type gas mask). (c) Eye Protection Eye protection shall be provided for any employee engaged in an operation where chloroform liquid or mist may enter the eye. Chemical-type goggles, safety glasses with splash shields, or plastic face shields made completely of chloroform resistant materials shall be used. Suitable eye protection shall be provided in accordance with 29 CFR 1910.133. # Section 5 -Informing Employees of Hazards from Chloroform At the beginning of employment in a chloroform area, each employee shall be informed of the hazards, relevant symptoms, effects of overexposure to and the proper conditions and precautions concerning safe use and handling of chloroform. The information explaining the hazards of working with chloroform shall be kept on file and readily accessible to the worker at all places of employment where chloroform is manufactured, used, stored, or transported. A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, proper maintenance procedures, and cleanup methods, and that they know how to correctly use respiratory protective equipment and protective clothing. Information on file and readily accessible to workers shall include that specified in Appendix II, on US Department of Labor Form 0SHA-2Q "Material Safety Data Sheet", or a similar form approved by the Occupa tional Safety and Health Administration, US Department of Labor. Where employees are required to enter confined areas where containers of chloroform are stored, such as a delivery van, entry shall not be made until the space has been ventilated or checked for concentrations of chloroform. (2) Storage containers, piping, and valves shall be periodically checked for leakage. (3) Storage facilities shall be designed to contain spills and prevent contamination of workroom air. (b) Contaminant Controls Suitable engineering controls designed to limit exposure to chloroform to that prescribed in subsection (a) of Section 1 shall be utilized where appropriate and feasible. Where ventilation systems are used to achieve such control, they shall be designed to prevent the accumulation or recirculation of chloroform in the workroom and to effectively remove chloroform from the breathing zones of workers. Ventilation systems shall be subjected to regular preventive maintenance and cleaning to ensure maximum effectiveness, which shall be verified by periodic airflow measurements. In addition, necessary measures shall be taken to ensure that discharge outdoors will be in conformance with all appropriate environmental regulations. # (c) Equipment Maintenance and Emergency Procedures Air saturated with chloroform is immediately dangerous to life and if a limited egress situation exists, emergency procedures must be established and followed. # Chloroform hazard areas Exits shall be plainly marked. Emergency exit doors shall be conveniently located and shall open to areas which will remain free of contamination in an emergency. (2) Confined spaces (A) Entry into confined spaces or in other situations of limited egress shall be controlled by a permit system. Permits shall be signed by an authorized representative of the employer certifying that preparation of the confined space, precautionary measures, personal protective equipment, and procedures to be used are all adequate. (B) Tanks, pits, tank cars, process vessels, tunnels, sewers, etc, which have contained chloroform, shall be thoroughly ventilated, tested for chloroform, and inspected prior to entry. (C) Inadvertent entry of chloroform into the confined space while work is in process inside shall be prevented by disconnecting and blanking off chloroform supply lines. (D) Confined spaces shall be ventilated or otherwise maintained to keep the chloroform concentration below the limit and to prevent oxygen deficiency. (E) Personnel entering confined spaces shall be equipped with a lifeline tended by another worker outside the space who shall be equipped with approved respiratory, eye, and skin protection. (F) Written operating instructions and emergency medical procedures shall be formulated and posted in conspicuous locations where accidental exposure to anesthetic concentrations of chloroform may occur. These instructions and procedures shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All illiterate workers shall receive such training. # (d) Showers and Eye Wash Fountains Showers and eye wash fountains shall be provided and so located as to be readily accessible in all areas where skin or eye splash with chloroform is likely. If chloroform is splashed on the skin, contaminated clothing shall be promptly removed and the skin washed with soap and water. If liquid chloroform contacts the eyes, they shall be thoroughly irrigated with clean water. Medical assistance shall be promptly provided in cases of eye splash. Such incidents shall be reported to the immediate supervisor by the affected employee or by a fellow worker. Chloroform was originally made from acetone and bleaching powder and can also be made by reduction of carbon tetrachloride. The principal method of manufacture is now chlorination of methane. Prior to World War II, chloroform was used primarily as an anesthetic and a pharmaceutical. The annual production of chloroform in the United States at that time was between 2,000,000 and 3,000,000 lbs. It is now seldom used as an anesthetic, but it is used by many manufacturers for pharmaceutical purposes. The production of chloroform for the manufacture of chlorodifluoromethane has grown over the years from 40,396,000 lbs in 1955 to 230,766,000 lbs in 1971, the latest year for which data are available. NIOSH estimates that 80,000 people are potentially exposed to chloroform in their working environment. # Historical Reports Simpson, a surgeon and obstetrician in Edinburgh, reported in an 1847 issue of Lancet on the merits of chloroform as an anesthetic agent. He advocated its use because it was pleasant to inhale, its action was more rapid and complete than that of ether, only a small amount was needed to produce narcosis, and it did not require the use of a special inhaler or instrument for its administration. He especially recommended it for use in obstetric practice because it alleviated maternal pain and recovery from anesthesia was rapid. In 1874, Witte observed that it required less chloroform to anesthetize frogs by absorption through the skin of the abdomen or thigh than by inhalation. He reported that rabbits also could be anesthetized by application of chloroform to the shaved abdomen, and he recommended that humans be anesthetized by absorption through the skin rather than by inhalation. One of the first detailed descriptions of death from liver damage following chloroform anesthesia published in the English literature appeared in the January 26, 1894 issue of Lancet. A 4-year old boy seemed to be well after an operation which lasted about 1 hour, but early the next morning he began to vomit, his pulse became weak, breathing was shallow and irregular, and he lapsed into unconsciousness. Vomiting continued (the vomitus being dark brown in color), little urine was passed, consciousness was never regained, and death occurred 30 hours after the operation. At autopsy, the liver was found to be small (14 1/2 oz), pale buff color, studded with minute purple dots, and greasy to the touch. Microscopy revealed intense fatty infiltration with no apparent fatty degeneration. In 1898, Desgrez and Nicloux reported that carbon monoxide was formed in dogs during chloroform anesthesia. They considered that the amount of carbon monoxide in the blood after 3-5 hours of anesthesia was equivalent to that present after exposure for 30 minutes to 100 ppm of carbon monoxide in air. Carbon monoxide was measured by a "grisoumeter" and chloroform did not interfere with the analytical method. In 1904 Schwenkenbecher reported that immersion of white mice up to their necks in aqueous solutions of chloroform was lethal. The solutions ranged from 0.3%-0.7% and the immersion time from 45-165 minutes. A special collar was used to preclude inhalation, and the genital and anal openings were closed. Moore and Roaf in 1906 reported that chloroform added to hemoglobin solutions at body temperature caused a change in color and a precipitation of the hemoglobin. In 1909, Whipple and Sperry published studies of liver necrosis in dogs following anesthesia with chloroform. They compared the liver damage observed in dogs to that seen in a 19-year old woman who died 3 days after anesthesia with chloroform for 35 minutes. They concluded that in dogs chloroform anesthesia for 1-2 hours would invariably cause central liver necrosis, and that the anatomic changes in the human autopsy were identical to those observed in the experimental dogs. Lehmann was the first to mention the industrial hygiene aspects of chloroform. He stated that in Germany more than 100 tons of chloroform was produced annually and that its manufacture in well designed factories did not create any danger to workers. Lewin in 1920 reported that the use of chloroform as a solvent for fats and resins was associated with a feeling of being "stoned", head ache, dizziness, breaking of the voice, sometimes an increase in saliva flow, bronchial catarrh, pounding of the heart, and with continued exposures, disturbances of metabolism, leading to a "real change in substance in the kidney and even to albumin in the urine." # Effects on Humans (a) Central Nervous System Effects The most outstanding effect of chloroform on the central nervous system is narcosis. Because of this property, chloroform was extensively used as an anesthetic. Featherstone concluded from a review of the literature that 20,000 ppm of chloroform was usually used to produce anesthesia and that 40,000 ppm, if continued for several minutes, could be an overdose. He suggested, for induction of anesthesia, gradually increasing the concentration of chloroform during the first 2 or 3 minutes to attain and maintain a concentration of 25,000 or 30,000 ppm until full anesthesia developed. The concentration used to produce anesthesia is usually not maintained for the duration of the operation but is replaced by a lower maintenance concentration such that the integrated exposure was actually much lower than 20,000 ppm. In the experiments reported by Lehmann and Hasegawa Fokina reported effects of chronic exposure in the work environment to mixtures of chlorinated methanes, including chloroform. Although the concentrations were not given, it was stated that the maximum permissible concentrations of individual components were exceeded at times. (There was no MAC for chloroform in Russia in 1965. ) The majority of workers showed signs of autonomic dysfunction, including diminution or disappearance of the corneal reflexes, dissociation between the deep (exaggerated) and superficial (sluggish) reflexes, marked persistent dermographism, general hyperhydrosis, acrohyperhydrosis, blotchiness of the skin of the hand and forearms, tenderness when pressure was applied to specific cervical points, and arterial hypotension. Autonomic dysfunction was mainly found in workers employed for less than 3 years. Workers employed for more than 5 years showed diencephalic disturbances and autonomic polyneuritis. In the case of delayed chloroform poisoning reported by Whipple and Sperry, urine specimens contained a trace of albumin, a few hyaline casts, and considerable quantities of leucine and tyrosine. At autopsy, the convoluted tubules of the kidneys showed a definite fatty degeneration with some of the epithelial cells having undergone necrosis. The capillaries were also found to be congested. In the studies by Gibberd and Lunt laboratory findings indicated renal dysfunction; there were albumin, red blood cells, and pus in the urine, congestion of cortical vessels, fatty deposits, and necrosis. # (d) Cardiovascular Effects Cardiac irregularities were found frequently by Kurtz et al in 1936 during electrocardiographic (ECG) surveillance of 113 surgical procedures. Arrhythmias were reported in all 6 cases in which chloroform was used for anesthesia and in 83 of 107 operations in which other anes thetics were used, including ethyl ether, cyclopropane, nitrous oxide, tribromoethanol, procaine, vinyl ether, and ethylene. The authors did not report the durations of anesthesia. In 1951, Orth et al stated that "this is a higher incidence of irregularities than is observed clinically with any other anesthetic agent except trichloroethylene". The irregularities were attributed to both reflex effects on cardiac automaticity and a direct depressant effect on the myocardium. In view of the high incidence of ECG abnormalities with all studied anesthetics, the possibility of all other factors in the etiology of the abnormalities needs to be considered in drawing conclusions from this study. For example Orth et al did not report the durations of anesthesia while Whitaker and Jones considered this to be important. Whitaker and Jones in 1965 found less frequent cardiovascular effects among 1,502 cases where chloroform was administered by a precision vaporizer in concentrations not exceeding 22,500 ppm. There were 9 cases of arrhythmia in the 1,164 operations in which anesthesia lasted 30 minutes or less and there were 10 cases of arrhythmia in 338 operations in which the duration of anesthesia was greater than 30 minutes. # (e) Hemolysis Belfiore and Zimmerman found that chloroform could affect the fragility of the red blood cell membrane without first being metabolized in the liver. Erythrocytes from 12 healthy adults were suspended in saline solution with chloroform ranging from 0.0125-0.10 mole/liter. The control was erythrocytes in a saline solution. At concentrations of 0.0125, 0.02, and 0.025 mole/liter there was no demonstrable effect. In concentrations of 0.05 mole/liter, erythrocyte leakage of hemoglobin, lactic dehydrogenase (LDH), and malic dehydrogenase began at 7 minutes and reached a maximum at 20 minutes for hemoglobin and at 10 minutes for the enzymes. Belfiore and Zimmerman found that incubation of cells with reduced glutathione (GSH) and oxidized glutathione (GSSG) inhibited hemolysis as measured by a loss of hemoglobin. They found that inhibition increased as the concentration of GSSG increased, but did not increase as the concentration of GSH increased. It has been suggested more recently, however, that it is only the GSSG that enters the intact red blood cell; the effect of GSH is due to its oxidation to GSSG. (f) Effects on the Skin Malten et al measured injury and regeneration of forearm skin exposed to liquid industrial solvents, including chloroform. The solvents were contained in glass cylinders 2 cm in diameter which were fixed to the skin by agar-agar for 15 minutes a day for 6 consecutive days. An unspeci fied number of sites served as controls. The rate of water evaporation from these sites was determined daily to evaluate the degree of skin damage and regeneration. Exposure to chloroform was reported to be similar in effect to ethanol and to cause an increase in the rate of water evaporation with repeated exposures. Recovery of normal water retention, indicative of the formation of a new horny layer, occurred slowly during the 30 days after the last exposure. Hoffman suggested that chloroform could be used on skin to combat mosquitoes and other biting insects. It seems doubtful that present-day dermatologists would recommend this use of such an irritating substance. Hoffman cautioned against getting chloroform into eyes and mucous membranes because of irritating effects. Oettel carried out systematic experiments with chloroform administered to the skin by way of a small glass vessel, 1 cm in diameter, one end of which was open, with glass hooks fused into it. Vessels were filled with chloroform and tied onto the arms of 5 subjects. Pure chloroform was used for various exposure times. Three minutes after application of chloroform, there was a sensation of burning and stinging. When exposure time was increased to 6 minutes, the pain became more intense and then subsided quickly. When the chloroform was removed, the pain increased again, only to be replaced by a loss of feeling. Erythema was noted and the hyperemia which also occurred after 3 minutes of exposure was somewhat stronger, more cherry red with a light yellow undertone. In a 30minute period after removal of the chloroform, there was a fading away of the erythema and hyperemia, and 5 hours later, little blisters formed at the edge of the area of application. Erythema and pigmentation disappeared 7 days after the exposure. From these studies, it can be concluded that exposure of the skin to liquid chloroform will cause irritation, erythema, hyperemia, and destruction of the epithelium. Much of this information on skin irritation from chloroform is based on prolonged contact. However, it should be noted that repeated, brief contact can cause skin defatting. Thereafter, the rate of elimination decreased, and "small amounts" were reported to have been detected in the blood 8 hours after exposure. Concentrations of chloroform in the blood were also measured by Cullen et al Breath concentrations of chloroform in a worker after an industrial exposure to a mixture of solvents including chloroform, carbon tetrachloride, trichloroethylene, and perchlorethylene were measured by Stewart et al in 1965. The exposure was defined as a "few minutes" without a gas mask followed by an unspecified time with a general purpose chemical respirator, to unknown concentrations with "strong" odors. The exposed worker experienced dizziness, weakness, nausea, and finally unconsciousness. The duration of unconsciousness is not known, but "10 minutes later" he was coherent, though uncoordinated and nauseated. Thirty minutes after his collapse, infrared analysis of his expired breath contained: perchlorethylene, 11 ppm; carbon tetrachloride, 9.5 ppm; chloroform, 7 ppm; and trichloroethylene, 11 ppm. Three days later, 0.1 ppm chloroform was found in the exhaled breath; 12 days after exposure, there was no chloroform found in the exhaled breath. Several authors have reported on the concentration of chloroform in tissues following suicide, homicide, or death during or after an operation. Gettler # Epidemiologic Studies There are very few reports of industrial workers exposed to chloroform. The studies of Challen et al and Bomski et al are the only studies that contain exposure concentration measurements, descriptions of symptoms and diagnoses, and comparisons with control groups. In 1958, Challen et al reported a study of a confectionery firm in England that manufactured medicinal lozenges. In 1950, the operators began to complain of the chloroform vapor given off during the production of the lozenges. A system of part-time work was initiated to alleviate complaints of lassitude, flatulence, water brash (British term indicative of symptoms of dyspepsia), dry mouth, thirst, depression, irritability, and frequent and "scalding" micturition, but this was not successful, and fi nally the operators refused to work on that particular process. In 1954, a new team of operators was engaged and in 1955 a system of exhaust ven tilation was installed, after which the work proceeded without interrup tion. In order to confirm the effectiveness of the ventilation system, Challen and his associates were asked to ascertain the concentrations of chloroform. Additionally, clinical investigations were performed and an attempt was made to simulate the original conditions in order to compare the chloroform concentrations before and after remedial measures were introduced. The original conditions were simulated by closing the doors and windows and shutting off the ventilation system. A single air sample was taken continously in the breathing zone of the operator of the ingredient mixing process during a period of 20 minutes coinciding with the duration of the process. Sampling at the rate of 2 liters/min was done by drawing air through 2 U tubes containing dried silica gel. Additionally, at a point in the operation where a peak concentration was expected, a 6-liter "grab" sample was taken. Air samples of 30-minute durations each were also taken in the breathing zones of cutting room operators. The samples were taken during 2 periods of production for 3 different operations on the same day (under current conditions) and during 3 periods on another day (during the simulated conditions Clinical investigations of 3 different groups of workers were per formed by Challen et al. One group of 8 employees was termed the "long service operators". These were people who refused to continue in the lozenge department after they experienced the previously described symptoms. This group of workers, when exposed to chloroform vapor in probable concentrations ranging from 77 to 237 ppm, had been observed staggering about the work area. After terminating work in the lozenge department the "long service operators" reported experiencing nausea and stomach upset after even short exposures to the smell of chloroform. A second group of 9 employees in this study, termed the "short service operators", were the replacements of the "long service operators". Two of these 9 employees did not report unpleasant experiences from chloroform exposure. Among the other 7, 5 reported dryness of the mouth and throat at work; 2 were subject to lassitude in the evening; 1 complained of lassitude and flatulence at work, and the experiences of 2 others were similar to those of the "long service operators". The "short service operators" worked in locations where the chloroform concentrations ranged from 23-71 ppm. A third group of 5 employees in this study who worked in other departments of the firm served as controls and exhibited no symptoms. Neither tests of liver function (thymol turbidity, thymol flocculation, direct van den Bergh, and serum bilirubin), clinical examinations, nor urinary urobilinogen showed significant differences among the 3 groups of workers. In 1967, Bomski et al reported on liver injury from chloroform among workers in a pharmaceutical factory in Poland. The study included the entire group of 294 workers who used chloroform in the course of production; of these, 68 were exposed to chloroform for 1-4 years and still had contact with chloroform, 39 had chloroform contact at one time, 23 had viral hepatitis with icterus 2-3 years earlier and were designated as posticterus controls and were working in a germ-free area, and 165 worked in a germ-free area with no history of viral hepatitis. Blood pressure, blood morphology, urinalysis, blood albumin, serum protein, thymol turbidity, zinc sulfate turbidity, the "Takata-Ara" sulfate (colorimetric) test, urobilinogen, SGOT, and SGPT were measured in all. A complete medical history was taken. Sixty of the people were hospitalized for determination of BSP clearance and urinary urobilinogen. The air in the production room was sampled and chloroform concentra tions were determined using the Grabowicz method. The concentration of chloroform ranged from 2-205 ppm. No other concentration measurements were reported nor was there any mention of the frequency of sampling. The authors compared the frequency of viral hepatitis and jaundice among a group of inhabitants of the city, 18 years and older, with that of the same 68 pharmaceutical workers who used chloroform. The results showed that in 1960, 0.35% of city inhabitants had viral hepatitis, while 16.67% of the chloroform exposed workers had viral hepatitis. In 1961, the frequency for city inhabitants was 0.22% and the frequency among the chloroform workers was 7.50%. In 1962 the frequency of viral hepatitis was 0.38% for city inhabitants and 4.4% for workers using chloroform. The authors suspected that the toxic liver changes occurring as a result of exposure to chloroform promoted a viral infection in such cases, but they did not give information on the incidence of viral hepatitis among other plant workers, which might have helped resolve questions about sanitary practices and facilities in the plant. The majority of the workers who were in contact with chloroform during the investigation period covered in this study complained of headache, nausea, belching, and loss of appetite. Among the 68 workers using chloroform, 10 cases of splenomegaly were found compared to none in the controls. They did not explain the splenomegaly but point out it was not present in controls. The frequency of enlarged livers (17 out of 68) among workers exposed to chloroform exceeded the frequency of enlarged livers in the other groups (5 out of 39, and 2 out of 23). Livers were judged to be enlarged if they extended at least 1 cm beyond the rib arch in the midclavicular line. The upper margin was apparently not measured. In 3 of the 17 chloroform workers with enlargement of the liver, toxic hepatitis was diagnosed on the basis of elevated serum enzyme activities and elevated serum gamma globulin. The measured amounts of these serum constituents in these 3 workers were not reported. In the remaining 14 cases of liver enlargement, fatty liver was diagnosed. It was claimed that the latter diagnoses were substantiated by a 79% reduction in the incidence of hepatomegaly in the people studied during a 12-month period when hygienic work conditions were improved as a consequence of the studies. In a continuing study by the Department of Labor and Industries, Commonwealth of Massachusetts, worker exposure to chloroform, methylene chloride, and toluene in a plant manufacturing plastic film was investigated. The workers were exposed to levels of chloroform from 7-170 ppm, with a mean of 47 ppm. Physical examinations and the following laboratory tests were performed regularly on all employees connected with the process: SGOT, LDH, alkaline phosphatase, blood bilirubin, BUN, creatinine, cholesterol, serum protein, urobilin, urobilinogen, urine bilirubin. The blood tests were performed yearly and urine tests quarterly. The liver function tests have been done for more than 2 years, the kidney function tests for only 1 year. Some of the employees at times experienced what was termed "dry heaves". Laboratory findings have been normal so far, but there appeared to be a significant number of findings in the upper normal range, particularly for the blood bilirubin and BUN. There was no evidence, though, that there was a progressive increase in the values found. However, the evaluations of the laboratory findings were based on the normal range for the general population rather than a specific control group for this particular investigation. It is not apparent from this study what the time-weighted average exposures were. # Animal Toxicity The majority of animal studies of chloroform toxicity have been con ducted to provide supplementary information relevant to the clinical use of chloroform as an anesthetic. Consequently these animal studies include concentrations of chloroform many times greater than would be experienced in daily occupational situations except in the case of accidents. The following subsection contains a summation of some of these studies. Jones et al in 1958 studied the relative hepatotoxicity of inhalation anesthetic drugs using chloroform as a standard of reference. Chloroform was given orally to 350 white mice, each weighing approximately 20 g. The mice were killed 72 hours after exposure and livers were fixed in formalin. The authors were able to estimate the following effects of acute injury from esophageal instillation of chloroform: Rats and guinea pigs given the 0.4 mg/kg dose of chloroform showed no changes in conditioned reflexes or in autonomic or cardiac activity, blood protein ratios, catalase concentrations, or phagocytic capacity. There was an increase in ascorbic acid in the adrenals of the guinea pigs. Some guinea pigs given doses of 35 mg/kg died during the course of the experiment. Five of the guinea pigs lived longer than 2 months, but only 2 of these lived longer than 3 months. The ratio of blood protein fractions in the guinea pigs given 35 mg/kg was altered by the end of the first month. These changes consisted of an increase in the globulin content (from 32.9±1.09 to 40.9±2.22%) involving the alpha and gamma fractions and a decrease in the albumin content, so that the albumin-globulin ratio decreased from 2.1-0.4. The change in this ratio was even more pronounced at the end of the second month. The guinea pigs in the 35 mg/kg groups also showed a decrease in blood catalase activity from 2.0±0.13-1.2±0.11 (no units given) in the second month of the experiment. The guinea pigs which had died from a dose of 35 mg/kg of chloroform had structural lesions of the liver, heart muscle, and stomach wall upon The effect of chloroform on rats exposed to 300 ppm was confused by changes in dietary intake. It was not possible to determine whether decreased food consumption was the result of loss of appetite or the inability to eat due to narcosis. Exposure of pregnant rats to 100 ppm on days 6 through 15 of gestation revealed a significant incidence of fetal abnormalities as compared to controls. There were significant increased incidences of acaudia, imperforate anus, subcutaneous edema, missing ribs, and delayed skull ossification. Rats exposed to 30 ppm showed significant incidences of delayed skull ossification and wavy ribs, but no other effects. The teratogenicity of oral doses of chloroform was studied in rats and rabbits. There was no evidence of teratogenicity in either species at any dosage level tested. However, in both species reduced birth weights (7.5% in rats and 1.1% in rabbits) were observed with the highest dosages, 126 and 50 mg/kg, respectively. tried to determine whether structural damage affecting protein synthesis occurs when chloroform acts on the liver of a rat. Twenty Sprague-Dawley rats were fasted for 10 hours and 4 were exposed to 1 vol % chloroform Preliminary examinations of all animals anesthetized showed a slight increase in respiratory acidosis but no signs of arterial hypoxemia or metabolic acidosis. After 4 1/2 hours of chloroform anesthesia, the livers of most exposed rats showed gross enlargement of the centrilobular hepatic cells. The cells also showed a striking paleness, and upon staining of frozen sections, fatty degeneration was also observed. On electron microscopy it was found that chloroform produced an early dilation of the granular endoplasmic reticulum with detachment of the ribosomes producing a marked reduction of centrilobular protein synthesis. Additionally, after anesthesia with chloroform, extensive necrosis of portions of the renal tubular epithelium was found, while the lung revealed severe leucocytic infiltrations in the alveolar septa. In light of this latter finding, it should be noted that in 1966 Wattenberg stated that kidney and lung tissue also contain hydroxylating enzyme systems. This enzymatic activity is less intense than in the liver, but can be increased by some lipid- All experiments showed reduced liver function as indicated by prolonged pentobarbital sleeping times and elevated BSP retention. The liver succinic dehydrogenase activity was depressed when chloroform was administered 12 or 24 hours after ethanol, but not when it was administered 48 hours after ethanol. Ethanol alone or chloroform alone did not significantly depress succinic dehydrogenase activity. In mice pretreated with ethanol 15 hours, or 1, 2, or 4 days before the administration of chloroform, microscopic examination revealed livers with cytoplasmic vacuolization in pericentral cells. The pericentral cells were also enlarged and almost completely devoid of eosinophilic material. In a similar study, Sipes et al pretreated rats with isopro panol and reported enhanced ability to covalently bind radioactive carbon labeled chloroform to microsomal protein. Dingell and Heimberg studied the hepatic metabolism of aminopyrine and hexobarbital in rat liver microsomes after the administration of chloroform or carbon tetrachloride or methylene chloride. The chlorinated hydrocarbons were administered in equimolar doses by gastric intubations and killed 24 hours later. Liver microsomes were prepared from rat livers weighing from 250-375 mg. Either 5 jumoles of aminopyrine or 1.9 /imoles of hexobarbital was added to a mixture of enzyme substrates. The rate of metabolism of hexobarbital was measured by estimation of the disappearance of substrate. The rate of déméthylation of aminopyrine was measured by estimation of the amount of formaldehyde formed. For both the aminopyrine and hexobarbital pretreatment before carbon tetrachloride decreased the rate of metabolism significantly to 14 and 29%, respectively, of control values. Chloroform, however, only decreased metabolism of aminopyrine to 61% and hexobarbital to 95% of control values. McLean fed male mice either stock diet or protein free diets for 1 week before intragastric administration of chloroform. Some of the mice of each group were also given sodium phénobarbital in the drinking water (1 mg/ml) for 1 week before chloroform administration; others were given a single subcutaneous injection of DDT (100 mg/kg) 1 week before chloroform. The purpose of DDT and the phénobarbital administration was to stimulate liver hydroxylating enzyme activity. The purpose of the protein deficient diet was to reduce the liver hydroxylating enzyme activity, but in this experiment this was not realized. Phénobarbital and DDT increased the liver hydroxylating enzyme activity and the toxicity of chloroform was more than doubled by the phénobarbital and DDT pretreatment as measured by the LD50. # Correlation of Exposure and Effect The use of chloroform as an anesthetic agent has provided information about the effects to be expected from acute exposure. Exposures during anesthesia have usually been to concentrations of around 20,000 ppm, and exposure times have been from 30-240 minutes. One or 2 days after chloroform anesthesia, nausea, jaundice, and vomiting may develop, often followed by elevated temperature and pulse, epigastric pain, muscle twitching, delirium, and coma. In some cases, death has occurred 3-10 days after anesthesia. Habitual inhalation of 1 oz daily of chloroform for 7 years followed by 2 oz/day for 5 more years was associated with delusions, restlessness, depression, convulsions, ataxia, dysarthria, tremor of the tongue and fin gers, and insomnia; at autopsy, the brain showed slightly thickened menin ges in the frontal lobe, many fibroblasts and dilated blood vessels. In other cases of habitual chloroform inhalation for periods of time ranging up to 30 years, hallucinations, delirium, and tremors were common manifestations. The exposures ( The data presented by Challen et al provide some quantitative information about exposure and effect, even though some of the information about exposure was obtained after the fact. Employees in a confectionery The incidence of enlarged livers among these 68 workers was sig nificantly higher than in the controls. It was noted that there was a reduction in hepatomegaly in 79% of the people studied during the 6-12 month period when hygienic conditions at work were improved. Schwetz et al studied the effects of 30, 100, and 300 ppm of chloroform on pregnant rats for 7 hours/day on days 6 through 15 of gestation. There were significant incidence of delayed skull ossification and "wavy ribs" in litters from dams exposed to 30 ppm of chloroform. The authors found that in litters from dams exposed to 100 ppm there were significant incidences of acaudia, imperforate anus, subcutaneous edema, missing ribs, and delayed sternebrae ossification. Rats exposed to chloroform at 300 ppm ate so little food (1 g/day) that it would be impossible to consider any of the other effects as characteristic of chloroform. Kylin et al found that mice exposed to 100 ppm chloroform for 4 hours showed moderate fatty infiltration and degeneration at the periphery of the liver lobules, one day after exposure. These effects were found less frequently 3 days after exposure, indicating a certain amount of regeneration. A direct dose-response relationship, evidenced by increasing liver alterations and necrosis, was observed at concentrations ranging from 100 to 800 ppm. Further indication of a dose-response relationship was the increase of the serum ornithine carbamoyl transferase with increasing concentrations of chloroform. Animal studies there are no studies on workroom concentrations of chloroform used in their production. Challen et al Air samples should be collected and transported to a laboratory, then desorbed or chemically treated, and finally analyzed quantitatively. Silica gel has been used extensively in the past as a collection medium. Silica gel is a polar adsorbent and shows pronounced selectivity in adsorbing polar molecules, particularly water. Hence, when sampling large volumes, the atmospheric moisture may compete for the adsorptions sites and displace the chloroform being sought. When sampling large volumes (more than 3 liters), the silica gel adsorption tube may become saturated with water thus impairing the retentive properties of the collec tion medium. Activated charcoal as a collection method has been used in conjunc tion with gas chromatography. Activated carbon is nonpolar and will consequently adsorb organic vapors in preference to water vapor so that sampling of volumes higher than 3 liters can be accomplished without noticeable moisture interferences. Williams and Umstead have developed a collection method in which atmospheric samples are concentrated on porous polymer beads. The same column utilized for sample collection is subsequently used for GC analysis. The advantage of this method is that it integrates collection and analysis into one operation. However, it has not yet been developed for field use. The dechlorination method (alkali hydrolysis) requires collection of the chloroform contaminated atmosphere over a suitable collection medium followed by hydrolysis in isopropyl alcohol. Solid KOH is added and the mixture is allowed to sit overnight (about 20 hours). After neutralization the liberated chloride ion is titrated with silver nitrate. The percentage of chlorine hydrolyzed is determined by comparison between samples and known controls. This method has the disadvantage of a long and elaborate procedure in which the amount of chloride ion liberated depends on the duration of the process of alkali dechlorination. When a mixture of chlorinated hydrocarbon vapors is analyzed, there is the additional problem of specificity; it is necessary then to differentiate the contribution of each chlorinated compound to the total amount of chloride ion liberated. The gas chromatographic method of analysis provides a specific when enveloped by an atmosphere contaminated with halogenated hydrocarbons. The instrument is sensitive to all halogens and halogenated compounds and consequently is nonspecific for chloroform. The Halide meter seems suitable for continuous monitoring if there is only chloroform present as the air contaminant. # (d) Conclusions and Recommendations (1) Compliance Method On the basis of the review of the analytical methods it is recommended that gas chromatography be chosen as the compliance method. The method is recommended in conjunction with activated charcoal tubes as a collection method and the use of carbon disulfide as a desorbent. However, a disadvantage of the method is the indirect system of measurement requiring collection and desorption prior to analysis. # 2) Monitoring Methods It is also recommended that direct reading colorimetric tubes (gas detection tubes) be used as an inexpensive way to determine whether exposure, as defined in Chapter I, exists. The tubes must be used with manufacturer's instructions and for monitoring purposes only. Chloroform concentrations in the blood have been measured during and following anesthesia. These data show that chloroform in the blood is eliminated rapidly at first but that some remains for at least 8 hours after exposure to anesthetic concentrations. These data are inadequate for evaluating industrial exposure. # V. DEVELOPMENT OF A STANDARD # Basis for Previous Standards In 1946, the Sub-Committee on Threshold Limits of the ACGIH published a list entitled "Maximum Allowable Concentrations of Air Contaminants for 1946", with the understanding that the list would be revised each year. The list of values was compiled from 3 sources: (a) The list reported by the Sub-Committee on Threshold Limits at the 5th Annual Meeting of the ACGIH in 1942. # (b) The then comprehensive list published by Cook in Industrial Medicine. (c) Published values of the Z-37 Committee of the American Stan dards Institute. The value proposed for chloroform by the ACGIH was 100 ppm. In 1959, the Threshold Limit Value (TLV) for chloroform was reduced to a time-weighted average of 50 ppm for a normal working day by the ACGIH in their annual review of the TLV values. In 1962, the ACGIH published its Documentation of Threshold Limit Values (TLV's) in which it cited the recommendations of Cook that exposures to chloroform be kept below 50 ppm, and the study of Challen et al. The 1968 TLV, which was unchanged from the 1962 recommendation, was promulgated $s a regulation by OSHA. This was published, apparently in error, as a ceiling value of 50 ppm, in the Federal Register, volume 39, page 23541, dated June 27, 1974. In 1969, the ACGIH changed the time-weighted average limit to a ceiling and documented this in 1971. This ceiling limit of 50 ppm was considered adequate to prevent any serious short-term effects on the liver, but it was recommended that chloroform be used with close medical surveillance, particularly with those workers who consume alcohol. The recommendation was based in part on the studies of Challen et al, Bomski et al, and unpublished data from the Massachusetts Division of Occupational Hygiene. A notice of intended change for chloroform from 50 (ceiling) to 25 ppm (time-weighted average) was made by the ACGIH in 1972 and 1973. The AIHA Hygienic Guide Series of 1965 for Chloroform suggested that a time-weighted average (TWA) of 10 ppm be used with a ceiling of 25 ppm. This recommendation was based on unpublished experimental animal data. In 1970, the International Labour Office in Geneva published tables of Permissible Levels of Toxic Substances in the Working Environment . for many countries. The chloroform standards for 8 different countries are listed below; it is not clear from the reference whether these are time-weighted averages or ceiling concentrations. The major exposure to chloroform has been as an anesthetic and most experiments have been related to this use. Cardiac arrhythmias have occurred, especially when chloroform anesthesia has been prolonged beyond 30 minutes. Liver and kidney injuries have also been found, sometimes resulting in death several days after anesthetic exposure. It is difficult to evaluate the total exposure to chloroform during anesthesia since concentrations frequently were not reported. However, it should be noted that the concentrations in anesthesia are extremely high and are not constant throughout the exposure period. # Country # Whipple and Sperry demonstrated in experiments with dogs that chloroform anesthesia for a period of 1-2 hours caused central liver necrosis. At autopsy of a woman who had died from delayed chloroform poisoning, they found liver changes that resembled changes found in dogs. The only other experimental study of liver changes after inhalation of chloroform was that by Kylin et al in 1963 who exposed 20 mice to 100, 200, 400, and 800 ppm for 4 hours. In this study, the mice exposed to 100 ppm did not develop demonstrable liver necrosis, however, moderate fatty infiltration of the liver was noted. In mice exposed to 200 ppm, some necrotic areas appeared in the liver and there was an increase in serum ornithine-carbamoyl transferase. Exposures to 400 and 800 ppm resulted in increasing necrosis and serum enzyme activity. Although Schwetz et al did not report detailed studies of liver changes in female rats exposed to chloroform 7 hours/day for 10 days, they did report that liver weights, both absolute and relative, increased as a result of exposure to 100 and 300 ppm but not to 30 ppm. However, embryo and fetal anomalies, including delayed skull ossification and the formation of wavy ribs, were found in the offspring of the rats exposed to 30 ppm. The only account of liver abnormalities among industrial workers exposed to chloroform is a report by Bomski et al. These investi gators found 17 cases of hepatomegaly in a group of 68 workers exposed to chloroform in concentrations ranging from 2-205 ppm for 1-4 years in a pharmaceutical firm. Three of the 17 workers with hepatomegaly were judged by the authors to have toxic hepatitis on the basis of elevated serum enzymes, and elevated serum gamma globulin. This group of workers was also considered to be much more susceptible to viral hepatitis than the inhabitants of the city in which the plant was located, but the basis for this inference is tenuous, since no information was given on possible contributions to the problem by poor sanitation, for example the incidence of viral hepatitis in other plant workers was not mentioned. In the study by Challen et al no liver abnormalities were found among 17 workers exposed to chloroform. Nine workers were exposed to chloroform at TWA concentrations ranging from 23-71 ppm, but for only 4 hours/day. These workers had been working under these conditions for 10-24 months. Another group of workers who had previously been exposed to chloroform in concentrations estimated to have ranged from 77-237 ppm for up to 8 hours/day, also had no abnormal liver findings. However, it had been many months since this latter group had been exposed to chloroform. These studies indicate that liver damage may occur in workers from exposure to chloroform in varying concentrations up to 205 ppm. The studies with mice showed some liver cell necrosis from 4 hours' exposure to 200 ppm and fatty infiltration of the liver from 100 ppm for 4 hours. The studies with rats showed increased liver weights from 10 consecutive 7hour daily exposures to 100 ppm, but not to 30 ppm exposures. The studies by Challen et al indicated no liver injury from 4 hours per day exposure of workers to 23-71 ppm chloroform. While the exposure conditions studied by Challen et al (23-71 ppm chloroform for 4 hours/day) seem below the threshold for liver injury, they are not adequate to protect workers from other undesirable responses such as dryness of the mouth and throat at work, and lassitude in the evening, which occurred among the workers exposed to 23-35 ppm chloroform for 4 hours a day. It seems reasonable to infer from these observations that the lassitude reflects central nervous system depression and that dry mouth and throat and the digestive tract symptoms reflect a local irritant action in those areas. It can be interpreted from the study of Challen and co-workers that a safe level to exposure for workers lies somewhere between 23 and 35 ppm for 4-hour workdays, or about 10 to about 18 ppm for 8-hour workdays. The appropriate limit within this range is not clear, but because of mild effects in this group (mouth and throat dryness and evening fatigue) and because of the fetal abnormalities found in rats exposed to 30 ppm, it is concluded that the environmental limit to be recommended should be the lowest in this range, namely 10 ppm, as a time-weighted average. The absorption of chloroform resulting from exposure to a given time-weighted average concentration for 8 hours a day, 5 days a week, would be about the same as that absorbed for 10 hours a day, 4 days a week. Thus, the same time-weighted average limit is applicable whether the 40hour workweek is applied over 5 8-hour days or 4 10-hour days. It is likely that a central nervous system depressant, such as chloroform, might at briefly high concentrations affect attention, judgment or perception sufficiently so that if an emergency were to occur the worker might not take appropriate action. This suggests the need for a ceiling concentration to be observed, as a limitation on excursions above the timeweighted average and as a limit applicable to occasional and brief use of chloroform. However, after detailed consideration of the data applicable to derivation of such a ceiling, no basis from the scientific data appears. The ceiling proposed by American Industrial Hygiene Association in its Hygienic Guide Series is based on animal data that seem more applicable to development of a time-weighted average limit. Thus, a ceiling limit of 50 ppm based on a 10-minute sampling period is proposed on the basis of good practice. It is recognized that many workers handle small amounts of chloroform or are working in situations where, regardless of amounts used, there is only negligible contact with the substance. Under these conditions, it should not be necessary to comply with all provisions of this recommended standard, which has been prepared primarily to protect worker health under hazardous circumstances. On the other hand, concern for worker health requires that protective measures be instituted below the enforceable limit to ensure that exposures stay below that limit. For these reasons, "exposure to chloroform" has been defined as exposure above half the environmental limit, thereby delineating those work situations which do not require the expenditure of health resources for environmental and medical monitoring and associated recordkeeping. Half the environmental limit has been chosen on the basis of professional judgment rather than on quantitative data that delineate nonhazardous areas from areas in which a hazard may exist. However, it is recommended that appropriate work practices and protective measures to prevent skin and eye contact and to prevent exposure to pyrolysis products be required, regardless of air concentrations of chloroform. # VI. WORK PRACTICES The principal method for the manufacture of chloroform is chlorination of methane, and suitable controls for safe use of methane Consideration should be given to pumping the diked spill to another tank. In addition, it is advisable to have facilities for transfer of the contents of a leaking tank to another suitable tank. Respirators generally fall into the following classification according to their mode of operation: leakage is the major limitation of these devices. From the test results, it has been demonstrated that the half mask or quarter mask facepiece may be Used for protection up to 10X the TWA. The full facepiece, operated with a negative pressure, may be used up to 100X the TWA. The majority of the wearers can obtain a higher degree of protection. However, for purposes of uniform regulations, covering the many face sizes and shapes of the US working population, it is necessary to use these guides. These maximum use concentration guides do not take into account additional leakage from filters or canisters. When providing respiratory protection against chloroform, the concentration immediately dangerous to life must be considered. In this document, it is assumed that any concentration of chloroform greater than 2,500 ppm is immediately dangerous to life. In selecting and using gas masks and chemical cartridge respirators, the service life must be considered. An approved, calibrated, battery-operated personal sampling pump plus an activated charcoal tube shall be used to collect the sample. The activated charcoal tube shall be attached to the clothing of the worker; the shirt collar is convenient for this purpose. (4) Breathing zone samples shall be collected to permit determination of TWA workday exposures for every job involving exposure to chloroform in sufficient numbers to express the variability of the work situation. The minimum number of TWA's to be determined is listed in Section 7 of this standard, according to the number of employees involved. (2) The smaller section of charcoal is used as a backup and should be positioned nearest the sampling pump. The charcoal tube should be placed in a vertical position during sampling with the inlet facing down. (4) Tubing may be used to connect the back of the tube to the pump, but air being sampled should not be passed through any hose or tubing before entering the charcoal tube. The flowrates, sampling time involved and/or the total volume of air sampled must be measured accurately. The sample can be taken at flow rates of 50-1000 ml/min. Total sample volumes of 1-30 liters are recommended. It is also recommended that the sampling be less than 4 hours. (6) Measure and record the temperature and pressure of the atmosphere being sampled. The charcoal tubes should be capped with the supplied plastic caps immediately after sampling. Under no circumstances should rubber caps be used. (8) One charcoal tube should be handled in the same man ner as the sample tube (break, seal, and transport) except that no air is sampled through this tube. This tube should be labeled as a blank. (9) Capped tubes should be packed tightly after sampling to minimize tube breakage during transport. (10) Charcoal tubes should be shipped separately from bulk samples. # Sample Analysis (a) Principle of the Method (1) A known volume of air is drawn through a charcoal tube to trap the chloroform vapor. The charcoal in the tube is transferred to a small test tube and desorbed with carbon disulfide. (3) An aliquot of the desorbed sample is injected into a gas chromatograph. The area of the resulting peak is determined and compared with areas obtained from the injection of standards. (b) Range and Sensitivity (1) The lower limit for detection of chloroform at a 16 x 1 attenuation on a gas chromatograph with a 10:1 splitter is 0.10 mg/sample. This value can be lowered by reducing the attenuation or by eliminating the 10:1 splitter. The upper limit value for chloroform is 2.0 mg/sample. This is the estimated amount of chloroform which the front section will hold before this compound is found on the backup section. If a particular atmosphere is suspected of containing a large amount of chloroform, it is recommended that a smaller sample volume be taken. # (c) Interferences (1) When the amount of water in the air is so great that condensation actually occurs in the tube, chloroform will not be trapped. (2) Any compound which has the same retention time as chloroform at the operating conditions described in this method could be an interference. # (d) Advantages of the Method (1) This method is advantageous in that it provides one basic method for determining many different organic compounds. The sampling device is small, portable, and involves no liquids. (3) Interferences are minimal, and most of those which do occur can be eliminated by altering chromatographic conditions. (4) The analysis of the tubes is accomplished by using a quick instrumental method. (e) Disadvantages of the Method (1) The amount of sample which can be taken is limited by the weight of chloroform which the tube will hold before overloading. (2) When the sample value obtained for the backup section of charcoal exceeds 25% of that found on the front section, the possibility of appreciable sample loss exists. The area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary sample results are read from a standard curve prepared as discussed below. (A) # Preparation of Standards It is convenient to prepare standards in terms of mg chloroform per 0.5 ml of carbon disulfide because samples are desorbed in this amount of carbon disulfide. To minimize error due to the volatility of carbon disulfide, 20 times the weight can be injected into 10 ml of carbon disulfide. For example, to prepare a 0.3 mg/0.5 ml standard, 6.0 mg is injected into exactly 10 ml of carbon disulfide in a glass stoppered flask. The density for chloroform is used to convert 6.0 mg into micro liters for easy measurement with a microliter syringe. (1) The name, address, and telephone number of the manufacturer or supplier of the product. (1) Chemical or widely recognized common name of all hazardous ingredients. ( Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled. This includes proper labeling and disposal of containers holding residues, contaminated absorbents, etc. (h) Section VIII. Special Protection Information. Requirements for personal protective equipment, such as respirators, eye protection, clothing, and ventilation, such as local exhaust (at site of product use or application), general, or other special types. Any other general precautionary information. (i) Section IX. Special Precautions. # U.S. DEPARTMENT OF LABOR # D E P A R T M E N T O F H E A L T H . E D U C A T IO N . A N D W E L F A R E P U B L IC H E A L T H S E R V IC E C E N T E R F O R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E F O R O C C U P A T IO N A L S A F E T Y A N D H E Atmosphere-Supplying Respirators (A) Self-contained. (B) Hose mask. (C) Airline. (D) Combination self-contained and airline. (2) Air-Purifying Respirators (A) Gas and vapor (gas mask and chemical cartridge). (B) Particulate (dust, fog, fume, mist, smoke, and sprays). (C) Combination gas, vapor, and particulate. (3) Combination Atmosphere-Supplying and Air-Purifying # Respirators The factors that affect the overall performance of an airpurifying respirator are the reliability of the face seal, the efficiency of the filters and/or absorbent canisters and other variables, such as leakage from exhalation valves. The performance of filters, canisters, and exhalation valves is predictable and controllable when test data are available. However, the current state of knowledge of the wearer's face size and shape and the respirator size and shape is such that the face seal is unpredictable and variable. During the past several years, NIOSH has funded research and development projects to make quantitative respirators-man tests on all types of respirators to measure their performance and/or efficiency. The results of these tests made on half mask and quarter mask facepieces, operated with a negative pressure in the facepiece, show that the facepiece 102. (3) A recorder and some method for determining peak area. (4) Glass stoppered microtubes. The 2.5-ml graduated microcentrifuge tubes are recommended. (5) Microsyringe of 10-jul capacity, and convenient sizes for making standards. (6) Pipets. 0.5-ml delivery pipets or 1.0-ml graduated pipets in 0.1-ml increments. (7) Volumetric flasks of 10-ml capacity or convenient sizes for making standard solutions. # (g) Reagents (1) Spectroquality carbon disulfide At least 5 tubes are prepared in this manner and allowed to stand at least overnight to assure complete adsorption of chloroform onto the charcoal. These 5 tubes will be referred to as the "desorption samples". A parallel blank tube should be treated in the same manner except that no chloroform is added to it. The desorption sample and blank tubes are desorbed and analyzed in exactly the same manner as previously described. Two or 3 desorption standards are prepared for analysis by injecting the same volume of compound into 0.	# I. RECOMMENDATIONS FOR A CHLOROFORM STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chloroform (CHC13) in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and safety of workers for up to a 10-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of chloroform on the health and safety of workers. The standard is measurable by techniques that are valid, reproducible, and available to industry and governmental agencies. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. "Exposure to chloroform" is defined as exposure above half the timeweighted average (TWA) environmental limit. Exposures at lower environmental concentrations will not require adherence to the following sections, except for Sections 4 (b) and (c) and Section 6 (d). # Section 1 -Environmental (Workplace Air) (a) Concentration Occupational exposure shall be controlled so that no worker will be exposed to chloroform in excess of 10 ppm (48.9 mg/cu m) determined as a time-weighted average exposure for up to a 10-hour workday, 40-hour workweek, or for any 10-minute period to more than 50 ppm (244 mg/cu m ) . # (b) Sampling and Analysis The procedure for sampling and analysis of workroom air for compli ance with the standard shall be as provided in Appendix I, or by any method shown to be equivalent or better in precision, sensitivity, accuracy, and specificity. Section 2 -Medical (a) Comprehensive preplacement medical examinations shall be made available to all workers subject to "exposure to chloroform" and yearly thereafter, unless a different frequency is indicated by professional medical judgment. (b) These examinations shall include, but shall not be limited to: (1) A comprehensive or interim medical and work history giving special attention to gastrointestinal symptoms and mental status. The worker's alcohol consumption should be reviewed. (2) A comprehensive medical examination, giving particular attention to cardiac rhythm, liver and kidney function. Liver function tests and urinalysis shall be performed. (3) An evaluation of the advisability of the worker's using negative-or positive-pressure respirators. Avoid breathing vapor. Avoid contact with skin. May generate toxic phosgene gas on contact with flame or very hot metal surface. This warning sign shall be printed both in English and in the pre dominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous conditions. All illiterate workers shall receive such training. If exposures to chloroform in the workroom exceed the recommended standard, and a variance permitting the use of respiratory controls has been granted, the following shall be added to the sign: No worker allowed to enter area without proper respiratory protection. # Section 4 -Personal Protective Equipment and Clothing When the limit of exposure to chloroform prescribed in subsection (a) of Section 1 cannot be met through application of available engineering controls in the design of equipment, systems, or operating procedures, an employer must utilize, as provided in subsection (a) of this Section, a program of respiratory protection to effect the required protection of every worker exposed. # (a) Respiratory Protection Appropriate respirators shall be provided and used when a variance has been granted to allow respirators as a means of control of exposure to routine operations and while the application is pending. Administrative controls can be used to reduce exposure. Respirators shall also be provided and used for nonroutine operations (occasional brief exposures above the standard and for emergencies); however, for these instances a variance is not required but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: (1) For the purpose of determining the type of r tor to be used, the employer shall measure the atmospheric concentration of chloroform in the workplace when the initial application for variance is made and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the chloroform concentration. This requirement shall not apply when only atmosphere-supplying positive pressure respirators are used. ( )2 The respirator and cartridge or canister used shall be of the appropriate class, as determined on the basis of exposure to chloroform. The employer shall ensure that no worker is being exposed to chloroform in excess of the standard because of improper respirator selection, fit, use, or maintenance. The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided. (5) Respiratory protective devices described in Table I-1 shall be those approved under provisions of 30 CFR 11. (6) Respirators specified for use in higher concentra tions of chloroform are permitted in atmospheres of lower concentrations. (7) Chemical cartridges and canisters shall not be used for periods of time in excess of those indicated in Table 1-1. (8) Employees shall be given instruction on the use of respirators assigned to them, cleaning of the respirators, and how to test for leakage. (9) Wherever bulk chloroform is handled, emergency and escape-type respirators shall be made readily available for each worker. Continuous contact must be maintained with employees working in enclosed spaces where chloroform concentration may become excessive. # (b) Protective Clothing In any operation where the worker may come into direct contact with liquid chloroform, protective clothing shall be worn. The clothing must be both impervious and resistant (such as neoprene or polyvinyl chloride) to chloroform. Bib-type aprons should be at least knee length, gloves should be lined to absorb perspiration, and boots or overshoes shall be provided when necessary. Impervious supplied air hoods or suits should be worn when entering areas with limited egress such as pits or tanks. All protective clothing should be well aired and inspected for physical defects prior to reuse. 1) Full face gas mask, chest or back mounted type, with industrial size organic vapor canister. Maximum service life of 2 hours. 2) Type C supplied air respirator, demand type (negative pressure), with full facepiece. 1) Type C supplied air respirator, con tinuous flow or pressure-demand type (positive pressure) with full face piece, hood or helmet. 1) Self-contained breathing apparatus with positive pressure in full facepiece. 2) Combination supplied air respirator pressure-demand type, with auxiliary self-contained air supply. 1) Self-contained breathing apparatus with positive pressure in facepiece. 2) Combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply. 1) Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure). 2) Full-face gas mask, front or back mount type with industrial size organic vapor canister. 3) Mouthpiece respirator with escape type organic vapor canister (escape type gas mask). (c) Eye Protection Eye protection shall be provided for any employee engaged in an operation where chloroform liquid or mist may enter the eye. Chemical-type goggles, safety glasses with splash shields, or plastic face shields made completely of chloroform resistant materials shall be used. Suitable eye protection shall be provided in accordance with 29 CFR 1910.133. # Section 5 -Informing Employees of Hazards from Chloroform At the beginning of employment in a chloroform area, each employee shall be informed of the hazards, relevant symptoms, effects of overexposure to and the proper conditions and precautions concerning safe use and handling of chloroform. The information explaining the hazards of working with chloroform shall be kept on file and readily accessible to the worker at all places of employment where chloroform is manufactured, used, stored, or transported. A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, proper maintenance procedures, and cleanup methods, and that they know how to correctly use respiratory protective equipment and protective clothing. Information on file and readily accessible to workers shall include that specified in Appendix II, on US Department of Labor Form 0SHA-2Q "Material Safety Data Sheet", or a similar form approved by the Occupa tional Safety and Health Administration, US Department of Labor. Where employees are required to enter confined areas where containers of chloroform are stored, such as a delivery van, entry shall not be made until the space has been ventilated or checked for concentrations of chloroform. (2) Storage containers, piping, and valves shall be periodically checked for leakage. (3) Storage facilities shall be designed to contain spills and prevent contamination of workroom air. (b) Contaminant Controls Suitable engineering controls designed to limit exposure to chloroform to that prescribed in subsection (a) of Section 1 shall be utilized where appropriate and feasible. Where ventilation systems are used to achieve such control, they shall be designed to prevent the accumulation or recirculation of chloroform in the workroom and to effectively remove chloroform from the breathing zones of workers. Ventilation systems shall be subjected to regular preventive maintenance and cleaning to ensure maximum effectiveness, which shall be verified by periodic airflow measurements. In addition, necessary measures shall be taken to ensure that discharge outdoors will be in conformance with all appropriate environmental regulations. # (c) Equipment Maintenance and Emergency Procedures Air saturated with chloroform is immediately dangerous to life and if a limited egress situation exists, emergency procedures must be established and followed. (1) # Chloroform hazard areas Exits shall be plainly marked. Emergency exit doors shall be conveniently located and shall open to areas which will remain free of contamination in an emergency. (2) Confined spaces (A) Entry into confined spaces or in other situations of limited egress shall be controlled by a permit system. Permits shall be signed by an authorized representative of the employer certifying that preparation of the confined space, precautionary measures, personal protective equipment, and procedures to be used are all adequate. (B) Tanks, pits, tank cars, process vessels, tunnels, sewers, etc, which have contained chloroform, shall be thoroughly ventilated, tested for chloroform, and inspected prior to entry. (C) Inadvertent entry of chloroform into the confined space while work is in process inside shall be prevented by disconnecting and blanking off chloroform supply lines. (D) Confined spaces shall be ventilated or otherwise maintained to keep the chloroform concentration below the limit and to prevent oxygen deficiency. (E) Personnel entering confined spaces shall be equipped with a lifeline tended by another worker outside the space who shall be equipped with approved respiratory, eye, and skin protection. (F) Written operating instructions and emergency medical procedures shall be formulated and posted in conspicuous locations where accidental exposure to anesthetic concentrations of chloroform may occur. These instructions and procedures shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All illiterate workers shall receive such training. # (d) Showers and Eye Wash Fountains Showers and eye wash fountains shall be provided and so located as to be readily accessible in all areas where skin or eye splash with chloroform is likely. If chloroform is splashed on the skin, contaminated clothing shall be promptly removed and the skin washed with soap and water. If liquid chloroform contacts the eyes, they shall be thoroughly irrigated with clean water. Medical assistance shall be promptly provided in cases of eye splash. Such incidents shall be reported to the immediate supervisor by the affected employee or by a fellow worker. Chloroform was originally made from acetone and bleaching powder and can also be made by reduction of carbon tetrachloride. The principal method of manufacture is now chlorination of methane. [1] Prior to World War II, chloroform was used primarily as an anesthetic and a pharmaceutical. The annual production of chloroform in the United States at that time was between 2,000,000 and 3,000,000 lbs. It is now seldom used as an anesthetic, [1] but it is used by many manufacturers for pharmaceutical purposes. [5,6] The production of chloroform for the manufacture of chlorodifluoromethane has grown over the years from 40,396,000 lbs in 1955 to 230,766,000 lbs in 1971, the latest year for which data are available. NIOSH estimates that 80,000 people are potentially exposed to chloroform in their working environment. # Historical Reports Simpson, [24] a surgeon and obstetrician in Edinburgh, reported in an 1847 issue of Lancet on the merits of chloroform as an anesthetic agent. He advocated its use because it was pleasant to inhale, its action was more rapid and complete than that of ether, only a small amount was needed to produce narcosis, and it did not require the use of a special inhaler or instrument for its administration. He especially recommended it for use in obstetric practice because it alleviated maternal pain and recovery from anesthesia was rapid. In 1874, Witte [25] observed that it required less chloroform to anesthetize frogs by absorption through the skin of the abdomen or thigh than by inhalation. He reported that rabbits also could be anesthetized by application of chloroform to the shaved abdomen, and he recommended that humans be anesthetized by absorption through the skin rather than by inhalation. One of the first detailed descriptions of death from liver damage following chloroform anesthesia published in the English literature appeared in the January 26, 1894 issue of Lancet. [26] A 4-year old boy seemed to be well after an operation which lasted about 1 hour, but early the next morning he began to vomit, his pulse became weak, breathing was shallow and irregular, and he lapsed into unconsciousness. Vomiting continued (the vomitus being dark brown in color), little urine was passed, consciousness was never regained, and death occurred 30 hours after the operation. At autopsy, the liver was found to be small (14 1/2 oz), pale buff color, studded with minute purple dots, and greasy to the touch. Microscopy revealed intense fatty infiltration with no apparent fatty degeneration. In 1898, Desgrez and Nicloux [27] reported that carbon monoxide was formed in dogs during chloroform anesthesia. They considered that the amount of carbon monoxide in the blood after 3-5 hours of anesthesia was equivalent to that present after exposure for 30 minutes to 100 ppm of carbon monoxide in air. Carbon monoxide was measured by a "grisoumeter" and chloroform did not interfere with the analytical method. In 1904 Schwenkenbecher [28] reported that immersion of white mice up to their necks in aqueous solutions of chloroform was lethal. The solutions ranged from 0.3%-0.7% and the immersion time from 45-165 minutes. A special collar was used to preclude inhalation, and the genital and anal openings were closed. Moore and Roaf [29] in 1906 reported that chloroform added to hemoglobin solutions at body temperature caused a change in color and a precipitation of the hemoglobin. In 1909, Whipple and Sperry [30] published studies of liver necrosis in dogs following anesthesia with chloroform. They compared the liver damage observed in dogs to that seen in a 19-year old woman who died 3 days after anesthesia with chloroform for 35 minutes. They concluded that in dogs chloroform anesthesia for 1-2 hours would invariably cause central liver necrosis, and that the anatomic changes in the human autopsy were identical to those observed in the experimental dogs. Lehmann [31] was the first to mention the industrial hygiene aspects of chloroform. He stated that in Germany more than 100 tons of chloroform was produced annually and that its manufacture in well designed factories did not create any danger to workers. Lewin [32] in 1920 reported that the use of chloroform as a solvent for fats and resins was associated with a feeling of being "stoned", head ache, dizziness, breaking of the voice, sometimes an increase in saliva flow, bronchial catarrh, pounding of the heart, and with continued exposures, disturbances of metabolism, leading to a "real change in substance in the kidney and even to albumin in the urine." # Effects on Humans (a) Central Nervous System Effects The most outstanding effect of chloroform on the central nervous system is narcosis. Because of this property, chloroform was extensively used as an anesthetic. Featherstone [33] concluded from a review of the literature that 20,000 ppm of chloroform was usually used to produce anesthesia and that 40,000 ppm, if continued for several minutes, could be an overdose. He suggested, for induction of anesthesia, gradually increasing the concentration of chloroform during the first 2 or 3 minutes to attain and maintain a concentration of 25,000 or 30,000 ppm until full anesthesia developed. The concentration used to produce anesthesia is usually not maintained for the duration of the operation but is replaced by a lower maintenance concentration such that the integrated exposure was actually much lower than 20,000 ppm. In the experiments reported by Lehmann and Hasegawa [34] Fokina [42] reported effects of chronic exposure in the work environment to mixtures of chlorinated methanes, including chloroform. Although the concentrations were not given, it was stated that the maximum permissible concentrations of individual components were exceeded at times. (There was no MAC for chloroform in Russia in 1965. [43] ) The majority of workers showed signs of autonomic dysfunction, including diminution or disappearance of the corneal reflexes, dissociation between the deep (exaggerated) and superficial (sluggish) reflexes, marked persistent dermographism, general hyperhydrosis, acrohyperhydrosis, blotchiness of the skin of the hand and forearms, tenderness when pressure was applied to specific cervical points, and arterial hypotension. Autonomic dysfunction was mainly found in workers employed for less than 3 years. Workers employed for more than 5 years showed diencephalic disturbances and autonomic polyneuritis. [ Although the cause of death in most cases of chloroform poisoning has been attributed to necrosis of the liver, there has also been evidence at autopsy of renal damage, including albumin and red blood cells in urine, elevated blood urea, necrosis, and fatty degeneration. [30, 45,49] In the case of delayed chloroform poisoning reported by Whipple and Sperry, [30] urine specimens contained a trace of albumin, a few hyaline casts, and considerable quantities of leucine and tyrosine. At autopsy, the convoluted tubules of the kidneys showed a definite fatty degeneration with some of the epithelial cells having undergone necrosis. The capillaries were also found to be congested. In the studies by Gibberd [45] and Lunt [49] laboratory findings indicated renal dysfunction; there were albumin, red blood cells, and pus in the urine, congestion of cortical vessels, fatty deposits, and necrosis. # (d) Cardiovascular Effects Cardiac irregularities were found frequently by Kurtz et al [56] in 1936 during electrocardiographic (ECG) surveillance of 113 surgical procedures. Arrhythmias were reported in all 6 cases in which chloroform was used for anesthesia and in 83 of 107 operations in which other anes thetics were used, including ethyl ether, cyclopropane, nitrous oxide, tribromoethanol, procaine, vinyl ether, and ethylene. The authors [56] did not report the durations of anesthesia. In 1951, Orth et al [57] [57] stated that "this is a higher incidence of irregularities than is observed clinically with any other anesthetic agent except trichloroethylene". The irregularities were attributed to both reflex effects on cardiac automaticity and a direct depressant effect on the myocardium. In view of the high incidence of ECG abnormalities with all studied anesthetics, [56] the possibility of all other factors in the etiology of the abnormalities needs to be considered in drawing conclusions from this study. For example Orth et al [57] did not report the durations of anesthesia while Whitaker and Jones [58] considered this to be important. Whitaker and Jones [58] in 1965 found less frequent cardiovascular effects among 1,502 cases where chloroform was administered by a precision vaporizer in concentrations not exceeding 22,500 ppm. There were 9 cases of arrhythmia in the 1,164 operations in which anesthesia lasted 30 minutes or less and there were 10 cases of arrhythmia in 338 operations in which the duration of anesthesia was greater than 30 minutes. # (e) Hemolysis Belfiore and Zimmerman [59] found that chloroform could affect the fragility of the red blood cell membrane without first being metabolized in the liver. Erythrocytes from 12 healthy adults were suspended in saline solution with chloroform ranging from 0.0125-0.10 mole/liter. The control was erythrocytes in a saline solution. At concentrations of 0.0125, 0.02, and 0.025 mole/liter there was no demonstrable effect. In concentrations of 0.05 mole/liter, erythrocyte leakage of hemoglobin, lactic dehydrogenase (LDH), and malic dehydrogenase began at 7 minutes and reached a maximum at 20 minutes for hemoglobin and at 10 minutes for the enzymes. Belfiore and Zimmerman [59] found that incubation of cells with reduced glutathione (GSH) and oxidized glutathione (GSSG) inhibited hemolysis as measured by a loss of hemoglobin. They found that inhibition increased as the concentration of GSSG increased, but did not increase as the concentration of GSH increased. It has been suggested more recently, however, that it is only the GSSG that enters the intact red blood cell; the effect of GSH is due to its oxidation to GSSG. [60] (f) Effects on the Skin Malten et al [61] measured injury and regeneration of forearm skin exposed to liquid industrial solvents, including chloroform. The solvents were contained in glass cylinders 2 cm in diameter which were fixed to the skin by agar-agar for 15 minutes a day for 6 consecutive days. An unspeci fied number of sites served as controls. The rate of water evaporation from these sites was determined daily to evaluate the degree of skin damage and regeneration. Exposure to chloroform was reported to be similar in effect to ethanol and to cause an increase in the rate of water evaporation with repeated exposures. Recovery of normal water retention, indicative of the formation of a new horny layer, occurred slowly during the 30 days after the last exposure. Hoffman [62] suggested that chloroform could be used on skin to combat mosquitoes and other biting insects. It seems doubtful that present-day dermatologists would recommend this use of such an irritating substance. Hoffman cautioned against getting chloroform into eyes and mucous membranes because of irritating effects. Oettel [63] carried out systematic experiments with chloroform administered to the skin by way of a small glass vessel, 1 cm in diameter, one end of which was open, with glass hooks fused into it. Vessels were filled with chloroform and tied onto the arms of 5 subjects. Pure chloroform was used for various exposure times. Three minutes after application of chloroform, there was a sensation of burning and stinging. When exposure time was increased to 6 minutes, the pain became more intense and then subsided quickly. When the chloroform was removed, the pain increased again, only to be replaced by a loss of feeling. Erythema was noted and the hyperemia which also occurred after 3 minutes of exposure was somewhat stronger, more cherry red with a light yellow undertone. In a 30minute period after removal of the chloroform, there was a fading away of the erythema and hyperemia, and 5 hours later, little blisters formed at the edge of the area of application. Erythema and pigmentation disappeared 7 days after the exposure. From these studies, [61][62][63] it can be concluded that exposure of the skin to liquid chloroform will cause irritation, erythema, hyperemia, and destruction of the epithelium. Much of this information on skin irritation from chloroform is based on prolonged contact. However, it should be noted that repeated, brief contact can cause skin defatting. Thereafter, the rate of elimination decreased, and "small amounts" were reported to have been detected in the blood 8 hours after exposure. Concentrations of chloroform in the blood were also measured by Cullen et al [44] Breath concentrations of chloroform in a worker after an industrial exposure to a mixture of solvents including chloroform, carbon tetrachloride, trichloroethylene, and perchlorethylene were measured by Stewart et al [64] in 1965. The exposure was defined as a "few minutes" without a gas mask followed by an unspecified time with a general purpose chemical respirator, to unknown concentrations with "strong" odors. The exposed worker experienced dizziness, weakness, nausea, and finally unconsciousness. The duration of unconsciousness is not known, but "10 minutes later" he was coherent, though uncoordinated and nauseated. Thirty minutes after his collapse, infrared analysis of his expired breath contained: perchlorethylene, 11 ppm; carbon tetrachloride, 9.5 ppm; chloroform, 7 ppm; and trichloroethylene, 11 ppm. Three days later, 0.1 ppm chloroform was found in the exhaled breath; 12 days after exposure, there was no chloroform found in the exhaled breath. Several authors have reported on the concentration of chloroform in tissues following suicide, homicide, or death during or after an operation. Gettler [65] # Epidemiologic Studies There are very few reports of industrial workers exposed to chloroform. The studies of Challen et al [67] and Bomski et al [55] are the only studies that contain exposure concentration measurements, descriptions of symptoms and diagnoses, and comparisons with control groups. In 1958, Challen et al [67] reported a study of a confectionery firm in England that manufactured medicinal lozenges. In 1950, the operators began to complain of the chloroform vapor given off during the production of the lozenges. A system of part-time work was initiated to alleviate complaints of lassitude, flatulence, water brash (British term indicative of symptoms of dyspepsia), dry mouth, thirst, depression, irritability, and frequent and "scalding" micturition, but this was not successful, and fi nally the operators refused to work on that particular process. In 1954, a new team of operators was engaged and in 1955 a system of exhaust ven tilation was installed, after which the work proceeded without interrup tion. In order to confirm the effectiveness of the ventilation system, Challen and his associates [67] were asked to ascertain the concentrations of chloroform. Additionally, clinical investigations were performed and an attempt was made to simulate the original conditions in order to compare the chloroform concentrations before and after remedial measures were introduced. The original conditions were simulated by closing the doors and windows and shutting off the ventilation system. A single air sample was taken continously in the breathing zone of the operator of the ingredient mixing process during a period of 20 minutes coinciding with the duration of the process. Sampling at the rate of 2 liters/min was done by drawing air through 2 U tubes containing dried silica gel. Additionally, at a point in the operation where a peak concentration was expected, a 6-liter "grab" sample was taken. Air samples of 30-minute durations each were also taken in the breathing zones of cutting room operators. The samples were taken during 2 periods of production for 3 different operations on the same day (under current conditions) and during 3 periods on another day (during the simulated conditions Clinical investigations of 3 different groups of workers were per formed by Challen et al. [67] One group of 8 employees was termed the "long service operators". These were people who refused to continue in the lozenge department after they experienced the previously described symptoms. This group of workers, when exposed to chloroform vapor in probable concentrations ranging from 77 to 237 ppm, had been observed staggering about the work area. After terminating work in the lozenge department the "long service operators" reported experiencing nausea and stomach upset after even short exposures to the smell of chloroform. A second group of 9 employees in this study, [67] termed the "short service operators", were the replacements of the "long service operators". Two of these 9 employees did not report unpleasant experiences from chloroform exposure. Among the other 7, 5 reported dryness of the mouth and throat at work; 2 were subject to lassitude in the evening; 1 complained of lassitude and flatulence at work, and the experiences of 2 others were similar to those of the "long service operators". The "short service operators" worked in locations where the chloroform concentrations ranged from 23-71 ppm. A third group of 5 employees in this study [67] who worked in other departments of the firm served as controls and exhibited no symptoms. Neither tests of liver function (thymol turbidity, thymol flocculation, direct van den Bergh, and serum bilirubin), clinical examinations, nor urinary urobilinogen showed significant differences among the 3 groups of workers. In 1967, Bomski et al [55] reported on liver injury from chloroform among workers in a pharmaceutical factory in Poland. The study included the entire group of 294 workers who used chloroform in the course of production; of these, 68 were exposed to chloroform for 1-4 years and still had contact with chloroform, 39 had chloroform contact at one time, 23 had viral hepatitis with icterus 2-3 years earlier and were designated as posticterus controls and were working in a germ-free area, and 165 worked in a germ-free area with no history of viral hepatitis. Blood pressure, blood morphology, urinalysis, blood albumin, serum protein, thymol turbidity, zinc sulfate turbidity, the "Takata-Ara" sulfate (colorimetric) test, urobilinogen, SGOT, and SGPT were measured in all. A complete medical history was taken. Sixty of the people were hospitalized for determination of BSP clearance and urinary urobilinogen. The air in the production room was sampled and chloroform concentra tions were determined using the Grabowicz [68] method. The concentration of chloroform ranged from 2-205 ppm. No other concentration measurements were reported nor was there any mention of the frequency of sampling. The authors [55] compared the frequency of viral hepatitis and jaundice among a group of inhabitants of the city, 18 years and older, with that of the same 68 pharmaceutical workers who used chloroform. The results showed that in 1960, 0.35% of city inhabitants had viral hepatitis, while 16.67% of the chloroform exposed workers had viral hepatitis. In 1961, the frequency for city inhabitants was 0.22% and the frequency among the chloroform workers was 7.50%. In 1962 the frequency of viral hepatitis was 0.38% for city inhabitants and 4.4% for workers using chloroform. The authors suspected that the toxic liver changes occurring as a result of exposure to chloroform promoted a viral infection in such cases, but they did not give information on the incidence of viral hepatitis among other plant workers, which might have helped resolve questions about sanitary practices and facilities in the plant. The majority of the workers who were in contact with chloroform during the investigation period covered in this study complained of headache, nausea, belching, and loss of appetite. Among the 68 workers using chloroform, 10 cases of splenomegaly were found compared to none in the controls. They did not explain the splenomegaly but point out it was not present in controls. The frequency of enlarged livers (17 out of 68) among workers exposed to chloroform exceeded the frequency of enlarged livers in the other groups (5 out of 39, and 2 out of 23). Livers were judged to be enlarged if they extended at least 1 cm beyond the rib arch in the midclavicular line. The upper margin was apparently not measured. In 3 of the 17 chloroform workers with enlargement of the liver, toxic hepatitis was diagnosed on the basis of elevated serum enzyme activities and elevated serum gamma globulin. The measured amounts of these serum constituents in these 3 workers were not reported. In the remaining 14 cases of liver enlargement, fatty liver was diagnosed. It was claimed that the latter diagnoses were substantiated by a 79% reduction in the incidence of hepatomegaly in the people studied during a 12-month period when hygienic work conditions were improved as a consequence of the studies. [55] In a continuing study [LD Pagnotto, written communication, December 1973] by the Department of Labor and Industries, Commonwealth of Massachusetts, worker exposure to chloroform, methylene chloride, and toluene in a plant manufacturing plastic film was investigated. The workers were exposed to levels of chloroform from 7-170 ppm, with a mean of 47 ppm. Physical examinations and the following laboratory tests were performed regularly on all employees connected with the process: SGOT, LDH, alkaline phosphatase, blood bilirubin, BUN, creatinine, cholesterol, serum protein, urobilin, urobilinogen, urine bilirubin. The blood tests were performed yearly and urine tests quarterly. The liver function tests have been done for more than 2 years, the kidney function tests for only 1 year. Some of the employees at times experienced what was termed "dry heaves". Laboratory findings have been normal so far, but there appeared to be a significant number of findings in the upper normal range, particularly for the blood bilirubin and BUN. There was no evidence, though, that there was a progressive increase in the values found. However, the evaluations of the laboratory findings were based on the normal range for the general population rather than a specific control group for this particular investigation. It is not apparent from this study what the time-weighted average exposures were. # Animal Toxicity The majority of animal studies of chloroform toxicity have been con ducted to provide supplementary information relevant to the clinical use of chloroform as an anesthetic. Consequently these animal studies include concentrations of chloroform many times greater than would be experienced in daily occupational situations except in the case of accidents. The following subsection contains a summation of some of these studies. Jones et al [74] in 1958 studied the relative hepatotoxicity of inhalation anesthetic drugs using chloroform as a standard of reference. Chloroform was given orally to 350 white mice, each weighing approximately 20 g. The mice were killed 72 hours after exposure and livers were fixed in formalin. The authors [74] were able to estimate the following effects of acute injury from esophageal instillation of chloroform: Rats and guinea pigs given the 0.4 mg/kg dose of chloroform showed no changes in conditioned reflexes or in autonomic or cardiac activity, blood protein ratios, catalase concentrations, or phagocytic capacity. There was an increase in ascorbic acid in the adrenals of the guinea pigs. [80] Some guinea pigs given doses of 35 mg/kg died during the course of the experiment. Five of the guinea pigs lived longer than 2 months, but only 2 of these lived longer than 3 months. The ratio of blood protein fractions in the guinea pigs given 35 mg/kg was altered by the end of the first month. These changes consisted of an increase in the globulin content (from 32.9±1.09 to 40.9±2.22%) involving the alpha and gamma fractions and a decrease in the albumin content, so that the albumin-globulin ratio decreased from 2.1-0.4. The change in this ratio was even more pronounced at the end of the second month. The guinea pigs in the 35 mg/kg groups also showed a decrease in blood catalase activity from 2.0±0.13-1.2±0.11 (no units given) in the second month of the experiment. [80] The guinea pigs which had died from a dose of 35 mg/kg of chloroform had structural lesions of the liver, heart muscle, and stomach wall upon The effect of chloroform on rats exposed to 300 ppm was confused by changes in dietary intake. It was not possible to determine whether decreased food consumption was the result of loss of appetite or the inability to eat due to narcosis. [83] Exposure of pregnant rats to 100 ppm on days 6 through 15 of gestation revealed a significant incidence of fetal abnormalities as compared to controls. There were significant increased incidences of acaudia, imperforate anus, subcutaneous edema, missing ribs, and delayed skull ossification. Rats exposed to 30 ppm showed significant incidences of delayed skull ossification and wavy ribs, but no other effects. [83] The teratogenicity of oral doses of chloroform was studied in rats and rabbits. [84] There was no evidence of teratogenicity in either species at any dosage level tested. However, in both species reduced birth weights (7.5% in rats and 1.1% in rabbits) were observed with the highest dosages, 126 and 50 mg/kg, respectively. tried to determine whether structural damage affecting protein synthesis occurs when chloroform acts on the liver of a rat. Twenty Sprague-Dawley rats were fasted for 10 hours and 4 were exposed to 1 vol % chloroform Preliminary examinations of all animals anesthetized showed a slight increase in respiratory acidosis but no signs of arterial hypoxemia or metabolic acidosis. After 4 1/2 hours of chloroform anesthesia, the livers of most exposed rats showed gross enlargement of the centrilobular hepatic cells. The cells also showed a striking paleness, and upon staining of frozen sections, fatty degeneration was also observed. On electron microscopy it was found that chloroform produced an early dilation of the granular endoplasmic reticulum with detachment of the ribosomes producing a marked reduction of centrilobular protein synthesis. Additionally, after anesthesia with chloroform, extensive necrosis of portions of the renal tubular epithelium was found, while the lung revealed severe leucocytic infiltrations in the alveolar septa. In light of this latter finding, it should be noted that in 1966 Wattenberg [89] stated that kidney and lung tissue also contain hydroxylating enzyme systems. This enzymatic activity is less intense than in the liver, but can be increased by some lipid- All experiments showed reduced liver function as indicated by prolonged pentobarbital sleeping times and elevated BSP retention. The liver succinic dehydrogenase activity was depressed when chloroform was administered 12 or 24 hours after ethanol, but not when it was administered 48 hours after ethanol. Ethanol alone or chloroform alone did not significantly depress succinic dehydrogenase activity. In mice pretreated with ethanol 15 hours, or 1, 2, or 4 days before the administration of chloroform, microscopic examination revealed livers with cytoplasmic vacuolization in pericentral cells. The pericentral cells were also enlarged and almost completely devoid of eosinophilic material. [90] In a similar study, Sipes et al [91] pretreated rats with isopro panol and reported enhanced ability to covalently bind radioactive carbon labeled chloroform to microsomal protein. Dingell and Heimberg [92] studied the hepatic metabolism of aminopyrine and hexobarbital in rat liver microsomes after the administration of chloroform or carbon tetrachloride or methylene chloride. The chlorinated hydrocarbons were administered in equimolar doses by gastric intubations and killed 24 hours later. Liver microsomes were prepared from rat livers weighing from 250-375 mg. Either 5 jumoles of aminopyrine or 1.9 /imoles of hexobarbital was added to a mixture of enzyme substrates. The rate of metabolism of hexobarbital was measured by estimation of the disappearance of substrate. The rate of déméthylation of aminopyrine was measured by estimation of the amount of formaldehyde formed. For both the aminopyrine and hexobarbital pretreatment before carbon tetrachloride decreased the rate of metabolism significantly to 14 and 29%, respectively, of control values. Chloroform, however, only decreased metabolism of aminopyrine to 61% and hexobarbital to 95% of control values. McLean [93] fed male mice either stock diet or protein free diets for 1 week before intragastric administration of chloroform. Some of the mice of each group were also given sodium phénobarbital in the drinking water (1 mg/ml) for 1 week before chloroform administration; others were given a single subcutaneous injection of DDT (100 mg/kg) 1 week before chloroform. The purpose of DDT and the phénobarbital administration was to stimulate liver hydroxylating enzyme activity. The purpose of the protein deficient diet was to reduce the liver hydroxylating enzyme activity, but in this experiment this was not realized. Phénobarbital and DDT increased the liver hydroxylating enzyme activity and the toxicity of chloroform was more than doubled by the phénobarbital and DDT pretreatment as measured by the LD50. # Correlation of Exposure and Effect The use of chloroform as an anesthetic agent has provided information about the effects to be expected from acute exposure. Exposures during anesthesia have usually been to concentrations of around 20,000 ppm, [58] and exposure times have been from 30-240 minutes. [30, 45,94] One or 2 days after chloroform anesthesia, nausea, jaundice, and vomiting may develop, often followed by elevated temperature and pulse, epigastric pain, muscle twitching, delirium, and coma. In some cases, death has occurred 3-10 days after anesthesia. Habitual inhalation of 1 oz daily of chloroform for 7 years followed by 2 oz/day for 5 more years was associated with delusions, restlessness, depression, convulsions, ataxia, dysarthria, tremor of the tongue and fin gers, and insomnia; at autopsy, the brain showed slightly thickened menin ges in the frontal lobe, many fibroblasts and dilated blood vessels. [36] In other cases of habitual chloroform inhalation for periods of time ranging up to 30 years, hallucinations, delirium, and tremors were common manifestations. [36] The exposures ( The data presented by Challen et al [67] provide some quantitative information about exposure and effect, even though some of the information about exposure was obtained after the fact. Employees in a confectionery The incidence of enlarged livers among these 68 workers was sig nificantly higher than in the controls. It was noted that there was a reduction in hepatomegaly in 79% of the people studied during the 6-12 month period when hygienic conditions at work were improved. [55] Schwetz et al [83] studied the effects of 30, 100, and 300 ppm of chloroform on pregnant rats for 7 hours/day on days 6 through 15 of gestation. There were significant incidence of delayed skull ossification and "wavy ribs" in litters from dams exposed to 30 ppm of chloroform. The authors [83] found that in litters from dams exposed to 100 ppm there were significant incidences of acaudia, imperforate anus, subcutaneous edema, missing ribs, and delayed sternebrae ossification. Rats exposed to chloroform at 300 ppm ate so little food (1 g/day) that it would be impossible to consider any of the other effects as characteristic of chloroform. [83] Kylin et al [78] found that mice exposed to 100 ppm chloroform for 4 hours showed moderate fatty infiltration and degeneration at the periphery of the liver lobules, one day after exposure. These effects were found less frequently 3 days after exposure, indicating a certain amount of regeneration. A direct dose-response relationship, evidenced by increasing liver alterations and necrosis, was observed at concentrations ranging from 100 to 800 ppm. Further indication of a dose-response relationship was the increase of the serum ornithine carbamoyl transferase with increasing concentrations of chloroform. Animal studies [95] [96] there are no studies on workroom concentrations of chloroform used in their production. Challen et al [67] Air samples should be collected and transported to a laboratory, then desorbed or chemically treated, and finally analyzed quantitatively. Silica gel has been used extensively in the past as a collection medium. [ 67,97] Silica gel is a polar adsorbent and shows pronounced selectivity in adsorbing polar molecules, particularly water. Hence, when sampling large volumes, the atmospheric moisture may compete for the adsorptions sites and displace the chloroform being sought. When sampling large volumes (more than 3 liters), the silica gel adsorption tube may become saturated with water thus impairing the retentive properties of the collec tion medium. [98] Activated charcoal as a collection method has been used in conjunc tion with gas chromatography. [99] Activated carbon is nonpolar and will consequently adsorb organic vapors in preference to water vapor so that sampling of volumes higher than 3 liters can be accomplished without noticeable moisture interferences. [98] Williams and Umstead [100] have developed a collection method in which atmospheric samples are concentrated on porous polymer beads. The same column utilized for sample collection is subsequently used for GC analysis. The advantage of this method is that it integrates collection and analysis into one operation. However, it has not yet been developed for field use. The dechlorination method (alkali hydrolysis) requires collection of the chloroform contaminated atmosphere over a suitable collection medium followed by hydrolysis in isopropyl alcohol. Solid KOH is added and the mixture is allowed to sit overnight (about 20 hours). After neutralization the liberated chloride ion is titrated with silver nitrate. [97] The percentage of chlorine hydrolyzed is determined by comparison between samples and known controls. This method has the disadvantage of a long and elaborate procedure in which the amount of chloride ion liberated depends on the duration of the process of alkali dechlorination. When a mixture of chlorinated hydrocarbon vapors is analyzed, there is the additional problem of specificity; it is necessary then to differentiate the contribution of each chlorinated compound to the total amount of chloride ion liberated. [ [107] The gas chromatographic method of analysis provides a specific when enveloped by an atmosphere contaminated with halogenated hydrocarbons. [107] The instrument is sensitive to all halogens and halogenated compounds and consequently is nonspecific for chloroform. The Halide meter seems suitable for continuous monitoring if there is only chloroform present as the air contaminant. # (d) Conclusions and Recommendations (1) Compliance Method On the basis of the review of the analytical methods it is recommended that gas chromatography be chosen as the compliance method. The method is recommended in conjunction with activated charcoal tubes as a collection method and the use of carbon disulfide as a desorbent. However, a disadvantage of the method is the indirect system of measurement requiring collection and desorption prior to analysis. ( # 2) Monitoring Methods It is also recommended that direct reading colorimetric tubes (gas detection tubes) be used as an inexpensive way to determine whether exposure, as defined in Chapter I, exists. The tubes must be used with manufacturer's instructions and for monitoring purposes only. Chloroform concentrations in the blood have been measured during and following anesthesia. [44,50] These data show that chloroform in the blood is eliminated rapidly at first but that some remains for at least 8 hours after exposure to anesthetic concentrations. These data are inadequate for evaluating industrial exposure. # V. DEVELOPMENT OF A STANDARD # Basis for Previous Standards In 1946, the Sub-Committee on Threshold Limits of the ACGIH published a list entitled "Maximum Allowable Concentrations of Air Contaminants for 1946", with the understanding that the list would be revised each year. [112] The list of values was compiled from 3 sources: (a) The list reported by the Sub-Committee on Threshold Limits at the 5th Annual Meeting of the ACGIH in 1942. # (b) The then comprehensive list published by Cook in Industrial Medicine. [113] (c) Published values of the Z-37 Committee of the American Stan dards Institute. The value proposed for chloroform by the ACGIH [112] was 100 ppm. In 1959, the Threshold Limit Value (TLV) for chloroform was reduced to a time-weighted average of 50 ppm for a normal working day by the ACGIH [114] in their annual review of the TLV values. In 1962, the ACGIH [115] published its Documentation of Threshold Limit Values (TLV's) in which it cited the recommendations of Cook [113] that exposures to chloroform be kept below 50 ppm, and the study of Challen et al. [67] The 1968 TLV, which was unchanged from the 1962 recommendation, was promulgated $s a regulation by OSHA. This was published, apparently in error, as a ceiling value of 50 ppm, in the Federal Register, volume 39, page 23541, dated June 27, 1974. In 1969, the ACGIH changed the time-weighted average limit to a ceiling and documented this in 1971. [116] This ceiling limit of 50 ppm was considered adequate to prevent any serious short-term effects on the liver, but it was recommended that chloroform be used with close medical surveillance, particularly with those workers who consume alcohol. The recommendation was based in part on the studies of Challen et al, [67] Bomski et al, [55] and unpublished data from the Massachusetts Division of Occupational Hygiene. A notice of intended change for chloroform from 50 (ceiling) to 25 ppm (time-weighted average) was made by the ACGIH in 1972 [117] and 1973. [118] The AIHA Hygienic Guide Series of 1965 for Chloroform [95] suggested that a time-weighted average (TWA) of 10 ppm be used with a ceiling of 25 ppm. This recommendation was based on unpublished experimental animal data. In 1970, the International Labour Office in Geneva published tables of Permissible Levels of Toxic Substances in the Working Environment . for many countries. [43] The chloroform standards for 8 different countries are listed below; it is not clear from the reference whether these are time-weighted averages or ceiling concentrations. The major exposure to chloroform has been as an anesthetic [33,44,50,58] and most experiments have been related to this use. Cardiac arrhythmias have occurred, especially when chloroform anesthesia has been prolonged beyond 30 minutes. [56,57] Liver and kidney injuries have also been found, sometimes resulting in death several days after anesthetic exposure. [30,36,44,46,47,53,94] It is difficult to evaluate the total exposure to chloroform during anesthesia since concentrations frequently were not reported. However, it should be noted that the concentrations in anesthesia are extremely high and are not constant throughout the exposure period. # Country # Whipple and Sperry [30] demonstrated in experiments with dogs that chloroform anesthesia for a period of 1-2 hours caused central liver necrosis. At autopsy of a woman who had died from delayed chloroform poisoning, they found liver changes that resembled changes found in dogs. The only other experimental study of liver changes after inhalation of chloroform was that by Kylin et al [78] in 1963 who exposed 20 mice to 100, 200, 400, and 800 ppm for 4 hours. In this study, the mice exposed to 100 ppm did not develop demonstrable liver necrosis, however, moderate fatty infiltration of the liver was noted. In mice exposed to 200 ppm, some necrotic areas appeared in the liver and there was an increase in serum ornithine-carbamoyl transferase. Exposures to 400 and 800 ppm resulted in increasing necrosis and serum enzyme activity. Although Schwetz et al [83] did not report detailed studies of liver changes in female rats exposed to chloroform 7 hours/day for 10 days, they did report that liver weights, both absolute and relative, increased as a result of exposure to 100 and 300 ppm but not to 30 ppm. However, embryo and fetal anomalies, including delayed skull ossification and the formation of wavy ribs, were found in the offspring of the rats exposed to 30 ppm. The only account of liver abnormalities among industrial workers exposed to chloroform is a report by Bomski et al. [55] These investi gators found 17 cases of hepatomegaly in a group of 68 workers exposed to chloroform in concentrations ranging from 2-205 ppm for 1-4 years in a pharmaceutical firm. Three of the 17 workers with hepatomegaly were judged by the authors to have toxic hepatitis on the basis of elevated serum enzymes, and elevated serum gamma globulin. This group of workers was also considered to be much more susceptible to viral hepatitis than the inhabitants of the city in which the plant was located, but the basis for this inference is tenuous, since no information was given on possible contributions to the problem by poor sanitation, for example the incidence of viral hepatitis in other plant workers was not mentioned. In the study by Challen et al [67] no liver abnormalities were found among 17 workers exposed to chloroform. Nine workers were exposed to chloroform at TWA concentrations ranging from 23-71 ppm, but for only 4 hours/day. These workers had been working under these conditions for 10-24 months. Another group of workers who had previously been exposed to chloroform in concentrations estimated to have ranged from 77-237 ppm for up to 8 hours/day, also had no abnormal liver findings. However, it had been many months since this latter group had been exposed to chloroform. These studies indicate that liver damage may occur in workers from exposure to chloroform in varying concentrations up to 205 ppm. [55] The studies with mice showed some liver cell necrosis from 4 hours' exposure to 200 ppm and fatty infiltration of the liver from 100 ppm for 4 hours. [78] The studies with rats showed increased liver weights from 10 consecutive 7hour daily exposures to 100 ppm, but not to 30 ppm exposures. [83] The studies by Challen et al [67] indicated no liver injury from 4 hours per day exposure of workers to 23-71 ppm chloroform. While the exposure conditions studied by Challen et al [67] (23-71 ppm chloroform for 4 hours/day) seem below the threshold for liver injury, they are not adequate to protect workers from other undesirable responses such as dryness of the mouth and throat at work, and lassitude in the evening, which occurred among the workers exposed to 23-35 ppm chloroform for 4 hours a day. It seems reasonable to infer from these observations that the lassitude reflects central nervous system depression and that dry mouth and throat and the digestive tract symptoms reflect a local irritant action in those areas. It can be interpreted from the study of Challen and co-workers [67] that a safe level to exposure for workers lies somewhere between 23 and 35 ppm for 4-hour workdays, or about 10 to about 18 ppm for 8-hour workdays. The appropriate limit within this range is not clear, but because of mild effects in this group (mouth and throat dryness and evening fatigue) and because of the fetal abnormalities found in rats exposed to 30 ppm, [83] it is concluded that the environmental limit to be recommended should be the lowest in this range, namely 10 ppm, as a time-weighted average. The absorption of chloroform resulting from exposure to a given time-weighted average concentration for 8 hours a day, 5 days a week, would be about the same as that absorbed for 10 hours a day, 4 days a week. Thus, the same time-weighted average limit is applicable whether the 40hour workweek is applied over 5 8-hour days or 4 10-hour days. It is likely that a central nervous system depressant, such as chloroform, might at briefly high concentrations affect attention, judgment or perception sufficiently so that if an emergency were to occur the worker might not take appropriate action. This suggests the need for a ceiling concentration to be observed, as a limitation on excursions above the timeweighted average and as a limit applicable to occasional and brief use of chloroform. However, after detailed consideration of the data applicable to derivation of such a ceiling, no basis from the scientific data appears. The ceiling proposed by American Industrial Hygiene Association [95] in its Hygienic Guide Series is based on animal data that seem more applicable to development of a time-weighted average limit. Thus, a ceiling limit of 50 ppm based on a 10-minute sampling period is proposed on the basis of good practice. It is recognized that many workers handle small amounts of chloroform or are working in situations where, regardless of amounts used, there is only negligible contact with the substance. Under these conditions, it should not be necessary to comply with all provisions of this recommended standard, which has been prepared primarily to protect worker health under hazardous circumstances. On the other hand, concern for worker health requires that protective measures be instituted below the enforceable limit to ensure that exposures stay below that limit. For these reasons, "exposure to chloroform" has been defined as exposure above half the environmental limit, thereby delineating those work situations which do not require the expenditure of health resources for environmental and medical monitoring and associated recordkeeping. Half the environmental limit has been chosen on the basis of professional judgment rather than on quantitative data that delineate nonhazardous areas from areas in which a hazard may exist. However, it is recommended that appropriate work practices and protective measures to prevent skin and eye contact and to prevent exposure to pyrolysis products be required, regardless of air concentrations of chloroform. # VI. WORK PRACTICES The principal method for the manufacture of chloroform is chlorination of methane, [1] and suitable controls for safe use of methane Consideration should be given to pumping the diked spill to another tank. In addition, it is advisable to have facilities for transfer of the contents of a leaking tank to another suitable tank. Respirators generally fall into the following classification according to their mode of operation: leakage is the major limitation of these devices. From the test results, it has been demonstrated that the half mask or quarter mask facepiece may be Used for protection up to 10X the TWA. The full facepiece, operated with a negative pressure, may be used up to 100X the TWA. The majority of the wearers can obtain a higher degree of protection. However, for purposes of uniform regulations, covering the many face sizes and shapes of the US working population, it is necessary to use these guides. These maximum use concentration guides do not take into account additional leakage from filters or canisters. When providing respiratory protection against chloroform, the concentration immediately dangerous to life must be considered. In this document, it is assumed that any concentration of chloroform greater than 2,500 ppm is immediately dangerous to life. In selecting and using gas masks and chemical cartridge respirators, the service life must be considered. An approved, calibrated, battery-operated personal sampling pump plus an activated charcoal tube shall be used to collect the sample. (3) The activated charcoal tube shall be attached to the clothing of the worker; the shirt collar is convenient for this purpose. (4) Breathing zone samples shall be collected to permit determination of TWA workday exposures for every job involving exposure to chloroform in sufficient numbers to express the variability of the work situation. The minimum number of TWA's to be determined is listed in Section 7 of this standard, according to the number of employees involved. (2) The smaller section of charcoal is used as a backup and should be positioned nearest the sampling pump. ( )3 The charcoal tube should be placed in a vertical position during sampling with the inlet facing down. (4) Tubing may be used to connect the back of the tube to the pump, but air being sampled should not be passed through any hose or tubing before entering the charcoal tube. (5) The flowrates, sampling time involved and/or the total volume of air sampled must be measured accurately. The sample can be taken at flow rates of 50-1000 ml/min. Total sample volumes of 1-30 liters are recommended. It is also recommended that the sampling be less than 4 hours. (6) Measure and record the temperature and pressure of the atmosphere being sampled. The charcoal tubes should be capped with the supplied plastic caps immediately after sampling. Under no circumstances should rubber caps be used. (8) One charcoal tube should be handled in the same man ner as the sample tube (break, seal, and transport) except that no air is sampled through this tube. This tube should be labeled as a blank. (9) Capped tubes should be packed tightly after sampling to minimize tube breakage during transport. (10) Charcoal tubes should be shipped separately from bulk samples. # Sample Analysis (a) Principle of the Method (1) A known volume of air is drawn through a charcoal tube to trap the chloroform vapor. (2) The charcoal in the tube is transferred to a small test tube and desorbed with carbon disulfide. (3) An aliquot of the desorbed sample is injected into a gas chromatograph. (4) The area of the resulting peak is determined and compared with areas obtained from the injection of standards. (b) Range and Sensitivity (1) The lower limit for detection of chloroform at a 16 x 1 attenuation on a gas chromatograph with a 10:1 splitter is 0.10 mg/sample. This value can be lowered by reducing the attenuation or by eliminating the 10:1 splitter. ( The upper limit value for chloroform is 2.0 mg/sample. This is the estimated amount of chloroform which the front section will hold before this compound is found on the backup section. If a particular atmosphere is suspected of containing a large amount of chloroform, it is recommended that a smaller sample volume be taken. # (c) Interferences (1) When the amount of water in the air is so great that condensation actually occurs in the tube, chloroform will not be trapped. (2) Any compound which has the same retention time as chloroform at the operating conditions described in this method could be an interference. # (d) Advantages of the Method (1) This method is advantageous in that it provides one basic method for determining many different organic compounds. (2) The sampling device is small, portable, and involves no liquids. (3) Interferences are minimal, and most of those which do occur can be eliminated by altering chromatographic conditions. (4) The analysis of the tubes is accomplished by using a quick instrumental method. (e) Disadvantages of the Method (1) The amount of sample which can be taken is limited by the weight of chloroform which the tube will hold before overloading. (2) When the sample value obtained for the backup section of charcoal exceeds 25% of that found on the front section, the possibility of appreciable sample loss exists. The area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary sample results are read from a standard curve prepared as discussed below. (A) # Preparation of Standards It is convenient to prepare standards in terms of mg chloroform per 0.5 ml of carbon disulfide because samples are desorbed in this amount of carbon disulfide. To minimize error due to the volatility of carbon disulfide, 20 times the weight can be injected into 10 ml of carbon disulfide. For example, to prepare a 0.3 mg/0.5 ml standard, 6.0 mg is injected into exactly 10 ml of carbon disulfide in a glass stoppered flask. The density for chloroform is used to convert 6.0 mg into micro liters for easy measurement with a microliter syringe. (1) The name, address, and telephone number of the manufacturer or supplier of the product. (1) Chemical or widely recognized common name of all hazardous ingredients. ( Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled. This includes proper labeling and disposal of containers holding residues, contaminated absorbents, etc. (h) Section VIII. Special Protection Information. Requirements for personal protective equipment, such as respirators, eye protection, clothing, and ventilation, such as local exhaust (at site of product use or application), general, or other special types. Any other general precautionary information. (i) Section IX. Special Precautions. # U.S. DEPARTMENT OF LABOR # D E P A R T M E N T O F H E A L T H . E D U C A T IO N . A N D W E L F A R E P U B L IC H E A L T H S E R V IC E C E N T E R F O R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E F O R O C C U P A T IO N A L S A F E T Y A N D H E # (1) Atmosphere-Supplying Respirators (A) Self-contained. (B) Hose mask. (C) Airline. (D) Combination self-contained and airline. (2) Air-Purifying Respirators (A) Gas and vapor (gas mask and chemical cartridge). (B) Particulate (dust, fog, fume, mist, smoke, and sprays). (C) Combination gas, vapor, and particulate. (3) Combination Atmosphere-Supplying and Air-Purifying # Respirators The factors that affect the overall performance of an airpurifying respirator are the reliability of the face seal, the efficiency of the filters and/or absorbent canisters and other variables, such as leakage from exhalation valves. The performance of filters, canisters, and exhalation valves is predictable and controllable when test data are available. However, the current state of knowledge of the wearer's face size and shape and the respirator size and shape is such that the face seal is unpredictable and variable. During the past several years, NIOSH has funded research and development projects to make quantitative respirators-man tests on all types of respirators to measure their performance and/or efficiency. The results of these tests made on half mask and quarter mask facepieces, operated with a negative pressure in the facepiece, show that the facepiece 102. (3) A recorder and some method for determining peak area. (4) Glass stoppered microtubes. The 2.5-ml graduated microcentrifuge tubes are recommended. (5) Microsyringe of 10-jul capacity, and convenient sizes for making standards. (6) Pipets. 0.5-ml delivery pipets or 1.0-ml graduated pipets in 0.1-ml increments. (7) Volumetric flasks of 10-ml capacity or convenient sizes for making standard solutions. # (g) Reagents (1) Spectroquality carbon disulfide At least 5 tubes are prepared in this manner and allowed to stand at least overnight to assure complete adsorption of chloroform onto the charcoal. These 5 tubes will be referred to as the "desorption samples". A parallel blank tube should be treated in the same manner except that no chloroform is added to it. The desorption sample and blank tubes are desorbed and analyzed in exactly the same manner as previously described. Two or 3 desorption standards are prepared for analysis by injecting the same volume of compound into 0.	None	None
40e19e6bab95b2bc5ab9666d78d70f421b35f545	cdc	None	The discussion on 3-NRTI regimens was removed from this section because 3-NRTI regimens are no longer recommended regimens for ART-naive patients. - Tables 5a, 5b, 6, and 7 were updated to reflect the above changes.- The term "early" HIV infection is now used when describing both the acute phase of HIV infection (i.e., immediately after HIV infection and before seroconversion) and recent (i.e., within first 6 months) HIV infection. - The recommendation for initiation of ART in patients with early infection was changed from "should be considered optional (CIII)" to "should be offered (BII)." - The section was updated to include a summary of recent randomized controlled trials that examined the role of time-limited ART in patients with early HIV infection.- The recommendation on use of efavirenz (EFV) during pregnancy was updated to be in accord with the recommendation in the Perinatal Antiretroviral Guidelines. The key update includes the following statement: "Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII)." - The Panel also recommends that intravenous zidovudine use during labor may be omitted in women who have HIV RNA < 400 copies/mL near delivery (BII). Oral combination ART should be continued during labor.- This section includes new information under the heading "Pharmacokinetic (PK) Enhancing." The additional text describes the roles and mechanisms of ritonavir (RTV) and cobicistat (COBI) as pharmacokinetic enhancers to increase the exposure of antiretroviral drugs. - Tables 14-16c have been updated with new pharmacokinetic interaction data, including known and predicted interactions involving EVG/COBI/TDF/FTC and other drugs.Minor revisions have also been made to the following sections:# - Introduction - Adverse Effects of Antiretroviral Agents (and Table 13) Antiretroviral therapy (ART) for the treatment of HIV infection has improved steadily since the advent of potent combination therapy in 1996. New drugs that offer new mechanisms of action, improvements in potency and activity even against multidrug-resistant viruses, dosing convenience, and tolerability have been approved. ART has dramatically reduced HIV-associated morbidity and mortality and has transformed HIV disease into a chronic, manageable condition. In addition, effective treatment of HIV-infected individuals with ART is highly effective at preventing transmission to sexual partners. 1 However, less than one-third of HIV-infected individuals in the United States have suppressed viral loads, 2 which is mostly a result of undiagnosed HIV infection and failure to link or retain diagnosed patients in care. Despite remarkable improvements in HIV treatment and prevention, economic and social barriers that result in continued morbidity, mortality, and new HIV infections persist. # Management of the # Considerations for Antiretroviral Use in # List of Tables The Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) is a working group of the Office of AIDS Research Advisory Council (OARAC). The primary goal of the Panel is to provide HIV care practitioners with recommendations based on current knowledge of antiretroviral (ARV) drugs used to treat adults and adolescents with HIV infection in the United States. The Panel reviews new evidence and updates recommendations in these guidelines when needed. The Panel's primary areas of attention have included baseline assessment, treatment goals, indications for initiation of ART, choice of the initial regimen for ART-naive patients, drugs or combinations to avoid, management of adverse effects and drug interactions, management of treatment failure, and special ART-related considerations in specific patient populations. For recommendations related to pre-exposure HIV prophylaxis (PrEP) for HIV-uninfected persons, please refer to recommendations from the Centers for Disease Control and Prevention (CDC). 3,4 These guidelines generally represent the state of knowledge regarding the use of ARV agents. However, because the science of HIV evolves rapidly, the availability of new agents and new clinical data may change therapeutic options and preferences. Information included in these guidelines may not be consistent with approved labeling for the particular products or indications in question, and the use of the terms "safe" and "effective" may not be synonymous with the Food and Drug Administration (FDA)-defined legal standards for product approval. The Panel frequently updates the guidelines (current and archived versions of the guidelines are available on the AIDSinfo website at ). However, the guidelines cannot always be updated apace with the rapid evolution of new data in the field of HIV and cannot offer guidance on care for all patients. Clinicians should exercise clinical judgment in management decisions tailored to unique patient circumstances. The Panel recognizes the importance of clinical research in generating evidence to address unanswered questions related to the optimal safety and efficacy of ART. The Panel encourages both the development of protocols and patient participation in well-designed, Institutional Review Board (IRB)-approved clinical trials. # Basis for Recommendations Recommendations in these guidelines are based upon scientific evidence and expert opinion. Each recommended statement includes a letter (A, B, or C) that represents the strength of the recommendation and with a Roman numeral (I, II, or III) that represents the quality of the evidence that supports the recommendation (see Table 2). # Table 2. Rating Scheme for Recommendations # HIV Expertise in Clinical Care Many studies have demonstrated that outcomes achieved in HIV-infected outpatients are better when care is delivered by a clinician with HIV expertise, which reflects the complexity of HIV infection and its treatment. Thus, appropriate training and experience, as well as ongoing continuing education, are important components of optimal care. Primary care providers without HIV experience, such as those who provide service in rural or underserved areas, should identify experts in their regions who will be available for consultation when needed. Baseline Evaluation (Last updated February 12, 2013; last reviewed February 12, 2013) Every HIV-infected patient entering into care should have a complete medical history, physical examination, and laboratory evaluation and should be counseled regarding the implications of HIV infection. The goals of the initial evaluation are to confirm the diagnosis of HIV infection, obtain appropriate baseline historical and laboratory data, ensure patient understanding about HIV infection and its transmission, and to initiate care as recommended in HIV primary care guidelines 1 and guidelines for prevention and treatment of HIV-associated opportunistic infections. 2 The initial evaluation also should include introductory discussion on the benefits of antiretroviral therapy (ART) for the patient's health and to prevent HIV transmission. Baseline information then can be used to define management goals and plans. In the case of previously treated patients who present for an initial evaluation with a new health care provider, it is critical to obtain a complete antiretroviral (ARV) history (including drug-resistance testing results, if available), preferably through the review of past medical records. Newly diagnosed patients should also be asked about any prior use of ARV agents for prevention of HIV infection. The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens: - HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay's limit of detection) (AI); - CD4 T-cell count (CD4 count) (AI); - Plasma HIV RNA (viral load) (AI); - Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses (AIII); - Fasting blood glucose and serum lipids (AIII); and - Genotypic resistance testing at entry into care, regardless of whether ART will be initiated immediately (AII). For patients who have HIV RNA levels <500 to 1,000 copies/mL, viral amplification for resistance testing may not always be successful (BII). In addition, other tests (including screening tests for sexually transmitted infections and tests for determining the risk of opportunistic infections and need for prophylaxis) should be performed as recommended in HIV primary care and opportunistic infections guidelines. 1,2 Patients living with HIV infection often must cope with many social, psychiatric, and medical issues that are best addressed through a patient-centered, multi-disciplinary approach to the disease. The baseline evaluation should include an evaluation of the patient's readiness for ART, including an assessment of high-risk behaviors, substance abuse, social support, mental illness, comorbidities, economic factors (e.g., unstable housing), medical insurance status and adequacy of coverage, and other factors that are known to impair adherence to ART and increase the risk of HIV transmission. Once evaluated, these factors should be managed accordingly. The baseline evaluation should also include a discussion of risk reduction and disclosure to sexual and/or needle sharing partners, especially with untreated patients who are still at high risk of HIV transmission. The CD4 T-cell count (CD4 count) serves as the major laboratory indicator of immune function in patients who have HIV infection. It is one of the key factors in determining both the urgency of antiretroviral therapy (ART) initiation and the need for prophylaxis for opportunistic infections. It is also the strongest predictor of subsequent disease progression and survival according to findings from clinical trials and cohort studies. 1,2 CD4 counts are highly variable; a significant change (2 standard deviations) between 2 tests is approximately a 30% change in the absolute count, or an increase or decrease in CD4 percentage by 3 percentage points. - Use of CD4 Count for Initial Assessment. The CD4 count is one of the most important factors in determining the urgency of ART initiation and the need for prophylaxis for opportunistic infections. All patients at entry into care should have a baseline CD4 count (AI). Recommendations for initiation of ART can be found in the Initiating Antiretroviral Therapy in Antiretroviral-Naive Patients section of these guidelines. - Use of CD4 Count for Monitoring Therapeutic Response. An adequate CD4 response for most patients on therapy is defined as an increase in CD4 count in the range of 50 to 150 cells/mm 3 per year, generally with an accelerated response in the first 3 months of treatment. Subsequent increases in patients with good virologic control average approximately 50 to 100 cells/mm 3 per year until a steady state level is reached. 3 Patients who initiate therapy with a low CD4 count 4 or at an older age 5 may have a blunted increase in their counts despite virologic suppression. Frequency of CD4 Count Monitoring. ART now is recommended for all HIV-infected patients. In untreated patients, CD4 counts should be monitored every 3 to 6 months to determine the urgency of ART initiation. In patients on ART, the CD4 count is used to assess the immunologic response to ART and the need for initiation or discontinuation of prophylaxis for opportunistic infections (AI). The CD4 count response to ART varies widely, but a poor CD4 response is rarely an indication for modifying a virologically suppressive antiretroviral (ARV) regimen. In patients with consistently suppressed viral loads who have already experienced ART-related immune reconstitution, the CD4 cell count provides limited information, and frequent testing may cause unnecessary anxiety in patients with clinically inconsequential fluctuations. Thus, for the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load. In such patients, CD4 count may be monitored every 6 to 12 months, unless there are changes in the patient's clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII). Factors that affect absolute CD4 count. The absolute CD4 count is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4+ T lymphocytes. This absolute number may fluctuate in individuals or may be influenced by factors that may affect the total WBC count and lymphocyte percentages, such as use of bone marrow-suppressive medications or the presence of acute infections. Splenectomy 6,7 or co-infection with human T-lymphotropic virus type I (HTLV-1) 8 may cause misleadingly elevated absolute CD4 counts. Alpha-interferon, on the other hand, may reduce the absolute CD4 count without changing the CD4 percentage. 9 In all these cases, CD4 percentage remains stable and may be a more appropriate parameter to assess the patient's immune function. Plasma HIV-1 RNA Testing (Last updated February 12, 2013; last reviewed February 12, 2013) Plasma HIV-1 RNA (viral load) should be measured in all HIV-1-infected patients at baseline and on a regular basis thereafter, especially in patients who are on treatment, because viral load is the most important indicator of response to antiretroviral therapy (ART) (AI). Commercially available HIV-1 RNA assays do not detect HIV-2 viral load. For further discussion on HIV-2 RNA monitoring in patients with HIV-1/HIV-2 coinfection or HIV-2 mono-infection, see HIV-2 Infection. Analysis of 18 trials that included more than 5,000 participants with viral load monitoring showed a significant association between a decrease in plasma viremia and improved clinical outcome. 1 Thus, viral load testing serves as a surrogate marker for treatment response 2 and can be useful in predicting clinical progression. 3,4 The minimal change in viral load considered to be statistically significant (2 standard deviations) is a threefold, or a 0.5 log 10 copies/mL change. Optimal viral suppression is generally defined as a viral load persistently below the level of detection (200 copies/mL, which eliminates most cases of apparent viremia caused by blips or assay variability. 9 This definition also may be useful in clinical practice (see Virologic and Immunologic Failure). For most individuals who are adherent to their antiretroviral (ARV) regimens and who do not harbor resistance mutations to the prescribed drugs, viral suppression is generally achieved in 12 to 24 weeks, although it may take longer in some patients. Recommendations for the frequency of viral load monitoring are summarized below. - At initiation or change in therapy. Plasma viral load should be measured before initiation of therapy and preferably within 2 to 4 weeks, and not more than 8 weeks, after treatment initiation or after treatment modification (BI). Repeat viral load measurement should be performed at 4-to 8-week intervals until the level falls below the assay's limit of detection (BIII). - In virologically suppressed patients in whom therapy was modified because of drug toxicity or for regimen simplification. Viral load measurement should be performed within 2 to 8 weeks after changing therapy. The purpose of viral load monitoring at this point is to confirm potency of the new regimen (BIII). - In patients on a stable ARV regimen. Viral load should be repeated every 3 to 4 months or as clinically indicated (BII). Clinicians may extend the interval to every 6 months for adherent patients who have suppressed viral loads for more than 2 to 3 years and whose clinical and immunologic status is stable (BIII). Monitoring in patients with suboptimal response. In addition to viral load monitoring, a number of additional factors should be assessed, such as adherence to prescribed medications, altered pharmacology, or drug interactions. Patients who fail to achieve viral suppression should undergo resistance testing to aid in the selection of an alternative regimen, as discussed in Drug-Resistance Testing and Virologic and Immunologic Failure (AI). Drug-Resistance Testing (Last updated February 12, 2013; last reviewed February 12, 2013) # Genotypic and Phenotypic Resistance Assays Genotypic and phenotypic resistance assays are used to assess viral strains and inform selection of treatment strategies. Standard assays provide information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Testing for integrase and fusion inhibitor resistance can also be ordered separately from several commercial laboratories. Co-receptor tropism assays should be performed whenever the use of a CCR5 antagonist is being considered. Phenotypic co-receptor tropism assays have been used in clinical practice. A genotypic assay to predict coreceptor use is now commercially available (see Co-receptor Tropism Assays). # Genotypic Assays Genotypic assays detect drug-resistance mutations present in relevant viral genes. Most genotypic assays involve sequencing of the RT and PR genes to detect mutations that are known to confer drug resistance. Genotypic assays that assess mutations in the integrase and gp41 (envelope) genes are also commercially available. Genotypic assays can be performed rapidly and results are available within 1 to 2 weeks of sample collection. Interpretation of test results requires knowledge of the mutations selected by different antiretroviral (ARV) drugs and of the potential for cross resistance to other drugs conferred by certain mutations. The International AIDS Society-USA (IAS-USA) maintains an updated list of significant resistance-associated mutations in the RT, PR, integrase, and envelope genes (see # Panel's Recommendations - HIV drug-resistance testing is recommended in persons with HIV infection at entry into care regardless of whether antiretroviral therapy (ART) will be initiated immediately or deferred (AII). If therapy is deferred, repeat testing should be considered at the time of ART initiation (CIII). - Genotypic testing is recommended as the preferred resistance testing to guide therapy in antiretroviral (ARV)-naive patients (AIII). - Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is a concern, providers may wish to supplement standard genotypic resistance testing with an INSTI genotype test (CIII). - HIV drug-resistance testing should be performed to assist in the selection of active drugs when changing ARV regimens in persons with virologic failure and HIV RNA levels >1,000 copies/mL (AI). In persons with HIV RNA levels >500 but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). - Drug-resistance testing should also be performed when managing suboptimal viral load reduction (AII). - In persons failing INSTI-based regimens, genotypic testing for INSTI resistance should be performed to determine whether to include a drug from this class in subsequent regimens (AII). - Drug-resistance testing in the setting of virologic failure should be performed while the person is taking prescribed ARV drugs or, if not possible, within 4 weeks after discontinuing therapy (AII). - Genotypic testing is recommended as the preferred resistance testing to guide therapy in patients with suboptimal virologic responses or virologic failure while on first or second regimens (AII). - The addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drugresistance mutation patterns, particularly to protease inhibitors (PIs) (BIII). - Genotypic resistance testing is recommended for all pregnant women before initiation of ART (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI) (see the Perinatal Treatment Guidelines for more detailed discussion). ). 1 The Stanford University HIV Drug Resistance Database () also provides helpful guidance for interpreting genotypic resistance test results. Various tools to assist the provider in interpreting genotypic test results are now available. Clinical trials have demonstrated that consultation with specialists in HIV drug resistance improves virologic outcomes. 6 Clinicians are thus encouraged to consult a specialist to facilitate interpretation of genotypic test results and design of an optimal new regimen. # Rating of Recommendations # Phenotypic Assays Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT and PR gene sequences and, more recently, integrase and envelope sequences derived from patient plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses that express the patient-derived HIV genes of interest. Replication of these viruses at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory concentration ) is calculated, and the ratio of the IC 50 of test and reference viruses is reported as the fold increase in IC 50 (i.e., fold resistance). Automated phenotypic assays that can produce results in 2 to 3 weeks are commercially available, but they cost more to perform than genotypic assays. In addition, interpretation of phenotypic assay results is complicated by incomplete information regarding the specific resistance level (i.e., fold increase in IC 50 ) that is associated with drug failure, although clinically significant fold increase cutoffs are now available for some drugs. Again, consultation with a specialist to interpret test results can be helpful. Further limitations of both genotypic and phenotypic assays include lack of uniform quality assurance testing for all available assays, relatively high cost, and insensitivity to minor viral species. Despite being present, drug-resistant viruses that constitute less than 10% to 20% of the circulating virus population will probably not be detected by commercially available assays. This limitation is important because after drugs exerting selective pressure on drug-resistant populations are discontinued, a wild-type virus often re-emerges as the predominant population in the plasma. As a consequence, the proportion of virus with resistance mutations decreases to below the 10% to 20% threshold. In the case of some drugs, this reversion to predominantly wild-type virus can occur in the first 4 to 6 weeks after the drugs are discontinued. Prospective clinical studies have shown that despite this plasma reversion, re-initiation of the same ARV agents (or those sharing similar resistance pathways) is usually associated with early drug failure, and that the virus present at failure is derived from previously archived resistant virus. 15 Therefore, resistance testing is of greatest value when performed before or within 4 weeks after drugs are discontinued (AII). Because resistant virus may persist in the plasma of some patients for longer periods of time, resistance testing done 4 to 6 weeks after discontinuation of drugs may still detect mutations. However, the absence of detectable resistance in such patients must be interpreted with caution when designing subsequent ARV regimens. # Use of Resistance Assays in Clinical Practice (See Table 4) # Use of Resistance Assays in Determining Initial Treatment Transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic response to initial antiretroviral therapy (ART). The likelihood that a patient will acquire drug-resistant virus is related to the prevalence of drug resistance in HIV-infected persons engaging in high-risk behaviors in the community. In the United States and Europe, recent studies suggest that the risk that transmitted virus will be resistant to at least one ARV drug is in the range of 6% to 16%. Up to 8%, but generally less than 5% of transmitted viruses will exhibit resistance to drugs from more than one class. 24, If the decision is made to initiate therapy in a person with early HIV infection, resistance testing at baseline can guide regimen selection to optimize virologic response. Therefore, resistance testing in this situation is recommended (AII). A genotypic assay is preferred for this purpose (AIII). In this setting, treatment initiation should not be delayed pending resistance testing results. Once results are obtained, the treatment regimen can be modified if warranted (see Acute and Recent HIV Infection). In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but when therapy is eventually initiated, resistant viruses even at a low level may still increase the risk of treatment failure. Therefore, if therapy is deferred, resistance testing should still be done during acute HIV infection (AIII). In this situation, the genotypic resistance test result may be kept on record until the patient is to be started on ART. Repeat resistance testing at the time treatment is started should be considered because it is possible for a patient to acquire drug-resistant virus (i.e., superinfection) between entry into care and initiation of ART (CIII). Performing drug-resistance testing before ART initiation in patients with chronic HIV infection is less straightforward. The rate at which transmitted resistance-associated mutations revert to wild-type virus has not been completely delineated, but mutations present at the time of HIV transmission are more stable than those selected under drug pressure. It is often possible to detect resistance-associated mutations in viruses that were transmitted several years earlier. No prospective trial has addressed whether drug-resistance testing before initiation of therapy confers benefit in this population. However, data from several, but not all, studies suggest that virologic responses in persons with baseline resistance mutations are suboptimal. In addition, a cost-effectiveness analysis of early genotypic resistance testing suggests that baseline testing in this population should be performed. 38 Therefore, resistance testing in chronically infected persons is recommended at the time of entry into HIV care (AII). Although no definitive prospective data exist to support the choice of one type of resistance testing over another, genotypic testing is generally preferred in this situation because of lower cost, more rapid turnaround time, the assay's ability to detect mixtures of wild-type and resistant virus, and the relative ease of interpreting test results (AIII). If therapy is deferred, repeat testing soon before initiation of ART should be considered because the patient may have acquired drug-resistant virus (i.e., superinfection) (CIII). Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the RT and PR genes. Although transmission of integrase strand transfer inhibitor (INSTI)-resistant virus has rarely been reported, as use of INSTIs increases, the potential for transmission of INSTI-resistant virus may also increase. Therefore, when INSTI resistance is suspected, providers may wish to supplement standard baseline genotypic resistance testing with genotypic testing for resistance to this class of drugs (CIII). # Use of Resistance Assays in the Event of Virologic Failure Resistance assays are useful in guiding treatment decisions for patients who experience virologic failure while on ART. Several prospective studies assessed the utility of resistance testing to guide ARV drug selection in patients with virologic failure. These studies involved genotypic assays, phenotypic assays, or both. 6, In general, these studies found that changes in therapy that were informed by resistance testing results produced better early virologic response to salvage regimens than regimen changes guided only by clinical judgment. In addition, one observational cohort study found that performance of genotypic drug-resistance testing in ART-experienced patients with detectable plasma HIV RNA was independently associated with improved survival. 46 Thus, resistance testing is recommended as a tool in selecting active drugs when changing ARV regimens because of virologic failure in persons with HIV RNA >1,000 copies/mL (AI) (see Virologic and Immunologic Failure). In persons with HIV RNA >500 copies/mL but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). Drug-resistance testing in persons with a plasma viral load <500 copies/mL is not usually recommended because resistance assays cannot be consistently performed given low HIV RNA levels (AIII). Resistance testing also can help guide treatment decisions for patients with suboptimal viral load reduction (AII). Virologic failure in the setting of combination ART is, for certain patients, associated with resistance to only one component of the regimen. In this situation, substituting individual drugs in a failing regimen may be a possible option, but this concept will require clinical validation (see Virologic and Immunologic Failure). In patients who are on a failing first or second ARV drug regimen and experiencing virologic failure or suboptimal viral load reduction, genotypic testing is generally preferred for resistance testing (AII). This is based on the fact that, when compared with phenotypic testing, genotypic testing costs less to perform, has a faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. In addition, observations show that the assays are comparable predictors of virologic response to subsequent ART regimens. 50 Addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drug-resistance mutation patterns, particularly to PIs (BIII). In patients failing INSTI-based regimens, testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII); genotypic testing is preferred for this purpose. When the use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI). Phenotypic co-receptor tropism assays have been used in clinical practice. A genotypic assay to predict co-receptor use is now commercially available and is less expensive than phenotypic assays. Evaluation of genotypic assays is ongoing, but current data suggest that such testing should be considered as an alternative assay. The same principles regarding testing for co-receptor use also apply to testing when patients exhibit virologic failure on a CCR5 antagonist. 51 Resistance to CCR5 antagonists in the absence of detectable CXCR4-using virus has been reported, but such resistance is uncommon (see Co-receptor Tropism Assays). # Use of Resistance Assays in Pregnant Women In pregnant women, the goal of ART is to maximally reduce plasma HIV RNA to provide optimal maternal therapy and to prevent perinatal transmission of HIV. Genotypic resistance testing is recommended for all pregnant women before initiation of therapy (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). Phenotypic testing in those found to have complex drug-resistance mutation patterns, particularly to PIs, may provide additional information (BIII). Optimal prevention of perinatal transmission may require initiation of ART pending resistance testing results. Once the results are available, the ARV regimen can be changed as needed. # Clinical Setting/Recommendation Rationale # Drug-resistance assay recommended In acute HIV infection: Drug-resistance testing is recommended regardless of whether antiretroviral therapy (ART) is initiated immediately or deferred (AII). A genotypic assay is generally preferred (AIII). If ART is deferred, repeat resistance testing should be considered at the time therapy is initiated (CIII). A genotypic assay generally is preferred (AIII). If ART is initiated immediately, drug-resistance testing can determine whether drug-resistant virus was transmitted. Test results will help in the design of initial regimens or to modify or change regimens if results are obtained after treatment initiation. Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. If ART is deferred, testing should still be performed because of the greater likelihood that transmitted resistance-associated mutations will be detected earlier in the course of HIV infection. Results of resistance testing may be important when treatment is initiated. Repeat testing at the time ART is initiated should be considered because the patient may have acquired a drug-resistant virus (i.e., superinfection). In ART-naive patients with chronic HIV infection: Drug-resistance testing is recommended at entry into HIV care, regardless of whether therapy is initiated immediately or deferred (AII). A genotypic assay is generally preferred (AIII). If therapy is deferred, repeat resistance testing should be considered before initiation of ART (CIII). A genotypic assay is generally preferred (AIII). If an INSTI is considered for an ART-naive patient and transmitted INSTI resistance is a concern, providers may supplement standard resistance testing with a specific INSTI genotypic resistance assay (CIII). If use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-receptor Tropism Assays) Transmitted HIV with baseline resistance to at least 1 drug is seen in 6% to 16% of patients, and suboptimal virologic responses may be seen in patients with baseline resistant mutations. Some drugresistance mutations can remain detectable for years in untreated, chronically infected patients. Repeat testing before initiation of ART should be considered because the patient may have acquired a drug-resistant virus (i.e., a superinfection). Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. Standard genotypic drug-resistance assays test only for mutations in the RT and PR genes. (see Co-receptor Tropism Assays) In patients with virologic failure: Drug-resistance testing is recommended in patients on combination ART with HIV RNA levels >1,000 copies/mL (AI). In patients with HIV RNA levels >500 copies/mL but <1,000 copies/mL, testing may not be successful but should still be considered (BII). A standard genotypic resistance assay is generally preferred for patients experiencing virologic failure on their first or second regimens (AII). In patients failing INSTI-based regimens, genotypic testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII). If use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-receptor Tropism Assays). Addition of phenotypic assay to genotypic assay is generally preferred in patients with known or suspected complex drugresistance patterns, particularly to protease inhibitors (PIs) (BIII). Testing can help determine the role of resistance in drug failure and maximize the clinician's ability to select active drugs for the new regimen. Drug-resistance testing should be performed while the patient is taking prescribed ARV drugs or, if not possible, within 4 weeks after discontinuing therapy. Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant HIV. Standard genotypic drug-resistance assays test only for mutations in the RT and PR genes. Phenotypic testing can provide additional useful information in patients with complex drug-resistance mutation patterns, particularly to PIs. # Clinical Setting/Recommendation Rationale # Drug-resistance assay recommended In patients with suboptimal suppression of viral load: Drugresistance testing is recommended in patients with suboptimal suppression of viral load after initiation of ART (AII). Testing can help determine the role of resistance and thus assist the clinician in identifying the number of active drugs available for a new regimen. In HIV-infected pregnant women: Genotypic resistance testing is recommended for all pregnant women before initiation of ART (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). The goal of ART in HIV-infected pregnant women is to achieve maximal viral suppression for treatment of maternal HIV infection and for prevention of perinatal transmission of HIV. Genotypic resistance testing will assist the clinician in selecting the optimal regimen for the patient. # Drug-resistance assay not usually recommended After therapy is discontinued: Drug-resistance testing is not usually recommended more than 4 weeks after discontinuation of ARV drugs (BIII). Drug-resistance mutations may become minor species in the absence of selective drug pressure, and available assays may not detect minor drug-resistant species. If testing is performed in this setting, the detection of drug resistance may be of value; however, the absence of resistance does not rule out the presence of minor drug-resistant species. In patients with low HIV RNA levels: Drug-resistance testing is not usually recommended in patients with a plasma viral load <500 copies/mL (AIII). Resistance assays cannot be consistently performed given low HIV RNA levels. HIV enters cells by a complex process that involves sequential attachment to the CD4 receptor followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cellular membranes. 1 CCR5 coreceptor antagonists prevent HIV entry into target cells by binding to the CCR5 receptors. 2 Phenotypic and, to a lesser degree, genotypic assays have been developed that can determine or predict the co-receptor tropism (i.e., CCR5, CXCR4, or both) of the patient's dominant virus population. An older generation assay (Trofile, Monogram Biosciences, Inc., South San Francisco, CA) was used to screen patients who were participating in clinical trials that led to the approval of maraviroc (MVC), the only CCR5 antagonist currently available. The assay has been improved and is now available with enhanced sensitivity. In addition, a genotypic assay to predict co-receptor usage is now commercially available. During acute/recent infection, the vast majority of patients harbor a CCR5-utilizing virus (R5 virus), which suggests that the R5 variant is preferentially transmitted. Viruses in many untreated patients eventually exhibit a shift in co-receptor tropism from CCR5 usage to either CXCR4 or both CCR5 and CXCR4 tropism (i.e., dual-or mixed-tropic; D/M-tropic). This shift is temporally associated with a more rapid decline in CD4 T-cell counts, 3,4 but whether this tropism shift is a cause or a consequence of progressive immunodeficiency remains undetermined. 1 Antiretroviral (ARV)-treated patients with extensive drug resistance are more likely to harbor X4-or D/M-tropic variants than untreated patients with comparable CD4 counts. 5 The prevalence of X4-or D/M-tropic variants increases to more than 50% in treated patients who have CD4 counts <100 cells/mm 3 . 5,6 # Phenotypic Assays Phenotypic assays characterize the co-receptor usage of plasma-derived virus. These assays involve the generation of laboratory viruses that express patient-derived envelope proteins (i.e., gp120 and gp41). These pseudoviruses, which are replication-defective, are used to infect target cell lines that express either CCR5 or CXCR4. 7,8 Using the Trofile assay, the co-receptor tropism of the patient-derived virus is confirmed by testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors in vitro. This assay takes about 2 weeks to perform and requires a plasma HIV RNA level ≥1,000 copies/mL. The performance characteristics of these assays have evolved. Most, if not all, patients enrolled in premarketing clinical trials of MVC and other CCR5 antagonists were screened with an earlier, less sensitive version of the Trofile assay. 8 This earlier assay failed to routinely detect low levels of CXCR4-utilizing variants. As a consequence, some patients enrolled in these clinical trials harbored low levels of CXCR4utilizing virus at baseline that were below the assay limit of detection and exhibited rapid virologic failure after initiation of a CCR5 antagonist. 9 The assay has been revised and is now able to detect lower levels of CXCR4-utlizing viruses. In vitro, the assay can detect CXCR4-utilizing clones with 100% sensitivity when those clones represent 0.3% or more of the virus population. 10 Although this more sensitive assay has had # Panel's Recommendations - A co-receptor tropism assay should be performed whenever the use of a CCR5 co-receptor antagonist is being considered (AI). - Co-receptor tropism testing is also recommended for patients who exhibit virologic failure on a CCR5 antagonist (BIII). - A phenotypic tropism assay is preferred to determine HIV-1 co-receptor usage (AI). - A genotypic tropism assay should be considered as an alternative test to predict HIV-1 co-receptor usage (BII). The ABC HSR is a multiorgan clinical syndrome typically seen within the initial 6 weeks of ABC treatment. This reaction has been reported in 5%-8% of patients participating in clinical trials when using clinical criteria for the diagnosis, and it is the major reason for early discontinuation of ABC. Discontinuing ABC usually promptly reverses HSR, whereas subsequent rechallenge can cause a rapid, severe, and even lifethreatening recurrence. 1 Studies that evaluated demographic risk factors for ABC HSR have shown racial background as a risk factor, with white patients generally having a higher risk (5%-8%) than black patients (2%-3%). Several groups reported a highly significant association between ABC HSR and the presence of the major histocompatibility complex (MHC) class I allele HLA-B5701. Because the clinical criteria used for ABC HSR are overly sensitive and may lead to false-positive ABC HSR diagnoses, an ABC skin patch test (SPT) was developed as a research tool to immunologically confirm ABC HSR. 4 A positive ABC SPT is an ABC-specific delayed HSR that results in redness and swelling at the skin site of application. All ABC SPT-positive patients studied were also positive for the HLA-B5701 allele. 5 The ABC SPT could be falsely negative for some patients with ABC HSR and, at this point, is not recommended for use as a clinical tool. The PREDICT-1 study randomized patients before starting ABC either to be prospectively screened for HLA-B5701 (with HLA-B5701-positive patients not offered ABC) or to standard of care at the time of the study (i.e., no HLA screening, with all patients receiving ABC). 6 The overall HLA-B5701 prevalence in this predominately white population was 5.6%. In this cohort, screening for HLA-B5701 eliminated immunologic ABC HSR (defined as ABC SPT positive) compared with standard of care (0% vs. 2.7%), yielding a 100% negative predictive value with respect to SPT and significantly decreasing the rate of clinically suspected ABC HSR (3.4% vs. 7.8%). The SHAPE study corroborated the low rate of immunologically validated ABC HSR in black patients and confirmed the utility of HLA-B5701 screening for the risk of ABC HSR (100% sensitivity in black and white populations). 7 On the basis of the results of these studies, the Panel recommends screening for HLA-B5701 before starting patients on an ABC-containing regimen (AI). HLA-B5701-positive patients should not be prescribed ABC (AI), and the positive status should be recorded as an ABC allergy in the patient's medical record (AII). HLA-B5701 testing is needed only once in a patient's lifetime; thus, efforts to carefully record and maintain the test result and to educate the patient about its implications are important. The specificity of the HLA-B5701 test in predicting ABC HSR is lower than the sensitivity (i.e., 33%-50% of HLA-B5701-positive patients would likely not develop confirmed ABC HSR if exposed to ABC). HLA-B5701 should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B5701 result does not absolutely rule out the possibility of some form of ABC HSR. When HLA-B5701 screening is not # Rating of Recommendations # Panel's Recommendations - The Panel recommends screening for HLA-B5701 before starting patients on an abacavir (ABC)-containing regimen to reduce the risk of hypersensitivity reaction (HSR) (AI). - HLA-B5701-positive patients should not be prescribed ABC (AI). - The positive status should be recorded as an ABC allergy in the patient's medical record (AII). - When HLA-B5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR (CIII). Eradication of HIV infection cannot be achieved with available antiretroviral (ARV) regimens even when new, potent drugs are added to a regimen that is already suppressing plasma viral load below the limits of detection of commercially available assays. 1 This is chiefly because the pool of latently infected CD4 T cells is established during the earliest stages of acute HIV infection 2 and persists with a long half-life, despite prolonged suppression of plasma viremia. Therefore the primary goals for initiating antiretroviral therapy (ART) are to: # Rating of Recommendations - reduce HIV-associated morbidity and prolong the duration and quality of survival, - restore and preserve immunologic function, - maximally and durably suppress plasma HIV viral load (see Plasma HIV RNA Testing), and - prevent HIV transmission. ART has reduced HIV-related morbidity and mortality and has reduced perinatal 12 and behavior-associated transmission of HIV. HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in HIV-infected cohorts. (See Initiating Antiretroviral Therapy.) Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves CD4 T-cell numbers, and confers substantial clinical benefits, all of which are important treatment goals. Achieving viral suppression requires the use of ARV regimens with at least two, and preferably three, active drugs from two or more drug classes. Baseline resistance testing and patient characteristics should guide design of the specific regimen. (See What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient.) When initial suppression is not achieved or is lost, rapidly changing to a new regimen with at least two active drugs is required. (See Virologic and Immunologic Failure.) The increasing number of drugs and drug classes makes viral suppression below detection limits an appropriate goal in all patients. Viral load reduction to below limits of assay detection in an ART-naive patient usually occurs within the first 12-24 weeks of therapy. Predictors of virologic success include: - high potency of ARV regimen, - excellent adherence to treatment regimen, 20 - low baseline viremia, 21 - higher baseline CD4 count (>200 cells/mm 3 ), 22 and - rapid reduction of viremia in response to treatment. 21,23 Successful outcomes are usually observed, although adherence difficulties may lower the success rate in clinical practice to below the 90% rate commonly seen in clinical trials. 24 # Strategies to Achieve Treatment Goals Achieving treatment goals requires a balance of sometimes competing considerations, outlined below. Providers and patients must work together to define individualized strategies to achieve treatment goals. # Selection of Initial Combination Regimen Several preferred and alternative ARV regimens are recommended for use. (See What to Start.) Many of these regimens have comparable efficacy but vary to some degree in dosing frequency and symmetry, pill # Introduction Without treatment, the vast majority of HIV-infected individuals will eventually develop progressive immunosuppression (as evident by CD4 count depletion), leading to AIDS-defining illnesses and premature death. The primary goal of antiretroviral therapy (ART) is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication so that plasma HIV RNA levels (viral load) remain below that detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Furthermore, high plasma HIV RNA is a major risk factor for HIV transmission and use of effective ART can reduce viremia and transmission of HIV to sexual partners. 1,2 Modelling studies suggest that the expanded use of ART may result in lower incidence and, eventually, prevalence of HIV on a community or population level. 3 Thus, a secondary goal of ART is to reduce the risk of HIV transmission. Historically, HIV-infected individuals have presented for care with low CD4 counts, 4 but increasingly there have been concerted efforts to both increase testing of at-risk patients and to link HIV-infected patients to medical care soon after HIV diagnosis (and before they have advanced HIV diseases). For those with high CD4 cell counts, whose short-term risk for death may be low, 5 the recommendation to initiate ART is based on growing evidence that untreated HIV infection or uncontrolled viremia is associated with development of non-AIDS-defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancies. Furthermore, newer ART regimens are more effective, more convenient, and better tolerated than regimens used in the past. Regardless of CD4 count, the decision to initiate ART should always include consideration of any co-morbid conditions, the willingness and readiness of the patient to initiate therapy, and the availability of resources. In settings where resources are not available to initiate ART in all patients, treatment should be prioritized for patients with the lowest CD4 counts and those with the following clinical conditions: pregnancy, CD4 count <200 cells/mm 3 , or history of an AIDS-defining illness, including HIV-associated dementia, HIV-associated nephropathy (HIVAN), hepatitis B virus (HBV), and acute HIV infection. # Panel's Recommendations - Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression. The strength and evidence for this recommendation vary by pretreatment CD4 cell count: CD4 count 500 cells/mm 3 (BIII). - ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV. The strength and evidence for this recommendation vary by transmission risks: perinatal transmission (AI); heterosexual transmission (AI); other transmission risk groups (AIII). - Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors. Tempering the enthusiasm to treat all patients regardless of CD4 count is the absence of randomized data that definitively demonstrate a clear clinical benefit of ART in patients with CD4 count >350 cells/mm 3 and mixed results from observational cohort studies on the definitive benefits of early ART. For some patients, the potential risks of short-or long-term, drug-related complications and non-adherence to long-term therapy in asymptomatic patients may offset possible benefits of earlier initiation of therapy. An ongoing randomized controlled trial to evaluate the role of immediate versus delayed ART in patients with CD4 count >500 cells/mm 3 will help to further define the role of ART in this patient population (ClinicalTrials.gov identifier NCT00867048). # Rating of Recommendations The known and potential benefits and limitations of ART overall, and in different patient populations are discussed below. # Benefits of Antiretroviral Therapy # Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count Patients with a history of an AIDS-defining illness or CD4 count 200 cells/mm 3 ) with later treatment (i.e., initiated at CD4 count 200 cells/mm 3 . CIPRA HT-001, a randomized clinical trial conducted in Haiti, enrolled 816 participants without AIDS. Participants were randomized to start ART with CD4 counts of 200 cells/mm 3 to 350 cells/mm 3 or to defer treatment until their CD4 counts dropped to <200 cells/mm 3 or they developed an AIDS-defining condition. An interim analysis of the study showed that, when compared with participants who began ART with CD4 counts of 200 cells/mm 3 to 350 cells/mm 3 , patients who deferred therapy had a higher mortality rate (23 versus 6 deaths; hazard ratio = 4.0; 95% confidence interval : 1.6-9.8) and a higher rate of incident tuberculosis (TB) (HR = 2.0, 95% CI: 1.2-3.6). 15 Collectively, these studies support the Panel's recommendation that ART should be initiated in patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm 3 (AI). Patients with CD4 counts between 350 and 500 cells/mm 3 Data supporting initiation of ART in patients with CD4 counts ranging from 350 cells/mm 3 to 500 cells/mm 3 are derived from large observational studies and secondary analysis of randomized controlled trials. Analysis of the findings from the observational studies involved use of advanced statistical methods that minimize the bias and confounding that arise when observational data are used to address the question of when to start ART. However, unmeasured confounders for which adjustment was not possible may have influenced the analysis. The ART Cohort Collaboration (ART-CC) included 45,691 patients from 18 cohort studies conducted primarily in North America and Europe. Data from ART-CC showed that the rate of progression to AIDS and/or death was higher when therapy was deferred until a patient's CD4 count fell to the 251 cells/mm 3 to 350 cells/mm 3 range than when ART was initiated at the 351 cells/mm 3 to 450 cells/mm 3 range (risk ratio: 1.28, 95% CI: 1.04-1.57). 11 When analysis of the data was restricted to mortality alone, the difference between the 2 strategies was weaker and not statistically significant (risk ratio: 1.13, 95% CI: 0.80-1.60). In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of whether they had started therapy, the 6,278 patients who deferred therapy until their CD4 counts were 500 cells/mm 3 who experienced declines in CD4 count to <500 cells/mm 3 . 14 The study estimated that delaying initiation of ART until CD4 count <350 cells/mm 3 was associated with a greater risk of AIDS-defining illness or death than initating ART with CD4 count between 350 cells/mm 3 and 500 cells/mm 3 (HR: 1.38, 95% CI: 1.23-1.56). There was, however, no evidence of a difference in mortality (HR: 1.01, 95% CI: 0.84-1.22). A collaboration of cohort studies from Europe, Australia, and Canada (the CASCADE Collaboration) included 5,527 ART-naive patients with CD4 counts in the 350 to 499 cells/mm 3 range. Compared with patients who deferred therapy until their CD4 counts fell to 350 cells/mm 3 to continuous ART or to treatment interruption until CD4 count dropped to <250 cells/mm 3 . In the subgroup of 249 participants who were ART naive at enrollment (median CD4 count: 437 cells/mm 3 ), participants who deferred therapy until CD4 count dropped to <250 cells/mm 3 had a greater risk of serious AIDS-and non-AIDS-related events than those who initiated therapy immediately (7 vs. 2 events, HR: 4.6, 95% CI: 1.0-22.2). 18 Second, the HPTN 052 was a large multinational, multicontinental (Africa, Asia, South America, and North America) randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their uninfected sexual partners. 2 A secondary objective of the study was to determine whether ART reduces clinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4 counts between 350 cells/mm 3 and 550 cells/mm 3 and their HIV-uninfected partners. The infected participants were randomized to initiate ART immediately or to delay initiation until they had 2 consecutive CD4 counts <250 cells/mm 3 . At a median follow-up of 2.1 years, there were 77 primary events in the delayed arm versus 57 in the immediate therapy arm (adjusted HR: 1.39, 95% CI: 0.98-1.96). The most frequent event was tuberculosis (34 cases in the delayed therapy arm versus 17 in the immediate therapy arm); deaths were relatively rare (15 cases in the delayed therapy arm; 11 in the immediate therapy arm). 19 Collectively, these studies suggest that initiating ART in patients with CD4 counts between 350 cells/mm 3 and 500 cells/mm 3 reduces HIV-related disease progression; whether there is a corresponding reduction in mortality is unclear. This benefit supports the Panel's recommendation that ART should be initiated in patients with CD4 counts 350 cells/mm 3 to 500 cells/mm 3 (AII). Recent evidence demonstrating the public health benefit of earlier intervention further supports the strength of this recommendation (see Prevention of Sexual Transmission). Patients with CD4 counts >500 cells/mm 3 The NA-ACCORD study also observed patients who started ART with CD4 counts >500 cells/mm 3 or after their CD4 counts dropped below this threshold. The adjusted mortality rates were significantly higher in the 6,935 patients who deferred therapy until their CD4 counts fell to 500 cells/mm 3 (risk ratio: 1.94, 95% CI: 1.37-2.79). 16 Although large and generally representative of the HIV-infected patients in care in the United States, the study has several limitations, including the small number of deaths and the potential for unmeasured confounders that might have influenced outcomes independent of ART. In contrast, results from 2 cohort studies did not identify a benefit of earlier initiation of therapy in reducing AIDS progression or death. In an analysis of the ART-CC cohort, 11 the rate of progression to AIDS/death associated with deferral of therapy until CD4 count is in the 351 to 450 cells/mm 3 range was similar to the rate with initiation of therapy with CD4 count in the 451 to 550 cells/mm 3 range (HR: 0.99, 95% CI: 0.76-1.29). There was no significant difference in rate of death identified between the two groups (HR: 0.93, 95% CI: 0.60-1.44). This study also found that the proportion of patients with CD4 counts between 451 and 550 cells/mm 3 who would progress to AIDS or death before having a CD4 count <450 cells/mm 3 was low (1.6%; 95% CI: 1.1%-2.1%). In the CASCADE Collaboration, 17 among the 5,162 patients with CD4 counts in the 500 to 799 cells/mm 3 range, compared with patients who deferred therapy, those who started ART immediately did not experience a significant reduction in the composite outcome of progression to AIDS/death (HR: 1.10, 95% CI: 0.67-1.79) or death (HR: 1.02, 95% CI: 0.49-2.12). While it was not a clinical endpoint study, a recent clinical trial (Setpoint Study) randomized patients within 6 months of HIV seroconversion to receive either immediate ART for 36 weeks or deferred treatment. More than 57% of the study participants had CD4 count >500 cells/mm 3 . The deferred treatment group had a statistically higher risk of meeting ART eligibility criteria than the immediate treatment group. The study was halted early and illustrated that the time from diagnosis of early infection to the need for initiation of ART was shorter than anticipated in the deferred therapy group. 20 The expanded use of ART to treat individuals with CD4 counts >500 cells/mm 3 has also demonstrated public health benefits. In 2010, a large, publicly-funded clinic in San Francisco adapted a universal ART approach to initiate ART in all HIV-infected persons and evaluated temporal trends in viral suppression. In 534 patients entering the clinic with CD4 counts >500 cells/mm 3 , the 1-year incidence of viral suppression increased from 9% to 14% before universal ART to >52% after the approach was adopted. After adjustment, this policy was associated with a six-fold increase in the probability of viral suppression six months after clinic entry. 21 Because the risk of HIV transmission is associated with level of viremia, from a public health standpoint, this reduction in community viral load can potentially reduce new HIV infections at the community level. With a better understanding of the pathogenesis of HIV infection, the growing awareness that untreated HIV infection increases the risk of many non-AIDS-defining diseases (as discussed below), and the benefit of ART in reducing transmission of HIV, the Panel recommends initiation of ART in patients with CD4 counts >500 cells/mm 3 (BIII). When discussing initiation of ART at high CD4 cell counts (i.e., >500 cells/mm 3 ), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels are not conclusive, especially for patients with very high CD4 counts. Clinicians should also inform patients that viral suppression from effective ART can reduce the risk of sexual transmission to others. Patients should also be told that untreated HIV infection will eventually lead to immunological deterioration and increased risk of clinical disease and death. Therefore, if therapy is not initiated, continued monitoring and close follow-up is necessary. Further ongoing research (both randomized clinical trials and cohort studies) to assess the short-and longterm clinical and public health benefits and cost effectiveness of starting therapy at higher CD4 counts is needed. Findings from such research will provide the Panel with guidance to make future recommendations. # Effects of Viral Replication on HIV-Related Morbidity Since the mid-1990s, it has been known that measures of viral replication are predictive of HIV disease progression. In untreated HIV-infected individuals, time to clinical progression and mortality is fastest in those with higher viral loads. 22 This finding is confirmed across the wide spectrum of HIV-infected patient The EuroSIDA collaboration evaluated HIV-infected individuals with CD4 counts >350 cells/ mm 3 segregated by three viral load strata (10,000 copies/mL, respectively, than in individuals with viral loads 350 cells/mm 3 . 33 Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and those who are on ART but continue to be viremic. The harm of ongoing viral replication in patients on ART is compounded by the risk of emergence of drug-resistant virus. Therefore, all patients on ART should be carefully monitored and counseled on the importance of adherence to therapy. # Effects of ART on HIV-Related Morbidity HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIVassociated inflammation on these organs all most likely contribute to HIV-related morbidity and mortality. In general, the available data demonstrate that - Untreated HIV infection may have detrimental effects at all stages of infection, - Earlier treatment may prevent the damage associated with HIV replication during early stages of infection, - ART is beneficial even when initiated later in infection; however, later therapy may not repair damage associated with viral replication that occurred during early stages of infection, and - Sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIVassociated kidney disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below. # HIV-associated nephropathy (HIVAN) HIVAN is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to end-stage kidney disease. 34 HIVAN is almost exclusively seen in black patients and can occur at any CD4 count. Ongoing viral replication appears to be directly involved in renal injury, 35 and HIVAN is extremely uncommon in virologically suppressed patients. 36 ART in patients with HIVAN has been associated with both preserved renal function and prolonged survival. Therefore, ART should be started in all patients with HIVAN, regardless of CD4 count, at the earliest sign of renal dysfunction (AII). # Coinfection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) HIV infection is associated with more rapid progression of viral hepatitis-related liver disease, including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure. The pathogenesis of accelerated liver disease in HIV-infected patients has not been fully elucidated, but HIV-related immunodeficiency and a direct interaction between HIV and hepatic stellate and Kupffer cells have been implicated. In individuals co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), ART may attenuate liver disease progression by preserving or restoring immune function and reducing HIVrelated immune activation and inflammation. ARV drugs active against both HIV and HBV (such as tenofovir disoproxil fumarate , lamivudine , and emtricitabine ) also may prevent development of significant liver disease by directly suppressing HBV replication. 50,51 Although ARV drugs do not inhibit HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts are increased. 52 In one prospective cohort, after controlling for liver and HIV disease stage, HCV co-infected patients receiving ART were approximately 66% less likely to experience end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure than patients not receiving ART. 53 While some studies have shown that chronic viral hepatitis increases the risk of ART-induced liver injury, the majority of coinfected persons do not develop clinically significant liver injury and the rate of hepatotoxicity may be greater in persons with more advanced HIV disease. Collectively, these data suggest that earlier treatment of HIV infection in persons coinfected with HBV (and likely HCV) may reduce the risk of liver disease progression. ART is recommended for patients coinfected with HBV; the ART regimen should include drugs with activity against both HIV and HBV (AII) (also see Hepatitis B Virus/HIV Co-Infection). ART also is recommended for most patients coinfected with HCV (BII), including those with high CD4 counts and those with cirrhosis. This recommendation is based on findings from retrospective and prospective cohort studies that indicated that the receipt of ART is associated with slower progression of hepatic fibrosis and reduced risk of liver disease outcomes. 53, Combined treatment of both HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be considered for HIV/HCV-co-infected patients regardless of CD4 cell count, for patients infected with HCV genotype 1, some clinicians may choose to defer ART in HIV treatment-naive patients with CD4 counts >500 cells/mm 3 until HCV treatment that includes the HCV NS3/4A protease inhibitors (PIs) is completed (also see HIV/Hepatitis C Virus Co-Infection). # Cardiovascular disease (CVD) In HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for one-third of serious non-AIDS conditions and at least 10% of deaths. A number of studies have found that, over time, HIV-infected persons are at greater risk for CVD events than age-matched uninfected individuals. In a metaanalysis and review of studies of CVD risk in HIV-infected individuals, the relative risk of CVD events was greater in untreated HIV-infected patients than in HIV-uninfected individuals (1.61: 95% CI 1.43 to 1.81). 63 It is important to note, however, that the selected studies made comparisons to the general population, did not control for smoking or other potential confounders that could be lead to excessive CVD in the HIV-infected individuals, and also did not attempt to account for competing risks. 64 Thus, questions remain regarding the relative contributions of host-, treatment-, and disease-related factors to excess number of CVD events in those with HIV infection. Persons living with HIV infection have higher rates of established CVD risk factors, particularly smoking and dyslipidemia than HIV-uninfected individuals. In the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort study such factors, including age; male gender; obesity; smoking; family history of CVD; diabetes; and dyslipidemia, were each strongly and independently associated with risk of myocardial infarction (MI). 65 This study also found that the risk of CVD was greater with exposure to some ARV drugs, including certain PIs and abacavir, than with exposure to other ARV drugs. 65,66 In terms of preventing the progression to CVD events, it has not been determined whether delaying ART initiation is preferable to immediate treatment. In the meta-analysis mentioned above, the risk of CVD in HIV-infected individuals was 1.5 times higher in those being treated with ART than in those not being treated with ART. 63 These analyses were limited by concern that the treated individuals may have been infected for longer periods of time and had prior episodes of untreated HIV disease, as well as the fact that the untreated people were at higher risk for competing events, including death. Furthermore, there is evidence that untreated HIV infection also may be associated with an increased risk of CVD. In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided treatment interruption than in participants who received continuous ART. 67 In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (such as interleukin 6 ), immune dysfunction (e.g., T cell activation, T cell senescence), monocyte activation (e.g., IL-6, CD163), hypercoagulation (e.g., D-dimers) and, most importantly, endothelial dysfunction. 68,69 Low nadir and/or proximal on-therapy CD4 cell count has been linked to CVD (MI and/or stroke), suggesting that low CD4 count might result in increased risk of CVD. Collectively, the increased risk of cardiovascular events with treatment interruption, the effects of ART on markers of inflammation and endothelial dysfunction, and the association between CVD and CD4 cell depletion suggest that early control of HIV replication with ART can be used as a strategy to reduce risk of CVD, particularly if drugs with potential cardiovascular toxicity are avoided. However, at this time no study has demonstrated that initiation of ART prevents CVD. Therefore, a role for early ART in preventing CVD remains to be established. For HIV-infected individuals with a significant risk of CVD, as assessed by medical history and established estimated risk calculations, risk of CVD should be taken into consideration when selecting a specific ART regimen. # Malignancies Population-based analyses suggest that the incidence of both AIDS-defining malignancies (i.e., Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining malignancies is increased in chronic HIV infection. The incidence of several malignancies (particularly liver, anal, oropharyngeal, and lung cancers, Hodgkin lymphoma, and melanoma) is higher in HIV-infected subjects than in matched HIVuninfected controls, 73,74 and the burden of these non-AIDS defining malignancies has continued to increase in the United States between 1996 and 2007. 75 Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (500 cells/mm 3 , an increased risk of anal cancer based on time with CD4 counts 350 to 500 cells/mm 3 reduces the overall incidence of AIDS-defining malignancies and may also reduce the risk of non-AIDS-defining malignancies. The effect on incidence is most likely heterogeneous across various cancer types. # Neurological diseases Although HIV RNA can be detected in the cerebrospinal fluid (CSF) of most untreated patients, 88,89 these patients usually do not present with overt symptoms of HIV-associated neurological disease. 90 In some patients, CNS infection progresses to HIV encephalitis and can present as HIV-associated dementia (HAD). This progression is usually in the context of more advanced untreated systemic HIV infection when severe CNS opportunistic infections (OIs) also cause high morbidity and mortality. 94 Effective viral suppression resulting from ART has dramatically reduced the incidence of HAD and severe CNS OIs. Suppressive ART usually reduces CSF HIV RNA to undetectable levels. 98,99 Exceptional cases of symptomatic and asymptomatic CNS viral escape, in which HIV RNA is detectable in CSF despite viral suppression in plasma, have been documented. 100,101 This suggests that in some settings it may be useful to monitor CSF HIV RNA. Recent attention has turned to milder forms of CNS dysfunction, defined by impairment on formal neuropsychological testing. 93,102 It is unclear whether this impairment is a consequence of injury sustained before treatment initiation or whether neurologic damage can continue or develop despite systemically effective ART. 103 The association between cognitive impairment and low nadir CD4 counts supports the hypothesis for pretreatment injury and bolsters the argument that earlier initiation of ART may prevent subsequent brain dysfunction. 104,105 The peripheral nervous system (PNS) also is a target in HIV infection, and several types of neuropathies have been identified. 106 Most common is HIV-associated polyneuropathy, a chronic, predominantly sensory and sometimes painful neuropathy. The impact of early treatment on this and other forms of neuropathy is not as clearly defined as that on HAD. 107,108 Age and treatment-related immune reconstitution (also see HIV and the Older Patient) The CD4 cell response to ART is an important predictor of short-and long-term morbidity and mortality. Treatment initiation at an older age is consistently associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes. # T-cell activation and inflammation Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation. The degree of T-cell activation during untreated HIV disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and peripheral CD4 T-cell count. 116,117 ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation. 87, Persistent T-cell activation and/or T-cell dysfunction is particularly evident in patients who delay therapy until later stage disease (CD4 count <350 cells/mm 3 ). 119,121,122 The degree of persistent inflammation during treatment, as represented by the levels of IL-6, D-dimers, sCD14, and sCD163, may be independently associated with risk of morbidity and mortality. Collectively, these observations support earlier use of ART for at least two reasons. First, treatment decreases the level of inflammation, which may be associated with reduced short-term risk of AIDS-and non-AIDS-related morbidity and mortality. 123,126,127 Second, because the degree of residual inflammation and/or T-cell dysfunction with ART appears to be higher in patients with lower CD4 cell nadirs, 119,121,122 earlier treatment may result in less residual immunological perturbations on therapy and, hence, less risk for AIDS-and non-AIDS-related complications (CIII). # Antiretroviral Therapy for Prevention of HIV Transmission # Prevention of perinatal transmission Effective ART reduces transmission of HIV. The most dramatic and well-established example of this effect is the use of ART in pregnant women to prevent perinatal transmission of HIV. Effective suppression of HIV replication, as reflected in plasma HIV RNA, is a key determinant in reducing perinatal transmission. In the setting of ART initiation before 28 weeks' gestation and an HIV RNA level <50 copies/mL near delivery, use of combination ART during pregnancy has reduced the rate of perinatal transmission of HIV from approximately 20% to 30% to <0.5%. 128 Thus, use of combination ART drug regimens is recommended for all HIV-infected pregnant women (AI). Following delivery, in the absence of breastfeeding, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as those regarding ART for other non-pregnant individuals. For detailed recommendations, see the Perinatal Guidelines. 129 # Prevention of sexual transmission Recent study results provide strong support for the premise that treatment of the HIV-infected individual can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions. 130,131 Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viremia and risk of transmission of HIV: when plasma HIV RNA levels are lower, transmission events are less common. 1, HPTN 052 was a multicontinental trial that enrolled 1,763 HIV-serodiscordant couples in which the HIVinfected partner was ART naive with CD4 count 350 cells/mm 3 to 550 cells/mm 3 at enrollment. The study compared immediate ART with delayed therapy (i.e., not started until CD4 count <250 cells/mm 3 ) for the HIV-infected partner. 2 At study entry, 98% of the participants were in heterosexual monogamous relationships. All study participants were counseled on behavioral modification and condom use. Twentyeight linked HIV transmission events were identified during the study period, but only 1 event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04, 95% CI: 0.01-0.27, P <0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioral and biomedical prevention interventions studied to date, including condom use, male circumcision, vaginal microbicides, HIV vaccination, and pre-exposure prophylaxis. This study, as well as other observational studies and modeling analyses showing a decreased rate of HIV transmission in serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viremia in ART-adherent patients with no concomitant sexually transmitted diseases (STDs) substantially reduces the risk of transmission of HIV. 3, HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing, but the prevention benefits of effective ART presumably apply to these populations as well. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners. (The strength of this recommendation varies according to mode of sexual transmission: AI for heterosexual transmission and AIII for male-to-male and other modes of sexual transmission.) Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioral modification and that ART does not protect against other STDs (also see Preventing Secondary Transmission of HIV). # Concerns Regarding Earlier Initiation of Therapy Despite increasing evidence for the benefits associated with earlier initiation of ART, three areas of concern have served as a rationale for deferral of HIV therapy: ARV drug toxicities have an adverse affect on quality of life and adherence. Earlier initiation of ART extends exposure to ARV agents by several years. The D:A:D study found an increased incidence of CVD associated with cumulative exposure to some drugs in the nucleoside reverse transcriptase inhibitor and PI drug classes. 65,139 In the SMART study, when compared with interruption or deferral of therapy, continuous exposure to ART was associated with significantly greater loss of bone density. 67 There may be unknown complications related to cumulative use of ARV drugs for many decades. A list of known ARV-associated toxicities can be found in Adverse Effects of Antiretroviral Agents. ART frequently improves quality of life for symptomatic patients. However, some side effects of ART may impair quality of life for some patients, especially those who are asymptomatic at initiation of therapy. For example, efavirenz (EFV) can cause neurocognitive or psychiatric side effects and PIs have been associated with gastrointestinal (GI) side effects. As noted above, it has been suggested that some therapies increase the risk of CVD. Some patients may find that the inconvenience of taking medication every day outweighs the overall benefit of early ART and may choose to delay therapy. # ARV non-adherence may have an impact on virologic efficacy. At any CD4 count, adherence to therapy is essential to achieve viral suppression and prevent emergence of drug-resistance mutations. Several behavioral and social factors associated with poor adherence, such as untreated major psychiatric disorders, active substance abuse, unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits, have been identified. Clinicians should identify areas where additional intervention is needed to improve adherence both before and after initiation of therapy. Some strategies to improve adherence are discussed in Adherence to Antiretroviral Therapy. # Earlier development of resistance may reduce therapeutic options at a later time. Despite concerns about the development of resistance to ARV drugs, the evidence thus far indicates that resistance occurs more frequently in individuals who initiate therapy later in the course of infection than in those who initiate ART earlier. 140 Furthermore, recent data have indicated a slight increase in the prevalence of 2-drug class resistance from 2000 to 2005. 141 # Cost. In resource-rich countries, the cost of ART exceeds $10,000 per year (see Appendix B, Table 8). Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis. One study reported that the annual cost of care is 2.5 times higher for patients with CD4 counts 350 cells/mm 3 . 145 A large proportion of the health care expenditure in patients with advanced infection is from non-ARV drugs and hospitalization. There are no cost comparisons for patients starting ART with CD4 count 350 to 500 cells/mm 3 and patients starting ART with CD4 count >500 cells/mm 3 . # Conditions Favoring More Rapid Initiation of Therapy Several conditions increase the urgency for therapy, including: - Pregnancy (AI) (Clinicians should refer to the Perinatal Guidelines for more detailed recommendations on the management of HIV-infected pregnant women.) 129 - AIDS-defining conditions, including HIV-associated dementia (AI) - Acute opportunistic infections (OIs) (see discussion below) - Lower CD4 counts (e.g., <200 cells/mm 3 ) (AI) - HIVAN (AII) - Acute/recent infection (BII) (see more discussion in the Acute and Recent (Early) Infection section) - HIV/HBV coinfection (AII) - HIV/HCV coinfection (BII) - Rapidly declining CD4 counts (e.g., >100 cells/mm 3 decrease per year) (AIII) - Higher viral loads (e.g., >100,000 copies/mL) (BII) # Acute opportunistic infections In patients with opportunistic conditions for which no effective therapy exists (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy) but in whom ART may improve outcomes by improving immune responses, the benefits of ART outweigh any increased risk; therefore, treatment should be started as soon as possible (AIII). In the setting of some OIs for which immediate therapy may increase the risk of immune reconstitution inflammatory syndrome (IRIS) (e.g., cryptococcal meningitis or nontuberculous mycobacterial infections), a short delay before initiating ART may be warranted (CIII). 146,147 In the setting of other OIs, such as Pneumocystis jiroveci pneumonia (PCP), early initiation of ART is associated with increased survival; 8 therefore, therapy should not be delayed (AI). In patients who have active TB, initiating ART during treatment for TB confers a significant survival advantage; 148-152 therefore, ART should be initiated as recommended in Mycobacterium Tuberculosis Disease with HIV Coinfection. Clinicians should refer to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 153 for more detailed discussion on when to initiate ART in the setting of a specific OI. # Conditions Where Deferral of Therapy May be Considered Some patients and their clinicians may decide to defer therapy for a period of time on the basis of clinical or personal circumstances. Deferring therapy for the reasons discussed below may be reasonable in patients with high CD4 counts (e.g., >500 cells/mm 3 ) but deferring therapy in patients with much lower CD4 counts (e.g., <200 cells/mm 3 ) should be considered only in rare situations and should be undertaken with close clinical follow-up. Briefly delaying therapy to allow a patient more time to prepare for lifelong treatment may be considered. When there are significant barriers to adherence (also see Adherence to Antiretroviral Therapy) In patients with higher CD4 counts who are at risk of poor adherence, it may be prudent to defer treatment while addressing the barriers to adherence. However, in patients with conditions that require urgent initiation of ART (see above), therapy should be started while simultaneously addressing the barriers to adherence. Several methodologies exist to help providers assess adherence. When the most feasible measure of adherence is self-report, this assessment should be completed at each clinic visit using one of the available reliable and valid instruments. 154,155 If other objective measures (e.g., pharmacy refill data, pill count) are available, these methods should be used to assess adherence at each follow-up visit. Continuous assessment and counseling make it possible for the clinician to intervene early to address barriers to adherence occurring at any point during treatment (see Adherence to Antiretroviral Therapy). Presence of comorbidities that complicate or prohibit antiretroviral therapy Deferral of ART may be considered when either the treatment or manifestations of other medical conditions may complicate the treatment of HIV infection or vice versa. Examples include: - Surgery that may result in an extended interruption of ART - Treatment with medications that have clinically significant drug interactions with ART and for which alternative medications are not available In each of these circumstances, the assumption is that the situation is temporary and that ART will be initiated after the conflicting condition has resolved. Some less common situations exist in which ART may not be indicated at any time while CD4 counts remain high. In particular, such situations include that of patients with a poor prognosis due to a concomitant medical condition who would not be expected to gain survival or quality-of-life benefits from ART. Examples include patients with incurable non-HIV-related malignancies or end-stage liver disease who are not being considered for liver transplantation. The decision to forego ART in such patients may be easier to make in those with higher CD4 counts; they are likely asymptomatic for HIV, and their survival is unlikely to be prolonged by ART. However, it should be noted that ART may improve outcomes, including survival, in patients with some HIV-associated malignancies (e.g., lymphoma or Kaposi sarcoma) and in patients with liver disease due to chronic HBV or HCV. # Long-term nonprogressors and elite HIV controllers A small subset of HIV-infected individuals (~3% to 5%) maintain normal CD4 counts for many years in the absence of therapy (long-term nonprogressors), and an even smaller subset (~1%) maintain undetectable HIV RNA level for years ("elite" controllers). 159,160 Many long-term non-progressors have detectable viremia while some elite controllers progress immunologically and/or clinically despite having no detectable viremia. The evidence on how to manage these individuals is limited. Given the potential harm associated with uncontrolled HIV replication, many of the preceding arguments for early therapy most likely apply to nonprogressors who have consistently detectable viremia (i.e., HIV RNA >200 to 1000 copies/mL). Also given that ongoing HIV replication occurs in elite controllers, ART is also recommended for those rare controllers who exhibit evidence of disease progression, as defined by declining CD4 counts or development of HIVrelated complications. The Panel has no recommendations for the management of controllers with high CD4 counts, but the fact that these individuals have higher than normal levels of inflammation and immune activation provides at least some rationale for treatment. Clinical trials assessing the potential benefit of therapy in these individuals are ongoing. # The Need for Early Diagnosis of HIV Fundamental to the earlier initiation of ART recommended in these guidelines is the assumption that patients will be diagnosed early in the course of HIV infection and linked to medical care, thereby, making earlier initiation of therapy an option. Unfortunately, most cases of HIV infection are not diagnosed until patients are at much later stages of disease, although the mean CD4 count at initial presentation for care has increased in more recent years. 4 Despite the 2006 Centers for Disease Control and Prevention (CDC) recommendations for routine, opt-out HIV screening in the health care setting regardless of perceptions about a patient's risk of infection, 165 the median CD4 count of newly diagnosed patients remains below 350 cells/mm 3 . 4 The exception is pregnant women whose infection was diagnosed during prenatal care; they have a much higher median initial CD4 count. Compared with other groups, diagnosis of HIV infection is more often delayed in nonwhites, IDUs, and older patients, and a substantial proportion of these individuals develop AIDS-defining illnesses within 1 year of diagnosis. Thus, for the current treatment guidelines to have maximum impact, routine HIV screening per current CDC recommendations is essential. It is also critical to educate all newly diagnosed patients about HIV disease and link them to care for full evaluation, follow-up, and management. Once patients are in care, focused effort is required to retain them in the health care system so that both infected individuals and their sexual partners can accrue the full benefits of early diagnosis and treatment. # Conclusion The current recommendations are based on greater evidence supporting earlier initiation of ART than was advocated in previous guidelines. The strength of the recommendations varies according to the quality and availability of existing evidence supporting each recommendation. In addition to benefitting the health of the HIV-infected individual, the evidence that effective ART reduces sexual transmission to HIV provides further reason for earlier initiation of ART. The Panel will continue to monitor and assess the results of ongoing and planned randomized clinical trials and observational studies. Findings from these studies will provide the Panel with additional guidance to form future recommendations. # Data Used for Making Recommendations The Panel's recommendations are primarily based on clinical trial data published in peer-reviewed journals and data prepared by manufacturers for Food and Drug Administration (FDA) review. In select cases, the Panel considers data presented in abstract format at major scientific meetings. The first criterion for selection of evidence on which to base recommendations is published information from a randomized, prospective clinical trial with an adequate sample size that demonstrates that an ARV regimen has shown durable viral suppression and immunologic enhancement (as evidenced by increase in CD4 count). Few of these trials include clinical endpoints, such as development of AIDS-defining illness or death. Thus, assessment of regimen efficacy and potency is primarily based on surrogate marker endpoints (HIV RNA and CD4 responses). The Panel reviewed data from randomized clinical trials and other reports to arrive at "preferred," "alternative," or "other" ratings for each regimen noted in Tables 5a and 5b. "Preferred regimens" are those regimens studied in randomized controlled trials and shown to have optimal and durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. "Alternative regimens" are those regimens that are effective but have potential disadvantages when compared with preferred regimens. In certain situations and based on individual patient characteristics and needs, a regimen listed as an alternative may actually be the preferred regimen for a specific patient. Some regimens are classified as "other regimens" because of reduced virologic activity, lack of efficacy data from large clinical trials, or other factors (such as greater # Panel's Recommendations - The Panel recommends the following as preferred regimens (listed in order of FDA approval) for antiretroviral (ARV)-naive patients: - efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) (AI) - ritonavir-boosted atazanavir + tenofovir disoproxil fumarate/emtricitabine (ATV/r + TDF/FTC) (AI) - ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine (DRV/r + TDF/FTC) (AI) - raltegravir + tenofovir disoproxil fumarate/emtricitabine (RAL + TDF/FTC) (AI) - Panel-recommended alternative and other regimens can be found in Table 5a and Table 5b. - Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions. - Based on individual patient characteristics and needs, in some instances, an alternative or other regimen may be a preferred regimen for a specific patient. toxicities, pill burden, drug interaction potential, or need for additional testing before use) when compared with preferred or alternative regimens. # Rating of Recommendations # Considerations When Selecting a First Antiretroviral Regimen for Antiretroviral Therapy-Naive Patients # Factors to Consider When Selecting an Initial Regimen Regimen selection should be individualized on the basis of several factors, including the following: - the patient's comorbid conditions (e.g., cardiovascular disease , chemical dependency, liver or renal disease, psychiatric illnesses, or tuberculosis ); - potential adverse drug effects; - known or potential drug interactions with other medications; - pregnancy or pregnancy potential; - results of genotypic drug-resistance testing; - pre-treatment HIV viral load; - gender and pretreatment CD4 count if considering nevirapine (NVP); - HLA-B5701 testing if considering abacavir (ABC); - coreceptor tropism assay if considering MVC; - patient preferences (when possible) and adherence potential; and - convenience (e.g., factors such as pill burden, dosing frequency, availability of fixed dose combination products, and food and fluid requirements). Potential advantages and disadvantages of the components recommended as initial therapy for ARV-naive patients are listed in Table 6 to guide prescribers in choosing the optimal regimen for an individual patient. Table 7 provides a list of agents or components not recommended for initial treatment. Appendix B, Tables 1-6 list characteristics of individual ARV agents, such as formulations, dosing recommendations, pharmacokinetics (PKs), and common adverse effects. Appendix B, Table 7 provides clinicians with ARV dosing recommendations for patients who have renal or hepatic insufficiency. # Choosing Between Preferred Initial Regimens Each of the four preferred initial regimens listed in Table 5a has shown potent virologic efficacy as measured by the proportion of subjects achieving and maintaining viral suppression in comparative clinical trials. Given the comparable efficacy of the preferred regimens, selection of an optimal regimen for a specific patient will depend on other factors, including characteristics of the regimen (e.g., adverse event profile, barrier to resistance, dosing frequency, pill burden, food restrictions, the availability of fixed-dose combination formulations, the potential for drug-drug interactions), the patient's pre-treatment resistance testing results, and whether the patient is a woman who may become pregnant. A complete description of the advantages and disadvantages of the preferred and alternative options for therapy are listed in Table 6. Currently, all of the preferred initial regimens include the NRTI combination of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), which is available as a fixed-dose combination tablet. In two comparative clinical trials, this NRTI combination was more effective than the alternative NRTI pair, abacavir/lamivudine (ABC/3TC), 8,9 but in a third study, the NRTI combinations showed comparable efficacy. 10 TDF may cause kidney injury in some patients, particularly in those who have pre-existing renal disease or are receiving concomitant nephrotoxic drugs. In addition, TDF induces a greater decline in bone mineral density than other ARV drugs. 11 Of the four preferred regimens, efavirenz (EFV) in combination with TDF/FTC has been studied in the greatest number of clinical trials. 6, This regimen is available in a single tablet, once-daily formulation, and is generally well tolerated. Disadvantages of the regimen include central nervous system (CNS) side effects that resolve over time in some (but not all) patients, a higher incidence of rash (including severe skin reactions) than with other preferred regimens, and dyslipidemia. Owing to concerns related to potential teratogenicity emerging from animal studies and some human case reports, ARV regimens that do not include EFV should be strongly considered in women who wish to conceive or are sexually active and not using effective contraception, assuming these alternative regimens are not thought to compromise the woman's health. Initial treatment with ritonavir (RTV) boosted PI-containing regimens is unique from the resistance perspective, as virologic failure rarely selects for PI-resistance and NRTI resistance is uncommon. As a result, some clinicians consider these the initial regimens of choice for patients at higher risk for virologic failure due to suboptimal adherence, inconsistent follow-up, or other factors. A disadvantage of RTV-boosted PI-based regimens is the large number of drug-drug interactions, in particular with medications metabolized through the cytochrome p450 pathway. As a result, RTV-boosted PI-based regimens may be difficult to use in patients who are taking many other medications. RTV-boosted atazanavir (ATV/r) is as effective as EFV, but causes less rash and has a more favorable lipid profile. 13 ATV induces reversible indirect hyperbilirubinemia, which may result in visible jaundice or scleral icterus in a small proportion of patients; ATV has also been associated with nephrolithiasis and cholelithiasis. Optimal absorption of ATV depends on presence of food and low gastric pH; if acid-reducing agents are needed, co-administration should be done according to the dosing guidelines shown in Table 15a. RTVboosted darunavir (DRV/r) shares many of the characteristics of boosted ATV, but does not cause hyperbilirubinemia and can be given with acid-reducing agents. There are no fully-powered clinical trials that compare the virologic efficacy of DRV/r and ATV/r. One small study found that these boosted-PIs had comparable effects on lipids. 16 Both ATV/r and DRV/r can be given once daily. Raltegravir (RAL) plus TDF/FTC demonstrated comparable antiviral efficacy to EFV/TDF/FTC, with fewer drug-related adverse effects and a more favorable lipid profile. 6 RAL has fewer drug-drug interactions than both boosted-PI and EFV-based regimens, and is therefore easier to add to a patient's complex medication regimen. Rare but severe side effects (e.g., rhabdomyolysis, severe skin, systemic hypersensitivity reactions) have been reported with RAL. RAL plus TDF/FTC is the only preferred regimen that requires twice-daily dosing. There are clinical scenarios in which options for initial therapy should be chosen from the list of alternative and other regimens rather than from the preferred list. Tables 5a and 5b provide a list of alternative and other regimens that may be prescribed for select patients. Table 6 lists the advantages and disadvantages of the individual ARV components of the regimens. Acute symptomatic HIV infection may be diagnosed while an individual is receiving TDF/FTC for preexposure prophylaxis (PrEP) (see Acute and Recent HIV Infection). As with all newly diagnosed cases of HIV-infection, genotype testing should be performed. In most cases, HIV infection in this setting is secondary to suboptimal adherence 17 to the prescribed daily TDF/FTC regimen, hence resistance in the setting of PrEP failure in clinical trials has been uncommon. Pending genotype testing results, a regimen consisting of a boosted PI (ATV/r or DRV/r) plus TDF/FTC (AIII) can be initiated. ARV drugs should be modified as needed based on the results of baseline resistance testing. # Table 5a. Preferred and Alternative Antiretroviral Regimens for Antiretroviral Therapy-Naive Patients A combination antiretroviral therapy (ART) regimen generally consists of two NRTIs plus one active drug from one of the following classes: NNRTI, PI (generally boosted with RTV), INSTI, or a CCR5 antagonist. Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, and the patient's resistance testing results and comorbid conditions. Refer to Table 6 for a list of advantages and disadvantages of the individual ARV agents listed below and to Appendix B, Tables 1-6 for dosing information. The regimens in each category are listed in alphabetical order. For more detailed recommendations on ARV use in HIV-infected pregnant women, refer to the latest perinatal guidelines available at . # Preferred Regimens Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use. # Comments - EFV is teratogenic in non-human primates. A regimen that does not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception. - TDF should be used with caution in patients with renal insufficiency. - ATV/r should not be used in patients who require >20 mg omeprazole equivalent per day. Refer to Table 15a for dosing recommendations regarding interactions between ATV/r and acid-lowering agents. # Alternative Regimens Regimens that are effective and tolerable, but have potential disadvantages when compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. # Comments - RPV is not recommended in patients with pretreatment HIV RNA >100,000 copies/mL. - Higher rate of virologic failures reported in patients with pre-ART CD4 count <200 cells/mm 3 who are treated with RPV + 2NRTI - Use of PPIs with RPV is contraindicated. - ABC should not be used in patients who test positive for HLA-B5701. - Use ABC with caution in patients with known high risk of CVD or with pretreatment HIV RNA >100,000 copies/mL (see text). - Once-daily LPV/r is not recommended for use in pregnant women. - EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl <70 ml/min, and should be changed to an alternative regimen if the patient's CrCl falls below 50 mL/min - COBI is a potent CYP 3A inhibitor. It can increase the concentration of other drugs metabolized by this pathway. Refer to Tables 15d and 16c for drug interaction information for concomitantly administered drugs. - EVG/COBI/TDF/FTC should not be used with other ARV drugs or with nephrotoxic drugs. a 3TC may substitute for FTC or vice versa. The following combinations in the recommended list above are available as coformulated fixeddose combinations: ABC/3TC, EFV/TDF/FTC, EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, TDF/FTC, and ZDV/3TC. NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs involve the prevalence of NNRTI-resistant viral strains in ART-naive patients and the NNRTIs' low genetic barrier for the development of resistance. Resistance testing should be performed to guide therapy selection for ART-naive patients (see Drug-Resistance Testing). High level resistance to all NNRTIs (except ETR) may occur with a single mutation; cross resistance is common. ETR has in vitro activity against some viruses with mutations that confer resistance to DLV, EFV, and NVP. 22 In RPV-treated patients, the presence of RPV-resistant mutations at virologic failure is common and may confer cross resistance to other NNRTIs including ETR. 14,23 Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens listed in Table 5a. # Key to Abbreviations # Comments - NVP should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C). b - NVP should not be used in women with pre-ART CD4 count >250 cells/mm 3 or in men with pre-ART CD4 count >400 cells/mm 3 . - Use NVP and ABC together with caution; both can cause HSRs within the first few weeks after initiation of therapy. - ZDV can cause bone marrow suppression, myopathy, lipoatrophy, and rarely lactic acidosis with hepatic steatosis. - ATV/r is generally preferred over unboosted ATV. - Perform tropism testing before initiation of therapy with MVC. MVC may be considered in patients who have only CCR5-tropic virus. - SQV/r was associated with PR and QT prolongation in a healthy volunteer study. Baseline ECG is recommended before initiation of SQV/r. - SQV/r is not recommended in patients with: - pretreatment QT interval >450 msec - refractory hypokalemia or hypomagnesemia - concomitant therapy with other drugs that prolong QT interval - complete AV block without implanted pacemaker, - risk of complete AV block Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens listed in Table 5a. a 3TC may be substituted with FTC or vice versa. b Refer to Appendix B, Table 7 for the criteria for Child-Pugh classification. The Panel recommends that EFV, RPV, or NVP may be used as part of an initial regimen. EFV is preferred on the basis of its potency (as discussed below). RPV may be used as an alternative NNRTI option in patients with pre-treatment HIV RNA < 100,000 copies/mL; NVP may be another NNRTI option in women with pretreatment CD4 counts ≤250 cells/mm 3 or in men with pretreatment CD4 counts ≤400 cells/mm 3 (see discussions below). # Key to Compared with the other NNRTIs, DLV has the highest dosing frequency (three times daily), the least supportive clinical trial data, and the least antiviral activity. Therefore, DLV is not recommended as part of an initial regimen (BIII). ETR at a dose of 200 mg twice daily is approved for use in treatment-experienced patients with virologic failure. 24 In a small, randomized, double-blinded, placebo-controlled trial, ETR 400 mg once daily was compared with EFV 600 mg once daily (both in combination with two NRTIs) in treatment-naive subjects (79 and 78 subjects in the ETR and EFV arms, respectively). Virologic responses were comparable at 48 weeks. 25 However, pending results from larger clinical trials, the panel cannot recommend ETR as initial therapy at this time. Following is a more detailed discussion of individual NNRTI-based regimens for initial therapy. # Preferred Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Efavirenz (EFV). Large randomized, controlled trials and cohort studies of ART-naive patients have demonstrated potent viral suppression in patients treated with EFV plus two NRTIs; a substantial proportion of these patients had HIV RNA <50 copies/mL at up to 7 years of follow-up. 1,2,26 Studies that compared EFV-based regimens with other regimens demonstrated that the combination of EFV with two NRTIs was superior or non-inferior virologically to ritonavir-boosted lopinavir (LPV/r), 4 NVP-, 27,28 RPV-, 14 ATV-, 5 elvitegravir (EVG)-, 15 RAL-, 6 and MVC-based 7 regimens. EFV can cause CNS adverse effects, such as abnormal dreams, dizziness, headache, and depression, which usually resolve over a few weeks in some (but not all) patients. In animal reproductive studies, EFV at drug exposure levels similar to those achieved in humans caused major congenital anomalies in the CNS of nonhuman primates. 29 In humans, several cases of neural tube defects in newborns of mothers exposed to EFV during the first trimester of pregnancy have been reported. 30,31 Although emerging information about the use of EFV in pregnancy is reassuring, 32,33 data remain insufficient to rule out a potential 2 to 3 fold increase in neural tube birth defects with first-trimester exposure to EFV. Therefore, alternative ARV regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health. Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (before pregnancy is usually recognized), and because unnecessary ARV changes during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression. 34 In # Alternative Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Rilpivirine (RPV). In two large, multinational, randomized, double-blind clinical trials, RPV (25 mg once daily) was compared with EFV (600 mg once daily), each agent in combination with two NRTIs. In a pooled analysis of the 2 studies, 76% of RPV-treated subjects and 77% of EFV-treated subjects had plasma HIV RNA 100,000 copies/mL), virologic failure occurred more frequently in those randomized to receive RPV. Moreover, more subjects with pre-treatment CD4 count <200 cells/mm 3 , regardless of baseline HIV RNA, experienced virologic failure than those with pre-ART CD4 count ≥200 cells/mm 3 . Subjects with virologic failure on RPV were also more likely to have genotypic resistance to other NNRTIs (i.e., EFV, ETR, and NVP) and to have TDF-and/or 3TC/FTC-associated genotypic resistance. Drug discontinuations because of adverse effects were more common with EFV than with RPV. The frequency of depressive disorders and discontinuations due to depressive disorders were similar between the two arms, whereas dizziness, abnormal dreams, rash, and hyperlipidemia were more frequent with EFV than with RPV. At higher than the approved dose of 25 mg, RPV (75 mg once daily or 300 mg once daily) may prolong the QTc interval. As a result, RPV should be used cautiously when co-administered with a drug that has a known risk of torsades de pointes. Although RPV has shown no teratogenicity in animal studies, data on PKs and safety of RPV in pregnant HIV-infected women are insufficient at this time. RPV is formulated both as an individual tablet and in a fixed-dose combination tablet of RPV/TDF/FTC. The latter allows for one-tablet once-daily dosing. RPV must be administered with a meal. Because the oral bioavailability of RPV may be significantly reduced in the presence of acid-lowering agents, RPV should be used with caution with antacids and H2-receptor antagonists. RPV use with proton pump inhibitors (PPIs) is contraindicated. Table 15b provides guidance on the timing of RPV administration when the agent is used with antacids or H2 receptor antagonists. In patients with high pretreatment viral load (HIV RNA >100,000 copies/mL) or low CD4 cell count (100,000 copies/mL. # Other Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Nevirapine (NVP). The 2NN trial compared NVP with EFV, both given d4T and 3TC, in ART-naive patients. In this trial, 65% of participants in the twice-daily NVP arm and 70% in the EFV arm achieved virologic suppression (defined as HIV RNA <50 copies/mL) at 48 weeks. This difference did not reach criteria necessary to demonstrate non-inferiority of NVP. 27 Two deaths were attributed to NVP use: one from fulminant hepatitis and one from staphylococcal sepsis as a complication of Stevens-Johnson syndrome (SJS). In the ARTEN trial, ART-naive participants were randomized to NVP 200 mg twice daily or 400 mg once daily, or to RTV-boosted ATV (ATV/r), all in combination with TDF/FTC. The proportion of participants in each arm who achieved the primary endpoint of having at least two consecutive plasma HIV RNA levels 250 cells/mm 3 at the time of NVP initiation than in women with CD4 counts ≤250 cells/mm 3 at NVP initiation (11.0% vs. 0.9%, respectively). The risk was also greater in men with pretreatment CD4 counts >400 cells/mm 3 than in with men with pre-treatment CD4 counts ≤400 cells/mm 3 (6.3% vs. 1.2%, respectively). Most of these patients had no identifiable underlying hepatic abnormalities. In some cases, hepatic injuries continued to progress despite discontinuation of NVP. 37,38 In contrast, other studies have not shown an association between baseline CD4 counts and severe NVP hepatotoxicity. 39,40 Symptomatic hepatic events have not been reported in mothers or infants given single-dose NVP to prevent perinatal HIV infection. On the basis of the safety and efficacy data discussed above, the Panel classifies NVP-based combinations in the Other NNRTI-Based Regimens category as initial therapy in women with pretreatment CD4 counts ≤250 cells/mm 3 or in men with pretreatment CD4 counts ≤400 cells/mm 3 (C). Patients whose CD4 count increases to levels above these thresholds as a result of NVP-containing therapy can safely continue therapy without an increased risk of adverse hepatic events. 41 NVP should be initiated at a dosage of 200 mg once daily for a 14-day lead-in period before being increased to the maintenance dosage of 400 mg per day (as an extended-release 400 mg tablet once daily or 200 mg immediate-release tablet twice daily). The lead-in period has been observed to decrease the incidence of rash. Some experts recommend monitoring serum transaminases at baseline, at 2 weeks, again 2 weeks after dose escalation, and then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each patient visit. # Protease Inhibitor-Based Regimens # Summary: Protease Inhibitor-Based Regimens PI-based regimens (particularly with RTV-boosting) have demonstrated virologic potency and durability in treatment-naive subjects. In contrast to NNRTI-and INSTI-based regimens, few or no PI mutations are detected in patients who developed virologic failure on their first PI-based regimen. 35,42 Each PI has its own virologic potency, adverse effect profile, and pharmacokinetic (PK) properties. The characteristics, advantages, and disadvantages of each PI are listed in Table 6 and Appendix B, Table 3. When selecting a boosted PI-based regimen for an ART-naive patient, clinicians should consider factors such as dosing frequency, food requirements, pill burden, daily RTV dose, drug interaction potential, toxicity profile of the individual PI, and baseline lipid profile and pregnancy status of the patient. See the Perinatal Guidelines for specific recommendations in pregnancy. 34 A number of metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which also depends on the dose of RTV used as a PK boosting agent. Two large observational cohort studies suggest that LPV/r, indinavir (IDV), fosamprenavir (FPV), or RTV-boosted FPV (FPV/r) may be associated with increased rates of myocardial infarction (MI) or stroke. 43,44 This association was not seen with ATV. 45 These studies had too few patients receiving DRV/r to be included in the analysis. RTV-boosted saquinavir (SQV/r) can prolong the PR and QT intervals on electrocardiogram (ECG). The degree of QT prolongation seen with SQV/r is greater than that seen with some other boosted PIs. Therefore, SQV/r should be used with caution in patients with underlying heart conditions such as heart rate or rhythm problems, or who use concomitant drugs that may increase the risk of developing these ECG abnormalities. 46 SQV/r is rarely used for initial therapy for this reason, and because, when compared with other PI-based regimens, the regimen has a higher pill burden and no clear advantages. The potent inhibitory effect of RTV on the cytochrome P (CYP) 450 3A isoenzyme allows the addition of low-dose RTV to other PIs as a PK enhancer to increase drug exposure and prolong the plasma half-life of the active PI. The drawbacks associated with this strategy are the potential for increased risk of hyperlipidemia and a greater potential of drug-drug interactions from the addition of RTV. RTV boosting is recommended in all PI-based regimens whenever possible; when boosting is not possible and a PI-based regimen is desired, only ATV should be used. In patients without pre-existing PI resistance, once-daily boosted PI regimens that use only 100 mg of RTV per day are preferred. These regimens tend to cause fewer gastrointestinal (GI) side effects and less metabolic toxicity than regimens that use RTV at a dose of 200 mg per day. The Panel uses the following criteria to distinguish between preferred, alternative, and other PIs for use in ART-naive patients: - Demonstrated superior or non-inferior virologic efficacy when compared with at least one other PI-based regimen, based on, at least, published 48-week data - RTV-boosted PI using no more than 100 mg of RTV per day - Once-daily dosing - Low pill count - Good tolerability. Using these criteria, the Panel recommends once-daily ATV/r and DRV/r as preferred PIs. # Preferred Protease Inhibitor-Based Regimens # In alphabetical order, by active PI component Ritonavir-Boosted Atazanavir (ATV/r). In a clinical trial, ATV/r enhanced ATV concentrations and improved virologic activity more than unboosted ATV. 47 The CASTLE study compared once-daily ATV/r with twice-daily LPV/r, each in combination with TDF/FTC, in 883 ARV-naive participants. In this openlabel, noninferiority study, the two regimens showed similar virologic and CD4 responses at 48 weeks 48 and at 96 weeks. 49 More hyperbilirubinemia and less GI toxicity were seen in the ATV/r arm than in the LPV/r arm. This study supports the designation of ATV/r + TDF/FTC as a preferred PI-based regimen (AI). The main adverse effect associated with ATV/r is indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations. Nephrolithiasis and cholelithiasis 53 also have been reported in patients who received ATV. ATV/r requires acidic gastric pH for dissolution. Thus, concomitant use of drugs that raise gastric pH (e.g., antacids, H2 antagonists, and particularly PPIs), may impair absorption of ATV. Table 15a provides recommendations for use of ATV/r with these agents. # Ritonavir-Boosted Darunavir (DRV/r). The ARTEMIS study compared DRV/r (800/100 mg once daily) with LPV/r (once or twice daily), both in combination with TDF/FTC, in a randomized, open-label, noninferiority trial. The study enrolled 689 ART-naive participants. DRV/r was non-inferior to LPV/r at 48 weeks 54 , and superior at week 192. 55 In participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm. Grades 2 to 4 adverse events, primarily diarrhea, were seen more frequently in LPV/r recipients than in DRV/r recipients. At virologic failure, no major PI mutations were detected in participants randomized to either arm. 42,55 Based on these data, the Panel recommends DRV/r + TDF/FTC as a preferred PI-based regimen (AI). No randomized controlled trial to evaluate the efficacy of DRV/r with other 2-NRTI combinations exists. A small retrospective study suggested that DRV/r plus ABC/3TC may be effective in treatment-naive patients for up to 48 weeks. 56 Based on this preliminary information, the Panel recommends this combination as an alternative PI-based regimen (BIII). # Alternative Protease Inhibitor-Based Regimens # In alphabetical order, by active PI component Ritonavir-Boosted Fosamprenavir (FPV/r, once or twice daily). FPV/r is an alternative PI. The KLEAN trial compared twice-daily FPV/r with LPV/r, each in combination with ABC and 3TC, in ART-naive patients. At Weeks 48 and 144, similar percentages of subjects achieved viral loads <400 copies/mL. 57,58 The frequency and severity of adverse events did not differ between the regimens. Twice-daily FPV/r was noninferior to twice-daily LPV/r. Based on the preference for once-daily regimens with no more than 100 mg/day of RTV, twice-daily FPV is considered an alternative choice. A comparative trial of once-daily FPV/r (1400/100 mg) and once-daily ATV/r, both in combination with TDF/FTC, was conducted in 106 ARV-naive participants. 59 The regimens showed similar virologic and CD4 benefits. The study's small sample size precludes the assessment of superior or non-inferior virologic efficacy required for a preferred PI. Collectively, FPV/r regimens, with once-or twice-daily dosing, are recommended as alternative PI-based regimens. # Ritonavir-Boosted Lopinavir (LPV/r, coformulated). LPV/r is the only available coformulated boosted PI. It can be given once or twice daily. However, because LPV/r must be boosted with 200 mg/day of RTV and is associated with higher rates of GI side effects and hyperlipidemia than other PIs boosted with 100 mg of RTV, LPV/r is recommended as an alternative PI for ART-naive patients. A 7-year follow-up study of LPV/r and 2 NRTIs showed sustained virologic suppression in patients who were maintained on the originally assigned regimen. 60 Results of clinical trials that compared LPV/r with ATV/r, DRV/r, FPV/r, or SQV/r are discussed in the related sections of this document. The ACTG 5142 study showed that, when compared with EFV plus 2 NRTIs, the regimen of twice-daily LPV/r plus 2 NRTIs had decreased virologic efficacy. However, the CD4 response was greater with LPV/r, and there was less drug resistance associated with virologic failure. 4 In addition to diarrhea, major adverse effects of LPV/r include insulin resistance and hyperlipidemia, especially hypertriglyceridemia; these required pharmacologic management in some patients. In the D:A:D and French observational cohorts, cumulative use of LPV/r was associated with a slightly increased risk of MI. 43,44 Once-daily LPV/r should not be used in patients who have HIV mutations associated with PI resistance, because higher LPV trough levels may be required to suppress resistant virus. Once-daily dosing should not be used in pregnant women, especially during the third trimester, when LPV levels are expected to decline. For more detailed information regarding ART drug choices and related issues in pregnancy, see the Perinatal Guidelines. 34 # Other Protease Inhibitor-Based Regimens Atazanavir (ATV). In a clinical trial, ATV concentrations were enhanced with the addition of RTV 100 mg when compared to once-daily unboosted ATV, as a result, better virologic activity was seen with ATV/r. 47 Nevertheless, unboosted ATV may be selected for some patients because it has fewer GI adverse effects including less hyperbilirubinemia and less impact on lipid profiles than ATV/r. Three studies compared unboosted ATV-based combination regimens with either NFV-or EFV-based regimens. These studies established that ATV 400 mg once daily and both comparator treatments had similar virologic efficacy in ARV-naive patients after 48 weeks of therapy. 5,47,61,62 In a multinational randomized trial comparing three initial treatment strategies, unboosted ATV + ddI + FTC was inferior to both EFV + TDF/FTC and EFV + ZDV/3TC. 63 Unboosted ATV may be used as initial therapy when a once-daily regimen without RTV is desired and in patients with underlying risk factors that indicate that hyperlipidemia may be particularly undesirable (C). However, in these situations, other NNRTI-and INSTI-based regimens should generally be used instead of unboosted ATV. When ATV is co-administered with TDF or EFV, it should be boosted with RTV because ATV concentrations are reduced in the presence of these drugs. ATV requires acidic gastric pH for dissolution. Thus, concomitant use of drugs that raise gastric pH (such as antacids, H2 antagonists, and PPIs) may significantly impair ATV absorption. PPIs should not be used in patients who are taking unboosted ATV. H2 antagonists and antacids should be used with caution and with careful dose separation (see Tables 14 and 15a). Ritonavir-Boosted Saquinavir (SQV/r). The GEMINI study compared SQV/r (1000/100 mg twice daily) and LPV/r, both given twice daily, in combination with TDF/FTC given once daily, in 337 ART-naive participants who were monitored over 48 weeks. Levels of viral suppression and increases in CD4 counts were similar in both arms of the study. 64 Triglyceride (TG) levels were higher in the LPV/r arm than in the SQV/r arm. The SQV/r regimen has a higher pill burden and requires twice-daily dosing and 200 mg of RTV. In a healthy volunteer study, SQV/r use at the recommended dose was associated with increases in both QT and PR intervals. The degree of QT prolongation with SQV/r was greater than that seen with some other boosted PIs used at their recommended doses. Rare cases of torsades de pointes and complete heart block have been reported in post-marketing surveillance. Based on these findings, an ECG before initiation of SQV/r is recommended. SQV/r is not recommended for patients with any of the following conditions: documented congenital or acquired QT prolongation, pretreatment QT interval of >450 milliseconds (msec), refractory hypokalemia or hypomagnesemia, complete atrioventricular (AV) block without implanted pacemakers, at risk of complete AV block, or receiving other drugs that prolong QT interval. 46 On the basis of these restrictions, and because several other preferred or alternative PI options are available, the Panel recommends that, although SQV/r may be acceptable, it should be used with caution in select ARV-naive patients (C). # Integrase Strand Transfer Inhibitor (INSTI)-Based Regimens # Preferred Integrase Strand Transfer Inhibitor-Based Regimen Raltegravir (RAL). RAL is an INSTI that is approved for use in ART-naive patients on the basis of results of STARTMRK, a Phase III study that compared RAL (400 mg twice daily) and EFV (600 mg once daily), each in combination with TDF/FTC, in ART-naive subjects. This multinational, double-blind, placebocontrolled study enrolled 563 subjects with plasma viral loads >5,000 copies/mL. At Week 48, similar percentages of subjects in both groups achieved viral loads <50 copies/mL (86.1% and 81.9% for RAL and EFV, respectively, P <0.001 for non-inferiority). CD4 counts rose by 189 cells/mm 3 in the RAL group and 163 cells/mm 3 in the EFV group. The frequency of serious adverse events was similar in both groups. 6 At 156 weeks, virologic and immunologic responses remained similar in both groups with no new safety concerns identified. 65 On the basis of these data, the Panel recommends RAL + TDF/FTC as a preferred regimen in ART-naive patients (AI). In a small single-arm pilot study of 35 subjects who received a regimen of RAL + ABC/3TC, 91% of subjects had viral loads <50 copies/mL at Week 48. 66 On the basis of these preliminary data, RAL + ABC/3TC may be used as an alternative INSTI-based regimen (BIII). RAL use has been associated with creatine kinase elevations. Myositis and rhabdomyolysis have been reported. Rare cases of severe skin reactions and systemic hypersensitivity reactions (HSRs) in patients who received RAL have been reported during post-marketing surveillance. 67 Comparisons of RAL-based regimens and boosted PI-based regimens in ART-naive subjects have not been reported. RAL must be administered twice daily-a potential disadvantage when comparing RAL-based treatment with some other regimens. RAL, like EFV, has a lower genetic barrier to resistance than RTVboosted PIs. In the STARTMRK comparative trial, resistance mutations were observed with approximately the same frequency in RAL-and EFV-treated participants. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents F-12 # Alternative Integrase Strand Transfer Inhibitor-Based Regimen Elvitegravir (EVG). EVG is an INSTI available as a fixed-dose combination product with cobicistat (COBI), TDF, and FTC (EVG/COBI/TDF/FTC), and is approved as a single-tablet, once-daily regimen for ART-naive patients. EVG is metabolized primarily by CYP3A enzymes; as a result, CYP3A inducers or inhibitors may alter EVG concentrations. COBI is a specific, potent CYP3A inhibitor with no activity against HIV. It acts as a PK enhancer of EVG, which allows for once daily dosing of the combination product. 68 EVG/COBI/TDF/FTC is not recommended for patients with pre-treatment estimated creatinine clearance less than 70 mL/min. 69 For more information on PK enhancement with RTV or COBI, see Drug-Drug Interactions-Pharmacokinetic Enhancing. In two Phase 3 randomized clinical studies, the safety and efficacy of this combination regimen in ART-naive HIV-infected subjects was compared to that of two currently recommended first-line regimens. Coformulated EVG/COBI/TDF/FTC was non-inferior to co-formulated EFV/TDF/FTC: 87.6% of the EVG/COBI/TDF/FTC-treated subjects versus 84.1% of the EFV/TDF/FTC-treated subjects achieved virologic suppression <50 copies/mL at 48 weeks (difference 3.5%, 95% CI -1.6, 8.8). 15 Similarly, EVG/COBI/TDF/FTC was non-inferior to ATV/r plus co-formulated TDF/FTC: 89.5% versus 86.8% of subjects achieved virologic suppression <50 copies/mL at 48 weeks, respectively (difference 3%, 95% CI -1.9, 7.8). 70 Rates of virologic failure were low and comparable across study arms, with non-inferior results for treatment arms maintained at 96 weeks. 71,72 At virologic failure, INSTI-associated mutations were detected in some EVG/COBI/TDF/FTC-treated patients who failed therapy. 15,70 These mutations conferred varying degrees of cross-resistance to RAL. The most common adverse events reported with EVG/COBI/TDF/FTC were diarrhea, nausea, and headache. COBI inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and a reduction in estimated creatinine clearance (CrCl) without reducing glomerular function. 73 Although the overall incidence of study drug discontinuation due to adverse events was lower in the EVG/COBI/TDF/FTC arms (3.7%) than in either comparator arm (5.1% each), more subjects in the EVG/COBI/TDF/FTC arms (8 subjects) discontinued study drugs because of renal adverse events than in the comparator arms (one in the ATV/r + TDF/FTC arm). Four of the eight subjects in the EVG/COBI/TDF/FTC arms who discontinued study drug had evidence of proximal tubular dysfunction; after drug discontinuation, abnormal lab values in these four patients improved but did not completely resolve. CrCl, urine glucose and urine protein should be assessed before starting therapy and monitored during therapy. Consideration should be given to periodic monitoring of serum phosphorus in patients at risk for renal impairment. Although COBI may cause modest increases in serum creatinine and modest declines in CrCl, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored and evaluated for evidence of tubulopathy. Proteinuria, normoglycemic glycosuria, and increased fractional excretion of phosphorous may represent the first signs of tubulopathy and precede any decline in renal function. Patients on EVG/COBI/TDF/FTC should be switched to an alternative ARV regimen if estimated CrCl decreases to less than 50 mL/min. Concomitant use of nephrotoxic drugs should be avoided. In summary, EVG/COBI/FTC/TDF has rates of virologic suppression comparable to two currently preferred regimens. As a co-formulated tablet, it can be given as one tablet, once daily. Limitations of this combination include a possible increased risk of proximal renal tubulopathy in addition to inhibition of active tubular secretion of creatinine, significant drug-drug interactions, limited data in patients with advanced HIV disease and in women, and food requirement. On the basis of these factors, the Panel recommends EVG/COBI/FTC/TDF as an alternative regimen in ART-naive patients (BI). # CCR5 Antagonist-Based Regimens Maraviroc (MVC). The MERIT study compared the CCR5 antagonist MVC with EFV, both in combination with ZDV/3TC, in a randomized, double-blind trial in ART-naive participants. 7 Only participants who had # Dual-Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Combination Therapy # Summary: Dual-Nucleoside Reverse Transcriptase Inhibitor Components Dual NRTIs are commonly used in combination with an NNRTI, a PI (usually boosted with RTV), an INSTI, or a CCR5 antagonist. Most dual-NRTI combinations used in clinical practice consist of a primary NRTI plus 3TC or FTC. Both 3TC and FTC have few adverse effects but may select for the M184V resistance mutation, which confers high-level resistance to both drugs; a modest decrease in susceptibility to ddI and ABC; and improved susceptibility to ZDV, d4T, and TDF. 75 All NRTIs except ddI can be taken with or without food. Adherence may be additionally improved with once-daily dosing (available for all NRTIs except d4T and ZDV) and with fixed-dosage combinations, such as ABC/3TC, TDF/FTC (with or without EFV, RPV, or EVG/COBI), or ZDV/3TC. The Panel's recommendations on specific dual-NRTI options are made on the basis of virologic potency and durability, short-and long-term toxicities, the propensity to select for resistance mutations, and dosing convenience. # Preferred Dual-Nucleoside Reverse Transcriptase Inhibitors Tenofovir/Emtricitabine (TDF/FTC, co-formulated). TDF is a nucleotide analog with potent activity against both HIV and hepatitis B virus (HBV) and a long intracellular half-life that allows for once-daily dosing. The fixed-dose combinations of TDF/FTC, EFV/TDF/FTC, RPV/TDF/FTC, and EVG/COBI/TDF/ FTC are administered as one tablet, once daily and are designed to improve adherence. TDF, when used with either 3TC or FTC as part of an EFV-based regimen in ART-naive patients, demonstrated potent virologic suppression 26 and was superior to ZDV/3TC in virologic efficacy up to 144 weeks. 76 In the 934 study, more participants in the ZDV/3TC arm than in the TDF/FTC arm developed loss of limb fat (as assessed by dual-energy x-ray absorptiometry ) and anemia at 96 and 144 weeks. 76 Emergence of the M184V mutation was less frequent with TDF/FTC than with ZDV/3TC, and by 144 weeks of therapy no participant had developed the K65R mutation. TDF + FTC or 3TC has also been studied in combination with RPV, several boosted PIs, EVG/COBI, and RAL in randomized clinical trials; all trials demonstrate good virologic benefit. 6,15,48,54,59,70,77 TDF/FTC was compared with ABC/3TC in the ACTG 5202 study 8 and the HEAT trial. 10 In the ACTG 5202 trial, inferior virologic responses were observed in participants randomized to ABC/3TC who had a pre- treatment HIV RNA >100,000 copies/mL. This was not observed in the HEAT trial or in other trials (see the ABC/3TC section below for more detailed discussion). Renal impairment, manifested by increases in serum creatinine, proteinuria, glycosuria, hypophosphatemia, proximal renal tubulopathy, and acute tubular necrosis, has been associated with TDF use. 78,79 Risk factors may include advanced HIV disease, longer treatment history, and pre-existing renal impairment. 80 In the HEAT trial, 15% of subjects receiving TDF/FTC versus 10% of those receiving ABC/3TC progressed to a more advanced stage of chronic kidney disease (CKD) on treatment. 10 Renal function, urinalysis, and electrolytes should be monitored in patients who are on TDF. In patients who have some degree of preexisting renal insufficiency (CrCl <50 mL/min), TDF dosage adjustment is required (see Appendix B, Table 7 for dosage recommendations). However, in this setting, the use of alternative NRTIs (for example, ABC) may be preferred over dose-adjusted TDF because available dosage adjustment guidelines for renal dysfunction are based on PK studies only and not on safety and efficacy data. Concomitant use of boosted PIs and COBI can increase TDF concentrations, and studies have suggested a greater risk of renal dysfunction when TDF is used in PI-and COBI-based regimens. 69,78, TDF has been used in combination with PIs without significant renal toxicity in several clinical trials that involved patients who had CrCl >50 mL/min to 60 mL/min. 49,85 Furthermore, in two randomized studies comparing TDF/FTC with ABC/3TC, participants receiving TDF/FTC experienced a significantly greater decline in bone mineral density than ABC/3TC-treated participants. 11,86 TDF plus FTC is the preferred NRTI combination, especially in HIV/HBV-coinfected patients because these drugs have activity against both viruses. The use of a single HBV-active NRTI (e.g., 3TC or FTC) can lead to HBV resistance and is not recommended (see HIV/Hepatitis B Co-infection). # Alternative Dual Nucleoside Reverse Transcriptase Inhibitors Abacavir/Lamivudine (ABC/3TC, co-formulated) for patients who test negative for HLA-B5701. In a comparative trial of ABC/3TC and ZDV/3TC (both given twice daily and combined with EFV), participants in both arms achieved similar virologic responses. CD4 T-cell increase at 48 weeks was greater in the ABCtreated participants than in the ZDV-treated participants. 87 The ACTG 5202 study, a randomized controlled trial in more than 1,800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when used in combination with either EFV or RTV-boosted ATV. Treatment randomization was stratified on the basis of a screening HIV RNA of <100,000 copies/mL or ≥100,000 copies/mL. HLA-B5701 testing was not required before study entry, which may have influenced the results of the trial with respect to some of the safety and tolerability endpoints. A Data Safety Monitoring Board recommended early termination of the ≥100,000 copies/mL stratification group because of a significantly shorter time to study-defined virologic failure in the ABC/3TC arm than in the TDF/FTC arm. 8 This difference in time to virologic failure between arms was observed regardless of whether the third active drug was EFV or ATV/r. There was no difference between ABC/3TC and TDF/FTC in time to virologic failure for participants who had plasma HIV RNA <100,000 copies/mL at screening. 88 In the HEAT study, 688 participants received ABC/3TC or TDF/FTC in combination with once-daily LPV/r. A subgroup analysis according to baseline HIV RNA <100,000 copies/mL or ≥100,000 copies/mL yielded similar percentages of participants with HIV RNA <50 copies/mL at 96 weeks in the two regimens (63% vs. 58% in those with HIV RNA <100,000 copies/mL and 56% vs. 58% in those with ≥100,000 copies/mL). 10 The An association between ABC use and MI was first reported in the D:A:D study. This large, multinational observational study group found that recent (within 6 months) or current use of ABC, but not TDF, was associated with an increased risk of MI, particularly in participants with pre-existing cardiac risk factors. 43,91 Since the report of this study, multiple studies have explored this association. Some studies have found an association; others have found a weak association or no association. 44, Several studies have also been conducted to evaluate potential mechanistic pathways that may underlie the association between ABC use and an increased risk of MI, including endothelial dysfunction, increased platelet reactivity, leukocyte adhesion, inflammation, and hypercoagulability. However, to date, no consensus on the association between ABC use and MI risk or the mechanism for such an association has been reached. The fixed-dose combination of ABC/3TC allows for once-daily dosing. Pending additional data, ABC/3TC should be used with caution in individuals who have plasma HIV RNA levels ≥100,000 copies/mL and in persons at high risk of CVD. However, the combination of ABC/3TC remains an alternative dual-NRTI option for some ART-naive patients (BI). # Other Dual Nucleoside Reverse Transcriptase Inhibitors Zidovudine/Lamivudine (ZDV/3TC, coformulated). The dual-NRTI combination of ZDV/3TC has extensive durability, safety, and tolerability experience. 3,5, In a multinational, randomized trial comparing three initial treatment strategies, EFV/ZDV/3TC and EFV/TDF/FTC showed similar virologic efficacy; both regimens were superior to ATV/ddI/FTC. 63 A fixed-dose combination of ZDV/3TC is available for one-tablet, twice-daily dosing. Selection of the 3TCassociated M184V mutation has been associated with increased susceptibility to ZDV. In a comparative trial of ABC/3TC and ZDV/3TC (both given twice daily and combined with EFV), the CD4 count increase was greater in the ABC/3TC-treated patients than in the ZDV/3TC-treated patients, 87 even though virologic responses were similar in both arms. Bone marrow suppression, manifested by macrocytic anemia and/or neutropenia, is seen in some patients. ZDV also is associated with GI toxicity, fatigue, and possibly mitochondrial toxicity, including lactic acidosis/hepatic steatosis and lipoatrophy. Because ZDV/3TC has greater toxicity than TDF/FTC or ABC/3TC and requires twice-daily dosing, the Panel classifies ZDV/3TC in the Other Dual-NRTI category, rather than as a preferred or alternative, dual-NRTI option (CI). ZDV/3TC remains as a preferred NRTI option in pregnant women because the two drugs have the most PK, safety, and efficacy data for both mother and newborn of any other ARVs. For more detailed information regarding ARV drug choices and related issues in pregnancy, see the Perinatal Guidelines. 34 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Hepatitis B Virus (HBV). Three of the currently approved NRTIs-FTC, 3TC, and TDF-have activity against HBV. Most HIV/HBV-coinfected patients should use coformulated TDF/FTC (or TDF + 3TC) as their NRTI backbone to provide additional activity against HBV and to avoid selection of HBV mutation that confers resistance to 3TC and FTC. Importantly, patients who have HIV/HBV coinfection may be at risk of acute exacerbation of hepatitis after initiation or discontinuation of TDF, 3TC, or FTC. Thus, these patients should be monitored closely for clinical or chemical hepatitis if these drugs are initiated or discontinued (see HIV/Hepatitis B Coinfection and Initiating Antiretroviral Therapy). # Antiretroviral Regimens Not Recommended Monotherapy with nucleoside reverse transcriptase inhibitor (NRTI). Single-NRTI therapy does not demonstrate potent and sustained antiviral activity and should not be used (AII). For prevention of motherto-child transmission (PMTCT), zidovudine (ZDV) monotherapy is not recommended but might be considered in certain unusual circumstances in women with HIV RNA <1,000 copies/mL, although the use of a potent combination regimen is preferred. (See Perinatal Guidelines, 1 available at .) Single-drug treatment regimens with a ritonavir (RTV)-boosted protease inhibitor (PI), either lopinavir (LPV), 2 atazanavir (ATV), 3 or darunavir (DRV) are under investigation with mixed results, and cannot be recommended outside of a clinical trial at this time. Dual-NRTI regimens. These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity compared with triple-drug combination regimens (AI). 6 Triple-NRTI regimens. In general, triple-NRTI regimens other than abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (BI) and possibly lamivudine/zidovudine + tenofovir (3TC/ZDV + TDF) (BII) should not be used because of suboptimal virologic activity or lack of data (AI). # Antiretroviral Components Not Recommended Atazanavir (ATV) + indinavir (IDV). Both of these PIs can cause Grade 3 to 4 hyperbilirubinemia and jaundice. Additive adverse effects may be possible when these agents are used concomitantly. Therefore, these two PIs are not recommended for combined use (AIII). # Didanosine (ddI) + stavudine (d4T). The combined use of ddI and d4T as a dual-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis. This combination has been implicated in the deaths of several HIV-infected pregnant women secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis. 14 Therefore, the combined use of ddI and d4T is not recommended (AII). # Didanosine (ddI) + tenofovir (TDF). Use of ddI + TDF may increase ddI concentrations 15 and serious ddIassociated toxicities including pancreatitis and lactic acidosis. These toxicities may be lessened by ddI dose reduction. The use of this combination has also been associated with immunologic nonresponse or CD4 cell decline despite viral suppression, high rates of early virologic failure, and rapid selection of resistance mutations. Because of these adverse outcomes, this dual-NRTI combination is not generally recommended (AII). Clinicians caring for patients who are clinically stable on regimens containing ddI + TDF should consider altering the NRTIs to avoid this combination. Two-non-nucleoside reverse transcriptase inhibitor (2-NNRTI) combinations. In the 2NN trial, ARVnaive participants were randomized to receive once-or twice-daily nevirapine (NVP) versus efavirenz (EFV) versus EFV plus NVP, all combined with d4T and 3TC. 23 A higher frequency of clinical adverse events that led to treatment discontinuation was reported in participants randomized to the two-NNRTI arm. Both EFV and NVP may induce metabolism of etravirine (ETR), which leads to reduction in ETR drug exposure. 24 Based on these findings, the Panel does not recommend using two NNRTIs in combination in any regimen (AI). Efavirenz (EFV) in first trimester of pregnancy and in women with significant childbearing potential. EFV use was associated with significant teratogenic effects in nonhuman primates at drug exposures similar to those representing human exposure. Several cases of congenital anomalies have been reported after early human gestational exposure to EFV. EFV should be avoided in pregnancy, particularly during the first trimester, and in women of childbearing potential who are trying to conceive or who are not using effective and consistent contraception (AIII). If no other ARV options are available for the woman who is pregnant or at risk of becoming pregnant, the provider should consult with a clinician who has expertise in both HIV infection and pregnancy. (See Perinatal Guidelines, 1 available at .) Emtricitabine (FTC) + lamivudine (3TC). Both of these drugs have similar resistance profiles and have minimal additive antiviral activity. Inhibition of intracellular phosphorylation may occur in vivo, as seen with other dual-cytidine analog combinations. 27 These two agents should not be used as a dual-NRTI combination (AIII). Etravirine (ETR) + unboosted PI. ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate doses of the PIs have not been established 24 (AII). # Etravirine (ETR) + ritonavir (RTV)-boosted atazanavir (ATV) or fosamprenavir (FPV). ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established 24 (AII). # Etravirine (ETR) + ritonavir (RTV)-boosted tipranavir (TPV). RTV-boosted TPV significantly reduces ETR concentrations. These drugs should not be co-administered 24 (AII). Nevirapine (NVP) initiated in ARV-naive women with CD4 counts >250 cells/mm 3 or in ARV-naive men with CD4 counts >400 cells/mm 3 . Greater risk of symptomatic hepatic events, including serious and life-threatening events, has been observed in these patient groups. NVP should not be initiated in these patients (BI) unless the benefit clearly outweighs the risk. Patients who experience CD4 count increases to levels above these thresholds as a result of antiretroviral therapy (ART) can be safely switched to NVP. 31 Unboosted darunavir (DRV), saquinavir (SQV), or tipranavir (TPV). The virologic benefit of these PIs has been demonstrated only when they were used with concomitant RTV. Therefore, use of these agents as part of a combination regimen without RTV is not recommended (AII). # Stavudine (d4T) + zidovudine (ZDV). These two NRTIs should not be used in combination because of antagonism demonstrated in vitro 32 and in vivo 33 (AII). # 2-NNRTI combination (AI) - When EFV combined with NVP, higher incidence of clinical adverse events seen when compared with either EFV-or NVP-based regimen. - Both EFV and NVP may induce metabolism and may lead to reductions in ETR exposure; thus, they should not be used in combination with ETR. # Virologic Definitions Virologic suppression: A confirmed HIV RNA level below the limit of assay detection (e.g., <48 copies/mL). # Virologic failure: The inability to achieve or maintain suppression of viral replication (to an HIV RNA level <200 copies/mL). # Incomplete virologic response: Two consecutive plasma HIV RNA levels >200 copies/mL after 24 weeks on an ARV regimen. Baseline HIV RNA may affect the time course of response, and some regimens will take longer than others to suppress HIV RNA levels. # Panel's Recommendations - Assessing and managing an antiretroviral (ARV)-experienced patient experiencing failure of antiretroviral therapy (ART) is complex. Expert advice is critical and should be sought. - Evaluation of virologic failure should include an assessment of the severity of the patient's HIV disease, ART history, use of concomitant medications with consideration of adverse drug interactions with ARV agents, HIV RNA and CD4 T-cell count trends over time, and prior drug-resistance testing results. - Drug-resistance testing should be obtained while the patient is taking the failing ARV regimen or within 4 weeks of treatment discontinuation (AII). - The goal of treatment for ARV-experienced patients with drug resistance who are experiencing virologic failure is to reestablish virologic suppression (e.g., HIV RNA <48 copies/mL) (AI). - To design a new regimen, the patient's treatment history and past and current resistance test results should be used to identify at least two (preferably three) fully active agents to combine with an optimized background ARV regimen (AI). A fully active agent is one that is likely to have ARV activity on the basis of the patient's treatment history, drug-resistance testing, and/or a novel mechanism of action. - In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII). - In patients with a high likelihood of clinical progression (e.g., CD4 count <100 cells/mm 3 ) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI). - For some highly ART-experienced patients, maximal virologic suppression is not possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and avoid clinical progression. - Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4 cell count and increases the risk of clinical progression. Therefore, this strategy is not recommended (AI). - In the setting of virologic suppression, there is no consensus on how to define or treat immunologic failure. Virologic rebound: Confirmed detectable HIV RNA (to >200 copies/mL) after virologic suppression. # Rating of Recommendations # Persistent low-level viremia: Confirmed detectable HIV RNA levels that are <1,000 copies/mL. # Virologic blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression. # Causes of Virologic Failure Virologic failure in a patient can occur for multiple reasons. Data from older patient cohorts suggested that suboptimal adherence and drug intolerance/toxicity accounted for 28%-40% of virologic failure and regimen discontinuations. More recent data suggest that most virologic failure on first-line regimens occurred due to either pre-existing (transmitted) drug resistance or suboptimal adherence. 3 Factors associated with virologic failure include: - Patient characteristics - higher pretreatment or baseline HIV RNA level (depending on the specific regimen used) - lower pretreatment or nadir CD4 T-cell count - prior AIDS diagnosis - comorbidities (e.g., active substance abuse, depression) - presence of drug-resistant virus, either transmitted or acquired - prior treatment failure - incomplete medication adherence and missed clinic appointments - tolerability of medications - concomitant medications and supplements (with consideration for adverse drug-drug interactions) - comorbidities (including substance abuse) In many cases, the cause(s) of virologic failure will be identified. In some cases, no obvious cause(s) may be identified. It is important to distinguish among the reasons for virologic failure because the approaches to subsequent therapy differ. The following potential causes of virologic failure should be explored in depth. - Adherence. Assess the patient's adherence to the regimen. For incomplete adherence, identify and address the underlying cause(s) (e.g., difficulties accessing or tolerating medications, depression, active substance abuse) and simplify the regimen if possible (e.g., decrease pill count or dosing frequency). (See Adherence.) - Medication Intolerance. Assess the patient's tolerance of the current regimen and the severity and duration of side effects, keeping in mind that even minor side effects can impact adherence. Management strategies for intolerance in the absence of drug resistance may include: - using symptomatic treatment (e.g., antiemetics, antidiarrheals) # Changing ART There is no consensus on the optimal time to change therapy for virologic failure. The goal of ART is to suppress HIV replication to a level where drug-resistance mutations do not emerge. However, the specific level of viral suppression needed to achieve durable virologic suppression remains unknown. Selection of drug resistance does not appear to occur in patients with persistent HIV RNA levels suppressed to 48 to 200 copies/mL often are associated with evidence of viral evolution and drugresistance mutation accumulation; 15 this is particularly common when HIV RNA levels are >500 copies/mL. 16 Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should therefore be considered as virologic failure. Viremia "blips" (e.g., viral suppression followed by a detectable HIV RNA level and then subsequent return to undetectable levels) usually are not associated with subsequent virologic failure. 17 # Management of Virologic Failure Once virologic failure is confirmed, generally the regimen should be changed as soon as possible to avoid progressive accumulation of resistance mutations. 18 Ideally, a new ARV regimen should contain at least two, and preferably three, fully active drugs on the basis of drug treatment history, resistance testing, or new mechanistic class (AI). Some ARV drugs (e.g., NRTIs) may contribute partial ARV activity to a regimen, despite drug resistance, 28 while others (e.g., T-20, NNRTIs, RAL) likely do not provide partial activity. Because of the potential for drug-class cross resistance that reduces drug activity, using a "new" drug that a patient has not yet taken may not mean that the drug is fully active. In addition, archived drug-resistance mutations may not be detected by standard drug-resistance tests, emphasizing the importance of considering treatment history and prior drug-resistance tests. Drug potency and viral susceptibility are more important than the number of drugs prescribed. Early studies of ART-experienced patients identified factors associated with better virologic responses to subsequent regimens. These factors included lower HIV RNA level and/or higher CD4 cell count at the time of therapy change, using a new (i.e. , not yet taken) class of ARV drugs, and using ritonavir (RTV)boosted PIs in PI-experienced patients. More recent clinical trials support the strategy of conducting reverse transcriptase (RT) and protease (PT) resistance testing (both genotype and phenotype) while an ART-experienced patient is taking a failing ARV regimen, designing a new regimen based on the treatment history and resistance testing results, and selecting at least two and preferably three active drugs for the new treatment regimen. 20-21, 23-24, 33 Higher genotypic and/or phenotypic susceptibility scores (quantitative measures of drug activity) are associated with better virologic responses. Patients who receive more active drugs have a better and more prolonged virologic response than those with fewer active drugs in the regimen. Active ARV drugs include those with activity against drug-resistant viral strains, including newer members of existing classes (the NNRTI-ETR, the # Clinical Scenarios of Virologic Failure - Low-level viremia (HIV RNA 48 copies/mL and 200 copies/mL often select out drugresistant viral variants, particularly when HIV RNA levels are >500 copies/mL. Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should be considered as possible virologic failure; resistance testing should be attempted if the HIV RNA level is >500 copies/mL. For individuals with sufficient therapeutic options, consider treatment change (BIII). - Repeated detectable viremia (HIV RNA >1,000 copies/mL) and NO drug resistance identified. Consider the timing of the drug-resistance test (e.g., was the patient off ARV for >4 weeks and/or nonadherent?). Consider resuming the same regimen or starting a new regimen and then repeating genotypic testing early (e.g., in 2-4 weeks) to determine whether a resistant viral strain emerges (CIII). - Repeated detectable viremia (HIV RNA >1,000 copies/mL) and drug resistance identified. The goals in this situation are to resuppress HIV RNA levels maximally (i.e., to <48 copies/mL) and to prevent further selection of resistance mutations. With the availability of multiple new ARVs, including some with new mechanisms of action, this goal is now possible in many patients, including those with extensive treatment experience and drug resistance. With virologic failure, consider changing the treatment regimen sooner, rather than later, to minimize continued selection of resistance mutations. In a patient with ongoing viremia and evidence of resistance, some drugs in a regimen (e.g., NNRTI, T-20, RAL) should be discontinued promptly to decrease the risk of selecting additional drug-resistance mutations in order to preserve the activity of these drug classes in future regimens. A new regimen should include at least two, and preferably three, fully active agents (AII). - Highly drug resistant HIV. There is a subset of patients who have experienced toxicity and/or developed resistance to all or most currently available regimens, and designing a regimen with two or three fully active drugs is not possible. Many of these patients received suboptimal ARV regimens (i.e., did not have access to more than one or two of the drugs at the time they became available) or have been unable to adhere to any regimen. If maximal virologic suppression cannot be achieved, the goals are to preserve immunologic function and to prevent clinical progression (even with ongoing viremia). There is no consensus on how to optimize the management of these patients. It is reasonable to observe a patient on the same regimen, rather than changing the regimen, depending on the stage of HIV disease (BII). Even partial virologic suppression of HIV RNA >0.5 log 10 copies/mL from baseline correlates with clinical benefits. 34 There is evidence from cohort studies that continuing therapy, even in the presence of viremia and the absence of CD4 T-cell count increases, reduces the risk of disease progression. 35 Other cohort studies suggest continued immunologic and clinical benefits if the HIV RNA level is maintained <10,000-20,000 copies/mL. However, these potential benefits all must be balanced with the ongoing risk of accumulating additional resistance mutations. In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII). However, in patients with a high likelihood of clinical progression (e.g., CD4 cell count <100 cells/mm 3 ) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI). Weighing the risks (e.g., selection of drug resistance) and benefits (e.g., ARV activity) of using a single active drug in the heavily ART-experienced patient is complicated, and consultation with an expert is advised. Patients with ongoing viremia and with an insufficient number of approved treatment options to construct a fully suppressive regimen may be candidates for research studies or expanded access programs, or singlepatient access of investigational new drug(s) (IND), as specified in Food and Drug Administration (FDA) regulations: . Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4 T-cell count and increases the risk of clinical progression. Therefore, this strategy is not recommended (AI). See Discontinuation or Interruption of Antiretroviral Therapy. - Prior treatment and suspected drug resistance, now presenting to care in need of therapy with limited information (i.e., incomplete or absence of self-reported history, medical records, or previous resistance data). Every effort should be made to obtain medical records and prior drugresistance testing results; however, this is not always possible. One strategy is to restart the most recent ARV regimen and assess drug resistance in 2-4 weeks to help guide the choice of the next regimen; another strategy is to start two or three drugs known to be active based on treatment history (e.g., MVC with R5 virus, RAL if no prior INSTI). # Immunologic Failure: Definition, Causes, and Management Immunologic failure can be defined as the failure to achieve and maintain an adequate CD4 response despite virologic suppression. Increases in CD4 counts in ARV-naive patients with initial ARV regimens are approximately 150 cells/mm 3 over the first year. 40 A CD4 count plateau may occur after 4-6 years of treatment with suppressed viremia. No accepted specific definition for immunologic failure exists, although some studies have focused on patients who fail to increase CD4 counts above a specific threshold (e.g., >350 or 500 cells/mm 3 ) over a specific period of time (e.g., 4-7 years). Others have focused on an inability to increase CD4 counts above pretherapy levels by a certain threshold (e.g., >50 or 100 cells/mm 3 ) over a given time period. The former criterion may be preferable because of data linking these thresholds with the risk of non-AIDS clinical events. 46 The proportion of patients experiencing immunologic failure depends on how failure is defined, the observation period, and the CD4 count when treatment was started. In the longest study conducted to date, the percentage of patients with suppressed viremia who reached a CD4 count >500 cells/mm 3 through 6 years of treatment was 42% in those starting treatment with a CD4 count 350 cells/mm 3 . 41 A persistently low CD4 count while on suppressive ART is associated with a small, but appreciable, risk of AIDS-and non-AIDS-related morbidity and mortality. For example, in the FIRST study, 49 a low CD4 count on therapy was associated with an increased risk of AIDS-related complications (adjusted hazard ratio of 0.56 per 100 cells/mm 3 higher CD4 count). Similarly, a low CD4 count was associated with an increased risk of non-AIDS events, including cardiovascular, hepatic, and renal disease and cancer. Other studies support these associations. Factors associated with poor CD4 T-cell response: - CD4 count <200/mm 3 when starting ART - Medications, both ARVs (e.g., ZDV, 54 TDF + didanosine ) and other medications. - Persistent immune activation Assessment of Immunologic Failure. CD4 count should be confirmed by repeat testing. Concomitant medications should be reviewed carefully, with a focus on those known to decrease white blood cells or, specifically, CD4 T-cells (e.g., cancer chemotherapy, interferon, prednisone, ZDV; combination of TDF and ddI), and consideration should be given to substituting or discontinuing these drugs, if possible. Untreated coinfections (e.g., HIV-2, HTLV-1, HTLV-2) and serious medical conditions (e.g., malignancy) also should be considered. In many cases, no obvious cause for immunologic failure can be identified. Management of Immunologic Failure. No consensus exists on when or how to treat immunologic failure. Given the risk of clinical events, it is reasonable to focus on patients with CD4 counts <200 cells/mm 3 because patients with higher CD4 counts have a lower risk of clinical events. It is not clear that immunologic failure in the setting of virologic suppression should prompt a change in the ARV regimen. Because ongoing immune activation occurs in some patients with suppressed HIV RNA levels, some have suggested adding a drug to an existing regimen. However, this strategy does not result in clear virologic or immunologic benefit. 58 Others suggest changing the regimen to another regimen (e.g., from NNRTI-based to PI-based, INSTI-based, or CCR5 antagonist-based regimens), but this strategy has not shown clear benefit. An immune-based therapy, interleukin-2, demonstrated CD4 count increases but no clinical benefit in two large randomized studies 59 and therefore is not recommended (AI). Other immune-based therapies (e.g., gene therapies, growth hormone, cyclosporine, interleukin-7) are under investigation. Currently, immune-based therapies should not be used unless in the context of a clinical trial (AIII). Regimen Simplification (Last updated January 10, 2011; last reviewed January 10, 2011) Regimen simplification can be defined broadly as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy (ART) may be considered candidates for regimen simplification, especially if (1) they are receiving treatments that are no longer recommended as preferred or alternative choices for initial therapy; (2) they were prescribed a regimen in the setting of treatment failure at a time when there was an incomplete understanding of resistance or drug-drug interaction data; or (3) they were prescribed a regimen prior to the availability of newer options or formulations that might be easier to administer and/or more tolerable. This section will review situations in which clinicians might consider simplifying treatment in a patient with virologic suppression. Importantly, this section will not review consideration of changes in treatment for reducing ongoing adverse effects. Regimens used in simplification strategies generally should be those that have proven high efficacy in antiretroviral (ARV)-naive patients (see What to Start) or that would be predicted to be highly active for a given patient based on the individual's past treatment history and resistance profile. # Rationale The major rationales behind regimen simplification are to improve the patient's quality of life, maintain longterm adherence, avoid toxicities that may develop with prolonged ARV use, and reduce the risk of virologic failure. Systematic reviews in the non-HIV literature have shown that adherence is inversely related to the number of daily doses. 1 Some prospective studies in HIV-infected individuals have shown that those on regimens with reduced dosing frequency have higher levels of adherence. Patient satisfaction with regimens that contain fewer pills and reduced dosing frequency is also higher. 4 # Candidates for Regimen Simplification Unlike ARV agents developed earlier in the HIV epidemic, many ARV medications approved in recent years have sufficiently long half-lives to allow for once-daily dosing, and most also do not have dietary restrictions. Patients on regimens initiated earlier in the era of potent combination ART with drugs that pose a high pill burden and/or frequent dosing requirements are often good candidates for regimen simplification. Patients without suspected drug-resistant virus. Patients on first (or modified) treatment regimens without a history of treatment failure are ideal candidates for regimen simplification. These patients are less likely to harbor drug-resistant virus, especially if a pretreatment genotype did not detect drug resistance. Prospective clinical studies have demonstrated that the likelihood of treatment failure is relatively low in patients after simplification and, indeed, may be lower than in patients who do not simplify treatment. 5 However, some patients may have unrecognized drug-resistant HIV, either acquired at the time of infection or as a consequence of prior treatment, such as patients who were treated with presumably nonsuppressive mono-or dual-nucleoside reverse transcriptase inhibitor (NRTI) regimens before the widespread availability of HIV RNA monitoring and resistance testing. Patients with documented or suspected drug resistance. Treatment simplification may also be appropriate for selected individuals who achieve viral suppression after having had documented or suspected drug resistance. Often, these patients are on regimens selected when management of drug resistance, understanding of potentially adverse drug-drug interactions, and understanding of treatment options were relatively limited. Regimen simplification may also be considered for patients on two ritonavir (RTV)boosted protease inhibitors (PIs). Although successful in suppressing viral replication, this treatment may cause patients to be on regimens that are cumbersome, costly, and associated with potential long-term adverse events. The ability to simplify regimens in this setting often reflects the availability of recently approved agents that have activity against drug-resistant virus and are easier to take without sacrificing ARV activity. Specific situations in which drug simplification could be considered in ART-experienced patients with viral drug resistance are outlined below. Simplifying regimens in patients who have extensive prior treatment histories is complicated. In such a case, a patient's treatment history, treatment responses and tolerance, and resistance test results should be thoroughly reviewed before designing a new regimen. Expert consultation should be considered whenever possible. # Types of Treatment Simplification Within-Class Simplifications. Within-class substitutions offer the advantage of not exposing patients to still-unused drug classes, which potentially preserves other classes for future regimens. In general, withinclass substitutions use a newer agent; coformulated drugs; or a formulation that has a lower pill burden, a lower dosing frequency, or would be less likely to cause toxicity. # NRTI Substitutions (e.g., changing from zidovudine or stavudine to tenofovir or abacavir ): This may be considered for a patient who has no history of viral resistance on an NRTI-containing regimen. Other NRTIs may be substituted to create a regimen with lower dosing frequency (e.g., once daily) that takes advantage of coformulated agents and potentially avoids some long-term toxicities (e.g., pancreatitis, peripheral neuropathy, lipoatrophy). # Switching of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g., from nevirapine to efavirenz ): This may be considered to reduce dosing frequency or to take advantage of coformulated agents. - Switching of PIs: This switch can be from one PI to another PI, to the same PI at a lower dosing frequency (such as from twice-daily to once-daily RTV-boosted lopinavir or RTV-boosted darunavir ) or, in the case of atazanavir (ATV), to administration without RTV boosting. 6 (Unboosted ATV is presently not a preferred PI component and not recommended if the patient is taking TDF or if the patient has HIV with reduced susceptibility to ATV.) Such changes can reduce dosing frequency, pill count, drug-drug or drug-food interactions, or dyslipidemia or can take advantage of coformulation. These switches can be done with relative ease in patients without PI-resistant virus. However, these switches are not recommended in patients who have a history of documented or suspected PI resistance because convincing data in this setting are lacking. Out-of-Class Substitutions. One common out-of-class substitution for regimen simplification involves a change from a PI-based to an NNRTI-based regimen. An important study in this regard was the NEFA trial, which evaluated substitution of a PI-based regimen in virologically suppressed patients with NVP, EFV, or ABC. 7 Although the baseline regimens in the study are no longer in widespread use, the NEFA findings are still relevant and provide information about the risks and benefits of switching treatment in patients with virologic suppression. In this study, 460 patients on stable, PI-based regimens with virologic suppression (<200 copies/mL for the previous 6 months) were switched to their randomized treatment arms. After 36 months of follow-up, virologic failure occurred more frequently in patients switched to ABC than in patients switched to EFV or NVP. The increased risk of treatment failure was particularly high in patients who had previous suboptimal treatment with mono-and dual-NRTI therapy. This emphasizes the need to consider the potential for drug-resistant virus prior to attempting simplification. 8 Newer agents that target different sites in the HIV life cycle, such as the integrase strand transfer inhibitor (INSTI) raltegravir (RAL) and the CCR5 antagonist maraviroc (MVC), also offer opportunities for out-ofclass substitutions, particularly in patients who have a history of virus resistant to older HIV drugs. Three randomized studies have evaluated replacing a boosted PI with RAL in virologically suppressed patients. In two of these studies, 9-10 the switch to RAL was associated with an increased risk of virologic failure in patients with documented or suspected pre-existing NRTI resistance; a third study did not find this higher risk, possibly due to a longer period of virologic suppression before the change. 11 Overall, these results suggest that in ART-experienced patients, RAL should be used with caution as a substitute for a boosted PI. # Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-13 This strategy should be avoided in patients with documented NRTI resistance unless there are other fully active drugs in the regimen. Because enfuvirtide (T-20) requires twice-daily injections, causes injection-site reactions, and is more expensive than other available ARV agents, patients who are virologically suppressed on T-20-containing regimens may wish to substitute T-20 with an active oral agent. Because the majority of patients on T-20 have highly drug-resistant virus, substitution must be with another fully active agent. Data from one randomized trial and one observational study suggest that RAL can safely substitute for T-20 in patients not previously treated with INSTI. Although this strategy generally maintains virologic suppression and is well tolerated, clinicians should be aware that any drug substitution may introduce unanticipated adverse effects or drug-drug interactions. 14 Other newer agents that might be considered as substitutes for T-20 are etravirine (ETR) or MVC. Use of ETR in this setting would optimally be considered only when viral susceptibility to ETR can be assured from resistance testing performed prior to virologic suppression and after carefully assessing for possible deleterious drug-drug interactions (e.g., ETR cannot be administered with several PIs ). In the ETR early access program, switching from T-20 to ETR showed promise in maintaining viral suppression at 24 weeks, but only 37 subjects were included in this report. 15 MVC is only active in those with documented R5-only virus, a determination that cannot routinely be made in those with undetectable HIV RNA on a stable regimen. Although there is a commercially available proviral DNA assay to assess viral tropism in virologically suppressed patients, there are no clinical data on whether results of this test predict the successful use of MVC as a substitute for another active drug. Reducing the number of active drugs in a regimen. This approach to treatment simplification involves switching a patient from a suppressive regimen to fewer active drugs. In early studies, this approach was associated with a higher risk of treatment failure than continuation of standard treatment with two NRTIs plus a PI. 16 More recently, studies have evaluated the use of an RTV-boosted PI as monotherapy after virologic suppression with a two-NRTI + boosted-PI regimen. The major motivations for this approach are a reduction in NRTI-related toxicity and lower cost. In a randomized clinical trial, 18 low-level viremia was more common in those on maintenance LPV/r alone than on a three-drug combination regimen. Viral suppression was achieved by resuming the NRTIs. Studies of DRV/r monotherapy, both as once-or twicedaily dosing, have reported mixed results. In aggregate, boosted-PI monotherapy as initial 21 or as simplification treatment has been somewhat less effective in achieving complete virologic suppression and avoiding resistance. Therefore, this strategy cannot be recommended outside of a clinical trial. # Monitoring After Treatment Simplification Patients should be evaluated 2-6 weeks after treatment simplification to assess tolerance and to undergo laboratory monitoring, including HIV RNA, CD4 cell count, and markers of renal and liver function. Assessment of fasting cholesterol subsets and triglycerides should be performed within 3 months after the change in therapy. In the absence of any specific complaints, laboratory abnormalities, or viral rebound at that visit, patients may resume regularly scheduled clinical and laboratory monitoring. Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents (Last updated January 10, 2011; last reviewed January 10, 2011) Knowledge of the relationship between systemic exposure (or concentration) and drug responses (beneficial and/or adverse) is key in selecting the dose of a drug, in understanding the variability in the response of patients to a drug, and in designing strategies to optimize response and tolerability. TDM is a strategy applied to certain antiarrhythmics, anticonvulsants, antineoplastics, and antibiotics that utilizes measured drug concentrations to design dosing regimens to improve the likelihood of the desired therapeutic and safety outcomes. The key characteristic of a drug that is a candidate for TDM is knowledge of the exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions. Several ARV agents meet most of the characteristics of agents that can be considered candidates for a TDM strategy. 1 The rationale for TDM in managing antiretroviral therapy (ART) derives from the following: - data showing that considerable interpatient variability in drug concentrations exists among patients who take the same dose; - data indicating that relationships exist between the concentration of drug in the body and anti-HIV effect and, in some cases, toxicities; and - data from small prospective studies demonstrating that TDM improved virologic response and/or decreased the incidence of concentration-related drug toxicities. # TDM for ARV agents, however, is not recommended for routine use in the management of the HIV-infected adult (CIII). Multiple factors limit the routine use of TDM in HIV-infected adults. These factors include: - lack of large prospective studies demonstrating that TDM improves clinical and virologic outcomes. (This is the most important limiting factor for the implementation of TDM at present.); - lack of established therapeutic range of concentrations for all ARV drugs that is associated with achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions; - intrapatient variability in ARV drug concentrations; - lack of widespread availability of clinical laboratories that perform quantitation of ARV concentrations under rigorous quality assurance/quality control standards; and - shortage of experts to assist with interpretation of ARV concentration data and application of such data to revise patients' dosing regimens. # Panel's Recommendations - Therapeutic drug monitoring (TDM) for antiretroviral (ARV) agents is not recommended for routine use in the management of the HIV-infected adult (CIII). - TDM may be considered in selected clinical scenarios, as discussed in the text below. # Rating of # Exposure-Response Relationships and TDM with Different ARV Classes Protease Inhibitors (PIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitors. Relationships between the systemic exposure to PIs and NNRTIs and treatment response have been reviewed in various publications. Although there are limitations and unanswered questions, the consensus among clinical pharmacologists from the United States and Europe is that the data provide a framework for the potential implementation of TDM for PIs and NNRTIs. However, information on relationships between concentrations and drug-associated toxicities are sparse. Clinicians who use TDM as a strategy to manage either ARV response or toxicities should consult the most current data on the proposed therapeutic concentration range. Exposure-response data for darunavir (DRV), etravirine (ETR), and raltegravir (RAL) are accumulating but are not sufficient to recommend minimum trough concentrations. The median trough concentrations for these agents in HIV-infected persons receiving the recommended dose are included in Table 9b. CCR5 Antagonists. Trough maraviroc (MVC) concentrations have been shown to be an important predictor of virologic success in studies conducted in ART-experienced persons. Clinical experience in the use of TDM for MVC, however, is very limited. Nonetheless, as with PIs and NNRTIs, the exposure-response data provide a framework for TDM, and that information is presented in these guidelines (Table 9b). # Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Relationships between plasma concentrations of NRTIs and their intracellular pharmacologically active moieties have not yet been established. Therefore, monitoring of plasma or intracellular NRTI concentrations for an individual patient largely remains a research tool. Measurement of plasma concentrations, however, is routinely used for studies of drug-drug interactions. Scenarios for Use of TDM. Multiple scenarios exist in which both ARV concentration data and expert opinion may be useful in patient management. Consultation with a clinical pharmacologist or a clinical pharmacist with HIV expertise may be advisable in these cases. These scenarios include the following: - Suspect clinically significant drug-drug or drug-food interactions that may result in reduced efficacy or increased dose-related toxicities; - Changes in pathophysiologic states that may impair gastrointestinal, hepatic, or renal function, thereby potentially altering drug absorption, distribution, metabolism, or elimination; - Pregnant women who may be at risk of virologic failure as a result of changes in their pharmacokinetic parameters during the later stage of pregnancy, which may result in plasma concentrations lower than those achieved in the earlier stages of pregnancy and in the nonpregnant patient; - Heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs; - Use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials; - Concentration-dependent, drug-associated toxicities; and - Lack of expected virologic response in medication-adherent persons. # TDM - For patients who have drug-susceptible virus. Table 9a includes a synthesis of recommendations for minimum target trough PI and NNRTI concentrations in persons with drug-susceptible virus. - For ART-experienced patients with virologic failure (see Table 9b). Fewer data are available to formulate suggestions for minimum target trough concentrations in ART-experienced patients who have viral isolates with reduced susceptibility to ARV agents. Concentration recommendations for tipranavir (TPV) and MVC were derived only from studies in ART-experienced persons. It is likely that use of PIs and NNRTIs in the setting of reduced viral susceptibility may require higher trough concentrations than those needed for wild-type virus. The inhibitory quotient (IQ), which is the ratio of ARV drug concentration to a measure of susceptibility (genotype or phenotype) of the patient's strain of HIV to that drug, may additionally improve prediction of virologic response-as has been shown, for example, with DRV in ART-experienced persons. Exposure-response data for DRV, ETR, and RAL are accumulating but are not sufficient to recommend minimum trough concentrations. The median trough concentrations for these agents in HIV-infected persons receiving the recommended dose are included in Table 9b. Using Drug Concentrations to Guide Therapy. There are several challenges and considerations for implementation of TDM in the clinical setting. Use of TDM to monitor ARV concentrations in a patient requires multiple steps: - quantification of the concentration of the drug, usually in plasma or serum; - determination of the patient's pharmacokinetic characteristics; - integration of information on patient adherence; - interpretation of the concentrations; and - adjustment of the drug dose to achieve concentrations within the therapeutic range, if necessary. Guidelines for the collection of blood samples and other practical suggestions can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee. 4 A final caveat to the use of measured drug concentrations in patient management is a general one-drug concentration information cannot be used alone; it must be integrated with other clinical information. In addition, as knowledge of associations between ARV concentrations and virologic response continues to accumulate, clinicians who employ a TDM strategy for patient management should consult the most current literature. # Drug Concentration (ng/mL) Suggested minimum target trough concentrations in patients with HIV-1 susceptible to the ARV drugs Fosamprenavir (FPV) 400 (measured as amprenavir concentration) Discontinuation of antiretroviral therapy (ART) may result in viral rebound, immune decompensation, and clinical progression. Unplanned interruption of ART may become necessary because of severe drug toxicity, intervening illness, surgery that precludes oral therapy, or unavailability of antiretroviral (ARV) medication. Some investigators have studied planned treatment discontinuation strategies in situations or for reasons that include: in patients who achieve viral suppression and wish to enhance adherence; to reduce inconvenience, long-term toxicities, and costs for patients; or in extensively treated patients who experience treatment failure due to resistant HIV, to allow reversion to wild-type virus. Potential risks and benefits of interruption vary according to a number of factors, including the clinical and immunologic status of the patient, the reason for the interruption, the type and duration of the interruption, and the presence or absence of resistant HIV at the time of interruption. Below are brief discussions on what is currently known about the risks and benefits of treatment interruption in some of these circumstances. # Short-Term Therapy Interruptions Reasons for short-term interruption (days to weeks) of ART vary and may include drug toxicity; intercurrent illnesses that preclude oral intake, such as gastroenteritis or pancreatitis; surgical procedures; or unavailability of drugs. Stopping ARV drugs for a short time (i.e., <1 to 2 days) due to medical/surgical procedures can usually be done by holding all drugs in the regimen. Recommendations for some other scenarios are listed below: # Unanticipated Need for Short-Term Interruption - When a patient experiences a severe or life-threatening toxicity or unexpected inability to take oral medications-all components of the drug regimen should be stopped simultaneously, regardless of drug half-life. # Planned Short Term Interruption (>2-3 days) - When all regimen components have similar half-lives and do not require food for proper absorption-all drugs may be given with a sip of water, if allowed; otherwise, all drugs should be stopped simultaneously. All discontinued regimen components should be restarted simultaneously. - When all regimen components have similar half-lives and require food for adequate absorption, and the patient cannot take anything by mouth for a sustained period of time-temporary discontinuation of all drug components is indicated. The regimen should be restarted as soon as the patient can resume oral intake. - When the ARV regimen contains drugs with differing half-lives-stopping all drugs simultaneously may result in functional monotherapy with the drug with the longest half-life (typically a non-nucleoside reverse transcriptase inhibitor ). Options in this circumstance are discussed below. (See Discontinuation of efavirenz, etravirine, or nevirapine.) # Interruption of Therapy after Pregnancy ARV drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. Following delivery, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as for other nonpregnant individuals. The decision of whether to continue therapy after delivery should take into account current recommendations for initiation of ART, current and nadir CD4 T-cell counts and trajectory, HIV RNA levels, adherence issues, and patient preference. # Planned Long-Term Therapy Interruptions Planned therapy interruptions have been contemplated in various scenarios, listed below. Research is ongoing in several of the scenarios. Therapy interruptions cannot be recommended at this time outside of controlled clinical trials (AI). - In patients who initiated therapy during acute HIV infection and achieved virologic suppressionthe optimal duration of treatment and the consequences of treatment interruption are not known at this time. (See Acute HIV Infection.) - In patients who have had exposure to multiple ARV agents, have experienced ARV treatment failure, and have few treatment options available because of extensive resistance mutationsinterruption is not recommended unless done in a clinical trial setting (AI). Several clinical trials, largely yielding negative results, but some with conflicting results, have been conducted to better understand the role of treatment interruption in these patients. The largest of these studies showed negative clinical impact of treatment interruption in these patients. 1 The Panel notes that partial virologic suppression from combination therapy has been associated with clinical benefit; 5 therefore, interruption of therapy is not recommended. - In patients on ART who have maintained a CD4 count above the level currently recommended for treatment initiation and irrespective of whether their baseline CD4 counts were either above or below that recommended threshold-interruption is also not recommended unless done in a clinical trial setting (BI). (See discussion below highlighting potential adverse outcomes seen in some treatment interruption trials.) Temporary treatment interruption to reduce inconvenience, potential long-term toxicity, and/or overall treatment cost has been considered as a strategy for patients on ART who have maintained CD4 counts above those currently recommended for initiating therapy. Several clinical trials have been designed to determine the safety of such interruptions, in which reinitiation is triggered by predetermined CD4 count thresholds. In these trials, various CD4 count levels have been set to guide both treatment interruption and reinitiation. In the SMART study, the largest of such trials with more than 5,000 subjects, interrupting treatment with CD4 counts >350 cells/mm 3 and reinitiating when 300/mm 3 compared with the continuous ART group. 8 Observational data from the EuroSIDA cohort noted a twofold increase in risk of death after a treatment interruption of >3 months. Factors linked to increased risk of death or progression included lower CD4 counts, higher viral loads, and a prior history of AIDS. 9 Other studies have reported no major safety concerns, but these studies had smaller sample sizes. Results have been reported from several small observational studies evaluating treatment interruption in patients doing well with nadir CD4 counts >350/mm 3 , but further studies are needed to determine the safety of treatment interruption in this population. There is concern that CD4 counts <500 cells/mm 3 are associated with a range of non-AIDS clinical events (e.g., cancer and heart, liver, and kidney disease). 6, Planned long-term therapy interruption strategies cannot be recommended at this time outside of controlled clinical trials (BI) based on available data and a range of ongoing concerns. If therapy has to be discontinued, patients should be counseled about the need for close clinical and laboratory monitoring. They should also be aware of the risks of viral rebound, acute retroviral syndrome, increased risk of HIV transmission, decline of CD4 count, HIV disease progression or death, development of minor HIV-associated manifestations such as oral thrush, development of serious non-AIDS complications, development of drug resistance, and the need for chemoprophylaxis against opportunistic infections depending on the CD4 count. Treatment interruptions often result in rapid reductions in CD4 counts. Prior to any planned treatment interruption, a number of ARV-specific issues should be taken into consideration. These include: - Discontinuation of efavirenz (EFV), etravirine (ETR), or nevirapine (NVP). The optimal interval between stopping EFV, ETR, or NVP and other ARV drugs is not known. The duration of detectable levels of EFV or NVP after discontinuation ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTIs because NNRTIs have much longer half-lives than other agents. This may increase the risk of selection of NNRTI-resistant mutations. It is further complicated by evidence that certain host genetic polymorphisms may result in slower rates of clearance. Such polymorphisms may be more common among specific ethnic groups, such as African Americans and Hispanics. Some experts recommend stopping the NNRTI but continuing the other ARV drugs for a period of time. The optimal time sequence for staggered component discontinuation has not been determined. A study in South Africa demonstrated that giving 4 or 7 days of zidovudine (ZDV) + lamivudine (3TC) after a single dose of NVP reduced the risk of postnatal NVP resistance from 60% to 10%-12%. 20 Use of nucleoside reverse transcriptase inhibitors (NRTIs) with a longer half-life such as tenofovir (TDF) plus emtricitabine (FTC) has also been shown to decrease NVP resistance after single-dose treatment. 21 The findings may, however, differ in patients on chronic NVP treatment. An alternative strategy is to substitute a protease inhibitor (PI) for the NNRTI and to continue the PI with dual NRTIs for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an NNRTI-to a PI-based regimen prior to interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of resuppression of HIV RNA after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the 2-NRTI. 22 The optimal duration needed to continue the PI-based regimen after stopping the NNRTI is not known. Given the potential of prolonged detectable NNRTI concentrations for more than 3 weeks, some suggest that the PI-based regimen may need to be continued for up to 4 weeks. Further research to determine the best approach to discontinuing NNRTIs is needed. Clinical data on ETR and treatment interruption is lacking but its long half-life of approximately 40 hours suggests that stopping ETR needs to be done carefully using the same suggestions for NVP and EFV for the time being. - Discontinuation and reintroduction of NVP. Because NVP is an inducer of the drug-metabolizing hepatic enzymes, administration of full therapeutic doses of NVP without a 2-week, low-dose escalation phase will result in excess plasma drug levels and potentially increase the risk of toxicity. Therefore, in a patient who has interrupted treatment with NVP for more than 2 weeks, NVP should be reintroduced with a dose escalation period of 200 mg once daily for 14 days and then a 200 mg twice-daily regimen (AII). # Definitions: Acute HIV infection is the phase of HIV disease immediately after infection during which the initial burst of viremia in newly infected patients occurs; anti-HIV antibodies are undetectable at this time while HIV RNA or p24 antigen are present. Recent infection generally is considered the phase up to 6 months after infection during which anti-HIV antibodies are detectable. Throughout this section, the term "early HIV infection" is used to refer to either acute or recent HIV infection. An estimated 40% to 90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms. Primary care clinicians, however, often do not recognize acute HIV infection because the selflimiting symptoms are similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic. Table 10 provides practitioners with guidance to recognize, diagnose, and manage acute HIV infection. # Panel's Recommendations - Antiretroviral therapy (ART) is recommended for all persons with HIV infection and should be offered to those with early- HIV infection (BII), although definitive data are lacking as to whether this approach will result in long-term virologic, immunologic, or clinical benefits. - All pregnant women with early HIV infection should start ART as soon as possible to prevent perinatal transmission of HIV (AI). - If treatment is initiated in a patient with early HIV infection, the goal is to suppress plasma HIV RNA to below detectable levels (AIII). - For patients with early HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels, CD4 count, and toxicity monitoring should be performed as described for patients with chronic HIV infection (AII). - Genotypic drug-resistance testing should be performed before initiation of ART to guide the selection of the regimen (AII). If therapy is deferred, genotypic resistance testing should still be performed because the results will be useful in selecting a regimen with the greatest potential for achieving optimal virologic response when therapy is ultimately initiated (AII). - For patients without transmitted drug resistant virus, therapy should be initiated with a regimen that is recommended for patients with chronic HIV infection (see What to Start) (AIII). - ART can be initiated before drug resistance test results are available. Since resistance to ritonavir (RTV)-boosted protease inhibitors (PIs) emerges slowly and since clinically significant transmitted resistance to PIs is uncommon, these drugs combined with nucleoside reverse transcriptase inhibitors (NRTIs) should be used in this setting (AIII). - Patients starting ART should be willing and able to commit to treatment and should understand the possible benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy because of clinical and/or psychosocial factors. - Early infection represents either acute or recent infection as defined in the first paragraph below. # Rating of Recommendations: A = Strong; B = Moderate; C = Optional # Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion # Diagnosis of Acute HIV Infection Health care providers should maintain a high level of suspicion of acute HIV infection in patients who have a compatible clinical syndrome-especially in those who report recent high-risk behavior (Table 10). 7 Patients may not always disclose or admit to high-risk behaviors or they may not perceive that their behaviors put them at risk for HIV acquisition. Thus, signs and symptoms consistent with acute retroviral syndrome should motivate consideration of a diagnosis of acute HIV infection even in the absence of reported high-risk behaviors. Acute HIV infection is usually defined as detectable HIV RNA or p24 antigen, the latter often used in currently available HIV antigen/antibody (Ag/Ab) combination assays, in serum or plasma in the setting of a negative or indeterminate HIV antibody test. 7,8 When the acute retroviral syndrome is suspected in a patient with a negative or indeterminate HIV antibody test result, a test for HIV RNA should be performed to diagnose acute infection (AII). A low-positive HIV RNA level (100,000 copies/mL). 5,6 A presumptive diagnosis of acute HIV infection can be made on the basis of a negative or indeterminate HIV antibody test result and a positive HIV RNA test result. However, if the results of an HIV RNA test are lowpositive, the test should be repeated using a different specimen from the same patient. It is highly unlikely that a second test will reproduce a false-positive result. 6 Interest in routine screening for acute infection has led select centers to use the HIV Ag/Ab test as the primary HIV screening assay or to test all HIV antibody negative samples for HIV RNA. 9 Combination HIV Ag/Ab tests (ARCHITECT HIV Ag/Ab Combo and GS HIV Combo Ag/Ab) now are approved by the Food and Drug Administration; however, the currently available tests do not differentiate between a positive antibody test result and a positive antigen result. Thus HIV Ag/Ab-reactive specimens should be tested with an antibody assay, and if the test results are negative or indeterminate and if acute HIV infection is suspected, be further tested for HIV RNA. 10,11 Because HIV RNA or Ag/Ab combination assays are not yet used routinely for HIV screening in all settings, clinicians should not assume that a laboratory report of a negative HIV test result indicates that screening for acute HIV infection has been conducted. Patients also should know that home HIV testing only detects HIV antibodies and therefore will not detect very early acute HIV infection. Persons diagnosed presumptively with acute HIV infection should have serologic testing repeated over the next 3 to 6 months to document seroconversion (AI) (see Table 10). # Treatment for Early HIV Infection Clinical trial data regarding the treatment of early HIV infection is limited. Many patients who enrolled in studies to assess the role of antiretroviral therapy (ART) in early HIV infection, as outlined below, were identified as trial participants because they presented with signs or symptoms of acute infection. With the introduction of HIV screening tests that include assays for HIV RNA or p24 antigen and wider HIV screening in healthcare systems, the number of asymptomatic patients identified with early infection may be increasing. The natural history of HIV disease in these patients may differ from that in persons with symptomatic infections, thus further studies on the impact of ART on the natural history of asymptomatic acute HIV infection are needed. The initial burst of high level viremia in infected adults usually declines shortly after acute infection (e.g., within 2 months); however, a rationale for treatment during recent infection (e.g., 2-6 months after infection) remains because the immune system may not yet have maximally contained viral replication in the lymphoid tissue during this time. 12 Several trials have addressed the question of the long-term benefit of potent treatment regimens initiated during early HIV infection. The potential benefits and risks of treating HIV during this stage of disease are discussed below: - Potential Benefits of Treatment During Early HIV Infection. Preliminary data indicate that treatment of early HIV infection with combination ART improves laboratory markers of disease progression. The data, though limited, indicate that treatment of early HIV infection may also decrease the severity of acute disease; lower the viral set point, which can affect disease progression rates in the event therapy is stopped; reduce the size of the viral reservoir; 21 and decrease the rate of viral mutation by suppressing viral replication and preserving immune function. 22 Because early HIV infection often is associated with high viral loads and increased infectiousness, 23 and ART use by HIV-infected individuals reduces transmission to serodiscordant sexual partners, 24 treatment during this stage of infection is expected to substantially reduce the risk of HIV transmission. In addition, although data are limited and the clinical relevance unclear, the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by initiating ART during early HIV infection. 25,26 Many of the potential benefits described above may be more likely to occur with treatment of acute infection, but they also may occur if treatment is initiated during recent HIV infection. - Potential Risks of Treatment During Early HIV Infection. The potential disadvantages of initiating therapy during early HIV infection include more prolonged exposure to ART without a known long-term clinical benefit. This could result in drug toxicities, development of drug resistance, and adverse effects on an individual's quality of life due to earlier initiation of lifelong therapy that requires strict adherence. Several randomized controlled trials have studied the effect of ART during acute and recent infection to assess whether initiating early therapy would allow patients to stop treatment and maintain lower viral loads and higher CD4 counts while off ART for prolonged periods of time. This objective was of interest when these studies were initiated but is less relevant in an era in which treatment is recommended for virtually all HIV-infected patients and treatment interruptions are not recommended (see Initiating Antiretroviral Therapy in Treatment-Naive Patients). The Setpoint Study (ACTG A5217 Study) randomized patients with recent but not acute HIV infection to either defer therapy or immediately initiate ART for 36 weeks and then stop. 18 The primary study end point was a composite of meeting criteria for ART or re-initiation of ART and viral load results at week 72 in both groups and at week 36 in the deferred treatment group. The study was stopped prematurely by the Data and Safety Monitoring Board because of an apparent benefit associated with early therapy that was driven mostly by greater proportion of participants meeting criteria for ART initiation in the deferred treatment group (50%) than in the immediate treatment group (10%). Nearly half of the patients in the deferred treatment group needed to start therapy during the first year of study enrollment. The Randomized Primo-SHM Trial randomized patients with acute (~70%) or recent (~30%) infection to either defer ART or to undergo treatment for 24 or 60 weeks and then stop. 19 Significantly lower viral loads were observed 36 weeks after treatment interruption in the patients who had been treated early. These patients also experienced a longer time before the need to initiate therapy, primarily on the basis of reaching a CD4 count of <350 cells/mm 3 . The median time to starting treatment was 0.7 years for the deferred therapy group and 3.0 and 1.8 years for the 24-and 60-week treatment arms, respectively. The time to reaching a CD4 count of <500 cells/mm 3 was only 0.5 years in the deferred group. Finally, the SPARTAC Trial included patients with acute and recent infection randomized to either defer therapy or to undergo treatment for 12 or 48 weeks and then stop. 20 In this case, the time to CD4 <350 cells/mm 3 or initiation of therapy was significantly longer in the group treated for 48 weeks than in the deferred treatment group or the group treated for 12 weeks. However, no difference was observed comparing persons who received 12 weeks of ART with those who deferred treatment during early infection. The strategies tested in these studies are of limited relevance in the current treatment era in which treatment interruption is not recommended. The study results may not fully reflect the natural history of HIV disease in persons with asymptomatic acute infection because most patients in these trials were enrolled on the basis of identified early symptomatic HIV infections. Nevertheless, the results do demonstrate that some immunologic and virologic benefits may be associated with the treatment of early HIV infection. Moreover, all the findings suggest, at least in the population recruited for these studies, that the time to initiating ART after identification of early infection is quite short when the threshold for ART initiation is 350 CD4 cells/mm 3 , and nonexistent when therapy is advised for all individuals regardless of CD4 cell count as currently recommended in these guidelines. These observations must be balanced with the risks of early treatment, risks that are largely the same as those of therapy initiated in chronically infected asymptomatic patients with high CD4 counts. Consequently, the health care provider and the patient should be fully aware that the rationale for initiating therapy during early HIV infection is based on theoretical benefits and the extrapolation of data from the strategy trials outlined above. These potential benefits must be weighed against the risks. For these reasons, and because ART is currently recommended for all HIV-infected patients (see Initiating Antiretroviral Therapy in Treatment-Naive Patients), ART should be offered to all patients with early HIV infection (BII). However, patients must be willing and able to commit to treatment and providers, on a case-by-case basis, may elect to defer therapy for clinical and/or psychosocial reasons. Providers also should consider enrolling patients with early HIV infection in clinical studies to further evaluate the natural history of this stage of HIV infection and to further define the role of ART in this setting. Providers can obtain information regarding such trials at www.clinicaltrials.gov or from local HIV treatment experts. # Treatment for Early HIV Infection During Pregnancy Because early HIV infection is associated with a high risk of perinatal transmission, all HIV-infected pregnant women should start combination ART as soon as possible to prevent perinatal transmission of HIV (AI). 27 # Treatment Regimen for Early HIV Infection Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least 1 antiretroviral in 6% to 16% of patients. Up to 21% of isolates from contemporary patients with acute HIV infection demonstrated resistance to at least 1 drug. 31 Therefore, before initiation of ART in a person with early HIV infection, genotypic antiretroviral drug-resistance testing should be performed to guide the selection of a regimen (AII). If the decision to initiate therapy during early infection is made, especially in the setting of acute infection, treatment initiation should not be delayed pending resistance testing results. Once results are available, the treatment regimen can be modified if warranted. If therapy is deferred, resistance testing still should be performed because the results will help guide selection of a regimen to optimize virologic response once therapy is initiated (AII). The goal of therapy during early HIV infection is to suppress plasma HIV RNA to undetectable levels (AIII). Because data to draw firm conclusions regarding specific drug combinations to use in this stage of HIV infection are insufficient, ART should be initiated with one of the combination regimens recommended for patients with chronic infection (AIII) (see What to Start). If therapy is started before the results of drugresistance testing are available, because resistance to RTV-boosted protease inhibitors (PIs) emerge slowly and clinically significant transmitted resistance to PIs is uncommon (AIII). If available, the results of ARV drug-resistance testing or the ARV resistance pattern of the source person's virus should be used to guide the selection of the ARV regimen. Given the recent approval of daily tenofovir DF/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP), early infection may be diagnosed in some patients while they are taking TDF/FTC as PrEP. In this setting, resistance testing should be performed; however, because PI resistance is unlikely, use of a RTV-boosted PI with TDF/FTC remains a reasonable option pending resistance testing results (see What to Start). # Patient Follow-up Testing for plasma HIV RNA levels, CD4 cell counts, and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2 to 8 weeks, then every 4 to 8 weeks until viral suppression, and thereafter, every 3 to 4 months) (AII). - Suspecting acute HIV infection: Signs or symptoms of acute HIV infection with recent (within 2 to 6 weeks) high risk of exposure to HIV a - Signs/symptoms/laboratory findings may include but are not limited to one or more of the following: fever, lymphadenopathy, skin rash, myalgia/arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, transaminase elevation. - High-risk exposures include sexual contact with an HIV-infected person or a person at risk of HIV infection, sharing injection drug use paraphernalia, or contact of mucous membranes or breaks in skin with potentially infectious fluids. - Differential diagnosis: Includes but is not limited to viral illnesses such as Epstein-Barr virus (EBV)-and non-EBV (e.g., cytomegalovirus) infectious mononucleosis syndromes, influenza, viral hepatitis, streptococcal infection, or syphilis. - Evaluation/diagnosis of acute HIV infection: - Acute infection is defined as detectable HIV RNA or p24 antigen (the antigen used in currently available HIV antigen/antibody combination assays), in serum or plasma in the setting of a negative or indeterminate HIV antibody test result - A reactive HIV antibody test or Ag/Ab test must be followed by supplemental confirmatory testing. - A negative or indeterminate HIV antibody test in a person with a positive Ag/Ab test or in whom acute HIV infection is suspected requires assessment of plasma HIV RNA b to assess for acute HIV infection. - A positive plasma HIV RNA test in the setting of a negative or indeterminate antibody result is consistent with acute HIV infection. - Patients presumptively diagnosed with acute HIV infection should have serologic testing repeated over the next 3 to 6 months to document seroconversion. - Considerations for antiretroviral therapy (ART) during early HIV infection: - All pregnant women with early HIV infection should begin taking combination ART as soon as possible because of the high risk of perinatal HIV transmission (AI). - Treatment for early HIV infection should be offered to all non-pregnant persons (BII). - The risks of ART during early HIV infection are largely the same as those for ART initiated in chronically infected asymptomatic patients with high CD4 counts. - If therapy is initiated, the goal should be sustained plasma virologic suppression (AIII). - Providers should consider enrolling patients with early HIV infection in clinical studies. a In some settings, behaviors conducive to acquisition of HIV infection might not be ascertained or might not be perceived as high risk by the health care provider or the patient or both. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors. b Plasma HIV RNA can be measured by a variety of quantitative assays, including branched DNA (bDNA) and reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays as well as by a qualitative transcription-mediated amplification assay (APTIMA, GenProbe). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents I-9 HIV-Infected Adolescents and Young Adults (Last updated January 10, 2011; last reviewed January 10, 2011) Older children and adolescents now make up the largest percentage of HIV-infected children cared for at pediatric HIV clinics in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 15% of the 35,314 new HIV diagnoses reported among the 33 states that participated in confidential, name-based HIV infection reporting in 2006 were among youth 13-24 years of age. 1 Recent trends in HIV prevalence reveal that the disproportionate burden of HIV/AIDS among racial minorities is even greater among youth 13-19 years of age than among young adults 20-24 years of age. 2 Furthermore, trends for all HIV/AIDS diagnoses in 33 states from 2001 to 2006 decreased for all transmission categories except among men who have sex with men (MSM). Notably, among all black MSM, the largest increase in HIV/AIDS diagnoses occurred among youth 13-24 years of age. 3 HIV-infected adolescents represent a heterogeneous group in terms of sociodemographics, mode of HIV infection, sexual and substance abuse history, clinical and immunologic status, psychosocial development, and readiness to adhere to medications. Many of these factors may influence decisions concerning when to start antiretroviral therapy (ART) and what antiretroviral (ARV) medications should be used. Most adolescents who acquire HIV are infected through high-risk behaviors. Many of them are recently infected and unaware of their HIV infection status. Thus, many are in an early stage of HIV infection, which makes them ideal candidates for early interventions, such as prevention counseling, linkage, and engagement to care. A recent study among HIV-infected adolescents and young adults presenting for care identified primary genotypic resistance mutations to ARV medications in up to 18% of the evaluable sample of recently infected youth, as determined by the detuned antibody testing assay strategy that defined recent infection as occurring within 180 days of testing. 4 This transmission dynamic reflects that a substantial proportion of youth's sexual partners are likely older and may be more ART experienced; thus, awareness of the importance of baseline resistance testing among recently infected youth naive to ART is imperative. A limited but increasing number of HIV-infected adolescents are long-term survivors of HIV infection acquired perinatally or in infancy through blood products. Such adolescents are usually heavily ART experienced and may have a unique clinical course that differs from that of adolescents infected later in life. 5 If these heavily ART-experienced adolescents harbor resistant virus, optimal ARV regimens should be based on the same guiding principles as for heavily ART-experienced adults. (See Virologic and Immunogic Failure.) Adolescents are developmentally at a difficult crossroad. Their needs for autonomy and independence and their evolving decisional capacity intersect and compete with concrete thinking processes, risk-taking behaviors, preoccupation with self-image, and the need to "fit in" with their peers. This makes it challenging to attract and sustain adolescents' focus on maintaining their health, particularly for those with chronic illnesses. These challenges are not specific to any particular transmission mode or stage of disease. Thus, irrespective of disease duration or mode of HIV transmission, every effort must be made to engage them in care so they can improve and maintain their health for the long term. # Antiretroviral Therapy Considerations in Adolescents Adult guidelines for ART are usually appropriate for postpubertal adolescents, because the clinical course of HIV-infected adolescents who were infected sexually or through injection drug use during adolescence is more similar to that of adults than to that of children. Adult guidelines can also be useful for postpubertal youth who were perinatally infected because these patients often have treatment challenges associated with the use of long-term ART that mirror those of ART-experienced adults, such as extensive resistance, complex regimens, and adverse drug effects. Dosage of medications for HIV infection and opportunistic infections should be prescribed according to Tanner staging of puberty and not solely on the basis of age. Adolescents in early puberty (i.e., Tanner Stages I and II) should be administered doses on pediatric schedules, whereas those in late puberty (i.e., Tanner Stage V) should follow adult dosing schedules. However, Tanner stage and age are not necessarily directly predictive of drug pharmacokinetics. Because puberty may be delayed in children who were infected with HIV perinatally, 8 continued use of pediatric doses in puberty-delayed adolescents can result in medication doses that are higher than the usual adult doses. Because data are not available to predict optimal medication doses for each ARV medication for this group of children, issues such as toxicity, pill or liquid volume burden, adherence, and virologic and immunologic parameters should be considered in determining when to transition from pediatric to adult doses. Youth who are in their growth spurt period (i.e., Tanner Stage III in females and Tanner Stage IV in males) and following adult or pediatric dosing guidelines and adolescents who have transitioned from pediatric to adult doses should be closely monitored for medication efficacy and toxicity. Therapeutic drug monitoring can be considered in selected circumstances to help guide therapy decisions in this context. Pharmacokinetic studies of drugs in youth are needed to better define appropriate dosing. For a more detailed discussion, see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 9 # Adherence Concerns in Adolescents HIV-infected adolescents are especially vulnerable to specific adherence problems based on their psychosocial and cognitive developmental trajectory. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with health care systems and who lack health insurance. Many HIV-infected adolescents face challenges in adhering to medical regimens for reasons that include: - denial and fear of their HIV infection; - misinformation; - distrust of the medical establishment; - fear and lack of belief in the effectiveness of medications; - low self-esteem; - unstructured and chaotic lifestyles; - mood disorders and other mental illness; - lack of familial and social support; - absence of or inconsistent access to care or health insurance; and - incumbent risk of inadvertent parental disclosure of the youth's HIV infection status if parental health insurance is used. In selecting treatment regimens for adolescents, clinicians must balance the goal of prescribing a maximally potent ART regimen with realistic assessment of existing and potential support systems to facilitate adherence. Adolescents benefit from reminder systems (e.g., beepers, timers, and pill boxes) that are stylish and inconspicuous. 10 It is important to make medication adherence as user friendly and as little stigmatizing as possible for the older child or adolescent. The concrete thought processes of adolescents make it difficult for them to take medications when they are asymptomatic, particularly if the medications have side effects. Adherence to complex regimens is particularly challenging at a time of life when adolescents do not want to be different from their peers. Directly observed therapy might be considered for selected HIV-infected adolescents such as those with mental illness. # Difficult Adherence Problems Because adolescence is characterized by rapid changes in physical maturation, cognitive processes, and life style, predicting long-term adherence in an adolescent can be very challenging. The ability of youth to adhere to therapy needs to be included as part of therapeutic decision making concerning the risks and benefits of starting treatment. Erratic adherence may result in the loss of future regimens because of the development of resistance mutations. Clinicians who care for HIV-infected adolescents frequently manage youth who, while needing therapy, pose significant concerns regarding their ability to adhere to therapy. In these cases, alternative considerations to initiation of therapy can be the following: (1) a short-term deferral of treatment until adherence is more likely or while adherence-related problems are aggressively addressed; (2) an adherence testing period in which a placebo (e.g., vitamin pill) is administered; and (3) the avoidance of any regimens with low genetic resistance barriers. Such decisions are ideally individualized to each patient and should be made carefully in context with the individual's clinical status. For a more detailed discussion on specific therapy and adherence issues for HIV-infected adolescents, see Guidelines for Use of Antiretroviral Agents in Pediatric HIV Infection. 9 # Special Considerations in Adolescents Sexually transmitted infections (STIs), in particular human papilloma virus (HPV), should also be addressed in all adolescents. For a more detailed discussion on STIs, see the most recent CDC guidelines 19 and the pediatric opportunistic infection treatment guidelines on HPV among HIV-infected adolescents. 20 Family planning counseling, including a discussion of the risks of perinatal transmission of HIV and methods to reduce risks, should be provided to all youth. Providing gynecologic care for the HIV-infected female adolescent is especially important. Contraception, including the interaction of specific ARV drugs on hormonal contraceptives, and the potential for pregnancy also may alter choices of ART. As an example, efavirenz (EFV) should be used with caution in females of childbearing age and should only be prescribed after intensive counseling and education about the potential effects on the fetus, the need for close monitoring-including periodic pregnancy testing-and a commitment on the part of the teen to use effective contraception. For a more detailed discussion, see HIV-Infected Women and the Perinatal Guidelines. 21 # Transitioning Care Given lifelong infection with HIV and the need for treatment through several stages of growth and development, HIV care programs and providers need flexibility to appropriately transition care for HIVinfected children, adolescents, and young adults. A successful transition requires an awareness of some fundamental differences between many adolescent and adult HIV care models. In most adolescent HIV clinics, care is more "teen-centered" and multidisciplinary, with primary care being highly integrated into HIV care. Teen services, such as sexual and reproductive health, substance abuse treatment, mental health, treatment education, and adherence counseling are all found in one clinic setting. In contrast, some adult HIV clinics may rely more on referral of the patient to separate subspecialty care settings, such as gynecology. Transitioning the care of an emerging young adult includes considerations of areas such as medical insurance, independence, autonomy, decisional capacity, confidentiality, and consent. Also, adult clinic settings tend to be larger and can easily intimidate younger, less motivated patients. As an additional complication to this transition, HIV-infected adolescents belong to two epidemiologically distinct subgroups: (1) those perinatally infected-who would likely have more disease burden history, complications, and chronicity; less functional autonomy; greater need for ART; and higher mortality risk; and (2) those more recently infected due to high-risk behaviors. Thus, these subgroups have unique biomedical and psychosocial considerations and needs. To maximize the likelihood of a successful transition, facilitators to successful transitioning are best implemented early on. These include the following: (1) optimizing provider communication between adolescent and adult clinics; (2) addressing patient/family resistance caused by lack of information, stigma or disclosure concerns, and differences in practice styles; (3) preparing youth for life skills development, including counseling them on the appropriate use of a primary care provider and appointment management, the importance of prompt symptom recognition and reporting, and the importance of self-efficacy with medication management, insurance, and entitlements; (4) identifying an optimal clinic model for a given setting (i.e., simultaneous transition of mental health and/or case management versus a gradual phase-in); ( 5) implementing ongoing evaluation to measure the success of a selected model; (6) engaging in regular multidisciplinary case conferences between adult and adolescent care providers; (7) implementing interventions that may be associated with improved outcomes, such as support groups and mental health consultation; and (8) incorporating a family planning component into clinical care. Attention to these key areas will likely improve adherence to appointments and avert the potential for a youth to "fall through the cracks," as it is commonly referred to in adolescent medicine. HIV and Illicit Drug Users (Last updated March 27, 2012; last reviewed March 27, 2012) # Treatment Challenges of HIV-Infected Illicit Drug Users Injection drug use is the second most common mode of HIV transmission in the United States. In addition, noninjection illicit drug use may facilitate sexual transmission of HIV. Injection and noninjection illicit drugs include the following: heroin, cocaine, marijuana, and club drugs (i.e., methamphetamine, ketamine, gammahydroxybutyrate , and amyl nitrate ). The most commonly used illicit drugs associated with HIV infection are heroin and stimulants (e.g., cocaine and amphetamines); however, the use of club drugs has increased substantially in the past several years and is common among individuals who have HIV infection or who are at risk of HIV infection. The association between club drugs and high-risk sexual behavior in men who have sex with men (MSM) is strongest for methamphetamine and amyl nitrate; this association is less consistent with the other club drugs. 1 Illicit drug use has been associated with depression and anxiety, either as part of the withdrawal process or as a consequence of repeated use. This is particularly relevant in the treatment of HIV infection because depression is one of the strongest predictors of poor adherence and poor treatment outcomes. 2 Treatment of HIV disease in illicit drug users can be successful but HIV-infected illicit drug users present special treatment challenges. These challenges may include the following: (1) an array of complicating comorbid medical and mental health conditions; (2) limited access to HIV care; (3) inadequate adherence to therapy; (4) medication side effects and toxicities; (5) the need for substance abuse treatment; and (6) drug interactions that can complicate HIV treatment. 3 Underlying health problems in injection and noninjection drug users result in increased morbidity and mortality, either independent of or accentuated by HIV disease. Many of these problems are the consequence of prior exposures to infectious pathogens from nonsterile needle and syringe use. Such problems can include hepatitis B or C virus infection, tuberculosis (TB), skin and soft tissue infections, recurrent bacterial pneumonia, and endocarditis. Other morbidities such as alteration in levels of consciousness and neurologic and renal disease are not uncommon. Furthermore, these comorbidities are associated with a higher risk of drug overdoses in illicit drug users with HIV disease than in HIV-uninfected illicit drug users, due in part to respiratory, hepatic, and neurological impairments associated with HIV infection. 4 Successful HIV therapy for illicit drug users often depends on clinicians becoming familiar with and managing these comorbid conditions and providing overdose prevention support. Illicit drug users have less access to HIV care and are less likely to receive antiretroviral therapy (ART) than other populations. Factors associated with low rates of ART use among illicit drug users include active drug use, younger age, female gender, suboptimal health care, recent incarceration, lack of access to rehabilitation programs, and health care providers' lack of expertise in HIV treatment. The typically unstable, chaotic life patterns of many illicit drug users; the powerful pull of addictive substances; and common misperceptions about the dangers, impact, and benefits of ART all contribute to decreased adherence. 7 The chronic and relapsing nature of substance abuse as a biologic and medical disease, compounded by the high rate of mental illness that antedates and/or is exacerbated by illicit substance use, additionally complicate the relationship between health care workers and illicit drug users. The first step in provision of care and treatment for these individuals is to recognize the existence of a substance abuse problem. It is often obvious that the problem exists, but some patients may hide these problem behaviors from clinicians. Assessment of a patient for substance abuse should be part of routine medical history taking and should be done in a professional, straightforward, and nonjudgmental manner. # Treatment Efficacy in HIV-Infected Illicit Drug Use Populations Although illicit drug users are underrepresented in HIV therapy clinical trials, available data indicate that efficacy of ART in illicit drug users-when they are not actively using drugs-is similar to that seen in other populations. 10 Furthermore, therapeutic failure in this population generally correlates with the degree that drug use disrupts daily activities rather than with drug use per se. 11 Providers need to remain attentive to the possible impact of disruptions caused by drug use on the patient both before and while receiving ART. Although many illicit drug users can sufficiently control their drug use for long enough time to benefit from care, substance abuse treatment is often necessary for successful HIV management. Close collaboration with substance abuse treatment programs and proper support and attention to this population's special multidisciplinary needs are critical components of successful HIV treatment. Essential to this end are accommodating, flexible, community-based HIV care sites that are characterized by familiarity with and nonjudgmental expertise in management of drug users' wide array of needs and in development of effective strategies to promote medication adherence. 9 These strategies should include, if available, the use of adherence support mechanisms such as modified directly observed therapy (mDOT), which has shown promise in this population. 12 # Antiretroviral Agents and Opioid Substitution Therapy Compared with noninjection drug users receiving ART, injection drug users (IDUs) receiving ART are more likely to experience an increased frequency of side effects and toxicities of ART. Although not systematically studied, this is likely because underlying hepatic, renal, neurologic, psychiatric, gastrointestinal (GI), and hematologic disorders are highly prevalent among IDUs. These comorbid conditions should be considered when selecting antiretroviral (ARV) agents in this population. Opioid substitution therapies such as methadone and buprenorphine/naloxone and extended-release naltrexone are commonly used for management of opioid dependence in HIV-infected patients. Methadone and Antiretroviral Therapy. Methadone, an orally administered, long-acting opioid agonist, is the most common pharmacologic treatment for opioid addiction. Its use is associated with decreased heroin use, decreased needle sharing, and improved quality of life. Because of its opioid-induced effects on gastric emptying and the metabolism of cytochrome P (CYP) 450 isoenzymes 2B6, 3A4, and 2D6, pharmacologic effects and interactions with ARV agents may commonly occur. 13 These may diminish the effectiveness of either or both therapies by causing opioid withdrawal or overdose, increased methadone toxicity, and/or decreased ARV efficacy. Efavirenz (EFV), nevirapine (NVP), and lopinavir/ritonavir (LPV/r) have been associated with significant decreases in methadone levels. Patients and substance abuse treatment facilities should be informed of the likelihood of this interaction. The clinical effect is usually seen after 7 days of coadministration and may be managed by increasing the methadone dosage, usually in 5-mg to 10-mg increments daily until the desired effect is achieved. Buprenorphine and Antiretroviral Therapy. Buprenorphine, a partial μ-opioid agonist, is administrated sublingually and is often coformulated with naloxone. It is increasingly used for opioid dependence treatment. Compared with methadone, buprenorphine has a lower risk of respiratory depression and overdose. This allows physicians in primary care to prescribe buprenorphine for the treatment of opioid dependency. The flexibility of the primary care setting can be of significant value to opioid-addicted HIVinfected patients who require ART because it enables one physician or program to provide both medical and substance abuse services. Limited information is currently available about interactions between buprenorphine and ARV agents. Findings from available studies show that the drug interaction profile of buprenorphine is more favorable than that of methadone. Naltrexone and Antiretroviral Therapy. A once-monthly extended-release intramuscular formulation of naltrexone was recently approved for prevention of relapse in patients who have undergone an opioid detoxification program. Naltrexone is also indicated for treatment of alcohol dependency. Naltrexone is not metabolized via the CYP450 enzyme system and is not expected to interact with protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). 15 Table 11 provides the currently available pharmacokinetic (PK) interaction data that clinicians can use as a guide for managing patients receiving ART and methadone or buprenorphine. Particular attention is needed concerning communication between HIV care providers and drug treatment programs regarding additive drug toxicities and drug interactions resulting in opiate withdrawal or excess. Methylenedioxymethamphetamine (MDMA), GHB, ketamine, and methamphetamine all have the potential to interact with ARV agents because all are metabolized, at least in part, by the CYP450 system. Overdoses secondary to interactions between the party drugs (i.e., MDMA or GHB) and PI-based ART have been reported. 16 # Summary It is usually possible over time to support most active drug users such that acceptable adherence levels with ARV agents can be achieved. Providers must work to combine all available resources to stabilize an active drug user in preparation for ART. This should include identification of concurrent medical and psychiatric illnesses, drug treatment and needle and syringe exchange programs, strategies to reduce highrisk sexual behavior, and harm-reduction strategies. A history of drug use alone is insufficient reason to withhold ART because individuals with a history of prior drug use have adherence rates similar to those who do not abuse drugs. Important considerations in the selection of successful regimens and the provision of appropriate patient monitoring in this population include need for supportive clinical sites; linkage to substance abuse treatment; and awareness of the interactions between illicit drugs and ARV agents, including the increased risk of side effects and toxicities. Simple regimens should be considered to enhance medication adherence. Preference should be given to ARV agents that have a lower risk of hepatic and neuropsychiatric side effects, simple dosing schedules, and minimal interaction with methadone. ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, SQV/r, TPV/r With ATV/r, DRV/r, FPV/r: R-methadone b AUC ↓ 16%−18%; With LPV/r: methadone AUC ↓ 26%-53%; With SQV/r 1000/100 mg BID: R-methadone AUC ↓ 19%; With TPV/r: R-methadone AUC ↓ 48% Opioid withdrawal unlikely but may occur. Adjustment of methadone dose usually not required; however, monitor for opioid withdrawal and increase methadone dose as clinically indicated. FPV No data with FPV (unboosted) With APV: R-methadone C min ↓ 21%, no significant change in AUC Monitor and titrate methadone as clinically indicated. The interaction with FPV is presumed to be similar. a Norbuprenorphine is an active metabolite of buprenorphine. b R-methadone is the active form of methadone. greatest risk. It is generally recommended that NVP not be prescribed to ARV-naive women who have CD4 counts >250 cells/mm 3 unless there is no other alternative and the benefit from NVP outweighs the risk of hepatotoxicity (AI). # Key to - Lactic acidosis: There is a female predominance in the increased incidence of symptomatic and even fatal lactic acidosis associated with prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTIs). Lactic acidosis is most common with stavudine (d4T), didanosine (ddI), and zidovudine (ZDV) but it can occur with other NRTIs. 13 - Metabolic complications: A few studies have compared women and men in terms of metabolic complications associated with ARV use. Compared with HIV-infected men, HIV-infected women are more likely to experience increases in central fat with ART and are less likely to have triglyceride elevations on treatment. 14,15 Women have an increased risk of osteopenia/osteoporosis, particularly after menopause, and this risk is exacerbated by HIV and ART. 16,17 At the present time, none of these differences requires women-specific recommendations regarding treatment or monitoring. # Women of Childbearing Potential All women of childbearing potential should be offered pre-conception counseling and care as a component of routine primary medical care. Counseling should include discussion of special considerations pertaining to ARV use when trying to conceive and during pregnancy (see Perinatal Guidelines 1 ). Safe sexual practices, reproductive desires and options for conception, HIV status of sexual partner(s), and use of effective contraception to prevent unintended pregnancy should be discussed. An HIV-infected woman who wishes to conceive with an HIV-uninfected male partner should be informed of options to prevent sexual transmission of HIV while attempting conception. Interventions include initiation of maximally suppressive ART, which significantly decreases the risk of sexual transmission (see Preventing Secondary Transmission of HIV), and artificial insemination, including the option to self-inseminate with the partner's sperm during the periovulatory period 18 (for more extensive discussion on this topic, see the Reproductive Options for HIV-Concordant and Serodiscordant Couples section of the Perinatal Guidelines. 1 Efavirenz (EFV) is teratogenic in non-human primates. Women of childbearing potential should undergo pregnancy testing before initiation of EFV and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-based regimens (AIII). Alternative regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health (BIII). The most vulnerable period in fetal organogenesis is early in gestation, before pregnancy is recognized. # Hormonal Contraception Safe and effective reproductive health and family planning services to reduce unintended pregnancy and perinatal transmission of HIV are an essential component of care for HIV-infected women of childbearing age. Counseling about reproductive issues should be provided on an ongoing basis. Providers should be aware of potential interactions between ARV drugs and hormonal contraceptives that could lower contraceptive efficacy. Several protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have drug interactions with combined oral contraceptives (COCs). Interactions include either a decrease or an increase in blood levels of ethinyl estradiol, norethindrone, or norgestimate (see Tables 15a and 15b), which potentially decreases contraceptive efficacy or increases estrogen-or progestinrelated adverse effects (e.g., thromboembolism). Small studies of HIV-infected women receiving injectable depot-medroxyprogesterone acetate (DMPA) while on ART showed no significant interactions between DMPA and EFV, NVP, nelfinavir (NFV), or NRTI drugs. Contraceptive failure of the etonogestrel implant in two patients on EFV-based therapy has been reported and a study has shown EFV may decrease plasma progestin concentrations of COCs containing ethinyl estradiol and norgestimate. 22,23 Several RTVboosted PIs decrease oral contraceptive estradiol levels. 24,25 A small study from Malawi showed that NVP use did not significantly affect estradiol or progestin levels in HIV-infected women. 26 Overall, data are relatively limited and the clinical implications of these findings are unclear. The magnitudes of change in drug levels that may reduce contraceptive efficacy or increase adverse effects are unknown. Concerns about pharmacokinetic interactions between oral and implant hormonal contraceptives and ARVs should not prevent clinicians from prescribing hormonal contraceptives for women on ART if that is their preferred contraceptive method. However, when women wish to use hormonal contraceptives and drug interactions with ARVs are known, additional or alternative contraceptive methods may be recommended (see drug interaction Tables 15a, 15b, and 15d and Perinatal Guidelines 1 ). Consistent use of male or female condoms to prevent transmission of HIV and protect against other sexually transmitted diseases (STDs) is recommended for all HIV-infected women and their partners, regardless of contraceptive use. The data on the association between hormonal contraception and the risk of acquisition of HIV are conflicting. 27 A retrospective secondary analysis of two studies of serodiscordant couples in Africa in which the HIV-infected partner was not receiving ART found that women using hormonal contraception (the vast majority using injectable DMPA) had a twofold increased risk of acquiring HIV (for HIV-infected male/HIVuninfected female couples) or transmitting HIV (HIV-infected female/HIV-uninfected male couples). HIV-infected women using hormonal contraception had higher genital HIV RNA concentrations than did women not using hormonal contraceptives. 28 Oral contraceptive use was not significantly associated with transmission of HIV; however, the number of women using oral contraceptives in this study was insufficient to adequately assess risk. It is important to note that not all studies have supported a link between hormonal contraception and transmission or acquisition of HIV and that the individuals in this study were not receiving ART. Further research is needed to definitively determine if hormonal contraceptive use is an independent risk factor for acquisition and transmission of HIV, particularly in the setting of ART. 27,29 Intrauterine devices (IUDs) appear to be a safe and effective contraceptive option for HIV-infected women. Although studies have focused primarily on non-hormone-containing IUDs (e.g., copper IUD), several small studies have also found levonorgestrel-releasing IUDs to be safe and not associated with increased genital tract shedding of HIV. 31,34,35 # Pregnant Women Clinicians should review the Perinatal Guidelines 1 for a detailed discussion of the management of HIVinfected pregnant women. The use of combination ARV regimens is recommended for all HIV-infected pregnant women, regardless of virologic, immunologic, or clinical parameters (AI). Pregnant HIV-infected women should be counseled regarding the known benefits and risks of ARV use during pregnancy to the woman, fetus, and newborn. A woman's decision regarding ARV use should be respected. Coercive and punitive approaches undermine provider-patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize maternal, fetal, and neonatal well-being. Prevention of Perinatal Transmission of HIV. The use of ARVs and the resultant reduction of HIV RNA levels decrease perinatal transmission of HIV. The goal of ARV use is to achieve maximal and sustained suppression of HIV RNA levels during pregnancy. As in non-pregnant individuals, genotypic resistance testing is recommended for all pregnant women before ARV initiation (AIII) and for pregnant women with detectable HIV RNA levels while on therapy (AI). Optimal prevention of perinatal transmission may require initiation of ARV drugs before results of resistance testing are available. If results demonstrate the presence of significant mutation(s) that may confer resistance to the prescribed ARV regimen, the regimen should be modified. Long-term follow-up is recommended for all infants born to women who have received ARVs during pregnancy, regardless of the infant's HIV status (see the Perinatal Guidelines 1 ). Regimen Considerations. Pregnancy should not preclude the use of optimal drug regimens. Because recommendations on ARVs to use for treatment of HIV-infected pregnant women are subject to unique considerations, recommendations specific to the timing of therapy initiation and the choice of ARVs for pregnant women may differ from those for non-pregnant individuals. These considerations include the following: - Potential changes in pharmacokinetics and, thus, dosing requirements, which result from physiologic changes associated with pregnancy; - potential ARV-associated adverse effects in pregnant women and the woman's ability to adhere to a particular regimen during pregnancy; and - potential short-and long-term effects of the ARV on the fetus and newborn, which are unknown for many drugs. Combination drug regimens are considered the standard of care in pregnancy, both for the treatment of HIV infection and for the prevention of perinatal transmission of HIV. Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, and unnecessary changes in ARV drugs during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII). Detailed recommendations on ARV choice in pregnancy are discussed in detail in the Perinatal Guidelines (see Perinatal Guidelines 1 ). Intravenous (IV) zidovudine (ZDV) infusion to the mother during labor is recommended if maternal HIV RNA is ≥400 copies/mL (or with unknown HIV RNA levels) near delivery, regardless of antepartum regimen or mode of delivery (AI). Consideration can be given to omitting IV ZDV infusion during labor for HIVinfected women receiving combination ART regimens who have HIV RNA <400 copies/mL near delivery (BII); however, the combination ART should continue to be administered during labor. Clinicians who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to ARVs (either administered alone or in combinations) to the Antiretroviral Pregnancy Registry (). The registry collects observational data regarding exposure to Food and Drug Administration-approved ARV drugs during pregnancy for the purpose of assessing potential teratogenicity. For more information regarding selection and use of ART during pregnancy, refer to the Perinatal Guidelines. 1 # Postpartum Management Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for non-pregnant adults and adolescents. Because maternal ART reduces but does not eliminate the risk of transmission of HIV in breast milk and postnatal transmission can occur despite maternal ART, women should also be counseled to avoid breastfeeding. 1 HIV-infected women should avoid pre-mastication of food fed to their infants because the practice has been associated with transmission of HIV from mother to child. 39 Considerations regarding continuation of ART for maternal therapeutic indications are the same as those for ART use in other non-pregnant individuals. For more information regarding postpartum discontinuation of ART, refer to the Perinatal Guidelines. 1 Several studies have demonstrated that adherence to ART may worsen in the postpartum period. Clinicians caring for women postpartum who are receiving ART should specifically address adherence, including an evaluation of specific facilitators and barriers to adherence. Clinicians may consider an intervention to improve adherence (see Adherence to Antiretroviral Therapy). The clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rates compared with HIV-1 infection. However, HIV-2 infection can progress to AIDS, and thus antiretroviral therapy (ART) may become necessary during the course of infection. Concomitant HIV-1 and HIV-2 infection may occur and should be considered in patients from an area with high prevalence of HIV-2. In the appropriate epidemiologic setting, HIV-2 infection should be suspected in patients with clinical conditions suggestive of HIV infection but with atypical serologic results (e.g., a positive screening assay with an indeterminate HIV-1 Western blot). 3 The possibility of HIV-2 infection should also be considered in the appropriate epidemiologic setting in patients with serologically confirmed HIV infection but low or undetectable viral loads or in those with declining CD4 counts despite apparent virologic suppression on ART. The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is Food and Drug Administration (FDA) approved for differentiating HIV-1 from HIV-2 infection. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2, and no HIV-2 commercial viral load assays are currently available. Most studies reporting HIV-2 viral loads use "in-house" assays that are not widely available, making it difficult to monitor virologic response in the clinical setting. In addition, no validated HIV-2 genotypic or phenotypic antiretroviral (ARV) resistance assays are available. To date, there have been no randomized trials addressing the question of when to start ART or the choice of initial or second-line therapy for HIV-2 infection; 6 thus, the optimal treatment strategy has not been defined. HIV-2 appears intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) 7 and to enfuvirtide. 8 In vitro data suggest HIV-2 is sensitive to the currently available nucleoside reverse transcriptase inhibitors (NRTIs), although with a lower barrier to resistance than HIV-1. 9-10 Variable sensitivity among protease inhibitors (PIs) has been reported; lopinavir (LPV), saquinavir (SQV), and darunavir (DRV) are more active against HIV-2 than other approved PIs. The integrase inhibitor, raltegravir (RAL), 15 and the CCR5 antagonist, maraviroc (MVC), appear active against some HIV-2 isolates, although no approved assays to determine HIV-2 coreceptor tropism exist and HIV-2 is known to utilize multiple minor coreceptors in addition to CCR5 and CXCR4. 16 Several small studies suggest poor responses among HIV-2 infected individuals treated with some ARV regimens, including dual-NRTI regimens, regimens containing two NRTIs + NNRTI, and some unboosted PI-based regimens including nelfinavir (NFV) or indinavir (IDV) plus zidovudine (ZDV) and lamivudine (3TC). 6, Clinical data on the utility of triple-NRTI regimens are conflicting. In general, boosted PI-containing regimens have resulted in more favorable virologic and immunologic responses. 21 One small study suggested satisfactory responses to lopinavir/ritonavir (LPV/r)-containing regimens in 17 of 29 (59%) of ARV-naive subjects. 22 Resistance-associated mutations develop commonly in HIV-2 patients on therapy. 17,21,23 Genotypic algorithms used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because pathways and mutational patterns leading to resistance may differ. 10,21,24 CD4 cell recovery on therapy may be poor, 25 suggesting that more reliable methods for monitoring disease progression and treatment efficacy in HIV-2 infection are needed. Some groups have recommended specific preferred and alternative regimens for initial therapy of HIV-2 infection, 24 though as yet there are no controlled trial data to reliably predict their success. Until more definitive data are available in an ART-naive patient with HIV-2 mono-infection or with HIV-1/HIV-2 dual infection who requires treatment, clinicians should initiate a regimen containing two NRTIs and a boosted PI. Monitoring of virologic response in such patients is problematic because of the lack of a commercially available HIV-2 viral load assay; however, clinical and CD4 count improvement can be used to assess treatment response. HIV and the Older Patient (Last updated March 27, 2012; last reviewed March 27, 2012) Effective antiretroviral therapy (ART) has increased survival in HIV-infected individuals, resulting in an increasing number of older individuals living with HIV infection. In the United States, approximately 30% of people currently living with HIV/AIDS are age 50 years or older and trends suggest that the proportion of older persons living with HIV/AIDS will increase steadily. 1 Care of HIV-infected patients increasingly will involve adults 60 to 80 years of age, a population for which data from clinical trials or pharmacokinetic studies are very limited. There are several distinct areas of concern regarding the association between age and HIV disease. 2 First, older HIV-infected patients may suffer from aging-related comorbid illnesses that can complicate the management of HIV infection, as outlined in detail below. Second, HIV disease may affect the biology of aging, possibly resulting in early manifestations of many clinical syndromes generally associated with advanced age. Third, reduced mucosal and immunologic defenses (such as post-menopausal atrophic vaginitis) and changes in risk behaviors (for example, decrease in condom use because of less concern about pregnancy and increased use of erectile dysfunction drugs) in older adults could lead to increased risk of acquisition and transmission of HIV. Finally, because older adults generally are perceived to be at low risk of HIV infection, screening for HIV in this population remains low. For these reasons, HIV infection in many older adults may not be diagnosed until late in the disease process. This section focuses on HIV diagnosis and treatment considerations in the older HIV-infected patient. # HIV Diagnosis and Prevention Even though many older individuals are engaged in risk behaviors associated with acquisition of HIV, they may be perceived to be at low risk of infection and, as a result, they are less likely to be tested for HIV than younger persons. 5 According to one U.S. survey, 71% of men and 51% of women age 60 years and older continue to be sexually active, 6 with less concern about the possibility of pregnancy contributing to less condom use. Another national survey reported that among individuals age 50 years or older, condoms were not used during most recent intercourse with 91% of casual partners or 70% of new partners. 7 In addition, # Key Considerations When Caring for Older HIV-Infected Patients - Antiretroviral therapy (ART) is recommended in patients >50 years of age, regardless of CD4 cell count (BIII), because the risk of non-AIDS related complications may increase and the immunologic response to ART may be reduced in older HIV-infected patients. - ART-associated adverse events may occur more frequently in older HIV-infected adults than in younger HIV-infected individuals. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older HIV-infected adults should be monitored closely. - The increased risk of drug-drug interactions between antiretroviral (ARV) drugs and other medications commonly used in older HIV-infected patients should be assessed regularly, especially when starting or switching ART and concomitant medications. - HIV experts and primary care providers should work together to optimize the medical care of older HIV-infected patients with complex comorbidities. - Counseling to prevent secondary transmission of HIV remains an important aspect of the care of the older HIVinfected patient. results from a CDC survey 8 show that in 2008 only 35% of adults age 45 to 64 years had ever been tested for HIV infection despite the 2006 CDC recommendation that individuals age 13 to 64 years be tested at least once and more often if sexually active. 9 Clinicians must be attuned to the possibility of HIV infection in older patients, including those older than 64 years of age who, based on CDC recommendations, would not be screened for HIV. Furthermore, sexual history taking, risk-reduction counseling, and screening for sexually transmitted diseases (STDs) (if indicated), are important components of general health care for HIVinfected and -uninfected older patients. # Rating of Recommendations Failure to consider a diagnosis of HIV in older persons likely contributes to later disease presentation and initiation of ART. 10 One surveillance report showed that the proportion of patients who progressed to AIDS within 1 year of diagnosis was greater among patients >60 years of age (52%) than among patients younger than 25 years (16%). 1 When individuals >50 years of age present with severe illnesses, AIDS-related opportunistic infections (OIs) need to be considered in the differential diagnosis of the illness. # Initiating Antiretroviral Therapy Concerns about decreased immune recovery and increased risk of serious non-AIDS events are factors that favor initiating ART in patients >50 years of age regardless of CD4 cell count (BIII). (See Initiating Antiretroviral Therapy in Treatment-Naive Patients.) Data that would favor use of any one of the Panel's recommended initial ART regimens (see What to Start) on the basis of age are not available. The choice of regimen should be informed by a comprehensive review of the patient's other medical conditions and medications. A noteworthy limitation of currently available information is lack of data on the long-term safety of specific antiretroviral (ARV) drugs in older patients, such as use of tenofovir disoproxil fumarate (TDF) in older patients with declining renal function. The recommendations on how frequently to monitor parameters of ART effectiveness and safety for adults age >50 years are similar to those for the general HIV-infected population; however, the recommendations for older adults focus particularly on the adverse events of ART pertaining to renal, liver, cardiovascular, metabolic, and bone health (see Table 13). # HIV, Aging, and Antiretroviral Therapy The efficacy, pharmacokinetics, adverse effects, and drug interaction potentials of ART in the older adult have not been studied systematically. There is no evidence that the virologic response to ART is different in older patients than in younger patients. However, CD4 T-cell recovery after starting ART generally is less robust in older patients than in younger patients. This observation suggests that starting ART at a younger age will result in better immunologic and possibly clinical outcomes. Hepatic metabolism and renal elimination are the major routes of drug clearance, including the clearance of ARV drugs. Both liver and kidney function may decrease with age, which may result in impaired drug elimination and drug accumulation. 15 Current ARV drug doses are based on pharmacokinetic and pharmacodynamic data derived from studies conducted in subjects with normal organ function. Most clinical trials include only a small proportion of study participants >50 years of age. Whether drug accumulation in the older patient may lead to greater incidence and severity of adverse effects than seen in younger patients is unknown. HIV-infected patients with aging-associated comorbidities may require additional pharmacologic intervention, making therapeutic management increasingly complex. In addition to taking medications to manage HIV infection and comorbid conditions, many older HIV-infected patients also are taking medications to ameliorate discomfort (e.g., pain medications, sedatives) or to manage adverse effects of medications (e.g., anti-emetics). They also may self-medicate with over-the-counter medicines or supplements. In the HIV-negative population, polypharmacy is a major cause of iatrogenic problems in geriatric patients. 16 This may be the result of medication errors (by prescribers or patients), nonadherence, additive drug toxicities, and drug-drug interactions. Older HIV-infected patients probably are at an even greater risk of polypharmacy and its attendant adverse consequences than younger HIV-infected or similarly aged HIV-uninfected patients. Drug-drug interactions are common with ART and easily can be overlooked by prescribers. 17 The available drug interaction information on ARV agents is derived primarily from pharmacokinetic studies performed in a small number of relatively young, HIV-uninfected subjects with normal organ function (see Tables 14-16b). Data from these studies provide clinicians with a basis to assess whether a significant interaction may exist. However, the magnitude of the interaction may be different in older HIV-infected patients than in younger HIV-infected patients. Nonadherence is the most common cause of treatment failure. Complex dosing requirements, high pill burden, inability to access medications because of cost or availability, limited health literacy including lack of numeracy skills, misunderstanding of instructions, depression, and neurocognitive impairment are among the key reasons for nonadherence. 18 Although many of these factors likely will be more prevalent in an aging HIV-infected population, some data suggest that older HIV-infected patients may be more adherent to ART than younger HIV-infected patients. Clinicians should assess adherence regularly to identify any factors, such as neurocognitive deficits, that may make adherence a challenge. One or more interventions such as discontinuation of unnecessary medications; regimen simplification; or use of adherence tools, including pillboxes, daily calendars, and evidence-based behavioral approaches may be necessary to facilitate medication adherence (see Adherence to Antiretroviral Therapy). # Non-AIDS HIV-Related Complications and other Comorbidities With the reduction in AIDS-related morbidity and mortality observed with effective use of ART, non-AIDS conditions constitute an increasing proportion of serious illnesses in ART-treated HIV-infected populations. Heart disease and cancer are the leading causes of death in older Americans. 25 Similarly, for HIV-infected patients on ART, non-AIDS events such as heart disease, liver disease, and cancer have emerged as major causes of morbidity and mortality. Neurocognitive impairment, already a major health problem in aging patients, may be exacerbated by the effect of HIV infection on the brain. 26 That the presence of multiple non-AIDS comorbidities coupled with the immunologic effects of HIV infection could add to the disease burden of an aging HIV-infected person is a concern. At present, primary care recommendations are the same for HIV-infected and HIV-uninfected adults and focus on identifying and managing risks of conditions such as heart, liver, and renal disease; cancer; and bone demineralization. # Discontinuing Antiretroviral Therapy in Older Patients Important issues to discuss with aging HIV-infected patients are living wills, advance directives, and longterm care planning including financial concerns. Health care cost sharing (e.g., co-pays, out-of-pocket costs), loss of employment, and other financial-related factors can cause interruptions in treatment. Clinic systems can minimize loss of treatment by helping patients maintain access to insurance. For the severely debilitated or terminally ill HIV-infected patient, adding palliative care medications, while perhaps beneficial, further increases the complexity and risk of negative drug interactions. For such patients, a balanced consideration of both the expected benefits of ART and the toxicities and negative quality-of-life effects of ART is needed. Few data exist on the use of ART in severely debilitated patients with chronic, severe, or non-AIDS terminal conditions. Withdrawal of ART usually results in rebound viremia and a decline in CD4 cell count. Acute retroviral syndrome after abrupt discontinuation of ART has been reported. In very debilitated patients, if there are no significant adverse reactions to ART, most clinicians would continue therapy. In cases where ART negatively affects quality of life, the decision to continue therapy should be made together with the patient and/or family members after a discussion on the risks and benefits of continuing or withdrawing ART. # Conclusion HIV infection may increase the risk of many major health conditions experienced by aging adults and possibly accelerate the aging process. 35 As HIV-infected adults age, their health problems become increasingly complex, placing additional demands on the health care system. This adds to the concern that outpatient clinics providing HIV care in the United States share the same financial problems as other chronic disease and primary care clinics and that reimbursement for care is not sufficient to maintain care at a sustainable level. 36 Continued involvement of HIV experts in the care of older HIV-infected patients is warranted. However, given that the current shortage of primary care providers and geriatricians is projected to continue, current HIV providers will need to adapt to the shifting need for expertise in geriatrics through continuing education and ongoing assessment of the evolving health needs of aging HIV-infected patients. 37 The aging of the HIV-infected population also signals a need for more information on long-term safety and efficacy of ARV drugs in older patients. coinfected patients. Therefore, 3TC or FTC should be used in combination with other anti-HBV drugs (AII). 10 - Immune reconstitution after initiation of treatment for HIV and/or HBV can be associated with elevation in transaminases, possibly because HBV is primarily an immune-mediated disease. 11 - Some ARV agents can cause increases in transaminase levels. The rate and magnitude of these increases are higher with HBV coinfection. The etiology and consequences of these changes in liver function tests are unclear because continuation of ART may be accompanied by resolution of the changes. Nevertheless, some experts suspend the implicated agent(s) when the serum alanine transferase (ALT) level is increased to 5-10 times the upper limit of normal. However, in HIV/HBV-coinfected persons, increases in transaminase levels can herald hepatitis B e antigen (HBeAg) seroconversion due to immune reconstitution, so the cause of the elevations should be investigated prior to the decision to discontinue medications. In persons with transaminase increases, HBeAg seroconversion should be evaluated by testing for HBeAg and anti-HBe as well as HBV DNA levels. # Recommendations for HBV/HIV-Coinfected Patients - All patients with chronic HBV should be advised to abstain from alcohol, assessed for immunity to hepatitis A virus (HAV) infection (anti-HAV antibody total) and vaccinated if nonimmune, advised on methods to prevent HBV transmission (methods that do not differ from those to prevent HIV transmission), and evaluated for the severity of HBV infection as outlined in the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. 14 - Prior to intiation of ART, all persons who test positive for HBsAg should be tested for HBV DNA using a quantitative assay to determine the level of HBV replication (AIII). Persons with chronic HBV infection already receiving ART active against HBV should undergo quantitative HBV DNA testing every 6-12 months to determine the effectiveness of therapy in suppressing HBV replication. The goal of HBV therapy with NRTIs is to prevent liver disease complications by sustained suppression of HBV replication to the lowest achievable level. If not yet on therapy and HBV or HIV treatment is needed: In persons without HIV infection, the recommended anti-HBV drugs for the treatment of persons naive to HBV therapy are TDF and entecavir. In HIV-infected patients, however, only TDF can be considered part of the ARV regimen; entecavir has weak anti-HIV activity and must not be considered part of an ARV regimen. In addition, only TDF is fully active for the treatment of persons with known or suspected 3TC-resistant HBV infection. To avoid selection of HBV-resistant variants, when possible, these agents should not be used as the only agent with anti-HBV activity in an ARV regimen (AIII). Preferred regimen. The combination of TDF + FTC or TDF + 3TC should be used as the NRTI backbone of a fully suppressive ARV regimen and for the treatment of HBV infection (AII). Alternative regimens. If TDF cannot safely be used, entecavir should be used in addition to a fully suppressive ARV regimen (AII); importantly, entecavir should not be considered to be a part of the ARV regimen 20 (BII). Due to a partially overlapping HBV-resistance pathway, it is not known if the combination of entectavir + 3TC or FTC will provide additional virologic or clinical benefit compared with entecavir alone. In persons with known or suspected 3TC-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day. However, entecavir resistance may emerge rapidly in patients with 3TC-resistant HBV infection. Therefore, entecavir should be used with caution in such patients with frequent monitoring (~ every 3 months) of the HBV DNA level to detect viral breakthrough. Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC or telbivudine in addition to a fully suppressive ARV regimen; 17, however, data on these regimens in persons with HIV/HBV coinfection are limited (BII). Due to safety concerns, peginterferon alfa should not be used in HIV/HBV-coinfected persons with cirrhosis. - Need to discontinue medications active against HBV: The patient's clinical course should be monitored with frequent liver function tests. The use of adefovir dipivoxil, entecavir, or telbivudine to prevent flares, especially in patients with marginal hepatic reserve such as persons with compensated or decompensated cirrhosis, can be considered. 8 These alternative HBV regimens should only be used in addition to a fully suppressive ARV regimen. - Need to change ART because of HIV resistance: If the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). infection should undergo repeat testing annually. HCV-seropositive patients should be tested for HCV RNA using a qualitative or quantitative assay to confirm the presence of active infection. 17 - Patients with HIV/HCV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others. HIV/HCV-coinfected patients who are susceptible to hepatitis A virus (HAV) or hepatitis B virus (HBV) infection should be vaccinated against these viruses. - All patients with HIV/HCV coinfection should be evaluated for HCV therapy. HCV treatment is recommended according to standard guidelines. 18,19 Strong preference should be given to commence HCV treatment in patients with higher CD4 counts. For patients with lower CD4 counts (e.g., <200 cells/mm 3 ), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of HIV treatment. 17, # Antiretroviral Therapy in HIV/Hepatitis C Virus Coinfection - When to start antiretroviral therapy: The rate of liver disease (liver fibrosis) progression is accelerated in HIV/HCV-coinfected patients, particularly in individuals with low CD4 counts (≤350 cells/mm 3 ). Data largely from retrospective cohort studies are inconsistent regarding the effect of ART on the natural history of HCV disease. 6,23,24 However, ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. Thus, for most coinfected patients, including those with high CD4 counts and those with cirrhosis, the benefits of ART outweigh concerns regarding DILI. Therefore, ART should be initiated for most HIV/HCVcoinfected patients, regardless of CD4 count (BII). However, in HIV treatment-naive patients with CD4 counts >500 cells/mm 3 , some clinicians may choose to defer ART until completion of HCV treatment. - What antiretroviral to start and what antiretroviral not to use: Initial ARV combination regimens for most HIV treatment-naive patients with HCV are the same as those for patients without HCV infection. Special considerations for ARV selection in HIV/HCV-coinfected patients include: - When both HIV and HCV treatments are indicated, the choice of ARV regimen should be guided by the HCV treatment regimen selected with careful consideration of potential drug-drug interactions and overlapping toxicities (as discussed below). - Cirrhotic patients should be carefully assessed for signs of liver decompensation according to the Child-Turcotte-Pugh classification system because hepatically metabolized ARV drugs may require dose modification or avoidance in patients with Child-Pugh class B and C disease. (See Appendix B, Table 7.) - Hepatotoxicity: DILI following initiation of ART is more common in HIV/HCV-coinfected patients than in those with HIV monoinfection. The greatest risk of DILI may be observed in coinfected individuals with advanced liver disease (e.g., cirrhosis or end-stage liver disease). 28 Eradication of HCV infection with treatment may decrease the likelihood of ARV-associated DILI. 29 - Given the substantial heterogeneity in patient populations and drug regimens, comparison of DILI incidence rates for individual ARV agents across clinical trials is difficult. In such studies, the highest incidence rates of significant elevations in liver enzyme levels (>5 times the upper limit of the laboratory reference range) have been observed during therapy with ARV drugs that are no longer commonly used in clinical practice, including stavudine (d4T) (with or without didanosine ), nevirapine (NVP), or full-dose ritonavir (RTV) (600 mg twice daily). 30 Additionally, certain ARV agents should be avoided if possible because they have been associated with higher incidence of serious liver-associated adverse effects, such as fatty liver disease with nucleoside reverse transcriptase inhibitors (NRTIs) such as d4T, ddI, or zidovudine (ZDV); 31 noncirrhotic portal hypertension associated with ddI; 32 and hepatotoxicity associated with RTV-boosted tipranavir. 33 coinfected patients have received HIV PIs and boceprevir during HCV treatment. Patients who are currently receiving these drug combinations should be advised not to stop any medication until contacting their health care providers. If therapy with HIV PIs and boceprevir is continued, patients should be closely monitored for HIV and HCV responses and consideration should be given to switching the HIV PI or EFV to RAL during boceprevir therapy. Additional clinical trial data are needed to determine if other ARVs may be co-administered with boceprevir. - Telaprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. Telaprevir is administered in combination with PegIFN/RBV for the initial 12 weeks of HCV therapy followed by 12 or 36 weeks of additional treatment with PegIFN/RBV. Data on the use of this regimen in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with telaprevir plus PegIFN/RBV (38 patients) than with PegIFN/RBV alone (22 patients). In this study, patients received ART containing EFV or ATV/r plus tenofovir/emtricitabine (TDF/FTC) or no ART during the HCV therapy. 44 Because telaprevir is a substrate and an inhibitor of CYP3A4 and p-gp enzymes, the drug may interact with ARVs metabolized by these pathways. On the basis of drug interaction studies in healthy volunteers and data on responses in coinfected patients enrolled in the small clinical trial noted above, telaprevir can be coadministered with ATV/r 45 and RAL 46 at the standard recommended dose of telaprevir (750 mg every 7-9 hours) and with EFV at an increased dose of telaprevir (1125 mg every 7-9 hours) (see Table 15b); however, co-administration of telaprevir with DRV/r, fosamprenavir/ritonavir (FPV/r), or LPV/r is not recommended because of bidirectional drug interactions. 45 Data on PK interactions of telaprevir with other ARVs including non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than EFV and with maraviroc (MVC) are not available; therefore, co-administration of telaprevir with other ARVs cannot be recommended. Patients receiving other ARV regimens: - If HCV disease is minimal (i.e., no or mild portal fibrosis), consider deferring HCV treatment given rapidly evolving HCV drug development. - If good prognostic factors for HCV treatment response are present-IL28B CC genotype or low HCV RNA level (<400,000 International Unit /mL)-consider use of PegIFN/RBV without HCV NS3/4A PI. - On the basis of ART history and HIV genotype testing results, if possible, consider switching to the ART regimens listed above to permit the use of boceprevir or telaprevir. - For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed. In such patients, telaprevir may be the preferred HCV NS3/4A PI because its duration of use (12 weeks) is shorter than that of boceprevir (24 to 44 weeks). # Summary: In summary, HCV coinfection and use of PegIFN/RBV with or without HCV NS3/4A PIs (telaprevir or boceprevir) to treat HCV may impact the treatment of HIV because of increased pill burden, toxicities, and drug-drug interactions. Because ART may slow the progression of HCV-related liver disease, ART should be considered for most HIV/HCV-coinfected patients, regardless of CD4 count. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (telaprevir or boceprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug-drug interactions and/or drug toxicities that may develop during the period of concurrent HIV and HCV treatment. The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly. HIV disease. It may be associated with a higher HIV viral load and more rapid progression of HIV disease. 3 Active pulmonary or extrapulmonary TB disease requires prompt initiation of TB treatment. The treatment of active TB disease in HIV-infected patients should follow the general principles guiding treatment for individuals without HIV (AI). Treatment of drug-susceptible TB disease should include a standard regimen that consists of isoniazid (INH) + a rifamycin (rifampin or rifabutin) + pyrazinamide + ethambutol given for 2 months, followed by INH + a rifamycin for 4 to 7 months. 4 The Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 4 include a more complete discussion of the diagnosis and treatment of TB disease in HIV-infected patients. All patients with HIV/TB disease should be treated with ART (AI). Important issues related to the use of ART in patients with active TB disease include: (1) when to start ART, (2) significant pharmacokinetic drugdrug interactions between rifamycins and some antiretroviral (ARV) agents, (3) the additive toxicities associated with concomitant ARV and TB drug use, ( 4) the development of TB-associated IRIS after ART initiation, and ( 5) the need for treatment support including DOT and the integration of HIV and TB care and treatment. # Antiretroviral Therapy in Patients with Active Tuberculosis # Patients Diagnosed with Tuberculosis While Receiving Antiretroviral Therapy When TB is diagnosed in a patient receiving ART, the patient's ARV regimen should be assessed with particular attention to potential pharmacokinetic interactions with rifamycins (discussed below). The patient's regimen may need to be modified to permit use of the optimal TB treatment regimen (see Tables 14-16 for dosing recommendations). # Patients Not Yet Receiving Antiretroviral Therapy Until recently, when to start ART in patients with active TB has been a subject of debate. Survival is improved when ART is started early following initiation of TB therapy, but a delay in initiating ART often was favored because of the potential complications of high pill burden, additive toxicities, drug interactions, adherence, and the potential for development of IRIS.Recent studies primarily conducted in resource-limited settings, including three randomized controlled trials, have helped clarify the question of when to start ART in patients with active TB. The SAPiT study conducted in South Africa convincingly demonstrated that starting ART during rather than after concluding treatment for TB can significantly reduce mortality. In this study, ambulatory HIV-infected patients with smear-positive TB and CD4 counts <500 cells/mm 3 were randomized to one of three treatment arms: integrated therapy with ART initiated either during the first 4 weeks of TB therapy or after the first 8 weeks of TB treatment (i.e., during the continuation phase of TB therapy) or sequential therapy with ART initiated after the conclusion of standard TB therapy. The median CD4 cell count of participants at study entry was 150 cells/mm 3 . The sequential therapy arm was stopped when an early analysis demonstrated that the mortality rate in the combined two integrated arms was 56% lower than the rate in the sequential therapy arm. Treatment was continued in the two integrated arms until study completion. 5 With the completion of SAPiT and 2 other randomized controlled trials, CAMELIA and STRIDE, the question on the optimal time to initiate ART during TB therapy has been addressed. Findings from these trials now serve as the basis for the Panel's recommendations on when to start ART in patients with active TB. In the final analysis of the SAPiT trial, there were no differences in rates of AIDS or death between the 2 integrated arms of the study (patients who started ART within 4 weeks after initiating TB treatment vs. those who started ART at 8-12 weeks ). However, in patients with baseline CD4 counts <50 cells/mm 3 (17% of the study population), the rate of AIDS or death was lower in the earlier therapy group than in the later therapy group (8.5 vs. 26.3 cases per 100 person-years, a strong trend favoring the earlier treatment arm, P = 0.06). For all patients, regardless of CD4 cell count, earlier therapy was associated with a higher incidence of IRIS and of adverse events that required a switch in ARV drugs than later therapy. Two deaths were attributed to IRIS. 6 In the CAMELIA study, which was conducted in Cambodia 7 , patients who had CD4 counts <200 cells/mm 3 were randomized to initiate ART at 2 weeks or 8 weeks after initiation of TB treatment. Study participants had advanced HIV disease, with a median entry CD4 count of 25 cells/mm 3 ; low BMIs (median = 16.8 kg/m 2 ), Karnofsky scores (87% <70), and hemoglobin levels (median = 8.7 g/dl); and high rates of disseminated TB disease. Compared with therapy initiated at 8 weeks, ART initiated at 2 weeks resulted in a 38% reduction in mortality (P = 0.006). A significant reduction in mortality was seen in patients with CD4 counts ≤50 cells/mm 3 and in patients with CD4 counts 51 to 200 cells/mm 3 . Overall, 6 deaths associated with TB-IRIS were reported. The ACTG 5221 (STRIDE) trial, a multinational study conducted at 28 sites, randomized ART-naive patients with confirmed or probable TB and CD4 counts <250 cells/mm 3 to earlier (<2 weeks) or later (8-12 weeks) ART. 8 At study entry, the participants' median CD4 count was 77 cells/mm 3 . The rates of mortality and AIDS diagnoses were not different between the earlier and later arms, although higher rates of IRIS were seen in the earlier arm. However, a significant reduction in AIDS or death was seen in the subset of patients with CD4 counts <50 cells/mm 3 who were randomized to the earlier ART arm (P = 0.02). In each of these 3 studies, IRIS was more common in patients initiating ART earlier than in patients starting ART later, but the syndrome was infrequently associated with mortality. Collectively these 3 trials demonstrate that in patients with active TB and with very low CD4 cell counts (i.e., <50 cells/mm 3 ), early initiation of ART can reduce mortality and AIDS progression, albeit at the risk of increased IRIS. These findings strongly favor initiation of ART within the first 2 weeks of TB treatment in patients with CD4 cell counts <50 cells/mm 3 (AI). The question of when to start ART in patients with CD4 counts ≥50 cells/mm 3 is also informed by these studies. The STRIDE and SAPiT studies-in which the patients with CD4 cell counts ≥50 cells/mm 3 were relatively healthy and with reasonable Karnofsky scores (note the SAPiT study excluded patients with Karnofsky scores 500 cells/mm 3 ). However, the CAMELIA study, which included more patients who were severely ill than the STRIDE and SAPiT studies, showed that early initiation of ART improved survival both in patients with CD4 counts ≤50 cells/mm 3 Of additional importance, each of the above studies demonstrated excellent responses to ART, with 90% and >95% of participants achieving suppressed viremia (HIV RNA <400 copies/mL) at 12 months in the SAPiT and CAMELIA studies, respectively, and 74% of participants at 2 years in the STRIDE study. Mortality rates in patients with MDR or XDR TB and HIV coinfection are very high. 9 Retrospective case control studies and case series provide growing evidence of better outcomes associated with receipt of ART in such coinfected patients, 10 but the optimal timing for initiation of ART is unknown. However, given the high rates and rapid mortality, most experts recommend that ART be initiated within 2 to 4 weeks after confirmation of the diagnosis of drug resistance and initiation of second-line TB therapy (BIII). All HIV-infected pregnant women with active TB should be started on ART as early as feasible, both for maternal health and to prevent perinatal transmission of HIV (AIII). The choice of ART should be based on efficacy and safety in pregnancy and take into account potential drug-drug interactions between ARVs and rifamycins (see Perinatal Guidelines for more detailed discussions). 11 TB meningitis often is associated with severe complications and high mortality rate. In a randomized study conducted in Vietnam, patients were randomized to immediate ART or to therapy deferred until 2 months after initiation of TB treatment. A higher rate of severe (Grade 4) adverse events was seen in patients who received immediate ART than in those who deferred therapy (80.3% vs. 69.1%, respectively; P = 0.04). 12 In this study 59.8% of the immediate ART patients and 55.5% of the delayed ART patients died within 9 months. However, in the United States, where patients may be more closely monitored and treated for severe adverse events such as central nervous system (CNS) IRIS, many experts feel that ART should be initiated as for other HIV/TB-coinfected patients (CIII). # Drug Interaction Considerations A rifamycin is a crucial component in treatment of drug-sensitive TB. However, both rifampin and rifabutin are inducers of the hepatic cytochrome P (CYP) 450 and uridine diphosphate gluconyltransferase (UGT) 1A1 enzymes and are associated with significant interactions with most ARV agents including all PIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), maraviroc (MVC), and raltegravir (RAL). Rifampin is a potent enzyme inducer, leading to accelerated drug clearance and significant reduction in ARV drug exposure. Despite these interactions, some observational studies suggest that good virologic, immunologic, and clinical outcomes may be achieved with standard doses of efavirenz (EFV) and, to a lesser extent, nevirapine (NVP) when combined with rifampin. However, rifampin is not recommended in combination with all PIs and the NNRTIs etravirine (ETR) and rilpivirine (RPV). When rifampin is used with MVC or RAL, increased dosage of the ARV is generally recommended. Rifabutin, a weaker enzyme inducer, is an alternative to rifampin. Because rifabutin is a substrate of the CYP 450 enzyme system, its metabolism may be affected by the NNRTI or PI. Tables 14, 15a, 15b, 15d, and 15e outline the magnitude of these interactions and provide dosing recommendations when rifamycins and selected ARV drugs are used concomitantly. After determining the drugs and doses to use, clinicians should monitor patients closely to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, subtherapeutic drug levels (consider therapeutic drug monitoring ), and acquired drug resistance. Rifapentine is a long-acting rifamycin that can be given once weekly with INH for the treatment of active or latent TB infection. Similar to rifampin and rifabutin, rifapentine is also a CYP3A4 inducer. No systematic study has been performed to assess the magnitude of the enzyme induction effect of rifapentine on the metabolism of ARV drugs and other concomitant drugs. Significant enzyme induction can result in reduced ARV drug exposure, which may compromise virologic efficacy. Rifapentine is not recommended for treatment of latent or active TB infection in patients receiving ART, unless given in the context of a clinical trial (AIII). # Anti-Tuberculosis/Antiretroviral Drug Toxicities ARV agents and TB drugs, particularly INH, rifamycin, and pyrazinamide, can cause drug-induced hepatitis. These first-line TB drugs should be used for treatment of active TB disease, even with co-administration of other potentially hepatotoxic drugs or when baseline liver disease is present (AIII). Patients receiving potentially hepatotoxic drugs should be monitored frequently for clinical symptoms and signs of hepatitis and have laboratory monitoring for hepatotoxicity. Peripheral neuropathy can occur with administration of INH, didanosine (ddI), or stavudine (d4T) or may be a manifestation of HIV infection. All patients receiving INH also should receive supplemental pyridoxine to reduce peripheral neuropathy. Patients should be monitored closely for signs of drug-related toxicities and receive alternative ARVs to ddI or d4T. # Immune Reconstitution Inflammatory Syndrome with Tuberculosis and Antiretroviral Agents IRIS occurs in two forms: unmasking and paradoxical. The mechanism of the syndrome is the same for both forms: restoration of immune competence by administration of ART, resulting in an exuberant host response to TB bacilli and/or antigens. Unmasking IRIS refers to the initial clinical manifestations of active TB that occurs soon after ART is started. Paradoxical IRIS refers to the worsening of TB clinical symptoms after ART is started in patients who are receiving TB treatment. Severity of IRIS ranges from mild to severe to life threatening. IRIS has been reported in 8% to more than 40% of patients starting ART after TB is diagnosed, although the incidence depends on the definition of IRIS and the intensity of monitoring. Predictors of IRIS include CD4 count <50 cells/mm 3 ; higher on-ART CD4 counts; high pre-ART and lower on-ART HIV viral loads; severity of TB disease, especially high pathogen burden; and less than 30-day interval between initiation of TB and HIV treatments. Most IRIS in HIV/TB disease occurs within 3 months of the start of TB treatment. Delaying initiation of ART for 2 to 8 weeks may reduce the incidence and severity of IRIS. However, this possible advantage of delayed ART must be weighed against the potential benefit of earlier ART in improving immune function and preventing progression of HIV disease and mortality. Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal anti-inflammatory agents. Patients with more severe IRIS can be treated successfully with corticosteroids. A recent randomized, placebo-controlled trial demonstrated benefit of corticosteroids in the management of IRIS symptoms (as measured by decreasing days of hospitalization and Karnofsky performance score) without adverse consequences. 23 In the presence of IRIS, neither TB therapy nor ART should be stopped because both therapies are necessary for the long-term health of the patient (AIII). # Immune Reconstitution with Antiretroviral Therapy: Conversion to Positive Tuberculin Skin Test and Interferon-Gamma Release Assay Immune reconstitution with ART may result in unmasking LTBI (i.e., conversion of a previously negative tuberculin skin test to a positive TST or a positive interferon-gamma release assay for Mycobacterium tuberculosis-specific proteins). A positive IGRA, similar to a positive TST, is indicative of LTBI in the absence of evidence of active TB disease. 24 Because treatment for LTBI is indicated in the absence of evidence of active TB disease, clinicians should be aware of this phenomenon. Patients with a negative TST or IGRA and advanced HIV disease (i.e., CD4 count 200 cells/mm 3 (BII). 25 # Factors Associated with Nonadherence Adherence to ART can be influenced by characteristics of the patient, the regimen, the clinical setting, and the provider/patient relationship. 3 To assure adherence, it is critical that the patient receive and understand information about HIV disease, the goal of therapy, and the specific regimen prescribed. A number of factors have been associated with poor adherence, including the following: - low levels of health literacy 4 or numeracy (ability to understand numerical-related health information); 5 - certain age-related challenges (e.g., polypharmacy, vision loss, cognitive impairment) 6 ; - younger age; - psychosocial issues (e.g., depression, homelessness, low social support, stressful life events, or psychosis); 7 - nondisclosure of HIV serostatus 8 - neurocognitive issues (e.g., cognitive impairment, dementia) - active (but not history of) substance abuse, particularly for patients who have experienced recent relapse; - stigma 9 ; - difficulty with taking medication (e.g., trouble swallowing pills, daily schedule issues); - complex regimens (e.g., high pill burden, high-frequency dosing, food requirements); - adverse drug effects; - nonadherence to clinic appointments 10 - cost and insurance coverage issues; and - treatment fatigue. Adherence studies conducted in the early era of combination ART with unboosted protease inhibitors (PIs) found that virologic failure is much less likely to occur in patients who adhere to more than 95% of their prescribed doses than in those who are less adherent. 11 More recent adherence studies were conducted using boosted PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). These studies suggest that the longer half-lives of boosted PIs and efavirenz may make the drugs more forgiving of lapses in adherence. Nonetheless, clinicians should encourage patients to adhere as closely as possible to the prescribed doses and schedules for all ART regimens. # Measurement of Adherence There is no gold standard for the assessment of adherence, 1 but there are many validated tools and strategies to choose from. Although patient self-report of adherence predictably overestimates adherence by as much as 20%, 14 this measure still is associated with viral load responses. 15 Thus, a patient's report of suboptimal adherence is a strong indicator of nonadherence and should be taken seriously. When ascertained in a simple, nonjudgmental, routine, and structured format that normalizes less-thanperfect adherence and minimizes socially desirable responses, patient self-report remains the most useful method for the assessment and longitudinal monitoring of a patient's adherence in the clinical setting. A survey of all doses missed during the past 3 days or the past week accurately reflects longitudinal adherence and is the most practical and readily available tool for adherence assessments in clinical trials and in clinical practice. 1 Other strategies also may be effective. One study found that asking patients to rate their adherence on a six-point scale during 1 month was more accurate than asking them about the frequency of missed doses or to estimate the percentage of doses taken during the previous 3 or 7 days. 16 Pharmacy records and pill counts also can be used in addition to simply asking the patient about adherence. 17 Other methods of assessing adherence include the use of electronic measurement devices (e.g., bottle caps, dispensing systems). However, these methods may not be feasible in some clinical settings. # Interventions to Improve Adherence Before writing the first prescriptions, the clinician should assess the patient's readiness to take medication, including information such as factors that may limit adherence (psychiatric illness, active drug use, etc.) and make additional support necessary; the patient's understanding of the disease and the regimen; and the patient's social support, housing, work and home situation, and daily schedules. During the past several years, a number of advances have simplified many regimens dramatically, particularly those for treatment-naive patients. Prescribing regimens that are simple to take, have a low pill burden and low-frequency dosing, have no food requirements, and have low incidence and severity of adverse effects will facilitate adherence. 18 The Panel considered both regimen simplicity and effectiveness when making current treatment recommendations (see What to Start). Patients should understand that their first regimen usually offers the best chance for a simple regimen that affords long-term treatment success and prevention of drug resistance. Given that effective response to ART is dependent on good adherence, clinicians should identify barriers to adherence such as a patient's schedule, competing psychosocial needs, learning needs, and literacy level before treatment is initiated. As appropriate, resources and strategies that will help the patient to achieve and maintain good adherence should be employed. Individualizing treatment with involvement of the patient in decision making is the cornerstone of any treatment plan. 17 The first principle of successful treatment is negotiation of an understandable plan to which the patient can commit. Establishing a trusting relationship over time and maintaining good communication will help to improve adherence and long-term outcomes. An increasing number of interventions have demonstrated efficacy in improving adherence to ART. A metaanalysis of 19 randomized controlled trials of ART adherence interventions found that intervention participants were 1.5 times as likely to report 95% adherence and 1.25 times as likely to achieve an undetectable viral load as participants in comparison conditions. 21 In a more recent synthesis, CDC provides new guidance to assist providers in selecting from among the many possible adherence interventions. 22 Since these reviews have been conducted, additional evidence also has accumulated regarding the efficacy and benefits of motivational interviewing. 23 In summary, effective adherence interventions vary in their modality and duration, providing clinics, providers, and patients with options to suit a range of needs and settings. Some effective interventions identified include multiple nurse home visits, five-session group intervention, pager messaging, and couplesbased interventions. Substance abuse therapy and strengthening social support also can improve adherence. All health care team members, including nurses, nurse practitioners, pharmacists, medication managers, and social workers, have integral roles in successful adherence programs. Directly observed therapy (DOT) has been shown to be effective in provision of ART to active drug users. 28 However, the benefits cannot be sustained after transitioning the drug users out of the methadone clinics and halting the provision of ART by DOT. 29 To routinely determine whether such additional adherence intervention is warranted, assessments should be done at each clinical encounter and should be the responsibility of the entire health care team. Routine monitoring of HIV viral load and pharmacy records are useful determinants for the need of intensified efforts. # Conclusion Significant progress has been made regarding determinants, measurements, and interventions to improve adherence to ART. Given the various assessment strategies and potential interventions available, the challenge for the treatment team is to select the techniques that provide the best fit for the treatment setting, resources available, and patient population. The complexity and the importance of adherence encourage clinicians to continue to seek novel, patient-centered ways to improve adherence and to tailor adherence interventions. Early detection of nonadherence and prompt intervention can reduce greatly the development of viral resistance and the likelihood of virologic failure. accumulation. Avoidance of concomitant use or dose reduction of the affected drug, with close monitoring for dose-related toxicities, may be warranted. # Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Unlike PIs, NNRTIs, EVG, and maraviroc (MVC), NRTIs do not undergo hepatic transformation through the CYP metabolic pathway. Significant pharmacodynamic interactions of NRTIs and other drugs, such as additive bone marrow suppressive effects of zidovudine (ZDV) and ganciclovir, have been reported. Pharmacokinetic (PK) interactions have also been reported; for example, atazanavir (ATV) concentration can be reduced when it is co-administered with TDF. 7 However, the mechanisms underlying some of these interactions are still unclear. Table 15c lists significant interactions with NRTIs. # CCR5 Antagonist MVC is a substrate of CYP3A enzymes and P-glycoprotein. As a consequence, the concentrations of MVC can be significantly increased in the presence of strong CYP3A inhibitors (such as RTV and other PIs, except for TPV/r) and are reduced when MVC is used with CYP3A inducers (such as EFV or rifampin). Dose adjustment is necessary when MVC is used in combination with these agents (see Table 16b or Appendix B, Table 6 for dosage recommendations). MVC is neither an inducer nor an inhibitor of the CYP3A system and does not alter the PKs of the drugs evaluated in interaction studies to date. # Fusion Inhibitor The fusion inhibitor enfuvirtide (T20) is a 36-amino-acid peptide that does not enter human cells. It is expected to undergo catabolism to its constituent amino acids with subsequent recycling of the amino acids in the body pool. No clinically significant drug-drug interaction with T20 has been identified to date. # Pharmacokinetic (PK) Enhancing PK enhancing is a strategy used in ARV treatment to increase the exposure of an ARV by concomitantly administering a drug that inhibits the specific drug metabolizing enzymes for which the ARV is a substrate. Currently two agents are used in clinical practice as PK enhancers: RTV and COBI. RTV is an HIV PI that is primarily used in clinical practice at a lower than approved dose (100 to 400 mg per day) as a PK enhancer for other PIs because of its inhibitory effects on CYP450, predominately CYP3A4 and P-glycoprotein (P-gp). RTV increases the trough concentration (C min ) and prolongs the half-life of the active PIs. 8 The higher C min allows for a greater C min : inhibitory concentration ratio, which reduces the risk that drug resistance will develop as a result of suboptimal drug exposure. The longer half-life of the PI allows for less frequent dosing, which may enhance medication adherence. Because RTV is a potent inhibitor, it may result in complex drug-drug interactions when used with PIs and with other ARVs or non ARVs. Tables 15a and 16a-c list interactions between RTV-containing PI regimens and other medications, as well as comments on the clinical management of these interactions. COBI is a specific, potent CYP3A inhibitor that has a weak to no effect on other CYP450 isoforms. COBI has no ARV activity. The high water solubility of COBI allows for its co-formulation with other agents. 9 COBI is currently available only as part of a fixed dose combination of EVG/COBI/TDF/FTC. COBI is used to increase the plasma concentrations of EVG, an INSTI. Like RTV, COBI has a complex drug-drug interaction profile. COBI also is an inhibitor of P-gp-mediated transport, which appears to be the mechanism by which COBI increases the systemic exposure to TDF. Table 15e lists interactions with COBI identified in PK studies conducted to date, projected interactions, and drugs that should not be co-administered with COBI. When using RTV-or COBI-containing regimens, clinicians should be vigilant in assessing the potential for adverse drug-drug interactions. This is especially important when prescribing CYP3A substrates for which no PK data are available. Despite substantial advances in prevention and treatment of HIV infection in the United States, the rate of new infections has remained stable. Although earlier prevention interventions mainly were behavioral, recent data demonstrate the strong impact of antiretroviral therapy (ART) on secondary HIV transmission. The most effective strategy to stem the spread of HIV will probably be a combination of behavioral, biological, and pharmacological interventions. 3 # Prevention Counseling Counseling and related behavioral interventions for those living with HIV infection can reduce behaviors associated with secondary transmission of HIV. Each patient encounter offers the clinician an opportunity to reinforce HIV prevention messages, but multiple studies show that prevention counseling is frequently neglected in clinical practice. Although delivering effective prevention interventions in a busy practice setting may be challenging, clinicians should be aware that patients often look to their providers for messages about HIV prevention. Multiple approaches to prevention counseling are available, including formal guidance from the Centers for Disease Control and Prevention (CDC) for incorporating HIV prevention into medical care settings. Such interventions have been demonstrated to be effective in changing sexual risk behavior and can reinforce self-directed behavior change early after diagnosis. 9 CDC has identified several prevention interventions for individuals infected with HIV that meet stringent criteria for efficacy and scientific rigor (). The following three interventions have proven effective in treatment settings and can be delivered by providers as brief messages during clinic visits: - Partnership for Health (), - Options (), - Positive Choice (). In addition, CDC's "Prevention Is Care" campaign () helps providers (and members of a multidisciplinary care team) integrate simple methods to prevent transmission by HIV-infected individuals into routine care. These prevention interventions are designed to reduce the risk of secondary HIV transmission through sexual contact. The interventions are designed generally for implementation at the community or group level, but some can be adapted and administered in clinical settings by a multidisciplinary care team. # Need for Screening for High-Risk Behaviors The primary care visit provides an opportunity to screen patients for ongoing high-risk drug and sexual behaviors for transmitting HIV infection. Routine screening and symptom-directed testing for and treatment of sexually transmitted diseases (STDs), as recommended by CDC, 10 remain essential adjuncts to prevention counseling. Genital ulcers may facilitate HIV transmission and STDs may increase HIV viral load in plasma and genital secretions. 7, They also provide objective evidence of unprotected sexual activity, which should prompt prevention counseling. The contribution of substance and alcohol use to HIV risk behaviors and transmission has been well established in multiple populations; therefore, effective counseling for injection and noninjection drug users is essential to prevent HIV transmission. Identifying the substance(s) of use is important because HIV prevalence, transmission risk, risk behaviors, transmission rates, and potential for pharmacologic intervention all vary according to the type of substance used. Risk-reduction strategies for injection drug users (IDUs), in addition to condom use, include needle exchange and instructions on cleaning drug paraphernalia. Evidence supporting the efficacy of interventions to reduce injection drug use risk behavior also exists. Interventions include both behavioral strategies 22 and opiate substitution treatment with methadone or buprenorphine. No successful pharmacologic interventions have been found for cocaine and methamphetamine users; cognitive and behavioral interventions demonstrate the greatest effect on reducing the risk behaviors of these users. Given the significant impact of cocaine and methamphetamine on sexual risk behavior, reinforcement of sexual risk-reduction strategies is important. 28 Antiretroviral Therapy as Prevention ART can play an important role in preventing HIV transmission. Lower levels of plasma HIV RNA have been associated with decreases in the concentration of virus in genital secretions. Observational studies have demonstrated the association between low serum or genital HIV RNA and a decreased rate of HIV transmission among serodiscordant heterosexual couples. 29, Ecological studies of communities with relatively high concentrations of men who have sex with men (MSM) and IDUs suggest increased use of ART is associated with decreased community viral load and reduced rates of new HIV diagnoses. These data suggest that the risk of HIV transmission is low when an individual's viral load is below 400 copies/mL, 35,38 but the threshold below which transmission of the virus becomes impossible is unknown. Furthermore, to be effective at preventing transmission it is assumed that: (1) ART is capable of durably and continuously suppressing viremia; (2) adherence to an effective ARV regimen is high; and (3) there is an absence of a concomitant STD. Importantly, detection of HIV RNA in genital secretions has been documented in individuals with controlled plasma HIV RNA and data describing a differential in concentration of most ARV drugs in the blood and genital compartments exist. 30,39 At least one case of HIV transmission from a patient with suppressed plasma viral load to a monogamous uninfected sexual partner has been reported. 40 In the HPTN 052 trial in HIV-discordant couples, the HIV-infected partners who were ART naive and had CD4 counts between 350 and 550 cells/mm 3 were randomized to initiate or delay ART. In this study, those who initiated ART had a 96% reduction in HIV transmission to the uninfected partners. 3 Almost all of the participants were in heterosexual relationships, all participants received risk-reduction counseling, and the absolute number of transmission events was low: 1 among ART initiators and 27 among ART delayers. Over the course of the study virologic failure rates were less than 5%, a value much lower than generally seen in individuals taking ART for their own health. These low virologic failure rates suggest high levels of adherence to ART in the study, which may have been facilitated by the frequency of study follow-up (study visits were monthly) and by participants' sense of obligation to protect their uninfected partners. Therefore, caution is indicated when interpreting the extent to which ART for the HIV-infected partner protects seronegative partners in contexts where adherence and, thus, rates of continuous viral suppression, may be lower. Furthermore, for HIV-infected MSM and IDUs, biological and observational data suggest suppressive ART also should protect against transmission, but the actual extent of protection has not been established. Rates of HIV risk behaviors can increase coincidently with the availability of potent combination ART, in some cases almost doubling compared with rates in the era prior to highly effective therapy. 9 A meta-analysis demonstrated that the prevalence of unprotected sex acts was increased in HIV-infected individuals who believed that receiving ART or having a suppressed viral load protected against transmitting HIV. 41 Attitudinal shifts away from safer sexual practices since the availability of potent ART underscore the role of provider-initiated HIV prevention counseling. With wider recognition that effective treatment decreases the risk of HIV transmission, it is particularly important for providers to help patients understand that a sustained viral load below the limits of detection will dramatically reduce but does not absolutely assure the absence of HIV in the genital and blood compartments and, hence, the inability to transmit HIV to others. Maximal suppression of viremia not only depends on the potency of the ARV regimen used but also on the patient's adherence to prescribed therapy. Suboptimal adherence can lead to viremia that not only harms the patient but also increases his/her risk of transmitting HIV (including drug-resistant strains) via sex or needle sharing. Screening for and treating behavioral conditions that can impact adherence, such as depression and alcohol and substance use, improve overall health and reduce the risk of secondary transmission. # Summary Consistent and effective use of ART resulting in a sustained reduction in viral load in conjunction with consistent condom usage, safer sex and drug use practices, and detection and treatment of STDs are essential tools for prevention of sexual and blood-borne transmission of HIV. Given these important considerations, medical visits provide a vital opportunity to reinforce HIV prevention messages, discuss sex-and drugrelated risk behaviors, diagnose and treat intercurrent STDs, review the importance of medication adherence, and foster open communication between provider and patient. # Duration of Therapy for Early HIV Infection The optimal duration of therapy for patients with early HIV infection is unknown. Recent studies of early HIV infection have evaluated the potential for starting and then stopping treatment. Although these studies showed some benefits associated with this strategy, a large randomized controlled trial of patients with chronic HIV infection found that treatment interruption was harmful in terms of increased risk of AIDS and non-AIDS events, 35 and that the strategy was associated with increased markers of inflammation, immune activation and coagulation. 36 For these reasons and because of the potential benefit of ART in reducing the risk of HIV transmission, the Panel recommends against discontinuation of ART in patients treated for early HIV infection (AIII). This section provides discussion of some basic principles and unique considerations to follow when caring for HIV-infected women, including during pregnancy. Clinicians who provide care for pregnant women should consult the current Perinatal Guidelines 1 for more in-depth discussion and management assistance. Additional guidance on the management of HIV-infected women can be found at . # Gender Considerations in Antiretroviral Therapy In general, studies to date have not shown gender differences in virologic responses to antritretroviral therapy (ART), but a number of studies have suggested that gender may influence the frequency, presentation, and severity of selected antiretroviral (ARV)-related adverse events. 5 Although data are limited, evidence also exists that pharmacokinetics for some ARV drugs may differ between men and women, possibly because of variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter function, and excretion activity. Adverse Effects: - Nevirapine (NVP)-associated hepatotoxicity: NVP has been associated with an increased risk of symptomatic, potentially fatal, and often rash-associated liver toxicity in ARV-naive individuals; women with higher CD4 counts (>250 cells/mm 3 ) or elevated baseline transaminase levels appear to be at # Panel's Recommendations - The indications for initiation of antiretroviral therapy (ART) and the goals of treatment are the same for HIV-infected women as for other HIV-infected adults and adolescents (AI). - Women taking antiretroviral (ARV) drugs that have significant pharmacokinetic interactions with oral contraceptives should use an additional or alternative contraceptive method to prevent unintended pregnancy (AIII). - In pregnant women, an additional goal of therapy is prevention of perinatal transmission of HIV, with a goal of maximal viral suppression to reduce the risk of transmission of HIV to the fetus and newborn (AI). - When selecting an ARV combination regimen for a pregnant woman, clinicians should consider the known safety, efficacy, and pharmacokinetic data on use during pregnancy for each agent (AIII). - Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz (EFV) and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-based regimens (AIII). - Alternative regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health (BIII). - Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII). - When designing a regimen for a pregnant woman, clinicians should consult the most current Health and Human Services (HHS) Perinatal Guidelines (AIII). Approximately 5%-10% of HIV-infected persons also have chronic HBV infection, defined as testing positive for HBsAg for more than 6 months. 1 The progression of chronic HBV to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma is more rapid in HIV-infected persons than in persons with chronic HBV alone. 2 Conversely, chronic HBV does not substantially alter the progression of HIV infection and does not influence HIV suppression or CD4 cell responses following ART initiation. However, several liverassociated complications that are ascribed to flares in HBV activity, discontinuation of dually active ARVs, or toxicity of ARVs can affect the treatment of HIV in patients with HBV coinfection. These include the following: # Rating of Recommendations - FTC, 3TC, and TDF are approved ARVs that also have antiviral activity against HBV. Discontinuation of these drugs may potentially cause serious hepatocellular damage resulting from reactivation of HBV. 8 - Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when used in HIV/HBV-coinfected patients (AII). 9 - 3TC-resistant HBV is observed in approximately 40% of patients after 2 years on 3TC for chronic HBV and in approximately 90% of patients after 4 years when 3TC is used as the only active drug for HBV in # Panel's Recommendations - Prior to initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) DNA using a quantitative assay to determine the level of HBV replication (AIII). - Because emtricitabine (FTC), lamivudine (3TC), and tenofovir (TDF) have activity against both HIV and HBV, if HBV or HIV treatment is needed, ART should be initiated with the combination of TDF + FTC or TDF + 3TC as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) regimen (AI). - If HBV treatment is needed and TDF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen (BI). Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC or telbivudine in addition to a fully suppressive ARV regimen (BII). - Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when used in HIV/HBV-coinfected patients (AII). - Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV; patients should be advised against self-discontinuation and carefully monitored during interruptions in HBV treatment (AII). - If ART needs to be modified due to HIV virologic failure and the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). # Rating of Recommendations Approximately one-third of patients with chronic hepatitis C virus (HCV) infection progress to cirrhosis at a median time of less than 20 years. 1,2 The rate of progression increases with older age, alcoholism, male sex, and HIV infection. In a meta-analysis, individuals coinfected with HIV/HCV were found to have three times greater risk of progression to cirrhosis or decompensated liver disease than were HCV-monoinfected patients. 5 This accelerated rate is magnified in HIV/HCV-coinfected patients with low CD4 counts. Although ART appears to slow the rate of HCV disease progression in HIV/HCV-coinfected patients, several studies have demonstrated that the rate continues to exceed that observed in those without HIV infection. 7,8 Whether HCV infection accelerates HIV progression, as measured by AIDS-related opportunistic infections (OIs) or death, 9 is unclear. If such an increased risk of HIV progression exists, it may reflect the impact of injection drug use, which is strongly linked to HCV infection. 10,11 The increased frequency of antiretroviral (ARV)associated hepatotoxicity with chronic HCV infection also complicates HIV treatment. 12,13 A combination regimen of peginterferon and ribavirin (PegIFN/RBV) has been the mainstay of treatment for HCV infection. In HCV genotype 1-infected patients without HIV, addition of an HCV NS3/4A protease inhibitor (PI) boceprevir or telaprevir to PegIFN/RBV significantly improves the rate of sustained virologic response (SVR). 14,15 Clinical trials of these HCV PIs in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients are currently under way. Both boceprevir and telaprevir are substrates and inhibitors of cytochrome P (CYP) 3A4/5 and p-glycoprotein (p-gp); boceprevir is also metabolized by aldo-keto reductase. These drugs have significant interactions with certain ARV drugs that are metabolized by the same pathways. As such, the presence of HCV infection and the treatment of HCV may influence HIV treatment as discussed below. # Assessment of HIV/Hepatitis C Virus Coinfection Before Initiation of Antiretroviral Therapy - All HIV-infected patients should be screened for HCV infection using sensitive immunoassays licensed for detection of antibody to HCV in blood. 16 HCV-seronegative patients at risk for the acquistion of HCV # Key Considerations When Managing Patients Coinfected with HIV and Hepatitis C Virus - All HIV-infected patients should be screened for hepatitis C virus (HCV) infection, preferably before starting antiretroviral therapy (ART). - ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. For most HIV/HCV-coinfected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury (DILI). Therefore, ART should be considered for HIV/HCV-coinfected patients, regardless of CD4 count (BII). - Initial ART combination regimens for most HIV/HCV-coinfected patients are the same as those for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, consideration of potential drug-drug interactions and overlapping toxicities should guide ART regimen selection or modification (see discussion in the text). - Combined treatment of HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be initiated for most HIV/HCV-coinfected patients regardless of CD4 cell count, in ARTnaive patients with CD4 counts >500 cells/mm 3 some clinicians may choose to defer ART until completion of HCV treatment. - In patients with lower CD4 counts (e.g., <200 cells/mm 3 ), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of ART. - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored at 1 month after initiation of ART and then every 3 to 6 months. Mild to moderate fluctuations in ALT and/or AST are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease these fluctuations do not require interruption of ART. Significant ALT and/or AST elevation should prompt careful evaluation for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, or alcoholic hepatitis); short-term interruption of the ART regimen or of the specific drug suspected to be responsible for the DILI may be required. 34 # Rating of Recommendations # Treating Both HIV and Hepatitis C Virus Infection Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of HCV disease stage. Some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment. # Considerations for using certain nucleoside reverse transcriptase inhibitors and hepatitis C virus treatments: - ddI should not be given with RBV because of the potential for drug-drug interactions leading to lifethreatening ddI-associated mitochondrial toxicity including hepatomegaly/steatosis, pancreatitis, and lactic acidosis (AII). 35 - Combined use of ZDV and RBV is associated with increased rates of anemia, making RBV dose reduction necessary. Therefore, this combination should be avoided when possible. 36 Because the risk of anemia may further increase when boceprevir or telaprevir is combined with PegIFN/RBV, ZDV should not be given with this combination (AIII). - Abacavir (ABC) has been associated with decreased response to PegIFN/RBV in some, but not all, retrospective studies; current evidence is insufficient to recommend avoiding this combination. # Considerations for the use of HCV NS3/4A protease inhibitors (boceprevir or telaprevir) and antiretroviral therapy: - Boceprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. After 4 weeks of PegIFN/RBV therapy, boceprevir is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy. Data on the use of an HCV regimen containing boceprevir together with ART in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with boceprevir plus PegIFN/RBV (64 patients) than with PegIFN/RBV alone (34 patients). In this study, patients received ART that included HIV-1 ritonavir-boosted atazanavir (ATV/r), darunavir (DRV/r), or lopinavir (LPV/r) or raltegravir (RAL) plus dual NRTIs. 40 Boceprevir is primarily metabolized by aldo-keto reductase, but because the drug is also a substrate and inhibitor of CYP3A4/5 and p-gp enzymes, it may interact with ARVs metabolized by these pathways. Based on drug interaction studies in healthy volunteers, boceprevir can be co-administered with RAL. 41 However, co-administration of boceprevir with ATV/r, DRV/r, LPV/r, or efavirenz (EFV) is not recommended because of bidirectional drug interactions (see Table 15a and 15b). 42,43 Importantly, the pharmacokinetic (PK) interactions of HIV PIs with boceprevir were not identified before the approval of boceprevir and before participant enrollment in the HIV/HCV-coinfection trial; consequently, some # Treatment of Active Tuberculosis in HIV-Infected Patients HIV infection significantly increases the risk of progression from latent to active TB disease. The CD4 cell count influences both the frequency and severity of active TB disease. Active TB also negatively affects # Panel's Recommendations - The principles for treatment of active tuberculosis (TB) disease in HIV-infected patients are the same as those for HIV-uninfected patients (AI). - All HIV-infected patients with diagnosed active TB should be started on TB treatment immediately (AI). - All HIV-infected patients with diagnosed active TB should be treated with antiretroviral therapy (ART) (AI). - In patients with CD4 counts <50 cells/mm 3 , ART should be initiated within 2 weeks of starting TB treatment (AI). - In patients with CD4 counts ≥50 cells/mm 3 who present with clinical disease of major severity as indicated by clinical evaluation (including low Karnofsky score, low body mass index , low hemoglobin, low albumin, organ system dysfunction, or extent of disease), ART should be initiated within 2 to 4 weeks of starting TB treatment. The strength of this recommendation varies on the basis of CD4 cell count: - CD4 count 50 to 200 cells/mm 3 (BI) - CD4 count >200 cells/mm 3 (BIII) - In patients with CD4 counts ≥50 cells/mm 3 who do not have severe clinical disease, ART can be delayed beyond 2 to 4 weeks of starting TB therapy but should be started within 8 to 12 weeks of TB therapy initiation. The strength of this recommendation also varies on the basis of CD4 cell count: - CD4 count 50 to 500 cells/mm 3 (AI) - CD4 count >500 cells/mm 3 (BIII) - In all HIV-infected pregnant women with active TB, ART should be started as early as feasible, both for maternal health and for prevention of mother-to-child transmission (PMTCT) of HIV (AIII). - In HIV-infected patients with documented multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, ART should be initiated within 2 to 4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy (BIII). - Despite pharmacokinetic drug interactions, a rifamycin (rifampin or rifabutin) should be included in TB regimens for patients receiving ART, with dosage adjustment if necessary (AII). - Rifabutin is the preferred rifamycin to use in HIV-infected patients with active TB disease on a protease inhibitor (PI)-based regimen because the risk of substantial drug interactions with PIs is lower with rifabutin than with rifampin (AII). - Co-administration of rifampin and PIs (with or without ritonavir boosting) is not recommended (AII). - Rifapentine (RPT) is NOT recommended in HIV-infected patients receiving ART for treatment of latent TB infection (LTBI) or active TB, unless in the context of a clinical trial (AIII). - Immune reconstitution inflammatory syndrome (IRIS) may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII). - Treatment support, which can include directly observed therapy (DOT) of TB treatment, is strongly recommended for HIV-infected patients with active TB disease (AII). # Rating of Recommendations # Caring for Patients with HIV and Tuberculosis Close collaboration among clinicians, health care institutions, and public health programs involved in the diagnosis and treatment of HIV-infected patients with active TB disease is necessary in order to integrate care and improve medication adherence and TB treatment completion rates, reduce drug toxicities, and maximize HIV outcomes. HIV-infected patients with active TB disease should receive treatment support, including adherence counseling and DOT, corresponding to their needs (AII). ART simplification or use of coformulated fixed-dose combinations also may help to improve drug adherence. # Strategies Examples Use a multidisciplinary team approach Provide an accessible, trusting health care team Adverse effects have been reported with use of all antiretroviral (ARV) drugs; they are among the most common reasons for switching or discontinuing therapy and for medication nonadherence. 1 However, with the use of newer ARV regimens, rates of treatment-limiting adverse events in antiretroviral therapy (ART)naive patients enrolled in randomized trials appear to be declining and are generally now occurring in less than 10% of study participants. However, because most clinical trials have a relatively short follow-up duration, the longer term complications of ART can be underestimated. In the Swiss Cohort study, during 6 years of follow-up, the presence of laboratory adverse events was associated with higher rates of mortality, which highlights the importance of adverse events in overall patient management. 2 Several factors may predispose individuals to adverse effects of ARV medications. For example, compared with men, women (especially ART-naive women with CD4 counts >250 cells/mm 3 ) seem to have a higher propensity to develop Stevens-Johnson syndrome, rashes, and hepatotoxicity from nevirapine (NVP) and have higher rates of lactic acidosis due to nucleoside reverse transcriptase inhibitors (NRTIs). Other factors may also contribute to the development of adverse events: - Concomitant use of medications with overlapping and additive toxicities; - Comorbid conditions that may increase the risk of or exacerbate adverse effects (e.g., alcoholism 9 or coinfection with viral hepatitis may increase the risk of hepatotoxicity); - Drug-drug interactions that may lead to an increase in drug toxicities (e.g., interactions that result from concomitant use of statins with protease inhibitors ); or - Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction (HSR). 13,14 The therapeutic goals of ART include achieving and maintaining viral suppression and improving immune function, but an overarching goal should be to select a regimen that is not only effective but also safe. This requires consideration of the toxicity potential of an ARV regimen, as well as the individual patient's underlying conditions, concomitant medications, and prior history of drug intolerances. In addition, it should be appreciated that, in general, the overall benefits of ART outweigh its risks and that some conditions (e.g., anemia, cardiovascular disease , renal impairment), may be more likely in the absence of ART. 15,16 Information on adverse events of ARVs is outlined in several tables in the guidelines. Table 13 provides clinicians with a list of the most common and/or severe known ARV-associated adverse events by drug class. The most common adverse effects of individual ARV agents are summarized in Appendix B, Tables 1-6. # NVP > other NNRTIs # NVP: - Severe hepatic toxicity with NVP is often associated with skin rash or symptoms of hypersensitivity. - In ARV-naive patients, risk is greater for women with pre-NVP CD4 count >250 cells/mm 3 and men with pre-NVP CD4 count >400 cells/mm 3 . Overall risk is higher for women than men. - Risk is greatest in the first few months of treatment. - 2-week dose escalation of NVP reduces risk of rash and possibly hepatotoxicity if related to hypersensitivity. - NVP is contraindicated in patients with moderate to severe hepatic insufficiency (Child-Pugh classification B or C). - Liver failure observed in HIV-uninfected individuals receiving NVP for postexposure prophylaxis. NVP should never be used for this indication. All PIs: Drug-induced hepatitis and hepatic decompensation (and rare cases of fatalities) have been reported with all PIs to varying degrees. The frequency of hepatic events is higher with TPV/r than with other PIs. - Symptoms worsen with continuation of ABC. - Median onset of reactions is 9 days; approximately 90% of reactions occur within the first 6 weeks of treatment. - The onset of re-challenge reactions is within hours of re-challenge dose - Patients, regardless of HLA-B*5701 status, should not be re-challenged with ABC if HSR is suspected. # NVP: - Hypersensitivity syndrome of hepatic toxicity and rash that may be accompanied by fever, general malaise, fatigue, myalgias, arthralgias, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. - In ARV-naive patients, risk is greater for women with pre-NVP CD4 count >250 cells/mm 3 and men with pre-NVP CD4 count >400 cells/mm 3 . Overall, risk is higher for women than men. - 2-week dose escalation of NVP reduces risk. # Overview Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an antiretroviral (ARV) regimen. A thorough review of concomitant medications can help in designing a regimen that minimizes undesirable interactions. In addition, the potential for drug interactions should be assessed when any new drug (including over-the-counter agents), is added to an existing ARV combination. Most drug interactions with ARV drugs are mediated through inhibition or induction of hepatic drug metabolism. 1 The mechanisms of drug interactions with each ARV drug class are briefly summarized below. Tables 14-16c list significant drug interactions with different ARV agents and recommendations on contraindications, dose modifications, and alternative agents. # Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) All NNRTIs are metabolized in the liver by cytochrome P450 (CYP) 3A isoenzymes. In addition, efavirenz # Protease Inhibitors (PIs) All PIs are metabolized in the liver by CYP3A isoenzymes; consequently their metabolic rates may be altered in the presence of CYP inducers or inhibitors. Co-administration of PIs with ritonavir (RTV), a potent CYP3A inhibitor, intentionally increases PI exposure (see Pharmacokinetic Enhancing below). Coadministration of PIs with a potent CYP3A inducer may lead to suboptimal drug concentrations and reduced therapeutic effects of the PI. These drug combinations should be avoided if alternative agents can be used. If this is not possible, close monitoring of plasma HIV RNA, with or without ARV dosage adjustment and therapeutic drug monitoring (TDM), may be warranted. For example, the rifamycins (i.e., rifampin and, to a lesser extent, rifabutin) are CYP3A4 inducers that can significantly reduce plasma concentrations of most PIs. 2,3 Rifabutin is a less potent CYP3A4 inducer than rifampin. Therefore, despite wider experience with rifampin use, rifabutin is generally considered a reasonable alternative to rifampin for the treatment of tuberculosis when used with a PI-based regimen. 4,5 Some PIs may also induce or inhibit CYP isoenzymes, P-glycoprotein, or other transporters in the gut and elsewhere. Tipranavir (TPV), for example, is a potent inducer of CYP3A4 and P-glycoprotein. The net effect of ritonavir-boosted tipranavir (TPV/r) on CYP3A in vivo, however, appears to be enzyme inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are most likely to be increased if the drugs are given with TPV/r. The net effect of TPV/r on a drug that is a substrate of both CYP3A and P-glycoprotein (Pgp) cannot be confidently predicted. Significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir (LPV) concentrations have been observed in vivo when the PIs were given with TPV/r. The use of a CYP3A substrate that has a narrow margin of safety in the presence of a potent CYP3A inhibitor, such as the PIs, may lead to markedly prolonged elimination half-life (t 1/2 ) and toxic drug b Certain listed drugs are contraindicated on the basis of theoretical considerations. Thus, drugs with narrow therapeutic indices and suspected metabolic involvement with CYP450 3A, 2D6, or unknown pathways are included in this table. Actual interactions may or may not occur in patients. c HIV-infected patients treated with rifapentine have a higher rate of tuberculosis (TB) relapse than those treated with other rifamycin-based regimens. Therefore an alternative agent to rifapentine is recommended. d A high rate of Grade 4 serum transaminase elevation was seen when a higher dose of RTV was added to LPV/r or SQV or when double-dose LPV/r was used with rifampin to compensate for rifampin's induction effect and therefore, these dosing strategies should not be used. e The manufacturer of cisapride has a limited-access protocol for patients who meet specific clinical eligibility criteria. f Use of oral midazolam is contraindicated. Parenteral midazolam can be used with caution as a single dose and can be given in a monitored situation for procedural sedation. # Suggested alternatives to: - Lovastatin, simvastatin: Fluvastatin, pitavastatin, and pravastatin (except for pravastatin with DRV/r) have the least potential for drug-drug interactions (see Table 15a). Use atorvastatin and rosuvastatin with caution; start with the lowest possible dose and titrate based on tolerance and lipid-lowering efficacy. - Rifampin: Rifabutin (with dosage adjustment, see Tables 15a and 15b # H2 Receptor Antagonists # RTV-boosted PIs ATV/r ↓ ATV H2 receptor antagonist dose should not exceed a dose equivalent to famotidine 40 mg BID in ART-naive patients or 20 mg BID in ART-experienced patients. Give ATV 300 mg + RTV 100 mg simultaneously with and/or ≥10 hours after the H2 receptor antagonist. If using TDF and H2 receptor antagonist in ART-experienced patients, use ATV 400 mg + RTV 100 mg. DRV/r, LPV/r No significant effect No dosage adjustment necessary. # PIs without RTV ATV ↓ ATV H2 receptor antagonist single dose should not exceed a dose equivalent of famotidine 20 mg or total daily dose equivalent of famotidine 20 mg BID in ART-naive patients. Give ATV at least 2 hours before and at least 10 hours after the H2 receptor antagonist. c Norbuprenorphine is an active metabolite of buprenorphine. No dosage recommendation. Consider alternative drug for malaria prophylaxis, if possible. a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 to 150 mg per dose. b Norbuprenorphine is an active metabolite of buprenorphine. c R-methadone is the active form of methadone. For treatment of gout flares: Colchicine 0.6 mg x 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days. # Key to For prophylaxis of gout flares: If original regimen was colchicine 0.6 mg BID, the regimen should be decreased to 0.3 mg once daily. If regimen was 0.6 mg once daily, the regimen should be decreased to 0.3 mg every other day. For treatment of familial Mediterranean fever: Do not exceed colchicine 0.6 mg once daily or 0.3 mg BID. # Salmeterol EVG/COBI/TDF/FTC ↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular events. # Concomitant Drug Class/Name Integrase Inhibitor # Dosing Recommendations and Clinical Comments Effect on Integrase Inhibitor or Concomitant Drug Concentrations # Miscellaneous Interactions Key to Abbreviations: AUC = area under the curve, BID = twice daily, CCB = calcium channel blocker, COBI = cobicistat, C max = maximum plasma concentration, C min = minimum plasma concentration, EVG = elvitegravir, PAH = pulmonary arterial hypertension, RAL = raltegravir a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 mg to 150 mg per dose. b Based on between-study comparison. c Use a combination of two LPV/r 200 mg/50 mg tablets + one LPV/r 100 mg/25 mg tablet to make a total dose of LPV/r 500 mg/125 mg. The Panel has carefully reviewed recent results from clinical trials in HIV therapy and considered how they inform appropriate care guidelines. The Panel appreciates that HIV care is highly complex and rapidly evolving. Guidelines are never fixed and must always be individualized. Where possible, the Panel has based recommendations on the best evidence from prospective trials with defined endpoints. When such evidence # Key to Abbreviations does not yet exist, the Panel attempted to reflect reasonable options in its conclusions. HIV care requires, as always, partnerships and open communication. The provider can make recommendations most likely to lead to positive outcomes only if the patient's own point of view and social context are well known. Guidelines are only a starting point for medical decision making. They can identify some of the boundaries of high-quality care but cannot substitute for sound judgment. As further research is conducted and reported, guidelines will be modified. The Panel anticipates continued progress in the simplicity of regimens, improved potency and barrier to resistance, and reduced toxicity. The Panel hopes the guidelines are useful and is committed to their continued adjustment and improvement. See the reference section following Table 7 for creatinine clearance (CrCl) calculation formulas and criteria for Child-Pugh classification. Child-Pugh Score # Key to # SWP a a SWP = Suggested Wholesale Price (source: AmerisourceBergen, accessed December 2012/January 2013) Note that this price may not represent the pharmacy acquisition price or the price paid by consumers. b Should be used in combination with ritonavir. Please refer to Appendix B, Table 3	The discussion on 3-NRTI regimens was removed from this section because 3-NRTI regimens are no longer recommended regimens for ART-naive patients. • Tables 5a, 5b, 6, and 7 were updated to reflect the above changes.• The term "early" HIV infection is now used when describing both the acute phase of HIV infection (i.e., immediately after HIV infection and before seroconversion) and recent (i.e., within first 6 months) HIV infection. • The recommendation for initiation of ART in patients with early infection was changed from "should be considered optional (CIII)" to "should be offered (BII)." • The section was updated to include a summary of recent randomized controlled trials that examined the role of time-limited ART in patients with early HIV infection.• The recommendation on use of efavirenz (EFV) during pregnancy was updated to be in accord with the recommendation in the Perinatal Antiretroviral Guidelines. The key update includes the following statement: "Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII)." • The Panel also recommends that intravenous zidovudine use during labor may be omitted in women who have HIV RNA < 400 copies/mL near delivery (BII). Oral combination ART should be continued during labor.• This section includes new information under the heading "Pharmacokinetic (PK) Enhancing." The additional text describes the roles and mechanisms of ritonavir (RTV) and cobicistat (COBI) as pharmacokinetic enhancers to increase the exposure of antiretroviral drugs. • Tables 14-16c have been updated with new pharmacokinetic interaction data, including known and predicted interactions involving EVG/COBI/TDF/FTC and other drugs.Minor revisions have also been made to the following sections:# • Introduction • Adverse Effects of Antiretroviral Agents (and Table 13) Antiretroviral therapy (ART) for the treatment of HIV infection has improved steadily since the advent of potent combination therapy in 1996. New drugs that offer new mechanisms of action, improvements in potency and activity even against multidrug-resistant viruses, dosing convenience, and tolerability have been approved. ART has dramatically reduced HIV-associated morbidity and mortality and has transformed HIV disease into a chronic, manageable condition. In addition, effective treatment of HIV-infected individuals with ART is highly effective at preventing transmission to sexual partners. 1 However, less than one-third of HIV-infected individuals in the United States have suppressed viral loads, 2 which is mostly a result of undiagnosed HIV infection and failure to link or retain diagnosed patients in care. Despite remarkable improvements in HIV treatment and prevention, economic and social barriers that result in continued morbidity, mortality, and new HIV infections persist. # Management of the # Considerations for Antiretroviral Use in # List of Tables The Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) is a working group of the Office of AIDS Research Advisory Council (OARAC). The primary goal of the Panel is to provide HIV care practitioners with recommendations based on current knowledge of antiretroviral (ARV) drugs used to treat adults and adolescents with HIV infection in the United States. The Panel reviews new evidence and updates recommendations in these guidelines when needed. The Panel's primary areas of attention have included baseline assessment, treatment goals, indications for initiation of ART, choice of the initial regimen for ART-naive patients, drugs or combinations to avoid, management of adverse effects and drug interactions, management of treatment failure, and special ART-related considerations in specific patient populations. For recommendations related to pre-exposure HIV prophylaxis (PrEP) for HIV-uninfected persons, please refer to recommendations from the Centers for Disease Control and Prevention (CDC). 3,4 These guidelines generally represent the state of knowledge regarding the use of ARV agents. However, because the science of HIV evolves rapidly, the availability of new agents and new clinical data may change therapeutic options and preferences. Information included in these guidelines may not be consistent with approved labeling for the particular products or indications in question, and the use of the terms "safe" and "effective" may not be synonymous with the Food and Drug Administration (FDA)-defined legal standards for product approval. The Panel frequently updates the guidelines (current and archived versions of the guidelines are available on the AIDSinfo website at http://www.aidsinfo.nih.gov). However, the guidelines cannot always be updated apace with the rapid evolution of new data in the field of HIV and cannot offer guidance on care for all patients. Clinicians should exercise clinical judgment in management decisions tailored to unique patient circumstances. The Panel recognizes the importance of clinical research in generating evidence to address unanswered questions related to the optimal safety and efficacy of ART. The Panel encourages both the development of protocols and patient participation in well-designed, Institutional Review Board (IRB)-approved clinical trials. # Basis for Recommendations Recommendations in these guidelines are based upon scientific evidence and expert opinion. Each recommended statement includes a letter (A, B, or C) that represents the strength of the recommendation and with a Roman numeral (I, II, or III) that represents the quality of the evidence that supports the recommendation (see Table 2). # Table 2. Rating Scheme for Recommendations # HIV Expertise in Clinical Care Many studies have demonstrated that outcomes achieved in HIV-infected outpatients are better when care is delivered by a clinician with HIV expertise, [5][6][7][8][9][10] which reflects the complexity of HIV infection and its treatment. Thus, appropriate training and experience, as well as ongoing continuing education, are important components of optimal care. Primary care providers without HIV experience, such as those who provide service in rural or underserved areas, should identify experts in their regions who will be available for consultation when needed. Baseline Evaluation (Last updated February 12, 2013; last reviewed February 12, 2013) Every HIV-infected patient entering into care should have a complete medical history, physical examination, and laboratory evaluation and should be counseled regarding the implications of HIV infection. The goals of the initial evaluation are to confirm the diagnosis of HIV infection, obtain appropriate baseline historical and laboratory data, ensure patient understanding about HIV infection and its transmission, and to initiate care as recommended in HIV primary care guidelines 1 and guidelines for prevention and treatment of HIV-associated opportunistic infections. 2 The initial evaluation also should include introductory discussion on the benefits of antiretroviral therapy (ART) for the patient's health and to prevent HIV transmission. Baseline information then can be used to define management goals and plans. In the case of previously treated patients who present for an initial evaluation with a new health care provider, it is critical to obtain a complete antiretroviral (ARV) history (including drug-resistance testing results, if available), preferably through the review of past medical records. Newly diagnosed patients should also be asked about any prior use of ARV agents for prevention of HIV infection. The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens: • HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay's limit of detection) (AI); • CD4 T-cell count (CD4 count) (AI); • Plasma HIV RNA (viral load) (AI); • Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses (AIII); • Fasting blood glucose and serum lipids (AIII); and • Genotypic resistance testing at entry into care, regardless of whether ART will be initiated immediately (AII). For patients who have HIV RNA levels <500 to 1,000 copies/mL, viral amplification for resistance testing may not always be successful (BII). In addition, other tests (including screening tests for sexually transmitted infections and tests for determining the risk of opportunistic infections and need for prophylaxis) should be performed as recommended in HIV primary care and opportunistic infections guidelines. 1,2 Patients living with HIV infection often must cope with many social, psychiatric, and medical issues that are best addressed through a patient-centered, multi-disciplinary approach to the disease. The baseline evaluation should include an evaluation of the patient's readiness for ART, including an assessment of high-risk behaviors, substance abuse, social support, mental illness, comorbidities, economic factors (e.g., unstable housing), medical insurance status and adequacy of coverage, and other factors that are known to impair adherence to ART and increase the risk of HIV transmission. Once evaluated, these factors should be managed accordingly. The baseline evaluation should also include a discussion of risk reduction and disclosure to sexual and/or needle sharing partners, especially with untreated patients who are still at high risk of HIV transmission. The CD4 T-cell count (CD4 count) serves as the major laboratory indicator of immune function in patients who have HIV infection. It is one of the key factors in determining both the urgency of antiretroviral therapy (ART) initiation and the need for prophylaxis for opportunistic infections. It is also the strongest predictor of subsequent disease progression and survival according to findings from clinical trials and cohort studies. 1,2 CD4 counts are highly variable; a significant change (2 standard deviations) between 2 tests is approximately a 30% change in the absolute count, or an increase or decrease in CD4 percentage by 3 percentage points. • Use of CD4 Count for Initial Assessment. The CD4 count is one of the most important factors in determining the urgency of ART initiation and the need for prophylaxis for opportunistic infections. All patients at entry into care should have a baseline CD4 count (AI). Recommendations for initiation of ART can be found in the Initiating Antiretroviral Therapy in Antiretroviral-Naive Patients section of these guidelines. • Use of CD4 Count for Monitoring Therapeutic Response. An adequate CD4 response for most patients on therapy is defined as an increase in CD4 count in the range of 50 to 150 cells/mm 3 per year, generally with an accelerated response in the first 3 months of treatment. Subsequent increases in patients with good virologic control average approximately 50 to 100 cells/mm 3 per year until a steady state level is reached. 3 Patients who initiate therapy with a low CD4 count 4 or at an older age 5 may have a blunted increase in their counts despite virologic suppression. Frequency of CD4 Count Monitoring. ART now is recommended for all HIV-infected patients. In untreated patients, CD4 counts should be monitored every 3 to 6 months to determine the urgency of ART initiation. In patients on ART, the CD4 count is used to assess the immunologic response to ART and the need for initiation or discontinuation of prophylaxis for opportunistic infections (AI). The CD4 count response to ART varies widely, but a poor CD4 response is rarely an indication for modifying a virologically suppressive antiretroviral (ARV) regimen. In patients with consistently suppressed viral loads who have already experienced ART-related immune reconstitution, the CD4 cell count provides limited information, and frequent testing may cause unnecessary anxiety in patients with clinically inconsequential fluctuations. Thus, for the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load. In such patients, CD4 count may be monitored every 6 to 12 months, unless there are changes in the patient's clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII). Factors that affect absolute CD4 count. The absolute CD4 count is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4+ T lymphocytes. This absolute number may fluctuate in individuals or may be influenced by factors that may affect the total WBC count and lymphocyte percentages, such as use of bone marrow-suppressive medications or the presence of acute infections. Splenectomy 6,7 or co-infection with human T-lymphotropic virus type I (HTLV-1) 8 may cause misleadingly elevated absolute CD4 counts. Alpha-interferon, on the other hand, may reduce the absolute CD4 count without changing the CD4 percentage. 9 In all these cases, CD4 percentage remains stable and may be a more appropriate parameter to assess the patient's immune function. Plasma HIV-1 RNA Testing (Last updated February 12, 2013; last reviewed February 12, 2013) Plasma HIV-1 RNA (viral load) should be measured in all HIV-1-infected patients at baseline and on a regular basis thereafter, especially in patients who are on treatment, because viral load is the most important indicator of response to antiretroviral therapy (ART) (AI). Commercially available HIV-1 RNA assays do not detect HIV-2 viral load. For further discussion on HIV-2 RNA monitoring in patients with HIV-1/HIV-2 coinfection or HIV-2 mono-infection, see HIV-2 Infection. Analysis of 18 trials that included more than 5,000 participants with viral load monitoring showed a significant association between a decrease in plasma viremia and improved clinical outcome. 1 Thus, viral load testing serves as a surrogate marker for treatment response 2 and can be useful in predicting clinical progression. 3,4 The minimal change in viral load considered to be statistically significant (2 standard deviations) is a threefold, or a 0.5 log 10 copies/mL change. Optimal viral suppression is generally defined as a viral load persistently below the level of detection (<20 to 75 copies/mL, depending on the assay used). However, isolated blips (viral loads transiently detectable at low levels, typically <400 copies/mL) are not uncommon in successfully treated patients and are not thought to represent viral replication or to predict virologic failure. 5 In addition, low-level positive viral load results (typically <200 copies/mL) appear to be more common with some viral load assays than with others. Furthermore, there is no definitive evidence that patients with viral loads quantified as <200 copies/mL using these assays are at increased risk for virologic failure. [6][7][8] For the purposes of clinical trials, the AIDS Clinical Trials Group (ACTG) currently defines virologic failure as a confirmed viral load >200 copies/mL, which eliminates most cases of apparent viremia caused by blips or assay variability. 9 This definition also may be useful in clinical practice (see Virologic and Immunologic Failure). For most individuals who are adherent to their antiretroviral (ARV) regimens and who do not harbor resistance mutations to the prescribed drugs, viral suppression is generally achieved in 12 to 24 weeks, although it may take longer in some patients. Recommendations for the frequency of viral load monitoring are summarized below. • At initiation or change in therapy. Plasma viral load should be measured before initiation of therapy and preferably within 2 to 4 weeks, and not more than 8 weeks, after treatment initiation or after treatment modification (BI). Repeat viral load measurement should be performed at 4-to 8-week intervals until the level falls below the assay's limit of detection (BIII). • In virologically suppressed patients in whom therapy was modified because of drug toxicity or for regimen simplification. Viral load measurement should be performed within 2 to 8 weeks after changing therapy. The purpose of viral load monitoring at this point is to confirm potency of the new regimen (BIII). • In patients on a stable ARV regimen. Viral load should be repeated every 3 to 4 months or as clinically indicated (BII). Clinicians may extend the interval to every 6 months for adherent patients who have suppressed viral loads for more than 2 to 3 years and whose clinical and immunologic status is stable (BIII). Monitoring in patients with suboptimal response. In addition to viral load monitoring, a number of additional factors should be assessed, such as adherence to prescribed medications, altered pharmacology, or drug interactions. Patients who fail to achieve viral suppression should undergo resistance testing to aid in the selection of an alternative regimen, as discussed in Drug-Resistance Testing and Virologic and Immunologic Failure (AI). Drug-Resistance Testing (Last updated February 12, 2013; last reviewed February 12, 2013) # Genotypic and Phenotypic Resistance Assays Genotypic and phenotypic resistance assays are used to assess viral strains and inform selection of treatment strategies. Standard assays provide information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Testing for integrase and fusion inhibitor resistance can also be ordered separately from several commercial laboratories. Co-receptor tropism assays should be performed whenever the use of a CCR5 antagonist is being considered. Phenotypic co-receptor tropism assays have been used in clinical practice. A genotypic assay to predict coreceptor use is now commercially available (see Co-receptor Tropism Assays). # Genotypic Assays Genotypic assays detect drug-resistance mutations present in relevant viral genes. Most genotypic assays involve sequencing of the RT and PR genes to detect mutations that are known to confer drug resistance. Genotypic assays that assess mutations in the integrase and gp41 (envelope) genes are also commercially available. Genotypic assays can be performed rapidly and results are available within 1 to 2 weeks of sample collection. Interpretation of test results requires knowledge of the mutations selected by different antiretroviral (ARV) drugs and of the potential for cross resistance to other drugs conferred by certain mutations. The International AIDS Society-USA (IAS-USA) maintains an updated list of significant resistance-associated mutations in the RT, PR, integrase, and envelope genes (see # Panel's Recommendations • HIV drug-resistance testing is recommended in persons with HIV infection at entry into care regardless of whether antiretroviral therapy (ART) will be initiated immediately or deferred (AII). If therapy is deferred, repeat testing should be considered at the time of ART initiation (CIII). • Genotypic testing is recommended as the preferred resistance testing to guide therapy in antiretroviral (ARV)-naive patients (AIII). • Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is a concern, providers may wish to supplement standard genotypic resistance testing with an INSTI genotype test (CIII). • HIV drug-resistance testing should be performed to assist in the selection of active drugs when changing ARV regimens in persons with virologic failure and HIV RNA levels >1,000 copies/mL (AI). In persons with HIV RNA levels >500 but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). • Drug-resistance testing should also be performed when managing suboptimal viral load reduction (AII). • In persons failing INSTI-based regimens, genotypic testing for INSTI resistance should be performed to determine whether to include a drug from this class in subsequent regimens (AII). • Drug-resistance testing in the setting of virologic failure should be performed while the person is taking prescribed ARV drugs or, if not possible, within 4 weeks after discontinuing therapy (AII). • Genotypic testing is recommended as the preferred resistance testing to guide therapy in patients with suboptimal virologic responses or virologic failure while on first or second regimens (AII). • The addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drugresistance mutation patterns, particularly to protease inhibitors (PIs) (BIII). • Genotypic resistance testing is recommended for all pregnant women before initiation of ART (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI) (see the Perinatal Treatment Guidelines for more detailed discussion). http://www.iasusa.org/resistance_mutations). 1 The Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu) also provides helpful guidance for interpreting genotypic resistance test results. Various tools to assist the provider in interpreting genotypic test results are now available. [2][3][4][5] Clinical trials have demonstrated that consultation with specialists in HIV drug resistance improves virologic outcomes. 6 Clinicians are thus encouraged to consult a specialist to facilitate interpretation of genotypic test results and design of an optimal new regimen. # Rating of Recommendations # Phenotypic Assays Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT and PR gene sequences and, more recently, integrase and envelope sequences derived from patient plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses that express the patient-derived HIV genes of interest. Replication of these viruses at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory concentration [IC 50 ]) is calculated, and the ratio of the IC 50 of test and reference viruses is reported as the fold increase in IC 50 (i.e., fold resistance). Automated phenotypic assays that can produce results in 2 to 3 weeks are commercially available, but they cost more to perform than genotypic assays. In addition, interpretation of phenotypic assay results is complicated by incomplete information regarding the specific resistance level (i.e., fold increase in IC 50 ) that is associated with drug failure, although clinically significant fold increase cutoffs are now available for some drugs. [7][8][9][10][11] Again, consultation with a specialist to interpret test results can be helpful. Further limitations of both genotypic and phenotypic assays include lack of uniform quality assurance testing for all available assays, relatively high cost, and insensitivity to minor viral species. Despite being present, drug-resistant viruses that constitute less than 10% to 20% of the circulating virus population will probably not be detected by commercially available assays. This limitation is important because after drugs exerting selective pressure on drug-resistant populations are discontinued, a wild-type virus often re-emerges as the predominant population in the plasma. As a consequence, the proportion of virus with resistance mutations decreases to below the 10% to 20% threshold. [12][13][14] In the case of some drugs, this reversion to predominantly wild-type virus can occur in the first 4 to 6 weeks after the drugs are discontinued. Prospective clinical studies have shown that despite this plasma reversion, re-initiation of the same ARV agents (or those sharing similar resistance pathways) is usually associated with early drug failure, and that the virus present at failure is derived from previously archived resistant virus. 15 Therefore, resistance testing is of greatest value when performed before or within 4 weeks after drugs are discontinued (AII). Because resistant virus may persist in the plasma of some patients for longer periods of time, resistance testing done 4 to 6 weeks after discontinuation of drugs may still detect mutations. However, the absence of detectable resistance in such patients must be interpreted with caution when designing subsequent ARV regimens. # Use of Resistance Assays in Clinical Practice (See Table 4) # Use of Resistance Assays in Determining Initial Treatment Transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic response to initial antiretroviral therapy (ART). [16][17][18][19] The likelihood that a patient will acquire drug-resistant virus is related to the prevalence of drug resistance in HIV-infected persons engaging in high-risk behaviors in the community. In the United States and Europe, recent studies suggest that the risk that transmitted virus will be resistant to at least one ARV drug is in the range of 6% to 16%. [20][21][22][23][24][25] Up to 8%, but generally less than 5% of transmitted viruses will exhibit resistance to drugs from more than one class. 24,[26][27][28] If the decision is made to initiate therapy in a person with early HIV infection, resistance testing at baseline can guide regimen selection to optimize virologic response. Therefore, resistance testing in this situation is recommended (AII). A genotypic assay is preferred for this purpose (AIII). In this setting, treatment initiation should not be delayed pending resistance testing results. Once results are obtained, the treatment regimen can be modified if warranted (see Acute and Recent HIV Infection). In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but when therapy is eventually initiated, resistant viruses even at a low level may still increase the risk of treatment failure. [29][30][31] Therefore, if therapy is deferred, resistance testing should still be done during acute HIV infection (AIII). In this situation, the genotypic resistance test result may be kept on record until the patient is to be started on ART. Repeat resistance testing at the time treatment is started should be considered because it is possible for a patient to acquire drug-resistant virus (i.e., superinfection) between entry into care and initiation of ART (CIII). Performing drug-resistance testing before ART initiation in patients with chronic HIV infection is less straightforward. The rate at which transmitted resistance-associated mutations revert to wild-type virus has not been completely delineated, but mutations present at the time of HIV transmission are more stable than those selected under drug pressure. It is often possible to detect resistance-associated mutations in viruses that were transmitted several years earlier. [32][33][34] No prospective trial has addressed whether drug-resistance testing before initiation of therapy confers benefit in this population. However, data from several, but not all, studies suggest that virologic responses in persons with baseline resistance mutations are suboptimal. [16][17][18][19][35][36][37] In addition, a cost-effectiveness analysis of early genotypic resistance testing suggests that baseline testing in this population should be performed. 38 Therefore, resistance testing in chronically infected persons is recommended at the time of entry into HIV care (AII). Although no definitive prospective data exist to support the choice of one type of resistance testing over another, genotypic testing is generally preferred in this situation because of lower cost, more rapid turnaround time, the assay's ability to detect mixtures of wild-type and resistant virus, and the relative ease of interpreting test results (AIII). If therapy is deferred, repeat testing soon before initiation of ART should be considered because the patient may have acquired drug-resistant virus (i.e., superinfection) (CIII). Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the RT and PR genes. Although transmission of integrase strand transfer inhibitor (INSTI)-resistant virus has rarely been reported, as use of INSTIs increases, the potential for transmission of INSTI-resistant virus may also increase. Therefore, when INSTI resistance is suspected, providers may wish to supplement standard baseline genotypic resistance testing with genotypic testing for resistance to this class of drugs (CIII). # Use of Resistance Assays in the Event of Virologic Failure Resistance assays are useful in guiding treatment decisions for patients who experience virologic failure while on ART. Several prospective studies assessed the utility of resistance testing to guide ARV drug selection in patients with virologic failure. These studies involved genotypic assays, phenotypic assays, or both. 6,[39][40][41][42][43][44][45] In general, these studies found that changes in therapy that were informed by resistance testing results produced better early virologic response to salvage regimens than regimen changes guided only by clinical judgment. In addition, one observational cohort study found that performance of genotypic drug-resistance testing in ART-experienced patients with detectable plasma HIV RNA was independently associated with improved survival. 46 Thus, resistance testing is recommended as a tool in selecting active drugs when changing ARV regimens because of virologic failure in persons with HIV RNA >1,000 copies/mL (AI) (see Virologic and Immunologic Failure). In persons with HIV RNA >500 copies/mL but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). Drug-resistance testing in persons with a plasma viral load <500 copies/mL is not usually recommended because resistance assays cannot be consistently performed given low HIV RNA levels (AIII). Resistance testing also can help guide treatment decisions for patients with suboptimal viral load reduction (AII). Virologic failure in the setting of combination ART is, for certain patients, associated with resistance to only one component of the regimen. [47][48][49] In this situation, substituting individual drugs in a failing regimen may be a possible option, but this concept will require clinical validation (see Virologic and Immunologic Failure). In patients who are on a failing first or second ARV drug regimen and experiencing virologic failure or suboptimal viral load reduction, genotypic testing is generally preferred for resistance testing (AII). This is based on the fact that, when compared with phenotypic testing, genotypic testing costs less to perform, has a faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. In addition, observations show that the assays are comparable predictors of virologic response to subsequent ART regimens. 50 Addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drug-resistance mutation patterns, particularly to PIs (BIII). In patients failing INSTI-based regimens, testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII); genotypic testing is preferred for this purpose. When the use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI). Phenotypic co-receptor tropism assays have been used in clinical practice. A genotypic assay to predict co-receptor use is now commercially available and is less expensive than phenotypic assays. Evaluation of genotypic assays is ongoing, but current data suggest that such testing should be considered as an alternative assay. The same principles regarding testing for co-receptor use also apply to testing when patients exhibit virologic failure on a CCR5 antagonist. 51 Resistance to CCR5 antagonists in the absence of detectable CXCR4-using virus has been reported, but such resistance is uncommon (see Co-receptor Tropism Assays). # Use of Resistance Assays in Pregnant Women In pregnant women, the goal of ART is to maximally reduce plasma HIV RNA to provide optimal maternal therapy and to prevent perinatal transmission of HIV. Genotypic resistance testing is recommended for all pregnant women before initiation of therapy (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). Phenotypic testing in those found to have complex drug-resistance mutation patterns, particularly to PIs, may provide additional information (BIII). Optimal prevention of perinatal transmission may require initiation of ART pending resistance testing results. Once the results are available, the ARV regimen can be changed as needed. # Clinical Setting/Recommendation Rationale # Drug-resistance assay recommended In acute HIV infection: Drug-resistance testing is recommended regardless of whether antiretroviral therapy (ART) is initiated immediately or deferred (AII). A genotypic assay is generally preferred (AIII). If ART is deferred, repeat resistance testing should be considered at the time therapy is initiated (CIII). A genotypic assay generally is preferred (AIII). If ART is initiated immediately, drug-resistance testing can determine whether drug-resistant virus was transmitted. Test results will help in the design of initial regimens or to modify or change regimens if results are obtained after treatment initiation. Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. If ART is deferred, testing should still be performed because of the greater likelihood that transmitted resistance-associated mutations will be detected earlier in the course of HIV infection. Results of resistance testing may be important when treatment is initiated. Repeat testing at the time ART is initiated should be considered because the patient may have acquired a drug-resistant virus (i.e., superinfection). In ART-naive patients with chronic HIV infection: Drug-resistance testing is recommended at entry into HIV care, regardless of whether therapy is initiated immediately or deferred (AII). A genotypic assay is generally preferred (AIII). If therapy is deferred, repeat resistance testing should be considered before initiation of ART (CIII). A genotypic assay is generally preferred (AIII). If an INSTI is considered for an ART-naive patient and transmitted INSTI resistance is a concern, providers may supplement standard resistance testing with a specific INSTI genotypic resistance assay (CIII). If use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-receptor Tropism Assays) Transmitted HIV with baseline resistance to at least 1 drug is seen in 6% to 16% of patients, and suboptimal virologic responses may be seen in patients with baseline resistant mutations. Some drugresistance mutations can remain detectable for years in untreated, chronically infected patients. Repeat testing before initiation of ART should be considered because the patient may have acquired a drug-resistant virus (i.e., a superinfection). Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. Standard genotypic drug-resistance assays test only for mutations in the RT and PR genes. (see Co-receptor Tropism Assays) In patients with virologic failure: Drug-resistance testing is recommended in patients on combination ART with HIV RNA levels >1,000 copies/mL (AI). In patients with HIV RNA levels >500 copies/mL but <1,000 copies/mL, testing may not be successful but should still be considered (BII). A standard genotypic resistance assay is generally preferred for patients experiencing virologic failure on their first or second regimens (AII). In patients failing INSTI-based regimens, genotypic testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII). If use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-receptor Tropism Assays). Addition of phenotypic assay to genotypic assay is generally preferred in patients with known or suspected complex drugresistance patterns, particularly to protease inhibitors (PIs) (BIII). Testing can help determine the role of resistance in drug failure and maximize the clinician's ability to select active drugs for the new regimen. Drug-resistance testing should be performed while the patient is taking prescribed ARV drugs or, if not possible, within 4 weeks after discontinuing therapy. Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant HIV. Standard genotypic drug-resistance assays test only for mutations in the RT and PR genes. Phenotypic testing can provide additional useful information in patients with complex drug-resistance mutation patterns, particularly to PIs. # Clinical Setting/Recommendation Rationale # Drug-resistance assay recommended In patients with suboptimal suppression of viral load: Drugresistance testing is recommended in patients with suboptimal suppression of viral load after initiation of ART (AII). Testing can help determine the role of resistance and thus assist the clinician in identifying the number of active drugs available for a new regimen. In HIV-infected pregnant women: Genotypic resistance testing is recommended for all pregnant women before initiation of ART (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). The goal of ART in HIV-infected pregnant women is to achieve maximal viral suppression for treatment of maternal HIV infection and for prevention of perinatal transmission of HIV. Genotypic resistance testing will assist the clinician in selecting the optimal regimen for the patient. # Drug-resistance assay not usually recommended After therapy is discontinued: Drug-resistance testing is not usually recommended more than 4 weeks after discontinuation of ARV drugs (BIII). Drug-resistance mutations may become minor species in the absence of selective drug pressure, and available assays may not detect minor drug-resistant species. If testing is performed in this setting, the detection of drug resistance may be of value; however, the absence of resistance does not rule out the presence of minor drug-resistant species. In patients with low HIV RNA levels: Drug-resistance testing is not usually recommended in patients with a plasma viral load <500 copies/mL (AIII). Resistance assays cannot be consistently performed given low HIV RNA levels. HIV enters cells by a complex process that involves sequential attachment to the CD4 receptor followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cellular membranes. 1 CCR5 coreceptor antagonists prevent HIV entry into target cells by binding to the CCR5 receptors. 2 Phenotypic and, to a lesser degree, genotypic assays have been developed that can determine or predict the co-receptor tropism (i.e., CCR5, CXCR4, or both) of the patient's dominant virus population. An older generation assay (Trofile, Monogram Biosciences, Inc., South San Francisco, CA) was used to screen patients who were participating in clinical trials that led to the approval of maraviroc (MVC), the only CCR5 antagonist currently available. The assay has been improved and is now available with enhanced sensitivity. In addition, a genotypic assay to predict co-receptor usage is now commercially available. During acute/recent infection, the vast majority of patients harbor a CCR5-utilizing virus (R5 virus), which suggests that the R5 variant is preferentially transmitted. Viruses in many untreated patients eventually exhibit a shift in co-receptor tropism from CCR5 usage to either CXCR4 or both CCR5 and CXCR4 tropism (i.e., dual-or mixed-tropic; D/M-tropic). This shift is temporally associated with a more rapid decline in CD4 T-cell counts, 3,4 but whether this tropism shift is a cause or a consequence of progressive immunodeficiency remains undetermined. 1 Antiretroviral (ARV)-treated patients with extensive drug resistance are more likely to harbor X4-or D/M-tropic variants than untreated patients with comparable CD4 counts. 5 The prevalence of X4-or D/M-tropic variants increases to more than 50% in treated patients who have CD4 counts <100 cells/mm 3 . 5,6 # Phenotypic Assays Phenotypic assays characterize the co-receptor usage of plasma-derived virus. These assays involve the generation of laboratory viruses that express patient-derived envelope proteins (i.e., gp120 and gp41). These pseudoviruses, which are replication-defective, are used to infect target cell lines that express either CCR5 or CXCR4. 7,8 Using the Trofile assay, the co-receptor tropism of the patient-derived virus is confirmed by testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors in vitro. This assay takes about 2 weeks to perform and requires a plasma HIV RNA level ≥1,000 copies/mL. The performance characteristics of these assays have evolved. Most, if not all, patients enrolled in premarketing clinical trials of MVC and other CCR5 antagonists were screened with an earlier, less sensitive version of the Trofile assay. 8 This earlier assay failed to routinely detect low levels of CXCR4-utilizing variants. As a consequence, some patients enrolled in these clinical trials harbored low levels of CXCR4utilizing virus at baseline that were below the assay limit of detection and exhibited rapid virologic failure after initiation of a CCR5 antagonist. 9 The assay has been revised and is now able to detect lower levels of CXCR4-utlizing viruses. In vitro, the assay can detect CXCR4-utilizing clones with 100% sensitivity when those clones represent 0.3% or more of the virus population. 10 Although this more sensitive assay has had # Panel's Recommendations • A co-receptor tropism assay should be performed whenever the use of a CCR5 co-receptor antagonist is being considered (AI). • Co-receptor tropism testing is also recommended for patients who exhibit virologic failure on a CCR5 antagonist (BIII). • A phenotypic tropism assay is preferred to determine HIV-1 co-receptor usage (AI). • A genotypic tropism assay should be considered as an alternative test to predict HIV-1 co-receptor usage (BII). The ABC HSR is a multiorgan clinical syndrome typically seen within the initial 6 weeks of ABC treatment. This reaction has been reported in 5%-8% of patients participating in clinical trials when using clinical criteria for the diagnosis, and it is the major reason for early discontinuation of ABC. Discontinuing ABC usually promptly reverses HSR, whereas subsequent rechallenge can cause a rapid, severe, and even lifethreatening recurrence. 1 Studies that evaluated demographic risk factors for ABC HSR have shown racial background as a risk factor, with white patients generally having a higher risk (5%-8%) than black patients (2%-3%). Several groups reported a highly significant association between ABC HSR and the presence of the major histocompatibility complex (MHC) class I allele HLA-B5701. [2][3] Because the clinical criteria used for ABC HSR are overly sensitive and may lead to false-positive ABC HSR diagnoses, an ABC skin patch test (SPT) was developed as a research tool to immunologically confirm ABC HSR. 4 A positive ABC SPT is an ABC-specific delayed HSR that results in redness and swelling at the skin site of application. All ABC SPT-positive patients studied were also positive for the HLA-B5701 allele. 5 The ABC SPT could be falsely negative for some patients with ABC HSR and, at this point, is not recommended for use as a clinical tool. The PREDICT-1 study randomized patients before starting ABC either to be prospectively screened for HLA-B5701 (with HLA-B5701-positive patients not offered ABC) or to standard of care at the time of the study (i.e., no HLA screening, with all patients receiving ABC). 6 The overall HLA-B5701 prevalence in this predominately white population was 5.6%. In this cohort, screening for HLA-B5701 eliminated immunologic ABC HSR (defined as ABC SPT positive) compared with standard of care (0% vs. 2.7%), yielding a 100% negative predictive value with respect to SPT and significantly decreasing the rate of clinically suspected ABC HSR (3.4% vs. 7.8%). The SHAPE study corroborated the low rate of immunologically validated ABC HSR in black patients and confirmed the utility of HLA-B5701 screening for the risk of ABC HSR (100% sensitivity in black and white populations). 7 On the basis of the results of these studies, the Panel recommends screening for HLA-B5701 before starting patients on an ABC-containing regimen (AI). HLA-B5701-positive patients should not be prescribed ABC (AI), and the positive status should be recorded as an ABC allergy in the patient's medical record (AII). HLA-B5701 testing is needed only once in a patient's lifetime; thus, efforts to carefully record and maintain the test result and to educate the patient about its implications are important. The specificity of the HLA-B5701 test in predicting ABC HSR is lower than the sensitivity (i.e., 33%-50% of HLA-B5701-positive patients would likely not develop confirmed ABC HSR if exposed to ABC). HLA-B5701 should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B5701 result does not absolutely rule out the possibility of some form of ABC HSR. When HLA-B5701 screening is not # Rating of Recommendations # Panel's Recommendations • The Panel recommends screening for HLA-B5701 before starting patients on an abacavir (ABC)-containing regimen to reduce the risk of hypersensitivity reaction (HSR) (AI). • HLA-B5701-positive patients should not be prescribed ABC (AI). • The positive status should be recorded as an ABC allergy in the patient's medical record (AII). • When HLA-B5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR (CIII). Eradication of HIV infection cannot be achieved with available antiretroviral (ARV) regimens even when new, potent drugs are added to a regimen that is already suppressing plasma viral load below the limits of detection of commercially available assays. 1 This is chiefly because the pool of latently infected CD4 T cells is established during the earliest stages of acute HIV infection 2 and persists with a long half-life, despite prolonged suppression of plasma viremia. [3][4][5][6][7] Therefore the primary goals for initiating antiretroviral therapy (ART) are to: # Rating of Recommendations • reduce HIV-associated morbidity and prolong the duration and quality of survival, • restore and preserve immunologic function, • maximally and durably suppress plasma HIV viral load (see Plasma HIV RNA Testing), and • prevent HIV transmission. ART has reduced HIV-related morbidity and mortality [8][9][10][11] and has reduced perinatal 12 and behavior-associated transmission of HIV. [13][14][15][16][17] HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in HIV-infected cohorts. (See Initiating Antiretroviral Therapy.) Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves CD4 T-cell numbers, and confers substantial clinical benefits, all of which are important treatment goals. [18][19] Achieving viral suppression requires the use of ARV regimens with at least two, and preferably three, active drugs from two or more drug classes. Baseline resistance testing and patient characteristics should guide design of the specific regimen. (See What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient.) When initial suppression is not achieved or is lost, rapidly changing to a new regimen with at least two active drugs is required. (See Virologic and Immunologic Failure.) The increasing number of drugs and drug classes makes viral suppression below detection limits an appropriate goal in all patients. Viral load reduction to below limits of assay detection in an ART-naive patient usually occurs within the first 12-24 weeks of therapy. Predictors of virologic success include: • high potency of ARV regimen, • excellent adherence to treatment regimen, 20 • low baseline viremia, 21 • higher baseline CD4 count (>200 cells/mm 3 ), 22 and • rapid reduction of viremia in response to treatment. 21,23 Successful outcomes are usually observed, although adherence difficulties may lower the success rate in clinical practice to below the 90% rate commonly seen in clinical trials. 24 # Strategies to Achieve Treatment Goals Achieving treatment goals requires a balance of sometimes competing considerations, outlined below. Providers and patients must work together to define individualized strategies to achieve treatment goals. # Selection of Initial Combination Regimen Several preferred and alternative ARV regimens are recommended for use. (See What to Start.) Many of these regimens have comparable efficacy but vary to some degree in dosing frequency and symmetry, pill # Introduction Without treatment, the vast majority of HIV-infected individuals will eventually develop progressive immunosuppression (as evident by CD4 count depletion), leading to AIDS-defining illnesses and premature death. The primary goal of antiretroviral therapy (ART) is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication so that plasma HIV RNA levels (viral load) remain below that detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Furthermore, high plasma HIV RNA is a major risk factor for HIV transmission and use of effective ART can reduce viremia and transmission of HIV to sexual partners. 1,2 Modelling studies suggest that the expanded use of ART may result in lower incidence and, eventually, prevalence of HIV on a community or population level. 3 Thus, a secondary goal of ART is to reduce the risk of HIV transmission. Historically, HIV-infected individuals have presented for care with low CD4 counts, 4 but increasingly there have been concerted efforts to both increase testing of at-risk patients and to link HIV-infected patients to medical care soon after HIV diagnosis (and before they have advanced HIV diseases). For those with high CD4 cell counts, whose short-term risk for death may be low, 5 the recommendation to initiate ART is based on growing evidence that untreated HIV infection or uncontrolled viremia is associated with development of non-AIDS-defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancies. Furthermore, newer ART regimens are more effective, more convenient, and better tolerated than regimens used in the past. Regardless of CD4 count, the decision to initiate ART should always include consideration of any co-morbid conditions, the willingness and readiness of the patient to initiate therapy, and the availability of resources. In settings where resources are not available to initiate ART in all patients, treatment should be prioritized for patients with the lowest CD4 counts and those with the following clinical conditions: pregnancy, CD4 count <200 cells/mm 3 , or history of an AIDS-defining illness, including HIV-associated dementia, HIV-associated nephropathy (HIVAN), hepatitis B virus (HBV), and acute HIV infection. # Panel's Recommendations • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression. The strength and evidence for this recommendation vary by pretreatment CD4 cell count: CD4 count <350 cells/mm 3 (AI); CD4 count 350-500 cells/mm 3 (AII); CD4 count >500 cells/mm 3 (BIII). • ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV. The strength and evidence for this recommendation vary by transmission risks: perinatal transmission (AI); heterosexual transmission (AI); other transmission risk groups (AIII). • Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors. Tempering the enthusiasm to treat all patients regardless of CD4 count is the absence of randomized data that definitively demonstrate a clear clinical benefit of ART in patients with CD4 count >350 cells/mm 3 and mixed results from observational cohort studies on the definitive benefits of early ART. For some patients, the potential risks of short-or long-term, drug-related complications and non-adherence to long-term therapy in asymptomatic patients may offset possible benefits of earlier initiation of therapy. An ongoing randomized controlled trial to evaluate the role of immediate versus delayed ART in patients with CD4 count >500 cells/mm 3 will help to further define the role of ART in this patient population (ClinicalTrials.gov identifier NCT00867048). # Rating of Recommendations The known and potential benefits and limitations of ART overall, and in different patient populations are discussed below. # Benefits of Antiretroviral Therapy # Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count Patients with a history of an AIDS-defining illness or CD4 count <350 cells/mm 3 HIV-infected patients with CD4 counts <200 cells/mm 3 are at higher risk of opportunistic diseases, non-AIDS morbidity, and death than HIV-infected patients with higher CD4 counts. Randomized controlled trials in patients with CD4 counts <200 cells/mm 3 and/or a history of an AIDS-defining condition provide strong evidence that ART improves survival and delays disease progression in these patients. [6][7][8] Long-term data from multiple observational cohort studies comparing earlier ART (i.e., initiated at CD4 count >200 cells/mm 3 ) with later treatment (i.e., initiated at CD4 count <200 cells/mm 3 ) also have provided strong support for these findings. [9][10][11][12][13][14] Few large, randomized controlled trials address when to start therapy in patients with CD4 counts >200 cells/mm 3 . CIPRA HT-001, a randomized clinical trial conducted in Haiti, enrolled 816 participants without AIDS. Participants were randomized to start ART with CD4 counts of 200 cells/mm 3 to 350 cells/mm 3 or to defer treatment until their CD4 counts dropped to <200 cells/mm 3 or they developed an AIDS-defining condition. An interim analysis of the study showed that, when compared with participants who began ART with CD4 counts of 200 cells/mm 3 to 350 cells/mm 3 , patients who deferred therapy had a higher mortality rate (23 versus 6 deaths; hazard ratio [HR] = 4.0; 95% confidence interval [CI]: 1.6-9.8) and a higher rate of incident tuberculosis (TB) (HR = 2.0, 95% CI: 1.2-3.6). 15 Collectively, these studies support the Panel's recommendation that ART should be initiated in patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm 3 (AI). Patients with CD4 counts between 350 and 500 cells/mm 3 Data supporting initiation of ART in patients with CD4 counts ranging from 350 cells/mm 3 to 500 cells/mm 3 are derived from large observational studies and secondary analysis of randomized controlled trials. Analysis of the findings from the observational studies involved use of advanced statistical methods that minimize the bias and confounding that arise when observational data are used to address the question of when to start ART. However, unmeasured confounders for which adjustment was not possible may have influenced the analysis. The ART Cohort Collaboration (ART-CC) included 45,691 patients from 18 cohort studies conducted primarily in North America and Europe. Data from ART-CC showed that the rate of progression to AIDS and/or death was higher when therapy was deferred until a patient's CD4 count fell to the 251 cells/mm 3 to 350 cells/mm 3 range than when ART was initiated at the 351 cells/mm 3 to 450 cells/mm 3 range (risk ratio: 1.28, 95% CI: 1.04-1.57). 11 When analysis of the data was restricted to mortality alone, the difference between the 2 strategies was weaker and not statistically significant (risk ratio: 1.13, 95% CI: 0.80-1.60). In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of whether they had started therapy, the 6,278 patients who deferred therapy until their CD4 counts were <350 cells/mm 3 had greater risk of death than the 2,084 patients who initiated therapy with CD4 counts between 351 cells/mm 3 and 500 cells/mm 3 (risk ratio: 1.69, 95% CI: 1.26-2.26) after adjustment for other factors that differed between these 2 groups. 16 Another collaboration of cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) included 8,392 ART-naive patients with initial CD4 counts >500 cells/mm 3 who experienced declines in CD4 count to <500 cells/mm 3 . 14 The study estimated that delaying initiation of ART until CD4 count <350 cells/mm 3 was associated with a greater risk of AIDS-defining illness or death than initating ART with CD4 count between 350 cells/mm 3 and 500 cells/mm 3 (HR: 1.38, 95% CI: 1.23-1.56). There was, however, no evidence of a difference in mortality (HR: 1.01, 95% CI: 0.84-1.22). A collaboration of cohort studies from Europe, Australia, and Canada (the CASCADE Collaboration) included 5,527 ART-naive patients with CD4 counts in the 350 to 499 cells/mm 3 range. Compared with patients who deferred therapy until their CD4 counts fell to <350 cells/mm 3 , patients who started ART immediately had a marginally lower risk of AIDS-defining illness or death (HR: 0.75, 95% CI: 0.49-1.14) and a lower risk of death (HR: 0.51, 95% CI: 0.33-0.80). 17 Randomized data showing clinical evidence favoring ART in patients with higher CD4 cell counts came from two studies. First, in a small subgroup analysis of the SMART trial, undertaken primarily in North and South America, Europe, and Australia, which randomized participants with CD4 counts >350 cells/mm 3 to continuous ART or to treatment interruption until CD4 count dropped to <250 cells/mm 3 . In the subgroup of 249 participants who were ART naive at enrollment (median CD4 count: 437 cells/mm 3 ), participants who deferred therapy until CD4 count dropped to <250 cells/mm 3 had a greater risk of serious AIDS-and non-AIDS-related events than those who initiated therapy immediately (7 vs. 2 events, HR: 4.6, 95% CI: 1.0-22.2). 18 Second, the HPTN 052 was a large multinational, multicontinental (Africa, Asia, South America, and North America) randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their uninfected sexual partners. 2 A secondary objective of the study was to determine whether ART reduces clinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4 counts between 350 cells/mm 3 and 550 cells/mm 3 and their HIV-uninfected partners. The infected participants were randomized to initiate ART immediately or to delay initiation until they had 2 consecutive CD4 counts <250 cells/mm 3 . At a median follow-up of 2.1 years, there were 77 primary events in the delayed arm versus 57 in the immediate therapy arm (adjusted HR: 1.39, 95% CI: 0.98-1.96). The most frequent event was tuberculosis (34 cases in the delayed therapy arm versus 17 in the immediate therapy arm); deaths were relatively rare (15 cases in the delayed therapy arm; 11 in the immediate therapy arm). 19 Collectively, these studies suggest that initiating ART in patients with CD4 counts between 350 cells/mm 3 and 500 cells/mm 3 reduces HIV-related disease progression; whether there is a corresponding reduction in mortality is unclear. This benefit supports the Panel's recommendation that ART should be initiated in patients with CD4 counts 350 cells/mm 3 to 500 cells/mm 3 (AII). Recent evidence demonstrating the public health benefit of earlier intervention further supports the strength of this recommendation (see Prevention of Sexual Transmission). Patients with CD4 counts >500 cells/mm 3 The NA-ACCORD study also observed patients who started ART with CD4 counts >500 cells/mm 3 or after their CD4 counts dropped below this threshold. The adjusted mortality rates were significantly higher in the 6,935 patients who deferred therapy until their CD4 counts fell to <500 cells/mm 3 than in the 2,200 patients who started therapy with CD4 counts >500 cells/mm 3 (risk ratio: 1.94, 95% CI: 1.37-2.79). 16 Although large and generally representative of the HIV-infected patients in care in the United States, the study has several limitations, including the small number of deaths and the potential for unmeasured confounders that might have influenced outcomes independent of ART. In contrast, results from 2 cohort studies did not identify a benefit of earlier initiation of therapy in reducing AIDS progression or death. In an analysis of the ART-CC cohort, 11 the rate of progression to AIDS/death associated with deferral of therapy until CD4 count is in the 351 to 450 cells/mm 3 range was similar to the rate with initiation of therapy with CD4 count in the 451 to 550 cells/mm 3 range (HR: 0.99, 95% CI: 0.76-1.29). There was no significant difference in rate of death identified between the two groups (HR: 0.93, 95% CI: 0.60-1.44). This study also found that the proportion of patients with CD4 counts between 451 and 550 cells/mm 3 who would progress to AIDS or death before having a CD4 count <450 cells/mm 3 was low (1.6%; 95% CI: 1.1%-2.1%). In the CASCADE Collaboration, 17 among the 5,162 patients with CD4 counts in the 500 to 799 cells/mm 3 range, compared with patients who deferred therapy, those who started ART immediately did not experience a significant reduction in the composite outcome of progression to AIDS/death (HR: 1.10, 95% CI: 0.67-1.79) or death (HR: 1.02, 95% CI: 0.49-2.12). While it was not a clinical endpoint study, a recent clinical trial (Setpoint Study) randomized patients within 6 months of HIV seroconversion to receive either immediate ART for 36 weeks or deferred treatment. More than 57% of the study participants had CD4 count >500 cells/mm 3 . The deferred treatment group had a statistically higher risk of meeting ART eligibility criteria than the immediate treatment group. The study was halted early and illustrated that the time from diagnosis of early infection to the need for initiation of ART was shorter than anticipated in the deferred therapy group. 20 The expanded use of ART to treat individuals with CD4 counts >500 cells/mm 3 has also demonstrated public health benefits. In 2010, a large, publicly-funded clinic in San Francisco adapted a universal ART approach to initiate ART in all HIV-infected persons and evaluated temporal trends in viral suppression. In 534 patients entering the clinic with CD4 counts >500 cells/mm 3 , the 1-year incidence of viral suppression increased from 9% to 14% before universal ART to >52% after the approach was adopted. After adjustment, this policy was associated with a six-fold increase in the probability of viral suppression six months after clinic entry. 21 Because the risk of HIV transmission is associated with level of viremia, from a public health standpoint, this reduction in community viral load can potentially reduce new HIV infections at the community level. With a better understanding of the pathogenesis of HIV infection, the growing awareness that untreated HIV infection increases the risk of many non-AIDS-defining diseases (as discussed below), and the benefit of ART in reducing transmission of HIV, the Panel recommends initiation of ART in patients with CD4 counts >500 cells/mm 3 (BIII). When discussing initiation of ART at high CD4 cell counts (i.e., >500 cells/mm 3 ), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels are not conclusive, especially for patients with very high CD4 counts. Clinicians should also inform patients that viral suppression from effective ART can reduce the risk of sexual transmission to others. Patients should also be told that untreated HIV infection will eventually lead to immunological deterioration and increased risk of clinical disease and death. Therefore, if therapy is not initiated, continued monitoring and close follow-up is necessary. Further ongoing research (both randomized clinical trials and cohort studies) to assess the short-and longterm clinical and public health benefits and cost effectiveness of starting therapy at higher CD4 counts is needed. Findings from such research will provide the Panel with guidance to make future recommendations. # Effects of Viral Replication on HIV-Related Morbidity Since the mid-1990s, it has been known that measures of viral replication are predictive of HIV disease progression. In untreated HIV-infected individuals, time to clinical progression and mortality is fastest in those with higher viral loads. 22 This finding is confirmed across the wide spectrum of HIV-infected patient The EuroSIDA collaboration evaluated HIV-infected individuals with CD4 counts >350 cells/ mm 3 segregated by three viral load strata (<500 copies/mL, 500-9,999 copies/mL, and ≥10,000 copies/mL) to determine the impact of viral load on fatal and non-fatal AIDS-related and non-AIDS-related events. The lower viral load stratum included more subjects on ART (92%) than the middle (62%) and high (31%) viral load strata. After adjustment for age, region, and ART, the rates of non-AIDS events were 61% (P = 0.001) and 66% (P = 0.004) higher in participants with viral loads 500 to 9,999 copies/mL and >10,000 copies/mL, respectively, than in individuals with viral loads <500 copies/mL. These data further confirm that unchecked viral replication is associated with adverse clinical outcomes in individuals with CD4 counts >350 cells/mm 3 . 33 Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and those who are on ART but continue to be viremic. The harm of ongoing viral replication in patients on ART is compounded by the risk of emergence of drug-resistant virus. Therefore, all patients on ART should be carefully monitored and counseled on the importance of adherence to therapy. # Effects of ART on HIV-Related Morbidity HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIVassociated inflammation on these organs all most likely contribute to HIV-related morbidity and mortality. In general, the available data demonstrate that • Untreated HIV infection may have detrimental effects at all stages of infection, • Earlier treatment may prevent the damage associated with HIV replication during early stages of infection, • ART is beneficial even when initiated later in infection; however, later therapy may not repair damage associated with viral replication that occurred during early stages of infection, and • Sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIVassociated kidney disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below. # HIV-associated nephropathy (HIVAN) HIVAN is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to end-stage kidney disease. 34 HIVAN is almost exclusively seen in black patients and can occur at any CD4 count. Ongoing viral replication appears to be directly involved in renal injury, 35 and HIVAN is extremely uncommon in virologically suppressed patients. 36 ART in patients with HIVAN has been associated with both preserved renal function and prolonged survival. [37][38][39] Therefore, ART should be started in all patients with HIVAN, regardless of CD4 count, at the earliest sign of renal dysfunction (AII). # Coinfection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) HIV infection is associated with more rapid progression of viral hepatitis-related liver disease, including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure. [40][41][42] The pathogenesis of accelerated liver disease in HIV-infected patients has not been fully elucidated, but HIV-related immunodeficiency and a direct interaction between HIV and hepatic stellate and Kupffer cells have been implicated. [43][44][45][46] In individuals co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), ART may attenuate liver disease progression by preserving or restoring immune function and reducing HIVrelated immune activation and inflammation. [47][48][49] ARV drugs active against both HIV and HBV (such as tenofovir disoproxil fumarate [TDF], lamivudine [3TC], and emtricitabine [FTC]) also may prevent development of significant liver disease by directly suppressing HBV replication. 50,51 Although ARV drugs do not inhibit HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts are increased. 52 In one prospective cohort, after controlling for liver and HIV disease stage, HCV co-infected patients receiving ART were approximately 66% less likely to experience end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure than patients not receiving ART. 53 While some studies have shown that chronic viral hepatitis increases the risk of ART-induced liver injury, the majority of coinfected persons do not develop clinically significant liver injury [54][55][56] and the rate of hepatotoxicity may be greater in persons with more advanced HIV disease. Collectively, these data suggest that earlier treatment of HIV infection in persons coinfected with HBV (and likely HCV) may reduce the risk of liver disease progression. ART is recommended for patients coinfected with HBV; the ART regimen should include drugs with activity against both HIV and HBV (AII) (also see Hepatitis B Virus/HIV Co-Infection). ART also is recommended for most patients coinfected with HCV (BII), including those with high CD4 counts and those with cirrhosis. This recommendation is based on findings from retrospective and prospective cohort studies that indicated that the receipt of ART is associated with slower progression of hepatic fibrosis and reduced risk of liver disease outcomes. 53,[57][58][59] Combined treatment of both HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be considered for HIV/HCV-co-infected patients regardless of CD4 cell count, for patients infected with HCV genotype 1, some clinicians may choose to defer ART in HIV treatment-naive patients with CD4 counts >500 cells/mm 3 until HCV treatment that includes the HCV NS3/4A protease inhibitors (PIs) is completed (also see HIV/Hepatitis C Virus Co-Infection). # Cardiovascular disease (CVD) In HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for one-third of serious non-AIDS conditions and at least 10% of deaths. [60][61][62] A number of studies have found that, over time, HIV-infected persons are at greater risk for CVD events than age-matched uninfected individuals. In a metaanalysis and review of studies of CVD risk in HIV-infected individuals, the relative risk of CVD events was greater in untreated HIV-infected patients than in HIV-uninfected individuals (1.61: 95% CI 1.43 to 1.81). 63 It is important to note, however, that the selected studies made comparisons to the general population, did not control for smoking or other potential confounders that could be lead to excessive CVD in the HIV-infected individuals, and also did not attempt to account for competing risks. 64 Thus, questions remain regarding the relative contributions of host-, treatment-, and disease-related factors to excess number of CVD events in those with HIV infection. Persons living with HIV infection have higher rates of established CVD risk factors, particularly smoking and dyslipidemia than HIV-uninfected individuals. In the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort study such factors, including age; male gender; obesity; smoking; family history of CVD; diabetes; and dyslipidemia, were each strongly and independently associated with risk of myocardial infarction (MI). 65 This study also found that the risk of CVD was greater with exposure to some ARV drugs, including certain PIs and abacavir, than with exposure to other ARV drugs. 65,66 In terms of preventing the progression to CVD events, it has not been determined whether delaying ART initiation is preferable to immediate treatment. In the meta-analysis mentioned above, the risk of CVD in HIV-infected individuals was 1.5 times higher in those being treated with ART than in those not being treated with ART. 63 These analyses were limited by concern that the treated individuals may have been infected for longer periods of time and had prior episodes of untreated HIV disease, as well as the fact that the untreated people were at higher risk for competing events, including death. Furthermore, there is evidence that untreated HIV infection also may be associated with an increased risk of CVD. In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided treatment interruption than in participants who received continuous ART. 67 In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (such as interleukin 6 [IL-6]), immune dysfunction (e.g., T cell activation, T cell senescence), monocyte activation (e.g., IL-6, CD163), hypercoagulation (e.g., D-dimers) and, most importantly, endothelial dysfunction. 68,69 Low nadir and/or proximal on-therapy CD4 cell count has been linked to CVD (MI and/or stroke), [70][71][72] suggesting that low CD4 count might result in increased risk of CVD. Collectively, the increased risk of cardiovascular events with treatment interruption, the effects of ART on markers of inflammation and endothelial dysfunction, and the association between CVD and CD4 cell depletion suggest that early control of HIV replication with ART can be used as a strategy to reduce risk of CVD, particularly if drugs with potential cardiovascular toxicity are avoided. However, at this time no study has demonstrated that initiation of ART prevents CVD. Therefore, a role for early ART in preventing CVD remains to be established. For HIV-infected individuals with a significant risk of CVD, as assessed by medical history and established estimated risk calculations, risk of CVD should be taken into consideration when selecting a specific ART regimen. # Malignancies Population-based analyses suggest that the incidence of both AIDS-defining malignancies (i.e., Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining malignancies is increased in chronic HIV infection. The incidence of several malignancies (particularly liver, anal, oropharyngeal, and lung cancers, Hodgkin lymphoma, and melanoma) is higher in HIV-infected subjects than in matched HIVuninfected controls, 73,74 and the burden of these non-AIDS defining malignancies has continued to increase in the United States between 1996 and 2007. 75 Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (<350 cells/mm 3 to 500 cells/mm 3 ) and the risk of AIDS-and/or non-AIDS-defining malignancies. 12,72,[76][77][78][79] The ANRS C04 Study demonstrated a statistically significant relative risk of all cancers evaluated (except for anal carcinoma) in patients with CD4 counts <500 cells/mm 3 compared with patients with current CD4 counts >500 cells/mm 3 , an increased risk of anal cancer based on time with CD4 counts <200 cells/mm 3 , and, regardless of CD4 count, a protective effect of ART for HIV-associated malignancies. 76 This potential effect of HIV-associated immunodeficiency is striking particularly with regard to cancers associated with chronic viral infections such as HBV, HCV, human papilloma virus (HPV), Epstein-Barr virus (EBV), and human herpes virus-8 (HHV-8). 80,81 Cumulative HIV viremia, independent of other factors, may also be associated with the risk of non-Hodgkin lymphoma and other AIDS-defining malignancies. 79,82 From the early 1990s through 2000, incidence rates for many cancers, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma, declined markedly in HIV-infected individuals in the United States, with more gradual declines noted after 2000. 83 However, for other AIDS-defining and non-AIDS defining cancers, such as Burkitt lymphoma, Hodgkin lymphoma, cervical cancer, and anal cancer, similar reductions in incidence have not been observed. 83,84 Declines in overall mortality and aging of HIV-infected cohorts increase overall cancer incidence, which may confound a clear assessment of the impact of ART on preventing the development of malignancies. 75,85 In the SMART study, 86 patients randomized to the drug conservation arm (i.e., those starting ART with CD4 count <250 cells/mm 3 ) had a higher incidence of AIDS-defining malignancies, but not non-AIDS defining malignancies, than patients in the viral suppression arm (i.e., those receiving continuous ART). In a pooled analysis of the ESPRIT and SMART studies, 87 history of an AIDSdefining event increased risk of any cancer. Taken together this evidence suggests that initiating ART to suppress HIV replication and maintain CD4 counts at levels >350 to 500 cells/mm 3 reduces the overall incidence of AIDS-defining malignancies and may also reduce the risk of non-AIDS-defining malignancies. The effect on incidence is most likely heterogeneous across various cancer types. # Neurological diseases Although HIV RNA can be detected in the cerebrospinal fluid (CSF) of most untreated patients, 88,89 these patients usually do not present with overt symptoms of HIV-associated neurological disease. 90 In some patients, CNS infection progresses to HIV encephalitis and can present as HIV-associated dementia (HAD). [91][92][93] This progression is usually in the context of more advanced untreated systemic HIV infection when severe CNS opportunistic infections (OIs) also cause high morbidity and mortality. 94 Effective viral suppression resulting from ART has dramatically reduced the incidence of HAD and severe CNS OIs. [95][96][97] Suppressive ART usually reduces CSF HIV RNA to undetectable levels. 98,99 Exceptional cases of symptomatic and asymptomatic CNS viral escape, in which HIV RNA is detectable in CSF despite viral suppression in plasma, have been documented. 100,101 This suggests that in some settings it may be useful to monitor CSF HIV RNA. Recent attention has turned to milder forms of CNS dysfunction, defined by impairment on formal neuropsychological testing. 93,102 It is unclear whether this impairment is a consequence of injury sustained before treatment initiation or whether neurologic damage can continue or develop despite systemically effective ART. 103 The association between cognitive impairment and low nadir CD4 counts supports the hypothesis for pretreatment injury and bolsters the argument that earlier initiation of ART may prevent subsequent brain dysfunction. 104,105 The peripheral nervous system (PNS) also is a target in HIV infection, and several types of neuropathies have been identified. 106 Most common is HIV-associated polyneuropathy, a chronic, predominantly sensory and sometimes painful neuropathy. The impact of early treatment on this and other forms of neuropathy is not as clearly defined as that on HAD. 107,108 Age and treatment-related immune reconstitution (also see HIV and the Older Patient) The CD4 cell response to ART is an important predictor of short-and long-term morbidity and mortality. Treatment initiation at an older age is consistently associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes. [109][110][111][112] # T-cell activation and inflammation Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation. [113][114][115] The degree of T-cell activation during untreated HIV disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and peripheral CD4 T-cell count. 116,117 ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation. 87,[118][119][120][121] Persistent T-cell activation and/or T-cell dysfunction is particularly evident in patients who delay therapy until later stage disease (CD4 count <350 cells/mm 3 ). 119,121,122 The degree of persistent inflammation during treatment, as represented by the levels of IL-6, D-dimers, sCD14, and sCD163, may be independently associated with risk of morbidity and mortality. [123][124][125] Collectively, these observations support earlier use of ART for at least two reasons. First, treatment decreases the level of inflammation, which may be associated with reduced short-term risk of AIDS-and non-AIDS-related morbidity and mortality. 123,126,127 Second, because the degree of residual inflammation and/or T-cell dysfunction with ART appears to be higher in patients with lower CD4 cell nadirs, 119,121,122 earlier treatment may result in less residual immunological perturbations on therapy and, hence, less risk for AIDS-and non-AIDS-related complications (CIII). # Antiretroviral Therapy for Prevention of HIV Transmission # Prevention of perinatal transmission Effective ART reduces transmission of HIV. The most dramatic and well-established example of this effect is the use of ART in pregnant women to prevent perinatal transmission of HIV. Effective suppression of HIV replication, as reflected in plasma HIV RNA, is a key determinant in reducing perinatal transmission. In the setting of ART initiation before 28 weeks' gestation and an HIV RNA level <50 copies/mL near delivery, use of combination ART during pregnancy has reduced the rate of perinatal transmission of HIV from approximately 20% to 30% to <0.5%. 128 Thus, use of combination ART drug regimens is recommended for all HIV-infected pregnant women (AI). Following delivery, in the absence of breastfeeding, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as those regarding ART for other non-pregnant individuals. For detailed recommendations, see the Perinatal Guidelines. 129 # Prevention of sexual transmission Recent study results provide strong support for the premise that treatment of the HIV-infected individual can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions. 130,131 Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viremia and risk of transmission of HIV: when plasma HIV RNA levels are lower, transmission events are less common. 1,[132][133][134][135] HPTN 052 was a multicontinental trial that enrolled 1,763 HIV-serodiscordant couples in which the HIVinfected partner was ART naive with CD4 count 350 cells/mm 3 to 550 cells/mm 3 at enrollment. The study compared immediate ART with delayed therapy (i.e., not started until CD4 count <250 cells/mm 3 ) for the HIV-infected partner. 2 At study entry, 98% of the participants were in heterosexual monogamous relationships. All study participants were counseled on behavioral modification and condom use. Twentyeight linked HIV transmission events were identified during the study period, but only 1 event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04, 95% CI: 0.01-0.27, P <0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioral and biomedical prevention interventions studied to date, including condom use, male circumcision, vaginal microbicides, HIV vaccination, and pre-exposure prophylaxis. This study, as well as other observational studies and modeling analyses showing a decreased rate of HIV transmission in serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viremia in ART-adherent patients with no concomitant sexually transmitted diseases (STDs) substantially reduces the risk of transmission of HIV. 3,[134][135][136][137][138] HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing, but the prevention benefits of effective ART presumably apply to these populations as well. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners. (The strength of this recommendation varies according to mode of sexual transmission: AI for heterosexual transmission and AIII for male-to-male and other modes of sexual transmission.) Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioral modification and that ART does not protect against other STDs (also see Preventing Secondary Transmission of HIV). # Concerns Regarding Earlier Initiation of Therapy Despite increasing evidence for the benefits associated with earlier initiation of ART, three areas of concern have served as a rationale for deferral of HIV therapy: ARV drug toxicities have an adverse affect on quality of life and adherence. Earlier initiation of ART extends exposure to ARV agents by several years. The D:A:D study found an increased incidence of CVD associated with cumulative exposure to some drugs in the nucleoside reverse transcriptase inhibitor and PI drug classes. 65,139 In the SMART study, when compared with interruption or deferral of therapy, continuous exposure to ART was associated with significantly greater loss of bone density. 67 There may be unknown complications related to cumulative use of ARV drugs for many decades. A list of known ARV-associated toxicities can be found in Adverse Effects of Antiretroviral Agents. ART frequently improves quality of life for symptomatic patients. However, some side effects of ART may impair quality of life for some patients, especially those who are asymptomatic at initiation of therapy. For example, efavirenz (EFV) can cause neurocognitive or psychiatric side effects and PIs have been associated with gastrointestinal (GI) side effects. As noted above, it has been suggested that some therapies increase the risk of CVD. Some patients may find that the inconvenience of taking medication every day outweighs the overall benefit of early ART and may choose to delay therapy. # ARV non-adherence may have an impact on virologic efficacy. At any CD4 count, adherence to therapy is essential to achieve viral suppression and prevent emergence of drug-resistance mutations. Several behavioral and social factors associated with poor adherence, such as untreated major psychiatric disorders, active substance abuse, unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits, have been identified. Clinicians should identify areas where additional intervention is needed to improve adherence both before and after initiation of therapy. Some strategies to improve adherence are discussed in Adherence to Antiretroviral Therapy. # Earlier development of resistance may reduce therapeutic options at a later time. Despite concerns about the development of resistance to ARV drugs, the evidence thus far indicates that resistance occurs more frequently in individuals who initiate therapy later in the course of infection than in those who initiate ART earlier. 140 Furthermore, recent data have indicated a slight increase in the prevalence of 2-drug class resistance from 2000 to 2005. 141 # Cost. In resource-rich countries, the cost of ART exceeds $10,000 per year (see Appendix B, Table 8). Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis. [142][143][144] One study reported that the annual cost of care is 2.5 times higher for patients with CD4 counts <50 cells/mm 3 than for patients with CD4 counts >350 cells/mm 3 . 145 A large proportion of the health care expenditure in patients with advanced infection is from non-ARV drugs and hospitalization. There are no cost comparisons for patients starting ART with CD4 count 350 to 500 cells/mm 3 and patients starting ART with CD4 count >500 cells/mm 3 . # Conditions Favoring More Rapid Initiation of Therapy Several conditions increase the urgency for therapy, including: • Pregnancy (AI) (Clinicians should refer to the Perinatal Guidelines for more detailed recommendations on the management of HIV-infected pregnant women.) 129 • AIDS-defining conditions, including HIV-associated dementia (AI) • Acute opportunistic infections (OIs) (see discussion below) • Lower CD4 counts (e.g., <200 cells/mm 3 ) (AI) • HIVAN (AII) • Acute/recent infection (BII) (see more discussion in the Acute and Recent (Early) Infection section) • HIV/HBV coinfection (AII) • HIV/HCV coinfection (BII) • Rapidly declining CD4 counts (e.g., >100 cells/mm 3 decrease per year) (AIII) • Higher viral loads (e.g., >100,000 copies/mL) (BII) # Acute opportunistic infections In patients with opportunistic conditions for which no effective therapy exists (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy) but in whom ART may improve outcomes by improving immune responses, the benefits of ART outweigh any increased risk; therefore, treatment should be started as soon as possible (AIII). In the setting of some OIs for which immediate therapy may increase the risk of immune reconstitution inflammatory syndrome (IRIS) (e.g., cryptococcal meningitis or nontuberculous mycobacterial infections), a short delay before initiating ART may be warranted (CIII). 146,147 In the setting of other OIs, such as Pneumocystis jiroveci pneumonia (PCP), early initiation of ART is associated with increased survival; 8 therefore, therapy should not be delayed (AI). In patients who have active TB, initiating ART during treatment for TB confers a significant survival advantage; 148-152 therefore, ART should be initiated as recommended in Mycobacterium Tuberculosis Disease with HIV Coinfection. Clinicians should refer to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 153 for more detailed discussion on when to initiate ART in the setting of a specific OI. # Conditions Where Deferral of Therapy May be Considered Some patients and their clinicians may decide to defer therapy for a period of time on the basis of clinical or personal circumstances. Deferring therapy for the reasons discussed below may be reasonable in patients with high CD4 counts (e.g., >500 cells/mm 3 ) but deferring therapy in patients with much lower CD4 counts (e.g., <200 cells/mm 3 ) should be considered only in rare situations and should be undertaken with close clinical follow-up. Briefly delaying therapy to allow a patient more time to prepare for lifelong treatment may be considered. When there are significant barriers to adherence (also see Adherence to Antiretroviral Therapy) In patients with higher CD4 counts who are at risk of poor adherence, it may be prudent to defer treatment while addressing the barriers to adherence. However, in patients with conditions that require urgent initiation of ART (see above), therapy should be started while simultaneously addressing the barriers to adherence. Several methodologies exist to help providers assess adherence. When the most feasible measure of adherence is self-report, this assessment should be completed at each clinic visit using one of the available reliable and valid instruments. 154,155 If other objective measures (e.g., pharmacy refill data, pill count) are available, these methods should be used to assess adherence at each follow-up visit. [156][157][158] Continuous assessment and counseling make it possible for the clinician to intervene early to address barriers to adherence occurring at any point during treatment (see Adherence to Antiretroviral Therapy). Presence of comorbidities that complicate or prohibit antiretroviral therapy Deferral of ART may be considered when either the treatment or manifestations of other medical conditions may complicate the treatment of HIV infection or vice versa. Examples include: • Surgery that may result in an extended interruption of ART • Treatment with medications that have clinically significant drug interactions with ART and for which alternative medications are not available In each of these circumstances, the assumption is that the situation is temporary and that ART will be initiated after the conflicting condition has resolved. Some less common situations exist in which ART may not be indicated at any time while CD4 counts remain high. In particular, such situations include that of patients with a poor prognosis due to a concomitant medical condition who would not be expected to gain survival or quality-of-life benefits from ART. Examples include patients with incurable non-HIV-related malignancies or end-stage liver disease who are not being considered for liver transplantation. The decision to forego ART in such patients may be easier to make in those with higher CD4 counts; they are likely asymptomatic for HIV, and their survival is unlikely to be prolonged by ART. However, it should be noted that ART may improve outcomes, including survival, in patients with some HIV-associated malignancies (e.g., lymphoma or Kaposi sarcoma) and in patients with liver disease due to chronic HBV or HCV. # Long-term nonprogressors and elite HIV controllers A small subset of HIV-infected individuals (~3% to 5%) maintain normal CD4 counts for many years in the absence of therapy (long-term nonprogressors), and an even smaller subset (~1%) maintain undetectable HIV RNA level for years ("elite" controllers). 159,160 Many long-term non-progressors have detectable viremia while some elite controllers progress immunologically and/or clinically despite having no detectable viremia. The evidence on how to manage these individuals is limited. Given the potential harm associated with uncontrolled HIV replication, many of the preceding arguments for early therapy most likely apply to nonprogressors who have consistently detectable viremia (i.e., HIV RNA >200 to 1000 copies/mL). Also given that ongoing HIV replication occurs in elite controllers, ART is also recommended for those rare controllers who exhibit evidence of disease progression, as defined by declining CD4 counts or development of HIVrelated complications. The Panel has no recommendations for the management of controllers with high CD4 counts, but the fact that these individuals have higher than normal levels of inflammation and immune activation provides at least some rationale for treatment. Clinical trials assessing the potential benefit of therapy in these individuals are ongoing. # The Need for Early Diagnosis of HIV Fundamental to the earlier initiation of ART recommended in these guidelines is the assumption that patients will be diagnosed early in the course of HIV infection and linked to medical care, thereby, making earlier initiation of therapy an option. Unfortunately, most cases of HIV infection are not diagnosed until patients are at much later stages of disease, [161][162][163][164] although the mean CD4 count at initial presentation for care has increased in more recent years. 4 Despite the 2006 Centers for Disease Control and Prevention (CDC) recommendations for routine, opt-out HIV screening in the health care setting regardless of perceptions about a patient's risk of infection, 165 the median CD4 count of newly diagnosed patients remains below 350 cells/mm 3 . 4 The exception is pregnant women whose infection was diagnosed during prenatal care; they have a much higher median initial CD4 count. Compared with other groups, diagnosis of HIV infection is more often delayed in nonwhites, IDUs, and older patients, and a substantial proportion of these individuals develop AIDS-defining illnesses within 1 year of diagnosis. [161][162][163][164] Thus, for the current treatment guidelines to have maximum impact, routine HIV screening per current CDC recommendations is essential. It is also critical to educate all newly diagnosed patients about HIV disease and link them to care for full evaluation, follow-up, and management. Once patients are in care, focused effort is required to retain them in the health care system so that both infected individuals and their sexual partners can accrue the full benefits of early diagnosis and treatment. # Conclusion The current recommendations are based on greater evidence supporting earlier initiation of ART than was advocated in previous guidelines. The strength of the recommendations varies according to the quality and availability of existing evidence supporting each recommendation. In addition to benefitting the health of the HIV-infected individual, the evidence that effective ART reduces sexual transmission to HIV provides further reason for earlier initiation of ART. The Panel will continue to monitor and assess the results of ongoing and planned randomized clinical trials and observational studies. Findings from these studies will provide the Panel with additional guidance to form future recommendations. # Data Used for Making Recommendations The Panel's recommendations are primarily based on clinical trial data published in peer-reviewed journals and data prepared by manufacturers for Food and Drug Administration (FDA) review. In select cases, the Panel considers data presented in abstract format at major scientific meetings. The first criterion for selection of evidence on which to base recommendations is published information from a randomized, prospective clinical trial with an adequate sample size that demonstrates that an ARV regimen has shown durable viral suppression and immunologic enhancement (as evidenced by increase in CD4 count). Few of these trials include clinical endpoints, such as development of AIDS-defining illness or death. Thus, assessment of regimen efficacy and potency is primarily based on surrogate marker endpoints (HIV RNA and CD4 responses). The Panel reviewed data from randomized clinical trials and other reports to arrive at "preferred," "alternative," or "other" ratings for each regimen noted in Tables 5a and 5b. "Preferred regimens" are those regimens studied in randomized controlled trials and shown to have optimal and durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. "Alternative regimens" are those regimens that are effective but have potential disadvantages when compared with preferred regimens. In certain situations and based on individual patient characteristics and needs, a regimen listed as an alternative may actually be the preferred regimen for a specific patient. Some regimens are classified as "other regimens" because of reduced virologic activity, lack of efficacy data from large clinical trials, or other factors (such as greater # Panel's Recommendations • The Panel recommends the following as preferred regimens (listed in order of FDA approval) for antiretroviral (ARV)-naive patients: • efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) (AI) • ritonavir-boosted atazanavir + tenofovir disoproxil fumarate/emtricitabine (ATV/r + TDF/FTC) (AI) • ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine (DRV/r + TDF/FTC) (AI) • raltegravir + tenofovir disoproxil fumarate/emtricitabine (RAL + TDF/FTC) (AI) • Panel-recommended alternative and other regimens can be found in Table 5a and Table 5b. • Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions. • Based on individual patient characteristics and needs, in some instances, an alternative or other regimen may be a preferred regimen for a specific patient. toxicities, pill burden, drug interaction potential, or need for additional testing before use) when compared with preferred or alternative regimens. # Rating of Recommendations # Considerations When Selecting a First Antiretroviral Regimen for Antiretroviral Therapy-Naive Patients # Factors to Consider When Selecting an Initial Regimen Regimen selection should be individualized on the basis of several factors, including the following: • the patient's comorbid conditions (e.g., cardiovascular disease [CVD], chemical dependency, liver or renal disease, psychiatric illnesses, or tuberculosis [TB]); • potential adverse drug effects; • known or potential drug interactions with other medications; • pregnancy or pregnancy potential; • results of genotypic drug-resistance testing; • pre-treatment HIV viral load; • gender and pretreatment CD4 count if considering nevirapine (NVP); • HLA-B5701 testing if considering abacavir (ABC); • coreceptor tropism assay if considering MVC; • patient preferences (when possible) and adherence potential; and • convenience (e.g., factors such as pill burden, dosing frequency, availability of fixed dose combination products, and food and fluid requirements). Potential advantages and disadvantages of the components recommended as initial therapy for ARV-naive patients are listed in Table 6 to guide prescribers in choosing the optimal regimen for an individual patient. Table 7 provides a list of agents or components not recommended for initial treatment. Appendix B, Tables 1-6 list characteristics of individual ARV agents, such as formulations, dosing recommendations, pharmacokinetics (PKs), and common adverse effects. Appendix B, Table 7 provides clinicians with ARV dosing recommendations for patients who have renal or hepatic insufficiency. # Choosing Between Preferred Initial Regimens Each of the four preferred initial regimens listed in Table 5a has shown potent virologic efficacy as measured by the proportion of subjects achieving and maintaining viral suppression in comparative clinical trials. Given the comparable efficacy of the preferred regimens, selection of an optimal regimen for a specific patient will depend on other factors, including characteristics of the regimen (e.g., adverse event profile, barrier to resistance, dosing frequency, pill burden, food restrictions, the availability of fixed-dose combination formulations, the potential for drug-drug interactions), the patient's pre-treatment resistance testing results, and whether the patient is a woman who may become pregnant. A complete description of the advantages and disadvantages of the preferred and alternative options for therapy are listed in Table 6. Currently, all of the preferred initial regimens include the NRTI combination of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), which is available as a fixed-dose combination tablet. In two comparative clinical trials, this NRTI combination was more effective than the alternative NRTI pair, abacavir/lamivudine (ABC/3TC), 8,9 but in a third study, the NRTI combinations showed comparable efficacy. 10 TDF may cause kidney injury in some patients, particularly in those who have pre-existing renal disease or are receiving concomitant nephrotoxic drugs. In addition, TDF induces a greater decline in bone mineral density than other ARV drugs. 11 Of the four preferred regimens, efavirenz (EFV) in combination with TDF/FTC has been studied in the greatest number of clinical trials. 6,[12][13][14][15] This regimen is available in a single tablet, once-daily formulation, and is generally well tolerated. Disadvantages of the regimen include central nervous system (CNS) side effects that resolve over time in some (but not all) patients, a higher incidence of rash (including severe skin reactions) than with other preferred regimens, and dyslipidemia. Owing to concerns related to potential teratogenicity emerging from animal studies and some human case reports, ARV regimens that do not include EFV should be strongly considered in women who wish to conceive or are sexually active and not using effective contraception, assuming these alternative regimens are not thought to compromise the woman's health. Initial treatment with ritonavir (RTV) boosted PI-containing regimens is unique from the resistance perspective, as virologic failure rarely selects for PI-resistance and NRTI resistance is uncommon. As a result, some clinicians consider these the initial regimens of choice for patients at higher risk for virologic failure due to suboptimal adherence, inconsistent follow-up, or other factors. A disadvantage of RTV-boosted PI-based regimens is the large number of drug-drug interactions, in particular with medications metabolized through the cytochrome p450 pathway. As a result, RTV-boosted PI-based regimens may be difficult to use in patients who are taking many other medications. RTV-boosted atazanavir (ATV/r) is as effective as EFV, but causes less rash and has a more favorable lipid profile. 13 ATV induces reversible indirect hyperbilirubinemia, which may result in visible jaundice or scleral icterus in a small proportion of patients; ATV has also been associated with nephrolithiasis and cholelithiasis. Optimal absorption of ATV depends on presence of food and low gastric pH; if acid-reducing agents are needed, co-administration should be done according to the dosing guidelines shown in Table 15a. RTVboosted darunavir (DRV/r) shares many of the characteristics of boosted ATV, but does not cause hyperbilirubinemia and can be given with acid-reducing agents. There are no fully-powered clinical trials that compare the virologic efficacy of DRV/r and ATV/r. One small study found that these boosted-PIs had comparable effects on lipids. 16 Both ATV/r and DRV/r can be given once daily. Raltegravir (RAL) plus TDF/FTC demonstrated comparable antiviral efficacy to EFV/TDF/FTC, with fewer drug-related adverse effects and a more favorable lipid profile. 6 RAL has fewer drug-drug interactions than both boosted-PI and EFV-based regimens, and is therefore easier to add to a patient's complex medication regimen. Rare but severe side effects (e.g., rhabdomyolysis, severe skin, systemic hypersensitivity reactions) have been reported with RAL. RAL plus TDF/FTC is the only preferred regimen that requires twice-daily dosing. There are clinical scenarios in which options for initial therapy should be chosen from the list of alternative and other regimens rather than from the preferred list. Tables 5a and 5b provide a list of alternative and other regimens that may be prescribed for select patients. Table 6 lists the advantages and disadvantages of the individual ARV components of the regimens. Acute symptomatic HIV infection may be diagnosed while an individual is receiving TDF/FTC for preexposure prophylaxis (PrEP) (see Acute and Recent [Early] HIV Infection). As with all newly diagnosed cases of HIV-infection, genotype testing should be performed. In most cases, HIV infection in this setting is secondary to suboptimal adherence 17 to the prescribed daily TDF/FTC regimen, hence resistance in the setting of PrEP failure in clinical trials has been uncommon. Pending genotype testing results, a regimen consisting of a boosted PI (ATV/r or DRV/r) plus TDF/FTC (AIII) can be initiated. ARV drugs should be modified as needed based on the results of baseline resistance testing. # Table 5a. Preferred and Alternative Antiretroviral Regimens for Antiretroviral Therapy-Naive Patients A combination antiretroviral therapy (ART) regimen generally consists of two NRTIs plus one active drug from one of the following classes: NNRTI, PI (generally boosted with RTV), INSTI, or a CCR5 antagonist. Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, and the patient's resistance testing results and comorbid conditions. Refer to Table 6 for a list of advantages and disadvantages of the individual ARV agents listed below and to Appendix B, Tables 1-6 for dosing information. The regimens in each category are listed in alphabetical order. For more detailed recommendations on ARV use in HIV-infected pregnant women, refer to the latest perinatal guidelines available at http://aidsinfo.nih.gov/guidelines. # Preferred Regimens Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use. # Comments • EFV is teratogenic in non-human primates. A regimen that does not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception. • TDF should be used with caution in patients with renal insufficiency. • ATV/r should not be used in patients who require >20 mg omeprazole equivalent per day. Refer to Table 15a for dosing recommendations regarding interactions between ATV/r and acid-lowering agents. # Alternative Regimens Regimens that are effective and tolerable, but have potential disadvantages when compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. # Comments • RPV is not recommended in patients with pretreatment HIV RNA >100,000 copies/mL. • Higher rate of virologic failures reported in patients with pre-ART CD4 count <200 cells/mm 3 who are treated with RPV + 2NRTI • Use of PPIs with RPV is contraindicated. • ABC should not be used in patients who test positive for HLA-B5701. • Use ABC with caution in patients with known high risk of CVD or with pretreatment HIV RNA >100,000 copies/mL (see text). • Once-daily LPV/r is not recommended for use in pregnant women. • EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl <70 ml/min, and should be changed to an alternative regimen if the patient's CrCl falls below 50 mL/min • COBI is a potent CYP 3A inhibitor. It can increase the concentration of other drugs metabolized by this pathway. Refer to Tables 15d and 16c for drug interaction information for concomitantly administered drugs. • EVG/COBI/TDF/FTC should not be used with other ARV drugs or with nephrotoxic drugs. a 3TC may substitute for FTC or vice versa. The following combinations in the recommended list above are available as coformulated fixeddose combinations: ABC/3TC, EFV/TDF/FTC, EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, TDF/FTC, and ZDV/3TC. NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs involve the prevalence of NNRTI-resistant viral strains in ART-naive patients [18][19][20][21] and the NNRTIs' low genetic barrier for the development of resistance. Resistance testing should be performed to guide therapy selection for ART-naive patients (see Drug-Resistance Testing). High level resistance to all NNRTIs (except ETR) may occur with a single mutation; cross resistance is common. ETR has in vitro activity against some viruses with mutations that confer resistance to DLV, EFV, and NVP. 22 In RPV-treated patients, the presence of RPV-resistant mutations at virologic failure is common and may confer cross resistance to other NNRTIs including ETR. 14,23 Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens listed in Table 5a. # Key to Abbreviations # Comments • NVP should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C). b • NVP should not be used in women with pre-ART CD4 count >250 cells/mm 3 or in men with pre-ART CD4 count >400 cells/mm 3 . • Use NVP and ABC together with caution; both can cause HSRs within the first few weeks after initiation of therapy. • ZDV can cause bone marrow suppression, myopathy, lipoatrophy, and rarely lactic acidosis with hepatic steatosis. • ATV/r is generally preferred over unboosted ATV. • Perform tropism testing before initiation of therapy with MVC. MVC may be considered in patients who have only CCR5-tropic virus. • SQV/r was associated with PR and QT prolongation in a healthy volunteer study. Baseline ECG is recommended before initiation of SQV/r. • SQV/r is not recommended in patients with: • pretreatment QT interval >450 msec • refractory hypokalemia or hypomagnesemia • concomitant therapy with other drugs that prolong QT interval • complete AV block without implanted pacemaker, • risk of complete AV block Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens listed in Table 5a. a 3TC may be substituted with FTC or vice versa. b Refer to Appendix B, Table 7 for the criteria for Child-Pugh classification. The Panel recommends that EFV, RPV, or NVP may be used as part of an initial regimen. EFV is preferred on the basis of its potency (as discussed below). RPV may be used as an alternative NNRTI option in patients with pre-treatment HIV RNA < 100,000 copies/mL; NVP may be another NNRTI option in women with pretreatment CD4 counts ≤250 cells/mm 3 or in men with pretreatment CD4 counts ≤400 cells/mm 3 (see discussions below). # Key to Compared with the other NNRTIs, DLV has the highest dosing frequency (three times daily), the least supportive clinical trial data, and the least antiviral activity. Therefore, DLV is not recommended as part of an initial regimen (BIII). ETR at a dose of 200 mg twice daily is approved for use in treatment-experienced patients with virologic failure. 24 In a small, randomized, double-blinded, placebo-controlled trial, ETR 400 mg once daily was compared with EFV 600 mg once daily (both in combination with two NRTIs) in treatment-naive subjects (79 and 78 subjects in the ETR and EFV arms, respectively). Virologic responses were comparable at 48 weeks. 25 However, pending results from larger clinical trials, the panel cannot recommend ETR as initial therapy at this time. Following is a more detailed discussion of individual NNRTI-based regimens for initial therapy. # Preferred Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Efavirenz (EFV). Large randomized, controlled trials and cohort studies of ART-naive patients have demonstrated potent viral suppression in patients treated with EFV plus two NRTIs; a substantial proportion of these patients had HIV RNA <50 copies/mL at up to 7 years of follow-up. 1,2,26 Studies that compared EFV-based regimens with other regimens demonstrated that the combination of EFV with two NRTIs was superior or non-inferior virologically to ritonavir-boosted lopinavir (LPV/r), 4 NVP-, 27,28 RPV-, 14 ATV-, 5 elvitegravir (EVG)-, 15 RAL-, 6 and MVC-based 7 regimens. EFV can cause CNS adverse effects, such as abnormal dreams, dizziness, headache, and depression, which usually resolve over a few weeks in some (but not all) patients. In animal reproductive studies, EFV at drug exposure levels similar to those achieved in humans caused major congenital anomalies in the CNS of nonhuman primates. 29 In humans, several cases of neural tube defects in newborns of mothers exposed to EFV during the first trimester of pregnancy have been reported. 30,31 Although emerging information about the use of EFV in pregnancy is reassuring, 32,33 data remain insufficient to rule out a potential 2 to 3 fold increase in neural tube birth defects with first-trimester exposure to EFV. Therefore, alternative ARV regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health. Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (before pregnancy is usually recognized), and because unnecessary ARV changes during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression. 34 In # Alternative Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Rilpivirine (RPV). In two large, multinational, randomized, double-blind clinical trials, RPV (25 mg once daily) was compared with EFV (600 mg once daily), each agent in combination with two NRTIs. In a pooled analysis of the 2 studies, 76% of RPV-treated subjects and 77% of EFV-treated subjects had plasma HIV RNA <50 copies/mL at 96 weeks. 23 Although RPV demonstrated non-inferiority to EFV overall, in participants with higher pretreatment HIV RNA (>100,000 copies/mL), virologic failure occurred more frequently in those randomized to receive RPV. Moreover, more subjects with pre-treatment CD4 count <200 cells/mm 3 , regardless of baseline HIV RNA, experienced virologic failure than those with pre-ART CD4 count ≥200 cells/mm 3 . Subjects with virologic failure on RPV were also more likely to have genotypic resistance to other NNRTIs (i.e., EFV, ETR, and NVP) and to have TDF-and/or 3TC/FTC-associated genotypic resistance. Drug discontinuations because of adverse effects were more common with EFV than with RPV. The frequency of depressive disorders and discontinuations due to depressive disorders were similar between the two arms, whereas dizziness, abnormal dreams, rash, and hyperlipidemia were more frequent with EFV than with RPV. At higher than the approved dose of 25 mg, RPV (75 mg once daily or 300 mg once daily) may prolong the QTc interval. As a result, RPV should be used cautiously when co-administered with a drug that has a known risk of torsades de pointes. Although RPV has shown no teratogenicity in animal studies, data on PKs and safety of RPV in pregnant HIV-infected women are insufficient at this time. RPV is formulated both as an individual tablet and in a fixed-dose combination tablet of RPV/TDF/FTC. The latter allows for one-tablet once-daily dosing. RPV must be administered with a meal. Because the oral bioavailability of RPV may be significantly reduced in the presence of acid-lowering agents, RPV should be used with caution with antacids and H2-receptor antagonists. RPV use with proton pump inhibitors (PPIs) is contraindicated. Table 15b provides guidance on the timing of RPV administration when the agent is used with antacids or H2 receptor antagonists. In patients with high pretreatment viral load (HIV RNA >100,000 copies/mL) or low CD4 cell count (<200 cells/mm 3 ), RPV has less virologic activity and a higher rate of resistance at virologic failure than EFV. The panel recommends RPV/TDF/FTC as an alternative regimen for initial therapy, which should only be used in patients with pre-treatment HIV RNA < 100,000 copies/mL (BI). RPV should not be used in patients with plasma HIV RNA >100,000 copies/mL. # Other Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Nevirapine (NVP). The 2NN trial compared NVP with EFV, both given d4T and 3TC, in ART-naive patients. In this trial, 65% of participants in the twice-daily NVP arm and 70% in the EFV arm achieved virologic suppression (defined as HIV RNA <50 copies/mL) at 48 weeks. This difference did not reach criteria necessary to demonstrate non-inferiority of NVP. 27 Two deaths were attributed to NVP use: one from fulminant hepatitis and one from staphylococcal sepsis as a complication of Stevens-Johnson syndrome (SJS). In the ARTEN trial, ART-naive participants were randomized to NVP 200 mg twice daily or 400 mg once daily, or to RTV-boosted ATV (ATV/r), all in combination with TDF/FTC. The proportion of participants in each arm who achieved the primary endpoint of having at least two consecutive plasma HIV RNA levels <50 copies/mL before Week 48 was similar (66.8% of NVP participants vs. 65.3% of ATV/r participants). However, more participants in the NVP arms than in the ATV/r arm discontinued study drugs before Week 48 because of adverse events (13.6% on NVP vs. 2.6% on ATV/r) or lack of efficacy (8.4% on NVP vs. 1.6% on ATV/r). NNRTI-and/or NRTI-resistance mutations were selected in 29 of 44 (65.9%) participants who experienced virologic failure while on NVP, whereas resistance mutations were not detected in any of the 28 participants who had virologic failure on ATV/r. 35 Serious hepatic events have been observed when NVP was initiated in ART-naive patients. These events generally occur within the first few weeks of treatment. In addition to experiencing elevated serum transaminases, approximately half of the patients also develop skin rash, with or without fever or flu-like symptoms. Some events, particularly those with rash and other systemic symptoms, have progressed to liver failure. Retrospective analysis of reported events suggests that women with higher CD4 counts appear to be at highest risk for serious hepatic events. 36, 37 A 12-fold higher incidence of symptomatic hepatic events was seen in women with CD4 counts >250 cells/mm 3 at the time of NVP initiation than in women with CD4 counts ≤250 cells/mm 3 at NVP initiation (11.0% vs. 0.9%, respectively). The risk was also greater in men with pretreatment CD4 counts >400 cells/mm 3 than in with men with pre-treatment CD4 counts ≤400 cells/mm 3 (6.3% vs. 1.2%, respectively). Most of these patients had no identifiable underlying hepatic abnormalities. In some cases, hepatic injuries continued to progress despite discontinuation of NVP. 37,38 In contrast, other studies have not shown an association between baseline CD4 counts and severe NVP hepatotoxicity. 39,40 Symptomatic hepatic events have not been reported in mothers or infants given single-dose NVP to prevent perinatal HIV infection. On the basis of the safety and efficacy data discussed above, the Panel classifies NVP-based combinations in the Other NNRTI-Based Regimens category as initial therapy in women with pretreatment CD4 counts ≤250 cells/mm 3 or in men with pretreatment CD4 counts ≤400 cells/mm 3 (C). Patients whose CD4 count increases to levels above these thresholds as a result of NVP-containing therapy can safely continue therapy without an increased risk of adverse hepatic events. 41 NVP should be initiated at a dosage of 200 mg once daily for a 14-day lead-in period before being increased to the maintenance dosage of 400 mg per day (as an extended-release 400 mg tablet once daily or 200 mg immediate-release tablet twice daily). The lead-in period has been observed to decrease the incidence of rash. Some experts recommend monitoring serum transaminases at baseline, at 2 weeks, again 2 weeks after dose escalation, and then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each patient visit. # Protease Inhibitor-Based Regimens # Summary: Protease Inhibitor-Based Regimens PI-based regimens (particularly with RTV-boosting) have demonstrated virologic potency and durability in treatment-naive subjects. In contrast to NNRTI-and INSTI-based regimens, few or no PI mutations are detected in patients who developed virologic failure on their first PI-based regimen. 35,42 Each PI has its own virologic potency, adverse effect profile, and pharmacokinetic (PK) properties. The characteristics, advantages, and disadvantages of each PI are listed in Table 6 and Appendix B, Table 3. When selecting a boosted PI-based regimen for an ART-naive patient, clinicians should consider factors such as dosing frequency, food requirements, pill burden, daily RTV dose, drug interaction potential, toxicity profile of the individual PI, and baseline lipid profile and pregnancy status of the patient. See the Perinatal Guidelines for specific recommendations in pregnancy. 34 A number of metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which also depends on the dose of RTV used as a PK boosting agent. Two large observational cohort studies suggest that LPV/r, indinavir (IDV), fosamprenavir (FPV), or RTV-boosted FPV (FPV/r) may be associated with increased rates of myocardial infarction (MI) or stroke. 43,44 This association was not seen with ATV. 45 These studies had too few patients receiving DRV/r to be included in the analysis. RTV-boosted saquinavir (SQV/r) can prolong the PR and QT intervals on electrocardiogram (ECG). The degree of QT prolongation seen with SQV/r is greater than that seen with some other boosted PIs. Therefore, SQV/r should be used with caution in patients with underlying heart conditions such as heart rate or rhythm problems, or who use concomitant drugs that may increase the risk of developing these ECG abnormalities. 46 SQV/r is rarely used for initial therapy for this reason, and because, when compared with other PI-based regimens, the regimen has a higher pill burden and no clear advantages. The potent inhibitory effect of RTV on the cytochrome P (CYP) 450 3A isoenzyme allows the addition of low-dose RTV to other PIs as a PK enhancer to increase drug exposure and prolong the plasma half-life of the active PI. The drawbacks associated with this strategy are the potential for increased risk of hyperlipidemia and a greater potential of drug-drug interactions from the addition of RTV. RTV boosting is recommended in all PI-based regimens whenever possible; when boosting is not possible and a PI-based regimen is desired, only ATV should be used. In patients without pre-existing PI resistance, once-daily boosted PI regimens that use only 100 mg of RTV per day are preferred. These regimens tend to cause fewer gastrointestinal (GI) side effects and less metabolic toxicity than regimens that use RTV at a dose of 200 mg per day. The Panel uses the following criteria to distinguish between preferred, alternative, and other PIs for use in ART-naive patients: • Demonstrated superior or non-inferior virologic efficacy when compared with at least one other PI-based regimen, based on, at least, published 48-week data • RTV-boosted PI using no more than 100 mg of RTV per day • Once-daily dosing • Low pill count • Good tolerability. Using these criteria, the Panel recommends once-daily ATV/r and DRV/r as preferred PIs. # Preferred Protease Inhibitor-Based Regimens # In alphabetical order, by active PI component Ritonavir-Boosted Atazanavir (ATV/r). In a clinical trial, ATV/r enhanced ATV concentrations and improved virologic activity more than unboosted ATV. 47 The CASTLE study compared once-daily ATV/r with twice-daily LPV/r, each in combination with TDF/FTC, in 883 ARV-naive participants. In this openlabel, noninferiority study, the two regimens showed similar virologic and CD4 responses at 48 weeks 48 and at 96 weeks. 49 More hyperbilirubinemia and less GI toxicity were seen in the ATV/r arm than in the LPV/r arm. This study supports the designation of ATV/r + TDF/FTC as a preferred PI-based regimen (AI). The main adverse effect associated with ATV/r is indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations. Nephrolithiasis [50][51][52] and cholelithiasis 53 also have been reported in patients who received ATV. ATV/r requires acidic gastric pH for dissolution. Thus, concomitant use of drugs that raise gastric pH (e.g., antacids, H2 antagonists, and particularly PPIs), may impair absorption of ATV. Table 15a provides recommendations for use of ATV/r with these agents. # Ritonavir-Boosted Darunavir (DRV/r). The ARTEMIS study compared DRV/r (800/100 mg once daily) with LPV/r (once or twice daily), both in combination with TDF/FTC, in a randomized, open-label, noninferiority trial. The study enrolled 689 ART-naive participants. DRV/r was non-inferior to LPV/r at 48 weeks 54 , and superior at week 192. 55 In participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm. Grades 2 to 4 adverse events, primarily diarrhea, were seen more frequently in LPV/r recipients than in DRV/r recipients. At virologic failure, no major PI mutations were detected in participants randomized to either arm. 42,55 Based on these data, the Panel recommends DRV/r + TDF/FTC as a preferred PI-based regimen (AI). No randomized controlled trial to evaluate the efficacy of DRV/r with other 2-NRTI combinations exists. A small retrospective study suggested that DRV/r plus ABC/3TC may be effective in treatment-naive patients for up to 48 weeks. 56 Based on this preliminary information, the Panel recommends this combination as an alternative PI-based regimen (BIII). # Alternative Protease Inhibitor-Based Regimens # In alphabetical order, by active PI component Ritonavir-Boosted Fosamprenavir (FPV/r, once or twice daily). FPV/r is an alternative PI. The KLEAN trial compared twice-daily FPV/r with LPV/r, each in combination with ABC and 3TC, in ART-naive patients. At Weeks 48 and 144, similar percentages of subjects achieved viral loads <400 copies/mL. 57,58 The frequency and severity of adverse events did not differ between the regimens. Twice-daily FPV/r was noninferior to twice-daily LPV/r. Based on the preference for once-daily regimens with no more than 100 mg/day of RTV, twice-daily FPV is considered an alternative choice. A comparative trial of once-daily FPV/r (1400/100 mg) and once-daily ATV/r, both in combination with TDF/FTC, was conducted in 106 ARV-naive participants. 59 The regimens showed similar virologic and CD4 benefits. The study's small sample size precludes the assessment of superior or non-inferior virologic efficacy required for a preferred PI. Collectively, FPV/r regimens, with once-or twice-daily dosing, are recommended as alternative PI-based regimens. # Ritonavir-Boosted Lopinavir (LPV/r, coformulated). LPV/r is the only available coformulated boosted PI. It can be given once or twice daily. However, because LPV/r must be boosted with 200 mg/day of RTV and is associated with higher rates of GI side effects and hyperlipidemia than other PIs boosted with 100 mg of RTV, LPV/r is recommended as an alternative PI for ART-naive patients. A 7-year follow-up study of LPV/r and 2 NRTIs showed sustained virologic suppression in patients who were maintained on the originally assigned regimen. 60 Results of clinical trials that compared LPV/r with ATV/r, DRV/r, FPV/r, or SQV/r are discussed in the related sections of this document. The ACTG 5142 study showed that, when compared with EFV plus 2 NRTIs, the regimen of twice-daily LPV/r plus 2 NRTIs had decreased virologic efficacy. However, the CD4 response was greater with LPV/r, and there was less drug resistance associated with virologic failure. 4 In addition to diarrhea, major adverse effects of LPV/r include insulin resistance and hyperlipidemia, especially hypertriglyceridemia; these required pharmacologic management in some patients. In the D:A:D and French observational cohorts, cumulative use of LPV/r was associated with a slightly increased risk of MI. 43,44 Once-daily LPV/r should not be used in patients who have HIV mutations associated with PI resistance, because higher LPV trough levels may be required to suppress resistant virus. Once-daily dosing should not be used in pregnant women, especially during the third trimester, when LPV levels are expected to decline. For more detailed information regarding ART drug choices and related issues in pregnancy, see the Perinatal Guidelines. 34 # Other Protease Inhibitor-Based Regimens Atazanavir (ATV). In a clinical trial, ATV concentrations were enhanced with the addition of RTV 100 mg when compared to once-daily unboosted ATV, as a result, better virologic activity was seen with ATV/r. 47 Nevertheless, unboosted ATV may be selected for some patients because it has fewer GI adverse effects including less hyperbilirubinemia and less impact on lipid profiles than ATV/r. Three studies compared unboosted ATV-based combination regimens with either NFV-or EFV-based regimens. These studies established that ATV 400 mg once daily and both comparator treatments had similar virologic efficacy in ARV-naive patients after 48 weeks of therapy. 5,47,61,62 In a multinational randomized trial comparing three initial treatment strategies, unboosted ATV + ddI + FTC was inferior to both EFV + TDF/FTC and EFV + ZDV/3TC. 63 Unboosted ATV may be used as initial therapy when a once-daily regimen without RTV is desired and in patients with underlying risk factors that indicate that hyperlipidemia may be particularly undesirable (C). However, in these situations, other NNRTI-and INSTI-based regimens should generally be used instead of unboosted ATV. When ATV is co-administered with TDF or EFV, it should be boosted with RTV because ATV concentrations are reduced in the presence of these drugs. ATV requires acidic gastric pH for dissolution. Thus, concomitant use of drugs that raise gastric pH (such as antacids, H2 antagonists, and PPIs) may significantly impair ATV absorption. PPIs should not be used in patients who are taking unboosted ATV. H2 antagonists and antacids should be used with caution and with careful dose separation (see Tables 14 and 15a). Ritonavir-Boosted Saquinavir (SQV/r). The GEMINI study compared SQV/r (1000/100 mg twice daily) and LPV/r, both given twice daily, in combination with TDF/FTC given once daily, in 337 ART-naive participants who were monitored over 48 weeks. Levels of viral suppression and increases in CD4 counts were similar in both arms of the study. 64 Triglyceride (TG) levels were higher in the LPV/r arm than in the SQV/r arm. The SQV/r regimen has a higher pill burden and requires twice-daily dosing and 200 mg of RTV. In a healthy volunteer study, SQV/r use at the recommended dose was associated with increases in both QT and PR intervals. The degree of QT prolongation with SQV/r was greater than that seen with some other boosted PIs used at their recommended doses. Rare cases of torsades de pointes and complete heart block have been reported in post-marketing surveillance. Based on these findings, an ECG before initiation of SQV/r is recommended. SQV/r is not recommended for patients with any of the following conditions: documented congenital or acquired QT prolongation, pretreatment QT interval of >450 milliseconds (msec), refractory hypokalemia or hypomagnesemia, complete atrioventricular (AV) block without implanted pacemakers, at risk of complete AV block, or receiving other drugs that prolong QT interval. 46 On the basis of these restrictions, and because several other preferred or alternative PI options are available, the Panel recommends that, although SQV/r may be acceptable, it should be used with caution in select ARV-naive patients (C). # Integrase Strand Transfer Inhibitor (INSTI)-Based Regimens # Preferred Integrase Strand Transfer Inhibitor-Based Regimen Raltegravir (RAL). RAL is an INSTI that is approved for use in ART-naive patients on the basis of results of STARTMRK, a Phase III study that compared RAL (400 mg twice daily) and EFV (600 mg once daily), each in combination with TDF/FTC, in ART-naive subjects. This multinational, double-blind, placebocontrolled study enrolled 563 subjects with plasma viral loads >5,000 copies/mL. At Week 48, similar percentages of subjects in both groups achieved viral loads <50 copies/mL (86.1% and 81.9% for RAL and EFV, respectively, P <0.001 for non-inferiority). CD4 counts rose by 189 cells/mm 3 in the RAL group and 163 cells/mm 3 in the EFV group. The frequency of serious adverse events was similar in both groups. 6 At 156 weeks, virologic and immunologic responses remained similar in both groups with no new safety concerns identified. 65 On the basis of these data, the Panel recommends RAL + TDF/FTC as a preferred regimen in ART-naive patients (AI). In a small single-arm pilot study of 35 subjects who received a regimen of RAL + ABC/3TC, 91% of subjects had viral loads <50 copies/mL at Week 48. 66 On the basis of these preliminary data, RAL + ABC/3TC may be used as an alternative INSTI-based regimen (BIII). RAL use has been associated with creatine kinase elevations. Myositis and rhabdomyolysis have been reported. Rare cases of severe skin reactions and systemic hypersensitivity reactions (HSRs) in patients who received RAL have been reported during post-marketing surveillance. 67 Comparisons of RAL-based regimens and boosted PI-based regimens in ART-naive subjects have not been reported. RAL must be administered twice daily-a potential disadvantage when comparing RAL-based treatment with some other regimens. RAL, like EFV, has a lower genetic barrier to resistance than RTVboosted PIs. In the STARTMRK comparative trial, resistance mutations were observed with approximately the same frequency in RAL-and EFV-treated participants. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents F-12 # Alternative Integrase Strand Transfer Inhibitor-Based Regimen Elvitegravir (EVG). EVG is an INSTI available as a fixed-dose combination product with cobicistat (COBI), TDF, and FTC (EVG/COBI/TDF/FTC), and is approved as a single-tablet, once-daily regimen for ART-naive patients. EVG is metabolized primarily by CYP3A enzymes; as a result, CYP3A inducers or inhibitors may alter EVG concentrations. COBI is a specific, potent CYP3A inhibitor with no activity against HIV. It acts as a PK enhancer of EVG, which allows for once daily dosing of the combination product. 68 EVG/COBI/TDF/FTC is not recommended for patients with pre-treatment estimated creatinine clearance less than 70 mL/min. 69 For more information on PK enhancement with RTV or COBI, see Drug-Drug Interactions-Pharmacokinetic Enhancing. In two Phase 3 randomized clinical studies, the safety and efficacy of this combination regimen in ART-naive HIV-infected subjects was compared to that of two currently recommended first-line regimens. Coformulated EVG/COBI/TDF/FTC was non-inferior to co-formulated EFV/TDF/FTC: 87.6% of the EVG/COBI/TDF/FTC-treated subjects versus 84.1% of the EFV/TDF/FTC-treated subjects achieved virologic suppression <50 copies/mL at 48 weeks (difference 3.5%, 95% CI -1.6, 8.8). 15 Similarly, EVG/COBI/TDF/FTC was non-inferior to ATV/r plus co-formulated TDF/FTC: 89.5% versus 86.8% of subjects achieved virologic suppression <50 copies/mL at 48 weeks, respectively (difference 3%, 95% CI -1.9, 7.8). 70 Rates of virologic failure were low and comparable across study arms, with non-inferior results for treatment arms maintained at 96 weeks. 71,72 At virologic failure, INSTI-associated mutations were detected in some EVG/COBI/TDF/FTC-treated patients who failed therapy. 15,70 These mutations conferred varying degrees of cross-resistance to RAL. The most common adverse events reported with EVG/COBI/TDF/FTC were diarrhea, nausea, and headache. COBI inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and a reduction in estimated creatinine clearance (CrCl) without reducing glomerular function. 73 Although the overall incidence of study drug discontinuation due to adverse events was lower in the EVG/COBI/TDF/FTC arms (3.7%) than in either comparator arm (5.1% each), more subjects in the EVG/COBI/TDF/FTC arms (8 subjects) discontinued study drugs because of renal adverse events than in the comparator arms (one in the ATV/r + TDF/FTC arm). Four of the eight subjects in the EVG/COBI/TDF/FTC arms who discontinued study drug had evidence of proximal tubular dysfunction; after drug discontinuation, abnormal lab values in these four patients improved but did not completely resolve. CrCl, urine glucose and urine protein should be assessed before starting therapy and monitored during therapy. Consideration should be given to periodic monitoring of serum phosphorus in patients at risk for renal impairment. Although COBI may cause modest increases in serum creatinine and modest declines in CrCl, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored and evaluated for evidence of tubulopathy. Proteinuria, normoglycemic glycosuria, and increased fractional excretion of phosphorous may represent the first signs of tubulopathy and precede any decline in renal function. Patients on EVG/COBI/TDF/FTC should be switched to an alternative ARV regimen if estimated CrCl decreases to less than 50 mL/min. Concomitant use of nephrotoxic drugs should be avoided. In summary, EVG/COBI/FTC/TDF has rates of virologic suppression comparable to two currently preferred regimens. As a co-formulated tablet, it can be given as one tablet, once daily. Limitations of this combination include a possible increased risk of proximal renal tubulopathy in addition to inhibition of active tubular secretion of creatinine, significant drug-drug interactions, limited data in patients with advanced HIV disease and in women, and food requirement. On the basis of these factors, the Panel recommends EVG/COBI/FTC/TDF as an alternative regimen in ART-naive patients (BI). # CCR5 Antagonist-Based Regimens Maraviroc (MVC). The MERIT study compared the CCR5 antagonist MVC with EFV, both in combination with ZDV/3TC, in a randomized, double-blind trial in ART-naive participants. 7 Only participants who had # Dual-Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Combination Therapy # Summary: Dual-Nucleoside Reverse Transcriptase Inhibitor Components Dual NRTIs are commonly used in combination with an NNRTI, a PI (usually boosted with RTV), an INSTI, or a CCR5 antagonist. Most dual-NRTI combinations used in clinical practice consist of a primary NRTI plus 3TC or FTC. Both 3TC and FTC have few adverse effects but may select for the M184V resistance mutation, which confers high-level resistance to both drugs; a modest decrease in susceptibility to ddI and ABC; and improved susceptibility to ZDV, d4T, and TDF. 75 All NRTIs except ddI can be taken with or without food. Adherence may be additionally improved with once-daily dosing (available for all NRTIs except d4T and ZDV) and with fixed-dosage combinations, such as ABC/3TC, TDF/FTC (with or without EFV, RPV, or EVG/COBI), or ZDV/3TC. The Panel's recommendations on specific dual-NRTI options are made on the basis of virologic potency and durability, short-and long-term toxicities, the propensity to select for resistance mutations, and dosing convenience. # Preferred Dual-Nucleoside Reverse Transcriptase Inhibitors Tenofovir/Emtricitabine (TDF/FTC, co-formulated). TDF is a nucleotide analog with potent activity against both HIV and hepatitis B virus (HBV) and a long intracellular half-life that allows for once-daily dosing. The fixed-dose combinations of TDF/FTC, EFV/TDF/FTC, RPV/TDF/FTC, and EVG/COBI/TDF/ FTC are administered as one tablet, once daily and are designed to improve adherence. TDF, when used with either 3TC or FTC as part of an EFV-based regimen in ART-naive patients, demonstrated potent virologic suppression 26 and was superior to ZDV/3TC in virologic efficacy up to 144 weeks. 76 In the 934 study, more participants in the ZDV/3TC arm than in the TDF/FTC arm developed loss of limb fat (as assessed by dual-energy x-ray absorptiometry [DXA]) and anemia at 96 and 144 weeks. 76 Emergence of the M184V mutation was less frequent with TDF/FTC than with ZDV/3TC, and by 144 weeks of therapy no participant had developed the K65R mutation. TDF + FTC or 3TC has also been studied in combination with RPV, several boosted PIs, EVG/COBI, and RAL in randomized clinical trials; all trials demonstrate good virologic benefit. 6,15,48,54,59,70,77 TDF/FTC was compared with ABC/3TC in the ACTG 5202 study 8 and the HEAT trial. 10 In the ACTG 5202 trial, inferior virologic responses were observed in participants randomized to ABC/3TC who had a pre- treatment HIV RNA >100,000 copies/mL. This was not observed in the HEAT trial or in other trials (see the ABC/3TC section below for more detailed discussion). Renal impairment, manifested by increases in serum creatinine, proteinuria, glycosuria, hypophosphatemia, proximal renal tubulopathy, and acute tubular necrosis, has been associated with TDF use. 78,79 Risk factors may include advanced HIV disease, longer treatment history, and pre-existing renal impairment. 80 In the HEAT trial, 15% of subjects receiving TDF/FTC versus 10% of those receiving ABC/3TC progressed to a more advanced stage of chronic kidney disease (CKD) on treatment. 10 Renal function, urinalysis, and electrolytes should be monitored in patients who are on TDF. In patients who have some degree of preexisting renal insufficiency (CrCl <50 mL/min), TDF dosage adjustment is required (see Appendix B, Table 7 for dosage recommendations). However, in this setting, the use of alternative NRTIs (for example, ABC) may be preferred over dose-adjusted TDF because available dosage adjustment guidelines for renal dysfunction are based on PK studies only and not on safety and efficacy data. Concomitant use of boosted PIs and COBI can increase TDF concentrations, and studies have suggested a greater risk of renal dysfunction when TDF is used in PI-and COBI-based regimens. 69,78,[81][82][83][84] TDF has been used in combination with PIs without significant renal toxicity in several clinical trials that involved patients who had CrCl >50 mL/min to 60 mL/min. 49,85 Furthermore, in two randomized studies comparing TDF/FTC with ABC/3TC, participants receiving TDF/FTC experienced a significantly greater decline in bone mineral density than ABC/3TC-treated participants. 11,86 TDF plus FTC is the preferred NRTI combination, especially in HIV/HBV-coinfected patients because these drugs have activity against both viruses. The use of a single HBV-active NRTI (e.g., 3TC or FTC) can lead to HBV resistance and is not recommended (see HIV/Hepatitis B Co-infection). # Alternative Dual Nucleoside Reverse Transcriptase Inhibitors Abacavir/Lamivudine (ABC/3TC, co-formulated) for patients who test negative for HLA-B5701. In a comparative trial of ABC/3TC and ZDV/3TC (both given twice daily and combined with EFV), participants in both arms achieved similar virologic responses. CD4 T-cell increase at 48 weeks was greater in the ABCtreated participants than in the ZDV-treated participants. 87 The ACTG 5202 study, a randomized controlled trial in more than 1,800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when used in combination with either EFV or RTV-boosted ATV. Treatment randomization was stratified on the basis of a screening HIV RNA of <100,000 copies/mL or ≥100,000 copies/mL. HLA-B5701 testing was not required before study entry, which may have influenced the results of the trial with respect to some of the safety and tolerability endpoints. A Data Safety Monitoring Board recommended early termination of the ≥100,000 copies/mL stratification group because of a significantly shorter time to study-defined virologic failure in the ABC/3TC arm than in the TDF/FTC arm. 8 This difference in time to virologic failure between arms was observed regardless of whether the third active drug was EFV or ATV/r. There was no difference between ABC/3TC and TDF/FTC in time to virologic failure for participants who had plasma HIV RNA <100,000 copies/mL at screening. 88 In the HEAT study, 688 participants received ABC/3TC or TDF/FTC in combination with once-daily LPV/r. A subgroup analysis according to baseline HIV RNA <100,000 copies/mL or ≥100,000 copies/mL yielded similar percentages of participants with HIV RNA <50 copies/mL at 96 weeks in the two regimens (63% vs. 58% in those with HIV RNA <100,000 copies/mL and 56% vs. 58% in those with ≥100,000 copies/mL). 10 The An association between ABC use and MI was first reported in the D:A:D study. This large, multinational observational study group found that recent (within 6 months) or current use of ABC, but not TDF, was associated with an increased risk of MI, particularly in participants with pre-existing cardiac risk factors. 43,91 Since the report of this study, multiple studies have explored this association. Some studies have found an association; [92][93][94][95] others have found a weak association or no association. 44,[96][97][98][99] Several studies have also been conducted to evaluate potential mechanistic pathways that may underlie the association between ABC use and an increased risk of MI, including endothelial dysfunction, increased platelet reactivity, leukocyte adhesion, inflammation, and hypercoagulability. [100][101][102][103][104][105][106][107] However, to date, no consensus on the association between ABC use and MI risk or the mechanism for such an association has been reached. The fixed-dose combination of ABC/3TC allows for once-daily dosing. Pending additional data, ABC/3TC should be used with caution in individuals who have plasma HIV RNA levels ≥100,000 copies/mL and in persons at high risk of CVD. However, the combination of ABC/3TC remains an alternative dual-NRTI option for some ART-naive patients (BI). # Other Dual Nucleoside Reverse Transcriptase Inhibitors Zidovudine/Lamivudine (ZDV/3TC, coformulated). The dual-NRTI combination of ZDV/3TC has extensive durability, safety, and tolerability experience. 3,5,[108][109][110][111][112] In a multinational, randomized trial comparing three initial treatment strategies, EFV/ZDV/3TC and EFV/TDF/FTC showed similar virologic efficacy; both regimens were superior to ATV/ddI/FTC. 63 A fixed-dose combination of ZDV/3TC is available for one-tablet, twice-daily dosing. Selection of the 3TCassociated M184V mutation has been associated with increased susceptibility to ZDV. In a comparative trial of ABC/3TC and ZDV/3TC (both given twice daily and combined with EFV), the CD4 count increase was greater in the ABC/3TC-treated patients than in the ZDV/3TC-treated patients, 87 even though virologic responses were similar in both arms. Bone marrow suppression, manifested by macrocytic anemia and/or neutropenia, is seen in some patients. ZDV also is associated with GI toxicity, fatigue, and possibly mitochondrial toxicity, including lactic acidosis/hepatic steatosis and lipoatrophy. Because ZDV/3TC has greater toxicity than TDF/FTC or ABC/3TC and requires twice-daily dosing, the Panel classifies ZDV/3TC in the Other Dual-NRTI category, rather than as a preferred or alternative, dual-NRTI option (CI). ZDV/3TC remains as a preferred NRTI option in pregnant women because the two drugs have the most PK, safety, and efficacy data for both mother and newborn of any other ARVs. For more detailed information regarding ARV drug choices and related issues in pregnancy, see the Perinatal Guidelines. 34 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Hepatitis B Virus (HBV). Three of the currently approved NRTIs-FTC, 3TC, and TDF-have activity against HBV. Most HIV/HBV-coinfected patients should use coformulated TDF/FTC (or TDF + 3TC) as their NRTI backbone to provide additional activity against HBV and to avoid selection of HBV mutation that confers resistance to 3TC and FTC. Importantly, patients who have HIV/HBV coinfection may be at risk of acute exacerbation of hepatitis after initiation or discontinuation of TDF, 3TC, or FTC. [113][114][115] Thus, these patients should be monitored closely for clinical or chemical hepatitis if these drugs are initiated or discontinued (see HIV/Hepatitis B Coinfection and Initiating Antiretroviral Therapy). # Antiretroviral Regimens Not Recommended Monotherapy with nucleoside reverse transcriptase inhibitor (NRTI). Single-NRTI therapy does not demonstrate potent and sustained antiviral activity and should not be used (AII). For prevention of motherto-child transmission (PMTCT), zidovudine (ZDV) monotherapy is not recommended but might be considered in certain unusual circumstances in women with HIV RNA <1,000 copies/mL, although the use of a potent combination regimen is preferred. (See Perinatal Guidelines, 1 available at http://aidsinfo.nih.gov.) Single-drug treatment regimens with a ritonavir (RTV)-boosted protease inhibitor (PI), either lopinavir (LPV), 2 atazanavir (ATV), 3 or darunavir (DRV) [4][5] are under investigation with mixed results, and cannot be recommended outside of a clinical trial at this time. Dual-NRTI regimens. These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity compared with triple-drug combination regimens (AI). 6 Triple-NRTI regimens. In general, triple-NRTI regimens other than abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (BI) and possibly lamivudine/zidovudine + tenofovir (3TC/ZDV + TDF) (BII) should not be used because of suboptimal virologic activity [7][8][9] or lack of data (AI). # Antiretroviral Components Not Recommended Atazanavir (ATV) + indinavir (IDV). Both of these PIs can cause Grade 3 to 4 hyperbilirubinemia and jaundice. Additive adverse effects may be possible when these agents are used concomitantly. Therefore, these two PIs are not recommended for combined use (AIII). # Didanosine (ddI) + stavudine (d4T). The combined use of ddI and d4T as a dual-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis. [10][11][12][13] This combination has been implicated in the deaths of several HIV-infected pregnant women secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis. 14 Therefore, the combined use of ddI and d4T is not recommended (AII). # Didanosine (ddI) + tenofovir (TDF). Use of ddI + TDF may increase ddI concentrations 15 and serious ddIassociated toxicities including pancreatitis and lactic acidosis. [16][17] These toxicities may be lessened by ddI dose reduction. The use of this combination has also been associated with immunologic nonresponse or CD4 cell decline despite viral suppression, [18][19] high rates of early virologic failure, [20][21] and rapid selection of resistance mutations. [20][21][22] Because of these adverse outcomes, this dual-NRTI combination is not generally recommended (AII). Clinicians caring for patients who are clinically stable on regimens containing ddI + TDF should consider altering the NRTIs to avoid this combination. Two-non-nucleoside reverse transcriptase inhibitor (2-NNRTI) combinations. In the 2NN trial, ARVnaive participants were randomized to receive once-or twice-daily nevirapine (NVP) versus efavirenz (EFV) versus EFV plus NVP, all combined with d4T and 3TC. 23 A higher frequency of clinical adverse events that led to treatment discontinuation was reported in participants randomized to the two-NNRTI arm. Both EFV and NVP may induce metabolism of etravirine (ETR), which leads to reduction in ETR drug exposure. 24 Based on these findings, the Panel does not recommend using two NNRTIs in combination in any regimen (AI). Efavirenz (EFV) in first trimester of pregnancy and in women with significant childbearing potential. EFV use was associated with significant teratogenic effects in nonhuman primates at drug exposures similar to those representing human exposure. Several cases of congenital anomalies have been reported after early human gestational exposure to EFV. [25][26] EFV should be avoided in pregnancy, particularly during the first trimester, and in women of childbearing potential who are trying to conceive or who are not using effective and consistent contraception (AIII). If no other ARV options are available for the woman who is pregnant or at risk of becoming pregnant, the provider should consult with a clinician who has expertise in both HIV infection and pregnancy. (See Perinatal Guidelines, 1 available at http://aidsinfo.nih.gov.) Emtricitabine (FTC) + lamivudine (3TC). Both of these drugs have similar resistance profiles and have minimal additive antiviral activity. Inhibition of intracellular phosphorylation may occur in vivo, as seen with other dual-cytidine analog combinations. 27 These two agents should not be used as a dual-NRTI combination (AIII). Etravirine (ETR) + unboosted PI. ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate doses of the PIs have not been established 24 (AII). # Etravirine (ETR) + ritonavir (RTV)-boosted atazanavir (ATV) or fosamprenavir (FPV). ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established 24 (AII). # Etravirine (ETR) + ritonavir (RTV)-boosted tipranavir (TPV). RTV-boosted TPV significantly reduces ETR concentrations. These drugs should not be co-administered 24 (AII). Nevirapine (NVP) initiated in ARV-naive women with CD4 counts >250 cells/mm 3 or in ARV-naive men with CD4 counts >400 cells/mm 3 . Greater risk of symptomatic hepatic events, including serious and life-threatening events, has been observed in these patient groups. NVP should not be initiated in these patients (BI) unless the benefit clearly outweighs the risk. [28][29][30] Patients who experience CD4 count increases to levels above these thresholds as a result of antiretroviral therapy (ART) can be safely switched to NVP. 31 Unboosted darunavir (DRV), saquinavir (SQV), or tipranavir (TPV). The virologic benefit of these PIs has been demonstrated only when they were used with concomitant RTV. Therefore, use of these agents as part of a combination regimen without RTV is not recommended (AII). # Stavudine (d4T) + zidovudine (ZDV). These two NRTIs should not be used in combination because of antagonism demonstrated in vitro 32 and in vivo 33 (AII). # 2-NNRTI combination (AI) • When EFV combined with NVP, higher incidence of clinical adverse events seen when compared with either EFV-or NVP-based regimen. • Both EFV and NVP may induce metabolism and may lead to reductions in ETR exposure; thus, they should not be used in combination with ETR. # Virologic Definitions Virologic suppression: A confirmed HIV RNA level below the limit of assay detection (e.g., <48 copies/mL). # Virologic failure: The inability to achieve or maintain suppression of viral replication (to an HIV RNA level <200 copies/mL). # Incomplete virologic response: Two consecutive plasma HIV RNA levels >200 copies/mL after 24 weeks on an ARV regimen. Baseline HIV RNA may affect the time course of response, and some regimens will take longer than others to suppress HIV RNA levels. # Panel's Recommendations • Assessing and managing an antiretroviral (ARV)-experienced patient experiencing failure of antiretroviral therapy (ART) is complex. Expert advice is critical and should be sought. • Evaluation of virologic failure should include an assessment of the severity of the patient's HIV disease, ART history, use of concomitant medications with consideration of adverse drug interactions with ARV agents, HIV RNA and CD4 T-cell count trends over time, and prior drug-resistance testing results. • Drug-resistance testing should be obtained while the patient is taking the failing ARV regimen or within 4 weeks of treatment discontinuation (AII). • The goal of treatment for ARV-experienced patients with drug resistance who are experiencing virologic failure is to reestablish virologic suppression (e.g., HIV RNA <48 copies/mL) (AI). • To design a new regimen, the patient's treatment history and past and current resistance test results should be used to identify at least two (preferably three) fully active agents to combine with an optimized background ARV regimen (AI). A fully active agent is one that is likely to have ARV activity on the basis of the patient's treatment history, drug-resistance testing, and/or a novel mechanism of action. • In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII). • In patients with a high likelihood of clinical progression (e.g., CD4 count <100 cells/mm 3 ) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI). • For some highly ART-experienced patients, maximal virologic suppression is not possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and avoid clinical progression. • Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4 cell count and increases the risk of clinical progression. Therefore, this strategy is not recommended (AI). • In the setting of virologic suppression, there is no consensus on how to define or treat immunologic failure. Virologic rebound: Confirmed detectable HIV RNA (to >200 copies/mL) after virologic suppression. # Rating of Recommendations # Persistent low-level viremia: Confirmed detectable HIV RNA levels that are <1,000 copies/mL. # Virologic blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression. # Causes of Virologic Failure Virologic failure in a patient can occur for multiple reasons. Data from older patient cohorts suggested that suboptimal adherence and drug intolerance/toxicity accounted for 28%-40% of virologic failure and regimen discontinuations. [1][2] More recent data suggest that most virologic failure on first-line regimens occurred due to either pre-existing (transmitted) drug resistance or suboptimal adherence. 3 Factors associated with virologic failure include: • Patient characteristics • higher pretreatment or baseline HIV RNA level (depending on the specific regimen used) • lower pretreatment or nadir CD4 T-cell count • prior AIDS diagnosis • comorbidities (e.g., active substance abuse, depression) • presence of drug-resistant virus, either transmitted or acquired • prior treatment failure • incomplete medication adherence and missed clinic appointments • tolerability of medications • • concomitant medications and supplements (with consideration for adverse drug-drug interactions) • comorbidities (including substance abuse) In many cases, the cause(s) of virologic failure will be identified. In some cases, no obvious cause(s) may be identified. It is important to distinguish among the reasons for virologic failure because the approaches to subsequent therapy differ. The following potential causes of virologic failure should be explored in depth. • Adherence. Assess the patient's adherence to the regimen. For incomplete adherence, identify and address the underlying cause(s) (e.g., difficulties accessing or tolerating medications, depression, active substance abuse) and simplify the regimen if possible (e.g., decrease pill count or dosing frequency). (See Adherence.) • Medication Intolerance. Assess the patient's tolerance of the current regimen and the severity and duration of side effects, keeping in mind that even minor side effects can impact adherence. Management strategies for intolerance in the absence of drug resistance may include: • using symptomatic treatment (e.g., antiemetics, antidiarrheals) • # Changing ART There is no consensus on the optimal time to change therapy for virologic failure. The goal of ART is to suppress HIV replication to a level where drug-resistance mutations do not emerge. However, the specific level of viral suppression needed to achieve durable virologic suppression remains unknown. Selection of drug resistance does not appear to occur in patients with persistent HIV RNA levels suppressed to <48 copies/mL, 6 although this remains controversial. 7 The clinical implications of HIV RNA in the range of >48 to <200 copies/mL in a patient on ART are controversial. Unlike the case with higher levels of HIV RNA, most, if not all, circulating virus from individuals with this level of HIV RNA results from the release of HIV from long-lived latently infected cells and does not signify ongoing viral replication with the emergence of drug-resistant virus. 8 Although some studies have suggested that viremia at this low level predicts subsequent failure 9 and can be associated with the evolution of drug resistance, 10 a large retrospective analysis showed that using an HIV RNA threshold for virologic failure of <200 copies/mL had the same predictive value as using a threshold of <50 copies/mL. 11 Newer technologies (e.g., Taqman assay) have made it possible to detect HIV RNA in more patients with low level viremia (<200 copies/mL) than was possible with previous assays. Use of these newer assays has resulted in more confirmatory viral load testing than may be necessary. [12][13][14] Persistent HIV RNA levels >200 copies/mL often are associated with evidence of viral evolution and drugresistance mutation accumulation; 15 this is particularly common when HIV RNA levels are >500 copies/mL. 16 Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should therefore be considered as virologic failure. Viremia "blips" (e.g., viral suppression followed by a detectable HIV RNA level and then subsequent return to undetectable levels) usually are not associated with subsequent virologic failure. 17 # Management of Virologic Failure Once virologic failure is confirmed, generally the regimen should be changed as soon as possible to avoid progressive accumulation of resistance mutations. 18 Ideally, a new ARV regimen should contain at least two, and preferably three, fully active drugs on the basis of drug treatment history, resistance testing, or new mechanistic class (AI). [19][20][21][22][23][24][25][26][27] Some ARV drugs (e.g., NRTIs) may contribute partial ARV activity to a regimen, despite drug resistance, 28 while others (e.g., T-20, NNRTIs, RAL) likely do not provide partial activity. [28][29][30] Because of the potential for drug-class cross resistance that reduces drug activity, using a "new" drug that a patient has not yet taken may not mean that the drug is fully active. In addition, archived drug-resistance mutations may not be detected by standard drug-resistance tests, emphasizing the importance of considering treatment history and prior drug-resistance tests. Drug potency and viral susceptibility are more important than the number of drugs prescribed. Early studies of ART-experienced patients identified factors associated with better virologic responses to subsequent regimens. [31][32] These factors included lower HIV RNA level and/or higher CD4 cell count at the time of therapy change, using a new (i.e. , not yet taken) class of ARV drugs, and using ritonavir (RTV)boosted PIs in PI-experienced patients. More recent clinical trials support the strategy of conducting reverse transcriptase (RT) and protease (PT) resistance testing (both genotype and phenotype) while an ART-experienced patient is taking a failing ARV regimen, designing a new regimen based on the treatment history and resistance testing results, and selecting at least two and preferably three active drugs for the new treatment regimen. 20-21, 23-24, 33 Higher genotypic and/or phenotypic susceptibility scores (quantitative measures of drug activity) are associated with better virologic responses. [23][24] Patients who receive more active drugs have a better and more prolonged virologic response than those with fewer active drugs in the regimen. Active ARV drugs include those with activity against drug-resistant viral strains, including newer members of existing classes (the NNRTI-ETR, the # Clinical Scenarios of Virologic Failure • Low-level viremia (HIV RNA <1,000 copies/mL). Assess adherence. Consider variability in HIV RNA assays. Patients with HIV RNA <48 copies/mL or isolated increases in HIV RNA ("blips") do not require a change in treatment 13 (AII). There is no consensus regarding how to manage patients with HIV RNA levels >48 copies/mL and <200 copies/mL; HIV RNA levels should be followed over time to assess the need for changes (AIII). Patients with persistent HIV RNA levels >200 copies/mL often select out drugresistant viral variants, particularly when HIV RNA levels are >500 copies/mL. Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should be considered as possible virologic failure; resistance testing should be attempted if the HIV RNA level is >500 copies/mL. For individuals with sufficient therapeutic options, consider treatment change (BIII). • Repeated detectable viremia (HIV RNA >1,000 copies/mL) and NO drug resistance identified. Consider the timing of the drug-resistance test (e.g., was the patient off ARV for >4 weeks and/or nonadherent?). Consider resuming the same regimen or starting a new regimen and then repeating genotypic testing early (e.g., in 2-4 weeks) to determine whether a resistant viral strain emerges (CIII). • Repeated detectable viremia (HIV RNA >1,000 copies/mL) and drug resistance identified. The goals in this situation are to resuppress HIV RNA levels maximally (i.e., to <48 copies/mL) and to prevent further selection of resistance mutations. With the availability of multiple new ARVs, including some with new mechanisms of action, this goal is now possible in many patients, including those with extensive treatment experience and drug resistance. With virologic failure, consider changing the treatment regimen sooner, rather than later, to minimize continued selection of resistance mutations. In a patient with ongoing viremia and evidence of resistance, some drugs in a regimen (e.g., NNRTI, T-20, RAL) should be discontinued promptly to decrease the risk of selecting additional drug-resistance mutations in order to preserve the activity of these drug classes in future regimens. A new regimen should include at least two, and preferably three, fully active agents (AII). • Highly drug resistant HIV. There is a subset of patients who have experienced toxicity and/or developed resistance to all or most currently available regimens, and designing a regimen with two or three fully active drugs is not possible. Many of these patients received suboptimal ARV regimens (i.e., did not have access to more than one or two of the drugs at the time they became available) or have been unable to adhere to any regimen. If maximal virologic suppression cannot be achieved, the goals are to preserve immunologic function and to prevent clinical progression (even with ongoing viremia). There is no consensus on how to optimize the management of these patients. It is reasonable to observe a patient on the same regimen, rather than changing the regimen, depending on the stage of HIV disease (BII). Even partial virologic suppression of HIV RNA >0.5 log 10 copies/mL from baseline correlates with clinical benefits. 34 There is evidence from cohort studies that continuing therapy, even in the presence of viremia and the absence of CD4 T-cell count increases, reduces the risk of disease progression. 35 Other cohort studies suggest continued immunologic and clinical benefits if the HIV RNA level is maintained <10,000-20,000 copies/mL. [36][37] However, these potential benefits all must be balanced with the ongoing risk of accumulating additional resistance mutations. In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII). However, in patients with a high likelihood of clinical progression (e.g., CD4 cell count <100 cells/mm 3 ) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI). Weighing the risks (e.g., selection of drug resistance) and benefits (e.g., ARV activity) of using a single active drug in the heavily ART-experienced patient is complicated, and consultation with an expert is advised. Patients with ongoing viremia and with an insufficient number of approved treatment options to construct a fully suppressive regimen may be candidates for research studies or expanded access programs, or singlepatient access of investigational new drug(s) (IND), as specified in Food and Drug Administration (FDA) regulations: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm163982.htm. Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4 T-cell count and increases the risk of clinical progression. [38][39] Therefore, this strategy is not recommended (AI). See Discontinuation or Interruption of Antiretroviral Therapy. • Prior treatment and suspected drug resistance, now presenting to care in need of therapy with limited information (i.e., incomplete or absence of self-reported history, medical records, or previous resistance data). Every effort should be made to obtain medical records and prior drugresistance testing results; however, this is not always possible. One strategy is to restart the most recent ARV regimen and assess drug resistance in 2-4 weeks to help guide the choice of the next regimen; another strategy is to start two or three drugs known to be active based on treatment history (e.g., MVC with R5 virus, RAL if no prior INSTI). # Immunologic Failure: Definition, Causes, and Management Immunologic failure can be defined as the failure to achieve and maintain an adequate CD4 response despite virologic suppression. Increases in CD4 counts in ARV-naive patients with initial ARV regimens are approximately 150 cells/mm 3 over the first year. 40 A CD4 count plateau may occur after 4-6 years of treatment with suppressed viremia. [41][42][43][44][45] No accepted specific definition for immunologic failure exists, although some studies have focused on patients who fail to increase CD4 counts above a specific threshold (e.g., >350 or 500 cells/mm 3 ) over a specific period of time (e.g., 4-7 years). Others have focused on an inability to increase CD4 counts above pretherapy levels by a certain threshold (e.g., >50 or 100 cells/mm 3 ) over a given time period. The former criterion may be preferable because of data linking these thresholds with the risk of non-AIDS clinical events. 46 The proportion of patients experiencing immunologic failure depends on how failure is defined, the observation period, and the CD4 count when treatment was started. In the longest study conducted to date, the percentage of patients with suppressed viremia who reached a CD4 count >500 cells/mm 3 through 6 years of treatment was 42% in those starting treatment with a CD4 count <200 cells/mm 3 , 66% in those starting with a CD4 count 200-350 cells/mm 3 , and 85% in those starting with a CD4 count >350 cells/mm 3 . 41 A persistently low CD4 count while on suppressive ART is associated with a small, but appreciable, risk of AIDS-and non-AIDS-related morbidity and mortality. [47][48] For example, in the FIRST study, 49 a low CD4 count on therapy was associated with an increased risk of AIDS-related complications (adjusted hazard ratio of 0.56 per 100 cells/mm 3 higher CD4 count). Similarly, a low CD4 count was associated with an increased risk of non-AIDS events, including cardiovascular, hepatic, and renal disease and cancer. Other studies support these associations. [50][51][52][53] Factors associated with poor CD4 T-cell response: • CD4 count <200/mm 3 when starting ART • Medications, both ARVs (e.g., ZDV, 54 TDF + didanosine [ddI] [55][56][57] ) and other medications. • Persistent immune activation Assessment of Immunologic Failure. CD4 count should be confirmed by repeat testing. Concomitant medications should be reviewed carefully, with a focus on those known to decrease white blood cells or, specifically, CD4 T-cells (e.g., cancer chemotherapy, interferon, prednisone, ZDV; combination of TDF and ddI), and consideration should be given to substituting or discontinuing these drugs, if possible. Untreated coinfections (e.g., HIV-2, HTLV-1, HTLV-2) and serious medical conditions (e.g., malignancy) also should be considered. In many cases, no obvious cause for immunologic failure can be identified. Management of Immunologic Failure. No consensus exists on when or how to treat immunologic failure. Given the risk of clinical events, it is reasonable to focus on patients with CD4 counts <200 cells/mm 3 because patients with higher CD4 counts have a lower risk of clinical events. It is not clear that immunologic failure in the setting of virologic suppression should prompt a change in the ARV regimen. Because ongoing immune activation occurs in some patients with suppressed HIV RNA levels, some have suggested adding a drug to an existing regimen. However, this strategy does not result in clear virologic or immunologic benefit. 58 Others suggest changing the regimen to another regimen (e.g., from NNRTI-based to PI-based, INSTI-based, or CCR5 antagonist-based regimens), but this strategy has not shown clear benefit. An immune-based therapy, interleukin-2, demonstrated CD4 count increases but no clinical benefit in two large randomized studies 59 and therefore is not recommended (AI). Other immune-based therapies (e.g., gene therapies, growth hormone, cyclosporine, interleukin-7) are under investigation. Currently, immune-based therapies should not be used unless in the context of a clinical trial (AIII). Regimen Simplification (Last updated January 10, 2011; last reviewed January 10, 2011) Regimen simplification can be defined broadly as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy (ART) may be considered candidates for regimen simplification, especially if (1) they are receiving treatments that are no longer recommended as preferred or alternative choices for initial therapy; (2) they were prescribed a regimen in the setting of treatment failure at a time when there was an incomplete understanding of resistance or drug-drug interaction data; or (3) they were prescribed a regimen prior to the availability of newer options or formulations that might be easier to administer and/or more tolerable. This section will review situations in which clinicians might consider simplifying treatment in a patient with virologic suppression. Importantly, this section will not review consideration of changes in treatment for reducing ongoing adverse effects. Regimens used in simplification strategies generally should be those that have proven high efficacy in antiretroviral (ARV)-naive patients (see What to Start) or that would be predicted to be highly active for a given patient based on the individual's past treatment history and resistance profile. # Rationale The major rationales behind regimen simplification are to improve the patient's quality of life, maintain longterm adherence, avoid toxicities that may develop with prolonged ARV use, and reduce the risk of virologic failure. Systematic reviews in the non-HIV literature have shown that adherence is inversely related to the number of daily doses. 1 Some prospective studies in HIV-infected individuals have shown that those on regimens with reduced dosing frequency have higher levels of adherence. [2][3] Patient satisfaction with regimens that contain fewer pills and reduced dosing frequency is also higher. 4 # Candidates for Regimen Simplification Unlike ARV agents developed earlier in the HIV epidemic, many ARV medications approved in recent years have sufficiently long half-lives to allow for once-daily dosing, and most also do not have dietary restrictions. Patients on regimens initiated earlier in the era of potent combination ART with drugs that pose a high pill burden and/or frequent dosing requirements are often good candidates for regimen simplification. Patients without suspected drug-resistant virus. Patients on first (or modified) treatment regimens without a history of treatment failure are ideal candidates for regimen simplification. These patients are less likely to harbor drug-resistant virus, especially if a pretreatment genotype did not detect drug resistance. Prospective clinical studies have demonstrated that the likelihood of treatment failure is relatively low in patients after simplification and, indeed, may be lower than in patients who do not simplify treatment. 5 However, some patients may have unrecognized drug-resistant HIV, either acquired at the time of infection or as a consequence of prior treatment, such as patients who were treated with presumably nonsuppressive mono-or dual-nucleoside reverse transcriptase inhibitor (NRTI) regimens before the widespread availability of HIV RNA monitoring and resistance testing. Patients with documented or suspected drug resistance. Treatment simplification may also be appropriate for selected individuals who achieve viral suppression after having had documented or suspected drug resistance. Often, these patients are on regimens selected when management of drug resistance, understanding of potentially adverse drug-drug interactions, and understanding of treatment options were relatively limited. Regimen simplification may also be considered for patients on two ritonavir (RTV)boosted protease inhibitors (PIs). Although successful in suppressing viral replication, this treatment may cause patients to be on regimens that are cumbersome, costly, and associated with potential long-term adverse events. The ability to simplify regimens in this setting often reflects the availability of recently approved agents that have activity against drug-resistant virus and are easier to take without sacrificing ARV activity. Specific situations in which drug simplification could be considered in ART-experienced patients with viral drug resistance are outlined below. Simplifying regimens in patients who have extensive prior treatment histories is complicated. In such a case, a patient's treatment history, treatment responses and tolerance, and resistance test results should be thoroughly reviewed before designing a new regimen. Expert consultation should be considered whenever possible. # Types of Treatment Simplification Within-Class Simplifications. Within-class substitutions offer the advantage of not exposing patients to still-unused drug classes, which potentially preserves other classes for future regimens. In general, withinclass substitutions use a newer agent; coformulated drugs; or a formulation that has a lower pill burden, a lower dosing frequency, or would be less likely to cause toxicity. # • NRTI Substitutions (e.g., changing from zidovudine [ZDV] or stavudine [d4T] to tenofovir [TDF] or abacavir [ABC] ): This may be considered for a patient who has no history of viral resistance on an NRTI-containing regimen. Other NRTIs may be substituted to create a regimen with lower dosing frequency (e.g., once daily) that takes advantage of coformulated agents and potentially avoids some long-term toxicities (e.g., pancreatitis, peripheral neuropathy, lipoatrophy). • # Switching of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g., from nevirapine [NVP] to efavirenz [EFV] ): This may be considered to reduce dosing frequency or to take advantage of coformulated agents. • Switching of PIs: This switch can be from one PI to another PI, to the same PI at a lower dosing frequency (such as from twice-daily to once-daily RTV-boosted lopinavir [LPV/r] or RTV-boosted darunavir [DRV/r]) or, in the case of atazanavir (ATV), to administration without RTV boosting. 6 (Unboosted ATV is presently not a preferred PI component and not recommended if the patient is taking TDF or if the patient has HIV with reduced susceptibility to ATV.) Such changes can reduce dosing frequency, pill count, drug-drug or drug-food interactions, or dyslipidemia or can take advantage of coformulation. These switches can be done with relative ease in patients without PI-resistant virus. However, these switches are not recommended in patients who have a history of documented or suspected PI resistance because convincing data in this setting are lacking. Out-of-Class Substitutions. One common out-of-class substitution for regimen simplification involves a change from a PI-based to an NNRTI-based regimen. An important study in this regard was the NEFA trial, which evaluated substitution of a PI-based regimen in virologically suppressed patients with NVP, EFV, or ABC. 7 Although the baseline regimens in the study are no longer in widespread use, the NEFA findings are still relevant and provide information about the risks and benefits of switching treatment in patients with virologic suppression. In this study, 460 patients on stable, PI-based regimens with virologic suppression (<200 copies/mL for the previous 6 months) were switched to their randomized treatment arms. After 36 months of follow-up, virologic failure occurred more frequently in patients switched to ABC than in patients switched to EFV or NVP. The increased risk of treatment failure was particularly high in patients who had previous suboptimal treatment with mono-and dual-NRTI therapy. This emphasizes the need to consider the potential for drug-resistant virus prior to attempting simplification. 8 Newer agents that target different sites in the HIV life cycle, such as the integrase strand transfer inhibitor (INSTI) raltegravir (RAL) and the CCR5 antagonist maraviroc (MVC), also offer opportunities for out-ofclass substitutions, particularly in patients who have a history of virus resistant to older HIV drugs. Three randomized studies have evaluated replacing a boosted PI with RAL in virologically suppressed patients. In two of these studies, 9-10 the switch to RAL was associated with an increased risk of virologic failure in patients with documented or suspected pre-existing NRTI resistance; a third study did not find this higher risk, possibly due to a longer period of virologic suppression before the change. 11 Overall, these results suggest that in ART-experienced patients, RAL should be used with caution as a substitute for a boosted PI. # Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-13 This strategy should be avoided in patients with documented NRTI resistance unless there are other fully active drugs in the regimen. Because enfuvirtide (T-20) requires twice-daily injections, causes injection-site reactions, and is more expensive than other available ARV agents, patients who are virologically suppressed on T-20-containing regimens may wish to substitute T-20 with an active oral agent. Because the majority of patients on T-20 have highly drug-resistant virus, substitution must be with another fully active agent. Data from one randomized trial and one observational study suggest that RAL can safely substitute for T-20 in patients not previously treated with INSTI. [12][13] Although this strategy generally maintains virologic suppression and is well tolerated, clinicians should be aware that any drug substitution may introduce unanticipated adverse effects or drug-drug interactions. 14 Other newer agents that might be considered as substitutes for T-20 are etravirine (ETR) or MVC. Use of ETR in this setting would optimally be considered only when viral susceptibility to ETR can be assured from resistance testing performed prior to virologic suppression and after carefully assessing for possible deleterious drug-drug interactions (e.g., ETR cannot be administered with several PIs [see Table 16b]). In the ETR early access program, switching from T-20 to ETR showed promise in maintaining viral suppression at 24 weeks, but only 37 subjects were included in this report. 15 MVC is only active in those with documented R5-only virus, a determination that cannot routinely be made in those with undetectable HIV RNA on a stable regimen. Although there is a commercially available proviral DNA assay to assess viral tropism in virologically suppressed patients, there are no clinical data on whether results of this test predict the successful use of MVC as a substitute for another active drug. Reducing the number of active drugs in a regimen. This approach to treatment simplification involves switching a patient from a suppressive regimen to fewer active drugs. In early studies, this approach was associated with a higher risk of treatment failure than continuation of standard treatment with two NRTIs plus a PI. 16 More recently, studies have evaluated the use of an RTV-boosted PI as monotherapy after virologic suppression with a two-NRTI + boosted-PI regimen. [17][18] The major motivations for this approach are a reduction in NRTI-related toxicity and lower cost. In a randomized clinical trial, 18 low-level viremia was more common in those on maintenance LPV/r alone than on a three-drug combination regimen. Viral suppression was achieved by resuming the NRTIs. Studies of DRV/r monotherapy, both as once-or twicedaily dosing, have reported mixed results. [19][20] In aggregate, boosted-PI monotherapy as initial 21 or as simplification treatment has been somewhat less effective in achieving complete virologic suppression and avoiding resistance. Therefore, this strategy cannot be recommended outside of a clinical trial. # Monitoring After Treatment Simplification Patients should be evaluated 2-6 weeks after treatment simplification to assess tolerance and to undergo laboratory monitoring, including HIV RNA, CD4 cell count, and markers of renal and liver function. Assessment of fasting cholesterol subsets and triglycerides should be performed within 3 months after the change in therapy. In the absence of any specific complaints, laboratory abnormalities, or viral rebound at that visit, patients may resume regularly scheduled clinical and laboratory monitoring. Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents (Last updated January 10, 2011; last reviewed January 10, 2011) Knowledge of the relationship between systemic exposure (or concentration) and drug responses (beneficial and/or adverse) is key in selecting the dose of a drug, in understanding the variability in the response of patients to a drug, and in designing strategies to optimize response and tolerability. TDM is a strategy applied to certain antiarrhythmics, anticonvulsants, antineoplastics, and antibiotics that utilizes measured drug concentrations to design dosing regimens to improve the likelihood of the desired therapeutic and safety outcomes. The key characteristic of a drug that is a candidate for TDM is knowledge of the exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions. Several ARV agents meet most of the characteristics of agents that can be considered candidates for a TDM strategy. 1 The rationale for TDM in managing antiretroviral therapy (ART) derives from the following: • data showing that considerable interpatient variability in drug concentrations exists among patients who take the same dose; • data indicating that relationships exist between the concentration of drug in the body and anti-HIV effect and, in some cases, toxicities; and • data from small prospective studies demonstrating that TDM improved virologic response and/or decreased the incidence of concentration-related drug toxicities. [2][3] # TDM for ARV agents, however, is not recommended for routine use in the management of the HIV-infected adult (CIII). Multiple factors limit the routine use of TDM in HIV-infected adults. [4][5] These factors include: • lack of large prospective studies demonstrating that TDM improves clinical and virologic outcomes. (This is the most important limiting factor for the implementation of TDM at present.); • lack of established therapeutic range of concentrations for all ARV drugs that is associated with achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions; • intrapatient variability in ARV drug concentrations; • lack of widespread availability of clinical laboratories that perform quantitation of ARV concentrations under rigorous quality assurance/quality control standards; and • shortage of experts to assist with interpretation of ARV concentration data and application of such data to revise patients' dosing regimens. # Panel's Recommendations • Therapeutic drug monitoring (TDM) for antiretroviral (ARV) agents is not recommended for routine use in the management of the HIV-infected adult (CIII). • TDM may be considered in selected clinical scenarios, as discussed in the text below. # Rating of # Exposure-Response Relationships and TDM with Different ARV Classes Protease Inhibitors (PIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitors. Relationships between the systemic exposure to PIs and NNRTIs and treatment response have been reviewed in various publications. [4][5][6][7] Although there are limitations and unanswered questions, the consensus among clinical pharmacologists from the United States and Europe is that the data provide a framework for the potential implementation of TDM for PIs and NNRTIs. However, information on relationships between concentrations and drug-associated toxicities are sparse. Clinicians who use TDM as a strategy to manage either ARV response or toxicities should consult the most current data on the proposed therapeutic concentration range. Exposure-response data for darunavir (DRV), etravirine (ETR), and raltegravir (RAL) are accumulating but are not sufficient to recommend minimum trough concentrations. The median trough concentrations for these agents in HIV-infected persons receiving the recommended dose are included in Table 9b. CCR5 Antagonists. Trough maraviroc (MVC) concentrations have been shown to be an important predictor of virologic success in studies conducted in ART-experienced persons. [8][9] Clinical experience in the use of TDM for MVC, however, is very limited. Nonetheless, as with PIs and NNRTIs, the exposure-response data provide a framework for TDM, and that information is presented in these guidelines (Table 9b). # Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Relationships between plasma concentrations of NRTIs and their intracellular pharmacologically active moieties have not yet been established. Therefore, monitoring of plasma or intracellular NRTI concentrations for an individual patient largely remains a research tool. Measurement of plasma concentrations, however, is routinely used for studies of drug-drug interactions. Scenarios for Use of TDM. Multiple scenarios exist in which both ARV concentration data and expert opinion may be useful in patient management. Consultation with a clinical pharmacologist or a clinical pharmacist with HIV expertise may be advisable in these cases. These scenarios include the following: • Suspect clinically significant drug-drug or drug-food interactions that may result in reduced efficacy or increased dose-related toxicities; • Changes in pathophysiologic states that may impair gastrointestinal, hepatic, or renal function, thereby potentially altering drug absorption, distribution, metabolism, or elimination; • Pregnant women who may be at risk of virologic failure as a result of changes in their pharmacokinetic parameters during the later stage of pregnancy, which may result in plasma concentrations lower than those achieved in the earlier stages of pregnancy and in the nonpregnant patient; • Heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs; • Use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials; • Concentration-dependent, drug-associated toxicities; and • Lack of expected virologic response in medication-adherent persons. # TDM • For patients who have drug-susceptible virus. Table 9a includes a synthesis of recommendations [2][3][4][5][6][7] for minimum target trough PI and NNRTI concentrations in persons with drug-susceptible virus. • For ART-experienced patients with virologic failure (see Table 9b). Fewer data are available to formulate suggestions for minimum target trough concentrations in ART-experienced patients who have viral isolates with reduced susceptibility to ARV agents. Concentration recommendations for tipranavir (TPV) and MVC were derived only from studies in ART-experienced persons. It is likely that use of PIs and NNRTIs in the setting of reduced viral susceptibility may require higher trough concentrations than those needed for wild-type virus. The inhibitory quotient (IQ), which is the ratio of ARV drug concentration to a measure of susceptibility (genotype or phenotype) of the patient's strain of HIV to that drug, may additionally improve prediction of virologic response-as has been shown, for example, with DRV in ART-experienced persons. [10][11] Exposure-response data for DRV, ETR, and RAL are accumulating but are not sufficient to recommend minimum trough concentrations. The median trough concentrations for these agents in HIV-infected persons receiving the recommended dose are included in Table 9b. Using Drug Concentrations to Guide Therapy. There are several challenges and considerations for implementation of TDM in the clinical setting. Use of TDM to monitor ARV concentrations in a patient requires multiple steps: • quantification of the concentration of the drug, usually in plasma or serum; • determination of the patient's pharmacokinetic characteristics; • integration of information on patient adherence; • interpretation of the concentrations; and • adjustment of the drug dose to achieve concentrations within the therapeutic range, if necessary. Guidelines for the collection of blood samples and other practical suggestions can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee. 4 A final caveat to the use of measured drug concentrations in patient management is a general one-drug concentration information cannot be used alone; it must be integrated with other clinical information. In addition, as knowledge of associations between ARV concentrations and virologic response continues to accumulate, clinicians who employ a TDM strategy for patient management should consult the most current literature. # Drug Concentration (ng/mL) Suggested minimum target trough concentrations in patients with HIV-1 susceptible to the ARV drugs [2][3][4][5][6][7][8][9] Fosamprenavir (FPV) 400 (measured as amprenavir concentration) Discontinuation of antiretroviral therapy (ART) may result in viral rebound, immune decompensation, and clinical progression. Unplanned interruption of ART may become necessary because of severe drug toxicity, intervening illness, surgery that precludes oral therapy, or unavailability of antiretroviral (ARV) medication. Some investigators have studied planned treatment discontinuation strategies in situations or for reasons that include: in patients who achieve viral suppression and wish to enhance adherence; to reduce inconvenience, long-term toxicities, and costs for patients; or in extensively treated patients who experience treatment failure due to resistant HIV, to allow reversion to wild-type virus. Potential risks and benefits of interruption vary according to a number of factors, including the clinical and immunologic status of the patient, the reason for the interruption, the type and duration of the interruption, and the presence or absence of resistant HIV at the time of interruption. Below are brief discussions on what is currently known about the risks and benefits of treatment interruption in some of these circumstances. # Short-Term Therapy Interruptions Reasons for short-term interruption (days to weeks) of ART vary and may include drug toxicity; intercurrent illnesses that preclude oral intake, such as gastroenteritis or pancreatitis; surgical procedures; or unavailability of drugs. Stopping ARV drugs for a short time (i.e., <1 to 2 days) due to medical/surgical procedures can usually be done by holding all drugs in the regimen. Recommendations for some other scenarios are listed below: # Unanticipated Need for Short-Term Interruption • When a patient experiences a severe or life-threatening toxicity or unexpected inability to take oral medications-all components of the drug regimen should be stopped simultaneously, regardless of drug half-life. # Planned Short Term Interruption (>2-3 days) • When all regimen components have similar half-lives and do not require food for proper absorption-all drugs may be given with a sip of water, if allowed; otherwise, all drugs should be stopped simultaneously. All discontinued regimen components should be restarted simultaneously. • When all regimen components have similar half-lives and require food for adequate absorption, and the patient cannot take anything by mouth for a sustained period of time-temporary discontinuation of all drug components is indicated. The regimen should be restarted as soon as the patient can resume oral intake. • When the ARV regimen contains drugs with differing half-lives-stopping all drugs simultaneously may result in functional monotherapy with the drug with the longest half-life (typically a non-nucleoside reverse transcriptase inhibitor [NNRTI]). Options in this circumstance are discussed below. (See Discontinuation of efavirenz, etravirine, or nevirapine.) # Interruption of Therapy after Pregnancy ARV drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. Following delivery, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as for other nonpregnant individuals. The decision of whether to continue therapy after delivery should take into account current recommendations for initiation of ART, current and nadir CD4 T-cell counts and trajectory, HIV RNA levels, adherence issues, and patient preference. # Planned Long-Term Therapy Interruptions Planned therapy interruptions have been contemplated in various scenarios, listed below. Research is ongoing in several of the scenarios. Therapy interruptions cannot be recommended at this time outside of controlled clinical trials (AI). • In patients who initiated therapy during acute HIV infection and achieved virologic suppressionthe optimal duration of treatment and the consequences of treatment interruption are not known at this time. (See Acute HIV Infection.) • In patients who have had exposure to multiple ARV agents, have experienced ARV treatment failure, and have few treatment options available because of extensive resistance mutationsinterruption is not recommended unless done in a clinical trial setting (AI). Several clinical trials, largely yielding negative results, but some with conflicting results, have been conducted to better understand the role of treatment interruption in these patients. [1][2][3][4] The largest of these studies showed negative clinical impact of treatment interruption in these patients. 1 The Panel notes that partial virologic suppression from combination therapy has been associated with clinical benefit; 5 therefore, interruption of therapy is not recommended. • In patients on ART who have maintained a CD4 count above the level currently recommended for treatment initiation and irrespective of whether their baseline CD4 counts were either above or below that recommended threshold-interruption is also not recommended unless done in a clinical trial setting (BI). (See discussion below highlighting potential adverse outcomes seen in some treatment interruption trials.) Temporary treatment interruption to reduce inconvenience, potential long-term toxicity, and/or overall treatment cost has been considered as a strategy for patients on ART who have maintained CD4 counts above those currently recommended for initiating therapy. Several clinical trials have been designed to determine the safety of such interruptions, in which reinitiation is triggered by predetermined CD4 count thresholds. In these trials, various CD4 count levels have been set to guide both treatment interruption and reinitiation. In the SMART study, the largest of such trials with more than 5,000 subjects, interrupting treatment with CD4 counts >350 cells/mm 3 and reinitiating when <250 cells/mm 3 was associated with an increased risk of disease progression and all cause mortality compared with the trial arm of continuous ART. 6 In the TRIVACAN study, the same CD4 count thresholds were used for stopping and restarting treatment. 7 This study also showed that interruption was an inferior strategy; the interventions in both trials were stopped early because of these findings. Data from the DART trial reported a twofold increase in rates of World Health Organization (WHO) Stage 4 events/deaths in the 12-week ART cycling group among African patients achieving a CD4 count >300/mm 3 compared with the continuous ART group. 8 Observational data from the EuroSIDA cohort noted a twofold increase in risk of death after a treatment interruption of >3 months. Factors linked to increased risk of death or progression included lower CD4 counts, higher viral loads, and a prior history of AIDS. 9 Other studies have reported no major safety concerns, [10][11][12] but these studies had smaller sample sizes. Results have been reported from several small observational studies evaluating treatment interruption in patients doing well with nadir CD4 counts >350/mm 3 , but further studies are needed to determine the safety of treatment interruption in this population. [13][14] There is concern that CD4 counts <500 cells/mm 3 are associated with a range of non-AIDS clinical events (e.g., cancer and heart, liver, and kidney disease). 6,[15][16] Planned long-term therapy interruption strategies cannot be recommended at this time outside of controlled clinical trials (BI) based on available data and a range of ongoing concerns. If therapy has to be discontinued, patients should be counseled about the need for close clinical and laboratory monitoring. They should also be aware of the risks of viral rebound, acute retroviral syndrome, increased risk of HIV transmission, decline of CD4 count, HIV disease progression or death, development of minor HIV-associated manifestations such as oral thrush, development of serious non-AIDS complications, development of drug resistance, and the need for chemoprophylaxis against opportunistic infections depending on the CD4 count. Treatment interruptions often result in rapid reductions in CD4 counts. Prior to any planned treatment interruption, a number of ARV-specific issues should be taken into consideration. These include: • Discontinuation of efavirenz (EFV), etravirine (ETR), or nevirapine (NVP). The optimal interval between stopping EFV, ETR, or NVP and other ARV drugs is not known. The duration of detectable levels of EFV or NVP after discontinuation ranges from less than 1 week to more than 3 weeks. [17][18] Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTIs because NNRTIs have much longer half-lives than other agents. This may increase the risk of selection of NNRTI-resistant mutations. It is further complicated by evidence that certain host genetic polymorphisms may result in slower rates of clearance. Such polymorphisms may be more common among specific ethnic groups, such as African Americans and Hispanics. [18][19] Some experts recommend stopping the NNRTI but continuing the other ARV drugs for a period of time. The optimal time sequence for staggered component discontinuation has not been determined. A study in South Africa demonstrated that giving 4 or 7 days of zidovudine (ZDV) + lamivudine (3TC) after a single dose of NVP reduced the risk of postnatal NVP resistance from 60% to 10%-12%. 20 Use of nucleoside reverse transcriptase inhibitors (NRTIs) with a longer half-life such as tenofovir (TDF) plus emtricitabine (FTC) has also been shown to decrease NVP resistance after single-dose treatment. 21 The findings may, however, differ in patients on chronic NVP treatment. An alternative strategy is to substitute a protease inhibitor (PI) for the NNRTI and to continue the PI with dual NRTIs for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an NNRTI-to a PI-based regimen prior to interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of resuppression of HIV RNA after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the 2-NRTI. 22 The optimal duration needed to continue the PI-based regimen after stopping the NNRTI is not known. Given the potential of prolonged detectable NNRTI concentrations for more than 3 weeks, some suggest that the PI-based regimen may need to be continued for up to 4 weeks. Further research to determine the best approach to discontinuing NNRTIs is needed. Clinical data on ETR and treatment interruption is lacking but its long half-life of approximately 40 hours suggests that stopping ETR needs to be done carefully using the same suggestions for NVP and EFV for the time being. • Discontinuation and reintroduction of NVP. Because NVP is an inducer of the drug-metabolizing hepatic enzymes, administration of full therapeutic doses of NVP without a 2-week, low-dose escalation phase will result in excess plasma drug levels and potentially increase the risk of toxicity. Therefore, in a patient who has interrupted treatment with NVP for more than 2 weeks, NVP should be reintroduced with a dose escalation period of 200 mg once daily for 14 days and then a 200 mg twice-daily regimen (AII). # Definitions: Acute HIV infection is the phase of HIV disease immediately after infection during which the initial burst of viremia in newly infected patients occurs; anti-HIV antibodies are undetectable at this time while HIV RNA or p24 antigen are present. Recent infection generally is considered the phase up to 6 months after infection during which anti-HIV antibodies are detectable. Throughout this section, the term "early HIV infection" is used to refer to either acute or recent HIV infection. An estimated 40% to 90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms. [1][2][3][4][5][6] Primary care clinicians, however, often do not recognize acute HIV infection because the selflimiting symptoms are similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic. Table 10 provides practitioners with guidance to recognize, diagnose, and manage acute HIV infection. # Panel's Recommendations • Antiretroviral therapy (ART) is recommended for all persons with HIV infection and should be offered to those with early* HIV infection (BII), although definitive data are lacking as to whether this approach will result in long-term virologic, immunologic, or clinical benefits. • All pregnant women with early HIV infection should start ART as soon as possible to prevent perinatal transmission of HIV (AI). • If treatment is initiated in a patient with early HIV infection, the goal is to suppress plasma HIV RNA to below detectable levels (AIII). • For patients with early HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels, CD4 count, and toxicity monitoring should be performed as described for patients with chronic HIV infection (AII). • Genotypic drug-resistance testing should be performed before initiation of ART to guide the selection of the regimen (AII). If therapy is deferred, genotypic resistance testing should still be performed because the results will be useful in selecting a regimen with the greatest potential for achieving optimal virologic response when therapy is ultimately initiated (AII). • For patients without transmitted drug resistant virus, therapy should be initiated with a regimen that is recommended for patients with chronic HIV infection (see What to Start) (AIII). • ART can be initiated before drug resistance test results are available. Since resistance to ritonavir (RTV)-boosted protease inhibitors (PIs) emerges slowly and since clinically significant transmitted resistance to PIs is uncommon, these drugs combined with nucleoside reverse transcriptase inhibitors (NRTIs) should be used in this setting (AIII). • Patients starting ART should be willing and able to commit to treatment and should understand the possible benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy because of clinical and/or psychosocial factors. * Early infection represents either acute or recent infection as defined in the first paragraph below. # Rating of Recommendations: A = Strong; B = Moderate; C = Optional # Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion # Diagnosis of Acute HIV Infection Health care providers should maintain a high level of suspicion of acute HIV infection in patients who have a compatible clinical syndrome-especially in those who report recent high-risk behavior (Table 10). 7 Patients may not always disclose or admit to high-risk behaviors or they may not perceive that their behaviors put them at risk for HIV acquisition. Thus, signs and symptoms consistent with acute retroviral syndrome should motivate consideration of a diagnosis of acute HIV infection even in the absence of reported high-risk behaviors. Acute HIV infection is usually defined as detectable HIV RNA or p24 antigen, the latter often used in currently available HIV antigen/antibody (Ag/Ab) combination assays, in serum or plasma in the setting of a negative or indeterminate HIV antibody test. 7,8 When the acute retroviral syndrome is suspected in a patient with a negative or indeterminate HIV antibody test result, a test for HIV RNA should be performed to diagnose acute infection (AII). A low-positive HIV RNA level (<10,000 copies/mL) may represent a falsepositive test result because values in acute infection are generally very high (>100,000 copies/mL). 5,6 A presumptive diagnosis of acute HIV infection can be made on the basis of a negative or indeterminate HIV antibody test result and a positive HIV RNA test result. However, if the results of an HIV RNA test are lowpositive, the test should be repeated using a different specimen from the same patient. It is highly unlikely that a second test will reproduce a false-positive result. 6 Interest in routine screening for acute infection has led select centers to use the HIV Ag/Ab test as the primary HIV screening assay or to test all HIV antibody negative samples for HIV RNA. 9 Combination HIV Ag/Ab tests (ARCHITECT HIV Ag/Ab Combo and GS HIV Combo Ag/Ab) now are approved by the Food and Drug Administration; however, the currently available tests do not differentiate between a positive antibody test result and a positive antigen result. Thus HIV Ag/Ab-reactive specimens should be tested with an antibody assay, and if the test results are negative or indeterminate and if acute HIV infection is suspected, be further tested for HIV RNA. 10,11 Because HIV RNA or Ag/Ab combination assays are not yet used routinely for HIV screening in all settings, clinicians should not assume that a laboratory report of a negative HIV test result indicates that screening for acute HIV infection has been conducted. Patients also should know that home HIV testing only detects HIV antibodies and therefore will not detect very early acute HIV infection. Persons diagnosed presumptively with acute HIV infection should have serologic testing repeated over the next 3 to 6 months to document seroconversion (AI) (see Table 10). # Treatment for Early HIV Infection Clinical trial data regarding the treatment of early HIV infection is limited. Many patients who enrolled in studies to assess the role of antiretroviral therapy (ART) in early HIV infection, as outlined below, were identified as trial participants because they presented with signs or symptoms of acute infection. With the introduction of HIV screening tests that include assays for HIV RNA or p24 antigen and wider HIV screening in healthcare systems, the number of asymptomatic patients identified with early infection may be increasing. The natural history of HIV disease in these patients may differ from that in persons with symptomatic infections, thus further studies on the impact of ART on the natural history of asymptomatic acute HIV infection are needed. The initial burst of high level viremia in infected adults usually declines shortly after acute infection (e.g., within 2 months); however, a rationale for treatment during recent infection (e.g., 2-6 months after infection) remains because the immune system may not yet have maximally contained viral replication in the lymphoid tissue during this time. 12 Several trials have addressed the question of the long-term benefit of potent treatment regimens initiated during early HIV infection. The potential benefits and risks of treating HIV during this stage of disease are discussed below: • Potential Benefits of Treatment During Early HIV Infection. Preliminary data indicate that treatment of early HIV infection with combination ART improves laboratory markers of disease progression. [13][14][15][16][17] The data, though limited, indicate that treatment of early HIV infection may also decrease the severity of acute disease; lower the viral set point, [18][19][20] which can affect disease progression rates in the event therapy is stopped; reduce the size of the viral reservoir; 21 and decrease the rate of viral mutation by suppressing viral replication and preserving immune function. 22 Because early HIV infection often is associated with high viral loads and increased infectiousness, 23 and ART use by HIV-infected individuals reduces transmission to serodiscordant sexual partners, 24 treatment during this stage of infection is expected to substantially reduce the risk of HIV transmission. In addition, although data are limited and the clinical relevance unclear, the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by initiating ART during early HIV infection. 25,26 Many of the potential benefits described above may be more likely to occur with treatment of acute infection, but they also may occur if treatment is initiated during recent HIV infection. • Potential Risks of Treatment During Early HIV Infection. The potential disadvantages of initiating therapy during early HIV infection include more prolonged exposure to ART without a known long-term clinical benefit. This could result in drug toxicities, development of drug resistance, and adverse effects on an individual's quality of life due to earlier initiation of lifelong therapy that requires strict adherence. Several randomized controlled trials have studied the effect of ART during acute and recent infection to assess whether initiating early therapy would allow patients to stop treatment and maintain lower viral loads and higher CD4 counts while off ART for prolonged periods of time. This objective was of interest when these studies were initiated but is less relevant in an era in which treatment is recommended for virtually all HIV-infected patients and treatment interruptions are not recommended (see Initiating Antiretroviral Therapy in Treatment-Naive Patients). The Setpoint Study (ACTG A5217 Study) randomized patients with recent but not acute HIV infection to either defer therapy or immediately initiate ART for 36 weeks and then stop. 18 The primary study end point was a composite of meeting criteria for ART or re-initiation of ART and viral load results at week 72 in both groups and at week 36 in the deferred treatment group. The study was stopped prematurely by the Data and Safety Monitoring Board because of an apparent benefit associated with early therapy that was driven mostly by greater proportion of participants meeting criteria for ART initiation in the deferred treatment group (50%) than in the immediate treatment group (10%). Nearly half of the patients in the deferred treatment group needed to start therapy during the first year of study enrollment. The Randomized Primo-SHM Trial randomized patients with acute (~70%) or recent (~30%) infection to either defer ART or to undergo treatment for 24 or 60 weeks and then stop. 19 Significantly lower viral loads were observed 36 weeks after treatment interruption in the patients who had been treated early. These patients also experienced a longer time before the need to initiate therapy, primarily on the basis of reaching a CD4 count of <350 cells/mm 3 . The median time to starting treatment was 0.7 years for the deferred therapy group and 3.0 and 1.8 years for the 24-and 60-week treatment arms, respectively. The time to reaching a CD4 count of <500 cells/mm 3 was only 0.5 years in the deferred group. Finally, the SPARTAC Trial included patients with acute and recent infection randomized to either defer therapy or to undergo treatment for 12 or 48 weeks and then stop. 20 In this case, the time to CD4 <350 cells/mm 3 or initiation of therapy was significantly longer in the group treated for 48 weeks than in the deferred treatment group or the group treated for 12 weeks. However, no difference was observed comparing persons who received 12 weeks of ART with those who deferred treatment during early infection. The strategies tested in these studies are of limited relevance in the current treatment era in which treatment interruption is not recommended. The study results may not fully reflect the natural history of HIV disease in persons with asymptomatic acute infection because most patients in these trials were enrolled on the basis of identified early symptomatic HIV infections. Nevertheless, the results do demonstrate that some immunologic and virologic benefits may be associated with the treatment of early HIV infection. Moreover, all the findings suggest, at least in the population recruited for these studies, that the time to initiating ART after identification of early infection is quite short when the threshold for ART initiation is 350 CD4 cells/mm 3 , and nonexistent when therapy is advised for all individuals regardless of CD4 cell count as currently recommended in these guidelines. These observations must be balanced with the risks of early treatment, risks that are largely the same as those of therapy initiated in chronically infected asymptomatic patients with high CD4 counts. Consequently, the health care provider and the patient should be fully aware that the rationale for initiating therapy during early HIV infection is based on theoretical benefits and the extrapolation of data from the strategy trials outlined above. These potential benefits must be weighed against the risks. For these reasons, and because ART is currently recommended for all HIV-infected patients (see Initiating Antiretroviral Therapy in Treatment-Naive Patients), ART should be offered to all patients with early HIV infection (BII). However, patients must be willing and able to commit to treatment and providers, on a case-by-case basis, may elect to defer therapy for clinical and/or psychosocial reasons. Providers also should consider enrolling patients with early HIV infection in clinical studies to further evaluate the natural history of this stage of HIV infection and to further define the role of ART in this setting. Providers can obtain information regarding such trials at www.clinicaltrials.gov or from local HIV treatment experts. # Treatment for Early HIV Infection During Pregnancy Because early HIV infection is associated with a high risk of perinatal transmission, all HIV-infected pregnant women should start combination ART as soon as possible to prevent perinatal transmission of HIV (AI). 27 # Treatment Regimen for Early HIV Infection Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least 1 antiretroviral in 6% to 16% of patients. [28][29][30] Up to 21% of isolates from contemporary patients with acute HIV infection demonstrated resistance to at least 1 drug. 31 Therefore, before initiation of ART in a person with early HIV infection, genotypic antiretroviral drug-resistance testing should be performed to guide the selection of a regimen (AII). If the decision to initiate therapy during early infection is made, especially in the setting of acute infection, treatment initiation should not be delayed pending resistance testing results. Once results are available, the treatment regimen can be modified if warranted. If therapy is deferred, resistance testing still should be performed because the results will help guide selection of a regimen to optimize virologic response once therapy is initiated (AII). The goal of therapy during early HIV infection is to suppress plasma HIV RNA to undetectable levels (AIII). Because data to draw firm conclusions regarding specific drug combinations to use in this stage of HIV infection are insufficient, ART should be initiated with one of the combination regimens recommended for patients with chronic infection (AIII) (see What to Start). If therapy is started before the results of drugresistance testing are available, because resistance to RTV-boosted protease inhibitors (PIs) emerge slowly and clinically significant transmitted resistance to PIs is uncommon (AIII). If available, the results of ARV drug-resistance testing or the ARV resistance pattern of the source person's virus should be used to guide the selection of the ARV regimen. Given the recent approval of daily tenofovir DF/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP), [32][33][34] early infection may be diagnosed in some patients while they are taking TDF/FTC as PrEP. In this setting, resistance testing should be performed; however, because PI resistance is unlikely, use of a RTV-boosted PI with TDF/FTC remains a reasonable option pending resistance testing results (see What to Start). # Patient Follow-up Testing for plasma HIV RNA levels, CD4 cell counts, and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2 to 8 weeks, then every 4 to 8 weeks until viral suppression, and thereafter, every 3 to 4 months) (AII). • Suspecting acute HIV infection: Signs or symptoms of acute HIV infection with recent (within 2 to 6 weeks) high risk of exposure to HIV a • Signs/symptoms/laboratory findings may include but are not limited to one or more of the following: fever, lymphadenopathy, skin rash, myalgia/arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, transaminase elevation. • High-risk exposures include sexual contact with an HIV-infected person or a person at risk of HIV infection, sharing injection drug use paraphernalia, or contact of mucous membranes or breaks in skin with potentially infectious fluids. • Differential diagnosis: Includes but is not limited to viral illnesses such as Epstein-Barr virus (EBV)-and non-EBV (e.g., cytomegalovirus) infectious mononucleosis syndromes, influenza, viral hepatitis, streptococcal infection, or syphilis. • Evaluation/diagnosis of acute HIV infection: • Acute infection is defined as detectable HIV RNA or p24 antigen (the antigen used in currently available HIV antigen/antibody [Ag/Ab] combination assays), in serum or plasma in the setting of a negative or indeterminate HIV antibody test result • A reactive HIV antibody test or Ag/Ab test must be followed by supplemental confirmatory testing. • A negative or indeterminate HIV antibody test in a person with a positive Ag/Ab test or in whom acute HIV infection is suspected requires assessment of plasma HIV RNA b to assess for acute HIV infection. • A positive plasma HIV RNA test in the setting of a negative or indeterminate antibody result is consistent with acute HIV infection. • Patients presumptively diagnosed with acute HIV infection should have serologic testing repeated over the next 3 to 6 months to document seroconversion. • Considerations for antiretroviral therapy (ART) during early HIV infection: • All pregnant women with early HIV infection should begin taking combination ART as soon as possible because of the high risk of perinatal HIV transmission (AI). • Treatment for early HIV infection should be offered to all non-pregnant persons (BII). • The risks of ART during early HIV infection are largely the same as those for ART initiated in chronically infected asymptomatic patients with high CD4 counts. • If therapy is initiated, the goal should be sustained plasma virologic suppression (AIII). • Providers should consider enrolling patients with early HIV infection in clinical studies. a In some settings, behaviors conducive to acquisition of HIV infection might not be ascertained or might not be perceived as high risk by the health care provider or the patient or both. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors. b Plasma HIV RNA can be measured by a variety of quantitative assays, including branched DNA (bDNA) and reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays as well as by a qualitative transcription-mediated amplification assay (APTIMA, GenProbe). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents I-9 HIV-Infected Adolescents and Young Adults (Last updated January 10, 2011; last reviewed January 10, 2011) Older children and adolescents now make up the largest percentage of HIV-infected children cared for at pediatric HIV clinics in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 15% of the 35,314 new HIV diagnoses reported among the 33 states that participated in confidential, name-based HIV infection reporting in 2006 were among youth 13-24 years of age. 1 Recent trends in HIV prevalence reveal that the disproportionate burden of HIV/AIDS among racial minorities is even greater among youth 13-19 years of age than among young adults 20-24 years of age. 2 Furthermore, trends for all HIV/AIDS diagnoses in 33 states from 2001 to 2006 decreased for all transmission categories except among men who have sex with men (MSM). Notably, among all black MSM, the largest increase in HIV/AIDS diagnoses occurred among youth 13-24 years of age. 3 HIV-infected adolescents represent a heterogeneous group in terms of sociodemographics, mode of HIV infection, sexual and substance abuse history, clinical and immunologic status, psychosocial development, and readiness to adhere to medications. Many of these factors may influence decisions concerning when to start antiretroviral therapy (ART) and what antiretroviral (ARV) medications should be used. Most adolescents who acquire HIV are infected through high-risk behaviors. Many of them are recently infected and unaware of their HIV infection status. Thus, many are in an early stage of HIV infection, which makes them ideal candidates for early interventions, such as prevention counseling, linkage, and engagement to care. A recent study among HIV-infected adolescents and young adults presenting for care identified primary genotypic resistance mutations to ARV medications in up to 18% of the evaluable sample of recently infected youth, as determined by the detuned antibody testing assay strategy that defined recent infection as occurring within 180 days of testing. 4 This transmission dynamic reflects that a substantial proportion of youth's sexual partners are likely older and may be more ART experienced; thus, awareness of the importance of baseline resistance testing among recently infected youth naive to ART is imperative. A limited but increasing number of HIV-infected adolescents are long-term survivors of HIV infection acquired perinatally or in infancy through blood products. Such adolescents are usually heavily ART experienced and may have a unique clinical course that differs from that of adolescents infected later in life. 5 If these heavily ART-experienced adolescents harbor resistant virus, optimal ARV regimens should be based on the same guiding principles as for heavily ART-experienced adults. (See Virologic and Immunogic Failure.) Adolescents are developmentally at a difficult crossroad. Their needs for autonomy and independence and their evolving decisional capacity intersect and compete with concrete thinking processes, risk-taking behaviors, preoccupation with self-image, and the need to "fit in" with their peers. This makes it challenging to attract and sustain adolescents' focus on maintaining their health, particularly for those with chronic illnesses. These challenges are not specific to any particular transmission mode or stage of disease. Thus, irrespective of disease duration or mode of HIV transmission, every effort must be made to engage them in care so they can improve and maintain their health for the long term. # Antiretroviral Therapy Considerations in Adolescents Adult guidelines for ART are usually appropriate for postpubertal adolescents, because the clinical course of HIV-infected adolescents who were infected sexually or through injection drug use during adolescence is more similar to that of adults than to that of children. Adult guidelines can also be useful for postpubertal youth who were perinatally infected because these patients often have treatment challenges associated with the use of long-term ART that mirror those of ART-experienced adults, such as extensive resistance, complex regimens, and adverse drug effects. Dosage of medications for HIV infection and opportunistic infections should be prescribed according to Tanner staging of puberty and not solely on the basis of age. [6][7] Adolescents in early puberty (i.e., Tanner Stages I and II) should be administered doses on pediatric schedules, whereas those in late puberty (i.e., Tanner Stage V) should follow adult dosing schedules. However, Tanner stage and age are not necessarily directly predictive of drug pharmacokinetics. Because puberty may be delayed in children who were infected with HIV perinatally, 8 continued use of pediatric doses in puberty-delayed adolescents can result in medication doses that are higher than the usual adult doses. Because data are not available to predict optimal medication doses for each ARV medication for this group of children, issues such as toxicity, pill or liquid volume burden, adherence, and virologic and immunologic parameters should be considered in determining when to transition from pediatric to adult doses. Youth who are in their growth spurt period (i.e., Tanner Stage III in females and Tanner Stage IV in males) and following adult or pediatric dosing guidelines and adolescents who have transitioned from pediatric to adult doses should be closely monitored for medication efficacy and toxicity. Therapeutic drug monitoring can be considered in selected circumstances to help guide therapy decisions in this context. Pharmacokinetic studies of drugs in youth are needed to better define appropriate dosing. For a more detailed discussion, see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 9 # Adherence Concerns in Adolescents HIV-infected adolescents are especially vulnerable to specific adherence problems based on their psychosocial and cognitive developmental trajectory. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with health care systems and who lack health insurance. Many HIV-infected adolescents face challenges in adhering to medical regimens for reasons that include: • denial and fear of their HIV infection; • misinformation; • distrust of the medical establishment; • fear and lack of belief in the effectiveness of medications; • low self-esteem; • unstructured and chaotic lifestyles; • mood disorders and other mental illness; • lack of familial and social support; • absence of or inconsistent access to care or health insurance; and • incumbent risk of inadvertent parental disclosure of the youth's HIV infection status if parental health insurance is used. In selecting treatment regimens for adolescents, clinicians must balance the goal of prescribing a maximally potent ART regimen with realistic assessment of existing and potential support systems to facilitate adherence. Adolescents benefit from reminder systems (e.g., beepers, timers, and pill boxes) that are stylish and inconspicuous. 10 It is important to make medication adherence as user friendly and as little stigmatizing as possible for the older child or adolescent. The concrete thought processes of adolescents make it difficult for them to take medications when they are asymptomatic, particularly if the medications have side effects. Adherence to complex regimens is particularly challenging at a time of life when adolescents do not want to be different from their peers. [11][12][13] Directly observed therapy might be considered for selected HIV-infected adolescents such as those with mental illness. [14][15][16][17][18] # Difficult Adherence Problems Because adolescence is characterized by rapid changes in physical maturation, cognitive processes, and life style, predicting long-term adherence in an adolescent can be very challenging. The ability of youth to adhere to therapy needs to be included as part of therapeutic decision making concerning the risks and benefits of starting treatment. Erratic adherence may result in the loss of future regimens because of the development of resistance mutations. Clinicians who care for HIV-infected adolescents frequently manage youth who, while needing therapy, pose significant concerns regarding their ability to adhere to therapy. In these cases, alternative considerations to initiation of therapy can be the following: (1) a short-term deferral of treatment until adherence is more likely or while adherence-related problems are aggressively addressed; (2) an adherence testing period in which a placebo (e.g., vitamin pill) is administered; and (3) the avoidance of any regimens with low genetic resistance barriers. Such decisions are ideally individualized to each patient and should be made carefully in context with the individual's clinical status. For a more detailed discussion on specific therapy and adherence issues for HIV-infected adolescents, see Guidelines for Use of Antiretroviral Agents in Pediatric HIV Infection. 9 # Special Considerations in Adolescents Sexually transmitted infections (STIs), in particular human papilloma virus (HPV), should also be addressed in all adolescents. For a more detailed discussion on STIs, see the most recent CDC guidelines 19 and the pediatric opportunistic infection treatment guidelines on HPV among HIV-infected adolescents. 20 Family planning counseling, including a discussion of the risks of perinatal transmission of HIV and methods to reduce risks, should be provided to all youth. Providing gynecologic care for the HIV-infected female adolescent is especially important. Contraception, including the interaction of specific ARV drugs on hormonal contraceptives, and the potential for pregnancy also may alter choices of ART. As an example, efavirenz (EFV) should be used with caution in females of childbearing age and should only be prescribed after intensive counseling and education about the potential effects on the fetus, the need for close monitoring-including periodic pregnancy testing-and a commitment on the part of the teen to use effective contraception. For a more detailed discussion, see HIV-Infected Women and the Perinatal Guidelines. 21 # Transitioning Care Given lifelong infection with HIV and the need for treatment through several stages of growth and development, HIV care programs and providers need flexibility to appropriately transition care for HIVinfected children, adolescents, and young adults. A successful transition requires an awareness of some fundamental differences between many adolescent and adult HIV care models. In most adolescent HIV clinics, care is more "teen-centered" and multidisciplinary, with primary care being highly integrated into HIV care. Teen services, such as sexual and reproductive health, substance abuse treatment, mental health, treatment education, and adherence counseling are all found in one clinic setting. In contrast, some adult HIV clinics may rely more on referral of the patient to separate subspecialty care settings, such as gynecology. Transitioning the care of an emerging young adult includes considerations of areas such as medical insurance, independence, autonomy, decisional capacity, confidentiality, and consent. Also, adult clinic settings tend to be larger and can easily intimidate younger, less motivated patients. As an additional complication to this transition, HIV-infected adolescents belong to two epidemiologically distinct subgroups: (1) those perinatally infected-who would likely have more disease burden history, complications, and chronicity; less functional autonomy; greater need for ART; and higher mortality risk; and (2) those more recently infected due to high-risk behaviors. Thus, these subgroups have unique biomedical and psychosocial considerations and needs. To maximize the likelihood of a successful transition, facilitators to successful transitioning are best implemented early on. These include the following: (1) optimizing provider communication between adolescent and adult clinics; (2) addressing patient/family resistance caused by lack of information, stigma or disclosure concerns, and differences in practice styles; (3) preparing youth for life skills development, including counseling them on the appropriate use of a primary care provider and appointment management, the importance of prompt symptom recognition and reporting, and the importance of self-efficacy with medication management, insurance, and entitlements; (4) identifying an optimal clinic model for a given setting (i.e., simultaneous transition of mental health and/or case management versus a gradual phase-in); ( 5) implementing ongoing evaluation to measure the success of a selected model; (6) engaging in regular multidisciplinary case conferences between adult and adolescent care providers; (7) implementing interventions that may be associated with improved outcomes, such as support groups and mental health consultation; and (8) incorporating a family planning component into clinical care. Attention to these key areas will likely improve adherence to appointments and avert the potential for a youth to "fall through the cracks," as it is commonly referred to in adolescent medicine. HIV and Illicit Drug Users (Last updated March 27, 2012; last reviewed March 27, 2012) # Treatment Challenges of HIV-Infected Illicit Drug Users Injection drug use is the second most common mode of HIV transmission in the United States. In addition, noninjection illicit drug use may facilitate sexual transmission of HIV. Injection and noninjection illicit drugs include the following: heroin, cocaine, marijuana, and club drugs (i.e., methamphetamine, ketamine, gammahydroxybutyrate [GHB], and amyl nitrate [i.e., poppers]). The most commonly used illicit drugs associated with HIV infection are heroin and stimulants (e.g., cocaine and amphetamines); however, the use of club drugs has increased substantially in the past several years and is common among individuals who have HIV infection or who are at risk of HIV infection. The association between club drugs and high-risk sexual behavior in men who have sex with men (MSM) is strongest for methamphetamine and amyl nitrate; this association is less consistent with the other club drugs. 1 Illicit drug use has been associated with depression and anxiety, either as part of the withdrawal process or as a consequence of repeated use. This is particularly relevant in the treatment of HIV infection because depression is one of the strongest predictors of poor adherence and poor treatment outcomes. 2 Treatment of HIV disease in illicit drug users can be successful but HIV-infected illicit drug users present special treatment challenges. These challenges may include the following: (1) an array of complicating comorbid medical and mental health conditions; (2) limited access to HIV care; (3) inadequate adherence to therapy; (4) medication side effects and toxicities; (5) the need for substance abuse treatment; and (6) drug interactions that can complicate HIV treatment. 3 Underlying health problems in injection and noninjection drug users result in increased morbidity and mortality, either independent of or accentuated by HIV disease. Many of these problems are the consequence of prior exposures to infectious pathogens from nonsterile needle and syringe use. Such problems can include hepatitis B or C virus infection, tuberculosis (TB), skin and soft tissue infections, recurrent bacterial pneumonia, and endocarditis. Other morbidities such as alteration in levels of consciousness and neurologic and renal disease are not uncommon. Furthermore, these comorbidities are associated with a higher risk of drug overdoses in illicit drug users with HIV disease than in HIV-uninfected illicit drug users, due in part to respiratory, hepatic, and neurological impairments associated with HIV infection. 4 Successful HIV therapy for illicit drug users often depends on clinicians becoming familiar with and managing these comorbid conditions and providing overdose prevention support. Illicit drug users have less access to HIV care and are less likely to receive antiretroviral therapy (ART) than other populations. [5][6] Factors associated with low rates of ART use among illicit drug users include active drug use, younger age, female gender, suboptimal health care, recent incarceration, lack of access to rehabilitation programs, and health care providers' lack of expertise in HIV treatment. [5][6] The typically unstable, chaotic life patterns of many illicit drug users; the powerful pull of addictive substances; and common misperceptions about the dangers, impact, and benefits of ART all contribute to decreased adherence. 7 The chronic and relapsing nature of substance abuse as a biologic and medical disease, compounded by the high rate of mental illness that antedates and/or is exacerbated by illicit substance use, additionally complicate the relationship between health care workers and illicit drug users. [8][9] The first step in provision of care and treatment for these individuals is to recognize the existence of a substance abuse problem. It is often obvious that the problem exists, but some patients may hide these problem behaviors from clinicians. Assessment of a patient for substance abuse should be part of routine medical history taking and should be done in a professional, straightforward, and nonjudgmental manner. # Treatment Efficacy in HIV-Infected Illicit Drug Use Populations Although illicit drug users are underrepresented in HIV therapy clinical trials, available data indicate that efficacy of ART in illicit drug users-when they are not actively using drugs-is similar to that seen in other populations. 10 Furthermore, therapeutic failure in this population generally correlates with the degree that drug use disrupts daily activities rather than with drug use per se. 11 Providers need to remain attentive to the possible impact of disruptions caused by drug use on the patient both before and while receiving ART. Although many illicit drug users can sufficiently control their drug use for long enough time to benefit from care, substance abuse treatment is often necessary for successful HIV management. Close collaboration with substance abuse treatment programs and proper support and attention to this population's special multidisciplinary needs are critical components of successful HIV treatment. Essential to this end are accommodating, flexible, community-based HIV care sites that are characterized by familiarity with and nonjudgmental expertise in management of drug users' wide array of needs and in development of effective strategies to promote medication adherence. 9 These strategies should include, if available, the use of adherence support mechanisms such as modified directly observed therapy (mDOT), which has shown promise in this population. 12 # Antiretroviral Agents and Opioid Substitution Therapy Compared with noninjection drug users receiving ART, injection drug users (IDUs) receiving ART are more likely to experience an increased frequency of side effects and toxicities of ART. Although not systematically studied, this is likely because underlying hepatic, renal, neurologic, psychiatric, gastrointestinal (GI), and hematologic disorders are highly prevalent among IDUs. These comorbid conditions should be considered when selecting antiretroviral (ARV) agents in this population. Opioid substitution therapies such as methadone and buprenorphine/naloxone and extended-release naltrexone are commonly used for management of opioid dependence in HIV-infected patients. Methadone and Antiretroviral Therapy. Methadone, an orally administered, long-acting opioid agonist, is the most common pharmacologic treatment for opioid addiction. Its use is associated with decreased heroin use, decreased needle sharing, and improved quality of life. Because of its opioid-induced effects on gastric emptying and the metabolism of cytochrome P (CYP) 450 isoenzymes 2B6, 3A4, and 2D6, pharmacologic effects and interactions with ARV agents may commonly occur. 13 These may diminish the effectiveness of either or both therapies by causing opioid withdrawal or overdose, increased methadone toxicity, and/or decreased ARV efficacy. Efavirenz (EFV), nevirapine (NVP), and lopinavir/ritonavir (LPV/r) have been associated with significant decreases in methadone levels. Patients and substance abuse treatment facilities should be informed of the likelihood of this interaction. The clinical effect is usually seen after 7 days of coadministration and may be managed by increasing the methadone dosage, usually in 5-mg to 10-mg increments daily until the desired effect is achieved. Buprenorphine and Antiretroviral Therapy. Buprenorphine, a partial μ-opioid agonist, is administrated sublingually and is often coformulated with naloxone. It is increasingly used for opioid dependence treatment. Compared with methadone, buprenorphine has a lower risk of respiratory depression and overdose. This allows physicians in primary care to prescribe buprenorphine for the treatment of opioid dependency. The flexibility of the primary care setting can be of significant value to opioid-addicted HIVinfected patients who require ART because it enables one physician or program to provide both medical and substance abuse services. Limited information is currently available about interactions between buprenorphine and ARV agents. [13][14] Findings from available studies show that the drug interaction profile of buprenorphine is more favorable than that of methadone. Naltrexone and Antiretroviral Therapy. A once-monthly extended-release intramuscular formulation of naltrexone was recently approved for prevention of relapse in patients who have undergone an opioid detoxification program. Naltrexone is also indicated for treatment of alcohol dependency. Naltrexone is not metabolized via the CYP450 enzyme system and is not expected to interact with protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). 15 Table 11 provides the currently available pharmacokinetic (PK) interaction data that clinicians can use as a guide for managing patients receiving ART and methadone or buprenorphine. Particular attention is needed concerning communication between HIV care providers and drug treatment programs regarding additive drug toxicities and drug interactions resulting in opiate withdrawal or excess. Methylenedioxymethamphetamine (MDMA), GHB, ketamine, and methamphetamine all have the potential to interact with ARV agents because all are metabolized, at least in part, by the CYP450 system. Overdoses secondary to interactions between the party drugs (i.e., MDMA or GHB) and PI-based ART have been reported. 16 # Summary It is usually possible over time to support most active drug users such that acceptable adherence levels with ARV agents can be achieved. [17][18] Providers must work to combine all available resources to stabilize an active drug user in preparation for ART. This should include identification of concurrent medical and psychiatric illnesses, drug treatment and needle and syringe exchange programs, strategies to reduce highrisk sexual behavior, and harm-reduction strategies. A history of drug use alone is insufficient reason to withhold ART because individuals with a history of prior drug use have adherence rates similar to those who do not abuse drugs. Important considerations in the selection of successful regimens and the provision of appropriate patient monitoring in this population include need for supportive clinical sites; linkage to substance abuse treatment; and awareness of the interactions between illicit drugs and ARV agents, including the increased risk of side effects and toxicities. Simple regimens should be considered to enhance medication adherence. Preference should be given to ARV agents that have a lower risk of hepatic and neuropsychiatric side effects, simple dosing schedules, and minimal interaction with methadone. ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, SQV/r, TPV/r With ATV/r, DRV/r, FPV/r: R-methadone b AUC ↓ 16%−18%; With LPV/r: methadone AUC ↓ 26%-53%; With SQV/r 1000/100 mg BID: R-methadone AUC ↓ 19%; With TPV/r: R-methadone AUC ↓ 48% Opioid withdrawal unlikely but may occur. Adjustment of methadone dose usually not required; however, monitor for opioid withdrawal and increase methadone dose as clinically indicated. FPV No data with FPV (unboosted) With APV: R-methadone C min ↓ 21%, no significant change in AUC Monitor and titrate methadone as clinically indicated. The interaction with FPV is presumed to be similar. a Norbuprenorphine is an active metabolite of buprenorphine. b R-methadone is the active form of methadone. greatest risk. [9][10][11][12] It is generally recommended that NVP not be prescribed to ARV-naive women who have CD4 counts >250 cells/mm 3 unless there is no other alternative and the benefit from NVP outweighs the risk of hepatotoxicity (AI). # Key to • Lactic acidosis: There is a female predominance in the increased incidence of symptomatic and even fatal lactic acidosis associated with prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTIs). Lactic acidosis is most common with stavudine (d4T), didanosine (ddI), and zidovudine (ZDV) but it can occur with other NRTIs. 13 • Metabolic complications: A few studies have compared women and men in terms of metabolic complications associated with ARV use. Compared with HIV-infected men, HIV-infected women are more likely to experience increases in central fat with ART and are less likely to have triglyceride elevations on treatment. 14,15 Women have an increased risk of osteopenia/osteoporosis, particularly after menopause, and this risk is exacerbated by HIV and ART. 16,17 At the present time, none of these differences requires women-specific recommendations regarding treatment or monitoring. # Women of Childbearing Potential All women of childbearing potential should be offered pre-conception counseling and care as a component of routine primary medical care. Counseling should include discussion of special considerations pertaining to ARV use when trying to conceive and during pregnancy (see Perinatal Guidelines 1 ). Safe sexual practices, reproductive desires and options for conception, HIV status of sexual partner(s), and use of effective contraception to prevent unintended pregnancy should be discussed. An HIV-infected woman who wishes to conceive with an HIV-uninfected male partner should be informed of options to prevent sexual transmission of HIV while attempting conception. Interventions include initiation of maximally suppressive ART, which significantly decreases the risk of sexual transmission (see Preventing Secondary Transmission of HIV), and artificial insemination, including the option to self-inseminate with the partner's sperm during the periovulatory period 18 (for more extensive discussion on this topic, see the Reproductive Options for HIV-Concordant and Serodiscordant Couples section of the Perinatal Guidelines. 1 Efavirenz (EFV) is teratogenic in non-human primates. Women of childbearing potential should undergo pregnancy testing before initiation of EFV and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-based regimens (AIII). Alternative regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health (BIII). The most vulnerable period in fetal organogenesis is early in gestation, before pregnancy is recognized. # Hormonal Contraception Safe and effective reproductive health and family planning services to reduce unintended pregnancy and perinatal transmission of HIV are an essential component of care for HIV-infected women of childbearing age. Counseling about reproductive issues should be provided on an ongoing basis. Providers should be aware of potential interactions between ARV drugs and hormonal contraceptives that could lower contraceptive efficacy. Several protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have drug interactions with combined oral contraceptives (COCs). Interactions include either a decrease or an increase in blood levels of ethinyl estradiol, norethindrone, or norgestimate (see Tables 15a and 15b), which potentially decreases contraceptive efficacy or increases estrogen-or progestinrelated adverse effects (e.g., thromboembolism). Small studies of HIV-infected women receiving injectable depot-medroxyprogesterone acetate (DMPA) while on ART showed no significant interactions between DMPA and EFV, NVP, nelfinavir (NFV), or NRTI drugs. [19][20][21] Contraceptive failure of the etonogestrel implant in two patients on EFV-based therapy has been reported and a study has shown EFV may decrease plasma progestin concentrations of COCs containing ethinyl estradiol and norgestimate. 22,23 Several RTVboosted PIs decrease oral contraceptive estradiol levels. 24,25 A small study from Malawi showed that NVP use did not significantly affect estradiol or progestin levels in HIV-infected women. 26 Overall, data are relatively limited and the clinical implications of these findings are unclear. The magnitudes of change in drug levels that may reduce contraceptive efficacy or increase adverse effects are unknown. Concerns about pharmacokinetic interactions between oral and implant hormonal contraceptives and ARVs should not prevent clinicians from prescribing hormonal contraceptives for women on ART if that is their preferred contraceptive method. However, when women wish to use hormonal contraceptives and drug interactions with ARVs are known, additional or alternative contraceptive methods may be recommended (see drug interaction Tables 15a, 15b, and 15d and Perinatal Guidelines 1 ). Consistent use of male or female condoms to prevent transmission of HIV and protect against other sexually transmitted diseases (STDs) is recommended for all HIV-infected women and their partners, regardless of contraceptive use. The data on the association between hormonal contraception and the risk of acquisition of HIV are conflicting. 27 A retrospective secondary analysis of two studies of serodiscordant couples in Africa in which the HIV-infected partner was not receiving ART found that women using hormonal contraception (the vast majority using injectable DMPA) had a twofold increased risk of acquiring HIV (for HIV-infected male/HIVuninfected female couples) or transmitting HIV (HIV-infected female/HIV-uninfected male couples). HIV-infected women using hormonal contraception had higher genital HIV RNA concentrations than did women not using hormonal contraceptives. 28 Oral contraceptive use was not significantly associated with transmission of HIV; however, the number of women using oral contraceptives in this study was insufficient to adequately assess risk. It is important to note that not all studies have supported a link between hormonal contraception and transmission or acquisition of HIV and that the individuals in this study were not receiving ART. Further research is needed to definitively determine if hormonal contraceptive use is an independent risk factor for acquisition and transmission of HIV, particularly in the setting of ART. 27,29 Intrauterine devices (IUDs) appear to be a safe and effective contraceptive option for HIV-infected women. [30][31][32][33] Although studies have focused primarily on non-hormone-containing IUDs (e.g., copper IUD), several small studies have also found levonorgestrel-releasing IUDs to be safe and not associated with increased genital tract shedding of HIV. 31,34,35 # Pregnant Women Clinicians should review the Perinatal Guidelines 1 for a detailed discussion of the management of HIVinfected pregnant women. The use of combination ARV regimens is recommended for all HIV-infected pregnant women, regardless of virologic, immunologic, or clinical parameters (AI). Pregnant HIV-infected women should be counseled regarding the known benefits and risks of ARV use during pregnancy to the woman, fetus, and newborn. A woman's decision regarding ARV use should be respected. Coercive and punitive approaches undermine provider-patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize maternal, fetal, and neonatal well-being. Prevention of Perinatal Transmission of HIV. The use of ARVs and the resultant reduction of HIV RNA levels decrease perinatal transmission of HIV. [36][37][38] The goal of ARV use is to achieve maximal and sustained suppression of HIV RNA levels during pregnancy. As in non-pregnant individuals, genotypic resistance testing is recommended for all pregnant women before ARV initiation (AIII) and for pregnant women with detectable HIV RNA levels while on therapy (AI). Optimal prevention of perinatal transmission may require initiation of ARV drugs before results of resistance testing are available. If results demonstrate the presence of significant mutation(s) that may confer resistance to the prescribed ARV regimen, the regimen should be modified. Long-term follow-up is recommended for all infants born to women who have received ARVs during pregnancy, regardless of the infant's HIV status (see the Perinatal Guidelines 1 ). Regimen Considerations. Pregnancy should not preclude the use of optimal drug regimens. Because recommendations on ARVs to use for treatment of HIV-infected pregnant women are subject to unique considerations, recommendations specific to the timing of therapy initiation and the choice of ARVs for pregnant women may differ from those for non-pregnant individuals. These considerations include the following: • Potential changes in pharmacokinetics and, thus, dosing requirements, which result from physiologic changes associated with pregnancy; • potential ARV-associated adverse effects in pregnant women and the woman's ability to adhere to a particular regimen during pregnancy; and • potential short-and long-term effects of the ARV on the fetus and newborn, which are unknown for many drugs. Combination drug regimens are considered the standard of care in pregnancy, both for the treatment of HIV infection and for the prevention of perinatal transmission of HIV. Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, and unnecessary changes in ARV drugs during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII). Detailed recommendations on ARV choice in pregnancy are discussed in detail in the Perinatal Guidelines (see Perinatal Guidelines 1 ). Intravenous (IV) zidovudine (ZDV) infusion to the mother during labor is recommended if maternal HIV RNA is ≥400 copies/mL (or with unknown HIV RNA levels) near delivery, regardless of antepartum regimen or mode of delivery (AI). Consideration can be given to omitting IV ZDV infusion during labor for HIVinfected women receiving combination ART regimens who have HIV RNA <400 copies/mL near delivery (BII); however, the combination ART should continue to be administered during labor. Clinicians who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to ARVs (either administered alone or in combinations) to the Antiretroviral Pregnancy Registry (http://www.apregistry.com). The registry collects observational data regarding exposure to Food and Drug Administration-approved ARV drugs during pregnancy for the purpose of assessing potential teratogenicity. For more information regarding selection and use of ART during pregnancy, refer to the Perinatal Guidelines. 1 # Postpartum Management Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for non-pregnant adults and adolescents. Because maternal ART reduces but does not eliminate the risk of transmission of HIV in breast milk and postnatal transmission can occur despite maternal ART, women should also be counseled to avoid breastfeeding. 1 HIV-infected women should avoid pre-mastication of food fed to their infants because the practice has been associated with transmission of HIV from mother to child. 39 Considerations regarding continuation of ART for maternal therapeutic indications are the same as those for ART use in other non-pregnant individuals. For more information regarding postpartum discontinuation of ART, refer to the Perinatal Guidelines. 1 Several studies have demonstrated that adherence to ART may worsen in the postpartum period. [40][41][42][43][44] Clinicians caring for women postpartum who are receiving ART should specifically address adherence, including an evaluation of specific facilitators and barriers to adherence. Clinicians may consider an intervention to improve adherence (see Adherence to Antiretroviral Therapy). The clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rates compared with HIV-1 infection. [1][2] However, HIV-2 infection can progress to AIDS, and thus antiretroviral therapy (ART) may become necessary during the course of infection. Concomitant HIV-1 and HIV-2 infection may occur and should be considered in patients from an area with high prevalence of HIV-2. In the appropriate epidemiologic setting, HIV-2 infection should be suspected in patients with clinical conditions suggestive of HIV infection but with atypical serologic results (e.g., a positive screening assay with an indeterminate HIV-1 Western blot). 3 The possibility of HIV-2 infection should also be considered in the appropriate epidemiologic setting in patients with serologically confirmed HIV infection but low or undetectable viral loads or in those with declining CD4 counts despite apparent virologic suppression on ART. The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is Food and Drug Administration (FDA) approved for differentiating HIV-1 from HIV-2 infection. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2, and no HIV-2 commercial viral load assays are currently available. [4][5] Most studies reporting HIV-2 viral loads use "in-house" assays that are not widely available, making it difficult to monitor virologic response in the clinical setting. In addition, no validated HIV-2 genotypic or phenotypic antiretroviral (ARV) resistance assays are available. To date, there have been no randomized trials addressing the question of when to start ART or the choice of initial or second-line therapy for HIV-2 infection; 6 thus, the optimal treatment strategy has not been defined. HIV-2 appears intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) 7 and to enfuvirtide. 8 In vitro data suggest HIV-2 is sensitive to the currently available nucleoside reverse transcriptase inhibitors (NRTIs), although with a lower barrier to resistance than HIV-1. 9-10 Variable sensitivity among protease inhibitors (PIs) has been reported; lopinavir (LPV), saquinavir (SQV), and darunavir (DRV) are more active against HIV-2 than other approved PIs. [11][12][13][14] The integrase inhibitor, raltegravir (RAL), 15 and the CCR5 antagonist, maraviroc (MVC), appear active against some HIV-2 isolates, although no approved assays to determine HIV-2 coreceptor tropism exist and HIV-2 is known to utilize multiple minor coreceptors in addition to CCR5 and CXCR4. 16 Several small studies suggest poor responses among HIV-2 infected individuals treated with some ARV regimens, including dual-NRTI regimens, regimens containing two NRTIs + NNRTI, and some unboosted PI-based regimens including nelfinavir (NFV) or indinavir (IDV) plus zidovudine (ZDV) and lamivudine (3TC). 6,[17][18][19] Clinical data on the utility of triple-NRTI regimens are conflicting. [20][21] In general, boosted PI-containing regimens have resulted in more favorable virologic and immunologic responses. 21 One small study suggested satisfactory responses to lopinavir/ritonavir (LPV/r)-containing regimens in 17 of 29 (59%) of ARV-naive subjects. 22 Resistance-associated mutations develop commonly in HIV-2 patients on therapy. 17,21,23 Genotypic algorithms used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because pathways and mutational patterns leading to resistance may differ. 10,21,24 CD4 cell recovery on therapy may be poor, 25 suggesting that more reliable methods for monitoring disease progression and treatment efficacy in HIV-2 infection are needed. Some groups have recommended specific preferred and alternative regimens for initial therapy of HIV-2 infection, 24 though as yet there are no controlled trial data to reliably predict their success. Until more definitive data are available in an ART-naive patient with HIV-2 mono-infection or with HIV-1/HIV-2 dual infection who requires treatment, clinicians should initiate a regimen containing two NRTIs and a boosted PI. Monitoring of virologic response in such patients is problematic because of the lack of a commercially available HIV-2 viral load assay; however, clinical and CD4 count improvement can be used to assess treatment response. HIV and the Older Patient (Last updated March 27, 2012; last reviewed March 27, 2012) Effective antiretroviral therapy (ART) has increased survival in HIV-infected individuals, resulting in an increasing number of older individuals living with HIV infection. In the United States, approximately 30% of people currently living with HIV/AIDS are age 50 years or older and trends suggest that the proportion of older persons living with HIV/AIDS will increase steadily. 1 Care of HIV-infected patients increasingly will involve adults 60 to 80 years of age, a population for which data from clinical trials or pharmacokinetic studies are very limited. There are several distinct areas of concern regarding the association between age and HIV disease. 2 First, older HIV-infected patients may suffer from aging-related comorbid illnesses that can complicate the management of HIV infection, as outlined in detail below. Second, HIV disease may affect the biology of aging, possibly resulting in early manifestations of many clinical syndromes generally associated with advanced age. Third, reduced mucosal and immunologic defenses (such as post-menopausal atrophic vaginitis) and changes in risk behaviors (for example, decrease in condom use because of less concern about pregnancy and increased use of erectile dysfunction drugs) in older adults could lead to increased risk of acquisition and transmission of HIV. [3][4] Finally, because older adults generally are perceived to be at low risk of HIV infection, screening for HIV in this population remains low. For these reasons, HIV infection in many older adults may not be diagnosed until late in the disease process. This section focuses on HIV diagnosis and treatment considerations in the older HIV-infected patient. # HIV Diagnosis and Prevention Even though many older individuals are engaged in risk behaviors associated with acquisition of HIV, they may be perceived to be at low risk of infection and, as a result, they are less likely to be tested for HIV than younger persons. 5 According to one U.S. survey, 71% of men and 51% of women age 60 years and older continue to be sexually active, 6 with less concern about the possibility of pregnancy contributing to less condom use. Another national survey reported that among individuals age 50 years or older, condoms were not used during most recent intercourse with 91% of casual partners or 70% of new partners. 7 In addition, # Key Considerations When Caring for Older HIV-Infected Patients • Antiretroviral therapy (ART) is recommended in patients >50 years of age, regardless of CD4 cell count (BIII), because the risk of non-AIDS related complications may increase and the immunologic response to ART may be reduced in older HIV-infected patients. • ART-associated adverse events may occur more frequently in older HIV-infected adults than in younger HIV-infected individuals. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older HIV-infected adults should be monitored closely. • The increased risk of drug-drug interactions between antiretroviral (ARV) drugs and other medications commonly used in older HIV-infected patients should be assessed regularly, especially when starting or switching ART and concomitant medications. • HIV experts and primary care providers should work together to optimize the medical care of older HIV-infected patients with complex comorbidities. • Counseling to prevent secondary transmission of HIV remains an important aspect of the care of the older HIVinfected patient. results from a CDC survey 8 show that in 2008 only 35% of adults age 45 to 64 years had ever been tested for HIV infection despite the 2006 CDC recommendation that individuals age 13 to 64 years be tested at least once and more often if sexually active. 9 Clinicians must be attuned to the possibility of HIV infection in older patients, including those older than 64 years of age who, based on CDC recommendations, would not be screened for HIV. Furthermore, sexual history taking, risk-reduction counseling, and screening for sexually transmitted diseases (STDs) (if indicated), are important components of general health care for HIVinfected and -uninfected older patients. # Rating of Recommendations Failure to consider a diagnosis of HIV in older persons likely contributes to later disease presentation and initiation of ART. 10 One surveillance report showed that the proportion of patients who progressed to AIDS within 1 year of diagnosis was greater among patients >60 years of age (52%) than among patients younger than 25 years (16%). 1 When individuals >50 years of age present with severe illnesses, AIDS-related opportunistic infections (OIs) need to be considered in the differential diagnosis of the illness. # Initiating Antiretroviral Therapy Concerns about decreased immune recovery and increased risk of serious non-AIDS events are factors that favor initiating ART in patients >50 years of age regardless of CD4 cell count (BIII). (See Initiating Antiretroviral Therapy in Treatment-Naive Patients.) Data that would favor use of any one of the Panel's recommended initial ART regimens (see What to Start) on the basis of age are not available. The choice of regimen should be informed by a comprehensive review of the patient's other medical conditions and medications. A noteworthy limitation of currently available information is lack of data on the long-term safety of specific antiretroviral (ARV) drugs in older patients, such as use of tenofovir disoproxil fumarate (TDF) in older patients with declining renal function. The recommendations on how frequently to monitor parameters of ART effectiveness and safety for adults age >50 years are similar to those for the general HIV-infected population; however, the recommendations for older adults focus particularly on the adverse events of ART pertaining to renal, liver, cardiovascular, metabolic, and bone health (see Table 13). # HIV, Aging, and Antiretroviral Therapy The efficacy, pharmacokinetics, adverse effects, and drug interaction potentials of ART in the older adult have not been studied systematically. There is no evidence that the virologic response to ART is different in older patients than in younger patients. However, CD4 T-cell recovery after starting ART generally is less robust in older patients than in younger patients. [11][12][13][14] This observation suggests that starting ART at a younger age will result in better immunologic and possibly clinical outcomes. Hepatic metabolism and renal elimination are the major routes of drug clearance, including the clearance of ARV drugs. Both liver and kidney function may decrease with age, which may result in impaired drug elimination and drug accumulation. 15 Current ARV drug doses are based on pharmacokinetic and pharmacodynamic data derived from studies conducted in subjects with normal organ function. Most clinical trials include only a small proportion of study participants >50 years of age. Whether drug accumulation in the older patient may lead to greater incidence and severity of adverse effects than seen in younger patients is unknown. HIV-infected patients with aging-associated comorbidities may require additional pharmacologic intervention, making therapeutic management increasingly complex. In addition to taking medications to manage HIV infection and comorbid conditions, many older HIV-infected patients also are taking medications to ameliorate discomfort (e.g., pain medications, sedatives) or to manage adverse effects of medications (e.g., anti-emetics). They also may self-medicate with over-the-counter medicines or supplements. In the HIV-negative population, polypharmacy is a major cause of iatrogenic problems in geriatric patients. 16 This may be the result of medication errors (by prescribers or patients), nonadherence, additive drug toxicities, and drug-drug interactions. Older HIV-infected patients probably are at an even greater risk of polypharmacy and its attendant adverse consequences than younger HIV-infected or similarly aged HIV-uninfected patients. Drug-drug interactions are common with ART and easily can be overlooked by prescribers. 17 The available drug interaction information on ARV agents is derived primarily from pharmacokinetic studies performed in a small number of relatively young, HIV-uninfected subjects with normal organ function (see Tables 14-16b). Data from these studies provide clinicians with a basis to assess whether a significant interaction may exist. However, the magnitude of the interaction may be different in older HIV-infected patients than in younger HIV-infected patients. Nonadherence is the most common cause of treatment failure. Complex dosing requirements, high pill burden, inability to access medications because of cost or availability, limited health literacy including lack of numeracy skills, misunderstanding of instructions, depression, and neurocognitive impairment are among the key reasons for nonadherence. 18 Although many of these factors likely will be more prevalent in an aging HIV-infected population, some data suggest that older HIV-infected patients may be more adherent to ART than younger HIV-infected patients. [19][20][21] Clinicians should assess adherence regularly to identify any factors, such as neurocognitive deficits, that may make adherence a challenge. One or more interventions such as discontinuation of unnecessary medications; regimen simplification; or use of adherence tools, including pillboxes, daily calendars, and evidence-based behavioral approaches may be necessary to facilitate medication adherence (see Adherence to Antiretroviral Therapy). # Non-AIDS HIV-Related Complications and other Comorbidities With the reduction in AIDS-related morbidity and mortality observed with effective use of ART, non-AIDS conditions constitute an increasing proportion of serious illnesses in ART-treated HIV-infected populations. [22][23][24] Heart disease and cancer are the leading causes of death in older Americans. 25 Similarly, for HIV-infected patients on ART, non-AIDS events such as heart disease, liver disease, and cancer have emerged as major causes of morbidity and mortality. Neurocognitive impairment, already a major health problem in aging patients, may be exacerbated by the effect of HIV infection on the brain. 26 That the presence of multiple non-AIDS comorbidities coupled with the immunologic effects of HIV infection could add to the disease burden of an aging HIV-infected person is a concern. [27][28][29] At present, primary care recommendations are the same for HIV-infected and HIV-uninfected adults and focus on identifying and managing risks of conditions such as heart, liver, and renal disease; cancer; and bone demineralization. [30][31][32] # Discontinuing Antiretroviral Therapy in Older Patients Important issues to discuss with aging HIV-infected patients are living wills, advance directives, and longterm care planning including financial concerns. Health care cost sharing (e.g., co-pays, out-of-pocket costs), loss of employment, and other financial-related factors can cause interruptions in treatment. Clinic systems can minimize loss of treatment by helping patients maintain access to insurance. For the severely debilitated or terminally ill HIV-infected patient, adding palliative care medications, while perhaps beneficial, further increases the complexity and risk of negative drug interactions. For such patients, a balanced consideration of both the expected benefits of ART and the toxicities and negative quality-of-life effects of ART is needed. Few data exist on the use of ART in severely debilitated patients with chronic, severe, or non-AIDS terminal conditions. [33][34] Withdrawal of ART usually results in rebound viremia and a decline in CD4 cell count. Acute retroviral syndrome after abrupt discontinuation of ART has been reported. In very debilitated patients, if there are no significant adverse reactions to ART, most clinicians would continue therapy. In cases where ART negatively affects quality of life, the decision to continue therapy should be made together with the patient and/or family members after a discussion on the risks and benefits of continuing or withdrawing ART. # Conclusion HIV infection may increase the risk of many major health conditions experienced by aging adults and possibly accelerate the aging process. 35 As HIV-infected adults age, their health problems become increasingly complex, placing additional demands on the health care system. This adds to the concern that outpatient clinics providing HIV care in the United States share the same financial problems as other chronic disease and primary care clinics and that reimbursement for care is not sufficient to maintain care at a sustainable level. 36 Continued involvement of HIV experts in the care of older HIV-infected patients is warranted. However, given that the current shortage of primary care providers and geriatricians is projected to continue, current HIV providers will need to adapt to the shifting need for expertise in geriatrics through continuing education and ongoing assessment of the evolving health needs of aging HIV-infected patients. 37 The aging of the HIV-infected population also signals a need for more information on long-term safety and efficacy of ARV drugs in older patients. coinfected patients. Therefore, 3TC or FTC should be used in combination with other anti-HBV drugs (AII). 10 • Immune reconstitution after initiation of treatment for HIV and/or HBV can be associated with elevation in transaminases, possibly because HBV is primarily an immune-mediated disease. 11 • Some ARV agents can cause increases in transaminase levels. The rate and magnitude of these increases are higher with HBV coinfection. [12][13] The etiology and consequences of these changes in liver function tests are unclear because continuation of ART may be accompanied by resolution of the changes. Nevertheless, some experts suspend the implicated agent(s) when the serum alanine transferase (ALT) level is increased to 5-10 times the upper limit of normal. However, in HIV/HBV-coinfected persons, increases in transaminase levels can herald hepatitis B e antigen (HBeAg) seroconversion due to immune reconstitution, so the cause of the elevations should be investigated prior to the decision to discontinue medications. In persons with transaminase increases, HBeAg seroconversion should be evaluated by testing for HBeAg and anti-HBe as well as HBV DNA levels. # Recommendations for HBV/HIV-Coinfected Patients • All patients with chronic HBV should be advised to abstain from alcohol, assessed for immunity to hepatitis A virus (HAV) infection (anti-HAV antibody total) and vaccinated if nonimmune, advised on methods to prevent HBV transmission (methods that do not differ from those to prevent HIV transmission), and evaluated for the severity of HBV infection as outlined in the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. 14 • Prior to intiation of ART, all persons who test positive for HBsAg should be tested for HBV DNA using a quantitative assay to determine the level of HBV replication (AIII). Persons with chronic HBV infection already receiving ART active against HBV should undergo quantitative HBV DNA testing every 6-12 months to determine the effectiveness of therapy in suppressing HBV replication. The goal of HBV therapy with NRTIs is to prevent liver disease complications by sustained suppression of HBV replication to the lowest achievable level. • If not yet on therapy and HBV or HIV treatment is needed: In persons without HIV infection, the recommended anti-HBV drugs for the treatment of persons naive to HBV therapy are TDF and entecavir. [15][16] In HIV-infected patients, however, only TDF can be considered part of the ARV regimen; entecavir has weak anti-HIV activity and must not be considered part of an ARV regimen. In addition, only TDF is fully active for the treatment of persons with known or suspected 3TC-resistant HBV infection. To avoid selection of HBV-resistant variants, when possible, these agents should not be used as the only agent with anti-HBV activity in an ARV regimen (AIII). Preferred regimen. The combination of TDF + FTC or TDF + 3TC should be used as the NRTI backbone of a fully suppressive ARV regimen and for the treatment of HBV infection (AII). [17][18][19] Alternative regimens. If TDF cannot safely be used, entecavir should be used in addition to a fully suppressive ARV regimen (AII); importantly, entecavir should not be considered to be a part of the ARV regimen 20 (BII). Due to a partially overlapping HBV-resistance pathway, it is not known if the combination of entectavir + 3TC or FTC will provide additional virologic or clinical benefit compared with entecavir alone. In persons with known or suspected 3TC-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day. However, entecavir resistance may emerge rapidly in patients with 3TC-resistant HBV infection. Therefore, entecavir should be used with caution in such patients with frequent monitoring (~ every 3 months) of the HBV DNA level to detect viral breakthrough. Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC or telbivudine in addition to a fully suppressive ARV regimen; 17,[21][22] however, data on these regimens in persons with HIV/HBV coinfection are limited (BII). Due to safety concerns, peginterferon alfa should not be used in HIV/HBV-coinfected persons with cirrhosis. • Need to discontinue medications active against HBV: The patient's clinical course should be monitored with frequent liver function tests. The use of adefovir dipivoxil, entecavir, or telbivudine to prevent flares, especially in patients with marginal hepatic reserve such as persons with compensated or decompensated cirrhosis, can be considered. 8 These alternative HBV regimens should only be used in addition to a fully suppressive ARV regimen. • Need to change ART because of HIV resistance: If the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). infection should undergo repeat testing annually. HCV-seropositive patients should be tested for HCV RNA using a qualitative or quantitative assay to confirm the presence of active infection. 17 • Patients with HIV/HCV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others. HIV/HCV-coinfected patients who are susceptible to hepatitis A virus (HAV) or hepatitis B virus (HBV) infection should be vaccinated against these viruses. • All patients with HIV/HCV coinfection should be evaluated for HCV therapy. HCV treatment is recommended according to standard guidelines. 18,19 Strong preference should be given to commence HCV treatment in patients with higher CD4 counts. For patients with lower CD4 counts (e.g., <200 cells/mm 3 ), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of HIV treatment. 17,[20][21][22] # Antiretroviral Therapy in HIV/Hepatitis C Virus Coinfection • When to start antiretroviral therapy: The rate of liver disease (liver fibrosis) progression is accelerated in HIV/HCV-coinfected patients, particularly in individuals with low CD4 counts (≤350 cells/mm 3 ). Data largely from retrospective cohort studies are inconsistent regarding the effect of ART on the natural history of HCV disease. 6,23,24 However, ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. [25][26][27] Thus, for most coinfected patients, including those with high CD4 counts and those with cirrhosis, the benefits of ART outweigh concerns regarding DILI. Therefore, ART should be initiated for most HIV/HCVcoinfected patients, regardless of CD4 count (BII). However, in HIV treatment-naive patients with CD4 counts >500 cells/mm 3 , some clinicians may choose to defer ART until completion of HCV treatment. • What antiretroviral to start and what antiretroviral not to use: Initial ARV combination regimens for most HIV treatment-naive patients with HCV are the same as those for patients without HCV infection. Special considerations for ARV selection in HIV/HCV-coinfected patients include: • When both HIV and HCV treatments are indicated, the choice of ARV regimen should be guided by the HCV treatment regimen selected with careful consideration of potential drug-drug interactions and overlapping toxicities (as discussed below). • Cirrhotic patients should be carefully assessed for signs of liver decompensation according to the Child-Turcotte-Pugh classification system because hepatically metabolized ARV drugs may require dose modification or avoidance in patients with Child-Pugh class B and C disease. (See Appendix B, Table 7.) • Hepatotoxicity: DILI following initiation of ART is more common in HIV/HCV-coinfected patients than in those with HIV monoinfection. The greatest risk of DILI may be observed in coinfected individuals with advanced liver disease (e.g., cirrhosis or end-stage liver disease). 28 Eradication of HCV infection with treatment may decrease the likelihood of ARV-associated DILI. 29 • Given the substantial heterogeneity in patient populations and drug regimens, comparison of DILI incidence rates for individual ARV agents across clinical trials is difficult. In such studies, the highest incidence rates of significant elevations in liver enzyme levels (>5 times the upper limit of the laboratory reference range) have been observed during therapy with ARV drugs that are no longer commonly used in clinical practice, including stavudine (d4T) (with or without didanosine [ddI]), nevirapine (NVP), or full-dose ritonavir (RTV) (600 mg twice daily). 30 Additionally, certain ARV agents should be avoided if possible because they have been associated with higher incidence of serious liver-associated adverse effects, such as fatty liver disease with nucleoside reverse transcriptase inhibitors (NRTIs) such as d4T, ddI, or zidovudine (ZDV); 31 noncirrhotic portal hypertension associated with ddI; 32 and hepatotoxicity associated with RTV-boosted tipranavir. 33 coinfected patients have received HIV PIs and boceprevir during HCV treatment. Patients who are currently receiving these drug combinations should be advised not to stop any medication until contacting their health care providers. If therapy with HIV PIs and boceprevir is continued, patients should be closely monitored for HIV and HCV responses and consideration should be given to switching the HIV PI or EFV to RAL during boceprevir therapy. Additional clinical trial data are needed to determine if other ARVs may be co-administered with boceprevir. • Telaprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. Telaprevir is administered in combination with PegIFN/RBV for the initial 12 weeks of HCV therapy followed by 12 or 36 weeks of additional treatment with PegIFN/RBV. Data on the use of this regimen in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with telaprevir plus PegIFN/RBV (38 patients) than with PegIFN/RBV alone (22 patients). In this study, patients received ART containing EFV or ATV/r plus tenofovir/emtricitabine (TDF/FTC) or no ART during the HCV therapy. 44 Because telaprevir is a substrate and an inhibitor of CYP3A4 and p-gp enzymes, the drug may interact with ARVs metabolized by these pathways. On the basis of drug interaction studies in healthy volunteers and data on responses in coinfected patients enrolled in the small clinical trial noted above, telaprevir can be coadministered with ATV/r 45 and RAL 46 at the standard recommended dose of telaprevir (750 mg every 7-9 hours) and with EFV at an increased dose of telaprevir (1125 mg every 7-9 hours) (see Table 15b); however, co-administration of telaprevir with DRV/r, fosamprenavir/ritonavir (FPV/r), or LPV/r is not recommended because of bidirectional drug interactions. 45 Data on PK interactions of telaprevir with other ARVs including non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than EFV and with maraviroc (MVC) are not available; therefore, co-administration of telaprevir with other ARVs cannot be recommended. Patients receiving other ARV regimens: • If HCV disease is minimal (i.e., no or mild portal fibrosis), consider deferring HCV treatment given rapidly evolving HCV drug development. • If good prognostic factors for HCV treatment response are present-IL28B CC genotype or low HCV RNA level (<400,000 International Unit [IU]/mL)-consider use of PegIFN/RBV without HCV NS3/4A PI. • On the basis of ART history and HIV genotype testing results, if possible, consider switching to the ART regimens listed above to permit the use of boceprevir or telaprevir. • For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed. In such patients, telaprevir may be the preferred HCV NS3/4A PI because its duration of use (12 weeks) is shorter than that of boceprevir (24 to 44 weeks). # Summary: In summary, HCV coinfection and use of PegIFN/RBV with or without HCV NS3/4A PIs (telaprevir or boceprevir) to treat HCV may impact the treatment of HIV because of increased pill burden, toxicities, and drug-drug interactions. Because ART may slow the progression of HCV-related liver disease, ART should be considered for most HIV/HCV-coinfected patients, regardless of CD4 count. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (telaprevir or boceprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug-drug interactions and/or drug toxicities that may develop during the period of concurrent HIV and HCV treatment. The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly. HIV disease. It may be associated with a higher HIV viral load and more rapid progression of HIV disease. 3 Active pulmonary or extrapulmonary TB disease requires prompt initiation of TB treatment. The treatment of active TB disease in HIV-infected patients should follow the general principles guiding treatment for individuals without HIV (AI). Treatment of drug-susceptible TB disease should include a standard regimen that consists of isoniazid (INH) + a rifamycin (rifampin or rifabutin) + pyrazinamide + ethambutol given for 2 months, followed by INH + a rifamycin for 4 to 7 months. 4 The Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 4 include a more complete discussion of the diagnosis and treatment of TB disease in HIV-infected patients. All patients with HIV/TB disease should be treated with ART (AI). Important issues related to the use of ART in patients with active TB disease include: (1) when to start ART, (2) significant pharmacokinetic drugdrug interactions between rifamycins and some antiretroviral (ARV) agents, (3) the additive toxicities associated with concomitant ARV and TB drug use, ( 4) the development of TB-associated IRIS after ART initiation, and ( 5) the need for treatment support including DOT and the integration of HIV and TB care and treatment. # Antiretroviral Therapy in Patients with Active Tuberculosis # Patients Diagnosed with Tuberculosis While Receiving Antiretroviral Therapy When TB is diagnosed in a patient receiving ART, the patient's ARV regimen should be assessed with particular attention to potential pharmacokinetic interactions with rifamycins (discussed below). The patient's regimen may need to be modified to permit use of the optimal TB treatment regimen (see Tables 14-16 for dosing recommendations). # Patients Not Yet Receiving Antiretroviral Therapy Until recently, when to start ART in patients with active TB has been a subject of debate. Survival is improved when ART is started early following initiation of TB therapy, but a delay in initiating ART often was favored because of the potential complications of high pill burden, additive toxicities, drug interactions, adherence, and the potential for development of IRIS.Recent studies primarily conducted in resource-limited settings, including three randomized controlled trials, have helped clarify the question of when to start ART in patients with active TB. [5][6][7][8] The SAPiT study conducted in South Africa convincingly demonstrated that starting ART during rather than after concluding treatment for TB can significantly reduce mortality. In this study, ambulatory HIV-infected patients with smear-positive TB and CD4 counts <500 cells/mm 3 were randomized to one of three treatment arms: integrated therapy with ART initiated either during the first 4 weeks of TB therapy or after the first 8 weeks of TB treatment (i.e., during the continuation phase of TB therapy) or sequential therapy with ART initiated after the conclusion of standard TB therapy. The median CD4 cell count of participants at study entry was 150 cells/mm 3 . The sequential therapy arm was stopped when an early analysis demonstrated that the mortality rate in the combined two integrated arms was 56% lower than the rate in the sequential therapy arm. Treatment was continued in the two integrated arms until study completion. 5 With the completion of SAPiT and 2 other randomized controlled trials, CAMELIA and STRIDE, the question on the optimal time to initiate ART during TB therapy has been addressed. Findings from these trials now serve as the basis for the Panel's recommendations on when to start ART in patients with active TB. In the final analysis of the SAPiT trial, there were no differences in rates of AIDS or death between the 2 integrated arms of the study (patients who started ART within 4 weeks after initiating TB treatment vs. those who started ART at 8-12 weeks [i.e., within 4 weeks after completing the intensive phase of TB treatment]). However, in patients with baseline CD4 counts <50 cells/mm 3 (17% of the study population), the rate of AIDS or death was lower in the earlier therapy group than in the later therapy group (8.5 vs. 26.3 cases per 100 person-years, a strong trend favoring the earlier treatment arm, P = 0.06). For all patients, regardless of CD4 cell count, earlier therapy was associated with a higher incidence of IRIS and of adverse events that required a switch in ARV drugs than later therapy. Two deaths were attributed to IRIS. 6 In the CAMELIA study, which was conducted in Cambodia 7 , patients who had CD4 counts <200 cells/mm 3 were randomized to initiate ART at 2 weeks or 8 weeks after initiation of TB treatment. Study participants had advanced HIV disease, with a median entry CD4 count of 25 cells/mm 3 ; low BMIs (median = 16.8 kg/m 2 ), Karnofsky scores (87% <70), and hemoglobin levels (median = 8.7 g/dl); and high rates of disseminated TB disease. Compared with therapy initiated at 8 weeks, ART initiated at 2 weeks resulted in a 38% reduction in mortality (P = 0.006). A significant reduction in mortality was seen in patients with CD4 counts ≤50 cells/mm 3 and in patients with CD4 counts 51 to 200 cells/mm 3 . Overall, 6 deaths associated with TB-IRIS were reported. The ACTG 5221 (STRIDE) trial, a multinational study conducted at 28 sites, randomized ART-naive patients with confirmed or probable TB and CD4 counts <250 cells/mm 3 to earlier (<2 weeks) or later (8-12 weeks) ART. 8 At study entry, the participants' median CD4 count was 77 cells/mm 3 . The rates of mortality and AIDS diagnoses were not different between the earlier and later arms, although higher rates of IRIS were seen in the earlier arm. However, a significant reduction in AIDS or death was seen in the subset of patients with CD4 counts <50 cells/mm 3 who were randomized to the earlier ART arm (P = 0.02). In each of these 3 studies, IRIS was more common in patients initiating ART earlier than in patients starting ART later, but the syndrome was infrequently associated with mortality. Collectively these 3 trials demonstrate that in patients with active TB and with very low CD4 cell counts (i.e., <50 cells/mm 3 ), early initiation of ART can reduce mortality and AIDS progression, albeit at the risk of increased IRIS. These findings strongly favor initiation of ART within the first 2 weeks of TB treatment in patients with CD4 cell counts <50 cells/mm 3 (AI). The question of when to start ART in patients with CD4 counts ≥50 cells/mm 3 is also informed by these studies. The STRIDE and SAPiT studies-in which the patients with CD4 cell counts ≥50 cells/mm 3 were relatively healthy and with reasonable Karnofsky scores (note the SAPiT study excluded patients with Karnofsky scores <70) and BMIs-demonstrated that ART initiation in these patients can be delayed until 8 to 12 weeks after initiation of TB therapy (AI for CD4 counts 51-500 cells/mm 3 and BIII for CD4 counts >500 cells/mm 3 ). However, the CAMELIA study, which included more patients who were severely ill than the STRIDE and SAPiT studies, showed that early initiation of ART improved survival both in patients with CD4 counts ≤50 cells/mm 3 Of additional importance, each of the above studies demonstrated excellent responses to ART, with 90% and >95% of participants achieving suppressed viremia (HIV RNA <400 copies/mL) at 12 months in the SAPiT and CAMELIA studies, respectively, and 74% of participants at 2 years in the STRIDE study. Mortality rates in patients with MDR or XDR TB and HIV coinfection are very high. 9 Retrospective case control studies and case series provide growing evidence of better outcomes associated with receipt of ART in such coinfected patients, 10 but the optimal timing for initiation of ART is unknown. However, given the high rates and rapid mortality, most experts recommend that ART be initiated within 2 to 4 weeks after confirmation of the diagnosis of drug resistance and initiation of second-line TB therapy (BIII). All HIV-infected pregnant women with active TB should be started on ART as early as feasible, both for maternal health and to prevent perinatal transmission of HIV (AIII). The choice of ART should be based on efficacy and safety in pregnancy and take into account potential drug-drug interactions between ARVs and rifamycins (see Perinatal Guidelines for more detailed discussions). 11 TB meningitis often is associated with severe complications and high mortality rate. In a randomized study conducted in Vietnam, patients were randomized to immediate ART or to therapy deferred until 2 months after initiation of TB treatment. A higher rate of severe (Grade 4) adverse events was seen in patients who received immediate ART than in those who deferred therapy (80.3% vs. 69.1%, respectively; P = 0.04). 12 In this study 59.8% of the immediate ART patients and 55.5% of the delayed ART patients died within 9 months. However, in the United States, where patients may be more closely monitored and treated for severe adverse events such as central nervous system (CNS) IRIS, many experts feel that ART should be initiated as for other HIV/TB-coinfected patients (CIII). # Drug Interaction Considerations A rifamycin is a crucial component in treatment of drug-sensitive TB. However, both rifampin and rifabutin are inducers of the hepatic cytochrome P (CYP) 450 and uridine diphosphate gluconyltransferase (UGT) 1A1 enzymes and are associated with significant interactions with most ARV agents including all PIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), maraviroc (MVC), and raltegravir (RAL). Rifampin is a potent enzyme inducer, leading to accelerated drug clearance and significant reduction in ARV drug exposure. Despite these interactions, some observational studies suggest that good virologic, immunologic, and clinical outcomes may be achieved with standard doses of efavirenz (EFV) [13][14] and, to a lesser extent, nevirapine (NVP) [15][16] when combined with rifampin. However, rifampin is not recommended in combination with all PIs and the NNRTIs etravirine (ETR) and rilpivirine (RPV). When rifampin is used with MVC or RAL, increased dosage of the ARV is generally recommended. Rifabutin, a weaker enzyme inducer, is an alternative to rifampin. Because rifabutin is a substrate of the CYP 450 enzyme system, its metabolism may be affected by the NNRTI or PI. Tables 14, 15a, 15b, 15d, and 15e outline the magnitude of these interactions and provide dosing recommendations when rifamycins and selected ARV drugs are used concomitantly. After determining the drugs and doses to use, clinicians should monitor patients closely to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, subtherapeutic drug levels (consider therapeutic drug monitoring [TDM]), and acquired drug resistance. Rifapentine is a long-acting rifamycin that can be given once weekly with INH for the treatment of active or latent TB infection. Similar to rifampin and rifabutin, rifapentine is also a CYP3A4 inducer. No systematic study has been performed to assess the magnitude of the enzyme induction effect of rifapentine on the metabolism of ARV drugs and other concomitant drugs. Significant enzyme induction can result in reduced ARV drug exposure, which may compromise virologic efficacy. Rifapentine is not recommended for treatment of latent or active TB infection in patients receiving ART, unless given in the context of a clinical trial (AIII). # Anti-Tuberculosis/Antiretroviral Drug Toxicities ARV agents and TB drugs, particularly INH, rifamycin, and pyrazinamide, can cause drug-induced hepatitis. These first-line TB drugs should be used for treatment of active TB disease, even with co-administration of other potentially hepatotoxic drugs or when baseline liver disease is present (AIII). Patients receiving potentially hepatotoxic drugs should be monitored frequently for clinical symptoms and signs of hepatitis and have laboratory monitoring for hepatotoxicity. Peripheral neuropathy can occur with administration of INH, didanosine (ddI), or stavudine (d4T) or may be a manifestation of HIV infection. All patients receiving INH also should receive supplemental pyridoxine to reduce peripheral neuropathy. Patients should be monitored closely for signs of drug-related toxicities and receive alternative ARVs to ddI or d4T. # Immune Reconstitution Inflammatory Syndrome with Tuberculosis and Antiretroviral Agents IRIS occurs in two forms: unmasking and paradoxical. The mechanism of the syndrome is the same for both forms: restoration of immune competence by administration of ART, resulting in an exuberant host response to TB bacilli and/or antigens. Unmasking IRIS refers to the initial clinical manifestations of active TB that occurs soon after ART is started. Paradoxical IRIS refers to the worsening of TB clinical symptoms after ART is started in patients who are receiving TB treatment. Severity of IRIS ranges from mild to severe to life threatening. IRIS has been reported in 8% to more than 40% of patients starting ART after TB is diagnosed, although the incidence depends on the definition of IRIS and the intensity of monitoring. [17][18] Predictors of IRIS include CD4 count <50 cells/mm 3 ; higher on-ART CD4 counts; high pre-ART and lower on-ART HIV viral loads; severity of TB disease, especially high pathogen burden; and less than 30-day interval between initiation of TB and HIV treatments. [19][20][21][22] Most IRIS in HIV/TB disease occurs within 3 months of the start of TB treatment. Delaying initiation of ART for 2 to 8 weeks may reduce the incidence and severity of IRIS. However, this possible advantage of delayed ART must be weighed against the potential benefit of earlier ART in improving immune function and preventing progression of HIV disease and mortality. Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal anti-inflammatory agents. Patients with more severe IRIS can be treated successfully with corticosteroids. A recent randomized, placebo-controlled trial demonstrated benefit of corticosteroids in the management of IRIS symptoms (as measured by decreasing days of hospitalization and Karnofsky performance score) without adverse consequences. 23 In the presence of IRIS, neither TB therapy nor ART should be stopped because both therapies are necessary for the long-term health of the patient (AIII). # Immune Reconstitution with Antiretroviral Therapy: Conversion to Positive Tuberculin Skin Test and Interferon-Gamma Release Assay Immune reconstitution with ART may result in unmasking LTBI (i.e., conversion of a previously negative tuberculin skin test [TST] to a positive TST or a positive interferon-gamma [IFN-γ] release assay [IGRA] for Mycobacterium tuberculosis-specific proteins). A positive IGRA, similar to a positive TST, is indicative of LTBI in the absence of evidence of active TB disease. 24 Because treatment for LTBI is indicated in the absence of evidence of active TB disease, clinicians should be aware of this phenomenon. Patients with a negative TST or IGRA and advanced HIV disease (i.e., CD4 count <200 cells/mm 3 ) should have a repeat TST or IGRA after initiation of ART and CD4 count increase to >200 cells/mm 3 (BII). 25 # Factors Associated with Nonadherence Adherence to ART can be influenced by characteristics of the patient, the regimen, the clinical setting, and the provider/patient relationship. 3 To assure adherence, it is critical that the patient receive and understand information about HIV disease, the goal of therapy, and the specific regimen prescribed. A number of factors have been associated with poor adherence, including the following: • low levels of health literacy 4 or numeracy (ability to understand numerical-related health information); 5 • certain age-related challenges (e.g., polypharmacy, vision loss, cognitive impairment) 6 ; • younger age; • psychosocial issues (e.g., depression, homelessness, low social support, stressful life events, or psychosis); 7 • nondisclosure of HIV serostatus 8 • neurocognitive issues (e.g., cognitive impairment, dementia) • active (but not history of) substance abuse, particularly for patients who have experienced recent relapse; • stigma 9 ; • difficulty with taking medication (e.g., trouble swallowing pills, daily schedule issues); • complex regimens (e.g., high pill burden, high-frequency dosing, food requirements); • adverse drug effects; • nonadherence to clinic appointments 10 • cost and insurance coverage issues; and • treatment fatigue. Adherence studies conducted in the early era of combination ART with unboosted protease inhibitors (PIs) found that virologic failure is much less likely to occur in patients who adhere to more than 95% of their prescribed doses than in those who are less adherent. 11 More recent adherence studies were conducted using boosted PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). These studies suggest that the longer half-lives of boosted PIs and efavirenz may make the drugs more forgiving of lapses in adherence. [12][13] Nonetheless, clinicians should encourage patients to adhere as closely as possible to the prescribed doses and schedules for all ART regimens. # Measurement of Adherence There is no gold standard for the assessment of adherence, 1 but there are many validated tools and strategies to choose from. Although patient self-report of adherence predictably overestimates adherence by as much as 20%, 14 this measure still is associated with viral load responses. 15 Thus, a patient's report of suboptimal adherence is a strong indicator of nonadherence and should be taken seriously. When ascertained in a simple, nonjudgmental, routine, and structured format that normalizes less-thanperfect adherence and minimizes socially desirable responses, patient self-report remains the most useful method for the assessment and longitudinal monitoring of a patient's adherence in the clinical setting. A survey of all doses missed during the past 3 days or the past week accurately reflects longitudinal adherence and is the most practical and readily available tool for adherence assessments in clinical trials and in clinical practice. 1 Other strategies also may be effective. One study found that asking patients to rate their adherence on a six-point scale during 1 month was more accurate than asking them about the frequency of missed doses or to estimate the percentage of doses taken during the previous 3 or 7 days. 16 Pharmacy records and pill counts also can be used in addition to simply asking the patient about adherence. 17 Other methods of assessing adherence include the use of electronic measurement devices (e.g., bottle caps, dispensing systems). However, these methods may not be feasible in some clinical settings. # Interventions to Improve Adherence Before writing the first prescriptions, the clinician should assess the patient's readiness to take medication, including information such as factors that may limit adherence (psychiatric illness, active drug use, etc.) and make additional support necessary; the patient's understanding of the disease and the regimen; and the patient's social support, housing, work and home situation, and daily schedules. During the past several years, a number of advances have simplified many regimens dramatically, particularly those for treatment-naive patients. Prescribing regimens that are simple to take, have a low pill burden and low-frequency dosing, have no food requirements, and have low incidence and severity of adverse effects will facilitate adherence. 18 The Panel considered both regimen simplicity and effectiveness when making current treatment recommendations (see What to Start). Patients should understand that their first regimen usually offers the best chance for a simple regimen that affords long-term treatment success and prevention of drug resistance. Given that effective response to ART is dependent on good adherence, clinicians should identify barriers to adherence such as a patient's schedule, competing psychosocial needs, learning needs, and literacy level before treatment is initiated. As appropriate, resources and strategies that will help the patient to achieve and maintain good adherence should be employed. Individualizing treatment with involvement of the patient in decision making is the cornerstone of any treatment plan. 17 The first principle of successful treatment is negotiation of an understandable plan to which the patient can commit. [19][20] Establishing a trusting relationship over time and maintaining good communication will help to improve adherence and long-term outcomes. An increasing number of interventions have demonstrated efficacy in improving adherence to ART. A metaanalysis of 19 randomized controlled trials of ART adherence interventions found that intervention participants were 1.5 times as likely to report 95% adherence and 1.25 times as likely to achieve an undetectable viral load as participants in comparison conditions. 21 In a more recent synthesis, CDC provides new guidance to assist providers in selecting from among the many possible adherence interventions. 22 Since these reviews have been conducted, additional evidence also has accumulated regarding the efficacy and benefits of motivational interviewing. 23 In summary, effective adherence interventions vary in their modality and duration, providing clinics, providers, and patients with options to suit a range of needs and settings. Some effective interventions identified include multiple nurse home visits, five-session group intervention, pager messaging, and couplesbased interventions. Substance abuse therapy and strengthening social support also can improve adherence. All health care team members, including nurses, nurse practitioners, pharmacists, medication managers, and social workers, have integral roles in successful adherence programs. [24][25][26][27] Directly observed therapy (DOT) has been shown to be effective in provision of ART to active drug users. 28 However, the benefits cannot be sustained after transitioning the drug users out of the methadone clinics and halting the provision of ART by DOT. 29 To routinely determine whether such additional adherence intervention is warranted, assessments should be done at each clinical encounter and should be the responsibility of the entire health care team. Routine monitoring of HIV viral load and pharmacy records are useful determinants for the need of intensified efforts. # Conclusion Significant progress has been made regarding determinants, measurements, and interventions to improve adherence to ART. Given the various assessment strategies and potential interventions available, the challenge for the treatment team is to select the techniques that provide the best fit for the treatment setting, resources available, and patient population. The complexity and the importance of adherence encourage clinicians to continue to seek novel, patient-centered ways to improve adherence and to tailor adherence interventions. Early detection of nonadherence and prompt intervention can reduce greatly the development of viral resistance and the likelihood of virologic failure. accumulation. Avoidance of concomitant use or dose reduction of the affected drug, with close monitoring for dose-related toxicities, may be warranted. # Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Unlike PIs, NNRTIs, EVG, and maraviroc (MVC), NRTIs do not undergo hepatic transformation through the CYP metabolic pathway. Significant pharmacodynamic interactions of NRTIs and other drugs, such as additive bone marrow suppressive effects of zidovudine (ZDV) and ganciclovir, have been reported. Pharmacokinetic (PK) interactions have also been reported; for example, atazanavir (ATV) concentration can be reduced when it is co-administered with TDF. 7 However, the mechanisms underlying some of these interactions are still unclear. Table 15c lists significant interactions with NRTIs. # CCR5 Antagonist MVC is a substrate of CYP3A enzymes and P-glycoprotein. As a consequence, the concentrations of MVC can be significantly increased in the presence of strong CYP3A inhibitors (such as RTV and other PIs, except for TPV/r) and are reduced when MVC is used with CYP3A inducers (such as EFV or rifampin). Dose adjustment is necessary when MVC is used in combination with these agents (see Table 16b or Appendix B, Table 6 for dosage recommendations). MVC is neither an inducer nor an inhibitor of the CYP3A system and does not alter the PKs of the drugs evaluated in interaction studies to date. # Fusion Inhibitor The fusion inhibitor enfuvirtide (T20) is a 36-amino-acid peptide that does not enter human cells. It is expected to undergo catabolism to its constituent amino acids with subsequent recycling of the amino acids in the body pool. No clinically significant drug-drug interaction with T20 has been identified to date. # Pharmacokinetic (PK) Enhancing PK enhancing is a strategy used in ARV treatment to increase the exposure of an ARV by concomitantly administering a drug that inhibits the specific drug metabolizing enzymes for which the ARV is a substrate. Currently two agents are used in clinical practice as PK enhancers: RTV and COBI. RTV is an HIV PI that is primarily used in clinical practice at a lower than approved dose (100 to 400 mg per day) as a PK enhancer for other PIs because of its inhibitory effects on CYP450, predominately CYP3A4 and P-glycoprotein (P-gp). RTV increases the trough concentration (C min ) and prolongs the half-life of the active PIs. 8 The higher C min allows for a greater C min : inhibitory concentration ratio, which reduces the risk that drug resistance will develop as a result of suboptimal drug exposure. The longer half-life of the PI allows for less frequent dosing, which may enhance medication adherence. Because RTV is a potent inhibitor, it may result in complex drug-drug interactions when used with PIs and with other ARVs or non ARVs. Tables 15a and 16a-c list interactions between RTV-containing PI regimens and other medications, as well as comments on the clinical management of these interactions. COBI is a specific, potent CYP3A inhibitor that has a weak to no effect on other CYP450 isoforms. COBI has no ARV activity. The high water solubility of COBI allows for its co-formulation with other agents. 9 COBI is currently available only as part of a fixed dose combination of EVG/COBI/TDF/FTC. COBI is used to increase the plasma concentrations of EVG, an INSTI. Like RTV, COBI has a complex drug-drug interaction profile. COBI also is an inhibitor of P-gp-mediated transport, which appears to be the mechanism by which COBI increases the systemic exposure to TDF. Table 15e lists interactions with COBI identified in PK studies conducted to date, projected interactions, and drugs that should not be co-administered with COBI. When using RTV-or COBI-containing regimens, clinicians should be vigilant in assessing the potential for adverse drug-drug interactions. This is especially important when prescribing CYP3A substrates for which no PK data are available. Despite substantial advances in prevention and treatment of HIV infection in the United States, the rate of new infections has remained stable. [1][2] Although earlier prevention interventions mainly were behavioral, recent data demonstrate the strong impact of antiretroviral therapy (ART) on secondary HIV transmission. The most effective strategy to stem the spread of HIV will probably be a combination of behavioral, biological, and pharmacological interventions. 3 # Prevention Counseling Counseling and related behavioral interventions for those living with HIV infection can reduce behaviors associated with secondary transmission of HIV. Each patient encounter offers the clinician an opportunity to reinforce HIV prevention messages, but multiple studies show that prevention counseling is frequently neglected in clinical practice. [4][5] Although delivering effective prevention interventions in a busy practice setting may be challenging, clinicians should be aware that patients often look to their providers for messages about HIV prevention. Multiple approaches to prevention counseling are available, including formal guidance from the Centers for Disease Control and Prevention (CDC) for incorporating HIV prevention into medical care settings. Such interventions have been demonstrated to be effective in changing sexual risk behavior [6][7][8] and can reinforce self-directed behavior change early after diagnosis. 9 CDC has identified several prevention interventions for individuals infected with HIV that meet stringent criteria for efficacy and scientific rigor (http://www.cdc.gov/hiv/topics/research/prs/index.htm). The following three interventions have proven effective in treatment settings and can be delivered by providers as brief messages during clinic visits: • Partnership for Health (http://effectiveinterventions.org/en/Interventions/PfH.aspx), • Options (http://www.cdc.gov/hiv/topics/research/prs/resources/factsheets/options.htm), • Positive Choice (http://www.cdc.gov/hiv/topics/research/prs/resources/factsheets/positive-choice.htm). In addition, CDC's "Prevention Is Care" campaign (http://www.actagainstaids.org/provider/pic/index.html) helps providers (and members of a multidisciplinary care team) integrate simple methods to prevent transmission by HIV-infected individuals into routine care. These prevention interventions are designed to reduce the risk of secondary HIV transmission through sexual contact. The interventions are designed generally for implementation at the community or group level, but some can be adapted and administered in clinical settings by a multidisciplinary care team. # Need for Screening for High-Risk Behaviors The primary care visit provides an opportunity to screen patients for ongoing high-risk drug and sexual behaviors for transmitting HIV infection. Routine screening and symptom-directed testing for and treatment of sexually transmitted diseases (STDs), as recommended by CDC, 10 remain essential adjuncts to prevention counseling. Genital ulcers may facilitate HIV transmission and STDs may increase HIV viral load in plasma and genital secretions. 7,[11][12][13] They also provide objective evidence of unprotected sexual activity, which should prompt prevention counseling. The contribution of substance and alcohol use to HIV risk behaviors and transmission has been well established in multiple populations; [14][15][16][17][18] therefore, effective counseling for injection and noninjection drug users is essential to prevent HIV transmission. Identifying the substance(s) of use is important because HIV prevalence, transmission risk, risk behaviors, transmission rates, and potential for pharmacologic intervention all vary according to the type of substance used. [19][20][21] Risk-reduction strategies for injection drug users (IDUs), in addition to condom use, include needle exchange and instructions on cleaning drug paraphernalia. Evidence supporting the efficacy of interventions to reduce injection drug use risk behavior also exists. Interventions include both behavioral strategies [14][15]22 and opiate substitution treatment with methadone or buprenorphine. [23][24] No successful pharmacologic interventions have been found for cocaine and methamphetamine users; cognitive and behavioral interventions demonstrate the greatest effect on reducing the risk behaviors of these users. [25][26][27] Given the significant impact of cocaine and methamphetamine on sexual risk behavior, reinforcement of sexual risk-reduction strategies is important. [14][15][16][17][18]28 Antiretroviral Therapy as Prevention ART can play an important role in preventing HIV transmission. Lower levels of plasma HIV RNA have been associated with decreases in the concentration of virus in genital secretions. [29][30][31][32] Observational studies have demonstrated the association between low serum or genital HIV RNA and a decreased rate of HIV transmission among serodiscordant heterosexual couples. 29,[33][34] Ecological studies of communities with relatively high concentrations of men who have sex with men (MSM) and IDUs suggest increased use of ART is associated with decreased community viral load and reduced rates of new HIV diagnoses. [35][36][37] These data suggest that the risk of HIV transmission is low when an individual's viral load is below 400 copies/mL, 35,38 but the threshold below which transmission of the virus becomes impossible is unknown. Furthermore, to be effective at preventing transmission it is assumed that: (1) ART is capable of durably and continuously suppressing viremia; (2) adherence to an effective ARV regimen is high; and (3) there is an absence of a concomitant STD. Importantly, detection of HIV RNA in genital secretions has been documented in individuals with controlled plasma HIV RNA and data describing a differential in concentration of most ARV drugs in the blood and genital compartments exist. 30,39 At least one case of HIV transmission from a patient with suppressed plasma viral load to a monogamous uninfected sexual partner has been reported. 40 In the HPTN 052 trial in HIV-discordant couples, the HIV-infected partners who were ART naive and had CD4 counts between 350 and 550 cells/mm 3 were randomized to initiate or delay ART. In this study, those who initiated ART had a 96% reduction in HIV transmission to the uninfected partners. 3 Almost all of the participants were in heterosexual relationships, all participants received risk-reduction counseling, and the absolute number of transmission events was low: 1 among ART initiators and 27 among ART delayers. Over the course of the study virologic failure rates were less than 5%, a value much lower than generally seen in individuals taking ART for their own health. These low virologic failure rates suggest high levels of adherence to ART in the study, which may have been facilitated by the frequency of study follow-up (study visits were monthly) and by participants' sense of obligation to protect their uninfected partners. Therefore, caution is indicated when interpreting the extent to which ART for the HIV-infected partner protects seronegative partners in contexts where adherence and, thus, rates of continuous viral suppression, may be lower. Furthermore, for HIV-infected MSM and IDUs, biological and observational data suggest suppressive ART also should protect against transmission, but the actual extent of protection has not been established. Rates of HIV risk behaviors can increase coincidently with the availability of potent combination ART, in some cases almost doubling compared with rates in the era prior to highly effective therapy. 9 A meta-analysis demonstrated that the prevalence of unprotected sex acts was increased in HIV-infected individuals who believed that receiving ART or having a suppressed viral load protected against transmitting HIV. 41 Attitudinal shifts away from safer sexual practices since the availability of potent ART underscore the role of provider-initiated HIV prevention counseling. With wider recognition that effective treatment decreases the risk of HIV transmission, it is particularly important for providers to help patients understand that a sustained viral load below the limits of detection will dramatically reduce but does not absolutely assure the absence of HIV in the genital and blood compartments and, hence, the inability to transmit HIV to others. [41][42] Maximal suppression of viremia not only depends on the potency of the ARV regimen used but also on the patient's adherence to prescribed therapy. Suboptimal adherence can lead to viremia that not only harms the patient but also increases his/her risk of transmitting HIV (including drug-resistant strains) via sex or needle sharing. Screening for and treating behavioral conditions that can impact adherence, such as depression and alcohol and substance use, improve overall health and reduce the risk of secondary transmission. # Summary Consistent and effective use of ART resulting in a sustained reduction in viral load in conjunction with consistent condom usage, safer sex and drug use practices, and detection and treatment of STDs are essential tools for prevention of sexual and blood-borne transmission of HIV. Given these important considerations, medical visits provide a vital opportunity to reinforce HIV prevention messages, discuss sex-and drugrelated risk behaviors, diagnose and treat intercurrent STDs, review the importance of medication adherence, and foster open communication between provider and patient. # Duration of Therapy for Early HIV Infection The optimal duration of therapy for patients with early HIV infection is unknown. Recent studies of early HIV infection have evaluated the potential for starting and then stopping treatment. [18][19][20] Although these studies showed some benefits associated with this strategy, a large randomized controlled trial of patients with chronic HIV infection found that treatment interruption was harmful in terms of increased risk of AIDS and non-AIDS events, 35 and that the strategy was associated with increased markers of inflammation, immune activation and coagulation. 36 For these reasons and because of the potential benefit of ART in reducing the risk of HIV transmission, the Panel recommends against discontinuation of ART in patients treated for early HIV infection (AIII). This section provides discussion of some basic principles and unique considerations to follow when caring for HIV-infected women, including during pregnancy. Clinicians who provide care for pregnant women should consult the current Perinatal Guidelines 1 for more in-depth discussion and management assistance. Additional guidance on the management of HIV-infected women can be found at http://hab.hrsa.gov/deliverhivaidscare/clinicalguide11. # Gender Considerations in Antiretroviral Therapy In general, studies to date have not shown gender differences in virologic responses to antritretroviral therapy (ART), [2][3][4] but a number of studies have suggested that gender may influence the frequency, presentation, and severity of selected antiretroviral (ARV)-related adverse events. 5 Although data are limited, evidence also exists that pharmacokinetics for some ARV drugs may differ between men and women, possibly because of variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter function, and excretion activity. [6][7][8] Adverse Effects: • Nevirapine (NVP)-associated hepatotoxicity: NVP has been associated with an increased risk of symptomatic, potentially fatal, and often rash-associated liver toxicity in ARV-naive individuals; women with higher CD4 counts (>250 cells/mm 3 ) or elevated baseline transaminase levels appear to be at # Panel's Recommendations • The indications for initiation of antiretroviral therapy (ART) and the goals of treatment are the same for HIV-infected women as for other HIV-infected adults and adolescents (AI). • Women taking antiretroviral (ARV) drugs that have significant pharmacokinetic interactions with oral contraceptives should use an additional or alternative contraceptive method to prevent unintended pregnancy (AIII). • In pregnant women, an additional goal of therapy is prevention of perinatal transmission of HIV, with a goal of maximal viral suppression to reduce the risk of transmission of HIV to the fetus and newborn (AI). • When selecting an ARV combination regimen for a pregnant woman, clinicians should consider the known safety, efficacy, and pharmacokinetic data on use during pregnancy for each agent (AIII). • Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz (EFV) and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-based regimens (AIII). • Alternative regimens that do not include EFV should be strongly considered in women who are planning to become pregnant or sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the woman's health (BIII). • Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, EFV can be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII). • When designing a regimen for a pregnant woman, clinicians should consult the most current Health and Human Services (HHS) Perinatal Guidelines (AIII). Approximately 5%-10% of HIV-infected persons also have chronic HBV infection, defined as testing positive for HBsAg for more than 6 months. 1 The progression of chronic HBV to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma is more rapid in HIV-infected persons than in persons with chronic HBV alone. 2 Conversely, chronic HBV does not substantially alter the progression of HIV infection and does not influence HIV suppression or CD4 cell responses following ART initiation. [3][4] However, several liverassociated complications that are ascribed to flares in HBV activity, discontinuation of dually active ARVs, or toxicity of ARVs can affect the treatment of HIV in patients with HBV coinfection. [5][6][7] These include the following: # Rating of Recommendations • FTC, 3TC, and TDF are approved ARVs that also have antiviral activity against HBV. Discontinuation of these drugs may potentially cause serious hepatocellular damage resulting from reactivation of HBV. 8 • Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when used in HIV/HBV-coinfected patients (AII). 9 • 3TC-resistant HBV is observed in approximately 40% of patients after 2 years on 3TC for chronic HBV and in approximately 90% of patients after 4 years when 3TC is used as the only active drug for HBV in # Panel's Recommendations • Prior to initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) DNA using a quantitative assay to determine the level of HBV replication (AIII). • Because emtricitabine (FTC), lamivudine (3TC), and tenofovir (TDF) have activity against both HIV and HBV, if HBV or HIV treatment is needed, ART should be initiated with the combination of TDF + FTC or TDF + 3TC as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) regimen (AI). • If HBV treatment is needed and TDF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen (BI). Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC or telbivudine in addition to a fully suppressive ARV regimen (BII). • Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when used in HIV/HBV-coinfected patients (AII). • Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV; patients should be advised against self-discontinuation and carefully monitored during interruptions in HBV treatment (AII). • If ART needs to be modified due to HIV virologic failure and the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). # Rating of Recommendations # 2012) Approximately one-third of patients with chronic hepatitis C virus (HCV) infection progress to cirrhosis at a median time of less than 20 years. 1,2 The rate of progression increases with older age, alcoholism, male sex, and HIV infection. [3][4][5][6] In a meta-analysis, individuals coinfected with HIV/HCV were found to have three times greater risk of progression to cirrhosis or decompensated liver disease than were HCV-monoinfected patients. 5 This accelerated rate is magnified in HIV/HCV-coinfected patients with low CD4 counts. Although ART appears to slow the rate of HCV disease progression in HIV/HCV-coinfected patients, several studies have demonstrated that the rate continues to exceed that observed in those without HIV infection. 7,8 Whether HCV infection accelerates HIV progression, as measured by AIDS-related opportunistic infections (OIs) or death, 9 is unclear. If such an increased risk of HIV progression exists, it may reflect the impact of injection drug use, which is strongly linked to HCV infection. 10,11 The increased frequency of antiretroviral (ARV)associated hepatotoxicity with chronic HCV infection also complicates HIV treatment. 12,13 A combination regimen of peginterferon and ribavirin (PegIFN/RBV) has been the mainstay of treatment for HCV infection. In HCV genotype 1-infected patients without HIV, addition of an HCV NS3/4A protease inhibitor (PI) boceprevir or telaprevir to PegIFN/RBV significantly improves the rate of sustained virologic response (SVR). 14,15 Clinical trials of these HCV PIs in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients are currently under way. Both boceprevir and telaprevir are substrates and inhibitors of cytochrome P (CYP) 3A4/5 and p-glycoprotein (p-gp); boceprevir is also metabolized by aldo-keto reductase. These drugs have significant interactions with certain ARV drugs that are metabolized by the same pathways. As such, the presence of HCV infection and the treatment of HCV may influence HIV treatment as discussed below. # Assessment of HIV/Hepatitis C Virus Coinfection Before Initiation of Antiretroviral Therapy • All HIV-infected patients should be screened for HCV infection using sensitive immunoassays licensed for detection of antibody to HCV in blood. 16 HCV-seronegative patients at risk for the acquistion of HCV # Key Considerations When Managing Patients Coinfected with HIV and Hepatitis C Virus • All HIV-infected patients should be screened for hepatitis C virus (HCV) infection, preferably before starting antiretroviral therapy (ART). • ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. For most HIV/HCV-coinfected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury (DILI). Therefore, ART should be considered for HIV/HCV-coinfected patients, regardless of CD4 count (BII). • Initial ART combination regimens for most HIV/HCV-coinfected patients are the same as those for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, consideration of potential drug-drug interactions and overlapping toxicities should guide ART regimen selection or modification (see discussion in the text). • Combined treatment of HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be initiated for most HIV/HCV-coinfected patients regardless of CD4 cell count, in ARTnaive patients with CD4 counts >500 cells/mm 3 some clinicians may choose to defer ART until completion of HCV treatment. • In patients with lower CD4 counts (e.g., <200 cells/mm 3 ), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of ART. • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored at 1 month after initiation of ART and then every 3 to 6 months. Mild to moderate fluctuations in ALT and/or AST are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease these fluctuations do not require interruption of ART. Significant ALT and/or AST elevation should prompt careful evaluation for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, or alcoholic hepatitis); short-term interruption of the ART regimen or of the specific drug suspected to be responsible for the DILI may be required. 34 # Rating of Recommendations # Treating Both HIV and Hepatitis C Virus Infection Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of HCV disease stage. Some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment. # Considerations for using certain nucleoside reverse transcriptase inhibitors and hepatitis C virus treatments: • ddI should not be given with RBV because of the potential for drug-drug interactions leading to lifethreatening ddI-associated mitochondrial toxicity including hepatomegaly/steatosis, pancreatitis, and lactic acidosis (AII). 35 • Combined use of ZDV and RBV is associated with increased rates of anemia, making RBV dose reduction necessary. Therefore, this combination should be avoided when possible. 36 Because the risk of anemia may further increase when boceprevir or telaprevir is combined with PegIFN/RBV, ZDV should not be given with this combination (AIII). • Abacavir (ABC) has been associated with decreased response to PegIFN/RBV in some, but not all, retrospective studies; current evidence is insufficient to recommend avoiding this combination. [37][38][39] # Considerations for the use of HCV NS3/4A protease inhibitors (boceprevir or telaprevir) and antiretroviral therapy: • Boceprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. After 4 weeks of PegIFN/RBV therapy, boceprevir is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy. Data on the use of an HCV regimen containing boceprevir together with ART in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with boceprevir plus PegIFN/RBV (64 patients) than with PegIFN/RBV alone (34 patients). In this study, patients received ART that included HIV-1 ritonavir-boosted atazanavir (ATV/r), darunavir (DRV/r), or lopinavir (LPV/r) or raltegravir (RAL) plus dual NRTIs. 40 Boceprevir is primarily metabolized by aldo-keto reductase, but because the drug is also a substrate and inhibitor of CYP3A4/5 and p-gp enzymes, it may interact with ARVs metabolized by these pathways. Based on drug interaction studies in healthy volunteers, boceprevir can be co-administered with RAL. 41 However, co-administration of boceprevir with ATV/r, DRV/r, LPV/r, or efavirenz (EFV) is not recommended because of bidirectional drug interactions (see Table 15a and 15b). 42,43 Importantly, the pharmacokinetic (PK) interactions of HIV PIs with boceprevir were not identified before the approval of boceprevir and before participant enrollment in the HIV/HCV-coinfection trial; consequently, some # Treatment of Active Tuberculosis in HIV-Infected Patients HIV infection significantly increases the risk of progression from latent to active TB disease. The CD4 cell count influences both the frequency and severity of active TB disease. [1][2] Active TB also negatively affects # Panel's Recommendations • The principles for treatment of active tuberculosis (TB) disease in HIV-infected patients are the same as those for HIV-uninfected patients (AI). • All HIV-infected patients with diagnosed active TB should be started on TB treatment immediately (AI). • All HIV-infected patients with diagnosed active TB should be treated with antiretroviral therapy (ART) (AI). • In patients with CD4 counts <50 cells/mm 3 , ART should be initiated within 2 weeks of starting TB treatment (AI). • In patients with CD4 counts ≥50 cells/mm 3 who present with clinical disease of major severity as indicated by clinical evaluation (including low Karnofsky score, low body mass index [BMI], low hemoglobin, low albumin, organ system dysfunction, or extent of disease), ART should be initiated within 2 to 4 weeks of starting TB treatment. The strength of this recommendation varies on the basis of CD4 cell count: • CD4 count 50 to 200 cells/mm 3 (BI) • CD4 count >200 cells/mm 3 (BIII) • In patients with CD4 counts ≥50 cells/mm 3 who do not have severe clinical disease, ART can be delayed beyond 2 to 4 weeks of starting TB therapy but should be started within 8 to 12 weeks of TB therapy initiation. The strength of this recommendation also varies on the basis of CD4 cell count: • CD4 count 50 to 500 cells/mm 3 (AI) • CD4 count >500 cells/mm 3 (BIII) • In all HIV-infected pregnant women with active TB, ART should be started as early as feasible, both for maternal health and for prevention of mother-to-child transmission (PMTCT) of HIV (AIII). • In HIV-infected patients with documented multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, ART should be initiated within 2 to 4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy (BIII). • Despite pharmacokinetic drug interactions, a rifamycin (rifampin or rifabutin) should be included in TB regimens for patients receiving ART, with dosage adjustment if necessary (AII). • Rifabutin is the preferred rifamycin to use in HIV-infected patients with active TB disease on a protease inhibitor (PI)-based regimen because the risk of substantial drug interactions with PIs is lower with rifabutin than with rifampin (AII). • Co-administration of rifampin and PIs (with or without ritonavir [RTV] boosting) is not recommended (AII). • Rifapentine (RPT) is NOT recommended in HIV-infected patients receiving ART for treatment of latent TB infection (LTBI) or active TB, unless in the context of a clinical trial (AIII). • Immune reconstitution inflammatory syndrome (IRIS) may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII). • Treatment support, which can include directly observed therapy (DOT) of TB treatment, is strongly recommended for HIV-infected patients with active TB disease (AII). # Rating of Recommendations # Caring for Patients with HIV and Tuberculosis Close collaboration among clinicians, health care institutions, and public health programs involved in the diagnosis and treatment of HIV-infected patients with active TB disease is necessary in order to integrate care and improve medication adherence and TB treatment completion rates, reduce drug toxicities, and maximize HIV outcomes. HIV-infected patients with active TB disease should receive treatment support, including adherence counseling and DOT, corresponding to their needs (AII). ART simplification or use of coformulated fixed-dose combinations also may help to improve drug adherence. # Strategies Examples Use a multidisciplinary team approach Provide an accessible, trusting health care team Adverse effects have been reported with use of all antiretroviral (ARV) drugs; they are among the most common reasons for switching or discontinuing therapy and for medication nonadherence. 1 However, with the use of newer ARV regimens, rates of treatment-limiting adverse events in antiretroviral therapy (ART)naive patients enrolled in randomized trials appear to be declining and are generally now occurring in less than 10% of study participants. However, because most clinical trials have a relatively short follow-up duration, the longer term complications of ART can be underestimated. In the Swiss Cohort study, during 6 years of follow-up, the presence of laboratory adverse events was associated with higher rates of mortality, which highlights the importance of adverse events in overall patient management. 2 Several factors may predispose individuals to adverse effects of ARV medications. For example, compared with men, women (especially ART-naive women with CD4 counts >250 cells/mm 3 ) seem to have a higher propensity to develop Stevens-Johnson syndrome, rashes, and hepatotoxicity from nevirapine (NVP) [3][4][5] and have higher rates of lactic acidosis due to nucleoside reverse transcriptase inhibitors (NRTIs). [6][7][8] Other factors may also contribute to the development of adverse events: • Concomitant use of medications with overlapping and additive toxicities; • Comorbid conditions that may increase the risk of or exacerbate adverse effects (e.g., alcoholism 9 or coinfection with viral hepatitis [10][11][12] may increase the risk of hepatotoxicity); • Drug-drug interactions that may lead to an increase in drug toxicities (e.g., interactions that result from concomitant use of statins with protease inhibitors [PIs]); or • Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction (HSR). 13,14 The therapeutic goals of ART include achieving and maintaining viral suppression and improving immune function, but an overarching goal should be to select a regimen that is not only effective but also safe. This requires consideration of the toxicity potential of an ARV regimen, as well as the individual patient's underlying conditions, concomitant medications, and prior history of drug intolerances. In addition, it should be appreciated that, in general, the overall benefits of ART outweigh its risks and that some conditions (e.g., anemia, cardiovascular disease [CVD], renal impairment), may be more likely in the absence of ART. 15,16 Information on adverse events of ARVs is outlined in several tables in the guidelines. Table 13 provides clinicians with a list of the most common and/or severe known ARV-associated adverse events by drug class. The most common adverse effects of individual ARV agents are summarized in Appendix B, Tables 1-6. # NVP > other NNRTIs # NVP: • Severe hepatic toxicity with NVP is often associated with skin rash or symptoms of hypersensitivity. • In ARV-naive patients, risk is greater for women with pre-NVP CD4 count >250 cells/mm 3 and men with pre-NVP CD4 count >400 cells/mm 3 . Overall risk is higher for women than men. • Risk is greatest in the first few months of treatment. • 2-week dose escalation of NVP reduces risk of rash and possibly hepatotoxicity if related to hypersensitivity. • NVP is contraindicated in patients with moderate to severe hepatic insufficiency (Child-Pugh classification B or C). • Liver failure observed in HIV-uninfected individuals receiving NVP for postexposure prophylaxis. NVP should never be used for this indication. All PIs: Drug-induced hepatitis and hepatic decompensation (and rare cases of fatalities) have been reported with all PIs to varying degrees. The frequency of hepatic events is higher with TPV/r than with other PIs. • Symptoms worsen with continuation of ABC. • Median onset of reactions is 9 days; approximately 90% of reactions occur within the first 6 weeks of treatment. • The onset of re-challenge reactions is within hours of re-challenge dose • Patients, regardless of HLA-B*5701 status, should not be re-challenged with ABC if HSR is suspected. # NVP: • Hypersensitivity syndrome of hepatic toxicity and rash that may be accompanied by fever, general malaise, fatigue, myalgias, arthralgias, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. • In ARV-naive patients, risk is greater for women with pre-NVP CD4 count >250 cells/mm 3 and men with pre-NVP CD4 count >400 cells/mm 3 . Overall, risk is higher for women than men. • 2-week dose escalation of NVP reduces risk. # Overview Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an antiretroviral (ARV) regimen. A thorough review of concomitant medications can help in designing a regimen that minimizes undesirable interactions. In addition, the potential for drug interactions should be assessed when any new drug (including over-the-counter agents), is added to an existing ARV combination. Most drug interactions with ARV drugs are mediated through inhibition or induction of hepatic drug metabolism. 1 The mechanisms of drug interactions with each ARV drug class are briefly summarized below. Tables 14-16c list significant drug interactions with different ARV agents and recommendations on contraindications, dose modifications, and alternative agents. # Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) All NNRTIs are metabolized in the liver by cytochrome P450 (CYP) 3A isoenzymes. In addition, efavirenz # Protease Inhibitors (PIs) All PIs are metabolized in the liver by CYP3A isoenzymes; consequently their metabolic rates may be altered in the presence of CYP inducers or inhibitors. Co-administration of PIs with ritonavir (RTV), a potent CYP3A inhibitor, intentionally increases PI exposure (see Pharmacokinetic Enhancing below). Coadministration of PIs with a potent CYP3A inducer may lead to suboptimal drug concentrations and reduced therapeutic effects of the PI. These drug combinations should be avoided if alternative agents can be used. If this is not possible, close monitoring of plasma HIV RNA, with or without ARV dosage adjustment and therapeutic drug monitoring (TDM), may be warranted. For example, the rifamycins (i.e., rifampin and, to a lesser extent, rifabutin) are CYP3A4 inducers that can significantly reduce plasma concentrations of most PIs. 2,3 Rifabutin is a less potent CYP3A4 inducer than rifampin. Therefore, despite wider experience with rifampin use, rifabutin is generally considered a reasonable alternative to rifampin for the treatment of tuberculosis when used with a PI-based regimen. 4,5 Some PIs may also induce or inhibit CYP isoenzymes, P-glycoprotein, or other transporters in the gut and elsewhere. Tipranavir (TPV), for example, is a potent inducer of CYP3A4 and P-glycoprotein. The net effect of ritonavir-boosted tipranavir (TPV/r) on CYP3A in vivo, however, appears to be enzyme inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are most likely to be increased if the drugs are given with TPV/r. The net effect of TPV/r on a drug that is a substrate of both CYP3A and P-glycoprotein (Pgp) cannot be confidently predicted. Significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir (LPV) concentrations have been observed in vivo when the PIs were given with TPV/r. The use of a CYP3A substrate that has a narrow margin of safety in the presence of a potent CYP3A inhibitor, such as the PIs, may lead to markedly prolonged elimination half-life (t 1/2 ) and toxic drug b Certain listed drugs are contraindicated on the basis of theoretical considerations. Thus, drugs with narrow therapeutic indices and suspected metabolic involvement with CYP450 3A, 2D6, or unknown pathways are included in this table. Actual interactions may or may not occur in patients. c HIV-infected patients treated with rifapentine have a higher rate of tuberculosis (TB) relapse than those treated with other rifamycin-based regimens. Therefore an alternative agent to rifapentine is recommended. d A high rate of Grade 4 serum transaminase elevation was seen when a higher dose of RTV was added to LPV/r or SQV or when double-dose LPV/r was used with rifampin to compensate for rifampin's induction effect and therefore, these dosing strategies should not be used. e The manufacturer of cisapride has a limited-access protocol for patients who meet specific clinical eligibility criteria. f Use of oral midazolam is contraindicated. Parenteral midazolam can be used with caution as a single dose and can be given in a monitored situation for procedural sedation. # Suggested alternatives to: • Lovastatin, simvastatin: Fluvastatin, pitavastatin, and pravastatin (except for pravastatin with DRV/r) have the least potential for drug-drug interactions (see Table 15a). Use atorvastatin and rosuvastatin with caution; start with the lowest possible dose and titrate based on tolerance and lipid-lowering efficacy. • Rifampin: Rifabutin (with dosage adjustment, see Tables 15a and 15b # H2 Receptor Antagonists # RTV-boosted PIs ATV/r ↓ ATV H2 receptor antagonist dose should not exceed a dose equivalent to famotidine 40 mg BID in ART-naive patients or 20 mg BID in ART-experienced patients. Give ATV 300 mg + RTV 100 mg simultaneously with and/or ≥10 hours after the H2 receptor antagonist. If using TDF and H2 receptor antagonist in ART-experienced patients, use ATV 400 mg + RTV 100 mg. DRV/r, LPV/r No significant effect No dosage adjustment necessary. # PIs without RTV ATV ↓ ATV H2 receptor antagonist single dose should not exceed a dose equivalent of famotidine 20 mg or total daily dose equivalent of famotidine 20 mg BID in ART-naive patients. Give ATV at least 2 hours before and at least 10 hours after the H2 receptor antagonist. c Norbuprenorphine is an active metabolite of buprenorphine. No dosage recommendation. Consider alternative drug for malaria prophylaxis, if possible. a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 to 150 mg per dose. b Norbuprenorphine is an active metabolite of buprenorphine. c R-methadone is the active form of methadone. For treatment of gout flares: Colchicine 0.6 mg x 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days. # Key to For prophylaxis of gout flares: If original regimen was colchicine 0.6 mg BID, the regimen should be decreased to 0.3 mg once daily. If regimen was 0.6 mg once daily, the regimen should be decreased to 0.3 mg every other day. For treatment of familial Mediterranean fever: Do not exceed colchicine 0.6 mg once daily or 0.3 mg BID. # Salmeterol EVG/COBI/TDF/FTC ↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular events. # Concomitant Drug Class/Name Integrase Inhibitor # Dosing Recommendations and Clinical Comments Effect on Integrase Inhibitor or Concomitant Drug Concentrations # Miscellaneous Interactions Key to Abbreviations: AUC = area under the curve, BID = twice daily, CCB = calcium channel blocker, COBI = cobicistat, C max = maximum plasma concentration, C min = minimum plasma concentration, EVG = elvitegravir, PAH = pulmonary arterial hypertension, RAL = raltegravir a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 mg to 150 mg per dose. b Based on between-study comparison. c Use a combination of two LPV/r 200 mg/50 mg tablets + one LPV/r 100 mg/25 mg tablet to make a total dose of LPV/r 500 mg/125 mg. The Panel has carefully reviewed recent results from clinical trials in HIV therapy and considered how they inform appropriate care guidelines. The Panel appreciates that HIV care is highly complex and rapidly evolving. Guidelines are never fixed and must always be individualized. Where possible, the Panel has based recommendations on the best evidence from prospective trials with defined endpoints. When such evidence # Key to Abbreviations does not yet exist, the Panel attempted to reflect reasonable options in its conclusions. HIV care requires, as always, partnerships and open communication. The provider can make recommendations most likely to lead to positive outcomes only if the patient's own point of view and social context are well known. Guidelines are only a starting point for medical decision making. They can identify some of the boundaries of high-quality care but cannot substitute for sound judgment. As further research is conducted and reported, guidelines will be modified. The Panel anticipates continued progress in the simplicity of regimens, improved potency and barrier to resistance, and reduced toxicity. The Panel hopes the guidelines are useful and is committed to their continued adjustment and improvement. See the reference section following Table 7 for creatinine clearance (CrCl) calculation formulas and criteria for Child-Pugh classification. Child-Pugh Score # Key to # SWP a a SWP = Suggested Wholesale Price (source: AmerisourceBergen, accessed December 2012/January 2013) Note that this price may not represent the pharmacy acquisition price or the price paid by consumers. b Should be used in combination with ritonavir. Please refer to Appendix B, Table 3	None	None
fb8089805e155c5dc7dcfba090aadcb8bbe2d5cf	cdc	None	Address all inquiries about the MMWR Series, including material to be considered for publication, to Editor,# Disclosure of Relationship CDC, our planners, and our content experts wish to disclose that they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This report includes discussion of the off-label use of bedaquiline in the following situations: - use in special populations: -children (aged 0-17 years), -elderly persons (aged ≥65 years), -HIV-infected persons, -pregnant women, -persons with extrapulmonary tuberculosis (TB), -patients with comorbid conditions on concomitant medications (e.g., underlying renal, hepatic, cardiac, respiratory conditions, diabetes, or other immunocompromised state), and -any other population in which use of the drug has not been studied; - use for >24 weeks in any patient; - use at any time during treatment for multidrug-resistant (MDR) TB (not just at the initiation of MDR TB treatment); and - use in MDR TB relapse or treatment failure. # Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis Prepared by Sundari Mase, MD Terence Chorba, MD Philip Lobue, MD Kenneth Castro, MD Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC # Summary Multidrug-resistant tuberculosis (MDR TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500) (Cox EM. FDA accelerated approval letter to Janssen Research and Development. Available at 2/204384Orig1s000ltr.pdf ). This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR TB who were not included in the clinical trials for the drug. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals who might use bedaquiline for the treatment of MDR TB for indicated and off-label uses. Aspects of these guidelines are not identical to current FDA-approved labeling for bedaquiline. Bedaquiline should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB (Food and Drug Administration. SIRTURO tablets label. Available at / label/2012/204384s000lbl.pdf). Use of the drug also can be considered for individual patients in other categories (e.g., persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions) when treatment options are limited. However, further study is required before routine use of bedaquiline can be recommended in these populations. A registry for persons treated with bedaquiline is being implemented by Janssen Therapeutics to track patient outcomes, adverse reactions, laboratory testing results (e.g., diagnosis, drug susceptibility, and development of drug resistance), use of concomitant medications, and presence of other comorbid conditions. Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported to Janssen Therapeutics at telephone 1-800-526-7736, to FDA at telephone 1-800-332-1088 or at . gov/medwatch, and to CDC's Emergency Operations Center at telephone 1-770-488-7100. # Introduction Tuberculosis (TB) is caused by the bacteria of the Mycobacterium tuberculosis complex, most commonly M. tuberculosis. TB usually is transmitted from one person to another by airborne droplet nuclei containing the bacteria. For most persons who have drug-susceptible TB, cure is achieved with a combination of first-line drugs (e.g., isoniazid , rifampin , ethambutol , and pyrazinamide ) administered as a 6-month standard regimen. In contrast, multidrug-resistant tuberculosis (MDR TB), defined as TB that is caused by M. tuberculosis resistant to at least INH and RIF, generally requires 18-24 months of treatment after sputum culture conversion (SCC) with five or six drugs (e.g., susceptible first-line drugs plus an injectable agent, a fluoroquinolone, and other second-line drugs as needed) that are less effective, more toxic, and more costly than a standard first-line regimen (1,2). MDR TB impacts communities worldwide and poses an urgent public health threat that transcends borders. In 2011, an estimated 630,000 cases of MDR TB (range: 460,000-790,000) occurred among the world's 12 million persons with prevalent cases of TB. An estimated 3.7% of persons with newly diagnosed TB and 20% of persons with previously treated TB have MDR TB. Extensively drug-resistant tuberculosis (XDR TB), defined as MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, amikacin, or capreomycin), has been reported in 84 countries; on average, 9% of persons with MDR TB have additional resistance qualifying as XDR TB. India and China contribute the greatest numbers of MDR TB cases to the global burden, but the Russian Federation has the highest MDR TB rates per 100,000 population (3,4). Compared with drug-susceptible TB, MDR TB causes greater morbidity and mortality, and overall patient outcomes are worse (i.e., death, relapse , treatment failure , or disability). Mortality rates for patients being treated for MDR-TB usually exceed 10% (range: 8%-21%) (5). A recently published individual patient data meta-analysis of 9,153 patients with MDR TB yielded a mortality rate of 15% (6). MDR TB develops when TB that is susceptible to first-line drugs is not treated adequately because of the selection of substandard treatment regimens or nonadherence with (or interruption in) treatment. Other factors (e.g., malabsorption of drugs or drug-drug interactions) also can lead to the selection of drug-resistant strains (2). Once drug-resistant TB has developed, person-to-person transmission is possible, potentially leading to outbreaks (7). MDR TB must be rapidly diagnosed and treated with an effective drug regimen to prevent further transmission of these difficult-to-cure strains of TB. One of the challenges in the treatment of MDR TB is the lack of effective, well-tolerated medications. There are very few medications and fewer classes of medications for treatment of MDR TB, and adverse drug reactions commonly necessitate discontinuing medications (2). On December 28, 2012, the Food and Drug Administration (FDA) approved the use of bedaquiline fumarate (Sirturo or bedaquiline) as part of combination therapy (minimum fourdrug therapy) administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB when an effective treatment regimen cannot otherwise be provided (e.g., because of extensive resistance, drug intolerance, or drug-drug interactions) (8). The recommended dose of bedaquiline for the treatment of pulmonary MDR TB in adults is 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally three times weekly, for an entire treatment duration of 24 weeks. Bedaquiline is taken with food and in combination with other anti-TB drugs. The drug is available in 100 mg tablets (9,10). FDA approves drug products for lawful marketing for specific intended uses based on data that establish safety and efficacy, and approves labeling specific to those uses. FDA approved bedaquline as part of combination therapy to treat adults with pulmonary MDR TB when other alternatives are not available. The drug was approved under FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (11). FDA approved bedaquiline with a black box warning alerting health-care professionals to an increase in all-cause mortality and to a prolongation of the QTcF- in patients treated with bedaquiline versus placebo. Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M. tuberculosis that has been approved by FDA since 1971 (12). FDA considered this new drug under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500) (11). Bedaquiline uses adenosine 5'-triphosphate (ATP) synthase inhibition as its mechanism of action, has in vitro activity against - The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias and a risk factor for sudden death. The QT interval is dependent on the heart rate and may be corrected by calculation to improve the detection of patients at increased risk of ventricular arrhythmia. One of several calculation correction formulas focuses on the QT interval divided by cube-root of RR (QTcF), where RR is the interval from the onset of one QRS complex (the graphical deflections seen on an electrocardiogram that correspond to the depolarization of the right and left ventricle with each heart beat) to the onset of the next QRS complex, measured in milliseconds. both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of TB infection. No cross-resistance was found between bedaquiline and the following drugs: INH, RIF, EMB, PZA, streptomycin, amikacin or moxifloxacin. A fourfold increase in bedaquiline minimal inhibitory concentration (MIC) values (suggesting acquired resistance) has been observed in 13 of 28 patients with paired M. tuberculosis (baseline and post-baseline) isolates during clinical studies; 10 of 13 patients had isolates with matching genotypes, which is evidence against reinfection with a new M. tuberculosis strain, and, of these, nine had evidence of treatment failure or relapse. In vitro studies have demonstrated that bedaquiline has a bacteriostatic effect at low serum levels (0.3 µg/ml) that might predispose to acquired resistance (9,10). This report provides provisional CDC guidelines for the use and safety monitoring of bedaquiline. Certain information included in these guidelines goes beyond the approved labeling for the particular products or indications in question. Clinicians should exercise judgment in management decisions modified as clinically indicated for unique patient circumstances. # Guideline Development Methods To develop treatment guidelines for the use and safety monitoring of bedaquiline in the treatment of MDR TB, CDC's Division of TB Elimination (DTBE) conducted a literature review of published clinical trials, reviewed results of other publicly available resources (transcript and background materials from the FDA Anti-Infectives Advisory Committee Meeting of November 27, 2012, new drug application reviews, approval letter, and approved drug label) (8)(9)(10)(11)13), and the proceedings of a CDC external consultation meeting held on January 15-16, 2013. Published trials: A systematic literature review was performed searching PubMed/Medline with key words and search terms "bedaquiline," "multidrug resistant-tuberculosis," and "clinical trials." The search identified two publications from one double-blind, randomized, placebo-controlled Phase IIb superiority trial, C208 Stage 1, an exploratory stage that assessed 8-week bedaquiline treatment in patients with MDR TB (14,15). Phase IIa early bactericidal activity studies and review articles were excluded. Other publicly available data: Information from the Anti-Infectives Advisory Committee Meeting Materials (9,10,13), FDA accelerated approval letter (11), and final printed label (8) were reviewed, including findings from 16 unpublished clinical pharmacology trials that evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of bedaquiline in healthy volunteers and drug interactions, and findings from two additional unpublished Phase IIb clinical trials presented to FDA at Stage 2 of drug approval by Janssen Therapeutics (C208 Stage 2, a proof-of efficacy, double-blind, randomized, placebo-controlled superiority trial separate and distinct from Stage 1, and C209, a noncomparative, singlearm, open-label trial). Both C208 Stage 1 and C208 Stage 2 had been completed, and C209 was ongoing at the time of the Advisory Committee Meeting. Expert consultation: Following FDA approval of bedaquiline on December 28, 2012, CDC convened an ad-hoc panel of 26 external consultants † , including three FDA representatives, on January 15-16, 2013. The purpose of the meeting was for the members of the panel to provide individual expert opinion to develop provisional guidelines for the use and safety monitoring of this new drug. Each of the consultants had demonstrated TB-specific expertise in at least one of the following areas: diagnosis, treatment, prevention, nursing case management, public health programs, surveillance, epidemiology, clinical research, pulmonology, infectious diseases, pediatrics, health communication and education, migrant worker health, patient advocacy, or health economics. The external consultants and CDC staff reviewed findings from the two Phase IIb clinical trials from FDA Advisory Committee meeting materials (documents prepared by both Janssen Therapeutics and FDA) and from presentations by FDA experts, and CDC summarized the presentations and discussions of available evidence and individual expert opinions. The expert group discussed a set of questions selected by a bedaquiline workgroup comprising DTBE personnel. A summary of this discussion was prepared. Assessment of evidence and drafting of guidelines: On the basis of the review of the literature, data from publicly available sources, and the summary of the external consultation, CDC staff drafted provisional guidelines for the use of bedaquiline. Each element of the guidelines for use of bedaquiline is rated according to the quality of the evidence. High-quality evidence is defined as data obtained from randomized controlled trials (RCTs). Low-quality evidence includes data obtained from observational studies or case series. The quality of evidence from RCTs could be downgraded to low if substantial degrees of any of the following were noted: - bias, e.g., adequate blinding was lacking despite randomization, with substantial differences in control and intervention groups; - indirectness, e.g., standard outcome measures were not used in the study; † A list of the members of the panel appears on page 12. All members of the panel submitted a signed form declaring that they had no conflicts of interest or competing interests. - imprecise evidence, e.g., there were wide confidence intervals; or - inconsistency and lack of evidence of reproducibility, e.g., different studies had discordant results or studies were insufficient to determine whether results are reproducible. When evidence was lacking, a rating of "insufficient" was given to certain questions considered at the expert consultation. However, because CDC decided that provisional guidelines for these questions was important, CDC expert opinion, informed by the external expert consultation, is provided in response to those questions. # Summary of Evidence from Clinical Pharmacology Studies and Clinical Trials of Bedaquiline Data below are presented from FDA's analysis of Janssen Therapeutics studies (9,10). # Clinical Pharmacology Studies Results from the 16 clinical pharmacology trials (Table 1) including participants with median age 32.5 years (range: 18-68 years) indicate that peak plasma concentration and plasma exposure of bedaquiline increased approximately twofold when administered with high-fat food. Bedaquiline is highly proteinbound (>99%), is metabolized chiefly through the cytochrome P450 (CYP) system, and is excreted primarily via the feces. The mean terminal half-life (t½ term) of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus attributable to bedaquiline. However, no adequate and well-controlled studies have been conducted in women, and consequently bedaquiline is considered to be an FDA-assigned pregnancy category B drug (16). Whether bedaquiline or its metabolites are excreted in human milk is not known, but studies in rats have demonstrated that the drug is concentrated in breast milk. Bedaquiline distribution into the central nervous system and cerebrospinal fluid have not been evaluated. The PK of bedaquiline in pediatric patients (aged 0-17 years) and elderly persons (aged ≥65years) has not been evaluated. Black patients have a clearance of bedaquiline that is 52% higher than that of patients who were classified as non-Hispanic white, Asian, Hispanic, or other. This could result in lower systemic exposure in black patients than in patients in these other racial/ethnic categories. CYP3A4 is the major CYP isoenzyme involved in the metabolism of bedaquiline. Drug-drug interactions occurred with CYP3A4 inducers (e.g., RIF reduced bedaquiline exposure by approximately 50%) and CYP3A4 inhibitors (e.g., ketoconazole increased bedaquiline exposure by approximately 22%). No significant PK interactions were observed with the anti-TB drugs INH, PZA, EMB, kanamycin, ofloxacin, or cycloserine, or with the antiretroviral drug nevirapine; however, lopinavir/ritonavir increased bedaquiline exposure by 22%. Additional information on drug-drug interactions is available in the bedaquiline label (8). (For additional information on use of bedaquiline in patients with renal and hepatic impairment, see Precautions and Monitoring for Adverse Events.) # Efficacy Studies Efficacy of bedaquiline was assessed in three Phase IIb studies: Studies C208 Stage 1, C208 Stage 2 (both randomized placebo-controlled trials), and C209 (a noncomparative, single-arm open-label trial) (Table 2). Study C208 evaluated efficacy in patients with newly diagnosed MDR TB in two completely separate studies conducted consecutively: an exploratory study of 8 weeks of bedaquiline with a standard five-drug background regimen consisting of ethionamide, kanamycin, PZA, ofloxacin, and cycloserine/terizidone (Stage 1) and a proof-of-efficacy study of 24 weeks of bedaquiline with the same standard background regimen (Stage 2). Study C209 assessed efficacy in patients with MDR TB with varying degrees of additional resistance who failed previous therapy and were on individualized background regimens tailored either to the susceptibility pattern of their M. tuberculosis isolate or to their treatment history. The primary endpoint in all studies was time to SCC, defined as two consecutive cultures from sputum that were negative for M. tuberculosis in a modified intention-to-treat analysis (mITT) (Tables 2-4). # % of treated patients Week- Source: Adapted from Food and Drug Administration clinical pharmacology review (9). - Time to SCC (two consecutive cultures from sputum samples that were negative for Mycobacterium tuberculosis) in weeks. Please note: An erratum has been published for this issue. To view the erratum, please click here. In Study C209, patients with laboratory-confirmed pulmonary MDR TB were treated with bedaquiline plus background regimen. The median time to SCC was 57 days (Figure 1) and consistent with both C208 Stage 1 and Stage 2 results (data not presented). # Safety Studies # Safety in Healthy Volunteers From 2005 to 2012, Janssen Therapeutics conducted 11 Phase I studies to evaluate bedaquiline. Analysis of pooled safety data from eight Phase 1 studies (five single-dose studies and three multiple-dose studies) enrolling 189 healthy adult patients who received at least 1 dose of bedaquiline support the safety and tolerability of bedaquiline administered either alone or with selected other medications. Of the 57 multiple-dose patients, 47 received bedaquiline for at least 14 days, and 37 received bedaquiline with other medication (INH and PZA: 22 patients; ketoconazole: 15 patients). Suspected adverse reactions were solicited actively at the time of drug administration. No deaths or serious adverse events were reported. No patient exposed to bedaquiline, either alone or in combination with other drugs, had a QTcF >500 milliseconds (ms). No subject discontinued treatment because of QTcF prolongation. # Safety in Patients with Drug-Susceptible Tuberculosis Treated for 7 days Trial C202 was a proof-of-principle, open-label, activecontrolled, randomized Phase IIa trial in 45 patients with drug-susceptible TB. Patients were randomized to five groups receiving 7 days of monotherapy with bedaquiline (25 mg, 100 mg, or 400 mg) or INH (300 mg) or RIF (600 mg). Of 75 patients enrolled, 45 received bedaquiline. No deaths occurred from an adverse drug reaction that started during the 7-day investigational study phase (bedaquiline, INH, or RIF) treatment period. Two patients (both of whom were in the bedaquiline 400 mg group) died during the follow-up period, after initiation of a treatment regimen for their drug-susceptible TB consisting of INH, RIF, EMB, and PZA; neither death was attributable to bedaquiline. The rate of serious adverse events was balanced in both treatment groups. A greater increase in QTcF was noted at 5 hours postdose compared with baseline in patients who received 400 mg (median increase: 24.5 ms) compared with patients who received 100 mg (median increase: 10.1 ms) or 25 mg (no increase) of bedaquiline or 300 mg of INH (median increase: 15.8 ms) or 600 mg of RIF (median increase: 13.1 ms). # Safety in Patients with Drug-Resistant TB The safety and tolerability of bedaquiline for the treatment of pulmonary MDR TB in adults as part of combination therapy was assessed by pooling of data from C208 Stage 1 and Stage 2 (207 TB patients, 102 of whom received bedaquiline: 23 for 8 weeks and 79 for 24 weeks) and C209 (233 TB patients, all of whom received bedaquiline for 24 weeks) to increase the likelihood of detecting infrequent adverse events attributable to the higher number of patients per pooled treatment group and to increase the sample size for subgroup analyses (Table 5). Excluding 233 patients treated in C209, comparative safety (to placebo plus background regimen) data were available for 102 of these 335 patients. The most frequent suspected adverse reactions (>20.0% of patients) during treatment with bedaquiline in the controlled trials (C208 Stages 1 and 2) were nausea (35.3%), arthralgia (29.4%), headache (23.5%), hyperuricemia (22.5%), and vomiting (20.6%). The incidence of these adverse drug reactions in the bedaquiline arm was similar to the placebo arm except for headache (in 23.5% and 11.4% of patients, respectively), nausea (35.3% and 25.7%, respectively), and arthralgia (29.4% and 20.0%, respectively). Over the 24-week study drug-treatment period in C208 Stage 2, hepatic-related adverse drug reactions and increase in QTcF were observed more commonly in the bedaquiline arm compared with the placebo arm (8). Two patients treated - Patients in the mortality analysis were followed for up to 6 months from the last recorded visit, as specified in the study safety procedures. with bedaquiline had serious hepatic adverse reactions, one of whom had elevation in total bilirubin (peak 52 µmol/L at 24 weeks). One (1.3%) patient in the bedaquiline arm had a QTcF value of >500 ms, compared with none in the placebo arm; one patient each from the bedaquiline and placebo arms developed QTcF values between 480 and 500 ms; and QTcF values between 450 and 480 ms were observed in 26.6% and 8.6% of patients in the bedaquiline and placebo arm, respectively. Seven (9.1%) patients in the bedaquiline arm had a >60 ms increase from baseline in QTcF compared with two (2.5%) patients in the placebo arm. Fifty-six percent of patients in the bedaquiline arm and 31.6% of patients in the placebo arm experienced increases in QTcF between 30 to 60 ms. No episodes of torsade de pointes (a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and is associated with QTcF prolongation) occurred in patients with QTcF prolongation. The magnitude of QTcF prolongation over baseline increased in the first 18 weeks of bedaquiline treatment, remained relatively stable until week 24, and then gradually decreased (Figure 2). The magnitude of QTcF prolongation was greater in patients treated concomitantly with clofazimine. - The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias and a risk factor for sudden death. The QT interval is dependent on the heart rate and may be corrected by calculation to improve the detection of patients at increased risk of ventricular arrhythmia. One of several calculation correction formulas focuses on the QT interval divided by cube-root of RR (QTcF), where RR is the interval from the onset of one QRS complex (the graphical deflections seen on an electrocardiogram (ECG) that correspond to the depolarization of the right and left ventricle with each heart beat) to the onset of the next QRS complex, measured in milliseconds. † Ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone. § Time to smear culture conversion (two consecutive cultures from sputum samples that were negative for Mycobacterium tuberculosis) in weeks. Please note: An erratum has been published for this issue. To view the erratum, please click here. # Deaths Among Clinical Trial Participants A total of 36 deaths were reported during the entire clinical development program of bedaquiline: 30 in the bedaquiline group and six in the placebo group (Table 6). In C208 Stage 2, nine of the 10 deaths in the bedaquiline arm, and two of the four deaths in the placebo arm occurred within the 120-week cutoff period for the efficacy analysis. For five of the nine bedaquiline-treated patients who died and both of the placebo patients who died, the cause of death was TB; no clear cause of death related to bedaquiline toxicity was identified. Detailed analysis of baseline characteristics and risk factors for poor treatment outcomes did not reveal relevant imbalances to explain the increased mortality observed in the bedaquiline arm. There was no relationship between bedaquiline serum levels or QTcF >500 ms and survival outcome. Nevertheless, because of the excess deaths and QT interval effects in the treatment group, the prescribing information included the following black box warnings: - An increased risk for death was observed in the Sirturo treatment group (9/79; 11.4%) compared with the placebo treatment group (2/81; 2.5%) in one placebo-controlled trial. Only use Sirturo when an effective treatment regimen cannot otherwise be provided; - QTcF prolongation can occur with Sirturo. Use with drugs that prolong the QT interval might cause additive QTcF prolongation. # CDC Provisional Guidelines for the Use of Bedaquiline Bedaquiline may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary MDR TB (TB with an isolate showing genotypic or phenotypic resistance to both INH and RIF) when an effective treatment regimen cannot otherwise be provided. Quality of evidence: low. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: One published RCT (C208 Stage 1) showed bedaquiline used for 8 weeks was superior to placebo at achieving an earlier time to SCC and a statistically significant increase in SCC rate at 8 weeks in patients with pulmonary MDR TB who were treated with optimized background regimen. The gold standard for outcomes of MDR TB treatment is persistent negative sputum culture 2 years after treatment completion, and time to SCC and 2-month SCC rate are imperfect surrogate markers. Only one RCT noted above evaluated a 8-week bedaquiline course and reproducibility of results cannot be determined. Therefore, quality of evidence was downgraded from high to low. However, FDA reviewed data from two additional unpublished studies that supported efficacy using the endpoint of SCC: an RCT demonstrating superiority of a 24-week bedaquiline course added to background regimen in both time to SCC and 24 week SCC rate (C208 Stage 2) and a single arm trial in patients who achieved similar time to SCC as that shown in both C208 Stage 1 and Stage 2, despite having failed previous therapy (C209) (9). The higher mortality rate associated with MDR TB when compared with drug-sensitive TB supports consideration of bedaquiline use in patients for whom an effective regimen cannot otherwise be provided, despite potential toxicity concerns described above. Bedaquiline may be used on a case-by-case basis in children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. Quality of evidence: insufficient. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: The effectiveness and safety of bedaquiline for the treatment of MDR TB have not been studied adequately in these populations to provide general guidance for or against its use. Because MDR TB has a high mortality rate and treatment options are limited, its use might be a reasonable option for providers to consider in treating certain patients in the groups listed above. Bedaquiline may be used on a case-by-case basis for durations longer than 24 weeks when an effective treatment regimen cannot be provided otherwise. Quality of evidence: insufficient. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: The effectiveness and safety of bedaquiline have not been studied beyond a duration of 24 weeks. Therefore, general guidance cannot be provided for or against its use for durations beyond 24 weeks. Because MDR TB has a high mortality rate and treatment options are limited, bedaquiline use beyond 24 weeks might be justified in some patients. # Additional Considerations # Dosing and Administration - The recommended dosage for bedaquiline is 400 mg once daily orally for 2 weeks, followed by 200 mg three times a week for 22 weeks taken orally with food in order to maximize absorption. - If a dose of bedaquiline is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. From Week 3 onward, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the three-times-a-week regimen with established intervals (i.e., days of the week). - Bedaquiline never should be used as a single drug and should be used only in combination with at least three other drugs (i.e., for a four-drug regimen) to which the patient's MDR TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment may be initiated with bedaquiline in combination with at least four other drugs (i.e., for a five-drug regimen) to which the patient's MDR TB isolate is likely to be susceptible (1,8). - The use of bedaquiline with rifamycins or other drugs that induce or suppress CYP3A4 should be avoided, unless the anticipated benefits outweigh the risks associated with inadequate treatment of MDR TB; if bedaquiline is given with these drugs, monitoring of serum drug levels should be performed to ensure adequate therapy and minimize the risk for acquired drug resistance. Providers are encouraged to contact CDC for technical assistance and referral for monitoring serum drug levels if necessary. - Because bedaquiline has an extremely long terminal halflife (4-5 months), acquired resistance might occur when bedaquiline is the sole effective anti-TB drug in circulation. Prescribers should consider discontinuation of bedaquiline 4-5 months before scheduled termination of other drugs in the regimen to reduce or avoid an extended period of exposure to low levels of bedaquiline as a single drug. - Bedaquiline should be administered only by directly observed therapy (DOT) and with case management strategies. Such strategies might include the use of incentives and enablers (e.g., food certificates, bus passes, cash, or housing) to ensure adherence to the treatment regimen. - Patients should be advised that nonadherence to a treatment regimen could result in treatment failure, relapse, or acquired resistance. An evaluation for the development of resistance to the anti-TB regimen (including repeat drug susceptibility testing, if indicated) is recommended for patients with treatment failure or relapse. # Monitoring - Persons receiving bedaquiline should be monitored weekly for nausea, headache, hemoptysis, chest pain, arthralgia and rash, and treatment should be modified as clinically indicated. - Monitoring for other suspected adverse reactions should be tailored to side effects specific to other drugs in the background regimen and the potential for drug interactions with bedaquiline. - Bedaquiline use in the treatment of pulmonary MDR TB should be accompanied by microbiologic monitoring with one sputum specimen submitted for culture monthly throughout and at end of treatment, even after conversion to negative culture, which is consistent with the standard approach to treatment and care of patients with MDR TB in the United States. Any monthly specimen that grows M. tuberculosis, including one before treatment initiation with bedaquiline, should be referred to a laboratory for surveillance of bedaquiline resistance in consultation with the state public health laboratory (1,(17)(18)(19). CDC will assist in identifying a laboratory that can perform bedaquiline susceptibility testing for this purpose. # Precautions and Monitoring for Adverse Events # Training, Education, and Medical Consultation - Training and education for bedaquiline administration, adverse event monitoring, clinical response monitoring, and reporting should be provided for public health programs/professionals, TB physicians, and others who will be involved in the care and management of patients receiving bedaquiline. - Treatment of MDR TB should be provided in consultation with an expert in the management of MDR TB. # Registry of Patients Treated With Bedaquiline Per postmarketing surveillance requirements (11), all persons started on bedaquiline should be enrolled in a patient registry. This registry should facilitate an expanded and standardized monitoring system to track systematically such variables as serious adverse events, less serious side effects, early and late patient outcomes (culture conversion, relapse, completion of treatment, and cure), laboratory data including collection and testing of patient isolates at the start of and during treatment, interaction with other drugs, use in multidrug regimens, drug administration practices, use in the operational setting, feasibility of implementation and cost effectiveness, drug distribution mechanisms and process, and drug utilization data. Janssen Therapeutics will maintain this registry and collect data prospectively on all patients started on bedaquiline through December 2018 with a final report anticipated in August 2019. CDC, in conjunction with Janssen Therapeutics, will provide guidance on the implementation plan for bedaquiline use (process for distribution through an identified point of contact for each of the 68 DTBE-funded jurisdictions in the United States). # Safety Reporting Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported to Janssen Therapeutics at telephone 1-800-526-7736, to FDA at telephone 1-800-332-1088 or at . gov/ medwatch, and to CDC's Emergency Operations Center at telephone 1-770-488-7100. # Planned Studies and Updates to CDC Provisional Guidelines Janssen Therapeutics is required to conduct a double-blind placebo-controlled multicenter Phase III RCT in patients with sputum smear-positive pulmonary MDR TB as part of the conditions associated with accelerated approval under 21CFR314.500 (11). Additional requirements include, but are not limited to, a study to define the quality control ranges of bedaquiline for MDR TB isolates using standard agar proportion and MIC methods, and a clinical trial to identify any unexpected serious risk of increased drug levels of bedaquiline in HIV patients co-infected with M. tuberculosis. CDC will revise these provisional CDC guidelines as needed when those data become available. The material in this report originated in National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention, Jonathan Mermin, MD, Director, and the Division of Tuberculosis Elimination, Kenneth G. Castro, MD, Director.	Address all inquiries about the MMWR Series, including material to be considered for publication, to Editor,# Disclosure of Relationship CDC, our planners, and our content experts wish to disclose that they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This report includes discussion of the off-label use of bedaquiline in the following situations: • use in special populations: -children (aged 0-17 years), -elderly persons (aged ≥65 years), -HIV-infected persons, -pregnant women, -persons with extrapulmonary tuberculosis (TB), -patients with comorbid conditions on concomitant medications (e.g., underlying renal, hepatic, cardiac, respiratory conditions, diabetes, or other immunocompromised state), and -any other population in which use of the drug has not been studied; • use for >24 weeks in any patient; • use at any time during treatment for multidrug-resistant (MDR) TB (not just at the initiation of MDR TB treatment); and • use in MDR TB relapse or treatment failure. # Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis Prepared by Sundari Mase, MD Terence Chorba, MD Philip Lobue, MD Kenneth Castro, MD Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC # Summary Multidrug-resistant tuberculosis (MDR TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500) (Cox EM. FDA accelerated approval letter to Janssen Research and Development. Available at http://www.accessdata.fda.gov/drugsatfda_docs/appletter/201 2/204384Orig1s000ltr.pdf ). This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR TB who were not included in the clinical trials for the drug. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals who might use bedaquiline for the treatment of MDR TB for indicated and off-label uses. Aspects of these guidelines are not identical to current FDA-approved labeling for bedaquiline. Bedaquiline should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB (Food and Drug Administration. SIRTURO [bedaquiline] tablets label. Available at http://www.accessdata.fda.gov/drugsatfda_docs/ label/2012/204384s000lbl.pdf). Use of the drug also can be considered for individual patients in other categories (e.g., persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions) when treatment options are limited. However, further study is required before routine use of bedaquiline can be recommended in these populations. A registry for persons treated with bedaquiline is being implemented by Janssen Therapeutics to track patient outcomes, adverse reactions, laboratory testing results (e.g., diagnosis, drug susceptibility, and development of drug resistance), use of concomitant medications, and presence of other comorbid conditions. Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported to Janssen Therapeutics at telephone 1-800-526-7736, to FDA at telephone 1-800-332-1088 or at http://www.fda. gov/medwatch, and to CDC's Emergency Operations Center at telephone 1-770-488-7100. # Introduction Tuberculosis (TB) is caused by the bacteria of the Mycobacterium tuberculosis complex, most commonly M. tuberculosis. TB usually is transmitted from one person to another by airborne droplet nuclei containing the bacteria. For most persons who have drug-susceptible TB, cure is achieved with a combination of first-line drugs (e.g., isoniazid [INH], rifampin [RIF], ethambutol [EMB], and pyrazinamide [PZA]) administered as a 6-month standard regimen. In contrast, multidrug-resistant tuberculosis (MDR TB), defined as TB that is caused by M. tuberculosis resistant to at least INH and RIF, generally requires 18-24 months of treatment after sputum culture conversion (SCC) with five or six drugs (e.g., susceptible first-line drugs plus an injectable agent, a fluoroquinolone, and other second-line drugs as needed) that are less effective, more toxic, and more costly than a standard first-line regimen (1,2). MDR TB impacts communities worldwide and poses an urgent public health threat that transcends borders. In 2011, an estimated 630,000 cases of MDR TB (range: 460,000-790,000) occurred among the world's 12 million persons with prevalent cases of TB. An estimated 3.7% of persons with newly diagnosed TB and 20% of persons with previously treated TB have MDR TB. Extensively drug-resistant tuberculosis (XDR TB), defined as MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, amikacin, or capreomycin), has been reported in 84 countries; on average, 9% of persons with MDR TB have additional resistance qualifying as XDR TB. India and China contribute the greatest numbers of MDR TB cases to the global burden, but the Russian Federation has the highest MDR TB rates per 100,000 population (3,4). Compared with drug-susceptible TB, MDR TB causes greater morbidity and mortality, and overall patient outcomes are worse (i.e., death, relapse [reverting to sputum culture-positive after becoming culture-negative while on treatment], treatment failure [remaining sputum culturepositive while on treatment], or disability). Mortality rates for patients being treated for MDR-TB usually exceed 10% (range: 8%-21%) (5). A recently published individual patient data meta-analysis of 9,153 patients with MDR TB yielded a mortality rate of 15% (6). MDR TB develops when TB that is susceptible to first-line drugs is not treated adequately because of the selection of substandard treatment regimens or nonadherence with (or interruption in) treatment. Other factors (e.g., malabsorption of drugs or drug-drug interactions) also can lead to the selection of drug-resistant strains (2). Once drug-resistant TB has developed, person-to-person transmission is possible, potentially leading to outbreaks (7). MDR TB must be rapidly diagnosed and treated with an effective drug regimen to prevent further transmission of these difficult-to-cure strains of TB. One of the challenges in the treatment of MDR TB is the lack of effective, well-tolerated medications. There are very few medications and fewer classes of medications for treatment of MDR TB, and adverse drug reactions commonly necessitate discontinuing medications (2). On December 28, 2012, the Food and Drug Administration (FDA) approved the use of bedaquiline fumarate (Sirturo or bedaquiline) as part of combination therapy (minimum fourdrug therapy) administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB when an effective treatment regimen cannot otherwise be provided (e.g., because of extensive resistance, drug intolerance, or drug-drug interactions) (8). The recommended dose of bedaquiline for the treatment of pulmonary MDR TB in adults is 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally three times weekly, for an entire treatment duration of 24 weeks. Bedaquiline is taken with food and in combination with other anti-TB drugs. The drug is available in 100 mg tablets (9,10). FDA approves drug products for lawful marketing for specific intended uses based on data that establish safety and efficacy, and approves labeling specific to those uses. FDA approved bedaquline as part of combination therapy to treat adults with pulmonary MDR TB when other alternatives are not available. The drug was approved under FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (11). FDA approved bedaquiline with a black box warning alerting health-care professionals to an increase in all-cause mortality and to a prolongation of the QTcF* in patients treated with bedaquiline versus placebo. Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M. tuberculosis that has been approved by FDA since 1971 (12). FDA considered this new drug under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500) (11). Bedaquiline uses adenosine 5'-triphosphate (ATP) synthase inhibition as its mechanism of action, has in vitro activity against * The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias and a risk factor for sudden death. The QT interval is dependent on the heart rate and may be corrected by calculation to improve the detection of patients at increased risk of ventricular arrhythmia. One of several calculation correction formulas focuses on the QT interval divided by cube-root of RR (QTcF), where RR is the interval from the onset of one QRS complex (the graphical deflections seen on an electrocardiogram [ECG] that correspond to the depolarization of the right and left ventricle with each heart beat) to the onset of the next QRS complex, measured in milliseconds. both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of TB infection. No cross-resistance was found between bedaquiline and the following drugs: INH, RIF, EMB, PZA, streptomycin, amikacin or moxifloxacin. A fourfold increase in bedaquiline minimal inhibitory concentration (MIC) values (suggesting acquired resistance) has been observed in 13 of 28 patients with paired M. tuberculosis (baseline and post-baseline) isolates during clinical studies; 10 of 13 patients had isolates with matching genotypes, which is evidence against reinfection with a new M. tuberculosis strain, and, of these, nine had evidence of treatment failure or relapse. In vitro studies have demonstrated that bedaquiline has a bacteriostatic effect at low serum levels (0.3 µg/ml) that might predispose to acquired resistance (9,10). This report provides provisional CDC guidelines for the use and safety monitoring of bedaquiline. Certain information included in these guidelines goes beyond the approved labeling for the particular products or indications in question. Clinicians should exercise judgment in management decisions modified as clinically indicated for unique patient circumstances. # Guideline Development Methods To develop treatment guidelines for the use and safety monitoring of bedaquiline in the treatment of MDR TB, CDC's Division of TB Elimination (DTBE) conducted a literature review of published clinical trials, reviewed results of other publicly available resources (transcript and background materials from the FDA Anti-Infectives Advisory Committee Meeting of November 27, 2012, new drug application reviews, approval letter, and approved drug label) (8)(9)(10)(11)13), and the proceedings of a CDC external consultation meeting held on January 15-16, 2013. Published trials: A systematic literature review was performed searching PubMed/Medline with key words and search terms "bedaquiline," "multidrug resistant-tuberculosis," and "clinical trials." The search identified two publications from one double-blind, randomized, placebo-controlled Phase IIb superiority trial, C208 Stage 1, an exploratory stage that assessed 8-week bedaquiline treatment in patients with MDR TB (14,15). Phase IIa early bactericidal activity studies and review articles were excluded. Other publicly available data: Information from the Anti-Infectives Advisory Committee Meeting Materials (9,10,13), FDA accelerated approval letter (11), and final printed label (8) were reviewed, including findings from 16 unpublished clinical pharmacology trials that evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of bedaquiline in healthy volunteers and drug interactions, and findings from two additional unpublished Phase IIb clinical trials presented to FDA at Stage 2 of drug approval by Janssen Therapeutics (C208 Stage 2, a proof-of efficacy, double-blind, randomized, placebo-controlled superiority trial separate and distinct from Stage 1, and C209, a noncomparative, singlearm, open-label trial). Both C208 Stage 1 and C208 Stage 2 had been completed, and C209 was ongoing at the time of the Advisory Committee Meeting. Expert consultation: Following FDA approval of bedaquiline on December 28, 2012, CDC convened an ad-hoc panel of 26 external consultants † , including three FDA representatives, on January 15-16, 2013. The purpose of the meeting was for the members of the panel to provide individual expert opinion to develop provisional guidelines for the use and safety monitoring of this new drug. Each of the consultants had demonstrated TB-specific expertise in at least one of the following areas: diagnosis, treatment, prevention, nursing case management, public health programs, surveillance, epidemiology, clinical research, pulmonology, infectious diseases, pediatrics, health communication and education, migrant worker health, patient advocacy, or health economics. The external consultants and CDC staff reviewed findings from the two Phase IIb clinical trials from FDA Advisory Committee meeting materials (documents prepared by both Janssen Therapeutics and FDA) and from presentations by FDA experts, and CDC summarized the presentations and discussions of available evidence and individual expert opinions. The expert group discussed a set of questions selected by a bedaquiline workgroup comprising DTBE personnel. A summary of this discussion was prepared. Assessment of evidence and drafting of guidelines: On the basis of the review of the literature, data from publicly available sources, and the summary of the external consultation, CDC staff drafted provisional guidelines for the use of bedaquiline. Each element of the guidelines for use of bedaquiline is rated according to the quality of the evidence. High-quality evidence is defined as data obtained from randomized controlled trials (RCTs). Low-quality evidence includes data obtained from observational studies or case series. The quality of evidence from RCTs could be downgraded to low if substantial degrees of any of the following were noted: • bias, e.g., adequate blinding was lacking despite randomization, with substantial differences in control and intervention groups; • indirectness, e.g., standard outcome measures were not used in the study; † A list of the members of the panel appears on page 12. All members of the panel submitted a signed form declaring that they had no conflicts of interest or competing interests. • imprecise evidence, e.g., there were wide confidence intervals; or • inconsistency and lack of evidence of reproducibility, e.g., different studies had discordant results or studies were insufficient to determine whether results are reproducible. When evidence was lacking, a rating of "insufficient" was given to certain questions considered at the expert consultation. However, because CDC decided that provisional guidelines for these questions was important, CDC expert opinion, informed by the external expert consultation, is provided in response to those questions. # Summary of Evidence from Clinical Pharmacology Studies and Clinical Trials of Bedaquiline Data below are presented from FDA's analysis of Janssen Therapeutics studies (9,10). # Clinical Pharmacology Studies Results from the 16 clinical pharmacology trials (Table 1) including participants with median age 32.5 years (range: 18-68 years) indicate that peak plasma concentration and plasma exposure of bedaquiline increased approximately twofold when administered with high-fat food. Bedaquiline is highly proteinbound (>99%), is metabolized chiefly through the cytochrome P450 (CYP) system, and is excreted primarily via the feces. The mean terminal half-life (t½ term) of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus attributable to bedaquiline. However, no adequate and well-controlled studies have been conducted in women, and consequently bedaquiline is considered to be an FDA-assigned pregnancy category B drug (16). Whether bedaquiline or its metabolites are excreted in human milk is not known, but studies in rats have demonstrated that the drug is concentrated in breast milk. Bedaquiline distribution into the central nervous system and cerebrospinal fluid have not been evaluated. The PK of bedaquiline in pediatric patients (aged 0-17 years) and elderly persons (aged ≥65years) has not been evaluated. Black patients have a clearance of bedaquiline that is 52% higher than that of patients who were classified as non-Hispanic white, Asian, Hispanic, or other. This could result in lower systemic exposure in black patients than in patients in these other racial/ethnic categories. CYP3A4 is the major CYP isoenzyme involved in the metabolism of bedaquiline. Drug-drug interactions occurred with CYP3A4 inducers (e.g., RIF reduced bedaquiline exposure by approximately 50%) and CYP3A4 inhibitors (e.g., ketoconazole increased bedaquiline exposure by approximately 22%). No significant PK interactions were observed with the anti-TB drugs INH, PZA, EMB, kanamycin, ofloxacin, or cycloserine, or with the antiretroviral drug nevirapine; however, lopinavir/ritonavir increased bedaquiline exposure by 22%. Additional information on drug-drug interactions is available in the bedaquiline label (8). (For additional information on use of bedaquiline in patients with renal and hepatic impairment, see Precautions and Monitoring for Adverse Events.) # Efficacy Studies Efficacy of bedaquiline was assessed in three Phase IIb studies: Studies C208 Stage 1, C208 Stage 2 (both randomized placebo-controlled trials), and C209 (a noncomparative, single-arm open-label trial) (Table 2). Study C208 evaluated efficacy in patients with newly diagnosed MDR TB in two completely separate studies conducted consecutively: an exploratory study of 8 weeks of bedaquiline with a standard five-drug background regimen consisting of ethionamide, kanamycin, PZA, ofloxacin, and cycloserine/terizidone (Stage 1) and a proof-of-efficacy study of 24 weeks of bedaquiline with the same standard background regimen (Stage 2). Study C209 assessed efficacy in patients with MDR TB with varying degrees of additional resistance who failed previous therapy and were on individualized background regimens tailored either to the susceptibility pattern of their M. tuberculosis isolate or to their treatment history. The primary endpoint in all studies was time to SCC, defined as two consecutive cultures from sputum that were negative for M. tuberculosis in a modified intention-to-treat analysis (mITT) (Tables 2-4). # % of treated patients Week* Source: Adapted from Food and Drug Administration clinical pharmacology review (9). * Time to SCC (two consecutive cultures from sputum samples that were negative for Mycobacterium tuberculosis) in weeks. Please note: An erratum has been published for this issue. To view the erratum, please click here. In Study C209, patients with laboratory-confirmed pulmonary MDR TB were treated with bedaquiline plus background regimen. The median time to SCC was 57 days (Figure 1) and consistent with both C208 Stage 1 and Stage 2 results (data not presented). # Safety Studies # Safety in Healthy Volunteers From 2005 to 2012, Janssen Therapeutics conducted 11 Phase I studies to evaluate bedaquiline. Analysis of pooled safety data from eight Phase 1 studies (five single-dose studies and three multiple-dose studies) enrolling 189 healthy adult patients who received at least 1 dose of bedaquiline support the safety and tolerability of bedaquiline administered either alone or with selected other medications. Of the 57 multiple-dose patients, 47 received bedaquiline for at least 14 days, and 37 received bedaquiline with other medication (INH and PZA: 22 patients; ketoconazole: 15 patients). Suspected adverse reactions were solicited actively at the time of drug administration. No deaths or serious adverse events were reported. No patient exposed to bedaquiline, either alone or in combination with other drugs, had a QTcF >500 milliseconds (ms). No subject discontinued treatment because of QTcF prolongation. # Safety in Patients with Drug-Susceptible Tuberculosis Treated for 7 days Trial C202 was a proof-of-principle, open-label, activecontrolled, randomized Phase IIa trial in 45 patients with drug-susceptible TB. Patients were randomized to five groups receiving 7 days of monotherapy with bedaquiline (25 mg, 100 mg, or 400 mg) or INH (300 mg) or RIF (600 mg). Of 75 patients enrolled, 45 received bedaquiline. No deaths occurred from an adverse drug reaction that started during the 7-day investigational study phase (bedaquiline, INH, or RIF) treatment period. Two patients (both of whom were in the bedaquiline 400 mg group) died during the follow-up period, after initiation of a treatment regimen for their drug-susceptible TB consisting of INH, RIF, EMB, and PZA; neither death was attributable to bedaquiline. The rate of serious adverse events was balanced in both treatment groups. A greater increase in QTcF was noted at 5 hours postdose compared with baseline in patients who received 400 mg (median increase: 24.5 ms) compared with patients who received 100 mg (median increase: 10.1 ms) or 25 mg (no increase) of bedaquiline or 300 mg of INH (median increase: 15.8 ms) or 600 mg of RIF (median increase: 13.1 ms). # Safety in Patients with Drug-Resistant TB The safety and tolerability of bedaquiline for the treatment of pulmonary MDR TB in adults as part of combination therapy was assessed by pooling of data from C208 Stage 1 and Stage 2 (207 TB patients, 102 of whom received bedaquiline: 23 for 8 weeks and 79 for 24 weeks) and C209 (233 TB patients, all of whom received bedaquiline for 24 weeks) to increase the likelihood of detecting infrequent adverse events attributable to the higher number of patients per pooled treatment group and to increase the sample size for subgroup analyses (Table 5). Excluding 233 patients treated in C209, comparative safety (to placebo plus background regimen) data were available for 102 of these 335 patients. The most frequent suspected adverse reactions (>20.0% of patients) during treatment with bedaquiline in the controlled trials (C208 Stages 1 and 2) were nausea (35.3%), arthralgia (29.4%), headache (23.5%), hyperuricemia (22.5%), and vomiting (20.6%). The incidence of these adverse drug reactions in the bedaquiline arm was similar to the placebo arm except for headache (in 23.5% and 11.4% of patients, respectively), nausea (35.3% and 25.7%, respectively), and arthralgia (29.4% and 20.0%, respectively). Over the 24-week study drug-treatment period in C208 Stage 2, hepatic-related adverse drug reactions and increase in QTcF were observed more commonly in the bedaquiline arm compared with the placebo arm (8). Two patients treated * Patients in the mortality analysis were followed for up to 6 months from the last recorded visit, as specified in the study safety procedures. with bedaquiline had serious hepatic adverse reactions, one of whom had elevation in total bilirubin (peak 52 µmol/L at 24 weeks). One (1.3%) patient in the bedaquiline arm had a QTcF value of >500 ms, compared with none in the placebo arm; one patient each from the bedaquiline and placebo arms developed QTcF values between 480 and 500 ms; and QTcF values between 450 and 480 ms were observed in 26.6% and 8.6% of patients in the bedaquiline and placebo arm, respectively. Seven (9.1%) patients in the bedaquiline arm had a >60 ms increase from baseline in QTcF compared with two (2.5%) patients in the placebo arm. Fifty-six percent of patients in the bedaquiline arm and 31.6% of patients in the placebo arm experienced increases in QTcF between 30 to 60 ms. No episodes of torsade de pointes (a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and is associated with QTcF prolongation) occurred in patients with QTcF prolongation. The magnitude of QTcF prolongation over baseline increased in the first 18 weeks of bedaquiline treatment, remained relatively stable until week 24, and then gradually decreased (Figure 2). The magnitude of QTcF prolongation was greater in patients treated concomitantly with clofazimine. * The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias and a risk factor for sudden death. The QT interval is dependent on the heart rate and may be corrected by calculation to improve the detection of patients at increased risk of ventricular arrhythmia. One of several calculation correction formulas focuses on the QT interval divided by cube-root of RR (QTcF), where RR is the interval from the onset of one QRS complex (the graphical deflections seen on an electrocardiogram (ECG) that correspond to the depolarization of the right and left ventricle with each heart beat) to the onset of the next QRS complex, measured in milliseconds. † Ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone. § Time to smear culture conversion (two consecutive cultures from sputum samples that were negative for Mycobacterium tuberculosis) in weeks. Please note: An erratum has been published for this issue. To view the erratum, please click here. # Deaths Among Clinical Trial Participants A total of 36 deaths were reported during the entire clinical development program of bedaquiline: 30 in the bedaquiline group and six in the placebo group (Table 6). In C208 Stage 2, nine of the 10 deaths in the bedaquiline arm, and two of the four deaths in the placebo arm occurred within the 120-week cutoff period for the efficacy analysis. For five of the nine bedaquiline-treated patients who died and both of the placebo patients who died, the cause of death was TB; no clear cause of death related to bedaquiline toxicity was identified. Detailed analysis of baseline characteristics and risk factors for poor treatment outcomes did not reveal relevant imbalances to explain the increased mortality observed in the bedaquiline arm. There was no relationship between bedaquiline serum levels or QTcF >500 ms and survival outcome. Nevertheless, because of the excess deaths and QT interval effects in the treatment group, the prescribing information included the following black box warnings: • An increased risk for death was observed in the Sirturo treatment group (9/79; 11.4%) compared with the placebo treatment group (2/81; 2.5%) in one placebo-controlled trial. Only use Sirturo when an effective treatment regimen cannot otherwise be provided; • QTcF prolongation can occur with Sirturo. Use with drugs that prolong the QT interval might cause additive QTcF prolongation. # CDC Provisional Guidelines for the Use of Bedaquiline Bedaquiline may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary MDR TB (TB with an isolate showing genotypic or phenotypic resistance to both INH and RIF) when an effective treatment regimen cannot otherwise be provided. Quality of evidence: low. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: One published RCT (C208 Stage 1) showed bedaquiline used for 8 weeks was superior to placebo at achieving an earlier time to SCC and a statistically significant increase in SCC rate at 8 weeks in patients with pulmonary MDR TB who were treated with optimized background regimen. The gold standard for outcomes of MDR TB treatment is persistent negative sputum culture 2 years after treatment completion, and time to SCC and 2-month SCC rate are imperfect surrogate markers. Only one RCT noted above evaluated a 8-week bedaquiline course and reproducibility of results cannot be determined. Therefore, quality of evidence was downgraded from high to low. However, FDA reviewed data from two additional unpublished studies that supported efficacy using the endpoint of SCC: an RCT demonstrating superiority of a 24-week bedaquiline course added to background regimen in both time to SCC and 24 week SCC rate (C208 Stage 2) and a single arm trial in patients who achieved similar time to SCC as that shown in both C208 Stage 1 and Stage 2, despite having failed previous therapy (C209) (9). The higher mortality rate associated with MDR TB when compared with drug-sensitive TB supports consideration of bedaquiline use in patients for whom an effective regimen cannot otherwise be provided, despite potential toxicity concerns described above. Bedaquiline may be used on a case-by-case basis in children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided. Quality of evidence: insufficient. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: The effectiveness and safety of bedaquiline for the treatment of MDR TB have not been studied adequately in these populations to provide general guidance for or against its use. Because MDR TB has a high mortality rate and treatment options are limited, its use might be a reasonable option for providers to consider in treating certain patients in the groups listed above. Bedaquiline may be used on a case-by-case basis for durations longer than 24 weeks when an effective treatment regimen cannot be provided otherwise. Quality of evidence: insufficient. Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk. Evidence basis and rationale: The effectiveness and safety of bedaquiline have not been studied beyond a duration of 24 weeks. Therefore, general guidance cannot be provided for or against its use for durations beyond 24 weeks. Because MDR TB has a high mortality rate and treatment options are limited, bedaquiline use beyond 24 weeks might be justified in some patients. # Additional Considerations # Dosing and Administration • The recommended dosage for bedaquiline is 400 mg once daily orally for 2 weeks, followed by 200 mg three times a week for 22 weeks taken orally with food in order to maximize absorption. • If a dose of bedaquiline is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. From Week 3 onward, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the three-times-a-week regimen with established intervals (i.e., days of the week). • Bedaquiline never should be used as a single drug and should be used only in combination with at least three other drugs (i.e., for a four-drug regimen) to which the patient's MDR TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment may be initiated with bedaquiline in combination with at least four other drugs (i.e., for a five-drug regimen) to which the patient's MDR TB isolate is likely to be susceptible (1,8). • The use of bedaquiline with rifamycins or other drugs that induce or suppress CYP3A4 should be avoided, unless the anticipated benefits outweigh the risks associated with inadequate treatment of MDR TB; if bedaquiline is given with these drugs, monitoring of serum drug levels should be performed to ensure adequate therapy and minimize the risk for acquired drug resistance. Providers are encouraged to contact CDC for technical assistance and referral for monitoring serum drug levels if necessary. • Because bedaquiline has an extremely long terminal halflife (4-5 months), acquired resistance might occur when bedaquiline is the sole effective anti-TB drug in circulation. Prescribers should consider discontinuation of bedaquiline 4-5 months before scheduled termination of other drugs in the regimen to reduce or avoid an extended period of exposure to low levels of bedaquiline as a single drug. • Bedaquiline should be administered only by directly observed therapy (DOT) and with case management strategies. Such strategies might include the use of incentives and enablers (e.g., food certificates, bus passes, cash, or housing) to ensure adherence to the treatment regimen. • Patients should be advised that nonadherence to a treatment regimen could result in treatment failure, relapse, or acquired resistance. An evaluation for the development of resistance to the anti-TB regimen (including repeat drug susceptibility testing, if indicated) is recommended for patients with treatment failure or relapse. # Monitoring • Persons receiving bedaquiline should be monitored weekly for nausea, headache, hemoptysis, chest pain, arthralgia and rash, and treatment should be modified as clinically indicated. • Monitoring for other suspected adverse reactions should be tailored to side effects specific to other drugs in the background regimen and the potential for drug interactions with bedaquiline. • Bedaquiline use in the treatment of pulmonary MDR TB should be accompanied by microbiologic monitoring with one sputum specimen submitted for culture monthly throughout and at end of treatment, even after conversion to negative culture, which is consistent with the standard approach to treatment and care of patients with MDR TB in the United States. Any monthly specimen that grows M. tuberculosis, including one before treatment initiation with bedaquiline, should be referred to a laboratory for surveillance of bedaquiline resistance in consultation with the state public health laboratory (1,(17)(18)(19). CDC will assist in identifying a laboratory that can perform bedaquiline susceptibility testing for this purpose. # Precautions and Monitoring for Adverse Events # Training, Education, and Medical Consultation • Training and education for bedaquiline administration, adverse event monitoring, clinical response monitoring, and reporting should be provided for public health programs/professionals, TB physicians, and others who will be involved in the care and management of patients receiving bedaquiline. • Treatment of MDR TB should be provided in consultation with an expert in the management of MDR TB. # Registry of Patients Treated With Bedaquiline Per postmarketing surveillance requirements (11), all persons started on bedaquiline should be enrolled in a patient registry. This registry should facilitate an expanded and standardized monitoring system to track systematically such variables as serious adverse events, less serious side effects, early and late patient outcomes (culture conversion, relapse, completion of treatment, and cure), laboratory data including collection and testing of patient isolates at the start of and during treatment, interaction with other drugs, use in multidrug regimens, drug administration practices, use in the operational setting, feasibility of implementation and cost effectiveness, drug distribution mechanisms and process, and drug utilization data. Janssen Therapeutics will maintain this registry and collect data prospectively on all patients started on bedaquiline through December 2018 with a final report anticipated in August 2019. CDC, in conjunction with Janssen Therapeutics, will provide guidance on the implementation plan for bedaquiline use (process for distribution through an identified point of contact for each of the 68 DTBE-funded jurisdictions in the United States). # Safety Reporting Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported to Janssen Therapeutics at telephone 1-800-526-7736, to FDA at telephone 1-800-332-1088 or at http://www.fda. gov/ medwatch, and to CDC's Emergency Operations Center at telephone 1-770-488-7100. # Planned Studies and Updates to CDC Provisional Guidelines Janssen Therapeutics is required to conduct a double-blind placebo-controlled multicenter Phase III RCT in patients with sputum smear-positive pulmonary MDR TB as part of the conditions associated with accelerated approval under 21CFR314.500 (11). Additional requirements include, but are not limited to, a study to define the quality control ranges of bedaquiline for MDR TB isolates using standard agar proportion and MIC methods, and a clinical trial to identify any unexpected serious risk of increased drug levels of bedaquiline in HIV patients co-infected with M. tuberculosis. CDC will revise these provisional CDC guidelines as needed when those data become available. # The material in this report originated in National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention, Jonathan Mermin, MD, Director, and the Division of Tuberculosis Elimination, Kenneth G. Castro, MD, Director.	None	None
2d400d00ad24d01a6784f157077d196f67d605bd	cdc	None	Less than or equal to 0.4 m g /cu m Less than or equal to 2.0 m g /c u m Less than or equal to 40 m g /cu m 40 m g /cu m or greater or unknown ( 1 ) H alf-m ask respirator with high-efficiency filter (s). ( 2 ) T ype C dem and-type (n eg ative pressure) supplied-air res pirator with half-m ask facepiece. (1 ) F ull facepiece respirator w ith high-efficiency filter (s). ( 2 ) T ype C dem and-type (n eg ative pressure) supplied-air res pirator with full facepiece. (3 ) Self-contained breathing ap paratus with full facepiece in de mand m ode (negative pressure). ( 1 ) Pow ered air-purifying (p osi tive pressure) respirator with high efficiency filter(s). (2 ) T ype C continuous-flow (positive pressure) supplied-air respirator. ( 1 ) Com bination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply. (2 ) Self-contained breathing ap paratus with full facepiece in positive pressure mode.# PREFACE T he O ccupational Safety and H ealth A ct of 1970 em phasizes the need for standards to protect the health and safety of w orkers exposed to an ever-increasing num ber of potential hazards at their w orkplace. T he N ational Institute for O ccu pational Safety and H ealth has projected a form al system of research, with prior ities determ ined on the basis of specified indices, to provide relevant data from which valid criteria for effective standards can be derived. R ecom m ended stan dards for occupational exposure, which are the result of this work, are based on the health effects of exposure. T he Secretary of L ab o r will weigh these recom m endations along w ith other considerations such as feasibility and means of im plem entation in developing regulatory standards. It is intended to present successive reports as research and epidemiologic studies are com pleted and sam pling and analytical m ethods are developed. C riteria and standards will be reviewed periodically to ensure continuing protection of the w orker. I am pleased to acknowledge the contributions to this report on cadm ium by m em bers of my staff, by the Review C onsultants on Cadm ium , by the ad hoc com m ittees of the A m erican Industrial Hygiene A ssociation and of the Society of Toxicology, by R obert B. O 'C onnor, M .D ., N IO SH consultant in occupational m edicine, and by E dw in C. H yatt on w ork practices and respiratory protection. T he N IO SH recom m endations for standards are not necessarily a consensus of all the consultants and professional societies th at reviewed this criteria docum ent on cadm ium . Lists of the N IO SH Review Com m ittee m em bers and of the Review C onsultants appear on the following pages. " C ad m iu m " refers to elem en tal cadm ium and all cadm ium com pounds. A n " actio n lev el" is defined as h alf th e tim e-w eighted average co n ce n tra tio n e n v iro n m en tal lim it o f cadm ium . " O ccupational exposure to cad m iu m " is d efin ed as exposure to cadm ium a t a c o n c e n tra tio n g re a te r th a n th e a c tio n level. E xposures a t low er en v iro n m ental c o n c en tratio n s will n o t req u ire a d h e re n c e to the fol lowing sections, ex cep t fo r S ection 6 (b ) and 7 (d ). Sam ples shall be analyzed by th e m ethod provided in A ppendix II o r by a m eth o d show n to be at least equivalent in precision and sensitivity. # Section 2 -Medical M edical m onitoring shall be m ade available to all w orkers subject to occu p atio n al exposure to cadm ium . (a ) P rep lac em e n t exam inations shall be m ade available to new o r reassigned em ployees p rio r to jo b placem en t, and, w ithin 6 m onths o f the prom ulgation o f a sta n d ard based on these reco m m endations, to em ployees already engaged in work involving exposure to cadm ium . P rep lacem en t exam inations shall include com prehensive w ork an d m edical histories, a 14" X 17" P.A . ch est X -ray, m easurem ent o f forced vital capacity (F V C ) and forced expiratory volum e d u r ing th e first second (F E V j), m easurem ent o f blood pressure, blood analysis (b lo o d u re a nitrogen, com plete blood co u n t, and serum glutam ic oxalo ace tate transam inase o r o th e r liver enzym es), and urinalysis (m icroscopic exam ination, sugar determ in atio n , q u antitative p rotein determ ination, and specific gravity m easurem ent). A judgm ent o f th e w o rk e r's ability to w ork in positive o r negative pressure respirators shall be m ade. T h e m ethod fo r p ro tein determ ination in urine shall be q u antitative and cap able o f detecting low m olecular w eight proteins (see A ppendix III). D eterm ination o f urine cadm ium levels is also recom m ended. (b ) P eriodic exam inations shall also be m ade available. E xcept fo r urine p ro tein determ inations, w hich shall b e m ade available every 4 m onths, these exam inations shall be offered yearly, o r as otherw ise d irec ted by th e responsible physician. T hese p eriodic exam inations shall include in terim w ork and m edical histories, urinalysis (w ith q u an titativ e p ro te in determ inations every 4 m o n th s), pulm onary function tests (FV C and F E V ,), an d blood pressu re. C h est radiographs shall be ta k e n if judged necessary by th e responsi ble physician. In # Section 4 -Personal Protective Equipment and Clothing E ngineering co n tro ls shall be used if needed to m aintain airb o rn e cadm ium co n cen tratio n s a t or below th e lim its recom m ended in Section 1. C o m pliance w ith these w orkplace environm ental limits by th e use o f resp irators is p erm itted only during installation a n d testing o f engineering controls, during perfo rm an ce o f n o n ro u tin e m aintenance or rep a ir, during single op eratio n s, o r during em er gencies. W hen use o f a resp irato r is perm itted, it shall be selected a n d used in acco rd a n ce w ith the follow ing requirem ents: (a ) F o r th e p u rpose o f determ ining the type o f re sp ira to r to be used, th e em ployer shall m ea sure th e c o n ce n tra tio n s o f cadm ium in th e w ork place initially and th e re a fter w henever control, process, o p eratio n , w orksite, o r clim ate changes o c c u r th a t are likely to increase the co n cen tratio n o f a irb o rn e cadm ium . # ( b ) T h e em p lo y er shall en su re th a t no w orker is exposed to cadm ium in excess o f th e re c o m m en d ed lim its b ecau se o f im p ro p er resp irato r selectio n , fit, use, o r m ain ten an ce. (c ) A resp irato ry p ro te c tio n p ro gram m eeting th e req u irem en ts o f 29 C F R 1910.134, w hich in c o rp o ra te s th e A m erican N atio n al S tan d ard P ra c tices fo r R espiratory P ro te c tio n , Z 8 8 .2-1969, shall be estab lish ed an d e n fo rc e d by th e em ployer. ( d ) T h e em p lo y er shall p ro v id e resp irato rs in ac c o rd a n ce w ith T ab le l -l , an d shall ensure th a t em ployees use th e resp irato rs p ro v id ed in a p ro p e r m an n er w h en w earing o f resp irato rs is required. (e ) R esp irato rs selected from th ose described in T ab le 1-1 shall be th o se ap p ro v ed u n d er the provisions o f 30 C F R 11. (f) T h e em ployer shall en su re th a t em ployees are p ro p erly in stru c te d in th e use o f resp irato rs as signed to th e ir use an d o n how to te st fo r leakage, p ro p e r fit, an d p ro p e r o p eratio n . (g ) R esp irato rs specified in T ab le 1-1 fo r use in atm o sp h eres o f h ig h er c o n c e n tra tio n s o f a ir borne cadm ium m ay be used in atm o sp h eres o f low er cadm iu m co n cen tratio n s. (h ) T h e em ployer shall estab lish and co n d u ct a p ro g ram o f cleaning, sanitizing, inspecting, m ain taining, repairing, an d sto rin g o f resp irato rs, to e n sure th a t em ployees a re p ro v id ed w ith clean resp irato rs th a t are in good o p eratin g condition. (i) T h e em ployer shall periodically m onitor th e use o f resp irato rs to en su re th a t th e p ro p er type o f re sp ira to r is w o rn , to ev alu ate th e effec tiveness o f th e resp irato ry p ro te c tio n program , and to elim in ate any deficien cies in use and care o f respirators. # Section 5 -Informing Employees of Hazards from Cadmium (a ) W o rk ers initially assigned o r reassigned to jo b s involving o cc u p a tio n a l expo su re to cadm ium shall be inform ed o f th e h azards, sym ptom s o f overex p o su re (in clu d in g in fo rm ation on the ch aracteristics o f o n se t a n d stages o f illness), ap pro p riate p ro c e d u re s to be ta k e n in th e ev ent o f an em ergen cy , and p re c a u tio n s to en sure safe use an d to m inim ize exposure. T h ey shall be advised o f th e availability o f relev an t in fo rm ation, includ ing th a t p rescrib ed in ( c ) below . T his inform ation shall be accessible to e a c h w o rk er occupationally exposed to cadm ium . # (b ) A co ntinuing ed u catio n program , co n d u c te d by a perso n o r persons qualified by ex p erien c e o r special training, shall be instituted to en su re th a t all w ork ers have c u rre n t know ledge of jo b hazards, p ro p e r m aintenance proced u res and clean u p m ethods, an d th a t they know how to use resp irato rs correctly. It shall include a description o f the general n atu re o f the m edical surveillance p ro c ed u res and w hy it is advantageous to the w o rk er to undergo th e se exam inations. (c ) R eq u ired inform ation shall be reco rd ed on a " M aterial Safety D ata S h e e t" as specified in A ppendix IV o r on any o th e r form approved for th e purpose by th e O ccu pational Safety and H ealth A dm inistration, US D e p artm en t o f Labor. # Section 6 -Work Practices ( a ) E xhaust System s O p eratio n s creatin g w orkplace exposure to c a d m ium shall be enclosed to the m axim um extent p racticab le and be provided with local exhaust ventilation unless app ro p riate air sam pling and analysis have d em o n strated th a t con cen tratio n s are a t o r below th e environm ental limits. M ethods o th e r th an en closure and ventilation for m eeting exposure lim its to cadm ium m ay be used if they bring co n ce n tra tio n s in w orkplace air to or below th e environm ental limits. E ffluent air shall be clean ed to m e et any em ission stan d ard s th a t may becom e prom ulgated. A ir from th e exhaust ven tilatio n system shall n o t be recircu lated into the w orkplace. E nclosures, exhaust hoods, an d ductw ork shall be k e p t in good re p air so th a t design airflows are m aintained. A irflow shall be m easured a t each h ood a t least sem iannually, and preferably m onthly. C o n tin u o u s airflow indicators are recom m ended, such as w a ter o r oil m anom eters properly m o u n ted a t th e ju n c tu re o f fum e hood and du ct th ro a t (m a rk ed to indicate a ccep tab le airflow ). A log show ing design airflow and results o f sem ian nual inspections shall be kept. (b ) W elding, B razing, and T h erm al C utting W elding, brazing, o r therm al cuttin g o f m aterial containing cadm ium shall be p erform ed using local exhaust ventilation d em o n strated by air sam pling an d analysis to k eep cadm ium co ncentrations w ithin th e lim its o f Section 1. F o r single o p e ra tions w here local ex h au st ventilation is n o t availa ble, w here air sam pling has n o t b een perform ed, # RESPIRATOR SELECTION GUIDE - r w here air sam pling has d e m o n strated a likelihood o f o v erexposure to cadm ium fum e or dust, resp irato rs shall be provided and w orn as -specified in Section 4. W here m olten cadm ium is u sed o r fo rm ed, te m p eratu res should be k e p t as low as possible c o n sistent w ith th e req u irem en ts o f th e o p eratio n to prev en t excessive fum e gen eratio n . A dditions of cadm ium should be m ad e in th e m an n er g e n e ra t ing th e least fum e. W h erev er possible, this should be accom plished by a u to m atic co n tro ls, with recording o f te m p e ra tu re and use o f alarm s o r in dicato rs fo r higher te m p eratu res. (c ) E m ergency P ro ced u res E m ergency p ro c e d u re s shall be established for any ev en t w hich m ay resu lt in sub stan tial release o f airb o rn e cadm ium . Such p ro c e d u re s shall in clude provision for a p p ro p ria te resp irato rs as specified in S ection 4. Specific em ergency p ro c ed u res shall be designed fo r fires, to p ro te c t b o th in-plant w orkers and firefighters. (d ) W ork C lothing W orkers shall w ear w ork clothing consisting of at least h a t, shirt o r blouse, pants o r skirt, and shoes. W ork clothing a n d stre e t clothing shall be exchanged at the beginning and th e end o f each w orkday, so th a t w ork clothing will n o t be w orn outside th e w orkplace. T h e em ployer shall provide for p ro p e r laundry o f clothing and shall instruct lau nderers on p ro ce d u re s to be ta k en to avoid in halation o f cadm ium -containing dusts. # Section 7 -Sanitation Practices (a ) W here th ere is cadm ium -containing dust, cleaning should be p erform ed by vacuum pickup o r w et m opping. N o dry sw eeping o r blowing shall be p erm itted . (b ) E m phasis shall be p laced upon p ro m p t cleanup o f spills, re p air o f eq u ip m en t and leaks, p ro p e r storage o f m aterials, and collection o f cadm ium -containing dust. (c ) C adm ium -containing and cadm ium -plated m etal p arts should be k e p t sep a ra te from parts n o t containing cadm ium and m ark ed appropriately so th a t accid en tal exposures resulting from w elding and cuttin g will n o t occur. (d ) Facilities shall b e m ain tain ed to p ro te c t foodstuffs an d food co n sum ption areas from co n tam ination by m aterials containing cadm ium . F ood storage, handling, and consum ption shall be sep a ra te from cadm ium w ork areas. Sm oking or carrying uncovered to b acco o r to b acco products in cadm ium w ork areas shall be prohibited. (e ) A d eq u ate handw ashing and show er facili ties shall be provided. W orkers shall wash th eir hands before eating o r before using tob acco to p rev en t th eir absorbing additional am ounts o f c a d m ium com pounds. # Section 8 -Monitoring and Recordkeeping W orkers are n o t considered to be occupationally exposed to cadm ium if environm ental c o n ce n tra tions, as d eterm in ed on the basis o f an industrial hygiene survey to b e perform ed w ithin 90 days o f th e prom ulgation o f a standard, do n o t exceed the actio n level, ie, h alf the recom m ended TW A en vironm ental lim it, o r if there is no operation, storage, o r handling o f cadm ium in any form o r co n tam in atio n o f w orkplace air by cadm ium from o th e r sources. T h ese industrial hygiene surveys shall be re p e a te d at least every 3 years and w ithin 30 days after any p ro cess o r o p eratin g change like ly to resu lt in increases o f airb o rn e con cen tratio n s o f cadm ium . R eco rd s o f these surveys, including th e basis fo r conclu d in g th a t airb o rn e co n c e n tra tions o f cadm ium are a t o r below th e action level, shall be m ain tain ed until th e n ex t survey has been com pleted. T h e follow ing req u irem en ts apply to o c c u p a tio n al exposure to cadm ium , ie, to w orkplaces w here th e actio n level is exceeded. E lectroplating is and has b een th e leading use fo r cadm ium , consum ing from 45 to 60% o f the am o u n t p ro d u ced ea ch year. A bout one m illion k ilogram s/year are used for stabilizers in plastics, and som ew hat less th a n a m illion kilogram s in pig m ents, w ith plastics a large con su m er o f the pig m e n ts. 12 O n e -q u arter to one-half m illion kilogram s o f cadm ium are used annually as an alloying agent in low m elting-point brazing alloys, in co p p er for autom obile rad iato rs, in silver-cadm ium electrical co n tacts, and in o th e r m etallurgical alloys. T hese 4 m ajor categories a c c o u n t fo r 80-90% o f the cadm i um used, with the rest d istributed am ong m inor uses such as nickel-cadm ium b atteries, fungicides, photography, and television picture tubes. C adm ium dusts, fum es, and m ists are com m only p re sen t in som e sm elting processes involving zinc, co p p er, and lead as well as in specific processes fo r extracting cad m iu m . 13 NIO SH estim ates th a t 100,000 persons in the w ork fo rce are potentially exposed to cadm ium . 1941-1946. Bonnell34 cited S tephens, in 1920, and M ancioli, in 1940, w ho d escribed cases o f chronic illness due to occupational exposure to cadm ium . D uring W orld W ar II, the superim position o f nutritional d eficiencies o n to cadm ium exposure was suggested by N icaud and cow orkers38 as contributing to bone disease (o steo m alacia) in cadm ium w orkers in F rance. C adm ium is also believed to have been one causal fa c to r in the developm ent o f Itai-Itai ( " o u c h -o u c h " ) episodes in J a p a n . 1 (pp 137' l s , ) '39' 41 # Extent of Exposure # Effects on Humans T his section review s th e effects o f cadm ium on hum ans, m ostly from evidence developed in epidem iologic studies, in term s o f types o f effects such as organs o r o rgan systems affected. M any o f th ese studies to g eth er w ith additional ones are review ed, often in m ore detail, in th e section on Epidemiologic Studies. In the la tte r section, th ere is m ore em phasis on p o pulation studies and on a c o r relation o f hum an effects w ith airborne cadm ium co ncentrations. (a ) # Pulm onary Effects (1 ) A cu te Effects A cu te intoxication from exposure to cadm ium oxide fum es in c o n cen tratio n s o f a t least several m illigram s/cubic m e te r has a characteristic clinical p ic tu re .42"45 Initially, th ere are virtually no sym p tom s; these usually ap p e ar 4-10 hours later, w hen dyspnea, cough, an d n o t infrequently a feeling o f co n striction in th e chest develop. O n occasion, w orkers m ay com plain o f substernal ch est pain o r a b urning sensation in th e ch e st th a t is a c c e n tu ated by coughing. Som e m ay also develop a flu like syndrom e c h a ra c teriz e d by shaky chills and m yalgia localized in th e b ack and limbs. U nder this la tte r circu m stan ce, th e illness m ay be m istaken fo r m etal-fum e fever. In any event, acu te pulm onary ed em a m ay develo p w ithin 24 hours. In such cases, physical ex am in atio n reveals an acutely ill p a tie n t w ith rales h e a rd on au scu ltatio n o f th e chest. C h est X -rays show b ilateral p u lm onary infil tra te s suggestive o f p u lm o n ary ed em a. Pulm onary function testing, w h en p erfo rm ed , has show n a d e creased fo rced vital cap acity (F V C ) and fo rced expiratory volum e durin g th e first seco nd (F E V ,). (b ) R enal Effects T h e m ost com m on abno rm ality fo u n d in w or kers exposed to cadm ium is p ro te in u ria .54,55,65 Friberg55 fo u n d p ro te in u ria in 81% o f 43 w orkers exposed to cadm ium fo r an av erage o f 2 0 years in th e alkaline storage battery industry and pointed o u t th a t the p ro tein ex creted w as n o t th e protein conventionally ex creted afte r kidney injury, ie, it w as o f low m olecular w eight, ab o u t 2 0 ,0 0 0 -30,000. Piscator6 exam ined p ro te in in urines o f 79 cadm ium w orkers, 55 o f whom had been previ ously studied by F rib e rg .55 H e found an average ex cretio n o f p ro tein o f 50 m g/day in 10 healthy, unexposed subjects and 70-2,600 m g/day in cadm i um w orkers. In m en excreting m ore th an 150 m g/day, th e e lectro p h o retic p a tte rn o f urine p ro tein was ch arac teriz ed by a low album in co n te n t and increased co n ten ts o f a 2-, /3-, and yglobulins. In 75% o f th e m en excreting m ore th an 400 m g/day, th ere was a distinct /3 -globulin peak. In a few , he found a post-y-globulin fraction. C ad m ium w orkers also had a significantly higher c o n c e n tra tio n o f 7 -globulin and o f pro tein -b o u n d hexoses in serum th an did unexposed w orkers. P otts65 studied 70 battery w orkers and found pro tein u ria in 34% o f those exposed 10-19 years, and 82% o f w orkers exposed fo r over 30 years. Kazantzis and associates54 n o ted th a t d u ratio n o f exposure to cadm ium was im p o rtan t in th e developm ent of pro tein u ria. T hey fo u n d no p ro tein u ria in those ex posed fo r less th an 2 years; p ro tein u ria was found in 3 o f th e 4 exposed fo r 12 to 14 years and in all o f th o se exposed fo r 25 years o r m ore. The p ro te in u ria was ch aracterize d by excretion o f uri nary p ro tein o f low m olecular w eight, betw een 2 0 ,000 and 25,000. T he pathogenesis o f the p ro te in u ria has n o t been fully delineated, but V igliani67 has suggested th a t p ro tein m ay app ear in th e urine because tu b u lar-b o u n d cadm ium in te r feres w ith th e ability o f th e norm al kidney to catabolize im m unoglobulins and o th e r proteins. O th e rs 1 (pp l0f''106)-68,69 believe th a t it results from a d ecreased reab so rp tio n o f norm ally present protein by th e renal tubules. T his latte r view seem s m ore likely, ie, it is likely th a t low m olecular w eight p ro tein s appearing in the urine o f persons intox icated by cadm ium w ould have b een reabsorbed by th e norm al kidney, so th a t th e ir app earan ce in u rin e is an early sign o f renal dysfunction. How ev er, as F riberg and associates1 < D 112) have sug gested, b o th altered catabolism and altered re a b so rp tio n o f pro tein s m ay exist. T h ere are few d a ta on acute renal effects. Bi lateral renal co rtical necrosis has been rep o rted in a fatal c a se . 44 T he co n c en tratio n o f cadm ium in th e kidney was given as .7 ppm w et w eight, O lfactory E ffects A p o te n tia l con seq u en ce o f cadm ium exposure is dam age to the olfactory apparatus, w hich may result in to tal anosm ia. As with lung and kidney dam age, d u ratio n and co n ce n tra tio n of exposure a re probably im p o rta n t factors. P otts65 found ol factory dam age in 53-65% o f w orkers exposed 10-29 years and in 91% o f those exposed for m ore th an 30 years. T hirty-seven p e rc e n t o f the 43 w or kers studied by F riberg 55 show ed olfactory im pair m ent. A dam s and C ra b tre e 78 rep o rted cases o f hyposm ia and anosm ia am ong w orkers exposed to cadm ium oxide dust as well as to nickel dust, in an alkaline-battery o p eration. A group o f 106 battery w orkers w ere co m p ared with 84 age-m atched co n trols. O lfactory acuity was ju d g ed from each sub je c t's evaluation o f his ow n acuity and from a ph enol sm elling test. B attery w orkers rep o rted sig nificantly m ore anosm ia (15% vs 0% ) and did less well on th e phenol sm elling te st (27% vs 5% ). T h ere was a positive correlation betw een p ro tein u ria and anosm ia; 17 w orkers w ith p roteinuria also w ere anosm ic. E xam ination o f noses showed m any cases o f local irritation from dust, som e subm u cosal fibrosis in m ild cases of deficient olfactory acuity, and cases o f ulceration, occasionally with dry crusting, in m ore advanced cases. Biopsy m aterial from one case show ed a m ild nonspecific subm ucosal chronic inflam m ation w ith a few small loose focal accum ulations o f lym phocytes and a few widely sc attere d eosinophils. T he authors a t trib u te d th e anosm ia to exposure to eith er cadm i um o r nickel, o r to a m ixture o f the two. T he p o p ulation studied by Friberg55 was also exposed to nickel. P otts65 did n o t re p o rt nickel exposures, b u t th e w orkers m ad e b atteries, so there w ere un doubtedly exposures to nickel dust, as well as to cadm ium . H ow ever, Tsuji e t al79 reported th a t several w orkers exposed to cadm ium in a zinc refinery, w ithout evidence o f exposure to nickel, had a so-called insensitiveness to smells. (d ) H em atopoietic System A cute effects on the blood a fte r respiratory ex posure at a high co n c en tratio n o f cadm ium have been no ted both in hum ans and in anim als.44,80 E levated hem oglobin in som e hum an subjects may well have been th e result o f h em o concentration from pulm onary e d e m a . 44 A nem ia has been described in w orkers exposed fo r a long tim e to cadm ium oxide dust and fu m e .38,55,81 T he anem ia was usually m oderate. In a g ro u p o f w orkers exposed to cadm ium 5-30 years, Piscator, in u n published studies review ed by F riberg, P iscato r, T h e Itai-Itai (" o u c h -o u c h " ) disease w hich o c cu rred in certain areas o f Ja p a n was attributed to pollution o f w ater an d crops by industrial, cadm i um -containing w aste. 1 40'41.89 The disease is apparently o steom alacia and involves painful jo in ts and bones, especially in th e back and legs. T hose affected w ere m ostly m ultiparous, post m enopausal w om en. A nutritionally deficient (low calcium and p ro te in ) d iet was perhaps an addi tional facto r. Low estrogen levels may also have had som e bearing on th e osteoporosis seen in these cases. (2 ) T eeth T h e d evelopm ent o f a yellow ring a t the neck o f th e to o th was re p o rte d in early epidem iologic sur veys in occupationally exposed persons and was at one tim e suggested to be a w arning sign o f chronic cadm ium in to x icatio n .62,90 W h eth er this is because o f surface ab so rp tio n o f cadm ium , reaction with In an epidem iologic study o f c an c er in persons exposed to cadm ium , K olonel101 co m pared the in cidences o f several types o f c a n c e r in persons hav ing an in ferred o ccu p atio n al history o f cadm ium w ork w ith those in a co n tro l population. The basis fo r inferring a history o f o ccu p ational exposure to cadm ium was ind irect, from jo b classification in fo rm atio n revealed in an interview on adm ission to a c a n c e r research hospital. T h e te st and control p opulations w ere all w hite m ales, aged 50-79 years, and w ere all referred to th e Roswell Park M em orial H ospital in Buffalo, N ew Y ork, because o f suspected neoplastic disease. O ne group of c o n trols w ere those found to have nonneoplastic gas troin testin al disease; a second group o f controls w ere those found to have colon cancer. Kolonel found a significant increase in ren al can cer, and a nonsignificant increase in p an creatic ca n ce r am ong th e p atien ts th o u g h t to have been exposed to ca d m ium . H e an ticip ated an increased incidence of p ro static can cer, b u t found none. H e looked for a sim ilar increase in c a n c e r am ong those exposed to cadm ium from dietary intake o f cadm ium o r from sm oking, b u t the association was questionable. In view o f th e deficiencies in his d a ta on o ccu p a tional histories, conclusions from this study are u n certain. In a later publication based on these data, K olonel102 co m m en ted on evidence o f a synergistic relationship betw een exposure to cadm ium and cig arette sm oking. In th e b elief th a t th e greater th a n additive effect could n o t be acco u n ted fo r by the in creased cadm ium exposure, he suggested th a t som e o th e r co m p o n en t o f cigarette sm oke C adm ium has also caused food poisoning from the use o f a cadm ium -plated refrig erato r sh elf as a grill to hold steak over c h a r coal for broiling.109 A 2-year old child with en cep h alopathy originally attrib u ted to lead was found to have a very high cadm ium concentration o f 710 (j.g/liter in his urine. It was found th a t the child was fond o f licking freshly polished w hite shoes (polish solution containing 275 pig C d/100 m l), occasionally a te silver polish (185 /xg/100 m l), and ate red p ain t (5 0 0 m g /100 g) from his c rib . 110 Bui e t al111 analyzed the chrom osom es in lym phocytes from Swedish battery-factory w orkers and Itai-Itai p atien ts from Jap a n , to gether with co n tro ls from Sw eden and Jap an , and found no significant differences in chrom osom al aberrations betw een cadm ium -exposed people and their respective controls. H ow ever, sizes o f populations studied w ere small in each case. M ean frequencies of ab erratio n s ranged from 2.0% in Swedish b a t tery w orkers to 6.7% in Itai-Itai patients. Shiraishi and co w orkers112'113 cu ltured cadm ium sulfide with h um an leukocyte cells and exam ined leukocyte chrom osom es from 7 Itai-Itai patients, and in each case found an increased incidence o f chrom osom al aberratio n s over controls. T he rate o f abnorm ali ties in th e Itai-Itai p atien ts112 ranged from 14 to 64% o f th e 50 cells exam ined, m uch higher than th e rate found by Bui e t a l. Bonnell34 exam ined 100 w orkers exposed to ca d m ium oxide fum es and 104 controls with sim ilar age distribution in 2 B ritish copper-cadm ium alloy facto ries. N in eteen o f th e 100 exposed w orkers h ad em physem a, p ro te in u ria , o r both, while 3 o f th e co n tro l group had e ith e r em physem a or p ro tein u ria. All 19 m en w ith signs and sym ptom s had been exposed to cadm ium for m ore th an 5 y ears and 13 o f them fo r m ore th a n 15 years. Four additional w orkers required hospitalization because o f shortness o f b reath. Significant dif feren ces in results from certain respiratory fu n c tion tests w ere found by K azantzis126 betw een the exposed and th e co n tro l groups in these sam e fac tories, particularly in th e tim e co n sta n t o f the ex p iratory forced vital capacity curve. In the group o f these w orkers exposed to cadm ium for m ore th an 10 years, B uxton 127 found th a t the volum e of residual air and th e residual q u o tie n t (ie, residual air as expressed as a p ercentage o f th e total lung volum e) w ere both significantly increased. This finding is consistent w ith F rib e rg 's . A hlm ark and associates76 rep o rted on 110 cadm ium -exposed w orkers and 22 controls. Several te st m easurem ents show ed th a t kidney functions w ere red u ced w ith long exposure. U rinary protein ex cretion increased regularly w ith length o f expo sure from 100 m g/24 hours (ranging from 50 to 170) at less th an 5 years to 955 (ranging from 370 to 1800) m g/24 ho u rs a t 31 years and over. T he incidence o f kidney stones increased from 9.1% in the controls to 12.3% in the 6 -to 10-year exposed group and to 43.6% in the g rea ter th an 15-year ex In th e age g ro u p 50-59, th ere was a statisti cally insignificant in crease in hyperten sion in ex posed w om en. T h e re w as a significant increase in average h aptoglobin an d sed im en tatio n ra te in the 40-49 age group and a nonsignificant increase in the 18-29 y ear age group. Serum iron was low er in th e 50-59 year group. T here w ere n o significant differences in urinary findings. A m ong the controls th e re was one case w ith a very high excretion of /32-m icroglobulin; th e p a tte rn obtained by elec tro p horesis o f urine suggested an effect on tu b u lar fu n ctio n b u t th e re was no glucose in the urine, and a b acterial infection involving th e tubules was sug gested as th e explanation. T here was a slight tu b u lar dysfunction in a 71-year-old exposed w om an, b u t w ithout in creased /32-m icroglobulin excretion. She had b een classified as a suspect case in 1969. P iscato r e t' a l131 also observed significant dif feren ces in blood and urine cadm ium , and found th a t u rin e cadm ium , b u t n o t blood cadm ium , in creased w ith age. T hey also n o ted a slight decrease in u rine zinc w ith exposure tim e, ex cept th a t urine zinc was increased by use o f drugs for trea tm en t of hypertension. S m okers had significantly higher blood cadm ium levels th an nonsm okers; dif feren ces betw een cadm ium -exposed sm okers and n onsm okers w ere n o t found in urinary excretion o f cadm ium b u t c o n tro l sm okers ex creted m ore cad m ium th an co n tro l nonsm okers. It was believed th a t cadm ium m ight have b een deposited on cig arettes during w ork, th en vaporized during sm oking and inhaled. T hey found a significant co r relation betw een blood and urine cadm ium in nonsm okers exposed less th a n 1 0 years but n o t in sm okers. K jellstrom and asso ciates132 studied the ex cre tion o f /3 2-m icroglobulin in m ale and fem ale w or kers in th e battery factory originally studied by F rib e rg .55 T h ere w ere 240 m ale and fem ale w or kers exposed to cadm ium oxide dust and to nickel hydroxide dust in th e study group, and there were 87 unexposed m ale controls. T he exposed w orkers w ere em ployed in th e d ep a rtm e n t w here m aterials fo r b attery electro d es w ere m ade (m aterial plant) o r w here th e electro d es and batteries w ere assem bled (assem bly p lan t). S tationary and personal sam ples w ere co llected on m illipore filters except in 1959 and p rio r years and analyzed by atom ic ab so rp tio n sp ectrophotom etry. P article size analy sis in 1972 show ed th a t 95% o f the particles w ere sm aller th an 5 /xm. E nvironm ental concentrations had been occasionally m easured in the factory from 1946 on, b u t system atic m easurem ents based on personal sam pling had n o t been perform ed. In dividual sam ples in the assem bly plant in 1946, based on stationary sam plers, averaged 6 . T he w orkers w ere draw n from 3 different fac to ries, an electro n ic w orkshop, a nickel-cadm ium storage battery factory, and a p la n t producing c a d m ium . E ach factory h a d a co ntrol group selected to m atch th e exposed group in sex, age, w eight, height, sm oking habits, and socioeconom ic status. Since no im p o rtan t m odifications had o ccu rred in th e different industrial processes since th eir institu tion, th e au thors believed th a t levels o f airborne cadm ium found in the 3 plants w ere quite rep resen tativ e o f p ast exposure. A description o f th e exposed groups and the w orkroom cadm ium levels found are given in T able III-1. C o n tro l groups w ere described as Cl, C 2, and C 3, co rresponding to the th re e exposed groups. E xposed groups w ere exposed to dust of cadm ium o r its com pounds; fo u r w orkers in G roup E3 w ere also interm ittently exposed to fum e. In group E l , th e only change was a slight in crease in urine cadm ium ; th ere w ere no significant differences in pulm onary function indices, b u t it was n o ted th a t an effect o f cigarette sm oking on pulm onary function was evident. In group E 2, in b o th sm okers and nonsm okers, all pulm onary indices w ere on the average low er th a n th e corresponding co ntrol group, b u t these differences w ere n o t statistically significant. Blood and urine cadm ium con cen tratio n s were higher th a n co n tro l levels. E lectrophoresis show ed evidence o f glom erular proteins in four w orkers. O ne w orker know n to have glom erulonephritis had w hat was described as excessive proteinuria. In group E3, pulm onary indices (FV C , F E V l and peak expiratory flow ra te ) w ere significantly low ered. C ough b u t n o t ex p ectoration was m ore com m on in E3 th a n in C3 w orkers. T here w ere slight b u t statistically significant changes in som e o f th e blood enzym es, viz, an increased /3 -galactosidase, an increased lactic dehydrogenase, and a decreased RBC acetylcholinesterase; h em atocrit was also low er in E3 th an C3. H ow ever, these changes w ere n o t sufficient to suggest adverse health effects. F u rth e r details o f these stu d ies133,134 as well as o f those on o th e r w orkers exposed to cadm ium have been published in a com prehensive rep o rt, also from th e C atholic U niversity o f Louvain, Belgium, by M atern e et a l. 135 Som e o f these w orker groups w ere also exposed to lead, w hich may m ake som e o f th e observations less clearly attrib u tab le to cad m ium . H ow ever, th e au th o rs co n cluded th at lead ab so rp tio n had little o r no role in the kidney changes, an d th a t th e effects in the kidneys w ere from cadm ium ab so rption by these w orkers. In F acto ry I, involving electronic m an u facture, 26 ex posed w om en and 26 control w om en w ere studied. T h e re w as no lead exposure in this group. In F ac tory II, w here nickel-cadm ium batteries w ere m ade, 2 1 exposed m ale and 6 exposed fem ale w or kers w ere studied, w ith 19 co n tro l m ales and 4 c o n tro l fem ales. In F actory III, involving cadm ium p ro d u ctio n , 25 exposed and 25 co ntrol m ales were studied. In F actory IV, also involving cadm ium p ro d u ctio n , 6 6 exposed and 65 control m en w ere studied. C ontrols w ere m atched with cadm ium -ex posed w orkers in age and in sm oking habits. A ir bo rn e cadm ium c o n c en tratio n s w ere variable, ranging betw een 7 and 19 /xg/cu m in F actory I, 6 -94 in F actory II, 1.2-97 in F actory III, and up to several m g/cu m in F actory IV, after om itting several values (eg, 27 m g/cu m ) th a t w ere believed du e to gross con tam in atio n o f sam ples. The co n ce n tratio n ranges m entioned w ere sm aller in specific w ork sites w ithin a factory. D ifferences betw een exposed and control groups w ere often less rem arkable th an differences betw een sm okers an d nonsm okers. In F actories II and III th ere w ere decreases in hem atocrit; while this m ight be attrib u te d to lead, airborne lead c o n ce n tra tio n s w ere in th e range o f 40-50 ¿tg/cu m, w hich seem s unlikely to be high enough to cause anem ia, so possibly the reduction in hem atocrit w as due to cadm ium alone o r to cadm ium and lead. A n o th er group consisting o f 108 exposed and 110 co n tro l w orkers w ere exposed a t 74-210 yxg/cu m total (2 0 -3 0 /xg/cu m respirable) cadm i um dust, o f whom 18 exposed w orkers had w hat w as d escribed as pathologic urine proteins on elec trophoresis. P ro tein u ria was also seen in som e w orkers in F acto ries III and IV, to g eth e r with p u l m onary function decreases. T he au th o rs concluded th a t, in o rd e r to p rev en t any renal im pairm ent, air b o rne cadm ium , w h eth e r dust o r fum e, should not exceed 50 ¿ig/cu m. # Animal Toxicity In th e ensuing discussion o f anim al toxicity, em phasis is given to th o se investigations w hich sig nificantly a d d to in fo rm atio n from hum an studies, eg, rep ro d u ctiv e effects an d ex p erim ental c a r cinogenesis, w ith a re su lta n t lack o f em phasis on those effects m ore extensively stu d ied in hum ans, such as ren al and p u lm o n ary effects. In addition, in such are a s as te stic u la r effects and biochem ical studies, w here th e re are m any p u b lished studies, the m ore rep resen tativ e o r im p o rta n t studies have been selected fo r discussion. D alham n and F rib erg143 adm inistered cadm ium sulfate sc to 3 groups o f rabbits, 6 /group, 6 days/w eek, for 10 w eeks, at 650 /xg C d/kg. Tw o of th e groups w ere in jected th rice daily with dim ercap ro l, one a t 4 an d th e o th er a t 12 m g/injection; th e th ird group received only cadm ium sulfate. F o u r o f th e anim als on the high dose o f dim ercaprol and 3 receiving only cadm ium sulfate died during the experim ent. T h ere was a progressive w eight loss in all groups, greatest in high-dose dim ercap ro l anim als. P ro tein u ria developed in all b u t tw o rabbits, ea rlie r in m ost of the anim als receiving th e higher dose o f dim ercaprol. T here was a significant and progressive decrease in hem oglobin co n c en tratio n s in th e blood, b u t a sig nificant decrease in ery th ro cy te count o ccurred only in the high dose dim ercaprol animals. P ost m o rtem exam ination show ed th a t all anim als had h e p atic cirrhosis, nephrosis, and splenic fibrosis. O th e rs146-151 have also found hypertensive effects o f C d (II) in anim als. P o rte r e t al152 found no elevation o f blood p res sure in C d(II) intoxication. T hey adm inistered c ad m ium ac etate ip a t 2 mg C d/kg to fem ale Sprague-D aw ley-derived rats, th en a second ip dose o f 1 mg C d/kg 3 w eeks later. From days 14 to 27 after th e seco n d adm inistration, various autonom ic drugs w ere adm inistered in sequence by vein, and systolic blood pressures w ere recorded. W ith norep in ep h rin e b u t n o t epinephrine, drugs causing elevated blood pressure in co n tro l rats, th ere was a lesser elevation in cadm ium -treated rats, with acetylcholine, isoproterenol, and atropine, b u t not pro p ranolol, drugs causing d ecreased blood pres sure in co ntrol rats, th ere was a lesser decrease in cad m iu m -treated rats. A ortic strips from cadm iumtre a te d rats had a dim inished reactivity to an giotensin, ep in ep h rin e, barium , and tyram ine. T he au th o rs co n cluded th a t cadm ium desensitizes rat vasculature to vasoconstrictors and dilators inde p en dently o f any ability to cause hypertension. found in all 80 anim als. Sim ilar d ata were developed by M ason e t al*55 a t various doses of cadm ium chloride (0.57-6.8 mg C d/kg) given sc to rats. A gain, edem a p reced ed an ischem ic necrosis w hich was associated w ith increased intratesticular pressure, hem orrhaging, and ultim ate interference w ith testicu lar blood supply. In this study, a doseresponse relation w as found a t th e low er dose levels, 0.57-1.4 m g/kg. A t the low est dose, no ef fe ct was observed, a t 0.85 m g/kg ischem ic necrosis o f sem iniferous tu b u les o c c u rre d in 32% o f the rats, a t 1.1 m g/kg th e re was a 90% incidence, and at 1.4 m g/kg 100% o f th e rats h a d these injuries. It was suggested th a t the unusual sensitivity o f the testes to cadm ium w as related to the unique vascu la tu re , ie, pulseless, sem istagnant flow, w hich m ight have facilitated alteratio n o f capillary e n dothelial perm eability by cadm ium . Sangalang and O 'H alloran 156 studied testicular injury and changes in androgen synthesis in brook tro u t exposed to C d (II) fo r 24 h o u rs at 1 ,2 , o r 25 ppm . T estes o f the fish tre a te d a t 25 ppm show ed extensive h em orrhagic dam age. Form ation o f 11k e to testo ste ro n e, 11-/3-hydroxy testosteron e, and testo stero n e from 14C -pregnenolone in vitro was used to study the effects o f C d (II) exposure on an drogen synthesis by th e testes. T h e results show ed th a t cadm ium inhibited th e form ation o f the ste roids in vitro; w h e th er this reflects the situation in vivo is n o t know n. H ow ever, the study suggests th a t cadm ium -induced testicu lar dam age is not confined to species w ith scrotal testes. In o rd e r to investigate the testicular dam age from cadm ium in m o re detail, Parizek91 injected rats and m ice w ith cadm ium chloride (2.2-4. Parizek e t al170 fo u n d th a t in jectio n o f cadm ium a c e ta te in th e range o f 30-40 ptm ole/kg in several groups o f p reg n an t rats cau sed 40% o f the p reg n an t rats to die w ithin th e first 24 hours after cadm ium adm inistratio n . T h e rats w ere injected on th e 2 1 st day o f p regnancy. In 80% o f these p reg n an t rats, b ilateral h em o rrh ag ic ren al necrosis was observed. M etallothionein w as first isolated by M argoshes and V allee194 from horse kidney cortex and was show n to co ntain a high co n c en tratio n o f cadm ium w ith a lesser am o u n t o f zinc. Subsequently, Kagi and V allee195,196 purified this m aterial, showing th a t it was a hom ogeneous, low m olecular w eight p ro te in (1 0 ,0 0 0 m ol w t) containing 5.9% cadm i um , 2.2% zinc, and 8.5% sulfur, and having very low spectral absorptivity at 280 nm , indicating a lack o f arom atic am ino acids in its com position b u t w ith a specific absorptivity a t 250 nm due to cadm ium -sulfur groupings. T hese investigators sug gested th a t th e m etal-free p ro tein be called thionein, and th a t th e cadm ium protein be called cadm ium -thionein. N inety-five p e rc e n t of all sulfur in th e m etal-free th ionein m olecule was presen t as th e sulfhydryl group o f cysteine. M oreover, cysteine a cc o u n ted for 1 o f every 3 to 4 am ino acids, ie, 25-30% o f the am ino acids o f this p rotein are cysteine m olecules. Pulido e t al 197 show ed th a t a sim ilar p ro tein co u ld be isolated from hum an ren al cortex. T his purified m etallothionein had a m o lecu lar w eight o f 10,500 and contained 4.2% cadm ium , 2.6% zinc, 0.5% m ercury, and 0.3% co p p er. As with th e equine pro tein , th e sulfur c o n te n t w as high, nam ely 8 . 1 %, and th e characteristic ultraviolet ab so rption ban d a t 250 nm was present. Follow ing these early reports from the H arvard g ro u p , 194 197 one gro u p o f w orkers a t the K arolinska Institute in Sw eden198 and an o th er a t Dalhousie U niversity in N ova S cotia199' # Correlation of Exposure and Effect C adm ium com pounds affect m any organs and body system s. T h e re is evidence from m an or low er anim als o f effects on the respiratory trac t, on th e nervous system , on th e liver, on form ed ele m ents o f th e blood, on vascular function, on m ale a n d fem ale gonads, on thyroids, o n p an creata, on bones, and, probably m ost im portantly, on kidney function. In addition, th ere is evidence th a t cadm i um m ay cause c a n c e r and birth deform ities. W ith increasing exposure m ore cadm ium th an can be bou n d by m etallothionein will even tually be accu m u lated in th e kidneys. C adm ium will th e n exchange w ith zinc in enzym es necessary fo r reab so rp tio n and catabolism o f proteins. . . As a result o f th ese anti-enzym atic actions less p ro te in will b e catabolized o r reab so rb ed , causing tu b u la r p ro tein u ria. C adm ium excretion will in crease also as less m etallothionein will be re ab sorbed. A t this stage the accum ulation rate o f c ad m ium will becom e slow er, b u t cadm ium will still be re ab so rb ed and cadm ium levels in the tissue m ay get still higher. T he reabsorption defect will be g reate r and eventually renal cadm ium will cease to increase. T u b u lar cells will be dam aged by cadm ium , and it is conceivable th a t cadm ium will be ex creted to g e th e r with desquam ated tu b u lar cells, resulting in a decrease in renal levels o f cadm ium . If glom erular function is im paired, there will also be less filtration o f m etallo th io n ein ." It is ap p are n t th a t urinary excretion o f low m o lecu lar w eight p ro tein s and perh ap s also urinary ex cretion o f glucose o r am ino acids constitute early evidence o f altered tu b u lar function. This evidence does n o t usually a p p e ar until som e tim e after exposure at sufficiently high cadm ium co n cen tratio n s has started . T suchiya64 found no p ro tein u ria in m en exposed a t an average o f 125 /xg/cu m for less th a n 9 m onths, and w orkers with m ore th an 5 y ea rs' experience had the highest urine p ro tein levels. Kazantzis e t al54 noted th at d u ra tio n o f exposure was im p o rtan t in the d ev elopm ent o f p ro teinuria; th e re w ere no w orkers w ith p ro tein u ria in th e group with less th an 2 y e ars' exposure, th e re w ere 3 w orkers with p ro tein u ria in th e group o f 4 exposed 12-14 years, and all w orkers exposed m ore th a n 25 years had p ro tein u ria. H ow ever, w ith th e rep lacem en t o f m ale w orkers w ith w om en, co n tro l m easures to im prove w or k room hygiene have also been instituted. Thus, the app aren tly g reate r resistance o f w om en to cadm i um , evidenced by few er effects in w om en th an in m en previously em ployed in th e sam e w orkplace, is probably due to the low er con cen tratio n s of cadm ium aerosols to w hich w om en w ere exposed. F o r exam ple, P iscator e t al131 studied w om en w or kers, m ost o f w hom w orked in the plan t previously p o p u lated by th e m en studied by Friberg,55 and fo u n d significantly few er effects th an in the m en studied previously; in fact, it is doubtful th a t his pop u latio n was adversely affected a t all. H ow ever, co n cen tratio n s to w hich the w om en w ere exposed w ere significantly less (u n d e r 100 yu.g/cu m ) than those o f th e m ale w orkers (3-15 m g/cu m ), w ho developed m any toxic effects, including em physem a and renal dysfunction. T svetkova95 studied fem ale w orkers in a p lan t w here co n ce n tratio n s o f cadm ium w ere reportedly 0.1-25 m g/cu m; she found no effects in th e w orkers (although she observed rick ets and d en tal troubles in off spring), b u t it is n o t evident th a t she investigated such effects as those on th e pulm onary and renal ap p aratu s. L auw erys e t a l133 found no adverse ef fects in fem ale w orkers b u t did observe evidence o f a ltered pulm onary and renal function in m ale w orkers. H ow ever, the fem ale w orkers w ere ex posed a t 31 /xg/cu m w hereas m ale w orkers w ere exposed at higher co n ce n tra tio n s (66 p-g/cu m and higher). Tsuji e t al79 did n o t p re sen t environm ental expo sure d ata, so it is n o t clear w h eth er th e ir m ale and fem ale w orkers w ere exposed at th e sam e co n ce n tratio n s. If they w ere, a conclusion th a t the m ale and fem ale w orkers did n o t differ significantly in sensitivity w ould be w arranted. T h e re was a 14.7% in cidence o f p ro tein u ria in th eir m ale w orkers and 15.5% in fem ale w orkers; th e re was a 7.8% in cid ence o f glucosuria in m ale w orkers and a 1.4% incidence in w om en, based on m easurem ent by te st ta p e, w hich m ay be an inadequately sensitive m ethod. (n ) Q u an titativ e R elationships P riority should be given to m ortality studies of cadm ium w orkers w ithout co n co m itan t exposure to o th e r toxic m aterials and to long-term anim al studies at doses up to m axim ally to lera te d ones. # SUM M ARY OF CANCER M ORTALITY D A T A OF KIPLING A N D W ATERHOUSE9 A N D OF LEM EN ET A L07 In view o f the p resen t u n certain ties in the evidence on teratogenicity and carcinogenicity of cadm ium in o ccu p atio n al exposure, a standard b ased on th ese effects is n o t now recom m ended. This reco m m en d atio n should be reconsidered if additional d a ta on these points th a t w arrant such reco n sid eratio n are developed. T h e reco m m en d ed lim its o f 40 /xg/cu m (T W A ) and 200 pig/cu m (ceiling) are fo r to tal particulate cadm ium . Thus, lim its based only on small, socalled respirable, p articles, are n o t recom m ended. C adm ium oxide and m any o th er form s o f cadm ium are n o t in ert, varying in th eir solubilities in w ater and probably in body fluids, so th a t large particles n o t reaching th e alveoli may still be toxicologically active because th ey can be rem oved from the u p p er respiratory tra c t by ciliary action and tra n s ferred to the gastrointestinal trac t. Thus, som e of th ese large particles w ould probably be swallowed and beco m e system ically toxic th ro u g h gastroin testinal absorption (th o u g h gastrointestinal absorp tio n w ould b e e x p ected to be less th an absorption from the respiratory tra c t). It has b een im plicit in the environm ental limits, such as T L V 's th a t have prevailed fo r m any years (see discussion o f previous stan d ard s in the section ab o v e ), th a t cadm ium oxide fum e is m ore toxic th a n cadm ium oxide dust. It seem s probable th a t th e basis fo r this is th e assum ption th a t fum es, being usually o f sm aller p article sizes th an dusts, will p e n e trate m ore efficiently into th e lungs and th u s be m ore efficiently absorbed by th e blood. It is proposed th a t m andatory m edical surveil lance include p rep lace m en t and periodic exam ina tio n s o f lungs, kidneys, and blood pressure. In ad dition, blood co u n ts, studies o f liver function, and, in m ale w orkers, palpation o f the prostate are recom m ended. Pulm onary fu n ctio n tests should be p erfo rm ed periodically, and ch est X-rays should be tak e n if indicated from results o f periodic ex am inations. F or com parison, prep lacem en t ex am inations and exam inations at term ination o f em ploym ent involving cadm ium exposure should in clude X -rays as well as pulm onary function tests. Q u antitative analysis o f urine p ro tein should be c o n d u cted frequently, since this should give early and probably the first indication o f adverse effects o f cadm ium . P ro tein u ria w ith its im plications o f renal dysfunction is less likely to be reversible as it continues, so early d etectio n o f low m olecular w eight proteins in th e urine, w ith the expected result o f steps to im prove hygiene and w ork p ra c tices, should p rev en t serious an d irreversible ef fects o f cadm ium . T herefo re, it is proposed th at analysis o f urine be cond u cted every 4 m onths as well as before p lacem en t an d a t term ination. P ro ced u res for estim ations o f proteins in urine are d escribed in A ppendix III; the conventional boiling te st is n o t ad e q u a te for cadm ium -induced proteinuria. If a w o rk er is found to begin to ex crete significant am ounts o f p rotein in his urine during exposure to cadm ium , electro p h o retic ex am ination o f th e urine fo r the p resence o f various proteins, especially for peaks in the /3-globulin re gion, will b e helpful in deciding w hether exposure to cadm ium is involved in th e genesis o f the proteinuria. A lternatively, specific analysis for /32m icroglobulin can be perform ed. It can be p e r form ed by radioim m unoassay o r radial im m unodif fusion, w hich give com parable results275; sem i-auto m atic p ro ced u res allowing sim ultaneous processing o f 24 sam ples have been described. (f) W ork P ractices W o rk practices are discussed in C h ap ter VI. B razing w ith alloys containing cadm ium (o ften re fe rred to as silver soldering) is especially h azardous b ecause o f the high concen tratio n o f cadm ium oxide fum e pro d u ced , so good local ven tilation and, o ften , respiratory p ro tection are n eeded. Storage, handling, and eating o f food in cadm ium exposure areas should be prohibited to p rev en t food con tam in atio n an d subsequent in gestion o f cadm ium . W hile cadm ium does n o t pose a fire hazard, its deposition on sm oking m aterials m ay result in g en eratio n and inhalation of cadm i um oxide fum e a t a later tim e, so th a t sm oking as well as the carrying o f u n covered sm oking m ateri als in th e w orkplace should be prohibited. T here isn 't good evidence th a t cadm ium aerosols will p e n e tra te the skin, b u t th e ir deposition on clothes m ay result in aerosol g en eration (eg, blow ing of d u st) away from w ork, w hich m ay increase the w o rk ers' exposure as well as cause his family to be exposed. F or this reason, it is pro p o sed th a t w or kers be req u ired to change w ork clothing before leaving w ork. U nder these conditions it should n o t be necessary to com ply w ith m any o f the provisions o f this recom m ended stan d ard , w hich has been p rep a re d prim arily to p ro te c t w o rk ers' health under m ore hazardous circum stances. C o ncern for w o rk ers' health requires th a t p ro tectiv e m easures be instituted below the en fo rceab le limit to ensure th a t exposures stay below th a t lim it. F or these reasons, an action level o f cadm ium has been defined as o ccu p atio n al exposure above half the recom m ended TW A environm ental limit, thereby delineating those w ork situations w hich do not require the expenditure o f health resources for e n vironm ental and m edical m onitoring and as sociated recordkeeping. T his level has been chosen on the basis o f professional ju d g m e n t ra th e r than on q u antitative d ata th a t d elineate nonhazardous areas from areas in w hich a hazard may exist. H ow ever, brazing, w elding, o r th erm al cutting with cadm ium alloys presents a significant hazard re gardless o f the T W A c o n cen tratio n , and such operations should be perform ed only in a c co rd an ce with the recom m ended standard. Sim ilarly, food storage, handling, and eating should be pro h ib ited in cadm ium w ork areas re gardless o f TW A co n cen trations. Silver Brazing Silver brazing, com m only called silver soldering, is the process o f joining m etals by heat with a silver alloy filler m etal. M any filler m etal alloys co n tain cadm ium , w hich can pro d u ce cadm ium oxide aerosol w hen o verheated, so care m ust be taken to control the tem p e ra tu re of silver brazing o p eratio n s if the alloy contains cadm ium . U nder no circum stances should a to rch flam e be applied directly to such an alloy. T he h eat o f the base m etal should be used to m elt the filler m etal and cause it to flow. Silver brazing w ith cadm ium -containing alloys should be perform ed only with satisfactory local exhaust or with appropriate respiratory p rotection. # V I. W O RK PR A C TIC ES (c ) W elding, C utting, and H eating W elding and therm al cutting o f m aterial co n taining cadm ium m ust be perform ed only with local exhaust ventilation dem o n strated by sam pling and analysis o f breathing zone atm ospheres to be sufficient to m aintain airborne cadm ium at or below recom m ended limits. For single operations, w here local exhaust ventilation is not available or w here air sam pling and analysis has not dem o n strated accep tab le air co n cen trations, suitable resp irators (listed in C h ap ter I) m ust be provided and worn. W here m olten cadm ium is used o r form ed, tem p eratu res should be k e p t as low as possible c o n sistent with th e re q u irem en ts o f th e w ork o p e ra tion to p rev en t g en eratio n o f excess fum e. W h er ever possible, this should be accom plished by au tom atic co n tro ls, with reco rd in g o f tem p eratu res and use o f alarm s o r o th e r in d icato rs o f excessive tem p eratu res. If possible, avoid using cadm iumcontain in g alloys for brazing. In any case, cadm ium co n tain in g m etals m ust be appropriately segregated and labeled, so th a t w o rkers will not unknow ingly apply h eat to cadm ium . A ir volum es ta b u la te d for w elding258-" 0 are cal culated fo r a co n tro l velocity o f 100 feet/m in. For cadm ium fum e, control velocities o f 150 feet/m in should be used, so th a t volum es 50% g rea ter than th e tab u lated volum es should be used. Local exh au st system s should be designed and o p erated in co n fo rm an ce w ith ANSI Z 9.2-1971, Effluent air should be cleaned, if necessary, to m eet any em ission standards th a t may be prom ul gated (th e re are now no EPA em issions standards for cadm ium ). Air from the exhaust ventilation system m ust n o t be recircu lated into the w ork place. (e ) R espiratory P rotection F o r ad e q u ate respiratory p ro tectio n against the m any conditions th a t may be en co u n tered in in dividual o p erations, m any types o f respirators have been developed and approved. E ach has particular applications and lim itations from the standpoint o f p ro te ctio n , and each has its advantages and disad vantages from the standpoint o f operation and m aintenance. D etailed inform ation on the selec tion and use o f resp irators can be obtained from R espiratory P ro tective D evices M anual.2™ ANSI Z 8 8 .2 -1 9 6 9 259 also classifies, describes, and gives lim itations o f respirators. R espirators fall into several classifications, ac cording to th eir m ode o f operation: (1 ) a t m osphere-supplying respirators, which include those to w hich suitable air is supplied by tanks carried by the w earer o r by a hose carrying air from a rem ote source (self-contained m asks, hose m asks, airline m asks, and com bination self-con tain ed and airline m asks); (2 ) air-purifying respira tors w hich filter o r absorb the contam inant (gas m ask with chem ical cartridge, particulate masks, and com bination m asks for gas, vapor, and p a r ticu late); and (3 ) com bination atm osphere-supply ing and air-purifying respirators. T he factors th at affect the overall perform ance of air-purifying respirators are the reliability of the face seal, the efficiency o f the filters, and o th e r variables such as leakage from exhalation valves. T he applicable regulation on certification and approval o f respirators is 29 CFR 11. This requires, am ong o th e r things, th a t all air-purifying respirators approved for dusts and fumes with an environm ental limit less than 0.05 m g/cu m be equ ip p ed w ith a high efficiency filter. (f) Protective C lothing P rotective clothing is n o t norm ally required for cadm ium operations. It is possible th at cadm ium dust co llected on clothing could be released into the air to cause a secondary exposure so th a t, if such clothing w ere w orn to the w o rk er's hom e, the w orker and oth ers m ight be exposed to cadm ium dust. T he b e tte r solution is to im prove w orkplace housekeeping to p rev en t clothing co n tam in atio n , but it seem s a wise p re c a u tio n th a t w ork clothing be changed at the end o f th e w orkshift and not carried hom e. T hus, th e re should be change room s with se p a ra te storage areas, such as lockers, and show er an d hand w ashing facilities should be p ro vided. ( W hile th ere isn 't good reason to believe th a t cadm ium co m pounds p e n e tra te the skin to a sig nificant extent, it is good p ractice to avoid skin c o n tac t and if c o n ta c t has o ccu rred to wash the af fected areas prom ptly. (i) Storage C adm ium -containing, including cadm ium -plated, m etal parts should be k ep t sep arate from p arts not containing cadm ium so th a t accidental exposures resulting from w elding and cutting will not occur. (j) E m ergency P ro ced u res E m ergency proced u res should be established for any ev ent th a t m ight result in substantial release of airb o rn e cadm ium . Such p ro c ed u res should in clude provisions to notify the attending physician th at exposure to high c o n ce n tratio n s of cadm ium fum e may cause lung edem a. T his edem a m ay not b ecom e evident until 8-24 hours a fter th e ex p o sure. E m ergency p ro ce d u res should also include provision fo r a p p ro p riate resp irato rs specified in C h ap te r I. It is im p o rtan t to design specific em ergency p ro c ed u res to be follow ed in the event of a fire, to p ro te c t both w orkers and firefighters. # VII. COMPATIBILITY WITH OTHER STANDARDS T h e E n vironm ental P ro te c tio n A gency has not classified cadm ium as a h azard o u s p o llu tan t and neith er em ission n o r am b ien t air stan d ard s have been issued. EPA has n o t p ro m u lg ated solid w aste reg u la tions for cadm ium . H ow ever, it has reaffirm ed the 1962 PHS drinking w ater sta n d a rd o f 0.01 m g /liter279 as an interim prim ary drinking w ater regulation, applicable to com m unity w ater supplies ( Federal Register 4 0 :5 9 5 7 0 , D ec em b e r 24, 1975). W hile this stan d ard is fo r com m unity w ater sup plies, and thus is n o t directly applicable to discharge o f cadm ium into stream s, it seem s clear th a t disposal o f cadm ium w aste, liquid o r solid, should be in a m an n er n o t leading to its in tro d u c tion into drinking w ater. A rea sam ples may be tak en with the ap p a ra tu s used for determ ining w orker exposure, or w ith electro static precipitators. # VIII. R EFER EN C ES (b ) T he sam ple should be taken at a site representative o f the a rea being contam inated. The site should be identified for fu ture sampling. # Calibration of Sampling Trains T he ac cu rate calibration o f a sam pling pum p is essential for the c o rre c t in terp retatio n o f the volum e indicator. T he necessary frequency of calibration is d ep en d e n t on the use, care, and han dling to w hich the pum p has been subjected. In addition to the norm ally scheduled calibration, pum ps should be recalib rated if they have been subjected to m isuse, just received from a m anufac-tu re r, or ju st repaired. If the pum p receives hard usage, m ore freq u en t calib ratio n m ay be necessa- ( 1 ) W hile th e p u m p is running, the voltage o f th e p u m p b attery is m easu red w ith a voltm eter to assure th a t the b a tte ry is charg ed ad eq uately for calibration. Place the cellulose m em brane filter with back u p pad in th e filter cassette. (3 ) T he calib ratio n setup is assem bled as shown in Figure X IV -1. (4 ) T he pum p is tu rn ed on and the inside of the soapbubble m ete r is m oistened by im m ersing the b u ret in the soap solution and draw ing bubbles up the tube until they are able to travel the entire length o f th e b u ret w ithout bursting. (5 ) T he pum p is adjusted to provide a flow rate o f 2.0 liters/m in. (6 ) T he w ater m an o m eter is ch eck ed to e n sure th at the pressure d ro p across the sam pling train does not exceed 13 conventional inches o f w ater (3.23 kP a) a t 2 liters/m in. (7 ) A soapbubble is started up the b u re t and the tim e it tak es the bubble to travel a m inim um o f 1.0 liter is m easured with a sto p w atch. (8 ) T he p ro c ed u re in ( 7) above is repeated at least th ree tim es, the results are averaged, and the flow rate is calculated by dividing the volum e betw een the p reselected m arks by the tim e req u ired for the soapbubble to travel the distance. (1 ) C o n c en tra te d nitric acid: redistilled or o f tra ce m etal quality. Use in subsequent steps w here nitric acid is designated. (2 ) W ater: double distilled o r distilled deionized. (3 ) S tandard cadm ium solution: 1000 /ng/ml. Dissolve 1.000 g o f m etallic cadm ium in nitric acid and dilute to 1 liter in a volum etric flask with sufficient w ater and nitric acid to yield a solution containing 10% nitric acid. This solution is com m ercially available. (4 ) A tom ic absorption ap paratus with a cadm ium hollow c a th o d e lam p, read o u t accessory, and gas supply system . O perating conditions recom m ended by th e m a n u factu rer should be fol low ed for gas flow rates and o th er instrum ental variables. T he resonance line for cadm ium is 2,288 A ngstrom s. (5 ) H ot p late, capable o f 300 C. (f) Q uality C ontrol E stablishm ent and m aintenance o f total analyti cal quality control system s to assure continued precision and accu racy o f laboratory reports in clude, as ap p ro p riate, these requirem ents: (1 ) Each test m ust be ch ecked on each day o f use. (2 ) A t least one standard (it may be an in stru m en t stan d ard ) and one control sam ple (w orking value established and run through the en tire analytical p ro c e d u re ) should be included with each run o f unknow n sam ples. W here the con tro l sam ple is not subject to th e in terferences in the unknow n sam ples, a previously run u n k nown should be in cluded as a blind ch eck sam ple. Sam ple, co ntrol sam ple (w orking value previ ously established by carrying through entire analytical p ro c e d u re ), and blank are placed in suitable acid-w ashed vessels. For personal sam plers em ploying 37 mm o r sim ilar filters, 50-ml G riffen b eak ers are suitable. N ext, 3 ml o f co n cen trated n itric acid is added and th e vessel is covered with a w atch glass. E ach sam ple is h eated on a hot plate in an exhaust hood until th e volum e o f nitric acid is red uced to approxim ately 0.5 ml and is pale yellow o r w ater w hite. F u rth er additions o f n itric acid may be necessary fo r com plete oxida tion o f the filter. T h e cooled sam ple is transferred to a suitable volum etric vessel, after rinsing the w atch glass. A 5-ml g raduated cylinder has been em ployed successfully. T he transfer and volum e ad justm ent are effected with 1% nitric acid solu tion. T he resulting blank, c o n tro 1 a. d sam ple solu tions are aspirated into the flam e oi - .e instrum ent and the in strum ent response recorded. Sam ples m ay be diluted o r co n cen trated to correspond to the standards. If co n c en tratio n is necessary, the aspiration flow rate should be ch ecked to assure th a t it is com parable to those for the standards. # Sulfosalicylic or Trichloroacetic Acid Analysis F or analysis o f urine protein by precipitation w ith sulfosalicylic o r trich o ro acetic acid, the m ethods described by H enry e t al280 and Meulem ans281 can be used. M easure the specific gravity and the volum e o f the urine sam ple, and, after gentle mixing, filter ab o u t 75 ml; the sam ple should be at room tem p eratu re. C heck for the ap proxim ate co n ce n tra tio n o f protein by some p ro ce d u re such as use o f A lbustix® If the esti m ated co n c en tratio n is higher than 150 m g /100 ml, dilute the sam ple with saline solution (0.99% ) to a p rotein c o n cen tratio n o f a b o u t 100 m g /100 ml. Pipet 0.5 ml o f urine into each o f 2 tubes. A dd to the first tube 2 ml o f saline solution and to the o th e r 2 ml o f 3% sulfosalicylic acid or trich lo racetic acid. Mix the co n ten ts o f each tube im m ediately after th e addition and let stand for 5 m inutes, follow ed by a second mixing and reading o f the absorbance in a sp ectro p h o to m eter a t 620 nm against a reagent blank. S u b tract the reading o f the reagent blank and the reading o f the urine sam ple to w hich saline was ad ded from the reading of the reag en t-treated urine sam ple. C alculate the total am o u n t of p ro tein (p e r unit o f volum e o r per unit o f tim e such as 12 o r 24 h o u rs) from the sta n dard curve. A ccording to M cG arry e t al, 282 n o r mal urine p ro tein ex cretio n is a b o u t 70 m g/day but m ay be as high as 90 m g/day; th ese values are eq uivalent to 5 and 6.4 m g /100 ml if daily urine excretion is ab o u t 1,400 ml. C hem ical substances should be listed according to th e ir com plete nam e derived from a recognized system o f n o m enclature. W here possible, avoid using com m on nam es and general class nam es such as " arom atic am in e," " safety solvent," or " aliphatic h y d ro c a rb o n " w hen th e specific nam e is known. T he " % " may be the approxim ate percentage by w eight o r volum e (indicate basis) w hich each hazardous in g redient o f the m ixture bears to the w hole m ixture. T his m ay be indicated as a range o r m axim um am o u n t, ie, " 10-40% vol" o r " 10% max w t" to avoid disclosure o f trad e secrets. T oxic hazard d a ta shall be stated in term s o f co n c en tra tio n , m ode o f exposure o r test, and anim al used, ie, " 100 ppm L C 5 0 -rat," " 25 m g/kg L D 50-skin-rabbit," " 75 ppm LC m an ," or " perm issible exposure from 29 C FR 1910. (g) Section VII. Spill o r L eak P rocedures D etailed p ro c ed u res for cleanup and disposal should be listed w ith em phasis on precautions to be tak en to p ro te c t w orkers assigned to cleanup detail. Specific neutralizing chem icals or p ro c ed u res should be described in detail. Disposal m ethods should be explicit including p ro p er label ing o f containers holding residues and ultim ate disposal m ethods such as " sanitary landfill," or " in cin eratio n ." W arnings such as " com ply with local, state, and federal antipollution o rd in an c es" a re p ro p er b u t n o t sufficient. P ertin en t specific local requirem ents shall be identified. (h ) Section VIII. Special P rotection Inform a tion Section VIII requires specific inform ation. S tate m ents such as " Y es," " N o ," o r " If necessary" are n o t inform ative. V entilation requirem ents should be specific as to type and p referred m ethods. R espirators shall be specified as to type and NIOSH o r US B ureau o f M ines approval class, ie, " Supplied a ir," " O rganic vapor can ister," " Suitable for dusts n o t m ore toxic than lead ," etc. P rotective equipm ent m ust be specified as to type and m aterials o f construction. (i) Section IX. Special Precautions " P recautionary S tate m e n ts" shall consist o f the label statem ents selected for use on the co ntainer o r placard. A dditional inform ation on any aspect o f safety o r health not covered in o th er sections should be inserted in Section IX. T he lower block can co ntain referen ces to published guides o r inhouse p ro cedures fo r handling and storage. D e p a rtm e n t o f T ra n sp o rtatio n m arkings and classifi cations and o th e r freight, handling, o r storage req u irem en ts and environm ental controls can be noted. (j) Signature an d Filing A n o th e r im p o rta n t a re a is in v ascular effects o f cadm ium exposure, since th e re is conflicting in fo r m ation ore th e role o f cadm ium in hypertension and becau se o f suggestions th a t v ascular effects m ediate such o th e r effects as those on renal fu n c tion. M ore evidence o n th e role o f cadm ium in d ev elo p m en t o f fetal ab n o rm alities in m an is needed. A dditional assu ran ce is n e e d e d th a t, if cadm ium ab so rp tio n is m ain tain ed at sufficiently low levels so th a t zinc availability to th e fetu s will not be a lte red , offspring o f cadm ium w o rkers will not be h arm ed by th e ir p a re n ts' exposure. In this co n n e c tio n , th e re is a n eed for a n atio n al surveil lance system th a t can g a th e r info rm atio n on fetal d eath s o r an om alies and erro rs in d ev elo p m en t o f child ren and relate these d a ta to o ccu p atio n al ex posures (o r o th e r en v iro n m en tal stresses) o f the parents. T he p re se n t in ad eq u acies and conflicts in infor m ation, from both hu m an an d low er anim al in vestigations, on w h eth er cadm ium can cause m u ta tions o r c a n c e r should be c o rre c ted . F u rth er epidem iologic investigations in p o p u latio n s n o t ex posed to o th e r possible causes o f these effects should be pursued. A t the sam e tim e, life-time stu dies in experim ental anim als at ap p ro p riate doses should be p erform ed. T hese doses should be high enough to cause significant toxic effects from cad m ium b u t n o t so high as to cause a significant d ecrease in longevity, for d a ta to be properly in terp re ta b le. F u rth er evidence bearing on the sug gestion th a t cadm ium is involved in the causation o f p ro sta te c a n c e r should be ob tain ed , preferably from w o rk er populations n o t also exposed to o th e r possible carcinogens. In this con n ectio n , a m ortali ty study now underw ay a t th e K arolinska Institute may shed fu rth e r light on this question. This study o f w orker populations exposed to cadm ium in volves two co h o rts, one o f ab o u t 200 and the o th e r sm aller. E valuation o f th e d ata developed may be com pleted w ithin the year (L Friberg, ver bal com m unication, Ju n e 1976). E vidence on adverse effects o f cadm ium on the nervous system , on the p ancreas, on the adrenals, and on thyroids and parathyroids should be c o n firm ed by additional investigations. In particular, conflicting inform ation on w hether cadm ium causes liver changes at w orkplace exposure co n c e n tra tio n s should be resolved. F u rth e r investigation is also n eed ed on the sug gestion, developed in som e re cen t epidem iologic studies, th a t cadm ium w orkers who sm oke may have a g re ater risk o f developm ent o f altered renal function. T # C E N T E R FO R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E FOR O C C U P A T IO N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R	Less than or equal to 0.4 m g /cu m Less than or equal to 2.0 m g /c u m Less than or equal to 40 m g /cu m 40 m g /cu m or greater or unknown ( 1 ) H alf-m ask respirator with high-efficiency filter (s). ( 2 ) T ype C dem and-type (n eg ative pressure) supplied-air res pirator with half-m ask facepiece. (1 ) F ull facepiece respirator w ith high-efficiency filter (s). ( 2 ) T ype C dem and-type (n eg ative pressure) supplied-air res pirator with full facepiece. (3 ) Self-contained breathing ap paratus with full facepiece in de mand m ode (negative pressure). ( 1 ) Pow ered air-purifying (p osi tive pressure) respirator with high efficiency filter(s). (2 ) T ype C continuous-flow (positive pressure) supplied-air respirator. ( 1 ) Com bination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply. (2 ) Self-contained breathing ap paratus with full facepiece in positive pressure mode.# PREFACE T he O ccupational Safety and H ealth A ct of 1970 em phasizes the need for standards to protect the health and safety of w orkers exposed to an ever-increasing num ber of potential hazards at their w orkplace. T he N ational Institute for O ccu pational Safety and H ealth has projected a form al system of research, with prior ities determ ined on the basis of specified indices, to provide relevant data from which valid criteria for effective standards can be derived. R ecom m ended stan dards for occupational exposure, which are the result of this work, are based on the health effects of exposure. T he Secretary of L ab o r will weigh these recom m endations along w ith other considerations such as feasibility and means of im plem entation in developing regulatory standards. It is intended to present successive reports as research and epidemiologic studies are com pleted and sam pling and analytical m ethods are developed. C riteria and standards will be reviewed periodically to ensure continuing protection of the w orker. I am pleased to acknowledge the contributions to this report on cadm ium by m em bers of my staff, by the Review C onsultants on Cadm ium , by the ad hoc com m ittees of the A m erican Industrial Hygiene A ssociation and of the Society of Toxicology, by R obert B. O 'C onnor, M .D ., N IO SH consultant in occupational m edicine, and by E dw in C. H yatt on w ork practices and respiratory protection. T he N IO SH recom m endations for standards are not necessarily a consensus of all the consultants and professional societies th at reviewed this criteria docum ent on cadm ium . Lists of the N IO SH Review Com m ittee m em bers and of the Review C onsultants appear on the following pages. " C ad m iu m " refers to elem en tal cadm ium and all cadm ium com pounds. A n " actio n lev el" is defined as h alf th e tim e-w eighted average co n ce n tra tio n e n v iro n m en tal lim it o f cadm ium . " O ccupational exposure to cad m iu m " is d efin ed as exposure to cadm ium a t a c o n c e n tra tio n g re a te r th a n th e a c tio n level. E xposures a t low er en v iro n m ental c o n c en tratio n s will n o t req u ire a d h e re n c e to the fol lowing sections, ex cep t fo r S ection 6 (b ) and 7 (d ). Sam ples shall be analyzed by th e m ethod provided in A ppendix II o r by a m eth o d show n to be at least equivalent in precision and sensitivity. # Section 2 -Medical M edical m onitoring shall be m ade available to all w orkers subject to occu p atio n al exposure to cadm ium . (a ) P rep lac em e n t exam inations shall be m ade available to new o r reassigned em ployees p rio r to jo b placem en t, and, w ithin 6 m onths o f the prom ulgation o f a sta n d ard based on these reco m m endations, to em ployees already engaged in work involving exposure to cadm ium . P rep lacem en t exam inations shall include com prehensive w ork an d m edical histories, a 14" X 17" P.A . ch est X -ray, m easurem ent o f forced vital capacity (F V C ) and forced expiratory volum e d u r ing th e first second (F E V j), m easurem ent o f blood pressure, blood analysis (b lo o d u re a nitrogen, com plete blood co u n t, and serum glutam ic oxalo ace tate transam inase o r o th e r liver enzym es), and urinalysis (m icroscopic exam ination, sugar determ in atio n , q u antitative p rotein determ ination, and specific gravity m easurem ent). A judgm ent o f th e w o rk e r's ability to w ork in positive o r negative pressure respirators shall be m ade. T h e m ethod fo r p ro tein determ ination in urine shall be q u antitative and cap able o f detecting low m olecular w eight proteins (see A ppendix III). D eterm ination o f urine cadm ium levels is also recom m ended. (b ) P eriodic exam inations shall also be m ade available. E xcept fo r urine p ro tein determ inations, w hich shall b e m ade available every 4 m onths, these exam inations shall be offered yearly, o r as otherw ise d irec ted by th e responsible physician. T hese p eriodic exam inations shall include in terim w ork and m edical histories, urinalysis (w ith q u an titativ e p ro te in determ inations every 4 m o n th s), pulm onary function tests (FV C and F E V ,), an d blood pressu re. C h est radiographs shall be ta k e n if judged necessary by th e responsi ble physician. In # Section 4 -Personal Protective Equipment and Clothing E ngineering co n tro ls shall be used if needed to m aintain airb o rn e cadm ium co n cen tratio n s a t or below th e lim its recom m ended in Section 1. C o m pliance w ith these w orkplace environm ental limits by th e use o f resp irators is p erm itted only during installation a n d testing o f engineering controls, during perfo rm an ce o f n o n ro u tin e m aintenance or rep a ir, during single op eratio n s, o r during em er gencies. W hen use o f a resp irato r is perm itted, it shall be selected a n d used in acco rd a n ce w ith the follow ing requirem ents: (a ) F o r th e p u rpose o f determ ining the type o f re sp ira to r to be used, th e em ployer shall m ea sure th e c o n ce n tra tio n s o f cadm ium in th e w ork place initially and th e re a fter w henever control, process, o p eratio n , w orksite, o r clim ate changes o c c u r th a t are likely to increase the co n cen tratio n o f a irb o rn e cadm ium . # ( b ) T h e em p lo y er shall en su re th a t no w orker is exposed to cadm ium in excess o f th e re c o m m en d ed lim its b ecau se o f im p ro p er resp irato r selectio n , fit, use, o r m ain ten an ce. (c ) A resp irato ry p ro te c tio n p ro gram m eeting th e req u irem en ts o f 29 C F R 1910.134, w hich in c o rp o ra te s th e A m erican N atio n al S tan d ard P ra c tices fo r R espiratory P ro te c tio n , Z 8 8 .2-1969, shall be estab lish ed an d e n fo rc e d by th e em ployer. ( d ) T h e em p lo y er shall p ro v id e resp irato rs in ac c o rd a n ce w ith T ab le l -l , an d shall ensure th a t em ployees use th e resp irato rs p ro v id ed in a p ro p e r m an n er w h en w earing o f resp irato rs is required. (e ) R esp irato rs selected from th ose described in T ab le 1-1 shall be th o se ap p ro v ed u n d er the provisions o f 30 C F R 11. (f) T h e em ployer shall en su re th a t em ployees are p ro p erly in stru c te d in th e use o f resp irato rs as signed to th e ir use an d o n how to te st fo r leakage, p ro p e r fit, an d p ro p e r o p eratio n . (g ) R esp irato rs specified in T ab le 1-1 fo r use in atm o sp h eres o f h ig h er c o n c e n tra tio n s o f a ir borne cadm ium m ay be used in atm o sp h eres o f low er cadm iu m co n cen tratio n s. (h ) T h e em ployer shall estab lish and co n d u ct a p ro g ram o f cleaning, sanitizing, inspecting, m ain taining, repairing, an d sto rin g o f resp irato rs, to e n sure th a t em ployees a re p ro v id ed w ith clean resp irato rs th a t are in good o p eratin g condition. (i) T h e em ployer shall periodically m onitor th e use o f resp irato rs to en su re th a t th e p ro p er type o f re sp ira to r is w o rn , to ev alu ate th e effec tiveness o f th e resp irato ry p ro te c tio n program , and to elim in ate any deficien cies in use and care o f respirators. # Section 5 -Informing Employees of Hazards from Cadmium (a ) W o rk ers initially assigned o r reassigned to jo b s involving o cc u p a tio n a l expo su re to cadm ium shall be inform ed o f th e h azards, sym ptom s o f overex p o su re (in clu d in g in fo rm ation on the ch aracteristics o f o n se t a n d stages o f illness), ap pro p riate p ro c e d u re s to be ta k e n in th e ev ent o f an em ergen cy , and p re c a u tio n s to en sure safe use an d to m inim ize exposure. T h ey shall be advised o f th e availability o f relev an t in fo rm ation, includ ing th a t p rescrib ed in ( c ) below . T his inform ation shall be accessible to e a c h w o rk er occupationally exposed to cadm ium . # (b ) A co ntinuing ed u catio n program , co n d u c te d by a perso n o r persons qualified by ex p erien c e o r special training, shall be instituted to en su re th a t all w ork ers have c u rre n t know ledge of jo b hazards, p ro p e r m aintenance proced u res and clean u p m ethods, an d th a t they know how to use resp irato rs correctly. It shall include a description o f the general n atu re o f the m edical surveillance p ro c ed u res and w hy it is advantageous to the w o rk er to undergo th e se exam inations. (c ) R eq u ired inform ation shall be reco rd ed on a " M aterial Safety D ata S h e e t" as specified in A ppendix IV o r on any o th e r form approved for th e purpose by th e O ccu pational Safety and H ealth A dm inistration, US D e p artm en t o f Labor. # Section 6 -Work Practices ( a ) E xhaust System s O p eratio n s creatin g w orkplace exposure to c a d m ium shall be enclosed to the m axim um extent p racticab le and be provided with local exhaust ventilation unless app ro p riate air sam pling and analysis have d em o n strated th a t con cen tratio n s are a t o r below th e environm ental limits. M ethods o th e r th an en closure and ventilation for m eeting exposure lim its to cadm ium m ay be used if they bring co n ce n tra tio n s in w orkplace air to or below th e environm ental limits. E ffluent air shall be clean ed to m e et any em ission stan d ard s th a t may becom e prom ulgated. A ir from th e exhaust ven tilatio n system shall n o t be recircu lated into the w orkplace. E nclosures, exhaust hoods, an d ductw ork shall be k e p t in good re p air so th a t design airflows are m aintained. A irflow shall be m easured a t each h ood a t least sem iannually, and preferably m onthly. C o n tin u o u s airflow indicators are recom m ended, such as w a ter o r oil m anom eters properly m o u n ted a t th e ju n c tu re o f fum e hood and du ct th ro a t (m a rk ed to indicate a ccep tab le airflow ). A log show ing design airflow and results o f sem ian nual inspections shall be kept. (b ) W elding, B razing, and T h erm al C utting W elding, brazing, o r therm al cuttin g o f m aterial containing cadm ium shall be p erform ed using local exhaust ventilation d em o n strated by air sam pling an d analysis to k eep cadm ium co ncentrations w ithin th e lim its o f Section 1. F o r single o p e ra tions w here local ex h au st ventilation is n o t availa ble, w here air sam pling has n o t b een perform ed, # RESPIRATOR SELECTION GUIDE o r w here air sam pling has d e m o n strated a likelihood o f o v erexposure to cadm ium fum e or dust, resp irato rs shall be provided and w orn as -specified in Section 4. W here m olten cadm ium is u sed o r fo rm ed, te m p eratu res should be k e p t as low as possible c o n sistent w ith th e req u irem en ts o f th e o p eratio n to prev en t excessive fum e gen eratio n . A dditions of cadm ium should be m ad e in th e m an n er g e n e ra t ing th e least fum e. W h erev er possible, this should be accom plished by a u to m atic co n tro ls, with recording o f te m p e ra tu re and use o f alarm s o r in dicato rs fo r higher te m p eratu res. (c ) E m ergency P ro ced u res E m ergency p ro c e d u re s shall be established for any ev en t w hich m ay resu lt in sub stan tial release o f airb o rn e cadm ium . Such p ro c e d u re s shall in clude provision for a p p ro p ria te resp irato rs as specified in S ection 4. Specific em ergency p ro c ed u res shall be designed fo r fires, to p ro te c t b o th in-plant w orkers and firefighters. (d ) W ork C lothing W orkers shall w ear w ork clothing consisting of at least h a t, shirt o r blouse, pants o r skirt, and shoes. W ork clothing a n d stre e t clothing shall be exchanged at the beginning and th e end o f each w orkday, so th a t w ork clothing will n o t be w orn outside th e w orkplace. T h e em ployer shall provide for p ro p e r laundry o f clothing and shall instruct lau nderers on p ro ce d u re s to be ta k en to avoid in halation o f cadm ium -containing dusts. # Section 7 -Sanitation Practices (a ) W here th ere is cadm ium -containing dust, cleaning should be p erform ed by vacuum pickup o r w et m opping. N o dry sw eeping o r blowing shall be p erm itted . (b ) E m phasis shall be p laced upon p ro m p t cleanup o f spills, re p air o f eq u ip m en t and leaks, p ro p e r storage o f m aterials, and collection o f cadm ium -containing dust. (c ) C adm ium -containing and cadm ium -plated m etal p arts should be k e p t sep a ra te from parts n o t containing cadm ium and m ark ed appropriately so th a t accid en tal exposures resulting from w elding and cuttin g will n o t occur. (d ) Facilities shall b e m ain tain ed to p ro te c t foodstuffs an d food co n sum ption areas from co n tam ination by m aterials containing cadm ium . F ood storage, handling, and consum ption shall be sep a ra te from cadm ium w ork areas. Sm oking or carrying uncovered to b acco o r to b acco products in cadm ium w ork areas shall be prohibited. (e ) A d eq u ate handw ashing and show er facili ties shall be provided. W orkers shall wash th eir hands before eating o r before using tob acco to p rev en t th eir absorbing additional am ounts o f c a d m ium com pounds. # Section 8 -Monitoring and Recordkeeping W orkers are n o t considered to be occupationally exposed to cadm ium if environm ental c o n ce n tra tions, as d eterm in ed on the basis o f an industrial hygiene survey to b e perform ed w ithin 90 days o f th e prom ulgation o f a standard, do n o t exceed the actio n level, ie, h alf the recom m ended TW A en vironm ental lim it, o r if there is no operation, storage, o r handling o f cadm ium in any form o r co n tam in atio n o f w orkplace air by cadm ium from o th e r sources. T h ese industrial hygiene surveys shall be re p e a te d at least every 3 years and w ithin 30 days after any p ro cess o r o p eratin g change like ly to resu lt in increases o f airb o rn e con cen tratio n s o f cadm ium . R eco rd s o f these surveys, including th e basis fo r conclu d in g th a t airb o rn e co n c e n tra tions o f cadm ium are a t o r below th e action level, shall be m ain tain ed until th e n ex t survey has been com pleted. T h e follow ing req u irem en ts apply to o c c u p a tio n al exposure to cadm ium , ie, to w orkplaces w here th e actio n level is exceeded. E lectroplating is and has b een th e leading use fo r cadm ium , consum ing from 45 to 60% o f the am o u n t p ro d u ced ea ch year. A bout one m illion k ilogram s/year are used for stabilizers in plastics, and som ew hat less th a n a m illion kilogram s in pig m ents, w ith plastics a large con su m er o f the pig m e n ts. 12 O n e -q u arter to one-half m illion kilogram s o f cadm ium are used annually as an alloying agent in low m elting-point brazing alloys, in co p p er for autom obile rad iato rs, in silver-cadm ium electrical co n tacts, and in o th e r m etallurgical alloys. T hese 4 m ajor categories a c c o u n t fo r 80-90% o f the cadm i um used, with the rest d istributed am ong m inor uses such as nickel-cadm ium b atteries, fungicides, photography, and television picture tubes. C adm ium dusts, fum es, and m ists are com m only p re sen t in som e sm elting processes involving zinc, co p p er, and lead as well as in specific processes fo r extracting cad m iu m . 13 NIO SH estim ates th a t 100,000 persons in the w ork fo rce are potentially exposed to cadm ium . 1941-1946. Bonnell34 cited S tephens, in 1920, and M ancioli, in 1940, w ho d escribed cases o f chronic illness due to occupational exposure to cadm ium . D uring W orld W ar II, the superim position o f nutritional d eficiencies o n to cadm ium exposure was suggested by N icaud and cow orkers38 as contributing to bone disease (o steo m alacia) in cadm ium w orkers in F rance. C adm ium is also believed to have been one causal fa c to r in the developm ent o f Itai-Itai ( " o u c h -o u c h " ) episodes in J a p a n . 1 (pp 137' l s , ) '39' 41 # Extent of Exposure # Effects on Humans T his section review s th e effects o f cadm ium on hum ans, m ostly from evidence developed in epidem iologic studies, in term s o f types o f effects such as organs o r o rgan systems affected. M any o f th ese studies to g eth er w ith additional ones are review ed, often in m ore detail, in th e section on Epidemiologic Studies. In the la tte r section, th ere is m ore em phasis on p o pulation studies and on a c o r relation o f hum an effects w ith airborne cadm ium co ncentrations. (a ) # Pulm onary Effects (1 ) A cu te Effects A cu te intoxication from exposure to cadm ium oxide fum es in c o n cen tratio n s o f a t least several m illigram s/cubic m e te r has a characteristic clinical p ic tu re .42"45 Initially, th ere are virtually no sym p tom s; these usually ap p e ar 4-10 hours later, w hen dyspnea, cough, an d n o t infrequently a feeling o f co n striction in th e chest develop. O n occasion, w orkers m ay com plain o f substernal ch est pain o r a b urning sensation in th e ch e st th a t is a c c e n tu ated by coughing. Som e m ay also develop a flu like syndrom e c h a ra c teriz e d by shaky chills and m yalgia localized in th e b ack and limbs. U nder this la tte r circu m stan ce, th e illness m ay be m istaken fo r m etal-fum e fever. In any event, acu te pulm onary ed em a m ay develo p w ithin 24 hours. In such cases, physical ex am in atio n reveals an acutely ill p a tie n t w ith rales h e a rd on au scu ltatio n o f th e chest. C h est X -rays show b ilateral p u lm onary infil tra te s suggestive o f p u lm o n ary ed em a. Pulm onary function testing, w h en p erfo rm ed , has show n a d e creased fo rced vital cap acity (F V C ) and fo rced expiratory volum e durin g th e first seco nd (F E V ,). (b ) R enal Effects T h e m ost com m on abno rm ality fo u n d in w or kers exposed to cadm ium is p ro te in u ria .54,55,65 Friberg55 fo u n d p ro te in u ria in 81% o f 43 w orkers exposed to cadm ium fo r an av erage o f 2 0 years in th e alkaline storage battery industry and pointed o u t th a t the p ro tein ex creted w as n o t th e protein conventionally ex creted afte r kidney injury, ie, it w as o f low m olecular w eight, ab o u t 2 0 ,0 0 0 -30,000. Piscator6 exam ined p ro te in in urines o f 79 cadm ium w orkers, 55 o f whom had been previ ously studied by F rib e rg .55 H e found an average ex cretio n o f p ro tein o f 50 m g/day in 10 healthy, unexposed subjects and 70-2,600 m g/day in cadm i um w orkers. In m en excreting m ore th an 150 m g/day, th e e lectro p h o retic p a tte rn o f urine p ro tein was ch arac teriz ed by a low album in co n te n t and increased co n ten ts o f a 2-, /3-, and yglobulins. In 75% o f th e m en excreting m ore th an 400 m g/day, th ere was a distinct /3 -globulin peak. In a few , he found a post-y-globulin fraction. C ad m ium w orkers also had a significantly higher c o n c e n tra tio n o f 7 -globulin and o f pro tein -b o u n d hexoses in serum th an did unexposed w orkers. P otts65 studied 70 battery w orkers and found pro tein u ria in 34% o f those exposed 10-19 years, and 82% o f w orkers exposed fo r over 30 years. Kazantzis and associates54 n o ted th a t d u ratio n o f exposure to cadm ium was im p o rtan t in th e developm ent of pro tein u ria. T hey fo u n d no p ro tein u ria in those ex posed fo r less th an 2 years; p ro tein u ria was found in 3 o f th e 4 exposed fo r 12 to 14 years and in all o f th o se exposed fo r 25 years o r m ore. The p ro te in u ria was ch aracterize d by excretion o f uri nary p ro tein o f low m olecular w eight, betw een 2 0 ,000 and 25,000. T he pathogenesis o f the p ro te in u ria has n o t been fully delineated, but V igliani67 has suggested th a t p ro tein m ay app ear in th e urine because tu b u lar-b o u n d cadm ium in te r feres w ith th e ability o f th e norm al kidney to catabolize im m unoglobulins and o th e r proteins. O th e rs 1 (pp l0f''106)-68,69 believe th a t it results from a d ecreased reab so rp tio n o f norm ally present protein by th e renal tubules. T his latte r view seem s m ore likely, ie, it is likely th a t low m olecular w eight p ro tein s appearing in the urine o f persons intox icated by cadm ium w ould have b een reabsorbed by th e norm al kidney, so th a t th e ir app earan ce in u rin e is an early sign o f renal dysfunction. How ev er, as F riberg and associates1 < D 112) have sug gested, b o th altered catabolism and altered re a b so rp tio n o f pro tein s m ay exist. T h ere are few d a ta on acute renal effects. Bi lateral renal co rtical necrosis has been rep o rted in a fatal c a se . 44 T he co n c en tratio n o f cadm ium in th e kidney was given as .7 ppm w et w eight, O lfactory E ffects A p o te n tia l con seq u en ce o f cadm ium exposure is dam age to the olfactory apparatus, w hich may result in to tal anosm ia. As with lung and kidney dam age, d u ratio n and co n ce n tra tio n of exposure a re probably im p o rta n t factors. P otts65 found ol factory dam age in 53-65% o f w orkers exposed 10-29 years and in 91% o f those exposed for m ore th an 30 years. T hirty-seven p e rc e n t o f the 43 w or kers studied by F riberg 55 show ed olfactory im pair m ent. A dam s and C ra b tre e 78 rep o rted cases o f hyposm ia and anosm ia am ong w orkers exposed to cadm ium oxide dust as well as to nickel dust, in an alkaline-battery o p eration. A group o f 106 battery w orkers w ere co m p ared with 84 age-m atched co n trols. O lfactory acuity was ju d g ed from each sub je c t's evaluation o f his ow n acuity and from a ph enol sm elling test. B attery w orkers rep o rted sig nificantly m ore anosm ia (15% vs 0% ) and did less well on th e phenol sm elling te st (27% vs 5% ). T h ere was a positive correlation betw een p ro tein u ria and anosm ia; 17 w orkers w ith p roteinuria also w ere anosm ic. E xam ination o f noses showed m any cases o f local irritation from dust, som e subm u cosal fibrosis in m ild cases of deficient olfactory acuity, and cases o f ulceration, occasionally with dry crusting, in m ore advanced cases. Biopsy m aterial from one case show ed a m ild nonspecific subm ucosal chronic inflam m ation w ith a few small loose focal accum ulations o f lym phocytes and a few widely sc attere d eosinophils. T he authors a t trib u te d th e anosm ia to exposure to eith er cadm i um o r nickel, o r to a m ixture o f the two. T he p o p ulation studied by Friberg55 was also exposed to nickel. P otts65 did n o t re p o rt nickel exposures, b u t th e w orkers m ad e b atteries, so there w ere un doubtedly exposures to nickel dust, as well as to cadm ium . H ow ever, Tsuji e t al79 reported th a t several w orkers exposed to cadm ium in a zinc refinery, w ithout evidence o f exposure to nickel, had a so-called insensitiveness to smells. (d ) H em atopoietic System A cute effects on the blood a fte r respiratory ex posure at a high co n c en tratio n o f cadm ium have been no ted both in hum ans and in anim als.44,80 E levated hem oglobin in som e hum an subjects may well have been th e result o f h em o concentration from pulm onary e d e m a . 44 A nem ia has been described in w orkers exposed fo r a long tim e to cadm ium oxide dust and fu m e .38,55,81 T he anem ia was usually m oderate. In a g ro u p o f w orkers exposed to cadm ium 5-30 years, Piscator, in u n published studies review ed by F riberg, P iscato r, T h e Itai-Itai (" o u c h -o u c h " ) disease w hich o c cu rred in certain areas o f Ja p a n was attributed to pollution o f w ater an d crops by industrial, cadm i um -containing w aste. 1 40'41.89 The disease is apparently o steom alacia and involves painful jo in ts and bones, especially in th e back and legs. T hose affected w ere m ostly m ultiparous, post m enopausal w om en. A nutritionally deficient (low calcium and p ro te in ) d iet was perhaps an addi tional facto r. Low estrogen levels may also have had som e bearing on th e osteoporosis seen in these cases. (2 ) T eeth T h e d evelopm ent o f a yellow ring a t the neck o f th e to o th was re p o rte d in early epidem iologic sur veys in occupationally exposed persons and was at one tim e suggested to be a w arning sign o f chronic cadm ium in to x icatio n .62,90 W h eth er this is because o f surface ab so rp tio n o f cadm ium , reaction with In an epidem iologic study o f c an c er in persons exposed to cadm ium , K olonel101 co m pared the in cidences o f several types o f c a n c e r in persons hav ing an in ferred o ccu p atio n al history o f cadm ium w ork w ith those in a co n tro l population. The basis fo r inferring a history o f o ccu p ational exposure to cadm ium was ind irect, from jo b classification in fo rm atio n revealed in an interview on adm ission to a c a n c e r research hospital. T h e te st and control p opulations w ere all w hite m ales, aged 50-79 years, and w ere all referred to th e Roswell Park M em orial H ospital in Buffalo, N ew Y ork, because o f suspected neoplastic disease. O ne group of c o n trols w ere those found to have nonneoplastic gas troin testin al disease; a second group o f controls w ere those found to have colon cancer. Kolonel found a significant increase in ren al can cer, and a nonsignificant increase in p an creatic ca n ce r am ong th e p atien ts th o u g h t to have been exposed to ca d m ium . H e an ticip ated an increased incidence of p ro static can cer, b u t found none. H e looked for a sim ilar increase in c a n c e r am ong those exposed to cadm ium from dietary intake o f cadm ium o r from sm oking, b u t the association was questionable. In view o f th e deficiencies in his d a ta on o ccu p a tional histories, conclusions from this study are u n certain. In a later publication based on these data, K olonel102 co m m en ted on evidence o f a synergistic relationship betw een exposure to cadm ium and cig arette sm oking. In th e b elief th a t th e greater th a n additive effect could n o t be acco u n ted fo r by the in creased cadm ium exposure, he suggested th a t som e o th e r co m p o n en t o f cigarette sm oke C adm ium has also caused food poisoning from the use o f a cadm ium -plated refrig erato r sh elf as a grill to hold steak over c h a r coal for broiling.109 A 2-year old child with en cep h alopathy originally attrib u ted to lead was found to have a very high cadm ium concentration o f 710 (j.g/liter in his urine. It was found th a t the child was fond o f licking freshly polished w hite shoes (polish solution containing 275 pig C d/100 m l), occasionally a te silver polish (185 /xg/100 m l), and ate red p ain t (5 0 0 m g /100 g) from his c rib . 110 Bui e t al111 analyzed the chrom osom es in lym phocytes from Swedish battery-factory w orkers and Itai-Itai p atien ts from Jap a n , to gether with co n tro ls from Sw eden and Jap an , and found no significant differences in chrom osom al aberrations betw een cadm ium -exposed people and their respective controls. H ow ever, sizes o f populations studied w ere small in each case. M ean frequencies of ab erratio n s ranged from 2.0% in Swedish b a t tery w orkers to 6.7% in Itai-Itai patients. Shiraishi and co w orkers112'113 cu ltured cadm ium sulfide with h um an leukocyte cells and exam ined leukocyte chrom osom es from 7 Itai-Itai patients, and in each case found an increased incidence o f chrom osom al aberratio n s over controls. T he rate o f abnorm ali ties in th e Itai-Itai p atien ts112 ranged from 14 to 64% o f th e 50 cells exam ined, m uch higher than th e rate found by Bui e t a l. Bonnell34 exam ined 100 w orkers exposed to ca d m ium oxide fum es and 104 controls with sim ilar age distribution in 2 B ritish copper-cadm ium alloy facto ries. N in eteen o f th e 100 exposed w orkers h ad em physem a, p ro te in u ria , o r both, while 3 o f th e co n tro l group had e ith e r em physem a or p ro tein u ria. All 19 m en w ith signs and sym ptom s had been exposed to cadm ium for m ore th an 5 y ears and 13 o f them fo r m ore th a n 15 years. Four additional w orkers required hospitalization because o f shortness o f b reath. Significant dif feren ces in results from certain respiratory fu n c tion tests w ere found by K azantzis126 betw een the exposed and th e co n tro l groups in these sam e fac tories, particularly in th e tim e co n sta n t o f the ex p iratory forced vital capacity curve. In the group o f these w orkers exposed to cadm ium for m ore th an 10 years, B uxton 127 found th a t the volum e of residual air and th e residual q u o tie n t (ie, residual air as expressed as a p ercentage o f th e total lung volum e) w ere both significantly increased. This finding is consistent w ith F rib e rg 's . A hlm ark and associates76 rep o rted on 110 cadm ium -exposed w orkers and 22 controls. Several te st m easurem ents show ed th a t kidney functions w ere red u ced w ith long exposure. U rinary protein ex cretion increased regularly w ith length o f expo sure from 100 m g/24 hours (ranging from 50 to 170) at less th an 5 years to 955 (ranging from 370 to 1800) m g/24 ho u rs a t 31 years and over. T he incidence o f kidney stones increased from 9.1% in the controls to 12.3% in the 6 -to 10-year exposed group and to 43.6% in the g rea ter th an 15-year ex In th e age g ro u p 50-59, th ere was a statisti cally insignificant in crease in hyperten sion in ex posed w om en. T h e re w as a significant increase in average h aptoglobin an d sed im en tatio n ra te in the 40-49 age group and a nonsignificant increase in the 18-29 y ear age group. Serum iron was low er in th e 50-59 year group. T here w ere n o significant differences in urinary findings. A m ong the controls th e re was one case w ith a very high excretion of /32-m icroglobulin; th e p a tte rn obtained by elec tro p horesis o f urine suggested an effect on tu b u lar fu n ctio n b u t th e re was no glucose in the urine, and a b acterial infection involving th e tubules was sug gested as th e explanation. T here was a slight tu b u lar dysfunction in a 71-year-old exposed w om an, b u t w ithout in creased /32-m icroglobulin excretion. She had b een classified as a suspect case in 1969. P iscato r e t' a l131 also observed significant dif feren ces in blood and urine cadm ium , and found th a t u rin e cadm ium , b u t n o t blood cadm ium , in creased w ith age. T hey also n o ted a slight decrease in u rine zinc w ith exposure tim e, ex cept th a t urine zinc was increased by use o f drugs for trea tm en t of hypertension. S m okers had significantly higher blood cadm ium levels th an nonsm okers; dif feren ces betw een cadm ium -exposed sm okers and n onsm okers w ere n o t found in urinary excretion o f cadm ium b u t c o n tro l sm okers ex creted m ore cad m ium th an co n tro l nonsm okers. It was believed th a t cadm ium m ight have b een deposited on cig arettes during w ork, th en vaporized during sm oking and inhaled. T hey found a significant co r relation betw een blood and urine cadm ium in nonsm okers exposed less th a n 1 0 years but n o t in sm okers. K jellstrom and asso ciates132 studied the ex cre tion o f /3 2-m icroglobulin in m ale and fem ale w or kers in th e battery factory originally studied by F rib e rg .55 T h ere w ere 240 m ale and fem ale w or kers exposed to cadm ium oxide dust and to nickel hydroxide dust in th e study group, and there were 87 unexposed m ale controls. T he exposed w orkers w ere em ployed in th e d ep a rtm e n t w here m aterials fo r b attery electro d es w ere m ade (m aterial plant) o r w here th e electro d es and batteries w ere assem bled (assem bly p lan t). S tationary and personal sam ples w ere co llected on m illipore filters except in 1959 and p rio r years and analyzed by atom ic ab so rp tio n sp ectrophotom etry. P article size analy sis in 1972 show ed th a t 95% o f the particles w ere sm aller th an 5 /xm. E nvironm ental concentrations had been occasionally m easured in the factory from 1946 on, b u t system atic m easurem ents based on personal sam pling had n o t been perform ed. In dividual sam ples in the assem bly plant in 1946, based on stationary sam plers, averaged 6 . T he w orkers w ere draw n from 3 different fac to ries, an electro n ic w orkshop, a nickel-cadm ium storage battery factory, and a p la n t producing c a d m ium . E ach factory h a d a co ntrol group selected to m atch th e exposed group in sex, age, w eight, height, sm oking habits, and socioeconom ic status. Since no im p o rtan t m odifications had o ccu rred in th e different industrial processes since th eir institu tion, th e au thors believed th a t levels o f airborne cadm ium found in the 3 plants w ere quite rep resen tativ e o f p ast exposure. A description o f th e exposed groups and the w orkroom cadm ium levels found are given in T able III-1. C o n tro l groups w ere described as Cl, C 2, and C 3, co rresponding to the th re e exposed groups. E xposed groups w ere exposed to dust of cadm ium o r its com pounds; fo u r w orkers in G roup E3 w ere also interm ittently exposed to fum e. In group E l , th e only change was a slight in crease in urine cadm ium ; th ere w ere no significant differences in pulm onary function indices, b u t it was n o ted th a t an effect o f cigarette sm oking on pulm onary function was evident. In group E 2, in b o th sm okers and nonsm okers, all pulm onary indices w ere on the average low er th a n th e corresponding co ntrol group, b u t these differences w ere n o t statistically significant. Blood and urine cadm ium con cen tratio n s were higher th a n co n tro l levels. E lectrophoresis show ed evidence o f glom erular proteins in four w orkers. O ne w orker know n to have glom erulonephritis had w hat was described as excessive proteinuria. In group E3, pulm onary indices (FV C , F E V l and peak expiratory flow ra te ) w ere significantly low ered. C ough b u t n o t ex p ectoration was m ore com m on in E3 th a n in C3 w orkers. T here w ere slight b u t statistically significant changes in som e o f th e blood enzym es, viz, an increased /3 -galactosidase, an increased lactic dehydrogenase, and a decreased RBC acetylcholinesterase; h em atocrit was also low er in E3 th an C3. H ow ever, these changes w ere n o t sufficient to suggest adverse health effects. F u rth e r details o f these stu d ies133,134 as well as o f those on o th e r w orkers exposed to cadm ium have been published in a com prehensive rep o rt, also from th e C atholic U niversity o f Louvain, Belgium, by M atern e et a l. 135 Som e o f these w orker groups w ere also exposed to lead, w hich may m ake som e o f th e observations less clearly attrib u tab le to cad m ium . H ow ever, th e au th o rs co n cluded th at lead ab so rp tio n had little o r no role in the kidney changes, an d th a t th e effects in the kidneys w ere from cadm ium ab so rption by these w orkers. In F acto ry I, involving electronic m an u facture, 26 ex posed w om en and 26 control w om en w ere studied. T h e re w as no lead exposure in this group. In F ac tory II, w here nickel-cadm ium batteries w ere m ade, 2 1 exposed m ale and 6 exposed fem ale w or kers w ere studied, w ith 19 co n tro l m ales and 4 c o n tro l fem ales. In F actory III, involving cadm ium p ro d u ctio n , 25 exposed and 25 co ntrol m ales were studied. In F actory IV, also involving cadm ium p ro d u ctio n , 6 6 exposed and 65 control m en w ere studied. C ontrols w ere m atched with cadm ium -ex posed w orkers in age and in sm oking habits. A ir bo rn e cadm ium c o n c en tratio n s w ere variable, ranging betw een 7 and 19 /xg/cu m in F actory I, 6 -94 in F actory II, 1.2-97 in F actory III, and up to several m g/cu m in F actory IV, after om itting several values (eg, 27 m g/cu m ) th a t w ere believed du e to gross con tam in atio n o f sam ples. The co n ce n tratio n ranges m entioned w ere sm aller in specific w ork sites w ithin a factory. D ifferences betw een exposed and control groups w ere often less rem arkable th an differences betw een sm okers an d nonsm okers. In F actories II and III th ere w ere decreases in hem atocrit; while this m ight be attrib u te d to lead, airborne lead c o n ce n tra tio n s w ere in th e range o f 40-50 ¿tg/cu m, w hich seem s unlikely to be high enough to cause anem ia, so possibly the reduction in hem atocrit w as due to cadm ium alone o r to cadm ium and lead. A n o th er group consisting o f 108 exposed and 110 co n tro l w orkers w ere exposed a t 74-210 yxg/cu m total (2 0 -3 0 /xg/cu m respirable) cadm i um dust, o f whom 18 exposed w orkers had w hat w as d escribed as pathologic urine proteins on elec trophoresis. P ro tein u ria was also seen in som e w orkers in F acto ries III and IV, to g eth e r with p u l m onary function decreases. T he au th o rs concluded th a t, in o rd e r to p rev en t any renal im pairm ent, air b o rne cadm ium , w h eth e r dust o r fum e, should not exceed 50 ¿ig/cu m. # Animal Toxicity In th e ensuing discussion o f anim al toxicity, em phasis is given to th o se investigations w hich sig nificantly a d d to in fo rm atio n from hum an studies, eg, rep ro d u ctiv e effects an d ex p erim ental c a r cinogenesis, w ith a re su lta n t lack o f em phasis on those effects m ore extensively stu d ied in hum ans, such as ren al and p u lm o n ary effects. In addition, in such are a s as te stic u la r effects and biochem ical studies, w here th e re are m any p u b lished studies, the m ore rep resen tativ e o r im p o rta n t studies have been selected fo r discussion. D alham n and F rib erg143 adm inistered cadm ium sulfate sc to 3 groups o f rabbits, 6 /group, 6 days/w eek, for 10 w eeks, at 650 /xg C d/kg. Tw o of th e groups w ere in jected th rice daily with dim ercap ro l, one a t 4 an d th e o th er a t 12 m g/injection; th e th ird group received only cadm ium sulfate. F o u r o f th e anim als on the high dose o f dim ercaprol and 3 receiving only cadm ium sulfate died during the experim ent. T h ere was a progressive w eight loss in all groups, greatest in high-dose dim ercap ro l anim als. P ro tein u ria developed in all b u t tw o rabbits, ea rlie r in m ost of the anim als receiving th e higher dose o f dim ercaprol. T here was a significant and progressive decrease in hem oglobin co n c en tratio n s in th e blood, b u t a sig nificant decrease in ery th ro cy te count o ccurred only in the high dose dim ercaprol animals. P ost m o rtem exam ination show ed th a t all anim als had h e p atic cirrhosis, nephrosis, and splenic fibrosis. O th e rs146-151 have also found hypertensive effects o f C d (II) in anim als. P o rte r e t al152 found no elevation o f blood p res sure in C d(II) intoxication. T hey adm inistered c ad m ium ac etate ip a t 2 mg C d/kg to fem ale Sprague-D aw ley-derived rats, th en a second ip dose o f 1 mg C d/kg 3 w eeks later. From days 14 to 27 after th e seco n d adm inistration, various autonom ic drugs w ere adm inistered in sequence by vein, and systolic blood pressures w ere recorded. W ith norep in ep h rin e b u t n o t epinephrine, drugs causing elevated blood pressure in co n tro l rats, th ere was a lesser elevation in cadm ium -treated rats, with acetylcholine, isoproterenol, and atropine, b u t not pro p ranolol, drugs causing d ecreased blood pres sure in co ntrol rats, th ere was a lesser decrease in cad m iu m -treated rats. A ortic strips from cadm iumtre a te d rats had a dim inished reactivity to an giotensin, ep in ep h rin e, barium , and tyram ine. T he au th o rs co n cluded th a t cadm ium desensitizes rat vasculature to vasoconstrictors and dilators inde p en dently o f any ability to cause hypertension. found in all 80 anim als. Sim ilar d ata were developed by M ason e t al55 a t various doses of cadm ium chloride (0.57-6.8 mg C d/kg) given sc to rats. A gain, edem a p reced ed an ischem ic necrosis w hich was associated w ith increased intratesticular pressure, hem orrhaging, and ultim ate interference w ith testicu lar blood supply. In this study, a doseresponse relation w as found a t th e low er dose levels, 0.57-1.4 m g/kg. A t the low est dose, no ef fe ct was observed, a t 0.85 m g/kg ischem ic necrosis o f sem iniferous tu b u les o c c u rre d in 32% o f the rats, a t 1.1 m g/kg th e re was a 90% incidence, and at 1.4 m g/kg 100% o f th e rats h a d these injuries. It was suggested th a t the unusual sensitivity o f the testes to cadm ium w as related to the unique vascu la tu re , ie, pulseless, sem istagnant flow, w hich m ight have facilitated alteratio n o f capillary e n dothelial perm eability by cadm ium . Sangalang and O 'H alloran 156 studied testicular injury and changes in androgen synthesis in brook tro u t exposed to C d (II) fo r 24 h o u rs at 1 ,2 , o r 25 ppm . T estes o f the fish tre a te d a t 25 ppm show ed extensive h em orrhagic dam age. Form ation o f 11k e to testo ste ro n e, 11-/3-hydroxy testosteron e, and testo stero n e from 14C -pregnenolone in vitro was used to study the effects o f C d (II) exposure on an drogen synthesis by th e testes. T h e results show ed th a t cadm ium inhibited th e form ation o f the ste roids in vitro; w h e th er this reflects the situation in vivo is n o t know n. H ow ever, the study suggests th a t cadm ium -induced testicu lar dam age is not confined to species w ith scrotal testes. In o rd e r to investigate the testicular dam age from cadm ium in m o re detail, Parizek91 injected rats and m ice w ith cadm ium chloride (2.2-4. Parizek e t al170 fo u n d th a t in jectio n o f cadm ium a c e ta te in th e range o f 30-40 ptm ole/kg in several groups o f p reg n an t rats cau sed 40% o f the p reg n an t rats to die w ithin th e first 24 hours after cadm ium adm inistratio n . T h e rats w ere injected on th e 2 1 st day o f p regnancy. In 80% o f these p reg n an t rats, b ilateral h em o rrh ag ic ren al necrosis was observed. M etallothionein w as first isolated by M argoshes and V allee194 from horse kidney cortex and was show n to co ntain a high co n c en tratio n o f cadm ium w ith a lesser am o u n t o f zinc. Subsequently, Kagi and V allee195,196 purified this m aterial, showing th a t it was a hom ogeneous, low m olecular w eight p ro te in (1 0 ,0 0 0 m ol w t) containing 5.9% cadm i um , 2.2% zinc, and 8.5% sulfur, and having very low spectral absorptivity at 280 nm , indicating a lack o f arom atic am ino acids in its com position b u t w ith a specific absorptivity a t 250 nm due to cadm ium -sulfur groupings. T hese investigators sug gested th a t th e m etal-free p ro tein be called thionein, and th a t th e cadm ium protein be called cadm ium -thionein. N inety-five p e rc e n t of all sulfur in th e m etal-free th ionein m olecule was presen t as th e sulfhydryl group o f cysteine. M oreover, cysteine a cc o u n ted for 1 o f every 3 to 4 am ino acids, ie, 25-30% o f the am ino acids o f this p rotein are cysteine m olecules. Pulido e t al 197 show ed th a t a sim ilar p ro tein co u ld be isolated from hum an ren al cortex. T his purified m etallothionein had a m o lecu lar w eight o f 10,500 and contained 4.2% cadm ium , 2.6% zinc, 0.5% m ercury, and 0.3% co p p er. As with th e equine pro tein , th e sulfur c o n te n t w as high, nam ely 8 . 1 %, and th e characteristic ultraviolet ab so rption ban d a t 250 nm was present. Follow ing these early reports from the H arvard g ro u p , 194 197 one gro u p o f w orkers a t the K arolinska Institute in Sw eden198 and an o th er a t Dalhousie U niversity in N ova S cotia199' # Correlation of Exposure and Effect C adm ium com pounds affect m any organs and body system s. T h e re is evidence from m an or low er anim als o f effects on the respiratory trac t, on th e nervous system , on th e liver, on form ed ele m ents o f th e blood, on vascular function, on m ale a n d fem ale gonads, on thyroids, o n p an creata, on bones, and, probably m ost im portantly, on kidney function. In addition, th ere is evidence th a t cadm i um m ay cause c a n c e r and birth deform ities. W ith increasing exposure m ore cadm ium th an can be bou n d by m etallothionein will even tually be accu m u lated in th e kidneys. C adm ium will th e n exchange w ith zinc in enzym es necessary fo r reab so rp tio n and catabolism o f proteins. . . As a result o f th ese anti-enzym atic actions less p ro te in will b e catabolized o r reab so rb ed , causing tu b u la r p ro tein u ria. C adm ium excretion will in crease also as less m etallothionein will be re ab sorbed. A t this stage the accum ulation rate o f c ad m ium will becom e slow er, b u t cadm ium will still be re ab so rb ed and cadm ium levels in the tissue m ay get still higher. T he reabsorption defect will be g reate r and eventually renal cadm ium will cease to increase. T u b u lar cells will be dam aged by cadm ium , and it is conceivable th a t cadm ium will be ex creted to g e th e r with desquam ated tu b u lar cells, resulting in a decrease in renal levels o f cadm ium . If glom erular function is im paired, there will also be less filtration o f m etallo th io n ein ." It is ap p are n t th a t urinary excretion o f low m o lecu lar w eight p ro tein s and perh ap s also urinary ex cretion o f glucose o r am ino acids constitute early evidence o f altered tu b u lar function. This evidence does n o t usually a p p e ar until som e tim e after exposure at sufficiently high cadm ium co n cen tratio n s has started . T suchiya64 found no p ro tein u ria in m en exposed a t an average o f 125 /xg/cu m for less th a n 9 m onths, and w orkers with m ore th an 5 y ea rs' experience had the highest urine p ro tein levels. Kazantzis e t al54 noted th at d u ra tio n o f exposure was im p o rtan t in the d ev elopm ent o f p ro teinuria; th e re w ere no w orkers w ith p ro tein u ria in th e group with less th an 2 y e ars' exposure, th e re w ere 3 w orkers with p ro tein u ria in th e group o f 4 exposed 12-14 years, and all w orkers exposed m ore th a n 25 years had p ro tein u ria. H ow ever, w ith th e rep lacem en t o f m ale w orkers w ith w om en, co n tro l m easures to im prove w or k room hygiene have also been instituted. Thus, the app aren tly g reate r resistance o f w om en to cadm i um , evidenced by few er effects in w om en th an in m en previously em ployed in th e sam e w orkplace, is probably due to the low er con cen tratio n s of cadm ium aerosols to w hich w om en w ere exposed. F o r exam ple, P iscator e t al131 studied w om en w or kers, m ost o f w hom w orked in the plan t previously p o p u lated by th e m en studied by Friberg,55 and fo u n d significantly few er effects th an in the m en studied previously; in fact, it is doubtful th a t his pop u latio n was adversely affected a t all. H ow ever, co n cen tratio n s to w hich the w om en w ere exposed w ere significantly less (u n d e r 100 yu.g/cu m ) than those o f th e m ale w orkers (3-15 m g/cu m ), w ho developed m any toxic effects, including em physem a and renal dysfunction. T svetkova95 studied fem ale w orkers in a p lan t w here co n ce n tratio n s o f cadm ium w ere reportedly 0.1-25 m g/cu m; she found no effects in th e w orkers (although she observed rick ets and d en tal troubles in off spring), b u t it is n o t evident th a t she investigated such effects as those on th e pulm onary and renal ap p aratu s. L auw erys e t a l133 found no adverse ef fects in fem ale w orkers b u t did observe evidence o f a ltered pulm onary and renal function in m ale w orkers. H ow ever, the fem ale w orkers w ere ex posed a t 31 /xg/cu m w hereas m ale w orkers w ere exposed at higher co n ce n tra tio n s (66 p-g/cu m and higher). Tsuji e t al79 did n o t p re sen t environm ental expo sure d ata, so it is n o t clear w h eth er th e ir m ale and fem ale w orkers w ere exposed at th e sam e co n ce n tratio n s. If they w ere, a conclusion th a t the m ale and fem ale w orkers did n o t differ significantly in sensitivity w ould be w arranted. T h e re was a 14.7% in cidence o f p ro tein u ria in th eir m ale w orkers and 15.5% in fem ale w orkers; th e re was a 7.8% in cid ence o f glucosuria in m ale w orkers and a 1.4% incidence in w om en, based on m easurem ent by te st ta p e, w hich m ay be an inadequately sensitive m ethod. (n ) Q u an titativ e R elationships P riority should be given to m ortality studies of cadm ium w orkers w ithout co n co m itan t exposure to o th e r toxic m aterials and to long-term anim al studies at doses up to m axim ally to lera te d ones. # SUM M ARY OF CANCER M ORTALITY D A T A OF KIPLING A N D W ATERHOUSE9 A N D OF LEM EN ET A L07 In view o f the p resen t u n certain ties in the evidence on teratogenicity and carcinogenicity of cadm ium in o ccu p atio n al exposure, a standard b ased on th ese effects is n o t now recom m ended. This reco m m en d atio n should be reconsidered if additional d a ta on these points th a t w arrant such reco n sid eratio n are developed. T h e reco m m en d ed lim its o f 40 /xg/cu m (T W A ) and 200 pig/cu m (ceiling) are fo r to tal particulate cadm ium . Thus, lim its based only on small, socalled respirable, p articles, are n o t recom m ended. C adm ium oxide and m any o th er form s o f cadm ium are n o t in ert, varying in th eir solubilities in w ater and probably in body fluids, so th a t large particles n o t reaching th e alveoli may still be toxicologically active because th ey can be rem oved from the u p p er respiratory tra c t by ciliary action and tra n s ferred to the gastrointestinal trac t. Thus, som e of th ese large particles w ould probably be swallowed and beco m e system ically toxic th ro u g h gastroin testinal absorption (th o u g h gastrointestinal absorp tio n w ould b e e x p ected to be less th an absorption from the respiratory tra c t). It has b een im plicit in the environm ental limits, such as T L V 's th a t have prevailed fo r m any years (see discussion o f previous stan d ard s in the section ab o v e ), th a t cadm ium oxide fum e is m ore toxic th a n cadm ium oxide dust. It seem s probable th a t th e basis fo r this is th e assum ption th a t fum es, being usually o f sm aller p article sizes th an dusts, will p e n e trate m ore efficiently into th e lungs and th u s be m ore efficiently absorbed by th e blood. It is proposed th a t m andatory m edical surveil lance include p rep lace m en t and periodic exam ina tio n s o f lungs, kidneys, and blood pressure. In ad dition, blood co u n ts, studies o f liver function, and, in m ale w orkers, palpation o f the prostate are recom m ended. Pulm onary fu n ctio n tests should be p erfo rm ed periodically, and ch est X-rays should be tak e n if indicated from results o f periodic ex am inations. F or com parison, prep lacem en t ex am inations and exam inations at term ination o f em ploym ent involving cadm ium exposure should in clude X -rays as well as pulm onary function tests. Q u antitative analysis o f urine p ro tein should be c o n d u cted frequently, since this should give early and probably the first indication o f adverse effects o f cadm ium . P ro tein u ria w ith its im plications o f renal dysfunction is less likely to be reversible as it continues, so early d etectio n o f low m olecular w eight proteins in th e urine, w ith the expected result o f steps to im prove hygiene and w ork p ra c tices, should p rev en t serious an d irreversible ef fects o f cadm ium . T herefo re, it is proposed th at analysis o f urine be cond u cted every 4 m onths as well as before p lacem en t an d a t term ination. P ro ced u res for estim ations o f proteins in urine are d escribed in A ppendix III; the conventional boiling te st is n o t ad e q u a te for cadm ium -induced proteinuria. If a w o rk er is found to begin to ex crete significant am ounts o f p rotein in his urine during exposure to cadm ium , electro p h o retic ex am ination o f th e urine fo r the p resence o f various proteins, especially for peaks in the /3-globulin re gion, will b e helpful in deciding w hether exposure to cadm ium is involved in th e genesis o f the proteinuria. A lternatively, specific analysis for /32m icroglobulin can be perform ed. It can be p e r form ed by radioim m unoassay o r radial im m unodif fusion, w hich give com parable results275; sem i-auto m atic p ro ced u res allowing sim ultaneous processing o f 24 sam ples have been described. (f) W ork P ractices W o rk practices are discussed in C h ap ter VI. B razing w ith alloys containing cadm ium (o ften re fe rred to as silver soldering) is especially h azardous b ecause o f the high concen tratio n o f cadm ium oxide fum e pro d u ced , so good local ven tilation and, o ften , respiratory p ro tection are n eeded. Storage, handling, and eating o f food in cadm ium exposure areas should be prohibited to p rev en t food con tam in atio n an d subsequent in gestion o f cadm ium . W hile cadm ium does n o t pose a fire hazard, its deposition on sm oking m aterials m ay result in g en eratio n and inhalation of cadm i um oxide fum e a t a later tim e, so th a t sm oking as well as the carrying o f u n covered sm oking m ateri als in th e w orkplace should be prohibited. T here isn 't good evidence th a t cadm ium aerosols will p e n e tra te the skin, b u t th e ir deposition on clothes m ay result in aerosol g en eration (eg, blow ing of d u st) away from w ork, w hich m ay increase the w o rk ers' exposure as well as cause his family to be exposed. F or this reason, it is pro p o sed th a t w or kers be req u ired to change w ork clothing before leaving w ork. U nder these conditions it should n o t be necessary to com ply w ith m any o f the provisions o f this recom m ended stan d ard , w hich has been p rep a re d prim arily to p ro te c t w o rk ers' health under m ore hazardous circum stances. C o ncern for w o rk ers' health requires th a t p ro tectiv e m easures be instituted below the en fo rceab le limit to ensure th a t exposures stay below th a t lim it. F or these reasons, an action level o f cadm ium has been defined as o ccu p atio n al exposure above half the recom m ended TW A environm ental limit, thereby delineating those w ork situations w hich do not require the expenditure o f health resources for e n vironm ental and m edical m onitoring and as sociated recordkeeping. T his level has been chosen on the basis o f professional ju d g m e n t ra th e r than on q u antitative d ata th a t d elineate nonhazardous areas from areas in w hich a hazard may exist. H ow ever, brazing, w elding, o r th erm al cutting with cadm ium alloys presents a significant hazard re gardless o f the T W A c o n cen tratio n , and such operations should be perform ed only in a c co rd an ce with the recom m ended standard. Sim ilarly, food storage, handling, and eating should be pro h ib ited in cadm ium w ork areas re gardless o f TW A co n cen trations. Silver Brazing Silver brazing, com m only called silver soldering, is the process o f joining m etals by heat with a silver alloy filler m etal. M any filler m etal alloys co n tain cadm ium , w hich can pro d u ce cadm ium oxide aerosol w hen o verheated, so care m ust be taken to control the tem p e ra tu re of silver brazing o p eratio n s if the alloy contains cadm ium . U nder no circum stances should a to rch flam e be applied directly to such an alloy. T he h eat o f the base m etal should be used to m elt the filler m etal and cause it to flow. Silver brazing w ith cadm ium -containing alloys should be perform ed only with satisfactory local exhaust or with appropriate respiratory p rotection. # V I. W O RK PR A C TIC ES (c ) W elding, C utting, and H eating W elding and therm al cutting o f m aterial co n taining cadm ium m ust be perform ed only with local exhaust ventilation dem o n strated by sam pling and analysis o f breathing zone atm ospheres to be sufficient to m aintain airborne cadm ium at or below recom m ended limits. For single operations, w here local exhaust ventilation is not available or w here air sam pling and analysis has not dem o n strated accep tab le air co n cen trations, suitable resp irators (listed in C h ap ter I) m ust be provided and worn. W here m olten cadm ium is used o r form ed, tem p eratu res should be k e p t as low as possible c o n sistent with th e re q u irem en ts o f th e w ork o p e ra tion to p rev en t g en eratio n o f excess fum e. W h er ever possible, this should be accom plished by au tom atic co n tro ls, with reco rd in g o f tem p eratu res and use o f alarm s o r o th e r in d icato rs o f excessive tem p eratu res. If possible, avoid using cadm iumcontain in g alloys for brazing. In any case, cadm ium co n tain in g m etals m ust be appropriately segregated and labeled, so th a t w o rkers will not unknow ingly apply h eat to cadm ium . A ir volum es ta b u la te d for w elding258-" 0 are cal culated fo r a co n tro l velocity o f 100 feet/m in. For cadm ium fum e, control velocities o f 150 feet/m in should be used, so th a t volum es 50% g rea ter than th e tab u lated volum es should be used. Local exh au st system s should be designed and o p erated in co n fo rm an ce w ith ANSI Z 9.2-1971, Effluent air should be cleaned, if necessary, to m eet any em ission standards th a t may be prom ul gated (th e re are now no EPA em issions standards for cadm ium ). Air from the exhaust ventilation system m ust n o t be recircu lated into the w ork place. (e ) R espiratory P rotection F o r ad e q u ate respiratory p ro tectio n against the m any conditions th a t may be en co u n tered in in dividual o p erations, m any types o f respirators have been developed and approved. E ach has particular applications and lim itations from the standpoint o f p ro te ctio n , and each has its advantages and disad vantages from the standpoint o f operation and m aintenance. D etailed inform ation on the selec tion and use o f resp irators can be obtained from R espiratory P ro tective D evices M anual.2™ ANSI Z 8 8 .2 -1 9 6 9 259 also classifies, describes, and gives lim itations o f respirators. R espirators fall into several classifications, ac cording to th eir m ode o f operation: (1 ) a t m osphere-supplying respirators, which include those to w hich suitable air is supplied by tanks carried by the w earer o r by a hose carrying air from a rem ote source (self-contained m asks, hose m asks, airline m asks, and com bination self-con tain ed and airline m asks); (2 ) air-purifying respira tors w hich filter o r absorb the contam inant (gas m ask with chem ical cartridge, particulate masks, and com bination m asks for gas, vapor, and p a r ticu late); and (3 ) com bination atm osphere-supply ing and air-purifying respirators. T he factors th at affect the overall perform ance of air-purifying respirators are the reliability of the face seal, the efficiency o f the filters, and o th e r variables such as leakage from exhalation valves. T he applicable regulation on certification and approval o f respirators is 29 CFR 11. This requires, am ong o th e r things, th a t all air-purifying respirators approved for dusts and fumes with an environm ental limit less than 0.05 m g/cu m be equ ip p ed w ith a high efficiency filter. (f) Protective C lothing P rotective clothing is n o t norm ally required for cadm ium operations. It is possible th at cadm ium dust co llected on clothing could be released into the air to cause a secondary exposure so th a t, if such clothing w ere w orn to the w o rk er's hom e, the w orker and oth ers m ight be exposed to cadm ium dust. T he b e tte r solution is to im prove w orkplace housekeeping to p rev en t clothing co n tam in atio n , but it seem s a wise p re c a u tio n th a t w ork clothing be changed at the end o f th e w orkshift and not carried hom e. T hus, th e re should be change room s with se p a ra te storage areas, such as lockers, and show er an d hand w ashing facilities should be p ro vided. ( W hile th ere isn 't good reason to believe th a t cadm ium co m pounds p e n e tra te the skin to a sig nificant extent, it is good p ractice to avoid skin c o n tac t and if c o n ta c t has o ccu rred to wash the af fected areas prom ptly. (i) Storage C adm ium -containing, including cadm ium -plated, m etal parts should be k ep t sep arate from p arts not containing cadm ium so th a t accidental exposures resulting from w elding and cutting will not occur. (j) E m ergency P ro ced u res E m ergency proced u res should be established for any ev ent th a t m ight result in substantial release of airb o rn e cadm ium . Such p ro c ed u res should in clude provisions to notify the attending physician th at exposure to high c o n ce n tratio n s of cadm ium fum e may cause lung edem a. T his edem a m ay not b ecom e evident until 8-24 hours a fter th e ex p o sure. E m ergency p ro ce d u res should also include provision fo r a p p ro p riate resp irato rs specified in C h ap te r I. It is im p o rtan t to design specific em ergency p ro c ed u res to be follow ed in the event of a fire, to p ro te c t both w orkers and firefighters. # VII. COMPATIBILITY WITH OTHER STANDARDS T h e E n vironm ental P ro te c tio n A gency has not classified cadm ium as a h azard o u s p o llu tan t and neith er em ission n o r am b ien t air stan d ard s have been issued. EPA has n o t p ro m u lg ated solid w aste reg u la tions for cadm ium . H ow ever, it has reaffirm ed the 1962 PHS drinking w ater sta n d a rd o f 0.01 m g /liter279 as an interim prim ary drinking w ater regulation, applicable to com m unity w ater supplies ( Federal Register 4 0 :5 9 5 7 0 , D ec em b e r 24, 1975). W hile this stan d ard is fo r com m unity w ater sup plies, and thus is n o t directly applicable to discharge o f cadm ium into stream s, it seem s clear th a t disposal o f cadm ium w aste, liquid o r solid, should be in a m an n er n o t leading to its in tro d u c tion into drinking w ater. A rea sam ples may be tak en with the ap p a ra tu s used for determ ining w orker exposure, or w ith electro static precipitators. # VIII. R EFER EN C ES (b ) T he sam ple should be taken at a site representative o f the a rea being contam inated. The site should be identified for fu ture sampling. # Calibration of Sampling Trains T he ac cu rate calibration o f a sam pling pum p is essential for the c o rre c t in terp retatio n o f the volum e indicator. T he necessary frequency of calibration is d ep en d e n t on the use, care, and han dling to w hich the pum p has been subjected. In addition to the norm ally scheduled calibration, pum ps should be recalib rated if they have been subjected to m isuse, just received from a m anufac-tu re r, or ju st repaired. If the pum p receives hard usage, m ore freq u en t calib ratio n m ay be necessa- ( 1 ) W hile th e p u m p is running, the voltage o f th e p u m p b attery is m easu red w ith a voltm eter to assure th a t the b a tte ry is charg ed ad eq uately for calibration. (2 ) Place the cellulose m em brane filter with back u p pad in th e filter cassette. (3 ) T he calib ratio n setup is assem bled as shown in Figure X IV -1. (4 ) T he pum p is tu rn ed on and the inside of the soapbubble m ete r is m oistened by im m ersing the b u ret in the soap solution and draw ing bubbles up the tube until they are able to travel the entire length o f th e b u ret w ithout bursting. (5 ) T he pum p is adjusted to provide a flow rate o f 2.0 liters/m in. (6 ) T he w ater m an o m eter is ch eck ed to e n sure th at the pressure d ro p across the sam pling train does not exceed 13 conventional inches o f w ater (3.23 kP a) a t 2 liters/m in. (7 ) A soapbubble is started up the b u re t and the tim e it tak es the bubble to travel a m inim um o f 1.0 liter is m easured with a sto p w atch. (8 ) T he p ro c ed u re in ( 7) above is repeated at least th ree tim es, the results are averaged, and the flow rate is calculated by dividing the volum e betw een the p reselected m arks by the tim e req u ired for the soapbubble to travel the distance. (1 ) C o n c en tra te d nitric acid: redistilled or o f tra ce m etal quality. Use in subsequent steps w here nitric acid is designated. (2 ) W ater: double distilled o r distilled deionized. (3 ) S tandard cadm ium solution: 1000 /ng/ml. Dissolve 1.000 g o f m etallic cadm ium in nitric acid and dilute to 1 liter in a volum etric flask with sufficient w ater and nitric acid to yield a solution containing 10% nitric acid. This solution is com m ercially available. (4 ) A tom ic absorption ap paratus with a cadm ium hollow c a th o d e lam p, read o u t accessory, and gas supply system . O perating conditions recom m ended by th e m a n u factu rer should be fol low ed for gas flow rates and o th er instrum ental variables. T he resonance line for cadm ium is 2,288 A ngstrom s. (5 ) H ot p late, capable o f 300 C. (f) Q uality C ontrol E stablishm ent and m aintenance o f total analyti cal quality control system s to assure continued precision and accu racy o f laboratory reports in clude, as ap p ro p riate, these requirem ents: (1 ) Each test m ust be ch ecked on each day o f use. (2 ) A t least one standard (it may be an in stru m en t stan d ard ) and one control sam ple (w orking value established and run through the en tire analytical p ro c e d u re ) should be included with each run o f unknow n sam ples. W here the con tro l sam ple is not subject to th e in terferences in the unknow n sam ples, a previously run u n k nown should be in cluded as a blind ch eck sam ple. Sam ple, co ntrol sam ple (w orking value previ ously established by carrying through entire analytical p ro c e d u re ), and blank are placed in suitable acid-w ashed vessels. For personal sam plers em ploying 37 mm o r sim ilar filters, 50-ml G riffen b eak ers are suitable. N ext, 3 ml o f co n cen trated n itric acid is added and th e vessel is covered with a w atch glass. E ach sam ple is h eated on a hot plate in an exhaust hood until th e volum e o f nitric acid is red uced to approxim ately 0.5 ml and is pale yellow o r w ater w hite. F u rth er additions o f n itric acid may be necessary fo r com plete oxida tion o f the filter. T h e cooled sam ple is transferred to a suitable volum etric vessel, after rinsing the w atch glass. A 5-ml g raduated cylinder has been em ployed successfully. T he transfer and volum e ad justm ent are effected with 1% nitric acid solu tion. T he resulting blank, c o n tro 1 a. d sam ple solu tions are aspirated into the flam e oi .e instrum ent and the in strum ent response recorded. Sam ples m ay be diluted o r co n cen trated to correspond to the standards. If co n c en tratio n is necessary, the aspiration flow rate should be ch ecked to assure th a t it is com parable to those for the standards. # Sulfosalicylic or Trichloroacetic Acid Analysis F or analysis o f urine protein by precipitation w ith sulfosalicylic o r trich o ro acetic acid, the m ethods described by H enry e t al280 and Meulem ans281 can be used. M easure the specific gravity and the volum e o f the urine sam ple, and, after gentle mixing, filter ab o u t 75 ml; the sam ple should be at room tem p eratu re. C heck for the ap proxim ate co n ce n tra tio n o f protein by some p ro ce d u re such as use o f A lbustix® If the esti m ated co n c en tratio n is higher than 150 m g /100 ml, dilute the sam ple with saline solution (0.99% ) to a p rotein c o n cen tratio n o f a b o u t 100 m g /100 ml. Pipet 0.5 ml o f urine into each o f 2 tubes. A dd to the first tube 2 ml o f saline solution and to the o th e r 2 ml o f 3% sulfosalicylic acid or trich lo racetic acid. Mix the co n ten ts o f each tube im m ediately after th e addition and let stand for 5 m inutes, follow ed by a second mixing and reading o f the absorbance in a sp ectro p h o to m eter a t 620 nm against a reagent blank. S u b tract the reading o f the reagent blank and the reading o f the urine sam ple to w hich saline was ad ded from the reading of the reag en t-treated urine sam ple. C alculate the total am o u n t of p ro tein (p e r unit o f volum e o r per unit o f tim e such as 12 o r 24 h o u rs) from the sta n dard curve. A ccording to M cG arry e t al, 282 n o r mal urine p ro tein ex cretio n is a b o u t 70 m g/day but m ay be as high as 90 m g/day; th ese values are eq uivalent to 5 and 6.4 m g /100 ml if daily urine excretion is ab o u t 1,400 ml. C hem ical substances should be listed according to th e ir com plete nam e derived from a recognized system o f n o m enclature. W here possible, avoid using com m on nam es and general class nam es such as " arom atic am in e," " safety solvent," or " aliphatic h y d ro c a rb o n " w hen th e specific nam e is known. T he " % " may be the approxim ate percentage by w eight o r volum e (indicate basis) w hich each hazardous in g redient o f the m ixture bears to the w hole m ixture. T his m ay be indicated as a range o r m axim um am o u n t, ie, " 10-40% vol" o r " 10% max w t" to avoid disclosure o f trad e secrets. T oxic hazard d a ta shall be stated in term s o f co n c en tra tio n , m ode o f exposure o r test, and anim al used, ie, " 100 ppm L C 5 0 -rat," " 25 m g/kg L D 50-skin-rabbit," " 75 ppm LC m an ," or " perm issible exposure from 29 C FR 1910. (g) Section VII. Spill o r L eak P rocedures D etailed p ro c ed u res for cleanup and disposal should be listed w ith em phasis on precautions to be tak en to p ro te c t w orkers assigned to cleanup detail. Specific neutralizing chem icals or p ro c ed u res should be described in detail. Disposal m ethods should be explicit including p ro p er label ing o f containers holding residues and ultim ate disposal m ethods such as " sanitary landfill," or " in cin eratio n ." W arnings such as " com ply with local, state, and federal antipollution o rd in an c es" a re p ro p er b u t n o t sufficient. P ertin en t specific local requirem ents shall be identified. (h ) Section VIII. Special P rotection Inform a tion Section VIII requires specific inform ation. S tate m ents such as " Y es," " N o ," o r " If necessary" are n o t inform ative. V entilation requirem ents should be specific as to type and p referred m ethods. R espirators shall be specified as to type and NIOSH o r US B ureau o f M ines approval class, ie, " Supplied a ir," " O rganic vapor can ister," " Suitable for dusts n o t m ore toxic than lead ," etc. P rotective equipm ent m ust be specified as to type and m aterials o f construction. (i) Section IX. Special Precautions " P recautionary S tate m e n ts" shall consist o f the label statem ents selected for use on the co ntainer o r placard. A dditional inform ation on any aspect o f safety o r health not covered in o th er sections should be inserted in Section IX. T he lower block can co ntain referen ces to published guides o r inhouse p ro cedures fo r handling and storage. D e p a rtm e n t o f T ra n sp o rtatio n m arkings and classifi cations and o th e r freight, handling, o r storage req u irem en ts and environm ental controls can be noted. (j) Signature an d Filing A n o th e r im p o rta n t a re a is in v ascular effects o f cadm ium exposure, since th e re is conflicting in fo r m ation ore th e role o f cadm ium in hypertension and becau se o f suggestions th a t v ascular effects m ediate such o th e r effects as those on renal fu n c tion. M ore evidence o n th e role o f cadm ium in d ev elo p m en t o f fetal ab n o rm alities in m an is needed. A dditional assu ran ce is n e e d e d th a t, if cadm ium ab so rp tio n is m ain tain ed at sufficiently low levels so th a t zinc availability to th e fetu s will not be a lte red , offspring o f cadm ium w o rkers will not be h arm ed by th e ir p a re n ts' exposure. In this co n n e c tio n , th e re is a n eed for a n atio n al surveil lance system th a t can g a th e r info rm atio n on fetal d eath s o r an om alies and erro rs in d ev elo p m en t o f child ren and relate these d a ta to o ccu p atio n al ex posures (o r o th e r en v iro n m en tal stresses) o f the parents. T he p re se n t in ad eq u acies and conflicts in infor m ation, from both hu m an an d low er anim al in vestigations, on w h eth er cadm ium can cause m u ta tions o r c a n c e r should be c o rre c ted . F u rth er epidem iologic investigations in p o p u latio n s n o t ex posed to o th e r possible causes o f these effects should be pursued. A t the sam e tim e, life-time stu dies in experim ental anim als at ap p ro p riate doses should be p erform ed. T hese doses should be high enough to cause significant toxic effects from cad m ium b u t n o t so high as to cause a significant d ecrease in longevity, for d a ta to be properly in terp re ta b le. F u rth er evidence bearing on the sug gestion th a t cadm ium is involved in the causation o f p ro sta te c a n c e r should be ob tain ed , preferably from w o rk er populations n o t also exposed to o th e r possible carcinogens. In this con n ectio n , a m ortali ty study now underw ay a t th e K arolinska Institute may shed fu rth e r light on this question. This study o f w orker populations exposed to cadm ium in volves two co h o rts, one o f ab o u t 200 and the o th e r sm aller. E valuation o f th e d ata developed may be com pleted w ithin the year (L Friberg, ver bal com m unication, Ju n e 1976). E vidence on adverse effects o f cadm ium on the nervous system , on the p ancreas, on the adrenals, and on thyroids and parathyroids should be c o n firm ed by additional investigations. In particular, conflicting inform ation on w hether cadm ium causes liver changes at w orkplace exposure co n c e n tra tio n s should be resolved. F u rth e r investigation is also n eed ed on the sug gestion, developed in som e re cen t epidem iologic studies, th a t cadm ium w orkers who sm oke may have a g re ater risk o f developm ent o f altered renal function. T # C E N T E R FO R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E FOR O C C U P A T IO N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R	None	None
9d1523a987ff4e2661869327f640cd80a1598523	cdc	None	Surfaces can be built of brick, stucco, wood, stone, cement/ concrete block, asbestos, vinyl, or other materials. DEFICIENCy: Not necessarily a deficiency; assessed because type of surface could lead inspector to other issues.(2003 IPMC CROSS-REFERENCES: 304.1 GENERAl; 304.2 PROTECTIVE TREATMENT) DEFICIENCy: There is a split, separation, or gap in the exterior walls. NOTE: If there is any doubt about the severity of the condition, request an inspection by a structural engineer. Healthy Housing Inspection Manual \| Page 65 ExTERIOR 54. Damaged Chimney (2003 IPMC CROSS-REFERENCE: 304.11 CHIMNEyS AND TOWERS) DEFICIENCy: The chimney, including the part that extends above the roof line, has separated from the wall or has cracks, spalling, missing pieces, or broken sections. ExTERIOR 55. Wall Surface Deterioration (2003 IPMC CROSS-REFERENCES: 304.1 GENERAl;DEFICIENCy: There is deterioration of the exterior wall surface, including missing pieces, holes, or spalling. This may also be attributed to rotting materials -OR-a concrete, stucco, or masonry wall that is flaking, chipping, or crumbling.If there is any doubt about the severity of the condition, request an inspection by a structural engineer.# APPENDIx 3: Additional Resources........................................................................................................ The agencies' initiatives related to healthy homes were created to develop a holistic approach to healthy housing based on the following broad objectives: - Broaden the scope of single-issue public health and safety programs-such as childhood lead poisoning prevention, residential asthma intervention, injury preventionto adopt a holistic approach addressing multiple housing deficiencies that affect health and safety. - Build competency among environmental public health practitioners, public health nurses, housing specialists, housing owners, housing managers, and others who work in the community so they can incorporate healthy housing activities into their professional activities. - Develop national healthy homes capacity through crossdisciplinary grants, contracts, and other activities at the federal, state, tribal, and community levels that research and demonstrate low-cost, effective home hazard assessment and intervention methods. - Develop effective education and outreach materials, with a particular focus on high-risk populations, to increase public awareness of residential hazards and highlight effective actions households can take to reduce the risk for illness and injury. The Healthy Housing Inspection Manual is a model reference tool that local jurisdictions or others may use as is or modify based on local needs. Use of the manual is expected to improve the effectiveness and efficiency of the public health, housing management, and workforces that identify, prevent, and control health problems associated with housing. The manual does not introduce any inspection requirements, nor does it modify any existing inspection requirements for housing agencies, residents, HUD, or CDC. The manual is not a substitute for the Federal Housing Administration (FHA) Minimum Property Standards. Finally, the manual does not propose to establish any regulatory authority for HUD or CDC with regard to residential inspection requirements. The Healthy Housing Inspection Manual takes environmental health professionals and housing managers, specialists, and inspectors through the elements of a holistic home inspection. It is also a useful reference tool for nurses, outreach workers, and others who are interested in preventing illness and injury due to residential health and safety hazards. The Healthy Housing Inspection Manual addresses the broad range of housing deficiencies and hazards that can affect residents' health and safety. The purpose of the manual is to - improve communication and collaboration among public health professionals, housing professionals, property owners and property managers, - increase the understanding of the relations among exposure to hazardous agents, conditions in the home, and adverse health outcomes, and - improve the ability of programs to address an array of housing deficiencies in an efficient, effective, and timely manner. HUD and CDC have also jointly developed and funded other important activities related to healthy homes, including - a healthy housing curriculum that addresses the training needs of environmental public health practitioners, public health nurses, housing specialists, and others interested in building local capacity to address housing-related health hazards (Healthy Homes Training Center and Network, ). - the Healthy Housing Reference Manual, which gives public health and housing professionals the tools necessary to ensure that housing stock is safe, decent, and healthy for our citizens, particularly children and the elderly, who are often most vulnerable and spend more time in the home (/ books/housing/housing.htm). # FORMAT OF THIS MANUAl HUD and CDC recommend that section 1, the Healthy Housing Model Resident Questionnaire (a voluntary health assessment), be completed first. The questionnaire should be used to collect information that cannot be determined visually. Information from the questionnaire can provide important clues that point to housing deficiencies. SECTION 2, the Visual Assessment Data Collection Form, should be used to collect information that can be determined without asking questions of a resident. This form includes detailed assessment of exterior housing, kitchen, bathroom, and living area, as well as a general building information. This manual also contains three supporting appendices: - a data dictionary that defines housing deficiencies listed in the Visual Assessment Data Collection Form; - a cross-reference to code provisions in the 2003 International Property Maintenance Code (2003 IPMC); and - additional resources (links to environmental sampling methods and to more information about substances or issues related to healthy housing). # Section 1 HEAlTHy HOMES MODEl RESIDENT QUESTIONNAIRE Information from questionnaire responses such as these can provide important clues that point to housing deficiencies. The Healthy Homes Model Resident Questionnaire is a tool that can be adapted by local jurisdictions to meet their specific needs. Be sure to follow local jurisdiction regulations for the collection and safeguarding of personal data. For example, jurisdictions may want to add questions about - whether the respondent owns or rents the building/unit - the name and contact information of the building/unit owner (rental units) - whether the building/unit is privately owned or owned by a public housing authority - whether the government pays some of the cost of the building/unit - the name of the person who is responding to the questionnaire. # INjURIES During the past 3 months, did you/did you or anyone in your family have an injury where any part of the body was hurt (including burns, electric shock, or falls)? 5 Did you talk to or see a medical professional about any of these injuries? Please describe the circumstances or events leading to the injury, and any objects, substances, or other people involved. Include what the person was doing at the time. # POISONINGS Have you or anyone in your family been poisoned in the house/unit by swallowing or breathing in a harmful substance such as bleach, carbon monoxide, or too many pills or prescription medications? Do not include food poisoning, sun poisoning, or poison ivy. - Select only one answer per question. If more than one answer is possible, record the most severe hazard and note the others in the comments section at the end of each section. - Complete one set of "site" observations for each building or housing development. - Complete one set of "exterior and building system" observations for each building. - Complete one set of "common area" observations for each building. Do not complete the common area section if no common area exists. - Complete one set of "unit" and "other" observations for each housing unit inspected. - Document deviations from inspection protocol in the comments section space (e.g., units not available for inspection) - Specific locations of specific hazards can be recorded in the comments section if desired. -OR-Pavement that sinks or rises because of the failure of sub-base materials. Five percent or more of the walkways must be impacted-50 out of 1,000 square feet, for example. Relief joints are there by design; do not consider them cracks. When observing traffic ability, consider the capacity to support pedestrians, wheelchairs, and people using walkers. Cracks greater than ¾ inch, hinging/tilting, or missing section(s) that affect traffic ability over more than 5% of the property's walkways/steps. A comment area for the common areas category is also included in this section. Common Areas 92. Peeling/Needs Paint q≥2 square feet: More than 2 square feet of peeling or deteriorated paint in one or more common areas q<2 square feet: Less than 2 square feet of peeling or deteriorated paint in one or more common areas qAll intact: All paint intact Common Areas 93. Water Stains/Water Damage q≥2 square feet: One or more ceilings(s) has evidence of a leak, water damage, or water staining (such as a darkened area) over a large area (more than 4 square feet) q<2 square feet: One or more ceiling(s) has evidence of a leak, water damage, or water staining (such as a darkened area) over a small area (less than 4 square feet) # ElEVATORS qNo water stains/water damage NOTE: This does not include visible mold on ceiling, which is addressed in Common Areas 94. Common Areas 94. Mold q≥4 square feet mold observed or musty odor detected: On one or more ceilings(s), mold is seen in a large area (more than 4 square feet) or there is a musty odor q<4 square feet visible mold: On one or more ceiling(s), mold is seen in a small area (less than 4 square feet) qNo mold or musty odor NOTE: This does not include water stains or damage on ceiling, which is addressed in Common Areas 93. Common Areas 98. Flooring/Tiles q≥50% missing or damaged: More than 50% of the flooring is affected by small holes and damage. -OR-The condition causes a safety problem q10%-<50% missing or damaged: An estimated 10%-50% of the flooring has small holes in areas of the floor surface, but there are no safety problems q<10% missing or damaged: For a single floor, there are small holes in areas of the floor surface. Less than 10% of the floor is affected and there are no safety problems. basins or ponding on paved areas such as parking lots. Detention/retention basins are covered in Site 24: Storm Drainage. Ponding on paved areas is covered in Site 7: Cracks in Pavement. If there has been measurable precipitation ( 1 /10 inch or more) during the previous 48 hours, consider its impact on the extent of the ponding. Determine that ponding has occurred only when there is clear evidence of a persistent or longstanding problem. An area for parking motorized vehicles begins at the curbside and includes all parking lots, driveways, or roads within the property lines that are under the control of the homeowner or housing provider. DEFICIENCy: There are visible faults (longitudinal, lateral, alligator, etc.) in the pavement. # NOTE: Do not include small cracks on walkways. Relief joints are there by design; do not consider them cracks. When observing traffic ability, consider the capacity to support people on foot, in wheelchairs, and using walkers-and the potential for problems and hazards. For parking lots only, note a deficiency if there are cracks on more than 5% of the parking spaces. For driveways/roads, note a deficiency if there are cracks on more than 5% of the driveways/roads. # CHIlDREN'S PlAy AREAS SITE 10. Equipment (2003 IPMC CROSS-REFERENCE: NONE) An outdoor area set aside for recreation or play, espe cially an area containing equipment such as seesaws and swings. Surfaces around playground equipment should have at least 12 inches of wood chips, mulch, sand, pea gravel, or mats made of safety-tested rubber or rubber-like materials. # DEFICIENCy: Playground equipment is danger ous or broken. IF ANy EQUIPMENT POSES AN IMMEDIATE THREAT: REPORT TO bUIlDING MANAGEMENT/OWNER IMMEDIATEly AND RECORD SPECIFICS IN THE COMMENTS SECTION NOTE: Except when safety is still a concern (sharp edges, dangerous leaning, etc.), do not evaluate equip ment that the owner states has been withdrawn from service. For example, if the owner removed the net and hoop from a basketball backboard and the back board poses no safety hazards, it is not a deficiency. The presence of large areas of bare soil in play areas can be a soil lead hazard. This is especially a concern near structures built before 1978 or near areas where older structures were demolished and new ones built on the site. Passages for walking and the structures that allow for changes in vertical orientation. Deficiencies: broken/ missing hand railing for four or more stairs, cracks/ settlement/heaving, or spalling. All buildings must have acceptable fire exits. This includes both stairway access doors and external exits. These can include external fire escapes, fire towers, operable windows on the lower floors with easy access to the ground, or a back door opening onto a porch with a stairway leading to the ground. DEFICIENCy: Any part of the fire escape-including ladders-is blocked, limiting or restricting people from exiting-OR-In multifamily buildings, fire exits are not properly marked-OR-A fire exit is cannot be used or the exit is limited because a door or window is nailed shut; a lock is broken; panic hardware is chained; or debris, storage, or other conditions cause the exit to be unusable. # NOTE: This includes fire escapes, fire towers, and windows on the ground floor that would be used in an emergency. Portion of the building system that safely provides electrical power throughout the building, including equipment that provides control, protection, metering, and service. # NOTE: This does not include transformers or metering that belongs to the providing utility, equip ment that is part of any emergency power generating system, or terminal equipment such as receptacles, switches, or panelboards located in the units or common areas (which are inspected in the Unit or Common Area sections). This inspectable item can have the following deficien cies: blocked access/improper storage, burnt or melted or missing breakers or improper fusing, evidence of leaks/corrosion, frayed wiring, missing breakers/fuses, or missing covers. DEFICIENCy: Breakers have carbon on the plastic body or the plastic body is melted or scarred. # FIRE PROTECTION (bUIlDING) Building systems designed to minimize the effects of a fire. These systems include fire walls and doors, portable fire extinguishers, and permanent sprinkler systems. Interior collection areas for trash/garbage common pick-up or conveyance. DEFICIENCIES: Trash on common area floor, containers missing covers or not sealed, or trash chutes damaged or missing components. The receptacle connected to a power supply or method to control the flow of electricity. This includes two-and three-prong outlets, ground fault circuit interrupters, pull cords, two-and three-pole switches, and dimmer switches. # OUTlETS, SWITCHES, COVER PlATES This inspectable item can have the following deficien cies: missing/broken wiring or exposed wiring. The visible overhead structure lining the inside of a room or area. This inspectable item can have the following defi ciencies: bulging/buckling, holes/missing tiles/panels/ cracks, peeling/needs paint, or water stains/water damage/mold/mildew. # DEFICIENCy: A ceiling is bowed, deflected, sagging, or is no longer aligned horizontally. # NOTE: If there is any doubt about the severity of the condition, request an inspection by a structural engineer. DEFICIENCy: There is a leaking roof or appliance or water pipe in wall or ceiling. # COMMON AREAS 91. Ceiling Holes # FlOORS Floors are defined as the visible horizontal surface system within a room or area underfoot; the horizontal division between two stories of a structure. # ElECTRICAl Portion of the unit that safely provides electrical power throughout the building. Includes equipment that provides control, protection, metering, and service. This inspectable item can have the following deficiencies: blocked access to electric panel, burnt breakers, evidence of leaks or corrosion, frayed wir ing, inoperable ground fault circuit interruptor, miss ing breakers/fuses, or missing covers. # COMMENTS, bUIlDING SySTEMS SECTION COMMENTS, COMMON AREAS SECTION oVerall coMMents on tHis inspection Add any other comments related to this inspection here. # APPENDIx 1: DESCRIPTION OF HEAlTH AND SAFETy CONDITIONS IDENTIFIED ON THE VISUAl ASSESSMENT FORM Adapted from the HUD Public Housing Assessment System (PHAS) and its Physical Assessment Subsystem (PASS) as well as from inspection protocols used by healthy homes grantees. This inspection protocol does not establish legal and/or complete compliance with local, state, federal or other applicable housing, building, health, safety or other applicable policies, codes, regulations, statutes and laws. DEFICIENCy: A fence or gate is rusted, deteriorated, or uprooted and may threaten security, health, or safety. If the fence has deteriorated paint in an area larger than 20 square feet and the property was built before 1978, record this as damaged but not functional. # NOTE: Gates for swimming pool fences are covered in Other Items/Swimming Pool, Spa, or Whirlpool. # SITE 2. Holes or Openings in Soil Below Fence (2003 IPMC CROSS-REFERENCE: NONE) DEFICIENCy: There is an opening or penetration in any fence or gate designed to keep intruders out or children in. Look for holes that could allow animals to enter or could threaten the safety of children. There is an opening/hole in soil beneath the fence. # NOTE: If the fence or gate is not designed to keep intruders out or children in (such as a rail fence), do not evaluate it for holes or openings. # GROUNDS OR PAVEMENT SITE 3. Areas of Erosion (2003 IPMC CROSS-REFERENCE: 302.2 GRADING AND DRAINAGE) The improved land adjacent to or surrounding the housing and related structures. This does not include land not owned or under the control of the homeowner or housing provider. DEFICIENCy: Natural processes-weathering, ero sion, or gravity-or human processes have caused any of these conditions: collection or removal of surface material or sunken tracks, ruts, grooves, or depressions. # NOTES: This does not include detention/retention ExTERIOR 46. Damaged Soffits/Fascia/Flashing DEFICIENCy: Damage to soffit, fascia, soffit vents, or associated components that may provide oppor tunity for water penetration or other damage from natural elements. # NOTE: If there is any doubt about the severity of the condition, an inspection by a roofing specialist is recommended. # WAllS The exterior enclosure of the building or structure. Materials for construction include concrete, masonry block, brick, stone, wood, and glass block. Surface fin ish materials include metal, wood, vinyl, and stucco. # NOTE: Paint that is lead-based and larger than 2 square feet in area is defined in regulations as a significant lead-based paint hazard. DEFICIENCy: There is evidence of mold or mildew (such as a darkening of the surface) that may have been caused by saturation, surface failure, leaks, or condensation. # Housing unit (iteMs 103-196) Items to inspect in the Housing Unit are as follows: # CEIlING, FlOORS, AND WAllS The inside envelope inside the housing unit, includ ing the visible overhead structure lining the inside of a room or area (ceiling), the walls, and the floors and associated trim (e.g. There is a leaking roof or appliance or water pipe in wall or ceiling. # DOORS Means of access to the interior of a unit, room within the unit, or closet. Doors provide privacy and security, control passage, provide fire and weather resistance. This inspectable item can have the following deficien cies: damaged surface (holes/paint/rusting/glass), dam aged frames/threshold/lintels/trim, damaged hardware/ locks, damaged/missing screen/storm/security door, deteriorated/missing seals (entry only), or missing door. # HOUSING UNIT 124. Door Surface # INTERIOR SURFACES) DEFICIENCy: There is damage to the door surface that may affect either the surface protection or the strength of the door-OR-that may compromise building security. This includes holes, peeling/cracking/ no paint, broken glass, and significant rust. The receptacle connected to a power supply or meth od to control the flow of electricity. Includes two-and three-prong outlets, ground-fault circuit interrupters, pull cords, two-and three-pole switches, and dimmer switches. This inspectable item can have the following deficiencies: missing or missing/broken cover plates. DEFICIENCy: An outlet, switch, or both are missing. # NOTE: This does not apply to empty junction boxes that were not intended to contain an outlet or switch. Environmental sampling for contaminants can sometimes yield additional useful information on housing related health hazards. Each sampling method has its strengths and weaknesses, inherent sampling and analytical error and interferences. Multiple methods exist to sample each contaminant. Sampling must be performed carefully, properly, and in a manner that protects both the person doing the sampling and the occupants. Instruments for certain contaminants may be able to measure the contaminant in real time. For some substances, sampling in the home environment may require a license or certification or training or other requirements in certain jurisdictions. Consult your local or state government to determine whether such requirements apply before undertaking any environmental sampling in the home environment. If laboratory analysis is required, consult with the analytic laboratory before collecting any sample. If you are uncertain about how to use a particular method or have not been trained, it is recommended that you consult with the local health or environmental department, a professional industrial hygienist or other environmental scientist. This list of methods and products is not intended to be exhaustive. Additional or other sampling procedures may be recommended in any individual situation. Use of detector tubes and any instrumentation must always be performed according to the manufacturer's instructions. Listing in this document is not intended to be an endorsement of any product or method by the National Center for Healthy Housing or any government agency. # Agency/orgAnizAtion key	Surfaces can be built of brick, stucco, wood, stone, cement/ concrete block, asbestos, vinyl, or other materials. DEFICIENCy: Not necessarily a deficiency; assessed because type of surface could lead inspector to other issues.(2003 IPMC CROSS-REFERENCES: 304.1 GENERAl; 304.2 PROTECTIVE TREATMENT) DEFICIENCy: There is a split, separation, or gap in the exterior walls. NOTE: If there is any doubt about the severity of the condition, request an inspection by a structural engineer. Healthy Housing Inspection Manual \| Page 65 ExTERIOR 54. Damaged Chimney (2003 IPMC CROSS-REFERENCE: 304.11 CHIMNEyS AND TOWERS) DEFICIENCy: The chimney, including the part that extends above the roof line, has separated from the wall or has cracks, spalling, missing pieces, or broken sections. ExTERIOR 55. Wall Surface Deterioration (2003 IPMC CROSS-REFERENCES: 304.1 GENERAl;DEFICIENCy: There is deterioration of the exterior wall surface, including missing pieces, holes, or spalling. This may also be attributed to rotting materials -OR-a concrete, stucco, or masonry wall that is flaking, chipping, or crumbling.If there is any doubt about the severity of the condition, request an inspection by a structural engineer.# APPENDIx 3: Additional Resources........................................................................................................ The agencies' initiatives related to healthy homes were created to develop a holistic approach to healthy housing based on the following broad objectives: • Broaden the scope of single-issue public health and safety programs-such as childhood lead poisoning prevention, residential asthma intervention, injury preventionto adopt a holistic approach addressing multiple housing deficiencies that affect health and safety. • Build competency among environmental public health practitioners, public health nurses, housing specialists, housing owners, housing managers, and others who work in the community so they can incorporate healthy housing activities into their professional activities. • Develop national healthy homes capacity through crossdisciplinary grants, contracts, and other activities at the federal, state, tribal, and community levels that research and demonstrate low-cost, effective home hazard assessment and intervention methods. • Develop effective education and outreach materials, with a particular focus on high-risk populations, to increase public awareness of residential hazards and highlight effective actions households can take to reduce the risk for illness and injury. The Healthy Housing Inspection Manual is a model reference tool that local jurisdictions or others may use as is or modify based on local needs. Use of the manual is expected to improve the effectiveness and efficiency of the public health, housing management, and workforces that identify, prevent, and control health problems associated with housing. The manual does not introduce any inspection requirements, nor does it modify any existing inspection requirements for housing agencies, residents, HUD, or CDC. The manual is not a substitute for the Federal Housing Administration (FHA) Minimum Property Standards. Finally, the manual does not propose to establish any regulatory authority for HUD or CDC with regard to residential inspection requirements. The Healthy Housing Inspection Manual takes environmental health professionals and housing managers, specialists, and inspectors through the elements of a holistic home inspection. It is also a useful reference tool for nurses, outreach workers, and others who are interested in preventing illness and injury due to residential health and safety hazards. The Healthy Housing Inspection Manual addresses the broad range of housing deficiencies and hazards that can affect residents' health and safety. The purpose of the manual is to • improve communication and collaboration among public health professionals, housing professionals, property owners and property managers, • increase the understanding of the relations among exposure to hazardous agents, conditions in the home, and adverse health outcomes, and • improve the ability of programs to address an array of housing deficiencies in an efficient, effective, and timely manner. HUD and CDC have also jointly developed and funded other important activities related to healthy homes, including • a healthy housing curriculum that addresses the training needs of environmental public health practitioners, public health nurses, housing specialists, and others interested in building local capacity to address housing-related health hazards (Healthy Homes Training Center and Network, http://www.healthyhomestraining.org). • the Healthy Housing Reference Manual, which gives public health and housing professionals the tools necessary to ensure that housing stock is safe, decent, and healthy for our citizens, particularly children and the elderly, who are often most vulnerable and spend more time in the home (http://www.cdc.gov/nceh/publications/ books/housing/housing.htm). # FORMAT OF THIS MANUAl HUD and CDC recommend that section 1, the Healthy Housing Model Resident Questionnaire (a voluntary health assessment), be completed first. The questionnaire should be used to collect information that cannot be determined visually. Information from the questionnaire can provide important clues that point to housing deficiencies. SECTION 2, the Visual Assessment Data Collection Form, should be used to collect information that can be determined without asking questions of a resident. This form includes detailed assessment of exterior housing, kitchen, bathroom, and living area, as well as a general building information. This manual also contains three supporting appendices: • a data dictionary that defines housing deficiencies listed in the Visual Assessment Data Collection Form; • a cross-reference to code provisions in the 2003 International Property Maintenance Code (2003 IPMC); and • additional resources (links to environmental sampling methods and to more information about substances or issues related to healthy housing). # Section 1 HEAlTHy HOMES MODEl RESIDENT QUESTIONNAIRE Information from questionnaire responses such as these can provide important clues that point to housing deficiencies. The Healthy Homes Model Resident Questionnaire is a tool that can be adapted by local jurisdictions to meet their specific needs. Be sure to follow local jurisdiction regulations for the collection and safeguarding of personal data. For example, jurisdictions may want to add questions about • whether the respondent owns or rents the building/unit • the name and contact information of the building/unit owner (rental units) • whether the building/unit is privately owned or owned by a public housing authority • whether the government pays some of the cost of the building/unit • the name of the person who is responding to the questionnaire. # INjURIES During the past 3 months, did you/did you or anyone in your family have an injury where any part of the body was hurt (including burns, electric shock, or falls)? 5 Did you talk to or see a medical professional about any of these injuries? Please describe the circumstances or events leading to the injury, and any objects, substances, or other people involved. Include what the person was doing at the time. # POISONINGS Have you or anyone in your family been poisoned in the house/unit by swallowing or breathing in a harmful substance such as bleach, carbon monoxide, or too many pills or prescription medications? Do not include food poisoning, sun poisoning, or poison ivy. • Select only one answer per question. If more than one answer is possible, record the most severe hazard and note the others in the comments section at the end of each section. • Complete one set of "site" observations for each building or housing development. • Complete one set of "exterior and building system" observations for each building. • Complete one set of "common area" observations for each building. Do not complete the common area section if no common area exists. • Complete one set of "unit" and "other" observations for each housing unit inspected. • Document deviations from inspection protocol in the comments section space (e.g., units not available for inspection) • Specific locations of specific hazards can be recorded in the comments section if desired. -OR-Pavement that sinks or rises because of the failure of sub-base materials. Five percent or more of the walkways must be impacted-50 out of 1,000 square feet, for example. Relief joints are there by design; do not consider them cracks. When observing traffic ability, consider the capacity to support pedestrians, wheelchairs, and people using walkers. Cracks greater than ¾ inch, hinging/tilting, or missing section(s) that affect traffic ability over more than 5% of the property's walkways/steps. A comment area for the common areas category is also included in this section. Common Areas 92. Peeling/Needs Paint q≥2 square feet: More than 2 square feet of peeling or deteriorated paint in one or more common areas q<2 square feet: Less than 2 square feet of peeling or deteriorated paint in one or more common areas qAll intact: All paint intact Common Areas 93. Water Stains/Water Damage q≥2 square feet: One or more ceilings(s) has evidence of a leak, water damage, or water staining (such as a darkened area) over a large area (more than 4 square feet) q<2 square feet: One or more ceiling(s) has evidence of a leak, water damage, or water staining (such as a darkened area) over a small area (less than 4 square feet) # ElEVATORS qNo water stains/water damage NOTE: This does not include visible mold on ceiling, which is addressed in Common Areas 94. Common Areas 94. Mold q≥4 square feet mold observed or musty odor detected: On one or more ceilings(s), mold is seen in a large area (more than 4 square feet) or there is a musty odor q<4 square feet visible mold: On one or more ceiling(s), mold is seen in a small area (less than 4 square feet) qNo mold or musty odor NOTE: This does not include water stains or damage on ceiling, which is addressed in Common Areas 93. Common Areas 98. Flooring/Tiles q≥50% missing or damaged: More than 50% of the flooring is affected by small holes and damage. -OR-The condition causes a safety problem q10%-<50% missing or damaged: An estimated 10%-50% of the flooring has small holes in areas of the floor surface, but there are no safety problems q<10% missing or damaged: For a single floor, there are small holes in areas of the floor surface. Less than 10% of the floor is affected and there are no safety problems. basins or ponding on paved areas such as parking lots. Detention/retention basins are covered in Site 24: Storm Drainage. Ponding on paved areas is covered in Site 7: Cracks in Pavement. If there has been measurable precipitation ( 1 /10 inch or more) during the previous 48 hours, consider its impact on the extent of the ponding. Determine that ponding has occurred only when there is clear evidence of a persistent or longstanding problem. An area for parking motorized vehicles begins at the curbside and includes all parking lots, driveways, or roads within the property lines that are under the control of the homeowner or housing provider. DEFICIENCy: There are visible faults (longitudinal, lateral, alligator, etc.) in the pavement. # NOTE: Do not include small cracks on walkways. Relief joints are there by design; do not consider them cracks. When observing traffic ability, consider the capacity to support people on foot, in wheelchairs, and using walkers-and the potential for problems and hazards. For parking lots only, note a deficiency if there are cracks on more than 5% of the parking spaces. For driveways/roads, note a deficiency if there are cracks on more than 5% of the driveways/roads. # CHIlDREN'S PlAy AREAS SITE 10. Equipment (2003 IPMC CROSS-REFERENCE: NONE) An outdoor area set aside for recreation or play, espe cially an area containing equipment such as seesaws and swings. Surfaces around playground equipment should have at least 12 inches of wood chips, mulch, sand, pea gravel, or mats made of safety-tested rubber or rubber-like materials. # DEFICIENCy: Playground equipment is danger ous or broken. IF ANy EQUIPMENT POSES AN IMMEDIATE THREAT: REPORT TO bUIlDING MANAGEMENT/OWNER IMMEDIATEly AND RECORD SPECIFICS IN THE COMMENTS SECTION NOTE: Except when safety is still a concern (sharp edges, dangerous leaning, etc.), do not evaluate equip ment that the owner states has been withdrawn from service. For example, if the owner removed the net and hoop from a basketball backboard and the back board poses no safety hazards, it is not a deficiency. The presence of large areas of bare soil in play areas can be a soil lead hazard. This is especially a concern near structures built before 1978 or near areas where older structures were demolished and new ones built on the site. Passages for walking and the structures that allow for changes in vertical orientation. Deficiencies: broken/ missing hand railing for four or more stairs, cracks/ settlement/heaving, or spalling. All buildings must have acceptable fire exits. This includes both stairway access doors and external exits. These can include external fire escapes, fire towers, operable windows on the lower floors with easy access to the ground, or a back door opening onto a porch with a stairway leading to the ground. DEFICIENCy: Any part of the fire escape-including ladders-is blocked, limiting or restricting people from exiting-OR-In multifamily buildings, fire exits are not properly marked-OR-A fire exit is cannot be used or the exit is limited because a door or window is nailed shut; a lock is broken; panic hardware is chained; or debris, storage, or other conditions cause the exit to be unusable. # NOTE: This includes fire escapes, fire towers, and windows on the ground floor that would be used in an emergency. Portion of the building system that safely provides electrical power throughout the building, including equipment that provides control, protection, metering, and service. # NOTE: This does not include transformers or metering that belongs to the providing utility, equip ment that is part of any emergency power generating system, or terminal equipment such as receptacles, switches, or panelboards located in the units or common areas (which are inspected in the Unit or Common Area sections). This inspectable item can have the following deficien cies: blocked access/improper storage, burnt or melted or missing breakers or improper fusing, evidence of leaks/corrosion, frayed wiring, missing breakers/fuses, or missing covers. DEFICIENCy: Breakers have carbon on the plastic body or the plastic body is melted or scarred. # FIRE PROTECTION (bUIlDING) Building systems designed to minimize the effects of a fire. These systems include fire walls and doors, portable fire extinguishers, and permanent sprinkler systems. Interior collection areas for trash/garbage common pick-up or conveyance. DEFICIENCIES: Trash on common area floor, containers missing covers or not sealed, or trash chutes damaged or missing components. The receptacle connected to a power supply or method to control the flow of electricity. This includes two-and three-prong outlets, ground fault circuit interrupters, pull cords, two-and three-pole switches, and dimmer switches. # OUTlETS, SWITCHES, COVER PlATES This inspectable item can have the following deficien cies: missing/broken wiring or exposed wiring. The visible overhead structure lining the inside of a room or area. This inspectable item can have the following defi ciencies: bulging/buckling, holes/missing tiles/panels/ cracks, peeling/needs paint, or water stains/water damage/mold/mildew. # DEFICIENCy: A ceiling is bowed, deflected, sagging, or is no longer aligned horizontally. # NOTE: If there is any doubt about the severity of the condition, request an inspection by a structural engineer. DEFICIENCy: There is a leaking roof or appliance or water pipe in wall or ceiling. # COMMON AREAS 91. Ceiling Holes # FlOORS Floors are defined as the visible horizontal surface system within a room or area underfoot; the horizontal division between two stories of a structure. # ElECTRICAl Portion of the unit that safely provides electrical power throughout the building. Includes equipment that provides control, protection, metering, and service. This inspectable item can have the following deficiencies: blocked access to electric panel, burnt breakers, evidence of leaks or corrosion, frayed wir ing, inoperable ground fault circuit interruptor, miss ing breakers/fuses, or missing covers. # COMMENTS, bUIlDING SySTEMS SECTION COMMENTS, COMMON AREAS SECTION oVerall coMMents on tHis inspection Add any other comments related to this inspection here. # APPENDIx 1: DESCRIPTION OF HEAlTH AND SAFETy CONDITIONS IDENTIFIED ON THE VISUAl ASSESSMENT FORM Adapted from the HUD Public Housing Assessment System (PHAS) and its Physical Assessment Subsystem (PASS) as well as from inspection protocols used by healthy homes grantees. This inspection protocol does not establish legal and/or complete compliance with local, state, federal or other applicable housing, building, health, safety or other applicable policies, codes, regulations, statutes and laws. DEFICIENCy: A fence or gate is rusted, deteriorated, or uprooted and may threaten security, health, or safety. If the fence has deteriorated paint in an area larger than 20 square feet and the property was built before 1978, record this as damaged but not functional. # NOTE: Gates for swimming pool fences are covered in Other Items/Swimming Pool, Spa, or Whirlpool. # SITE 2. Holes or Openings in Soil Below Fence (2003 IPMC CROSS-REFERENCE: NONE) DEFICIENCy: There is an opening or penetration in any fence or gate designed to keep intruders out or children in. Look for holes that could allow animals to enter or could threaten the safety of children. There is an opening/hole in soil beneath the fence. # NOTE: If the fence or gate is not designed to keep intruders out or children in (such as a rail fence), do not evaluate it for holes or openings. # GROUNDS OR PAVEMENT SITE 3. Areas of Erosion (2003 IPMC CROSS-REFERENCE: 302.2 GRADING AND DRAINAGE) The improved land adjacent to or surrounding the housing and related structures. This does not include land not owned or under the control of the homeowner or housing provider. DEFICIENCy: Natural processes-weathering, ero sion, or gravity-or human processes have caused any of these conditions: collection or removal of surface material or sunken tracks, ruts, grooves, or depressions. # NOTES: This does not include detention/retention ExTERIOR 46. Damaged Soffits/Fascia/Flashing DEFICIENCy: Damage to soffit, fascia, soffit vents, or associated components that may provide oppor tunity for water penetration or other damage from natural elements. # NOTE: If there is any doubt about the severity of the condition, an inspection by a roofing specialist is recommended. # WAllS The exterior enclosure of the building or structure. Materials for construction include concrete, masonry block, brick, stone, wood, and glass block. Surface fin ish materials include metal, wood, vinyl, and stucco. # NOTE: Paint that is lead-based and larger than 2 square feet in area is defined in regulations as a significant lead-based paint hazard. DEFICIENCy: There is evidence of mold or mildew (such as a darkening of the surface) that may have been caused by saturation, surface failure, leaks, or condensation. # Housing unit (iteMs 103-196) Items to inspect in the Housing Unit are as follows: # CEIlING, FlOORS, AND WAllS The inside envelope inside the housing unit, includ ing the visible overhead structure lining the inside of a room or area (ceiling), the walls, and the floors and associated trim (e.g. There is a leaking roof or appliance or water pipe in wall or ceiling. # DOORS Means of access to the interior of a unit, room within the unit, or closet. Doors provide privacy and security, control passage, provide fire and weather resistance. This inspectable item can have the following deficien cies: damaged surface (holes/paint/rusting/glass), dam aged frames/threshold/lintels/trim, damaged hardware/ locks, damaged/missing screen/storm/security door, deteriorated/missing seals (entry only), or missing door. # HOUSING UNIT 124. Door Surface # INTERIOR SURFACES) DEFICIENCy: There is damage to the door surface that may affect either the surface protection or the strength of the door-OR-that may compromise building security. This includes holes, peeling/cracking/ no paint, broken glass, and significant rust. The receptacle connected to a power supply or meth od to control the flow of electricity. Includes two-and three-prong outlets, ground-fault circuit interrupters, pull cords, two-and three-pole switches, and dimmer switches. This inspectable item can have the following deficiencies: missing or missing/broken cover plates. DEFICIENCy: An outlet, switch, or both are missing. # NOTE: This does not apply to empty junction boxes that were not intended to contain an outlet or switch. Environmental sampling for contaminants can sometimes yield additional useful information on housing related health hazards. Each sampling method has its strengths and weaknesses, inherent sampling and analytical error and interferences. Multiple methods exist to sample each contaminant. Sampling must be performed carefully, properly, and in a manner that protects both the person doing the sampling and the occupants. Instruments for certain contaminants may be able to measure the contaminant in real time. For some substances, sampling in the home environment may require a license or certification or training or other requirements in certain jurisdictions. Consult your local or state government to determine whether such requirements apply before undertaking any environmental sampling in the home environment. If laboratory analysis is required, consult with the analytic laboratory before collecting any sample. If you are uncertain about how to use a particular method or have not been trained, it is recommended that you consult with the local health or environmental department, a professional industrial hygienist or other environmental scientist. This list of methods and products is not intended to be exhaustive. Additional or other sampling procedures may be recommended in any individual situation. Use of detector tubes and any instrumentation must always be performed according to the manufacturer's instructions. Listing in this document is not intended to be an endorsement of any product or method by the National Center for Healthy Housing or any government agency. # Agency/orgAnizAtion key	None	None
57ba64cc0b4eec0efef84e52bdc032445c03a8f2	cdc	None	NIOSH recommends the procedures set forth in the following sections as a means of protecting the health, and significantly reducing accidental injury and death associated with entering, working in, and exiting from confined spaces. The standard is designed not only to make the confined space safe for the worker, but also to make the worker cognizant of the hazards associated with this work area and the safe work practices necessary to deal with these hazards. The criteria and standard will be reviewed and revised as necessary. Refers to the gases, vapors, mists, fumes, and dusts within a confined space. The maximum airborne concentration of a toxic agent to which an employee may be exposed for a specified period of time. A dust capable of undergoing combustion or of burning when subjected to a source of ignition. Refers to a space which by design has limited openings for entry and exit; unfavorable natural ventilation which could contain or produce dangerous air contaminants, and which is not intended for continuous employee occupancy. Confined spaces include but are not limited to storage tanks, compartments of ships, process vessels, pits, silos, vats, degreasers, reaction vessels, boilers, ventilation and exhaust ducts, sewers, tunnels, underground utility vaults, and pipelines. A confined space that presents a situation that is immediately dangerous to life or health (IDLH). These include but are not limited to oxygen deficiency, explosive or flammable atmospheres, and/or concentrations of toxic substances. A confined space that has the potential for causing injury and illness, if preventive measures are not u s e d , but not immediately dangerous to life and health. A confined space in which the potential hazard would not require any special modification of the work procedure. Any work involving burning, welding, riveting, or similar fire producing operations, as well as work which produces a source of ignition, such as drilling, abrasive blasting, and space heating. Displacement of the atmosphere by a non reactive gas (such as nitrogen) to such an extent that the resulting atmosphere is noncombustible. A process whereby the confined space is removed from service and completely protected against the inadvertent release of material by the following: blanking off (skillet type metal blank between flanges), misaligning sections of all lines and pipes, a double block and bleed system, electrical lockout of all sources of power, and blocking or disconnecting all mechanical linkages. # Lower Flammable Limit (LFL) The minimum concentration of a combustible gas or vapor in air (usually expressed in percent by volume at sea l e v e l ) , which will ignite if an ignition source (sufficient ignition energy) is present. # Oxygen Deficiency Refers to an atmosphere wit h a partial pressure of oxygen (P02) less than 132 mm Hg. Normal air at sea level contains approximately 21% oxygen at a P 0 2 of 160 mm Hg. At # Purging The method by which gases, vapors, or other airborne impurities are displaced from a confined space. # Inerting Isolation exposure to hazardous substances or other unsafe conditions in a confined space. This person shall be capable of specifying necessary control and/or protective action to insure worker safety. # Respirator (Approved) A device which has met the requirements of 30 CFR Fart 11 and is designed to protect the wearer from inhalation of harmful atmospheres and has been approved by the Bureau of Mines and the National Institute for Occupational Safety and Health, and Mine Safety and Health Administration (formerly, Mining Enforcement and Safety Administration). # Standby Person A person trained in emergency rescue procedures and assigned to remain on the outside of the confined space and to be in communication with those working inside. # Section 2 -Entry and Rescue The Confined Space Classification Table on page 4 is based on existing or potential hazards relative to the confined space. The classification is based upon the characteristics of the confined space, oxygen level, flammability and toxicity. If any of the hazards present a situation which is immediately dangerous to life or health (IDLH) , the confined space shall be designated Class A. The classification shall be determined by the most hazardous condition of entering, working in, and exiting a confined space. Class B confined space has the potential for causing injury and illness but is not immediately dangerous to life and health. A Class C entry would be one in which the hazard potential would not require any special modification of the work procedure. The Check List of Consideration on page 5 delineates the minimum preparation required for each class of confined space entry. In the recommended standard where specific procedures, activities or requirements are correlated with a classification: the procedure, activity or requirement is mandatory. As an example, Section 3 -Permit System (Class A, B and C) means that a permit is mandatory for Class A, B, and C confined space entry. If the work practice involved in the confined space has the potential to increase existing hazards' or generate additional o n e s , it shall be necessary to frequently evaluate the space to determine if a classification change is warranted. # CONFINED SPACE CLASSIFICATION TABLE Parameters Rescue procedures shall be specifically designed for each entry. If a confined space has an A or B Classification, there shall be a trained standby person assigned to that confined space with a fully charged, positive pressure, self-contained breathing apparatus (SCBA) at hand. Additional duties of the standby person are to maintain unobstructed life lines and communications to all workers within the confined space, and to summon rescue personnel if necessary. Under no circumstances will the standby person enter the confined space until he is relieved and is assured that adequate assistance is present. However, while awaiting rescue personnel the standby person will make rescue attempts utilizing the life lines from outside the confined space. Rescue teams entering a Class A or B confined space shall be equipped with all the aforementioned safety equipment of the standby person and required life lines. In the event of a Class C confined space rescue, a supplied-air respirator or a self-contained breathing apparatus shall be used. A person summoned or one who recognizes the need for rescue shall summon assistance and await their arrival outside the confined space. Respirators and life lines shall be donned by rescue personnel with necessary equipment for removal of the victim(s). Section 3 -Permit System (Class A, B, and C) Entry into a confined space shall be by permit only. The permit is an authorization and approval in writing that specifies the location and type of work to be done, and certifies that all existing hazards have been evaluated by the qualified person, and necessary protective measures have been taken to insure the safety of each worker. The supervisor or a qualified person shall be responsible for securing the permit and both shall sign off when the following areas and actions have been reviewed and confirmed: (1) Blanking and/or disconnecting. (2) Electrical lockout. (3) Mechanical lockout. (d) Special clothing and equipment. (Class A and B) (1) Personal protective equipment and clothing (2) Safety harness and/or lines. (3) Tools approved for use in accordance with the Hazardous Location Classification (NEC-1978). (4) Approved electrical equipment. (e) Atmospheric test readings. (Class A, B, and C) (1) Oxygen level. (2) Flammability and/or explosive levels. (3) Toxic substance levels. This permit shall be dated and carry an expiration time that will be valid for one shift only. The permit shall be updated for each shift with the same requirements. The permit for a Class A or B confined space shall be posted in a conspicuous place, close to the entrance, with a copy on file with the employer. The sample permit in Appendix III should serve as a guide and not be limited to the areas mentioned. The training requirements of personnel entering and/or working in confined spaces shall be suitable for the nature of the hazard and the work to be performed and will therefore vary with the confined space classification. The permit will vary among different industrial activities. However, it should serve the same purpose for all industries, to insure the safety of the worker. Section 4 -Medi c a l (Class A, B) (a) Workers who enter a Class A or B confined space shall have a preplacement physical examination made available to them. The employer shall provide to the physician performing or responsible for the medical surveillance program information such as the type of confined space the employee may be required to enter, the type of substances the employee may encounter, and a description of any protective devices or equipment the employee may be required to use. The physical examination shall include: (1) A demonstration of the worker's ability to use negative and positive pressure respirators as cited in 29 CFR 1910.134. (2) A demonstration of the workers ability to see and hear warnings, such as flashing lights, buzzers or sirens. (3) The examination should place emphasis on general evaluations of the employee's ability to carry out his assigned duties and the detection of any diseases or abnormalities which may make it difficult to work within confined spaces. (b) Following completion of the examinations, the physician shall give to the employer a written statement specifying any condition or abnormality found which would increase risk to the employee's health by working in confined spaces. (c) Periodic medical examinations shall be made available to employees required to work in Class A or B confined spaces. # (d) First Aid Provisions (1) For Class A and B entry there shall always be someone readily available in the area of the confined space who is currently trained in cardio-pulmonary resuscitation (CPR) and basic first-aid procedures. (2) Employees shall be aware of the location of the nearest firstaid equipment, and how to obtain emergency assistance and medical attention. A n adequate supply of first-aid equipment shall be within easy access of the confined space. (e) Records of exposure to known health hazards shall be included in that employee's medical record. These records shall be made available to the designated medical representatives of the Secretary of Health, Education and Welfare, of the Secretary of Labor, of the employer and of the employee or former employee. Training shall not be considered as complete until the supervisor or other employer-designated official, safety or training officer, judges that the employee has attained an acceptable degree of proficiency for entering and working in confined spaces. The trainee's judgment of the adequacy of his training should be properly considered. Section 6 -Testing and Monitoring (Class A, B, and C) Entry into a confined space is prohibited until initial testing of the atmosphere has been done from the outside . Appropriate tests shall be made to insure that the atmosphere is safe. The tests performed shall include those for oxygen content, flammability, and toxic materials. Any necessary additional tests will be selected and performed to the satisfaction of the qualified person. Monitoring of a Class A confined space shall be done on a continuous basis. Class B and C shall be monitored as determined by the qualified person. Entry into a confined space for any type of hot work shall be prohibited when tests indicate the concentration of flammable gases in the atmosphere is greater than 10% of the lower flammability limit (LFL). It is necessary to determine the oxygen level (by appropriate testing) prior to measuring the range of flammability to make necessary corrections in the flammability measurement. Monitoring of the atmosphere shall be performed in accordance with the permit. Equipment for continuous monitoring of gases and vapors shall be explosion proof and equipped with an audible alarm or danger signaling device that will alert employees when a hazardous condition develops. Instruments used for testing the atmosphere in a confined space shall be selected for their functional ability to measure hazardous concentrations. Instruments shall be calibrated in accordance with the manufacturer's guidelines or manuals. Each calibration shall be recorded, filed by the employer, and available for inspection for 1 year after the last calibration date. In any confined space classified as a Class II or Class III hazardous location according to the 1978 National Electrical Code, Article 500 Sections 5 and 6 , a fire watch shall be established as part of the entry procedure. In such areas surface dust and fibers shall be removed and no hot work shall be initiated until the airborne particulate level is below 10% of the LFL for the material. When combustible dusts or ignitable fibers/flyings are present, all equipment and ventilation systems used in the confined space shall comply with Articles 502 and 503 of the National Electrical Code. The percentage of oxygen for entry into a confined space shall be no less than 19.5% nor greater than 25% at 760 mm Hg. At sea level the normal atmospheric pressure for air (20.9% 0 2 + 78.1% N 2 + 1% Ar + trace amounts of various inert gases) is 14.7 psi or 760 m m Hg absolute. The partial pressure of oxygen ( P O 2) at sea level will be approximately 160 mm Hg. P O 2 can be reduced by reducing the 0 2 level in air at a given elevation or through increasing altitude. If tests indicate the oxygen level to be greater than 25% hot work is prohibited until ventilating techniques have reduced the oxygen level to approximately 21%. If the percentage of oxygen falls below 19.5% approved respiratory equipment shall be used in accordance with Section 8 and Appendix II. When the contaminants in the atmosphere cannot be kept within permissible exposure levels as set down in 29 CFR Part 1910 Sub Part Z, then the employee shall wear an approved respirator. Section 7 -Labeling and Posting (Class A, B, and C) (a) All warning signs shall be printed both in English and in the predominant language of non-English reading workers. Where established symbols exist, they shall also be used. Workers unable to read labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on the signs. (b) All entrances to any confined space shall be posted. Signs shall include but not necessarily be limited to the following information: DANGER CONFINED SPACE ENTRY BY PERMIT ONLY (c) When a specific work practice is performed or specific safety equipment is necessary, the following statement shall be added, in large letters, to the warning sign: RESPIRATOR REQUIRED FOR ENTRY LIFELINE REQUIRED FOR ENTRY HOT WORK PERMITTED OR NO HOT WORK (d) Emergency procedures, including phone numbers of fire departments and emergency medical services shall be posted conspicuously within the immediate area of the confined space, or at the telephone from which help would be summoned. Section 8 -Safety Equipment and Clothing (Class A, B, and C) The entry permit shall include a list of necessary protective equipment to be used in the confined space as determined by the qualified person. The employer shall be responsible for the proper use of the safety equipment, and the inspection and maintenance procedures performed on the safety equipment. The type of protective equipment required, will be determined by the qualified person. Those items normally used to protect against traumatic injury include: safety glasses, hardhats, footwear and protective clothing. (a) Eye and Face Protection -For persons who wear corrective spectacles, either prescription ground safety glasses or plano-goggles shall be provided. Additionally if eye-irritating chemicals, vapors, or dusts are present, safety goggles shall be required, and if both the face and eyes are exposed to a hazard, as during scrapping scale or cutting rivets, a full coverage face shield with goggles shall be used. During welding operations the special goggles or shields required shall be in accordance with 29 CFR 1910. (d) Body Protection -All personnel entering a confined space shall wear full coverage work clothing as specified by the qualified person. Gloves and clothing made of impervious rubber or similar material are to be worn to protect against toxic or irritating materials. If the hazards of heat or cold stress exist in the confined space, clothing which has been tested to provide protection from over-exposure to these hazards shall be worn. Other body protection required In specific operations such as welding (flame proofed) , riveting (heat resistant) and abrasive blasting (abrasion resistant) shall be provided to insure worker safety. (e) Hearing Protection -Shall be required when engineering technology is insufficient to control the noise level, and the ambient exposure limit exceeds those allowed in Table G-16 of 29 CFR 1910.95. Emergency alarms shall be distinguishable when hearing protection is worn. The sound level meters used to measure noise levels shall be certified by NIOSH in accordance with 24 CFR 82. Where the potential for explosion exists, the sound level meters shall be of an explosion proof design. (f) Respiratory Protection -Shall be determined by the qualified person based upon conditions and test results of the confined space, and the work activity to be performed. Halfmask respirators are not recommended for use in any atmosphere greater than 10 x PEL because of the probability of accidently breaking the facepiece to face seal due to the work condition in a confined space. Also, gas masks designed for the same respiratory protection may be substituted for chemical cartridge respirators in the table (see Appendix I I ) , but they are more cumbersome and restrictive to movement. The minimum service time of self-contained breathing apparatus shall be calculated on the entry time, plus the maximum work period, plus twice the estimated escape time for safety margin. The respirators used shall be NIOSH and MSHA approved devices and shall be fitted and maintained in accordance with 29 CFR 1910.134. However, suppliedair respirators purchased before 1975 and bearing Bureau of Mines approval may be used until March 31, 1980. Self-contained breathing apparatus, with audible alarms and all gas masks, approved by the Bureau of Mines may be used until further notice. (g) Hand Protection -If hands are exposed to rough surfaces or sharp edges, the degree of protection can range from canvas to metal mesh gloves, depending on the material handled. Gloves made of impervious rubber or similar material are to be worn to protect against toxic or irritating materials. Heat protective gloves are required when employees handle objects with temperatures greater than 60 C (140 F ) . Where a current flow through the body of more than 5 milliamperes may result from contact with energized electrical equipment, employees shall wear insulating gloves that have been visually inspected before each use. Above 5,000 volts, rubber gloves in accordance with 29 CFR 1910.137 shall be worn. Additional safety equipment that is necessary to protect the worker in the environment of a confined space: a safety belt with "D" rings for attaching a life line shall be worn at all times; the combination of a body harness and/or safety belt with life line shall be used when an employee is required to enter to complete the gas analysis; when an employee is working in an area where entry for purposes of rescue would be contraindicated (special limitations or fire hazard); when any failure of ventilation would allow the build-up of toxic or explosive gases within the time necessary to evacuate the area, or when the atmosphere is Immediately dangerous to life and health. Safety belts may be used as the primary means of suspension for the life line only when rescue may be made by keeping the disabled body in a position that will maintain easy passage through exit openings. If the exit opening is less than 18 inches (45 cm) in diameter, then a wrist type harness shall be used. When it is determined by the qualified person that none of the special hazards associated with confined spaces pose an immediate threat to life, as in a Class C entry, then life lines shall be readily available but not used during entry and work procedures. Other protective measures shall include: safety nets used to protect employees working 10 feet (3 m) above ground or grade level when other protective devices are impractical; life jackets worn if the workers are exposed to falls into liquid over 4 feet (1.2 m) in depth; and insulated floor mats when hot work requires use of electrical energy. When employees enter a confined space, a barricade shall be erected if inadvertent entry poses a problem. The barricade shall have a mechanism to prevent closure of the escapeway, signs warning of the danger present, a physical barrier (fence) to keep the area clear, and an adequate platform (3 feet x 3 feet as a minimum) for entry or exit. Such added features as a tripod with block and tackle for safety lines and communication equipment should be considered when the entry plan is formulated. The employer shall be responsible for maintenance of the barricade system. Section 9 -Work Practices (Class A, B, and C) Before entering a confined space, employees shall review the specific guidelines appropriate for safe entry and emergency exit. These guidelines or standards shall be compiled by the qualified person and be definitive on all the possible hazards. Areas covered by such guidelines shall follow this recommended standard. (a) Purging and Ventilating (Class A, B) Environmental control within a confined space is accomplished by purging and ventilating. The method used will be determined by the potential hazards that arise due to the product stored or produced, suspected contaminants, the work to be performed, and the design of the confined space. When ventilating and/or purging operations are to be performed, the blower controls shall be at a safe distance from the confined space. In a Class A entry, an audible warning device shall be installed in all equipment to signal when there is a ventilation failure. When a ventilation system is operational, air flow measurements shall be made before each workshift to ensure that a safe environmental level is maintained. Initial testing of the atmosphere shall be performed from outside the confined space before ventilation begins to determine what precautions are necessary in purging and ventilating. Testing of more remote regions within the confined space may be performed once the immediate area within the confined space has been made safe. Exhaust systems shall be designed to protect workers in the surrounding area from contaminated air. If flammable concentrations are present all electrical equipment shall comply with the requirements of NEC (NFPA no. 70) hazardous locations, and the bonding requirements of Article 250 of NEC, 1978. Where continuous ventilation is not a part of the operating procedure, the atmosphere shall be tested until continuous acceptable levels of oxygen and contaminants are maintained for three tests at 5-minute intervals. Care shall be taken to prevent recirculation of contaminated air and interaction of airborne contaminants. Continuous general ventilation shall be maintained where toxic atmospheres are produced as part of a work procedure, such as welding or painting, or where a toxic atmosphere may develop due to the nature of the confined space, as in the case of desorption from walls, or evaporation of residual chemicals. General ventilation is an effective procedure for distributing contaminants from a local generation point throughout the work space to obtain maximum dilution. However, special precautions shall be taken if the ventilating system partially blocks the exit opening. These precautions include a method for providing respirable air to each worker for the time necessary for exit, and a method of maintaining communications. Local exhaust ventilation shall be provided when general ventilation is not effective due to restrictions in the confined space or when high concentrations of contaminants occur in the breathing zone of the worker. Local high concentrations of contaminants may occur during work activities such as welding, painting, and chemical cleaning. The worker shall not be exposed to concentrations of contaminants in excess of those specified in 29 CFR Part 1910 Sub Part Z. Therefore, respiratory protection, as recommended in Section 8 , may be needed in addition to engineering controls. The use of respiratory protection will be determined by the qualified person. However, when fumes may be generated that contain highly toxic or other airborne metal contaminants, the provisions of 29 CFR 1910.252 shall be observed. When freely moving exhaust hoods are used to provide control of fumes generated during welding, such hoods shall maintain a velocity of 100 feet per/minute in the zone of the welding. The effective force of freely moving exhaust hoods is decreased by approximately 90% at a distance of one duct diameter from the plane of the exhaust opening. Therefore, to obtain maximum effectiveness the welder shall re-position the exhaust hood as he changes welding locations to keep the hood in close proximity to the fume source. Special precautions shall be taken when outgassing or vaporization of toxic and/or flammable substances are likely. If the vapor-generating rate can be determined, the exhaust rate required can be calculated to dilute the atmosphere below the PEL and/or 10% of the LFL, whichever is the lower. This shall be the lowest acceptable ventilation rate. If the area of concern is relatively small, diffusion of the contaminants may be controlled by enclosure with a relatively low volume exhaust for control, or by exhaust hoods located as close as possible to the area of vaporization or outgassing. If the area to be ventilated is too extensive to be controlled by local exhaust, then general ventilation procedures shall be used to control the contaminant level. When the problem of outgassing is due to the application of protective coatings or paint, ventilation shall be continued until the build-up of a flammable and/or toxic atmosphere is no longer possible. There are three components necessary for combustionr fuel, oxygen, and a source of ignition. If work with fire becomes necessary in a confined space and the source of fuel cannot be controlled, then the atmosphere shall be inerted. This is a highly hazardous work situation, and continuous monitoring of the inert make-up ventilation is mandatory. Monitoring shall include flow measurement as well as gas analysis. The inerting operation shall be continuously monitored and supervised by the qualified person. Since every confined space will have its own infiltration rate, inerting shall continue for the entire duration of the work at a rate that will prevent air from entering the confined space. The isolation procedures shall be specific for each type of confined space. Safety equipment required during this procedure shall be designated by the qualified person and be dependent upon the potential hazards involved. A Class A or B confined space shall be completely isolated from all other systems by physical disconnection, double block and bleed, or blanking off all lines. In continuous systems, where complete isolation is not possible, such as sewers or utility tunnels, specific written safety procedures that are approved and enforced by the employer shall be used. Blanks used to seal off lines shall be capable of withstanding the maximum working pressure or load of the line (with a minimum safety factor of 4), be provided with a gasket on the pressure side to insure a leakproof seal, and be made of chemically nonreactive material. Shutoff valves serving the confined space, shall be locked in the closed position and tagged for Identification. In addition to blanking, pumps and compressors serving these lines entering the confined space shall be locked out to prevent accidental activation. All blanks for that specific confined space shall be recorded on the entry permit and recorded in the employer' s file, which shall be available for inspection. If a drain line is located within the confined space, provision shall be made when necessary to tag it and leave it open. This shall also be recorded on the entry permit. Additional procedures, which are necessary when the confined space is of a double wall type construction, eg, water jacketed or similar type, shall be determined by the qualified person and noted on the entry permit. # Electrical isolation of the confined space to prevent accidental activation of moving parts that would be hazardous to the worker is achieved by locking circuit breakers and/or disconnects in the open (off) position with a key-type padlock. The only key is to remain with the person working inside the confined space. If more than one person is inside the confined space, each person shall place his own lock on the circuit breaker. In addition to the lockout system, there must be an accompanying tag that identifies the operation and prohibits use. Mechanical isolation of moving parts can be achieved by disconnecting linkages, or removing drive belts or chains. Equipment with moving mechanical parts shall also be blocked in such a manner that there can be no accidental rotation. (c) Cleaning (Class A, B, and C) Procedures and processes used to clean the inside of a confined space shall be reviewed and authorized by the qualified person. The method to be prescribed shall be dependent upon the product in the space. If the confined space contains a flammable atmosphere above the upper flammable limit, it shall be purged with an inert gas to remove the flammable substance before ventilating with air. Initial cleaning shall be done from outside the tank if at all possible. Special procedures should be adopted to handle the hazards created by the cleaning process itself. For example: if the tank is steamed, (1) it shall be allowed to cool prior to entry; (2) ventilation shall be maintained during neutralization procedures to prevent build-up of toxic materials; (3) steaming shall not be used as a cleaning method vrtien the product stored was a liquid with an autoignition temperature 120% or less of the steam temperature, and (4) the pipe or nozzle of the steam hose shall be bonded to the tank to decrease the generation of static electricity that could accumulate in tanks during steaming procedures. These and other hazards and controls shall be evaluated by the qualified person. # (d) Equipment and Tools (Class A, B, and C) Equipment and tools to be used in a confined space shall be carefully inspected and shall meet the following requirements: (1) Hand tools shall be kept clean and in good repair. (2) Portable electric tools, equipment, and lighting shall be approved in accordance with 29 CFR Part 1910 Sub Part S and be equipped with a ground fault circuit interrupter that meets the requirements of 29 CFR 1910.309. All grounds shall be checked before electrical equipment is used in a confined space. (3) All electrical cords, tools, and equipment shall be of heavy duty type with heavy duty insulation and inspected for visually detectable defects before use in a confined space. (4) Air driven power tools shall be used when flammable liquids are present. The use of air driven power tools will reduce the risk of explosion, not eliminate it. Explosions can arise by tools overheating (drilling), sparks produced by striking (percussion), grinding or discharge of accumulated electrostatic charges developed from the flow of compressed air. (5) Lighting used in Class A and B confined spaces shall be of explosion proof design and where necessary, equipped with guards. Only equipment listed by the Underwriters Laboratories for use in Division 1, atmospheres of the appropriate class and group, or approved by U.S. # Bureau of Mines or Mining Enforcement and Safety Administration or Mine Safety and Health Administration, or the US Coast Guard shall be used. Lighting shall not be hung by electric cords, unless specifically designed for that purpose. The illumination of the work area shall be sufficient to provide for safe work conditions as referenced in the ANSI standard All-1-1965, or the revision, 1970. Under no circumstances will matches or open flames be used in a confined space for illumination. (6) Cylinders of compressed gases shall never be taken into a confined space, and shall be turned off at the cylinder valve when not in use. Exempt from this rule are cylinders that are part of self-contained breathing apparatus or resuscitation equipment. (8) Scaffolding and staging shall be properly designed to carry maximum expected load (safety factor of 4), be equipped with traction type planking, and meet the requirements of 29 CFR 1910.28. (9) Electrical lines, junctions and appurtenances will be in accordance with National Electrical Code (NEC) and National Fire code (NFC) as cited in 29 CFR 1910.309. (10) Only hose lines and components designed specially for the compressed gas and working pressure shall be used, and such systems shall have a pressure relief valve outside the confined space. (11) All equipment that may be used in a flammable atmosphere shall be approved as explosion proof or intrinsically safe for the atmosphere involved by a recognized testing laboratory such as the US Bureau of Mines, MESA, or MSHA for methane and by the Underwriters Laboratories or by Factory Mutual for all cases. (e) Recordkeeping (Class A, B) The employer shall maintain a written record of training including safety drills, inspections, tests, and maintenance. The records shall be retained 1 year after the last date of training, inspection, test, or maintenance. In the event of separation of the employee, disposal of equipment or appliance, records may be disposed of after 1 year. Where atmospheric testing indicates the presence of a toxic substance, records shall be maintained in accordance with the existing Federal regulation(s). These records shall include the dates and times of measurements, duties and location of the employees within the confined space, sampling and analytical methods used, number, duration, and results of the samples taken, PEL concentrations estimated from these samples, type of personal protective equipment used, if any, and employees' names. These records shall be made available to the designated representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, of the employer, and of the employee or former employee. # I I . INTRODUCTION This document presents the criteria and the recommended standard based thereon that were prepared to meet the need for preventing occupational injuries and deaths associated with persons entering, working in, and exiting confined spaces. This document does not address the specialized areas of radiation, inert atmospheres or hyperbaric atmospheres; except to recognize they do exist and represent a potential hazard. The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare, under Section 20(a)(2) of the Occupational Safety and Health Act of 1970 to "...develop and establish recommended occupational safety and health standards." After reviewing data and consulting with others, NIOSH developed criteria upon which standards can be established to protect the health and to provide for the safety of workers exposed to occupational hazards. It should be noted that criteria for a recommended standard should enable management and labor to develop better work practices and more appropriate training programs that will result in safer work environments. Simply complying with the recommended standard should not be the final goal. The worker who enters a confined space may be, or often is exposed to multiple hazards due primarily either to ignorance of the potential hazards or negligence in the enforcement of safety regulations. Ignorance and negligence have led to deaths by asphyxiation, by fire and explosion, and by fatal exposure to toxic materials. NIOSH is aware that a number of deaths occur each year when workers must enter and work in a confined space, and it recognizes that due to current data collection m e t h o d s , an estimate of the injuries and deaths which do occur will be inaccurate. Also, since there is no specific Standard Industrial Classification where these injuries and deaths are recorded for confined spaces, they are recorded in several different categories, thereby giving the appearance of a limited exposure to the hazard. These criteria for a standard are a part of a continuing series of documents published by NIOSH. The proposed standard applies only to entering into, working in, and exiting from confined spaces as applicable under the Occupational Safety and Health Act of 1970. The method used in this study consisted of developing, evaluating, and recording information from extensive literature searches, site visits to various industries, and consultation with reviewers knowledgeable on the subject of confined spaces. Standards covering issues of occupational safety and health that are of general application without regard to any specific industry are intended to be applicable to this recommended standard even though no specific reference is made to them. Examples of these general areas are: exposure to toxic chemicals, noise, temperature extremes, and general duty requirements. # III. CONFINED SPACE HAZARDS (a) Overview The hazards encountered and associated with entering and working In confined spaces are capable of causing bodily Injury, Illness, and death to the worker. Accidents occur among workers because of failure to recognize that a confined space is a potential hazard. It should therefore be considered that the most unfavorable situation exists in every case and that the danger of explosion, poisoning, and asphyxiation will be present at the onset of entry. Before forced ventilation is initiated, information such as restricted areas within the confined space, voids, the nature of the contaminants present, the size of the space, the type of work to be performed, and the number of people involved should be considered. The ventilation air should not create an additional hazard due to recirculation of contaminants, improper arrangement of the inlet duct, or by the substitution of anything other than fresh (normal) air (approximately 20.9% oxygen, 79.1% nitrogen by volume). The terms air and oxygen are sometimes considered synonymous. However, this is a dangerous assumption, since the use of oxygen in place of fresh (normal) air for ventilation will expand the limits of flammability and increase the hazards of fire and explosion. Hazardous conditions to be discussed in this Chapter include: Hazardous Atmospheres (flammable, toxic, irritant, and asphyxiating), and General Safety Hazards (mechanical, communications, entry and exit, and physical). An estimation of the number of workers potentially exposed to confined spaces would be difficult to produce. A report prepared under contract for NIOSH shows that the rate of confined space related injuries in the shipbuilding and repair industry is 4.8%. Projected on a national level, 2,448 accidents per year may be attributed to the hazards of working in confined spaces in this single Industry. The Bureau of Labor Statistics shows that the Standard Industrial Classification (SIC) 373, Shipbuilding and Repair Industry, has a 23.9% injury rate. Based on this injury rate 5% of all accidents in the Shipbuilding and Repair Industry occur while working in and around confined spaces. Because of the lack of data it is not possible at this time to project this proportion of confined space related injuries to other industries . Based on the total working population of selected specific SIC codes, and a rough estimate of the percentage of each category who may work in confined spaces at some time, NIOSH estimates that millions of workers may be exposed to hazards in confined spaces each year. # (b) Types of Confined Spaces Confined spaces can be categorized generally as those with open tops and with a depth that will restrict the natural movement of air, and enclosed spaces with very limited openings for entry . In either of these cases the space may contain mechanical equipment with moving par t s . Any combination of these parameters will change the nature of the hazards encountered. Degreasers, pits, and certain types of storage tanks may be classified as open Overview and Magni t u d e of the P r o b l e m topped confined spaces that usually contain no moving parts. However, gases that are heavier than air (butane, propane, and other hydrocarbons) remain in depressions and will flow to low points where they are difficult to remove . Open topped water tanks that appear harmless may develop toxic atmospheres such as hydrogen sulfide from the vaporization of contaminated water . Therefore, these gases (heavier than air) are a primary concern when entry into such a confined space is being planned. Other hazards may develop due to the work performed in the confined space or because of corrosive residues that accelerate the decomposition of scaffolding supports and electrical components. Confined spaces such as sewers, casings, tanks, silos, vaults, and compartments of ships usually have limited access. The problems arising in these areas are similar to those that occur in open topped confined spaces. However, the limited access increases the risk of injury. Gases which are heavier than air such as carbon dioxide and propane, may lie in a tank or vault for hours or even days after the containers have been opened . Because some gases are odorless, the hazard may be overlooked with fatal results. Gases that are lighter than air may also be trapped within an enclosed type confined space, especially those with access from the bottom or side. Hazards specific to a confined space are dictated by: (1) the material stored or used in the confined space; as an example, damp activated carbon in a filtration tank will absorb oxygen thus creating an oxygen deficient atmosphere ; (2) the activity carried out, such as the fermentation of molasses that creates ethyl alcohol vapors and decreases the oxygen content of the atmosphere ; or (3) the external environment, as in the case of sewer systems that may be affected by high tides, heavier than air gases, or flash floods . The most hazardous kind of confined space is the type that combines limited access and mechanical devices. All the hazards of open top and limited access confined spaces may be present together with the additional hazard of moving parts. Digesters and boilers usually contain power-driven equipment which, unless properly isolated, may be inadvertently activated after entry. Such equipment may also contain physical hazards that further complicate the work environment and the entry and exit process. # (c) Reasons for Entering Confined Spaces Entering a confined space as part of the industrial activity may be done for various reasons. It is done usually to perform a necessary function, such as inspection, repair, maintenance (cleaning or painting), or similar operations which would be an infrequent or irregular function of the total industrial activity . Entry may also be made during new construction. Potential hazards should be easier to recognize during construction since the confined space has not been used. The types of hazards involved will be limited by the specific work practices. When the area meets the criteria for a confined space, all ventilation and other requirements should be enforced. One of the most difficult entries to control is that of unauthorized entry, especially when there are large numbers of workers and trades involved, such as welders, painters, electricians, and safety monitors. A final and most important reason for entry would be emergency rescue. This, and all other reasons for entry, must be well planned before initial entry is made and the hazards must be thoroughly reviewed. The standby person and all rescue personnel should be aware of the structural design of the space, emergency exit procedures, and life support systems required. # Hazardous Atmospheres Hazardous atmospheres encountered in confined spaces can be divided into four distinct categories: (a) Flammable, (b) Toxic, (c) Irritant and/or Corrosive, and (d) Asphyxiating. (a) Flammable Atmosphere A flammable atmosphere generally arises from enriched oxygen atmospheres, vaporization of flammable liquids, byproducts of work, chemical reactions, concentrations of combustible dusts, and desorption of chemicals from inner surfaces of the confined space. Alther reported on a case involving workers in an enriched oxygen atmosphere. Two men entered a newly constructed tank to repair a bulge which had formed after the flange of the manhole was welded to the tank. The planned repair procedure was to have two men enter the tank with a jack to force the flange of the manhole into place while a third worker heated the bulge from the outside. To accomplish this procedure the men had to close the manhole. To improve the air within the tank, oxygen used for welding was blown in through an opening. A worker on the outside noticed through the opening that the hair of one of the workmen inside was on fire. The cover was immediately removed and one of the workers managed to escape, his clothing was burning rapidly, the second worker had collapsed and remained unconscious inside. It became necessary to invert the tank to remove the unconscious workman. Both workmen who were doing the work inside suffered serious burns. One died a short time later; the second was hospitalized for several months. A rescuer in the operation was burned on the hands. Investigation of the accident revealed the use of oxygen in place of normal air increased the flammability range of combustibles. Enrichment of the atmosphere with only a few percent of oxygen above 21% will cause an increase in the range of flammability, hair as well as clothing will absorb the oxygen and burn violently. Enriched oxygen atmospheres which expand the region of flammability could be the result of improper blanking off of oxygen lines, chemical reactions which liberate oxygen, or inadvertently purging the space with oxygen in place of air . An atmosphere becomes flammable when the ratio of oxygen to combustible material in the air is neither too rich nor too lean for combustion to occur. Combustible gases or vapors will accumulate when there is inadequate ventilation in areas such as a confined space. Flammable gases such as acetylene, butane, propane, hydrogen, methane, natural or manufactured gases or vapors from liquid hydrocarbons can be trapped in confined spaces, and since many gases are heavier than air, they will seek lower levels as in pits, sewers, and various types of storage tanks and vessels . In a closed top tank, it should also be noted that lighter than air gases may rise and develop a flammable concentration if trapped above the opening. The byproducts of work procedures can generate flammable or explosive conditions within a confined space. Specific kinds of work such as spray painting can result in the release of explosive gases or vapors . Table III-3 shows that approximately one-third of the events identified as "atmospheric condition" were the result of the victims performing activities that generated fumes or depleted the oxygen supply. The most common of these activities was welding in a confined space. Welding in a confined space was a major cause for explosions in areas that contained combustible gas , Chemical reactions forming flammable atmospheres occur when surfaces are initially exposed to the atmosphere, or when chemicals combine to form flammable gases. This condition arises when dilute sulfuric acid reacts with iron to form hydrogen or when calcium carbide makes contact with water to form acetylene. Other examples of spontaneous chemical reactions that may produce explosions from small amounts of unstable compounds are acetylene-metal compounds, peroxides, and nitrates. In a dry state these compounds have the potential to explode upon percussion or exposure to increased temperature. Another class of chemical reactions that form flammable atmospheres arise from deposits of pyrophoric substances (carbon, ferrous oxide, ferrous sulfate, iron, etc) that can be found in tanks used by the chemical and petroleum industry. Th^se tanks containing flammable deposits, will spontaneously ignite upon exposure to air . Combustible dust concentrations are usually found during the process of loading, unloading, and conveying grain products, nitrated fertilizers, finely ground chemical products, and any other combustible material. It has been reported that high charges of static electricity, which rapidly accumulate during periods of relatively low humidity (below 50%) , can cause certain substances to accumulate electrostatic charges of sufficient energy to produce sparks and ignite a flammable atmosphere . These sparks may also cause explosions when the right air or oxygen to dust or gas mixture is present. Desorption of chemicals from the inner surfaces of a confined space is another process that may produce a flammable atmosphere. This is often a natural phenomenon in which the partial pressure at the interface between the surfaces and the stored chemical is radically reduced. For example, after liquid propane is removed from a storage tank the walls of the vessel may desorb the remaining gas from the porous surface of the confined space. Dorias reported on an explosive gas-air mixture in a horizontal cylindrical container (1000 m3), which had contained liquid propane. The cylinder was emptied to check for stress cracking. The space was to be filled with water to expell the gas, and drained so it could automatically fill with normal air. The container was presumably filled full of water and drained. The gas analysis of the resulting space showed an explosive gas-air mixture. The procedure of filling with water and draining was repeated and the test results were the same, an explosive gas-air mixture. To speed up the process, a man climbed into the cylinder and sprayed the interior with water for 3 hours, and allowed the interior to air dry. On the 4th day, a mechanic entered the tank and prepared the areas to be inspected for stress. Following this, a m a n entered the tank with a test device and a Katel lamp (220 volts not of an explosion-proof design). There was a sudden explosion and flame streamed out of the entry manhole. The m a n who was testing the atmosphere suffered severe injuries from which he died 6 days later. Investigation of the events revealed that the tanks were filled only 50% full the first time and only 80-90% full the second time. Therefore, it was concluded the space was never thoroughly emptied of all gas. Reconstruction of the operation showed that the spraying operation did not remove all the propane, and left a gas-air mixture of approximately 5% propane by volume, an extremely explosive condition . # (b) Toxic Atmospheres The substances to be regarded as toxic in a confined space can cover the entire spectrum of gases, vapors, and finely-divided airborne dust in industry . The sources of toxic atmospheres encountered may arise from the following: (1) The manufacturing process (for example, in producing polyvinyl chloride, hydrogen chloride is used as well as vinyl chloride monomer which is carcinogenic). (2) The product stored (removing decomposed organic material from a tank can liberate toxic substances such as H^S ) . (3) The operation performed in the confined space (for example, welding or brazing with metals capable of producing toxic fumes). Zavon reported, in 1970, that four employees of a local utility were repairing a water meter in an underground vault 18 feet x 6 feet x 5 feet with an opening 24 inches in diameter. To make the repairs, it was necessary to cut 26 cadmium plated bolts with an oxygen propane torch. Two men worked in the vault with one m a n cutting and the other standing beside him. Neither man wore a respirator and no ventilation was provided. Two other men remained on the surface. During the cutting of the bolts with the oxygen propane torch, a "heavy blue smoke" filled the vault. This smoke was exhausted after the cutting was completed. The 56-year-old m a n who had cut the bolts died 17 days after exposure. He became nauseated shortly after the job and was seen by his family physician the next day for fever (102-103 F ) , chest pain, cough, and sore throat. On the 4th day following the incident he was in greater distress and was hospitalized. Death occurred in 2 weeks and was attributed to massive coronary infarction and corpulmonale. The 29-year-old assistant complained of chills, nausea, cough and difficulty in breathing. He was treated for pneumonia and made a slow recovery. A reenactment of the work demonstrated that the exposure to cadmium was well above the threshold limit value of "0.1 m g/ m 3 " . Symptoms attributed to cadmium poisoning include: severe labored breathing and wheezing, chest pain, persistent cough, weakness and malaise, and loss of appetite. The clinical course is similar in most cases. The injured frequently are well enough to work the day after exposure, but their conditions deteriorate until approximately the 5th day. At this point, the exposed worker will either get much worse or begin to improve . Toxic gases may be evolved when acids are used for cleaning. Hydrochloric acid can react chemically w ith iron sulfide to produce hydrogen sulfide , Iron sulfide is formed on the walls of cooling jackets when only several parts per million sulfide are in the water used in the cooling p r o c e s s . As an example, 5 m e n were overcome while cleaning a heat exchanger using a hydrochloric acid solution . Another area where the hydrogen sulfide hazard exists is in the tanning industry. Lime pits used in the process of removing hair from the hides contain in addition to lime, a 1% solution of sodium sulfate (Na^SOit). Acid dichromate solution is also used in the tanning process. If these two solutions (sodium sulfate and acid dichromate) are combined accidentally, hydrogen sulfide (H2S) will be produced. One such incident occurred when several unused pits at a tannery were being cleaned. Sludge had formed on the bottom of the pit due to drainage from the hides when they had been treated with lime and acid dichromate. When men entered the pit to clear the drain line, they were overcome. Because of the high specific gravity of hydrogen sulfide, the gas formed by the sodium sulfide-dichromate reaction had settled in the pit, and when the sludge was stirred the released gas overcame the workers. In this instance, 5 men became unconscious and two died . The particular hazard associated with hydrogen sulfide at higher concentrations is due to its physiological effect of anesthetizing the olfactory nerves and can also cause a loss of reasoning, paralysis of the respiratory system, unconsciousness, and death . During loading, unloading, formulation, and production, mechanical and/or human error m a y also produce toxic gases which are not part of the planned operation. Toxic solvents, which present problems , such as trichloroethylene, methyl chloroform, and dichloromethane, are used in industry for cleaning and degreasing. Acrylonitrile, infrequently used, has been encountered as an ingredient in a protective coating applied to tank interiors . Trichloroethane and dichloroethane are widely used in industry as cleaning solvents because they are among the least toxic of the chlorinated aliphatic hydrocarbons. These solvents have been used as a replacement for carbon tetrachloride and trichloroethylene . In a case report by Hatfield and Maykoski trichloroethane, also known as methyl chloroform was substituted for trichloroethylene because of the high toxicity of the latter. A radiator and metal tank repairman was involved in an aircraft tip tank cleaning and assembly operation. The technique of cleaning the interior of the tanks varied among workers. Some workmen would moisten a pad with solvent and would hand wipe the metal surfaces by reaching through an opening on the end of the tank; some would use pads on the end of a shaft, while others would climb inside and clean. One particular worker would saturate a pad with solvent and lower himself head first into the down-tilted tip of the tank and clean as fast as possible. This worker was found with his legs protruding from the upper end of the 450 gallon tank and was unresponsive. He was removed immediately and was given artificial respiration until a physician arrived and pronounced him dead. Reconstruction of the fatal accident revealed the concentration of methyl chloroform in the tank had reached 62,000 ppm. The workers assumed that since the new cleaning solvent was less toxic than the one previously used, there was less danger. However, the new cleaning solvent, methyl chloroform, is a potent anesthetic at 30,000 ppm, which was less than half the concentration level in the worker's breathing zone. The compatibility of materials must be considered when structural members and equipment are introduced in confined spaces. The previous history of the confined space must be carefully evaluated to avoid reactions with residual chemicals, wall scale, and sludge which can be highly reactive. One such case was reported in M a y of 1968, when an aluminum ladder was used for entry into a chemical evaporating tank which had contained aqueous sodium arsenite (Na As02 H 20) and sodium hydroxide (NaOH). The aluminum reacted with the NaAs02 dnd the NaOH to liberate hydrogen, which in turn reacted with the arsenic to form arsine , Other cases of incompatability arise from the use of chemical cleaning agents. The initial step in chemical cleaning usually is the conversion of the scale or sludge into a liquid state which may cause poisonous gases to be liberated. In 1974, several employees who were cleaning a boiler tank prior to repairing a leak used a cleaning fluid, Vestan 675. The cleaning action caused the release of ammonia fumes that were not properly exhausted. The m e n were hospitalized with severe chest pains, but recovered . Another hazardous gas that may build up in a confined space is carbon monoxide (CO). This odorless colorless gas that has approximately the same density of air is formed from Incomplete combustion of organic materials such as wood, coal, gas, oil, and gasoline ; it can be formed from microbial decomposition of organic matter In sewers, silos, and fermentation tanks. Carbon monoxide is an insidious toxic gas because of Its poor warning properties. Early stages of carbon monoxide intoxication are nausea and headache. Carbon monoxide m a y be fatal at 1000 ppm in air, and is considered dangerous at 200 ppm, because it forms carboxyhemoglobin in the blood which prevents the distribution of oxygen in the body. Carbon monoxide (CO) is a relatively abundant colorless, odorless gas, therefore, any untested atmosphere must be suspect. It must also be noted that a safe reading on a combustible gas indicator does not ensure that CO is not present . Carbon monoxide must be tested for specifically. The formation of CO m a y result from chemical reactions or work activities, therefore, fatalities due to CO poisoning are not confined to any particular industry. There have been fatal accidents in sewage treatment plants due to decomposition products and lack of ventilation in confined spaces. Another area where CO results as a product of decomposition is in the formation of silo gas in grain storage elevators . In another area, the paint industry, varnish is manufactured by introducing the various Ingredients into a kettle, and heating them in an inert atmosphere, usually town gas, which is a mixture of carbon dioxide and nitrogen. In one accident report, a maintenance engineer entered a kettle that had been vented for 12-24 hours to check a blocked sampling tube. He was found dead some time later. Death was due to carbon monoxide poisoning. Investigation into the inert gas supply system revealed that the CO content of the town gas was over 1% (10,000 ppm), and that there were minor faults in the protective valves into the kettle so that a small leak was occurring. The employee had entered an atmosphere of reduced oxygen partial pressure containing CO and had succumbed before he could save himself . In many cases CO poisoning occurs because of poor work practices. In welding operations, oxides of nitrogen and ozone are gases of major toxicologic importance, and incomplete oxidation may occur and carbon monoxide can form as a byproduct . One such case, documented in the Pennsylvania Occupational Injury Files of 1975, involved an employee who was overcome by carbon monoxide while welding inside a copper heat-treating oven with the door partially closed. Another poor w ork practice, which has led to fatalities, is the recirculation of diesel exhaust emissions . Tests have shown that although the initial hazard due to exhaust toxicants may be from increased CO2 levels (or depleted 0 2) » the most immediate hazard to life processes is CO . Increased CO levels can only be prevented by strict control of the ventilation or the use of catalytic convertors. # (c) Irritant (Corrosive) Atmosphere Irritant or corrosive atmospheres can be divided into primary and secondary groups. The primary irritants exert no systemic toxic effects because the products formed by them on tissues of the respiratory tract are non-irritant, and other Irritant effects are so violent as to obscure any systemic toxic action. Examples of primary irritants are chlorine (CI2 ), ozone ( 0 3), hydrochloric acid (HC1), hydrofluoric acid (HF), sulfuric acid (H2S0^), nitrogen dioxide (NO2) , ammonia (NH3), and sulfur dioxide (S02). A secondary irritant is one that may produce systemic toxic effects in addition to surface irritation. Examples of secondary irritants Include benzene (C6He), carbon tetrachloride (CCl^ ) , ethyl chloride (CH3CH2CI), trichloroethane (CH^CCL3), trichloroethylene (CHC1CC12 ), and chloropropene (allyl chloride-CH2CHCH2C1) . Irritant gases vary widely among all areas of industrial activity. They can be found in plastics plants, chemical plants, the petroleum industry, tanneries, refrigeration industries, paint manufacturing, and mining operations . Prolonged exposure at irritant or corrosive concentrations in a confined space m a y produce little or no evidence of irritation. # This has been interpreted to mean that the worker has become adapted to the harmful agent involved. In reality, it means there has been a general weakening of the defense reflexes from changes in sensitivity, due to damage of the nerve endings in the mucous membranes of the conjunctivae and upper respiratory tract. The danger in this situation is that the worker is usually not aware of any increase in his exposure to toxic substances . # (d) Asphyxiating Atmosphere The normal atmosphere is composed approximately of 20.9% oxygen and 78.1% nitrogen, and 1% argon with small amounts of various other gases. Reduction of oxygen (02 ) in a confined space may be the result of either consumption or displacement . The consumption of oxygen takes place during combustion of flammable substances, as in welding, heating, cutting, and brazing. A more subtle consumption of oxygen occurs during bacterial action, as in the fermentation process. Oxygen m a y also be consumed during chemical reactions as in the formation of rust on the exposed surface of the confined space (iron oxide). The number of people working in a confined space and the amount of their physical activity will also influence the oxygen consumption rate. A second factor in oxygen deficiency is displacement by another gas. Examples of gases that are used to displace air, and therefore reduce the oxygen level are helium, argon, and nitrogen. Carbon dioxide may also be used to displace air and can occur naturally in sewers, storage bins, wells, tunnels, wine vats, and grain elevators. Aside from the natural development of these gases, or their use in the chemical process, certain gases are also used as inerting agents to displace flammable substances and retard pyrophoric reactions. Gases such as nitrogen, argon, helium, and carbon dioxide, are frequently referred to as non-toxic inert gases but have claimed many lives . The use of nitrogen to inert a confined space has claimed more lives than carbon dioxide. The total displacement of oxygen by nitrogen will cause immediate collapse and death. Carbon dioxide and argon, with specific gravities of 1.53 and 1.38, respectively, (air =» 1) may lie in a tank or manhole for hours or days after opening . Since these gases are colorless and odorless, they pose an immediate hazard to health unless appropriate oxygen measurements and ventilation are adequately carried out. In a report by the Ontario (Canada) Health Department, an underground oil storage tank which required cleaning, had been blanketed with nitrogen to prevent oxidation of the oil. The m a n assigned to clean the tank dropped an air hose into the tank before entering. As he reached the bottom of the ladder, he passed out. His helper outside the tank went in to help and feeling faint, left without getting the man out. He went to get assistance from a nearby maintenance shop. Three m e n came to the tank and climbed down and all were overcome. Finally, after about 20 minutes, all four men were recovered with the help of the fire department. The only reason that there were no fatalities was that an airline in the tank was blowing air into the vicinity of the fallen workers . Oxygen deprivation is one form of asphyxiation. While it is desirable to maintain the atmospheric oxygen level at 21% by volume, the body can tolerate deviation from this ideal. When the oxygen level falls to 17%, the first sign of hypoxia is a deterioration to night vision which is not noticeable until a normal oxygen concentration is restored. Physiologic effects are increased breathing volume and accelerated heartbeat. Between 14-16% physiologic effects are increased breathing volume, accelerated heartbeat, very poor muscular coordination, rapid fatigue, and intermittent respiration. Between the effects are nausea, vomiting, inability to perform, and unconsciousness. Less than 6%, spasmatic breathing, convulsive movements, and death in minutes . In discussing oxygen and what constitutes an oxygen deficient atmosphere from a physiologic view, one must address the concept of partial pressures. At sea level the normal atmospheric pressure for air (20.9% 0 2 + 78.1% N 2 + 1% Ar + trace amounts of various inert gases) is 14.7 psi or 760 m m Hg absolute. The partial pressure of 02 (P0¿) at sea level will be approximately 160 m m Hg. The concept of partial pressures is that in any mixture of gases, the total gas pressure is the sum of the partial pressures of all the gases . The P 0 2 in ambient air can be decreased by a reduction in the 0 2 level at constant pressure or by maintaining the percentage of 0 2 constant and decreasing the total atmospheric pressure as in the case at high altitudes. It is important not only to know the O 2 percent by volume, but to understand the relationship of 0 2 to altitude and the concept of partial pressure. For example, 20.9% 0 2 in air at sea level constitutes a greater P 0 2 than 20.9% 0â t 5,000 feet because the total atmospheric pressure at 5,000 feet is less. As the P 0 2 in the atmosphere drops, the volume of air required to maintain a P 0 2 of 60 m m Hg in the alveolar space of the lungs increases. A P 0 2 below 60 m m Hg in the alveolar space is considered oxygen deficient . Absorption of oxygen by the vessel or the product stored therein is another mechanism by which the P 0 2 may be reduced and result in an oxygen deficient atmosphere. For example, activated carbon, usually considered as an innocuous material free of occupational hazard and toxicity, was responsible for two fatalities in a carbon filtration tank. Damp activated carbon absorbs oxygen and has been known to decrease the oxygen level from 21% to 4% in a closed vessel . Montgomery et al reported on two fatalities caused by the use of activated carbon in a water filtration vessel, (12.5 feet in diameter and 17 feet high). The space was newly constructed, filled halfway with granular carbon in a slurry form (water m edium), the water was drained off through a bottom drain, and the tank was closed off to protect it from the weather. The next morning two workers entered the filtration vessel to perform necessary adjustment^ to the carbon bed and the interior sprinkler mechanism. When the workmen failed to appear at lunch time, they were found dead on the carbon bed. However, a rescuer entered the tank without any type of respiratory protection and with no ill affects. Tests of the atmosphere revealed no cause of death, the oxygen level was 21%, hydrocarbon and hydrogen sulfide tests were negative. The investigation of the fatalities revealed the following: the tank was re-closed and re-opened the following day. No toxic gases were found; however, the oxygen level had dropped from 21% to 12% by volume. Other vessels checked at this location which had been closed for several weeks revealed the oxygen level was down to 2%. In summary, it was discovered that dry carbon would not reduce the oxygen level significantly. Damp activated carbon, however, supposedly an innocuous material and free from toxicity, contributed to the death of two workers as a result of selective absorption of oxygen in a confined space with no ventilation. # General Safety Hazards (a) Mechanical If activation of electrical or mechanical equipment would cause injury, each piece of equipment should be manually isolated to prevent inadvertent activation before workers enter or while they work in a confined space. . The interplay of hazards associated with a confined space, such as the potential of flammable vapors or gases being present, and the build-up of static charge due to mechanical cleaning, such as abrasive blasting, all influence the precautions which must be taken. To prevent vapoi^ leaks, flashbacks, and other hazards, workers should completely Isolate the space . To completely Isolate a confined space the closing of valves is not sufficient. All pipes must be physically disconnected or isolation blanks bolted in place . Other special precautions must be taken in cases where flammable liquids or vapors may recontaminate the confirmed space. The pipes blanked or disconnected should be inspected and tested for leakage to check the effectiveness of the procedure. Other areas of concern) are steam valves, pressure lines, and chemical transfer pipes. A less apparent hazard is the,space referred to as a void, such as double walled vessels, which must be given special consideration in blanking off and inerting. # (b) Communication Problems Communication between the worker inside and the standby person outside is of utmost importance. If the worker should suddenly feel distressed and not be able to summon h e l p , an injury could become a fatality. Frequently, the body positions that are assumed in a confined space make it difficult for the standby person to detect an unconscious worker . When visual monitoring of the worker is not possible because of the design of the confined space or location of the entry hatch, a voice or alarm-activated explosion proof type of communication system will be necessary . # Suitable illumination of an approved type is required to provide sufficient visibility for work in accordance with the recommendations made in the Illuminating Engineering Society Lighting Handbook. # (c) Entry and Exit Entry and exit time is of major significance as a physical limitation and is directly related to the potential hazard of the confined space. The extent of precautions taken and the standby equipment needed to maintain a safe work area will be determined by the means of access and rescue. The following should be considered: type of confined space to be entered, access to the entrance, number and size of openings, barriers within the space, the occupancy load, and the time requirement for exiting in event of fire, or vapor incursion, and the time required to rescue injured workers . # (d) Physical The hazards described in this section include non-chemical, physiologic stressors. These include thermal effects (heat and cold), noise, vibration, radiation, and fatigue while working in a confined space. (1) Thermal Effects Four factors influence the interchange of heat between man and his environment. They are: (1) air temperature, (2) air velocity, (3) moisture contained in the air, and (4) radiant heat . Because of the nature and design of most confined spaces, moisture content and radiant heat are difficult to control. As the body temperature rises progressively, workers will continue to function until the body temperature reaches 38.3 -39.4 C. When this body temperature is exceeded, the workers are less efficient, and are prone to heat exhaustion, heat cramps, or heat stroke . In a cold environment certain physiologic mechanisms come into play, which tend to limit heat loss and Increase heat production. The most severe strain In cold conditions Is chilling of the extremities so that activity Is restricted . Special precautions must be taken In cold environments to prevent frostbite, trench foot, and general hypothermia. Protective insulated clothing for both hot and cold environments will add additional bulk to the worker and must be considered in allowing for movement in the confined space and exit time. Therefore, air temperature of the environment becomes an important consideration when evaluating working conditions in confined spaces. (2) Noise Noise problems are usually intensified in confined spaces because the interior tends to cause sound t o reverberate and thus expose the worker to higher sound levels than those found in an open environment. This intensified noise increases the risk of hearing damage to workers which could result in temporary or permanent loss of hearing. Noise in a confined space which may not be intense enough to cause hearing damage may still disrupt verbal communication with the emergency standby person on the exterior of the confined space. If the workers inside are not able to hear commands or danger signals due to excessive noise, the probability of severe accidents can increase . (3) Vibration Wholebody vibration may be regarded as a "generalized stressor" and may affect multiple body parts and organs depending upon the vibration characteristics. Segmental vibration, unlike wholebody vibration, appears to be more localized in creating injury to the fingers and hands of workers using tools, such as pneumatic hammers, rotary grinders or other hand tools which cause vibration . (4) General/Physical Some physical hazards cannot be eliminated because of the nature of the confined space or the work to be performed. These hazards include such items as scaffolding, surface residues, and structural hazards. The use of scaffolding in confined spaces has contributed to many accidents caused by workers or materials falling, improper use of guard rails, and lack of maintenance to insure worker safety. The choice of material used for scaffolding depends upon the type of work to be performed, the calculated weight to be supported, the surface on which the scaffolding is placed, and the substance previously stored in the confined space. Surface residues in confined spaces can Increase the already hazardous conditions of electrical shock, reaction of incompatible materials, liberation of toxic substances, and bodily injury due to slips and falls. Without protective clothing, additional hazards to health may arise due to surface residues. Structural hazards within a confined space such as baffles in horizontal tanks, trays in vertical towers, bends in tunnels, overhead structural members, or scaffolding installed for maintenance constitute physical hazards, which are exacerbated by the physical surroundings. In dealing with structural hazards, workers must review and enforce safety precautions to assure safety. Rescue procedures nay require withdrawal of an injured or unconscious person. Careful planning must be given to the relationship between the internal structure, the exit opening, and the worker. If the worker is above the opening, the system must include a rescue arrangement operated from outside the confined space, if possible, by which the employee can be lowered and removed without injury Statistical Data Accidents in confined spaces, like all others, are required by Federal regulations to be reported only if medical attention or loss of time from work, or death is involved. Some states and workers' compensation carriers have slightly more stringent requirements, but none require the reporting of incidents which can be considered near misses. The report by Safety Sciences prepared under contract for NIOSH tended to show that fatalities occurred more frequently In confined spaces. For example, death by asphyxiation would be reported; however, if an employee experienced shortness of breath or dizziness, but managed to escape the confined space, and was not treated by a physican, this would probably not be a reported case. The criteria used in selecting cases was based on the definition published in the Federal Register 42:213, November 4, 1977 and specific circumstances likely to be found on injury and fatality records. Table III-l shows the number of "events", injuries, and fatalities from each data source. "Events" refers to the number of separate occasions in which one or more confined space-related injuries or illnesses occurred . Table III-2 shows the number of events, injuries and fatalities obtained for each of the 15 basic accident and illness types which are described in Appendix 4 of this document. A total of 276 confined space related events were identified, which resulted In a total of 234 injuries and 193 fatalities. The table shows that the most hazardous conditions in a confined space are a result of atmospheric related events . Table III-3 shows the number of events by SIC code for each of the 15 confined space-related accident and illness types . # Previous Standards The basis for most of the previous standards were safety codes-designed for specific industrial activities, and dealt with areas such as open surface tanks, welding and cutting, and the pulp and paper, and shipping industries. The most recent standard published on confined spaces is the 12-year effort compiled by the American National Standards Institute, Z117. 1-1977. Despite the effort, the ANSI standard does not address the vitally important areas of training of personnel and specific recommendations for the safety equipment required in a confined space. All personal protective equipment is referenced to different ANSI Standards, which are broad based and do not address the specific problems of confined spaces. The ANSI Standard also accepts the use of tagging as a reliable method of locking out a potentially hazardous situation. The tagging system as a substitute for locking out all lines or pipes, or de-energizing systems of a confined space does not provide sufficient protection to the worker against accidental activation. The ANSI Standard does mention the use of life lines; however, the only recommendation is for their use in an oxygen deficient atmosphere. The General Industry Safety and Health Standards of the Occupational Safety and Health Administration (OSHA) address safety in confined spaces in over 50 different sections of 29 CFR 1910. The defining parameters of a confined space as given in the OSHA regulations are: (1) limited means of exit, (2) a space subject to accumulation of toxic or flammable contaminants or, (3) one where an oxygen deficient atmosphere may develop. It includes but is not limited to such spaces as storage tanks, process vessels, bins, boilers and open top spaces more than 4 feet in depth. This is essentially the same definition used to establish the scope of this recommended criteria. However the "Classification of open-surface tank operation" (1910.94(d) (2) (i-ii)) differs from the classification system proposed in this document. This proposed classification system is Intended to apply to all confined spaces and is based upon the evaluation of several additional parameters. Such a classification will allow the application of a wider range of safety measures and ease the enforcement of the OSHA regulation. The confined space classification system was designed to create a focal point by drawing together over 140 references in the OSHA standards. For example, the use of life lines in all confined spaces, has been addressed in this document and a solution to their excessive use has been proposed. The two documents agree on many areas of good work practices, such as the use of standby personnel, blanked-off lines, and main shutoff valves. Another area of agreement is the acceptance of 19.5% as the minimal oxygen level for safe work practice. There are some areas of the OSHA regulations that appear to accept tagging as a sufficient measure to ensure against opening of valves or energizing equipment during entry or while working in confined spaces. The proposed standard is more stringent in that only locking-out, blanking-off or disconnection are acceptable. Canadian and Australian regulations and standards on confined space entry were reviewed. The Canadian Standard uses a hazard evaluation report, which appears to be a condensed form of the recommended permit system. The Canadian Standard also relies on the qualified person to make decisions for entry and necessary precautions for working in and for making emergency escape. A minimum safe level of oxygen for entry is not stated, only what is considered an oxygen deficient atmosphere (less than 17% by volume). The Australian Standard, which comes under the Factories' Regulations, states the confined space shall be emptied and flushed of hazardous substances and be ventilated with fresh air before entry. The Australian Standard is concerned primarily with entry and exit, not with isolation or safe oxygen level. The Australian Standard does; however, refer to a competent person similar to the qualified person for testing the atmosphere for flammable level. Other countries published guidelines or standards for entering and working in confined spaces. Many of those reviewed follow recommendations similar to the Australian and Candadian standards. Therefore, it would be redundant to make a lengthy comparative list of standards. The state standards reviewed and those from industry were also closely evaluated. The number of references involved prohibits the citing of each one, although valuable concepts were obtained. # Basis for the Recommended Standard Workers who enter and work in confined spaces are confronted with many potentially hazardous conditions. The hazards can range from an oxygen deficient atmosphere or liberation of a toxic agent, to mechanical equipment accidentally energized. The hazardous atmospheres that can be encountered in a confined space are; flammable, toxic, Irritant and/or corrosive, and asphyxiation. These atmospheric conditions are discussed in Chapter III, along with cited accident cases to emphasize the hazards involved with confined space entry. The limited statistical data available on accidents and injuries directly related to confined spaces indicate a very high mortality level. This disproportionately high mortality level for the number of reported accidents and injuries could be the result of Inadequate reporting methods, as not reporting a near miss with death, or data collection systems failing to list a confined space as a causative or other factor in traumatic accidents. In the accident and injury cases tabulated for this document, atmospheric conditions in confined spaces were responsible for the most frequent accident type in terms of events and number of persons killed or injured . The work practices section in Chapter I of the recommended standard was developed after extensive review of published literature, 31,33,36, the current Federal, State, and local applicable codes, , international codes or recommendations 102], and site visits to facilities where working in confined spaces is part of the industrial activity. # (a) Testing and Monitoring Prior to entry into a confined space, workers should know the space's potential hazards. Deaths have occurred because a presumably safe space was not tested prior to initial entry . The various tests to be performed prior to entry shall include tests for flammability, toxic agents, oxygen deficiency, and harmful physical agents. Specific instruments are required for testing the atmosphere for flammability, oxygen deficiency, carbon monoxide, and physical agents. For example, combustible gas Indicators are designed for the purpose of measuring the concentration of flammable gases, and will not measure or indicate the presence of carbon monoxide at toxic levels, conversely a carbon monoxide detector Is designed for the measurement of carbon monoxide only. It should be noted that combustible gas indicators respond differently to different flammable hydrocarbons and should be calibrated for the specific contaminant if known. The flammability measurement may be erroneous if the oxygen level is less or greater than normal atmospheric concentrations. Therefore, it is recommended that the oxygen level be determined prior to flammability testing to make any necessary corrections in the flammability measurement. # When the materials may form a combustible dust mixture, special precautions must be taken to prevent an explosive atmosphere from developing. There are numerous instruments available for measuring airborne dust concentrations; however, none appear to have automatic alarm systems and would require constant personal monitoring. The only practical approach to the control of combustible dusts is to eliminate the hazard by preventive measures, such as, (1) engineering controls, (2) good housekeeping, (3) elimination of ignition sources, (4) isolation of dust producing operations and, (5) training and education of the employees. The oxygen deficiency measuring instrument is designed to measure the volume of oxygen present, usually scaled with a range of 0.0-25%. If the percentage of oxygen in a confined space atmosphere is less than 19.5% or greater than 25%, special precautions, as determined by the qualified person, shall be taken. In accordance with OSHA Safety and Health Standard 29 CFR Part 1910 and other references , a minimum oxygen level of 19.5% has been adopted for worker safety. The upper oxygen limit has been set at 25% because an increase above this level will greatly increase the rate of combustion of flammable materials . Continuous and/or frequent monitoring becomes necessary in cases where the work being performed within the confined space has the potential of generating toxic agents . Data collected for NIOSH by Safety Sciences shows that in 28 out of 80 accident events, the toxic gas or oxygen deficiency was not in the confined space at the time of entry, but was either generated by the work occurring in the space, or by gas being unexpectedly admitted into the confined space after the worker had entered. In these cases, only continuous and/or frequent monitoring would be a possible countermeasure. # (b) Medical Medical requirements for workers who might enter a confined space should take into consideration the increased hazard potential of confined spaces. In this setting, the workers must rely more heavily upon their physical, mental, and sensory attributes, especially under emergency conditions. Workers should be evaluated by competent medical personnel to insure that they are physically and mentally able to wear respirators under simulated and actual working conditions. Because of the additional stress placed on the cardiopulmonary system, some pathologic conditions, such as cardiovascular diseases or those associated with hypoxemia, should preclude the use of respiratory protective devices . In areas where the hazard potential is high, a person certified in CPR and first aid should be in attendance. Since irreversible brain damage can occur in approximately 4 minutes in an oxygen deficient atmosphere, it is essential that resuscitation attempts occur within that time . (c) Safety Equipment and Clothing Many cases of accidental dermal exposure, respiratory distress, and traumatic injury due to falling objects have occurred in confined spaces; therefore, a general safety standard should address the problem of whole body protection . Another area of concern is the use of life lines in all confined spaces. Part of the recommended standard should be an evaluation of the confined space to define when life lines shall be used and when a safety belt with D rings for attaching life lines would be sufficient . # (d) Training Training of employees for entering and working in confined spaces is essential because of the potential hazards and the use of life saving equipment. To insure worker safety, the training program should be especially designed for the type of confined space involved and the problems associated with entry and exit. If different types of confined spaces are involved, this will require additional training. Areas that should be covered in an effective training program are: Emergency entry and exit procedures 2. Use of applicable respiratory equipment 3. First Aid and Cardio-Pulmonary Resuscitation (CPR) 4. Lockout procedures 5. Safety equipment use 6. Rescue drills 7. # Fire protection 8. Communications Training of employees should be done by the qualified person or someone knowledgeable in all relevant aspects of confined space entry, hazard recognition, use of safety equipment, and rescue . For training to be effective, classroom sessions, on-the-job training, or simulated conditions, appear to be the most satisfactory methods. Classroom sessions should include all applicable Federal, state, and local regulations that govern the specific industrial activity in which the employee will be working, as well as the hazards of a confined space (physical and chemical). The training guidelines in Chapter V can be used as a format for additional classroom activity. On-the-job training should be closely supervised until the employee has a complete understanding of all potential hazards. Testing of the employee should take place to evaluate the person's competency and determine if retraining is necessary. (1) Purging and ventilation -poor natural ventilation is one of the defining parameters of a confined space, therefore purging and mechanical ventilation must be closely evaluated when safe work practices are developed for entering and working in confined spaces. Purging is the initial step in adjusting the atmosphere in a confined space to acceptable standards (PGL's, LEL's, and LFL's). This is accomplished either by displacing the atmosphere in the confined space with fluid or vapor (inert gas, water, steam and/or cleaning solution), or by forced air ventilation. According to the literature 20 air changes should bring the atmosphere in the confined space into equilibrium with the external environment. After purging, one establishes general and/or local exhaust ventilation to maintain a safe uncontaminated level. Guidelines for establishing ventilation rates are referenced in the ANSI Standard Z9. 2-1972 and NIOSH Recommended Industrial Ventilation Guidelines . In addition, other information applicable to the special problems of confined spaces must be considered such as the Occupational Safety and Health Standard 29 CFR 1915.31(b) . Entering into an inert atmosphere is one of the most hazardous activities associated with working in a confined space. Work in an inert atmosphere is usually performed by employees of companies who specialize in this because of the high degree of training and expertise needed to perform inert entry operations safely. The scope of this document deals with the necessary precautions but does not cover the specialized training for entry into a confined space containing an inert atmosphere . (2) Isolation/Lockout/Tagging -a review of the statistical data provided to NIOSH demonstrated an obvious need for lockout procedures. The use of tags, while valuable for identification and/or information purposes, appears to have been inadequate in preventing accidents. A review of the literature has shown that proper isolation and lockout procedures are more effective than tagging . (3) Cleaning -decontaminating a space by cleaning is necessary to provide for worker safety. However, it must be recognized that the cleaning process itself can generate additional hazards. Continuous and/or frequent monitoring is required during this process to determine that flammable mixtures and hazardous concentrations of contaminants are adequately diluted before safe entry can be made . (4) Equipment and tools -the literature reviewed , has shown the potential for explosion is greatly increased when explosion proof equipped tools and equipment are not used or improperly maintained. Also the potential for electrocution is increased when low voltage or ground fault circuit interrupters are not used. (5) Permit System -the inherent dangers associated with a confined space clearly indicate the need for strict control measures of employees and equipment. The literature has shown that the use of a permit system is a very effective method of attaining control. The permit provides written authorization for entering and working in confined spaces, clearly states all known or potential hazards, and identifies the safety equipment required to insure the safety of the worker. (e ) Work P r a c t i c e s (6) Entry and Rescue -the potential hazards associated with a confined space must be evaluated prior to entry. These hazards would include the following: oxygen level, flammability characteristics, toxic agents, and physical hazards ie, limited openings and communications. To simplify entry and rescue it would appear logical to set up a classification table for easy reference. The literature reviewed has provided necessary information to set up an entry classification table and allow for flexibility in the selection of personal protective equipment. It is essential that well planned rescue procedures and the proper use of personal protective equipment be followed. The literature and data reviewed have shown a very poor record in successful rescue efforts. Spontaneous reaction instead of well planned and executed rescue procedures has led to multiple fatalities in confined spaces. In 19 of the 25 cases in which rescue was attempted, the rescuers were injured or killed. These cases resulted in 13 deaths and 30 injuries to rescuers, even though only 5 victims were successfully saved. One particular case resulted in injury to 15 rescuers; however, they were successful in saving 3 lives . Therefore, the standby and/or rescue team shall be properly equipped and trained in all aspects of rescue. (7) Recordkeeping -from a review of the limited data available (no SIC code for confined spaces) and the information collected from the plant site visits on accidents in confined spaces, it is apparent that recordkeeping systems must be changed to identify areas where accidents occur, so that underlying causes can be determined. The records to be kept by the employer should contain such information as employee name, age, training, job description, number of years on the job, accident location and severity, underlying causes, and action taken to insure future worker safety. # V. TRAINING GUIDELINES The very nature of the hazards encountered in a confined space is of paramount importance in structuring an effective training program which will provide for safe work practices and techniques. The training program should be based on the specific hazards to be encountered, approved by a trained safety person and given to all individuals who will perform the work or may be assigned as standby or rescue persons. Orientation of all new employees. This type of training would consist of classroom sessions along with a walk-through of the physical plant layout to give the trainee a basic understanding of the Industrial activity. (2) On-the-job training. This would be a second phase of training. After classroom sessions and after the trainee has gained a basic understanding of the operation and hazards involved, on-the-job instruction should include observation and closely supervised participation in actual work practices or simulated conditions. (3) Retraining. This should be performed periodically and as frequently as needed. Many industrial activities are quite complex and operations are frequently updated to keep up with modern innovations. It is necessary, therefore, for a formal retraining program to be planned so that all personnel concerned may be kept abreast of changes. Retraining should also be considered necessary if a supervisor notices a weakness in employee performance. # (c) Training Evaluation The effectiveness of the training program can be determined of the employee by the qualified person to see if safe work being followed, testing the employee for knowledge of the haza r d s , and a reduction in the accident rate due to safe work techniques which have been learned and are being practiced. # (d) Training Program The work practices section presented in Chapter I was designed to set a formalized standard that could, when complied with, eliminate or minimize accidents and injuries occurring in confined spaces. The standard would not be sufficient without a formal written training program and job planning to convey safe work practices and their relationship to the entire operation. The employer is responsible for ensuring that each employee is adequately trained and given refresher courses in assigned duties, and that the employee understands and applies safe work practices. The following are recommended areas that should be covered thoroughly in training: (1) The types of confined spaces that are found in the industrial complex. This should cover physical location, size, and any pertinent information that would inform the worker of its function. (2) Physical and chemical hazards involved. The physical hazards would include structural members within a confined space, equipment that will be used, eg, scaffolding or ladders, size of openings, flooring, and other. Chemical hazards discussed will cover the product which has been stored, chemical cleaners used, and air contaminants which can be liberated due to the work practices. (3) Atmospheric testing of the confined space. This phase of the instruction should emphasize the contaminants which should be tested for and the safe levels for entry. (5) Ventilation of the space by mechanical methods to reduce or eliminate toxic airborne contaminants. This category should be covered sufficiently to alert the employee of potential hazards, and the need for warning devices to signal when there is a ventilation failure. (6) Isolation and lockout of the confined space. The worker should be able to recognize a hazard by visual observation of the connecting lines to a confined space. The lockout of electrical circuits and mechanical disconnects to complete confined space isolation should be explained as should the employees' responsibilities in this area. This should include the type of protective shoes, gloves, face protection, protective clothing, head protection, and safety belts and harnesses that are to be worn as well as the rationale for their use. A major area in this section will be the use of respirators: the types required, their use, quantitative fit (test), respirator cleaning procedures, and proper storage. It should be emphasized that different type respirators are required for different atmospheres and the dangers involved when the wrong type is used . The mandatory wearing of safety belts should be stressed. The use of safety belts and harnesses should be demonstrated so that each individual understands the importance of having the rescue system available, and operative, and is constantly aware of the necessity of keeping life lines clear to the point of exit. Satisfactory completion of this safety training, and refresher courses, should be entered into the employee's permanent record. # V I. RESEARCH NEEDS The primary research need in the area of confined spaces is the development of a data system that would have the capability of recording injury and mortality information specific to the causative factor eg, confined space and be readily accessible. It is now impossible to retrieve data directly related to confined space injuries and mortality, since data are currently collected by general classifications, such as SIC codes. Feasibility studies are being done by NIOSH on a system that could correct this weakness in data recording and retrieval and provide a more accurate picture in areas such as confined space hazards. These data are essential to the proper evaluation of the causes of injuries and deaths. Specific data will provide a base for establishing training programs and standards aimed toward the more hazardous areas and permit the evaluation of current standards. These data would also provide a background for analyzing unusual accidents to establish causal factors and prevent recurrence. A final step that would be accomplished by an approved data base on confined spaces would be to standardize the degree of hazards throughout industry and provide justification for a uniform standard. This uniform standard would serve as the basis for a training program, which could be tailored to meet the needs of large as well as small industries. The second area of research needed is development of more adequate methods for preventing and detecting gas leaks into confined spaces. Many accidents have occurred because the atmosphere in a confined space, which was presumed to be safe by the nature of the contents or obvious safe history of the confined space, had suddenly become lethal. Historical cases reported have shown that faulty seals in storage or processing vessels may allow seepage from an external source, which could be naturally lethal or could form a lethal substance when combined with residual material in the tank. A third area for research is the analytical devices used in confined spaces, such as Intrinsically safe continuous monitors for gases as well as explosive dusts, personal dosimeters, and test meters designed to withstand rugged field use and maintain their integrity. It becomes difficult to calibrate a gas detection meter after continued field use and to be sure of its accuracy. The instrument, for field use, should be of the internal calibration type that will allow for more accurate testing. A fourth area of research is the need to define and evaluate the stresses on employees who are required to work in confined spaces. This evaluation should include physical stressors (eg heat stress, cold stress) and sensory deprivation with respect to the work practice and length of work period. self-contained breathing apparatus with full facepiece operated in the pressure demand mode or a combination supplied air respirator with full facepiece operated in any positive pressure mode with an auxiliary self-contained breathing apparatus emergency entry unknown self-contained breathing apparatus with full facepiece operated in the pressure demand mode or a combination supplied-air respirator with full facepiece operated in any positive pressure mode with an auxilary self-contained breathing apparatus If the concentration forms a flammable atmosphere only the self-contained breathing apparatus with full facepiece operated in the pressure-demand mode may be used. Any respirator recommended for a higher concentration may be used at a lower concentration. These respirators may not be used if the toxic material is carcinogenic. If the concentration forms an atmosphere which is immediately dangerous to life then only the self-contained breathing apparatus operated in the pressure mode or the combination supplied-air respirator with full facepiece operated in any positive mode with an auxilary self-contained breathing apparatus may be used. Cases in which an employee was welding, using a power tool, or some other spark generating activity at the entry point to the CS. Driving an automobile near to a CS containing combustible materials. Must appear to be result, at least in part, of the CS. Frequently the result of the conductive walls of the CS. Cases in which a CS exploded for "no apparent reason" or for a reason unconnected with the activity of the employee near the C S , e g , "just walking by and it blew up." Cases in which the employee was welding (or performing some other spark-generating activity) on a CS which is too small for, and would almost certainly never be used to contain an employee, eg, 55 gal oil drums. Welding drums containing flammable liquids or left over vapors is an extremely common cause of fatalities, and has causal factors similar to CSrelated cases were not typical of the problem NIOSH is addressing. Cases in which an electrically "hot" source just happened to be in a CS eg, "I picked up a cable with a frayed wire". Ingress/Egress Strains, bodily reactions, abrasions, or falls as the result of entering or leaving a cramped, sharp-edged, high-level, or otherwise hazardous point-ofentry to a CS. (Must be a bonafide C S , eg, ingress/egress of vehicle cabs, though subject to similar hazards, are not included because they are not a CS.) O'» 1 0 # Insufficient Maneuver Strains, bodily reactions, abrasions, contact with caustic substances, etc. when they are in part the result of attempting to maneuver in a CS. Cases of insufficient space when the employee is working under a machine (even though cramped), because these are not considered a CS. # Contact with Temperature Burns or scalds from hot steam discharged into CS. Safety Sciences, San Diego, California -1977 Cases in which an employee entered a machine and failed to "lock-out". The machine is activated and the employee is crushed inside the machine. The victim must be inside a machine which it was intended that he should enter and he must have entered deliberately. Elevator shafts, or cases in which the employee was on top of an elevator and crushed in the "CS" when it was elevated. Cases in which the machine is too small for the employee to ever place his entire body inside eg, caught in conveyor gear's. Cases in which the employee was under (not in) a machine or machine part. In particular, being trapped under a vehicle eg, when the jack slips or under a falling bed of a dump truck are not included. Cases in which the employee is drawn into the machine. Examples of such machines include rock crushers. Elevator injuries if person is inside the elevator.	# NIOSH recommends the procedures set forth in the following sections as a means of protecting the health, and significantly reducing accidental injury and death associated with entering, working in, and exiting from confined spaces. The standard is designed not only to make the confined space safe for the worker, but also to make the worker cognizant of the hazards associated with this work area and the safe work practices necessary to deal with these hazards. The criteria and standard will be reviewed and revised as necessary. Refers to the gases, vapors, mists, fumes, and dusts within a confined space. The maximum airborne concentration of a toxic agent to which an employee may be exposed for a specified period of time. A dust capable of undergoing combustion or of burning when subjected to a source of ignition. Refers to a space which by design has limited openings for entry and exit; unfavorable natural ventilation which could contain or produce dangerous air contaminants, and which is not intended for continuous employee occupancy. Confined spaces include but are not limited to storage tanks, compartments of ships, process vessels, pits, silos, vats, degreasers, reaction vessels, boilers, ventilation and exhaust ducts, sewers, tunnels, underground utility vaults, and pipelines. A confined space that presents a situation that is immediately dangerous to life or health (IDLH). These include but are not limited to oxygen deficiency, explosive or flammable atmospheres, and/or concentrations of toxic substances. A confined space that has the potential for causing injury and illness, if preventive measures are not u s e d , but not immediately dangerous to life and health. A confined space in which the potential hazard would not require any special modification of the work procedure. Any work involving burning, welding, riveting, or similar fire producing operations, as well as work which produces a source of ignition, such as drilling, abrasive blasting, and space heating. Displacement of the atmosphere by a non reactive gas (such as nitrogen) to such an extent that the resulting atmosphere is noncombustible. A process whereby the confined space is removed from service and completely protected against the inadvertent release of material by the following: blanking off (skillet type metal blank between flanges), misaligning sections of all lines and pipes, a double block and bleed system, electrical lockout of all sources of power, and blocking or disconnecting all mechanical linkages. # Lower Flammable Limit (LFL) The minimum concentration of a combustible gas or vapor in air (usually expressed in percent by volume at sea l e v e l ) , which will ignite if an ignition source (sufficient ignition energy) is present. # Oxygen Deficiency Refers to an atmosphere wit h a partial pressure of oxygen (P02) less than 132 mm Hg. Normal air at sea level contains approximately 21% oxygen at a P 0 2 of 160 mm Hg. At # Purging The method by which gases, vapors, or other airborne impurities are displaced from a confined space. # Inerting Isolation exposure to hazardous substances or other unsafe conditions in a confined space. This person shall be capable of specifying necessary control and/or protective action to insure worker safety. # Respirator (Approved) A device which has met the requirements of 30 CFR Fart 11 and is designed to protect the wearer from inhalation of harmful atmospheres and has been approved by the Bureau of Mines and the National Institute for Occupational Safety and Health, and Mine Safety and Health Administration (formerly, Mining Enforcement and Safety Administration). # Standby Person A person trained in emergency rescue procedures and assigned to remain on the outside of the confined space and to be in communication with those working inside. # Section 2 -Entry and Rescue The Confined Space Classification Table on page 4 is based on existing or potential hazards relative to the confined space. The classification is based upon the characteristics of the confined space, oxygen level, flammability and toxicity. If any of the hazards present a situation which is immediately dangerous to life or health (IDLH) , the confined space shall be designated Class A. The classification shall be determined by the most hazardous condition of entering, working in, and exiting a confined space. Class B confined space has the potential for causing injury and illness but is not immediately dangerous to life and health. A Class C entry would be one in which the hazard potential would not require any special modification of the work procedure. The Check List of Consideration on page 5 delineates the minimum preparation required for each class of confined space entry. In the recommended standard where specific procedures, activities or requirements are correlated with a classification: the procedure, activity or requirement is mandatory. As an example, Section 3 -Permit System (Class A, B and C) means that a permit is mandatory for Class A, B, and C confined space entry. If the work practice involved in the confined space has the potential to increase existing hazards' or generate additional o n e s , it shall be necessary to frequently evaluate the space to determine if a classification change is warranted. # CONFINED SPACE CLASSIFICATION TABLE Parameters Rescue procedures shall be specifically designed for each entry. If a confined space has an A or B Classification, there shall be a trained standby person assigned to that confined space with a fully charged, positive pressure, self-contained breathing apparatus (SCBA) at hand. Additional duties of the standby person are to maintain unobstructed life lines and communications to all workers within the confined space, and to summon rescue personnel if necessary. Under no circumstances will the standby person enter the confined space until he is relieved and is assured that adequate assistance is present. However, while awaiting rescue personnel the standby person will make rescue attempts utilizing the life lines from outside the confined space. Rescue teams entering a Class A or B confined space shall be equipped with all the aforementioned safety equipment of the standby person and required life lines. In the event of a Class C confined space rescue, a supplied-air respirator or a self-contained breathing apparatus shall be used. A person summoned or one who recognizes the need for rescue shall summon assistance and await their arrival outside the confined space. Respirators and life lines shall be donned by rescue personnel with necessary equipment for removal of the victim(s). Section 3 -Permit System (Class A, B, and C) Entry into a confined space shall be by permit only. The permit is an authorization and approval in writing that specifies the location and type of work to be done, and certifies that all existing hazards have been evaluated by the qualified person, and necessary protective measures have been taken to insure the safety of each worker. The supervisor or a qualified person shall be responsible for securing the permit and both shall sign off when the following areas and actions have been reviewed and confirmed: (1) Blanking and/or disconnecting. (2) Electrical lockout. (3) Mechanical lockout. (d) Special clothing and equipment. (Class A and B) (1) Personal protective equipment and clothing (2) Safety harness and/or lines. (3) Tools approved for use in accordance with the Hazardous Location Classification (NEC-1978). (4) Approved electrical equipment. (e) Atmospheric test readings. (Class A, B, and C) (1) Oxygen level. (2) Flammability and/or explosive levels. (3) Toxic substance levels. This permit shall be dated and carry an expiration time that will be valid for one shift only. The permit shall be updated for each shift with the same requirements. The permit for a Class A or B confined space shall be posted in a conspicuous place, close to the entrance, with a copy on file with the employer. The sample permit in Appendix III should serve as a guide and not be limited to the areas mentioned. The training requirements of personnel entering and/or working in confined spaces shall be suitable for the nature of the hazard and the work to be performed and will therefore vary with the confined space classification. The permit will vary among different industrial activities. However, it should serve the same purpose for all industries, to insure the safety of the worker. Section 4 -Medi c a l (Class A, B) (a) Workers who enter a Class A or B confined space shall have a preplacement physical examination made available to them. The employer shall provide to the physician performing or responsible for the medical surveillance program information such as the type of confined space the employee may be required to enter, the type of substances the employee may encounter, and a description of any protective devices or equipment the employee may be required to use. The physical examination shall include: (1) A demonstration of the worker's ability to use negative and positive pressure respirators as cited in 29 CFR 1910.134. (2) A demonstration of the workers ability to see and hear warnings, such as flashing lights, buzzers or sirens. (3) The examination should place emphasis on general evaluations of the employee's ability to carry out his assigned duties and the detection of any diseases or abnormalities which may make it difficult to work within confined spaces. (b) Following completion of the examinations, the physician shall give to the employer a written statement specifying any condition or abnormality found which would increase risk to the employee's health by working in confined spaces. (c) Periodic medical examinations shall be made available to employees required to work in Class A or B confined spaces. # (d) First Aid Provisions (1) For Class A and B entry there shall always be someone readily available in the area of the confined space who is currently trained in cardio-pulmonary resuscitation (CPR) and basic first-aid procedures. (2) Employees shall be aware of the location of the nearest firstaid equipment, and how to obtain emergency assistance and medical attention. A n adequate supply of first-aid equipment shall be within easy access of the confined space. (e) Records of exposure to known health hazards shall be included in that employee's medical record. These records shall be made available to the designated medical representatives of the Secretary of Health, Education and Welfare, of the Secretary of Labor, of the employer and of the employee or former employee. Training shall not be considered as complete until the supervisor or other employer-designated official, safety or training officer, judges that the employee has attained an acceptable degree of proficiency for entering and working in confined spaces. The trainee's judgment of the adequacy of his training should be properly considered. Section 6 -Testing and Monitoring (Class A, B, and C) Entry into a confined space is prohibited until initial testing of the atmosphere has been done from the outside . Appropriate tests shall be made to insure that the atmosphere is safe. The tests performed shall include those for oxygen content, flammability, and toxic materials. Any necessary additional tests will be selected and performed to the satisfaction of the qualified person. Monitoring of a Class A confined space shall be done on a continuous basis. Class B and C shall be monitored as determined by the qualified person. Entry into a confined space for any type of hot work shall be prohibited when tests indicate the concentration of flammable gases in the atmosphere is greater than 10% of the lower flammability limit (LFL). It is necessary to determine the oxygen level (by appropriate testing) prior to measuring the range of flammability to make necessary corrections in the flammability measurement. Monitoring of the atmosphere shall be performed in accordance with the permit. Equipment for continuous monitoring of gases and vapors shall be explosion proof and equipped with an audible alarm or danger signaling device that will alert employees when a hazardous condition develops. Instruments used for testing the atmosphere in a confined space shall be selected for their functional ability to measure hazardous concentrations. Instruments shall be calibrated in accordance with the manufacturer's guidelines or manuals. Each calibration shall be recorded, filed by the employer, and available for inspection for 1 year after the last calibration date. In any confined space classified as a Class II or Class III hazardous location according to the 1978 National Electrical Code, Article 500 Sections 5 and 6 , a fire watch shall be established as part of the entry procedure. In such areas surface dust and fibers shall be removed and no hot work shall be initiated until the airborne particulate level is below 10% of the LFL for the material. When combustible dusts or ignitable fibers/flyings are present, all equipment and ventilation systems used in the confined space shall comply with Articles 502 and 503 of the National Electrical Code. The percentage of oxygen for entry into a confined space shall be no less than 19.5% nor greater than 25% at 760 mm Hg. At sea level the normal atmospheric pressure for air (20.9% 0 2 + 78.1% N 2 + 1% Ar + trace amounts of various inert gases) is 14.7 psi or 760 m m Hg absolute. The partial pressure of oxygen ( P O 2) at sea level will be approximately 160 mm Hg. P O 2 can be reduced by reducing the 0 2 level in air at a given elevation or through increasing altitude. If tests indicate the oxygen level to be greater than 25% hot work is prohibited until ventilating techniques have reduced the oxygen level to approximately 21%. If the percentage of oxygen falls below 19.5% approved respiratory equipment shall be used in accordance with Section 8 and Appendix II. When the contaminants in the atmosphere cannot be kept within permissible exposure levels as set down in 29 CFR Part 1910 Sub Part Z, then the employee shall wear an approved respirator. Section 7 -Labeling and Posting (Class A, B, and C) (a) All warning signs shall be printed both in English and in the predominant language of non-English reading workers. Where established symbols exist, they shall also be used. Workers unable to read labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on the signs. (b) All entrances to any confined space shall be posted. Signs shall include but not necessarily be limited to the following information: DANGER CONFINED SPACE ENTRY BY PERMIT ONLY (c) When a specific work practice is performed or specific safety equipment is necessary, the following statement shall be added, in large letters, to the warning sign: RESPIRATOR REQUIRED FOR ENTRY LIFELINE REQUIRED FOR ENTRY HOT WORK PERMITTED OR NO HOT WORK (d) Emergency procedures, including phone numbers of fire departments and emergency medical services shall be posted conspicuously within the immediate area of the confined space, or at the telephone from which help would be summoned. Section 8 -Safety Equipment and Clothing (Class A, B, and C) The entry permit shall include a list of necessary protective equipment to be used in the confined space as determined by the qualified person. The employer shall be responsible for the proper use of the safety equipment, and the inspection and maintenance procedures performed on the safety equipment. The type of protective equipment required, will be determined by the qualified person. Those items normally used to protect against traumatic injury include: safety glasses, hardhats, footwear and protective clothing. (a) Eye and Face Protection -For persons who wear corrective spectacles, either prescription ground safety glasses or plano-goggles shall be provided. Additionally if eye-irritating chemicals, vapors, or dusts are present, safety goggles shall be required, and if both the face and eyes are exposed to a hazard, as during scrapping scale or cutting rivets, a full coverage face shield with goggles shall be used. During welding operations the special goggles or shields required shall be in accordance with 29 CFR 1910. (d) Body Protection -All personnel entering a confined space shall wear full coverage work clothing as specified by the qualified person. Gloves and clothing made of impervious rubber or similar material are to be worn to protect against toxic or irritating materials. If the hazards of heat or cold stress exist in the confined space, clothing which has been tested to provide protection from over-exposure to these hazards shall be worn. Other body protection required In specific operations such as welding (flame proofed) , riveting (heat resistant) and abrasive blasting (abrasion resistant) shall be provided to insure worker safety. (e) Hearing Protection -Shall be required when engineering technology is insufficient to control the noise level, and the ambient exposure limit exceeds those allowed in Table G-16 of 29 CFR 1910.95. Emergency alarms shall be distinguishable when hearing protection is worn. The sound level meters used to measure noise levels shall be certified by NIOSH in accordance with 24 CFR 82. Where the potential for explosion exists, the sound level meters shall be of an explosion proof design. (f) Respiratory Protection -Shall be determined by the qualified person based upon conditions and test results of the confined space, and the work activity to be performed. Halfmask respirators are not recommended for use in any atmosphere greater than 10 x PEL because of the probability of accidently breaking the facepiece to face seal due to the work condition in a confined space. Also, gas masks designed for the same respiratory protection may be substituted for chemical cartridge respirators in the table (see Appendix I I ) , but they are more cumbersome and restrictive to movement. The minimum service time of self-contained breathing apparatus shall be calculated on the entry time, plus the maximum work period, plus twice the estimated escape time for safety margin. The respirators used shall be NIOSH and MSHA approved devices and shall be fitted and maintained in accordance with 29 CFR 1910.134. However, suppliedair respirators purchased before 1975 and bearing Bureau of Mines approval may be used until March 31, 1980. Self-contained breathing apparatus, with audible alarms and all gas masks, approved by the Bureau of Mines may be used until further notice. (g) Hand Protection -If hands are exposed to rough surfaces or sharp edges, the degree of protection can range from canvas to metal mesh gloves, depending on the material handled. Gloves made of impervious rubber or similar material are to be worn to protect against toxic or irritating materials. Heat protective gloves are required when employees handle objects with temperatures greater than 60 C (140 F ) . Where a current flow through the body of more than 5 milliamperes may result from contact with energized electrical equipment, employees shall wear insulating gloves that have been visually inspected before each use. Above 5,000 volts, rubber gloves in accordance with 29 CFR 1910.137 shall be worn. Additional safety equipment that is necessary to protect the worker in the environment of a confined space: a safety belt with "D" rings for attaching a life line shall be worn at all times; the combination of a body harness and/or safety belt with life line shall be used when an employee is required to enter to complete the gas analysis; when an employee is working in an area where entry for purposes of rescue would be contraindicated (special limitations or fire hazard); when any failure of ventilation would allow the build-up of toxic or explosive gases within the time necessary to evacuate the area, or when the atmosphere is Immediately dangerous to life and health. Safety belts may be used as the primary means of suspension for the life line only when rescue may be made by keeping the disabled body in a position that will maintain easy passage through exit openings. If the exit opening is less than 18 inches (45 cm) in diameter, then a wrist type harness shall be used. When it is determined by the qualified person that none of the special hazards associated with confined spaces pose an immediate threat to life, as in a Class C entry, then life lines shall be readily available but not used during entry and work procedures. Other protective measures shall include: safety nets used to protect employees working 10 feet (3 m) above ground or grade level when other protective devices are impractical; life jackets worn if the workers are exposed to falls into liquid over 4 feet (1.2 m) in depth; and insulated floor mats when hot work requires use of electrical energy. When employees enter a confined space, a barricade shall be erected if inadvertent entry poses a problem. The barricade shall have a mechanism to prevent closure of the escapeway, signs warning of the danger present, a physical barrier (fence) to keep the area clear, and an adequate platform (3 feet x 3 feet as a minimum) for entry or exit. Such added features as a tripod with block and tackle for safety lines and communication equipment should be considered when the entry plan is formulated. The employer shall be responsible for maintenance of the barricade system. Section 9 -Work Practices (Class A, B, and C) Before entering a confined space, employees shall review the specific guidelines appropriate for safe entry and emergency exit. These guidelines or standards shall be compiled by the qualified person and be definitive on all the possible hazards. Areas covered by such guidelines shall follow this recommended standard. (a) Purging and Ventilating (Class A, B) Environmental control within a confined space is accomplished by purging and ventilating. The method used will be determined by the potential hazards that arise due to the product stored or produced, suspected contaminants, the work to be performed, and the design of the confined space. When ventilating and/or purging operations are to be performed, the blower controls shall be at a safe distance from the confined space. In a Class A entry, an audible warning device shall be installed in all equipment to signal when there is a ventilation failure. When a ventilation system is operational, air flow measurements shall be made before each workshift to ensure that a safe environmental level is maintained. Initial testing of the atmosphere shall be performed from outside the confined space before ventilation begins to determine what precautions are necessary in purging and ventilating. Testing of more remote regions within the confined space may be performed once the immediate area within the confined space has been made safe. Exhaust systems shall be designed to protect workers in the surrounding area from contaminated air. If flammable concentrations are present all electrical equipment shall comply with the requirements of NEC (NFPA no. 70) hazardous locations, and the bonding requirements of Article 250 of NEC, 1978. Where continuous ventilation is not a part of the operating procedure, the atmosphere shall be tested until continuous acceptable levels of oxygen and contaminants are maintained for three tests at 5-minute intervals. Care shall be taken to prevent recirculation of contaminated air and interaction of airborne contaminants. Continuous general ventilation shall be maintained where toxic atmospheres are produced as part of a work procedure, such as welding or painting, or where a toxic atmosphere may develop due to the nature of the confined space, as in the case of desorption from walls, or evaporation of residual chemicals. General ventilation is an effective procedure for distributing contaminants from a local generation point throughout the work space to obtain maximum dilution. However, special precautions shall be taken if the ventilating system partially blocks the exit opening. These precautions include a method for providing respirable air to each worker for the time necessary for exit, and a method of maintaining communications. Local exhaust ventilation shall be provided when general ventilation is not effective due to restrictions in the confined space or when high concentrations of contaminants occur in the breathing zone of the worker. Local high concentrations of contaminants may occur during work activities such as welding, painting, and chemical cleaning. The worker shall not be exposed to concentrations of contaminants in excess of those specified in 29 CFR Part 1910 Sub Part Z. Therefore, respiratory protection, as recommended in Section 8 , may be needed in addition to engineering controls. The use of respiratory protection will be determined by the qualified person. However, when fumes may be generated that contain highly toxic or other airborne metal contaminants, the provisions of 29 CFR 1910.252 shall be observed. When freely moving exhaust hoods are used to provide control of fumes generated during welding, such hoods shall maintain a velocity of 100 feet per/minute in the zone of the welding. The effective force of freely moving exhaust hoods is decreased by approximately 90% at a distance of one duct diameter from the plane of the exhaust opening. Therefore, to obtain maximum effectiveness the welder shall re-position the exhaust hood as he changes welding locations to keep the hood in close proximity to the fume source. Special precautions shall be taken when outgassing or vaporization of toxic and/or flammable substances are likely. If the vapor-generating rate can be determined, the exhaust rate required can be calculated to dilute the atmosphere below the PEL and/or 10% of the LFL, whichever is the lower. This shall be the lowest acceptable ventilation rate. If the area of concern is relatively small, diffusion of the contaminants may be controlled by enclosure with a relatively low volume exhaust for control, or by exhaust hoods located as close as possible to the area of vaporization or outgassing. If the area to be ventilated is too extensive to be controlled by local exhaust, then general ventilation procedures shall be used to control the contaminant level. When the problem of outgassing is due to the application of protective coatings or paint, ventilation shall be continued until the build-up of a flammable and/or toxic atmosphere is no longer possible. There are three components necessary for combustionr fuel, oxygen, and a source of ignition. If work with fire becomes necessary in a confined space and the source of fuel cannot be controlled, then the atmosphere shall be inerted. This is a highly hazardous work situation, and continuous monitoring of the inert make-up ventilation is mandatory. Monitoring shall include flow measurement as well as gas analysis. The inerting operation shall be continuously monitored and supervised by the qualified person. Since every confined space will have its own infiltration rate, inerting shall continue for the entire duration of the work at a rate that will prevent air from entering the confined space. The isolation procedures shall be specific for each type of confined space. Safety equipment required during this procedure shall be designated by the qualified person and be dependent upon the potential hazards involved. A Class A or B confined space shall be completely isolated from all other systems by physical disconnection, double block and bleed, or blanking off all lines. In continuous systems, where complete isolation is not possible, such as sewers or utility tunnels, specific written safety procedures that are approved and enforced by the employer shall be used. Blanks used to seal off lines shall be capable of withstanding the maximum working pressure or load of the line (with a minimum safety factor of 4), be provided with a gasket on the pressure side to insure a leakproof seal, and be made of chemically nonreactive material. Shutoff valves serving the confined space, shall be locked in the closed position and tagged for Identification. In addition to blanking, pumps and compressors serving these lines entering the confined space shall be locked out to prevent accidental activation. All blanks for that specific confined space shall be recorded on the entry permit and recorded in the employer' s file, which shall be available for inspection. If a drain line is located within the confined space, provision shall be made when necessary to tag it and leave it open. This shall also be recorded on the entry permit. Additional procedures, which are necessary when the confined space is of a double wall type construction, eg, water jacketed or similar type, shall be determined by the qualified person and noted on the entry permit. # Electrical isolation of the confined space to prevent accidental activation of moving parts that would be hazardous to the worker is achieved by locking circuit breakers and/or disconnects in the open (off) position with a key-type padlock. The only key is to remain with the person working inside the confined space. If more than one person is inside the confined space, each person shall place his own lock on the circuit breaker. In addition to the lockout system, there must be an accompanying tag that identifies the operation and prohibits use. Mechanical isolation of moving parts can be achieved by disconnecting linkages, or removing drive belts or chains. Equipment with moving mechanical parts shall also be blocked in such a manner that there can be no accidental rotation. (c) Cleaning (Class A, B, and C) Procedures and processes used to clean the inside of a confined space shall be reviewed and authorized by the qualified person. The method to be prescribed shall be dependent upon the product in the space. If the confined space contains a flammable atmosphere above the upper flammable limit, it shall be purged with an inert gas to remove the flammable substance before ventilating with air. Initial cleaning shall be done from outside the tank if at all possible. Special procedures should be adopted to handle the hazards created by the cleaning process itself. For example: if the tank is steamed, (1) it shall be allowed to cool prior to entry; (2) ventilation shall be maintained during neutralization procedures to prevent build-up of toxic materials; (3) steaming shall not be used as a cleaning method vrtien the product stored was a liquid with an autoignition temperature 120% or less of the steam temperature, and (4) the pipe or nozzle of the steam hose shall be bonded to the tank to decrease the generation of static electricity that could accumulate in tanks during steaming procedures. These and other hazards and controls shall be evaluated by the qualified person. # (d) Equipment and Tools (Class A, B, and C) Equipment and tools to be used in a confined space shall be carefully inspected and shall meet the following requirements: (1) Hand tools shall be kept clean and in good repair. (2) Portable electric tools, equipment, and lighting shall be approved in accordance with 29 CFR Part 1910 Sub Part S and be equipped with a ground fault circuit interrupter that meets the requirements of 29 CFR 1910.309. All grounds shall be checked before electrical equipment is used in a confined space. (3) All electrical cords, tools, and equipment shall be of heavy duty type with heavy duty insulation and inspected for visually detectable defects before use in a confined space. (4) Air driven power tools shall be used when flammable liquids are present. The use of air driven power tools will reduce the risk of explosion, not eliminate it. Explosions can arise by tools overheating (drilling), sparks produced by striking (percussion), grinding or discharge of accumulated electrostatic charges developed from the flow of compressed air. (5) Lighting used in Class A and B confined spaces shall be of explosion proof design and where necessary, equipped with guards. Only equipment listed by the Underwriters Laboratories for use in Division 1, atmospheres of the appropriate class and group, or approved by U.S. # Bureau of Mines or Mining Enforcement and Safety Administration or Mine Safety and Health Administration, or the US Coast Guard shall be used. Lighting shall not be hung by electric cords, unless specifically designed for that purpose. The illumination of the work area shall be sufficient to provide for safe work conditions as referenced in the ANSI standard All-1-1965, or the revision, 1970. Under no circumstances will matches or open flames be used in a confined space for illumination. (6) Cylinders of compressed gases shall never be taken into a confined space, and shall be turned off at the cylinder valve when not in use. Exempt from this rule are cylinders that are part of self-contained breathing apparatus or resuscitation equipment. (8) Scaffolding and staging shall be properly designed to carry maximum expected load (safety factor of 4), be equipped with traction type planking, and meet the requirements of 29 CFR 1910.28. (9) Electrical lines, junctions and appurtenances will be in accordance with National Electrical Code (NEC) and National Fire code (NFC) as cited in 29 CFR 1910.309. (10) Only hose lines and components designed specially for the compressed gas and working pressure shall be used, and such systems shall have a pressure relief valve outside the confined space. (11) All equipment that may be used in a flammable atmosphere shall be approved as explosion proof or intrinsically safe for the atmosphere involved by a recognized testing laboratory such as the US Bureau of Mines, MESA, or MSHA for methane and by the Underwriters Laboratories or by Factory Mutual for all cases. (e) Recordkeeping (Class A, B) The employer shall maintain a written record of training including safety drills, inspections, tests, and maintenance. The records shall be retained 1 year after the last date of training, inspection, test, or maintenance. In the event of separation of the employee, disposal of equipment or appliance, records may be disposed of after 1 year. Where atmospheric testing indicates the presence of a toxic substance, records shall be maintained in accordance with the existing Federal regulation(s). These records shall include the dates and times of measurements, duties and location of the employees within the confined space, sampling and analytical methods used, number, duration, and results of the samples taken, PEL concentrations estimated from these samples, type of personal protective equipment used, if any, and employees' names. These records shall be made available to the designated representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, of the employer, and of the employee or former employee. # I I . INTRODUCTION This document presents the criteria and the recommended standard based thereon that were prepared to meet the need for preventing occupational injuries and deaths associated with persons entering, working in, and exiting confined spaces. This document does not address the specialized areas of radiation, inert atmospheres or hyperbaric atmospheres; except to recognize they do exist and represent a potential hazard. The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare, under Section 20(a)(2) of the Occupational Safety and Health Act of 1970 to "...develop and establish recommended occupational safety and health standards." After reviewing data and consulting with others, NIOSH developed criteria upon which standards can be established to protect the health and to provide for the safety of workers exposed to occupational hazards. It should be noted that criteria for a recommended standard should enable management and labor to develop better work practices and more appropriate training programs that will result in safer work environments. Simply complying with the recommended standard should not be the final goal. The worker who enters a confined space may be, or often is exposed to multiple hazards due primarily either to ignorance of the potential hazards or negligence in the enforcement of safety regulations. Ignorance and negligence have led to deaths by asphyxiation, by fire and explosion, and by fatal exposure to toxic materials. NIOSH is aware that a number of deaths occur each year when workers must enter and work in a confined space, and it recognizes that due to current data collection m e t h o d s , an estimate of the injuries and deaths which do occur will be inaccurate. Also, since there is no specific Standard Industrial Classification where these injuries and deaths are recorded for confined spaces, they are recorded in several different categories, thereby giving the appearance of a limited exposure to the hazard. These criteria for a standard are a part of a continuing series of documents published by NIOSH. The proposed standard applies only to entering into, working in, and exiting from confined spaces as applicable under the Occupational Safety and Health Act of 1970. The method used in this study consisted of developing, evaluating, and recording information from extensive literature searches, site visits to various industries, and consultation with reviewers knowledgeable on the subject of confined spaces. Standards covering issues of occupational safety and health that are of general application without regard to any specific industry are intended to be applicable to this recommended standard even though no specific reference is made to them. Examples of these general areas are: exposure to toxic chemicals, noise, temperature extremes, and general duty requirements. # III. CONFINED SPACE HAZARDS (a) Overview The hazards encountered and associated with entering and working In confined spaces are capable of causing bodily Injury, Illness, and death to the worker. Accidents occur among workers because of failure to recognize that a confined space is a potential hazard. It should therefore be considered that the most unfavorable situation exists in every case and that the danger of explosion, poisoning, and asphyxiation will be present at the onset of entry. Before forced ventilation is initiated, information such as restricted areas within the confined space, voids, the nature of the contaminants present, the size of the space, the type of work to be performed, and the number of people involved should be considered. The ventilation air should not create an additional hazard due to recirculation of contaminants, improper arrangement of the inlet duct, or by the substitution of anything other than fresh (normal) air (approximately 20.9% oxygen, 79.1% nitrogen by volume). The terms air and oxygen are sometimes considered synonymous. However, this is a dangerous assumption, since the use of oxygen in place of fresh (normal) air for ventilation will expand the limits of flammability and increase the hazards of fire and explosion. Hazardous conditions to be discussed in this Chapter include: Hazardous Atmospheres (flammable, toxic, irritant, and asphyxiating), and General Safety Hazards (mechanical, communications, entry and exit, and physical). An estimation of the number of workers potentially exposed to confined spaces would be difficult to produce. A report prepared under contract for NIOSH [1] shows that the rate of confined space related injuries in the shipbuilding and repair industry is 4.8%. Projected on a national level, 2,448 accidents per year may be attributed to the hazards of working in confined spaces in this single Industry. The Bureau of Labor Statistics shows that the Standard Industrial Classification (SIC) 373, Shipbuilding and Repair Industry, has a 23.9% injury rate. Based on this injury rate 5% of all accidents in the Shipbuilding and Repair Industry occur while working in and around confined spaces. Because of the lack of data it is not possible at this time to project this proportion of confined space related injuries to other industries [2]. Based on the total working population of selected specific SIC codes, and a rough estimate of the percentage of each category who may work in confined spaces at some time, NIOSH estimates that millions of workers may be exposed to hazards in confined spaces each year. # (b) Types of Confined Spaces Confined spaces can be categorized generally as those with open tops and with a depth that will restrict the natural movement of air, and enclosed spaces with very limited openings for entry [3]. In either of these cases the space may contain mechanical equipment with moving par t s . Any combination of these parameters will change the nature of the hazards encountered. Degreasers, pits, and certain types of storage tanks may be classified as open Overview and Magni t u d e of the P r o b l e m topped confined spaces that usually contain no moving parts. However, gases that are heavier than air (butane, propane, and other hydrocarbons) remain in depressions and will flow to low points where they are difficult to remove [4]. Open topped water tanks that appear harmless may develop toxic atmospheres such as hydrogen sulfide from the vaporization of contaminated water [5]. Therefore, these gases (heavier than air) are a primary concern when entry into such a confined space is being planned. Other hazards may develop due to the work performed in the confined space or because of corrosive residues that accelerate the decomposition of scaffolding supports and electrical components. Confined spaces such as sewers, casings, tanks, silos, vaults, and compartments of ships usually have limited access. The problems arising in these areas are similar to those that occur in open topped confined spaces. However, the limited access increases the risk of injury. Gases which are heavier than air such as carbon dioxide and propane, may lie in a tank or vault for hours or even days after the containers have been opened [6]. Because some gases are odorless, the hazard may be overlooked with fatal results. Gases that are lighter than air may also be trapped within an enclosed type confined space, especially those with access from the bottom or side. Hazards specific to a confined space are dictated by: (1) the material stored or used in the confined space; as an example, damp activated carbon in a filtration tank will absorb oxygen thus creating an oxygen deficient atmosphere [7]; (2) the activity carried out, such as the fermentation of molasses that creates ethyl alcohol vapors and decreases the oxygen content of the atmosphere [8]; or (3) the external environment, as in the case of sewer systems that may be affected by high tides, heavier than air gases, or flash floods [9]. The most hazardous kind of confined space is the type that combines limited access and mechanical devices. All the hazards of open top and limited access confined spaces may be present together with the additional hazard of moving parts. Digesters and boilers usually contain power-driven equipment which, unless properly isolated, may be inadvertently activated after entry. Such equipment may also contain physical hazards that further complicate the work environment and the entry and exit process. # (c) Reasons for Entering Confined Spaces Entering a confined space as part of the industrial activity may be done for various reasons. It is done usually to perform a necessary function, such as inspection, repair, maintenance (cleaning or painting), or similar operations which would be an infrequent or irregular function of the total industrial activity [10]. Entry may also be made during new construction. Potential hazards should be easier to recognize during construction since the confined space has not been used. The types of hazards involved will be limited by the specific work practices. When the area meets the criteria for a confined space, all ventilation and other requirements should be enforced. One of the most difficult entries to control is that of unauthorized entry, especially when there are large numbers of workers and trades involved, such as welders, painters, electricians, and safety monitors. A final and most important reason for entry would be emergency rescue. This, and all other reasons for entry, must be well planned before initial entry is made and the hazards must be thoroughly reviewed. The standby person and all rescue personnel should be aware of the structural design of the space, emergency exit procedures, and life support systems required. # Hazardous Atmospheres Hazardous atmospheres encountered in confined spaces can be divided into four distinct categories: (a) Flammable, (b) Toxic, (c) Irritant and/or Corrosive, and (d) Asphyxiating. (a) Flammable Atmosphere A flammable atmosphere generally arises from enriched oxygen atmospheres, vaporization of flammable liquids, byproducts of work, chemical reactions, concentrations of combustible dusts, and desorption of chemicals from inner surfaces of the confined space. Alther [11] reported on a case involving workers in an enriched oxygen atmosphere. Two men entered a newly constructed tank to repair a bulge which had formed after the flange of the manhole was welded to the tank. The planned repair procedure was to have two men enter the tank with a jack to force the flange of the manhole into place while a third worker heated the bulge from the outside. To accomplish this procedure the men had to close the manhole. To improve the air within the tank, oxygen used for welding was blown in through an opening. A worker on the outside noticed through the opening that the hair of one of the workmen inside was on fire. The cover was immediately removed and one of the workers managed to escape, his clothing was burning rapidly, the second worker had collapsed and remained unconscious inside. It became necessary to invert the tank to remove the unconscious workman. Both workmen who were doing the work inside suffered serious burns. One died a short time later; the second was hospitalized for several months. A rescuer in the operation was burned on the hands. Investigation of the accident revealed the use of oxygen in place of normal air increased the flammability range of combustibles. Enrichment of the atmosphere with only a few percent of oxygen above 21% will cause an increase in the range of flammability, hair as well as clothing will absorb the oxygen and burn violently. Enriched oxygen atmospheres which expand the region of flammability could be the result of improper blanking off of oxygen lines, chemical reactions which liberate oxygen, or inadvertently purging the space with oxygen in place of air [11]. An atmosphere becomes flammable when the ratio of oxygen to combustible material in the air is neither too rich nor too lean for combustion to occur. Combustible gases or vapors will accumulate when there is inadequate ventilation in areas such as a confined space. Flammable gases such as acetylene, butane, propane, hydrogen, methane, natural or manufactured gases or vapors from liquid hydrocarbons can be trapped in confined spaces, and since many gases are heavier than air, they will seek lower levels as in pits, sewers, and various types of storage tanks and vessels [12,13]. In a closed top tank, it should also be noted that lighter than air gases may rise and develop a flammable concentration if trapped above the opening. The byproducts of work procedures can generate flammable or explosive conditions within a confined space. Specific kinds of work such as spray painting can result in the release of explosive gases or vapors [14]. Table III-3 shows that approximately one-third of the events identified as "atmospheric condition" were the result of the victims performing activities that generated fumes or depleted the oxygen supply. The most common of these activities was welding in a confined space. Welding in a confined space was a major cause for explosions in areas that contained combustible gas [1], Chemical reactions forming flammable atmospheres occur when surfaces are initially exposed to the atmosphere, or when chemicals combine to form flammable gases. This condition arises when dilute sulfuric acid reacts with iron to form hydrogen or when calcium carbide makes contact with water to form acetylene. Other examples of spontaneous chemical reactions that may produce explosions from small amounts of unstable compounds are acetylene-metal compounds, peroxides, and nitrates. In a dry state these compounds have the potential to explode upon percussion or exposure to increased temperature. Another class of chemical reactions that form flammable atmospheres arise from deposits of pyrophoric substances (carbon, ferrous oxide, ferrous sulfate, iron, etc) that can be found in tanks used by the chemical and petroleum industry. Th^se tanks containing flammable deposits, will spontaneously ignite upon exposure to air [15]. Combustible dust concentrations are usually found during the process of loading, unloading, and conveying grain products, nitrated fertilizers, finely ground chemical products, and any other combustible material. It has been reported that high charges of static electricity, which rapidly accumulate during periods of relatively low humidity (below 50%) , can cause certain substances to accumulate electrostatic charges of sufficient energy to produce sparks and ignite a flammable atmosphere [14]. These sparks may also cause explosions when the right air or oxygen to dust or gas mixture is present. Desorption of chemicals from the inner surfaces of a confined space is another process that may produce a flammable atmosphere. This is often a natural phenomenon in which the partial pressure at the interface between the surfaces and the stored chemical is radically reduced. For example, after liquid propane is removed from a storage tank the walls of the vessel may desorb the remaining gas from the porous surface of the confined space. Dorias [16] reported on an explosive gas-air mixture in a horizontal cylindrical container (1000 m3), which had contained liquid propane. The cylinder was emptied to check for stress cracking. The space was to be filled with water to expell the gas, and drained so it could automatically fill with normal air. The container was presumably filled full of water and drained. The gas analysis of the resulting space showed an explosive gas-air mixture. The procedure of filling with water and draining was repeated and the test results were the same, an explosive gas-air mixture. To speed up the process, a man climbed into the cylinder and sprayed the interior with water for 3 hours, and allowed the interior to air dry. On the 4th day, a mechanic entered the tank and prepared the areas to be inspected for stress. Following this, a m a n entered the tank with a test device and a Katel lamp (220 volts not of an explosion-proof design). There was a sudden explosion and flame streamed out of the entry manhole. The m a n who was testing the atmosphere suffered severe injuries from which he died 6 days later. Investigation of the events revealed that the tanks were filled only 50% full the first time and only 80-90% full the second time. Therefore, it was concluded the space was never thoroughly emptied of all gas. Reconstruction of the operation showed that the spraying operation did not remove all the propane, and left a gas-air mixture of approximately 5% propane by volume, an extremely explosive condition [16]. # (b) Toxic Atmospheres The substances to be regarded as toxic in a confined space can cover the entire spectrum of gases, vapors, and finely-divided airborne dust in industry [17]. The sources of toxic atmospheres encountered may arise from the following: (1) The manufacturing process (for example, in producing polyvinyl chloride, hydrogen chloride is used as well as vinyl chloride monomer which is carcinogenic). (2) The product stored (removing decomposed organic material from a tank can liberate toxic substances such as H^S ) . (3) The operation performed in the confined space (for example, welding or brazing with metals capable of producing toxic fumes). Zavon [18] reported, in 1970, that four employees of a local utility were repairing a water meter in an underground vault 18 feet x 6 feet x 5 feet with an opening 24 inches in diameter. To make the repairs, it was necessary to cut 26 cadmium plated bolts with an oxygen propane torch. Two men worked in the vault with one m a n cutting and the other standing beside him. Neither man wore a respirator and no ventilation was provided. Two other men remained on the surface. During the cutting of the bolts with the oxygen propane torch, a "heavy blue smoke" filled the vault. This smoke was exhausted after the cutting was completed. The 56-year-old m a n who had cut the bolts died 17 days after exposure. He became nauseated shortly after the job and was seen by his family physician the next day for fever (102-103 F ) , chest pain, cough, and sore throat. On the 4th day following the incident he was in greater distress and was hospitalized. Death occurred in 2 weeks and was attributed to massive coronary infarction and corpulmonale. The 29-year-old assistant complained of chills, nausea, cough and difficulty in breathing. He was treated for pneumonia and made a slow recovery. A reenactment of the work demonstrated that the exposure to cadmium was well above the threshold limit value of "0.1 m g/ m 3 " [18]. Symptoms attributed to cadmium poisoning include: severe labored breathing and wheezing, chest pain, persistent cough, weakness and malaise, and loss of appetite. The clinical course is similar in most cases. The injured frequently are well enough to work the day after exposure, but their conditions deteriorate until approximately the 5th day. At this point, the exposed worker will either get much worse or begin to improve [19]. Toxic gases may be evolved when acids are used for cleaning. Hydrochloric acid can react chemically w ith iron sulfide to produce hydrogen sulfide [20], Iron sulfide is formed on the walls of cooling jackets when only several parts per million sulfide are in the water used in the cooling p r o c e s s . As an example, 5 m e n were overcome while cleaning a heat exchanger using a hydrochloric acid solution [20]. Another area where the hydrogen sulfide hazard exists is in the tanning industry. Lime pits used in the process of removing hair from the hides contain in addition to lime, a 1% solution of sodium sulfate (Na^SOit). Acid dichromate solution is also used in the tanning process. If these two solutions (sodium sulfate and acid dichromate) are combined accidentally, hydrogen sulfide (H2S) will be produced. One such incident occurred when several unused pits at a tannery were being cleaned. Sludge had formed on the bottom of the pit due to drainage from the hides when they had been treated with lime and acid dichromate. When men entered the pit to clear the drain line, they were overcome. Because of the high specific gravity of hydrogen sulfide, the gas formed by the sodium sulfide-dichromate reaction had settled in the pit, and when the sludge was stirred the released gas overcame the workers. In this instance, 5 men became unconscious and two died [21]. The particular hazard associated with hydrogen sulfide at higher concentrations is due to its physiological effect of anesthetizing the olfactory nerves and can also cause a loss of reasoning, paralysis of the respiratory system, unconsciousness, and death [22,23]. During loading, unloading, formulation, and production, mechanical and/or human error m a y also produce toxic gases which are not part of the planned operation. Toxic solvents, which present problems [24], such as trichloroethylene, methyl chloroform, and dichloromethane, are used in industry for cleaning and degreasing. Acrylonitrile, infrequently used, has been encountered as an ingredient in a protective coating applied to tank interiors [17]. Trichloroethane and dichloroethane are widely used in industry as cleaning solvents because they are among the least toxic of the chlorinated aliphatic hydrocarbons. These solvents have been used as a replacement for carbon tetrachloride and trichloroethylene [25][26][27]. In a case report by Hatfield and Maykoski [28] trichloroethane, also known as methyl chloroform was substituted for trichloroethylene because of the high toxicity of the latter. A radiator and metal tank repairman was involved in an aircraft tip tank cleaning and assembly operation. The technique of cleaning the interior of the tanks varied among workers. Some workmen would moisten a pad with solvent and would hand wipe the metal surfaces by reaching through an opening on the end of the tank; some would use pads on the end of a shaft, while others would climb inside and clean. One particular worker would saturate a pad with solvent and lower himself head first into the down-tilted tip of the tank and clean as fast as possible. This worker was found with his legs protruding from the upper end of the 450 gallon tank and was unresponsive. He was removed immediately and was given artificial respiration until a physician arrived and pronounced him dead. Reconstruction of the fatal accident revealed the concentration of methyl chloroform in the tank had reached 62,000 ppm. The workers assumed that since the new cleaning solvent was less toxic than the one previously used, there was less danger. However, the new cleaning solvent, methyl chloroform, is a potent anesthetic at 30,000 ppm, which was less than half the concentration level in the worker's breathing zone. The compatibility of materials must be considered when structural members and equipment are introduced in confined spaces. The previous history of the confined space must be carefully evaluated to avoid reactions with residual chemicals, wall scale, and sludge which can be highly reactive. One such case was reported in M a y of 1968, when an aluminum ladder was used for entry into a chemical evaporating tank which had contained aqueous sodium arsenite (Na As02 H 20) and sodium hydroxide (NaOH). The aluminum reacted with the NaAs02 dnd the NaOH to liberate hydrogen, which in turn reacted with the arsenic to form arsine [29], Other cases of incompatability arise from the use of chemical cleaning agents. The initial step in chemical cleaning usually is the conversion of the scale or sludge into a liquid state which may cause poisonous gases to be liberated. In 1974, several employees who were cleaning a boiler tank prior to repairing a leak used a cleaning fluid, Vestan 675. The cleaning action caused the release of ammonia fumes that were not properly exhausted. The m e n were hospitalized with severe chest pains, but recovered [29]. Another hazardous gas that may build up in a confined space is carbon monoxide (CO). This odorless colorless gas that has approximately the same density of air is formed from Incomplete combustion of organic materials such as wood, coal, gas, oil, and gasoline [30]; it can be formed from microbial decomposition of organic matter In sewers, silos, and fermentation tanks. Carbon monoxide is an insidious toxic gas because of Its poor warning properties. Early stages of carbon monoxide intoxication are nausea and headache. Carbon monoxide m a y be fatal at 1000 ppm in air, and is considered dangerous at 200 ppm, because it forms carboxyhemoglobin in the blood which prevents the distribution of oxygen in the body. Carbon monoxide (CO) is a relatively abundant colorless, odorless gas, therefore, any untested atmosphere must be suspect. It must also be noted that a safe reading on a combustible gas indicator does not ensure that CO is not present [14]. Carbon monoxide must be tested for specifically. The formation of CO m a y result from chemical reactions or work activities, therefore, fatalities due to CO poisoning are not confined to any particular industry. There have been fatal accidents in sewage treatment plants [8] due to decomposition products and lack of ventilation in confined spaces. Another area where CO results as a product of decomposition is in the formation of silo gas in grain storage elevators [8 ]. In another area, the paint industry, varnish is manufactured by introducing the various Ingredients into a kettle, and heating them in an inert atmosphere, usually town gas, which is a mixture of carbon dioxide and nitrogen. In one accident report, a maintenance engineer entered a kettle that had been vented for 12-24 hours to check a blocked sampling tube. He was found dead some time later. Death was due to carbon monoxide poisoning. Investigation into the inert gas supply system revealed that the CO content of the town gas was over 1% (10,000 ppm), and that there were minor faults in the protective valves into the kettle so that a small leak was occurring. The employee had entered an atmosphere of reduced oxygen partial pressure containing CO and had succumbed before he could save himself [21]. In many cases CO poisoning occurs because of poor work practices. In welding operations, oxides of nitrogen and ozone are gases of major toxicologic importance, and incomplete oxidation may occur and carbon monoxide can form as a byproduct [31]. One such case, documented in the Pennsylvania Occupational Injury Files of 1975, involved an employee who was overcome by carbon monoxide while welding inside a copper heat-treating oven with the door partially closed. Another poor w ork practice, which has led to fatalities, is the recirculation of diesel exhaust emissions [32]. Tests have shown that although the initial hazard due to exhaust toxicants may be from increased CO2 levels (or depleted 0 2) » the most immediate hazard to life processes is CO [33]. Increased CO levels can only be prevented by strict control of the ventilation or the use of catalytic convertors. # (c) Irritant (Corrosive) Atmosphere Irritant or corrosive atmospheres can be divided into primary and secondary groups. The primary irritants exert no systemic toxic effects because the products formed by them on tissues of the respiratory tract are non-irritant, and other Irritant effects are so violent as to obscure any systemic toxic action. Examples of primary irritants are chlorine (CI2 ), ozone ( 0 3), hydrochloric acid (HC1), hydrofluoric acid (HF), sulfuric acid (H2S0^), nitrogen dioxide (NO2) , ammonia (NH3), and sulfur dioxide (S02). A secondary irritant is one that may produce systemic toxic effects in addition to surface irritation. Examples of secondary irritants Include benzene (C6He), carbon tetrachloride (CCl^ ) , ethyl chloride (CH3CH2CI), trichloroethane (CH^CCL3), trichloroethylene (CHC1CC12 ), and chloropropene (allyl chloride-CH2CHCH2C1) [34]. Irritant gases vary widely among all areas of industrial activity. They can be found in plastics plants, chemical plants, the petroleum industry, tanneries, refrigeration industries, paint manufacturing, and mining operations [17]. Prolonged exposure at irritant or corrosive concentrations in a confined space m a y produce little or no evidence of irritation. # This has been interpreted to mean that the worker has become adapted to the harmful agent involved. In reality, it means there has been a general weakening of the defense reflexes from changes in sensitivity, due to damage of the nerve endings in the mucous membranes of the conjunctivae and upper respiratory tract. The danger in this situation is that the worker is usually not aware of any increase in his exposure to toxic substances [17]. # (d) Asphyxiating Atmosphere The normal atmosphere is composed approximately of 20.9% oxygen and 78.1% nitrogen, and 1% argon with small amounts of various other gases. Reduction of oxygen (02 ) in a confined space may be the result of either consumption or displacement [35]. The consumption of oxygen takes place during combustion of flammable substances, as in welding, heating, cutting, and brazing. A more subtle consumption of oxygen occurs during bacterial action, as in the fermentation process. Oxygen m a y also be consumed during chemical reactions as in the formation of rust on the exposed surface of the confined space (iron oxide). The number of people working in a confined space and the amount of their physical activity will also influence the oxygen consumption rate. A second factor in oxygen deficiency is displacement by another gas. Examples of gases that are used to displace air, and therefore reduce the oxygen level are helium, argon, and nitrogen. Carbon dioxide may also be used to displace air and can occur naturally in sewers, storage bins, wells, tunnels, wine vats, and grain elevators. Aside from the natural development of these gases, or their use in the chemical process, certain gases are also used as inerting agents to displace flammable substances and retard pyrophoric reactions. Gases such as nitrogen, argon, helium, and carbon dioxide, are frequently referred to as non-toxic inert gases but have claimed many lives [36]. The use of nitrogen to inert a confined space has claimed more lives than carbon dioxide. The total displacement of oxygen by nitrogen will cause immediate collapse and death. Carbon dioxide and argon, with specific gravities of 1.53 and 1.38, respectively, (air =» 1) may lie in a tank or manhole for hours or days after opening [36]. Since these gases are colorless and odorless, they pose an immediate hazard to health unless appropriate oxygen measurements and ventilation are adequately carried out. In a report by the Ontario (Canada) Health Department, an underground oil storage tank which required cleaning, had been blanketed with nitrogen to prevent oxidation of the oil. The m a n assigned to clean the tank dropped an air hose into the tank before entering. As he reached the bottom of the ladder, he passed out. His helper outside the tank went in to help and feeling faint, left without getting the man out. He went to get assistance from a nearby maintenance shop. Three m e n came to the tank and climbed down and all were overcome. Finally, after about 20 minutes, all four men were recovered with the help of the fire department. The only reason that there were no fatalities was that an airline in the tank was blowing air into the vicinity of the fallen workers [37]. Oxygen deprivation is one form of asphyxiation. While it is desirable to maintain the atmospheric oxygen level at 21% by volume, the body can tolerate deviation from this ideal. When the oxygen level falls to 17%, the first sign of hypoxia is a deterioration to night vision which is not noticeable until a normal oxygen concentration is restored. Physiologic effects are increased breathing volume and accelerated heartbeat. Between 14-16% physiologic effects are increased breathing volume, accelerated heartbeat, very poor muscular coordination, rapid fatigue, and intermittent respiration. Between # 6-10% the effects are nausea, vomiting, inability to perform, and unconsciousness. Less than 6%, spasmatic breathing, convulsive movements, and death in minutes [12,38]. In discussing oxygen and what constitutes an oxygen deficient atmosphere from a physiologic view, one must address the concept of partial pressures. At sea level the normal atmospheric pressure for air (20.9% 0 2 + 78.1% N 2 + 1% Ar + trace amounts of various inert gases) is 14.7 psi or 760 m m Hg absolute. The partial pressure of 02 (P0¿) at sea level will be approximately 160 m m Hg. The concept of partial pressures is that in any mixture of gases, the total gas pressure is the sum of the partial pressures of all the gases [39]. The P 0 2 in ambient air can be decreased by a reduction in the 0 2 level at constant pressure or by maintaining the percentage of 0 2 constant and decreasing the total atmospheric pressure as in the case at high altitudes. It is important not only to know the O 2 percent by volume, but to understand the relationship of 0 2 to altitude and the concept of partial pressure. For example, 20.9% 0 2 in air at sea level constitutes a greater P 0 2 than 20.9% 0â t 5,000 feet because the total atmospheric pressure at 5,000 feet is less. As the P 0 2 in the atmosphere drops, the volume of air required to maintain a P 0 2 of 60 m m Hg in the alveolar space of the lungs increases. A P 0 2 below 60 m m Hg in the alveolar space is considered oxygen deficient [39]. Absorption of oxygen by the vessel or the product stored therein is another mechanism by which the P 0 2 may be reduced and result in an oxygen deficient atmosphere. For example, activated carbon, usually considered as an innocuous material free of occupational hazard and toxicity, was responsible for two fatalities in a carbon filtration tank. Damp activated carbon absorbs oxygen and has been known to decrease the oxygen level from 21% to 4% in a closed vessel [7]. Montgomery et al [7] reported on two fatalities caused by the use of activated carbon in a water filtration vessel, (12.5 feet in diameter and 17 feet high). The space was newly constructed, filled halfway with granular carbon in a slurry form (water m edium), the water was drained off through a bottom drain, and the tank was closed off to protect it from the weather. The next morning two workers entered the filtration vessel to perform necessary adjustment^ to the carbon bed and the interior sprinkler mechanism. When the workmen failed to appear at lunch time, they were found dead on the carbon bed. However, a rescuer entered the tank without any type of respiratory protection and with no ill affects. Tests of the atmosphere revealed no cause of death, the oxygen level was 21%, hydrocarbon and hydrogen sulfide tests were negative. The investigation of the fatalities revealed the following: the tank was re-closed and re-opened the following day. No toxic gases were found; however, the oxygen level had dropped from 21% to 12% by volume. Other vessels checked at this location which had been closed for several weeks revealed the oxygen level was down to 2%. In summary, it was discovered that dry carbon would not reduce the oxygen level significantly. Damp activated carbon, however, supposedly an innocuous material and free from toxicity, contributed to the death of two workers as a result of selective absorption of oxygen in a confined space with no ventilation. # General Safety Hazards (a) Mechanical If activation of electrical or mechanical equipment would cause injury, each piece of equipment should be manually isolated to prevent inadvertent activation before workers enter or while they work in a confined space. [12,40]. The interplay of hazards associated with a confined space, such as the potential of flammable vapors or gases being present, and the build-up of static charge due to mechanical cleaning, such as abrasive blasting, all influence the precautions which must be taken. To prevent vapoi^ leaks, flashbacks, and other hazards, workers should completely Isolate the space [41]. To completely Isolate a confined space the closing of valves is not sufficient. All pipes must be physically disconnected or isolation blanks bolted in place [5]. Other special precautions must be taken in cases where flammable liquids or vapors may recontaminate the confirmed space. The pipes blanked or disconnected should be inspected and tested for leakage to check the effectiveness of the procedure. Other areas of concern) are steam valves, pressure lines, and chemical transfer pipes. A less apparent hazard is the,space referred to as a void, such as double walled vessels, which must be given special consideration in blanking off and inerting. # (b) Communication Problems Communication between the worker inside and the standby person outside is of utmost importance. If the worker should suddenly feel distressed and not be able to summon h e l p , an injury could become a fatality. Frequently, the body positions that are assumed in a confined space make it difficult for the standby person to detect an unconscious worker [10]. When visual monitoring of the worker is not possible because of the design of the confined space or location of the entry hatch, a voice or alarm-activated explosion proof type of communication system will be necessary [15]. # Suitable illumination of an approved type is required to provide sufficient visibility for work in accordance with the recommendations made in the Illuminating Engineering Society Lighting Handbook. # (c) Entry and Exit Entry and exit time is of major significance as a physical limitation and is directly related to the potential hazard of the confined space. The extent of precautions taken and the standby equipment needed to maintain a safe work area will be determined by the means of access and rescue. The following should be considered: type of confined space to be entered, access to the entrance, number and size of openings, barriers within the space, the occupancy load, and the time requirement for exiting in event of fire, or vapor incursion, and the time required to rescue injured workers [41]. # (d) Physical The hazards described in this section include non-chemical, physiologic stressors. These include thermal effects (heat and cold), noise, vibration, radiation, and fatigue while working in a confined space. (1) Thermal Effects Four factors influence the interchange of heat between man and his environment. They are: (1) air temperature, (2) air velocity, (3) moisture contained in the air, and (4) radiant heat [42,43]. Because of the nature and design of most confined spaces, moisture content and radiant heat are difficult to control. As the body temperature rises progressively, workers will continue to function until the body temperature reaches 38.3 -39.4 C. When this body temperature is exceeded, the workers are less efficient, and are prone to heat exhaustion, heat cramps, or heat stroke [44]. In a cold environment certain physiologic mechanisms come into play, which tend to limit heat loss and Increase heat production. The most severe strain In cold conditions Is chilling of the extremities so that activity Is restricted [42]. Special precautions must be taken In cold environments to prevent frostbite, trench foot, and general hypothermia. Protective insulated clothing for both hot and cold environments will add additional bulk to the worker and must be considered in allowing for movement in the confined space and exit time. Therefore, air temperature of the environment becomes an important consideration when evaluating working conditions in confined spaces. (2) Noise Noise problems are usually intensified in confined spaces because the interior tends to cause sound t o reverberate and thus expose the worker to higher sound levels than those found in an open environment. This intensified noise increases the risk of hearing damage to workers which could result in temporary or permanent loss of hearing. Noise in a confined space which may not be intense enough to cause hearing damage may still disrupt verbal communication with the emergency standby person on the exterior of the confined space. If the workers inside are not able to hear commands or danger signals due to excessive noise, the probability of severe accidents can increase [42]. (3) Vibration Wholebody vibration may be regarded as a "generalized stressor" and may affect multiple body parts and organs depending upon the vibration characteristics. Segmental vibration, unlike wholebody vibration, appears to be more localized in creating injury to the fingers and hands of workers using tools, such as pneumatic hammers, rotary grinders or other hand tools which cause vibration [42]. (4) General/Physical Some physical hazards cannot be eliminated because of the nature of the confined space or the work to be performed. These hazards include such items as scaffolding, surface residues, and structural hazards. The use of scaffolding in confined spaces has contributed to many accidents caused by workers or materials falling, improper use of guard rails, and lack of maintenance to insure worker safety. The choice of material used for scaffolding depends upon the type of work to be performed, the calculated weight to be supported, the surface on which the scaffolding is placed, and the substance previously stored in the confined space. Surface residues in confined spaces can Increase the already hazardous conditions of electrical shock, reaction of incompatible materials, liberation of toxic substances, and bodily injury due to slips and falls. Without protective clothing, additional hazards to health may arise due to surface residues. Structural hazards within a confined space such as baffles in horizontal tanks, trays in vertical towers, bends in tunnels, overhead structural members, or scaffolding installed for maintenance constitute physical hazards, which are exacerbated by the physical surroundings. In dealing with structural hazards, workers must review and enforce safety precautions to assure safety. Rescue procedures nay require withdrawal of an injured or unconscious person. Careful planning must be given to the relationship between the internal structure, the exit opening, and the worker. If the worker is above the opening, the system must include a rescue arrangement operated from outside the confined space, if possible, by which the employee can be lowered and removed without injury Statistical Data Accidents in confined spaces, like all others, are required by Federal regulations to be reported only if medical attention or loss of time from work, or death is involved. Some states and workers' compensation carriers have slightly more stringent requirements, but none require the reporting of incidents which can be considered near misses. The report by Safety Sciences prepared under contract for NIOSH [1] tended to show that fatalities occurred more frequently In confined spaces. For example, death by asphyxiation would be reported; however, if an employee experienced shortness of breath or dizziness, but managed to escape the confined space, and was not treated by a physican, this would probably not be a reported case. The criteria used in selecting cases was based on the definition published in the Federal Register 42:213, November 4, 1977 and specific circumstances likely to be found on injury and fatality records. Table III-l shows the number of "events", injuries, and fatalities from each data source. "Events" refers to the number of separate occasions in which one or more confined space-related injuries or illnesses occurred [1]. Table III-2 shows the number of events, injuries and fatalities obtained for each of the 15 basic accident and illness types which are described in Appendix 4 of this document. A total of 276 confined space related events were identified, which resulted In a total of 234 injuries and 193 fatalities. The table shows that the most hazardous conditions in a confined space are a result of atmospheric related events [1]. Table III-3 shows the number of events by SIC code for each of the 15 confined space-related accident and illness types [1]. # Previous Standards The basis for most of the previous standards were safety codes-designed for specific industrial activities, and dealt with areas such as open surface tanks, welding and cutting, and the pulp and paper, and shipping industries. The most recent standard published on confined spaces is the 12-year effort compiled by the American National Standards Institute, Z117. 1-1977. Despite the effort, the ANSI standard does not address the vitally important areas of training of personnel and specific recommendations for the safety equipment required in a confined space. All personal protective equipment is referenced to different ANSI Standards, which are broad based and do not address the specific problems of confined spaces. The ANSI Standard also accepts the use of tagging as a reliable method of locking out a potentially hazardous situation. The tagging system as a substitute for locking out all lines or pipes, or de-energizing systems of a confined space does not provide sufficient protection to the worker against accidental activation. The ANSI Standard does mention the use of life lines; however, the only recommendation is for their use in an oxygen deficient atmosphere. The General Industry Safety and Health Standards of the Occupational Safety and Health Administration (OSHA) address safety in confined spaces in over 50 different sections of 29 CFR 1910. The defining parameters of a confined space as given in the OSHA regulations are: (1) limited means of exit, (2) a space subject to accumulation of toxic or flammable contaminants or, (3) one where an oxygen deficient atmosphere may develop. It includes but is not limited to such spaces as storage tanks, process vessels, bins, boilers and open top spaces more than 4 feet in depth. This is essentially the same definition used to establish the scope of this recommended criteria. However the "Classification of open-surface tank operation" (1910.94(d) (2) (i-ii)) differs from the classification system proposed in this document. This proposed classification system is Intended to apply to all confined spaces and is based upon the evaluation of several additional parameters. Such a classification will allow the application of a wider range of safety measures and ease the enforcement of the OSHA regulation. The confined space classification system was designed to create a focal point by drawing together over 140 references in the OSHA standards. For example, the use of life lines in all confined spaces, has been addressed in this document and a solution to their excessive use has been proposed. The two documents agree on many areas of good work practices, such as the use of standby personnel, blanked-off lines, and main shutoff valves. Another area of agreement is the acceptance of 19.5% as the minimal oxygen level for safe work practice. There are some areas of the OSHA regulations that appear to accept tagging as a sufficient measure to ensure against opening of valves or energizing equipment during entry or while working in confined spaces. The proposed standard is more stringent in that only locking-out, blanking-off or disconnection are acceptable. Canadian [45] and Australian [46,47] regulations and standards on confined space entry were reviewed. The Canadian Standard uses a hazard evaluation report, which appears to be a condensed form of the recommended permit system. The Canadian Standard also relies on the qualified person to make decisions for entry and necessary precautions for working in and for making emergency escape. A minimum safe level of oxygen for entry is not stated, only what is considered an oxygen deficient atmosphere (less than 17% by volume). The Australian Standard, which comes under the Factories' Regulations, states the confined space shall be emptied and flushed of hazardous substances and be ventilated with fresh air before entry. The Australian Standard is concerned primarily with entry and exit, not with isolation or safe oxygen level. The Australian Standard does; however, refer to a competent person similar to the qualified person for testing the atmosphere for flammable level. Other countries [14,[48][49][50] published guidelines or standards for entering and working in confined spaces. Many of those reviewed follow recommendations similar to the Australian and Candadian standards. Therefore, it would be redundant to make a lengthy comparative list of standards. The state standards reviewed [8,12,[51][52][53][54] and those from industry [40,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] were also closely evaluated. The number of references involved prohibits the citing of each one, although valuable concepts were obtained. # Basis for the Recommended Standard Workers who enter and work in confined spaces are confronted with many potentially hazardous conditions. The hazards can range from an oxygen deficient atmosphere or liberation of a toxic agent, to mechanical equipment accidentally energized. The hazardous atmospheres that can be encountered in a confined space are; flammable, toxic, Irritant and/or corrosive, and asphyxiation. These atmospheric conditions are discussed in Chapter III, along with cited accident cases to emphasize the hazards involved with confined space entry. The limited statistical data available on accidents and injuries directly related to confined spaces indicate a very high mortality level. This disproportionately high mortality level for the number of reported accidents and injuries could be the result of Inadequate reporting methods, as not reporting a near miss with death, or data collection systems failing to list a confined space as a causative or other factor in traumatic accidents. In the accident and injury cases tabulated for this document, atmospheric conditions in confined spaces were responsible for the most frequent accident type in terms of events and number of persons killed or injured [1]. The work practices section in Chapter I of the recommended standard was developed after extensive review of published literature, [2,11,[15][16][17]31,33,36, the current Federal, State, and local applicable codes, [8,12,[51][52][53][54][93][94][95][96][97][98][99][100][101], international codes or recommendations [3,[45][46][47][48][49][50]102], and site visits to facilities where working in confined spaces is part of the industrial activity. # (a) Testing and Monitoring Prior to entry into a confined space, workers should know the space's potential hazards. Deaths have occurred because a presumably safe space was not tested prior to initial entry [7,13]. The various tests to be performed prior to entry shall include tests for flammability, toxic agents, oxygen deficiency, and harmful physical agents. Specific instruments are required for testing the atmosphere for flammability, oxygen deficiency, carbon monoxide, and physical agents. For example, combustible gas Indicators are designed for the purpose of measuring the concentration of flammable gases, and will not measure or indicate the presence of carbon monoxide at toxic levels, conversely a carbon monoxide detector Is designed for the measurement of carbon monoxide only. It should be noted that combustible gas indicators respond differently to different flammable hydrocarbons and should be calibrated for the specific contaminant if known. The flammability measurement may be erroneous if the oxygen level is less or greater than normal atmospheric concentrations. Therefore, it is recommended that the oxygen level be determined prior to flammability testing to make any necessary corrections in the flammability measurement. # When the materials may form a combustible dust mixture, special precautions must be taken to prevent an explosive atmosphere from developing. There are numerous instruments available for measuring airborne dust concentrations; however, none appear to have automatic alarm systems and would require constant personal monitoring. The only practical approach to the control of combustible dusts is to eliminate the hazard by preventive measures, such as, (1) engineering controls, (2) good housekeeping, (3) elimination of ignition sources, (4) isolation of dust producing operations and, (5) training and education of the employees. The oxygen deficiency measuring instrument is designed to measure the volume of oxygen present, usually scaled with a range of 0.0-25%. If the percentage of oxygen in a confined space atmosphere is less than 19.5% or greater than 25%, special precautions, as determined by the qualified person, shall be taken. In accordance with OSHA Safety and Health Standard 29 CFR Part 1910 and other references [12,33,51,76,87], a minimum oxygen level of 19.5% has been adopted for worker safety. The upper oxygen limit has been set at 25% because an increase above this level will greatly increase the rate of combustion of flammable materials [11]. Continuous and/or frequent monitoring becomes necessary in cases where the work being performed within the confined space has the potential of generating toxic agents [4,5,14,54,58,64,74,81,83,84,86,87]. Data collected for NIOSH by Safety Sciences [1] shows that in 28 out of 80 accident events, the toxic gas or oxygen deficiency was not in the confined space at the time of entry, but was either generated by the work occurring in the space, or by gas being unexpectedly admitted into the confined space after the worker had entered. In these cases, only continuous and/or frequent monitoring would be a possible countermeasure. # (b) Medical Medical requirements for workers who might enter a confined space should take into consideration the increased hazard potential of confined spaces. In this setting, the workers must rely more heavily upon their physical, mental, and sensory attributes, especially under emergency conditions. Workers should be evaluated by competent medical personnel to insure that they are physically and mentally able to wear respirators under simulated and actual working conditions. Because of the additional stress placed on the cardiopulmonary system, some pathologic conditions, such as cardiovascular diseases or those associated with hypoxemia, should preclude the use of respiratory protective devices [101]. In areas where the hazard potential is high, a person certified in CPR and first aid should be in attendance. Since irreversible brain damage can occur in approximately 4 minutes in an oxygen deficient atmosphere, it is essential that resuscitation attempts occur within that time [102]. (c) Safety Equipment and Clothing Many cases of accidental dermal exposure, respiratory distress, and traumatic injury due to falling objects have occurred in confined spaces; therefore, a general safety standard should address the problem of whole body protection [3]. Another area of concern is the use of life lines in all confined spaces. Part of the recommended standard should be an evaluation of the confined space to define when life lines shall be used and when a safety belt with D rings for attaching life lines would be sufficient [12,14,17,53,58,61,73,93,97,103,104]. # (d) Training Training of employees for entering and working in confined spaces is essential because of the potential hazards and the use of life saving equipment. To insure worker safety, the training program should be especially designed for the type of confined space involved and the problems associated with entry and exit. If different types of confined spaces are involved, this will require additional training. Areas that should be covered in an effective training program are: 1. Emergency entry and exit procedures 2. Use of applicable respiratory equipment 3. First Aid and Cardio-Pulmonary Resuscitation (CPR) 4. Lockout procedures 5. Safety equipment use 6. Rescue drills 7. # Fire protection 8. Communications Training of employees should be done by the qualified person or someone knowledgeable in all relevant aspects of confined space entry, hazard recognition, use of safety equipment, and rescue [3,33,53,58,63,68,84,90,97]. For training to be effective, classroom sessions, on-the-job training, or simulated conditions, appear to be the most satisfactory methods. Classroom sessions should include all applicable Federal, state, and local regulations that govern the specific industrial activity in which the employee will be working, as well as the hazards of a confined space (physical and chemical). The training guidelines in Chapter V can be used as a format for additional classroom activity. On-the-job training should be closely supervised until the employee has a complete understanding of all potential hazards. Testing of the employee should take place to evaluate the person's competency and determine if retraining is necessary. (1) Purging and ventilation -poor natural ventilation is one of the defining parameters of a confined space, therefore purging and mechanical ventilation must be closely evaluated when safe work practices are developed for entering and working in confined spaces. Purging is the initial step in adjusting the atmosphere in a confined space to acceptable standards (PGL's, LEL's, and LFL's). This is accomplished either by displacing the atmosphere in the confined space with fluid or vapor (inert gas, water, steam and/or cleaning solution), or by forced air ventilation. According to the literature [11] 20 air changes should bring the atmosphere in the confined space into equilibrium with the external environment. After purging, one establishes general and/or local exhaust ventilation to maintain a safe uncontaminated level. Guidelines for establishing ventilation rates are referenced in the ANSI Standard Z9. 2-1972 [105] and NIOSH Recommended Industrial Ventilation Guidelines [106] . In addition, other information applicable to the special problems of confined spaces must be considered such as the Occupational Safety and Health Standard 29 CFR 1915.31(b) [31,45,69,[107][108][109]. Entering into an inert atmosphere is one of the most hazardous activities associated with working in a confined space. Work in an inert atmosphere is usually performed by employees of companies who specialize in this because of the high degree of training and expertise needed to perform inert entry operations safely. The scope of this document deals with the necessary precautions but does not cover the specialized training for entry into a confined space containing an inert atmosphere [11,106]. (2) Isolation/Lockout/Tagging -a review of the statistical data provided to NIOSH [1] demonstrated an obvious need for lockout procedures. The use of tags, while valuable for identification and/or information purposes, appears to have been inadequate in preventing accidents. A review of the literature has shown that proper isolation and lockout procedures are more effective than tagging [5,6,12,45,55,57,61,64,88,103]. (3) Cleaning -decontaminating a space by cleaning is necessary to provide for worker safety. However, it must be recognized that the cleaning process itself can generate additional hazards. Continuous and/or frequent monitoring is required during this process to determine that flammable mixtures and hazardous concentrations of contaminants are adequately diluted before safe entry can be made [3,5,15,20,48,49,59,61,79,80,91]. (4) Equipment and tools -the literature reviewed [15,58,63,64,109], has shown the potential for explosion is greatly increased when explosion proof equipped tools and equipment are not used or improperly maintained. Also the potential for electrocution is increased when low voltage or ground fault circuit interrupters are not used. (5) Permit System -the inherent dangers associated with a confined space clearly indicate the need for strict control measures of employees and equipment. The literature has shown [50,52,55,56,63,69,77,86,88,90] that the use of a permit system is a very effective method of attaining control. The permit provides written authorization for entering and working in confined spaces, clearly states all known or potential hazards, and identifies the safety equipment required to insure the safety of the worker. (e ) Work P r a c t i c e s (6) Entry and Rescue -the potential hazards associated with a confined space must be evaluated prior to entry. These hazards would include the following: oxygen level, flammability characteristics, toxic agents, and physical hazards ie, limited openings and communications. To simplify entry and rescue it would appear logical to set up a classification table for easy reference. The literature reviewed [5,12,51,63,69,76] has provided necessary information to set up an entry classification table and allow for flexibility in the selection of personal protective equipment. It is essential that well planned rescue procedures and the proper use of personal protective equipment be followed. The literature and data reviewed have shown a very poor record in successful rescue efforts. Spontaneous reaction instead of well planned and executed rescue procedures has led to multiple fatalities in confined spaces. In 19 of the 25 cases in which rescue was attempted, the rescuers were injured or killed. These cases resulted in 13 deaths and 30 injuries to rescuers, even though only 5 victims were successfully saved. One particular case resulted in injury to 15 rescuers; however, they were successful in saving 3 lives [1]. Therefore, the standby and/or rescue team shall be properly equipped and trained in all aspects of rescue. (7) Recordkeeping -from a review of the limited data available (no SIC code for confined spaces) and the information collected from the plant site visits on accidents in confined spaces, it is apparent that recordkeeping systems must be changed to identify areas where accidents occur, so that underlying causes can be determined. The records to be kept by the employer should contain such information as employee name, age, training, job description, number of years on the job, accident location and severity, underlying causes, and action taken to insure future worker safety. # V. TRAINING GUIDELINES The very nature of the hazards encountered in a confined space is of paramount importance in structuring an effective training program which will provide for safe work practices and techniques. The training program should be based on the specific hazards to be encountered, approved by a trained safety person and given to all individuals who will perform the work or may be assigned as standby or rescue persons. Orientation of all new employees. This type of training would consist of classroom sessions along with a walk-through of the physical plant layout to give the trainee a basic understanding of the Industrial activity. (2) On-the-job training. This would be a second phase of training. After classroom sessions and after the trainee has gained a basic understanding of the operation and hazards involved, on-the-job instruction should include observation and closely supervised participation in actual work practices or simulated conditions. (3) Retraining. This should be performed periodically and as frequently as needed. Many industrial activities are quite complex and operations are frequently updated to keep up with modern innovations. It is necessary, therefore, for a formal retraining program to be planned so that all personnel concerned may be kept abreast of changes. Retraining should also be considered necessary if a supervisor notices a weakness in employee performance. # (c) Training Evaluation The effectiveness of the training program can be determined of the employee by the qualified person to see if safe work being followed, testing the employee for knowledge of the haza r d s , and a reduction in the accident rate due to safe work techniques which have been learned and are being practiced. # (d) Training Program The work practices section presented in Chapter I was designed to set a formalized standard that could, when complied with, eliminate or minimize accidents and injuries occurring in confined spaces. The standard would not be sufficient without a formal written training program and job planning to convey safe work practices and their relationship to the entire operation. The employer is responsible for ensuring that each employee is adequately trained and given refresher courses in assigned duties, and that the employee understands and applies safe work practices. The following are recommended areas that should be covered thoroughly in training: (1) The types of confined spaces that are found in the industrial complex. This should cover physical location, size, and any pertinent information that would inform the worker of its function. (2) Physical and chemical hazards involved. The physical hazards would include structural members within a confined space, equipment that will be used, eg, scaffolding or ladders, size of openings, flooring, and other. Chemical hazards discussed will cover the product which has been stored, chemical cleaners used, and air contaminants which can be liberated due to the work practices. (3) Atmospheric testing of the confined space. This phase of the instruction should emphasize the contaminants which should be tested for and the safe levels for entry. (5) Ventilation of the space by mechanical methods to reduce or eliminate toxic airborne contaminants. This category should be covered sufficiently to alert the employee of potential hazards, and the need for warning devices to signal when there is a ventilation failure. (6) Isolation and lockout of the confined space. The worker should be able to recognize a hazard by visual observation of the connecting lines to a confined space. The lockout of electrical circuits and mechanical disconnects to complete confined space isolation should be explained as should the employees' responsibilities in this area. This should include the type of protective shoes, gloves, face protection, protective clothing, head protection, and safety belts and harnesses that are to be worn as well as the rationale for their use. A major area in this section will be the use of respirators: the types required, their use, quantitative fit (test), respirator cleaning procedures, and proper storage. It should be emphasized that different type respirators are required for different atmospheres and the dangers involved when the wrong type is used [39]. The mandatory wearing of safety belts should be stressed. The use of safety belts and harnesses should be demonstrated so that each individual understands the importance of having the rescue system available, and operative, and is constantly aware of the necessity of keeping life lines clear to the point of exit. Satisfactory completion of this safety training, and refresher courses, should be entered into the employee's permanent record. # V I. RESEARCH NEEDS The primary research need in the area of confined spaces is the development of a data system that would have the capability of recording injury and mortality information specific to the causative factor eg, confined space and be readily accessible. It is now impossible to retrieve data directly related to confined space injuries and mortality, since data are currently collected by general classifications, such as SIC codes. Feasibility studies are being done by NIOSH on a system that could correct this weakness in data recording and retrieval and provide a more accurate picture in areas such as confined space hazards. These data are essential to the proper evaluation of the causes of injuries and deaths. Specific data will provide a base for establishing training programs and standards aimed toward the more hazardous areas and permit the evaluation of current standards. These data would also provide a background for analyzing unusual accidents to establish causal factors and prevent recurrence. A final step that would be accomplished by an approved data base on confined spaces would be to standardize the degree of hazards throughout industry and provide justification for a uniform standard. This uniform standard would serve as the basis for a training program, which could be tailored to meet the needs of large as well as small industries. The second area of research needed is development of more adequate methods for preventing and detecting gas leaks into confined spaces. Many accidents have occurred because the atmosphere in a confined space, which was presumed to be safe by the nature of the contents or obvious safe history of the confined space, had suddenly become lethal. Historical cases reported have shown that faulty seals in storage or processing vessels may allow seepage from an external source, which could be naturally lethal or could form a lethal substance when combined with residual material in the tank. A third area for research is the analytical devices used in confined spaces, such as Intrinsically safe continuous monitors for gases as well as explosive dusts, personal dosimeters, and test meters designed to withstand rugged field use and maintain their integrity. It becomes difficult to calibrate a gas detection meter after continued field use and to be sure of its accuracy. The instrument, for field use, should be of the internal calibration type that will allow for more accurate testing. A fourth area of research is the need to define and evaluate the stresses on employees who are required to work in confined spaces. This evaluation should include physical stressors (eg heat stress, cold stress) and sensory deprivation with respect to the work practice and length of work period. self-contained breathing apparatus with full facepiece operated in the pressure demand mode or a combination supplied air respirator with full facepiece operated in any positive pressure mode with an auxiliary self-contained breathing apparatus emergency entry unknown self-contained breathing apparatus with full facepiece operated in the pressure demand mode or a combination supplied-air respirator with full facepiece operated in any positive pressure mode with an auxilary self-contained breathing apparatus If the concentration forms a flammable atmosphere only the self-contained breathing apparatus with full facepiece operated in the pressure-demand mode may be used. Any respirator recommended for a higher concentration may be used at a lower concentration. These respirators may not be used if the toxic material is carcinogenic. **If the concentration forms an atmosphere which is immediately dangerous to life then only the self-contained breathing apparatus operated in the pressure mode or the combination supplied-air respirator with full facepiece operated in any positive mode with an auxilary self-contained breathing apparatus may be used. Cases in which an employee was welding, using a power tool, or some other spark generating activity at the entry point to the CS. Driving an automobile near to a CS containing combustible materials. Must appear to be result, at least in part, of the CS. Frequently the result of the conductive walls of the CS. Cases in which a CS exploded for "no apparent reason" or for a reason unconnected with the activity of the employee near the C S , e g , "just walking by and it blew up." Cases in which the employee was welding (or performing some other spark-generating activity) on a CS which is too small for, and would almost certainly never be used to contain an employee, eg, 55 gal oil drums. Welding drums containing flammable liquids or left over vapors is an extremely common cause of fatalities, and has causal factors similar to CSrelated cases were not typical of the problem NIOSH is addressing. Cases in which an electrically "hot" source just happened to be in a CS eg, "I picked up a cable with a frayed wire". Ingress/Egress Strains, bodily reactions, abrasions, or falls as the result of entering or leaving a cramped, sharp-edged, high-level, or otherwise hazardous point-ofentry to a CS. (Must be a bonafide C S , eg, ingress/egress of vehicle cabs, though subject to similar hazards, are not included because they are not a CS.) O'» 1 0 # Insufficient Maneuver Strains, bodily reactions, abrasions, contact with caustic substances, etc. when they are in part the result of attempting to maneuver in a CS. Cases of insufficient space when the employee is working under a machine (even though cramped), because these are not considered a CS. # Contact with Temperature Burns or scalds from hot steam discharged into CS. Safety Sciences, San Diego, California -1977 [1] # Cases in which an employee entered a machine and failed to "lock-out". The machine is activated and the employee is crushed inside the machine. The victim must be inside a machine which it was intended that he should enter and he must have entered deliberately. Elevator shafts, or cases in which the employee was on top of an elevator and crushed in the "CS" when it was elevated. Cases in which the machine is too small for the employee to ever place his entire body inside eg, caught in conveyor gear's. Cases in which the employee was under (not in) a machine or machine part. In particular, being trapped under a vehicle eg, when the jack slips or under a falling bed of a dump truck are not included. Cases in which the employee is drawn into the machine. Examples of such machines include rock crushers. Elevator injuries if person is inside the elevator.	None	None
63729dda5c379a7bb63f750e70f8521dffff75c8	cdc	None	Groups potentially involved in dog bite prevention 2. Model dog and cat control ordinance 3. Recommended data elements for reports of dog bites 4. Model legislation for the identification and regulation of "dangerous" dogs 5. Suggested reading for professionals MEMBERS OF THE TASK FORCE# Introduction and Problem Statement Dog bites are a serious public health problem that inflicts considerable physical and emotional damage on victims and incurs immeasurable hidden costs to communities. Bites have been tolerated as a job-related hazard for utility and postal workers, but for many communities the problem may be more encompassing. Following a severe attack, there is usually an outcry to do something, and the something that is done often reflects a knee-jerk response. Only later do officials realize that the response was not effective and, in fact, may have been divisive for the community. To assist communities in avoiding such ineffective responses, the AVMA convened a Task Force on Canine Aggression and Human-Canine Interactions. Although the number of injuries will never be reduced to zero, Task Force members believe a well-planned proactive community approach can make a substantial impact. The information contained in this report is intended to help leaders find effective ways to address their community' s dog bite concerns. a # Scope of the problem Dogs have shared their lives with humans for more than 12,000 years, 1 and that coexistence has contributed substantially to humans' quality of life. In the United States, there are slightly more than 53 million dogs sharing the human-canine bond, 2,3 more dogs per capita than in any other country in the world. 1 Unfortunately, a few dogs do not live up to their image as mankind' s best friend, and an estimated 4.5 million people are bitten each year, 4,5 although the actual number injured is unknown. 6 Approximately 334,000 people are admitted to US emergency departments annually with dog bite-associated injuries, and another 466,000 are seen in other medical settings. 6 An unknown number of other people who have been bitten do not sustain injuries deemed serious enough to require medical attention. Still another group of individuals is not represented by these data, those that incur injuries secondary to a bite or attempted bite. For example, a jogger may trip and break an arm while fleeing from a threatening dog. Of concern too are the demographics of typical dog bite victims. Almost half are children younger than 12 years old. People more than 70 years old comprise 10% of those bitten and 20% of those killed. 9,10 Direct costs of dog bite injuries are high. The insurance industry estimates it pays more than $1 billion/y in homeowners' liability claims resulting from dog bites. 11 Hospital expenses for dog bite-related emergency visits are estimated at $102.4 million. 6 There are also medical insurance claims, workmen' s compensation claims, lost wages, and sick leave-associated business costs that have not been calculated. # Which dogs bite? An often-asked question is what breed or breeds of dogs are most "dangerous"? This inquiry can be prompted by a serious attack by a specific dog, or it may be the result of media-driven portrayals of a specific breed as "dangerous." 12,13 Although this is a common concern, singling out 1 or 2 breeds for control can result in a false sense of accomplishment. 14 Doing so ignores the true scope of the problem and will not result in a responsible approach to protecting a community' s citizens. Dog bite statistics are not really statistics, and they do not give an accurate picture of dogs that bite. 7 Invariably the numbers will show that dogs from popular large breeds are a problem. This should be expected, because big dogs can physically do more damage if they do bite, and any popular breed has more individuals that could bite. Dogs from small breeds also bite and are capable of causing severe injury. There are several reasons why it is not possible to calculate a bite rate for a breed or to compare rates between breeds. First, the breed of the biting dog may not be accurately recorded, and mixed-breed dogs are commonly described as if they were purebreds. Second, the actual number of bites that occur in a community is not known, especially if they did not result in serious injury. Third, the number of dogs of a particular breed or combination of breeds in a community is not known, because it is rare for all dogs in a community to be licensed, and existing licensing data is then incomplete. 7 Breed data likely vary between communities, states, or regions, and can even vary between neighborhoods within a community. Wolf hybrids are just that: hybrids between wild and domestic canids. Their behavior is unpredictable because of this hybridization, and they are usually treated as wild animals by local or state statutes. Wolf hybrids are not addressed by this program. Sex differences do emerge from data on various types of aggression. Intact (unneutered) male dogs represented 80% of dogs presented to veterinary behaviorists for dominance aggression, the most commonly diagnosed type of aggression. 1 Intact males are also involved in 70 to 76% of reported dog bite incidents. 7,15 The sex distribution of dogs inflicting unreported bites is not known. Unspayed females that are not part of a carefully planned breeding program may attract freeroaming males, which increases bite risk to people through increased exposure to unfamiliar dogs. Dams are protective of their puppies and may bite those who try to handle the young. Unspayed females may also contribute to the population of unwanted dogs that are often acquired by people who do not understand the long-term commitment they have undertaken, that are surrendered to animal shelters where many are destroyed, or that are turned loose under the misconception that they can successfully fend for themselves. 16 # Dog bite costs to a community Costs associated with dog bite injuries cannot be readily measured, because so many intangible quality of life issues are involved. This makes it more difficult for community councils to justify the time, effort, and expense necessary to institute a bite reduction program when compared to a new fire truck, street paving, or city park. Intangible costs include time spent by volunteer and paid community officials on animal-related issues, deterioration of relationships between neighbors, building appropriate medical support, citizens' concerns about neighborhood safety for children, homeowners' insurance costs within the community, and animal shelter support for unwanted pets. These are quality of life issues that ultimately determine the desirability of a community to its citizens and that can motivate proactive community officials to institute a prevention program. # This program Reducing the incidence of dog bites requires active community involvement; passive attention or a token commitment is not sufficient. By actively focusing on dog bite prevention, the State of Nevada was able to reduce the incidence of bites by approximately 15%. b Members of the Task Force represented a broad range of disciplines and designed the program presented here. It was recognized that the community approach must be multidisciplinary and that different communities will have different needs based on their level of commitment, preexisting programs, and available resources. Although the best results will be obtained by adopting the entire prevention program, the program is designed so that it may be adopted as a whole or in part. Either way, the goal remains to reduce the incidence of dog bites within communities and improve quality of life for their citizens. # Multidisciplinary and Multiprofessional Groups It is unlikely that a dog bite prevention program will begin in a complete vacuum. Typically, some formal program is already in place under the auspices of animal control, the health department, or local law enforcement. Efforts may also be under way by other groups such as educators or dog breeders. It makes sense to identify related activities to determine what needs are not being met, find likely sources of support or resistance, and avoid duplication of effort and potential turf battles (Appendix 1). c # Identify dog bite issues in the community Each community has a unique set of dog bite-related problems and its own approaches to confronting them. A central task is to identify these particular issues. The project begins by assessing the political landscape regarding dog bites and dog bite prevention. Before launching a program, it is useful to pinpoint the degree of current and potential support among corporate and community leaders as well as legislators and senior staff in the dog bite prevention program' s sponsoring agency. Recognize hot buttons-Crafting a program is easier if the objectives mesh with a highly visible community issue. For example, there may be public outcry about dog waste or a publicized dog attack. Such a situation may provide impetus for a campaign to support licensing and leash laws or ordinances pertaining to reporting dog bites. When community groups and the media have already invested in finding a solution to the dog bite problem, program organizers can dovetail their efforts and work collaboratively with these groups. Community interest-Knowing the degree of support that exists for a prevention program is important. The prior existence of a program suggests support, but this may not always be the case. The active support of a commissioner or health department head (local or state) is critical, because without his/her backing, a fledgling dog bite prevention program is vulnerable to shifting funding initiatives and political pressure. Public officials are influenced by vocal well-organized constituencies, so it is important to know what dog bite-related agendas are getting politicians' attention. It also helps to know whether any legislators have a strong interest in the dog bite issue. Dogs in the news-News accounts can provide clues as to how dog-related issues have played out over time. Compare these accounts with available statistical data and scientific assessments for reliability. # Identify potential partners, allies, support, and funding sources Determine which organizations in the community are likely to support program efforts or resist them. Some individuals and organizations will emerge as natural allies; some old hands will be glad to work with a new partner in the dog bite prevention field, and some will actively welcome a new focal point for dog bite prevention activity. Learning about various entities and their interest and involvement in dog bite control can help answer questions in the following areas. Community resources-Organizations, agencies, businesses, and individuals offering training, assistance, consulting, library or computer search capabilities, in-kind contributions, volunteer help, or supplemental funding must be identified. Currently available data-Before launching a major effort to collect dog bite data, it is wise to determine whether an assessment has already been done. Ask about reports related to injuries and costs from dog bites, surveys that include dog bite or dog ownership information, opinion surveys or other studies describing community perceptions about the need for dog bite prevention, and similar information. If possible, find out what happened to existing assessments and related recommendations. Knowing the history of previous evaluation and prevention efforts will help in development of a new program. If an assessment has been done, determine whether methods and conclusions are sound. # Legislation-It is important to know what inter- ventions (eg, leash laws, "dangerous" dog ordinances) have been previously introduced and their history of success. Individuals involved in these efforts may be valuable allies in new programs. In addition, current ordinances should be evaluated to determine whether enforcement or revision could increase their effectiveness. Barriers-Ownership of particular dog bite issues and potential turf battles should be confronted realistically. In addition, it must be acknowledged that a dog bite prevention program may attract opposition from groups on philosophical grounds (eg, groups that strongly support personal freedom argue that the gov-ernment should not mandate licensing of dogs). Clubs for specific breeds may not be supportive if they fear their breed will be singled out in a negative way. Barriers can be overcome by a fresh approach to old problems or by agreeing to carve out areas of responsibility among interested groups. Typically, there are many more problems than there are organizations to tackle them, so it makes sense to avoid attacking similar issues. # Develop an advisory council Obtaining community input can be as sophisticated as conducting public opinion surveys or holding focus groups to learn about what the community sees as pressing dog bite issues. More likely, there will be limited funds at the outset of the program, so more informal but also potentially valuable approaches may be required. These include meetings with potential partners and interested groups to learn about their constituencies' concerns. This type of informal interview can be a great help in uncovering key dog-related issues as perceived by the community. Talking with people in neighborhoods most affected by dog bite problems is important. For example, if there is a problem with dog bites in low-income neighborhoods, obtaining the views of people living there can help identify the nature of the problem and potential solutions. An advisory council or task force that represents a wide spectrum of community concerns and perspectives creates a source of support for program initiatives. Advisory groups provide guidance for a dog bite prevention program and may focus on specific high-priority dog bite issues. Although organizing and maintaining an advisory council is labor-intensive, it can substantially benefit the program. Members may be able to provide access to useful information that is not otherwise easy for the coordinator to obtain. Members can also identify ways in which the program can work with appropriate voluntary organizations and associations. People with experience in dog bite control can offer perspective about the program and help identify potential pitfalls as well as successful strategies. Participation by members representing community organizations builds a sense of ownership in the dog bite prevention program. Logistics in starting an advisory council include identifying organizations and individuals that should participate (Appendix 1), determining the size of the council, establishing a structure and operating procedures for the council and its regular meetings, assigning staff support, determining the relationship between the staff and the council, and reaching an agreement about key tasks. When community members and government officials work together to support the creation and development of a local task force, it enhances the group' s visibility and impact. To foster an involved and active advisory council, professionals agree that several criteria must be met. The number of participants should be kept manageable; 10 to 12 is a size that works well. If it is necessary to have more members for political reasons, breaking the group into smaller committees or working groups will improve the dynamics. For example, groups could coalesce around data issues, legislation and policy, and so on. Involving participants from the start in meaningful tasks will underscore that this is a productive group. In addition, people are more likely to support a program they participated in creating, because they have a sense of ownership. Because each community' s needs and priorities differ, the advisory council' s major tasks will vary. The advisory council or one of its working groups may consider the following activities: ? coordinating efforts among participating organizations ? developing an action plan ? establishing dog bite prevention priorities ? generating public and legislative support for dog bite control ? identifying dog bite reporting sources ? interpreting data ? identifying and obtaining resources for program activities (educational, financial, staffing) ? providing technical expertise for the program ? recommending goals and objectives for prevention It is recommended that the program be overseen by a paid coordinator. The program coordinator and other staff involved can contribute to the advisory council' s success by good meeting planning and preparation, regular communication with members, working with the advisory council chairperson to set the agenda, and helping to solve problems that threaten to derail the process. As with any volunteer effort, a dog bite prevention advisory council is likely to thrive if the coordinator nurtures its members with regular expressions of appreciation. # Infrastructure A coordinated effort is essential for success in any venture, and each individual or organization involved must have a clear sense of their/its responsibilities. Reducing the incidence of dog bites requires the cooperation of many groups, including animal control agencies, the human and veterinary medical communities, educators, departments of health, and the local licensing authority. Open and consistent communication is an integral part of an effective program, and one entity should be designated as the coordinating agency. A logical coordinating agency would be the health department or animal control. In addition, it is imperative that an appropriate agency be granted authority to conduct investigations and make recommendations. # Program coordinator As previously mentioned, dog bite prevention efforts should be assisted by a paid staff person. Because the diversity of input is so great, it is recommended that the office of the advisory council' s program coordinator be located within the municipality' s coordinating agency. Individuals, agencies, or organizations that come into contact with or are aware of a "dangerous" dog or risky situation should provide this information to the coordinator. The coordinator should then relay all information to the proper recipients. # Animal control agencies Animal control officers are the frontline in controlling animal bites. A well-resourced animal control agency is vital for public health and safety within any community. In some communities, animal control is a stand-alone agency. In others it is administered through the local city or county health director or is a subsidiary of the local police department or sheriff' s office. Wherever located, the functions of animal control within communities are multiple, including: ? training of animal control officers and ancillary personnel ? licensing of dogs and cats ? enforcement of leash laws, ordinances, regulations, and statutes ? control of unrestrained and free-roaming animal populations ? investigation of animal bite-related incidents ? administration of rabies quarantine programs after an animal bites ? bite data management, analysis, and dissemination regulation of "dangerous" animals ? educational outreach within the community regarding responsible ownership, spay/neuter programs, control of "dangerous" animals, rabies vaccinations ? coordination of efforts Larger communities often possess more resources to properly fund animal control agencies and provide adequate staff 17 and training; however, smaller animal control programs can also be effective, even when they operate on a limited budget. Dedicated personnel can accomplish much if they have community support, including support from law enforcement and the judiciary. # Preventive measures Preventive measures are designed to minimize risk and should be addressed by all communities. Control of unrestrained and free-roaming animals-Reasonable and enforceable laws or ordinances are required for good control of unrestrained or freeroaming animals ( Appendix 2 ). 18 Laws written to ensure that owned animals are confined to their property or kept on a leash make freeing a community of unrestrained and free-roaming animals easier. Although most dog bites occur on the property where the dog lives, unrestrained or free-roaming dogs do pose a substantial threat to the public. Enforcement of restraint laws is, therefore, essential if the incidence of dog bites is to be reduced. It is important to protect animal owners by providing an adequate amount of time for them to claim animals that have been impounded. Because of economic constraints, the current standard in the industry is 3 working days; however, 5 days may be more reasonable to ensure successful owner-animal reunions. Control of unrestrained and free-roaming animal populations requires an adequately staffed, trained, and funded animal control agency. # Licensing of dogs-The primary benefit of licens- ing animals is identification, should that animal become lost. Licensing also ensures rabies vaccinations are current, allows quick identification in case of a bite incident, and provides revenue to help offset the costs of administering the animal control program. An effective program can be a source of reliable demographic data as well. Vaccinations-Rabies vaccinations are normally a prerequisite for licensing dogs and cats, because they are an important control measure for a major public health concern. In addition to protecting pets, rabies vaccinations provide a barrier between infected wild animals and humans. Vaccination has reduced confirmed cases of rabies in dogs from 6,949 in 1947 to 126 in 1997. 19 Breed or type bans-Concerns about "dangerous" dogs have caused many local governments to consider supplementing existing animal control laws with ordinances directed toward control of specific breeds or types of dogs. Members of the Task Force believe such ordinances are inappropriate and ineffective. Statistics on fatalities and injuries caused by dogs cannot be responsibly used to document the "dangerousness" of a particular breed, relative to other breeds, for several reasons. First, a dog' s tendency to bite depends on at least 5 interacting factors: heredity, early experience, later socialization and training, health (medical and behavioral), and victim behavior. 7 Second, there is no reliable way to identify the number of dogs of a particular breed in the canine population at any given time (eg, 10 attacks by Doberman Pinschers relative to a total population of 10 dogs implies a different risk than 10 attacks by Labrador Retrievers relative to a population of 1,000 dogs). Third, statistics may be skewed, because often they do not consider multiple incidents caused by a single animal. Fourth, breed is often identified by individuals who are not familiar with breed characteristics and who commonly identify dogs of mixed ancestry as if they were purebreds. Fifth, the popularity of breeds changes over time, making comparison of breed-specific bite rates unreliable. Breed-specific ordinances imply that there is an objective method of determining the breed of a particular dog, when in fact, there is not at this time. Owners of mixed-breed dogs or dogs that have not been registered with a national kennel club have no way of knowing whether their dog is one of the types identified and whether they are required to comply with a breed-specific ordinance. In addition, law enforcement personnel typically have no scientific means for determining a dog' s breed that can withstand the rigors of legal challenge, nor do they have a foolproof method for deciding whether owners are in compliance or in violation of laws. Such laws assume that all dogs of a certain breed are likely to bite, instead of acknowledging that most dogs are not a problem. These laws often fail to take normal dog behavior into account and may not assign appropriate responsibilities to owners. Some municipalities have attempted to address notice and enforcement problems created by unregistered and mixed-breed dogs by including in the ordinance a description of the breed at which the ordi-nance is directed. Unfortunately, such descriptions are usually vague, rely on subjective visual observation, and result in many more dogs than those of the intended breed being subject to the restrictions of the ordinance. Animal control legislation has traditionally been considered a constitutionally legitimate exercise of local government power to protect public safety and welfare. Breed-specific ordinances, however, raise constitutional questions concerning dog owners' fourteenth amendment rights of due process and equal protection. 20 When a specific breed of dog is selected for control, 2 constitutional questions are raised: first, because all types of dogs may inflict injury to people and property, ordinances addressing only 1 breed of dog appear to be underinclusive and, therefore, violate owners' equal protection rights; and second, because identification of a dog' s breed with the certainty necessary to impose sanctions on the dog' s owner is impossible, such ordinances have been considered unconstitutionally vague and, therefore, to violate due process. # After a bite occurs It is important to have a well-defined postbite program in place to minimize physical and emotional pain for dog bite victims. This allows animal control personnel to work efficiently, protects animals that are victims of false allegations, and provides the judiciary with reasonable alternatives that address a variety of situations. State laws may dictate parts of this process. # Investigation of animal bite-related incidents- Any animal bite or incident must be thoroughly investigated and substantiated by an agent of the empowered investigating authority such as an animal control officer, police officer, or peace officer. Ideally, the investigating authority should be the same authority that enforces related ordinances or laws to give continuity and credibility to all investigations. Investigating officers must be given authority to perform their duties by statute or ordinance. Clear, concise, standardized information concerning the incident must be obtained to ensure its successful resolution and facilitate longterm data collection (Appendix 3). Postbite rabies quarantine programs-A healthy dog that is currently vaccinated against rabies and that bites a human should be examined by a licensed veterinarian to determine its health status. If no signs of illness compatible with rabies are detected, the dog should be quarantined. The Centers for Disease Control and Prevention has set the quarantine period for dogs, cats, and ferrets at 10 days, including the day of the bite. Vaccinated dogs can be allocated to 2 categories: those that have bitten a member of the immediate family and those that have bitten an individual outside the immediate family. Home quarantine can be considered for vaccinated dogs that have bitten a member of the immediate family, assuming the owner can confine the dog in a manner that prevents further exposure. Vaccinated dogs that have bitten a human outside of the immediate family generally should be quarantined at the local shelter or veterinarian' s office. At the end of the quarantine period, the dog should undergo a physical examination. In addition, interim evaluations are highly recommended. A dog that is not currently vaccinated against rabies and that bites a human should be considered a rabies suspect and be appropriately quarantined. Contact with the dog during the quarantine period should be strictly limited to individuals who have completed rabies prophylaxis and are up-to-date on serologic testing and booster vaccinations. Physical examinations should be conducted at the beginning and end of the quarantine period to determine the dog's health status. Quarantined dogs may be treated by a veterinarian, but rabies vaccines should not be administered to the dog until the quarantine period is complete. If at any time during the quarantine period the dog has signs of illness compatible with rabies, it should be humanely euthanatized and samples submitted for rabies testing. Records of all bites must be kept, including information specifically identifying the dog and owner. These should be crosschecked with each incident for evidence of a chronic problem. Identification and regulation of "dangerous" dogs-Certain dogs may be identified within a community as being "dangerous," usually as the result of a serious injury or threat. That classification, because it carries with it serious implications, should be well defined by law (Appendix 4). Any such definition should include an exclusion for justifiable actions of dogs. Procedures should be outlined that take into account the potential public health threat, are reasonable to enforce, and convey the seriousness of the situation to the owner. Although animal control officers or their statuary counterparts are responsible for collecting information, a judge or justice will hear evidence from animal control officers and the dog' s owner to determine whether that dog fits established criteria for "dangerousness." In some municipalities, a hearing panel comprising a cross section of private citizens hears alleged "dangerous" dog evidence and has been given the authority to declare a dog "dangerous" if deemed appropriate. Any declaration by a hearing panel, judge, or justice is subject to judicial review. A judge, justice, or hearing panel may promulgate orders directing an animal control officer to seize and hold an alleged "dangerous" dog pending judicial review. If a dog is determined to be "dangerous" by a judge, justice, or hearing panel, the owner of that dog is usually required to register the dog with the appropriate health department or animal control facility. The judicial process may also require the owner to follow other rigid requirements, including but not limited to permanent identification of offending dogs, training and assessment of dogs and owners, and having offending dogs spayed or neutered. Because the judicial branch is such an integral part of any enforcement action, the judiciary must assist during formulation of "dangerous" dog laws. If the judiciary is involved, its members will be aware of the process that must be followed to declare a dog "dangerous." In addition, they will be aware of steps that have already been completed and the options available when a particular case reaches the courts. # Bite Data Reporting Accurate and complete reporting of dog bites is an essential element of a bite prevention program. These reports are vital not only for case management and judicial review but for planning, implementing, and evaluating the status of the problem. Major goals of comprehensive dog bite data reporting include: ? accurately defining victim demographics to identify populations at greatest risk for bites and allow targeting of educational efforts ? defining dog and owner characteristics associated with higher risk so that an actuarial approach to the dog bite problem is possible (this facilitates effective program planning and proper targeting of control measures) ? defining high risk geographic areas at city, county, or neighborhood levels so that limited resources for animal control and public education can be appropriately deployed ? establishing baseline data so that the impact of specific elements of the bite prevention program can be assessed ? providing an accurate, detailed, unbiased, objective source of information for decision makers, media, and the public interested in the dog bite problem and its prevention ? providing critical information for proper management of dog bite cases What should be reported? At a minimum, a dog bite case should be defined as any medically-attended dog bite or any dog bite resulting in a report to an animal control or law enforcement agency. This would presumably cover those instances consuming public resources and would also include cases that may result in litigation. A number of data elements should be captured on a report form such that it is comprehensive in scope without placing unnecessary burdens on reporting agencies (Appendix 3). Fatal and severe dog attacks on humans have been associated with prior or concurrent attacks on pets or livestock, so it is important that communities also track those incidents. Maintaining records of incidents of menacing behaviors of owned dogs running at large in the community may be found useful in later legal actions. # Who should report? The goal is to report any medically treated dog bite or any bite resulting in a report to, or response from, an animal control agency, humane society with animal control responsibilities, or law enforcement agency. Therefore, the primary sources of data should be: ? animal control or law enforcement agencies responding to a dog bite complaint ? health professionals attending to a bite injury (hospital emergency staff, urgent care facility staff, private physicians, school or camp medical staff, medical staff of other entities such as military bases or reservations, and veterinarians) Recognizing that many dog bites go unreported, a comprehensive program to assess dog bite incidence should consider possible secondary sources of data. These may include: ? anonymous surveys of high-risk populations (eg, school-age children) that may clarify the true extent of risk in a community ? anonymous surveys of the public (eg, phone surveys) that can help document the extent of bite injuries and provide a basis for estimating the ratio of unreported to reported bites ? reports from professionals including veterinarians, animal behaviorists, dog trainers, groomers, and kennel operators who are informed of a bite incident (mandating that any or all of these professions report bites may be unrealistic given the potential legal consequences of identifying an animal as a biter) Reporting mandates are often inconsistent between jurisdictions or are poorly enforced. Current local and state reporting regulations should be reviewed, as should directives from health or veterinary officials. If current provisions are adequate, it may be necessary to implement procedures to reeducate professionals concerning their reporting obligations and periodically remind them of these obligations. When a failure to report is uncovered, it may be an opportunity to gain the attention of the professional, because sanctions may be imposed. # Who should receive reports? Reporting should be coordinated by one agency. Logical agencies to coordinate reports include animal control or the public health department. The coordinating agency, perhaps through the dog bite prevention program coordinator, must assume responsibility for maintaining all information and disseminating that information to other appropriate individuals or agencies (eg, veterinarians, physicians, the dog owner, and those involved in follow-up educational efforts). To insure consistency and compliance, regulations or procedures should unambiguously state to whom reports should be submitted and within what time frame the reports should be submitted. # Data management, analysis, interpretation, and dissemination Because multiple sources may report the same case, procedures should be in place to permit combination of data from multiple sources into a single report. Avenues should be developed for electronic submission of reports to assist in rapid response, to streamline reporting to higher levels of government, and to facilitate data analysis. Whereas disposition of individual incidents is the first goal for reporting, there is much to be learned from looking at the overall picture. Keeping information in an electronic database simplifies the latter. Data should be reviewed at regular intervals (no less than yearly) to determine whether the incidence and severity of dog bites is getting better, worse, or staying the same. Basic analysis consists of studying the characteristics of incidents # Education Education is key to reducing dog bites within a community. The list of those to be educated and those who may educate includes everyone who regularly comes into contact with dog owners and potential victims (eg, veterinarians, veterinary technicians and assistants, animal control officers, animal behaviorists, dog trainers, humane society personnel, physicians, school nurses, public health officials, teachers, and parents). The purposes of this section are to educate city officials and community leaders about the role of various professionals in an educational program to reduce dog bites, provide starting references to ensure a core of knowledge for those professionals (Appendix 5), and assist in identification of the educational needs of various constituencies within a community. # Public officials and community leaders Public officials and community leaders are the people to whom residents look for assistance with social problems. Their influence is important and well recognized. If a community dog bite prevention program is to gain public acceptance and be effective, community leaders must be well-informed about dogrelated issues within their community and in general. # Professionals Professionals from many backgrounds need to be involved in bite prevention programs. Their expertise is essential to making realistic decisions about what should and can be done to prevent or follow up on dog bite incidents and in recognizing what is normal or abnormal behavior for a dog. Several of these professionals will likely be members of the advisory commit-tee, but all should be encouraged to be a part of a community' s efforts to decrease the impact of a dog bite problem. Many professions mentioned in this document are science-based. This means their members are used to making decisions on the basis of peer-reviewed datasupported information rather than gut feelings. This approach to decision making results in improved outcomes. Because the dog bite problem impacts so many different groups, networking between community leaders and professionals is important. The following sections describe ways that various professionals and community leaders can work together toward a common goal. Veterinarians-Veterinarians are scientists trained for a minimum of 7 to 8 years and then licensed to diagnose and treat animal problems both medical and behavioral. Although most people think of veterinarians as performing animal vaccinations and surgical neutering, the practice of veterinary medicine includes all subdisciplines typically associated with human medicine. The study of animal behavior both normal and abnormal has become more important within the profession as animals have become more important to their owners. Dogs are now four-legged members of the family, rather than farm animals that help bring cows into the barn at milking time. With this change in the dog' s role have come unrealistic owner expectations about what constitutes normal behavior for a dog. Veterinarians can educate dog owners as to what behavior is normal, can help dog owners teach their dogs to respond appropriately in various environments and provide referrals to reputable dog trainers, and can assist owners with behavioral problems, including those that have a medical basis or are responsive to medication. Until recently, animal behavior was not often taught in veterinary curricula. Many veterinarians have had to acquire their knowledge of normal and abnormal canine behavior from continuing education programs and professional textbooks. For this reason, different veterinarians have different degrees of knowledge about behavior. All veterinarians, however, have access to board-certified veterinary behaviorists for help with behavioral problems beyond their expertise. Although the time, physical, and emotional demands of veterinary practice can be overwhelming and leave limited time to devote to a formal community prevention program, veterinarians can substantially impact prevention efforts through their professional contact with prospective and current dog owners. This contact should begin before the pet is acquired. Providing unbiased information on pet selection can help prevent inappropriate owner-dog pairings. Prospective dog owners often make spur-of-themoment selections that are based on warm-and-fuzzy feelings and unrealistic expectations. Encouraging prospective dog owners to seek information from their veterinarian about the characteristics and needs of various types of pets and encouraging future dog owners to ask for guarantees from puppy providers can minimize future problems. When owners take their newly acquired dogs to their veterinarian for an initial examination and immunizations, the veterinarian has a second opportunity to provide these owners with good medical, nutritional, and behavioral advice. 21 Finally, veterinarians can educate owners during their dogs' routine examinations (asking appropriate questions can reveal problems an owner may not have recognized) or when their dogs are evaluated for specific problems. # Board-certified veterinary behaviorists-The American College of Veterinary Behaviorists (ACVB), an American Veterinary Medical Association-recognized veterinary specialty organization, certifies graduate veterinarians in the specialty of veterinary behavior. To become certified, a veterinarian must have extensive postgraduate training, sufficient experience, and pass a credential review and examination set by the ACVB. Diplomates of this organization work with problem animals by referral from the animal' s regular veterinarian, consult with practitioners on cases, and give continuing education seminars on animal behavior. Although many communities may not have the benefit of a resident board-certified veterinary behaviorist, veterinarians have access to and may consult with their specialist colleagues when necessary. Veterinary technicians-Veterinary technicians are integral members of the veterinary health care team who have been educated in the care and handling of animals, basic principles of normal and abnormal life processes, and routine laboratory and clinical procedures. They perform many of the same tasks for veterinarians that nurses and others perform for physicians. Veterinary technicians are often frontline people when it comes to educating pet owners, particularly in general veterinary practices; they greet clients and answer initial inquiries, clarify instructions, provide clients with appropriate print, audio, and video educational material, and answer questions. Certainly, they are an important part of the educational team when it comes to dog bite prevention. Like veterinarians, veterinary technicians have several opportunities to educate clients. Veterinarians may be consulted prior to owners acquiring a new pet, and veterinary technicians can help provide information on appropriate pet selection. Veterinary technicians regularly counsel owners during new puppy appointments, and this is a particularly good opportunity to provide owners with information on bite prevention, including the importance of socialization and training. Routine physical examinations are times when veterinary technicians can reinforce the importance of these early lessons and training, and they can help veterinarians identify potential aggression problems through observation and dialog with owners. Veterinary technicians can also be tapped to educate nonpet-owning children and adults through school or other programs. Veterinary technology programs do not always offer curricula in animal behavior and, consequently, many technicians do not have formal training in this area when they enter practice. Continuing education that includes basic principles of animal behavior is essential for veterinary technicians, just as it is for their employers. Maintaining a clinic reference library of appropriate print, audio, and video material for reinforcement and enrichment and for client education is useful. Behavioral education for veterinary technicians relative to dog bite prevention should include recognition of classic canine behavioral displays and an understanding of the basic types of canine aggression and their prevention. The aim is to assist technicians in conveying dog bite prevention information to owners. Veterinary technicians must not be placed in the role of diagnosing or treating canine aggression. Animal behaviorists-There are a number of scientists with PhD degrees in academic fields related to animal behavior who can serve as valuable resources for communities attempting to reduce dog bite injuries. Because of their science-based backgrounds, they can be particularly helpful in setting up protocols to determine the extent of the problem within a community and whether ongoing programs are having a substantial impact. As a note of caution, the terms animal behaviorist or animal psychologist are often used by individuals who do not have strong scientific backgrounds but who want to work with problem dogs. There is no method to evaluate the competence of these individuals, and they may be more harmful than helpful to a community' s efforts. Dog trainers-This is a diverse group of individuals with no uniformly recognized credentialing body or measures of competence. Although there are many good dog trainers, there are also trainers that use inappropriate methods of behavioral modification that can negatively affect a dog' s behavior, making the dog more dangerous to the owner and the community. It is important that communities make a concerted effort to work with responsible trainers who interact closely with veterinarians and PhD-degreed animal behaviorists. A qualified responsible dog trainer can be a valuable asset to a community advisory group. Obedience training by itself does not prevent the development of behavior problems, 22 and animals that are sent to a training facility may not learn how to obey their owners, because the owners do not learn how to give commands. For problem animals, training is only part of the solution. Physicians and nurses-With a dog residing in 1 of every 3 US homes and approximately 53 million dogs in the United States, 2,3,6 exposure of the physician or nurse, their family members, or their patients to dogs during the course of daily life is inevitable. Dogs have become important members of many families, and the presence of a pet in the home can affect an individual' s own decisions about care. Most physicians are familiar with at least 1 example of a person refusing hospitalization, because there was no one else in the home to care for their pet. Because 334,000 Americans are seen in emergency departments for dog bite injuries each year, 466,000 are seen in other medical practice settings, and 6,000 are hospitalized, 6 it behooves human healthcare providers to acquaint themselves with community and personal strategies to prevent dog bites. Furthermore, just as occurrences of infectious diseases such as measles are reported to enable investigation of outbreaks and development of control measures to protect the public, dog bites must be reported so that cause and prevention can be addressed. Communities differ in their requirements for reporting, and practitioners must understand what is required in their area. Traditionally, when confronted with patients seeking care for dog bites, physicians and nurses have confined their roles to providing medical treatment. With the expanding roles of physicians and nurses, however, disease prevention has become an important issue. In addition to competently treating dog bites and their complications, healthcare providers need to be aware of critical roles they can play in reducing dog bite injuries. Advising patients about safe behaviors appears effective in preventing injury. Teaching children, parents, and patients who own dogs about proper behavior around dogs and responsible dog ownership is advisable given the frequency of human-canine contact in our society. Physicians can recommend contacting a veterinarian for pet selection information and advice if an individual or family is considering dog ownership, and for information about canine behavior and obedience training if a dog is already part of the family. Pediatricians provide age-appropriate injury prevention counseling during wellness visits. 26 Dog bite prevention should be a part of this counseling. Dog safety tips can also be included in packets of materials routinely sent home with new mothers. When a patient is being treated for a bite, an opportunity exists to prevent future injury by teaching bite-avoidance strategies. Probing into the circumstances of the current bite may reveal which strategies should be emphasized. Taking advantage of teachable moments should be considered part of curative care. Consulting with a veterinarian may help human health care providers identify subjects they can address during postbite sessions. As witnesses to the health-related outcomes of dog bites, physicians and nurses are particularly credible sources of information and can be effective spokespersons. Pediatricians and nurses should be full partners in community efforts to reduce dog bite injuries. Animal control personnel-The staff of a wellresourced animal control program often includes an education coordinator who can train teachers, school nurses, and volunteers to become dog bite prevention educators within the community' s school system (similar to volunteers in the McGruff crime prevention program presented to primary-school children). For animal control personnel, job-related continuing education is important. Programs are available through the National Animal Control Association. Humane society/animal shelter/rescue group personnel-Dog bite injuries have negative repercussions for dogs as well as people, and humane society/animal shelter/rescue group personnel must deal with these issues. Dogs causing severe injuries may be brought to humane facilities for rabies quarantine or euthanasia. Dogs that have threatened to bite or that have nipped may be surrendered to shelters or rescue groups, sometimes without full acknowledgment by their owners. 16 Shelter personnel are forced to decide which dogs can be placed in new homes and which are not suitable for adoption. Progressive organizations work with veterinarians and animal control officers to educate their staff about safe dog handling and objective evaluation techniques. Record keeping and follow-up studies expand their knowledge base about what works in their community and what does not. Well-trained and dedicated humane society/animal shelter/rescue group personnel can be valuable community resources for public education as well. # Public Public education is critical to the success of any dog bite prevention program, because half of all bites are inflicted by the family dog. 27 Only about 10% of bites are inflicted by dogs unknown to the victim. 7,15 A public education effort must target a variety of individuals and age groups, and one individual should be assigned to integrate its components. If a special advisory council or task force is convened, its paid coordinator would be a logical choice to coordinate the public education effort. Alternatively, the public education coordinator could be a member of a municipal group such as the local health department, animal control agency, or board of education, or a member of a stakeholder group such as a humane society or veterinary association. Many educational programs targeted at various audiences exist and are included in the dog bite prevention resource list found on the American Veterinary Medical Association Web site (www.avma.org). As new materials become available, they will be added to this resource list. Children-Children are the most common victims of serious dog bites. Seventy percent of fatal dog attacks and more than half of bite wounds requiring medical attention involve children. 7,9,15 In addition, almost half of all children are bitten before 18 years of age. 27,28 The most vulnerable youngsters are 5-to 9year-old boys, 6,7,8 but smaller children can also be seriously injured. 29 Dog bite injuries rank third only to bicycle and baseball/softball injuries as a leading cause of emergency admission of children to hospitals. 6 Children's natural behaviors, including running, yelling, grabbing, hitting, quick and darting movements, and maintaining eye contact, put them at risk for dog bite injuries. Proximity of a child' s face to the dog also increases the likelihood that facial injuries will occur. 6,7, Target group-The first step in a child education effort is determining what population of children to target and when. The logical primary audience is those at greatest risk: children in grades kindergarten through 4. Late winter or early spring appears to be the best time to institute a campaign, because the school year is concluding and, as children spend more time outside, exposure risk increases. 32 It is critical that school administrators buy into the concept of a dog bite prevention program; therefore, requests to the school district must be made by committed convincing well-organized individuals. Because school curricula are crowded, time blocks for dog bite prevention education should be requested early within the school system' s calendar year. If such a block of time is not available, an alternative is to have a veterinarian or physician present a 1-hour lecture or assembly program to the entire student body. Once dog bite prevention education has been included within the curriculum (or has been scheduled to be provided through a special lecture or assembly program), teachers, nurses, and volunteers should consider addressing the school's parent-teacher organization to inform parents of upcoming dog bite prevention training for their children. Secondary efforts-Secondary targets include children in other settings, such as early education programs (eg, Head Start, day care centers, recreational centers, and camps). Identifying instructors-Who teaches the material will depend on expertise within the community. For classroom instruction, teachers who have had in-service training, school nursing staff, health educators, or trained volunteers are logical choices. Stakeholder groups (eg, veterinarians, veterinary technicians, animal control officers, physicians, nurses, humane society staff) may provide a ready source of volunteers for classroom instruction and special programs. Adults-Adult citizens must understand the need for and support a strong dog bite prevention program not only for their own safety but for the safety of others in their community. It is this understanding that gives a prevention program long-term stability. All adults should learn appropriate behaviors around dogs so that they can protect themselves, teach their own children, serve as an example for others, and reinforce appropriate behaviors in other children at every opportunity. Adults also serve as local eyes for animal control so that roaming dogs are controlled. Educational materials sent home with school children, distributed by pediatricians during well-child visits, inserted in public utility bills, and produced by an enlightened local media are all reasonable approaches. Involving representatives of service organizations and community groups during a prevention program' s planning and active stages will strengthen commitment. Active adults (eg, joggers, bicyclists, golfers) whose outdoor activities provide greater exposure to dogs are most at risk for injury. To reach these individuals, bite prevention information should be provided to local interest groups, recreational facilities, and health clubs. Target group-Primary adult targets within the community are those who have children and who are active in outdoor activities. # Secondary efforts-Secondary targets include individuals between the ages of 21 and 65 years. Identifying instructors-Materials can be developed or selected by animal control personnel, veterinarians, veterinary technicians, or other people knowledgeable about dog behavior. Information can be distributed through a number of channels such as those identified above. The elderly-As people age, they become more susceptible to injury and disease. Thinning skin increases risk of bruising, and a bite producing a simple puncture wound in a younger individual can cause a severe laceration in a senior citizen. Sensory perception decreases so that an elderly person may not see a threatening dog or may not be able to read its behavioral signals accurately. In addition, diminished motor skills mean that the elderly are less able to physically protect themselves or escape. Another concern for the elderly is that their beloved pet may not be trustworthy around their grandchildren. Dogs not raised around small children or not frequently exposed to them may not be socialized toward them. 1 This increases the likelihood of aggressive behavior being directed toward these children. An educational program for senior citizens can be implemented in various settings. Materials may be provided through community services for the elderly such as church groups, visiting nurse programs, meals-onwheels, recreational centers, or travel groups. Secondary targets are shopping malls and the media. Trained volunteers, especially from dog-associated professions, are logical sources of information. Human healthcare professionals can be an important source of information for the elderly because of the frequency of their interactions. Target group-Primary targets are grandparents and people aged 60 years or older who have dogs in their homes. Secondary efforts-Secondary targets include other individuals who are at least 60 years old. Identifying instructors-Physicians can interact with these people during clinic visits. Animal control personnel, veterinarians, veterinary technicians, and people knowledgeable about dog behavior can select or produce resource information. Animal owners-People who own dogs have a wide variety of views about their responsibilities. For some, dog care means providing food and water when the thought occurs to them. At the other end of this spectrum is the person who actively makes sure the pet is appropriately fed, well-trained, licensed, and healthy. Some individuals view dogs as disposable items that can be abandoned at any sign of trouble or expense. Once a community establishes acceptable standards for responsible ownership, dog owners must be informed of these expectations and related ordinances, and rules must be enforced. Owners and future owners must be educated about their unique set of responsibilities, which include appropriate pet selection, providing quality nutrition, housing, and medical care, compliance with confinement and licensing requirements, appropriate behavioral training, and supervision of interactions between dogs and children. Citizens must understand that pet ownership is an ongoing responsibility, not a passive activity. Dog owners can be provided with information through various avenues. Veterinarians and their staff are logical educators and distributors. Local dog clubs and trainers provide services to more conscientious owners. Businesses that sell pet foods and supplies should also be encouraged to provide bite prevention materials to their customers. Information can be distributed with utility bills, and animal shelters can provide classes for people who are considering acquiring a pet. Incentives for attendance at bite prevention classes could include reduced fees for licenses and coupons for vaccinations, food, and obedience classes. The most difficult group of dog owners to reach is those with minimal attachment to their pets. Although strong enforcement of local regulations will change some owners into former owners, most will continue to own dogs. Therefore, education should be an integral part of any enforcement program. A good working relationship with the judiciary is critical so that offenders of animal-related ordinances are required to take courses that emphasize responsible ownership. Target group-Primary targets are adults who already own dogs. # Secondary efforts-Secondary targets are adults who are considering getting a new dog. Identifying instructors-Information for this target audience can come from various sources, and its distribution should be approached in a number of ways. Animal control officers and members of the legal profession can describe what is expected regarding local regulations and the serious consequences if these regulations are violated. Veterinarians and their staff can educate owners about vaccinations, neutering, restraint, and other health care issues. Dog club members and trainers can assist by providing socialization and training instruction and can help educate owners about being good dog-owning neighbors. Victims-When someone becomes a dog bite victim, a teachable moment is created. How useful that moment becomes in preventing future incidents depends tremendously on the seriousness of the bite and the fear response of the victim. Scare-producing or threatening events are good times for dog bite prevention information to be conveyed. However, the time surrounding a serious injury is generally too emotionally charged to be of value for dog bite prevention education. Who provides information to victims depends, in part, on who is contacted about the incident. In addition to medical personnel, animal control' s investigative efforts usually require a home visit. Routine visits to a physician should include gathering historical information about the patient' s interactions with dogs to identify patients who would benefit from additional education. Media stories that reinforce correct approaches to prevention can also touch many when they are most receptive. Target group-Individuals who have recently been bitten by a dog seriously enough to require medical attention but not so seriously as to have sustained severe injuries are the primary target. Secondary efforts-Secondary targets are individuals who have been bitten by a dog in the past. Identifying instructors-Medical professionals and animal control personnel are the individuals who encounter this group. Businesses-Community businesses need to address dog bite prevention as well. Certain businesses (eg, veterinary clinics, grooming and boarding facilities, animal control, pet sitting agencies) revolve around direct contact with dogs, and employee education is critical from a safety and liability standpoint. Employees of other businesses will occasionally encounter dogs in the course of their daily job activities (eg, utility workers, police officers, parcel carriers, and emergency medical technicians). Training conducted by an animal control officer or other knowledgeable professional may provide employees with the tools they need to safely handle contacts with at-large animals, attack/guard dogs, or dogs who simply reside on the premises of those facilities where they do business. Target group-Primary targets are employees and business owners who will be working with dogs on a daily basis. Secondary efforts-Employees of companies who are likely to encounter dogs in their daily business activities can be considered secondary targets. Identifying instructors-Animal control personnel, veterinarians, veterinary technicians, and dog trainers who are experienced at dealing with dogs in a variety of environments. These individuals will need to customize presentations to the type of situations most likely encountered by the target audiences. # Media The local media play an important role in a community' s efforts at bite prevention. For this reason, it is suggested that 1 member of the advisory council or task force be a media representative. In addition, the advisory council can be proactive in helping the media convey important and appropriate messages. Sensational events provide an opportunity to convey important messages. Regular features can reinforce principles and keep educational efforts flowing. # Know the media Your key to the public eye and ear is a selective upto-date list of local media contacts who have an interest in animal issues. Such a list can be developed by undertaking a comprehensive media survey. Check the local library for publications that list names, telephone numbers, and short descriptions of your community' s media outlets. Call each office or studio to discover which desks or departments should receive your inquiries and press releases. Read local newspapers and listen to local radio and television news and feature programs to identify reporters and hosts who address animal issues. Finding out whether these individuals gather their own news or use wire services will allow you to target press releases and materials to those who are most likely to use them. Contact local freelance writers to see whether they would be willing to feature a bite prevention message in an upcoming piece. Be aware that your media list will be dynamic, and take time to update the names of specific contacts. Once a helpful story is published, or a reporter conveys your message during a broadcast, be sure to acknowledge that effort by sending a thank-you note or making an appreciative telephone call. # A spokesperson The community should identify a spokesperson who has the expertise to address complicated dog biterelated issues, and this individual should be provided with media training so that he/she becomes an effective communicator with the print and broadcast media. It is the spokesperson' s responsibility to convey information clearly, accurately, and promptly. In various situations, this individual can identify when there are not enough animal control officers to prevent dog packs from forming or when a dog has been "sicced" on a person as a weapon. A knowledgeable and effective communicator can turn a publicized bite into a learning opportunity by providing suggestions on how that bite could have been prevented (eg, the dog was not appropriately controlled or confined, or a child was left unsupervised). # Have information readily available The advisory council or task force should create a 1-page fact sheet for use by the media and the spokesperson. This fact sheet should include the number of dog bite incidents occurring in the community during the past year, the number of dogs in the community, the number of licensed dogs in the community, what local laws govern dog ownership and control, and to whom problems should be reported. A list of community resources should also be available. # Ways to effectively convey information Because animal stories are popular with the media, there are numerous opportunities to convey bite prevention information. Local broadcast programs and newspapers find regular segments about animals popular with viewers/listeners/readers, and most of those spots have enough time for short lessons. Another approach is to proactively bring animal stories to the media. Examples include a story about a shelter dog that visits nursing homes after being rescued and appropriately trained, a description of a guide or "hero" dog' s training, or warm-weather tips for pets. Effective mechanisms for providing information vary with the medium but include: News releases-Releases may be provided to print, radio, or television outlets. Releases should be double-space typed on stationery that provides the source of the announcement (ie, the advisory council or task force). Include the subject of the news release and contact information in the upper left corner. The mailing date of the release should be indicated along the right margin. The release should be written in inverted pyramid style, placing the most important information at the beginning. Releases should be limited to 1 page if possible. Interviews-Interviews may be conducted by print, radio, or television reporters or hosts and, in the case of television and radio, may be live or taped. The individual being interviewed must be an excellent communicator and intimately familiar with dog bite issues and prevention. The interviewee may request a preinterview to get a grasp of the direction of the interview. It is advisable to tell the interviewer which issues you would definitely like to see addressed. Answers should be structured according to the program' s time limits. Talk shows-Most of the principles that apply to interviews also apply to talk shows, but in this situation there usually will be interaction with guests (who often hold opposing views), potentially with an audience, and with the host. Running through mock discussions prior to participation is helpful. Responses to questions or comments from those with opposing views should always be factual, sincere, and polite. Public affairs programs-Many stations air 2 or 3 programs a week in which the station' s news staff or station management interview a newsmaker, a spokesperson from an activist group, or a public relations representative from an industry. Issues in the news are often addressed by such programming. These provide a good opportunity to make your community aware of bite prevention efforts and to elicit support. Access to these programs may be requested by sending a letter to the station manager. # Bulletin board and community announcements- Many local television stations donate air time to announcements of community events. These are often broadcast in calendar format. This is an easy way to publicize educational events and responsible pet ownership classes. Editorials-Editorials are used by print, radio, and television reporters to present their views on issues of public interest. Prepared statements describing the advisory council' s approach to dog bite prevention can be provided to reporters for use in preparing an editorial or may be provided if a reporter presents an opposing viewpoint. Public service announcements-Many radio and television stations donate time for public service announcements (PSA); however, public service groups cannot specify when your PSA is to be aired. It is acceptable to suggest when you believe airing your PSA will be most effective. Most PSAs run for 30 to 60 seconds, although 10-and 20-second spots are also used. To mitigate the costs associated with production, you may want to contact local stations to see whether they offer sponsored placements, in which local advertisers donate time for specific public service messages. Public service announcements may consist of script only, sight and sound (simple or complex), or 16-mm film or videotape. # Appendix 2 # Model dog and cat control ordinance Originally produced and published jointly by the American Veterinary Medical Association, the American Humane Association, the Humane Society of the United States, and the Pet Food Institute in 1976. Modifications have been made from the original version to reflect updated US Public Laws, current titles of other referenced documents, and present favored terminology and definitions concerning "dangerous" animals. # Section 1. Definitions As used in this ordinance the following terms mean: Animal-For the purpose of this ordinance, animal shall mean dog or cat. Animal control authority-The person or persons designated to enforce this ordinance. Animal establishment-Any pet shop, grooming shop, animal auction, performing-animal exhibition, kennel or animal shelter, except this term shall not include veterinary medical facilities, licensed research facilities, facilities operated by government agencies, or licensed animal dealers regulated by the USDA under the provisions of US Public Laws 89-544, 91-579, 94-279, 99-198, and 101-624. Animal shelter-Facility designated or recognized by the - for the purpose of impounding and caring for animals. At large-A dog or cat shall be deemed to be at large when off the property of the owner and not under restraint. Humane manner-Care of an animal to include, but not be limited to, adequate heat, ventilation and sanitary shelter, wholesome food and water, consistent with the normal requirements and feedings habits of the animal's size, species, and breed. Kennel-An establishment kept for the purpose of breeding, selling, or boarding dogs or cats or engaged in training dogs or cats. Licensing authority-The agency or department of or any designated representative thereof charged with administering the issuance and/or revocation of permits and licenses under the provisions of this ordinance. Livestock guarding dogs-Dogs kept for the primary purpose of protecting livestock from predatory attacks. Neutered-Rendered permanently incapable of reproduction. Nuisance-A dog or cat shall be considered a nuisance if it: damages, soils, defiles, or defecates on private property other than the owner's or on public walks and recreation areas unless such waste is immediately removed and properly disposed of by the owner; causes unsanitary, "dangerous," or offensive conditions; causes a disturbance by excessive barking or other noise making; or chases vehicles, or molests, attacks, or interferes with persons or other domestic animals on public property. Owner-A person having the right of property or custody of a dog or cat or who keeps or harbors a dog or cat or knowingly permits a dog or cat to remain on or about any premises occupied by that person. Person-Any individual, corporation, partnership, organization, or institution commonly recognized by law as a unit. Pet shop-An establishment engaged in the business of buying or selling, at retail, dogs or cats or other animals for profit-making purposes. Restraint-A dog or cat shall be considered under restraint if it is within the real property limits of its owner or secured by a leash or lead or under the control of a responsible person. "Dangerous" dog or cat-A dog or cat that without justification attacks a person or domestic animal causing physical injury or death, or behaves in a manner that a reasonable person would believe poses an unjustified imminent threat or serious injury or death to one (1) or more persons or domestic animals. Written application for a dog or cat license shall be made to the and shall include the name and address of the owner and the name, breed, color, age, and sex of the dog or cat. Applicants also shall pay the prescribed licensing fee and provide proof of current rabies vaccination. e. The licensing period shall be for ‡ year(s). License renewal may be applied for within sixty (60) days prior to the expiration date. New residents must apply for a license within thirty (30) days of establishing residence. f. A license shall be issued after payment of a fee of $____ for each unneutered dog or cat and $____ for each neutered dog or cat. § Persons who fail to obtain a license as required within the time period specified in this section will be subjected to a delinquent fee of $____ . g. License fees shall be waived for dogs serving the blind or deaf or government-owned dogs used for law enforcement. All other licensing provisions shall apply. h. Upon acceptance of the license application and fee, the shall issue a durable license tag including an identifying number, year of issuance, city, county, and state. Both rabies and license tags must be attached to the collar of the dog or cat.II Tags must be worn at all times and are not transferable. shall maintain a record of all licenses issued, and such records shall be available to the . Section 3. Permits a. No person shall operate an animal establishment without first obtaining a permit in compliance with this section b. The permit period shall begin with the first day of the fiscal year and shall run for one (1) year. Renewal applications for permits may be made within sixty (60) days prior to the expiration date. Application for a permit to establish a new breeding animal establishment under the provisions of this ordinance may be made at any time. c. Annual permits shall be issued upon payment of the applicable fee: i. For each kennel authorized to house less than six (6) dogs or cats $ ____ ii. For each kennel authorized to house six (6) but not more than forty-nine (49) dogs or cats $ ____ iii. For each kennel authorized to house fifty (50) or more dogs and cats $ ____ iv. For each pet shop $ ____ v. For other animal establishments $ ____ d. A person who maintains a kennel of six ( 6) or more dogs or cats for breeding purposes may pay an annual permit fee or may elect to license individual dogs or cats as provided under Section 2. Every facility regulated by this ordinance shall be considered a separate enterprise, requiring an individual permit. e. Under the provisions of this ordinance, no permit fee shall be required of any animal shelter. All other provisions shall apply. Any change in the category under which a permit is issued shall be reported to the within sixty (60) days, whereupon reclassification and appropriate adjustment of the permit fee shall be made. f. Failure to comply with the provisions of this section is subject to a fine of $____. Section 4. Issuance and revocation of permits and licenses a. The may revoke any permit or license if the person holding the permit or license refuses or fails to comply with this ordinance, the regulations promulgated by the or any other law governing the protection and keeping of animals. b. If an applicant is shown to have withheld or falsified any material information on the application, the may refuse to issue or may revoke a permit or license. c. It shall be a condition of issuance of any permit for an animal establishment that the [appro- priate authority] shall be permitted to inspect any and all animals and the premises where such animals are kept at any reasonable time during normal business hours. Where a permit is revoked for any cause, or pending appeal of any such action, the shall have power of entry on the premises and into all areas where animals are being kept. A person denied a permit may not reapply for a period of at least thirty (30) days. Each reapplication shall disclose any previous denial or revocation and shall be accompanied by a $____ fee. Section 5. Owner responsibility a. All dogs and cats shall be kept under restraint. b. Every "dangerous" dog or cat, as determined by the , shall be confined by its owner within a building or secure enclosure and shall be securely muzzled or caged whenever off the premises of its owner. c. No dog or cat shall be allowed to cause a nuisance. The owner of every dog or cat shall be held responsible for every behavior of such dog or cat under the provisions of this ordinance. d. Failure to comply with the provisions of this section shall be subject to a fine of $_____. e. Dog and cat owners shall ensure that their dog or cat carries identification at all times in the form of microchip, tag, or other means to allow easy determination of the owners. f. Livestock guarding dogs shall be exempt from nuisance regulations when performing duties protecting livestock on premises owned or controlled by the owner. Section 6. Impoundment a. Any dog or cat found running at large shall be impounded by the in an animal shelter and confined in a humane manner. Immediately upon impounding a dog or cat, the shall make every reasonable effort to notify the owner and inform such owner of the conditions whereby custody of the animal may be regained. Dogs and cats not claimed by their owners within a period of ¶ in which the shelter is open to the public shall become the property of the . b. When a dog or cat is found running at large and its ownership is verified by the , the authority may exercise the option of serving the owner with a notice of violation in lieu of impounding the animal. c. In the event that the finds dogs or cats to be suffering, it shall have the right forthwith to remove or cause to have removed any such animals to a safe place for care at the owner's expense or to euthanatize them when necessary to prevent further suffering. Return to the owner may be withheld until the owner shall have made full payment for all expenses so incurred. d. Disposal of an animal by any method specified here in does not relieve the owner of liability for violations and any accrued charges. Section 7. Redemption a. Any animal impounded may be redeemed by the owner thereof within five (5) days upon payment of an impoundment fee of $____ , provided that if any such animal has been previously impounded, the impoundment fee shall be $____ . Payment of impoundment fees is not considered to be in lieu of any fine, penalty, or license fees. b. Any animal confined for rabies quarantine, evidence, or other purpose may be redeemed by the owner thereof upon payment of a fee of $____ . c. No animal required to be licensed or vaccinated under this ordinance may be redeemed until provisions for such licensing have been fulfilled. # Section 8. Adoption An adoption fee of $____ shall be assessed at the time of adoption. No dog or cat shall be released for adoption as a pet without being neutered or without a written agreement from the adopter guaranteeing that the animal will be neutered. Vaccination fees, licensing fees, and veterinary costs may be assessed above and beyond the adoption fee. # Section 9. Interference No person shall interfere with, hinder, or molest any agent of the in the performance of any duty as herein provided. Any person violating this section shall be deemed guilty of a misdemeanor and shall be subject to a fine of not less than $____ or more than $____ . # Section 10. Repeals (conflicting ordinances) All other ordinances of the that are in conflict with this ordinance are hereby repealed to the extent of such conflict. # Section 11. Severability If any part of this ordinance shall be held invalid, such part shall be deemed severable and the invalidity thereof shall not affect the remaining parts of this ordinance. # Section 12. Applicability This ordinance shall be in full force and effect upon the expiration of days after its passage and publication. # Section 13. Safety clause The hereby finds, determines, and declares that this ordinance is necessary for the immediate preservation of the public health, safety, and welfare of the and the inhabitants thereof. *For all occurrences of , communities should insert their applicable agency. †The organizations developing this model ordinance recommended that licensing tags show, in addition to the license number, the city or county and state in which the animal is registered. This helps to alleviate the problem of an animal being left unidentified or unclaimed because it has been transported from one state to another and has no reference to the issuing city or county on the license tag. ‡Where blanks are found without insertions, communities should insert applicable fees or conditions. §Differential license fees for neutered animals serve as an incentive for responsible pet ownership. IIBreakaway collars are recommended when tags are affixed to collars worn by cats. ¶It is recognized that holding periods will be determined to some degree by availability of facilities; however, it is important to ensure a reasonable opportunity for owners to reclaim their dog or cat. # Appendix 3 Recommended data elements for reports of dog bites # Data element Comment Notifications of dog attacks on humans. Continued on next page. # Appendix 4 Model legislation for the identification and regulation of "dangerous" dogs A. Actions allowed by authorized persons prior to hearing 1. If any dog shall attack a person or domestic animal who was peaceably conducting himself in any place where he may lawfully be, any person, for the purpose preventing imminent injury or further injury, may use such force as is required to stop the attack. 2. A police officer or peace officer acting pursuant to his statutory duties may, where the threat of serious injury to a person or domestic animal is imminent and unjustified, use such force as is required to prevent such injury. B. Definitions 1. a. "Dangerous dog" means any dog which without justification attacks a person or domestic animal causing physical injury or death, or behaves in a manner that a reasonable person would believe poses an unjustified imminent threat of serious injury or death to one or more persons or domestic animals. A dog's breed shall not be considered in determining whether or not it is "dangerous." Further, b. No dog may be declared "dangerous" i. If the dog was protecting or defending a person within the immediate vicinity of the dog from an attack or assault; ii. If at the time the person was committing a crime or offense upon the property of the owner, or custodian, of the dog; iii. If the person was teasing, tormenting, abusing or assaulting the dog, or in the past had teased, tormented, abused or assaulted the dog; iv. If the dog was attacked or menaced by the domestic animal, or the domestic animal was on the property of the owner, or custodian, of the dog; v. If the dog was responding to pain or injury, or protecting itself, its kennels or its offspring; vi. If the person or domestic animal was disturbing the dog's natural functions such as sleeping or eating. vii. Neither growling nor barking, nor both, shall alone constitute grounds upon which to find a dog to be "dangerous." 2. "Attack" means aggressive physical contact initiated by the dog. 3. "Serious injury" means any physical injury consisting of broken bones or a permanently disfiguring laceration requiring either multiple stitches or cosmetic surgery. 4. "Domestic animal" means any animal commonly kept as a pet in family households in the United States, including, but not limited to dogs, cats, guinea pigs, rabbits and hamsters; and any animals commonly kept for companion or commercial purposes. C. Hearing procedure 1. Any person may make a complaint of an alleged "dangerous" dog as that term is defined herein to a police officer or peace officer of the appropriate municipality. Such officers shall immediately inform the complainant of his right to commence a proceeding provided for in Paragraph 2, immediately below, and, if there is reason to believe the dog is a "dangerous" dog, the officer shall forthwith commence such proceeding himself. 2. Any person may, and any police officer, or peace officer acting within the scope of his statutory duties, shall make a complaint under oath or affirmation of an allege dangerous" dog as that term is defined herein to any municipal judge or justice. Thereupon, the judge or justice, or hearing panel subject to judicial review, shall immediately determine if there is probable cause to believe the dog is a "dangerous" dog and, if so, shall issue an order to any police officer or peace officer pursuant to his statutory duties or animal control officer directing such officer to immediately seize such dog and hold same pending judicial determination as herein provided. Whether or not the judge or justice, or hearing panel subject to judicial review, finds there is probable cause for such seizure, he shall, within five (5) days and upon written notice of not less than three (3) days to the owner of the dog, hold a hearing on the complaint. D. Where a dog is determined pursuant to clear and convincing evidence at a duly constituted hearing to be "dangerous," the judge or justice, or hearing panel subject to judicial review, shall require the owner of said animal to register such animal (with the appropriate Health Department or animal control facility), and to provide prompt notification to (the appropriate Health Department or animal control facility) of any changes in the ownership of the animal; names, addresses and telephone numbers of new owners; any change in the health status of the animal; any further instances of attack; any claims made or lawsuits brought as a result of further instances of attack; the death of the animal. In addition, the judge or justice, or hearing panel subject to judicial review, may require any or all of the following, but items 5, 6 and 11, or any one of them, may only be imposed where there has been serious injury to a person. 1. Indoors, when not alone, the dog be under the control of a person eighteen ( 18) years or older. (Provisions for the dog to be outdoors must also be made.) 2. Outdoors and unattended, the dog be kept within a locked fenced area from which it cannot escape. 3. When outdoors the dog must be attended and kept within a fenced area from which it cannot escape. 4. When outdoors the dog must be attended and kept on a leash no longer than six (6) feet and under the control of a person eighteen (18) years of age or older. 5. When outdoors the dog must be attended and muzzled. Such muzzle shall not cause injury to the dog or interfere with its vision or respiration but shall prevent it from biting any person or animal. 6. Outdoors and unattended, the dog must be confined to an escape-proof kennel of the following description: a. Such kennel shall allow the dog to stand normally and without restriction, and shall be at least two and one half (2.5) times the length of the dog, and shall protect the dog from the elements. b. Fencing materials shall not have openings with a diameter of more than two (2) inches, and in the case of wooden fences, the gaps shall not be more than two (2) inches. c. Any gates within such kennel or structure shall be lockable and of such design as to prevent the entry of children or the escape of the animal, and when the dog is confined to such kennel and unattended such locks shall be kept locked. d. The kennel may be required to have double exterior walls to prevent the insertion of fingers, hands or other objects. 7. Placement of a sign or signs of a description and in places directed by the judge or justice, advising the public of the presence and tendencies of said animal. 8. Attendance by the dog and its owner/custodian at training sessions conducted by a certified applied animal behaviorist, board certified veterinary behaviorist or other recognized expert in the field and completion of training or any other treatment as deemed appropriate by such expert. The owners of the dog shall be responsible for all costs associated with the evaluation and training ordered under this section. 9. Neutering or spaying of the dog at the owner's expense, unless medically contraindicated. 10. That the dog be permanently identified by tattooing or by injecting an identification microchip, using standard veterinary procedures and practices, identification number and the identification of the person performing the procedure to be registered with the (appropriate health department or animal control facility) as indicated above. 11. The procurement of liability insurance in an amount to be determined by the judge or justice, but in no case in an amount of less than fifty thousand dollars ($50,000), covering the medical and or veterinary costs resulting from future actions of the dog (a determination of liability shall be made in accordance with the laws of the jurisdiction). This condition may not be imposed if it is shown that no such insurance is available for a reasonable premium. 12. If any of the above conditions ordered by a judge or justice, or hearing panel subject to judicial review, are not complied with, the owner shall be subject to a fine of not more than ten thousand dollars ($10,000). 13. If a further incident of attack occurs under such circumstances that the dog, after a hearing as described above, is determined to be a "dangerous" dog, the judge or justice, or hearing panel subject to judicial review, may impose or reimpose any applicable directives listed above; additionally, humane destruction of the dog may be ordered, but only where the further incident involves serious injury to a person. # Appendix 5 Suggested reading for professionals (numbers correspond to cited references)	Groups potentially involved in dog bite prevention 2. Model dog and cat control ordinance 3. Recommended data elements for reports of dog bites 4. Model legislation for the identification and regulation of "dangerous" dogs 5. Suggested reading for professionals MEMBERS OF THE TASK FORCE# Introduction and Problem Statement Dog bites are a serious public health problem that inflicts considerable physical and emotional damage on victims and incurs immeasurable hidden costs to communities. Bites have been tolerated as a job-related hazard for utility and postal workers, but for many communities the problem may be more encompassing. Following a severe attack, there is usually an outcry to do something, and the something that is done often reflects a knee-jerk response. Only later do officials realize that the response was not effective and, in fact, may have been divisive for the community. To assist communities in avoiding such ineffective responses, the AVMA convened a Task Force on Canine Aggression and Human-Canine Interactions. Although the number of injuries will never be reduced to zero, Task Force members believe a well-planned proactive community approach can make a substantial impact. The information contained in this report is intended to help leaders find effective ways to address their community' s dog bite concerns. a # Scope of the problem Dogs have shared their lives with humans for more than 12,000 years, 1 and that coexistence has contributed substantially to humans' quality of life. In the United States, there are slightly more than 53 million dogs sharing the human-canine bond, 2,3 more dogs per capita than in any other country in the world. 1 Unfortunately, a few dogs do not live up to their image as mankind' s best friend, and an estimated 4.5 million people are bitten each year, 4,5 although the actual number injured is unknown. 6 Approximately 334,000 people are admitted to US emergency departments annually with dog bite-associated injuries, and another 466,000 are seen in other medical settings. 6 An unknown number of other people who have been bitten do not sustain injuries deemed serious enough to require medical attention. Still another group of individuals is not represented by these data, those that incur injuries secondary to a bite or attempted bite. For example, a jogger may trip and break an arm while fleeing from a threatening dog. Of concern too are the demographics of typical dog bite victims. Almost half are children younger than 12 years old. [6][7][8] People more than 70 years old comprise 10% of those bitten and 20% of those killed. 9,10 Direct costs of dog bite injuries are high. The insurance industry estimates it pays more than $1 billion/y in homeowners' liability claims resulting from dog bites. 11 Hospital expenses for dog bite-related emergency visits are estimated at $102.4 million. 6 There are also medical insurance claims, workmen' s compensation claims, lost wages, and sick leave-associated business costs that have not been calculated. # Which dogs bite? An often-asked question is what breed or breeds of dogs are most "dangerous"? This inquiry can be prompted by a serious attack by a specific dog, or it may be the result of media-driven portrayals of a specific breed as "dangerous." 12,13 Although this is a common concern, singling out 1 or 2 breeds for control can result in a false sense of accomplishment. 14 Doing so ignores the true scope of the problem and will not result in a responsible approach to protecting a community' s citizens. Dog bite statistics are not really statistics, and they do not give an accurate picture of dogs that bite. 7 Invariably the numbers will show that dogs from popular large breeds are a problem. This should be expected, because big dogs can physically do more damage if they do bite, and any popular breed has more individuals that could bite. Dogs from small breeds also bite and are capable of causing severe injury. There are several reasons why it is not possible to calculate a bite rate for a breed or to compare rates between breeds. First, the breed of the biting dog may not be accurately recorded, and mixed-breed dogs are commonly described as if they were purebreds. Second, the actual number of bites that occur in a community is not known, especially if they did not result in serious injury. Third, the number of dogs of a particular breed or combination of breeds in a community is not known, because it is rare for all dogs in a community to be licensed, and existing licensing data is then incomplete. 7 Breed data likely vary between communities, states, or regions, and can even vary between neighborhoods within a community. Wolf hybrids are just that: hybrids between wild and domestic canids. Their behavior is unpredictable because of this hybridization, and they are usually treated as wild animals by local or state statutes. Wolf hybrids are not addressed by this program. Sex differences do emerge from data on various types of aggression. Intact (unneutered) male dogs represented 80% of dogs presented to veterinary behaviorists for dominance aggression, the most commonly diagnosed type of aggression. 1 Intact males are also involved in 70 to 76% of reported dog bite incidents. 7,15 The sex distribution of dogs inflicting unreported bites is not known. Unspayed females that are not part of a carefully planned breeding program may attract freeroaming males, which increases bite risk to people through increased exposure to unfamiliar dogs. Dams are protective of their puppies and may bite those who try to handle the young. Unspayed females may also contribute to the population of unwanted dogs that are often acquired by people who do not understand the long-term commitment they have undertaken, that are surrendered to animal shelters where many are destroyed, or that are turned loose under the misconception that they can successfully fend for themselves. 16 # Dog bite costs to a community Costs associated with dog bite injuries cannot be readily measured, because so many intangible quality of life issues are involved. This makes it more difficult for community councils to justify the time, effort, and expense necessary to institute a bite reduction program when compared to a new fire truck, street paving, or city park. Intangible costs include time spent by volunteer and paid community officials on animal-related issues, deterioration of relationships between neighbors, building appropriate medical support, citizens' concerns about neighborhood safety for children, homeowners' insurance costs within the community, and animal shelter support for unwanted pets. These are quality of life issues that ultimately determine the desirability of a community to its citizens and that can motivate proactive community officials to institute a prevention program. # This program Reducing the incidence of dog bites requires active community involvement; passive attention or a token commitment is not sufficient. By actively focusing on dog bite prevention, the State of Nevada was able to reduce the incidence of bites by approximately 15%. b Members of the Task Force represented a broad range of disciplines and designed the program presented here. It was recognized that the community approach must be multidisciplinary and that different communities will have different needs based on their level of commitment, preexisting programs, and available resources. Although the best results will be obtained by adopting the entire prevention program, the program is designed so that it may be adopted as a whole or in part. Either way, the goal remains to reduce the incidence of dog bites within communities and improve quality of life for their citizens. # Multidisciplinary and Multiprofessional Groups It is unlikely that a dog bite prevention program will begin in a complete vacuum. Typically, some formal program is already in place under the auspices of animal control, the health department, or local law enforcement. Efforts may also be under way by other groups such as educators or dog breeders. It makes sense to identify related activities to determine what needs are not being met, find likely sources of support or resistance, and avoid duplication of effort and potential turf battles (Appendix 1). c # Identify dog bite issues in the community Each community has a unique set of dog bite-related problems and its own approaches to confronting them. A central task is to identify these particular issues. The project begins by assessing the political landscape regarding dog bites and dog bite prevention. Before launching a program, it is useful to pinpoint the degree of current and potential support among corporate and community leaders as well as legislators and senior staff in the dog bite prevention program' s sponsoring agency. Recognize hot buttons-Crafting a program is easier if the objectives mesh with a highly visible community issue. For example, there may be public outcry about dog waste or a publicized dog attack. Such a situation may provide impetus for a campaign to support licensing and leash laws or ordinances pertaining to reporting dog bites. When community groups and the media have already invested in finding a solution to the dog bite problem, program organizers can dovetail their efforts and work collaboratively with these groups. Community interest-Knowing the degree of support that exists for a prevention program is important. The prior existence of a program suggests support, but this may not always be the case. The active support of a commissioner or health department head (local or state) is critical, because without his/her backing, a fledgling dog bite prevention program is vulnerable to shifting funding initiatives and political pressure. Public officials are influenced by vocal well-organized constituencies, so it is important to know what dog bite-related agendas are getting politicians' attention. It also helps to know whether any legislators have a strong interest in the dog bite issue. Dogs in the news-News accounts can provide clues as to how dog-related issues have played out over time. Compare these accounts with available statistical data and scientific assessments for reliability. # Identify potential partners, allies, support, and funding sources Determine which organizations in the community are likely to support program efforts or resist them. Some individuals and organizations will emerge as natural allies; some old hands will be glad to work with a new partner in the dog bite prevention field, and some will actively welcome a new focal point for dog bite prevention activity. Learning about various entities and their interest and involvement in dog bite control can help answer questions in the following areas. Community resources-Organizations, agencies, businesses, and individuals offering training, assistance, consulting, library or computer search capabilities, in-kind contributions, volunteer help, or supplemental funding must be identified. Currently available data-Before launching a major effort to collect dog bite data, it is wise to determine whether an assessment has already been done. Ask about reports related to injuries and costs from dog bites, surveys that include dog bite or dog ownership information, opinion surveys or other studies describing community perceptions about the need for dog bite prevention, and similar information. If possible, find out what happened to existing assessments and related recommendations. Knowing the history of previous evaluation and prevention efforts will help in development of a new program. If an assessment has been done, determine whether methods and conclusions are sound. # Legislation-It is important to know what inter- ventions (eg, leash laws, "dangerous" dog ordinances) have been previously introduced and their history of success. Individuals involved in these efforts may be valuable allies in new programs. In addition, current ordinances should be evaluated to determine whether enforcement or revision could increase their effectiveness. Barriers-Ownership of particular dog bite issues and potential turf battles should be confronted realistically. In addition, it must be acknowledged that a dog bite prevention program may attract opposition from groups on philosophical grounds (eg, groups that strongly support personal freedom argue that the gov-ernment should not mandate licensing of dogs). Clubs for specific breeds may not be supportive if they fear their breed will be singled out in a negative way. Barriers can be overcome by a fresh approach to old problems or by agreeing to carve out areas of responsibility among interested groups. Typically, there are many more problems than there are organizations to tackle them, so it makes sense to avoid attacking similar issues. # Develop an advisory council Obtaining community input can be as sophisticated as conducting public opinion surveys or holding focus groups to learn about what the community sees as pressing dog bite issues. More likely, there will be limited funds at the outset of the program, so more informal but also potentially valuable approaches may be required. These include meetings with potential partners and interested groups to learn about their constituencies' concerns. This type of informal interview can be a great help in uncovering key dog-related issues as perceived by the community. Talking with people in neighborhoods most affected by dog bite problems is important. For example, if there is a problem with dog bites in low-income neighborhoods, obtaining the views of people living there can help identify the nature of the problem and potential solutions. An advisory council or task force that represents a wide spectrum of community concerns and perspectives creates a source of support for program initiatives. Advisory groups provide guidance for a dog bite prevention program and may focus on specific high-priority dog bite issues. Although organizing and maintaining an advisory council is labor-intensive, it can substantially benefit the program. Members may be able to provide access to useful information that is not otherwise easy for the coordinator to obtain. Members can also identify ways in which the program can work with appropriate voluntary organizations and associations. People with experience in dog bite control can offer perspective about the program and help identify potential pitfalls as well as successful strategies. Participation by members representing community organizations builds a sense of ownership in the dog bite prevention program. Logistics in starting an advisory council include identifying organizations and individuals that should participate (Appendix 1), determining the size of the council, establishing a structure and operating procedures for the council and its regular meetings, assigning staff support, determining the relationship between the staff and the council, and reaching an agreement about key tasks. When community members and government officials work together to support the creation and development of a local task force, it enhances the group' s visibility and impact. To foster an involved and active advisory council, professionals agree that several criteria must be met. The number of participants should be kept manageable; 10 to 12 is a size that works well. If it is necessary to have more members for political reasons, breaking the group into smaller committees or working groups will improve the dynamics. For example, groups could coalesce around data issues, legislation and policy, and so on. Involving participants from the start in meaningful tasks will underscore that this is a productive group. In addition, people are more likely to support a program they participated in creating, because they have a sense of ownership. Because each community' s needs and priorities differ, the advisory council' s major tasks will vary. The advisory council or one of its working groups may consider the following activities: ? coordinating efforts among participating organizations ? developing an action plan ? establishing dog bite prevention priorities ? generating public and legislative support for dog bite control ? identifying dog bite reporting sources ? interpreting data ? identifying and obtaining resources for program activities (educational, financial, staffing) ? providing technical expertise for the program ? recommending goals and objectives for prevention It is recommended that the program be overseen by a paid coordinator. The program coordinator and other staff involved can contribute to the advisory council' s success by good meeting planning and preparation, regular communication with members, working with the advisory council chairperson to set the agenda, and helping to solve problems that threaten to derail the process. As with any volunteer effort, a dog bite prevention advisory council is likely to thrive if the coordinator nurtures its members with regular expressions of appreciation. # Infrastructure A coordinated effort is essential for success in any venture, and each individual or organization involved must have a clear sense of their/its responsibilities. Reducing the incidence of dog bites requires the cooperation of many groups, including animal control agencies, the human and veterinary medical communities, educators, departments of health, and the local licensing authority. Open and consistent communication is an integral part of an effective program, and one entity should be designated as the coordinating agency. A logical coordinating agency would be the health department or animal control. In addition, it is imperative that an appropriate agency be granted authority to conduct investigations and make recommendations. # Program coordinator As previously mentioned, dog bite prevention efforts should be assisted by a paid staff person. Because the diversity of input is so great, it is recommended that the office of the advisory council' s program coordinator be located within the municipality' s coordinating agency. Individuals, agencies, or organizations that come into contact with or are aware of a "dangerous" dog or risky situation should provide this information to the coordinator. The coordinator should then relay all information to the proper recipients. # Animal control agencies Animal control officers are the frontline in controlling animal bites. A well-resourced animal control agency is vital for public health and safety within any community. In some communities, animal control is a stand-alone agency. In others it is administered through the local city or county health director or is a subsidiary of the local police department or sheriff' s office. Wherever located, the functions of animal control within communities are multiple, including: ? training of animal control officers and ancillary personnel ? licensing of dogs and cats ? enforcement of leash laws, ordinances, regulations, and statutes ? control of unrestrained and free-roaming animal populations ? investigation of animal bite-related incidents ? administration of rabies quarantine programs after an animal bites ? bite data management, analysis, and dissemination regulation of "dangerous" animals ? educational outreach within the community regarding responsible ownership, spay/neuter programs, control of "dangerous" animals, rabies vaccinations ? coordination of efforts Larger communities often possess more resources to properly fund animal control agencies and provide adequate staff 17 and training; however, smaller animal control programs can also be effective, even when they operate on a limited budget. Dedicated personnel can accomplish much if they have community support, including support from law enforcement and the judiciary. # Preventive measures Preventive measures are designed to minimize risk and should be addressed by all communities. Control of unrestrained and free-roaming animals-Reasonable and enforceable laws or ordinances are required for good control of unrestrained or freeroaming animals ( Appendix 2 ). 18 Laws written to ensure that owned animals are confined to their property or kept on a leash make freeing a community of unrestrained and free-roaming animals easier. Although most dog bites occur on the property where the dog lives, unrestrained or free-roaming dogs do pose a substantial threat to the public. Enforcement of restraint laws is, therefore, essential if the incidence of dog bites is to be reduced. It is important to protect animal owners by providing an adequate amount of time for them to claim animals that have been impounded. Because of economic constraints, the current standard in the industry is 3 working days; however, 5 days may be more reasonable to ensure successful owner-animal reunions. Control of unrestrained and free-roaming animal populations requires an adequately staffed, trained, and funded animal control agency. # Licensing of dogs-The primary benefit of licens- ing animals is identification, should that animal become lost. Licensing also ensures rabies vaccinations are current, allows quick identification in case of a bite incident, and provides revenue to help offset the costs of administering the animal control program. An effective program can be a source of reliable demographic data as well. Vaccinations-Rabies vaccinations are normally a prerequisite for licensing dogs and cats, because they are an important control measure for a major public health concern. In addition to protecting pets, rabies vaccinations provide a barrier between infected wild animals and humans. Vaccination has reduced confirmed cases of rabies in dogs from 6,949 in 1947 to 126 in 1997. 19 Breed or type bans-Concerns about "dangerous" dogs have caused many local governments to consider supplementing existing animal control laws with ordinances directed toward control of specific breeds or types of dogs. Members of the Task Force believe such ordinances are inappropriate and ineffective. Statistics on fatalities and injuries caused by dogs cannot be responsibly used to document the "dangerousness" of a particular breed, relative to other breeds, for several reasons. First, a dog' s tendency to bite depends on at least 5 interacting factors: heredity, early experience, later socialization and training, health (medical and behavioral), and victim behavior. 7 Second, there is no reliable way to identify the number of dogs of a particular breed in the canine population at any given time (eg, 10 attacks by Doberman Pinschers relative to a total population of 10 dogs implies a different risk than 10 attacks by Labrador Retrievers relative to a population of 1,000 dogs). Third, statistics may be skewed, because often they do not consider multiple incidents caused by a single animal. Fourth, breed is often identified by individuals who are not familiar with breed characteristics and who commonly identify dogs of mixed ancestry as if they were purebreds. Fifth, the popularity of breeds changes over time, making comparison of breed-specific bite rates unreliable. Breed-specific ordinances imply that there is an objective method of determining the breed of a particular dog, when in fact, there is not at this time. Owners of mixed-breed dogs or dogs that have not been registered with a national kennel club have no way of knowing whether their dog is one of the types identified and whether they are required to comply with a breed-specific ordinance. In addition, law enforcement personnel typically have no scientific means for determining a dog' s breed that can withstand the rigors of legal challenge, nor do they have a foolproof method for deciding whether owners are in compliance or in violation of laws. Such laws assume that all dogs of a certain breed are likely to bite, instead of acknowledging that most dogs are not a problem. These laws often fail to take normal dog behavior into account and may not assign appropriate responsibilities to owners. Some municipalities have attempted to address notice and enforcement problems created by unregistered and mixed-breed dogs by including in the ordinance a description of the breed at which the ordi-nance is directed. Unfortunately, such descriptions are usually vague, rely on subjective visual observation, and result in many more dogs than those of the intended breed being subject to the restrictions of the ordinance. Animal control legislation has traditionally been considered a constitutionally legitimate exercise of local government power to protect public safety and welfare. Breed-specific ordinances, however, raise constitutional questions concerning dog owners' fourteenth amendment rights of due process and equal protection. 20 When a specific breed of dog is selected for control, 2 constitutional questions are raised: first, because all types of dogs may inflict injury to people and property, ordinances addressing only 1 breed of dog appear to be underinclusive and, therefore, violate owners' equal protection rights; and second, because identification of a dog' s breed with the certainty necessary to impose sanctions on the dog' s owner is impossible, such ordinances have been considered unconstitutionally vague and, therefore, to violate due process. # After a bite occurs It is important to have a well-defined postbite program in place to minimize physical and emotional pain for dog bite victims. This allows animal control personnel to work efficiently, protects animals that are victims of false allegations, and provides the judiciary with reasonable alternatives that address a variety of situations. State laws may dictate parts of this process. # Investigation of animal bite-related incidents- Any animal bite or incident must be thoroughly investigated and substantiated by an agent of the empowered investigating authority such as an animal control officer, police officer, or peace officer. Ideally, the investigating authority should be the same authority that enforces related ordinances or laws to give continuity and credibility to all investigations. Investigating officers must be given authority to perform their duties by statute or ordinance. Clear, concise, standardized information concerning the incident must be obtained to ensure its successful resolution and facilitate longterm data collection (Appendix 3). Postbite rabies quarantine programs-A healthy dog that is currently vaccinated against rabies and that bites a human should be examined by a licensed veterinarian to determine its health status. If no signs of illness compatible with rabies are detected, the dog should be quarantined. The Centers for Disease Control and Prevention has set the quarantine period for dogs, cats, and ferrets at 10 days, including the day of the bite. Vaccinated dogs can be allocated to 2 categories: those that have bitten a member of the immediate family and those that have bitten an individual outside the immediate family. Home quarantine can be considered for vaccinated dogs that have bitten a member of the immediate family, assuming the owner can confine the dog in a manner that prevents further exposure. Vaccinated dogs that have bitten a human outside of the immediate family generally should be quarantined at the local shelter or veterinarian' s office. At the end of the quarantine period, the dog should undergo a physical examination. In addition, interim evaluations are highly recommended. A dog that is not currently vaccinated against rabies and that bites a human should be considered a rabies suspect and be appropriately quarantined. Contact with the dog during the quarantine period should be strictly limited to individuals who have completed rabies prophylaxis and are up-to-date on serologic testing and booster vaccinations. Physical examinations should be conducted at the beginning and end of the quarantine period to determine the dog's health status. Quarantined dogs may be treated by a veterinarian, but rabies vaccines should not be administered to the dog until the quarantine period is complete. If at any time during the quarantine period the dog has signs of illness compatible with rabies, it should be humanely euthanatized and samples submitted for rabies testing. Records of all bites must be kept, including information specifically identifying the dog and owner. These should be crosschecked with each incident for evidence of a chronic problem. Identification and regulation of "dangerous" dogs-Certain dogs may be identified within a community as being "dangerous," usually as the result of a serious injury or threat. That classification, because it carries with it serious implications, should be well defined by law (Appendix 4). Any such definition should include an exclusion for justifiable actions of dogs. Procedures should be outlined that take into account the potential public health threat, are reasonable to enforce, and convey the seriousness of the situation to the owner. Although animal control officers or their statuary counterparts are responsible for collecting information, a judge or justice will hear evidence from animal control officers and the dog' s owner to determine whether that dog fits established criteria for "dangerousness." In some municipalities, a hearing panel comprising a cross section of private citizens hears alleged "dangerous" dog evidence and has been given the authority to declare a dog "dangerous" if deemed appropriate. Any declaration by a hearing panel, judge, or justice is subject to judicial review. A judge, justice, or hearing panel may promulgate orders directing an animal control officer to seize and hold an alleged "dangerous" dog pending judicial review. If a dog is determined to be "dangerous" by a judge, justice, or hearing panel, the owner of that dog is usually required to register the dog with the appropriate health department or animal control facility. The judicial process may also require the owner to follow other rigid requirements, including but not limited to permanent identification of offending dogs, training and assessment of dogs and owners, and having offending dogs spayed or neutered. Because the judicial branch is such an integral part of any enforcement action, the judiciary must assist during formulation of "dangerous" dog laws. If the judiciary is involved, its members will be aware of the process that must be followed to declare a dog "dangerous." In addition, they will be aware of steps that have already been completed and the options available when a particular case reaches the courts. # Bite Data Reporting Accurate and complete reporting of dog bites is an essential element of a bite prevention program. These reports are vital not only for case management and judicial review but for planning, implementing, and evaluating the status of the problem. Major goals of comprehensive dog bite data reporting include: ? accurately defining victim demographics to identify populations at greatest risk for bites and allow targeting of educational efforts ? defining dog and owner characteristics associated with higher risk so that an actuarial approach to the dog bite problem is possible (this facilitates effective program planning and proper targeting of control measures) ? defining high risk geographic areas at city, county, or neighborhood levels so that limited resources for animal control and public education can be appropriately deployed ? establishing baseline data so that the impact of specific elements of the bite prevention program can be assessed ? providing an accurate, detailed, unbiased, objective source of information for decision makers, media, and the public interested in the dog bite problem and its prevention ? providing critical information for proper management of dog bite cases What should be reported? At a minimum, a dog bite case should be defined as any medically-attended dog bite or any dog bite resulting in a report to an animal control or law enforcement agency. This would presumably cover those instances consuming public resources and would also include cases that may result in litigation. A number of data elements should be captured on a report form such that it is comprehensive in scope without placing unnecessary burdens on reporting agencies (Appendix 3). Fatal and severe dog attacks on humans have been associated with prior or concurrent attacks on pets or livestock, so it is important that communities also track those incidents. Maintaining records of incidents of menacing behaviors of owned dogs running at large in the community may be found useful in later legal actions. # Who should report? The goal is to report any medically treated dog bite or any bite resulting in a report to, or response from, an animal control agency, humane society with animal control responsibilities, or law enforcement agency. Therefore, the primary sources of data should be: ? animal control or law enforcement agencies responding to a dog bite complaint ? health professionals attending to a bite injury (hospital emergency staff, urgent care facility staff, private physicians, school or camp medical staff, medical staff of other entities such as military bases or reservations, and veterinarians) Recognizing that many dog bites go unreported, a comprehensive program to assess dog bite incidence should consider possible secondary sources of data. These may include: ? anonymous surveys of high-risk populations (eg, school-age children) that may clarify the true extent of risk in a community ? anonymous surveys of the public (eg, phone surveys) that can help document the extent of bite injuries and provide a basis for estimating the ratio of unreported to reported bites ? reports from professionals including veterinarians, animal behaviorists, dog trainers, groomers, and kennel operators who are informed of a bite incident (mandating that any or all of these professions report bites may be unrealistic given the potential legal consequences of identifying an animal as a biter) Reporting mandates are often inconsistent between jurisdictions or are poorly enforced. Current local and state reporting regulations should be reviewed, as should directives from health or veterinary officials. If current provisions are adequate, it may be necessary to implement procedures to reeducate professionals concerning their reporting obligations and periodically remind them of these obligations. When a failure to report is uncovered, it may be an opportunity to gain the attention of the professional, because sanctions may be imposed. # Who should receive reports? Reporting should be coordinated by one agency. Logical agencies to coordinate reports include animal control or the public health department. The coordinating agency, perhaps through the dog bite prevention program coordinator, must assume responsibility for maintaining all information and disseminating that information to other appropriate individuals or agencies (eg, veterinarians, physicians, the dog owner, and those involved in follow-up educational efforts). To insure consistency and compliance, regulations or procedures should unambiguously state to whom reports should be submitted and within what time frame the reports should be submitted. # Data management, analysis, interpretation, and dissemination Because multiple sources may report the same case, procedures should be in place to permit combination of data from multiple sources into a single report. Avenues should be developed for electronic submission of reports to assist in rapid response, to streamline reporting to higher levels of government, and to facilitate data analysis. Whereas disposition of individual incidents is the first goal for reporting, there is much to be learned from looking at the overall picture. Keeping information in an electronic database simplifies the latter. Data should be reviewed at regular intervals (no less than yearly) to determine whether the incidence and severity of dog bites is getting better, worse, or staying the same. Basic analysis consists of studying the characteristics of incidents # Education Education is key to reducing dog bites within a community. The list of those to be educated and those who may educate includes everyone who regularly comes into contact with dog owners and potential victims (eg, veterinarians, veterinary technicians and assistants, animal control officers, animal behaviorists, dog trainers, humane society personnel, physicians, school nurses, public health officials, teachers, and parents). The purposes of this section are to educate city officials and community leaders about the role of various professionals in an educational program to reduce dog bites, provide starting references to ensure a core of knowledge for those professionals (Appendix 5), and assist in identification of the educational needs of various constituencies within a community. # Public officials and community leaders Public officials and community leaders are the people to whom residents look for assistance with social problems. Their influence is important and well recognized. If a community dog bite prevention program is to gain public acceptance and be effective, community leaders must be well-informed about dogrelated issues within their community and in general. # Professionals Professionals from many backgrounds need to be involved in bite prevention programs. Their expertise is essential to making realistic decisions about what should and can be done to prevent or follow up on dog bite incidents and in recognizing what is normal or abnormal behavior for a dog. Several of these professionals will likely be members of the advisory commit-tee, but all should be encouraged to be a part of a community' s efforts to decrease the impact of a dog bite problem. Many professions mentioned in this document are science-based. This means their members are used to making decisions on the basis of peer-reviewed datasupported information rather than gut feelings. This approach to decision making results in improved outcomes. Because the dog bite problem impacts so many different groups, networking between community leaders and professionals is important. The following sections describe ways that various professionals and community leaders can work together toward a common goal. Veterinarians-Veterinarians are scientists trained for a minimum of 7 to 8 years and then licensed to diagnose and treat animal problems both medical and behavioral. Although most people think of veterinarians as performing animal vaccinations and surgical neutering, the practice of veterinary medicine includes all subdisciplines typically associated with human medicine. The study of animal behavior both normal and abnormal has become more important within the profession as animals have become more important to their owners. Dogs are now four-legged members of the family, rather than farm animals that help bring cows into the barn at milking time. With this change in the dog' s role have come unrealistic owner expectations about what constitutes normal behavior for a dog. Veterinarians can educate dog owners as to what behavior is normal, can help dog owners teach their dogs to respond appropriately in various environments and provide referrals to reputable dog trainers, and can assist owners with behavioral problems, including those that have a medical basis or are responsive to medication. Until recently, animal behavior was not often taught in veterinary curricula. Many veterinarians have had to acquire their knowledge of normal and abnormal canine behavior from continuing education programs and professional textbooks. For this reason, different veterinarians have different degrees of knowledge about behavior. All veterinarians, however, have access to board-certified veterinary behaviorists for help with behavioral problems beyond their expertise. Although the time, physical, and emotional demands of veterinary practice can be overwhelming and leave limited time to devote to a formal community prevention program, veterinarians can substantially impact prevention efforts through their professional contact with prospective and current dog owners. This contact should begin before the pet is acquired. Providing unbiased information on pet selection can help prevent inappropriate owner-dog pairings. Prospective dog owners often make spur-of-themoment selections that are based on warm-and-fuzzy feelings and unrealistic expectations. Encouraging prospective dog owners to seek information from their veterinarian about the characteristics and needs of various types of pets and encouraging future dog owners to ask for guarantees from puppy providers can minimize future problems. When owners take their newly acquired dogs to their veterinarian for an initial examination and immunizations, the veterinarian has a second opportunity to provide these owners with good medical, nutritional, and behavioral advice. 21 Finally, veterinarians can educate owners during their dogs' routine examinations (asking appropriate questions can reveal problems an owner may not have recognized) or when their dogs are evaluated for specific problems. # Board-certified veterinary behaviorists-The American College of Veterinary Behaviorists (ACVB), an American Veterinary Medical Association-recognized veterinary specialty organization, certifies graduate veterinarians in the specialty of veterinary behavior. To become certified, a veterinarian must have extensive postgraduate training, sufficient experience, and pass a credential review and examination set by the ACVB. Diplomates of this organization work with problem animals by referral from the animal' s regular veterinarian, consult with practitioners on cases, and give continuing education seminars on animal behavior. Although many communities may not have the benefit of a resident board-certified veterinary behaviorist, veterinarians have access to and may consult with their specialist colleagues when necessary. Veterinary technicians-Veterinary technicians are integral members of the veterinary health care team who have been educated in the care and handling of animals, basic principles of normal and abnormal life processes, and routine laboratory and clinical procedures. They perform many of the same tasks for veterinarians that nurses and others perform for physicians. Veterinary technicians are often frontline people when it comes to educating pet owners, particularly in general veterinary practices; they greet clients and answer initial inquiries, clarify instructions, provide clients with appropriate print, audio, and video educational material, and answer questions. Certainly, they are an important part of the educational team when it comes to dog bite prevention. Like veterinarians, veterinary technicians have several opportunities to educate clients. Veterinarians may be consulted prior to owners acquiring a new pet, and veterinary technicians can help provide information on appropriate pet selection. Veterinary technicians regularly counsel owners during new puppy appointments, and this is a particularly good opportunity to provide owners with information on bite prevention, including the importance of socialization and training. Routine physical examinations are times when veterinary technicians can reinforce the importance of these early lessons and training, and they can help veterinarians identify potential aggression problems through observation and dialog with owners. Veterinary technicians can also be tapped to educate nonpet-owning children and adults through school or other programs. Veterinary technology programs do not always offer curricula in animal behavior and, consequently, many technicians do not have formal training in this area when they enter practice. Continuing education that includes basic principles of animal behavior is essential for veterinary technicians, just as it is for their employers. Maintaining a clinic reference library of appropriate print, audio, and video material for reinforcement and enrichment and for client education is useful. Behavioral education for veterinary technicians relative to dog bite prevention should include recognition of classic canine behavioral displays and an understanding of the basic types of canine aggression and their prevention. The aim is to assist technicians in conveying dog bite prevention information to owners. Veterinary technicians must not be placed in the role of diagnosing or treating canine aggression. Animal behaviorists-There are a number of scientists with PhD degrees in academic fields related to animal behavior who can serve as valuable resources for communities attempting to reduce dog bite injuries. Because of their science-based backgrounds, they can be particularly helpful in setting up protocols to determine the extent of the problem within a community and whether ongoing programs are having a substantial impact. As a note of caution, the terms animal behaviorist or animal psychologist are often used by individuals who do not have strong scientific backgrounds but who want to work with problem dogs. There is no method to evaluate the competence of these individuals, and they may be more harmful than helpful to a community' s efforts. Dog trainers-This is a diverse group of individuals with no uniformly recognized credentialing body or measures of competence. Although there are many good dog trainers, there are also trainers that use inappropriate methods of behavioral modification that can negatively affect a dog' s behavior, making the dog more dangerous to the owner and the community. It is important that communities make a concerted effort to work with responsible trainers who interact closely with veterinarians and PhD-degreed animal behaviorists. A qualified responsible dog trainer can be a valuable asset to a community advisory group. Obedience training by itself does not prevent the development of behavior problems, 22 and animals that are sent to a training facility may not learn how to obey their owners, because the owners do not learn how to give commands. For problem animals, training is only part of the solution. Physicians and nurses-With a dog residing in 1 of every 3 US homes and approximately 53 million dogs in the United States, 2,3,6 exposure of the physician or nurse, their family members, or their patients to dogs during the course of daily life is inevitable. Dogs have become important members of many families, and the presence of a pet in the home can affect an individual' s own decisions about care. Most physicians are familiar with at least 1 example of a person refusing hospitalization, because there was no one else in the home to care for their pet. Because 334,000 Americans are seen in emergency departments for dog bite injuries each year, 466,000 are seen in other medical practice settings, and 6,000 are hospitalized, 6 it behooves human healthcare providers to acquaint themselves with community and personal strategies to prevent dog bites. Furthermore, just as occurrences of infectious diseases such as measles are reported to enable investigation of outbreaks and development of control measures to protect the public, dog bites must be reported so that cause and prevention can be addressed. Communities differ in their requirements for reporting, and practitioners must understand what is required in their area. Traditionally, when confronted with patients seeking care for dog bites, physicians and nurses have confined their roles to providing medical treatment. With the expanding roles of physicians and nurses, however, disease prevention has become an important issue. In addition to competently treating dog bites and their complications, healthcare providers need to be aware of critical roles they can play in reducing dog bite injuries. Advising patients about safe behaviors appears effective in preventing injury. [23][24][25][26] Teaching children, parents, and patients who own dogs about proper behavior around dogs and responsible dog ownership is advisable given the frequency of human-canine contact in our society. Physicians can recommend contacting a veterinarian for pet selection information and advice if an individual or family is considering dog ownership, and for information about canine behavior and obedience training if a dog is already part of the family. Pediatricians provide age-appropriate injury prevention counseling during wellness visits. 26 Dog bite prevention should be a part of this counseling. Dog safety tips can also be included in packets of materials routinely sent home with new mothers. When a patient is being treated for a bite, an opportunity exists to prevent future injury by teaching bite-avoidance strategies. Probing into the circumstances of the current bite may reveal which strategies should be emphasized. Taking advantage of teachable moments should be considered part of curative care. Consulting with a veterinarian may help human health care providers identify subjects they can address during postbite sessions. As witnesses to the health-related outcomes of dog bites, physicians and nurses are particularly credible sources of information and can be effective spokespersons. Pediatricians and nurses should be full partners in community efforts to reduce dog bite injuries. Animal control personnel-The staff of a wellresourced animal control program often includes an education coordinator who can train teachers, school nurses, and volunteers to become dog bite prevention educators within the community' s school system (similar to volunteers in the McGruff crime prevention program presented to primary-school children). For animal control personnel, job-related continuing education is important. Programs are available through the National Animal Control Association. Humane society/animal shelter/rescue group personnel-Dog bite injuries have negative repercussions for dogs as well as people, and humane society/animal shelter/rescue group personnel must deal with these issues. Dogs causing severe injuries may be brought to humane facilities for rabies quarantine or euthanasia. Dogs that have threatened to bite or that have nipped may be surrendered to shelters or rescue groups, sometimes without full acknowledgment by their owners. 16 Shelter personnel are forced to decide which dogs can be placed in new homes and which are not suitable for adoption. Progressive organizations work with veterinarians and animal control officers to educate their staff about safe dog handling and objective evaluation techniques. Record keeping and follow-up studies expand their knowledge base about what works in their community and what does not. Well-trained and dedicated humane society/animal shelter/rescue group personnel can be valuable community resources for public education as well. # Public Public education is critical to the success of any dog bite prevention program, because half of all bites are inflicted by the family dog. 27 Only about 10% of bites are inflicted by dogs unknown to the victim. 7,15 A public education effort must target a variety of individuals and age groups, and one individual should be assigned to integrate its components. If a special advisory council or task force is convened, its paid coordinator would be a logical choice to coordinate the public education effort. Alternatively, the public education coordinator could be a member of a municipal group such as the local health department, animal control agency, or board of education, or a member of a stakeholder group such as a humane society or veterinary association. Many educational programs targeted at various audiences exist and are included in the dog bite prevention resource list found on the American Veterinary Medical Association Web site (www.avma.org). As new materials become available, they will be added to this resource list. Children-Children are the most common victims of serious dog bites. Seventy percent of fatal dog attacks and more than half of bite wounds requiring medical attention involve children. 7,9,15 In addition, almost half of all children are bitten before 18 years of age. 27,28 The most vulnerable youngsters are 5-to 9year-old boys, 6,7,8 but smaller children can also be seriously injured. 29 Dog bite injuries rank third only to bicycle and baseball/softball injuries as a leading cause of emergency admission of children to hospitals. 6 Children's natural behaviors, including running, yelling, grabbing, hitting, quick and darting movements, and maintaining eye contact, put them at risk for dog bite injuries. Proximity of a child' s face to the dog also increases the likelihood that facial injuries will occur. 6,7,[29][30][31] Target group-The first step in a child education effort is determining what population of children to target and when. The logical primary audience is those at greatest risk: children in grades kindergarten through 4. Late winter or early spring appears to be the best time to institute a campaign, because the school year is concluding and, as children spend more time outside, exposure risk increases. 32 It is critical that school administrators buy into the concept of a dog bite prevention program; therefore, requests to the school district must be made by committed convincing well-organized individuals. Because school curricula are crowded, time blocks for dog bite prevention education should be requested early within the school system' s calendar year. If such a block of time is not available, an alternative is to have a veterinarian or physician present a 1-hour lecture or assembly program to the entire student body. Once dog bite prevention education has been included within the curriculum (or has been scheduled to be provided through a special lecture or assembly program), teachers, nurses, and volunteers should consider addressing the school's parent-teacher organization to inform parents of upcoming dog bite prevention training for their children. Secondary efforts-Secondary targets include children in other settings, such as early education programs (eg, Head Start, day care centers, recreational centers, and camps). Identifying instructors-Who teaches the material will depend on expertise within the community. For classroom instruction, teachers who have had in-service training, school nursing staff, health educators, or trained volunteers are logical choices. Stakeholder groups (eg, veterinarians, veterinary technicians, animal control officers, physicians, nurses, humane society staff) may provide a ready source of volunteers for classroom instruction and special programs. Adults-Adult citizens must understand the need for and support a strong dog bite prevention program not only for their own safety but for the safety of others in their community. It is this understanding that gives a prevention program long-term stability. All adults should learn appropriate behaviors around dogs so that they can protect themselves, teach their own children, serve as an example for others, and reinforce appropriate behaviors in other children at every opportunity. Adults also serve as local eyes for animal control so that roaming dogs are controlled. Educational materials sent home with school children, distributed by pediatricians during well-child visits, inserted in public utility bills, and produced by an enlightened local media are all reasonable approaches. Involving representatives of service organizations and community groups during a prevention program' s planning and active stages will strengthen commitment. Active adults (eg, joggers, bicyclists, golfers) whose outdoor activities provide greater exposure to dogs are most at risk for injury. To reach these individuals, bite prevention information should be provided to local interest groups, recreational facilities, and health clubs. Target group-Primary adult targets within the community are those who have children and who are active in outdoor activities. # Secondary efforts-Secondary targets include individuals between the ages of 21 and 65 years. Identifying instructors-Materials can be developed or selected by animal control personnel, veterinarians, veterinary technicians, or other people knowledgeable about dog behavior. Information can be distributed through a number of channels such as those identified above. The elderly-As people age, they become more susceptible to injury and disease. Thinning skin increases risk of bruising, and a bite producing a simple puncture wound in a younger individual can cause a severe laceration in a senior citizen. Sensory perception decreases so that an elderly person may not see a threatening dog or may not be able to read its behavioral signals accurately. In addition, diminished motor skills mean that the elderly are less able to physically protect themselves or escape. Another concern for the elderly is that their beloved pet may not be trustworthy around their grandchildren. Dogs not raised around small children or not frequently exposed to them may not be socialized toward them. 1 This increases the likelihood of aggressive behavior being directed toward these children. An educational program for senior citizens can be implemented in various settings. Materials may be provided through community services for the elderly such as church groups, visiting nurse programs, meals-onwheels, recreational centers, or travel groups. Secondary targets are shopping malls and the media. Trained volunteers, especially from dog-associated professions, are logical sources of information. Human healthcare professionals can be an important source of information for the elderly because of the frequency of their interactions. Target group-Primary targets are grandparents and people aged 60 years or older who have dogs in their homes. Secondary efforts-Secondary targets include other individuals who are at least 60 years old. Identifying instructors-Physicians can interact with these people during clinic visits. Animal control personnel, veterinarians, veterinary technicians, and people knowledgeable about dog behavior can select or produce resource information. Animal owners-People who own dogs have a wide variety of views about their responsibilities. For some, dog care means providing food and water when the thought occurs to them. At the other end of this spectrum is the person who actively makes sure the pet is appropriately fed, well-trained, licensed, and healthy. Some individuals view dogs as disposable items that can be abandoned at any sign of trouble or expense. Once a community establishes acceptable standards for responsible ownership, dog owners must be informed of these expectations and related ordinances, and rules must be enforced. Owners and future owners must be educated about their unique set of responsibilities, which include appropriate pet selection, providing quality nutrition, housing, and medical care, compliance with confinement and licensing requirements, appropriate behavioral training, and supervision of interactions between dogs and children. Citizens must understand that pet ownership is an ongoing responsibility, not a passive activity. Dog owners can be provided with information through various avenues. Veterinarians and their staff are logical educators and distributors. Local dog clubs and trainers provide services to more conscientious owners. Businesses that sell pet foods and supplies should also be encouraged to provide bite prevention materials to their customers. Information can be distributed with utility bills, and animal shelters can provide classes for people who are considering acquiring a pet. Incentives for attendance at bite prevention classes could include reduced fees for licenses and coupons for vaccinations, food, and obedience classes. The most difficult group of dog owners to reach is those with minimal attachment to their pets. Although strong enforcement of local regulations will change some owners into former owners, most will continue to own dogs. Therefore, education should be an integral part of any enforcement program. A good working relationship with the judiciary is critical so that offenders of animal-related ordinances are required to take courses that emphasize responsible ownership. Target group-Primary targets are adults who already own dogs. # Secondary efforts-Secondary targets are adults who are considering getting a new dog. Identifying instructors-Information for this target audience can come from various sources, and its distribution should be approached in a number of ways. Animal control officers and members of the legal profession can describe what is expected regarding local regulations and the serious consequences if these regulations are violated. Veterinarians and their staff can educate owners about vaccinations, neutering, restraint, and other health care issues. Dog club members and trainers can assist by providing socialization and training instruction and can help educate owners about being good dog-owning neighbors. Victims-When someone becomes a dog bite victim, a teachable moment is created. How useful that moment becomes in preventing future incidents depends tremendously on the seriousness of the bite and the fear response of the victim. Scare-producing or threatening events are good times for dog bite prevention information to be conveyed. However, the time surrounding a serious injury is generally too emotionally charged to be of value for dog bite prevention education. Who provides information to victims depends, in part, on who is contacted about the incident. In addition to medical personnel, animal control' s investigative efforts usually require a home visit. Routine visits to a physician should include gathering historical information about the patient' s interactions with dogs to identify patients who would benefit from additional education. Media stories that reinforce correct approaches to prevention can also touch many when they are most receptive. Target group-Individuals who have recently been bitten by a dog seriously enough to require medical attention but not so seriously as to have sustained severe injuries are the primary target. Secondary efforts-Secondary targets are individuals who have been bitten by a dog in the past. Identifying instructors-Medical professionals and animal control personnel are the individuals who encounter this group. Businesses-Community businesses need to address dog bite prevention as well. Certain businesses (eg, veterinary clinics, grooming and boarding facilities, animal control, pet sitting agencies) revolve around direct contact with dogs, and employee education is critical from a safety and liability standpoint. Employees of other businesses will occasionally encounter dogs in the course of their daily job activities (eg, utility workers, police officers, parcel carriers, and emergency medical technicians). Training conducted by an animal control officer or other knowledgeable professional may provide employees with the tools they need to safely handle contacts with at-large animals, attack/guard dogs, or dogs who simply reside on the premises of those facilities where they do business. Target group-Primary targets are employees and business owners who will be working with dogs on a daily basis. Secondary efforts-Employees of companies who are likely to encounter dogs in their daily business activities can be considered secondary targets. Identifying instructors-Animal control personnel, veterinarians, veterinary technicians, and dog trainers who are experienced at dealing with dogs in a variety of environments. These individuals will need to customize presentations to the type of situations most likely encountered by the target audiences. # Media The local media play an important role in a community' s efforts at bite prevention. For this reason, it is suggested that 1 member of the advisory council or task force be a media representative. In addition, the advisory council can be proactive in helping the media convey important and appropriate messages. Sensational events provide an opportunity to convey important messages. Regular features can reinforce principles and keep educational efforts flowing. # Know the media Your key to the public eye and ear is a selective upto-date list of local media contacts who have an interest in animal issues. Such a list can be developed by undertaking a comprehensive media survey. Check the local library for publications that list names, telephone numbers, and short descriptions of your community' s media outlets. Call each office or studio to discover which desks or departments should receive your inquiries and press releases. Read local newspapers and listen to local radio and television news and feature programs to identify reporters and hosts who address animal issues. Finding out whether these individuals gather their own news or use wire services will allow you to target press releases and materials to those who are most likely to use them. Contact local freelance writers to see whether they would be willing to feature a bite prevention message in an upcoming piece. Be aware that your media list will be dynamic, and take time to update the names of specific contacts. Once a helpful story is published, or a reporter conveys your message during a broadcast, be sure to acknowledge that effort by sending a thank-you note or making an appreciative telephone call. # A spokesperson The community should identify a spokesperson who has the expertise to address complicated dog biterelated issues, and this individual should be provided with media training so that he/she becomes an effective communicator with the print and broadcast media. It is the spokesperson' s responsibility to convey information clearly, accurately, and promptly. In various situations, this individual can identify when there are not enough animal control officers to prevent dog packs from forming or when a dog has been "sicced" on a person as a weapon. A knowledgeable and effective communicator can turn a publicized bite into a learning opportunity by providing suggestions on how that bite could have been prevented (eg, the dog was not appropriately controlled or confined, or a child was left unsupervised). # Have information readily available The advisory council or task force should create a 1-page fact sheet for use by the media and the spokesperson. This fact sheet should include the number of dog bite incidents occurring in the community during the past year, the number of dogs in the community, the number of licensed dogs in the community, what local laws govern dog ownership and control, and to whom problems should be reported. A list of community resources should also be available. # Ways to effectively convey information Because animal stories are popular with the media, there are numerous opportunities to convey bite prevention information. Local broadcast programs and newspapers find regular segments about animals popular with viewers/listeners/readers, and most of those spots have enough time for short lessons. Another approach is to proactively bring animal stories to the media. Examples include a story about a shelter dog that visits nursing homes after being rescued and appropriately trained, a description of a guide or "hero" dog' s training, or warm-weather tips for pets. Effective mechanisms for providing information vary with the medium but include: News releases-Releases may be provided to print, radio, or television outlets. Releases should be double-space typed on stationery that provides the source of the announcement (ie, the advisory council or task force). Include the subject of the news release and contact information in the upper left corner. The mailing date of the release should be indicated along the right margin. The release should be written in inverted pyramid style, placing the most important information at the beginning. Releases should be limited to 1 page if possible. Interviews-Interviews may be conducted by print, radio, or television reporters or hosts and, in the case of television and radio, may be live or taped. The individual being interviewed must be an excellent communicator and intimately familiar with dog bite issues and prevention. The interviewee may request a preinterview to get a grasp of the direction of the interview. It is advisable to tell the interviewer which issues you would definitely like to see addressed. Answers should be structured according to the program' s time limits. Talk shows-Most of the principles that apply to interviews also apply to talk shows, but in this situation there usually will be interaction with guests (who often hold opposing views), potentially with an audience, and with the host. Running through mock discussions prior to participation is helpful. Responses to questions or comments from those with opposing views should always be factual, sincere, and polite. Public affairs programs-Many stations air 2 or 3 programs a week in which the station' s news staff or station management interview a newsmaker, a spokesperson from an activist group, or a public relations representative from an industry. Issues in the news are often addressed by such programming. These provide a good opportunity to make your community aware of bite prevention efforts and to elicit support. Access to these programs may be requested by sending a letter to the station manager. # Bulletin board and community announcements- Many local television stations donate air time to announcements of community events. These are often broadcast in calendar format. This is an easy way to publicize educational events and responsible pet ownership classes. Editorials-Editorials are used by print, radio, and television reporters to present their views on issues of public interest. Prepared statements describing the advisory council' s approach to dog bite prevention can be provided to reporters for use in preparing an editorial or may be provided if a reporter presents an opposing viewpoint. Public service announcements-Many radio and television stations donate time for public service announcements (PSA); however, public service groups cannot specify when your PSA is to be aired. It is acceptable to suggest when you believe airing your PSA will be most effective. Most PSAs run for 30 to 60 seconds, although 10-and 20-second spots are also used. To mitigate the costs associated with production, you may want to contact local stations to see whether they offer sponsored placements, in which local advertisers donate time for specific public service messages. Public service announcements may consist of script only, sight and sound (simple or complex), or 16-mm film or videotape. # Appendix 2 # Model dog and cat control ordinance Originally produced and published jointly by the American Veterinary Medical Association, the American Humane Association, the Humane Society of the United States, and the Pet Food Institute in 1976. Modifications have been made from the original version to reflect updated US Public Laws, current titles of other referenced documents, and present favored terminology and definitions concerning "dangerous" animals. # Section 1. Definitions As used in this ordinance the following terms mean: Animal-For the purpose of this ordinance, animal shall mean dog or cat. Animal control authority-The person or persons designated to enforce this ordinance. Animal establishment-Any pet shop, grooming shop, animal auction, performing-animal exhibition, kennel or animal shelter, except this term shall not include veterinary medical facilities, licensed research facilities, facilities operated by government agencies, or licensed animal dealers regulated by the USDA under the provisions of US Public Laws 89-544, 91-579, 94-279, 99-198, and 101-624. Animal shelter-Facility designated or recognized by the [jurisdiction]* for the purpose of impounding and caring for animals. At large-A dog or cat shall be deemed to be at large when off the property of the owner and not under restraint. Humane manner-Care of an animal to include, but not be limited to, adequate heat, ventilation and sanitary shelter, wholesome food and water, consistent with the normal requirements and feedings habits of the animal's size, species, and breed. Kennel-An establishment kept for the purpose of breeding, selling, or boarding dogs or cats or engaged in training dogs or cats. Licensing authority-The agency or department of [jurisdiction] or any designated representative thereof charged with administering the issuance and/or revocation of permits and licenses under the provisions of this ordinance. Livestock guarding dogs-Dogs kept for the primary purpose of protecting livestock from predatory attacks. Neutered-Rendered permanently incapable of reproduction. Nuisance-A dog or cat shall be considered a nuisance if it: damages, soils, defiles, or defecates on private property other than the owner's or on public walks and recreation areas unless such waste is immediately removed and properly disposed of by the owner; causes unsanitary, "dangerous," or offensive conditions; causes a disturbance by excessive barking or other noise making; or chases vehicles, or molests, attacks, or interferes with persons or other domestic animals on public property. Owner-A person having the right of property or custody of a dog or cat or who keeps or harbors a dog or cat or knowingly permits a dog or cat to remain on or about any premises occupied by that person. Person-Any individual, corporation, partnership, organization, or institution commonly recognized by law as a unit. Pet shop-An establishment engaged in the business of buying or selling, at retail, dogs or cats or other animals for profit-making purposes. Restraint-A dog or cat shall be considered under restraint if it is within the real property limits of its owner or secured by a leash or lead or under the control of a responsible person. "Dangerous" dog or cat-A dog or cat that without justification attacks a person or domestic animal causing physical injury or death, or behaves in a manner that a reasonable person would believe poses an unjustified imminent threat or serious injury or death to one (1) or more persons or domestic animals. Written application for a dog or cat license shall be made to the [licensing authority] and shall include the name and address of the owner and the name, breed, color, age, and sex of the dog or cat. Applicants also shall pay the prescribed licensing fee and provide proof of current rabies vaccination. e. The licensing period shall be for ‡ year(s). License renewal may be applied for within sixty (60) days prior to the expiration date. New residents must apply for a license within thirty (30) days of establishing residence. f. A license shall be issued after payment of a fee of $____ for each unneutered dog or cat and $____ for each neutered dog or cat. § Persons who fail to obtain a license as required within the time period specified in this section will be subjected to a delinquent fee of $____ . g. License fees shall be waived for dogs serving the blind or deaf or government-owned dogs used for law enforcement. All other licensing provisions shall apply. h. Upon acceptance of the license application and fee, the [licensing authority] shall issue a durable license tag including an identifying number, year of issuance, city, county, and state. Both rabies and license tags must be attached to the collar of the dog or cat.II Tags must be worn at all times and are not transferable. [Licensing authority] shall maintain a record of all licenses issued, and such records shall be available to the [animal control authority]. Section 3. Permits a. No person shall operate an animal establishment without first obtaining a permit in compliance with this section b. The permit period shall begin with the first day of the fiscal year and shall run for one (1) year. Renewal applications for permits may be made within sixty (60) days prior to the expiration date. Application for a permit to establish a new breeding animal establishment under the provisions of this ordinance may be made at any time. c. Annual permits shall be issued upon payment of the applicable fee: i. For each kennel authorized to house less than six (6) dogs or cats $ ____ ii. For each kennel authorized to house six (6) but not more than forty-nine (49) dogs or cats $ ____ iii. For each kennel authorized to house fifty (50) or more dogs and cats $ ____ iv. For each pet shop $ ____ v. For other animal establishments $ ____ d. A person who maintains a kennel of six ( 6) or more dogs or cats for breeding purposes may pay an annual permit fee or may elect to license individual dogs or cats as provided under Section 2. Every facility regulated by this ordinance shall be considered a separate enterprise, requiring an individual permit. e. Under the provisions of this ordinance, no permit fee shall be required of any animal shelter. All other provisions shall apply. Any change in the category under which a permit is issued shall be reported to the [licensing authority] within sixty (60) days, whereupon reclassification and appropriate adjustment of the permit fee shall be made. f. Failure to comply with the provisions of this section is subject to a fine of $____. Section 4. Issuance and revocation of permits and licenses a. The [appropriate authority] may revoke any permit or license if the person holding the permit or license refuses or fails to comply with this ordinance, the regulations promulgated by the [appropriate authority] or any other law governing the protection and keeping of animals. b. If an applicant is shown to have withheld or falsified any material information on the application, the [licensing authority] may refuse to issue or may revoke a permit or license. c. It shall be a condition of issuance of any permit for an animal establishment that the [appro- priate authority] shall be permitted to inspect any and all animals and the premises where such animals are kept at any reasonable time during normal business hours. Where a permit is revoked for any cause, or pending appeal of any such action, the [appropriate authority] shall have power of entry on the premises and into all areas where animals are being kept. A person denied a permit may not reapply for a period of at least thirty (30) days. Each reapplication shall disclose any previous denial or revocation and shall be accompanied by a $____ fee. Section 5. Owner responsibility a. All dogs and cats shall be kept under restraint. b. Every "dangerous" dog or cat, as determined by the [appropriate authority], shall be confined by its owner within a building or secure enclosure and shall be securely muzzled or caged whenever off the premises of its owner. c. No dog or cat shall be allowed to cause a nuisance. The owner of every dog or cat shall be held responsible for every behavior of such dog or cat under the provisions of this ordinance. d. Failure to comply with the provisions of this section shall be subject to a fine of $_____. e. Dog and cat owners shall ensure that their dog or cat carries identification at all times in the form of microchip, tag, or other means to allow easy determination of the owners. f. Livestock guarding dogs shall be exempt from nuisance regulations when performing duties protecting livestock on premises owned or controlled by the owner. Section 6. Impoundment a. Any dog or cat found running at large shall be impounded by the [animal control authority] in an animal shelter and confined in a humane manner. Immediately upon impounding a dog or cat, the [animal control authority] shall make every reasonable effort to notify the owner and inform such owner of the conditions whereby custody of the animal may be regained. Dogs and cats not claimed by their owners within a period of [five (5) full days] ¶ in which the shelter is open to the public shall become the property of the [jurisdiction]. b. When a dog or cat is found running at large and its ownership is verified by the [animal control authority], the authority may exercise the option of serving the owner with a notice of violation in lieu of impounding the animal. c. In the event that the [appropriate authority] finds dogs or cats to be suffering, it shall have the right forthwith to remove or cause to have removed any such animals to a safe place for care at the owner's expense or to euthanatize them when necessary to prevent further suffering. Return to the owner may be withheld until the owner shall have made full payment for all expenses so incurred. d. Disposal of an animal by any method specified here in does not relieve the owner of liability for violations and any accrued charges. Section 7. Redemption a. Any animal impounded may be redeemed by the owner thereof within five (5) days upon payment of an impoundment fee of $____ , provided that if any such animal has been previously impounded, the impoundment fee shall be $____ . Payment of impoundment fees is not considered to be in lieu of any fine, penalty, or license fees. b. Any animal confined for rabies quarantine, evidence, or other purpose may be redeemed by the owner thereof upon payment of a fee of $____ . c. No animal required to be licensed or vaccinated under this ordinance may be redeemed until provisions for such licensing have been fulfilled. # Section 8. Adoption An adoption fee of $____ shall be assessed at the time of adoption. No dog or cat shall be released for adoption as a pet without being neutered or without a written agreement from the adopter guaranteeing that the animal will be neutered. Vaccination fees, licensing fees, and veterinary costs may be assessed above and beyond the adoption fee. # Section 9. Interference No person shall interfere with, hinder, or molest any agent of the [animal control authority] in the performance of any duty as herein provided. Any person violating this section shall be deemed guilty of a misdemeanor and shall be subject to a fine of not less than $____ or more than $____ . # Section 10. Repeals (conflicting ordinances) All other ordinances of the [jurisdiction] that are in conflict with this ordinance are hereby repealed to the extent of such conflict. # Section 11. Severability If any part of this ordinance shall be held invalid, such part shall be deemed severable and the invalidity thereof shall not affect the remaining parts of this ordinance. # Section 12. Applicability This ordinance shall be in full force and effect upon the expiration of days after its passage and publication. # Section 13. Safety clause The [jurisdiction] hereby finds, determines, and declares that this ordinance is necessary for the immediate preservation of the public health, safety, and welfare of the [jurisdiction] and the inhabitants thereof. *For all occurrences of [ ], communities should insert their applicable agency. †The organizations developing this model ordinance recommended that licensing tags show, in addition to the license number, the city or county and state in which the animal is registered. This helps to alleviate the problem of an animal being left unidentified or unclaimed because it has been transported from one state to another and has no reference to the issuing city or county on the license tag. ‡Where blanks are found without insertions, communities should insert applicable fees or conditions. §Differential license fees for neutered animals serve as an incentive for responsible pet ownership. IIBreakaway collars are recommended when tags are affixed to collars worn by cats. ¶It is recognized that holding periods will be determined to some degree by availability of facilities; however, it is important to ensure a reasonable opportunity for owners to reclaim their dog or cat. # Appendix 3 Recommended data elements for reports of dog bites # Data element Comment Notifications of dog attacks on humans. Continued on next page. # Appendix 4 Model legislation for the identification and regulation of "dangerous" dogs A. Actions allowed by authorized persons prior to hearing 1. If any dog shall attack a person or domestic animal who was peaceably conducting himself in any place where he may lawfully be, any person, for the purpose preventing imminent injury or further injury, may use such force as is required to stop the attack. 2. A police officer or peace officer acting pursuant to his statutory duties may, where the threat of serious injury to a person or domestic animal is imminent and unjustified, use such force as is required to prevent such injury. B. Definitions 1. a. "Dangerous dog" means any dog which without justification attacks a person or domestic animal causing physical injury or death, or behaves in a manner that a reasonable person would believe poses an unjustified imminent threat of serious injury or death to one or more persons or domestic animals. A dog's breed shall not be considered in determining whether or not it is "dangerous." Further, b. No dog may be declared "dangerous" i. If the dog was protecting or defending a person within the immediate vicinity of the dog from an attack or assault; ii. If at the time the person was committing a crime or offense upon the property of the owner, or custodian, of the dog; iii. If the person was teasing, tormenting, abusing or assaulting the dog, or in the past had teased, tormented, abused or assaulted the dog; iv. If the dog was attacked or menaced by the domestic animal, or the domestic animal was on the property of the owner, or custodian, of the dog; v. If the dog was responding to pain or injury, or protecting itself, its kennels or its offspring; vi. If the person or domestic animal was disturbing the dog's natural functions such as sleeping or eating. vii. Neither growling nor barking, nor both, shall alone constitute grounds upon which to find a dog to be "dangerous." 2. "Attack" means aggressive physical contact initiated by the dog. 3. "Serious injury" means any physical injury consisting of broken bones or a permanently disfiguring laceration requiring either multiple stitches or cosmetic surgery. 4. "Domestic animal" means any animal commonly kept as a pet in family households in the United States, including, but not limited to dogs, cats, guinea pigs, rabbits and hamsters; and any animals commonly kept for companion or commercial purposes. C. Hearing procedure 1. Any person may make a complaint of an alleged "dangerous" dog as that term is defined herein to a police officer or peace officer of the appropriate municipality. Such officers shall immediately inform the complainant of his right to commence a proceeding provided for in Paragraph 2, immediately below, and, if there is reason to believe the dog is a "dangerous" dog, the officer shall forthwith commence such proceeding himself. 2. Any person may, and any police officer, or peace officer acting within the scope of his statutory duties, shall make a complaint under oath or affirmation of an allege dangerous" dog as that term is defined herein to any municipal judge or justice. Thereupon, the judge or justice, or hearing panel subject to judicial review, shall immediately determine if there is probable cause to believe the dog is a "dangerous" dog and, if so, shall issue an order to any police officer or peace officer pursuant to his statutory duties or animal control officer directing such officer to immediately seize such dog and hold same pending judicial determination as herein provided. Whether or not the judge or justice, or hearing panel subject to judicial review, finds there is probable cause for such seizure, he shall, within five (5) days and upon written notice of not less than three (3) days to the owner of the dog, hold a hearing on the complaint. D. Where a dog is determined pursuant to clear and convincing evidence at a duly constituted hearing to be "dangerous," the judge or justice, or hearing panel subject to judicial review, shall require the owner of said animal to register such animal (with the appropriate Health Department or animal control facility), and to provide prompt notification to (the appropriate Health Department or animal control facility) of any changes in the ownership of the animal; names, addresses and telephone numbers of new owners; any change in the health status of the animal; any further instances of attack; any claims made or lawsuits brought as a result of further instances of attack; the death of the animal. In addition, the judge or justice, or hearing panel subject to judicial review, may require any or all of the following, but items 5, 6 and 11, or any one of them, may only be imposed where there has been serious injury to a person. 1. Indoors, when not alone, the dog be under the control of a person eighteen ( 18) years or older. (Provisions for the dog to be outdoors must also be made.) 2. Outdoors and unattended, the dog be kept within a locked fenced area from which it cannot escape. 3. When outdoors the dog must be attended and kept within a fenced area from which it cannot escape. 4. When outdoors the dog must be attended and kept on a leash no longer than six (6) feet and under the control of a person eighteen (18) years of age or older. 5. When outdoors the dog must be attended and muzzled. Such muzzle shall not cause injury to the dog or interfere with its vision or respiration but shall prevent it from biting any person or animal. 6. Outdoors and unattended, the dog must be confined to an escape-proof kennel of the following description: a. Such kennel shall allow the dog to stand normally and without restriction, and shall be at least two and one half (2.5) times the length of the dog, and shall protect the dog from the elements. b. Fencing materials shall not have openings with a diameter of more than two (2) inches, and in the case of wooden fences, the gaps shall not be more than two (2) inches. c. Any gates within such kennel or structure shall be lockable and of such design as to prevent the entry of children or the escape of the animal, and when the dog is confined to such kennel and unattended such locks shall be kept locked. d. The kennel may be required to have double exterior walls to prevent the insertion of fingers, hands or other objects. 7. Placement of a sign or signs of a description and in places directed by the judge or justice, advising the public of the presence and tendencies of said animal. 8. Attendance by the dog and its owner/custodian at training sessions conducted by a certified applied animal behaviorist, board certified veterinary behaviorist or other recognized expert in the field and completion of training or any other treatment as deemed appropriate by such expert. The owners of the dog shall be responsible for all costs associated with the evaluation and training ordered under this section. 9. Neutering or spaying of the dog at the owner's expense, unless medically contraindicated. 10. That the dog be permanently identified by tattooing or by injecting an identification microchip, using standard veterinary procedures and practices, identification number and the identification of the person performing the procedure to be registered with the (appropriate health department or animal control facility) as indicated above. 11. The procurement of liability insurance in an amount to be determined by the judge or justice, but in no case in an amount of less than fifty thousand dollars ($50,000), covering the medical and or veterinary costs resulting from future actions of the dog (a determination of liability shall be made in accordance with the laws of the jurisdiction). This condition may not be imposed if it is shown that no such insurance is available for a reasonable premium. 12. If any of the above conditions ordered by a judge or justice, or hearing panel subject to judicial review, are not complied with, the owner shall be subject to a fine of not more than ten thousand dollars ($10,000). 13. If a further incident of attack occurs under such circumstances that the dog, after a hearing as described above, is determined to be a "dangerous" dog, the judge or justice, or hearing panel subject to judicial review, may impose or reimpose any applicable directives listed above; additionally, humane destruction of the dog may be ordered, but only where the further incident involves serious injury to a person. # Appendix 5 Suggested reading for professionals (numbers correspond to cited references)	None	None
d18dac42cd9fb17d8f37e826aba3e51b838629f6	cdc	None	Mention o f the name o f any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health. Copies o f this and other NIOSH documents are available from# G L O S S A R Y Where possible, die definition is quoted from the appropriate American National Standards Institute (ANSI) standard, ANSI S l.1 -1 9 9 4 or ANSI S 3.20-1995 , under the tenn(s) used in that standard. E x c h a n g e r a t e : An increment o f decibels that requires the halving o f exposure time, or a decrement o f decibels that requires the doubling o f exposure time. For example, a 3-dB exchange rate requires that noise exposure tim e be halved for each 3-dB increase in noise level; likew ise, a 5-dB exchange rate requires that exposure tim e be halved for each 5-dB increase. F e n c e : The hearing threshold level above which a material impairment o f hearing is considered to have occurred. F r e q u e n c y : For a function periodic in time, the reciprocal o f the period. Unit, hertz (Hz) (ANSI S l.1 -1 9 9 4 : frequency). # H e a r i n g t h r e s h o l d l e v e l ( H T L ) : For a specified signal, amount in decibels by which the hearing threshold for a listener, for one or both ears, exceeds a specified reference equivalent threshold level. Unit, dB (ANSI S l.1 -1 9 9 4 : hearing level; hearing threshold level). # I m m i s s i o n l e v e l : A descriptor for noise exposure, in decibels, representing the total sound energy incident on the ear over a specified period o f tim e (e.g., months, years). I m p a c t : Single collision o f one mass in motion with a second mass that may be in motion or at rest (ANSI S l.1 -1 9 9 4 : impact). I m p u l s e : Product o f a force and the tim e during which the force is applied; more specifically, impulse is the time integral o f force from an initial tim e to a final time, the force being Noise Exposure I m p u l s i v e n o i s e : Impulsive noise is characterized by a sharp rise and rapid decay in sound levels and is less than 1 sec in duration. For the purposes o f this document, it refers to impact or impulse noise. I n t e r m i t t e n t n o i s e : N oise levels that are interrupted by intervals o f relatively low sound levels. # N o i s e : (1) Undesired sound. B y extension, noise is any unwarranted disturbance within a useful frequency band, such as undesired electric waves in a transmission channel or device. (2) Erratic, intermittent, or statistically random oscillation (ANSI S I .1-1994: noise). # N o i s e r e d u c t i o n r a t i n g ( N R R ) : The NRR, which indicates a hearing protector's noise reduction capabilities, is a single-number rating that is required by law to be shown on the label o f each hearing protector sold in the United States. Unit, dB. # P e r m a n e n t t h r e s h o l d s h i f t ( P T S ) : Permanent increase in the threshold o f audibility for an ear. Unit, dB (ANSI S3.20-1995: permanent threshold shift; permanent hearing loss; PTS). P u l s e r a n g e : Difference in decibels between the peak level o f an impulsive signal and the root-mean-square level o f a continuous noise. # S i g n i f i c a n t t h r e s h o l d s h i f t : A shift in hearing threshold, outside the range o f audiometric testing variability (±5 dB), that warrants followup action to prevent further hearing loss. NIOSH defines significant threshold shift as an increase in the HTL o f 15 dB or more at any frequency (5 0 0 ,1 0 0 0 , 2 0 0 0 ,3 0 0 0 ,4 0 0 0 , or 6000 Hz) in either ear that is confirmed for die same ear and frequency by a second test within 30 days o f the first te s t S o u n d : (1) Oscillation in pressure, stress, particle displacement, particle velocity, etc. in a medium with internal forces (e.g ., elastic or viscous), or the superposition o f such propagated oscillations. (2) Auditory sensation evoked by the oscillation described above (ANSI S I .1-1994: sound). # S o u n d i n t e n s i t y : Average rate o f sound energy transmitted in a specified direction at a point through a unit area normal to this direction at die point considered. Unit, watt per square meter (W /nr); symbol, I (ANSI S I .1-1994: sound intensity; sound-energy flux density; sound-power density). # S o u n d i n t e n s i t y l e v e l : Ten tim es the logarithm to the base ten o f the ratio o f the intensity o f a given sound in a stated direction to the reference sound intensity o f 1 picoWatt per square meter (pW/m2). Unit, dB; symbol, L (ANSI S I .1-1994: sound intensity level). S o u n d p r e s s u r e : Root-mean-square instantaneous sound pressure at a point during a given tim e interval. Unit, Pascal (Pa) (ANSI S I .1-1994: sound pressure; effective sound pressure). tu n e -d e p e n d e n t a n d e q u a l t o z e ro b e fo re th e in it ia l tim e a n d a fte r th e f in a l tim e ( A N S I S I . 1 -1 9 9 4 : im p u ls e ) . x rv # Glossary # S o u n d p r e s s u r e l e v e l : (1) Ten times the logarithm to the base ten o f die ratio o f the time-mean-square pressure o f a sound, in a stated frequency band, to the square o f the reference sound pressure in gases o f 20 micropascals QiPa). Unit, dB; symbol, L p . (2) For sound in media other than gases, unless otherwise specified, reference sound pressure in 1 pPa (ANSI S L 1-1994: sound pressure level). T e m p o r a r y t h r e s h o l d s h i f t : Temporary increase in die threshold o f audibility for an ear caused by exposure to high-intensity acoustic stimuli. Such a shift may be caused by other means such as use o f aspirin or other drugs. Unit, dB. (ANSI S3.20-1995: temporary threshold shift; temporary hearing loss). # T i m e -w e i g h t e d a v e r a g e ( T W A ) : The averaging o f different exposure levels during an exposure period. For noise, given an 85-dBA exposure lim it and a 3-dB exchange rate, the TWA is calculated according to the follow ing formula: TWA = 10.0 x Log(D/100) + 85 where D = dose. V a r y in g n o i s e : N oise, with or without audible tones, for which the level varies substantially during the period o f observation (ANSI S3.20-1995: nonstationary noise; nonsteady noise; time-varying noise). Occupational noise exposure shall be controlled so that worker exposures are less than the combination o f exposure level ( L ) and duration (7 ), as calculated by the follow ing formula (or as shown in Table 1 -1 ). # r(min)=^-M)/3 where 3 = die exchange rate. # . . 2 T i m e -W e i g h t e d A v e r a g e ( T W A ) In accordance with Section 1.1.1, the REL for an 8-hr work shift is a TWA o f 85 dBA us ing a 3-decibel (dB) exchange rate. # . . 3 D a i l y N o i s e D o s e When the daily noise exposure consists o f periods o f different noise lev els, the daily dose (D ) shall not equal or exceed 100, as calculated according to the follow ing formula: Noise Exposure d = [c ,/r ,+ c j t 2 + . . . + c y r j x 100 where C^-total tim e o f exposure at a specified noise level, and r , = exposure duration for which noise at this level becom es hazardous. The daily dose can be converted into an 8-hr TWA according to die follow ing formula (or as shown in Table 1-2 Noise Exposure 1 . 2 H e a r i n g L o s s P r e v e n t i o n P r o g r a m The employer shall institute an effective hearing loss prevention program (HLPP) de scribed in Sections 1 3 through 1.11 when any worker's 8-hr TWA exposure equals or exceeds 85 dBA. # . 3 N o i s e E x p o s u r e A s s e s s m e n t The employer shall conduct a noise exposure assessment when any worker's 8-hr TWA exposure equals or exceeds 85 dBA. Exposure measurements shall conform to the A m e r i c a n N a t i o n a l S t a n d a r d M e a s u r e m e n t o f O c c u p a t io n a l N o i s e E x p o s u r e , ANSI S 12. 19-199619- . N oise exposure is to be measured without regard for the wearing o f hearing protectors. # . 3 . I n i t i a l M o n i t o r i n g When a new HLPP is initiated, an initial monitoring o f the worksite or o f noisy work tasks shall be conducted to determine the noise exposure levels representative o f all workers w hose 8-hr TWA noise exposures may equal or exceed 85 dBA. For workers remaining in essentially stationary, continuous noise levels, either a sound level meter or a dosimeter may be used. However, for workers who move around frequently or who perform different tasks with intermittent or varying noise levels, a task-based exposure monitoring strategy may provide a more accurate assessment o f the extent o f exposures. # . 3 . 2 P e r i o d i c M o n i t o r i n g I f any worker's 8-hr TWA exposure to noise equals or exceeds 85 dBA, monitoring shall be repeated at least every 2 years. Monitoring shall be repeated within 3 months o f die occurrence when there is a change in equipment, production processes or maintenance routines. It may also be prudent to assess noise exposures when work practices have changed and/or i f workers are developing significant threshold shifts (see Section 1.6.4). # . 3 . 3 I n s t r u m e n t a t i o n Instruments used to measure workers' noise exposures shall be calibrated to ensure measurement accuracy and, at a m inim um , they shall conform to the A m e r i c a n N a t i o n a l S t In determining TWA exposures, all continuous, varying, intermittent, and impulsive sound levels from 80 to 140 dBA shall be integrated into die noise measurements. Chapter 1. Recommendations fa r a Noise Standard 1 A E n g i n e e r i n g a n d A d m i n i s t r a t i v e C o n t r o l s a n d W o r k Practices To the extent feasible, engineering controls, administrative controls, and work practices shall be used to ensure that workers are not exposed to noise at or above 85 dBA as an 8-hr TWA. The use o f administrative controls shall not result in exposing more workers to noise. 1 . 5 H e a r i n g P r o t e c t o r s Workers shall be required to wear hearing protectors when engaged in work that ex poses them to noise that equals or exceeds 85 dBA as an 8-hr TWA.- The employer shall provide hearing protectors at no cost to the workers. Hearing protectors shall attenuate noise sufficiently to keep the worker's "real-world" exposure (Le., the noise exposure at die worker's ear when hearing protectors are worn) below 85 dBA as an 8-hr TWA. Workers whose 8-hr TWA exposures exceed 100 dBA should wear double hearing protection (i.e., they should wear earplugs and earmuffs si multaneously)T o compensate for known differences between laboratory-derived attenuation values and the protection obtained by a worker in the real world, the labeled noise reduction rat ings (NRRs) shall be derated as follow s: (1) earmuffs-subtract 25% from the manufac turers' labeled NRR; (2) slow-recovery formable earplugs-subtract 50%; and (3) all other earplugs-subtract 70% from the manufacturers' labeled NRR. These derating val ues shall be used until such time as manufacturers test and label their products in accor dance with a subject-fit method such as method B o f ANSI S 12.6-1997, A m e r i c a n This recommendation should not be construed to imply that workers need not wear hearing protection unless their 8-hr TWAs equal or exceed 85 dBA For example, it would be prudent for a worker in and out of noise or habitually exposed to loud noise (e.g., 91 dBA for 1 hr and 59 min) to wear hearing pro tection while in noise-even though his or her dose was less than 100%. tThe intent of this section is not to advocate hearing protectors as die primary means of control; however, when engineering controls, administrative controls, and work practices cannot keep workers' exposures below 85 dBA as an 8-hr TWA, the use of hearing protectors shall he required For most TWA expo sures exceeding 105 dBA, hearing protectors will be necessary to supplement engineering and adminis trative controls. # N a t i o n a l S t a n d a r d M e t h o d s f o r M e a s u r i n g t h e R e a l -E a r A t t e n u a t i o n o f H e a r i n g Noise Exposure # . 6 . A u d i o m e t r y Audiometrìe tests shall be performed by a physician, an audiologist, or an occupational hearing conservationist certified by the Council for Accreditation in Occupational Hear ing Conservation (CAOHC) or die equivalent, working under the supervision o f an au diologist or physician. The appropriate professional notation (e.g., licensure, certification, or CAOHC certification number) shall be recorded on each worker's audiogram. Audiometrìe testing shall consist ofair-conduction, pure-tone, hearing threshold meas ures at no less than 500, 1 0 0 0 ,2 0 0 0 ,3 0 0 0 ,4 0 0 0 , and6000 hertz ( For permanent onsite testing facilities, ambient noise levels shall be checked at least an nually. For m obile testing facilities, ambient noise levels shall be tested daily or each time the facility is moved, whichever is more often. Ambient noise measurements shall b e obtained under conditions representing the typical acoustical environment likely to b e present when audiometrìe testing is performed. Ambient noise levels shall be re corded on each audiogram or made otherwise accessible to the professional reviewer o f the audiograms. # . 6 . 2 B a s e l i n e A u d i o g r a m A baseline audiogram shall be obtained before employment or within 30 days o f em ployment for all workers who must be enrolled in the HLPP. Workers shall not be ex posed to noise levels at or above 85 dBA for a mmimum o f 12 hr before receiving a baseline audiometrìe te s t Hearing protectors shall not be used in lieu o f the required quiet period. Chapter 1. Recommendations fo r a Noise Standard 1 . 6 . 3 M o n i t o r i n g A u d i o g r a m a n d R e # t e s t A u d i o g r a m A ll workers enrolled in die HLPP shall have their hearing threshold levels (HTLs) meas ured annually. These audiometric tests shall be conducted during the worker's normal work sh ift This audiogram shall be referred to as the ''monitoring audiogram." The monitoring audiogram shall be examined immediately to determine whether a worker has a change in hearing relative to his or her baseline audiogram. When the monitoring audiogram detects a change in the HTL in either ear that equals or exceeds 15 dB at 5 0 0 ,1 0 0 0 ,2 0 0 0 ,3 0 0 0 ,4 0 0 0 , or 6000 Hz, an optional retest may be conducted immediately to determine whether die significant threshold shift is persistent In most cases, die retest w ill demonstrate that the worker does n o t have a persistent threshold shift, thereby eliminating die need for a confirmation audiogram and followup action. I f a persistent threshold shift h a s occurred, the worker shall be informed that his or her hearing may have worsened and additional hearing tests w ill be necessary. 1 . 6 . 4 C o n f i r m a t i o n A u d i o g r a m , S i g n i f i c a n t T h r e s h o l d S h i f t , a n d F o l l o w u p A c t i o n When a worker's monitoring audiogram detects a threshold shift as outlined in Section 1.6.3, he or she shall receive a confirmation audiogram within 30 days. This confirma tion test shall be conducted under the same conditions as those o f a baseline audiometric te s t I f die confirmation audiogram shows die persistence o f a threshold shift, the audio grams and other appropriate records shall be reviewed by an audiologist or physician. I f this review validates the threshold shift, the threshold shift is considered to be a sig nificant threshold sh ift This shift shall be recorded in die worker's medical record, and die confirmation audiogram shall serve as the new baseline and shall be used to calculate any subsequent significant threshold shift. Whenever possible, the worker should re ceive immediate feedback on die results o f his or her hearing test; however, in no case shall die worker be required to wait more than 30 days. When a significant threshold shift has been validated, die employer shall take appropri ate action to protect the worker from additional hearing loss due to occupational noise exposure. Examples o f appropriate action include explanation o f the effects o f hearing loss, reinstruction and refitting ofhearing protectors, additional training o f die worker in hearing loss prevention, and reassignment o f the worker to a quieter work area. When die reviewing audiologist or physician suspects a hearing change is due to a nonoccupational etiology, the worker shall receive appropriate counseling, which may in clude referral to his or her physician. Noise Exposure 1 . 6 . 5 E x i t A u d i o g r a m The employer should obtain an exit audiogram from a worker who is leaving employ ment or w hose job no longer involves exposure to hazardous noise. The exit audiogram should be conducted under the same conditions as those o f baseline audiometry. 1 . 7 H a z a r d C o m m u n i c a t i o n 1 . 7 . 1 W a r n i n g S i g n s A warning sign shall be clearly visible at the entrance to or die periphery o f areas where noise exposures routinely equal or exceed 85 dBA as an 8-hr TWA. A ll warning signs shall be in English and, where applicable, in the predominant language o f workers who do not read English. Workers unable to read the warning signs shall be informed ver bally about the instructions printed on signs in hazardous work areas o f the facility. The warning sign shall textually or graphically contain the follow ing information: W A R N I N G N O I S E A R E A H E A R I N G H A Z A R D U s e o f H e a r i n g P r o t e c t o r s R e q u i r e d 1 . 7 . 2 N o t i f i c a t i o n t o W o r k e r s A ll workers who are exposed to noise at or above 85 dBA as an 8-hr TWA shall be in formed about the potential consequences o f noise exposure and the methods o f prevent ing noise-induced hearing lo ss (NIHL). When noise measurements are initially con ducted and confirm the presence o f hazardous noise, or when followup noise meas urements identify additional noise hazards, workers shall be notified within 30 days. N ew workers shall be alerted about the presence o f hazardous noise before they are ex posed to i t # . 8 T r a i n i n g The employer shall institute a training program in occupational hearing loss prevention for all workers who are exposed to noise at or above 85 dBA as an 8-hr TWA; the em ployer shall ensure worker participation in such a program. The training program shall be repeated annually for each worker included in the HLPP. Information provided shall be updated to be consistent with changes in protective equipment and work processes. # . 9 P r o g r a m E v a l u a t i o n Criteria The effectiveness o f the HLPP shall be evaluated at the level o f the individual worker and at die programmatic level. The evaluation at die worker level shall take place at die tim e o f the annual audiometry. I f a worker demonstrates a significant threshold shift that is presumed to be occupation ally related, all possible steps shall be taken to ensure that die worker does not incur ad ditional occupational hearing loss. The evaluation at the programmatic level shall take place annually. The incidence rate o f significant threshold shift for noise-exposed workers shall be compared with that for a population not exposed to occupational noise. Similar incidence rates from this com parison indicate an effective HLPP. Data for calculating an incidence rate for a popula tion not exposed to occupational noise should be drawn from Annex C in the A m e r i c a n # N a t i o n a l S t a n d a r d D e t e r m in a t i o n o f O c c u p a t io n a l N o i s e E x p o s u r e a n d E s t i m a t i o n o f N o i s e -I n d u c e d H e a r i n g I m p a i r m e n t y ANSI S3 . 44-199644- unless more ap propriate data are available. # . 0 R e c o r d k e e p i n g The employer shall establish and maintain records in accordance with die requirements in Sections 1.10.1 through 1.10.5. The employer shall establish and maintain an accurate record for each worker subject to die medical surveillance specified in Section 1.6. These records shall include, at a mini mum, die name o f die worker being tested; identification number; duties performed and job locations; m edical, employment, and noise-exposure history; dates, tim es, and types o f tests (i.e., baseline, annual, retest, confirmation); hours since last noise exposure be fore each test; HTLs at the required audiometric frequencies; tester's identification and assessment o f test reliability; the etiology o f any significant threshold shift; and the identification o f the reviewer. NIHL is caused by exposure to sound levels or durations that damage the hair cells o f the cochlea. Initially, the noise exposure may cause a temporary threshold shift-that is, a decrease in hearing sensitivity that typically returns to its former level within a few minutes to a few hours. Repeated exposures lead to a permanent threshold shift, which is an irreversible sensorineural hearing loss. Noise Exposure # . 6 S c o p e o f T h i s R e v i s i o n o f t h e N o i s e Criteria D o c u m e n t The focus o f this document is on the prevention o f occupational hearing loss rather than on conservation. ASHA makes a distinction between the tom s "impairment" and "handicap"; however, for the purpose o f die subsequent discussion in this criteria document, only the tom "material hearing impairment" is used. The Prince et al. paper reports the use o f a modified ASHA Task Force definition. This modification incorporates frequency-specific weights based on the articulation index for each fre quency . Negligible differences were found between excess risk estimates generated using die modified and the unmodified definitions. The excess risk estimates presented in this criteria docu ment are based on die unmodified ASHA Task Force definition. tHistorical note, ASHA did not deliberate on die definition proposed by the ASHA Task Force. Prince et al. found that the excess risk estimates at exposure levels below 85 dBA w oe not well defined. Insufficient data for workers with average daily exposures below 85 dBA led to considerable variability in the estimation, depending on the statistical assumptions used in the modeling. '1997-N10SH model for the 1-2-3-4-lcHz definition of hearing impairment ^¡confidence interval. # N o i s e E x p o s u r e T a b l e 3 -4 . C o m p a r i s o n o f m o d e l s f o r e s t i m a t i n g t h e e x c e s s r i s k o f m a t e r i a l h e a r i n g i m p a i r m e n t a t a g e 6 0 a f t e r a 4 0 -y e a r w o r k i n g f i f e t i m e e x p o s u r e t o o c c u p a t i o n a l n o i s e , b y d e f i n i t i o n o f m a t e r i a l h e a r i n g i m p a i r m e n t Average cxponre fcvd(4 BA) # .2 C e ilin g Limit Because NIOSH is recommending a 3-dB exchange rate with an 85-dBA REL, a ceiling limit for continuous-type noise is unnecessary. For example, with an 85-dBA REL and a 3-dB exchange rate, an exposure duration o f less than 28 sec would be allowed at a 115-dBAlevel. TTie generally accepted ceiling limit o f 140 dB peak SPL for impulsive noise is based on areportbyKryteretaL . Ward indicated that "this number was little more than a guess when h was first proposed. To date, a proposal for a different limit has not been supported. Henderson etaL indicated that the critical level for chinchillas is between 119 and 125 dB; and ifa20-dB adjustment is used to account for the difference in susceptibility between chinchillas and humans, the critical level extrapolated for humans would be between 139 and 145 dB. Based on the 85-dBA REL and the 3-dB ex change rate, the allowable exposure time at 140 dBA is less than 0.1 sec; thus, 140 dBA is a reasonable ceiling limit for impulsive noise. # .E x ch a n g e R ate Health 2. All noise exposures that produce a given TTS2 will be equally hazardous (the equal temporary effect theory). 3. Permanent threshold shift produced after many years of habitual noise exposures for 8 hr per day is about the same as the TTS2 produced in normal ears by an 8-hr exposure to the same noise. However, these CHABA postulates were not validated. Research has been unable to demonstrate a simple relationship between temporary threshold shift, permanent thresh old shift, and cochlear damage . The CHABA criteria assumed that worker exposures could be characterized by regularly spaced noise bursts inter spersed with periods that were sufficiently quiet to allow hearing to recover. However, this assumption is not characteristic o f many typical industrial noise exposures. Workers will always develop temporary threshold shift before sustaining permanent threshold shift, barring an ototraumatic incident Temporary threshold shift is a useful metric for monitoring the effects of noise exposure; these studies do not imply otherwise. In general, the CHABA hearing damage risk criteria proved too complicated for general use. Botsfoid published a simplified set of criteria based on the CHABA criteria. One o f the simplifications inherent to the Botsford method was the assumption that interruptions would be o f "equal length and spacing so that a number o f identical ex posure cycles would be distributed uniformly throughout the day." These interruptions would occur during coffee breaks, trips to the washroom, lunch, and periods when ma chines were temporarily shut down. One response to the evidence from the animal studies and certain field studies would be to select the 3-dB exchange rate but to allow an adjustment (increase) to the PEL for cer tain intermittent noise exposures, as suggested by EPA and Johansson et aL . This response would be in contrast to a 5-dB exchange rate, for which there is lit tle scientific justification. Ideally, if an adjustment is needed, the amount should be de termined by the temporal pattern o f die noise and the levels o f quiet between noise bursts. At this time, however, little quantitative information is available about these pa rameters in industrial environments. Therefore, the need for an adjustment should be clarified by further research. Although the 3-dB rule may be somewhat conservative in truly intermittent conditions, the 5-dB rule will be underprotective in most others. The 3-dB exchange rate is die method most firmly supported by the scientific evidence for assessing hearing impairment as a function o f noise level and duration, whether or not an adjustment is used for certain intermittent exposures. # .4 Im p u lsiv e N o is e The OSHA occupational noise standard states: "Exposure to impul sive or impact noise should not exceed 140 dB peak sound pressure." Thus, in this con text, the 140-dB limit is advisory rather than mandatory. This number was first proposed by Kryter et al. and later acknowledged by Ward as little more than a guess. NIOSH did not address the hazard o f impulsive (i.e., impulse or impact) noise, although NIOSH stated that the provisions o f the recommended standard in the criteria document were intended to apply for all noise. Although there is yet no unanim ity as to which criteria best describe die relationship between NIHL and exposure to im pulsive noise, either by itself or in die presence o f continuous-type (i.e., continuous, varying, or intermittent) noise, diere is an international standard that has become widely used by most industrial nations. This standard, ISO 1999, Acoustics-An Estimation o f Noise-Induced Hearing Impairment (ISO 1990], integrates both impulsive and continuous-type noise (and uses die 3-dB exchange rate of die equal-energy rule) when calculating sound exposures over any specified time period. NIOSH concurs with this # N o i s e E x p o s u r e approach and recommends that noise exposure levels be calculated by integrating all noises (both impulsive and continuous-type) over die duration o f die measurement Despite its simplicity, die equal-energy rule is not universally accepted as a method for characterizing exposures that consist o f both impulsive and continuous-type noises. Another approach favors evaluating impulsive noise separate from that o f continuoustype noise. Studies that would argue for this approach will be discussed first, followed by a discussion o f studies elucidating the rationale for the NIOSH position on the equalenergy rule. # . 4 . 1 E v i d e n c e T h a t I m p u l s i v e N o i s e E f f e c t s D o N o t C o n f o r m t o t h e E q u a l -E n e r g y R u l e In her evaluation o f the effects o f continuous and varying noises on hearing, Passchier-Vermeer found that the HTLs o f workers in steel construction works did not con form to the equal-energy hypothesis; that is, the hearing losses in these workers, who were exposed to noise levels with impulsive components, were higher than predicted. . The ob served and predicted values differed in that the observed hearing loss was smaller than predicted at the lower audiometric frequencies, but the observed hearing loss was greater than predicted at the higher audiometric frequencies. In their study of hearing loss in weavers, who were exposed to continuous noise, and drop-forge hammer men, # C h a p t e r S . B a s i s f o r t h e E x p o s u r e S t a n d a r d who were exposed to impact noise o f equivalent energy, Sulkowski et al. found that the hammer men had substantially worse hearing than the weavers. Thiery and Meyer-Bisch conducted a cross-sectional epidemiologic study at an automobile manufacturing plant The automotive workers were exposed to continuous and impulsive noises at ¿Acq^ ranging from 87 to 90 dBA. When their HTLs were com pared with those o f workers exposed to continuous noise at o f 95 dBA for the same exposure time, the automotive workers showed greater hearing losses at the 6000-Hz audiometric frequency than the reference population after 9 years o f exposure. compared at the4000-Hz audiometric frequency the HTLs of forest workers using chain saws and shipyard workers using hammers and chippers. The forest workers were exposed to continuous-type noise, whereas the shipyard workers were ex posed to impact noise. Starck et al. also used the immission model developed by Bums and Robinson to predict the HTLs for both groups. They found that the Bums and Robinson model was accurate at 4000 Hz for the forest workers; however, it substantially underestimated die HTLs at 4000 Hz for the shipyard workers. # Staxck et aL The studies described here provide evidence that the effects o f combined exposure to impulsive and continuous-type noises are synergistic rather than additive, as die equal- energy hypothesis would support One measure for protecting a worker from such syn ergistic effects would be to require that a correction factor be added to a measured TWA noise exposure level when impulsive components are present in the noise. The magni tude o f such a correction has not been quantified. The matter becomes more complicated when other parameters o f impulsive noise are considered. Noise energy does not appear to be the only factor that affects hearing. The amplitude, duration, rise time, number of impulses, repetition rate, and crest factor also appear to be involved . The criteria for expo sure to impulsive noise based on die interrelationships o f these parameters await the re sults o f further research. # . 4 . 2 E v i d e n c e T h a t I m p u l s i v e N o i s e E f f e c t s C o n f o r m t o t h e E q u a l - E n e r g y R u l e # . 4 . C o m b i n e d E x p o s u r e t o I m p u l s i v e a n d C o n t i n u o u s -T y p e N o i s e s # Instrumentation for Noise Measurement No single method or process exists for measuring occupational noise. Hearing safety and health professionals can use a variety o f instruments to measure noise and can choose from a variety o f instruments and software to analyze their measurements. The choice o f a particular instrument and approach for measuring and analyzing occupa tional noise depends on many factors, not die least of which will be die purpose for the measurement and the environment in which die measurement will be made. # . 1 . 1 F r e q u e n c y W e i g h t i n g N e t w o r k s The human ear is not equally responsive to all frequencies; it is most sensitive around 4000Hz and least sensitive in the low frequencies. The responses o f die sound level me ter are modified with frequency-weighting networks that represent some responses of the human ear. These empirically derived networks approximate die equal loudnessweighting networks or scales; some also have a B-scale. The A-scale, which approxi mates the ear's response to moderate-level sounds, is commonly used in measuring noise to evaluate its effect on humans and has been incorporated in many occupational noise standards. Table 4-1 shows die characteristics o f these scales. # . 1 . 2 E x p o n e n t i a l T i m e W e i g h t i n g A sound level meter's response is generally based on either a FAST or SLOW expo nential averaging. FAST corresponds to a 125-millisecond (ms) time constant; SLOW The correct use o f die microphone is extremely important in obtaining accurate meas urements. Microphones come in many types and sizes. A microphone is typically de signed for use in a particular environment across a specific range o f SPLs and frequencies. In addition, microphones differ in their directionality. For example, some are intended to be pointed directly at the sound; and others are designed to measure sound from a "grazing" angle o f incidence. Thus users should follow the sound level meter manufacturer's instructions regarding the type and size o f microphone and its ori entation toward a sound. Also, care should be taken to avoid shielding the microphone by persons or objects . When measuring a diffuse sound field, the person conducting the measurement should hold the microphone as far from his or her body as practical . "Meters that are set to integrate or avenge sound do not use either the FAST or SLOW time constant; they will sample many times each second. For a more detailed description o f exponential time weighting, re fer to Yeager and March . "Whenever the unit dB is used in sudiometric testing, it actually refers to dB HTL. # C h a p t e r 5 . H e a r i n g L o s s P r e v e n t i o n P r o g r a m s ( H L P P s ) T a b l e 5 -1 . C l a s s i f i a b l e f i r s t t a g s - a c r o s s 1 5 d a t a b a s e s - a n d f i r s t t a g s c l a s s i f i e d a s t r u e p o s i t i v e f o r e a c h o f t h e 8 -s h i f t c r i t e r i a # No criterion evaluated is best in every respect The relative merits o f each are tabu lated in # A v e r a g e s t o g e t h e r f r e q u e n c i e s t h a t v a r y in s u s c e p t i b i l i t y t o n o i s e X X U s e s a s h i f t m a g n i t u d e w i t h i n t h e r a n g e o f n o r m a l a u d i o m e t r i c v a r i a b i l i t y X Chapter 5. Hearing Loss Prevention Programs (HLPPs) # N o i s e E x p o s u r e unlikely to be affected by NIHL, but it may be useful as an indicator o f excess ambient noise in the audiometrie test booth and as an indicator o f the presence o f medical ear conditions sudi as conductive ear pathologies. The 6000-Hz audiometrìe frequency is one o f the three high frequencies (3000,4000, and 6000 Hz) at which hearing is most likely to be affected soonest and to die greatest degree by NIHL. This audiometrie fre quency is more susceptible than others to measurement variability if there is inconsis tent earphone placement If the immediate retest is not performed, NIOSH recommends that the significant threshold shift be confirmed by a followup test within 30 days o f the testing that showed the significant threshold shift This followup test is called the confirmation test and is preceded by a 12-hr quiet period. If the significant threshold shift is confirmed and later validated by an audiologist or physician, the confirmation audiogram should be the one with which all subsequent audiograms are compared. To comply with this recommendation and to provide m a x i m u m protection for workers and maximum documentation for employers, NIOSH advocates that audiograms be per formed on the following occasions: 1. Before employment or before initial assignment into a hearing hazard work area. # Annually for any worker whose noise exposure equals or exceeds 85 dB A as an 8-hr TWA (monitoring audiometry) . Annual testing may lead to a number o f retests if a significant threshold shill occurs. In addition, it may be a good practice to provide audiometry twice per year to workers exposed to more than 100 dBA, because die most susceptible 10% o f a population exposed to daily average noise levels of 100 dBA with inadequate hearing protectors could develop significant hearing loss well before the end o f 1 year . # At the # M o n i t o r i n g A u d i o g r a m s Monitoring audiometry shall be conducted no less than annually. Unlike baseline audio metry, these annual tests should be scheduled at the end of, or well into, the work shift so that temporary changes in hearing due to insufficient noise controls or inadequate use of hearing protection will be noted. The results should be compared immediately with the baseline audiogram to check for any change in hearing sensitivity. The collection of au diograms for later batch comparison with baseline audiograms in another location is an unacceptable practice because it does not afford the opportunity to conduct retests or to discuss the findings with workers in a timely manner. # . . 1 . 3 R e t e s t A u d i o g r a m s As good practice, NIOSH suggests that audiometry be repeated immediately after any monitoring audiogram that indicates a threshold shift o f 15 dB or more at 500, 1000, 2000,3000,4000, or 6000 Hz in either ear. The worker should be reinstructed and the headphones refitted before conducting the retest Those who employ the retest strategy The audiometric manager should be responsible for making whatever recommen dations he or she deems necessary and for seeing that they are carried out # . . 1 . E x i t A u d i o g r a m Audiometry should be conducted when a worker leaves employment or is permanently rotated out o f an occupational noise exposure at or above 85 dBA as an 8-hr TWA. This exit audiogram, like the baseline, should be performed after a minimum o f 12 hr of quiet The use ofhearing protectors as a substitute for quiet is not acceptable. NIOSH suggests that hearing tests be offered as a health benefit to workers who are not exposed to hazardous noise levels. The tests in these workers can be conducted early in the day^when it is not recommended that noise-exposed employees be tested for changes in hearing thresholds. In addition to providing a valuable internal control group for comparison to the noise-exposed workers, this policy elevates the perceived impor tance o f the HLPP for management and workers . 1. Requirements o fa n d rationale fo r the occupational noise standard. # 5 . 2 A u d i o m e t e r s Effects o f noise on hearing. This should cover both die audiometrìe effects (i.e., how noise effects show up on an audiogram) and die functional effects (i.e., the impact of NIHL on everyday life). Company policy fo r the elimination o f noise as a hazard, including noise controls al ready implemented or plannedfor thefuture. This topic is very important and helps ensure that workers do not accidentally interfere with control measures. # Hazardous noise # C h a p t e r 5 . H e a r i n g L o s s P r e v e n t i o n P r o g r a m s ( H L P P s ) In addition to these episodic training sessions, an ongoing educational process should be offered. HLPP personnel, especially die program implementor, should visit the work ers' jobsites to see how they are doing. They should talk to workers about the program when they meet them in the halls, at lunch, etc. Posters, bulletin boards, informational pamphlets, etc., can be used as a constant reminder of the importance that the company places on hearing conservation. Contests or awards for effective hearing conservation practices can be used to promote safe behavior Royster 1986,1990]; how ever, incentive programs should be planned and implemented with full worker partici pation or they may be perceived by the workers as manipulative attempts by management to control worker behavior . # .8 R e c o r d k e e p in g (C o m p o n e n t 7 ) Recordkeeping # .1 0 A g e C o rr ectio n NIOSH does not recommend that age correction be applied to an individual's audio gram for significant threshold shift calculations. Although many people experience some decrease in hearing sensitivity with age, some do not It is not possible to know who will and who will not have an age-related hearing loss. Thus, applying age correc tions to a person's hearing thresholds for calculation o f significant threshold shift will overestimate the expected hearing loss for some and underestimate it for others, because The adjustment o f audiometric thresholds for aging has become a common practice in woriceis- compensation litigation. In this application, age corrections reduce the amount ofhearing loss attributable to noise exposure, with a consequent reduction in the amount o f compensation paid to workers for their hearing losses. However common "age cor recting" is and regardless o f the extent to which it is applied, it is technically inappropri ate to apply population statistics to an individuaL Each age correctionnuinber is nothing more than a median value from a population distribution. In age-correcting an audio gram, the underlying assumption is that the individual value is given the 50th percentile, when in feet the 10th or 90th percentile may be the correct value. Thus age-correction formulas cannot be applied to determine with certainty how much o f an individual's hearing loss is due to age and how much is due to noise exposure. Age-correcting audiograms obtained as part o f an occupational HLPP are even less ap propriate. This is not a compensation issue. The purpose o f the program is to prevent hearing loss. If an audiogram is age corrected, regardless o f the source o f the correction values, the time required for a significant threshold shift to be noted will be prolonged. Delaying the identification o f a worker with a significant threshold shift is completely contrary to the purpose o f an HLPP. # Hearing Protectors A personal hearing protection device (or hearing protector) is any device designed to re duce the level o f sound reaching the eardrum. Earmufls, earplugs, and ear canal caps (also called semi-inserts) are the mam types ofhearing protectors. A wide range ofhearing protectors exists within each of these categories. For example, earplugs maybe sub categorized into foam, user-formable (such as silicon or spun mineral fiber), premolded, and custom-molded earplugs. In addition, some The OSHA methods arc a simplification o f NIOSH methods #2 and #3 . One problem inherent to using single-number descriptors of sound attenuation is the need to ensure that the resulting value does not sacrifice the estimated protection for the sake o f simplicity. Thus these calculations will typically underestimate laboratoryderived "long methods" for estimating sound attenuation. To get around some o f the limitations associated with NRR calculations, other methods have been developed for estimating hearing protector performance. The single-number rating method and the high-middle-low method may be used when a person needs to estimate performance more accurately than possible with the NRR but does not want to resort to octave-band To summarize, the best hearing protection for any worker is die removal o f hazardous noise from the workplace. Until that happens, die best hearing protector for a worker is die one he or she will wear willingly and consistently. The following factors are ex tremely important determinants ofworker acceptance ofhearing protectors and die like lihood that workers will wear them consistently: - Convenience and availability - Belief that the device can be worn correctly - Belief that the device will prevent hearing loss - Belief that the device will not impair a worker's ability to hear important sounds Foam: Crawfotd and Nozza Hachey and Roberts Lempert and Edwards Edwards and Green Edwards and Green Abel et aL A beletal. Behar Pfeiffer et aL Casali and Part Casali and Raric Berger and Kieper Premolded: Ultra-Fit Casali and Park Casali and Park Royster et aL V- 51R Royster et aL Abel et al. Edwards et al. Fleming Padilla [1976 Management procedures for workers identified with substantial hearing impairment need to be studied. They would include training in listening strategies, speech reading, and optimal utilization ofhearing aids. Research also needs to be directed at developing bearing instruments designed to help workers continue to function in noise while pro tecting bearing and enhancing communication. E-A-R Rehabilitation communication strategies need to be studied. Currently, if hearingloss-prevention service providers were to suggest that noise-exposed workers with NIHL could benefit from amplification, they would be fired. In such a hostile environ ment, it is very difficult to define, develop, deliver, and evaluate a rehabilitation program. Taylor # MTRODUCTION The most common goal for protecting workers from the auditory effects o f occupational noise has historically been the preservation o f hearing for speech discrimination. With tins protection goal in mind, the National Institute for Occu pational Safety and Health (NIOSH) defined hearing handi cap as a b ia u ra l avera g e o f hearing levels exceeding 25 dB at the ancfiometric test frequencies o f 1, 2, and 3 kHz and 0 5 , 1. and 2 kHz (NIOSH, 1972). Here, the term " bianral average" is used to identify die mean value for the left and right ears. Using these definitions, NIOSH (1972) estimated die excess risk o f hearing handicap as a function o f age, sound levels and duration o f occupational noise exposure. Excess risk, also known as percentage risk, is defined as the percentage o f individuals with hearing handicap among indi viduals exposed to daily 8^iour occupational noise exposure after subtracting die percentage o f individuals who would typically incur such a handicap doe to aging in an unexposed population. For a 40-year lifetime exposure to average daily (8-hour) noise levels o f 8 0 ,8 5 , and 90 dB in the workplace, NIOSH (1972) estimated the excess risk to be 3%, 15%, and 29%, respectively for the biaural average over 1, 2, and 3 kHz. Table I com pares die NIOSH (1972) excess risk estimates fo r die biaural average over 0.5, 1, and 2 kHz to those developed by other organizations at approximately the same time. Since the publication o f the 1972 NIOSH Criteria Docu ment, statistical methods for analyzing categorical data out comes have been improved to assess risk o f disease (Breslow and Day, 1980a). The aim o f this paper is to reevaluate the models used to generate excess risk estimates from data col lected for the NIOSH 1968-72 Occupational Noise and Hearing Survey (ONHS) (Lempert and Henderson, 1973). Using these newer statistical methods, the paper examines die relationship between exposure to noise and risk o f noiseinduced hearing handicap (NIHH) and highlights s e a s o f uncertainty in estimating risks. These results will be com pared to the 1972 NIOSH analysis (NIOSH, 1972) and to the ANSI S3.44 (ANSI, 1996) standard, which adopted the methods developed by die In te rn a tio n a l Standards Organiza tion (ISO 1971(ISO , 1990. The data collected in the NIOSH survey are o f continuing interest since they were obtained before hearing protection devices were widely used in the U.S. Observations by NIOSH investigators during sound level surveys and management's impressions o f their respec tive plants did not indicate that participating companies had policies req u irin g hearing protection use. Use o f protectors, if available at all, were left to the discretion o f the workers. No mass use o f hearing protectors was noted in any o f the companies surveyed (Cohen, personal communications, 1996). # L RELEVANCE TO COMPARABLE STUDIES OF NCMSE-MDUCED HEARING LOSS Several investigators (Robinson and Sutton, 1975;Royster and Thomas, 1979;NCHS, 1965;Robinson, 1970;Yexg e t a l-, 1978) have examined the relationship o f noiseinduced permanent threshold shift (NÏPTS) and occupational noise exposure. Studies similar to the NIOSH 1968-72 Noise Survey with respect to time period and methods of data collection include Baughn (1973), Passchier-Vermeer (1968 and Bums and Robinson (1970). These studies will be the main focus o f our review o f die relevant noise and hearing surveys from this period. These studies have been used by ISO 1999(1971) and ANSI S3.44 (ANSI, 1996 to estimate the risk o f N1HH or NIPTS. Table II presents major study characteristics o f each o f these studies. As shown in Table D, only die Baughn (1973) study did not screen their workers for otologic abnormalities. These studies report that their populations were restricted to work ers with daily constant levels o f steady state noise exposure for the entire length o f employment A review o f these stud ies' limitations has been addressed by Ward and Glorig (1975) and Yeig e t aL (1975). They include possible con tamination o f non-steady state noise exposure in the popula tion and small sample sizes for subjects exposed to continu ous steady state for daily sound levels below 90 dB. The Passchier-Vermeer report (1968) reviewed published studies and was not specifically designed to address criteria for a noise standard. The NIOSH study (Lempert and Henderson, 1973) was specifically designed to examine risk o f noise- NIOSH in 1972. The aim o f the survey was " to characterize noise exposure levels in a variety o f industries, to describe die hearing status o f workers exposed to such noise condi tions, and to establish a relationship between occupational noise exposure and hearing handicap that would be appli cable to general industry." Subjects for the study were re cruited through notices at industrial hygiene conferences and through the regional offices o f the UJS. Public Health Ser vice. All companies interested in participating were consid ered if certain priority considerations applied. These in cluded (1) existence o f a factory o r occupational noise conditions having noise levels relevant to developing noise standards and criteria, and (2) a work force with a wide range o f years o f exposure to sudi noise levels. The data collected in the survey included noise measure ments, personal background information, medical and oto logica! data and audiometrie examinations. Noise level mea surements (using Bruel-Kjaer Sound Level Meters) were taken at different areas o f each plant and tape recordings were used for laboratory analysis o f noise characteristics. A questionnaire was used to obtain information on each work er's jo b history, military service, hobbies, and medical his tory pertinent to ear abnormalities and hearing difficulty. An otoscopìe inspection o f the ears was also made, usually after die completion o f the questionnaire. Measurements o f hear ing levels (using a Rndmose RA-108 audiometer) for pure tone frequencies o f 0 .5 ,1 , 2, 3 ,4 , and 6 kHz in die right and left ears o f the workers were conducted in a Rndmose audio metrie travel van (model RA-113). Workers from noisy workplaces were always tested at die beginning o f their work s h ift For plants with less than 500 employees, the entire work force was tested. For larger plants, a random sample was selected. Individuals from each plant who worked in offices or other quiet work areas were also included in the survey to provide control data. # B. S c re e n e d popu latio n fo r a n a ly sis The survey population was " screened" to exclude indi viduals with prior noise exposure (from occupational and non-occupational sources) and medical or otologie condi tions that might affect a person's risk o f hearing loss, inde pendent o f occupational noise levels at the time o f the sur vey. Criteria for data exclusion included (I ) uncertainty in the noise exposure history or validity o f audiometrie tests and (2) evidence that hearing loss might have b e a i caused by factors other than occupational noise exposure (e^., military history, other non-occupational noise exposures, head trauma, other audiological/otologic medical conditions). Workers exposed to noise that was not continuous (e.g., dis crete impact sounds or noise with highly variable and unpre dictable levels) and all maintenance workers were also ex cluded. Due to die relatively small number o f females in the survey population, all analyses were limited to 1172 males (792 noise-exposed and 380 controls). # C. V ariable d efin itio n s # D e f i n i t i o n o f h e a r i n g h a n d i c a p The major outcome o f interest is hearing handicap, de fined as a biaural average hearing threshold level o f greater than 25 dB for a selected set o f frequencies. In tins analysis, the set o f frequencies includes (a) 0 .5 ,1 , and 2 kHz, (b) 1,2, and 3 kHz and (c) 1 ,2 , 3, and 4 kHz (heron denoted as 1 -4 kHz). The 1 -4 kHz frequency average was recommended by an American Speech-Language-Hearing Association (ASHA) Task Force (ASHA, 1981), which focused on die need to indude frequencies most affected by noise exposure. The ASHA Task Force recommended that percentage formu las should include hearing threshold levels for 1, 2, 3, and 4 kHz, with low and high fences o f 25 and 75 dB, representing 0 percent and 100 percent hearing handicap boundaries, re spectively (ASHA, 1981). In this analysis, the ASHA recom mendation was modified by calculating a weighted average across frequencies rather than an arithmetic average over the test frequencies o f 1 ,2 ,3 , and 4 kHz. Weights were assigned according to frequency specific articulation indexes (ANSI, 1969). The articulation index (AI) is a weighted fraction rep resenting (for a given listening situation) the effective pro portion o f the speech signal that is available (above a mask ing noise level o r hearing threshold) to a listener for conveying speech intelligibility (ANSI, 1969). Average hearing threshold levels (HTL^g) using the ar ticulation indexes as weights were calculated and then averaged over both ears: ____ h T L \| « W i K ~f~ I f l l^t W a H r L^t = W i + W2+ W i +W 4 (1) where, W, = 0.24, W2= 0 3 8 , W3= 0 3 4 , and WA= 0 2 4 are die weights at 1, 2, 3, and 4 kHz, respectively. This defini tion will be referred to as the 1-4 kHz AI average" defi nition o f NIHH. # . M e a s u r e m e n t o f n o i s e e x p o s u r e Daily 8-hour time-weighted average (TWA) noise exposure was estimated for each worker or worker group using (1) area survey samples, (2) interviews with workmen and supervisors to establish typical workday patterns and (3) time-study charts. These charts segmented the workday into a succession o f exposures at specific noise levels and for specified durations. Discussions with both management and workmen were necessary to determine changes in noise ex posure over the course o f many years. Consideration was given to variations in occupational noise conditions due to placement or relocation o f machinery and as well as changes in workers' work routine and locations. The reported noise 111 die 1972 NIOSH analysis, those exposed to noise for less d m 6 months were coded as "0" for duntioa of exposure. In die current analysis, con trols were coded as "0 for duration of exposure and exposed individuals with less than 6 months of exposure were given a value of 0-25. levels for the study population represent A-weighted eight hour TWA sound levels calculated assuming a 5 dB ex change rate (i.e., 5 dB increase in sound level is exchanged against a factor o f 2 in duration within the workday). All levels were measured with sound level meters set to " slow" response. The A-weighted daily noise levels were available on the 792 noise-exposed individuals but not available for the 380 controls. Although sound levels for the control popu lation were not recorded, they were reported to be below 80 dB (Lempert and Henderson, 1973). # . O t h e r c o v a r i a t e s Other covariates o f interest in this paper were age and duration o f exposure in years. Tbe risk o f hearing handicap was examined in relation to die covariates defined in Table m . For models that included categorical variables for age (reference: 17-27 years) and duration (reference: 0 -1 years), four indicator variables were created for different levels o f age and duration exposed (Table III). For models that in cluded continuous variables for duration exposed, all con trols were reassigned a duration value o f zero because it was assumed that duration has no effect on the bearing o f the controls. Exposed individuals with less than six months were coded as 0.25 years (midpoint between 0 and 0.5 years). Logistic regression models were used to analyze hearing handicap, defined as the proportion o f individuals whose biaural hearing level is greater than 25 dB for averages over selected frequencies. These logistic regression models were fit using the SAS LOGISTIC procedure (SAS Institute, Inc., 1989) and the nonlinear minimization (NLMINB) routine in S-PLUS (Statistical Sciences, Inc., 1993). Stratified contingency table analyses (Breslow and Day, 1980a) w o e performed to assess these data for qualitative evidence o f hearing handicap due to exposure to noise after controlling for age. The 2X2 contingency tables were strati fied by one year age groups and the prevalence o f bearing handicap among tbe three noise-exposed categories o f 80-84 dB, 85-89 dB, and 90-102 dB were contrasted to the preva lence among controls. One-sided tests for detecting increased rides were computed nsing Mantel-Haenszel methods. Fur ther details o f this method are found in Breslow and Day (1980a). The quantitative relationship between hearing handicap and the covariates (defined below) was modeled using logis tic regression methods (Breslow and Day, 1980b). These models can be expressed as e F i X ,a ,f i .- .L 0 ) P = MY=\\X)= l+eFtX:a^). where, p -the expected proportion with average hearing level greater than 25 dB (indicated by Y= I), given X. (Y = 0 indicates an average hearing level is less than or equal to 25 dB); X = a vector o f explanatory variables containing infor mation on age, sound level, and duration o f exposure; F(X;a;fi;^h0)=a+fil (Age) + , where LnE= A-weighted 8-hour TWA sound level for noiseexposed workers in dB; L)=parameter for nominal TWA sound level in control population in dB; shape parameter on dB effect; or-intercept parameter; 0i = slope coefficient for age effect; $ 2 , = the slope coefficient for die jth duration o f expo sure (years) interval, where 7 = 1,2,3 represent ex posure intervals o f 2 -4 years, 5 -1 0 years, and > 10 years o f exposure, respectively. # m o d e l d e v e l o p m e n t The first step in the analysis was to fit several hierarchi cal logistic regression models and compare nested models using likelihood ratio tests (LRTs) to identify which param eters significantly improved the fit to the data (Fienberg, 1987). The fit of the model to the data was evaluated using a likelihood ratio test and examining the log likelihood statis tic, G, which is defined by the expression where the summation is over all individuals in the sample (Breslow and Day, 1980b). In general, die lower the value o f G , the better the fit between die model and die data. Differences in G statistics for nested models may be interpreted as chi-squares (Breslow and Day, 1980b). To be consistent with the methodology used in the 1972 NIOSH Noise Criteria Document (NIOSH, 1972), the model was initially fit assuming that the sound level for die control population ( was 79 dB and the shape parameter ( ¿ ) was I. This was accomplished by first fitting models with main effects only and then adding interaction terms between (a) duration exposed and daily TWA sound level (L); (b) dura tion exposed and age; and (c) age and sound leveL These interaction terms tested whether there should be allowance for differing slopes by levels o f other variables. Models with linear main effect o f age, duration exposed, and sound levels were fit with an assumption that all control 8-hour TWA sound levels ( Lq) were 79 dB. This assumption was made because individual noise exposure data for controls were un available but were known to be less than 80 dB (Lempert and Henderson, 1973). Other models with categorical main ef fects o f age and duration were also examined. The final steps of the analysis involved further model refinements that in cluded (1) assuming there is a nondecreasing relationship o f prevalence with sound level and duration; (2) refitting func tional fbnns identified by the LRT strategy accordingly; (3) assuming more flexible models for incorporating the effects o f sound level by permitting the shape parameter (^) to vary; (4) permitting the control sound level (L^) to vary from 79 dB; and (5) conducting sensitivity analyses o f the impact o f critical assumptions. A final fonn o f the model was fit such that all the pa rameters (including Lq and ^) were solved for simulta neously. This model form was fit with the following restric tion: the control level, L^, was bounded at 55 dB and 79 dB. For the final model, a two-sided 90 percent confidence inter val was calculated for several noise levels nsing the paramet ric percentile bootstrap method (Efron and Tibshirani, 1986;Efron, 1982). The same restrictions on w o e applied to 1000 bootstrap samples generated to obtain the confidence limits for excess risk. Graphical displays o f bootstrap-based confidence limits were smoothed nsing localized linear re gression smoothers in S-PLUS (Statistical Sciences, Inc., 1993). # . E x c e s s r i s k e s t i m a t i o n Excess risk for a particular age is defined as die differ ence between the risk o f hearing handicap for the noiseexposed population, given exposure duration, and the expo sure sound level, (where > L<j), « id the risk o f hearing handicap among controls. The excess risk associated with exposure to noise evaluated at a given age was esti mated from logistic models using the following relationship: Excess R isk=Pi -Pi. Hence, excess risk is assumed to be equivalent to the in crease in risk o f hearing handicap associated with noise ex posure. # . S e n s i t i v i t y a n a l y s e s Sensitivity analyses were performed to examine how model assumptions may affect the results (ix. excess risk estimates). Assumptions evaluated in this analysis included (1) die shape o f the dose-response relationship; (2) the sound level, Lq, for the control population; and (3) the effect o f using different definitions o f hearing handicap. The first two issues were addressed during model development, where each assumption was varied while die other remained fixed. A comparison o f how excess risk estimates varied with different definition o f hearing handicap was also examined in this analysis. The new definition (1 -4 kHz A1 average) was compared to definitions previously used by NIOSH (1972)biaural hearing levels averaged over 1 -3 kHz and 0.5-2 kHz. The analyses o f different hearing handicap definitions were based on oar final model for each definition o f hearing handicap: the model in which the control sound level ( I q) and shape parameter (^) were simultaneously estimated. # L RESULTS Figure 1 shows the hearing threshold level distributions (10th, 50th, 90th percentiles) for different frequencies by age and sound level categories for exposed and control workers. All hearing thresholds shown are averages over the left and right ears. Data are classified into five age groups and three noise exposure categories (80-87 dB, 88 -9 2 dB, 92-102 dB). The boundaries for the age and sound level categories w o e selected to provide adequate sample size (Le., at least 30) in each cell. Sample sizes for the noise-exposed groups are provided for each graph with median exposure duration. The sample sizes for the controls are die same, within age groups (shown in top panel o f each col umn). The graphs show similar exposure durations within each age cell and increasing trends for median hearing threshold levels with age and sound level. In all cases, con trol bearing threshold levels are lower than the noiseexposed population. The tendency o f median hearing thresh olds to increase with increasing age and sound level is also illustrated. The spread o f the distribution (given by the 10th and 90th percentiles) is most marked at 3 and 4 kHz. Despite the limited amount o f data in the low exposure region, the M antel-Haenszel age-stratified analysis provided evidence o f positive excess risk associated with sound lew is ranging from 80 to 84 dB ip =0.02), as well as 85 to 89 dB (p= 0.02) and 90 to 102 dB (p < 0.001). Age was found to be a highly significant predictor o f hearing handicap d u e to noise whether it was modeled using a continuous variable ( - 2=211, d f-l) or a set o f categori cal variables (jr2=213, df=4). The fitted categorical effects for age suggested a linear trend (data not shown). This trend was also apparent when models including sound level and duration w o e f it Therefore, the simpler models with linear effects for age (as a continuous variable) were subsequently considered in the final models. The addition o f either years of exposure or sound level ( L^) significantly improved the fit erf the model containing age. The addition o f both terms further increased the goodness o f f it A statistically signifi cant interaction (^2=29.6. 20 years combined to > 10 years) and the model with separate parameters for each duration category. This sug gested that risks remain essentially flat after 10 years of ex posure, and that these two categories could be combined. This initial model was further refined to describe predicted risks o f hearing handicap as a nondecreasing function o f ex posure duration and sound level. The models also assume that the effects o f sound level depend on durations greater than or equal to two years. To test whether a linear sound level effect ( $ = I) ad equately described the relationship between noise exposure and risk o f bearing handicap, higher order terms for the sound level effect were tested in the analysis. Using a qua dratic sound level term for exposure (^= 2 ) appreciably im IV. Also shown are the results from fitting a final model in which the control value and the shape parameter were found to be 73 dB and 3.4, respectively (model 4, Table IV). Model 4 is denoted as the "best fitting model,' because it produced (be best fit to die data. These results indicate considerable vari ability in excess risk estimates depending on model form and is likely due to lade o f data at lower sound levels. H us was most marked at average daily sound levels less than or equal to 85 dB. Figure 3 presents excess risk estimates with smoothed 90 percent confidence limits for 65-year-old males with greater than 10 years o f exposure as a function o f sound level for the " best fitting model" (model 4). # A. S en sitiv ity a n a ly se s f . A s s u m p tio n r e g a r d in g c o n tr o l B -h o u r TW A m o u n d le v e ls To examine tbe sensitivity o f risk estimates to the as sumed sound level for the control group, the value o f L- was varied from 60 to 79 dB and optimum values o f tbe shape parameter, were estimated. As Lq is varied, there is very little variation in the log likelihood statistic, G , whereas the excess risk estimate for noise exposure at a level o f 80 dB varies between 0.06 and 2.9 (Table V). The results also show that the optimum value o f ^ decreases considerably as tbe assumed value o f I - increases. This analysis suggests that information regarding the distribution o f occupational sound levels within the control population is important in estimat ing the risk o f noise-induced handicap in noise-exposed populations. The variability of excess risk estimates below 85 dB seen in Fig. 3 may be attributed to the lack o f accurate Risk estim ai« «an be generated nsmg die following equation: L o g it \ T r iY > 25 dB HL)] » -5X 857 + 00612(Age) + (D urabon=l)K ( Le-L)/ (102-73) 1. where. /$ = 2^653, 3.989, and 6.4206, respectively, fotfte/i dotation o f exposure for 2-4 yean, 5-10 yean, and > 1 0 years, tespectively and y ii die AI-dgfcced faiaunl avenge over 1-4 kHz. For the l o t fitting no d rl, ÿ was estimated to be 1 4 and L- = 73 dB. The term (1 0 2 -7 3 ) in f e denominator o f fte coefficient describing the effect o f datation and w a d level, standardize- the exposure t e n « e h t o t die au» ¡mom capoaire equals one. This was done for ease o f comparison to « id i differing wrimm- for 1« and sound level data among control subjects and the sparseness of the data for workers exposed at sound levels below 85 dB. # . D e f i n i t i o n o f h e a r i n g h a n d i c a p To examine whether excess risk estimates varied by the definition o f hearing handicap used, we compared the 1 -4 kHz AI average definition to two other definitions using (he same fence ( > 25 dB HL), die unweighted biaural frequency averages o f 0 5 -2 kHz and 1 -3 kHz. All three definitions were examined using a model that included age and a dose metric effect defined as ( L^-tim e s duration catego ries (e.g., 2 -4 , 5 -1 0 , and > 1 0 years). The resultant esti mated shape parameters for the 0 i -2 kHz and 1 -3 kHz biaural averages were 4.5 and 4.9, respectively, with Lq equal to 55 dB for both. Under these models, excess risk estimates were affected by both die definition of hearing handicap and die age o f the worker. We also found that changing from the articulation index to a simple average o f 1-4 kHz did not substantially affect excess risk estimates (results not shown). For workers aged 65 years (with > 10 years of exposure), excess risks for the 1 -3 kHz definition are high»' than excess risk for the new definition, particularly for sound levels above 85 dB (Fig. 4A). However, among workers aged 45 with similar years o f exposure, excess risk estimates are similar for all sound levels for the 1-3 kHz definition and the new defini tion (Fig. 4B). For younger workers (aged 30 years) with 5 to 10 years o f exposure, excess risk estimates for the definitions that included 3 kHz and/or 4 kHz, are similar for all sound levels (Fig. 4C). # IV. DISCUSSION The results o f these analyses indicate that there is an excess risk o f noise-induced hearing handicap (NIHH) at 8-hour time-weighted average (TWA) sound levels greater than o r equal to 85 dB. The excess risk below 85 dB was not well defined in our analysis. However, the M antel-Haenszel test result suggests that there is a positive and statistically significant excess risk at levels between 80 and 84 dB. These findings also indicate two major areas o f uncer tainty for quantifying the risk o f noise-induced hearing handicap. The first concerns the sensitivity o f the analysis to the assumed sound level for the control group ( 1^). The second relates to the shape o f the dose-response relationship between the sound levels among the noise-exposed group (¿ me) , duration exposed, and the risk o f NIHH. Risk esti mates w o e found to vary considerably for values of below 85 dB, depending on the assumed control sound level (Lq ), and the shape parameter ( 0 ) for the sound level effect (e.g., linear, quadratic, or cubic) in the models. Sound Lawel to <B HG. 3. f a « 1 » risk (percent) of bearing (¿/-weighing. 1-4 kHz) and bootstrap-based 90% confidence limits from model 4 (Table IV) far 65-year-old males exposed far greater than 10 years to vatying levels o f noise ( L^) . The previous NIOSH (1972) estimate o f excess risk for a 40-year working lifetime o f exposure to noise was approxi mately IS percent at 85 dB. A linear regression model o f log bearing levels was used in the previous analysis (NIOSH, 1972) to estimate the risk o f hearing handicap. NIHH was defined as an average biaural hearing level greater than 25 dB based on unweighted averages o f 0 .5 -2 kHz o r 1 -3 kHz. The model described in the 1972 NIOSH criteria document (NIOSH, 1972) is mathematically equivalent to a probit model in which the risk o f a hearing level greater than 25 dB is o f interest The results from the previous NIOSH analysis (NIOSH, 1972) also appear to be consistent with the assump tion that the control group was exposed to sound levels near 79 dB. It is clear that models which include a quadratic or cubic effect for die sound level effect fit significantly better than the linear effect model and produce lower excess risk esti mates for sound levels below 85 dB than similar models used in the 1972 NIOSH analysis (NIOSH, 1972). As shown in Table IV, the point estimates o f excess risk at 85 dB from die quadratic and cubic models are 8 percent and 3 percent, re spectively. The quadratic and cubic models fit better than the linear model, mainly due to the effect o f sound level in the low exposure region. For sound levels less than or equal to 90 dB, the excess risk estimates from fitting a linear model (Table IV) are slightly higher than those in die NIOSH (1972) analysis. Thus, the disparity in excess risk estimates presented in Table IV may be attributed primarily to the different functional forms (i.e., shape o f the sound level ef fect) o f die fitted models. The logistic model used in this analysis assumes the existence o f a plateau in risk after 10 years o f exposure duration. The analysis comparing different indicators o f NIHH show that patterns o f excess risk as a function o f average daily sound level depend on age. Differences in excess risk were nominal for die 1-4 kHz average, irrespective o f whether HTLs were weighted by the frequency-specific ar ticulation indexes. These differing results by age may be attributable to the fact that the effect o f aging on risk of hearing handicap may overshadow any incremental increases in excess risk due to noise exposure. In the upper range o f duration and sound level, the dose-response curve shows signs of a plateau effect The analysis also suggests »hat the effect o f sound intensity and duration o f exposure is depen dent on frequency. Hearing damage at 3 and 4 kHz is ex pected to occur sooner than loss at lower frequencies (0 .5 ,1 , or 2 kHz). Definitions that exclude the higher frequencies tend to. be less sensitive to noise damage and may require longer durations o f exposure to a given sound level to see significant excess risks in die population. Figure 4A and B suggests that the most suitable defini tion o f hearing handicap may depend on the population char acteristics, such as age, exposure duration, and degree o f hearing handicap already accrued, as well as whether one chooses to identify preclinical or later stages o f hearing handicap. The addition of the most sensitive frequencies to a hearing handicap definition is a valid option if the goal is to have a measure that addresses both prevention and identifi cation o f hearing handicap A. Data lim itations The cross-sectional design o f this study presented limi tations for estimating die risk o f noise-induced hearing handicap. For example, the 8-hour TWA sound levels, ¿ NE^ were determined at one point in time and are assumed to be representative o f exposure over the entire length o f an em ployee's jo b experience. This may have introduced a sub stantial source o f error in the estimation o f . As a means o f reducing this error, die screened ONHS population in cluded only workers who remained in the same job for the entire time that they worked at the study facility. These workers were then assigned an 8-hour TWA sound level based on noise measurements and job activities at the time of the survey. It is possible that larger errors in estimating 8-hour TWA sound levels over a long period o f time may have occurred for workers with longer durations o f exposure. It is also possible that die workers with long durations in cluded in this study represented a population which may have been less sensitive to the adverse effects o f noise on hearing. This may have contributed to the observed decrease in risk with increasing sound level, for durations greater than 20 years. Hence, the cross-sectional design o f the survey introduces areas o f concern for predicting NIHH risks over a working lifetime. # B. M odeling c a v e a ts The data limitations described above also placed limita tions on the modeling approach and interpretations presented in this paper. One data limitation with implications for mod eling the risk of noise-induced hearing handicap, was the lack o f in fo rm a tio n on the distribution o f 8-hour TWA sound levels among the control population. This is a crucial omis sion because all excess risk estimates depend on die risk of handicap among workers with low levels o f occupational noise exposure (in this study, defined as exposure to sound levels less than 80 dB). Due to this lack o f data, a very simplistic assumption was made: sound levels in the control population could be represented by a single number. This is problematic in terms o f model interpretation. First, it ignores the possibility that there may be a distribution o f sound levels below 80 dB for this population. Second, this assumption results in a model that implies that the estimated value (Lq) is a threshold sound level at which no excess risk o f noise-induced hearing handicap is predicted regardless o f the duration o f exposure. Hence, the statistical criteria used in model development are valid only if all of the controls were below a defined thresh old. These modeling issues underscore the fact that all mod els are likely to be dependent on assumptions used to ac count for uncertainty in the available data. This analysis did not model hearing threshold levels as a continuous variable. Therefore, calculation o f NIPTS using these models are not possible. The analysis also did not extensively explore other possible shapes for die sound level function other than (Z*he-Furthermore, modeling exposure duration as a categorical variable limits finer examination o f the relation ship o f duration o f exposure on risk o f hearing handicap. Given this updated analysis o f the NIOSH (1972) data, it is o f interest to compare these results to estimates generated using methodology developed by the International Standards Organization (ISO 1971(ISO , 1990. which was adopted in the ANSI S3.44 standard (ANSI, 1996). This standard was is sued to provide a more accurate and more generalized model of the relationship between NUTS and occupational noise exposure for people at different ages and duration o f expo sure. ANSI S3.44 (ANSI, 1996) provides mathematical pro cedures for estimating bearing handicap due to noise expo sure for populations free from auditory impairment (other than that due to noise). The data from studies by Passchier-Venneer (1968) « id by Bums and Robinson (1970) are the basis o f die ANSI S3.44 (ANSI, 1996) standard for estimating NIKI'S. As with the NIOSH (1972) study, most o f die noise-exposed workers were exposed to daily noise levels ranging from 85 to 95 dB. The Passchier-Venneer (1968) and Robinson (1970) models are represented by different mathematical equations which include an aging (non-noise) component in dB and a N1PTS component in dB. For each model, the equation for NIPTS was determined by age correcting the noise-exposed workers' hearing threshold levels to get the NIFFS compo nent. An empirical equation was developed for NlFTS in terms o f noise level and exposure time. For each model, the aging and NIPTS components were combined to compute total hearing threshold level in dB (ANSI, 1996) 53.44 (ANSI, 1996). Johnson (1978) provides the methodol ogy used to develop risk percent calculations using the per centage o f die population expected to exceed a specific hear ing threshold level (e.g., 25 dB) for a given population. The excess risks generated from our analysis o f the 1-4 kHz AI definition are compared to excess risk estimates gen erated using the ANSI S3.44 (ANSI, 1996) methodology and Annex A as die unexposed population. Annex A was chosen over Annex B since the NIOSH study population was highly screened. Hence, the Annex A highly screened control popu lation is the most appropriate comparison to our study popu lation. As shown in Fig. 5, excess risk estimates from our best fitting model are similar to those estimated by ANSI 53.44 (ANSI, 1996) for workers aged 65 years with 45 years o f exposure. However, among workers aged 45 years with 25 years of exposure, excess risk estimates at sound levels great«' than 90 dB are higher for this analysis as compared to ANSI S3.44 (ANSI, 1996). These results particularly in the range o f 80-90 dB are not surprising given the similarities in study design, data collection and time period for all o f these studies. Although these are qualitative comparisons, the dif ferences in estimates o f lifetime excess risk between ANSI S3.44 (ANSI, 1996) and this analysis do not appear to be substantial. This is illustrated in Fig. 6, which shows that excess risk estimates generated from ANSI S3.44 are located between the bootstrap-based 90% upper and lower confi dence limits from the best fitting logistic model. At age 45 years and 25 years o f exposure, excess risk estimates below 89 dB are within die lowo- bound o f the confidence limits from the logistic model. Thereafter, point estimates from ANSI S3.44 are found to be lower, particularly at sound levels greater than 92 dB. For other definitions o f hearing handicap (0 .5 -2 kHz and 1 -3 kHz), ANSI S3.44 estimates o f excess risk are con siderably lower at 85 dB for workers aged 65 years with 25 years o f exposure. For the 0 .5 -2 kHz definition, excess risks at 85 dB from our logistic model and ANSI S3.44 (ANSI, 1996) are 12% and 1%, respectively. For die 1-3 kHz defi nition, the values are 16% for our model and 4% using ANSI S3.44 (ANSI, 1996) methods. At 80 dB, ANSI S3.44 gener ates excess risks o f 0% for both definitions, while «rim atps from this analysis axe 5% and 6% for die 0 3 -2 kHz and 1-3 kHz definitions, respectively. Some o f the divergen t results may be due to differences in population characteristics o f the studies used to generate excess risks. The NIOSH data set represented a heterogeneous population o f workers from a variety o f geographic regions and worksites within the United States. The study populations used to develop the ANSI S3.44 (ANSI, 1996) models were likely to be more homogeneous with respect to industry, demographic and so cioeconomic (e.g., access to medical care) characteristics. # D. F u tu re cfirectiorts a n d d a ta ne e d s This analysis indicates a need to collect and m alyze data from populations exposed to noise at sound levels below 85 dB to leani more about the shape o f the dose-response rela tionship below 85 dB. Like nm ilar studies conducted in the late 1960 and early 1970's, the screened ONHS data set had few subjects with exposures at levels below 85 dB. This contributed to a high degree o f instability in the risk esti mates as the modeling assumptions were varied. Although logistic modeling techniques were used in this analysis, other methods for evaluating excess risks can reasonably be ap plied to these data. Nonetheless, it seems plausible that the observed instability below 85 dB would persist using ocher modeling methods. Risk estimates in the range o f 88-95 dB are probably more reliable than the estimates for the lower ranges o f sound level. More recent longitudinal data sets may be useful in examining risk below 85 dB. To examine whether noisc-induced bearing handicap remains a problem for workers enrolled in OSHA-mandated bearing conserva tion programs (Department o f Labor, 1981a,1981b), we are currently examining appropriate longitudinal audxm etric da tabases. The present analysis indicates that new studies should be implemented to (1) characterize noise exposure for presumably " non-noise" o r low noise populations (includ ing populations exposed to nonoccupational sources o f noise); and (2) examine dose-response relationships for noise and hearing handicap among workers exposed to noise levels below 90 dB.	Mention o f the name o f any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health. Copies o f this and other NIOSH documents are available from# G L O S S A R Y Where possible, die definition is quoted from the appropriate American National Standards Institute (ANSI) standard, ANSI S l.1 -1 9 9 4 [ANSI 1994] or ANSI S 3.20-1995 [ANSI 1995], under the tenn(s) used in that standard. E x c h a n g e r a t e : An increment o f decibels that requires the halving o f exposure time, or a decrement o f decibels that requires the doubling o f exposure time. For example, a 3-dB exchange rate requires that noise exposure tim e be halved for each 3-dB increase in noise level; likew ise, a 5-dB exchange rate requires that exposure tim e be halved for each 5-dB increase. F e n c e : The hearing threshold level above which a material impairment o f hearing is considered to have occurred. F r e q u e n c y : For a function periodic in time, the reciprocal o f the period. Unit, hertz (Hz) (ANSI S l.1 -1 9 9 4 : frequency). # H e a r i n g t h r e s h o l d l e v e l ( H T L ) : For a specified signal, amount in decibels by which the hearing threshold for a listener, for one or both ears, exceeds a specified reference equivalent threshold level. Unit, dB (ANSI S l.1 -1 9 9 4 : hearing level; hearing threshold level). # I m m i s s i o n l e v e l : A descriptor for noise exposure, in decibels, representing the total sound energy incident on the ear over a specified period o f tim e (e.g., months, years). I m p a c t : Single collision o f one mass in motion with a second mass that may be in motion or at rest (ANSI S l.1 -1 9 9 4 : impact). I m p u l s e : Product o f a force and the tim e during which the force is applied; more specifically, impulse is the time integral o f force from an initial tim e to a final time, the force being Noise Exposure I m p u l s i v e n o i s e : Impulsive noise is characterized by a sharp rise and rapid decay in sound levels and is less than 1 sec in duration. For the purposes o f this document, it refers to impact or impulse noise. I n t e r m i t t e n t n o i s e : N oise levels that are interrupted by intervals o f relatively low sound levels. # N o i s e : (1) Undesired sound. B y extension, noise is any unwarranted disturbance within a useful frequency band, such as undesired electric waves in a transmission channel or device. (2) Erratic, intermittent, or statistically random oscillation (ANSI S I .1-1994: noise). # N o i s e r e d u c t i o n r a t i n g ( N R R ) : The NRR, which indicates a hearing protector's noise reduction capabilities, is a single-number rating that is required by law to be shown on the label o f each hearing protector sold in the United States. Unit, dB. # P e r m a n e n t t h r e s h o l d s h i f t ( P T S ) : Permanent increase in the threshold o f audibility for an ear. Unit, dB (ANSI S3.20-1995: permanent threshold shift; permanent hearing loss; PTS). P u l s e r a n g e : Difference in decibels between the peak level o f an impulsive signal and the root-mean-square level o f a continuous noise. # S i g n i f i c a n t t h r e s h o l d s h i f t : A shift in hearing threshold, outside the range o f audiometric testing variability (±5 dB), that warrants followup action to prevent further hearing loss. NIOSH defines significant threshold shift as an increase in the HTL o f 15 dB or more at any frequency (5 0 0 ,1 0 0 0 , 2 0 0 0 ,3 0 0 0 ,4 0 0 0 , or 6000 Hz) in either ear that is confirmed for die same ear and frequency by a second test within 30 days o f the first te s t S o u n d : (1) Oscillation in pressure, stress, particle displacement, particle velocity, etc. in a medium with internal forces (e.g ., elastic or viscous), or the superposition o f such propagated oscillations. (2) Auditory sensation evoked by the oscillation described above (ANSI S I .1-1994: sound). # S o u n d i n t e n s i t y : Average rate o f sound energy transmitted in a specified direction at a point through a unit area normal to this direction at die point considered. Unit, watt per square meter (W /nr); symbol, I (ANSI S I .1-1994: sound intensity; sound-energy flux density; sound-power density). # S o u n d i n t e n s i t y l e v e l : Ten tim es the logarithm to the base ten o f the ratio o f the intensity o f a given sound in a stated direction to the reference sound intensity o f 1 picoWatt per square meter (pW/m2). Unit, dB; symbol, L (ANSI S I .1-1994: sound intensity level). S o u n d p r e s s u r e : Root-mean-square instantaneous sound pressure at a point during a given tim e interval. Unit, Pascal (Pa) (ANSI S I .1-1994: sound pressure; effective sound pressure). tu n e -d e p e n d e n t a n d e q u a l t o z e ro b e fo re th e in it ia l tim e a n d a fte r th e f in a l tim e ( A N S I S I . 1 -1 9 9 4 : im p u ls e ) . x rv # Glossary # S o u n d p r e s s u r e l e v e l : (1) Ten times the logarithm to the base ten o f die ratio o f the time-mean-square pressure o f a sound, in a stated frequency band, to the square o f the reference sound pressure in gases o f 20 micropascals QiPa). Unit, dB; symbol, L p . (2) For sound in media other than gases, unless otherwise specified, reference sound pressure in 1 pPa (ANSI S L 1-1994: sound pressure level). T e m p o r a r y t h r e s h o l d s h i f t : Temporary increase in die threshold o f audibility for an ear caused by exposure to high-intensity acoustic stimuli. Such a shift may be caused by other means such as use o f aspirin or other drugs. Unit, dB. (ANSI S3.20-1995: temporary threshold shift; temporary hearing loss). # T i m e -w e i g h t e d a v e r a g e ( T W A ) : The averaging o f different exposure levels during an exposure period. For noise, given an 85-dBA exposure lim it and a 3-dB exchange rate, the TWA is calculated according to the follow ing formula: TWA = 10.0 x Log(D/100) + 85 where D = dose. V a r y in g n o i s e : N oise, with or without audible tones, for which the level varies substantially during the period o f observation (ANSI S3.20-1995: nonstationary noise; nonsteady noise; time-varying noise). Occupational noise exposure shall be controlled so that worker exposures are less than the combination o f exposure level ( L ) and duration (7 ), as calculated by the follow ing formula (or as shown in Table 1 -1 ). # r(min)=^-M)/3 where 3 = die exchange rate. # . . 2 T i m e -W e i g h t e d A v e r a g e ( T W A ) In accordance with Section 1.1.1, the REL for an 8-hr work shift is a TWA o f 85 dBA us ing a 3-decibel (dB) exchange rate. # . . 3 D a i l y N o i s e D o s e When the daily noise exposure consists o f periods o f different noise lev els, the daily dose (D ) shall not equal or exceed 100, as calculated according to the follow ing formula: Noise Exposure d = [c ,/r ,+ c j t 2 + . . . + c y r j x 100 where C^-total tim e o f exposure at a specified noise level, and r , = exposure duration for which noise at this level becom es hazardous. The daily dose can be converted into an 8-hr TWA according to die follow ing formula (or as shown in Table 1-2 Noise Exposure 1 . 2 H e a r i n g L o s s P r e v e n t i o n P r o g r a m The employer shall institute an effective hearing loss prevention program (HLPP) de scribed in Sections 1 3 through 1.11 when any worker's 8-hr TWA exposure equals or exceeds 85 dBA. # . 3 N o i s e E x p o s u r e A s s e s s m e n t The employer shall conduct a noise exposure assessment when any worker's 8-hr TWA exposure equals or exceeds 85 dBA. Exposure measurements shall conform to the A m e r i c a n N a t i o n a l S t a n d a r d M e a s u r e m e n t o f O c c u p a t io n a l N o i s e E x p o s u r e , ANSI S 12. 19-199619- [ANSI 1996a]. N oise exposure is to be measured without regard for the wearing o f hearing protectors. # . 3 . I n i t i a l M o n i t o r i n g When a new HLPP is initiated, an initial monitoring o f the worksite or o f noisy work tasks shall be conducted to determine the noise exposure levels representative o f all workers w hose 8-hr TWA noise exposures may equal or exceed 85 dBA. For workers remaining in essentially stationary, continuous noise levels, either a sound level meter or a dosimeter may be used. However, for workers who move around frequently or who perform different tasks with intermittent or varying noise levels, a task-based exposure monitoring strategy may provide a more accurate assessment o f the extent o f exposures. # . 3 . 2 P e r i o d i c M o n i t o r i n g I f any worker's 8-hr TWA exposure to noise equals or exceeds 85 dBA, monitoring shall be repeated at least every 2 years. Monitoring shall be repeated within 3 months o f die occurrence when there is a change in equipment, production processes or maintenance routines. It may also be prudent to assess noise exposures when work practices have changed and/or i f workers are developing significant threshold shifts (see Section 1.6.4). # . 3 . 3 I n s t r u m e n t a t i o n Instruments used to measure workers' noise exposures shall be calibrated to ensure measurement accuracy and, at a m inim um , they shall conform to the A m e r i c a n N a t i o n a l S t In determining TWA exposures, all continuous, varying, intermittent, and impulsive sound levels from 80 to 140 dBA shall be integrated into die noise measurements. Chapter 1. Recommendations fa r a Noise Standard 1 A E n g i n e e r i n g a n d A d m i n i s t r a t i v e C o n t r o l s a n d W o r k Practices To the extent feasible, engineering controls, administrative controls, and work practices shall be used to ensure that workers are not exposed to noise at or above 85 dBA as an 8-hr TWA. The use o f administrative controls shall not result in exposing more workers to noise. 1 . 5 H e a r i n g P r o t e c t o r s Workers shall be required to wear hearing protectors when engaged in work that ex poses them to noise that equals or exceeds 85 dBA as an 8-hr TWA.* The employer shall provide hearing protectors at no cost to the workers. Hearing protectors shall attenuate noise sufficiently to keep the worker's "real-world" exposure (Le., the noise exposure at die worker's ear when hearing protectors are worn) below 85 dBA as an 8-hr TWA. Workers whose 8-hr TWA exposures exceed 100 dBA should wear double hearing protection (i.e., they should wear earplugs and earmuffs si multaneously)T o compensate for known differences between laboratory-derived attenuation values and the protection obtained by a worker in the real world, the labeled noise reduction rat ings (NRRs) shall be derated as follow s: (1) earmuffs-subtract 25% from the manufac turers' labeled NRR; (2) slow-recovery formable earplugs-subtract 50%; and (3) all other earplugs-subtract 70% from the manufacturers' labeled NRR. These derating val ues shall be used until such time as manufacturers test and label their products in accor dance with a subject-fit method such as method B o f ANSI S 12.6-1997, A m e r i c a n This recommendation should not be construed to imply that workers need not wear hearing protection unless their 8-hr TWAs equal or exceed 85 dBA For example, it would be prudent for a worker in and out of noise or habitually exposed to loud noise (e.g., 91 dBA for 1 hr and 59 min) to wear hearing pro tection while in noise-even though his or her dose was less than 100%. tThe intent of this section is not to advocate hearing protectors as die primary means of control; however, when engineering controls, administrative controls, and work practices cannot keep workers' exposures below 85 dBA as an 8-hr TWA, the use of hearing protectors shall he required For most TWA expo sures exceeding 105 dBA, hearing protectors will be necessary to supplement engineering and adminis trative controls. # N a t i o n a l S t a n d a r d M e t h o d s f o r M e a s u r i n g t h e R e a l -E a r A t t e n u a t i o n o f H e a r i n g Noise Exposure # . 6 . A u d i o m e t r y Audiometrìe tests shall be performed by a physician, an audiologist, or an occupational hearing conservationist certified by the Council for Accreditation in Occupational Hear ing Conservation (CAOHC) or die equivalent, working under the supervision o f an au diologist or physician. The appropriate professional notation (e.g., licensure, certification, or CAOHC certification number) shall be recorded on each worker's audiogram. Audiometrìe testing shall consist ofair-conduction, pure-tone, hearing threshold meas ures at no less than 500, 1 0 0 0 ,2 0 0 0 ,3 0 0 0 ,4 0 0 0 , and6000 hertz ( For permanent onsite testing facilities, ambient noise levels shall be checked at least an nually. For m obile testing facilities, ambient noise levels shall be tested daily or each time the facility is moved, whichever is more often. Ambient noise measurements shall b e obtained under conditions representing the typical acoustical environment likely to b e present when audiometrìe testing is performed. Ambient noise levels shall be re corded on each audiogram or made otherwise accessible to the professional reviewer o f the audiograms. # . 6 . 2 B a s e l i n e A u d i o g r a m A baseline audiogram shall be obtained before employment or within 30 days o f em ployment for all workers who must be enrolled in the HLPP. Workers shall not be ex posed to noise levels at or above 85 dBA for a mmimum o f 12 hr before receiving a baseline audiometrìe te s t Hearing protectors shall not be used in lieu o f the required quiet period. Chapter 1. Recommendations fo r a Noise Standard 1 . 6 . 3 M o n i t o r i n g A u d i o g r a m a n d R e # t e s t A u d i o g r a m A ll workers enrolled in die HLPP shall have their hearing threshold levels (HTLs) meas ured annually. These audiometric tests shall be conducted during the worker's normal work sh ift This audiogram shall be referred to as the ''monitoring audiogram." The monitoring audiogram shall be examined immediately to determine whether a worker has a change in hearing relative to his or her baseline audiogram. When the monitoring audiogram detects a change in the HTL in either ear that equals or exceeds 15 dB at 5 0 0 ,1 0 0 0 ,2 0 0 0 ,3 0 0 0 ,4 0 0 0 , or 6000 Hz, an optional retest may be conducted immediately to determine whether die significant threshold shift is persistent In most cases, die retest w ill demonstrate that the worker does n o t have a persistent threshold shift, thereby eliminating die need for a confirmation audiogram and followup action. I f a persistent threshold shift h a s occurred, the worker shall be informed that his or her hearing may have worsened and additional hearing tests w ill be necessary. 1 . 6 . 4 C o n f i r m a t i o n A u d i o g r a m , S i g n i f i c a n t T h r e s h o l d S h i f t , a n d F o l l o w u p A c t i o n When a worker's monitoring audiogram detects a threshold shift as outlined in Section 1.6.3, he or she shall receive a confirmation audiogram within 30 days. This confirma tion test shall be conducted under the same conditions as those o f a baseline audiometric te s t I f die confirmation audiogram shows die persistence o f a threshold shift, the audio grams and other appropriate records shall be reviewed by an audiologist or physician. I f this review validates the threshold shift, the threshold shift is considered to be a sig nificant threshold sh ift This shift shall be recorded in die worker's medical record, and die confirmation audiogram shall serve as the new baseline and shall be used to calculate any subsequent significant threshold shift. Whenever possible, the worker should re ceive immediate feedback on die results o f his or her hearing test; however, in no case shall die worker be required to wait more than 30 days. When a significant threshold shift has been validated, die employer shall take appropri ate action to protect the worker from additional hearing loss due to occupational noise exposure. Examples o f appropriate action include explanation o f the effects o f hearing loss, reinstruction and refitting ofhearing protectors, additional training o f die worker in hearing loss prevention, and reassignment o f the worker to a quieter work area. When die reviewing audiologist or physician suspects a hearing change is due to a nonoccupational etiology, the worker shall receive appropriate counseling, which may in clude referral to his or her physician. Noise Exposure 1 . 6 . 5 E x i t A u d i o g r a m The employer should obtain an exit audiogram from a worker who is leaving employ ment or w hose job no longer involves exposure to hazardous noise. The exit audiogram should be conducted under the same conditions as those o f baseline audiometry. 1 . 7 H a z a r d C o m m u n i c a t i o n 1 . 7 . 1 W a r n i n g S i g n s A warning sign shall be clearly visible at the entrance to or die periphery o f areas where noise exposures routinely equal or exceed 85 dBA as an 8-hr TWA. A ll warning signs shall be in English and, where applicable, in the predominant language o f workers who do not read English. Workers unable to read the warning signs shall be informed ver bally about the instructions printed on signs in hazardous work areas o f the facility. The warning sign shall textually or graphically contain the follow ing information: W A R N I N G N O I S E A R E A H E A R I N G H A Z A R D U s e o f H e a r i n g P r o t e c t o r s R e q u i r e d 1 . 7 . 2 N o t i f i c a t i o n t o W o r k e r s A ll workers who are exposed to noise at or above 85 dBA as an 8-hr TWA shall be in formed about the potential consequences o f noise exposure and the methods o f prevent ing noise-induced hearing lo ss (NIHL). When noise measurements are initially con ducted and confirm the presence o f hazardous noise, or when followup noise meas urements identify additional noise hazards, workers shall be notified within 30 days. N ew workers shall be alerted about the presence o f hazardous noise before they are ex posed to i t # . 8 T r a i n i n g The employer shall institute a training program in occupational hearing loss prevention for all workers who are exposed to noise at or above 85 dBA as an 8-hr TWA; the em ployer shall ensure worker participation in such a program. The training program shall be repeated annually for each worker included in the HLPP. Information provided shall be updated to be consistent with changes in protective equipment and work processes. # . 9 P r o g r a m E v a l u a t i o n Criteria The effectiveness o f the HLPP shall be evaluated at the level o f the individual worker and at die programmatic level. The evaluation at die worker level shall take place at die tim e o f the annual audiometry. I f a worker demonstrates a significant threshold shift that is presumed to be occupation ally related, all possible steps shall be taken to ensure that die worker does not incur ad ditional occupational hearing loss. The evaluation at the programmatic level shall take place annually. The incidence rate o f significant threshold shift for noise-exposed workers shall be compared with that for a population not exposed to occupational noise. Similar incidence rates from this com parison indicate an effective HLPP. Data for calculating an incidence rate for a popula tion not exposed to occupational noise should be drawn from Annex C in the A m e r i c a n # N a t i o n a l S t a n d a r d D e t e r m in a t i o n o f O c c u p a t io n a l N o i s e E x p o s u r e a n d E s t i m a t i o n o f N o i s e -I n d u c e d H e a r i n g I m p a i r m e n t y ANSI S3 . 44-199644- [ANSI 1996c] unless more ap propriate data are available. # . 0 R e c o r d k e e p i n g The employer shall establish and maintain records in accordance with die requirements in Sections 1.10.1 through 1.10.5. The employer shall establish and maintain an accurate record for each worker subject to die medical surveillance specified in Section 1.6. These records shall include, at a mini mum, die name o f die worker being tested; identification number; duties performed and job locations; m edical, employment, and noise-exposure history; dates, tim es, and types o f tests (i.e., baseline, annual, retest, confirmation); hours since last noise exposure be fore each test; HTLs at the required audiometric frequencies; tester's identification and assessment o f test reliability; the etiology o f any significant threshold shift; and the identification o f the reviewer. NIHL is caused by exposure to sound levels or durations that damage the hair cells o f the cochlea. Initially, the noise exposure may cause a temporary threshold shift-that is, a decrease in hearing sensitivity that typically returns to its former level within a few minutes to a few hours. Repeated exposures lead to a permanent threshold shift, which is an irreversible sensorineural hearing loss. Noise Exposure # . 6 S c o p e o f T h i s R e v i s i o n o f t h e N o i s e Criteria D o c u m e n t The focus o f this document is on the prevention o f occupational hearing loss rather than on conservation. ASHA makes a distinction between the tom s "impairment" and "handicap"; however, for the purpose o f die subsequent discussion in this criteria document, only the tom "material hearing impairment" is used. The Prince et al. [1997] paper reports the use o f a modified ASHA Task Force definition. This modification incorporates frequency-specific weights based on the articulation index for each fre quency [ANSI 1969]. Negligible differences were found between excess risk estimates generated using die modified and the unmodified definitions. The excess risk estimates presented in this criteria docu ment are based on die unmodified ASHA Task Force definition. tHistorical note, ASHA did not deliberate on die definition proposed by the ASHA Task Force. Prince et al. [1997] found that the excess risk estimates at exposure levels below 85 dBA w oe not well defined. Insufficient data for workers with average daily exposures below 85 dBA led to considerable variability in the estimation, depending on the statistical assumptions used in the modeling. '1997-N10SH model for the 1-2-3-4-lcHz definition of hearing impairment ^¡■confidence interval. # N o i s e E x p o s u r e T a b l e 3 -4 . C o m p a r i s o n o f m o d e l s f o r e s t i m a t i n g t h e e x c e s s r i s k o f m a t e r i a l h e a r i n g i m p a i r m e n t a t a g e 6 0 a f t e r a 4 0 -y e a r w o r k i n g f i f e t i m e e x p o s u r e t o o c c u p a t i o n a l n o i s e , b y d e f i n i t i o n o f m a t e r i a l h e a r i n g i m p a i r m e n t Average cxponre fcvd(4 BA) # .2 C e ilin g Limit Because NIOSH is recommending a 3-dB exchange rate with an 85-dBA REL, a ceiling limit for continuous-type noise is unnecessary. For example, with an 85-dBA REL and a 3-dB exchange rate, an exposure duration o f less than 28 sec would be allowed at a 115-dBAlevel. TTie generally accepted ceiling limit o f 140 dB peak SPL for impulsive noise is based on areportbyKryteretaL [1966]. Ward [1986] indicated that "this number was little more than a guess when h was first proposed.* To date, a proposal for a different limit has not been supported. Henderson etaL [1991] indicated that the critical level for chinchillas is between 119 and 125 dB; and ifa20-dB adjustment is used to account for the difference in susceptibility between chinchillas and humans, the critical level extrapolated for humans would be between 139 and 145 dB. Based on the 85-dBA REL and the 3-dB ex change rate, the allowable exposure time at 140 dBA is less than 0.1 sec; thus, 140 dBA is a reasonable ceiling limit for impulsive noise. # .E x ch a n g e R ate Health 2. All noise exposures that produce a given TTS2 will be equally hazardous (the equal temporary effect theory). 3. Permanent threshold shift produced after many years of habitual noise exposures for 8 hr per day is about the same as the TTS2 produced in normal ears by an 8-hr exposure to the same noise. However, these CHABA postulates were not validated. Research has been unable to demonstrate a simple relationship between temporary threshold shift, permanent thresh old shift, and cochlear damage [Bums and Robinson 1970;Ward 1970Ward ,1980Ward and Turner 1982;Hetu 1982;Bohne 1978,1986]. The CHABA criteria assumed that worker exposures could be characterized by regularly spaced noise bursts inter spersed with periods that were sufficiently quiet to allow hearing to recover. However, this assumption is not characteristic o f many typical industrial noise exposures. Workers will always develop temporary threshold shift before sustaining permanent threshold shift, barring an ototraumatic incident Temporary threshold shift is a useful metric for monitoring the effects of noise exposure; these studies do not imply otherwise. In general, the CHABA hearing damage risk criteria proved too complicated for general use. Botsfoid [1967] published a simplified set of criteria based on the CHABA criteria. One o f the simplifications inherent to the Botsford [1967] method was the assumption that interruptions would be o f "equal length and spacing so that a number o f identical ex posure cycles would be distributed uniformly throughout the day." These interruptions would occur during coffee breaks, trips to the washroom, lunch, and periods when ma chines were temporarily shut down. One response to the evidence from the animal studies and certain field studies would be to select the 3-dB exchange rate but to allow an adjustment (increase) to the PEL for cer tain intermittent noise exposures, as suggested by EPA [1974] and Johansson et aL [1973]. This response would be in contrast to a 5-dB exchange rate, for which there is lit tle scientific justification. Ideally, if an adjustment is needed, the amount should be de termined by the temporal pattern o f die noise and the levels o f quiet between noise bursts. At this time, however, little quantitative information is available about these pa rameters in industrial environments. Therefore, the need for an adjustment should be clarified by further research. Although the 3-dB rule may be somewhat conservative in truly intermittent conditions, the 5-dB rule will be underprotective in most others. The 3-dB exchange rate is die method most firmly supported by the scientific evidence for assessing hearing impairment as a function o f noise level and duration, whether or not an adjustment is used for certain intermittent exposures. # .4 Im p u lsiv e N o is e The OSHA occupational noise standard [29 CFR 1910.95] states: "Exposure to impul sive or impact noise should not exceed 140 dB peak sound pressure." Thus, in this con text, the 140-dB limit is advisory rather than mandatory. This number was first proposed by Kryter et al. [1966] and later acknowledged by Ward [1986] as little more than a guess. NIOSH [1972] did not address the hazard o f impulsive (i.e., impulse or impact) noise, although NIOSH stated that the provisions o f the recommended standard in the criteria document were intended to apply for all noise. Although there is yet no unanim ity as to which criteria best describe die relationship between NIHL and exposure to im pulsive noise, either by itself or in die presence o f continuous-type (i.e., continuous, varying, or intermittent) noise, diere is an international standard that has become widely used by most industrial nations. This standard, ISO 1999, Acoustics-An Estimation o f Noise-Induced Hearing Impairment (ISO 1990], integrates both impulsive and continuous-type noise (and uses die 3-dB exchange rate of die equal-energy rule) when calculating sound exposures over any specified time period. NIOSH concurs with this # N o i s e E x p o s u r e approach and recommends that noise exposure levels be calculated by integrating all noises (both impulsive and continuous-type) over die duration o f die measurement Despite its simplicity, die equal-energy rule is not universally accepted as a method for characterizing exposures that consist o f both impulsive and continuous-type noises. Another approach favors evaluating impulsive noise separate from that o f continuoustype noise. Studies that would argue for this approach will be discussed first, followed by a discussion o f studies elucidating the rationale for the NIOSH position on the equalenergy rule. # . 4 . 1 E v i d e n c e T h a t I m p u l s i v e N o i s e E f f e c t s D o N o t C o n f o r m t o t h e E q u a l -E n e r g y R u l e In her evaluation o f the effects o f continuous and varying noises on hearing, Passchier-Vermeer [1971] found that the HTLs o f workers in steel construction works did not con form to the equal-energy hypothesis; that is, the hearing losses in these workers, who were exposed to noise levels with impulsive components, were higher than predicted. [1970]. The ob served and predicted values differed in that the observed hearing loss was smaller than predicted at the lower audiometric frequencies, but the observed hearing loss was greater than predicted at the higher audiometric frequencies. In their study of hearing loss in weavers, who were exposed to continuous noise, and drop-forge hammer men, # C h a p t e r S . B a s i s f o r t h e E x p o s u r e S t a n d a r d who were exposed to impact noise o f equivalent energy, Sulkowski et al. [1983] found that the hammer men had substantially worse hearing than the weavers. Thiery and Meyer-Bisch [1988] conducted a cross-sectional epidemiologic study at an automobile manufacturing plant The automotive workers were exposed to continuous and impulsive noises at ¿Acq^ ranging from 87 to 90 dBA. When their HTLs were com pared with those o f workers exposed to continuous noise at o f 95 dBA for the same exposure time, the automotive workers showed greater hearing losses at the 6000-Hz audiometric frequency than the reference population after 9 years o f exposure. [1988] compared at the4000-Hz audiometric frequency the HTLs of forest workers using chain saws and shipyard workers using hammers and chippers. The forest workers were exposed to continuous-type noise, whereas the shipyard workers were ex posed to impact noise. Starck et al. [1988] also used the immission model developed by Bums and Robinson [1970] to predict the HTLs for both groups. They found that the Bums and Robinson model was accurate at 4000 Hz for the forest workers; however, it substantially underestimated die HTLs at 4000 Hz for the shipyard workers. # Staxck et aL The studies described here provide evidence that the effects o f combined exposure to impulsive and continuous-type noises are synergistic rather than additive, as die equal* energy hypothesis would support One measure for protecting a worker from such syn ergistic effects would be to require that a correction factor be added to a measured TWA noise exposure level when impulsive components are present in the noise. The magni tude o f such a correction has not been quantified. The matter becomes more complicated when other parameters o f impulsive noise are considered. Noise energy does not appear to be the only factor that affects hearing. The amplitude, duration, rise time, number of impulses, repetition rate, and crest factor also appear to be involved [Henderson and Hamemik 1986;Starck and Pekkarinen 1987;Pekkarinen 1989]. The criteria for expo sure to impulsive noise based on die interrelationships o f these parameters await the re sults o f further research. # . 4 . 2 E v i d e n c e T h a t I m p u l s i v e N o i s e E f f e c t s C o n f o r m t o t h e E q u a l - E n e r g y R u l e # . 4 . C o m b i n e d E x p o s u r e t o I m p u l s i v e a n d C o n t i n u o u s -T y p e N o i s e s # Instrumentation for Noise Measurement No single method or process exists for measuring occupational noise. Hearing safety and health professionals can use a variety o f instruments to measure noise and can choose from a variety o f instruments and software to analyze their measurements. The choice o f a particular instrument and approach for measuring and analyzing occupa tional noise depends on many factors, not die least of which will be die purpose for the measurement and the environment in which die measurement will be made. # . 1 . 1 F r e q u e n c y W e i g h t i n g N e t w o r k s The human ear is not equally responsive to all frequencies; it is most sensitive around 4000Hz and least sensitive in the low frequencies. The responses o f die sound level me ter are modified with frequency-weighting networks that represent some responses of the human ear. These empirically derived networks approximate die equal loudnessweighting networks or scales; some also have a B-scale. The A-scale, which approxi mates the ear's response to moderate-level sounds, is commonly used in measuring noise to evaluate its effect on humans and has been incorporated in many occupational noise standards. Table 4-1 shows die characteristics o f these scales. # . 1 . 2 E x p o n e n t i a l T i m e W e i g h t i n g A sound level meter's response is generally based on either a FAST or SLOW expo nential averaging. FAST corresponds to a 125-millisecond (ms) time constant; SLOW The correct use o f die microphone is extremely important in obtaining accurate meas urements. Microphones come in many types and sizes. A microphone is typically de signed for use in a particular environment across a specific range o f SPLs and frequencies. In addition, microphones differ in their directionality. For example, some are intended to be pointed directly at the sound; and others are designed to measure sound from a "grazing" angle o f incidence. Thus users should follow the sound level meter manufacturer's instructions regarding the type and size o f microphone and its ori entation toward a sound. Also, care should be taken to avoid shielding the microphone by persons or objects [ANSI 1996a]. When measuring a diffuse sound field, the person conducting the measurement should hold the microphone as far from his or her body as practical [Earshen 1986]. "Meters that are set to integrate or avenge sound do not use either the FAST or SLOW time constant; they will sample many times each second. For a more detailed description o f exponential time weighting, re fer to Yeager and March [1991]. "Whenever the unit dB is used in sudiometric testing, it actually refers to dB HTL. # C h a p t e r 5 . H e a r i n g L o s s P r e v e n t i o n P r o g r a m s ( H L P P s ) T a b l e 5 -1 . C l a s s i f i a b l e f i r s t t a g s * a c r o s s 1 5 d a t a b a s e s * a n d f i r s t t a g s c l a s s i f i e d a s t r u e p o s i t i v e f o r e a c h o f t h e 8 -s h i f t c r i t e r i a * # No criterion evaluated is best in every respect The relative merits o f each are tabu lated in # A v e r a g e s t o g e t h e r f r e q u e n c i e s t h a t v a r y in s u s c e p t i b i l i t y t o n o i s e X X U s e s a s h i f t m a g n i t u d e w i t h i n t h e r a n g e o f n o r m a l a u d i o m e t r i c v a r i a b i l i t y X Chapter 5. Hearing Loss Prevention Programs (HLPPs) # N o i s e E x p o s u r e unlikely to be affected by NIHL, but it may be useful as an indicator o f excess ambient noise in the audiometrie test booth and as an indicator o f the presence o f medical ear conditions sudi as conductive ear pathologies. The 6000-Hz audiometrìe frequency is one o f the three high frequencies (3000,4000, and 6000 Hz) at which hearing is most likely to be affected soonest and to die greatest degree by NIHL. This audiometrie fre quency is more susceptible than others to measurement variability if there is inconsis tent earphone placement If the immediate retest is not performed, NIOSH recommends that the significant threshold shift be confirmed by a followup test within 30 days o f the testing that showed the significant threshold shift This followup test is called the confirmation test and is preceded by a 12-hr quiet period. If the significant threshold shift is confirmed and later validated by an audiologist or physician, the confirmation audiogram should be the one with which all subsequent audiograms are compared. To comply with this recommendation and to provide m a x i m u m protection for workers and maximum documentation for employers, NIOSH advocates that audiograms be per formed on the following occasions: 1. Before employment or before initial assignment into a hearing hazard work area. # Annually for any worker whose noise exposure equals or exceeds 85 dB A as an 8-hr TWA (monitoring audiometry) . Annual testing may lead to a number o f retests if a significant threshold shill occurs. In addition, it may be a good practice to provide audiometry twice per year to workers exposed to more than 100 dBA, because die most susceptible 10% o f a population exposed to daily average noise levels of 100 dBA with inadequate hearing protectors could develop significant hearing loss well before the end o f 1 year [NIOSH 1996]. # At the # M o n i t o r i n g A u d i o g r a m s Monitoring audiometry shall be conducted no less than annually. Unlike baseline audio metry, these annual tests should be scheduled at the end of, or well into, the work shift so that temporary changes in hearing due to insufficient noise controls or inadequate use of hearing protection will be noted. The results should be compared immediately with the baseline audiogram to check for any change in hearing sensitivity. The collection of au diograms for later batch comparison with baseline audiograms in another location is an unacceptable practice because it does not afford the opportunity to conduct retests or to discuss the findings with workers in a timely manner. # . . 1 . 3 R e t e s t A u d i o g r a m s As good practice, NIOSH suggests that audiometry be repeated immediately after any monitoring audiogram that indicates a threshold shift o f 15 dB or more at 500, 1000, 2000,3000,4000, or 6000 Hz in either ear. The worker should be reinstructed and the headphones refitted before conducting the retest Those who employ the retest strategy The audiometric manager should be responsible for making whatever recommen dations he or she deems necessary and for seeing that they are carried out # . . 1 . E x i t A u d i o g r a m Audiometry should be conducted when a worker leaves employment or is permanently rotated out o f an occupational noise exposure at or above 85 dBA as an 8-hr TWA. This exit audiogram, like the baseline, should be performed after a minimum o f 12 hr of quiet The use ofhearing protectors as a substitute for quiet is not acceptable. NIOSH suggests that hearing tests be offered as a health benefit to workers who are not exposed to hazardous noise levels. The tests in these workers can be conducted early in the day^when it is not recommended that noise-exposed employees be tested for changes in hearing thresholds. In addition to providing a valuable internal control group for comparison to the noise-exposed workers, this policy elevates the perceived impor tance o f the HLPP for management and workers [NIOSH 1996]. 1. Requirements o fa n d rationale fo r the occupational noise standard. # 5 . 2 A u d i o m e t e r s # 2. Effects o f noise on hearing. This should cover both die audiometrìe effects (i.e., how noise effects show up on an audiogram) and die functional effects (i.e., the impact of NIHL on everyday life). # 3. Company policy fo r the elimination o f noise as a hazard, including noise controls al ready implemented or plannedfor thefuture. This topic is very important and helps ensure that workers do not accidentally interfere with control measures. # Hazardous noise # C h a p t e r 5 . H e a r i n g L o s s P r e v e n t i o n P r o g r a m s ( H L P P s ) In addition to these episodic training sessions, an ongoing educational process should be offered. HLPP personnel, especially die program implementor, should visit the work ers' jobsites to see how they are doing. They should talk to workers about the program when they meet them in the halls, at lunch, etc. Posters, bulletin boards, informational pamphlets, etc., can be used as a constant reminder of the importance that the company places on hearing conservation. Contests or awards for effective hearing conservation practices can be used to promote safe behavior Royster 1986,1990]; how ever, incentive programs should be planned and implemented with full worker partici pation or they may be perceived by the workers as manipulative attempts by management to control worker behavior [Merry 1995]. # .8 R e c o r d k e e p in g (C o m p o n e n t 7 ) Recordkeeping # .1 0 A g e C o rr ectio n NIOSH does not recommend that age correction be applied to an individual's audio gram for significant threshold shift calculations. Although many people experience some decrease in hearing sensitivity with age, some do not It is not possible to know who will and who will not have an age-related hearing loss. Thus, applying age correc tions to a person's hearing thresholds for calculation o f significant threshold shift will overestimate the expected hearing loss for some and underestimate it for others, because The adjustment o f audiometric thresholds for aging has become a common practice in woriceis* compensation litigation. In this application, age corrections reduce the amount ofhearing loss attributable to noise exposure, with a consequent reduction in the amount o f compensation paid to workers for their hearing losses. However common "age cor recting" is and regardless o f the extent to which it is applied, it is technically inappropri ate to apply population statistics to an individuaL Each age correctionnuinber is nothing more than a median value from a population distribution. In age-correcting an audio gram, the underlying assumption is that the individual value is given the 50th percentile, when in feet the 10th or 90th percentile may be the correct value. Thus age-correction formulas cannot be applied to determine with certainty how much o f an individual's hearing loss is due to age and how much is due to noise exposure. Age-correcting audiograms obtained as part o f an occupational HLPP are even less ap propriate. This is not a compensation issue. The purpose o f the program is to prevent hearing loss. If an audiogram is age corrected, regardless o f the source o f the correction values, the time required for a significant threshold shift to be noted will be prolonged. Delaying the identification o f a worker with a significant threshold shift is completely contrary to the purpose o f an HLPP. # Hearing Protectors A personal hearing protection device (or hearing protector) is any device designed to re duce the level o f sound reaching the eardrum. Earmufls, earplugs, and ear canal caps (also called semi-inserts) are the mam types ofhearing protectors. A wide range ofhearing protectors exists within each of these categories. For example, earplugs maybe sub categorized into foam, user-formable (such as silicon or spun mineral fiber), premolded, and custom-molded earplugs. In addition, some The OSHA methods arc a simplification o f NIOSH methods #2 and #3 [NIOSH 1975[NIOSH ,1994L enp o t 1984]. One problem inherent to using single-number descriptors of sound attenuation is the need to ensure that the resulting value does not sacrifice the estimated protection for the sake o f simplicity. Thus these calculations will typically underestimate laboratoryderived "long methods" for estimating sound attenuation. To get around some o f the limitations associated with NRR calculations, other methods have been developed for estimating hearing protector performance. The single-number rating method and the high-middle-low method may be used when a person needs to estimate performance more accurately than possible with the NRR but does not want to resort to octave-band To summarize, the best hearing protection for any worker is die removal o f hazardous noise from the workplace. Until that happens, die best hearing protector for a worker is die one he or she will wear willingly and consistently. The following factors are ex tremely important determinants ofworker acceptance ofhearing protectors and die like lihood that workers will wear them consistently: • Convenience and availability • Belief that the device can be worn correctly • Belief that the device will prevent hearing loss • Belief that the device will not impair a worker's ability to hear important sounds Foam: Crawfotd and Nozza [1981] Hachey and Roberts [1983] Lempert and Edwards [1983] Edwards and Green [1987] Edwards and Green [1987 Lempert and Edwards [1983] Abel et aL [1978] A beletal. [1978 Behar [1985] Behar [1985] Pfeiffer et aL [1989] Casali and Part [1991] Casali and Raric [1991 Hempstock and Hill [1990] Berger and Kieper [1991] Premolded: Ultra-Fit Casali and Park [1991] Casali and Park [1991] Royster et aL [1984 Berger and Kieper [1991] V- 51R Royster et aL [1984] Abel et al. [1978] Edwards et al. [1978] Fleming [1980] Padilla [1976 Management procedures for workers identified with substantial hearing impairment need to be studied. They would include training in listening strategies, speech reading, and optimal utilization ofhearing aids. Research also needs to be directed at developing bearing instruments designed to help workers continue to function in noise while pro tecting bearing and enhancing communication. E-A-R Rehabilitation communication strategies need to be studied. Currently, if hearingloss-prevention service providers were to suggest that noise-exposed workers with NIHL could benefit from amplification, they would be fired. In such a hostile environ ment, it is very difficult to define, develop, deliver, and evaluate a rehabilitation program. Taylor # MTRODUCTION The most common goal for protecting workers from the auditory effects o f occupational noise has historically been the preservation o f hearing for speech discrimination. With tins protection goal in mind, the National Institute for Occu pational Safety and Health (NIOSH) defined hearing handi cap as a b ia u ra l avera g e o f hearing levels exceeding 25 dB at the ancfiometric test frequencies o f 1, 2, and 3 kHz and 0 5 , 1. and 2 kHz (NIOSH, 1972). Here, the term " bianral average" is used to identify die mean value for the left and right ears. Using these definitions, NIOSH (1972) estimated die excess risk o f hearing handicap as a function o f age, sound levels and duration o f occupational noise exposure. Excess risk, also known as percentage risk, is defined as the percentage o f individuals with hearing handicap among indi viduals exposed to daily 8^iour occupational noise exposure after subtracting die percentage o f individuals who would typically incur such a handicap doe to aging in an unexposed population. For a 40-year lifetime exposure to average daily (8-hour) noise levels o f 8 0 ,8 5 , and 90 dB in the workplace, NIOSH (1972) estimated the excess risk to be 3%, 15%, and 29%, respectively for the biaural average over 1, 2, and 3 kHz. [Unless otherwise noted, " dB" implies an A-weighted 8-hour time-weighted average sound level.] Table I com pares die NIOSH (1972) excess risk estimates fo r die biaural average over 0.5, 1, and 2 kHz to those developed by other organizations at approximately the same time. Since the publication o f the 1972 NIOSH Criteria Docu ment, statistical methods for analyzing categorical data out comes have been improved to assess risk o f disease (Breslow and Day, 1980a). The aim o f this paper is to reevaluate the models used to generate excess risk estimates from data col lected for the NIOSH 1968-72 Occupational Noise and Hearing Survey (ONHS) (Lempert and Henderson, 1973). Using these newer statistical methods, the paper examines die relationship between exposure to noise and risk o f noiseinduced hearing handicap (NIHH) and highlights s e a s o f uncertainty in estimating risks. These results will be com pared to the 1972 NIOSH analysis (NIOSH, 1972) and to the ANSI S3.44 (ANSI, 1996) standard, which adopted the methods developed by die In te rn a tio n a l Standards Organiza tion (ISO 1971(ISO , 1990. The data collected in the NIOSH survey are o f continuing interest since they were obtained before hearing protection devices were widely used in the U.S. Observations by NIOSH investigators during sound level surveys and management's impressions o f their respec tive plants did not indicate that participating companies had policies req u irin g hearing protection use. Use o f protectors, if available at all, were left to the discretion o f the workers. No mass use o f hearing protectors was noted in any o f the companies surveyed (Cohen, personal communications, 1996). # L RELEVANCE TO COMPARABLE STUDIES OF NCMSE-MDUCED HEARING LOSS Several investigators (Robinson and Sutton, 1975;Royster and Thomas, 1979;NCHS, 1965;Robinson, 1970;Yexg e t a l-, 1978) have examined the relationship o f noiseinduced permanent threshold shift (NÏPTS) and occupational noise exposure. Studies similar to the NIOSH 1968-72 Noise Survey with respect to time period and methods of data collection include Baughn (1973), Passchier-Vermeer (1968 and Bums and Robinson (1970). These studies will be the main focus o f our review o f die relevant noise and hearing surveys from this period. These studies have been used by ISO 1999(1971) and ANSI S3.44 (ANSI, 1996 to estimate the risk o f N1HH or NIPTS. Table II presents major study characteristics o f each o f these studies. As shown in Table D, only die Baughn (1973) study did not screen their workers for otologic abnormalities. These studies report that their populations were restricted to work ers with daily constant levels o f steady state noise exposure for the entire length o f employment A review o f these stud ies' limitations has been addressed by Ward and Glorig (1975) and Yeig e t aL (1975). They include possible con tamination o f non-steady state noise exposure in the popula tion and small sample sizes for subjects exposed to continu ous steady state for daily sound levels below 90 dB. The Passchier-Vermeer report (1968) reviewed published studies and was not specifically designed to address criteria for a noise standard. The NIOSH study (Lempert and Henderson, 1973) was specifically designed to examine risk o f noise- NIOSH in 1972. The aim o f the survey was " to characterize noise exposure levels in a variety o f industries, to describe die hearing status o f workers exposed to such noise condi tions, and to establish a relationship between occupational noise exposure and hearing handicap that would be appli cable to general industry." Subjects for the study were re cruited through notices at industrial hygiene conferences and through the regional offices o f the UJS. Public Health Ser vice. All companies interested in participating were consid ered if certain priority considerations applied. These in cluded (1) existence o f a factory o r occupational noise conditions having noise levels relevant to developing noise standards and criteria, and (2) a work force with a wide range o f years o f exposure to sudi noise levels. The data collected in the survey included noise measure ments, personal background information, medical and oto logica! data and audiometrie examinations. Noise level mea surements (using Bruel-Kjaer Sound Level Meters) were taken at different areas o f each plant and tape recordings were used for laboratory analysis o f noise characteristics. A questionnaire was used to obtain information on each work er's jo b history, military service, hobbies, and medical his tory pertinent to ear abnormalities and hearing difficulty. An otoscopìe inspection o f the ears was also made, usually after die completion o f the questionnaire. Measurements o f hear ing levels (using a Rndmose RA-108 audiometer) for pure tone frequencies o f 0 .5 ,1 , 2, 3 ,4 , and 6 kHz in die right and left ears o f the workers were conducted in a Rndmose audio metrie travel van (model RA-113). Workers from noisy workplaces were always tested at die beginning o f their work s h ift For plants with less than 500 employees, the entire work force was tested. For larger plants, a random sample was selected. Individuals from each plant who worked in offices or other quiet work areas were also included in the survey to provide control data. # B. S c re e n e d popu latio n fo r a n a ly sis The survey population was " screened" to exclude indi viduals with prior noise exposure (from occupational and non-occupational sources) and medical or otologie condi tions that might affect a person's risk o f hearing loss, inde pendent o f occupational noise levels at the time o f the sur vey. Criteria for data exclusion included (I ) uncertainty in the noise exposure history or validity o f audiometrie tests and (2) evidence that hearing loss might have b e a i caused by factors other than occupational noise exposure (e^., military history, other non-occupational noise exposures, head trauma, other audiological/otologic medical conditions). Workers exposed to noise that was not continuous (e.g., dis crete impact sounds or noise with highly variable and unpre dictable levels) and all maintenance workers were also ex cluded. Due to die relatively small number o f females in the survey population, all analyses were limited to 1172 males (792 noise-exposed and 380 controls). # C. V ariable d efin itio n s # D e f i n i t i o n o f h e a r i n g h a n d i c a p The major outcome o f interest is hearing handicap, de fined as a biaural average hearing threshold level o f greater than 25 dB for a selected set o f frequencies. In tins analysis, the set o f frequencies includes (a) 0 .5 ,1 , and 2 kHz, (b) 1,2, and 3 kHz and (c) 1 ,2 , 3, and 4 kHz (heron denoted as 1 -4 kHz). The 1 -4 kHz frequency average was recommended by an American Speech-Language-Hearing Association (ASHA) Task Force (ASHA, 1981), which focused on die need to indude frequencies most affected by noise exposure. The ASHA Task Force recommended that percentage formu las should include hearing threshold levels for 1, 2, 3, and 4 kHz, with low and high fences o f 25 and 75 dB, representing 0 percent and 100 percent hearing handicap boundaries, re spectively (ASHA, 1981). In this analysis, the ASHA recom mendation was modified by calculating a weighted average across frequencies rather than an arithmetic average over the test frequencies o f 1 ,2 ,3 , and 4 kHz. Weights were assigned according to frequency specific articulation indexes (ANSI, 1969). The articulation index (AI) is a weighted fraction rep resenting (for a given listening situation) the effective pro portion o f the speech signal that is available (above a mask ing noise level o r hearing threshold) to a listener for conveying speech intelligibility (ANSI, 1969). Average hearing threshold levels (HTL^g) using the ar ticulation indexes as weights were calculated [Eq. (1)] and then averaged over both ears: ____ h T L \| « W i K ~f~ I f l l^t W a H r L^t = W i + W2+ W i +W 4 • (1) where, W, = 0.24, W2= 0 3 8 , W3= 0 3 4 , and WA= 0 2 4 are die weights at 1, 2, 3, and 4 kHz, respectively. This defini tion will be referred to as the 1-4 kHz AI average" defi nition o f NIHH. # . M e a s u r e m e n t o f n o i s e e x p o s u r e Daily 8-hour time-weighted average (TWA) noise exposure was estimated for each worker or worker group using (1) area survey samples, (2) interviews with workmen and supervisors to establish typical workday patterns and (3) time-study charts. These charts segmented the workday into a succession o f exposures at specific noise levels and for specified durations. Discussions with both management and workmen were necessary to determine changes in noise ex posure over the course o f many years. Consideration was given to variations in occupational noise conditions due to placement or relocation o f machinery and as well as changes in workers' work routine and locations. The reported noise 111 die 1972 NIOSH analysis, those exposed to noise for less d m 6 months were coded as "0" for duntioa of exposure. In die current analysis, con trols were coded as "0** for duration of exposure and exposed individuals with less than 6 months of exposure were given a value of 0-25. levels for the study population represent A-weighted eight hour TWA sound levels calculated assuming a 5 dB ex change rate (i.e., 5 dB increase in sound level is exchanged against a factor o f 2 in duration within the workday). All levels were measured with sound level meters set to " slow" response. The A-weighted daily noise levels were available on the 792 noise-exposed individuals but not available for the 380 controls. Although sound levels for the control popu lation were not recorded, they were reported to be below 80 dB (Lempert and Henderson, 1973). # . O t h e r c o v a r i a t e s Other covariates o f interest in this paper were age and duration o f exposure in years. Tbe risk o f hearing handicap was examined in relation to die covariates defined in Table m . For models that included categorical variables for age (reference: 17-27 years) and duration (reference: 0 -1 years), four indicator variables were created for different levels o f age and duration exposed (Table III). For models that in cluded continuous variables for duration exposed, all con trols were reassigned a duration value o f zero because it was assumed that duration has no effect on the bearing o f the controls. Exposed individuals with less than six months were coded as 0.25 years (midpoint between 0 and 0.5 years). Logistic regression models were used to analyze hearing handicap, defined as the proportion o f individuals whose biaural hearing level is greater than 25 dB for averages over selected frequencies. These logistic regression models were fit using the SAS LOGISTIC procedure (SAS Institute, Inc., 1989) and the nonlinear minimization (NLMINB) routine in S-PLUS (Statistical Sciences, Inc., 1993). Stratified contingency table analyses (Breslow and Day, 1980a) w o e performed to assess these data for qualitative evidence o f hearing handicap due to exposure to noise after controlling for age. The 2X2 contingency tables were strati fied by one year age groups and the prevalence o f bearing handicap among tbe three noise-exposed categories o f 80-84 dB, 85-89 dB, and 90-102 dB were contrasted to the preva lence among controls. One-sided tests for detecting increased rides were computed nsing Mantel-Haenszel methods. Fur ther details o f this method are found in Breslow and Day (1980a). The quantitative relationship between hearing handicap and the covariates (defined below) was modeled using logis tic regression methods (Breslow and Day, 1980b). These models can be expressed as e F i X ,a ,f i .* .L 0 ) P = MY=\\X)= l+eFtX:a^). ( )2 where, p -the expected proportion with average hearing level greater than 25 dB (indicated by Y= I), given X. (Y = 0 indicates an average hearing level is less than or equal to 25 dB); X = a vector o f explanatory variables containing infor mation on age, sound level, and duration o f exposure; F(X;a;fi;^h0)=a+fil (Age) + [ 0 , ( L^-L * ) * ], where LnE= A-weighted 8-hour TWA sound level for noiseexposed workers in dB; L)=parameter for nominal TWA sound level in control population in dB; shape parameter on dB effect; or-intercept parameter; 0i = slope coefficient for age effect; $ 2 , = the slope coefficient for die jth duration o f expo sure (years) interval, where 7 = 1,2,3 represent ex posure intervals o f 2 -4 years, 5 -1 0 years, and > 10 years o f exposure, respectively. # m o d e l d e v e l o p m e n t The first step in the analysis was to fit several hierarchi cal logistic regression models and compare nested models using likelihood ratio tests (LRTs) to identify which param eters significantly improved the fit to the data (Fienberg, 1987). The fit of the model to the data was evaluated using a likelihood ratio test and examining the log likelihood statis tic, G, which is defined by the expression where the summation is over all individuals in the sample (Breslow and Day, 1980b). In general, die lower the value o f G , the better the fit between die model and die data. Differences in G statistics for nested models may be interpreted as chi-squares (Breslow and Day, 1980b). To be consistent with the methodology used in the 1972 NIOSH Noise Criteria Document (NIOSH, 1972), the model was initially fit assuming that the sound level for die control population ( was 79 dB and the shape parameter ( ¿ ) was I. This was accomplished by first fitting models with main effects only and then adding interaction terms between (a) duration exposed and daily TWA sound level (L); (b) dura tion exposed and age; and (c) age and sound leveL These interaction terms tested whether there should be allowance for differing slopes by levels o f other variables. Models with linear main effect o f age, duration exposed, and sound levels were fit with an assumption that all control 8-hour TWA sound levels ( Lq) were 79 dB. This assumption was made because individual noise exposure data for controls were un available but were known to be less than 80 dB (Lempert and Henderson, 1973). Other models with categorical main ef fects o f age and duration were also examined. The final steps of the analysis involved further model refinements that in cluded (1) assuming there is a nondecreasing relationship o f prevalence with sound level and duration; (2) refitting func tional fbnns identified by the LRT strategy accordingly; (3) assuming more flexible models for incorporating the effects o f sound level by permitting the shape parameter (^) to vary; (4) permitting the control sound level (L^) to vary from 79 dB; and (5) conducting sensitivity analyses o f the impact o f critical assumptions. A final fonn o f the model was fit such that all the pa rameters (including Lq and ^) were solved for simulta neously. This model form was fit with the following restric tion: the control level, L^, was bounded at 55 dB and 79 dB. For the final model, a two-sided 90 percent confidence inter val was calculated for several noise levels nsing the paramet ric percentile bootstrap method (Efron and Tibshirani, 1986;Efron, 1982). The same restrictions on w o e applied to 1000 bootstrap samples generated to obtain the confidence limits for excess risk. Graphical displays o f bootstrap-based confidence limits were smoothed nsing localized linear re gression smoothers in S-PLUS (Statistical Sciences, Inc., 1993). # . E x c e s s r i s k e s t i m a t i o n Excess risk for a particular age is defined as die differ ence between the risk o f hearing handicap for the noiseexposed population, given exposure duration, and the expo sure sound level, (where > L<j), « id the risk o f hearing handicap among controls. The excess risk associated with exposure to noise evaluated at a given age was esti mated from logistic models using the following relationship: Excess R isk=Pi[K = l\|a g e , duration, and intensity of exposure] -Pi[ K = 1 Jage, control]. (5) Hence, excess risk is assumed to be equivalent to the in crease in risk o f hearing handicap associated with noise ex posure. # . S e n s i t i v i t y a n a l y s e s Sensitivity analyses were performed to examine how model assumptions may affect the results (ix. excess risk estimates). Assumptions evaluated in this analysis included (1) die shape o f the dose-response relationship; (2) the sound level, Lq, for the control population; and (3) the effect o f using different definitions o f hearing handicap. The first two issues were addressed during model development, where each assumption was varied while die other remained fixed. A comparison o f how excess risk estimates varied with different definition o f hearing handicap was also examined in this analysis. The new definition (1 -4 kHz A1 average) was compared to definitions previously used by NIOSH (1972)biaural hearing levels averaged over 1 -3 kHz and 0.5-2 kHz. The analyses o f different hearing handicap definitions were based on oar final model for each definition o f hearing handicap: the model in which the control sound level ( I q) and shape parameter (^) were simultaneously estimated. # ■L RESULTS Figure 1 shows the hearing threshold level distributions (10th, 50th, 90th percentiles) for different frequencies by age and sound level categories for exposed and control workers. All hearing thresholds shown are averages over the left and right ears. Data are classified into five age groups and three noise exposure categories (80-87 dB, 88 -9 2 dB, 92-102 dB). The boundaries for the age and sound level categories w o e selected to provide adequate sample size (Le., at least 30) in each cell. Sample sizes for the noise-exposed [n (tf£ )] groups are provided for each graph with median exposure duration. The sample sizes for the controls [« (C )] are die same, within age groups (shown in top panel o f each col umn). The graphs show similar exposure durations within each age cell and increasing trends for median hearing threshold levels with age and sound level. In all cases, con trol bearing threshold levels are lower than the noiseexposed population. The tendency o f median hearing thresh olds to increase with increasing age and sound level is also illustrated. The spread o f the distribution (given by the 10th and 90th percentiles) is most marked at 3 and 4 kHz. Despite the limited amount o f data in the low exposure region, the M antel-Haenszel age-stratified analysis provided evidence o f positive excess risk associated with sound lew is ranging from 80 to 84 dB ip =0.02), as well as 85 to 89 dB (p= 0.02) and 90 to 102 dB (p < 0.001). Age was found to be a highly significant predictor o f hearing handicap d u e to noise whether it was modeled using a continuous variable ( * 2=211, d f-l) or a set o f categori cal variables (jr2=213, df=4). The fitted categorical effects for age suggested a linear trend (data not shown). This trend was also apparent when models including sound level and duration w o e f it Therefore, the simpler models with linear effects for age (as a continuous variable) were subsequently considered in the final models. The addition o f either years of exposure or sound level ( L^) significantly improved the fit erf the model containing age. The addition o f both terms further increased the goodness o f f it A statistically signifi cant interaction (^2=29.6. <//= 4) was observed between sound level and categories o f years of exposure. No signifi cant interactions between age and duration exposed, nor age and sound level were observed in this data s e t Based on this preliminary analysis, the best fitting linear model is a function o f continuous age, categorical levels o f duration o f exposure, -and sound level. However, this model initially appeared to be inappropriate for risk assessment be cause the excess risk o f hearing handicap predicted by this model decreased over limited ranges o f sound level and du ration o f exposure. For example, die parameter estimates of this model suggested that the risk o f hearing handicap was lower for individuals with greater than 20 years o f exposure than it was for individuals with 11-20 years o f exposure when the sound level was above 90 dB. We found no statis tically significant difference between die fit o f the model that combined the two highest duration categories (11-20 years and > 20 years combined to > 10 years) and the model with separate parameters for each duration category. This sug gested that risks remain essentially flat after 10 years of ex posure, and that these two categories could be combined. This initial model was further refined to describe predicted risks o f hearing handicap as a nondecreasing function o f ex posure duration and sound level. The models also assume that the effects o f sound level depend on durations greater than or equal to two years. To test whether a linear sound level effect ( $ = I) ad equately described the relationship between noise exposure and risk o f bearing handicap, higher order terms for the sound level effect were tested in the analysis. Using a qua dratic sound level term for exposure (^= 2 ) appreciably im IV. Also shown are the results from fitting a final model in which the control value and the shape parameter were found to be 73 dB and 3.4, respectively (model 4, Table IV). Model 4 is denoted as the "best fitting model,' because it produced (be best fit to die data. These results indicate considerable vari ability in excess risk estimates depending on model form and is likely due to lade o f data at lower sound levels. H us was most marked at average daily sound levels less than or equal to 85 dB. Figure 3 presents excess risk estimates with smoothed 90 percent confidence limits for 65-year-old males with greater than 10 years o f exposure as a function o f sound level for the " best fitting model" (model 4). # A. S en sitiv ity a n a ly se s f . A s s u m p tio n r e g a r d in g c o n tr o l B -h o u r TW A m o u n d le v e ls To examine tbe sensitivity o f risk estimates to the as sumed sound level for the control group, the value o f L was varied from 60 to 79 dB and optimum values o f tbe shape parameter, were estimated. As Lq is varied, there is very little variation in the log likelihood statistic, G , whereas the excess risk estimate for noise exposure at a level o f 80 dB varies between 0.06 and 2.9 (Table V). The results also show that the optimum value o f ^ decreases considerably as tbe assumed value o f I * increases. This analysis suggests that information regarding the distribution o f occupational sound levels within the control population is important in estimat ing the risk o f noise-induced handicap in noise-exposed populations. The variability of excess risk estimates below 85 dB seen in Fig. 3 may be attributed to the lack o f accurate ■Risk estim ai« «an be generated nsmg die following equation: L o g it \ T r iY > 25 dB HL)] » -5X 857 + 00612(Age) + (D urabon=l)K ( Le-L)/ (102-73) 1. where. /$ = 2^653, 3.989, and 6.4206, respectively, fotfte/i dotation o f exposure for 2-4 yean, 5-10 yean, and > 1 0 years, tespectively and y ii die AI-dgfcced faiaunl avenge over 1-4 kHz. For the l o t fitting no d rl, ÿ was estimated to be 1 4 and L* = 73 dB. The term (1 0 2 -7 3 ) in f e denominator o f fte coefficient describing the effect o f datation and w a d level, standardize* the exposure t e n « e h t o t die au» ¡mom capoaire equals one. This was done for ease o f comparison to « id i differing wrimm* for 1« and sound level data among control subjects and the sparseness of the data for workers exposed at sound levels below 85 dB. # . D e f i n i t i o n o f h e a r i n g h a n d i c a p To examine whether excess risk estimates varied by the definition o f hearing handicap used, we compared the 1 -4 kHz AI average definition to two other definitions using (he same fence ( > 25 dB HL), die unweighted biaural frequency averages o f 0 5 -2 kHz and 1 -3 kHz. All three definitions were examined using a model that included age and a dose metric effect defined as ( L^-tim e s duration catego ries (e.g., 2 -4 , 5 -1 0 , and > 1 0 years). The resultant esti mated shape parameters for the 0 i -2 kHz and 1 -3 kHz biaural averages were 4.5 and 4.9, respectively, with Lq equal to 55 dB for both. Under these models, excess risk estimates were affected by both die definition of hearing handicap and die age o f the worker. We also found that changing from the articulation index to a simple average o f 1-4 kHz did not substantially affect excess risk estimates (results not shown). For workers aged 65 years (with > 10 years of exposure), excess risks for the 1 -3 kHz definition are high»' than excess risk for the new definition, particularly for sound levels above 85 dB (Fig. 4A). However, among workers aged 45 with similar years o f exposure, excess risk estimates are similar for all sound levels for the 1-3 kHz definition and the new defini tion (Fig. 4B). For younger workers (aged 30 years) with 5 to 10 years o f exposure, excess risk estimates for the definitions that included 3 kHz and/or 4 kHz, are similar for all sound levels (Fig. 4C). # IV. DISCUSSION The results o f these analyses indicate that there is an excess risk o f noise-induced hearing handicap (NIHH) at 8-hour time-weighted average (TWA) sound levels greater than o r equal to 85 dB. The excess risk below 85 dB was not well defined in our analysis. However, the M antel-Haenszel test result suggests that there is a positive and statistically significant excess risk at levels between 80 and 84 dB. These findings also indicate two major areas o f uncer tainty for quantifying the risk o f noise-induced hearing handicap. The first concerns the sensitivity o f the analysis to the assumed sound level for the control group ( 1^). The second relates to the shape o f the dose-response relationship between the sound levels among the noise-exposed group (¿ me) , duration exposed, and the risk o f NIHH. Risk esti mates w o e found to vary considerably for values of below 85 dB, depending on the assumed control sound level (Lq ), and the shape parameter ( 0 ) for the sound level effect (e.g., linear, quadratic, or cubic) in the models. Sound Lawel to <B HG. 3. f a « 1 » risk (percent) of bearing (¿/-weighing. 1-4 kHz) and bootstrap-based 90% confidence limits from model 4 (Table IV) far 65-year-old males exposed far greater than 10 years to vatying levels o f noise ( L^) . The previous NIOSH (1972) estimate o f excess risk for a 40-year working lifetime o f exposure to noise was approxi mately IS percent at 85 dB. A linear regression model o f log bearing levels was used in the previous analysis (NIOSH, 1972) to estimate the risk o f hearing handicap. NIHH was defined as an average biaural hearing level greater than 25 dB based on unweighted averages o f 0 .5 -2 kHz o r 1 -3 kHz. The model described in the 1972 NIOSH criteria document (NIOSH, 1972) is mathematically equivalent to a probit model in which the risk o f a hearing level greater than 25 dB is o f interest The results from the previous NIOSH analysis (NIOSH, 1972) also appear to be consistent with the assump tion that the control group was exposed to sound levels near 79 dB. It is clear that models which include a quadratic or cubic effect for die sound level effect fit significantly better than the linear effect model and produce lower excess risk esti mates for sound levels below 85 dB than similar models used in the 1972 NIOSH analysis (NIOSH, 1972). As shown in Table IV, the point estimates o f excess risk at 85 dB from die quadratic and cubic models are 8 percent and 3 percent, re spectively. The quadratic and cubic models fit better than the linear model, mainly due to the effect o f sound level in the low exposure region. For sound levels less than or equal to 90 dB, the excess risk estimates from fitting a linear model (Table IV) are slightly higher than those in die NIOSH (1972) analysis. Thus, the disparity in excess risk estimates presented in Table IV may be attributed primarily to the different functional forms (i.e., shape o f the sound level ef fect) o f die fitted models. The logistic model used in this analysis assumes the existence o f a plateau in risk after 10 years o f exposure duration. The analysis comparing different indicators o f NIHH show that patterns o f excess risk as a function o f average daily sound level depend on age. Differences in excess risk were nominal for die 1-4 kHz average, irrespective o f whether HTLs were weighted by the frequency-specific ar ticulation indexes. These differing results by age may be attributable to the fact that the effect o f aging on risk of hearing handicap may overshadow any incremental increases in excess risk due to noise exposure. In the upper range o f duration and sound level, the dose-response curve shows signs of a plateau effect The analysis also suggests »hat the effect o f sound intensity and duration o f exposure is depen dent on frequency. Hearing damage at 3 and 4 kHz is ex pected to occur sooner than loss at lower frequencies (0 .5 ,1 , or 2 kHz). Definitions that exclude the higher frequencies tend to. be less sensitive to noise damage and may require longer durations o f exposure to a given sound level to see significant excess risks in die population. Figure 4A and B suggests that the most suitable defini tion o f hearing handicap may depend on the population char acteristics, such as age, exposure duration, and degree o f hearing handicap already accrued, as well as whether one chooses to identify preclinical or later stages o f hearing handicap. The addition of the most sensitive frequencies to a hearing handicap definition is a valid option if the goal is to have a measure that addresses both prevention and identifi cation o f hearing handicap A. Data lim itations The cross-sectional design o f this study presented limi tations for estimating die risk o f noise-induced hearing handicap. For example, the 8-hour TWA sound levels, ¿ NE^ were determined at one point in time and are assumed to be representative o f exposure over the entire length o f an em ployee's jo b experience. This may have introduced a sub stantial source o f error in the estimation o f . As a means o f reducing this error, die screened ONHS population in cluded only workers who remained in the same job for the entire time that they worked at the study facility. These workers were then assigned an 8-hour TWA sound level based on noise measurements and job activities at the time of the survey. It is possible that larger errors in estimating 8-hour TWA sound levels over a long period o f time may have occurred for workers with longer durations o f exposure. It is also possible that die workers with long durations in cluded in this study represented a population which may have been less sensitive to the adverse effects o f noise on hearing. This may have contributed to the observed decrease in risk with increasing sound level, for durations greater than 20 years. Hence, the cross-sectional design o f the survey introduces areas o f concern for predicting NIHH risks over a working lifetime. # B. M odeling c a v e a ts The data limitations described above also placed limita tions on the modeling approach and interpretations presented in this paper. One data limitation with implications for mod eling the risk of noise-induced hearing handicap, was the lack o f in fo rm a tio n on the distribution o f 8-hour TWA sound levels among the control population. This is a crucial omis sion because all excess risk estimates depend on die risk of handicap among workers with low levels o f occupational noise exposure (in this study, defined as exposure to sound levels less than 80 dB). Due to this lack o f data, a very simplistic assumption was made: sound levels in the control population could be represented by a single number. This is problematic in terms o f model interpretation. First, it ignores the possibility that there may be a distribution o f sound levels below 80 dB for this population. Second, this assumption results in a model that implies that the estimated value (Lq) is a threshold sound level at which no excess risk o f noise-induced hearing handicap is predicted regardless o f the duration o f exposure. Hence, the statistical criteria used in model development are valid only if all of the controls were below a defined thresh old. These modeling issues underscore the fact that all mod els are likely to be dependent on assumptions used to ac count for uncertainty in the available data. This analysis did not model hearing threshold levels as a continuous variable. Therefore, calculation o f NIPTS using these models are not possible. The analysis also did not extensively explore other possible shapes for die sound level function other than (Zhe-Furthermore, modeling exposure duration as a categorical variable limits finer examination o f the relation ship o f duration o f exposure on risk o f hearing handicap. Given this updated analysis o f the NIOSH (1972) data, it is o f interest to compare these results to estimates generated using methodology developed by the International Standards Organization (ISO 1971(ISO , 1990. which was adopted in the ANSI S3.44 standard (ANSI, 1996). This standard was is sued to provide a more accurate and more generalized model of the relationship between NUTS and occupational noise exposure for people at different ages and duration o f expo sure. ANSI S3.44 (ANSI, 1996) provides mathematical pro cedures for estimating bearing handicap due to noise expo sure for populations free from auditory impairment (other than that due to noise). The data from studies by Passchier-Venneer (1968) « id by Bums and Robinson (1970) are the basis o f die ANSI S3.44 (ANSI, 1996) standard for estimating NIKI'S. As with the NIOSH (1972) study, most o f die noise-exposed workers were exposed to daily noise levels ranging from 85 to 95 dB. The Passchier-Venneer (1968) and Robinson (1970) models are represented by different mathematical equations which include an aging (non-noise) component in dB and a N1PTS component in dB. For each model, the equation for NIPTS was determined by age correcting the noise-exposed workers' hearing threshold levels to get the NIFFS compo nent. An empirical equation was developed for NlFTS in terms o f noise level and exposure time. For each model, the aging and NIPTS components were combined to compute total hearing threshold level in dB (ANSI, 1996) 53.44 (ANSI, 1996). Johnson (1978) provides the methodol ogy used to develop risk percent calculations using the per centage o f die population expected to exceed a specific hear ing threshold level (e.g., 25 dB) for a given population. The excess risks generated from our analysis o f the 1-4 kHz AI definition are compared to excess risk estimates gen erated using the ANSI S3.44 (ANSI, 1996) methodology and Annex A as die unexposed population. Annex A was chosen over Annex B since the NIOSH study population was highly screened. Hence, the Annex A highly screened control popu lation is the most appropriate comparison to our study popu lation. As shown in Fig. 5, excess risk estimates from our best fitting model are similar to those estimated by ANSI 53.44 (ANSI, 1996) for workers aged 65 years with 45 years o f exposure. However, among workers aged 45 years with 25 years of exposure, excess risk estimates at sound levels great«' than 90 dB are higher for this analysis as compared to ANSI S3.44 (ANSI, 1996). These results particularly in the range o f 80-90 dB are not surprising given the similarities in study design, data collection and time period for all o f these studies. Although these are qualitative comparisons, the dif ferences in estimates o f lifetime excess risk between ANSI S3.44 (ANSI, 1996) and this analysis do not appear to be substantial. This is illustrated in Fig. 6, which shows that excess risk estimates generated from ANSI S3.44 are located between the bootstrap-based 90% upper and lower confi dence limits from the best fitting logistic model. At age 45 years and 25 years o f exposure, excess risk estimates below 89 dB are within die lowo* bound o f the confidence limits from the logistic model. Thereafter, point estimates from ANSI S3.44 are found to be lower, particularly at sound levels greater than 92 dB. For other definitions o f hearing handicap (0 .5 -2 kHz and 1 -3 kHz), ANSI S3.44 estimates o f excess risk are con siderably lower at 85 dB for workers aged 65 years with 25 years o f exposure. For the 0 .5 -2 kHz definition, excess risks at 85 dB from our logistic model and ANSI S3.44 (ANSI, 1996) are 12% and 1%, respectively. For die 1-3 kHz defi nition, the values are 16% for our model and 4% using ANSI S3.44 (ANSI, 1996) methods. At 80 dB, ANSI S3.44 gener ates excess risks o f 0% for both definitions, while «rim atps from this analysis axe 5% and 6% for die 0 3 -2 kHz and 1-3 kHz definitions, respectively. Some o f the divergen t results may be due to differences in population characteristics o f the studies used to generate excess risks. The NIOSH data set represented a heterogeneous population o f workers from a variety o f geographic regions and worksites within the United States. The study populations used to develop the ANSI S3.44 (ANSI, 1996) models were likely to be more homogeneous with respect to industry, demographic and so cioeconomic (e.g., access to medical care) characteristics. # D. F u tu re cfirectiorts a n d d a ta ne e d s This analysis indicates a need to collect and m alyze data from populations exposed to noise at sound levels below 85 dB to leani more about the shape o f the dose-response rela tionship below 85 dB. Like nm ilar studies conducted in the late 1960 and early 1970's, the screened ONHS data set had few subjects with exposures at levels below 85 dB. This contributed to a high degree o f instability in the risk esti mates as the modeling assumptions were varied. Although logistic modeling techniques were used in this analysis, other methods for evaluating excess risks can reasonably be ap plied to these data. Nonetheless, it seems plausible that the observed instability below 85 dB would persist using ocher modeling methods. Risk estimates in the range o f 88-95 dB are probably more reliable than the estimates for the lower ranges o f sound level. More recent longitudinal data sets may be useful in examining risk below 85 dB. To examine whether noisc-induced bearing handicap remains a problem for workers enrolled in OSHA-mandated bearing conserva tion programs (Department o f Labor, 1981a,1981b), we are currently examining appropriate longitudinal audxm etric da tabases. The present analysis indicates that new studies should be implemented to (1) characterize noise exposure for presumably " non-noise" o r low noise populations (includ ing populations exposed to nonoccupational sources o f noise); and (2) examine dose-response relationships for noise and hearing handicap among workers exposed to noise levels below 90 dB. # ACKNOWLEDGMENTS The authors wish to thank Dr. John (ranks for his useful comments and advice in the development o f this work and Barry Lempen for supplying an electronic version o f die data for this analysis. # Research Needs Considerable progress has been made in our understanding o f occupational hearing loss prevention. However, additional research is needed to clarify the risks associated with various noise and ototoxic exposures and to reduce the incidence o f hearing loss among workers. Furthermore, investigations o f possible biological indicators o f susceptibility to NIHL would be welcome. For example, although tinnitus is a frequent complaint of the noise-exposed worker, its relationship to permanent hearing loss is not well understood. The additional topics listed in the sections below do not include all areas that would benefit from further investigations, but they represent persistent problems or emerging trends. # .1 N o is e C o n tro l Research is needed to reduce noise exposures through engineering controls in work places where the noise exposures are still being controlled primarily by hearing protec tors. An HLPP is complex and difficult to manage effectively, and the need for one can be obviated by noise control procedures that reduce noise levels to less than 85 dBA. As important as such noise reduction technologies are, it is equally important to apply tra ditional noise control engineering concepts to the building o f new facilities and equip ment Research also is needed to improve the retrofitting o f noise controls to existing operations. A database o f effective solutions (best practices) should be created and made accessible to the public. # .2 Im p u lsiv e N o is e Research is needed to define the hazardous parameters o f impulsive noise and their in terrelationships. These parameters should include amplitude, duration, rise time, number o f impulses, repetition rate, and crest factor. In the absence o f any other op tion, impulsive noise is integrated with continuous noise to determine the hazard. Labo ratory research with animals and retrospective studies of workers indicate that impul sive noise is more hazardous to hearing than continuous noise o f the same spectrum and intensity. However, sufficient data are not available to support the development of damage risk criteria for impulsive noises. # .3 N o n a u d ito r y E ffects Research is needed to define dose-response relationships between noise and nonaudi tory effects such as hypertension and psychological stress. Studies ofhypertension con ducted on noise-exposed workers have established a relationship between hypertension and NIHL but have not established a relationship between noise exposure and N o i s e E x p o s u r e hypertension. Workplace accidents need to be analyzed to determine whether noise in terference with oral communication or audio alarms has been a contributing factor. Technologies must be developed to allow easy identification o f warning signals and ef ficient communication in noisy environments while providing effective hearing protection. # .4 A u d ito ry E ffects o f O to to x ic C h em ic a l E x p o su re s The ototoxic properties o f industrial chemicals and their interaction with noise have been investigated for only a few substances. Research in animals is needed to investigate the range o f chemicals known to be ototoxic or neurotoxic and to appraise the risk of hearing loss from exposures to these chemicals alone or in combination with noise. Re search is needed to support damage risk criteria for combined exposure.	None	None
1ec338a5c13557af59f690204941a21f44b8f42b	cdc	None	These revised recommendations of the Advisory Committee on Immunization Practices update the previous recommendations on rabies prevention (MMWR 1991;40:1-14) to reflect the current status of rabies and antirabies biologics in the United States. This report includes new information about a human rabies vaccine approved for U.S. use in 1997, recommendations regarding exposure to bats, recommendations regarding an observation period for domestic ferrets, and changes in the local administration of rabies immune globulin. # Members of the Rabies Working Group Advisory Committee on Immunization Practices (ACIP) INTRODUCTION Rabies is a viral infection transmitted in the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost always fatal. After the marked decrease of rabies cases among domestic animals in the United States in the 1940s and 1950s, indigenously acquired rabies among humans decreased substantially (1 ). In 1950, for example, 4,979 cases of rabies were reported among dogs, and 18 cases were reported among humans. Between 1980 and 1997, 95-247 cases were reported each year among dogs, and on average only two human cases were reported each year in which rabies was attributable to variants of the virus associated with indigenous dogs (2 ). Thus, the likelihood of human exposure to a rabid domestic animal in the United States has decreased greatly. However, during the same period, 12 cases of human rabies were attributed to variants of the rabies virus associated with dogs from outside the United States (3,4 ). Therefore, international travelers to areas where canine rabies is still endemic have an increased risk of exposure to rabies. Rabies among wildlife -especially raccoons, skunks, and bats -has become more prevalent since the 1950s, accounting for >85% of all reported cases of animal rabies every year since 1976 (1 ). Rabies among wildlife occurs throughout the continental United States; only Hawaii remains consistently rabies-free. Wildlife is the most important potential source of infection for both humans and domestic animals in the United States. Since 1980, a total of 21 (58%) of the 36 human cases of rabies diagnosed in the United States have been associated with bat variants (2,5,6 ). In most other countries -including most of Asia, Africa, and Latin America -dogs remain the major species with rabies and the most common source of rabies among humans. Twelve (33%) of the 36 human rabies deaths reported to the Centers for Disease Control and Prevention (CDC) from 1980 through 1997 appear to have been related to rabid animals outside the United States (2,6 ). For assistance with problems or questions about rabies prophylaxis, contact your local or state health department. If local or state health department personnel are unavailable, call the Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC at (404) 639-1050 during working hours or (404) 639-2888 during nights, weekends, and holidays. Although rabies among humans is rare in the United States, every year approximately 16,000-39,000 persons receive postexposure prophylaxis (7 ). To appropriately manage potential human exposures to rabies, the risk of infection must be accurately assessed. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Systemic prophylactic treatments occasionally are complicated by adverse reactions, but these reactions are rarely severe (8)(9)(10)(11)(12). Data on the safety, immunogenicity, and efficacy of active and passive rabies immunization have come from both human and animal studies. Although controlled human trials have not been performed, extensive field experience from many areas of the world indicates that postexposure prophylaxis combining wound treatment, passive immunization, and vaccination is uniformly effective when appropriately applied (13)(14)(15)(16)(17)(18). However, rabies has occasionally developed among humans when key elements of the rabies postexposure prophylaxis regimens were omitted or incorrectly administered (see Treatment Outside the United States). # RABIES BIOLOGICS Two types of rabies immunizing products are available in the United States (Table 1): - Rabies vaccines induce an active immune response that includes the production of neutralizing antibodies. This antibody response requires approximately 7-10 days to develop and usually persists for ≥2 years. - Rabies immune globulin (RIG) provides a rapid, passive immunity that persists for only a short time (half-life of approximately 21 days) (19 ). In all postexposure prophylaxis regimens, except for persons previously immunized, both products should be used concurrently. # Vaccines Licensed for Use in the United States Four formulations of three inactivated rabies vaccines are currently licensed for preexposure and postexposure prophylaxis in the United States (Table 1). When used as indicated, all three types of rabies vaccines are considered equally safe and efficacious. The potency of one dose is ≥2.5 international units (IU) per 1.0 mL of rabies virus antigen, which is the World Health Organization recommended standard (20 ). A full 1.0-mL dose can be used for both preexposure and postexposure prophylaxis. However, only the Imovax ® Rabies I.D. vaccine (human diploid cell vaccine ) has been evaluated and approved by the Food and Drug Administration (FDA) for the intradermal dose and route for preexposure vaccination (21)(22)(23)(24). Therefore, rabies vaccine adsorbed (RVA) and purified chick embryo cell vaccine (PCEC) should not be used intradermally. Usually, an immunization series is initiated and completed with one vaccine product. No clinical studies have been conducted that document a change in efficacy or the frequency of adverse reactions when the series is completed with a second vaccine product. # Human Diploid Cell Vaccine (HDCV) HDCV is prepared from the Pitman-Moore strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration, and inactivated with betapropiolactone (16 ). It is supplied in two forms: - Intramuscular (IM) administration, a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying diluent to a final volume of 1.0 mL just before administration. - Intradermal (ID) administration, a single-dose syringe containing lyophilized vaccine that is reconstituted in the syringe to a final volume of 0.1 mL just before administration (25 ). # Rabies Vaccine Adsorbed (RVA) RVA was developed and is currently manufactured and distributed in the state of Michigan by BioPort Corporation. The vaccine is prepared from the Kissling strain of Challenge Virus Standard (CVS) rabies virus adapted to fetal rhesus lung diploid cell culture (26)(27)(28)(29)(30)(31). The vaccine virus is inactivated with betapropiolactone and concentrated by adsorption to aluminum phosphate. Because RVA is adsorbed to aluminum phosphate, it is liquid rather than lyophilized. It is approved for IM administration only as a 1.0-mL dose. # Purified Chick Embryo Cell Vaccine (PCEC) PCEC became available in the United States in autumn 1997 (32 ). It is prepared from the fixed rabies virus strain Flury LEP grown in primary cultures of chicken fibroblasts. The virus is inactivated with betapropiolactone and further processed by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration only. PCEC is available in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying diluent to a final volume of 1.0 mL just before administration. # Rabies Immune Globulin Licensed for Use in the United States The two RIG products, BayRab™ and Imogam® Rabies-HT (Table 1), are an antirabies immunoglobulin (IgG) preparation concentrated by cold ethanol fractionation from plasma of hyperimmunized human donors. Rabies neutralizing antibody, standardized at a concentration of 150 IU per mL, is supplied in 2-mL (300 IU) vials for pediatric use and 10-mL (1,500 IU) vials for adult use; the recommended dose is 20 IU/kg body weight. Both RIG preparations are considered equally efficacious when used as described in this report (see Treatment of Wounds and Immunization). # PRIMARY OR PREEXPOSURE VACCINATION Preexposure vaccination should be offered to persons in high-risk groups, such as veterinarians, animal handlers, and certain laboratory workers. Preexposure vaccination also should be considered for other persons whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies. In addition, international travelers might be candidates for preexposure vaccination if they are likely to come in contact with animals in areas where dog rabies is enzootic and immediate access to appropriate medical care, including biologics, might be limited. Routine preexposure prophylaxis for other situations might not be indicated (33,34 ). Preexposure prophylaxis is administered for several reasons. First, although preexposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies therapy by eliminating the need for RIG and decreasing the number of doses of vaccine needed -a point of particular importance for persons at high risk for being exposed to rabies in areas where immunizing products might not be available or where they might be at high risk for adverse reactions. Second, preexposure prophylaxis might protect persons whose postexposure therapy is delayed. Finally, it might provide protection to persons at risk for inapparent exposures to rabies. # Intramuscular Primary Vaccination Three 1.0-mL injections of HDCV, RVA, or PCEC should be administered intramuscularly (deltoid area) -one injection per day on days 0, 7, and 21 or 28 (Table 2). In a study in the United States, >1,000 persons received HDCV according to this regimen. Antibody was found in serum samples of all subjects when tested by the rapid fluorescent focus inhibition test (RFFIT). Studies with other products have produced comparable results (21,(35)(36)(37)(38)(39). # Intradermal Primary Vaccination A regimen of three 0.1-mL ID doses of HDCV, one each on days 0, 7, and 21 or 28, is also used for preexposure vaccination (Table 2) as an alternative to the 1.0-mL IM regimen for rabies preexposure prophylaxis with HDCV (8,21,22,24,(35)(36)(37)40 ). A single dose of lyophilized HDCV (Imovax ® Rabies I.D.) is available prepackaged for reconstitution in the syringe just before administration. The syringe is designed to deliver 0.1 mL of HDCV reliably and has been approved by the FDA since 1986 (25). The 0.1-mL ID doses, administered in the area over the deltoid (lateral aspect of the upper arm) on days 0, 7, and 21 or 28, are used for primary preexposure vaccination. One 0.1-mL ID dose is used for routine preexposure booster vaccination (Table 2). The 1.0-mL vial is not approved for multidose ID use. RVA and PCEC are not approved for and should not be administered intradermally (26 ). When chloroquine phosphate was used routinely for malaria prophylaxis, investigators discovered that the drug decreased the antibody response to concomitantly administered HDCV (41). Although interference with the immune response to rabies vaccine by other antimalarials structurally related to chloroquine (e.g., mefloquine) has not been evaluated, precautions for persons receiving these drugs should be followed. Accordingly, HDCV should not be administered intradermally to a person traveling to malaria-endemic countries while the person is receiving one of these antimalarials (42 ). The IM administration of three doses of 1.0 mL of vaccine for preexposure prophylaxis provides a sufficient margin of safety in this situation (42 ). For persons who will be receiving both rabies preexposure prophylaxis and antimalarial chemoprophylaxis in preparation for travel to a rabies-enzootic area, the ID regimen should be initiated at least 1 month before travel to allow for completion of the full three-dose vaccine series before antimalarial prophylaxis begins. If this schedule is not possible, the IM regimen should be used. # Preexposure Booster Doses of Vaccine Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category ) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies antibody every 6 months. Booster doses (IM or ID ) of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT. The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), spelunkers, veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic. Persons in this group should have a serum sample tested for rabies antibody every 2 years; if the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and animal-control and wildlife officers working in areas with low rabies rates (infrequent exposure group) and at-risk international travelers do not require routine preexposure booster doses of vaccine after completion of primary preexposure vaccination. # Postexposure Therapy for Previously Vaccinated Persons If exposed to rabies, previously vaccinated persons should receive two IM doses (1.0 mL each) of vaccine, one immediately and one 3 days later. Previously vaccinated persons are those who have received one of the recommended preexposure or postexposure regimens of HDCV, RVA, or PCEC, or those who received another vaccine and had a documented rabies antibody titer. RIG is unnecessary and should not be administered to these persons because an anamnestic response will follow the administration of a booster regardless of the prebooster antibody titer (44 ). - Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor (43 ). † Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level. # Preexposure Vaccination and Serologic Testing Because the antibody response has been satisfactory after these recommended preexposure prophylaxis vaccine regimens, routine serologic testing to confirm seroconversion is not necessary except for persons suspected of being immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When that is not possible, immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their antibody titers checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public health officials. # POSTEXPOSURE PROPHYLAXIS # Rationale for Treatment Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency. Physicians should evaluate each possible exposure to rabies and, if necessary, consult with local or state public health officials regarding the need for rabies prophylaxis (Table 4). In the United States, the following factors should be considered before specific antirabies postexposure prophylaxis is initiated. *During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. † The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if immunofluorescence test results of the animal are negative. # OBJECTIVE This MMWR provides recommendations for preventing rabies among humans. These recommendations were developed by CDC staff members and the Rabies Working Group of the ACIP. This report is intended to guide clinical practice and policy development related to appropriate management of persons at risk for rabies. Upon completion of this educational activity, the reader should be able to identify groups for whom rabies preexposure prophylaxis is indicated; identify groups for whom rabies serologic testing and booster dosing are indicated; identify some of the common rabies reservoirs in the United States; describe the essential elements of rabies postexposure prophylaxis; and describe appropriate management of persons exposed to bats. # ACCREDITATION Continuing Medical Education (CME): This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) by CDC. CDC is accredited by the ACCME to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1 hour in category 1 credit toward the AMA Physician's Recognition Award. Continuing Education Units (CEU): CDC awards 0.1 hours of CEUs. This activity has been structured following the International Association for Continuing Education and Training (IACET) Criteria and Guidelines and therefore is awarding CEUs. The CEU is a nationally recognized unit designed to provide a record of an individual's continuing education accomplishments. Continuing Nursing Education (CNE) Credit: This activity for 1.2 contact hours is provided by CDC, which is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC) Commission on Accreditation. # EXPIRATION -January 8, 2000 The response form must be completed and returned electronically, by fax, or by mail, postmarked no later than one year from the publication date of this report, for eligibility to receive continuing education credit. 1. In which of the following situations would it be appropriate to administer rabies postexposure prophylaxis? (Indicate all that are true.) # INSTRUCTIONS A. A family discovers a colony of bats in the garage of their home. B. The family cat brings a dead bat into the yard and the 5-year-old son handles it. C. A dead bat (which is tested and found to be positive for rabies) is found in the crib of a 6-month-old baby. D. A troop of Boy Scouts witnesses the emergence of a colony of bats from a cave. # Which of the following are not components of postexposure prophylaxis in the United States? (Indicate all that are false.) A. Thorough cleaning of the wound with at least soap and water. B. Administration of as much rabies immune globulin as possible at the exposure site. C. Intradermal administration of rabies vaccine. D. Intramuscular administration of rabies vaccine. 3. Which of the following statements are true about rabies preexposure prophylaxis? (Indicate all that are true.) A. It is indicated for international travelers only if they will be in a country where rabies is enzootic for greater than 30 days. B. It consists of 3 doses of rabies vaccine administered intramuscularly or intradermally. C. In the event of an exposure, persons who have received preexposure prophylaxis still require 2 booster doses of rabies vaccine, but no rabies immune globulin. D. Veterinarians in areas where rabies is enzootic should have titers checked every 2 years. # Which of the following would be appropriate responses to concerns about nosocomial transmission of rabies from a hospitalized patient suspected of having rabies ? (Indicate all that are true.) A. Contact your local or state health department for assistance. B. Advise that the patient be placed in a negative pressure isolation room. C. Advise immediate vaccination of all hospital personnel involved in the care of the patient. D. Encourage adherence to standard precautions. A. For postexposure prophylaxis to be effective, it must always be administered on the same day the exposure occurred. # A person reports an B. Postexposure prophylaxis should be administered regardless of any delay after a true exposure. C. If rabies immune globulin was not administered when vaccination was begun, it can be administered through the seventh day after the administration of the first dose of vaccine. D. Day 0 refers to the day the first dose of vaccine was administered. 8. Which of the following statements are true? (Indicate all that are true.) A. Human rabies is a fatal disease 50% of the time. B. In the last 2 decades, most human rabies cases in the United States have been associated with bat variants of the rabies virus. C. U.S. citizens traveling abroad can be at risk of exposure to canine rabies. D. Although human rabies cases in the United States are rare, exposure to rabid or potentially rabid animals remains a relatively common event. 9. Indicate your work setting. A Fill in the appropriate block(s) to indicate your answer(s). To receive continuing education credit, you must answer all of the questions. A B C D E F 2. A B C D E F 3. A B C D E F 4. A B C D E F 5. A B C D E F 6. A B C D E F 7. A B C D E F 8. A B C D E F 9. A B C D E F 10. A B C D E F 11. A B C D E F 12. A B C D E F 13. A B C D E F 14. A B C D E F 15. A B C D E F 16. A B C D E F 17. A B C D E F Detach or photocopy. # Types of Exposure Rabies is transmitted only when the virus is introduced into bite wounds or open cuts in skin or onto mucous membranes. If no exposure has occurred (i.e., no bite or nonbite exposure), postexposure prophylaxis is not necessary. The likelihood of rabies infection varies with the nature and extent of exposure. Two categories of exposure -bite and nonbite -should be considered. # Bite Any penetration of the skin by teeth constitutes a bite exposure. All bites, regardless of location, represent a potential risk of rabies transmission. Bites by some animals, such as bats, can inflict minor injury and thus be undetected (45 ). # Nonbite Nonbite exposures from terrestrial animals rarely cause rabies. However, occasional reports of transmission by nonbite exposure suggest that such exposures constitute sufficient reason to consider postexposure prophylaxis (46 ). The nonbite exposures of highest risk appear to be among persons exposed to large amounts of aerosolized rabies virus and surgical recipients of corneas transplanted from patients who died of rabies. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies have been attributed to possible airborne exposures in caves containing millions of free-tailed bats (Tadarida brasiliensis) in the Southwest (47)(48)(49)(50)(51). The contamination of open wounds, abrasions, mucous membranes, or theoretically, scratches, with saliva or other potentially infectious material (such as neural tissue) from a rabid animal also constitutes a nonbite exposure. Other contact by itself, such as petting a rabid animal and contact with blood, urine, or feces (e.g., guano) of a rabid animal, does not constitute an exposure and is not an indication for prophylaxis. Because the rabies virus is inactivated by desiccation and ultraviolet irradiation, in general, if the material containing the virus is dry, the virus can be considered noninfectious. # Human-to-Human Transmission Human-to-human transmission has occurred among eight recipients of transplanted corneas. Investigations revealed each of the donors had died of an illness compatible with or proven to be rabies (52)(53)(54)(55)(56)(57)(58). The eight cases occurred in five countries: Thailand (two cases), India (two cases), Iran (two cases), the United States (one case), and France (one case). Stringent guidelines for acceptance of donor corneas have been implemented to reduce this risk. Apart from corneal transplants, bite and nonbite exposures inflicted by infected humans could theoretically transmit rabies, but no laboratory-diagnosed cases occurring under such situations have been documented (59 ). Two nonlaboratory-confirmed cases of human-to-human rabies transmission in Ethiopia have been described (60 ). The reported route of exposure in both cases was direct salivary contact from another human (a bite and a kiss). Routine delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless exposure of mucous membranes or nonintact skin to potentially infectious body fluids has occurred. Adherence to standard precautions as outlined by the Hospital Infection Control Practices Advisory Committee will minimize the risk of exposure (61 ). # Animal Rabies Epidemiology and Evaluation of Involved Species Bats Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important wildlife reservoirs for variants of rabies virus transmitted to humans (1 ). Recent epidemiologic data suggest that transmission of rabies virus can occur from minor, seemingly unimportant, or unrecognized bites from bats (5,6,62 ). The limited injury inflicted by a bat bite (in contrast to lesions caused by terrestrial carnivores) and an often inaccurate recall of the exact exposure history might limit the ability of health-care providers to determine the risk of rabies resulting from an encounter with a bat (45 ). Human and domestic animal contact with bats should be minimized, and bats should never be handled by untrained and unvaccinated persons or be kept as pets (6,63 ). In all instances of potential human exposures involving bats, the bat in question should be safely collected, if possible, and submitted for rabies diagnosis. Rabies postexposure prophylaxis is recommended for all persons with bite, scratch, or mucous membrane exposure to a bat, unless the bat is available for testing and is negative for evidence of rabies. Postexposure prophylaxis might be appropriate even if a bite, scratch, or mucous membrane exposure is not apparent when there is reasonable probability that such exposure might have occurred. On the basis of the available but sometimes conflicting information from the 21 bat-associated cases of human rabies reported since 1980, in 1-2 cases, a bite was reported; in 10-12 cases, apparent contact occurred but no bite was detected; and in 7-10 cases, no exposure to bats was reported, but an undetected or unreported bat bite remains the most plausible hypothesis. Clustering of bat-associated human cases within the same household has never been reported. Consequently, postexposure prophylaxis should be considered when direct contact between a human and a bat has occurred, unless the exposed person can be certain a bite, scratch, or mucous membrane exposure did not occur. In instances in which a bat is found indoors and there is no history of bat-human contact, the likely effectiveness of postexposure prophylaxis must be balanced against the low risk such exposures appear to present. In this setting, postexposure prophylaxis can be considered for persons who were in the same room as the bat and who might be unaware that a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person) and rabies cannot be ruled out by testing the bat. Postexposure prophylaxis would not be warranted for other household members. # Wild Terrestrial Carnivores Raccoons, skunks, foxes, and coyotes are the terrestrial animals most often infected with rabies. All bites by such wildlife must be considered possible exposures to the rabies virus. Postexposure prophylaxis should be initiated as soon as possible after patients are exposed to wildlife unless the animal has already been tested and shown not to be rabid. If postexposure prophylaxis has been initiated and subsequent immunofluorescence testing shows that the exposing animal was not rabid, postexposure prophylaxis can be discontinued. Signs of rabies among wildlife cannot be interpreted reliably; therefore, any such animal that exposes a person should be euthanized at once (without unnecessary damage to the head) and the brain should be submitted for rabies testing (64 ). If the results of testing are negative by immunofluorescence, the saliva can be assumed to contain no virus, and the person bitten does not require postexposure prophylaxis. # Other Wild Animals Small rodents (e.g., squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (including rabbits and hares) are almost never found to be infected with rabies and have not been known to transmit rabies to humans. From 1990 through 1996, in areas of the country where raccoon rabies was enzootic, woodchucks accounted for 93% of the 371 cases of rabies among rodents reported to CDC (1,65,66). In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate antirabies postexposure prophylaxis (67 ). The offspring of wild animals crossbred to domestic dogs and cats (wild animal hybrids) are considered wild animals by the National Association of State and Public Health Veterinarians (NASPHV) and the Council of State and Territorial Epidemiologists (CSTE). Because the period of rabies virus shedding in these animals is unknown, these animals should be euthanized and tested rather than confined and observed when they bite humans. Wild animals and wild animal hybrids should not be kept as pets (63 ). Animals maintained in United States Department of Agriculturelicensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis. # Domestic Dogs, Cats, and Ferrets The likelihood of rabies in a domestic animal varies by region; hence, the need for postexposure prophylaxis also varies. In the continental United States, rabies among dogs is reported most commonly along the United States-Mexico border and sporadically in areas of the United States with enzootic wildlife rabies. During most of the 1990s, more cats than dogs were reported rabid in the United States. The majority of these cases were associated with the epizootic of rabies among raccoons in the eastern United States. The large number of rabies-infected cats might be attributed to fewer cat vaccination laws, fewer leash laws, and the roaming habits of cats. In many developing countries, dogs are the major vector of rabies; exposures to dogs in such countries represent an increased risk of rabies transmission. On the basis of new information regarding rabies pathogenesis and viral shedding patterns in ferrets, ferrets are now considered in this category with dogs and cats rather than as wild terrestrial carnivores (68 ). A healthy domestic dog, cat, or ferret that bites a person may be confined and observed for 10 days. Any illness in the animal during confinement or before release should be evaluated by a veterinarian and reported immediately to the local public health department. If signs suggestive of rabies develop, the animal should be euthanized and its head removed and shipped, under refrigeration, for examination by a qualified laboratory. If the biting animal is stray or unwanted, it should either be observed for 10 days or be euthanized immediately and submitted for rabies examination (63 ). # Circumstances of Biting Incident and Vaccination Status of Exposing Animal An unprovoked attack by an animal is more likely than a provoked attack to indicate that the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked. A currently vaccinated dog, cat, or ferret is unlikely to become infected with rabies (68)(69)(70)(71). # Treatment of Wounds and Immunization The essential components of rabies postexposure prophylaxis are wound treatment and, for previously unvaccinated persons, the administration of both RIG and vaccine (Table 5 ). Persons who have been bitten by animals suspected or proven to be rabid should begin postexposure prophylaxis immediately. Incubation periods of >1 year have been reported in humans (73 ). Thus, when a documented or likely exposure has occurred, postexposure prophylaxis is indicated regardless of the length of the delay, provided the clinical signs of rabies are not present. In 1977, the World Health Organization recommended a regimen of RIG and six doses of HDCV over a 90-day period. This recommendation was based on studies in Germany and Iran (14,18 ). When used this way, the vaccine was found to be safe and effective in protecting persons bitten by animals proven to be rabid and induced an excellent antibody response in all recipients (14 ). Studies conducted in the United States by CDC have documented that a regimen of one dose of RIG and five doses of HDCV over a 28-day period was safe and induced an excellent antibody response in all recipients (13 ). Clinical trials with RVA and PCEC have demonstrated immunogenicity equivalent to that of HDCV (26,74 ). # Treatment of Wounds Immediate and thorough washing of all bite wounds and scratches with soap and water and a virucidal agent such as a povidone-iodine solution irrigation are important measures for preventing rabies (72 ). In studies of animals, thorough wound cleansing alone without other postexposure prophylaxis has been shown to reduce markedly the likelihood of rabies (75,76 ). Tetanus prophylaxis and measures to control bacterial infection also should be administered as indicated (77 ). The decision to suture large wounds should take into account cosmetic factors and the potential for bacterial infections. # Immunization Postexposure antirabies vaccination should always include administration of both passive antibody and vaccine, with the exception of persons who have previously received complete vaccination regimens (preexposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have had documented rabies antibody titers. These persons should receive only vaccine (see Postexposure Therapy for Previously Vaccinated Persons). The combination of RIG and vaccine is recommended for both bite and nonbite exposures (see Rationale for Treatment), regardless of the interval between exposure and initiation of treatment. Rabies Immune Globulin Use. RIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate antibodies until the patient responds to HDCV, RVA, or PCEC by actively producing antibodies. If RIG was not administered when vaccination was begun, it can be administered through the seventh day after the administration of the first dose of vaccine (78 ). Beyond the seventh day, RIG is not indicated since an antibody response to cell culture vaccine is presumed to have occurred. Because RIG can partially suppress active production of antibody, no more than the recommended dose should be administered (79 ). The recommended dose of human RIG is 20 IU/kg body weight. This formula is applicable to all age groups, including children. If anatomically feasible, the † The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area. § Day 0 is the day the first dose of vaccine is administered. ¶ Any person with a history of preexposure vaccination with HDCV, RVA or PCEC; prior postexposure prophylaxis with HDCV, RVA, or PCEC; or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination. full dose of RIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume should be injected intramuscularly at a site distant from vaccine administration. This change in the recommendations for RIG administration is based on reports of rare failures of postexposure prophylaxis when smaller amounts of RIG were infiltrated at the exposure sites (80 ). RIG should never be administered in the same syringe or in the same anatomical site as vaccine. Vaccine Use. Three rabies vaccines are currently available in the United States (Table 1); any one of the three can be administered in conjunction with RIG at the beginning of postexposure therapy. A regimen of five 1-mL doses of HDCV, RVA, or PCEC should be administered intramuscularly. The first dose of the five-dose course should be administered as soon as possible after exposure. Additional doses should be administered on days 3, 7, 14, and 28 after the first vaccination. For adults, the vaccination should always be administered IM in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for HDCV, RVA, or PCEC injections because administration of HDCV in this area results in lower neutralizing antibody titers (81 ). # Treatment Outside the United States U.S. citizens who are exposed to rabies while traveling outside the United States in countries where rabies is enzootic might sometimes receive postexposure therapy with regimens or biologics that are not used in the United States (Table 6). This information is provided to familiarize physicians with some of the regimens used more widely abroad. The regimens described in the references in this report have not been submitted for approval by the FDA for use in the United States (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). If postexposure prophylaxis is begun outside the United States using one of these regimens or biologics of nerve tissue origin, it might be necessary to provide additional therapy when the patient reaches the United States. State or local health departments should be contacted for specific advice in such cases. If titers are obtained, specimens collected 2-4 weeks after preexposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. Purified equine rabies immune globulin (ERIG) has been used effectively in developing countries where RIG might not have been available. The incidence of adverse reactions has been low (0.8%-6.0%), and most of those that occurred were minor (94-96 ). In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither RIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis (97 ). Although no postexposure vaccine failures have occurred in the United States since cell culture vaccines have been routinely used, failures have occurred abroad when some deviation was made from the recommended postexposure treatment protocol or when less than the currently recommended amount of antirabies sera was administered (80,(98)(99)(100). Specifically, patients who contracted rabies after postexposure prophylaxis did not have their wounds cleansed with soap and water, did not receive their rabies vaccine injections in the deltoid area (i.e., vaccine was administered in the gluteal area), or did not receive RIG around the wound site. # VACCINATION AND SEROLOGIC TESTING # Serologic Response Shortly After Vaccination All persons tested during several CDC studies 2-4 weeks after completion of preexposure and postexposure rabies prophylaxis in accordance with ACIP guidelines have demonstrated an antibody response to rabies (13,38,101,102 ). Therefore, serum samples from patients completing preexposure or postexposure prophylaxis do not need to be tested to document seroconversion unless the person is immunosuppressed (see Precautions and Contraindications). If titers are obtained, specimens collected 2-4 weeks after preexposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. In animal studies, neutralizing antibody titers have been shown to be imperfect markers of protection. Antibody titers will vary with time since the last vaccination. Differences among laboratories that test blood samples also can influence the results. Cell culture vaccines have been used effectively with RIG or ERIG worldwide to treat persons bitten by various rabid animals (13,14 ). Worldwide, the World Health Organization estimates that 10-12 million persons are started on postexposure therapy annually (74 ). An estimated 16,000-39,000 persons in the United States receive a full postexposure course with HDCV each year (7 ). When postexposure prophylaxis has been properly administered, no treatment failures have occurred in the United States. # Serologic Response and Preexposure Booster Doses of Vaccine Although antibody levels do not define a person's immune status, they are a marker of continuing immune response (103 ). To ensure the continuity of an immune response, titers should be checked periodically, with booster doses administered as needed. Two years after primary preexposure vaccination, a 1:5 serum dilution will neutralize challenge virus completely (by the RFFIT) among 93%-98% of persons who received the three-dose preexposure series intramuscularly and 83%-95% of persons who received the three-dose series intradermally (104 ). If the titer falls below the minimum acceptable antibody level, a preexposure booster dose of vaccine is recommended for a person at continuous or frequent risk for exposure to rabies (Table 3). The following guidelines are recommended for determining when serum testing should be performed after primary preexposure vaccination: - A person in the continuous-risk category (Table 3) should have a serum sample tested for rabies antibody every 6 months (43 ). - A person in the frequent-risk category (Table 3) should have a serum sample tested for rabies antibody every 2 years (105 ). State or local health departments can provide the names and addresses of laboratories performing rabies serologic testing. # ADVERSE REACTIONS HDCV, RVA, and PCEC Reactions after vaccination with HDCV, RVA, and PCEC are less serious and less common than with previously available vaccines (74,106,107 ). In previous studies with HDCV, local reactions (e.g., pain, erythema, and swelling or itching at the injection site) have been reported among 30%-74% of recipients (108 ). Systemic reactions (e.g., headache, nausea, abdominal pain, muscle aches, and dizziness) have been reported among 5%-40% of recipients. Three cases of neurologic illness resembling Guillain-Barré syndrome that resolved without sequelae in 12 weeks have been reported (8,109,110 ). In addition, other central and peripheral nervous system disorders have been temporally associated with HDCV vaccine, but a causal relationship has not been established in these rare reports (111 ). An immune complex-like reaction occurred among approximately 6% of persons who received booster doses of HDCV 2-21 days after administration of the booster dose (9,10 ). The patients developed generalized urticaria, sometimes accompanied by arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise. In no cases have these reactions been life-threatening. This reaction occurred less frequently among persons receiving primary vaccination. The reactions have been associated with the presence of betapropiolactone-altered human albumin in the HDCV and the development of immunoglobulin E (IgE) antibodies to this allergen (112)(113)(114). # Rabies Immune Globulin (Human) Local pain and low-grade fever might follow receipt of RIG. Although not reported specifically for RIG, angioneurotic edema, nephrotic syndrome, and anaphylaxis have been reported after injection of immune globulin (IG), a product similar in biochemical composition but without antirabies activity. These reactions occur so rarely that a causal relationship between IG and these reactions has not been established. Both formulations of RIG, BayRab™ and Imogam ® Rabies-HT, undergo multiple viral clearance procedures during preparation. There is no evidence that any viruses have ever been transmitted by commercially available RIG in the United States. # Vaccines and Immune Globulins Used in Other Countries Many developing countries use inactivated nerve tissue vaccines made from the brains of adult animals or suckling mice. Nerve tissue vaccine (NTV) is reported to induce neuroparalytic reactions among approximately 1 per 200 to 1 per 2,000 persons vaccinated; suckling mouse brain vaccine (SMBV) causes reactions in approximately 1 per 8,000 persons vaccinated (15,115 ). The vaccines HDCV, PCEC, PDEV, and purified vero cell rabies vaccine (PVRV) (Table 6) are cell culture-derived and not of nerve tissue origin. In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither RIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis. # Management of Adverse Reactions Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. Usually, such reactions can be successfully managed with antiinflammatory and antipyretic agents, such as ibuprofen or acetaminophen. When a person with a history of serious hypersensitivity to rabies vaccine must be revaccinated, antihistamines can be administered. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination. Although serious systemic, anaphylactic, or neuroparalytic reactions are rare during and after the administration of rabies vaccines, such reactions pose a serious dilemma for the patient and the attending physician (9 ). A patient's risk of acquiring rabies must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious adverse reactions for persons receiving rabies vaccines may be sought from the state health department or CDC. All serious systemic, neuroparalytic, or anaphylactic reactions should be reported to the Vaccine Adverse Event Reporting System (VAERS) via a 24-hour toll-free telephone number ( 822-7967). # PRECAUTIONS AND CONTRAINDICATIONS Immunosuppression Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination (41,116 ). For persons with immunosuppression, preexposure prophylaxis should be administered with the awareness that the immune response might be inadequate (see Primary or Preexposure Vaccination). Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should be vaccinated by the IM route and their antibody titers checked. Failure to seroconvert after the third dose should be managed in consultation with appropriate public health officials (see Preexposure Vaccination and Serologic Testing). Immunosuppressive agents should not be administered during postexposure therapy unless essential for the treatment of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, it is especially The following CDC staff member prepared this report: important that a serum sample be tested for rabies antibody to ensure that an acceptable antibody response has developed. # Pregnancy Because of the potential consequences of inadequately treated rabies exposure, and because there is no indication that fetal abnormalities have been associated with rabies vaccination, pregnancy is not considered a contraindication to postexposure prophylaxis (117,118 ). If the risk of exposure to rabies is substantial, preexposure prophylaxis might also be indicated during pregnancy. # Allergies Persons who have a history of serious hypersensitivity to rabies vaccine should be revaccinated with caution (see Management of Adverse Reactions). All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1998-733-228/87050 Region IV MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	These revised recommendations of the Advisory Committee on Immunization Practices update the previous recommendations on rabies prevention (MMWR 1991;40[No.RR-3]:1-14) to reflect the current status of rabies and antirabies biologics in the United States. This report includes new information about a human rabies vaccine approved for U.S. use in 1997, recommendations regarding exposure to bats, recommendations regarding an observation period for domestic ferrets, and changes in the local administration of rabies immune globulin. # Members of the Rabies Working Group Advisory Committee on Immunization Practices (ACIP) INTRODUCTION Rabies is a viral infection transmitted in the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost always fatal. After the marked decrease of rabies cases among domestic animals in the United States in the 1940s and 1950s, indigenously acquired rabies among humans decreased substantially (1 ). In 1950, for example, 4,979 cases of rabies were reported among dogs, and 18 cases were reported among humans. Between 1980 and 1997, 95-247 cases were reported each year among dogs, and on average only two human cases were reported each year in which rabies was attributable to variants of the virus associated with indigenous dogs (2 ). Thus, the likelihood of human exposure to a rabid domestic animal in the United States has decreased greatly. However, during the same period, 12 cases of human rabies were attributed to variants of the rabies virus associated with dogs from outside the United States (3,4 ). Therefore, international travelers to areas where canine rabies is still endemic have an increased risk of exposure to rabies. Rabies among wildlife -especially raccoons, skunks, and bats -has become more prevalent since the 1950s, accounting for >85% of all reported cases of animal rabies every year since 1976 (1 ). Rabies among wildlife occurs throughout the continental United States; only Hawaii remains consistently rabies-free. Wildlife is the most important potential source of infection for both humans and domestic animals in the United States. Since 1980, a total of 21 (58%) of the 36 human cases of rabies diagnosed in the United States have been associated with bat variants (2,5,6 ). In most other countries -including most of Asia, Africa, and Latin America -dogs remain the major species with rabies and the most common source of rabies among humans. Twelve (33%) of the 36 human rabies deaths reported to the Centers for Disease Control and Prevention (CDC) from 1980 through 1997 appear to have been related to rabid animals outside the United States (2,6 ). For assistance with problems or questions about rabies prophylaxis, contact your local or state health department. If local or state health department personnel are unavailable, call the Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC at (404) 639-1050 during working hours or (404) 639-2888 during nights, weekends, and holidays. Although rabies among humans is rare in the United States, every year approximately 16,000-39,000 persons receive postexposure prophylaxis (7 ). To appropriately manage potential human exposures to rabies, the risk of infection must be accurately assessed. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions must not be delayed. Systemic prophylactic treatments occasionally are complicated by adverse reactions, but these reactions are rarely severe (8)(9)(10)(11)(12). Data on the safety, immunogenicity, and efficacy of active and passive rabies immunization have come from both human and animal studies. Although controlled human trials have not been performed, extensive field experience from many areas of the world indicates that postexposure prophylaxis combining wound treatment, passive immunization, and vaccination is uniformly effective when appropriately applied (13)(14)(15)(16)(17)(18). However, rabies has occasionally developed among humans when key elements of the rabies postexposure prophylaxis regimens were omitted or incorrectly administered (see Treatment Outside the United States). # RABIES BIOLOGICS Two types of rabies immunizing products are available in the United States (Table 1): • Rabies vaccines induce an active immune response that includes the production of neutralizing antibodies. This antibody response requires approximately 7-10 days to develop and usually persists for ≥2 years. • Rabies immune globulin (RIG) provides a rapid, passive immunity that persists for only a short time (half-life of approximately 21 days) (19 ). In all postexposure prophylaxis regimens, except for persons previously immunized, both products should be used concurrently. # Vaccines Licensed for Use in the United States Four formulations of three inactivated rabies vaccines are currently licensed for preexposure and postexposure prophylaxis in the United States (Table 1). When used as indicated, all three types of rabies vaccines are considered equally safe and efficacious. The potency of one dose is ≥2.5 international units (IU) per 1.0 mL of rabies virus antigen, which is the World Health Organization recommended standard (20 ). A full 1.0-mL dose can be used for both preexposure and postexposure prophylaxis. However, only the Imovax ® Rabies I.D. vaccine (human diploid cell vaccine [HDCV] ) has been evaluated and approved by the Food and Drug Administration (FDA) for the intradermal dose and route for preexposure vaccination (21)(22)(23)(24). Therefore, rabies vaccine adsorbed (RVA) and purified chick embryo cell vaccine (PCEC) should not be used intradermally. Usually, an immunization series is initiated and completed with one vaccine product. No clinical studies have been conducted that document a change in efficacy or the frequency of adverse reactions when the series is completed with a second vaccine product. # Human Diploid Cell Vaccine (HDCV) HDCV is prepared from the Pitman-Moore strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration, and inactivated with betapropiolactone (16 ). It is supplied in two forms: • Intramuscular (IM) administration, a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying diluent to a final volume of 1.0 mL just before administration. • Intradermal (ID) administration, a single-dose syringe containing lyophilized vaccine that is reconstituted in the syringe to a final volume of 0.1 mL just before administration (25 ). # Rabies Vaccine Adsorbed (RVA) RVA was developed and is currently manufactured and distributed in the state of Michigan by BioPort Corporation. The vaccine is prepared from the Kissling strain of Challenge Virus Standard (CVS) rabies virus adapted to fetal rhesus lung diploid cell culture (26)(27)(28)(29)(30)(31). The vaccine virus is inactivated with betapropiolactone and concentrated by adsorption to aluminum phosphate. Because RVA is adsorbed to aluminum phosphate, it is liquid rather than lyophilized. It is approved for IM administration only as a 1.0-mL dose. # Purified Chick Embryo Cell Vaccine (PCEC) PCEC became available in the United States in autumn 1997 (32 ). It is prepared from the fixed rabies virus strain Flury LEP grown in primary cultures of chicken fibroblasts. The virus is inactivated with betapropiolactone and further processed by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration only. PCEC is available in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying diluent to a final volume of 1.0 mL just before administration. # Rabies Immune Globulin Licensed for Use in the United States The two RIG products, BayRab™ and Imogam® Rabies-HT (Table 1), are an antirabies immunoglobulin (IgG) preparation concentrated by cold ethanol fractionation from plasma of hyperimmunized human donors. Rabies neutralizing antibody, standardized at a concentration of 150 IU per mL, is supplied in 2-mL (300 IU) vials for pediatric use and 10-mL (1,500 IU) vials for adult use; the recommended dose is 20 IU/kg body weight. Both RIG preparations are considered equally efficacious when used as described in this report (see Treatment of Wounds and Immunization). # PRIMARY OR PREEXPOSURE VACCINATION Preexposure vaccination should be offered to persons in high-risk groups, such as veterinarians, animal handlers, and certain laboratory workers. Preexposure vaccination also should be considered for other persons whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies. In addition, international travelers might be candidates for preexposure vaccination if they are likely to come in contact with animals in areas where dog rabies is enzootic and immediate access to appropriate medical care, including biologics, might be limited. Routine preexposure prophylaxis for other situations might not be indicated (33,34 ). Preexposure prophylaxis is administered for several reasons. First, although preexposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies therapy by eliminating the need for RIG and decreasing the number of doses of vaccine needed -a point of particular importance for persons at high risk for being exposed to rabies in areas where immunizing products might not be available or where they might be at high risk for adverse reactions. Second, preexposure prophylaxis might protect persons whose postexposure therapy is delayed. Finally, it might provide protection to persons at risk for inapparent exposures to rabies. # Intramuscular Primary Vaccination Three 1.0-mL injections of HDCV, RVA, or PCEC should be administered intramuscularly (deltoid area) -one injection per day on days 0, 7, and 21 or 28 (Table 2). In a study in the United States, >1,000 persons received HDCV according to this regimen. Antibody was found in serum samples of all subjects when tested by the rapid fluorescent focus inhibition test (RFFIT). Studies with other products have produced comparable results (21,(35)(36)(37)(38)(39). # Intradermal Primary Vaccination A regimen of three 0.1-mL ID doses of HDCV, one each on days 0, 7, and 21 or 28, is also used for preexposure vaccination (Table 2) as an alternative to the 1.0-mL IM regimen for rabies preexposure prophylaxis with HDCV (8,21,22,24,(35)(36)(37)40 ). A single dose of lyophilized HDCV (Imovax ® Rabies I.D.) is available prepackaged for reconstitution in the syringe just before administration. The syringe is designed to deliver 0.1 mL of HDCV reliably and has been approved by the FDA since 1986 (25). The 0.1-mL ID doses, administered in the area over the deltoid (lateral aspect of the upper arm) on days 0, 7, and 21 or 28, are used for primary preexposure vaccination. One 0.1-mL ID dose is used for routine preexposure booster vaccination (Table 2). The 1.0-mL vial is not approved for multidose ID use. RVA and PCEC are not approved for and should not be administered intradermally (26 ). When chloroquine phosphate was used routinely for malaria prophylaxis, investigators discovered that the drug decreased the antibody response to concomitantly administered HDCV (41). Although interference with the immune response to rabies vaccine by other antimalarials structurally related to chloroquine (e.g., mefloquine) has not been evaluated, precautions for persons receiving these drugs should be followed. Accordingly, HDCV should not be administered intradermally to a person traveling to malaria-endemic countries while the person is receiving one of these antimalarials (42 ). The IM administration of three doses of 1.0 mL of vaccine for preexposure prophylaxis provides a sufficient margin of safety in this situation (42 ). For persons who will be receiving both rabies preexposure prophylaxis and antimalarial chemoprophylaxis in preparation for travel to a rabies-enzootic area, the ID regimen should be initiated at least 1 month before travel to allow for completion of the full three-dose vaccine series before antimalarial prophylaxis begins. If this schedule is not possible, the IM regimen should be used. # Preexposure Booster Doses of Vaccine Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category [Table 3] [43 ]) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies antibody every 6 months. Booster doses (IM or ID [Table 2]) of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT. The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), spelunkers, veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic. Persons in this group should have a serum sample tested for rabies antibody every 2 years; if the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and animal-control and wildlife officers working in areas with low rabies rates (infrequent exposure group) and at-risk international travelers do not require routine preexposure booster doses of vaccine after completion of primary preexposure vaccination. # Postexposure Therapy for Previously Vaccinated Persons If exposed to rabies, previously vaccinated persons should receive two IM doses (1.0 mL each) of vaccine, one immediately and one 3 days later. Previously vaccinated persons are those who have received one of the recommended preexposure or postexposure regimens of HDCV, RVA, or PCEC, or those who received another vaccine and had a documented rabies antibody titer. RIG is unnecessary and should not be administered to these persons because an anamnestic response will follow the administration of a booster regardless of the prebooster antibody titer (44 ). * Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor (43 ). † Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level. # Preexposure Vaccination and Serologic Testing Because the antibody response has been satisfactory after these recommended preexposure prophylaxis vaccine regimens, routine serologic testing to confirm seroconversion is not necessary except for persons suspected of being immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When that is not possible, immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their antibody titers checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public health officials. # POSTEXPOSURE PROPHYLAXIS # Rationale for Treatment Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency. Physicians should evaluate each possible exposure to rabies and, if necessary, consult with local or state public health officials regarding the need for rabies prophylaxis (Table 4). In the United States, the following factors should be considered before specific antirabies postexposure prophylaxis is initiated. *During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. † The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if immunofluorescence test results of the animal are negative. # OBJECTIVE This MMWR provides recommendations for preventing rabies among humans. These recommendations were developed by CDC staff members and the Rabies Working Group of the ACIP. This report is intended to guide clinical practice and policy development related to appropriate management of persons at risk for rabies. Upon completion of this educational activity, the reader should be able to identify groups for whom rabies preexposure prophylaxis is indicated; identify groups for whom rabies serologic testing and booster dosing are indicated; identify some of the common rabies reservoirs in the United States; describe the essential elements of rabies postexposure prophylaxis; and describe appropriate management of persons exposed to bats. # ACCREDITATION Continuing Medical Education (CME): This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) by CDC. CDC is accredited by the ACCME to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1 hour in category 1 credit toward the AMA Physician's Recognition Award. Continuing Education Units (CEU): CDC awards 0.1 hours of CEUs. This activity has been structured following the International Association for Continuing Education and Training (IACET) Criteria and Guidelines and therefore is awarding CEUs. The CEU is a nationally recognized unit designed to provide a record of an individual's continuing education accomplishments. Continuing Nursing Education (CNE) Credit: This activity for 1.2 contact hours is provided by CDC, which is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC) Commission on Accreditation. # EXPIRATION -January 8, 2000 The response form must be completed and returned electronically, by fax, or by mail, postmarked no later than one year from the publication date of this report, for eligibility to receive continuing education credit. 1. In which of the following situations would it be appropriate to administer rabies postexposure prophylaxis? (Indicate all that are true.) # INSTRUCTIONS A. A family discovers a colony of bats in the garage of their home. B. The family cat brings a dead bat into the yard and the 5-year-old son handles it. C. A dead bat (which is tested and found to be positive for rabies) is found in the crib of a 6-month-old baby. D. A troop of Boy Scouts witnesses the emergence of a colony of bats from a cave. # Which of the following are not components of postexposure prophylaxis in the United States? (Indicate all that are false.) A. Thorough cleaning of the wound with at least soap and water. B. Administration of as much rabies immune globulin as possible at the exposure site. C. Intradermal administration of rabies vaccine. D. Intramuscular administration of rabies vaccine. 3. Which of the following statements are true about rabies preexposure prophylaxis? (Indicate all that are true.) A. It is indicated for international travelers only if they will be in a country where rabies is enzootic for greater than 30 days. B. It consists of 3 doses of rabies vaccine administered intramuscularly or intradermally. C. In the event of an exposure, persons who have received preexposure prophylaxis still require 2 booster doses of rabies vaccine, but no rabies immune globulin. D. Veterinarians in areas where rabies is enzootic should have titers checked every 2 years. # Which of the following would be appropriate responses to concerns about nosocomial transmission of rabies from a hospitalized patient suspected of having rabies ? (Indicate all that are true.) A. Contact your local or state health department for assistance. B. Advise that the patient be placed in a negative pressure isolation room. C. Advise immediate vaccination of all hospital personnel involved in the care of the patient. D. Encourage adherence to standard precautions. A. For postexposure prophylaxis to be effective, it must always be administered on the same day the exposure occurred. # A person reports an B. Postexposure prophylaxis should be administered regardless of any delay after a true exposure. C. If rabies immune globulin was not administered when vaccination was begun, it can be administered through the seventh day after the administration of the first dose of vaccine. D. Day 0 refers to the day the first dose of vaccine was administered. 8. Which of the following statements are true? (Indicate all that are true.) A. Human rabies is a fatal disease 50% of the time. B. In the last 2 decades, most human rabies cases in the United States have been associated with bat variants of the rabies virus. C. U.S. citizens traveling abroad can be at risk of exposure to canine rabies. D. Although human rabies cases in the United States are rare, exposure to rabid or potentially rabid animals remains a relatively common event. 9. Indicate your work setting. A Fill in the appropriate block(s) to indicate your answer(s). To receive continuing education credit, you must answer all of the questions. # [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 2. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 3. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 4. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 5. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 6. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 7. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 8. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 9. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 10. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 11. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 12. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 13. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 14. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 15. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 16. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 17. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F Detach or photocopy. # Types of Exposure Rabies is transmitted only when the virus is introduced into bite wounds or open cuts in skin or onto mucous membranes. If no exposure has occurred (i.e., no bite or nonbite exposure), postexposure prophylaxis is not necessary. The likelihood of rabies infection varies with the nature and extent of exposure. Two categories of exposure -bite and nonbite -should be considered. # Bite Any penetration of the skin by teeth constitutes a bite exposure. All bites, regardless of location, represent a potential risk of rabies transmission. Bites by some animals, such as bats, can inflict minor injury and thus be undetected (45 ). # Nonbite Nonbite exposures from terrestrial animals rarely cause rabies. However, occasional reports of transmission by nonbite exposure suggest that such exposures constitute sufficient reason to consider postexposure prophylaxis (46 ). The nonbite exposures of highest risk appear to be among persons exposed to large amounts of aerosolized rabies virus and surgical recipients of corneas transplanted from patients who died of rabies. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies have been attributed to possible airborne exposures in caves containing millions of free-tailed bats (Tadarida brasiliensis) in the Southwest (47)(48)(49)(50)(51). The contamination of open wounds, abrasions, mucous membranes, or theoretically, scratches, with saliva or other potentially infectious material (such as neural tissue) from a rabid animal also constitutes a nonbite exposure. Other contact by itself, such as petting a rabid animal and contact with blood, urine, or feces (e.g., guano) of a rabid animal, does not constitute an exposure and is not an indication for prophylaxis. Because the rabies virus is inactivated by desiccation and ultraviolet irradiation, in general, if the material containing the virus is dry, the virus can be considered noninfectious. # Human-to-Human Transmission Human-to-human transmission has occurred among eight recipients of transplanted corneas. Investigations revealed each of the donors had died of an illness compatible with or proven to be rabies (52)(53)(54)(55)(56)(57)(58). The eight cases occurred in five countries: Thailand (two cases), India (two cases), Iran (two cases), the United States (one case), and France (one case). Stringent guidelines for acceptance of donor corneas have been implemented to reduce this risk. Apart from corneal transplants, bite and nonbite exposures inflicted by infected humans could theoretically transmit rabies, but no laboratory-diagnosed cases occurring under such situations have been documented (59 ). Two nonlaboratory-confirmed cases of human-to-human rabies transmission in Ethiopia have been described (60 ). The reported route of exposure in both cases was direct salivary contact from another human (a bite and a kiss). Routine delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless exposure of mucous membranes or nonintact skin to potentially infectious body fluids has occurred. Adherence to standard precautions as outlined by the Hospital Infection Control Practices Advisory Committee will minimize the risk of exposure (61 ). # Animal Rabies Epidemiology and Evaluation of Involved Species Bats Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important wildlife reservoirs for variants of rabies virus transmitted to humans (1 ). Recent epidemiologic data suggest that transmission of rabies virus can occur from minor, seemingly unimportant, or unrecognized bites from bats (5,6,62 ). The limited injury inflicted by a bat bite (in contrast to lesions caused by terrestrial carnivores) and an often inaccurate recall of the exact exposure history might limit the ability of health-care providers to determine the risk of rabies resulting from an encounter with a bat (45 ). Human and domestic animal contact with bats should be minimized, and bats should never be handled by untrained and unvaccinated persons or be kept as pets (6,63 ). In all instances of potential human exposures involving bats, the bat in question should be safely collected, if possible, and submitted for rabies diagnosis. Rabies postexposure prophylaxis is recommended for all persons with bite, scratch, or mucous membrane exposure to a bat, unless the bat is available for testing and is negative for evidence of rabies. Postexposure prophylaxis might be appropriate even if a bite, scratch, or mucous membrane exposure is not apparent when there is reasonable probability that such exposure might have occurred. On the basis of the available but sometimes conflicting information from the 21 bat-associated cases of human rabies reported since 1980, in 1-2 cases, a bite was reported; in 10-12 cases, apparent contact occurred but no bite was detected; and in 7-10 cases, no exposure to bats was reported, but an undetected or unreported bat bite remains the most plausible hypothesis. Clustering of bat-associated human cases within the same household has never been reported. Consequently, postexposure prophylaxis should be considered when direct contact between a human and a bat has occurred, unless the exposed person can be certain a bite, scratch, or mucous membrane exposure did not occur. In instances in which a bat is found indoors and there is no history of bat-human contact, the likely effectiveness of postexposure prophylaxis must be balanced against the low risk such exposures appear to present. In this setting, postexposure prophylaxis can be considered for persons who were in the same room as the bat and who might be unaware that a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person) and rabies cannot be ruled out by testing the bat. Postexposure prophylaxis would not be warranted for other household members. # Wild Terrestrial Carnivores Raccoons, skunks, foxes, and coyotes are the terrestrial animals most often infected with rabies. All bites by such wildlife must be considered possible exposures to the rabies virus. Postexposure prophylaxis should be initiated as soon as possible after patients are exposed to wildlife unless the animal has already been tested and shown not to be rabid. If postexposure prophylaxis has been initiated and subsequent immunofluorescence testing shows that the exposing animal was not rabid, postexposure prophylaxis can be discontinued. Signs of rabies among wildlife cannot be interpreted reliably; therefore, any such animal that exposes a person should be euthanized at once (without unnecessary damage to the head) and the brain should be submitted for rabies testing (64 ). If the results of testing are negative by immunofluorescence, the saliva can be assumed to contain no virus, and the person bitten does not require postexposure prophylaxis. # Other Wild Animals Small rodents (e.g., squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (including rabbits and hares) are almost never found to be infected with rabies and have not been known to transmit rabies to humans. From 1990 through 1996, in areas of the country where raccoon rabies was enzootic, woodchucks accounted for 93% of the 371 cases of rabies among rodents reported to CDC (1,65,66). In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate antirabies postexposure prophylaxis (67 ). The offspring of wild animals crossbred to domestic dogs and cats (wild animal hybrids) are considered wild animals by the National Association of State and Public Health Veterinarians (NASPHV) and the Council of State and Territorial Epidemiologists (CSTE). Because the period of rabies virus shedding in these animals is unknown, these animals should be euthanized and tested rather than confined and observed when they bite humans. Wild animals and wild animal hybrids should not be kept as pets (63 ). Animals maintained in United States Department of Agriculturelicensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis. # Domestic Dogs, Cats, and Ferrets The likelihood of rabies in a domestic animal varies by region; hence, the need for postexposure prophylaxis also varies. In the continental United States, rabies among dogs is reported most commonly along the United States-Mexico border and sporadically in areas of the United States with enzootic wildlife rabies. During most of the 1990s, more cats than dogs were reported rabid in the United States. The majority of these cases were associated with the epizootic of rabies among raccoons in the eastern United States. The large number of rabies-infected cats might be attributed to fewer cat vaccination laws, fewer leash laws, and the roaming habits of cats. In many developing countries, dogs are the major vector of rabies; exposures to dogs in such countries represent an increased risk of rabies transmission. On the basis of new information regarding rabies pathogenesis and viral shedding patterns in ferrets, ferrets are now considered in this category with dogs and cats rather than as wild terrestrial carnivores (68 ). A healthy domestic dog, cat, or ferret that bites a person may be confined and observed for 10 days. Any illness in the animal during confinement or before release should be evaluated by a veterinarian and reported immediately to the local public health department. If signs suggestive of rabies develop, the animal should be euthanized and its head removed and shipped, under refrigeration, for examination by a qualified laboratory. If the biting animal is stray or unwanted, it should either be observed for 10 days or be euthanized immediately and submitted for rabies examination (63 ). # Circumstances of Biting Incident and Vaccination Status of Exposing Animal An unprovoked attack by an animal is more likely than a provoked attack to indicate that the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked. A currently vaccinated dog, cat, or ferret is unlikely to become infected with rabies (68)(69)(70)(71). # Treatment of Wounds and Immunization The essential components of rabies postexposure prophylaxis are wound treatment and, for previously unvaccinated persons, the administration of both RIG and vaccine (Table 5 [72 ]). Persons who have been bitten by animals suspected or proven to be rabid should begin postexposure prophylaxis immediately. Incubation periods of >1 year have been reported in humans (73 ). Thus, when a documented or likely exposure has occurred, postexposure prophylaxis is indicated regardless of the length of the delay, provided the clinical signs of rabies are not present. In 1977, the World Health Organization recommended a regimen of RIG and six doses of HDCV over a 90-day period. This recommendation was based on studies in Germany and Iran (14,18 ). When used this way, the vaccine was found to be safe and effective in protecting persons bitten by animals proven to be rabid and induced an excellent antibody response in all recipients (14 ). Studies conducted in the United States by CDC have documented that a regimen of one dose of RIG and five doses of HDCV over a 28-day period was safe and induced an excellent antibody response in all recipients (13 ). Clinical trials with RVA and PCEC have demonstrated immunogenicity equivalent to that of HDCV (26,74 ). # Treatment of Wounds Immediate and thorough washing of all bite wounds and scratches with soap and water and a virucidal agent such as a povidone-iodine solution irrigation are important measures for preventing rabies (72 ). In studies of animals, thorough wound cleansing alone without other postexposure prophylaxis has been shown to reduce markedly the likelihood of rabies (75,76 ). Tetanus prophylaxis and measures to control bacterial infection also should be administered as indicated (77 ). The decision to suture large wounds should take into account cosmetic factors and the potential for bacterial infections. # Immunization Postexposure antirabies vaccination should always include administration of both passive antibody and vaccine, with the exception of persons who have previously received complete vaccination regimens (preexposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types of vaccines and have had documented rabies antibody titers. These persons should receive only vaccine (see Postexposure Therapy for Previously Vaccinated Persons). The combination of RIG and vaccine is recommended for both bite and nonbite exposures (see Rationale for Treatment), regardless of the interval between exposure and initiation of treatment. Rabies Immune Globulin Use. RIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate antibodies until the patient responds to HDCV, RVA, or PCEC by actively producing antibodies. If RIG was not administered when vaccination was begun, it can be administered through the seventh day after the administration of the first dose of vaccine (78 ). Beyond the seventh day, RIG is not indicated since an antibody response to cell culture vaccine is presumed to have occurred. Because RIG can partially suppress active production of antibody, no more than the recommended dose should be administered (79 ). The recommended dose of human RIG is 20 IU/kg body weight. This formula is applicable to all age groups, including children. If anatomically feasible, the † The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area. § Day 0 is the day the first dose of vaccine is administered. ¶ Any person with a history of preexposure vaccination with HDCV, RVA or PCEC; prior postexposure prophylaxis with HDCV, RVA, or PCEC; or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination. full dose of RIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume should be injected intramuscularly at a site distant from vaccine administration. This change in the recommendations for RIG administration is based on reports of rare failures of postexposure prophylaxis when smaller amounts of RIG were infiltrated at the exposure sites (80 ). RIG should never be administered in the same syringe or in the same anatomical site as vaccine. Vaccine Use. Three rabies vaccines are currently available in the United States (Table 1); any one of the three can be administered in conjunction with RIG at the beginning of postexposure therapy. A regimen of five 1-mL doses of HDCV, RVA, or PCEC should be administered intramuscularly. The first dose of the five-dose course should be administered as soon as possible after exposure. Additional doses should be administered on days 3, 7, 14, and 28 after the first vaccination. For adults, the vaccination should always be administered IM in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for HDCV, RVA, or PCEC injections because administration of HDCV in this area results in lower neutralizing antibody titers (81 ). # Treatment Outside the United States U.S. citizens who are exposed to rabies while traveling outside the United States in countries where rabies is enzootic might sometimes receive postexposure therapy with regimens or biologics that are not used in the United States (Table 6). This information is provided to familiarize physicians with some of the regimens used more widely abroad. The regimens described in the references in this report have not been submitted for approval by the FDA for use in the United States (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). If postexposure prophylaxis is begun outside the United States using one of these regimens or biologics of nerve tissue origin, it might be necessary to provide additional therapy when the patient reaches the United States. State or local health departments should be contacted for specific advice in such cases. If titers are obtained, specimens collected 2-4 weeks after preexposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. Purified equine rabies immune globulin (ERIG) has been used effectively in developing countries where RIG might not have been available. The incidence of adverse reactions has been low (0.8%-6.0%), and most of those that occurred were minor (94-96 ). In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither RIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis (97 ). Although no postexposure vaccine failures have occurred in the United States since cell culture vaccines have been routinely used, failures have occurred abroad when some deviation was made from the recommended postexposure treatment protocol or when less than the currently recommended amount of antirabies sera was administered (80,(98)(99)(100). Specifically, patients who contracted rabies after postexposure prophylaxis did not have their wounds cleansed with soap and water, did not receive their rabies vaccine injections in the deltoid area (i.e., vaccine was administered in the gluteal area), or did not receive RIG around the wound site. # VACCINATION AND SEROLOGIC TESTING # Serologic Response Shortly After Vaccination All persons tested during several CDC studies 2-4 weeks after completion of preexposure and postexposure rabies prophylaxis in accordance with ACIP guidelines have demonstrated an antibody response to rabies (13,38,101,102 ). Therefore, serum samples from patients completing preexposure or postexposure prophylaxis do not need to be tested to document seroconversion unless the person is immunosuppressed (see Precautions and Contraindications). If titers are obtained, specimens collected 2-4 weeks after preexposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. In animal studies, neutralizing antibody titers have been shown to be imperfect markers of protection. Antibody titers will vary with time since the last vaccination. Differences among laboratories that test blood samples also can influence the results. Cell culture vaccines have been used effectively with RIG or ERIG worldwide to treat persons bitten by various rabid animals (13,14 ). Worldwide, the World Health Organization estimates that 10-12 million persons are started on postexposure therapy annually (74 ). An estimated 16,000-39,000 persons in the United States receive a full postexposure course with HDCV each year (7 ). When postexposure prophylaxis has been properly administered, no treatment failures have occurred in the United States. # Serologic Response and Preexposure Booster Doses of Vaccine Although antibody levels do not define a person's immune status, they are a marker of continuing immune response (103 ). To ensure the continuity of an immune response, titers should be checked periodically, with booster doses administered as needed. Two years after primary preexposure vaccination, a 1:5 serum dilution will neutralize challenge virus completely (by the RFFIT) among 93%-98% of persons who received the three-dose preexposure series intramuscularly and 83%-95% of persons who received the three-dose series intradermally (104 ). If the titer falls below the minimum acceptable antibody level, a preexposure booster dose of vaccine is recommended for a person at continuous or frequent risk for exposure to rabies (Table 3). The following guidelines are recommended for determining when serum testing should be performed after primary preexposure vaccination: • A person in the continuous-risk category (Table 3) should have a serum sample tested for rabies antibody every 6 months (43 ). • A person in the frequent-risk category (Table 3) should have a serum sample tested for rabies antibody every 2 years (105 ). State or local health departments can provide the names and addresses of laboratories performing rabies serologic testing. # ADVERSE REACTIONS HDCV, RVA, and PCEC Reactions after vaccination with HDCV, RVA, and PCEC are less serious and less common than with previously available vaccines (74,106,107 ). In previous studies with HDCV, local reactions (e.g., pain, erythema, and swelling or itching at the injection site) have been reported among 30%-74% of recipients (108 ). Systemic reactions (e.g., headache, nausea, abdominal pain, muscle aches, and dizziness) have been reported among 5%-40% of recipients. Three cases of neurologic illness resembling Guillain-Barré syndrome that resolved without sequelae in 12 weeks have been reported (8,109,110 ). In addition, other central and peripheral nervous system disorders have been temporally associated with HDCV vaccine, but a causal relationship has not been established in these rare reports (111 ). An immune complex-like reaction occurred among approximately 6% of persons who received booster doses of HDCV 2-21 days after administration of the booster dose (9,10 ). The patients developed generalized urticaria, sometimes accompanied by arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise. In no cases have these reactions been life-threatening. This reaction occurred less frequently among persons receiving primary vaccination. The reactions have been associated with the presence of betapropiolactone-altered human albumin in the HDCV and the development of immunoglobulin E (IgE) antibodies to this allergen (112)(113)(114). # Rabies Immune Globulin (Human) Local pain and low-grade fever might follow receipt of RIG. Although not reported specifically for RIG, angioneurotic edema, nephrotic syndrome, and anaphylaxis have been reported after injection of immune globulin (IG), a product similar in biochemical composition but without antirabies activity. These reactions occur so rarely that a causal relationship between IG and these reactions has not been established. Both formulations of RIG, BayRab™ and Imogam ® Rabies-HT, undergo multiple viral clearance procedures during preparation. There is no evidence that any viruses have ever been transmitted by commercially available RIG in the United States. # Vaccines and Immune Globulins Used in Other Countries Many developing countries use inactivated nerve tissue vaccines made from the brains of adult animals or suckling mice. Nerve tissue vaccine (NTV) is reported to induce neuroparalytic reactions among approximately 1 per 200 to 1 per 2,000 persons vaccinated; suckling mouse brain vaccine (SMBV) causes reactions in approximately 1 per 8,000 persons vaccinated (15,115 ). The vaccines HDCV, PCEC, PDEV, and purified vero cell rabies vaccine (PVRV) (Table 6) are cell culture-derived and not of nerve tissue origin. In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither RIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis. # Management of Adverse Reactions Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. Usually, such reactions can be successfully managed with antiinflammatory and antipyretic agents, such as ibuprofen or acetaminophen. When a person with a history of serious hypersensitivity to rabies vaccine must be revaccinated, antihistamines can be administered. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination. Although serious systemic, anaphylactic, or neuroparalytic reactions are rare during and after the administration of rabies vaccines, such reactions pose a serious dilemma for the patient and the attending physician (9 ). A patient's risk of acquiring rabies must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious adverse reactions for persons receiving rabies vaccines may be sought from the state health department or CDC. All serious systemic, neuroparalytic, or anaphylactic reactions should be reported to the Vaccine Adverse Event Reporting System (VAERS) via a 24-hour toll-free telephone number ([800] 822-7967). # PRECAUTIONS AND CONTRAINDICATIONS Immunosuppression Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination (41,116 ). For persons with immunosuppression, preexposure prophylaxis should be administered with the awareness that the immune response might be inadequate (see Primary or Preexposure Vaccination). Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should be vaccinated by the IM route and their antibody titers checked. Failure to seroconvert after the third dose should be managed in consultation with appropriate public health officials (see Preexposure Vaccination and Serologic Testing). Immunosuppressive agents should not be administered during postexposure therapy unless essential for the treatment of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, it is especially # The following CDC staff member prepared this report: important that a serum sample be tested for rabies antibody to ensure that an acceptable antibody response has developed. # Pregnancy Because of the potential consequences of inadequately treated rabies exposure, and because there is no indication that fetal abnormalities have been associated with rabies vaccination, pregnancy is not considered a contraindication to postexposure prophylaxis (117,118 ). If the risk of exposure to rabies is substantial, preexposure prophylaxis might also be indicated during pregnancy. # Allergies Persons who have a history of serious hypersensitivity to rabies vaccine should be revaccinated with caution (see Management of Adverse Reactions). All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1998-733-228/87050 Region IV MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	None	None
a3642068c9b48e24f7e0da0e265480e7c95aa4c2	cdc	None	has indicated that she has a financial relationship with CDC because she is the Director of a Food Safe Schools project that is funded under a cooperative agreement by CDC. The remaining preparers have signed a conflict of interest disclosure form that verifies no conflict of interest.An earlier edition of this Primer, covering different foodborne illnesses, was published in MMWR in 2001 (MMWR 2001;50) and also as a separate publication by the American Medical Association, CDC, the Food and Drug Administration, and the U.S. Department of Agriculture. This report updates and supplements the previous edition. It is being reprinted here as a courtesy to the collaborating agencies and the MMWR readers.# - Obtain stool cultures in appropriate settings, and recognize that testing for some specific pathogens, eg, E. coli O157:H7, Vibrio spp., must be requested; - Report suspect cases to appropriate public health officials; - Talk with patients about ways to prevent food-related diseases; and - Appreciate that any patient with foodborne illness may represent the sentinel case of a more widespread outbreak. Foodborne illness is considered to be any illness that is related to food ingestion; gastrointestinal tract symptoms are the most common clinical manifestations of foodborne illnesses. This document provides detailed summary tables and charts, references, and resources for health care professionals. Patient scenarios and clinical vignettes are included for selfevaluation and to reinforce information presented in this primer. Also included is a CME component. This primer is not a clinical guideline or definitive resource for the diagnosis and treatment of foodborne illness. Safe food handling practices and technologies (eg, irradiation, food processing and storage) also are not addressed. More detailed information on these topics is available in the references and resources listed in this document, as well as from medical specialists and medical specialty societies, state and local public health authorities, and federal government agencies. # Recognizing Foodborne Illness Patients with foodborne illnesses typically present with gastrointestional tract symptoms (eg, vomiting, diarrhea, abdominal pain); however, nonspecific symptoms and neurologic symptoms may also occur. Every outbreak begins with an index patient who may not be severely ill. A physician or health care professional who encounters this person may be the only one with the opportunity to make an early and expeditious diagnosis. Thus, the physician or health care professional must have a high degree of suspicion and ask appropriate questions to recognize that an illness may have a foodborne etiology. Important clues to determining the etiology of a foodborne disease are the - Incubation period; - Duration of the resultant illness; - Predominant clinical symptoms; and - Population involved in the outbreak. Additional clues may be derived by asking whether the patient has consumed raw or poorly cooked foods (eg, raw or undercooked eggs, meats, shellfish, fish), unpasteurized milk or juices, home-canned goods, fresh produce, or soft cheeses made from unpasteurized milk. Inquire as to whether any of the patient's family members or close friends have similar symptoms. Inquiries about living on or visiting a farm, pet contact, day care attendance, occupation, foreign travel, travel to coastal areas, camping excursions to mountains or other areas where untreated water is consumed, and attendance at group picnics or similar outings also may provide clues for determining the etiology of the illness. If a foodborne illness is suspected, submit appropriate specimens for laboratory testing and contact the state or local health department for advice about epidemiologic investigation. For the physician or other health care professional, implication of a specific source in disease transmission is difficult from a single patient encounter. Attempts to identify the source of the outbreak are best left to public health authorities. Because infectious diarrhea can be contagious and is easily spread, rapid and definitive identification of an etiologic agent may help control a disease outbreak. Early identification of a case of foodborne illness can prevent further exposures. An individual physician who obtains testing can contribute the clue that ultimately leads to identification of the source of an outbreak. Finally, health care professionals should recognize that while deliberate contamination of food is a rare event, it has been documented in the past. The following events may suggest that intentional contamination has occurred: an unusual agent or pathogen in a common food, a common agent or pathogen affecting an unusually large number of people, or a common agent or pathogen that is uncommonly seen in clinical practice, as might occur with pesticide poisoning. # Diagnosing Foodborne Illnesses Differential Diagnosis As shown in Table 1 and the Foodborne Illnesses Tables, a variety of infectious and noninfectious agents should be considered in patients suspected of having a foodborne illness. Establishing a diagnosis can be difficult, however, particularly in patients with persistent or chronic diarrhea, those with severe abdominal pain, and when there is an underlying dis- # TABLE 1. Etiologic agents to consider for various manifestations of foodborne illness Clinical presentation Gastroenteritis (vomiting as primary symptom; fever and/or diarrhea also may be present) Noninflammatory diarrhea (acute watery diarrhea without fever/dysentery; some patients may present with fever)- Inflammatory diarrhea (invasive gastroenteritis; grossly bloody stool and fever may be present) † Persistent diarrhea (lasting >14 days) Neurologic manifestations (eg, paresthesias, respiratory depression, bronchospasm, cranial nerve palsies) Systemic illness (eg, fever, weakness, arthritis, jaundice) Potential food-related agents to consider Viral gastroenteritis, most commonly rotavirus in an infant or norovirus and other caliciviruses in an older child or adult; or food poisoning due to preformed toxins (eg, vomitoxin, Staphylococcus aureus toxin, Bacillus cereus toxin) and heavy metals. Can be caused by virtually all enteric pathogens (bacterial, viral, parasitic) Prolonged illness should prompt examination for parasites, particularly in travelers to mountainous or other areas where untreated water is consumed. Consider Cyclospora cayetanensis, Cryptosporidium, Entamoeba histolytica, and Giardia lamblia. Botulism (Clostridium botulinum toxin) Organophosphate pesticides Thallium poisoning Scombroid fish poisoning (histamine, saurine) Ciguatera fish poisoning (ciguatoxin) Tetradon fish poisoning (tetradotoxin) Neurotoxic shellfish poisoning (brevitoxin) Paralytic shellfish poisoning (saxitoxin) Amnesic shellfish poisoning (domoic acid) Mushroom poisoning Guillain-Barré syndrome (associated with infectious diarrhea due to Campylobacter jejuni) # Listeria monocytogenes Brucella species Trichinella spiralis Toxoplasma gondii Vibrio vulnificus Hepatitis A and E viruses Salmonella Typhi and Salmonella Paratyphi Amebic liver abscess - Noninflammatory diarrhea is characterized by mucosal hypersecretion or decreased absorption without mucosal destruction and generally involves the small intestine. Some affected patients may be dehydrated because of severe watery diarrhea and may appear seriously ill. This is more common in the young and the elderly. Most patients experience minimal dehydration and appear mildly ill with scant physical findings. Illness typically occurs with abrupt onset and brief duration. Fever and systemic symptoms usually are absent (except for symptoms related directly to intestinal fluid loss). † Inflammatory diarrhea is characterized by mucosal invasion with resulting inflammation and is caused by invasive or cytotoxigenic microbial pathogens. The diarrheal illness usually involves the large intestine and may be associated with fever, abdominal pain and tenderness, headache, nausea, vomiting, malaise, and myalgia. Stools may be bloody and may contain many fecal leukocytes. ease process. The extent of diagnostic evaluation depends on the clinical picture, the differential diagnosis considered, and clinical judgment. The presentation of a patient with a foodborne illness is often only slightly different from that of a patient who presents with a viral syndrome. In addition, viral syndromes are so common that it is reasonable to assume that a percentage of those diagnosed with a viral syndrome have actually contracted a foodborne illness. Therefore, the viral syndrome must be excluded in order to suspect the foodborne illness and take appropriate public health action. Fever, diarrhea, and abdominal cramps can be present or absent in both cases so they are not very helpful. The absence of myalgias or arthralgias would make a viral syndrome less likely and a foodborne illness (that does not target the neurologic system) more likely. Foodborne illnesses that do target the neurologic system tend to cause paraesthesias, weakness and paralysis that are distinguishable from myalgias or arthralgias (see below). The presence of dysentery (bloody diarrhea) is also more indicative of a foodborne illness, particularly if it is early in the course. If any of the following signs and symptoms occur in patients, either alone or in combination, laboratory testing may provide important diagnostic clues (particular attention should be given to very young and elderly patients and to immunocompromised patients, all of whom are more vulnerable): - Bloody diarrhea - Weight loss - Diarrhea leading to dehydration - Fever - Prolonged diarrhea (3 or more unformed stools per day, persisting several days) - Neurologic involvement, such as paresthesias, motor weakness, cranial nerve palsies - Sudden onset of nausea, vomiting, diarrhea - Severe abdominal pain In addition to foodborne causes, a differential diagnosis of gastrointestinal tract disease should include underlying medical conditions such as irritable bowel syndrome; inflammatory bowel diseases such as Crohn's disease or ulcerative colitis; malignancy; medication use (including antibiotic-related Clostridium difficile toxin colitis); gastrointestinal tract surgery or radiation; malabsorption syndromes; immune deficiencies; and numerous other structural, functional, and metabolic etiologies. Consideration also should be given to exogenous factors such as the association of the illness with travel, occupation, emotional stress, sexual habits, exposure to other ill persons, recent hospitalization, child care center attendance, and nursing home residence. The differential diagnosis of patients presenting with neurologic symptoms due to a foodborne illness is also complex. Possible food-related causes to consider include recent ingestion of contaminated seafood, mushroom poisoning, and chemical poisoning. Because the ingestion of certain toxins (eg, botulinum toxin, tetrodotoxin) and chemicals (eg, organophosphates) can be life-threatening, a differential diagnosis must be made quickly with concern for aggressive therapy and life support measures (eg, respiratory support, administration of antitoxin or atropine), and possible hospital admission. # Clinical Microbiology Testing When submitting specimens for microbiologic testing, it is important to realize that clinical microbiology laboratories differ in protocols used for the detection of pathogens. To optimize recovery of an etiologic agent, physicians and other health care professionals should understand routine specimencollection and testing procedures as well as circumstances and procedures for making special test requests. Some complex tests (eg, toxin testing, serotyping, molecular techniques) may only be available from large commercial or public health laboratories. Contact your microbiology laboratory for more information. Stool cultures are indicated if the patient is immunocompromised, febrile, has bloody diarrhea, has severe abdominal pain, or if the illness is clinically severe or persistent. Stool cultures are also recommended if many fecal leukocytes are present. This indicates diffuse colonic inflammation and is suggestive of invasive bacterial pathogens such as Shigella, Salmonella, and Campylobacter species and invasive E. coli. In most laboratories, routine stool cultures are limited to screening for Salmonella and Shigella species and Campylobacter jejuni/coli. Cultures for Vibrio and Yersinia species, E. coli O157:H7, and Campylobacter species other than jejuni/coli require additional media or incubation conditions and therefore require advance notification or communication with laboratory and infectious disease personnel. Stool examination for parasites generally is indicated for patients with suggestive travel histories, who are immunocompromised, who suffer chronic or persistent diarrhea, or when the diarrheal illness is unresponsive to appropriate antimicrobial therapy. Stool examination for parasites is also indicated for gastrointestinal tract illnesses that appear to have a long incubation period. Requests for ova and parasite examination of a stool specimen will often enable identification of Giardia lamblia and Entamoeba histolytica, but a special request may be needed for detection of Cryptosporidium and Cyclospora cayetanensis. Each laboratory may vary in its rou-tine procedures for detecting parasites, so it is important to contact your laboratory. Blood cultures should be obtained when bacteremia or systemic infection is suspected. Direct antigen detection tests and molecular biology techniques are available for rapid identification of certain bacterial, viral, and parasitic agents in clinical specimens. In some circumstances, microbiologic and chemical laboratory testing of vomitus or implicated food items also is warranted. For more information on laboratory procedures for the detection of foodborne pathogens, consult an appropriate medical specialist, clinical microbiologist, or state public health laboratory. # Treating Foodborne Illness Selection of appropriate treatment depends on identification of the responsible pathogen (if possible) and determining if specific therapy is available. Many episodes of acute gastroenteritis are self-limiting and require fluid replacement and supportive care. Oral rehydration is indicated for patients who are mildly to moderately dehydrated; intravenous therapy may be required for more severe dehydration. Routine use of antidiarrheal agents is not recommended because many of these agents have potentially serious adverse effects in infants and young children. Choice of antimicrobial therapy should be based on - Clinical signs and symptoms; - Organism detected in clinical specimens; - Antimicrobial susceptibility tests; and - Appropriateness of treating with an antibiotic (some enteric bacterial infections are best not treated). Knowledge of the infectious agent and its antimicrobial susceptibility pattern allows the physician to initiate, change, or discontinue antimicrobial therapy. Such information also can support public health surveillance of infectious disease and antimicrobial resistance trends in the community. Antimicrobial resistance has increased for some enteric pathogens, which dictates judicious use of this therapy. Suspected cases of botulism are treated with botulinum antitoxin. Equine botulinum antitoxin for types A, B, and E can prevent the progression of neurologic dysfunction if administered early in the course of illness. Physicians and other health care professionals should notify their local and state health departments regarding suspected cases of botulism. CDC maintains a 24-hour consultation service to assist health care professionals with the diagnosis and management of this rare disease. # Surveillance and Reporting of Foodborne Illness Reporting of foodborne illnesses in the United States began more than 50 years ago when state health officers, concerned about the high morbidity and mortality caused by typhoid fever and infantile diarrhea, recommended that cases of "enteric fever" be investigated and reported. The intent of investigating and reporting these cases was to obtain information about the role of food, milk, and water in outbreaks of gastrointestinal tract illness as the basis for public health actions. These early reporting efforts led to the enactment of important public health measures (eg, the Pasteurized Milk Ordinance) that profoundly decreased the incidence of foodborne illnesses. Often health care professionals may suspect foodborne illness either because of the organism involved or because of other available information, such as several ill patients who have eaten the same food. Health care professionals can serve as the eyes and ears for the health department by providing such information to local or state public health authorities. Foodborne disease reporting is not only important for disease prevention and control, but more accurate assessments of the burden of foodborne illness in the community occur when physicians and other health care professionals report foodborne illnesses to the local and state health department. In addition, reporting of cases of foodborne illness by practicing physicians to the local health department may help the health officer identify a foodborne disease outbreak in the community. This may lead to early identification and removal of contaminated products from the commercial market. If a restaurant or other food service establishment is identified as the source of the outbreak, health officers will work to correct inadequate food preparation practices, if necessary. If the home is the likely source of the contamination, health officers can institute public education about proper food handling practices. Occasionally, reporting may lead to the identification of a previously unrecognized agent of foodborne illness. Reporting also may lead to identification and appropriate management of human carriers of known foodborne pathogens, especially those with high-risk occupations for disease transmission such as foodworkers. Typically, the appropriate procedure for health care professionals to follow in reporting foodborne illnesses is to contact the local or state health department whenever they identify a specific notifiable foodborne disease. However, it is often unclear if a patient has a foodborne illness prior to diagnostic tests, so health care professionals should also report potential foodborne illnesses, such as when 2 or more patients present with a similar illness that may have resulted from the ingestion of a common food. Local health departments then report the illnesses to the state health departments and determine if further investigation is warranted. Each state health department reports foodborne illnesses to CDC. CDC compiles these data nationally and disseminates information via the weekly Morbidity and Mortality Weekly Report and annual summary reports. CDC assists state and local public health authorities with epidemiologic investigations and the design of interventions to prevent and control foodrelated outbreaks. CDC also coordinates a national network of public health laboratories, called PulseNet, which performs "molecular fingerprinting" of bacteria (by pulsed-field gel electrophoresis) to support epidemiologic investigations. Thus, in addition to reporting cases of potential foodborne illnesses, it is important for physicians to report noticeable increases in unusual illnesses, symptom complexes, or disease patterns (even without definitive diagnosis) to public health authorities. Prompt reporting of unusual patterns of diarrheal/ gastrointestinal tract illness, for example, can allow public health officials to initiate an epidemiologic investigation earlier than would be possible if the report awaited definitive etiologic diagnosis. Finally, new information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated whenever new data about preventing foodborne illness become available. Physicians and other health care professionals need to be aware of and follow the most current information on food safety. Identification of metal in food. Radioassay for toxin in fish or a consistent history. Identification of metal in beverage or food. Analysis of blood, hair. Typical syndrome and mushroom identified or demonstration of the toxin. Typical syndrome and mushroom identified and/or demonstration of the toxin. Analysis of the food, blood. Analysis of the food, blood. # Patient Scenarios The learning scenarios in this section can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the previous sections of this primer. The case studies provide questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # Congenital Toxoplasmosis, A Patient Scenario Susan, a 6-month-old infant, is brought to your office for evaluation of apparent blindness. Her mother reports that she had been well during the pregnancy and the delivery was uncomplicated. The baby appeared healthy until age 4 months, when the parents became concerned about her vision. Physical examination was normal except for bilateral macular scars, microphthalmos, and unresponsiveness to visual stimuli. There were no other neurologic abnormalities, and her growth and development were appropriate for her age. A computed tomography (CT) scan of the head was obtained. The CT scan of the child's head showed periventricular calcifications and asymmetric dilation of the lateral ventricles. The mother is 35 years old and reiterated that she does not recall being ill during the pregnancy; however, she also indicated that she would not necessarily remember every little symptom. She also denied having a history of STDs. She had received the mumps-measles-rubella (MMR) vaccine as a child but no vaccines during pregnancy. The mother recalled eating insufficiently cooked meat while traveling in France during the first trimester of pregnancy. The family does not own a cat, and she does not recall having been exposed to cats during her pregnancy. # Congenital infection with # What diagnostic tests are needed? Serologic evaluation of both mother and child focusing on potential congenital infection (ie, a ToRCH profile) based on the history of the mother ingesting raw meat while traveling in a foreign country during first trimester of pregnancy and the clinical findings (blindness, cerebral calcifications, and hydrocephalus). Results of serologic testing detected both IgG and IgM antibodies to Toxoplasma gondii in both the baby's and mother's serum. The mother's IgM titer was 1:6400 and IgG titer was 1:6400, while those of the baby were IgM titer of 1:160 and IgG titer of 1:6400. # How does this information assist with the diagnosis? Diagnosis of toxoplasmosis is usually confirmed by serologic tests. Occasionally, organisms are identified in tissue or body fluids or isolated by culture or animal inoculation. Polymerase chain reaction (PCR)-based assays are available from some laboratories for diagnosis of fetal infection and infection in compromised hosts. For immunocompetent persons, seroconversion or a 4-fold rise of specific IgG antibodies or demonstration of specific IgM antibodies indicate recent infection. High titers of IgG antibodies in the absence of IgM antibodies are consistent with chronic latent infection acquired in the past. The IgM-capture enzyme-linked immunosorbent assay (ELISA) is more sensitive than the IgM-indirect fluorescent-antibody assay (IFA) test. However, IgM tests may be false-positive, and true-positive IgM tests may persist for a year or more. Therefore, to determine if infection occurred during pregnancy, additional tests, such as an anti-Toxoplasma avidity test, may be required at a reference laboratory. Immunodeficient persons usually do not have measurable IgM antibodies, even in the presence of active disease. The diagnosis of central nervous system (CNS) toxoplasmosis in such persons is therefore based on clinical picture, typical CT scan or magnetic resonance imaging (MRI) showing multiple ring-enhancing hypodense nodules, and a positive IgG test. Brain biopsy is reserved for cases that fail to respond to an empiric trial of anti-Toxoplasma drugs. The baby was diagnosed with congenital toxoplasmosis. # How is toxoplasmosis best treated? Toxoplasmosis in immunocompetent persons rarely requires treatment, whereas infection in immunodeficient persons or in infants with congenital infections usually requires treatment. The combination of pyrimethamine and sulfadiazine is the treatment of choice. Folinic acid (leucovorin) is given to prevent bone marrow suppression. Treatment must be continued for the duration of immunosuppression and for life in AIDS patients whose immunity is not reconstituted by highly aggressive antiretroviral therapy (HAART). For persons unable to tolerate the pyrimethamine and sulfadiazine combination, high doses of pyrimethamine (and leucovorin) and clindamycin are effective. The management of toxoplasmosis acquired during pregnancy is controversial. Testing of newly pregnant women for T. gondii infection is not routinely done, and routine testing is not recommended by CDC or by the American College of Obstetricians and Gynecologists. To prevent fetal infection, one approach is to administer spiramycin (a macrolide antibiotic, which is concentrated in the placenta and is not harmful to the fetus). At the same time, amniotic fluid is submitted for PCR-based testing to determine whether fetal infection has occurred. If so, options may include pyrimethamine and sulfadiazine given after the 16th week of pregnancy (since pyrimethamine is potentially teratogenic) or consideration of terminating the pregnancy. If the fetus is shown to be uninfected, spiramycin is continued throughout pregnancy. Different protocols exist for treatment of infants born with congenital infection. The most commonly recommended treatment is pyrimethamine and sulfadiazine plus leucovorin during the first year of life. In the present case, the child was treated for 6 months with pyrimethamine and sulfadiazine plus leucovorin. Human infection with the intracellular protozoan parasite Toxoplasma gondii occurs globally. Infection is usually subclinical or produces a mild illness, except in immunodeficient persons and fetuses infected in utero. Most infants with congenital toxoplasmosis appear healthy at birth but have a high incidence of developing serious ophthalmologic and neurologic sequelae during the next 20 years of life. Severe congenital toxoplasmosis may be apparent at birth or become apparent during the first 6 months of life. Chorioretinitis, intracerebral calcifications, and hydrocephalus, as in the present case, are typical features The child was treated with pyrimethamine, sulfadiazine, and folinic acid for 6 months. She remains blind, and has developed moderate psychomotor retardation. # How could Toxoplasma infection have been prevented in this child? Toxoplasma gondii may be transmitted transplacentally to the fetus if the mother acquired toxoplasmosis during pregnancy. There is almost no risk of transplacental transmission if the mother was infected prior to conception; accordingly, women with positive IgG antibody tests for toxoplasmosis at the onset of pregnancy are not at risk for developing acute toxoplasmosis. Women with negative IgG antibody tests during pregnancy should avoid eating insufficiently cooked or uncooked meat and should avoid ingestion of soil and water or food that may be contaminated with cat feces. Transmission occurs by a) ingestion of tissue cysts in raw or insufficiently cooked meat, especially lamb, pork, and wild game; b) accidental ingestion of food, water, or soil contaminated with cat feces that contain infective oocysts; c) transplacental passage of infective tachyzoites; d) transfusion of infected white blood cells or transplantation of an infected organ; and e) laboratory accidents. Prevention of toxoplasmosis is particularly important for uninfected (ie, seronegative) pregnant mothers, HIVinfected persons, and other immunocompromised patients: - Avoid ingestion of raw or insufficiently cooked meat and poultry; cook meat to 160°F (71°C) or freeze to -4°F (-20°C). For more details on preventing toxoplasmosis, please see the Suggested Resources and Suggested Reading List. - Avoid ingestion of environmental oocysts by avoiding contact with cat litter, soil, water, and vegetables potentially contaminated with cat feces. Infection acquired by healthy persons is usually asymptomatic or may lead to painless lymphadenopathy or a mononucleosis syndrome. Maternal infection is usually unrecognized. Disease in persons with depressed cellular immunity (eg, persons with AIDS, transplant recipients, persons receiving immunosuppressants) usually is due to reactivation of latent infection but can result from acute infection. Toxoplasmosis in these persons leads to lethal meningoencephalitis, focal lesions of the CNS, and less commonly, myocarditis or pneumonitis. The clinical picture may include headache, seizures, mental status changes, focal neurologic signs, and aseptic meningitis. Thirty to forty percent of AIDS patients with IgG antibodies to T. gondii (indicating chronic latent infection) develop active toxoplasmosis unless they take preventive medication. Congenital infection occurs when a previously uninfected mother develops infection during pregnancy. Infection prior to conception, demonstrated by specific IgG antibodies, in nearly all cases guarantees against infection of the fetus. However, transplacental transmission occurs from mothers whose prior infections reactivate when they receive immunosuppressant medications or develop AIDS. Congenital toxoplasmosis may result in abortion, stillbirth, mental retardation, and retinal damage. Recurrent toxoplasmic chorioretinitis in children and young adults is frequently the result of congenital infection that was asymptomatic at birth. # Acute Hepatitis A: A Patient Scenario While working in an emergency room, you are asked to see a 31-year-old Asian-American woman who has had fever, nausea, and fatigue for the past 24 hours. She also reports dark urine and has had 3 light colored stools since yesterday. She has previously been healthy and has no previous history of jaundice. Her physical examination shows a low-grade fever of 100.6°F/38.1°C, faint scleral icterus, and hepatomegaly. Her blood pressure and neurologic exam are normal and there is no rash. Initial laboratory studies show an alanine aminotransferase (ALT) result of 877 IU/L, aspartate amino transferase (AST) enzyme levels of 650 IU/L, an alkaline phosphatase of 58 IU/L and a total bilirubin of 3.4 mg/dL. White blood cell count is 4.6, with a normal differential; electrolytes are normal; the blood urea nitrogen level is 18 mg/dL; and serum creatinine level is 0.6 mg/dL. Pregnancy test is negative. What should be included in the differential diagnosis of acute hepatitis? She has no children, and her boyfriend is not ill. She has been in a monogamous relationship with her boyfriend for 2 years. She was born in the United States; her parents immigrated to the United States from Taiwan in the 1950s. She works as a food preparer for a catering business. She returned 4 weeks ago from a 1-week vacation in Mexico (Mexico City and nearby areas), where she stayed with her boyfriend in several hotels. She drank only bottled water but ate both cooked and uncooked food at numerous restaurants while in Mexico, and she visited a family friend and her 3 young children in a Mexico City suburb. She did not receive hepatitis A vaccine or immune globulin before going on vacation. She is not sure if she has received hepatitis B vaccine. She has not gone camping or hiking and had no recent tick exposures. She has never used illicit drugs, drinks alcohol rarely, and has never received a transfusion. She is taking oral contraceptives but no other prescription medication, and took 500 milligrams of Tylenol ® once after onset of her current symptoms. She has a pet cat but no other animal exposures. She had chickenpox and mononucleosis during childhood. # How does this information assist with the diagnosis? Lack of animal or tick exposures makes leptospirosis and Rocky Mountain spotted fever unlikely, and Q fever less likely. Yellow fever and typhoid fever are very unlikely with no history of travel to rural endemic areas, and assuming exposure occurred in Mexico, inconsistent with the long incubation period. Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV) infection are all possible diagnoses. A drug reaction to the oral contraceptive is a possible cause of hepatitis. The history of travel to an endemic area makes hepatitis A the most likely diagnosis. # What diagnostic tests are needed? Specific diagnostic serologic studies are necessary to distinguish one form of viral hepatitis from another. Testing for total (IgG+ IgM) anti-HAV does not distinguish between a past history of hepatitis A virus infection and current infection and is not useful in diagnosing acute hepatitis A. Hepatitis A can be easily confirmed with an anti-IgM anti-HAV test. This test is widely available and results are usually available within 24 hours. A hepatitis panel is ordered, and results from such a panel are shown here. You obtain the following results from the serologic testing: - Total anti-HAV: positive - IgM anti-HAV: positive - Total anti-HBc: positive - IgM anti-hepatitis B core antigen: negative - HBsAg: negative - anti-HBs: positive - anti-HCV: negative # What is the diagnosis? The diagnosis is hepatitis A. The hepatitis B serologic tests indicate past, resolved infection with no chronic infection. Acute hepatitis C is also possible; the appearance of anti-HCV may be delayed for as long as 9 months after exposure. However, with a confirmed diagnosis of hepatitis A, further testing for HCV RNA is not indicated at this point. Finally, note that hepatitis E is rarely reported in travelers, and results of serologic tests for hepatitis E virus (HEV) are difficult to interpret. Tests for HEV should only be performed if other more common causes of hepatitis have been excluded. The incubation period for hepatitis A is 15-50 days, with an average of 28 days. The most common signs and symptoms associated with acute hepatitis A include jaundice, fever, malaise, anorexia, and abdominal discomfort. The illness can be severe and approximately 10% to 20% of reported cases require hospitalization. The likelihood of having symptoms with HAV infection is related to the person's age. In children <6 years of age, most (70%) infection is asymptomatic; if illness does occur it is not usually accompanied by jaundice. Older children and adults are more likely to have symptomatic disease, although jaundice may be absent in as many as one third of adults with HAV infection. In many developing countries in Asia, Africa, and Central and South America, infection is nearly universal during early childhood and is often asymptomatic. # What treatment is indicated? There is no specific treatment for hepatitis A. Bed rest does not hasten recovery. Hepatitis A is never a chronic infection, although 10% to 15% of symptomatic persons have prolonged or relapsing disease lasting up to 6 months. While rarely fatal in younger persons, the case-fatality rate is nearly 2% among reported patients who are more than 50 years old. Following is a depiction of a typical course, including times of peak fecal excretion of HAV, liver function test abnormalities, and clinical symptoms. # How is hepatitis A virus transmitted, and who is at risk for this disease? HAV is an RNA virus that only infects primates. HAV has a fecal-oral route of transmission and is easily transmitted person to person. HAV is also transmitted through contaminated food or water. Because HAV is present in the blood during acute infection, bloodborne transmission is also possible, but rare. The highest levels of HAV are found in the stool, and peak levels occur in the 2 weeks before onset of illness. Groups at increased risk for hepatitis A include travelers to developing countries, men who have sex with men, and injecting and noninjecting drug users. In the United States, 4% to 6% of reported cases occur among international travelers, many of whom presumably acquired HAV infection from contaminated food or water. Approximately 50% of persons with hepatitis A do not report any known risk factors, and some of these infections may be from unrecognized transmission via HAV-contaminated food. # How might this illness have been prevented? Persons planning to travel to an endemic region should receive hepatitis A vaccine or immune globulin before departure. Hepatitis A vaccination can be given to anyone 2 years of age and older, and has the advantage of providing long-term protection (at least 20 years). Hepatitis A vaccine is an inactivated HAV preparation; the first dose of vaccine provides protective anti-HAV levels within 30 days for >90% of vaccine recipients. Licensed hepatitis A vaccines available in the United States are considered to be equivalent in effectiveness, and include Havrix ® (manufactured by Glaxo SmithKline), VAQTA ® (Merck & Co.), and Twinrix ® (combined hepatitis A and hepatitis B vaccine, Glaxo SmithKline). Vaccination is administered in a 2-dose schedule (0, 6 months) for Havrix ® and VAQTA ® , and a 3-dose schedule (0, 1, 6 months) for Twinrix ® . The second (or third) dose is provided to ensure protection in those who did not respond to the first dose of vaccine. Ninety-nine percent of vaccinees will be protected after 2 doses of vaccine. For persons who present for hepatitis A immunoprophylaxis <30 days before departure to an endemic region and for children <2 years old, immune globulin (IG) is an effective means of preventing hepatitis A. IG is the appropriate immunoprophylaxis for children <2 years old. IG is a sterile preparation of concentrated antibodies (immunoglobulins) made from pooled human plasma. IG provides protection against hepatitis A for 3-5 months, depending on dosage, through passive transfer of antibody. Vaccine and IG may be given simultaneously. Hepatitis A is the most common vaccine-preventable disease among travelers. The risk varies according to region visited and the length of stay, and is increased even among travelers who report observing measures to protect themselves against enteric infection or stay only in urban areas. In the United States, children account for approximately one third of reported travel-related cases. # What else needs to be done? Cases of hepatitis A should be reported to the local health department immediately. The patient's boyfriend and any other household or sexual contacts whose last exposure to the patient was <14 days ago should be given IG. Screening for immunity before administering IG is not recommended in this situation because it is more costly than IG and would delay its administration. IG is not indicated for family members or friends not living in the household. Prompt reporting of hepatitis A cases allows time to decide on a course of action and provide timely immunoprophylaxis when appropriate. Because this patient works as a food preparer, the health department will need to visit the establishment to assess the likelihood that her duties and hygiene practices pose a significant risk of food contamination. IG is often recommended for co-workers of commercial food handlers with hepatitis A. In addition, if she worked at any time during the 2 weeks before onset of jaundice to 1 week after onset, persons who ate food prepared or handled by this patient may be candidates for IG prophylaxis. Determina- tions of the need for IG prophylaxis are made on a case-bycase basis by experienced health department personnel. Again, immediate reporting of hepatitis A cases allows time to decide on a course of action and provide timely treatment and intervention when appropriate. # Norovirus Infection: A Patient Scenario Nancy is a 25-year-old previously well graduate student who presents to the emergency department with a 12-hour history of nausea, diarrhea, abdominal cramping, and vomiting (about 6 episodes), malaise, and a low-grade fever. She describes her onset of symptoms as sudden. Physical examination shows that Nancy is afebrile with a supine blood pressure of 123/74 mm Hg. She has a diffusely tender abdomen and is dehydrated. Stool examination is negative for occult blood. # What is the possible differential diagnosis for her chief complaint? - Infectious gastroenteritis - Food intoxication (noninfectious gastroenteritis) - Inflammatory bowel disease - Appendicitis - Pelvic inflammatory disease # What additional information would assist with the diagnosis? - Did anyone in her household experience similar illness within the week prior to onset of symptoms? - Has she been in contact with anyone outside her household with similar symptoms within the previous week? - Has she had such symptoms before? - Does she know if anyone else became ill? - Has she traveled outside the United States within the last month? - Has she previously had a sexually transmitted diseases or does she have multiple sex partners? Nancy reports that she rarely has diarrhea or vomiting. She also reports no contact with anyone who was ill in the past week, nor has she been out of the country in the past month. Her boyfriend, who does not live with her, has similar symptoms with an almost identical onset time. Both attended a wedding 2 days ago. The meal at the wedding reception, which was held at a local reception hall, was the only meal they shared in the past several days. Nancy does not know if anyone else who attended the wedding became ill. Nancy reports that she has no history of a sexually transmitted disease and that she and her boyfriend have a monogamous sexual relationship. # How does this information assist with the diagnosis? Based on the rapid onset of symptoms, Nancy's reported past history of good health, and the fact that her boyfriend has an almost identical history, inflammatory bowel disease, appendicitis, and pelvic inflammatory disease are the least likely diagnoses. Food intoxication is also not very likely. Assuming that the wedding reception was the source of the toxin, and this was their most recent common meal, the time from exposure to onset of symptoms is too long. Toxins usually cause illness within minutes to hours after ingestion. The most likely diagnosis is infectious gastroenteritis. There is a possibility that Nancy's and her boyfriend's illness may be associated with an outbreak of gastroenteritis. # What additional information would assist with the identification of the etiologic agent? - What sorts of foods were served at the wedding reception? - When did the couple last share a meal prior to the wedding reception? - Has an outbreak of gastroenteritis associated with this reception has been reported to the local health department?. The health department may be able to aid in determining what the etiologic agent was if it is currently investigating the outbreak. At the wedding, the couple had a choice of meal. Nancy had lobster tail and filet mignon. Her boyfriend had chicken. They both consumed stuffed mushrooms, salad, and hors d'oeuvres preceding the main meal. For dessert they both had wedding cake and fresh fruit. Both drank wine or beer during the reception. The couple attended a barbecue the previous week. This outing was a function sponsored by Nancy's employer. Nancy tells you that none of her co-workers have been ill with vomiting and diarrhea. You place an inquiry with the local health department about the possible outbreak. The health department notifies you that an investigation is currently under way. Illness has also been reported among 75% of attendees at a wedding the day before the one Nancy attended, at the same reception hall. The only common food between the 2 weddings is the salad, and the health department currently suspects a food handler who worked during both weddings who was experiencing diarrhea. Most patients have reported nausea, vomiting (about 90%), and diarrhea (70%), with some fever, malaise, headache, chills, and abdominal pain. The mean incubation period for those who have reported illness is 28.6 hours, with a mean duration of 31.8 hours. The health department suspects viral gastroenteritis caused by a norovirus. A norovirus is suspected because of the rapid onset of symptoms, the short 36-hour incubation period and relatively short duration of illness, the absence of bloody diarrhea, and the high percentage of vomiting. Bacterial cultures are negative for enteric pathogens on stool samples collected thus far. # What are the complications of norovirus infection? Noroviruses are common causes of self-limiting acute gastroenteritis, with illness frequently lasting no longer than 60 hours. They commonly cause outbreaks in such settings as restaurants, catered events, cruise ships, schools, and nursing homes. The viruses can be spread person to person through the fecal-oral route, through contaminated food or water, or by raw or undercooked shellfish. # How should norovirus infections be managed? There is no antiviral agent that can be used to treat norovirus infections. Supportive care such as oral or intravenous fluids for rehydration should be provided. To reduce the spread of illness, patients should be educated to use good hand washing practices, particularly after using the bathroom and before preparing and handling food. The health department requests that a stool sample be collected. The sample should be collected in a sterile container without transport media, and kept at 4°C (40°F) until shipped. The sample should be shipped on ice packs to the local health department laboratory for testing. The health department also asks you to encourage Nancy's boyfriend to submit a stool sample. # How could this norovirus infection have been prevented? The food handler with diarrhea should not have returned to work for at least 24-48 hours after symptoms subsided. Proper hand washing procedures can prevent the spread of the virus between persons. Hands should be washed under warm water with soap for approximately 15 seconds to prevent fecal-oral transmission. # Antibiotic-Resistant Salmonellosis: A Patient Scenario Andrea brings her 3-year-old son, Marcus, to your office with a 2-day history of low-grade fever, nausea, and 6-8 watery stools per day. Marcus has also been complaining of abdominal pain and feeling tired. He has been eating and drinking less than usual. His medical history is remarkable for recurrent otitis media, for which he was prescribed oral antibiotics 10 days prior to this visit. Physical examination reveals a well-developed boy who appears fatigued. Vital signs are remarkable for low-grade fever (99.5°F/37.5°C). He does not have signs of dehydration. His otitis appears resolved and he has a normal cardiopulmonary exam. The abdominal exam reveals hyperactive bowel sounds, mild diffuse tenderness, and stool negative for occult blood. - Has he traveled in the month prior to the onset of illness? If yes, where? - Has he had contact with pet reptiles or farm animals or visited petting zoos in the week prior to his symptom onset? # What is the differential diagnosis for Marcus has not had similar episodes of diarrhea in the past. He attends preschool and is cared for by his grandmother after school in her home. He last visited a petting farm 3 months prior to this illness. Their family returned the previous day from a 5-day Caribbean cruise. Marcus was diagnosed with otitis media 4 days prior to their departure and was prescribed a 1-week course of oral antibiotics. Andrea has had nausea and 3-4 loose stools per day for the previous 2 days. She has not had any fever, abdominal pain, or vomiting. Marcus' father and two sisters also traveled on the cruise and are asymptomatic. None of the family members took prophylactic antibiotics for travelers' diarrhea during the cruise. # How does this information assist with the diagnosis? The additional history suggests that Marcus' and Andrea's illness may be an infectious gastroenteritis related to their recent travel. Antibiotic-associated colitis caused by Clostridium difficile infection must be considered since the child was prescribed antibiotics for otitis 8 days prior to this illness. Given the recent onset, travel history, and his mother's symptoms, it is unlikely that appendicitis, celiac disease, or inflammatory bowel disease are the etiologies of Marcus' illness. The most likely diagnosis is infectious gastroenteritis. # What additional historical information will assist in the identification of the etiologic organism? - What foods did Marcus and Andrea consume in the previous week? In particular, which foods/ beverages did they consume that the other family members did not? - Did either Marcus or Andrea consume undercooked meats, runny eggs, unpasteurized milk, raw shellfish, or untreated water? - Is there a reptile in the home? - Marcus was prescribed antibiotics for otitis media 1 week prior to the onset of his gastrointestinal symptoms. Has Andrea been prescribed antibiotics during the month prior to the onset of her diarrheal illness? - Have there been other cases of diarrhea recognized in the cruise ship travelers, in their community, or at Marcus' school? An open-ended food history reveals multiple common meals eaten by Andrea and Marcus. Andrea denies the consumption of unpasteurized milk, raw shellfish, and undercooked meats. She does report that, unlike the rest of the family, she and Marcus used to wake up early enough to enjoy the breakfasts served on board the cruise. Breakfast served on the cruise consisted of a choice of French toast or pancakes with fruit compote, scrambled eggs or omelets made to order, potatoes, and fresh fruit along with a choice of beverages, including milk, coffee, and tea. Andrea complained that the eggs were occasionally runny. Several fellow passengers told Andrea at breakfast that they were experiencing vomiting and diarrhea. Andrea and Marcus ate the remainder of their meals with the entire family. They did not drink any untreated water or eat items purchased from street vendors at ports of call. In response to your other questions, Marcus does not have a reptile at home. Andrea has not been prescribed antibiotics for more than 1 year. The family lives in a city and has access to municipal water. Based on the additional historical details, it appears that many people on board the cruise were experiencing symptoms of vomiting and diarrhea. This suggests an outbreak of infectious gastroenteritis that may be related to a common food or water source on the ship. The etiologic agent may be bacterial, viral, or parasitic. The most likely bacterial organisms causing this diarrheal illness are Campylobacter jejuni, Escherichia coli, Shigella species, and Salmonella. C. jejuni is the most common bacterial cause of diarrheal illness in the United States. Outbreaks of C. jejuni have been linked to raw milk, poultry, eggs, and water. Enterotoxigenic E. coli (ETEC) is recognized as the most common cause of "travelers' diarrhea" and can be transmitted via food or water. Salmonella is an important bacterial cause of foodborne illness, ranking just behind C. jejuni in its frequency. Vehicles most commonly implicated in foodborne outbreaks of salmonellosis include beef, poultry, produce, eggs, pork, and dairy products. Large waterborne outbreaks of salmonellosis have occurred rarely. # Why is identification of the cause of the diarrhea important? Identification of the cause of diarrhea in these two cases is important because of the impact on treatment, identification of related cases, and detection of an outbreak and identification of the responsible vehicle. Stool cultures should be performed to detect common bacterial pathogens such as Campylobacter, Salmonella, Shigella, or E. coli O157:H7. Antimicrobial susceptibility results can guide antibiotic therapy if a resistant organism is detected. Additional testing may be conducted to detect nonbacterial organisms. Stool examination for ova and parasites (O&P) will reveal parasitic causes of foodborne and waterborne illness such as Cyclospora cayetanensis. Rotavirus infection, one of the most common etiologies of pediatric diarrhea, may be diagnosed with enzyme immunoassay (EIA). The presence of fecal leukocytes suggests bacterial infection but may be found in other infectious or inflammatory states. Testing for the presence of Shiga toxin to detect infection with enterohemorrhagic E. coli (EHEC) would be appropriate if Marcus or Andrea had bloody diarrhea. What approaches would you take to treating Marcus' and Andrea's illness? Are antibiotics indicated for both Marcus and Andrea? What other therapeutic measures are useful for the management of diarrheal illness? Because Andrea's symptoms are mild, she does not wish to receive antibiotics. For Marcus, you prescribe trimethoprim-sulfamethoxazole at appropriate doses. You encourage Andrea to monitor for worsening fever, diarrhea, vomiting, and dehydration. You obtain stool specimens for culture and O&P from both Marcus and Andrea to confirm the etiologic agent. The primary goal of therapy for Marcus and Andrea is the maintenance of adequate hydration and electrolyte balance. A commercial oral rehydration solution (ORS) may be used, particularly for Marcus, to provide glucose and salts. You encourage Andrea to give Marcus ORS to prevent dehydration. Bismuth subsalicylate or loperamide may be used to decrease the number of unformed stools and shorten the duration of diarrhea, although neither is available over the counter for children of Marcus' age. Loperamide should not be used in those patients who develop fever or dysentery. Finally, empiric antibiotic therapy can be used to treat "travelers' diarrhea," which is most commonly caused by ETEC, after obtaining the stool samples but prior to obtaining results of stool cultures. Three days after the initial visit, Andrea feels better with fewer stools per day, but Marcus has had worsening vomiting and diarrhea. He has had several episodes of high fever and has not been drinking ORS adequately. In the office, Marcus is febrile (102°F/38.8°C) and appears dehydrated with dry mucous membranes and decreased skin turgor. No significant change is noted in the abdominal examination. You admit Marcus for intravenous hydration and encouragement of oral rehydration and consider a change in antibiotic therapy. Because of the progressive systemic nature of his illness, you also obtain blood cultures at this time. # What information will guide your therapy at this time? The use of intravenous fluids to improve volume status is reasonable given Marcus' inability to maintain hydration with ORS. However, during hospitalization, he should be encouraged to resume drinking ORS as early as possible. The decision to change from oral to intravenous antibiotics may be based on Marcus' increased vomiting and on his clinical decline. The choice of antibiotics should reflect the results of stool culture and antimicrobial sensitivities. The laboratory reports the growth of Salmonella Typhimurium from Marcus' stool cultures. Susceptibility testing reveals an organism resistant to multiple antibiotics, including ampicillin and sulfamethoxazole. Multidrugresistant S. Typhimurium has been on the rise in the United States since the early 1990s and now accounts for at least 25% of these isolates. Definitive type 104 (DT 104), the most common phage type of multidrug-resistant S. Typhimurium, may be responsible for more invasive disease than other phage types. In an outbreak, resistant organisms appear to cause more cases than do sensitive strains. Marcus' recent exposure to antibiotics for otitis media likely increased his susceptibility to Salmonella infection, perhaps by decreasing the usual protection offered by normal bowel flora, and thus decreasing the infectious dose necessary to cause illness. In addition, he was placed at increased risk for infection with a resistant strain of S. Typhimurium if he was exposed while still taking the antibiotic. Treatment of Salmonella gastroenteritis with antibiotic therapy is controversial because of the resulting increase in asymptomatic carriage, particularly among children less than 5 years of age. However, given the systemic nature of his illness, you choose to treat Marcus with several days of an intravenous third-generation cephalosporin. This is a reasonable choice in light of the antimicrobial resistance and the reluctance to use fluoroquinolones in the pediatric population. # Should these cases be reported to the local health department? What are the public health implications of these two cases of salmonellosis? Salmonellosis is a nationally notifiable disease, and most states require clinicians to report cases to local or state public health agencies. The health department and its public health partners can conduct studies to determine whether these cases indicated an outbreak of salmonellosis aboard the cruise ship. If an outbreak is confirmed, additional investigation is necessary to identify the contaminated food or the ill food worker infected with Salmonella, and whether there were correctable food-handling errors. If a food vehicle is identified, traceback and recall may be necessary to remove it from the market and prevent the occurrence of other cases. Given the increasing prevalence of drugresistant strains of S. Typhimurium, public health laboratories may perform bacteriophage typing or pulsed-field gel electrophoresis (PFGE) to further characterize the drugresistance patterns of these organisms. Reporting of these cases will contribute to essential nationwide surveillance of salmonellosis, foodborne outbreaks, and antimicrobial resistance. # What prevention measures will you recommend to Marcus and Andrea? Are repeat stool cultures necessary? To prevent Salmonella infections, all meat and egg dishes should be fully cooked. Andrea can purchase eggs that are pasteurized in the shell, and irradiated ground beef and poultry to reduce the risk of contamination. Basic food safety practices in the kitchen can also help prevent such infections, such as refrigerating leftovers promptly, washing hands and utensils after contact with raw meat and poultry, and keeping raw meat and poultry separate from ready-to-eat foods. Marcus and Andrea should be reminded to wash their hands with warm running water and soap after using the bathroom and before and after meals to avoid transmitting the infection to others. Marcus is likely to have prolonged carriage of Salmonella in the intestines. While he may return to preschool as soon as he is feeling well enough to do so because direct spread from one child to another is rare, clinicians should defer to their local health departments regarding their clearance policies for convalescing children attending preschool. With adequate hydration and your chosen antimicrobial therapy, Marcus will likely recover fully from this diarrheal illness without residual complications. # Unexplained Illness: A Patient Scenario You have been a primary care practitioner in Manhattan, New York, for several years. Jack, a 29-year-old otherwise healthy male, has been your patient for the past year. At 8:00 a.m. he calls your triage nurse complaining of a very sudden onset of nausea, cramps, coughing, and sweating. The nurse is concerned about the suddenness of onset and wants to know what you would like to do. # Should you have him call again later if he does not improve? Should you have him make an acute-visit appointment, or should you send him to the emergency room? You are concerned about the suddenness of the onset of symptoms but not the severity, so you decide to have him come to the office immediately. Jack presents in your office 30 minutes later. In addition to nausea, cramps, coughing, and sweating, his eyes have begun to tear uncontrollably and he complains of having had difficulty breathing while en route to the office. Upon arrival, he immediately asks to use the bathroom. Jack reports that he started his morning routine as usual with a run. Upon returning home, he finished drinking the bottle of water he had purchased earlier from the local deli and began to get ready for work. By the time he had finished showering and dressing, he began to feel sick to his stomach. He then developed cramping but no diarrhea. Shortly thereafter, he began to have bouts of coughing uncontrollably. He does not know when the sweating started. He states that he had difficulty breathing while en route to the office, and that the tearing just started. He denies vomiting, hemoptysis, hematuria, bright red blood per rectum (BRBPR), chills, fever, headache, myalgia, arthralgia, or diarrhea. Jack also denies the use of any medication, other drugs or alcohol. "That stuff rots your gut." Jack reports that he finished his run at about 7:00 a.m. It is now 9:00 a.m.. Despite having just urinated, he states that he must go again and immediately. However, Jack experiences incontinence on his way to the bathroom. Upon his return to the exam room, you notice a slight tremor in his left arm. He states that this has only just begun. # What preliminary diagnosis can you make at this point? - An anxiety attack - A viral syndrome - A potential foodborne illness - Anticholinergic poisoning You are not ready to reach a conclusion at this point, so you move to a physical exam and observe the following: Objective: Respiration rate: 20 BP: 92/60 mm Hg. Heart rate: 50 Temperature: 98.6°F (37°C) You note that Jack is anxious but oriented to time, place, and person. His head, ears, eyes, nose, throat (HEENT) examination shows bilateral miosis and decreased reactivity. There are no signs of trauma or bleeding. His heart has regular rate and rhythm, no murmur, and good perfusion. Radial and dorsal pulses are 2+. His lung examination reveals scattered wheezing. His abdomen is soft, nontender, not distended, with increased bowel sounds, and no mass. Extremities appear within normal limits. The neurologic exam reveals the slight tremor in his left arm, slightly slurred speech, excessive salivation, and transient fasciculations in both upper extremities. You note negative Babinski and his cranial nerves (CN) 2-11 appear intact, while CN 12 appears slightly abnormal. # What other information would assist with the diagnosis? More history from Jack, including most recent activity and diet. You now seek additional history. Jack lives alone and does not believe that he has been in contact with anyone who is ill. He works in an office as a lawyer. His run takes him up 5th Avenue and then over to 3rd Avenue, then back home. He does not run through Central Park. He does not have plants and does not garden as a hobby. His most recent meal was the night before, about 10 hours prior to the onset of his symptoms. It consisted of boiled pasta, steamed broccoli, and olive oil. He prepared the meal himself. He states that he carefully washed the broccoli, the oil was from a bottle he opened last week, and the pasta was from a box he had already used 2 days before. All he had to drink was tap water with dinner last evening and the bottled water from this morning. # Jack's presentation appears to involve which of the following systems? - Autonomic nervous system - Lymphatic system - Central nervous system The signs and symptoms in Jack's presentation predominantly involve increased autonomic responses, and are perhaps progressing to include the central nervous system as well. You decide that immediate treatment is called for and order oxygen, atropine, and pralidoxime (2-PAM). Given that Jack does not appear to have been exposed dermally, the most likely route appears to have been oral. Therefore, you also appropriately begin an IV with normal saline # What is the initial diagnosis? This presentation is not consistent with bacterial, viral, or parasitic food poisoning. While the signs and symptoms indicate acute organophosphate poisoning, the history provides no indication, and indeed seemingly contradicts this theory because of the lack of exposure. There has been no exposure to places where organophosphates are typically used, such as on lawns, house plants, and parks. Nevertheless, Jack has presented with a fairly classic case of organophosphate poisoning. Therefore, ingestion must be considered. Since you have no suggestion of deliberate ingestion on Jack's part, it must be assumed that he has consumed it unintentionally. Organophosphate poisoning has an onset of 30 minutes to 2 hours. Jack has actually made it easy to identify the most likely source: the only thing he has consumed in 10 hours is water. The broccoli could have had pesticides on it that may not have been removed when Jack washed it, but then he would have developed his symptoms during the night. Taking into account the temporal relationship between his ingestion of the bottled water and the onset of his symptoms, the bottled water seems the most likely candidate. # Given this information, what are key questions you should consider? - Is the water truly contaminated? - If it is, how did it become contaminated? - Who else may have ingested it? - Who else is at risk? - What action should be taken? You realize that if your diagnosis and conclusions are correct then a public health hazard may exist. Two things need to be done. First, the health department must be contacted, and second, tests need to be done that will confirm your diagnosis. While the usual work-up for organophosphate poisoning is clinical diagnosis, there are assays available to measure cholinesterase activity in plasma and red blood cells. It is also possible to detect some pesticides in urine. You decide to order both tests as this will provide the greatest insight into what the possible exposure is for other people in Jack's building, neighborhood, or even his city. When communicating with the local public health department, whom should you ask to speak to concerning this situation? - The medical epidemiologist? - The medical director? - The infectious disease officer? You ask to speak with the medical director. You present Jack's case, making careful note of the time course, and also inform the medical director of your suspicions of the source. The medical director takes this information and agrees with your concerns. She then asks you to speak with the chief epidemiologist so that an investigation can begin. In many large cities, there is a city health department; in smaller cities or towns, it will usually be necessary to contact the local or state health department. Try to match the level with the greatest number of people who may become affected. Other persons who may be of immediate help if you cannot reach the medical officer are the epidemiologist or even an environmental health officer. These people will most likely know what to do with the information you have. Most health departments across the country have been working to increase their knowledge or at least their awareness of the possibility of intentional contamination. Many have also created positions solely devoted to this task. Therefore, it is possible that you will be directed to such an individual. The health department initiates an investigation that includes testing the water; looking for other cases of organophosphate poisoning; interviewing the patient; notifying other parts of the public health system, including law enforcement, CDC, and the state health department. They may even issue a public notice. There is another possible cause for the case you have just seen: sarin gas can cause a similar presentation. If sarin gas had been sprayed into the air, it is possible that Jack could have respiratory exposure to the nerve gas. # If this were true, how would it change what you did? Persons exposed to sarin, and possibly other nerve agents, will have a clinical presenation similar to those with organophosphate poisoning. Hence, medical management will likely be similar. Finally, you are gratified to have helped detect a possible act of contamination that could potentially harm or even kill a great many people. Afterward, while making rounds in the hospital that day you are told by a colleague that a number of runners from a 5K race in Central Park this morning and tourists visiting the Empire State Building were brought to the emergency room complaining of sudden onset of nausea, cramps, and coughing. It was reported that all had been drinking bottled water. # Clinical Vignettes: What's Your Call? The following clinical vignettes are provided for your selfevaluation. All are possible situations that may present at your practice. The "Diagnostic Considerations" section and the tables of etiologic agents that are also part of this primer will provide the information necessary for you to adequately address these clinical situations. Note that these vignettes include both infectious and noninfectious forms of foodborne illness. For the following clinical vignettes, choose the best answer from the choices listed at the end of the vignettes: A -likely diagnosis; choose the best possible answer listed on "answer selections" page under A selections. B -most appropriate choice to confirm the diagnosis (there may be more than one correct answer -list all of them). Choose from the possible answers listed on "answer selections" page under the B section. Finally, decide whether the situation warrants reporting to the local or state health department. # Clinical Vignettes I. You receive a long-distance call from a patient who is an outdoorsman. He is with a group that collected and ate some wild mushrooms less than 2 hours ago. Several members of the group have since developed vomiting, diarrhea, and some mental confusion. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No II. A newborn child has symptoms of sepsis. Cerebrospinal fluid studies are consistent with meningitis. The mother had a flu-like syndrome prior to delivery. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No III. This patient has just returned today from Latin America following a 2-day business trip. He reports having eaten several meals of fish that he bought from street vendors around his hotel. He feels very ill with profuse, watery diarrhea, and vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No IV. An 18-month-old child is brought to your office with fever, bloody diarrhea, and some vomiting. She has been drinking unpasteurized milk in the last 48 hours. No other family members are ill. Report to the health department? ___Yes ___No XVI. Sally arrives at your office with acute gastrointestinal illness characterized by diarrhea, abdominal cramps, chills, fever, and body aches. She also informs you that about 3 days before she started getting sick, she had consumed raw ground beef that was seasoned with onions and an herb mix. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XVII. James presents to the emergency room with a lowgrade fever and complaining of fatigue and nausea for the past 24 hours. He also describes his urine as being dark and states that he has had 4 bowel movements in the past 24 hours, all of which were light colored. Upon further questioning, James says that he has no history of jaundice and that he returned from a business trip to the Philippines a month ago. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XVIII. You are halfway through your shift in the ER. There are four patients, two adults and two children, with a history of nausea, vomiting, abdominal pain, and profuse (especially in the children) watery diarrhea in the absence of fever. They each report that these symptoms began 5 days ago and resolved after 1 day. They had all been symptom free for 3 days, but now the symptoms have returned. There is also a new onset of jaundice and bloody diarrhea. Lab results indicate elevated LFTs. The patients do not know each other, but all report eating hamburgers several hours before the initial onset of symptoms. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XIX. A mother has brought in a 5-month-old child with apparent blindness. She reports that the child had been healthy until the past month when the vision problems appeared. The mother states that she had been well during the pregnancy, but further questioning reveals that the mother had two young cats at home for which she was the sole care provider. The cats were given away just before the birth of the child because of concerns about the child being smothered by the cats. Recommendations and Reports # Which of the following is not a safe food-handling behavior? A. Using the same cutting board for raw foods and cooked foods. B. Using a food thermometer to check the internal temperature of food before eating it. C. Rinsing raw produce with water. D. Washing hands before and after handling food. # What is the appropriate method to use in determining if a hamburger is cooked to a proper temperature? A. Cooking it until it is brown inside. B. Using a food thermometer to ensure that the internal temperature reaches 160 º F. C. Determining if a hamburger is cooked to a proper temperature is not necessary because it is too small. D. Taking a bite of the hamburger to ensure that it tastes cooked. # When a foodborne outbreak is suspected, who would be a helpful contact at the health department? A. Medical officer. B. Epidemiology officer. C. Environmental health officer. D. Any of the above would be helpful. # Which of the following is not consistent with inflammatory diarrhea? A. Presence of fecal leukocytes. B. Grossly bloody stool. C. Infection with invasive or cytotoxigenic bacterial and protozoan species. D. Involvement of the small intestine. # Goal and Objectives This MMWR provides recommendations for physicians and other health-care professionals who have a critical role in diagnosing, treating, and reporting food-related disease outbreaks. These recommendations were developed by the American Medical Association, the American Nurses Association-American Nurse Foundation, the Centers for Disease Control and Prevention, the Food and Drug Administration's Center for Food Safety and Nutrition, and the United States Department of Agriculture's Food Safety and Inspection Service. The goal of this report is to provide health-care providers with guidance and patient-education materials regarding foodborne illness. After completing this continuing education activity, the reader should be able to 1) differentiate between the six etiologic agents that should be considered regarding manifestations of foodborne illness; 2) describe four criteria to consider when treating a diagnosed foodborne illness; 3) summarize the reporting requirements for foodborne illness; and 4) identify three groups of persons who are at higher risk for foodborne illnesses. To receive continuing education credit, please answer all of the following questions: 8. Intentional contamination of food is uncommon, but which of the following would make you suspect that such an act had occurred (i.e., the unusual nature of the situation would induce suspicion of intentional contamination)? A. An unusual agent or pathogen in a common food. B. A common agent or pathogen affecting an unusually large number of persons. C. A common agent or pathogen that is uncommonly seen in clinical practice. D. All of the above. 9. Multidrug-resistant Salmonella typhimurium cases . . . A. have been on the rise in the United States since the 1990s. B. might be responsible for more invasive disease than other types. C. often are resistant to ampicillin and sulfamethoxazole. D. cause more cases in an outbreak than do sensitive strains. E. all of the above.	has indicated that she has a financial relationship with CDC because she is the Director of a Food Safe Schools project that is funded under a cooperative agreement by CDC. The remaining preparers have signed a conflict of interest disclosure form that verifies no conflict of interest.An earlier edition of this Primer, covering different foodborne illnesses, was published in MMWR in 2001 (MMWR 2001;50[No. RR-2]) and also as a separate publication by the American Medical Association, CDC, the Food and Drug Administration, and the U.S. Department of Agriculture. This report updates and supplements the previous edition. It is being reprinted here as a courtesy to the collaborating agencies and the MMWR readers.# • Obtain stool cultures in appropriate settings, and recognize that testing for some specific pathogens, eg, E. coli O157:H7, Vibrio spp., must be requested; • Report suspect cases to appropriate public health officials; • Talk with patients about ways to prevent food-related diseases; and • Appreciate that any patient with foodborne illness may represent the sentinel case of a more widespread outbreak. Foodborne illness is considered to be any illness that is related to food ingestion; gastrointestinal tract symptoms are the most common clinical manifestations of foodborne illnesses. This document provides detailed summary tables and charts, references, and resources for health care professionals. Patient scenarios and clinical vignettes are included for selfevaluation and to reinforce information presented in this primer. Also included is a CME component. This primer is not a clinical guideline or definitive resource for the diagnosis and treatment of foodborne illness. Safe food handling practices and technologies (eg, irradiation, food processing and storage) also are not addressed. More detailed information on these topics is available in the references and resources listed in this document, as well as from medical specialists and medical specialty societies, state and local public health authorities, and federal government agencies. # Recognizing Foodborne Illness Patients with foodborne illnesses typically present with gastrointestional tract symptoms (eg, vomiting, diarrhea, abdominal pain); however, nonspecific symptoms and neurologic symptoms may also occur. Every outbreak begins with an index patient who may not be severely ill. A physician or health care professional who encounters this person may be the only one with the opportunity to make an early and expeditious diagnosis. Thus, the physician or health care professional must have a high degree of suspicion and ask appropriate questions to recognize that an illness may have a foodborne etiology. Important clues to determining the etiology of a foodborne disease are the • Incubation period; • Duration of the resultant illness; • Predominant clinical symptoms; and • Population involved in the outbreak. Additional clues may be derived by asking whether the patient has consumed raw or poorly cooked foods (eg, raw or undercooked eggs, meats, shellfish, fish), unpasteurized milk or juices, home-canned goods, fresh produce, or soft cheeses made from unpasteurized milk. Inquire as to whether any of the patient's family members or close friends have similar symptoms. Inquiries about living on or visiting a farm, pet contact, day care attendance, occupation, foreign travel, travel to coastal areas, camping excursions to mountains or other areas where untreated water is consumed, and attendance at group picnics or similar outings also may provide clues for determining the etiology of the illness. If a foodborne illness is suspected, submit appropriate specimens for laboratory testing and contact the state or local health department for advice about epidemiologic investigation. For the physician or other health care professional, implication of a specific source in disease transmission is difficult from a single patient encounter. Attempts to identify the source of the outbreak are best left to public health authorities. Because infectious diarrhea can be contagious and is easily spread, rapid and definitive identification of an etiologic agent may help control a disease outbreak. Early identification of a case of foodborne illness can prevent further exposures. An individual physician who obtains testing can contribute the clue that ultimately leads to identification of the source of an outbreak. Finally, health care professionals should recognize that while deliberate contamination of food is a rare event, it has been documented in the past. The following events may suggest that intentional contamination has occurred: an unusual agent or pathogen in a common food, a common agent or pathogen affecting an unusually large number of people, or a common agent or pathogen that is uncommonly seen in clinical practice, as might occur with pesticide poisoning. # Diagnosing Foodborne Illnesses Differential Diagnosis As shown in Table 1 and the Foodborne Illnesses Tables, a variety of infectious and noninfectious agents should be considered in patients suspected of having a foodborne illness. Establishing a diagnosis can be difficult, however, particularly in patients with persistent or chronic diarrhea, those with severe abdominal pain, and when there is an underlying dis- # TABLE 1. Etiologic agents to consider for various manifestations of foodborne illness Clinical presentation Gastroenteritis (vomiting as primary symptom; fever and/or diarrhea also may be present) Noninflammatory diarrhea (acute watery diarrhea without fever/dysentery; some patients may present with fever)* Inflammatory diarrhea (invasive gastroenteritis; grossly bloody stool and fever may be present) † Persistent diarrhea (lasting >14 days) Neurologic manifestations (eg, paresthesias, respiratory depression, bronchospasm, cranial nerve palsies) Systemic illness (eg, fever, weakness, arthritis, jaundice) Potential food-related agents to consider Viral gastroenteritis, most commonly rotavirus in an infant or norovirus and other caliciviruses in an older child or adult; or food poisoning due to preformed toxins (eg, vomitoxin, Staphylococcus aureus toxin, Bacillus cereus toxin) and heavy metals. Can be caused by virtually all enteric pathogens (bacterial, viral, parasitic) Prolonged illness should prompt examination for parasites, particularly in travelers to mountainous or other areas where untreated water is consumed. Consider Cyclospora cayetanensis, Cryptosporidium, Entamoeba histolytica, and Giardia lamblia. Botulism (Clostridium botulinum toxin) Organophosphate pesticides Thallium poisoning Scombroid fish poisoning (histamine, saurine) Ciguatera fish poisoning (ciguatoxin) Tetradon fish poisoning (tetradotoxin) Neurotoxic shellfish poisoning (brevitoxin) Paralytic shellfish poisoning (saxitoxin) Amnesic shellfish poisoning (domoic acid) Mushroom poisoning Guillain-Barré syndrome (associated with infectious diarrhea due to Campylobacter jejuni) # Listeria monocytogenes Brucella species Trichinella spiralis Toxoplasma gondii Vibrio vulnificus Hepatitis A and E viruses Salmonella Typhi and Salmonella Paratyphi Amebic liver abscess * Noninflammatory diarrhea is characterized by mucosal hypersecretion or decreased absorption without mucosal destruction and generally involves the small intestine. Some affected patients may be dehydrated because of severe watery diarrhea and may appear seriously ill. This is more common in the young and the elderly. Most patients experience minimal dehydration and appear mildly ill with scant physical findings. Illness typically occurs with abrupt onset and brief duration. Fever and systemic symptoms usually are absent (except for symptoms related directly to intestinal fluid loss). † Inflammatory diarrhea is characterized by mucosal invasion with resulting inflammation and is caused by invasive or cytotoxigenic microbial pathogens. The diarrheal illness usually involves the large intestine and may be associated with fever, abdominal pain and tenderness, headache, nausea, vomiting, malaise, and myalgia. Stools may be bloody and may contain many fecal leukocytes. ease process. The extent of diagnostic evaluation depends on the clinical picture, the differential diagnosis considered, and clinical judgment. The presentation of a patient with a foodborne illness is often only slightly different from that of a patient who presents with a viral syndrome. In addition, viral syndromes are so common that it is reasonable to assume that a percentage of those diagnosed with a viral syndrome have actually contracted a foodborne illness. Therefore, the viral syndrome must be excluded in order to suspect the foodborne illness and take appropriate public health action. Fever, diarrhea, and abdominal cramps can be present or absent in both cases so they are not very helpful. The absence of myalgias or arthralgias would make a viral syndrome less likely and a foodborne illness (that does not target the neurologic system) more likely. Foodborne illnesses that do target the neurologic system tend to cause paraesthesias, weakness and paralysis that are distinguishable from myalgias or arthralgias (see below). The presence of dysentery (bloody diarrhea) is also more indicative of a foodborne illness, particularly if it is early in the course. If any of the following signs and symptoms occur in patients, either alone or in combination, laboratory testing may provide important diagnostic clues (particular attention should be given to very young and elderly patients and to immunocompromised patients, all of whom are more vulnerable): • Bloody diarrhea • Weight loss • Diarrhea leading to dehydration • Fever • Prolonged diarrhea (3 or more unformed stools per day, persisting several days) • Neurologic involvement, such as paresthesias, motor weakness, cranial nerve palsies • Sudden onset of nausea, vomiting, diarrhea • Severe abdominal pain In addition to foodborne causes, a differential diagnosis of gastrointestinal tract disease should include underlying medical conditions such as irritable bowel syndrome; inflammatory bowel diseases such as Crohn's disease or ulcerative colitis; malignancy; medication use (including antibiotic-related Clostridium difficile toxin colitis); gastrointestinal tract surgery or radiation; malabsorption syndromes; immune deficiencies; and numerous other structural, functional, and metabolic etiologies. Consideration also should be given to exogenous factors such as the association of the illness with travel, occupation, emotional stress, sexual habits, exposure to other ill persons, recent hospitalization, child care center attendance, and nursing home residence. The differential diagnosis of patients presenting with neurologic symptoms due to a foodborne illness is also complex. Possible food-related causes to consider include recent ingestion of contaminated seafood, mushroom poisoning, and chemical poisoning. Because the ingestion of certain toxins (eg, botulinum toxin, tetrodotoxin) and chemicals (eg, organophosphates) can be life-threatening, a differential diagnosis must be made quickly with concern for aggressive therapy and life support measures (eg, respiratory support, administration of antitoxin or atropine), and possible hospital admission. # Clinical Microbiology Testing When submitting specimens for microbiologic testing, it is important to realize that clinical microbiology laboratories differ in protocols used for the detection of pathogens. To optimize recovery of an etiologic agent, physicians and other health care professionals should understand routine specimencollection and testing procedures as well as circumstances and procedures for making special test requests. Some complex tests (eg, toxin testing, serotyping, molecular techniques) may only be available from large commercial or public health laboratories. Contact your microbiology laboratory for more information. Stool cultures are indicated if the patient is immunocompromised, febrile, has bloody diarrhea, has severe abdominal pain, or if the illness is clinically severe or persistent. Stool cultures are also recommended if many fecal leukocytes are present. This indicates diffuse colonic inflammation and is suggestive of invasive bacterial pathogens such as Shigella, Salmonella, and Campylobacter species and invasive E. coli. In most laboratories, routine stool cultures are limited to screening for Salmonella and Shigella species and Campylobacter jejuni/coli. Cultures for Vibrio and Yersinia species, E. coli O157:H7, and Campylobacter species other than jejuni/coli require additional media or incubation conditions and therefore require advance notification or communication with laboratory and infectious disease personnel. Stool examination for parasites generally is indicated for patients with suggestive travel histories, who are immunocompromised, who suffer chronic or persistent diarrhea, or when the diarrheal illness is unresponsive to appropriate antimicrobial therapy. Stool examination for parasites is also indicated for gastrointestinal tract illnesses that appear to have a long incubation period. Requests for ova and parasite examination of a stool specimen will often enable identification of Giardia lamblia and Entamoeba histolytica, but a special request may be needed for detection of Cryptosporidium and Cyclospora cayetanensis. Each laboratory may vary in its rou-tine procedures for detecting parasites, so it is important to contact your laboratory. Blood cultures should be obtained when bacteremia or systemic infection is suspected. Direct antigen detection tests and molecular biology techniques are available for rapid identification of certain bacterial, viral, and parasitic agents in clinical specimens. In some circumstances, microbiologic and chemical laboratory testing of vomitus or implicated food items also is warranted. For more information on laboratory procedures for the detection of foodborne pathogens, consult an appropriate medical specialist, clinical microbiologist, or state public health laboratory. # Treating Foodborne Illness Selection of appropriate treatment depends on identification of the responsible pathogen (if possible) and determining if specific therapy is available. Many episodes of acute gastroenteritis are self-limiting and require fluid replacement and supportive care. Oral rehydration is indicated for patients who are mildly to moderately dehydrated; intravenous therapy may be required for more severe dehydration. Routine use of antidiarrheal agents is not recommended because many of these agents have potentially serious adverse effects in infants and young children. Choice of antimicrobial therapy should be based on • Clinical signs and symptoms; • Organism detected in clinical specimens; • Antimicrobial susceptibility tests; and • Appropriateness of treating with an antibiotic (some enteric bacterial infections are best not treated). Knowledge of the infectious agent and its antimicrobial susceptibility pattern allows the physician to initiate, change, or discontinue antimicrobial therapy. Such information also can support public health surveillance of infectious disease and antimicrobial resistance trends in the community. Antimicrobial resistance has increased for some enteric pathogens, which dictates judicious use of this therapy. Suspected cases of botulism are treated with botulinum antitoxin. Equine botulinum antitoxin for types A, B, and E can prevent the progression of neurologic dysfunction if administered early in the course of illness. Physicians and other health care professionals should notify their local and state health departments regarding suspected cases of botulism. CDC maintains a 24-hour consultation service to assist health care professionals with the diagnosis and management of this rare disease. # Surveillance and Reporting of Foodborne Illness Reporting of foodborne illnesses in the United States began more than 50 years ago when state health officers, concerned about the high morbidity and mortality caused by typhoid fever and infantile diarrhea, recommended that cases of "enteric fever" be investigated and reported. The intent of investigating and reporting these cases was to obtain information about the role of food, milk, and water in outbreaks of gastrointestinal tract illness as the basis for public health actions. These early reporting efforts led to the enactment of important public health measures (eg, the Pasteurized Milk Ordinance) that profoundly decreased the incidence of foodborne illnesses. Often health care professionals may suspect foodborne illness either because of the organism involved or because of other available information, such as several ill patients who have eaten the same food. Health care professionals can serve as the eyes and ears for the health department by providing such information to local or state public health authorities. Foodborne disease reporting is not only important for disease prevention and control, but more accurate assessments of the burden of foodborne illness in the community occur when physicians and other health care professionals report foodborne illnesses to the local and state health department. In addition, reporting of cases of foodborne illness by practicing physicians to the local health department may help the health officer identify a foodborne disease outbreak in the community. This may lead to early identification and removal of contaminated products from the commercial market. If a restaurant or other food service establishment is identified as the source of the outbreak, health officers will work to correct inadequate food preparation practices, if necessary. If the home is the likely source of the contamination, health officers can institute public education about proper food handling practices. Occasionally, reporting may lead to the identification of a previously unrecognized agent of foodborne illness. Reporting also may lead to identification and appropriate management of human carriers of known foodborne pathogens, especially those with high-risk occupations for disease transmission such as foodworkers. Typically, the appropriate procedure for health care professionals to follow in reporting foodborne illnesses is to contact the local or state health department whenever they identify a specific notifiable foodborne disease. However, it is often unclear if a patient has a foodborne illness prior to diagnostic tests, so health care professionals should also report potential foodborne illnesses, such as when 2 or more patients present with a similar illness that may have resulted from the ingestion of a common food. Local health departments then report the illnesses to the state health departments and determine if further investigation is warranted. Each state health department reports foodborne illnesses to CDC. CDC compiles these data nationally and disseminates information via the weekly Morbidity and Mortality Weekly Report and annual summary reports. CDC assists state and local public health authorities with epidemiologic investigations and the design of interventions to prevent and control foodrelated outbreaks. CDC also coordinates a national network of public health laboratories, called PulseNet, which performs "molecular fingerprinting" of bacteria (by pulsed-field gel electrophoresis) to support epidemiologic investigations. Thus, in addition to reporting cases of potential foodborne illnesses, it is important for physicians to report noticeable increases in unusual illnesses, symptom complexes, or disease patterns (even without definitive diagnosis) to public health authorities. Prompt reporting of unusual patterns of diarrheal/ gastrointestinal tract illness, for example, can allow public health officials to initiate an epidemiologic investigation earlier than would be possible if the report awaited definitive etiologic diagnosis. Finally, new information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated whenever new data about preventing foodborne illness become available. Physicians and other health care professionals need to be aware of and follow the most current information on food safety. Identification of metal in food. Radioassay for toxin in fish or a consistent history. Identification of metal in beverage or food. Analysis of blood, hair. Typical syndrome and mushroom identified or demonstration of the toxin. Typical syndrome and mushroom identified and/or demonstration of the toxin. Analysis of the food, blood. Analysis of the food, blood. # Patient Scenarios The learning scenarios in this section can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the previous sections of this primer. The case studies provide questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # Congenital Toxoplasmosis, A Patient Scenario Susan, a 6-month-old infant, is brought to your office for evaluation of apparent blindness. Her mother reports that she had been well during the pregnancy and the delivery was uncomplicated. The baby appeared healthy until age 4 months, when the parents became concerned about her vision. Physical examination was normal except for bilateral macular scars, microphthalmos, and unresponsiveness to visual stimuli. There were no other neurologic abnormalities, and her growth and development were appropriate for her age. A computed tomography (CT) scan of the head was obtained. The CT scan of the child's head showed periventricular calcifications and asymmetric dilation of the lateral ventricles. The mother is 35 years old and reiterated that she does not recall being ill during the pregnancy; however, she also indicated that she would not necessarily remember every little symptom. She also denied having a history of STDs. She had received the mumps-measles-rubella (MMR) vaccine as a child but no vaccines during pregnancy. The mother recalled eating insufficiently cooked meat while traveling in France during the first trimester of pregnancy. The family does not own a cat, and she does not recall having been exposed to cats during her pregnancy. # Congenital infection with # What diagnostic tests are needed? Serologic evaluation of both mother and child focusing on potential congenital infection (ie, a ToRCH profile) based on the history of the mother ingesting raw meat while traveling in a foreign country during first trimester of pregnancy and the clinical findings (blindness, cerebral calcifications, and hydrocephalus). Results of serologic testing detected both IgG and IgM antibodies to Toxoplasma gondii in both the baby's and mother's serum. The mother's IgM titer was 1:6400 and IgG titer was 1:6400, while those of the baby were IgM titer of 1:160 and IgG titer of 1:6400. # How does this information assist with the diagnosis? Diagnosis of toxoplasmosis is usually confirmed by serologic tests. Occasionally, organisms are identified in tissue or body fluids or isolated by culture or animal inoculation. Polymerase chain reaction (PCR)-based assays are available from some laboratories for diagnosis of fetal infection and infection in compromised hosts. For immunocompetent persons, seroconversion or a 4-fold rise of specific IgG antibodies or demonstration of specific IgM antibodies indicate recent infection. High titers of IgG antibodies in the absence of IgM antibodies are consistent with chronic latent infection acquired in the past. The IgM-capture enzyme-linked immunosorbent assay (ELISA) is more sensitive than the IgM-indirect fluorescent-antibody assay (IFA) test. However, IgM tests may be false-positive, and true-positive IgM tests may persist for a year or more. Therefore, to determine if infection occurred during pregnancy, additional tests, such as an anti-Toxoplasma avidity test, may be required at a reference laboratory. Immunodeficient persons usually do not have measurable IgM antibodies, even in the presence of active disease. The diagnosis of central nervous system (CNS) toxoplasmosis in such persons is therefore based on clinical picture, typical CT scan or magnetic resonance imaging (MRI) showing multiple ring-enhancing hypodense nodules, and a positive IgG test. Brain biopsy is reserved for cases that fail to respond to an empiric trial of anti-Toxoplasma drugs. The baby was diagnosed with congenital toxoplasmosis. # How is toxoplasmosis best treated? Toxoplasmosis in immunocompetent persons rarely requires treatment, whereas infection in immunodeficient persons or in infants with congenital infections usually requires treatment. The combination of pyrimethamine and sulfadiazine is the treatment of choice. Folinic acid (leucovorin) is given to prevent bone marrow suppression. Treatment must be continued for the duration of immunosuppression and for life in AIDS patients whose immunity is not reconstituted by highly aggressive antiretroviral therapy (HAART). For persons unable to tolerate the pyrimethamine and sulfadiazine combination, high doses of pyrimethamine (and leucovorin) and clindamycin are effective. The management of toxoplasmosis acquired during pregnancy is controversial. Testing of newly pregnant women for T. gondii infection is not routinely done, and routine testing is not recommended by CDC or by the American College of Obstetricians and Gynecologists. To prevent fetal infection, one approach is to administer spiramycin (a macrolide antibiotic, which is concentrated in the placenta and is not harmful to the fetus). At the same time, amniotic fluid is submitted for PCR-based testing to determine whether fetal infection has occurred. If so, options may include pyrimethamine and sulfadiazine given after the 16th week of pregnancy (since pyrimethamine is potentially teratogenic) or consideration of terminating the pregnancy. If the fetus is shown to be uninfected, spiramycin is continued throughout pregnancy. Different protocols exist for treatment of infants born with congenital infection. The most commonly recommended treatment is pyrimethamine and sulfadiazine plus leucovorin during the first year of life. In the present case, the child was treated for 6 months with pyrimethamine and sulfadiazine plus leucovorin. Human infection with the intracellular protozoan parasite Toxoplasma gondii occurs globally. Infection is usually subclinical or produces a mild illness, except in immunodeficient persons and fetuses infected in utero. Most infants with congenital toxoplasmosis appear healthy at birth but have a high incidence of developing serious ophthalmologic and neurologic sequelae during the next 20 years of life. Severe congenital toxoplasmosis may be apparent at birth or become apparent during the first 6 months of life. Chorioretinitis, intracerebral calcifications, and hydrocephalus, as in the present case, are typical features The child was treated with pyrimethamine, sulfadiazine, and folinic acid for 6 months. She remains blind, and has developed moderate psychomotor retardation. # How could Toxoplasma infection have been prevented in this child? Toxoplasma gondii may be transmitted transplacentally to the fetus if the mother acquired toxoplasmosis during pregnancy. There is almost no risk of transplacental transmission if the mother was infected prior to conception; accordingly, women with positive IgG antibody tests for toxoplasmosis at the onset of pregnancy are not at risk for developing acute toxoplasmosis. Women with negative IgG antibody tests during pregnancy should avoid eating insufficiently cooked or uncooked meat and should avoid ingestion of soil and water or food that may be contaminated with cat feces. Transmission occurs by a) ingestion of tissue cysts in raw or insufficiently cooked meat, especially lamb, pork, and wild game; b) accidental ingestion of food, water, or soil contaminated with cat feces that contain infective oocysts; c) transplacental passage of infective tachyzoites; d) transfusion of infected white blood cells or transplantation of an infected organ; and e) laboratory accidents. Prevention of toxoplasmosis is particularly important for uninfected (ie, seronegative) pregnant mothers, HIVinfected persons, and other immunocompromised patients: • Avoid ingestion of raw or insufficiently cooked meat and poultry; cook meat to 160°F (71°C) or freeze to -4°F (-20°C). For more details on preventing toxoplasmosis, please see the Suggested Resources and Suggested Reading List. • Avoid ingestion of environmental oocysts by avoiding contact with cat litter, soil, water, and vegetables potentially contaminated with cat feces. Infection acquired by healthy persons is usually asymptomatic or may lead to painless lymphadenopathy or a mononucleosis syndrome. Maternal infection is usually unrecognized. Disease in persons with depressed cellular immunity (eg, persons with AIDS, transplant recipients, persons receiving immunosuppressants) usually is due to reactivation of latent infection but can result from acute infection. Toxoplasmosis in these persons leads to lethal meningoencephalitis, focal lesions of the CNS, and less commonly, myocarditis or pneumonitis. The clinical picture may include headache, seizures, mental status changes, focal neurologic signs, and aseptic meningitis. Thirty to forty percent of AIDS patients with IgG antibodies to T. gondii (indicating chronic latent infection) develop active toxoplasmosis unless they take preventive medication. Congenital infection occurs when a previously uninfected mother develops infection during pregnancy. Infection prior to conception, demonstrated by specific IgG antibodies, in nearly all cases guarantees against infection of the fetus. However, transplacental transmission occurs from mothers whose prior infections reactivate when they receive immunosuppressant medications or develop AIDS. Congenital toxoplasmosis may result in abortion, stillbirth, mental retardation, and retinal damage. Recurrent toxoplasmic chorioretinitis in children and young adults is frequently the result of congenital infection that was asymptomatic at birth. # Acute Hepatitis A: A Patient Scenario While working in an emergency room, you are asked to see a 31-year-old Asian-American woman who has had fever, nausea, and fatigue for the past 24 hours. She also reports dark urine and has had 3 light colored stools since yesterday. She has previously been healthy and has no previous history of jaundice. Her physical examination shows a low-grade fever of 100.6°F/38.1°C, faint scleral icterus, and hepatomegaly. Her blood pressure and neurologic exam are normal and there is no rash. Initial laboratory studies show an alanine aminotransferase (ALT) result of 877 IU/L, aspartate amino transferase (AST) enzyme levels of 650 IU/L, an alkaline phosphatase of 58 IU/L and a total bilirubin of 3.4 mg/dL. White blood cell count is 4.6, with a normal differential; electrolytes are normal; the blood urea nitrogen level is 18 mg/dL; and serum creatinine level is 0.6 mg/dL. Pregnancy test is negative. What should be included in the differential diagnosis of acute hepatitis? She has no children, and her boyfriend is not ill. She has been in a monogamous relationship with her boyfriend for 2 years. She was born in the United States; her parents immigrated to the United States from Taiwan in the 1950s. She works as a food preparer for a catering business. She returned 4 weeks ago from a 1-week vacation in Mexico (Mexico City and nearby areas), where she stayed with her boyfriend in several hotels. She drank only bottled water but ate both cooked and uncooked food at numerous restaurants while in Mexico, and she visited a family friend and her 3 young children in a Mexico City suburb. She did not receive hepatitis A vaccine or immune globulin before going on vacation. She is not sure if she has received hepatitis B vaccine. She has not gone camping or hiking and had no recent tick exposures. She has never used illicit drugs, drinks alcohol rarely, and has never received a transfusion. She is taking oral contraceptives but no other prescription medication, and took 500 milligrams of Tylenol ® once after onset of her current symptoms. She has a pet cat but no other animal exposures. She had chickenpox and mononucleosis during childhood. # How does this information assist with the diagnosis? Lack of animal or tick exposures makes leptospirosis and Rocky Mountain spotted fever unlikely, and Q fever less likely. Yellow fever and typhoid fever are very unlikely with no history of travel to rural endemic areas, and assuming exposure occurred in Mexico, inconsistent with the long incubation period. Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV) infection are all possible diagnoses. A drug reaction to the oral contraceptive is a possible cause of hepatitis. The history of travel to an endemic area makes hepatitis A the most likely diagnosis. # What diagnostic tests are needed? Specific diagnostic serologic studies are necessary to distinguish one form of viral hepatitis from another. Testing for total (IgG+ IgM) anti-HAV does not distinguish between a past history of hepatitis A virus infection and current infection and is not useful in diagnosing acute hepatitis A. Hepatitis A can be easily confirmed with an anti-IgM anti-HAV test. This test is widely available and results are usually available within 24 hours. A hepatitis panel is ordered, and results from such a panel are shown here. You obtain the following results from the serologic testing: • Total anti-HAV: positive • IgM anti-HAV: positive • Total anti-HBc: positive • IgM anti-hepatitis B core antigen: negative • HBsAg: negative • anti-HBs: positive • anti-HCV: negative # What is the diagnosis? The diagnosis is hepatitis A. The hepatitis B serologic tests indicate past, resolved infection with no chronic infection. Acute hepatitis C is also possible; the appearance of anti-HCV may be delayed for as long as 9 months after exposure. However, with a confirmed diagnosis of hepatitis A, further testing for HCV RNA is not indicated at this point. Finally, note that hepatitis E is rarely reported in travelers, and results of serologic tests for hepatitis E virus (HEV) are difficult to interpret. Tests for HEV should only be performed if other more common causes of hepatitis have been excluded. The incubation period for hepatitis A is 15-50 days, with an average of 28 days. The most common signs and symptoms associated with acute hepatitis A include jaundice, fever, malaise, anorexia, and abdominal discomfort. The illness can be severe and approximately 10% to 20% of reported cases require hospitalization. The likelihood of having symptoms with HAV infection is related to the person's age. In children <6 years of age, most (70%) infection is asymptomatic; if illness does occur it is not usually accompanied by jaundice. Older children and adults are more likely to have symptomatic disease, although jaundice may be absent in as many as one third of adults with HAV infection. In many developing countries in Asia, Africa, and Central and South America, infection is nearly universal during early childhood and is often asymptomatic. # What treatment is indicated? There is no specific treatment for hepatitis A. Bed rest does not hasten recovery. Hepatitis A is never a chronic infection, although 10% to 15% of symptomatic persons have prolonged or relapsing disease lasting up to 6 months. While rarely fatal in younger persons, the case-fatality rate is nearly 2% among reported patients who are more than 50 years old. Following is a depiction of a typical course, including times of peak fecal excretion of HAV, liver function test abnormalities, and clinical symptoms. # How is hepatitis A virus transmitted, and who is at risk for this disease? HAV is an RNA virus that only infects primates. HAV has a fecal-oral route of transmission and is easily transmitted person to person. HAV is also transmitted through contaminated food or water. Because HAV is present in the blood during acute infection, bloodborne transmission is also possible, but rare. The highest levels of HAV are found in the stool, and peak levels occur in the 2 weeks before onset of illness. Groups at increased risk for hepatitis A include travelers to developing countries, men who have sex with men, and injecting and noninjecting drug users. In the United States, 4% to 6% of reported cases occur among international travelers, many of whom presumably acquired HAV infection from contaminated food or water. Approximately 50% of persons with hepatitis A do not report any known risk factors, and some of these infections may be from unrecognized transmission via HAV-contaminated food. # How might this illness have been prevented? Persons planning to travel to an endemic region should receive hepatitis A vaccine or immune globulin before departure. Hepatitis A vaccination can be given to anyone 2 years of age and older, and has the advantage of providing long-term protection (at least 20 years). Hepatitis A vaccine is an inactivated HAV preparation; the first dose of vaccine provides protective anti-HAV levels within 30 days for >90% of vaccine recipients. Licensed hepatitis A vaccines available in the United States are considered to be equivalent in effectiveness, and include Havrix ® (manufactured by Glaxo SmithKline), VAQTA ® (Merck & Co.), and Twinrix ® (combined hepatitis A and hepatitis B vaccine, Glaxo SmithKline). Vaccination is administered in a 2-dose schedule (0, 6 months) for Havrix ® and VAQTA ® , and a 3-dose schedule (0, 1, 6 months) for Twinrix ® . The second (or third) dose is provided to ensure protection in those who did not respond to the first dose of vaccine. Ninety-nine percent of vaccinees will be protected after 2 doses of vaccine. For persons who present for hepatitis A immunoprophylaxis <30 days before departure to an endemic region and for children <2 years old, immune globulin (IG) is an effective means of preventing hepatitis A. IG is the appropriate immunoprophylaxis for children <2 years old. IG is a sterile preparation of concentrated antibodies (immunoglobulins) made from pooled human plasma. IG provides protection against hepatitis A for 3-5 months, depending on dosage, through passive transfer of antibody. Vaccine and IG may be given simultaneously. Hepatitis A is the most common vaccine-preventable disease among travelers. The risk varies according to region visited and the length of stay, and is increased even among travelers who report observing measures to protect themselves against enteric infection or stay only in urban areas. In the United States, children account for approximately one third of reported travel-related cases. # What else needs to be done? Cases of hepatitis A should be reported to the local health department immediately. The patient's boyfriend and any other household or sexual contacts whose last exposure to the patient was <14 days ago should be given IG. Screening for immunity before administering IG is not recommended in this situation because it is more costly than IG and would delay its administration. IG is not indicated for family members or friends not living in the household. Prompt reporting of hepatitis A cases allows time to decide on a course of action and provide timely immunoprophylaxis when appropriate. Because this patient works as a food preparer, the health department will need to visit the establishment to assess the likelihood that her duties and hygiene practices pose a significant risk of food contamination. IG is often recommended for co-workers of commercial food handlers with hepatitis A. In addition, if she worked at any time during the 2 weeks before onset of jaundice to 1 week after onset, persons who ate food prepared or handled by this patient may be candidates for IG prophylaxis. Determina- tions of the need for IG prophylaxis are made on a case-bycase basis by experienced health department personnel. Again, immediate reporting of hepatitis A cases allows time to decide on a course of action and provide timely treatment and intervention when appropriate. # Norovirus Infection: A Patient Scenario Nancy is a 25-year-old previously well graduate student who presents to the emergency department with a 12-hour history of nausea, diarrhea, abdominal cramping, and vomiting (about 6 episodes), malaise, and a low-grade fever. She describes her onset of symptoms as sudden. Physical examination shows that Nancy is afebrile with a supine blood pressure of 123/74 mm Hg. She has a diffusely tender abdomen and is dehydrated. Stool examination is negative for occult blood. # What is the possible differential diagnosis for her chief complaint? • Infectious gastroenteritis • Food intoxication (noninfectious gastroenteritis) • Inflammatory bowel disease • Appendicitis • Pelvic inflammatory disease # What additional information would assist with the diagnosis? • Did anyone in her household experience similar illness within the week prior to onset of symptoms? • Has she been in contact with anyone outside her household with similar symptoms within the previous week? • Has she had such symptoms before? • Does she know if anyone else became ill? • Has she traveled outside the United States within the last month? • Has she previously had a sexually transmitted diseases or does she have multiple sex partners? Nancy reports that she rarely has diarrhea or vomiting. She also reports no contact with anyone who was ill in the past week, nor has she been out of the country in the past month. Her boyfriend, who does not live with her, has similar symptoms with an almost identical onset time. Both attended a wedding 2 days ago. The meal at the wedding reception, which was held at a local reception hall, was the only meal they shared in the past several days. Nancy does not know if anyone else who attended the wedding became ill. Nancy reports that she has no history of a sexually transmitted disease and that she and her boyfriend have a monogamous sexual relationship. # How does this information assist with the diagnosis? Based on the rapid onset of symptoms, Nancy's reported past history of good health, and the fact that her boyfriend has an almost identical history, inflammatory bowel disease, appendicitis, and pelvic inflammatory disease are the least likely diagnoses. Food intoxication is also not very likely. Assuming that the wedding reception was the source of the toxin, and this was their most recent common meal, the time from exposure to onset of symptoms is too long. Toxins usually cause illness within minutes to hours after ingestion. The most likely diagnosis is infectious gastroenteritis. There is a possibility that Nancy's and her boyfriend's illness may be associated with an outbreak of gastroenteritis. # What additional information would assist with the identification of the etiologic agent? • What sorts of foods were served at the wedding reception? • When did the couple last share a meal prior to the wedding reception? • Has an outbreak of gastroenteritis associated with this reception has been reported to the local health department?. The health department may be able to aid in determining what the etiologic agent was if it is currently investigating the outbreak. At the wedding, the couple had a choice of meal. Nancy had lobster tail and filet mignon. Her boyfriend had chicken. They both consumed stuffed mushrooms, salad, and hors d'oeuvres preceding the main meal. For dessert they both had wedding cake and fresh fruit. Both drank wine or beer during the reception. The couple attended a barbecue the previous week. This outing was a function sponsored by Nancy's employer. Nancy tells you that none of her co-workers have been ill with vomiting and diarrhea. You place an inquiry with the local health department about the possible outbreak. The health department notifies you that an investigation is currently under way. Illness has also been reported among 75% of attendees at a wedding the day before the one Nancy attended, at the same reception hall. The only common food between the 2 weddings is the salad, and the health department currently suspects a food handler who worked during both weddings who was experiencing diarrhea. Most patients have reported nausea, vomiting (about 90%), and diarrhea (70%), with some fever, malaise, headache, chills, and abdominal pain. The mean incubation period for those who have reported illness is 28.6 hours, with a mean duration of 31.8 hours. The health department suspects viral gastroenteritis caused by a norovirus. A norovirus is suspected because of the rapid onset of symptoms, the short 36-hour incubation period and relatively short duration of illness, the absence of bloody diarrhea, and the high percentage of vomiting. Bacterial cultures are negative for enteric pathogens on stool samples collected thus far. # What are the complications of norovirus infection? Noroviruses are common causes of self-limiting acute gastroenteritis, with illness frequently lasting no longer than 60 hours. They commonly cause outbreaks in such settings as restaurants, catered events, cruise ships, schools, and nursing homes. The viruses can be spread person to person through the fecal-oral route, through contaminated food or water, or by raw or undercooked shellfish. # How should norovirus infections be managed? There is no antiviral agent that can be used to treat norovirus infections. Supportive care such as oral or intravenous fluids for rehydration should be provided. To reduce the spread of illness, patients should be educated to use good hand washing practices, particularly after using the bathroom and before preparing and handling food. The health department requests that a stool sample be collected. The sample should be collected in a sterile container without transport media, and kept at 4°C (40°F) until shipped. The sample should be shipped on ice packs to the local health department laboratory for testing. The health department also asks you to encourage Nancy's boyfriend to submit a stool sample. # How could this norovirus infection have been prevented? The food handler with diarrhea should not have returned to work for at least 24-48 hours after symptoms subsided. Proper hand washing procedures can prevent the spread of the virus between persons. Hands should be washed under warm water with soap for approximately 15 seconds to prevent fecal-oral transmission. # Antibiotic-Resistant Salmonellosis: A Patient Scenario Andrea brings her 3-year-old son, Marcus, to your office with a 2-day history of low-grade fever, nausea, and 6-8 watery stools per day. Marcus has also been complaining of abdominal pain and feeling tired. He has been eating and drinking less than usual. His medical history is remarkable for recurrent otitis media, for which he was prescribed oral antibiotics 10 days prior to this visit. Physical examination reveals a well-developed boy who appears fatigued. Vital signs are remarkable for low-grade fever (99.5°F/37.5°C). He does not have signs of dehydration. His otitis appears resolved and he has a normal cardiopulmonary exam. The abdominal exam reveals hyperactive bowel sounds, mild diffuse tenderness, and stool negative for occult blood. • Has he traveled in the month prior to the onset of illness? If yes, where? • Has he had contact with pet reptiles or farm animals or visited petting zoos in the week prior to his symptom onset? # What is the differential diagnosis for Marcus has not had similar episodes of diarrhea in the past. He attends preschool and is cared for by his grandmother after school in her home. He last visited a petting farm 3 months prior to this illness. Their family returned the previous day from a 5-day Caribbean cruise. Marcus was diagnosed with otitis media 4 days prior to their departure and was prescribed a 1-week course of oral antibiotics. Andrea has had nausea and 3-4 loose stools per day for the previous 2 days. She has not had any fever, abdominal pain, or vomiting. Marcus' father and two sisters also traveled on the cruise and are asymptomatic. None of the family members took prophylactic antibiotics for travelers' diarrhea during the cruise. # How does this information assist with the diagnosis? The additional history suggests that Marcus' and Andrea's illness may be an infectious gastroenteritis related to their recent travel. Antibiotic-associated colitis caused by Clostridium difficile infection must be considered since the child was prescribed antibiotics for otitis 8 days prior to this illness. Given the recent onset, travel history, and his mother's symptoms, it is unlikely that appendicitis, celiac disease, or inflammatory bowel disease are the etiologies of Marcus' illness. The most likely diagnosis is infectious gastroenteritis. # What additional historical information will assist in the identification of the etiologic organism? • What foods did Marcus and Andrea consume in the previous week? In particular, which foods/ beverages did they consume that the other family members did not? • Did either Marcus or Andrea consume undercooked meats, runny eggs, unpasteurized milk, raw shellfish, or untreated water? • Is there a reptile in the home? • Marcus was prescribed antibiotics for otitis media 1 week prior to the onset of his gastrointestinal symptoms. Has Andrea been prescribed antibiotics during the month prior to the onset of her diarrheal illness? • Have there been other cases of diarrhea recognized in the cruise ship travelers, in their community, or at Marcus' school? An open-ended food history reveals multiple common meals eaten by Andrea and Marcus. Andrea denies the consumption of unpasteurized milk, raw shellfish, and undercooked meats. She does report that, unlike the rest of the family, she and Marcus used to wake up early enough to enjoy the breakfasts served on board the cruise. Breakfast served on the cruise consisted of a choice of French toast or pancakes with fruit compote, scrambled eggs or omelets made to order, potatoes, and fresh fruit along with a choice of beverages, including milk, coffee, and tea. Andrea complained that the eggs were occasionally runny. Several fellow passengers told Andrea at breakfast that they were experiencing vomiting and diarrhea. Andrea and Marcus ate the remainder of their meals with the entire family. They did not drink any untreated water or eat items purchased from street vendors at ports of call. In response to your other questions, Marcus does not have a reptile at home. Andrea has not been prescribed antibiotics for more than 1 year. The family lives in a city and has access to municipal water. Based on the additional historical details, it appears that many people on board the cruise were experiencing symptoms of vomiting and diarrhea. This suggests an outbreak of infectious gastroenteritis that may be related to a common food or water source on the ship. The etiologic agent may be bacterial, viral, or parasitic. The most likely bacterial organisms causing this diarrheal illness are Campylobacter jejuni, Escherichia coli, Shigella species, and Salmonella. C. jejuni is the most common bacterial cause of diarrheal illness in the United States. Outbreaks of C. jejuni have been linked to raw milk, poultry, eggs, and water. Enterotoxigenic E. coli (ETEC) is recognized as the most common cause of "travelers' diarrhea" and can be transmitted via food or water. Salmonella is an important bacterial cause of foodborne illness, ranking just behind C. jejuni in its frequency. Vehicles most commonly implicated in foodborne outbreaks of salmonellosis include beef, poultry, produce, eggs, pork, and dairy products. Large waterborne outbreaks of salmonellosis have occurred rarely. # Why is identification of the cause of the diarrhea important? Identification of the cause of diarrhea in these two cases is important because of the impact on treatment, identification of related cases, and detection of an outbreak and identification of the responsible vehicle. Stool cultures should be performed to detect common bacterial pathogens such as Campylobacter, Salmonella, Shigella, or E. coli O157:H7. Antimicrobial susceptibility results can guide antibiotic therapy if a resistant organism is detected. Additional testing may be conducted to detect nonbacterial organisms. Stool examination for ova and parasites (O&P) will reveal parasitic causes of foodborne and waterborne illness such as Cyclospora cayetanensis. Rotavirus infection, one of the most common etiologies of pediatric diarrhea, may be diagnosed with enzyme immunoassay (EIA). The presence of fecal leukocytes suggests bacterial infection but may be found in other infectious or inflammatory states. Testing for the presence of Shiga toxin to detect infection with enterohemorrhagic E. coli (EHEC) would be appropriate if Marcus or Andrea had bloody diarrhea. What approaches would you take to treating Marcus' and Andrea's illness? Are antibiotics indicated for both Marcus and Andrea? What other therapeutic measures are useful for the management of diarrheal illness? Because Andrea's symptoms are mild, she does not wish to receive antibiotics. For Marcus, you prescribe trimethoprim-sulfamethoxazole at appropriate doses. You encourage Andrea to monitor for worsening fever, diarrhea, vomiting, and dehydration. You obtain stool specimens for culture and O&P from both Marcus and Andrea to confirm the etiologic agent. The primary goal of therapy for Marcus and Andrea is the maintenance of adequate hydration and electrolyte balance. A commercial oral rehydration solution (ORS) may be used, particularly for Marcus, to provide glucose and salts. You encourage Andrea to give Marcus ORS to prevent dehydration. Bismuth subsalicylate or loperamide may be used to decrease the number of unformed stools and shorten the duration of diarrhea, although neither is available over the counter for children of Marcus' age. Loperamide should not be used in those patients who develop fever or dysentery. Finally, empiric antibiotic therapy can be used to treat "travelers' diarrhea," which is most commonly caused by ETEC, after obtaining the stool samples but prior to obtaining results of stool cultures. Three days after the initial visit, Andrea feels better with fewer stools per day, but Marcus has had worsening vomiting and diarrhea. He has had several episodes of high fever and has not been drinking ORS adequately. In the office, Marcus is febrile (102°F/38.8°C) and appears dehydrated with dry mucous membranes and decreased skin turgor. No significant change is noted in the abdominal examination. You admit Marcus for intravenous hydration and encouragement of oral rehydration and consider a change in antibiotic therapy. Because of the progressive systemic nature of his illness, you also obtain blood cultures at this time. # What information will guide your therapy at this time? The use of intravenous fluids to improve volume status is reasonable given Marcus' inability to maintain hydration with ORS. However, during hospitalization, he should be encouraged to resume drinking ORS as early as possible. The decision to change from oral to intravenous antibiotics may be based on Marcus' increased vomiting and on his clinical decline. The choice of antibiotics should reflect the results of stool culture and antimicrobial sensitivities. The laboratory reports the growth of Salmonella Typhimurium from Marcus' stool cultures. Susceptibility testing reveals an organism resistant to multiple antibiotics, including ampicillin and sulfamethoxazole. Multidrugresistant S. Typhimurium has been on the rise in the United States since the early 1990s and now accounts for at least 25% of these isolates. Definitive type 104 (DT 104), the most common phage type of multidrug-resistant S. Typhimurium, may be responsible for more invasive disease than other phage types. In an outbreak, resistant organisms appear to cause more cases than do sensitive strains. Marcus' recent exposure to antibiotics for otitis media likely increased his susceptibility to Salmonella infection, perhaps by decreasing the usual protection offered by normal bowel flora, and thus decreasing the infectious dose necessary to cause illness. In addition, he was placed at increased risk for infection with a resistant strain of S. Typhimurium if he was exposed while still taking the antibiotic. Treatment of Salmonella gastroenteritis with antibiotic therapy is controversial because of the resulting increase in asymptomatic carriage, particularly among children less than 5 years of age. However, given the systemic nature of his illness, you choose to treat Marcus with several days of an intravenous third-generation cephalosporin. This is a reasonable choice in light of the antimicrobial resistance and the reluctance to use fluoroquinolones in the pediatric population. # Should these cases be reported to the local health department? What are the public health implications of these two cases of salmonellosis? Salmonellosis is a nationally notifiable disease, and most states require clinicians to report cases to local or state public health agencies. The health department and its public health partners can conduct studies to determine whether these cases indicated an outbreak of salmonellosis aboard the cruise ship. If an outbreak is confirmed, additional investigation is necessary to identify the contaminated food or the ill food worker infected with Salmonella, and whether there were correctable food-handling errors. If a food vehicle is identified, traceback and recall may be necessary to remove it from the market and prevent the occurrence of other cases. Given the increasing prevalence of drugresistant strains of S. Typhimurium, public health laboratories may perform bacteriophage typing or pulsed-field gel electrophoresis (PFGE) to further characterize the drugresistance patterns of these organisms. Reporting of these cases will contribute to essential nationwide surveillance of salmonellosis, foodborne outbreaks, and antimicrobial resistance. # What prevention measures will you recommend to Marcus and Andrea? Are repeat stool cultures necessary? To prevent Salmonella infections, all meat and egg dishes should be fully cooked. Andrea can purchase eggs that are pasteurized in the shell, and irradiated ground beef and poultry to reduce the risk of contamination. Basic food safety practices in the kitchen can also help prevent such infections, such as refrigerating leftovers promptly, washing hands and utensils after contact with raw meat and poultry, and keeping raw meat and poultry separate from ready-to-eat foods. Marcus and Andrea should be reminded to wash their hands with warm running water and soap after using the bathroom and before and after meals to avoid transmitting the infection to others. Marcus is likely to have prolonged carriage of Salmonella in the intestines. While he may return to preschool as soon as he is feeling well enough to do so because direct spread from one child to another is rare, clinicians should defer to their local health departments regarding their clearance policies for convalescing children attending preschool. With adequate hydration and your chosen antimicrobial therapy, Marcus will likely recover fully from this diarrheal illness without residual complications. # Unexplained Illness: A Patient Scenario You have been a primary care practitioner in Manhattan, New York, for several years. Jack, a 29-year-old otherwise healthy male, has been your patient for the past year. At 8:00 a.m. he calls your triage nurse complaining of a very sudden onset of nausea, cramps, coughing, and sweating. The nurse is concerned about the suddenness of onset and wants to know what you would like to do. # Should you have him call again later if he does not improve? Should you have him make an acute-visit appointment, or should you send him to the emergency room? You are concerned about the suddenness of the onset of symptoms but not the severity, so you decide to have him come to the office immediately. Jack presents in your office 30 minutes later. In addition to nausea, cramps, coughing, and sweating, his eyes have begun to tear uncontrollably and he complains of having had difficulty breathing while en route to the office. Upon arrival, he immediately asks to use the bathroom. Jack reports that he started his morning routine as usual with a run. Upon returning home, he finished drinking the bottle of water he had purchased earlier from the local deli and began to get ready for work. By the time he had finished showering and dressing, he began to feel sick to his stomach. He then developed cramping but no diarrhea. Shortly thereafter, he began to have bouts of coughing uncontrollably. He does not know when the sweating started. He states that he had difficulty breathing while en route to the office, and that the tearing just started. He denies vomiting, hemoptysis, hematuria, bright red blood per rectum (BRBPR), chills, fever, headache, myalgia, arthralgia, or diarrhea. Jack also denies the use of any medication, other drugs or alcohol. "That stuff rots your gut." Jack reports that he finished his run at about 7:00 a.m. It is now 9:00 a.m.. Despite having just urinated, he states that he must go again and immediately. However, Jack experiences incontinence on his way to the bathroom. Upon his return to the exam room, you notice a slight tremor in his left arm. He states that this has only just begun. # What preliminary diagnosis can you make at this point? • An anxiety attack • A viral syndrome • A potential foodborne illness • Anticholinergic poisoning You are not ready to reach a conclusion at this point, so you move to a physical exam and observe the following: Objective: Respiration rate: 20 BP: 92/60 mm Hg. Heart rate: 50 Temperature: 98.6°F (37°C) You note that Jack is anxious but oriented to time, place, and person. His head, ears, eyes, nose, throat (HEENT) examination shows bilateral miosis and decreased reactivity. There are no signs of trauma or bleeding. His heart has regular rate and rhythm, no murmur, and good perfusion. Radial and dorsal pulses are 2+. His lung examination reveals scattered wheezing. His abdomen is soft, nontender, not distended, with increased bowel sounds, and no mass. Extremities appear within normal limits. The neurologic exam reveals the slight tremor in his left arm, slightly slurred speech, excessive salivation, and transient fasciculations in both upper extremities. You note negative Babinski and his cranial nerves (CN) 2-11 appear intact, while CN 12 appears slightly abnormal. # What other information would assist with the diagnosis? More history from Jack, including most recent activity and diet. You now seek additional history. Jack lives alone and does not believe that he has been in contact with anyone who is ill. He works in an office as a lawyer. His run takes him up 5th Avenue and then over to 3rd Avenue, then back home. He does not run through Central Park. He does not have plants and does not garden as a hobby. His most recent meal was the night before, about 10 hours prior to the onset of his symptoms. It consisted of boiled pasta, steamed broccoli, and olive oil. He prepared the meal himself. He states that he carefully washed the broccoli, the oil was from a bottle he opened last week, and the pasta was from a box he had already used 2 days before. All he had to drink was tap water with dinner last evening and the bottled water from this morning. # Jack's presentation appears to involve which of the following systems? • Autonomic nervous system • Lymphatic system • Central nervous system The signs and symptoms in Jack's presentation predominantly involve increased autonomic responses, and are perhaps progressing to include the central nervous system as well. You decide that immediate treatment is called for and order oxygen, atropine, and pralidoxime (2-PAM). Given that Jack does not appear to have been exposed dermally, the most likely route appears to have been oral. Therefore, you also appropriately begin an IV with normal saline # What is the initial diagnosis? This presentation is not consistent with bacterial, viral, or parasitic food poisoning. While the signs and symptoms indicate acute organophosphate poisoning, the history provides no indication, and indeed seemingly contradicts this theory because of the lack of exposure. There has been no exposure to places where organophosphates are typically used, such as on lawns, house plants, and parks. Nevertheless, Jack has presented with a fairly classic case of organophosphate poisoning. Therefore, ingestion must be considered. Since you have no suggestion of deliberate ingestion on Jack's part, it must be assumed that he has consumed it unintentionally. Organophosphate poisoning has an onset of 30 minutes to 2 hours. Jack has actually made it easy to identify the most likely source: the only thing he has consumed in 10 hours is water. The broccoli could have had pesticides on it that may not have been removed when Jack washed it, but then he would have developed his symptoms during the night. Taking into account the temporal relationship between his ingestion of the bottled water and the onset of his symptoms, the bottled water seems the most likely candidate. # Given this information, what are key questions you should consider? • Is the water truly contaminated? • If it is, how did it become contaminated? • Who else may have ingested it? • Who else is at risk? • What action should be taken? You realize that if your diagnosis and conclusions are correct then a public health hazard may exist. Two things need to be done. First, the health department must be contacted, and second, tests need to be done that will confirm your diagnosis. While the usual work-up for organophosphate poisoning is clinical diagnosis, there are assays available to measure cholinesterase activity in plasma and red blood cells. It is also possible to detect some pesticides in urine. You decide to order both tests as this will provide the greatest insight into what the possible exposure is for other people in Jack's building, neighborhood, or even his city. When communicating with the local public health department, whom should you ask to speak to concerning this situation? • The medical epidemiologist? • The medical director? • The infectious disease officer? You ask to speak with the medical director. You present Jack's case, making careful note of the time course, and also inform the medical director of your suspicions of the source. The medical director takes this information and agrees with your concerns. She then asks you to speak with the chief epidemiologist so that an investigation can begin. In many large cities, there is a city health department; in smaller cities or towns, it will usually be necessary to contact the local or state health department. Try to match the level with the greatest number of people who may become affected. Other persons who may be of immediate help if you cannot reach the medical officer are the epidemiologist or even an environmental health officer. These people will most likely know what to do with the information you have. Most health departments across the country have been working to increase their knowledge or at least their awareness of the possibility of intentional contamination. Many have also created positions solely devoted to this task. Therefore, it is possible that you will be directed to such an individual. The health department initiates an investigation that includes testing the water; looking for other cases of organophosphate poisoning; interviewing the patient; notifying other parts of the public health system, including law enforcement, CDC, and the state health department. They may even issue a public notice. There is another possible cause for the case you have just seen: sarin gas can cause a similar presentation. If sarin gas had been sprayed into the air, it is possible that Jack could have respiratory exposure to the nerve gas. # If this were true, how would it change what you did? Persons exposed to sarin, and possibly other nerve agents, will have a clinical presenation similar to those with organophosphate poisoning. Hence, medical management will likely be similar. Finally, you are gratified to have helped detect a possible act of contamination that could potentially harm or even kill a great many people. Afterward, while making rounds in the hospital that day you are told by a colleague that a number of runners from a 5K race in Central Park this morning and tourists visiting the Empire State Building were brought to the emergency room complaining of sudden onset of nausea, cramps, and coughing. It was reported that all had been drinking bottled water. # Clinical Vignettes: What's Your Call? The following clinical vignettes are provided for your selfevaluation. All are possible situations that may present at your practice. The "Diagnostic Considerations" section and the tables of etiologic agents that are also part of this primer will provide the information necessary for you to adequately address these clinical situations. Note that these vignettes include both infectious and noninfectious forms of foodborne illness. For the following clinical vignettes, choose the best answer from the choices listed at the end of the vignettes: A -likely diagnosis; choose the best possible answer listed on "answer selections" page under A selections. B -most appropriate choice to confirm the diagnosis (there may be more than one correct answer -list all of them). Choose from the possible answers listed on "answer selections" page under the B section. Finally, decide whether the situation warrants reporting to the local or state health department. # Clinical Vignettes I. You receive a long-distance call from a patient who is an outdoorsman. He is with a group that collected and ate some wild mushrooms less than 2 hours ago. Several members of the group have since developed vomiting, diarrhea, and some mental confusion. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No II. A newborn child has symptoms of sepsis. Cerebrospinal fluid studies are consistent with meningitis. The mother had a flu-like syndrome prior to delivery. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No III. This patient has just returned today from Latin America following a 2-day business trip. He reports having eaten several meals of fish that he bought from street vendors around his hotel. He feels very ill with profuse, watery diarrhea, and vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No IV. An 18-month-old child is brought to your office with fever, bloody diarrhea, and some vomiting. She has been drinking unpasteurized milk in the last 48 hours. No other family members are ill. Report to the health department? ___Yes ___No XVI. Sally arrives at your office with acute gastrointestinal illness characterized by diarrhea, abdominal cramps, chills, fever, and body aches. She also informs you that about 3 days before she started getting sick, she had consumed raw ground beef that was seasoned with onions and an herb mix. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XVII. James presents to the emergency room with a lowgrade fever and complaining of fatigue and nausea for the past 24 hours. He also describes his urine as being dark and states that he has had 4 bowel movements in the past 24 hours, all of which were light colored. Upon further questioning, James says that he has no history of jaundice and that he returned from a business trip to the Philippines a month ago. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XVIII. You are halfway through your shift in the ER. There are four patients, two adults and two children, with a history of nausea, vomiting, abdominal pain, and profuse (especially in the children) watery diarrhea in the absence of fever. They each report that these symptoms began 5 days ago and resolved after 1 day. They had all been symptom free for 3 days, but now the symptoms have returned. There is also a new onset of jaundice and bloody diarrhea. Lab results indicate elevated LFTs. The patients do not know each other, but all report eating hamburgers several hours before the initial onset of symptoms. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? ___Yes ___No XIX. A mother has brought in a 5-month-old child with apparent blindness. She reports that the child had been healthy until the past month when the vision problems appeared. The mother states that she had been well during the pregnancy, but further questioning reveals that the mother had two young cats at home for which she was the sole care provider. The cats were given away just before the birth of the child because of concerns about the child being smothered by the cats. Recommendations and Reports # Which of the following is not a safe food-handling behavior? A. Using the same cutting board for raw foods and cooked foods. B. Using a food thermometer to check the internal temperature of food before eating it. C. Rinsing raw produce with water. D. Washing hands before and after handling food. # What is the appropriate method to use in determining if a hamburger is cooked to a proper temperature? A. Cooking it until it is brown inside. B. Using a food thermometer to ensure that the internal temperature reaches 160 º F. C. Determining if a hamburger is cooked to a proper temperature is not necessary because it is too small. D. Taking a bite of the hamburger to ensure that it tastes cooked. # When a foodborne outbreak is suspected, who would be a helpful contact at the health department? A. Medical officer. B. Epidemiology officer. C. Environmental health officer. D. Any of the above would be helpful. # Which of the following is not consistent with inflammatory diarrhea? A. Presence of fecal leukocytes. B. Grossly bloody stool. C. Infection with invasive or cytotoxigenic bacterial and protozoan species. D. Involvement of the small intestine. # Goal and Objectives This MMWR provides recommendations for physicians and other health-care professionals who have a critical role in diagnosing, treating, and reporting food-related disease outbreaks. These recommendations were developed by the American Medical Association, the American Nurses Association-American Nurse Foundation, the Centers for Disease Control and Prevention, the Food and Drug Administration's Center for Food Safety and Nutrition, and the United States Department of Agriculture's Food Safety and Inspection Service. The goal of this report is to provide health-care providers with guidance and patient-education materials regarding foodborne illness. After completing this continuing education activity, the reader should be able to 1) differentiate between the six etiologic agents that should be considered regarding manifestations of foodborne illness; 2) describe four criteria to consider when treating a diagnosed foodborne illness; 3) summarize the reporting requirements for foodborne illness; and 4) identify three groups of persons who are at higher risk for foodborne illnesses. To receive continuing education credit, please answer all of the following questions: 8. Intentional contamination of food is uncommon, but which of the following would make you suspect that such an act had occurred (i.e., the unusual nature of the situation would induce suspicion of intentional contamination)? A. An unusual agent or pathogen in a common food. B. A common agent or pathogen affecting an unusually large number of persons. C. A common agent or pathogen that is uncommonly seen in clinical practice. D. All of the above. 9. Multidrug-resistant Salmonella typhimurium cases . . . A. have been on the rise in the United States since the 1990s. B. might be responsible for more invasive disease than other types. C. often are resistant to ampicillin and sulfamethoxazole. D. cause more cases in an outbreak than do sensitive strains. E. all of the above.	None	None
b24211a1e1e994c7cc1677c1d0763645d1c4bc52	cdc	None	Front cover photos: Top row, left to right: colorimetric biotinidase assay; thin layer chromatography analysis for mucopolysaccharidoses, a group of lysosomal disorders; laboratorian using tandem mass spectrometry. Second row, left to right: sleeping newborn; acylcarnitine profile indicating elevated C8, a biochemical marker for medium-chain acyl-CoA dehydrogenase deficiency; mother and her son, who are able to skate together because of effective laboratory monitoring and clinical management of an inherited metabolic disorder. Bottom left: dried blood spot samples for proficiency testing.CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use. CDC does not accept commercial support.# Introduction Inherited metabolic diseases, often referred to as inborn errors of metabolism, comprise a large class of genetic diseases involving disorders of metabolism; collectively, these diseases have an incidence of at least one in 1,500 persons in the United States (1). Biochemical genetic testing and newborn screening tests are essential for early recognition of and timely intervention for these disorders to reduce morbidity and mortality rates and improve health outcomes. Biochemical genetic tests encompass a diverse spectrum of laboratory analyses of metabolites, enzyme activities, and functional assays for evaluation, diagnosis, treatment monitoring, disease management, and assessing a person's risk for carrying a specific disease trait (i.e., carrier status assessment), such as inborn errors of metabolism. Newborn screening is a vital state-based public health system in the United States that aims to test all newborns for an increasing number of inherited metabolic diseases and other congenital disorders, many of which require immediate treatment (2). The nationwide implementation of a recommended uniform screening panel of inherited metabolic diseases (Table 1) (3) and the consideration of additional conditions by state newborn screening programs present continuing quality assurance challenges for public health laboratories and other newborn screening facilities as well as for biochemical genetic testing laboratories that perform subsequent diagnostic testing. As advances in laboratory technology and knowledge of the genetic basis of disease increase the necessity of accurate and reliable laboratory testing in the screening, diagnosis, classification, and treatment of inherited metabolic diseases, guidelines are necessary for quality assurance and quality improvement in these areas of laboratory testing. CDC has collaborated with the Centers for Medicare & Medicaid Services (CMS), the Food and Drug Administration (FDA), and other federal agencies; state programs; professional organizations; standard-setting institutions; and federal advisory committees to promote the quality of genetic testing and provide guidance for appropriate use of genetic tests in clinical and public health practices. In the 2009 report Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions, CDC provided recommendations for good laboratory practices in molecular genetic testing and indicated the need for recommendations in other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and testing of acquired genetic variations (4). This report complements the 2009 CDC recommendations by providing recommendations for good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic diseases. Recommendations for additional areas of genetic testing will be considered based on continued monitoring and evaluation of laboratory practices, technology advancements, and the development of professional practice guidelines. The purposes of this report are to 1) clarify CLIA requirements that are applicable to biochemical genetic testing and newborn screening for inherited metabolic diseases and 2) provide recommendations for additional quality assurance practices that are not specifically addressed by CLIA requirements. The recommended practices address the benefits of the quality management system (QMS) approach, factors to consider before introducing new biochemical genetic tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and laboratory personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations provide a comprehensive guide for laboratories that perform biochemical genetic testing for ensuring the quality of laboratory services and highlight laboratory practices critical for quality improvement in newborn screening for inherited metabolic diseases. This report also is intended as a resource for users of laboratory services (e.g., authorized persons under applicable state law, health-care professionals, patients, and referring laboratories) to aid in their collaboration in newborn screening systems and effective use of biochemical genetic tests. This report also might assist standard-setting organizations and professional societies with development of future laboratory quality standards and practices, federal and state agencies with strategies and policies related to genetic testing, medical and public health professionals with evaluating laboratory practices, manufacturers of in vitro diagnostics with developing new testing products, and patients and families with improving their knowledge of good laboratory practices for genetic testing. Incorporation of these recommended practices into laboratory systems can improve the quality and appropriate use of genetic testing services, leading to better health outcomes for patients and their families. Abbreviations and a glossary of terms used in this report are provided (Appendices A and B). # Background Inborn errors of metabolism are inherited genetic disorders that affect one or more of the hundreds of biochemical pathways in the human body. Patients with these disorders are unable to properly use or synthesize certain compounds, such as fatty acids, amino acids, organic acids, or macromolecules, because of defects in the enzymes or other components of various metabolic pathways. These conditions frequently are identified in infants and young children with acute or chronic symptoms. When possible, early diagnoses with timely and effective interventions are essential for preventing permanent neurologic sequelae, disabilities, and other severe adverse outcomes. Biochemical genetic testing is a critical discipline in laboratory medicine for the evaluation, diagnosis, treatment monitoring, clinical management, and in some cases, carrier status assessment, of inherited metabolic diseases. These tests comprise highly complex and specialized laboratory procedures performed for evaluating enzyme activity, functional status of proteins, and levels of metabolites such as amino acids, organic acids, and fatty acids using a wide variety of specimen types including urine, whole blood, plasma, serum, cerebrospinal fluid, muscle biopsy, and other tissue types. Biochemical genetic tests also are among the critical follow-up procedures for diagnosing presumptive cases detected during newborn screening. † Core conditions are the conditions that newborn screening is specifically designed to identify. A core condition for newborn screening should have the following features: a specific and sensitive test is available to detect the condition, the health outcomes are well understood, treatment is available and effective, and identification of the condition could affect the future reproductive decisions of the family. § Secondary conditions are the genetic conditions that can be identified when screening for one of the core conditions or as a consequence of confirmatory testing for an out-of-range result of a core condition. Both the number of laboratories in the United States that perform biochemical genetic tests and the numbers of tests being performed are not certain. Although a nationwide survey identified laboratories that performed biochemical genetic testing in 2003 (5), more recent comprehensive data are not available, and information from voluntary laboratory directories are likely to be underestimates (6). However, information from the College of American Pathologists (CAP) Biochemical Genetic Testing Proficiency Survey Program indicated that the number of participating laboratories increased by 15% in 6 years, from 93 laboratories in 2002 to 107 laboratories in 2010 (7). Despite the limited nationwide data, biochemical genetic tests are performed for approximately 270 metabolic disorders spanning diverse disease categories (Table 2). As advances in biomedical research and laboratory technology lead to better understanding of the effects of genetic variations in biochemical pathways and metabolic diseases, the use of biochemical genetic tests in diagnosis, classification, and management of inherited metabolic diseases will likely continue to increase. Newborn screening is a state-based public health system that tests infants shortly after birth for serious or life-threatening metabolic and other conditions that, when detected early, might be managed or treated to prevent death, disability, or other severe consequences such as mental retardation. The newborn screening programs test almost all (≥97%) of the 4 million babies born in the United States each year. These tests are conducted by public health laboratories using a few drops of blood, often collected from newborns before hospital discharge, that are spotted on filter paper cards (2). Most states collect a fee for newborn screening, which varies depending on the state and can be paid by third-party payers. Although newborn screening programs are primarily funded by user fees, state and federal public health system funding often is necessary to support the comprehensive programs, which include education, laboratory screening, follow-up and tracking, diagnosis, treatment and management, and evaluation. Over the last decade, the increasing use of tandem mass spectrometry in newborn screening has substantially increased the number of metabolic disorders that can be detected from dried blood spot specimens (3,8,9). In 2010, the Secretary of the U.S. Department of Health and Human Services (HHS) adopted the recommendation of the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) for a uniform screening panel (including screening for 30 core conditions and reporting 26 secondary conditions) as a national standard for newborn screening programs together with the recommendation to facilitate the inclusion of this recommended panel into all state newborn screening programs (10). The expansion of inherited metabolic conditions screened by newborn screening programs has presented challenges to ensuring the quality of performance and delivery of testing services not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories that perform subsequent diagnostic testing (11). # CLIA Oversight of Biochemical Genetic Testing and Newborn Screening In 1988, Congress enacted Public Law 100-578, a revision of Section 353 of the Public Health Service Act (42 U.S.C. 263a) that amended the Clinical Laboratory Improvement Act of 1967 and required HHS to establish regulations to ensure the quality and reliability of laboratory testing on human specimens for disease diagnosis, prevention or treatment, or health assessment purposes (12). Under the CLIA regulations, laboratory testing is categorized based on the level of testing complexity as 1) waived (from routine regulatory oversight), 2) moderate complexity, or 3) high complexity. Moderate-and high-complexity testing is nonwaived testing. For nonwaived testing, CLIA regulations include requirements for proficiency testing, facility administration, quality systems for the total testing process (which consists of the preanalytic, analytic, and postanalytic phases), personnel for moderate-and high-complexity testing, and when applicable, more specific requirements for testing specialties and subspecialties (13). CMS administers the CLIA laboratory certification program and collaborates with FDA and CDC in providing CLIA oversight. FDA is responsible for test categorization and waiver determinations, and CDC is responsible for quality improvement studies, convening the Clinical Laboratory Improvement Advisory Committee (CLIAC), and providing scientific and technical support. CLIAC was chartered by HHS to provide recommendations and advice to HHS, CDC, CMS, and FDA regarding CLIA regulations, the impact of CLIA regulations on medical and laboratory practices, and modifications to CLIA standards to accommodate technological advances (14). Although not defined as specialties or subspecialties under CLIA, biochemical genetic tests and newborn screening tests are considered high-complexity tests. Laboratories that perform these tests must meet the applicable general CLIA requirements for nonwaived testing and the personnel requirements for high-complexity testing. These laboratories may be accredited by a deemed-status accreditation program approved by CMS to meet the CLIA certification requirements (13). Additional state requirements also might be applicable to newborn screening laboratories. # Concerns Related to Biochemical Genetic Testing The test procedures used to perform biochemical genetic tests are generally complex and technically demanding. Laboratory interpretation of test results is crucial for the clinical use of test result information in specific patient contexts and should be provided by trained and qualified personnel. Although data are limited, studies and reports since 2003 have revealed various concerns related to quality assurance practices in biochemical genetic testing, including test performance establishment, quality control procedures, proficiency testing, personnel qualifications and training, and results reporting (5,15,16). These concerns indicate areas of biochemical genetic testing practices that are in need of improvement or will likely benefit from the development and implementation of good laboratory practices. # Establishing Test Performance A comprehensive survey on quality assurance practices in biochemical genetic testing indicated that most laboratories that performed these tests used laboratory-developed methods and had variable practices for establishing test performance specifications such as reference intervals (5). The difficulty of obtaining sufficiently large numbers of samples from apparently healthy persons has made it challenging to establish reference intervals for certain analytes, especially when sample collection requires invasive techniques. The same challenge also affects the establishment of specific reference intervals by sex, age group, and other clinically relevant parameters (15,16). The lack of commercially available standards and reference materials presents another major challenge in establishing test performance specifications for biochemical genetic tests (15). Expanded newborn screening programs also present challenges to biochemical genetic testing laboratories, such as establishing age-specific reference intervals for infants and characterizing interfering substances to facilitate disease diagnosis primarily based on metabolic alterations and often in the absence of characteristic clinical symptoms or physical signs of disorders that are more commonly detected in older children (11). In addition, the establishment of clinical validity for new tests might involve a substantial literature review or research before introducing these tests into clinical use (11). # Quality Assurance During the Three Phases of the Testing Process # Preanalytic Phase The preanalytic phase of the testing process generally encompasses test selection and ordering; specimen collection, processing, handling, and delivery to the testing site; and the receipt of the patient's specimens with the test request information by the laboratory (17). Biochemical genetic tests are associated with a wide range of preanalytic variables that might affect test performance and test results because of the diverse specimen types and conditions, patient preparation status, and highly complex test procedures (18). Obtaining necessary clinical, medication, nutritional status, and other patient information that is critical for effective test result interpretation also can be challenging (5,18). # Analytic Phase The analytic phase of the testing process includes specimen preparation, performance of test procedures, monitoring and verification of accuracy and reliability of test results, and documentation of test findings (17). Significant variability in quality control practices was reported for biochemical genetic tests (5). For example, 14% of participating laboratories reported omission of normal controls in each test run, whereas 53% and 19% of the laboratories, respectively, included controls representing affected persons or carriers in enzyme-based assays designed to identify carriers and affected persons (5). The scarcity of commercially available reference materials also presents a challenge to performing quality control procedures, evaluating and verifying laboratory-prepared solutions, and standardizing calibration and calibration verification practices so that test results are comparable between laboratories (15). # Postanalytic Phase The postanalytic phase of the testing process includes reporting test results and archiving records, reports, and tested specimens (17). Variable postanalytic practices were reported for biochemical genetic tests (5). For example, only 24% of the surveyed laboratories reported the inclusion of a summary of test methods in biochemical genetic test reports, and only 12% had a specific written policy about confidentiality of genetic testing results (5). Among laboratories that performed amino acid analysis, 37% did not include results interpretation on test reports (5). Although these practices are not explicitly specified in CLIA regulations, they have been recommended in professional guidelines as necessary quality assurance procedures for biochemical genetic tests (18). # Proficiency Testing Proficiency testing is a well-established practice for monitoring laboratory testing performance and is a key component of the external quality assessment process. Participation in proficiency testing has been reported to help laboratories reduce analytic deficiencies, improve testing procedures, and take actions necessary to prevent future errors (19,20). Proficiency testing samples that simulate actual patient specimens could allow the evaluation of the total testing process (which consists of the preanalytic, analytic, and postanalytic phases) and improve the monitoring of laboratory performance (21)(22)(23). These samples might be derived from tissue samples or cell lines made from patients with a known condition or might be synthesized by adding known concentrations of analytes into a matrix such as serum or urine. CLIA regulations do not include proficiency testing requirements specifically for biochemical genetic or newborn screening tests. Laboratories that perform these tests must meet the general CLIA requirement to verify, at least twice annually, the accuracy of the genetic tests they perform ( §493.1236) (13). Laboratories may participate in available proficiency testing programs for the biochemical genetic tests they perform to meet this CLIA alternative performance assessment requirement. Proficiency testing participation helps laboratories that perform biochemical genetic testing to improve quality assurance procedures through identification of areas that need improvement, such as variability in analytic performance and the lack of standardization for reportable units of measurement (7,20). Formal proficiency testing or external quality assessment programs are available only for a limited number of biochemical genetic tests, such as those included in the Biochemical Genetics survey program provided by CAP and the European Research Network for Evaluation and Improvement of Screening, Diagnosis, and Treatment of Inherited Disorders of Metabolism (ERNDIM) (Appendix C) (24,25). Practical and technical challenges, such as the lack of proficiency testing materials, might limit the availability of comprehensive proficiency testing programs that assess both the quantitative and qualitative test methods for each analyte and examine the entire testing process. For many rare genetic conditions (i.e., conditions that affect <200,000 U.S. persons at any given time) for which testing is performed by one or a few laboratories, substantial barriers to developing formal proficiency testing programs have been recognized. Professional guidelines have been developed for laboratories to evaluate and monitor test performance when proficiency testing programs are not available (26), and online registry services have been developed to facilitate sample exchange among genetic testing laboratories (27). # Personnel Qualifications and Training Qualifications of laboratory personnel, including training and experience, are critical for ensuring quality performance of genetic testing because human errors can have a substantial impact on the quality of laboratory test results (5,28). The qualifications of persons directing or supervising biochemical genetic testing laboratories, including specialized training, experience, and board certification in clinical biochemical genetics, correlate significantly with laboratory adherence to voluntary quality standards and guidelines for biochemical genetic testing (5). The need for trained, qualified personnel to ensure the quality of biochemical genetic testing also has been recognized internationally (29). # Quality Improvement for Laboratory Practices in Newborn Screening Ensuring high-quality testing and achieving continuous quality improvement has been challenging for newborn screening laboratories as the number of inherited metabolic diseases that are included in newborn screening programs has continued to increase. For example, variability has been reported in certain newborn screening laboratory practices, including criteria for acceptance of dried blood spot specimens and cutoff values for each analyte, which might vary by state program depending on specific populations and case definitions (30,31). Most state programs provide training and continuing education to hospital staff members and others who submit specimens from newborns regarding appropriate collection procedures for dried blood spot specimens (32). Performance metrics and quality indicators have been described to meet the evaluation and improvement needs of the national newborn screening system (33,34). Laboratories in the United States that test dried blood spot specimens have been voluntarily participating in the CDC Newborn Screening Quality Assurance Program (NSQAP), which enables newborn screening laboratories to meet the CLIA alternative performance assessment requirement for verifying test result accuracy at least twice per year (35). Laboratories gain testing proficiency through comparisons of peer performance within and among methods. Four times per year, NSQAP provides newborn screening laboratories with blind-coded dried blood spot samples that represent analytes detected for newborn screening disorders. Participating laboratories include these samples in their routine testing and test them in the same way they test dried blood spot specimens from newborns. Test performance is evaluated based on identification of test results that require additional follow-up testing (out-of-range results) compared with those that do not (in-range results) (30). NSQAP summarizes annual falsepositive and false-negative rates for the performance assessment samples to help laboratories investigate potential sources of errors and areas of laboratory practices that need improvement. In 2008, NSQAP found that the false-positive rate for performance assessment samples was <1% for all newborn screening markers except decenoylcarnitinine (a secondary marker for medium chain acyl-CoA dehydrogenase deficiency), immunoreactive trypsinogen (a primary marker for cystic fibrosis), and succinylacetone (a specific marker for tyrosinemia type 1), whereas the false-negative rate was 1.1%-3.3% for phenylalanine (a primary marker for phenylketonuria), tyrosine (a primary marker for tyrosinemia), and immunoreactive trypsinogen (a primary marker for cystic fibrosis) (30). The decrease in the false-negative rate from 2002 to 2008 supports NSQAP in improving laboratory performance. NSQAP also provides quality control materials to help newborn screening laboratories monitor the quality of test performance (30). Collaborative efforts by many federal agencies, advisory groups, and the private sector have led to the development of standards and mechanisms for electronic reporting of newborn screening results (36)(37)(38). For example, the National Library of Medicine (NLM) and Health Resources and Services Administration (HRSA) have developed guidelines for standardized terminology, coding, and electronic messaging for ordering newborn screening tests and reporting test results to facilitate complete and accurate data collection, prompt results delivery and communication, and improved patient management (37,38). These guidelines have called for uniform laboratory practices in the newborn screening process, including the collection and documentation of demographic and clinical information (e.g., birth weight, gestational age, nutritional status, and transfusion information) in the preanalytic phase and the laboratory interpretation and reporting of results in the postanalytic phase (36,(38)(39)(40). # Methods The development and preparation of the recommendations in this report involved a multistep process that included 1) initial information collection and evaluation by CDC scientists to assess the quality assurance practices and potential areas needing improvement in biochemical genetic testing and newborn screening, 2) development of CLIAC recommendations to be considered by CDC for inclusion in a CDC guideline, 3) solicitation of input from other federal advisory committees and stakeholders that also address quality of genetic testing and newborn screening to complement the CLIAC recommendations, and 4) evaluation of all recommendations and advice received and preparation of this report by CDC scientists. # Initial Information Review and Assessment (2008-2009) An initial information review and assessment was conducted by CDC scientists from the Division of Laboratory Science and Standards in collaboration with the CDC Newborn Screening Quality Assurance Program. The purposes of this review and assessment were to 1) identify laboratory practice issues in biochemical genetic testing and newborn screening that would benefit from recommendations for good laboratory practices; 2) define issues for consideration by a CLIAC workgroup and assess areas of expertise needed for this workgroup; 3) assess information needed to facilitate the workgroup's evaluation of current standards, guidelines, practices; and 4) help gauge the usefulness and impact of the CDC recommendations on laboratory testing quality and public health. The information review and assessment consisted of a literature review, gathering data from existing databases and resources, and a review of regulatory and voluntary standards that are specific or applicable to biochemical genetic testing and newborn screening. A search of biomedical literature published since 2006 was conducted using the Medline and the PubMed databases with search terms including inherited metabolic diseases, inborn errors of metabolism, newborn screening, biochemical genetic testing, laboratory quality, good laboratory practice, laboratory standard, quality assurance, proficiency testing, quality assessment, and quality management. Approximately 400 English-language publications were identified, of which 18 contained information on laboratory performance or quality management practices and were specifically reviewed (3,5,11,15,19,20,30,33,34,(41)(42)(43)(44)(45)(46)(47)(48)(49). Data also were collected from state programs (50,51), CDC studies (8,52,53), and publicly available directories and databases of laboratories and laboratory testing (6, 7,24,25,29,32,54,55). Review of these data and information sources focused on 1) assessing the scope and growth of biochemical genetic testing and newborn screening in the United States, including the number of laboratories that perform biochemical genetic testing and newborn screening, the number and type of inherited metabolic diseases for which biochemical genetic testing and newborn screening is performed, the test methods and technology used to perform these tests, test volume, availability of proficiency testing and external quality assessment programs, and the changes of these aspects over time; 2) evaluating factors in biochemical genetic testing and newborn screening that might affect testing quality; and 3) identifying concerns and deficiencies in quality assurance practices in biochemical genetic testing and newborn screening and areas that would benefit from good laboratory practice guidelines. Considering the information gaps and the small number of published studies that specifically collected information on quality assurance issues in biochemical genetic testing laboratories, this initial information gathering and review was intended to be inclusive to provide background information to the CLIAC workgroup, enable workgroup evaluation of the information gathered and issues identified, and elicit additional insights. CDC scientists also reviewed regulatory and voluntary laboratory standards that are specific or applicable to biochemical genetic testing and newborn screening, including the American College of Medical Genetics (ACMG) Standards and Guidelines for Clinical Genetic Laboratories (56), Clinical and Laboratory Standards Institute (CLSI) guidelines (17,26,(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73), CLIA regulations (13,74), FDA guidance documents (75,76), state requirements (77,78), accreditation checklists (79-82), national practice guidelines (11,83), and international standards and guidelines (84)(85)(86). To facilitate the assessment of the extent to which the identified quality assurance needs were addressed by existing standards and guidelines, CDC scientists included these regulatory and voluntary standards in comprehensive comparison documents for each of the laboratory practice areas in which quality assurance concerns or the need for specific quality assurance guidance were identified. These documents compared existing CLIA regulations with other relevant federal requirements, state regulations, accreditation standards, professional guidelines, and other voluntary national and international standards and guidelines. Sixteen comparison documents of laboratory standards and recommendations were developed to address preanalytic practices (including the laboratory responsibility to provide test information to users of laboratory services, informed consent, test request, specimen submission and referral, and preanalytic systems assessment), analytic practices (including performance characteristics for biochemical genetic testing and newborn screening, establishment and verification of test performance specifications, calibration and calibration verification, control procedures, proficiency testing and alternative performance assessment, and equipment, instruments, and reagents), postanalytic practices (including test report and retention of records, reports, and specimens), personnel qualifications and responsibilities, and quality management practices. # Development of CLIAC Recommendations Since 1997, CLIAC has provided HHS with recommendations on approaches and mechanisms for ensuring the quality of laboratory genetic testing (14). At the September 2008 CLIAC meeting, the committee provided recommendations for good laboratory practices in molecular genetic testing for heritable diseases and conditions, which were subsequently included in the 2009 CDC recommendations (4); CLIAC also recommended the formation of a workgroup to consider similar good laboratory practices for biochemical genetic testing (87). The CLIAC Biochemical Genetic Testing Good Laboratory Practices Workgroup subsequently was formed in 2009. Workgroup members were selected by expertise needed to address the identified quality assurance issues and provide suggestions for laboratory practices, the potential impact and effectiveness of the laboratory practices to be recommended, and the representation of CLIAC as required by the Federal Advisory Committee Act (88). Factors for selection of workgroup members included expertise in diverse testing technology and diagnostic issues (e.g., common and rare disease testing); representation of diverse laboratory environments (e.g., large and small laboratories; laboratories in academic, private, and public health sectors; and specialized and general laboratories); representation of newborn screening and public health perspectives; expertise in laboratory performance evaluation, laboratory inspection, and laboratory accreditation; the perspective of users of laboratory services (including health-care providers, patients, and referring laboratories) and other stakeholders; experience in federal and state regulatory oversight; experience in developing accreditation standards or professional practice guidelines; experience and expertise in providing and evaluating proficiency testing and interlaboratory exchange programs; representation of in vitro diagnostic manufacturers; and representation of general laboratory services. The members of the workgroup, which included 13 nonfederal experts and representatives of CDC, CMS, and FDA, are listed at the end of this report. The workgroup was charged with the responsibility of providing input to CLIAC for developing recommendations for good laboratory practices for biochemical genetic testing. Specific workgroup tasks included 1) suggesting the scope of the CLIAC considerations in developing good laboratory practice recommendations for biochemical genetic testing, 2) recognizing and identifying issues in biochemical genetic testing that need guidance for quality assurance, 3) identifying additional sources of data and information needed for workgroup discussion, 4) reviewing relevant practice guidelines and standards, 5) suggesting strategies for issues or areas of laboratory practices for which current standards and practice guidelines are lacking or inconsistent, and 6) formulating workgroup input for CLIAC consideration. The workgroup was advised that issues on which they could not reach consensus should also be reported to CLIAC. Through a series of meetings and teleconferences in 2009, the workgroup considered the scope of laboratory practice recommendations for biochemical genetic testing and testing for inherited metabolic diseases and suggested that recommendations be developed to apply to biochemical genetic testing as well as to newborn screening for inborn errors of metabolism. After reviewing the background information and the concerns in quality assurance practices that were identified by CDC scientists, workgroup members suggested additional information sources and issues that could affect the quality and performance of biochemical genetic testing and newborn screening. The workgroup then reviewed the 16 comprehensive comparison documents of laboratory standards and guidelines, which included federal and state regulatory requirements, professional guidelines, accreditation checklists, and international standards and guidelines that provided general or specific quality standards applicable to biochemical genetic testing and newborn screening. The workgroup also reviewed information on the HHS-approved and other certification boards for laboratory personnel, including the number of persons certified in each of the specialties for which certification is available. Suggestions and clarifications for good laboratory practices were provided by the workgroup for all issues that were recognized as needing quality assurance guidance. The outcomes of the workgroup discussions were summarized by CDC scientists into a workgroup report. The workgroup report was presented to CLIAC at the February 2010 CLIAC meeting. CLIAC recommendations were formed from the committee discussion during the meeting by reviewing the workgroup report and making modifications and additional recommendations, as summarized in the CLIAC meeting summary (89). CLIAC recommended that the planned CDC recommendations include the CLIAC-recommended good laboratory practices for biochemical genetic testing and newborn screening for inborn errors of metabolism (89). The CLIAC members involved in developing the recommendations are acknowledged at the end of this report. # Solicitation of Additional Input To ensure that the recommendations provided in this report were adequately vetted with stakeholders, CDC collaborated with the National Institutes of Health (NIH) in obtaining additional input from the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) and with HRSA in obtaining consultation from SACHDNC during 2010-2011. To complement the CLIAC recommendations, advice was solicited from both federal advisory committees regarding 1) any issue that CDC should explain or clarify for laboratories that perform biochemical genetic testing or newborn screening, 2) any additional issue pertaining to biochemical genetic testing or newborn screening laboratory practices that CDC should address in these recommendations, and 3) efforts that should be taken to encourage the implementation of the recommended practices once this report is published. Presentations regarding the CLIAC recommendations also were made at the annual conference of the Association of Public Health Laboratories (APHL), the APHL Newborn Screening and Genetics Symposium, and the ACMG annual meeting during 2010-2011. CDC scientists also convened with the APHL Newborn Screening and Genetics in Public Health Committee and its quality assurance and quality control subcommittee to discuss any recommendations needed in addition to the CLIAC recommendations and the effective approach to providing the recommendations specific for newborn screening. # Preparation of the Recommendations in this Report CDC scientists prepared a draft of the recommended good laboratory practices based on the CLIAC recommendations and the additional input from SACGHS, SACHDNC, and APHL. In May 2011, an initial draft was provided to CLIAC, the CLIAC workgroup, CMS, FDA, CDC programs, the NIH Office of Biotechnology Activities, and HRSA for review and comment by SACHDNC and other interested groups and organizations. Comments and suggestions also were received from the Society for Inherited Metabolic Disorders, March of Dimes, and the APHL Newborn Screening and Genetics in Public Health Committee. CDC scientists reviewed all comments and suggestions. Modifications and clarifications have been incorporated in this report. # Recommended Practices for Laboratory Testing for Inherited Metabolic Disorders The following recommended practices apply to laboratory testing for screening, detection, diagnosis, and monitoring of inherited metabolic disorders, including biochemical genetic testing and newborn screening. These recommendations are intended to provide guidelines for specific quality assurance concerns in these testing processes by addressing the following areas of laboratory practices: - The QMS approach - Factors to consider before introducing new biochemical genetic tests - Establishment and verification of test performance specifications - The preanalytic, analytic, and postanalytic testing phases - Personnel qualifications, responsibilities, and competency assessment - Confidentiality of patient information and test results Many of the recommendations that follow apply generally to both biochemical genetic testing and newborn screening for inborn errors of metabolism, whereas issues that are specific for either laboratory area are discussed separately. # The QMS Approach QMS is a systematic approach for managing and ensuring the quality and effectiveness of an organization's work operations and services (90). A laboratory QMS provides a framework for the implementation of policies, processes, and procedures for the quality system essentials to ensure the quality of activities throughout the laboratory's workflow (17). The recommended practices in this report are provided with consideration of the QMS principles and concepts and in accordance with the laboratory's workflow, including consideration and planning for introducing testing services for patient testing, establishment or verification of test performance specifications, and providing laboratory services to meet the needs in clinical and public health practices. QMS is the basis for many international quality standards, such as the International Organization for Standardization (ISO) standards ISO 9001, ISO 17025, and ISO 15189 (84,90,91) and CLSI guidelines (17,(66)(67)(68)92,93). QMS principles also have been adopted in state program requirements and accreditation standards in the United States (77,82). Although the QMS standards and guidelines are distinct from CLIA regulations, a QMS framework facilitates the implementation of practices to meet CLIA and other regulatory requirements, conform to professional standards, and deliver quality laboratory services. Therefore, having a QMS in place will help laboratories that perform testing for inherited metabolic disorders apply the recommended practices in this report to improve test performance, laboratory service delivery, and the effectiveness of laboratory operations. # Considerations Before Introducing Biochemical Genetic Testing or Offering New Biochemical Genetic Tests Recommendations described in this report should be considered, in addition to appropriate professional guidelines and recommendations, when planning and preparing for the introduction of biochemical genetic testing or offering new biochemical genetic tests. Factors to be considered in this stage should at least include the following: # Establishment and Verification of Test Performance Specifications CLIA requires laboratories to establish or verify the analytic performance of each nonwaived test or test system before the test is introduced for patient testing. The calibration and control procedures also must be determined based on each test's performance specifications. Verification of test performance specifications is required when a laboratory introduces an unmodified FDA-cleared or unmodified FDA-approved test system. An FDA-cleared test system has been determined by FDA to be substantially equivalent to another legally marketed test system. A premarket notification, referred to as a 510(k), must be submitted to FDA for clearance. An FDA-approved test system is a system for which FDA has approved a premarket approval (PMA) application before marketing begins. This approval process is generally reserved for high-risk medical devices and involves a more rigorous premarket review than a premarket notification submitted to FDA for clearance. Before reporting patient test results, the laboratory must 1) demonstrate that the manufacturer-established performance specifications for accuracy, precision, and reportable range of test results can be reproduced or verified in the laboratory setting and 2) verify that the manufacturer-provided reference intervals (or normal values) are appropriate for the laboratory's patient population (42 CFR §493.1253) (13). Laboratories are subject to more stringent requirements when introducing 1) FDA-cleared or FDA-approved test systems that have been modified by the laboratory, 2) laboratory-developed tests or test systems that are not subject to FDA clearance or approval (e.g., standardized methods and textbook procedures), or 3) test systems with no manufacturer-provided performance specifications. In these instances, before reporting patient test results, laboratories must conduct more extensive procedures to establish performance specifications for accuracy, precision, analytic sensitivity, analytic specificity, reportable range of test results, reference intervals or normal values, and other applicable performance characteristics (13). Laboratories that perform biochemical genetic testing or newborn screening must comply with these general CLIA requirements and should adhere to the additional recommendations that follow for establishment and verification of test performance specifications. These recommendations are intended to specifically address test performance establishment for laboratory-developed biochemical genetic tests to ensure valid and reliable test performance and results interpretation. The recommendations also might be used by laboratories to verify performance specifications of unmodified FDA-cleared or FDA-approved biochemical genetic test systems to be used for patient testing. # General Principles When establishing or verifying test performance, laboratories should review and follow professional guidelines, such as those provided by CLSI and ACMG, that are applicable and appropriate for the planned testing. Laboratories should ensure that the professional guidance is followed consistently throughout the performance establishment and verification phase and the subsequent patient testing process. Factors that should be considered include the intended use of the test, the analytes or panel of analytes to be measured, intended patient populations, test methods, and samples needed for performance establishment (76). For establishing performance specifications of new biochemical genetic tests, the following practices should be considered as general principles: - Review scientific studies and pertinent references to assess the test methods and clinical usefulness of the test. - Define the patient populations for which the test might be performed. - Select appropriate test methods for the disease (or condition) or analyte being evaluated. - Establish or verify test performance specifications and determine quality control parameters for the test. # Samples for Establishment of Test Performance In general, test performance specifications should be established with an adequate number, type, and variety of samples to ensure that test results can be interpreted in the context of specific patient conditions and that the limitations of the testing and test results are known. The number and type of both positive and normal samples should be considered when selecting and determining samples needed. The numbers of both positive and normal samples should be adequate for determining the performance specifications of the assay being established. Both disease prevalence and sample characteristics might influence sample availability, thus the availability of samples and reference materials also should be considered. For example, a large number of positive samples (and in certain circumstances, normal samples) might not be available for rare conditions; unstable samples or samples that need to be collected invasively (such as cerebrospinal fluid or muscle biopsy samples) might be limited. Laboratories should consider these factors and define test performance specifications and limitations based on the samples that are available and included in the performance establishment. The types of samples should represent the types of patient specimens that are expected for the assay (e.g., whole blood, serum, urine, dried blood spot, fresh or frozen tissue, or prenatal specimens). For example, if the laboratory intends to perform amino acid analysis for urine, plasma, and cerebrospinal fluid specimens, test performance specifications need to be established for all three specimen types because each specimen type might be associated with a different total testing process as a result of differences in specimen collection and handling, specimen stability, interfering substances, analyte extraction, reference ranges, results interpretation, and other preanalytic, analytic, and postanalytic factors. If the condition of the patient specimens that the laboratory anticipates to receive represent significant variance that might affect patient test results or suggest the presence of interfering substances (e.g., insufficient specimen volume or amount, specimen hemolysis, or clotting), the laboratory should include samples representing these conditions when determining test performance, specimen acceptance criteria, and the influences of the specimen variances on test results interpretation. # Analytic Performance Specifications Performance Characteristics For each new biochemical genetic test, laboratories should determine specifications for the following performance characteristics: Accuracy. Accuracy is the closeness of agreement between an individual value and a true value. For each quantitative test, the laboratory is responsible for determining the ability of the test method to produce accurate results. For qualitative methods, the laboratory should establish the capacity of the test method to identify the presence or absence of the analyte (74). Test performance establishment also should determine trueness, or the closeness of agreement between the mean value of a measurement series and the true value. Accuracy and trueness might be assessed by testing reference materials, comparing assay results to a reference method (i.e., gold standard), comparing split-sample results with results obtained from a method shown to provide clinically valid results, or correlating research results with the clinical presentation when establishing a test system for a new analyte, such as a newly identified disease marker (74). Precision. The laboratory is responsible for determining the precision of each new test by assessing repeatability (i.e., closeness of agreement between independent test results for the same measurand and under the same conditions) and reproducibility (i.e., closeness of agreement between independent test results for the same measurand under changed conditions). Precision can be verified or established by assessing day-to-day, run-to-run, and within-run variation (as well as operator variance) by repeat testing of known patient samples, quality control materials, or calibration materials over time (74). Analytical sensitivity, including limit of quantification (LOQ) and limit of detection (LOD). Laboratories should follow professional guidelines in establishing LOD and LOQ for each analyte to be measured or detected (61). For modified test systems, the laboratory may use the lower limit of the manufacturer's reportable range if the laboratory has demonstrated that the modification has not affected the lower limit (74). Analytical specificity. Determination of analytical specificity should include the ability of the test to detect or measure the target analytes distinctly from potential interfering substances, including factors associated with specimens (e.g., specimen hemolysis, anticoagulant, lipemia, and turbidity) and factors associated with patients (e.g., clinical conditions, disease states, and medications) (74). Laboratories must document information regarding interfering substances using product information, literature, or the laboratory's own testing (74). Laboratories should adhere to professional guidelines, such as those developed by ACMG, when establishing or verifying analytical specificity for each biochemical genetic test (18). Reference range or normal values. The laboratory should establish a reference range that is appropriate for the laboratory's patient population (i.e., a normal range that reflects the type of specimen and demographic variables such as age, sex, and physiologic ranges expected for the laboratory's patient population) (74). When possible, laboratories should establish their own reference ranges by evaluating an appropriate number of samples to verify the reference ranges provided in literature or textbooks or by manufacturers. If the samples used in these verifications are from tested patient specimens rather than from healthy controls, laboratories should systematically evaluate the reference ranges and monitor the need to make adjustments over time. If samples that represent the specimen types (or specimen matrices) expected in patient testing are not available, laboratories may use the manufacturer-suggested or published reference ranges if they are appropriate for the laboratory's patient populations. Laboratories should monitor these reference values, make adjustments when appropriate, and inform their clients of the sources of their reference values (e.g., whether they are published values or values established or verified by the laboratory). Reportable range of test results for the test system. The laboratory is responsible for determining the reportable range of test results for each test the laboratory performs (13). The reportable range of patient test results can be established or verified by assaying low and high reference materials or by evaluating known samples of abnormally high and low values (74). Other performance characteristics required for test performance. For example, if a laboratory performs other test procedures in conjunction with a biochemical genetic test and reports the additional test results to aid in patient care, the laboratory should document the performance characteristics of the additional test procedures. Cutoff values for analytes detected in newborn screening often need to be age adjusted with consideration of infant term and birth weight (71). # Multiple-Analyte or Profile Analysis If analyses of multiple-analyte or metabolic profiles (e.g., acylcarnitine profile and organic acids profile) include pattern recognition (i.e., recognition of abnormal concentrations of specific analytes or patterns of analytes), test performance establishment or verification should include the following additional practices: - The reference ranges for all analytes to be reported should be established or verified for the laboratory's patient population with consideration of age, sex, physiologic state, and other clinically relevant factors. - Both normal and abnormal samples, or both samples that generate results within the expected normal or negative range of test results established for a particular condition (i.e., in-range results) and those that are associated with out-of-range results, should be analyzed and the analyte patterns verified in comparison with the reference ranges and the documented patterns of analytes in abnormal concentrations that indicate disease states. - As many different known samples as possible should be analyzed to ensure that common elements of a diagnostic pattern are detected. - Substances that have the potential to interfere with the analysis should be identified (94). # Changes to Established Performance Specifications Laboratories should recognize that changes to a test procedure, such as using a different sample matrix (plasma vs. urine), using or promoting the test for another purpose (screening vs. diagnostic use), and changing the type of analysis (qualitative results vs. quantitative), could affect the established test system performance specifications for accuracy, precision, analytical sensitivity, analytical specificity, and clinical use. These changes might result in a modified test system for which the performance specifications must be reestablished (74). # Determination of Quality Control Procedures CLIA requires laboratories to determine the calibration and control procedures for nonwaived tests or test systems as part of the verification or establishment of performance specifications for the tests (42 CFR §493.1253 ) (13). Laboratories must meet these requirements and should consider the recommended quality control practices for each new test before the test is introduced for patient testing. # Documentation of Information on Clinical Validity Although CLIA regulations do not include validation of clinical performance specifications of new tests or test systems, laboratories are required to ensure that the tests being performed meet clinical expectations. For tests of high complexity such as biochemical genetic tests, laboratory directors and technical supervisors are responsible for ensuring that the testing method is appropriate for the clinical use of the test results and can provide the quality of results needed for patient care (13). Laboratory directors and clinical consultants must ensure laboratory consultations are available for laboratory clients regarding the appropriateness of the tests ordered and interpretation of test results (13). Documentation of available clinical validity information will help laboratories performing biochemical genetic testing to fulfill their responsibilities for providing consultation to health-care professionals and other users of laboratory services. Laboratories should ensure that the tests they perform are clinically relevant and can be interpreted for specific clinical situations. Laboratory responsibilities for clinical validity include the following: - (95). Laboratories should monitor the progress of clinical research and advances in understanding in this area, especially for newly discovered gene-disease associations, rare disorders, and conditions with highly variable expression or uncertain clinical sensitivity. Laboratory directors and technical supervisors are responsible for using professional judgment to evaluate the results of such studies and should adhere to professional guidelines and accreditation standards to ensure that the testing performed and results interpretation are appropriate for specific clinical settings (11,18,81,96,97). # Additional Recommendations for Newborn Screening Performance establishment for newborn screening tests presents special challenges because of the time-sensitive need for specimen collection so that infants with positive screening results can receive timely follow-up confirmatory testing and effective intervention. The recommendations that follow provide additional guidelines for laboratories that perform newborn screening when establishing or verifying test performance specifications. Specimen collection time frame. Laboratories should consider the impact of the specimen collection time frame on the screening for each disorder when establishing or verifying test performance specifications. The majority of newborn screening dried blood spot specimens are initially collected from infants before age 72 hours or before hospital discharge (98). The specimens collected from each infant typically are used in multiple test procedures for the detection of many disorders, each of which might have a screening window (i.e., time interval with the greatest likelihood for disease diagnosis and effective treatment before overt symptoms or permanent damage occurs). For example, some conditions, such as maple syrup urine disease and galactosemia, warrant specimen collection in the first 24-48 hours to enable the detection of abnormal analyte levels and initiate early treatment. For other conditions such as homocystinuria, the abnormal analytes might be more readily detected on a later day. Therefore, laboratories should document the course of the abnormal analyte presentation for the diseases for which they screen and use age-adjusted reference intervals, with consideration of infant term, birth weight, and health status in test performance establishment and verification. Number and source of samples. The number of samples included in performance establishment or verification should be sufficiently large to enable the determination of test performance specifications for population-based screening (72). Although samples might be available from various sources, such as tested patient specimens, reference materials, proficiency testing materials, and control materials, laboratories should consider using samples that have the same dried blood spot matrix as that used for specimen collection from newborns (72). Unsatisfactory and invalid samples. If the laboratory accepts specimens that are considered unsatisfactory or invalid, such as a dried blood spot specimen that is of insufficient quantity for testing, oversaturated, scratched or abraded, or not completely dry before mailing (69), these specimen variances should be addressed in test performance establishment. Cut-off and critical values. Determination of the reportable range of test results for the test system should include appropriate cut-off values and critical values that require prompt follow-up and clinical intervention. Determination of the cut-off values for each analyte should be based on considerations for statistically derived values and testing of patient samples with a confirmed diagnosis. Continuous monitoring of test performance. Laboratories should continuously monitor the performance of their newborn screening tests and determine the need for reevaluating performance specifications as new disease information or test performance data become available (99). # Preanalytic Testing Phase Test Information to Provide to Users of Laboratory Services CLIA regulations require laboratories that perform nonwaived testing to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR §493.1241 and §1242) (13). Laboratories also must ensure that a qualified clinical consultant is available to assist clients with appropriate test ordering to meet clinical expectations (42 CFR §493.1457) (13). This section describes laboratory responsibilities for ensuring appropriate test requests and specimen submission for the biochemical genetic and newborn screening tests they perform in addition to meeting these CLIA requirements. The recommendations that follow emphasize the role of laboratories in providing specific information to users (e.g., authorized persons under applicable state law, health-care professionals, patients, referring laboratories, and payers of laboratory services) regarding the tests performed by the laboratory before the users select and order laboratory tests. For each biochemical genetic test, the following information should be provided to facilitate appropriate test selection and requests, specimen collection and handling, and submission of patient specimens together with relevant information to the laboratory: - Information necessary for appropriate test selection -Intended use of the test to specify the analytes or panel of analytes to be measured, the purpose of testing and appropriate use of the test, and the recommended patient populations; for example, the intended use of an amino acid analysis being described as "analyses of amino acids in plasma, intended for diagnosis and management of amino acid disorders in newborns, infants, children, or adults" and an enzyme assay being described as "analysis of galactose-1-phosphate uridyltransferase in red blood cells, intended for the diagnosis of galactosemia in patients suspected to have the disorder and/or for carrier testing in family members" -Indications for testing, such as the symptoms, clinical findings, family history, or newborn screening results for which the biochemical genetic tests might be needed -Performance specifications for the test (when appropriate), as well as test limitations and conditions that could affect test results and result interpretation (e.g., sources of assay interference; specimen types and containers; specimen collection methods and the timing of specimen collection; the patient's conditions such as fasting, transfusion, medications, and disease states; and the disease to be evaluated) -Test method and testing procedures to be used, including current CPT codes when appropriate -Whether testing is performed with an FDA-cleared or FDA-approved test system, a laboratory-developed test, or investigational test under FDA oversight - Information on appropriate collection, handling, and submission of specimens, including the following: -Any necessary patient preparation, when appropriate -Specimen type, amount or volume, and collection container or device -Specimen preparation -Specimen stability and transport conditions -Reasons for rejection of specimens (discussed in more detail in next section) - Types of patient information required to perform and interpret the test (including, as applicable, any required patient consent information in compliance with federal, state, local, and accreditation requirements and whether preauthorization is required) - Availability of consultation and discussion from the laboratory - If test results might indicate genotype information, implications of test results for relatives or family members Laboratories should review the biochemical genetic tests they perform and the procedures they use to provide and update the recommended test information. At a minimum, laboratories should ensure that the test information is available from accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. Laboratories that already provide the information from these sources should continue to do so. However, laboratories also might decide to provide the information more directly to their users and should determine the situations in which such direct communication is necessary. The complexity of the language used should be appropriate for the targeted user groups (e.g., for patients, language understandable by the general public). Laboratories should also ensure the information provided in this preanalytic phase is consistent with information included on test reports. In the United States, state newborn screening programs provide health-care providers with information on the panel of disorders screened in their states as well as educational materials for parents and the general public. The National Newborn Screening and Genetics Resource Center provides up-to-date information on the disorders for which screening is performed in each state and model brochures for providers, parents, and grandparents (32). Information on laboratory screening procedures often is provided as part of the state newborn screening program, together with disease information, counseling, and follow-up services for presumptive-positive infants. The number of diseases detected by newborn screening programs is expanding, thus the following information is critical for health-care professionals and others to ensure the effectiveness of the public health program: - Appropriate collection, handling, transport, and submission of dried blood spot specimens - The laboratory's specimen acceptance and rejection criteria - Test performance, possible test results, and follow-up confirmatory testing when necessary - Test limitations that could affect test results and results interpretation, such as sources of assay interference, timing of specimen collection, and infant factors (e.g., fasting or fed, receipt of transfusion, medications, or diseases) - Types of information about the infant as well as the parents that might be needed to perform and interpret test results (including, gestational age, birth weight, and racial/ethnic background) - Availability of consultation and discussion from the laboratory - Information on retesting, if indicated - Opt-out documentation, if necessary # Informed Consent Biochemical Genetic Testing A person who voluntarily confirms the willingness to participate in a particular test, after having been informed of all aspects of the test that are relevant to the decision to participate, is providing informed consent (85). Informed consent for genetic testing or specific types of genetic tests is required by law in some states; as of June 2008, a total of 12 states required informed consent before the request or performance of a genetic test (100). Certain states, such as Massachusetts (101), Michigan (102), Nebraska (103), New York (104), and South Dakota (105), specified the required components for informed consent documentation in their statutes. No professional practice guideline specifically recommends informed consent for biochemical genetic tests. In medical practice, the persons authorized to order the tests also are responsible for obtaining the appropriate level of informed consent (106). Unless mandated by state or local requirements, obtaining informed consent generally is not considered a laboratory responsibility. However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision making, laboratories should ensure that certain practices are followed. Laboratories should be available to assist users of laboratory services with determining the appropriate level of informed consent by providing useful and necessary information regarding the test being considered and implications of test results. Laboratories also should include appropriate methods for documenting informed consent on test request forms (e.g., check-off boxes, attestation statements, and space for signature) and evaluate whether the consent information is provided with the test request before initiating testing. Laboratories may determine the situations in which a patient specimen can be stabilized until informed consent is obtained, following the practices for specimen retention recommended in these guidelines. Laboratories should refer to professional guidelines and any local requirements for additional information regarding informed consent for genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent. # Newborn Screening Few states require explicit parental consent for participation in mandated public health newborn screening programs. Most states allow parents to opt out of the program on religious grounds, and certain state programs provide parents the option to refuse newborn screening or the retention of dried blood spot specimens after newborn screening for public health use (107,108). Laboratories that perform public health newborn screening should have procedures and processes in place in accordance with their state requirements. When required by state law, appropriate information about informed consent or opting out for newborn screening should be provided to the public in compliance with applicable federal, state, and local requirements. # Test Requests CLIA requirements (42 CFR §493.1241) specify that laboratories that perform nonwaived testing must ensure that the test request solicits the following information: 1) the name and address or other suitable identifiers of the authorized person requesting the test and (when appropriate) the person responsible for using the test results, or the name and address of the laboratory referring the specimen, including a contact person to facilitate reporting of imminently life-threatening laboratory results or critical values; 2) patient name or a unique patient identifier; 3) sex and either age or date of birth of the patient; 4) the tests to be performed; 5) the source of the specimen (if appropriate); 6) date and time (if appropriate) of specimen collection; and 7) any additional information relevant and necessary for a specific test to ensure accurate and timely testing and reporting of results, including interpretation (if applicable) (13). # Biochemical Genetic Testing In addition to meeting the CLIA test request requirements, laboratories that perform biochemical genetic testing should solicit the following additional or more specific information on test requests: - Patient name and any other unique identifiers needed for testing - Date of birth - Date and time of specimen collection (relative to symptoms and initiation of treatment when appropriate) - The reason for referral and information on the clinical, medication, and nutritional status of the patient, including International Classification of Diseases (ICD) codes or other codes indicating the diseases or conditions to be tested for and patient preparation when indicated (e.g., how the patient was prepared) to indicate that informed consent has been obtained in compliance with federal, state, and local requirements - Emergency contact information for the responsible clinician (for additional information or abnormal results) For biochemical genetic testing and newborn screening, laboratory electronic information systems (both current versions and those in development) should support and ensure the collection, transmission, and retention of all test request information recommended in this report. Laboratories may specify critical information elements as required for test requisition submission and have preanalytic quality assessment procedures in place for monitoring the provision of the needed information. # Specimen Submission, Handling, and Referral CLIA requires laboratories to establish and follow written policies and procedures for patient preparation, specimen collection, specimen labeling (including patient name or unique patient identifier and, when appropriate, specimen source), specimen storage and preservation, conditions for specimen transportation, specimen processing, specimen acceptability and rejection, and referral of specimens to another laboratory (42 CFR §493.1242) (13). If a laboratory accepts a referral specimen, appropriate written instructions providing information on specimen handling and submission must be available to the referring laboratory (13). Laboratories that perform testing for inherited metabolic diseases must meet these general CLIA requirements and should implement all of the additional practices that follow to ensure the quality of specimen submission, handling, and referral: - Provide specific instructions for the proper identification, collection, handling, transport, and submission of patient specimens to laboratory clients as specified in the section on the role of laboratories in providing information to users of their services. - Provide information on any need for patient preparation before specimen collection, and specifically communicate with clinicians regarding the circumstances that might involve risk (e.g., fasting and certain challenge tests). - Specify procedures for handling specimen submission for time-sensitive testing, testing that requires rapid or short turnaround time, or critical or labile specimens to meet the need for clinical care and patient management. These procedures also should address situations in which direct communication with the submitting clinician is needed. # Criteria for Specimen Acceptance and Rejection Specimen acceptance criteria should be consistent with the types and conditions of the samples used to establish test performance specifications to the extent practical and feasible. Laboratories should have written criteria for acceptance and rejection of specimens, including determination and handling of situations such as - improper handling or transport of specimen; - mislabeling, use of inappropriate anticoagulants or media, specimen degradation, or inappropriate specimen type; - potentially deteriorated specimen (e.g., specimens with bacterial overgrowth); - potentially contaminated specimen that might affect results of testing procedures; - lack of unique identifiers on the specimen or the requisition form; - specimen not held at appropriate temperature (e.g., unfrozen specimens for urine organic acid analysis); and - insufficient specimen quantity. Because of the complexity and diversity of the specimens that might be encountered and the influence of specimen conditions on the quality of test results and results interpretation, the specimen acceptance and handling procedures should address common variances in specimen conditions and those that might occur in patient testing. Laboratories should have criteria for determining acceptable and unacceptable specimens, including determining whether specific variances in specimen conditions (e.g., hemolyzed whole blood specimen) still meet the specimen acceptance criteria and which tests can be performed with such specimens. If a laboratory accepts specimens that deviate substantially from the established criteria and might contain interfering substances that could affect the quality of patient test results, the laboratory should have documentation of studies based on the scientific literature or internal data to prove that the test to be performed and its performance specifications will not be compromised. If multiple tests or test panels are requested for a single specimen, determination of specimen acceptability might be made for the different test procedures. In such circumstances, appropriate terminology should be used so that a specimen can be determined unacceptable for particular tests rather than for all tests to be performed. For example, a quantity of specimen that is not large enough to allow necessary repeat testing needs to be addressed differently than a potentially compromised specimen such as a hemolyzed specimen. In rare circumstances, when testing specimens that deviate from the laboratory's specimen acceptance criteria is critical, the laboratory should follow established procedures to note the exceptions on the test report. In specific situations, testing of nonideal specimens might be considered. For example, critical specimens that should not be rejected include those from a deceased patient from whom no additional specimen can be submitted, specimens for which a rapid response is required for management, specimens that were collected while the patient was acutely ill or as part of a timed test or challenge, or specimens that were collected using an invasive method (e.g., cerebrospinal fluid or muscle biopsy specimens). If specimens that are not ideal but still meet the laboratory criteria for acceptability are analyzed, a repeat specimen should be requested for clarification, if necessary. # Additional Considerations for Newborn Screening Newborn screening laboratories should have policies and procedures to address the time-sensitive issues of testing and the handling of varying conditions of the infants, including specimen collection for infants who are preterm or low birth weight, too sick to be fed, or in need of special care (71). Written procedures addressing specimen-related issues, such as the preferred and necessary specimens and the timing of specimen collection, should be consistently applied. The laboratory should inform submitters that dried blood spot specimens should be transported or mailed to the laboratory within 24 hours after specimen collection (regardless of weekends and holidays), and delays in specimen submission should be avoided (69). Terms such as unsatisfactory or invalid may be used in reference to dried blood spot specimens that are not properly collected; are of insufficient or excessive quantity; are clotted, smeared, or contaminated (69); or are acceptable for some but not all testing. The specimen acceptance procedures of the laboratory should address whether dried blood spot specimens that are considered unsatisfactory (e.g., a dried blood spot specimen that does not adequately fill the circle) meet the established acceptance criteria. For all unsatisfactory specimens, a second specimen should be requested. # Test Referral Factors that should be considered when selecting laboratories for test referral might include laboratory quality, personnel expertise, turnaround time, and cost. However, cost should not be the only or the primary factor for consideration when selecting referral laboratories. CLIA regulations at §493.1242(c) require laboratories to refer a specimen for patient testing only to a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by CMS (13). Specimens should not be sent to laboratories that do not meet these requirements. The laboratory demographics lookup feature on the CMS CLIA website provides a resource to facilitate searches for laboratories that meet the CLIA certification requirements (109). # Preanalytic Systems Quality Assessment Laboratories must have written policies and procedures for assessing and correcting problems identified in test requests, specimen submission and handling, test referral, and other steps of the preanalytic testing process (42 CFR §493.1249) (13). The preanalytic systems assessment for biochemical genetic testing and newborn screening should include the following practices: - Laboratories must make a reasonable effort to verify or clarify test requests that are unclear or lack critical information, submitted with inappropriate specimens, or inconsistent with the intended use of test results. For rapid or time-sensitive testing, procedures for handling situations that require prompt initiation of patient testing are necessary. - Laboratories should have policies and procedures to ensure that information necessary for selection of appropriate test methods, performance of testing procedures, and provision of test results and results interpretation is retained throughout specimen submission, results reporting, and specimen referral. - When a laboratory recognizes that necessary information in test requests has been lost during specimen submission or test referral, the laboratory should contact the test requestor or referring laboratory to request the needed information. Effective test submission or referral procedures should then be established to prevent or minimize similar occurrences. Improving the communication between laboratories and users in the preanalytic phase also should result in improved result reporting practices. - Laboratories should monitor and document the extent to which specimen problems occur and develop measures to reduce the frequency of these problems. Examples of preanalytic quality assessment include the following: -Monitoring the frequency of unacceptable specimens and specimen handling problems, such as the use of an improper blood collection tube and inadequate mixing of blood specimens with anticoagulant after collection -Monitoring the frequency of delays in specimen transport -Identifying clients who repeatedly refer unacceptable specimens or improperly complete requisition forms -Documenting the laboratory's efforts to reduce the recurrence of these problems # Analytic Testing Phase Control Procedures The analytic phase of a laboratory test typically includes the following steps: specimen processing and preparation, analyte detection or measurement, evaluation of the quality of the analytic results, and documentation of testing data and test results. Laboratories that perform testing for inherited metabolic diseases must meet the general CLIA requirements for nonwaived testing (42 CFR §493.1256), including the following quality control requirements: - Laboratories must have control procedures in place to monitor the accuracy and precision of the entire analytic process for each test system. - The number and type of control materials and the frequency of control procedures must be established using the applicable performance specifications verified or established by the laboratory. - Control procedures must detect immediate errors caused by test system failure, adverse environmental conditions, or operator performance and must monitor the accuracy and precision of test performance over time. - Each day that testing of patient specimens is performed, the laboratory must include the following: -At least two control materials of different concentrations for each quantitative procedure -A negative and positive control material for each qualitative procedure -A negative control material and a control material with graded or titered reactivity, respectively, for each test procedure producing graded or titered results -Two control materials, including one that is capable of detecting errors in the extraction process, for each test system that has an extraction phase - If control materials are not available, the laboratory must have an alternative method for detecting immediate errors and monitoring test system performance over time; the performance of the alternative control procedures also must be documented (13). Laboratories that perform testing for inherited metabolic disorders must meet these general CLIA quality control requirements and should implement the specific practices that follow to ensure the quality of laboratory test performance: - Laboratories should validate and monitor sampling instruments to ensure there is no carryover between samples on automated instruments. - Control procedures should be performed each time patient specimens are assayed or with each batch (i.e., group of specimens run concurrently or sequentially) of patient testing. - Controls should be selected based on patient population, prevalence of the disease, and the purpose of the test, while being as comprehensive as possible. For example, enzyme testing for carrier status should have a normal control and a carrier control, if available. Examples of sources that have reference materials for biochemical genetic tests or newborn screening are listed (Appendix C). # Considerations for Control Materials for Rare Disease Testing and Alternative Control Procedures When performing testing for rare diseases, if positive controls are difficult to obtain for certain test procedures, laboratories may consider using deidentified samples (i.e., samples from which individual identifiers have been removed) from interlaboratory exchange or other mechanisms. For example, if having a positive control of the same tissue type is not practical for testing procedures performed using white blood cells, laboratories may consider using a more stable tissue type, such as cultured skin fibroblasts, when available. In these circumstances, if the control materials bypass certain preparative analytic steps of the patient testing process (e.g., extraction procedures), the laboratory should have procedures for monitoring the complete analytic process including the preparative steps. If control materials are not practical or available for rare disease testing, alternative control procedures should be developed to adequately monitor test performance. For example, spiking or enriching a normal sample with analytes to simulate abnormal samples is an acceptable alternative control procedure for certain test procedures. The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provide general guidelines for alternative control procedures, such as splitting specimens for testing by another method or in another laboratory, including previously tested patient specimens (both positive and negative) as surrogate controls, testing each patient specimen in duplicate, performing serial dilutions of positive specimens to confirm positive reactions, and conducting an additional supervisory review of results before release (74). Laboratories should use multiple mechanisms as applicable to their test procedures to ensure testing quality. # Special Quality Control Issues with Sequential Testing in Single-Channel Analyzers Certain test procedures are performed with single-channel or single-column instruments (e.g., amino acid analyses) on which the run time of each specimen might take a significant portion of a working day. For these tests, acceptable control procedures include the following options, provided 1) the laboratory director is responsible for demonstrating that the control procedures are adequate for monitoring test system performance and detecting immediate errors, and 2) the laboratory has performance establishment or verification data to demonstrate that the control procedures and calibration procedures are appropriate for the laboratory's testing of patient specimens: - Testing a mixed-level control pool (which for amino acid analysis might contain all of the amino acids to be measured at various concentrations) once during each day or 24 hours of patient specimen testing and spiking at least one internal control material (e.g., S-2-aminoethyl-1-cysteine for amino acid analysis) into each patient specimen, an approach that helps monitor the analytic process for each specimen as well as specimen-to-specimen variability. - Testing a single-level control pool (which for amino acid analysis might contain the amino acids to be measured at the same concentration) once during each day or 24 hours of patient specimen testing and spiking an internal control material into each patient specimen - Testing a previously tested patient specimen that showed abnormal levels of certain amino acids once each day and spiking an internal control material into each patient specimen - If batches of patient specimens are in a test run that exceeds 24 hours, the test run may be bracketed by running a control sample at the beginning and another control sample at the end of the run. If the run time is >48 hours, a control sample should be inserted into the run within each 24-hour span. At least one internal control material should be spiked into each patient specimen. The laboratory director should be responsible for ensuring and demonstrating that the test system has stable accuracy and precision during the defined time period for both the control samples and patient specimens. The laboratory also should consider the turnaround time needed for reporting patient results in determining the length of a test run. Test Systems, Equipment, Instruments, Reagents, Materials, and Supplies CLIA requires laboratories to perform patient testing by following the manufacturer's instructions and in a way that provides test results within the laboratory's stated performance specifications for each test system as determined under §493.1253 (13). Laboratories must meet the following requirements for the test systems, equipment, instruments, reagents, materials, and supplies that are used for performing patient testing: - Define essential conditions for proper storage of reagents and specimens, accurate and reliable test system operation, and reporting of test results. The criteria must be consistent with the manufacturer's instructions, if provided. These conditions must be monitored and documented and, if applicable, include water quality, temperature, humidity, and protection of equipment and instruments from fluctuations and interruptions in electrical current that adversely affect patient test results and test reports. - Label reagents, solutions, culture media, control materials, calibration materials, and other supplies, as appropriate, to indicate the identity and, when significant, titer, strength or concentration, storage requirements, preparation and expiration dates, and other pertinent information required for proper use. - Reagents, solutions, culture media, control materials, calibration materials, and other supplies must not be used when they have exceeded their expiration date, have deteriorated, or are of substandard quality. - Components of reagent kits of different lot numbers must not be interchanged unless otherwise specified by the manufacturer. - Reagent, media, and supply checks must include checking each batch (if prepared in the laboratory), lot number (if commercially prepared), and shipment of reagents, disks, stains, antisera, and identification systems (i.e., systems using two or more substrates or two or more reagents, or a combination) when prepared or opened for positive and negative reactivity, as well as graded reactivity, if applicable. Laboratories performing testing for inherited metabolic diseases must comply with these CLIA requirements and should implement the following additional practices: - Reagents, supplies, and instruments used during routine testing should be the same as those used in test performance establishment or verification. - New reagent lots and shipments should be tested in parallel with old lots before or concurrently with being placed in service to ensure that the new lot of reagent has maintained consistent results for patient specimens. - Test performance specifications should be reestablished if the test system has been modified with changes that could affect its performance specifications. Such changes include using different or additional equipment or instruments, changing any critical reagent such as a conjugate or substrate, using different control or reference materials, or using a different specimen collection device. - Equipment should be evaluated and monitored to account for basic detection or measurement drift through analysis of quality control data, function checks, and internal electronic checks. - Laboratories are encouraged to use available mechanisms for standardizing laboratory practices for preparing and validating reagents and reference materials that are not commercially available. When available, FDA-cleared reagents should be used for patient testing. Laboratories should be aware of FDA regulations that require FDA clearance or approval for reagents and instruments (including software programs) that are developed or prepared in one laboratory and provided to another laboratory for use in patient testing (110). However, special issues in biochemical genetic testing are associated with the lack of availability of certain essential reagents that have received FDA clearance or approval. The lack of FDA-cleared reagents increases the responsibility of the laboratory to validate any internally developed or shared reagents, standards, or controls. Laboratories also should consider relevant professional guidelines, such as those developed by CLSI and ACMG, that provide additional guidance for specific test methods. # Calibration and Calibration Verification Procedures Under CLIA, calibration and calibration verification procedures are required to substantiate the continued accuracy of the test system throughout the laboratory's reportable range of test results (13). Calibration procedures for each test system must be performed and documented either by - following the manufacturer's instructions using calibration materials provided or specified and with at least the manufacturer-recommended frequency or - using criteria verified or established by the laboratory, including the acceptable limits for and the frequency of calibration and the number, type, and concentration of calibration materials, which must be appropriate for the test system and, if possible, traceable to a reference method or reference material of known value. Calibration verification procedures must be performed and documented either by following the manufacturer's instructions or using the criteria verified or established by the laboratory under §493.1253(b)(3), including the number, type, and concentration of the materials; acceptable limits for calibration verification; and at least a minimal (or zero) value, a midpoint value, and a maximum value near the upper limit of the range to verify the laboratory's reportable range of test results for the test system (13). Calibration verification procedures must be performed at least once every 6 months and when any of the following occur: - A complete change of reagents for a procedure is introduced, unless the laboratory can demonstrate and document that changing reagent lot numbers does not affect the range used to report patient test results, and control values are not adversely affected by reagent lot number changes. - Major preventive maintenance or replacement of critical parts occurs that might influence test performance. - Control materials reflect an unusual trend or shift or are outside of the laboratory's acceptable limits. - Other means of assessing and correcting unacceptable control values have failed to identify and correct the problem. - The laboratory's established schedule for verifying the reportable range for patient test results requires more frequent calibration verification (13). Laboratories performing testing for inherited metabolic diseases must comply with these CLIA calibration and calibration verification requirements and should implement the following additional practices: - When reference materials for calibration are commercially available and stable, laboratories should consider obtaining quantities adequate for a reasonable period of testing to reduce variability in these materials (but not to exceed their expiration date). - When reference materials for calibration are not commercially available, each laboratory preparing these materials at its own facility should ensure their validation, including verifying each new batch of the calibration or reference materials against an old batch, and ensure that appropriate calibration and calibration verification procedures are in place. - Laboratories should refer to available professional guidelines (e.g., ACMG Standards and Guidelines for Clinical Genetic Laboratories and CLSI methodspecific guidelines ) for additional guidance on performing calibration and calibration verification to ensure the test accuracy and reliability. # Proficiency Testing and Alternative Performance Assessment Proficiency testing is an important tool for assessing laboratory competence, evaluating the laboratory testing process, and providing education for laboratory personnel (67). CLIA regulations specifically require proficiency testing for some analytes or testing specialties, which might be provided by private-sector, nonprofit, or state-operated programs approved by HHS as meeting CLIA standards (42 CFR Part 493) (13). These approved programs also might provide proficiency testing for analytes and specialties for which proficiency testing is not specified, including biochemical genetic tests and other tests (111). Although the CLIA regulations do not include proficiency testing requirements specific for biochemical genetic tests or newborn screening tests, laboratories that perform these tests must comply with the general requirements for alternative performance assessment for any test or analyte not specified in the regulations to, at least twice annually, verify the accuracy of the tests or procedures they perform (42 CFR §493.1236) (13). Laboratories may meet this requirement by participating in available proficiency testing programs for the biochemical genetic or newborn screening tests they perform (112). A list of available proficiency testing programs for biochemical genetic testing is included in this report (Appendix C). # Biochemical Genetic Testing The following recommended practices provide more specific and stringent measures than the current CLIA requirements for test performance assessment for laboratories that perform biochemical genetic testing to monitor and evaluate the ongoing quality of the testing they perform: - Participate in available proficiency testing at least twice per year for each biochemical genetic test the laboratory performs. Laboratories are encouraged to participate in available proficiency testing programs that examine the entire testing process encompassing the preanalytic, analytic, and postanalytic phases. Laboratories should regularly review information on the development of additional proficiency testing programs and ensure participation as new programs become available. - Test analyte-specific or disease-specific proficiency testing challenges with the laboratory's regular patient testing workload by personnel who routinely perform the tests in the laboratory, as required by CLIA for analytes and specialties specified in the regulation. - When possible, laboratories performing quantitative assays should enroll in proficiency testing programs that provide feedback for specific analyte values. Qualitative proficiency testing is appropriate for tests for which quantitative technology is lacking and for certain tests, such as enzyme assays that lack consensus quantitative measurements. - Evaluate proficiency testing results reported by the proficiency testing program and take steps to investigate the causes for disparate results, including results that might indicate bias but are within acceptable ranges. The corrective actions to be taken after disparate proficiency testing results might include reevaluation of previous patient test results and, if possible, of retained patient specimens that were previously tested, depending on the cause identified for the disparate results. # Newborn Screening The following recommendations are for laboratories that perform newborn screening to assess test performance: - Participate in the NSQAP and adhere to the program directions. Participation in other proficiency testing programs for monitoring test performance is encouraged. - Include cutoff values for all analytes when reporting proficiency test results to NSQAP so that the specific cutoffs can be taken into account in the NSQAP grading algorithm to facilitate the evaluation of the laboratory results (30,113). # Implications for Proficiency Testing and Interlaboratory Comparison Programs Proficiency testing and interlaboratory comparison programs should consider the need for external quality assessment for all testing for inherited metabolic diseases in improving program availability and result evaluation. To the extent possible, proficiency testing should be available for each analyte at least twice per year. Comprehensive proficiency testing programs (e.g., NSQAP) are needed that examine the entire testing process (which consists of the preanalytic, analytic, and postanalytic phases) and are able to assess both the quantitative and qualitative test methods. Although practical and technical challenges might limit the ability of proficiency testing programs to address all testing phases for each analyte, comprehensive programs for core tests (e.g., amino acid and organic acid analyses) that combine the strengths of existing programs should be pursued (8,24). When possible, proficiency testing samples should simulate patient specimens; at a minimum, samples simulating patient specimens should be used for proficiency testing for the most common genetic tests. If residual patient samples are used in proficiency testing or interlaboratory comparisons, any required consent issues and deidentification procedures should be addressed according to federal, state, and local requirements and guidance. # Alternative Performance Assessment Organized proficiency testing programs do not exist for many tests performed for inherited metabolic diseases, including biochemical genetic tests and, occasionally, new tests for newborn screening. Alternative performance assessment must be performed at least twice per year for each test for which no proficiency testing program is available and for tests for which CLIA regulations do not specify proficiency testing requirements. Laboratories should implement the following practices for alternative performance assessment: - Although data on the effectiveness of alternative performance assessments compared with proficiency testing are unavailable, laboratories should follow professional guidelines, such as those developed by CLSI (26) and CAP (82), that provide guidance on acceptable alternative performance assessment approaches. - Alternative assessment ideally should be performed by interlaboratory exchange or using externally derived materials. - For circumstances in which interlaboratory exchange or externally derived materials are not practical or feasible, such as testing for rare diseases, testing performed by only one laboratory, or analysis of unstable analytes (e.g. enzymes), laboratories may consider options such as repeat testing of blinded samples, possible exchange with either a research facility or international laboratory, or interlaboratory data comparison. - Newborn screening laboratories that consider testing for new disorders not covered by the CDC NSQAP should make the program aware of their plans to facilitate the availability of the needed proficiency testing. # Evaluation of External Quality Assessment Performance Laboratories should document and track their performance in proficiency testing and alternative performance assessment. Quality improvement assessment should be performed periodically to evaluate performance and ensure adequate investigation of failures or concerns, implementation of corrective actions, and documentation of outcomes. Additional guidance for using proficiency testing as a quality improvement tool is available in professional guidelines (26). Various resources for proficiency testing and external quality assessment and for facilitating interlaboratory sample exchanges are available to help laboratories consider approaches to meeting the proficiency testing and alternative performance assessment needs (Appendix C). # Postanalytic Testing Phase Test Reports Test reports must comply with the CLIA general test report requirements (42 CFR §493.1291) and should include the recommended additional information that follows to ensure accurate understanding and interpretation of test results. CLIA requires that test reports for nonwaived testing include the following information: - Patient name and identification number or a unique patient identifier and identification number - Name and address of the laboratory where the test was performed - Test report date - Test performed - Specimen source (when appropriate) - Test result and (if applicable) units of measurement or interpretation - Information regarding the condition and disposition of specimens that did not meet laboratory criteria for acceptability (13) For laboratory-developed tests using analyte-specific reagents, test reports must include the following statement: "This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration" (21 CFR 809.30) (75). # Biochemical Genetic Test Reports Biochemical genetic test reports should include the following more specific information to ensure accurate results interpretation, patient management, and the ordering of any needed additional tests by persons receiving or using the test results: - Patient's name and any other necessary unique identifiers - Patient's date of birth - The reason for testing that was provided on the test requisition and is needed for results interpretation - The date and time of specimen collection and receipt by the testing laboratory, which should be distinguished, when possible, from the date and time when the test request was made and, for test referrals, the date and time when the specimen was received by the referral laboratory, or a specific indication that the "specimen collection date and/or time are unknown" if such information is not provided - Name of the referring clinician or other authorized person who ordered the test - When appropriate, an interpretive guide (e.g., a table or reference to literature or a website) to aid in interpretation of results - Analytes tested, type of test method, or both - The reference intervals or normal range appropriate for the patient (based on sex, age, and population as appropriate), other performance specifications needed for results interpretation (e.g., accuracy, LOD, LOQ, or analytic specificity), and limitations of the test (e.g., a statement on the intended use and the technical limitation of the test method) that affect the understanding and clinical use of the test results - Test results in appropriate measurement units and current recommended standard nomenclature, including clarifications and commonly used terms if different from those currently recommended - Interpretation of results for complex tests, profiles, testing for carrier status, and testing that involves response to challenges or multiple samples over time; should be linked to the reasons for testing and communicated in a timely and clinically relevant manner - Test results in reference to information on family members (e.g., information regarding abnormalities previously detected in a relative used for the selection of the test method) when appropriate and necessary to ensure appropriate interpretation of the test results and understanding of their implications - The name of the laboratory personnel providing the interpretation - Notation to indicate whether report is preliminary, final, amended, or corrected - If applicable, an indication that other biochemical genetic tests have been performed for the patient, or, when available, results of other relevant tests that the laboratory performed for the patient - When appropriate, recommendations for additional testing of patient or for family members - References to the literature, if applicable - Recommendation for consultation with a genetics professional, when appropriate and indicated, that encompasses genetic counseling provided by trained, qualified genetic professionals such as genetic counselors, clinical geneticists, or other qualified professionals, to health-care providers, patients, or family members at risk for the conditions and also can be an educational initiative to improve understanding of genetic tests in the medical community - The date and, when appropriate, time the test report is released Laboratories should assess the needs of laboratory users when determining the media, format, style, and language of biochemical genetic test reports. To the extent possible, the terminology and nomenclature should be understandable by health-care professionals who are not geneticists or experts in the specific field. This practice should be part of the laboratory quality management policies. Test reports should include all necessary information, be easy to understand, and be structured in a way that encourages users to read the entire report, rather than just a positive or negative indication. Following the format recommended in accepted practice guidelines should help ensure that the reports are structured effectively (18). # Newborn Screening Test Reports Newborn screening test reports must comply with the CLIA general test report requirements (42 CFR §493.1291) and applicable state requirements. Results should be reported in a way that is consistent with the urgency of any needed intervention. For a screening result that is outside the expected range of normal test results established for a particular condition (i.e., out-of-range result) or indicates problems with the specimen or the testing process that might compromise the quality of test results according to established criteria (i.e., invalid screen), the following information should be communicated to the newborn's primary care provider without delay: - The newborn's identifying information (name, date of birth, and time of birth), place of birth, and national or local health number - Parent information (mother's name, home telephone number, and address if available) - The date and time of specimen collection and arrival in the laboratory - Analytes evaluated and type of test method, or whichever is appropriate - Screening test results in appropriate measurement units - The normal range and cutoff values appropriate for the newborn's conditions, including gestational age, birth weight, and health or disease status - Notation of whether the results are out-of-range or invalid - Required actions, including a repeat screen, confirmatory testing, clinical actions, and evaluation, as well as the timeline, steps, and instructions to complete the necessary actions - Instructions to notify the newborn screening program when the primary care provider has been unable to contact the parents or when the primary care provider has changed - Contact information (e.g., name, phone number, e-mail address, and fax number) for the follow-up personnel of the newborn screening program - The date and time the test results are reported - For all out-of-range results, the following information should be provided to the newborn's primary care provider: -Pediatric subspecialists resource information (including telephone numbers) for consultation or referral -Information about the suspected diagnosis (disease or condition) and consequences if untreated -Reporting requirements to the newborn screening program, including confirmatory test results, treatment date, and other information on the newborn's health outcome For all out-of-range or invalid results, the laboratory should take actions that lead to timely additional testing and evaluation for the infant and allow the newborn screening program to evaluate the effectiveness of screening. Follow-up should occur without delay to enable timely intervention. For results requiring urgent actions, laboratories should first notify both the primary health-care provider and the designated specialist by telephone and then by paper or electronic notification. Laboratories should monitor the development and application of guidelines and recommendations that address electronic reporting of newborn screening results, such as the HRSA/NLM guidance for sending electronic newborn screening results with Health Level Seven International (HL7) messaging ( 37) and the HL7 implementation guide developed by the Public Health Informatics Institute (40). When implementing the electronic reporting mechanisms, laboratories should ensure that the information systems accommodate the inclusion and delivery of the test report elements that are recommended in this report. Laboratories also should develop quality assurance procedures for the electronic reporting systems used. # Retention of Records, Reports, and Tested Specimens # Records CLIA requires laboratories to retain records of patient testing, including test requests and authorizations, test procedures, analytic systems records, records of test system performance specifications, proficiency testing records, and quality system assessment records, for a minimum of 2 years (42 CFR §493.1105) (13). These requirements apply to testing for inherited metabolic diseases. Retention policies and procedures also must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited). Laboratories may retain records for longer periods for quality management purposes and should consider the following recommendations when establishing record retention policies: - Primary data from which reports are generated should be kept along with the reports, preferably electronically. - Records of tests that generated normal results also should be retained. - Laboratories should ensure that electronic records are accessible as electronic storage technology continues to evolve. # Reports CLIA requires laboratories to retain or have the ability to retrieve a copy of an original test report (including final, preliminary, and corrected reports) for at least 2 years after the date of reporting and to retain pathology test reports for at least 10 years after the date of reporting (42 CFR §493.1105) (13). Biochemical genetic test reports that indicate genotypic information for the disease or condition should be retained for at least 21 years after the date of reporting. This retention period is recommended as an acceptable length of time of one biological generation that is necessary to provide useful continuity of clinical history for patient management and diagnosis or treatment of family members. The laboratory policies and procedures for test report retention also must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited) and should follow practice guidelines developed by recognized professional or standard-setting organizations. If state regulations require retention of biochemical genetic test reports for >21 years after the date of results reporting, laboratories must comply. Laboratories also might decide that retaining reports for >21 years is necessary for biochemical genetic test reports to accommodate patient testing needs and ongoing quality assessment activities. Because test reports may be retained using electronic methods, laboratories are encouraged to consider technology availability in addition to space and financial issues when determining solutions to test report retention. The retention period for newborn screening test reports must be in compliance with CLIA and applicable state requirements. Certain states require different retention periods for newborn screening test reports depending on the results. # Tested Specimens CLIA requires laboratories to establish and follow written policies and procedures that ensure positive identification and optimum integrity of patient specimens from the time of collection or receipt in the laboratory through completion of testing and reporting of test results (42 CFR §493.1232) (13). Depending on sample stability and integrity, technology, space, and cost, tested specimens for biochemical genetic testing should be retained as long as possible after the completion of testing and reporting of results. Patient specimens should be retained until after the final reporting of results for quality assurance and any need for additional testing of the same specimen, with adequate provisions for specimen stability. When possible, tested specimens may be retained until the next proficiency testing or the next alternative performance assessment to allow for identification of problems in patient testing and for corrective action to be taken. Laboratories also may retain tested specimens for a longer period or indefinitely for quality assurance and educational purposes (e.g., tested specimens from abnormal cases). The laboratory director is responsible for ensuring that the laboratory policies and procedures for specimen retention comply with applicable federal, state, and local requirements (including laboratory accreditation requirements, if applicable) and are consistent with the laboratory quality assurance and quality assessment activities. In circumstances in which required patient consent is not provided with the test request, the laboratory should notify the test requestor and determine the period after which the test request might be rejected and the specimen discarded because of specimen degradation or deterioration. Laboratory specimen retention procedures should be consistent with patient decisions. The retention of residual newborn screening specimens is subject to federal, state, and local requirements. Residual specimens are valuable for the laboratory's ongoing quality assurance, quality assessment, and personnel competency assessment activities. Certain states have established policies under state law to retain residual dried blood spot specimens without personal identifiers for public health and research uses after newborn screening testing is completed and to allow parents to request that their children's residual specimens be destroyed after newborn screening tests are completed (107). # Postanalytic Systems Assessment The CLIA postanalytic systems assessment requirements apply to testing for inherited metabolic diseases. Quality assessment of the postanalytic system generally includes the following: - Practices and other issues related to test reports: assessing, monitoring, and evaluating the accuracy and completeness of the laboratory's test reports (e.g., patient information, test results, reference ranges, and the disposition of unacceptable specimens) - The time required by the laboratory to complete testing and report test results - Procedures for notifying the test requestor about the test results, including routine tests, urgent testing, abnormal results, and critical values or alert values that warrant immediate medical attention - If the laboratory uses an electronic information system, a mechanism to periodically verify the accuracy of data and calculations, the results transmitted to interfaced systems, and patient-specific information - The record retention procedures and practices of the laboratory - The specimen retention policies and procedures of the laboratory # Biochemical Genetic Testing Laboratories that perform biochemical genetic testing should have procedures in place to address the following postanalytic or interpretive issues, which often are unique to biochemical genetic testing: - When diagnostic testing shows an abnormality, testing of other analytes might be critical to clarify the diagnosis (e.g., elevated methylmalonic acid suggesting that testing of homocysteine level is needed). - Reflex testing (i.e., follow-up testing that is automatically initiated when certain test results are observed in the laboratory) might be needed when useful and appropriate to clarify or expand primary or initial test results. - Testing by another method or with another tissue type might clarify or confirm the diagnosis for more effective clinical management of the patient or the patient's family. - Additional specimens might be needed when testing unstable analytes to verify that the initial specimen quality was not compromised. In addition, the laboratory should have a system in place to facilitate the consideration of the preanalytic information needed for adequate interpretation of test results and the inclusion of such information on the test report. For example, circumstances when more than one biochemical genetic test has been requested on a patient should be recognized and noted in test reports. Specimen collection time often is critical for accurate interpretation of test results, particularly for conditions such as intermittent maple syrup urine disease that present normal analyte (e.g., amino acids) levels during asymptomatic intervals. Inclusion of the reasons for testing in test reports, even though the specific reasons for a test might not always be provided with the test requisition, is helpful for the users of test results because test reports might be sent to health-care providers different from the test requestors. The laboratory's policies and procedures for postanalytic systems assessment should address monitoring of these recommended practices and assessment of their effectiveness. # Newborn Screening Newborn screening laboratories should have policies and procedures for postanalytic systems assessment that address all postanalytic laboratory practices in newborn screening. In particular, an ongoing review process should be in place to monitor and assess the effectiveness of the following procedures: - Procedures for immediate reporting of results that are considered out of range or are indicative of a clinical emergency, including notification of the newborn's primary care provider and documentation of the reporting and report receipt - Procedures for obtaining a second, freshly collected specimen for confirmatory analysis for each abnormal screening result - Immediate reporting of unsuitable specimens to facilitate timely repeat testing - Laboratory responsibilities in the comprehensive system for follow-up of each positive screening result, including facilitating the reporting of the medical care decisions and actions to the newborn screening program by specifying the reporting requirements in test reports # Ensuring Confidentiality of Patient Information CLIA requires laboratories to ensure the confidentiality of patient information throughout all phases of the testing process that are under laboratory control (42 CFR §493.1231) (13). Laboratories should follow more specific requirements and comply with additional guidelines (e.g., the Health Insurance Portability and Accountability Act of 1996 privacy rule , state requirements, accreditation standards, and professional guidelines) to establish procedures to protect the confidentiality of patient information, including information related to genetic testing. Laboratories that perform testing for inherited metabolic diseases should establish and follow procedures that include defined responsibilities of all employees to ensure appropriate access, documentation, storage, release, and transfer of confidential information and prohibit unauthorized or unnecessary access or disclosure. # Information Regarding Family Members In certain circumstances, information about family members is needed for selection of test methods and test performance or should be included in test reports to ensure appropriate interpretation of test results. Therefore, laboratories must have procedures and systems to ensure confidentiality of all patient information, including that of family members, in all testing procedures and reports in compliance with CLIA requirements and other applicable federal, state, and local regulations. # Requests for Test Results to Assist with Health Care for a Family Member When a health-care provider requests the genetic test information of a patient to assist with providing care for a family member of the patient, the following practices are recommended: - Requests should be handled following established laboratory procedures regarding release and transfer of confidential patient information. - Laboratories may release patient test information only to the authorized person ordering the test, the persons responsible for using the test results (e.g., health-care providers of the patient designated by the authorized person to receive test results), and the laboratory that initially requested the test. If a health-care provider who provides care for a family member of the patient is authorized to request the patient's test information, the laboratory should request the patient's authorization before releasing the genetic test results to the health-care provider. - When patient consent is required for testing, the consent form should include the laboratory confidentiality policies and procedures and should describe situations in which test results might be requested by health-care providers caring for family members of the patient. - Laboratory directors are responsible for determining and approving circumstances in which access to confidential patient information is appropriate, including when, how, and to whom information is to be released, in compliance with federal, state, and local requirements. The HIPAA privacy rule and CLIA regulations are federal regulations intended to provide minimum standards for ensuring confidentiality of patient information; states or localities might have more restrictive standards. Although the HIPAA privacy rule allows health-care providers that are covered entities (i.e., health-care providers that conduct certain transactions in electronic form, health-care clearinghouses, and health plans) to use or disclose protected health information for treatment purposes without patient authorization and to share protected health information to consult with other providers to treat a different patient or to refer a patient, the regulation indicates that states or institutions may implement stricter standards to protect the privacy of patients and the confidentiality of patient information (115). Laboratories must comply with applicable requirements and follow professional practice guidelines in establishing policies and procedures to ensure confidentiality of patient information, including information and test results on biochemical genetic testing and newborn screening. # Personnel Qualifications, Responsibilities, and Competency Assessments Laboratory Director Qualifications and Responsibilities Qualifications CLIA requires directors of laboratories that perform highcomplexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1443) ( 13): - Be a doctor of medicine or a doctor of osteopathy and have board certification in anatomic or clinical pathology or both - Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have at least 1 year of laboratory training during residency or at least 2 years of experience directing or supervising high-complexity testing - Have an earned doctoral degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution and current certification by a board approved by HHS (116) Directors of laboratories that perform testing for inherited metabolic diseases must meet these qualification requirements. Because CLIA requirements are minimum qualifications, laboratories that perform testing for inherited metabolic diseases should evaluate the tests they perform to determine whether additional knowledge, training, or expertise is necessary to fulfill the responsibilities of laboratory director. # Responsibilities CLIA requires directors of laboratories that perform highcomplexity testing to be responsible for the overall operation and administration of the laboratory, which includes responsibility for the following (42 CFR §493.1445): - Ensuring the quality of all aspects of test performance and results reporting for each test performed in the laboratory - Ensuring that the physical and environmental conditions of the laboratory are appropriate and safe - Ensuring enrollment in HHS-approved proficiency testing programs - Employing a sufficient number of laboratory personnel with appropriate education, experience, training, and competency required for patient testing - Establishing policies and procedures for personnel competency assessment and monitoring - Specifying the responsibilities and duties of each consultant, supervisor, and testing employee - Ensuring compliance with applicable requirements and regulations Directors of laboratories that perform testing for inherited metabolic diseases must fulfill these CLIA responsibility requirements. In addition, laboratory directors should have responsibility for the following: - Ensuring documentation of the clinical validity of any biochemical genetic or newborn screening test the laboratory performs, following the recommended practices in this report - Determining specific policies and procedures for assessing and ensuring the competency of all laboratory personnel, including technical supervisors, clinical consultants, general supervisors, and testing personnel # Technical Supervisor Qualifications and Responsibilities Qualifications CLIA regulations set forth minimum qualifications of technical supervisors for high-complexity testing in chemistry, clinical cytogenetics, and other specialties and subspecialties but do not specify qualification requirements for technical supervisors for biochemical genetic testing or newborn screening. Because CLIA requirements are intended to be minimum standards, laboratory directors should assess the tests their laboratories perform to determine whether additional qualifications are necessary for the technical supervisors to ensure quality throughout the testing process. Technical supervisors of testing for inherited metabolic diseases should have the qualifications that are appropriate for the section they are supervising, the types of testing performed, and the purpose for performing the testing. The recommended technical supervisor qualifications that follow are based on the complexity of testing for inherited metabolic diseases and the training, experience, and expertise required to provide technical supervision of laboratories performing these tests. These recommended qualifications are not regulatory requirements; rather, they should be considered part of recommended laboratory practices for ensuring the quality of testing for inherited metabolic diseases. Biochemical genetic testing. Technical supervisors of laboratories that perform biochemical genetic testing should have either one of the following sets of qualifications: # Clinical Consultant Qualifications and Responsibilities Qualifications CLIA requires clinical consultants for high-complexity testing to have either one of the following sets of qualifications (42 CFR §493.1455) ( 13): - Be qualified as a laboratory director for high-complexity testing as specified in the regulations - Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine licensed to practice medicine, osteopathy, or podiatry in the state in which the laboratory is located These CLIA requirements provide minimum qualifications required for persons who provide clinical consultations for high-complexity testing. For laboratory testing for inherited metabolic diseases, clinical consultants should also have relevant training or experience in the testing for which they provide clinical consultation. Biochemical genetic testing. Clinical consultants for biochemical genetic testing should have any one of the following additional sets of qualifications, which are more specific than those required by CLIA: - Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and be either board-certified or boardeligible in clinical genetics or clinical biochemical genetics - Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have 2 years of experience in biochemical genetic testing, diagnosis and management of inborn errors of metabolism, or both - Have an earned doctoral degree in a relevant discipline, be currently certified by a board approved by HHS, and have 2 years of training or experience in biochemical genetic testing # Responsibilities CLIA regulations require clinical consultants for highcomplexity testing to be responsible for providing consultation to laboratory clients regarding the appropriateness of the testing ordered and the interpretation of test results (42 CFR §493.1457) (13). Persons providing clinical consultations for testing for inherited metabolic diseases must meet the following CLIA responsibility requirements for clinical consultants for high-complexity testing: - Be available to provide consultation to laboratory clients, including assisting them with ordering appropriate tests to meet clinical expectations and discussing the quality and interpretation of test results - Ensure that test reports include pertinent information required for interpretation of specific patient conditions # General Supervisor Qualifications and Responsibilities Qualifications CLIA requires general supervisors of laboratories that perform high-complexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1461) ( 13): # Responsibilities CLIA regulations require general supervisors for highcomplexity testing to be responsible for day-to-day supervision or oversight of the laboratory operation and personnel performing testing and reporting test results (42 CFR §493.1463) (13). General supervisors of laboratories that perform testing for inherited metabolic diseases must meet the following CLIA responsibility requirements for general supervisors for high-complexity testing: - Be accessible to testing personnel at all times testing is performed - Provide day-to-day supervision and direct supervision of all testing personnel - Monitor testing procedures to ensure the quality of analytical performance - Fulfill the following duties when delegated by the laboratory director or technical supervisor: -Ensure that remedial actions are taken when test systems deviate from the established performance specifications. -Ensure that patient test results are not reported until all corrective actions have been taken and the test system is functioning properly. -Provide orientation for all testing personnel. -Annually evaluate and document the competency of all testing personnel to perform authorized testing. # Testing Personnel Qualifications and Responsibilities Qualifications CLIA requires testing personnel who perform highcomplexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1489) ( 13): - Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine - Have an earned doctoral, master's, or bachelor's degree in a chemical, physical, biological, or clinical laboratory science or medical technology from an accredited institution - Have an earned associate's degree in a laboratory science or medical laboratory technology from an accredited institution Biochemical genetic testing. These CLIA qualification requirements apply to testing personnel who perform biochemical genetic testing. Laboratories should ensure that testing personnel have received adequate training, including on-the-job training, and demonstrate competency in highcomplexity biochemical genetic testing before performing patient testing. Newborn screening. Testing personnel who perform public health newborn screening must meet the CLIA qualification requirements for testing personnel for high-complexity testing and should also meet any additional state or local qualification requirement that might be more stringent than the CLIA requirements. # Responsibilities CLIA requires persons who perform high-complexity testing to follow laboratory procedures for test performance, quality control, results reporting, documentation, and problem identification and correction (42 CFR §493.1495) (13). Personnel who perform biochemical genetic testing or newborn screening must meet these requirements. # Personnel Competency Assessment CLIA requires laboratories to establish and follow written policies and procedures to assess employee competency, and if applicable, consultant competency (42 CFR §493.1235) (13). CLIA requirements for laboratory director responsibilities (42 CFR §493.1445 ) specify that laboratory directors must ensure that policies and procedures are established for monitoring and ensuring the competency of testing personnel and for identifying needs for remedial training or continuing education to improve knowledge and skills. Technical supervisors are responsible for implementing the personnel competency assessment policies and procedures, including evaluating and ensuring competency of testing personnel (42 CFR §493.1451 ) (13). Laboratories that perform testing for inherited metabolic diseases must meet these general personnel competency assessment requirements because regular competency assessment is an important element of ensuring all personnel are capable of performing their duties appropriately. Laboratories also should follow the applicable CMS guidelines to establish and implement policies and procedures specific for assessing and ensuring the competency of all types of laboratory personnel, including technical supervisors, clinical consultants, general supervisors, and testing personnel, in performing duties and responsibilities (74). For example, the performance of testing personnel must be evaluated and documented at least semiannually during the first year a person tests patient specimens. Thereafter, evaluations must be performed at least annually; however, if test methods or instrumentation changes, performance must be reevaluated to include the use of the new test methods or instrumentation before testing personnel can report patient test results. Personnel competency assessments should identify training needs and ensure that persons responsible for test performance receive regular in-service training and education appropriate for the services performed (74). # Conclusion The recommendations in this report are intended to provide laboratory professionals and others with information to ensure and improve the quality of laboratory testing performed for screening, detection, diagnosis, monitoring, and clinical management of persons with inherited metabolic diseases. Although the recommended practices are primarily intended for laboratories performing biochemical genetic testing and newborn screening, many recommendations reflect general good laboratory practices for ensuring the quality of laboratory services. Recommendations beyond the CLIA requirements are included as guidelines rather than requirements; therefore, general laboratories may also implement these recommendations, when appropriate, to improve testing quality. # Usefulness for Users of Laboratory Services These recommendations serve as a resource for health-care professionals and other users of laboratory services to improve the delivery and usefulness of biochemical genetic and newborn screening test results in clinical and public health practices. In particular, these recommendations inform users of laboratory services about the responsibilities and practices to be expected of laboratories when providing biochemical genetic test results and newborn screening services. An understanding of these recommendations by users of laboratory services might prevent or reduce errors or problems relating to test selection, specimen submission, test performance, and reporting and interpretation of results. These practices should lead to improved use of biochemical genetic tests and better collaboration and follow-up to newborn screening, resulting in better health outcomes for patients and their families. # Usefulness for Evaluators of Laboratory Practices These recommendations also are a resource for medical and public health professionals, including laboratory inspectors and surveyors, payers, and persons who evaluate laboratory practices and policies to improve quality assurance procedures and quality systems. The recommendations are intended to clarify CLIA requirements that are applicable to biochemical genetic testing and newborn screening for inherited metabolic diseases, provide recommendations for additional quality assurance practices that are not specifically addressed by CLIA requirements, and facilitate assessment of laboratory practices, especially the specific recommended quality management practices in addition to CLIA regulations. # Usefulness for Development of Future Professional Guidelines and Accreditation Standards The recommendations in this report were developed with consideration of existing relevant regulatory requirements (both federal and state), accreditation standards, professional guidelines, and other standards. These CDC recommendations are expected to help address quality assurance concerns in laboratory practices and clarify or provide guidance for areas and issues that are inconsistent among existing standards. These recommendations also can serve as a resource for accrediting agencies that are evaluating whether laboratories are performing properly and adhering to established requirements, standards, and recommendations. In addition, these recommendations can be updated in future documents to reflect changes in laboratory testing for inherited metabolic diseases, such as new technologies or practices that might be adopted in the future. # Usefulness for Development and Use of Standards for Electronic Communication in Clinical and Public Health Practice The recommendations in this report should be considered in the development of information technology systems to be used for biochemical genetic testing or newborn screening to ensure that they accommodate the nationally recommended laboratory practices. For example, the health information technology standards for newborn screening results reporting, created collaboratively by many federal agencies, advisory groups, and the newborn screening system vendors, are directly relevant to laboratory practices for newborn screening, particularly in the preanalytic and postanalytic phases of the testing process (36)(37)(38)40). Consistently following the CDC recommendations can help expedite the delivery of newborn screening results and provide the data needed to manage and improve the newborn screening process. # Usefulness for In Vitro Diagnostic Manufacturers The recommendations in this report focus on parameters important in the development and application of biochemical genetic and newborn screening tests, including introduction of new tests for patient testing, analytic and clinical validity, quality control, proficiency testing, and communication of test results to health-care providers and other users. Some of these parameters are already considered in the FDA review process for test systems, control materials, and other in vitro diagnostic products used in performing biochemical genetic or newborn screening tests. Therefore, an understanding of the recommendations in this report can assist in vitro diagnostic manufacturers in providing products in accordance with recommended good laboratory practices. # Usefulness for Patients and Families Knowledge of these CDC recommendations might also help patients and their families to understand the test information that should be provided and the responsibilities of the laboratory. For example, understanding that laboratories must maintain the confidentiality of information regarding patients and their family members should facilitate the ability of patients and families to make informed decisions. In addition, knowledge of the recommended laboratory practices for retention of records, reports, and tested specimens should also be helpful for patients and families. # cut-off value Quantitative value of the analyte that is used as the decision point between a positive and a negative result drift A slow or systematic change of a metrological characteristic of a measuring instrument or system, such as accuracy, trueness, and precision genetics The study of inheritance patterns of specific traits genome The complete genetic content of an organism genotype The genetic makeup of an organism or group of organisms with reference to a single trait, set of traits, or an entire complex of traits Health Level Seven International (HL7) A standards-development organization that has produced international standards for electronic reporting of laboratory results and orders in-range result Newborn screening result that is within the expected range of normal or negative test results established for a particular condition informed consent A process by which persons voluntarily confirm their willingness to participate in a particular testing act after having been informed of all aspects of the act that are relevant to the decision to participate in the act internal control material A control material that is placed in the same reaction tube as the specimen being analyzed and therefore is subjected to exactly the same internal conditions and external parameters as any analyte present in the tube # International Classification of Diseases (ICD) The international standard diagnostic classification for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, as maintained by the World Health Organization limit of detection (LOD) The lowest amount of analyte in a sample that can be detected (with stated probability), although the amount might not be quantified as an exact value limit of quantitation (LOQ) The lowest concentration at which an analyte can be quantitatively determined with stated acceptable precision and trueness under stated experimental conditions; might be equal to the limit of detection or could be at a higher concentration measurand Quantity to be measured newborn screening A system that identifies, shortly after birth, infants who are at increased risk for genetic and other congenital conditions so that treatment can begin as soon as possible; need to confirm positive newborn screening results with additional diagnostic testing nonwaived testing Test systems, assays, or examinations that have not been determined to be waived testing. Nonwaived testing encompasses moderate-and high-complexity testing for which CLIA regulations provide requirements for laboratory certification, quality systems, performance assessment, and laboratory personnel out-of-range result Newborn screening result that is outside the expected range of normal or negative test results established for a particular condition, including carrier results and any need for additional testing phenotype The observed biochemical, physiological, and morphological characteristics of an individual as determined by the genotype and the environment in which the genotype is expressed; also, in a more limited sense, the expression of a particular gene or genes precision Closeness of agreement between independent test results from the same sample obtained under stipulated conditions, often determined by assessing repeatability and reproducibility proficiency testing A program in which multiple samples are periodically sent to members of a group of laboratories for analysis or identification (or both) in which each laboratory's results are compared with those of other laboratories in the group or with an assigned value (or both) and are reported to the participating laboratory and others repeatability Closeness of agreement between independent test results for the same measurand under the same conditions reproducibility Closeness of agreement between independent test results for the same measurand under changed conditions qualitative test A characterization applied to laboratory tests that detect or identify a particular analyte, constituent, or condition quality assessment A group of activities to monitor and evaluate the total testing process to help ensure that test results are reliable, improve the testing process, and promote good quality testing practices quality control Operational techniques and activities that are used to fulfill requirements for quality; the procedures used to detect and correct errors that occur due to test system failure, adverse environmental conditions, and variance in operator performance, as well as the monitoring of the accuracy and precision of the test performance over time quality management system (QMS) Coordinated activities to direct and control an organization with regard to quality quantitative test A characterization applied to laboratory tests that provide results expressed in a numerical amount or level (concentration) of an analyte in a sample or specimen reagent A substance that produces a chemical or biological reaction with a patient specimen that allows detection or measurement of the analyte for which the test is designed reference interval The range of test values expected for a designated population of persons (e.g., 95% of persons that are presumed to be healthy ) reference material Material sufficiently homogeneous and stable with respect to one or more specified properties (quantitative or qualitative) that has been established to be fit for its intended use in a measurement process; might be used to calibrate a measurement system, to assess a measurement procedure, to assign values to other materials, and for quality control; can only be used for a single purpose in a given measurement reportable range of test results The span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response total testing process Series of activities or path of workflow for performing testing that can be divided into three major phases: preanalytic, analytic, and postanalytic trueness Closeness of agreement between the average of an infinite number of replicate-measured quantity values and a reference quantity value waived test A test system, an assay, or an examination that has been found to meet the statutory criteria specified in the Public Health Service Act ( §353 ) (12)	Front cover photos: Top row, left to right: colorimetric biotinidase assay; thin layer chromatography analysis for mucopolysaccharidoses, a group of lysosomal disorders; laboratorian using tandem mass spectrometry. Second row, left to right: sleeping newborn; acylcarnitine profile indicating elevated C8, a biochemical marker for medium-chain acyl-CoA dehydrogenase deficiency; mother and her son, who are able to skate together because of effective laboratory monitoring and clinical management of an inherited metabolic disorder. Bottom left: dried blood spot samples for proficiency testing.CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use. CDC does not accept commercial support.# Introduction Inherited metabolic diseases, often referred to as inborn errors of metabolism, comprise a large class of genetic diseases involving disorders of metabolism; collectively, these diseases have an incidence of at least one in 1,500 persons in the United States (1). Biochemical genetic testing and newborn screening tests are essential for early recognition of and timely intervention for these disorders to reduce morbidity and mortality rates and improve health outcomes. Biochemical genetic tests encompass a diverse spectrum of laboratory analyses of metabolites, enzyme activities, and functional assays for evaluation, diagnosis, treatment monitoring, disease management, and assessing a person's risk for carrying a specific disease trait (i.e., carrier status assessment), such as inborn errors of metabolism. Newborn screening is a vital state-based public health system in the United States that aims to test all newborns for an increasing number of inherited metabolic diseases and other congenital disorders, many of which require immediate treatment (2). The nationwide implementation of a recommended uniform screening panel of inherited metabolic diseases (Table 1) (3) and the consideration of additional conditions by state newborn screening programs present continuing quality assurance challenges for public health laboratories and other newborn screening facilities as well as for biochemical genetic testing laboratories that perform subsequent diagnostic testing. As advances in laboratory technology and knowledge of the genetic basis of disease increase the necessity of accurate and reliable laboratory testing in the screening, diagnosis, classification, and treatment of inherited metabolic diseases, guidelines are necessary for quality assurance and quality improvement in these areas of laboratory testing. CDC has collaborated with the Centers for Medicare & Medicaid Services (CMS), the Food and Drug Administration (FDA), and other federal agencies; state programs; professional organizations; standard-setting institutions; and federal advisory committees to promote the quality of genetic testing and provide guidance for appropriate use of genetic tests in clinical and public health practices. In the 2009 report Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions, CDC provided recommendations for good laboratory practices in molecular genetic testing and indicated the need for recommendations in other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and testing of acquired genetic variations (4). This report complements the 2009 CDC recommendations by providing recommendations for good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic diseases. Recommendations for additional areas of genetic testing will be considered based on continued monitoring and evaluation of laboratory practices, technology advancements, and the development of professional practice guidelines. The purposes of this report are to 1) clarify CLIA requirements that are applicable to biochemical genetic testing and newborn screening for inherited metabolic diseases and 2) provide recommendations for additional quality assurance practices that are not specifically addressed by CLIA requirements. The recommended practices address the benefits of the quality management system (QMS) approach, factors to consider before introducing new biochemical genetic tests, establishment and verification of test performance specifications, the total laboratory testing process (which consists of the preanalytic, analytic, and postanalytic phases), confidentiality of patient information and test results, and laboratory personnel qualifications and responsibilities for laboratory testing for inherited metabolic diseases. These recommendations provide a comprehensive guide for laboratories that perform biochemical genetic testing for ensuring the quality of laboratory services and highlight laboratory practices critical for quality improvement in newborn screening for inherited metabolic diseases. This report also is intended as a resource for users of laboratory services (e.g., authorized persons under applicable state law, health-care professionals, patients, and referring laboratories) to aid in their collaboration in newborn screening systems and effective use of biochemical genetic tests. This report also might assist standard-setting organizations and professional societies with development of future laboratory quality standards and practices, federal and state agencies with strategies and policies related to genetic testing, medical and public health professionals with evaluating laboratory practices, manufacturers of in vitro diagnostics with developing new testing products, and patients and families with improving their knowledge of good laboratory practices for genetic testing. Incorporation of these recommended practices into laboratory systems can improve the quality and appropriate use of genetic testing services, leading to better health outcomes for patients and their families. Abbreviations and a glossary of terms used in this report are provided (Appendices A and B). # Background Inborn errors of metabolism are inherited genetic disorders that affect one or more of the hundreds of biochemical pathways in the human body. Patients with these disorders are unable to properly use or synthesize certain compounds, such as fatty acids, amino acids, organic acids, or macromolecules, because of defects in the enzymes or other components of various metabolic pathways. These conditions frequently are identified in infants and young children with acute or chronic symptoms. When possible, early diagnoses with timely and effective interventions are essential for preventing permanent neurologic sequelae, disabilities, and other severe adverse outcomes. Biochemical genetic testing is a critical discipline in laboratory medicine for the evaluation, diagnosis, treatment monitoring, clinical management, and in some cases, carrier status assessment, of inherited metabolic diseases. These tests comprise highly complex and specialized laboratory procedures performed for evaluating enzyme activity, functional status of proteins, and levels of metabolites such as amino acids, organic acids, and fatty acids using a wide variety of specimen types including urine, whole blood, plasma, serum, cerebrospinal fluid, muscle biopsy, and other tissue types. Biochemical genetic tests also are among the critical follow-up procedures for diagnosing presumptive cases detected during newborn screening. † Core conditions are the conditions that newborn screening is specifically designed to identify. A core condition for newborn screening should have the following features: a specific and sensitive test is available to detect the condition, the health outcomes are well understood, treatment is available and effective, and identification of the condition could affect the future reproductive decisions of the family. § Secondary conditions are the genetic conditions that can be identified when screening for one of the core conditions or as a consequence of confirmatory testing for an out-of-range result of a core condition. Both the number of laboratories in the United States that perform biochemical genetic tests and the numbers of tests being performed are not certain. Although a nationwide survey identified laboratories that performed biochemical genetic testing in 2003 (5), more recent comprehensive data are not available, and information from voluntary laboratory directories are likely to be underestimates (6). However, information from the College of American Pathologists (CAP) Biochemical Genetic Testing Proficiency Survey Program indicated that the number of participating laboratories increased by 15% in 6 years, from 93 laboratories in 2002 to 107 laboratories in 2010 (7). Despite the limited nationwide data, biochemical genetic tests are performed for approximately 270 metabolic disorders spanning diverse disease categories (Table 2). As advances in biomedical research and laboratory technology lead to better understanding of the effects of genetic variations in biochemical pathways and metabolic diseases, the use of biochemical genetic tests in diagnosis, classification, and management of inherited metabolic diseases will likely continue to increase. Newborn screening is a state-based public health system that tests infants shortly after birth for serious or life-threatening metabolic and other conditions that, when detected early, might be managed or treated to prevent death, disability, or other severe consequences such as mental retardation. The newborn screening programs test almost all (≥97%) of the 4 million babies born in the United States each year. These tests are conducted by public health laboratories using a few drops of blood, often collected from newborns before hospital discharge, that are spotted on filter paper cards (2). Most states collect a fee for newborn screening, which varies depending on the state and can be paid by third-party payers. Although newborn screening programs are primarily funded by user fees, state and federal public health system funding often is necessary to support the comprehensive programs, which include education, laboratory screening, follow-up and tracking, diagnosis, treatment and management, and evaluation. Over the last decade, the increasing use of tandem mass spectrometry in newborn screening has substantially increased the number of metabolic disorders that can be detected from dried blood spot specimens (3,8,9). In 2010, the Secretary of the U.S. Department of Health and Human Services (HHS) adopted the recommendation of the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) for a uniform screening panel (including screening for 30 core conditions and reporting 26 secondary conditions) as a national standard for newborn screening programs together with the recommendation to facilitate the inclusion of this recommended panel into all state newborn screening programs (10). The expansion of inherited metabolic conditions screened by newborn screening programs has presented challenges to ensuring the quality of performance and delivery of testing services not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories that perform subsequent diagnostic testing (11). # CLIA Oversight of Biochemical Genetic Testing and Newborn Screening In 1988, Congress enacted Public Law 100-578, a revision of Section 353 of the Public Health Service Act (42 U.S.C. 263a) that amended the Clinical Laboratory Improvement Act of 1967 and required HHS to establish regulations to ensure the quality and reliability of laboratory testing on human specimens for disease diagnosis, prevention or treatment, or health assessment purposes (12). Under the CLIA regulations, laboratory testing is categorized based on the level of testing complexity as 1) waived (from routine regulatory oversight), 2) moderate complexity, or 3) high complexity. Moderate-and high-complexity testing is nonwaived testing. For nonwaived testing, CLIA regulations include requirements for proficiency testing, facility administration, quality systems for the total testing process (which consists of the preanalytic, analytic, and postanalytic phases), personnel for moderate-and high-complexity testing, and when applicable, more specific requirements for testing specialties and subspecialties (13). CMS administers the CLIA laboratory certification program and collaborates with FDA and CDC in providing CLIA oversight. FDA is responsible for test categorization and waiver determinations, and CDC is responsible for quality improvement studies, convening the Clinical Laboratory Improvement Advisory Committee (CLIAC), and providing scientific and technical support. CLIAC was chartered by HHS to provide recommendations and advice to HHS, CDC, CMS, and FDA regarding CLIA regulations, the impact of CLIA regulations on medical and laboratory practices, and modifications to CLIA standards to accommodate technological advances (14). Although not defined as specialties or subspecialties under CLIA, biochemical genetic tests and newborn screening tests are considered high-complexity tests. Laboratories that perform these tests must meet the applicable general CLIA requirements for nonwaived testing and the personnel requirements for high-complexity testing. These laboratories may be accredited by a deemed-status accreditation program approved by CMS to meet the CLIA certification requirements (13). Additional state requirements also might be applicable to newborn screening laboratories. # Concerns Related to Biochemical Genetic Testing The test procedures used to perform biochemical genetic tests are generally complex and technically demanding. Laboratory interpretation of test results is crucial for the clinical use of test result information in specific patient contexts and should be provided by trained and qualified personnel. Although data are limited, studies and reports since 2003 have revealed various concerns related to quality assurance practices in biochemical genetic testing, including test performance establishment, quality control procedures, proficiency testing, personnel qualifications and training, and results reporting (5,15,16). These concerns indicate areas of biochemical genetic testing practices that are in need of improvement or will likely benefit from the development and implementation of good laboratory practices. # Establishing Test Performance A comprehensive survey on quality assurance practices in biochemical genetic testing indicated that most laboratories that performed these tests used laboratory-developed methods and had variable practices for establishing test performance specifications such as reference intervals (5). The difficulty of obtaining sufficiently large numbers of samples from apparently healthy persons has made it challenging to establish reference intervals for certain analytes, especially when sample collection requires invasive techniques. The same challenge also affects the establishment of specific reference intervals by sex, age group, and other clinically relevant parameters (15,16). The lack of commercially available standards and reference materials presents another major challenge in establishing test performance specifications for biochemical genetic tests (15). Expanded newborn screening programs also present challenges to biochemical genetic testing laboratories, such as establishing age-specific reference intervals for infants and characterizing interfering substances to facilitate disease diagnosis primarily based on metabolic alterations and often in the absence of characteristic clinical symptoms or physical signs of disorders that are more commonly detected in older children (11). In addition, the establishment of clinical validity for new tests might involve a substantial literature review or research before introducing these tests into clinical use (11). # Quality Assurance During the Three Phases of the Testing Process # Preanalytic Phase The preanalytic phase of the testing process generally encompasses test selection and ordering; specimen collection, processing, handling, and delivery to the testing site; and the receipt of the patient's specimens with the test request information by the laboratory (17). Biochemical genetic tests are associated with a wide range of preanalytic variables that might affect test performance and test results because of the diverse specimen types and conditions, patient preparation status, and highly complex test procedures (18). Obtaining necessary clinical, medication, nutritional status, and other patient information that is critical for effective test result interpretation also can be challenging (5,18). # Analytic Phase The analytic phase of the testing process includes specimen preparation, performance of test procedures, monitoring and verification of accuracy and reliability of test results, and documentation of test findings (17). Significant variability in quality control practices was reported for biochemical genetic tests (5). For example, 14% of participating laboratories reported omission of normal controls in each test run, whereas 53% and 19% of the laboratories, respectively, included controls representing affected persons or carriers in enzyme-based assays designed to identify carriers and affected persons (5). The scarcity of commercially available reference materials also presents a challenge to performing quality control procedures, evaluating and verifying laboratory-prepared solutions, and standardizing calibration and calibration verification practices so that test results are comparable between laboratories (15). # Postanalytic Phase The postanalytic phase of the testing process includes reporting test results and archiving records, reports, and tested specimens (17). Variable postanalytic practices were reported for biochemical genetic tests (5). For example, only 24% of the surveyed laboratories reported the inclusion of a summary of test methods in biochemical genetic test reports, and only 12% had a specific written policy about confidentiality of genetic testing results (5). Among laboratories that performed amino acid analysis, 37% did not include results interpretation on test reports (5). Although these practices are not explicitly specified in CLIA regulations, they have been recommended in professional guidelines as necessary quality assurance procedures for biochemical genetic tests (18). # Proficiency Testing Proficiency testing is a well-established practice for monitoring laboratory testing performance and is a key component of the external quality assessment process. Participation in proficiency testing has been reported to help laboratories reduce analytic deficiencies, improve testing procedures, and take actions necessary to prevent future errors (19,20). Proficiency testing samples that simulate actual patient specimens could allow the evaluation of the total testing process (which consists of the preanalytic, analytic, and postanalytic phases) and improve the monitoring of laboratory performance (21)(22)(23). These samples might be derived from tissue samples or cell lines made from patients with a known condition or might be synthesized by adding known concentrations of analytes into a matrix such as serum or urine. CLIA regulations do not include proficiency testing requirements specifically for biochemical genetic or newborn screening tests. Laboratories that perform these tests must meet the general CLIA requirement to verify, at least twice annually, the accuracy of the genetic tests they perform ( §493.1236[c]) (13). Laboratories may participate in available proficiency testing programs for the biochemical genetic tests they perform to meet this CLIA alternative performance assessment requirement. Proficiency testing participation helps laboratories that perform biochemical genetic testing to improve quality assurance procedures through identification of areas that need improvement, such as variability in analytic performance and the lack of standardization for reportable units of measurement (7,20). Formal proficiency testing or external quality assessment programs are available only for a limited number of biochemical genetic tests, such as those included in the Biochemical Genetics survey program provided by CAP and the European Research Network for Evaluation and Improvement of Screening, Diagnosis, and Treatment of Inherited Disorders of Metabolism (ERNDIM) (Appendix C) (24,25). Practical and technical challenges, such as the lack of proficiency testing materials, might limit the availability of comprehensive proficiency testing programs that assess both the quantitative and qualitative test methods for each analyte and examine the entire testing process. For many rare genetic conditions (i.e., conditions that affect <200,000 U.S. persons at any given time) for which testing is performed by one or a few laboratories, substantial barriers to developing formal proficiency testing programs have been recognized. Professional guidelines have been developed for laboratories to evaluate and monitor test performance when proficiency testing programs are not available (26), and online registry services have been developed to facilitate sample exchange among genetic testing laboratories (27). # Personnel Qualifications and Training Qualifications of laboratory personnel, including training and experience, are critical for ensuring quality performance of genetic testing because human errors can have a substantial impact on the quality of laboratory test results (5,28). The qualifications of persons directing or supervising biochemical genetic testing laboratories, including specialized training, experience, and board certification in clinical biochemical genetics, correlate significantly with laboratory adherence to voluntary quality standards and guidelines for biochemical genetic testing (5). The need for trained, qualified personnel to ensure the quality of biochemical genetic testing also has been recognized internationally (29). # Quality Improvement for Laboratory Practices in Newborn Screening Ensuring high-quality testing and achieving continuous quality improvement has been challenging for newborn screening laboratories as the number of inherited metabolic diseases that are included in newborn screening programs has continued to increase. For example, variability has been reported in certain newborn screening laboratory practices, including criteria for acceptance of dried blood spot specimens and cutoff values for each analyte, which might vary by state program depending on specific populations and case definitions (30,31). Most state programs provide training and continuing education to hospital staff members and others who submit specimens from newborns regarding appropriate collection procedures for dried blood spot specimens (32). Performance metrics and quality indicators have been described to meet the evaluation and improvement needs of the national newborn screening system (33,34). Laboratories in the United States that test dried blood spot specimens have been voluntarily participating in the CDC Newborn Screening Quality Assurance Program (NSQAP), which enables newborn screening laboratories to meet the CLIA alternative performance assessment requirement for verifying test result accuracy at least twice per year (35). Laboratories gain testing proficiency through comparisons of peer performance within and among methods. Four times per year, NSQAP provides newborn screening laboratories with blind-coded dried blood spot samples that represent analytes detected for newborn screening disorders. Participating laboratories include these samples in their routine testing and test them in the same way they test dried blood spot specimens from newborns. Test performance is evaluated based on identification of test results that require additional follow-up testing (out-of-range results) compared with those that do not (in-range results) (30). NSQAP summarizes annual falsepositive and false-negative rates for the performance assessment samples to help laboratories investigate potential sources of errors and areas of laboratory practices that need improvement. In 2008, NSQAP found that the false-positive rate for performance assessment samples was <1% for all newborn screening markers except decenoylcarnitinine (a secondary marker for medium chain acyl-CoA dehydrogenase deficiency), immunoreactive trypsinogen (a primary marker for cystic fibrosis), and succinylacetone (a specific marker for tyrosinemia type 1), whereas the false-negative rate was 1.1%-3.3% for phenylalanine (a primary marker for phenylketonuria), tyrosine (a primary marker for tyrosinemia), and immunoreactive trypsinogen (a primary marker for cystic fibrosis) (30). The decrease in the false-negative rate from 2002 to 2008 supports NSQAP in improving laboratory performance. NSQAP also provides quality control materials to help newborn screening laboratories monitor the quality of test performance (30). Collaborative efforts by many federal agencies, advisory groups, and the private sector have led to the development of standards and mechanisms for electronic reporting of newborn screening results (36)(37)(38). For example, the National Library of Medicine (NLM) and Health Resources and Services Administration (HRSA) have developed guidelines for standardized terminology, coding, and electronic messaging for ordering newborn screening tests and reporting test results to facilitate complete and accurate data collection, prompt results delivery and communication, and improved patient management (37,38). These guidelines have called for uniform laboratory practices in the newborn screening process, including the collection and documentation of demographic and clinical information (e.g., birth weight, gestational age, nutritional status, and transfusion information) in the preanalytic phase and the laboratory interpretation and reporting of results in the postanalytic phase (36,(38)(39)(40). # Methods The development and preparation of the recommendations in this report involved a multistep process that included 1) initial information collection and evaluation by CDC scientists to assess the quality assurance practices and potential areas needing improvement in biochemical genetic testing and newborn screening, 2) development of CLIAC recommendations to be considered by CDC for inclusion in a CDC guideline, 3) solicitation of input from other federal advisory committees and stakeholders that also address quality of genetic testing and newborn screening to complement the CLIAC recommendations, and 4) evaluation of all recommendations and advice received and preparation of this report by CDC scientists. # Initial Information Review and Assessment (2008-2009) An initial information review and assessment was conducted by CDC scientists from the Division of Laboratory Science and Standards in collaboration with the CDC Newborn Screening Quality Assurance Program. The purposes of this review and assessment were to 1) identify laboratory practice issues in biochemical genetic testing and newborn screening that would benefit from recommendations for good laboratory practices; 2) define issues for consideration by a CLIAC workgroup and assess areas of expertise needed for this workgroup; 3) assess information needed to facilitate the workgroup's evaluation of current standards, guidelines, practices; and 4) help gauge the usefulness and impact of the CDC recommendations on laboratory testing quality and public health. The information review and assessment consisted of a literature review, gathering data from existing databases and resources, and a review of regulatory and voluntary standards that are specific or applicable to biochemical genetic testing and newborn screening. A search of biomedical literature published since 2006 was conducted using the Medline and the PubMed databases with search terms including inherited metabolic diseases, inborn errors of metabolism, newborn screening, biochemical genetic testing, laboratory quality, good laboratory practice, laboratory standard, quality assurance, proficiency testing, quality assessment, and quality management. Approximately 400 English-language publications were identified, of which 18 contained information on laboratory performance or quality management practices and were specifically reviewed (3,5,11,15,19,20,30,33,34,(41)(42)(43)(44)(45)(46)(47)(48)(49). Data also were collected from state programs (50,51), CDC studies (8,52,53), and publicly available directories and databases of laboratories and laboratory testing (6, 7,24,25,29,32,54,55). Review of these data and information sources focused on 1) assessing the scope and growth of biochemical genetic testing and newborn screening in the United States, including the number of laboratories that perform biochemical genetic testing and newborn screening, the number and type of inherited metabolic diseases for which biochemical genetic testing and newborn screening is performed, the test methods and technology used to perform these tests, test volume, availability of proficiency testing and external quality assessment programs, and the changes of these aspects over time; 2) evaluating factors in biochemical genetic testing and newborn screening that might affect testing quality; and 3) identifying concerns and deficiencies in quality assurance practices in biochemical genetic testing and newborn screening and areas that would benefit from good laboratory practice guidelines. Considering the information gaps and the small number of published studies that specifically collected information on quality assurance issues in biochemical genetic testing laboratories, this initial information gathering and review was intended to be inclusive to provide background information to the CLIAC workgroup, enable workgroup evaluation of the information gathered and issues identified, and elicit additional insights. CDC scientists also reviewed regulatory and voluntary laboratory standards that are specific or applicable to biochemical genetic testing and newborn screening, including the American College of Medical Genetics (ACMG) Standards and Guidelines for Clinical Genetic Laboratories (56), Clinical and Laboratory Standards Institute (CLSI) guidelines (17,26,(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73), CLIA regulations (13,74), FDA guidance documents (75,76), state requirements (77,78), accreditation checklists (79-82), national practice guidelines (11,83), and international standards and guidelines (84)(85)(86). To facilitate the assessment of the extent to which the identified quality assurance needs were addressed by existing standards and guidelines, CDC scientists included these regulatory and voluntary standards in comprehensive comparison documents for each of the laboratory practice areas in which quality assurance concerns or the need for specific quality assurance guidance were identified. These documents compared existing CLIA regulations with other relevant federal requirements, state regulations, accreditation standards, professional guidelines, and other voluntary national and international standards and guidelines. Sixteen comparison documents of laboratory standards and recommendations were developed to address preanalytic practices (including the laboratory responsibility to provide test information to users of laboratory services, informed consent, test request, specimen submission and referral, and preanalytic systems assessment), analytic practices (including performance characteristics for biochemical genetic testing and newborn screening, establishment and verification of test performance specifications, calibration and calibration verification, control procedures, proficiency testing and alternative performance assessment, and equipment, instruments, and reagents), postanalytic practices (including test report and retention of records, reports, and specimens), personnel qualifications and responsibilities, and quality management practices. # Development of CLIAC Recommendations Since 1997, CLIAC has provided HHS with recommendations on approaches and mechanisms for ensuring the quality of laboratory genetic testing (14). At the September 2008 CLIAC meeting, the committee provided recommendations for good laboratory practices in molecular genetic testing for heritable diseases and conditions, which were subsequently included in the 2009 CDC recommendations (4); CLIAC also recommended the formation of a workgroup to consider similar good laboratory practices for biochemical genetic testing (87). The CLIAC Biochemical Genetic Testing Good Laboratory Practices Workgroup subsequently was formed in 2009. Workgroup members were selected by expertise needed to address the identified quality assurance issues and provide suggestions for laboratory practices, the potential impact and effectiveness of the laboratory practices to be recommended, and the representation of CLIAC as required by the Federal Advisory Committee Act (88). Factors for selection of workgroup members included expertise in diverse testing technology and diagnostic issues (e.g., common and rare disease testing); representation of diverse laboratory environments (e.g., large and small laboratories; laboratories in academic, private, and public health sectors; and specialized and general laboratories); representation of newborn screening and public health perspectives; expertise in laboratory performance evaluation, laboratory inspection, and laboratory accreditation; the perspective of users of laboratory services (including health-care providers, patients, and referring laboratories) and other stakeholders; experience in federal and state regulatory oversight; experience in developing accreditation standards or professional practice guidelines; experience and expertise in providing and evaluating proficiency testing and interlaboratory exchange programs; representation of in vitro diagnostic manufacturers; and representation of general laboratory services. The members of the workgroup, which included 13 nonfederal experts and representatives of CDC, CMS, and FDA, are listed at the end of this report. The workgroup was charged with the responsibility of providing input to CLIAC for developing recommendations for good laboratory practices for biochemical genetic testing. Specific workgroup tasks included 1) suggesting the scope of the CLIAC considerations in developing good laboratory practice recommendations for biochemical genetic testing, 2) recognizing and identifying issues in biochemical genetic testing that need guidance for quality assurance, 3) identifying additional sources of data and information needed for workgroup discussion, 4) reviewing relevant practice guidelines and standards, 5) suggesting strategies for issues or areas of laboratory practices for which current standards and practice guidelines are lacking or inconsistent, and 6) formulating workgroup input for CLIAC consideration. The workgroup was advised that issues on which they could not reach consensus should also be reported to CLIAC. Through a series of meetings and teleconferences in 2009, the workgroup considered the scope of laboratory practice recommendations for biochemical genetic testing and testing for inherited metabolic diseases and suggested that recommendations be developed to apply to biochemical genetic testing as well as to newborn screening for inborn errors of metabolism. After reviewing the background information and the concerns in quality assurance practices that were identified by CDC scientists, workgroup members suggested additional information sources and issues that could affect the quality and performance of biochemical genetic testing and newborn screening. The workgroup then reviewed the 16 comprehensive comparison documents of laboratory standards and guidelines, which included federal and state regulatory requirements, professional guidelines, accreditation checklists, and international standards and guidelines that provided general or specific quality standards applicable to biochemical genetic testing and newborn screening. The workgroup also reviewed information on the HHS-approved and other certification boards for laboratory personnel, including the number of persons certified in each of the specialties for which certification is available. Suggestions and clarifications for good laboratory practices were provided by the workgroup for all issues that were recognized as needing quality assurance guidance. The outcomes of the workgroup discussions were summarized by CDC scientists into a workgroup report. The workgroup report was presented to CLIAC at the February 2010 CLIAC meeting. CLIAC recommendations were formed from the committee discussion during the meeting by reviewing the workgroup report and making modifications and additional recommendations, as summarized in the CLIAC meeting summary (89). CLIAC recommended that the planned CDC recommendations include the CLIAC-recommended good laboratory practices for biochemical genetic testing and newborn screening for inborn errors of metabolism (89). The CLIAC members involved in developing the recommendations are acknowledged at the end of this report. # Solicitation of Additional Input To ensure that the recommendations provided in this report were adequately vetted with stakeholders, CDC collaborated with the National Institutes of Health (NIH) in obtaining additional input from the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) and with HRSA in obtaining consultation from SACHDNC during 2010-2011. To complement the CLIAC recommendations, advice was solicited from both federal advisory committees regarding 1) any issue that CDC should explain or clarify for laboratories that perform biochemical genetic testing or newborn screening, 2) any additional issue pertaining to biochemical genetic testing or newborn screening laboratory practices that CDC should address in these recommendations, and 3) efforts that should be taken to encourage the implementation of the recommended practices once this report is published. Presentations regarding the CLIAC recommendations also were made at the annual conference of the Association of Public Health Laboratories (APHL), the APHL Newborn Screening and Genetics Symposium, and the ACMG annual meeting during 2010-2011. CDC scientists also convened with the APHL Newborn Screening and Genetics in Public Health Committee and its quality assurance and quality control subcommittee to discuss any recommendations needed in addition to the CLIAC recommendations and the effective approach to providing the recommendations specific for newborn screening. # Preparation of the Recommendations in this Report CDC scientists prepared a draft of the recommended good laboratory practices based on the CLIAC recommendations and the additional input from SACGHS, SACHDNC, and APHL. In May 2011, an initial draft was provided to CLIAC, the CLIAC workgroup, CMS, FDA, CDC programs, the NIH Office of Biotechnology Activities, and HRSA for review and comment by SACHDNC and other interested groups and organizations. Comments and suggestions also were received from the Society for Inherited Metabolic Disorders, March of Dimes, and the APHL Newborn Screening and Genetics in Public Health Committee. CDC scientists reviewed all comments and suggestions. Modifications and clarifications have been incorporated in this report. # Recommended Practices for Laboratory Testing for Inherited Metabolic Disorders The following recommended practices apply to laboratory testing for screening, detection, diagnosis, and monitoring of inherited metabolic disorders, including biochemical genetic testing and newborn screening. These recommendations are intended to provide guidelines for specific quality assurance concerns in these testing processes by addressing the following areas of laboratory practices: • The QMS approach • Factors to consider before introducing new biochemical genetic tests • Establishment and verification of test performance specifications • The preanalytic, analytic, and postanalytic testing phases • Personnel qualifications, responsibilities, and competency assessment • Confidentiality of patient information and test results Many of the recommendations that follow apply generally to both biochemical genetic testing and newborn screening for inborn errors of metabolism, whereas issues that are specific for either laboratory area are discussed separately. # The QMS Approach QMS is a systematic approach for managing and ensuring the quality and effectiveness of an organization's work operations and services (90). A laboratory QMS provides a framework for the implementation of policies, processes, and procedures for the quality system essentials to ensure the quality of activities throughout the laboratory's workflow (17). The recommended practices in this report are provided with consideration of the QMS principles and concepts and in accordance with the laboratory's workflow, including consideration and planning for introducing testing services for patient testing, establishment or verification of test performance specifications, and providing laboratory services to meet the needs in clinical and public health practices. QMS is the basis for many international quality standards, such as the International Organization for Standardization (ISO) standards ISO 9001, ISO 17025, and ISO 15189 (84,90,91) and CLSI guidelines (17,(66)(67)(68)92,93). QMS principles also have been adopted in state program requirements and accreditation standards in the United States (77,82). Although the QMS standards and guidelines are distinct from CLIA regulations, a QMS framework facilitates the implementation of practices to meet CLIA and other regulatory requirements, conform to professional standards, and deliver quality laboratory services. Therefore, having a QMS in place will help laboratories that perform testing for inherited metabolic disorders apply the recommended practices in this report to improve test performance, laboratory service delivery, and the effectiveness of laboratory operations. # Considerations Before Introducing Biochemical Genetic Testing or Offering New Biochemical Genetic Tests Recommendations described in this report should be considered, in addition to appropriate professional guidelines and recommendations, when planning and preparing for the introduction of biochemical genetic testing or offering new biochemical genetic tests. Factors to be considered in this stage should at least include the following: • # Establishment and Verification of Test Performance Specifications CLIA requires laboratories to establish or verify the analytic performance of each nonwaived test or test system before the test is introduced for patient testing. The calibration and control procedures also must be determined based on each test's performance specifications. Verification of test performance specifications is required when a laboratory introduces an unmodified FDA-cleared or unmodified FDA-approved test system. An FDA-cleared test system has been determined by FDA to be substantially equivalent to another legally marketed test system. A premarket notification, referred to as a 510(k), must be submitted to FDA for clearance. An FDA-approved test system is a system for which FDA has approved a premarket approval (PMA) application before marketing begins. This approval process is generally reserved for high-risk medical devices and involves a more rigorous premarket review than a premarket notification submitted to FDA for clearance. Before reporting patient test results, the laboratory must 1) demonstrate that the manufacturer-established performance specifications for accuracy, precision, and reportable range of test results can be reproduced or verified in the laboratory setting and 2) verify that the manufacturer-provided reference intervals (or normal values) are appropriate for the laboratory's patient population (42 CFR §493.1253) (13). Laboratories are subject to more stringent requirements when introducing 1) FDA-cleared or FDA-approved test systems that have been modified by the laboratory, 2) laboratory-developed tests or test systems that are not subject to FDA clearance or approval (e.g., standardized methods and textbook procedures), or 3) test systems with no manufacturer-provided performance specifications. In these instances, before reporting patient test results, laboratories must conduct more extensive procedures to establish performance specifications for accuracy, precision, analytic sensitivity, analytic specificity, reportable range of test results, reference intervals or normal values, and other applicable performance characteristics (13). Laboratories that perform biochemical genetic testing or newborn screening must comply with these general CLIA requirements and should adhere to the additional recommendations that follow for establishment and verification of test performance specifications. These recommendations are intended to specifically address test performance establishment for laboratory-developed biochemical genetic tests to ensure valid and reliable test performance and results interpretation. The recommendations also might be used by laboratories to verify performance specifications of unmodified FDA-cleared or FDA-approved biochemical genetic test systems to be used for patient testing. # General Principles When establishing or verifying test performance, laboratories should review and follow professional guidelines, such as those provided by CLSI and ACMG, that are applicable and appropriate for the planned testing. Laboratories should ensure that the professional guidance is followed consistently throughout the performance establishment and verification phase and the subsequent patient testing process. Factors that should be considered include the intended use of the test, the analytes or panel of analytes to be measured, intended patient populations, test methods, and samples needed for performance establishment (76). For establishing performance specifications of new biochemical genetic tests, the following practices should be considered as general principles: • Review scientific studies and pertinent references to assess the test methods and clinical usefulness of the test. • Define the patient populations for which the test might be performed. • Select appropriate test methods for the disease (or condition) or analyte being evaluated. • Establish or verify test performance specifications and determine quality control parameters for the test. # Samples for Establishment of Test Performance In general, test performance specifications should be established with an adequate number, type, and variety of samples to ensure that test results can be interpreted in the context of specific patient conditions and that the limitations of the testing and test results are known. The number and type of both positive and normal samples should be considered when selecting and determining samples needed. The numbers of both positive and normal samples should be adequate for determining the performance specifications of the assay being established. Both disease prevalence and sample characteristics might influence sample availability, thus the availability of samples and reference materials also should be considered. For example, a large number of positive samples (and in certain circumstances, normal samples) might not be available for rare conditions; unstable samples or samples that need to be collected invasively (such as cerebrospinal fluid or muscle biopsy samples) might be limited. Laboratories should consider these factors and define test performance specifications and limitations based on the samples that are available and included in the performance establishment. The types of samples should represent the types of patient specimens that are expected for the assay (e.g., whole blood, serum, urine, dried blood spot, fresh or frozen tissue, or prenatal specimens). For example, if the laboratory intends to perform amino acid analysis for urine, plasma, and cerebrospinal fluid specimens, test performance specifications need to be established for all three specimen types because each specimen type might be associated with a different total testing process as a result of differences in specimen collection and handling, specimen stability, interfering substances, analyte extraction, reference ranges, results interpretation, and other preanalytic, analytic, and postanalytic factors. If the condition of the patient specimens that the laboratory anticipates to receive represent significant variance that might affect patient test results or suggest the presence of interfering substances (e.g., insufficient specimen volume or amount, specimen hemolysis, or clotting), the laboratory should include samples representing these conditions when determining test performance, specimen acceptance criteria, and the influences of the specimen variances on test results interpretation. # Analytic Performance Specifications Performance Characteristics For each new biochemical genetic test, laboratories should determine specifications for the following performance characteristics: Accuracy. Accuracy is the closeness of agreement between an individual value and a true value. For each quantitative test, the laboratory is responsible for determining the ability of the test method to produce accurate results. For qualitative methods, the laboratory should establish the capacity of the test method to identify the presence or absence of the analyte (74). Test performance establishment also should determine trueness, or the closeness of agreement between the mean value of a measurement series and the true value. Accuracy and trueness might be assessed by testing reference materials, comparing assay results to a reference method (i.e., gold standard), comparing split-sample results with results obtained from a method shown to provide clinically valid results, or correlating research results with the clinical presentation when establishing a test system for a new analyte, such as a newly identified disease marker (74). Precision. The laboratory is responsible for determining the precision of each new test by assessing repeatability (i.e., closeness of agreement between independent test results for the same measurand and under the same conditions) and reproducibility (i.e., closeness of agreement between independent test results for the same measurand under changed conditions). Precision can be verified or established by assessing day-to-day, run-to-run, and within-run variation (as well as operator variance) by repeat testing of known patient samples, quality control materials, or calibration materials over time (74). Analytical sensitivity, including limit of quantification (LOQ) and limit of detection (LOD). Laboratories should follow professional guidelines in establishing LOD and LOQ for each analyte to be measured or detected (61). For modified test systems, the laboratory may use the lower limit of the manufacturer's reportable range if the laboratory has demonstrated that the modification has not affected the lower limit (74). Analytical specificity. Determination of analytical specificity should include the ability of the test to detect or measure the target analytes distinctly from potential interfering substances, including factors associated with specimens (e.g., specimen hemolysis, anticoagulant, lipemia, and turbidity) and factors associated with patients (e.g., clinical conditions, disease states, and medications) (74). Laboratories must document information regarding interfering substances using product information, literature, or the laboratory's own testing (74). Laboratories should adhere to professional guidelines, such as those developed by ACMG, when establishing or verifying analytical specificity for each biochemical genetic test (18). Reference range or normal values. The laboratory should establish a reference range that is appropriate for the laboratory's patient population (i.e., a normal range that reflects the type of specimen and demographic variables such as age, sex, and physiologic ranges expected for the laboratory's patient population) (74). When possible, laboratories should establish their own reference ranges by evaluating an appropriate number of samples to verify the reference ranges provided in literature or textbooks or by manufacturers. If the samples used in these verifications are from tested patient specimens rather than from healthy controls, laboratories should systematically evaluate the reference ranges and monitor the need to make adjustments over time. If samples that represent the specimen types (or specimen matrices) expected in patient testing are not available, laboratories may use the manufacturer-suggested or published reference ranges if they are appropriate for the laboratory's patient populations. Laboratories should monitor these reference values, make adjustments when appropriate, and inform their clients of the sources of their reference values (e.g., whether they are published values or values established or verified by the laboratory). Reportable range of test results for the test system. The laboratory is responsible for determining the reportable range of test results for each test the laboratory performs (13). The reportable range of patient test results can be established or verified by assaying low and high reference materials or by evaluating known samples of abnormally high and low values (74). Other performance characteristics required for test performance. For example, if a laboratory performs other test procedures in conjunction with a biochemical genetic test and reports the additional test results to aid in patient care, the laboratory should document the performance characteristics of the additional test procedures. Cutoff values for analytes detected in newborn screening often need to be age adjusted with consideration of infant term and birth weight (71). # Multiple-Analyte or Profile Analysis If analyses of multiple-analyte or metabolic profiles (e.g., acylcarnitine profile and organic acids profile) include pattern recognition (i.e., recognition of abnormal concentrations of specific analytes or patterns of analytes), test performance establishment or verification should include the following additional practices: • The reference ranges for all analytes to be reported should be established or verified for the laboratory's patient population with consideration of age, sex, physiologic state, and other clinically relevant factors. • Both normal and abnormal samples, or both samples that generate results within the expected normal or negative range of test results established for a particular condition (i.e., in-range results) and those that are associated with out-of-range results, should be analyzed and the analyte patterns verified in comparison with the reference ranges and the documented patterns of analytes in abnormal concentrations that indicate disease states. • As many different known samples as possible should be analyzed to ensure that common elements of a diagnostic pattern are detected. • Substances that have the potential to interfere with the analysis should be identified (94). # Changes to Established Performance Specifications Laboratories should recognize that changes to a test procedure, such as using a different sample matrix (plasma vs. urine), using or promoting the test for another purpose (screening vs. diagnostic use), and changing the type of analysis (qualitative results vs. quantitative), could affect the established test system performance specifications for accuracy, precision, analytical sensitivity, analytical specificity, and clinical use. These changes might result in a modified test system for which the performance specifications must be reestablished (74). # Determination of Quality Control Procedures CLIA requires laboratories to determine the calibration and control procedures for nonwaived tests or test systems as part of the verification or establishment of performance specifications for the tests (42 CFR §493.1253[b] [3]) (13). Laboratories must meet these requirements and should consider the recommended quality control practices for each new test before the test is introduced for patient testing. # Documentation of Information on Clinical Validity Although CLIA regulations do not include validation of clinical performance specifications of new tests or test systems, laboratories are required to ensure that the tests being performed meet clinical expectations. For tests of high complexity such as biochemical genetic tests, laboratory directors and technical supervisors are responsible for ensuring that the testing method is appropriate for the clinical use of the test results and can provide the quality of results needed for patient care (13). Laboratory directors and clinical consultants must ensure laboratory consultations are available for laboratory clients regarding the appropriateness of the tests ordered and interpretation of test results (13). Documentation of available clinical validity information will help laboratories performing biochemical genetic testing to fulfill their responsibilities for providing consultation to health-care professionals and other users of laboratory services. Laboratories should ensure that the tests they perform are clinically relevant and can be interpreted for specific clinical situations. Laboratory responsibilities for clinical validity include the following: • (95). Laboratories should monitor the progress of clinical research and advances in understanding in this area, especially for newly discovered gene-disease associations, rare disorders, and conditions with highly variable expression or uncertain clinical sensitivity. Laboratory directors and technical supervisors are responsible for using professional judgment to evaluate the results of such studies and should adhere to professional guidelines and accreditation standards to ensure that the testing performed and results interpretation are appropriate for specific clinical settings (11,18,81,96,97). # Additional Recommendations for Newborn Screening Performance establishment for newborn screening tests presents special challenges because of the time-sensitive need for specimen collection so that infants with positive screening results can receive timely follow-up confirmatory testing and effective intervention. The recommendations that follow provide additional guidelines for laboratories that perform newborn screening when establishing or verifying test performance specifications. Specimen collection time frame. Laboratories should consider the impact of the specimen collection time frame on the screening for each disorder when establishing or verifying test performance specifications. The majority of newborn screening dried blood spot specimens are initially collected from infants before age 72 hours or before hospital discharge (98). The specimens collected from each infant typically are used in multiple test procedures for the detection of many disorders, each of which might have a screening window (i.e., time interval with the greatest likelihood for disease diagnosis and effective treatment before overt symptoms or permanent damage occurs). For example, some conditions, such as maple syrup urine disease and galactosemia, warrant specimen collection in the first 24-48 hours to enable the detection of abnormal analyte levels and initiate early treatment. For other conditions such as homocystinuria, the abnormal analytes might be more readily detected on a later day. Therefore, laboratories should document the course of the abnormal analyte presentation for the diseases for which they screen and use age-adjusted reference intervals, with consideration of infant term, birth weight, and health status in test performance establishment and verification. Number and source of samples. The number of samples included in performance establishment or verification should be sufficiently large to enable the determination of test performance specifications for population-based screening (72). Although samples might be available from various sources, such as tested patient specimens, reference materials, proficiency testing materials, and control materials, laboratories should consider using samples that have the same dried blood spot matrix as that used for specimen collection from newborns (72). Unsatisfactory and invalid samples. If the laboratory accepts specimens that are considered unsatisfactory or invalid, such as a dried blood spot specimen that is of insufficient quantity for testing, oversaturated, scratched or abraded, or not completely dry before mailing (69), these specimen variances should be addressed in test performance establishment. Cut-off and critical values. Determination of the reportable range of test results for the test system should include appropriate cut-off values and critical values that require prompt follow-up and clinical intervention. Determination of the cut-off values for each analyte should be based on considerations for statistically derived values and testing of patient samples with a confirmed diagnosis. Continuous monitoring of test performance. Laboratories should continuously monitor the performance of their newborn screening tests and determine the need for reevaluating performance specifications as new disease information or test performance data become available (99). # Preanalytic Testing Phase Test Information to Provide to Users of Laboratory Services CLIA regulations require laboratories that perform nonwaived testing to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR §493.1241 and §1242) (13). Laboratories also must ensure that a qualified clinical consultant is available to assist clients with appropriate test ordering to meet clinical expectations (42 CFR §493.1457[b]) (13). This section describes laboratory responsibilities for ensuring appropriate test requests and specimen submission for the biochemical genetic and newborn screening tests they perform in addition to meeting these CLIA requirements. The recommendations that follow emphasize the role of laboratories in providing specific information to users (e.g., authorized persons under applicable state law, health-care professionals, patients, referring laboratories, and payers of laboratory services) regarding the tests performed by the laboratory before the users select and order laboratory tests. For each biochemical genetic test, the following information should be provided to facilitate appropriate test selection and requests, specimen collection and handling, and submission of patient specimens together with relevant information to the laboratory: • Information necessary for appropriate test selection -Intended use of the test to specify the analytes or panel of analytes to be measured, the purpose of testing and appropriate use of the test, and the recommended patient populations; for example, the intended use of an amino acid analysis being described as "analyses of amino acids in plasma, intended for diagnosis and management of amino acid disorders in newborns, infants, children, or adults" and an enzyme assay being described as "analysis of galactose-1-phosphate uridyltransferase in red blood cells, intended for the diagnosis of galactosemia in patients suspected to have the disorder and/or for carrier testing in family members" -Indications for testing, such as the symptoms, clinical findings, family history, or newborn screening results for which the biochemical genetic tests might be needed -Performance specifications for the test (when appropriate), as well as test limitations and conditions that could affect test results and result interpretation (e.g., sources of assay interference; specimen types and containers; specimen collection methods and the timing of specimen collection; the patient's conditions such as fasting, transfusion, medications, and disease states; and the disease to be evaluated) -Test method and testing procedures to be used, including current CPT codes when appropriate -Whether testing is performed with an FDA-cleared or FDA-approved test system, a laboratory-developed test, or investigational test under FDA oversight • Information on appropriate collection, handling, and submission of specimens, including the following: -Any necessary patient preparation, when appropriate -Specimen type, amount or volume, and collection container or device -Specimen preparation -Specimen stability and transport conditions -Reasons for rejection of specimens (discussed in more detail in next section) • Types of patient information required to perform and interpret the test (including, as applicable, any required patient consent information in compliance with federal, state, local, and accreditation requirements and whether preauthorization is required) • Availability of consultation and discussion from the laboratory • If test results might indicate genotype information, implications of test results for relatives or family members Laboratories should review the biochemical genetic tests they perform and the procedures they use to provide and update the recommended test information. At a minimum, laboratories should ensure that the test information is available from accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. Laboratories that already provide the information from these sources should continue to do so. However, laboratories also might decide to provide the information more directly to their users and should determine the situations in which such direct communication is necessary. The complexity of the language used should be appropriate for the targeted user groups (e.g., for patients, language understandable by the general public). Laboratories should also ensure the information provided in this preanalytic phase is consistent with information included on test reports. In the United States, state newborn screening programs provide health-care providers with information on the panel of disorders screened in their states as well as educational materials for parents and the general public. The National Newborn Screening and Genetics Resource Center provides up-to-date information on the disorders for which screening is performed in each state and model brochures for providers, parents, and grandparents (32). Information on laboratory screening procedures often is provided as part of the state newborn screening program, together with disease information, counseling, and follow-up services for presumptive-positive infants. The number of diseases detected by newborn screening programs is expanding, thus the following information is critical for health-care professionals and others to ensure the effectiveness of the public health program: • Appropriate collection, handling, transport, and submission of dried blood spot specimens • The laboratory's specimen acceptance and rejection criteria • Test performance, possible test results, and follow-up confirmatory testing when necessary • Test limitations that could affect test results and results interpretation, such as sources of assay interference, timing of specimen collection, and infant factors (e.g., fasting or fed, receipt of transfusion, medications, or diseases) • Types of information about the infant as well as the parents that might be needed to perform and interpret test results (including, gestational age, birth weight, and racial/ethnic background) • Availability of consultation and discussion from the laboratory • Information on retesting, if indicated • Opt-out documentation, if necessary # Informed Consent Biochemical Genetic Testing A person who voluntarily confirms the willingness to participate in a particular test, after having been informed of all aspects of the test that are relevant to the decision to participate, is providing informed consent (85). Informed consent for genetic testing or specific types of genetic tests is required by law in some states; as of June 2008, a total of 12 states required informed consent before the request or performance of a genetic test (100). Certain states, such as Massachusetts (101), Michigan (102), Nebraska (103), New York (104), and South Dakota (105), specified the required components for informed consent documentation in their statutes. No professional practice guideline specifically recommends informed consent for biochemical genetic tests. In medical practice, the persons authorized to order the tests also are responsible for obtaining the appropriate level of informed consent (106). Unless mandated by state or local requirements, obtaining informed consent generally is not considered a laboratory responsibility. However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision making, laboratories should ensure that certain practices are followed. Laboratories should be available to assist users of laboratory services with determining the appropriate level of informed consent by providing useful and necessary information regarding the test being considered and implications of test results. Laboratories also should include appropriate methods for documenting informed consent on test request forms (e.g., check-off boxes, attestation statements, and space for signature) and evaluate whether the consent information is provided with the test request before initiating testing. Laboratories may determine the situations in which a patient specimen can be stabilized until informed consent is obtained, following the practices for specimen retention recommended in these guidelines. Laboratories should refer to professional guidelines and any local requirements for additional information regarding informed consent for genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent. # Newborn Screening Few states require explicit parental consent for participation in mandated public health newborn screening programs. Most states allow parents to opt out of the program on religious grounds, and certain state programs provide parents the option to refuse newborn screening or the retention of dried blood spot specimens after newborn screening for public health use (107,108). Laboratories that perform public health newborn screening should have procedures and processes in place in accordance with their state requirements. When required by state law, appropriate information about informed consent or opting out for newborn screening should be provided to the public in compliance with applicable federal, state, and local requirements. # Test Requests CLIA requirements (42 CFR §493.1241[c]) specify that laboratories that perform nonwaived testing must ensure that the test request solicits the following information: 1) the name and address or other suitable identifiers of the authorized person requesting the test and (when appropriate) the person responsible for using the test results, or the name and address of the laboratory referring the specimen, including a contact person to facilitate reporting of imminently life-threatening laboratory results or critical values; 2) patient name or a unique patient identifier; 3) sex and either age or date of birth of the patient; 4) the tests to be performed; 5) the source of the specimen (if appropriate); 6) date and time (if appropriate) of specimen collection; and 7) any additional information relevant and necessary for a specific test to ensure accurate and timely testing and reporting of results, including interpretation (if applicable) (13). # Biochemical Genetic Testing In addition to meeting the CLIA test request requirements, laboratories that perform biochemical genetic testing should solicit the following additional or more specific information on test requests: • Patient name and any other unique identifiers needed for testing • Date of birth • Date and time of specimen collection (relative to symptoms and initiation of treatment when appropriate) • The reason for referral and information on the clinical, medication, and nutritional status of the patient, including International Classification of Diseases (ICD) codes or other codes indicating the diseases or conditions to be tested for and patient preparation when indicated (e.g., how the patient was prepared) to indicate that informed consent has been obtained in compliance with federal, state, and local requirements • Emergency contact information for the responsible clinician (for additional information or abnormal results) For biochemical genetic testing and newborn screening, laboratory electronic information systems (both current versions and those in development) should support and ensure the collection, transmission, and retention of all test request information recommended in this report. Laboratories may specify critical information elements as required for test requisition submission and have preanalytic quality assessment procedures in place for monitoring the provision of the needed information. • # Specimen Submission, Handling, and Referral CLIA requires laboratories to establish and follow written policies and procedures for patient preparation, specimen collection, specimen labeling (including patient name or unique patient identifier and, when appropriate, specimen source), specimen storage and preservation, conditions for specimen transportation, specimen processing, specimen acceptability and rejection, and referral of specimens to another laboratory (42 CFR §493.1242) (13). If a laboratory accepts a referral specimen, appropriate written instructions providing information on specimen handling and submission must be available to the referring laboratory (13). Laboratories that perform testing for inherited metabolic diseases must meet these general CLIA requirements and should implement all of the additional practices that follow to ensure the quality of specimen submission, handling, and referral: • Provide specific instructions for the proper identification, collection, handling, transport, and submission of patient specimens to laboratory clients as specified in the section on the role of laboratories in providing information to users of their services. • Provide information on any need for patient preparation before specimen collection, and specifically communicate with clinicians regarding the circumstances that might involve risk (e.g., fasting and certain challenge tests). • Specify procedures for handling specimen submission for time-sensitive testing, testing that requires rapid or short turnaround time, or critical or labile specimens to meet the need for clinical care and patient management. These procedures also should address situations in which direct communication with the submitting clinician is needed. # Criteria for Specimen Acceptance and Rejection Specimen acceptance criteria should be consistent with the types and conditions of the samples used to establish test performance specifications to the extent practical and feasible. Laboratories should have written criteria for acceptance and rejection of specimens, including determination and handling of situations such as • improper handling or transport of specimen; • mislabeling, use of inappropriate anticoagulants or media, specimen degradation, or inappropriate specimen type; • potentially deteriorated specimen (e.g., specimens with bacterial overgrowth); • potentially contaminated specimen that might affect results of testing procedures; • lack of unique identifiers on the specimen or the requisition form; • specimen not held at appropriate temperature (e.g., unfrozen specimens for urine organic acid analysis); and • insufficient specimen quantity. Because of the complexity and diversity of the specimens that might be encountered and the influence of specimen conditions on the quality of test results and results interpretation, the specimen acceptance and handling procedures should address common variances in specimen conditions and those that might occur in patient testing. Laboratories should have criteria for determining acceptable and unacceptable specimens, including determining whether specific variances in specimen conditions (e.g., hemolyzed whole blood specimen) still meet the specimen acceptance criteria and which tests can be performed with such specimens. If a laboratory accepts specimens that deviate substantially from the established criteria and might contain interfering substances that could affect the quality of patient test results, the laboratory should have documentation of studies based on the scientific literature or internal data to prove that the test to be performed and its performance specifications will not be compromised. If multiple tests or test panels are requested for a single specimen, determination of specimen acceptability might be made for the different test procedures. In such circumstances, appropriate terminology should be used so that a specimen can be determined unacceptable for particular tests rather than for all tests to be performed. For example, a quantity of specimen that is not large enough to allow necessary repeat testing needs to be addressed differently than a potentially compromised specimen such as a hemolyzed specimen. In rare circumstances, when testing specimens that deviate from the laboratory's specimen acceptance criteria is critical, the laboratory should follow established procedures to note the exceptions on the test report. In specific situations, testing of nonideal specimens might be considered. For example, critical specimens that should not be rejected include those from a deceased patient from whom no additional specimen can be submitted, specimens for which a rapid response is required for management, specimens that were collected while the patient was acutely ill or as part of a timed test or challenge, or specimens that were collected using an invasive method (e.g., cerebrospinal fluid or muscle biopsy specimens). If specimens that are not ideal but still meet the laboratory criteria for acceptability are analyzed, a repeat specimen should be requested for clarification, if necessary. # Additional Considerations for Newborn Screening Newborn screening laboratories should have policies and procedures to address the time-sensitive issues of testing and the handling of varying conditions of the infants, including specimen collection for infants who are preterm or low birth weight, too sick to be fed, or in need of special care (71). Written procedures addressing specimen-related issues, such as the preferred and necessary specimens and the timing of specimen collection, should be consistently applied. The laboratory should inform submitters that dried blood spot specimens should be transported or mailed to the laboratory within 24 hours after specimen collection (regardless of weekends and holidays), and delays in specimen submission should be avoided (69). Terms such as unsatisfactory or invalid may be used in reference to dried blood spot specimens that are not properly collected; are of insufficient or excessive quantity; are clotted, smeared, or contaminated (69); or are acceptable for some but not all testing. The specimen acceptance procedures of the laboratory should address whether dried blood spot specimens that are considered unsatisfactory (e.g., a dried blood spot specimen that does not adequately fill the circle) meet the established acceptance criteria. For all unsatisfactory specimens, a second specimen should be requested. # Test Referral Factors that should be considered when selecting laboratories for test referral might include laboratory quality, personnel expertise, turnaround time, and cost. However, cost should not be the only or the primary factor for consideration when selecting referral laboratories. CLIA regulations at §493.1242(c) require laboratories to refer a specimen for patient testing only to a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by CMS (13). Specimens should not be sent to laboratories that do not meet these requirements. The laboratory demographics lookup feature on the CMS CLIA website provides a resource to facilitate searches for laboratories that meet the CLIA certification requirements (109). # Preanalytic Systems Quality Assessment Laboratories must have written policies and procedures for assessing and correcting problems identified in test requests, specimen submission and handling, test referral, and other steps of the preanalytic testing process (42 CFR §493.1249) (13). The preanalytic systems assessment for biochemical genetic testing and newborn screening should include the following practices: • Laboratories must make a reasonable effort to verify or clarify test requests that are unclear or lack critical information, submitted with inappropriate specimens, or inconsistent with the intended use of test results. For rapid or time-sensitive testing, procedures for handling situations that require prompt initiation of patient testing are necessary. • Laboratories should have policies and procedures to ensure that information necessary for selection of appropriate test methods, performance of testing procedures, and provision of test results and results interpretation is retained throughout specimen submission, results reporting, and specimen referral. • When a laboratory recognizes that necessary information in test requests has been lost during specimen submission or test referral, the laboratory should contact the test requestor or referring laboratory to request the needed information. Effective test submission or referral procedures should then be established to prevent or minimize similar occurrences. Improving the communication between laboratories and users in the preanalytic phase also should result in improved result reporting practices. • Laboratories should monitor and document the extent to which specimen problems occur and develop measures to reduce the frequency of these problems. Examples of preanalytic quality assessment include the following: -Monitoring the frequency of unacceptable specimens and specimen handling problems, such as the use of an improper blood collection tube and inadequate mixing of blood specimens with anticoagulant after collection -Monitoring the frequency of delays in specimen transport -Identifying clients who repeatedly refer unacceptable specimens or improperly complete requisition forms -Documenting the laboratory's efforts to reduce the recurrence of these problems # Analytic Testing Phase Control Procedures The analytic phase of a laboratory test typically includes the following steps: specimen processing and preparation, analyte detection or measurement, evaluation of the quality of the analytic results, and documentation of testing data and test results. Laboratories that perform testing for inherited metabolic diseases must meet the general CLIA requirements for nonwaived testing (42 CFR §493.1256), including the following quality control requirements: • Laboratories must have control procedures in place to monitor the accuracy and precision of the entire analytic process for each test system. • The number and type of control materials and the frequency of control procedures must be established using the applicable performance specifications verified or established by the laboratory. • Control procedures must detect immediate errors caused by test system failure, adverse environmental conditions, or operator performance and must monitor the accuracy and precision of test performance over time. • Each day that testing of patient specimens is performed, the laboratory must include the following: -At least two control materials of different concentrations for each quantitative procedure -A negative and positive control material for each qualitative procedure -A negative control material and a control material with graded or titered reactivity, respectively, for each test procedure producing graded or titered results -Two control materials, including one that is capable of detecting errors in the extraction process, for each test system that has an extraction phase • If control materials are not available, the laboratory must have an alternative method for detecting immediate errors and monitoring test system performance over time; the performance of the alternative control procedures also must be documented (13). Laboratories that perform testing for inherited metabolic disorders must meet these general CLIA quality control requirements and should implement the specific practices that follow to ensure the quality of laboratory test performance: • Laboratories should validate and monitor sampling instruments to ensure there is no carryover between samples on automated instruments. • Control procedures should be performed each time patient specimens are assayed or with each batch (i.e., group of specimens run concurrently or sequentially) of patient testing. • Controls should be selected based on patient population, prevalence of the disease, and the purpose of the test, while being as comprehensive as possible. For example, enzyme testing for carrier status should have a normal control and a carrier control, if available. Examples of sources that have reference materials for biochemical genetic tests or newborn screening are listed (Appendix C). # Considerations for Control Materials for Rare Disease Testing and Alternative Control Procedures When performing testing for rare diseases, if positive controls are difficult to obtain for certain test procedures, laboratories may consider using deidentified samples (i.e., samples from which individual identifiers have been removed) from interlaboratory exchange or other mechanisms. For example, if having a positive control of the same tissue type is not practical for testing procedures performed using white blood cells, laboratories may consider using a more stable tissue type, such as cultured skin fibroblasts, when available. In these circumstances, if the control materials bypass certain preparative analytic steps of the patient testing process (e.g., extraction procedures), the laboratory should have procedures for monitoring the complete analytic process including the preparative steps. If control materials are not practical or available for rare disease testing, alternative control procedures should be developed to adequately monitor test performance. For example, spiking or enriching a normal sample with analytes to simulate abnormal samples is an acceptable alternative control procedure for certain test procedures. The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provide general guidelines for alternative control procedures, such as splitting specimens for testing by another method or in another laboratory, including previously tested patient specimens (both positive and negative) as surrogate controls, testing each patient specimen in duplicate, performing serial dilutions of positive specimens to confirm positive reactions, and conducting an additional supervisory review of results before release (74). Laboratories should use multiple mechanisms as applicable to their test procedures to ensure testing quality. # Special Quality Control Issues with Sequential Testing in Single-Channel Analyzers Certain test procedures are performed with single-channel or single-column instruments (e.g., amino acid analyses) on which the run time of each specimen might take a significant portion of a working day. For these tests, acceptable control procedures include the following options, provided 1) the laboratory director is responsible for demonstrating that the control procedures are adequate for monitoring test system performance and detecting immediate errors, and 2) the laboratory has performance establishment or verification data to demonstrate that the control procedures and calibration procedures are appropriate for the laboratory's testing of patient specimens: • Testing a mixed-level control pool (which for amino acid analysis might contain all of the amino acids to be measured at various concentrations) once during each day or 24 hours of patient specimen testing and spiking at least one internal control material (e.g., S-2-aminoethyl-1-cysteine for amino acid analysis) into each patient specimen, an approach that helps monitor the analytic process for each specimen as well as specimen-to-specimen variability. • Testing a single-level control pool (which for amino acid analysis might contain the amino acids to be measured at the same concentration) once during each day or 24 hours of patient specimen testing and spiking an internal control material into each patient specimen • Testing a previously tested patient specimen that showed abnormal levels of certain amino acids once each day and spiking an internal control material into each patient specimen • If batches of patient specimens are in a test run that exceeds 24 hours, the test run may be bracketed by running a control sample at the beginning and another control sample at the end of the run. If the run time is >48 hours, a control sample should be inserted into the run within each 24-hour span. At least one internal control material should be spiked into each patient specimen. The laboratory director should be responsible for ensuring and demonstrating that the test system has stable accuracy and precision during the defined time period for both the control samples and patient specimens. The laboratory also should consider the turnaround time needed for reporting patient results in determining the length of a test run. Test Systems, Equipment, Instruments, Reagents, Materials, and Supplies CLIA requires laboratories to perform patient testing by following the manufacturer's instructions and in a way that provides test results within the laboratory's stated performance specifications for each test system as determined under §493.1253 (13). Laboratories must meet the following requirements for the test systems, equipment, instruments, reagents, materials, and supplies that are used for performing patient testing: • Define essential conditions for proper storage of reagents and specimens, accurate and reliable test system operation, and reporting of test results. The criteria must be consistent with the manufacturer's instructions, if provided. These conditions must be monitored and documented and, if applicable, include water quality, temperature, humidity, and protection of equipment and instruments from fluctuations and interruptions in electrical current that adversely affect patient test results and test reports. • Label reagents, solutions, culture media, control materials, calibration materials, and other supplies, as appropriate, to indicate the identity and, when significant, titer, strength or concentration, storage requirements, preparation and expiration dates, and other pertinent information required for proper use. • Reagents, solutions, culture media, control materials, calibration materials, and other supplies must not be used when they have exceeded their expiration date, have deteriorated, or are of substandard quality. • Components of reagent kits of different lot numbers must not be interchanged unless otherwise specified by the manufacturer. • Reagent, media, and supply checks must include checking each batch (if prepared in the laboratory), lot number (if commercially prepared), and shipment of reagents, disks, stains, antisera, and identification systems (i.e., systems using two or more substrates or two or more reagents, or a combination) when prepared or opened for positive and negative reactivity, as well as graded reactivity, if applicable. Laboratories performing testing for inherited metabolic diseases must comply with these CLIA requirements and should implement the following additional practices: • Reagents, supplies, and instruments used during routine testing should be the same as those used in test performance establishment or verification. • New reagent lots and shipments should be tested in parallel with old lots before or concurrently with being placed in service to ensure that the new lot of reagent has maintained consistent results for patient specimens. • Test performance specifications should be reestablished if the test system has been modified with changes that could affect its performance specifications. Such changes include using different or additional equipment or instruments, changing any critical reagent such as a conjugate or substrate, using different control or reference materials, or using a different specimen collection device. • Equipment should be evaluated and monitored to account for basic detection or measurement drift through analysis of quality control data, function checks, and internal electronic checks. • Laboratories are encouraged to use available mechanisms for standardizing laboratory practices for preparing and validating reagents and reference materials that are not commercially available. When available, FDA-cleared reagents should be used for patient testing. Laboratories should be aware of FDA regulations that require FDA clearance or approval for reagents and instruments (including software programs) that are developed or prepared in one laboratory and provided to another laboratory for use in patient testing (110). However, special issues in biochemical genetic testing are associated with the lack of availability of certain essential reagents that have received FDA clearance or approval. The lack of FDA-cleared reagents increases the responsibility of the laboratory to validate any internally developed or shared reagents, standards, or controls. Laboratories also should consider relevant professional guidelines, such as those developed by CLSI and ACMG, that provide additional guidance for specific test methods. # Calibration and Calibration Verification Procedures Under CLIA, calibration and calibration verification procedures are required to substantiate the continued accuracy of the test system throughout the laboratory's reportable range of test results (13). Calibration procedures for each test system must be performed and documented either by • following the manufacturer's instructions using calibration materials provided or specified and with at least the manufacturer-recommended frequency or • using criteria verified or established by the laboratory, including the acceptable limits for and the frequency of calibration and the number, type, and concentration of calibration materials, which must be appropriate for the test system and, if possible, traceable to a reference method or reference material of known value. Calibration verification procedures must be performed and documented either by following the manufacturer's instructions or using the criteria verified or established by the laboratory under §493.1253(b)(3), including the number, type, and concentration of the materials; acceptable limits for calibration verification; and at least a minimal (or zero) value, a midpoint value, and a maximum value near the upper limit of the range to verify the laboratory's reportable range of test results for the test system (13). Calibration verification procedures must be performed at least once every 6 months and when any of the following occur: • A complete change of reagents for a procedure is introduced, unless the laboratory can demonstrate and document that changing reagent lot numbers does not affect the range used to report patient test results, and control values are not adversely affected by reagent lot number changes. • Major preventive maintenance or replacement of critical parts occurs that might influence test performance. • Control materials reflect an unusual trend or shift or are outside of the laboratory's acceptable limits. • Other means of assessing and correcting unacceptable control values have failed to identify and correct the problem. • The laboratory's established schedule for verifying the reportable range for patient test results requires more frequent calibration verification (13). Laboratories performing testing for inherited metabolic diseases must comply with these CLIA calibration and calibration verification requirements and should implement the following additional practices: • When reference materials for calibration are commercially available and stable, laboratories should consider obtaining quantities adequate for a reasonable period of testing to reduce variability in these materials (but not to exceed their expiration date). • When reference materials for calibration are not commercially available, each laboratory preparing these materials at its own facility should ensure their validation, including verifying each new batch of the calibration or reference materials against an old batch, and ensure that appropriate calibration and calibration verification procedures are in place. • Laboratories should refer to available professional guidelines (e.g., ACMG Standards and Guidelines for Clinical Genetic Laboratories [18] and CLSI methodspecific guidelines [65,69,72]) for additional guidance on performing calibration and calibration verification to ensure the test accuracy and reliability. # Proficiency Testing and Alternative Performance Assessment Proficiency testing is an important tool for assessing laboratory competence, evaluating the laboratory testing process, and providing education for laboratory personnel (67). CLIA regulations specifically require proficiency testing for some analytes or testing specialties, which might be provided by private-sector, nonprofit, or state-operated programs approved by HHS as meeting CLIA standards (42 CFR Part 493) (13). These approved programs also might provide proficiency testing for analytes and specialties for which proficiency testing is not specified, including biochemical genetic tests and other tests (111). Although the CLIA regulations do not include proficiency testing requirements specific for biochemical genetic tests or newborn screening tests, laboratories that perform these tests must comply with the general requirements for alternative performance assessment for any test or analyte not specified in the regulations to, at least twice annually, verify the accuracy of the tests or procedures they perform (42 CFR §493.1236[c]) (13). Laboratories may meet this requirement by participating in available proficiency testing programs for the biochemical genetic or newborn screening tests they perform (112). A list of available proficiency testing programs for biochemical genetic testing is included in this report (Appendix C). # Biochemical Genetic Testing The following recommended practices provide more specific and stringent measures than the current CLIA requirements for test performance assessment for laboratories that perform biochemical genetic testing to monitor and evaluate the ongoing quality of the testing they perform: • Participate in available proficiency testing at least twice per year for each biochemical genetic test the laboratory performs. Laboratories are encouraged to participate in available proficiency testing programs that examine the entire testing process encompassing the preanalytic, analytic, and postanalytic phases. Laboratories should regularly review information on the development of additional proficiency testing programs and ensure participation as new programs become available. • Test analyte-specific or disease-specific proficiency testing challenges with the laboratory's regular patient testing workload by personnel who routinely perform the tests in the laboratory, as required by CLIA for analytes and specialties specified in the regulation. • When possible, laboratories performing quantitative assays should enroll in proficiency testing programs that provide feedback for specific analyte values. Qualitative proficiency testing is appropriate for tests for which quantitative technology is lacking and for certain tests, such as enzyme assays that lack consensus quantitative measurements. • Evaluate proficiency testing results reported by the proficiency testing program and take steps to investigate the causes for disparate results, including results that might indicate bias but are within acceptable ranges. The corrective actions to be taken after disparate proficiency testing results might include reevaluation of previous patient test results and, if possible, of retained patient specimens that were previously tested, depending on the cause identified for the disparate results. # Newborn Screening The following recommendations are for laboratories that perform newborn screening to assess test performance: • Participate in the NSQAP and adhere to the program directions. Participation in other proficiency testing programs for monitoring test performance is encouraged. • Include cutoff values for all analytes when reporting proficiency test results to NSQAP so that the specific cutoffs can be taken into account in the NSQAP grading algorithm to facilitate the evaluation of the laboratory results (30,113). # Implications for Proficiency Testing and Interlaboratory Comparison Programs Proficiency testing and interlaboratory comparison programs should consider the need for external quality assessment for all testing for inherited metabolic diseases in improving program availability and result evaluation. To the extent possible, proficiency testing should be available for each analyte at least twice per year. Comprehensive proficiency testing programs (e.g., NSQAP) are needed that examine the entire testing process (which consists of the preanalytic, analytic, and postanalytic phases) and are able to assess both the quantitative and qualitative test methods. Although practical and technical challenges might limit the ability of proficiency testing programs to address all testing phases for each analyte, comprehensive programs for core tests (e.g., amino acid and organic acid analyses) that combine the strengths of existing programs should be pursued (8,24). When possible, proficiency testing samples should simulate patient specimens; at a minimum, samples simulating patient specimens should be used for proficiency testing for the most common genetic tests. If residual patient samples are used in proficiency testing or interlaboratory comparisons, any required consent issues and deidentification procedures should be addressed according to federal, state, and local requirements and guidance. # Alternative Performance Assessment Organized proficiency testing programs do not exist for many tests performed for inherited metabolic diseases, including biochemical genetic tests and, occasionally, new tests for newborn screening. Alternative performance assessment must be performed at least twice per year for each test for which no proficiency testing program is available and for tests for which CLIA regulations do not specify proficiency testing requirements. Laboratories should implement the following practices for alternative performance assessment: • Although data on the effectiveness of alternative performance assessments compared with proficiency testing are unavailable, laboratories should follow professional guidelines, such as those developed by CLSI (26) and CAP (82), that provide guidance on acceptable alternative performance assessment approaches. • Alternative assessment ideally should be performed by interlaboratory exchange or using externally derived materials. • For circumstances in which interlaboratory exchange or externally derived materials are not practical or feasible, such as testing for rare diseases, testing performed by only one laboratory, or analysis of unstable analytes (e.g. enzymes), laboratories may consider options such as repeat testing of blinded samples, possible exchange with either a research facility or international laboratory, or interlaboratory data comparison. • Newborn screening laboratories that consider testing for new disorders not covered by the CDC NSQAP should make the program aware of their plans to facilitate the availability of the needed proficiency testing. # Evaluation of External Quality Assessment Performance Laboratories should document and track their performance in proficiency testing and alternative performance assessment. Quality improvement assessment should be performed periodically to evaluate performance and ensure adequate investigation of failures or concerns, implementation of corrective actions, and documentation of outcomes. Additional guidance for using proficiency testing as a quality improvement tool is available in professional guidelines (26). Various resources for proficiency testing and external quality assessment and for facilitating interlaboratory sample exchanges are available to help laboratories consider approaches to meeting the proficiency testing and alternative performance assessment needs (Appendix C). # Postanalytic Testing Phase Test Reports Test reports must comply with the CLIA general test report requirements (42 CFR §493.1291) and should include the recommended additional information that follows to ensure accurate understanding and interpretation of test results. CLIA requires that test reports for nonwaived testing include the following information: • Patient name and identification number or a unique patient identifier and identification number • Name and address of the laboratory where the test was performed • Test report date • Test performed • Specimen source (when appropriate) • Test result and (if applicable) units of measurement or interpretation • Information regarding the condition and disposition of specimens that did not meet laboratory criteria for acceptability (13) For laboratory-developed tests using analyte-specific reagents, test reports must include the following statement: "This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration" (21 CFR 809.30[e]) (75). # Biochemical Genetic Test Reports Biochemical genetic test reports should include the following more specific information to ensure accurate results interpretation, patient management, and the ordering of any needed additional tests by persons receiving or using the test results: • Patient's name and any other necessary unique identifiers • Patient's date of birth • The reason for testing that was provided on the test requisition and is needed for results interpretation • The date and time of specimen collection and receipt by the testing laboratory, which should be distinguished, when possible, from the date and time when the test request was made and, for test referrals, the date and time when the specimen was received by the referral laboratory, or a specific indication that the "specimen collection date and/or time are unknown" if such information is not provided • Name of the referring clinician or other authorized person who ordered the test • When appropriate, an interpretive guide (e.g., a table or reference to literature or a website) to aid in interpretation of results • Analytes tested, type of test method, or both • The reference intervals or normal range appropriate for the patient (based on sex, age, and population as appropriate), other performance specifications needed for results interpretation (e.g., accuracy, LOD, LOQ, or analytic specificity), and limitations of the test (e.g., a statement on the intended use and the technical limitation of the test method) that affect the understanding and clinical use of the test results • Test results in appropriate measurement units and current recommended standard nomenclature, including clarifications and commonly used terms if different from those currently recommended • Interpretation of results for complex tests, profiles, testing for carrier status, and testing that involves response to challenges or multiple samples over time; should be linked to the reasons for testing and communicated in a timely and clinically relevant manner • Test results in reference to information on family members (e.g., information regarding abnormalities previously detected in a relative used for the selection of the test method) when appropriate and necessary to ensure appropriate interpretation of the test results and understanding of their implications • The name of the laboratory personnel providing the interpretation • Notation to indicate whether report is preliminary, final, amended, or corrected • If applicable, an indication that other biochemical genetic tests have been performed for the patient, or, when available, results of other relevant tests that the laboratory performed for the patient • When appropriate, recommendations for additional testing of patient or for family members • References to the literature, if applicable • Recommendation for consultation with a genetics professional, when appropriate and indicated, that encompasses genetic counseling provided by trained, qualified genetic professionals such as genetic counselors, clinical geneticists, or other qualified professionals, to health-care providers, patients, or family members at risk for the conditions and also can be an educational initiative to improve understanding of genetic tests in the medical community • The date and, when appropriate, time the test report is released Laboratories should assess the needs of laboratory users when determining the media, format, style, and language of biochemical genetic test reports. To the extent possible, the terminology and nomenclature should be understandable by health-care professionals who are not geneticists or experts in the specific field. This practice should be part of the laboratory quality management policies. Test reports should include all necessary information, be easy to understand, and be structured in a way that encourages users to read the entire report, rather than just a positive or negative indication. Following the format recommended in accepted practice guidelines should help ensure that the reports are structured effectively (18). # Newborn Screening Test Reports Newborn screening test reports must comply with the CLIA general test report requirements (42 CFR §493.1291) and applicable state requirements. Results should be reported in a way that is consistent with the urgency of any needed intervention. For a screening result that is outside the expected range of normal test results established for a particular condition (i.e., out-of-range result) or indicates problems with the specimen or the testing process that might compromise the quality of test results according to established criteria (i.e., invalid screen), the following information should be communicated to the newborn's primary care provider without delay: • The newborn's identifying information (name, date of birth, and time of birth), place of birth, and national or local health number • Parent information (mother's name, home telephone number, and address if available) • The date and time of specimen collection and arrival in the laboratory • Analytes evaluated and type of test method, or whichever is appropriate • Screening test results in appropriate measurement units • The normal range and cutoff values appropriate for the newborn's conditions, including gestational age, birth weight, and health or disease status • Notation of whether the results are out-of-range or invalid • Required actions, including a repeat screen, confirmatory testing, clinical actions, and evaluation, as well as the timeline, steps, and instructions to complete the necessary actions • Instructions to notify the newborn screening program when the primary care provider has been unable to contact the parents or when the primary care provider has changed • Contact information (e.g., name, phone number, e-mail address, and fax number) for the follow-up personnel of the newborn screening program • The date and time the test results are reported • For all out-of-range results, the following information should be provided to the newborn's primary care provider: -Pediatric subspecialists resource information (including telephone numbers) for consultation or referral -Information about the suspected diagnosis (disease or condition) and consequences if untreated -Reporting requirements to the newborn screening program, including confirmatory test results, treatment date, and other information on the newborn's health outcome For all out-of-range or invalid results, the laboratory should take actions that lead to timely additional testing and evaluation for the infant and allow the newborn screening program to evaluate the effectiveness of screening. Follow-up should occur without delay to enable timely intervention. For results requiring urgent actions, laboratories should first notify both the primary health-care provider and the designated specialist by telephone and then by paper or electronic notification. Laboratories should monitor the development and application of guidelines and recommendations that address electronic reporting of newborn screening results, such as the HRSA/NLM guidance for sending electronic newborn screening results with Health Level Seven International (HL7) messaging ( 37) and the HL7 implementation guide developed by the Public Health Informatics Institute (40). When implementing the electronic reporting mechanisms, laboratories should ensure that the information systems accommodate the inclusion and delivery of the test report elements that are recommended in this report. Laboratories also should develop quality assurance procedures for the electronic reporting systems used. # Retention of Records, Reports, and Tested Specimens # Records CLIA requires laboratories to retain records of patient testing, including test requests and authorizations, test procedures, analytic systems records, records of test system performance specifications, proficiency testing records, and quality system assessment records, for a minimum of 2 years (42 CFR §493.1105) (13). These requirements apply to testing for inherited metabolic diseases. Retention policies and procedures also must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited). Laboratories may retain records for longer periods for quality management purposes and should consider the following recommendations when establishing record retention policies: • Primary data from which reports are generated should be kept along with the reports, preferably electronically. • Records of tests that generated normal results also should be retained. • Laboratories should ensure that electronic records are accessible as electronic storage technology continues to evolve. # Reports CLIA requires laboratories to retain or have the ability to retrieve a copy of an original test report (including final, preliminary, and corrected reports) for at least 2 years after the date of reporting and to retain pathology test reports for at least 10 years after the date of reporting (42 CFR §493.1105) (13). Biochemical genetic test reports that indicate genotypic information for the disease or condition should be retained for at least 21 years after the date of reporting. This retention period is recommended as an acceptable length of time of one biological generation that is necessary to provide useful continuity of clinical history for patient management and diagnosis or treatment of family members. The laboratory policies and procedures for test report retention also must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited) and should follow practice guidelines developed by recognized professional or standard-setting organizations. If state regulations require retention of biochemical genetic test reports for >21 years after the date of results reporting, laboratories must comply. Laboratories also might decide that retaining reports for >21 years is necessary for biochemical genetic test reports to accommodate patient testing needs and ongoing quality assessment activities. Because test reports may be retained using electronic methods, laboratories are encouraged to consider technology availability in addition to space and financial issues when determining solutions to test report retention. The retention period for newborn screening test reports must be in compliance with CLIA and applicable state requirements. Certain states require different retention periods for newborn screening test reports depending on the results. # Tested Specimens CLIA requires laboratories to establish and follow written policies and procedures that ensure positive identification and optimum integrity of patient specimens from the time of collection or receipt in the laboratory through completion of testing and reporting of test results (42 CFR §493.1232) (13). Depending on sample stability and integrity, technology, space, and cost, tested specimens for biochemical genetic testing should be retained as long as possible after the completion of testing and reporting of results. Patient specimens should be retained until after the final reporting of results for quality assurance and any need for additional testing of the same specimen, with adequate provisions for specimen stability. When possible, tested specimens may be retained until the next proficiency testing or the next alternative performance assessment to allow for identification of problems in patient testing and for corrective action to be taken. Laboratories also may retain tested specimens for a longer period or indefinitely for quality assurance and educational purposes (e.g., tested specimens from abnormal cases). The laboratory director is responsible for ensuring that the laboratory policies and procedures for specimen retention comply with applicable federal, state, and local requirements (including laboratory accreditation requirements, if applicable) and are consistent with the laboratory quality assurance and quality assessment activities. In circumstances in which required patient consent is not provided with the test request, the laboratory should notify the test requestor and determine the period after which the test request might be rejected and the specimen discarded because of specimen degradation or deterioration. Laboratory specimen retention procedures should be consistent with patient decisions. The retention of residual newborn screening specimens is subject to federal, state, and local requirements. Residual specimens are valuable for the laboratory's ongoing quality assurance, quality assessment, and personnel competency assessment activities. Certain states have established policies under state law to retain residual dried blood spot specimens without personal identifiers for public health and research uses after newborn screening testing is completed and to allow parents to request that their children's residual specimens be destroyed after newborn screening tests are completed (107). # Postanalytic Systems Assessment The CLIA postanalytic systems assessment requirements apply to testing for inherited metabolic diseases. Quality assessment of the postanalytic system generally includes the following: • Practices and other issues related to test reports: assessing, monitoring, and evaluating the accuracy and completeness of the laboratory's test reports (e.g., patient information, test results, reference ranges, and the disposition of unacceptable specimens) • The time required by the laboratory to complete testing and report test results • Procedures for notifying the test requestor about the test results, including routine tests, urgent testing, abnormal results, and critical values or alert values that warrant immediate medical attention • If the laboratory uses an electronic information system, a mechanism to periodically verify the accuracy of data and calculations, the results transmitted to interfaced systems, and patient-specific information • The record retention procedures and practices of the laboratory • The specimen retention policies and procedures of the laboratory # Biochemical Genetic Testing Laboratories that perform biochemical genetic testing should have procedures in place to address the following postanalytic or interpretive issues, which often are unique to biochemical genetic testing: • When diagnostic testing shows an abnormality, testing of other analytes might be critical to clarify the diagnosis (e.g., elevated methylmalonic acid suggesting that testing of homocysteine level is needed). • Reflex testing (i.e., follow-up testing that is automatically initiated when certain test results are observed in the laboratory) might be needed when useful and appropriate to clarify or expand primary or initial test results. • Testing by another method or with another tissue type might clarify or confirm the diagnosis for more effective clinical management of the patient or the patient's family. • Additional specimens might be needed when testing unstable analytes to verify that the initial specimen quality was not compromised. In addition, the laboratory should have a system in place to facilitate the consideration of the preanalytic information needed for adequate interpretation of test results and the inclusion of such information on the test report. For example, circumstances when more than one biochemical genetic test has been requested on a patient should be recognized and noted in test reports. Specimen collection time often is critical for accurate interpretation of test results, particularly for conditions such as intermittent maple syrup urine disease that present normal analyte (e.g., amino acids) levels during asymptomatic intervals. Inclusion of the reasons for testing in test reports, even though the specific reasons for a test might not always be provided with the test requisition, is helpful for the users of test results because test reports might be sent to health-care providers different from the test requestors. The laboratory's policies and procedures for postanalytic systems assessment should address monitoring of these recommended practices and assessment of their effectiveness. # Newborn Screening Newborn screening laboratories should have policies and procedures for postanalytic systems assessment that address all postanalytic laboratory practices in newborn screening. In particular, an ongoing review process should be in place to monitor and assess the effectiveness of the following procedures: • Procedures for immediate reporting of results that are considered out of range or are indicative of a clinical emergency, including notification of the newborn's primary care provider and documentation of the reporting and report receipt • Procedures for obtaining a second, freshly collected specimen for confirmatory analysis for each abnormal screening result • Immediate reporting of unsuitable specimens to facilitate timely repeat testing • Laboratory responsibilities in the comprehensive system for follow-up of each positive screening result, including facilitating the reporting of the medical care decisions and actions to the newborn screening program by specifying the reporting requirements in test reports # Ensuring Confidentiality of Patient Information CLIA requires laboratories to ensure the confidentiality of patient information throughout all phases of the testing process that are under laboratory control (42 CFR §493.1231) (13). Laboratories should follow more specific requirements and comply with additional guidelines (e.g., the Health Insurance Portability and Accountability Act of 1996 [HIPAA] privacy rule [114], state requirements, accreditation standards, and professional guidelines) to establish procedures to protect the confidentiality of patient information, including information related to genetic testing. Laboratories that perform testing for inherited metabolic diseases should establish and follow procedures that include defined responsibilities of all employees to ensure appropriate access, documentation, storage, release, and transfer of confidential information and prohibit unauthorized or unnecessary access or disclosure. # Information Regarding Family Members In certain circumstances, information about family members is needed for selection of test methods and test performance or should be included in test reports to ensure appropriate interpretation of test results. Therefore, laboratories must have procedures and systems to ensure confidentiality of all patient information, including that of family members, in all testing procedures and reports in compliance with CLIA requirements and other applicable federal, state, and local regulations. # Requests for Test Results to Assist with Health Care for a Family Member When a health-care provider requests the genetic test information of a patient to assist with providing care for a family member of the patient, the following practices are recommended: • Requests should be handled following established laboratory procedures regarding release and transfer of confidential patient information. • Laboratories may release patient test information only to the authorized person ordering the test, the persons responsible for using the test results (e.g., health-care providers of the patient designated by the authorized person to receive test results), and the laboratory that initially requested the test. If a health-care provider who provides care for a family member of the patient is authorized to request the patient's test information, the laboratory should request the patient's authorization before releasing the genetic test results to the health-care provider. • When patient consent is required for testing, the consent form should include the laboratory confidentiality policies and procedures and should describe situations in which test results might be requested by health-care providers caring for family members of the patient. • Laboratory directors are responsible for determining and approving circumstances in which access to confidential patient information is appropriate, including when, how, and to whom information is to be released, in compliance with federal, state, and local requirements. The HIPAA privacy rule and CLIA regulations are federal regulations intended to provide minimum standards for ensuring confidentiality of patient information; states or localities might have more restrictive standards. Although the HIPAA privacy rule allows health-care providers that are covered entities (i.e., health-care providers that conduct certain transactions in electronic form, health-care clearinghouses, and health plans) to use or disclose protected health information for treatment purposes without patient authorization and to share protected health information to consult with other providers to treat a different patient or to refer a patient, the regulation indicates that states or institutions may implement stricter standards to protect the privacy of patients and the confidentiality of patient information (115). Laboratories must comply with applicable requirements and follow professional practice guidelines in establishing policies and procedures to ensure confidentiality of patient information, including information and test results on biochemical genetic testing and newborn screening. # Personnel Qualifications, Responsibilities, and Competency Assessments Laboratory Director Qualifications and Responsibilities Qualifications CLIA requires directors of laboratories that perform highcomplexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1443) ( 13): • Be a doctor of medicine or a doctor of osteopathy and have board certification in anatomic or clinical pathology or both • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have at least 1 year of laboratory training during residency or at least 2 years of experience directing or supervising high-complexity testing • Have an earned doctoral degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution and current certification by a board approved by HHS (116) Directors of laboratories that perform testing for inherited metabolic diseases must meet these qualification requirements. Because CLIA requirements are minimum qualifications, laboratories that perform testing for inherited metabolic diseases should evaluate the tests they perform to determine whether additional knowledge, training, or expertise is necessary to fulfill the responsibilities of laboratory director. # Responsibilities CLIA requires directors of laboratories that perform highcomplexity testing to be responsible for the overall operation and administration of the laboratory, which includes responsibility for the following (42 CFR §493.1445): • Ensuring the quality of all aspects of test performance and results reporting for each test performed in the laboratory • Ensuring that the physical and environmental conditions of the laboratory are appropriate and safe • Ensuring enrollment in HHS-approved proficiency testing programs • Employing a sufficient number of laboratory personnel with appropriate education, experience, training, and competency required for patient testing • Establishing policies and procedures for personnel competency assessment and monitoring • Specifying the responsibilities and duties of each consultant, supervisor, and testing employee • Ensuring compliance with applicable requirements and regulations Directors of laboratories that perform testing for inherited metabolic diseases must fulfill these CLIA responsibility requirements. In addition, laboratory directors should have responsibility for the following: • Ensuring documentation of the clinical validity of any biochemical genetic or newborn screening test the laboratory performs, following the recommended practices in this report • Determining specific policies and procedures for assessing and ensuring the competency of all laboratory personnel, including technical supervisors, clinical consultants, general supervisors, and testing personnel # Technical Supervisor Qualifications and Responsibilities Qualifications CLIA regulations set forth minimum qualifications of technical supervisors for high-complexity testing in chemistry, clinical cytogenetics, and other specialties and subspecialties but do not specify qualification requirements for technical supervisors for biochemical genetic testing or newborn screening. Because CLIA requirements are intended to be minimum standards, laboratory directors should assess the tests their laboratories perform to determine whether additional qualifications are necessary for the technical supervisors to ensure quality throughout the testing process. Technical supervisors of testing for inherited metabolic diseases should have the qualifications that are appropriate for the section they are supervising, the types of testing performed, and the purpose for performing the testing. The recommended technical supervisor qualifications that follow are based on the complexity of testing for inherited metabolic diseases and the training, experience, and expertise required to provide technical supervision of laboratories performing these tests. These recommended qualifications are not regulatory requirements; rather, they should be considered part of recommended laboratory practices for ensuring the quality of testing for inherited metabolic diseases. Biochemical genetic testing. Technical supervisors of laboratories that perform biochemical genetic testing should have either one of the following sets of qualifications: • # Clinical Consultant Qualifications and Responsibilities Qualifications CLIA requires clinical consultants for high-complexity testing to have either one of the following sets of qualifications (42 CFR §493.1455) ( 13): • Be qualified as a laboratory director for high-complexity testing as specified in the regulations • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine licensed to practice medicine, osteopathy, or podiatry in the state in which the laboratory is located These CLIA requirements provide minimum qualifications required for persons who provide clinical consultations for high-complexity testing. For laboratory testing for inherited metabolic diseases, clinical consultants should also have relevant training or experience in the testing for which they provide clinical consultation. Biochemical genetic testing. Clinical consultants for biochemical genetic testing should have any one of the following additional sets of qualifications, which are more specific than those required by CLIA: • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and be either board-certified or boardeligible in clinical genetics or clinical biochemical genetics • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have 2 years of experience in biochemical genetic testing, diagnosis and management of inborn errors of metabolism, or both • Have an earned doctoral degree in a relevant discipline, be currently certified by a board approved by HHS, and have 2 years of training or experience in biochemical genetic testing # Responsibilities CLIA regulations require clinical consultants for highcomplexity testing to be responsible for providing consultation to laboratory clients regarding the appropriateness of the testing ordered and the interpretation of test results (42 CFR §493.1457) (13). Persons providing clinical consultations for testing for inherited metabolic diseases must meet the following CLIA responsibility requirements for clinical consultants for high-complexity testing: • Be available to provide consultation to laboratory clients, including assisting them with ordering appropriate tests to meet clinical expectations and discussing the quality and interpretation of test results • Ensure that test reports include pertinent information required for interpretation of specific patient conditions # General Supervisor Qualifications and Responsibilities Qualifications CLIA requires general supervisors of laboratories that perform high-complexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1461) ( 13): • # Responsibilities CLIA regulations require general supervisors for highcomplexity testing to be responsible for day-to-day supervision or oversight of the laboratory operation and personnel performing testing and reporting test results (42 CFR §493.1463) (13). General supervisors of laboratories that perform testing for inherited metabolic diseases must meet the following CLIA responsibility requirements for general supervisors for high-complexity testing: • Be accessible to testing personnel at all times testing is performed • Provide day-to-day supervision and direct supervision of all testing personnel • Monitor testing procedures to ensure the quality of analytical performance • Fulfill the following duties when delegated by the laboratory director or technical supervisor: -Ensure that remedial actions are taken when test systems deviate from the established performance specifications. -Ensure that patient test results are not reported until all corrective actions have been taken and the test system is functioning properly. -Provide orientation for all testing personnel. -Annually evaluate and document the competency of all testing personnel to perform authorized testing. # Testing Personnel Qualifications and Responsibilities Qualifications CLIA requires testing personnel who perform highcomplexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1489) ( 13): • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine • Have an earned doctoral, master's, or bachelor's degree in a chemical, physical, biological, or clinical laboratory science or medical technology from an accredited institution • Have an earned associate's degree in a laboratory science or medical laboratory technology from an accredited institution Biochemical genetic testing. These CLIA qualification requirements apply to testing personnel who perform biochemical genetic testing. Laboratories should ensure that testing personnel have received adequate training, including on-the-job training, and demonstrate competency in highcomplexity biochemical genetic testing before performing patient testing. Newborn screening. Testing personnel who perform public health newborn screening must meet the CLIA qualification requirements for testing personnel for high-complexity testing and should also meet any additional state or local qualification requirement that might be more stringent than the CLIA requirements. # Responsibilities CLIA requires persons who perform high-complexity testing to follow laboratory procedures for test performance, quality control, results reporting, documentation, and problem identification and correction (42 CFR §493.1495) (13). Personnel who perform biochemical genetic testing or newborn screening must meet these requirements. # Personnel Competency Assessment CLIA requires laboratories to establish and follow written policies and procedures to assess employee competency, and if applicable, consultant competency (42 CFR §493.1235) (13). CLIA requirements for laboratory director responsibilities (42 CFR §493.1445[e] [13]) specify that laboratory directors must ensure that policies and procedures are established for monitoring and ensuring the competency of testing personnel and for identifying needs for remedial training or continuing education to improve knowledge and skills. Technical supervisors are responsible for implementing the personnel competency assessment policies and procedures, including evaluating and ensuring competency of testing personnel (42 CFR §493.1451[b] [8]) (13). Laboratories that perform testing for inherited metabolic diseases must meet these general personnel competency assessment requirements because regular competency assessment is an important element of ensuring all personnel are capable of performing their duties appropriately. Laboratories also should follow the applicable CMS guidelines to establish and implement policies and procedures specific for assessing and ensuring the competency of all types of laboratory personnel, including technical supervisors, clinical consultants, general supervisors, and testing personnel, in performing duties and responsibilities (74). For example, the performance of testing personnel must be evaluated and documented at least semiannually during the first year a person tests patient specimens. Thereafter, evaluations must be performed at least annually; however, if test methods or instrumentation changes, performance must be reevaluated to include the use of the new test methods or instrumentation before testing personnel can report patient test results. Personnel competency assessments should identify training needs and ensure that persons responsible for test performance receive regular in-service training and education appropriate for the services performed (74). # Conclusion The recommendations in this report are intended to provide laboratory professionals and others with information to ensure and improve the quality of laboratory testing performed for screening, detection, diagnosis, monitoring, and clinical management of persons with inherited metabolic diseases. Although the recommended practices are primarily intended for laboratories performing biochemical genetic testing and newborn screening, many recommendations reflect general good laboratory practices for ensuring the quality of laboratory services. Recommendations beyond the CLIA requirements are included as guidelines rather than requirements; therefore, general laboratories may also implement these recommendations, when appropriate, to improve testing quality. # Usefulness for Users of Laboratory Services These recommendations serve as a resource for health-care professionals and other users of laboratory services to improve the delivery and usefulness of biochemical genetic and newborn screening test results in clinical and public health practices. In particular, these recommendations inform users of laboratory services about the responsibilities and practices to be expected of laboratories when providing biochemical genetic test results and newborn screening services. An understanding of these recommendations by users of laboratory services might prevent or reduce errors or problems relating to test selection, specimen submission, test performance, and reporting and interpretation of results. These practices should lead to improved use of biochemical genetic tests and better collaboration and follow-up to newborn screening, resulting in better health outcomes for patients and their families. # Usefulness for Evaluators of Laboratory Practices These recommendations also are a resource for medical and public health professionals, including laboratory inspectors and surveyors, payers, and persons who evaluate laboratory practices and policies to improve quality assurance procedures and quality systems. The recommendations are intended to clarify CLIA requirements that are applicable to biochemical genetic testing and newborn screening for inherited metabolic diseases, provide recommendations for additional quality assurance practices that are not specifically addressed by CLIA requirements, and facilitate assessment of laboratory practices, especially the specific recommended quality management practices in addition to CLIA regulations. # Usefulness for Development of Future Professional Guidelines and Accreditation Standards The recommendations in this report were developed with consideration of existing relevant regulatory requirements (both federal and state), accreditation standards, professional guidelines, and other standards. These CDC recommendations are expected to help address quality assurance concerns in laboratory practices and clarify or provide guidance for areas and issues that are inconsistent among existing standards. These recommendations also can serve as a resource for accrediting agencies that are evaluating whether laboratories are performing properly and adhering to established requirements, standards, and recommendations. In addition, these recommendations can be updated in future documents to reflect changes in laboratory testing for inherited metabolic diseases, such as new technologies or practices that might be adopted in the future. # Usefulness for Development and Use of Standards for Electronic Communication in Clinical and Public Health Practice The recommendations in this report should be considered in the development of information technology systems to be used for biochemical genetic testing or newborn screening to ensure that they accommodate the nationally recommended laboratory practices. For example, the health information technology standards for newborn screening results reporting, created collaboratively by many federal agencies, advisory groups, and the newborn screening system vendors, are directly relevant to laboratory practices for newborn screening, particularly in the preanalytic and postanalytic phases of the testing process (36)(37)(38)40). Consistently following the CDC recommendations can help expedite the delivery of newborn screening results and provide the data needed to manage and improve the newborn screening process. # Usefulness for In Vitro Diagnostic Manufacturers The recommendations in this report focus on parameters important in the development and application of biochemical genetic and newborn screening tests, including introduction of new tests for patient testing, analytic and clinical validity, quality control, proficiency testing, and communication of test results to health-care providers and other users. Some of these parameters are already considered in the FDA review process for test systems, control materials, and other in vitro diagnostic products used in performing biochemical genetic or newborn screening tests. Therefore, an understanding of the recommendations in this report can assist in vitro diagnostic manufacturers in providing products in accordance with recommended good laboratory practices. # Usefulness for Patients and Families Knowledge of these CDC recommendations might also help patients and their families to understand the test information that should be provided and the responsibilities of the laboratory. For example, understanding that laboratories must maintain the confidentiality of information regarding patients and their family members should facilitate the ability of patients and families to make informed decisions. In addition, knowledge of the recommended laboratory practices for retention of records, reports, and tested specimens should also be helpful for patients and families. # cut-off value Quantitative value of the analyte that is used as the decision point between a positive and a negative result drift A slow or systematic change of a metrological characteristic of a measuring instrument or system, such as accuracy, trueness, and precision genetics The study of inheritance patterns of specific traits genome The complete genetic content of an organism genotype The genetic makeup of an organism or group of organisms with reference to a single trait, set of traits, or an entire complex of traits Health Level Seven International (HL7) A standards-development organization that has produced international standards for electronic reporting of laboratory results and orders in-range result Newborn screening result that is within the expected range of normal or negative test results established for a particular condition informed consent A process by which persons voluntarily confirm their willingness to participate in a particular testing act after having been informed of all aspects of the act that are relevant to the decision to participate in the act internal control material A control material that is placed in the same reaction tube as the specimen being analyzed and therefore is subjected to exactly the same internal conditions and external parameters as any analyte present in the tube # International Classification of Diseases (ICD) The international standard diagnostic classification for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, as maintained by the World Health Organization limit of detection (LOD) The lowest amount of analyte in a sample that can be detected (with stated probability), although the amount might not be quantified as an exact value limit of quantitation (LOQ) The lowest concentration at which an analyte can be quantitatively determined with stated acceptable precision and trueness under stated experimental conditions; might be equal to the limit of detection or could be at a higher concentration measurand Quantity to be measured newborn screening A system that identifies, shortly after birth, infants who are at increased risk for genetic and other congenital conditions so that treatment can begin as soon as possible; need to confirm positive newborn screening results with additional diagnostic testing nonwaived testing Test systems, assays, or examinations that have not been determined to be waived testing. Nonwaived testing encompasses moderate-and high-complexity testing for which CLIA regulations provide requirements for laboratory certification, quality systems, performance assessment, and laboratory personnel out-of-range result Newborn screening result that is outside the expected range of normal or negative test results established for a particular condition, including carrier results and any need for additional testing phenotype The observed biochemical, physiological, and morphological characteristics of an individual as determined by the genotype and the environment in which the genotype is expressed; also, in a more limited sense, the expression of a particular gene or genes precision Closeness of agreement between independent test results from the same sample obtained under stipulated conditions, often determined by assessing repeatability and reproducibility proficiency testing A program in which multiple samples are periodically sent to members of a group of laboratories for analysis or identification (or both) in which each laboratory's results are compared with those of other laboratories in the group or with an assigned value (or both) and are reported to the participating laboratory and others repeatability Closeness of agreement between independent test results for the same measurand under the same conditions reproducibility Closeness of agreement between independent test results for the same measurand under changed conditions qualitative test A characterization applied to laboratory tests that detect or identify a particular analyte, constituent, or condition quality assessment A group of activities to monitor and evaluate the total testing process to help ensure that test results are reliable, improve the testing process, and promote good quality testing practices quality control Operational techniques and activities that are used to fulfill requirements for quality; the procedures used to detect and correct errors that occur due to test system failure, adverse environmental conditions, and variance in operator performance, as well as the monitoring of the accuracy and precision of the test performance over time quality management system (QMS) Coordinated activities to direct and control an organization with regard to quality quantitative test A characterization applied to laboratory tests that provide results expressed in a numerical amount or level (concentration) of an analyte in a sample or specimen reagent A substance that produces a chemical or biological reaction with a patient specimen that allows detection or measurement of the analyte for which the test is designed reference interval The range of test values expected for a designated population of persons (e.g., 95% of persons that are presumed to be healthy [or normal]) reference material Material sufficiently homogeneous and stable with respect to one or more specified properties (quantitative or qualitative) that has been established to be fit for its intended use in a measurement process; might be used to calibrate a measurement system, to assess a measurement procedure, to assign values to other materials, and for quality control; can only be used for a single purpose in a given measurement reportable range of test results The span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response total testing process Series of activities or path of workflow for performing testing that can be divided into three major phases: preanalytic, analytic, and postanalytic trueness Closeness of agreement between the average of an infinite number of replicate-measured quantity values and a reference quantity value waived test A test system, an assay, or an examination that has been found to meet the statutory criteria specified in the Public Health Service Act ( §353[d] [3]) (12) # Acknowledgments	None	None
e7650d69a77c55f119c89b2d44e159db3a9ac298	cdc	None	# Jit # RESOURCES O- # RESOURCES O- What Is Safe Routes to School? - ----------------------------o This inventory contains information and hyperlinks to the corresponding curriculum summary provided later in this guide. # Skills Based Education # Type of Instruction W hen using this tool in electronic form, you can easily navigate between the inventory and the summaries by clicking on their hyperlinks in the inventory and the simple "Return to Inventory" button located at the bottom of each summary page.. An excel database of this information is available here. The curricula included in this inventory were compiled and reported by the curriculum owner. If you do not see your curriculum included, you can submit it for future inclusion by filling out this form. # Pedestrian Only Child ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- -------------------------------------------------------------------------------o ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------- --------------------------------------------------------------------- --------------------------------------------------------------------- #--------------------------------------------------------------------o Safe Routes to School Alameda C o u n ty ................... 80 --------------------------------------------------------------------- ---------------------------------------------------------------------o - --------------------------------------------------------------------- While preferably used in conjunction with the train-thetrainer course, the ETSEG can be purchased online. Parties interested in thetrain-the-trainer model can be trained in Florida and receive the companion teacher's guide that contains a thorough safety curriculum that is researchbased and classroom tested. The Elementary Traffic Safety Education Guide includes pedestrian/school bus safety and bicycle safety lessons, designed for 30 and 45 minute increments respectively. These include videos (DVD format), detailed activity sheets to accompany each lesson and suggestions for optional video (DVD selections and ordering information. #--------------------------------------------------------------------o #------------------------------------------------------------------------------------------------o # City of Madison -Traffic Engineering #--------------------------------------------------------------------o #--------------------------------------------------------------------o Additional components include a section for student activities, enrichment activities and a guide to adapt the modules for special needs students. The Elementary Traffic Safety Education Guide is an in-depth resource that offers a step-by-step approach to implementing an appropriate and economical pedestrian and bicycle safety education program. # Example of Success Story: The Florida Traffic and Bicycle Safety Education Program has been utilized in schools in Florida and has served as a starting point for bicycle and pedestrian curricula that have been developed across the country. Challenges: Requires a fleet of bicycles and access to the classroom as well as dedicated funding to ensure ongoing training o f teachers. # Example of Success Story: The Chicago Public School system, after carefully evaluating the pedestrian and school bus safety kit, decided to implement the program in approximately 250 Head Start programs Child Safety Solutions is currently working with the administration to monitor program implementation and results to confirm the program's effectiveness in addressing mandated Head Start pedestrian and school bus safety requirements. # Challenges: The challenge is to provide teachers with a low-cost, comprehensive teaching package that uses a growth and developmental^ appropriate teaching approach and can be successfully delivered with a minimum level o f additional training and preparation. Another challenge is to provide teachers with a flexible teaching approach that can be used to implement the program to address Head Start certification requirements. The program features a large black, plastic roadway used to practice crossing the street under different circumstances. For 1 st grade students, emphasis is made on crossing with an adult. # Contact for # Example of Success Story: The PATH Ped Ed program has reached more than 3,000 students since restarting in March o f 2009, and more than 22 people have been trained on its implementation. 100% o f teachers have requested the program's return through satisfaction surveys. # Challenges: The program does require a trained instructor and specifically manufactured equipment to deliver a consistent and accurate message. The biggest challenge is finding funding for the program. Often up to six classes will be scheduled per day, over three to five days to reach all grades. # Contact for # O ther Instructional Content: None Requires Equipment: Yes. Requires a custom designed "roadway", vocabulary flash cards, safety rhyme poster, coloring handouts and a take home letter to families are all available from PATH. Lessons focus on rules of the road, safe cycling skills and practices and how to improve walking and bicycling within their school vicinity. Also included are master pages in English and Spanish. The Cycling Across the Curriculum section enables math, science, English and arts teachers to introduce bicycle education into their educational activities. # Cost: Free # Meets Since 1998, the curriculum has been only available as a part of a certification process. More than 3,700 Texas teachers and youth community workers have been trained. In addition, trained college faculty has presented the material to more than 3,000 students studying to be physical education teachers. Based on past surveys o f trained teachers, we estimate more than 200,000 Texas students a year receive part o f the SafeCyclist bicycle safety lessons. # Walk Across Illinois -Afterschool Challenge Dan Persky, (312) 427-3325, educatio n@ active trans.org Creator: Active Transportation Alliance Program Summary: Walk Across Illinois Afterschool Challenge empowers supplemental learning providers with a standards-based, engaging and free curriculum to encourage physical activity and literacy growth for elementary school children.The program introduces students to athletes and other inspiring individuals who set goals to overcome their personal challenges, and then provides the experience o f the sports o f those athletes. In the body challenge activities, the students build their physical skills with a special emphasis on walking, bicycling and other forms of active transportation. Students in the program use a full range of sports to help students exceed national standards for physical activity. The brain challenge sessions focus on literacy development. Students read about the inspiring individuals and make text-to-life connections. They engage in small group and full-class activities that promote team building and problem solving. Walk Across Illinois Afterschool Challenge is designed for implementation in schools, recreation centers and other afterschool settings. The curriculum is easy-to-understand, and was created by a team o f classroom and physical education curriculum writers and consultants. # Example of Success Story: In the first fall semester of its release in 2010, the Afterschool Challenge was used by 660 children in Chicago. One afterschool program provider had the following to say about the program: "The children have enjoyed the activities so far. They have asked us when our next lesson plan is going to happen or what our next activity will be on. I've enjoyed using the Afterschool Challenge because it has made it easier to introduce activities to the children and be able to have their cooperation as well as their participation!"-One Hope United Challenges: One challenge that teachers have faced when using this curriculum has been learning how to fit this program into their schedules. Often after-school care providers only have an hour or two with the children, so they may have difficulty implementing an 80-hour program. # Subject: Bicycle and pedestrian Skill Based Education: Yes. In terms of bicycle and pedestrian safety, skill based education is included in the form o f simulated street crossing practice, simulated street bicycling skills and in-class bicycle and pedestrian safety role play. Grades: 3rd -4th (can be adapted for other grades) Type of Instruction: Teacher-led. This scripted curriculum is designed to guide teachers or afterschool providers through the lessons as they teach their students. Program Duration: 1-80 hours. There are 40 literacy based lessons and 40 physical activity based lessons to be used in whole over the course of a school year, or to be broken down into smaller units. Other Instructional Content: English and physical development. Requires Equipment: Yes. All equipment required for the Afterschool Challenge program can already typically be found in a classroom or PE class setting. A master list of required materials is provided within the program, and every lesson has a required materials section in order to help the educator prepare in advanced. However, the Afterschool Challenge is flexible enough to be used in most situations. Lessons use a spiraling approach but they also can be implemented as stand-alone activities or as a unit (seven units total in the program). Program staff members are also available to help instructors make necessary adaptations. The lessons encourage students to think about ways in which they, their families and their communities can help reduce traffic and associated air pollution through walking, bicycling and using public transportation. The lessons help students see that walking is a fun and easy form o f daily exercise that is good for their overall health. # Cost: Free Meets # Contact for The curriculum includes both in classroom and out-ofclass field activities, such as mapping routes from students' homes to their schools, creating a simple air pollution tester and measuring breathing and heart rates before and after physical activity. Many o f the lessons are ideal for collaborative efforts among classroom teachers, physical education teachers and computer lab instructors.The curriculum includes ten lessons for 3rd-5th grades and five lessons for kindergarten-2nd grades.The lessons have been reviewed by Massachusetts teachers and tested in classrooms with outstanding results. # Example of Success Story: Teachers have reported that the "lesson plans are age appropriate, very resourceful, easy to implement, and the students loved the lessons!" and that the activities have led children to have great discussions about walking and the environment. # Challenges: The lesson plans are ready to use "off the shelf" and do not require outside assistance or special equipment. # Subject: Pedestrian # Skill Based Education: No # Grades: K-5th Program Duration: 30 minutes to two hours variable in-class and outdoor time.	# Jit ---------------------------------- # RESOURCES O- ------------------------------------------------------- # RESOURCES O- ------------------------------------------------------------- o----------------------------------------------------------------------------- ---------------------------------------------------------------------------- --------------------------------------------------------- What Is Safe Routes to School? - ----------------------------o This inventory contains information and hyperlinks to the corresponding curriculum summary provided later in this guide. # Skills Based Education # Type of Instruction W hen using this tool in electronic form, you can easily navigate between the inventory and the summaries by clicking on their hyperlinks in the inventory and the simple "Return to Inventory" button located at the bottom of each summary page.. An excel database of this information is available here. The curricula included in this inventory were compiled and reported by the curriculum owner. If you do not see your curriculum included, you can submit it for future inclusion by filling out this form. # Pedestrian Only Child ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- -------------------------------------------------------------------------------o ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- ------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------- --------------------------------------------------------------------- --------------------------------------------------------------------- # ---------------------------------------------------------------------o Safe Routes to School Alameda C o u n ty ................... 80 --------------------------------------------------------------------- ---------------------------------------------------------------------o - --------------------------------------------------------------------- While preferably used in conjunction with the train-thetrainer course, the ETSEG can be purchased online. Parties interested in thetrain-the-trainer model can be trained in Florida and receive the companion teacher's guide that contains a thorough safety curriculum that is researchbased and classroom tested. The Elementary Traffic Safety Education Guide includes pedestrian/school bus safety and bicycle safety lessons, designed for 30 and 45 minute increments respectively. These include videos (DVD format), detailed activity sheets to accompany each lesson and suggestions for optional video (DVD selections and ordering information. # ---------------------------------------------------------------------o # -------------------------------------------------------------------------------------------------o # City of Madison -Traffic Engineering # ---------------------------------------------------------------------o # ---------------------------------------------------------------------o Additional components include a section for student activities, enrichment activities and a guide to adapt the modules for special needs students. The Elementary Traffic Safety Education Guide is an in-depth resource that offers a step-by-step approach to implementing an appropriate and economical pedestrian and bicycle safety education program. # Example of Success Story: The Florida Traffic and Bicycle Safety Education Program has been utilized in schools in Florida and has served as a starting point for bicycle and pedestrian curricula that have been developed across the country. Challenges: Requires a fleet of bicycles and access to the classroom as well as dedicated funding to ensure ongoing training o f teachers. # Example of Success Story: The Chicago Public School system, after carefully evaluating the pedestrian and school bus safety kit, decided to implement the program in approximately 250 Head Start programs Child Safety Solutions is currently working with the administration to monitor program implementation and results to confirm the program's effectiveness in addressing mandated Head Start pedestrian and school bus safety requirements. # Challenges: The challenge is to provide teachers with a low-cost, comprehensive teaching package that uses a growth and developmental^ appropriate teaching approach and can be successfully delivered with a minimum level o f additional training and preparation. Another challenge is to provide teachers with a flexible teaching approach that can be used to implement the program to address Head Start certification requirements. The program features a large black, plastic roadway used to practice crossing the street under different circumstances. For 1 st grade students, emphasis is made on crossing with an adult. # Contact for # Example of Success Story: The PATH Ped Ed program has reached more than 3,000 students since restarting in March o f 2009, and more than 22 people have been trained on its implementation. 100% o f teachers have requested the program's return through satisfaction surveys. # Challenges: The program does require a trained instructor and specifically manufactured equipment to deliver a consistent and accurate message. The biggest challenge is finding funding for the program. Often up to six classes will be scheduled per day, over three to five days to reach all grades. # Contact for # O ther Instructional Content: None Requires Equipment: Yes. Requires a custom designed "roadway", vocabulary flash cards, safety rhyme poster, coloring handouts and a take home letter to families are all available from PATH. Lessons focus on rules of the road, safe cycling skills and practices and how to improve walking and bicycling within their school vicinity. Also included are master pages in English and Spanish. The Cycling Across the Curriculum section enables math, science, English and arts teachers to introduce bicycle education into their educational activities. # Cost: Free # Meets Since 1998, the curriculum has been only available as a part of a certification process. More than 3,700 Texas teachers and youth community workers have been trained. In addition, trained college faculty has presented the material to more than 3,000 students studying to be physical education teachers. Based on past surveys o f trained teachers, we estimate more than 200,000 Texas students a year receive part o f the SafeCyclist bicycle safety lessons. # Walk Across Illinois -Afterschool Challenge Dan Persky, (312) 427-3325, educatio n@ active trans.org Creator: Active Transportation Alliance Program Summary: Walk Across Illinois Afterschool Challenge empowers supplemental learning providers with a standards-based, engaging and free curriculum to encourage physical activity and literacy growth for elementary school children.The program introduces students to athletes and other inspiring individuals who set goals to overcome their personal challenges, and then provides the experience o f the sports o f those athletes. In the body challenge activities, the students build their physical skills with a special emphasis on walking, bicycling and other forms of active transportation. Students in the program use a full range of sports to help students exceed national standards for physical activity. The brain challenge sessions focus on literacy development. Students read about the inspiring individuals and make text-to-life connections. They engage in small group and full-class activities that promote team building and problem solving. Walk Across Illinois Afterschool Challenge is designed for implementation in schools, recreation centers and other afterschool settings. The curriculum is easy-to-understand, and was created by a team o f classroom and physical education curriculum writers and consultants. # Example of Success Story: In the first fall semester of its release in 2010, the Afterschool Challenge was used by 660 children in Chicago. One afterschool program provider had the following to say about the program: "The children have enjoyed the activities so far. They have asked us when our next lesson plan is going to happen or what our next activity will be on. I've enjoyed using the Afterschool Challenge because it has made it easier to introduce activities to the children and be able to have their cooperation as well as their participation!"-One Hope United Challenges: One challenge that teachers have faced when using this curriculum has been learning how to fit this program into their schedules. Often after-school care providers only have an hour or two with the children, so they may have difficulty implementing an 80-hour program. # Subject: Bicycle and pedestrian Skill Based Education: Yes. In terms of bicycle and pedestrian safety, skill based education is included in the form o f simulated street crossing practice, simulated street bicycling skills and in-class bicycle and pedestrian safety role play. Grades: 3rd -4th (can be adapted for other grades) Type of Instruction: Teacher-led. This scripted curriculum is designed to guide teachers or afterschool providers through the lessons as they teach their students. Program Duration: 1-80 hours. There are 40 literacy based lessons and 40 physical activity based lessons to be used in whole over the course of a school year, or to be broken down into smaller units. Other Instructional Content: English and physical development. Requires Equipment: Yes. All equipment required for the Afterschool Challenge program can already typically be found in a classroom or PE class setting. A master list of required materials is provided within the program, and every lesson has a required materials section in order to help the educator prepare in advanced. However, the Afterschool Challenge is flexible enough to be used in most situations. Lessons use a spiraling approach but they also can be implemented as stand-alone activities or as a unit (seven units total in the program). Program staff members are also available to help instructors make necessary adaptations. The lessons encourage students to think about ways in which they, their families and their communities can help reduce traffic and associated air pollution through walking, bicycling and using public transportation. The lessons help students see that walking is a fun and easy form o f daily exercise that is good for their overall health. # Cost: Free Meets # Contact for The curriculum includes both in classroom and out-ofclass field activities, such as mapping routes from students' homes to their schools, creating a simple air pollution tester and measuring breathing and heart rates before and after physical activity. Many o f the lessons are ideal for collaborative efforts among classroom teachers, physical education teachers and computer lab instructors.The curriculum includes ten lessons for 3rd-5th grades and five lessons for kindergarten-2nd grades.The lessons have been reviewed by Massachusetts teachers and tested in classrooms with outstanding results. # Example of Success Story: Teachers have reported that the "lesson plans are age appropriate, very resourceful, easy to implement, and the students loved the lessons!" and that the activities have led children to have great discussions about walking and the environment. # Challenges: The lesson plans are ready to use "off the shelf" and do not require outside assistance or special equipment. # Subject: Pedestrian # Skill Based Education: No # Grades: K-5th Program Duration: 30 minutes to two hours variable in-class and outdoor time. # Acknowledgements # The Elementary Traffic Education Program by Journeys from Home is research-based, uses established countermeasures and focuses on attainable behavior changes that can reduce children's risk. It provides repetitive practice under close supervision by taking children outside, on foot, on bicycle, on the playground and in the neighborhood street. This curriculum is designed with lessons that are developmental^ appropriate and grow with the children. Many regional on-bicycle programs have used this material as a model for their own programs. This curriculum is taught in schools by state licensed teachers who know the children and their developmental abilities, and has been integrated into the Montana Health Enhancement school district curriculum, rather than depending on grants and funding each year. # Example of Success Story: Because this curriculum is a school-based comprehensive curriculum that is taught by existing physical education teachers year after year, many of the participating schools have experienced a school wide dynamic shift to independent travel. The K-5th grades program has been in Montana and Florida schools since the mid 90's. Challenges: Any adult can facilitate the introductory lessons for each grade level. JFH requires classroom and health enhancement teachers to be trained when using the full curriculum. Bicycles and helmets are required to complete the on-bicycle activities and support staff is required for the on-street sessions. Each grade level has age-specific lessons that stand alone. The teacher may spend 30 minutes to more than three hours as they sees fit. # O ther Instructional Content: None Requires Equipment: Yes. Requires a DVD player/screen, inside space, outside play space and neighborhood streets as well as 16 Bicycles and 32 helmets. Cost: $200.00 to $500.00 -one-time fee per school. The curriculum, which draws from the examples of Portland, Oregon and Fort Collins, Colorado, focuses on including activities that can be done in the classroom but still highlight im portant safety concepts. An opportunity to apply these concepts is also made possible in several hands on activities. Each module identifies the grade level, subject areas, objectives, materials needed and the amount of time necessary to complete the lesson. # Meets The Iowa Kids on the Move curriculum provides comprehensive materials so that the program can be administered by a classroom teacher or by a trained instructor. Program Sum m ary:This Safe Routes to School Curriculum was created by the Kentucky Transportation Cabinet for the purpose of equipping teachers with the tools needed to instruct students about the connections between walking, bicycling, health and environmental quality. A series of lesson plans that range from kindergarten through 8th grades encourage students to think about ways in which they, their families and community can help reduce traffic and air pollution by walking or bicycling. While much of the curriculum includes cross-curricular activities there are also lessons that aim to teach students fundamental pedestrian and bicycle skills. O ther Instructional Content: English, science, social studies and math. # Contact for ordering # Neighborhood Navigators Lynne M u trie , (503)329-6469, lyn nem utrie@ zerow aste .org Link for Download: http://w w w .oregon.g0v/ODOT/TS/saferoutes.shtml#SRTS_Curriculum_Now_Available Creator: Oregon Safe Routes to School program Program Summary: Neighborhood Navigators is a K-8th curriculum package which focuses on safe, efficient and healthy transportation choices, pedestrian safety and community and neighborhood design. It is divided into three grade level sections: K-3rd, 4th-5th and 6th-8th. Each level has five lessons with extension activities and walks to reinforce each lesson give students the opportunity to get out and about and help develop healthy active lifestyles. The curriculum helps students understand the need for safe transportation and emphasizes the need for environmentally friendly transportation. It was developed with examples o f existing programs and considers the needs o f classroom teachers. After development, Neighborhood Navigators was tested and vetted by school teachers, trained using the Healthy Kids Learn Better best practices model and is supported by research. # Success Story: This curriculum is new and currently being used in Corvallis, Klamath Falls and Oakland. 22 teachers have been trained in this curriculum. Several say it is easy to follow and gives ample opportunity for individual experiences, and location-specific modifications are obvious and encouraged. Corvallis school district has passed a policy to teach Neighborhood Navigators in grades 2-5 and Oakland school district teaches the program in middle school. # Challenges: The biggest challenge is to decide how it fits into a teacher's yearly plan. It is recommend that teachers become trained to experience the scope and sequence of the lessons, but it is designed to be self-contained and easy to follow and/or modify. Program Summary: The Organizer's Guide to Bicycle Rodeos was created as a step-by-step approach to designing a successful bicycle skills event in a community setting. Drawing many o f its attributes from the Burden/Williams Guide published through Adventure Cycling, and written by a League o f American Bicyclists Certified Instructor and youth development specialist, the Organizer's Guide to Bicycle Rodeos works to address the various developmental stages of youth. It also provides guidance in the form o f questions to ask and age appropriate procedures for teaching bicycle handling and traffic skills. Overall, this guide provides an excellent simplified approach to hosting a bicycle skills course. # Contact for # Challenges: The greatest challenge in implementing this program is ensuring that the adult who is interested in bringing bicycle safety to children is familiar with bicycling. In order to ensure overall success o f the program, there must be teachers who are familiar with and can demonstrate the skills outlined throughout the guide. The curriculum is based on the Smart Cycling content from the League o f American Bicyclists and needs to be taught by a League Certified Instructor and trained assistant instructors in a ratio of no more than 1:10. The curriculum focuses on four o f the five layers of bicycle safety: control, rules, avoidance and passive safety. Lane positioning is unable to be covered because students are not taken out to the road environment. The program is being offered in Hawaii County with plans to expand to other islands as resources become available. # Example of Success Story: The PATH Bike Ed program has reached more than 1,000 students since restarting in March of 2009. It is part of a broader effort to grow the bicycle movement in Hawaii, and is well-loved by teachers, students and parents. # Challenges: The program requires a lot o f equipment and skilled instructors to deliver a high-quality and consistent experience. The biggest challenge is securing funding to pay League Certified Instructors to teach the curriculum. Program Summary: The BTA's Pedestrian Safety Education curriculum consists o f two 45-minutes lessons using on street and simulated street practice to give the students the knowledge to identify safe and unsafe places to walk as well as demonstrate overall safe pedestrian skills. # Contact for O rdering/M ore The curriculum covers safely walking on sidewalks, crossing at unmarked crosswalks, crossing at marked crosswalks, using a pedestrian signal and crossing driveways. It was developed by instructors with more than five years o f handson experience teaching pedestrian safety in the Portland metro area. The curriculum is used annually throughout 40 schools in Portland, Oregon. # Example of Success Story: The BTA has been teaching pedestrian safety since 2005. In 2009, the BTA taught 2,400 2nd graders pedestrian safety in Portland and during that time 36.5% o f families surveyed by the Portland Safe Routes to School program said they use active transportation on the trip to school. # Challenges: The curriculum requires a simulated street and some visual aides (detailed plans to make a road and visuals included in the curriculum), 20ft x 20ft o f space for Lesson one and a near-by route suitable for taking 30 students on a walk. # Contact for O rdering # Example of Success Story: The BTA has taught bicycle safety education using the Safe Routes for Kids curriculum to approximately 40,000 students since 1998. The BTA currently has nine trained Walk+Bike Ambassadors that teach 5,000 students yearly, partnering with local governments, school districts, parents, teachers and students in seven communities. In other communities, teachers and district employees teach the curriculum with training provide by the BTA. The program's effectiveness is closely related to Safe Routes to School and other programs that address the Five E's. # O ther Instructional Content: None Requires Equipment: Yes. Requires bicycles, cones, chalk and tools for routine bicycle maintenance. Cost: Free -$250. The Safe Routes for Kids pdf is free for use in Oregon. Cost is $38 for a hard copy and a $250 fee for copyright for use outside of Oregon. # Meets Oregon # Creator: Bicycle Coalition o f Greater Philadelphia Program Summary: Safe Routes Philly's pedestrian and bicycle safety lessons are geared towards the 2nd and 5th grade audience. The lessons are in modular form, giving teachers the option to teach shorter or longer lessons and all off bicycle tutorials that range from ten minutes to 45 minutes. The primary lessons can be identified on our website and/or below under the heading: Core Lessons. The pedestrian curriculum was adapted from the WalkSafe™ Miami program.The bicycle curriculum is a combination of many different lessons with adaptations from experiences in the Philadelphia setting that includes bicycle safety videos to assist teachers with the Bicycle ABCs and helmet fitting (videos can be found on the website).The curriculum was developed to meet the Pennsylvania state standards and connect with the reality and needs of the Philadelphia teachers and students. In Philadelphia some of the biggest concerns for children include their knowledge to ride with traffic, obeying road rules and making sure their bicycles are safe to ride prior to riding. The core lessons cover these three issues, along with many other important issues that are important for kids in the urban environment to learn. There are a multitude of lessons available that can be taught consecutively or broken out into smaller, less comprehensive lessons based on the available class time. Challenges: Because the Philadelphia School District is as overburdened as it is, it has been a challenge to get the approval o f the school district to mandate that their teachers teach these lessons. However, this was also why the lesson plans were developed in a modular format. The focus on PE teachers, by offering credit through professional development trainings, has brought out a lot of the target school teachers. Approximately two-thirds of all public elementary school teachers in the district have received training and teaching materials, and about one-third o f that number have taught lessons since November 2010. Because the current core lessons do not require a fleet of bicycles, it allows teachers a realistic option in teaching students off bicycle and pedestrian safety lessons more easily. Based on previously successful curricula, Safe Routes to School Traffic Safety Program builds on tried and true modules to include a well-rounded program that will get more kids walking and riding safely. # Subject: Bicycle and pedestrian Skill Based Education: Yes, includes hands-on practice such as street crossing, traffic signal and pedestrian sign identifications and how to identify the safest route possible. # Grades: K-5th Type of Instruction: Teacher-led /Train-thetrainer. Educators will have the option to participate in a Walk and Roll K-5 Educator Guide workshop, and will then engage their students in a teacher to student format. Including adaptations from the Livable Streets Middle School Curriculum, this guide has been designed to encourage middle school youth to take ownership and participate in their community, work with their peers and affect change in their neighborhoods and school environment. While the guide is in the initial stages o f release, it is based on activities that have been tested and are being used in the New York City public schools. O ther Instructional Content: Community, health and environment. # Example of success story Requires Equipment: Yes. Some activities require cones, Internet, art supplies, a speed radar device (that can be checked out from their office) and other materials. All necessary supplies are listed at the beginning o f each activity. Trips presentation is intended to be taught to small or large groups inside o f one class period. # Cost: Free # Meets The presentation itself works to provide critical information to students about various pedestrian safety scenarios but also allows time for students to practice skills in a simulated environment and includes a question and answer format. Evaluation o f the program showed beneficial impacts on child pedestrian behavior and test scores resulting from both the initial training and a retraining 12 months later. The findings o f the program evaluation have been published in the Journal of the Transportation Research Board. Example of Success Story: More than 10,000 K-8th grade students have been trained at 44 schools (public and charter) within the City o f Detroit. The violation rates of child pedestrians traveling to/from school decreased by approximately 7% after receiving the program and pre/post test scores improved by approximate 23%. Retraining 1 year later at selected schools provided incremental improvement in both violation rates and test scores. # Challenges: Poor or aging facilities within many of the schools in Detroit made it challenging to present the content effectively. While it can be done, crowd control is difficult with larger assemblies, and this should be closely considered when choosing the size o f the group presentation. Program Duration: Four to 12 hours. The curriculum is scaleablefrom an optional quick one week course that focuses on five primary lessons to a three week, fifteen lesson course. Requires Equipment: Yes. Since bicycles are usually not available to schools, the basics of the course can be taught using "virtual bicycles" (handlebars made from pvc pipe or even paper towel tubes). In addition cones, poly spots, sponges and sidewalk chalk are useful. Activity cards and traffic signs are part of the course and need to be copied and laminated ahead o f time. Cost: $100. SafeCyclist curricula are $100 each plus train the trainer fees. # Meets Texas and National Education Standards: Yes # Intended Skill Level Trained: Beginner # Measures Student Learning Through Pre/Post Testing: Yes Wrap Around Materials: Yes, in English and Spanish. # A daptations for Special Needs Students (or scalable to various skill levels): No adaptations, but is scaleable to various skill levels. Program Summary: The Safety City curriculum was developed specifically for third grade students because they are at an age where they are both receptive and able to retain safety information. The curriculum covers a variety of traffic safety topics with emphasis on pedestrian and bike safety. It has been cited by the NYC Department of Education as meeting NYC school day performance standards. The curriculum covers all issues of concern for pedestrians and bicyclists including: traffic signs and signals, how to see and be seen by drivers, staying alert, and the importance of wearing properly fitted helmets. The curriculum provides hands-on lessons where children practice crossing the street and driving bicycles on a realistic intersection with real signs, signals and markings. The Safety City curriculum has been consistently used in the borough of Manhattan since 1989. Its use was expanded in 1993 and it is now being used throughout New York City. Since the inception of the first Safety City in Central Harlem in 1989, the Harlem Hospital Pediatric Trauma Unit has reported 50% fewer admissions resulting from traffic crashes. Safety City has won awards from AAA and Allstate for its unique and effective teaching methods and is considered to be a model curriculum which has been used in the development of hands-on traffic safety instruction programs in other cities and countries. # Example O f Success Story: Six facilities across the five boroughs serve approximately 20,000 children and New Yorkers o f all ages with special needs on-site each year. In addition, 20,000 children receive traffic safety training from Safety City staff at their own schools. # Challenges: The curriculum requires a classroom and an outdoor space with a simulated streetscape for hands-on practice as well as two professional instructors, bikes and other equipment and requires several funding sources. The Sprockids introduction to bicycling program teaches four skills areas o f cycling: safety and etiquette, riding skills (1st and 2nd gear) and bicycle maintenance.The program allows participants to progress in all areas at their own pace and promotes values, respect for others, empathy, appreciation and responsibility for the environment. # Contact For As participants gain the skills demonstrated in the class they record their personal progress in their "Passport". This program is intended to be led by trained individuals so that they can adequately pass on the program's life skills while helping students develop a healthy, positive philosophy toward bicycling and learning as lifelong activities. # Example of Success Story: Sprockids is now used in 19 countries by teachers, coaches, cycling clubs, youth organizations, law enforcement agencies and parents. # Challenges: The Sprockids program was designed to allow the organization delivering the program to be able to utilize the instructional material in a manner to best suit the needs o f their clientele. The course, which is currently used in King County, Washington (the Greater Seattle Area) with a variety of public and private groups, consists of four parts: in-class instruction, in-class hands-on, on bike skills/drills and extended road ride. # Contact for At the end o f the course, students will be able to be safely ride on the road with other vehicular traffic. Students will have improved handling o f their bicycles and will be able to make independent decisions about when and how to enter traffic. Students will be made aware o f some common hazards in riding on the road and how to avoid those hazards. Finally, attendees will be able to properly fit their own helmets and to check their bicycles to make sure they are mechanically sound. This program addresses common concerns of new cyclists: in particular, dealing with car traffic. The program emphasizes good decision-making as a means to gaining the respect of parents, other adults and peers. # Adaptations for Special Needs Students (or scalable to various skill levels): Yes. Curriculum is scalable to various skill levels but will not work well for groups containing widely divergent skill levels. # RETURN TO CURRICULA INVENTORY Required Equipment: working bicycles and helmets for each student and instructor, waivers, class roster, clipboard, pens, display intersection on portable magnetic whiteboard with magnetic cars and bicycles; dry erase markers, permanent marker, honeydew melon, crash helmet for melon drop, sidewalk chalk, small cones (half tennis balls), red licorice (or other suitable, non-allergen treat), route maps (for intersections), "Safe Routes for Kids: City Biking Handbook" (or similar bicycle safety handouts), swag (slap bracelets, reflective stickers, patch kits, water bottles etc.), floor pump, basic repair tools (specifically 15mm box wrench or adjustable crescent wrench for non-quick release wheels), a variety of spare tubes in common sizes (20" 24" 26"), first aid kit, instructor backpack or panniers to carry gear, an empty, paved parking lot or playground where students can practice skills. # Bicycle Transportation Alliance # Sprockids Walking Wisdom and Bike Driver's Ed Bike Driver's Ed was developed for 5th and 6th graders as a 10 hour program while the multilevel Walking Wisdom program is geared towards the individual abilities of 1 st, 2nd, and 3rd graders. Bike Driver's Ed can be condensed and slightly altered to be appropriate for students in 7th through 9th grade. Bike Driver's Ed consists o f nine hours of lessons plans so that there is one extra hour to devote to the skills and concepts that are difficult for each particular class. Most often, this "extra day" is an additional session of on bike practice devoted to turning and yielding to each other in intersections. Alternately, if the school and parents are supportive, the last day o f the program can be a neighborhood ride during class, rather than on Saturday morning. All programs are multi-day and combine in-class teaching with on-bike or on-foot activities. The lesson plans are intended to be one hour each, thus the 10 hour bicycle education program is 10 school days or two weeks long while Walking Wisdom is two or three days. # Challenges: The curriculum is time intensive and requires equipment such as bicycles and helmets. # Walking with Bucklebear W einer/S eam an P roductions, (310) 479-0922 Linkfor Download: http://w w w .bucklebear.com /catalog/kits.htm l (scroll to bottom) Creator: Weiner/Seaman Productions Program Summary: Since 1982 Bucklebear traffic safety materials have presented basic concepts of bicycle and pedestrian safety to preschool children and their parent/ caregivers, thereby encouraging young children to take some responsibility for their own safety. The Walking with Bucklebear curriculum provide teachers with easily presented materials addressing importance o f adult supervision, wearing bright colors so walkers can be seen, safe places to walk and walking practice. The original presented concepts were reviewed and approved by early childhood educators at CSUN preschool lab and addresses the critical traffic safety issues that preschoolers face. The Bucklebear materials have been used across the nation for more than 25 years by Head Start groups, educators, health pros, fire/police and safety advocates with frequent reorders for additional program materials. Its'positive approach enables young children to be happy and careful pedestrians. The curriculum is intended to be taught over a three-day period (30 minutes per day), with implementation typically coinciding with International Walk to School Day in October. # Example of Success It is available in three versions -one for kindergarten-1 st grades, one for 2nd-3rd grades, and one for 4th-5th grades -ensuring that program recipients receive age-and gradeappropriate education. In addition to the core lessons, the WalkSafe™ educational curriculum also contains optional and supplemental activities that support key reading and mathematics benchmarks while reiterating im portant concepts. The curriculum also includes materials and strategies developed by curriculum specialists that can be used with students of varying learning and linguistic abilities. # A daptations for Special Needs Students (or scalable to various skill levels): Yes (additionally, modified curriculum for children with special needs will be available in summer 2011). RETURN TO CURRICULA INVENTORY a significant countermeasure for juvenile pedestrian-struck crashes by outside agencies. Challenges: Since the program is designed to be taught in a school setting, it requires instructional class time. This has presented an obstacle for some schools and teachers due to the increased focus on academic standards and time needed to prepare for standardized testing. However, many schools have overcome this obstacle by distributing the load o f implementation among classroom teachers (who typically teach lesson one), physical education teachers (who teach lesson two), and art teachers (who teach lesson three). What differentiates the Walk Smart program from traditional safety curricula is the emphasis on breaking down complex skills such as street crossing into component parts: responding to signals, discriminating dangerous vehicles and understanding traffic distance.The program then teaches each of these skills to mastery before integrating them into the more complex task o f walking safely across a busy street. # Contact for # Example of Success Story: The program was evaluated in a study involving 36 students. The study found that students identified hazardous vehicles significantly better in both video simulations and simulated outdoor intersections after using the program than they had prior to using the program. The study also found that even children with no computer or reading skills were able to use the program. # Challenges: The Walk Smart program incorporates several interactive tools. The use of animations to present traffic situations provides a means for removing irrelevant stimuli. The abstracted situations permit children to focus on critical details and respond to specific elements in the environment. By gradually replacing the animations with semi-abstracted examples (e.g., actual photographs of streets and intersections with animated cars, 3-D models with photographic backgrounds), generalizations from the abstracted scenes to the complex and dynamic situations are induced. The video materials used in the programs enable the effective teaching o f pedestrian skills by presenting real-life examples o f traffic related scenarios, which can greatly reinforce classroom lectures and printed material.The interactivity requires the learner to pay careful attention and respond overtly and frequently. Students get immediate corrective feedback as needed. Creator: Center for Health and Learning Program Summary: The WalkSmart/BikeSmart Vermont! curriculum is a walking and bicycling safety skills program that has been vetted by curriculum experts and addresses the most significant concerns for child bicyclists and pedestrians.The lessons are designed to keep children actively engaged, integrate their experience and skills into the activities and help them practice decision-making skills for healthy and safe choices. Complete with pre and post tests, handouts, overheads and step-by-step instructions, the WalkSmart/BikeSmart Vermont! curriculum is a complete resource for groups looking to implement bicycle and pedestrian safety. # Example of Success Story: The WalkSmart evaluation showed significant change in knowledge and attitudes among 175 students kindergarten through 4th grades in Vermont and BikeSmart showed the same among 245 students in 2nd-6th grades. More than 3,000 children received this instruction in 2008 alone. The WalkSmart/ BikeSmart program is taught in dozens of schools throughout Vermont. Through performance evaluation both students and instructors see student accomplishment and learn to tweak instruction to ensure better learner outcomes in future programs. Students, staff and parents continue to support the WalkSmart/BikeSmart program feeling that it is beneficial to the children. # Challenges: There is nothing inherent in the program that is a challenge; the delivery is straight-forward and easyto-comprehend with a good amount o f hands-on activity for the children. There are a lot of demands on schools for instructional time. All activities include a description o f the skills to be practiced, discussion questions, suggestions for additional activities and basic information to get started.The success indicator listed for each activity is an excellent way to evaluate the youth's progress. Each lesson is broken out to indicate required materials, necessary preparations, skills and the "do" part o f each activity, a question and answer section, a section on interesting additional information and finally, a section dedicated to taking the activity a little further for eager participants. The curriculum includes several modules on bicycle maintenance, advanced road skills and bicycling for life. National 4-H suggests that this curriculum be used in tandem with 4-H's Bicycle Helper's Guide, which includes "learning by doing"activities that incorporate preparing to ride, riding, skill activities, and games to play with the group. Wise Rides will be an interactive online program to reinforce active transport safety skills for children in 4th-8th grades. The centerpiece o f the program will be student-focused, with additional brief content targeting parents and school staff. The program will cover: teen brain development, rules of the road, hazard identification and avoidance and use of helmets and other protective gear. Unique features include: a school-wide approach involving students, educators and parents; use of interactive media tailored for this audience; incorporation o f instructional design features that have been shown to maximize learning; application of safety skills in video-based examples o f real-life traffic situations and decision making and problem solving in simulated traffic situations. # Example of Success The program will be grounded in behavior change theory and will incorporate computer-based assessment with remediation to ensure content mastery. The program will include a comprehensive set of active transport safety skills; a peer-led training activity; school-wide implementation guidelines; lesson plans for teachers; and expansion materials for parents. Curriculum is a comprehensive course on bicycle and traffic safety designed for upper-elementary, middle, and high-school youth. The course is designed as a 16-lesson afterschool "bicycle club," which the YBike Program runs at numerous schools in San Francisco, but is adaptable for other programs and course lengths and objectives. YBike also uses an adapted version for its 10-day physical education program. The curriculum focuses on the teaching of bicycle handling skills, the safe negotiation of complex traffic situations, addressing key youth bicyclists'concerns such as driveway hazards, safe city riding practices, and practicing right-of-way and intersection negotiation without driver safety training. There are also lessons devoted to healthy nutrition, environmental awareness, mapping and bicycle advocacy. Student leadership is encouraged throughout. The YBike curriculum was developed in 2004 and went through a major update and redesign in 2008 with support from the San Francisco Bicycle Coalition. It draws on the experience o f YBike's many youth bicycle safety educators, as well as from leading youth bicycle safety curricula such as that from Portland's BTA, as well as Safe Routes to School programs in Marin Country, California and Pima County, Arizona. Example of Success Story: More than 1,250 students have successfully completed this curriculum since 2004, roughly 250 who had never been on a bicycle before taking this course. The program has helped develop a culture of bicycling at all San Francisco schools, and has encouraged and trained some students to bicycle to school. Students completing the program significantly improve their traffic safety knowledge, as shown by pre-post-test scores. Challenges: This program is specifically designed to train students in the skills needed to ride their bicycles safely on urban streets, i.e., to be vehicular cyclists -often w ithout any prior driver education training. Significant risk management concerns are involved in running a program with this design, requiring highly skilled, trained and certified instructors to run the program. Liability and insurance should be fully	None	None
dc7a5bdbb538a641f4cd6ae06e8f03f8d100c7a4	cdc	None	# PREFACE # R E S P I R A T O R SELECTION GUIDE FOR M E T A L L I C V A N A D I U M AND V # IV FIRE AND EXPLOSION # FIG U R E X l l -l C A LIB R A TIO N SETUP FOR PERSONAL SAM PLING W ITH FIL TE R CASSETTE # TTHTTTTTTTT D E P A R T M E N T O F H E A L T H , E D U C A T IO N , A N D W E L F A R E P U B L IC H E A L T H S E R V IC E CENTER FOR D ISE (1) Beakers, 50-ml, w i t h covers. (2) Pipettes, delivery, 1, 5, and 10 ml and other convenient sizes for m a k i n g standards. V olumetric flasks, 10-ml, 25 ml, 1000 ml. (4) Automatic m i c r o l i t e r pipette.	# PREFACE # R E S P I R A T O R SELECTION GUIDE FOR M E T A L L I C V A N A D I U M AND V # IV FIRE AND EXPLOSION # FIG U R E X l l -l C A LIB R A TIO N SETUP FOR PERSONAL SAM PLING W ITH FIL TE R CASSETTE # TTHTTTTTTTT D E P A R T M E N T O F H E A L T H , E D U C A T IO N , A N D W E L F A R E P U B L IC H E A L T H S E R V IC E CENTER FOR D ISE # 215,227,2 3 4 , 2 4 0 , 2 5 0 -5 1 , 3 4 2 , 3 4 4 , 3 4 8 , 3 5 (1) Beakers, 50-ml, w i t h covers. (2) Pipettes, delivery, 1, 5, and 10 ml and other convenient sizes for m a k i n g standards. (3) V olumetric flasks, 10-ml, 25 ml, 1000 ml. (4) Automatic m i c r o l i t e r pipette. (	None	None
41b4775612dcb088163c2d7b0a68ef2a517db78a	cdc	None	The following item numbers are being clarified in response to industry questions. Text from the VSP 2011 Operations Manual is printed first, then the clarification.# 6.0 Recreational Water Facilities # Fill Level and Turnover Rates (10) For RWF with skim gutters, the fill level of the RWF must be to the skim gutter level. An RWF slide that is combined with a pool must have a TURNOVER rate that matches the rate for the pool. # Clarification Use flow rates from flow meters to calculate TURNOVER rates. Do not use the manufacturer's pump rate to calculate TURNOVER rates. For the statement "An RWF slide that is combined with a pool must have a TURNOVER rate that matches the rate for the pool," pool refers to either WADING or SWIMMING POOLS but not CHILDREN'S POOLS. In addition, the water for the slide must come directly from the basin of the pool and return directly to the basin of the pool. For facilities that meet the definition of more than one type of RWF, the more protective TURNOVER rate applies. For example, if a CHILDREN'S POOL also has features of an interactive RWF or ACTIVITY POOL, the TURNOVER rate must be 0.5 hours. The only exception is that when a slide is combined with a pool, the TURNOVER rate for the combined system may match the rate for the pool. However, if a pool and slide combination is also combined with another facility, the most protective TURNOVER rate applies. Finally, if a facility is modified, the most protective TURNOVER rate applies. (See also clarification for 6.2.2.1.1 for HALOGEN residual.) # Filter Housing Cleaning and Disinfection (10) The filter housing must be cleaned, rinsed, and disinfected before the new filter media is placed in it. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. # Clarification The filter housing must be cleaned, rinsed, and disinfected each time the filter media-including cartridge filter-is changed. # Hair and Lint Strainer (10) The hair and lint strainer and hair and lint strainer housing on all RWFs must be cleaned, rinsed, and disinfected weekly. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. # Clarification If there is not a hair and lint strainer but there is a filter before the pump, this filter must be cleaned, rinsed, and sanitized. # Bather Loads (10) Documentation must be maintained on the maximum bather load for each RWF. The maximum bather load must be based on the following factor: One person per five gallons (19 liters) per minute of recirculation flow. # Clarification Use flow rates from flow meters to calculate bather loads. Do not use the manufacturer's pump rate to calculate bather loads. # Water Chemistry (10) The RWF's flow rates, free and combined HALOGEN levels, PH, total alkalinity, and clarity must be monitored and adjusted as recommended by the manufacturer and to maintain optimum public health protection and water chemistry. Evaluate bather load and make adjustments to water parameters to maintain optimum water quality. # Clarification Install flow meters to monitor flow rates. Only combined chlorine must be monitored. Combined bromine does not need to be monitored. "Manufacturer" refers to the RWF manufacturer and also to manufacturers of the pumps, filters, flow meters, and any other associated equipment. # Fecal and Vomit Accident (10) A fecal and vomit accident response procedure that meets or exceeds the procedure provided in Annex 13.8 must be available for review during inspections. # Clarification CDC recommends a pH range of 7.2 to 7.5 for loose stool accidents for inactivating Cryptosporidium. This clarification also applies to Annex 13.8. # Residual (09) A free residual HALOGEN in the ranges detailed in the table below must be maintained in recirculated RWFs. # Recreational Water Facility Free # Clarification For facilities that meet the definition of more than one type of RWF, the more protective HALOGEN residual applies. For example, if a children's pool also has features of an interactive RWF or ACTIVITY POOL, the HALOGEN range must be 2.0 to 5.0 ppm. Finally, if a facility is modified, the most protective HALOGEN residual applies. (See also clarification for 6.2.1.1 for TURNOVER rates.) Manual readings must be recorded on a chart or log, retained for at least 12 months, and available for review during inspections. # Automated Free Halogen Repairs on malfunctioning HALOGEN analyzer-chart recorders must be completed within 30 days of EQUIPMENT failure. Provide an audible alarm in a continuously occupied watch station (e.g., the engine control room) to indicate low and high free HALOGEN and PH readings in each RWF. # Clarification If two RWFs are combined and the water for one RWF comes from and returns to the basin of the other RWF (not the compensation tank), separate monitoring systems are not required. Monitoring is then only required on the main RWF (e.g., a slide and SWIMMING POOL). Note: During operational inspections, VSP will take manual samples of both RWFs. # Data Logger (10) If an electronic data logger is used in lieu of a chart recorder, it must have certified data security features. For RWFs open longer than 24 hours, a manual comparison test must be conducted every 24 hours. # Clarification Electronic data logging must be in increments of ≤ 15 minutes. # Shock Halogenation (10) The free residual HALOGEN must be increased to at least 10.0 MG/L (ppm) and circulated for at least 1 hour every 24 hours. The free residual HALOGEN must be tested at both the start and completion of shock halogenation. The water in the entire RWF system must be superhalogenated to 10 ppm to include the WHIRLPOOL SPA/SPA POOL tub, compensation tank, filter housing, and all associated piping before starting the 1-hour timing. Batch halogenation of the tub and compensation tank may help in reaching the minimum 10 ppm residual quickly. Facilities filled only with SEAWATER are exempt from this requirement. Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 7 # Clarification # Life Saving (10) A rescue or shepherd's hook and an APPROVED flotation device must be provided at a prominent location (visible from the full perimeter of the pool) at each RWF that has a depth of 1 meter (3 feet) or greater. These devices must be mounted in a manner that allows for easy access during an emergency. The pole of the rescue or shepherd's hook must be long enough to reach the center of the deepest portion of the pool from the side plus 2 feet (0.6 meters). It must be a light, strong, nontelescoping material with rounded, nonsharp ends. The APPROVED flotation device must include an attached rope that is at least 2/3 of the maximum pool width. # Clarification The rescue or shepherd's hook must be long enough to touch the bottom center of the deepest portion of the RWF plus 2 feet (0.6 meters) as measured from the closest edge without an obstruction. This edge can only be used for measurement if someone could freely walk down both sides without an obstruction such as a waterfall, fountain, statue, etc. For a rectangular pool, the shorter distance would be from the long side of the rectangle as long as there are no obstructions (Figure 1). The 2 feet (0.6 meters) is measured from where the shepherd's hook crosses the fill line of the RWF. # Figure 1. Shortest Distance in a Rectangular Pool For RWFs with a beach level, the measurement can be from the edge of the tub (Figure 2). # Figure 2. Measurement in RWFs with a Beach Level Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 9 # Spas (10) In addition to the safety sign requirements in section 6.7.1.1.1, install a sign at each WHIRLPOOL SPA and SPA POOL entrance listing precautions and risks associated with the use of these facilities. Include, at a minimum, cautions against use by the following: Individuals who are immunocompromised. Individuals on medication or who have underlying medical conditions such as cardiovascular disease, diabetes, or high or low blood pressure. Pregnant women, elderly persons, and children. Additionally, caution against exceeding 15 minutes of exposure. # Vessels can submit existing signs for review by VSP. It is advisable to post additional cautions and concerns on signs. # Clarification Those under 16 years of age are considered children for the purpose of whirlpool safety sign requirements. # Antientrapment Drain (10) ANTIENTRAPMENT/ANTIENTANGLEMENT requirements for drain covers and SUCTION FITTINGS in RWFs are shown in Table 6.7.1.2.2 (below). This does not apply to facilities with zero depth where the drains are not under direct suction. VSP is aware that the requirements shown in Table 6.7.1.2.2 for existing vessels may not fully meet the letter of the Virginia Graeme Baker Act, but we also recognize the life-safety concerns for rapid dumping of RWFs in conditions of instability at sea. Therefore, it is the owner's decision to meet or exceed the VSP requirements. Testing of manufactured drain covers must be by a nationally or internationally recognized testing laboratory. The information below must be stamped on each manufactured ANTIENTRAPMENT drain cover: Certification standard and year. A letter from the shipyard must accompany each custom/shipyard constructed (field fabricated) drain cover fitting. At a minimum the letter must specify the shipyard, name of the vessel, specifications and dimensions of the drain cover, as detailed above, as well as the exact location of the RWF for which it was designed. The name of and contact information for the REGISTERED DESIGN PROFESSIONAL and signature must be on the letter. Definitions: Alarm = the audible alarm must sound in a continuously manned space AND at the RWF. This alarm is for all draining: accidental, routine, and emergency. GDS (GRAVITY DRAINAGE system) = a drainage system that uses a collector tank from which the pump draws water. Water moves from the RWF to the collector tank due to atmospheric pressure, gravity, and the displacement of water by bathers. There is no direct suction at the RWF. SVRS (safety vacuum release system) = a system which stops the operation of the pump, reverses the circulation flow, or otherwise provides a vacuum release at a suction outlet when a blockage is detected. System must be tested by an independent third party and found to conform with ASME/ANSI A112.19.17 or ASTM standard F2387. - APS (automatic pump shut-off system) = a device that detects a blockage and shuts off the pump system. A manual shut-off near the RWF does not qualify as an APS. - Describe or show the flow of POTENTIALLY HAZARDOUS FOOD from when last in temperature control to placement in time control and discard. # Clarification Time control plans must identify all refrigeration and hot holding units on time control, but only cabinets and compartments on time control must be labeled. EQUIPMENT that does not have cabinets or compartments does not need to be labeled as time control. Such EQUIPMENT includes bains marie, cold tops, and soup wells. Containers of POTENTIALLY HAZARDOUS FOOD under time control and placed on preparation counters must be labeled with the discard time, even if the outlet is open less than 4 hours. # Handwashing and Toilet Facilities This applies to toilet facilities for galley personnel even if ACCESSIBLE to other crew members. # Clarification Sections 9. 1.1.1.7 and 9.1.1.1.8 also apply to this section. # Hands-free Exit (41) Passenger and crew public toilet facilities must be equipped so that persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-hands-free contact must begin in the toilet stall. Toilet facilities with multiple exits, such as spa dressing rooms, must have bare-hands-free contact at each exit. This may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, removing doors, or using other effective means. # Sign (41) A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels as written in section 9.1.1.1.7 may be used in lieu of a sign. # Convenient (29C) Each FOOD PREPARATION AREA, bar, WAREWASHING area, and garbageprocessing area must have at least one handwashing facility in it. Clarification ASME A112.19.8-2007 has been replaced by ANSI/APSP-16 2011. ANTIENTRAPMENT protection equipment (covers, suction fittings, safety vacuum release system-SVRS, etc.) must comply with ASME A112.19.8-2007-or any successor standards-whether the equipment is manufactured or field fabricated. Food Safety # Clarification This applies to partial beards (such as goatees) and to heavy, pronounced mustaches. # Food Storage and Protection # Clarification This applies to storage of candy and other food items sold in candy shops, including self-service candy shops and shops where the candy is served by a crew member. Food Display and Service # Clarification This applies to self-service candy shops where customers serve themselves from candy displays or dispensers. # Time Control Plan (16 C) A written time control plan(s) that ensures compliance with these guidelines must be maintained on the vessel and made available for review during inspections (Annex 13.11). A time control plan must be posted at each outlet where time control is used. The plan(s) must Include set-up and discard times for each outlet. List refrigeration and hot holding units (compartments and cabinets) on time control (the physical units must also be labeled as such). # Clarification This applies to self-service and served candy shops where employees serve candy, refill self-service containers, etc. # Decks, Bulkheads, and Deckheads # Clarification This applies to self-service and served candy shops where employees serve candy and refill self-service containers and consumers serve themselves. # Lighting # Clarification This applies to self-service and served candy shops where employees serve candy and refill self-service containers and consumers serve themselves. # Child Activity Centers # Facilities # Clarification Sections 9.1.1.1.6, 9.1.1.1.7, and 9.1.1.1.8 also apply to this section, except that the sign advising users to wash hands (in section 9.1.1.1.6) is not required. # Public Toilet Facilities (41) Passenger and crew public toilets (not including food-area toilets) must be provided with a handwashing station that includes the following: Hot and cold running water. Soap. A method to dry hands (e.g., sanitary hand-drying device, paper towels). A sign advising users to wash hands (pictograms are acceptable). Hands-free Exit (41) Passenger and crew public toilet facilities must be equipped so that persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-hands-free contact must begin in the toilet stall. Toilet facilities with multiple exits, such as spa dressing rooms, must have bare-hands-free contact at each exit. This may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, removing doors, or using other effective means. Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 14 # Sign (41) A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels as written in section 9.1.1.1.7 may be used in lieu of a sign. # Child-size Toilet (42) If toilet rooms are located in a CHILD ACTIVITY CENTER, child-size toilet(s) or child-accessible toilet(s) (child-size seat and step stool) and handwashing facilities must be provided. Child-size toilets (to include the toilet seat) must have a maximum height of 280 millimeters (11 inches) and a toilet seat opening no greater than 203 millimeters (8 inches). Handwashing sinks must have a maximum height of 560 millimeters (22 inches) above the deck or a step stool must be provided. # Clarification Sink height does not apply to handwashing stations outside of the toilet room. However, VSP recommends a maximum height of 560 millimeters (22 inches) above the deck for all children's handwashing stations. If the sink is higher than 560 millimeters (22 inches), VSP recommends providing a step stool. # Ventilation # Showers (43) Shower heads must be cleaned and disinfected every 6 months. DISINFECTION must be accomplished with an appropriate HALOGENbased DISINFECTANT at 10 ppm for 60 minutes, or an equivalent CT VALUE. # Clarification Shower head cleaning and DISINFECTION must be recorded in a log and maintained on the vessel. 12.0 Administrative Guidelines # Corrective Actions Signed corrective-action statements (Annex 13.16) must be submitted to the VSP Chief by the master, owner, or operator. Corrective-action statements must detail each deficiency identified during the inspection and the corrective action taken. # Clarification Corrective-action statements (Annex 13.16) must be submitted to the VSP Chief by the master, owner, or operator within 2 weeks of receiving the final inspection report. # Annex Baby-only Water Facility # Safety Sign A safety sign must be posted by the facility with letters at least 26 millimeters (1 inch) high at each entrance to the BABY-ONLY WATER FACILITY feature that states, at a minimum, the following: This facility is only for use by children in diapers or who are not completely toilet trained. Children who have a medical condition that may put them at increased risk for illness should not use these facilities. Children who are experiencing symptoms such as vomiting, fever, or diarrhea are prohibited from using these facilities. Children must be accompanied by an adult at all times. Children must wear a clean swim diaper before using these facilities. Frequent swim diaper changes are recommended. Do not change diapers in the area of the BABY-ONLY WATER FACILITY. A diaper changing station has been provided (exact location) for your convenience. # Clarification The letters on the sign heading must be at least 26 millimeters (1 inch) high, but all other lettering must be at least 13 millimeters (1/2 inch) high. # Fecal, Vomit, and Blood Accident Response for RWFs The clarification in 6.2.1.6.2 also applies to 13.8: # Fecal and Vomit Accident (10) A fecal and vomit accident response procedure that meets or exceeds the procedure provided in Annex 13.8 must be available for review during inspections. # Clarification CDC recommends a pH range of 7.2 to 7.5 for loose stool accidents for inactivating Cryptosporidium. This clarification also applies to Annex 13.8.	The following item numbers are being clarified in response to industry questions. Text from the VSP 2011 Operations Manual is printed first, then the clarification.# 6.0 Recreational Water Facilities # Fill Level and Turnover Rates (10) For RWF with skim gutters, the fill level of the RWF must be to the skim gutter level. An RWF slide that is combined with a pool must have a TURNOVER rate that matches the rate for the pool. # Clarification Use flow rates from flow meters to calculate TURNOVER rates. Do not use the manufacturer's pump rate to calculate TURNOVER rates. For the statement "An RWF slide that is combined with a pool must have a TURNOVER rate that matches the rate for the pool," pool refers to either WADING or SWIMMING POOLS but not CHILDREN'S POOLS. In addition, the water for the slide must come directly from the basin of the pool and return directly to the basin of the pool. For facilities that meet the definition of more than one type of RWF, the more protective TURNOVER rate applies. For example, if a CHILDREN'S POOL also has features of an interactive RWF or ACTIVITY POOL, the TURNOVER rate must be 0.5 hours. The only exception is that when a slide is combined with a pool, the TURNOVER rate for the combined system may match the rate for the pool. However, if a pool and slide combination is also combined with another facility, the most protective TURNOVER rate applies. Finally, if a facility is modified, the most protective TURNOVER rate applies. (See also clarification for 6.2.2.1.1 for HALOGEN residual.) # Filter Housing Cleaning and Disinfection (10) The filter housing must be cleaned, rinsed, and disinfected before the new filter media is placed in it. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. # Clarification The filter housing must be cleaned, rinsed, and disinfected each time the filter media-including cartridge filter-is changed. # Hair and Lint Strainer (10) The hair and lint strainer and hair and lint strainer housing on all RWFs must be cleaned, rinsed, and disinfected weekly. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. # Clarification If there is not a hair and lint strainer but there is a filter before the pump, this filter must be cleaned, rinsed, and sanitized. # Bather Loads (10) Documentation must be maintained on the maximum bather load for each RWF. The maximum bather load must be based on the following factor: One person per five gallons (19 liters) per minute of recirculation flow. # Clarification Use flow rates from flow meters to calculate bather loads. Do not use the manufacturer's pump rate to calculate bather loads. # Water Chemistry (10) The RWF's flow rates, free and combined HALOGEN levels, PH, total alkalinity, and clarity must be monitored and adjusted as recommended by the manufacturer and to maintain optimum public health protection and water chemistry. Evaluate bather load and make adjustments to water parameters to maintain optimum water quality. # Clarification Install flow meters to monitor flow rates. Only combined chlorine must be monitored. Combined bromine does not need to be monitored. "Manufacturer" refers to the RWF manufacturer and also to manufacturers of the pumps, filters, flow meters, and any other associated equipment. # Fecal and Vomit Accident (10) A fecal and vomit accident response procedure that meets or exceeds the procedure provided in Annex 13.8 must be available for review during inspections. # Clarification CDC recommends a pH range of 7.2 to 7.5 for loose stool accidents for inactivating Cryptosporidium. This clarification also applies to Annex 13.8. # Residual (09) A free residual HALOGEN in the ranges detailed in the table below must be maintained in recirculated RWFs. # Recreational Water Facility Free # Clarification For facilities that meet the definition of more than one type of RWF, the more protective HALOGEN residual applies. For example, if a children's pool also has features of an interactive RWF or ACTIVITY POOL, the HALOGEN range must be 2.0 to 5.0 ppm. Finally, if a facility is modified, the most protective HALOGEN residual applies. (See also clarification for 6.2.1.1 for TURNOVER rates.) Manual readings must be recorded on a chart or log, retained for at least 12 months, and available for review during inspections. # Automated Free Halogen Repairs on malfunctioning HALOGEN analyzer-chart recorders must be completed within 30 days of EQUIPMENT failure. Provide an audible alarm in a continuously occupied watch station (e.g., the engine control room) to indicate low and high free HALOGEN and PH readings in each RWF. # Clarification If two RWFs are combined and the water for one RWF comes from and returns to the basin of the other RWF (not the compensation tank), separate monitoring systems are not required. Monitoring is then only required on the main RWF (e.g., a slide and SWIMMING POOL). Note: During operational inspections, VSP will take manual samples of both RWFs. # Data Logger (10) If an electronic data logger is used in lieu of a chart recorder, it must have certified data security features. For RWFs open longer than 24 hours, a manual comparison test must be conducted every 24 hours. # Clarification Electronic data logging must be in increments of ≤ 15 minutes. # Shock Halogenation (10) The free residual HALOGEN must be increased to at least 10.0 MG/L (ppm) and circulated for at least 1 hour every 24 hours. The free residual HALOGEN must be tested at both the start and completion of shock halogenation. The water in the entire RWF system must be superhalogenated to 10 ppm to include the WHIRLPOOL SPA/SPA POOL tub, compensation tank, filter housing, and all associated piping before starting the 1-hour timing. Batch halogenation of the tub and compensation tank may help in reaching the minimum 10 ppm residual quickly. Facilities filled only with SEAWATER are exempt from this requirement. Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 7 # Clarification # Life Saving (10) A rescue or shepherd's hook and an APPROVED flotation device must be provided at a prominent location (visible from the full perimeter of the pool) at each RWF that has a depth of 1 meter (3 feet) or greater. These devices must be mounted in a manner that allows for easy access during an emergency.  The pole of the rescue or shepherd's hook must be long enough to reach the center of the deepest portion of the pool from the side plus 2 feet (0.6 meters). It must be a light, strong, nontelescoping material with rounded, nonsharp ends.  The APPROVED flotation device must include an attached rope that is at least 2/3 of the maximum pool width. # Clarification The rescue or shepherd's hook must be long enough to touch the bottom center of the deepest portion of the RWF plus 2 feet (0.6 meters) as measured from the closest edge without an obstruction. This edge can only be used for measurement if someone could freely walk down both sides without an obstruction such as a waterfall, fountain, statue, etc. For a rectangular pool, the shorter distance would be from the long side of the rectangle as long as there are no obstructions (Figure 1). The 2 feet (0.6 meters) is measured from where the shepherd's hook crosses the fill line of the RWF. # Figure 1. Shortest Distance in a Rectangular Pool For RWFs with a beach level, the measurement can be from the edge of the tub (Figure 2). # Figure 2. Measurement in RWFs with a Beach Level Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 9 # Spas (10) In addition to the safety sign requirements in section 6.7.1.1.1, install a sign at each WHIRLPOOL SPA and SPA POOL entrance listing precautions and risks associated with the use of these facilities. Include, at a minimum, cautions against use by the following:  Individuals who are immunocompromised.  Individuals on medication or who have underlying medical conditions such as cardiovascular disease, diabetes, or high or low blood pressure.  Pregnant women, elderly persons, and children. Additionally, caution against exceeding 15 minutes of exposure. # Vessels can submit existing signs for review by VSP. It is advisable to post additional cautions and concerns on signs. # Clarification Those under 16 years of age are considered children for the purpose of whirlpool safety sign requirements. # Antientrapment Drain (10) ANTIENTRAPMENT/ANTIENTANGLEMENT requirements for drain covers and SUCTION FITTINGS in RWFs are shown in Table 6.7.1.2.2 (below). This does not apply to facilities with zero depth where the drains are not under direct suction. VSP is aware that the requirements shown in Table 6.7.1.2.2 for existing vessels may not fully meet the letter of the Virginia Graeme Baker Act, but we also recognize the life-safety concerns for rapid dumping of RWFs in conditions of instability at sea. Therefore, it is the owner's decision to meet or exceed the VSP requirements. Testing of manufactured drain covers must be by a nationally or internationally recognized testing laboratory. The information below must be stamped on each manufactured ANTIENTRAPMENT drain cover:  Certification standard and year. A letter from the shipyard must accompany each custom/shipyard constructed (field fabricated) drain cover fitting. At a minimum the letter must specify the shipyard, name of the vessel, specifications and dimensions of the drain cover, as detailed above, as well as the exact location of the RWF for which it was designed. The name of and contact information for the REGISTERED DESIGN PROFESSIONAL and signature must be on the letter. Definitions:  Alarm = the audible alarm must sound in a continuously manned space AND at the RWF. This alarm is for all draining: accidental, routine, and emergency.  GDS (GRAVITY DRAINAGE system) = a drainage system that uses a collector tank from which the pump draws water. Water moves from the RWF to the collector tank due to atmospheric pressure, gravity, and the displacement of water by bathers. There is no direct suction at the RWF.  SVRS (safety vacuum release system) = a system which stops the operation of the pump, reverses the circulation flow, or otherwise provides a vacuum release at a suction outlet when a blockage is detected. System must be tested by an independent third party and found to conform with ASME/ANSI A112.19.17 or ASTM standard F2387.  APS (automatic pump shut-off system) = a device that detects a blockage and shuts off the pump system. A manual shut-off near the RWF does not qualify as an APS.  Describe or show the flow of POTENTIALLY HAZARDOUS FOOD from when last in temperature control to placement in time control and discard. # Clarification Time control plans must identify all refrigeration and hot holding units on time control, but only cabinets and compartments on time control must be labeled. EQUIPMENT that does not have cabinets or compartments does not need to be labeled as time control. Such EQUIPMENT includes bains marie, cold tops, and soup wells. Containers of POTENTIALLY HAZARDOUS FOOD under time control and placed on preparation counters must be labeled with the discard time, even if the outlet is open less than 4 hours. # Handwashing and Toilet Facilities This applies to toilet facilities for galley personnel even if ACCESSIBLE to other crew members. # Clarification Sections 9. 1.1.1.7 and 9.1.1.1.8 [below] also apply to this section. # Hands-free Exit (41) Passenger and crew public toilet facilities must be equipped so that persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-hands-free contact must begin in the toilet stall. Toilet facilities with multiple exits, such as spa dressing rooms, must have bare-hands-free contact at each exit. This may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, removing doors, or using other effective means. # Sign (41) A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels as written in section 9.1.1.1.7 may be used in lieu of a sign. # Convenient (29C) Each FOOD PREPARATION AREA, bar, WAREWASHING area, and garbageprocessing area must have at least one handwashing facility in it. # 6.7.1.2.2 Clarification ASME A112.19.8-2007 has been replaced by ANSI/APSP-16 2011. ANTIENTRAPMENT protection equipment (covers, suction fittings, safety vacuum release system-SVRS, etc.) must comply with ASME A112.19.8-2007-or any successor standards-whether the equipment is manufactured or field fabricated. # 7.0 Food Safety # Clarification This applies to partial beards (such as goatees) and to heavy, pronounced mustaches. # Food Storage and Protection # Clarification This applies to storage of candy and other food items sold in candy shops, including self-service candy shops and shops where the candy is served by a crew member. # 7.3.3.6 Food Display and Service # Clarification This applies to self-service candy shops where customers serve themselves from candy displays or dispensers. # Time Control Plan (16 C) A written time control plan(s) that ensures compliance with these guidelines must be maintained on the vessel and made available for review during inspections (Annex 13.11). A time control plan must be posted at each outlet where time control is used. The plan(s) must  Include set-up and discard times for each outlet.  List refrigeration and hot holding units (compartments and cabinets) on time control (the physical units must also be labeled as such). # Clarification This applies to self-service and served candy shops where employees serve candy, refill self-service containers, etc. # Decks, Bulkheads, and Deckheads # Clarification This applies to self-service and served candy shops where employees serve candy and refill self-service containers and consumers serve themselves. # Lighting # Clarification This applies to self-service and served candy shops where employees serve candy and refill self-service containers and consumers serve themselves. # Child Activity Centers # Facilities # Clarification Sections 9.1.1.1.6, 9.1.1.1.7, and 9.1.1.1.8 also apply to this section, except that the sign advising users to wash hands (in section 9.1.1.1.6) is not required. # Public Toilet Facilities (41) Passenger and crew public toilets (not including food-area toilets) must be provided with a handwashing station that includes the following:  Hot and cold running water.  Soap.  A method to dry hands (e.g., sanitary hand-drying device, paper towels).  A sign advising users to wash hands (pictograms are acceptable). # 9.1.1.1.7 Hands-free Exit (41) Passenger and crew public toilet facilities must be equipped so that persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-hands-free contact must begin in the toilet stall. Toilet facilities with multiple exits, such as spa dressing rooms, must have bare-hands-free contact at each exit. This may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, removing doors, or using other effective means. Clarifications to the VSP 2011 Operations Manual (December 2013 Revision); 14 # Sign (41) A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels as written in section 9.1.1.1.7 may be used in lieu of a sign. # Child-size Toilet (42) If toilet rooms are located in a CHILD ACTIVITY CENTER, child-size toilet(s) or child-accessible toilet(s) (child-size seat and step stool) and handwashing facilities must be provided. Child-size toilets (to include the toilet seat) must have a maximum height of 280 millimeters (11 inches) and a toilet seat opening no greater than 203 millimeters (8 inches). Handwashing sinks must have a maximum height of 560 millimeters (22 inches) above the deck or a step stool must be provided. # Clarification Sink height does not apply to handwashing stations outside of the toilet room. However, VSP recommends a maximum height of 560 millimeters (22 inches) above the deck for all children's handwashing stations. If the sink is higher than 560 millimeters (22 inches), VSP recommends providing a step stool. # Ventilation # Showers (43) Shower heads must be cleaned and disinfected every 6 months. DISINFECTION must be accomplished with an appropriate HALOGENbased DISINFECTANT at 10 ppm for 60 minutes, or an equivalent CT VALUE. # Clarification Shower head cleaning and DISINFECTION must be recorded in a log and maintained on the vessel. 12.0 Administrative Guidelines # Corrective Actions Signed corrective-action statements (Annex 13.16) must be submitted to the VSP Chief by the master, owner, or operator. Corrective-action statements must detail each deficiency identified during the inspection and the corrective action taken. # Clarification Corrective-action statements (Annex 13.16) must be submitted to the VSP Chief by the master, owner, or operator within 2 weeks of receiving the final inspection report. # Annex # 13.7 Baby-only Water Facility # Safety Sign A safety sign must be posted by the facility with letters at least 26 millimeters (1 inch) high at each entrance to the BABY-ONLY WATER FACILITY feature that states, at a minimum, the following:  This facility is only for use by children in diapers or who are not completely toilet trained.  Children who have a medical condition that may put them at increased risk for illness should not use these facilities.  Children who are experiencing symptoms such as vomiting, fever, or diarrhea are prohibited from using these facilities.  Children must be accompanied by an adult at all times.  Children must wear a clean swim diaper before using these facilities. Frequent swim diaper changes are recommended.  Do not change diapers in the area of the BABY-ONLY WATER FACILITY. A diaper changing station has been provided (exact location) for your convenience. # Clarification The letters on the sign heading must be at least 26 millimeters (1 inch) high, but all other lettering must be at least 13 millimeters (1/2 inch) high. # Fecal, Vomit, and Blood Accident Response for RWFs The clarification in 6.2.1.6.2 also applies to 13.8: # Fecal and Vomit Accident (10) A fecal and vomit accident response procedure that meets or exceeds the procedure provided in Annex 13.8 must be available for review during inspections. # Clarification CDC recommends a pH range of 7.2 to 7.5 for loose stool accidents for inactivating Cryptosporidium. This clarification also applies to Annex 13.8.	None	None
a388d527300c767b97a4942cd3ada36219c64b68	cdc	None	# Summary: Lead exposure is a continuing urgent health problem for Roma in Kosovo. The Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO) and the United Nations International Children's' Emergency Fund (UNICEF) have collaborated in blood lead surveillance of the Roma children living in displacement camps in Kosovo. In the last 3 rounds of blood lead testing, conducted between 2005 and 2007, on average, 30% of children tested had capillary blood lead levels > 45 µg/dL, the level at which CDC recommends chelation therapy. Few if any children in the camps have maintained a blood lead level < 10 µg/dL for their entire childhood. These children are at tremendous risk for a lifetime of developmental and behavioral disabilities and other adverse health conditions. The Cesmin Lug camp is the most highly contaminated camp and should be closed immediately. The situation in Cesmin Lug is made more critical because Roma living in Serbia and Montenegro are now moving into vacant dwellings in the camp. Dwellings that are currently vacant should be demolished immediately. These dwellings are not only contaminated by lead but a clear and present fire hazard. In addition, uncontrolled informal smelting at the now closed Kablar camp must be stopped. These activities result in lead exposure to children in both Cesmin Lug and Osterode Camps. Lack of data has hampered decision making and resulted in confusion on the part of Roma and others as to the seriousness of the problem and the extent of the environmental contamination. A periodic, systematic review of the data would provide important information about the quality of the children's clinical care. Reportedly 39 children have been chelated. Perhaps as many as 90 children are candidates for therapy. The actual number cannot be determined at this time. Lead exposure should be a priority for repatriation to the Roma Mahala. Plans should be developed for continued medical surveillance of these children when they are repatriated to Roma Mahala. # Background: Kosovo is a Province within the borders of the former Yugoslavia that is currently controlled by the United Nations (UN). This territory has experienced multiple infrastructure, economic, human rights, and public health problems as a result of the conflicts in the Balkans. International aid has been focused on maintaining peace and establishing basic services. However, economic development has recently become a priority for the UN Mission in Kosovo (UNMIK), the United States Office in Pristina (USOP) and USAID. The Trepca mining and smelting complex, established in the 1930s, constituted the biggest mining company in Europe. The Trepca smelter in Mitrovica extracted metals including zinc, arsenic, lead, and cadmium from the products of nearby mines. Trepca operations have been an important part of the Mitrovica economy in the past, providing employment in both the smelter and the mines to people in the region, but the UN halted operations in 2000 after UN peace keeper forces in the area were discovered to have high blood lead levels (BLLs). Work is underway to reopen the Trepca smelter and mining compound in North Mitrovica. Currently ( 2007) about 3000 people are employed in the facility. The Trepca board of directors has requested funding from a donor nation to purchase a briquetting machine to increase production in the secondary smelting operation. This fall the World Bank intends to begin discussions about reopening the Treca complex, potentially enabling many people to gain employment. Although the smelter has been closed since 2000, the environment remains heavily contaminated. Three mine tailing dams (2 unremediated and 1 remediated) are located in northern Mitrovica and the nearby town of Zvecan/ Zhikoc. Results from soil samples taken by staff of the World Health Organization (WHO) in 2004 as part of a health risk assessment for heavy metals in Mitrovica and Zvecan showed that more than 90% of the samples exceeded the UK limits for lead (450 mg/Kg), with many samples having levels more than 10 times higher than the limit; more than 40% exceeded the limit for arsenic levels; and almost 30% exceeded the limit for cadmium levels. Both the northern and southern areas of Mitrovica are contaminated by lead. However, the results of both environmental testing and blood testing indicate that Mitrovica is more contaminated north of the river where the Trepca smelter is located. The results of tests on drinking water show that generally drinking water quality appears to be acceptable. Testing conducted by WHO in the general Mitrovica area in 2004 found that BLLs in the general population had fallen; however, BLLs remained dangerously high in the Roma, Ashkali, and Egyptian (RAE) communities. The RAE, also referred to collectively as "Roma," have lived in Mitrovica for many years. Before the Balkan conflict (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999) they lived in a southern Mitrovica neighborhood known as Roma Mahala. In the immediate period following the 1999 Kosovo conflict, Roma Mahala was destroyed. The Office of the United Nations High Commissioner for Refugees (UNHCR) constructed two internal displacement (IDP) camps as a temporary housing solution for the Roma who were left homeless. A third unofficial camp, Kablar, was developed after the occupation of French KFOR barracks in 2001. Unfortunately, the camps were established in highly lead-contaminated areas in northern Mitrovica and Zvecan/ Zhikoc. The camps are located within 3 kilometers of the Trepca smelter and within 300 meters of two mine tailing sites. In June 2005, reports of symptomatic lead poisoning among children in Mitrovica, Kosovo, reached the Centers for Disease Control and Prevention (CDC). The children most affected by the lead contamination in Mitrovica are the Roma whose homes were destroyed during the war and who have been relocated to camps on land contaminated with lead and other heavy metals near the Trepca smelter in Mitrovica. In addition, the Roma engage in informal smelting of car batteries and computers. Initial blood lead testing of children in the 3 IDP camps Cesmin Lug, Kablar and Zitkovac/Zhikoc indicated that all children had blood lead levels (BLLs) > 65 µg/dL, the highest value reported out using the hand held LeadCare analyzer. As a result, in July 2005 the World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF) requested assistance from CDC. Specifically CDC was requested to make recommendations for 1) a medical facility to identify and treat children with lead poisoning, 2) outreach and health education to the affected community and 3) a strategy for primary prevention of childhood lead poisoning. During a 5-day visit in August 2005, CDC staff met with Roma community leaders, representatives from nongovernmental organizations (NGOs), and officials from United Nations agencies to discuss current and planned activities related to lead exposure and prevention of lead poisoning. A detailed plan for a heavy metals treatment facility was provided to WHO and UNICEF. CDC continued to maintain contact with these agencies providing technical assistance and support as needed through telephone calls and email. In January 2006, the Kosovo Office of UNICEF invited CDC to revisit the Mitrovica area. The main objectives of the 2-week visit in January 2006 were 1) to review the status of progress on the CDC recommendations for BLL surveillance and medical treatment of children with lead poisoning, 2) assist in the efforts to assess and remediate lead hazards in the three Roma camps (Cesmin Lug, Kablar,and Zitkovac/Zhikoc), and 3) evaluate the lead hazards at the proposed new camp location at Osterode. The inspection of Osterode camp determined that the camp was lead safe. As a result, UNMK requested and received $US 1 million from USOP to set up a medical treatment facility at Osterode camp. CDC continued to provide technical assistance and support regarding treating lead poisoning among Roma children and prevention of lead exposure. In August 2006, 2 laboratorians from the WHO-sponsored Public Health Institute in Pristina came to the environmental laboratory at CDC to be trained in the use of graphite furnace atomic absorption spectrophotometery for blood lead analysis. Since their visit the laboratory in Pristina has participated in a quality assurance and control program at CDC. The results of the proficiency testing indicate that the laboratory in Pristina meets standards for blood lead testing laboratories established in Europe and the United States. In May 2007, as a result of continued concern about the clinical services provided by the treatment unit in Osterode camp, the US State Department, USOP and USAID requested that CDC inspect the facility and make recommendations about future activities. What follows are the assessment of the IDP camps, the lead treatment center and ancillary services as well as recommendations for future activities to prevent childhood lead poisoning among the Roma. The visit was conducted by Dr. Mary Jean Brown Chief, Lead Poisoning Prevention Branch CDC and Mr. Barry Brooks Acting Team Lead, Lead Poisoning Prevention Branch CDC. # Assessment: Lead Contamination of the Sites: Cesmin Lug: This camp has at least 4 sources of lead exposure for children. 1)The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) There is evidence of informal lead smelting activity in the camp. Informal smelting is a cottage industry for the Roma. Ingots are collected by a local businessman in a building within easy walking distance of the camp. Currently Roma receive 30-40 cents per kilo of lead. Collection and distribution of the product is sophisticated and involves large corporations. According to the Trepca mine directors, the lead produced by the Roma finds its way to the world market. Burn areas in the camp adjacent to the houses are undoubtedly heavily contaminated. Children play in these areas, and the dust is walked into the house by children and adults, particularly those who don't wear shoes. 3) Many of the doors and window frames are painted with lead paint, and they are peeling profusely. 4) There is evidence of recent informal lead smelting in the old Kablar camp which is adjacent to Cesmin Lug. The education activities conducted by trained health education workers (facilitators) in the camps are undoubtedly responsible for moving the informal smelting activity from Cesmin Lug to Kablar. Nonetheless, the smoke and dust from lead smelting can be carried home by the individuals who are engaging in it and contaminate the home environment. Osterode: This camp has at least 2 sources of lead exposure for children. 1) The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) Individuals in Osterode may also be engaged in the informal lead smelting in the old Kablar camp. The smoke and dust from these activities can be carried home by the individuals who are engaging in them and contaminate the home environment. However, in 2006 the site was inspected by Mr. Brooks, a licensed lead inspector from CDC. The site was found to be lead-safe. Recommendations for maintaining lead safety─ including washing down paved surfaces every day─are in place and were visible during the visit in June 2007. In addition, families in Osterode are visited by health educators (facilitators) who reinforce the need for families to implement measures to decrease lead contamination including removal of shoes when entering the house and good hygiene. These activities were also in evidence during the June 2007 site visit. # Roma Mahala: There is no obvious source of lead exposure in the Mahala. The Trepca directors informed CDC that in the past the Mahala was perhaps the least contaminated area in Mitrovica. Although in the past there were reports that informal smelting was also occurring in the Mahala near the river, the onsite police and the headman deny this. The policeman could describe what to look for to identify a smelting site, i.e. burn areas and discarded battery casings. # Population: Most Roma camp residents are younger than 30 years of age. They appear in general good health, although oral health is quite a problem. The average age of first birth is about 15 years old for girls. The infants are well nourished and active. However, several toddlers appeared pale and listless. There was one report of a child with a seizure disorder and several complaints of back aches and shortness of breath among the few elderly people we talked to. A total of about 395 people live in Osterode and 134 in Cesman Lug (NCA census 4/3/07). At least at this time, 30 percent of the total number of residents of Osterode and Cesmin Lug camp do not have a right to return to the Mahala, because they did not live there in 1999. A total of 80 people are considered 'illegal' because they are not former residents of the lead-contaminated camps (Kablar, Cesmin Lug or Zitkovack Camps). Of these 80, 5 families (24 people) that cannot return to the Mahala live in Cesmin Lug. These include Roma families from Serbia and Montenegro that are reportedly moving into Cesmin Lug. It seems likely that at least 2 families have recently moved into Cesmin Lug from outside Kosovo, but this needs to be verified. # Blood Lead Surveillance Program: There are 300 children younger than 14 years old living in both camps; approximately 70 in Cesmin Lug (NCA census 4/3/07) and 230 in Osterode (214 by latest NCA census of 4/3/07). Both WHO and the clinic medical director estimated that 95% of these children have had at least one BLL test. The BLL data have been reported to parents but have not been formally released by WHO because interpretation of these data is difficult due to non-statndardized collection, relocation of families among the camps and to the Mahala and selection bias. The clinic medical director, WHO, and a cursory review of the clinic records by CDC's Dr.Brown, showed that 3 rounds of blood lead surveillance of about 100 children each were conducted recently: in Fall 2005, January 15-26, 2007, and June 4-8, 2007 Approximately 39 children in the first round, 32 children in the second round, and 29 children in the third round had capillary BLLs > 45 µg/dL. Attempts are made to collect venous BLLs during the surveillance screening; however, not all children will submit to the test. These children are recalled if necessary. All blood lead analysis is done at the Institute of Public Health in North Mitrovica, where capillary samples are analyzed using the hand held Lead Care analyzer. It is not clear what method is used for the venous confirmation. However, the Institue plans to purchase a graphite furnace atomic absorption spectrophotometer . # Lead Clinic: The clinic medical director in Osterode is following CDC recommendations for treatment; treating children with venous blood lead levels (BLLs) >45µg/dL with DMSA 200 mg/twice a day. He has modified the protocol slightly and is also treating children with first capillary BLLs >45µg/dL and follow up venous BLLs >35 µg/dL and ZPP > 40 µg/dL, because he has found that venous samples from the Public Health Institute in North Mitrovicia tend to be lower than those from the CDC quality assurance program or the capillary samples. The causes of this bias are unclear but may relate both to the instrumentation used in the laboratory at the Public Health Institute and the expected difference between venous and capillary BLL. Follow up of children was hampered by a 2-month-long job action by the physicians. This also hampered repeat testing of those children from the second round of surveillance testing. Children with elevated capillary tests in January, 2007 had repeat BLLs the first week of June according to the medical director. Of the 31/2 who required testing 15 have been repeated, 7 have moved to the Mahala and 9 ) have refused the test. Discrepancies in record keeping and movement within and into the camps makes a full accounting difficult, thus the reported number of individuals does not sum to the total. We were unable to determine the status of confirmatory testing for the 29 children tested during the third round of surveillance testing,. The medical director seemed unaware of this last round of surveillance testing; however, the records are in the clinic. # Ancillary Services: An early childhood education center provides PATCH education support to 10 children less than 6 years old whose BLLs are currently elevated, although if other children stop by they are not turned away. One child receives in-home education under this program. A nutritional survey on the Roma children less than 6 years old was conducted by WHO and identified malnutrition. Food packages are delivered to each family in both camps. Distribution occurs at Osterode camp. Families at Cesmin Lug come to Osterode to pick up the food. There are reports that families who live in the Mahala but who maintain a residence at one of the camps also may be receiving the supplemental food packages. The purpose of the food distribution is to reduce lead absorption among children by ensuring adequate iron, calcium and zinc intake. Although prevention of micro-nutrient deficiencies is essential for growth and overall good health, few data exist to support a supplemental food program to treat or prevent lead poisoning. Many Roma told us how important the food supplements were to them, and in the Mahala, families that no longer received the food supplements complained bitterly. However, the amount of snack food wrappers and other food-related litter in the camps indicate the families may have other sources of food available. Camp administrators feel that food distribution has lead to a 'culture of dependency' with the result that the Roma are not employed, have not been integrated in to the wider Mitrovica society and are reluctant to relocate to the Roma Mahala where food packages are available only for the first month of residence. # Recommendations	# Summary: Lead exposure is a continuing urgent health problem for Roma in Kosovo. The Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO) and the United Nations International Children's' Emergency Fund (UNICEF) have collaborated in blood lead surveillance of the Roma children living in displacement camps in Kosovo. In the last 3 rounds of blood lead testing, conducted between 2005 and 2007, on average, 30% of children tested had capillary blood lead levels > 45 µg/dL, the level at which CDC recommends chelation therapy. Few if any children in the camps have maintained a blood lead level < 10 µg/dL for their entire childhood. These children are at tremendous risk for a lifetime of developmental and behavioral disabilities and other adverse health conditions. The Cesmin Lug camp is the most highly contaminated camp and should be closed immediately. The situation in Cesmin Lug is made more critical because Roma living in Serbia and Montenegro are now moving into vacant dwellings in the camp. Dwellings that are currently vacant should be demolished immediately. These dwellings are not only contaminated by lead but a clear and present fire hazard. In addition, uncontrolled informal smelting at the now closed Kablar camp must be stopped. These activities result in lead exposure to children in both Cesmin Lug and Osterode Camps. Lack of data has hampered decision making and resulted in confusion on the part of Roma and others as to the seriousness of the problem and the extent of the environmental contamination. A periodic, systematic review of the data would provide important information about the quality of the children's clinical care. Reportedly 39 children have been chelated. Perhaps as many as 90 children are candidates for therapy. The actual number cannot be determined at this time. Lead exposure should be a priority for repatriation to the Roma Mahala. Plans should be developed for continued medical surveillance of these children when they are repatriated to Roma Mahala. # Background: Kosovo is a Province within the borders of the former Yugoslavia that is currently controlled by the United Nations (UN). This territory has experienced multiple infrastructure, economic, human rights, and public health problems as a result of the conflicts in the Balkans. International aid has been focused on maintaining peace and establishing basic services. However, economic development has recently become a priority for the UN Mission in Kosovo (UNMIK), the United States Office in Pristina (USOP) and USAID. The Trepca mining and smelting complex, established in the 1930s, constituted the biggest mining company in Europe. The Trepca smelter in Mitrovica extracted metals including zinc, arsenic, lead, and cadmium from the products of nearby mines. Trepca operations have been an important part of the Mitrovica economy in the past, providing employment in both the smelter and the mines to people in the region, but the UN halted operations in 2000 after UN peace keeper forces in the area were discovered to have high blood lead levels (BLLs). Work is underway to reopen the Trepca smelter and mining compound in North Mitrovica. Currently ( 2007) about 3000 people are employed in the facility. The Trepca board of directors has requested funding from a donor nation to purchase a briquetting machine to increase production in the secondary smelting operation. This fall the World Bank intends to begin discussions about reopening the Treca complex, potentially enabling many people to gain employment. Although the smelter has been closed since 2000, the environment remains heavily contaminated. Three mine tailing dams (2 unremediated and 1 remediated) are located in northern Mitrovica and the nearby town of Zvecan/ Zhikoc. Results from soil samples taken by staff of the World Health Organization (WHO) in 2004 as part of a health risk assessment for heavy metals in Mitrovica and Zvecan showed that more than 90% of the samples exceeded the UK limits for lead (450 mg/Kg), with many samples having levels more than 10 times higher than the limit; more than 40% exceeded the limit for arsenic levels; and almost 30% exceeded the limit for cadmium levels. Both the northern and southern areas of Mitrovica are contaminated by lead. However, the results of both environmental testing and blood testing indicate that Mitrovica is more contaminated north of the river where the Trepca smelter is located. The results of tests on drinking water show that generally drinking water quality appears to be acceptable. Testing conducted by WHO in the general Mitrovica area in 2004 found that BLLs in the general population had fallen; however, BLLs remained dangerously high in the Roma, Ashkali, and Egyptian (RAE) communities. The RAE, also referred to collectively as "Roma," have lived in Mitrovica for many years. Before the Balkan conflict (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999) they lived in a southern Mitrovica neighborhood known as Roma Mahala. In the immediate period following the 1999 Kosovo conflict, Roma Mahala was destroyed. The Office of the United Nations High Commissioner for Refugees (UNHCR) constructed two internal displacement (IDP) camps as a temporary housing solution for the Roma who were left homeless. A third unofficial camp, Kablar, was developed after the occupation of French KFOR barracks in 2001. Unfortunately, the camps were established in highly lead-contaminated areas in northern Mitrovica and Zvecan/ Zhikoc. The camps are located within 3 kilometers of the Trepca smelter and within 300 meters of two mine tailing sites. In June 2005, reports of symptomatic lead poisoning among children in Mitrovica, Kosovo, reached the Centers for Disease Control and Prevention (CDC). The children most affected by the lead contamination in Mitrovica are the Roma whose homes were destroyed during the war and who have been relocated to camps on land contaminated with lead and other heavy metals near the Trepca smelter in Mitrovica. In addition, the Roma engage in informal smelting of car batteries and computers. Initial blood lead testing of children in the 3 IDP camps Cesmin Lug, Kablar and Zitkovac/Zhikoc indicated that all children had blood lead levels (BLLs) > 65 µg/dL, the highest value reported out using the hand held LeadCare analyzer. As a result, in July 2005 the World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF) requested assistance from CDC. Specifically CDC was requested to make recommendations for 1) a medical facility to identify and treat children with lead poisoning, 2) outreach and health education to the affected community and 3) a strategy for primary prevention of childhood lead poisoning. During a 5-day visit in August 2005, CDC staff met with Roma community leaders, representatives from nongovernmental organizations (NGOs), and officials from United Nations agencies to discuss current and planned activities related to lead exposure and prevention of lead poisoning. A detailed plan for a heavy metals treatment facility was provided to WHO and UNICEF. CDC continued to maintain contact with these agencies providing technical assistance and support as needed through telephone calls and email. In January 2006, the Kosovo Office of UNICEF invited CDC to revisit the Mitrovica area. The main objectives of the 2-week visit in January 2006 were 1) to review the status of progress on the CDC recommendations for BLL surveillance and medical treatment of children with lead poisoning, 2) assist in the efforts to assess and remediate lead hazards in the three Roma camps (Cesmin Lug, Kablar,and Zitkovac/Zhikoc), and 3) evaluate the lead hazards at the proposed new camp location at Osterode. The inspection of Osterode camp determined that the camp was lead safe. As a result, UNMK requested and received $US 1 million from USOP to set up a medical treatment facility at Osterode camp. CDC continued to provide technical assistance and support regarding treating lead poisoning among Roma children and prevention of lead exposure. In August 2006, 2 laboratorians from the WHO-sponsored Public Health Institute in Pristina came to the environmental laboratory at CDC to be trained in the use of graphite furnace atomic absorption spectrophotometery for blood lead analysis. Since their visit the laboratory in Pristina has participated in a quality assurance and control program at CDC. The results of the proficiency testing indicate that the laboratory in Pristina meets standards for blood lead testing laboratories established in Europe and the United States. In May 2007, as a result of continued concern about the clinical services provided by the treatment unit in Osterode camp, the US State Department, USOP and USAID requested that CDC inspect the facility and make recommendations about future activities. What follows are the assessment of the IDP camps, the lead treatment center and ancillary services as well as recommendations for future activities to prevent childhood lead poisoning among the Roma. The visit was conducted by Dr. Mary Jean Brown Chief, Lead Poisoning Prevention Branch CDC and Mr. Barry Brooks Acting Team Lead, Lead Poisoning Prevention Branch CDC. # Assessment: Lead Contamination of the Sites: Cesmin Lug: This camp has at least 4 sources of lead exposure for children. 1)The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) There is evidence of informal lead smelting activity in the camp. Informal smelting is a cottage industry for the Roma. Ingots are collected by a local businessman in a building within easy walking distance of the camp. Currently Roma receive 30-40 cents per kilo of lead. Collection and distribution of the product is sophisticated and involves large corporations. According to the Trepca mine directors, the lead produced by the Roma finds its way to the world market. Burn areas in the camp adjacent to the houses are undoubtedly heavily contaminated. Children play in these areas, and the dust is walked into the house by children and adults, particularly those who don't wear shoes. 3) Many of the doors and window frames are painted with lead paint, and they are peeling profusely. 4) There is evidence of recent informal lead smelting in the old Kablar camp which is adjacent to Cesmin Lug. The education activities conducted by trained health education workers (facilitators) in the camps are undoubtedly responsible for moving the informal smelting activity from Cesmin Lug to Kablar. Nonetheless, the smoke and dust from lead smelting can be carried home by the individuals who are engaging in it and contaminate the home environment. Osterode: This camp has at least 2 sources of lead exposure for children. 1) The camp is downwind of lead mine tailings, raising ambient soil and air lead levels. 2) Individuals in Osterode may also be engaged in the informal lead smelting in the old Kablar camp. The smoke and dust from these activities can be carried home by the individuals who are engaging in them and contaminate the home environment. However, in 2006 the site was inspected by Mr. Brooks, a licensed lead inspector from CDC. The site was found to be lead-safe. Recommendations for maintaining lead safety─ including washing down paved surfaces every day─are in place and were visible during the visit in June 2007. In addition, families in Osterode are visited by health educators (facilitators) who reinforce the need for families to implement measures to decrease lead contamination including removal of shoes when entering the house and good hygiene. These activities were also in evidence during the June 2007 site visit. # Roma Mahala: There is no obvious source of lead exposure in the Mahala. The Trepca directors informed CDC that in the past the Mahala was perhaps the least contaminated area in Mitrovica. Although in the past there were reports that informal smelting was also occurring in the Mahala near the river, the onsite police and the headman deny this. The policeman could describe what to look for to identify a smelting site, i.e. burn areas and discarded battery casings. # Population: Most Roma camp residents are younger than 30 years of age. They appear in general good health, although oral health is quite a problem. The average age of first birth is about 15 years old for girls. The infants are well nourished and active. However, several toddlers appeared pale and listless. There was one report of a child with a seizure disorder and several complaints of back aches and shortness of breath among the few elderly people we talked to. A total of about 395 people live in Osterode and 134 in Cesman Lug (NCA census 4/3/07). At least at this time, 30 percent of the total number of residents of Osterode and Cesmin Lug camp do not have a right to return to the Mahala, because they did not live there in 1999. A total of 80 people are considered 'illegal' because they are not former residents of the lead-contaminated camps (Kablar, Cesmin Lug or Zitkovack Camps). Of these 80, 5 families (24 people) that cannot return to the Mahala live in Cesmin Lug. These include Roma families from Serbia and Montenegro that are reportedly moving into Cesmin Lug. It seems likely that at least 2 families have recently moved into Cesmin Lug from outside Kosovo, but this needs to be verified. # Blood Lead Surveillance Program: There are 300 children younger than 14 years old living in both camps; approximately 70 in Cesmin Lug (NCA census 4/3/07) and 230 in Osterode (214 by latest NCA census of 4/3/07). Both WHO and the clinic medical director estimated that 95% of these children have had at least one BLL test. The BLL data have been reported to parents but have not been formally released by WHO because interpretation of these data is difficult due to non-statndardized collection, relocation of families among the camps and to the Mahala and selection bias. The clinic medical director, WHO, and a cursory review of the clinic records by CDC's Dr.Brown, showed that 3 rounds of blood lead surveillance of about 100 children each were conducted recently: in Fall 2005, January 15-26, 2007, and June 4-8, 2007 Approximately 39 children in the first round, 32 children in the second round, and 29 children in the third round had capillary BLLs > 45 µg/dL. Attempts are made to collect venous BLLs during the surveillance screening; however, not all children will submit to the test. These children are recalled if necessary. All blood lead analysis is done at the Institute of Public Health in North Mitrovica, where capillary samples are analyzed using the hand held Lead Care analyzer. It is not clear what method is used for the venous confirmation. However, the Institue plans to purchase a graphite furnace atomic absorption spectrophotometer . # Lead Clinic: The clinic medical director in Osterode is following CDC recommendations for treatment; treating children with venous blood lead levels (BLLs) >45µg/dL with DMSA 200 mg/twice a day. He has modified the protocol slightly and is also treating children with first capillary BLLs >45µg/dL and follow up venous BLLs >35 µg/dL and ZPP > 40 µg/dL, because he has found that venous samples from the Public Health Institute in North Mitrovicia tend to be lower than those from the CDC quality assurance program or the capillary samples. The causes of this bias are unclear but may relate both to the instrumentation used in the laboratory at the Public Health Institute and the expected difference between venous and capillary BLL. Follow up of children was hampered by a 2-month-long job action by the physicians. This also hampered repeat testing of those children from the second round of surveillance testing. Children with elevated capillary tests in January, 2007 had repeat BLLs the first week of June according to the medical director. Of the 31/2 who required testing 15 have been repeated, 7 have moved to the Mahala and 9 ) have refused the test. Discrepancies in record keeping and movement within and into the camps makes a full accounting difficult, thus the reported number of individuals does not sum to the total. We were unable to determine the status of confirmatory testing for the 29 children tested during the third round of surveillance testing,. The medical director seemed unaware of this last round of surveillance testing; however, the records are in the clinic. # Ancillary Services: An early childhood education center provides PATCH education support to 10 children less than 6 years old whose BLLs are currently elevated, although if other children stop by they are not turned away. One child receives in-home education under this program. A nutritional survey on the Roma children less than 6 years old was conducted by WHO and identified malnutrition. Food packages are delivered to each family in both camps. Distribution occurs at Osterode camp. Families at Cesmin Lug come to Osterode to pick up the food. There are reports that families who live in the Mahala but who maintain a residence at one of the camps also may be receiving the supplemental food packages. The purpose of the food distribution is to reduce lead absorption among children by ensuring adequate iron, calcium and zinc intake. Although prevention of micro-nutrient deficiencies is essential for growth and overall good health, few data exist to support a supplemental food program to treat or prevent lead poisoning. Many Roma told us how important the food supplements were to them, and in the Mahala, families that no longer received the food supplements complained bitterly. However, the amount of snack food wrappers and other food-related litter in the camps indicate the families may have other sources of food available. Camp administrators feel that food distribution has lead to a 'culture of dependency' with the result that the Roma are not employed, have not been integrated in to the wider Mitrovica society and are reluctant to relocate to the Roma Mahala where food packages are available only for the first month of residence. # Recommendations	None	None
3ae07efc12a37681ab962b803d8a13b3f50a8305	cdc	None	Not in excess of 0.5 mg/m3 Any dust and mist respirator, except single-use, Not in excess of 1 mg/m3 Any dust and mist respirator, except single-use respirator or quarter mask. Any fume respirator or high efficiency particulate filter respirator. Not in excess of 5 mg/m^A ny supplied-air respirator. Any self-contained breathing apparatus. A high efficiency particulate filter respirator with a full facepiece. Any supplied-air respirator with a full facepiece. Any self-contained breathing apparatus with a full facepiece. Not in excess of 100 mg/m^ A powered air-purifying respirator with a high efficiency particulate filter.standard, enviromental levels shall be monitored every 3 months. This increased frequency of monitoring shall be continued at least 6 months (i.e. two more quarterly monitoring periods) after the last sampling that demonstrated levels at or above the environmental limit. Periodic environmental sampling shall be performed to coincide with periodic biologic sampling, i.e. shall be performed within 2 weeks of biologic sampling.Breathing zone samples shall be collected to permit construction of a timeweighted average exposure for every operation.- (b) Records shall be maintained for all sampling schedules to include the sampling methods, analytical methods, type of respiratory protection in use (if applicable), and the concentrations of inorganic lead in each work area. Records shall be maintained so that they can be classified by employee. Each employee shall be able to obtain information on his own environmental exposure. (c) Medical records shall include information on all biologic determinations and of all required medical examinations. These records shall be kept for at least 30 years following the last occupational exposure to inorganic l e a d . Guidance for establishing worker exposure measurements are given in DHEW(NIOSH) Publication No 77-173, Occupational Exposure Sampling Strategy Manual, available from the Division of Technical Services# I. REVISED RECOMMENDATION FOR AN INORGANIC LEAD STANDARD The Procedures for sampling and analysis of blood for lead shall be as described in Appendix II, or by any method shown to be equivalent in precision and accuracy. All workers subject to "exposure to inorganic lead" shall be offered biologic monitoring at least every 6 months. The schedule of biologic monitoring may be made more frequent if indicated by a professional industrial hygiene survey. If environmental sampling and analysis show that environmental levels are at or greater than the recommended environmental levels, the Interval of biologic monitoring shall be halved, I.e. blood analysis shall be conducted quarterly. This increased frequency shall be continued for at least 6 months after the high environmental level has been shown. If a blood lead level of 0.060 mg Pb/100 g or greater is found, and confirmed by a second sample to be taken within two weeks, steps to reduce absorption of lead shall be taken as soon as the high levels are confirmed. Steps to be considered should include improvement of environmental controls, of personal protection or personal hygiene, and use of administrative controls. A medical examination for possible lead poisoning shall be made available to workers with unacceptable blood lead levels. Engineering controls shall be used wherever feasible to maintain inorganic lead concentrations at or below the prescribed limits. Compliance with the prescribed limits by the use of respirators is allowed only when inorganic lead concentrations are in excess of the workplace environmental limit because required engineering controls are being installed or tested, when nonroutine maintenance or repair is being accomplished, or during emergencies. Appropriate respirators as described in Table 1-1 shall only be selected and used pursuant to the following requirements: (1) For the purpose of determining the class of respirator to be used, the employer shall measure the atmospheric concentration of inorganic lead in the workplace initially and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the inorganic lead concentration. (2) The employer shall ensure that no employee is exposed to inorganic lead above the recommended limit because of improper respirator selection, fit, use, or maintenance. (3) Employees experiencing breathing difficulty while using respirators shall be referred to a physician for evaluation. This evaluation should investigate if the employee has adequate ventilatory capacity, any evidence of obstructive lung disease, and the employees ability to use negative or positive pressure respirators. (5) The employer shall provide respirators in accordance with the Table 1-1, below and shall assure that the employee uses the respirator provided at all times when the concentration of inorganic lead exceeds the permissible limit. (6) If both fume and dust are present, the recommended usage is that for fume. (7) The employer shall provide respirators in accordance with (2) Respirators shall be available for wearing during evacuation procedures if long distances need to be traversed; supplied air respirators shall be available for employee use where equipment or operations cannot be abandoned. # (b) Exhaust Systems Where a local exhaust ventilation and collection system is used, it shall be designed and maintained to prevent the accumulation of lead dust and fume. (1) Hazardous types of exposure should not be scattered throughout a plant but, rather, concentrated in a single area where special control procedures can be utilized. (2) Air from the exhaust ventilation systems shall not be recirculated into the workroom, and should not be discharged outside the plant so as to create an air pollution problem. # (c) General Housekeeping (1) Vacuuming shall be used wherever practicable and no dry sw ^eping or blowing shall be performed. The refining and processing necessary to form these products include heating, grinding, and volatilization and therefore produce potentially hazardous industrial atmospheres. The impression should not be left that all workers in these industries are jeopardized, but rather that such uses of lead places them at risk of lead absorption. The prevalence of lead poisoning in ancient times is speculated upon, and it has been suggested that Rome fell because of the prevalence of lead III-2 poisoning (plumbism) in its citizens. It seems likely that, with the ignorance that existed on the hazards of lead and on methods of limiting exposure, there was a significant incidence of plumbism until Its recognition in recent times generated preventive procedures. There was a non-significant increase in chest disease among older retired workers, attributed to other causes, since most of these pensioners lived in an urban area with a higher rate of death from chest disease than that in the country as a whole. # Effects on Humans # Concentrations of lead In blood are expressed as weight units (such as mg) per 100 ml or 100 g of whole blood. European workers more commonly express blood lead as weight units per 100 ml of blood, while American workers more commonly express blood lead as weight units per 100 g of blood. This document will follow the American custom except In referring to studies reporting blood lead in weight units per 100 ml. The difference between the two expressions Is small, about 5% or less. Thus, a blood lead concentration of 0.080 mg/100 g would be equivalent to about 0.084 mg/100 ml. # III-8 Unlike the findings of earlier investigators (Dingwall-Fordyce and Lane, APPENDIX II. and # DITHIZONE METHOD OF ANALYSIS OF LEAD IN AIR AND BIOLOGIC SAMPLES The Phenol Red -0.1% aqueous solution. Ashing Aid Acid -Dissolve 25 g potassium sulfate in sufficient redistilled concentrated nitric acid to make 1 0 0 ml. # VIII-6 White Petrolatum -Supplied in a glass jar, for greasing stopcocks. To check on the purity, put a pinch of this petrolatum in a beaker, add a few milliliters of the standard dithizone and swirl. If the dithizone is no longer green after a few minutes, the material is unsatisfactory for greasing stopcocks. # APPARATUS Set the instrument at zero absorbance using the zero lead standard solution. Read the absorbances of the samples and of the reagent blank. V III-11 (3) 0.5 ml of blood plus 4.5 ml of 2% Triton X (4) 0.5 ml blood plus 1.0 ml of Unisol. Let the mixture stand overnight, then add 3.5 ml of doubly distilled water It is unlikely that we will soon be able to fully evaluate the contribution of the many factors involved in lead poisoning. Thus far, it is known that dietary sources, physiological state, age, sex, and parameters of exposure conditions (e.g., solubility, particle size) are all involved in the production of lead intoxication. # and finishing machines such as saws, bevelers, planers and routers # Adapted from reference ^ REPRESENTATIVE LEAD EXPOSURE IN PRINTING OPERATIONS # Subacute and Chronic Toxicity of Inorganic Lead (Cont'd) Animal Properly designed studies may be able to more fully characterize these relationships, while also identifying situations where individuals may be at increased risk of poisoning. # VIII. RESEARCH NEEDS X I -68 The literature search strategy employed in preparing this update consisted of both computerized and manual techniques. Major reliance for bibliographic information was placed on a computer-generated NIOSHTIC search. In order to supplement this citation source, several steps were taken to insure that: (1 ) all relevant articles would be retrieved, and (2 ) very recent articles of relevance to the literature review would not be overlooked. An on-line search using lead and related keywords (e.g., plumbism, pica, ALAD, protoporphyrin) was undertaken using the following data bases: # V-10 # VI. REFERENCES Westerman and coworkers were not able to correlate lead absorption with the development of multiple sclerosis in humans. # Renal Damage Occupational lead nephropathy in adults is a relatively uncommon occurrence in the United States and, thus far, has been poorly characterized in its pathogenesis. However, recent studies have suggested that chronic lead nephropathy may be going unrecognized due to a lack of correlation with blood lead concentrations. An excessive incidence of kidney dysfunction (elevated blood urea nitrogen and creatinine) was found among lead plant workers [1 1 # Intratracheal injection # Se i z u r e s ob s e r v e d in lead-treated adu l t s a l o n g w i t h g e n eralized 172 c e rebral edema of the wh i t e matt e r and focal cortical necroses, p r o b a b l y d u e to epi leptic convulsions. In the infant, generalized edema of the wh i t e mat t e r w a s observed; the animal died on day 117. # 09-IX # ppm lead a s lead a c e t a t e f r o m a g e 6 to 18 w e e k s fed wi t h a c a lciuma n d -p h o s p h o r u s -l o w purified diet # Cyclic response m a n i fested as an initial anorexic phase (first 4 weeks) followed by an accI i m a t i z a t i o n phase (weeks 4 to 7) and a terminal debil i t a t l v e cachectic stage (after c o n s u m i ng 191 mg lead/kg body weight). S ignificant anemia, leukopenia, and n ormoblastocytosis w i t h i n 6 weeks. A l s o present w e r e nonspecific serum en z y m e alterations, hydropic d e g e n e r a t i o n of s p e r m a t o gonia, and h i s t o p a t h ologic c h a n g e s in # Increased blood and ur i n e lead levels. Increased urinary A L A excretion, a n d d e c reased eryth r o c y t e A L A D a c t i v i t y in all groups. No effect on d e c r e a s e d AT P a s e a c # Harked r ed u c t i o n in e r y t h r o cyte A L A D activ i t y but no changes in l evels of exc r e t e d h eme precursors. No c h a nges detected in se r u m che m i s t r y or hematology; no h i s t o p athologic damage. # Ibb # Signs of hema t o l o g i c a l t e r a t i o n not evident before 8 weeks. Effects included dep r e s s e d o x i d a t i v e a c t i v i t y in reticulocytes and # XII-20 D E P A R T M E N T OF HEALTH, EDUCATION, A N D W E L F A R E PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R	Not in excess of 0.5 mg/m3 Any dust and mist respirator, except single-use, Not in excess of 1 mg/m3 Any dust and mist respirator, except single-use respirator or quarter mask. Any fume respirator or high efficiency particulate filter respirator. Not in excess of 5 mg/m^A ny supplied-air respirator. Any self-contained breathing apparatus. A high efficiency particulate filter respirator with a full facepiece. Any supplied-air respirator with a full facepiece. Any self-contained breathing apparatus with a full facepiece. Not in excess of 100 mg/m^ A powered air-purifying respirator with a high efficiency particulate filter.standard, enviromental levels shall be monitored every 3 months. This increased frequency of monitoring shall be continued at least 6 months (i.e. two more quarterly monitoring periods) after the last sampling that demonstrated levels at or above the environmental limit. Periodic environmental sampling shall be performed to coincide with periodic biologic sampling, i.e. shall be performed within 2 weeks of biologic sampling.Breathing zone samples shall be collected to permit construction of a timeweighted average exposure for every operation.* (b) Records shall be maintained for all sampling schedules to include the sampling methods, analytical methods, type of respiratory protection in use (if applicable), and the concentrations of inorganic lead in each work area. Records shall be maintained so that they can be classified by employee. Each employee shall be able to obtain information on his own environmental exposure. (c) Medical records shall include information on all biologic determinations and of all required medical examinations. These records shall be kept for at least 30 years following the last occupational exposure to inorganic l e a d . Guidance for establishing worker exposure measurements are given in DHEW(NIOSH) Publication No 77-173, Occupational Exposure Sampling Strategy Manual, available from the Division of Technical Services# I. REVISED RECOMMENDATION FOR AN INORGANIC LEAD STANDARD The Procedures for sampling and analysis of blood for lead shall be as described in Appendix II, or by any method shown to be equivalent in precision and accuracy. All workers subject to "exposure to inorganic lead" shall be offered biologic monitoring at least every 6 months. The schedule of biologic monitoring may be made more frequent if indicated by a professional industrial hygiene survey. If environmental sampling and analysis show that environmental levels are at or greater than the recommended environmental levels, the Interval of biologic monitoring shall be halved, I.e. blood analysis shall be conducted quarterly. This increased frequency shall be continued for at least 6 months after the high environmental level has been shown. # 1-2 If a blood lead level of 0.060 mg Pb/100 g or greater is found, and confirmed by a second sample to be taken within two weeks, steps to reduce absorption of lead shall be taken as soon as the high levels are confirmed. Steps to be considered should include improvement of environmental controls, of personal protection or personal hygiene, and use of administrative controls. A medical examination for possible lead poisoning shall be made available to workers with unacceptable blood lead levels. Engineering controls shall be used wherever feasible to maintain inorganic lead concentrations at or below the prescribed limits. Compliance with the prescribed limits by the use of respirators is allowed only when inorganic lead concentrations are in excess of the workplace environmental limit because required engineering controls are being installed or tested, when nonroutine maintenance or repair is being accomplished, or during emergencies. Appropriate respirators as described in Table 1-1 shall only be selected and used pursuant to the following requirements: (1) For the purpose of determining the class of respirator to be used, the employer shall measure the atmospheric concentration of inorganic lead in the workplace initially and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the inorganic lead concentration. (2) The employer shall ensure that no employee is exposed to inorganic lead above the recommended limit because of improper respirator selection, fit, use, or maintenance. # 1-5 (3) Employees experiencing breathing difficulty while using respirators shall be referred to a physician for evaluation. This evaluation should investigate if the employee has adequate ventilatory capacity, any evidence of obstructive lung disease, and the employees ability to use negative or positive pressure respirators. (5) The employer shall provide respirators in accordance with the Table 1-1, below and shall assure that the employee uses the respirator provided at all times when the concentration of inorganic lead exceeds the permissible limit. (6) If both fume and dust are present, the recommended usage is that for fume. (7) The employer shall provide respirators in accordance with (2) Respirators shall be available for wearing during evacuation procedures if long distances need to be traversed; supplied air respirators shall be available for employee use where equipment or operations cannot be abandoned. # (b) Exhaust Systems Where a local exhaust ventilation and collection system is used, it shall be designed and maintained to prevent the accumulation of lead dust and fume. (1) Hazardous types of exposure should not be scattered throughout a plant but, rather, concentrated in a single area where special control procedures can be utilized. (2) Air from the exhaust ventilation systems shall not be recirculated into the workroom, and should not be discharged outside the plant so as to create an air pollution problem. # (c) General Housekeeping (1) Vacuuming shall be used wherever practicable and no dry sw ^eping or blowing shall be performed. The refining and processing necessary to form these products include heating, grinding, and volatilization and therefore produce potentially hazardous industrial atmospheres. The impression should not be left that all workers in these industries are jeopardized, but rather that such uses of lead places them at risk of lead absorption. The prevalence of lead poisoning in ancient times is speculated upon, and it has been suggested that Rome fell because of the prevalence of lead III-2 poisoning (plumbism) in its citizens. It seems likely that, with the ignorance that existed on the hazards of lead and on methods of limiting exposure, there was a significant incidence of plumbism until Its recognition in recent times generated preventive procedures. There was a non-significant increase in chest disease among older retired workers, attributed to other causes, since most of these pensioners lived in an urban area with a higher rate of death from chest disease than that in the country as a whole. # Effects on Humans # Concentrations of lead In blood are expressed as weight units (such as mg) per 100 ml or 100 g of whole blood. European workers more commonly express blood lead as weight units per 100 ml of blood, while American workers more commonly express blood lead as weight units per 100 g of blood. This document will follow the American custom except In referring to studies reporting blood lead in weight units per 100 ml. The difference between the two expressions Is small, about 5% or less. Thus, a blood lead concentration of 0.080 mg/100 g would be equivalent to about 0.084 mg/100 ml. # III-8 Unlike the findings of earlier investigators (Dingwall-Fordyce and Lane, APPENDIX II. and # •DITHIZONE METHOD OF ANALYSIS OF LEAD IN AIR AND BIOLOGIC SAMPLES The Phenol Red -0.1% aqueous solution. Ashing Aid Acid -Dissolve 25 g potassium sulfate in sufficient redistilled concentrated nitric acid to make 1 0 0 ml. # VIII-6 White Petrolatum -Supplied in a glass jar, for greasing stopcocks. To check on the purity, put a pinch of this petrolatum in a beaker, add a few milliliters of the standard dithizone and swirl. If the dithizone is no longer green after a few minutes, the material is unsatisfactory for greasing stopcocks. # APPARATUS # 12. Set the instrument at zero absorbance using the zero lead standard solution. # 13. Read the absorbances of the samples and of the reagent blank. V III-11 (3) 0.5 ml of blood plus 4.5 ml of 2% Triton X (4) 0.5 ml blood plus 1.0 ml of Unisol. Let the mixture stand overnight, then add 3.5 ml of doubly distilled water It is unlikely that we will soon be able to fully evaluate the contribution of the many factors involved in lead poisoning. Thus far, it is known that dietary sources, physiological state, age, sex, and parameters of exposure conditions (e.g., solubility, particle size) are all involved in the production of lead intoxication. # and finishing machines such as saws, bevelers, planers and routers # Adapted from reference ^ REPRESENTATIVE LEAD EXPOSURE IN PRINTING OPERATIONS # Subacute and Chronic Toxicity of Inorganic Lead (Cont'd) Animal Properly designed studies may be able to more fully characterize these relationships, while also identifying situations where individuals may be at increased risk of poisoning. # VIII. RESEARCH NEEDS X I -68 The literature search strategy employed in preparing this update consisted of both computerized and manual techniques. Major reliance for bibliographic information was placed on a computer-generated NIOSHTIC search. In order to supplement this citation source, several steps were taken to insure that: (1 ) all relevant articles would be retrieved, and (2 ) very recent articles of relevance to the literature review would not be overlooked. An on-line search using lead and related keywords (e.g., plumbism, pica, ALAD, protoporphyrin) was undertaken using the following data bases: # V-10 # VI. REFERENCES # Westerman and coworkers [130] were not able to correlate lead absorption with the development of multiple sclerosis in humans. # Renal Damage Occupational lead nephropathy in adults is a relatively uncommon occurrence in the United States and, thus far, has been poorly characterized in its pathogenesis. However, recent studies have suggested that chronic lead nephropathy may be going unrecognized due to a lack of correlation with blood lead concentrations. An excessive incidence of kidney dysfunction (elevated blood urea nitrogen and creatinine) was found among lead plant workers [1 1 # Intratracheal injection # Se i z u r e s ob s e r v e d in lead-treated adu l t s a l o n g w i t h g e n eralized 172 c e rebral edema of the wh i t e matt e r and focal cortical necroses, p r o b a b l y d u e to epi leptic convulsions. In the infant, generalized edema of the wh i t e mat t e r w a s observed; the animal died on day 117. # 09-IX # ppm lead a s lead a c e t a t e f r o m a g e 6 to 18 w e e k s fed wi t h a c a lciuma n d -p h o s p h o r u s -l o w purified diet # Cyclic response m a n i fested as an initial anorexic phase (first 4 weeks) followed by an accI i m a t i z a t i o n phase (weeks 4 to 7) and a terminal debil i t a t l v e cachectic stage (after c o n s u m i ng 191 mg lead/kg body weight). S ignificant anemia, leukopenia, and n ormoblastocytosis w i t h i n 6 weeks. A l s o present w e r e nonspecific serum en z y m e alterations, hydropic d e g e n e r a t i o n of s p e r m a t o gonia, and h i s t o p a t h ologic c h a n g e s in # Increased blood and ur i n e lead levels. Increased urinary A L A excretion, a n d d e c reased eryth r o c y t e A L A D a c t i v i t y in all groups. No effect on d e c r e a s e d AT P a s e a c # Harked r ed u c t i o n in e r y t h r o cyte A L A D activ i t y but no changes in l evels of exc r e t e d h eme precursors. No c h a nges detected in se r u m che m i s t r y or hematology; no h i s t o p athologic damage. # Ibb # Signs of hema t o l o g i c a l t e r a t i o n not evident before 8 weeks. Effects included dep r e s s e d o x i d a t i v e a c t i v i t y in reticulocytes and # XII-20 D E P A R T M E N T OF HEALTH, EDUCATION, A N D W E L F A R E PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A. T A F T L A B O R	None	None
9a885197d2d2308a21e1951fe3fffde34185f6fb	cdc	None	Suicide is a public health issue. Media and online coverage of suicide should be informed by using best practices. Some suicide deaths may be newsworthy. However, the way media cover suicide can influence behavior negatively by contributing to contagion or positively by encouraging help-seeking. References and additional information can be found at: www.ReportingOnSuicide.org. # Important poInts for coverIng suIcIde More than 50 research studies worldwide have found that certain types of news coverage can increase the likelihood of suicide in vulnerable individuals. The magnitude of the increase is related to the amount, duration and prominence of coverage. - Risk of additional suicides increases when the story explicitly describes the suicide method, uses dramatic/ graphic headlines or images, and repeated/extensive coverage sensationalizes or glamorizes a death. - Covering suicide carefully, even briefly, can change public misperceptions and correct myths, which can encourage those who are vulnerable or at risk to seek help. - Big or sensationalistic headlines, or prominent placement (e.g., "Kurt Cobain Used Shotgun to Commit Suicide"). - Including photos/videos of the location or method of death, grieving family, friends, memorials or funerals. - Describing recent suicides as an "epidemic, " "skyrocketing," or other strong terms. - Describing a suicide as inexplicable or "without warning." - "John Doe left a suicide note saying…". - Investigating and reporting on suicide similar to reporting on crimes. - Quoting/interviewing police or first responders about the causes of suicide. - Referring to suicide as "successful," "unsuccessful" or a "failed attempt." do thIs: - Inform the audience without sensationalizing the suicide and minimize prominence (e.g., "Kurt Cobain Dead at 27"). - Use school/work or family photo; include hotline logo or local crisis phone numbers. - Carefully investigate the most recent CDC data and use non-sensational words like "rise" or "higher." - Most, but not all, people who die by suicide exhibit warning signs. Include the "Warning Signs" and "What to Do" sidebar (from p. 2) in your article if possible. - "A note from the deceased was found and is being reviewed by the medical examiner." - Report on suicide as a public health issue. - Seek advice from suicide prevention experts. - Describe as "died by suicide" or "completed" -r "killed him/herself." suicide contagion or "copycat suicide" occurs when one or more suicides are reported in a way that contributes to another suicide. # suggestIons for onlIne medIa, message Boards, Bloggers & cItIzen JournalIsts - Bloggers, citizen journalists and public commentators can help reduce risk of contagion with posts or links to treatment services, warning signs and suicide hotlines. - Include stories of hope and recovery, information on how to overcome suicidal thinking and increase coping skills. - The potential for online reports, photos/videos and stories to go viral makes it vital that online coverage of suicide follow site or industry safety recommendations. - Refer to research findings that mental disorders and/or substance abuse have been found in 90% of people who have died by suicide. - Avoid reporting that death by suicide was preceded by a single event, such as a recent job loss, divorce or bad grades. Reporting like this leaves the public with an overly simplistic and misleading understanding of suicide. - Consider quoting a suicide prevention expert on causes and treatments. Avoid putting expert opinions in a sensationalistic context. - Use your story to inform readers about the causes of suicide, its warning signs, trends in rates and recent treatment advances. - Add statement(s) about the many treatment options available, stories of those who overcame a suicidal crisis and resources for help. - Include up-to-date local/national resources where readers/viewers can find treatment, information and advice that promotes help-seeking.	# Suicide is a public health issue. Media and online coverage of suicide should be informed by using best practices. Some suicide deaths may be newsworthy. However, the way media cover suicide can influence behavior negatively by contributing to contagion or positively by encouraging help-seeking. References and additional information can be found at: www.ReportingOnSuicide.org. # Important poInts for coverIng suIcIde # • More than 50 research studies worldwide have found that certain types of news coverage can increase the likelihood of suicide in vulnerable individuals. The magnitude of the increase is related to the amount, duration and prominence of coverage. • Risk of additional suicides increases when the story explicitly describes the suicide method, uses dramatic/ graphic headlines or images, and repeated/extensive coverage sensationalizes or glamorizes a death. • Covering suicide carefully, even briefly, can change public misperceptions and correct myths, which can encourage those who are vulnerable or at risk to seek help. • Big or sensationalistic headlines, or prominent placement (e.g., "Kurt Cobain Used Shotgun to Commit Suicide"). • Including photos/videos of the location or method of death, grieving family, friends, memorials or funerals. • Describing recent suicides as an "epidemic, " "skyrocketing," or other strong terms. • Describing a suicide as inexplicable or "without warning." • "John Doe left a suicide note saying…". • Investigating and reporting on suicide similar to reporting on crimes. • Quoting/interviewing police or first responders about the causes of suicide. • Referring to suicide as "successful," "unsuccessful" or a "failed attempt." do thIs: • Inform the audience without sensationalizing the suicide and minimize prominence (e.g., "Kurt Cobain Dead at 27"). • Use school/work or family photo; include hotline logo or local crisis phone numbers. • Carefully investigate the most recent CDC data and use non-sensational words like "rise" or "higher." • Most, but not all, people who die by suicide exhibit warning signs. Include the "Warning Signs" and "What to Do" sidebar (from p. 2) in your article if possible. • "A note from the deceased was found and is being reviewed by the medical examiner." • Report on suicide as a public health issue. • Seek advice from suicide prevention experts. • Describe as "died by suicide" or "completed" or "killed him/herself." suicide contagion or "copycat suicide" occurs when one or more suicides are reported in a way that contributes to another suicide. # suggestIons for onlIne medIa, message Boards, Bloggers & cItIzen JournalIsts • Bloggers, citizen journalists and public commentators can help reduce risk of contagion with posts or links to treatment services, warning signs and suicide hotlines. • Include stories of hope and recovery, information on how to overcome suicidal thinking and increase coping skills. • The potential for online reports, photos/videos and stories to go viral makes it vital that online coverage of suicide follow site or industry safety recommendations. • Refer to research findings that mental disorders and/or substance abuse have been found in 90% of people who have died by suicide. • Avoid reporting that death by suicide was preceded by a single event, such as a recent job loss, divorce or bad grades. Reporting like this leaves the public with an overly simplistic and misleading understanding of suicide. • Consider quoting a suicide prevention expert on causes and treatments. Avoid putting expert opinions in a sensationalistic context. • Use your story to inform readers about the causes of suicide, its warning signs, trends in rates and recent treatment advances. • Add statement(s) about the many treatment options available, stories of those who overcame a suicidal crisis and resources for help. • Include up-to-date local/national resources where readers/viewers can find treatment, information and advice that promotes help-seeking.	None	None
55a910c3339d175c25a50c593f9cd664ad7e526d	cdc	None	All material in this publication is in the public domain and may be used and reprinted without permission; citation of the source is, however, appreciated. References to non-CDC sites on the Internet are provided as a service to readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of these sites. URL addresses listed were current as of the date of publication.# Introduction This document is intended to assist health care providers in the United States who are sharing information with men and parents of male infants during decision making about male circumcision conducted by health care providers (i.e. medically performed) as it relates to the prevention of human immunodeficiency virus (HIV) infection, sexually transmitted infections (STIs), and other health outcomes. Such decision-making involves not only health considerations, but also social, cultural, ethical, and religious factors. Counseling regarding these issues can be incorporated into routine discussions of sexual, newborn, and child health. Much of the data related to HIV and STI prevention are from randomized clinical trials conducted among men in sub-Saharan Africa in regions with high rates of heterosexually acquired HIV infection. In the United States, the prevalence of HIV and lifetime risk of HIV infection are generally much lower than that in sub-Saharan Africa. Also, most new HIV infections in the United States are attributed to male-male sexual contact. Pooled data from observational studies 1 in the U.S. and abroad indicate that male circumcision was associated with reduced HIV acquisition among men who have sex with men (MSM) who practiced mainly or exclusively insertive anal sex. However, randomized clinical trials of male circumcision have not included a large enough number of MSM, and many MSM practice both insertive and receptive anal sex. Therefore, although biologically plausible, we are unable to definitively conclude whether male circumcision among MSM practicing mainly or exclusively insertive anal sex reduced the risk of HIV acquisition. While such factors limit the impact of medically performed male circumcision in reducing the overall HIV epidemic in the U.S., 8% of the estimated annual HIV diagnoses in 2014 in the United States were among males with infection attributed to heterosexual contact. 2 _In addition, African-American and Hispanic men have higher risk of HIV infection and lower male circumcision rates than white non-Hispanic males. Similar randomized clinical trials have not been conducted in the United States, but based on evidence from the African trials of the efficacy of male circumcision to prevent HIV transmission, uncircumcised heterosexual men living in areas with high HIV prevalence are likely to experience the most riskreduction benefit from elective male circumcision. # Methods A CDC 2-day symposium was held in April 2007 to obtain input on the potential role of male circumcision in preventing transmission of HIV in the United States. A summary of the 2-day symposium, including a list of the participants has been previously published. 3 The 2-day symposium helped define key issues for inclusion in this informational document. The methods used to gather and summarize evidence supporting this information are reported in "Background, Methods, and Synthesis of Scientific Information Used to Inform 'Information for Providers to Share with Male Patients and Parents regarding Male Circumcision and the Prevention of HIV infection, STIs, and other Health Outcomes.'" The information provided in this document is based on an evaluation of available evidence on the health risks and benefits associated with medically performed male circumcision and were developed to pertain to male adults, adolescents, children, and newborns, and caregivers of male minors charged in the United States. 4 In this document, the preventive benefits of male circumcision are generally expressed as relative-risk reductions (e.g., a 50% reduction from a 2% risk of an STI to a 1% risk), whereas any associated harm is expressed as an absolute risk (e.g., a 2%-4% risk of adverse events). Appropriate denominators are not available in many cases to establish an absolute risk for HIV and other STIs in higher-risk populations (e.g., heterosexual males at increased risk for infection). The citations associated with the information in this document have been graded by adapting a previously published grading scheme. 5 The grading scheme and criteria for inclusion of citations and specific considerations for use of the scheme are described in Appendix 1. The specific grade for each citation in this document can be found in Appendix 2. On December 2, 2014, CDC published a notice in the Federal Register announcing the posting of a draft informational document to obtain public comments (79 FR 71433). CDC received over 3,200 public comments from the public, physicians, and professional organizations. All comments were carefully reviewed and considered in preparation of this final document. In addition to obtaining public comments on the draft informational document, CDC shared a summary of public comments with external experts who conducted a peer review of the evidence on this topic. Their review included an evaluation of completeness, accuracy, interpretation, and generalizability of the evidence to the United States and whether the evidence was sufficient to support the draft informational document. # Review of Evidence Clinical trials conducted in Africa during 2005-2010 have demonstrated safety and significant efficacy of voluntary adult male circumcision performed by clinicians for reducing the risk of acquisition of HIV by males during penile-vaginal sex ("heterosexual sex"). Three randomized clinical trials showed that adult male circumcision significantly reduced the risk for HIV acquisition among heterosexual males by 51%-60% (95% confidence interval 16%-76%) over time. These trials also found that medically performed adult circumcision significantly reduced the risk of men acquiring two common sexually transmitted infections (STIs), including genital ulcer disease (GUD) prevalence by 47% and incidence by 48% 9 and high-risk (i.e. oncogenic) types of human papilloma virus (HR-HPV) prevalence by 23%-47%. In a prospective cohort study nested in a large randomized clinical trial of HIV preexposure prophylaxis in Kenyan and Ugandan HIV-serodiscordant heterosexual couples, male circumcision was associated with a percentage reduction in the incidence of syphilis (42% in men and 59% in women). 13 Because the foreskin can serve as a portal of entry for STIs (including HIV), it is biologically plausible that circumcision plays a role in preventing STI and HIV acquisition through insertive sexual intercourse. Since the release of these trial data, various organizations have updated their recommendations about adult male 14 and infant male circumcision. 15,16 Information to Share # Consideration of factors associated with decision making Health benefits and risks of elective neonatal, adolescent, or adult medically performed male circumcision should be considered in consultation with medical providers while taking into account factors associated with decision-making around male circumcision, including religion, societal norms and social customs, hygiene, aesthetic preference, and ethical considerations. # Providing information to sexually active adolescent and adult males regardless of circumcision status All sexually active adolescent and adult males should consider using other proven HIV and STI risk-reduction strategies such as reducing the number of partners, correct and consistent use of male latex condoms, and HIV preexposure or postexposure prophylaxis. a # Providing information to uncircumcised sexually active adolescent and adult males Prior to sharing information about medically performed male circumcision, uncircumcised sexually active adolescent and adult males should be assessed to determine their HIV risk behaviors, HIV infection status, and the gender of their sexual partner(s). 17 The results of these assessments will inform the discussion with men about the risks and benefits of medically performed male circumcision. 3A-3. Uncircumcised, HIV-uninfected men and male adolescents at increased risk for HIV acquisition through heterosexual sex should be provided information about the risk and benefits of male circumcision (See Box 1). When a decision is made to undergo male circumcision, a referral for surgical consultation and access to medically performed male circumcision surgical services should be provided. # 3A. Providing information # 3B. Providing information to men who have sex with men (exclusively) Healthcare providers should explain that the data regarding the relationship between male circumcision and the acquisition of HIV and other STIs among MSM have a number of limitations and results differ based on predominance of insertive or receptive sexual practice. Based on data from heterosexuals, it is biologically plausible that male circumcision could benefit MSM who practice mainly or exclusively insertive anal sex. Pooled data from observational studies of male circumcision among MSM indicated that overall, male circumcision provided partial protection from HIV acquisition for the partner who practiced mainly or exclusively insertive anal sex. However, because clinical trials of male circumcision did not include large enough numbers of MSM and because many MSM practice both insertive and receptive anal sex, definitive statements cannot be made about whether male circumcision can reduce the risk of acquiring HIV and other STIs. 1 In contrast, male circumcision provides no direct biologically plausible risk-reduction benefit for the receptive anal sex partner and receptive anal intercourse carries a substantially higher risk for acquisition of HIV than insertive sex. # Providing information to parents of male newborns, children, or adolescents Health benefits and risks of elective neonatal, pediatric, or adolescent male circumcision should be considered in consultation with medical providers. Ideally, discussions about neonatal circumcision should occur prior to the birth of the child. Ultimately, whether to circumcise a male neonate or child is a decision made by parents or guardians on behalf of their newborn son or dependent child. When providing information to parents about male circumcision for an adolescent minor, the adolescent should be included in the decision-making process about undergoing elective male circumcision. When providing information to an adolescent inquiring about male circumcision, parents should be engaged in the discussion, unless the adolescent is legally emancipated. Minors may be deemed emancipated, giving them sole authority to make health care decisions on their own behalf under certain circumstances, which vary by state law; for example, if the minor 1) lives independently and is self-supporting, 2) is married, 3) is pregnant or a parent, 4) is in the military, or 5) is declared emancipated by a court as defined in the mature minor section. 20 - Neonatal male circumcision is safer, less expensive, and heals more rapidly than circumcision performed on older boys, adolescent males, and men. - Most of the health benefits of male circumcision occur after sexual debut (i.e. after becoming sexually active). - Male circumcision can also be conducted in adulthood when the individual can make the decision for himself. However, male circumcision after sexual debut could result in missed opportunities for:  HIV and STI prevention during the window period between sexual debut and circumcision  Prevention of UTIs during infancy. - Complications of medically performed male circumcision in the United States are typically uncommon and easily managed. Severe complications are rare in all age groups and occur in 0.23% of all circumcised males overall. 24 - Among newborns and children aged 1-9 years, most frequently reported complications include bleeding and inflammation of the penis or incomplete wound healing or adhesions requiring corrective procedures. b Complications occur in 0.2% of infants aged ≤ 1 month, 0.4% of infants aged <1 year, 24 and approximately 9% in children aged 1-9 years. 24 - Among persons aged 10 years and older, the most frequently reported complications include those complications reported in younger children as well as wounds of the penis. c Complications occur in approximately 5% of persons in this age group. 24 There are not specific data about the frequency of complications in the adolescent age group (13-18 years). o The American Academy of Pediatrics Taskforce on Circumcision states that the health benefits of newborn male circumcision outweigh the risks and that the benefits of newborn male circumcision justify access to this procedure for families who choose it. o In the United States, the estimated lifetime risk of penile cancer for males is about 1 in 1,400 (0.07%) and that of prostate cancer is about 15%. Neonatal male circumcision reduces the risk of invasive penile carcinoma by about 77% and may reduce the risk of prostate cancer by 15% compared to men who are uncircumcised or those circumcised after first sexual intercourse. - Adverse events and risks associated with neonatal, infant, and child male circumcision performed by clinicians: o In the United States, during 2001-2010, - The rates of reported adverse events, not including severe adverse events, a were as follows  0.4% in infants aged <12 months  9.1% in children age 1-9 years  5.3% in persons aged 10 years and older - Most commonly reported complications among newborns and children aged 1 to 9 years: bleeding and inflammation of the penis or incomplete wound healing or adhesions requiring corrective procedures. b o The incidence of severe adverse events associated with male circumcision performed by clinicians, such as permanent disabilities, disfigurements, and death are rare. Other major complications requiring intervention such as major bleeding, and severe infection, are uncommon. o Some men enjoy the sensation of the foreskin during sexual relations, and such a sensation will not be experienced after circumcision; however, the bulk of scientific evidence states that men, on average, do not experience a loss of sexual pleasure or function because of circumcision. a Severe adverse events include outcomes such as permanent disabilities, disfigurements, and death b Frequently reported corrective procedures include repair of incomplete circumcision, lysis or excision of penile post-circumcision adhesions, and division of penile adhesions. # Box 1: Health Benefits and Risks of Elective Medically Performed Male Circumcision - Health benefits of elective male circumcision in adults and adolescents: - Male circumcision reduces the risk of acquiring HIV infection through penile-vaginal sex by 50%-60%, as demonstrated in 3 well-conducted clinical trials among adult men living in sub-Saharan Africa. o In clinical trials involving heterosexual males living in sub-Saharan Africa, male circumcision reduces the risk of some sexually transmitted infections. - Male circumcision reduces the risk of circumcised men acquiring new infections of:  Genital ulcer disease (GUD) (by 48%)  Herpes simplex virus type-2 (HSV-2) (by 28%-45%)  Oncogenic types of human papilloma virus (HPV) (by 24%-47%) - Male circumcision reduces the risk of circumcised men having existing infections of:  GUD (by 47%)  Oncogenic types of HPV (by 25%-47%)  T. vaginalis (by 53%)  M. genitalium (by 46%) - Male circumcision reduces the risk of the female partners of circumcised men having existing infections of:  GUD (by 22%)  Oncogenic types of HPV (by 22%)  T. vaginalis (by 45%)  Bacterial vaginosis (by 40%) - Male circumcision reduces the risk of penile cancer # Adverse events and risks associated with elective male circumcision of adults: - The rate of adverse events, not including severe adverse events in persons aged 10 years and older is 5%, 24 with pain, bleeding, infection and unsatisfactory post-surgical appearance most commonly reported. Severe and/or long-term complications have been reported, but they are so rare that rates of such complications have not been precisely established. o On average, adult men who undergo circumcision generally report minimal or no change in sexual satisfaction or function. Those who enjoy the sensation of the foreskin during sexual relations will no longer experience that sensation. - Health benefits of neonatal male circumcision: o The estimated risk of urinary tract infections (UTIs) in uncircumcised males: - aged 0.1 years is 1.3% (uncircumcised), 0.3% (circumcised) - aged 1-16 years is 2.78% (uncircumcised), 0.4% (circumcised) - aged >16 years is 28.2% (uncircumcised), 8.3% (circumcised) - over a lifetime is 32.1% (uncircumcised), 8.8% (circumcised) o Male circumcision reduces the risk of UTIs in circumcised males: - aged 0-1 years by 90% - aged 1-16 years by 85% - aged >16 years by 71% - over a lifetime by 23%	All material in this publication is in the public domain and may be used and reprinted without permission; citation of the source is, however, appreciated. References to non-CDC sites on the Internet are provided as a service to readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of these sites. URL addresses listed were current as of the date of publication.# Introduction This document is intended to assist health care providers in the United States who are sharing information with men and parents of male infants during decision making about male circumcision conducted by health care providers (i.e. medically performed) as it relates to the prevention of human immunodeficiency virus (HIV) infection, sexually transmitted infections (STIs), and other health outcomes. Such decision-making involves not only health considerations, but also social, cultural, ethical, and religious factors. Counseling regarding these issues can be incorporated into routine discussions of sexual, newborn, and child health. Much of the data related to HIV and STI prevention are from randomized clinical trials conducted among men in sub-Saharan Africa in regions with high rates of heterosexually acquired HIV infection. In the United States, the prevalence of HIV and lifetime risk of HIV infection are generally much lower than that in sub-Saharan Africa. Also, most new HIV infections in the United States are attributed to male-male sexual contact. Pooled data from observational studies 1 in the U.S. and abroad indicate that male circumcision was associated with reduced HIV acquisition among men who have sex with men (MSM) who practiced mainly or exclusively insertive anal sex. However, randomized clinical trials of male circumcision have not included a large enough number of MSM, and many MSM practice both insertive and receptive anal sex. Therefore, although biologically plausible, we are unable to definitively conclude whether male circumcision among MSM practicing mainly or exclusively insertive anal sex reduced the risk of HIV acquisition. While such factors limit the impact of medically performed male circumcision in reducing the overall HIV epidemic in the U.S., 8% of the estimated annual HIV diagnoses in 2014 in the United States were among males with infection attributed to heterosexual contact. 2 _In addition, African-American and Hispanic men have higher risk of HIV infection and lower male circumcision rates than white non-Hispanic males. Similar randomized clinical trials have not been conducted in the United States, but based on evidence from the African trials of the efficacy of male circumcision to prevent HIV transmission, uncircumcised heterosexual men living in areas with high HIV prevalence are likely to experience the most riskreduction benefit from elective male circumcision. # Methods A CDC 2-day symposium was held in April 2007 to obtain input on the potential role of male circumcision in preventing transmission of HIV in the United States. A summary of the 2-day symposium, including a list of the participants has been previously published. 3 The 2-day symposium helped define key issues for inclusion in this informational document. The methods used to gather and summarize evidence supporting this information are reported in "Background, Methods, and Synthesis of Scientific Information Used to Inform 'Information for Providers to Share with Male Patients and Parents regarding Male Circumcision and the Prevention of HIV infection, STIs, and other Health Outcomes.'" The information provided in this document is based on an evaluation of available evidence on the health risks and benefits associated with medically performed male circumcision and were developed to pertain to male adults, adolescents, children, and newborns, and caregivers of male minors charged in the United States. 4 In this document, the preventive benefits of male circumcision are generally expressed as relative-risk reductions (e.g., a 50% reduction from a 2% risk of an STI to a 1% risk), whereas any associated harm is expressed as an absolute risk (e.g., a 2%-4% risk of adverse events). Appropriate denominators are not available in many cases to establish an absolute risk for HIV and other STIs in higher-risk populations (e.g., heterosexual males at increased risk for infection). The citations associated with the information in this document have been graded by adapting a previously published grading scheme. 5 The grading scheme and criteria for inclusion of citations and specific considerations for use of the scheme are described in Appendix 1. The specific grade for each citation in this document can be found in Appendix 2. On December 2, 2014, CDC published a notice in the Federal Register announcing the posting of a draft informational document to obtain public comments (79 FR 71433). CDC received over 3,200 public comments from the public, physicians, and professional organizations. All comments were carefully reviewed and considered in preparation of this final document. In addition to obtaining public comments on the draft informational document, CDC shared a summary of public comments with external experts who conducted a peer review of the evidence on this topic. Their review included an evaluation of completeness, accuracy, interpretation, and generalizability of the evidence to the United States and whether the evidence was sufficient to support the draft informational document. # Review of Evidence Clinical trials conducted in Africa during 2005-2010 have demonstrated safety and significant efficacy of voluntary adult male circumcision performed by clinicians for reducing the risk of acquisition of HIV by males during penile-vaginal sex ("heterosexual sex"). Three randomized clinical trials showed that adult male circumcision significantly reduced the risk for HIV acquisition among heterosexual males by 51%-60% (95% confidence interval 16%-76%) over time. [6][7][8] These trials also found that medically performed adult circumcision significantly reduced the risk of men acquiring two common sexually transmitted infections (STIs), including genital ulcer disease (GUD) prevalence by 47% and incidence by 48% 9 and high-risk (i.e. oncogenic) types of human papilloma virus (HR-HPV) prevalence by 23%-47%. [10][11][12] In a prospective cohort study nested in a large randomized clinical trial of HIV preexposure prophylaxis in Kenyan and Ugandan HIV-serodiscordant heterosexual couples, male circumcision was associated with a percentage reduction in the incidence of syphilis (42% in men and 59% in women). 13 Because the foreskin can serve as a portal of entry for STIs (including HIV), it is biologically plausible that circumcision plays a role in preventing STI and HIV acquisition through insertive sexual intercourse. Since the release of these trial data, [6][7][8] various organizations have updated their recommendations about adult male 14 and infant male circumcision. 15,16 Information to Share # Consideration of factors associated with decision making Health benefits and risks of elective neonatal, adolescent, or adult medically performed male circumcision should be considered in consultation with medical providers while taking into account factors associated with decision-making around male circumcision, including religion, societal norms and social customs, hygiene, aesthetic preference, and ethical considerations. # Providing information to sexually active adolescent and adult males regardless of circumcision status All sexually active adolescent and adult males should consider using other proven HIV and STI risk-reduction strategies such as reducing the number of partners, correct and consistent use of male latex condoms, and HIV preexposure or postexposure prophylaxis. a # Providing information to uncircumcised sexually active adolescent and adult males Prior to sharing information about medically performed male circumcision, uncircumcised sexually active adolescent and adult males should be assessed to determine their HIV risk behaviors, HIV infection status, and the gender of their sexual partner(s). 17 The results of these assessments will inform the discussion with men about the risks and benefits of medically performed male circumcision. 3A-3. Uncircumcised, HIV-uninfected men and male adolescents at increased risk for HIV acquisition through heterosexual sex should be provided information about the risk and benefits of male circumcision (See Box 1). When a decision is made to undergo male circumcision, a referral for surgical consultation and access to medically performed male circumcision surgical services should be provided. # 3A. Providing information # 3B. Providing information to men who have sex with men (exclusively) Healthcare providers should explain that the data regarding the relationship between male circumcision and the acquisition of HIV and other STIs among MSM have a number of limitations and results differ based on predominance of insertive or receptive sexual practice. Based on data from heterosexuals, it is biologically plausible that male circumcision could benefit MSM who practice mainly or exclusively insertive anal sex. Pooled data from observational studies of male circumcision among MSM indicated that overall, male circumcision provided partial protection from HIV acquisition for the partner who practiced mainly or exclusively insertive anal sex. However, because clinical trials of male circumcision did not include large enough numbers of MSM and because many MSM practice both insertive and receptive anal sex, definitive statements cannot be made about whether male circumcision can reduce the risk of acquiring HIV and other STIs. 1 In contrast, male circumcision provides no direct biologically plausible risk-reduction benefit for the receptive anal sex partner and receptive anal intercourse carries a substantially higher risk for acquisition of HIV than insertive sex. # Providing information to parents of male newborns, children, or adolescents Health benefits and risks of elective neonatal, pediatric, or adolescent male circumcision should be considered in consultation with medical providers. Ideally, discussions about neonatal circumcision should occur prior to the birth of the child. Ultimately, whether to circumcise a male neonate or child is a decision made by parents or guardians on behalf of their newborn son or dependent child. When providing information to parents about male circumcision for an adolescent minor, the adolescent should be included in the decision-making process about undergoing elective male circumcision. When providing information to an adolescent inquiring about male circumcision, parents should be engaged in the discussion, unless the adolescent is legally emancipated. Minors may be deemed emancipated, giving them sole authority to make health care decisions on their own behalf under certain circumstances, which vary by state law; for example, if the minor 1) lives independently and is self-supporting, 2) is married, 3) is pregnant or a parent, 4) is in the military, or 5) is declared emancipated by a court as defined in the mature minor section. 20 • Neonatal male circumcision is safer, less expensive, and heals more rapidly than circumcision performed on older boys, adolescent males, and men. • Most of the health benefits of male circumcision occur after sexual debut (i.e. after becoming sexually active). • Male circumcision can also be conducted in adulthood when the individual can make the decision for himself. However, male circumcision after sexual debut could result in missed opportunities for:  HIV and STI prevention during the window period between sexual debut and circumcision  Prevention of UTIs during infancy. o Complications of medically performed male circumcision in the United States are typically uncommon and easily managed. Severe complications are rare in all age groups and occur in 0.23% of all circumcised males overall. 24 • Among newborns and children aged 1-9 years, most frequently reported complications include bleeding and inflammation of the penis or incomplete wound healing or adhesions requiring corrective procedures. b Complications occur in 0.2% of infants aged ≤ 1 month, [25][26][27] 0.4% of infants aged <1 year, 24 and approximately 9% in children aged 1-9 years. 24 • Among persons aged 10 years and older, the most frequently reported complications include those complications reported in younger children as well as wounds of the penis. c Complications occur in approximately 5% of persons in this age group. 24 There are not specific data about the frequency of complications in the adolescent age group (13-18 years). o The American Academy of Pediatrics Taskforce on Circumcision states that the health benefits of newborn male circumcision outweigh the risks and that the benefits of newborn male circumcision justify access to this procedure for families who choose it. o In the United States, the estimated lifetime risk of penile cancer for males is about 1 in 1,400 (0.07%) and that of prostate cancer is about 15%. Neonatal male circumcision reduces the risk of invasive penile carcinoma by about 77% and may reduce the risk of prostate cancer by 15% compared to men who are uncircumcised or those circumcised after first sexual intercourse. • Adverse events and risks associated with neonatal, infant, and child male circumcision performed by clinicians: o In the United States, during 2001-2010, • The rates of reported adverse events, not including severe adverse events, a were as follows  0.4% in infants aged <12 months  9.1% in children age 1-9 years  5.3% in persons aged 10 years and older • Most commonly reported complications among newborns and children aged 1 to 9 years: bleeding and inflammation of the penis or incomplete wound healing or adhesions requiring corrective procedures. b o The incidence of severe adverse events associated with male circumcision performed by clinicians, such as permanent disabilities, disfigurements, and death are rare. Other major complications requiring intervention such as major bleeding, and severe infection, are uncommon. o Some men enjoy the sensation of the foreskin during sexual relations, and such a sensation will not be experienced after circumcision; however, the bulk of scientific evidence states that men, on average, do not experience a loss of sexual pleasure or function because of circumcision. a Severe adverse events include outcomes such as permanent disabilities, disfigurements, and death b Frequently reported corrective procedures include repair of incomplete circumcision, lysis or excision of penile post-circumcision adhesions, and division of penile adhesions. # Box 1: Health Benefits and Risks of Elective Medically Performed Male Circumcision • Health benefits of elective male circumcision in adults and adolescents: o Male circumcision reduces the risk of acquiring HIV infection through penile-vaginal sex by 50%-60%, as demonstrated in 3 well-conducted clinical trials among adult men living in sub-Saharan Africa. o In clinical trials involving heterosexual males living in sub-Saharan Africa, male circumcision reduces the risk of some sexually transmitted infections. • Male circumcision reduces the risk of circumcised men acquiring new infections of:  Genital ulcer disease (GUD) (by 48%)  Herpes simplex virus type-2 (HSV-2) (by 28%-45%)  Oncogenic types of human papilloma virus (HPV) (by 24%-47%) • Male circumcision reduces the risk of circumcised men having existing infections of:  GUD (by 47%)  Oncogenic types of HPV (by 25%-47%)  T. vaginalis (by 53%)  M. genitalium (by 46%) • Male circumcision reduces the risk of the female partners of circumcised men having existing infections of:  GUD (by 22%)  Oncogenic types of HPV (by 22%)  T. vaginalis (by 45%)  Bacterial vaginosis (by 40%) • Male circumcision reduces the risk of penile cancer # • Adverse events and risks associated with elective male circumcision of adults: o The rate of adverse events, not including severe adverse events in persons aged 10 years and older is 5%, 24 with pain, bleeding, infection and unsatisfactory post-surgical appearance most commonly reported. Severe and/or long-term complications have been reported, but they are so rare that rates of such complications have not been precisely established. o On average, adult men who undergo circumcision generally report minimal or no change in sexual satisfaction or function. Those who enjoy the sensation of the foreskin during sexual relations will no longer experience that sensation. • Health benefits of neonatal male circumcision: o The estimated risk of urinary tract infections (UTIs) in uncircumcised males: • aged 0.1 years is 1.3% (uncircumcised), 0.3% (circumcised) • aged 1-16 years is 2.78% (uncircumcised), 0.4% (circumcised) • aged >16 years is 28.2% (uncircumcised), 8.3% (circumcised) • over a lifetime is 32.1% (uncircumcised), 8.8% (circumcised) o Male circumcision reduces the risk of UTIs in circumcised males: • aged 0-1 years by 90% • aged 1-16 years by 85% • aged >16 years by 71% • over a lifetime by 23%	None	None
77cdc6078d9a6a7e6c47b141e21100af6b78f86b	cdc	None	Information that has changed from the 2011 version of the VSP Operations Manual is marked with a yellow highlight and a vertical rule.# Foreword; ii # Foreword The Centers for Disease Control and Prevention (CDC) established the Vessel Sanitation Program (VSP) in the 1970s as a cooperative activity with the cruise ship industry. The program assists the cruise ship industry in fulfilling its responsibility for developing and implementing comprehensive sanitation programs to minimize the risk for acute gastroenteritis. Every vessel that has a foreign itinerary and carries 13 or more passengers is subject to twice-yearly unannounced inspections and, when necessary, reinspection. VSP operated continuously at all major U.S. ports from the early 1970s through 1986, when CDC terminated portions of the program. Industry and public pressures resulted in Congress directing CDC through specific language included in CDC appropriations to resume the program. CDC's National Center for Environmental Health (NCEH) became responsible for VSP in 1986. NCEH held a series of public meetings to determine the needs and desires of the public and cruise ship industry and on March 1, 1987, a restructured program began. In 1988, the program was further modified by introducing user fees to reimburse the U.S. government for costs. A fee based on the vessel's size is charged for inspections and reinspections. A VSP Operations Manual based on the Food and Drug Administration (FDA) 1976 model code for food service and the World Health Organization's Guide to Ship Sanitation was published in 1989 to assist the cruise ship industry in educating shipboard personnel. In 1998, it became apparent that it was time to update the 1989 version of the VSP Operations Manual. Changes in the FDA Food Code, new science on food safety and protection, and newer technology in the cruise ship industry contributed to the need for a revised operations manual. Over the next 2 years, VSP solicited comments from and conducted public meetings with representatives of the cruise industry, the general public, FDA, and the international public health community to ensure that the 2000 manual would appropriately address current public health issues related to cruise ship sanitation. A similar process was followed to update the VSP 2000 Operations Manual in 2005 and the VSP 2005 Operations Manual in 2011. Although the VSP 2011 Operations Manual was in use for almost 6 years, new technology, advanced food science, and emerging pathogens require updates to the manual. The VSP 2018 Operations Manual reflects comments and corrections submitted by cooperative partners in government and private industry as well as the public. We would like to thank all those who submitted comments and participated throughout this process. As new information, technology, and input are received, we will continue to review and record that information and maintain a public process to keep the VSP Operations Manual current. The VSP 2018 Operations Manual continues the more than 40 years of government and industry working together to achieve a successful and cooperative program that benefits millions of travelers each year. # Aimee Treffiletti (CDR, USPHS) Vessel Sanitation Program	Information that has changed from the 2011 version of the VSP Operations Manual is marked with a yellow highlight and a vertical rule.# Foreword; ii # Foreword The Centers for Disease Control and Prevention (CDC) established the Vessel Sanitation Program (VSP) in the 1970s as a cooperative activity with the cruise ship industry. The program assists the cruise ship industry in fulfilling its responsibility for developing and implementing comprehensive sanitation programs to minimize the risk for acute gastroenteritis. Every vessel that has a foreign itinerary and carries 13 or more passengers is subject to twice-yearly unannounced inspections and, when necessary, reinspection. VSP operated continuously at all major U.S. ports from the early 1970s through 1986, when CDC terminated portions of the program. Industry and public pressures resulted in Congress directing CDC through specific language included in CDC appropriations to resume the program. CDC's National Center for Environmental Health (NCEH) became responsible for VSP in 1986. NCEH held a series of public meetings to determine the needs and desires of the public and cruise ship industry and on March 1, 1987, a restructured program began. In 1988, the program was further modified by introducing user fees to reimburse the U.S. government for costs. A fee based on the vessel's size is charged for inspections and reinspections. A VSP Operations Manual based on the Food and Drug Administration (FDA) 1976 model code for food service and the World Health Organization's Guide to Ship Sanitation was published in 1989 to assist the cruise ship industry in educating shipboard personnel. In 1998, it became apparent that it was time to update the 1989 version of the VSP Operations Manual. Changes in the FDA Food Code, new science on food safety and protection, and newer technology in the cruise ship industry contributed to the need for a revised operations manual. Over the next 2 years, VSP solicited comments from and conducted public meetings with representatives of the cruise industry, the general public, FDA, and the international public health community to ensure that the 2000 manual would appropriately address current public health issues related to cruise ship sanitation. A similar process was followed to update the VSP 2000 Operations Manual in 2005 and the VSP 2005 Operations Manual in 2011. Although the VSP 2011 Operations Manual was in use for almost 6 years, new technology, advanced food science, and emerging pathogens require updates to the manual. The VSP 2018 Operations Manual reflects comments and corrections submitted by cooperative partners in government and private industry as well as the public. We would like to thank all those who submitted comments and participated throughout this process. As new information, technology, and input are received, we will continue to review and record that information and maintain a public process to keep the VSP Operations Manual current. The VSP 2018 Operations Manual continues the more than 40 years of government and industry working together to achieve a successful and cooperative program that benefits millions of travelers each year. # Aimee Treffiletti (CDR, USPHS) Vessel Sanitation Program # Acknowledgments VSP would like to acknowledge the following organizations and companies for their cooperative efforts in the revisions of the VSP 2018 Operations Manual. # Information to Assist the User on the Manual Format Organization The Vessel Sanitation Program Operations Manual is divided into chapters and subsections that focus on each operational area important to safeguarding public health aboard vessels. # Section Number The international numbering system is used to organize the guidelines in this document. # Keywords Each guideline is formatted with a title, keyword, or phrase after the section number. # Description The public health compliance recommendation is provided in this statement. # Green Bold Text Portions of some sections of these guidelines are written in green bold. These provisions are not requirements. They are provided to convey relevant information about specific exceptions and alternative means for compliance. # Inspection Report Number The individual inspection report item number is shown in parentheses after the section number and keywords; for example, 7.2.5.1.1 Hair Restraints (14). # Critical Items Critical compliance items are written in bold red underlined text in parentheses after the section number and keywords; for example, 7.5.5.1 Food-Contact Surfaces (24 C). The number in parentheses is the individual inspection report item number. # Noncritical Items Noncritical compliance items are the other items in this manual. # Changes Information that has changed from the 2011 version of the VSP Operations Manual is marked with a yellow highlight and a vertical rule. # Manual Update Process Revisions to the VSP Operations Manual and VSP Construction Guidelines are made via a change request process. Change requests include information on the public health significance for the reason and benefit of the suggested change. They are also substantiated based on technical information, published scientific studies, evidence of experience, and other references. To update these versions of the documents, VSP provided a change request form format and instructions to industry partners March 2015 for revisions. VSP and stakeholders held 14 days of in-person meetings and two web-based meetings between April 2015 and October 2016 to review the change requests. During these meetings, submitters presented their changes and discussed the reasons and evidence for requesting the changes. During group discussion, VSP accepted change requests as submitted, accepted them as amended, or did not take action. A total of 307 change requests were submitted during the review process for the VSP Operations Manual and VSP Construction Guidelines. Of these, 112 were accepted as submitted or as amended, and 34 were withdrawn. After the revision meetings ended, VSP staff updated the documents, sent drafts to industry for a 45-day review period, and announced availability of the documents for review in the Federal Register. # Introduction # Cooperation The program fosters cooperation between the cruise ship industry and government to define and reduce health risks associated with vessels and to ensure a healthful and clean environment for vessels' passengers and crew. The industry's aggressive and ongoing efforts to achieve and maintain high standards of FOOD safety and environmental sanitation are critical to the success of protecting public health. # Activities # Prevention # Inspections VSP conducts a comprehensive FOOD safety and environmental sanitation inspection on vessels that have a foreign itinerary, call on a U.S. port, and carry 13 or more passengers. # Surveillance The program conducts ongoing surveillance of ACUTE GASTROENTERITIS (AGE) and coordinates/conducts OUTBREAK investigations on vessels. # Information # Training VSP provides FOOD safety and environmental sanitation training 1.0 Introduction; 4 seminars for vessel and shore operations management personnel. # Plan Review The program provides consultative services for reviewing plans for renovations and new construction. # Construction Inspections The program conducts construction inspections at the shipyards and when the vessel makes its initial call at a U.S. port. # Information The program disseminates information to the public. # Operations Manual # Revisions # Manual The VSP 2018 Operations Manual has been modified to address emerging public health issues, industry recommendations, introduction of new technologies within the industry, new guidance from sources used in the previous edition, and CDC's experience. # Program Guidance Program operations and inspections are based on this manual. # Periodic Review The VSP 2018 Operations Manual will be reviewed at the annual meeting with written submissions for revision based on emerging public health issues and new technologies that may better address the public health issues on vessels. # Clarifications VSP will circulate proposed clarifications to the operations manual along with supporting information on their public health significance in advance of the annual meeting. These clarifications will be considered during the meeting. Proposed clarifications VSP considers time critical can be circulated to the industry and others for review and coordination through other collaborative means (e.g., email, web-based forum, etc.) for more timely dissemination and further review, as needed, during the annual meeting. The VSP Operations Manual requires several types of records to be maintained on board for periods of 30 days to 1 year, including the following: # Authority • Medical. • POTABLE WATER. • Recreational water. • FOOD safety. • Housekeeping. These records are reviewed during operational inspections. VSP has and will continue to cite violations identified in the record review, even if the ship was not sailing in U.S. waters when the violation occurred. If the record review reveals violations that could result in illness when the ship arrives in a U.S. port, points may be deducted according to the violations identified during the inspection. An example of these violations is ships producing water in ports, HARBORS, and polluted waterways. # Definitions This section includes the following subsections: 3.1 Scope 3.2 Definitions 3.3 Acronyms # Scope This VSP 2018 Operations Manual provides definitions to clarify commonly used terminology in this manual. The definition section is organized alphabetically. Where a definition specifically applies to a section of the manual, it will be noted in the definition. Terms defined in section 3.2 are identified in the text of these guidelines by CAPITAL LETTERS. For example, section 5.7.1.1.4 states "A CROSS-CONNECTION control program must include at a minimum: …" CROSS-CONNECTION is in CAPITAL LETTERS and is defined in section 3.2. # Definitions Accessible: Exposed for cleaning and inspection with the use of simple tools including a screwdriver, pliers, or wrench. This definition applies to use in FOOD AREAS of the vessel only. # Accredited program: A FOOD protection manager certification program that has been evaluated and listed by an accrediting agency as conforming to national standards for organizations that certify individuals. • An accredited program refers to the certification process and is a designation based on an independent evaluation of factors such as the sponsor's mission; organizational structure; staff resources; revenue sources; policies; public information regarding program scope, eligibility requirements, recertification, discipline and grievance procedures; and test development and administration. • Accredited program does not refer to training functions or educational programs. Adequate: Sufficient in number, features, or capacity to accomplish the purpose for which something is intended and to such a degree that there is no unreasonable risk to health or safety. Adulterated: As stated in the Federal FOOD, Drug, and Cosmetic Act, §402. # Air-break: A piping arrangement in which a drain from a fixture, appliance, or device discharges indirectly into another fixture, receptacle, or interceptor at a point below the flood-level rim (Figure 1). # Air gap (AG): The unobstructed vertical distance through the free atmosphere between the lowest opening from any pipe or faucet supplying water to a tank, PLUMBING FIXTURE, or other device and the flood-level rim of the receptacle or receiving fixture. The AIR GAP must be at least twice the inside diameter of the supply pipe or faucet and not less than 25 millimeters (1 inch) (Figure 2). # Antientanglement cover: A cover for a drain/SUCTION FITTING designed to prevent hair from tangling in a drain cover or SUCTION FITTING in a RECREATIONAL WATER FACILITY. Antientrapment cover: A cover for a drain/SUCTION FITTING designed to prevent any portion of the body or hair from becoming lodged or otherwise forced onto a drain cover or SUCTION FITTING in a RECREATIONAL WATER FACILITY. Approved: Acceptable based on a determination of conformity with principles, practices, and generally recognized standards that protect public health, federal regulations, or equivalent international standards and regulations. Example of these standards include those from the American National Standards Institute (ANSI), National Sanitation Foundation International (NSF International), American Society of Mechanical Engineers (ASME), American Society of Safety Engineers (ASSE), and Underwriter's Laboratory (UL). # Attack rate: (1) The proportion of individuals exposed to an infectious agent who become clinically ill. (2) The cumulative incidence of infection in a group observed over a period during an epidemic. # Atmospheric vacuum breaker (AVB): A BACKFLOW PREVENTION DEVICE that consists of an air inlet valve, a check seat or float valve, and air inlet ports. The device is not APPROVED for use under continuous water pressure and must be installed downstream of the last valve. Backpressure: An elevation of pressure in the downstream piping system (by pump, elevation of piping, or steam and/or air pressure) above the supply pressure at the point of consideration that would cause a reversal of normal direction of flow. # Backsiphonage: The reversal or flowing back of used, contaminated, or polluted water from a PLUMBING FIXTURE or vessel or other source into a water supply pipe as a result of negative pressure in the pipe. # Barometric loop: A continuous section of supply piping that rises at least 35 feet above the supply point and returns back down to the supply. Typically the loop will be in the shape of an upside-down "U." A barometric loop only protects against BACKSIPHONAGE because it operates under the principle that a water column cannot rise above 33.9 feet at sea-level pressure. Beverage: A liquid for drinking, including water. # Child activity center: A facility for child-related activities where children under the age of 6 are placed to be cared for by vessel staff. Children's pool: A pool that has a depth of 1 meter (3 feet) or less and is intended for use by children who are toilet trained. Child-size toilet: Toilets whose toilet seat height is no more than 280 millimeters (11 inches) and the toilet seat opening is no greater than 203 millimeters (8 inches). # CIP (cleaned in place): Use of a detergent solution, water rinse, and sanitizing solution by circulating or flowing mechanically through a piping system onto or over EQUIPMENT surfaces that require cleaning (for example, the method used-in part-to clean and sanitize a frozen dessert machine). CIP does not include the cleaning of EQUIPMENT such as band saws, slicers, or mixers subjected to in-place manual cleaning without the use of a CIP system. Cleaning locker: A room or cabinet specifically designed or modified for storage of cleaning EQUIPMENT such as mops, brooms, floor-scrubbing machines, and cleaning chemicals. Comminuted: Reduced in size by chopping, flaking, grinding, or mincing. Examples include FISH or MEAT products reduced in size and restructured or reformulated (e.g., gefilte FISH, gyros, ground beef, and sausage) and mixtures of two or more types of MEAT that have been reduced in size and combined (e.g., sausages made from two or more MEATS). Confirmed disease outbreak: A FOODBORNE or WATERBORNE DISEASE OUTBREAK in which laboratory analysis of appropriate specimens identifies a causative agent and epidemiologic analysis implicates the FOOD or water as the source of the illness. Consumer: A person who takes possession of FOOD, is not functioning as an operator of a FOOD establishment or FOOD-PROCESSING PLANT, and does not offer the FOOD for resale. # Contamination: The presence of an infectious agent on a body surface, in clothes, in bedding, on toys, on surgical instruments or dressings, or on other inanimate articles or substances including FOOD and water. # Continuous pressure (CP) backflow prevention device: A device generally consisting of two check valves and an intermediate atmospheric vent that has been specifically designed to be used under conditions of continuous pressure (greater than 12 hours out of a 24-hour period). Coving: A concave surface, molding, or other design that eliminates the usual angles of 90° or less at deck junctures (Figures 3, 4, and 5). # Critical item: A provision of these guidelines that, if in noncompliance, is more likely than other deficiencies to contribute to FOOD or water CONTAMINATION, illness, or environmental HEALTH HAZARD. These are denoted in these guidelines in bold red underlined text in parentheses after the section number and keywords; for example, 7.5.5.1 Food-Contact Surfaces (24 C). The number indicates the individual inspection report item number. # Critical control point: A point or procedure in a specific system where loss of control may result in an unacceptable health risk. # Critical limit: The maximum or minimum value at a CRITICAL CONTROL POINT to which a physical, biologic, or chemical parameter must be controlled to minimize the occurrence of risk from an identified safety HAZARD. Cross-connection: An actual or potential connection or structural arrangement between a POTABLE WATER system and any other source or system through which it is possible to introduce into any part of the POTABLE WATER system any used water, industrial fluid, gas, or substance other than the intended POTABLE WATER with which the system is supplied. Fish: Fresh water or saltwater finfish, crustaceans, and other forms of aquatic life (including alligator, frog, aquatic turtle, jellyfish, sea cucumber, sea urchin, and the roe of such animals) other than birds or mammals, and all mollusks, if such animal life is intended for human consumption. Fish includes an edible human FOOD product derived in whole or in part from fish, including fish processed in any manner. Food: Raw, cooked, or processed edible substance; ice; BEVERAGE; or ingredient used or intended for use or for sale in whole or in part for human consumption. Chewing gum is classified as FOOD. Food area: Includes food and BEVERAGE display, handling, preparation, service, and storage areas; warewash areas; clean EQUIPMENT storage areas; and LINEN storage and handling areas. Food-contact surface: Surfaces (food zone, splash zone) of EQUIPMENT and UTENSILS with which food normally comes in contact and surfaces from which food may drain, drip, or splash back into a food or surfaces normally in contact with food (Figures 6a and 6b). # Food display areas: Any area where food is displayed for consumption by passengers and/or crew. Applies to displays served by vessel staff or self-service. Food employee: A person working with unpackaged food, food EQUIPMENT or UTENSILS, LINENS, or FOOD-CONTACT SURFACES. Food-handling areas: Any area where food is stored, processed, prepared, or served. # Food preparation areas: Any area where food is processed, cooked, or prepared for service. # Food-processing plant: A commercial operation that manufactures, packages, labels, or stores food for human consumption and does not provide food directly to a CONSUMER. Food service areas: Any area where food is presented to passengers or crew members (excluding individual cabin service). Food storage areas: Any area where food or food products are stored. # Food transportation corridors: Areas primarily intended to move food during food preparation, storage, and service operations (e.g., service lift [elevator] vestibules to food preparation service and storage areas, provision corridors, and corridors connecting preparation areas and service areas). Corridors primarily intended to move only closed beverages and packaged foods (e.g., bottled/canned beverages, crackers, chips, etc.) are not considered food transportation corridors, but the deck/BULKHEAD juncture must be coved. Excluded: • Passenger and crew corridors, public areas, individual cabin service, and dining rooms connected to galleys. • Food loading areas used solely for delivery of food to the vessel. Food waste system: A system used to collect, transport, and process food waste from FOOD AREAS to a waste disposal system (e.g., pulper, vacuum system). Foodborne disease outbreak: An incident in which two or more persons experience a similar illness resulting from the ingestion of a common food. Game animal: An animal, the products of which are food, that is not classified as • Cattle, sheep, swine, goat, horse, mule, or other equine in 9 CFR Subchapter A -Mandatory MEAT Inspection, Part 301, • POULTRY in 9 CFR Subchapter C -Mandatory POULTRY Products Inspection, Part 381, or • FISH as defined under Subparagraph 1-201.10(B) (25). Game animal includes mammals such as reindeer, elk, deer, antelope, water buffalo, bison, rabbit, squirrel, opossum, raccoon, nutria, or muskrat, and nonaquatic reptiles such as land snakes. Game animal does not include RATITES such as ostrich, emu, and rhea. Gap: An open juncture of more than 3 millimeters (1/8 inch). # General-use pesticide: A pesticide not classified by EPA for restricted use as specified in 40 CFR 152.175. Grade A standards: Requirements of the FDA Grade A Pasteurized Milk Ordinance and Grade A Condensed and Dry Milk Ordinance with which certain fluid and dry milk and milk products comply. # Gravity drain: A drain fitting used to drain the body of water in a RECREATIONAL WATER FACILITY by gravity and with no pump downstream of the fitting. Gravity drainage system: A water collection system whereby a collection tank is located between the RECREATIONAL WATER FACILITY and the suction pumps. Halogen: The group of elements including chlorine, bromine, and iodine used for DISINFECTION of water. Hand antiseptic: Antiseptic products applied to human skin. Harbor: The portion of a port area set aside for vessel anchorage or for ports including wharves; piers; quays; and service areas, the boundaries are the highwater shore line; and others as determined by legal definition, citation of coordinates, or other means. Hazard: A biological, chemical, or physical property that may cause an unacceptable CONSUMER health risk. # Heated (RWF): Any RECREATIONAL WATER FACILITY with a water temperature exceeding 32°C (90°F). Health hazard: An impairment that creates an actual hazard to the public health through poisoning or through the spread of disease. For example, water quality that creates an actual hazard to the public health through the spread of disease by SEWAGE, industrial fluids, waste, etc. (e.g., sluice machine connection). # Hermetically sealed container: A container designed to be secure against the entry of microorganisms and, in the case of low-acid canned FOODS, to maintain the commercial sterility of its contents after processing. # Hose bib connection vacuum breaker (HVB): A BACKFLOW PREVENTION DEVICE that attaches directly to a hose bib by way of a threaded head. This device uses a single check valve and vacuum breaker vent. It is a form of an AVB specifically designed for a hose connection. A hose bib connection vacuum breaker is not APPROVED for use under CONTINUOUS PRESSURE (e.g., when a shut-off valve is located downstream from the device). Immediate contact: Someone sharing a cabin either full-time or part-time or sharing a cabin's bathroom facilities. This includes boyfriends, girlfriends, spouses, and significant others. # Imminent health hazard: A significant threat or danger to health that is considered to exist when evidence is sufficient to show that a product, practice, circumstance, or event creates a situation that requires immediate correction or cessation of operation to prevent injury. Injected meats: Manipulating MEAT so that infectious or toxigenic microoganisms may be introduced from its surface to its interior through tenderizing with deep penetration or injecting the MEAT such as with juices, which may be referred to as injecting, pinning, or stitch pumping. This does not include routine temperature monitoring. # Integrated pest management (IPM): A documented, organized system of controlling pests through a combination of methods including inspections, baits, traps, effective sanitation and maintenance, and judicious use of chemical compounds. Interactive recreational water facility: An indoor or outdoor recreational water facility that includes misting, jetting, waterfalls, or sprinkling features that involve water recirculation systems that come into contact with bathers. Additional features or facilities, such as decorations or fountains, will designate the facility as an interactive RWF if there is any piping connected through the recirculation system. These facilities may be zero depth. Fully or partially enclosed water slides are considered interactive recreational water facilities. # Isolation: The separation of persons who have a specific infectious illness from those who are healthy and the restriction of ill persons' movement to stop the spread of that illness. For VSP's purposes, isolation for passengers with AGE symptoms is advised and isolation for crew with AGE symptoms is required. # Kitchenware: FOOD preparation and storage UTENSILS. Law: Applicable local, state, federal, or other equivalent international statutes, regulations, and ordinances. Linens: Fabric items such as cloth hampers, cloth napkins, tablecloths, wiping cloths, and work garments including cloth gloves. # Making way: Progressing through the water by mechanical or wind power. # Meat: The flesh of animals used as FOOD including the dressed flesh of cattle, swine, sheep, or goats and other edible animals, except FISH, POULTRY, and wild GAME ANIMALS. Mechanically tenderized: Manipulating MEAT with deep penetration by processes that may be referred to as blade tenderizing; jaccarding; pinning; needling; or using blades, pins, needles, or any mechanical device. This does not include processes by which solutions are injected into MEAT. mg/L: Milligrams per liter, the metric equivalent of parts per million (ppm). Molluscan shellfish: Any edible species of fresh or frozen oysters, clams, mussels, and scallops or edible portions thereof, except when the scallop product consists only of the shucked adductor muscle. Noncorroding: Material that maintains its original surface characteristics through prolonged influence by the use environment, FOOD contact, and normal use of cleaning compounds and sanitizing solutions. # Nonfood-contact surfaces (nonfood zone): All exposed surfaces, other than FOOD-CONTACT SURFACES, of EQUIPMENT located in FOOD AREAS (Figures 6a and 6b). # Outbreak: See AGE OUTBREAK. Packaged: Bottled, canned, cartoned, securely bagged, or securely wrapped, whether packaged in a FOOD establishment or a FOOD-PROCESSING PLANT. Packaged does not include a wrapper, carry-out box, or other nondurable container used to facilitate FOOD protection during service and receipt of FOOD by the CONSUMER. Permeate water: Water produced by a reverse osmosis unit. Permeate water lines: Pipes carrying PERMEATE WATER from the reverse osmosis nit that may be directed to the POTABLE WATER SYSTEM. This is the VSP definition for pipe striping purposes. # Person in charge: The individual present on a vessel who is responsible for the FOOD operation at the time of inspection such as the FOOD and BEVERAGE Manager, FOOD Manager, or Chef. Personal-care items: Items or substances that may be poisonous, toxic, or a source of CONTAMINATION and are used to maintain or enhance a person's health, hygiene, or appearance. Personal-care items include items such as medicines, first-aid supplies, and cosmetics and toiletries (e.g., toothpaste, mouthwash). Pesticide: Any substance or mixture of substances intended to prevent, destroy, repel, or mitigate any pest. For the purposes of this manual, pesticides are considered either general use or restricted use. # pH (potens hydrogen): The symbol for the negative logarithm of the hydrogen ion concentration, which is a measure of the degree of acidity or alkalinity of a solution. Values between 0 and 7 indicate acidity and values between 7 and 14 indicate alkalinity. The value for pure distilled water is 7, which is neutral. Plumbing fixture: A receptacle or device that • Is permanently or temporarily connected to the water-distribution system of the vessel and demands a supply of water from the system; or • Discharges used water, waste materials, or SEWAGE directly or indirectly to the drainage system of the vessel. Plumbing system: The water supply and distribution pipes; PLUMBING FIXTURES and traps; soil, waste, and vent pipes; sanitary sewer drains and vessel drains, including their respective connections, devices, and appurtenances within the vessel; and water-treating EQUIPMENT. Poisonous or toxic materials: Substances not intended for ingestion. These substances are in four categories: • Cleaners and SANITIZERS, which include cleaning and sanitizing agents and agents such as caustics, acids, drying agents, polishes, and other chemicals. • PESTICIDES [except SANITIZERS] that include substances such as insecticides and rodenticides. • Substances necessary for the operation and maintenance of the establishment such as nonfood-grade lubricants and PERSONAL-CARE ITEMS that may be deleterious to health. • Substances not necessary for the operation and maintenance of the vessel and are on the vessel, such as petroleum products and paints. # Pollution: The presence of any foreign substance (organic, inorganic, radiologic, or biologic) that tends to degrade water quality to create a HEALTH HAZARD. Portable: A description of EQUIPMENT that is READILY REMOVABLE or mounted on casters, gliders, or rollers; provided with a mechanical means so that it can be tilted safely for cleaning; or readily movable by one person. Potable water: Water that is halogenated and pH controlled and is intended for • Drinking, washing, bathing, or showering; • Using in fresh water SWIMMING POOLS and WHIRLPOOL SPAS; • Using in the vessel's hospital; • Handling, preparing, or cooking FOOD; and • Cleaning FOOD STORAGE and FOOD PREPARATION areas, UTENSILS, and EQUIPMENT. Potable water is free from impurities in amounts sufficient to cause disease or harmful physiological effects. The water quality must conform to requirements of the World Health Organization DRINKING WATER standards. Potable water tanks: All tanks in which POTABLE WATER is stored. # Potentially hazardous food (PHF) (or time/temperature control for safety food [TCS]): Natural or synthetic food that requires time/temperature control because it is in a form capable of supporting one of the following: • Rapid and progressive growth of infectious or toxigenic microorganisms. • Growth and toxin production of Clostridium botulinum. • Growth of Salmonella enteritidis [in raw shell eggs]. PHF includes an animal FOOD (a FOOD of animal origin) that is raw or heattreated; a FOOD of plant origin that is heat-treated or consists of raw seed sprouts; cut melons; CUT LEAFY GREENS; cut tomatoes or mixtures of cut tomatoes; and garlic and oil mixtures that are not acidified or otherwise modified at a FOOD-PROCESSING PLANT in a way that results in mixtures that do not support growth as specified under subparagraph (a) of this definition or any FOOD classified by the FDA as a PHF/TCS. PHF does not include the following: a. An air-cooled hard-boiled egg with shell intact, or a shell egg that is not hard-boiled, but has been treated to destroy all viable Salmonellae. b. A FOOD with an AW value of 0.85 or less. # c. A FOOD with a pH level of 4.6 or below when measured at 24°C (75°F). d. A FOOD in an unopened HERMETICALLY SEALED CONTAINER that is commercially processed to achieve and maintain commercial sterility under conditions of nonrefrigerated storage and distribution. e. A FOOD for which laboratory evidence demonstrates that the rapid and progressive growth of infectious or toxigenic microorganisms or the growth of S. enteritidis in eggs or C. botulinum cannot occur, such as a FOOD that has an AW and a pH above the levels specified under subparagraphs (b) and (c) of this definition and that may contain a preservative, other barrier to the growth of microorganisms, or a combination of barriers that inhibit the growth of microorganisms. f. A FOOD that may contain an infectious or toxigenic microorganism or chemical or physical contaminant at a level sufficient to cause illness, but that does not support the growth of microorganisms as specified under subparagraph (a) of this definition. # Poultry: • Any domesticated bird such as chicken, turkey, duck, goose, or guinea, whether live or dead, as defined in 9 CFR 381 Poultry Products Inspection Regulations. • Any migratory waterfowl, game bird, or squab such as pheasant, partridge, quail, grouse, or guinea, whether live or dead, as defined in 9 CFR 362 Voluntary Poultry Inspection Program. Poultry does not include RATITE. # Pressure vacuum breaker assembly (PVB): A device consisting of an independently loaded internal check valve and a spring-loaded air inlet valve. This device is also equipped with two resilient seated gate valves and test cocks. Primal cut: A basic major cut into which carcasses and sides of MEAT are separated, such as a beef round, pork loin, lamb flank, or veal breast. # Quarantine: The limitation of movement of apparently well persons who have been exposed to a case of communicable (infectious) disease during its period of communicability to prevent disease TRANSMISSION during the incubation period if infection should occur. # Ratite: A flightless bird such as an emu, ostrich, or rhea. Readily accessible: Exposed or capable of being exposed for cleaning or inspection without the use of tools. Readily removable: Capable of being detached from the main unit without the use of tools. Ready-to-eat (RTE) food: Food in a form that is edible without washing, cooking, or additional preparation by the food establishment or the CONSUMER and is reasonably expected to be consumed in that form. # RTE food includes • POTENTIALLY HAZARDOUS FOOD that is unpackaged and cooked to the temperature and time required for the specific food. • Raw, washed, cut fruits and vegetables. • Whole, raw fruits and vegetables presented for consumption without the need for further washing, such as at a buffet. • Other food presented for consumption for which further washing or cooking is not required and from which rinds, peels, husks, or shells are removed. • Fruits and vegetables cooked for hot holding, as specified under section 7. # Recreational water facility (RWF): A water facility that has been modified, improved, constructed, or installed for the purpose of public swimming or recreational bathing. RWFs include, but are not limited to, • ACTIVITY POOLS. • BABY-ONLY WATER FACILITIES. • CHILDREN'S POOLS. • Diving pools. • Hot tubs. • Hydrotherapy pools. • INTERACTIVE RECREATIONAL WATER FACILITIES. • Slides. • SPA POOLS. • SWIMMING POOLS. • Therapeutic pools. • WADING POOLS. • WHIRLPOOLS. Recreational seawater: Seawater taken onboard while MAKING WAY at a position at least 12 miles at sea and routed directly to the RWFs for either sea-tosea exchange or recirculation. # Reduced pressure principle backflow prevention assembly (RP assembly): An assembly containing two independently acting internally loaded check valves together with a hydraulically operating, mechanically independent pressure differential relief valve located between the check valves and at the same time below the first check valve. The unit must include properly located resilient seated test cocks and tightly closing resilient seated shutoff valves at each end of the assembly. Refuse: Solid waste not carried by water through the SEWAGE system. Registered design professional: An individual registered or licensed to practice his or her respective design profession as defined by the statutory requirements of the professional registration LAWS of the state or jurisdiction in which the project is to be constructed (per ASME A112.19.8-2007). Regulatory authority: Local, state, or federal or equivalent international enforcement body or authorized representative having jurisdiction over FOOD processing, transportation, or warehousing or other FOOD establishment. Removable: Capable of being detached from the main unit with the use of simple tools such as a screwdriver, pliers, or an open-end wrench. # Reportable AGE case (VSP definition): A case of AGE with one of the following characteristics: • Diarrhea (three or more episodes of loose stools in a 24-hour period or what is above normal for the individual, e.g., individuals with underlying medical conditions) OR • Vomiting and one additional symptom including one or more episodes of loose stools in a 24-hour period, or abdominal cramps, or headache, or muscle aches, or fever (temperature of ≥38°C [100.4°F]); AND • Reported to the master of the vessel, the medical staff, or other designated staff by a passenger or a crew member. # Nausea, although a common symptom of AGE, is specifically excluded from this definition to avoid misclassifying seasickness (nausea and vomiting) as ACUTE GASTROENTERITIS. Restricted-use pesticide: A pesticide product that contains the active ingredients specified in 40 CFR 152.175 Pesticides classified for restricted use and is limited to use by or under the direct supervision of a certified applicator. # Safety vacuum release system (SVRS): A system capable of releasing a vacuum at a suction outlet caused by a high vacuum due to a blockage in the outlet flow. These systems shall be designed and certified in accordance with ASTM F2387-04 or ANSI/ASME A 112.19.17-2002. Sanitizer: Chemical or physical agents that reduce microorganism CONTAMINATION levels present on inanimate environmental surfaces. # Two classes of sanitizers: • Sanitizers of NONFOOD-CONTACT SURFACES: The performance standard used by the U.S. Environmental Protection Agency (EPA) for these sanitizers requires a reduction of the target microorganism by 99.9% or 3 logs (1000, 1/1000, or 10 3 ) after 5 minutes of contact time. • Sanitizers of FOOD-CONTACT SURFACES: The EPA performance standard for these sanitizers requires a 99.999% or 5-log reduction of the target microorganism in 30 seconds. # Sanitization: The application of cumulative heat or chemicals on cleaned FOOD-CONTACT and NONFOOD-CONTACT SURFACES that, when evaluated for efficacy, provides a sufficient reduction of pathogens. Scupper: A conduit or collection basin that channels liquid runoff to a DECK DRAIN. Sealant: Material used to fill SEAMS. Seam: An open juncture greater than 0.8 millimeters (1/32 inch) but less than 3 millimeters (1/8 inch). Sewage: Liquid waste containing animal or vegetable matter in suspension or solution and may include liquids containing chemicals in solution. Shellstock: Raw, in-shell MOLLUSCAN SHELLFISH. Shucked shellfish: MOLLUSCAN SHELLFISH with one or both shells removed. Single-service articles: TABLEWARE, carry-out UTENSILS, and other items such as bags, containers, placemats, stirrers, straws, toothpicks, and wrappers designed and constructed for one-time, one-person use. Single-use articles: UTENSILS and bulk FOOD containers designed and constructed to be used once and discarded. Single-use articles include items such as wax paper, butcher paper, plastic wrap, formed aluminum FOOD containers, jars, plastic tubs or buckets, bread wrappers, pickle barrels, ketchup bottles, and number 10 cans that do not meet materials, durability, strength, and cleanability specifications. Slacking: Process of moderating the temperature of a FOOD such as allowing a FOOD to gradually increase from a temperature of -23°C (-10°F) to -4°C (25°F) in preparation for deep-fat frying or to facilitate even heat penetration during the cooking of previously block-frozen FOOD such as spinach. # Smooth: • A FOOD-CONTACT SURFACE having a surface free of pits and inclusions with a cleanability equal to or exceeding that of (100-grit) number stainless steel. • A NONFOOD-CONTACT SURFACE of EQUIPMENT having a surface equal to that of commercial grade hot-rolled steel free of visible scale. • Deck, BULKHEAD, or DECKHEAD that has an even or level surface with no roughness or projections to make it difficult to clean. # Spa pool: A POTABLE WATER or saltwater-supplied pool with temperatures and turbulence comparable to a WHIRLPOOL SPA. • Depth of more than 1 meter (3 feet) and • Tub volume of more than 6 tons of water. # Spill-resistant vacuum breaker (SVB): A specific modification to a PRESSURE VACUUM BREAKER ASSEMBLY to minimize water spillage. Spray pad: Play and water contact area designed to have no standing water. # Suction fitting: A fitting in a RECREATIONAL WATER FACILITY under direct suction through which water is drawn by a pump. Swimming pool: A RECREATIONAL WATER FACILITY greater than 1 meter in depth. This does not include SPA POOLS that meet this depth. Technical water: Water that has not been chlorinated or pH controlled on board the vessel and that originates from a bunkering or condensate collection process, or seawater processed through the evaporators or reverse osmosis plant and is intended for storage and use in the technical water system. # Temperature-measuring device (TMD): A thermometer, thermocouple, thermistor, or other device that indicates the temperature of FOOD, air, or water and is numerically scaled in Celsius and/or Fahrenheit. Time/temperature control for safety food (TCS): See POTENTIALLY HAZARDOUS FOOD (PHF). # Transmission (of infection): Any mechanism by which an infectious agent is spread from a source or reservoir to another person. These mechanisms are defined as follows: • Direct transmission (includes person-to-person transmission): Direct and essentially immediate transfer of infectious agents to a receptive portal of entry through which human or animal infection may take place. • Indirect transmission: When an infectious agent is transferred or carried by some intermediate item, organism, means, or process to a susceptible host, resulting in disease. This includes airborne, foodborne, waterborne, vehicleborne (e.g., fomites), and vectorborne modes of transmission. Turnover: The circulation, through the recirculation system, of a quantity of water equal to the pool volume. Utility sink: Any sink located in FOOD SERVICE AREAS not intended for handwashing and/or WAREWASHING. Variance: A written document issued by VSP that authorizes a modification or waiver of one or more requirements of these guidelines if, in the opinion of VSP, a HEALTH HAZARD or nuisance will not result from the modification or waiver. Wading pool: RECREATIONAL WATER FACILITY with a maximum depth of less than 1 meter. # Warewashing: The cleaning and sanitizing of TABLEWARE, UTENSILS, and FOOD-CONTACT SURFACES of EQUIPMENT. Waterborne outbreak: An OUTBREAK involving at least two people who experience a similar illness after ingesting or using water intended for drinking or after being exposed to or unintentionally ingesting or inhaling fresh or marine water used for recreational purposes and epidemiological evidence implicates the water as the source of illness. A single case of chemical poisoning or a laboratoryconfirmed case of primary amebic meningoencephalitis is considered an OUTBREAK. Whirlpool spa: A freshwater or seawater pool equipped with either water or air jets and designed to operate at a minimum temperature of 32°C (90°F) and a 3.0 Definitions; 29 maximum temperature of 40°C (104°F). Whole-muscle, intact beef: Whole-muscle beef that is not injected, MECHANICALLY TENDERIZED, reconstructed, or scored and marinated; and from which beef steaks may be cut. # Acronyms # AGE # Onset Time (02) The REPORTABLE AGE CASES must include crew members with a symptom onset time of up to 3 days before boarding the vessel. Maintain documentation of the 3-day assessment for each crew member with symptoms on the vessel for review during inspections. Retain this documentation for 12 months. # Definition Purpose Use these case definitions for identifying and classifying cases for reporting purposes. These case definitions should not be used as criteria for clinical intervention or public health action. For many conditions of public health importance, action to contain disease should be initiated as soon as a problem is identified; in many circumstances, appropriate public health action should be undertaken even though insufficient information is available to determine whether cases meet the case definition. # Responsibility (02) A standardized AGE surveillance log for each cruise must be maintained daily by the master of the vessel, the medical staff, or other designated staff. # Required Information (02) The AGE surveillance log must list • The name of the vessel, cruise dates, and cruise number. • All REPORTABLE CASES of AGE. • All passengers and crew members who are dispensed antidiarrheal medication from the master of the vessel, medical staff, or other designated staff. # Log Details (02) The AGE surveillance log must include a header containing the following information about the voyage: • Vessel name. • Voyage number. • Date from. • Date to. • Total number of passengers.* • Reportable total number of passengers ill. • Total number of crew.* • Reportable total number of crew ill. Total number of passengers and total number of crew must be the totals at the beginning of the voyage (i.e., totals on "date from"). The AGE surveillance log entry for each passenger or crew member must contain the following information in separate columns: • Patient I.D. • Date of the first medical visit or report to staff of illness. • Time of the first medical visit or report to staff of illness. • Person's last name. • Person's first name. • Person's age. • Person's sex. • Designation as passenger or crew member. • Cabin number. • Crew member position or job on the vessel, if applicable. • DATE OF ILLNESS ONSET. • TIME OF ILLNESS ONSET. • Illness symptoms, including the presence or absence of the following selected signs and symptoms, with a separate column for each of the following: • Number of episodes of diarrhea in a 24-hour period. • Bloody stools (yes/no). • Number of episodes of vomiting in a 24-hour period. • Fever (yes/no). • Recorded temperature. • Abdominal cramps (yes/no). • Headaches (yes/no). • Myalgia (yes/no). • Date of last symptom. • Time of last symptom. • Entry (yes/no) for whether a specimen was requested. • Entry (yes/no) for whether a specimen was received. • Entry (yes/no) for antidiarrheal medications sold or dispensed by designated medical staff. • Entry (yes/no) for whether this was a REPORTABLE CASE. • Presence of underlying medical conditions that may affect interpretation of AGE; for example, diabetic diarrhea, inflammatory bowel disease, gastrectomy, antibioticinduced diarrhea, vomiting from chemotherapy, ear infections in children or others. If none, write "none," "not applicable," "N/A," or similar wording. Comments may also be added to the log in this column after the information about underlying illness. The AGE surveillance log must contain the above information in this exact order and entered in the template in Annex 13.2.2. The log data must be exported in the exact order as in the example template in Annex 13.2.2 with analyzable formats such as Microsoft Excel or Microsoft Access. Any additional data fields must be entered only outside of the form margins exported to VSP. # Medications Sold or Dispensed (02) Antidiarrheal medications must not be sold or dispensed to passengers or crew except by designated medical staff. # Questionnaires # Food/Beverage Questionnaire (02) Questionnaires detailing activities and meal locations for the 72 hours before illness onset must be distributed to all passengers and crew members who are identified as REPORTABLE CASES. At a minimum, self-administered questionnaires must contain the following data elements: • Vessel name. • Voyage number. • Person's name. • Person's age. • Person's sex. • Cabin number. • Designation as a passenger or crew member. • Total number in cabin. • Meal seating information (seating and table number). • DATE AND TIME OF ILLNESS ONSET. • Other people with the same symptoms. • Travel and boarding information prior to joining the vessel. • Tour group information, if applicable. • Ports went ashore prior to illness onset. • Excursions attended. • FOOD and BEVERAGE consumption while ashore, including drinks with ice. • Meals and activities aboard the vessel for 72 hours before illness (breakfast, lunch, dinner, snacks). • Activities attended onboard. An example questionnaire template containing all of the required data elements can be found in Annex 13.2.2. To assist passengers and crew members with filling out the selfadministered questionnaires, the following information for the most current cruise may be maintained at the medical center: • Menus, FOOD, and drink selections available at each venue on the vessel, from room service, and on private islands. • Menus, FOOD, and drink selections available for each vessel-sponsored excursion. • Organized activities on the vessel or private islands. • Cruise line sponsored pre-embarkation activities. To assist memory recall for guests and crew completing the 72-hour self-administered questionnaire, an electronic listing of the above information on an interactive system available via an onboard video system can be substituted for the package in the medical center. # Retention # Retention and Review (02) The following records must be maintained on board for 12 months and available for review by VSP during inspections and OUTBREAK investigations: port. • The AGE surveillance log must include all segments from the start of the voyage, unless 67% (two-thirds) or more of the passengers are disembarked in any one segment. For cruises lasting longer than 15 days before entering a U.S. port, the 2% or 3% special AGE report must include all cases for the entire voyage. maintain appropriate refrigerant materials to keep clinical specimens cool. For guidance, see Annex 13.4 of this manual. # Clinical Specimen Submission Collection Procedures # When to Collect (02) When a vessel reaches 2% REPORTABLE AGE in either passengers or crew members, the medical staff will begin collecting clinical specimens (stool or vomitus specimens) for bacterial and/or viral analysis. If the etiologic agent is suspected to be parasitic, the medical staff should consult with VSP epidemiology staff for clinical specimen collection requirements. Specimens should be requested before issuing antibiotic medications, but this patient treatment should not be contingent on specimen collection. Specimens collected after administration of antibiotic medications must not be submitted for CDC analysis unless directed by VSP. # Proper Packing (02) Before the specimens are PACKAGED and shipped for laboratory testing, VSP will give instructions to vessel/cruise line medical staff about the specific container (i.e., bacterial or viral) for transport to a laboratory. All clinical specimens must be packed and shipped in accordance with the guidelines outlined in Annex 13.4. The specimen packaging must include the proper documentation as required by the receiving laboratory. # Requirements for Isolating # Symptomatic and Meeting the Case Definition for Acute Gastroenteritis (AGE) (11 C) FOOD EMPLOYEES: • Isolate in cabin or designated restricted area until symptomfree for a minimum of 48 hours. • Follow-up with and receive approval by designated medical personnel before returning crew to work. • Document date and time of last symptom and clearance to return to work. The FOOD EMPLOYEE's supervisor or PERSON IN CHARGE must conduct an assessment of FOOD prepared or served by the FOOD EMPLOYEE while symptomatic and take appropriate corrective actions. Corrective actions taken as a result of the assessment must be documented. Records must be maintained for 1 year and available for review during inspections. • Review [when possible] any AGE CASES among passengers or crew reported after the ill FOOD EMPLOYEE's symptom onset for epidemiologic link/connection. # Appropriate corrective actions could include discarding READY-TO-EAT FOOD, thoroughly cooking raw FOOD, and disinfecting the FOOD AREA and EQUIPMENT. Nonfood employees: • ISOLATION in cabin or designated restricted area until symptom-free for a minimum of 24 hours. • Follow-up with and receive approval by designated medical personnel before returning crew to work. • Document the date and time of last symptom and clearance to return to work. # Hygiene and Handwashing Facts (02) Advise symptomatic crew of hygiene and handwashing facts and provide written handwashing and hygiene fact sheets. # Cabin Mates/Contacts (02) # Asymptomatic Cabin Mates or Immediate Contacts of Symptomatic Crew FOOD and nonfood employees: • Restrict exposure to symptomatic crew member(s). • Undergo a verbal interview with medical or supervisory staff, who will confirm their condition, provide facts and a written fact sheet about hygiene and handwashing, and instruct them to report immediately to medical if they develop illness symptoms. • Complete a verbal interview daily with medical or supervisory staff until 48 hours after the ill crew members' symptoms began. The first verbal interview must be conducted within 8 hours from the time the ill crew member initially reported to the medical staff. If the asymptomatic IMMEDIATE CONTACT or cabin mate is at work, he or she must be contacted by medical or supervisory staff as soon as possible. The date and time of verbal interviews must be documented. An IMMEDIATE CONTACT is someone sharing a cabin either full-time or part-time or sharing a cabin's bathroom facilities. This includes boyfriends, girlfriends, spouses, and significant others. If the symptomatic crew member has no cabin mate or other IMMEDIATE CONTACT, this must be documented. # Passengers # Isolate Ill Passengers (11 C) Advise symptomatic passengers and those meeting the case definition to remain isolated in their cabins until well for a minimum of 24 hours after symptom resolution. Follow-up by infirmary personnel is advised. # Hygiene and Handwashing Facts (02) Advise symptomatic passengers of hygiene and handwashing facts and provide written handwashing and hygiene fact sheets. # 4.5 Acute Gastroenteritis Surveillance Knowledge # Demonstration of Knowledge (44) The supervisor or PERSON IN CHARGE of medical operations related to AGE on the vessel must demonstrate to VSP-on request during inspectionsknowledge of medical operations related to AGE. The supervisor or PERSON IN CHARGE must demonstrate this knowledge by compliance with this section of these guidelines or by responding correctly to the inspector's questions as they relate to the specific operation. In addition, the supervisor or PERSON IN CHARGE of medical operations related to AGE on the vessel must ensure that employees are properly trained to comply with this section of the guidelines in this manual as it relates to their assigned duties. # Potable Water This section includes the following subsections: 5. References for 5.0 Potable Water can be found in Annex 14.5. # Source # Bunkering # Standards # Safe Source (03 C) DRINKING WATER bunkered from shore supplies must be from a potable source that meets World Health Organization standards for POTABLE WATER. # Microbiologic Sample Reports # Water Report (06) Where available, the vessel must have a copy of the most recent microbiologic report from each port before bunkering POTABLE WATER to verify that the water meets potable standards. The date of the analysis report must be 30 days or less from the date of POTABLE WATER bunkering and must include an analysis for Escherichia coli at a minimum. # Onboard Test (06) Water samples collected and analyzed by the vessel for the presence of E. coli may be substituted for the microbiologic report from each port water system. Samples must be analyzed using a method accepted in Standard Methods for the Examination of Water and Wastewater or international Environmental Protection Agency (EPA) APPROVED equivalent. Test kits, incubators, and associated EQUIPMENT must be operated and maintained in accordance with the manufacturers' specifications. If a vessel bunkers POTABLE WATER from the same port more 5.0 Potable Water; 44 than once per month, only one test per month is required. # Review (06) These records must be maintained on the vessel for 12 months and must be available for review during inspections. # Water Production # Location # Polluted Harbors (03 C) A reverse osmosis unit, distillation plant, or other process that supplies water to the vessel's POTABLE WATER system must only operate while the vessel is MAKING WAY. These processes must not operate in polluted areas, HARBORS, or at anchor. # Technical Water A reverse osmosis unit or evaporator with a completely separate plant/process, piping system, and connections from the POTABLE WATER system may be used to produce TECHNICAL WATER while in polluted areas, HARBORS, at anchor, or while not MAKING WAY. # Onboard Water Sources Onboard water sources such as TECHNICAL WATER, air conditioning condensate, or wastewater of any kind (treated or untreated) are not allowed for POTABLE WATER production. # Bunkering and Production Halogenation and pH Control # Procedures # Residual Halogen and pH # Halogen and pH Level (03 C) POTABLE WATER must be continuously halogenated to at least 2.0 MG/L (ppm) free residual HALOGEN at the time of bunkering or production with an automatic halogenation device. Adjust the pH so it does not exceed 7.8. The amount of HALOGEN injected during bunkering or production must be controlled by a flow meter or a free HALOGEN analyzer. 5.0 Potable Water; 45 # Within 30 Minutes (08) The free HALOGEN residual level must be adjusted to at least 2.0 MG/L (ppm) and the pH adjusted not to exceed 7.8 within 30 minutes of the start of the bunkering and production processes. # Monitoring # Bunkering Pretest (08) A free HALOGEN residual and pH test must be conducted on the shore-side water supply before starting the POTABLE WATER bunkering process to establish the correct HALOGEN dosage. The results of the pretest must be recorded and available for review during inspections. # Bunkering/Production Test (08) After the free residual HALOGEN level of at least 2.0 MG/L (ppm) and pH level not exceeding 7.8 have been reached, the free residual HALOGEN and pH monitoring must be performed at least hourly during the bunkering of POTABLE WATER. After the free residual HALOGEN level of at least 2.0 MG/L (ppm) and pH level not exceeding 7.8 have been reached, the free residual HALOGEN and pH monitoring must be performed at least once every 4 hours during the bunkering of POTABLE WATER. A test kit must be available for testing free HALOGEN levels and pH. Test kits must be accurate to within 0.2 MG/L (ppm) for HALOGEN and must have a testing range of free residual HALOGEN normally maintained in the POTABLE WATER system. Test kits for pH must be accurate to within 0.2. # Records (08) Accurate records of this monitoring must be maintained aboard for 12 months and must be available for review during inspections. # Analyzer-Chart Recorders (06) HALOGEN and pH analyzer-chart recorders used in lieu of manual tests and logs must be calibrated at the beginning of bunkering or production, and the calibration must be recorded on a chart or in a logbook. # Potable Water; 46 The free residual HALOGEN and pH measured by the HALOGEN/pH analyzer must be accurate to within 0.2 mg/L (ppm) of the free residual HALOGEN and 0.2 of the pH as measured by the manual test. Calibration is required at the beginning of bunkering or production and each time bunkering or production is restarted. # Construction (06) HALOGEN and pH analyzer-chart recorders used on bunker water systems must be constructed and installed according to the manufacturer's guidelines. # Data Logger Electronic data loggers with CERTIFIED DATA SECURITY FEATURES may be used in lieu of chart recorders. If electronic data loggers are used, written documentation from the data logger manufacturer, such as a letter or instruction manual, must be provided to verify that the features are secure. # Halogen Injection (08) Water samples for HALOGEN and pH testing must be obtained from a sample cock and/or a HALOGEN analyzer probe located on the bunker or production water line at least 3 meters (10 feet) after the HALOGEN injection point and before the storage tank. A static mixer may be used to reduce the distance between the HALOGEN injection point and the sample cock or HALOGEN analyzer sample point. If used, the mixer must be installed per the manufacturer's recommendations. A copy of all manufacturers' literature for installation, operation, and maintenance must be maintained. # Tank Sample In the event of EQUIPMENT failure, bunker or production water HALOGEN samples may also be taken from previously empty POTABLE WATER TANKS. # Potable Water System # Potable Water Tanks # Protection # Potable Water Tank Walls (07 C) POTABLE WATER TANKS must not share a common wall with the hull of the vessel or with tanks or piping containing nonpotable water or other liquids. # Nonpotable Piping (08) Piping systems carrying SEWAGE or other nonpotable liquids must not pass through POTABLE WATER TANKS. Minimize the use of nonpotable lines above POTABLE WATER TANKS. Nonpotable lines above POTABLE WATER TANKS must not have any mechanical couplings. For SCUPPER lines, factory assembled transition fittings for steel to plastic pipes are allowed when manufactured per American Society for Testing and Materials (ASTM) F1973 or equivalent standard. # Coatings (08) Interior coatings on POTABLE WATER TANKS must be APPROVED for POTABLE WATER contact by a certification organization. Follow all manufacturers' recommendations for application, drying, and curing. The following must be maintained on board for the tank coatings used: • Written documentation of approval from the certification organization (independent of the coating manufacturer). • Manufacturers' recommendations for application, drying, and curing. • Written documentation that the manufacturers' recommendations have been followed for application, drying, and curing. # Tank Construction # Identification (08) POTABLE WATER TANKS must be identified with a number and the words "POTABLE WATER" in letters at least 13 millimeters (0.5 inch) high. # Sample Cocks (08) POTABLE WATER TANKS must have labeled, turned-down sample cocks. They must be identified and numbered with the appropriate tank number. # Vent/Overflow (08) The POTABLE WATER TANKS, vents, and overflows must be protected from CONTAMINATION. # Level Measurement (08) Any device for determining the depth of water in the POTABLE WATER TANKS must be constructed and maintained so as to prevent contaminated substances or liquids from entering the tanks. # Manual Sounding (08) Manual sounding of POTABLE WATER TANKS must be performed only in emergencies and must be performed in a sanitary manner. # Potable Water Piping # Protection # Identification (08) POTABLE WATER lines must be striped or painted either in accordance with ISO 14726 (blue/green/blue) or blue only. DISTILLATE and PERMEATE lines directed to the POTABLE WATER system must be striped or painted in accordance with ISO 14726 (blue/gray/blue). Other lines must not have the above color designations. These lines must be striped or painted at 5 meter (15 feet) intervals and on each side of partitions, decks, and BULKHEADS except where decor would be marred by such markings. This includes POTABLE WATER supply lines in technical lockers. POTABLE WATER lines after REDUCED PRESSURE ASSEMBLIES must not be striped or painted as POTABLE WATER. Striping is not required in FOOD AREAS of the vessel because only POTABLE WATER is permitted in these areas. # Potable Water System Contamination # Cleaning and Disinfection # Disinfecting (07 C) POTABLE WATER TANKS and all affected parts of the POTABLE WATER distribution system must be cleaned, disinfected, and flushed with POTABLE WATER: • Before being placed in service; • Before returning to operation after repair, replacement; or • After being subjected to any CONTAMINATION, including entry into a POTABLE WATER tank. During dry docks and wet docks, if any work is done to the POTABLE WATER distribution system and piping system that affects a POTABLE WATER TANK(s), the affected POTABLE 5.0 Potable Water; 52 WATER TANK(s) must be cleaned and disinfected. # Inspection (08) POTABLE WATER TANKS must be inspected, cleaned, and disinfected at least every 2 years. # Record Retention (08) Documentation of all inspections, maintenance, cleaning, and DISINFECTION must be maintained for 12 months and must be available for review during inspections. Records must include method of DISINFECTION, concentration and contact time of the DISINFECTANT, and a recorded HALOGEN value of less than or equal to 5 ppm before the tank is put back into service. # Disinfection Residual (07 C) DISINFECTION after potential CONTAMINATION must be accomplished by increasing the free residual HALOGEN to at least 50 MG/L (ppm) throughout the affected area and maintaining this concentration for 4 hours or by way of another procedure submitted to and accepted by VSP. In an emergency, this contact time may be shortened to 1 hour by increasing free residual HALOGEN to at least 200 MG/L (ppm) throughout the affected area. Refer to Annex 13.6 for DISINFECTION method examples. # Documentation (08) The free HALOGEN residual level must be documented. # Flush (08) The disinfected parts of the system must be flushed with POTABLE WATER or otherwise dechlorinated until the free residual HALOGEN is ≤5.00 MG/L (ppm). The free HALOGEN test result must be documented. # Potable Water Tank Disinfection Methods # Method for Disinfecting Filled Tanks (08) DISINFECTION must be accomplished by increasing the free residual HALOGEN to at least 50 MG/L (ppm) throughout the tank and maintaining it for 4 hours. Maintain a pH value of 7.8 or less. The DISINFECTION concentration and contact time must be documented. 5.0 Potable Water; 53 . Verify that the free residual HALOGEN level is ≤ 5.0 MG/L (ppm) and document the measured level before placing the tank back into service. # Method for Disinfecting Empty Tanks (08) The empty tank cleaning and DISINFECTION procedure is only APPROVED for routine cleaning and DISINFECTION. It is not APPROVED for known or suspected contaminated tanks 1. Remove (strip) all water from the tank. 2. Clean all tank surfaces, including filling lines, with an appropriate detergent. 3. Rinse all surfaces of the tank thoroughly with POTABLE WATER. 4. Remove (strip) the rinse water from the tank. 5. Wet all surfaces of the tank with at least a 200-MG/L (ppm) solution of chlorine (this can be done using new, clean mops, rollers, sprayers, etc.). Ensure the tank surfaces remain wet with the chlorine solution for at least 2 hours. Check, monitor, and document the DISINFECTION concentration and contact time. 6. Refill the tank and verify the free residual HALOGEN is ≤5.0 MG/L (ppm) before placing the tank back into service. Document the free residual HALOGEN level. # 5.4 Potable Water System Chemical Treatment # Chemical Injection Equipment # Construction and Installation # Recommended Engineering Practices (06) All distribution water system chemical injection EQUIPMENT must be constructed and installed in accordance with recommended engineering practices. # Operation # Halogen Residual (04 C) The halogenation injection EQUIPMENT must provide continuous halogenation of the POTABLE WATER distribution system and must maintain a free residual HALOGEN of ≥0.2 MG/L (ppm) and ≤5.0 MG/L (ppm) throughout the distribution system. # Controlled (08) The amount of chemicals injected into the POTABLE WATER system must be analyzer controlled. # Halogen Backup Pump (06) At least one backup HALOGEN pump must be installed with an active, automatic switchover feature to maintain the free residual HALOGEN in the event that the primary pump fails, an increase in demand occurs, or the low chlorine alarm sounds. # Chemical Injection Dosing Point (06) A check valve or nonreturn valve must be installed between the distribution halogen and pH pumps and the injection points. In addition, • The potable water distribution halogenation and pH chemical injection dosing points must be located on the delivery line downstream of the potable water pumps, OR • If the injection dosing point is before the potable water pumps, it must be located above the chemical dosing tanks. # Potable Water # Distant Point (06) A HALOGEN analyzer-chart recorder must be installed at a distant point in the POTABLE WATER distribution system where a significant water flow exists and represents the entire distribution system. In cases where multiple distribution loops exist and no pipes connect the loops, there must be an analyzer and chart recorder for each loop. # Data Logger Electronic data loggers with CERTIFIED DATA SECURITY FEATURES may be used in lieu of chart recorders. If used, written documentation from the data logger manufacturer, such as a letter or instruction manual, must be provided to verify that the features are secure. # Operation # Maintenance (06) The HALOGEN analyzer-chart recorder must be properly maintained and must be operated in accordance with the manufacturer's instructions. # Potable Water; 55 A manual comparison test must be conducted daily to verify calibration. Calibration must be made whenever the manual test value is >0.2 MG/L (ppm) higher or lower than the analyzer reading. # Calibration (06) The daily manual comparison test or calibration must be recorded either on the recorder chart or in a log. # Accuracy (05) The free residual HALOGEN measured by the HALOGEN analyzer must be ±0.2 MG/L (ppm) of the free residual HALOGEN measured by the manual test. # Test Kit (06) The HALOGEN test kit used to calibrate the HALOGEN analyzer must be accurate to within 0.2 MG/L (ppm) for HALOGEN and graduated in increments no greater than 0.2 MG/L (ppm) in the range of free residual HALOGEN normally maintained in the POTABLE WATER system. Ensure all reagents used with the test kit are not past their expiration dates. Where available, ensure appropriate secondary standards are onboard for electronic test kits to verify test kit operation. # Halogen Analyzer Charts # Chart Design # Range (06) HALOGEN analyzer-chart recorder charts must have a range of 0.0 to 5.0 MG/L (ppm) and have a recording period of-and limited to-24 hours. # Data Logger (06) Electronic data loggers with CERTIFIED DATA SECURITY FEATURES used in lieu of chart recorders must produce records that conform to the principles of operation and data display required of the analog charts, including printing the records. # Increments (06) Electronic data logging must be in increments of ≤15 minutes. # Operation # Charts (06) HALOGEN analyzer-chart recorder charts must be changed, initialed, and dated daily. Charts must contain notations of any unusual events in the POTABLE WATER system. If electronic data loggers are used in lieu of chart recorders, notations of any unusual events in the POTABLE WATER system must be recorded in a log. # Retention (06) HALOGEN analyzer-chart recorder charts must be retained for at least 12 months and must be available for review during inspections. # Chart Review (06) Records from the HALOGEN analyzer-chart recorder must verify the free residual HALOGEN of ≥0.2 MG/L (ppm) and ≤5.0 MG/L (ppm) in the water distribution system for at least 16 hours in each 24-hour period since the last inspection of the vessel. # Manual Halogen Monitoring # Equipment Failure # Every 4 hours (06) Free residual HALOGEN must be measured by a manual test kit at the HALOGEN analyzer at least every 4 hours in the event of EQUIPMENT failure. # Recording (06) Manual readings must be recorded on a chart or log, retained for at least 12 months, and available for review during inspections. # Limit (06) Repairs on malfunctioning HALOGEN analyzer-chart recorders must be completed within 10 days of EQUIPMENT failure. # Alarm (06) Provide an audible alarm in a continuously occupied watch station (e.g., the engine control room) to indicate low and high free HALOGEN readings at the distant point analyzer. # Protection (07 C) The POTABLE WATER system must be protected against BACKFLOW or other CONTAMINATION by BACKFLOW PREVENTION DEVICES or AIR GAPS. The PERMEATE lines and DISTILLATE lines directed toward the POTABLE WATER system must also be protected. # Control/Program (08) The vessel must provide a comprehensive CROSS-CONNECTION control program. # Log (08) A CROSS-CONNECTION control program must include, at a minimum, a complete listing of CROSS-CONNECTIONS and the BACKFLOW prevention method or device for each so there is a match to the PLUMBING SYSTEM component and location. AIR GAPS must be included in the listing. # AIR GAPS on faucet taps do not need to be included on the CROSS-CONNECTION control program listing. The program must set a schedule for inspection frequency. Repeat devices such as toilets may be grouped under a single device type. A log documenting the inspection and maintenance in written or electronic form must be maintained and be available for review during inspections. # Device Installation # Air Gaps and Backflow Prevention Devices (08) AIR GAPS should be used where feasible and where water under pressure is not required. BACKFLOW PREVENTION DEVICES must be installed when AIR GAPS are impractical or when water under pressure is required. Provide an AIR GAP for the atmospheric vent of all BACKFLOW PREVENTION DEVICES. A mechanical BACKFLOW PREVENTION DEVICE must have an atmospheric vent. # 2X Diameter (08) AIR GAPS must be at least twice the diameter of the delivery fixture opening and a minimum of 25 millimeters (1 inch). # Flood-Level Rim (08) An ATMOSPHERIC VACUUM BREAKER must be installed at least 150 millimeters (6 inches) above the flood-level rim of the fixtures. # After Valve (08) An ATMOSPHERIC VACUUM BREAKER must be installed only in the supply line on the discharge side of the last control valve. # Continuous Pressure (08) A CONTINUOUS PRESSURE-type BACKFLOW PREVENTION DEVICE must be installed when a valve is located downstream from the BACKFLOW PREVENTION DEVICE. # Backflow Prevention Devices (08) BACKFLOW PREVENTION DEVICES must be provided on all fixtures using POTABLE WATER and that have submerged inlets. # Vacuum Toilets (08) An ATMOSPHERIC VACUUM BREAKER must be installed on a POTABLE WATER supply connected to a vacuum toilet system. An ATMOSPHERIC VACUUM BREAKER must be located on the discharge side of the last control valve (flushing device). # Diversion Valves (08) Lines to divert POTABLE WATER to other systems by valves or interchangeable pipe fittings must have an AIR GAP after the valve. # Location (08) BACKFLOW PREVENTION DEVICES and AIR GAPS must be ACCESSIBLE for inspection, testing, service, and maintenance. If access panels are required, provide panels large enough for testing, service, and maintenance. # Air Supply Connections # Air Supply (08) A compressed air system that supplies pressurized air to both nonpotable and POTABLE WATER pneumatic tanks must be connected through a press-on (manual) air valve or hose. # Separate Compressor A fixed connection may be used when the air supply is from a separate compressor used exclusively for POTABLE WATER pneumatic tanks. # Backflow Prevention Device Inspection and Testing # Maintenance # Maintained (08) BACKFLOW PREVENTION DEVICES must be maintained in good repair. # Inspection and Service # Schedule (08) BACKFLOW PREVENTION DEVICES should be periodically inspected and any failed units must be replaced. A visual check must be completed for all nontestable BACKFLOW PREVENTION DEVICES and AIR GAPS at least annually. # Test Annually (08) BACKFLOW PREVENTION DEVICES requiring testing (e.g., reduced pressure BACKFLOW PREVENTION DEVICES and PRESSURE VACUUM BREAKERS) must be inspected and tested with a test kit after installation and at least annually. Test results showing the pressure differences on both sides of the valves must be maintained for each device. # Records (08) The visual inspection and/or test results for BACKFLOW PREVENTION DEVICES and AIR GAPS must be retained for at least 12 months and must be available for review during inspections. # 5.8 # Recreational Water Facilities (RWFs) This section includes the following subsections: 6.1 RWFs 6.2 Flow-Through Seawater RWFs 6.3 Recirculating RWFs 6.4 WHIRLPOOL SPAS and SPA POOLS 6.5 Maintenance and Operating Standards for Combined Facilities 6.6 Private Cabin Operations 6.7 Individual Hydrotherapy Pools 6.8 Safety 6.9 Restrictions 6.10 Knowledge References for 6.0 Recreational Water Facilities (RWFs) can be found in Annex 14.6. # RWFs # Source # Potable Water or Seawater (09 C) The water source for all RWFs must be POTABLE WATER or RECREATIONAL SEAWATER. # Maintenance # Management RWFs must be kept clean of debris, organic materials, and slime/biofilm in ACCESSIBLE areas in the water and on surfaces. It is recommended to conduct periodic biofilm management in WHIRLPOOL SPAS, SPA POOLS, and interactive RWFs. # Flow-Through Seawater RWFs # Operation # At Sea # 12 miles (10) Flow-through seawater supply systems for RWFs must be used only while the vessel is MAKING WAY and at sea beyond 20 kilometers (12 miles) from nearest land. # In Port # Drained or Switched to Recirculation (10) Before arriving to a port or HARBOR, the RWF must be drained before the vessel reaches the 20-kilometer (12-mile) mark or any point of land-based discharge as detailed in section 6.2.1.1.1 and it must remain empty while in port or at anchor. # OR The RECREATIONAL SEAWATER filling system must be shut off 20 kilometers (12 miles) before reaching the nearest land or land-based discharge point, and a recirculation system must be used with appropriate filtration and halogenation systems. # Halogen and pH (09 C) When switching from flow-through operations to recirculation operations, the RWF must be closed until the free residual HALOGEN and pH levels are within the acceptable limits of this manual. The sample must be taken from the body of the RWF, not from the pump room. While the RWF is closed, batch HALOGEN and pH control chemicals may be used to obtain ADEQUATE free HALOGEN residuals and pH levels in a more-timely manner. Sufficient time should be allowed before opening the RWF for use to ensure proper mixing of batch chemicals. # Recirculating RWFs (See individual sections for additional requirements for whirlpools and SPA POOLS. See Annex 13.8 for requirements for BABY-ONLY WATER FACILITIES.) # Operation # Fill Level and Turnover Rates (10) For RWF with skim gutters, the fill level of the RWF must be to the skim gutter level. An RWF slide combined with a pool must have a TURNOVER rate that matches the rate for the pool. Use flow rates from flow meters to calculate TURNOVER rates. Do not use the manufacturer's pump rate to calculate TURNOVER rates. The pool in "An RWF slide combined with a pool must have a TURNOVER rate that matches the rate for the pool" refers to either WADING or SWIMMING POOLS but not to CHILDREN'S POOLS. In addition, the water for the slide must come directly from the basin of the pool and return directly to the basin of the pool. For facilities that meet the definition of more than one type of RWF, the more protective TURNOVER rate applies. For example, if a CHILDREN'S POOL also has features of an interactive RWF or ACTIVITY POOL, the TURNOVER rate must be 0.5 hours. The only exception is that when a slide is combined with a pool, the TURNOVER rate for the combined system may match the rate for the pool. However, if a pool and slide combination is also combined with another facility, the most protective TURNOVER rate applies. Finally, if a facility is modified, the most protective TURNOVER rate applies. 4. Consider media replacement if after 30 minutes of settling, a measurable layer of sediment is within or on top of the filter media or fine, colored particles are suspended in the water. This condition can mean the organic loading may be excessive. Granular filter media for WHIRLPOOL SPAS and SPA POOLS must be changed based on the inspection and sedimentation test results or every 12 months, whichever is more frequent. For all other RWFs, granular filter media must be changed based on the inspection and sedimentation results or per the manufacturer's recommendations, whichever is more frequent. Results of both the filter inspection and sedimentation test must be recorded. # Cartridge Filter Inspection and Filter Change (10) Cartridge or canister-type filters must be inspected weekly for WHIRLPOOL SPAS and SPA POOLS. For all other RWFs, cartridge filters must be inspected every 2 weeks, or in accordance with the manufacturer's recommendation, whichever is more frequent. The filters must be inspected for cracks, breaks, damaged components, and excessive organic accumulation. Cartridge or canister-type filters must be changed based on the inspection results, or as recommended by the manufacturer, whichever is more frequent. At least one replacement cartridge or canister-type filter must be available. # Other Filter Media (10) Inspect and change filters based on the manufacturer's recommendations. # Filter Housing Cleaning and Disinfection (10) The filter housing must be cleaned, rinsed, and disinfected before the new filter media is placed in it. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. The filter housing must be cleaned, rinsed, and disinfected each time the filter media-including cartridge filter-is changed. Install flow meters to monitor flow rates. Only combined chlorine must be monitored. Combined bromine does not need to be monitored. "Manufacturer" refers to the RWF manufacturer and also to manufacturers of the pumps, filters, flow meters, and any other associated EQUIPMENT. # Fecal and Vomit Accident (10) A fecal and vomit accident response procedure that meets or exceeds the procedure provided in Annex 13.9 must be available for review during inspections. # Record of Fecal and Vomit Accidents (10) A written or electronic record must be made of all accidents involving fecal material or vomit. The record must include the name of the RWF, date and time of the accident, type of accident, response steps taken, and free residual HALOGEN level and contact time reached during DISINFECTION. For a fecal accident, the record must also include whether the fecal material was formed or loose. # Halogenation # Residual Halogen: Halogen and pH Dosing Systems (10) Automated systems must be installed for HALOGEN-based DISINFECTION and pH control dosing. The amounts injected must be controlled by flow meters or free HALOGEN and pH analyzers. # When conducting manual tests, consideration should be given to the HALOGEN and pH levels in the RWF over the HALOGEN and pH readings from the pump room. Initial chemistry balance can be achieved by manual dosing methods following events such as fecal or vomit accidents and when changing from flow-through seawater to recirculation mode. # Residual Halogen and pH Monitoring # Test Kit (10) A test kit must be available for testing water quality parameters including free and total HALOGEN levels (chlorine and bromine, where applicable), pH, and total alkalinity. Test kits must be accurate to within 0.2 MG/L (ppm) for HALOGEN and must have a testing range of free residual HALOGEN normally maintained in the RWF. Test kits for PH must be accurate to within 0.2. Reagents must not be not past their expiration dates. # Test Kit Maintenance and Verification (10) Where available, appropriate secondary standards must be onboard for electronic test kits to verify test kit operation. # Automated Free Halogen Residual and pH Testing (10) Install chart recorders or electronic data loggers with CERTIFIED DATA SECURITY FEATURES that record PH and HALOGEN measurements for each individual RWF. The sample line for the analyzer probe (monitoring) must be either directly from the RWF or on the return line from each RWF and before the compensation tank. Install appropriate sample taps for analyzer calibration. In the event of EQUIPMENT failure, free residual HALOGEN and pH must be measured by a manual test kit at the RWF or return line at least hourly for WHIRLPOOL SPAS, SPA POOLS, CHILDREN'S POOLS, and WADING POOLS and every 4 hours for all other RWFs. If two RWFs are combined and the water for one RWF comes from and returns to the basin of the other RWF (not the compensation tank), separate monitoring systems are not required. Monitoring is then only required on the main RWF (e.g., a slide and SWIMMING POOL). Note: During operational inspections, VSP will take manual samples of both RWFs. Manual samples from the RWF tub should be compared to the analyzer samples in the pump room to assess potential water quality differences in the RWF. # Water Quality # Changed (10) The WHIRLPOOL SPA water, including compensation tank, filter housing, and associated piping, must be changed every 72 hours, provided that the system is operated continuously and that the correct water chemistry levels are maintained during that period, including daily shock halogenation. SPA POOL water must be changed as often as necessary to maintain proper water chemistry. The water must be changed at least every 30 days. The date and time of WHIRLPOOL SPA and SPA POOL water changes must be recorded in the log. # Halogenation # Residual Halogen # Prolonged Maintenance (10) For facilities undergoing maintenance for longer than 72 hours, the free HALOGEN residual and pH levels must be maintained or the entire system must be drained completely of all water. This includes the WHIRLPOOL SPA and SPA POOL tubs, compensation tanks, filter housings, and all associated piping and blowers. Records must be maintained for the free HALOGEN and pH levels or the complete draining of the system. # Shock Halogenation (10) The free residual HALOGEN must be increased to at least 10.0 MG/L (ppm) and circulated for at least 1 hour every 24 hours. The free residual HALOGEN must be tested at both the start and completion of shock halogenation. The water in the entire RWF system must be superhalogenated to 10 ppm to include the WHIRLPOOL SPA/SPA POOL tub, compensation tank, filter housing, and all associated piping before starting the 1-hour timing. HEATED ACTIVITY POOLS, including interactive RWFs, that have features that break the water surface of the RWF or create a mist must be shock halogenated as described. This includes DISINFECTION must be accomplished with an appropriate HALOGENbased DISINFECTANT at 10 ppm for 60 minutes, or an equivalent CT VALUE. # Maintenance (10) Manufacturer's operation and maintenance instructions must be available to personnel who service the units. # Records (10) A record must be maintained outlining the frequency of cleaning and DISINFECTION. The record must include the type, concentration, and contact time of the DISINFECTANT. Records must be retained on the vessel for 12 months. # 6.7 Individual Hydrotherapy Pools 6.7.1 Maintenance # Cleaning (10) Individual hydrotherapy pools must be cleaned and disinfected, including associated recirculation systems, between customers. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT at 10 ppm for 60 minutes, or an equivalent CT VALUE. # Maintenance (10) Manufacturer's operation and maintenance instructions must be available to personnel who service the units. # Records (10) A record must be maintained outlining the frequency of cleaning and DISINFECTION. The record must include the type, concentration, and contact time of the DISINFECTANT. Records must be retained on the vessel for 12 months. See section 6.3.1.5 for bather load calculations. # Depth Markers (10) The depth of each RWF deeper than 1 meter (3 feet) must be displayed prominently so it can be seen from the deck and in the pool. Depth markers should be labeled in both feet and meters. Additionally, depth markers must be installed for every 1-meter (3-foot) change in depth. # Spas (10) In addition to the safety sign requirements in section 6.7.1.1.1, install a sign at each WHIRLPOOL SPA and SPA POOL entrance listing precautions and risks associated with the use of these facilities. At a minimum, include cautions against use by the following: • Individuals who are immunocompromised. • Individuals on medication or who have underlying medical conditions such as cardiovascular disease, diabetes, or high or low blood pressure. • Children, pregnant women, and elderly persons. Additionally, caution against exceeding 15 minutes of use. # Vessels can submit existing signs for review by VSP. # It is advisable to post additional cautions and concerns on signs. Those under 16 years of age are considered children for the purpose of whirlpool safety sign requirements. # Equipment # Life Saving (10) A rescue or shepherd's hook and an APPROVED flotation device must be provided at a prominent location (visible from the full perimeter of the pool) at each RWF that has a depth of 1 meter (3 feet) or greater. These devices must be mounted in a manner that allows for easy access during an emergency. • The pole of the rescue or shepherd's hook must be long enough to reach the center of the deepest portion of the pool from the side plus 0.6 meters (2 feet). It must be a light, strong, nontelescoping material with rounded, nonsharp ends. • The APPROVED flotation device must include an attached rope that is at least two-thirds of the maximum pool width. The rescue or shepherd's hook must be long enough to touch the bottom center of the deepest portion of the RWF plus 2 feet (0.6 meters) as measured from the closest edge without an obstruction. This edge can only be used for measurement if someone could freely walk down both sides without an obstruction such as a waterfall, fountain, statue, etc. For a rectangular pool, the shorter distance would be from the long side of the rectangle as long as there are no obstructions (Figure 6-1). The 2 feet (0.6 meters) is measured from where the shepherd's hook crosses the fill line of the RWF. For RWFs with a beach level, the measurement can be from the edge of the tub (Figure 6-2). # Antientrapment Drain (10) ANTIENTRAPMENT/ANTIENTANGLEMENT requirements for drain covers and SUCTION FITTINGS in RWFs are shown in Testing of manufactured drain covers must be by a nationally or internationally recognized testing laboratory. The information below must be stamped on each manufactured ANTIENTRAPMENT drain cover: • Certification standard and year. • Type of drain use (single or multiple). • Maximum flow rate (in gallons or liters per minute). • Type of fitting (suction outlet). • Life expectancy of cover. • Mounting orientation (wall, floor, or both). • Manufacturer's name or trademark. • Model designation. A letter from the shipyard must accompany each custom/shipyard constructed (field fabricated) drain cover fitting. At a minimum the letter must specify the shipyard, name of the vessel, specifications and dimensions of the drain cover, as detailed above, as well as the exact location of the RWF for which it was designed. The name of and contact information for the REGISTERED DESIGN PROFESSIONAL and signature must be on the letter. Options 1 through 5 are for fittings not under direct suction. These include both fittings to drain the RWF and fittings used to recirculate the water. Options 6 through 8 are for fittings under direct suction. These include fittings to drain the RWF and fittings used to recirculate the water. *Definitions: • Alarm: The audible alarm must sound in a continuously manned space AND at the RWF. This alarm is for all draining: accidental, routine, and emergency. • GDS (GRAVITY DRAINAGE system): A drainage system that uses a collector tank from which the pump draws water. Water moves from the RWF to the collector tank due to atmospheric pressure, gravity, and the displacement of water by bathers. There is no direct suction at the RWF. • SVRS (safety vacuum release system): A system that stops operation of the pump, reverses the circulation flow, or otherwise provides a vacuum release at a suction outlet when a blockage is detected. System must be tested by an independent third party and found to conform with ASME/ANSI A112.19.17 or ASTM standard F2387. • APS (automatic pump shut-off system): A device that detects a blockage and shuts off the pump system. A manual shut-off near the RWF does not qualify as an APS. # Temperature (10) A temperature-control mechanism to prevent the temperature from exceeding 40°C (104°F) must be provided on WHIRLPOOL SPAS and SPA POOLS. The water temperature must be measured within the WHIRLPOOL SPA or SPA POOL tub itself. # RWF Showers and Toilet Facilities Vessels constructed to the 2018 Construction Guidelines or later must have toilets and showers installed. # Temperature and Location Showers must provide POTABLE WATER at a temperature not to exceed 43°C (110°F) during normal operations. Showers must be installed within 10 meters (33 feet) of every entry point to each RWF. For beach entry RWFs, a minimum of one showerhead must be installed per 10 meters (33 feet) of perimeter within 10 meters (33 feet) of the beach perimeter. A minimum of one shower must be installed at each water slide staircase entrance. # Showers for Children RWFs designed for use by children under 6 years of age must have appropriately sized shower facilities. Standard height is acceptable, but the mechanism to operate the flow of water must not be more than 1 meter above the deck. # Toilet Facilities Toilet facilities must be located within one fire zone (approximately 48 meters [157 feet]) of each RWF and on the same deck or adjacent decks if there is no obstruction between RWF area and entrances to the toilets. If toilets are not located on the same deck they must be easily visible and ACCESSIBLE from the RWF area. A minimum of two separate toilet rooms (either two unisex or one male and one female) must be installed. Each toilet facility must include a toilet and a handwashing facility. Urinals may be installed in addition to the required toilet, but may not replace the toilet. # Restrictions # Diapers (10) Children in diapers or who are not toilet trained must be prohibited from using any RWF not specifically designed and APPROVED for use by children in diapers. # Food Safety This section includes the following subsections: The excluded individual must not be allowed to return to the above duties until they are symptom free for a minimum of 48 hours. # Other Symptoms (11 C) FOOD EMPLOYEES who have conditions or symptoms of boils, open sores, infected wounds, diarrhea, jaundice, fever, vomiting, sore throat with fever, or discharges from the nose or mouth must report these conditions or symptoms to the vessel's medical staff and must be restricted from working with exposed FOOD, WAREWASHING, clean EQUIPMENT, UTENSILS, LINENS, and unwrapped SINGLE-SERVICE and SINGLE-USE ARTICLES. # Sneeze/Cough (11 C) FOOD EMPLOYEES experiencing persistent sneezing, coughing, or a runny nose that causes discharges from the eyes, nose, or mouth must not work with exposed FOOD; WAREWASHING; clean EQUIPMENT, UTENSILS, and LINENS; or unwrapped SINGLE-SERVICE or SINGLE-USE ARTICLES. • After engaging in other activities that contaminate the hands. # Hand Antiseptic (14) A HAND ANTISEPTIC, a HAND ANTISEPTIC used as a hand dip, or a HAND ANTISEPTIC soap must comply with applicable formulation and use LAWS under FDA 21 CFR 170.39,178,182,184, or 186. # Apply to Clean Hands (12 C) HAND ANTISEPTIC, HAND ANTISEPTIC used as a hand dip, or HAND ANTISEPTIC soap must only be applied to hands cleaned as described in section 7.2.3.1.2. # Fingernails # Fingernails (14) FOOD EMPLOYEES must keep their fingernails trimmed, filed, and maintained so the edges and surfaces are cleanable and not rough. # Fingernail Polish/Artificial Nails (14) A FOOD EMPLOYEE must not wear fingernail polish or artificial fingernails when preparing exposed FOOD. # Jewelry # Jewelry (14) While preparing FOOD, FOOD EMPLOYEES, including bartenders, must not wear jewelry on their arms and hands. FOOD EMPLOYEES may wear a plain ring such as a SMOOTH simple wedding band. # Food Service Uniform or Apron # Uniform or Apron (14) FOOD EMPLOYEES must wear a clean uniform or apron to prevent CONTAMINATION of FOOD, EQUIPMENT, UTENSILS, LINENS, and SINGLE-SERVICE and SINGLE-USE ARTICLES. # Hygienic # Toilet Room Use (Food Employees) While in working uniforms, FOOD EMPLOYEES must not use toilet rooms designated for passenger use. # FOOD EMPLOYEES at bars where the only FOOD preparation includes garnish slicing in the pantry and drink making in the pantry and bar are excluded. • Fluid and dry milk and milk products complying with GRADE A STANDARDS as specified in LAW must be obtained pasteurized. • Frozen milk products, such as ice cream, must be obtained pasteurized as specified in 21 CFR 135 Frozen Desserts. • Cheese must be obtained pasteurized unless alternative procedures to pasteurization are specified in the CFR, such as 21 CFR 133 Cheeses and Related Cheese Products for curing certain cheese varieties. # Package Integrity (15 C) FOOD packages must be in good condition and protect the integrity of the contents so the FOOD is not exposed to adulteration or potential contaminants. Canned goods with dents on end or side SEAMS must not be used. # Ice (15 C) Ice for use as a FOOD or a cooling medium must be made from DRINKING WATER. # Shucked Shellfish (15 C) Raw SHUCKED SHELLFISH must be obtained in nonreturnable packages that bear a legible label as specified in the FDA National Shellfish Sanitation Program Guide for the Control of MOLLUSCAN SHELLFISH. # Shellstock Shellfish (15 C) SHELLSTOCK must be obtained in containers bearing legible source identification tags or labels affixed by the harvester and by each dealer that depurates (cleanses), ships, or reships the SHELLSTOCK, as specified in the National Shellfish Sanitation Program Guide for the Control of MOLLUSCAN SHELLFISH. # Shellstock Condition (19) SHELLSTOCK must be reasonably free of mud, dead shellfish, and shellfish with broken shells when received by a vessel. Dead shellfish or SHELLSTOCK with badly broken shells must be discarded. # Maintaining Molluscan Shellfish Identification # Shucked Identification (15 C) Shucked MOLLUSCAN SHELLFISH must not be removed from the container in which they are received other than immediately before preparation for service. 7.0 Food Safety; 96 physically touch and so that one product does not drip into another. • Separating types of raw animal FOODS such as beef, FISH, lamb, pork, and POULTRY from each other-except when combined as ingredients-during storage, preparation, holding, and display by using separate EQUIPMENT for each type, or by arranging each type of FOOD in EQUIPMENT so that CROSS-CONTAMINATION of one type with another is prevented, or by preparing each type of FOOD at different times or in separate areas. Frozen, commercially processed and PACKAGED raw animal FOOD may be stored or displayed with or above frozen, commercially processed and PACKAGED, READY-TO-EAT FOOD. • Cleaning and sanitizing EQUIPMENT and UTENSILS. • Storing the FOOD in packages, covered containers, or wrappings. • Cleaning visible soil on HERMETICALLY SEALED CONTAINERS of FOOD before opening. • Protecting FOOD containers that are received PACKAGED together in a case or overwrapped from cuts when the case or overwrap is opened. • Separating damaged, spoiled, or recalled FOOD being held on the vessel. • Separating unwashed fruits and vegetables from READY-TO-EAT FOOD. # 7.3.3.3.4 Raw Fruit/Vegetables Whole, raw fruits or vegetables; cut, raw vegetables such as celery, carrot sticks, or cut potatoes; and tofu may be immersed in ice or water. # Raw Chicken/Fish Raw chicken and raw FISH received immersed in ice in shipping containers may remain in that condition while in storage awaiting preparation, display, or service. # Ongoing Meal Service Other unpackaged FOODS in a raw, cooked, or partially cooked state may be immersed in ice as part of an ongoing meal service process, such as liquid egg product, individual eggs, pasta, and reconstituted powdered mixes. # Equipment, Utensils, and Linens # Cleaned/Sanitized (26 C) FOOD must only contact surfaces of cleaned and sanitized EQUIPMENT and UTENSILS. # Storage During Use (19) During pauses in FOOD preparation or dispensing, FOOD preparation and dispensing UTENSILS must be stored in one of the following ways: • In the FOOD with their handles above the top of the FOOD and the container. • Under other sources of CONTAMINATION from nonfood items such as ice blocks, ice carvings, and flowers. • In areas not finished in accordance with 7.7.5 and 7.7.6 for FOOD STORAGE AREAS. # Potentially Hazardous Food Packages in Vending Machines (19) POTENTIALLY HAZARDOUS FOOD dispensed through a vending machine must be in the package in which it was placed in the galley or FOOD-PROCESSING PLANT at which it was prepared. # Preparation (19) During preparation, unpackaged FOOD must be protected from environmental sources of CONTAMINATION such as rain. # Food Display and Service This section applies to self-service candy shops where customers serve themselves from candy displays or dispensers. # Display Preparation (19) FOOD on display must be protected from CONTAMINATION by the use of packaging; counter, service line, or salad bar FOOD guards; display cases; self-closing hinged lids; or other effective means. Install side protection for sneeze guards if the distance between exposed FOOD and where CONSUMERS are expected to stand is less than 1 meter (40 inches). # Condiments (19) Condiments must be protected from CONTAMINATION by being kept in one of the following: • Dispensers designed to provide protection. • Protected FOOD DISPLAYS provided with the proper UTENSILS. • Original containers designed for dispensing. • Individual packages or portions. Condiments at a vending machine location must be in individual packages or provided in dispensers that are filled at an APPROVED location, such as the galley that provides FOOD to the vending machine location, a FOOD-PROCESSING PLANT, or a properly equipped facility located on the site of the vending machine location. Where there is self-service of scooped frozen dessert, service must be out of shallow pans no deeper than 4 inches (100 millimeters) and no longer than 12 inches (300 millimeters). # 7.3.3.6.4 Utensils, Consumer Self-service 7.3.3.6.4.1 Dispensing Utensil ( 19) A FOOD-dispensing UTENSIL must be available for each container of FOOD displayed at a CONSUMER selfservice unit such as a buffet or salad bar. The FOOD contact portion of each self-service FOODdispensing UTENSIL must be covered or located beneath shielding during service. Dishware, glassware, and UTENSILS out for service must be inverted or covered. # Food Reservice (15 C) After being served and in the possession of a CONSUMER or being placed on a buffet service line, FOOD that is unused or returned by the CONSUMER must not be offered as FOOD for human consumption. # Exceptions: • A container of FOOD that is not POTENTIALLY HAZARDOUS may be transferred from one CONSUMER to another if the FOOD is dispensed so that it is protected from CONTAMINATION and the container is closed between uses (such as a narrow-neck bottle containing catsup, steak sauce, or wine) OR the FOOD (such as crackers, salt, or pepper) is in an unopened original package and is maintained in sound condition. • Whole beef roasts, corned beef roasts, pork roasts, and cured pork roasts such as ham, must be cooked as detailed in sections a and b below. a. Food cooked in an oven preheated to the temperature specified below for the roast's weight and oven type AND If FOODS, such as gravlax, ceviche/seviche, FISH carpaccio, or sashimi, are prepared in a FOOD-PROCESSING PLANT and certified as parasite free, they may be served raw, rawmarinated, or partially cooked READY-TO-EAT without freezing the product onboard the vessel. # Records (17) If raw, raw-marinated, partially cooked, or marinated partially cooked FISH are served in READY-TO-EAT form, • The supervisor or PERSON IN CHARGE must record the freezing temperature and time to which the FISH are subjected and must retain the records on the vessel for 90 calendar days beyond the time of service or sale of the FISH; OR • If the FISH are frozen by a supplier, a written letter from the supplier must specify the FISH species involved and both the temperature to which the FISH was frozen and the total time period at that temperature. If the supplier provides any of the same FISH species to the vessel in a fresh state, the outer packaging must designate which one is the parasite-free FISH. For FISH exempt from freezing requirements based on section 7.3.4.2.1, a written letter from the supplier must state both the species of FISH and the conditions in which they were raised and fed. # Slacking (17) Frozen POTENTIALLY HAZARDOUS FOOD that is SLACKED to moderate the temperature must be held • Under refrigeration that maintains the FOOD temperature at 5°C (41°F) or less; or • At any temperature if the FOOD remains frozen. # Thawing (17) POTENTIALLY HAZARDOUS FOOD must be thawed by one of the following: • Under refrigeration that maintains the FOOD temperature at 5°C (41°F) or less. • Completely submerged under running water at a water temperature of 21°C (70°F) or below, with sufficient water velocity to agitate and float off loose particles in an overflow, and for a period of time that does not allow thawed portions of READY-TO-EAT FOOD to rise above 5°C (41°F). • Completely submerged under running water at a water temperature of 21°C (70°F) or below with sufficient water velocity to agitate and float off loose particles in an overflow and for a period of time that does not allow thawed portions of a raw animal FOOD requiring cooking to be above 5°C (41°F) for more than 4 hours, including o The time the FOOD is exposed to the running water and the time needed for preparation for cooking, OR o The time it takes under refrigeration to lower the FOOD temperature to 5°C (41°F). • As part of a cooking process if the frozen FOOD is cooked or thawed in a microwave oven. If a portion of frozen READY-TO-EAT FOOD is thawed and prepared for immediate service in response to an individual CONSUMER'S order, it can be thawed using any procedure. # Food Cooling # Cooling Times/Temperatures (16 C) Cooked POTENTIALLY HAZARDOUS FOOD must be cooled • From 57°C (135°F) to 21°C (70°F) within 2 hours and • From 21°C (70°F) to 5°C (41°F) or less within 4 hours. when 5°C (41°F) is reached, must also be maintained for a 30-day period beginning with the day of preparation. # Food Holding Temperatures and Times # 7.3.5.3.1 Holding Temperature/Time (16 C) Except during preparation, cooking, or cooling, or when time is used as the public health control, POTENTIALLY HAZARDOUS FOOD must be maintained at • 57°C (135°F) or above, except that roasts may be held at a temperature of 54°C (130°F); or • 5°C (41°F) or less. # RTE PHF Shelf-Life: Date Marking (16 C) Refrigerated, READY-TO-EAT, POTENTIALLY HAZARDOUS FOOD • Prepared on a vessel and held refrigerated for more than 24 hours must be clearly marked at the time of preparation to indicate the date or day by which the FOOD must be consumed (7 calendar days or fewer from the day the FOOD is prepared). The day of preparation is counted as day 1. • Prepared and PACKAGED by a FOOD-PROCESSING PLANT and held on the vessel after opening for more than 24 hours must be clearly marked at the time the original container is opened to indicate the date by which the FOOD must be consumed (7 calendar days or fewer after the original container is opened). The day of package opening is counted as day 1. The date marking requirement can be accomplished with a calendar date, day of the week, color-code, or other system, provided it is effective. The date marking requirement does not apply to the following FOODS prepared and PACKAGED by a FOOD-PROCESSING PLANT inspected by a REGULATORY AUTHORITY: • Deli salads (such as ham salad, seafood salad, chicken salad, egg salad, pasta salad, potato salad, and macaroni salad) manufactured in accordance with 21 CFR 110. • Hard cheeses containing not more than 39% moisture as defined in 21 CFR 133 (such as cheddar, gruyere, parmesan and reggiano, and romano). • Semisoft cheeses containing more than 39% moisture but not more than 50% moisture, as defined in 21 CFR 133 (such as blue, edam, gorgonzola, gouda, and monterey jack). • Cultured dairy products as defined in 21 CFR 131 (such as yogurt, sour cream, and buttermilk). • Preserved FISH products (such as pickled herring and dried or salted cod) and other acidified FISH products defined in 21 CFR 114. • Shelf stable, dry fermented sausages (such as pepperoni and Genoa salami) not labeled "keep refrigerated" as specified in 9 CFR 317. [Retain the original casing on the product.] • Shelf stable salt-cured products (such as prosciutto and Parma [ham]) not labeled "keep refrigerated" as specified in 9 CFR 317. These products are exempted from date marking even after being opened, cut, shredded, etc. # Discarding RTE PHF (16 C) Refrigerated, READY-TO-EAT, POTENTIALLY HAZARDOUS FOOD must be discarded if not consumed within 7 calendar days from the date of preparation or opening. # Retain Date (16 C) A refrigerated, potentially hazardous, READY-TO-EAT FOOD ingredient or a portion of a refrigerated, potentially hazardous, READY-TO-EAT FOOD subsequently combined with additional ingredients or portions of FOOD must retain the date marking of the earliest or first-prepared ingredient. # Time as a Public Health Control (16 C) If time only-rather than time in conjunction with temperature-is used as the public health control for a working supply of POTENTIALLY HAZARDOUS FOOD before cooking, or for READY-TO-EAT POTENTIALLY HAZARDOUS FOOD that is displayed or held for service for immediate consumption, the FOOD • Must have an initial temperature of 5°C (41°F) or less or 57°C (135°F) or greater before placement on time control. • Must not be placed on temperature control again. • Must be marked or otherwise identified to indicate the time 4 hours past the point in time when the FOOD is removed from temperature control (if the time between service setup and closing is greater than 4 hours). • Must be discarded within hours of placement on time control. o If FOOD is on/in a time control unit (bain marie, cold basin, soup wells) and service is under 4 hours, a 4-hour discard label is not needed. o If the time control unit meant to be cold holding or hot holding is not operational or used as intended, the unit is considered a counter and the FOOD stored within it must be labeled with its 4-hour discard time. o Containers of POTENTIALLY HAZARDOUS FOOD under time control and placed on preparation counters must be labeled with the discard time, even if the outlet is open less than 4 hours. EQUIPMENT that does not have cabinets or compartments does not need to be labeled as time control. Such EQUIPMENT includes bains marie, cold tops, and soup wells. # Time Control Plan (17) A written time control plan(s) that ensures compliance with these guidelines must be maintained on the vessel and made available for review during inspections (Annex 13.13). A time control plan must be posted and ACCESSIBLE to all crew working at each outlet where time control is used. The plan(s)must • Include set-up and discard times for each outlet. Include all services and events where POTENTIALLY HAZARDOUS FOODS are kept on time control. If used, colored labels must correspond to the discard times stated in the plan. • List all units (to include preparation counters, cabinets, compartments, and EQUIPMENT) on time control. • Describe or show the flow of POTENTIALLY HAZARDOUS FOOD from when last in temperature control to placement in time control and discard. # Consumer Information # Consumer Advisory # Raw Shell Egg Preparations (16 C) Raw shell egg preparations are prohibited in uncooked products as described in 7.3.3.2.3. # Animal Food (16 C) If an animal FOOD such as beef, eggs, FISH, lamb, milk, pork, POULTRY, or shellfish that is raw, undercooked, or not otherwise processed to eliminate pathogens is offered in a READY-TO-EAT form or as a raw ingredient in another READY-TO-EAT FOOD, the CONSUMER must be informed by way of disclosure as specified below using menu advisories, placards, or other easily visible written means of the significantly increased risk to certain especially vulnerable CONSUMERS eating such FOODS in raw or undercooked form. The advisory must be located at the outlets where these types of FOOD are served. Disclosure must be made by one of the two following methods: • On a sign describing the animal-derived FOODS (e.g., "oysters on the half-shell," "hamburgers," "steaks," or "eggs") AND that they can be cooked to order or may be served raw or undercooked AND a statement indicating that consuming raw or undercooked MEATS, seafood, shellfish, eggs, milk, or POULTRY may increase your risk for foodborne illness, especially if you have certain medical conditions. The advisory must be posted at the specific station where the FOOD is served raw, undercooked, or cooked to order. # OR • On a menu using an asterisk at the animal-derived FOODS requiring disclosure and a footnote with a statement indicating that consuming raw or undercooked MEATS, seafood, shellfish, eggs, milk, or POULTRY may increase your risk for foodborne illness, especially if you have certain medical conditions. It is acceptable to limit the list of animal-derived FOODS in the CONSUMER advisory to only the type(s) of animalderived FOOD served raw, undercooked, or cooked to order at a specific location. For example, at a sushi counter, the CONSUMER advisory might only refer to seafood. • Resistant to pitting, chipping, crazing, scratching, scoring, distortion, and decomposition. # Cast Iron (20) Cast iron must not be used for UTENSILS or FOOD-CONTACT SURFACES of EQUIPMENT. Cast iron may be used as a surface for cooking. Cast iron may be used in UTENSILS for serving FOOD if the UTENSILS are used only as part of an uninterrupted process from cooking through service. Cast iron FOOD DISPLAY dishes heated to a temperature of 74°C (165°F) for 15 seconds may be used for the immediate service of FOOD. # Lead (20) Limitation of lead use must be as follows: • Ceramic, china, crystal UTENSILS, and decorative UTENSILS such as hand-painted ceramic or china used in contact with FOOD must be lead-free or contain levels of lead not exceeding the limits for specific UTENSIL categories as allowed by LAW. • Pewter alloys containing lead in excess of 0.05% must not be used as a FOOD-CONTACT SURFACE. • Solder and flux containing lead in excess of 0.2% must not be used as a FOOD-CONTACT SURFACE. # Copper/Brass (26 C) Copper and copper alloys such as brass must not be used in contact with a FOOD that has a pH below 6 (such as vinegar, fruit juice, or wine) or for a fitting or tubing installed between a BACKFLOW PREVENTION DEVICE and a carbonator. Copper and copper alloys may be used in contact with beer brewing ingredients that have a pH below 6 in the prefermentation and fermentation steps of a beer brewing operation such as a brewpub or microbrewery. # Galvanized (26 C) Galvanized metal must not be used for UTENSILS or FOOD-CONTACT SURFACES of EQUIPMENT. 7.0 Food Safety; 120 drips, and dust from openings into the FOOD; the opening must be flanged at least 5 millimeters (2/10 of an inch). # Beverage/Ice Dispensing (20) In EQUIPMENT that dispenses liquid FOOD or ice in unpackaged form, • The delivery tube, chute, orifice, and splash surfaces directly above the container receiving the FOOD must be designed in a manner (such as with barriers, baffles, or drip aprons) so that drips from condensation and splash are diverted from the opening of the container receiving the FOOD. • The delivery tube, chute, and orifice must be protected from manual contact (such as by being recessed). • The delivery tube or chute and orifice of EQUIPMENT used to vend liquid FOOD or ice in unpackaged form to self-service CONSUMERS must be designed so the delivery tube or chute and orifice are protected from dust, insects, rodents, and other CONTAMINATION by a selfclosing door if the EQUIPMENT o Is in an outside area that does not otherwise afford protection against rain, windblown debris, insects, rodents, and other contaminants present in the environment OR o Is available for self service during hours when it is not under the full-time supervision of a FOOD EMPLOYEE. The dispensing EQUIPMENT actuating lever or mechanism and filling device of CONSUMER self-service BEVERAGE dispensing EQUIPMENT must be designed to prevent contact with the lip-contact surface of glasses or cups that are refilled. # Bearings/Gears (21) EQUIPMENT containing bearings and gears that require lubricants must be designed and constructed so the lubricant cannot leak, drip, or be forced into FOOD or onto FOOD-CONTACT SURFACES. # Beverage Line Cooling (20) BEVERAGE tubing and cold-plate BEVERAGE cooling devices must not be installed in contact with stored ice. This guidance does not apply to cold plates constructed integrally without SEAMS in an ice storage bin. # Equipment Drainage (21) EQUIPMENT compartments subject to accumulation of moisture because of conditions such as condensation, FOOD or BEVERAGE drip, or water from melting ice must be sloped to an outlet that allows complete draining. # Drain Lines (20) Liquid waste drain lines must not pass through an ice machine or ice storage bin. # Condenser Unit (21) If a condenser unit is an integral component of EQUIPMENT, the condenser unit must be separated from the FOOD and FOOD STORAGE space by a dustproof barrier. # Ambient Air TMDs (21) TEMPERATURE-MEASURING DEVICES must conform to the following guidelines: • In a mechanically refrigerated FOOD storage unit, the sensor of a TEMPERATURE-MEASURING DEVICE must be located to measure the air temperature in the warmest part of the unit. • In a hot-FOOD storage unit, the sensor of a TEMPERATURE-MEASURING DEVICE must be located to measure the air temperature in the coolest part of the unit. • Cold or hot holding EQUIPMENT used for POTENTIALLY HAZARDOUS FOOD must be designed to include and must be equipped with at least one integral or affixed TEMPERATURE-MEASURING DEVICE that is located to allow easy viewing of the device's temperature display. • The above bullets do not apply to EQUIPMENT for which the placement of a TEMPERATURE-MEASURING DEVICE is not a practical means for measuring the ambient air surrounding the FOOD because of the design, 7.0 Food Safety; 122 type, and use of the EQUIPMENT (such as calrod units, heat lamps, cold plates, bains-marie, steam tables, insulated FOOD transport containers, and salad bars). • TEMPERATURE-MEASURING DEVICES must be easily readable. # Ventilation Hood Systems # Ventilation Hood (37) Ventilation hood systems and devices must be sufficient in number and capacity to prevent grease or condensation from collecting on BULKHEADS and DECKHEADS. # Warewasher Data Plate (22) A WAREWASHING machine must be provided with an easily ACCESSIBLE and readable data plate affixed to or posted adjacent to the machine that indicates the machine's design and operating specifications including the • Wash tank, rinse tank(s) if present, and final sanitizing rinse temperatures. • Pressure required for the fresh water sanitizing rinse unless the machine is designed to use only a pumped sanitizing rinse. • Conveyor speed in meters or feet per minute or minimum transit time for belt conveyor machines, minimum transit time for rack conveyor machines, and wash and final sanitizing rinse times as specified by the manufacturer for stationary rack machines. 7.5.5 Sanitizing 7.5.5.1 Food-Contact Surfaces (24 C) FOOD-CONTACT SURFACES of EQUIPMENT and UTENSILS must be sanitized. # Sanitizing Temperatures # Manual Hot-Water Sanitizing (24 C) In a manual operation, if immersion in hot water is used for sanitizing, • The temperature of the water must be maintained at 77°C (171°F) or above and • The FOOD-CONTACT SURFACE must be immersed for at least 30 seconds. # Warewasher Hot-Water Sanitizing (24 C) In a mechanical operation, the temperature of the fresh hot water sanitizing rinse as it enters the manifold must not be more than 90°C (194°F) or less than • 74°C (165°F) for a stationary rack, single-temperature machine. • 82°C (180°F) for all other machines. The UTENSIL surface temperature must not be less than 71°C (160°F) as measured by an irreversible registering temperature indicator. The maximum temperature of 90°C (194°F) does not apply to the high pressure and temperature systems with wand-type, hand-held spraying devices used for in-place cleaning and sanitizing of EQUIPMENT such as MEAT saws. # Warewasher Hot-Water Sanitizing Pressure (22) The flow pressure of the fresh hot water sanitizing rinse in a WAREWASHING machine must not be less than 34.5 kilopascals (5 pounds per square inch or 0.34 bars) or more than 207 kilopascals (30 pounds per square inch or 2.07 bars) as measured in the water line immediately downstream or upstream from the fresh hot water sanitizing rinse control valve. # Passenger Entries Provide handwashing stations at each minor passenger entry to the main buffet areas proportional to the passenger flow, with at least one per entry. These handwash stations can count toward the requirement of one station per 100 passengers. # Self-Service Stations Outside the Main Buffet Provide at least one handwashing station at the passenger entrance of each self-service station outside of the main buffet. BEVERAGE stations are excluded. # Equipment and Supplies The handwashing station must include a handwash sink with hot and cold water, soap dispenser, and SINGLE-USE paper towel dispenser. Electric hand dryers can be installed in addition to paper towel dispensers. Each handwashing station must have a supply of hand-cleansing soap or detergent and a supply of SINGLE-SERVICE paper towels available. Waste receptacles must be provided in close proximity to the handwash sink and sized to accommodate the quantity of paper towel waste generated. The handwashing station may be decorative but must be nonabsorbent, durable, and EASILY CLEANABLE. # Automatic Handwashing System An automatic handwashing system in lieu of a handwash sink is acceptable. # Sign Each handwashing station must have a sign advising passengers to wash hands before eating. A pictogram can be used in lieu of words on the sign. # Location Stations can be installed just outside of the entry. Position the handwashing stations along the passenger flow to the buffets. # Lighting The light intensity must be at least 110 lux (10 foot candles) at passenger handwashing stations. The light intensity must be at least 110 lux (10 foot candles) behind and around mounted EQUIPMENT, including countermounted EQUIPMENT. # Bars and Waiter Stations (36) The light intensity must be at least 110 lux (10 foot candles) at handwashing stations in bars. In bars and dining room waiter stations, provide 220 lux (20 foot candles) light intensity during cleaning operations. • Duties and responsibilities of each department and their staff for all passenger and crew public areas. • Steps in OUTBREAK management and control and the trigger required for action at each step. At a minimum, triggers must address a graduated approach to OUTBREAK management in response to increasing case counts. Additionally, triggers may be based on events, such as reports of public vomiting/diarrhea, increased room service requests, meal or excursion cancellations, missed events, or others. Cruise ship AGE surveillance data has shown that a 0.45% daily ATTACK RATE is indicative of a pending OUTBREAK. • DISINFECTANT products or systems used, including the surfaces or items the DISINFECTANTS will be applied to, concentrations, and required contact times. The DISINFECTANT products or systems must be effective against human norovirus or an acceptable surrogate (e.g., caliciviruses). • Procedures for informing passengers and crew members of the OUTBREAK. This section should address the procedures for notification of passengers embarking the vessel after an OUTBREAK voyage. In the case of an extended voyage separated into segments, such as a world cruise, this requirement applies to passengers embarking for the segment after an OUTBREAK segment. • Procedures for returning the vessel to normal operating conditions after an OUTBREAK. • Procedures to protect the passengers and crew from exposure to DISINFECTANTS, if not already included in the vessel's safety management system. At a minimum, this must include the following: o Material safety data sheets (MSDSs). demonstrate this knowledge by compliance with this section of these guidelines or by responding correctly to the inspector's questions as they relate to the specific operation. In addition, the supervisor or PERSON IN CHARGE of housekeeping operations on the vessel must ensure that employees are properly trained to comply with this section of the guidelines in this manual as it relates to their assigned duties. # Followup Reasons Follow-up inspections may be conducted to resolve a contested inspection or to inspect IMMINENT HEALTH HAZARDS that resulted in a recommendation to prohibit the vessel from sailing. # Next Arrival These inspections will be conducted as soon as possible after the routine inspection or reinspection, preferably the next time the vessel arrives at a U.S. port. # Limited Follow-up inspections will be limited to inspection of deficiencies in question. For example, if an item under the refrigerator section of the inspection was a deficiency and was the only item contested, only refrigeration would be checked during the follow-up inspection. # Other Items Any other problems noted during the follow-up inspection will be brought to the attention of the vessel's master or designee so the deficiencies can be corrected. # No Score No inspection score will be provided and no fee will be charged for follow-up inspections. 12.11 Construction/Renovation Inspections 12.11.1 Procedures 12.11.1.1 Construction Whenever possible, VSP staff will conduct inspections of vessels being constructed or undergoing major retrofits on request of the vessel owner or operator. # Requesting Inspection An official written request will be submitted to the VSP Chief requesting a voluntary construction renovation inspection. CDC's ability to honor these requests will be based on the availability of the VSP staff. # Time Frame Construction/renovation inspections are normally conducted at the shipyard 4 to 6 weeks before completion. An additional inspection may also be conducted on completion of the work and before the vessel enters operational status. # Rescinding Variance VARIANCE approval may be rescinded at any time for noncompliance with these conditions or if it is determined that public health could be compromised. # Areas Not Identified (44) Procedures, systems, EQUIPMENT, technology, processes, or activities not identified in the scope of this manual must not be tested or introduced operationally onboard any vessel until the concept is submitted in writing to the VSP Chief for review. If the review determines the concept is within the scope of the VSP Operations Manual, written procedures, control measures, or a complete VARIANCE submission may be required. The Surgeon General, with the approval of the Secretary, is authorized to make and enforce such regulations as in his judgment are necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession. For purposes of carrying out and enforcing such regulations, the Surgeon General may provide for such inspection, fumigation, disinfection, sanitation, pest extermination, destruction of animals or articles found to be so infected or contaminated as to be sources of dangerous infection to human beings, and other measures, as in his judgment may be necessary. # Annexes # (b) Apprehension, detention, or conditional release of individuals Regulations prescribed under this section shall not provide for the apprehension, detention, or conditional release of individuals except for the purpose of preventing the introduction, transmission, or spread of such communicable diseases as may be specified from time to time in Executive orders of the President upon the recommendation of the National Advisory Health Council and the Surgeon General. # (c) Application of regulations to persons entering from foreign countries Except as provided in subsection (d) of this section, regulations prescribed under this section, insofar as they provide for the apprehension, detention, examination, or conditional release of individuals, shall be applicable only to individuals coming into a State or possession from a foreign country or a possession. # (d) Apprehension and examination of persons reasonably believed to be infected On recommendation of the National Advisory Health Council, regulations prescribed under this section may provide for the apprehension and examination of any individual reasonably believed to be infected with a communicable disease in a communicable stage and (1) to be moving or about to move from a State to another State; or (2) to be a probable source of infection to individuals who, while infected with such disease in a communicable stage, will be moving from a State to another State. Such regulations may provide that if upon examination any such individual is found to be infected, he may be detained for such time and in such manner as may be reasonably necessary. For purposes of this subsection, the term "State" includes, in addition to the several States, only the District of Columbia. (July 1, 1944, ch. 373, title III, Sec. 361, 58 Stat. 703;1953Reorg. Plan No. 1, Secs. 5, 8, eff. Apr. 11, 1953, 18 F.R. 2053July 12, 1960, Pub. L. 86-624, Sec. 29(c), 74 Stat. 419;June 23, 1976, Pub. L. 94-317, title III, Sec. 301(b)(1), 90 Stat. 707.) # Sec. 269. Bills of Health (a) Detail of medical officer; conditions precedent to issuance; consular officer to receive fees Except as otherwise prescribed in regulations, any vessel at any foreign port or place clearing or departing for any port or place in a State or possession shall be required to obtain from the consular officer of the United States or from the Public Health Service officer, or other medical officer of the United States designated by the Surgeon General, at the port or place of departure, a bill of health in duplicate, in the form prescribed by the Surgeon General. The President, from time to time, shall specify the ports at which a medical officer shall be stationed for this purpose. Such bill of health shall set forth the sanitary history and condition of said vessel, and shall state that it has in all respects complied with the regulations prescribed pursuant to subsection (c) of this section. Before granting such duplicate bill of health, such consular or medical officer shall be satisfied that the matters and things therein stated are true. The consular officer shall be entitled to demand and receive the fees for bills of health and such fees shall be established by regulation. # (b) Collectors of customs to receive originals; duplicate copies as part of ship's papers Original bills of health shall be delivered to the collectors of customs at the port of entry. Duplicate copies of such bills of health shall be delivered at the time of inspection to quarantine officers at such port. The bills of health herein prescribed shall be considered as part of the ship's papers, and when duly certified to by the proper consular or other officer of the United States, over his official signature and seal, shall be accepted as evidence of the statements therein contained in any court of the United States. # (c) Regulations to secure sanitary conditions of vessels The Surgeon General shall from time to time prescribe regulations, applicable to vessels referred to in subsection (a) of this section for the purpose of preventing the introduction into the States or possessions of the United States of any communicable disease by securing the best sanitary condition of such vessels, their cargoes, passengers, and crews. Such regulations shall be observed by such vessels prior to departure, during the course of the voyage, and also during inspection, disinfection, or other quarantine procedure upon arrival at any United States quarantine station. # (d) Vessels from ports near frontier The provisions of subsections (a) and (b) of this section shall not apply to vessels plying between such foreign ports on or near the frontiers of the United States and ports of the United States as are designated by treaty. # (e) Compliance with regulations It shall be unlawful for any vessel to enter any port in any State or possession of the United States to discharge its cargo, or land its passengers, except upon a certificate of the quarantine officer that regulations prescribed under subsection (c) of this section have in all respects been complied with by such officer, the vessel, and its master. The master of every such vessel shall deliver such certificate to the collector of customs at the port of entry, together with the original bill of health and other papers of the vessel. The certificate required by this subsection shall be procurable from the quarantine officer, upon arrival of the vessel at the quarantine station and satisfactory inspection thereof, at any time within which quarantine services are performed at such station. (July 1, 1944, ch. 373, title III, Sec. 366, 58 Stat. 705.) # Sec. 271. Penalties for violation of quarantine laws (a) Penalties for persons violating quarantine laws Any person who violates any regulation prescribed under sections 264 to 266 of this title, or any provision of section 269 of this title or any regulation prescribed thereunder, or who enters or departs from the limits of any quarantine station, ground, or anchorage in disregard of quarantine rules and regulations or without permission of the quarantine officer in charge, shall be punished by a fine of not more than $1,000 or by imprisonment for not more than one year, or both. # (b) Penalties for vessels violating quarantine laws Any vessel which violates section 269 of this title, or any regulations thereunder or under section 267 of this title, or which enters within or departs from the limits of any quarantine station, ground, or anchorage in disregard of the quarantine rules and regulations or without permission of the officer in charge, shall forfeit to the United States not more than $5,000, the amount to be determined by the court, which shall be a lien on such vessel, to be recovered by proceedings in the proper district court of the United States. In all such proceedings the United States attorney shall appear on behalf of the United States; and all such proceedings shall be conducted in accordance with the rules and laws governing cases of seizure of vessels for violation of the revenue laws of the United States. # (c) Remittance or mitigation of forfeitures With the approval of the Secretary, the Surgeon General may, upon application therefore, remit or mitigate any forfeiture provided for under subsection (b) of this section, and he shall have authority to ascertain the facts upon all such applications. ( 1, 1944, ch. 373, title III, Sec. 368, 58 Stat. 706;June 25, 1948, ch. 646, Sec. 1, 62 Stat. 909;1953Reorg. Plan No. 1, Secs. 5, 8, eff. Apr. 11, 1953, 18 F.R. 2053 Stat. 631.) (a) The master of a ship destined for a U.S. port shall report immediately to the quarantine station at or nearest the port at which the ship will arrive, the occurrence, on board, of any death or any ill person among passengers or crew (including those who have disembarked or have been removed) during the 15-day period preceding the date of expected arrival or during the period since departure from a U.S. port (whichever period of time is shorter). # Title 42 Code of Federal Regulations (b) The commander of an aircraft destined for a U.S. airport shall report immediately to the quarantine station at or nearest the airport at which the aircraft will arrive, the occurrence, on board, of any death or ill person among passengers or crew. (c) In addition to paragraph (a) of this section, the master of a ship carrying 13 or more passengers must report by radio 24 hours before arrival the number of cases (including zero) of diarrhea in passengers and crew recorded in the ship's medical log during the current cruise. All cases of diarrhea that occur after the 24 hour report must also be reported not less than 4 hours before arrival. (a) Upon arrival at a U.S. port, a carrier will not undergo inspection unless the Director determines that a failure to inspect will present a threat of introduction of communicable diseases into the United States, as may exist when the carrier has on board individual(s) reportable in accordance with Sec. 71.21 or meets the circumstances described in Sec. 71.42. Carriers not subject to inspection under this section will be subject to sanitary inspection under Sec. 71.41 of this part. (b) The Director may require detention of a carrier until the completion of the measures outlined in this part that are necessary to prevent the introduction or spread of a communicable disease. The Director may issue a controlled free pratique to the carrier stipulating what measures are to be met, but such issuance does not prevent the periodic boarding of a carrier and the inspection of persons and records to verify that the conditions have been met for granting the pratique. Sec. 71.32 Persons, carriers, and things. (a) Whenever the Director has reason to believe that any arriving person is infected with or has been exposed to any of the communicable diseases listed in paragraph (b) of this section, he/she may detain, isolate, or place the person under surveillance and may order disinfection or disinfestation as he/she considers necessary to prevent the introduction, transmission, or spread of the listed communicable diseases. (b) The communicable diseases authorizing the application of sanitary, detention, and/or isolation measures under paragraph (a) of this section are: cholera or suspected cholera, diphtheria, infectious tuberculosis, plague, suspected smallpox, yellow fever, or suspected viral hemorrhagic fevers (Lassa, Marburg, Ebola, Congo-Crimean, and others not yet isolated or named). (c) Whenever the Director has reason to believe that any arriving carrier or article or thing on board the carrier is or may be infected or contaminated with a communicable disease, he/she may require detention, disinsection, disinfection, disinfestation, fumigation, or other related measures respecting the carrier or article or thing as he/ she considers necessary to prevent the introduction, transmission, or spread of communicable diseases. Sec. 71.33 Persons: Isolation and surveillance. (a) Persons held in isolation under this subpart may be held in facilities suitable for isolation and treatment. (b) The Director may require isolation where surveillance is authorized in this subpart whenever the Director considers the risk of transmission of infection to be exceptionally serious. (a) Every seaport and airport shall be provided with a supply of potable water from a watering point approved by the Commissioner of FOOD and Drugs, FOOD and Drug Administration, in accordance with standards established in title 21, Code of Federal Regulations, parts 1240 and 1250. (b) All FOOD and potable water taken on board a ship or aircraft at any seaport or airport intended for human consumption thereon shall be obtained from sources approved in accordance with regulations cited in paragraph (a) of this section. (c) Aircraft inbound or outbound on an international voyage shall not discharge over the United States any excrement, or waste water or other polluting materials. Arriving aircraft shall discharge such matter only at servicing areas approved under regulations cited in paragraph (a) of this section. # Sec. 71.48 Carriers in intercoastal and interstate traffic. Carriers, on an international voyage, which are in traffic between U.S. ports, shall be subject to inspection as described in Secs. 71.31 and 71.41 when there occurs on board, among passengers or crew, any death, or any ill person, or when illness is suspected to be caused by insanitary conditions. # 13.4 Acute Gastroenteritis Outbreak Investigation # Vigilance Ongoing vigilance and rapid OUTBREAK detection and response are still warranted. Because so many people share the same environment, meals, and water, disease can often spread quickly to passengers and crew members on the vessel and overwhelm the vessel's medical system. The infection can also continue unabated between cruises if proper interventions are not instituted. # Consultation An OUTBREAK of AGE occurs aboard a vessel when the number of cases is in excess of expected levels for a given time period. When the cumulative proportion of REPORTABLE CASES of AGE reaches 2% among passengers or 2% among crew and the vessel is within 15 days of arrival at a U.S. port, the vessel must submit a special report to VSP. This provides an early opportunity for consultation to potentially avert more illness among passengers and crew members. # Monitoring In most instances, a 2% proportion of illness will not lead to an investigation aboard the vessel but will provide the opportunity to discuss and monitor illness patterns and collaboratively develop intervention strategies. VSP staff members are always available to discuss disease TRANSMISSION and intervention questions. # Investigation OUTBREAKS of AGE aboard cruise ships are relatively infrequent occurrences. If the proportion of illness in either passenger or crew populations crests VSP's 3% OUTBREAK threshold or for subsequent voyages that crest the 2% or 3% thresholds, an onboard investigation may occur. # Special Circumstances Under special circumstances, when an unusual AGE pattern or disease characteristic is found, an investigation may be conducted when the proportion of cases is less than 3%. These special circumstances may include a high incidence of illness in successive cruises, unusual severity of illnesses or complications, or a large number of persons reporting the illness over a brief period of time. # Rapid Response Conducting an OUTBREAK investigation aboard a vessel demands a rapid, organized, and comprehensive response. Because of the TURNOVER of passengers, and sometimes crew members, the investigation must be rapid in order to collect data needed to identify the cause. # Collaboration The investigation is a collaborative effort of the cruise line, passengers and crew members aboard the vessel, and VSP. Therefore, an organized plan drafted between the organizations and individuals involved is crucial in conducting a successful investigation-a comprehensive effort that includes epidemiologic, environmental, and laboratory studies. Recommendations based on the success of the investigation can then be implemented to prevent a recurrence on the following cruise. # Objectives The objectives of an investigation are to • Determine the extent of the AGE among passengers and crew. • Identify the agent causing the illness. • Identify risk factors associated with the illness. • Formulate control measures to prevent the spread of the illness. # Outbreak Investigation Procedures # Contingency Plan The early stages of an investigation are usually coordinated aboard the vessel by the vessel's medical staff in cooperation with engineering and hotel staff. It is important to have a coordinated contingency plan in place on board the vessel before implementation is needed. All staff with a potential for involvement in an investigation should be familiar with the contingency plan. # Periodic Review This preliminary preparation will assist the vessel with the necessary rapid implementation of investigation and response measures before the arrival of the VSP team. The OUTBREAK contingency plan should be periodically reviewed to ensure it will still meet the vessel's needs in dealing with an OUTBREAK. • Sterile pipettes. • 20 serum separator tubes (containing no anticoagulant [red tops]). • 20 nunc tubes for serum separation. • Shipping containers (for diagnostic specimens). • Shipping container labels and markings (as required by current shipping regulations for diagnostic specimens). As noted in Annex 13.4.3.4, vessels with no medical staff aboard may choose to stock only the starred items unless a qualified staff member aboard is capable of performing venipuncture for collection of serum specimens. # Specimen Collection # Request Procedures It may be advisable to collect clinical specimens of stool, vomitus, or serum from passengers and crew members with REPORTABLE CASES of AGE. Timely notification of the vessel as to what samples and information will be required is essential. Collection of specimens for analysis for viruses, bacteria, or parasites may be recommended depending on the likely etiology of illness. It is recommended that specimens be requested from patients during clinical evaluation in the infirmary or after infirmary visits by direct contact with or a letter from medical staff. Each individual asked to provide specimens should be given disposable gloves, two specimen cups, a disposable spoon, and plastic wrap. Following are • Suggested language for a passenger letter requesting stool specimens. • Instructions to passengers and crew for collection of stool. # Request to Passengers for Stool Specimens The [U.S. Public Health Service/Name of Cruise Line/Medical Department] is requesting stool specimens from some people who became ill with AGE on this cruise. Please give one cup to a friend who has recently become ill and use the other cup for yourself. Put your next bowel movement into the cup and return the cup to the vessel's medical center as soon possible so it can be refrigerated. # Patient Instructions 1. Urinate into the toilet (if you feel the need). 2. Wash and dry your hands. 3. Lift the toilet seat. 4. Place sheets of plastic wrap over the toilet bowl, leaving a slight dip in the center. 5. Put the toilet seat down. 6. Pass some stool onto the plastic wrap. Do not let urine or water touch the stool specimen, if possible. 7. Using the spoon given to you, place bloody, slimy, or whitish areas of the stool into the container first. Fill the cup at least 2/3 full, if possible. 8. Tighten the cap. 9. Wash your hands. 10. Label the specimen jar with your name, the date, and your cabin number. # Medical Staff Instructions Specimen Labeling Please ensure that each specimen is properly labeled with the following: • Date of collection. • Unique identifying number. (A separate log containing unique identifying number linked to case name must be kept on the ship.) • Notation on use of antidiarrheal or antibiotic medication. # Collection, Storage, and Transport Complete guidelines for collection and storage of specimens for viral, bacterial, and parasite analysis are listed below, although it may not be necessary to implement all procedures during each investigation. Transport of specimens will be arranged in collaboration with VSP. 4. If a centrifuge is available, centrifuge the specimen for 10 minutes and remove the serum using a pipette. If no centrifuge is available, the blood specimens can sit in a refrigerator until a clot has formed; remove the serum using pipettes, as above. # Guidelines for 5. Place the serum into an empty nunc tube, label, then refrigerate. Do not freeze. # Other Specimens for Viral Diagnosis Water, FOOD, and Environmental Samples Viruses causing AGE are not routinely detected in water or FOOD, but may be detectable on surfaces with environmental swabbing. Swabbing may be completed under the guidance of VSP staff or the CDC National Calicivirus Laboratory. Viruses have been successfully detected in vomitus specimens. These should be collected and sent using same methodology as for stool specimens. # Guidelines for Collecting Fecal Specimens for Bacteriologic Diagnosis Before use, the transport media should be stored in a refrigerator or at room temperature. If the transport media is stored at room temperature, it should normally be chilled for 1 to 2 hours by refrigeration before use. At least two rectal swabs or swabs of fresh stools should normally be collected for bacterial analysis and placed in refrigerated Cary-Blair transport media. It is recommended that the swabs be inserted initially into the transport media to moisten, then inserted about 1 to 1-1/2 inches (approximately 25 to 38 millimeters) into the rectum, gently rotated, and removed for insertion individually into the same tube of transport media. If possible, there should be visible fecal material on the swabs. Both swabs should be inserted into the same tube of media and the swabs pushed completely to the bottom of the tube. The top portion of the stick touching the fingers should be broken off and discarded. Refrigeration during transport may be accomplished by shipping in an insulated box with frozen refrigerant packs. The specimens must never be frozen during storage or transport. # Guidelines for Collecting Fecal Specimens for Parasite Diagnosis # Parasite Specimens In the event a disease of parasitic etiology is suspected, arrangements will be made for shipment of appropriate specimen containers containing 10% formalin and PVA (polyvinyl alcohol). # Sample Temperatures FOOD and water samples should be held below 5°C (41°F) but not frozen. Sufficient frozen refrigerant packs should be used to maintain cold sample temperatures during transport to the laboratory. # 13.5 Disinfection Calculations for Water and Equipment 13.5.1 Introduction POTABLE WATER systems and EQUIPMENT, SWIMMING POOLS, and WHIRLPOOL SPAS on a vessel may need to be disinfected when there is a possibility of CONTAMINATION and as a routine part of maintenance. This annex provides tables for calculating the amount of chlorine to be used in emergency chlorination of POTABLE WATER and for the routine DISINFECTION of POTABLE WATER systems and EQUIPMENT, SWIMMING POOLS, and WHIRLPOOL SPAS. # Water Chlorination Tables 1 and 2 (Annex 13.5.4) are for calculating the amount of chlorine to be used in the DISINFECTION of POTABLE WATER systems, SWIMMING POOLS, and EQUIPMENT. The chlorine compound column in Tables 1 and 2 refers to the amount of available chlorine in the compound as stated on the product label. Requirements varying from those shown in the table-for example: metric tons of water, available chlorine compounds, or final chlorine concentrations-may be extrapolated. # Amounts of chlorine compound shown in For example, POTABLE WATER TANKS or fresh water tanks must be superchlorinated to at least 50 MG/L (ppm) available chlorine when samples taken from these tanks indicate potential CONTAMINATION with fecal coliform bacteria. The total amount of 70% chlorine compound required to obtain 50 MG/L (ppm) in 166 metric tons of water is calculated in Example 1, which illustrates how to use the tables. Example 1. The capacity of a potable tank from which a coliform-positive sample was obtained is 166 metric tons. The vessel has a compound on board containing 70% available chlorine. The amount of chlorine required for 50 ppm is determined as follows: • Use the 70% chlorine compound columns in Table 1. • Find the 70% row that corresponds to 100 metric tons of water. • Follow this 70%/100 ton row across until you reach the "50 ppm" column (7,150 grams). • Do the same using the 50, 10, 5, and 1 metric ton columns to determine the totals for 166 metric tons. • Total each column as shown in the calculation table below. In this example, the amount of 70% chlorine compound required for 166 tons of water at 50 parts per million is 11,869.0 grams or 11.87 kilograms. # Calculation # Equipment Disinfection The Available Chlorine in Compounds table lists the various chlorine compounds and the amount of the compound required in grams per liter of water to produce a solution containing 100 ppm of chlorine. The 100-ppm chlorine solution should be applied as outlined in this manual. 50 200.00 400.00 1,000.00 2,000.00 10,000.00 20,000.00 25% 100 400.00 800.00 2,000.00 4,000.00 20,000.00 40,000.00 # Potable Water Pipe and System Disinfection Method Examples (Nonemergency) Examples in this section relate to nonemergency situations. In an emergency, see section 5.3.4.1.4 for concentration and contact time. To achieve the proper DISINFECTION of a section of pipe being replaced, • Fill the pipe with 50 MG/L (ppm) of free residual HALOGEN, cap on both ends, and let it sit for 4 hours OR Place small sections of pipes in a large container filled with 50 MG/L (ppm) of free residual HALOGEN for 4 hours. • Drain and flush disinfected parts of the system with POTABLE WATER. To achieve the proper DISINFECTION of a section of pipe already installed on part of the distribution system, 1. Install temporary shut-off valves at each end of the new section. 2. Close the valves. 3. Inject 50 MG/L (ppm) of free residual HALOGEN through a temporary injection port. 4. Let it stand for 4 hours. 5. Drain and flush disinfected parts of the system with POTABLE WATER. # In Port Before arriving to a port or HARBOR, the seawater supply system must be shut down and the facility closed for use before the vessel reaches the 20-kilometer (12-mile) mark or any point of land-based discharge. The system must remain empty while in port or at anchor or the flow-through supply must be switched to POTABLE WATER. # Recirculation Fill water must be provided only to the compensation tank and not directly to the BABY-ONLY WATER FACILITY. # TURNOVER Rate The entire volume of water must pass through all parts of the system to include filtration, secondary UV DISINFECTION, and halogenation at least once per half hour. The filtration, UV DISINFECTION, and HALOGEN and pH control systems must be operated 24 hours a day. This is required even when the facilities are not in use. The systems may only be shut down for required maintenance or cleaning of system components. # Filtration BABY-ONLY WATER FACILITY water must be filtered. At least one replacement cartridge or canister-type filter must be available. Cartridge or canister-type filters must be inspected weekly for cracks, breaks, damaged components, and accumulation of excessive organic material. Granular filters must be backwashed daily. Backwashing must be repeated until the water viewed through the sight glass or discharge point is clean flowing. The granular filters must be opened monthly and examined for channeling, mounds, or holes in the filter media. Inspection method: Drain the water from the filter housing and inspect the granular filter for cracks, mounds, or holes. A core sample must be examined monthly for accumulation of excessive organic material. Core sample method: 1. Take a sand sample from the filter core after inspection and place it in a clear container. A core sample can be taken by inserting a rigid hollow tube or pipe in to the filter media. 2. Add clean water to the clear container, cover, and shake. 3. Allow the container to rest undisturbed for 30 minutes. 4. Evaluate sample. If, after 30 minutes of settling, a measurable layer of sediment is within or on top of the filter media or fine, colored particles are suspended in the water, the organic loading may be excessive. Consider media replacement. 5. Record results of filter inspection and sedimentation test in a log. Cartridge filters must be replaced based on inspection results or manufacturer's recommendations, whichever is sooner. The granular filter media must be replaced at least every 6 months. Before the new filter media is placed in the filter housing, the housing must be scrubbed with an appropriate cleanser, rinsed, and disinfected. DISINFECTION must be accomplished with an appropriate HALOGENbased DISINFECTANT at 1 ppm for 50 minutes, or an equivalent CT VALUE. Record the filter replacement date and cleaning and DISINFECTION of the filter housing in a log. The log must include the DISINFECTANT residual and contact time or CT VALUE. Filter pressure gauges and valves must be replaced when they are defective. The operating manuals for all components such as filters, pumps, HALOGEN and pH control EQUIPMENT, and UV DISINFECTION systems must be maintained aboard the vessel in a location ACCESSIBLE to crew members who are responsible for the operation and maintenance of these facilities. # Halogen and pH Control Automated HALOGEN dosing and pH control systems must be installed and maintained. Halogenation must be by use of chlorine or bromine. A free residual of HALOGEN must be maintained between 3.0-10.0 ppm for chlorine and 4.0-10.0 ppm for bromine. The pH levels must be maintained between 7.2 and 7.6. # UV Disinfection A UV DISINFECTION system must be installed after filtration and before HALOGEN-based DISINFECTION. The UV DISINFECTION system must be maintained at an intensity that inactivates Cryptosporidium parvum and Giardia. # 13.9 Fecal, Vomit, and Blood Accident Response for RWFs # Fecal and Vomit Accident Response for RWFs This annex includes a sample fecal accident plan and sample fecal accident log required data elements. The sample fecal accident plan is based in part on recommendations found on CDC's Healthy Swimming website (www.cdc.gov/healthywater/swimming). In the sample plan (13.9.1.1), two tables address chlorine residuals and contact times to be used for DISINFECTION after an accident involving fecal material or vomitus. Each table has chlorine residuals and contact times that reduce the risk for recreational water illness based on the pathogenic organisms that might be present as a result of a fecal or vomit accident. • The Residual and Contact Time for Loose Stool table shows chlorine residuals and contact times to address loose stools. The primary pathogenic organism of concern in loose stool is Cryptosporidum. This organism is highly chlorine resistant; to destroy it, a CT VALUE of 15,300 is required. This means that when the chlorine residual in ppm is multiplied by the contact time in minutes, a minimum of 15,300 is required. o Concentration (ppm) X Contact Time (minutes) ≥ 15,300 • The Residual and Contact Time for Formed Stool or Vomitus table shows chlorine residuals and contact times to address accidents involving formed stools or vomitus. The disease-causing organisms of primary concern are Giardia, E. coli 0157:H7, and Shigella. To destroy the more highly chlorine resistant of these organisms (Giardia), a CT VALUE of 45 is required. This means that when the chlorine residual in ppm is multiplied by the contact time in minutes, a minimum of 45 is required. o Concentration (ppm) X Contact Time (minutes) ≥ 45 To determine the appropriate chlorine residual and contact time, operators should observe the nature of the accident. • If the fecal accident is loose (diarrhea), the loose-stool table should be used for DISINFECTION. • If the fecal material is solid or formed or if the accident involves vomitus, the formed stool or vomitus table should be used for DISINFECTION. It is important to remember that the DISINFECTION capabilities of chlorine diminish as pH increases. Operators should ensure that pH levels are maintained 7.5 or less at 77°F (25°C) or higher during this DISINFECTION process. Record all fecal/vomit accidents in a log with all of the following information: • Name of RWF. • Date of event. • Time of event. • Number of bathers. • Formed stool, loose stool, or vomitus. • Chlorine residual for DISINFECTION. • Contact time for DISINFECTION. • pH level for DISINFECTION. • Chlorine residual for reopening. • pH for reopening. 13.9.1.1 Fecal/Vomit Accident Plan 13.9.2 Blood Response Q and A Excerpt from www.cdc.gov/healthywater/swimming/pools/vomit-bloodcontamination.html. # Blood in Pool Water Germs (for example, Hepatitis B virus or HIV) found in blood are spread when infected blood or certain body fluids get into the body and bloodstream (for example, by sharing needles and by sexual contact). Chlorine kills germs found in blood and CDC is not aware of any instances in which a person has become infected with these germs after being exposed to a blood spill in a pool. Q: Does chlorine kill the germs in blood? A: Yes. These germs do not survive long when diluted into properly chlorinated pool water. Q: Swimmers want something to be done after a blood spill. Should the pool be closed for a short period of time? A: There is no public health reason to recommend closing the pool after a blood spill. However, some pool staff choose to do so temporarily to satisfy patrons. # Sanitize: To remove or prevent biofilms, algae, and bacteria growing on the cartridge, add 1 quart (0.95 L) of household bleach per 5 gallons (19 L) of clean water and soak 1 hour before rinsing. # Rinse: Remove the clean cartridge from the SANITIZATION soak water and rinse thoroughly with a hose. # Dry: After the filter is cleaned and degreased, it should be allowed to dry completely. Some bacteria (for example, Legionella spp.) that survive the cleaning process can be killed by drying. Do not allow the filter to become contaminated with dirt or soil after it is cleaned. Put the cartridges in a clean plastic trash bag if they are to be transported and the original boxes are not available. # Acid Wash (Only if Necessary): Excessive calcium or mineral deposits on the filter media can be cleaned with a 1:20 solution of clean water and muriatic acid. Put a few drops of muriatic acid on the filter. If it foams, it might need to be acid washed. Very few filters need to be acid washed. # 13.11 Food Cooking Temperature Alternatives # Introduction To be effective in eliminating pathogens, cooking must be adjusted to a number of factors. These include the anticipated level of pathogenic bacteria in the raw product, the initial temperature of the FOOD, and the FOOD's bulk, which affects the time to achieve the needed internal product temperature. Other factors to be considered include postcooking heat rise and the time the FOOD must be held at a specified internal temperature. To kill microorganisms, FOOD must be held at a sufficient temperature for the specified time. Cooking is a scheduled process in which each of a series of continuous TIME/TEMPERATURE combinations can be equally effective. For example, in cooking a beef roast, the microbial lethality achieved at 112 minutes after it has reached 54°C (130°F) is the same lethality attained as if it were cooked for 4 minutes after it has reached 63°C (145°F). Cooking requirements are based in part on the biology of pathogens. The thermal destruction of a microorganism is determined by its ability to survive heat. Different species of microorganisms have different susceptibilities to heat. Also, the growing stage of a species (such as the vegetative cell of bacteria, the trophozoite of protozoa, or the larval form of worms) is less resistant than the same organism's survival form (the bacterial spore, protozoan cyst, or worm egg). FOOD characteristics also affect the lethality of cooking temperatures. Heat penetrates different FOODS at different rates. High fat content in FOOD reduces the effective lethality of heat. High humidity within the cooking vessel and the moisture content of FOOD aids thermal destruction. Heating a large roast too quickly with a high oven temperature may char or dry the outside, creating a layer of insulation that shields the inside from efficient heat penetration. To kill all pathogens in FOOD, cooking must bring all parts of the FOOD up to the required temperatures for the correct length of time. The TEMPERATURE AND TIME COMBINATION CRITERIA specified in Annex 13.11.2 are based on the destruction of Salmonellae. This section includes temperature and time parameters that provide "D" values (decimal log reduction values) that may surpass 7D. For example, at 63°C (145°F), a time span of 15 seconds will provide a 3D reduction of Salmonella enteritidis in eggs. This organism, if present in raw shell eggs, is generally found in relatively low numbers. Other FOODS, FISH, and MEATS that have not been ground or mincedincluding commercially raised GAME ANIMAL MEAT specified as acceptable Chemicals may be safely used to wash or to assist in the peeling of fruits and vegetables in accordance with the following conditions: (a) The chemicals consist of one or more of the following: (1) Substances generally recognized as safe in FOOD or covered by prior sanctions for use in washing fruits and vegetables. (2) Substances identified in this subparagraph and subject to such limitations as are provided: Adduct Mixture Substance: A mixture of alkylene oxide adducts of alkyl alcohols and phosphate esters of alkylene oxide adducts of alkyl alcohols consisting of: [alpha]-alkyl (C12-C18)-omega-hydroxy-poly (oxyethylene) (7.5-8.5 moles)/poly (oxypropylene) block copolymer having an average molecular weight of 810; [alpha]alkyl (C12-C18)-omega-hydroxy-poly (oxyethylene) (3.3-3.7 moles) polymer having an average molecular weight of 380, and subsequently esterified with 1.25 moles phosphoric anhydride; and [alpha]-alkyl (C10-C12)-omega-hydroxypoly (oxyethylene) (11.9-12.9 moles)/poly (oxypropylene) copolymer, having an average molecular copolymer, having an average molecular weight of 810, and subsequently esterified with 1.25 moles phosphoric anhydride. Limitations: May be used at a level not to exceed 0.2 percent in lye-peeling solution to assist in the lye peeling of fruit and vegetables. # Ethylene Dichloride Substance: Ethylene dichloride Limitations: Not to exceed 0.2 ppm. # Tetrasodium ethylenediaminetetraacetate Substance: Tetrasodium ethylenediaminetetraacetate Limitations: Not to exceed 0.1 ppm. (5) Substances identified in this paragraph (a)(5) for use on fruits and vegetables that are not raw agricultural commodities and subject to the limitations provided: Hydrogen Peroxide Substance: Hydrogen peroxide Limitations: Used in combination with acetic acid to form peroxyacetic acid. Not to exceed 59 ppm in wash water. # 1-Hydroxyethylidene-1,1-diphosphonic Acid Substance: 1-Hydroxyethylidene-1,1-diphosphonic acid Limitations: May be used only with peroxyacetic acid. Not to exceed 4.8 ppm in wash water. # Peroxyacetic Acid Substance: Peroxyacetic acid Limitations: Prepared by reacting acetic acid with hydrogen peroxide. Not to exceed 80 ppm in wash water. (b) The chemicals are used in amounts not in excess of the minimum required to accomplish their intended effect. (c) The use of the chemicals listed under paragraphs (a)(1), (a)(2), and (a)(4) is followed by rinsing with POTABLE WATER to remove, to the extent possible, residues of the chemicals. (d) To assure safe use of the ADDITIVE: (1) The label and labeling of the ADDITIVE container shall bear, in addition to the other information required by the act, the name of the ADDITIVE or a statement of its composition. (2) The label or labeling of the ADDITIVE container shall bear ADEQUATE use directions to assure use in compliance with all provisions of this section. # Notification # Routine Report # Routine Report Timing # 24-Hour Report (01 C) The master, medical staff, or other designated staff of a vessel destined for a U.S. port from a foreign port must submit at least one standardized AGE report based on the number of REPORTABLE CASES in the AGE log to VSP no less than 24 hours-but not more than 36 hours-before the vessel's expected arrival at the U.S. port. # 4-Hour Update Report (01 C) If the number of cases changes after submission of the initial report, an updated report must be submitted no less than 4 hours before the vessel's arrival at the U.S. port. The 4-hour update report must be a cumulative total count of the reported crew and passengers during the entire cruise, including the additional cases. If there is an update to the AGE surveillance log after the 4-hour report is submitted, an additional 4-hour report must be submitted only if the vessel is still more than 4 hours from arrival in the U.S. port. If the vessel is less than 4 hours from arrival in the U.S. port, no additional 4-hour report is needed. # Report Submission (02) 4.2.1.1.3 Submit routine 24-hour and 4-hour update reports electronically. In lieu of electronic notification, the reports may be submitted by telephone or fax. The vessel must maintain proof onboard that the report was successfully received by VSP. # Report Contents # Contents (01 C) The AGE report must contain the following: • Name of the vessel. • Port of embarkation. • Date of embarkation. • Port of disembarkation. • Date of disembarkation. • Total numbers of REPORTABLE CASES of AGE among passengers, including those who have disembarked because A telephone notification to VSP must accompany the special 2% report. A second special report must be submitted when the cumulative percentage of REPORTABLE CASES entered in the AGE surveillance log reaches 3% among passengers or 3% among crew and the vessel is within 15 days of expected arrival at a U.S. port. # Daily Updates (01) Daily updates of illness status must be submitted as requested by VSP after the initial submission of a special report. Daily updates may be submitted electronically, by telephone, by fax, by email, or as requested by VSP. # Routine Reporting Continues (01) Routine reports (24-hour and 4-hour) must continue to be submitted by the master or designated corporate representative of a vessel that has submitted a special report. # Report Retention # Retention # Retention (02) The 24-hour, 4-hour, and special reports must be maintained on the vessel for 12 months. # Review (02) The reports must be available for review by VSP during inspections and OUTBREAK investigations. # Clinical Specimens # Clinical Specimen Submission See Annex 13.4 for a list of recommended specimen collection supplies. # Specimen/Shipping Containers (02) The medical staff will be responsible for maintaining a supply of at least 10 clinical specimen collection containers for both viral and bacterial agents (10 for each), as well as a shipping container that meets the latest shipping requirements of the International Air Transport Association (IATA) and U.S. Department of Transportation for Biological Substances, Category B designated shipments (or higher). The vessel must maintain the appropriate labels and markings required for shipping Biological Substances, Category B shipments. The vessel must # Filtration Systems # Filtered (10) Recirculated RWF water must be filtered. # Filter Backwash and Cleaning (10) Filter pressure differentials must be monitored. Granular filter media must be backwashed until the water viewed through a sight glass runs clear and at the following frequency: • WHIRLPOOL SPA and SPA POOL: every 72 hours, or sooner if the WHIRLPOOL SPA is drained. • BABY-ONLY WATER FACILITY: daily. • All other RWFs: at a frequency recommended by the manufacturer. For automatic backwashing systems, an individual must be present in the filter room to ensure that backwashing is repeated as necessary until the water runs clear. Cartridge filters must be cleaned according to the manufacturer's recommendations. A written or electronic record of the filter backwashing and cleaning must be available for review during inspections. # Granular Filter Inspection, Core Sample Test, and Filter Change (10) Granular filter media must be examined for channels, mounds, or holes. A core sample of the filter media must be inspected for excessive organic material accumulation using a recommended sedimentation method. Inspections and sedimentation tests must be conducted quarterly for all RWFs. # Inspection method: Drain the water from the filter housing and inspect the granular filter for channels, mounds, or holes. # Core sample method: 1. After inspection, take a sand sample from the filter core and place it in a clear container. A core sample can be taken by inserting a rigid hollow tube or pipe into the filter media. 2. Add clean water to the container, cover, and shake. 3. Allow the container to rest undisturbed for 30 minutes. # 6.3.1.2.7 Hair and Lint Strainer (10) The hair and lint strainer and hair and lint strainer housing on all RWFs must be cleaned, rinsed, and disinfected weekly. DISINFECTION must be accomplished with an appropriate HALOGEN-based DISINFECTANT. At a minimum, a 50-ppm solution for 1 minute, or equivalent CT VALUE, must be used. Records must be maintained on all inspection and cleaning procedures. If there is not a hair and lint strainer but there is a filter before the pump, this filter must be cleaned, rinsed, and disinfected weekly. # All Filters (10) The manufacturer's maintenance procedures and recommendations for all filters must be maintained on the vessel. # Gauges (10) RWF filter pressure gauges, flow meters, and valves must be replaced when they are defective. # Manuals (10) The operating manuals for all RWF components such as filters, pumps, halogenation and PH control systems, and UV DISINFECTION systems must be maintained in a location ACCESSIBLE to crew members responsible for the technical operation and maintenance of these facilities. # Bather Loads (10) Documentation must be maintained on the maximum bather load for each RWF. The maximum bather load must be based on the following factor: One person per five gallons (19 liters) per minute of recirculation flow. Use flow rates from flow meters to calculate bather loads. Do not use the manufacturer's pump rate to calculate bather loads. # Water Quality # Water Chemistry (10) The RWF's flow rates, free and combined HALOGEN levels, pH, total alkalinity, and clarity must be monitored and adjusted as recommended by the manufacturer to maintain optimum public health protection and water chemistry. Evaluate bather load and make adjustments to water parameters to maintain optimum water quality. # Residual (09 C) A free residual HALOGEN in the range detailed in the table below must be maintained in recirculated RWFs. # RECREATIONAL WATER FACILITY Free For facilities that meet the definition of more than one type of RWF, the more protective HALOGEN residual applies. For example, if a CHILDREN'S POOL also has features of an interactive RWF or ACTIVITY POOL, the HALOGEN range must be 2.0 to 5.0 MG/L (ppm). Finally, if a facility is modified, the most-protective HALOGEN residual applies. # pH (09 C) The pH level in all RWFs must be maintained between 7.0 and 7.8. Facilities not maintained within these HALOGEN and pH ranges must be immediately closed. # Maintenance (10) Halogenation and pH control systems must be maintained in good repair and operated in accordance with the manufacturer's recommendations. # Procedures for Water Sampling (10) Manual samples from the RWF tub must be compared to the analyzer samples in the pump (mechanical) room to assess potential water quality differences in the RWF. Recommended manual sampling procedures-All samples should be obtained from a location with the following qualities: • At least 18 inches (45.7 cm) below the surface of the water, and • At water depth of between 3 and 4 feet (91.4 cm to 1.2 m) when available, and • Between water inlets. Recommended manual sampling procedures-All samples should be obtained from a location with the following qualities: • At least 18 inches (45.7 cm) below the surface of the water, and • At water depth of between 3 and 4 feet (91.4 cm to 1.2 m) when available, and • Between water inlets. Manual readings must be recorded on a chart or log, retained for at least 12 months, and available for review during inspections. Repairs on malfunctioning HALOGEN analyzer-chart recorders must be completed within 30 days of EQUIPMENT failure. Provide an audible alarm in a continuously occupied watch station (e.g., the engine control room) to indicate low and high free HALOGEN and pH readings in each RWF. # Whirlpool and Spa Pool Probes (10) For WHIRLPOOL SPAS and SPA POOLS, the analyzer probes for dosing and recording systems must be capable of measuring and recording levels up to 10 MG/L (10 ppm). # Analyzer-Chart Recorder (10) The HALOGEN and PH analyzer-chart recorder must be properly maintained and operated in accordance with the manufacturer's instructions. A manual comparison test must be conducted before opening the RWF to verify calibration for free HALOGEN residual and PH. The analyzer reading must be within 0.2 MG/L (ppm) for free HALOGEN and between pH 7.0-7.8. For RWFs open longer than 24 hours, a manual comparison test must be conducted every 24 hours. # Data Logger (10) If an electronic data logger is used in lieu of a chart recorder, it must have CERTIFIED DATA SECURITY FEATURES. Manual comparison tests for free HALOGEN residual and pH must be conducted before opening the RWF to verify calibration. The analyzer reading must be within 0.2 MG/L (ppm) for free HALOGEN and 0.2 for pH. For RWFs open longer than 24 hours, a manual comparison test must be conducted every 24 hours. Electronic data logging must be in increments of ≤15 minutes. # Charts (10) HALOGEN analyzer-chart recorder charts must be initialed, dated, and changed daily. Strip recorder charts must be initialed and dated daily and 24-hour increments must be indicated. Dual-scale HALOGEN analyzer-chart recorder charts used in RWFs must be able to measure the full range of HALOGEN/pH of the facility type to which the chart is installed; for example, chlorine/bromine to 10.0 MG/L (ppm) and pH 0-14 for WHIRLPOOL SPAS. # Logs (10) Logs and charts must contain notations outlining actions taken when the free HALOGEN residual or pH levels are outside of the acceptable ranges in this manual. Additionally, records must include any major maintenance work on the filtration and halogenation systems and UV DISINFECTION systems. A written or electronic log of RWF filter inspection results, granular filter sedimentation test results, backwashing frequency and length of backwashing, and date and time of water dumping must be available for review during inspections. # Retention (10) Logs and charts must be retained for 12 months and must be available for review during inspections. # 6.4 Whirlpool Spas and Spa Pools 6.4.1 Public Operations 6.4.1.1 Filters # Replacement (10) At least one replacement cartridge or canister-type filter must be available. ACTIVITY POOLS and INTERACTIVE RWFs that can be HEATED by the sun and/or exterior temperature. Batch halogenation of the tub and compensation tank may help in reaching the minimum 10 ppm residual quickly. Facilities filled only with seawater are exempt from this requirement. # Records (10) A written or electronic record of the date and time of water dumping and shock halogenation (concentration in MG/L [ppm] at the start and completion and time) must be available for review during inspections. # Retention (10) Records must be retained on the vessel for 12 months. # 6.5. Maintenance and Operating Standards for Combined Facilities # Pool with Attached Whirlpool Spa (10) For any pool with an attached WHIRLPOOL SPA where the water, recirculation system EQUIPMENT, or filters are shared with the spa, all elements of the WHIRLPOOL SPA standards must apply to the pool. # Fecal Accidents (10) For combined facilities subject to fecal accidents, fecal accident procedures must include all features of these combined facilities. # Private Cabin Operations WHIRLPOOL SPAS similar in design and construction to public WHIRLPOOL SPAS but located for the sole use of an individual cabin or groups of cabins must comply with the public WHIRLPOOL SPA requirements if the WHIRLPOOL SPA • Has a tub capacity of more than 4 individuals OR • Can be accessed without entering the cabin. 6.6.1 Maintenance 6.6.1.1 Cleaning (10) Private WHIRLPOOL SPAS located in individual passenger cabins must be cleaned and disinfected, including associated recirculation systems, between occupancies or weekly, whichever is more frequent. Specifications and requirements for BABY-ONLY WATER FACILITIES can be found in Annex 13.8. # 6.11 Recreational Water Facilities Knowledge 6.11.1 Demonstration of Knowledge (44) The supervisor or PERSON IN CHARGE of RECREATIONAL WATER FACILITIES operations on the vessel must demonstrate to VSP-on request during inspections-knowledge of RWF operations. The supervisor or PERSON IN CHARGE must demonstrate this knowledge by compliance with this section of these guidelines or by responding correctly to the inspector's questions as they relate to the specific operation. In addition, the supervisor or PERSON IN CHARGE of RWF operations on the vessel must ensure that employees are properly trained to comply with this section of the guidelines in this manual as it relates to their assigned duties. # Restrictions Removal (11 C) The restriction must not be removed until the supervisor or PERSON IN CHARGE of the FOOD operation obtains written approval from the vessel's physician or equivalent medical staff. # Record of Restriction and Release (02) A written or electronic record of both the work restriction and release from restriction must be maintained onboard the vessel for 12 months for inspection review. # Employee Cleanliness # Hands and Arms # Hands and Arms Clean (12 C) FOOD EMPLOYEES must keep their hands and exposed portions of their arms clean. # Cleaning Procedures (12 C) FOOD EMPLOYEES must clean their hands and exposed portions of their arms with a cleaning compound in a handwashing sink by vigorously rubbing together the surfaces of their lathered hands and arms for at least 20 seconds and thoroughly rinsing with clean water. Employees must pay particular attention to the areas underneath the fingernails and between the fingers. # When to Wash Hands (12 C) FOOD EMPLOYEES must clean their hands and exposed portions of their arms immediately before engaging in FOOD preparation, including working with exposed FOOD, clean EQUIPMENT and UTENSILS, and unwrapped SINGLE-SERVICE and SINGLE-USE ARTICLES and • After touching bare human body parts other than clean hands and clean, exposed portions of arms. • After using the toilet room. • After coughing, sneezing, using a handkerchief or disposable tissue, using tobacco, eating, or drinking. • After handling soiled EQUIPMENT or UTENSILS. • During FOOD preparation (as often as necessary to remove soil and CONTAMINATION and to prevent CROSS-CONTAMINATION when changing tasks). • When switching between working with raw FOOD and working with READY-TO-EAT FOOD. • Before putting on gloves for working with FOOD or clean EQUIPMENT and between glove changes. # Hermetically Sealed Container (15 C) FOOD in a HERMETICALLY SEALED CONTAINER must be obtained from a FOOD-PROCESSING PLANT regulated by the FOOD regulatory agency that has jurisdiction over the plant. # Milk (15 C) Fluid milk and milk products by U.S. suppliers must be obtained from sources that comply with GRADE A STANDARDS as specified in LAW. Milk received in interstate commerce must be from sources listed in the FDA Interstate Milk Shippers List. Non-U.S. sourced fluid milk and milk products must be obtained from sources that meet or exceed the standards of the health authorities from the source country. # Fish and Molluscan Shellfish Sources (15 C) FISH received for service must be commercially and legally caught or harvested or otherwise APPROVED for service by VSP through an APPROVED VARIANCE. Recreationally caught MOLLUSCAN SHELLFISH must not be received for service. MOLLUSCAN SHELLFISH must be obtained from sources according to LAW and the requirements specified in the FDA National Shellfish Sanitation Program Guide for the Control of MOLLUSCAN SHELLFISH, or equivalent standards. MOLLUSCAN SHELLFISH received in interstate commerce must be from sources listed in the FDA Interstate Certified Shellfish Shippers List or equivalent foreign certified shellfish listing. # Wild Mushrooms (15 C) Mushroom species picked in the wild must be obtained from sources where each mushroom is individually inspected and found to be safe by an APPROVED mushroom identification expert. This requirement does not apply to • Cultivated wild mushroom species grown, harvested, and processed in an operation regulated by the FOOD regulatory agency that has jurisdiction over the operation. • Wild mushroom species if they are in PACKAGED form and are the product of a FOOD-PROCESSING PLANT regulated by the FOOD regulatory agency that has jurisdiction over the plant. A GAME ANIMAL must not be received for service if it is a species of wildlife listed in 50 CFR 17 Endangered and Threatened Wildlife and Plants. # Receiving Condition # Receiving Temperatures (16 C) Receiving temperatures must be as follows: • Refrigerated POTENTIALLY HAZARDOUS FOOD must be at a temperature of 5°C (41°F) or below when received. If a temperature other than 5°C (41°F) for a POTENTIALLY HAZARDOUS FOOD is specified in LAW governing its distribution, such as LAWS governing milk, MOLLUSCAN SHELLFISH, and shell eggs, the FOOD may be received at the specified temperature. • POTENTIALLY HAZARDOUS FOOD that is cooked and received hot must be at a temperature of 57°C (135°F) or above. • A FOOD labeled and shipped frozen by a FOOD-PROCESSING PLANT must be received frozen. • Upon receipt, POTENTIALLY HAZARDOUS FOOD must be free of evidence of previous temperature abuse. # Food Additives (15 C) FOOD must not contain unapproved FOOD ADDITIVES or ADDITIVES that exceed amounts specified in LAW, as specified in the current version of the FDA FOOD Code, including annexes. # Shell Eggs (15 C) Shell eggs must be received clean and sound and must not exceed the restricted egg tolerances specified in LAW, as specified in the current version of the FDA FOOD Code, including annexes. # Egg and Milk Products (15 C) Eggs and milk products must be received as follows: • Liquid, frozen, and dry eggs and egg products must be obtained pasteurized. # Shellstock Identification (15 C) SHELLSTOCK shellfish tags must • Remain attached to the container in which the SHELLSTOCK are received until the container is empty. • Be maintained by retaining SHELLSTOCK tags or labels for 90 calendar days from the date the container is emptied by using an APPROVED record-keeping system that keeps the tags or labels in chronologic order correlated to the date when the SHELLSTOCK are served. The date when the last SHELLSTOCK from the container is served must be recorded on the tag or label. # Food Protection # Employee Contamination # Wash Hands (12 C) FOOD EMPLOYEES must wash their hands. # RTE Food -Hand Contact Prohibited (12 C) Except when washing fruits and vegetables or when otherwise APPROVED, FOOD EMPLOYEES must not contact exposed, READY-TO-EAT FOOD with their bare hands. They must use suitable UTENSILS such as deli tissue, spatulas, tongs, SINGLE-USE gloves, or dispensing EQUIPMENT. # Not RTE Food -Minimize Contact (19) FOOD EMPLOYEES must minimize bare hand and arm contact with exposed FOOD not in a READY-TO-EAT form. # Tasting (12 C) A FOOD EMPLOYEE must not use the same UTENSIL more than once to taste FOOD that will be served. # Food and Ingredient Contamination # Cross-Contamination (18 C) FOOD must be protected from cross-CONTAMINATION or other sources of CONTAMINATION by the following methods: • Physically separating raw animal FOODS during storage, preparation, holding, and display from raw READY-TO-EAT FOOD (including other raw animal FOOD such as FISH for sushi or MOLLUSCAN SHELLFISH, or other raw READY-TO-EAT FOOD such as vegetables, and cooked READY-TO-EAT FOOD) so products do not # Container Identity (19) Containers holding FOOD or FOOD ingredients removed from their original packages for use on the vessel, such as cooking oils, flour, herbs, potato flakes, salt, spices, and sugar must be identified with the common name of the FOOD. Containers holding FOOD that can be readily and unmistakably recognized such as dry pasta do not need to be identified. Ingredients located at active cooking or preparation stations do not need to be identified. # Pasteurized Eggs (18 C) Pasteurized eggs or egg products must be substituted for raw shell eggs in the preparation of FOODS such as Caesar salad, hollandaise or béarnaise sauce mayonnaise, eggnog, ice cream, and egg-fortified BEVERAGES or dessert items that are not cooked. # Wash Fruits/Vegetables (19) Raw fruits and vegetables must be thoroughly rinsed in water to remove soil and other contaminants before being cut, combined with other ingredients, cooked, served, or offered for human consumption in READY-TO-EAT form. # Vegetable Washes Fruits and vegetables may be washed by using chemicals specified under 21 CFR 173.315 (Annex 13.12). # Ice as Coolant # Ice Used as a Coolant (19) Ice must not be used as FOOD after use as a medium for cooling the exterior surfaces of FOOD such as melons or FISH, PACKAGED FOODS such as canned BEVERAGES, or cooling coils and tubes of EQUIPMENT. # Coolant (19) PACKAGED FOOD must not be stored in direct contact with ice or water if the FOOD is subject to the entry of water because of the nature of its packaging, wrapping, or container, or its positioning in the ice or water. # Undrained Ice (19) Except as specified in 7.3.3.3.4 through 7.3.3.3.6,unpackaged FOOD must not be stored in direct contact with undrained ice. # Linen/Napkins (19) LINENS and napkins must not be used in contact with FOOD unless they are used to line a container for the service of FOODS and the LINENS and napkins are replaced each time the container is refilled for a new CONSUMER. # Wiping Cloths (25) Wiping cloths must be restricted to the following: • Cloths used for wiping FOOD spills must be used for no other purpose. # Glove Use (19) Gloves must be used as follows: • SINGLE-USE gloves must be used for only one handcontact task with READY-TO-EAT FOOD and no other purpose. These SINGLE-USE gloves must be discarded when damaged or soiled or when operation is interrupted. • Slash-resistant gloves used to protect hands during operations requiring cutting must be used in direct contact only with FOOD that is subsequently cooked (such as frozen FOOD or a PRIMAL CUT of MEAT). • Slash-resistant gloves may be used with READY-TO-EAT FOOD that will not be subsequently cooked if the slashresistant gloves have a SMOOTH, durable, and nonabsorbent outer surface or if the slash-resistant gloves are covered with a SMOOTH, durable, nonabsorbent glove or a SINGLE-USE glove. • Cloth gloves must not be used in direct contact with FOOD unless the FOOD is subsequently cooked (such as frozen FOOD or a PRIMAL CUT of MEAT). # Second Portions and Refills (19) Procedures for second portions and refills must be as follows: • FOOD EMPLOYEES must not use TABLEWARE soiled by the CONSUMER-including SINGLE-SERVICE ARTICLES-except for refilling a CONSUMER'S drinking cup or container without contact between the pouring UTENSIL and the lip-contact area of the drinking cup or container. • Self-service CONSUMERS must not be allowed to use soiled TABLEWARE-including SINGLE-SERVICE ARTICLES-to obtain additional FOOD from the display and serving EQUIPMENT except as specified in the bullet below. • Self-service CONSUMERS may reuse drinking cups and containers if refilling is a CONTAMINATION-free process. # Food Storage and Preparation This section applies to storage of candy and other FOOD items sold in candy shops, including self-service candy shops and shops where candy is served by a crew member. # Storage Protection (19) FOOD must be protected from CONTAMINATION by storing it as follows: • Covered or otherwise protected; • In a clean, dry location; • Where it is not exposed to splash, dust, or other CONTAMINATION; and • At least 150 millimeters (6 inches) above the deck. FOOD in packages and working containers on pallets, skids, and racks may be 127 millimeters (5 inches) above the deck. Shelving units must be 150 millimeters (6 inches) above the deck. # Prohibited Storage (19) FOOD must not be stored as follows: • In locker rooms. • In toilet rooms. • In dressing rooms. • In garbage rooms. • In mechanical rooms. • Under sewer lines that are not continuously sleeve welded. • Under leaking water lines, including leaking automatic fire sprinkler heads, or under lines on which water has that it meets the definition of "WHOLE-MUSCLE, INTACT BEEF" and the steak is cooked on both the top and bottom to a surface temperature of 63°C (145°F) or above and a cooked color change is achieved on all external surfaces. # Microwave (16 C) Raw animal FOODS cooked in a microwave oven must be • Rotated or stirred throughout or midway during cooking to compensate for uneven distribution of heat. • Covered to retain surface moisture. • Heated to a temperature of at least 74°C (165°F) in all parts of the FOOD. • Allowed to stand covered for 2 minutes after cooking to obtain temperature equilibrium. # Fruits/Vegetables (17) Fruits and vegetables cooked for hot holding must be cooked to a temperature of 57°C (135°F). # Parasite Destruction # Parasite Destruction (16 C) Before service in READY-TO-EAT form, raw, raw-marinated, partially cooked, or marinated-partially cooked FISH and fishery products other than MOLLUSCAN SHELLFISH must be frozen throughout to a temperature of -20°C (-4°F) or below for 168 hours (7 days) in a freezer or to -35°C (-31°F) or below for 15 hours in a BLAST CHILLER. # Reheating # Immediate Service Cooked and refrigerated FOOD prepared for immediate service in response to an individual CONSUMER order (such as a roast beef sandwich au jus) may be served at any temperature. # 74°C/165°F (16 C) POTENTIALLY HAZARDOUS FOOD that is cooked, cooled, and reheated for hot holding must be reheated so that all parts of the FOOD reach a temperature of at least 74°C (165°F) for 15 seconds. # Microwave Heating (16 C) If reheated in a microwave oven for hot holding, POTENTIALLY HAZARDOUS FOOD must be reheated so that all parts of the FOOD reach a temperature of at least 74°C (165°F) and the FOOD is rotated or stirred, covered, and allowed to stand covered for 2 minutes after reheating. # Commercial Products (17) READY-TO-EAT POTENTIALLY HAZARDOUS FOOD taken from a commercially processed, HERMETICALLY SEALED CONTAINER, or from an intact package from a FOOD-PROCESSING PLANT inspected by the FOOD REGULATORY AUTHORITY that has jurisdiction over the plant, must be heated to a temperature of at least 57°C (135°F) for hot holding. # Rapid Reheat (16 C) Reheating for hot holding must be done rapidly. The time the FOOD is between 5°C (41°F) and 74°C (165°F) must not exceed 2 hours. # Reheat Roast Beef Remaining unsliced portions of roasts of beef cooked on the vessel may be reheated for hot holding using the oven parameters and minimum time and temperature conditions used in the original cooking process. # Cooling Methods (17) Cooling must be accomplished using one or more of the following methods based on the type of FOOD being cooled: • Placing the FOOD in shallow pans. • Separating the FOOD into smaller or thinner portions. • Using BLAST CHILLERS, freezers, or other rapid cooling EQUIPMENT. • Stirring the FOOD in a container placed in an ice water bath. • Using containers that facilitate heat transfer. • Adding ice as an ingredient. • Using other effective methods. When placed in cooling or cold-holding EQUIPMENT, FOOD containers in which FOOD is being cooled must be arranged in the EQUIPMENT to provide maximum heat transfer through the container walls and must be loosely covered-or uncovered if protected from overhead CONTAMINATION-during the cooling period to facilitate heat transfer from the surface of the FOOD. # 7.3.5.2.6 Cooling Logs (17) Logs documenting cooked POTENTIALLY HAZARDOUS FOOD cooling temperatures and times from the starting points designated in 7.3.5.2.1 through the control points at 2 and 6 hours must be maintained onboard the vessel for a period of 30 days from the date the FOOD was placed in a cooling process. A FOOD that is unsafe or ADULTERATED must be discarded. # Unapproved Source (18 C) FOOD that is not from an APPROVED source must be discarded. # Restricted or Excluded Employee (18 C) READY-TO-EAT FOOD that may have been contaminated by an employee who has been restricted or excluded for FOOD EMPLOYEE health issues must be discarded. # Contaminated by Others (18 C) FOOD that is contaminated by FOOD EMPLOYEES, CONSUMERS, or other persons through contact with their hands, bodily discharges (such as nasal or oral discharges), or other means must be discarded. Use low profile, nonslotted, NONCORRODING, and easy-to-clean fasteners on FOOD-CONTACT SURFACES and in splash zones. The use of exposed slotted screws, Phillips head screws, or pop rivets in these areas is prohibited. # CIP Equipment Design/Construction (20) Clean-in-place EQUIPMENT must be designed and constructed so cleaning and sanitizing solutions circulate throughout a fixed system and contact all interior FOOD-CONTACT SURFACES and so the system self drains or can be completely drained of cleaning and sanitizing solutions. Clean-in-place EQUIPMENT not designed to be disassembled for cleaning must be designed with inspection access points to ensure that all interior FOOD-CONTACT SURFACES throughout the fixed system are being effectively cleaned. # "V" Type Threads (20) Except for hot oil cooking or filtering EQUIPMENT, "V" type threads must not be used on FOOD-CONTACT SURFACES. # Oil Filtering Equipment (20) Hot oil filtering EQUIPMENT must be READILY ACCESSIBLE for filter replacement and filter cleaning. # Can Openers (20) Cutting or piercing parts of can openers must be READILY REMOVABLE for cleaning and replacement. # Nonfood-Contact Design (21) NONFOOD-CONTACT SURFACES must be free of unnecessary ledges, projections, and crevices, and must be designed and constructed to allow easy cleaning and facilitate maintenance. # Kick Plates (21) Kick plates must be designed so that the areas behind them are ACCESSIBLE for inspection and cleaning by being easily REMOVABLE or capable of being rotated open without unlocking EQUIPMENT doors. # Grease Filters (21) If not designed to be CLEANED IN PLACE, filters or other grease-extracting EQUIPMENT must be designed to be READILY REMOVABLE for cleaning and replacement. # Equipment Openings, Closures, and Deflectors (20) EQUIPMENT openings, closures, and deflectors must conform to the following: • A cover or lid for EQUIPMENT must overlap the opening and be sloped to drain. • An opening in the top of a unit of EQUIPMENT and designed for use with a cover or lid must be flanged upward at least 5 millimeters (2/10 of an inch). • Fixed piping, TEMPERATURE-MEASURING DEVICES, rotary shafts, and other parts extending into EQUIPMENT must be provided with a watertight joint at the point where the item enters the EQUIPMENT. • If a watertight joint is not provided, the piping, TEMPERATURE-MEASURING DEVICES, rotary shafts, and other parts extending through the openings must be equipped with an apron designed to deflect condensation, # Equipment Location and Installation # Fixed Equipment, Spacing or Sealing # Fixed Equipment Installation (21) EQUIPMENT that is fixed because it is not EASILY MOVABLE must be installed in one of the following ways: • Spaced to allow access for cleaning along the sides, behind, under, and above the EQUIPMENT. • Spaced from adjoining EQUIPMENT, BULKHEAD, and DECKHEAD at a distance of not more than 0.8 millimeters or 1/32 inch. • Sealed to adjoining EQUIPMENT or BULKHEAD (if the EQUIPMENT is exposed to spillage or seepage). # Table-Mounted Sealed or Elevated (21) TABLE-MOUNTED EQUIPMENT that is not EASILY MOVABLE must be installed to allow cleaning of the EQUIPMENT and areas underneath and around the EQUIPMENT in one of the following ways: • Sealed to the table. • Elevated on legs. # Fixed Equipment, Elevation or Sealing # Deck-Mounted Sealed or Elevated (21) Deck-mounted EQUIPMENT that is not EASILY MOVABLE must be sealed to the deck or elevated on legs that provide at least a 150-millimeter (6-inch) clearance between the deck and the EQUIPMENT. # Deck-Mounted Clearance If no part of the deck under the deck-mounted EQUIPMENT is more than 150 millimeters (6 inches) from the point of cleaning access, the clearance space may be only 100 millimeters (4 inches). # Table-Mounted Elevated (21) TABLE-MOUNTED EQUIPMENT that is not EASILY MOVABLE must be elevated on legs that provide at least a 100millimeter (4-inch) clearance between the table and the EQUIPMENT. # Table-Mounted Clearance The clearance space between the table and # Food-Contact Equipment in Good Repair (20) FOOD-contact EQUIPMENT must be maintained in good repair and proper adjustment, including the following: • EQUIPMENT must be maintained in a state of repair and condition that meets the materials, design, construction, and operation specifications of these guidelines. • Can opener parts that cut or pierce must be kept sharp to minimize the creation of metal fragments that can contaminate FOOD when the container is opened. # Nonfood-Contact Equipment in Good Repair (21) Nonfood-CONTACT EQUIPMENT must be maintained in good repair and proper adjustment, including the following: • EQUIPMENT must be maintained in a state of repair and condition that meets the materials, design, construction, and operation specifications of these guidelines. • EQUIPMENT components such as doors, seals, hinges, fasteners, and kick plates must be kept intact and tight and adjusted in accordance with manufacturer's specifications. # Cutting Boards (20) Surfaces such as cutting blocks and boards subject to scratching and scoring must be resurfaced if they can no longer be effectively cleaned and sanitized or discarded if they cannot be resurfaced. # Microwave Ovens (20) Microwave ovens must meet the safety standards specified in 21 CFR 1030.10 Microwave Ovens, or equivalent. # Good Repair and Calibration # Utensils and TMDs in Good Repair and Calibration (20) UTENSILS and TEMPERATURE-MEASURING DEVICES must be maintained in good repair and proper adjustment, including the following: • UTENSILS must be maintained in a state of repair or condition that meets the materials, design, and construction specifications of these guidelines or must be discarded. • FOOD TEMPERATURE-MEASURING DEVICES must be calibrated in accordance with manufacturer's specifications as necessary to ensure their accuracy. # Ambient Air TMDs Good Repair and Calibration (21) Ambient air TEMPERATURE-MEASURING DEVICES must be maintained in good repair and be accurate within the intended range of use. # Single-Service and Single-Use Articles # No Reuse (28) SINGLE-SERVICE and SINGLE-USE ARTICLES must not be reused. # Bulk Milk Tubes (20) Bulk milk container dispensing tubes must be cut on the diagonal, leaving no more than 25 millimeters (1 inch) protruding from the chilled dispensing head. # Shell Reuse (28) Mollusk and crustacean shells must not be used more than once as serving containers. # Warewashing # Warewashing Design and Construction # Warewashing Measuring Device Accuracy (22) Provide a maximum registering TEMPERATURE-MEASURING DEVICE to verify the temperature in the warewash machines and the three-compartment sink. # Baffles/Curtains (22) WAREWASHING machine wash and rinse tanks must be equipped with baffles, curtains, or other means to minimize internal CROSS-CONTAMINATION of the solutions in wash and rinse tanks. # Warewash TMDs (22) A WAREWASHING machine must be equipped with a TEMPERATURE-MEASURING DEVICE that indicates the temperature of the water in each wash tank, in rinse tank(s) if present, and in the final sanitizing rinse manifold. # Pressure Gauge (22) WAREWASHING machines that provide a fresh hot water sanitizing rinse must be equipped with a pressure gauge or similar device such as a transducer that measures and displays the water pressure in the supply line immediately before entering the WAREWASHING machine. If the flow pressure measuring device is upstream of the fresh hot water sanitizing rinse control valve, the device must be mounted in a 6.4-millimeter (1/4-inch) iron pipe size (IPS) valve. These guidelines do not apply to a machine that uses only a pumped or recirculated sanitizing rinse. # Manual Sanitizing Booster Heater (22) If hot water is used for SANITIZATION in manual WAREWASHING operations, the sanitizing compartment of the sink must be designed with an integral heating device capable of maintaining water at a temperature not less than 77°C (171°F). # Self Draining (22) Sinks and drainboards of WAREWASHING sinks and machines must be self draining. # Warewashing Numbers and Capacities # Three-Compartment Sinks # Three-Compartment Sink (22) A sink with at least three compartments must be provided for manually washing, rinsing, and sanitizing EQUIPMENT and UTENSILS. # Size (22) Sink compartments must be large enough to accommodate immersion of the largest EQUIPMENT and UTENSILS. If EQUIPMENT or UTENSILS are too large for the WAREWASHING sink, a WAREWASHING machine or alternative EQUIPMENT, such as a three-bucket system, must be used. # Manual Warewashing Alternatives Alternative manual WAREWASHING EQUIPMENT may be used when there are special cleaning needs or constraints and its use is APPROVED. Alternative manual WAREWASHING EQUIPMENT may include the following: • High-pressure detergent sprayers. • Low-or line-pressure spray detergent foamers. • Other task-specific cleaning EQUIPMENT. • Brushes or other implements. • Receptacles such as a three-bucket system that substitute for the compartments of a threecompartment sink. # Drainboards # Soiled/Clean Storage (22) Drainboards, UTENSIL racks, or tables large enough to accommodate all soiled and cleaned items that may accumulate during hours of operation must be provided for UTENSIL holding before cleaning and after sanitizing. # Sanitizing Solutions, Testing Devices # Test Kit (22) A test kit or other device that accurately measures the concentration in milligrams per liter (parts per million) of sanitizing solutions must be provided. # Warewashing Equipment Maintenance and Operation # Good Repair and Proper Adjustment # Warewash Equipment Repair (22) WAREWASHING EQUIPMENT must be maintained in good repair and proper adjustment, including the following: • WAREWASHING EQUIPMENT must be maintained in a state of repair and condition that meets the standards of the materials, design, and construction of these guidelines. • Water pressure and water TEMPERATURE-MEASURING DEVICES must be maintained in good repair and be accurate within the intended range of use. # Warewash Equipment Cleaning (22) WAREWASHING machines, drainboards, and the compartments of sinks, basins, or other receptacles used for washing and rinsing EQUIPMENT, UTENSILS, or raw FOODS, or laundering wiping cloths must be cleaned as follows: • Before use. • Throughout the day at a frequency necessary to prevent recontamination and accumulation of debris and to ensure the EQUIPMENT performs its intended function. • At least every 24 hours (if used). # Warewash Equipment Operation (22) A WAREWASHING machine and its auxiliary components must be operated in accordance with the machine's data plate and other manufacturer's instructions. A WAREWASHING machine's conveyor speed or automatic cycle times must be maintained accurately timed in accordance with manufacturer's specifications. # Cleaners (22) When used for WAREWASHING, the wash compartment of a sink, mechanical warewasher, or wash receptacle of alternative manual WAREWASHING EQUIPMENT must contain a wash solution of soap, detergent, acid cleaner, alkaline cleaner, degreaser, abrasive cleaner, or other cleaning agent according to the cleaning agent manufacturer's label instructions. # Solution Clean (22) The wash, rinse, and sanitize solutions must be maintained clean. # Wash Temperatures # Manual Wash Temperature (23) The temperature of the wash solution in manual WAREWASHING EQUIPMENT must be maintained at not less than the temperature specified on the cleaning agent manufacturer's label instructions. # Warewash Wash Temperatures (23) The temperature of the wash solution in spray type warewashers that use hot water to sanitize must not be less than • 74°C (165°F) for a stationary-rack, single-temperature machine. • 66°C (150°F) for a stationary-rack, dual-temperature machine. • 71°C (160°F) for a single-tank, conveyor, dual-temperature machine. • 66°C (150°F) for a multi-tank, conveyor, multitemperature machine. High wash tank temperatures do not compensate for low auxiliary rinse and/or hot water final rinse sanitizing temperatures. # Wash Temperatures for Chemical Machines (23) The temperature of the wash solution in spray-type warewashers that use chemicals to sanitize must not be less than 49°C (120°F). # Alarm (22) Warewash machines for vessels built to VSP 2005 Construction Guidelines or later or installed/replaced on existing vessels after July 2005 must be equipped with an audible or visual alarm that indicates when the sanitizing temperature or chemical SANITIZER level drops below the levels stated on the machine data plate. # Cleaning Equipment and Utensils # Cleaning Frequency # Food-Contact Surfaces Clean (26 C) FOOD-CONTACT SURFACES of EQUIPMENT and UTENSILS must be clean to sight and touch. # Encrusted (26 C) FOOD-CONTACT SURFACES of cooking EQUIPMENT and pans must be kept free of encrusted grease deposits and other soil accumulations. # Nonfood-Contact Surfaces (27) NONFOOD-CONTACT SURFACES of EQUIPMENT must be kept free of an accumulation of dust, dirt, FOOD residue, and other debris. # Food-Contact Cleaning Frequency (26 C) FOOD-CONTACT SURFACES of EQUIPMENT and UTENSILS must be washed, rinsed, and sanitized as follows: • Before each use with a different type of raw animal FOOD such as beef, FISH, lamb, pork, or POULTRY. • Each time there is a change from working with raw FOODS to working with READY-TO-EAT FOODS. • Between uses with raw fruits and vegetables and with POTENTIALLY HAZARDOUS FOOD. • Before using or storing a FOOD TEMPERATURE-MEASURING DEVICE. • Any time during the operation when CONTAMINATION might have occurred. # In-Use Food-Contact Equipment (28) If used with POTENTIALLY HAZARDOUS FOOD, FOOD-CONTACT SURFACES of EQUIPMENT and UTENSILS used on a continuing basis must be washed, rinsed, and sanitized at least every 4 hours. # Dispensing Equipment Cleaning (28) Cleaning of EQUIPMENT such as ice bins; BEVERAGE dispensing nozzles; and enclosed components of EQUIPMENT such as ice makers, cooking oil storage tanks, and distribution lines, BEVERAGE dispensing lines, and syrup dispensing lines or tubes; and coffee bean grinders must be conducted • At a frequency specified by the manufacturer, or • In the absence of manufacturer specifications, at a frequency necessary to preclude accumulation of soil or mold. # Cooking/Baking Equipment Cleaning (28) Cooking and baking EQUIPMENT must be cleaned as follows: • FOOD-CONTACT SURFACES of cooking and baking EQUIPMENT must be cleaned at least every 24 hours. • Cavities and door seals of microwave ovens must be cleaned at least every 24 hours by using the manufacturer's recommended cleaning procedure. # Dry Cleaning Methods # Dry Cleaning (28) If dry cleaning is used, it must be conducted as follows: • Methods such as brushing, scraping, and vacuuming must contact only surfaces soiled with dry FOOD residues that are not potentially hazardous. • Cleaning EQUIPMENT used in dry cleaning FOOD-CONTACT SURFACES must not be used for any other purpose. # Precleaning and Racking # Precleaning/Scrapping (23) FOOD debris on EQUIPMENT and UTENSILS must be scrapped over a waste disposal unit, pulper, or garbage receptacle or must be removed in a WAREWASHING machine with a prewash cycle. # Presoak/Scrubbed (23) If necessary for effective cleaning, EQUIPMENT and UTENSILS must be preflushed, presoaked, or scrubbed with abrasives. # Racking (22) Soiled items to be cleaned in a WAREWASHING machine must be loaded into racks, trays, or baskets or onto conveyors in a position that • Exposes the items to the unobstructed spray from all cycles and • Allows the items to drain. # Wet Cleaning # Washing (23) FOOD-CONTACT SURFACES of EQUIPMENT and UTENSILS must be effectively washed to remove or completely loosen soils by using whatever manual or mechanical means is necessary (such as application of detergents containing wetting agents and emulsifiers; acid, alkaline, or abrasive cleaners; hot water; brushes; scouring pads; high-pressure sprays; or ultrasonic devices). # Soil Specific (22) The washing procedures selected must be based on the type and purpose of the EQUIPMENT or UTENSIL and on the type of soil to be removed. # Alternative Manual Warewashing Procedures # Alternative Warewashing Procedures (23) If washing in sink compartments or a WAREWASHING machine is impractical (such as when the EQUIPMENT is fixed or the UTENSILS are too large), washing must be done by using alternative manual WAREWASHING EQUIPMENT in accordance with the following procedures: • EQUIPMENT must be disassembled as necessary to allow access of the detergent solution to all parts. • EQUIPMENT components and UTENSILS must be scrapped or rough-cleaned to remove FOOD particle accumulation. • EQUIPMENT and UTENSILS must be washed. # Sponges Limited (22) Sponges must not be used in contact with cleaned and sanitized or in-use FOOD-CONTACT SURFACES. # Rinsing Procedures # Rinsing (23) Washed EQUIPMENT and UTENSILS must be rinsed so that abrasives are removed and cleaning chemicals are removed or diluted with water by using one of the following procedures: • Use of a distinct, separate water rinse after washing and before sanitizing (if using a three-compartment sink, alternative manual WAREWASHING EQUIPMENT equivalent to a three-compartment sink, or a three-step washing, rinsing, and sanitizing procedure in a WAREWASHING system for CIP EQUIPMENT). • Use of a nondistinct water rinse integrated in the application of the sanitizing solution and wasted immediately after each application (if using a WAREWASHING machine that does not recycle the sanitizing solution or if using alternative manual WAREWASHING EQUIPMENT such as sprayers). • Use of a nondistinct water rinse integrated in the application of the sanitizing solution (if using a WAREWASHING machine that recycles the sanitizing solution for use in the next wash cycle). # Sanitizing Concentrations # Chemical Sanitizing Solutions (24 C) A chemical SANITIZER used in a sanitizing solution for a manual or mechanical operation must be listed in 40 CFR 180.940 Sanitizing Solutions. # Chemical Sanitizing Exposure (24 C) A chemical SANITIZER must be used in accordance with the EPA-APPROVED manufacturer's label use instructions at a minimum temperature of 24°C (75°F) with an exposure time of 7 seconds for a chlorine solution and 30 seconds for other chemical SANITIZERS. # Chemical Sanitizing Concentration (24 C) Sanitizing solutions must be used with the following concentrations: • A chlorine solution must have a concentration between 50 MG/L (ppm) and 200 MG/L (ppm). • An iodine solution must have a pH of 5.0 or less or a pH no higher than the level for which the manufacturer specifies the solution is effective AND a concentration between 12.5 MG/L (ppm) and 25 MG/L (ppm). • A quaternary ammonium compound solution must have a concentration as specified in 40 CFR 180.940 Sanitizing Solutions AND as indicated by the manufacturer's use directions included in the labeling. If another solution concentration or pH of a chlorine, iodine, or quaternary ammonium compound is used, the vessel must demonstrate to VSP that the solution achieves SANITIZATION and the use of the solution must be APPROVED. If a chemical SANITIZER other than a chlorine, iodine, or quaternary ammonium compound is used, it must be applied in accordance with the manufacturer's use directions included in the labeling. # Sanitizer Concentration Testing (22) Concentration of the sanitizing solution must be accurately determined by using a test kit or other device. # Lubricating (28) Lubricants must be applied to FOOD-CONTACT SURFACES that require lubrication in a manner that does not contaminate FOOD-CONTACT SURFACES. # Assembling (28) EQUIPMENT must be reassembled so that FOOD-CONTACT SURFACES are not contaminated. Exposed GREY WATER and BLACK WATER lines must not to be in unfinished EQUIPMENT lockers if they are push-fit or coupled. These lines can be solid pipe, butt-welded, or sleeve-welded. If plastic pipe, the lines can be heat fused or chemically welded. # Storing Inverted (28) Clean EQUIPMENT and UTENSILS must be stored • In a self-draining position that allows air drying. • Covered or inverted. # Preset Tableware (28) TABLEWARE preset longer than 4 hours before the beginning of service must be protected from CONTAMINATION by being wrapped, covered, or inverted. When TABLEWARE is preset, exposed unused settings must be • removed at the time a CONSUMER is seated or • washed, rinsed, and sanitized before further use if the settings are not removed when a CONSUMER is seated. # 7.5.6.3.4 Original Package (28) SINGLE-SERVICE and SINGLE-USE ARTICLES must be kept in the original protective package or stored by using other means that afford protection from CONTAMINATION until used. # Utensil Dispensing (28) Eating UTENSILS dispensed at a CONSUMER self-service unit such as a buffet or salad bar must be protected from CONTAMINATION. 7.5.7 Laundering 7.5.7.1 Laundry Facilities # Laundry Equipment (28) If LINENS used in FOOD AREAS are laundered on the vessel, a mechanical clothes washer and dryer must be provided and used. # Laundry Operations Location (28) Laundry operations must be located to protect operations from CONTAMINATION and only located where there are none of the following: Exposed FOOD; clean EQUIPMENT, UTENSILS, and LINENS; or unwrapped SINGLE-SERVICE and SINGLE-USE ARTICLES. # Laundry Procedures # Laundry Frequency (28) LINENS that do not come in direct contact with FOOD must be laundered between operations if they become wet, sticky, or visibly soiled. # Cloth Gloves (28) Cloth gloves must be laundered before being used with a different type of raw animal FOOD such as beef, lamb, pork, and FISH. # Linens/Napkins (28) LINENS and napkins used to line FOOD-service containers and cloth napkins must be laundered between each use. # Wet Wiping Cloths (28) Wet wiping cloths must be laundered daily. # Dry Wiping Cloths (28) Dry wiping cloths must be laundered as necessary to prevent CONTAMINATION of FOOD and clean serving UTENSILS. # Use Conditions (31 C) POISONOUS OR TOXIC MATERIALS must be used according to the following: • LAW and these guidelines. • Manufacturer's use directions included in labeling (and, for a PESTICIDE, manufacturer's label instructions stating that use is allowed in a FOOD AREA). • Conditions of certification (if certification is required) for use of the pest-control materials. # Application (31 C) POISONOUS OR TOXIC MATERIALS must be applied in a manner that prevents • A HAZARD to employees or other persons. • CONTAMINATION including toxic residues resulting from drip, drain, fog, splash, or spray on FOOD; EQUIPMENT; UTENSILS; LINENS; and SINGLE-SERVICE and SINGLE-USE ARTICLES. # Restricted-Use Applications (31 C) When a RESTRICTED-USE PESTICIDE is applied, FOOD, EQUIPMENT, UTENSILS, LINENS, and SINGLE-SERVICE and SINGLE-USE ARTICLES must be removed; covered with impermeable covers; or other precautions taken. # Restricted-Use Applicator (31 C) A RESTRICTED-USE PESTICIDE must be applied only by an applicator certified as defined in 7 USC 136(e) Certified Applicator of the Federal Insecticide, Fungicide, and Rodenticide Act or a person under the direct supervision of a certified applicator. # Equipment Cleaning and Sanitizing (31 C) FOOD EQUIPMENT and UTENSILS in the area treated must be cleaned and sanitized after the application. # Containers (31 C) A container previously used to store cleanser, chemicals, or POISONOUS OR TOXIC MATERIALS must not be used to store, transport, or dispense FOOD. Additionally, FOOD containers must not be used to store, transport, or dispense cleanser, chemicals, or POISONOUS OR TOXIC MATERIALS. # Sanitizers and Other Food Area Chemicals # Sanitizers (31 C) Chemical SANITIZERS and other chemical antimicrobials applied to FOOD-CONTACT SURFACES must meet the requirements specified in 21 CFR 178.1010 Sanitizing Solutions. # Fruit/Vegetable Wash (31 C) Chemicals used to wash or peel raw whole fruits and vegetables must meet the requirements specified in 21 CFR 173.315 Chemicals Used in Washing or to Assist in the Peeling of Fruits and Vegetables (Annex 13.12). # Boiler Water Additives (31 C) Chemicals used as boiler water ADDITIVES for culinary steam or other FOOD AREA purposes must meet the requirements specified in 21 CFR 173.310 Boiler Water ADDITIVES. # Drying Agents (31 C) Drying agents used in conjunction with SANITIZATION must contain only components listed as one of the following: • Generally recognized as safe for use in FOOD as specified in 21 CFR 182 Substances Generally Recognized as Safe or in 21 CFR 184 Direct FOOD Substances Affirmed as Generally Recognized as Safe. • Generally recognized as safe for the intended use as specified in 21 CFR 186 Indirect FOOD Substances Affirmed as Generally Recognized as Safe. • APPROVED for use as a drying agent under a prior sanction specified in 21 CFR 181 Prior-Sanctioned FOOD Ingredients. • Specifically regulated as an indirect FOOD ADDITIVE for use as a drying agent as specified in 21 CFR Parts 175-178. • APPROVED for use as a drying agent under the threshold of regulation process established by 21 CFR 170.39 Threshold of Regulation for Substances Used in FOOD-Contact Articles. # Approved for Use with Chemical Sanitizers (31 C) When used with chemical SANITIZATION, drying agents must be specifically APPROVED for use with chemical sanitizing solutions. # Lubricants (31 C) Lubricants must meet the requirements specified in 21 CFR 178.3570 Lubricants with Incidental FOOD CONTACT if they are used on FOOD-CONTACT SURFACES; on bearings and gears on or within FOOD-CONTACT SURFACES; or on bearings and gears located so that lubricants may leak, drip, or be forced into FOOD or onto FOOD-CONTACT SURFACES. # Pesticides and Rodenticides # Restricted-Use Pesticides (31 C) RESTRICTED-USE PESTICIDES used in FOOD AREAS must meet the requirements specified in 40 CFR 152 Subpart I Classification of PESTICIDES. # Rodent Bait (31 C) Rodent bait used in FOOD AREAS must be contained in a covered, tamper-resistant bait station. # Tracking Powder Pesticides (31 C) A tracking powder PESTICIDE must not be used in a FOOD AREA. # Nontoxic Tracking Powders (19) A nontoxic tracking powder such as talcum or flour, if used, must not contaminate FOOD. This applies to self-service and served candy shops where employees serve candy, refill self-service containers, etc. # 8 Meters/26 Feet (29 C) The handwashing facility must be within 8 meters (26 feet) of all parts of the area and should not be located in an adjacent area that requires passage through a closed door where users make hand contact with the door. Handwash sinks must be at least 750 millimeters (30 inches) above the deck so users do not have to reach excessively to wash their hands. Counter-mounted handwash sinks may be installed a minimum of 600 millimeters (24 inches) above the deck, as measured at the counter level. # Tempered Water (29 C) A handwashing sink must be equipped to provide water at a temperature of at least 38°C (100°F) through a mixing valve or combination faucet. For handwash sinks with electronic sensors and other types of handwash sinks where users cannot make temperature adjustments, the temperature after the mixing valve must not exceed 49°C (120°F). # Metered Faucet (30) A self-closing, slow-closing, or metering faucet must provide a flow of water for at least 15 seconds without the need to reactivate the faucet. # Automatic Systems (30) An automatic handwashing facility must be installed in accordance with manufacturer's instructions. VSP 2018 Operations Manual 7.0 Food Safety; # Dispenser/Receptacle (30) A handwashing facility must include a sink, soap dispenser, singleuse towel dispenser, and waste receptacle. # Sign (30) A sign stating "wash hands often," "wash hands frequently," or similar wording in a language that the FOOD EMPLOYEES understand must be posted over handwashing sinks. # Toilet Facility Installation # Convenient (29 C) Toilet rooms must be provided and conveniently located. # Handwashing Facilities (29 C) Handwashing facilities must be in or immediately adjacent to toilet rooms or vestibules. # Sign (30) A sign must be conspicuously posted on the BULKHEAD adjacent to the door of the toilet or on the back of the door. The sign must state "WASH HANDS AFTER USING TOILET" in a language the FOOD EMPLOYEES understand. A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels may be used in lieu of a sign. Toilet facilities must be equipped so persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-handsfree contact must begin in the toilet stall. Toilet facilities with multiple exits must have bare-hands-free contact at each exit. Bare-hands-free contact may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, or using other effective means. # Enclosed/Doors (30) Toilet rooms must be completely enclosed and must have tightfitting, self-closing doors that must be kept closed except during cleaning or maintenance. # Waste Receptacle (30) EASILY CLEANABLE receptacles must be provided for waste materials. # Unlocked (29 C) Toilet facilities intended for use by galley personnel must not be locked when the galley is in service. # Handwashing and Toilet Facility Maintenance # Accessible (29 C) Handwashing facilities must be used for no other purpose and must be ACCESSIBLE at all times. # Facilities Clean/Good Repair (30) Handwashing facilities must be kept clean and in good repair. # Soap/Towels (30) Each handwashing facility must have a supply of hand-cleansing soap or detergent and a supply of SINGLE-SERVICE paper towels available. # Toilets Clean/Good Repair (30) Toilet fixtures must be kept clean and in good repair. # Toilet Tissue (30) A supply of toilet tissue must be provided at each toilet at all times. # Passenger Self-Service Buffet Handwashing Stations (30) # Installation Date The following section applies to all vessels with a keel laid date of June 1, 2018 or later and any FOOD self-service areas that have been modified since June 1, 2018, including replacement, relocation, or addition of buffet self-service counter(s) or self-service EQUIPMENT. # Number Provide one obvious handwashing station per 100-passenger seating or fraction thereof. Stations should be equally distributed between the major passenger entry points to the buffet area and must be separate from a toilet room. leakproof. # Insect/Rodent Resistant (32) Receptacles and waste-handling containers for REFUSE and recyclables and for use with materials containing FOOD residue must be insect and rodent resistant and must have tight-fitting lids. # Covered/Provided (32) Receptacles and waste-handling containers must be kept covered when not in continuous use and after they are filled. # Location (32) A receptacle or waste-handling container must be provided in each area of the vessel or premise where REFUSE is generated or commonly discarded or where recyclables are placed. # Wash Facilities (32) Facilities suitable for washing receptacles and waste-handling containers must be provided separate from FOOD EQUIPMENT and UTENSIL storage areas or FOOD PREPARATION AREAS. # Design/Supplies (32) The designated container wash area must be EASILY CLEANABLE and must have tempered water, access to detergent, and suitable drainage. # Cleaned (32) Receptacles and waste-handling containers must be cleaned when emptied. # Garbage and Refuse Storage Room # Easily Cleanable/Durable (32) The dry and refrigerated garbage and REFUSE storage room must be constructed of EASILY CLEANABLE, corrosion-resistant, nonabsorbent, and durable materials. # Size (32) The garbage and REFUSE storage room must be large enough to store and process the garbage and REFUSE. # Prevent Contamination (32) The garbage and REFUSE storage room must be located so as to prevent CONTAMINATION in FOOD PREPARATION, FOOD STORAGE, and UTENSIL washing areas. # Good Repair/Clean (32) The garbage and REFUSE storage room must be maintained in good repair and kept clean. # Heat Lamps (36) An infrared or other heat lamp must be protected against breakage by a shield surrounding and extending beyond the bulb so only the face of the bulb is exposed. # Monitoring (40) The IPM plan must set a schedule for periodic active monitoring inspections, including some at night or during periods of no or minimal activity. # Logs (40) The IPM plan must include provisions for logs for active monitoring of pest sightings in operational areas of the vessel. The IPM plan also must include provisions for training of crew members in charge of log completion. The time of the active monitoring inspections must be recorded in the log. # Passive Surveillance (40) The IPM plan must include passive surveillance procedures such as glue traps or other passive monitoring devices and must include the location of each. A passive device monitoring log must be maintained. # Action and Follow Up (40) When pests are observed during an inspection, the log must include action taken as well as follow-up inspection results. # Plan Evaluation # Evaluation (40) The vessel's IPM plan must be evaluated for effectiveness periodically or whenever there is a significant change in the vessel's operation or structure (e.g., renovation). Evaluation may be required more frequently in areas where pest infestations cannot be controlled. # Reviews (40) IPM plan evaluations and changes must be documented in the IPM plan. # Inspections (40) The IPM plan, monitoring records, and other documentation must be available for review during inspections. # IPM and Pesticide Use # Pesticide Application # Pesticide Record (40) The IPM plan must include a record of GENERAL-USE and RESTRICTED-USE PESTICIDES used to control pests and vectors. The record must include all GENERAL-USE and RESTRICTED-USE PESTICIDES currently onboard the vessel and those used in the previous 12 months. # Restricted Use (39 C) A RESTRICTED-USE PESTICIDE must be applied only by a certified applicator or a person with training and testing equivalent to that of a certified applicator. # Applicator Training (40) Training of the pest-control personnel must be documented. # Safety (40) The IPM plan must establish health and safety procedures to protect the passengers and crew. # Pest Control # Exclusion # Food Areas # Effective Control (39 C) The presence of insects, rodents, and other pests must be effectively controlled to minimize their presence in the FOOD STORAGE, preparation, and service areas and WAREWASHING and UTENSIL storage areas aboard a vessel. # Exclusion (40) Entry points where pests may enter the FOOD AREAS must be protected. Rat guards must be made of a durable and nonchewable material. Single-line, multiple-line, or conical shape rat guards should be used according to the manufacturer's specifications. Rat guards must be on all lines that go ashore on arrival and until 1 hour before the ship leaves port. Each line must have at least one rat guard placed either as far as practicable from the pier or as far as practicable from the ship but still close enough for any openings to be stuffed with nonchewable material. Rat guards must not be staggered on adjacent lines, and a group of lines must not be merged onto one rat guard. # Incoming Food and Other Supplies (40) Incoming shipments of FOOD and all other supplies must be routinely inspected for evidence of insects, rodents, and other pests. A record of these inspections must be maintained onboard the vessel and must be available for review during inspections. # IPM Inspections (40) All FOOD AREAS must be inspected at a frequency that can quickly detect the evidence of pests, harborage conditions, cleanliness, and protection of outer openings. # Nonfood Areas Reasonable care must be given to conduct inspections in nonfood areas for the presence of insects, rodents, and other pests. The garbage handling areas of the vessel must be inspected at least weekly for the presence of insects, rodents, and other pests. The results of these inspections must be maintained in a log. These results may be included in the log of the FOOD AREA inspections. # Control Measures # Chemical # Chemical Controls (39 C) Chemical control measures must conform to products and application procedures specifically allowed in the FOOD safety section of these guidelines and the vessel's IPM plan. # Physical # Insect-Control Devices (40) Insect-control devices that electrocute or stun flying insects are not permitted in FOOD AREAS. # Food Protection (19) Insect control devices such as insect light traps must not be located over FOOD STORAGE, FOOD PREPARATION AREAS, FOOD SERVICE stations, or clean EQUIPMENT. Dead insects and insect fragments must be prevented from falling on exposed FOOD. # Utensil Protection (28) Insect-control devices must not be located over WAREWASHING, UTENSIL storage areas, EQUIPMENT, UTENSILS, LINENS, or unwrapped SINGLE-SERVICE or SINGLE-USE ARTICLES. Dead insects and insect fragments must be prevented from falling on clean items. # Cleaning (40) Dead or trapped insects, rodents, and other pests must be removed from control devices and the vessel at a frequency that prevents their accumulation or decomposition or the attraction of other pests. # Integrated Pest Management Knowledge # Demonstration of Knowledge (44) The supervisor or PERSON IN CHARGE of IPM operations on the vessel must demonstrate to VSP-on request during inspections-knowledge of IPM operations. The supervisor or PERSON IN CHARGE must demonstrate this knowledge by compliance with this section of these guidelines or by responding correctly to the inspector's questions as they relate to the specific operation. In addition, the supervisor or PERSON IN CHARGE of IPM operations on the vessel must ensure that employees are properly trained to comply with this section of the guidelines in this manual as it relates to their assigned duties. # Housekeeping This section includes the following subsections: 9.1 OUTBREAK Prevention and Management Procedures 9.2 Knowledge References for 9.0 Housekeeping can be found in Annex 14.9. # Outbreak Prevention and Management Procedures # Disinfection # Public Areas # Continuous Disinfection (41) When the cumulative proportion of cases of AGE among passengers or crew members is ≥2%, the OUTBREAK management response must include cleaning and disinfecting all public areas, including handrails and restrooms, on a continuous basis while passengers and/or crew are circulating in those areas. This process involves DISINFECTION of hand-contact surfaces of all public areas, including restrooms and handrails, throughout the ship and identified in the OPRP. Workers disinfect these surfaces without interruption along a logical route by deck, venue, and area when people are present or circulating in these areas. # Cabin Cleaning (41) Cabins that house passengers or crew with AGE must be cleaned and disinfected daily while the occupants are ill. # Precautionary Measures (41) Precautionary measures by housekeeping personnel must be taken in consultation with the vessel's medical staff to prevent the spread of AGE from cabin to cabin. # Example Precautionary measures by the housekeeping personnel may include using disposable personal protection EQUIPMENT, including gloves that are changed after each cabin; cleaning cabins with ill passengers or crew after all other cabins; or having specific crew members only clean cabins of ill passengers or crew. o Personal protective EQUIPMENT for crew. o Health and safety procedures to minimize respiratory and dermal exposures to both passengers and crew. # Public Toilet Facilities (41) Passenger and crew public toilets (not including FOOD-area toilets) must be provided with a handwashing station that includes the following: • Hot and cold running water. • Soap. • A method to dry hands (e.g., sanitary hand-drying device, paper towels). • A sign advising users to wash hands (pictograms are acceptable). # Hands-Free Exit (41) Passenger and crew public toilet facilities must be equipped so persons exiting the toilet room are not required to touch the door handle with bare hands. Where toilet stalls include handwashing facilities, the bare-handsfree contact must begin in the toilet stall. Toilet facilities with multiple exits, such as spa dressing rooms, must have bare-handsfree contact at each exit. Bare-hands-free contact may be accomplished by methods such as locating paper towel dispensers at sinks and waste containers near the room door, installing mechanically operated doors, removing doors, or using other effective means. # Sign (41) A sign must be posted advising users of toilet facilities to use hand towel, paper towel, or tissue to open the door unless the exit is hands free. A pictogram that illustrates the correct use and disposal of paper towels may be used in lieu of a sign. # Housekeeping Knowledge # Demonstration of Knowledge (44) The # Diaper Changing (42) If children who wear diapers are accepted in the CHILD ACTIVITY CENTER, diaper-changing stations and disposal facilities must be provided. # Diaper-Changing Stations (42) Each station must include the following: • A changing table that is nonabsorbent, nontoxic, SMOOTH, durable, EASILY CLEANABLE, and designed for diaper changing. • A supply of disposable diapers, gloves, wipes, table cleanser, and DISINFECTANT. • An airtight soiled-diaper receptacle. • An adjacent handwashing station. # Signs (42) Signs must be posted in the diaper changing area advising handwashing after each diaper change. # Toilets and Handwashing # Employee Handwashing (42) Vessels constructed to the VSP 2005 Construction Guidelines or later must have at least one handwashing station separate from the toilet room(s). The handwashing station must be maintained clean and available at all times. # Facilities Sections 9.1.1.1.6-9.1.1.1.8 also apply to this section, except that the sign advising users to wash hands (section 9.1.1.1.8) is not required. # Design # Child-Size Toilet (42) If toilet rooms are located in a CHILD ACTIVITY CENTER, CHILD-SIZE TOILET(s) or child-ACCESSIBLE toilet(s) (childsize seat and step stool) and handwashing facilities must be provided. CHILD-SIZE TOILETS (to include the toilet seat) must have a maximum height of 280 millimeters (11 inches) and a toilet seat opening no greater than 203 millimeters (8 inches). Handwashing sinks must have a maximum height of 560 millimeters (22 inches) above the deck or a step stool must be provided. # Toilet Supplies (42) Each child's toilet facility must be provided with a supply of toilet tissue, disposable gloves, and sanitary wipes. # Waste Receptacle (42) An airtight, washable waste receptacle must be conveniently located to dispose of excrement, soiled sanitary wipes, and soiled gloves. Waste materials must be removed from the CHILD ACTIVITY CENTER each day. # Handwashing Supplies (42) Soap, paper towels or air dryers, and a waste towel receptacle must be located at handwashing stations. # Signs (42) Signs must be posted in children's toilet room advising providers to wash their hands and the children's hands after assisting children with using the toilet. # Assistance (42) Children under 6 years old must be assisted in washing their hands in the CHILD ACTIVITY CENTER after using the toilet room, before eating, and after otherwise contaminating their hands. # Separate (42) Separate toilet facilities must be provided for CHILD ACTIVITY CENTER staff. CHILD ACTIVITY CENTER staff must not use the children's toilet facilities. Public toilet facilities are acceptable. # Exiting (41) Toilet rooms must be equipped so that persons exiting the toilet room are not required to handle the door with bare hands. # Temperature (42) The maximum water temperature for a handwashing station must not exceed 43°C (110°F). # Outside Toilet Rooms (42) Handwashing stations designated for children and located outside toilet rooms must meet the requirements in sections 10.2.2.1.1 and 10.2.2.1.9. # 10.3 Cleaning and Disinfection # Employee Handwashing # When to Wash Hands (12 C) Child care providers must wash their hands before giving FOOD or BEVERAGES to children. # Furnishings and Toys # Construction # Cleanable (42) Surfaces of tables, chairs, and other furnishings that children touch with their hands must be cleanable. # Condition (42) Toys used in the CHILD ACTIVITY CENTER must be maintained in a clean condition. # Procedures # Hard Surfaces (42) Surfaces that children touch with their hands must be cleaned and disinfected daily with products labeled by the manufacturer for that purpose. # Toy Cleaning/Ball Pits (42) Toys used in the CHILD ACTIVITY CENTER must be cleaned and disinfected daily. Balls used in ball pits/pens must be cleaned when contaminated or at least once per week. If a CHEMICAL DISINFECTANT is used, toys must be air dried before use. # Tables/High Chairs (42) Tables and high chair trays must be cleaned and disinfected before and after they are used for eating. # Decks (42) Carpeting must be vacuumed daily and must be periodically cleaned when it becomes visibly soiled. Decks must be washed and disinfected when soiled or at least daily. # Facility Cleaning/Disinfecting (42) Diaper changing stations, handwashing facilities, and toilet rooms must be cleaned and disinfected daily and when soiled during use. # Linens Laundered (42) LINENS such as blankets, sheets, and pillow cases must be laundered between each use. # Costumes (42) Costumes worn by children-including clothing items, masks, and hats-must be laundered, cleaned and disinfected, discarded, retained by the guest, or dry cleaned between each use. # Exclusions # Children with Infectious Illness # Procedures # Written Guidance (42) Written guidance on symptoms of common childhood infectious illnesses must be posted at the entrance of the CHILD ACTIVITY CENTER. # Exclusion Policy (42) The CHILD ACTIVITY CENTER must have a written exclusion policy on procedures to be followed when a child develops symptoms of an infectious illness while at the center. The policy must include a requirement for written clearance from the medical staff before a child with symptoms of infectious illness can be allowed in the CHILD ACTIVITY CENTER. This policy must be posted at the entrance of the CHILD ACTIVITY CENTER. # Infectious Illness (42) Children with infectious illness must not be allowed in the CHILD ACTIVITY CENTER without written permission from the vessel's medical staff. # 10.5 Child Activity Center Knowledge 10.5. # Self Draining (43) Condensation collection pans must be self draining. # Potable Water (43) Only POTABLE WATER can be used for cleaning the HVAC distribution system. # Maintenance # Air Handling Units (43) Air handling units must be kept clean. # Condensers (43) Evaporative condensers must be inspected at least annually and cleaned as necessary to remove scale and sediment. Cooling coils and condensate pans must be cleaned as necessary to remove dirt and organic material. # Inspection and Maintenance Plan (43) Vessels must have a plan to inspect and maintain HVAC systems in accordance with the manufacturer's recommendations and industry standards. The written inspection, cleaning, and maintenance plan for the HVAC system must be maintained on the vessel and available for review during inspections. Documentation of the inspection, cleaning, and maintenance plan must be available for review during inspections. An electronic maintenance tracking system is acceptable for both the plan and the documentation if the work description and action completed are available. # Sprays (43) Only POTABLE WATER can be used for water sprays, decorative fountains, humidifiers, and misting systems. The water must be further treated to avoid microbial buildup in the operation of water sprays, fountains, humidifiers, and misting systems. # Fountains and Misting Systems # Clean (43) Decorative fountains and misting systems must be maintained free of Mycobacterium, Legionella, algae, and mold growth. For systems installed after the adoption of the VSP 2011 Operations Manual, • Provide an automated treatment system (halogenation, UV, or other effective DISINFECTANT) to prevent the growth of Mycobacterium and Legionella in any decorative fountain, misting system, or similar facility. • Ensure that nozzles are REMOVABLE for cleaning and DISINFECTION. • Ensure that pipes and reservoirs can be drained when the fountain/system is not in use. PORTABLE units must be maintained clean. # Shock Treatment (43) For misting systems and similar facilities, ensure that these systems can also be manually disinfected (halogenation, heat, etc.). If heat is used as a DISINFECTANT, ensure that the water temperature, as measured at the misting nozzle, can be maintained at 65°C (149°F) for a minimum of 10 minutes. # Hot-Water System (43) The potable hot-water system-including shower heads-must be maintained to preclude growth of Mycobacterium or Legionella. # Administrative Guidelines # Inspections # Inspection Procedures # Routine Inspections An unannounced, complete sanitation inspection by VSP Environmental Health Officers (EHOs) will be done twice each federal fiscal year if the vessel is available. # IHR Ship Sanitation Inspections The Vessel Sanitation Program will conduct International Health Regulations (IHR) ship sanitation inspections during unannounced routine operational inspections of cruise ships using the final APPROVED IHR inspection manual from the World Health Organization (WHO). The IHR inspection will only be conducted if there is sufficient time to do both inspections while the ship is in port. There will be no additional fee charged for a dual inspection. The IHR inspection will not be conducted if the cruise line involved has invoices from other ship inspections unpaid for more than 60 days from receipt of those invoices. VSP will also provide extensions to existing ship sanitation control exemption certificates. Because the standard for the IHR inspections is set by WHO, the ship will be issued the certificate appropriate to the findings of the inspection. The findings specific to the IHR will be so designated in the inspection report narrative. # Inspectors VSP EHOs will be trained in the interpretation and application of the current VSP Operations Manual. # Boarding The VSP EHO or EHOs will board the vessel and immediately inform the master of the vessel or a designated agent that a vessel sanitation inspection is to be conducted. # Sequence The VSP EHO or EHOs will then conduct the inspection in a logical sequence until all areas identified in this manual have been inspected. # Imminent Health Hazard Detection The VSP EHO or EHOs will contact the master of the vessel or a designated agent and the VSP Chief immediately during an inspection about a possible recommendation that the vessel not sail • If an IMMINENT HEALTH HAZARD as specified in section 12.9.1 is found to exist on the vessel AND • If these deficiencies possibly cannot be corrected before the inspection is completed. # Incomplete Inspections Once an inspection has begun, it will be completed in that same visit. If the inspection cannot be completed, the results of an incomplete inspection will be discussed with the vessel's staff. A complete inspection will be conducted at a later date. # Inspection Report # Draft Report # Provided The VSP EHO or EHOs will provide a draft inspection report to the master of the vessel, or a designated agent, at the conclusion of the inspection. # Information The draft inspection report will provide administrative information, AGE log review details, and inspection score. # Deficiency Descriptions The draft inspection report will provide a written description of the items found deficient and where the deficiency was observed. # Final Report # Report Form The VSP EHO or EHOs will use the Vessel Sanitation Inspection Report (Annex 13.17) to summarize the inspection score. The inspection report will contain the elements in 12.2.2.2 through 12.2.2.5. # Administrative The inspection report includes administrative information that identifies the vessel and its master or designee. It also includes the inspection report score, which is calculated by subtracting credit point values for all observed deficiencies from 100. # Deviations The item number and the credit point value for that item number will be indicated if the vessel does not meet the current VSP Operations Manual standard for that item. # Medical Review The medical documentation (e.g., GI logs, medical logs, special reports, etc.) will be available for review by VSP for accuracy and timeliness of reporting. # Report Detail A written description of the items found deficient will be included. The deficiencies will be itemized with references to the section of the current VSP Operations Manual. The description will include the deficiency location and citation of the appropriate VSP Operations Manual section. # Risk-Based Scoring and Correction Priority # Scoring System # Weighted Items The inspection report scoring system is based on inspection items with a total value of 100 points. # Risk Based Inspection items are weighted according to their probability of increasing the risk for an AGE OUTBREAK. # Critical Items CRITICAL ITEMS are those with a weight of 3 to 5 credit point values on the inspection report. # Critical Designation CRITICAL ITEMS are designated in this VSP Operations Manual in bold red underlined text. In addition, the text CRITICAL ITEM appears in parentheses after the section number and keywords; for example, 7.5.5.1 Food-Contact Surfaces (24 C). The section numbers of the CRITICAL ITEMS in this manual are also provided in red text. # Noncritical Items Noncritical items are those with a weight of 1 to 2 credit point values on the inspection report. # Scoring Each weighted deficiency found on an inspection will be deducted from 100 possible credit points. # Risk-Based Correction Priority # Critical Correction Time Frame At the time of inspection, a vessel will correct a critical deficiency as defined in the current VSP Operations Manual and implement a corrective-action plan for monitoring the CRITICAL ITEM for continued compliance. # Extension Considering the nature of the potential HAZARD involved and the complexity of the corrective action needed, VSP may agree to, or specify, a longer time frame (not to exceed 10 calendar days after the inspection) for the vessel to correct critical deficiencies. # 12.4 Closing Conference # Procedures # Closing Conference The results of the inspection will be explained to the master or a designee before the VSP EHO or EHOs leave the vessel. # Report Copy The VSP EHO or EHOs will leave a copy of the draft inspection report with the master or designee. The report will be reviewed in detail and opportunity provided for discussions of the findings. The draft report is provided so vessel personnel can begin correcting deficiencies immediately. # Invoice The VSP EHO or EHOs will provide the master or a designee with a payment invoice for signature. The VSP EHO or EHOs will provide one copy of the signed invoice to the master or designee and will forward one copy to the vessel's company office along with the final inspection report. # Fee Schedule The fee for inspections is based on the existing fee schedule for routine inspections of passenger cruise vessels. The schedule is published annually in the Federal Register. 12.5 Inspection Review # Inspection Report Review Requests # Contested Results The vessel owner or operator must notify VSP within 72 hours of the inspection closing conference of their intent to contest results of the inspection. After the initial notification and within 2 weeks of the inspection, the vessel owner or operator must provide VSP with the specific reference and facts concerning the contested deficiencies documented by the VSP EHO or EHOs during the inspection. # Interim Report At the request of the owner or operator, the VSP EHO or EHOs will complete an interim report if an inspection is under review. The interim report will indicate the item(s) under review. VSP will modify the final inspection report, as necessary, after the review by the VSP Chief. # Report Remarks After receiving a request for review, the VSP EHO or EHOs will mark the vessel's inspection report as under review at the request of the vessel owner or operator. # Review The VSP Chief will review the matter and respond within 2 weeks of receiving the request for a review. In the response, the VSP Chief will state whether the inspection report will be changed. # No Score No numerical score will be published before the VSP Chief makes a final determination on the review. Publication of inspection results will indicate the vessel's status as under review at the request of the vessel owner or operator. # Report Copies Copies of the contested inspection results released before the VSP Chief makes a final determination on the review will have each contested deficiency clearly marked as under review at the request of the vessel owner or operator. # Final Report The interim report will be issued as a final report if the written request for review is not received within 2 weeks of the inspection. # Appeal If the ship owner does not agree with the review and decision of the VSP Chief, he or she may appeal the decision to the Director, Division of Emergency and Environmental Health Services, National Center for Environmental Health. # Other Recommendations Review # Review A vessel owner or operator has the right to request a review of recommendations made during a technical consultation or inspection if the owner or operator believes VSP officials have imposed requirements inconsistent with or beyond the scope of this manual. # Written Request The owner or operator must send a written statement explaining the problem in detail to the VSP Chief within 30 days of the date the recommendation was made. # Review The VSP Chief will review the issue and respond within 2 weeks of receiving the statement, advising whether the recommendation will be revised. # Appeal If the ship owner does not agree with the review and decision of the VSP Chief, he or she may appeal the decision to the Director, Division of Emergency and Environmental Health Services, National Center for Environmental Health. # 12.6 Corrective Action Statement 12.6.1 Procedures # Corrective Actions Signed corrective-action statements (Annex 13.18) must be submitted to the VSP Chief by the master, owner, or operator. Corrective-action statements must detail each deficiency identified during the inspection and the corrective action taken. Corrective-action statements (Annex 13.18) must be submitted to the VSP Chief by the master, owner, or operator within 2 weeks of receiving the final inspection report. # Critical-Item Corrective Actions Critical-item deficiencies must also include standard operating procedures and monitoring procedures implemented to prevent the recurrence of the critical deficiency. # Clarification Requests The corrective-action statement may contain requests for clarification of items noted on the inspection report. The request for clarification must be included in the cover letter from the vessel's master, owner, or operator. Clarification of these items will be provided in writing to the requestor by the VSP Chief or the EHO or EHOs who conducted the inspection in question. # Public Distribution The corrective-action statement will be appended to the final inspection report for future reference and, if requested, made available for public distribution. 12.6.1.5 Same Score A corrective-action statement will not affect the inspection score. # Correction Affidavit # Procedures # Procedures An affidavit of correction from the owner or operator, certifying that corrective action has been completed, may be submitted to the VSP Chief. The procedure may be used only one time for an item. The item must be structure-or EQUIPMENT-related and must be corrected within a reasonable period. # Conditions At least one of the following conditions must apply for an item to qualify for an affidavit of correction. The item must be a • Longstanding deficiency that has not been identified during previous inspections OR • Deficiency in which the function of the EQUIPMENT is being accomplished by an alternative method. # Requested at Inspection After the inspection, but before the VSP EHO or EHOs leave the vessel, the vessel's master or a representative must provide notification of the intent to submit an affidavit of correction. This notice must specify the deficiency or deficiencies to be corrected and the corrective action to be taken. The draft inspection report will include a notation of the items to be corrected. # Final Inspection Score After acceptance of the affidavit, the final inspection score will be recalculated to include credit for the items corrected. # Inspection Publication # Methods # Report Availability on Website CDC publishes inspection reports and scores (the Green Sheet report) on the VSP website (www.cdc.gov/nceh/vsp). # Data The website will include, at a minimum, the names of the vessels in the inspection program, the dates of their most recent inspections, and the numerical score achieved by each vessel. # Public Record Reports, including corrective-action statements, are available on the VSP website. Paper copies are available to the public on request. # 12.9 Recommendation That the Vessel Not Sail 12.9.1 Imminent Health Hazards # Imminent Health Hazard An IMMINENT HEALTH HAZARD will be determined to be, but not limited to, one of the following situations: • Free HALOGEN residual in the POTABLE WATER distribution system is less than 0.2 MG/L (ppm) and this deficiency is not corrected before the inspection ends. • Inadequate facilities for maintaining safe temperatures for POTENTIALLY HAZARDOUS FOOD. • Inadequate facilities for cleaning and sanitizing EQUIPMENT. • Continuous problems with liquid and solid waste disposal, such as inoperative or overflowing toilets or shower stalls in passenger and crew member cabins. • Infectious disease OUTBREAK among passengers or crew, and where it is suspected that continuing normal operations may subject newly arriving passengers to disease. # Procedures # Notify VSP Chief The VSP EHO or EHOs will immediately notify the VSP Chief when any of these IMMINENT HEALTH HAZARDS or similar imminent threats to public health are found aboard a vessel. # No Sail CDC will recommend or direct the master of a vessel not to sail when an IMMINENT HEALTH HAZARD is identified and cannot be immediately corrected. Such a recommendation will be signed by the VSP Chief, with concurrence of the Director, National Center for Environmental Health/Agency for Toxic Substances and Disease Registry or the Director's designee. # 12.10 Reinspection and Follow-up Inspections 12.10.1 Reinspection Procedures # Failing Vessels Reinspections A reinspection is a complete sanitation inspection performed on vessels that did not score at least 86 on the previous inspection. # Reasonable Time Vessels that fail a routine inspection will be reinspected within a reasonable time, depending on vessel schedules and receipt of the corrective-action statement from the vessel's management. # Unannounced Reinspections will be unannounced. # No-Sail Reinspections If a no-sail recommendation is made, a follow-up inspection will be conducted as soon as requested. # Scheduling Priority In scheduling inspections, VSP will give priority to the reinspection of vessels that failed routine inspections. # One Reinspection Vessels that fail a routine inspection will undergo only one reinspection. # Written Requests Exceptions to 12.10.1.6 may be made when the owner or operator submits a written request for an additional reinspection to the VSP Chief stating why the additional reinspection is warranted. # Unannounced/Inspection Fee Additional reinspections are unannounced and the vessel will be charged the standard inspection fee. # Followup Inspection Procedures # Follow Up A follow-up inspection is a partial inspection to review the status of deficiencies identified during the previous periodic inspection or reinspection. # Not Periodic or Reinspection A follow-up inspection cannot be a substitute for a periodic inspection or reinspection. # Construction Compliance Construction/renovation inspections will document the vessel's compliance with CDC's VSP Construction Guidelines, which provide a framework for consistency in the sanitary design, construction, and construction inspections of cruise vessels. # New Vessels The CDC VSP 2018 Construction Guidelines will apply to all new vessels in which the keel is laid after June 1, 2018. # Major Renovations The construction guidelines will also apply to major renovations planned after June 1, 2018. A major renovation is a renovation where a new FOOD AREA (e.g., galley, bar, buffet) is installed, a new facility (e.g., recreational water, CHILD ACTIVITY CENTER) is installed, or an existing FOOD AREA or facility is changed by size or EQUIPMENT by 30% or more from the original. It also includes the addition of or change to an area/facility or a technical system (e.g., POTABLE WATER, wastewater, air systems) through the introduction of new technology. # Minor Renovations These guidelines will not apply to minor renovations. # Fee Schedule The fee for construction/renovation inspections is based on the existing fee schedule for routine inspections. # Construction/Renovation Inspection Reports # Report A written report will be issued by VSP after a construction/renovation inspection. These reports will summarize any changes recommended to ensure conformity with CDC guidelines. # Guides The reports prepared by VSP personnel in the shipyards during construction will be used as guides if VSP conducts a final construction/renovation inspection on the vessel before the vessel enters operational service. # No Score There is no score for construction/renovation inspections. 12.12 Other Environmental Investigations 12.12.1 Procedures 12.12.1.1 Environmental Investigations VSP may conduct or coordinate other activities such as investigating disease OUTBREAKS, checking a specific condition such as HALOGEN residual in the POTABLE WATER distribution system, or investigating complaints of unsanitary conditions on a vessel. # Problems Noted Public health problems noted during other environmental investigations will be brought to the attention of the vessel's master or designee when these investigations are performed. # No Score No inspection score will be provided and no fee will be charged for other environmental investigations. # VSP Records If a VARIANCE is granted, VSP will retain the information in its records for the vessel or, if applicable, multiple vessels. # Vessel Records If a VARIANCE is granted, the vessel using the VARIANCE must retain the information in its records for ready reference. # Existing Variances If changes are submitted for an existing APPROVED VARIANCE, the entire VARIANCE will be reviewed. If a new vessel is added to an existing APPROVED VARIANCE, the VARIANCE will be reviewed for that vessel. If new technology or science has been developed since approval of a VARIANCE, that section of the VARIANCE where the new technology or science was developed will be reviewed. # Documentation # Detailed Justification Before a VARIANCE from a requirement of the VSP 2018 Operations Manual is APPROVED, the person requesting the VARIANCE must provide the following, which will be retained in VSP's file on the vessel or vessels: • A statement of the proposed VARIANCE from the VSP 2018 Operations Manual requirement including relevant section number citations. • An analysis of the rationale for how the potential public health HAZARDS and nuisances addressed by the relevant VSP 2018 Operations Manual requirement will be alternatively addressed by the proposed VARIANCE. • If required, a HACCP PLAN, standard operating procedures, training plan, and monitoring plan that includes all the information as it is relevant to the VARIANCE requested. • Additional scientific data or other information as required to support the determination that public health will not be compromised by the proposal. # Conformance # Conformance If VSP grants a VARIANCE, the vessel must • Comply with the HACCP PLANS, standard operating procedures, training plan, and monitoring plan submitted and APPROVED as a basis for the modification or waiver. • Maintain and provide to VSP, on request, records to demonstrate that o procedures monitoring CRITICAL CONTROL POINTS are effective, o monitoring of the CRITICAL CONTROL POINT are routinely used, o necessary corrective actions are taken if there is failure at a CRITICAL CONTROL POINT, and o effectiveness of the operation or process in protection of public health is periodically verified. (c) Every person who is placed under surveillance by authority of this subpart shall, during the period of surveillance: (1) Give information relative to his/her health and his/her intended destination and report, in person or by telephone, to the local health officer having jurisdiction over the areas to be visited, and report for medical examinations as may be required; (2) Upon arrival at any address other than that stated as the intended destination when placed under surveillance, or prior to departure from the United States, inform, in person or by telephone, the health officer serving the health jurisdiction from which he/she is departing. (Approved by the Office of Management and Budget under control number 0920-0134) [50 FR 1519, Jan. 11, 198550 FR 3910, Jan. 29, 1985] Sec. 71.34 Carriers of U.S. military services. Carriers arriving at a U.S. port from a foreign area shall be subject to a sanitary inspection to determine whether there exists rodent, insect, or other vermin infestation, contaminated FOOD or water, or other insanitary conditions requiring measures for the prevention of the introduction, transmission, or spread of communicable disease. Sec. 71.45 FOOD, potable water, and waste: U.S. seaports and airports. # Acute Gastroenteritis Surveillance System # Introduction The following three forms are provided as guides to standardize the collection of information required to assess the patterns of AGE and monitor for OUTBREAKS aboard vessels: • Vessel Sanitation Program -ACUTE GASTROENTERITIS (AGE) Surveillance Log Following are some sample itineraries of vessels that may call upon a U.S. port. The ports where the routine AGE surveillance report is required at least 24 hours before arrival, but not more than 36 hours, are marked with ⇐. # Acute Gastroenteritis Surveillance # Sample Itineraries # Submission Procedures # Mechanism Routine AGE surveillance reports may be submitted as follows: • Telephone: 800-323-2132 or 954-356-6650, • Fax: 954-356-6671, • Email: [email protected], or • Website (user ID and password required): https://wwwn.cdc.gov/midrs/gilogin.aspx # Telephone Call Required A telephone notification to VSP at the telephone numbers listed above must accompany a special 2% report required when the vessel is within 15 days of expected arrival at a U.S. port, even when the special 2% report is submitted via fax, electronic mail, or website. # Specimens and Samples Timely collection of medical specimens and FOOD and water samples is important in the disease investigative process. The proper materials and techniques for collection and preservation are a part of the planning. It is important to periodically review these to make sure they are on hand and ready to use in the event they are needed. # Ready to Use A list of recommended medical specimen and FOOD sample collection supplies for investigating AGE OUTBREAKS can be found in sections 13.4.5 and 13.4.6 of this annex. Vessels with no medical staff aboard may choose to stock only the starred items in 13.4.5.1 unless a qualified staff member aboard is capable of performing venipuncture for collection of serum specimens. # Useful Information To assist in the rapid evaluation of the extent of illness among passengers and crew and identify the causative pathogen and associated risk factors, VSP may request the following items: • AGE OUTBREAK Action Plan for turnaround day. • General OUTBREAK Prevention and Response Plan. • AGE surveillance logs (previous and current voyages). • AGE 72-hour questionnaires. • Vessel's itinerary (previous and current voyages). • List of shore excursions, including lunch and BEVERAGE menus. • Public vomiting/diarrhea logs (previous and current voyages). • POTABLE WATER bunkering, production, and distribution logs. • POTABLE WATER bacteriological testing records. • POTABLE WATER maintenance records. • Recreational water logs, including information about fecal and vomit accidents. • Vessel map of cabins with AGE CASES. • Dining room seating maps with AGE passenger cases indicated. • Dining room seating maps with AGE waiter and assistant waiter stations indicated. • All menus. • Cooling logs for POTENTIALLY HAZARDOUS FOOD. • Vessel daily newsletters indicating guest activities. • Letter for passengers embarking on turnaround day. • Manifests for all groups of ≥15 people (groups traveling together). • Manifests for shore excursions within 48 hours of first peak of cases. • Security gangway records for AGE CASES within 48 hours of illness onset. # Survey VSP may also request distribution of a survey to all passengers and crew members. VSP will provide this survey to the vessel. Completed surveys should be held in the infirmary until collection by VSP staff for epidemiologic analysis. # Interviews Interviews with cases may also be useful for identifying the etiology and associated risk factors of an OUTBREAK. When distributing the surveys, medical staff should advise cases that interviews may be requested when VSP arrives at the vessel. # Report # Preliminary Report After an OUTBREAK investigation, a preliminary report of findings based on available clinical and epidemiologic information, environmental inspection reports of the investigation, and interim recommendations will be presented to the master of the vessel. Based on preliminary findings, additional materials (including additional passenger and crew information) may be requested from the cruise line or the vessel and follow-up studies may be undertaken to address specific suspicions or concerns. # Final Report The report presented to the master of the vessel will remain preliminary until completion of more-extensive epidemiologic and laboratory studies and distribution of a final report containing summary recommendations. # AGE Specimens # AGE Specimen Supplies Supplies recommended for specimen collection include the following: • 20-50 wide-mouth plastic jars or specimen cups with screw caps for stool specimens. • 20 plastic bags for storing specimen cups. • Disposable medical gloves. • Plastic disposable spoons for collecting stool. • 20 sterile bottles or tubes containing bacterial preservative and transport medium (e.g., Cary-Blair). • Sterile swabs. • Rectal swabs. • Stool preservative medium for parasites. • A large commercial roll of plastic wrap. • Sterile phlebotomy supplies for obtaining serum specimens (needles, syringes, swabs). # Food and Water Samples # Food and Water Sample Collection Kit A recommended FOOD and water sampling kit includes the following: • Sterile sampling containers (15 or more sealable plastic bags and wide-mouth screw top jars; 15 water sample bottles with sodium thiosulfate solution to provide concentration of 100 mg per mL of sample volume; foil or heavy wrapping paper). • Sterile specimen collection devices (spoons, tongs, scoop, knife, scissors, swabs, and pipettes). • DISINFECTION agents (sanitizing solution, 95% ethyl alcohol, and propane torch). • Support EQUIPMENT (plastic gloves, plastic container liners for iced samples, waterproof marking pen for sample identification, roll of adhesive or masking tape, labels, waterproof cardboard tags with ties, insulated ice chests, and frozen refrigerant packs). # Food and Water Sampling Procedures # Sample Plan Environmental sampling should be directed toward suspect FOOD and sources identified by the preliminary epidemiologic investigation. # Aseptic Techniques FOOD and water samples should be collected using aseptic techniques. Washed and gloved hands and sterile sampling UTENSILS and containers protect the integrity of the sample during collection. Taps used for water collection should be sterilized with heat or chemicals. The sample should be collected after 1 minute of flow time. # Sample Amount Approximately 200 grams or 200 mL of sample will usually suffice for the laboratory analytical requirements. Carefully squeeze most of the air out of the bag before sealing FOOD samples. # Sample Identification Sample numbers should be assigned on each collection container and recorded on a sample log that will accompany samples to the laboratory. Record information that identifies the date, time, and location of collection; product information; codes; storage # Sample Cross-Connection Control Program Guideline # Background Unprotected CROSS-CONNECTIONS to the POTABLE WATER system can result in mild changes to the aesthetic quality of the water affecting taste, odor, and color or severe changes that can result in illness or death. The purpose of a CROSS-CONNECTION control program is to identify these connections and provide appropriate protection. # Introduction Use this outline to either develop a comprehensive CROSS-CONNECTION control program or update and maintain an existing program. # Cross-Connection Survey One of the first steps in developing a CROSS-CONNECTION control program is to conduct a thorough survey of the POTABLE WATER system to identify all actual or potential CROSS-CONNECTIONS. Although an initial survey of the vessel can be time consuming, it is essential to ensure that all connections are identified so that appropriate protection can be decided on. Protection of POTABLE WATER can take two forms-containment or complete protection. Although the former may be the objective for a water supplier and requires less time and detail, the latter is the objective for this guidance. Example: A surveyor enters a structure and identifies numerous connections to the POTABLE WATER-both nonhealth-HAZARD and health-HAZARD connections. For containment purposes, an RP ASSEMBLY on the exterior supply line downstream of the water meter would contain all of the HAZARDS within the structure but would do nothing to protect the individual connections within the facility. If complete protection is the goal, each CROSS-CONNECTION in the structure must be identified and a decision made as to the appropriate BACKFLOW PREVENTION METHOD to be used. For vessels under VSP, the goal is complete protection. Surveyors should be • Knowledgeable in basic plumbing. • Knowledgeable in the principles of BACKFLOW, including BACKSIPHONAGE and BACKPRESSURE. • Able to identify both potential and actual CROSS-CONNECTIONS. • Familiar with the level of HAZARD posed by each connection. Surveyors should physically inspect all areas of the vessel supplied with POTABLE WATER. The best approach for this may be to go deck by deck, starting with the decks with connections that pose the greatest risk to health. # Cross-Connections on Vessels # List of Connections Requiring Backflow Prevention on Vessels A log listing of all CROSS-CONNECTIONS on the vessel must be developed. At a minimum the log should contain the data elements in numbers 2, 3, 6, 7, and 8. Inclusion of the additional data in numbers 1, 4, and 5 is recommended. 1. Deck (A, B, C, 1, 2, 3… # Specific Backflow Protection Choices on Vessels: Air Gaps and Backflow Prevention Devices Use this section to provide information to vessel staff on the specific BACKFLOW PREVENTION DEVICES used on the vessel. For each device, a copy of the specification sheets or technical sheets as well as the manufacturer's installation recommendations should be included in the program documentation file. Generally these documents are available online from the websites of each device manufacturer. # AIR GAPS # Baby-Only Water Facility For use by children who are in diapers or who are not completely toilet trained. # Introduction VSP recognizes the increased desire of passengers to allow children who are in diapers or who are not completely toilet trained to use RWFs. With that in mind, following are requirements for operating a RWF for the sole use by children who are in diapers or who are not completely toilet trained. Each cruise line is required to submit a VARIANCE request to operate this type of facility. Administrative Note: This section does not apply to vessels that have an APPROVED VARIANCE from section 6.9.1 at the time of issuance of the VSP 2018 Operations Manual. Those vessels must continue to comply with all of the requirements of the VARIANCE. # Design and Construction Facilities must be designed and constructed in accordance with the latest version of the VSP Construction Guidelines, regardless of the date the keel was laid. Before new construction or remodeling of an existing RWF, all plans must be submitted for review and approval by VSP. Once APPROVED, no parts of the system or its operation may be changed without prior written approval from VSP. For maintenance purposes, system components of at least equal performance specifications may be changed without prior approval. # Water Source # Recirculation The water source for this facility must only be POTABLE WATER for recirculation systems. # Flow-Through Seawater or POTABLE WATER may be used for a flow-through system. # Operation The system must be designed to operate in flow-through only or recirculation only. # Flow-Through At Sea A flow-through seawater supply system must be used only while the vessel is MAKING WAY and at sea beyond 20 kilometers (12 miles) from nearest land or any point of land discharge. The UV DISINFECTION system must be maintained and operated in accordance with the manufacturer's recommendation. At least one spare UV lamp must be available. # System Shutdown An automatic shutdown must be maintained whereby any failure in maintaining the required free residual HALOGEN level, pH level, or UV lamp intensity must cause the water to completely divert from the BABY-ONLY WATER FACILITY and instead loop back to the compensation tank. Additionally, this system must be equipped with an audible alarm that sounds in a continuously manned space, such as the bridge or engine control room. # Shutdown and Alarm Testing The emergency shutdown and alarms systems must be tested monthly. Testing procedures and results must be recorded. # System Cleaning and Disinfection # Daily Cleaning of Spray Pad Surface Every 24 hours, the SPRAY PAD surface and any associated features must be cleaned with an appropriate cleaner. The surface must be rinsed and disinfected at 50-ppm free residual HALOGEN for 1 minute, or the equivalent CT VALUE. Ensure that the liquid waste from this process is not directed to the compensation tank. At least every 72 hours, the facility must be shut down and these procedures must be followed: 1. The entire volume of water within the system must be discharged. This includes the BABY-ONLY WATER FACILITY, compensation tank, filter housing, and all associated piping. • Charts must be reviewed and signed daily by trained supervisory staff. • Charts must be dated and changed daily. • Records must be retained for 12 months. In the event of a failure in the automated analyzer-chart recorder, manual tests must be conducted and recorded for each required parameter on an hourly basis. A maximum of 72 hours will be allowed for manual tests while repairs are under way. If more than 72 hours pass, the facilities must be shut down until repairs are completed. A log must be kept to detail all maintenance activities, including the following: • Filter changes including filter housing cleaning and DISINFECTION (including ppm and contact time). • Backwashing time. • Fecal accidents. • Injury accidents. • Facility opening and closing times. One test must be conducted at the end of each day for the presence of Escherichia coli (E. coli) using a test in accordance with the latest edition of Standard Methods for the Examination of Water and Wastewater. Test kits, incubators, and associated EQUIPMENT must be operated and maintained in accordance with the manufacturers' specifications. For positive E. coli tests, follow this procedure: • Discharge the entire volume of water within the system. This includes the BABY-ONLY WATER FACILITY, compensation tank, filter housing, and all associated piping. • Use an appropriate cleaner on the BABY-ONLY WATER FACILITY, compensation tank, and filter housing (cartridge filter), then rinse and disinfect them (chlorine or bromine). DISINFECTION must be accomplished with a solution of at least 50 MG/L (ppm) for 1 minute, or the equivalent CT VALUE. • Conduct follow-up testing. The facility must not be put back in operation unless follow-up test results are negative for the presence of E. coli. A record of the test results must be maintained onboard the vessel and must be available for review during inspections. Retain records for 12 months. The maintenance logs, records, and charts must be kept for 12 months. # Training At least one person trained in the maintenance and operation of RWFs must be on the vessel and available at all times the facility is open for use. Such training includes the requirements of this manual, prevention of recreational water illnesses and injuries, HALOGEN and pH control chemicals, UV DISINFECTION systems, recreational water safety, and using test kits for HALOGEN-based DISINFECTANTS and pH. A record must be kept with the names of all trained individuals. # Monitor At least one individual must be available in the immediate area of the facility when it is open for use. This individual must monitor the area to ensure all of the following: • Children are wearing swim diapers. • Diapers are changed at suitable diaper-changing stations and not at the facility. • All children are under adult supervision. • FOOD, BEVERAGES, and glass are not used near the facility. • There is no running or boisterous play near the facility. • Children who are ill are prohibited from using the facility. # Safety # Eye Damage Ensure that water sprays are designed with pressures and directional flow controls to prevent eye damage to users. # Safety Sign A safety sign must be posted by the facility with letters at least 26 millimeters (1 inch) high at each entrance to the BABY-ONLY WATER FACILITY feature that states, at a minimum, the following: • This facility is only for use by children in diapers or who are not completely toilet trained. • Children who have a medical condition which may put them at increased risk for illness should not use these facilities. • Children who are experiencing symptoms such as vomiting, fever, or diarrhea are prohibited from using these facilities. • Children must be accompanied by an adult at all times. • Children must wear a clean swim diaper before using these facilities. Frequent swim diaper changes are recommended. • Do not change diapers in the area of the BABY-ONLY WATER FACILITY. A diaper changing station has been provided (exact location) for your convenience. The letters on the sign heading must be at least 26 millimeters (1 inch) high, but all other lettering must be at least 13 millimeters (1/2 inch) high. # Pictograms may replace words as appropriate or available. This information may be included on multiple signs, as long as they are posted at the entrances to the facility. # Swim Diapers Swim diapers in a variety of sizes must be available in close proximity to this facility. # Cartridge Filter Cleaning Procedures Cartridges should be cleaned in accordance with manufacturer's instructions where available and complete. In the absence of instructions, clean filters when the gauge pressure differential is 10 psi (68.9 KPa). Cleaning EQUIPMENT should include a soaking container properly sized to immerse the filter elements, a rinsing area with proper drainage, and a drying area protected from CONTAMINATION (e.g., birds and insects). New filters do not regain 100% of their capacity. Perhaps only about 80% of the capacity is recoverable, regardless of the treatment. If the recommended design flow rate exceeds 80% of the maximum flow allowed on the filter, the filter may be undersized. Facilities with cartridge filters are recommended to have EQUIPMENT on-site to clean the cartridges. This includes a basin or tub large enough to immerse the entire cartridge. Water from the cleaning and soaking process must be discharged to the sanitary sewer. Proper cleaning is critical. Failure to clean the cartridge properly can lead to disease OUTBREAKS. # How to Clean Cartridge Filters: 1. Rinse Thoroughly: Rinse the cartridge of as much dirt and debris as possible by washing inside and out with a garden hose and spray nozzle. DO NOT use a pressure washer. High flow/pressure can drive dirt into the interior and permanently damage the cartridge. It can also aerosolize pathogens in the filter. # Degrease: Cartridge filters need to be degreased each time they are cleaned. Body oil, suntan oil, cosmetics, hair products, and/or algae and biofilms can form a greasy coating on the filter pleats, which will clog the pores and reduce the filter capacity. Soak the cartridge overnight in one of the following: • Filter cleaner/degreaser OR • A solution of water with 1 cup (236.6 g) of TSP (trisodium phosphate) OR • One cup (236.6 g) of automatic dishwashing detergent per 5 gallons (3.8 L) of water. Never use muriatic acid or products with acid in them before degreasing. Acid may permanently set the grease and ruin the cartridge. Rinse thoroughly. for cooking at this temperature and time parameter-are expected to have a low level of internal CONTAMINATION. The parameters are expected to provide destruction of the surface contaminants on these FOODS. (1991), andFOOD Code (2013). ANSI/NSF 3-2017, Commercial Spray-type Dishwashing and Glasswashing Machines, and the VSP 2018 Operations Manual should be consulted for recommended construction and operational parameters. # Recommended Evaluation Equipment The following EQUIPMENT to conduct WAREWASHING evaluations is recommended: • Thermocouple or thermistor TEMPERATURE-MEASURING DEVICE for warewasher operational temperatures. • Maximum registering TEMPERATURE-MEASURING DEVICE or temperature-sensitive tapes for verifying hot water warewasher final rinse temperature, 73°C (160°F). • Optional: Calibrated melting temperature wax crayons with melt points set at 82°C (180°F) and another at 91°C (195°F). • Pressure gauge, as applicable, for determining in-line pressure of hot water at injection point of warewasher in the range of 100-170 kilopascals (15-25 pounds per square inch). • Chemical test kits for different chemical SANITIZER types used on the vessel. • Flashlight. • Tape measure. • Watch or stopwatch. # Calibration Calibrate TEMPERATURE-MEASURING DEVICES and pressure gauges against standards to ensure reliable warewasher evaluations. Maintain chemical test kits and temperature sensitive tapes as specified by their manufacturers to ensure accuracy. # Mercury Spills Use mercury-filled maximum registering TEMPERATURE-MEASURING DEVICES carefully during the evaluations; these devices are subject to breakage. If they break, clean up thoroughly before WAREWASHING operations resume. • If the data plate indicates a flow pressure, the machine must have a gauge or a gauge valve to measure it. • If the data plate does not indicate a flow pressure, the machine is not required to have a gauge or a gauge valve. # Temperature Requirements Temperatures stated on the warewash machine data plate are considered minimums unless a specified range is given. # Conform to ANSI/NSF 3-1996 The warewash machine temperatures must conform to those specified in these guidelines for the specific type of machine. For those manufactured to different temperature standards, evidence must be furnished that they at least conform to the minimum equivalent standards of ANSI/NSF 3-2008, Commercial Spray-type Dishwashing and Glasswashing Machines. # Evaluation Procedures # Operational Evaluation The VSP EHO will evaluate the WAREWASHING as follows: • Dishes properly prescraped and racked. • Machine prewash scrap trays clear of excessive soil and debris. • Curtains and baffles on conveyor type machines intact and in their proper position. • Conveyor speed and cycle times set according to manufacturer's specifications. • Overflow standpipe installed and not blocked or leaking. • Wash and rinse nozzles properly aligned and providing a uniform spray pattern. • Wash and rinse nozzles clear of obstructions. • Wash and rinse manifolds in good repair, properly installed in the machine, and end caps installed. • Heating elements used in tanks free of mineral or other deposits. • Rinse supply line strainer clear of debris. • Wash and rinse tanks and final rinse manifold TEMPERATURE-MEASURING DEVICES accurate to ± 1.5 °C (± 3 °F). • Pressure regulator functioning properly. • Flow pressure within the range specified on the data plate and between 34.5-207 kilopascals (5-30 pounds per square inch). # Temperature Evaluation # Manufacturer's Instructions Install and operate the machine in accordance to the manufacturer's instructions. # Warmup Run the machine through at least two complete cycles before testing unless it has been operating just before the evaluation. On conveyor machines, run at least two racks through the machine. # Additional Warmup When minimum temperatures are not indicated on machinemounted TEMPERATURE-MEASURING DEVICES, additional pre-evaluation cycles may be run to determine if higher temperatures are possible. # Tank Thermometer Calibration Take temperatures of the wash water and pumped rinse directly from the tanks of the machines and compare them against the machine-mounted TEMPERATURE-MEASURING DEVICES. If possible, place the evaluation TEMPERATURE-MEASURING DEVICE probe in the tank near the machine-mounted TEMPERATURE-MEASURING DEVICE probe. # Sanitizing Rinse TMDs Use a maximum registering TEMPERATURE-MEASURING DEVICE, remote sensing thermocouple, or nonreversible thermolabels such as paper TEMPERATURE-MEASURING DEVICES that turn from silver to black or similar device to confirm the effectiveness of heat SANITIZATION. # Rinse Exposure Attach the maximum registering TEMPERATURE-MEASURING DEVICE in a vertical position in a rack that is exposed to the final sanitizing rinse spray at the approximate level of a plate. Attach nonreversible thermolabels to the center of a dry ceramic plate. # High Wash/Rinse Temperature Factor Factor the effect of the temperatures of the wash water and pumped rinse into the evaluation if tank thermometers indicate they are above 71°C (160°F). If the wash and or rinse tank temperatures are greater than or equal to 71°C (160°F), verify the final sanitizing rinse temperature using one of the methods in section 13.16.3.2.9 or another ISOLATION method where a rapid response TEMPERATURE-MEASURING DEVICE is held at plate level in the final sanitizing rinse spray for at least 8 seconds. The maximum-registering TEMPERATURE-MEASURING DEVICE may also be checked at the end of each part of the cycle to verify that the wash and rinse temperatures have not been in excess of 71°C (160°F). # Effective Sanitation Evaluate effective SANITIZATION by noting that in a mechanical operation, the temperature of the fresh hot water sanitizing rinse as it enters the manifold must not be more than 90°C (194°F) or less than • 74°C (165°F) for a stationary rack, single-temperature machine. • 82°C (180°F) for all other machines. • 71°C (160°F) at the UTENSIL surface, as measured by an irreversible registering temperature indicator. # Indirect Methods The final rinse spray temperature may be indirectly evaluated by using a nonreversible thermolabel attached to the manifold or final rinse spray arm near the hub or by using calibrated melting temperature wax crayons. Make a mark on a dry portion of the final sanitizing rinse manifold or supply line with a crayon that melts at 82°C (180°F) and another that melts at 91°C (195°F). Another acceptable test to establish the final sanitizing rinse temperature (manifold) is to dry the final sanitizing rinse spray arm as near to the manifold entry into the machine as possible and affix an 82°C (180°F) thermolabel. The thermolabel should be left in place through one full warewash cycle. There may be slight temperature decreases at positions distant from the manifold entry into the machine. A third method is to attach a maximum registering thermometer to the end of a rod and hold the thermometer in the final rinse spray at plate level for 8 seconds. After any of the three of the indirect method tests above, assess the spray pattern from the final rinse spray arm to ensure that the spray pattern is effective. For a stationary rack machine, the final rinse temperature can be evaluated by running the machine with a maximum registering thermometer at plate level. Stop the machine at the end of the wash cycle to check the temperature, and again at the end of the final rinse cycle. # Chemical Sanitizing Evaluation Obtain sample at the end of the final chemical sanitizing rinse cycle and use a SANITIZER test kit to confirm the SANITIZER level is at the minimum specified on machine data plate and in these guidelines. # Routine Monitoring # Periodic Detailed Evaluations Proper WAREWASHING is critical to protecting the health of a vessel's passengers. The procedures provided in this annex may assist the vessel crew in periodically verifying the proper operation of its WAREWASHING machines. Following the manufacturer's recommendations for maintenance and operation will ensure the WAREWASHING machines continue to meet the criteria of these guidelines and standards of ANSI/NSF 3-1996, Commercial Spray-type Dishwashing and Glasswashing Machines. # Startup Evaluations During each WAREWASHING machine's startup, the proper setup and operation of the EQUIPMENT should be verified with basic checks. These include checks of the tank, manifold, and curtain assemblies to ensure they are properly installed. Proper operating temperatures should be verified to meet the minimum required temperatures during the startup. # Routine Operation Evaluations Periodic operation and temperature checks by the WAREWASHING crew during the WAREWASHING time should detect problems soon after they occur. The person removing the clean and sanitized ware must examine each piece to determine if it is clean. Periodic management checks of the WAREWASHING process during operation verify that the machines are operating properly and the UTENSILS processed are indeed clean and sanitized. # Simple Records Simple records can assist in the warewash machine monitoring process. A review of these records can ensure proper monitoring is being conducted and assist in determining a gradual or severe malfunction of the machine. # Inspection Report # Report Form A copy of the VSP Inspection Report form follows on the next page. During the implementation of the VSP 2018 Operations Manual, an electronic version of this form will also be used. Copies of the electronic version will be returned to the cruise line by email. # 13.18 Corrective-Action Statement 13.18.1 Introduction 13.18.1.1 Purpose VSP established a procedure for postinspection reporting of corrective actions to encourage the correction of deficiencies noted during an inspection. A signed corrective action statement will not affect the inspection score. # Critical Item Monitoring The corrective-action statement, particularly for CRITICAL ITEMS, should include a management monitoring plan to ensure that the procedure or process that was out of control will be monitored and controlled in the future. The public health goal of the inspection is to prevent the recurrence of the critical deficiency in the specific instance where it was found and generally in future similar operations aboard the vessel. # Publicly Available The corrective-action statement will be appended to the final inspection report for future reference and public distribution via the VSP website. # Email Submission The corrective action statement may be submitted to VSP by electronic mail. Please send the statement to [email protected]; include the vessel name, corrective-action statement, and inspection date in the message subject line. Submission as an attached word processing format file is preferable. # Mail Submission The corrective-action statement may also be mailed to the following: # Introduction Every vessel that has a foreign itinerary and carries 13 or more passengers is subject to twice-yearly inspections and, when necessary, to reinspection by the Centers for Disease Control and Prevention's VSP. To ensure a clean and healthful environment, cruise ships must meet the criteria established by VSP. The score and the complete report for each inspection are published on the VSP website (www.cdc.gov/nceh/vsp). The ship's level of sanitation is acceptable to VSP if its score on the inspection is 86 or higher. # Online Information The VSP website has a searchable database of inspection report summaries and lists. The complete inspection report information is also retrievable. Lists available on the VSP website include the following: • Advanced Cruise Ship Inspection Search. • Green Sheet Report. • Cruise Ship Inspection Score 100. • VARIANCES by Section. These lists show the data by • Ship name. • Cruise line. • Inspection date. • Score (all scores, scores of 86 or higher [satisfactory scores], and scores of 85 or lower [unsatisfactory scores]). Further information can be obtained on a particular ship, including all scores for that ship and an inspection report preview. The VSP website also provides the Inspection Detail Report for each ship inspection. This report provides a categorical review of the deficiencies noted along with the number of points deducted for that category and the numerical score for the inspection of a particular ship. Details of the inspection with the specific deficiencies and recommendations are also available from this page. Inspection report data are also searchable from the VSP database for the following search categories: • Ship name. • Cruise line. • Inspection date. • Most recent date. • All dates. • Range of dates. • Score (all scores, scores of 86 or higher [satisfactory scores], and scores of 85 or lower [unsatisfactory scores]). # Contact Information Further information on VSP, inspection results, and vessels' corrective action statements may be obtained • On the VSP website (www.cdc.gov/nceh/vsp • Through email ([email protected] • By telephone (800-323-2132). • By fax (770-488-4127). ). ).	None	None
5f367dc013f53fdf33f275a4e9af70aacd6faf20	cdc	None	# (a) Preplacement medical examinations shall include at least: (1) Comprehensive medical and work histories with emphasis on skin conditions. (2) A complete physical examination giving special attention to the skin for evidence of dermatitis. (b) Periodic examinations shall be made available at a frequency to be determined by the responsible physician, but at least every 3 years. These examinations shall include at least: (1) Interim medical and work histories. (2) A physical examination as described for the preplacement examination. (c) During examinations, applicants or employees having medical conditions that could be directly or indirectly aggravated by exposure to benzoyl peroxide or formulations containing benzoyl peroxide shall be counseled on the increased risk of impairment to their health from working with these substances. (d) Initial medical examinations shall be made available to all employees within 6 months of the promulgation of a standard based on these recommendat ions. (e) Pertinent medical records shall be maintained for all employees occupationally exposed to benzoyl peroxide. Such records shall be kept for at least 30 years after termination of employment. These records shall be made available to the designated aedical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee or former employee. All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers. Illiterate workers and workers reading languages other than those used on labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on labels and signs. # (a) Containers All containers of benzoyl peroxide shall have a label containing the following information, in addition to such other information as may be required by other statutes, regulations, or ordinances or believed needed by the employer: First Aid: In case of eye contact, flush eyes thoroughly with copious amounts of water. Consult a physician. State % of benzoyl peroxide in product. In addition to the above information, labels for containers of pure benzoyl peroxide shall add the following: Do not add to hot materials; do not grind or subject to friction or shock-explosive decomposition may result. (2) Labels for containers of pastes containing benzoyl peroxide shall add the following: Do not freeze. (3) Labels for containers of wet benzoyl peroxide shall add the following: Keep container tightly closed to prevent drying out. # (b) Work Areas Areas where benzoyl peroxide is used, manufactured, or stored shall be posted with a sign reading: The employer shall provide chemical safety goggles, glasses, or face shields (8-inch minimum) with goggles and shall ensure that employees wear them during any operation in which benzoyl peroxide may enter the eyes. The applicable regulation is 29 CFR 1910.133. BENZOYL The employer shall provide fire-resistant clothing treated with an antistatic agent to employees using or handling pure benzoyl peroxide. Additional protective clothing shall be worn when needed. The employer shall ensure that precautions are taken to protect personnel who launder clothing contaminated with pure benzoyl peroxide. (3) Protective gloves and aprons shall be worn during operations where pure benzoyl peroxide is handled and may contact the skin. (4) Measures, such as the wearing of conductive shoes, designed to dissipate static electricity should be required by the employer hen large amounts of pure benzoyl peroxide are handled. The employer shall ensure that all personal protective devices, including conductive shoes, and conductive flooring are inspected regularly, cleaned, and maintained in working condition. # (b) Respiratory Protection Engineering controls shall be used when needed to maintain airborne benzoyl peroxide concentrations at or below the recommended environmental limit. Compliance with the permissible exposure limit by the use of respirators is permitted only during installation and testing of engineering controls, during performance of nonroutine maintenance or repair, when working in confined spaces, or during emergencies. When use of a respirator is permitted, it shall be selected and used in accordance with the following requirements: (1) To determine the type of respirator to be used, the employer shall measure, when possible, the concentrations of airborne benzoyl peroxide in the workplace initially and thereafter whenever control, process, operation, worksite, or climatic changes occur that are likely to increase the concentration of airborne benzoyl peroxide. This provision does not apply when only atmosphere-supplying positive pressure respirators are used. The employer shall ensure that no employee is exposed to benzoyl peroxide above the recommended limit because of improper respirator selection, fit, use, or maintenance. The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employees properly use the respirators provided when wearing respirators is required. The respiratory protective devices provided in conformance with Table 1-1 shall be those approved by NIOSH and the Mining Enforcement and Safety Administration (MESA) as specified under the provisions of 30 CFR 11. (5) Respirators specified for use in higher concentrations of airborne benzoyl peroxide may be used in atmospheres with lower concentrations. When an emergency involving benzoyl peroxide requires evacuation, the employees shall leave the area immediately, stopping to put on respirators only if absolutely necessary. (7) Respirators shall be easily accessible, and employees shall be informed of their location. 1,000 mg/cu m or less Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure mode or with full facepiece, helmet, or hood operated in continuous-flow mode Greater than 1,000 mg/cu m or entry into area of unknown concentration (1) Self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode (2) Combination respirator which includes a Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and an auxiliary self-contained breath ing apparatus operated in pressure-demand or other positive pressure mode Benzoyl peroxide is a strong oxidizer and should not come in contact with oxidizable materials. Some cartridges and canisters may contain activated charcoal and shall not be used to provide protection against benzoyl per oxide. Only nonoxidizable sorbents are allowed. (a) The employer shall ensure that each employee working in areas where bçnzoyl peroxide is used, handled, manufactured, or stored is informed at the beginning of employment, and at least annually thereafter, of the presence of benzoyl peroxide in the workplace, including the trade name substances, if any, that contain benzoyl peroxide, the hazards, relevant symptoms, appropriate emergency procedures, and proper conditions and precautions for the safe use of benzoyl peroxide. to the employee of undergoing these examinations. Each employee shall be advised of pertinent information, including that required for the material safety data sheet prescribed by paragraph (c) of this section, which shall be kept on file and shall be readily accessible to employees at all places of employment where there is occupational exposure to benzoyl peroxide. Engineering controls, such as process enclosure or local exhaust ventilation, shall be used where needed to maintain benzoyl peroxide concentrations at or within the limit recommended in Section 1(a). All engineering controls shall be sparkproof. Ventilation systems shall be designed to prevent recirculation of benzoyl peroxide into the workplaces. Dead airspaces that would allow accumulation of benzoyl peroxide shall be minimized. Consideration must be given to applicable local, state, and federal air pollution regulations in designing exhaust ventilation systems discharging into outside air so that they do not constitute a hazard to the employees or to the general public. Ventilation systems shall be subject to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by airflow measurements taken at least every 3 months. (b) Storage, Handling, and General Work Practices (1) Containers of benzoyl peroxide shall be kept tightly closed at all times. Containers shall be handled carefully to minimize accidental breakage or spillage and stored in a cool, well-ventilated area away from heat, combustible substances, acids, and oxidizers. No screw-top or metal containers may be used for pure benzoyl peroxide. (2) Employers shall ensure that shipping containers of benzoyl peroxide are not reused unless they have been properly cleaned. (3) Employers shall take precautions to minimize benzoyl peroxide contact with the skin and eyes of employees. Equipment, walls, and floors should be kept clean to limit employee exposure. Section 6 -Work Practices (4) Before maintenance work, sources of benzoyl peroxide shall be eliminated to the maximum extent feasible. If concentrations of airborne benzoyl peroxide cannot be maintained at or below the limit recommended in Section 1(a), respiratory protective equipment as described in Section 4 shall be used during such maintenance work. (5) Sources of ignition, such as smoking materials and open flames, shall be prohibited in areas where benzoyl peroxide is used, handled, manufactured, or stored. (6) All spills of benzoyl peroxide shall be wetted down and cleaned up immediately. Spills of pure benzoyl peroxide and solid formulations containing benzoyl peroxide shall be thoroughly wetted down or mixed with water-wetted vermiculite, perlite, sand, clay, or other suitable material before being placed in closed containers made of polyethylene or other suitable material and used exclusively for benzoyl peroxide wastes. Transportation and use of benzoyl peroxide shall comply with all applicable federal, state, and local regulations. (c) Waste Disposal (1) Pure benzoyl peroxide may be burned if local, state, and federal regulations permit. It shall be mixed with an inert material, such as vermiculite, and only 1 pound or less shall be burned at one time. The material shall be placed in a trench and ignited from a distance. (2) Employers shall ensure that no pure benzoyl peroxide is flushed into sewage systems. (3) Water slurries of benzoyl peroxide wastes and dry, solid, or powder formulations shall be mixed with 4-10 times their weight of a 10% aqueous sodium hydroxide solution and neutralized before being flushed into any sewage system. (d) Vessel Entry (1) Entry into confined spaces, such as tanks, pits, tank cars, and process vessels which have contained benzoyl peroxide, shall be controlled by a permit system. Permits shall be signed by an authorized employer representative, certifying that preparation of the confined space, precautionary measures, and personal protective equipment are adequate and that prescribed procedures will be followed. (2) Confined spaces which have contained benzoyl peroxide shall be thoroughly ventilated, cleaned, washed, inspected, and tested for oxygen deficiency and for the presence of benzoyl peroxide and other contaminants before entry. (3) All efforts shall be made to prevent release of benzoyl peroxide into the confined space while work is in progress. (4) Confined spaces shall be ventilated while work is in progress to keep concentrations of airborne benzoyl peroxide at or below the recommended environmental limit and to prevent oxygen deficiency. (5) Individuals entering confined spaces where they may be exposed to benzoyl peroxide shall wear respirators as outlined in Section 4(b) and lifelines tended by another employee outside the space who shall also be equipped with the necessary protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephones, radio, or other suitable means) with the employee inside the confined or enclosed space shall be maintained by the standby person. The third employee, equipped to aid the other two if necessary, shall have general surveillance of their activities. (6) Hatch openings shall be large enough for two people to enter or exit simultaneously. # (e) Emergency Procedures For all work areas where there is a reasonable potential for emergencies involving benzoyl peroxide, employers shall formulate in advance the procedures specified below and any others appropriate for the specific operation or process and shall instruct employees in their implementation. The employees shall be trained by periodic drills that simulate emergencies in a work situation. These drills shall involve evacuation procedures with a method of accounting for all personnel present in case of fire or explosion, handling of spills and leaks, location of remote controls for sprinkler systems, location and use of emergency water supplies and equipment and shutoff valves, and entry procedures for restricted areas. Procedures and emergency phone numbers for obtaining firefighting assistance, emergency medical care, and transportation of injured personnel shall be included. (2) Approved eye, skin, and respiratory protective devices as specified in Section 4 shall be used by personnel essential to emergency operations. (3) Employees not essential to emergency operations shall be evacuated from hazardous areas where benzoyl peroxide inhalation, skin or eye contact, or explosions may occur. The perimeters of these areas shall be delineated, posted, and secured. (b) If it has been determined that the concentration of benzoyl peroxide exceeds or may exceed the limit recommended in Section la, then the employer shall fulfill the following requirements: (1) A program of personal monitoring shall be instituted to identify and measure, or permit calculation of, the exposure of each employee occupationally exposed to airborne benzoyl peroxide. Source and area monitoring may be used to supplement personal monitoring. (2) In all personal monitoring, samples representative of the exposure to airborne benzoyl peroxide in the breathing zone of the employee shall be collected. (3) For each determination of the TWA concentration, a sufficient number of samples shall be taken to characterize employee exposure during each work shift. Variations in the employee's work schedule, location, or duties and changes in production schedules shall be considered in deciding when samples are to be collected. # III. BIOLOGIC EFFECTS OF EXPOSURE # Extent of Exposure Benzoyl peroxide, (C6H5C0)202, also called dibenzoyl peroxide, is a rhombic crystalline solid at room temperature . Benzoyl peroxide is a flammable, solid, diacyl organic peroxide, which may decompose explosively if subjected to excessive heat, friction, or sudden shock . If benzoyl peroxide is exposed to temperatures of 75-80 C for prolonged periods, it becomes unstable and may spontaneously decompose . This type of sudden decomposition, a deflagration, is the rapid spreading of fire through a mass of reactive material . This decomposition is accompanied by a 200-fold increase in volume and yields a dense white smoke consisting of benzoic acid, phenyl benzoate, terphenyls, biphenyls, benzene, and carbon dioxide . The resulting biphenyls promote the further decomposition of benzoyl peroxide into products which can catch fire and ignite the remaining benzoyl peroxide. If this happens, or if the benzoyl peroxide itself ignites, a dense black smoke results . The peroxide reacts violently with various organic and inorganic acids, amines, alcohols, metallic naphthanates, and other chemicals that are easily oxidized. Benzoyl peroxide also reacts violently with polymerization accelerators . The presence of small quantities of water diminishes some of the hazardous properties of benzoyl peroxide . During a series of tests on the ease of ignition of pure benzoyl peroxide and benzoyl peroxide with various proportions of water, pure benzoyl peroxide was shown to ignite violently with a loud noise, but benzoyl peroxide containing 5% water did not ignite at all. It was also observed that during this ignition test it did not make any difference whether the total moisture content of the sample was equally divided between each granule or concentrated in 10-20% of the granules, as long as those granules were uniformly dispersed throughout the sample. Additional chemical and physical properties of benzoyl peroxide are presented in Table XIV Benzoyl peroxide is synthesized commercially by a reaction of benzoyl chloride, sodium hydroxide, and hydrogen peroxide . Excess water is removed to obtain pure benzoyl peroxide; the trace impurities remaining are benzoic acid and water. Water, plasticizers, corn starch, or other diluents are added to make the numerous commercial products containing benzoyl peroxide. Benzoyl peroxide has been produced commercially in the United States since 1927 . By 1954, its yearly production was 1,768,000 pounds ; 8,829,000 pounds, 9,092,000 pounds, and 7,885,000 pounds were produced in 1973 , 1974 , and 1975 , respectively. Since benzoyl peroxide is a good source of free radicals, it is used in a number of industrial processes, particularly in the manufacture of plastics . Benzoyl peroxide is a curing agent for silicone rubber , a source of free radicals in the resin cements used in dentistry , automobile body putty , and roof bolting systems in the mining industry , and an initiator in the synthesis of polyvinyl chloride . It is also a component of flour and cheese bleaches . In the early 1900's, benzoyl peroxide was used to bleach edible oils, but this practice is now rare . In the past, textiles and paper were also treated with it . In medicine, it now is used in the treatment of acne and of decubitus ulcers (bed sores) . Formerly, it was applied as an aid in the treatment of poison ivy . NIOSH estimates that 25,000 workers in the United States are potentially exposed to benzoyl peroxide or its formulations. Occupations involving possible exposure to benzoyl peroxide are listed in Table XIV-2. # Historical Reports Little was known about benzoyl peroxide until the end of the 19th century. In the Encyclopedia of Chemical Technology, Hooft noted that Brodie synthesized benzoyl peroxide in 1858. One of the earliest references to benzoyl peroxide appeared in 1899 when Nencki and Zaleski reported that it was converted to benzoic acid in the intestines of dogs. As early as 1921, benzoyl peroxide was used in Germany as a fixing agent in light microscopy . It was also used at that time as an antiseptic and local anesthetic in the treatment of burns and ulcers, as reported by Farmer . Benzoyl peroxide had previously been taken internally, but that practice was discontinued because of its poisonous action on the blood, which was not specifically described. However, in 1964, Tiunov noted that Smirnova, using unspecified chemical methods, found that benzoyl peroxide had almost no hemolytic action. In 1930, Lamson stated that powdered benzoyl peroxide was a theoretically ideal treatment for skin lesions caused by poison ivy because it reduced the spread of the rash and relieved itching. The flammability hazard of benzoyl peroxide treatment was not mentioned in the literature until 1931 when it was reported that a man whose poison ivy rash was being treated with benzoyl peroxide was injured by the ignition of bandages that were covering the powdered benzoyl peroxide on his hands . When the bandages were ignited by a lighted cigarette, the benzoyl peroxide exploded, and the skin and several muscles of his right hand were destroyed. The author retracted his recommendation of powdered benzoyl peroxide as a useful therapeutic agent, emphasizing its explosive properties; he recommended, instead, an ointment of an unspecified concentration of benzoyl peroxide in lubricating jelly, which he considered neither explosive nor extremely flammable. No references have been found indicating further use of benzoyl peroxide for the treatment of poison ivy. # Effects on Humans The effects of occupational exposure to and treatment with benzoyl given which defined the efficiency of standard impingers containing water for collecting benzoyl peroxide and alum, and there was insufficient analytical information to assess the reliability of the determinations. In addition, it was noted that the proportions of benzoyl peroxide to alum were extremely variable and did not reflect the proportion of the two chemicals in the flour bleach being processed. (1) polyethylene glycol, (2) polyethylene glycol containing 1% sulfur, polyethylene glycol containing 10% benzoyl peroxide, and polyethylene glycol containing 1% sulfur and 10% benzoyl peroxide . All the subjects reacted to the benzoyl peroxide whether or not sulfur was present, but none reacted to the polyethylene glycol or sulfur. In 1973, Ede discussed a double-blind study of 196 acne patients who were randomly divided into 4 groups. Three acne lotions and a placebo were tested. The lotions contained 5.5% benzoyl peroxide, 0.25% chlorohydroxyquinollne, and 0.5% hydrocortisone; 5.5% benzoyl peroxide and 0.25% chlorohydroxyquinollne; or 5.5% benzoyl peroxide. The placebo contained only the base lotion. The lotion was applied to affected areas 1 to 4 times daily for 4 weeks; however, the mean number of applications/day for the groups ranged from 2,2 to 2.5. The lotion was left on the skin for at least 3-4 hours. None of the patients exhibited any skin sensitivity to the lotions containing benzoyl peroxide at the end of the 4 weeks; however, 10 patients dropped out of the study for unspecified reasons. The following laboratory tests were performed during the study on the blood and urine of 20 of the patients, 10 men and 10 women, to determine whether there were any systemic effects of the lotions: calcium, inorganic phosphorus, glucose, blood urea nitrogen, uric acid, cholesterol, total protein, albumin, and total bilirubin concentrations; activities of alkaline phosphatase, lactate dehydrogenase, and serum glutamic-oxaloacetic transaminase; complete blood count (hemoglobin, hematocrit, RBC, WBC with differential count) and urinalysis (specific gravity, pH, color, appearance, sugar, microscopic examination, albumin, and acetone). The results were within the normal ranges and indicated no systemic effects from any of the lotions. # Bloom , in 1975, reported that welders employed in the manufacture of diesel locomotives were exposed to a plastic body filler made of a talc-polyester resin and benzoyl peroxide. Two of four welders who were interviewed thought that the coughing they experienced during the day was caused by exposure to welding fumes and to plastic body filler dust. There was no evidence of skin irritation or sensitization. # A NIOSH Health Hazard Evaluation Determination discussed by Kingsley , indicated that telephone repair workers were exposed to a styrene hardener containing 50% benzoyl peroxide and 50% butyl benzoyl phthalate when new and replacement telephone cables were installed. A worker who was wearing disposable gloves would add the hardener to the polyester, manually knead the mass until it was the right consistency, and drop it down into a vault where another gloved worker would shape the compound around the splice. Each such operation required two or three tubes of hardener and took about 30 minutes. One crew normally coated splices once or twice a week. The vaults were naturally ventilated through the manhole covers. The workers did not report adverse effects from using the compound. # Accidents Hazardous properties of benzoyl peroxide, such as explosion and flammability, have resulted in accidents and serious injuries or death. The following incidents demonstrate that injuries were usually caused by ignorance of the hazards or by negligent handling. Other accidents that did not produce injury are discussed in Chapter V. Twelve pounds of pure benzoyl peroxide being added through a stainless steel funnel into a polymerization kettle exploded, killing the operator . There were three possible reasons for thè explosion: the funnel may have become heated during the operation, so that excessive heat may have caused the peroxide to explode; (2) the peroxide may have become contaminated with residual vinyl acetate from the polymerization reaction; or (3) a static discharge may have occurred. In another case, an employee escaped serious injury when a flash fire erupted in a 1-pound container of benzoyl peroxide and covered his safety glasses with melted benzoyl peroxide . He was using a glass spatula to transfer benzoyl peroxide from the container to a laboratory scale . As the spatula, which had just been cleaned and dried, was inserted into the container, the benzoyl peroxide burst into flame. The account of the accident indicated that contamination of the benzoyl peroxide may have caused the fire. It is also possible that the friction from the insertion of the spatula may have started it. In still another case, the owner of a plant that manufactured benzoyl peroxide sustained second degree burns from a fire started by an unknown quantity of benzoyl peroxide dust exposed to an arcing electric light switch . The fire generated smoke and chemical fumes; eventually, there was an explosion. Lappin found that a laboratory worker received hand injuries and lacerations when benzoyl peroxide in a 4-ounce, brown-glass container exploded as the plastic screwcap was being removed. The author thought that some benzoyl peroxide, along with other organic dust present in the laboratory, was caught in the threads and, as the cap was unscrewed, the friction caused the top layer of peroxide in the bottle to explode. The explosiveness of benzoyl peroxide was further illustrated when several thousand pounds of the compound exploded in a truck, causing severe property damage within a radius of several city blocks and injuring four people, one seriously . A fire was seen seconds before the explosion occurred, but the exact cause of the accident was unknown. Investigators speculated that perhaps other chemicals had come in contact with the cargo of benzoyl peroxide or that an all-day exposure to hot sun had caused drying of the benzoyl peroxide. Another possibility was that the truck might have been bumped, dislodging the cargo. # Animal Toxicity There are few data on the effects of benzoyl peroxide on animals. The effects of inhalation, ingestion, skin painting, and injection of benzoyl peroxide have been examined. Two eye irritation tests with granular 78% benzoyl peroxide were conducted on eight albino rabbits by Wazeter and Goldenthal . Though not specified in the report, 78% benzoyl peroxide granules commonly consist of 22% water and benzoic acid. Sodium fluorescein was put into the eyes when they were examined under ultraviolet light so that corneal damage could be detected. The eyes were examined before treatment with benzoyl peroxide and periodically afterwards. In the one test, 111.4 mg of 78% benzoyl peroxide (0.1 ml measured by volume) was put in the cupped conjunctival sac of the right eye of each of five rabbits; the eyelid was held shut for 1 second. The left eyes served as controls. After 5 minutes, the test eyes were washed with a gentle stream of water, regulated to deliver 300 ml in 2 minutes. The corneas showed no ulceration or opacity after 1, 24, 48, or 72 hours or after 7 days . The irises appeared unaffected. The conjunctivae of two rabbits showed slight redness 1 hour and 24 hours after the washing, but this disappeared in 48 hours. Three of five rabbits exhibited conjunctival edema 1 hour after the washing, but this was not apparent at 24 hours. The authors concluded that, under these test In another eye irritation test , 120.7 mg of 78% benzoyl peroxide was placed in the cupped conjunctival sac of the right eye of each of three rabbits where it remained for 24 hours; the left eyes were controls. After 24 hours, the benzoyl peroxide was washed out with 300 ml of water for 2 minutes. The eyes were examined under ultraviolet light as described in the first test. The irises appeared normal after 1, 24, 48, and 72 hours and after 7 days. The conjunctivae of the rabbits exhibited various degrees of redness and conjunctival edema at 1, 24, 48, and 72 hours, but all adverse effects disappeared in 7 days. One rabbit had blanched conjunctival tissue at 1 hour, but normal color had returned within 24 hours. Examinations under ultraviolet light showed corneal opacity in the three rabbits after 24 hours but no corneal opacities at 48 hours. The only corneal damage in this experiment was revealed in one rabbit by the eye examinations done at 72 hours, and it had disappeared by the 7th day. Wazeter and Goldenthal concluded that benzoyl peroxide was neither irritating nor corrosive to the eyes of albino rabbits if it was washed out within 5 minutes after being placed in the conjunctival sac; however, if 78% benzoyl peroxide was not washed out until 24 hours later, it proved to be a strongly irritating substance. It was not considered corrosive because corneal opacity lasted less than 6 days. In a third experiment, Wazeter and Goldenthal tested the skin irritation potential of benzoyl peroxide on three male and three female New Zealand white rabbits. No control animals were mentioned. The hair was shaved from an area on the back of each rabbit, and the skin was then abraded with a scalpel blade. Five hundred milligrams of 78% benzoyl conditions, benzoyl peroxide was not irritating or corrosive to the eyes. peroxide was applied to each patch of skin and held in place for 4 hours with a gauze bandage. After 4 hours, the bandages were removed and the exposed areas washed with lukewarm water. The skin was examined for any injury or irritation from benzoyl peroxide at 4, 24, and 72 hours. The skin on the six rabbits appeared unaffected. The authors concluded that 78% benzoyl peroxide was neither a primary skin irritant nor a corrosive substance. Wazeter and Goldenthal also performed a short-term inhalation study on 10 male Spartan rats housed in groups of 2 or 3. The rats were exposed at an atmospheric concentration of 24.3 mg/liter of 78% benzoyl peroxide added to a 59.1-liter glass test chamber supplied by two Wright dust feeders with a regulated airflow. None of the rats died during the test or the subsequent 14-day observation period . The rats showed the following signs during the 4hour exposure period: eye squint, increased and decreased respiratory rates, difficulty in breathing, salivation, lacrimation, erythema (location unspecified), and an increase followed by a decrease in motor activity. All of the rats appeared normal at 24 and 48 hours. An unspecified number of rats exhibited signs of eye irritation consisting of corneal opacity and ulceration from the 5th to the 14th day. The authors concluded that 78% benzoyl peroxide was not highly toxic by the inhalation route of administration under the conditions of the experiment. A short-term oral toxicity test was performed by Wazeter and Goldenthal with 78% benzoyl peroxide in water on five male Spartan albino rats. Each rat received one 5,000 mg/kg dose of 78% benzoyl peroxide suspended in corn oil. The rats took food and water ad libitum and were maintained in temperature-and humidity-controlled quarters during the 14-day study. No control animals were reported. Body weights of all the rats were recorded initially and at 14 days. None of the rats died during the study, and all exhibited normal weight gain. Under the test conditions, 78% benzoyl peroxide was not toxic by the oral route of administration. In 1958, Kuchle described an experiment in which 15 organic peroxides, including benzoyl peroxide, were tested for their effects on rabbits' eyes. A "lentil-sized" amount of an undefined paste containing 50% benzoyl peroxide was placed in the conjunctival sacs of each of several rabbits, and unspecified amounts of a 93% benzoyl peroxide powder were placed in the conjunctival sacs of several other rabbits. No controls were mentioned. After 1 minute, the eyes were rinsed with tapwater, and any solid residues were removed with a cottovi swab. The eyes were then examined after 20 minutes, after 24 hours, then every other day for 1 week, and finally twice a week for 6 weeks. Neither form of benzoyl peroxide was considered to have had harmful effects on the rabbits' eyes; no evidence of burning or irritation was observed, and the corneas of the test animals were clear and had no opacities. Radomski et al published, in 1948, a study in which three dogs were given a diet containing benzoyl peroxide-treated flour for 6 weeks. The purpose of the experiment was to determine the toxicity of candidate replacements, including benzoyl peroxide, for agene, an improving agent used to treat flour, which consisted of 1% nitrogen trichloride in air saturated with water vapor. Benzoyl peroxide was added to the flour (1 oz benzoyl peroxide/100 pounds flour or 0.625 g/kg). A short time before it was fed to the dogs, the mixture was steamed for 90 minutes, and nutrients were added to it. The nutritionally balanced diet contained 71.6% treated flour on a dry-weight basis. Because the authors did not state the amount of food consumed by each dog, the actual intake of benzoyl peroxide is unknown. The effects of steaming on benzoyl peroxide were not considered. The authors stated that, since the 1920's, canine hysteria, sometimes called running fits, had been observed in dogs that had eaten agene-treated flour. No canine hysteria was observed in the dogs given the diet containing benzoyl peroxide, and, unlike dogs fed agene-treated flour, they behaved in a normal manner. In 1949, Arnold described a study in which dogs were provided with a diet in which flour had been treated with 0.8 g of benzoyl peroxide/100 pounds of flour (0.02 g/kg). Chlorine at 20 g/100 pounds (0.44 g/kg), ammonium persulfate at 15 g/100 pounds (0.33 g/kg), and potassium bromate at 5 g/100 pounds (0.11 g/kg) were also used to treat the flour; the amounts were greater than those used commercially in flour bleaching. The diet contained about 80% treated flour on a dry-weight basis. This diet and other experimental diets were given intermittently to six dogs for periods ranging from 21 to 38 days with intervening times of 3-16 days. The dogs were observed for canine hysteria, but it was not seen in those dogs fed benzoyl peroxide-treated flour. One group of investigators attempted to determine the oral LD50 of benzoyl peroxide in rats. Groups of two fasted rats each were given oral doses of benzoyl peroxide placed on a small amount of pea soup concentrate at 200, 400, and 950 mg/kg. None died. One of the rats that received 400 mg/kg had some vasodilatation, and one that received 950 mg/kg showed slight muscular weakness. The investigators concluded that the oral LD50 of benzoyl peroxide in rats is greater than 950 mg/kg. Skin irritation by benzoyl peroxide in an unspecified number of guinea pigs was also tested . Patches of skin were chemically depilated, and pure benzoyl peroxide, in doses ranging from 0.25 to 1.0 g/kg, was held against the depilated skin under patches for 24 hours. The skin under the benzoyl peroxide was examined for any irritation or other injury. Slight erythema with some delayed scarring of the epidermis resulted. There were no deaths. A similar test was run on guinea pigs with a 10% solution of benzoyl peroxide in propylene glycol. The doses ranged from 5 to 20 ml/kg. Only slight erythema was observed; no deaths occurred. An inhalation test also described in this study showed that an unspecified number of rats had no observable ill effects after being exposed to airborne benzoyl peroxide at an unspecified concentration for 3 hours. reported the results of a series of tests to determine the effects of benzoyl peroxide incorporated in the diet or administered by subcutaneous injection or by skin painting on rats and mice. Each test lasted 120 weeks for rats and 80 weeks for mice; moribund animals were killed during the study. The age and weight of the animals at the start of the experiment were not reported. Three experimental groups, each composed of 25 male and 25 female rats and 25 male and 25 female mice, were given nutritionally balanced diets of wholemeal flour that was treated with a commercial flour bleach consisting of 18% benzoyl peroxide, 78% calcium sulfate, and 4% magnesium carbonate . The control group contained the same number of animals as the experimental group but received untreated flour in their diet. The resulting benzoyl peroxide concentrations in the diet were 2,800 ppm, 280 ppm, and 28 ppm. These concentrations were selected because they were estimated to be 1,000, 100, and 10 times the normal human intake based on a yearly consumption of 200 pounds of flour/person. How much the animals actually ate was not reported, so exact dosages cannot be determined. Weight gains were recorded only for the rats during the first 16 months of the test. The rats whose diets contained flour treated with 2,800 ppm and 280 ppm benzoyl peroxide gained weight at a slower rate than the controls; the authors reported that this effect was not seen when the rats were caged singly in a diet preference test and an individual caging test . Seventeen mice that received the 280-ppm diet were killed accidentally, and a large number of rats and mice in the entire colony showed signs of infection, the nature of which was not specified by the investigators. For these reasons, the statistical significance of the results cannot be accurately evaluated. A diet preference test and an individual caging test were conducted with 10 pairs of male rat littermates to determine if any differences in weight gain in the animals were the result of greater food intake with 1 of the diets . One of each pair of the male littermates was given a flour-based diet containing benzoyl peroxide at 2,800 ppm, and the other was given the same diet without any benzoyl peroxide. Each rat was caged singly. The weight gain for the two groups was reported to be similar . After 30 weeks, each of the control rats had gained an average of 355 g and had consumed an average of 4,870 g of the supplied diet; the experimental group had gained 350 g each and eaten 4,902 g of the supplied diet. Rats caged singly tended to increase food intake slightly. On the basis of the diet preference test and the caging test, they concluded that concentrations of 1,000 and 100 times the normal human daily intake of benzoyl peroxide in the diets may have reduced the nutritional value of the diet; whereas the diet containing 10 times the normal daily intake of benzoyl peroxide did not. Sharratt et al provided diets of breadcrumbs made from flour treated with benzoyl peroxide to two groups of animals. The breadcrumbs given to 100 male and 100 female mice and 100 male and 100 female rats were prepared from bread made with flour containing benzoyl peroxide at 28 ppm. A group of 25 male and 25 female mice and 25 male and 25 female rats received a breadcrumb diet in which the flour had contained 2.8 ppm benzoyl peroxide. A control group of 100 male and 100 female mice and 100 male and 100 female rats was given a breadcrumb-based diet made from flour containing no benzoyl peroxide. Weight gains were reported only for the rats during the first 16 months of the test. There were no significant differences in the body weights of the rats given treated breadcrumbs made with treated flour and those of the controls except at 16 months, when the male rats that received the breadcrumbs made from flour containing 2.8 ppm of benzoyl peroxide weighed significantly more than the male control rats . The authors considered this of doubtful importance, since all rats began to gain and lose weight erratically because of chronic infection in the colony. In another part of the study , rats and mice were given a single subcutaneous injection of what was described as a freshly prepared 20% suspension of benzoyl peroxide in starch solution. The dose for 25 male and 25 female rats was 120 mg of benzoyl peroxide, and, for 25 male and 25 female mice, it was 50 mg of benzoyl peroxide. Control rats and mice, 25 of each sex of each species, were each given an injection of the starch solution. All the rats and mice were provided with a commercial pellet diet. Body weights were reported only for the rats for the first 16 months. There was no difference in the rate of weight gain in the rats administered benzoyl peroxide and in their controls. No tumors were found at the injection sites in any of the rats or mice; there was no significant difference in the tumor incidence in the experimental animals and in the controls. Sharratt et al also painted benzoyl peroxide on the back of the neck of 25 male and 25 female mice for 6 consecutive days. One drop (about 50 mg) of a freshly prepared 50% suspension of benzoyl peroxide in flour paste was applied to each animal. A similar number of control mice were painted with only the flour paste. Both groups of mice were fed a commercial pellet diet. No tumors appeared at the sites of painting, and there was no significant difference in the overall tumor incidence between the experimental animals and the controls. Sharratt et al also administered a multiple treatment to groups of 25 male and 25 female rats and 25 male and 25 female mice. There were no control animals for this part of the experiment. The rats and mice received the flour-based diet containing 2,800 ppm benzoyl peroxide and subcutaneous injections of benzoyl peroxide as in the previously described tests. The mice were also painted with flour paste containing benzoyl peroxide in the manner described previously. Body weights were reported only for the rats for the first 16 months. Except for a slight decrease at the 8th month, the weight gain of the rats in this multiple treatment group was not significantly different from that of the controls in the other tests described previously. No tumors were found at the sites of injection or painting. Sharratt et al observed that the entire colony of mice and rats used in their experiments with benzoyl peroxide had many abnormal changes irrespective of the test performed on the animal. There was a statistically significant incidence of atrophy of the testicles in the rats given the diet based on flour treated with benzoyl peroxide at 2,800 ppm and in the rats receiving diets of breadcrumbs made with flour treated with benzoyl peroxide at 28 ppm and 2.8 ppm. The authors suggested that this atrophy was caused by benzoyl peroxide, which probably marginally decreased the amount of vitamin E in the diet. This conclusion was not supported by any analyses of the diets, and the degree of testicular atrophy in each rat was not stated; therefore, no definitive conclusion can be made. While the authors concluded that benzoyl peroxide was not carcinogenic in rats or in mice under the test conditions, it does not seem that this was a definite experiment of carcinogenicity or of other types of chronic toxicity. The length of the observation periods and the experimental design were probably adequate; however, there may have been insufficient numbers of animals to detect carcinogenicity. In addition, it is uncertain how much benzoyl peroxide remained unchanged after it was added to the diets. Other investigators have studied the action of benzoyl peroxide in animals to ascertain whether it is carcinogenic. Hueper conducted a study to determine if benzoyl peroxide, when used as a polymerization catalyst for silicone rubber, had carcinogenic properties. According to the manufacturer, benzoyl peroxide was totally destroyed in the rubber curing process. A piece of silicone rubber that had been cured with benzoyl peroxide was Implanted subcutaneously in the neck of each of 21 male and 14 female Bethesda black rats. In another group of Bethesda black rats, a gelatin capsule containing 50 mg of benzoyl peroxide was implanted subcutaneously in the nape of the neck of 20 males and 15 females. No control animals were used. The rats were observed for 24 months. In the rats with silicone rubber implants, 10 sarcomas occurred at the implantation sites, and there were neoplasms at other sites, viz, 4 round cell sarcomas of the ileocecal lymph nodes, 3 mesotheliomas of the peritoneum, and 1 carcinoma of the bladder . There were no tumors at the implantation sites in the rats with the encapsulated benzoyl peroxide, although seven of these rats had malignancies at other sites, including four round cell sarcomas of the ileocecal lymph nodes, one mesothelioma of the peritoneum, one epidermoid carcinoma of the snout, and one myxosarcoma of the anal region. Benign tumors, including two adenofibromas of the breast and one cystic cholangioma, appeared in three other rats in the group with the benzoyl peroxide implants. Hueper concluded that the absence of tumors at the sites of implantation provided conclusive evidence that benzoyl peroxide was not implicated in the induction of polymer cancers. Van Duuren and his colleagues studied the carcinogenicity of a group of epoxides, lactones, and peroxides including benzoyl peroxide. The backs of 30 male Swiss-Millerton mice were painted 3 times weekly with about 100 mg of a 5% benzene solution of benzoyl peroxide. Controls were similarly painted 3 times weekly with 100 mg of benzene alone. The median survival times were 292 days for the mice exposed to benzoyl peroxide and 264, 262, 412, and 292 days for the four control groups. The animals were examined regularly for tumors. None of the mice developed carcinomas; one mouse exposed to benzoyl peroxide developed a benign tumor. The authors concluded that benzoyl peroxide showed no carcinogenic activity in this experiment. In 1972, Epstein et al tested 174 agents, including benzoyl peroxide, for dominant lethal mutations in ICR/Ha Swiss mice. Benzoyl peroxide at doses of 54 and 62 mg/kg was administered by intraperitoneal (ip) injection to seven and nine male mice, respectively. Each animal was then caged with three untreated virgin female mice for 1 week. The females were replaced each week for a total of 8 weeks and then killed and examined for pregnancy (total implants), early fetal deaths, and late fetal deaths. Since late fetal deaths were very rare, total implants and early fetal deaths were the only implant features analyzed. The results obtained in the experimental mice were not significantly different from the results in the control mice . Benzoyl peroxide, in the dose range and in the strain of mice used, met none of the screening criteria for these dominant lethal mutations. The authors recommended additional tests to confirm the apparent lack of mutagenicity of benzoyl peroxide. An evaluation of the mutagenic properties of 78% benzoyl peroxide was reported in 1975 . The yeast Saccharomyces cerevisiae, strain D4, and the bacterium, Salmonella typhimurium, strains TA-1535, TA-1537, and TA-1538, were used in modified Ames assays. Tissue homogenates from mice, rats, and monkeys were added to the culture media to see if benzoyl peroxide might be activated to a mutagenic compound. It was concluded that benzoyl peroxide exhibited no mutagenic activity in any of the in vitro microbial assays performed; this conclusion is consistent with the data presented. However, the benzoyl peroxide was added in dimethylsulfoxide, a solvent in which it is not soluble, although it did, nevertheless, allow the benzoyl peroxide to come in contact with the yeast and bacteria. # Correlation of Exposure and Effect The one report on the effects of inhalation of airborne dust containing benzoyl peroxide on humans stated that two plant inspectors had symptoms of nose and throat irritation on 2 days when the concentrations of benzoyl peroxide ranged from 1.34 to 17.0 mg/cu m. On the 3rd day, when the concentrations of airborne benzoyl peroxide were 2.58-82.5 mg/cu m, they had symptoms of eye irritation, as well as of nose and throat irritation. However, no definite conclusions can be made from this report because the analytical information provided is insufficient for the reliability of the determinations to be assessed, so the concentrations of airborne benzoyl peroxide are questionable. Also, the presence of alum in the airborne dusts may have caused or contributed to the irritation. observed that only 1 of 180 patients treated with benzoyl peroxide could not tolerate the treatment. It was not stated whether this patient had an allergic response or a skin irritation. There has been no evidence of systemic toxicity caused by benzoyl peroxide. Dogs given diets containing flour treated wih 0.8-28 g of benzoyl peroxide/100 pounds of flour had no apparent adverse effects . No data were presented that would indicate the amount of benzoyl peroxide that remained in their diets after they were prepared, which involved steaming the flour treated with the compound. Sharratt and his colleagues noted that male and female rats given benzoyl peroxide at concentrations of 280 or 28 ppm in a flour-based diet gained weight at a slower rate than the control rats; male rats given a diet with breadcrumbs made from flour treated with benzoyl peroxide at a concentration of 2.8 ppm gained weight at a rate similar to that of the controls. In another study , single dietary doses of 950, 400, or 200 mg/kg produced no ill effects. Ingestion of benzoyl peroxide in amounts far greater than those normally used to treat commercial flour had no apparent toxic effects in rats and dogs 49]. However, much of the benzoyl peroxide in the diets of these animals may have decomposed to benzoic acid by the time it was consumed. Horgan et al reported that, in mice, the LD50 of benzoyl peroxide administered through ip injection was 4.8 mg/mouse; later, Philpot and Roodyn calculated an LD50 in mice of 4.1 mg/mouse for benzoyl peroxide given by ip injection. Sharratt et al reported that a subcutaneous injection of 50 mg of benzoyl peroxide/mouse (2,500 mg/kg) caused an abscess that healed in several weeks; no deaths occurred. Sharratt et al also gave rats 120 mg of benzoyl peroxide by subcutaneous injection with no apparent adverse effects. The absorption of benzoyl peroxide in mice appears to vary greatly depending on the site of injection. Laboratory tests reported by Ede on 10 men and 10 women using acne medications containing benzoyl peroxide were normal, indicating no systemic effects from dermally applied benzoyl peroxide. No data were found that dealt specifically with absorption of benzoyl peroxide through the skin or from different sites of injection in humans or animals. The flammability and explosiveness of pure benzoyl peroxide have been the cause of accidents involving serious injuries and fatalities . Accidents involving only property damage are summarized in Chapter V. # Carcinogenicity, Mutagenicity, Teratogenicity, and Effects on Reproduction The results of experiments designed to show if benzoyl peroxide has any carcinogenic activity when it is implanted , painted on skin , or injected were negative. The results of tests to detect mutagenic effects of benzoyl peroxide in a modified dominant-lethal assay with mice and in Ames assays with bacteria and yeast were also negative. No data on teratogenesis or other effects of benzoyl peroxide on reproduction were found. Another sample taken during another packing operation indicated that the total dust concentration was 0.16 mg/cu m. Both of these dust concentrations were below the existing federal environmental limit for benzoyl peroxide of 5 mg/cu m. # Sampling and Analysis During industrial operations, benzoyl peroxide may escape into the environment as airborne dust ; however, there currently are no validated sampling and analytical methods specific for airborne benzoyl peroxide. Kaznina used a method for sampling and analysis in which the air samples were drawn through a filter into an absorber containing 5 ml of ethyl alcohol. Analyses of the samples for benzoyl peroxide were performed by ultraviolet spectrophotometry. The method was sensitive for benzoyl peroxide to a concentration of 1.0 ;ug/ml. Benzoyl peroxide, styrene, and dimethylaniline are present simultaneously where styrene-containing plastics are prepared . The method was reported to have limited use because of interference by dimethylaniline and styrene, which were also present in the operation. Therefore, an analysis based on ultraviolet spectrophotometry would be of limited value because much of the benzoyl peroxide produced each year in the United States is used in the production of polystyrene . Dugan and Dugan and O'Neil determined benzoyl peroxide by an analytical colorimetric method. A colored complex resulted when benzoyl peroxide was used to accelerate the reaction between methanol and N,Ndimethyl-p-phenylene diamine sulfate. The relationship of the color intensity and the amount of benzoyl peroxide present in solution followed Beer's Law at peroxide concentrations of 5-30 Mg/ml but deviated at 40 ¿¿g/ml. For this analytical method to be accurate, time and temperature must be held constant because the reaction proceeds slowly without the addition of peroxide . The authors stated that molecular oxygen might interfere with the reaction as it does with many colorimetric methods. The time and temperature requirements, as well as the possible interference of molecular oxygen, make this method undesirable for analysis. Banerjee and Budke also used a colorimetric method of analysis for benzoyl peroxide. Benzoyl peroxide was dissolved in a mixture of acetic acid and chloroform; potassium iodide was then added. The absorption of the liberated iodine was measured at 470 nm, and the amount of benzoyl peroxide in the sample was determined from a standard curve. This method may be hazardous because explosions have occurred when chloroform and benzoyl peroxide were mixed and then heated above room temperature . Furthermore, NIOSH has concluded that chloroform is carcinogenic (letter from Director, NIOSH, to Assistant Secretary of Labor, OSHA, June 1976). This analytical method is not specific for benzoyl peroxide but determines total peroxides. Airborne methylethylketone peroxide (MEKO) was analyzed by a colorimetric method (T Anania, written communication, January 1977). A known volume of air containing MEKO was drawn through a U-tube filled with dimethyl phthalate in which the benzoyl peroxide dissolved. The solution was transferred to a test tube, and diphenylcarbohydrazide, a color reagent, was added. This solution was compared to a standard solution in a spectrophotometer. When benzoyl peroxide was analyzed by this method, at the lowest level, 50 jug/sample, the color intensity was equivalent to that produced by 1.5 Mg of MEKO. After an initial relative linearity in the range of 0-100 Mg/sample, benzoyl peroxide, in increasing quantities, developed a progressively lower color intensity/unit and gave a curvilinear standard curve. Although no recommendations were made by the author, this degree of curvature is undesirable for a quantitative analysis. Dolin used methods for sampling and analysis that were not specific for benzoyl peroxide. One cubic foot of air/minute was drawn through a Greenburg-Smith impinger containing 75 ml of doubly distilled water for times varying from 13 to 37 minutes. Aliquots of the sampling solution were added to flasks containing a mixture of 0 .75% aqueous potassium iodide and a freshly prepared 0.50% starch solution, which were then allowed to stand from 1 hour to overnight. The color intensity was measured in a spectrophotometer or visually compared with a set of color standards prepared from known concentrations of benzoyl peroxide. The relationship of the developed color in the standards to the concentration of benzoyl peroxide followed Beer's Law, and a standard curve was constructed. The concentrations of benzoyl peroxide in the samples were read from the standard curve. Dolin found that, unless the standards were prepared at the same time as the sample solutions, the measurement error was as high as 25%. With this method, a spectrophotometer can detect as little as 1 jug of benzoyl peroxide; as little as 3 f i g can be detected visually. The method was not specific for benzoyl peroxide but indicated total peroxides. Dolin used a standard impinger in his sampling method but gave no data on the collection efficiency of the impinger with distilled water as an absorbent. Sampling and analytical methods have been developed that allow specific analysis for benzoyl peroxide. A known volume of air is drawn through a membrane filter. The benzoyl peroxide is subsequently extracted from the filter and analyzed by high pressure liquid chromatography . When an air sample size of 90 liters was collected, by drawing air at a rate of 1.5 liters/minute through a 37-mm diameter mixed cellulose ester membrane filter with a pore size of 0.8 ¿¿m, a collection efficiency of 1.00 was determined. Storage stability studies on samples collected from a test atmosphere at a concentration of 7.30 mg/cu m indicated that, after 1 week with the samples held in the filter cassettes at room temperature, there was a 9.3% decrease in the amount of benzoyl peroxide recovered from the filter. Benzoyl peroxide was extracted from the filter with ethyl ether . Tests showed that benzoyl peroxide is stable in ethyl ether at room temperature for at least 1 week. Thus, there may be up to a 9.3% loss of benzoyl peroxide if the samples are not extracted immediately or refrigerated. Analysis of the samples by high pressure liquid chromatography is subject to interference from any compound that has the same retention time as benzoyl peroxide at the operating conditions used . Although retention time data on a single column cannot be considered proof of chemical identity, an interfering compound can be eliminated as an interference by altering operating conditions, using a different column packing, or using a selective detector. The coefficient of variation for the total sampling and analytical method in the range of 3.12-19.10 mg/cu m was 0.060, which corresponds to a standard deviation of 0.30 mg/cu m at an air concentration of benzoyl peroxide of 5 mg/cu m. The sampling device is small and portable, and it involves no liquids. The samples collected on membrane filters are analyzed by means of a quick instrumental method. This method has been shown to provide sufficient accuracy, sensitivity, and precision within the range required to determine compliance with this standard for benzoyl peroxide. Other methods have been reported for the determination of benzoyl peroxide in pharmaceuticals , flour , cheese , fats , and oils . In 1967, Gruber and Klein reported the comparison of spectrophotometric, titrimetric, and polarographic techniques in testing the stability of pharmaceuticals containing benzoyl peroxide. The results of the polarographic and spectrophotometric methods, when they were used to show the degradation of benzoyl peroxide at high temperatures, were in good agreement. The titrimetric method was far less sensitive than the other two and did not differentiate between benzoyl peroxide and some of its decomposition products. All three methods are colorimetric, and none is specific for benzoyl peroxide. In 1975, Daly et al reported difficulty in reproducing the results of Gruber and Klein and suggested another titrimetric method as a more accurate means for determining the content of benzoyl peroxide in pharmaceuticals. The authors noted that, although alkylhydroperoxides and dialkyl peroxides would interfere with this method, commercial pharmaceutical creams and lotions containing benzoyl peroxide would probably not contain these other classes of peroxides. The American Oil Chemists Society (AOCS) published their official method for analyzing total peroxide in fats and oils in 1960; it was reapproved in 1973. The described method was a titrimetric procedure that was not specific for benzoyl peroxide. It is recommended that total dust concentrations be monitored routinely by collecting breathing zone samples on a preweighed glass-fiber filter as detailed in Appendix I. Glass-fiber filters have been selected for sampling because they will efficiently collect airborne dust particles. In addition, being relatively free of organic matter, they are less likely to form explosive mixtures with benzoyl peroxide than filters like cellulose paper. After the sample is collected, the weight of total dust is determined by gravimetric analysis. The filter is reweighed with the same balance that was used for the preweighing, and the difference between the tare and final weights is determined. Before each weighing, the filter should be equilibrated in a constant humidity chamber, and a static charge neutralizer should be used to improve the reproducibility of the weight determinations and thus enhance gravimetric accuracy. The recommended gravimetric method is described in detail in Appendix II. In many applications, one should not have to do more than measure total dust. However, if the total airborne dust exceeds the recommended benzoyl peroxide environmental limit of 5 mg/cu m, the gravimetric analysis must be followed by a colorimetric analysis for total peroxide developed from a method by Dolin . The filter is placed in a flask containing a mixture of potassium iodide and starch solution which is oxidized by benzoyl peroxide and other peroxides to form a blue iodide-starch complex. The filter should remain in the solution for 12 hours to permit the blue color to develop from the iodide-starch complex. The color intensity is measured in a spectrophotometer or visually compared with a set of color standards. The concentration of total peroxides should be calculated as benzoyl peroxide. Other oxidizing agents would also produce the iodidestarch complex and give erroneously high concentrations when they are present with benzoyl peroxide in the sample. This interference, however, would never produce a calculated benzoyl peroxide concentration lower than the actual concentration. The recommended analytical method is described in detail in Appendix II. # Engineering Controls Benzoyl peroxide should be protected from contact with sparks, All metal surfaces that benzoyl peroxide comes in contact with should be grounded and bonded . Conductive flooring or mats will also aid in the control of static electricity . Benzoyl peroxide and its formulations should be stored where there are no sources of excessive heat or ignition, such as open flames, electrical devices , and exposed steam lines or wall radiators, in the storage area . Futhermore, benzoyl peroxide should not be exposed to direct sunlight . If benzoyl peroxide is exposed to temperatures of 75-80 C for prolonged periods of time, it becomes unstable and may spontaneously decompose; if heated to just above its melting point (104 C), it will instantaneously and violently decompose . When benzoyl peroxide must be mixed with other materials, the temperature of these other materials should be below 50 C . Benzoyl peroxide may react violently with various organic and inorganic acids, amines, alcohols, metallic naphthanates, polymerization accelerators, and other chemicals that are easily oxidized . Benzoyl peroxide will decompose at room temperature in the presence of small amounts of tertiary arylalkylamines which are used in curing polyester resins. Many transition metal ions also catalyze the decomposition of benzoyl peroxide . Direct or reflected sunlight may cause decomposition of benzoyl peroxide . Decomposition of benzoyl peroxide is accompanied by a 200-fold increase in volume and yields a dense white smoke consisting of benzoic acid, phenyl benzoate, terphenyls, biphenyls, benzene, and carbon dioxide . The decomposition of benzoyl peroxide may be preceded or followed by fire . If benzoyl peroxide or its decomposition products catch fire, dense black smoke is produced . The resulting biphenyls promote the further decomposition of benzoyl peroxide . Formulations of benzoyl peroxide are generally less hazardous than the pure compound . In safety tests, the burning rate of a benzoyl peroxide formulation containing 25% water was not as intensive as that of pure benzoyl peroxide . Formulations containing plasticizers also generally burn slower than does pure benzoyl peroxide; however, a 50% benzoyl peroxide paste with tricresyl phosphate decomposed at a lower temperature than that required to explode pure benzoyl peroxide . Appendix IV explains two hazard classification sytems that relate to the physical properties of all organic peroxides and indicate the precautions that should be observed for their safe handling, use, and transporation; they give no indication of toxicity. Tests that evaluate the total energy release of a compound, the rate at which the energy is released, and the ease of ignition and decomposition are the basis for such hazard classifications. Employers should be aware of the appropriate hazard classification of the benzoyl peroxide formulations used in the workplace and should institute pertinent work practices. # Accidents The flammability and explosiveness of benzoyl peroxide have caused accidents; those which resulted in injuries or fatalities are discussed in Chapter III. Other accidents, involving damage, have been described. Knowledge of the physical properties of benzoyl peroxide and correct work practices might have prevented some of the accidents or at least lessened their severity. Malkemus reported that 1 pound of benzoyl peroxide exploded after it had been removed from its original shipping container, placed in an open 1-quart can, and set under a window exposed to the sun. He stated that the heat from the sunlight contributed to the explosion and that the can may have been contaminated with a reactive chemical. A report from the American Insurance Association included accounts of several accidents. A tractor-trailer carrying 300 pounds of benzoyl peroxide in 1-pound containers sideswiped another trailer, and the benzoyl peroxide exploded. All of the benzoyl peroxide was consumed in the explosion, and no fire resulted. In another accident, an unspecified quantity of benzoyl peroxide caught fire because friction was generated by a broom used to sweep it off the floor. The fire spread to benzoyl peroxide stored on the second floor of the building. A third accident reported by the American Insurance Association occurred at a reinforced-plastics manufacturing plant. There was an explosion in a warehouse where 1,000 pounds of organic peroxides were stored. The report implied that benzoyl peroxide was present. The resulting fire spread to several adjoining buildings. Spilled peroxide and careless smoking were given in the report as possible causes of the accident. A blended mixture of 30% benzoyl peroxide and unknown quantities of magnesium carbonate, hydrogen peroxide, sodium hydroxide, and oleic acid exploded while being dried in a steam-heated continuous drying oven . There was a secondary explosion and flash fire in the building. The benzoyl peroxide apparently decomposed inside the oven, releasing what was described as a white, copious, flammable gas. Three sides and the top of the oven were blown out as much as 2 feet. In 1974, Bolt and Joyce described explosions which occurred during the alkylation of polyhalomethanes by alkanes and alkadienes in the presence of catalytic amounts of benzoyl peroxide. A reactor was charged with 100 g of carbon tetrachloride and 0.40 g of benzoyl peroxide. The reactor was then pressurized with ethylene and heated with agitation. Twenty minutes after the reaction had started, when the temperature was 94 C and the pressure was about 14,230 pounds per square inch (psi), an explosion occurred which blew out the gas inlet line near the reactor. An increased ratio of water to carbon tetrachloride resulted in no further explosions when the reactor was operated at 9,600 psi and 110 C; 100 g of carbon tetrachloride, 100 g of water, and 0.23 g of benzoyl peroxide were used. The investigators stated that the reaction can occur without incident at a lower pressure, such as 1,400 psi with a temperature as high as 120 C when 0. acclerators, that will readily react with benzoyl peroxide . Benzoyl peroxide and its formulations should always be stored in their original containers. In addition, because of possible contamination, no benzoyl peroxide which has been removed should be returned to its original container. Benzoyl peroxide containers should be kept closed when not in use to prevent contamination . Contamination of benzoyl peroxide may result in decomposition or fire . No screw tops should be permitted on containers used for formulations of benzoyl peroxide if pure benzoyl peroxide could accumulate in the screw threads ; an accident occurred when a screwcap bottle of benzoyl peroxide was being opened . Precautions should be taken so that wet benzoyl peroxide formulations do not dry out. Ultraviolet radiation will, like heat, increase the rate of decomposition of benzoyl peroxide . Sufficient open space should be left between stacks of peroxide containers in storage areas. When hazardous benzoyl peroxide formulations must be refrigerated, explosionproof refrigerators should be used for this purpose . Only clean, properly designed equipment should be used for benzoyl peroxide and its formulations; containers should be made of polyethylene or stainless steel. The use of copper, brass, lead, zinc, and galvanized equipment should be avoided because reactions in such equipment may accelerate decomposition of organic peroxides . Benzoyl peroxide should be brought into the process area in the original shipping container and in quantities limited to the amounts required for daily use. Only small quantities of pure benzoyl peroxide, definitely not more than 1 pound, should be handled at a time . If large quantities of the peroxide start to decompose, the decomposition of the outside layer confines the inner mass and increases the rate of decomposition, causing an explosion . A separate area should be provided for premixing benzoyl peroxide with resins , The accelerator should be mixed with the resin before benzoyl peroxide is added to prevent violent decomposition . Work practices for fibrous glass and plastic fabricators have been recommended to minimize the hazardous properties of benzoyl peroxide . No pure benzoyl peroxide, without diluents, should be allowed in any grinding operation because explosive decomposition may occur . Benzoyl peroxide may explode if it is recrystallized from hot chloroform . The peroxide can be safely recrystallized from chloroform at room temperature if methanol is added to the solution , However, as was mentioned in Chapter IV, Sampling and Analysis, chloroform has been implicated as a carcinogen, so an alternative solvent should be considered. All containers of benzoyl peroxide and its formulations should be properly labeled. Labels for benzoyl peroxide formulations should follow the regulations in Hazardous Industrial Chemicals, ANSI, Z129.1. Shipping labels should comply with the US Department of Transportation regulations and other applicable statutes, regulations, and ordinances . Warnings should be posted in places where benzoyl peroxide is used and stored. The warnings should briefly and concisely state the important safety precautions to be adhered to within the area . These warning placards should also indicate that these areas are accessible only to authorized personnel. Exits should be easily accessible and clearly marked. The location of emergency and first-aid equipment should also be easily accessible and clearly marked. The Department of Transportation regulations, 49 CFR 173.157 and 178.58, specify that benzoyl peroxide wet with at least 30% water by weight should be packaged in quantities not to exceed 1 pound. It is important that fire-resistant material separates the individual bags so that the decomposition of benzoyl peroxide in one bag is less apt to affect the other bags in the box . # Housekeeping and Maintenance The hazardous nature of benzoyl peroxide makes it imperative that housekeeping duties be performed continually under adequate supervision. Failure to follow these procedures has caused fires and accidents . Even small amounts of benzoyl peroxide are potentially dangerous, and they may unpredictably decompose if subjected to any friction, heat, or shock . Benzoyl peroxide formulations, such as pastes or the wet peroxide, may separate into their respective components through evaporation or freezing . Thus, these small amounts of benzoyl peroxide formulations may be dangerous if not cleaned up from the floor and from the equipment in the process areas. The accidental decomposition of these traces of benzoyl peroxide could initiate the decomposition of all the benzoyl peroxide in the surrounding area . Wet mops or other implements that will minimize sparks and friction should be used to clean up spills; a fire has resulted when the friction between a broom and benzoyl peroxide on the floor ignited the peroxide . All equipment should be cleaned meticulously to avoid possible violent reactions between benzoyl peroxide and reactive chemicals. Ducts should be cleaned and inspected regularly to prevent the accumulation of benzoyl peroxide. Benzoyl peroxide should either be removed or covered during maintenance and repair work . Where benzoyl peroxide formulations are used to bleach flour or catalyze certain organic reactions, the proportion of benzoyl peroxide is generally so small in relation to other chemicals present that the nature of these chemicals, rather than that of benzoyl peroxide, may dictate the housekeeping and maintenance procedures . The grounds surrounding process and storage buildings must be kept cleared of vegetation and all other combustible materials, such as trash, to prevent the spread of fire if one should occur . Maintenance and repair work in areas where benzoyl peroxide is used, stored, or manufactured should be authorized by the appropriate supervisor . # Spills and Waste Disposal Spills should be wetted with water and cleaned up immediately with a wet mop or other nonsparking implements . Vacuum units should be operated from a remote location away from electrical contacts; filter bags, as well as the vacuum lines, should be grounded to prevent static charge buildup. Care should be taken that benzoyl peroxide wastes are not mixed with other materials or chemicals, such as oxidizing or reducing agents, that might create hazardous conditions. A nonreactive container, such as one made of polyethylene, reserved only for benzoyl peroxide wastes, should be used to store the wastes until their disposal. Benzoyl peroxide should not be disposed of by burning unless it has been thoroughly wetted down or mixed with water-wetted vermiculite, perlite, or another inert substance . Water slurries of benzoyl peroxide wastes may be destroyed by gradually adding small amounts of the slurry to 10 times its weight of 10% sodium hydroxide solutions . There should be sufficient agitation or stirring of the mixture so that there is no lump formation or settling. Water may be added to prevent thickening of the mixture that would make stirring difficult. The resulting slurry of sodium benzoate should be checked for neutrality and may be flushed into the sewage system if local regulations permit. Pure benzoyl peroxide itself should never be flushed into the sewage system . Additional details of inactivating and disposing of benzoyl peroxide are described in Appendix V. If wetted vermiculite or perlite has been added to a benzoyl peroxide spill, the water should be drained off and the waste water added to the waste slurry. The remaining material may be burned in an open incinerator or otherwise disposed of in accordance with local, state, and federal laws. If the material is burned, it should be placed in a shallow trench and ignited from a distance of at least 6 feet. When benzoyl peroxide becomes mixed with an unknown material, it should be considered contaminated and disposed of properly , If bags and cartons that formerly contained benzoyl peroxide are to be destroyed, they should be placed in a special waste collection drum provided for that purpose. The contents of the drum should be kept wet until they can be carefully burned in an area reserved for that purpose be worn by employees for protection when they are opening shipping boxes of pure benzoyl peroxide or otherwise handling pure benzoyl peroxide. Aprons made of rubber or another appropriate material are recommended for added protection when handling benzoyl peroxide and its formulations. Plastic aprons that generate static electricity should not be used . All personal protective clothing and equipment should be cleaned, inspected on a regular schedule, and replaced when worn out or broken. The employer is responsible for ensuring that such clothing and equipment are stored in suitable designated containers or locations when not in use. Respiratory protection as specified in Chapter I must be used whenever airborne concentrations of benzoyl peroxide cannot be controlled to the recommended workplace environmental limit by either engineering or administrative contro.ls. # Sanitation Protective clothing should be kept apart from the workers' street clothing in lockers with two compartments provided for that purpose. To minimize the potential for explosion or fire, workers must not eat or smoke where benzoyl peroxide is manufactured, used, or stored. Workers should also wash their hands before eating, smoking, or using the lavatory. A supply of potable water must be available near all places where there is potential contact with benzoyl peroxide and its formulations. and ensure that it is clearly marked, located in an easily accessible place, and maintained in working order. Firefighters should be informed that the dense smoke produced by benzoyl peroxide necessitates the use of a lifeline and a self-contained breathing apparatus in addition to their standard firefighting clothing . Local fire units and rescue squads should be apprised of the types of emergencies that may arise before any emergencies occur. The necessary phone numbers for such emergency assistance must be prominently posted in areas where emergencies are likely to occur. Areas where pure benzoyl peroxide is manufactured, packaged, and stored should not contain firefighting equipment; if a fire occurs, these areas should be evacuated immediately; employees should not attempt to control this type of fire. However, firefighting equipment should be well marked and located in every room and area where formulations of benzoyl peroxide are stored. If a fire occurs near an organic peroxide storage area, the containers within the storage area should be kept continually wetted to prevent overheating. Appropriate warning alarms that are automatically activated by heat or smoke should be installed in all benzoyl peroxide storage and work areas. In addition, an independent alarm system that can be controlled manually and whose controls are readily accessible to employees is advisable if smoke or heat is considered insufficient to trigger the automatic alarms. The inspection report did not specifically state that benzoyl peroxide was the cause of the discomfort or whether potassium aluminum sulfate or magnesium carbonate in the dust caused or contributed to the irritating effects. The methods of analyses were not described. Since there is no validated method of sampling and analysis for benzoyl peroxide, the method used to analyze the collected samples was probably not specific for this compound. The possible toxic effects of airborne benzoyl peroxide on humans cannot be accurately assessed because the report lacks essential data. Studies have indicated no carcinogenic or mutagenic effects from benzoyl peroxide. Sharratt et al found that benzoyl peroxide had no carcinogenic activity from skin painting of mice, subcutaneous injection in mice and rats, and feeding studies in mice and rats. Van Duuren et al reported that benzoyl peroxide showed no carcinogenic activity when used in skin painting experiments in mice, Hueper found that rats implanted with encapsulated benzoyl peroxide developed no tumors at the site of implantation. Epstein et al observed that benzoyl peroxide demonstrated no mutagenic activity when tested in a modified dominant lethal assay. Benzoyl peroxide exhibited no mutagenic activity in bacteria and yeast . No teratogenic studies or epidemiologic surveys were found. The Few pertinent toxicologic data on humans have been found in the literature. The animal data in the literature suggest that benzoyl peroxide is not a toxic compound, although no definitive studies have been found. The major hazard is injury or death resulting from fires and explosions caused by benzoyl peroxide . The available epidemiologic and toxicologic evidence on benzoyl peroxide is insufficient to allow derivation of a new environmental limit or to warrant a change in the present environmental limit. It is recommended, therefore, that the present permissible exposure limit of 5 mg/cu m as a TWA concentration be retained. Because of the apparently low degree of toxicity of benzoyl peroxide, the action level is defined as equal to the environmental limit. (b) # Sampling and Analysis It is recommended that airborne dust containing benzoyl peroxide be collected on a glass-fiber filter and analyzed gravimetrically. If the total airborne dust concentration is 5 mg/cu m or less, no further analysis need be done. If the total airborne dust concentration is greater than 5 mg/cu m, a total peroxide analysis should be performed on the material collected on the filter. A colorimetric analysis, developed from a method by Dolin , was selected for benzoyl peroxide because it is simple, reliable, and sensitive. However, the selected method is not specific for benzoyl peroxide; other peroxides can interfere. A method specific for benzoyl peroxide, involving high pressure liquid chromatography, as described in Chapter IV, should be used if other, nonspecific methods, such as total peroxide analysis, show concentrations greater than 5 mg/cu m. # (c) Medical Surveillance and Recordkeeping Little information has been found on the toxicity of benzoyl peroxide, so frequent comprehensive medical examinations are not proposed as a requirement. However, there is some evidence that benzoyl peroxide and its degradation products, including benzoic acid, cause sensitization. This sensitization should especially be looked for in the preplacement examinations, which should include an examination of the skin. The workplace environment should be monitored semiannually and the records retained for 30 years. Since no chronic effects of benzoyl peroxide have been found, retention of environmental and medical records of employees for more than 30 years after termination of a worker's employment is unnecessary. (g) Monitoring and Recordkeeping Requirements # V I I . RESEARCH NEEDS Further study is needed to properly assess the toxicity of benzoyl peroxide and to evaluate its potential hazard to the working population. Presently, little is known about its toxic effects. The effects of long term exposure to benzoyl peroxide, particularly those caused by ingestion and inhalation, should be studied, especially to determine if there are any carcinogenic, mutagenic, teratogenic, or other systemic changes. Little information has been found concerning the possibility of absorption benzoyl peroxide through the skin, although skin contact is the most common route of human exposure. Studies should determine if benzoyl peroxide is altered during specific manufacturing processes and if the resulting residues can cause skin irritation or other adverse effects. Metabolic studies might provide information about the extent to which metabolites of benzoyl peroxide are responsible for toxic effects. If the total airborne dust exceeds the environmental limit for benzoyl peroxide, a colorimetric analysis, adapted from the method described by Dolin , should be performed on the particles trapped in the filter. (2) Treat portions of each of the standard aqueous benzoyl peroxide solutions in a similar manner. (3) Determine the absorption of the sample solution and of the standards at the absorption band maximum in the spectrophotometer. Make dilutions of the sample solutions if necessary. (4) Construct a standard curve of the percent transmittance versus f i g benzoyl peroxide, using the data obtained from the standard solutions. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50- The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple c> components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees. Hazard classifications are based on tests designed to evaluate the total energy release, the rate of energy release, and the ease of ignition and/or decomposition and storage containers when exposed to normal temperatures and when exposed to heat, fire, or mechanical shock. These tests include: burning rate (solids or pastes); flash point (liquids); impact sensitivity (drop weight test); self-accelerating decomposition temperature (temperature at which self-heating to decomposition is initiated) and the evaluation of the violence of this decomposition; heat exposure to a sample in a vented pressure vessel to evaluate rate and violence of decomposition; and lead block deformation test (exposure to heavy shock) to evaluate violence of decomposition. Peroxides frequently do not react consistently in the various tests. Therefore, a peroxide may be classified on the basis of the most hazardous rating attained in any one of the series of tests. Classification of each peroxide is based on its normal shipping container. If a peroxide is shipped in a different container or transferred to a different container, the normal hazard classification may no longer apply. In general, a stronger container will increase the hazard. Classification is also based on a specific product of a specific manufacturer. The same type product in the same type of container by various manufacturers will not necessarily be in the same class. Differences in manufacturing procedures may have an effect on the hazard of a peroxide which can be determined only by tests. # The classifications are as follows: Class I. Class I peroxides present a high explosion hazard through easily initiated, rapid explosive decomposition. This group may include peroxides that are relatively safe under highly controlled temperatures or in a liquid solution where loss of temperature control or crystallization out of solution can result in severe explosive decomposition. # Class II. Class II peroxides present an intermediate explosion hazard. That is, an explosive decomposition is not as rapid, violent or complete as that produced by a Class I material. As with Class I materials, this group may also contain peroxides that are relatively safe under controlled temperatures or when mixed with a diluent. # Class III. Class III peroxides present moderate explosion and severe fire hazards. They have characteristics of rapid burning, high heat liberation or vapor-air explosion hazards of the products of decomposition. # Class IV. Class IV peroxides have moderate fire hazard characteristics that can be easily contained by normal sprinkler systems and fire walls. # Class V. Class V peroxides present a low or negligible fire hazard. With these peroxides, combustible packing materials may present a greater hazard than the peroxide itself. # XIII. APPENDIX V INACTIVATION OF BENZOYL PEROXIDE The following method for inactivating benzoyl peroxde for subsequent disposal is recommended for pure benzoyl peroxide (96-99%) and wet benzoyl peroxide formulations; "BPO-78" means 78% benzoyl peroxide plus 22% water. Pure benzoyl peroxide (98+%) and water-wet benzoyl peroxide formulations (70% or 78% wetted products) can be hydrolyzed with dilute sodium hydroxide to form sodium benzoate and a solution of hydrogen peroxide in caustic. The hydrogen peroxide decomposes in the caustic solution. # Procedure Slowly add the BPO-98 (BPO-78 or BP0-70) in small portions to a rapidly stirred 10% sodium hydroxide solution, the amount of such solution being 10 times the weight of the actual benzoyl peroxide to be hydrolyzed. The sodium hydroxide solution must be no warmer than room temperature at the time of addition. The reaction is only mildly exothermic, so cooling is not necessary. When all the benzoyl peroxide has been added, continue stirring until the solution is free of solids. The solution will be cloudy. When the temperature is maintained at about 25 C, the time for hydrolysis will be about three hours. When the solution is free of solids, the benzoyl peroxide has been hydrolyzed and the solution can be disposed of, in accordance with any regulations which apply to disposal of a dilute sodium hydroxide solution containing benzoic acid salts (0 Mageli, written communication, January 1977). # XIV. TABLES # Macht DJ: Dtsch Med Wochenschr 57: 678, 1931 (Ger) 31. Moskowitz S, Burke W J : Lucidol Division-Novadel-Agene Corporation, report No. L-430-50. Tonawanda, NY, New York City Division of Industrial Hygiene and Safety Standards, Chemical Unit, 1950, 9 pp 32. Baird KA: Allergy to chemicals in flour-A case of dermatitis due to benzoic acid. J Allergy 16:195-98, 1945 33. Knight RA, Kent-Jones DW: Some observations on the determination of benzoyl peroxide in flour and bread. Analyst The concentration of benzoyl peroxide in the sample can also be determined visually by comparing the color of the sample to standard solutions of known concentrations. # Range and Sensitivity With a spectrophotometer, the lower limit of the working range is 1 Mg/sample; when visual comparisons are made, the lower limit is 3 Mg/sample. There is no upper limit because the sample solutions can always be sufficiently diluted to allow spectrophotometric readings within the limits set by standard curves or to match the absorption of standard solutions. # Interferences Other peroxides will also react in the colorimetric analysis to release the iodine, and other oxidizing or reducing agents present in the sample may interfere. # Advantages of the Method (a) It provides a method suitable for determination of total peroxides in the air. # (b) The sampling device is small and portable and involves no liquids. # (c) The analysis is readily accomplished. (1) A glass-fiber filter is placed in a chamber over an aqueous sulfuric acid solution for 24 hours to bring the filter to a constant weight at 50% relative humidity. The initial weight of the glass-fiber filter is recorded to the nearest 0.01 mg. A nuclear static eliminator on the balance will remove static charges that might interfere with obtaining accurate, reproducible weights of the filter. (3) A known volume of air is drawn through the preweighed glass-fiber filter to collect airborne dust, including airborne benzoyl peroxide. (4) After sampling, the filter is replaced in the chamber for 24 hours and again brought to a constant weight at 50% humidity. The filter is reweighed on the balance used for the preweighing, and the weight is recorded to the nearest 0.01 mg. If the difference in the initial and final weights of the filter, divided by the known volume of air sampled, equals or is less than the environmental limit for benzoyl peroxide, nothing further need be done. Filter(s) found to contain a dust concentration higher than the environmental limit should be analyzed by the following colorimetric procedure. (b) Colorimetric analysis (1) Put each glass-fiber filter that was used for the sampling of total dust in a clean, dry flask with 10 ml of double-distilled water, 1 ml of potassium iodide solution, and	# (a) Preplacement medical examinations shall include at least: (1) Comprehensive medical and work histories with emphasis on skin conditions. (2) A complete physical examination giving special attention to the skin for evidence of dermatitis. (b) Periodic examinations shall be made available at a frequency to be determined by the responsible physician, but at least every 3 years. These examinations shall include at least: (1) Interim medical and work histories. (2) A physical examination as described for the preplacement examination. (c) During examinations, applicants or employees having medical conditions that could be directly or indirectly aggravated by exposure to benzoyl peroxide or formulations containing benzoyl peroxide shall be counseled on the increased risk of impairment to their health from working with these substances. (d) Initial medical examinations shall be made available to all employees within 6 months of the promulgation of a standard based on these recommendat ions. (e) Pertinent medical records shall be maintained for all employees occupationally exposed to benzoyl peroxide. Such records shall be kept for at least 30 years after termination of employment. These records shall be made available to the designated aedical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee or former employee. All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers. Illiterate workers and workers reading languages other than those used on labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on labels and signs. # (a) Containers All containers of benzoyl peroxide shall have a label containing the following information, in addition to such other information as may be required by other statutes, regulations, or ordinances or believed needed by the employer: First Aid: In case of eye contact, flush eyes thoroughly with copious amounts of water. Consult a physician. State % of benzoyl peroxide in product. (1) In addition to the above information, labels for containers of pure benzoyl peroxide shall add the following: Do not add to hot materials; do not grind or subject to friction or shock-explosive decomposition may result. (2) Labels for containers of pastes containing benzoyl peroxide shall add the following: Do not freeze. (3) Labels for containers of wet benzoyl peroxide shall add the following: Keep container tightly closed to prevent drying out. # (b) Work Areas Areas where benzoyl peroxide is used, manufactured, or stored shall be posted with a sign reading: The employer shall provide chemical safety goggles, glasses, or face shields (8-inch minimum) with goggles and shall ensure that employees wear them during any operation in which benzoyl peroxide may enter the eyes. The applicable regulation is 29 CFR 1910.133. BENZOYL ( The employer shall provide fire-resistant clothing treated with an antistatic agent to employees using or handling pure benzoyl peroxide. Additional protective clothing shall be worn when needed. The employer shall ensure that precautions are taken to protect personnel who launder clothing contaminated with pure benzoyl peroxide. (3) Protective gloves and aprons shall be worn during operations where pure benzoyl peroxide is handled and may contact the skin. (4) Measures, such as the wearing of conductive shoes, designed to dissipate static electricity should be required by the employer hen large amounts of pure benzoyl peroxide are handled. ( The employer shall ensure that all personal protective devices, including conductive shoes, and conductive flooring are inspected regularly, cleaned, and maintained in working condition. # (b) Respiratory Protection Engineering controls shall be used when needed to maintain airborne benzoyl peroxide concentrations at or below the recommended environmental limit. Compliance with the permissible exposure limit by the use of respirators is permitted only during installation and testing of engineering controls, during performance of nonroutine maintenance or repair, when working in confined spaces, or during emergencies. When use of a respirator is permitted, it shall be selected and used in accordance with the following requirements: (1) To determine the type of respirator to be used, the employer shall measure, when possible, the concentrations of airborne benzoyl peroxide in the workplace initially and thereafter whenever control, process, operation, worksite, or climatic changes occur that are likely to increase the concentration of airborne benzoyl peroxide. This provision does not apply when only atmosphere-supplying positive pressure respirators are used. (2) The employer shall ensure that no employee is exposed to benzoyl peroxide above the recommended limit because of improper respirator selection, fit, use, or maintenance. The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employees properly use the respirators provided when wearing respirators is required. The respiratory protective devices provided in conformance with Table 1-1 shall be those approved by NIOSH and the Mining Enforcement and Safety Administration (MESA) as specified under the provisions of 30 CFR 11. (5) Respirators specified for use in higher concentrations of airborne benzoyl peroxide may be used in atmospheres with lower concentrations. When an emergency involving benzoyl peroxide requires evacuation, the employees shall leave the area immediately, stopping to put on respirators only if absolutely necessary. (7) Respirators shall be easily accessible, and employees shall be informed of their location. 1,000 mg/cu m or less Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure mode or with full facepiece, helmet, or hood operated in continuous-flow mode Greater than 1,000 mg/cu m or entry into area of unknown concentration (1) Self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode (2) Combination respirator which includes a Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and an auxiliary self-contained breath ing apparatus operated in pressure-demand or other positive pressure mode Benzoyl peroxide is a strong oxidizer and should not come in contact with oxidizable materials. Some cartridges and canisters may contain activated charcoal and shall not be used to provide protection against benzoyl per oxide. Only nonoxidizable sorbents are allowed. (a) The employer shall ensure that each employee working in areas where bçnzoyl peroxide is used, handled, manufactured, or stored is informed at the beginning of employment, and at least annually thereafter, of the presence of benzoyl peroxide in the workplace, including the trade name substances, if any, that contain benzoyl peroxide, the hazards, relevant symptoms, appropriate emergency procedures, and proper conditions and precautions for the safe use of benzoyl peroxide. to the employee of undergoing these examinations. Each employee shall be advised of pertinent information, including that required for the material safety data sheet prescribed by paragraph (c) of this section, which shall be kept on file and shall be readily accessible to employees at all places of employment where there is occupational exposure to benzoyl peroxide. Engineering controls, such as process enclosure or local exhaust ventilation, shall be used where needed to maintain benzoyl peroxide concentrations at or within the limit recommended in Section 1(a). All engineering controls shall be sparkproof. Ventilation systems shall be designed to prevent recirculation of benzoyl peroxide into the workplaces. Dead airspaces that would allow accumulation of benzoyl peroxide shall be minimized. Consideration must be given to applicable local, state, and federal air pollution regulations in designing exhaust ventilation systems discharging into outside air so that they do not constitute a hazard to the employees or to the general public. Ventilation systems shall be subject to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by airflow measurements taken at least every 3 months. (b) Storage, Handling, and General Work Practices (1) Containers of benzoyl peroxide shall be kept tightly closed at all times. Containers shall be handled carefully to minimize accidental breakage or spillage and stored in a cool, well-ventilated area away from heat, combustible substances, acids, and oxidizers. No screw-top or metal containers may be used for pure benzoyl peroxide. (2) Employers shall ensure that shipping containers of benzoyl peroxide are not reused unless they have been properly cleaned. (3) Employers shall take precautions to minimize benzoyl peroxide contact with the skin and eyes of employees. Equipment, walls, and floors should be kept clean to limit employee exposure. Section 6 -Work Practices (4) Before maintenance work, sources of benzoyl peroxide shall be eliminated to the maximum extent feasible. If concentrations of airborne benzoyl peroxide cannot be maintained at or below the limit recommended in Section 1(a), respiratory protective equipment as described in Section 4 shall be used during such maintenance work. (5) Sources of ignition, such as smoking materials and open flames, shall be prohibited in areas where benzoyl peroxide is used, handled, manufactured, or stored. (6) All spills of benzoyl peroxide shall be wetted down and cleaned up immediately. Spills of pure benzoyl peroxide and solid formulations containing benzoyl peroxide shall be thoroughly wetted down or mixed with water-wetted vermiculite, perlite, sand, clay, or other suitable material before being placed in closed containers made of polyethylene or other suitable material and used exclusively for benzoyl peroxide wastes. Transportation and use of benzoyl peroxide shall comply with all applicable federal, state, and local regulations. (c) Waste Disposal (1) Pure benzoyl peroxide may be burned if local, state, and federal regulations permit. It shall be mixed with an inert material, such as vermiculite, and only 1 pound or less shall be burned at one time. The material shall be placed in a trench and ignited from a distance. (2) Employers shall ensure that no pure benzoyl peroxide is flushed into sewage systems. (3) Water slurries of benzoyl peroxide wastes and dry, solid, or powder formulations shall be mixed with 4-10 times their weight of a 10% aqueous sodium hydroxide solution and neutralized before being flushed into any sewage system. (d) Vessel Entry (1) Entry into confined spaces, such as tanks, pits, tank cars, and process vessels which have contained benzoyl peroxide, shall be controlled by a permit system. Permits shall be signed by an authorized employer representative, certifying that preparation of the confined space, precautionary measures, and personal protective equipment are adequate and that prescribed procedures will be followed. (2) Confined spaces which have contained benzoyl peroxide shall be thoroughly ventilated, cleaned, washed, inspected, and tested for oxygen deficiency and for the presence of benzoyl peroxide and other contaminants before entry. (3) All efforts shall be made to prevent release of benzoyl peroxide into the confined space while work is in progress. (4) Confined spaces shall be ventilated while work is in progress to keep concentrations of airborne benzoyl peroxide at or below the recommended environmental limit and to prevent oxygen deficiency. (5) Individuals entering confined spaces where they may be exposed to benzoyl peroxide shall wear respirators as outlined in Section 4(b) and lifelines tended by another employee outside the space who shall also be equipped with the necessary protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephones, radio, or other suitable means) with the employee inside the confined or enclosed space shall be maintained by the standby person. The third employee, equipped to aid the other two if necessary, shall have general surveillance of their activities. (6) Hatch openings shall be large enough for two people to enter or exit simultaneously. # (e) Emergency Procedures For all work areas where there is a reasonable potential for emergencies involving benzoyl peroxide, employers shall formulate in advance the procedures specified below and any others appropriate for the specific operation or process and shall instruct employees in their implementation. (1) The employees shall be trained by periodic drills that simulate emergencies in a work situation. These drills shall involve evacuation procedures with a method of accounting for all personnel present in case of fire or explosion, handling of spills and leaks, location of remote controls for sprinkler systems, location and use of emergency water supplies and equipment and shutoff valves, and entry procedures for restricted areas. Procedures and emergency phone numbers for obtaining firefighting assistance, emergency medical care, and transportation of injured personnel shall be included. (2) Approved eye, skin, and respiratory protective devices as specified in Section 4 shall be used by personnel essential to emergency operations. (3) Employees not essential to emergency operations shall be evacuated from hazardous areas where benzoyl peroxide inhalation, skin or eye contact, or explosions may occur. The perimeters of these areas shall be delineated, posted, and secured. (b) If it has been determined that the concentration of benzoyl peroxide exceeds or may exceed the limit recommended in Section la, then the employer shall fulfill the following requirements: (1) A program of personal monitoring shall be instituted to identify and measure, or permit calculation of, the exposure of each employee occupationally exposed to airborne benzoyl peroxide. Source and area monitoring may be used to supplement personal monitoring. (2) In all personal monitoring, samples representative of the exposure to airborne benzoyl peroxide in the breathing zone of the employee shall be collected. (3) For each determination of the TWA concentration, a sufficient number of samples shall be taken to characterize employee exposure during each work shift. Variations in the employee's work schedule, location, or duties and changes in production schedules shall be considered in deciding when samples are to be collected. # III. BIOLOGIC EFFECTS OF EXPOSURE # Extent of Exposure Benzoyl peroxide, (C6H5C0)202, also called dibenzoyl peroxide, is a rhombic crystalline solid at room temperature [1,2]. Benzoyl peroxide is a flammable, solid, diacyl organic peroxide, which may decompose explosively if subjected to excessive heat, friction, or sudden shock [3][4][5]. If benzoyl peroxide is exposed to temperatures of 75-80 C for prolonged periods, it becomes unstable and may spontaneously decompose [4]. This type of sudden decomposition, a deflagration, is the rapid spreading of fire through a mass of reactive material [6]. This decomposition is accompanied by a 200-fold increase in volume [5] and yields a dense white smoke consisting of benzoic acid, phenyl benzoate, terphenyls, biphenyls, benzene, and carbon dioxide [7]. The resulting biphenyls promote the further decomposition of benzoyl peroxide [5,7] into products which can catch fire and ignite the remaining benzoyl peroxide. If this happens, or if the benzoyl peroxide itself ignites, a dense black smoke results [8] . The peroxide reacts violently with various organic and inorganic acids, amines, alcohols, metallic naphthanates, and other chemicals that are easily oxidized. Benzoyl peroxide also reacts violently with polymerization accelerators [4]. The presence of small quantities of water diminishes some of the hazardous properties of benzoyl peroxide [9]. During a series of tests on the ease of ignition of pure benzoyl peroxide and benzoyl peroxide with various proportions of water, pure benzoyl peroxide was shown to ignite violently with a loud noise, but benzoyl peroxide containing 5% water did not ignite at all. It was also observed that during this ignition test [9] it did not make any difference whether the total moisture content of the sample was equally divided between each granule or concentrated in 10-20% of the granules, as long as those granules were uniformly dispersed throughout the sample. Additional chemical and physical properties of benzoyl peroxide are presented in Table XIV -1 [1*2] . Benzoyl peroxide is synthesized commercially by a reaction of benzoyl chloride, sodium hydroxide, and hydrogen peroxide [10 (pp 14,85,187) , 11] . Excess water is removed to obtain pure benzoyl peroxide; the trace impurities remaining are benzoic acid and water. Water, plasticizers, corn starch, or other diluents are added to make the numerous commercial products containing benzoyl peroxide. Benzoyl peroxide has been produced commercially in the United States since 1927 [12]. By 1954, its yearly production was 1,768,000 pounds [13]; 8,829,000 pounds, 9,092,000 pounds, and 7,885,000 pounds were produced in 1973 [14], 1974 [15], and 1975 [16], respectively. Since benzoyl peroxide is a good source of free radicals, it is used in a number of industrial processes, particularly in the manufacture of plastics [5]. Benzoyl peroxide is a curing agent for silicone rubber [17], a source of free radicals in the resin cements used in dentistry [18], automobile body putty [10 (p 283),19], and roof bolting systems in the mining industry [20], and an initiator in the synthesis of polyvinyl chloride [3]. It is also a component of flour and cheese bleaches [21,22]. In the early 1900's, benzoyl peroxide was used to bleach edible oils, but this practice is now rare [10 (p 27 6)]. In the past, textiles and paper were also treated with it [11]. In medicine, it now is used in the treatment of acne [23] and of decubitus ulcers (bed sores) [24]. Formerly, it was applied as an aid in the treatment of poison ivy [25]. NIOSH estimates that 25,000 workers in the United States are potentially exposed to benzoyl peroxide or its formulations. Occupations involving possible exposure to benzoyl peroxide are listed in Table XIV-2. # Historical Reports Little was known about benzoyl peroxide until the end of the 19th century. In the Encyclopedia of Chemical Technology, Hooft [11] noted that Brodie synthesized benzoyl peroxide in 1858. One of the earliest references to benzoyl peroxide appeared in 1899 when Nencki and Zaleski [26] reported that it was converted to benzoic acid in the intestines of dogs. As early as 1921, benzoyl peroxide was used in Germany as a fixing agent in light microscopy [27]. It was also used at that time as an antiseptic and local anesthetic in the treatment of burns and ulcers, as reported by Farmer [27]. Benzoyl peroxide had previously been taken internally, but that practice was discontinued because of its poisonous action on the blood, which was not specifically described. However, in 1964, Tiunov [28] noted that Smirnova, using unspecified chemical methods, found that benzoyl peroxide had almost no hemolytic action. In 1930, Lamson [25] stated that powdered benzoyl peroxide was a theoretically ideal treatment for skin lesions caused by poison ivy because it reduced the spread of the rash and relieved itching. The flammability hazard of benzoyl peroxide treatment was not mentioned in the literature until 1931 when it was reported that a man whose poison ivy rash was being treated with benzoyl peroxide was injured by the ignition of bandages that were covering the powdered benzoyl peroxide on his hands [29,30]. When the bandages were ignited by a lighted cigarette, the benzoyl peroxide exploded, and the skin and several muscles of his right hand were destroyed. The author [29] retracted his recommendation of powdered benzoyl peroxide as a useful therapeutic agent, emphasizing its explosive properties; he recommended, instead, an ointment of an unspecified concentration of benzoyl peroxide in lubricating jelly, which he considered neither explosive nor extremely flammable. No references have been found indicating further use of benzoyl peroxide for the treatment of poison ivy. # Effects on Humans The effects of occupational exposure to and treatment with benzoyl given which defined the efficiency of standard impingers containing water for collecting benzoyl peroxide and alum, and there was insufficient analytical information to assess the reliability of the determinations. In addition, it was noted that the proportions of benzoyl peroxide to alum were extremely variable and did not reflect the proportion of the two chemicals in the flour bleach being processed. (1) polyethylene glycol, (2) polyethylene glycol containing 1% sulfur, polyethylene glycol containing 10% benzoyl peroxide, and polyethylene glycol containing 1% sulfur and 10% benzoyl peroxide [36]. All the subjects reacted to the benzoyl peroxide whether or not sulfur was present, but none reacted to the polyethylene glycol or sulfur. In 1973, Ede [38] discussed a double-blind study of 196 acne patients who were randomly divided into 4 groups. Three acne lotions and a placebo were tested. The lotions contained 5.5% benzoyl peroxide, 0.25% chlorohydroxyquinollne, and 0.5% hydrocortisone; 5.5% benzoyl peroxide and 0.25% chlorohydroxyquinollne; or 5.5% benzoyl peroxide. The placebo contained only the base lotion. The lotion was applied to affected areas 1 to 4 times daily for 4 weeks; however, the mean number of applications/day for the groups ranged from 2,2 to 2.5. The lotion was left on the skin for at least 3-4 hours. None of the patients exhibited any skin sensitivity to the lotions containing benzoyl peroxide at the end of the 4 weeks; however, 10 patients dropped out of the study for unspecified reasons. The following laboratory tests were performed during the study [38] on the blood and urine of 20 of the patients, 10 men and 10 women, to determine whether there were any systemic effects of the lotions: calcium, inorganic phosphorus, glucose, blood urea nitrogen, uric acid, cholesterol, total protein, albumin, and total bilirubin concentrations; activities of alkaline phosphatase, lactate dehydrogenase, and serum glutamic-oxaloacetic transaminase; complete blood count (hemoglobin, hematocrit, RBC, WBC with differential count) and urinalysis (specific gravity, pH, color, appearance, sugar, microscopic examination, albumin, and acetone). The results were within the normal ranges and indicated no systemic effects from any of the lotions. # Bloom [19], in 1975, reported that welders employed in the manufacture of diesel locomotives were exposed to a plastic body filler made of a talc-polyester resin and benzoyl peroxide. Two of four welders who were interviewed thought that the coughing they experienced during the day was caused by exposure to welding fumes and to plastic body filler dust. There was no evidence of skin irritation or sensitization. # A NIOSH Health Hazard Evaluation Determination discussed by Kingsley [39], indicated that telephone repair workers were exposed to a styrene hardener containing 50% benzoyl peroxide and 50% butyl benzoyl phthalate when new and replacement telephone cables were installed. A worker who was wearing disposable gloves would add the hardener to the polyester, manually knead the mass until it was the right consistency, and drop it down into a vault where another gloved worker would shape the compound around the splice. Each such operation required two or three tubes of hardener and took about 30 minutes. One crew normally coated splices once or twice a week. The vaults were naturally ventilated through the manhole covers. The workers did not report adverse effects from using the compound. # Accidents Hazardous properties of benzoyl peroxide, such as explosion and flammability, have resulted in accidents and serious injuries or death. The following incidents demonstrate that injuries were usually caused by ignorance of the hazards or by negligent handling. Other accidents that did not produce injury are discussed in Chapter V. Twelve pounds of pure benzoyl peroxide being added through a stainless steel funnel into a polymerization kettle exploded, killing the operator [3]. There were three possible reasons for thè explosion: (1) the funnel may have become heated during the operation, so that excessive heat may have caused the peroxide to explode; (2) the peroxide may have become contaminated with residual vinyl acetate from the polymerization reaction; or (3) a static discharge may have occurred. In another case, an employee escaped serious injury when a flash fire erupted in a 1-pound container of benzoyl peroxide and covered his safety glasses with melted benzoyl peroxide [3]. He was using a glass spatula to transfer benzoyl peroxide from the container to a laboratory scale [3]. As the spatula, which had just been cleaned and dried, was inserted into the container, the benzoyl peroxide burst into flame. The account of the accident indicated that contamination of the benzoyl peroxide may have caused the fire. It is also possible that the friction from the insertion of the spatula may have started it. In still another case, the owner of a plant that manufactured benzoyl peroxide sustained second degree burns from a fire started by an unknown quantity of benzoyl peroxide dust exposed to an arcing electric light switch [3]. The fire generated smoke and chemical fumes; eventually, there was an explosion. Lappin [40] found that a laboratory worker received hand injuries and lacerations when benzoyl peroxide in a 4-ounce, brown-glass container exploded as the plastic screwcap was being removed. The author thought that some benzoyl peroxide, along with other organic dust present in the laboratory, was caught in the threads and, as the cap was unscrewed, the friction caused the top layer of peroxide in the bottle to explode. The explosiveness of benzoyl peroxide was further illustrated when several thousand pounds of the compound exploded in a truck, causing severe property damage within a radius of several city blocks and injuring four people, one seriously [41]. A fire was seen seconds before the explosion occurred, but the exact cause of the accident was unknown. Investigators speculated that perhaps other chemicals had come in contact with the cargo of benzoyl peroxide or that an all-day exposure to hot sun had caused drying of the benzoyl peroxide. Another possibility was that the truck might have been bumped, dislodging the cargo. # Animal Toxicity There are few data on the effects of benzoyl peroxide on animals. The effects of inhalation, ingestion, skin painting, and injection of benzoyl peroxide have been examined. Two eye irritation tests with granular 78% benzoyl peroxide were conducted on eight albino rabbits by Wazeter and Goldenthal [42] . Though not specified in the report, 78% benzoyl peroxide granules commonly consist of 22% water and benzoic acid. Sodium fluorescein was put into the eyes when they were examined under ultraviolet light so that corneal damage could be detected. The eyes were examined before treatment with benzoyl peroxide and periodically afterwards. In the one test, 111.4 mg of 78% benzoyl peroxide (0.1 ml measured by volume) was put in the cupped conjunctival sac of the right eye of each of five rabbits; the eyelid was held shut for 1 second. The left eyes served as controls. After 5 minutes, the test eyes were washed with a gentle stream of water, regulated to deliver 300 ml in 2 minutes. The corneas showed no ulceration or opacity after 1, 24, 48, or 72 hours or after 7 days [42]. The irises appeared unaffected. The conjunctivae of two rabbits showed slight redness 1 hour and 24 hours after the washing, but this disappeared in 48 hours. Three of five rabbits exhibited conjunctival edema 1 hour after the washing, but this was not apparent at 24 hours. The authors concluded that, under these test In another eye irritation test [42], 120.7 mg of 78% benzoyl peroxide was placed in the cupped conjunctival sac of the right eye of each of three rabbits where it remained for 24 hours; the left eyes were controls. After 24 hours, the benzoyl peroxide was washed out with 300 ml of water for 2 minutes. The eyes were examined under ultraviolet light as described in the first test. The irises appeared normal after 1, 24, 48, and 72 hours and after 7 days. The conjunctivae of the rabbits exhibited various degrees of redness and conjunctival edema at 1, 24, 48, and 72 hours, but all adverse effects disappeared in 7 days. One rabbit had blanched conjunctival tissue at 1 hour, but normal color had returned within 24 hours. Examinations under ultraviolet light showed corneal opacity in the three rabbits after 24 hours but no corneal opacities at 48 hours. The only corneal damage in this experiment was revealed in one rabbit by the eye examinations done at 72 hours, and it had disappeared by the 7th day. Wazeter and Goldenthal [42] concluded that benzoyl peroxide was neither irritating nor corrosive to the eyes of albino rabbits if it was washed out within 5 minutes after being placed in the conjunctival sac; however, if 78% benzoyl peroxide was not washed out until 24 hours later, it proved to be a strongly irritating substance. It was not considered corrosive because corneal opacity lasted less than 6 days. In a third experiment, Wazeter and Goldenthal [42] tested the skin irritation potential of benzoyl peroxide on three male and three female New Zealand white rabbits. No control animals were mentioned. The hair was shaved from an area on the back of each rabbit, and the skin was then abraded with a scalpel blade. Five hundred milligrams of 78% benzoyl conditions, benzoyl peroxide was not irritating or corrosive to the eyes. peroxide was applied to each patch of skin and held in place for 4 hours with a gauze bandage. After 4 hours, the bandages were removed and the exposed areas washed with lukewarm water. The skin was examined for any injury or irritation from benzoyl peroxide at 4, 24, and 72 hours. The skin on the six rabbits appeared unaffected. The authors concluded that 78% benzoyl peroxide was neither a primary skin irritant nor a corrosive substance. Wazeter and Goldenthal [42] also performed a short-term inhalation study on 10 male Spartan rats housed in groups of 2 or 3. The rats were exposed at an atmospheric concentration of 24.3 mg/liter of 78% benzoyl peroxide added to a 59.1-liter glass test chamber supplied by two Wright dust feeders with a regulated airflow. None of the rats died during the test or the subsequent 14-day observation period [42]. The rats showed the following signs during the 4hour exposure period: eye squint, increased and decreased respiratory rates, difficulty in breathing, salivation, lacrimation, erythema (location unspecified), and an increase followed by a decrease in motor activity. All of the rats appeared normal at 24 and 48 hours. An unspecified number of rats exhibited signs of eye irritation consisting of corneal opacity and ulceration from the 5th to the 14th day. The authors concluded that 78% benzoyl peroxide was not highly toxic by the inhalation route of administration under the conditions of the experiment. A short-term oral toxicity test was performed by Wazeter and Goldenthal [42] with 78% benzoyl peroxide in water on five male Spartan albino rats. Each rat received one 5,000 mg/kg dose of 78% benzoyl peroxide suspended in corn oil. The rats took food and water ad libitum and were maintained in temperature-and humidity-controlled quarters during the 14-day study. No control animals were reported. Body weights of all the rats were recorded initially and at 14 days. None of the rats died during the study, and all exhibited normal weight gain. Under the test conditions, 78% benzoyl peroxide was not toxic by the oral route of administration. In 1958, Kuchle [43] described an experiment in which 15 organic peroxides, including benzoyl peroxide, were tested for their effects on rabbits' eyes. A "lentil-sized" amount of an undefined paste containing 50% benzoyl peroxide was placed in the conjunctival sacs of each of several rabbits, and unspecified amounts of a 93% benzoyl peroxide powder were placed in the conjunctival sacs of several other rabbits. No controls were mentioned. After 1 minute, the eyes were rinsed with tapwater, and any solid residues were removed with a cottovi swab. The eyes were then examined after 20 minutes, after 24 hours, then every other day for 1 week, and finally twice a week for 6 weeks. Neither form of benzoyl peroxide was considered to have had harmful effects on the rabbits' eyes; no evidence of burning or irritation was observed, and the corneas of the test animals were clear and had no opacities. Radomski et al [44] published, in 1948, a study in which three dogs were given a diet containing benzoyl peroxide-treated flour for 6 weeks. The purpose of the experiment was to determine the toxicity of candidate replacements, including benzoyl peroxide, for agene, an improving agent used to treat flour, which consisted of 1% nitrogen trichloride in air saturated with water vapor. Benzoyl peroxide was added to the flour (1 oz benzoyl peroxide/100 pounds flour or 0.625 g/kg). A short time before it was fed to the dogs, the mixture was steamed for 90 minutes, and nutrients were added to it. The nutritionally balanced diet contained 71.6% treated flour on a dry-weight basis. Because the authors did not state the amount of food consumed by each dog, the actual intake of benzoyl peroxide is unknown. The effects of steaming on benzoyl peroxide were not considered. The authors [44] stated that, since the 1920's, canine hysteria, sometimes called running fits, had been observed in dogs that had eaten agene-treated flour. No canine hysteria was observed in the dogs given the diet containing benzoyl peroxide, and, unlike dogs fed agene-treated flour, they behaved in a normal manner. In 1949, Arnold [45] described a study in which dogs were provided with a diet in which flour had been treated with 0.8 g of benzoyl peroxide/100 pounds of flour (0.02 g/kg). Chlorine at 20 g/100 pounds (0.44 g/kg), ammonium persulfate at 15 g/100 pounds (0.33 g/kg), and potassium bromate at 5 g/100 pounds (0.11 g/kg) were also used to treat the flour; the amounts were greater than those used commercially in flour bleaching. The diet contained about 80% treated flour on a dry-weight basis. This diet and other experimental diets were given intermittently to six dogs for periods ranging from 21 to 38 days with intervening times of 3-16 days. The dogs were observed for canine hysteria, but it was not seen in those dogs fed benzoyl peroxide-treated flour. One group of investigators [46] attempted to determine the oral LD50 of benzoyl peroxide in rats. Groups of two fasted rats each were given oral doses of benzoyl peroxide placed on a small amount of pea soup concentrate at 200, 400, and 950 mg/kg. None died. One of the rats that received 400 mg/kg had some vasodilatation, and one that received 950 mg/kg showed slight muscular weakness. The investigators concluded that the oral LD50 of benzoyl peroxide in rats is greater than 950 mg/kg. Skin irritation by benzoyl peroxide in an unspecified number of guinea pigs was also tested [46]. Patches of skin were chemically depilated, and pure benzoyl peroxide, in doses ranging from 0.25 to 1.0 g/kg, was held against the depilated skin under patches for 24 hours. The skin under the benzoyl peroxide was examined for any irritation or other injury. Slight erythema with some delayed scarring of the epidermis resulted. There were no deaths. A similar test was run on guinea pigs with a 10% solution of benzoyl peroxide in propylene glycol. The doses ranged from 5 to 20 ml/kg. Only slight erythema was observed; no deaths occurred. An inhalation test also described in this study [46] showed that an unspecified number of rats had no observable ill effects after being exposed to airborne benzoyl peroxide at an unspecified concentration for 3 hours. [49] reported the results of a series of tests to determine the effects of benzoyl peroxide incorporated in the diet or administered by subcutaneous injection or by skin painting on rats and mice. Each test lasted 120 weeks for rats and 80 weeks for mice; moribund animals were killed during the study. The age and weight of the animals at the start of the experiment were not reported. Three experimental groups, each composed of 25 male and 25 female rats and 25 male and 25 female mice, were given nutritionally balanced diets of wholemeal flour that was treated with a commercial flour bleach consisting of 18% benzoyl peroxide, 78% calcium sulfate, and 4% magnesium carbonate [49]. The control group contained the same number of animals as the experimental group but received untreated flour in their diet. The resulting benzoyl peroxide concentrations in the diet were 2,800 ppm, 280 ppm, and 28 ppm. These concentrations were selected because they were estimated to be 1,000, 100, and 10 times the normal human intake based on a yearly consumption of 200 pounds of flour/person. How much the animals actually ate was not reported, so exact dosages cannot be determined. Weight gains were recorded only for the rats during the first 16 months of the test. The rats whose diets contained flour treated with 2,800 ppm and 280 ppm benzoyl peroxide gained weight at a slower rate than the controls; the authors reported that this effect was not seen when the rats were caged singly in a diet preference test and an individual caging test [49]. Seventeen mice that received the 280-ppm diet were killed accidentally, and a large number of rats and mice in the entire colony showed signs of infection, the nature of which was not specified by the investigators. For these reasons, the statistical significance of the results cannot be accurately evaluated. A diet preference test and an individual caging test were conducted with 10 pairs of male rat littermates to determine if any differences in weight gain in the animals were the result of greater food intake with 1 of the diets [49]. One of each pair of the male littermates was given a flour-based diet containing benzoyl peroxide at 2,800 ppm, and the other was given the same diet without any benzoyl peroxide. Each rat was caged singly. The weight gain for the two groups was reported to be similar [49]. After 30 weeks, each of the control rats had gained an average of 355 g and had consumed an average of 4,870 g of the supplied diet; the experimental group had gained 350 g each and eaten 4,902 g of the supplied diet. Rats caged singly tended to increase food intake slightly. On the basis of the diet preference test and the caging test, they concluded that concentrations of 1,000 and 100 times the normal human daily intake of benzoyl peroxide in the diets may have reduced the nutritional value of the diet; whereas the diet containing 10 times the normal daily intake of benzoyl peroxide did not. Sharratt et al [49] provided diets of breadcrumbs made from flour treated with benzoyl peroxide to two groups of animals. The breadcrumbs given to 100 male and 100 female mice and 100 male and 100 female rats were prepared from bread made with flour containing benzoyl peroxide at 28 ppm. A group of 25 male and 25 female mice and 25 male and 25 female rats received a breadcrumb diet in which the flour had contained 2.8 ppm benzoyl peroxide. A control group of 100 male and 100 female mice and 100 male and 100 female rats was given a breadcrumb-based diet made from flour containing no benzoyl peroxide. Weight gains were reported only for the rats during the first 16 months of the test. There were no significant differences in the body weights of the rats given treated breadcrumbs made with treated flour and those of the controls except at 16 months, when the male rats that received the breadcrumbs made from flour containing 2.8 ppm of benzoyl peroxide weighed significantly more than the male control rats [49]. The authors considered this of doubtful importance, since all rats began to gain and lose weight erratically because of chronic infection in the colony. In another part of the study [49], rats and mice were given a single subcutaneous injection of what was described as a freshly prepared 20% suspension of benzoyl peroxide in starch solution. The dose for 25 male and 25 female rats was 120 mg of benzoyl peroxide, and, for 25 male and 25 female mice, it was 50 mg of benzoyl peroxide. Control rats and mice, 25 of each sex of each species, were each given an injection of the starch solution. All the rats and mice were provided with a commercial pellet diet. Body weights were reported only for the rats for the first 16 months. There was no difference in the rate of weight gain in the rats administered benzoyl peroxide and in their controls. No tumors were found at the injection sites in any of the rats or mice; there was no significant difference in the tumor incidence in the experimental animals and in the controls. Sharratt et al [49] also painted benzoyl peroxide on the back of the neck of 25 male and 25 female mice for 6 consecutive days. One drop (about 50 mg) of a freshly prepared 50% suspension of benzoyl peroxide in flour paste was applied to each animal. A similar number of control mice were painted with only the flour paste. Both groups of mice were fed a commercial pellet diet. No tumors appeared at the sites of painting, and there was no significant difference in the overall tumor incidence between the experimental animals and the controls. Sharratt et al [49] also administered a multiple treatment to groups of 25 male and 25 female rats and 25 male and 25 female mice. There were no control animals for this part of the experiment. The rats and mice received the flour-based diet containing 2,800 ppm benzoyl peroxide and subcutaneous injections of benzoyl peroxide as in the previously described tests. The mice were also painted with flour paste containing benzoyl peroxide in the manner described previously. Body weights were reported only for the rats for the first 16 months. Except for a slight decrease at the 8th month, the weight gain of the rats in this multiple treatment group was not significantly different from that of the controls in the other tests described previously. No tumors were found at the sites of injection or painting. Sharratt et al [49] observed that the entire colony of mice and rats used in their experiments with benzoyl peroxide had many abnormal changes irrespective of the test performed on the animal. There was a statistically significant incidence of atrophy of the testicles in the rats given the diet based on flour treated with benzoyl peroxide at 2,800 ppm and in the rats receiving diets of breadcrumbs made with flour treated with benzoyl peroxide at 28 ppm and 2.8 ppm. The authors suggested that this atrophy was caused by benzoyl peroxide, which probably marginally decreased the amount of vitamin E in the diet. This conclusion was not supported by any analyses of the diets, and the degree of testicular atrophy in each rat was not stated; therefore, no definitive conclusion can be made. While the authors [49] concluded that benzoyl peroxide was not carcinogenic in rats or in mice under the test conditions, it does not seem that this was a definite experiment of carcinogenicity or of other types of chronic toxicity. The length of the observation periods and the experimental design were probably adequate; however, there may have been insufficient numbers of animals to detect carcinogenicity. In addition, it is uncertain how much benzoyl peroxide remained unchanged after it was added to the diets. Other investigators have studied the action of benzoyl peroxide in animals to ascertain whether it is carcinogenic. Hueper [50] conducted a study to determine if benzoyl peroxide, when used as a polymerization catalyst for silicone rubber, had carcinogenic properties. According to the manufacturer, benzoyl peroxide was totally destroyed in the rubber curing process. A piece of silicone rubber that had been cured with benzoyl peroxide was Implanted subcutaneously in the neck of each of 21 male and 14 female Bethesda black rats. In another group of Bethesda black rats, a gelatin capsule containing 50 mg of benzoyl peroxide was implanted subcutaneously in the nape of the neck of 20 males and 15 females. No control animals were used. The rats were observed for 24 months. In the rats with silicone rubber implants, 10 sarcomas occurred at the implantation sites, and there were neoplasms at other sites, viz, 4 round cell sarcomas of the ileocecal lymph nodes, 3 mesotheliomas of the peritoneum, and 1 carcinoma of the bladder [50]. There were no tumors at the implantation sites in the rats with the encapsulated benzoyl peroxide, although seven of these rats had malignancies at other sites, including four round cell sarcomas of the ileocecal lymph nodes, one mesothelioma of the peritoneum, one epidermoid carcinoma of the snout, and one myxosarcoma of the anal region. Benign tumors, including two adenofibromas of the breast and one cystic cholangioma, appeared in three other rats in the group with the benzoyl peroxide implants. Hueper concluded that the absence of tumors at the sites of implantation provided conclusive evidence that benzoyl peroxide was not implicated in the induction of polymer cancers. Van Duuren and his colleagues [51] studied the carcinogenicity of a group of epoxides, lactones, and peroxides including benzoyl peroxide. The backs of 30 male Swiss-Millerton mice were painted 3 times weekly with about 100 mg of a 5% benzene solution of benzoyl peroxide. Controls were similarly painted 3 times weekly with 100 mg of benzene alone. The median survival times were 292 days for the mice exposed to benzoyl peroxide and 264, 262, 412, and 292 days for the four control groups. The animals were examined regularly for tumors. None of the mice developed carcinomas; one mouse exposed to benzoyl peroxide developed a benign tumor. The authors concluded that benzoyl peroxide showed no carcinogenic activity in this experiment. In 1972, Epstein et al [52] tested 174 agents, including benzoyl peroxide, for dominant lethal mutations in ICR/Ha Swiss mice. Benzoyl peroxide at doses of 54 and 62 mg/kg was administered by intraperitoneal (ip) injection to seven and nine male mice, respectively. Each animal was then caged with three untreated virgin female mice for 1 week. The females were replaced each week for a total of 8 weeks and then killed and examined for pregnancy (total implants), early fetal deaths, and late fetal deaths. Since late fetal deaths were very rare, total implants and early fetal deaths were the only implant features analyzed. The results obtained in the experimental mice were not significantly different from the results in the control mice [52]. Benzoyl peroxide, in the dose range and in the strain of mice used, met none of the screening criteria for these dominant lethal mutations. The authors recommended additional tests to confirm the apparent lack of mutagenicity of benzoyl peroxide. An evaluation of the mutagenic properties of 78% benzoyl peroxide was reported in 1975 [53]. The yeast Saccharomyces cerevisiae, strain D4, and the bacterium, Salmonella typhimurium, strains TA-1535, TA-1537, and TA-1538, were used in modified Ames assays. Tissue homogenates from mice, rats, and monkeys were added to the culture media to see if benzoyl peroxide might be activated to a mutagenic compound. It was concluded that benzoyl peroxide exhibited no mutagenic activity in any of the in vitro microbial assays performed; this conclusion is consistent with the data presented. However, the benzoyl peroxide was added in dimethylsulfoxide, a solvent in which it is not soluble, although it did, nevertheless, allow the benzoyl peroxide to come in contact with the yeast and bacteria. # Correlation of Exposure and Effect The one report [31] on the effects of inhalation of airborne dust containing benzoyl peroxide on humans stated that two plant inspectors had symptoms of nose and throat irritation on 2 days when the concentrations of benzoyl peroxide ranged from 1.34 to 17.0 mg/cu m. On the 3rd day, when the concentrations of airborne benzoyl peroxide were 2.58-82.5 mg/cu m, they had symptoms of eye irritation, as well as of nose and throat irritation. However, no definite conclusions can be made from this report because the analytical information provided is insufficient for the reliability of the determinations to be assessed, so the concentrations of airborne benzoyl peroxide are questionable. Also, the presence of alum in the airborne dusts may have caused or contributed to the irritation. observed that only 1 of 180 patients treated with benzoyl peroxide could not tolerate the treatment. It was not stated whether this patient had an allergic response or a skin irritation. There has been no evidence of systemic toxicity caused by benzoyl peroxide. Dogs given diets containing flour treated wih 0.8-28 g of benzoyl peroxide/100 pounds of flour had no apparent adverse effects [44,45]. No data were presented that would indicate the amount of benzoyl peroxide that remained in their diets after they were prepared, which involved steaming the flour treated with the compound. Sharratt and his colleagues [49] noted that male and female rats given benzoyl peroxide at concentrations of 280 or 28 ppm in a flour-based diet gained weight at a slower rate than the control rats; male rats given a diet with breadcrumbs made from flour treated with benzoyl peroxide at a concentration of 2.8 ppm gained weight at a rate similar to that of the controls. In another study [46], single dietary doses of 950, 400, or 200 mg/kg produced no ill effects. Ingestion of benzoyl peroxide in amounts far greater than those normally used to treat commercial flour had no apparent toxic effects in rats and dogs [42,[44][45][46]49]. However, much of the benzoyl peroxide in the diets of these animals may have decomposed to benzoic acid by the time it was consumed. Horgan et al [47] reported that, in mice, the LD50 of benzoyl peroxide administered through ip injection was 4.8 mg/mouse; later, Philpot and Roodyn [48] calculated an LD50 in mice of 4.1 mg/mouse for benzoyl peroxide given by ip injection. Sharratt et al [49] reported that a subcutaneous injection of 50 mg of benzoyl peroxide/mouse (2,500 mg/kg) caused an abscess that healed in several weeks; no deaths occurred. Sharratt et al [49] also gave rats 120 mg of benzoyl peroxide by subcutaneous injection with no apparent adverse effects. The absorption of benzoyl peroxide in mice appears to vary greatly depending on the site of injection. Laboratory tests reported by Ede [38] on 10 men and 10 women using acne medications containing benzoyl peroxide were normal, indicating no systemic effects from dermally applied benzoyl peroxide. No data were found that dealt specifically with absorption of benzoyl peroxide through the skin or from different sites of injection in humans or animals. The flammability and explosiveness of pure benzoyl peroxide have been the cause of accidents involving serious injuries and fatalities [3,40]. Accidents involving only property damage are summarized in Chapter V. # Carcinogenicity, Mutagenicity, Teratogenicity, and Effects on Reproduction The results of experiments designed to show if benzoyl peroxide has any carcinogenic activity when it is implanted [50], painted on skin [49,51], or injected [49] were negative. The results of tests to detect mutagenic effects of benzoyl peroxide in a modified dominant-lethal assay with mice [52] and in Ames assays with bacteria and yeast [53] were also negative. No data on teratogenesis or other effects of benzoyl peroxide on reproduction were found. Another sample taken during another packing operation indicated that the total dust concentration was 0.16 mg/cu m. Both of these dust concentrations were below the existing federal environmental limit for benzoyl peroxide of 5 mg/cu m. # Sampling and Analysis During industrial operations, benzoyl peroxide may escape into the environment as airborne dust [10 (p 16)]; however, there currently are no validated sampling and analytical methods specific for airborne benzoyl peroxide. Kaznina [54] used a method for sampling and analysis in which the air samples were drawn through a filter into an absorber containing 5 ml of ethyl alcohol. Analyses of the samples for benzoyl peroxide were performed by ultraviolet spectrophotometry. The method was sensitive for benzoyl peroxide to a concentration of 1.0 ;ug/ml. Benzoyl peroxide, styrene, and dimethylaniline are present simultaneously where styrene-containing plastics are prepared [54]. The method was reported to have limited use because of interference by dimethylaniline and styrene, which were also present in the operation. Therefore, an analysis based on ultraviolet spectrophotometry would be of limited value because much of the benzoyl peroxide produced each year in the United States is used in the production of polystyrene [5]. Dugan [55] and Dugan and O'Neil [56] determined benzoyl peroxide by an analytical colorimetric method. A colored complex resulted when benzoyl peroxide was used to accelerate the reaction between methanol and N,Ndimethyl-p-phenylene diamine sulfate. The relationship of the color intensity and the amount of benzoyl peroxide present in solution followed Beer's Law at peroxide concentrations of 5-30 Mg/ml but deviated at 40 ¿¿g/ml. For this analytical method to be accurate, time and temperature must be held constant because the reaction proceeds slowly without the addition of peroxide [57]. The authors [56] stated that molecular oxygen might interfere with the reaction as it does with many colorimetric methods. The time and temperature requirements, as well as the possible interference of molecular oxygen, make this method undesirable for analysis. Banerjee and Budke [58] also used a colorimetric method of analysis for benzoyl peroxide. Benzoyl peroxide was dissolved in a mixture of acetic acid and chloroform; potassium iodide was then added. The absorption of the liberated iodine was measured at 470 nm, and the amount of benzoyl peroxide in the sample was determined from a standard curve. This method may be hazardous because explosions have occurred when chloroform and benzoyl peroxide were mixed and then heated above room temperature [59][60][61]. Furthermore, NIOSH has concluded that chloroform is carcinogenic (letter from Director, NIOSH, to Assistant Secretary of Labor, OSHA, June 1976). This analytical method is not specific for benzoyl peroxide but determines total peroxides. Airborne methylethylketone peroxide (MEKO) was analyzed by a colorimetric method (T Anania, written communication, January 1977). A known volume of air containing MEKO was drawn through a U-tube filled with dimethyl phthalate in which the benzoyl peroxide dissolved. The solution was transferred to a test tube, and diphenylcarbohydrazide, a color reagent, was added. This solution was compared to a standard solution in a spectrophotometer. When benzoyl peroxide was analyzed by this method, at the lowest level, 50 jug/sample, the color intensity was equivalent to that produced by 1.5 Mg of MEKO. After an initial relative linearity in the range of 0-100 Mg/sample, benzoyl peroxide, in increasing quantities, developed a progressively lower color intensity/unit and gave a curvilinear standard curve. Although no recommendations were made by the author, this degree of curvature is undesirable for a quantitative analysis. Dolin [62] used methods for sampling and analysis that were not specific for benzoyl peroxide. One cubic foot of air/minute was drawn through a Greenburg-Smith impinger containing 75 ml of doubly distilled water for times varying from 13 to 37 minutes. Aliquots of the sampling solution were added to flasks containing a mixture of 0 .75% aqueous potassium iodide and a freshly prepared 0.50% starch solution, which were then allowed to stand from 1 hour to overnight. The color intensity was measured in a spectrophotometer or visually compared with a set of color standards prepared from known concentrations of benzoyl peroxide. The relationship of the developed color in the standards to the concentration of benzoyl peroxide followed Beer's Law, and a standard curve was constructed. The concentrations of benzoyl peroxide in the samples were read from the standard curve. Dolin found that, unless the standards were prepared at the same time as the sample solutions, the measurement error was as high as 25%. With this method, a spectrophotometer can detect as little as 1 jug of benzoyl peroxide; as little as 3 f i g can be detected visually. The method was not specific for benzoyl peroxide but indicated total peroxides. Dolin used a standard impinger in his sampling method but gave no data on the collection efficiency of the impinger with distilled water as an absorbent. Sampling and analytical methods have been developed that allow specific analysis for benzoyl peroxide. A known volume of air is drawn through a membrane filter. The benzoyl peroxide is subsequently extracted from the filter and analyzed by high pressure liquid chromatography [63]. When an air sample size of 90 liters was collected, by drawing air at a rate of 1.5 liters/minute through a 37-mm diameter mixed cellulose ester membrane filter with a pore size of 0.8 ¿¿m, a collection efficiency of 1.00 was determined. Storage stability studies on samples collected from a test atmosphere at a concentration of 7.30 mg/cu m indicated that, after 1 week with the samples held in the filter cassettes at room temperature, there was a 9.3% decrease in the amount of benzoyl peroxide recovered from the filter. Benzoyl peroxide was extracted from the filter with ethyl ether [63]. Tests showed that benzoyl peroxide is stable in ethyl ether at room temperature for at least 1 week. Thus, there may be up to a 9.3% loss of benzoyl peroxide if the samples are not extracted immediately or refrigerated. Analysis of the samples by high pressure liquid chromatography is subject to interference from any compound that has the same retention time as benzoyl peroxide at the operating conditions used [63]. Although retention time data on a single column cannot be considered proof of chemical identity, an interfering compound can be eliminated as an interference by altering operating conditions, using a different column packing, or using a selective detector. The coefficient of variation for the total sampling and analytical method in the range of 3.12-19.10 mg/cu m was 0.060, which corresponds to a standard deviation of 0.30 mg/cu m at an air concentration of benzoyl peroxide of 5 mg/cu m. The sampling device is small and portable, and it involves no liquids. The samples collected on membrane filters are analyzed by means of a quick instrumental method. This method has been shown to provide sufficient accuracy, sensitivity, and precision within the range required to determine compliance with this standard for benzoyl peroxide. Other methods have been reported for the determination of benzoyl peroxide in pharmaceuticals [64,65], flour [66], cheese [22], fats [67], and oils [67]. In 1967, Gruber and Klein [64] reported the comparison of spectrophotometric, titrimetric, and polarographic techniques in testing the stability of pharmaceuticals containing benzoyl peroxide. The results of the polarographic and spectrophotometric methods, when they were used to show the degradation of benzoyl peroxide at high temperatures, were in good agreement. The titrimetric method was far less sensitive than the other two and did not differentiate between benzoyl peroxide and some of its decomposition products. All three methods are colorimetric, and none is specific for benzoyl peroxide. In 1975, Daly et al [65] reported difficulty in reproducing the results of Gruber and Klein [64] and suggested another titrimetric method as a more accurate means for determining the content of benzoyl peroxide in pharmaceuticals. The authors [65] noted that, although alkylhydroperoxides and dialkyl peroxides would interfere with this method, commercial pharmaceutical creams and lotions containing benzoyl peroxide would probably not contain these other classes of peroxides. The American Oil Chemists Society (AOCS) [67] published their official method for analyzing total peroxide in fats and oils in 1960; it was reapproved in 1973. The described method was a titrimetric procedure that was not specific for benzoyl peroxide. It is recommended that total dust concentrations be monitored routinely by collecting breathing zone samples on a preweighed glass-fiber filter as detailed in Appendix I. Glass-fiber filters have been selected for sampling because they will efficiently collect airborne dust particles. In addition, being relatively free of organic matter, they are less likely to form explosive mixtures with benzoyl peroxide than filters like cellulose paper. After the sample is collected, the weight of total dust is determined by gravimetric analysis. The filter is reweighed with the same balance that was used for the preweighing, and the difference between the tare and final weights is determined. Before each weighing, the filter should be equilibrated in a constant humidity chamber, and a static charge neutralizer should be used to improve the reproducibility of the weight determinations and thus enhance gravimetric accuracy. The recommended gravimetric method is described in detail in Appendix II. In many applications, one should not have to do more than measure total dust. However, if the total airborne dust exceeds the recommended benzoyl peroxide environmental limit of 5 mg/cu m, the gravimetric analysis must be followed by a colorimetric analysis for total peroxide developed from a method by Dolin [62]. The filter is placed in a flask containing a mixture of potassium iodide and starch solution which is oxidized by benzoyl peroxide and other peroxides to form a blue iodide-starch complex. The filter should remain in the solution for 12 hours to permit the blue color to develop from the iodide-starch complex. The color intensity is measured in a spectrophotometer or visually compared with a set of color standards. The concentration of total peroxides should be calculated as benzoyl peroxide. Other oxidizing agents would also produce the iodidestarch complex and give erroneously high concentrations when they are present with benzoyl peroxide in the sample. This interference, however, would never produce a calculated benzoyl peroxide concentration lower than the actual concentration. The recommended analytical method is described in detail in Appendix II. # Engineering Controls Benzoyl peroxide should be protected from contact with sparks, All metal surfaces that benzoyl peroxide comes in contact with should be grounded and bonded [4]. Conductive flooring or mats will also aid in the control of static electricity [4]. Benzoyl peroxide and its formulations should be stored where there are no sources of excessive heat or ignition, [4] such as open flames, electrical devices [71], and exposed steam lines or wall radiators, in the storage area [4]. Futhermore, benzoyl peroxide should not be exposed to direct sunlight [4,71]. If benzoyl peroxide is exposed to temperatures of 75-80 C for prolonged periods of time, it becomes unstable and may spontaneously decompose; if heated to just above its melting point (104 C), it will instantaneously and violently decompose [4]. When benzoyl peroxide must be mixed with other materials, the temperature of these other materials should be below 50 C [4]. Benzoyl peroxide may react violently with various organic and inorganic acids, amines, alcohols, metallic naphthanates, polymerization accelerators, and other chemicals that are easily oxidized [4]. Benzoyl peroxide will decompose at room temperature in the presence of small amounts of tertiary arylalkylamines which are used in curing polyester resins. Many transition metal ions also catalyze the decomposition of benzoyl peroxide [77]. Direct or reflected sunlight may cause decomposition of benzoyl peroxide [71]. Decomposition of benzoyl peroxide is accompanied by a 200-fold increase in volume [5] and yields a dense white smoke consisting of benzoic acid, phenyl benzoate, terphenyls, biphenyls, benzene, and carbon dioxide [7]. The decomposition of benzoyl peroxide may be preceded or followed by fire [5]. If benzoyl peroxide or its decomposition products catch fire, dense black smoke is produced [8 ]. The resulting biphenyls promote the further decomposition of benzoyl peroxide [5,7]. Formulations of benzoyl peroxide are generally less hazardous than the pure compound [9,77]. In safety tests, the burning rate of a benzoyl peroxide formulation containing 25% water was not as intensive as that of pure benzoyl peroxide [7]. Formulations containing plasticizers also generally burn slower than does pure benzoyl peroxide; however, a 50% benzoyl peroxide paste with tricresyl phosphate decomposed at a lower temperature than that required to explode pure benzoyl peroxide [78]. Appendix IV explains two hazard classification sytems that relate to the physical properties of all organic peroxides and indicate the precautions that should be observed for their safe handling, use, and transporation; they give no indication of toxicity. Tests that evaluate the total energy release of a compound, the rate at which the energy is released, and the ease of ignition and decomposition are the basis for such hazard classifications. Employers should be aware of the appropriate hazard classification of the benzoyl peroxide formulations used in the workplace and should institute pertinent work practices. # Accidents The flammability and explosiveness of benzoyl peroxide have caused accidents; those which resulted in injuries or fatalities are discussed in Chapter III. Other accidents, involving damage, have been described. Knowledge of the physical properties of benzoyl peroxide and correct work practices might have prevented some of the accidents or at least lessened their severity. Malkemus [5] reported that 1 pound of benzoyl peroxide exploded after it had been removed from its original shipping container, placed in an open 1-quart can, and set under a window exposed to the sun. He [5] stated that the heat from the sunlight contributed to the explosion and that the can may have been contaminated with a reactive chemical. A report from the American Insurance Association [3] included accounts of several accidents. A tractor-trailer carrying 300 pounds of benzoyl peroxide in 1-pound containers sideswiped another trailer, and the benzoyl peroxide exploded. All of the benzoyl peroxide was consumed in the explosion, and no fire resulted. In another accident, an unspecified quantity of benzoyl peroxide caught fire because friction was generated by a broom used to sweep it off the floor. The fire spread to benzoyl peroxide stored on the second floor of the building. A third accident reported by the American Insurance Association [3] occurred at a reinforced-plastics manufacturing plant. There was an explosion in a warehouse where 1,000 pounds of organic peroxides were stored. The report implied that benzoyl peroxide was present. The resulting fire spread to several adjoining buildings. Spilled peroxide and careless smoking were given in the report as possible causes of the accident. A blended mixture of 30% benzoyl peroxide and unknown quantities of magnesium carbonate, hydrogen peroxide, sodium hydroxide, and oleic acid exploded while being dried in a steam-heated continuous drying oven [3 ]. There was a secondary explosion and flash fire in the building. The benzoyl peroxide apparently decomposed inside the oven, releasing what was described as a white, copious, flammable gas. Three sides and the top of the oven were blown out as much as 2 feet. In 1974, Bolt and Joyce [79] described explosions which occurred during the alkylation of polyhalomethanes by alkanes and alkadienes in the presence of catalytic amounts of benzoyl peroxide. A reactor was charged with 100 g of carbon tetrachloride and 0.40 g of benzoyl peroxide. The reactor was then pressurized with ethylene and heated with agitation. Twenty minutes after the reaction had started, when the temperature was 94 C and the pressure was about 14,230 pounds per square inch (psi), an explosion occurred which blew out the gas inlet line near the reactor. An increased ratio of water to carbon tetrachloride resulted in no further explosions when the reactor was operated at 9,600 psi and 110 C; 100 g of carbon tetrachloride, 100 g of water, and 0.23 g of benzoyl peroxide were used. The investigators [79] stated that the reaction can occur without incident at a lower pressure, such as 1,400 psi with a temperature as high as 120 C when 0. acclerators, that will readily react with benzoyl peroxide [3]. Benzoyl peroxide and its formulations should always be stored in their original containers. In addition, because of possible contamination, no benzoyl peroxide which has been removed should be returned to its original container. Benzoyl peroxide containers should be kept closed when not in use to prevent contamination [71]. Contamination of benzoyl peroxide may result in decomposition or fire [3]. No screw tops should be permitted on containers used for formulations of benzoyl peroxide if pure benzoyl peroxide could accumulate in the screw threads [78]; an accident occurred when a screwcap bottle of benzoyl peroxide was being opened [40]. Precautions should be taken so that wet benzoyl peroxide formulations do not dry out. Ultraviolet radiation will, like heat, increase the rate of decomposition of benzoyl peroxide [80]. Sufficient open space should be left between stacks of peroxide containers in storage areas. When hazardous benzoyl peroxide formulations must be refrigerated, explosionproof refrigerators should be used for this purpose [72]. Only clean, properly designed equipment should be used for benzoyl peroxide and its formulations; containers should be made of polyethylene or stainless steel. The use of copper, brass, lead, zinc, and galvanized equipment should be avoided because reactions in such equipment may accelerate decomposition of organic peroxides [71]. Benzoyl peroxide should be brought into the process area in the original shipping container and in quantities limited to the amounts required for daily use. Only small quantities of pure benzoyl peroxide, definitely not more than 1 pound, should be handled at a time [5]. If large quantities of the peroxide start to decompose, the decomposition of the outside layer confines the inner mass and increases the rate of decomposition, causing an explosion [5]. A separate area should be provided for premixing benzoyl peroxide with resins [72], The accelerator should be mixed with the resin before benzoyl peroxide is added to prevent violent decomposition [71]. Work practices for fibrous glass and plastic fabricators have been recommended to minimize the hazardous properties of benzoyl peroxide [81,82]. No pure benzoyl peroxide, without diluents, should be allowed in any grinding operation because explosive decomposition may occur [71]. Benzoyl peroxide may explode if it is recrystallized from hot chloroform [59][60][61] . The peroxide can be safely recrystallized from chloroform at room temperature if methanol is added to the solution [59], However, as was mentioned in Chapter IV, Sampling and Analysis, chloroform has been implicated as a carcinogen, so an alternative solvent should be considered. All containers of benzoyl peroxide and its formulations should be properly labeled. Labels for benzoyl peroxide formulations should follow the regulations in Hazardous Industrial Chemicals, ANSI, Z129.1. Shipping labels should comply with the US Department of Transportation regulations and other applicable statutes, regulations, and ordinances [4]. Warnings should be posted in places where benzoyl peroxide is used and stored. The warnings should briefly and concisely state the important safety precautions to be adhered to within the area [4]. These warning placards should also indicate that these areas are accessible only to authorized personnel. Exits should be easily accessible and clearly marked. The location of emergency and first-aid equipment should also be easily accessible and clearly marked. The Department of Transportation regulations, 49 CFR 173.157 and 178.58, specify that benzoyl peroxide wet with at least 30% water by weight should be packaged in quantities not to exceed 1 pound. It is important that fire-resistant material separates the individual bags so that the decomposition of benzoyl peroxide in one bag is less apt to affect the other bags in the box [5]. # Housekeeping and Maintenance The hazardous nature of benzoyl peroxide makes it imperative that housekeeping duties be performed continually under adequate supervision. Failure to follow these procedures has caused fires and accidents [71]. Even small amounts of benzoyl peroxide are potentially dangerous, and they may unpredictably decompose if subjected to any friction, heat, or shock [4]. Benzoyl peroxide formulations, such as pastes or the wet peroxide, may separate into their respective components through evaporation or freezing [6,76,83]. Thus, these small amounts of benzoyl peroxide formulations may be dangerous if not cleaned up from the floor and from the equipment in the process areas. The accidental decomposition of these traces of benzoyl peroxide could initiate the decomposition of all the benzoyl peroxide in the surrounding area [61] . Wet mops or other implements that will minimize sparks and friction should be used to clean up spills; a fire has resulted when the friction between a broom and benzoyl peroxide on the floor ignited the peroxide [3]. All equipment should be cleaned meticulously to avoid possible violent reactions between benzoyl peroxide and reactive chemicals. Ducts should be cleaned and inspected regularly to prevent the accumulation of benzoyl peroxide. Benzoyl peroxide should either be removed or covered during maintenance and repair work [71]. Where benzoyl peroxide formulations are used to bleach flour or catalyze certain organic reactions, the proportion of benzoyl peroxide is generally so small in relation to other chemicals present that the nature of these chemicals, rather than that of benzoyl peroxide, may dictate the housekeeping and maintenance procedures [4] . The grounds surrounding process and storage buildings must be kept cleared of vegetation and all other combustible materials, such as trash, to prevent the spread of fire if one should occur [71,72]. Maintenance and repair work in areas where benzoyl peroxide is used, stored, or manufactured should be authorized by the appropriate supervisor [3,71]. # Spills and Waste Disposal Spills should be wetted with water and cleaned up immediately with a wet mop or other nonsparking implements [10 (p 9)]. Vacuum units should be operated from a remote location away from electrical contacts; filter bags, as well as the vacuum lines, should be grounded to prevent static charge buildup. Care should be taken that benzoyl peroxide wastes are not mixed with other materials or chemicals, such as oxidizing or reducing agents, that might create hazardous conditions. A nonreactive container, such as one made of polyethylene, reserved only for benzoyl peroxide wastes, should be used to store the wastes until their disposal. Benzoyl peroxide should not be disposed of by burning unless it has been thoroughly wetted down or mixed with water-wetted vermiculite, perlite, or another inert substance [84]. Water slurries of benzoyl peroxide wastes may be destroyed by gradually adding small amounts of the slurry to 10 times its weight of 10% sodium hydroxide solutions [4,84] . There should be sufficient agitation or stirring of the mixture so that there is no lump formation or settling. Water may be added to prevent thickening of the mixture that would make stirring difficult. The resulting slurry of sodium benzoate should be checked for neutrality and may be flushed into the sewage system if local regulations permit. Pure benzoyl peroxide itself should never be flushed into the sewage system [78]. Additional details of inactivating and disposing of benzoyl peroxide are described in Appendix V. If wetted vermiculite or perlite has been added to a benzoyl peroxide spill, the water should be drained off and the waste water added to the waste slurry. The remaining material may be burned in an open incinerator or otherwise disposed of in accordance with local, state, and federal laws. If the material is burned, it should be placed in a shallow trench and ignited from a distance of at least 6 feet. When benzoyl peroxide becomes mixed with an unknown material, it should be considered contaminated and disposed of properly [72], If bags and cartons that formerly contained benzoyl peroxide are to be destroyed, they should be placed in a special waste collection drum provided for that purpose. The contents of the drum should be kept wet until they can be carefully burned in an area reserved for that purpose be worn by employees for protection when they are opening shipping boxes of pure benzoyl peroxide [4] or otherwise handling pure benzoyl peroxide. Aprons made of rubber or another appropriate material are recommended for added protection when handling benzoyl peroxide and its formulations. Plastic aprons that generate static electricity should not be used [4]. All personal protective clothing and equipment should be cleaned, inspected on a regular schedule, and replaced when worn out or broken. The employer is responsible for ensuring that such clothing and equipment are stored in suitable designated containers or locations when not in use. Respiratory protection as specified in Chapter I must be used whenever airborne concentrations of benzoyl peroxide cannot be controlled to the recommended workplace environmental limit by either engineering or administrative contro.ls. # Sanitation Protective clothing should be kept apart from the workers' street clothing in lockers with two compartments provided for that purpose. To minimize the potential for explosion or fire, workers must not eat or smoke where benzoyl peroxide is manufactured, used, or stored. Workers should also wash their hands before eating, smoking, or using the lavatory. A supply of potable water must be available near all places where there is potential contact with benzoyl peroxide and its formulations. and ensure that it is clearly marked, located in an easily accessible place, and maintained in working order. Firefighters should be informed that the dense smoke produced by benzoyl peroxide necessitates the use of a lifeline and a self-contained breathing apparatus [4,10 (p 86)] in addition to their standard firefighting clothing [4]. Local fire units and rescue squads should be apprised of the types of emergencies that may arise before any emergencies occur. The necessary phone numbers for such emergency assistance must be prominently posted in areas where emergencies are likely to occur. Areas where pure benzoyl peroxide is manufactured, packaged, and stored should not contain firefighting equipment; if a fire occurs, these areas should be evacuated immediately; employees should not attempt to control this type of fire. However, firefighting equipment should be well marked and located in every room and area where formulations of benzoyl peroxide are stored. If a fire occurs near an organic peroxide storage area, the containers within the storage area should be kept continually wetted to prevent overheating. Appropriate warning alarms that are automatically activated by heat or smoke should be installed in all benzoyl peroxide storage and work areas. In addition, an independent alarm system that can be controlled manually and whose controls are readily accessible to employees is advisable if smoke or heat is considered insufficient to trigger the automatic alarms. The inspection report did not specifically state that benzoyl peroxide was the cause of the discomfort or whether potassium aluminum sulfate or magnesium carbonate in the dust caused or contributed to the irritating effects. The methods of analyses were not described. Since there is no validated method of sampling and analysis for benzoyl peroxide, the method used to analyze the collected samples was probably not specific for this compound. The possible toxic effects of airborne benzoyl peroxide on humans cannot be accurately assessed because the report lacks essential data. Studies have indicated no carcinogenic [49][50][51] or mutagenic [52,53] effects from benzoyl peroxide. Sharratt et al [49] found that benzoyl peroxide had no carcinogenic activity from skin painting of mice, subcutaneous injection in mice and rats, and feeding studies in mice and rats. Van Duuren et al [51] reported that benzoyl peroxide showed no carcinogenic activity when used in skin painting experiments in mice, Hueper [50] found that rats implanted with encapsulated benzoyl peroxide developed no tumors at the site of implantation. Epstein et al [52] observed that benzoyl peroxide demonstrated no mutagenic activity when tested in a modified dominant lethal assay. Benzoyl peroxide exhibited no mutagenic activity in bacteria and yeast [53]. No teratogenic studies or epidemiologic surveys were found. The Few pertinent toxicologic data on humans have been found in the literature. The animal data in the literature suggest that benzoyl peroxide is not a toxic compound, although no definitive studies have been found. The major hazard is injury or death resulting from fires and explosions caused by benzoyl peroxide [3,40,41]. The available epidemiologic and toxicologic evidence on benzoyl peroxide is insufficient to allow derivation of a new environmental limit or to warrant a change in the present environmental limit. It is recommended, therefore, that the present permissible exposure limit of 5 mg/cu m as a TWA concentration be retained. Because of the apparently low degree of toxicity of benzoyl peroxide, the action level is defined as equal to the environmental limit. (b) # Sampling and Analysis It is recommended that airborne dust containing benzoyl peroxide be collected on a glass-fiber filter and analyzed gravimetrically. If the total airborne dust concentration is 5 mg/cu m or less, no further analysis need be done. If the total airborne dust concentration is greater than 5 mg/cu m, a total peroxide analysis should be performed on the material collected on the filter. A colorimetric analysis, developed from a method by Dolin [62], was selected for benzoyl peroxide because it is simple, reliable, and sensitive. However, the selected method is not specific for benzoyl peroxide; other peroxides can interfere. A method [63] specific for benzoyl peroxide, involving high pressure liquid chromatography, as described in Chapter IV, should be used if other, nonspecific methods, such as total peroxide analysis, show concentrations greater than 5 mg/cu m. # (c) Medical Surveillance and Recordkeeping Little information has been found on the toxicity of benzoyl peroxide, so frequent comprehensive medical examinations are not proposed as a requirement. However, there is some evidence that benzoyl peroxide and its degradation products, including benzoic acid, cause sensitization. This sensitization should especially be looked for in the preplacement examinations, which should include an examination of the skin. The workplace environment should be monitored semiannually and the records retained for 30 years. Since no chronic effects of benzoyl peroxide have been found, retention of environmental and medical records of employees for more than 30 years after termination of a worker's employment is unnecessary. (g) Monitoring and Recordkeeping Requirements # V I I . RESEARCH NEEDS Further study is needed to properly assess the toxicity of benzoyl peroxide and to evaluate its potential hazard to the working population. Presently, little is known about its toxic effects. The effects of long term exposure to benzoyl peroxide, particularly those caused by ingestion and inhalation, should be studied, especially to determine if there are any carcinogenic, mutagenic, teratogenic, or other systemic changes. Little information has been found concerning the possibility of absorption benzoyl peroxide through the skin, although skin contact is the most common route of human exposure. Studies should determine if benzoyl peroxide is altered during specific manufacturing processes and if the resulting residues can cause skin irritation or other adverse effects. Metabolic studies might provide information about the extent to which metabolites of benzoyl peroxide are responsible for toxic effects. If the total airborne dust exceeds the environmental limit for benzoyl peroxide, a colorimetric analysis, adapted from the method described by Dolin [62], should be performed on the particles trapped in the filter. (2) Treat portions of each of the standard aqueous benzoyl peroxide solutions in a similar manner. (3) Determine the absorption of the sample solution and of the standards at the absorption band maximum in the spectrophotometer. Make dilutions of the sample solutions if necessary. (4) Construct a standard curve of the percent transmittance versus f i g benzoyl peroxide, using the data obtained from the standard solutions. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50- The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple c> components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees. Hazard classifications are based on tests designed to evaluate the total energy release, the rate of energy release, and the ease of ignition and/or decomposition and storage containers when exposed to normal temperatures and when exposed to heat, fire, or mechanical shock. These tests include: burning rate (solids or pastes); flash point (liquids); impact sensitivity (drop weight test); self-accelerating decomposition temperature (temperature at which self-heating to decomposition is initiated) and the evaluation of the violence of this decomposition; heat exposure to a sample in a vented pressure vessel to evaluate rate and violence of decomposition; and lead block deformation test (exposure to heavy shock) to evaluate violence of decomposition. Peroxides frequently do not react consistently in the various tests. Therefore, a peroxide may be classified on the basis of the most hazardous rating attained in any one of the series of tests. Classification of each peroxide is based on its normal shipping container. If a peroxide is shipped in a different container or transferred to a different container, the normal hazard classification may no longer apply. In general, a stronger container will increase the hazard. Classification is also based on a specific product of a specific manufacturer. The same type product in the same type of container by various manufacturers will not necessarily be in the same class. Differences in manufacturing procedures may have an effect on the hazard of a peroxide which can be determined only by tests. # The classifications are as follows: Class I. Class I peroxides present a high explosion hazard through easily initiated, rapid explosive decomposition. This group may include peroxides that are relatively safe under highly controlled temperatures or in a liquid solution where loss of temperature control or crystallization out of solution can result in severe explosive decomposition. # Class II. Class II peroxides present an intermediate explosion hazard. That is, an explosive decomposition is not as rapid, violent or complete as that produced by a Class I material. As with Class I materials, this group may also contain peroxides that are relatively safe under controlled temperatures or when mixed with a diluent. # Class III. Class III peroxides present moderate explosion and severe fire hazards. They have characteristics of rapid burning, high heat liberation or vapor-air explosion hazards of the products of decomposition. # Class IV. Class IV peroxides have moderate fire hazard characteristics that can be easily contained by normal sprinkler systems and fire walls. # Class V. Class V peroxides present a low or negligible fire hazard. With these peroxides, combustible packing materials may present a greater hazard than the peroxide itself. # XIII. APPENDIX V INACTIVATION OF BENZOYL PEROXIDE The following method for inactivating benzoyl peroxde for subsequent disposal is recommended for pure benzoyl peroxide (96-99%) and wet benzoyl peroxide formulations; "BPO-78" means 78% benzoyl peroxide plus 22% water. Pure benzoyl peroxide (98+%) and water-wet benzoyl peroxide formulations (70% or 78% wetted products) can be hydrolyzed with dilute sodium hydroxide to form sodium benzoate and a solution of hydrogen peroxide in caustic. The hydrogen peroxide decomposes in the caustic solution. # Procedure Slowly add the BPO-98 (BPO-78 or BP0-70) in small portions to a rapidly stirred 10% sodium hydroxide solution, the amount of such solution being 10 times the weight of the actual benzoyl peroxide to be hydrolyzed. The sodium hydroxide solution must be no warmer than room temperature [25 C] at the time of addition. The reaction is only mildly exothermic, so cooling is not necessary. When all the benzoyl peroxide has been added, continue stirring until the solution is free of solids. The solution will be cloudy. When the temperature is maintained at about 25 C, the time for hydrolysis will be about three hours. When the solution is free of solids, the benzoyl peroxide has been hydrolyzed and the solution can be disposed of, in accordance with any regulations which apply to disposal of a dilute sodium hydroxide solution containing benzoic acid salts (0 Mageli, written communication, January 1977). # XIV. TABLES # Macht DJ: [Untoward aftereffects of the therapeutic use of benzoyl peroxide.] Dtsch Med Wochenschr 57: 678, 1931 (Ger) 31. Moskowitz S, Burke W J : Lucidol Division-Novadel-Agene Corporation, report No. L-430-50. Tonawanda, NY, New York City Division of Industrial Hygiene and Safety Standards, Chemical Unit, 1950, 9 pp 32. Baird KA: Allergy to chemicals in flour-A case of dermatitis due to benzoic acid. J Allergy 16:195-98, 1945 33. Knight RA, Kent-Jones DW: Some observations on the determination of benzoyl peroxide in flour and bread. Analyst The concentration of benzoyl peroxide in the sample can also be determined visually by comparing the color of the sample to standard solutions of known concentrations. # Range and Sensitivity With a spectrophotometer, the lower limit of the working range is 1 Mg/sample; when visual comparisons are made, the lower limit is 3 Mg/sample. There is no upper limit because the sample solutions can always be sufficiently diluted to allow spectrophotometric readings within the limits set by standard curves or to match the absorption of standard solutions. # Interferences Other peroxides will also react in the colorimetric analysis to release the iodine, and other oxidizing or reducing agents present in the sample may interfere. # Advantages of the Method (a) It provides a method suitable for determination of total peroxides in the air. # (b) The sampling device is small and portable and involves no liquids. # (c) The analysis is readily accomplished. (1) A glass-fiber filter is placed in a chamber over an aqueous sulfuric acid solution for 24 hours to bring the filter to a constant weight at 50% relative humidity. ( The initial weight of the glass-fiber filter is recorded to the nearest 0.01 mg. A nuclear static eliminator on the balance will remove static charges that might interfere with obtaining accurate, reproducible weights of the filter. (3) A known volume of air is drawn through the preweighed glass-fiber filter to collect airborne dust, including airborne benzoyl peroxide. (4) After sampling, the filter is replaced in the chamber for 24 hours and again brought to a constant weight at 50% humidity. ( The filter is reweighed on the balance used for the preweighing, and the weight is recorded to the nearest 0.01 mg. If the difference in the initial and final weights of the filter, divided by the known volume of air sampled, equals or is less than the environmental limit for benzoyl peroxide, nothing further need be done. Filter(s) found to contain a dust concentration higher than the environmental limit should be analyzed by the following colorimetric procedure. (b) Colorimetric analysis (1) Put each glass-fiber filter that was used for the sampling of total dust in a clean, dry flask with 10 ml of double-distilled water, 1 ml of potassium iodide solution, and	None	None
36272e06cf7b5923c559c9b377440ec929c68b18	cdc	None	Sexually transmitted diseases (STDs) constitute an epidemic of tremendous magnitude, with an estimated 15 million persons in the United States acquiring a new STD each year. Effective clinical management of STDs is a strategic common element in efforts to prevent HIV infection and to improve reproductive and sexual health. Sexually transmitted diseases may result in severe, longterm, costly complications, including facilitation of HIV infection, tubal infertility, adverse outcomes of pregnancy, and cervical and other types of anogenital cancer. The publication of national guidelines for the management of STDs, by the U.S. Centers for Disease Control and Prevention (CDC), has been a key component of federal initiatives to improve the health of the U.S. population by preventing and controlling STDs and their sequelae. This paper presents new recommendations from the 2002 CDC Guidelines for the Treatment of Sexually Transmitted Diseases in the context of current disease trends and public health.# S exually transmitted diseases (STDs) have been called the "hidden epidemic" by the U.S. Institute of Medicine (1) because their scope and consequences are underrecognized by public and health care professionals. In the United States, STDs constitute an epidemic of tremendous magnitude, with an estimated 15 million persons acquiring a new STD each year (2). Reported disease rates, which grossly underestimate the true burden of infection both because most STDs are asymptomatic and because of underreporting, echo the huge scope of this epidemic. Two STDs, chlamydia and gonorrhea, are the first and second most commonly reported notifiable diseases in the United States, and they alone made up 80% of the cases of all notifiable diseases reported to the U.S. Centers for Disease Control and Prevention (CDC) in 2000 (3). As the Institute of Medicine has highlighted, reported STD rates in the United States are the highest in the industrialized world; in some U.S. communities, they rival those of developing countries. Effective clinical management of STDs is a strategic common element in prevention of HIV infection and in efforts to improve the health of women, adolescents, and infants. This is because, if untreated, STDs often result in severe, long-term, costly complications. These diseases biologically increase risk for HIV acquisition and HIV transmission at least three-to fivefold (4). They are the leading preventable cause of involuntary infertility and potentially fatal ectopic pregnancy, and they play a major role in other adverse outcomes of pregnancy, ranging from fetal wastage to low birthweight, prematurity, and congenital infection (5). One STD, human papillomavirus infection, can cause cervical and other types of anogenital cancer (6). Indeed, because STDs are communicable diseases with far-reaching public health consequences, early detection and treatment are important, and clinicians can thus play a pivotal role in improving not only the sexual and reproductive health of individual patients but also the long-term health and health care costs of their communities. In this paper, we examine new recommendations presented in the 2002 CDC Guidelines for the Treatment of Sexually Transmitted Diseases (7) (Tables 1 and 2) and discuss key, ongoing approaches to the treatment of STDs in the context of current disease trends and public health needs and opportunities. We highlight the crucial role of clinicians in reducing the severe, long-term effect of STDs on adolescents and young adults in the United States. # PREVENTION OF STD-RELATED HIV TRANSMISSION Because of compelling data linking STD acquisition and HIV transmission, early detection and appropriate treatment of STDs are considered key components of a comprehensive strategy for HIV prevention (8). Among persons with STDs, those with ulcerative STDs typically have a higher prevalence of HIV co-infection, reflecting the fact that ulcerative STDs and HIV infection have shared risk factors and strong mutually reinforcing effects: Ulcerative STDs can increase HIV transmissibility, and HIV infection can cause ulcer persistence (4). Several recent advances have been made in the management and treatment of genital ulcer disease. In the United States, most sexually active persons with genital ulcers have genital herpes, syphilis, or chancroid (9). However, diagnosis of these conditions on the basis of medical history and physical examination is often inaccurate unless accompanied by specific diagnostic testing (10). Therefore, evaluation of all patients with genital ulcers should include a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should be done. Biopsy of ulcers may help identify the cause of unusual ulcers or ulcers that do not respond to initial therapy. Testing for HIV should be done in the evaluation of all patients with genital ulcer disease. # Syphilis A readily curable, bacterial genital ulcer disease, syphilis continues to be one of the most important STDs because of its biological effect on HIV acquisition and transmission (4) and its effect on infant health. Currently, syphilis is an important problem in the southern United States and in some urban areas in other U.S. regions, and recent outbreaks have been seen among men who have sex with men (11,12). The 2000 rate of primary and secondary syphilis, 2.2 per 100 000, is the lowest rate seen since reporting began in 1941. This historic low rate is complemented by extreme geographic clustering of disease, with half of all new cases reported from only 22 of the 3115 U.S. counties (Ͻ1%). These factors have created an unprecedented opportunity for the elimination of syphilis. This elimination would address one of our most glaring ethnic disparities in health and would result in substantial savings in health care costs. Reported cases of syphilis continue to disproportionately affect black persons, who had rates as much as 23 times greater than those in white persons in 2000 (11). The annual direct and indirect costs of syphilis in the United States are an estimated $966 million, including the cost of care for adult and congenital syphilis ($214 million) and for HIV infection attributable to syphilis ($752 million) (13). Therefore, the CDC launched a national plan to eliminate syphilis from the United States (14). Syphilis elimination has been defined at the national level as the absence of sustained transmission in the United States and at the local level as the absence of new cases within a local jurisdiction (except within 90 days of an imported index case). The national goal of the syphilis elimination program is to reduce primary and secondary syphilis to no more than 1000 cases (0.4 per 100 000 population) and to increase the percentage of syphilis-free counties to 90% by 2005. Between 1997 and 2000, the incidence of adult syphilis decreased by 30%, more than a 50% reduction in congenital syphilis was seen, and the ratio of syphilis rates in black persons to those in white persons was almost halved (11). Long-acting preparations of penicillin remain the treatment of choice for all stages of syphilis. This treatment is supported by more than 40 years of clinical experience and a few recent clinical trials (15). Primary, secondary, and early latent syphilis are effectively treated with a single dose of 2.4 million units of benzathine penicillin G, while late latent syphilis requires three benzathine penicillin G injections given 1 week apart. Persons with HIV infection who have early syphilis (primary, secondary, or early latent) should be managed according to these standard treatment recommendations, but they may be at increased risk for neurologic complications and may have higher rates of treatment failure. Management of late latent syphilis in HIV-infected persons should include a cerebrospinal fluid examination before treatment. Assessment of therapeutic efficacy for the various stages of syphilis, regardless of HIV infection, remains complicated by lack of a well-defined, consistently observed response in the nontreponemal serologic titer. As a prospective study of early-stage syphilis recently showed (16), approximately 15% of patients did not meet standard criteria for serologic cure 12 months after appropriate treatment; this outcome was not improved by more intensive treatment regimens that provide extended, high penetration of cerebrospinal fluid. Because the relation between serologic and clinical response remains unclear in such cases and in the absence of data supporting greater effectiveness of alternative antimicrobial regimens, we continue to recommend benzathine penicillin G for early-stage syphilis, regardless of HIV status. Despite limited data supporting the use of alternatives to penicillin in the treatment of early-stage syphilis, the treatment guidelines suggest several new alternative therapies that seem promising in nonpregnant, penicillin-allergic patients with primary or secondary syphilis. Limited clinical studies, along with biological and pharmacologic considerations, suggest that ceftriaxone should be effective for early-stage syphilis (17), but proper dose, proper duration of treatment, and efficacy have not been definitively established. Azithromycin is active against Treponema pallidum in in vitro models and seems to be effective in a small cohort of patients with early-stage disease, but it may prove most useful as single-dose therapy for incubating syphilis (18,19). In the management of neurosyphilis in penicillin-allergic persons, ceftriaxone may be considered a new alternative treatment regimen. The use of any of these alternatives to penicillin in the treatment of syphilis in HIV-infected persons has not been well studied. # Genital Herpes Genital herpes simplex virus type 2 (HSV-2) infection is the most common infectious cause of genital ulcers in the United States, with a reported seroprevalence rate of 22% in adults in the early 1990s. This rate represents a 32% increase relative to the previous decade (20). Whereas most cases of genital herpes are caused by HSV-2, genital infections with herpes simplex virus type 1 (HSV-1) are # Table 1. New Findings in the Centers for Disease Control and Prevention 2002 Guidelines for the Treatment of Sexually Transmitted Diseases Evaluation for chlamydial infection 3 to 4 months after primary infection Emergence of quinolone-resistant gonorrhea and implications for treatment Alternative treatment regimens for early syphilis and neurosyphilis in persons allergic to penicillin Commercial availability of type-specific serologic tests for genital herpes Treatment options for genital herpes in persons with HIV infection Screening and treatment for bacterial vaginosis before abortion or hysterectomy to reduce postoperative infectious complications Nucleic acid testing for human papillomavirus infection in the management of women with Papanicolaou smears showing atypical squamous cells of undetermined significance # Academia and Clinic Sexually Transmitted Diseases increasingly recognized (21). Most genital herpes infections are transmitted by persons who are unaware that they have the infection or are asymptomatic when transmission occurs. In a large population-based study (20), only 9% of HSV-2-seropositive persons reported that they had genital herpes. Because of the high proportion of unrecognized infection, the diagnosis of genital herpes should be confirmed by sensitive diagnostic tests, such as viral culture or HSV type-specific serologic tests. Accurate type-specific assays for HSV rely on the detection of antibodies to HSVspecific glycoprotein G1 and G2. Such assays became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 antibody from HSV-2 antibody remain on the market. The new type-specific assays are discussed in the CDC's STD treatment guidelines and may be useful in the diagnosis of unrecognized infection and the management of sexual partners of persons with genital herpes. Optimal management of genital herpes includes antiviral therapy and appropriate counseling on the natural history of infection, risk for sexual and perinatal transmission, and methods to prevent further transmission. Systemic antiviral drugs partially control the symptoms and signs of herpes episodes when used to treat first clinical episodes and recurrent episodes or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk for, frequency of, or severity of recurrences after use of the drug is discontinued. Effective antiviral regimens that provide clinical benefit for patients with genital herpes include acyclovir, valacyclovir, and famciclovir (22). Suppressive antiviral therapy reduces, but does not eliminate, subclinical viral shedding (23). Most genital herpes in HIV-infected persons responds to antiviral agents, although clinical improvement is often slower than in immunocompetent persons. Isolates from patients with persistent HSV infections unresponsive to antiviral agents should be tested for antiviral resistance. Clinically significant acyclovir resistance has not emerged among immunocompetent persons. Additional research is needed to investigate the extent to which suppressive therapy may prevent HSV transmission, regardless of HIV infection status, and HIV transmission among co-infected persons. # Chancroid Chancroid is the ulcerative STD that has been most strongly linked to HIV transmission (4), and healing of chancroid may be slowed in persons with HIV infection. The incidence of chancroid is very low in the United States, with only 78 cases reported in 2000 (11), but this disorder is substantially underdiagnosed. Clinicians treating genital ulcers should be alert to the possibility of chancroid, which can be easily treated with single-dose azithromycin or ceftriaxone or with multiday regimens of ciprofloxacin or erythromycin. Persons with HIV infection may require longer courses of therapy than those recom-mended for HIV-negative persons. In addition, data are limited on the therapeutic efficacy of the recommended single-dose ceftriaxone or azithromycin regimens in HIVinfected patients, and these regimens should be used only if follow-up can be ensured. # PREVENTION OF STD-RELATED INFERTILITY Prompt recognition and appropriate treatment of chlamydial and gonococcal infections are crucial not only in the prevention of STD-associated HIV transmission but also in the primary prevention of STD-related infertility. In women, chlamydial and gonococcal infections are often asymptomatic. Untreated, they may result in pelvic inflammatory disease; this, in turn, results in infertility, ectopic pregnancy, and chronic pelvic pain in 10% to 20% of cases (24). # Chlamydia Chlamydia trachomatis infection is the most common bacterial STD in the United States, with an estimated 3 million cases occurring annually (2). The highest rates are in adolescent girls, and studies done in a range of venues, including secondary schools, family planning clinics, and the Job Corps, reveal prevalences of chlamydia that usually range from 4% to 15% (11,25). Reported rates of chlamydial infection have increased dramatically over the past decade, reflecting expansion of chlamydial screening activities and the advent of a new generation of highly sensitive nucleic acid amplification tests. However, many women who are at risk for chlamydia are still not screened appropriately because of lack of awareness among some providers and limited resources available for screening. Chlamydia screening and reporting are likely to expand further in response to the recent screening recommendations from the third U.S. Preventive Services Task Force (USPSTF) (26) and the inclusion of a chlamydia screening measure in the Health Plan Employer Data and Information Set (HEDIS), which assesses the performance of managed care organizations (27). The USPSTF, the HEDIS measure, and the STD treatment guidelines recommend routine screening of all sexually active women 25 years of age or younger and other asymptomatic women at increased risk for infection (for example, women with new or multiple sexual partners, a previous STD, or inconsistent use of barrier contraceptives). In parts of the United States where chlamydia screening and treatment programs have been widely implemented, rates of positivity for chlamydia among women attending family planning clinics have decreased by as much as two thirds (11). However, these declines have recently plateaued or reversed in most of the United States, possibly because of failure to extend screening coverage to more at-risk women and to men. This is particularly disturbing because selective chlamydia screening and treatment in women have been shown to reduce the incidence of pelvic inflammatory disease (the critical link between chlamydia and reproductive sequelae) by almost 60% (28). Efficacious regimens for the treatment of chlamydia include azithromycin or doxycycline. Azithromycin, which can be given as single-dose, directly observed therapy, may be the more cost-effective drug in many settings, especially in persons who are unlikely to complete the 7-day doxycycline regimen (29). A test of cure is not necessary after completion of treatment with azithromycin or doxycycline unless symptoms persist or reinfection is suspected. However, because of the high incidence of new chlamydial infections in women who have had chlamydia in the preceding several months, the new CDC treatment guidelines suggest rescreening for chlamydia 3 to 4 months after treatment, especially in adolescents. # Gonorrhea Infections due to Neisseria gonorrhoeae, like those resulting from C. trachomatis, are a major cause of cervicitis, urethritis, proctitis, and pelvic inflammatory disease. In the United States, an estimated 650 000 cases of gonorrhea occur each year (2). The reported gonorrhea rate increased approximately 10% from 1997 to 1999, after a 72% decrease from 1975 to 1997 (11). Because gonococcal infections in women are often asymptomatic, an important component of gonorrhea control continues to be the screening of women at high risk for STDs. Several antibiotics are effective in the single-dose treatment of gonorrhea, including cefixime, ceftriaxone, ciprofloxacin, and ofloxacin (7). Concomitant therapy with a regimen effective against chlamydia is recommended because of the frequency of dual infections. Recently, quinolone-resistant gonorrhea has been reported from southeast Asia, Hawaii, and California (7,30). Persons with gonorrhea who have recently traveled to Asia or the Pacific, Hawaii, and California and persons who have a sexual partner who has recently traveled to these areas, should receive a nonquinolone treatment regimen. However, because the national prevalence of quinolone resistance remains very low (31), the recommended treatment regimens remain appropriate for most cases of gonorrhea in the continental United States and Alaska. The prevalence of quinoloneresistant gonorrhea may increase in the next several years because of the importation of infection, and culture and susceptibility testing should be done in persons with apparent treatment failure. Spectinomycin remains an important option for treatment of gonorrhea in cephalosporinallergic persons when quinolones cannot be used (for example, during pregnancy or in areas with a high rate of quinolone-resistant infections), although availability has recently been a concern (32). # PREVENTION OF STD-RELATED ADVERSE OUTCOMES OF PREGNANCY Many sexually transmitted infectious agents are an important cause of adverse outcomes of pregnancy, including spontaneous abortion, stillbirth, premature birth, and congenital infection (5). Among the ulcerative STDs, syphilis remains an important cause of illness and death during pregnancy, despite the widespread availability of inexpensive serologic tests and substantial efforts to encourage routine screening through early prenatal care. Parenteral penicillin G, if provided at least 1 month before delivery, is effective in preventing maternal transmission and treating fetal infection. The appropriate dose and duration of penicillin therapy depend on the clinical stage of syphilis in the mother. Women with a history of allergy to penicillin should be desensitized and treated with penicillin; no proven alternative regimens exist for the treatment of syphilis in pregnancy. # Genital Herpes The other genital ulcer disease frequently associated with poor pregnancy outcomes is genital herpes. The risk for neonatal HSV infection is much greater after first-episode infection than after reactivation during pregnancy (33). Primary HSV infection during late pregnancy has been associated with spontaneous abortion, premature birth, and low birthweight (34). Prevention of neonatal herpes depends on preventing herpes acquisition during late pregnancy and possible exposure of the infant to herpetic lesions during delivery. Type-specific HSV serologic screening to identify HSV-negative women has been proposed as a strategy to prevent neonatal herpes, but the feasibility and effectiveness of this approach are unknown. Seronegative women at risk for HSV infection should be counseled to avoid acquiring herpes infection in late pregnancy by refraining from genital intercourse with partners known to have or suspected to have genital herpes and from direct orogenital contact with partners known to have or suspected of having orolabial herpes. Antiviral therapy during pregnancy is recommended in women with primary HSV infection or severe herpes infection. There seems to be no increased risk for major birth defects after prenatal exposure to acyclovir. Data are insufficient to provide useful information on pregnancy outcomes with exposure to either valacyclovir or famciclovir. # Chlamydia and Gonorrhea Cervical and vaginal infections also compromise pregnancy outcomes. Various studies (35) have inconsistently linked C. trachomatis infection to premature birth. However, perinatal infection can result from the acquisition of chlamydial infection during parturition. Clinical manifestations of neonatal chlamydial infection include inclusion conjunctivitis, subacute pneumonia, and rectogenital infections. Erythromycin is the recommended regimen for chlamydial infection in infants. Prenatal screening and treatment of pregnant women for chlamydia prevents chlamydial infection among neonates. Pregnant women who are younger than 25 years of age or have new or multiple sex partners should receive the highest priority for chlamydia screening. Gonococcal infection can also affect the health of the fetus and infant in such ways as premature delivery, pre- # Academia and Clinic Sexually Transmitted Diseases mature rupture of membranes, and perinatal distress (36). The most serious manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, including arthritis and meningitis. Although N. gonorrhoeae is a less frequent cause of ophthalmia neonatorum in the United States than C. trachomatis and nonsexually transmitted agents are, this infection is especially important because it may result in perforation of the globe of the eye and blindness. Instillation of a prophylactic agent (silver nitrate, erythromycin, or tetracycline ointments) into the eyes of all newborn infants is recommended to prevent gonococcal ophthalmia neonatorum. Diagnosing and treating gonococcal infection in pregnant women are the best ways to prevent neonatal gonococcal disease. # Bacterial Vaginosis Bacterial vaginosis, a sexually associated infection, has also been associated with adverse pregnancy outcomes, including chorioamnionitis, premature rupture of membranes, premature birth, and postpartum endometritis (37). Although no national surveillance data are available, bacterial vaginosis is probably the most prevalent infectious cause of abnormal vaginal discharge (38). The principal goal of therapy has been to relieve vaginal symptoms, which can be accomplished with oral metronidazole, clindamycin cream, or metronidazole gel. Treatment trials show that the oral and vaginal metronidazole regimens are similarly efficacious and seem to be more effective than clindamycin cream (7). However, reported cure rates for all regimens fall short of cure rates for most other reproductive tract infections. Studies are now under way to evaluate the efficacy of vaginal lactobacilli suppositories, in addition to oral metronidazole, for initial treatment and prevention of recurrent infection. Several studies suggest that treatment of bacterial vaginosis in pregnant women with a history of preterm birth may reduce subsequent risk for prematurity (39,40). No randomized trial has shown a reduction in adverse outcomes of pregnancy among asymptomatic women without a history of preterm birth. Additional studies are under way to clarify this difficult issue. Current evidence does not support universal screening for bacterial vaginosis in pregnancy (41). # Trichomoniasis Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, but limited data show that treatment of asymptomatic infection during pregnancy lessens the association (42). Metronidazole remains the only recommended treatment for trichomoniasis. Metronidazole use during pregnancy has not been shown to have a consistent association with teratogenic or mutagenic effects in the infant. Infections with strains that show diminished susceptibility to metronidazole can occur. Most nonpregnant women respond to a higher metronidazole dose and extended therapy. No published data on the use of these enhanced metronidazole regimens in pregnant women ex-ist, and pregnant women should be managed in consultation with an expert in infectious diseases. # PREVENTION OF STD-RELATED CANCER It is well established that persistent infection with human papillomavirus (HPV) plays a central role in the pathogenesis of most types of squamous-cell cancer of the cervix, vagina, vulva, anus, and penis. Recent estimates of the cost of treating HPV and cervical cancer exceed $4.5 billion; this is more than the cost of any other single STD with the exception of HIV infection (1). Most invasive types of anogenital squamous-cell cancer of the genital tract and anus have been associated with HPV types 16, 18, 31, or 45, whereas most external genital warts are associated with HPV types 6 or 11 (6). Subclinical genital HPV infection occurs more frequently than visible genital warts and refers to manifestations of infection in the absence of visible genital warts, including situations where infection is diagnosed on the basis of characteristic cytologic features, squamous intraepithelial lesions (SIL), or on any genital skin by a viral nucleic acid (DNA or RNA) or capsid protein test for HPV. Recognition of the role of specific HPV types in cervical cancer and the advent of type-specific HPV tests have stimulated a focus on the use of HPV diagnostic tests in prevention of cervical cancer. Testing for HPV was recently proposed as a strategy to determine which women with low-grade cervical cytologic abnormalities require colposcopic evaluation. Several trials designed to clarify the role of HPV testing in the evaluation of low-grade cervical abnormalities indicate that HPV testing can be useful in the management of women with Papanicolaou tests that show atypical squamous cells of undetermined significance, but not in the management of low-grade SIL (43,44). At this time, data are insufficient to recommend routine HPV testing for other clinical purposes. No therapy has been identified that effectively eradicates persistent subclinical HPV infection. In the presence of coexistent SIL, management should be based on histopathologic findings and includes cryotherapy, laser ablation, cone biopsy, or loop electrosurgical excision procedure. A strong relation exists among persistent HPV infection, anal SIL, and anal cancer, showing the same spectrum of HPV types as those associated with cervical cancer (45). Prevalence of anal SIL and anal cancer is substantially increased among men who have sex with men and men with HIV infection (46). Clinicians should be aware of the importance of intra-anal manifestations of HPV infection in such men, given the association of HPV with anal dysplasia, and they should consider anoscopic examination in persons with symptoms referable to the anal canal. However, high-grade anal SIL has been shown in normalappearing anal mucosal biopsy specimens from men with and without HIV infection (47). The appropriate clinical management for persons with high-grade anal SIL is uncertain, but ablation or surgical removal has been sug-gested. Because of the increased incidence of anal cancer in HIV-infected men who have sex with men, screening for anal SIL by anal cytologic examination has been proposed (48). However, because the natural history of anal SIL has not been established and management strategies are not clearly defined, such a screening approach cannot currently be recommended in the STD treatment guidelines. # CONCLUSIONS For more than 20 years, the CDC's publication of national guidelines for STD management has been a key component of federal initiatives to improve the health of the U.S. population by preventing and controlling STDs and their sequelae. These public health goals can be attained only if they are supported by knowledgeable clinicians and if clinicians are, in turn, supported by health care systems that make it possible for them to deliver optimal care for patients with STDs and to incorporate new guidelines into clinical practice. The 2002 guidelines should therefore be viewed as the starting point for a process that requires the ongoing efforts of residency program directors, providers of continuing medical education, clinic managers, and health plan administrators in public and private sectors. As recommendations for STD treatment continue to evolve in response to basic and clinical research advances, emerging antimicrobial resistance, and changing sexual and health care behaviors, clinical practice-at both the individual and the system level-must reflect these changes. New, more effective treatment regimens; highly sensitive screening tests for asymptomatic infection; improvements in counseling of patients and their sexual partners; and new vaccines for sexually transmitted pathogens will benefit individual patients and be crucial to the achievement of our broader public health goal of improving sexual and reproductive health in the United States. From Centers for Disease Control and Prevention, Atlanta, Georgia; and the Fred Hutchinson Cancer Research Center, Seattle, Washington.	Sexually transmitted diseases (STDs) constitute an epidemic of tremendous magnitude, with an estimated 15 million persons in the United States acquiring a new STD each year. Effective clinical management of STDs is a strategic common element in efforts to prevent HIV infection and to improve reproductive and sexual health. Sexually transmitted diseases may result in severe, longterm, costly complications, including facilitation of HIV infection, tubal infertility, adverse outcomes of pregnancy, and cervical and other types of anogenital cancer. The publication of national guidelines for the management of STDs, by the U.S. Centers for Disease Control and Prevention (CDC), has been a key component of federal initiatives to improve the health of the U.S. population by preventing and controlling STDs and their sequelae. This paper presents new recommendations from the 2002 CDC Guidelines for the Treatment of Sexually Transmitted Diseases in the context of current disease trends and public health.# S exually transmitted diseases (STDs) have been called the "hidden epidemic" by the U.S. Institute of Medicine (1) because their scope and consequences are underrecognized by public and health care professionals. In the United States, STDs constitute an epidemic of tremendous magnitude, with an estimated 15 million persons acquiring a new STD each year (2). Reported disease rates, which grossly underestimate the true burden of infection both because most STDs are asymptomatic and because of underreporting, echo the huge scope of this epidemic. Two STDs, chlamydia and gonorrhea, are the first and second most commonly reported notifiable diseases in the United States, and they alone made up 80% of the cases of all notifiable diseases reported to the U.S. Centers for Disease Control and Prevention (CDC) in 2000 (3). As the Institute of Medicine has highlighted, reported STD rates in the United States are the highest in the industrialized world; in some U.S. communities, they rival those of developing countries. Effective clinical management of STDs is a strategic common element in prevention of HIV infection and in efforts to improve the health of women, adolescents, and infants. This is because, if untreated, STDs often result in severe, long-term, costly complications. These diseases biologically increase risk for HIV acquisition and HIV transmission at least three-to fivefold (4). They are the leading preventable cause of involuntary infertility and potentially fatal ectopic pregnancy, and they play a major role in other adverse outcomes of pregnancy, ranging from fetal wastage to low birthweight, prematurity, and congenital infection (5). One STD, human papillomavirus infection, can cause cervical and other types of anogenital cancer (6). Indeed, because STDs are communicable diseases with far-reaching public health consequences, early detection and treatment are important, and clinicians can thus play a pivotal role in improving not only the sexual and reproductive health of individual patients but also the long-term health and health care costs of their communities. In this paper, we examine new recommendations presented in the 2002 CDC Guidelines for the Treatment of Sexually Transmitted Diseases (7) (Tables 1 and 2) and discuss key, ongoing approaches to the treatment of STDs in the context of current disease trends and public health needs and opportunities. We highlight the crucial role of clinicians in reducing the severe, long-term effect of STDs on adolescents and young adults in the United States. # PREVENTION OF STD-RELATED HIV TRANSMISSION Because of compelling data linking STD acquisition and HIV transmission, early detection and appropriate treatment of STDs are considered key components of a comprehensive strategy for HIV prevention (8). Among persons with STDs, those with ulcerative STDs typically have a higher prevalence of HIV co-infection, reflecting the fact that ulcerative STDs and HIV infection have shared risk factors and strong mutually reinforcing effects: Ulcerative STDs can increase HIV transmissibility, and HIV infection can cause ulcer persistence (4). Several recent advances have been made in the management and treatment of genital ulcer disease. In the United States, most sexually active persons with genital ulcers have genital herpes, syphilis, or chancroid (9). However, diagnosis of these conditions on the basis of medical history and physical examination is often inaccurate unless accompanied by specific diagnostic testing (10). Therefore, evaluation of all patients with genital ulcers should include a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should be done. Biopsy of ulcers may help identify the cause of unusual ulcers or ulcers that do not respond to initial therapy. Testing for HIV should be done in the evaluation of all patients with genital ulcer disease. # Syphilis A readily curable, bacterial genital ulcer disease, syphilis continues to be one of the most important STDs because of its biological effect on HIV acquisition and transmission (4) and its effect on infant health. Currently, syphilis is an important problem in the southern United States and in some urban areas in other U.S. regions, and recent outbreaks have been seen among men who have sex with men (11,12). The 2000 rate of primary and secondary syphilis, 2.2 per 100 000, is the lowest rate seen since reporting began in 1941. This historic low rate is complemented by extreme geographic clustering of disease, with half of all new cases reported from only 22 of the 3115 U.S. counties (Ͻ1%). These factors have created an unprecedented opportunity for the elimination of syphilis. This elimination would address one of our most glaring ethnic disparities in health and would result in substantial savings in health care costs. Reported cases of syphilis continue to disproportionately affect black persons, who had rates as much as 23 times greater than those in white persons in 2000 (11). The annual direct and indirect costs of syphilis in the United States are an estimated $966 million, including the cost of care for adult and congenital syphilis ($214 million) and for HIV infection attributable to syphilis ($752 million) (13). Therefore, the CDC launched a national plan to eliminate syphilis from the United States (14). Syphilis elimination has been defined at the national level as the absence of sustained transmission in the United States and at the local level as the absence of new cases within a local jurisdiction (except within 90 days of an imported index case). The national goal of the syphilis elimination program is to reduce primary and secondary syphilis to no more than 1000 cases (0.4 per 100 000 population) and to increase the percentage of syphilis-free counties to 90% by 2005. Between 1997 and 2000, the incidence of adult syphilis decreased by 30%, more than a 50% reduction in congenital syphilis was seen, and the ratio of syphilis rates in black persons to those in white persons was almost halved (11). Long-acting preparations of penicillin remain the treatment of choice for all stages of syphilis. This treatment is supported by more than 40 years of clinical experience and a few recent clinical trials (15). Primary, secondary, and early latent syphilis are effectively treated with a single dose of 2.4 million units of benzathine penicillin G, while late latent syphilis requires three benzathine penicillin G injections given 1 week apart. Persons with HIV infection who have early syphilis (primary, secondary, or early latent) should be managed according to these standard treatment recommendations, but they may be at increased risk for neurologic complications and may have higher rates of treatment failure. Management of late latent syphilis in HIV-infected persons should include a cerebrospinal fluid examination before treatment. Assessment of therapeutic efficacy for the various stages of syphilis, regardless of HIV infection, remains complicated by lack of a well-defined, consistently observed response in the nontreponemal serologic titer. As a prospective study of early-stage syphilis recently showed (16), approximately 15% of patients did not meet standard criteria for serologic cure 12 months after appropriate treatment; this outcome was not improved by more intensive treatment regimens that provide extended, high penetration of cerebrospinal fluid. Because the relation between serologic and clinical response remains unclear in such cases and in the absence of data supporting greater effectiveness of alternative antimicrobial regimens, we continue to recommend benzathine penicillin G for early-stage syphilis, regardless of HIV status. Despite limited data supporting the use of alternatives to penicillin in the treatment of early-stage syphilis, the treatment guidelines suggest several new alternative therapies that seem promising in nonpregnant, penicillin-allergic patients with primary or secondary syphilis. Limited clinical studies, along with biological and pharmacologic considerations, suggest that ceftriaxone should be effective for early-stage syphilis (17), but proper dose, proper duration of treatment, and efficacy have not been definitively established. Azithromycin is active against Treponema pallidum in in vitro models and seems to be effective in a small cohort of patients with early-stage disease, but it may prove most useful as single-dose therapy for incubating syphilis (18,19). In the management of neurosyphilis in penicillin-allergic persons, ceftriaxone may be considered a new alternative treatment regimen. The use of any of these alternatives to penicillin in the treatment of syphilis in HIV-infected persons has not been well studied. # Genital Herpes Genital herpes simplex virus type 2 (HSV-2) infection is the most common infectious cause of genital ulcers in the United States, with a reported seroprevalence rate of 22% in adults in the early 1990s. This rate represents a 32% increase relative to the previous decade (20). Whereas most cases of genital herpes are caused by HSV-2, genital infections with herpes simplex virus type 1 (HSV-1) are # Table 1. New Findings in the Centers for Disease Control and Prevention 2002 Guidelines for the Treatment of Sexually Transmitted Diseases Evaluation for chlamydial infection 3 to 4 months after primary infection Emergence of quinolone-resistant gonorrhea and implications for treatment Alternative treatment regimens for early syphilis and neurosyphilis in persons allergic to penicillin Commercial availability of type-specific serologic tests for genital herpes Treatment options for genital herpes in persons with HIV infection Screening and treatment for bacterial vaginosis before abortion or hysterectomy to reduce postoperative infectious complications Nucleic acid testing for human papillomavirus infection in the management of women with Papanicolaou smears showing atypical squamous cells of undetermined significance # Academia and Clinic Sexually Transmitted Diseases increasingly recognized (21). Most genital herpes infections are transmitted by persons who are unaware that they have the infection or are asymptomatic when transmission occurs. In a large population-based study (20), only 9% of HSV-2-seropositive persons reported that they had genital herpes. Because of the high proportion of unrecognized infection, the diagnosis of genital herpes should be confirmed by sensitive diagnostic tests, such as viral culture or HSV type-specific serologic tests. Accurate type-specific assays for HSV rely on the detection of antibodies to HSVspecific glycoprotein G1 and G2. Such assays became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 antibody from HSV-2 antibody remain on the market. The new type-specific assays are discussed in the CDC's STD treatment guidelines and may be useful in the diagnosis of unrecognized infection and the management of sexual partners of persons with genital herpes. Optimal management of genital herpes includes antiviral therapy and appropriate counseling on the natural history of infection, risk for sexual and perinatal transmission, and methods to prevent further transmission. Systemic antiviral drugs partially control the symptoms and signs of herpes episodes when used to treat first clinical episodes and recurrent episodes or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk for, frequency of, or severity of recurrences after use of the drug is discontinued. Effective antiviral regimens that provide clinical benefit for patients with genital herpes include acyclovir, valacyclovir, and famciclovir (22). Suppressive antiviral therapy reduces, but does not eliminate, subclinical viral shedding (23). Most genital herpes in HIV-infected persons responds to antiviral agents, although clinical improvement is often slower than in immunocompetent persons. Isolates from patients with persistent HSV infections unresponsive to antiviral agents should be tested for antiviral resistance. Clinically significant acyclovir resistance has not emerged among immunocompetent persons. Additional research is needed to investigate the extent to which suppressive therapy may prevent HSV transmission, regardless of HIV infection status, and HIV transmission among co-infected persons. # Chancroid Chancroid is the ulcerative STD that has been most strongly linked to HIV transmission (4), and healing of chancroid may be slowed in persons with HIV infection. The incidence of chancroid is very low in the United States, with only 78 cases reported in 2000 (11), but this disorder is substantially underdiagnosed. Clinicians treating genital ulcers should be alert to the possibility of chancroid, which can be easily treated with single-dose azithromycin or ceftriaxone or with multiday regimens of ciprofloxacin or erythromycin. Persons with HIV infection may require longer courses of therapy than those recom-mended for HIV-negative persons. In addition, data are limited on the therapeutic efficacy of the recommended single-dose ceftriaxone or azithromycin regimens in HIVinfected patients, and these regimens should be used only if follow-up can be ensured. # PREVENTION OF STD-RELATED INFERTILITY Prompt recognition and appropriate treatment of chlamydial and gonococcal infections are crucial not only in the prevention of STD-associated HIV transmission but also in the primary prevention of STD-related infertility. In women, chlamydial and gonococcal infections are often asymptomatic. Untreated, they may result in pelvic inflammatory disease; this, in turn, results in infertility, ectopic pregnancy, and chronic pelvic pain in 10% to 20% of cases (24). # Chlamydia Chlamydia trachomatis infection is the most common bacterial STD in the United States, with an estimated 3 million cases occurring annually (2). The highest rates are in adolescent girls, and studies done in a range of venues, including secondary schools, family planning clinics, and the Job Corps, reveal prevalences of chlamydia that usually range from 4% to 15% (11,25). Reported rates of chlamydial infection have increased dramatically over the past decade, reflecting expansion of chlamydial screening activities and the advent of a new generation of highly sensitive nucleic acid amplification tests. However, many women who are at risk for chlamydia are still not screened appropriately because of lack of awareness among some providers and limited resources available for screening. Chlamydia screening and reporting are likely to expand further in response to the recent screening recommendations from the third U.S. Preventive Services Task Force (USPSTF) (26) and the inclusion of a chlamydia screening measure in the Health Plan Employer Data and Information Set (HEDIS), which assesses the performance of managed care organizations (27). The USPSTF, the HEDIS measure, and the STD treatment guidelines recommend routine screening of all sexually active women 25 years of age or younger and other asymptomatic women at increased risk for infection (for example, women with new or multiple sexual partners, a previous STD, or inconsistent use of barrier contraceptives). In parts of the United States where chlamydia screening and treatment programs have been widely implemented, rates of positivity for chlamydia among women attending family planning clinics have decreased by as much as two thirds (11). However, these declines have recently plateaued or reversed in most of the United States, possibly because of failure to extend screening coverage to more at-risk women and to men. This is particularly disturbing because selective chlamydia screening and treatment in women have been shown to reduce the incidence of pelvic inflammatory disease (the critical link between chlamydia and reproductive sequelae) by almost 60% (28). Efficacious regimens for the treatment of chlamydia include azithromycin or doxycycline. Azithromycin, which can be given as single-dose, directly observed therapy, may be the more cost-effective drug in many settings, especially in persons who are unlikely to complete the 7-day doxycycline regimen (29). A test of cure is not necessary after completion of treatment with azithromycin or doxycycline unless symptoms persist or reinfection is suspected. However, because of the high incidence of new chlamydial infections in women who have had chlamydia in the preceding several months, the new CDC treatment guidelines suggest rescreening for chlamydia 3 to 4 months after treatment, especially in adolescents. # Gonorrhea Infections due to Neisseria gonorrhoeae, like those resulting from C. trachomatis, are a major cause of cervicitis, urethritis, proctitis, and pelvic inflammatory disease. In the United States, an estimated 650 000 cases of gonorrhea occur each year (2). The reported gonorrhea rate increased approximately 10% from 1997 to 1999, after a 72% decrease from 1975 to 1997 (11). Because gonococcal infections in women are often asymptomatic, an important component of gonorrhea control continues to be the screening of women at high risk for STDs. Several antibiotics are effective in the single-dose treatment of gonorrhea, including cefixime, ceftriaxone, ciprofloxacin, and ofloxacin (7). Concomitant therapy with a regimen effective against chlamydia is recommended because of the frequency of dual infections. Recently, quinolone-resistant gonorrhea has been reported from southeast Asia, Hawaii, and California (7,30). Persons with gonorrhea who have recently traveled to Asia or the Pacific, Hawaii, and California and persons who have a sexual partner who has recently traveled to these areas, should receive a nonquinolone treatment regimen. However, because the national prevalence of quinolone resistance remains very low (31), the recommended treatment regimens remain appropriate for most cases of gonorrhea in the continental United States and Alaska. The prevalence of quinoloneresistant gonorrhea may increase in the next several years because of the importation of infection, and culture and susceptibility testing should be done in persons with apparent treatment failure. Spectinomycin remains an important option for treatment of gonorrhea in cephalosporinallergic persons when quinolones cannot be used (for example, during pregnancy or in areas with a high rate of quinolone-resistant infections), although availability has recently been a concern (32). # PREVENTION OF STD-RELATED ADVERSE OUTCOMES OF PREGNANCY Many sexually transmitted infectious agents are an important cause of adverse outcomes of pregnancy, including spontaneous abortion, stillbirth, premature birth, and congenital infection (5). Among the ulcerative STDs, syphilis remains an important cause of illness and death during pregnancy, despite the widespread availability of inexpensive serologic tests and substantial efforts to encourage routine screening through early prenatal care. Parenteral penicillin G, if provided at least 1 month before delivery, is effective in preventing maternal transmission and treating fetal infection. The appropriate dose and duration of penicillin therapy depend on the clinical stage of syphilis in the mother. Women with a history of allergy to penicillin should be desensitized and treated with penicillin; no proven alternative regimens exist for the treatment of syphilis in pregnancy. # Genital Herpes The other genital ulcer disease frequently associated with poor pregnancy outcomes is genital herpes. The risk for neonatal HSV infection is much greater after first-episode infection than after reactivation during pregnancy (33). Primary HSV infection during late pregnancy has been associated with spontaneous abortion, premature birth, and low birthweight (34). Prevention of neonatal herpes depends on preventing herpes acquisition during late pregnancy and possible exposure of the infant to herpetic lesions during delivery. Type-specific HSV serologic screening to identify HSV-negative women has been proposed as a strategy to prevent neonatal herpes, but the feasibility and effectiveness of this approach are unknown. Seronegative women at risk for HSV infection should be counseled to avoid acquiring herpes infection in late pregnancy by refraining from genital intercourse with partners known to have or suspected to have genital herpes and from direct orogenital contact with partners known to have or suspected of having orolabial herpes. Antiviral therapy during pregnancy is recommended in women with primary HSV infection or severe herpes infection. There seems to be no increased risk for major birth defects after prenatal exposure to acyclovir. Data are insufficient to provide useful information on pregnancy outcomes with exposure to either valacyclovir or famciclovir. # Chlamydia and Gonorrhea Cervical and vaginal infections also compromise pregnancy outcomes. Various studies (35) have inconsistently linked C. trachomatis infection to premature birth. However, perinatal infection can result from the acquisition of chlamydial infection during parturition. Clinical manifestations of neonatal chlamydial infection include inclusion conjunctivitis, subacute pneumonia, and rectogenital infections. Erythromycin is the recommended regimen for chlamydial infection in infants. Prenatal screening and treatment of pregnant women for chlamydia prevents chlamydial infection among neonates. Pregnant women who are younger than 25 years of age or have new or multiple sex partners should receive the highest priority for chlamydia screening. Gonococcal infection can also affect the health of the fetus and infant in such ways as premature delivery, pre- # Academia and Clinic Sexually Transmitted Diseases mature rupture of membranes, and perinatal distress (36). The most serious manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, including arthritis and meningitis. Although N. gonorrhoeae is a less frequent cause of ophthalmia neonatorum in the United States than C. trachomatis and nonsexually transmitted agents are, this infection is especially important because it may result in perforation of the globe of the eye and blindness. Instillation of a prophylactic agent (silver nitrate, erythromycin, or tetracycline ointments) into the eyes of all newborn infants is recommended to prevent gonococcal ophthalmia neonatorum. Diagnosing and treating gonococcal infection in pregnant women are the best ways to prevent neonatal gonococcal disease. # Bacterial Vaginosis Bacterial vaginosis, a sexually associated infection, has also been associated with adverse pregnancy outcomes, including chorioamnionitis, premature rupture of membranes, premature birth, and postpartum endometritis (37). Although no national surveillance data are available, bacterial vaginosis is probably the most prevalent infectious cause of abnormal vaginal discharge (38). The principal goal of therapy has been to relieve vaginal symptoms, which can be accomplished with oral metronidazole, clindamycin cream, or metronidazole gel. Treatment trials show that the oral and vaginal metronidazole regimens are similarly efficacious and seem to be more effective than clindamycin cream (7). However, reported cure rates for all regimens fall short of cure rates for most other reproductive tract infections. Studies are now under way to evaluate the efficacy of vaginal lactobacilli suppositories, in addition to oral metronidazole, for initial treatment and prevention of recurrent infection. Several studies suggest that treatment of bacterial vaginosis in pregnant women with a history of preterm birth may reduce subsequent risk for prematurity (39,40). No randomized trial has shown a reduction in adverse outcomes of pregnancy among asymptomatic women without a history of preterm birth. Additional studies are under way to clarify this difficult issue. Current evidence does not support universal screening for bacterial vaginosis in pregnancy (41). # Trichomoniasis Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, but limited data show that treatment of asymptomatic infection during pregnancy lessens the association (42). Metronidazole remains the only recommended treatment for trichomoniasis. Metronidazole use during pregnancy has not been shown to have a consistent association with teratogenic or mutagenic effects in the infant. Infections with strains that show diminished susceptibility to metronidazole can occur. Most nonpregnant women respond to a higher metronidazole dose and extended therapy. No published data on the use of these enhanced metronidazole regimens in pregnant women ex-ist, and pregnant women should be managed in consultation with an expert in infectious diseases. # PREVENTION OF STD-RELATED CANCER It is well established that persistent infection with human papillomavirus (HPV) plays a central role in the pathogenesis of most types of squamous-cell cancer of the cervix, vagina, vulva, anus, and penis. Recent estimates of the cost of treating HPV and cervical cancer exceed $4.5 billion; this is more than the cost of any other single STD with the exception of HIV infection (1). Most invasive types of anogenital squamous-cell cancer of the genital tract and anus have been associated with HPV types 16, 18, 31, or 45, whereas most external genital warts are associated with HPV types 6 or 11 (6). Subclinical genital HPV infection occurs more frequently than visible genital warts and refers to manifestations of infection in the absence of visible genital warts, including situations where infection is diagnosed on the basis of characteristic cytologic features, squamous intraepithelial lesions (SIL), or on any genital skin by a viral nucleic acid (DNA or RNA) or capsid protein test for HPV. Recognition of the role of specific HPV types in cervical cancer and the advent of type-specific HPV tests have stimulated a focus on the use of HPV diagnostic tests in prevention of cervical cancer. Testing for HPV was recently proposed as a strategy to determine which women with low-grade cervical cytologic abnormalities require colposcopic evaluation. Several trials designed to clarify the role of HPV testing in the evaluation of low-grade cervical abnormalities indicate that HPV testing can be useful in the management of women with Papanicolaou tests that show atypical squamous cells of undetermined significance, but not in the management of low-grade SIL (43,44). At this time, data are insufficient to recommend routine HPV testing for other clinical purposes. No therapy has been identified that effectively eradicates persistent subclinical HPV infection. In the presence of coexistent SIL, management should be based on histopathologic findings and includes cryotherapy, laser ablation, cone biopsy, or loop electrosurgical excision procedure. A strong relation exists among persistent HPV infection, anal SIL, and anal cancer, showing the same spectrum of HPV types as those associated with cervical cancer (45). Prevalence of anal SIL and anal cancer is substantially increased among men who have sex with men and men with HIV infection (46). Clinicians should be aware of the importance of intra-anal manifestations of HPV infection in such men, given the association of HPV with anal dysplasia, and they should consider anoscopic examination in persons with symptoms referable to the anal canal. However, high-grade anal SIL has been shown in normalappearing anal mucosal biopsy specimens from men with and without HIV infection (47). The appropriate clinical management for persons with high-grade anal SIL is uncertain, but ablation or surgical removal has been sug-gested. Because of the increased incidence of anal cancer in HIV-infected men who have sex with men, screening for anal SIL by anal cytologic examination has been proposed (48). However, because the natural history of anal SIL has not been established and management strategies are not clearly defined, such a screening approach cannot currently be recommended in the STD treatment guidelines. # CONCLUSIONS For more than 20 years, the CDC's publication of national guidelines for STD management has been a key component of federal initiatives to improve the health of the U.S. population by preventing and controlling STDs and their sequelae. These public health goals can be attained only if they are supported by knowledgeable clinicians and if clinicians are, in turn, supported by health care systems that make it possible for them to deliver optimal care for patients with STDs and to incorporate new guidelines into clinical practice. The 2002 guidelines should therefore be viewed as the starting point for a process that requires the ongoing efforts of residency program directors, providers of continuing medical education, clinic managers, and health plan administrators in public and private sectors. As recommendations for STD treatment continue to evolve in response to basic and clinical research advances, emerging antimicrobial resistance, and changing sexual and health care behaviors, clinical practice-at both the individual and the system level-must reflect these changes. New, more effective treatment regimens; highly sensitive screening tests for asymptomatic infection; improvements in counseling of patients and their sexual partners; and new vaccines for sexually transmitted pathogens will benefit individual patients and be crucial to the achievement of our broader public health goal of improving sexual and reproductive health in the United States. From Centers for Disease Control and Prevention, Atlanta, Georgia; and the Fred Hutchinson Cancer Research Center, Seattle, Washington. # Acknowledgment: The authors thank Garrett Mallory for administrative assistance.	None	None
7f5f2869d4bf11950d36d75720d1a77f2c7e9580	cdc	None	recommends that worker exposure to ammonia be controlled by requiring com pliance with the following sections. The standard is designed to protect the health and safety of workers for a 40-hour workweek over a working lifetime. Compliance with all sections of the standard should prevent adverse effects of exposure to ammonia in the workplace air. The standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. "Ammonia" is defined as gaseous or liquified anhydrous ammonia and aqueous solutions thereof (aqua ammonia, ammonium hydroxide). "Strong aqua ammonia" is defined as aqueous solutions containing more than 10% ammonia. "Weak aqua ammonia" is defined as solutions of 10% or less. Section 1 -Environmental (Workplace Air) (a) Concentration Occupational exposure shall be controlled so that no worker Is exposed to ammonia at greater than a celling concentration of 50 ppm as determined by a 5-minute sampling period. (b) Sampling and Analysis Procedures for sampling, calibration of equipment, and analysis of ammonia samples shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. I. RECOMMENDATIONS FOR AN AMMONIA STANDARD Section 2 -Medical (a) Preplacement medical examinations shall be made available for all workers whose employment may involve potential exposure to ammonia con centrations in excess of 50 ppm. The examination shall be directed toward, but not limited, to the eyes, skin, and upper respiratory system. Pulmonary function tests should be carried out at the time of the preplacement examination. An evaluation of the advisability of the worker's using negative or positive pressure respirators shall be made. (b) Medical surveillance shall be made available for all workers in whose eyes liquid ammonia has been splashed, who have signs and symptoms of eye irritation after exposure to ammonia, who exhibit signs or symptoms of respiratory tract (throat, trachea, lungs) irritation caused by ammonia exposure, or who experience skin irritation as a result of ammonia exposure. (c) Initial examinations for presently employed workers shall be made available within 6 months of the promulgation of a standard incorpor ating these recommendations. (d) Records of preplacement medical examinations and of required medical surveillance shall be maintained for the period of employment. The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee shall have access to all medical records. Section 3 -Labeling (Posting) (a) Containers of anhydrous ammonia shall be marked in accordance with 29 CFR 1910.111 as amended and shall bear the following label in Form 0 -> :A Rev. Mb > 7*# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR AMMONIA # Table of Contents In addition to the respiratory protection specified in Table 1-1, personnel required to enter atmospheric ammonia concentrations likely to be more than 10,000 ppm shall wear, under an impervious full body suit, a self-contained breathing apparatus with a positive pressure in a full facepiece or a combination supplied air impervious suit, continuous flow type, with auxiliary self-contained air supply. When the worker is using the impervious suit over a self-contained breathing apparatus, stay time in the area shall be limited with due consideration to the heat stress factors involved. (3) The employer shall supply and maintain all protective clothing in a clean, sanitary, and workable condition. # (b) Respiratory Protection The employer shall provide appropriate respirators and ensure proper use when a variance has been granted under the provisions of the Occupa tional Safety and Health Act to allow respirators as a means of control of exposure in routine operations, while the application for variance is pending, or whenever atmospheric concentrations of ammonia exceed 50 ppm, eg, for nonroutine operations, for occasional brief concentrations above the ceiling, cr for emergencies. For these instances a variance is not required, but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: ( First aid procedures will be included, with emphasis on the importance of prompt, copious irrigation of the eyes despite the initial lack of pain. The information shall be posted in the work area, and kept on file, readily accessible to the worker at all places of employment where ammonia is involved in unit processes and operations, or is released as a product, byproduct, or contaminant. A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, first aid procedures, proper maintenance procedures and cleanup methods, and that they know how to correctly use respiratory protective equipment and protective clothing. # Retention of this information by workers in areas required # Effects on Humans Ammonium ions are produced in the body as a protein metabolite. Ammonium ions produced by deamination are rapidly converted in the liver into relatively harmless urea and excreted by the kidney or are used to make new amino acids. Ammonium ions are also produced in the kidney, conserving fixed base, thus maintaining electrolyte balance. # A. Odor Threshold Available odor threshold data show a wide variation. Fieldner et al in 1921 reported a threshold of 50 ppm in human exposure experiments. Smyth found that 1 ppm was detected and identified by 10 subjects. The lower concentrations were found at the beginning of the growing period for broiler production, and the higher concentrations at the end when the chickens were caught and the chicken houses were cleaned. # Details of these experiments Ventilation intakes near the ceiling of chicken production buildings did not control the ammonia which was produced near the floor. Recommended remedial measures included complete redesign of chicken production facilities, with interim relocation of ventilation intakes to floor level. concluded that 300-500 ppm, following a period of adaptation, could be tolerated for a prolonged period without harm, and further, that concentrations of 1,000-2,000 ppm were safe for short periods. Lehmann recommended that prolonged exposure to concentrations over 500 ppm should definitely not be allowed. Ammonia concentrations of 70-110 ppm in a gas works were said to be at the threshold of irritation. September 1973] exposures suggest that one can quickly become accustomed to concentrations of ammonia that at first had been disagreeable. Although the nasal dryness reported at 50 ppm during a 5-minute exposure might become irritating after extended exposure, the con centration of ammonia inhaled appears to be the more important factor, the irritating or annoying effects being more dependent upon concentration than length of exposure. For this reason, a standard expressed as a timeweighted average is inappropriate since it would permit fluctuations to concentrations considerably higher than 50 ppm. Therefore, in order to minimize the discomfort felt by some unacclimatized individuals, to # H. Fire and explosion hazards While not considered to be a serious fire or explosion hazard,	recommends that worker exposure to ammonia be controlled by requiring com pliance with the following sections. The standard is designed to protect the health and safety of workers for a 40-hour workweek over a working lifetime. Compliance with all sections of the standard should prevent adverse effects of exposure to ammonia in the workplace air. The standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. "Ammonia" is defined as gaseous or liquified anhydrous ammonia and aqueous solutions thereof (aqua ammonia, ammonium hydroxide). "Strong aqua ammonia" is defined as aqueous solutions containing more than 10% ammonia. "Weak aqua ammonia" is defined as solutions of 10% or less. Section 1 -Environmental (Workplace Air) (a) Concentration Occupational exposure shall be controlled so that no worker Is exposed to ammonia at greater than a celling concentration of 50 ppm as determined by a 5-minute sampling period. (b) Sampling and Analysis Procedures for sampling, calibration of equipment, and analysis of ammonia samples shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. I. RECOMMENDATIONS FOR AN AMMONIA STANDARD Section 2 -Medical (a) Preplacement medical examinations shall be made available for all workers whose employment may involve potential exposure to ammonia con centrations in excess of 50 ppm. The examination shall be directed toward, but not limited, to the eyes, skin, and upper respiratory system. Pulmonary function tests should be carried out at the time of the preplacement examination. An evaluation of the advisability of the worker's using negative or positive pressure respirators shall be made. (b) Medical surveillance shall be made available for all workers in whose eyes liquid ammonia has been splashed, who have signs and symptoms of eye irritation after exposure to ammonia, who exhibit signs or symptoms of respiratory tract (throat, trachea, lungs) irritation caused by ammonia exposure, or who experience skin irritation as a result of ammonia exposure. (c) Initial examinations for presently employed workers shall be made available within 6 months of the promulgation of a standard incorpor ating these recommendations. (d) Records of preplacement medical examinations and of required medical surveillance shall be maintained for the period of employment. The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee shall have access to all medical records. Section 3 -Labeling (Posting) (a) Containers of anhydrous ammonia shall be marked in accordance with 29 CFR 1910.111 as amended and shall bear the following label in Form 0 -> :A Rev. Mb > 7*# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR AMMONIA # Table of Contents (2) In addition to the respiratory protection specified in Table 1-1, personnel required to enter atmospheric ammonia concentrations likely to be more than 10,000 ppm shall wear, under an impervious full body suit, a self-contained breathing apparatus with a positive pressure in a full facepiece or a combination supplied air impervious suit, continuous flow type, with auxiliary self-contained air supply. When the worker is using the impervious suit over a self-contained breathing apparatus, stay time in the area shall be limited with due consideration to the heat stress factors involved. (3) The employer shall supply and maintain all protective clothing in a clean, sanitary, and workable condition. # (b) Respiratory Protection The employer shall provide appropriate respirators and ensure proper use when a variance has been granted under the provisions of the Occupa tional Safety and Health Act to allow respirators as a means of control of exposure in routine operations, while the application for variance is pending, or whenever atmospheric concentrations of ammonia exceed 50 ppm, eg, for nonroutine operations, for occasional brief concentrations above the ceiling, cr for emergencies. For these instances a variance is not required, but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: ( First aid procedures will be included, with emphasis on the importance of prompt, copious irrigation of the eyes despite the initial lack of pain. The information shall be posted in the work area, and kept on file, readily accessible to the worker at all places of employment where ammonia is involved in unit processes and operations, or is released as a product, byproduct, or contaminant. A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, first aid procedures, proper maintenance procedures and cleanup methods, and that they know how to correctly use respiratory protective equipment and protective clothing. # Retention of this information by workers in areas required # Effects on Humans Ammonium ions are produced in the body as a protein metabolite. [12] Ammonium ions produced by deamination are rapidly converted in the liver into relatively harmless urea and excreted by the kidney or are used to make new amino acids. Ammonium ions are also produced in the kidney, conserving fixed base, thus maintaining electrolyte balance. # A. Odor Threshold Available odor threshold data show a wide variation. Fieldner et al in 1921 [13] reported a threshold of 50 ppm in human exposure experiments. Smyth [14] found that 1 ppm was detected and identified by 10 subjects. The lower concentrations were found at the beginning of the growing period for broiler production, and the higher concentrations at the end when the chickens were caught and the chicken houses were cleaned. # Details of these experiments Ventilation intakes near the ceiling of chicken production buildings did not control the ammonia which was produced near the floor. Recommended remedial measures included complete redesign of chicken production facilities, with interim relocation of ventilation intakes to floor level. concluded that 300-500 ppm, following a period of adaptation, could be tolerated for a prolonged period without harm, and further, that concentrations of 1,000-2,000 ppm were safe for short periods. Lehmann recommended that prolonged exposure to concentrations over 500 ppm should definitely not be allowed. Ammonia concentrations of 70-110 ppm in a gas works were said to be at the threshold of irritation. September 1973] exposures suggest that one can quickly become accustomed to concentrations of ammonia that at first had been disagreeable. Although the nasal dryness reported at 50 ppm during a 5-minute exposure [38] might become irritating after extended exposure, the con centration of ammonia inhaled appears to be the more important factor, the irritating or annoying effects being more dependent upon concentration than length of exposure. For this reason, a standard expressed as a timeweighted average is inappropriate since it would permit fluctuations to concentrations considerably higher than 50 ppm. Therefore, in order to minimize the discomfort felt by some unacclimatized individuals, to # H. Fire and explosion hazards While not considered to be a serious fire or explosion hazard,	None	None
658aea9cf3a241deb3177313b5c9b9d76b3ab1c5	cdc	None	- The yellow bar for varicella vaccine has been extended through all age groups, indicating that the vaccine is recommended for all adults without evidence of immunity to varicella. - Zoster vaccine has been added, with a yellow bar indicating that the vaccine is recommended for persons aged >60 years. Medical/Other Indications Schedule (Figure 2) - The title has been changed to "Vaccines that might be indicated for adults based on medical and other indications," indicating that not all of the vaccines are recommended based on medical indications. - The word "contraindicated" has been added to the red bars and removed from the legend. - The "immunocompromising conditions" column heading has been shortened by removing the list of conditions. - The "human immunodeficiency virus (HIV) infection" column has been moved next to the "immunocompromising conditions" column. - The HIV column has been split into CD4+ T lymphocyte counts of 200 cells/µL. - The indication "recipients of clotting factor concentrates" has been removed from the column heading "chronic liver disease" because only one vaccine has this recommendation. The indication remains in the hepatitis A vaccine footnote. - The varicella vaccine yellow bar has been extended to include persons infected with HIV who have CD4+ T lymphocyte counts of >200 cells/µL (1).# - The influenza vaccine yellow bar for "health-care personnel" indicates that health-care personnel can receive either trivalent inactivated influenza vaccine (TIV) or live, attenuated influenza vaccine (LAIV). - The yellow bar for influenza vaccine has been extended to include persons in the "asplenia" risk group. - The bar for meningococcal vaccine has been revised to indicate that 1 or more doses might be indicated. - Zoster vaccine has been added to the schedule with a yellow bar to indicate that the vaccine is recommended for all indications except pregnancy, immunocompromising conditions, and HIV. A red bar, indicating a contraindication, has been inserted for pregnancy, immunocompromising conditions, and HIV infection with a CD4+ T lymphocyte count of <200 cells/µL. # Footnotes (Figures 1 and 2) - Text for vaccine contraindications in pregnancy has been removed from the footnotes of human papillomavirus (HPV) (#2); measles, mumps, rubella (MMR) (#3); and varicella (#4) to be consistent with the intent of the footnotes to summarize the indications for vaccine use. Pregnancy contraindications are indicated with a red bar. - The HPV footnote (#2) has been revised to clarify evidence of prior infection, clarify that HPV vaccine is not specifically indicated based on medical conditions, and indicate that efficacy and immunogenicity might be lower in persons with certain medical conditions. - The varicella footnote (#4) has been revised to clarify that birth before 1980 for immunocompromised persons is not evidence of immunity and to add a requirement for evidence of immunity. - The pneumococcal polysaccharide vaccine (PPV) footnote (#6) has been revised by adding chronic alcoholism and cerebrospinal fluid leaks and deleting the immunocompromising conditions. - The hepatitis B footnote (#9) has been revised by removing persons who receive clotting factor concentrates as a risk group and by clarifying the special formulations dose. - The meningococcal vaccine footnote (#10) has been revised to clarify that persons who remain at increased risk for infection might be indicated for revaccination. - A footnote (#11) has been added to reflect ACIP recommendations for herpes zoster vaccination for persons aged >60 years. - A footnote (#13) has been added to provide a reference for vaccines in persons with immunocompromising conditions. Reference 1. CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(No. RR-4). The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians. The standard MMWR footnote format has been modified for publication of this schedule. # Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination Tdap should replace a single dose of Td for adults aged <65 years who have not previously received a dose of Tdap. Only one of two Tdap products (Adacel ® ) is licensed for use in adults. Adults with uncertain histories of a complete primary vaccination series with tetanus and diphtheria toxoid-containing vaccines should begin or complete a primary vaccination series. A primary series for adults is 3 doses of tetanus and diphtheria toxoid-containing vaccines; administer the first 2 doses at least 4 weeks apart and the third dose 6-12 months after the second. However, Tdap can substitute for any one of the doses of Td in the 3-dose primary series. The booster dose of tetanus and diphtheria toxoid-containing vaccine should be administered to adults who have completed a primary series and if the last vaccination was received >10 years previously. Tdap or Td vaccine may be used, as indicated. If the person is pregnant and received the last Td vaccination >10 years previously, administer Td during the second or third trimester; if the person received the last Td vaccination in <10 years, administer Tdap during the immediate postpartum period. A one-time administration of 1 dose of Tdap with an interval as short as 2 years from a previous Td vaccination is recommended for postpartum women, close contacts of infants aged <12 months, and all health-care workers with direct patient contact. In certain situations, Td can be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap can be administered instead of Td to a pregnant woman after an informed discussion with the woman. Consult the ACIP statement for recommendations for administering Td as prophylaxis in wound management. # Human papillomavirus (HPV) vaccination HPV vaccination is recommended for all females aged <26 years who have not completed the vaccine series. History of genital warts, abnormal Papanicolaou test, or positive HPV DNA test is not evidence of prior infection with all vaccine HPV types; HPV vaccination is still recommended for these persons. Ideally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated. Sexually active females who have not been infected with any of the HPV vaccine types receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. A complete series consists of 3 doses. The second dose should be administered 2 months after the first dose; the third dose should be administered 6 months after the first dose. Although HPV vaccination is not specifically recommended for females with the medical indications described in Figure 2, "Vaccines that might be indicated for adults based on medical and other indications," it is not a live-virus vaccine and can be administered. However, immune response and vaccine efficacy might be less than in persons who do not have the medical indications described or who are immunocompetent. # Measles, mumps, rubella (MMR) vaccination Measles component: adults born before 1957 can be considered immune to measles. Adults born during or after 1957 should receive >1 dose of MMR unless they have a medical contraindication, documentation of >1 dose, history of measles based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) have been previously vaccinated with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963-1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Mumps component: adults born before 1957 can generally be A second dose of MMR is recommended for adults who 1) are in an age group that is affected during a mumps outbreak; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. For unvaccinated healthcare workers born before 1957 who do not have other evidence of mumps immunity, consider administering 1 dose on a routine basis and strongly consider administering a second dose during an outbreak. Rubella component: administer 1 dose of MMR vaccine to women whose rubella vaccination history is unreliable or who lack laboratory evidence of immunity. For women of childbearing age, regardless of birth year, routinely determine rubella immunity and counsel women regarding congenital rubella syndrome. Women who do not have evidence of immunity should receive MMR vaccine on completion or termination of pregnancy and before discharge from the health-care facility. # Varicella vaccination All adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of immunocompromised persons) or 2) are at high risk for exposure or transmission (e.g., teachers; child care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or presenting with an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or to a laboratoryconfirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on health-care provider diagnosis; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Assess pregnant women for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4-8 weeks after the first dose. # Influenza vaccination Medical indications: chronic disorders of the cardiovascular or pulmonary systems, including asthma; chronic metabolic diseases, including diabetes mellitus, renal or hepatic dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or human immunodeficiency virus ); any condition that compromises respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration (e.g., cognitive dysfunction, spinal cord injury, or seizure disorder or other neuromuscular disorder); and pregnancy during the influenza season. No data exist on the risk for severe or complicated influenza disease among persons with asplenia; however, influenza is a risk factor for secondary bacterial infections that can cause severe disease among persons with asplenia. Occupational indications: health-care personnel and employees of long-term-care and assisted-living facilities. # FIGURE 2. Vaccines that might be indicated for adults based on medical and other indications - Other indications: residents of nursing homes and other long-termcare and assisted-living facilities; persons likely to transmit influenza to persons at high risk (e.g., in-home household contacts and caregivers of children aged 0-59 months, or persons of all ages with high-risk conditions); and anyone who would like to be vaccinated. Healthy, nonpregnant adults aged <49 years without high-risk medical conditions who are not contacts of severely immunocompromised persons in special care units can receive either intranasally administered live, attenuated influenza vaccine (FluMist ® ) or inactivated vaccine. Other persons should receive the inactivated vaccine. # Pneumococcal polysaccharide vaccination Medical indications: chronic pulmonary disease (excluding asthma); chronic cardiovascular diseases; diabetes mellitus; chronic liver diseases, including liver disease as a result of alcohol abuse (e.g., cirrhosis); chronic alcoholism, chronic renal failure, or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy ); immunosuppressive conditions; and cochlear implants and cerebrospinal fluid leaks. Vaccinate as close to HIV diagnosis as possible. Other indications: Alaska Natives and certain American Indian populations and residents of nursing homes or other long-term-care facilities. # Revaccination with pneumococcal polysaccharide vaccine One-time revaccination after 5 years for persons with chronic renal failure or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); or immunosuppressive conditions. For persons aged >65 years, one-time revaccination if they were vaccinated >5 years previously and were aged <65 years at the time of primary vaccination. # Hepatitis A vaccination Medical indications: persons with chronic liver disease and persons who receive clotting factor concentrates. Behavioral indications: men who have sex with men and persons who use illegal drugs. Occupational indications: persons working with hepatitis A virus (HAV)-infected primates or with HAV in a research laboratory setting. Other indications: persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A (a list of countries is available at ) and any person seeking protection from HAV infection. Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6-12 months (Havrix ® ), or 0 and 6-18 months (Vaqta ® ). If the combined hepatitis A and hepatitis B vaccine (Twinrix ® ) is used, administer 3 doses at 0, 1, and 6 months. # Hepatitis B vaccination Medical indications: persons with end-stage renal disease, including patients receiving hemodialysis; persons seeking evaluation or treatment for a sexually transmitted disease (STD); persons with HIV infection; and persons with chronic liver disease. Occupational indications: health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids. Behavioral indications: sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); current or recent injection-drug users; and men who have sex with men. Other indications: household contacts and sex partners of persons with chronic hepatitis B virus (HBV) infection; clients and staff members of institutions for persons with developmental disabilities; international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at / travel/contentdiseases.aspx); and any adult seeking protection from # HBV infection. Settings where hepatitis B vaccination is recommended for all adults: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day care facilities for persons with developmental disabilities. Special formulation indications: for adult patients receiving hemodialysis and other immunocompromised adults, 1 dose of 40 µg/mL (Recombivax HB ® ) or 2 doses of 20 µg/mL (Engerix-B ® ), administered simultaneously. # Meningococcal vaccination Medical indications: adults with anatomic or functional asplenia or terminal complement component deficiencies. Other indications: first-year college students living in dormitories; microbiologists who are routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season ), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Meningococcal conjugate vaccine is preferred for adults with any of the preceding indications who are aged <55 years, although meningococcal polysaccharide vaccine (MPSV4) is an acceptable alternative. Revaccination after 3-5 years might be indicated for adults previously vaccinated with MPSV4 who remain at increased risk for infection (e.g., persons residing in areas in which disease is epidemic). # Herpes zoster vaccination A single dose of zoster vaccine is recommended for adults aged >60 years regardless of whether they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their condition. # Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used Hib conjugate vaccines are licensed for children aged 6 weeks-71 months. No efficacy data are available on which to base a recommendation concerning use of Hib vaccine for older children and adults with the chronic conditions associated with an increased risk for Hib disease. However, studies suggest good immunogenicity in patients who have sickle cell disease, leukemia, or HIV infection or who have had splenectomies; administering vaccine to these patients is not contraindicated. # Immunocompromising conditions Inactivated vaccines generally are acceptable (e.g., pneumococcal, meningococcal, and influenza ) and live vaccines generally are avoided in persons with immune deficiencies or immune suppressive conditions. Information on specific conditions is available at . This schedule indicates the recommended age groups and medical indications for routine administration of currently licensed vaccines for persons aged >19 years, as of October 1, 2007. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or those issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (available at ). Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at or by telephone, 800-822-7967. Information on how to file a Vaccine Injury Compensation Program claim is available at or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005;telephone, 202-357-6400. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.	• The yellow bar for varicella vaccine has been extended through all age groups, indicating that the vaccine is recommended for all adults without evidence of immunity to varicella. • Zoster vaccine has been added, with a yellow bar indicating that the vaccine is recommended for persons aged >60 years. Medical/Other Indications Schedule (Figure 2) • The title has been changed to "Vaccines that might be indicated for adults based on medical and other indications," indicating that not all of the vaccines are recommended based on medical indications. • The word "contraindicated" has been added to the red bars and removed from the legend. • The "immunocompromising conditions" column heading has been shortened by removing the list of conditions. • The "human immunodeficiency virus (HIV) infection" column has been moved next to the "immunocompromising conditions" column. • The HIV column has been split into CD4+ T lymphocyte counts of <200 cells/µL and >200 cells/µL. • The indication "recipients of clotting factor concentrates" has been removed from the column heading "chronic liver disease" because only one vaccine has this recommendation. The indication remains in the hepatitis A vaccine footnote. • The varicella vaccine yellow bar has been extended to include persons infected with HIV who have CD4+ T lymphocyte counts of >200 cells/µL (1).# • The influenza vaccine yellow bar for "health-care personnel" indicates that health-care personnel can receive either trivalent inactivated influenza vaccine (TIV) or live, attenuated influenza vaccine (LAIV). • The yellow bar for influenza vaccine has been extended to include persons in the "asplenia" risk group. • The bar for meningococcal vaccine has been revised to indicate that 1 or more doses might be indicated. • Zoster vaccine has been added to the schedule with a yellow bar to indicate that the vaccine is recommended for all indications except pregnancy, immunocompromising conditions, and HIV. A red bar, indicating a contraindication, has been inserted for pregnancy, immunocompromising conditions, and HIV infection with a CD4+ T lymphocyte count of <200 cells/µL. # Footnotes (Figures 1 and 2) • Text for vaccine contraindications in pregnancy has been removed from the footnotes of human papillomavirus (HPV) (#2); measles, mumps, rubella (MMR) (#3); and varicella (#4) to be consistent with the intent of the footnotes to summarize the indications for vaccine use. Pregnancy contraindications are indicated with a red bar. • The HPV footnote (#2) has been revised to clarify evidence of prior infection, clarify that HPV vaccine is not specifically indicated based on medical conditions, and indicate that efficacy and immunogenicity might be lower in persons with certain medical conditions. • The varicella footnote (#4) has been revised to clarify that birth before 1980 for immunocompromised persons is not evidence of immunity and to add a requirement for evidence of immunity. • The pneumococcal polysaccharide vaccine (PPV) footnote (#6) has been revised by adding chronic alcoholism and cerebrospinal fluid leaks and deleting the immunocompromising conditions. • The hepatitis B footnote (#9) has been revised by removing persons who receive clotting factor concentrates as a risk group and by clarifying the special formulations dose. • The meningococcal vaccine footnote (#10) has been revised to clarify that persons who remain at increased risk for infection might be indicated for revaccination. • A footnote (#11) has been added to reflect ACIP recommendations for herpes zoster vaccination for persons aged >60 years. • A footnote (#13) has been added to provide a reference for vaccines in persons with immunocompromising conditions. Reference 1. CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(No. RR-4). The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians. The standard MMWR footnote format has been modified for publication of this schedule. # Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination Tdap should replace a single dose of Td for adults aged <65 years who have not previously received a dose of Tdap. Only one of two Tdap products (Adacel ® [Sanofi Pasteur]) is licensed for use in adults. Adults with uncertain histories of a complete primary vaccination series with tetanus and diphtheria toxoid-containing vaccines should begin or complete a primary vaccination series. A primary series for adults is 3 doses of tetanus and diphtheria toxoid-containing vaccines; administer the first 2 doses at least 4 weeks apart and the third dose 6-12 months after the second. However, Tdap can substitute for any one of the doses of Td in the 3-dose primary series. The booster dose of tetanus and diphtheria toxoid-containing vaccine should be administered to adults who have completed a primary series and if the last vaccination was received >10 years previously. Tdap or Td vaccine may be used, as indicated. If the person is pregnant and received the last Td vaccination >10 years previously, administer Td during the second or third trimester; if the person received the last Td vaccination in <10 years, administer Tdap during the immediate postpartum period. A one-time administration of 1 dose of Tdap with an interval as short as 2 years from a previous Td vaccination is recommended for postpartum women, close contacts of infants aged <12 months, and all health-care workers with direct patient contact. In certain situations, Td can be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap can be administered instead of Td to a pregnant woman after an informed discussion with the woman. Consult the ACIP statement for recommendations for administering Td as prophylaxis in wound management. # Human papillomavirus (HPV) vaccination HPV vaccination is recommended for all females aged <26 years who have not completed the vaccine series. History of genital warts, abnormal Papanicolaou test, or positive HPV DNA test is not evidence of prior infection with all vaccine HPV types; HPV vaccination is still recommended for these persons. Ideally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated. Sexually active females who have not been infected with any of the HPV vaccine types receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. A complete series consists of 3 doses. The second dose should be administered 2 months after the first dose; the third dose should be administered 6 months after the first dose. Although HPV vaccination is not specifically recommended for females with the medical indications described in Figure 2, "Vaccines that might be indicated for adults based on medical and other indications," it is not a live-virus vaccine and can be administered. However, immune response and vaccine efficacy might be less than in persons who do not have the medical indications described or who are immunocompetent. # Measles, mumps, rubella (MMR) vaccination Measles component: adults born before 1957 can be considered immune to measles. Adults born during or after 1957 should receive >1 dose of MMR unless they have a medical contraindication, documentation of >1 dose, history of measles based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) have been previously vaccinated with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963-1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Mumps component: adults born before 1957 can generally be A second dose of MMR is recommended for adults who 1) are in an age group that is affected during a mumps outbreak; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. For unvaccinated healthcare workers born before 1957 who do not have other evidence of mumps immunity, consider administering 1 dose on a routine basis and strongly consider administering a second dose during an outbreak. Rubella component: administer 1 dose of MMR vaccine to women whose rubella vaccination history is unreliable or who lack laboratory evidence of immunity. For women of childbearing age, regardless of birth year, routinely determine rubella immunity and counsel women regarding congenital rubella syndrome. Women who do not have evidence of immunity should receive MMR vaccine on completion or termination of pregnancy and before discharge from the health-care facility. # Varicella vaccination All adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of immunocompromised persons) or 2) are at high risk for exposure or transmission (e.g., teachers; child care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or presenting with an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or to a laboratoryconfirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on health-care provider diagnosis; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Assess pregnant women for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4-8 weeks after the first dose. # Influenza vaccination Medical indications: chronic disorders of the cardiovascular or pulmonary systems, including asthma; chronic metabolic diseases, including diabetes mellitus, renal or hepatic dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or human immunodeficiency virus [HIV]); any condition that compromises respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration (e.g., cognitive dysfunction, spinal cord injury, or seizure disorder or other neuromuscular disorder); and pregnancy during the influenza season. No data exist on the risk for severe or complicated influenza disease among persons with asplenia; however, influenza is a risk factor for secondary bacterial infections that can cause severe disease among persons with asplenia. Occupational indications: health-care personnel and employees of long-term-care and assisted-living facilities. # FIGURE 2. Vaccines that might be indicated for adults based on medical and other indications - Other indications: residents of nursing homes and other long-termcare and assisted-living facilities; persons likely to transmit influenza to persons at high risk (e.g., in-home household contacts and caregivers of children aged 0-59 months, or persons of all ages with high-risk conditions); and anyone who would like to be vaccinated. Healthy, nonpregnant adults aged <49 years without high-risk medical conditions who are not contacts of severely immunocompromised persons in special care units can receive either intranasally administered live, attenuated influenza vaccine (FluMist ® ) or inactivated vaccine. Other persons should receive the inactivated vaccine. # Pneumococcal polysaccharide vaccination Medical indications: chronic pulmonary disease (excluding asthma); chronic cardiovascular diseases; diabetes mellitus; chronic liver diseases, including liver disease as a result of alcohol abuse (e.g., cirrhosis); chronic alcoholism, chronic renal failure, or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy [if elective splenectomy is planned, vaccinate at least 2 weeks before surgery]); immunosuppressive conditions; and cochlear implants and cerebrospinal fluid leaks. Vaccinate as close to HIV diagnosis as possible. Other indications: Alaska Natives and certain American Indian populations and residents of nursing homes or other long-term-care facilities. # Revaccination with pneumococcal polysaccharide vaccine One-time revaccination after 5 years for persons with chronic renal failure or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); or immunosuppressive conditions. For persons aged >65 years, one-time revaccination if they were vaccinated >5 years previously and were aged <65 years at the time of primary vaccination. # Hepatitis A vaccination Medical indications: persons with chronic liver disease and persons who receive clotting factor concentrates. Behavioral indications: men who have sex with men and persons who use illegal drugs. Occupational indications: persons working with hepatitis A virus (HAV)-infected primates or with HAV in a research laboratory setting. Other indications: persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A (a list of countries is available at http://wwwn.cdc.gov/travel/contentdiseases.aspx) and any person seeking protection from HAV infection. Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6-12 months (Havrix ® ), or 0 and 6-18 months (Vaqta ® ). If the combined hepatitis A and hepatitis B vaccine (Twinrix ® ) is used, administer 3 doses at 0, 1, and 6 months. # Hepatitis B vaccination Medical indications: persons with end-stage renal disease, including patients receiving hemodialysis; persons seeking evaluation or treatment for a sexually transmitted disease (STD); persons with HIV infection; and persons with chronic liver disease. Occupational indications: health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids. Behavioral indications: sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); current or recent injection-drug users; and men who have sex with men. # Other indications: household contacts and sex partners of persons with chronic hepatitis B virus (HBV) infection; clients and staff members of institutions for persons with developmental disabilities; international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at http://wwwn.cdc.gov/ travel/contentdiseases.aspx); and any adult seeking protection from # HBV infection. Settings where hepatitis B vaccination is recommended for all adults: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day care facilities for persons with developmental disabilities. Special formulation indications: for adult patients receiving hemodialysis and other immunocompromised adults, 1 dose of 40 µg/mL (Recombivax HB ® ) or 2 doses of 20 µg/mL (Engerix-B ® ), administered simultaneously. # Meningococcal vaccination Medical indications: adults with anatomic or functional asplenia or terminal complement component deficiencies. Other indications: first-year college students living in dormitories; microbiologists who are routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season [December-June]), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Meningococcal conjugate vaccine is preferred for adults with any of the preceding indications who are aged <55 years, although meningococcal polysaccharide vaccine (MPSV4) is an acceptable alternative. Revaccination after 3-5 years might be indicated for adults previously vaccinated with MPSV4 who remain at increased risk for infection (e.g., persons residing in areas in which disease is epidemic). # Herpes zoster vaccination A single dose of zoster vaccine is recommended for adults aged >60 years regardless of whether they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their condition. # Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used Hib conjugate vaccines are licensed for children aged 6 weeks-71 months. No efficacy data are available on which to base a recommendation concerning use of Hib vaccine for older children and adults with the chronic conditions associated with an increased risk for Hib disease. However, studies suggest good immunogenicity in patients who have sickle cell disease, leukemia, or HIV infection or who have had splenectomies; administering vaccine to these patients is not contraindicated. # Immunocompromising conditions Inactivated vaccines generally are acceptable (e.g., pneumococcal, meningococcal, and influenza [trivalent inactivated influenza vaccine]) and live vaccines generally are avoided in persons with immune deficiencies or immune suppressive conditions. Information on specific conditions is available at http://www.cdc.gov/vaccines/pubs/aciplist.htm. This schedule indicates the recommended age groups and medical indications for routine administration of currently licensed vaccines for persons aged >19 years, as of October 1, 2007. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or those issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (available at http://www.cdc.gov/vaccines/pubs/acip-list.htm). Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at http://www.vaers.hhs.gov or by telephone, 800-822-7967. Information on how to file a Vaccine Injury Compensation Program claim is available at http://www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005;telephone, 202-357-6400. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.	None	None
6773b775a84968271899d52b048124fd2ef2ebf1	cdc	None	# Introduction # Y -uth-serving organizations strive to create a safe environment for youth, employees, and volunteers so that youth can grow, learn, and have fun. Part of creating a safe environment is making sure that youth are not harmed in any way while participating in organization-sponsored activities. One risk in any organization working directly with youth is child sexual abuse. It is vital that organizations create a culture where child sexual abuse is discussed, addressed, and prevented. This report is designed for representatives of youth-serving organizations who are interested in adopting strategies to prevent child sexual abuse. Whether these strategies are developed within the context of an overall risk management plan or are addressed separately, organizations need to examine how they can protect youth from sexual abuse. # Definitions - Children and youth -Anyone between the ages of zero and 17 years. In this document, these terms are used interchangeably. - Child sexual abuse -"Child sexual abuse involves any sexual activity with a child where consent is not or cannot be given. This includes sexual contact that is accomplished by force or threat of force, regardless of the age of the participants, and all sexual contact between an adult and a child, regardless of whether there is deception or the child understands the sexual nature of the activity. Sexual contact between an older and a younger child also can be abusive if there is a significant disparity in age, development, or size, rendering the younger child incapable of giving informed consent. The sexually abusive acts may include sexual penetration, sexual touching, or non-contact sexual acts such as exposure or voyeurism." 1 -Legal definitions vary by state, so look up your state guidelines using the Child Welfare Information Gateway (www.childwelfare.gov/systemwide/laws_policies/search/index.cfm). # What You Will Find in This Report In the first section, you will find six key components of child sexual abuse prevention for organizations. These components were identified by the Centers for Disease Control and Prevention (CDC) in conjunction with experts: 1. Screening and selecting employees and volunteers 2. Guidelines on interactions between individuals 3. Monitoring behavior 4. Ensuring safe environments 5. Responding to inappropriate behavior, breaches in policy, and allegations and suspicions of child sexual abuse 6. Training about child sexual abuse prevention. Each component is described in detail, including the prevention goals, critical strategies, and additional strategies that could be considered depending on the context and resources of individual organizations. The sections that follow offer suggestions for addressing challenges to developing and implementing a strategy to prevent child sexual abuse and provide tools to help organizations move forward. A list of publications and organizations that can provide helpful information is provided in Appendix B. # Contextual Issues Every organization does not have to take on all strategies presented in this document. The process of implementing child sexual abuse prevention strategies takes time and will evolve differently in each organization. Not all strategies presented in this document will apply to all organizations. However, it is very important that organizations abide by their youth protection policies and procedures to avoid being criticized for not adhering to them if a youth is sexually abused. Adoption of strategies will depend on the following contextual issues: - Organization's mission and individual activities. For example, though all youth-serving organizations are interested in helping youth develop into healthy adults, the mission of mentoring or religious organizations is often focused on fostering nurturing relationships between individual adults and youth. Because this mission results in more one-on-one activities between employees/volunteers and youth, these organizations need to adopt child sexual abuse prevention strategies that protect youth in one-on-one situations with adults. - Culture and language of youth served by the organization. - Insurance requirements. - Available resources. - State and national laws. Organizations should consult with legal representation and review state and national laws before adopting and implementing child sexual abuse prevention strategies. A good place to start is the Child Welfare Information Gateway, which provides state-specific information (www.childwelfare.gov/systemwide/laws_policies/search/index.cfm). # Balancing Caution and Caring The same dynamics that create a nurturing environment, and may ultimately protect against child sexual abuse, can also open the doors to sexually abusive behaviors. Research has shown that youth who are emotionally insecure, needy, and unsupported may be more vulnerable to the attentions of offenders. 2 By promoting close and caring relationships between youth and adults, organizations can help youth feel supported and loved and thus reduce their risk of child sexual abuse. But that same closeness between a youth and an adult can also provide the opportunity for abuse to occur. When developing policies for child sexual abuse prevention, organizations must balance the need to keep youth safe with the need to nurture and care for them. # Components of Child Sexual Abuse Prevention T he components that follow were identified during a meeting of experts sponsored by CDC in August 2004. The experts included advocates, child sexual abuse researchers, professionals who provide prevention resources for organizations, and representatives of youth-serving organizations that have child sexual abuse prevention programs. For a list of meeting participants, see Appendix A. # Component 1: Screening and Selecting Employees and Volunteers # Goal To select the best possible people for staff and volunteer positions and to screen out individuals who have sexually abused youth or are at risk to abuse. # General Principles Screening for child sexual abuse prevention should be integrated into the general screening and selection process that organizations already employ to choose the best possible candidates for positions. Child sexual abuse prevention should be one of the many areas considered when deciding whom to select. While employee/volunteer screening and selection are important, they should not be the only efforts adopted to prevent child sexual abuse. # Before you start screening - Develop criteria that define how screening information will be used to determine an applicant's suitability. - Identify who will make the final selection. - Define areas of concern such as a fixation on a particular age or gender of youth or a history of crimes related to sex or violence. - Develop consistent and systematic policies and processes for screening and selection, including a sequence and timeline for the various components of the process. - Consult with an attorney to ensure that your screening and selection policies do not violate Title VII of the Civil Rights Act or other federal or state laws prohibiting discrimination in the workplace. # Who should be screened? - Screen all applicants, both adults and adolescents, for all positions that will have contact with youth. - Consider more in-depth written applications and personal interviews for adolescents, for whom work history and criminal background checks may be unavailable. - Rigorously screen applicants who will have more autonomy as employees or volunteers. - Do not make exceptions for people you know or have worked with in the past. # Critical Strategies for Screening and Selecting Employees and Volunteers (These strategies are presented in roughly the order that they should be completed.) # Education about your organization and youth-protection policies By letting applicants know your organization is serious about protecting youth, you may deter some people at risk of abusing youth from applying for staff or volunteer positions. - Inform applicants about your organization's policies and procedures relevant to child sexual abuse prevention. - Share your code of conduct or ethics. - Require applicants to sign a document describing the policies and procedures of your organization to demonstrate their understanding and agreement. - Ask applicants if they have a problem with any of the policies and procedures. # Written application The written application provides the information you need to assess the background and interests of applicants. Questions should help you determine whether applicants have mature, adult relationships as well as clear boundaries and ethical standards for their conduct with youth. The sidebar on page 6 may help you develop appropriate questions. - Ask about previous work and volunteer experiences. - Ask questions pertinent to child sexual abuse screening. - Provide a permission form for contacting personal references and performing a criminal background check. The permission statement should include an indemnification clause developed by an attorney to protect your organization from false allegations or other legal issues. - Ask open-ended questions that encourage broad answers. These will provide material for follow-up in the personal interview and throughout the screening and selection process. - Use disclosure statements to ask applicants about previous criminal histories of sexual offenses, violence against youth, and other criminal offenses. The applicant may not disclose past offenses, but the inquiry will demonstrate your organization's seriousness about protecting youth and potentially discourage applicants at risk for perpetrating child sexual abuse. - Clarify that you are interested in learning about an applicant's past perpetration of child sexual abuse rather than a history of victimization. # Personal interview The personal interview provides an opportunity to meet applicants, determine if they are a good fit for your organization, and ask additional questions to screen for child sexual abuse risk factors. The sidebar on page 6 may help you develop interview questions. - Ask open-ended questions that encourage discussion. - Clarify and expand upon the applicant's answers to questions from the written application. The following questions may be used in a written application or personal interview. A single answer should not determine whether an applicant is selected or rejected. Along with other forms of information, answers to these questions can help you build a more complete picture of an applicant. Additional questions may be found in various publications and policies in the "Resource List and Sample Policies" section. (See Appendix B.) - What type of supervisory situation do you prefer? If applicants are very independent, they may not fit in an organization whose policies and procedures require close supervision. - What age/sex of youth do you want to work with? How would you feel about working with a different age/sex? If an applicant seems fixated on one age/sex, be wary. However, it may be that the applicant has experience or is gifted with working with certain age groups. Asking follow-up questions about why an applicant has a strong preference can help you determine if there is cause for concern. - Is there anyone who might suggest that you should not work with youth? Why or why not? - Why do you want the job? - What would you do in a particular situation? Set up scenarios that involve potential concerns, boundary issues, or youth protection policies and interactions to gauge the applicant's response. Be concerned if applicants disregard the organization's policies and procedures or handle a situation poorly. - What makes you a good candidate for working with youth? What would your friends or colleagues say about how you interact with youth? - What other hobbies or activities do you enjoy? Determine if applicants have mature, adult relationships-not just relationships with youth. The following questions may be used in a written application or personal interview. A single answer should not determine whether an applicant is selected or rejected. Along with other forms of information, answers to these questions can help you build a more complete picture of an applicant. Additional questions may be found in various publications and policies in the "Resource List and Sample Policies" section. (See Appendix B.) - What type of supervisory situation do you prefer? If applicants are very independent, they may not fit in an organization whose policies and procedures require close supervision. - What age/sex of youth do you want to work with? How would you feel about working with a different age/sex? If an applicant seems fixated on one age/sex, be wary. However, it may be that the applicant has experience or is gifted with working with certain age groups. Asking follow-up questions about why an applicant has a strong preference can help you determine if there is cause for concern. - Is there anyone who might suggest that you should not work with youth? Why or why not? - Why do you want the job? - What would you do in a particular situation? Set up scenarios that involve potential concerns, boundary issues, or youth protection policies and interactions to gauge the applicant's response. Be concerned if applicants disregard the organization's policies and procedures or handle a situation poorly. - What makes you a good candidate for working with youth? What would your friends or colleagues say about how you interact with youth? - What other hobbies or activities do you enjoy? Determine if applicants have mature, adult relationships-not just relationships with youth. # Questions for Screening and Selecting Employees and Volunteers # Reference checks Reference checks provide additional information about applicants and help verify previous work and volunteer history. - Obtain verbal-not just written-references for applicants. Conversations can elicit much more information than written responses. - Match references with employment and volunteer history. Is anyone important missing from the references, such as the supervisor from the applicant's most recent job? To provide a more complete picture of the applicant, the references should come from a variety of sources and should not be limited to family members or friends. - Be aware that many employers will only provide basic information, such as dates of employment or rehiring eligibility. If a former employer will only provide limited information, clarify whether the person providing the reference is limiting information because of company policy. The following questions may be useful for reference checks: - How would you describe the personal characteristics of the applicant? - How does the applicant interact with youth? - Why would this person be a good candidate for working with youth? Is there any reason this person should not work with youth? - Have you seen the applicant discipline youth (other than his or her own children)? - Would you hire this person again? Would you want him or her in your organization in the future? # Criminal background checks Criminal background checks are an important tool in screening and selection. However, they have limitations. Criminal background checks will not identify most sexual offenders because most have not been caught. When this report was published, an efficient, effective, and affordable national background screening system was not available. - Use background checks as one part of child sexual abuse prevention efforts. Using background checks alone may give your organization a false sense of security. - Save time and resources by delaying criminal background checks until the end of the screening and selection process. Applicants who do not make it through the written applications, personal interviews, and reference checks will not need a criminal background check. - Obtain permission from applicants before beginning a criminal background check. - Determine the type and level of check required for each applicant. Types of checks include name, fingerprint, sex offender registries, and social security number. Checks may be implemented at county, state, and national levels. Records are not always linked or comprehensive, so a thorough search may be needed to address concerns about an applicant. For example, if an applicant has moved frequently, checks in multiple states may be necessary. - Plan for the time and financial resources needed to conduct background checks. - Decide which offenses to examine in the background checks and which offenses will disqualify applicants. For child sexual abuse, absolute disqualifiers include violent behavior and child sexual abuse perpetration history. Depending on the risk of the situation or the mission of your organization, drug and driving offenses may also be disqualifiers. Arrest data are not grounds for disqualification; only offenses resulting in convictions may be used. - Develop procedures to keep the results of criminal background checks confidential. Select a secure storage location and limit access to the files. - Ensure that your organization's process for conducting criminal background checks is legally sound. Consult county, state, and national laws and regulations, as well as your organization's attorney and insurance company, as needed. # Additional Strategies to Consider # Assessment of home environment The need for assessing an applicant's home environment depends on the mission of your organization. This may be an essential strategy for mentoring programs where youth meet with mentors at their homes, but it may be irrelevant and inappropriate for other organizations, such as sleep-away camps or after-school programs. # Checking applicants against internal records This strategy involves keeping lists of applicants who are disqualified during the screening process and employees/volunteers who are dismissed because of an offense. During the screening and selection process, your organization would then check current applicants against these lists to make sure the applicant has not been previously disqualified or dismissed. # Internet search Some organizations may choose to search the internet to find additional relevant information about an applicant. Be aware that more than one person can share the same name and that it may be difficult to verify the accuracy of information found on the internet. # Component 2: # Guidelines on Interactions Between Individuals # Goal To ensure the safety of youth in their interactions with employees/volunteers and with each other. # General Principles Guidelines on interactions between individuals should be determined by an organization's mission and activities. For example, organizations that promote one-on-one activities between adults and youth may need different interaction guidelines than programs built around group activities. Organizations should develop interaction policies before situations arise. The strategies listed below should be tailored to the developmental age and maturity of the youth and employees/volunteers. Strategies should also match the cultural context of the population served by the organization. In this section, "adult" refers to any individual in a supervisory position, including youth. # Balancing positive and negative - Find a balance between encouraging positive and appropriate interactions and discouraging inappropriate and harmful interactions. - Adopt strategies with this balance in mind to ensure that youth benefit from your program without risk of sexual abuse or harm. # Critical Strategies for Guidelines on Interactions between Individuals # Ratios of employees/volunteers to youth The goal of setting ratios for the numbers of employees/volunteers to youth is to ensure the safety of the youth. There is no standard ratio for all situations. When making decisions about ratios, consider contextual variables such as: - Age and developmental level of youth and employees/volunteers. If youth or employees/volunteers are young, you may need a lower ratio, that is, fewer youth per adult. - Risk of the activity. Does it involve a great deal of isolation from others? - Location of the activity. Is it in a classroom that is easy to monitor or at a park, where it is easier to lose track of individuals? Encourage employees/volunteers to actively interact with the youth to maintain adequate supervision and monitoring. Even with a satisfactory ratio of employees/volunteers to youth, the youth are not being monitored if all of the employees/volunteers are immersed in their own conversations in a corner of the room. # Examples of Appropriate/Inappropriate/Harmful Behavior from Youth-serving Organizations Sometimes it is unclear if a behavior is appropriate, inappropriate, or harmful. For example, intimate contact, such as kissing, may be developmentally appropriate for older youth, but may be inappropriate within the confines of the organization. It may even be harmful if the kissing is coercive. Another example involves hugging. Hugging may be appropriate and positive in some circumstances, but it can also be inappropriate if the child is not receptive, if the employee/volunteer is hugging too often or for too long, or if the contact is romanticized or sexually intimate. # Verbal communication # One-on-one interactions Some organizations have a policy to limit one-on-one interactions between youth and adults (i.e., having at least two adults present at all times with youth). The goal of such a policy is to prevent the isolation of one adult and one youth, a situation that elevates the risk for child sexual abuse. This strategy must be modified based on the mission of your organization. - Limit one-on-one interactions whenever possible by having at least two adults present at all times with youth. - Choose one of three options relating to this policy: -Make this a mandatory policy at all times. -Make this policy dependent on the risk of the activity or situation, such as overnight trips. -Maintain other safeguards such as extra supervision or contact with youth and employees/volunteers and more stringent screening if the mission of your organization requires one-on-one time between employees/ volunteers and youth (e.g., mentoring programs). # Risk of interactions between youth Your organization needs to address interactions among youth in addition to monitoring interactions between employees/volunteers and youth. Many strategies that focus on the interactions between employees/volunteers and youth can be tailored to address interactions among youth. - Address all situations where unsupervised youth can sexually or physically abuse other youth. For example, if your organization has a policy that prevents adults from being present in locker rooms because of the risk of child sexual abuse, this may result in a situation where unsupervised youth can sexually or physically abuse other youth. A potential solution is adopting a policy that requires more than one adult to be present at all times. - Develop policies to deal with bullying and sexual abuse so that positive interactions can be promoted while acknowledging that some interactions are inappropriate or harmful. # Prohibitions and restrictions on certain activities Some activities, such as hazing and secret ceremonies, overnight trips, bathing, changing, bathroom interactions, and nighttime activities, pose greater risks for child sexual abuse. Prohibiting or restricting such activities will depend largely on the context of your organization. For example, a sleep-away camp would not be able to prohibit overnight trips or bathing. # Out-of-program contact restrictions There are two types of out-of-program contact restrictions. The first type involves the contact of youth with employees/volunteers outside the context of the program. Your organization should limit contact between employees/volunteers and youth to organization-sanctioned activities and programs and/or to certain locations, such as activities within your organization's building. The second type is contact between youth and people not affiliated with your organization that occurs while youth are under the care of your organization. - Develop a system for monitoring the comings and goings of all youth and adults who enter and leave your facility. This system might include procedures for signing in and out. - Develop specific policies about interactions between youth and people not affiliated with your organization if it is located in a building that houses more than just your program or if your organization's activities take place in public areas (e.g., sports field). # Caregiver information and permission Your organization should obtain addresses and contact information for youth and caregivers (i.e., parents and guardians). This information should never be released to unauthorized individuals. Your organization also should obtain permission from caregivers for youth to participate in certain activities, such as field trips, late-night activities, and overnight trips. - Inform caregivers about what their children/ youth will be doing and where they will be going. # Allow caregivers to have input on what activities -r interactions they are comfortable with for their children. # Responsibility for youth Your organization should clarify when it is responsible for youth and when caregivers are responsible. - Develop a policy on when your organization starts and stops being responsible for youth. - Consider who is responsible for youth before and after activities officially begin. - Communicate the policy to caregivers and youth in writing. Organizations may also want caregivers to sign an acknowledgement that they have read and understand the policy. # Additional Strategies to Consider # Other ways to control interactions between individuals Identify ways to monitor interactions, such as instituting a buddy system to prevent isolation of youth with employees/volunteers. # Component 3: Monitoring Behavior # Goal To prevent, recognize, and respond to inappropriate and harmful behaviors and to reinforce appropriate behaviors. # General Principles Monitoring involves observing interactions and reacting appropriately. This includes both employee/volunteer-youth and youth-youth interactions. Youth leaders often require more supervision and monitoring because they are young, may lack judgment, and are harder to screen. Define areas for monitoring based on the organization's mission and activities. Monitor inappropriate or harmful behaviors # Monitor potential risk situations	# Introduction # Y outh-serving organizations strive to create a safe environment for youth, employees, and volunteers so that youth can grow, learn, and have fun. Part of creating a safe environment is making sure that youth are not harmed in any way while participating in organization-sponsored activities. One risk in any organization working directly with youth is child sexual abuse. It is vital that organizations create a culture where child sexual abuse is discussed, addressed, and prevented. This report is designed for representatives of youth-serving organizations who are interested in adopting strategies to prevent child sexual abuse. Whether these strategies are developed within the context of an overall risk management plan or are addressed separately, organizations need to examine how they can protect youth from sexual abuse. # Definitions • Children and youth -Anyone between the ages of zero and 17 years. In this document, these terms are used interchangeably. • Child sexual abuse -"Child sexual abuse involves any sexual activity with a child where consent is not or cannot be given. This includes sexual contact that is accomplished by force or threat of force, regardless of the age of the participants, and all sexual contact between an adult and a child, regardless of whether there is deception or the child understands the sexual nature of the activity. Sexual contact between an older and a younger child also can be abusive if there is a significant disparity in age, development, or size, rendering the younger child incapable of giving informed consent. The sexually abusive acts may include sexual penetration, sexual touching, or non-contact sexual acts such as exposure or voyeurism." 1 -Legal definitions vary by state, so look up your state guidelines using the Child Welfare Information Gateway (www.childwelfare.gov/systemwide/laws_policies/search/index.cfm). # What You Will Find in This Report In the first section, you will find six key components of child sexual abuse prevention for organizations. These components were identified by the Centers for Disease Control and Prevention (CDC) in conjunction with experts: 1. Screening and selecting employees and volunteers 2. Guidelines on interactions between individuals 3. Monitoring behavior 4. Ensuring safe environments 5. Responding to inappropriate behavior, breaches in policy, and allegations and suspicions of child sexual abuse 6. Training about child sexual abuse prevention. Each component is described in detail, including the prevention goals, critical strategies, and additional strategies that could be considered depending on the context and resources of individual organizations. The sections that follow offer suggestions for addressing challenges to developing and implementing a strategy to prevent child sexual abuse and provide tools to help organizations move forward. A list of publications and organizations that can provide helpful information is provided in Appendix B. # Contextual Issues Every organization does not have to take on all strategies presented in this document. The process of implementing child sexual abuse prevention strategies takes time and will evolve differently in each organization. Not all strategies presented in this document will apply to all organizations. However, it is very important that organizations abide by their youth protection policies and procedures to avoid being criticized for not adhering to them if a youth is sexually abused. Adoption of strategies will depend on the following contextual issues: • Organization's mission and individual activities. For example, though all youth-serving organizations are interested in helping youth develop into healthy adults, the mission of mentoring or religious organizations is often focused on fostering nurturing relationships between individual adults and youth. Because this mission results in more one-on-one activities between employees/volunteers and youth, these organizations need to adopt child sexual abuse prevention strategies that protect youth in one-on-one situations with adults. • Culture and language of youth served by the organization. • Insurance requirements. • Available resources. • State and national laws. Organizations should consult with legal representation and review state and national laws before adopting and implementing child sexual abuse prevention strategies. A good place to start is the Child Welfare Information Gateway, which provides state-specific information (www.childwelfare.gov/systemwide/laws_policies/search/index.cfm). # Balancing Caution and Caring The same dynamics that create a nurturing environment, and may ultimately protect against child sexual abuse, can also open the doors to sexually abusive behaviors. Research has shown that youth who are emotionally insecure, needy, and unsupported may be more vulnerable to the attentions of offenders. 2 By promoting close and caring relationships between youth and adults, organizations can help youth feel supported and loved and thus reduce their risk of child sexual abuse. But that same closeness between a youth and an adult can also provide the opportunity for abuse to occur. When developing policies for child sexual abuse prevention, organizations must balance the need to keep youth safe with the need to nurture and care for them. # Components of Child Sexual Abuse Prevention T he components that follow were identified during a meeting of experts sponsored by CDC in August 2004. The experts included advocates, child sexual abuse researchers, professionals who provide prevention resources for organizations, and representatives of youth-serving organizations that have child sexual abuse prevention programs. For a list of meeting participants, see Appendix A. # Component 1: Screening and Selecting Employees and Volunteers # Goal To select the best possible people for staff and volunteer positions and to screen out individuals who have sexually abused youth or are at risk to abuse. # General Principles Screening for child sexual abuse prevention should be integrated into the general screening and selection process that organizations already employ to choose the best possible candidates for positions. Child sexual abuse prevention should be one of the many areas considered when deciding whom to select. While employee/volunteer screening and selection are important, they should not be the only efforts adopted to prevent child sexual abuse. # Before you start screening • Develop criteria that define how screening information will be used to determine an applicant's suitability. • Identify who will make the final selection. • Define areas of concern such as a fixation on a particular age or gender of youth or a history of crimes related to sex or violence. • Develop consistent and systematic policies and processes for screening and selection, including a sequence and timeline for the various components of the process. • Consult with an attorney to ensure that your screening and selection policies do not violate Title VII of the Civil Rights Act or other federal or state laws prohibiting discrimination in the workplace. # Who should be screened? • Screen all applicants, both adults and adolescents, for all positions that will have contact with youth. • Consider more in-depth written applications and personal interviews for adolescents, for whom work history and criminal background checks may be unavailable. • Rigorously screen applicants who will have more autonomy as employees or volunteers. • Do not make exceptions for people you know or have worked with in the past. # Critical Strategies for Screening and Selecting Employees and Volunteers (These strategies are presented in roughly the order that they should be completed.) # Education about your organization and youth-protection policies By letting applicants know your organization is serious about protecting youth, you may deter some people at risk of abusing youth from applying for staff or volunteer positions. • Inform applicants about your organization's policies and procedures relevant to child sexual abuse prevention. • Share your code of conduct or ethics. • Require applicants to sign a document describing the policies and procedures of your organization to demonstrate their understanding and agreement. • Ask applicants if they have a problem with any of the policies and procedures. # Written application The written application provides the information you need to assess the background and interests of applicants. Questions should help you determine whether applicants have mature, adult relationships as well as clear boundaries and ethical standards for their conduct with youth. The sidebar on page 6 may help you develop appropriate questions. • Ask about previous work and volunteer experiences. • Ask questions pertinent to child sexual abuse screening. • Provide a permission form for contacting personal references and performing a criminal background check. The permission statement should include an indemnification clause developed by an attorney to protect your organization from false allegations or other legal issues. • Ask open-ended questions that encourage broad answers. These will provide material for follow-up in the personal interview and throughout the screening and selection process. • Use disclosure statements to ask applicants about previous criminal histories of sexual offenses, violence against youth, and other criminal offenses. The applicant may not disclose past offenses, but the inquiry will demonstrate your organization's seriousness about protecting youth and potentially discourage applicants at risk for perpetrating child sexual abuse. • Clarify that you are interested in learning about an applicant's past perpetration of child sexual abuse rather than a history of victimization. # Personal interview The personal interview provides an opportunity to meet applicants, determine if they are a good fit for your organization, and ask additional questions to screen for child sexual abuse risk factors. The sidebar on page 6 may help you develop interview questions. • Ask open-ended questions that encourage discussion. • Clarify and expand upon the applicant's answers to questions from the written application. The following questions may be used in a written application or personal interview. A single answer should not determine whether an applicant is selected or rejected. Along with other forms of information, answers to these questions can help you build a more complete picture of an applicant. Additional questions may be found in various publications and policies in the "Resource List and Sample Policies" section. (See Appendix B.) • What type of supervisory situation do you prefer? If applicants are very independent, they may not fit in an organization whose policies and procedures require close supervision. • What age/sex of youth do you want to work with? How would you feel about working with a different age/sex? If an applicant seems fixated on one age/sex, be wary. However, it may be that the applicant has experience or is gifted with working with certain age groups. Asking follow-up questions about why an applicant has a strong preference can help you determine if there is cause for concern. • Is there anyone who might suggest that you should not work with youth? Why or why not? • Why do you want the job? • What would you do in a particular situation? Set up scenarios that involve potential concerns, boundary issues, or youth protection policies and interactions to gauge the applicant's response. Be concerned if applicants disregard the organization's policies and procedures or handle a situation poorly. • What makes you a good candidate for working with youth? What would your friends or colleagues say about how you interact with youth? • What other hobbies or activities do you enjoy? Determine if applicants have mature, adult relationships-not just relationships with youth. The following questions may be used in a written application or personal interview. A single answer should not determine whether an applicant is selected or rejected. Along with other forms of information, answers to these questions can help you build a more complete picture of an applicant. Additional questions may be found in various publications and policies in the "Resource List and Sample Policies" section. (See Appendix B.) • What type of supervisory situation do you prefer? If applicants are very independent, they may not fit in an organization whose policies and procedures require close supervision. • What age/sex of youth do you want to work with? How would you feel about working with a different age/sex? If an applicant seems fixated on one age/sex, be wary. However, it may be that the applicant has experience or is gifted with working with certain age groups. Asking follow-up questions about why an applicant has a strong preference can help you determine if there is cause for concern. • Is there anyone who might suggest that you should not work with youth? Why or why not? • Why do you want the job? • What would you do in a particular situation? Set up scenarios that involve potential concerns, boundary issues, or youth protection policies and interactions to gauge the applicant's response. Be concerned if applicants disregard the organization's policies and procedures or handle a situation poorly. • What makes you a good candidate for working with youth? What would your friends or colleagues say about how you interact with youth? • What other hobbies or activities do you enjoy? Determine if applicants have mature, adult relationships-not just relationships with youth. # Questions for Screening and Selecting Employees and Volunteers # Reference checks Reference checks provide additional information about applicants and help verify previous work and volunteer history. • Obtain verbal-not just written-references for applicants. Conversations can elicit much more information than written responses. • Match references with employment and volunteer history. Is anyone important missing from the references, such as the supervisor from the applicant's most recent job? To provide a more complete picture of the applicant, the references should come from a variety of sources and should not be limited to family members or friends. • Be aware that many employers will only provide basic information, such as dates of employment or rehiring eligibility. If a former employer will only provide limited information, clarify whether the person providing the reference is limiting information because of company policy. The following questions may be useful for reference checks: • How would you describe the personal characteristics of the applicant? • How does the applicant interact with youth? • Why would this person be a good candidate for working with youth? Is there any reason this person should not work with youth? • Have you seen the applicant discipline youth (other than his or her own children)? • Would you hire this person again? Would you want him or her in your organization in the future? # Criminal background checks Criminal background checks are an important tool in screening and selection. However, they have limitations. Criminal background checks will not identify most sexual offenders because most have not been caught. When this report was published, an efficient, effective, and affordable national background screening system was not available. • Use background checks as one part of child sexual abuse prevention efforts. Using background checks alone may give your organization a false sense of security. • Save time and resources by delaying criminal background checks until the end of the screening and selection process. Applicants who do not make it through the written applications, personal interviews, and reference checks will not need a criminal background check. • Obtain permission from applicants before beginning a criminal background check. • Determine the type and level of check required for each applicant. Types of checks include name, fingerprint, sex offender registries, and social security number. Checks may be implemented at county, state, and national levels. Records are not always linked or comprehensive, so a thorough search may be needed to address concerns about an applicant. For example, if an applicant has moved frequently, checks in multiple states may be necessary. • Plan for the time and financial resources needed to conduct background checks. • Decide which offenses to examine in the background checks and which offenses will disqualify applicants. For child sexual abuse, absolute disqualifiers include violent behavior and child sexual abuse perpetration history. Depending on the risk of the situation or the mission of your organization, drug and driving offenses may also be disqualifiers. Arrest data are not grounds for disqualification; only offenses resulting in convictions may be used. • Develop procedures to keep the results of criminal background checks confidential. Select a secure storage location and limit access to the files. • Ensure that your organization's process for conducting criminal background checks is legally sound. Consult county, state, and national laws and regulations, as well as your organization's attorney and insurance company, as needed. # Additional Strategies to Consider # Assessment of home environment The need for assessing an applicant's home environment depends on the mission of your organization. This may be an essential strategy for mentoring programs where youth meet with mentors at their homes, but it may be irrelevant and inappropriate for other organizations, such as sleep-away camps or after-school programs. # Checking applicants against internal records This strategy involves keeping lists of applicants who are disqualified during the screening process and employees/volunteers who are dismissed because of an offense. During the screening and selection process, your organization would then check current applicants against these lists to make sure the applicant has not been previously disqualified or dismissed. # Internet search Some organizations may choose to search the internet to find additional relevant information about an applicant. Be aware that more than one person can share the same name and that it may be difficult to verify the accuracy of information found on the internet. # Component 2: # Guidelines on Interactions Between Individuals # Goal To ensure the safety of youth in their interactions with employees/volunteers and with each other. # General Principles Guidelines on interactions between individuals should be determined by an organization's mission and activities. For example, organizations that promote one-on-one activities between adults and youth may need different interaction guidelines than programs built around group activities. Organizations should develop interaction policies before situations arise. The strategies listed below should be tailored to the developmental age and maturity of the youth and employees/volunteers. Strategies should also match the cultural context of the population served by the organization. In this section, "adult" refers to any individual in a supervisory position, including youth. # Balancing positive and negative • Find a balance between encouraging positive and appropriate interactions and discouraging inappropriate and harmful interactions. • Adopt strategies with this balance in mind to ensure that youth benefit from your program without risk of sexual abuse or harm. # Critical Strategies for Guidelines on Interactions between Individuals # Ratios of employees/volunteers to youth The goal of setting ratios for the numbers of employees/volunteers to youth is to ensure the safety of the youth. There is no standard ratio for all situations. When making decisions about ratios, consider contextual variables such as: • Age and developmental level of youth and employees/volunteers. If youth or employees/volunteers are young, you may need a lower ratio, that is, fewer youth per adult. • Risk of the activity. Does it involve a great deal of isolation from others? • Location of the activity. Is it in a classroom that is easy to monitor or at a park, where it is easier to lose track of individuals? Encourage employees/volunteers to actively interact with the youth to maintain adequate supervision and monitoring. Even with a satisfactory ratio of employees/volunteers to youth, the youth are not being monitored if all of the employees/volunteers are immersed in their own conversations in a corner of the room. # 0 # Examples of Appropriate/Inappropriate/Harmful Behavior from Youth-serving Organizations Sometimes it is unclear if a behavior is appropriate, inappropriate, or harmful. For example, intimate contact, such as kissing, may be developmentally appropriate for older youth, but may be inappropriate within the confines of the organization. It may even be harmful if the kissing is coercive. Another example involves hugging. Hugging may be appropriate and positive in some circumstances, but it can also be inappropriate if the child is not receptive, if the employee/volunteer is hugging too often or for too long, or if the contact is romanticized or sexually intimate. # Verbal communication # One-on-one interactions Some organizations have a policy to limit one-on-one interactions between youth and adults (i.e., having at least two adults present at all times with youth). The goal of such a policy is to prevent the isolation of one adult and one youth, a situation that elevates the risk for child sexual abuse. This strategy must be modified based on the mission of your organization. • Limit one-on-one interactions whenever possible by having at least two adults present at all times with youth. • Choose one of three options relating to this policy: -Make this a mandatory policy at all times. -Make this policy dependent on the risk of the activity or situation, such as overnight trips. -Maintain other safeguards such as extra supervision or contact with youth and employees/volunteers and more stringent screening if the mission of your organization requires one-on-one time between employees/ volunteers and youth (e.g., mentoring programs). # Risk of interactions between youth Your organization needs to address interactions among youth in addition to monitoring interactions between employees/volunteers and youth. Many strategies that focus on the interactions between employees/volunteers and youth can be tailored to address interactions among youth. • Address all situations where unsupervised youth can sexually or physically abuse other youth. For example, if your organization has a policy that prevents adults from being present in locker rooms because of the risk of child sexual abuse, this may result in a situation where unsupervised youth can sexually or physically abuse other youth. A potential solution is adopting a policy that requires more than one adult to be present at all times. • Develop policies to deal with bullying and sexual abuse so that positive interactions can be promoted while acknowledging that some interactions are inappropriate or harmful. # Prohibitions and restrictions on certain activities Some activities, such as hazing and secret ceremonies, overnight trips, bathing, changing, bathroom interactions, and nighttime activities, pose greater risks for child sexual abuse. Prohibiting or restricting such activities will depend largely on the context of your organization. For example, a sleep-away camp would not be able to prohibit overnight trips or bathing. # Out-of-program contact restrictions There are two types of out-of-program contact restrictions. The first type involves the contact of youth with employees/volunteers outside the context of the program. Your organization should limit contact between employees/volunteers and youth to organization-sanctioned activities and programs and/or to certain locations, such as activities within your organization's building. The second type is contact between youth and people not affiliated with your organization that occurs while youth are under the care of your organization. • Develop a system for monitoring the comings and goings of all youth and adults who enter and leave your facility. This system might include procedures for signing in and out. • Develop specific policies about interactions between youth and people not affiliated with your organization if it is located in a building that houses more than just your program or if your organization's activities take place in public areas (e.g., sports field). # Caregiver information and permission Your organization should obtain addresses and contact information for youth and caregivers (i.e., parents and guardians). This information should never be released to unauthorized individuals. Your organization also should obtain permission from caregivers for youth to participate in certain activities, such as field trips, late-night activities, and overnight trips. • Inform caregivers about what their children/ youth will be doing and where they will be going. # • Allow caregivers to have input on what activities or interactions they are comfortable with for their children. # Responsibility for youth Your organization should clarify when it is responsible for youth and when caregivers are responsible. • Develop a policy on when your organization starts and stops being responsible for youth. • Consider who is responsible for youth before and after activities officially begin. • Communicate the policy to caregivers and youth in writing. Organizations may also want caregivers to sign an acknowledgement that they have read and understand the policy. # Additional Strategies to Consider # Other ways to control interactions between individuals Identify ways to monitor interactions, such as instituting a buddy system to prevent isolation of youth with employees/volunteers. # Component 3: Monitoring Behavior # Goal To prevent, recognize, and respond to inappropriate and harmful behaviors and to reinforce appropriate behaviors. # General Principles Monitoring involves observing interactions and reacting appropriately. This includes both employee/volunteer-youth and youth-youth interactions. Youth leaders often require more supervision and monitoring because they are young, may lack judgment, and are harder to screen. Define areas for monitoring based on the organization's mission and activities. Monitor inappropriate or harmful behaviors # Monitor potential risk situations Acknowledge that some situations pose more risk for inappropriate or harmful behavior than others. For example, interactions during an overnight trip are harder to monitor than interactions in a classroom. # Monitor appropriate behaviors • Acknowledge, praise, and encourage appropriate behaviors. • Reward and reinforce positive interactions between employees/volunteers and youth. # Critical Strategies for Monitoring Behavior # Responding to what is observed Your organization must be prepared to respond to interactions among youth and between employees/volunteers and youth. • Develop a monitoring protocol so that employees/volunteers are clear about their roles and responsibilities. Employees/volunteers should be prepared to respond immediately to inappropriate or harmful behavior, potential risk situations, and potential boundary violations. # Clear reporting structure within organization Your organization should have a well-defined reporting structure so people know who to contact if they observe potentially inappropriate or harmful behavior. • Require employees/volunteers to report any behaviors and practices that may be harmful. • Establish direct-line and back-up reporting systems within your organization. The back-up option should be used if the incident involves the direct-line authority. • Create a climate that encourages people to question confusing or uncertain behaviors and practices. # Observation and contact with employees/volunteers Your organization should use multiple monitoring methods to get a clear picture of how individuals are interacting. • Use formal supervision, including regular evaluations. • Use informal supervision, including regular and random observation (e.g., roving and checking interactions throughout an activity period), and maintain frequent contact with employees/ volunteers and youth who interact off-site. # Documentation that monitoring has occurred Although it may be clear when other child sexual abuse prevention strategies, such as screening or environmental policies, have been implemented in your organization, it is harder to be sure that adequate monitoring is occurring. Documenting that monitoring has occurred emphasizes to employees/volunteers that it is an essential, nonnegotiable part of your organization's child sexual abuse prevention efforts. • Use written records. • Provide positive reinforcement when good supervision occurs. # Component 4: Ensuring Safe Environments # Goal To keep youth from situations in which they are at increased risk for sexual abuse. # General Principles Environmental strategies will vary depending on the organization. Strategies will be different for organizations with physical sites (e.g., a day care, school), organizations with multiple sites for activities (e.g., some sports and recreation organizations), and organizations with leased or undefined space (e.g., mentoring organizations). The risk of the environment should be considered regardless of an organization's physical space. If an organization does not control its own space, back-up strategies should be used to ensure youth and employees/ volunteers can be monitored. # Critical Strategies for Ensuring Safe Environments # Visibility Building or choosing spaces that are open and visible to multiple people can create an environment where individuals at risk for sexually abusive behaviors do not feel comfortable abusing. Use the following methods to increase visibility: • Landscape to ensure open visible spaces with no possible concealment. • Have clear lines of sight throughout the building. • Secure areas not used for program purposes to prevent youth from being isolated (e.g., lock closets and storerooms). • Install windows in doors. • Institute a "no closed door" policy. • Install bright lighting in all areas. # Privacy when toileting, showering, changing clothes Your organization should develop policies and procedures for reducing risk during activities such as toileting, showering, and changing clothes that consider not just the risk of employee/volunteer sexual abuse, but also the risk of inappropriate or harmful contact among youth. # Access control Your organization should monitor who is present at all times. • Develop policies and procedures for admitting and releasing youth so their whereabouts are always known. • Have policies and procedures for monitoring which people outside of your organization are allowed in and under what circumstances. # Off-site activity guidelines Your organization should define and communicate its on-site and off-site physical boundaries. • Decide and communicate when and where your organization is responsible for the youth it serves. This is particularly important in a multi-organization facility and on field trips. • Develop environmental policies for field trips and other off-site activities, such as how to handle off-site bathroom breaks and use of public transportation. # Transportation policies Your organization should define who is responsible for transporting youth to and from regular activities and special events (e.g., field trips, overnight trips). Decide how to answer the following questions: • When is your organization responsible for transportation? • When are caregivers responsible? • Can a youth ride in a car with an employee/volunteer? If yes, under what circumstances? For example, can a youth be alone with an employee/volunteer in a car? • What are pick-up procedures at the end of the day or the event? # Additional Strategies to Consider # Territoriality The goal of this strategy is to visually send a message that the program is unified, cohesive, and not permeable to threats. Some examples of this strategy include making navigation easy with signage and overstating the appearance of staff with uniforms or similar clothing. # Monitoring devices (e.g., video cameras) This strategy implies that there is an infrastructure or staff behind the monitoring devices. If you install these devices, be sure to provide the infrastructure to uphold that implicit promise. # Component 5: # Responding to Inappropriate Behavior, Breaches in Policy, and Allegations and Suspicions of Child Sexual Abuse # Goal To respond quickly and appropriately to (1) inappropriate or harmful behavior, (2) infractions of child sexual abuse prevention policies, and (3) evidence or allegations of child sexual abuse. # General Principles The ultimate aim of child sexual abuse prevention efforts within youth-serving organizations is to prevent child sexual abuse from ever occurring; however, an organization needs to have communicated clearly what it and its employees/volunteers should do if policies are violated or if child sexual abuse occurs. # Define inappropriate and appropriate strategies • Clarify that it is not the role of an employee/ volunteer or your organization to evaluate or investigate an allegation or suspicion. • Let child protective services, law enforcement, and child advocacy centers investigate allegations or suspicions. • Know that an organization's investigation can harm the youth or the legal investigative process. # Partnering with others • Work with a lawyer to develop a reporting policy to ensure that it is appropriate and legal. • Partner with child protective services, law enforcement, and child advocacy centers (www.nca-online.org) before any allegations arise to form relationships and ensure that policies are in line with the law. # Critical Strategies for Responding to Inappropriate Behavior, Breaches in Policy, and Allegations and Suspicions of Child Sexual Abuse # What to respond to within the organization and what to report to the authorities As discussed previously, it is often difficult to find the balance between being vigilant and protective of youth and being so hyper-vigilant that the positive parts of programs (e.g., relationships between adults and youth) are lost. In responding, the need for this balance involves recognizing the tension between over-reacting and under-reacting. By developing policies before any inappropriate behavior occurs, your organization can set reasonable expectations for responding. • Define the continuum of appropriate, inappropriate, and harmful behavior. • Delineate what behaviors your organization will respond to internally and what behaviors will require reporting to the authorities. For example, if a youth tells a sexually risqué joke, your organization may inform a direct-line supervisor and/or the youth's caregiver; provide the youth with guidance, redirection, and instruction; and/or file an incident report. However, if a youth or employee/volunteer forces sexual contact with a youth, this violation should always be reported to the appropriate authorities in accord with the procedures outlined in your policy. • Act on infractions of your organization's child sexual abuse prevention policy. If an employee/ volunteer has breached a policy, such as having contact with youth outside of your organization, your organization must take action, even when child sexual abuse is not suspected. The consequences of violating policies should be explicit and violations should be addressed immediately. However, if abuse is suspected, it should be reported to authorities immediately. • Report when an employee/volunteer witnesses or learns about sexual abuse of youth by any of the following individuals: -Volunteer/employee. -Another youth within the organization. -Someone outside of the organization (e.g., caregiver). • Tailor strategies and policies to each type of child sexual abuse. For example, identify to whom reports are made. In most states, child protective services is responsible for caretaker abuse, and law enforcement is responsible for abuse by all other individuals. Responsibility can vary by state, so consult experts such as those in your nearest child advocacy center, your state sexual violence coalition, or your local rape crisis center in order to incorporate state guidelines into your policies. # Reporting process If evidence of child sexual abuse has surfaced or an allegation has been made, a formal report needs to be made to an outside agency. Ensure that your organization's reporting policies are consistent with current state law. The following strategies address policies related to reporting evidence or allegations of child sexual abuse to outside agencies. • Who must report -Mandatory reporters (i.e., those individuals required by the state to report suspicions of child abuse and neglect to the authorities). To research laws about mandatory reporters in your state, go to www.childwelfare.gov/systemwide/laws_policies/search/ index.cfm. -Employees/volunteers if they are state-designated mandatory reporters or if your organization requires that they report suspicions of child abuse and neglect. • To whom to report -Have clear guidelines about how and when to report allegations and suspicions to authorities. Allegations and suspicions should be reported to very few people inside the organization before authorities are contacted to expedite the process and minimize the number of times a youth has to repeat allegations. -Be explicit that the head of your organization is professionally and legally accountable for ensuring that all cases of abuse are reported to the proper authorities. -Delineate which external authorities (i.e., child protective services or law enforcement) should be contacted in different types of abuse cases. Consult state guidelines to ensure your policies are consistent with them. • When to report -Report to the authorities any time there is a reasonable suspicion of child abuse or neglect. • Consult child protective services, law enforcement, or a child advocacy center to ensure your organization is defining reasonable suspicion appropriately according to your state guidelines. • Obtain the help of a child advocacy center in deciding if reporting an allegation is appropriate because these centers work with law enforcement, social workers, lawyers, and mental health professionals. More information on these organizations is available in the "Resource List and Sample Policies" section. (See Appendix B.) • Do not conduct your own investigation, but depending on the circumstances, it may be appropriate to ask a few clarifying questions of the youth or the person making the allegation to adequately report the suspicion or allegation to the authorities. For example, in one case, a young girl said, "My daddy put his thing in my mouth and it hurt." When asked what she meant, the youth replied that her father had stuck his fingers too far into her mouth when attempting to get out a loose tooth. The person who was speaking with the girl at first thought that a report needed to be made, but then slowed down to clarify what had occurred. After doing so, it was clear no report was needed. # Internal records Although your organization should not investigate allegations or suspicions of child sexual abuse in lieu of reporting them to the authorities, it should develop a system to track allegations and suspicions of child sexual abuse cases. • Include child sexual abuse as a category on general incident reporting forms for significant physical injuries. These forms should be completed by employees/volunteers who first learn of the abuse through hearing an allegation or making an observation. • Review the general incident reporting forms. This step should be carried out by the supervisor of the employee/ volunteer. • Refer child sexual abuse reports to a higher-level individual, preferably a trained internal or hired investigator, for the purpose of reviewing your organization's procedures. This individual should do an incident review after each allegation to determine what went wrong and how a similar scenario can be prevented in the future. For example, was a policy or a step in a policy not followed? How can policies be modified to prevent another occurrence? • Record the resolutions of child sexual abuse cases. # 0 # Confidentiality policy Because of the sensitive nature of child sexual abuse cases, your organization should decide in advance what information should remain private and what information can be made public. • Withhold the names of potential victims, the accused perpetrator, and the people who made the report to the authorities. • Decide whether to inform the community that an allegation has been made. • Ensure that your organization's confidentiality policy is consistent with state legal requirements. # Response to the press and the community Your organization should decide on a strategy for responding to the press and the community before an allegation has been made. • Designate a spokesperson for questions and inquiries. • Have employees/volunteers go through training on how to deal with the press and the community, if appropriate. # Membership/employment of alleged offenders Remember that an allegation of child sexual abuse does not equate to guilt. The person alleged to have engaged in sexually abusive behavior should not be labeled as an offender or sexual abuser. However, once a suspicion or allegation has been communicated, it needs to be reported to the authorities, and your organization must take certain steps to protect the youth under its care. A decision must be made whether to suspend membership or employment. • Suspend membership or employment immediately after reporting the child sexual abuse or put the alleged offender on probation until the case is resolved legally. Have an appeal process in which people found not guilty of perpetration in court may apply to return to their former positions in the organization. • Develop policies on how to deal appropriately and responsibly with alleged or convicted offenders if your organization decides that it may not be appropriate to revoke membership or employment. Some organizations, particularly faith-based ones or those dealing with youth-on-youth sexual abuse, may decide that revoking membership sends the wrong message. Because these organizations need to manage circumstances in which alleged victims and offenders may be together, a well-constructed policy can help deal with this difficult situation. -Require limited access agreements in which alleged or convicted offenders can attend a worship service or activity that does not involve youth but may not be involved in any activities specific to youth. These individuals may also be required to attend permitted services and activities with a "buddy" or another adult who has agreed to stay with them at all times. -Require informed supervision. Make sure at least one staff member is informed of the sexual abuse and is instructed to supervise vigilantly the accused adult or youth in his or her interaction with the program and/or organization. -Employ restorative practices. (See "Additional Strategies to Consider" below.) # Additional Strategies to Consider # Support for victims and families Organizations may want to provide support for victims and their families to help them cope with the sexual abuse. • Provide referrals for victims and their families to child sexual abuse organizations and counselors or therapists. • Reimburse victims and families for counseling. • Offer restorative justice approaches. Restorative practices are a way to have a respectful and safe dialogue when a misunderstanding or a harm has occurred. If your organization is interested in using restorative justice, seek assistance from organizations with expertise in these techniques and refer to the "Resource List and Sample Policies" section. (See Appendix B.) # Coping process for the organization and community The organization and community as a whole may need help getting past the child sexual abuse that has occurred. • Adopt strategies such as showing that steps are being taken to deal appropriately with the situation, providing support groups, and having forums to discuss the topic and answer questions. • Adopt a policy for notifying the wider organization and caregivers that child sexual abuse has happened. But before doing so, determine what information is appropriate to share. (See "Confidentiality Policy" on page 20.) • Train caregivers on how to talk to youth about child sexual abuse. • Debrief or offer support and counseling for reporters and bystanders. • Seek assistance in using restorative justice approaches to help the community heal. # Component 6: Training about Child Sexual Abuse Prevention # Goal To give people information and skills to help them prevent and respond to child sexual abuse. This section will first present general training guidelines and will then cover specific information on education and training for three types of people related to organizations: employees/volunteers, caregivers, and youth. # General Principles To ensure that child sexual abuse training is effective and fits with other strategies, organizations should follow several guidelines. # Goals in training • Set measurable goals. What are the desired behaviors or performance changes in trainees? What is essential that people gain from the training? • Plan the training to meet goals. • Evaluate the training periodically to ensure that it meets goals. • Decide if your organization wants to use an overarching frame. Two that have been used in other organizations are (1) healthy sexuality and (2) rights and responsibilities. The healthy sexuality frame for child sexual abuse education helps individuals distinguish child sexual abuse from something that is healthy and normal. The rights and responsibilities frame involves teaching individuals that they have the right to be treated appropriately and the responsibility to treat others appropriately. # Integration of content into the entire organization # Training Techniques There are many ways to provide information and teach skills to individuals. Delivery mechanisms, level of interactivity, frequency, and training methods all need to be considered when designing a training or education program. # Delivery mechanisms Delivery mechanisms can use a great deal of technology or none at all. Training messages, numbers of trainees, resources, flexibility, and integration with other training within the organization should be considered when choosing a delivery mechanism. Be sensitive to dealing with the emotional topic of child sexual abuse in impersonal formats (e.g., online, videos, CDs). • Online. Interaction is key to making sure that people learn the material, so using interactive online techniques may work better than passive ones. • Videos/CDs. • In person. • Written. • Combinations of delivery mechanisms (e.g., some online, some in person). # Interactivity Training can be passive, interactive, or somewhere in between. • Use passive training, in which trainees do not interact with anyone else (e.g., video), for raising awareness. • Use interactive training, in which trainees interact with the trainer and/or other trainees, for skills building. # Frequency Your organization needs to reinforce the content of child sexual abuse training. • Ensure that training is ongoing and not just a one-time event. • Educate in both formal training sessions and in informal settings, such as conversations. # Methods Using several methods to train individuals on child sexual abuse reinforces messages and allows individuals with different learning styles to absorb information and skills. • Present case studies to elicit discussion and suggestions for handling situations and walking through problem-solving. • Ask people to role play situations. • Use journaling. • Have outside professionals conduct training; this may emphasize the importance of the topic. # Mechanisms to ensure that training happens Because training can be expensive and time-consuming, mechanisms must be in place to ensure that training is conducted. • For organizations: develop a regular training schedule or repeat trainings when a specified number of new employees/volunteers have been hired. In addition, integrate training into the overall child sexual abuse prevention policy and into some staff member's work plans. • For individuals: require periodic certification based on training completion. • To save time, money, and resources, your organization can do the following: --Ask for help from groups who have already done this type of training. --Work together with a group of similar organizations to develop and implement training. --Partner with other organizations, including child advocacy centers, sexual violence coalitions, and universities. # Creation of a safe space Create an environment in which trainees feel comfortable raising questions and concerns. Being receptive to questions reduces barriers to coming forward, reporting, and being proactive about preventing and responding to child sexual abuse. # Point of contact for child sexual abuse • Designate one point of contact for questions and concerns to ensure messages about child sexual abuse are communicated consistently. This point of contact can be one individual or a group within a division of your organization. • State explicitly that every employee/volunteer is still responsible for preventing and responding to child sexual abuse. # Training Employees/Volunteers # Who needs training? The following employees/volunteers should be trained in child sexual abuse prevention: • People with access to or supervision over youth, including adults and youth in leadership positions. • People responsible for enforcing child sexual abuse policies or overseeing people in the chain of command (e.g., supervisors of employees/volunteers with access to or control over youth). • Management and leaders in your organization, even those without contact with youth, so concepts can be reinforced throughout the culture of your organization. • New and current employees/volunteers. # Differences between employees and volunteers Depending on the organization, education/training for employees and volunteers may differ. For example, employees and volunteers may need varied curricula in a mentoring organization, whereas an after-school program may choose to educate employees and volunteers together. # Critical Content for Training Employees/Volunteers # All policies and procedures organization chooses Employees/volunteers should be trained on all of the policies and procedures discussed in this document that your organization chooses to adopt. # Child sexual abuse information To prevent child sexual abuse, employees/volunteers need to understand general information about child sexual abuse (e.g., what child sexual abuse is, how often it occurs). • Provide a definition of child sexual abuse. • Define the continuum of appropriate, inappropriate, and harmful behavior from your organization's perspective. • Provide information about the prevalence of child sexual abuse. • Describe risk and protective factors for victimization and perpetration. • Address common myths about offenders, such as the myth that most people who sexually abuse are strangers to the youth. # Importance of preventing child sexual abuse Employees/volunteers need to understand why they should be concerned with preventing child sexual abuse. • Emphasize that employees/volunteers are an integral part of your organization's efforts to create a safe, healthy, and respectful environment. • Explain that child sexual abuse policies protect youth from sexual abuse, adults and youth from allegations of sexual abuse, and organizations from being accused of not doing enough to prevent child sexual abuse. • Help employees/volunteers feel comfortable and motivated to prevent child sexual abuse. For example, provide employees/volunteers with information about preventing child sexual abuse and opportunities to practice how to handle situations (e.g., monitoring interactions). • Give employees/volunteers opportunities to ask questions and express concerns about child sexual abuse prevention. # Personal conduct In addition to training on the elements of child sexual abuse prevention related to interactions between individuals, your organization may want to train employees/volunteers on how to conduct themselves with youth and with other employees/volunteers. • Define appropriate conduct. • Describe how to deal appropriately with risky or compromising situations, such as romantic crushes of youth on employees/volunteers or of employees/volunteers on youth. • Acknowledge the power differential between adults and youth and between youth leaders and youth. • Inform employees/volunteers of their responsibility to act when they see or hear about inappropriate or harmful behavior. # Healthy development of youth Employees/volunteers should learn about healthy youth development so they can (1) promote positive development in the areas of self-confidence, independence, and social interactivity and (2) understand and be aware of risk behaviors in which youth may engage. • Teach employees/volunteers about healthy youth development and when certain behaviors are appropriate. • Educate employees/volunteers about sexual development and how to distinguish between healthy and inappropriate or harmful behaviors when monitoring interactions. • Keep in mind that some behavior that is considered developmentally appropriate may create problems for organizations when it is done at inappropriate times. # Protective factors Employees/volunteers should know that youthserving organizations exist in order to provide a healthy and safe environment where youth can thrive. The very things that youth-serving organizations do may be protective against child sexual abuse. For example, close, caring, and connected relationships between youth and employees/ volunteers can be extremely beneficial for youth development and can help youth feel supported and loved. This may protect youth from child sexual abuse. Because of the nature of the interactions in these relationships, however, they can also put youth at risk of being sexually abused by employees/volunteers. • Help employees/volunteers learn to maintain a balance between providing a nurturing environment and working to prevent child sexual abuse. • Assist employees/volunteers in learning to interact with youth with care and concern in order to foster youth development. # Handling disclosures Employees/volunteers need to be able to respond appropriately to the person making the disclosure. • Teach employees/volunteers what they should and should not say to a victim who is disclosing child sexual abuse. • Instruct employees/volunteers to report sexual abuse allegations, suspicious, and disclosures to the authorities according to your organization's policies. (See "Reporting Process" on page 18.) • Seek the counsel of the nearest child advocacy center for advice on training about these matters. # Immunity and support for reporters Employees/volunteers need to know whether they are immune from civil or criminal liability when making a required or authorized report of known or suspected child sexual abuse. • Check with state laws on whether employees/volunteers are immune from civil or criminal liability when making a report. • Share immunity information with employees/volunteers. • Reassure employees/volunteers that they will be supported by your organization and its management in their efforts to protect youth and that debriefing and/or counseling will be available to reporters and bystanders should abuse occur. # Training Caregivers Two main areas of education should be emphasized with caregivers (i.e., parents and guardians) of youth in youth-serving organizations: (1) education specific to child sexual abuse and (2) education about the organization's child sexual abuse prevention policies and procedures. # Critical Content for Training Caregivers Child sexual abuse information # Training Youth Child sexual abuse education and training for youth should be both developmentally appropriate and at the proper skill level. For example, different skills and knowledge may be provided to adolescents and younger children. # Critical Content for Training Youth # Child sexual abuse information Your organization needs to provide youth with some basic child sexual abuse information. • Provide general information about child sexual abuse, including what constitutes appropriate, inappropriate, and harmful behavior from adults and other youth. For example, youth need to know that no one has the right to force, trick, or coerce them into sexual situations and that sexual offenders, not their victims, are responsible for their behavior. • Teach youth how to interact appropriately with each other. • Discuss the importance of reporting sexual abuse. • Tell youth to whom they should report what they believe is inappropriate or harmful behavior. • Seek assistance from other organizations that have created personal safety programs if your organization is interested in implementing one. # Protective factors There are factors that can help prevent youth from getting sexually abused or abusing. Youth should be educated about how they can make themselves and others safer. • Educate youth about the bystander approach. Empower youth to intervene or tell someone when they see inappropriate or harmful interactions between adults and youth or between youth. Encourage youth to tell a trusted adult about inappropriate or harmful things that have happened to themselves or their friends. • Empower youth as partners in the prevention process. Encourage them to adopt healthy strategies to protect themselves, such as checking with a caregiver/adult before doing activities, going places with friends instead of alone, and identifying trusted adults. • Educate youth about healthy sexuality. Teach youth to recognize appropriate behavior and to avoid exploitive or inappropriate behavior toward others. # Overcoming Challenges to Child Sexual Abuse Prevention in Youth-serving Organizations O rganizations that are committed to preventing child sexual abuse will likely face challenges in implementing prevention policies and strategies. Which challenges an organization faces will depend largely on its type, size, and level of commitment to child sexual abuse prevention. Not all challenges described in this document will apply to your organization. Awareness of potential challenges, however, will better prepare you for such encounters. Most challenges that organizations face in child sexual abuse prevention fall into two broad categories: beliefs and structural issues. The following tables present some of the challenges within these categories and suggest some of the strategies that organizations have used to overcome them. # Denial related to child sexual abuse • Belief that child sexual abuse never happens in "my organization." • Belief that offenders can be identified by a stereotype (e.g., offenders are "monsters" and not the nice employees/volunteers that you know in your organization). • Use statistics to justify your organization's efforts. • Use current events to highlight the need for child sexual abuse prevention within your organization. • Present actual cases (i.e., personal stories) to make people aware of the need for child sexual abuse prevention and to show that offenders are not easily identified by stereotypes. # 0 Fear that people will think something is wrong within your organization because it is focusing on the issue of child sexual abuse. Be persistent in addressing myths, denial, and fear related to child sexual abuse prevention. Continue to train all levels of employees/volunteers about the importance of this issue. Fear of uncovering child sexual abuse cases when adopting child sexual abuse prevention strategies. When your organization adopts child sexual abuse prevention strategies and policies, you may initially encounter an increase in the number of disclosures of child sexual abuse. This is because the strategies are uncovering cases that have been hidden. The hope is that once these cases have been uncovered and prevention strategies are consistently implemented, the number of reported cases will decrease. Poor employee/volunteer retention can make it very difficult to implement child sexual abuse policies because your organization needs to constantly screen, train, and orient new employees/volunteers. These difficulties may be caused by the seasonality of employees/volunteers (e.g., at camps) or simply by a high turnover of employees/volunteers. Other retention issues that may inhibit your organization from adopting child sexual abuse prevention strategies include the fear that much-needed volunteers will not want to go through the screening process and the nature of compassion fatigue (i.e., people just want to be employees/volunteers and do not want to deal with child sexual abuse and/or other difficult topics). To overcome this challenge, the importance of ongoing and frequent training cannot be overemphasized. Regularly scheduled training sessions should be complemented by the incorporation of training and supervision into everyday work. In addition, to combat some fears that you may have about employee/volunteer reluctance to engage in child sexual abuse prevention, explain to all applicants and employees/volunteers the reasoning behind the screening process and child sexual abuse prevention policies-they are a piece of your organization's mission to make youth safer. Understanding the motivation behind your efforts may make individuals more willing to participate. Tendency to rely on one strategy (e.g., criminal background checks) as the sole effort in child sexual abuse prevention. The first step to combating this tendency is to read this document. Then, have conversations with other organizations, which will enable you to see that child sexual abuse prevention, like other safety promotion strategies, requires many efforts at multiple levels to make up a comprehensive prevention approach. There is no single, simple way to prevent child sexual abuse. Policies" section for more information (Appendix B). # Conclusion: Moving Forward # I mplementing a child sexual abuse prevention policy and making the changes necessary to protect youth from child sexual abuse in organizations are not easy tasks. Although organizations should take on as many individual strategies to prevent child sexual abuse as they are able, organizations must have a strong infrastructure in place to serve as a foundation for efforts to prevent child sexual abuse. In addition, because the number of recommended child sexual abuse prevention strategies can be overwhelming, organizations should use the planning tool provided at the end of this section to help prioritize their efforts. If your organization is committed to preventing child sexual abuse and takes this charge on thoughtfully and with careful planning, it can and will succeed in creating a safer place for the youth under its care. # Organizational Processes for Developing and Implementing Child Sexual Abuse Prevention Policies Organizations should take several steps to effectively implement child sexual abuse prevention strategies. # Create a safe space To ensure the effectiveness of child sexual abuse prevention, your organization needs to create an open environment in which employees/volunteers feel comfortable discussing child sexual abuse. # Have clear goals When deciding what child sexual abuse prevention policies and practices to implement in your organization, always identify clear goals. • Know why a certain strategy, policy, or practice is being considered and/or adopted to ensure that the most effective means are used to obtain goals. # Create a process for developing child sexual abuse prevention policies and practices This involves obtaining buy-in from all levels of your organization so that policies and practices are accepted and owned by everyone. All processes can be specific to child sexual abuse planning or may be integrated into a current risk management planning process. • Develop the policy. For example, gather a group of stakeholders, such as caregivers, employees/volunteers, and attorneys, to do the work. • Approve the policy, which includes making sure it complies with organizational policies, state and national laws, and child protective services and law enforcement. • Adopt the policy. • Develop a system to track allegations of child sexual abuse and outcomes of cases. (See "Internal records" on page 19.) • Inform your organization about the policy. • Implement the policy. • Evaluate the policy to continuously measure whether goals are being met. For example, the goal of setting criteria for screening and selection of employees/volunteers may be to make sure that employees/volunteers are appropriate for working with the youth within your organization. Once that goal is agreed upon and the screening and selection policies are adopted, your organization needs to reassess on a regular basis if that goal is being met. If it is not, what needs to be changed to meet the goal? If it is, consider more efficient ways to meet the goal. # Include appropriate child sexual abuse polices and practices in the prevention plan In choosing child sexual abuse prevention policies and practices to adopt, your organization should gather information from several sources. • Consider the strategies raised in this document. • Use other organizations' experiences in this area. For example, look at the resources and sample policies included in the "Resource List and Sample Policies" section. (See Appendix B.) You may also consider discussing prevention policies with other organizations. # Acknowledgements The authors would like to acknowledge the individuals and organizations that participated in the meeting of experts sponsored by CDC in August 2004. The authors would also like to thank Kristin Leydig Bryant for facilitating the meeting and Deborah A. Ausburn, Attorney at Law, for reviewing the document. # Child Sexual Abuse Prevention Planning Tool for Organizations This checklist can help your organization plan child sexual abuse prevention efforts in the next year and beyond. It summarizes the critical strategies discussed in this document. Because so many of the additional strategies to consider were specific to certain types of organizations, these are not included in the matrix. Space has been left at the bottom of the tool to add additional strategies.	None	None
7347ea72db4b1f8b8845c3dc1f4cce33f9ef9c13	cdc	None	and Prevention cognitive impairment, and those with cancer and at the end of life, can be at risk for inadequate pain treatment (4). Patients can experience persistent pain that is not well controlled. There are clinical, psychological, and social consequences associated with chronic pain including limitations in complex activities, lost work productivity, reduced quality of life, and stigma, emphasizing the importance of appropriate and compassionate patient care (4). Patients should receive appropriate pain treatment based on a careful consideration of the benefits and risks of treatment options. Chronic pain has been variably defined but is defined within this guideline as pain that typically lasts >3 months or past the time of normal tissue healing (5). Chronic pain can be the result of an underlying medical disease or condition, injury, medical treatment, inflammation, or an unknown cause (4). Estimates of the prevalence of chronic pain vary, but it is clear that the number of persons experiencing chronic pain in the United States is substantial. The 1999-2002 National Health and Nutrition Examination Survey estimated that 14.6% of adults have current widespread or localized pain lasting at least 3 months (6). Based on a survey conducted during 2001-2003 (7), the overall prevalence of common, predominantly musculoskeletal pain conditions (e.g., arthritis, rheumatism, chronic back or neck problems, and frequent severe headaches) was estimated at 43% among adults in the# position paper on prescription drug abuse. CDC provided 100% of the funding for the supplemental evidence review tasks and meeting support. No foundation or industry support was accepted. The Opioid Guideline Workgroup (OGW) members disclose that they have no financial conflicts of interest. Experts disclose the following activities related to the content of this guideline: Anne Burns discloses that she participated in a congressional briefing sponsored by Reps. Carter and DeSaulnier on the pharmacist's role of furnishing Naloxone and that she participates on the National Advisory Board for the Prescription Drug Abuse and Heroin Summit. Chinazo Cunningham discloses that her husband is employed by Quest Diagnostics and Dr. Cunningham was recused from any discussion related to urine drug testing. Traci Green discloses that she was previously employed by Inflexxion, a small business that conducts Small Business Innovation Research on behavioral interventions for behavioral health and chronic pain and created several psychometric tools for conducting risk assessment for prescription opioid abuse potential. Dr. Green also discloses that while at the hospital where she is employed, she provided consultation to Purdue Pharma Ltd to design overdose prevention brochures for persons who use diverted prescription opioids non-medically with an emphasis on persons who inject prescription drugs, and not for patients using opioid therapy for pain. Dr. Green was recused from any discussion related to risk assessment tools and patient education materials. Erin Krebs discloses that she served on the CDC Opioid Prescribing Guideline CEG. Christina Porucznik discloses that she served on the CDC Opioid Prescribing Guideline CEG. Greg Terman discloses that he serves as the President of the American Pain Society. Mark Wallace discloses that he served on a Kempharma advisory panel for an abuse-deterrent hydrocodone formulation to treat acute postoperative pain and Dr. Wallace was recused form any discussion related to abuse-deterrent drugs. The NCIPC Board of Scientific Counselors (BSC) members disclose that they have no financial conflicts of interest. Two BSC members, Traci Green and Christina Porucznik, served on the Opioid Guideline Workgroup. Traci Green discloses that she was previously employed by Inflexxion, a small business that conducts Small Business Innovation Research on behavioral interventions for behavioral health and chronic pain and created several psychometric tools for conducting risk assessment for prescription opioid abuse potential. Dr. Green also discloses that while at the hospital where she is employed, she provided consultation to Purdue Pharma Ltd to design overdose prevention brochures for persons who use diverted prescription opioids non-medically with an emphasis on persons who inject prescription drugs, and not for patients using opioid therapy for pain. Dr. Green was recused from any discussion related to risk assessment tools and patient education materials. Christina Porucznik discloses that she served on the CDC Opioid Prescribing Guideline CEG. # Introduction Background Opioids are commonly prescribed for pain. An estimated 20% of patients presenting to physician offices with noncancer pain symptoms or pain-related diagnoses (including acute and chronic pain) receive an opioid prescription (1). In 2012, health care providers wrote 259 million prescriptions for opioid pain medication, enough for every adult in the United States to have a bottle of pills (2). Opioid prescriptions per capita increased 7.3% from 2007 to 2012, with opioid prescribing rates increasing more for family practice, general practice, and internal medicine compared with other specialties (3). Rates of opioid prescribing vary greatly across states in ways that cannot be explained by the underlying health status of the population, highlighting the lack of consensus among clinicians on how to use opioid pain medication (2). Prevention, assessment, and treatment of chronic pain are challenges for health providers and systems. Pain might go unrecognized, and patients, particularly members of racial and ethnic minority groups, women, the elderly, persons with United States, although minimum duration of symptoms was not specified. Most recently, analysis of data from the 2012 National Health Interview Study showed that 11.2% of adults report having daily pain (8). Clinicians should consider the full range of therapeutic options for the treatment of chronic pain. However, it is hard to estimate the number of persons who could potentially benefit from opioid pain medication long term. Evidence supports short-term efficacy of opioids for reducing pain and improving function in noncancer nociceptive and neuropathic pain in randomized clinical trials lasting primarily ≤12 weeks (9,10), and patients receiving opioid therapy for chronic pain report some pain relief when surveyed (11)(12)(13). However, few studies have been conducted to rigorously assess the long-term benefits of opioids for chronic pain (pain lasting >3 months) with outcomes examined at least 1 year later (14). On the basis of data available from health systems, researchers estimate that 9.6-11.5 million adults, or approximately 3%-4% of the adult U.S. population, were prescribed long-term opioid therapy in 2005 (15). Opioid pain medication use presents serious risks, including overdose and opioid use disorder. From 1999 to 2014, more than 165,000 persons died from overdose related to opioid pain medication in the United States (16). In the past decade, while the death rates for the top leading causes of death such as heart disease and cancer have decreased substantially, the death rate associated with opioid pain medication has increased markedly (17). Sales of opioid pain medication have increased in parallel with opioid-related overdose deaths (18). The Drug Abuse Warning Network estimated that >420,000 emergency department visits were related to the misuse or abuse of narcotic pain relievers in 2011, the most recent year for which data are available (19). Although clinical criteria have varied over time, opioid use disorder is a problematic pattern of opioid use leading to clinically significant impairment or distress. This disorder is manifested by specific criteria such as unsuccessful efforts to cut down or control use and use resulting in social problems and a failure to fulfill major role obligations at work, school, or home (20). This diagnosis has also been referred to as "abuse or dependence" and "addiction" in the literature, and is different from tolerance (diminished response to a drug with repeated use) and physical dependence (adaptation to a drug that produces symptoms of withdrawal when the drug is stopped), both of which can exist without a diagnosed disorder. In 2013, on the basis of DSM-IV diagnosis criteria, an estimated 1.9 million persons abused or were dependent on prescription opioid pain medication (21). Having a history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder (22)(23)(24), highlighting the value of guidance on safer prescribing practices for clinicians. For example, a recent study of patients aged 15-64 years receiving opioids for chronic noncancer pain and followed for up to 13 years revealed that one in 550 patients died from opioid-related overdose at a median of 2.6 years from their first opioid prescription, and one in 32 patients who escalated to opioid dosages >200 morphine milligram equivalents (MME) died from opioid-related overdose (25). This guideline provides recommendations for the prescribing of opioid pain medication by primary care clinicians for chronic pain (i.e., pain conditions that typically last >3 months or past the time of normal tissue healing) in outpatient settings outside of active cancer treatment, palliative care, and endof-life care. Although the guideline does not focus broadly on pain management, appropriate use of long-term opioid therapy must be considered within the context of all pain management strategies (including nonopioid pain medications and nonpharmacologic treatments). CDC's recommendations are made on the basis of a systematic review of the best available evidence, along with input from experts, and further review and deliberation by a federally chartered advisory committee. The guideline is intended to ensure that clinicians and patients consider safer and more effective treatment, improve patient outcomes such as reduced pain and improved function, and reduce the number of persons who develop opioid use disorder, overdose, or experience other adverse events related to these drugs. Clinical decision making should be based on a relationship between the clinician and patient, and an understanding of the patient's clinical situation, functioning, and life context. The recommendations in the guideline are voluntary, rather than prescriptive standards. They are based on emerging evidence, including observational studies or randomized clinical trials with notable limitations. Clinicians should consider the circumstances and unique needs of each patient when providing care. # Rationale Primary care clinicians report having concerns about opioid pain medication misuse, find managing patients with chronic pain stressful, express concern about patient addiction, and report insufficient training in prescribing opioids (26). Across specialties, physicians believe that opioid pain medication can be effective in controlling pain, that addiction is a common consequence of prolonged use, and that long-term opioid therapy often is overprescribed for patients with chronic noncancer pain (27). These attitudes and beliefs, combined with increasing trends in opioid-related overdose, underscore the need for better clinician guidance on opioid prescribing. Clinical practice guidelines focused on prescribing can improve clinician knowledge, change prescribing practices (28), and ultimately benefit patient health. # Scope and Audience This guideline is intended for primary care clinicians (e.g., family physicians and internists) who are treating patients with chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing) in outpatient settings. Prescriptions by primary care clinicians account for nearly half of all dispensed opioid prescriptions, and the growth in prescribing rates among these clinicians has been above average (3). Primary care clinicians include physicians as well as nurse practitioners and physician assistants. Although the focus is on primary care clinicians, because clinicians work within team-based care, the recommendations refer to and promote integrated pain management and collaborative working relationships with other providers (e.g., behavioral health providers, pharmacists, and pain management specialists). Although the transition from use of opioid therapy for acute pain to use for chronic pain is hard to predict and identify, the guideline is intended to inform clinicians who are considering prescribing opioid pain medication for painful conditions that can or have become chronic. This guideline is intended to apply to patients aged ≥18 years with chronic pain outside of palliative and end-of-life care. For this guideline, palliative care is defined in a manner consistent with that of the Institute of Medicine as care that provides relief from pain and other symptoms, supports quality of life, and is focused on patients with serious advanced illness. Palliative care can begin early in the course of treatment for any serious illness that requires excellent management of pain or other distressing symptoms (35). End-of-life care is defined as care for persons with a terminal illness or at high risk for dying in the near future in hospice care, hospitals, long-term care settings, or at home. Patients within the scope of this guideline include cancer survivors with chronic pain who have completed cancer treatment, are in clinical remission, and are under cancer surveillance only. The guideline is not intended for patients undergoing active cancer treatment, palliative care, or endof-life care because of the unique therapeutic goals, ethical considerations, opportunities for medical supervision, and balance of risks and benefits with opioid therapy in such care. The recommendations address the use of opioid pain medication in certain special populations (e.g., older adults and pregnant women) and in populations with conditions posing special risks (e.g., a history of substance use disorder). The recommendations do not address the use of opioid pain medication in children or adolescents aged <18 years. The available evidence concerning the benefits and harms of long-term opioid therapy in children and adolescents is limited, and few opioid medications provide information on the label regarding safety and effectiveness in pediatric patients. However, observational research shows significant increases in opioid prescriptions for pediatric populations from 2001 to 2010 (36), and a large proportion of adolescents are commonly prescribed opioid pain medications for conditions such as headache and sports injuries (e.g., in one study, 50% of adolescents presenting with headache received a prescription for an opioid pain medication ). Adolescents who misuse opioid pain medication often misuse medications from their own previous prescriptions (39), with an estimated 20% of adolescents with currently prescribed opioid medications reporting using them intentionally to get high or increase the effects of alcohol or other drugs (40). Use of prescribed opioid pain medication before high school graduation is associated with a 33% increase in the risk of later opioid misuse (41). Misuse of opioid pain medications in adolescence strongly predicts later onset of heroin use (42). Thus, risk of opioid medication use in pediatric populations is of great concern. Additional clinical trial and observational research is needed, and encouraged, to inform development of future guidelines for this critical population. The recommendations are not intended to provide guidance on use of opioids as part of medication-assisted treatment for opioid use disorder. Some of the recommendations might be relevant for acute care settings or other specialists, such as emergency physicians or dentists, but use in these settings or by other specialists is not the focus of this guideline. Readers are referred to other sources for prescribing recommendations within acute care settings and in dental practice, such as the American College of Emergency Physicians' guideline for prescribing of opioids in the emergency department (43); the American Society of Anesthesiologists' guideline for acute pain management in the perioperative setting (44); the Washington Agency Medical Directors' Group Interagency Guideline on Prescribing Opioids for Pain, Part II: Prescribing Opioids in the Acute and Subacute Phase (30); and the Pennsylvania Guidelines on the Use of Opioids in Dental Practice (45). In addition, given the challenges of managing the painful complications of sickle cell disease, readers are referred to the NIH National Heart, Lung, and Blood Institute's Evidence Based Management of Sickle Cell Disease Expert Panel Report for management of sickle cell disease (46). # Guideline Development Methods # Guideline Development Using the Grading of Recommendations Assessment, Development, and Evaluation Method CDC developed this guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method (). This method specifies the systematic review of scientific evidence and offers a transparent approach to grading quality of evidence and strength of recommendations. The method has been adapted by the CDC Advisory Committee on Immunization Practices (ACIP) (47). CDC has applied the ACIP translation of the GRADE framework in this guideline. Within the ACIP GRADE framework, the body of evidence is categorized in a hierarchy. This hierarchy reflects degree of confidence in the effect of a clinical action on health outcomes. The categories include type 1 evidence (randomized clinical trials or overwhelming evidence from observational studies), type 2 evidence (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 evidence (observational studies or randomized clinical trials with notable limitations), and type 4 evidence (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). Type of evidence is categorized by study design as well as limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and a constellation of plausible biases that could change observations of effects. Type 1 evidence indicates that one can be very confident that the true effect lies close to that of the estimate of the effect; type 2 evidence means that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; type 3 evidence means that confidence in the effect estimate is limited and the true effect might be substantially different from the estimate of the effect; and type 4 evidence indicates that one has very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of the effect (47,48). When no studies are present, evidence is considered to be insufficient. The ACIP GRADE framework places recommendations in two categories, Category A and Category B. Four major factors determine the category of the recommendation: the quality of evidence, the balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendations apply to all persons in a specified group and indicate that most patients should receive the recommended course of action. Category B recommendations indicate that there should be individual decision making; different choices will be appropriate for different patients, so clinicians must help patients arrive at a decision consistent with patient values and preferences, and specific clinical situations (47). According to the GRADE methodology, a particular quality of evidence does not necessarily imply a particular strength of recommendation (48)(49)(50). Category A recommendations can be made based on type 3 or type 4 evidence when the advantages of a clinical action greatly outweigh the disadvantages based on a consideration of benefits and harms, values and preferences, and costs. Category B recommendations are made when the advantages and disadvantages of a clinical action are more balanced. GRADE methodology is discussed extensively elsewhere (47,51). The U.S. Preventive Services Task Force (USPSTF) follows different methods for developing and categorizing recommendations (. uspreventiveservicestaskforce.org). USPSTF recommendations focus on preventive services and are categorized as A, B, C, D, and I. Under the Affordable Care Act, all "nongrandfathered" health plans (that is, those health plans not in existence prior to March 23, 2010 or those with significant changes to their coverage) and expanded Medicaid plans are required to cover preventive services recommended by USPSTF with a category A or B rating with no cost sharing. The coverage requirements went into effect September 23, 2010. Similar requirements are in place for vaccinations recommended by ACIP, but do not exist for other recommendations made by CDC, including recommendations within this guideline. A previously published systematic review sponsored by the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness and risks of long-term opioid treatment of chronic pain (14,52) initially served to directly inform the recommendation statements. This systematic clinical evidence review addressed the effectiveness of long-term opioid therapy for outcomes related to pain, function, and quality of life; the comparative effectiveness of different methods for initiating and titrating opioids; the harms and adverse events associated with opioids; and the accuracy of risk-prediction instruments and effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse. For the current guideline development, CDC conducted additional literature searches to update the evidence review to include more recently available publications and to answer an additional clinical question about the effect of opioid therapy for acute pain on long-term use. More details about the literature search strategies and GRADE methods applied are provided in the Clinical Evidence Review (). CDC developed GRADE evidence tables to illustrate the quality of the evidence for each clinical question. As identified in the AHRQ-sponsored clinical evidence review, the overall evidence base for the effectiveness and risks of long-term opioid therapy is low in quality per the GRADE criteria. Thus, contextual evidence is needed to provide information about the benefits and harms of nonpharmacologic and nonopioid pharmacologic therapy and the epidemiology of opioid pain medication overdose and inform the recommendations. Further, as elucidated by the GRADE Working Group, supplemental information on clinician and patient values and preferences and resource allocation can inform judgments of benefits and harms and be helpful for translating the evidence into recommendations. CDC conducted a contextual evidence review to supplement the clinical evidence review based on systematic searches of the literature. The review focused on the following four areas: effectiveness of nonpharmacologic and nonopioid pharmacologic treatments; benefits and harms related to opioid therapy (including additional studies not included in the clinical evidence review such as studies that evaluated outcomes at any duration or used observational study designs related to specific opioid pain medications, high-dose opioid therapy, co-prescription of opioids with other controlled substances, duration of opioid use, special populations, risk stratification/mitigation approaches, and effectiveness of treatments for addressing potential harms of opioid therapy); clinician and patient values and preferences; and resource allocation. CDC constructed narrative summaries of this contextual evidence and used the information to support the clinical recommendations. More details on methods for the contextual evidence review are provided in the Contextual Evidence Review (). On the basis of a review of the clinical and contextual evidence (review methods are described in more detail in subsequent sections of this report), CDC drafted recommendation statements focused on determining when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use. To help assure the draft guideline's integrity and credibility, CDC then began a multistep review process to obtain input from experts, stakeholders, and the public to help refine the recommendations. # Solicitation of Expert Opinion CDC sought the input of experts to assist in reviewing the evidence and providing perspective on how CDC used the evidence to develop the draft recommendations. These experts, referred to as the "Core Expert Group" (CEG) included subject matter experts, representatives of primary care professional societies and state agencies, and an expert in guideline development methodology.- CDC identified subject matter experts with high scientific standing; appropriate academic and clinical training and relevant clinical experience; and proven scientific excellence in opioid prescribing, substance use disorder treatment, and pain management. CDC identified representatives from leading primary care professional organizations to represent the audience for this guideline. Finally, CDC identified state agency officials and representatives based on their experience with state guidelines for opioid prescribing that were developed with multiple agency stakeholders and informed by scientific literature and existing evidence-based guidelines. Prior to their participation, CDC asked potential experts to reveal possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Experts could not serve if they had conflicts that might have a direct and predictable effect on the recommendations. CDC excluded experts who had a financial or promotional relationship with a company that makes a product that might be affected by the guideline. CDC reviewed potential nonfinancial conflicts carefully (e.g., intellectual property, travel, public statements or positions such as congressional testimony) to determine if the activities would have a direct and predictable effect on the recommendations. CDC determined the risk of these types of activities to be minimal for the identified experts. All experts completed a statement certifying that there was no potential or actual conflict of interest. Activities that did not pose a conflict (e.g., participation in Food and Drug Administration activities or other guideline efforts) are disclosed. CDC provided to each expert written summaries of the scientific evidence (both the clinical and contextual evidence reviews conducted for this guideline) and CDC's draft recommendation statements. Experts provided individual ratings for each draft recommendation statement based on the balance of benefits and harms, evidence strength, certainty of values and preferences, cost, recommendation strength, rationale, importance, clarity, and ease of implementation. CDC hosted an in-person meeting of the experts that was held on June 23-24, 2015, in Atlanta, Georgia, to seek their views on the evidence and draft recommendations and to better understand their premeeting ratings. CDC sought the experts' individual opinions at the meeting. Although there was widespread agreement on some of the recommendations, there was disagreement on others. Experts did not vote on the recommendations or seek to come to a consensus. Decisions about recommendations to be included in the guideline, and their rationale, were made by CDC. After revising the guideline, CDC sent written copies of it to each of the experts for review and asked for any additional comments; CDC reviewed these written comments and considered them when making further revisions to the draft guideline. The experts have not reviewed the final version of the guideline. # Federal Partner Engagement Given the scope of this guideline and the interest of agencies across the federal government in appropriate pain management, opioid prescribing, and related outcomes, CDC invited its National Institute of Occupational Safety and Health and CDC's federal partners to observe the expert meeting, provide written comments on the full draft guideline after the meeting, and review the guideline through an agency clearance process; CDC reviewed comments and incorporated changes. Interagency collaboration will be critical for translating these recommendations into clinical practice. # Stakeholder Comment Given the importance of the guideline for a wide variety of stakeholders, CDC also invited review from a Stakeholder Review Group (SRG) to provide comment so that CDC could consider modifications that would improve the recommendations' specificity, applicability, and ease of implementation. The SRG included representatives from professional organizations that represent specialties that commonly prescribe opioids (e.g., pain medicine, physical medicine and rehabilitation), delivery systems within which opioid prescribing occurs (e.g., hospitals), and representation from community organizations with interests in pain management and opioid prescribing.- Representatives from each of the SRG organizations were provided a copy of the guideline for comment. Each of these representatives provided written comments. Once input was received from the full SRG, CDC reviewed all comments and carefully considered them when revising the draft guideline. # Constituent Engagement To obtain initial perspectives from constituents on the recommendation statements, including clinicians and prospective patients, CDC convened a constituent engagement webinar and circulated information about the webinar in advance through announcements to partners. CDC hosted the webinar on September 16 and 17, 2015, provided information about the methodology for developing the guideline, and presented the key recommendations. A fact sheet was posted on the CDC Injury Center website (/ injury) summarizing the guideline development process and clinical practice areas addressed in the guideline; instructions were included on how to submit comments via email. CDC received comments during and for 2 days following the first webinar. Over 1,200 constituent comments were received. Comments were reviewed and carefully considered when revising the draft guideline. # Peer Review Per the final information quality bulletin for peer review (/ memoranda/fy2005/m05-03.pdf ), peer review requirements applied to this guideline because it provides influential scientific information that could have a clear and substantial impact on public-and private-sector decisions. Three experts independently reviewed the guideline to determine the reasonableness and strength of recommendations; the clarity with which scientific uncertainties were clearly identified; and the rationale, importance, clarity, and ease of implementation of the recommendations.- CDC selected peer reviewers based on expertise, diversity of scientific viewpoints, and independence from the guideline development process. CDC assessed and managed potential conflicts of interest using a process similar to the one as described for solicitation of expert opinion. No financial interests were identified in the disclosure and review process, and nonfinancial activities were determined to be of minimal risk; thus, no significant conflict of interest concerns were identified. CDC placed the names of peer reviewers on the CDC and the National Center for Injury Prevention and Control Peer Review Agenda websites that are used to provide information about the peer review of influential documents. CDC reviewed peer review comments and revised the draft guideline accordingly. # Public Comment To obtain comments from the public on the full guideline, CDC published a notice in the Federal Register (80 FR 77351) announcing the availability of the guideline and the supporting clinical and contextual evidence reviews for public comment. The comment period closed January 13, 2016. CDC received more than 4,350 comments from the general public, including patients with chronic pain, clinicians, families who have lost loved ones to overdose, medical associations, professional organizations, academic institutions, state and local governments, and industry. CDC reviewed each of the comments and carefully considered them when revising the draft guideline. # Federal Advisory Committee Review and Recommendation The National Center for Injury Prevention and Control (NCIPC) Board of Scientific Counselors (BSC) is a federal advisory committee that advises and makes recommendations to the Secretary of the Department of Health and Human Services, the Director of CDC, and the Director of NCIPC.- The BSC makes recommendations regarding policies, strategies, objectives, and priorities, and reviews progress toward injury and violence prevention. CDC sought the BSC's advice on the draft guideline. BSC members are special government employees appointed as CDC advisory committee members; as such, all members completed an OGE Form 450 to disclose relevant interests. BSC members also reported on their disclosures during meetings. Disclosures for the BSC are reported in the guideline. To assist in guideline review, on December 14, 2015, via Federal Register notice, CDC announced the intent to form an Opioid Guideline Workgroup (OGW) to provide observations on the draft guideline to the BSC. CDC provided the BSC with the draft guideline as well as summaries of comments provided to CDC by stakeholders, constituents, and peer reviewers, and edits made to the draft guideline in response. During an open meeting held on January 7, 2016, the BSC recommended the formation of the OGW. The OGW included a balance of perspectives from audiences directly affected by the guideline, audiences that would be directly involved with implementing the recommendations, and audiences qualified to provide representation. The OGW comprised clinicians, subject matter experts, and a patient representative, with the following perspectives represented: primary care, pain medicine, public health, behavioral health, substance abuse treatment, pharmacy, patients, and research.- Additional sought-after attributes were appropriate academic and clinical training and relevant clinical experience; high scientific standing; and knowledge of the patient, clinician, and caregiver perspectives. In accordance with CDC policy, two BSC committee members also served as OGW members, with one serving as the OGW Chair. The professional credentials and interests of OGW members were carefully reviewed to identify possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Only OGW members whose interests were determined to be minimal were selected. When an activity was perceived as having the potential to affect a specific aspect of the recommendations, the activity was disclosed, and the OGW member was recused from discussions related to that specific aspect of the recommendations (e.g., urine drug testing and abuse-deterrent formulations). Disclosures for the OGW are reported. CDC and the OGW identified ad-hoc consultants to supplement the workgroup expertise, when needed, in the areas of pediatrics, occupational medicine, obstetrics and gynecology, medical ethics, addiction psychiatry, physical medicine and rehabilitation, guideline development methodology, and the perspective of a family member who lost a loved one to opioid use disorder or overdose. The BSC charged the OGW with reviewing the quality of the clinical and contextual evidence reviews and reviewing each of the recommendation statements and accompanying rationales. For each recommendation statement, the OGW considered the quality of the evidence, the balance of benefits and risks, the values and preferences of clinicians and patients, the cost feasibility, and the category designation of the recommendation (A or B). The OGW also reviewed supplementary documents, including input provided by the CEG, SRG, peer reviewers, and the public. OGW members discussed the guideline accordingly during virtual meetings and drafted a summary report of members' observations, including points of agreement and disagreement, and delivered the report to the BSC. NCIPC announced an open meeting of the NCIPC BSC in the Federal Register on January 11, 2015. The BSC met on January 28, 2016, to discuss the OGW report and deliberate on the draft guideline itself. Members of the public provided comments at this meeting. After discussing the OGW report, deliberating on specific issues about the draft guideline identified at the meeting, and hearing public comment, the BSC voted unanimously: to support the observations made by the OGW; that CDC adopt the guideline recommendations that, according to the workgroup's report, had unanimous or majority support; and that CDC further consider the guideline recommendations for which the group had mixed opinions. CDC carefully considered the OGW observations, public comments, and BSC recommendations, and revised the guideline in response. # Summary of the Clinical Evidence Review Primary Clinical Questions CDC conducted a clinical systematic review of the scientific evidence to identify the effectiveness, benefits, and harms of long-term opioid therapy for chronic pain, consistent with the GRADE approach (47,48). Long-term opioid therapy is defined as use of opioids on most days for >3 months. A previously published AHRQ-funded systematic review on the effectiveness and risks of long-term opioid therapy for chronic pain comprehensively addressed four clinical questions (14,52). CDC, with the assistance of a methodology expert, searched the literature to identify newly published studies on these four original questions. Because long-term opioid use might be affected by use of opioids for acute pain, CDC subsequently developed a fifth clinical question (last in the series below), and in collaboration with a methodologist conducted a systematic review of the scientific evidence to address it. In brief, five clinical questions were addressed: - prescribing opioid therapy for acute pain on long-term use (KQ5). The review was focused on the effectiveness of long-term opioid therapy on long-term (>1 year) outcomes related to pain, function, and quality of life to ensure that findings are relevant to patients with chronic pain and long-term opioid prescribing. The effectiveness of short-term opioid therapy has already been established (10). However, opioids have unique effects such as tolerance and physical dependence that might influence assessments of benefit over time. These effects raise questions about whether findings on short-term effectiveness of opioid therapy can be extrapolated to estimate benefits of long-term therapy for chronic pain. Thus, it is important to consider studies that provide data on long-term benefit. For certain opioid-related harms (overdose, fractures, falls, motor vehicle crashes), observational studies were included with outcomes measured at shorter intervals because such outcomes can occur early during opioid therapy, and such harms are not captured well in short-term clinical trials. A detailed listing of the key questions is provided in the Clinical Evidence Review (). # Clinical Evidence Systematic Review Methods Complete methods and data for the 2014 AHRQ report, upon which this updated systematic review is based, have been published previously (14,52). Study authors developed the protocol using a standardized process (53) with input from experts and the public and registered the protocol in the PROSPERO database (54). For the 2014 AHRQ report, a research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL for Englishlanguage articles published January 2008 through August 2014, using search terms for opioid therapy, specific opioids, chronic pain, and comparative study designs. Also included were relevant studies from an earlier review (10) in which searches were conducted without a date restriction, reference lists were reviewed, and ClinicalTrials.gov was searched. CDC updated the AHRQ literature search using the same search strategies as in the original review including studies published before April, 2015. Seven additional studies met inclusion criteria and were added to the review. CDC used the GRADE approach outlined in the ACIP Handbook for Developing Evidence-Based Recommendations (47) to rate the quality of evidence for the full body of evidence (evidence from the 2014 AHRQ review plus the update) for each clinical question. Evidence was categorized into the following types: type 1 (randomized clinical trials or overwhelming evidence from observational studies), type 2 (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 (observational studies, or randomized clinical trials with notable limitations), or type 4 (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). When no studies were present, evidence was considered to be insufficient. Per GRADE methods, type of evidence was categorized by study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and constellation of plausible biases that could change effects. Results were synthesized qualitatively, highlighting new evidence identified during the update process. Meta-analysis was not attempted due to the small numbers of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of the studies. More detailed information about data sources and searches, study selection, data extraction and quality assessment, data synthesis, and update search yield and new evidence for the current review is provided in the Clinical Evidence Review (). # Summary of Findings for Clinical Questions The main findings of this updated review are consistent with the findings of the 2014 AHRQ report (14). In summary, evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited, with insufficient evidence to determine long-term benefits versus no opioid therapy, though evidence suggests risk for serious harms that appears to be dose-dependent. These findings supplement findings from a previous review of the effectiveness of opioids for adults with chronic noncancer pain. In this previous review, based on randomized trials predominantly ≤12 weeks in duration, opioids were found to be moderately effective for pain relief, with small benefits for functional outcomes; although estimates vary, based on uncontrolled studies, a high percentage of patients discontinued long-term opioid use because of lack of efficacy and because of adverse events (10). The GRADE evidence summary with type of evidence ratings for the five clinical questions for the current evidence review are outlined (Table 1). This summary is based on studies included in the AHRQ 2014 review (35 studies) plus additional studies identified in the updated search (seven studies). Additional details on findings from the original review are provided in the full 2014 AHRQ report (14,52). Full details on the clinical evidence review findings supporting this guideline are provided in the Clinical Evidence Review (). # Effectiveness For KQ1, no study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy for chronic pain evaluated long-term (≥1 year) outcomes related to pain, function, or quality of life. Most placebo-controlled randomized clinical trials were ≤6 weeks in duration. Thus, the body of evidence for KQ1 is rated as insufficient (0 studies contributing) (14). # Harms For KQ2, the body of evidence is rated as type 3 (12 studies contributing; 11 from the original review plus one new study). One fair-quality cohort study found that long-term opioid therapy is associated with increased risk for an opioid abuse or dependence diagnosis (as defined by ICD-9-CM codes) versus no opioid prescription (22). Rates of opioid abuse or dependence diagnosis ranged from 0.7% with lower-dose (≤36 MME) chronic therapy to 6.1% with higher-dose (≥120 MME) chronic therapy, versus 0.004% with no opioids prescribed. Ten fair-quality uncontrolled studies reported estimates of opioid abuse, addiction, and related outcomes (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). In primary care settings, prevalence of opioid dependence (using DSM-IV criteria) ranged from 3% to 26% (55,56,59). In pain clinic settings, prevalence of addiction ranged from 2% to 14% (57,58,60,61,(63)(64)(65). Factors associated with increased risk for misuse included history of substance use disorder, younger age, major depression, and use of psychotropic medications (55,62). Two studies reported on the association between opioid use and risk for overdose (66,67). One large fair-quality retrospective cohort study found that recent opioid use was associated with increased risk for any overdose events and serious overdose events versus nonuse (66) Findings of increased fracture risk for current opioid use, versus nonuse, were mixed in two studies (68,69). Two studies found an association between opioid use and increased risk for cardiovascular events (70,71). Indirect evidence was found for endocrinologic harms (increased use of medications for erectile dysfunction or testosterone from one previously included study; laboratory-defined androgen deficiency from one newly reviewed study) (72,73). One study found that opioid dosages ≥20 MME/day were associated with increased odds of road trauma among drivers (74). # Opioid Dosing Strategies For KQ3, the body of evidence is rated as type 4 (14 studies contributing; 12 from the original review plus two new studies). For initiation and titration of opioids, the 2014 AHRQ report found insufficient evidence from three fair-quality, open-label trials to determine comparative effectiveness of ER/LA versus immediate-release opioids for titrating patients to stable pain control (75,76). One new fair-quality cohort study of Veterans Affairs patients found initiation of therapy with an ER/LA opioid associated with greater risk for nonfatal overdose than initiation with an immediate-release opioid, with risk greatest in the first 2 weeks after initiation of treatment (77). For comparative effectiveness and harms of ER/LA opioids, the 2014 AHRQ report included three randomized, headto-head trials of various ER/LA opioids that found no clear differences in 1-year outcomes related to pain or function (78)(79)(80) # but had methodological shortcomings. A fair-quality retrospective cohort study based on national Veterans Health Administration system pharmacy data found that methadone was associated with lower overall risk for all-cause mortality versus morphine (81), and a fair-quality retrospective cohort study based on Oregon Medicaid data found no statistically significant differences between methadone and long-acting morphine in risk for death or overdose symptoms (82). However, a new observational study (83) found methadone associated with increased risk for overdose versus sustainedrelease morphine among Tennessee Medicaid patients. The observed inconsistency in study findings suggests that risks of methadone might vary in different settings as a function of different monitoring and management protocols, though more research is needed to understand factors associated with safer methadone prescribing. For dose escalation, the 2014 AHRQ report included one fair-quality randomized trial that found no differences between more liberal dose escalation and maintenance of current doses after 12 months in pain, function, all-cause withdrawals, or withdrawals due to opioid misuse (84). However, the difference in opioid dosages prescribed at the end of the trial was relatively small (mean 52 MME/day with more liberal dosing versus 40 MME/day). Evidence on other comparisons related to opioid dosing strategies (ER/LA versus immediaterelease opioids; immediate-release plus ER/LA opioids versus ER/LA opioids alone; scheduled continuous dosing versus as-needed dosing; or opioid rotation versus maintenance of current therapy; long-term effects of strategies for treating acute exacerbations of chronic pain) was not available or too limited to determine effects on long-term clinical outcomes. For example, evidence on the comparative effectiveness of opioid tapering or discontinuation versus maintenance, and of different opioid tapering strategies, was limited to small, poor-quality studies (85)(86)(87). # Risk Assessment and Mitigation For KQ4, the body of evidence is rated as type 3 for the accuracy of risk assessment tools and insufficient for the effectiveness of use of risk assessment tools and mitigation strategies in reducing harms (six studies contributing; four from the original review plus two new studies). The 2014 AHRQ report included four studies (88-91) on the accuracy of risk assessment instruments, administered prior to opioid therapy initiation, for predicting opioid abuse or misuse. Results for the Opioid Risk Tool (ORT) (89-91) were extremely inconsistent; evidence for other risk assessment instruments was very sparse, and studies had serious methodological shortcomings. One additional fair-quality ( 92) and one poor-quality ( 93) study identified for this update compared the predictive accuracy of the ORT, the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), and the Brief Risk Interview. For the ORT, sensitivity was 0.58 and 0.75 and specificity 0.54 and 0.86; for the SOAPP-R, sensitivity was 0.53 and 0.25 and specificity 0.62 and 0.73; and for the Brief Risk Interview, sensitivity was 0.73 and 0.83 and specificity 0.43 and 0.88. For the ORT, positive likelihood ratios ranged from noninformative (positive likelihood ratio close to 1) to moderately useful (positive likelihood ratio >5). The SOAPP-R was associated with noninformative likelihood ratios (estimates close to 1) in both studies. No study evaluated the effectiveness of risk mitigation strategies (use of risk assessment instruments, opioid management plans, patient education, urine drug testing, use of PDMP data, use of monitoring instruments, more frequent monitoring intervals, pill counts, or use of abuse-deterrent formulations) for improving outcomes related to overdose, addiction, abuse, or misuse. # Effects of Opioid Therapy for Acute Pain on Long-Term Use For KQ5, the body of evidence is rated as type 3 (two new studies contributing). Two fair-quality retrospective cohort studies found opioid therapy prescribed for acute pain associated with greater likelihood of long-term use. One study evaluated opioid-naïve patients who had undergone low-risk surgery, such as cataract surgery and varicose vein stripping (94). Use of opioids within 7 days of surgery was associated with increased risk for use at 1 year. The other study found that among patients with a workers' compensation claim for acute low back pain, compared to patients who did not receive opioids early after injury (defined as use within 15 days following onset of pain), patients who did receive early opioids had an increased likelihood of receiving five or more opioid prescriptions 30-730 days following onset that increased with greater early exposure. Versus no early opioid use, the adjusted OR was 2.08 (95% CI = 1.55-2.78) for 1-140 MME/day and increased to 6.14 (95% confidence interval = 4.92-7.66) for ≥450 MME/day (95). # Summary of the Contextual Evidence Review Primary Areas of Focus Contextual evidence is complementary information that assists in translating the clinical research findings into recommendations. CDC conducted contextual evidence reviews on four topics to supplement the clinical evidence review findings: - Effectiveness of nonpharmacologic (e.g., cognitive behavioral therapy , exercise therapy, interventional treatments, and multimodal pain treatment) and nonopioid pharmacologic treatments (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs , antidepressants, and anticonvulsants), including studies of any duration. - Benefits and harms of opioid therapy (including additional studies not included in the clinical evidence review, such as studies that were not restricted to patients with chronic pain, evaluated outcomes at any duration, performed ecological analyses, or used observational study designs other than cohort and case-cohort control studies) related to specific opioids, high-dose therapy, co-prescription with other controlled substances, duration of use, special populations, and potential usefulness of risk stratification/ mitigation approaches, in addition to effectiveness of treatments associated with addressing potential harms of opioid therapy (opioid use disorder). - Clinician and patient values and preferences related to opioids and medication risks, benefits, and use. - Resource allocation including costs and economic efficiency of opioid therapy and risk mitigation strategies. CDC also reviewed clinical guidelines that were relevant to opioid prescribing and could inform or complement the CDC recommendations under development (e.g., guidelines on nonpharmacologic and nonopioid pharmacologic treatments and guidelines with recommendations related to specific clinician actions such as urine drug testing or opioid tapering protocols). # Contextual Evidence Review Methods CDC conducted a contextual evidence review to assist in developing the recommendations by providing an assessment of the balance of benefits and harms, values and preferences, and cost, consistent with the GRADE approach. Given the public health urgency for developing opioid prescribing recommendations, a rapid review was required for the contextual evidence review for the current guideline. Rapid reviews are used when there is a need to streamline the systematic review process to obtain evidence quickly (96). Methods used to streamline the process include limiting searches by databases, years, and languages considered, and truncating quality assessment and data abstraction protocols. CDC conducted "rapid reviews" of the contextual evidence on nonpharmacologic and nonopioid pharmacologic treatments, benefits and harms, values and preferences, and resource allocation. Detailed information about contextual evidence data sources and searches, inclusion criteria, study selection, and data extraction and synthesis are provided in the Contextual Evidence Review (). In brief, CDC conducted systematic literature searches to identify original studies, systematic reviews, and clinical guidelines, depending on the topic being searched. CDC also solicited publication referrals from subject matter experts. Given the need for a rapid review process, grey literature (e.g., literature by academia, organizations, or government in the forms of reports, documents, or proceedings not published by commercial publishers) was not systematically searched. Database sources, including MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, varied by topic. Multiple reviewers scanned study abstracts identified through the database searches and extracted relevant studies for review. CDC constructed narrative summaries and tables based on relevant articles that met inclusion criteria, which are provided in the Contextual Evidence Review (/ view/cdc/38027). Findings from the contextual reviews provide indirect evidence and should be interpreted accordingly. CDC did not formally rate the quality of evidence for the studies included in the contextual evidence review using the GRADE method. The studies that addressed benefits and harms, values and preferences, and resource allocation most often employed observational methods, used short follow-up periods, and evaluated selected samples. Therefore the strength of the evidence from these contextual review areas was considered to be low, comparable to type 3 or type 4 evidence. The quality of evidence for nonopioid pharmacologic and nonpharmacologic pain treatments was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines (e.g., for treatment of chronic neuropathic pain, low back pain, osteoarthritis, and fibromyalgia). Similarly, the quality of evidence on pharmacologic and psychosocial opioid use disorder treatment was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines. # Summary of Findings for Contextual Areas Full narrative reviews and tables that summarize key findings from the contextual evidence review are provided in the Contextual Evidence Review (). # Effectiveness of Nonpharmacologic and Nonopioid Pharmacologic Treatments Several nonpharmacologic and nonopioid pharmacologic treatments have been shown to be effective in managing chronic pain in studies ranging in duration from 2 weeks to 6 months. For example, CBT that trains patients in behavioral techniques and helps patients modify situational factors and cognitive processes that exacerbate pain has small positive effects on disability and catastrophic thinking (97). Exercise therapy can help reduce pain and improve function in chronic low back pain (98), improve function and reduce pain in osteoarthritis of the knee (99) and hip (100), and improve well-being, fibromyalgia symptoms, and physical function in fibromyalgia (101). Multimodal and multidisciplinary therapies (e.g., therapies that combine exercise and related therapies with psychologically based approaches) can help reduce pain and improve function more effectively than single modalities (102,103). Nonopioid pharmacologic approaches used for pain include analgesics such as acetaminophen, NSAIDs, and cyclooxygenase 2 (COX-2) inhibitors; selected anticonvulsants; and selected antidepressants (particularly tricyclics and serotonin and norepinephrine reuptake inhibitors ). Multiple guidelines recommend acetaminophen as first-line pharmacotherapy for osteoarthritis (104)(105)(106)(107)(108)(109) or for low back pain ( 110) but note that it should be avoided in liver failure and that dosage should be reduced in patients with hepatic insufficiency or a history of alcohol abuse (109). Although guidelines also recommend NSAIDs as first-line treatment for osteoarthritis or low back pain (106,110), NSAIDs and COX-2 inhibitors do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks (111). FDA has recently strengthened existing label warnings that NSAIDs increase risks for heart attack and stroke, including that these risks might increase with longer use or at higher doses (112). Several guidelines agree that first-and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs (113)(114)(115)(116). Interventional approaches such as epidural injection for certain conditions (e.g., lumbar radiculopathy) can provide short-term improvement in pain (117)(118)(119). Epidural injection has been associated with rare but serious adverse events, including loss of vision, stroke, paralysis, and death (120). # Benefits and Harms of Opioid Therapy Balance between benefits and harms is a critical factor influencing the strength of clinical recommendations. In particular, CDC considered what is known from the epidemiology research about benefits and harms related to specific opioids and formulations, high dose therapy, co-prescription with other controlled substances, duration of use, special populations, and risk stratification and mitigation approaches. Additional information on benefits and harms of long-term opioid therapy from studies meeting rigorous selection criteria is provided in the clinical evidence review (e.g., see KQ2). CDC also considered the number of persons experiencing chronic pain, numbers potentially benefiting from opioids, and numbers affected by opioid-related harms. A review of these data is presented in the background section of this document, with detailed information provided in the Contextual Evidence Review (/ cdc/38027). Finally, CDC considered the effectiveness of treatments that addressed potential harms of opioid therapy (opioid use disorder). Regarding specific opioids and formulations, as noted by FDA, there are serious risks of ER/LA opioids, and the indication for this class of medications is for management of pain severe enough to require daily, around-the-clock, longterm opioid treatment in patients for whom other treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain (121). Time-scheduled opioid use was associated with substantially higher average daily opioid dosage than as-needed opioid use in one study (122). Methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for pain. Methadone has been found to account for as much as a third of opioidrelated overdose deaths involving single or multiple drugs in states that participated in the Drug Abuse Warning Network, which was more than any opioid other than oxycodone, despite representing <2% of opioid prescriptions outside of opioid treatment programs in the United States; further, methadone was involved in twice as many single-drug deaths as any other prescription opioid (123). Regarding high-dose therapy, several epidemiologic studies that were excluded from the clinical evidence review because patient samples were not restricted to patients with chronic pain also examined the association between opioid dosage and overdose risk (23,24,(124)(125)(126). Consistent with the clinical evidence review, the contextual review found that opioid-related overdose risk is dosedependent, with higher opioid dosages associated with increased overdose risk. Two of these studies (23,24), as well as the two studies in the clinical evidence review (66,67), evaluated similar MME/day dose ranges for association with overdose risk. In these four studies, compared with opioids prescribed at <20 MME/ day, the odds of overdose among patients prescribed opioids for chronic nonmalignant pain were between 1.3 (67) and 1.9 (24) for dosages of 20 to <50 MME/day, between 1.9 (67) and 4.6 (24) for dosages of 50 to <100 MME/day, and between 2.0 (67) and 8.9 (66) for dosages of ≥100 MME/day. Compared with dosages of 1-<20 MME/day, absolute risk difference approximation for 50-<100 MME/day was 0.15% for fatal overdose (24) and 1.40% for any overdose (66), and for ≥100 MME/day was 0.25% for fatal overdose (24) and 4.04% for any overdose (66). A recent study of Veterans Health Administration patients with chronic pain found that patients who died of overdoses related to opioids were prescribed higher opioid dosages (mean: 98 MME/day; median: 60 MME/day) than controls (mean: 48 MME/day, median: 25 MME/day) (127). Finally, another recent study of overdose deaths among state residents with and without opioid prescriptions revealed that prescription opioid-related overdose mortality rates rose rapidly up to prescribed doses of 200 MME/day, after which the mortality rates continued to increase but grew more gradually (128). A listing of common opioid medications and their MME equivalents is provided (Table 2). Regarding coprescription of opioids with benzodiazepines, epidemiologic studies suggest that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31%-61% of decedents (67,128,129). In one of these studies (67), among decedents who received an opioid prescription, those whose deaths were related to opioids were more likely to have obtained opioids from multiple physicians and pharmacies than decedents whose deaths were not related to opioids. Regarding duration of use, patients can experience tolerance and loss of effectiveness of opioids over time (130). Patients who do not experience clinically meaningful pain relief early in treatment (i.e., within 1 month) are unlikely to experience pain relief with longer-term use (131). Regarding populations potentially at greater risk for harm, risk is greater for patients with sleep apnea or other causes of sleep-disordered breathing, patients with renal or hepatic insufficiency, older adults, pregnant women, patients with depression or other mental health conditions, and patients with alcohol or other substance use disorders. Interpretation of clinical data on the effects of opioids on sleep-disordered breathing is difficult because of the types of study designs and methods employed, and there is no clear consensus regarding association with risk for developing obstructive sleep apnea syndrome (132). However, opioid therapy can decrease respiratory drive, a high percentage of patients on long-term opioid therapy have been reported to have an abnormal apneahypopnea index (133), opioid therapy can worsen central sleep apnea in obstructive sleep apnea patients, and it can cause further desaturation in obstructive sleep apnea patients not on continuous positive airway pressure (CPAP) (31). Reduced renal or hepatic function can result in greater peak effect and longer duration of action and reduce the dose at which respiratory depression and overdose occurs (134). Age-related changes in patients aged ≥65 years, such as reduced renal function and medication clearance, even in the absence of renal disease (135), result in a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose. Older adults might also be at increased risk for falls and fractures related to opioids (136)(137)(138). Opioids used in pregnancy can be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with birth defects, including neural tube defects (139,140), congenital heart defects (140), and gastroschisis (140); preterm delivery (141), poor fetal growth (141), and stillbirth (141). Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal syndrome (142). Patients with mental health comorbidities and patients with histories of substance use disorders might be at higher risk than other patients for opioid use disorder (62,143,144). Recent analyses found that depressed patients were at higher risk for drug overdose than patients without depression, particularly at higher opioid dosages, although investigators were unable to distinguish unintentional overdose from suicide attempts (145). In case-control and case-cohort studies, substance abuse/dependence was more prevalent among patients experiencing overdose than among patients not experiencing overdose (12% versus 6% , 40% versus 10% , and 26% versus 9% ). Regarding risk stratification approaches, limited evidence was found regarding benefits and harms. Potential benefits of PDMPs and urine drug testing include the ability to identify patients who might be at higher risk for opioid overdose or opioid use disorder, and help determine which patients will benefit from greater caution and increased monitoring or interventions when risk factors are present. For example, one study found that most fatal overdoses could be identified retrospectively on the basis of two pieces of information, multiple prescribers and high total daily opioid dosage, both important risk factors for overdose (124,146) that are available to prescribers in the PDMP (124). However, limited evaluation of PDMPs at the state level has revealed mixed effects on changes in prescribing and mortality outcomes (28). Potential harms of risk stratification include underestimation of risks of opioid therapy when screening tools are not adequately sensitive, as well as potential overestimation of risk, which could lead to inappropriate clinical decisions. Regarding risk mitigation approaches, limited evidence was found regarding benefits and harms. Although no studies were found to examine prescribing of naloxone with opioid pain medication in primary care settings, naloxone distribution through community-based programs providing prevention services for substance users has been demonstrated to be associated with decreased risk for opioid overdose death at the community level (147). Concerns have been raised that prescribing changes such as dose reduction might be associated with unintended negative consequences, such as patients seeking heroin or other illicitly obtained opioids (148) or interference with appropriate pain treatment (149). With the exception of a study noting an association between an abuse-deterrent formulation of OxyContin and heroin use, showing that some patients in qualitative interviews reported switching to another opioid, including heroin, for many reasons, including cost and availability as well as ease of use (150), CDC did not identify studies evaluating these potential outcomes. Finally, regarding the effectiveness of opioid use disorder treatments, methadone and buprenorphine for opioid use disorder have been found to increase retention in treatment and to decrease illicit opioid use among patients with opioid use disorder involving heroin (151)(152)(153). Although findings are mixed, some studies suggest that effectiveness is enhanced when psychosocial treatments (e.g., contingency management, community reinforcement, psychotherapeutic counseling, and family therapy) are used in conjunction with medicationassisted therapy; for example, by reducing opioid misuse and increasing retention during maintenance therapy, and improving compliance after detoxification (154,155). # Clinician and Patient Values and Preferences Clinician and patient values and preferences can inform how benefits and harms of long-term opioid therapy are weighted and estimate the effort and resources required to effectively provide implementation support. Many physicians lack confidence in their ability to prescribe opioids safely (156), to predict (157) or detect (158) prescription drug abuse, and to discuss abuse with their patients (158). Although clinicians have reported favorable beliefs and attitudes about improvements in pain and quality of life attributed to opioids (159), most consider prescription drug abuse to be a "moderate" or "big" problem in their community, and large proportions are "very" concerned about opioid addiction (55%) and death (48%) (160). Clinicians do not consistently use practices intended to decrease the risk for misuse, such as PDMPs (161,162), urine drug testing (163), and opioid treatment agreements (164). This is likely due in part to challenges related to registering for PDMP access and logging into the PDMP (which can interrupt normal clinical workflow if data are not integrated into electronic health record systems) (165), competing clinical demands, perceived inadequate time to discuss the rationale for urine drug testing and to order confirmatory testing, and feeling unprepared to interpret and address results (166). Many patients do not have an opinion about "opioids" or know what this term means (167). Most are familiar with the term "narcotics." About a third associated "narcotics" with addiction or abuse, and about half feared "addiction" from long-term "narcotic" use (168). Most patients taking opioids experience side effects (73% of patients taking hydrocodone for noncancer pain , 96% of patients taking opioids for chronic pain ), and side effects, rather than pain relief, have been found to explain most of the variation in patients' preferences related to taking opioids (12). For example, patients taking hydrocodone for noncancer pain commonly reported side effects including dizziness, headache, fatigue, drowsiness, nausea, vomiting, and constipation (11). Patients with chronic pain in focus groups emphasized effectiveness of goal setting for increasing motivation and functioning (168). Patients taking high dosages report reliance on opioids despite ambivalence about their benefits (169) and regardless of pain reduction, reported problems, concerns, side effects, or perceived helpfulness (13). # Resource Allocation Resource allocation (cost) is an important consideration in understanding the feasibility of clinical recommendations. CDC searched for evidence on opioid therapy compared with other treatments; costs of misuse, abuse, and overdose from prescription opioids; and costs of specific risk mitigation strategies (e.g., urine drug testing). Yearly direct and indirect costs related to prescription opioids have been estimated (based on studies published since 2010) to be $53.4 billion for nonmedical use of prescription opioids (170); $55.7 billion for abuse, dependence (i.e., opioid use disorder), and misuse of prescription opioids (171); and $20.4 billion for direct and indirect costs related to opioid-related overdose alone (172). In 2012, total expenses for outpatient prescription opioids were estimated at $9.0 billion, an increase of 120% from 2002 (173). Although there are perceptions that opioid therapy for chronic pain is less expensive than more timeintensive nonpharmacologic management approaches, many pain treatments, including acetaminophen, NSAIDs, tricyclic antidepressants, and massage therapy, are associated with lower mean and median annual costs compared with opioid therapy (174). COX-2 inhibitors, SNRIs, anticonvulsants, topical analgesics, physical therapy, and CBT are also associated with lower median annual costs compared with opioid therapy (174). Limited information was found on costs of strategies to decrease risks associated with opioid therapy; however, urine drug testing, including screening and confirmatory tests, has been estimated to cost $211-$363 per test (175). # Recommendations The recommendations are grouped into three areas for consideration: - Determining when to initiate or continue opioids for chronic pain. - Opioid selection, dosage, duration, follow-up, and discontinuation. - Assessing risk and addressing harms of opioid use. There are 12 recommendations (Box 1). Each recommendation is followed by a rationale for the recommendation, with considerations for implementation noted. In accordance with the ACIP GRADE process, CDC based the recommendations on consideration of the clinical evidence, contextual evidence (including benefits and harms, values and preferences, resource allocation), and expert opinion. For each recommendation statement, CDC notes the recommendation category (A or B) and the type of the evidence (1, 2, 3, or 4) supporting the statement (Box 2). Expert opinion is reflected within each of the recommendation rationales. While there was not an attempt to reach consensus among experts, experts from the Core Expert Group and from the Opioid Guideline Workgroup ("experts") expressed overall, general support for all recommendations. Where differences in expert opinion emerged for detailed actions within the clinical recommendations or for implementation considerations, CDC notes the differences of opinion in the supporting rationale statements. Category A recommendations indicate that most patients should receive the recommended course of action; category B recommendations indicate that different choices will be appropriate for different patients, requiring clinicians to help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. Consistent with the ACIP (47) and GRADE process (48), category A recommendations were made, even with type 3 and 4 evidence, when there was broad agreement that the advantages of a clinical action greatly outweighed the disadvantages based on a consideration of benefits and harms, values and preferences, and resource allocation. Category B recommendations were made when there was broad agreement that the advantages and disadvantages of a clinical action were more balanced, but advantages were significant enough to warrant a recommendation. All recommendations are category A recommendations, with the exception of recommendation 10, which is rated as category B. Recommendations were associated with a range of evidence types, from type 2 to type 4. In summary, the categorization of recommendations was based on the following assessment: - No evidence shows a long-term benefit of opioids in pain and function versus no opioids for chronic pain with outcomes examined at least 1 year later (with most placebocontrolled randomized trials ≤6 weeks in duration). - Extensive evidence shows the possible harms of opioids (including opioid use disorder, overdose, and motor vehicle injury). - Extensive evidence suggests some benefits of nonpharmacologic and nonopioid pharmacologic treatments compared with long-term opioid therapy, with less harm. # h a r m a c o l o g i c t h e r a p y, a s a p p r o p r i a t e (recommendation category: A, evidence type: 3). Patients with pain should receive treatment that provides the greatest benefits relative to risks. The contextual evidence review found that many nonpharmacologic therapies, including physical therapy, weight loss for knee osteoarthritis, psychological therapies such as CBT, and certain interventional procedures can ameliorate chronic pain. There is high-quality evidence that exercise therapy (a prominent modality in physical therapy) for hip (100) or knee (99) osteoarthritis reduces pain and improves function immediately after treatment and that the improvements are sustained for at least 2-6 months. Previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip (176). Exercise therapy also can help reduce pain and improve function in low back pain and can improve global well-being and physical function in fibromyalgia (98,101). Multimodal therapies and multidisciplinary biopsychosocial rehabilitation-combining approaches (e.g., psychological therapies with exercise) can reduce long-term pain and disability compared with usual care and compared with physical treatments (e.g., exercise) alone. Multimodal therapies are not always available or reimbursed by insurance and can be time-consuming and costly for patients. Interventional approaches such as arthrocentesis and intraarticular glucocorticoid injection for pain associated with rheumatoid arthritis (117) or osteoarthritis (118) and subacromial corticosteroid injection for rotator cuff disease (119) can provide short-term improvement in pain and function. Evidence is insufficient to determine the extent to which repeated glucocorticoid injection increases potential risks such as articular cartilage changes (in osteoarthritis) and sepsis (118). Serious adverse events are rare but have been reported with epidural injection (120). Several nonopioid pharmacologic therapies (including acetaminophen, NSAIDs, and selected antidepressants and anticonvulsants) are effective for chronic pain. In particular, acetaminophen and NSAIDs can be useful for arthritis and low back pain. Selected anticonvulsants such as pregabalin and gabapentin can improve pain in diabetic neuropathy and post-herpetic neuralgia (contextual evidence review). Pregabalin, gabapentin, and carbamazepine are FDA-approved for treatment of certain neuropathic pain conditions, and pregabalin is FDA approved for fibromyalgia management. In patients with or without depression, tricyclic antidepressants and SNRIs provide effective analgesia for neuropathic pain conditions including diabetic neuropathy and post-herpetic neuralgia, often at lower dosages and with a shorter time to onset of effect than for treatment of depression (see contextual evidence review). Tricyclics and SNRIs can also relieve fibromyalgia symptoms. The SNRI duloxetine is FDA-approved for the treatment of diabetic neuropathy and fibromyalgia. Because patients with chronic pain often suffer from concurrent depression (144), and depression can exacerbate physical symptoms including pain (177), patients with co-occurring pain and depression are especially likely to benefit from antidepressant medication (see Recommendation 8). Nonopioid pharmacologic therapies # BOX 2. Interpretation of recommendation categories and evidence type # Recommendation Categories Based on evidence type, balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendation: Applies to all persons; most patients should receive the recommended course of action. Category B recommendation: Individual decision making needed; different choices will be appropriate for different patients. Clinicians help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. # Evidence Type Based on study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, doseresponse gradient, and constellation of plausible biases that could change effects. Type 1 evidence: Randomized clinical trials or overwhelming evidence from observational studies. Type 2 evidence: Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies. Type 3 evidence: Observational studies or randomized clinical trials with notable limitations. Type 4 evidence: Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations. are not generally associated with substance use disorder, and the numbers of fatal overdoses associated with nonopioid medications are a fraction of those associated with opioid medications (contextual evidence review). For example, acetaminophen, NSAIDs, and opioid pain medication were involved in 881, 228, and 16,651 pharmaceutical overdose deaths in the United States in 2010 (178). However, nonopioid pharmacologic therapies are associated with certain risks, particularly in older patients, pregnant patients, and patients with certain co-morbidities such as cardiovascular, renal, gastrointestinal, and liver disease (see contextual evidence review). For example, acetaminophen can be hepatotoxic at dosages of >3-4 grams/day and at lower dosages in patients with chronic alcohol use or liver disease (109). NSAID use has been associated with gastritis, peptic ulcer disease, cardiovascular events (111,112), and fluid retention, and most NSAIDs (choline magnesium trilisate and selective COX-2 inhibitors are exceptions) interfere with platelet aggregation (179). Clinicians should review FDA-approved labeling including boxed warnings before initiating treatment with any pharmacologic therapy. Although opioids can reduce pain during short-term use, the clinical evidence review found insufficient evidence to determine whether pain relief is sustained and whether function or quality of life improves with long-term opioid therapy (KQ1). While benefits for pain relief, function, and quality of life with long-term opioid use for chronic pain are uncertain, risks associated with long-term opioid use are clearer and significant. Based on the clinical evidence review, long-term opioid use for chronic pain is associated with serious risks including increased risk for opioid use disorder, overdose, myocardial infarction, and motor vehicle injury (KQ2). At a population level, more than 165,000 persons in the United States have died from opioid pain-medication-related overdoses since 1999 (see Contextual Evidence Review). Integrated pain management requires coordination of medical, psychological, and social aspects of health care and includes primary care, mental health care, and specialist services when needed (180). Nonpharmacologic physical and psychological treatments such as exercise and CBT are approaches that encourage active patient participation in the care plan, address the effects of pain in the patient's life, and can result in sustained improvements in pain and function without apparent risks. Despite this, these therapies are not always or fully covered by insurance, and access and cost can be barriers for patients. For many patients, aspects of these approaches can be used even when there is limited access to specialty care. For example, previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip (176) and maintenance of activity for patients with low back pain (110). A randomized trial found no difference in reduced chronic low back pain intensity, frequency or disability between patients assigned to relatively low-cost group aerobics and individual physiotherapy or muscle reconditioning sessions (181). Low-cost options to integrate exercise include brisk walking in public spaces or use of public recreation facilities for group exercise. CBT addresses psychosocial contributors to pain and improves function (97). Primary care clinicians can integrate elements of a cognitive behavioral approach into their practice by encouraging patients to take an active role in the care plan, by supporting patients in engaging in beneficial but potentially anxiety-provoking activities, such as exercise (179), or by providing education in relaxation techniques and coping strategies. In many locations, there are free or low-cost patient support, self-help, and educational community-based programs that can provide stress reduction and other mental health benefits. Patients with more entrenched anxiety or fear related to pain, or other significant psychological distress, can be referred for formal therapy with a mental health specialist (e.g., psychologist, psychiatrist, clinical social worker). Multimodal therapies should be considered for patients not responding to single-modality therapy, and combinations should be tailored depending on patient needs, cost, and convenience. To guide patient-specific selection of therapy, clinicians should evaluate patients and establish or confirm the diagnosis. Detailed recommendations on diagnosis are provided in other guidelines (110,179), but evaluation should generally include a focused history, including history and characteristics of pain and potentially contributing factors (e.g., function, psychosocial stressors, sleep) and physical exam, with imaging or other diagnostic testing only if indicated (e.g., if severe or progressive neurologic deficits are present or if serious underlying conditions are suspected) (110,179). For complex pain syndromes, pain specialty consultation can be considered to assist with diagnosis as well as management. Diagnosis can help identify disease-specific interventions to reverse or ameliorate pain; for example, improving glucose control to prevent progression of diabetic neuropathy; immune-modulating agents for rheumatoid arthritis; physical or occupational therapy to address posture, muscle weakness, or repetitive occupational motions that contribute to musculoskeletal pain; or surgical intervention to relieve mechanical/compressive pain (179). The underlying mechanism for most pain syndromes can be categorized as neuropathic (e.g., diabetic neuropathy, postherpetic neuralgia, fibromyalgia), or nociceptive (e.g., osteoarthritis, muscular back pain). The diagnosis and pathophysiologic mechanism of pain have implications for symptomatic pain treatment with medication. For example, evidence is limited or insufficient for improved pain or function with long-term use of opioids for several chronic pain conditions for which opioids are commonly prescribed, such as low back pain (182), headache (183), and fibromyalgia (184). Although NSAIDs can be used for exacerbations of nociceptive pain, other medications (e.g., tricyclics, selected anticonvulsants, or transdermal lidocaine) generally are recommended for neuropathic pain. In addition, improvement of neuropathic pain can begin weeks or longer after symptomatic treatment is initiated (179). Medications should be used only after assessment and determination that expected benefits outweigh risks given patient-specific factors. For example, clinicians should consider falls risk when selecting and dosing potentially sedating medications such as tricyclics, anticonvulsants, or opioids, and should weigh risks and benefits of use, dose, and duration of NSAIDs when treating older adults as well as patients with hypertension, renal insufficiency, or heart failure, or those with risk for peptic ulcer disease or cardiovascular disease. Some guidelines recommend topical NSAIDs for localized osteoarthritis (e.g., knee osteoarthritis) over oral NSAIDs in patients aged ≥75 years to minimize systemic effects (176). Experts agreed that opioids should not be considered firstline or routine therapy for chronic pain (i.e., pain continuing or expected to continue >3 months or past the time of normal tissue healing) outside of active cancer, palliative, and endof-life care, given small to moderate short-term benefits, uncertain long-term benefits, and potential for serious harms; although evidence on long-term benefits of nonopioid therapies is also limited, these therapies are also associated with short-term benefits, and risks are much lower. This does not mean that patients should be required to sequentially "fail" nonpharmacologic and nonopioid pharmacologic therapy before proceeding to opioid therapy. Rather, expected benefits specific to the clinical context should be weighed against risks before initiating therapy. In some clinical contexts (e.g., headache or fibromyalgia), expected benefits of initiating opioids are unlikely to outweigh risks regardless of previous nonpharmacologic and nonopioid pharmacologic therapies used. In other situations (e.g., serious illness in a patient with poor prognosis for return to previous level of function, contraindications to other therapies, and clinician and patient agreement that the overriding goal is patient comfort), opioids might be appropriate regardless of previous therapies used. In addition, when opioid pain medication is used, it is more likely to be effective if integrated with nonpharmacologic therapy. Nonpharmacologic approaches such as exercise and CBT should be used to reduce pain and improve function in patients with chronic pain. Nonopioid pharmacologic therapy should be used when benefits outweigh risks and should be combined with nonpharmacologic therapy to reduce pain and improve function. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate, to provide greater benefits to patients in improving pain and function. # Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety (recommendation category: A, evidence type: 4). The clinical evidence review found insufficient evidence to determine long-term benefits of opioid therapy for chronic pain and found an increased risk for serious harms related to long-term opioid therapy that appears to be dose-dependent. In addition, studies on currently available risk assessment instruments were sparse and showed inconsistent results (KQ4). The clinical evidence review for the current guideline considered studies with outcomes examined at ≥1 year that compared opioid use versus nonuse or placebo. Studies of opioid therapy for chronic pain that did not have a nonopioid control group have found that although many patients discontinue opioid therapy for chronic noncancer pain due to adverse effects or insufficient pain relief, there is weak evidence that patients who are able to continue opioid therapy for at least 6 months can experience clinically significant pain relief and insufficient evidence that function or quality of life improves (185). These findings suggest that it is very difficult for clinicians to predict whether benefits of opioids for chronic pain will outweigh risks of ongoing treatment for individual patients. Opioid therapy should not be initiated without consideration of an "exit strategy" to be used if the therapy is unsuccessful. Experts agreed that before opioid therapy is initiated for chronic pain outside of active cancer, palliative, and end-oflife care, clinicians should determine how effectiveness will be evaluated and should establish treatment goals with patients. Because the line between acute pain and initial chronic pain is not always clear, it might be difficult for clinicians to determine when they are initiating opioids for chronic pain rather than treating acute pain. Pain lasting longer than 3 months or past the time of normal tissue healing (which could be substantially shorter than 3 months, depending on the condition) is generally no longer considered acute. However, establishing treatment goals with a patient who has already received opioid therapy for 3 months would defer this discussion well past the point of initiation of opioid therapy for chronic pain. Clinicians often write prescriptions for long-term use in 30-day increments, and opioid prescriptions written for ≥30 days are likely to represent initiation or continuation of long-term opioid therapy. Before writing an opioid prescription for ≥30 days, clinicians should establish treatment goals with patients. Clinicians seeing new patients already receiving opioids should establish treatment goals for continued opioid therapy. Although the clinical evidence review did not find studies evaluating the effectiveness of written agreements or treatment plans (KQ4), clinicians and patients who set a plan in advance will clarify expectations regarding how opioids will be prescribed and monitored, as well as situations in which opioids will be discontinued or doses tapered (e.g., if treatment goals are not met, opioids are no longer needed, or adverse events put the patient at risk) to improve patient safety. Experts thought that goals should include improvement in both pain relief and function (and therefore in quality of life). However, there are some clinical circumstances under which reductions in pain without improvement in physical function might be a more realistic goal (e.g., diseases typically associated with progressive functional impairment or catastrophic injuries such as spinal cord trauma). Experts noted that function can include emotional and social as well as physical dimensions. In addition, experts emphasized that mood has important interactions with pain and function. Experts agreed that clinicians may use validated instruments such as the threeitem "Pain average, interference with Enjoyment of life, and interference with General activity" (PEG) Assessment Scale (186) to track patient outcomes. Clinically meaningful improvement has been defined as a 30% improvement in scores for both pain and function (187). Monitoring progress toward patient-centered functional goals (e.g., walking the dog or walking around the block, returning to part-time work, attending family sports or recreational activities) can also contribute to the assessment of functional improvement. Clinicians should use these goals in assessing benefits of opioid therapy for individual patients and in weighing benefits against risks of continued opioid therapy (see Recommendation 7, including recommended intervals for follow-up). Because depression, anxiety, and other psychological co-morbidities often coexist with and can interfere with resolution of pain, clinicians should use validated instruments to assess for these conditions (see Recommendation 8) and ensure that treatment for these conditions is optimized. If patients receiving opioid therapy for chronic pain do not experience meaningful improvements in both pain and function compared with prior to initiation of opioid therapy, clinicians should consider working with patients to taper and discontinue opioids (see Recommendation 7) and should use nonpharmacologic and nonopioid pharmacologic approaches to pain management (see Recommendation 1). # Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy (recommendation category: A, evidence type: 3). The clinical evidence review did not find studies evaluating effectiveness of patient education or opioid treatment plans as risk-mitigation strategies (KQ4). However, the contextual evidence review found that many patients lack information about opioids and identified concerns that some clinicians miss opportunities to effectively communicate about safety. Given the substantial evidence gaps on opioids, uncertain benefits of long-term use, and potential for serious harms, patient education and discussion before starting opioid therapy are critical so that patient preferences and values can be understood and used to inform clinical decisions. Experts agreed that essential elements to communicate to patients before starting and periodically during opioid therapy include realistic expected benefits, common and serious harms, and expectations for clinician and patient responsibilities to mitigate risks of opioid therapy. Clinicians should involve patients in decisions about whether to start or continue opioid therapy. Given potentially serious risks of long-term opioid therapy, clinicians should ensure that patients are aware of potential benefits of, harms of, and alternatives to opioids before starting or continuing opioid therapy. Clinicians are encouraged to have open and honest discussions with patients to inform mutual decisions about whether to start or continue opioid therapy. Important considerations include the following: - Be explicit and realistic about expected benefits of opioids, explaining that while opioids can reduce pain during shortterm use, there is no good evidence that opioids improve pain or function with long-term use, and that complete relief of pain is unlikely (clinical evidence review, KQ1). - Emphasize improvement in function as a primary goal and that function can improve even when pain is still present. - Advise patients about serious adverse effects of opioids, including potentially fatal respiratory depression and development of a potentially serious lifelong opioid use disorder that can cause distress and inability to fulfill major role obligations. - Advise patients about common effects of opioids, such as constipation, dry mouth, nausea, vomiting, drowsiness, confusion, tolerance, physical dependence, and withdrawal symptoms when stopping opioids. To prevent constipation associated with opioid use, advise patients to increase hydration and fiber intake and to maintain or increase physical activity. Stool softeners or laxatives might be needed. - Discuss effects that opioids might have on ability to safely operate a vehicle, particularly when opioids are initiated, when dosages are increased, or when other central nervous system depressants, such as benzodiazepines or alcohol, are used concurrently. - Discuss increased risks for opioid use disorder, respiratory depression, and death at higher dosages, along with the importance of taking only the amount of opioids prescribed, i.e., not taking more opioids or taking them more often. - Review increased risks for respiratory depression when opioids are taken with benzodiazepines, other sedatives, alcohol, illicit drugs such as heroin, or other opioids. - Discuss risks to household members and other individuals if opioids are intentionally or unintentionally shared with others for whom they are not prescribed, including the possibility that others might experience overdose at the same or at lower dosage than prescribed for the patient, and that young children are susceptible to unintentional ingestion. Discuss storage of opioids in a secure, preferably locked location and options for safe disposal of unused opioids (188). - Discuss the importance of periodic reassessment to ensure that opioids are helping to meet patient goals and to allow opportunities for opioid discontinuation and consideration of additional nonpharmacologic or nonopioid pharmacologic treatment options if opioids are not effective or are harmful. - Discuss planned use of precautions to reduce risks, including use of prescription drug monitoring program information (see Recommendation 9) and urine drug testing (see Recommendation 10). Consider including discussion of naloxone use for overdose reversal (see Recommendation 8). - Consider whether cognitive limitations might interfere with management of opioid therapy (for older adults in particular) and, if so, determine whether a caregiver can responsibly co-manage medication therapy. Discuss the importance of reassessing safer medication use with both the patient and caregiver. Given the possibility that benefits of opioid therapy might diminish or that risks might become more prominent over time, it is important that clinicians review expected benefits and risks of continued opioid therapy with patients periodically, at least every 3 months (see Recommendation 7). # Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation # When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4). ER/LA opioids include methadone, transdermal fentanyl, and extended-release versions of opioids such as oxycodone, oxymorphone, hydrocodone, and morphine. The clinical evidence review found a fair-quality study showing a higher risk for overdose among patients initiating treatment with ER/LA opioids than among those initiating treatment with immediate-release opioids (77). The clinical evidence review did not find evidence that continuous, time-scheduled use of ER/LA opioids is more effective or safer than intermittent use of immediate-release opioids or that time-scheduled use of ER/ LA opioids reduces risks for opioid misuse or addiction (KQ3). In 2014, the FDA modified the labeling for ER/LA opioid pain medications, noting serious risks and recommending that ER/LA opioids be reserved for "management of pain severe enough to require daily, around-the-clock, long-term opioid treatment" when "alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain" and not used as "as needed" pain relievers (121). FDA has also noted that some ER/LA opioids are only appropriate for opioid-tolerant patients, defined as patients who have received certain dosages of opioids (e.g., 60 mg daily of oral morphine, 30 mg daily of oral oxycodone, or equianalgesic dosages of other opioids) for at least 1 week (189). Time-scheduled opioid use can be associated with greater total average daily opioid dosage compared with intermittent, as-needed opioid use (contextual evidence review). In addition, experts indicated that there was not enough evidence to determine the safety of using immediate-release opioids for breakthrough pain when ER/ LA opioids are used for chronic pain outside of active cancer pain, palliative care, or end-of-life care, and that this practice might be associated with dose escalation. Abuse-deterrent technologies have been employed to prevent manipulation intended to defeat extended-release properties of ER/LA opioids and to prevent opioid use by unintended routes of administration, such as injection of oral opioids. As indicated in FDA guidance for industry on evaluation and labeling of abuse-deterrent opioids (190), although abusedeterrent technologies are expected to make manipulation of opioids more difficult or less rewarding, they do not prevent opioid abuse through oral intake, the most common route of opioid abuse, and can still be abused by nonoral routes. The "abuse-deterrent" label does not indicate that there is no risk for abuse. No studies were found in the clinical evidence review assessing the effectiveness of abuse-deterrent technologies as a risk mitigation strategy for deterring or preventing abuse. In addition, abuse-deterrent technologies do not prevent unintentional overdose through oral intake. Experts agreed that recommendations could not be offered at this time related to use of abuse-deterrent formulations. In comparing different ER/LA formulations, the clinical evidence review found inconsistent results for overdose risk with methadone versus other ER/LA opioids used for chronic pain (KQ3). The contextual evidence review found that methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for chronic pain. In addition, methadone is associated with cardiac arrhythmias along with QT prolongation on the electrocardiogram, and it has complicated pharmacokinetics and pharmacodynamics, including a long and variable halflife and peak respiratory depressant effect occurring later and lasting longer than peak analgesic effect. Experts noted that the pharmacodynamics of methadone are subject to more interindividual variability than other opioids. In regard to other ER/ LA opioid formulations, experts noted that the absorption and pharmacodynamics of transdermal fentanyl are complex, with gradually increasing serum concentration during the first part of the 72-hour dosing interval, as well as variable absorption based on factors such as external heat. In addition, the dosing of transdermal fentanyl in mcg/hour, which is not typical for a drug used by outpatients, can be confusing. Experts thought that these complexities might increase the risk for fatal overdose when methadone or transdermal fentanyl is prescribed to a patient who has not used it previously or by clinicians who are not familiar with its effects. Experts agreed that for patients not already receiving opioids, clinicians should not initiate opioid treatment with ER/LA opioids and should not prescribe ER/LA opioids for intermittent use. ER/LA opioids should be reserved for severe, continuous pain and should be considered only for patients who have received immediate-release opioids daily for at least 1 week. When changing to an ER/LA opioid for a patient previously receiving a different immediate-release opioid, clinicians should consult product labeling and reduce total daily dosage to account for incomplete opioid cross-tolerance. Clinicians should use additional caution with ER/LA opioids and consider a longer dosing interval when prescribing to patients with renal or hepatic dysfunction because decreased clearance of drugs among these patients can lead to accumulation of drugs to toxic levels and persistence in the body for longer durations. Although there might be situations in which clinicians need to prescribe immediate-release and ER/LA opioids together (e.g., transitioning patients from ER/LA opioids to immediate-release opioids by temporarily using lower dosages of both), in general, avoiding the use of immediate-release opioids in combination with ER/LA opioids is preferable, given potentially increased risk and diminishing returns of such an approach for chronic pain. When an ER/LA opioid is prescribed, using one with predictable pharmacokinetics and pharmacodynamics is preferred to minimize unintentional overdose risk. In particular, unusual characteristics of methadone and of transdermal fentanyl make safe prescribing of these medications for pain especially challenging. - Methadone should not be the first choice for an ER/LA opioid. Only clinicians who are familiar with methadone's unique risk profile and who are prepared to educate and closely monitor their patients, including risk assessment f o r QT p ro l o n g a t i o n a n d c o n s i d e r a t i o n o f electrocardiographic monitoring, should consider prescribing methadone for pain. A clinical practice guideline that contains further guidance regarding methadone prescribing for pain has been published previously (191). - Because dosing effects of transdermal fentanyl are often misunderstood by both clinicians and patients, only clinicians who are familiar with the dosing and absorption properties of transdermal fentanyl and are prepared to educate their patients about its use should consider prescribing it. # When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (recommendation category: A, evidence type: 3). Benefits of high-dose opioids for chronic pain are not established. The clinical evidence review found only one study (84) addressing effectiveness of dose titration for outcomes related to pain control, function, and quality of life (KQ3). This randomized trial found no difference in pain or function between a more liberal opioid dose escalation strategy and maintenance of current dosage. (These groups were prescribed average dosages of 52 and 40 MME/day, respectively, at the end of the trial.) At the same time, risks for serious harms US Department of Health and Human Services/Centers for Disease Control and Prevention related to opioid therapy increase at higher opioid dosage. The clinical evidence review found that higher opioid dosages are associated with increased risks for motor vehicle injury, opioid use disorder, and overdose (KQ2). The clinical and contextual evidence reviews found that opioid overdose risk increases in a dose-response manner, that dosages of 50-<100 MME/day have been found to increase risks for opioid overdose by factors of 1.9 to 4.6 compared with dosages of 1-<20 MME/day, and that dosages ≥100 MME/day are associated with increased risks of overdose 2.0-8.9 times the risk at 1-<20 MME/day. In a national sample of Veterans Health Administration patients with chronic pain who were prescribed opioids, mean prescribed opioid dosage among patients who died from opioid overdose was 98 MME (median 60 MME) compared with mean prescribed opioid dosage of 48 MME (median 25 MME) among patients not experiencing fatal overdose (127). The contextual evidence review found that although there is not a single dosage threshold below which overdose risk is eliminated, holding dosages <50 MME/day would likely reduce risk among a large proportion of patients who would experience fatal overdose at higher prescribed dosages. Experts agreed that lower dosages of opioids reduce the risk for overdose, but that a single dosage threshold for safe opioid use could not be identified. Experts noted that daily opioid dosages close to or greater than 100 MME/day are associated with significant risks, that dosages <50 MME/day are safer than dosages of 50-100 MME/day, and that dosages <20 MME/day are safer than dosages of 20-50 MME/day. One expert thought that a specific dosage at which the benefit/risk ratio of opioid therapy decreases could not be identified. Most experts agreed that, in general, increasing dosages to 50 or more MME/day increases overdose risk without necessarily adding benefits for pain control or function and that clinicians should carefully reassess evidence of individual benefits and risks when considering increasing opioid dosages to ≥50 MME/day. Most experts also agreed that opioid dosages should not be increased to ≥90 MME/day without careful justification based on diagnosis and on individualized assessment of benefits and risks. When opioids are used for chronic pain outside of active cancer, palliative, and end-of-life care, clinicians should start opioids at the lowest possible effective dosage (the lowest starting dosage on product labeling for patients not already taking opioids and according to product labeling guidance regarding tolerance for patients already taking opioids). Clinicians should use additional caution when initiating opioids for patients aged ≥65 years and for patients with renal or hepatic insufficiency because decreased clearance of drugs in these patients can result in accumulation of drugs to toxic levels. Clinicians should use caution when increasing opioid dosages and increase dosage by the smallest practical amount because overdose risk increases with increases in opioid dosage. Although there is limited evidence to recommend specific intervals for dosage titration, a previous guideline recommended waiting at least five half-lives before increasing dosage and waiting at least a week before increasing dosage of methadone to make sure that full effects of the previous dosage are evident (31). Clinicians should re-evaluate patients after increasing dosage for changes in pain, function, and risk for harm (see Recommendation 7). Before increasing total opioid dosage to ≥50 MME/day, clinicians should reassess whether opioid treatment is meeting the patient's treatment goals (see Recommendation 2). If a patient's opioid dosage for all sources of opioids combined reaches or exceeds 50 MME/day, clinicians should implement additional precautions, including increased frequency of follow-up (see Recommendation 7) and considering offering naloxone and overdose prevention education to both patients and the patients' household members (see Recommendation 8). Clinicians should avoid increasing opioid dosages to ≥90 MME/day or should carefully justify a decision to increase dosage to ≥90 MME/day based on individualized assessment of benefits and risks and weighing factors such as diagnosis, incremental benefits for pain and function relative to harms as dosages approach 90 MME/day, other treatments and effectiveness, and recommendations based on consultation with pain specialists. If patients do not experience improvement in pain and function at ≥90 MME/day, or if there are escalating dosage requirements, clinicians should discuss other approaches to pain management with the patient, consider working with patients to taper opioids to a lower dosage or to taper and discontinue opioids (see Recommendation 7), and consider consulting a pain specialist. Some states require clinicians to implement clinical protocols at specific dosage levels. For example, before increasing long-term opioid therapy dosage to >120 MME/day, clinicians in Washington state must obtain consultation from a pain specialist who agrees that this is indicated and appropriate (30). Clinicians should be aware of rules related to MME thresholds and associated clinical protocols established by their states. Established patients already taking high dosages of opioids, as well as patients transferring from other clinicians, might consider the possibility of opioid dosage reduction to be anxiety-provoking, and tapering opioids can be especially challenging after years on high dosages because of physical and psychological dependence. However, these patients should be offered the opportunity to re-evaluate their continued use of opioids at high dosages in light of recent evidence regarding the association of opioid dosage and overdose risk. Clinicians should explain in a nonjudgmental manner to patients already taking high opioid dosages (≥90 MME/day) that there is now an established body of scientific evidence showing that overdose risk is increased at higher opioid dosages. Clinicians should empathically review benefits and risks of continued high-dosage opioid therapy and should offer to work with the patient to taper opioids to safer dosages. For patients who agree to taper opioids to lower dosages, clinicians should collaborate with the patient on a tapering plan (see Recommendation 7). Experts noted that patients tapering opioids after taking them for years might require very slow opioid tapers as well as pauses in the taper to allow gradual accommodation to lower opioid dosages. Clinicians should remain alert to signs of anxiety, depression, and opioid use disorder (see Recommendations 8 and 12) that might be unmasked by an opioid taper and arrange for management of these co-morbidities. For patients agreeing to taper to lower opioid dosages as well as for those remaining on high opioid dosages, clinicians should establish goals with the patient for continued opioid therapy (see Recommendation 2), maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 1), and consider consulting a pain specialist as needed to assist with pain management. # Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed (recommendation category: A, evidence type: 4). The clinical evidence review found that opioid use for acute pain (i.e., pain with abrupt onset and caused by an injury or other process that is not ongoing) is associated with long-term opioid use, and that a greater amount of early opioid exposure is associated with greater risk for long-term use (KQ5). Several guidelines on opioid prescribing for acute pain from emergency departments (192)(193)(194) and other settings (195,196) have recommended prescribing ≤3 days of opioids in most cases, whereas others have recommended ≤7 days (197) or <14 days (30). Because physical dependence on opioids is an expected physiologic response in patients exposed to opioids for more than a few days (contextual evidence review), limiting days of opioids prescribed also should minimize the need to taper opioids to prevent distressing or unpleasant withdrawal symptoms. Experts noted that more than a few days of exposure to opioids significantly increases hazards, that each day of unnecessary opioid use increases likelihood of physical dependence without adding benefit, and that prescriptions with fewer days' supply will minimize the number of pills available for unintentional or intentional diversion. Experts agreed that when opioids are needed for acute pain, clinicians should prescribe opioids at the lowest effective dose and for no longer than the expected duration of pain severe enough to require opioids to minimize unintentional initiation of long-term opioid use. The lowest effective dose can be determined using product labeling as a starting point with calibration as needed based on the severity of pain and on other clinical factors such as renal or hepatic insufficiency (see Recommendation 8). Experts thought, based on clinical experience regarding anticipated duration of pain severe enough to require an opioid, that in most cases of acute pain not related to surgery or trauma, a ≤3 days' supply of opioids will be sufficient. For example, in one study of the course of acute low back pain (not associated with malignancies, infections, spondylarthropathies, fractures, or neurological signs) in a primary care setting, there was a large decrease in pain until the fourth day after treatment with paracetamol, with smaller decreases thereafter (198). Some experts thought that because some types of acute pain might require more than 3 days of opioid treatment, it would be appropriate to recommend a range of ≤3-5 days or ≤3-7 days when opioids are needed. Some experts thought that a range including 7 days was too long given the expected course of severe acute pain for most acute pain syndromes seen in primary care. Acute pain can often be managed without opioids. It is important to evaluate the patient for reversible causes of pain, for underlying etiologies with potentially serious sequelae, and to determine appropriate treatment. When the diagnosis and severity of nontraumatic, nonsurgical acute pain are reasonably assumed to warrant the use of opioids, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids, often 3 days or less, unless circumstances clearly warrant additional opioid therapy. More than 7 days will rarely be needed. Opioid treatment for post-surgical pain is outside the scope of this guideline but has been addressed elsewhere (30). Clinicians should not prescribe additional opioids to patients "just in case" pain continues longer than expected. Clinicians should re-evaluate the subset of patients who experience severe acute pain that continues longer than the expected duration to confirm or revise the initial diagnosis and to adjust management accordingly. Given longer half-lives and longer duration of effects (e.g., respiratory depression) with ER/LA opioids such as methadone, fentanyl patches, or extended release versions of opioids such as oxycodone, oxymorphone, or morphine, clinicians should not prescribe ER/LA opioids for the treatment of acute pain. : 4). Although the clinical evidence review did not find studies evaluating the effectiveness of more frequent monitoring intervals (KQ4), it did find that continuing opioid therapy for 3 months substantially increases risk for opioid use disorder (KQ2); therefore, follow-up earlier than 3 months might be necessary to provide the greatest opportunity to prevent the development of opioid use disorder. In addition, risk for overdose associated with ER/LA opioids might be particularly high during the first 2 weeks of treatment (KQ3). The contextual evidence review found that patients who do not have pain relief with opioids at 1 month are unlikely to experience pain relief with opioids at 6 months. Although evidence is insufficient to determine at what point within the first 3 months of opioid therapy the risks for opioid use disorder increase, reassessment of pain and function within 1 month of initiating opioids provides an opportunity to minimize risks of long-term opioid use by discontinuing opioids among patients not receiving a clear benefit from these medications. Experts noted that risks for opioid overdose are greatest during the first 3-7 days after opioid initiation or increase in dosage, particularly when methadone or transdermal fentanyl are prescribed; that follow-up within 3 days is appropriate when initiating or increasing the dosage of methadone; and that follow-up within 1 week might be appropriate when initiating or increasing the dosage of other ER/LA opioids. Clinicians should evaluate patients to assess benefits and harms of opioids within 1 to 4 weeks of starting long-term opioid therapy or of dose escalation. Clinicians should consider follow-up intervals within the lower end of this range when ER/LA opioids are started or increased or when total daily opioid dosage is ≥50 MME/day. Shorter follow-up intervals (within 3 days) should be strongly considered when starting or increasing the dosage of methadone. At follow up, clinicians should assess benefits in function, pain control, and quality of life using tools such as the three-item "Pain average, interference with Enjoyment of life, and interference with General activity" (PEG) Assessment Scale (186) and/or asking patients about progress toward functional goals that have meaning for them (see Recommendation 2). Clinicians should also ask patients about common adverse effects such as constipation and drowsiness (see Recommendation 3), as well as asking about and assessing for effects that might be early warning signs for more serious problems such as overdose (e.g., sedation or slurred speech) or opioid use disorder (e.g., craving, wanting to take opioids in greater quantities or more frequently than prescribed, or difficulty controlling use). Clinicians should ask patients about their preferences for continuing opioids, given their effects on pain and function relative to any adverse effects experienced. Because of potential changes in the balance of benefits and risks of opioid therapy over time, clinicians should regularly reassess all patients receiving long-term opioid therapy, including patients who are new to the clinician but on longterm opioid therapy, at least every 3 months. At reassessment, clinicians should determine whether opioids continue to meet treatment goals, including sustained improvement in pain and function, whether the patient has experienced common or serious adverse events or early warning signs of serious adverse events, signs of opioid use disorder (e.g., difficulty controlling use, work or family problems related to opioid use), whether benefits of opioids continue to outweigh risks, and whether opioid dosage can be reduced or opioids can be discontinued. Ideally, these reassessments would take place in person and be conducted by the prescribing clinician. In practice contexts where virtual visits are part of standard care (e.g., in remote areas where distance or other issues make follow-up visits challenging), follow-up assessments that allow the clinician to communicate with and observe the patient through video and audio could be conducted, with in-person visits occurring at least once per year. Clinicians should re-evaluate patients who are exposed to greater risk of opioid use disorder or overdose (e.g., patients with depression or other mental health conditions, a history of substance use disorder, a history of overdose, taking ≥50 MME/day, or taking other central nervous system depressants with opioids) more frequently than every 3 months. If clinically meaningful improvements in pain and function are not sustained, if patients are taking high-risk regimens (e.g., dosages ≥50 MME/day or opioids combined with benzodiazepines) without evidence of benefit, if patients believe benefits no longer outweigh risks or if they request dosage reduction or discontinuation, or if patients experience overdose or other serious adverse events (e.g., an event leading to hospitalization or disability) or warning signs of serious adverse events, clinicians should work with patients to reduce opioid dosage or to discontinue opioids when possible. Clinicians should maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to assist with pain management. # Considerations for Tapering Opioids Although the clinical evidence review did not find highquality studies comparing the effectiveness of different tapering protocols for use when opioid dosage is reduced or opioids are discontinued (KQ3), tapers reducing weekly dosage by 10%-50% of the original dosage have been recommended by other clinical guidelines (199), and a rapid taper over 2-3 weeks has been recommended in the case of a severe adverse event such as overdose (30). Experts noted that tapers slower than 10% per week (e.g., 10% per month) also might be appropriate and better tolerated than more rapid tapers, particularly when patients have been taking opioids for longer durations (e.g., for years). Opioid withdrawal during pregnancy has been associated with spontaneous abortion and premature labor. When opioids are reduced or discontinued, a taper slow enough to minimize symptoms and signs of opioid withdrawal (e.g., drug craving, anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, or piloerection) should be used. A decrease of 10% of the original dose per week is a reasonable starting point; experts agreed that tapering plans may be individualized based on patient goals and concerns. Experts noted that at times, tapers might have to be paused and restarted again when the patient is ready and might have to be slowed once patients reach low dosages. Tapers may be considered successful as long as the patient is making progress. Once the smallest available dose is reached, the interval between doses can be extended. Opioids may be stopped when taken less frequently than once a day. More rapid tapers might be needed for patient safety under certain circumstances (e.g., for patients who have experienced overdose on their current dosage). Ultrarapid detoxification under anesthesia is associated with substantial risks, including death, and should not be used (200). Clinicians should access appropriate expertise if considering tapering opioids during pregnancy because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal. Patients who are not taking opioids (including patients who are diverting all opioids they obtain) do not require tapers. Clinicians should discuss with patients undergoing tapering the increased risk for overdose on abrupt return to a previously prescribed higher dose. Primary care clinicians should collaborate with mental health providers and with other specialists as needed to optimize nonopioid pain management (see Recommendation 1), as well as psychosocial support for anxiety related to the taper. More detailed guidance on tapering, including management of withdrawal symptoms has been published previously (30,201). If a patient exhibits signs of opioid use disorder, clinicians should offer or arrange for treatment of opioid use disorder (see Recommendation 12) and consider offering naloxone for overdose prevention (see Recommendation 8). # Assessing Risk and Addressing Harms of Opioid Use # Before starting and periodically during continuation -f opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present (recommendation category: A, evidence type: 4). The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on patient demographics or patient comorbidities (KQ2). However, based on the contextual evidence review and expert opinion, certain risk factors are likely to increase susceptibility to opioidassociated harms and warrant incorporation of additional strategies into the management plan to mitigate risk. Clinicians should assess these risk factors periodically, with frequency varying by risk factor and patient characteristics. For example, factors that vary more frequently over time, such as alcohol use, require more frequent follow up. In addition, clinicians should consider offering naloxone, re-evaluating patients more frequently (see Recommendation 7), and referring to pain and/or behavioral health specialists when factors that increase risk for harm, such as history of overdose, history of substance use disorder, higher dosages of opioids (≥50 MME/day), and concurrent use of benzodiazepines with opioids, are present. # Patients with Sleep-Disordered Breathing, Including Sleep Apnea Risk factors for sleep-disordered breathing include congestive heart failure, and obesity. Experts noted that careful monitoring and cautious dose titration should be used if opioids are prescribed for patients with mild sleep-disordered breathing. Clinicians should avoid prescribing opioids to patients with moderate or severe sleep-disordered breathing whenever possible to minimize risks for opioid overdose (contextual evidence review). # Pregnant Women Opioids used in pregnancy might be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with stillbirth, poor fetal growth, pre-term delivery, and birth defects (contextual evidence review). Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal syndrome. Clinicians and patients together should carefully weigh risks and benefits when making decisions about whether to initiate opioid therapy for chronic pain during pregnancy. In addition, before initiating opioid therapy for chronic pain for reproductive-age women, clinicians should discuss family planning and how long-term opioid use might affect any future pregnancy. For pregnant women already receiving opioids, clinicians should access appropriate expertise if considering tapering opioids because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal (see Recommendation 7). For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine or methadone has been associated with improved maternal outcomes and should be offered (202) (see Recommendation 12). Clinicians caring for pregnant women receiving opioids for pain or receiving buprenorphine or methadone for opioid use disorder should arrange for delivery at a facility prepared to monitor, evaluate for, and treat neonatal opioid withdrawal syndrome. In instances when travel to such a facility would present an undue burden on the pregnant woman, it is appropriate to deliver locally, monitor and evaluate the newborn for neonatal opioid withdrawal syndrome, and transfer the newborn for additional treatment if needed. Neonatal toxicity and death have been reported in breastfeeding infants whose mothers are taking codeine (contextual evidence review); previous guidelines have recommended that codeine be avoided whenever possible among mothers who are breast feeding and, if used, should be limited to the lowest possible dose and to a 4-day supply (203). # Patients with Renal or Hepatic Insufficiency Clinicians should use additional caution and increased monitoring (see Recommendation 7) to minimize risks of opioids prescribed for patients with renal or hepatic insufficiency, given their decreased ability to process and excrete drugs, susceptibility to accumulation of opioids, and reduced therapeutic window between safe dosages and dosages associated with respiratory depression and overdose (contextual evidence review; see Recommendations 4, 5, and 7). # Patients Aged ≥65 Years Inadequate pain treatment among persons aged ≥65 years has been documented (204). Pain management for older patients can be challenging given increased risks of both nonopioid pharmacologic therapies (see Recommendation 1) and opioid therapy in this population. Given reduced renal function and medication clearance even in the absence of renal disease, patients aged ≥65 years might have increased susceptibility to accumulation of opioids and a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose (contextual evidence review). Some older adults suffer from cognitive impairment, which can increase risk for medication errors and make opioid-related confusion more dangerous. In addition, older adults are more likely than younger adults to experience co-morbid medical conditions and more likely to receive multiple medications, some of which might interact with opioids (such as benzodiazepines). Clinicians should use additional caution and increased monitoring (see Recommendations 4, 5, and 7) to minimize risks of opioids prescribed for patients aged ≥65 years. Experts suggested that clinicians educate older adults receiving opioids to avoid risky medication-related behaviors such as obtaining controlled medications from multiple prescribers and saving unused medications. Clinicians should also implement interventions to mitigate common risks of opioid therapy among older adults, such as exercise or bowel regimens to prevent constipation, risk assessment for falls, and patient monitoring for cognitive impairment. # Patients with Mental Health Conditions Because psychological distress frequently interferes with improvement of pain and function in patients with chronic pain, using validated instruments such as the Generalized Anxiety Disorder (GAD)-7 and the Patient Health Questionnaire (PHQ)-9 or the PHQ-4 to assess for anxiety, post-traumatic stress disorder, and/or depression (205), might help clinicians improve overall pain treatment outcomes. Experts noted that clinicians should use additional caution and increased monitoring (see Recommendation 7) to lessen the increased risk for opioid use disorder among patients with mental health conditions (including depression, anxiety disorders, and PTSD), as well as increased risk for drug overdose among patients with depression. Previous guidelines have noted that opioid therapy should not be initiated during acute psychiatric instability or uncontrolled suicide risk, and that clinicians should consider behavioral health specialist consultation for any patient with a history of suicide attempt or psychiatric disorder (31). In addition, patients with anxiety disorders and other mental health conditions are more likely to receive benzodiazepines, which can exacerbate opioid-induced respiratory depression and increase risk for overdose (see Recommendation 11). Clinicians should ensure that treatment for depression and other mental health conditions is optimized, consulting with behavioral health specialists when needed. Treatment for depression can improve pain symptoms as well as depression and might decrease overdose risk (contextual evidence review). For treatment of chronic pain in patients with depression, clinicians should strongly consider using tricyclic or SNRI antidepressants for analgesic as well as antidepressant effects if these medications are not otherwise contraindicated (see Recommendation 1). # Patients with Substance Use Disorder Illicit drugs and alcohol are listed as contributory factors on a substantial proportion of death certificates for opioid-related overdose deaths (contextual evidence review). Previous guidelines have recommended screening or risk assessment tools to identify patients at higher risk for misuse or abuse of opioids. However, the clinical evidence review found that currently available riskstratification tools (e.g., Opioid Risk Tool, Screener and Opioid Assessment for Patients with Pain Version 1, SOAPP-R, and Brief Risk Interview) show insufficient accuracy for classification of patients as at low or high risk for abuse or misuse (KQ4). Clinicians should always exercise caution when considering or prescribing opioids for any patient with chronic pain outside of active cancer, palliative, and end-of-life care and should not overestimate the ability of these tools to rule out risks from long-term opioid therapy. Clinicians should ask patients about their drug and alcohol use. Single screening questions can be used (206). For example, the question "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" (with an answer of one or more considered positive) was found in a primary care setting to be 100% sensitive and 73.5% specific for the detection of a drug use disorder compared with a standardized diagnostic interview (207). Validated screening tools such as the Drug Abuse Screening Test (DAST) (208) and the Alcohol Use Disorders Identification Test (AUDIT) (209) can also be used. Clinicians should use PDMP data (see Recommendation 9) and drug testing (see Recommendation 10) as appropriate to assess for concurrent substance use that might place patients at higher risk for opioid use disorder and overdose. Clinicians should also provide specific counseling on increased risks for overdose when opioids are combined with other drugs or alcohol (see Recommendation 3) and ensure that patients receive effective treatment for substance use disorders when needed (see Recommendation 12). The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on past or current substance use disorder (KQ2), although a history of substance use disorder was associated with misuse. Similarly, based on contextual evidence, patients with drug or alcohol use disorders are likely to experience greater risks for opioid use disorder and overdose than persons without these conditions. If clinicians consider opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care for patients with drug or alcohol use disorders, they should discuss increased risks for opioid use disorder and overdose with patients, carefully consider whether benefits of opioids outweigh increased risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed. Because pain management in patients with substance use disorder can be complex, clinicians should consider consulting substance use disorder specialists and pain specialists regarding pain management for persons with active or recent past history of substance abuse. Experts also noted that clinicians should communicate with patients' substance use disorder treatment providers if opioids are prescribed. # Patients with Prior Nonfatal Overdose Although studies were not identified that directly addressed the risk for overdose among patients with prior nonfatal overdose who are prescribed opioids, based on clinical experience, experts thought that prior nonfatal overdose would substantially increase risk for future nonfatal or fatal opioid overdose. If patients experience nonfatal opioid overdose, clinicians should work with them to reduce opioid dosage and to discontinue opioids when possible (see Recommendation 7). If clinicians continue opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care in patients with prior opioid overdose, they should discuss increased risks for overdose with patients, carefully consider whether benefits of opioids outweigh substantial risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed. # Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present Naloxone is an opioid antagonist that can reverse severe respiratory depression; its administration by lay persons, such as friends and family of persons who experience opioid overdose, can save lives. Naloxone precipitates acute withdrawal among patients physically dependent on opioids. Serious adverse effects, such as pulmonary edema, cardiovascular instability, and seizures, have been reported but are rare at doses consistent with labeled use for opioid overdose (210). The contextual evidence review did not find any studies on effectiveness of prescribing naloxone for overdose prevention among patients prescribed opioids for chronic pain. However, there is evidence for effectiveness of naloxone provision in preventing opioid-related overdose death at the community level through community-based distribution (e.g., through overdose education and naloxone distribution programs in community service agencies) to persons at risk for overdose (mostly due to illicit opiate use), and it is plausible that effectiveness would be observed when naloxone is provided in the clinical setting as well. Experts agreed that it is preferable not to initiate opioid treatment when factors that increase risk for opioid-related harms are present. Opinions diverged about the likelihood of naloxone being useful to patients and the circumstances under which it should be offered. However, most experts agreed that clinicians should consider offering naloxone when prescribing opioids to patients at increased risk for overdose, including patients with a history of overdose, patients with a history of substance use disorder, patients taking benzodiazepines with opioids (see Recommendation 11), patients at risk for returning to a high dose to which they are no longer tolerant (e.g., patients recently released from prison), and patients taking higher dosages of opioids (≥50 MME/day). Practices should provide education on overdose prevention and naloxone use to patients receiving naloxone prescriptions and to members of their households. Experts noted that naloxone co-prescribing can be facilitated by clinics or practices with resources to provide naloxone training and by collaborative practice models with pharmacists. Resources for prescribing naloxone in primary care settings can be found through Prescribe to Prevent at . Clinicians should review the patient's history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4). PDMPs are state-based databases that collect information on controlled prescription drugs dispensed by pharmacies in most states and, in select states, by dispensing physicians as well. In addition, some clinicians employed by the federal government, including some clinicians in the Indian Health Care Delivery System, are not licensed in the states where they practice, and do not have access to PDMP data. Certain states require clinicians to review PDMP data prior to writing each opioid prescription (see state-level PDMP-related policies on the National Alliance for Model State Drug Laws website at . cfm). The clinical evidence review did not find studies evaluating the effectiveness of PDMPs on outcomes related to overdose, addiction, abuse, or misuse (KQ4). However, even though evidence is limited on the effectiveness of PDMP implementation at the state level on prescribing and mortality outcomes (28), the contextual evidence review found that most fatal overdoses were associated with patients receiving opioids from multiple prescribers and/or with patients receiving high total daily opioid dosages; information on both of these risk factors for overdose are available to prescribers in the PDMP. PDMP data also can be helpful when patient medication history is not otherwise available (e.g., for patients from other locales) and when patients transition care to a new clinician. The contextual evidence review also found that PDMP information could be used in a way that is harmful to patients. For example, it has been used to dismiss patients from clinician practices (211), which might adversely affect patient safety. The contextual review found variation in state policies that affect timeliness of PDMP data (and therefore benefits of reviewing PDMP data) as well as time and workload for clinicians in accessing PDMP data. In states that permit delegating access to other members of the health care team, workload for prescribers can be reduced. These differences might result in a different balance of benefits to clinician workload in different states. Experts agreed that PDMPs are useful tools that should be consulted when starting a patient on opioid therapy and periodically during long-term opioid therapy. However, experts disagreed on how frequently clinicians should check the PDMP during long-term opioid therapy, given PDMP access issues and the lag time in reporting in some states. Most experts agreed that PDMP data should be reviewed every 3 months or more frequently during longterm opioid therapy. A minority of experts noted that, given the current burden of accessing PDMP data in some states and the lack of evidence surrounding the most effective interval for PDMP review to improve patient outcomes, annual review of PDMP data during long-term opioid therapy would be reasonable when factors that increase risk for opioid-related harms are not present. Clinicians should review PDMP data for opioids and other controlled medications patients might have received from additional prescribers to determine whether a patient is receiving high total opioid dosages or dangerous combinations (e.g., opioids combined with benzodiazepines) that put him or her at high risk for overdose. Ideally, PDMP data should be reviewed before every opioid prescription. This is recommended in all states with well-functioning PDMPs and where PDMP access policies make this practicable (e.g., clinician and delegate access permitted), but it is not currently possible in states without functional PDMPs or in those that do not permit certain prescribers to access them. As vendors and practices facilitate integration of PDMP information into regular clinical workflow (e.g., data made available in electronic health records), clinicians' ease of access in reviewing PDMP data is expected to improve. In addition, improved timeliness of PDMP data will improve their value in identifying patient risks. If patients are found to have high opioid dosages, dangerous combinations of medications, or multiple controlled substance prescriptions written by different clinicians, several actions can be taken to augment clinicians' abilities to improve patient safety: - Clinicians should discuss information from the PDMP with their patient and confirm that the patient is aware of the additional prescriptions. Occasionally, PDMP information can be incorrect (e.g., if the wrong name or birthdate has been entered, the patient uses a nickname or maiden name, or another person has used the patient's identity to obtain prescriptions). - Clinicians should discuss safety concerns, including increased risk for respiratory depression and overdose, with patients found to be receiving opioids from more than one prescriber or receiving medications that increase risk when combined with opioids (e.g., benzodiazepines) and consider offering naloxone (see Recommendation 8). - Clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. Clinicians should communicate with others managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care (see Recommendation 11). - Clinicians should calculate the total MME/day for concurrent opioid prescriptions to help assess the patient's overdose risk (see Recommendation 5). If patients are found to be receiving high total daily dosages of opioids, clinicians should discuss their safety concerns with the patient, consider tapering to a safer dosage (see Recommendations 5 and 7), and consider offering naloxone (see Recommendation 8). - Clinicians should discuss safety concerns with other clinicians who are prescribing controlled substances for their patient. Ideally clinicians should first discuss concerns with their patient and inform him or her that they plan to coordinate care with the patient's other prescribers to improve the patient's safety. - Clinicians should consider the possibility of a substance use disorder and discuss concerns with their patient (see Recommendation 12). - If clinicians suspect their patient might be sharing or selling opioids and not taking them, clinicians should consider urine drug testing to assist in determining whether opioids can be discontinued without causing withdrawal (see Recommendations 7 and 10). A negative drug test for prescribed opioids might indicate the patient is not taking prescribed opioids, although clinicians should consider other possible reasons for this test result (see Recommendation 10). Experts agreed that clinicians should not dismiss patients from their practice on the basis of PDMP information. Doing so can adversely affect patient safety, could represent patient abandonment, and could result in missed opportunities to provide potentially lifesaving information (e.g., about risks of opioids and overdose prevention) and interventions (e.g., safer prescriptions, nonopioid pain treatment , naloxone , and effective treatment for substance use disorder ). # When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs (recommendation category: B, evidence type: 4). Concurrent use of opioid pain medications with other opioid pain medications, benzodiazepines, or heroin can increase patients' risk for overdose. Urine drug tests can provide information about drug use that is not reported by the patient. In addition, urine drug tests can assist clinicians in identifying when patients are not taking opioids prescribed for them, which might in some cases indicate diversion or other clinically important issues such as difficulties with adverse effects. Urine drug tests do not provide accurate information about how much or what dose of opioids or other drugs a patient took. The clinical evidence review did not find studies evaluating the effectiveness of urine drug screening for risk mitigation during opioid prescribing for pain (KQ4). The contextual evidence review found that urine drug testing can provide useful information about patients assumed not to be using unreported drugs. Urine drug testing results can be subject to misinterpretation and might sometimes be associated with practices that might harm patients (e.g., stigmatization, inappropriate termination from care). Routine use of urine drug tests with standardized policies at the practice or clinic level might destigmatize their use. Although random drug testing also might destigmatize urine drug testing, experts thought that truly random testing was not feasible in clinical practice. Some clinics obtain a urine specimen at every visit, but only send it for testing on a random schedule. Experts noted that in addition to direct costs of urine drug testing, which often are not covered fully by insurance and can be a burden for patients, clinician time is needed to interpret, confirm, and communicate results. Experts agreed that prior to starting opioids for chronic pain and periodically during opioid therapy, clinicians should use urine drug testing to assess for prescribed opioids as well as other controlled substances and illicit drugs that increase risk for overdose when combined with opioids, including nonprescribed opioids, benzodiazepines, and heroin. There was some difference of opinion among experts as to whether this recommendation should apply to all patients, or whether this recommendation should entail individual decision making with different choices for different patients based on values, preferences, and clinical situations. While experts agreed that clinicians should use urine drug testing before initiating opioid therapy for chronic pain, they disagreed on how frequently urine drug testing should be conducted during long-term opioid therapy. Most experts agreed that urine drug testing at least annually for all patients was reasonable. Some experts noted that this interval might be too long in some cases and too short in others, and that the follow-up interval should be left to the discretion of the clinician. Previous guidelines have recommended more frequent urine drug testing in patients thought to be at higher risk for substance use disorder (30). However, experts thought that predicting risk prior to urine drug testing is challenging and that currently available tools do not allow clinicians to reliably identify patients who are at low risk for substance use disorder. In most situations, initial urine drug testing can be performed with a relatively inexpensive immunoassay panel for commonly prescribed opioids and illicit drugs. Patients prescribed less commonly used opioids might require specific testing for those agents. The use of confirmatory testing adds substantial costs and should be based on the need to detect specific opioids that cannot be identified on standard immunoassays or on the presence of unexpected urine drug test results. Clinicians should be familiar with the drugs included in urine drug testing panels used in their practice and should understand how to interpret results for these drugs. For example, a positive "opiates" immunoassay detects morphine, which might reflect patient use of morphine, codeine, or heroin, but this immunoassay does not detect synthetic opioids (e.g., fentanyl or methadone) and might not detect semisynthetic opioids (e.g., oxycodone). However, many laboratories use an oxycodone immunoassay that detects oxycodone and oxymorphone. In some cases, positive results for specific opioids might reflect metabolites from opioids the patient is taking and might not mean the patient is taking the specific opioid for which the test was positive. For example, hydromorphone is a metabolite of hydrocodone, and oxymorphone is a metabolite of oxycodone. Detailed guidance on interpretation of urine drug test results, including which tests to order and expected results, drug detection time in urine, drug metabolism, and other considerations has been published previously (30). Clinicians should not test for substances for which results would not affect patient management or for which implications for patient management are unclear. For example, experts noted that there might be uncertainty about the clinical implications of a positive urine drug test for tetrahyrdocannabinol (THC). In addition, restricting confirmatory testing to situations and substances for which results can reasonably be expected to affect patient management can reduce costs of urine drug testing, given the substantial costs associated with confirmatory testing methods. Before ordering urine drug testing, clinicians should have a plan for responding to unexpected results. Clinicians should explain to patients that urine drug testing is intended to improve their safety and should also explain expected results (e.g., presence of prescribed medication and absence of drugs, including illicit drugs, not reported by the patient). Clinicians should ask patients about use of prescribed and other drugs and ask whether there might be unexpected results. This will provide an opportunity for patients to provide information about changes in their use of prescribed opioids or other drugs. Clinicians should discuss unexpected results with the local laboratory or toxicologist and with the patient. Discussion with patients prior to specific confirmatory testing can sometimes yield a candid explanation of why a particular substance is present or absent and obviate the need for expensive confirmatory testing on that visit. For example, a patient might explain that the test is negative for prescribed opioids because she felt opioids were no longer helping and discontinued them. If unexpected results are not explained, a confirmatory test using a method selective enough to differentiate specific opioids and metabolites (e.g., gas or liquid chromatography/mass spectrometry) might be warranted to clarify the situation. Clinicians should use unexpected results to improve patient safety (e.g., change in pain management strategy , tapering or discontinuation of opioids , more frequent re-evaluation , offering naloxone , or referral for treatment for substance use disorder , all as appropriate). If tests for prescribed opioids are repeatedly negative, confirming that the patient is not taking the prescribed opioid, clinicians can discontinue the prescription without a taper. Clinicians should not dismiss patients from care based on a urine drug test result because this could constitute patient abandonment and could have adverse consequences for patient safety, potentially including the patient obtaining opioids from alternative sources and the clinician missing opportunities to facilitate treatment for substance use disorder. # Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3). Benzodiazepines and opioids both cause central nervous system depression and can decrease respiratory drive. Concurrent use is likely to put patients at greater risk for potentially fatal overdose. The clinical evidence review did not address risks of benzodiazepine co-prescription among patients prescribed opioids. However, the contextual evidence review found evidence in epidemiologic series of concurrent benzodiazepine use in large proportions of opioid-related overdose deaths, and a case-cohort study found concurrent benzodiazepine prescription with opioid prescription to be associated with a near quadrupling of risk for overdose death compared with opioid prescription alone (212). Experts agreed that although there are circumstances when it might be appropriate to prescribe opioids to a patient receiving benzodiazepines (e.g., severe acute pain in a patient taking longterm, stable low-dose benzodiazepine therapy), clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. In addition, given that other central nervous system depressants (e.g., muscle relaxants, hypnotics) can potentiate central nervous system depression associated with opioids, clinicians should consider whether benefits outweigh risks of concurrent use of these drugs. Clinicians should check the PDMP for concurrent controlled medications prescribed by other clinicians (see Recommendation 9) and should consider involving pharmacists and pain specialists as part of the management team when opioids are co-prescribed with other central nervous system depressants. Because of greater risks of benzodiazepine withdrawal relative to opioid withdrawal, and because tapering opioids can be associated with anxiety, when patients receiving both benzodiazepines and opioids require tapering to reduce risk for fatal respiratory depression, it might be safer and more practical to taper opioids first (see Recommendation 7). Clinicians should taper benzodiazepines gradually if discontinued because abrupt withdrawal can be associated with rebound anxiety, hallucinations, seizures, delirium tremens, and, in rare cases, death (contextual evidence review). A commonly used tapering schedule that has been used safely and with moderate success is a reduction of the benzodiazepine dose by 25% every 1-2 weeks (213,214). CBT increases tapering success rates and might be particularly helpful for patients struggling with a benzodiazepine taper (213). If benzodiazepines prescribed for anxiety are tapered or discontinued, or if patients receiving opioids require treatment for anxiety, evidence-based psychotherapies (e.g., CBT) and/or specific anti-depressants or other nonbenzodiazepine medications approved for anxiety should be offered. Experts emphasized that clinicians should communicate with mental health professionals managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care. The clinical evidence review found prevalence of opioid dependence (using DSM-IV diagnosis criteria) in primary care settings among patients with chronic pain on opioid therapy to be 3%-26% (KQ2). As found in the contextual evidence review and supported by moderate quality evidence, opioid agonist or partial agonist treatment with methadone maintenance therapy or buprenorphine has been shown to be more effective in preventing relapse among patients with opioid use disorder (151)(152)(153). Some studies suggest that using behavioral therapies in combination with these treatments can reduce opioid misuse and increase retention during maintenance therapy and improve compliance after detoxification (154,155); behavioral therapies are also recommended by clinical practice guidelines (215). The cited studies primarily evaluated patients with a history of illicit opioid use, rather than prescription opioid use for chronic pain. Recent studies among patients with prescription opioid dependence (based on DSM-IV criteria) have found maintenance therapy with buprenorphine and buprenorphinenaloxone effective in preventing relapse (216,217). Treatment need in a community is often not met by capacity to provide buprenorphine or methadone maintenance therapy (218), and patient cost can be a barrier to buprenorphine treatment because insurance coverage of buprenorphine for opioid use disorder is often limited (219). Oral or long-acting injectable formulations of naltrexone can also be used as medicationassisted treatment for opioid use disorder in nonpregnant adults, particularly for highly motivated persons (220,221). Experts agreed that clinicians prescribing opioids should identify treatment resources for opioid use disorder in the community and should work together to ensure sufficient treatment capacity for opioid use disorder at the practice level. If clinicians suspect opioid use disorder based on patient concerns or behaviors or on findings in prescription drug monitoring program data (see Recommendation 9) or from urine drug testing (see Recommendation 10), they should discuss their concern with their patient and provide an opportunity for the patient to disclose related concerns or problems. Clinicians should assess for the presence of opioid use disorder using DSM-5 criteria (20). Alternatively, clinicians can arrange for a substance use disorder treatment specialist to assess for the presence of opioid use disorder. For patients meeting criteria for opioid use disorder, clinicians should offer or arrange for patients to receive evidence-based treatment, usually medication-assisted treatment with buprenorphine or methadone maintenance therapy in combination with behavioral therapies. Oral or long-acting injectable naltrexone, a long-acting opioid antagonist, can also be used in nonpregnant adults. Naltrexone blocks the effects of opioids if they are used but requires adherence to daily oral therapy or monthly injections. For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine (without naloxone) or methadone has been associated with improved maternal outcomes and should be offered (see Recommendation 8). Clinicians should also consider offering naloxone for overdose prevention to patients with opioid use disorder (see Recommendation 8). For patients with problematic opioid use that does not meet criteria for opioid use disorder, experts noted that clinicians can offer to taper and discontinue opioids (see Recommendation 7). For patients who choose to but are unable to taper, clinicians may reassess for opioid use disorder and offer opioid agonist therapy if criteria are met. Physicians not already certified to provide buprenorphine in an office-based setting can undergo training to receive a waiver from the Substance Abuse and Mental Health Services Administration (SAMHSA) that allows them to prescribe buprenorphine to treat patients with opioid use disorder. Physicians prescribing opioids in communities without sufficient treatment capacity for opioid use disorder should strongly consider obtaining this waiver. Information about qualifications and the process to obtain a waiver are available from SAMHSA (222). Clinicians do not need a waiver to offer naltrexone for opioid use disorder as part of their practice. Additional guidance has been published previously (215) on induction, use, and monitoring of buprenorphine treatment (see Part 5) and naltrexone treatment (see Part 6) for opioid use disorder and on goals, components of, and types of effective psychosocial treatment that are recommended in conjunction with pharmacological treatment of opioid use disorder (see Part 7). Clinicians unable to provide treatment themselves should arrange for patients with opioid use disorder to receive care from a substance use disorder treatment specialist, such as an office-based buprenorphine or naltrexone treatment provider, or from an opioid treatment program certified by SAMHSA to provide supervised medication-assisted treatment for patients with opioid use disorder. Clinicians should assist patients in finding qualified treatment providers and should arrange for patients to follow up with these providers, as well as arranging for ongoing coordination of care. Clinicians should not dismiss patients from their practice because of a substance use disorder because this can adversely affect patient safety and could represent patient abandonment. Identification of substance use disorder represents an opportunity for a clinician to initiate potentially life-saving interventions, and it is important for the clinician to collaborate with the patient regarding their safety to increase the likelihood of successful treatment. In addition, although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. Clinicians should continue to use nonpharmacologic and nonopioid pharmacologic pain treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to provide optimal pain management. Resources to help with arranging for treatment include SAMHSA's buprenorphine physician locator (http:// buprenorphine.samhsa.gov/bwns_locator); SAMHSA's Opioid Treatment Program Directory (. gov/treatment/directory.aspx); SAMHSA's Provider Clinical Support System for Opioid Therapies (), which offers extensive experience in the treatment of substance use disorders and specifically of opioid use disorder, as well as expertise on the interface of pain and opioid misuse; and SAMHSA's Provider's Clinical Support System for Medication-Assisted Treatment (), which offers expert physician mentors to answer questions about assessment for and treatment of substance use disorders. # Conclusions and Future Directions Clinical guidelines represent one strategy for improving prescribing practices and health outcomes. Efforts are required to disseminate the guideline and achieve widespread adoption and implementation of the recommendations in clinical settings. CDC will translate this guideline into user-friendly materials for distribution and use by health systems, medical professional societies, insurers, public health departments, health information technology developers, and clinicians and engage in dissemination efforts. CDC has provided a checklist for prescribing opioids for chronic pain (http:// stacks.cdc.gov/view/cdc/38025), additional resources such as fact sheets (/ resources.html), and will provide a mobile application to guide clinicians in implementing the recommendations. CDC will also work with partners to support clinician education on pain management options, opioid therapy, and risk mitigation strategies (e.g., urine drug testing). Activities such as development of clinical decision support in electronic health records to assist clinicians' treatment decisions at the point of care; identification of mechanisms that insurers and pharmacy benefit plan managers can use to promote safer prescribing within plans; and development of clinical quality improvement measures and initiatives to improve prescribing and patient care within health systems have promise for increasing guideline adoption and improving practice. In addition, policy initiatives that address barriers to implementation of the guidelines, such as increasing accessibility of PDMP data within and across states, e-prescribing, and availability of clinicians who can offer medication-assisted treatment for opioid use disorder, are strategies to consider to enhance implementation of the recommended practices. CDC will work with federal partners and payers to evaluate strategies such as payment reform and health care delivery models that could improve patient health and safety. For example, strategies might include strengthened coverage for nonpharmacologic treatments, appropriate urine drug testing, and medication-assisted treatment; reimbursable time for patient counseling; and payment models that improve access to interdisciplinary, coordinated care. As highlighted in the forthcoming report on the National Pain Strategy, an overarching federal effort that outlines a comprehensive population-level health strategy for addressing pain as a public health problem, clinical guidelines complement other strategies aimed at preventing illnesses and injuries that lead to pain. A draft of the National Pain Strategy has been published previously (180). These strategies include strengthening the evidence base for pain prevention and treatment strategies, reducing disparities in pain treatment, improving service delivery and reimbursement, supporting professional education and training, and providing public education. It is important that overall improvements be made in developing the workforce to address pain management in general, in addition to opioid prescribing specifically. This guideline also complements other federal efforts focused on addressing the opioid overdose epidemic including prescriber training and education, improving access to treatment for opioid use disorder, safe storage and disposal programs, utilization management mechanisms, naloxone distribution programs, law enforcement and supply reduction efforts, prescription drug monitoring program improvements, and support for community coalitions and state prevention programs. This guideline provides recommendations that are based on the best available evidence that was interpreted and informed by expert opinion. The clinical scientific evidence informing the recommendations is low in quality. To inform future guideline development, more research is necessary to fill in critical evidence gaps. The evidence reviews forming the basis of this guideline clearly illustrate that there is much yet to be learned about the effectiveness, safety, and economic efficiency of long-term opioid therapy. As highlighted by an expert panel in a recent workshop sponsored by the National Institutes of Health on the role of opioid pain medications in the treatment of chronic pain, "evidence is insufficient for every clinical decision that a provider needs to make about the use of opioids for chronic pain" (223). The National Institutes of Health panel recommended that research is needed to improve our understanding of which types of pain, specific diseases, and patients are most likely to be associated with benefit and harm from opioid pain medications; evaluate multidisciplinary pain interventions; estimate cost-benefit; develop and validate tools for identification of patient risk and outcomes; assess the effectiveness and harms of opioid pain medications with alternative study designs; and investigate risk identification and mitigation strategies and their effects on patient and public health outcomes. It is also important to obtain data to inform the cost feasibility and cost-effectiveness of recommended actions, such as use of nonpharmacologic therapy and urine drug testing. Research that contributes to safer and more effective pain treatment can be implemented across public health entities and federal agencies (4). Additional research can inform the development of future guidelines for special populations that could not be adequately addressed in this guideline, such as children and adolescents, where evidence and guidance is needed but currently lacking. CDC is committed to working with partners to identify the highest priority research areas to build the evidence base. Yet, given that chronic pain is recognized as a significant public health problem, the risks associated with long-term opioid therapy, the availability of effective nonpharmacological and nonopioid pharmacologic treatment options for pain, and the potential for improvement in the quality of health care with the implementation of recommended practices, a guideline for prescribing is warranted with the evidence that is currently available. The balance between the benefits and the risks of long-term opioid therapy for chronic pain based on both clinical and contextual evidence is strong enough to support the issuance of category A recommendations in most cases. CDC will revisit this guideline as new evidence becomes available to determine when evidence gaps have been sufficiently closed to warrant an update of the guideline. Until this research is conducted, clinical practice guidelines will have to be based on the best available evidence and expert opinion. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with longterm opioid therapy, including opioid use disorder, overdose, and death. CDC is committed to evaluating the guideline to identify the impact of the recommendations on clinician and patient outcomes, both intended and unintended, and revising the recommendations in future updates when warranted. Abbreviations: CI = confidence interval; ER/LA = extended release/long-acting; HR = hazard ratio; MME = morphine milligram equivalents; OR = odds ratio. - Ratings were made per GRADE quality assessment criteria; "no limitations" indicates that limitations assessed through the GRADE method were not identified. † Not applicable as no evidence was available for rating.	and Prevention cognitive impairment, and those with cancer and at the end of life, can be at risk for inadequate pain treatment (4). Patients can experience persistent pain that is not well controlled. There are clinical, psychological, and social consequences associated with chronic pain including limitations in complex activities, lost work productivity, reduced quality of life, and stigma, emphasizing the importance of appropriate and compassionate patient care (4). Patients should receive appropriate pain treatment based on a careful consideration of the benefits and risks of treatment options. Chronic pain has been variably defined but is defined within this guideline as pain that typically lasts >3 months or past the time of normal tissue healing (5). Chronic pain can be the result of an underlying medical disease or condition, injury, medical treatment, inflammation, or an unknown cause (4). Estimates of the prevalence of chronic pain vary, but it is clear that the number of persons experiencing chronic pain in the United States is substantial. The 1999-2002 National Health and Nutrition Examination Survey estimated that 14.6% of adults have current widespread or localized pain lasting at least 3 months (6). Based on a survey conducted during 2001-2003 (7), the overall prevalence of common, predominantly musculoskeletal pain conditions (e.g., arthritis, rheumatism, chronic back or neck problems, and frequent severe headaches) was estimated at 43% among adults in the# position paper on prescription drug abuse. CDC provided 100% of the funding for the supplemental evidence review tasks and meeting support. No foundation or industry support was accepted. The Opioid Guideline Workgroup (OGW) members disclose that they have no financial conflicts of interest. Experts disclose the following activities related to the content of this guideline: Anne Burns discloses that she participated in a congressional briefing sponsored by Reps. Carter and DeSaulnier on the pharmacist's role of furnishing Naloxone and that she participates on the National Advisory Board for the Prescription Drug Abuse and Heroin Summit. Chinazo Cunningham discloses that her husband is employed by Quest Diagnostics and Dr. Cunningham was recused from any discussion related to urine drug testing. Traci Green discloses that she was previously employed by Inflexxion, a small business that conducts Small Business Innovation Research on behavioral interventions for behavioral health and chronic pain and created several psychometric tools for conducting risk assessment for prescription opioid abuse potential. Dr. Green also discloses that while at the hospital where she is employed, she provided consultation to Purdue Pharma Ltd to design overdose prevention brochures for persons who use diverted prescription opioids non-medically with an emphasis on persons who inject prescription drugs, and not for patients using opioid therapy for pain. Dr. Green was recused from any discussion related to risk assessment tools and patient education materials. Erin Krebs discloses that she served on the CDC Opioid Prescribing Guideline CEG. Christina Porucznik discloses that she served on the CDC Opioid Prescribing Guideline CEG. Greg Terman discloses that he serves as the President of the American Pain Society. Mark Wallace discloses that he served on a Kempharma advisory panel for an abuse-deterrent hydrocodone formulation to treat acute postoperative pain and Dr. Wallace was recused form any discussion related to abuse-deterrent drugs. The NCIPC Board of Scientific Counselors (BSC) members disclose that they have no financial conflicts of interest. Two BSC members, Traci Green and Christina Porucznik, served on the Opioid Guideline Workgroup. Traci Green discloses that she was previously employed by Inflexxion, a small business that conducts Small Business Innovation Research on behavioral interventions for behavioral health and chronic pain and created several psychometric tools for conducting risk assessment for prescription opioid abuse potential. Dr. Green also discloses that while at the hospital where she is employed, she provided consultation to Purdue Pharma Ltd to design overdose prevention brochures for persons who use diverted prescription opioids non-medically with an emphasis on persons who inject prescription drugs, and not for patients using opioid therapy for pain. Dr. Green was recused from any discussion related to risk assessment tools and patient education materials. Christina Porucznik discloses that she served on the CDC Opioid Prescribing Guideline CEG. # Introduction Background Opioids are commonly prescribed for pain. An estimated 20% of patients presenting to physician offices with noncancer pain symptoms or pain-related diagnoses (including acute and chronic pain) receive an opioid prescription (1). In 2012, health care providers wrote 259 million prescriptions for opioid pain medication, enough for every adult in the United States to have a bottle of pills (2). Opioid prescriptions per capita increased 7.3% from 2007 to 2012, with opioid prescribing rates increasing more for family practice, general practice, and internal medicine compared with other specialties (3). Rates of opioid prescribing vary greatly across states in ways that cannot be explained by the underlying health status of the population, highlighting the lack of consensus among clinicians on how to use opioid pain medication (2). Prevention, assessment, and treatment of chronic pain are challenges for health providers and systems. Pain might go unrecognized, and patients, particularly members of racial and ethnic minority groups, women, the elderly, persons with United States, although minimum duration of symptoms was not specified. Most recently, analysis of data from the 2012 National Health Interview Study showed that 11.2% of adults report having daily pain (8). Clinicians should consider the full range of therapeutic options for the treatment of chronic pain. However, it is hard to estimate the number of persons who could potentially benefit from opioid pain medication long term. Evidence supports short-term efficacy of opioids for reducing pain and improving function in noncancer nociceptive and neuropathic pain in randomized clinical trials lasting primarily ≤12 weeks (9,10), and patients receiving opioid therapy for chronic pain report some pain relief when surveyed (11)(12)(13). However, few studies have been conducted to rigorously assess the long-term benefits of opioids for chronic pain (pain lasting >3 months) with outcomes examined at least 1 year later (14). On the basis of data available from health systems, researchers estimate that 9.6-11.5 million adults, or approximately 3%-4% of the adult U.S. population, were prescribed long-term opioid therapy in 2005 (15). Opioid pain medication use presents serious risks, including overdose and opioid use disorder. From 1999 to 2014, more than 165,000 persons died from overdose related to opioid pain medication in the United States (16). In the past decade, while the death rates for the top leading causes of death such as heart disease and cancer have decreased substantially, the death rate associated with opioid pain medication has increased markedly (17). Sales of opioid pain medication have increased in parallel with opioid-related overdose deaths (18). The Drug Abuse Warning Network estimated that >420,000 emergency department visits were related to the misuse or abuse of narcotic pain relievers in 2011, the most recent year for which data are available (19). Although clinical criteria have varied over time, opioid use disorder is a problematic pattern of opioid use leading to clinically significant impairment or distress. This disorder is manifested by specific criteria such as unsuccessful efforts to cut down or control use and use resulting in social problems and a failure to fulfill major role obligations at work, school, or home (20). This diagnosis has also been referred to as "abuse or dependence" and "addiction" in the literature, and is different from tolerance (diminished response to a drug with repeated use) and physical dependence (adaptation to a drug that produces symptoms of withdrawal when the drug is stopped), both of which can exist without a diagnosed disorder. In 2013, on the basis of DSM-IV diagnosis criteria, an estimated 1.9 million persons abused or were dependent on prescription opioid pain medication (21). Having a history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder (22)(23)(24), highlighting the value of guidance on safer prescribing practices for clinicians. For example, a recent study of patients aged 15-64 years receiving opioids for chronic noncancer pain and followed for up to 13 years revealed that one in 550 patients died from opioid-related overdose at a median of 2.6 years from their first opioid prescription, and one in 32 patients who escalated to opioid dosages >200 morphine milligram equivalents (MME) died from opioid-related overdose (25). This guideline provides recommendations for the prescribing of opioid pain medication by primary care clinicians for chronic pain (i.e., pain conditions that typically last >3 months or past the time of normal tissue healing) in outpatient settings outside of active cancer treatment, palliative care, and endof-life care. Although the guideline does not focus broadly on pain management, appropriate use of long-term opioid therapy must be considered within the context of all pain management strategies (including nonopioid pain medications and nonpharmacologic treatments). CDC's recommendations are made on the basis of a systematic review of the best available evidence, along with input from experts, and further review and deliberation by a federally chartered advisory committee. The guideline is intended to ensure that clinicians and patients consider safer and more effective treatment, improve patient outcomes such as reduced pain and improved function, and reduce the number of persons who develop opioid use disorder, overdose, or experience other adverse events related to these drugs. Clinical decision making should be based on a relationship between the clinician and patient, and an understanding of the patient's clinical situation, functioning, and life context. The recommendations in the guideline are voluntary, rather than prescriptive standards. They are based on emerging evidence, including observational studies or randomized clinical trials with notable limitations. Clinicians should consider the circumstances and unique needs of each patient when providing care. # Rationale Primary care clinicians report having concerns about opioid pain medication misuse, find managing patients with chronic pain stressful, express concern about patient addiction, and report insufficient training in prescribing opioids (26). Across specialties, physicians believe that opioid pain medication can be effective in controlling pain, that addiction is a common consequence of prolonged use, and that long-term opioid therapy often is overprescribed for patients with chronic noncancer pain (27). These attitudes and beliefs, combined with increasing trends in opioid-related overdose, underscore the need for better clinician guidance on opioid prescribing. Clinical practice guidelines focused on prescribing can improve clinician knowledge, change prescribing practices (28), and ultimately benefit patient health. # Scope and Audience This guideline is intended for primary care clinicians (e.g., family physicians and internists) who are treating patients with chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing) in outpatient settings. Prescriptions by primary care clinicians account for nearly half of all dispensed opioid prescriptions, and the growth in prescribing rates among these clinicians has been above average (3). Primary care clinicians include physicians as well as nurse practitioners and physician assistants. Although the focus is on primary care clinicians, because clinicians work within team-based care, the recommendations refer to and promote integrated pain management and collaborative working relationships with other providers (e.g., behavioral health providers, pharmacists, and pain management specialists). Although the transition from use of opioid therapy for acute pain to use for chronic pain is hard to predict and identify, the guideline is intended to inform clinicians who are considering prescribing opioid pain medication for painful conditions that can or have become chronic. This guideline is intended to apply to patients aged ≥18 years with chronic pain outside of palliative and end-of-life care. For this guideline, palliative care is defined in a manner consistent with that of the Institute of Medicine as care that provides relief from pain and other symptoms, supports quality of life, and is focused on patients with serious advanced illness. Palliative care can begin early in the course of treatment for any serious illness that requires excellent management of pain or other distressing symptoms (35). End-of-life care is defined as care for persons with a terminal illness or at high risk for dying in the near future in hospice care, hospitals, long-term care settings, or at home. Patients within the scope of this guideline include cancer survivors with chronic pain who have completed cancer treatment, are in clinical remission, and are under cancer surveillance only. The guideline is not intended for patients undergoing active cancer treatment, palliative care, or endof-life care because of the unique therapeutic goals, ethical considerations, opportunities for medical supervision, and balance of risks and benefits with opioid therapy in such care. The recommendations address the use of opioid pain medication in certain special populations (e.g., older adults and pregnant women) and in populations with conditions posing special risks (e.g., a history of substance use disorder). The recommendations do not address the use of opioid pain medication in children or adolescents aged <18 years. The available evidence concerning the benefits and harms of long-term opioid therapy in children and adolescents is limited, and few opioid medications provide information on the label regarding safety and effectiveness in pediatric patients. However, observational research shows significant increases in opioid prescriptions for pediatric populations from 2001 to 2010 (36), and a large proportion of adolescents are commonly prescribed opioid pain medications for conditions such as headache and sports injuries (e.g., in one study, 50% of adolescents presenting with headache received a prescription for an opioid pain medication [37,38]). Adolescents who misuse opioid pain medication often misuse medications from their own previous prescriptions (39), with an estimated 20% of adolescents with currently prescribed opioid medications reporting using them intentionally to get high or increase the effects of alcohol or other drugs (40). Use of prescribed opioid pain medication before high school graduation is associated with a 33% increase in the risk of later opioid misuse (41). Misuse of opioid pain medications in adolescence strongly predicts later onset of heroin use (42). Thus, risk of opioid medication use in pediatric populations is of great concern. Additional clinical trial and observational research is needed, and encouraged, to inform development of future guidelines for this critical population. The recommendations are not intended to provide guidance on use of opioids as part of medication-assisted treatment for opioid use disorder. Some of the recommendations might be relevant for acute care settings or other specialists, such as emergency physicians or dentists, but use in these settings or by other specialists is not the focus of this guideline. Readers are referred to other sources for prescribing recommendations within acute care settings and in dental practice, such as the American College of Emergency Physicians' guideline for prescribing of opioids in the emergency department (43); the American Society of Anesthesiologists' guideline for acute pain management in the perioperative setting (44); the Washington Agency Medical Directors' Group Interagency Guideline on Prescribing Opioids for Pain, Part II: Prescribing Opioids in the Acute and Subacute Phase (30); and the Pennsylvania Guidelines on the Use of Opioids in Dental Practice (45). In addition, given the challenges of managing the painful complications of sickle cell disease, readers are referred to the NIH National Heart, Lung, and Blood Institute's Evidence Based Management of Sickle Cell Disease Expert Panel Report for management of sickle cell disease (46). # Guideline Development Methods # Guideline Development Using the Grading of Recommendations Assessment, Development, and Evaluation Method CDC developed this guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method (http://www.gradeworkinggroup.org). This method specifies the systematic review of scientific evidence and offers a transparent approach to grading quality of evidence and strength of recommendations. The method has been adapted by the CDC Advisory Committee on Immunization Practices (ACIP) (47). CDC has applied the ACIP translation of the GRADE framework in this guideline. Within the ACIP GRADE framework, the body of evidence is categorized in a hierarchy. This hierarchy reflects degree of confidence in the effect of a clinical action on health outcomes. The categories include type 1 evidence (randomized clinical trials or overwhelming evidence from observational studies), type 2 evidence (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 evidence (observational studies or randomized clinical trials with notable limitations), and type 4 evidence (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). Type of evidence is categorized by study design as well as limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and a constellation of plausible biases that could change observations of effects. Type 1 evidence indicates that one can be very confident that the true effect lies close to that of the estimate of the effect; type 2 evidence means that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; type 3 evidence means that confidence in the effect estimate is limited and the true effect might be substantially different from the estimate of the effect; and type 4 evidence indicates that one has very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of the effect (47,48). When no studies are present, evidence is considered to be insufficient. The ACIP GRADE framework places recommendations in two categories, Category A and Category B. Four major factors determine the category of the recommendation: the quality of evidence, the balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendations apply to all persons in a specified group and indicate that most patients should receive the recommended course of action. Category B recommendations indicate that there should be individual decision making; different choices will be appropriate for different patients, so clinicians must help patients arrive at a decision consistent with patient values and preferences, and specific clinical situations (47). According to the GRADE methodology, a particular quality of evidence does not necessarily imply a particular strength of recommendation (48)(49)(50). Category A recommendations can be made based on type 3 or type 4 evidence when the advantages of a clinical action greatly outweigh the disadvantages based on a consideration of benefits and harms, values and preferences, and costs. Category B recommendations are made when the advantages and disadvantages of a clinical action are more balanced. GRADE methodology is discussed extensively elsewhere (47,51). The U.S. Preventive Services Task Force (USPSTF) follows different methods for developing and categorizing recommendations (http://www. uspreventiveservicestaskforce.org). USPSTF recommendations focus on preventive services and are categorized as A, B, C, D, and I. Under the Affordable Care Act, all "nongrandfathered" health plans (that is, those health plans not in existence prior to March 23, 2010 or those with significant changes to their coverage) and expanded Medicaid plans are required to cover preventive services recommended by USPSTF with a category A or B rating with no cost sharing. The coverage requirements went into effect September 23, 2010. Similar requirements are in place for vaccinations recommended by ACIP, but do not exist for other recommendations made by CDC, including recommendations within this guideline. A previously published systematic review sponsored by the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness and risks of long-term opioid treatment of chronic pain (14,52) initially served to directly inform the recommendation statements. This systematic clinical evidence review addressed the effectiveness of long-term opioid therapy for outcomes related to pain, function, and quality of life; the comparative effectiveness of different methods for initiating and titrating opioids; the harms and adverse events associated with opioids; and the accuracy of risk-prediction instruments and effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse. For the current guideline development, CDC conducted additional literature searches to update the evidence review to include more recently available publications and to answer an additional clinical question about the effect of opioid therapy for acute pain on long-term use. More details about the literature search strategies and GRADE methods applied are provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026). CDC developed GRADE evidence tables to illustrate the quality of the evidence for each clinical question. As identified in the AHRQ-sponsored clinical evidence review, the overall evidence base for the effectiveness and risks of long-term opioid therapy is low in quality per the GRADE criteria. Thus, contextual evidence is needed to provide information about the benefits and harms of nonpharmacologic and nonopioid pharmacologic therapy and the epidemiology of opioid pain medication overdose and inform the recommendations. Further, as elucidated by the GRADE Working Group, supplemental information on clinician and patient values and preferences and resource allocation can inform judgments of benefits and harms and be helpful for translating the evidence into recommendations. CDC conducted a contextual evidence review to supplement the clinical evidence review based on systematic searches of the literature. The review focused on the following four areas: effectiveness of nonpharmacologic and nonopioid pharmacologic treatments; benefits and harms related to opioid therapy (including additional studies not included in the clinical evidence review such as studies that evaluated outcomes at any duration or used observational study designs related to specific opioid pain medications, high-dose opioid therapy, co-prescription of opioids with other controlled substances, duration of opioid use, special populations, risk stratification/mitigation approaches, and effectiveness of treatments for addressing potential harms of opioid therapy); clinician and patient values and preferences; and resource allocation. CDC constructed narrative summaries of this contextual evidence and used the information to support the clinical recommendations. More details on methods for the contextual evidence review are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). On the basis of a review of the clinical and contextual evidence (review methods are described in more detail in subsequent sections of this report), CDC drafted recommendation statements focused on determining when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use. To help assure the draft guideline's integrity and credibility, CDC then began a multistep review process to obtain input from experts, stakeholders, and the public to help refine the recommendations. # Solicitation of Expert Opinion CDC sought the input of experts to assist in reviewing the evidence and providing perspective on how CDC used the evidence to develop the draft recommendations. These experts, referred to as the "Core Expert Group" (CEG) included subject matter experts, representatives of primary care professional societies and state agencies, and an expert in guideline development methodology.* CDC identified subject matter experts with high scientific standing; appropriate academic and clinical training and relevant clinical experience; and proven scientific excellence in opioid prescribing, substance use disorder treatment, and pain management. CDC identified representatives from leading primary care professional organizations to represent the audience for this guideline. Finally, CDC identified state agency officials and representatives based on their experience with state guidelines for opioid prescribing that were developed with multiple agency stakeholders and informed by scientific literature and existing evidence-based guidelines. Prior to their participation, CDC asked potential experts to reveal possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Experts could not serve if they had conflicts that might have a direct and predictable effect on the recommendations. CDC excluded experts who had a financial or promotional relationship with a company that makes a product that might be affected by the guideline. CDC reviewed potential nonfinancial conflicts carefully (e.g., intellectual property, travel, public statements or positions such as congressional testimony) to determine if the activities would have a direct and predictable effect on the recommendations. CDC determined the risk of these types of activities to be minimal for the identified experts. All experts completed a statement certifying that there was no potential or actual conflict of interest. Activities that did not pose a conflict (e.g., participation in Food and Drug Administration [FDA] activities or other guideline efforts) are disclosed. CDC provided to each expert written summaries of the scientific evidence (both the clinical and contextual evidence reviews conducted for this guideline) and CDC's draft recommendation statements. Experts provided individual ratings for each draft recommendation statement based on the balance of benefits and harms, evidence strength, certainty of values and preferences, cost, recommendation strength, rationale, importance, clarity, and ease of implementation. CDC hosted an in-person meeting of the experts that was held on June 23-24, 2015, in Atlanta, Georgia, to seek their views on the evidence and draft recommendations and to better understand their premeeting ratings. CDC sought the experts' individual opinions at the meeting. Although there was widespread agreement on some of the recommendations, there was disagreement on others. Experts did not vote on the recommendations or seek to come to a consensus. Decisions about recommendations to be included in the guideline, and their rationale, were made by CDC. After revising the guideline, CDC sent written copies of it to each of the experts for review and asked for any additional comments; CDC reviewed these written comments and considered them when making further revisions to the draft guideline. The experts have not reviewed the final version of the guideline. # Federal Partner Engagement Given the scope of this guideline and the interest of agencies across the federal government in appropriate pain management, opioid prescribing, and related outcomes, CDC invited its National Institute of Occupational Safety and Health and CDC's federal partners to observe the expert meeting, provide written comments on the full draft guideline after the meeting, and review the guideline through an agency clearance process; CDC reviewed comments and incorporated changes. Interagency collaboration will be critical for translating these recommendations into clinical practice. # Stakeholder Comment Given the importance of the guideline for a wide variety of stakeholders, CDC also invited review from a Stakeholder Review Group (SRG) to provide comment so that CDC could consider modifications that would improve the recommendations' specificity, applicability, and ease of implementation. The SRG included representatives from professional organizations that represent specialties that commonly prescribe opioids (e.g., pain medicine, physical medicine and rehabilitation), delivery systems within which opioid prescribing occurs (e.g., hospitals), and representation from community organizations with interests in pain management and opioid prescribing.* Representatives from each of the SRG organizations were provided a copy of the guideline for comment. Each of these representatives provided written comments. Once input was received from the full SRG, CDC reviewed all comments and carefully considered them when revising the draft guideline. # Constituent Engagement To obtain initial perspectives from constituents on the recommendation statements, including clinicians and prospective patients, CDC convened a constituent engagement webinar and circulated information about the webinar in advance through announcements to partners. CDC hosted the webinar on September 16 and 17, 2015, provided information about the methodology for developing the guideline, and presented the key recommendations. A fact sheet was posted on the CDC Injury Center website (http://www.cdc.gov/ injury) summarizing the guideline development process and clinical practice areas addressed in the guideline; instructions were included on how to submit comments via email. CDC received comments during and for 2 days following the first webinar. Over 1,200 constituent comments were received. Comments were reviewed and carefully considered when revising the draft guideline. # Peer Review Per the final information quality bulletin for peer review (https://www.whitehouse.gov/sites/default/files/omb/ memoranda/fy2005/m05-03.pdf ), peer review requirements applied to this guideline because it provides influential scientific information that could have a clear and substantial impact on public-and private-sector decisions. Three experts independently reviewed the guideline to determine the reasonableness and strength of recommendations; the clarity with which scientific uncertainties were clearly identified; and the rationale, importance, clarity, and ease of implementation of the recommendations.* CDC selected peer reviewers based on expertise, diversity of scientific viewpoints, and independence from the guideline development process. CDC assessed and managed potential conflicts of interest using a process similar to the one as described for solicitation of expert opinion. No financial interests were identified in the disclosure and review process, and nonfinancial activities were determined to be of minimal risk; thus, no significant conflict of interest concerns were identified. CDC placed the names of peer reviewers on the CDC and the National Center for Injury Prevention and Control Peer Review Agenda websites that are used to provide information about the peer review of influential documents. CDC reviewed peer review comments and revised the draft guideline accordingly. # Public Comment To obtain comments from the public on the full guideline, CDC published a notice in the Federal Register (80 FR 77351) announcing the availability of the guideline and the supporting clinical and contextual evidence reviews for public comment. The comment period closed January 13, 2016. CDC received more than 4,350 comments from the general public, including patients with chronic pain, clinicians, families who have lost loved ones to overdose, medical associations, professional organizations, academic institutions, state and local governments, and industry. CDC reviewed each of the comments and carefully considered them when revising the draft guideline. # Federal Advisory Committee Review and Recommendation The National Center for Injury Prevention and Control (NCIPC) Board of Scientific Counselors (BSC) is a federal advisory committee that advises and makes recommendations to the Secretary of the Department of Health and Human Services, the Director of CDC, and the Director of NCIPC.* The BSC makes recommendations regarding policies, strategies, objectives, and priorities, and reviews progress toward injury and violence prevention. CDC sought the BSC's advice on the draft guideline. BSC members are special government employees appointed as CDC advisory committee members; as such, all members completed an OGE Form 450 to disclose relevant interests. BSC members also reported on their disclosures during meetings. Disclosures for the BSC are reported in the guideline. To assist in guideline review, on December 14, 2015, via Federal Register notice, CDC announced the intent to form an Opioid Guideline Workgroup (OGW) to provide observations on the draft guideline to the BSC. CDC provided the BSC with the draft guideline as well as summaries of comments provided to CDC by stakeholders, constituents, and peer reviewers, and edits made to the draft guideline in response. During an open meeting held on January 7, 2016, the BSC recommended the formation of the OGW. The OGW included a balance of perspectives from audiences directly affected by the guideline, audiences that would be directly involved with implementing the recommendations, and audiences qualified to provide representation. The OGW comprised clinicians, subject matter experts, and a patient representative, with the following perspectives represented: primary care, pain medicine, public health, behavioral health, substance abuse treatment, pharmacy, patients, and research.* Additional sought-after attributes were appropriate academic and clinical training and relevant clinical experience; high scientific standing; and knowledge of the patient, clinician, and caregiver perspectives. In accordance with CDC policy, two BSC committee members also served as OGW members, with one serving as the OGW Chair. The professional credentials and interests of OGW members were carefully reviewed to identify possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Only OGW members whose interests were determined to be minimal were selected. When an activity was perceived as having the potential to affect a specific aspect of the recommendations, the activity was disclosed, and the OGW member was recused from discussions related to that specific aspect of the recommendations (e.g., urine drug testing and abuse-deterrent formulations). Disclosures for the OGW are reported. CDC and the OGW identified ad-hoc consultants to supplement the workgroup expertise, when needed, in the areas of pediatrics, occupational medicine, obstetrics and gynecology, medical ethics, addiction psychiatry, physical medicine and rehabilitation, guideline development methodology, and the perspective of a family member who lost a loved one to opioid use disorder or overdose. The BSC charged the OGW with reviewing the quality of the clinical and contextual evidence reviews and reviewing each of the recommendation statements and accompanying rationales. For each recommendation statement, the OGW considered the quality of the evidence, the balance of benefits and risks, the values and preferences of clinicians and patients, the cost feasibility, and the category designation of the recommendation (A or B). The OGW also reviewed supplementary documents, including input provided by the CEG, SRG, peer reviewers, and the public. OGW members discussed the guideline accordingly during virtual meetings and drafted a summary report of members' observations, including points of agreement and disagreement, and delivered the report to the BSC. NCIPC announced an open meeting of the NCIPC BSC in the Federal Register on January 11, 2015. The BSC met on January 28, 2016, to discuss the OGW report and deliberate on the draft guideline itself. Members of the public provided comments at this meeting. After discussing the OGW report, deliberating on specific issues about the draft guideline identified at the meeting, and hearing public comment, the BSC voted unanimously: to support the observations made by the OGW; that CDC adopt the guideline recommendations that, according to the workgroup's report, had unanimous or majority support; and that CDC further consider the guideline recommendations for which the group had mixed opinions. CDC carefully considered the OGW observations, public comments, and BSC recommendations, and revised the guideline in response. # Summary of the Clinical Evidence Review Primary Clinical Questions CDC conducted a clinical systematic review of the scientific evidence to identify the effectiveness, benefits, and harms of long-term opioid therapy for chronic pain, consistent with the GRADE approach (47,48). Long-term opioid therapy is defined as use of opioids on most days for >3 months. A previously published AHRQ-funded systematic review on the effectiveness and risks of long-term opioid therapy for chronic pain comprehensively addressed four clinical questions (14,52). CDC, with the assistance of a methodology expert, searched the literature to identify newly published studies on these four original questions. Because long-term opioid use might be affected by use of opioids for acute pain, CDC subsequently developed a fifth clinical question (last in the series below), and in collaboration with a methodologist conducted a systematic review of the scientific evidence to address it. In brief, five clinical questions were addressed: • prescribing opioid therapy for acute pain on long-term use (KQ5). The review was focused on the effectiveness of long-term opioid therapy on long-term (>1 year) outcomes related to pain, function, and quality of life to ensure that findings are relevant to patients with chronic pain and long-term opioid prescribing. The effectiveness of short-term opioid therapy has already been established (10). However, opioids have unique effects such as tolerance and physical dependence that might influence assessments of benefit over time. These effects raise questions about whether findings on short-term effectiveness of opioid therapy can be extrapolated to estimate benefits of long-term therapy for chronic pain. Thus, it is important to consider studies that provide data on long-term benefit. For certain opioid-related harms (overdose, fractures, falls, motor vehicle crashes), observational studies were included with outcomes measured at shorter intervals because such outcomes can occur early during opioid therapy, and such harms are not captured well in short-term clinical trials. A detailed listing of the key questions is provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026). # Clinical Evidence Systematic Review Methods Complete methods and data for the 2014 AHRQ report, upon which this updated systematic review is based, have been published previously (14,52). Study authors developed the protocol using a standardized process (53) with input from experts and the public and registered the protocol in the PROSPERO database (54). For the 2014 AHRQ report, a research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL for Englishlanguage articles published January 2008 through August 2014, using search terms for opioid therapy, specific opioids, chronic pain, and comparative study designs. Also included were relevant studies from an earlier review (10) in which searches were conducted without a date restriction, reference lists were reviewed, and ClinicalTrials.gov was searched. CDC updated the AHRQ literature search using the same search strategies as in the original review including studies published before April, 2015. Seven additional studies met inclusion criteria and were added to the review. CDC used the GRADE approach outlined in the ACIP Handbook for Developing Evidence-Based Recommendations (47) to rate the quality of evidence for the full body of evidence (evidence from the 2014 AHRQ review plus the update) for each clinical question. Evidence was categorized into the following types: type 1 (randomized clinical trials or overwhelming evidence from observational studies), type 2 (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 (observational studies, or randomized clinical trials with notable limitations), or type 4 (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). When no studies were present, evidence was considered to be insufficient. Per GRADE methods, type of evidence was categorized by study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and constellation of plausible biases that could change effects. Results were synthesized qualitatively, highlighting new evidence identified during the update process. Meta-analysis was not attempted due to the small numbers of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of the studies. More detailed information about data sources and searches, study selection, data extraction and quality assessment, data synthesis, and update search yield and new evidence for the current review is provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026). # Summary of Findings for Clinical Questions The main findings of this updated review are consistent with the findings of the 2014 AHRQ report (14). In summary, evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited, with insufficient evidence to determine long-term benefits versus no opioid therapy, though evidence suggests risk for serious harms that appears to be dose-dependent. These findings supplement findings from a previous review of the effectiveness of opioids for adults with chronic noncancer pain. In this previous review, based on randomized trials predominantly ≤12 weeks in duration, opioids were found to be moderately effective for pain relief, with small benefits for functional outcomes; although estimates vary, based on uncontrolled studies, a high percentage of patients discontinued long-term opioid use because of lack of efficacy and because of adverse events (10). The GRADE evidence summary with type of evidence ratings for the five clinical questions for the current evidence review are outlined (Table 1). This summary is based on studies included in the AHRQ 2014 review (35 studies) plus additional studies identified in the updated search (seven studies). Additional details on findings from the original review are provided in the full 2014 AHRQ report (14,52). Full details on the clinical evidence review findings supporting this guideline are provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026). # Effectiveness For KQ1, no study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy for chronic pain evaluated long-term (≥1 year) outcomes related to pain, function, or quality of life. Most placebo-controlled randomized clinical trials were ≤6 weeks in duration. Thus, the body of evidence for KQ1 is rated as insufficient (0 studies contributing) (14). # Harms For KQ2, the body of evidence is rated as type 3 (12 studies contributing; 11 from the original review plus one new study). One fair-quality cohort study found that long-term opioid therapy is associated with increased risk for an opioid abuse or dependence diagnosis (as defined by ICD-9-CM codes) versus no opioid prescription (22). Rates of opioid abuse or dependence diagnosis ranged from 0.7% with lower-dose (≤36 MME) chronic therapy to 6.1% with higher-dose (≥120 MME) chronic therapy, versus 0.004% with no opioids prescribed. Ten fair-quality uncontrolled studies reported estimates of opioid abuse, addiction, and related outcomes (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). In primary care settings, prevalence of opioid dependence (using DSM-IV criteria) ranged from 3% to 26% (55,56,59). In pain clinic settings, prevalence of addiction ranged from 2% to 14% (57,58,60,61,(63)(64)(65). Factors associated with increased risk for misuse included history of substance use disorder, younger age, major depression, and use of psychotropic medications (55,62). Two studies reported on the association between opioid use and risk for overdose (66,67). One large fair-quality retrospective cohort study found that recent opioid use was associated with increased risk for any overdose events and serious overdose events versus nonuse (66) Findings of increased fracture risk for current opioid use, versus nonuse, were mixed in two studies (68,69). Two studies found an association between opioid use and increased risk for cardiovascular events (70,71). Indirect evidence was found for endocrinologic harms (increased use of medications for erectile dysfunction or testosterone from one previously included study; laboratory-defined androgen deficiency from one newly reviewed study) (72,73). One study found that opioid dosages ≥20 MME/day were associated with increased odds of road trauma among drivers (74). # Opioid Dosing Strategies For KQ3, the body of evidence is rated as type 4 (14 studies contributing; 12 from the original review plus two new studies). For initiation and titration of opioids, the 2014 AHRQ report found insufficient evidence from three fair-quality, open-label trials to determine comparative effectiveness of ER/LA versus immediate-release opioids for titrating patients to stable pain control (75,76). One new fair-quality cohort study of Veterans Affairs patients found initiation of therapy with an ER/LA opioid associated with greater risk for nonfatal overdose than initiation with an immediate-release opioid, with risk greatest in the first 2 weeks after initiation of treatment (77). For comparative effectiveness and harms of ER/LA opioids, the 2014 AHRQ report included three randomized, headto-head trials of various ER/LA opioids that found no clear differences in 1-year outcomes related to pain or function (78)(79)(80) # but had methodological shortcomings. A fair-quality retrospective cohort study based on national Veterans Health Administration system pharmacy data found that methadone was associated with lower overall risk for all-cause mortality versus morphine (81), and a fair-quality retrospective cohort study based on Oregon Medicaid data found no statistically significant differences between methadone and long-acting morphine in risk for death or overdose symptoms (82). However, a new observational study (83) found methadone associated with increased risk for overdose versus sustainedrelease morphine among Tennessee Medicaid patients. The observed inconsistency in study findings suggests that risks of methadone might vary in different settings as a function of different monitoring and management protocols, though more research is needed to understand factors associated with safer methadone prescribing. For dose escalation, the 2014 AHRQ report included one fair-quality randomized trial that found no differences between more liberal dose escalation and maintenance of current doses after 12 months in pain, function, all-cause withdrawals, or withdrawals due to opioid misuse (84). However, the difference in opioid dosages prescribed at the end of the trial was relatively small (mean 52 MME/day with more liberal dosing versus 40 MME/day). Evidence on other comparisons related to opioid dosing strategies (ER/LA versus immediaterelease opioids; immediate-release plus ER/LA opioids versus ER/LA opioids alone; scheduled continuous dosing versus as-needed dosing; or opioid rotation versus maintenance of current therapy; long-term effects of strategies for treating acute exacerbations of chronic pain) was not available or too limited to determine effects on long-term clinical outcomes. For example, evidence on the comparative effectiveness of opioid tapering or discontinuation versus maintenance, and of different opioid tapering strategies, was limited to small, poor-quality studies (85)(86)(87). # Risk Assessment and Mitigation For KQ4, the body of evidence is rated as type 3 for the accuracy of risk assessment tools and insufficient for the effectiveness of use of risk assessment tools and mitigation strategies in reducing harms (six studies contributing; four from the original review plus two new studies). The 2014 AHRQ report included four studies (88-91) on the accuracy of risk assessment instruments, administered prior to opioid therapy initiation, for predicting opioid abuse or misuse. Results for the Opioid Risk Tool (ORT) (89-91) were extremely inconsistent; evidence for other risk assessment instruments was very sparse, and studies had serious methodological shortcomings. One additional fair-quality ( 92) and one poor-quality ( 93) study identified for this update compared the predictive accuracy of the ORT, the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), and the Brief Risk Interview. For the ORT, sensitivity was 0.58 and 0.75 and specificity 0.54 and 0.86; for the SOAPP-R, sensitivity was 0.53 and 0.25 and specificity 0.62 and 0.73; and for the Brief Risk Interview, sensitivity was 0.73 and 0.83 and specificity 0.43 and 0.88. For the ORT, positive likelihood ratios ranged from noninformative (positive likelihood ratio close to 1) to moderately useful (positive likelihood ratio >5). The SOAPP-R was associated with noninformative likelihood ratios (estimates close to 1) in both studies. No study evaluated the effectiveness of risk mitigation strategies (use of risk assessment instruments, opioid management plans, patient education, urine drug testing, use of PDMP data, use of monitoring instruments, more frequent monitoring intervals, pill counts, or use of abuse-deterrent formulations) for improving outcomes related to overdose, addiction, abuse, or misuse. # Effects of Opioid Therapy for Acute Pain on Long-Term Use For KQ5, the body of evidence is rated as type 3 (two new studies contributing). Two fair-quality retrospective cohort studies found opioid therapy prescribed for acute pain associated with greater likelihood of long-term use. One study evaluated opioid-naïve patients who had undergone low-risk surgery, such as cataract surgery and varicose vein stripping (94). Use of opioids within 7 days of surgery was associated with increased risk for use at 1 year. The other study found that among patients with a workers' compensation claim for acute low back pain, compared to patients who did not receive opioids early after injury (defined as use within 15 days following onset of pain), patients who did receive early opioids had an increased likelihood of receiving five or more opioid prescriptions 30-730 days following onset that increased with greater early exposure. Versus no early opioid use, the adjusted OR was 2.08 (95% CI = 1.55-2.78) for 1-140 MME/day and increased to 6.14 (95% confidence interval [CI] = 4.92-7.66) for ≥450 MME/day (95). # Summary of the Contextual Evidence Review Primary Areas of Focus Contextual evidence is complementary information that assists in translating the clinical research findings into recommendations. CDC conducted contextual evidence reviews on four topics to supplement the clinical evidence review findings: • Effectiveness of nonpharmacologic (e.g., cognitive behavioral therapy [CBT], exercise therapy, interventional treatments, and multimodal pain treatment) and nonopioid pharmacologic treatments (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs], antidepressants, and anticonvulsants), including studies of any duration. • Benefits and harms of opioid therapy (including additional studies not included in the clinical evidence review, such as studies that were not restricted to patients with chronic pain, evaluated outcomes at any duration, performed ecological analyses, or used observational study designs other than cohort and case-cohort control studies) related to specific opioids, high-dose therapy, co-prescription with other controlled substances, duration of use, special populations, and potential usefulness of risk stratification/ mitigation approaches, in addition to effectiveness of treatments associated with addressing potential harms of opioid therapy (opioid use disorder). • Clinician and patient values and preferences related to opioids and medication risks, benefits, and use. • Resource allocation including costs and economic efficiency of opioid therapy and risk mitigation strategies. CDC also reviewed clinical guidelines that were relevant to opioid prescribing and could inform or complement the CDC recommendations under development (e.g., guidelines on nonpharmacologic and nonopioid pharmacologic treatments and guidelines with recommendations related to specific clinician actions such as urine drug testing or opioid tapering protocols). # Contextual Evidence Review Methods CDC conducted a contextual evidence review to assist in developing the recommendations by providing an assessment of the balance of benefits and harms, values and preferences, and cost, consistent with the GRADE approach. Given the public health urgency for developing opioid prescribing recommendations, a rapid review was required for the contextual evidence review for the current guideline. Rapid reviews are used when there is a need to streamline the systematic review process to obtain evidence quickly (96). Methods used to streamline the process include limiting searches by databases, years, and languages considered, and truncating quality assessment and data abstraction protocols. CDC conducted "rapid reviews" of the contextual evidence on nonpharmacologic and nonopioid pharmacologic treatments, benefits and harms, values and preferences, and resource allocation. Detailed information about contextual evidence data sources and searches, inclusion criteria, study selection, and data extraction and synthesis are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). In brief, CDC conducted systematic literature searches to identify original studies, systematic reviews, and clinical guidelines, depending on the topic being searched. CDC also solicited publication referrals from subject matter experts. Given the need for a rapid review process, grey literature (e.g., literature by academia, organizations, or government in the forms of reports, documents, or proceedings not published by commercial publishers) was not systematically searched. Database sources, including MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, varied by topic. Multiple reviewers scanned study abstracts identified through the database searches and extracted relevant studies for review. CDC constructed narrative summaries and tables based on relevant articles that met inclusion criteria, which are provided in the Contextual Evidence Review (http://stacks.cdc.gov/ view/cdc/38027). Findings from the contextual reviews provide indirect evidence and should be interpreted accordingly. CDC did not formally rate the quality of evidence for the studies included in the contextual evidence review using the GRADE method. The studies that addressed benefits and harms, values and preferences, and resource allocation most often employed observational methods, used short follow-up periods, and evaluated selected samples. Therefore the strength of the evidence from these contextual review areas was considered to be low, comparable to type 3 or type 4 evidence. The quality of evidence for nonopioid pharmacologic and nonpharmacologic pain treatments was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines (e.g., for treatment of chronic neuropathic pain, low back pain, osteoarthritis, and fibromyalgia). Similarly, the quality of evidence on pharmacologic and psychosocial opioid use disorder treatment was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines. # Summary of Findings for Contextual Areas Full narrative reviews and tables that summarize key findings from the contextual evidence review are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). # Effectiveness of Nonpharmacologic and Nonopioid Pharmacologic Treatments Several nonpharmacologic and nonopioid pharmacologic treatments have been shown to be effective in managing chronic pain in studies ranging in duration from 2 weeks to 6 months. For example, CBT that trains patients in behavioral techniques and helps patients modify situational factors and cognitive processes that exacerbate pain has small positive effects on disability and catastrophic thinking (97). Exercise therapy can help reduce pain and improve function in chronic low back pain (98), improve function and reduce pain in osteoarthritis of the knee (99) and hip (100), and improve well-being, fibromyalgia symptoms, and physical function in fibromyalgia (101). Multimodal and multidisciplinary therapies (e.g., therapies that combine exercise and related therapies with psychologically based approaches) can help reduce pain and improve function more effectively than single modalities (102,103). Nonopioid pharmacologic approaches used for pain include analgesics such as acetaminophen, NSAIDs, and cyclooxygenase 2 (COX-2) inhibitors; selected anticonvulsants; and selected antidepressants (particularly tricyclics and serotonin and norepinephrine reuptake inhibitors [SNRIs]). Multiple guidelines recommend acetaminophen as first-line pharmacotherapy for osteoarthritis (104)(105)(106)(107)(108)(109) or for low back pain ( 110) but note that it should be avoided in liver failure and that dosage should be reduced in patients with hepatic insufficiency or a history of alcohol abuse (109). Although guidelines also recommend NSAIDs as first-line treatment for osteoarthritis or low back pain (106,110), NSAIDs and COX-2 inhibitors do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks (111). FDA has recently strengthened existing label warnings that NSAIDs increase risks for heart attack and stroke, including that these risks might increase with longer use or at higher doses (112). Several guidelines agree that first-and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs (113)(114)(115)(116). Interventional approaches such as epidural injection for certain conditions (e.g., lumbar radiculopathy) can provide short-term improvement in pain (117)(118)(119). Epidural injection has been associated with rare but serious adverse events, including loss of vision, stroke, paralysis, and death (120). # Benefits and Harms of Opioid Therapy Balance between benefits and harms is a critical factor influencing the strength of clinical recommendations. In particular, CDC considered what is known from the epidemiology research about benefits and harms related to specific opioids and formulations, high dose therapy, co-prescription with other controlled substances, duration of use, special populations, and risk stratification and mitigation approaches. Additional information on benefits and harms of long-term opioid therapy from studies meeting rigorous selection criteria is provided in the clinical evidence review (e.g., see KQ2). CDC also considered the number of persons experiencing chronic pain, numbers potentially benefiting from opioids, and numbers affected by opioid-related harms. A review of these data is presented in the background section of this document, with detailed information provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/ cdc/38027). Finally, CDC considered the effectiveness of treatments that addressed potential harms of opioid therapy (opioid use disorder). Regarding specific opioids and formulations, as noted by FDA, there are serious risks of ER/LA opioids, and the indication for this class of medications is for management of pain severe enough to require daily, around-the-clock, longterm opioid treatment in patients for whom other treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain (121). Time-scheduled opioid use was associated with substantially higher average daily opioid dosage than as-needed opioid use in one study (122). Methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for pain. Methadone has been found to account for as much as a third of opioidrelated overdose deaths involving single or multiple drugs in states that participated in the Drug Abuse Warning Network, which was more than any opioid other than oxycodone, despite representing <2% of opioid prescriptions outside of opioid treatment programs in the United States; further, methadone was involved in twice as many single-drug deaths as any other prescription opioid (123). Regarding high-dose therapy, several epidemiologic studies that were excluded from the clinical evidence review because patient samples were not restricted to patients with chronic pain also examined the association between opioid dosage and overdose risk (23,24,(124)(125)(126). Consistent with the clinical evidence review, the contextual review found that opioid-related overdose risk is dosedependent, with higher opioid dosages associated with increased overdose risk. Two of these studies (23,24), as well as the two studies in the clinical evidence review (66,67), evaluated similar MME/day dose ranges for association with overdose risk. In these four studies, compared with opioids prescribed at <20 MME/ day, the odds of overdose among patients prescribed opioids for chronic nonmalignant pain were between 1.3 (67) and 1.9 (24) for dosages of 20 to <50 MME/day, between 1.9 (67) and 4.6 (24) for dosages of 50 to <100 MME/day, and between 2.0 (67) and 8.9 (66) for dosages of ≥100 MME/day. Compared with dosages of 1-<20 MME/day, absolute risk difference approximation for 50-<100 MME/day was 0.15% for fatal overdose (24) and 1.40% for any overdose (66), and for ≥100 MME/day was 0.25% for fatal overdose (24) and 4.04% for any overdose (66). A recent study of Veterans Health Administration patients with chronic pain found that patients who died of overdoses related to opioids were prescribed higher opioid dosages (mean: 98 MME/day; median: 60 MME/day) than controls (mean: 48 MME/day, median: 25 MME/day) (127). Finally, another recent study of overdose deaths among state residents with and without opioid prescriptions revealed that prescription opioid-related overdose mortality rates rose rapidly up to prescribed doses of 200 MME/day, after which the mortality rates continued to increase but grew more gradually (128). A listing of common opioid medications and their MME equivalents is provided (Table 2). Regarding coprescription of opioids with benzodiazepines, epidemiologic studies suggest that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31%-61% of decedents (67,128,129). In one of these studies (67), among decedents who received an opioid prescription, those whose deaths were related to opioids were more likely to have obtained opioids from multiple physicians and pharmacies than decedents whose deaths were not related to opioids. Regarding duration of use, patients can experience tolerance and loss of effectiveness of opioids over time (130). Patients who do not experience clinically meaningful pain relief early in treatment (i.e., within 1 month) are unlikely to experience pain relief with longer-term use (131). Regarding populations potentially at greater risk for harm, risk is greater for patients with sleep apnea or other causes of sleep-disordered breathing, patients with renal or hepatic insufficiency, older adults, pregnant women, patients with depression or other mental health conditions, and patients with alcohol or other substance use disorders. Interpretation of clinical data on the effects of opioids on sleep-disordered breathing is difficult because of the types of study designs and methods employed, and there is no clear consensus regarding association with risk for developing obstructive sleep apnea syndrome (132). However, opioid therapy can decrease respiratory drive, a high percentage of patients on long-term opioid therapy have been reported to have an abnormal apneahypopnea index (133), opioid therapy can worsen central sleep apnea in obstructive sleep apnea patients, and it can cause further desaturation in obstructive sleep apnea patients not on continuous positive airway pressure (CPAP) (31). Reduced renal or hepatic function can result in greater peak effect and longer duration of action and reduce the dose at which respiratory depression and overdose occurs (134). Age-related changes in patients aged ≥65 years, such as reduced renal function and medication clearance, even in the absence of renal disease (135), result in a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose. Older adults might also be at increased risk for falls and fractures related to opioids (136)(137)(138). Opioids used in pregnancy can be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with birth defects, including neural tube defects (139,140), congenital heart defects (140), and gastroschisis (140); preterm delivery (141), poor fetal growth (141), and stillbirth (141). Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal syndrome (142). Patients with mental health comorbidities and patients with histories of substance use disorders might be at higher risk than other patients for opioid use disorder (62,143,144). Recent analyses found that depressed patients were at higher risk for drug overdose than patients without depression, particularly at higher opioid dosages, although investigators were unable to distinguish unintentional overdose from suicide attempts (145). In case-control and case-cohort studies, substance abuse/dependence was more prevalent among patients experiencing overdose than among patients not experiencing overdose (12% versus 6% [66], 40% versus 10% [24], and 26% versus 9% [23]). Regarding risk stratification approaches, limited evidence was found regarding benefits and harms. Potential benefits of PDMPs and urine drug testing include the ability to identify patients who might be at higher risk for opioid overdose or opioid use disorder, and help determine which patients will benefit from greater caution and increased monitoring or interventions when risk factors are present. For example, one study found that most fatal overdoses could be identified retrospectively on the basis of two pieces of information, multiple prescribers and high total daily opioid dosage, both important risk factors for overdose (124,146) that are available to prescribers in the PDMP (124). However, limited evaluation of PDMPs at the state level has revealed mixed effects on changes in prescribing and mortality outcomes (28). Potential harms of risk stratification include underestimation of risks of opioid therapy when screening tools are not adequately sensitive, as well as potential overestimation of risk, which could lead to inappropriate clinical decisions. Regarding risk mitigation approaches, limited evidence was found regarding benefits and harms. Although no studies were found to examine prescribing of naloxone with opioid pain medication in primary care settings, naloxone distribution through community-based programs providing prevention services for substance users has been demonstrated to be associated with decreased risk for opioid overdose death at the community level (147). Concerns have been raised that prescribing changes such as dose reduction might be associated with unintended negative consequences, such as patients seeking heroin or other illicitly obtained opioids (148) or interference with appropriate pain treatment (149). With the exception of a study noting an association between an abuse-deterrent formulation of OxyContin and heroin use, showing that some patients in qualitative interviews reported switching to another opioid, including heroin, for many reasons, including cost and availability as well as ease of use (150), CDC did not identify studies evaluating these potential outcomes. Finally, regarding the effectiveness of opioid use disorder treatments, methadone and buprenorphine for opioid use disorder have been found to increase retention in treatment and to decrease illicit opioid use among patients with opioid use disorder involving heroin (151)(152)(153). Although findings are mixed, some studies suggest that effectiveness is enhanced when psychosocial treatments (e.g., contingency management, community reinforcement, psychotherapeutic counseling, and family therapy) are used in conjunction with medicationassisted therapy; for example, by reducing opioid misuse and increasing retention during maintenance therapy, and improving compliance after detoxification (154,155). # Clinician and Patient Values and Preferences Clinician and patient values and preferences can inform how benefits and harms of long-term opioid therapy are weighted and estimate the effort and resources required to effectively provide implementation support. Many physicians lack confidence in their ability to prescribe opioids safely (156), to predict (157) or detect (158) prescription drug abuse, and to discuss abuse with their patients (158). Although clinicians have reported favorable beliefs and attitudes about improvements in pain and quality of life attributed to opioids (159), most consider prescription drug abuse to be a "moderate" or "big" problem in their community, and large proportions are "very" concerned about opioid addiction (55%) and death (48%) (160). Clinicians do not consistently use practices intended to decrease the risk for misuse, such as PDMPs (161,162), urine drug testing (163), and opioid treatment agreements (164). This is likely due in part to challenges related to registering for PDMP access and logging into the PDMP (which can interrupt normal clinical workflow if data are not integrated into electronic health record systems) (165), competing clinical demands, perceived inadequate time to discuss the rationale for urine drug testing and to order confirmatory testing, and feeling unprepared to interpret and address results (166). Many patients do not have an opinion about "opioids" or know what this term means (167). Most are familiar with the term "narcotics." About a third associated "narcotics" with addiction or abuse, and about half feared "addiction" from long-term "narcotic" use (168). Most patients taking opioids experience side effects (73% of patients taking hydrocodone for noncancer pain [11], 96% of patients taking opioids for chronic pain [12]), and side effects, rather than pain relief, have been found to explain most of the variation in patients' preferences related to taking opioids (12). For example, patients taking hydrocodone for noncancer pain commonly reported side effects including dizziness, headache, fatigue, drowsiness, nausea, vomiting, and constipation (11). Patients with chronic pain in focus groups emphasized effectiveness of goal setting for increasing motivation and functioning (168). Patients taking high dosages report reliance on opioids despite ambivalence about their benefits (169) and regardless of pain reduction, reported problems, concerns, side effects, or perceived helpfulness (13). # Resource Allocation Resource allocation (cost) is an important consideration in understanding the feasibility of clinical recommendations. CDC searched for evidence on opioid therapy compared with other treatments; costs of misuse, abuse, and overdose from prescription opioids; and costs of specific risk mitigation strategies (e.g., urine drug testing). Yearly direct and indirect costs related to prescription opioids have been estimated (based on studies published since 2010) to be $53.4 billion for nonmedical use of prescription opioids (170); $55.7 billion for abuse, dependence (i.e., opioid use disorder), and misuse of prescription opioids (171); and $20.4 billion for direct and indirect costs related to opioid-related overdose alone (172). In 2012, total expenses for outpatient prescription opioids were estimated at $9.0 billion, an increase of 120% from 2002 (173). Although there are perceptions that opioid therapy for chronic pain is less expensive than more timeintensive nonpharmacologic management approaches, many pain treatments, including acetaminophen, NSAIDs, tricyclic antidepressants, and massage therapy, are associated with lower mean and median annual costs compared with opioid therapy (174). COX-2 inhibitors, SNRIs, anticonvulsants, topical analgesics, physical therapy, and CBT are also associated with lower median annual costs compared with opioid therapy (174). Limited information was found on costs of strategies to decrease risks associated with opioid therapy; however, urine drug testing, including screening and confirmatory tests, has been estimated to cost $211-$363 per test (175). # Recommendations The recommendations are grouped into three areas for consideration: • Determining when to initiate or continue opioids for chronic pain. • Opioid selection, dosage, duration, follow-up, and discontinuation. • Assessing risk and addressing harms of opioid use. There are 12 recommendations (Box 1). Each recommendation is followed by a rationale for the recommendation, with considerations for implementation noted. In accordance with the ACIP GRADE process, CDC based the recommendations on consideration of the clinical evidence, contextual evidence (including benefits and harms, values and preferences, resource allocation), and expert opinion. For each recommendation statement, CDC notes the recommendation category (A or B) and the type of the evidence (1, 2, 3, or 4) supporting the statement (Box 2). Expert opinion is reflected within each of the recommendation rationales. While there was not an attempt to reach consensus among experts, experts from the Core Expert Group and from the Opioid Guideline Workgroup ("experts") expressed overall, general support for all recommendations. Where differences in expert opinion emerged for detailed actions within the clinical recommendations or for implementation considerations, CDC notes the differences of opinion in the supporting rationale statements. Category A recommendations indicate that most patients should receive the recommended course of action; category B recommendations indicate that different choices will be appropriate for different patients, requiring clinicians to help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. Consistent with the ACIP (47) and GRADE process (48), category A recommendations were made, even with type 3 and 4 evidence, when there was broad agreement that the advantages of a clinical action greatly outweighed the disadvantages based on a consideration of benefits and harms, values and preferences, and resource allocation. Category B recommendations were made when there was broad agreement that the advantages and disadvantages of a clinical action were more balanced, but advantages were significant enough to warrant a recommendation. All recommendations are category A recommendations, with the exception of recommendation 10, which is rated as category B. Recommendations were associated with a range of evidence types, from type 2 to type 4. In summary, the categorization of recommendations was based on the following assessment: • No evidence shows a long-term benefit of opioids in pain and function versus no opioids for chronic pain with outcomes examined at least 1 year later (with most placebocontrolled randomized trials ≤6 weeks in duration). • Extensive evidence shows the possible harms of opioids (including opioid use disorder, overdose, and motor vehicle injury). • Extensive evidence suggests some benefits of nonpharmacologic and nonopioid pharmacologic treatments compared with long-term opioid therapy, with less harm. # h a r m a c o l o g i c t h e r a p y, a s a p p r o p r i a t e (recommendation category: A, evidence type: 3). Patients with pain should receive treatment that provides the greatest benefits relative to risks. The contextual evidence review found that many nonpharmacologic therapies, including physical therapy, weight loss for knee osteoarthritis, psychological therapies such as CBT, and certain interventional procedures can ameliorate chronic pain. There is high-quality evidence that exercise therapy (a prominent modality in physical therapy) for hip (100) or knee (99) osteoarthritis reduces pain and improves function immediately after treatment and that the improvements are sustained for at least 2-6 months. Previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip (176). Exercise therapy also can help reduce pain and improve function in low back pain and can improve global well-being and physical function in fibromyalgia (98,101). Multimodal therapies and multidisciplinary biopsychosocial rehabilitation-combining approaches (e.g., psychological therapies with exercise) can reduce long-term pain and disability compared with usual care and compared with physical treatments (e.g., exercise) alone. Multimodal therapies are not always available or reimbursed by insurance and can be time-consuming and costly for patients. Interventional approaches such as arthrocentesis and intraarticular glucocorticoid injection for pain associated with rheumatoid arthritis (117) or osteoarthritis (118) and subacromial corticosteroid injection for rotator cuff disease (119) can provide short-term improvement in pain and function. Evidence is insufficient to determine the extent to which repeated glucocorticoid injection increases potential risks such as articular cartilage changes (in osteoarthritis) and sepsis (118). Serious adverse events are rare but have been reported with epidural injection (120). Several nonopioid pharmacologic therapies (including acetaminophen, NSAIDs, and selected antidepressants and anticonvulsants) are effective for chronic pain. In particular, acetaminophen and NSAIDs can be useful for arthritis and low back pain. Selected anticonvulsants such as pregabalin and gabapentin can improve pain in diabetic neuropathy and post-herpetic neuralgia (contextual evidence review). Pregabalin, gabapentin, and carbamazepine are FDA-approved for treatment of certain neuropathic pain conditions, and pregabalin is FDA approved for fibromyalgia management. In patients with or without depression, tricyclic antidepressants and SNRIs provide effective analgesia for neuropathic pain conditions including diabetic neuropathy and post-herpetic neuralgia, often at lower dosages and with a shorter time to onset of effect than for treatment of depression (see contextual evidence review). Tricyclics and SNRIs can also relieve fibromyalgia symptoms. The SNRI duloxetine is FDA-approved for the treatment of diabetic neuropathy and fibromyalgia. Because patients with chronic pain often suffer from concurrent depression (144), and depression can exacerbate physical symptoms including pain (177), patients with co-occurring pain and depression are especially likely to benefit from antidepressant medication (see Recommendation 8). Nonopioid pharmacologic therapies # BOX 2. Interpretation of recommendation categories and evidence type # Recommendation Categories Based on evidence type, balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendation: Applies to all persons; most patients should receive the recommended course of action. Category B recommendation: Individual decision making needed; different choices will be appropriate for different patients. Clinicians help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. # Evidence Type Based on study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, doseresponse gradient, and constellation of plausible biases that could change effects. Type 1 evidence: Randomized clinical trials or overwhelming evidence from observational studies. Type 2 evidence: Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies. Type 3 evidence: Observational studies or randomized clinical trials with notable limitations. Type 4 evidence: Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations. are not generally associated with substance use disorder, and the numbers of fatal overdoses associated with nonopioid medications are a fraction of those associated with opioid medications (contextual evidence review). For example, acetaminophen, NSAIDs, and opioid pain medication were involved in 881, 228, and 16,651 pharmaceutical overdose deaths in the United States in 2010 (178). However, nonopioid pharmacologic therapies are associated with certain risks, particularly in older patients, pregnant patients, and patients with certain co-morbidities such as cardiovascular, renal, gastrointestinal, and liver disease (see contextual evidence review). For example, acetaminophen can be hepatotoxic at dosages of >3-4 grams/day and at lower dosages in patients with chronic alcohol use or liver disease (109). NSAID use has been associated with gastritis, peptic ulcer disease, cardiovascular events (111,112), and fluid retention, and most NSAIDs (choline magnesium trilisate and selective COX-2 inhibitors are exceptions) interfere with platelet aggregation (179). Clinicians should review FDA-approved labeling including boxed warnings before initiating treatment with any pharmacologic therapy. Although opioids can reduce pain during short-term use, the clinical evidence review found insufficient evidence to determine whether pain relief is sustained and whether function or quality of life improves with long-term opioid therapy (KQ1). While benefits for pain relief, function, and quality of life with long-term opioid use for chronic pain are uncertain, risks associated with long-term opioid use are clearer and significant. Based on the clinical evidence review, long-term opioid use for chronic pain is associated with serious risks including increased risk for opioid use disorder, overdose, myocardial infarction, and motor vehicle injury (KQ2). At a population level, more than 165,000 persons in the United States have died from opioid pain-medication-related overdoses since 1999 (see Contextual Evidence Review). Integrated pain management requires coordination of medical, psychological, and social aspects of health care and includes primary care, mental health care, and specialist services when needed (180). Nonpharmacologic physical and psychological treatments such as exercise and CBT are approaches that encourage active patient participation in the care plan, address the effects of pain in the patient's life, and can result in sustained improvements in pain and function without apparent risks. Despite this, these therapies are not always or fully covered by insurance, and access and cost can be barriers for patients. For many patients, aspects of these approaches can be used even when there is limited access to specialty care. For example, previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip (176) and maintenance of activity for patients with low back pain (110). A randomized trial found no difference in reduced chronic low back pain intensity, frequency or disability between patients assigned to relatively low-cost group aerobics and individual physiotherapy or muscle reconditioning sessions (181). Low-cost options to integrate exercise include brisk walking in public spaces or use of public recreation facilities for group exercise. CBT addresses psychosocial contributors to pain and improves function (97). Primary care clinicians can integrate elements of a cognitive behavioral approach into their practice by encouraging patients to take an active role in the care plan, by supporting patients in engaging in beneficial but potentially anxiety-provoking activities, such as exercise (179), or by providing education in relaxation techniques and coping strategies. In many locations, there are free or low-cost patient support, self-help, and educational community-based programs that can provide stress reduction and other mental health benefits. Patients with more entrenched anxiety or fear related to pain, or other significant psychological distress, can be referred for formal therapy with a mental health specialist (e.g., psychologist, psychiatrist, clinical social worker). Multimodal therapies should be considered for patients not responding to single-modality therapy, and combinations should be tailored depending on patient needs, cost, and convenience. To guide patient-specific selection of therapy, clinicians should evaluate patients and establish or confirm the diagnosis. Detailed recommendations on diagnosis are provided in other guidelines (110,179), but evaluation should generally include a focused history, including history and characteristics of pain and potentially contributing factors (e.g., function, psychosocial stressors, sleep) and physical exam, with imaging or other diagnostic testing only if indicated (e.g., if severe or progressive neurologic deficits are present or if serious underlying conditions are suspected) (110,179). For complex pain syndromes, pain specialty consultation can be considered to assist with diagnosis as well as management. Diagnosis can help identify disease-specific interventions to reverse or ameliorate pain; for example, improving glucose control to prevent progression of diabetic neuropathy; immune-modulating agents for rheumatoid arthritis; physical or occupational therapy to address posture, muscle weakness, or repetitive occupational motions that contribute to musculoskeletal pain; or surgical intervention to relieve mechanical/compressive pain (179). The underlying mechanism for most pain syndromes can be categorized as neuropathic (e.g., diabetic neuropathy, postherpetic neuralgia, fibromyalgia), or nociceptive (e.g., osteoarthritis, muscular back pain). The diagnosis and pathophysiologic mechanism of pain have implications for symptomatic pain treatment with medication. For example, evidence is limited or insufficient for improved pain or function with long-term use of opioids for several chronic pain conditions for which opioids are commonly prescribed, such as low back pain (182), headache (183), and fibromyalgia (184). Although NSAIDs can be used for exacerbations of nociceptive pain, other medications (e.g., tricyclics, selected anticonvulsants, or transdermal lidocaine) generally are recommended for neuropathic pain. In addition, improvement of neuropathic pain can begin weeks or longer after symptomatic treatment is initiated (179). Medications should be used only after assessment and determination that expected benefits outweigh risks given patient-specific factors. For example, clinicians should consider falls risk when selecting and dosing potentially sedating medications such as tricyclics, anticonvulsants, or opioids, and should weigh risks and benefits of use, dose, and duration of NSAIDs when treating older adults as well as patients with hypertension, renal insufficiency, or heart failure, or those with risk for peptic ulcer disease or cardiovascular disease. Some guidelines recommend topical NSAIDs for localized osteoarthritis (e.g., knee osteoarthritis) over oral NSAIDs in patients aged ≥75 years to minimize systemic effects (176). Experts agreed that opioids should not be considered firstline or routine therapy for chronic pain (i.e., pain continuing or expected to continue >3 months or past the time of normal tissue healing) outside of active cancer, palliative, and endof-life care, given small to moderate short-term benefits, uncertain long-term benefits, and potential for serious harms; although evidence on long-term benefits of nonopioid therapies is also limited, these therapies are also associated with short-term benefits, and risks are much lower. This does not mean that patients should be required to sequentially "fail" nonpharmacologic and nonopioid pharmacologic therapy before proceeding to opioid therapy. Rather, expected benefits specific to the clinical context should be weighed against risks before initiating therapy. In some clinical contexts (e.g., headache or fibromyalgia), expected benefits of initiating opioids are unlikely to outweigh risks regardless of previous nonpharmacologic and nonopioid pharmacologic therapies used. In other situations (e.g., serious illness in a patient with poor prognosis for return to previous level of function, contraindications to other therapies, and clinician and patient agreement that the overriding goal is patient comfort), opioids might be appropriate regardless of previous therapies used. In addition, when opioid pain medication is used, it is more likely to be effective if integrated with nonpharmacologic therapy. Nonpharmacologic approaches such as exercise and CBT should be used to reduce pain and improve function in patients with chronic pain. Nonopioid pharmacologic therapy should be used when benefits outweigh risks and should be combined with nonpharmacologic therapy to reduce pain and improve function. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate, to provide greater benefits to patients in improving pain and function. # Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety (recommendation category: A, evidence type: 4). The clinical evidence review found insufficient evidence to determine long-term benefits of opioid therapy for chronic pain and found an increased risk for serious harms related to long-term opioid therapy that appears to be dose-dependent. In addition, studies on currently available risk assessment instruments were sparse and showed inconsistent results (KQ4). The clinical evidence review for the current guideline considered studies with outcomes examined at ≥1 year that compared opioid use versus nonuse or placebo. Studies of opioid therapy for chronic pain that did not have a nonopioid control group have found that although many patients discontinue opioid therapy for chronic noncancer pain due to adverse effects or insufficient pain relief, there is weak evidence that patients who are able to continue opioid therapy for at least 6 months can experience clinically significant pain relief and insufficient evidence that function or quality of life improves (185). These findings suggest that it is very difficult for clinicians to predict whether benefits of opioids for chronic pain will outweigh risks of ongoing treatment for individual patients. Opioid therapy should not be initiated without consideration of an "exit strategy" to be used if the therapy is unsuccessful. Experts agreed that before opioid therapy is initiated for chronic pain outside of active cancer, palliative, and end-oflife care, clinicians should determine how effectiveness will be evaluated and should establish treatment goals with patients. Because the line between acute pain and initial chronic pain is not always clear, it might be difficult for clinicians to determine when they are initiating opioids for chronic pain rather than treating acute pain. Pain lasting longer than 3 months or past the time of normal tissue healing (which could be substantially shorter than 3 months, depending on the condition) is generally no longer considered acute. However, establishing treatment goals with a patient who has already received opioid therapy for 3 months would defer this discussion well past the point of initiation of opioid therapy for chronic pain. Clinicians often write prescriptions for long-term use in 30-day increments, and opioid prescriptions written for ≥30 days are likely to represent initiation or continuation of long-term opioid therapy. Before writing an opioid prescription for ≥30 days, clinicians should establish treatment goals with patients. Clinicians seeing new patients already receiving opioids should establish treatment goals for continued opioid therapy. Although the clinical evidence review did not find studies evaluating the effectiveness of written agreements or treatment plans (KQ4), clinicians and patients who set a plan in advance will clarify expectations regarding how opioids will be prescribed and monitored, as well as situations in which opioids will be discontinued or doses tapered (e.g., if treatment goals are not met, opioids are no longer needed, or adverse events put the patient at risk) to improve patient safety. Experts thought that goals should include improvement in both pain relief and function (and therefore in quality of life). However, there are some clinical circumstances under which reductions in pain without improvement in physical function might be a more realistic goal (e.g., diseases typically associated with progressive functional impairment or catastrophic injuries such as spinal cord trauma). Experts noted that function can include emotional and social as well as physical dimensions. In addition, experts emphasized that mood has important interactions with pain and function. Experts agreed that clinicians may use validated instruments such as the threeitem "Pain average, interference with Enjoyment of life, and interference with General activity" (PEG) Assessment Scale (186) to track patient outcomes. Clinically meaningful improvement has been defined as a 30% improvement in scores for both pain and function (187). Monitoring progress toward patient-centered functional goals (e.g., walking the dog or walking around the block, returning to part-time work, attending family sports or recreational activities) can also contribute to the assessment of functional improvement. Clinicians should use these goals in assessing benefits of opioid therapy for individual patients and in weighing benefits against risks of continued opioid therapy (see Recommendation 7, including recommended intervals for follow-up). Because depression, anxiety, and other psychological co-morbidities often coexist with and can interfere with resolution of pain, clinicians should use validated instruments to assess for these conditions (see Recommendation 8) and ensure that treatment for these conditions is optimized. If patients receiving opioid therapy for chronic pain do not experience meaningful improvements in both pain and function compared with prior to initiation of opioid therapy, clinicians should consider working with patients to taper and discontinue opioids (see Recommendation 7) and should use nonpharmacologic and nonopioid pharmacologic approaches to pain management (see Recommendation 1). # Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy (recommendation category: A, evidence type: 3). The clinical evidence review did not find studies evaluating effectiveness of patient education or opioid treatment plans as risk-mitigation strategies (KQ4). However, the contextual evidence review found that many patients lack information about opioids and identified concerns that some clinicians miss opportunities to effectively communicate about safety. Given the substantial evidence gaps on opioids, uncertain benefits of long-term use, and potential for serious harms, patient education and discussion before starting opioid therapy are critical so that patient preferences and values can be understood and used to inform clinical decisions. Experts agreed that essential elements to communicate to patients before starting and periodically during opioid therapy include realistic expected benefits, common and serious harms, and expectations for clinician and patient responsibilities to mitigate risks of opioid therapy. Clinicians should involve patients in decisions about whether to start or continue opioid therapy. Given potentially serious risks of long-term opioid therapy, clinicians should ensure that patients are aware of potential benefits of, harms of, and alternatives to opioids before starting or continuing opioid therapy. Clinicians are encouraged to have open and honest discussions with patients to inform mutual decisions about whether to start or continue opioid therapy. Important considerations include the following: • Be explicit and realistic about expected benefits of opioids, explaining that while opioids can reduce pain during shortterm use, there is no good evidence that opioids improve pain or function with long-term use, and that complete relief of pain is unlikely (clinical evidence review, KQ1). • Emphasize improvement in function as a primary goal and that function can improve even when pain is still present. • Advise patients about serious adverse effects of opioids, including potentially fatal respiratory depression and development of a potentially serious lifelong opioid use disorder that can cause distress and inability to fulfill major role obligations. • Advise patients about common effects of opioids, such as constipation, dry mouth, nausea, vomiting, drowsiness, confusion, tolerance, physical dependence, and withdrawal symptoms when stopping opioids. To prevent constipation associated with opioid use, advise patients to increase hydration and fiber intake and to maintain or increase physical activity. Stool softeners or laxatives might be needed. • Discuss effects that opioids might have on ability to safely operate a vehicle, particularly when opioids are initiated, when dosages are increased, or when other central nervous system depressants, such as benzodiazepines or alcohol, are used concurrently. • Discuss increased risks for opioid use disorder, respiratory depression, and death at higher dosages, along with the importance of taking only the amount of opioids prescribed, i.e., not taking more opioids or taking them more often. • Review increased risks for respiratory depression when opioids are taken with benzodiazepines, other sedatives, alcohol, illicit drugs such as heroin, or other opioids. • Discuss risks to household members and other individuals if opioids are intentionally or unintentionally shared with others for whom they are not prescribed, including the possibility that others might experience overdose at the same or at lower dosage than prescribed for the patient, and that young children are susceptible to unintentional ingestion. Discuss storage of opioids in a secure, preferably locked location and options for safe disposal of unused opioids (188). • Discuss the importance of periodic reassessment to ensure that opioids are helping to meet patient goals and to allow opportunities for opioid discontinuation and consideration of additional nonpharmacologic or nonopioid pharmacologic treatment options if opioids are not effective or are harmful. • Discuss planned use of precautions to reduce risks, including use of prescription drug monitoring program information (see Recommendation 9) and urine drug testing (see Recommendation 10). Consider including discussion of naloxone use for overdose reversal (see Recommendation 8). • Consider whether cognitive limitations might interfere with management of opioid therapy (for older adults in particular) and, if so, determine whether a caregiver can responsibly co-manage medication therapy. Discuss the importance of reassessing safer medication use with both the patient and caregiver. Given the possibility that benefits of opioid therapy might diminish or that risks might become more prominent over time, it is important that clinicians review expected benefits and risks of continued opioid therapy with patients periodically, at least every 3 months (see Recommendation 7). # Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation # When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4). ER/LA opioids include methadone, transdermal fentanyl, and extended-release versions of opioids such as oxycodone, oxymorphone, hydrocodone, and morphine. The clinical evidence review found a fair-quality study showing a higher risk for overdose among patients initiating treatment with ER/LA opioids than among those initiating treatment with immediate-release opioids (77). The clinical evidence review did not find evidence that continuous, time-scheduled use of ER/LA opioids is more effective or safer than intermittent use of immediate-release opioids or that time-scheduled use of ER/ LA opioids reduces risks for opioid misuse or addiction (KQ3). In 2014, the FDA modified the labeling for ER/LA opioid pain medications, noting serious risks and recommending that ER/LA opioids be reserved for "management of pain severe enough to require daily, around-the-clock, long-term opioid treatment" when "alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain" and not used as "as needed" pain relievers (121). FDA has also noted that some ER/LA opioids are only appropriate for opioid-tolerant patients, defined as patients who have received certain dosages of opioids (e.g., 60 mg daily of oral morphine, 30 mg daily of oral oxycodone, or equianalgesic dosages of other opioids) for at least 1 week (189). Time-scheduled opioid use can be associated with greater total average daily opioid dosage compared with intermittent, as-needed opioid use (contextual evidence review). In addition, experts indicated that there was not enough evidence to determine the safety of using immediate-release opioids for breakthrough pain when ER/ LA opioids are used for chronic pain outside of active cancer pain, palliative care, or end-of-life care, and that this practice might be associated with dose escalation. Abuse-deterrent technologies have been employed to prevent manipulation intended to defeat extended-release properties of ER/LA opioids and to prevent opioid use by unintended routes of administration, such as injection of oral opioids. As indicated in FDA guidance for industry on evaluation and labeling of abuse-deterrent opioids (190), although abusedeterrent technologies are expected to make manipulation of opioids more difficult or less rewarding, they do not prevent opioid abuse through oral intake, the most common route of opioid abuse, and can still be abused by nonoral routes. The "abuse-deterrent" label does not indicate that there is no risk for abuse. No studies were found in the clinical evidence review assessing the effectiveness of abuse-deterrent technologies as a risk mitigation strategy for deterring or preventing abuse. In addition, abuse-deterrent technologies do not prevent unintentional overdose through oral intake. Experts agreed that recommendations could not be offered at this time related to use of abuse-deterrent formulations. In comparing different ER/LA formulations, the clinical evidence review found inconsistent results for overdose risk with methadone versus other ER/LA opioids used for chronic pain (KQ3). The contextual evidence review found that methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for chronic pain. In addition, methadone is associated with cardiac arrhythmias along with QT prolongation on the electrocardiogram, and it has complicated pharmacokinetics and pharmacodynamics, including a long and variable halflife and peak respiratory depressant effect occurring later and lasting longer than peak analgesic effect. Experts noted that the pharmacodynamics of methadone are subject to more interindividual variability than other opioids. In regard to other ER/ LA opioid formulations, experts noted that the absorption and pharmacodynamics of transdermal fentanyl are complex, with gradually increasing serum concentration during the first part of the 72-hour dosing interval, as well as variable absorption based on factors such as external heat. In addition, the dosing of transdermal fentanyl in mcg/hour, which is not typical for a drug used by outpatients, can be confusing. Experts thought that these complexities might increase the risk for fatal overdose when methadone or transdermal fentanyl is prescribed to a patient who has not used it previously or by clinicians who are not familiar with its effects. Experts agreed that for patients not already receiving opioids, clinicians should not initiate opioid treatment with ER/LA opioids and should not prescribe ER/LA opioids for intermittent use. ER/LA opioids should be reserved for severe, continuous pain and should be considered only for patients who have received immediate-release opioids daily for at least 1 week. When changing to an ER/LA opioid for a patient previously receiving a different immediate-release opioid, clinicians should consult product labeling and reduce total daily dosage to account for incomplete opioid cross-tolerance. Clinicians should use additional caution with ER/LA opioids and consider a longer dosing interval when prescribing to patients with renal or hepatic dysfunction because decreased clearance of drugs among these patients can lead to accumulation of drugs to toxic levels and persistence in the body for longer durations. Although there might be situations in which clinicians need to prescribe immediate-release and ER/LA opioids together (e.g., transitioning patients from ER/LA opioids to immediate-release opioids by temporarily using lower dosages of both), in general, avoiding the use of immediate-release opioids in combination with ER/LA opioids is preferable, given potentially increased risk and diminishing returns of such an approach for chronic pain. When an ER/LA opioid is prescribed, using one with predictable pharmacokinetics and pharmacodynamics is preferred to minimize unintentional overdose risk. In particular, unusual characteristics of methadone and of transdermal fentanyl make safe prescribing of these medications for pain especially challenging. • Methadone should not be the first choice for an ER/LA opioid. Only clinicians who are familiar with methadone's unique risk profile and who are prepared to educate and closely monitor their patients, including risk assessment f o r QT p ro l o n g a t i o n a n d c o n s i d e r a t i o n o f electrocardiographic monitoring, should consider prescribing methadone for pain. A clinical practice guideline that contains further guidance regarding methadone prescribing for pain has been published previously (191). • Because dosing effects of transdermal fentanyl are often misunderstood by both clinicians and patients, only clinicians who are familiar with the dosing and absorption properties of transdermal fentanyl and are prepared to educate their patients about its use should consider prescribing it. # When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (recommendation category: A, evidence type: 3). Benefits of high-dose opioids for chronic pain are not established. The clinical evidence review found only one study (84) addressing effectiveness of dose titration for outcomes related to pain control, function, and quality of life (KQ3). This randomized trial found no difference in pain or function between a more liberal opioid dose escalation strategy and maintenance of current dosage. (These groups were prescribed average dosages of 52 and 40 MME/day, respectively, at the end of the trial.) At the same time, risks for serious harms US Department of Health and Human Services/Centers for Disease Control and Prevention related to opioid therapy increase at higher opioid dosage. The clinical evidence review found that higher opioid dosages are associated with increased risks for motor vehicle injury, opioid use disorder, and overdose (KQ2). The clinical and contextual evidence reviews found that opioid overdose risk increases in a dose-response manner, that dosages of 50-<100 MME/day have been found to increase risks for opioid overdose by factors of 1.9 to 4.6 compared with dosages of 1-<20 MME/day, and that dosages ≥100 MME/day are associated with increased risks of overdose 2.0-8.9 times the risk at 1-<20 MME/day. In a national sample of Veterans Health Administration patients with chronic pain who were prescribed opioids, mean prescribed opioid dosage among patients who died from opioid overdose was 98 MME (median 60 MME) compared with mean prescribed opioid dosage of 48 MME (median 25 MME) among patients not experiencing fatal overdose (127). The contextual evidence review found that although there is not a single dosage threshold below which overdose risk is eliminated, holding dosages <50 MME/day would likely reduce risk among a large proportion of patients who would experience fatal overdose at higher prescribed dosages. Experts agreed that lower dosages of opioids reduce the risk for overdose, but that a single dosage threshold for safe opioid use could not be identified. Experts noted that daily opioid dosages close to or greater than 100 MME/day are associated with significant risks, that dosages <50 MME/day are safer than dosages of 50-100 MME/day, and that dosages <20 MME/day are safer than dosages of 20-50 MME/day. One expert thought that a specific dosage at which the benefit/risk ratio of opioid therapy decreases could not be identified. Most experts agreed that, in general, increasing dosages to 50 or more MME/day increases overdose risk without necessarily adding benefits for pain control or function and that clinicians should carefully reassess evidence of individual benefits and risks when considering increasing opioid dosages to ≥50 MME/day. Most experts also agreed that opioid dosages should not be increased to ≥90 MME/day without careful justification based on diagnosis and on individualized assessment of benefits and risks. When opioids are used for chronic pain outside of active cancer, palliative, and end-of-life care, clinicians should start opioids at the lowest possible effective dosage (the lowest starting dosage on product labeling for patients not already taking opioids and according to product labeling guidance regarding tolerance for patients already taking opioids). Clinicians should use additional caution when initiating opioids for patients aged ≥65 years and for patients with renal or hepatic insufficiency because decreased clearance of drugs in these patients can result in accumulation of drugs to toxic levels. Clinicians should use caution when increasing opioid dosages and increase dosage by the smallest practical amount because overdose risk increases with increases in opioid dosage. Although there is limited evidence to recommend specific intervals for dosage titration, a previous guideline recommended waiting at least five half-lives before increasing dosage and waiting at least a week before increasing dosage of methadone to make sure that full effects of the previous dosage are evident (31). Clinicians should re-evaluate patients after increasing dosage for changes in pain, function, and risk for harm (see Recommendation 7). Before increasing total opioid dosage to ≥50 MME/day, clinicians should reassess whether opioid treatment is meeting the patient's treatment goals (see Recommendation 2). If a patient's opioid dosage for all sources of opioids combined reaches or exceeds 50 MME/day, clinicians should implement additional precautions, including increased frequency of follow-up (see Recommendation 7) and considering offering naloxone and overdose prevention education to both patients and the patients' household members (see Recommendation 8). Clinicians should avoid increasing opioid dosages to ≥90 MME/day or should carefully justify a decision to increase dosage to ≥90 MME/day based on individualized assessment of benefits and risks and weighing factors such as diagnosis, incremental benefits for pain and function relative to harms as dosages approach 90 MME/day, other treatments and effectiveness, and recommendations based on consultation with pain specialists. If patients do not experience improvement in pain and function at ≥90 MME/day, or if there are escalating dosage requirements, clinicians should discuss other approaches to pain management with the patient, consider working with patients to taper opioids to a lower dosage or to taper and discontinue opioids (see Recommendation 7), and consider consulting a pain specialist. Some states require clinicians to implement clinical protocols at specific dosage levels. For example, before increasing long-term opioid therapy dosage to >120 MME/day, clinicians in Washington state must obtain consultation from a pain specialist who agrees that this is indicated and appropriate (30). Clinicians should be aware of rules related to MME thresholds and associated clinical protocols established by their states. Established patients already taking high dosages of opioids, as well as patients transferring from other clinicians, might consider the possibility of opioid dosage reduction to be anxiety-provoking, and tapering opioids can be especially challenging after years on high dosages because of physical and psychological dependence. However, these patients should be offered the opportunity to re-evaluate their continued use of opioids at high dosages in light of recent evidence regarding the association of opioid dosage and overdose risk. Clinicians should explain in a nonjudgmental manner to patients already taking high opioid dosages (≥90 MME/day) that there is now an established body of scientific evidence showing that overdose risk is increased at higher opioid dosages. Clinicians should empathically review benefits and risks of continued high-dosage opioid therapy and should offer to work with the patient to taper opioids to safer dosages. For patients who agree to taper opioids to lower dosages, clinicians should collaborate with the patient on a tapering plan (see Recommendation 7). Experts noted that patients tapering opioids after taking them for years might require very slow opioid tapers as well as pauses in the taper to allow gradual accommodation to lower opioid dosages. Clinicians should remain alert to signs of anxiety, depression, and opioid use disorder (see Recommendations 8 and 12) that might be unmasked by an opioid taper and arrange for management of these co-morbidities. For patients agreeing to taper to lower opioid dosages as well as for those remaining on high opioid dosages, clinicians should establish goals with the patient for continued opioid therapy (see Recommendation 2), maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 1), and consider consulting a pain specialist as needed to assist with pain management. # Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed (recommendation category: A, evidence type: 4). The clinical evidence review found that opioid use for acute pain (i.e., pain with abrupt onset and caused by an injury or other process that is not ongoing) is associated with long-term opioid use, and that a greater amount of early opioid exposure is associated with greater risk for long-term use (KQ5). Several guidelines on opioid prescribing for acute pain from emergency departments (192)(193)(194) and other settings (195,196) have recommended prescribing ≤3 days of opioids in most cases, whereas others have recommended ≤7 days (197) or <14 days (30). Because physical dependence on opioids is an expected physiologic response in patients exposed to opioids for more than a few days (contextual evidence review), limiting days of opioids prescribed also should minimize the need to taper opioids to prevent distressing or unpleasant withdrawal symptoms. Experts noted that more than a few days of exposure to opioids significantly increases hazards, that each day of unnecessary opioid use increases likelihood of physical dependence without adding benefit, and that prescriptions with fewer days' supply will minimize the number of pills available for unintentional or intentional diversion. Experts agreed that when opioids are needed for acute pain, clinicians should prescribe opioids at the lowest effective dose and for no longer than the expected duration of pain severe enough to require opioids to minimize unintentional initiation of long-term opioid use. The lowest effective dose can be determined using product labeling as a starting point with calibration as needed based on the severity of pain and on other clinical factors such as renal or hepatic insufficiency (see Recommendation 8). Experts thought, based on clinical experience regarding anticipated duration of pain severe enough to require an opioid, that in most cases of acute pain not related to surgery or trauma, a ≤3 days' supply of opioids will be sufficient. For example, in one study of the course of acute low back pain (not associated with malignancies, infections, spondylarthropathies, fractures, or neurological signs) in a primary care setting, there was a large decrease in pain until the fourth day after treatment with paracetamol, with smaller decreases thereafter (198). Some experts thought that because some types of acute pain might require more than 3 days of opioid treatment, it would be appropriate to recommend a range of ≤3-5 days or ≤3-7 days when opioids are needed. Some experts thought that a range including 7 days was too long given the expected course of severe acute pain for most acute pain syndromes seen in primary care. Acute pain can often be managed without opioids. It is important to evaluate the patient for reversible causes of pain, for underlying etiologies with potentially serious sequelae, and to determine appropriate treatment. When the diagnosis and severity of nontraumatic, nonsurgical acute pain are reasonably assumed to warrant the use of opioids, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids, often 3 days or less, unless circumstances clearly warrant additional opioid therapy. More than 7 days will rarely be needed. Opioid treatment for post-surgical pain is outside the scope of this guideline but has been addressed elsewhere (30). Clinicians should not prescribe additional opioids to patients "just in case" pain continues longer than expected. Clinicians should re-evaluate the subset of patients who experience severe acute pain that continues longer than the expected duration to confirm or revise the initial diagnosis and to adjust management accordingly. Given longer half-lives and longer duration of effects (e.g., respiratory depression) with ER/LA opioids such as methadone, fentanyl patches, or extended release versions of opioids such as oxycodone, oxymorphone, or morphine, clinicians should not prescribe ER/LA opioids for the treatment of acute pain. : 4). Although the clinical evidence review did not find studies evaluating the effectiveness of more frequent monitoring intervals (KQ4), it did find that continuing opioid therapy for 3 months substantially increases risk for opioid use disorder (KQ2); therefore, follow-up earlier than 3 months might be necessary to provide the greatest opportunity to prevent the development of opioid use disorder. In addition, risk for overdose associated with ER/LA opioids might be particularly high during the first 2 weeks of treatment (KQ3). The contextual evidence review found that patients who do not have pain relief with opioids at 1 month are unlikely to experience pain relief with opioids at 6 months. Although evidence is insufficient to determine at what point within the first 3 months of opioid therapy the risks for opioid use disorder increase, reassessment of pain and function within 1 month of initiating opioids provides an opportunity to minimize risks of long-term opioid use by discontinuing opioids among patients not receiving a clear benefit from these medications. Experts noted that risks for opioid overdose are greatest during the first 3-7 days after opioid initiation or increase in dosage, particularly when methadone or transdermal fentanyl are prescribed; that follow-up within 3 days is appropriate when initiating or increasing the dosage of methadone; and that follow-up within 1 week might be appropriate when initiating or increasing the dosage of other ER/LA opioids. Clinicians should evaluate patients to assess benefits and harms of opioids within 1 to 4 weeks of starting long-term opioid therapy or of dose escalation. Clinicians should consider follow-up intervals within the lower end of this range when ER/LA opioids are started or increased or when total daily opioid dosage is ≥50 MME/day. Shorter follow-up intervals (within 3 days) should be strongly considered when starting or increasing the dosage of methadone. At follow up, clinicians should assess benefits in function, pain control, and quality of life using tools such as the three-item "Pain average, interference with Enjoyment of life, and interference with General activity" (PEG) Assessment Scale (186) and/or asking patients about progress toward functional goals that have meaning for them (see Recommendation 2). Clinicians should also ask patients about common adverse effects such as constipation and drowsiness (see Recommendation 3), as well as asking about and assessing for effects that might be early warning signs for more serious problems such as overdose (e.g., sedation or slurred speech) or opioid use disorder (e.g., craving, wanting to take opioids in greater quantities or more frequently than prescribed, or difficulty controlling use). Clinicians should ask patients about their preferences for continuing opioids, given their effects on pain and function relative to any adverse effects experienced. Because of potential changes in the balance of benefits and risks of opioid therapy over time, clinicians should regularly reassess all patients receiving long-term opioid therapy, including patients who are new to the clinician but on longterm opioid therapy, at least every 3 months. At reassessment, clinicians should determine whether opioids continue to meet treatment goals, including sustained improvement in pain and function, whether the patient has experienced common or serious adverse events or early warning signs of serious adverse events, signs of opioid use disorder (e.g., difficulty controlling use, work or family problems related to opioid use), whether benefits of opioids continue to outweigh risks, and whether opioid dosage can be reduced or opioids can be discontinued. Ideally, these reassessments would take place in person and be conducted by the prescribing clinician. In practice contexts where virtual visits are part of standard care (e.g., in remote areas where distance or other issues make follow-up visits challenging), follow-up assessments that allow the clinician to communicate with and observe the patient through video and audio could be conducted, with in-person visits occurring at least once per year. Clinicians should re-evaluate patients who are exposed to greater risk of opioid use disorder or overdose (e.g., patients with depression or other mental health conditions, a history of substance use disorder, a history of overdose, taking ≥50 MME/day, or taking other central nervous system depressants with opioids) more frequently than every 3 months. If clinically meaningful improvements in pain and function are not sustained, if patients are taking high-risk regimens (e.g., dosages ≥50 MME/day or opioids combined with benzodiazepines) without evidence of benefit, if patients believe benefits no longer outweigh risks or if they request dosage reduction or discontinuation, or if patients experience overdose or other serious adverse events (e.g., an event leading to hospitalization or disability) or warning signs of serious adverse events, clinicians should work with patients to reduce opioid dosage or to discontinue opioids when possible. Clinicians should maximize pain treatment with nonpharmacologic and nonopioid pharmacologic treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to assist with pain management. # Considerations for Tapering Opioids Although the clinical evidence review did not find highquality studies comparing the effectiveness of different tapering protocols for use when opioid dosage is reduced or opioids are discontinued (KQ3), tapers reducing weekly dosage by 10%-50% of the original dosage have been recommended by other clinical guidelines (199), and a rapid taper over 2-3 weeks has been recommended in the case of a severe adverse event such as overdose (30). Experts noted that tapers slower than 10% per week (e.g., 10% per month) also might be appropriate and better tolerated than more rapid tapers, particularly when patients have been taking opioids for longer durations (e.g., for years). Opioid withdrawal during pregnancy has been associated with spontaneous abortion and premature labor. When opioids are reduced or discontinued, a taper slow enough to minimize symptoms and signs of opioid withdrawal (e.g., drug craving, anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, or piloerection) should be used. A decrease of 10% of the original dose per week is a reasonable starting point; experts agreed that tapering plans may be individualized based on patient goals and concerns. Experts noted that at times, tapers might have to be paused and restarted again when the patient is ready and might have to be slowed once patients reach low dosages. Tapers may be considered successful as long as the patient is making progress. Once the smallest available dose is reached, the interval between doses can be extended. Opioids may be stopped when taken less frequently than once a day. More rapid tapers might be needed for patient safety under certain circumstances (e.g., for patients who have experienced overdose on their current dosage). Ultrarapid detoxification under anesthesia is associated with substantial risks, including death, and should not be used (200). Clinicians should access appropriate expertise if considering tapering opioids during pregnancy because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal. Patients who are not taking opioids (including patients who are diverting all opioids they obtain) do not require tapers. Clinicians should discuss with patients undergoing tapering the increased risk for overdose on abrupt return to a previously prescribed higher dose. Primary care clinicians should collaborate with mental health providers and with other specialists as needed to optimize nonopioid pain management (see Recommendation 1), as well as psychosocial support for anxiety related to the taper. More detailed guidance on tapering, including management of withdrawal symptoms has been published previously (30,201). If a patient exhibits signs of opioid use disorder, clinicians should offer or arrange for treatment of opioid use disorder (see Recommendation 12) and consider offering naloxone for overdose prevention (see Recommendation 8). # Assessing Risk and Addressing Harms of Opioid Use # Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present (recommendation category: A, evidence type: 4). The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on patient demographics or patient comorbidities (KQ2). However, based on the contextual evidence review and expert opinion, certain risk factors are likely to increase susceptibility to opioidassociated harms and warrant incorporation of additional strategies into the management plan to mitigate risk. Clinicians should assess these risk factors periodically, with frequency varying by risk factor and patient characteristics. For example, factors that vary more frequently over time, such as alcohol use, require more frequent follow up. In addition, clinicians should consider offering naloxone, re-evaluating patients more frequently (see Recommendation 7), and referring to pain and/or behavioral health specialists when factors that increase risk for harm, such as history of overdose, history of substance use disorder, higher dosages of opioids (≥50 MME/day), and concurrent use of benzodiazepines with opioids, are present. # Patients with Sleep-Disordered Breathing, Including Sleep Apnea Risk factors for sleep-disordered breathing include congestive heart failure, and obesity. Experts noted that careful monitoring and cautious dose titration should be used if opioids are prescribed for patients with mild sleep-disordered breathing. Clinicians should avoid prescribing opioids to patients with moderate or severe sleep-disordered breathing whenever possible to minimize risks for opioid overdose (contextual evidence review). # Pregnant Women Opioids used in pregnancy might be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with stillbirth, poor fetal growth, pre-term delivery, and birth defects (contextual evidence review). Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal syndrome. Clinicians and patients together should carefully weigh risks and benefits when making decisions about whether to initiate opioid therapy for chronic pain during pregnancy. In addition, before initiating opioid therapy for chronic pain for reproductive-age women, clinicians should discuss family planning and how long-term opioid use might affect any future pregnancy. For pregnant women already receiving opioids, clinicians should access appropriate expertise if considering tapering opioids because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal (see Recommendation 7). For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine or methadone has been associated with improved maternal outcomes and should be offered (202) (see Recommendation 12). Clinicians caring for pregnant women receiving opioids for pain or receiving buprenorphine or methadone for opioid use disorder should arrange for delivery at a facility prepared to monitor, evaluate for, and treat neonatal opioid withdrawal syndrome. In instances when travel to such a facility would present an undue burden on the pregnant woman, it is appropriate to deliver locally, monitor and evaluate the newborn for neonatal opioid withdrawal syndrome, and transfer the newborn for additional treatment if needed. Neonatal toxicity and death have been reported in breastfeeding infants whose mothers are taking codeine (contextual evidence review); previous guidelines have recommended that codeine be avoided whenever possible among mothers who are breast feeding and, if used, should be limited to the lowest possible dose and to a 4-day supply (203). # Patients with Renal or Hepatic Insufficiency Clinicians should use additional caution and increased monitoring (see Recommendation 7) to minimize risks of opioids prescribed for patients with renal or hepatic insufficiency, given their decreased ability to process and excrete drugs, susceptibility to accumulation of opioids, and reduced therapeutic window between safe dosages and dosages associated with respiratory depression and overdose (contextual evidence review; see Recommendations 4, 5, and 7). # Patients Aged ≥65 Years Inadequate pain treatment among persons aged ≥65 years has been documented (204). Pain management for older patients can be challenging given increased risks of both nonopioid pharmacologic therapies (see Recommendation 1) and opioid therapy in this population. Given reduced renal function and medication clearance even in the absence of renal disease, patients aged ≥65 years might have increased susceptibility to accumulation of opioids and a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose (contextual evidence review). Some older adults suffer from cognitive impairment, which can increase risk for medication errors and make opioid-related confusion more dangerous. In addition, older adults are more likely than younger adults to experience co-morbid medical conditions and more likely to receive multiple medications, some of which might interact with opioids (such as benzodiazepines). Clinicians should use additional caution and increased monitoring (see Recommendations 4, 5, and 7) to minimize risks of opioids prescribed for patients aged ≥65 years. Experts suggested that clinicians educate older adults receiving opioids to avoid risky medication-related behaviors such as obtaining controlled medications from multiple prescribers and saving unused medications. Clinicians should also implement interventions to mitigate common risks of opioid therapy among older adults, such as exercise or bowel regimens to prevent constipation, risk assessment for falls, and patient monitoring for cognitive impairment. # Patients with Mental Health Conditions Because psychological distress frequently interferes with improvement of pain and function in patients with chronic pain, using validated instruments such as the Generalized Anxiety Disorder (GAD)-7 and the Patient Health Questionnaire (PHQ)-9 or the PHQ-4 to assess for anxiety, post-traumatic stress disorder, and/or depression (205), might help clinicians improve overall pain treatment outcomes. Experts noted that clinicians should use additional caution and increased monitoring (see Recommendation 7) to lessen the increased risk for opioid use disorder among patients with mental health conditions (including depression, anxiety disorders, and PTSD), as well as increased risk for drug overdose among patients with depression. Previous guidelines have noted that opioid therapy should not be initiated during acute psychiatric instability or uncontrolled suicide risk, and that clinicians should consider behavioral health specialist consultation for any patient with a history of suicide attempt or psychiatric disorder (31). In addition, patients with anxiety disorders and other mental health conditions are more likely to receive benzodiazepines, which can exacerbate opioid-induced respiratory depression and increase risk for overdose (see Recommendation 11). Clinicians should ensure that treatment for depression and other mental health conditions is optimized, consulting with behavioral health specialists when needed. Treatment for depression can improve pain symptoms as well as depression and might decrease overdose risk (contextual evidence review). For treatment of chronic pain in patients with depression, clinicians should strongly consider using tricyclic or SNRI antidepressants for analgesic as well as antidepressant effects if these medications are not otherwise contraindicated (see Recommendation 1). # Patients with Substance Use Disorder Illicit drugs and alcohol are listed as contributory factors on a substantial proportion of death certificates for opioid-related overdose deaths (contextual evidence review). Previous guidelines have recommended screening or risk assessment tools to identify patients at higher risk for misuse or abuse of opioids. However, the clinical evidence review found that currently available riskstratification tools (e.g., Opioid Risk Tool, Screener and Opioid Assessment for Patients with Pain Version 1, SOAPP-R, and Brief Risk Interview) show insufficient accuracy for classification of patients as at low or high risk for abuse or misuse (KQ4). Clinicians should always exercise caution when considering or prescribing opioids for any patient with chronic pain outside of active cancer, palliative, and end-of-life care and should not overestimate the ability of these tools to rule out risks from long-term opioid therapy. Clinicians should ask patients about their drug and alcohol use. Single screening questions can be used (206). For example, the question "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" (with an answer of one or more considered positive) was found in a primary care setting to be 100% sensitive and 73.5% specific for the detection of a drug use disorder compared with a standardized diagnostic interview (207). Validated screening tools such as the Drug Abuse Screening Test (DAST) (208) and the Alcohol Use Disorders Identification Test (AUDIT) (209) can also be used. Clinicians should use PDMP data (see Recommendation 9) and drug testing (see Recommendation 10) as appropriate to assess for concurrent substance use that might place patients at higher risk for opioid use disorder and overdose. Clinicians should also provide specific counseling on increased risks for overdose when opioids are combined with other drugs or alcohol (see Recommendation 3) and ensure that patients receive effective treatment for substance use disorders when needed (see Recommendation 12). The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on past or current substance use disorder (KQ2), although a history of substance use disorder was associated with misuse. Similarly, based on contextual evidence, patients with drug or alcohol use disorders are likely to experience greater risks for opioid use disorder and overdose than persons without these conditions. If clinicians consider opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care for patients with drug or alcohol use disorders, they should discuss increased risks for opioid use disorder and overdose with patients, carefully consider whether benefits of opioids outweigh increased risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed. Because pain management in patients with substance use disorder can be complex, clinicians should consider consulting substance use disorder specialists and pain specialists regarding pain management for persons with active or recent past history of substance abuse. Experts also noted that clinicians should communicate with patients' substance use disorder treatment providers if opioids are prescribed. # Patients with Prior Nonfatal Overdose Although studies were not identified that directly addressed the risk for overdose among patients with prior nonfatal overdose who are prescribed opioids, based on clinical experience, experts thought that prior nonfatal overdose would substantially increase risk for future nonfatal or fatal opioid overdose. If patients experience nonfatal opioid overdose, clinicians should work with them to reduce opioid dosage and to discontinue opioids when possible (see Recommendation 7). If clinicians continue opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care in patients with prior opioid overdose, they should discuss increased risks for overdose with patients, carefully consider whether benefits of opioids outweigh substantial risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed. # Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present Naloxone is an opioid antagonist that can reverse severe respiratory depression; its administration by lay persons, such as friends and family of persons who experience opioid overdose, can save lives. Naloxone precipitates acute withdrawal among patients physically dependent on opioids. Serious adverse effects, such as pulmonary edema, cardiovascular instability, and seizures, have been reported but are rare at doses consistent with labeled use for opioid overdose (210). The contextual evidence review did not find any studies on effectiveness of prescribing naloxone for overdose prevention among patients prescribed opioids for chronic pain. However, there is evidence for effectiveness of naloxone provision in preventing opioid-related overdose death at the community level through community-based distribution (e.g., through overdose education and naloxone distribution programs in community service agencies) to persons at risk for overdose (mostly due to illicit opiate use), and it is plausible that effectiveness would be observed when naloxone is provided in the clinical setting as well. Experts agreed that it is preferable not to initiate opioid treatment when factors that increase risk for opioid-related harms are present. Opinions diverged about the likelihood of naloxone being useful to patients and the circumstances under which it should be offered. However, most experts agreed that clinicians should consider offering naloxone when prescribing opioids to patients at increased risk for overdose, including patients with a history of overdose, patients with a history of substance use disorder, patients taking benzodiazepines with opioids (see Recommendation 11), patients at risk for returning to a high dose to which they are no longer tolerant (e.g., patients recently released from prison), and patients taking higher dosages of opioids (≥50 MME/day). Practices should provide education on overdose prevention and naloxone use to patients receiving naloxone prescriptions and to members of their households. Experts noted that naloxone co-prescribing can be facilitated by clinics or practices with resources to provide naloxone training and by collaborative practice models with pharmacists. Resources for prescribing naloxone in primary care settings can be found through Prescribe to Prevent at http://prescribetoprevent.org. # 9. Clinicians should review the patient's history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4). PDMPs are state-based databases that collect information on controlled prescription drugs dispensed by pharmacies in most states and, in select states, by dispensing physicians as well. In addition, some clinicians employed by the federal government, including some clinicians in the Indian Health Care Delivery System, are not licensed in the states where they practice, and do not have access to PDMP data. Certain states require clinicians to review PDMP data prior to writing each opioid prescription (see state-level PDMP-related policies on the National Alliance for Model State Drug Laws website at http://www.namsdl.org/prescription-monitoring-programs. cfm). The clinical evidence review did not find studies evaluating the effectiveness of PDMPs on outcomes related to overdose, addiction, abuse, or misuse (KQ4). However, even though evidence is limited on the effectiveness of PDMP implementation at the state level on prescribing and mortality outcomes (28), the contextual evidence review found that most fatal overdoses were associated with patients receiving opioids from multiple prescribers and/or with patients receiving high total daily opioid dosages; information on both of these risk factors for overdose are available to prescribers in the PDMP. PDMP data also can be helpful when patient medication history is not otherwise available (e.g., for patients from other locales) and when patients transition care to a new clinician. The contextual evidence review also found that PDMP information could be used in a way that is harmful to patients. For example, it has been used to dismiss patients from clinician practices (211), which might adversely affect patient safety. The contextual review found variation in state policies that affect timeliness of PDMP data (and therefore benefits of reviewing PDMP data) as well as time and workload for clinicians in accessing PDMP data. In states that permit delegating access to other members of the health care team, workload for prescribers can be reduced. These differences might result in a different balance of benefits to clinician workload in different states. Experts agreed that PDMPs are useful tools that should be consulted when starting a patient on opioid therapy and periodically during long-term opioid therapy. However, experts disagreed on how frequently clinicians should check the PDMP during long-term opioid therapy, given PDMP access issues and the lag time in reporting in some states. Most experts agreed that PDMP data should be reviewed every 3 months or more frequently during longterm opioid therapy. A minority of experts noted that, given the current burden of accessing PDMP data in some states and the lack of evidence surrounding the most effective interval for PDMP review to improve patient outcomes, annual review of PDMP data during long-term opioid therapy would be reasonable when factors that increase risk for opioid-related harms are not present. Clinicians should review PDMP data for opioids and other controlled medications patients might have received from additional prescribers to determine whether a patient is receiving high total opioid dosages or dangerous combinations (e.g., opioids combined with benzodiazepines) that put him or her at high risk for overdose. Ideally, PDMP data should be reviewed before every opioid prescription. This is recommended in all states with well-functioning PDMPs and where PDMP access policies make this practicable (e.g., clinician and delegate access permitted), but it is not currently possible in states without functional PDMPs or in those that do not permit certain prescribers to access them. As vendors and practices facilitate integration of PDMP information into regular clinical workflow (e.g., data made available in electronic health records), clinicians' ease of access in reviewing PDMP data is expected to improve. In addition, improved timeliness of PDMP data will improve their value in identifying patient risks. If patients are found to have high opioid dosages, dangerous combinations of medications, or multiple controlled substance prescriptions written by different clinicians, several actions can be taken to augment clinicians' abilities to improve patient safety: • Clinicians should discuss information from the PDMP with their patient and confirm that the patient is aware of the additional prescriptions. Occasionally, PDMP information can be incorrect (e.g., if the wrong name or birthdate has been entered, the patient uses a nickname or maiden name, or another person has used the patient's identity to obtain prescriptions). • Clinicians should discuss safety concerns, including increased risk for respiratory depression and overdose, with patients found to be receiving opioids from more than one prescriber or receiving medications that increase risk when combined with opioids (e.g., benzodiazepines) and consider offering naloxone (see Recommendation 8). • Clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. Clinicians should communicate with others managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care (see Recommendation 11). • Clinicians should calculate the total MME/day for concurrent opioid prescriptions to help assess the patient's overdose risk (see Recommendation 5). If patients are found to be receiving high total daily dosages of opioids, clinicians should discuss their safety concerns with the patient, consider tapering to a safer dosage (see Recommendations 5 and 7), and consider offering naloxone (see Recommendation 8). • Clinicians should discuss safety concerns with other clinicians who are prescribing controlled substances for their patient. Ideally clinicians should first discuss concerns with their patient and inform him or her that they plan to coordinate care with the patient's other prescribers to improve the patient's safety. • Clinicians should consider the possibility of a substance use disorder and discuss concerns with their patient (see Recommendation 12). • If clinicians suspect their patient might be sharing or selling opioids and not taking them, clinicians should consider urine drug testing to assist in determining whether opioids can be discontinued without causing withdrawal (see Recommendations 7 and 10). A negative drug test for prescribed opioids might indicate the patient is not taking prescribed opioids, although clinicians should consider other possible reasons for this test result (see Recommendation 10). Experts agreed that clinicians should not dismiss patients from their practice on the basis of PDMP information. Doing so can adversely affect patient safety, could represent patient abandonment, and could result in missed opportunities to provide potentially lifesaving information (e.g., about risks of opioids and overdose prevention) and interventions (e.g., safer prescriptions, nonopioid pain treatment [see Recommendation 1], naloxone [see Recommendation 8], and effective treatment for substance use disorder [see Recommendation 12]). # When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs (recommendation category: B, evidence type: 4). Concurrent use of opioid pain medications with other opioid pain medications, benzodiazepines, or heroin can increase patients' risk for overdose. Urine drug tests can provide information about drug use that is not reported by the patient. In addition, urine drug tests can assist clinicians in identifying when patients are not taking opioids prescribed for them, which might in some cases indicate diversion or other clinically important issues such as difficulties with adverse effects. Urine drug tests do not provide accurate information about how much or what dose of opioids or other drugs a patient took. The clinical evidence review did not find studies evaluating the effectiveness of urine drug screening for risk mitigation during opioid prescribing for pain (KQ4). The contextual evidence review found that urine drug testing can provide useful information about patients assumed not to be using unreported drugs. Urine drug testing results can be subject to misinterpretation and might sometimes be associated with practices that might harm patients (e.g., stigmatization, inappropriate termination from care). Routine use of urine drug tests with standardized policies at the practice or clinic level might destigmatize their use. Although random drug testing also might destigmatize urine drug testing, experts thought that truly random testing was not feasible in clinical practice. Some clinics obtain a urine specimen at every visit, but only send it for testing on a random schedule. Experts noted that in addition to direct costs of urine drug testing, which often are not covered fully by insurance and can be a burden for patients, clinician time is needed to interpret, confirm, and communicate results. Experts agreed that prior to starting opioids for chronic pain and periodically during opioid therapy, clinicians should use urine drug testing to assess for prescribed opioids as well as other controlled substances and illicit drugs that increase risk for overdose when combined with opioids, including nonprescribed opioids, benzodiazepines, and heroin. There was some difference of opinion among experts as to whether this recommendation should apply to all patients, or whether this recommendation should entail individual decision making with different choices for different patients based on values, preferences, and clinical situations. While experts agreed that clinicians should use urine drug testing before initiating opioid therapy for chronic pain, they disagreed on how frequently urine drug testing should be conducted during long-term opioid therapy. Most experts agreed that urine drug testing at least annually for all patients was reasonable. Some experts noted that this interval might be too long in some cases and too short in others, and that the follow-up interval should be left to the discretion of the clinician. Previous guidelines have recommended more frequent urine drug testing in patients thought to be at higher risk for substance use disorder (30). However, experts thought that predicting risk prior to urine drug testing is challenging and that currently available tools do not allow clinicians to reliably identify patients who are at low risk for substance use disorder. In most situations, initial urine drug testing can be performed with a relatively inexpensive immunoassay panel for commonly prescribed opioids and illicit drugs. Patients prescribed less commonly used opioids might require specific testing for those agents. The use of confirmatory testing adds substantial costs and should be based on the need to detect specific opioids that cannot be identified on standard immunoassays or on the presence of unexpected urine drug test results. Clinicians should be familiar with the drugs included in urine drug testing panels used in their practice and should understand how to interpret results for these drugs. For example, a positive "opiates" immunoassay detects morphine, which might reflect patient use of morphine, codeine, or heroin, but this immunoassay does not detect synthetic opioids (e.g., fentanyl or methadone) and might not detect semisynthetic opioids (e.g., oxycodone). However, many laboratories use an oxycodone immunoassay that detects oxycodone and oxymorphone. In some cases, positive results for specific opioids might reflect metabolites from opioids the patient is taking and might not mean the patient is taking the specific opioid for which the test was positive. For example, hydromorphone is a metabolite of hydrocodone, and oxymorphone is a metabolite of oxycodone. Detailed guidance on interpretation of urine drug test results, including which tests to order and expected results, drug detection time in urine, drug metabolism, and other considerations has been published previously (30). Clinicians should not test for substances for which results would not affect patient management or for which implications for patient management are unclear. For example, experts noted that there might be uncertainty about the clinical implications of a positive urine drug test for tetrahyrdocannabinol (THC). In addition, restricting confirmatory testing to situations and substances for which results can reasonably be expected to affect patient management can reduce costs of urine drug testing, given the substantial costs associated with confirmatory testing methods. Before ordering urine drug testing, clinicians should have a plan for responding to unexpected results. Clinicians should explain to patients that urine drug testing is intended to improve their safety and should also explain expected results (e.g., presence of prescribed medication and absence of drugs, including illicit drugs, not reported by the patient). Clinicians should ask patients about use of prescribed and other drugs and ask whether there might be unexpected results. This will provide an opportunity for patients to provide information about changes in their use of prescribed opioids or other drugs. Clinicians should discuss unexpected results with the local laboratory or toxicologist and with the patient. Discussion with patients prior to specific confirmatory testing can sometimes yield a candid explanation of why a particular substance is present or absent and obviate the need for expensive confirmatory testing on that visit. For example, a patient might explain that the test is negative for prescribed opioids because she felt opioids were no longer helping and discontinued them. If unexpected results are not explained, a confirmatory test using a method selective enough to differentiate specific opioids and metabolites (e.g., gas or liquid chromatography/mass spectrometry) might be warranted to clarify the situation. Clinicians should use unexpected results to improve patient safety (e.g., change in pain management strategy [see Recommendation 1], tapering or discontinuation of opioids [see Recommendation 7], more frequent re-evaluation [see Recommendation 7], offering naloxone [see Recommendation 8], or referral for treatment for substance use disorder [see Recommendation 12], all as appropriate). If tests for prescribed opioids are repeatedly negative, confirming that the patient is not taking the prescribed opioid, clinicians can discontinue the prescription without a taper. Clinicians should not dismiss patients from care based on a urine drug test result because this could constitute patient abandonment and could have adverse consequences for patient safety, potentially including the patient obtaining opioids from alternative sources and the clinician missing opportunities to facilitate treatment for substance use disorder. # Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3). Benzodiazepines and opioids both cause central nervous system depression and can decrease respiratory drive. Concurrent use is likely to put patients at greater risk for potentially fatal overdose. The clinical evidence review did not address risks of benzodiazepine co-prescription among patients prescribed opioids. However, the contextual evidence review found evidence in epidemiologic series of concurrent benzodiazepine use in large proportions of opioid-related overdose deaths, and a case-cohort study found concurrent benzodiazepine prescription with opioid prescription to be associated with a near quadrupling of risk for overdose death compared with opioid prescription alone (212). Experts agreed that although there are circumstances when it might be appropriate to prescribe opioids to a patient receiving benzodiazepines (e.g., severe acute pain in a patient taking longterm, stable low-dose benzodiazepine therapy), clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. In addition, given that other central nervous system depressants (e.g., muscle relaxants, hypnotics) can potentiate central nervous system depression associated with opioids, clinicians should consider whether benefits outweigh risks of concurrent use of these drugs. Clinicians should check the PDMP for concurrent controlled medications prescribed by other clinicians (see Recommendation 9) and should consider involving pharmacists and pain specialists as part of the management team when opioids are co-prescribed with other central nervous system depressants. Because of greater risks of benzodiazepine withdrawal relative to opioid withdrawal, and because tapering opioids can be associated with anxiety, when patients receiving both benzodiazepines and opioids require tapering to reduce risk for fatal respiratory depression, it might be safer and more practical to taper opioids first (see Recommendation 7). Clinicians should taper benzodiazepines gradually if discontinued because abrupt withdrawal can be associated with rebound anxiety, hallucinations, seizures, delirium tremens, and, in rare cases, death (contextual evidence review). A commonly used tapering schedule that has been used safely and with moderate success is a reduction of the benzodiazepine dose by 25% every 1-2 weeks (213,214). CBT increases tapering success rates and might be particularly helpful for patients struggling with a benzodiazepine taper (213). If benzodiazepines prescribed for anxiety are tapered or discontinued, or if patients receiving opioids require treatment for anxiety, evidence-based psychotherapies (e.g., CBT) and/or specific anti-depressants or other nonbenzodiazepine medications approved for anxiety should be offered. Experts emphasized that clinicians should communicate with mental health professionals managing the patient to discuss the patient's needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care. The clinical evidence review found prevalence of opioid dependence (using DSM-IV diagnosis criteria) in primary care settings among patients with chronic pain on opioid therapy to be 3%-26% (KQ2). As found in the contextual evidence review and supported by moderate quality evidence, opioid agonist or partial agonist treatment with methadone maintenance therapy or buprenorphine has been shown to be more effective in preventing relapse among patients with opioid use disorder (151)(152)(153). Some studies suggest that using behavioral therapies in combination with these treatments can reduce opioid misuse and increase retention during maintenance therapy and improve compliance after detoxification (154,155); behavioral therapies are also recommended by clinical practice guidelines (215). The cited studies primarily evaluated patients with a history of illicit opioid use, rather than prescription opioid use for chronic pain. Recent studies among patients with prescription opioid dependence (based on DSM-IV criteria) have found maintenance therapy with buprenorphine and buprenorphinenaloxone effective in preventing relapse (216,217). Treatment need in a community is often not met by capacity to provide buprenorphine or methadone maintenance therapy (218), and patient cost can be a barrier to buprenorphine treatment because insurance coverage of buprenorphine for opioid use disorder is often limited (219). Oral or long-acting injectable formulations of naltrexone can also be used as medicationassisted treatment for opioid use disorder in nonpregnant adults, particularly for highly motivated persons (220,221). Experts agreed that clinicians prescribing opioids should identify treatment resources for opioid use disorder in the community and should work together to ensure sufficient treatment capacity for opioid use disorder at the practice level. If clinicians suspect opioid use disorder based on patient concerns or behaviors or on findings in prescription drug monitoring program data (see Recommendation 9) or from urine drug testing (see Recommendation 10), they should discuss their concern with their patient and provide an opportunity for the patient to disclose related concerns or problems. Clinicians should assess for the presence of opioid use disorder using DSM-5 criteria (20). Alternatively, clinicians can arrange for a substance use disorder treatment specialist to assess for the presence of opioid use disorder. For patients meeting criteria for opioid use disorder, clinicians should offer or arrange for patients to receive evidence-based treatment, usually medication-assisted treatment with buprenorphine or methadone maintenance therapy in combination with behavioral therapies. Oral or long-acting injectable naltrexone, a long-acting opioid antagonist, can also be used in nonpregnant adults. Naltrexone blocks the effects of opioids if they are used but requires adherence to daily oral therapy or monthly injections. For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine (without naloxone) or methadone has been associated with improved maternal outcomes and should be offered (see Recommendation 8). Clinicians should also consider offering naloxone for overdose prevention to patients with opioid use disorder (see Recommendation 8). For patients with problematic opioid use that does not meet criteria for opioid use disorder, experts noted that clinicians can offer to taper and discontinue opioids (see Recommendation 7). For patients who choose to but are unable to taper, clinicians may reassess for opioid use disorder and offer opioid agonist therapy if criteria are met. Physicians not already certified to provide buprenorphine in an office-based setting can undergo training to receive a waiver from the Substance Abuse and Mental Health Services Administration (SAMHSA) that allows them to prescribe buprenorphine to treat patients with opioid use disorder. Physicians prescribing opioids in communities without sufficient treatment capacity for opioid use disorder should strongly consider obtaining this waiver. Information about qualifications and the process to obtain a waiver are available from SAMHSA (222). Clinicians do not need a waiver to offer naltrexone for opioid use disorder as part of their practice. Additional guidance has been published previously (215) on induction, use, and monitoring of buprenorphine treatment (see Part 5) and naltrexone treatment (see Part 6) for opioid use disorder and on goals, components of, and types of effective psychosocial treatment that are recommended in conjunction with pharmacological treatment of opioid use disorder (see Part 7). Clinicians unable to provide treatment themselves should arrange for patients with opioid use disorder to receive care from a substance use disorder treatment specialist, such as an office-based buprenorphine or naltrexone treatment provider, or from an opioid treatment program certified by SAMHSA to provide supervised medication-assisted treatment for patients with opioid use disorder. Clinicians should assist patients in finding qualified treatment providers and should arrange for patients to follow up with these providers, as well as arranging for ongoing coordination of care. Clinicians should not dismiss patients from their practice because of a substance use disorder because this can adversely affect patient safety and could represent patient abandonment. Identification of substance use disorder represents an opportunity for a clinician to initiate potentially life-saving interventions, and it is important for the clinician to collaborate with the patient regarding their safety to increase the likelihood of successful treatment. In addition, although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. Clinicians should continue to use nonpharmacologic and nonopioid pharmacologic pain treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to provide optimal pain management. Resources to help with arranging for treatment include SAMHSA's buprenorphine physician locator (http:// buprenorphine.samhsa.gov/bwns_locator); SAMHSA's Opioid Treatment Program Directory (http://dpt2.samhsa. gov/treatment/directory.aspx); SAMHSA's Provider Clinical Support System for Opioid Therapies (http://pcss-o.org), which offers extensive experience in the treatment of substance use disorders and specifically of opioid use disorder, as well as expertise on the interface of pain and opioid misuse; and SAMHSA's Provider's Clinical Support System for Medication-Assisted Treatment (http://pcssmat.org), which offers expert physician mentors to answer questions about assessment for and treatment of substance use disorders. # Conclusions and Future Directions Clinical guidelines represent one strategy for improving prescribing practices and health outcomes. Efforts are required to disseminate the guideline and achieve widespread adoption and implementation of the recommendations in clinical settings. CDC will translate this guideline into user-friendly materials for distribution and use by health systems, medical professional societies, insurers, public health departments, health information technology developers, and clinicians and engage in dissemination efforts. CDC has provided a checklist for prescribing opioids for chronic pain (http:// stacks.cdc.gov/view/cdc/38025), additional resources such as fact sheets (http://www.cdc.gov/drugoverdose/prescribing/ resources.html), and will provide a mobile application to guide clinicians in implementing the recommendations. CDC will also work with partners to support clinician education on pain management options, opioid therapy, and risk mitigation strategies (e.g., urine drug testing). Activities such as development of clinical decision support in electronic health records to assist clinicians' treatment decisions at the point of care; identification of mechanisms that insurers and pharmacy benefit plan managers can use to promote safer prescribing within plans; and development of clinical quality improvement measures and initiatives to improve prescribing and patient care within health systems have promise for increasing guideline adoption and improving practice. In addition, policy initiatives that address barriers to implementation of the guidelines, such as increasing accessibility of PDMP data within and across states, e-prescribing, and availability of clinicians who can offer medication-assisted treatment for opioid use disorder, are strategies to consider to enhance implementation of the recommended practices. CDC will work with federal partners and payers to evaluate strategies such as payment reform and health care delivery models that could improve patient health and safety. For example, strategies might include strengthened coverage for nonpharmacologic treatments, appropriate urine drug testing, and medication-assisted treatment; reimbursable time for patient counseling; and payment models that improve access to interdisciplinary, coordinated care. As highlighted in the forthcoming report on the National Pain Strategy, an overarching federal effort that outlines a comprehensive population-level health strategy for addressing pain as a public health problem, clinical guidelines complement other strategies aimed at preventing illnesses and injuries that lead to pain. A draft of the National Pain Strategy has been published previously (180). These strategies include strengthening the evidence base for pain prevention and treatment strategies, reducing disparities in pain treatment, improving service delivery and reimbursement, supporting professional education and training, and providing public education. It is important that overall improvements be made in developing the workforce to address pain management in general, in addition to opioid prescribing specifically. This guideline also complements other federal efforts focused on addressing the opioid overdose epidemic including prescriber training and education, improving access to treatment for opioid use disorder, safe storage and disposal programs, utilization management mechanisms, naloxone distribution programs, law enforcement and supply reduction efforts, prescription drug monitoring program improvements, and support for community coalitions and state prevention programs. This guideline provides recommendations that are based on the best available evidence that was interpreted and informed by expert opinion. The clinical scientific evidence informing the recommendations is low in quality. To inform future guideline development, more research is necessary to fill in critical evidence gaps. The evidence reviews forming the basis of this guideline clearly illustrate that there is much yet to be learned about the effectiveness, safety, and economic efficiency of long-term opioid therapy. As highlighted by an expert panel in a recent workshop sponsored by the National Institutes of Health on the role of opioid pain medications in the treatment of chronic pain, "evidence is insufficient for every clinical decision that a provider needs to make about the use of opioids for chronic pain" (223). The National Institutes of Health panel recommended that research is needed to improve our understanding of which types of pain, specific diseases, and patients are most likely to be associated with benefit and harm from opioid pain medications; evaluate multidisciplinary pain interventions; estimate cost-benefit; develop and validate tools for identification of patient risk and outcomes; assess the effectiveness and harms of opioid pain medications with alternative study designs; and investigate risk identification and mitigation strategies and their effects on patient and public health outcomes. It is also important to obtain data to inform the cost feasibility and cost-effectiveness of recommended actions, such as use of nonpharmacologic therapy and urine drug testing. Research that contributes to safer and more effective pain treatment can be implemented across public health entities and federal agencies (4). Additional research can inform the development of future guidelines for special populations that could not be adequately addressed in this guideline, such as children and adolescents, where evidence and guidance is needed but currently lacking. CDC is committed to working with partners to identify the highest priority research areas to build the evidence base. Yet, given that chronic pain is recognized as a significant public health problem, the risks associated with long-term opioid therapy, the availability of effective nonpharmacological and nonopioid pharmacologic treatment options for pain, and the potential for improvement in the quality of health care with the implementation of recommended practices, a guideline for prescribing is warranted with the evidence that is currently available. The balance between the benefits and the risks of long-term opioid therapy for chronic pain based on both clinical and contextual evidence is strong enough to support the issuance of category A recommendations in most cases. CDC will revisit this guideline as new evidence becomes available to determine when evidence gaps have been sufficiently closed to warrant an update of the guideline. Until this research is conducted, clinical practice guidelines will have to be based on the best available evidence and expert opinion. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with longterm opioid therapy, including opioid use disorder, overdose, and death. CDC is committed to evaluating the guideline to identify the impact of the recommendations on clinician and patient outcomes, both intended and unintended, and revising the recommendations in future updates when warranted. Abbreviations: CI = confidence interval; ER/LA = extended release/long-acting; HR = hazard ratio; MME = morphine milligram equivalents; OR = odds ratio. * Ratings were made per GRADE quality assessment criteria; "no limitations" indicates that limitations assessed through the GRADE method were not identified. † Not applicable as no evidence was available for rating. # Acknowledgments # TABLE 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain * Multiply the dose for each opioid by the conversion factor to determine the dose in MMEs. For example, tablets containing hydrocodone 5 mg and acetaminophen 300 mg taken four times a day would contain a total of 20 mg of hydrocodone daily, equivalent to 20 MME daily; extended-release tablets containing oxycodone 10mg and taken twice a day would contain a total of 20mg of oxycodone daily, equivalent to 30 MME daily. The following cautions should be noted: 1) All doses are in mg/day except for fentanyl, which is mcg/ hr. 2) Equianalgesic dose conversions are only estimates and cannot account for individual variability in genetics and pharmacokinetics. 3) Do not use the calculated dose in MMEs to determine the doses to use when converting opioid to another; when converting opioids the new opioid is typically dosed at substantially lower than the calculated MME dose to avoid accidental overdose due to incomplete cross-tolerance and individual variability in opioid pharmacokinetics. 4) Use particular caution with methadone dose conversions because the conversion factor increases at higher doses. 5) Use particular caution with fentanyl since it is dosed in mcg/hr instead of mg/day, and its absorption is affected by heat and other factors. † Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor. MMEs are based on degree of mu-receptor agonist activity, but it is unknown if this drug is associated with overdose in the same dose-dependent manner as observed with medications that are solely mu receptor agonists.	None	None
eaa41a872fba66c23c440c4049c88694fd9a3fc7	cdc	None	The expert panelists who participated in the development of this guidance reported no potential competing interests to the steering committee with the following exceptions: J. Michael Lane, MD, disclosed that he has worked on data and safety monitoring boards for clinical trials sponsored by the NIH and by Bavarian Nordic and was supported by Acambis (the manufacturer of ACAM2000 before being purchased by Sanofi Pasteur) to review photos of the arms of vaccinees in their initial trial of the ACAM2000 vaccine to determine if a major or equivocal cutaneous reaction had occurred; Sharon E. Frey, MD, disclosed that she has worked on several clinical trials for smallpox vaccines in the past that were funded by the current manufacturers of smallpox vaccines (i.e., Sanofi Pasteur and Bavarian Nordic) and by the NIH, received funding from the current smallpox vaccine manufacturers for past travel expenses to present at conferences and a training session, and will organize one study site for a clinical trial investigating Imvamune funded by the NIH and Bavarian Nordic. Following the workshop and during the writing of the guidance, Dr. Frey disclosed that she accepted an offer by Bavarian Nordic before initiation of guidance development to serve as the chair of a committee evaluating the ability of smallpox vaccine to induce a major or equivocal cutaneous reaction in participants of a clinical study. This report includes recommendations for two investigational smallpox vaccines (i.e., Imvamune and Aventis Pasteur Smallpox Vaccine ) that are anticipated to be used under emergency use authorization or investigational new drug protocols in the event of a declared public health emergency involving smallpox.# Introduction Smallpox is a febrile rash illness caused by Orthopoxvirus variola (1). Through most of human history, the disease caused high morbidity and mortality leading to the deaths of approximately 500 million persons in the 20th century alone (1,2). An intensive public health vaccination campaign was initiated in the 1960s and succeeded in eradicating smallpox as a human disease (1). As a result, routine childhood smallpox vaccination was no longer recommended, and vaccination of the U.S. general public ceased in 1971 (3). Surveillance and containment strategies during the intensified smallpox eradication campaign focused on the vaccination of close contacts of persons with disease in combination with isolation and/or quarantine (1). The last case of smallpox in the United States was in 1949, and the last naturally occurring case in the world was in Somalia in 1977 (1). The World Health Organization (WHO) officially declared the disease eradicated in 1980 (1). Subsequently, all remaining variola virus was consolidated into two official repositories that currently are kept at two separate WHO collaborating centers: the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Novosibirsk, Russia and CDC in Atlanta, Georgia, United States (4). Although naturally occurring smallpox no longer exists, the threat of smallpox remains because of concerns that variola virus might exist outside of these repositories and could be used as an agent of bioterrorism or biowarfare (5). Although the risk for an intentional or accidental smallpox virus release is believed to be low, preparing for a potential event is critical to mitigate the devastating consequences of such an event. The U.S. government has purchased and stockpiled smallpox vaccines that would be provided to persons at high risk for infection in the event of a smallpox release. In 1991, CDC issued recommendations from the Advisory Committee on Immunization Practices (ACIP) and clinical guidance regarding smallpox vaccine and its use in a pre-event vaccination program (i.e., one with no cases of smallpox) (6)(7)(8)(9). However, these recommendations did not fully address the use of smallpox vaccine in a postevent emergency response setting in which a single laboratoryconfirmed case of smallpox identified anywhere in the world would require urgent notification of WHO as outlined under International Health Regulations (10). Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease. They do not contain variola virus, the causative agent of smallpox. In 2007, a new smallpox vaccine (ACAM2000) was licensed by the Food and Drug Administration (FDA) and replaced the previously licensed vaccine (Dryvax), which was subsequently destroyed (11). In addition, a newly developed smallpox vaccine (Imvamune) has been purchased and stockpiled by the U.S. government for use in a public health emergency involving smallpox. For these reasons, recommendations for the use of these vaccines in a postevent emergency response setting are needed for healthcare providers and public health personnel. This guidance outlines recommendations for the clinical use of the three smallpox vaccines in the U.S. Strategic National Stockpile (SNS) for persons at risk for smallpox infection after an intentional or accidental release of the virus. The three smallpox vaccines stockpiled are ACAM2000, Aventis Pasteur Smallpox Vaccine (APSV), and Imvamune. Surveillance and containment activities including vaccination with replicationcompetent smallpox vaccine (i.e., vaccine viruses capable of replicating in mammalian cells such as ACAM2000 and APSV) will be the primary response strategy for achieving epidemic control. # Methods In collaboration with the National Association of County and City Health Officials (NACCHO) and the American Academy of Pediatrics (AAP), CDC developed postevent clinical guidance for the three smallpox vaccines that currently are stored in the U.S. SNS. A multi-agency steering committee, comprising representatives from CDC, the National Institutes of Health (NIH), FDA, and the Office of the Assistant Secretary for Preparedness and Response (ASPR) was established to oversee the guidance development process.- During May 2013, an expert panel workshop was convened comprising persons with expertise in public health, clinical medicine, and public policy to provide individual expert opinion to inform the clinical recommendations. The 40-member panel possessed historic knowledge of smallpox and the eradication campaign; contributed clinical expertise in internal medicine, family medicine, dermatology, infectious diseases, human immunodeficiency virus (HIV) medicine, public health, nursing, obstetrics and gynecology, and pediatrics; and represented federal government agencies, including CDC, the Department of Defense (DoD), NIH, FDA, and ASPR. † All nonfederal expert panelists completed CDC-approved competing interest disclosure forms. Federal panelists were obligated to consider potential competing interests related to their official acts as public officials and employees. All panelists who disclosed competing interests were assessed and evaluated by the steering committee before participation in workshop activities. No major conflicts or competing interests were reported to the steering committee that prohibited participant involvement in the workshop or development of the guidance. However, two members declared potential competing interests as noted in the Disclosure of Competing Interests statement. These were reviewed extensively by the steering committee, and a determination was made that these participants could participate fully in meeting deliberations after public declaration of these activities. Subject matter experts provided oral presentations on various aspects of smallpox and smallpox vaccines, including a review of the smallpox eradication campaign, U.S. government vaccine response strategies, surveillance and research data from the DoD smallpox vaccination program, regulatory considerations for the use of smallpox vaccines, and incidence, severity, and treatment of adverse events. Vaccine manufacturers presented data and answered questions from the expert panel members, but did not observe or participate in any other aspect of the meeting to avoid introducing bias because of potential competing interests. The primary evidence base for the development of clinical guidance included relevant studies that were identified by literature searches of the PubMed database, manual searches of subject matter experts' personal libraries, and communication with vaccine manufacturers and researchers. Nonsystematic literature searches were performed using standard term indices to cover the terms "smallpox vaccine," "ACAM2000," "Imvamune," "Modified Vaccinia Ankara," "MVA," "Aventis Pasteur Smallpox Vaccine," and "APSV." Identified publications were screened for relevance and fulfillment of predefined inclusion and exclusion criteria. Inclusion criteria were any published or unpublished randomized clinical trials involving ACAM2000, Imvamune, or Aventis Pasteur Smallpox Vaccine (APSV), surveillance data from the historic use of Dryvax in the United States from the 1960s, and cohort studies, survey studies, case series, and case reports involving smallpox vaccine complications among persons with atopic dermatitis (eczema), persons with HIV infection, pregnant women, and pediatric populations. Publications without abstracts, articles in languages other than English, policy guidelines, editorials, and review articles were excluded. A summary of the literature, including data on adverse event rates when available, was provided to the expert panel members for review. Panel members were requested to apply their professional experience and clinical judgment in assessing the quality of the evidence and evaluating the risks and benefits of each vaccine. Draft recommendations were developed by CDC and select expert panel members before the workshop on the basis of literature reviews and individual expert opinion and presented at the workshop as a framework to initiate discussion. During the workshop, expert panel members were asked to consider the data from the literature reviews and presentations when participating in discussions on modifications to the draft recommendations. These draft recommendations were then revised to incorporate input provided by expert review of the data at the workshop and adjusted for novel issues raised. The post-workshop recommendations were distributed for review and commentary to workshop participants as well as various professional organizations and government agencies. The final CDC recommendations contained in this report represent the current state of knowledge of smallpox vaccines and their recommended use. These recommendations will be updated as more data on vaccine safety and efficacy become available. # Background Smallpox Pathogenesis and Disease Variola virus is a strictly human pathogen with no known animal reservoir (1). Variola major strains caused a disease with severe prodrome, fever, and prostration whereas variola minor strains produced less severe infection (12). During the smallpox eradication campaign, WHO used four main clinical descriptors to categorize smallpox caused by variola major virus on the basis of disease presentation and rash burden: ordinary, modified, flat, and hemorrhagic (13). The most common type was ordinary smallpox, which accounted for approximately 85% of cases in smallpox outbreaks (1). The clinical course of ordinary smallpox was characterized by an asymptomatic incubation period lasting 10-14 days (range of 7-17 days). Illness onset generally presented with sudden onset of fever and malaise associated with headache, backache, abdominal pain, vomiting, and symptoms of pharyngitis (1). These prodromal symptoms lasted approximately 2-3 days before the first appearance of mucosal and cutaneous lesions (1). Lesions usually appeared first on the oropharynx followed by the face and extremities before spreading to the trunk, palms, and soles following a centrifugal pattern of distribution. Lesions progressed from macules to papules to vesicles over the course of 4-5 days. Within another 1-2 days, the vesicles often umbilicated and evolved to pustules that were round, tense, firm to the touch, and deep seated within the dermis. Lesions typically exhibited the same stage of development in any one area of the body at any given time (1,12). Crusting and scab formation typically began by the ninth day of exanthema followed by sloughing of crusts around 14 days after rash onset. Modified smallpox was characterized by a milder prodrome, fewer lesions, and an accelerated clinical course compared with ordinary smallpox as a result of the disease being attenuated, or "modified," by previous vaccination. This type accounted for approximately 5%-7% of all cases and was rarely fatal (1,13). Another mild manifestation of smallpox seen rarely in previously vaccinated persons and characterized by fever without rash was termed variola sine eruptione. In contrast, flat smallpox was usually fatal and occurred at a similar frequency as modified smallpox (1,14). The lesions of flat smallpox were slow to develop and generally persisted as soft, velvety vesicles without pustulation that often coalesced into large confluent edematous vesicular plaques (15). Flat smallpox occurred most frequently in children who might have had deficient immune responses although no studies were undertaken to confirm this (1). The rarest (<1% of cases) and deadliest form was hemorrhagic smallpox. This type of smallpox involved extensive bleeding into the skin and mucous membranes followed almost invariably by death within 1 week of disease onset (12). Hemorrhagic smallpox occurred mostly among adults, particularly pregnant women (1). The relative frequency and case-fatality rates of the clinical types of smallpox in vaccinated and unvaccinated subjects from one large sample of patients hospitalized in India have been described (Table 1). Death from smallpox usually occurred during the second week of illness. The exact cause of death in smallpox remains unclear; the most severe hemorrhagic and flat forms of disease likely had a different pathogenesis from ordinary smallpox possibly related to underlying host immune deficiencies (1,16). Complications of renal failure, hypovolemic shock, and respiratory compromise induced by cytopathic effects of the virus were implicated in smallpox mortality based on a retrospective analysis of pathology records (17). Toxemia associated with viral antigens in plasma and immune complexes of antigen and antibody also has been proposed as contributing factors to the lethality of the disease (1,5). Epidemiologic studies indicate that the density of rash lesions had prognostic value because a higher rash burden portended a higher likelihood of death (1). Population studies indicated that case-fatality rates were highest in the very young and older age groups (18,19) (Table 2). Pregnant women were also at high risk for severe disease (particularly hemorrhagic smallpox) with an overall case-fatality rate of 34.3% and nearly 70% for unvaccinated pregnant women (1,(20)(21)(22). Survivors of smallpox appeared to have lifelong protection from reinfection with the virus (1,23). In contrast, vaccineinduced immunity was most effective in the first 1-3 years following vaccination, and complete protection was not lifelong (1). Effectiveness of vaccine approached 100% when administered before exposure occurred, and substantial protection might have endured for up to 15-20 years (1,12,24,25). Even when administered postexposure, vaccination against smallpox appeared to have been effective in preventing and/or ameliorating disease when administered to contacts of patients with smallpox. Such postexposure prophylaxis is believed to have been most effective when administered as soon as possible following viral exposure, particularly in previously vaccinated persons capable of mounting an anamnestic response. Data from the eradication era suggest that vaccination >3 days after exposure to the virus was less effective but might still have decreased morbidity and mortality (26)(27)(28)(29). # Smallpox Transmission and Control Smallpox virus was transmitted most commonly from an infected person to another person via respiratory droplets following direct face-to-face contact. The ulceration of oropharynx lesions released large amounts of virus into saliva (5,30). Viral shedding was highest during the first 7-10 days after lesion onset; consequently, almost all transmission occurred following the onset of exanthema (1,31,32). Rarely, smallpox virus also was transmitted via airborne dissemination or direct contact with lesions or fomites contaminated with lesion exudates (e.g., soiled clothing or bed linens) (1,16,33). Transmission occurred primarily in households, hospitals, and other health-care settings. Inadequate infection control practices likely played a role in cases of health-care-associated transmission (34,35). For reasons that are not well understood, substantial outbreaks of disease and viral transmission generally were not associated with schools, trains, planes, or buses (5,36). During the eradication campaign, surveillance and containment strategies were identified as key components of an outbreak response. These methods relied on rapid identification of smallpox patients through active searches for cases, vaccination of persons at high risk for infection (e.g., household members and others with close contact), rigorous isolation of infected persons to break the chain of transmission, and close monitoring of patient contacts for development of disease. When implemented effectively, these measures demonstrated success in interrupting disease transmission even in areas with low vaccination coverage (1,18). Surveillance and containment sometimes were supplemented with vaccination of other persons in the local geographic area affected by smallpox based on the epidemiologic characteristics of the outbreak or resource availability. Although this approach to vaccination might have decreased the opportunity for disease transmission from cases before their identification and isolation, surveillance and containment activities were the primary strategies used in achieving epidemic control. The eradication of smallpox as a human disease is a testament to the effectiveness of surveillance and containment. # Control and Prevention # Reduction of Risk for Exposure Appropriate public health and infection-control measures are expected to be instituted according to recommendations in the CDC Smallpox Response Plan and Guidelines (37). Such measures may include quarantine of potentially exposed persons, isolation of infected persons, and the use of personal protective equipment. # Vaccination The primary strategy for controlling the spread of disease after confirmation of one or more human smallpox cases involves the use of smallpox vaccine in combination with other surveillance and containment activities. As demonstrated during the eradication campaign, the immune response generated by smallpox vaccination is one of the most effective tools for halting the transmission of smallpox (1). Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease (1). They do not contain variola virus, the causative agent of smallpox (1). The U.S. government has three different smallpox vaccines available in the U.S. SNS: ACAM2000, Imvamune, and Aventis Pasteur Smallpox Vaccine (APSV). ACAM2000 is licensed by FDA whereas Imvamune and APSV are expected to be used under Investigational New Drug (IND) or Emergency Use Authorization (EUA) regulatory mechanisms. Although an EUA cannot be issued until an emergency determination and declaration are in place, FDA can review submitted product data as a pre-EUA before a formal EUA request (38). ACAM2000 and APSV are considered replication-competent vaccinia virus vaccines because of their ability to replicate in mammalian cells. Replication-competent vaccines are associated with serious adverse events and produce infectious lesions that can cause vaccinia virus infections attributed to autoinoculation and inadvertent transmission. In contrast, Imvamune is derived from a replication-deficient vaccinia virus strain that has been attenuated through multiple passages in tissue culture and has lost the ability to replicate in mammalian cells (39)(40)(41)(42). Replication-deficient vaccines were developed for use in persons at high risk for vaccination complications involving systemic viral spread (i.e., progressive vaccinia and eczema vaccinatum) (9,43). These vaccines are described and summarized (Table 3). ACAM2000 Description ACAM2000, Smallpox (Vaccinia) Vaccine, Live, is a vaccinia virus vaccine derived from a plaque-purified clone of the same New York City Board of Health (NYCBOH) strain that was used to manufacture Dryvax vaccine. ACAM2000 is grown in African green monkey kidney (Vero) cells and tested to be free of known adventitious agents (44). Available safety data from the ACAM2000 clinical trials indicate a similar safety profile to Dryvax (45). ACAM2000 is provided as a lyophilized preparation of purified live virus containing the following nonactive excipients: 6-8 mM HEPES (pH 6.5-7.5), 2% human serum albumin USP, 0.5%-0.7% sodium chloride USP, 5% mannitol USP, and trace amounts of neomycin and polymyxin B (46). Diluent for ACAM2000 contains 50% (v/v) Glycerin USP and 0.25% (v/v) Phenol USP in Water for Injection USP. Diluent is supplied as 0.6 mL of liquid in 3 mL clear glass vials (46). # Administration and Dosing ACAM2000 is administered in a single dose (~2.5 uL) by the percutaneous route (scarification) using 15 jabs of a stainless steel bifurcated needle that has been dipped into the vaccine. The vaccine is licensed for administration in the upper arm over the deltoid muscle. Although other anatomic sites of smallpox vaccine administration were used historically, the efficacy of ACAM2000 administered at other sites has not been studied and is not known. Following administration of ACAM2000, the development of a major cutaneous reaction or "take" indicates a successful immune response to the vaccine (9). A major cutaneous reaction is characterized by the development of a vesicle or pustule at the site of inoculation that is documented between days 6-8 following vaccination. After reconstitution, each vial of ACAM2000 vaccine contains approximately 100 doses (0.0025 mL/dose). The concentration of vaccinia virus is 1.0-5.0 x 10 8 plaque-forming units (PFU)/mL or 2.5-12.5 x 10 5 PFU/dose determined by plaque assay in Vero cells (46). # Regulatory Status ACAM2000 has been licensed by FDA since August 2007. The licensed indication for administration of ACAM2000 is for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection regardless of age (46). # Efficacy The clinical effectiveness of ACAM2000 is based on two pivotal clinical trials that demonstrated noninferiority to Dryvax (the smallpox vaccine licensed at the time of the trial) (47) (Table 4). The surrogate endpoints evaluated in these trials included major cutaneous reactions (i.e., "take" rates) and serum-neutralizing antibodies. ACAM2000 met two of the four primary endpoint criteria established in these trials. Among vaccinia virus-naïve subjects, ACAM2000 was determined to be noninferior to Dryvax in eliciting a major cutaneous reaction. Although ACAM2000 and Dryvax demonstrated similar trends in generating a serum-neutralizing antibody response (GMTs of 166 and 255 respectively on day 30), ACAM2000 did not meet the predefined criterion for noninferiority to Dryvax for this outcome. Among previously vaccinated subjects, ACAM2000 was determined to be noninferior to Dryvax in generating a serum neutralizing antibody response but did not meet the criterion for noninferiority in eliciting a major cutaneous reaction. The major cutaneous reaction is considered the primary determinant for an effective immune response in vaccinia virus-naïve subjects (47). However, the serum neutralizing antibody response might be a more informative measure of immune response in previously vaccinated subjects because pre-existing immunity can modify the cutaneous response to vaccination and add difficulty in evaluating for a major cutaneous reaction among revaccinees (47). Therefore, ACAM2000 was noninferior to Dryvax in the two most relevant surrogate endpoints (47). A summary of these clinical trials is provided (Table 4). # Safety The safety of ACAM2000 was evaluated in six clinical trials involving 2,983 subjects (1,307 vaccinia virus-naïve and 1,676 previously vaccinated) (44,47). The doses administered in these trials ranged from 3.4 x 10 6 to 2.2 x 10 8 PFU/mL. No deaths were reported, and serious adverse events were rare (<1%). Serious adverse events are defined by FDA as events that result in permanent disability, hospitalization, - Subjects who received study vaccine and were evaluated for a local cutaneous reaction within the protocol-designated timeframe were included in the efficacy evaluable population. † Results for vaccine lots, A, B, and C were 95%, 98%, and 96%, respectively. § Results for vaccine lots, A, B, and C were 79%, 87%, and 86%, respectively. ¶ Because the critical value for the evaluation was declared to be -5%, ACAM2000 is considered to be noninferior to Dryvax for this parameter. Because the critical value for the evaluation was declared to be -10%, ACAM2000 is not considered to be noninferior to Dryvax for this parameter. † † A randomly selected sample of subjects who received study vaccine and had samples collected for neutralizing antibody response at baseline and at the designated time-point post-treatment were included in the antibody evaluable population. § § Because the critical value for the evaluation was declared to be -0.301, ACAM2000 is not considered to be noninferior to Dryvax for this parameter. ¶ ¶ Because the critical value for the evaluation was declared to be -0.301, ACAM2000 is considered to be noninferior to Dryvax for this parameter. life-threatening illnesses, or death (48). The most common serious adverse event was myocarditis/pericarditis, which was reported in seven subjects receiving ACAM2000. Phase 3 clinical trials provide the best estimate of risk for myocarditis/ pericarditis from ACAM2000 as a result of active monitoring for these complications. These studies identified five cases of suspected myocarditis and pericarditis out of a total of 873 vaccinia virus-naïve subjects for an incidence of 5.7 per 1,000 primary vaccinees. No myocarditis or pericarditis cases were identified among previously vaccinated subjects. Three other serious cardiac events considered to have a possible relationship to ACAM2000 were reported and included single reports of atrial fibrillation, chest discomfort, and chest pain. New-onset seizure in a single subject also was reported as a serious adverse event that possibly was related to ACAM2000. However, other predisposing factors were identified that were considered contributory in this subject. Pregnancy and infection with HIV was identified in a total of five and one ACAM2000 recipients, respectively. Postlicensure monitoring of adverse events in persons receiving ACAM2000 remains ongoing in studies sponsored by Sanofi Pasteur as listed at www.clinicaltrials.gov. Although the safety of ACAM2000 has not been studied in persons with HIV infection, such persons are likely at high risk for serious vaccine complications, including progressive vaccinia (progressive destruction of skin and other tissues at the vaccination site), if they are immunosuppressed. One case of disseminated vaccinia virus infection was reported in an HIV-infected person receiving a primary vaccination with Dryvax (49). The patient was evaluated 3 weeks after vaccination and treated for cryptococcal meningitis; the patient's CD4 cell count was <25 cells/mm 3 at this time, and HIV infection was diagnosed. The patient survived following treatment with vaccinia immune globulin intravenous (VIGIV), but died the following year from other complications of HIV. In clinical trials evaluating ACAM2000, one previously vaccinated person was determined to be HIV-positive at the time of vaccination (50). This person received prophylactic vaccinia immune globulin and reported no notable complications during the 3 months he was able to be followed after being vaccinated. ACAM2000 has not been studied in pregnant women. Fetal vaccinia has been reported in fetuses and newborns of pregnant women vaccinated with replication-competent smallpox vaccines. Fewer than 50 cases of fetal vaccinia have been documented, and estimated incidence rates range from 1 per 10,000 to 1 per 100,000 in primary vaccinees (1,51). Although fetal vaccinia is a rare complication of smallpox vaccination, fetal and neonatal deaths have been reported as a result of this complication (1,51). Analysis of pregnancy outcomes among 376 women inadvertently vaccinated against smallpox with Dryvax vaccine during 2003-2006 did not demonstrate higher-than-expected rates of pregnancy loss, preterm birth, low birthweight, or birth defects (51). Five clinical trial participants who received ACAM2000 were determined to be pregnant within 30 days after vaccination resulting in two spontaneous abortions, one live birth, and one elective termination; one subject was lost to follow-up (50). No fetal vaccinia, congenital anomalies, or birth defects were reported (50). Of the two spontaneous abortions, one was deemed unrelated to ACAM2000, and neither ACAM2000 nor vaccinia immune globulin administration could be ruled out as causally associated in the other (50). The safety of ACAM2000 in persons with heart disease or cardiac risk factors is unknown because such persons have been excluded from clinical trials investigating this vaccine. Cardiac complications have been associated with smallpox vaccination in civilian and military personnel vaccinated in the United States during recent vaccination campaigns involving replicationcompetent smallpox vaccine (52,53). Although temporallyassociated cardiac ischemia and myocardial infarction have been observed among recipients of replication-competent smallpox vaccines, the incidence of these complications does not appear to significantly exceed expected background rates (54)(55)(56). There is no evidence to suggest a causal association of smallpox vaccination with cardiac ischemia or myocardial infarction. In contrast, myopericarditis has been associated with replication-competent smallpox vaccine and is estimated to occur at a rate of 5.7 per 1,000 primary vaccinees using clinical trial data with ACAM2000 (44,57,58). Significant long-term sequelae from myopericarditis appear to be rare as most cases are mild and self-limited with few documented reports of dilated cardiomyopathy (54,59). ACAM2000 has been used only in patients who have undergone intensive screening to exclude persons with known risk factors for adverse events. Because ACAM2000 is derived from the same NYCBOH strain that was used to manufacture Dryvax vaccine, it is anticipated that the safety profile of ACAM2000 is probably similar, if not identical, to that of Dryvax. Serious adverse events, including encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome), myocarditis/pericarditis, and eczema vaccinatum (severe and destructive infection of skin affected by eczema or other chronic skin disorder caused by spread of vaccinia virus) resulting in permanent sequelae or death, ocular complications, blindness, and fetal death have occurred following either primary vaccination or revaccination with replication-competent smallpox vaccines including Dryvax (9,43,46). Two studies conducted by CDC in 1968 are among the most comprehensive to evaluate the incidence of adverse events following routine smallpox vaccination with Dryvax. The first study relied on passive reporting of patients with suspected complications of smallpox vaccination to seven separate national surveillance systems (60). The second study implemented an active surveillance system whereby all physicians in 10 states were prospectively requested to record all smallpox vaccine adverse events they saw in practice (61). The physicians were then surveyed to collect the reports of these vaccine adverse events. The adverse event rates observed using the active surveillance from the 10 statewide surveys (Tables 5 and 6) were overall higher than those calculated from the passive national surveillance. The rates reported from the 10 statewide surveys often are considered to be more accurate on the basis of the methodology of the active surveillance employed in contrast to the passive data collection of the national surveillance systems (1,61). Rates of adverse events following revaccination were much lower than those for primary vaccination (with the exception of those in immunocompromised patients). Inadvertent inoculation (including auto-inoculation and inoculation of others via contact transmission or fomites) was the most frequently reported adverse event during 1968 and occurred at a rate of 529.2 cases per million primary vaccinations and was also reported during the 2002-2005 smallpox vaccination campaigns (46,53,61). (Tables 5 and 7) Vaccinia virus transmitted by inadvertent inoculation can result in the same complications seen following vaccination. In some cases (e.g., eczema vaccinatum), the disease resulting from contact transmission was reported to be more severe than that following vaccination (60). A recent study that evaluated data from U.S. military personnel and civilian first responders vaccinated with Dryvax during smallpox vaccination campaigns that were initiated in 2002 indicated that the incidence of serious adverse events was overall lower than those from 1968, particularly for preventable adverse events (e.g., eczema vaccinatum, contact transmission, and auto-inoculation) (53). These findings are presumably attributable to the current more stringent prevaccination screening procedures designed to decrease morbidity in adults with contraindications to administration of vaccine (persons aged <18 years were not vaccinated), increased use of protective bandages to cover the vaccination site, and enhanced education of vaccinees compared with the routine vaccination practices in place in the 1960s. Myocarditis and pericarditis had not been commonly reported following smallpox vaccination in previous studies and were newly recognized as a potential serious adverse event during these vaccination campaigns. Enhanced surveillance for adverse events, closer monitoring and technological advances (e.g., monitoring of electrocardiograms, cardiac ultrasonography, and serum cardiac enzymes) likely contributed to the increased detection of cardiac events in these vaccination campaigns. Nearly all of the cases of myopericarditis detected among military vaccinees were asymptomatic. The incidences of serious adverse events from this study are summarized (Table 7). # Aventis Pasteur Smallpox Vaccine Description APSV, also known as "WetVax," is a liquid formulation of calf-lymph-origin vaccinia virus vaccine that has been maintained at -4°F (-20°C) since it was manufactured in 1956 and 1957 (62). APSV was produced from a vaccinia virus seed stock derived from the NYCBOH strain (62). The original seed #17633 was received from the Michigan Department of Health in 1947. The bulk material was manufactured under license to Aventis Pasteur and was released previously under then acceptable release criteria to the DoD vaccine reserves. The formulation contains live vaccinia virus in 50% glycerol, 0.4% phenol, and 0.00017% Brilliant Green. No antibiotics or other additives are present. Fourteen bottles tested for bioburden met specifications of <200 colony forming units of bacteria per mL of product. This is the same specification for the previously licensed lyophilized smallpox vaccine, Dryvax. # Administration and Dosing APSV is administered in a single dose (~2.5 uL) by the percutaneous route (scarification) using 15 jabs of a stainless steel bifurcated needle that has been dipped into the vaccine. The site of vaccination is the upper arm over the deltoid muscle (62). Studies of undiluted vaccine potency found a titer of 10 x 10 7.6 plaque-forming units (PFU)/mL and there was no difference in vaccine success rates when comparing diluted (1:5) and undiluted vaccine (62). Yearly monitoring of APSV potency remains ongoing. Vaccine is provided in 0.25 mL aliquots in sterile 2 mL glass vials. Each vial must be further diluted with the appropriate companion diluent to achieve the 1:5 dilution specified in the current pre-EUA filed with FDA. For a 1:5 dilution to be achieved, 1 mL of diluent must be added to one vial of APSV, which will yield approximately 500 doses of vaccine per vial. # Regulatory Status APSV is an investigational product and is stored in the U.S. SNS. CDC holds IND applications for both undiluted and 1:5 diluted uses (CDC Regulatory Affairs, personal communication, 2014). CDC also submitted a pre-EUA to FDA for the use of APSV diluted 1:5 to vaccinate persons during a declared public health emergency invoving smallpox to increase the number of available doses of smallpox vaccine. # Efficacy APSV contains the same NYCBOH vaccinia virus strain that was used to produce Dryvax and is expected to have the same clinical effectiveness for both undiluted and 1:5 diluted uses (62). Live replication-competent vaccines derived from viruses used during the smallpox eradication campaign like Dryvax and APSV are estimated to be >95% effective when used as pre-exposure prophylaxis (1). # Safety The safety profile of APSV is anticipated to be similar to that of Dryvax and ACAM2000 (Tables 5 and 6). The overall risks of serious complications of smallpox vaccination with the NYCBOH strain of vaccinia virus are low and occur more frequently in persons receiving their first dose of vaccine and in young children (61). The most frequent serious complications of vaccination are encephalitis, progressive vaccinia, and eczema vaccinatum (61). The risk for myopericarditis has not been evaluated for APSV but is expected to occur at a rate similar to Dryvax and ACAM2000. # Imvamune Description Imvamune is a third-generation smallpox vaccine under development for active immunization for the prevention of smallpox disease (39)(40)(41)(42). Imvamune is an attenuated live virus vaccine containing Modified Vaccinia Ankara (MVA), a vaccinia virus strain that became replication-restricted to avian cells following >570 passages in primary chicken embryo fibroblast cells (40). It is assumed to have a favorable safety profile in humans when compared with replication-competent smallpox vaccines (39)(40)(41)(42). Imvamune does not contain any adjuvants or preservatives but might contain trace amounts of residual host cell DNA and protein, benzonase, and the antibiotic gentamicin. Imvamune is manufactured by Bavarian Nordic (BN) and has received marketing authorization under exceptional circumstances from the European Commission for active immunization against smallpox infection and disease in persons aged ≥18 years. The indication includes healthy populations as well as persons with immune deficiencies and skin disorders such as those who are HIV infected (CD4 cell counts ≥200 cells/mm 3 ) and those who have atopic dermatitis or allergic rhinitis. # Administration and Dosing The route of administration of the vaccine is subcutaneous (40). In contrast to ACAM2000, Imvamune 0.5 ml is injected in 2 doses at 0 and 4 weeks for primary vaccinees (63). Subjects previously vaccinated against smallpox receive a single 0.5 mL dose. Imvamune does not produce a visible cutaneous reaction following administration (40). Imvamune is supplied as a sterile frozen liquid product (0.5 mL in 2 ml vials stored at 5°F (-15°C) to -13°F (-25°C). Each vial contains 1 dose of Imvamune. Each dose contains a minimum of 1 x 10 8 TCID 50 (50% Tissue Culture Infective Dosage) per mL of live attenuated vaccinia virus, strain MVA-BN. # Regulatory Status Imvamune is an investigational product that is stored in the U.S. SNS. CDC has submitted a pre-EUA submission to FDA for its potential use during a declared public health emergency involving smallpox. On the basis of the clinical trial information available to date, the pre-EUA submitted to FDA for review and authorization during an emergency would allow the use of Imvamune for persons of all ages with a diagnosis of HIV or atopic dermatitis during a postevent, pre-exposure setting. # Efficacy The efficacy of Imvamune against smallpox is unproven and cannot be tested clinically because of the global eradication of the disease in humans. However, the clinical effectiveness of Imvamune to generate an immune response has been evaluated in six published clinical studies (39,41,42,(63)(64)(65). Overall, Imvamune was determined to elicit a humoral immune response when evaluated using total IgG antibody enzymelinked immunosorbent assay (ELISA) and plaque reduction neutralization (PRNT) assays. A study determined that 30 (100%) vaccinia virus-naïve subjects seroconverted 2 weeks following administration of a second dose of Imvamune (1 x 10 8 TCID 50 ) when evaluated by vaccinia virus-specific total IgG ELISA (geometric mean titer >100); 25 (83%) of these subjects seroconverted when evaluated by vaccinia virus-specific PRNT (GMT >10) (41). GMTs were similar between groups receiving vaccine subcutaneously and intramuscularly by both ELISA (GMT 743.37 SC, 899.75 IM) and PRNT (GMT 29.30 SC, 30.30 IM) (41). Another study reported that 52 (100%) vaccinia virus-naïve subjects seroconverted 2 weeks following administration of a second dose of Imvamune (1 x 10 8 TCID 50 ) by vaccinia virus-specific total IgG ELISA (titer >50) (GMT 813.8); 37 (71.2%) of these subjects seroconverted by vaccinia virus-specific PRNT (titer >20) (GMT 19.43) (42). Similar humoral immune responses were reported by a study that also compared the humoral response to Imvamune with that of Dryvax (39). The humoral responses observed with Imvamune and Dryvax were comparable overall, but antibody titers were higher among subjects receiving Dryvax when evaluated with Dryvax-specific total IgG ELISA and PRNT assays and antibody titers were higher among subjects receiving Imvamune when evaluated with Imvamune-specific total IgG ELISA and PRNT assays (39). Sera from this study were evaluated later with a variolaspecific PRNT assay and the 2-dose Imvamune vaccination regimen was found to have elicited similar variola-specificneutralizing antibody responses compared with the standard Dryvax vaccination regimen (66). A subanalysis suggested that subcutaneous administration of Imvamune might result in an increased variola neutralizing antibody response compared with Dryvax (66). Imvamune vaccination before Dryvax administration decreased the size of the cutaneous reaction, shortened healing time, and reduced virus replication at the site of Dryvax administration (39). A study comparing humoral responses to Imvamune (1 x 10 8 TCID 50 ) 2 weeks following administration of a second dose found that lower GMTs were observed in HIV-infected subjects with CD4 cell counts ≥350 cells/mm 3 when compared with uninfected subjects (GMTs of 779 and 1,939 respectively; p = 0.01) (64). Although a similar trend was seen when evaluated with a Western Reserve vaccinia virus-specific PRNT assay, no significant difference was identified between GMTs and seroconversion rates among HIV-infected and uninfected subjects 2 weeks following administration of a second dose of Imvamune (GMTs of 95 and 188 and seroconversion rates of 89% and 96% respectively) (64). A study evaluated the safety and immunogenicity of Imvamune (1 x 10 7 TCID 50 and 1 x 10 8 TCID 50 ) in 24 subjects (20 who received Imvamune and four controls) who had received a hematopoietic stem cell transplant at least 2 years before enrollment (65). Transient local reactions were observed but no serious adverse events were identified (65). Immunogenicity was evaluated using a luciferase-based assay of neutralizing antibody activity and an IFN-γ ELISPOT assay, and both provided greater results in the higher-dose group (65). Finally, a study that compared two different Imvamune vaccination schedules determined that the recommended schedule with a second dose of Imvamune at Day 28 compared with Day 7 produced a higher antibody response by PRNT and the maximal number of responders by ELISA (63). IFN-γ ELISPOT responses were similar for both groups 14 days following the second dose (63). A pivotal Phase III clinical trial comparing Imvamune and ACAM2000 is planned. # Safety The safety of Imvamune has been evaluated in six published clinical trials involving a total of 687 subjects (562 vaccinia virus-naïve and 125 previously vaccinated) (39,41,42,(63)(64)(65). Subjects varied in age (range: 18-60 years) and all were healthy with the exception of 91 HIV-infected subjects. The doses of vaccine administered in these trials ranged from 1 x 10 6 to 1 x 10 8 TCID 50 . Vaccinia-naïve subjects received 2 doses of vaccine whereas previously vaccinated subjects received only 1 dose. Vaccine was administered either subcutaneously or intramuscularly. No deaths were reported. One serious adverse event involving a case of thyroid cancer occurred and was considered vaccine-related by the medical monitor but unrelated by the investigator. Common adverse events reported were typical for subcutaneously administered vaccines (local and general systemic reactions ). Almost all reactions were mild to moderate in severity and all resolved without sequelae. Imvamune does not produce a lesion at the vaccination site and does not present any risk for secondary transmission. A total of 91 HIV-infected subjects (30 vaccinia virusnaïve and 61 previously vaccinated) with HIV-1 RNA <400 copies/mL and ≥350 CD4 cells/mm 3 received Imvamune in one published clinical trial (64). No deaths or vaccine-related serious adverse events were reported among these subjects. Overall, the safety profile of Imvamune in these HIV-infected subjects was comparable to that of uninfected subjects. Because Imvamune has not been studied in pregnant or breastfeeding women, the risks and efficacy of Imvamune are unknown in this population. The only report of Imvamune associated with pregnancy involved a woman aged 27 years who was determined to be pregnant after receiving 2 doses of Imvamune (42). On the basis of pregnancy dating estimates, conception occurred at least 17 days after administration of the second dose of vaccine, and pregnancy exposure to vaccine was not confirmed. Ultimately, the pregnancy progressed to term without complications and resulted in the delivery of a healthy, normal infant. No cases of myopericarditis have been identified following vaccination with Imvamune. However, a complete evaluation of the potential risk for myopericarditis with this vaccine is not possible because of the exclusion of clinical trial participants with known heart disease or cardiac risk factors, the limited number of total recipients of IMVAMUNE, and uncertainties related to disease pathophysiology for this complication. The predecessor MVA strain used to develop Imvamune was authorized for use in Germany in 1976 as a pre-immunization vaccine administered before Lister vaccine to decrease the potential for adverse events (40,67). Over 120,000 persons received a low dose of MVA (1 x 10 6 TCID 50 ) with no reported serious adverse events although rigorous follow-up of vaccinees was not performed (40,67). Prior clinical trials evaluating MVA safety also showed no serious adverse events among 7,098 subjects including 5,691 children aged <3 years (40). Imvamune has not been studied in persons aged <18 years. # Recommended Uses of Smallpox Vaccine Major Principles and Considerations In a public health emergency involving smallpox, vaccination with replication-competent (i.e., ACAM2000 and APSV) smallpox vaccine will be the primary response strategy for stopping the chain of transmission and achieving epidemic control. Persons exposed to smallpox virus are at high risk for developing smallpox and transmitting the virus to others thereby allowing continued propagation (1). Postexposure vaccination effectiveness is based on the principle that vaccination of exposed persons will provide rapid protection from disease. During the eradication campaign, single dose replication-competent smallpox vaccines from which ACAM2000 and APSV are derived were used successfully Persons at high risk for smallpox infection without a known smallpox virus exposure identified by public health authorities should be screened for relative contraindications to smallpox vaccination (Figure 2). Such persons with relative contraindications to smallpox vaccination should be vaccinated with Imvamune when available and authorized for use by FDA. Supplies of Imvamune might be limited in scenarios in which widespread smallpox vaccination is required. Consequently, Imvamune should be reserved for persons with relative contraindications to smallpox vaccination because they are likely to receive the most benefit because of their risk for serious adverse events. Although the current plan under the pre-EUA is to allow the use of Imvamune only in persons with atopic dermatitis or HIV infection, additional regulatory approvals might be requested from FDA to allow Imvamune administration among other persons with relative contraindications to smallpox vaccination. When Imvamune is not available or regulatory authorization for its use is lacking, an individual risk-benefit assessment should be performed to determine whether the benefits of vaccination with ACAM2000 outweigh the risks. Ultimately, the primary concern is that persons exposed to smallpox virus or at high risk for smallpox infection should be vaccinated; the choice of vaccine is a secondary consideration. Because of their similarities (ACAM2000 is a clonal derivative of the vaccinia virus strain used to produce APSV), ACAM2000 and APSV are expected to exhibit similar effectiveness and safety profiles when used during a response. Clinical utilization of ACAM2000 and APSV would be identical although APSV would be used only after the supply of ACAM2000 is exhausted. ACAM2000 is preferred to APSV because it is a licensed vaccine produced using modern good manufacturing practices. Recommendations and anticipatory guidance related to the use of ACAM2000 also apply to the use of APSV in situations where ACAM2000 is not available. ACAM2000 and APSV are currently stockpiled in sufficient quantities to vaccinate the entire U.S. population. # Anticipatory Guidance After administration of ACAM2000, there are various infection control and vaccine site care practices that need to be followed to minimize the chance of spread of vaccinia virus from the vaccine site. To prevent contact transmission after vaccination, vaccinees should cover the vaccination site with a loose gauze or similar absorbent material to absorb exudates and long-sleeved clothing should be worn (9). For all vaccine site care, thorough hand hygiene with soap and water/disinfectant use is required. Clothing, towels, and other cloth materials in contact with the vaccination site should be separated from other household laundry until they to break the chain of transmission and ultimately eradicate the disease from the human population (1). In contrast, the strain of vaccinia virus contained in Imvamune was not used during the eradication of smallpox and its efficacy in preventing smallpox in humans is less certain. Furthermore, Imvamune requires 2 doses administered 4 weeks apart to achieve an immune response comparable to that of replicationcompetent smallpox vaccines. Although persons vaccinated with Imvamune might have a lower risk for serious adverse events, this might be outweighed by the uncertainty in clinical effectiveness to prevent disease and provide rapid protection. Persons at high risk for complications from replicationcompetent smallpox vaccines are often at higher risk for severe smallpox. For these reasons, persons with a known exposure to smallpox virus should be vaccinated with a replicationcompetent smallpox vaccine unless severely immunodeficient (i.e., bone marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm 3 , and persons with severe combined immunodeficiency, complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation) (Figure 1). Persons exposed to smallpox virus include those directly exposed to an accidental or intentional smallpox virus release or those identified as a contact of a person with a confirmed, probable, or suspected case of smallpox as defined by the CDC Smallpox Response Plan and Guidelines (37) (Box 1). Contacts of a smallpox patient include household family members of such cases, others spending ≥3 hours in the household since the case's onset of fever, and nonhousehold members with ≥3 hours of contact <2 m (<6.5 feet) with a case with rash (37) (Box 2). Persons without smallpox virus exposure might still be at risk for developing smallpox infection depending on the magnitude of the outbreak and the effectiveness of the public health response in successfully implementing vaccination and other control measures when disease is present. A person's risk for exposure is thus dependent on multiple factors and cannot be quantified for all possible scenarios. For example, the response to a limited outbreak involving a few cases and limited geographic spread might focus on contact tracing and targeted vaccination informed by case identification to achieve epidemic control. In contrast, a widespread outbreak involving multiple cases in multiple locations might warrant a different public health strategy (e.g., a more extensive vaccination campaign to supplement these surveillance and containment efforts). Public health authorities will determine the scope of the response and provide guidance for appropriate vaccination strategies on the basis of the epidemiologic characteristics of the outbreak (e.g., the magnitude of the outbreak and the effectiveness of the public health response) (Box 3). can be decontaminated with routine laundering in soapy hot water (8). Education should be provided to vaccinees regarding the risk for contact/spread to household and other close contacts, particularly with certain activities (e.g., sexual contact). Although persons within a household are likely to be vaccinated together because of shared risks for smallpox infection, infection-control precautions should be followed to prevent inadvertent inoculation before the onset of protection, particularly when persons within the household are at higher risk for adverse events (e.g., persons with atopic dermatitis). Recommendations for monitoring the vaccine response to replication-competent smallpox vaccines have been published previously (9). Vaccinees should be evaluated 6-8 days postvaccination to assess the vaccination site for development of a major cutaneous reaction or "take." Persons exposed to smallpox virus or at high risk for smallpox infection for whom evidence of a major cutaneous reaction is lacking should be revaccinated and receive the same patient education and symptom monitoring information that is provided to unvaccinated persons described below. If a major cutaneous reaction is not observed following revaccination, further consultation with a health-care provider and/or public health authorities should be sought. Vaccinees receiving ACAM2000 should be evaluated for adverse events at the 1-week assessment and at any other time as clinically indicated. CDC provides guidelines regarding the signs and symptoms to monitor for adverse events after vaccination (9). Medical care providers for immunized mothers with infants and infants of immunized caregivers should emphasize infection control precautions to avoid inadvertent inoculation of the infant during breastfeeding or other caregiver activities. Recipients of ACAM2000 can be considered successfully vaccinated once the development of a major cutaneous reaction is apparent. Because there is no discernible cutaneous reaction with Imvamune, the success of vaccination and onset of protection is harder to determine. Recipients of Imvamune achieve a maximal immune response after two inoculations approximately 9. † Persons not vaccinated because of medical conditions, resource constraints, or otherwise and persons revaccinated following a failure to develop a major cutaneous reaction should receive clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur. In addition, they should be monitored for signs and symptoms suggestive of smallpox, including fever and prostration. Although persons with severe immunodeficiency might not benefit from vaccination, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in such persons when antivirals are not immediately available. § CDC provides guidance regarding the signs and symptoms to monitor for vaccine adverse events (9). ¶ If a major cutaneous reaction is not seen upon revaccination, further consultation with a health-care provider and/or public health authorities should be sought. Severely immunode cient? 6 weeks from initial vaccine administration (63). Although limited animal studies suggest a single dose of Imvamune might provide some protection, the 2-dose regimen provides maximum protection and persons should not be considered fully protected until after the second dose (63,(68)(69)(70). Vaccinees should be educated on the anticipated time to develop protection following vaccination. Prior to full protection, all vaccinees should avoid persons with smallpox and intimate contact with persons known to be vaccinated with replication-competent vaccine with active vaccination site lesions, satellite lesions, or rashes possibly containing vaccinia virus to decrease the likelihood of exposure to either smallpox or vaccinia virus. Every effort should be made to adhere to the schedule of the 2-dose regimen for Imvamune. Persons with a delay in receipt of the second dose should be vaccinated immediately. The need for an additional booster dose of Imvamune should be considered in consultation with a health-care provider and/or public health authorities. # Guidance for Vaccination by Contraindication or Medical Condition No absolute contraindications exist for smallpox vaccination in a postevent setting. However, several relative contraindications exist among persons with certain medical conditions. CDC recommendations for smallpox vaccine use were developed in consideration of the risk for smallpox infection, risk for adverse event following vaccination, and benefit from vaccination and are summarized (Table 8). If certain circumstances (e.g., medical conditions, resource constraints, or otherwise) prevent vaccination of persons exposed to smallpox virus or at high risk for smallpox infection as determined by public health authorities, these unvaccinated persons should be provided clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur (9,37). In addition, they should be monitored for signs and symptoms suggestive of smallpox, including fever, prostration, etc. If these symptoms are present, these persons should be isolated immediately (37). In these situations, antiviral medications are expected to be available for treatment of disease, but the efficacy of these products has not been established in # BOX 3. Definition of high risk for smallpox infection - Persons at high risk for smallpox infection will be defined by public health authorities during an outbreak on the basis of their risk for exposure to smallpox virus and the epidemiologic characteristics of the outbreak. # BOX 2. Definition of smallpox virus exposure - Persons directly exposed to an accidental or intentional smallpox virus release - Household family members of persons with confirmed, probable, or suspected cases and others spending ≥3 hours in the household since onset of fever in a person with a case - Nonhousehold members with ≥3 hours of contact 2 weeks per episode PLUS two or more of the following: 1) facial, neck, or extensor involvement in infants and children or flexural lesions in any age group, 2) onset at age ≤5 years, 3) personal history of atopy (e.g., asthma or seasonal allergies), or 4) first-degree relative with atopic dermatitis An individual risk-benefit assessment should be performed to determine whether the benefits of vaccination with ACAM2000 outweigh the risks. † † Current regulatory mechanisms only allow for the use of Imvamune in persons with AD or HIV infection, additional regulatory approvals may be requested from FDA to allow Imavamune administration among other persons with relative contraindications to ACAM2000. § § If a major cutaneous reaction is not seen upon revaccination, further consultation with a health-care provider and/or public health authorities should be sought. ¶ ¶ CDC provides guidance regarding the signs and symptoms to monitor for vaccine adverse events (9). Severely immunode cient? # Absolute Contraindications The risk-benefit analysis of the use of smallpox vaccine is inherently different in a postevent vaccination program compared with a pre-event vaccination program. In a postevent vaccination program, the risk for adverse events from smallpox vaccination is outweighed more often by the risk for severe smallpox disease. Consequently, contraindications that would apply in a pre-event vaccination program might no longer apply in a postevent vaccination program. Because of the high case-fatality rate and severity of smallpox, no clear absolute contraindications exist for the use of smallpox vaccines, including replication-competent vaccines, for persons exposed to smallpox virus or at high risk for smallpox infection. However, certain medical conditions discussed below have a substantial impact on the risk-benefit analysis and should be incorporated into the vaccination decision-making process. (Figures 1 and 2). Provide clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur. Monitor for signs and symptoms suggestive of smallpox, including fever and prostration. - Persons with a relative contraindication should be classified on the basis of the relative contraindication rather than on their pregnancy, breastfeeding, age, cardiac, or health-care worker status. # Severe Immunodeficiency Recommendations - Persons with severe immunodeficiency who are not expected to benefit from vaccine should not receive any smallpox vaccine. - Persons with severe immunodeficiency who are exposed to smallpox virus may receive IMVAMUNE when antivirals are not immediately available. Persons with severe immunodeficiency have a high likelihood of poor immune response and an increased risk for adverse events following administration of smallpox vaccine. As such, vaccination with any smallpox vaccine should be avoided in persons with severe immunodeficiency who are not expected to benefit from vaccine. Such persons might include bone-marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm 3 and persons with severe combined immunodeficiency (SCID), complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation for the person's protection (72) (Box 4). CD4 cell counts for children aged <13 years with HIV infection should be adjusted (Table 9) (73). Although persons with severe immunodeficiency might not benefit from vaccination, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure to such persons when antivirals are not immediately available on the basis of their high risk for smallpox infection. # Relative Contraindications Persons with relative contraindications might be at higher risk for adverse events from replication-competent smallpox vaccine. Such populations include persons with atopic dermatitis (eczema), HIV infection with CD4 cell counts of 50-199 cells/mm 3 § , other immunocompromised states (i.e., solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies), and persons with vaccine or vaccine-component allergies (Box 5). Although these populations are at higher risk for adverse events, replication-competent vaccines still are recommended for those exposed to smallpox virus. The potential for developing severe smallpox is considered a higher risk than the risk for severe adverse events, and the benefits of vaccine-provided protection outweigh the risks of vaccine-associated adverse events. However, among these populations, in circumstances when the risk for smallpox is minimal and a delay in the onset of immunity would not increase this risk to an unacceptable level, administration of the 2-dose regimen of Imvamune is preferable when available and authorized for use by FDA. Recommendations and further guidance for each of these populations are discussed in detail below. # Persons with Atopic Dermatitis Recommendations - Persons with atopic dermatitis who are exposed to smallpox virus should be vaccinated with ACAM2000. - Persons with atopic dermatitis at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune. - Persons with atopic dermatitis who were vaccinated previously against smallpox should receive ACAM2000. During a public health emergency involving smallpox, atopic dermatitis (also referred to as eczema) can be defined using published clinical findings and criteria (Box 6) (74). A history or presence of atopic dermatitis is a risk factor for developing eczema vaccinatum following vaccination with replication-competent smallpox vaccines. However, atopic dermatitis is not an absolute contraindication to vaccination § CD4 cell counts should be adjusted for children aged <13 years with HIV infection (Table 9). with ACAM2000 for those exposed to smallpox virus or at high risk for smallpox infection. Following exposure to smallpox virus, the risk for severe smallpox likely outweighs the risk for experiencing a severe adverse event secondary to ACAM2000. Treatment for severe adverse events with medical countermeasures including VIGIV and antivirals is expected to be available. For these reasons, ACAM2000 is preferred to Imvamune for persons with atopic dermatitis exposed to smallpox virus because of its ability to achieve protection in a single dose. In contrast, persons with atopic dermatitis at high risk for smallpox infection without a known smallpox virus exposure would likely benefit from vaccination with Imvamune. In this situation, the risk for acutely developing smallpox is lower and there is a higher likelihood of successfully administering both doses of Imvamune and achieving greater protection before disease develops or a smallpox virus exposure occurs. Existing data suggest that previously vaccinated persons have a lower risk for developing adverse events (1,60,61). As such, ACAM2000 is preferred to Imvamune for persons with atopic dermatitis with a history of previous smallpox vaccination without complications. # Persons with HIV Infection Recommendations - Persons with HIV infection with CD4 cell counts >200 cells/mm 3 § who are exposed to smallpox virus or at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with ACAM2000. - Persons with HIV infection with CD4 cell counts of 50-199 cells/mm 3 § who are exposed to smallpox virus should be vaccinated with ACAM2000. - Persons with HIV infection with CD4 cell counts of 50-199 cells/mm 3 § at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune. - Persons with HIV infection with CD4 cell counts of <50 cells/mm 3 § might not benefit from smallpox vaccine. The eradication of smallpox from the human population before the introduction of HIV precludes direct knowledge of potential interactions between these two pathogens in humans. It is likely that persons with HIV infection are at higher risk for severe disease from smallpox infection because of the known pathophysiology and immunosuppressive nature of HIV disease. Similarly, little is known about the risk for serious vaccine complications from ACAM2000 and APSV among the HIV-infected population because there are no studies evaluating these vaccines in this population. The safety and efficacy of IMVAMUNE in the limited number of HIV-infected subjects evaluated has been comparable to uninfected subjects (64). # Other Immunocompromised Persons Recommendations - Immunocompromised persons exposed to smallpox virus should be vaccinated with ACAM2000 unless they have a severe immunodeficiency and are not expected to benefit from vaccine (Box 4; Figure 1). - Solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune when available and authorized for use by FDA. Diseases and conditions that cause immunodeficiency or immunosuppression are believed to predispose affected persons for serious adverse events. These same diseases and conditions also might increase the risk for severe disease from smallpox infection. The impact of the degree of immunodeficiency or immunosuppression on the risks for severe smallpox and serious adverse events is difficult to assess. Vaccination with Imvamune is recommended for certain immunocompromised persons at high risk for smallpox infection. Although no regulatory mechanism exists at this time to provide vaccine to persons without atopic dermatitis or HIV infection, additional regulatory approvals might be requested from FDA to allow administration of Imvamune to other persons with relative contraindications. Such persons include solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies (including alkylating agents, antimetabolites, radiation, tumor necrosis factor inhibitors, and high-dose corticosteroids ). Although other chronic conditions such as heart disease, diabetes mellitus and arthritis might have some component of immunosuppression, the benefits of vaccination with ACAM2000 likely outweigh the risk for a serious adverse event because of the relatively lower degree of immunosuppression. Similarly, ACAM2000 is preferred to Imvamune for persons with other immunocompromising conditions such as complement or phagocytic deficiencies who are likely to produce sufficient immune responses to vaccination with no known increased risk for serious adverse events. Persons with HIV infection determined to be at high risk for smallpox infection by public health authorities should be evaluated carefully for smallpox virus exposures because of the potential risk for severe smallpox among this population. ACAM2000 should be administered to HIV-infected persons with CD4 cell counts ≥50 cells/mm 3 § with any smallpox virus exposure since the risk for severe smallpox likely outweighs the risk for a serious vaccine complication under these circumstances. Medical countermeasures including VIGIV and antivirals are expected to be available to treat serious vaccine complications including progressive vaccinia. If no smallpox virus exposure is identified, HIV-infected persons at high risk for smallpox infection with CD4 cell counts of 50-199 cells/mm 3 § should be vaccinated with Imvamune. Although there are no data on the efficacy or safety of Imvamune in this population, they are likely to benefit from a replication-deficient vaccine because of the increased risk for serious adverse events because of the higher degree of immunosuppression compared with HIV-infected persons with CD4 cell counts ≥200. HIV-infected persons with CD4 cell counts <50 cells/mm 3 § might not benefit from smallpox vaccine as they are unlikely to mount a sufficient immune response to any of the stockpiled smallpox vaccines. However, vaccination with Imvamune may be considered in the setting of a smallpox virus exposure when antivirals are not immediately available. HIV-infected persons exposed to smallpox virus who do not have a recent (within 1 year) CD4 count available should be evaluated for AIDS-defining conditions as defined by current surveillance case definitions (73). ACAM2000 should be administered unless an AIDS-defining condition is present because of the high risk for severe smallpox in this scenario. Persons with HIV infection at high risk for smallpox infection without a known smallpox virus exposure should have a CD4 cell count performed before administering smallpox vaccine when possible if this information is not available as this test can be performed in less than 24 hours in most cases. This short delay is unlikely to result in significantly increased risk for smallpox infection when there is no known smallpox virus exposure. # Persons with Vaccine or Vaccine Component Allergies # Recommendations - Prior to vaccination and regardless of a smallpox virus exposure, persons suspected of having a severe allergy to smallpox vaccine or a vaccine component should be counseled on the risks of a severe allergic reaction. - For persons exposed to smallpox virus: -Persons with a severe allergy to a previous dose of smallpox vaccine should be vaccinated with ACAM2000 in a facility capable of treating an anaphylactic reaction. -Persons with a severe allergy to ACAM2000 or a vaccine component of ACAM2000 should be vaccinated with APSV, if available. If APSV is unavailable, ACAM2000 should be administered in a facility capable of treating an anaphylactic reaction. - For persons at high risk for smallpox infection without a known smallpox virus exposure: -Persons with a severe allergy to a vaccine component or previous dose of smallpox vaccine should be vaccinated with any available smallpox vaccine that does not contain the vaccine strain or vaccine component associated with severe allergy. -If a smallpox vaccine that does not contain the vaccine strain or vaccine component associated with the severe allergy is unavailable, the person should be offered vaccination with any available smallpox vaccine in a facility capable of treating an anaphylactic reaction. In persons exposed to smallpox virus, the risk for severe smallpox likely outweighs the risk for a serious allergic reaction to vaccination. Studies evaluating smallpox vaccine complications in 1968 found that severe allergic reactions such as erythema multiforme occurred at a rate of 165 cases per 1 million primary vaccinations (60,61). No cases of anaphylaxis or death from an allergic reaction were reported (60,61). However, the risk for anaphylaxis, a potentially life-threatening reaction, cannot be excluded in persons with a history of severe allergies to a previous dose of smallpox vaccine or a vaccine component. Smallpox vaccines to be used in an emergency response have different vaccine components as detailed in their respective product descriptions. Smallpox vaccine should be administered in a facility capable of treating an anaphylactic reaction to mitigate this risk. # Guidance for Other Special Populations Pregnant and Breastfeeding Women Recommendations - Pregnant and breastfeeding women exposed to smallpox or at high risk for smallpox infection should be vaccinated with ACAM2000. - Pregnant and breastfeeding women with atopic dermatitis, HIV infection, or other relative contraindication should be classified on the basis of the relative contraindication rather than on their pregnancy or breastfeeding status. Data from the smallpox eradication era indicate that pregnant women were particularly susceptible to severe disease, including hemorrhagic smallpox, and had extraordinarily high case-fatality rates from smallpox (34.3% overall and nearly 70% for unvaccinated pregnant women) (1,20,21). Although vaccination with replication-competent smallpox vaccines poses a risk for fetal vaccinia because of direct viral infection of the fetus, the risk is presumed to be very low on the basis of the number of cases reported during periods of active immunization (1,51). Increased rates of other serious adverse events have not been reported among vaccinated pregnant women. The protective benefits of vaccination with ACAM2000 likely outweigh the risk for fetal vaccinia considering the high disease-related mortality for both the mother and fetus. ACAM2000 is preferred to Imvamune for pregnant women exposed to smallpox virus or at high risk for smallpox infection because the clinical effectiveness and safety of Imvamune are uncertain in this population and the 2-dose regimen might delay full protection from disease. Lactating women are not known to be at increased risk for severe smallpox or serious adverse events when compared with the general population. However, similar to other situations of intimate contact (e.g., sexual activity), inadvertent transmission of live vaccinia virus from the vaccine site to infants of vaccinated mothers is a potential risk during feeding (75). The risk for inadvertent transmission might be similar with breast or bottle feeding because both methods could result in intimate contact. Similar to other recommendations for intimate contact among vaccinated persons, these risks can be mitigated with infection control precautions (9). It is not known whether smallpox vaccine virus or antibodies are excreted in human breast milk or whether exposure to vaccinia virus through viral excretion into breast milk results in neonatal vaccinia virus infections. Lactating women exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000 and counseled on proper infection control precautions to avoid inadvertent transmission of vaccinia virus from the vaccination site to breastfeeding infants (9). The well-known infant and maternal benefits of breastfeeding outweigh the small potential risk for viral transmission to infants through consumption of breast milk. Discontinuation of breastfeeding or infant feeding with expressed human breast milk is not recommended unless there is a cutaneous breast lesion suspicious for vaccinia virus infection. Because infant contact with cutaneous breast lesions has been demonstrated to cause oral lesions, if such a lesion is present, breastfeeding or expression of milk would not be advisable until the lesion completely resolves. # Pediatric and Geriatric Populations Recommendations - Persons exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000 regardless of age. - Persons with HIV, atopic dermatitis, or other relative contraindications should be classified on the basis of the relative contraindication regardless of age. ACAM2000 should be administered to persons exposed to smallpox virus or at high risk for smallpox infection regardless of age, including pediatric and geriatric populations because of the increased risk for severe smallpox in the very young and older age groups. ACAM2000 is preferred to Imvamune for these age groups because the clinical efficacy and safety of Imvamune is uncertain in these populations and the 2-dose regimen might delay full protection from disease. Population studies from the smallpox eradication era including both vaccinated and unvaccinated subjects revealed that smallpox case-fatality rates were highest in the very young and older age groups (Table 2) (18,19). In addition, children aged <2 years vaccinated with ACAM2000 are believed to be at increased risk for serious adverse events, particularly central nervous system disease including postvaccinial encephalitis, on the basis of experience with its predecessor vaccine Dryvax (1,60,61). No cases of postvaccinial encephalitis associated with Imvamune or other similar vaccinia virus vaccine strains have been reported. However, the likelihood of observing this rare complication in the number of persons vaccinated with Imvamune to date is very low, particularly because that no persons aged <18 years have received this vaccine. Therefore, clinical data are insufficient to determine whether Imvamune would provide additional safety benefits in populations at higher risk for postvaccinial encephalitis. Older populations might be at increased risk for serious adverse events because of the relative immunosuppression of advanced age and higher likelihood of comorbidities that might predispose to adverse events with replication-competent smallpox vaccines. However, the efficacy and safety of Imvamune has not been established in older persons and the potential delay in development of protection because of the 2-dose regimen might place them at risk for severe smallpox. # Persons with Known Heart Disease or Cardiac Risk Factors Recommendations - Persons with known heart disease or cardiac risk factors exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000. Myopericarditis is known to occur in healthy persons after receipt of replication-competent smallpox vaccines (i.e., ACAM2000 and Dryvax) (46,57,59). Whether persons with known heart disease or cardiac risk factors have an increased frequency of serious adverse events compared with persons without these conditions is unknown. Although the specific risk factors for myopericarditis following smallpox vaccination have not been identified, the consequences of myopericarditis in persons with known heart disease or cardiac risk factors are more likely to be severe than in persons without known heart disease or cardiac risk factors. The pathophysiology of this adverse event remains unclear because of the absence of viral damage in the histopathologic examination of myocardial tissue from vaccinees with myopericarditis (54,55). Although no cases of myopericarditis have been observed in the Imvamune clinical trials to date, the total number of persons vaccinated in clinical trials is not enough to preclude the possibility that this complication occurs at a low rate. Since both vaccines have only been tested in healthy populations, and the cardiac complications in the ACAM2000 trial were transient and resolved with no apparent long-term consequences, the benefit from vaccination with Imvamune over ACAM2000 for persons with known heart disease or cardiac risk factors is unknown. For these reasons, ACAM2000 is preferred to Imvamune in these populations. # Health-Care Workers Recommendations - During a public health emergency involving smallpox, public health authorities will identify health-care workers at high risk for smallpox infection. - These health-care workers should be vaccinated with ACAM2000 unless they are severely immunodeficient or relatively contraindicated. During the smallpox eradication era, health-care workers (HCWs) were found to be at high risk for smallpox infection (1,34). Because society today is highly mobile, the re-emergence of smallpox would have worldwide ramifications. In the event of a public health emergency involving smallpox anywhere in the world, public health authorities in the United States will likely recommend smallpox vaccination for selected HCWs. Such HCWs at high risk for smallpox infection should receive ACAM2000 unless the HCW is severely immunodeficient or relatively contraindicated. In the setting of a smallpox response, pregnant HCWs are not expected to provide direct patient care in an initial emergency response and should not be vaccinated unless exposed to smallpox virus or otherwise determined to be at high risk for smallpox infection by public health authorities. Past experiences vaccinating HCWs and first responders in the United States during a pre-event vaccination campaign during 2002-2004 suggest that acceptance of smallpox vaccination might be low when concerns of experiencing an adverse event outweigh the perceived threat of smallpox exposure (76). Smallpox vaccine acceptance among this workforce might be higher with Imvamune than with ACAM2000 because of the potentially favorable safety profile. However, HCW perceptions of risk might change in a postevent setting with the knowledge that smallpox has been identified in humans leading to a greater desire for protection from vaccination. Imvamune should be administered to HCWs at high risk for smallpox infection with relative contraindications to smallpox vaccination as outlined (Figure 2). HCW eligibility for vaccination with Imvamune will depend on the availability of the vaccine. Although the inability of Imvamune to spread via contact transmission makes it advantageous to HCWs, the risk for transmission of ACAM2000 in a hospital setting is low, particularly with the implementation of sound hygiene practices and barrier protection. HCWs who have been vaccinated with smallpox vaccine should not be furloughed nor have their activities limited. However, previously vaccinated HCWs without active vaccination site lesions would ideally care for patients with severe immunosuppression. When previously vaccinated HCWs are unavailable, HCWs with active vaccination site lesions working with severely compromised patients should use enhanced infection control precautions and additional personal protective equipment (e.g., occlusive bandages to cover the vaccine site and/or nonpermeable gowns) (9). # Knowledge Gaps and Future Research These recommendations for use of smallpox vaccines in a postevent vaccination program are constrained by the limited recent use of smallpox vaccines in select populations and the current lack of clinical guidance for other medical countermeasures including antivirals in postevent settings. As such guidance is developed, these recommendations will evolve, in particular for persons with increased risks of serious adverse events or for severely immunodeficient persons who are unlikely to benefit from vaccination. Because the supply of Imvamune is limited, situations could occur that will limit its potential uses. As knowledge develops regarding the safety and efficacy of Imvamune (e.g., the potential for use of 1 dose of vaccine or the use of Imvamune before administration of ACAM2000 to decrease the risk for adverse events) recommendations regarding its use will change. The ability to advance knowledge is constrained by the limited use of vaccine since smallpox eradication. Should an event occur, it will be critical to monitor the safety and effectiveness of all smallpox vaccines, in particular among those populations where current knowledge is limited (e.g., pregnant women, children, the elderly, and immunocompromised persons).	The expert panelists who participated in the development of this guidance reported no potential competing interests to the steering committee with the following exceptions: J. Michael Lane, MD, disclosed that he has worked on data and safety monitoring boards for clinical trials sponsored by the NIH and by Bavarian Nordic and was supported by Acambis (the manufacturer of ACAM2000 before being purchased by Sanofi Pasteur) to review photos of the arms of vaccinees in their initial trial of the ACAM2000 vaccine to determine if a major or equivocal cutaneous reaction had occurred; Sharon E. Frey, MD, disclosed that she has worked on several clinical trials for smallpox vaccines in the past that were funded by the current manufacturers of smallpox vaccines (i.e., Sanofi Pasteur and Bavarian Nordic) and by the NIH, received funding from the current smallpox vaccine manufacturers for past travel expenses to present at conferences and a training session, and will organize one study site for a clinical trial investigating Imvamune funded by the NIH and Bavarian Nordic. Following the workshop and during the writing of the guidance, Dr. Frey disclosed that she accepted an offer by Bavarian Nordic before initiation of guidance development to serve as the chair of a committee evaluating the ability of smallpox vaccine to induce a major or equivocal cutaneous reaction in participants of a clinical study. This report includes recommendations for two investigational smallpox vaccines (i.e., Imvamune and Aventis Pasteur Smallpox Vaccine [APSV]) that are anticipated to be used under emergency use authorization or investigational new drug protocols in the event of a declared public health emergency involving smallpox.# Introduction Smallpox is a febrile rash illness caused by Orthopoxvirus variola (1). Through most of human history, the disease caused high morbidity and mortality leading to the deaths of approximately 500 million persons in the 20th century alone (1,2). An intensive public health vaccination campaign was initiated in the 1960s and succeeded in eradicating smallpox as a human disease (1). As a result, routine childhood smallpox vaccination was no longer recommended, and vaccination of the U.S. general public ceased in 1971 (3). Surveillance and containment strategies during the intensified smallpox eradication campaign focused on the vaccination of close contacts of persons with disease in combination with isolation and/or quarantine (1). The last case of smallpox in the United States was in 1949, and the last naturally occurring case in the world was in Somalia in 1977 (1). The World Health Organization (WHO) officially declared the disease eradicated in 1980 (1). Subsequently, all remaining variola virus was consolidated into two official repositories that currently are kept at two separate WHO collaborating centers: the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Novosibirsk, Russia and CDC in Atlanta, Georgia, United States (4). Although naturally occurring smallpox no longer exists, the threat of smallpox remains because of concerns that variola virus might exist outside of these repositories and could be used as an agent of bioterrorism or biowarfare (5). Although the risk for an intentional or accidental smallpox virus release is believed to be low, preparing for a potential event is critical to mitigate the devastating consequences of such an event. The U.S. government has purchased and stockpiled smallpox vaccines that would be provided to persons at high risk for infection in the event of a smallpox release. In 1991, CDC issued recommendations from the Advisory Committee on Immunization Practices (ACIP) and clinical guidance regarding smallpox vaccine and its use in a pre-event vaccination program (i.e., one with no cases of smallpox) (6)(7)(8)(9). However, these recommendations did not fully address the use of smallpox vaccine in a postevent emergency response setting in which a single laboratoryconfirmed case of smallpox identified anywhere in the world would require urgent notification of WHO as outlined under International Health Regulations (10). Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease. They do not contain variola virus, the causative agent of smallpox. In 2007, a new smallpox vaccine (ACAM2000) was licensed by the Food and Drug Administration (FDA) and replaced the previously licensed vaccine (Dryvax), which was subsequently destroyed (11). In addition, a newly developed smallpox vaccine (Imvamune) has been purchased and stockpiled by the U.S. government for use in a public health emergency involving smallpox. For these reasons, recommendations for the use of these vaccines in a postevent emergency response setting are needed for healthcare providers and public health personnel. This guidance outlines recommendations for the clinical use of the three smallpox vaccines in the U.S. Strategic National Stockpile (SNS) for persons at risk for smallpox infection after an intentional or accidental release of the virus. The three smallpox vaccines stockpiled are ACAM2000, Aventis Pasteur Smallpox Vaccine (APSV), and Imvamune. Surveillance and containment activities including vaccination with replicationcompetent smallpox vaccine (i.e., vaccine viruses capable of replicating in mammalian cells such as ACAM2000 and APSV) will be the primary response strategy for achieving epidemic control. # Methods In collaboration with the National Association of County and City Health Officials (NACCHO) and the American Academy of Pediatrics (AAP), CDC developed postevent clinical guidance for the three smallpox vaccines that currently are stored in the U.S. SNS. A multi-agency steering committee, comprising representatives from CDC, the National Institutes of Health (NIH), FDA, and the Office of the Assistant Secretary for Preparedness and Response (ASPR) was established to oversee the guidance development process.* During May 2013, an expert panel workshop was convened comprising persons with expertise in public health, clinical medicine, and public policy to provide individual expert opinion to inform the clinical recommendations. The 40-member panel possessed historic knowledge of smallpox and the eradication campaign; contributed clinical expertise in internal medicine, family medicine, dermatology, infectious diseases, human immunodeficiency virus (HIV) medicine, public health, nursing, obstetrics and gynecology, and pediatrics; and represented federal government agencies, including CDC, the Department of Defense (DoD), NIH, FDA, and ASPR. † All nonfederal expert panelists completed CDC-approved competing interest disclosure forms. Federal panelists were obligated to consider potential competing interests related to their official acts as public officials and employees. All panelists who disclosed competing interests were assessed and evaluated by the steering committee before participation in workshop activities. No major conflicts or competing interests were reported to the steering committee that prohibited participant involvement in the workshop or development of the guidance. However, two members declared potential competing interests as noted in the Disclosure of Competing Interests statement. These were reviewed extensively by the steering committee, and a determination was made that these participants could participate fully in meeting deliberations after public declaration of these activities. Subject matter experts provided oral presentations on various aspects of smallpox and smallpox vaccines, including a review of the smallpox eradication campaign, U.S. government vaccine response strategies, surveillance and research data from the DoD smallpox vaccination program, regulatory considerations for the use of smallpox vaccines, and incidence, severity, and treatment of adverse events. Vaccine manufacturers presented data and answered questions from the expert panel members, but did not observe or participate in any other aspect of the meeting to avoid introducing bias because of potential competing interests. The primary evidence base for the development of clinical guidance included relevant studies that were identified by literature searches of the PubMed database, manual searches of subject matter experts' personal libraries, and communication with vaccine manufacturers and researchers. Nonsystematic literature searches were performed using standard term indices to cover the terms "smallpox vaccine," "ACAM2000," "Imvamune," "Modified Vaccinia Ankara," "MVA," "Aventis Pasteur Smallpox Vaccine," and "APSV." Identified publications were screened for relevance and fulfillment of predefined inclusion and exclusion criteria. Inclusion criteria were any published or unpublished randomized clinical trials involving ACAM2000, Imvamune, or Aventis Pasteur Smallpox Vaccine (APSV), surveillance data from the historic use of Dryvax in the United States from the 1960s, and cohort studies, survey studies, case series, and case reports involving smallpox vaccine complications among persons with atopic dermatitis (eczema), persons with HIV infection, pregnant women, and pediatric populations. Publications without abstracts, articles in languages other than English, policy guidelines, editorials, and review articles were excluded. A summary of the literature, including data on adverse event rates when available, was provided to the expert panel members for review. Panel members were requested to apply their professional experience and clinical judgment in assessing the quality of the evidence and evaluating the risks and benefits of each vaccine. Draft recommendations were developed by CDC and select expert panel members before the workshop on the basis of literature reviews and individual expert opinion and presented at the workshop as a framework to initiate discussion. During the workshop, expert panel members were asked to consider the data from the literature reviews and presentations when participating in discussions on modifications to the draft recommendations. These draft recommendations were then revised to incorporate input provided by expert review of the data at the workshop and adjusted for novel issues raised. The post-workshop recommendations were distributed for review and commentary to workshop participants as well as various professional organizations and government agencies. The final CDC recommendations contained in this report represent the current state of knowledge of smallpox vaccines and their recommended use. These recommendations will be updated as more data on vaccine safety and efficacy become available. # Background Smallpox Pathogenesis and Disease Variola virus is a strictly human pathogen with no known animal reservoir (1). Variola major strains caused a disease with severe prodrome, fever, and prostration whereas variola minor strains produced less severe infection (12). During the smallpox eradication campaign, WHO used four main clinical descriptors to categorize smallpox caused by variola major virus on the basis of disease presentation and rash burden: ordinary, modified, flat, and hemorrhagic (13). The most common type was ordinary smallpox, which accounted for approximately 85% of cases in smallpox outbreaks (1). The clinical course of ordinary smallpox was characterized by an asymptomatic incubation period lasting 10-14 days (range of 7-17 days). Illness onset generally presented with sudden onset of fever and malaise associated with headache, backache, abdominal pain, vomiting, and symptoms of pharyngitis (1). These prodromal symptoms lasted approximately 2-3 days before the first appearance of mucosal and cutaneous lesions (1). Lesions usually appeared first on the oropharynx followed by the face and extremities before spreading to the trunk, palms, and soles following a centrifugal pattern of distribution. Lesions progressed from macules to papules to vesicles over the course of 4-5 days. Within another 1-2 days, the vesicles often umbilicated and evolved to pustules that were round, tense, firm to the touch, and deep seated within the dermis. Lesions typically exhibited the same stage of development in any one area of the body at any given time (1,12). Crusting and scab formation typically began by the ninth day of exanthema followed by sloughing of crusts around 14 days after rash onset. Modified smallpox was characterized by a milder prodrome, fewer lesions, and an accelerated clinical course compared with ordinary smallpox as a result of the disease being attenuated, or "modified," by previous vaccination. This type accounted for approximately 5%-7% of all cases and was rarely fatal (1,13). Another mild manifestation of smallpox seen rarely in previously vaccinated persons and characterized by fever without rash was termed variola sine eruptione. In contrast, flat smallpox was usually fatal and occurred at a similar frequency as modified smallpox (1,14). The lesions of flat smallpox were slow to develop and generally persisted as soft, velvety vesicles without pustulation that often coalesced into large confluent edematous vesicular plaques (15). Flat smallpox occurred most frequently in children who might have had deficient immune responses although no studies were undertaken to confirm this (1). The rarest (<1% of cases) and deadliest form was hemorrhagic smallpox. This type of smallpox involved extensive bleeding into the skin and mucous membranes followed almost invariably by death within 1 week of disease onset (12). Hemorrhagic smallpox occurred mostly among adults, particularly pregnant women (1). The relative frequency and case-fatality rates of the clinical types of smallpox in vaccinated and unvaccinated subjects from one large sample of patients hospitalized in India have been described (Table 1). Death from smallpox usually occurred during the second week of illness. The exact cause of death in smallpox remains unclear; the most severe hemorrhagic and flat forms of disease likely had a different pathogenesis from ordinary smallpox possibly related to underlying host immune deficiencies (1,16). Complications of renal failure, hypovolemic shock, and respiratory compromise induced by cytopathic effects of the virus were implicated in smallpox mortality based on a retrospective analysis of pathology records (17). Toxemia associated with viral antigens in plasma and immune complexes of antigen and antibody also has been proposed as contributing factors to the lethality of the disease (1,5). Epidemiologic studies indicate that the density of rash lesions had prognostic value because a higher rash burden portended a higher likelihood of death (1). Population studies indicated that case-fatality rates were highest in the very young and older age groups (18,19) (Table 2). Pregnant women were also at high risk for severe disease (particularly hemorrhagic smallpox) with an overall case-fatality rate of 34.3% and nearly 70% for unvaccinated pregnant women (1,(20)(21)(22). Survivors of smallpox appeared to have lifelong protection from reinfection with the virus (1,23). In contrast, vaccineinduced immunity was most effective in the first 1-3 years following vaccination, and complete protection was not lifelong (1). Effectiveness of vaccine approached 100% when administered before exposure occurred, and substantial protection might have endured for up to 15-20 years (1,12,24,25). Even when administered postexposure, vaccination against smallpox appeared to have been effective in preventing and/or ameliorating disease when administered to contacts of patients with smallpox. Such postexposure prophylaxis is believed to have been most effective when administered as soon as possible following viral exposure, particularly in previously vaccinated persons capable of mounting an anamnestic response. Data from the eradication era suggest that vaccination >3 days after exposure to the virus was less effective but might still have decreased morbidity and mortality (26)(27)(28)(29). # Smallpox Transmission and Control Smallpox virus was transmitted most commonly from an infected person to another person via respiratory droplets following direct face-to-face contact. The ulceration of oropharynx lesions released large amounts of virus into saliva (5,30). Viral shedding was highest during the first 7-10 days after lesion onset; consequently, almost all transmission occurred following the onset of exanthema (1,31,32). Rarely, smallpox virus also was transmitted via airborne dissemination or direct contact with lesions or fomites contaminated with lesion exudates (e.g., soiled clothing or bed linens) (1,16,33). Transmission occurred primarily in households, hospitals, and other health-care settings. Inadequate infection control practices likely played a role in cases of health-care-associated transmission (34,35). For reasons that are not well understood, substantial outbreaks of disease and viral transmission generally were not associated with schools, trains, planes, or buses (5,36). During the eradication campaign, surveillance and containment strategies were identified as key components of an outbreak response. These methods relied on rapid identification of smallpox patients through active searches for cases, vaccination of persons at high risk for infection (e.g., household members and others with close contact), rigorous isolation of infected persons to break the chain of transmission, and close monitoring of patient contacts for development of disease. When implemented effectively, these measures demonstrated success in interrupting disease transmission even in areas with low vaccination coverage (1,18). Surveillance and containment sometimes were supplemented with vaccination of other persons in the local geographic area affected by smallpox based on the epidemiologic characteristics of the outbreak or resource availability. Although this approach to vaccination might have decreased the opportunity for disease transmission from cases before their identification and isolation, surveillance and containment activities were the primary strategies used in achieving epidemic control. The eradication of smallpox as a human disease is a testament to the effectiveness of surveillance and containment. # Control and Prevention # Reduction of Risk for Exposure Appropriate public health and infection-control measures are expected to be instituted according to recommendations in the CDC Smallpox Response Plan and Guidelines (37). Such measures may include quarantine of potentially exposed persons, isolation of infected persons, and the use of personal protective equipment. # Vaccination The primary strategy for controlling the spread of disease after confirmation of one or more human smallpox cases involves the use of smallpox vaccine in combination with other surveillance and containment activities. As demonstrated during the eradication campaign, the immune response generated by smallpox vaccination is one of the most effective tools for halting the transmission of smallpox (1). Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease (1). They do not contain variola virus, the causative agent of smallpox (1). The U.S. government has three different smallpox vaccines available in the U.S. SNS: ACAM2000, Imvamune, and Aventis Pasteur Smallpox Vaccine (APSV). ACAM2000 is licensed by FDA whereas Imvamune and APSV are expected to be used under Investigational New Drug (IND) or Emergency Use Authorization (EUA) regulatory mechanisms. Although an EUA cannot be issued until an emergency determination and declaration are in place, FDA can review submitted product data as a pre-EUA before a formal EUA request (38). ACAM2000 and APSV are considered replication-competent vaccinia virus vaccines because of their ability to replicate in mammalian cells. Replication-competent vaccines are associated with serious adverse events and produce infectious lesions that can cause vaccinia virus infections attributed to autoinoculation and inadvertent transmission. In contrast, Imvamune is derived from a replication-deficient vaccinia virus strain that has been attenuated through multiple passages in tissue culture and has lost the ability to replicate in mammalian cells (39)(40)(41)(42). Replication-deficient vaccines were developed for use in persons at high risk for vaccination complications involving systemic viral spread (i.e., progressive vaccinia and eczema vaccinatum) (9,43). These vaccines are described and summarized (Table 3). ACAM2000 Description ACAM2000, Smallpox (Vaccinia) Vaccine, Live, is a vaccinia virus vaccine derived from a plaque-purified clone of the same New York City Board of Health (NYCBOH) strain that was used to manufacture Dryvax vaccine. ACAM2000 is grown in African green monkey kidney (Vero) cells and tested to be free of known adventitious agents (44). Available safety data from the ACAM2000 clinical trials indicate a similar safety profile to Dryvax (45). ACAM2000 is provided as a lyophilized preparation of purified live virus containing the following nonactive excipients: 6-8 mM HEPES (pH 6.5-7.5), 2% human serum albumin USP, 0.5%-0.7% sodium chloride USP, 5% mannitol USP, and trace amounts of neomycin and polymyxin B (46). Diluent for ACAM2000 contains 50% (v/v) Glycerin USP and 0.25% (v/v) Phenol USP in Water for Injection USP. Diluent is supplied as 0.6 mL of liquid in 3 mL clear glass vials (46). # Administration and Dosing ACAM2000 is administered in a single dose (~2.5 uL) by the percutaneous route (scarification) using 15 jabs of a stainless steel bifurcated needle that has been dipped into the vaccine. The vaccine is licensed for administration in the upper arm over the deltoid muscle. Although other anatomic sites of smallpox vaccine administration were used historically, the efficacy of ACAM2000 administered at other sites has not been studied and is not known. Following administration of ACAM2000, the development of a major cutaneous reaction or "take" indicates a successful immune response to the vaccine (9). A major cutaneous reaction is characterized by the development of a vesicle or pustule at the site of inoculation that is documented between days 6-8 following vaccination. After reconstitution, each vial of ACAM2000 vaccine contains approximately 100 doses (0.0025 mL/dose). The concentration of vaccinia virus is 1.0-5.0 x 10 8 plaque-forming units (PFU)/mL or 2.5-12.5 x 10 5 PFU/dose determined by plaque assay in Vero cells (46). # Regulatory Status ACAM2000 has been licensed by FDA since August 2007. The licensed indication for administration of ACAM2000 is for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection regardless of age (46). # Efficacy The clinical effectiveness of ACAM2000 is based on two pivotal clinical trials that demonstrated noninferiority to Dryvax (the smallpox vaccine licensed at the time of the trial) (47) (Table 4). The surrogate endpoints evaluated in these trials included major cutaneous reactions (i.e., "take" rates) and serum-neutralizing antibodies. ACAM2000 met two of the four primary endpoint criteria established in these trials. Among vaccinia virus-naïve subjects, ACAM2000 was determined to be noninferior to Dryvax in eliciting a major cutaneous reaction. Although ACAM2000 and Dryvax demonstrated similar trends in generating a serum-neutralizing antibody response (GMTs of 166 and 255 respectively on day 30), ACAM2000 did not meet the predefined criterion for noninferiority to Dryvax for this outcome. Among previously vaccinated subjects, ACAM2000 was determined to be noninferior to Dryvax in generating a serum neutralizing antibody response but did not meet the criterion for noninferiority in eliciting a major cutaneous reaction. The major cutaneous reaction is considered the primary determinant for an effective immune response in vaccinia virus-naïve subjects (47). However, the serum neutralizing antibody response might be a more informative measure of immune response in previously vaccinated subjects because pre-existing immunity can modify the cutaneous response to vaccination and add difficulty in evaluating for a major cutaneous reaction among revaccinees (47). Therefore, ACAM2000 was noninferior to Dryvax in the two most relevant surrogate endpoints (47). A summary of these clinical trials is provided (Table 4). # Safety The safety of ACAM2000 was evaluated in six clinical trials involving 2,983 subjects (1,307 vaccinia virus-naïve and 1,676 previously vaccinated) (44,47). The doses administered in these trials ranged from 3.4 x 10 6 to 2.2 x 10 8 PFU/mL. No deaths were reported, and serious adverse events were rare (<1%). Serious adverse events are defined by FDA as events that result in permanent disability, hospitalization, * Subjects who received study vaccine and were evaluated for a local cutaneous reaction within the protocol-designated timeframe were included in the efficacy evaluable population. † Results for vaccine lots, A, B, and C were 95%, 98%, and 96%, respectively. § Results for vaccine lots, A, B, and C were 79%, 87%, and 86%, respectively. ¶ Because the critical value for the evaluation was declared to be -5%, ACAM2000 is considered to be noninferior to Dryvax for this parameter. ** Because the critical value for the evaluation was declared to be -10%, ACAM2000 is not considered to be noninferior to Dryvax for this parameter. † † A randomly selected sample of subjects who received study vaccine and had samples collected for neutralizing antibody response at baseline and at the designated time-point post-treatment were included in the antibody evaluable population. § § Because the critical value for the evaluation was declared to be -0.301, ACAM2000 is not considered to be noninferior to Dryvax for this parameter. ¶ ¶ Because the critical value for the evaluation was declared to be -0.301, ACAM2000 is considered to be noninferior to Dryvax for this parameter. life-threatening illnesses, or death (48). The most common serious adverse event was myocarditis/pericarditis, which was reported in seven subjects receiving ACAM2000. Phase 3 clinical trials provide the best estimate of risk for myocarditis/ pericarditis from ACAM2000 as a result of active monitoring for these complications. These studies identified five cases of suspected myocarditis and pericarditis out of a total of 873 vaccinia virus-naïve subjects for an incidence of 5.7 per 1,000 primary vaccinees. No myocarditis or pericarditis cases were identified among previously vaccinated subjects. Three other serious cardiac events considered to have a possible relationship to ACAM2000 were reported and included single reports of atrial fibrillation, chest discomfort, and chest pain. New-onset seizure in a single subject also was reported as a serious adverse event that possibly was related to ACAM2000. However, other predisposing factors were identified that were considered contributory in this subject. Pregnancy and infection with HIV was identified in a total of five and one ACAM2000 recipients, respectively. Postlicensure monitoring of adverse events in persons receiving ACAM2000 remains ongoing in studies sponsored by Sanofi Pasteur as listed at www.clinicaltrials.gov. Although the safety of ACAM2000 has not been studied in persons with HIV infection, such persons are likely at high risk for serious vaccine complications, including progressive vaccinia (progressive destruction of skin and other tissues at the vaccination site), if they are immunosuppressed. One case of disseminated vaccinia virus infection was reported in an HIV-infected person receiving a primary vaccination with Dryvax (49). The patient was evaluated 3 weeks after vaccination and treated for cryptococcal meningitis; the patient's CD4 cell count was <25 cells/mm 3 at this time, and HIV infection was diagnosed. The patient survived following treatment with vaccinia immune globulin intravenous (VIGIV), but died the following year from other complications of HIV. In clinical trials evaluating ACAM2000, one previously vaccinated person was determined to be HIV-positive at the time of vaccination (50). This person received prophylactic vaccinia immune globulin and reported no notable complications during the 3 months he was able to be followed after being vaccinated. ACAM2000 has not been studied in pregnant women. Fetal vaccinia has been reported in fetuses and newborns of pregnant women vaccinated with replication-competent smallpox vaccines. Fewer than 50 cases of fetal vaccinia have been documented, and estimated incidence rates range from 1 per 10,000 to 1 per 100,000 in primary vaccinees (1,51). Although fetal vaccinia is a rare complication of smallpox vaccination, fetal and neonatal deaths have been reported as a result of this complication (1,51). Analysis of pregnancy outcomes among 376 women inadvertently vaccinated against smallpox with Dryvax vaccine during 2003-2006 did not demonstrate higher-than-expected rates of pregnancy loss, preterm birth, low birthweight, or birth defects (51). Five clinical trial participants who received ACAM2000 were determined to be pregnant within 30 days after vaccination resulting in two spontaneous abortions, one live birth, and one elective termination; one subject was lost to follow-up (50). No fetal vaccinia, congenital anomalies, or birth defects were reported (50). Of the two spontaneous abortions, one was deemed unrelated to ACAM2000, and neither ACAM2000 nor vaccinia immune globulin administration could be ruled out as causally associated in the other (50). The safety of ACAM2000 in persons with heart disease or cardiac risk factors is unknown because such persons have been excluded from clinical trials investigating this vaccine. Cardiac complications have been associated with smallpox vaccination in civilian and military personnel vaccinated in the United States during recent vaccination campaigns involving replicationcompetent smallpox vaccine (52,53). Although temporallyassociated cardiac ischemia and myocardial infarction have been observed among recipients of replication-competent smallpox vaccines, the incidence of these complications does not appear to significantly exceed expected background rates (54)(55)(56). There is no evidence to suggest a causal association of smallpox vaccination with cardiac ischemia or myocardial infarction. In contrast, myopericarditis has been associated with replication-competent smallpox vaccine and is estimated to occur at a rate of 5.7 per 1,000 primary vaccinees using clinical trial data with ACAM2000 (44,57,58). Significant long-term sequelae from myopericarditis appear to be rare as most cases are mild and self-limited with few documented reports of dilated cardiomyopathy (54,59). ACAM2000 has been used only in patients who have undergone intensive screening to exclude persons with known risk factors for adverse events. Because ACAM2000 is derived from the same NYCBOH strain that was used to manufacture Dryvax vaccine, it is anticipated that the safety profile of ACAM2000 is probably similar, if not identical, to that of Dryvax. Serious adverse events, including encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome), myocarditis/pericarditis, and eczema vaccinatum (severe and destructive infection of skin affected by eczema or other chronic skin disorder caused by spread of vaccinia virus) resulting in permanent sequelae or death, ocular complications, blindness, and fetal death have occurred following either primary vaccination or revaccination with replication-competent smallpox vaccines including Dryvax (9,43,46). Two studies conducted by CDC in 1968 are among the most comprehensive to evaluate the incidence of adverse events following routine smallpox vaccination with Dryvax. The first study relied on passive reporting of patients with suspected complications of smallpox vaccination to seven separate national surveillance systems (60). The second study implemented an active surveillance system whereby all physicians in 10 states were prospectively requested to record all smallpox vaccine adverse events they saw in practice (61). The physicians were then surveyed to collect the reports of these vaccine adverse events. The adverse event rates observed using the active surveillance from the 10 statewide surveys (Tables 5 and 6) were overall higher than those calculated from the passive national surveillance. The rates reported from the 10 statewide surveys often are considered to be more accurate on the basis of the methodology of the active surveillance employed in contrast to the passive data collection of the national surveillance systems (1,61). Rates of adverse events following revaccination were much lower than those for primary vaccination (with the exception of those in immunocompromised patients). Inadvertent inoculation (including auto-inoculation and inoculation of others via contact transmission or fomites) was the most frequently reported adverse event during 1968 and occurred at a rate of 529.2 cases per million primary vaccinations and was also reported during the 2002-2005 smallpox vaccination campaigns (46,53,61). (Tables 5 and 7) Vaccinia virus transmitted by inadvertent inoculation can result in the same complications seen following vaccination. In some cases (e.g., eczema vaccinatum), the disease resulting from contact transmission was reported to be more severe than that following vaccination (60). A recent study that evaluated data from U.S. military personnel and civilian first responders vaccinated with Dryvax during smallpox vaccination campaigns that were initiated in 2002 indicated that the incidence of serious adverse events was overall lower than those from 1968, particularly for preventable adverse events (e.g., eczema vaccinatum, contact transmission, and auto-inoculation) (53). These findings are presumably attributable to the current more stringent prevaccination screening procedures designed to decrease morbidity in adults with contraindications to administration of vaccine (persons aged <18 years were not vaccinated), increased use of protective bandages to cover the vaccination site, and enhanced education of vaccinees compared with the routine vaccination practices in place in the 1960s. Myocarditis and pericarditis had not been commonly reported following smallpox vaccination in previous studies and were newly recognized as a potential serious adverse event during these vaccination campaigns. Enhanced surveillance for adverse events, closer monitoring and technological advances (e.g., monitoring of electrocardiograms, cardiac ultrasonography, and serum cardiac enzymes) likely contributed to the increased detection of cardiac events in these vaccination campaigns. Nearly all of the cases of myopericarditis detected among military vaccinees were asymptomatic. The incidences of serious adverse events from this study are summarized (Table 7). # Aventis Pasteur Smallpox Vaccine Description APSV, also known as "WetVax," is a liquid formulation of calf-lymph-origin vaccinia virus vaccine that has been maintained at -4°F (-20°C) since it was manufactured in 1956 and 1957 (62). APSV was produced from a vaccinia virus seed stock derived from the NYCBOH strain (62). The original seed #17633 was received from the Michigan Department of Health in 1947. The bulk material was manufactured under license to Aventis Pasteur and was released previously under then acceptable release criteria to the DoD vaccine reserves. The formulation contains live vaccinia virus in 50% glycerol, 0.4% phenol, and 0.00017% Brilliant Green. No antibiotics or other additives are present. Fourteen bottles tested for bioburden met specifications of <200 colony forming units of bacteria per mL of product. This is the same specification for the previously licensed lyophilized smallpox vaccine, Dryvax. # Administration and Dosing APSV is administered in a single dose (~2.5 uL) by the percutaneous route (scarification) using 15 jabs of a stainless steel bifurcated needle that has been dipped into the vaccine. The site of vaccination is the upper arm over the deltoid muscle (62). Studies of undiluted vaccine potency found a titer of 10 x 10 7.6 plaque-forming units (PFU)/mL and there was no difference in vaccine success rates when comparing diluted (1:5) and undiluted vaccine (62). Yearly monitoring of APSV potency remains ongoing. Vaccine is provided in 0.25 mL aliquots in sterile 2 mL glass vials. Each vial must be further diluted with the appropriate companion diluent to achieve the 1:5 dilution specified in the current pre-EUA filed with FDA. For a 1:5 dilution to be achieved, 1 mL of diluent must be added to one vial of APSV, which will yield approximately 500 doses of vaccine per vial. # Regulatory Status APSV is an investigational product and is stored in the U.S. SNS. CDC holds IND applications for both undiluted and 1:5 diluted uses (CDC Regulatory Affairs, personal communication, 2014). CDC also submitted a pre-EUA to FDA for the use of APSV diluted 1:5 to vaccinate persons during a declared public health emergency invoving smallpox to increase the number of available doses of smallpox vaccine. # Efficacy APSV contains the same NYCBOH vaccinia virus strain that was used to produce Dryvax and is expected to have the same clinical effectiveness for both undiluted and 1:5 diluted uses (62). Live replication-competent vaccines derived from viruses used during the smallpox eradication campaign like Dryvax and APSV are estimated to be >95% effective when used as pre-exposure prophylaxis (1). # Safety The safety profile of APSV is anticipated to be similar to that of Dryvax and ACAM2000 (Tables 5 and 6). The overall risks of serious complications of smallpox vaccination with the NYCBOH strain of vaccinia virus are low and occur more frequently in persons receiving their first dose of vaccine and in young children (61). The most frequent serious complications of vaccination are encephalitis, progressive vaccinia, and eczema vaccinatum (61). The risk for myopericarditis has not been evaluated for APSV but is expected to occur at a rate similar to Dryvax and ACAM2000. # Imvamune Description Imvamune is a third-generation smallpox vaccine under development for active immunization for the prevention of smallpox disease (39)(40)(41)(42). Imvamune is an attenuated live virus vaccine containing Modified Vaccinia Ankara (MVA), a vaccinia virus strain that became replication-restricted to avian cells following >570 passages in primary chicken embryo fibroblast cells (40). It is assumed to have a favorable safety profile in humans when compared with replication-competent smallpox vaccines (39)(40)(41)(42). Imvamune does not contain any adjuvants or preservatives but might contain trace amounts of residual host cell DNA and protein, benzonase, and the antibiotic gentamicin. Imvamune is manufactured by Bavarian Nordic (BN) and has received marketing authorization under exceptional circumstances from the European Commission for active immunization against smallpox infection and disease in persons aged ≥18 years. The indication includes healthy populations as well as persons with immune deficiencies and skin disorders such as those who are HIV infected (CD4 cell counts ≥200 cells/mm 3 ) and those who have atopic dermatitis or allergic rhinitis. # Administration and Dosing The route of administration of the vaccine is subcutaneous (40). In contrast to ACAM2000, Imvamune 0.5 ml is injected in 2 doses at 0 and 4 weeks for primary vaccinees (63). Subjects previously vaccinated against smallpox receive a single 0.5 mL dose. Imvamune does not produce a visible cutaneous reaction following administration (40). Imvamune is supplied as a sterile frozen liquid product (0.5 mL in 2 ml vials stored at 5°F (-15°C) to -13°F (-25°C). Each vial contains 1 dose of Imvamune. Each dose contains a minimum of 1 x 10 8 TCID 50 (50% Tissue Culture Infective Dosage) per mL of live attenuated vaccinia virus, strain MVA-BN. # Regulatory Status Imvamune is an investigational product that is stored in the U.S. SNS. CDC has submitted a pre-EUA submission to FDA for its potential use during a declared public health emergency involving smallpox. On the basis of the clinical trial information available to date, the pre-EUA submitted to FDA for review and authorization during an emergency would allow the use of Imvamune for persons of all ages with a diagnosis of HIV or atopic dermatitis during a postevent, pre-exposure setting. # Efficacy The efficacy of Imvamune against smallpox is unproven and cannot be tested clinically because of the global eradication of the disease in humans. However, the clinical effectiveness of Imvamune to generate an immune response has been evaluated in six published clinical studies (39,41,42,(63)(64)(65). Overall, Imvamune was determined to elicit a humoral immune response when evaluated using total IgG antibody enzymelinked immunosorbent assay (ELISA) and plaque reduction neutralization (PRNT) assays. A study determined that 30 (100%) vaccinia virus-naïve subjects seroconverted 2 weeks following administration of a second dose of Imvamune (1 x 10 8 TCID 50 ) when evaluated by vaccinia virus-specific total IgG ELISA (geometric mean titer [GMT] >100); 25 (83%) of these subjects seroconverted when evaluated by vaccinia virus-specific PRNT (GMT >10) (41). GMTs were similar between groups receiving vaccine subcutaneously and intramuscularly by both ELISA (GMT 743.37 SC, 899.75 IM) and PRNT (GMT 29.30 SC, 30.30 IM) (41). Another study reported that 52 (100%) vaccinia virus-naïve subjects seroconverted 2 weeks following administration of a second dose of Imvamune (1 x 10 8 TCID 50 ) by vaccinia virus-specific total IgG ELISA (titer >50) (GMT 813.8); 37 (71.2%) of these subjects seroconverted by vaccinia virus-specific PRNT (titer >20) (GMT 19.43) (42). Similar humoral immune responses were reported by a study that also compared the humoral response to Imvamune with that of Dryvax (39). The humoral responses observed with Imvamune and Dryvax were comparable overall, but antibody titers were higher among subjects receiving Dryvax when evaluated with Dryvax-specific total IgG ELISA and PRNT assays and antibody titers were higher among subjects receiving Imvamune when evaluated with Imvamune-specific total IgG ELISA and PRNT assays (39). Sera from this study were evaluated later with a variolaspecific PRNT assay and the 2-dose Imvamune vaccination regimen was found to have elicited similar variola-specificneutralizing antibody responses compared with the standard Dryvax vaccination regimen (66). A subanalysis suggested that subcutaneous administration of Imvamune might result in an increased variola neutralizing antibody response compared with Dryvax (66). Imvamune vaccination before Dryvax administration decreased the size of the cutaneous reaction, shortened healing time, and reduced virus replication at the site of Dryvax administration (39). A study comparing humoral responses to Imvamune (1 x 10 8 TCID 50 ) 2 weeks following administration of a second dose found that lower GMTs were observed in HIV-infected subjects with CD4 cell counts ≥350 cells/mm 3 when compared with uninfected subjects (GMTs of 779 and 1,939 respectively; p = 0.01) (64). Although a similar trend was seen when evaluated with a Western Reserve vaccinia virus-specific PRNT assay, no significant difference was identified between GMTs and seroconversion rates among HIV-infected and uninfected subjects 2 weeks following administration of a second dose of Imvamune (GMTs of 95 and 188 and seroconversion rates of 89% and 96% respectively) (64). A study evaluated the safety and immunogenicity of Imvamune (1 x 10 7 TCID 50 and 1 x 10 8 TCID 50 ) in 24 subjects (20 who received Imvamune and four controls) who had received a hematopoietic stem cell transplant at least 2 years before enrollment (65). Transient local reactions were observed but no serious adverse events were identified (65). Immunogenicity was evaluated using a luciferase-based assay of neutralizing antibody activity and an IFN-γ ELISPOT assay, and both provided greater results in the higher-dose group (65). Finally, a study that compared two different Imvamune vaccination schedules determined that the recommended schedule with a second dose of Imvamune at Day 28 compared with Day 7 produced a higher antibody response by PRNT and the maximal number of responders by ELISA (63). IFN-γ ELISPOT responses were similar for both groups 14 days following the second dose (63). A pivotal Phase III clinical trial comparing Imvamune and ACAM2000 is planned. # Safety The safety of Imvamune has been evaluated in six published clinical trials involving a total of 687 subjects (562 vaccinia virus-naïve and 125 previously vaccinated) (39,41,42,(63)(64)(65). Subjects varied in age (range: 18-60 years) and all were healthy with the exception of 91 HIV-infected subjects. The doses of vaccine administered in these trials ranged from 1 x 10 6 to 1 x 10 8 TCID 50 . Vaccinia-naïve subjects received 2 doses of vaccine whereas previously vaccinated subjects received only 1 dose. Vaccine was administered either subcutaneously or intramuscularly. No deaths were reported. One serious adverse event involving a case of thyroid cancer occurred and was considered vaccine-related by the medical monitor but unrelated by the investigator. Common adverse events reported were typical for subcutaneously administered vaccines (local [injection site] and general systemic reactions [fatigue, headache, and myalgia]). Almost all reactions were mild to moderate in severity and all resolved without sequelae. Imvamune does not produce a lesion at the vaccination site and does not present any risk for secondary transmission. A total of 91 HIV-infected subjects (30 vaccinia virusnaïve and 61 previously vaccinated) with HIV-1 RNA <400 copies/mL and ≥350 CD4 cells/mm 3 received Imvamune in one published clinical trial (64). No deaths or vaccine-related serious adverse events were reported among these subjects. Overall, the safety profile of Imvamune in these HIV-infected subjects was comparable to that of uninfected subjects. Because Imvamune has not been studied in pregnant or breastfeeding women, the risks and efficacy of Imvamune are unknown in this population. The only report of Imvamune associated with pregnancy involved a woman aged 27 years who was determined to be pregnant after receiving 2 doses of Imvamune (42). On the basis of pregnancy dating estimates, conception occurred at least 17 days after administration of the second dose of vaccine, and pregnancy exposure to vaccine was not confirmed. Ultimately, the pregnancy progressed to term without complications and resulted in the delivery of a healthy, normal infant. No cases of myopericarditis have been identified following vaccination with Imvamune. However, a complete evaluation of the potential risk for myopericarditis with this vaccine is not possible because of the exclusion of clinical trial participants with known heart disease or cardiac risk factors, the limited number of total recipients of IMVAMUNE, and uncertainties related to disease pathophysiology for this complication. The predecessor MVA strain used to develop Imvamune was authorized for use in Germany in 1976 as a pre-immunization vaccine administered before Lister vaccine to decrease the potential for adverse events (40,67). Over 120,000 persons received a low dose of MVA (1 x 10 6 TCID 50 ) with no reported serious adverse events although rigorous follow-up of vaccinees was not performed (40,67). Prior clinical trials evaluating MVA safety also showed no serious adverse events among 7,098 subjects including 5,691 children aged <3 years (40). Imvamune has not been studied in persons aged <18 years. # Recommended Uses of Smallpox Vaccine Major Principles and Considerations In a public health emergency involving smallpox, vaccination with replication-competent (i.e., ACAM2000 and APSV) smallpox vaccine will be the primary response strategy for stopping the chain of transmission and achieving epidemic control. Persons exposed to smallpox virus are at high risk for developing smallpox and transmitting the virus to others thereby allowing continued propagation (1). Postexposure vaccination effectiveness is based on the principle that vaccination of exposed persons will provide rapid protection from disease. During the eradication campaign, single dose replication-competent smallpox vaccines from which ACAM2000 and APSV are derived were used successfully Persons at high risk for smallpox infection without a known smallpox virus exposure identified by public health authorities should be screened for relative contraindications to smallpox vaccination (Figure 2). Such persons with relative contraindications to smallpox vaccination should be vaccinated with Imvamune when available and authorized for use by FDA. Supplies of Imvamune might be limited in scenarios in which widespread smallpox vaccination is required. Consequently, Imvamune should be reserved for persons with relative contraindications to smallpox vaccination because they are likely to receive the most benefit because of their risk for serious adverse events. Although the current plan under the pre-EUA is to allow the use of Imvamune only in persons with atopic dermatitis or HIV infection, additional regulatory approvals might be requested from FDA to allow Imvamune administration among other persons with relative contraindications to smallpox vaccination. When Imvamune is not available or regulatory authorization for its use is lacking, an individual risk-benefit assessment should be performed to determine whether the benefits of vaccination with ACAM2000 outweigh the risks. Ultimately, the primary concern is that persons exposed to smallpox virus or at high risk for smallpox infection should be vaccinated; the choice of vaccine is a secondary consideration. Because of their similarities (ACAM2000 is a clonal derivative of the vaccinia virus strain used to produce APSV), ACAM2000 and APSV are expected to exhibit similar effectiveness and safety profiles when used during a response. Clinical utilization of ACAM2000 and APSV would be identical although APSV would be used only after the supply of ACAM2000 is exhausted. ACAM2000 is preferred to APSV because it is a licensed vaccine produced using modern good manufacturing practices. Recommendations and anticipatory guidance related to the use of ACAM2000 also apply to the use of APSV in situations where ACAM2000 is not available. ACAM2000 and APSV are currently stockpiled in sufficient quantities to vaccinate the entire U.S. population. # Anticipatory Guidance After administration of ACAM2000, there are various infection control and vaccine site care practices that need to be followed to minimize the chance of spread of vaccinia virus from the vaccine site. To prevent contact transmission after vaccination, vaccinees should cover the vaccination site with a loose gauze or similar absorbent material to absorb exudates and long-sleeved clothing should be worn (9). For all vaccine site care, thorough hand hygiene with soap and water/disinfectant use is required. Clothing, towels, and other cloth materials in contact with the vaccination site should be separated from other household laundry until they to break the chain of transmission and ultimately eradicate the disease from the human population (1). In contrast, the strain of vaccinia virus contained in Imvamune was not used during the eradication of smallpox and its efficacy in preventing smallpox in humans is less certain. Furthermore, Imvamune requires 2 doses administered 4 weeks apart to achieve an immune response comparable to that of replicationcompetent smallpox vaccines. Although persons vaccinated with Imvamune might have a lower risk for serious adverse events, this might be outweighed by the uncertainty in clinical effectiveness to prevent disease and provide rapid protection. Persons at high risk for complications from replicationcompetent smallpox vaccines are often at higher risk for severe smallpox. For these reasons, persons with a known exposure to smallpox virus should be vaccinated with a replicationcompetent smallpox vaccine unless severely immunodeficient (i.e., bone marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm 3 , and persons with severe combined immunodeficiency, complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation) (Figure 1). Persons exposed to smallpox virus include those directly exposed to an accidental or intentional smallpox virus release or those identified as a contact of a person with a confirmed, probable, or suspected case of smallpox as defined by the CDC Smallpox Response Plan and Guidelines (37) (Box 1). Contacts of a smallpox patient include household family members of such cases, others spending ≥3 hours in the household since the case's onset of fever, and nonhousehold members with ≥3 hours of contact <2 m (<6.5 feet) with a case with rash (37) (Box 2). Persons without smallpox virus exposure might still be at risk for developing smallpox infection depending on the magnitude of the outbreak and the effectiveness of the public health response in successfully implementing vaccination and other control measures when disease is present. A person's risk for exposure is thus dependent on multiple factors and cannot be quantified for all possible scenarios. For example, the response to a limited outbreak involving a few cases and limited geographic spread might focus on contact tracing and targeted vaccination informed by case identification to achieve epidemic control. In contrast, a widespread outbreak involving multiple cases in multiple locations might warrant a different public health strategy (e.g., a more extensive vaccination campaign to supplement these surveillance and containment efforts). Public health authorities will determine the scope of the response and provide guidance for appropriate vaccination strategies on the basis of the epidemiologic characteristics of the outbreak (e.g., the magnitude of the outbreak and the effectiveness of the public health response) (Box 3). can be decontaminated with routine laundering in soapy hot water (8). Education should be provided to vaccinees regarding the risk for contact/spread to household and other close contacts, particularly with certain activities (e.g., sexual contact). Although persons within a household are likely to be vaccinated together because of shared risks for smallpox infection, infection-control precautions should be followed to prevent inadvertent inoculation before the onset of protection, particularly when persons within the household are at higher risk for adverse events (e.g., persons with atopic dermatitis). Recommendations for monitoring the vaccine response to replication-competent smallpox vaccines have been published previously (9). Vaccinees should be evaluated 6-8 days postvaccination to assess the vaccination site for development of a major cutaneous reaction or "take." Persons exposed to smallpox virus or at high risk for smallpox infection for whom evidence of a major cutaneous reaction is lacking should be revaccinated and receive the same patient education and symptom monitoring information that is provided to unvaccinated persons described below. If a major cutaneous reaction is not observed following revaccination, further consultation with a health-care provider and/or public health authorities should be sought. Vaccinees receiving ACAM2000 should be evaluated for adverse events at the 1-week assessment and at any other time as clinically indicated. CDC provides guidelines regarding the signs and symptoms to monitor for adverse events after vaccination (9). Medical care providers for immunized mothers with infants and infants of immunized caregivers should emphasize infection control precautions to avoid inadvertent inoculation of the infant during breastfeeding or other caregiver activities. Recipients of ACAM2000 can be considered successfully vaccinated once the development of a major cutaneous reaction is apparent. Because there is no discernible cutaneous reaction with Imvamune, the success of vaccination and onset of protection is harder to determine. Recipients of Imvamune achieve a maximal immune response after two inoculations approximately 9. † Persons not vaccinated because of medical conditions, resource constraints, or otherwise and persons revaccinated following a failure to develop a major cutaneous reaction should receive clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur. In addition, they should be monitored for signs and symptoms suggestive of smallpox, including fever and prostration. Although persons with severe immunodeficiency might not benefit from vaccination, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in such persons when antivirals are not immediately available. § CDC provides guidance regarding the signs and symptoms to monitor for vaccine adverse events (9). ¶ If a major cutaneous reaction is not seen upon revaccination, further consultation with a health-care provider and/or public health authorities should be sought. Severely immunode cient? 6 weeks from initial vaccine administration (63). Although limited animal studies suggest a single dose of Imvamune might provide some protection, the 2-dose regimen provides maximum protection and persons should not be considered fully protected until after the second dose (63,(68)(69)(70). Vaccinees should be educated on the anticipated time to develop protection following vaccination. Prior to full protection, all vaccinees should avoid persons with smallpox and intimate contact with persons known to be vaccinated with replication-competent vaccine with active vaccination site lesions, satellite lesions, or rashes possibly containing vaccinia virus to decrease the likelihood of exposure to either smallpox or vaccinia virus. Every effort should be made to adhere to the schedule of the 2-dose regimen for Imvamune. Persons with a delay in receipt of the second dose should be vaccinated immediately. The need for an additional booster dose of Imvamune should be considered in consultation with a health-care provider and/or public health authorities. # Guidance for Vaccination by Contraindication or Medical Condition No absolute contraindications exist for smallpox vaccination in a postevent setting. However, several relative contraindications exist among persons with certain medical conditions. CDC recommendations for smallpox vaccine use were developed in consideration of the risk for smallpox infection, risk for adverse event following vaccination, and benefit from vaccination and are summarized (Table 8). If certain circumstances (e.g., medical conditions, resource constraints, or otherwise) prevent vaccination of persons exposed to smallpox virus or at high risk for smallpox infection as determined by public health authorities, these unvaccinated persons should be provided clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur (9,37). In addition, they should be monitored for signs and symptoms suggestive of smallpox, including fever, prostration, etc. If these symptoms are present, these persons should be isolated immediately (37). In these situations, antiviral medications are expected to be available for treatment of disease, but the efficacy of these products has not been established in # BOX 3. Definition of high risk for smallpox infection • Persons at high risk for smallpox infection will be defined by public health authorities during an outbreak on the basis of their risk for exposure to smallpox virus and the epidemiologic characteristics of the outbreak. # BOX 2. Definition of smallpox virus exposure • Persons directly exposed to an accidental or intentional smallpox virus release • Household family members of persons with confirmed, probable, or suspected cases and others spending ≥3 hours in the household since onset of fever in a person with a case • Nonhousehold members with ≥3 hours of contact <2 meters (<6.5 feet) with a person with a case with rash * CD4 cell counts for children aged <13 years with HIV infection should be adjusted as per Table 9. † Persons not vaccinated because of medical conditions, resource constraints, or otherwise and persons revaccinated following a failure to develop a major cutaneous reaction should receive clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur. In addition, they should be monitored for signs and symptoms suggestive of smallpox, including fever and prostration. Although persons with severe immunodeficiency might not benefit from vaccination, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in such persons when antivirals are not immediately available. § Relative contraindications: persons with atopic dermatitis; persons infected with HIV; persons with other immunocompromised states (i.e., solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immuno-suppressive therapies); and persons with vaccine or vaccine-component allergies. ¶ Atopic dermatitis, also referred to as childhood eczema (or simply eczema), can be defined as a history (or presence) of chronic or relapsing pruritic, xerotic, eczematous dermatitis that lasted (or lasts) >2 weeks per episode PLUS two or more of the following: 1) facial, neck, or extensor involvement in infants and children or flexural lesions in any age group, 2) onset at age ≤5 years, 3) personal history of atopy (e.g., asthma or seasonal allergies), or 4) first-degree relative with atopic dermatitis ** An individual risk-benefit assessment should be performed to determine whether the benefits of vaccination with ACAM2000 outweigh the risks. † † Current regulatory mechanisms only allow for the use of Imvamune in persons with AD or HIV infection, additional regulatory approvals may be requested from FDA to allow Imavamune administration among other persons with relative contraindications to ACAM2000. § § If a major cutaneous reaction is not seen upon revaccination, further consultation with a health-care provider and/or public health authorities should be sought. ¶ ¶ CDC provides guidance regarding the signs and symptoms to monitor for vaccine adverse events (9). Severely immunode cient? # Absolute Contraindications The risk-benefit analysis of the use of smallpox vaccine is inherently different in a postevent vaccination program compared with a pre-event vaccination program. In a postevent vaccination program, the risk for adverse events from smallpox vaccination is outweighed more often by the risk for severe smallpox disease. Consequently, contraindications that would apply in a pre-event vaccination program might no longer apply in a postevent vaccination program. Because of the high case-fatality rate and severity of smallpox, no clear absolute contraindications exist for the use of smallpox vaccines, including replication-competent vaccines, for persons exposed to smallpox virus or at high risk for smallpox infection. However, certain medical conditions discussed below have a substantial impact on the risk-benefit analysis and should be incorporated into the vaccination decision-making process. (Figures 1 and 2). Provide clear information about prodromal and disease-specific manifestations, how to self-assess for these symptoms, and when and where to seek care if these symptoms occur. Monitor for signs and symptoms suggestive of smallpox, including fever and prostration. * Persons with a relative contraindication should be classified on the basis of the relative contraindication rather than on their pregnancy, breastfeeding, age, cardiac, or health-care worker status. # Severe Immunodeficiency Recommendations • Persons with severe immunodeficiency who are not expected to benefit from vaccine should not receive any smallpox vaccine. • Persons with severe immunodeficiency who are exposed to smallpox virus may receive IMVAMUNE when antivirals are not immediately available. Persons with severe immunodeficiency have a high likelihood of poor immune response and an increased risk for adverse events following administration of smallpox vaccine. As such, vaccination with any smallpox vaccine should be avoided in persons with severe immunodeficiency who are not expected to benefit from vaccine. Such persons might include bone-marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm 3 and persons with severe combined immunodeficiency (SCID), complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation for the person's protection (72) (Box 4). CD4 cell counts for children aged <13 years with HIV infection should be adjusted (Table 9) (73). Although persons with severe immunodeficiency might not benefit from vaccination, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure to such persons when antivirals are not immediately available on the basis of their high risk for smallpox infection. # Relative Contraindications Persons with relative contraindications might be at higher risk for adverse events from replication-competent smallpox vaccine. Such populations include persons with atopic dermatitis (eczema), HIV infection with CD4 cell counts of 50-199 cells/mm 3 § , other immunocompromised states (i.e., solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies), and persons with vaccine or vaccine-component allergies (Box 5). Although these populations are at higher risk for adverse events, replication-competent vaccines still are recommended for those exposed to smallpox virus. The potential for developing severe smallpox is considered a higher risk than the risk for severe adverse events, and the benefits of vaccine-provided protection outweigh the risks of vaccine-associated adverse events. However, among these populations, in circumstances when the risk for smallpox is minimal and a delay in the onset of immunity would not increase this risk to an unacceptable level, administration of the 2-dose regimen of Imvamune is preferable when available and authorized for use by FDA. Recommendations and further guidance for each of these populations are discussed in detail below. # Persons with Atopic Dermatitis Recommendations • Persons with atopic dermatitis who are exposed to smallpox virus should be vaccinated with ACAM2000. • Persons with atopic dermatitis at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune. • Persons with atopic dermatitis who were vaccinated previously against smallpox should receive ACAM2000. During a public health emergency involving smallpox, atopic dermatitis (also referred to as eczema) can be defined using published clinical findings and criteria (Box 6) (74). A history or presence of atopic dermatitis is a risk factor for developing eczema vaccinatum following vaccination with replication-competent smallpox vaccines. However, atopic dermatitis is not an absolute contraindication to vaccination § CD4 cell counts should be adjusted for children aged <13 years with HIV infection (Table 9). with ACAM2000 for those exposed to smallpox virus or at high risk for smallpox infection. Following exposure to smallpox virus, the risk for severe smallpox likely outweighs the risk for experiencing a severe adverse event secondary to ACAM2000. Treatment for severe adverse events with medical countermeasures including VIGIV and antivirals is expected to be available. For these reasons, ACAM2000 is preferred to Imvamune for persons with atopic dermatitis exposed to smallpox virus because of its ability to achieve protection in a single dose. In contrast, persons with atopic dermatitis at high risk for smallpox infection without a known smallpox virus exposure would likely benefit from vaccination with Imvamune. In this situation, the risk for acutely developing smallpox is lower and there is a higher likelihood of successfully administering both doses of Imvamune and achieving greater protection before disease develops or a smallpox virus exposure occurs. Existing data suggest that previously vaccinated persons have a lower risk for developing adverse events (1,60,61). As such, ACAM2000 is preferred to Imvamune for persons with atopic dermatitis with a history of previous smallpox vaccination without complications. # Persons with HIV Infection Recommendations • Persons with HIV infection with CD4 cell counts >200 cells/mm 3 § who are exposed to smallpox virus or at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with ACAM2000. • Persons with HIV infection with CD4 cell counts of 50-199 cells/mm 3 § who are exposed to smallpox virus should be vaccinated with ACAM2000. • Persons with HIV infection with CD4 cell counts of 50-199 cells/mm 3 § at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune. • Persons with HIV infection with CD4 cell counts of <50 cells/mm 3 § might not benefit from smallpox vaccine. The eradication of smallpox from the human population before the introduction of HIV precludes direct knowledge of potential interactions between these two pathogens in humans. It is likely that persons with HIV infection are at higher risk for severe disease from smallpox infection because of the known pathophysiology and immunosuppressive nature of HIV disease. Similarly, little is known about the risk for serious vaccine complications from ACAM2000 and APSV among the HIV-infected population because there are no studies evaluating these vaccines in this population. The safety and efficacy of IMVAMUNE in the limited number of HIV-infected subjects evaluated has been comparable to uninfected subjects (64). # Other Immunocompromised Persons Recommendations • Immunocompromised persons exposed to smallpox virus should be vaccinated with ACAM2000 unless they have a severe immunodeficiency and are not expected to benefit from vaccine (Box 4; Figure 1). • Solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies at high risk for smallpox infection without a known smallpox virus exposure should be vaccinated with Imvamune when available and authorized for use by FDA. Diseases and conditions that cause immunodeficiency or immunosuppression are believed to predispose affected persons for serious adverse events. These same diseases and conditions also might increase the risk for severe disease from smallpox infection. The impact of the degree of immunodeficiency or immunosuppression on the risks for severe smallpox and serious adverse events is difficult to assess. Vaccination with Imvamune is recommended for certain immunocompromised persons at high risk for smallpox infection. Although no regulatory mechanism exists at this time to provide vaccine to persons without atopic dermatitis or HIV infection, additional regulatory approvals might be requested from FDA to allow administration of Imvamune to other persons with relative contraindications. Such persons include solid organ transplant recipients within 3 months of transplantation, bone marrow transplant recipients during the 4-24 month time period following transplantation, transplant recipients with active graft-versus-host disease, and persons receiving immunosuppressive therapies (including alkylating agents, antimetabolites, radiation, tumor necrosis factor [TNF] inhibitors, and high-dose corticosteroids [i.e., >2 mg/kg body weight or 20 mg/day of prednisone for >2 weeks]). Although other chronic conditions such as heart disease, diabetes mellitus and arthritis might have some component of immunosuppression, the benefits of vaccination with ACAM2000 likely outweigh the risk for a serious adverse event because of the relatively lower degree of immunosuppression. Similarly, ACAM2000 is preferred to Imvamune for persons with other immunocompromising conditions such as complement or phagocytic deficiencies who are likely to produce sufficient immune responses to vaccination with no known increased risk for serious adverse events. Persons with HIV infection determined to be at high risk for smallpox infection by public health authorities should be evaluated carefully for smallpox virus exposures because of the potential risk for severe smallpox among this population. ACAM2000 should be administered to HIV-infected persons with CD4 cell counts ≥50 cells/mm 3 § with any smallpox virus exposure since the risk for severe smallpox likely outweighs the risk for a serious vaccine complication under these circumstances. Medical countermeasures including VIGIV and antivirals are expected to be available to treat serious vaccine complications including progressive vaccinia. If no smallpox virus exposure is identified, HIV-infected persons at high risk for smallpox infection with CD4 cell counts of 50-199 cells/mm 3 § should be vaccinated with Imvamune. Although there are no data on the efficacy or safety of Imvamune in this population, they are likely to benefit from a replication-deficient vaccine because of the increased risk for serious adverse events because of the higher degree of immunosuppression compared with HIV-infected persons with CD4 cell counts ≥200. HIV-infected persons with CD4 cell counts <50 cells/mm 3 § might not benefit from smallpox vaccine as they are unlikely to mount a sufficient immune response to any of the stockpiled smallpox vaccines. However, vaccination with Imvamune may be considered in the setting of a smallpox virus exposure when antivirals are not immediately available. HIV-infected persons exposed to smallpox virus who do not have a recent (within 1 year) CD4 count available should be evaluated for AIDS-defining conditions as defined by current surveillance case definitions (73). ACAM2000 should be administered unless an AIDS-defining condition is present because of the high risk for severe smallpox in this scenario. Persons with HIV infection at high risk for smallpox infection without a known smallpox virus exposure should have a CD4 cell count performed before administering smallpox vaccine when possible if this information is not available as this test can be performed in less than 24 hours in most cases. This short delay is unlikely to result in significantly increased risk for smallpox infection when there is no known smallpox virus exposure. # Persons with Vaccine or Vaccine Component Allergies # Recommendations • Prior to vaccination and regardless of a smallpox virus exposure, persons suspected of having a severe allergy to smallpox vaccine or a vaccine component should be counseled on the risks of a severe allergic reaction. • For persons exposed to smallpox virus: -Persons with a severe allergy to a previous dose of smallpox vaccine should be vaccinated with ACAM2000 in a facility capable of treating an anaphylactic reaction. -Persons with a severe allergy to ACAM2000 or a vaccine component of ACAM2000 should be vaccinated with APSV, if available. If APSV is unavailable, ACAM2000 should be administered in a facility capable of treating an anaphylactic reaction. • For persons at high risk for smallpox infection without a known smallpox virus exposure: -Persons with a severe allergy to a vaccine component or previous dose of smallpox vaccine should be vaccinated with any available smallpox vaccine that does not contain the vaccine strain or vaccine component associated with severe allergy. -If a smallpox vaccine that does not contain the vaccine strain or vaccine component associated with the severe allergy is unavailable, the person should be offered vaccination with any available smallpox vaccine in a facility capable of treating an anaphylactic reaction. In persons exposed to smallpox virus, the risk for severe smallpox likely outweighs the risk for a serious allergic reaction to vaccination. Studies evaluating smallpox vaccine complications in 1968 found that severe allergic reactions such as erythema multiforme occurred at a rate of 165 cases per 1 million primary vaccinations (60,61). No cases of anaphylaxis or death from an allergic reaction were reported (60,61). However, the risk for anaphylaxis, a potentially life-threatening reaction, cannot be excluded in persons with a history of severe allergies to a previous dose of smallpox vaccine or a vaccine component. Smallpox vaccines to be used in an emergency response have different vaccine components as detailed in their respective product descriptions. Smallpox vaccine should be administered in a facility capable of treating an anaphylactic reaction to mitigate this risk. # Guidance for Other Special Populations Pregnant and Breastfeeding Women Recommendations • Pregnant and breastfeeding women exposed to smallpox or at high risk for smallpox infection should be vaccinated with ACAM2000. • Pregnant and breastfeeding women with atopic dermatitis, HIV infection, or other relative contraindication should be classified on the basis of the relative contraindication rather than on their pregnancy or breastfeeding status. Data from the smallpox eradication era indicate that pregnant women were particularly susceptible to severe disease, including hemorrhagic smallpox, and had extraordinarily high case-fatality rates from smallpox (34.3% overall and nearly 70% for unvaccinated pregnant women) (1,20,21). Although vaccination with replication-competent smallpox vaccines poses a risk for fetal vaccinia because of direct viral infection of the fetus, the risk is presumed to be very low on the basis of the number of cases reported during periods of active immunization (1,51). Increased rates of other serious adverse events have not been reported among vaccinated pregnant women. The protective benefits of vaccination with ACAM2000 likely outweigh the risk for fetal vaccinia considering the high disease-related mortality for both the mother and fetus. ACAM2000 is preferred to Imvamune for pregnant women exposed to smallpox virus or at high risk for smallpox infection because the clinical effectiveness and safety of Imvamune are uncertain in this population and the 2-dose regimen might delay full protection from disease. Lactating women are not known to be at increased risk for severe smallpox or serious adverse events when compared with the general population. However, similar to other situations of intimate contact (e.g., sexual activity), inadvertent transmission of live vaccinia virus from the vaccine site to infants of vaccinated mothers is a potential risk during feeding (75). The risk for inadvertent transmission might be similar with breast or bottle feeding because both methods could result in intimate contact. Similar to other recommendations for intimate contact among vaccinated persons, these risks can be mitigated with infection control precautions (9). It is not known whether smallpox vaccine virus or antibodies are excreted in human breast milk or whether exposure to vaccinia virus through viral excretion into breast milk results in neonatal vaccinia virus infections. Lactating women exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000 and counseled on proper infection control precautions to avoid inadvertent transmission of vaccinia virus from the vaccination site to breastfeeding infants (9). The well-known infant and maternal benefits of breastfeeding outweigh the small potential risk for viral transmission to infants through consumption of breast milk. Discontinuation of breastfeeding or infant feeding with expressed human breast milk is not recommended unless there is a cutaneous breast lesion suspicious for vaccinia virus infection. Because infant contact with cutaneous breast lesions has been demonstrated to cause oral lesions, if such a lesion is present, breastfeeding or expression of milk would not be advisable until the lesion completely resolves. # Pediatric and Geriatric Populations Recommendations • Persons exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000 regardless of age. • Persons with HIV, atopic dermatitis, or other relative contraindications should be classified on the basis of the relative contraindication regardless of age. ACAM2000 should be administered to persons exposed to smallpox virus or at high risk for smallpox infection regardless of age, including pediatric and geriatric populations because of the increased risk for severe smallpox in the very young and older age groups. ACAM2000 is preferred to Imvamune for these age groups because the clinical efficacy and safety of Imvamune is uncertain in these populations and the 2-dose regimen might delay full protection from disease. Population studies from the smallpox eradication era including both vaccinated and unvaccinated subjects revealed that smallpox case-fatality rates were highest in the very young and older age groups (Table 2) (18,19). In addition, children aged <2 years vaccinated with ACAM2000 are believed to be at increased risk for serious adverse events, particularly central nervous system disease including postvaccinial encephalitis, on the basis of experience with its predecessor vaccine Dryvax (1,60,61). No cases of postvaccinial encephalitis associated with Imvamune or other similar vaccinia virus vaccine strains have been reported. However, the likelihood of observing this rare complication in the number of persons vaccinated with Imvamune to date is very low, particularly because that no persons aged <18 years have received this vaccine. Therefore, clinical data are insufficient to determine whether Imvamune would provide additional safety benefits in populations at higher risk for postvaccinial encephalitis. Older populations might be at increased risk for serious adverse events because of the relative immunosuppression of advanced age and higher likelihood of comorbidities that might predispose to adverse events with replication-competent smallpox vaccines. However, the efficacy and safety of Imvamune has not been established in older persons and the potential delay in development of protection because of the 2-dose regimen might place them at risk for severe smallpox. # Persons with Known Heart Disease or Cardiac Risk Factors Recommendations • Persons with known heart disease or cardiac risk factors exposed to smallpox virus or at high risk for smallpox infection should be vaccinated with ACAM2000. Myopericarditis is known to occur in healthy persons after receipt of replication-competent smallpox vaccines (i.e., ACAM2000 and Dryvax) (46,57,59). Whether persons with known heart disease or cardiac risk factors have an increased frequency of serious adverse events compared with persons without these conditions is unknown. Although the specific risk factors for myopericarditis following smallpox vaccination have not been identified, the consequences of myopericarditis in persons with known heart disease or cardiac risk factors are more likely to be severe than in persons without known heart disease or cardiac risk factors. The pathophysiology of this adverse event remains unclear because of the absence of viral damage in the histopathologic examination of myocardial tissue from vaccinees with myopericarditis (54,55). Although no cases of myopericarditis have been observed in the Imvamune clinical trials to date, the total number of persons vaccinated in clinical trials is not enough to preclude the possibility that this complication occurs at a low rate. Since both vaccines have only been tested in healthy populations, and the cardiac complications in the ACAM2000 trial were transient and resolved with no apparent long-term consequences, the benefit from vaccination with Imvamune over ACAM2000 for persons with known heart disease or cardiac risk factors is unknown. For these reasons, ACAM2000 is preferred to Imvamune in these populations. # Health-Care Workers Recommendations • During a public health emergency involving smallpox, public health authorities will identify health-care workers at high risk for smallpox infection. • These health-care workers should be vaccinated with ACAM2000 unless they are severely immunodeficient or relatively contraindicated. During the smallpox eradication era, health-care workers (HCWs) were found to be at high risk for smallpox infection (1,34). Because society today is highly mobile, the re-emergence of smallpox would have worldwide ramifications. In the event of a public health emergency involving smallpox anywhere in the world, public health authorities in the United States will likely recommend smallpox vaccination for selected HCWs. Such HCWs at high risk for smallpox infection should receive ACAM2000 unless the HCW is severely immunodeficient or relatively contraindicated. In the setting of a smallpox response, pregnant HCWs are not expected to provide direct patient care in an initial emergency response and should not be vaccinated unless exposed to smallpox virus or otherwise determined to be at high risk for smallpox infection by public health authorities. Past experiences vaccinating HCWs and first responders in the United States during a pre-event vaccination campaign during 2002-2004 suggest that acceptance of smallpox vaccination might be low when concerns of experiencing an adverse event outweigh the perceived threat of smallpox exposure (76). Smallpox vaccine acceptance among this workforce might be higher with Imvamune than with ACAM2000 because of the potentially favorable safety profile. However, HCW perceptions of risk might change in a postevent setting with the knowledge that smallpox has been identified in humans leading to a greater desire for protection from vaccination. Imvamune should be administered to HCWs at high risk for smallpox infection with relative contraindications to smallpox vaccination as outlined (Figure 2). HCW eligibility for vaccination with Imvamune will depend on the availability of the vaccine. Although the inability of Imvamune to spread via contact transmission makes it advantageous to HCWs, the risk for transmission of ACAM2000 in a hospital setting is low, particularly with the implementation of sound hygiene practices and barrier protection. HCWs who have been vaccinated with smallpox vaccine should not be furloughed nor have their activities limited. However, previously vaccinated HCWs without active vaccination site lesions would ideally care for patients with severe immunosuppression. When previously vaccinated HCWs are unavailable, HCWs with active vaccination site lesions working with severely compromised patients should use enhanced infection control precautions and additional personal protective equipment (e.g., occlusive bandages to cover the vaccine site and/or nonpermeable gowns) (9). # Knowledge Gaps and Future Research These recommendations for use of smallpox vaccines in a postevent vaccination program are constrained by the limited recent use of smallpox vaccines in select populations and the current lack of clinical guidance for other medical countermeasures including antivirals in postevent settings. As such guidance is developed, these recommendations will evolve, in particular for persons with increased risks of serious adverse events or for severely immunodeficient persons who are unlikely to benefit from vaccination. Because the supply of Imvamune is limited, situations could occur that will limit its potential uses. As knowledge develops regarding the safety and efficacy of Imvamune (e.g., the potential for use of 1 dose of vaccine or the use of Imvamune before administration of ACAM2000 to decrease the risk for adverse events) recommendations regarding its use will change. The ability to advance knowledge is constrained by the limited use of vaccine since smallpox eradication. Should an event occur, it will be critical to monitor the safety and effectiveness of all smallpox vaccines, in particular among those populations where current knowledge is limited (e.g., pregnant women, children, the elderly, and immunocompromised persons). # Acknowledgments	None	None
288b81c9a670aff6b998a2fc2b347c9a4f5e936e	cdc	None	A. Physician. B. Nurse. C. Health educator. D. Office staff. E. Other. 12. I plan to use these recommendations as the basis for . . . (Indicate all that apply.) A. health education materials. B. insurance reimbursement policies. C. local practice guidelines. D. public policy. E. other. Vol. 54 / No. RR-7 Recommendations and Reports CE-3 Detach or photocopy.# Introduction Neisseria meningitidis has become a leading cause of bacterial meningitis in the United States after dramatic reductions in the incidence of Streptococcus pneumoniae (1) and Haemophilus influenzae type b (Hib) (2) infections have been achieved as a result of using conjugate vaccines. CDC's Advisory Committee on Immunization Practices (ACIP) previously recommended a tetravalent polysaccharide vaccine (Menomune ® -A,C,Y,W-135, manufactured by Sanofi Pasteur, # Prevention and Control of Meningococcal Disease # Recommendations of the Advisory Committee on Immunization Practices (ACIP) Prepared by Oleg O. Bilukha, MD, PhD Nancy Rosenstein, MD Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases # Summary In January 2005, a tetravalent meningococcal polysaccharide-protein conjugate vaccine ( Menactra,™ manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) was licensed for use among persons aged 11-55 years. CDC's Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of young adolescents (defined in this report as persons aged 11-12 years) with MCV4 at the preadolescent health-care visit (at age 11-12 years). Introducing a recommendation for MCV4 vaccination among young adolescents might strengthen the role of the preadolescent visit and have a positive effect on vaccine coverage among adolescents. For those persons who have not previously received MCV4, ACIP recommends vaccination before high-school entry (at approximately age 15 years) as an effective strategy to reduce meningococcal disease incidence among adolescents and young adults. By 2008, the goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Routine vaccination with meningococcal vaccine also is recommended for college freshmen living in dormitories and for other populations at increased risk (i.e., military recruits, travelers to areas in which meningococcal disease is hyperendemic or epidemic, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, patients with anatomic or functional asplenia, and patients with terminal complement deficiency). Other adolescents, college students, and persons infected with human immunodeficiency virus who wish to decrease their risk for meningococcal disease may elect to receive vaccine. This report updates previous reports from ACIP concerning prevention and control of meningococcal disease. It also provides updated recommendations regarding use of the tetravalent meningococcal polysaccharide vaccine (MPSV4) and on antimicrobial chemoprophylaxis. Inc., Swiftwater, Pennsylvania) for use among certain populations at increased risk, including travelers to countries with epidemic or hyperendemic meningococcal disease, persons who have certain medical conditions (i.e., terminal complement component deficiencies and anatomic or functional asplenia), and laboratory personnel who are routinely exposed to N. meningitdis in solutions that might be aerosolized (3). Use of this vaccine also was recommended for control of meningococcal disease outbreaks (4). Recommendations permitting use of MPSV4 among college freshmen have been published previously (5). The new tetravalent A, C, Y, W-135 conjugate vaccine (Menactra™, manufactured by Sanofi Pasteur, Inc.) licensed for persons aged 11-55 years should become a key addition to existing meningococcal disease prevention measures. This report provides ACIP's recommendations on prevention and control of meningococcal disease, including recommendations on use of the new tetravalent conjugate vaccine (MCV4) as well as updated recommendations on use of the polysaccharide vaccine (MPSV4) and on antimicrobial chemoprophylaxis. # MMWR May 27, # Background Epidemiology of Meningococcal Disease Each year, an estimated 1,400-2,800 cases of meningococcal disease occur in the United States, a rate of 0.5-1.1/100,000 population (CDC, unpublished data, 2004). N. meningitidis colonizes mucosal surfaces of nasopharynx and is transmitted through direct contact with large droplet respiratory secretions from the patients or asymptomatic carriers. Humans are the only host. Despite the continued sensitivity of meningococcus to multiple widely available antibiotics, including penicillin (6,7), the case-fatality ratio for meningococcal disease is 10%-14% (CDC, unpublished data, 2004). Meningococcal disease also causes substantial morbidity; 11%-19% of survivors have sequelae (e.g., neurologic disability, limb loss, and hearing loss) (8,9). During 1991-2002, the highest rate of meningococcal disease (9.2/100,000) occurred among infants aged 11 years (CDC, unpublished data, 2004). In the United States, >98% of cases of meningococcal disease are sporadic; however, since 1991, the frequency of localized outbreaks has increased (10,11). The proportion of meningococcal cases caused by serogroup Y increased from 2% during 1989-1991 (12) to 37% during 1997-2002 (CDC, unpublished data, 2004). Serogroups B, C, and Y are the major causes of meningococcal disease in the United States, each being responsible for approximately one third of cases. The proportion of cases caused by each serogroup varies by age group. Among infants aged 50% of cases are caused by serogroup B, for which no vaccine is licensed or available in the United States (13,14). Of all cases of meningococcal disease among persons aged >11 years, 75% are caused by serogroups (C, Y, or W-135), which are included in vaccines available in the United States (CDC, unpublished data, 2004). Persons who have deficiencies in the terminal common complement pathway (C3, C5-9) (15,16) and those with anatomic or functional asplenia (17) are at increased risk for acquiring meningococcal disease. Antecedent viral infection, household crowding, chronic underlying illness, and both active and passive smoking also are associated with increased risk for meningococcal disease (18)(19)(20)(21)(22)(23)(24)(25). During outbreaks, bar or nightclub patronage and alcohol use also have been associated with higher risk for meningococcal disease (26)(27)(28). In the United States, blacks and persons of low socioeconomic status (SES) have been consistently at higher risk for meningococcal disease (12,13). However, race and low SES are likely risk markers rather than risk factors for this disease. A multistate case-control study in which controls were matched to case-patients by age group indicated that in a multivariable analysis (controlling for sex and education), active and passive smoking, recent respiratory illness, corticosteroid use, new residence, new school, Medicaid insurance, and household crowding all were associated with increased risk for meningococcal disease, whereas income and race were not (18). Additional research is needed to identify groups at risk that might benefit from prevention efforts. # Meningococcal Disease and College Students Multiple studies have been conducted in the United States (29)(30)(31) and the United Kingdom (32,33) concerning the risk for meningococcal disease among college students. The risk for meningococcal disease among U.S. college students was higher for those who resided in dormitories than for those residing in other types of accommodations. Overall incidence among college students usually is similar to or somewhat lower than that observed among persons in the general population of similar age. The earliest of these studies (conducted during the 1990-91 and 1991-92 academic years) had a poor response rate (38%) and indicated a low overall incidence of meningococcal disease among U.S. college students (1.0/100,000 population/year) (31). Cases of meningococcal disease occurred 9-23 times more frequently among students living in dormitories than among those living in other types of accommoda- A retrospective cohort study conducted in Maryland during 1992-1997 (30) indicated that the overall incidence of meningococcal disease among college students was similar to that among the U.S. population of persons the same age (1.7/100,000 and 1.4/100,000, respectively); however, rates of disease among students living in dormitories were higher than rates among students living off campus (3.2/100,000 and 1.0/100,000, respectively; p = 0.05). U.S. surveillance data from the 1998-99 school year (29) indicated that the overall rate of meningococcal disease among undergraduate college students was lower than the rate among persons aged 18-23 years who were not enrolled in college (0.7 and 1.4/100,000, respectively) (Table 1). Rates were somewhat higher among freshmen (1.9/100,000). Among the approximately 600,000 freshmen living in dormitories, rates were higher (5.1/100,000) than among any age group in the population other than children aged <2 years but lower than the threshold (10/100,000) recommended for initiating meningococcal vaccination campaigns (4). In a case-control study involving 50 cases detected among college students (29), multivariate analysis indicated that freshmen living in dormitories were at higher risk for meningococcal disease than other students (matched odds ratio : 3.6; 95% confidence interval = 1.6-8.5). In the United Kingdom, rates of meningococcal disease were higher among university students than among nonstudents of similar age (32). Regression analysis indicated that the main risk factor was catered hall accommodations (the U.K. equivalent of U.S. dormitories). A recent study conducted in the United Kingdom demonstrated a rapid increase in carriage rates of meningococci among university students in the first week of the fall semester, although rates of disease peaked later in the academic year (33). The increased rate of disease among university students has prompted the United Kingdom to initiate routine vaccination of incoming university students with a bivalent A/C polysaccharide vaccine as part of a new vaccination program (34). In 2000, ACIP and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) concluded that college students, especially those living in dormitories, are at moderately increased risk for meningococcal disease compared with other persons their age (5). ACIP and AAP recommended that 1) college students and their parents be informed by health-care providers of the risks of meningococcal disease and of the potential benefits of vaccination with MPSV4; 2) college and university health services facilitate implementation of educational programs about meningococcal disease and the availability of vaccination services; and 3) MPSV4 be made available to those persons requesting vaccination. As of November 2004, a total of 31 states had adopted legislation requiring colleges to provide information on risks of meningococcal disease either to matriculating students or to students residing on campus, and 10 states had mandated vaccination for certain students, unless a vaccination waiver is provided (Figure 2) (35). In 2004, the American College Health Association conducted an Internet-based survey of college policies and practices related to meningococcal vaccination (36). Of the 72 (10%) contacted colleges and universities that responded, 60% reported having a written policy on meningococcal vaccination, and 80% reported conducting some type of outreach awareness program among college students or their parents. Median vaccination rates reported for the 2002-03 and 2003-04 academic years were 20% and 35%, respectively; # Evaluation and Management of Suspected Outbreaks of Meningococcal Disease Since the early 1990s, outbreaks of meningococcal disease have occurred with increasing frequency in the United States. During July 1994-June 2002, a total of 76 outbreaks were identified (annual median: 10; range: 4-16) (11), including 48 (63%) outbreaks caused by serogroup C, 19 (25%) by serogroup B, and nine (12%) by serogroup Y. These outbreaks occurred in 32 states and involved 247 patients (accounting for <2% of total cases of meningococcal disease in the United States during this period). Of the 76 outbreaks, 26 (34%) were community-based and accounted for 53% of all outbreakrelated cases. Of the 50 (65%) outbreaks that were organization-based, 13 (26%) occurred in colleges; 19 (38%) in primary and secondary schools; and nine (18%) in nursing homes. Vaccination campaigns (using an average of 2,500 doses of MPSV4 per outbreak) were conducted in 34 outbreaks (30 of which were caused by serogroup C and four by serogroup Y) (11). The decision to implement a mass vaccination campaign to prevent meningococcal disease depends on whether the occurrence of more than one case represents an outbreak or an unusual clustering of endemic disease. Because the number of cases in outbreaks is usually not substantial, this determination often requires evaluation and analysis of the patterns of disease occurrence. Mass vaccination campaigns are expensive, require a massive public health effort, and can create unwarranted concern among the public. Detailed information on evaluation and management of suspected outbreaks has been published previously (4) and is presented in this report. # Case Definitions The following case definitions are used in this report: - Confirmed case. A confirmed case of meningococcal disease is one that is defined by isolation of N. meningitdis from a normally sterile site (e.g., blood or cerebrospinal fluid) from a person with clinically compatible illness. - Probable case. A probable case of meningococcal disease is one that is defined by detection of polysaccharide antigen in cerebrospinal fluid (e.g., by latex agglutination, polymerase chain reaction, or immunohistochemistry) or the presence of clinical purpura fulminans in the absence of diagnostic culture from a person with clinically compatible illness (37). - P P P P Primar rimar rimar rimar rimary case. y case. y case. y case. y case. A primary case of meningococcal disease is one that occurs in the absence of previous known close contact with another patient. - Secondary case. A secondary case of meningococcal disease is one that occurs among close contacts of a primary patient >24 hours after onset of illness in the primary patient. - Co-primary cases. Co-primary cases are two or more cases that occur among a group of close contacts with onset of illness separated by <24 hours. - Close contacts. Close contacts of a patient who has meningococcal disease include 1) household members; 2) child-care center contacts; and 3) persons directly exposed to the patient's oral secretions (e.g., by kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). # Organization-and Community-Based Outbreaks An outbreak usually is classified as organization-based if it involves the occurrence of three or more confirmed or probable cases of meningococcal disease of the same serogroup in 10 cases/100,000 persons. Calculation of attack rates for organization-based outbreaks is most useful for large organizations (e.g., universities). However, in the majority of organization-based outbreaks with three or even two cases of disease, the rate will be >10 cases/100,000 population. In such situations, public health officials also might consider vaccination after only two primary cases are identified. An outbreak is classified as community-based if it involves the occurrence of three or more confirmed or probable cases of meningococcal disease in 10 cases/100,000 persons. Distinguishing whether an outbreak should be classified as organizationor community-based is complicated by the fact that, in certain instances, these types of outbreaks occur simultaneously. # Population at Risk In addition to close contacts, persons considered to be at increased risk for meningococcal disease compared with historical rates of disease in the same population in the general U.S. population are classified as being at risk. The population at risk is used as the denominator in calculations of the disease attack rate. The population at risk is usually defined on the basis of organizational affiliation or community of residence. In organization-based outbreaks, cases are linked by a common affiliation other than a shared, geographically delineated community; the population at risk is thus usually the group of persons who best represent that affiliation. For example, if the only association between patients is attending the same school or university, the population at risk is all persons attending the school or university. In community-based outbreaks, patients have no common affiliation other than a shared, geographically defined community. The population at risk can be defined as the smallest geographically contiguous population that includes all (or nearly all) patients. This population is usually a neighborhood, town, city, or county, whose size is obtained from census data. # Attack Rate and Decision To Vaccinate For a primary attack rate to be calculated, all confirmed cases of the same serogroup should be summed; secondary cases should be excluded and each set of co-primary cases counted as one case. Because attack rates are calculated both to characterize the risk for disease among the general population and to determine whether overall rates have increased, related cases (secondary and co-primary) should not be included. From an epidemiologic perspective, secondary and co-primary cases can be considered as representing single episodes of disease with direct spread to one or more close contact(s), which is consistent with endemic disease. If three or more cases have occurred in either an organization-or a community-based outbreak during <3 months (starting at the time of the first confirmed or probable case), a primary attack rate should be calculated. Because of the limited number of cases typically involved and the seasonal patterns of meningococcal disease (more cases occur during fall than other times of the year), rate calculations should not be annualized. The following formula is used to calculate attack rates: Attack rate per 100,000 = x 100,000 Vaccination of the population at risk should be considered if the attack rate is >10 cases/100,000 persons. The actual attack rate at which the decision to vaccinate is made varies. Public health personnel should consider the following factors: 1) completeness of case reporting and number of possible cases of meningococcal disease for which bacteriologic confirmation or serogroup data are not available; 2) occurrence of additional cases of meningococcal disease after recognition of a suspected outbreak (e.g., if the outbreak occurred 2 months previously and if no additional cases have occurred, in which case vaccination might be unlikely to prevent additional cases of meningococcal disease); and 3) logistic and financial considerations. Because available vaccines are not effective against N. meningitdis serogroup B, vaccination should not be considered during serogroup B outbreaks. # Vaccination Group Those persons designated to be administered vaccine during a vaccination campaign comprise a vaccination group. The vaccination group usually includes either the whole or a subset of the population of risk. Because meningococcal disease outbreak cases occur predominantly among persons aged <30 years (10,11), and available vaccines are not recommended among children aged <2 years, the vaccination group usually is that portion of the population at risk aged 2-29 years. In the majority of organization-based outbreaks, the vaccination group includes the whole population at risk, provided that all persons are aged >2 years. If a substantial proportion of patients are aged 10 cases/100,000 persons, vaccination should be considered for part or all of the population at risk aged >2 years. In certain organization-based outbreaks, a vaccination group larger than the population at risk might be designated. For example, in a high school in which all outbreak-associated cases occurred among students, authorities might decide to offer vaccine to staff. In community-based outbreaks, the vaccination group usually can be defined as a subset of the population at risk (e.g., persons aged 2-29 years). If a substantial proportion of patients are aged 29 years, the entire population aged >2 years might be considered for vaccination. For more substantial populations, this decision would be costly in terms of finances and human resources, and restricting the vaccination group to the persons in age groups with the highest attack rates might be more appropriate. Age-specific attack rates can be calculated by using the formula previously provided and by restricting the numerator and denominator to # Genotyping of N. meningitdis Isolates Genotyping of N. meningitdis isolates by using such methods as pulsed-field gel electrophoresis or ribotyping might provide useful information for determining whether a group of cases represents an outbreak (38). Outbreaks of meningococcal disease usually are caused by closely related strains. Genotyping data can allow identification of an outbreak strain and help to better define the extent of the outbreak. If strains from a group of patients are unrelated by genotyping, the group of cases most likely does not represent an outbreak. Because molecular subtyping testing might not be readily available or accessible, initiation of outbreak-control efforts should not be delayed until genotyping results are available. # Other Control Measures Mass chemoprophylaxis (i.e., administration of antibiotics to substantial populations) is not recommended to control large outbreaks of disease. Disadvantages of mass chemoprophylaxis include cost of the drug and administration, difficulty of ensuring simultaneous administration of drugs to substantial populations, drug side effects, and emergence of resistant organisms. In addition, multiple sources and prolonged risk for exposure make this approach impractical and unlikely to succeed. In the majority of outbreak settings, these disadvantages outweigh the possible benefit in disease prevention. However, in outbreaks involving limited populations (e.g., an outbreak in a single school), administration of chemoprophylaxis might be considered (39), especially in serogroup B outbreaks, for which available vaccines are not effective (40). When making a decision about initiating mass chemoprophylaxis in these settings, public health officials should consider not only the potential for prevention of new cases but also the logistics, cost, and potential for developing antimicrobial resistance (39,41). If mass chemoprophylaxis is undertaken, it should be administered to all targeted persons at the same time. In the United States, measures that have not been recommended for control of meningococcal disease outbreaks include restricting travel to areas with an outbreak, closing schools or universities, or canceling sporting or social events. Educating communities, physicians, and other health-care workers about meningococcal disease to promote an early case recognition and early care-seeking behaviors is an important part of managing suspected meningococcal disease outbreaks. Education efforts should be initiated as soon as an outbreak of meningococcal disease is suspected (4). Information about the signs and symptoms of meningococcal disease is available at / meningococcal_g.htm. # Meningococcal Tetravalent Polysaccharide Vaccine Vaccine Composition MPSV4 is a tetravalent meningococcal polysaccharide vaccine (Menomune-A,C,Y,W-135, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) available in the United States (42). Each dose consists of the four (A, C, Y, W-135) purified bacterial capsular polysaccharides (50 µg each). MPSV4 (Menomune) is available in single-dose (0.5-mL) and 10-dose (5-mL) vials; 50-dose vials are no longer available. # Vaccine Immunogenicity and Efficacy The immunogenicity and clinical efficacy of the serogroups A and C meningococcal vaccines have been well established. The serogroup A polysaccharide induces antibody response among certain children as young as age 3 months, although a response comparable with that occurring in adults is not achieved until age 4-5 years; the serogroup C component is poorly immunogenic among recipients aged 85% among school-aged children and adults and are useful in controlling outbreaks (45)(46)(47)(48)(49). Serogroups Y and W-135 polysaccharides are safe and immunogenic among adults and children aged >2 years (50)(51)(52); although clinical protection has not been documented, vaccination with these polysaccharides induces production of bactericidal antibodies. The antibody responses to each of the four polysaccharides in the tetravalent vaccine are serogroup specific and independent. Persons whose spleens have been removed because of trauma or nonlymphoid tumors and persons who have inherited complement deficiencies have acceptable antibody responses to polysaccharide meningococcal vaccine (53)(54)(55). A 2003 study indicated that tetravalent polysaccharide vaccine substantially reduced the incidence of invasive meningococcal disease among patients with terminal complement deficiency compared with similar patients who were unvaccinated (16). Reduced clinical efficacy has not been demonstrated among persons who have received multiple doses of vaccine. However, recent serologic studies have reported that multiple doses of serogroup A and C polysaccharide vaccine might cause immunologic hyporesponsiveness (i.e., a reduced antibody response after subsequent challenge with the same polysaccharide antigen) to group A (56,57) and C (58,59) polysaccharide. The clinical relevance of such hyporesponsiveness is unclear. # Duration of Protection Among infants and children aged 3 years, the efficacy of the group A vaccine among children aged 90% to 4 years when vaccinated (64). # Precautions and Contraindications Meningococcal polysaccharide vaccines have been used extensively in mass vaccination programs as well as in the military and among international travelers. Adverse reactions to polysaccharide meningococcal vaccines are usually mild; the most frequent reaction is pain and redness at the injection site, lasting for 1-2 days. Estimates of the incidence of such local reactions have varied (range: 4%-56%) (65,66). In certain studies, transient fever occurred among <5% of persons vaccinated, more commonly among infants (44,67). Severe reactions to polysaccharide meningococcal vaccine are uncommon (44,52,(65)(66)(67)(68)(69)(70)(71). The majority of studies report the rate of systemic allergic reactions (e.g., urticaria, wheezing, and rash) as 0-0.1/100,000 vaccine doses (44,71). Anaphylaxis has been documented among <0.1/100,000 vaccine recipients (42,70). Neurologic reactions (e.g., seizures, anesthesias, and paresthesias) have also been observed infrequently (65,70). # Meningococcal Conjugate Vaccines # Advantages of Meningococcal Conjugate Vaccines Bacterial polysaccharides, including those comprising the capsule of N. meningitdis, are T-cell-independent antigens. T-cell-independent antigens do not elicit a memory response; they stimulate mature B-lymphocytes but not T-lymphocytes, thus inducing a response that is neither long-lasting nor characterized by an anamnestic response after subsequent challenge with the same polysaccharide antigen (72). Thus, meningococcal polysaccharide vaccines have inherent limitations. The serogroup C polysaccharide is poorly immunogenic among children aged <2 years (73)(74)(75). The A polysaccharide induces antibody response in infants, but vaccine efficacy declines rapidly (64). Meningococcal polysaccharide vaccines do not confer long-lasting immunity (61,64); they also do not cause a sustainable reduction of nasopharyngeal carriage of N. meningitdis (76,77) and therefore do not substantially interrupt transmission to elicit herd immunity. Finally, multiple doses of serogroup A and C polysaccharide vaccine might cause immunologic hyporesponsiveness to the group A (56,57) and C (58,59) polysaccharide, although clinical implications of this phenomenon are unknown. Conjugation (i.e., covalent coupling) of polysaccharide to a protein carrier that contains T-cell epitopes changes the nature of immune response to polysaccharide from T-cellindependent to T-cell-dependent, leading to a substantial primary response among infants and a strong anamnestic response at re-exposure (78). Both conjugate Hib and conjugate S. pneumoniae vaccines (introduced for mass infant immunization in the United States in 1990 and 2000, respectively) have reduced incidence of disease caused by vaccinepreventable serotypes (1,79). In addition, both vaccines reduce asymptomatic carriage of respective bacteria (80-82), thus protecting unvaccinated persons through a herd immunity effect (1). # Meningococcal Serogroup C Conjugate Vaccine in the United Kingdom In November 1999, monovalent serogroup C conjugate vaccines were introduced in the United Kingdom. The national vaccination campaign introduced a routine 3-dose infant vaccination series and implemented a mass catch-up campaign during 1999-2000 targeting all persons aged 12 months-17 years (34) (83,84). The serogroup C conjugate meningococcal vaccines used in this campaign were licensed on the basis of data on safety and immunogenicity but without data on clinical efficacy (85). By 2001-2002, vaccine coverage in the United Kingdom was estimated as 80% among infants, 84% among toddlers, 76% among preschoolers, and 86%-87% among schoolchildren (86). Effectiveness of the vaccine within the first year of vaccination ranged from 88% to 98% among different age groups (87)(88)(89). Insufficient data are available to differentiate efficacy of the three meningococcal conjugate vaccines. Because the vaccine campaign was initiated only in 1999, long-term data on duration of protection are not yet available. However, among infants who received 3 doses of vaccine at ages 2, 3, and 4 months, efficacy declined to -81% (95% CI = -7,430-71) after only 1 year (88). Although the number of cases remains low, likely in part as a result of vaccineinduced herd immunity, this study raises questions about the meningococcal vaccine schedule and the need for a booster dose. During 1999-2000, carriage rates of group C meningococci in the United Kingdom declined 66% (90). In addition, incidence of meningococcal serogroup C disease declined 67% among unvaccinated persons aged 1-17 years and 35% among persons aged >25 years who were not targeted for vaccination, indicating the additional vaccine benefit of eliciting herd immunity (86). # Meningococcal Tetravalent Conjugate Vaccine Vaccine Composition MCV4 is a tetravalent meningococcal conjugate vaccine (Menactra, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) that was licensed for use in the United States in January 2005. A 0.5-mL single dose of vaccine contains 4 µg each of capsular polysaccharide from serogroups A, C, Y, and W-135 conjugated to 48 µg of diphtheria toxoid. MCV4 is available only in single-dose vials. # Immunologic Correlates of Protection Studies among U.S. military recruits conducted in the 1960s indicated that the absence of naturally acquired bactericidal antibodies, measured by a serum bactericidal antibody assay (SBA) using an intrinsic human complement source, was associated with susceptibility to meningococcal group C disease. SBA titers >4 using human serum as an exogenous complement source (hSBA) are considered the standard correlate of clinical protection against serogroup C meningococcal disease (91). Serogroup C conjugate meningococcal vaccines were licensed in the United Kingdom on the basis of data on safety and immunogenicity, without data on clinical efficacy (85). The immunologic data supporting the use of conjugate serogroup C vaccines were generated by serum bactericidal assay by using baby rabbit complement (rSBA). The threshold values were validated by comparing rSBA titers with those obtained by using hSBA (85,92). For licensure in the United Kingdom, rSBA titers of >128 were considered to predict protection; however, only 60% of rSBA titers in the range of 8-64 had hSBA titers of >4. For rSBA titers in this equivocal range, a fourfold rise in titers pre-to postvaccination was also proposed as a correlate of protection (92). Further evaluation of these threshold values was performed by using vaccine efficacy estimates from postlicensure surveillance, which indicated that these threshold values provided a conservative estimate of short-term clinical efficacy; rSBA threshold of >128 underestimated efficacy, with rSBA cutoffs of >4->8 at 4 weeks after vaccination being most consistent with observed clinical efficacy (93). On the basis of these efficacy estimates, the proportion of responders in multiple clinical trials of meningococcal C conjugate vaccines, and the group C seroprevalence study conducted before introduction of group C conjugate vaccines (94), rSBA titers of 8 have been proposed to correlate with short-term protection (95). Limited or no similar data exist to link immune response with clinical efficacy for serogroups A, Y, or W-135. In 1981, MPSV4 (Menomune) was licensed in the United States on the basis of data on safety and immunogenicity. Immunogenicity of this vaccine was compared with that of the vaccine then licensed for use in the United States, A/C meningococcal polysaccharide vaccine, which had demonstrated 97% efficacy against serogroup A and 90% efficacy against serogroup C (96). The immunologic criterion used for licensing was a fourfold or greater rise in SBA among 90% of adults at 3-4 weeks after vaccination. As a result, in 2005, MCV4 (Menactra) was licensed on the basis of findings indicating that it was not inferior to MPSV4 in terms of immunogenicity and safety (i.e., demonstrated noninferiority). A primary criterion in determining immunogenic noninferiority of the new vaccine was the percentage of vaccinees having a fourfold or greater increase in bactericidal antibody for MCV4 compared with MPSV4. # Immunogenicity Immunogenicity Among Persons Aged 11-18 Years A randomized controlled trial conducted among persons aged 11-18 years compared immunogenicity of MCV4 with that of MPSV4 at 28 days after vaccination. A similar percentage of subjects achieved at least a fourfold rise in rSBA titers in MCV4 and MPSV groups (Table 2). The percentage of subjects with at least a fourfold rise in rSBA was highest for serogroup W-135 (96.7% in MCV4 group and 95.3% in MPSV4 group), and lowest for serogroup Y (81.8% and 80.1%, respectively). The percentage of subjects achieving an rSBA geometric mean titer (GMT) of >128 was high (>98% for all serogroups) in both MCV4 and MPSV4 groups (97,98). # Immunogenicity Among Persons Aged 18-55 Years Another randomized controlled trial conducted among persons aged 18-55 years compared immunogenicity of MCV4 and that of MPSV4 at 28 days after vaccination. Although the percentage of subjects achieving at least a fourfold increase in rSBA titer for each serogroup was higher in the MPSV4 group than in the MCV4 group (Table 2), the criteria for demonstrating immunologic noninferiority to MPSV4 were still achieved. As was the case among persons aged 11-18 years, this percentage was highest for serogroup W-135 (89.4% in the MCV4 group and 94.4% in the MPSV4 group) and lowest for serogroup Y (73.5% and 79.4%, respectively). The percentage of subjects achieving an rSBA GMT of >128 was high (>97% for all serogroups) in both MCV4 and MPSV4 groups (97,98). # Persistence of Antibodies After 3 Years and Response to Revaccination MCV4 was administered to 76 subjects previously vaccinated with MCV4, 77 subjects previously vaccinated with MPSV4, and 88 age-matched vaccine-naïve subjects (97) (Sanofi Pasteur, Inc., unpublished data, 2004). Immunologic indices were measured before revaccination (day 0) and at days 8 and 28 after revaccination (Table 3). Subjects initially vaccinated with MCV4 had higher rSBA GMT at day 0 than those vaccinated with MPSV4 (Table 3); this difference was statistically significant for serogroups A (p128 than those initially vaccinated with MPSV4 (Table 3). Vaccine-naïve subjects had lower rSBA on day 0 than subjects previously vaccinated with either MCV4 or MPSV4. Response to revaccination with MCV4 was assessed by administering MCV4 to subjects previously vaccinated with MPSV4 or MCV4 and to vaccine-naïve control subjects. All subjects in all three groups achieved rSBA titers of >128 at both 8 and 28 days after receiving MCV4 (Table 3). Subjects initially primed with MCV4 achieved higher rSBA GMTs than naïve control subjects for all serogroups except A. In contrast, rSBA GMTs of those primed with MPSV4 were lower than those of vaccine-naïve control subjects on both days 8 and 28 for all serogroups (Table 3). # Concomitant Administration of MCV and Other Vaccines The concomitant administration of MCV4 and tetanus and diphtheria toxoids adsorbed for adult use (Td, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) was evaluated in a double-blind, controlled trial of participants aged 11-17 years. One group received Td and MCV4 concomitantly at separate injection sites, followed by a saline placebo 28 days later; the other group received Td and a saline placebo at separate injection sites, followed 28 days later by MCV4. Concomitant administration of Td and MCV4 did not adversely affect immune response to either vaccine (97,98). When MCV4 and Td were administered concomitantly, antibody response to diphtheria antigen 28 days after vaccination was greater (diphtheria GMT 120.9 IU/mL) than when Td and MCV4 were administered sequentially, Td first (diphtheria GMT 8.4 IU/mL 28 days after Td dose) followed by MCV4 28 days after Td (diphtheria GMT 16.9 IU/mL 28 days after MCV4 dose) (97). The prelicensure data demonstrated comparable overall safety profiles among adolescents who received simultaneous and sequential vaccination (Td followed by MCV4 28 days later). The immunological and safety profiles among adolescents receiving MCV4 followed by Td on a later date were not evaluated during prelicensure trials (see "Safety of Concomitant Administration of MCV4 and Other Vaccines"). Among adults aged 18-55 years, a randomized controlled trial assessed immunogenicity of MCV4 and typhoid vaccine 1) when MCV4 and typhoid vaccine were administered concomitantly and 2) when typhoid vaccine was administered concomitantly with placebo and MCV4 was administered 28 days later. Concomitant administration did not adversely affect immune response to either typhoid vaccine or MCV4 (97,98). # Safety Systemic and Local Adverse Reactions Among persons aged 11-18 years, safety of MCV4 and MPSV4 was assessed in two randomized controlled trials (97,98). The percentage of subjects reporting systemic adverse events was similar for persons who received either vaccine. In one study, approximately half of the participants experienced at least one systemic adverse reaction, and 100 º F ) was reported by 5.1% of those who received MCV4 and by 3.0% of those who received MPSV4 (Table 4). Among persons aged 18-55 years, the safety of MCV4 and of MPSV4 also were compared in two randomized controlled trials. The percentage of subjects reporting systemic adverse events was similar for persons who received either vaccine. In one study, 62% of participants experienced at least one systemic adverse reaction, and <4% experienced severe systemic reaction after receiving MCV4. Fever was reported by 1.5% of those who received MCV4 and by 0.5% of those who received MPSV4 (Table 4). Local adverse reactions were more common among those persons aged 11-18 years who received MCV4 than among those who received MPSV4 (Table 5); 13% of those who received MCV4 reported pain that limited movement in the arm of injection, compared with 3% of those who received MPSV4. These differences in frequency of local reactions are related to the amount of diphtheria toxoid contained in each vaccine (99). The frequency of local adverse reactions reported after MCV4 was similar to that reported after Td vaccine (97,98). # TABLE 3. Geometric mean titer (GMT) of serum bactericidal activity by using baby rabbit complement (rSBA) and percentage of subjects aged 14-21 years achieving rSBA GMT of >128 before (day 0) and at days 8 and 28 after revaccination with meningococcal conjugate vaccine (MCV4) at 3 years after previous vaccination in three groups (primed with MCV4, primed with meningococcal polysaccharide vaccine , and vaccine-naïve) As with persons aged 11-18 years, local adverse reactions among persons aged 18-55 years were reported more commonly by those who received MCV4 than by those who received MPSV4 (Table 5). However, the frequency of local adverse reactions reported by adults after MCV4 was similar to that reported after typhoid vaccine (97,98). # Safety of Concomitant Administration of MCV4 and Other Vaccines Among persons aged 11-17 years, frequency of reported local adverse effects at MCV4 injection site in the group for which MCV4 was administered concomitantly with Td was similar to those in which MCV4 was administered 28 days after Td. The percentage (58.6%) of subjects reporting at least one systemic adverse reaction after concomitant administration of MCV4 and Td was similar to the percentage (54.1%) of systemic reactions reported after Td was administered concomitantly with a placebo. Among persons aged 18-55 years, the frequency of local and systemic adverse effects was similar for those receiving concomitant administration of MCV4 and typhoid vaccine and those who received MCV4 28 days after receiving typhoid vaccine (97,98). # Serious Adverse Events in All Safety Studies A total of 5,453 subjects aged 11-55 years who received MCV4 and 2,923 subjects in the same age group who received MPSV4 completed follow-up 6 months after vaccination. Serious adverse events reported within a 6-month period after vaccination occurred at the same rate (1.3%) in the MCV4 and MPSV4 groups. The events reported were consistent with events expected among healthy adolescent and adult populations (98). # Cost-Effectiveness Analyses # Cost-Effectiveness Analysis of MPSV4 Vaccine Among College Students From a societal perspective, the economic costs and benefits of vaccinating 1) a cohort of 591,587 freshmen who live in dormitories and 2) all freshmen enrolled in U.S. colleges, regardless of housing status (N = 2.4 million) were evaluated, on the basis of an assumption that the benefits of vaccination would last 4 years (100). Best-and worst-case scenarios were evaluated by varying the cost of vaccine and administration (range: $54-$88), costs per hospitalization ($10,924-$24,030), the value of premature death on the basis of lifetime productivity ($1.3 million-$4.8 million), the cost per case of vaccine side effects ($7,000-$24,540/1 million doses), and the average long-term cost of treating a case of sequelae of disease ($1,298-$14,600). Vaccination coverage (60% and 100%, respectively) and vaccine efficacy (80% and 90%, respectively) also were varied for evaluation purposes. Vaccination of freshmen who live in dormitories would result in the administration of approximately 354,950-591,590 doses of vaccine each year, preventing 16-30 cases of meningococcal disease and one to three deaths each year. The cost per case prevented would be an estimated $617,000-$1.85 million, at a cost per death prevented of $6.8-$20.4 million and a cost per life-year saved (LYS)- of $62,042-$489,185 (100). Vaccination of all freshmen would result in the administration of approximately 1,364,400-2,274,000 doses of vaccine each year, preventing 37-69 cases of meningococcal disease and two to five deaths each year. The cost per case prevented would be $1.4-$2.9 million, at a cost per death prevented of $22-$48 million (100). These data are similar to data derived from previous studies (101). # Cost-Effectiveness Analysis of MCV4 Vaccine Among Adolescents Aged 11 Years From a societal perspective, the economic costs and benefits of vaccinating a cohort of approximately 4,238,670 U.S. adolescents aged 11 years were evaluated, on the basis of an assumption that the benefits of vaccination would last 22 years (102). A multivariable (Monte Carlo) analysis was performed in which multiple parameters were varied simultaneously over specified probability distributions. These parameters included disease incidence (46%-120% of the 10-year average), casefatality ratio (34%-131% of the 10-year average), rates of longterm sequelae, acute meningococcal disease costs (i.e., inpatient care, parents' work loss, and public health response), lifetime costs of meningococcal disease sequelae, and cost of vaccine and administration (range: $64-$114). Vaccination coverage (16%-95%) and vaccine efficacy (39%-99%) also were varied for evaluation purposes. Median program costs for vaccination of adolescents aged 11 years would be $227 million (5th-95th percentile: $158-$406 million). If a 3% discount rate were used for costs and benefits, during a 22-year period, vaccination among adolescents would prevent 270 cases and 36 deaths (21 cases and three deaths in the first year). The median cost would be $633,000 (5th-95th percentile: $329,000-$1,299,000)/case prevented; $5.0 million (5th-95th percentile: $2.4-$10.9 million)/death prevented; and $121,000 (5th-95th percentile: $69,000-$249,000)/LYS saved (102). # Cost-Effectiveness Analysis of a Catch-Up Vaccination Campaign with MCV4 The direct and indirect (herd immunity) benefits of a onetime catch-up vaccination campaign with MCV4 of adolescents aged 11-17 years followed by routine annual vaccination of adolescents aged 11 years were analyzed (CDC, unpublished data, 2005). For this purpose, a probabilistic model of disease burden and economic impacts was built for a 10-year period with and without an adolescent catch-up program. U.S. age-and serogroup-specific surveillance data on incidence and case fatality rates were used, as were hypothetical age-specific reductions in attack rates among unvaccinated persons obtained on the basis of U.K. data (86,103). Medical, work loss, and public response costs were estimated with and without a catch-up campaign, as were lifetime costs of meningococcal disease sequelae. After disease and vaccination program costs were projected, estimated costs per case averted, deaths prevented, LYS, and quality-adjusted life years (QALY) † saved were estimated. With herd immunity effects equivalent to recent experience in the United Kingdom, catch-up vaccination of adolescents plus an added routine program would prevent 5,263 cases - The number of life-years saved as a result of a preventive intervention (i.e., the number of potential years of life expected if disease-specific events leading to premature death not occur ). The number of lifeyears saved will be less or at the most equal to the number of potential years lost pre-intervention. Because life expectancy is age-specific, life-years saved is often calculated as the difference between the age-specific healthy life expectancy and the age when a disease-specific event leading to premature mortality could occur without the intervention. † A measure based on individual preferences for states of health that assigns a value of 1 to a year of perfect health and 0 to death. QALYs measure not only years of life saved but also functioning and health preserved. QALYs are highly relevant when disease-specific outcomes lead to both mortality (i.e., premature death) and substantial morbidity (i.e., temporal or permanent disability). Thus, effectiveness outcomes are expressed as change in health status. during a 10-year period, a 32% reduction in the number of cases. Excluding program costs, the catch-up program would save $338 million in medical and public response costs and $591 million in time off from work, long-term disability, and premature death. At a hypothetical cost of $83 per vaccinee, a catch-up vaccination program (including 9 years of routine vaccination) would cost society approximately $3.6 billion (45% of this sum in the first year). At a 3% discount rate, the catch-up program would cost society $532,000/case averted, $5.9 million/death prevented, $138,000/LYS, and $64,000/ QALY saved. A 20% reduction in herd immunity effects would increase the cost per LYS by $21,000; a $30 decrease in the cost of vaccination would decrease the cost per LYS by $55,000. On the basis of the assumption that herd immunity can be generated, targeting only those U.S. counties in which the disease is highly endemic would decrease the cost per LYS by two thirds. Catch-up vaccination of adolescents can have a substantial impact on disease burden and costs. However, these data demonstrate that catch-up and routine vaccination programs with MCV4 among adolescents are more costly per health outcome than existing vaccination strategies for Hib and S. pneumoniae (104,105). Compared with routine vaccination of children aged 11 years, catch-up vaccination could cost up to 20% more/LYS. # Recommendations for Use of Meningococcal Vaccines Routine Vaccination of Adolescents ACIP recommends routine vaccination of young adolescents (defined in this report as persons aged 11-12 years) with MCV4 at the preadolescent health-care visit (i.e., a visit to a health-care provider at age 11-12 years, at which time ACIP and other professional organizations recommend that persons aged 11-12 years receive appropriate vaccinations and other preventive services ). Introducing a recommendation for MCV4 vaccination among persons aged 11-12 years might strengthen the role of the preadolescent health-care visit and have a positive effect on vaccine coverage during adolescence. For those adolescents who have not previously received MCV4, ACIP recommends vaccination before high school entry (at approximately age 15 years) as an effective strategy to reduce meningococcal disease incidence among adolescents and young adults. By 2008, the goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Other adolescents who wish to decrease their risk for meningococcal disease may elect to receive vaccine. # Other Populations at Increased Risk for Meningococcal Disease Routine vaccination also is recommended for certain persons who have increased risk for meningococcal disease (Table 6). Use of MCV4 is preferred among persons aged 11-55 years; however, use of MPSV4 is recommended among children aged 2-10 years and persons aged >55 years. If MCV4 is unavailable, MPSV4 is an acceptable alternative for persons aged 11-55 years. The following populations are at increased risk for meningococcal disease: - college freshmen living in dormitories (29,30); - microbiologists who are routinely exposed to isolates of N. meningitdis (110); - military recruits (111); - persons who travel to or reside in countries in which N. meningitdis is hyperendemic or epidemic, particularly if contact with the local population will be prolonged (112); - persons who have terminal complement component deficiencies (15,16,113); and - persons who have anatomic or functional asplenia (17). Because of feasibility constraints in targeting freshmen in dormitories, colleges can elect to target their vaccination campaigns to all matriculating freshmen. The risk for meningococcal disease among nonfreshmen college students is similar to that for the general population of similar age (age 18-24 years) (29). However, the vaccines are safe and immunogenic and therefore can be provided to nonfreshmen college students who want to reduce their risk for meningococcal disease. For travelers, vaccination is especially recommended to those visiting the parts of sub-Saharan Africa known as the "meningitis belt" (112) during the dry season (December-June). Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Advisories for travelers to other countries will be issued when epidemics of meningococcal disease caused by vaccine-preventable serogroups are detected. Travelers' health information is available from CDC at 877-FYI-TRIP (toll-free) or at / travel. Further information concerning geographic areas for which vaccination is recommended can be obtained from international health clinics for travelers and state health departments. Patients with human immunodeficiency virus (HIV) are likely at increased risk for meningococcal disease, although not to the extent that they are at risk for invasive S. pneumoniae infection (20,114). Although the efficacy of MCV4 among HIV-infected patients is unknown, HIV-infected patients may May 27, elect vaccination. For persons aged 11-55 years who have been previously vaccinated with MPSV4, revaccination with MCV4 is not indicated unless vaccination occurred 3-5 years previously and the person still remains at increased risk for meningococcal disease (see Revaccination). # Adults Aged 20-55 Years MCV4 is licensed for use among adults aged 20-55 years. It is safe, immunogenic (97,98,115,116), and likely to provide relatively long-lasting protection against meningococcal disease caused by serogroups A, C, Y, and W-135. The rates of meningococcal disease are low in this age group, and vaccination will decrease but not eliminate risk. Therefore, routine vaccination is not recommended; however, persons who wish to decrease their risk for meningococcal disease may elect to be vaccinated. # Children Aged 55 Years MCV 4 is not licensed for use among children aged 55 years. Routine vaccination with MPSV4 is not recommended for children aged 55 years who are not identified as being at increased risk for meningococcal disease. # Outbreaks of Meningococcal Disease Both MPSV4 (4) and MCV4 are recommended for use in control of meningococcal outbreaks caused by vaccinepreventable serogroups (A, C, W-135, and Y) of N. meningitdis. An outbreak is defined by the occurrence of at least three § confirmed or probable primary ¶ cases of serogroup C meningococcal disease in 10 cases/100,000 population. For calculation of this threshold, population-based rates are used rather than age-specific attack rates. These recommendations are based on experience with serogroup C meningococcal outbreaks, but these principles might be applicable to outbreaks caused by the other vaccine-preventable meningococcal serogroups, including Y, W-135, and A. Both MCV4 and MPSV4 can be used for outbreak control, although use of for sizable organizations (e.g., certain universities). However, for the majority of organization-based outbreaks with three cases of disease, the rate will be >10 cases/100,000 population. Thus, occurrence of three cases in these settings should prompt consideration of vaccination. In certain situations, public health officials also might consider vaccination after only two primary cases are identified. ¶ To calculate a primary attack rate, sum all confirmed cases; exclude secondary cases, and count each set of co-primary cases as one case. A primary case is one that occurs in the absence of previous known close contact with another patient. A secondary case is one that occurs among close contacts of a primary patient >24 hours after onset of illness in the primary patient. If two or more cases occur among a group of close contacts with onset of illness separated by <24 hours, these cases are considered to be co-primary. MCV4 is preferred if the population targeted for vaccination includes age groups for which MCV4 is licensed. Detailed recommendations on evaluation and management of suspected outbreaks of meningococcal disease have been published previously (4). # Administration For persons aged 11-55 years, MCV4 is administered intramuscularly as a single 0.5-mL dose. MPSV4 is administered subcutaneously as a single 0.5-mL dose to persons aged >2 years. MCV4 and MPSV4 can be administered concomitantly with other vaccines, but at a different anatomic site (4,117). Protective levels of antibodies are usually achieved within 7-10 days of vaccination (60,118). # Revaccination Revaccination might be indicated for persons previously vaccinated with MPSV4 who remain at increased risk for infection (e.g., persons residing in areas in which disease is epidemic), particularly children who were first vaccinated at age <4 years. Such children should be considered for revaccination after 2-3 years if they remain at increased risk. Although the need for revaccination among adults and older children after receiving MPSV4 has not been determined, antibody levels decline rapidly after 2-3 years, and, if indications still exist for vaccination, revaccination might be considered after 5 years (4). Repeated vaccination with serogroup A and C polysaccharide vaccine might induce immunologic hyporesponsiveness (56)(57)(58)(59), although clinical implications of such hyporesponsiveness are not known. Hyporesponsiveness to serogroup C polysaccharide can be overcome by vaccination with serogroup C conjugate vaccine (119,120). MCV4 is recommended for revaccination of persons aged 11-55 years; however, use of MSPV4 is acceptable. ACIP expects that MCV4 will provide longer protection than MPSV4; however, studies are needed to confirm this assumption (87). More data will likely become available within the next 5 years to guide recommendations on revaccination for persons who were previously vaccinated with MCV4. # Precautions and Contraindications Recommended vaccinations can be administered to persons with minor acute illness (e.g., diarrhea or mild upperrespiratory tract infection with or without fever) (117). Vaccination should be deferred for persons with moderate or severe acute illness until the person's condition improves. Vaccination with MCV4 or MPSV4 is contraindicated among persons known to have a severe allergic reaction to any component of the vaccine, including dipththeria toxoid (for MCV4), or to dry natural rubber latex. Any adverse effect suspected to be associated with MCV4 or MPSV4 vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). More information about VAERS is available at 800-822-7967 (toll-free) or from . Because both MCV4 and MPSV4 are inactivated vaccines, they may be administered to persons who are immunosuppressed as a result of disease or medications; however, response to the vaccine might be less than optimal (117). Studies of vaccination with MPSV4 during pregnancy have not documented adverse effects among either pregnant women or newborns (121)(122)(123). On the basis of these data, pregnancy should not preclude vaccination with MPSV4, if indicated. MCV4 is safe and immunogenic among nonpregnant persons aged 11-55 years, but no data are available on the safety of MCV4 during pregnancy. Women of childbearing age who become aware that they were pregnant at the time of MCV4 vaccination should contact their health-care provider or the vaccine manufacturer. # Future Meningococcal Vaccines, Areas for Research, and Public Education MCV4 has been licensed on the basis of data regarding safety and short-term immunogenicity. Postmarketing studies are planned (98), including a study to evaluate the duration of the antibody response among participants who had received a single dose of MCV4 vaccine or MPSV4 vaccine 5 and 10 years earlier and a study to evaluate safety and immunogenicity when MCV4 is given concomitantly with tetanus and reduced diphtheria and acellular pertussis vaccine adsorbed (Tdap). However, immunogenicity data alone are insufficient to predict vaccine effectiveness and herd immunity effect, which depends largely on the ability of vaccine to alter transmission patterns. Additional studies are needed to evaluate vaccine effectiveness, vaccine impact on nasopharyngeal carriage of meningococci, and indirect effects of vaccine on disease rates among unvaccinated populations. Meningococcal conjugate vaccines might be considered for licensing in the United States among persons in other age groups, including infants and children aged <10 years (98). These vaccines are undergoing clinical trials and are likely to have better immunogenicity among infants and young children than MPSV4 (124)(125)(126), which is the only vaccine available for these age groups in the United States. Information on vaccine effectiveness, duration of protection, and herd Certain sources recommend revaccination after 3 years (4). # MMWR May 27, immunity obtained from MCV4 evaluation studies will be valuable in guiding prevention policies and formulating recommendations for vaccination of persons in other age groups. Because serogroup B capsular polysaccharide is poorly immunogenic in humans, vaccine development for serogroup B meningococci have focused on common proteins, including the outer membrane proteins (OMP) of specific epidemic strains. Efficacy of OMP vaccines has been demonstrated among older children and adults but not among infants and young children, in whom rates of disease are highest (127)(128)(129)(130). In addition, the variability in OMP strains causing endemic disease will likely limit their usefulness in the United States (131,132). Because of the potential limitations of these vaccines, other new approaches to serogroup B vaccines are being pursued, including the conjugation of a modified serogroup B polysaccharide (after substitution of the N-acetyl group with an N-propionyl group) to a recombinant serogroup B meningococcal porin protein. Although this vaccine is immunogenic in mice and nonhuman primates, concern exists that the vaccine might not be safe (132). In addition, with the recent sequencing of the serogroup B meningococcal genome, new genes encoding putative membrane proteins have been identified, indicating potential new targets for serogroup B vaccines (133)(134)(135). The availability of new meningococcal conjugate vaccines and the development of new vaccine strategies should lead to substantial improvements in global control and prevention of meningococcal disease. Although the signs and symptoms of meningococcal disease are frequently nonspecific, increasing awareness for meningococcal disease can result in earlier medical care-seeking behavior and improved clinical outcomes. In addition, educating adolescents and their parents about the benefits of receiving MCV4 is key to preventing a substantial number of cases of meningococcal disease. Finally, educating policy makers and the general public about the benefits of receiving MCV4 vaccine might improve vaccination coverage rates and substantially decrease the burden of meningococcal disease in the United States. # Antimicrobial Chemoprophylaxis In the United States, the primary means for prevention of sporadic meningococcal disease is antimicrobial chemoprophylaxis of close contacts of a patient with invasive meningococcal disease (Table 7). Close contacts include 1) household members (136,137), 2) child-care center contacts (136,138), and 3) anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index-patient or for anyone seated directly next to an index-patient on a prolonged flight (i.e., one lasting >8 hours). Guidelines for chemoprophylaxis of travelers have been published previously (139). The attack rate for household contacts exposed to patients who have sporadic meningococcal disease was estimated to be four cases/1,000 persons exposed, which is 500-800 times greater than the rate for the total population (137). In the United Kingdom, the attack rate among health-care workers exposed to patients with meningococcal disease was determined to be 25 times higher than among the general population (140). Because the rate of secondary disease for close contacts is highest immediately after onset of disease in the index patient, antimicrobial chemoprophylaxis should be administered as soon as possible (ideally 14 days after onset of illness in the index patient is probably of limited or no value. Oropharyngeal or nasopharyngeal cultures are not helpful in determining the need for chemoprophylaxis and might unnecessarily delay institution of this preventive measure. † Not recommended for pregnant women because it is teratogenic in laboratory animals. Because the reliability of oral contraceptives might be affected by rifampin therapy, consideration should be given to using alternative contraceptive measures while rifampin is being administered. § Not usually recommended for persons aged <18 years or for pregnant and lactating women because it causes cartilage damage in immature laboratory animals. Can be used for chemoprophylaxis of children when no acceptable alternative therapy is available. Recent literature review identified no reports of irreversible cartilage toxicity or age-associated adverse events among children and adolescents (Source: Burstein GR, Berman SM, Blumer JL, Moran JS. Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk? Clin Infect Dis 2002;35:S191-9). ¶ Intramuscular. Rifampin, ciprofloxacin, and ceftriaxone are 90%-95% effective in reducing nasopharyngeal carriage of N. meningitdis and are all acceptable antimicrobial agents for chemoprophylaxis (141)(142)(143)(144). Systemic antimicrobial therapy of meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins might not reliably eradicate nasopharyngeal carriage of N. meningitdis. If other agents have been used for treatment, the index patient should receive chemoprophylactic antibiotics for eradication of nasopharyngeal carriage before being discharged from the hospital (145). One recent study has reported that a single 500-mg oral dose of azithromycin was effective in eradicating nasopharyngeal carriage of N. meningitdis (146). Azithromycin, in addition to being safe and easy to administer, is also available in a suspension form and is approved for use among children. Further evaluation is warranted of both the effectiveness of azithromycin in eradicating carriage of N. meningitdis and potential for development of microbial resistance to this drug if it is widely used for chemoprophylaxis. # Recommendations and Reports # Goal and Objectives This report provides recommendations on use of the newly licensed tetravalent meningococcal polysaccharide-protein conjugate vaccine (MCV4). The recommendations were developed by CDC's Advisory Committee on Immunization Practices (ACIP). The goal of this report is to provide recommendations for clinicians, public health officials, and other persons concerned with controlling and preventing meningococcal disease in the United States on the use of MCV4 and to update previous ACIP recommendations on prevention and control of meningococcal disease, including recommendations on use of the tetravalent meningococcal polysaccharide vaccine (MPSV4). Upon completion of this educational activity, the reader should be able to 1) describe the epidemiology of meningococcal disease in the United States; 2) describe the differences between polysaccharide and polysaccharide-protein conjugate meningococcal vaccines; 3) identify the populations for which MCV4 and MPSV4 are recommended; 4) describe the principles of evaluation and management of suspected outbreaks of meningococcal disease; and 5) identify indications with appropriate drug schedules for antimicrobial chemoprophylaxis of meningococcal disease. To receive continuing education credit, please answer all of the following questions. E. Persons who have terminal complement component deficiency.	A. Physician. B. Nurse. C. Health educator. D. Office staff. E. Other. 12. I plan to use these recommendations as the basis for . . . (Indicate all that apply.) A. health education materials. B. insurance reimbursement policies. C. local practice guidelines. D. public policy. E. other. Vol. 54 / No. RR-7 Recommendations and Reports CE-3 Detach or photocopy.# Introduction Neisseria meningitidis has become a leading cause of bacterial meningitis in the United States after dramatic reductions in the incidence of Streptococcus pneumoniae (1) and Haemophilus influenzae type b (Hib) (2) infections have been achieved as a result of using conjugate vaccines. CDC's Advisory Committee on Immunization Practices (ACIP) previously recommended a tetravalent polysaccharide vaccine (Menomune ® -A,C,Y,W-135, manufactured by Sanofi Pasteur, # Prevention and Control of Meningococcal Disease # Recommendations of the Advisory Committee on Immunization Practices (ACIP) Prepared by Oleg O. Bilukha, MD, PhD Nancy Rosenstein, MD Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases # Summary In January 2005, a tetravalent meningococcal polysaccharide-protein conjugate vaccine ([MCV4] Menactra,™ manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) was licensed for use among persons aged 11-55 years. CDC's Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of young adolescents (defined in this report as persons aged 11-12 years) with MCV4 at the preadolescent health-care visit (at age 11-12 years). Introducing a recommendation for MCV4 vaccination among young adolescents might strengthen the role of the preadolescent visit and have a positive effect on vaccine coverage among adolescents. For those persons who have not previously received MCV4, ACIP recommends vaccination before high-school entry (at approximately age 15 years) as an effective strategy to reduce meningococcal disease incidence among adolescents and young adults. By 2008, the goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Routine vaccination with meningococcal vaccine also is recommended for college freshmen living in dormitories and for other populations at increased risk (i.e., military recruits, travelers to areas in which meningococcal disease is hyperendemic or epidemic, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, patients with anatomic or functional asplenia, and patients with terminal complement deficiency). Other adolescents, college students, and persons infected with human immunodeficiency virus who wish to decrease their risk for meningococcal disease may elect to receive vaccine. This report updates previous reports from ACIP concerning prevention and control of meningococcal disease. It also provides updated recommendations regarding use of the tetravalent meningococcal polysaccharide vaccine (MPSV4) and on antimicrobial chemoprophylaxis. Inc., Swiftwater, Pennsylvania) for use among certain populations at increased risk, including travelers to countries with epidemic or hyperendemic meningococcal disease, persons who have certain medical conditions (i.e., terminal complement component deficiencies and anatomic or functional asplenia), and laboratory personnel who are routinely exposed to N. meningitdis in solutions that might be aerosolized (3). Use of this vaccine also was recommended for control of meningococcal disease outbreaks (4). Recommendations permitting use of MPSV4 among college freshmen have been published previously (5). The new tetravalent A, C, Y, W-135 conjugate vaccine (Menactra™, manufactured by Sanofi Pasteur, Inc.) licensed for persons aged 11-55 years should become a key addition to existing meningococcal disease prevention measures. This report provides ACIP's recommendations on prevention and control of meningococcal disease, including recommendations on use of the new tetravalent conjugate vaccine (MCV4) as well as updated recommendations on use of the polysaccharide vaccine (MPSV4) and on antimicrobial chemoprophylaxis. # MMWR May 27, # Background Epidemiology of Meningococcal Disease Each year, an estimated 1,400-2,800 cases of meningococcal disease occur in the United States, a rate of 0.5-1.1/100,000 population (CDC, unpublished data, 2004). N. meningitidis colonizes mucosal surfaces of nasopharynx and is transmitted through direct contact with large droplet respiratory secretions from the patients or asymptomatic carriers. Humans are the only host. Despite the continued sensitivity of meningococcus to multiple widely available antibiotics, including penicillin (6,7), the case-fatality ratio for meningococcal disease is 10%-14% (CDC, unpublished data, 2004). Meningococcal disease also causes substantial morbidity; 11%-19% of survivors have sequelae (e.g., neurologic disability, limb loss, and hearing loss) (8,9). During 1991-2002, the highest rate of meningococcal disease (9.2/100,000) occurred among infants aged <1 year; the rate for persons aged 11-19 years (1.2/ 100,000) also was higher than that for the general population (Figure 1). Although rates of disease are highest among children aged <2 years, 62% of meningococcal disease in the United States occurs among persons aged >11 years (CDC, unpublished data, 2004). In the United States, >98% of cases of meningococcal disease are sporadic; however, since 1991, the frequency of localized outbreaks has increased (10,11). The proportion of meningococcal cases caused by serogroup Y increased from 2% during 1989-1991 (12) to 37% during 1997-2002 (CDC, unpublished data, 2004). Serogroups B, C, and Y are the major causes of meningococcal disease in the United States, each being responsible for approximately one third of cases. The proportion of cases caused by each serogroup varies by age group. Among infants aged <1 year, >50% of cases are caused by serogroup B, for which no vaccine is licensed or available in the United States (13,14). Of all cases of meningococcal disease among persons aged >11 years, 75% are caused by serogroups (C, Y, or W-135), which are included in vaccines available in the United States (CDC, unpublished data, 2004). Persons who have deficiencies in the terminal common complement pathway (C3, C5-9) (15,16) and those with anatomic or functional asplenia (17) are at increased risk for acquiring meningococcal disease. Antecedent viral infection, household crowding, chronic underlying illness, and both active and passive smoking also are associated with increased risk for meningococcal disease (18)(19)(20)(21)(22)(23)(24)(25). During outbreaks, bar or nightclub patronage and alcohol use also have been associated with higher risk for meningococcal disease (26)(27)(28). In the United States, blacks and persons of low socioeconomic status (SES) have been consistently at higher risk for meningococcal disease (12,13). However, race and low SES are likely risk markers rather than risk factors for this disease. A multistate case-control study in which controls were matched to case-patients by age group indicated that in a multivariable analysis (controlling for sex and education), active and passive smoking, recent respiratory illness, corticosteroid use, new residence, new school, Medicaid insurance, and household crowding all were associated with increased risk for meningococcal disease, whereas income and race were not (18). Additional research is needed to identify groups at risk that might benefit from prevention efforts. # Meningococcal Disease and College Students Multiple studies have been conducted in the United States (29)(30)(31) and the United Kingdom (32,33) concerning the risk for meningococcal disease among college students. The risk for meningococcal disease among U.S. college students was higher for those who resided in dormitories than for those residing in other types of accommodations. Overall incidence among college students usually is similar to or somewhat lower than that observed among persons in the general population of similar age. The earliest of these studies (conducted during the 1990-91 and 1991-92 academic years) had a poor response rate (38%) and indicated a low overall incidence of meningococcal disease among U.S. college students (1.0/100,000 population/year) (31). Cases of meningococcal disease occurred 9-23 times more frequently among students living in dormitories than among those living in other types of accommoda- A retrospective cohort study conducted in Maryland during 1992-1997 (30) indicated that the overall incidence of meningococcal disease among college students was similar to that among the U.S. population of persons the same age (1.7/100,000 and 1.4/100,000, respectively); however, rates of disease among students living in dormitories were higher than rates among students living off campus (3.2/100,000 and 1.0/100,000, respectively; p = 0.05). U.S. surveillance data from the 1998-99 school year (29) indicated that the overall rate of meningococcal disease among undergraduate college students was lower than the rate among persons aged 18-23 years who were not enrolled in college (0.7 and 1.4/100,000, respectively) (Table 1). Rates were somewhat higher among freshmen (1.9/100,000). Among the approximately 600,000 freshmen living in dormitories, rates were higher (5.1/100,000) than among any age group in the population other than children aged <2 years but lower than the threshold (10/100,000) recommended for initiating meningococcal vaccination campaigns (4). In a case-control study involving 50 cases detected among college students (29), multivariate analysis indicated that freshmen living in dormitories were at higher risk for meningococcal disease than other students (matched odds ratio [OR]: 3.6; 95% confidence interval [CI] = 1.6-8.5). In the United Kingdom, rates of meningococcal disease were higher among university students than among nonstudents of similar age (32). Regression analysis indicated that the main risk factor was catered hall accommodations (the U.K. equivalent of U.S. dormitories). A recent study conducted in the United Kingdom demonstrated a rapid increase in carriage rates of meningococci among university students in the first week of the fall semester, although rates of disease peaked later in the academic year (33). The increased rate of disease among university students has prompted the United Kingdom to initiate routine vaccination of incoming university students with a bivalent A/C polysaccharide vaccine as part of a new vaccination program (34). In 2000, ACIP and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) concluded that college students, especially those living in dormitories, are at moderately increased risk for meningococcal disease compared with other persons their age (5). ACIP and AAP recommended that 1) college students and their parents be informed by health-care providers of the risks of meningococcal disease and of the potential benefits of vaccination with MPSV4; 2) college and university health services facilitate implementation of educational programs about meningococcal disease and the availability of vaccination services; and 3) MPSV4 be made available to those persons requesting vaccination. As of November 2004, a total of 31 states had adopted legislation requiring colleges to provide information on risks of meningococcal disease either to matriculating students or to students residing on campus, and 10 states had mandated vaccination for certain students, unless a vaccination waiver is provided (Figure 2) (35). In 2004, the American College Health Association conducted an Internet-based survey of college policies and practices related to meningococcal vaccination (36). Of the 72 (10%) contacted colleges and universities that responded, 60% reported having a written policy on meningococcal vaccination, and 80% reported conducting some type of outreach awareness program among college students or their parents. Median vaccination rates reported for the 2002-03 and 2003-04 academic years were 20% and 35%, respectively; # Evaluation and Management of Suspected Outbreaks of Meningococcal Disease Since the early 1990s, outbreaks of meningococcal disease have occurred with increasing frequency in the United States. During July 1994-June 2002, a total of 76 outbreaks were identified (annual median: 10; range: 4-16) (11), including 48 (63%) outbreaks caused by serogroup C, 19 (25%) by serogroup B, and nine (12%) by serogroup Y. These outbreaks occurred in 32 states and involved 247 patients (accounting for <2% of total cases of meningococcal disease in the United States during this period). Of the 76 outbreaks, 26 (34%) were community-based and accounted for 53% of all outbreakrelated cases. Of the 50 (65%) outbreaks that were organization-based, 13 (26%) occurred in colleges; 19 (38%) in primary and secondary schools; and nine (18%) in nursing homes. Vaccination campaigns (using an average of 2,500 doses of MPSV4 per outbreak) were conducted in 34 outbreaks (30 of which were caused by serogroup C and four by serogroup Y) (11). The decision to implement a mass vaccination campaign to prevent meningococcal disease depends on whether the occurrence of more than one case represents an outbreak or an unusual clustering of endemic disease. Because the number of cases in outbreaks is usually not substantial, this determination often requires evaluation and analysis of the patterns of disease occurrence. Mass vaccination campaigns are expensive, require a massive public health effort, and can create unwarranted concern among the public. Detailed information on evaluation and management of suspected outbreaks has been published previously (4) and is presented in this report. # Case Definitions The following case definitions are used in this report: • Confirmed case. A confirmed case of meningococcal disease is one that is defined by isolation of N. meningitdis from a normally sterile site (e.g., blood or cerebrospinal fluid) from a person with clinically compatible illness. • Probable case. A probable case of meningococcal disease is one that is defined by detection of polysaccharide antigen in cerebrospinal fluid (e.g., by latex agglutination, polymerase chain reaction, or immunohistochemistry) or the presence of clinical purpura fulminans in the absence of diagnostic culture from a person with clinically compatible illness (37). • P P P P Primar rimar rimar rimar rimary case. y case. y case. y case. y case. A primary case of meningococcal disease is one that occurs in the absence of previous known close contact with another patient. • Secondary case. A secondary case of meningococcal disease is one that occurs among close contacts of a primary patient >24 hours after onset of illness in the primary patient. • Co-primary cases. Co-primary cases are two or more cases that occur among a group of close contacts with onset of illness separated by <24 hours. • Close contacts. Close contacts of a patient who has meningococcal disease include 1) household members; 2) child-care center contacts; and 3) persons directly exposed to the patient's oral secretions (e.g., by kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). # Organization-and Community-Based Outbreaks An outbreak usually is classified as organization-based if it involves the occurrence of three or more confirmed or probable cases of meningococcal disease of the same serogroup in <3 months among persons who have a common affiliation but no close contact with each other, resulting in primary disease attack rate of >10 cases/100,000 persons. Calculation of attack rates for organization-based outbreaks is most useful for large organizations (e.g., universities). However, in the majority of organization-based outbreaks with three or even two cases of disease, the rate will be >10 cases/100,000 population. In such situations, public health officials also might consider vaccination after only two primary cases are identified. An outbreak is classified as community-based if it involves the occurrence of three or more confirmed or probable cases of meningococcal disease in <3 months among persons residing in the same area who are not close contacts of each other and who do not share a common affiliation, with a primary disease attack rate of >10 cases/100,000 persons. Distinguishing whether an outbreak should be classified as organizationor community-based is complicated by the fact that, in certain instances, these types of outbreaks occur simultaneously. # Population at Risk In addition to close contacts, persons considered to be at increased risk for meningococcal disease compared with historical rates of disease in the same population in the general U.S. population are classified as being at risk. The population at risk is used as the denominator in calculations of the disease attack rate. The population at risk is usually defined on the basis of organizational affiliation or community of residence. In organization-based outbreaks, cases are linked by a common affiliation other than a shared, geographically delineated community; the population at risk is thus usually the group of persons who best represent that affiliation. For example, if the only association between patients is attending the same school or university, the population at risk is all persons attending the school or university. In community-based outbreaks, patients have no common affiliation other than a shared, geographically defined community. The population at risk can be defined as the smallest geographically contiguous population that includes all (or nearly all) patients. This population is usually a neighborhood, town, city, or county, whose size is obtained from census data. # Attack Rate and Decision To Vaccinate For a primary attack rate to be calculated, all confirmed cases of the same serogroup should be summed; secondary cases should be excluded and each set of co-primary cases counted as one case. Because attack rates are calculated both to characterize the risk for disease among the general population and to determine whether overall rates have increased, related cases (secondary and co-primary) should not be included. From an epidemiologic perspective, secondary and co-primary cases can be considered as representing single episodes of disease with direct spread to one or more close contact(s), which is consistent with endemic disease. If three or more cases have occurred in either an organization-or a community-based outbreak during <3 months (starting at the time of the first confirmed or probable case), a primary attack rate should be calculated. Because of the limited number of cases typically involved and the seasonal patterns of meningococcal disease (more cases occur during fall than other times of the year), rate calculations should not be annualized. The following formula is used to calculate attack rates: Attack rate per 100,000 = [(number of primary confirmed or probable cases during a 3-month period) / (number of population at risk)] x 100,000 Vaccination of the population at risk should be considered if the attack rate is >10 cases/100,000 persons. The actual attack rate at which the decision to vaccinate is made varies. Public health personnel should consider the following factors: 1) completeness of case reporting and number of possible cases of meningococcal disease for which bacteriologic confirmation or serogroup data are not available; 2) occurrence of additional cases of meningococcal disease after recognition of a suspected outbreak (e.g., if the outbreak occurred 2 months previously and if no additional cases have occurred, in which case vaccination might be unlikely to prevent additional cases of meningococcal disease); and 3) logistic and financial considerations. Because available vaccines are not effective against N. meningitdis serogroup B, vaccination should not be considered during serogroup B outbreaks. # Vaccination Group Those persons designated to be administered vaccine during a vaccination campaign comprise a vaccination group. The vaccination group usually includes either the whole or a subset of the population of risk. Because meningococcal disease outbreak cases occur predominantly among persons aged <30 years (10,11), and available vaccines are not recommended among children aged <2 years, the vaccination group usually is that portion of the population at risk aged 2-29 years. In the majority of organization-based outbreaks, the vaccination group includes the whole population at risk, provided that all persons are aged >2 years. If a substantial proportion of patients are aged <2 years and thus are not eligible to receive vaccine, patients aged <2 years should be excluded, and, if at least three patients remain, the attack rate should be recalculated. If the recalculated attack rate remains >10 cases/100,000 persons, vaccination should be considered for part or all of the population at risk aged >2 years. In certain organization-based outbreaks, a vaccination group larger than the population at risk might be designated. For example, in a high school in which all outbreak-associated cases occurred among students, authorities might decide to offer vaccine to staff. In community-based outbreaks, the vaccination group usually can be defined as a subset of the population at risk (e.g., persons aged 2-29 years). If a substantial proportion of patients are aged <2 years, these patients might be excluded from calculation of an attack rate. In rare situations (e.g., in a town with a limited population) in which multiple cases have occurred among adults aged >29 years, the entire population aged >2 years might be considered for vaccination. For more substantial populations, this decision would be costly in terms of finances and human resources, and restricting the vaccination group to the persons in age groups with the highest attack rates might be more appropriate. Age-specific attack rates can be calculated by using the formula previously provided and by restricting the numerator and denominator to # Genotyping of N. meningitdis Isolates Genotyping of N. meningitdis isolates by using such methods as pulsed-field gel electrophoresis or ribotyping might provide useful information for determining whether a group of cases represents an outbreak (38). Outbreaks of meningococcal disease usually are caused by closely related strains. Genotyping data can allow identification of an outbreak strain and help to better define the extent of the outbreak. If strains from a group of patients are unrelated by genotyping, the group of cases most likely does not represent an outbreak. Because molecular subtyping testing might not be readily available or accessible, initiation of outbreak-control efforts should not be delayed until genotyping results are available. # Other Control Measures Mass chemoprophylaxis (i.e., administration of antibiotics to substantial populations) is not recommended to control large outbreaks of disease. Disadvantages of mass chemoprophylaxis include cost of the drug and administration, difficulty of ensuring simultaneous administration of drugs to substantial populations, drug side effects, and emergence of resistant organisms. In addition, multiple sources and prolonged risk for exposure make this approach impractical and unlikely to succeed. In the majority of outbreak settings, these disadvantages outweigh the possible benefit in disease prevention. However, in outbreaks involving limited populations (e.g., an outbreak in a single school), administration of chemoprophylaxis might be considered (39), especially in serogroup B outbreaks, for which available vaccines are not effective (40). When making a decision about initiating mass chemoprophylaxis in these settings, public health officials should consider not only the potential for prevention of new cases but also the logistics, cost, and potential for developing antimicrobial resistance (39,41). If mass chemoprophylaxis is undertaken, it should be administered to all targeted persons at the same time. In the United States, measures that have not been recommended for control of meningococcal disease outbreaks include restricting travel to areas with an outbreak, closing schools or universities, or canceling sporting or social events. Educating communities, physicians, and other health-care workers about meningococcal disease to promote an early case recognition and early care-seeking behaviors is an important part of managing suspected meningococcal disease outbreaks. Education efforts should be initiated as soon as an outbreak of meningococcal disease is suspected (4). Information about the signs and symptoms of meningococcal disease is available at http://www.cdc.gov/ncidod/dbmd/diseaseinfo/ meningococcal_g.htm. # Meningococcal Tetravalent Polysaccharide Vaccine Vaccine Composition MPSV4 is a tetravalent meningococcal polysaccharide vaccine (Menomune-A,C,Y,W-135, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) available in the United States (42). Each dose consists of the four (A, C, Y, W-135) purified bacterial capsular polysaccharides (50 µg each). MPSV4 (Menomune) is available in single-dose (0.5-mL) and 10-dose (5-mL) vials; 50-dose vials are no longer available. # Vaccine Immunogenicity and Efficacy The immunogenicity and clinical efficacy of the serogroups A and C meningococcal vaccines have been well established. The serogroup A polysaccharide induces antibody response among certain children as young as age 3 months, although a response comparable with that occurring in adults is not achieved until age 4-5 years; the serogroup C component is poorly immunogenic among recipients aged <18-24 months (43,44). The serogroups A and C vaccines have demonstrated estimated clinical efficacies of >85% among school-aged children and adults and are useful in controlling outbreaks (45)(46)(47)(48)(49). Serogroups Y and W-135 polysaccharides are safe and immunogenic among adults and children aged >2 years (50)(51)(52); although clinical protection has not been documented, vaccination with these polysaccharides induces production of bactericidal antibodies. The antibody responses to each of the four polysaccharides in the tetravalent vaccine are serogroup specific and independent. Persons whose spleens have been removed because of trauma or nonlymphoid tumors and persons who have inherited complement deficiencies have acceptable antibody responses to polysaccharide meningococcal vaccine (53)(54)(55). A 2003 study indicated that tetravalent polysaccharide vaccine substantially reduced the incidence of invasive meningococcal disease among patients with terminal complement deficiency compared with similar patients who were unvaccinated (16). Reduced clinical efficacy has not been demonstrated among persons who have received multiple doses of vaccine. However, recent serologic studies have reported that multiple doses of serogroup A and C polysaccharide vaccine might cause immunologic hyporesponsiveness (i.e., a reduced antibody response after subsequent challenge with the same polysaccharide antigen) to group A (56,57) and C (58,59) polysaccharide. The clinical relevance of such hyporesponsiveness is unclear. # Duration of Protection Among infants and children aged <5 years, measurable levels of antibodies against group A and C polysaccharides decreased substantially during the first 3 years after a single dose of vaccine; among healthy adults, antibody levels also decreased, but antibodies were still detectable <10 years after vaccine administration (43,(60)(61)(62)(63). Similarly, although vaccine-induced clinical protection likely persists among school-aged children and adults for >3 years, the efficacy of the group A vaccine among children aged <5 years might decrease markedly within this period. In one study, efficacy among children aged <4 years at the time of vaccination declined from >90% to <10% within 3 years after vaccination; efficacy was 67% among children who were aged >4 years when vaccinated (64). # Precautions and Contraindications Meningococcal polysaccharide vaccines have been used extensively in mass vaccination programs as well as in the military and among international travelers. Adverse reactions to polysaccharide meningococcal vaccines are usually mild; the most frequent reaction is pain and redness at the injection site, lasting for 1-2 days. Estimates of the incidence of such local reactions have varied (range: 4%-56%) (65,66). In certain studies, transient fever occurred among <5% of persons vaccinated, more commonly among infants (44,67). Severe reactions to polysaccharide meningococcal vaccine are uncommon (44,52,(65)(66)(67)(68)(69)(70)(71). The majority of studies report the rate of systemic allergic reactions (e.g., urticaria, wheezing, and rash) as 0-0.1/100,000 vaccine doses (44,71). Anaphylaxis has been documented among <0.1/100,000 vaccine recipients (42,70). Neurologic reactions (e.g., seizures, anesthesias, and paresthesias) have also been observed infrequently (65,70). # Meningococcal Conjugate Vaccines # Advantages of Meningococcal Conjugate Vaccines Bacterial polysaccharides, including those comprising the capsule of N. meningitdis, are T-cell-independent antigens. T-cell-independent antigens do not elicit a memory response; they stimulate mature B-lymphocytes but not T-lymphocytes, thus inducing a response that is neither long-lasting nor characterized by an anamnestic response after subsequent challenge with the same polysaccharide antigen (72). Thus, meningococcal polysaccharide vaccines have inherent limitations. The serogroup C polysaccharide is poorly immunogenic among children aged <2 years (73)(74)(75). The A polysaccharide induces antibody response in infants, but vaccine efficacy declines rapidly (64). Meningococcal polysaccharide vaccines do not confer long-lasting immunity (61,64); they also do not cause a sustainable reduction of nasopharyngeal carriage of N. meningitdis (76,77) and therefore do not substantially interrupt transmission to elicit herd immunity. Finally, multiple doses of serogroup A and C polysaccharide vaccine might cause immunologic hyporesponsiveness to the group A (56,57) and C (58,59) polysaccharide, although clinical implications of this phenomenon are unknown. Conjugation (i.e., covalent coupling) of polysaccharide to a protein carrier that contains T-cell epitopes changes the nature of immune response to polysaccharide from T-cellindependent to T-cell-dependent, leading to a substantial primary response among infants and a strong anamnestic response at re-exposure (78). Both conjugate Hib and conjugate S. pneumoniae vaccines (introduced for mass infant immunization in the United States in 1990 and 2000, respectively) have reduced incidence of disease caused by vaccinepreventable serotypes (1,79). In addition, both vaccines reduce asymptomatic carriage of respective bacteria (80-82), thus protecting unvaccinated persons through a herd immunity effect (1). # Meningococcal Serogroup C Conjugate Vaccine in the United Kingdom In November 1999, monovalent serogroup C conjugate vaccines were introduced in the United Kingdom. The national vaccination campaign introduced a routine 3-dose infant vaccination series and implemented a mass catch-up campaign during 1999-2000 targeting all persons aged 12 months-17 years (34) (83,84). The serogroup C conjugate meningococcal vaccines used in this campaign were licensed on the basis of data on safety and immunogenicity but without data on clinical efficacy (85). By 2001-2002, vaccine coverage in the United Kingdom was estimated as 80% among infants, 84% among toddlers, 76% among preschoolers, and 86%-87% among schoolchildren (86). Effectiveness of the vaccine within the first year of vaccination ranged from 88% to 98% among different age groups (87)(88)(89). Insufficient data are available to differentiate efficacy of the three meningococcal conjugate vaccines. Because the vaccine campaign was initiated only in 1999, long-term data on duration of protection are not yet available. However, among infants who received 3 doses of vaccine at ages 2, 3, and 4 months, efficacy declined to -81% (95% CI = -7,430-71) after only 1 year (88). Although the number of cases remains low, likely in part as a result of vaccineinduced herd immunity, this study raises questions about the meningococcal vaccine schedule and the need for a booster dose. During 1999-2000, carriage rates of group C meningococci in the United Kingdom declined 66% (90). In addition, incidence of meningococcal serogroup C disease declined 67% among unvaccinated persons aged 1-17 years and 35% among persons aged >25 years who were not targeted for vaccination, indicating the additional vaccine benefit of eliciting herd immunity (86). # Meningococcal Tetravalent Conjugate Vaccine Vaccine Composition MCV4 is a tetravalent meningococcal conjugate vaccine (Menactra, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) that was licensed for use in the United States in January 2005. A 0.5-mL single dose of vaccine contains 4 µg each of capsular polysaccharide from serogroups A, C, Y, and W-135 conjugated to 48 µg of diphtheria toxoid. MCV4 is available only in single-dose vials. # Immunologic Correlates of Protection Studies among U.S. military recruits conducted in the 1960s indicated that the absence of naturally acquired bactericidal antibodies, measured by a serum bactericidal antibody assay (SBA) using an intrinsic human complement source, was associated with susceptibility to meningococcal group C disease. SBA titers >4 using human serum as an exogenous complement source (hSBA) are considered the standard correlate of clinical protection against serogroup C meningococcal disease (91). Serogroup C conjugate meningococcal vaccines were licensed in the United Kingdom on the basis of data on safety and immunogenicity, without data on clinical efficacy (85). The immunologic data supporting the use of conjugate serogroup C vaccines were generated by serum bactericidal assay by using baby rabbit complement (rSBA). The threshold values were validated by comparing rSBA titers with those obtained by using hSBA (85,92). For licensure in the United Kingdom, rSBA titers of >128 were considered to predict protection; however, only 60% of rSBA titers in the range of 8-64 had hSBA titers of >4. For rSBA titers in this equivocal range, a fourfold rise in titers pre-to postvaccination was also proposed as a correlate of protection (92). Further evaluation of these threshold values was performed by using vaccine efficacy estimates from postlicensure surveillance, which indicated that these threshold values provided a conservative estimate of short-term clinical efficacy; rSBA threshold of >128 underestimated efficacy, with rSBA cutoffs of >4->8 at 4 weeks after vaccination being most consistent with observed clinical efficacy (93). On the basis of these efficacy estimates, the proportion of responders in multiple clinical trials of meningococcal C conjugate vaccines, and the group C seroprevalence study conducted before introduction of group C conjugate vaccines (94), rSBA titers of <8 have been proposed to be predictive of susceptibility to invasive meningococcal disease, and rSBA titers of >8 have been proposed to correlate with short-term protection (95). Limited or no similar data exist to link immune response with clinical efficacy for serogroups A, Y, or W-135. In 1981, MPSV4 (Menomune) was licensed in the United States on the basis of data on safety and immunogenicity. Immunogenicity of this vaccine was compared with that of the vaccine then licensed for use in the United States, A/C meningococcal polysaccharide vaccine, which had demonstrated 97% efficacy against serogroup A and 90% efficacy against serogroup C (96). The immunologic criterion used for licensing was a fourfold or greater rise in SBA among 90% of adults at 3-4 weeks after vaccination. As a result, in 2005, MCV4 (Menactra) was licensed on the basis of findings indicating that it was not inferior to MPSV4 in terms of immunogenicity and safety (i.e., demonstrated noninferiority). A primary criterion in determining immunogenic noninferiority of the new vaccine was the percentage of vaccinees having a fourfold or greater increase in bactericidal antibody for MCV4 compared with MPSV4. # Immunogenicity Immunogenicity Among Persons Aged 11-18 Years A randomized controlled trial conducted among persons aged 11-18 years compared immunogenicity of MCV4 with that of MPSV4 at 28 days after vaccination. A similar percentage of subjects achieved at least a fourfold rise in rSBA titers in MCV4 and MPSV groups (Table 2). The percentage of subjects with at least a fourfold rise in rSBA was highest for serogroup W-135 (96.7% in MCV4 group and 95.3% in MPSV4 group), and lowest for serogroup Y (81.8% and 80.1%, respectively). The percentage of subjects achieving an rSBA geometric mean titer (GMT) of >128 was high (>98% for all serogroups) in both MCV4 and MPSV4 groups (97,98). # Immunogenicity Among Persons Aged 18-55 Years Another randomized controlled trial conducted among persons aged 18-55 years compared immunogenicity of MCV4 and that of MPSV4 at 28 days after vaccination. Although the percentage of subjects achieving at least a fourfold increase in rSBA titer for each serogroup was higher in the MPSV4 group than in the MCV4 group (Table 2), the criteria for demonstrating immunologic noninferiority to MPSV4 were still achieved. As was the case among persons aged 11-18 years, this percentage was highest for serogroup W-135 (89.4% in the MCV4 group and 94.4% in the MPSV4 group) and lowest for serogroup Y (73.5% and 79.4%, respectively). The percentage of subjects achieving an rSBA GMT of >128 was high (>97% for all serogroups) in both MCV4 and MPSV4 groups (97,98). # Persistence of Antibodies After 3 Years and Response to Revaccination MCV4 was administered to 76 subjects previously vaccinated with MCV4, 77 subjects previously vaccinated with MPSV4, and 88 age-matched vaccine-naïve subjects (97) (Sanofi Pasteur, Inc., unpublished data, 2004). Immunologic indices were measured before revaccination (day 0) and at days 8 and 28 after revaccination (Table 3). Subjects initially vaccinated with MCV4 had higher rSBA GMT at day 0 than those vaccinated with MPSV4 (Table 3); this difference was statistically significant for serogroups A (p<0.001) and W-135 (p<0.001). In addition, a higher percentage of those initially vaccinated with MCV4 had rSBA titers of >128 than those initially vaccinated with MPSV4 (Table 3). Vaccine-naïve subjects had lower rSBA on day 0 than subjects previously vaccinated with either MCV4 or MPSV4. Response to revaccination with MCV4 was assessed by administering MCV4 to subjects previously vaccinated with MPSV4 or MCV4 and to vaccine-naïve control subjects. All subjects in all three groups achieved rSBA titers of >128 at both 8 and 28 days after receiving MCV4 (Table 3). Subjects initially primed with MCV4 achieved higher rSBA GMTs than naïve control subjects for all serogroups except A. In contrast, rSBA GMTs of those primed with MPSV4 were lower than those of vaccine-naïve control subjects on both days 8 and 28 for all serogroups (Table 3). # Concomitant Administration of MCV and Other Vaccines The concomitant administration of MCV4 and tetanus and diphtheria toxoids adsorbed for adult use (Td, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) was evaluated in a double-blind, controlled trial of participants aged 11-17 years. One group received Td and MCV4 concomitantly at separate injection sites, followed by a saline placebo 28 days later; the other group received Td and a saline placebo at separate injection sites, followed 28 days later by MCV4. Concomitant administration of Td and MCV4 did not adversely affect immune response to either vaccine (97,98). When MCV4 and Td were administered concomitantly, antibody response to diphtheria antigen 28 days after vaccination was greater (diphtheria GMT 120.9 IU/mL) than when Td and MCV4 were administered sequentially, Td first (diphtheria GMT 8.4 IU/mL 28 days after Td dose) followed by MCV4 28 days after Td (diphtheria GMT 16.9 IU/mL 28 days after MCV4 dose) (97). The prelicensure data demonstrated comparable overall safety profiles among adolescents who received simultaneous and sequential vaccination (Td followed by MCV4 28 days later). The immunological and safety profiles among adolescents receiving MCV4 followed by Td on a later date were not evaluated during prelicensure trials (see "Safety of Concomitant Administration of MCV4 and Other Vaccines"). Among adults aged 18-55 years, a randomized controlled trial assessed immunogenicity of MCV4 and typhoid vaccine 1) when MCV4 and typhoid vaccine were administered concomitantly and 2) when typhoid vaccine was administered concomitantly with placebo and MCV4 was administered 28 days later. Concomitant administration did not adversely affect immune response to either typhoid vaccine or MCV4 (97,98). # Safety Systemic and Local Adverse Reactions Among persons aged 11-18 years, safety of MCV4 and MPSV4 was assessed in two randomized controlled trials (97,98). The percentage of subjects reporting systemic adverse events was similar for persons who received either vaccine. In one study, approximately half of the participants experienced at least one systemic adverse reaction, and <5% experienced at least one severe systemic reaction. Fever (i.e., temperature >100 º F [>38 º C]) was reported by 5.1% of those who received MCV4 and by 3.0% of those who received MPSV4 (Table 4). Among persons aged 18-55 years, the safety of MCV4 and of MPSV4 also were compared in two randomized controlled trials. The percentage of subjects reporting systemic adverse events was similar for persons who received either vaccine. In one study, 62% of participants experienced at least one systemic adverse reaction, and <4% experienced severe systemic reaction after receiving MCV4. Fever was reported by 1.5% of those who received MCV4 and by 0.5% of those who received MPSV4 (Table 4). Local adverse reactions were more common among those persons aged 11-18 years who received MCV4 than among those who received MPSV4 (Table 5); 13% of those who received MCV4 reported pain that limited movement in the arm of injection, compared with 3% of those who received MPSV4. These differences in frequency of local reactions are related to the amount of diphtheria toxoid contained in each vaccine (99). The frequency of local adverse reactions reported after MCV4 was similar to that reported after Td vaccine (97,98). # TABLE 3. Geometric mean titer (GMT) of serum bactericidal activity by using baby rabbit complement (rSBA) and percentage of subjects aged 14-21 years achieving rSBA GMT of >128 before (day 0) and at days 8 and 28 after revaccination with meningococcal conjugate vaccine (MCV4) at 3 years after previous vaccination in three groups (primed with MCV4, primed with meningococcal polysaccharide vaccine [MPSV4], and vaccine-naïve) As with persons aged 11-18 years, local adverse reactions among persons aged 18-55 years were reported more commonly by those who received MCV4 than by those who received MPSV4 (Table 5). However, the frequency of local adverse reactions reported by adults after MCV4 was similar to that reported after typhoid vaccine (97,98). # Safety of Concomitant Administration of MCV4 and Other Vaccines Among persons aged 11-17 years, frequency of reported local adverse effects at MCV4 injection site in the group for which MCV4 was administered concomitantly with Td was similar to those in which MCV4 was administered 28 days after Td. The percentage (58.6%) of subjects reporting at least one systemic adverse reaction after concomitant administration of MCV4 and Td was similar to the percentage (54.1%) of systemic reactions reported after Td was administered concomitantly with a placebo. Among persons aged 18-55 years, the frequency of local and systemic adverse effects was similar for those receiving concomitant administration of MCV4 and typhoid vaccine and those who received MCV4 28 days after receiving typhoid vaccine (97,98). # Serious Adverse Events in All Safety Studies A total of 5,453 subjects aged 11-55 years who received MCV4 and 2,923 subjects in the same age group who received MPSV4 completed follow-up 6 months after vaccination. Serious adverse events reported within a 6-month period after vaccination occurred at the same rate (1.3%) in the MCV4 and MPSV4 groups. The events reported were consistent with events expected among healthy adolescent and adult populations (98). # Cost-Effectiveness Analyses # Cost-Effectiveness Analysis of MPSV4 Vaccine Among College Students From a societal perspective, the economic costs and benefits of vaccinating 1) a cohort of 591,587 freshmen who live in dormitories and 2) all freshmen enrolled in U.S. colleges, regardless of housing status (N = 2.4 million) were evaluated, on the basis of an assumption that the benefits of vaccination would last 4 years (100). Best-and worst-case scenarios were evaluated by varying the cost of vaccine and administration (range: $54-$88), costs per hospitalization ($10,924-$24,030), the value of premature death on the basis of lifetime productivity ($1.3 million-$4.8 million), the cost per case of vaccine side effects ($7,000-$24,540/1 million doses), and the average long-term cost of treating a case of sequelae of disease ($1,298-$14,600). Vaccination coverage (60% and 100%, respectively) and vaccine efficacy (80% and 90%, respectively) also were varied for evaluation purposes. Vaccination of freshmen who live in dormitories would result in the administration of approximately 354,950-591,590 doses of vaccine each year, preventing 16-30 cases of meningococcal disease and one to three deaths each year. The cost per case prevented would be an estimated $617,000-$1.85 million, at a cost per death prevented of $6.8-$20.4 million and a cost per life-year saved (LYS)* of $62,042-$489,185 (100). Vaccination of all freshmen would result in the administration of approximately 1,364,400-2,274,000 doses of vaccine each year, preventing 37-69 cases of meningococcal disease and two to five deaths each year. The cost per case prevented would be $1.4-$2.9 million, at a cost per death prevented of $22-$48 million (100). These data are similar to data derived from previous studies (101). # Cost-Effectiveness Analysis of MCV4 Vaccine Among Adolescents Aged 11 Years From a societal perspective, the economic costs and benefits of vaccinating a cohort of approximately 4,238,670 U.S. adolescents aged 11 years were evaluated, on the basis of an assumption that the benefits of vaccination would last 22 years (102). A multivariable (Monte Carlo) analysis was performed in which multiple parameters were varied simultaneously over specified probability distributions. These parameters included disease incidence (46%-120% of the 10-year average), casefatality ratio (34%-131% of the 10-year average), rates of longterm sequelae, acute meningococcal disease costs (i.e., inpatient care, parents' work loss, and public health response), lifetime costs of meningococcal disease sequelae, and cost of vaccine and administration (range: $64-$114). Vaccination coverage (16%-95%) and vaccine efficacy (39%-99%) also were varied for evaluation purposes. Median program costs for vaccination of adolescents aged 11 years would be $227 million (5th-95th percentile: $158-$406 million). If a 3% discount rate were used for costs and benefits, during a 22-year period, vaccination among adolescents would prevent 270 cases and 36 deaths (21 cases and three deaths in the first year). The median cost would be $633,000 (5th-95th percentile: $329,000-$1,299,000)/case prevented; $5.0 million (5th-95th percentile: $2.4-$10.9 million)/death prevented; and $121,000 (5th-95th percentile: $69,000-$249,000)/LYS saved (102). # Cost-Effectiveness Analysis of a Catch-Up Vaccination Campaign with MCV4 The direct and indirect (herd immunity) benefits of a onetime catch-up vaccination campaign with MCV4 of adolescents aged 11-17 years followed by routine annual vaccination of adolescents aged 11 years were analyzed (CDC, unpublished data, 2005). For this purpose, a probabilistic model of disease burden and economic impacts was built for a 10-year period with and without an adolescent catch-up program. U.S. age-and serogroup-specific surveillance data on incidence and case fatality rates were used, as were hypothetical age-specific reductions in attack rates among unvaccinated persons obtained on the basis of U.K. data (86,103). Medical, work loss, and public response costs were estimated with and without a catch-up campaign, as were lifetime costs of meningococcal disease sequelae. After disease and vaccination program costs were projected, estimated costs per case averted, deaths prevented, LYS, and quality-adjusted life years (QALY) † saved were estimated. With herd immunity effects equivalent to recent experience in the United Kingdom, catch-up vaccination of adolescents plus an added routine program would prevent 5,263 cases * The number of life-years saved as a result of a preventive intervention (i.e., the number of potential years of life expected if disease-specific events leading to premature death not occur [healthy life expectancy]). The number of lifeyears saved will be less or at the most equal to the number of potential years lost pre-intervention. Because life expectancy is age-specific, life-years saved is often calculated as the difference between the age-specific healthy life expectancy and the age when a disease-specific event leading to premature mortality could occur without the intervention. † A measure based on individual preferences for states of health that assigns a value of 1 to a year of perfect health and 0 to death. QALYs measure not only years of life saved but also functioning and health preserved. QALYs are highly relevant when disease-specific outcomes lead to both mortality (i.e., premature death) and substantial morbidity (i.e., temporal or permanent disability). Thus, effectiveness outcomes are expressed as change in health status. during a 10-year period, a 32% reduction in the number of cases. Excluding program costs, the catch-up program would save $338 million in medical and public response costs and $591 million in time off from work, long-term disability, and premature death. At a hypothetical cost of $83 per vaccinee, a catch-up vaccination program (including 9 years of routine vaccination) would cost society approximately $3.6 billion (45% of this sum in the first year). At a 3% discount rate, the catch-up program would cost society $532,000/case averted, $5.9 million/death prevented, $138,000/LYS, and $64,000/ QALY saved. A 20% reduction in herd immunity effects would increase the cost per LYS by $21,000; a $30 decrease in the cost of vaccination would decrease the cost per LYS by $55,000. On the basis of the assumption that herd immunity can be generated, targeting only those U.S. counties in which the disease is highly endemic would decrease the cost per LYS by two thirds. Catch-up vaccination of adolescents can have a substantial impact on disease burden and costs. However, these data demonstrate that catch-up and routine vaccination programs with MCV4 among adolescents are more costly per health outcome than existing vaccination strategies for Hib and S. pneumoniae (104,105). Compared with routine vaccination of children aged 11 years, catch-up vaccination could cost up to 20% more/LYS. # Recommendations for Use of Meningococcal Vaccines Routine Vaccination of Adolescents ACIP recommends routine vaccination of young adolescents (defined in this report as persons aged 11-12 years) with MCV4 at the preadolescent health-care visit (i.e., a visit to a health-care provider at age 11-12 years, at which time ACIP and other professional organizations [e.g., AAP and the American Medical Association] recommend that persons aged 11-12 years receive appropriate vaccinations and other preventive services [106][107][108][109]). Introducing a recommendation for MCV4 vaccination among persons aged 11-12 years might strengthen the role of the preadolescent health-care visit and have a positive effect on vaccine coverage during adolescence. For those adolescents who have not previously received MCV4, ACIP recommends vaccination before high school entry (at approximately age 15 years) as an effective strategy to reduce meningococcal disease incidence among adolescents and young adults. By 2008, the goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Other adolescents who wish to decrease their risk for meningococcal disease may elect to receive vaccine. # Other Populations at Increased Risk for Meningococcal Disease Routine vaccination also is recommended for certain persons who have increased risk for meningococcal disease (Table 6). Use of MCV4 is preferred among persons aged 11-55 years; however, use of MPSV4 is recommended among children aged 2-10 years and persons aged >55 years. If MCV4 is unavailable, MPSV4 is an acceptable alternative for persons aged 11-55 years. The following populations are at increased risk for meningococcal disease: • college freshmen living in dormitories (29,30); • microbiologists who are routinely exposed to isolates of N. meningitdis (110); • military recruits (111); • persons who travel to or reside in countries in which N. meningitdis is hyperendemic or epidemic, particularly if contact with the local population will be prolonged (112); • persons who have terminal complement component deficiencies (15,16,113); and • persons who have anatomic or functional asplenia (17). Because of feasibility constraints in targeting freshmen in dormitories, colleges can elect to target their vaccination campaigns to all matriculating freshmen. The risk for meningococcal disease among nonfreshmen college students is similar to that for the general population of similar age (age 18-24 years) (29). However, the vaccines are safe and immunogenic and therefore can be provided to nonfreshmen college students who want to reduce their risk for meningococcal disease. For travelers, vaccination is especially recommended to those visiting the parts of sub-Saharan Africa known as the "meningitis belt" (112) during the dry season (December-June). Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Advisories for travelers to other countries will be issued when epidemics of meningococcal disease caused by vaccine-preventable serogroups are detected. Travelers' health information is available from CDC at 877-FYI-TRIP (toll-free) or at http://www.cdc.gov/ travel. Further information concerning geographic areas for which vaccination is recommended can be obtained from international health clinics for travelers and state health departments. Patients with human immunodeficiency virus (HIV) are likely at increased risk for meningococcal disease, although not to the extent that they are at risk for invasive S. pneumoniae infection (20,114). Although the efficacy of MCV4 among HIV-infected patients is unknown, HIV-infected patients may May 27, elect vaccination. For persons aged 11-55 years who have been previously vaccinated with MPSV4, revaccination with MCV4 is not indicated unless vaccination occurred 3-5 years previously and the person still remains at increased risk for meningococcal disease (see Revaccination). # Adults Aged 20-55 Years MCV4 is licensed for use among adults aged 20-55 years. It is safe, immunogenic (97,98,115,116), and likely to provide relatively long-lasting protection against meningococcal disease caused by serogroups A, C, Y, and W-135. The rates of meningococcal disease are low in this age group, and vaccination will decrease but not eliminate risk. Therefore, routine vaccination is not recommended; however, persons who wish to decrease their risk for meningococcal disease may elect to be vaccinated. # Children Aged <11 Years and Adults Aged >55 Years MCV 4 is not licensed for use among children aged <11 years or adults aged >55 years. Routine vaccination with MPSV4 is not recommended for children aged <2 years because it is relatively ineffective and offers a short duration of protection. Routine vaccination with MPSV4 is not recommended for children aged 2-10 years and adults aged >55 years who are not identified as being at increased risk for meningococcal disease. # Outbreaks of Meningococcal Disease Both MPSV4 (4) and MCV4 are recommended for use in control of meningococcal outbreaks caused by vaccinepreventable serogroups (A, C, W-135, and Y) of N. meningitdis. An outbreak is defined by the occurrence of at least three § confirmed or probable primary ¶ cases of serogroup C meningococcal disease in <3 months, with a resulting primary attack rate of >10 cases/100,000 population. For calculation of this threshold, population-based rates are used rather than age-specific attack rates. These recommendations are based on experience with serogroup C meningococcal outbreaks, but these principles might be applicable to outbreaks caused by the other vaccine-preventable meningococcal serogroups, including Y, W-135, and A. Both MCV4 and MPSV4 can be used for outbreak control, although use of for sizable organizations (e.g., certain universities). However, for the majority of organization-based outbreaks with three cases of disease, the rate will be >10 cases/100,000 population. Thus, occurrence of three cases in these settings should prompt consideration of vaccination. In certain situations, public health officials also might consider vaccination after only two primary cases are identified. ¶ To calculate a primary attack rate, sum all confirmed cases; exclude secondary cases, and count each set of co-primary cases as one case. A primary case is one that occurs in the absence of previous known close contact with another patient. A secondary case is one that occurs among close contacts of a primary patient >24 hours after onset of illness in the primary patient. If two or more cases occur among a group of close contacts with onset of illness separated by <24 hours, these cases are considered to be co-primary. MCV4 is preferred if the population targeted for vaccination includes age groups for which MCV4 is licensed. Detailed recommendations on evaluation and management of suspected outbreaks of meningococcal disease have been published previously (4). # Administration For persons aged 11-55 years, MCV4 is administered intramuscularly as a single 0.5-mL dose. MPSV4 is administered subcutaneously as a single 0.5-mL dose to persons aged >2 years. MCV4 and MPSV4 can be administered concomitantly with other vaccines, but at a different anatomic site (4,117). Protective levels of antibodies are usually achieved within 7-10 days of vaccination (60,118). # Revaccination Revaccination might be indicated for persons previously vaccinated with MPSV4 who remain at increased risk for infection (e.g., persons residing in areas in which disease is epidemic), particularly children who were first vaccinated at age <4 years. Such children should be considered for revaccination after 2-3 years if they remain at increased risk. Although the need for revaccination among adults and older children after receiving MPSV4 has not been determined, antibody levels decline rapidly after 2-3 years, and, if indications still exist for vaccination, revaccination might be considered after 5 years (4). Repeated vaccination with serogroup A and C polysaccharide vaccine might induce immunologic hyporesponsiveness (56)(57)(58)(59), although clinical implications of such hyporesponsiveness are not known. Hyporesponsiveness to serogroup C polysaccharide can be overcome by vaccination with serogroup C conjugate vaccine (119,120). MCV4 is recommended for revaccination of persons aged 11-55 years; however, use of MSPV4 is acceptable. ACIP expects that MCV4 will provide longer protection than MPSV4; however, studies are needed to confirm this assumption (87). More data will likely become available within the next 5 years to guide recommendations on revaccination for persons who were previously vaccinated with MCV4. # Precautions and Contraindications Recommended vaccinations can be administered to persons with minor acute illness (e.g., diarrhea or mild upperrespiratory tract infection with or without fever) (117). Vaccination should be deferred for persons with moderate or severe acute illness until the person's condition improves. Vaccination with MCV4 or MPSV4 is contraindicated among persons known to have a severe allergic reaction to any component of the vaccine, including dipththeria toxoid (for MCV4), or to dry natural rubber latex. Any adverse effect suspected to be associated with MCV4 or MPSV4 vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). More information about VAERS is available at 800-822-7967 (toll-free) or from http://www.vaers.org. Because both MCV4 and MPSV4 are inactivated vaccines, they may be administered to persons who are immunosuppressed as a result of disease or medications; however, response to the vaccine might be less than optimal (117). Studies of vaccination with MPSV4 during pregnancy have not documented adverse effects among either pregnant women or newborns (121)(122)(123). On the basis of these data, pregnancy should not preclude vaccination with MPSV4, if indicated. MCV4 is safe and immunogenic among nonpregnant persons aged 11-55 years, but no data are available on the safety of MCV4 during pregnancy. Women of childbearing age who become aware that they were pregnant at the time of MCV4 vaccination should contact their health-care provider or the vaccine manufacturer. # Future Meningococcal Vaccines, Areas for Research, and Public Education MCV4 has been licensed on the basis of data regarding safety and short-term immunogenicity. Postmarketing studies are planned (98), including a study to evaluate the duration of the antibody response among participants who had received a single dose of MCV4 vaccine or MPSV4 vaccine 5 and 10 years earlier and a study to evaluate safety and immunogenicity when MCV4 is given concomitantly with tetanus and reduced diphtheria and acellular pertussis vaccine adsorbed (Tdap). However, immunogenicity data alone are insufficient to predict vaccine effectiveness and herd immunity effect, which depends largely on the ability of vaccine to alter transmission patterns. Additional studies are needed to evaluate vaccine effectiveness, vaccine impact on nasopharyngeal carriage of meningococci, and indirect effects of vaccine on disease rates among unvaccinated populations. Meningococcal conjugate vaccines might be considered for licensing in the United States among persons in other age groups, including infants and children aged <10 years (98). These vaccines are undergoing clinical trials and are likely to have better immunogenicity among infants and young children than MPSV4 (124)(125)(126), which is the only vaccine available for these age groups in the United States. Information on vaccine effectiveness, duration of protection, and herd Certain sources recommend revaccination after 3 years (4). # MMWR May 27, immunity obtained from MCV4 evaluation studies will be valuable in guiding prevention policies and formulating recommendations for vaccination of persons in other age groups. Because serogroup B capsular polysaccharide is poorly immunogenic in humans, vaccine development for serogroup B meningococci have focused on common proteins, including the outer membrane proteins (OMP) of specific epidemic strains. Efficacy of OMP vaccines has been demonstrated among older children and adults but not among infants and young children, in whom rates of disease are highest (127)(128)(129)(130). In addition, the variability in OMP strains causing endemic disease will likely limit their usefulness in the United States (131,132). Because of the potential limitations of these vaccines, other new approaches to serogroup B vaccines are being pursued, including the conjugation of a modified serogroup B polysaccharide (after substitution of the N-acetyl group with an N-propionyl group) to a recombinant serogroup B meningococcal porin protein. Although this vaccine is immunogenic in mice and nonhuman primates, concern exists that the vaccine might not be safe (132). In addition, with the recent sequencing of the serogroup B meningococcal genome, new genes encoding putative membrane proteins have been identified, indicating potential new targets for serogroup B vaccines (133)(134)(135). The availability of new meningococcal conjugate vaccines and the development of new vaccine strategies should lead to substantial improvements in global control and prevention of meningococcal disease. Although the signs and symptoms of meningococcal disease are frequently nonspecific, increasing awareness for meningococcal disease can result in earlier medical care-seeking behavior and improved clinical outcomes. In addition, educating adolescents and their parents about the benefits of receiving MCV4 is key to preventing a substantial number of cases of meningococcal disease. Finally, educating policy makers and the general public about the benefits of receiving MCV4 vaccine might improve vaccination coverage rates and substantially decrease the burden of meningococcal disease in the United States. # Antimicrobial Chemoprophylaxis In the United States, the primary means for prevention of sporadic meningococcal disease is antimicrobial chemoprophylaxis of close contacts of a patient with invasive meningococcal disease (Table 7). Close contacts include 1) household members (136,137), 2) child-care center contacts (136,138), and 3) anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index-patient or for anyone seated directly next to an index-patient on a prolonged flight (i.e., one lasting >8 hours). Guidelines for chemoprophylaxis of travelers have been published previously (139). The attack rate for household contacts exposed to patients who have sporadic meningococcal disease was estimated to be four cases/1,000 persons exposed, which is 500-800 times greater than the rate for the total population (137). In the United Kingdom, the attack rate among health-care workers exposed to patients with meningococcal disease was determined to be 25 times higher than among the general population (140). Because the rate of secondary disease for close contacts is highest immediately after onset of disease in the index patient, antimicrobial chemoprophylaxis should be administered as soon as possible (ideally <24 hours after identification of the index patient). Conversely, chemoprophylaxis administered >14 days after onset of illness in the index patient is probably of limited or no value. Oropharyngeal or nasopharyngeal cultures are not helpful in determining the need for chemoprophylaxis and might unnecessarily delay institution of this preventive measure. † Not recommended for pregnant women because it is teratogenic in laboratory animals. Because the reliability of oral contraceptives might be affected by rifampin therapy, consideration should be given to using alternative contraceptive measures while rifampin is being administered. § Not usually recommended for persons aged <18 years or for pregnant and lactating women because it causes cartilage damage in immature laboratory animals. Can be used for chemoprophylaxis of children when no acceptable alternative therapy is available. Recent literature review identified no reports of irreversible cartilage toxicity or age-associated adverse events among children and adolescents (Source: Burstein GR, Berman SM, Blumer JL, Moran JS. Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk? Clin Infect Dis 2002;35:S191-9). ¶ Intramuscular. Rifampin, ciprofloxacin, and ceftriaxone are 90%-95% effective in reducing nasopharyngeal carriage of N. meningitdis and are all acceptable antimicrobial agents for chemoprophylaxis (141)(142)(143)(144). Systemic antimicrobial therapy of meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins might not reliably eradicate nasopharyngeal carriage of N. meningitdis. If other agents have been used for treatment, the index patient should receive chemoprophylactic antibiotics for eradication of nasopharyngeal carriage before being discharged from the hospital (145). One recent study has reported that a single 500-mg oral dose of azithromycin was effective in eradicating nasopharyngeal carriage of N. meningitdis (146). Azithromycin, in addition to being safe and easy to administer, is also available in a suspension form and is approved for use among children. Further evaluation is warranted of both the effectiveness of azithromycin in eradicating carriage of N. meningitdis and potential for development of microbial resistance to this drug if it is widely used for chemoprophylaxis. # Recommendations and Reports # Goal and Objectives This report provides recommendations on use of the newly licensed tetravalent meningococcal polysaccharide-protein conjugate vaccine (MCV4). The recommendations were developed by CDC's Advisory Committee on Immunization Practices (ACIP). The goal of this report is to provide recommendations for clinicians, public health officials, and other persons concerned with controlling and preventing meningococcal disease in the United States on the use of MCV4 and to update previous ACIP recommendations on prevention and control of meningococcal disease, including recommendations on use of the tetravalent meningococcal polysaccharide vaccine (MPSV4). Upon completion of this educational activity, the reader should be able to 1) describe the epidemiology of meningococcal disease in the United States; 2) describe the differences between polysaccharide and polysaccharide-protein conjugate meningococcal vaccines; 3) identify the populations for which MCV4 and MPSV4 are recommended; 4) describe the principles of evaluation and management of suspected outbreaks of meningococcal disease; and 5) identify indications with appropriate drug schedules for antimicrobial chemoprophylaxis of meningococcal disease. To receive continuing education credit, please answer all of the following questions. E. Persons who have terminal complement component deficiency.	None	None
3cf0cc955e5cff6d8baf02f28d80f69a275da260	cdc	None	This report updates 1999 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use of influenza vaccine and antiviral agents (MMWR 1999;48:1-29). These recommendations include five principal changes: a) the age for universal vaccination has been lowered to 50 years from 65 years; b) scheduling of large, organized vaccination campaigns after mid-October may be considered because the availability of vaccine in any location cannot be assured consistently in the early fall; c) 2000-2001 trivalent vaccine virus strains are A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)like, and B/Beijing/184/93-like strains; d) information on neuraminidase-inhibitor antiviral drugs has been added; and e) a list of other influenza-related infection control documents for special populations has been added. This report and other information on influenza can be accessed at the website for the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC at .These recommendations include five principal changes: - The age for universal vaccination has been lowered to 50 years from 65 years. - Scheduling of large, organized vaccination campaigns after mid-October may be considered because the availability of vaccine in any location cannot be assured consistently in the early fall.# INTRODUCTION Epidemics of influenza occur during the winter months nearly every year and are responsible for an average of approximately 20,000 deaths per year in the United States (1,2 ). Influenza viruses also can cause global epidemics of disease, known as pandemics, during which rates of illness and death from influenza-related complications can increase dramatically. Influenza viruses cause disease in all age groups (3)(4)(5). Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged ³65 years and persons of any age who have medical conditions that place them at high risk for complications from influenza (3,(6)(7)(8). Influenza vaccine is the primary method for preventing influenza and its more severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target group for influenza vaccination includes persons who are at high risk for serious complications from influenza, including approximately 35 million persons aged ³65 years and approximately 33-39 million persons aged <65 years who have chronic underlying medical conditions (National Immunization Program, CDC, unpublished data, 2000). Beginning with the 2000-2001 influenza season, the ACIP has added persons aged 50-64 years to the primary target group for annual influenza vaccination. This age group was added because a substantial proportion of persons aged 50-64 years (24%-32%) have one or more chronic medical conditions that place them at high risk for influenzarelated hospitalization and death. Rates of influenza-related excess hospitalization among adults aged <65 years with one or more high-risk conditions have been estimated at 56-635 per 100,000 persons compared with 13-60 per 100,000 among those without high-risk conditions (7,9 ). Despite the increased risk of severe illness, only an estimated 40%-41% of persons aged 50-64 years with chronic medical conditions and 28%-29% of those without high-risk conditions were vaccinated against influenza in 1997 (National Immunization Program, CDC, unpublished data, 2000). Age-based strategies have been more successful than patient-selection strategies based on medical conditions; thus, targeting all persons 50-64 years of age will likely increase vaccination rates among persons in this age group with high-risk conditions (10,11 ). In addition, this strategy will also likely help to increase vaccination of persons without high-risk conditions for whom annual vaccination is recommended because they live with or care for persons at increased risk of influenza-related complications. Of the approximately 41 million persons in the United States aged 50-64 years, 28-31 million are without identified chronic underlying medical conditions (National Immunization Program, CDC, unpublished data, 2000). Although healthy adults are at low risk for severe illness, influenza can result in substantial morbidity, health-care provider visits, and lost work days. Vaccination of healthy adults aged <65 years can reduce the number of illnesses and physician visits, work absenteeism, and antibiotic use (12)(13)(14)(15). Further, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (10 ). # Vaccination Coverage Levels Among persons aged ³65 years, influenza vaccination levels increased from 33% in 1989 (16 ) to 63% in 1997 (17 ), surpassing the Healthy People 2000 goal of 60% (18 ). Although influenza vaccination coverage increased in black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind those among whites (17,19 ). Possible reasons for the increase in influenza vaccination levels among persons aged ³65 years include greater acceptance of preventive medical services by practitioners, increased delivery and administration of vaccine by health-care providers and sources other than physicians, and the initiation of Medicare reimbursement for influenza vaccination in 1993 (20 ). The Healthy People 2010 objective is to achieve vaccination coverage for 90% of persons aged ³65 years (21 ). In 1997, the vaccination rate for persons at high risk aged <65 years was <30%, far short of the Healthy People 2000 goal of 60% (17,22 ), despite reported benefits of vaccination. Increasing vaccination coverage among persons at high risk aged <65 years now is the highest priority for expanding influenza vaccine use. Although annual vaccination is recommended for health-care workers, in the 1997 National Health Interview Survey, only 34% of health-care workers reported that they received influenza vaccine (23 ). Vaccination of health-care workers has been associated with reduced work absenteeism (13 ) and decreased deaths among nursing home patients (24,25 ). Efforts should be made to educate health-care workers about the benefits of vaccination and the potential health consequences of influenza illness for themselves and their patients. Measures should be taken to provide all health-care workers convenient access to influenza vaccine at the work site free of charge as part of employee health programs. - Information on neuraminidase-inhibitor antiviral drugs has been added. - A list of other influenza-related infection control documents for special populations has been added. # Influenza and Its Burden # Biology of Influenza Influenza A and B are the two types of influenza viruses that cause epidemic human disease (26 ). Influenza A viruses are further categorized into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B viruses are not categorized into subtypes. Both influenza A and B viruses are further separated into groups based on antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. A person's immunity to the surface antigens, especially hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs (27 ). However, antibody against one influenza virus type or subtype confers little or no protection against another virus type or subtype. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype (28 ). The frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the incorporation of one or more new strains in each year's influenza vaccine. # Clinical Signs and Symptoms of Influenza The incubation period for influenza is 1-4 days with an average of 2 days (29 ). Persons can be infectious starting the day before symptoms begin through approximately 5 days after illness onset; children can be infectious for a longer period. Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis) (30 ). Illness typically resolves after several days for most persons, although cough and malaise can persist for 2 or more weeks. In some persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease) or lead to secondary bacterial pneumonia or primary influenza viral pneumonia (31 ). # MMWR April 14, 2000 # Hospitalizations and Deaths from Influenza The risks for complications, hospitalizations, and deaths from influenza are higher among persons aged ³65 years, very young children, and persons of any age with some underlying health conditions than among healthy older children and younger adults (1,(31)(32)(33)(34). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics: - Among children aged 0-4 years, rates have ranged from approximately 500 per 100,000 population for those with high-risk conditions to 100 per 100,000 population for those without high-risk conditions (35 ). Among children without high-risk conditions, rates differ substantially within the 0-4-year age group: babies aged <6 months have the highest hospitalization rate at approximately 1,040 per 100,000 population, and children aged 2-4 years are hospitalized at a rate of approximately 8-136 per 100,000 population (36,37 ). - Among children aged 5-14 years, rates have ranged from approximately 200 per 100,000 population for those with high-risk conditions to 20-40 per 100,000 population for those without high-risk conditions (35,37 ). - Among persons aged 15-44 years, rates have ranged from approximately 40-60 per 100,000 population for those with high-risk conditions to approximately 20-30 per 100,000 population for those without high-risk conditions (6,7 ). - Among persons aged 45-64 years, rates have ranged from approximately 80-400 per 100,000 population for those with high-risk medical conditions to approximately 20-40 per 100,000 population for those without high-risk conditions (7,35 ). - Among persons aged ³65 years, rates have ranged from approximately 200 to >1,000 per 100,000 population (7,35,38 ). During influenza epidemics from 1969-1970 through 1993-1994, the estimated overall number of influenza-associated hospitalizations in the United States has ranged from approximately 20,000 to >300,000 per epidemic. An analysis of national hospital discharge data indicates an average of approximately 114,000 excess hospitalizations per year are related to influenza. Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A(H3N2) viruses, with an estimated average of 142,000 influenzaassociated hospitalizations per year (39 ). During influenza epidemics, deaths can increase from influenza and pneumonia as well as from exacerbations of cardiopulmonary conditions and other chronic diseases. In studies of influenza epidemics occurring from 1972-1973 through 1994-1995, excess deaths (i.e., the number of influenza-related deaths above a projected baseline of expected deaths) occurred during 19 of 23 influenza epidemics (40 ) (Influenza Branch, Division of Viral and Rickettsial Diseases , National Center for Infectious Diseases , CDC, unpublished data, 1998). During those 19 influenza seasons, estimated rates of influenza-associated deaths ranged from approximately 30 to >150 deaths per 100,000 persons aged ³65 years (Influenza Branch, DVRD, NCID, CDC, unpublished data 1998). These older adults currently account for >90% of the deaths attributed to pneumonia and influenza (41 ). From 1972From -1973From through 1994From -1995, more than 20,000 influenza-associated deaths were estimated to occur during each of 11 different U.S. epidemics, and more than 40,000 influenza-associated deaths were estimated for each of six of these 11 epidemics (40 ) (Influenza Branch, DVRD, NCID, CDC, unpublished data, 1998). In the United States, pneumonia and influenza deaths might be increasing in part because the number of elderly persons is increasing (42 ). # Options for Controlling Influenza In the United States, the main option for reducing the impact of influenza is immunoprophylaxis with inactivated (i.e., killed-virus) vaccine (see Recommendations for the Use of Influenza Vaccine). In addition, the use of influenza-specific antiviral drugs for chemoprophylaxis or treatment of influenza is an important adjunct to vaccine (see Recommendations for the Use of Antiviral Agents for Influenza). Vaccinating persons at high risk for complications before the influenza season each year is the most effective means of reducing the impact of influenza. Vaccination coverage can be increased by administering vaccine to persons during hospitalizations or routine health-care visits before the influenza season, making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains are well matched, achieving high vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing herd immunity (43 ). Vaccination of health-care workers and other persons in close contact with persons in high-risk groups can also help reduce transmission of influenza and subsequent influenza-related complications. # Effectiveness of Inactivated Influenza Vaccine Influenza vaccine contains three strains (two type A and one type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter. The vaccine is made from highly purified, egg-grown viruses that have been made noninfectious (i.e., inactivated) (44 ). Whole-virus, subvirion, and purified-surface-antigen preparations are available. Most vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titers (45,46 ). These antibody titers are protective against illness caused by strains similar to those in the vaccine (46)(47)(48). The effectiveness of influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. When the antigenic match between vaccine and circulating viruses is close, influenza vaccine prevents illness in approximately 70%-90% of healthy persons aged <65 years (49 ). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources when the vaccine and circulating viruses are well matched (13)(14)(15)50 ). Other studies suggest that the use of trivalent inactivated influenza vaccine or live attenuated influenza vaccine decreases the incidence of otitis media and the use of antibiotics among children (51)(52)(53). Elderly persons and persons with certain chronic diseases might develop lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza-related upper respiratory tract infection (54)(55)(56). However, among such persons, the vaccine can be effective in preventing secondary complications and reducing the risk for influenza-related hospitalization and death (43,57,58 ). Among elderly persons living outside of nursing homes or similar chronic-care facilities, influenza vaccine is 30%-70% effective in preventing hospitalization for pneumonia and influenza (12,58 ). Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. In this population, the vaccine can be 50%-60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death, even though the effectiveness in preventing influenza illness often ranges from 30% to 40% (59,60 ). # Composition of the 2000-2001 Influenza Vaccine The trivalent influenza vaccine prepared for the 2000-2001 season will include A/ Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Beijing/184/93like antigens. For the A/Moscow/10/99 (H3N2)-like antigen, U.S. manufacturers will use the antigenically equivalent A/Panama/2007/99 (H3N2) virus and for the B/Beijing/184/ 93-like antigen, they will use the antigenically equivalent B/Yamanashi/166/98 virus; these viruses will be used because of their growth properties and because they are representative of currently circulating A (H3N2) and B viruses. Because the vaccine viruses are initially grown in embryonated hens' eggs, the vaccine might contain small amounts of residual egg protein. Influenza vaccine distributed in the United States might also contain thimerosal, a mercury-containing compound, as the preservative. Manufacturing processes differ by manufacturer. Some manufacturers might use additional compounds to inactivate the influenza viruses, and they might use an antibiotic to prevent bacterial contamination. The package inserts should be consulted for additional information. # RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE Influenza vaccine is strongly recommended for any person aged ³6 months whobecause of age or underlying medical condition -is at increased risk for complications of influenza. In addition, health-care workers and other individuals (including household members) in close contact with persons in high-risk groups should be vaccinated to decrease the risk of transmitting influenza to persons at high risk. Influenza vaccine also can be administered to any person aged ³6 months to reduce the chance of becoming infected with influenza. # Target Groups for Vaccination # Groups at Increased Risk for Complications Vaccination is recommended for the following groups of persons who are at increased risk for complications from influenza or who have a higher prevalence of chronic medical conditions that place them at risk for influenza-related complications: - persons aged ³50 years; - residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions; - adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma; - adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus); - children and teenagers (aged 6 months to 18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza infection; and - women who will be in the second or third trimester of pregnancy during the influenza season. # Persons Who Can Transmit Influenza to Those at High Risk Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from care givers to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies suggests that vaccination of health-care workers is associated with decreased deaths among nursing home patients (24,25 ). Vaccination of health-care workers and others in close contact with persons at high risk is recommended. The following groups should be vaccinated: - physicians, nurses, and other personnel in both hospital and outpatient-care settings, including emergency response workers; - employees of nursing homes and chronic-care facilities who have contact with patients or residents; - employees of assisted living and other residences for persons in high-risk groups; - persons who provide home care to persons in high-risk groups; - household members (including children) of persons in high-risk groups. # Additional Information on Vaccination of Specific Populations Pregnant Women Influenza-associated excess deaths among pregnant women were documented during the pandemics of 1918-1919 and 1957-1958 (61-64 ). Case reports and limited studies also suggest that pregnancy can increase the risk for serious medical complications of influenza as a result of increases in heart rate, stroke volume, and oxygen consumption; decreases in lung capacity; and changes in immunologic function (65)(66)(67)(68). A study of the impact of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42 in comparison with women who were 1-6 months postpartum (69 ). Women in their third trimester of pregnancy were hospitalized at a rate (250 per 100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Using data from this study, researchers estimated that an average of 1-2 hospitalizations could be prevented for every 1,000 pregnant women vaccinated. Women who will be beyond the first trimester of pregnancy (³14 weeks' gestation) during the influenza season should be vaccinated. Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy. Because currently available influenza vaccine is an inactivated vaccine, many experts consider influenza vaccination safe during any stage of pregnancy. A study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (70 ). However, more data are needed to confirm the safety of vaccination during pregnancy. Some experts prefer to administer influenza vaccine during the second trimester to avoid a coincidental association with spontaneous abortion, which is common in the first trimester, and because exposures to vaccines traditionally have been avoided during the first trimester. # Persons Infected with Human Immunodeficiency Virus Limited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with human immunodeficiency virus (HIV) infection (71,72 ). However, a recent retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program found that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than in the peri-influenza periods. The risk of hospitalization for HIV-infected women was higher than the risk for women with other well-recognized high-risk conditions for influenza complications, including chronic heart and lung diseases (9). Other reports suggest that influenza symptoms might be prolonged and the risk for complications from influenza increased for some HIV-infected persons (73,74 ). Influenza vaccination has been shown to produce substantial antibody titers against influenza in vaccinated HIV-infected persons who have minimal acquired immunodeficiency syndrome-related symptoms and high CD4+ T-lymphocyte cell counts (75)(76)(77)(78). A small, randomized, placebo-controlled trial found that influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIVinfected persons with a mean of 400 CD4+ T-lymphocyte cells/mm 3 ; few persons with CD4+ T-lymphocyte cell counts of <200 were included in this study (72 ). In patients who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, influenza vaccine might not induce protective antibody titers (77,78 ); a second dose of vaccine does not improve the immune response in these persons (78,79 ). One study found that HIV RNA levels increased transiently in one HIV-infected patient after influenza infection (80 ). Some studies have demonstrated a transient (i.e., 2-4week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (77,81 ). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (82)(83)(84). Deterioration of CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIV-infected persons following influenza vaccination. The effect of antiretroviral therapy on potential increases in HIV RNA levels following either natural influenza infection or influenza vaccination is unknown (71 ). Because influenza can result in serious illness and complications and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit many HIV-infected patients, including HIV-infected pregnant women. # Breastfeeding Mothers Influenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination. # Travelers The risk of exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, most influenza activity occurs from April through September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups that include persons from areas of the world where influenza viruses are circulating. Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to - travel to the tropics; - travel with large organized tourist groups at any time of year; or - travel to the Southern Hemisphere from April through September. No information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who received the previous season's vaccine before travel should be revaccinated with the current vaccine in the following fall or winter. Persons aged ³50 years and others at high risk might wish to consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks of influenza and the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza. # General Population Physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children as young as 6 months). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics. # Persons Who Should Not Be Vaccinated Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of the antiviral agents amantadine or rimantadine is an option for preventing influenza A among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications of MMWR April 14, 2000 influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information about vaccine components can be found in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate the use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis. # Optimal Timing for Annual Vaccination The optimal time to vaccinate persons in high-risk groups is usually from the beginning of October through mid-November, because influenza activity in the United States generally peaks between late December and early March. Although vaccine generally becomes available in August or September, in some years, vaccine for the upcoming influenza season might not be available in some locations until later in the fall. To minimize the possibility that large organized vaccination campaigns will need to be canceled because vaccine is unavailable, persons planning large organized vaccination campaigns may consider scheduling these events after mid-October because the availability of vaccine in any location cannot be assured consistently in the early fall. Administering vaccine before October should generally be avoided in facilities such as nursing homes, because antibody levels can begin to decline within a few months after vaccination (85,86 ). # Vaccination Outside of Optimal Period To avoid missed opportunities for vaccination, beginning each September, influenza vaccine should be offered to persons at high risk when they are seen by health-care providers for routine care or are hospitalized, provided that vaccine is available. If regional influenza activity is expected to begin earlier than December, vaccination programs also can be undertaken as early as September. Health-care providers should offer vaccine to unvaccinated persons even after influenza virus activity is documented in a community and should continue to offer vaccine throughout the influenza season. (For information on vaccination of travelers, see Travelers.) # Dosage Dosage recommendations vary according to age group (Table 1). Among previously unvaccinated children aged <9 years, two doses administered at least 1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. Among adults, studies have indicated little or no improvement in antibody response when a second dose is administered during the same season (87)(88)(89)(90). Even when the current influenza vaccine contains one or more of the antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year following vaccination (85,86 ). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season. # Route The intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle; a needle length ³1 inch can be considered for these age groups. Infants and young children should be vaccinated in the anterolateral aspect of the thigh (91 ). # Side Effects and Adverse Reactions When educating patients about potential side effects, clinicians should emphasize that a) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and b) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination. # Local Reactions In placebo-controlled blinded studies, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts up to 2 days (92-94 ). These local reactions generally are mild and rarely interfere with the person's ability to conduct usual daily activities. # Systemic Reactions Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children) (95,96 ). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials suggest that among elderly persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (92)(93)(94). Immediate -presumably allergic -reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (97 ). These reactions probably result from hypersensitivity to some vaccine component; most reactions likely are caused by residual egg protein. Although current influenza vaccines contain only a small quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggsincluding those who have had occupational asthma or other allergic responses to egg protein -might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (98,99 ). Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, most patients do not develop reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (100,101 ). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed-type hypersensitivity reactions (100 ). # Guillain-Barré Syndrome The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS) (102,103 ). Among persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was slightly less than 10 cases per million persons vaccinated. Evidence for a causal relationship of GBS with subsequent vaccines prepared from other influenza viruses is less clear. Obtaining strong epidemiologic evidence for a possible small increase in risk is difficult for a rare condition such as GBS, which has an annual incidence of only 10-20 cases per million adults (104 ), and stretches the limits of epidemiologic investigation. More definitive data probably will require the use of other methodologies, such as laboratory studies of the pathophysiology of GBS. During three of four influenza seasons studied from 1977 through 1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (105)(106)(107). However, in a study of the 1992-1993 and 1993-1994 seasons, the overall relative risk for GBS was 1.7 (95% confidence interval = 1.0-2.8; p = 0.04) during the 6 weeks following vaccination, representing an excess of slightly more than one additional case of GBS per million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination (108 ). Thus, investigations to date suggest no large increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976) and that if influenza vaccine does pose a risk, it is probably quite small -slightly more than one additional case per million persons vaccinated. Cases of GBS following influenza infection have been reported, but no epidemiologic studies have documented such an association (109,110 ). Good evidence exists that several infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections in general are associated with GBS (104,(111)(112)(113). Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of slightly more than one additional case per million persons vaccinated is substantially less than the risk for severe influenza, which could be prevented by vaccination in all age groups, especially persons aged ³65 years and those who have medical indications for influenza vaccination. During different epidemics occurring from 1972 through 1981, estimated rates of influenza-associated hospitalization have ranged from approximately 200 to 300 hospitalizations per million population for previously healthy persons aged 5-44 years and from 2,000 to >10,000 hospitalizations per million population for persons aged ³65 years (6,7,35,38 ). During epidemics from 1972-1973 through 1994-1995, estimated rates of influenza-associated death have ranged from approximately 300 to >1,500 per million persons aged ³65 years, who account for more than 90% of all influenza-associated deaths (see Introduction for more information about influenza-associated illness and death). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death greatly outweigh the possible risks for developing vaccine-associated GBS. The average case-fatality ratio for GBS is 6% and increases with age (104,114 ). However, no evidence indicates that the case-fatality ratio for GBS differs among vaccinated persons and those not vaccinated. The incidence of GBS in the general population is very low, but persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history (105,115 ). Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is not known. Therefore, it would seem prudent to avoid vaccinating persons who are not at high risk for severe influenza complications and who are known to have developed GBS within 6 weeks after a previous influenza vaccination. However, many experts believe that for most persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination. # Simultaneous Administration of Other Vaccines, Including Childhood Vaccines The target groups for influenza and pneumococcal vaccination overlap considerably (116 ). For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering pneumococcal and influenza vaccines concurrently. Both vaccines can be administered at the same time at different sites without increasing side effects (117,118 ). However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not. Children at high risk for influenza-related complications can receive influenza vaccine at the same time they receive other routine vaccinations. # MMWR April 14, 2000 # Strategies for Implementing These Recommendations in Health-Care Settings Successful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk (usually by medical record review), use of reminder/recall systems, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine (119 ). Use of standing orders programs are recommended for long-term care facilities (e.g., nursing homes and skilled nursing facilities) under the supervision of a medical director to ensure the administration of recommended vaccinations for adults. Other settings (e.g., inpatient and outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, adult workplaces, and home health care agencies) are encouraged to introduce standing orders programs as well (120 ). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following paragraphs. # Outpatient Facilities Providing Ongoing Care Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccine. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccine and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended who do not have regularly scheduled visits during the fall should be reminded by mail or telephone of the need for vaccination. # Outpatient Facilities Providing Episodic or Acute Care Acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer vaccine to persons for whom vaccination is recommended or provide written information on why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility. # Nursing Homes and Other Residential Long-Term Care Facilities Vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted during the winter months after completion of the vaccination program should be vaccinated at the time of admission. # Acute-Care Hospitals Persons of all ages (including children) with high-risk conditions and persons aged ³50 years who are hospitalized at any time from September through March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. # Visiting Nurses and Others Providing Home Care to Persons at High Risk Nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Care givers and other persons in the household (including children) should be referred for vaccination. # Other Facilities Providing Services to Persons Aged ³50 Years Facilities such as assisted-living facilities, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccine on site before the influenza season. Staff education should emphasize the need for influenza vaccine. # Health-Care Workers Before the influenza season, health-care facilities should offer influenza vaccine to all personnel, including night and weekend staff. Particular emphasis should be placed on persons who care for members of high-risk groups. # Evolving Developments Related to Influenza Vaccine Potential New Vaccines Intranasally administered, cold-adapted, live, attenuated, influenza virus vaccines (LAIVs) are being used in Russia and have been under development in the United States since the 1960s (121)(122)(123)(124)(125). The viruses in these vaccines replicate in the upper respiratory tract and elicit a specific protective immune response. LAIVs have been studied as monovalent, bivalent, and trivalent formulations (124,125 ). LAIVs consist of live viruses that induce minimal symptoms (i.e., attenuated) and that replicate poorly at temperatures found in the lower respiratory tract (i.e., temperature-sensitive). The possible advantages of LAIVs are their potential to induce a broad mucosal and systemic immune response, ease of administration, and the acceptability of an intranasal route of administration compared with injectable vaccines. In a 5-year study that compared trivalent inactivated vaccine and bivalent LAIVs (administered by nose drops) and that used related but different vaccine strains, the two vaccines were found to be approximately equivalent in terms of effectiveness (126 ). In a recent study of children aged 15-71 months, an intranasally administered trivalent LAIV was 93% effective in preventing culture-positive influenza A (H3N2) and B infections, reduced otitis media among vaccinated children by 30%, and reduced otitis media with concomitant antibiotic use by 35% compared with unvaccinated children (51 ). In a follow-up study during the 1997-1998 season, the trivalent LAIV was 86% effective in preventing culture-positive influenza in children, despite a poor match between the vaccine's influenza A (H3N2) component and the predominant circulating influenza A (H3N2) virus (127 ). A study conducted among healthy adults during the same season found a 9%-24% reduction in febrile respiratory illnesses and 13%-28% reduction in lost work days (128 ). No study has directly compared the efficacy or effectiveness of trivalent inactivated vaccine and trivalent LAIV. # Potential Addition of Young Children to Groups Recommended for Vaccination During 1998, the ACIP formed a working group to explore issues related to the potential expansion of recommendations for the use of influenza vaccine. The ACIP influenza working group is considering the impact of influenza in young children as well as the MMWR April 14, 2000 potential safety issues and logistic and economic consequences of recommending routine vaccination of young healthy children. Several studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (35,38,129,130 ). The increased rates of hospitalization are comparable with rates for other high-risk groups. However, the interpretation of these findings has been confounded by cocirculation of respiratory syncytial viruses, which are a major cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (131)(132)(133). Recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children aged <5 years who do not have high-risk conditions (36,37 ). Both studies indicate that otherwise healthy children <2 years of age, and possibly children 2-4 years of age, are at increased risk for influenza-related hospitalization compared with older healthy children. # RECOMMENDATIONS FOR THE USE OF ANTIVIRAL AGENTS FOR INFLUENZA Antiviral drugs for influenza are an important adjunct to influenza vaccine for the control and prevention of influenza. However, they are not a substitute for vaccination. Four currently licensed agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine are chemically related antiviral drugs with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for prophylaxis of influenza A (H2N2) infection and was later approved in 1976 for the treatment and prophylaxis of influenza type A virus infections in adults and children aged ³1 year. Rimantadine was approved in 1993 for treatment and prophylaxis of infection in adults. Although rimantadine was approved only for prophylaxis of infection in children, many experts consider it appropriate for treatment among children. Zanamivir and oseltamivir are neuraminidase inhibitors with activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for the treatment of uncomplicated influenza infections, but neither have yet been approved for prophylaxis. Zanamivir was approved for treatment for persons aged ³12 years, and oseltamivir was approved for treatment for persons aged ³18 years. The four drugs differ in terms of their pharmacokinetics, side effects, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections; however, readers should consult the package inserts for more information. # Role of Laboratory Diagnosis The appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. The early diagnosis of influenza can help reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because some bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated if suspected. In addition, bacterial infections can occur as a complication of influenza. Influenza surveillance information as well as diagnostic testing (e.g., viral culture and rapid tests for influenza) can aid clinical judgment and help guide treatment decisions. Influenza surveillance by state and local health departments and CDC can provide information about the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza. Several commercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (29,134 ). Some of these rapid tests detect only influenza A viruses, whereas other rapid tests detect both influenza A and B viruses but do not distinguish between the two types. Additional commercial diagnostic tests are available for use by laboratories performing tests of high complexity (29 ). Despite the availability of rapid diagnostic tests, the collection of clinical specimens for viral culture is important because only culture isolates can provide specific information on circulating influenza subtypes and strains. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions about influenza treatment and prophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance. # Indications for Use Treatment When administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day (135)(136)(137)(138)(139)(140)(141)(142)(143)(144). More clinical data are available concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (137,145,146 ). However, in vitro data (147)(148)(149)(150)(151)(152) and data from studies of treatment in mice and ferrets (149,150,153,154 ) document that zanamivir and oseltamivir have activity against influenza B viruses. None of the four antiviral agents has been demonstrated to be effective in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is based principally on studies of patients with uncomplicated influenza (155 ). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, and zanamivir for treatment of influenza in persons at high risk for serious complications of influenza (135,137,138,140,(156)(157)(158)(159), and no published data are available concerning the effectiveness of oseltamivir for treatment of influenza in high-risk populations. Studies of the efficacy of any of the four drugs for treatment in children are limited (135,(159)(160)(161). To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days. # Prophylaxis Chemoprophylactic drugs are not a substitute for vaccination, although they are important adjuncts in the prevention and control of influenza. Both amantadine and rimantadine are indicated for the prophylaxis of influenza A infection but are not effective MMWR April 14, 2000 against influenza B. Both drugs are approximately 70%-90% effective in preventing illness from influenza A infection (135,144,159 ). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and the development of protective antibody against circulating influenza viruses. Therefore, some persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (135 ). Both drugs have been studied extensively in nursing home populations as a component of influenza outbreak control programs (135,158,(162)(163)(164). Zanamivir and oseltamivir have not been approved for prophylaxis, but recent community studies suggest that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (165,166 ). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited (167)(168)(169). Use of zanamivir has not been found to impair the immunologic response to influenza vaccine (170,171 ). When determining the timing and duration for administering amantadine or rimantadine for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community (172 ). # Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks (173,174 ). When influenza vaccine is given while influenza A viruses are circulating, chemoprophylaxis with amantadine or rimantadine should be considered for persons at high risk during the time from vaccination until immunity has developed. Children who receive influenza vaccine for the first time can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose). # Persons Who Provide Care to Those at High Risk To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis with amantadine or rimantadine during peak influenza A activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza A that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status. # Persons Who Have Immune Deficiency Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with human immunodeficiency virus (HIV), especially those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered. # Other Persons Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Amantadine or rimantadine also can be administered prophylactically to persons who wish to avoid influenza A illness. Health-care providers and patients should make this decision on an individual basis. # Control of Influenza Outbreaks in Institutions Most published reports on the use of amantadine or rimantadine to control institutional outbreaks of influenza A are based on studies of nursing home populations. When confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice is extremely useful. When institutional outbreaks occur, chemoprophylaxis should be administered to all residents -regardless of whether they received influenza vaccine during the previous fall -and should continue for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not well matched by the vaccine. Chemoprophylaxis has been used successfully to control an influenza A outbreak aboard a large cruise ship (175 ). Chemoprophylaxis also can be considered for controlling influenza A outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). To limit the potential transmission of drug-resistant virus during institutional outbreaks, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis. In addition to using antiviral drugs for treatment and prophylaxis of influenza, other outbreak control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, reoffering influenza vaccine to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (176)(177)(178). (For more information on outbreak control in specific settings, refer to additional references in Additional Information on Influenza Infection Control in Specific Populations.) # Dosage Dosage recommendations vary by age group and medical conditions (Table 2). Oseltamivir is manufactured by Hoffman-LaRoche (Tamiflu® -tablet). - Consult the drug package insert for dosage recommendations for administering amantadine to persons with creatinine clearance £50 mL/min/1.73m 2 . † 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. § Children ³10 years of age who weigh <40 kg should be administered amantadine or rimantadine at a dosage of 5 mg/kg/day. ¶ A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance £10 mL/min. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. NA = Not applicable. † † Elderly nursing home residents should be administered only 100 mg/day of rimantadine. A reduction in dosage to 100 mg/day should be considered for all persons ³65 years of age if they experience possible side effects when taking 200 mg/day. § § Zanamivir is approved for persons ³12 years of age and is administered as two 5-mg inhalations of medicated powder twice a day (i.e., 10 mg twice a day). The medication is administered via inhalation using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of proper use of the device. ¶ ¶ Neither zanamivir nor oseltamivir are approved for prophylaxis. * Oseltamivir is approved for persons ³18 years of age. A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance <30 mL/min. # MMWR 21 # Children Amantadine The use of amantadine among children aged <1 year has not been adequately evaluated. The U.S. Food and Drug Administration-approved dosage for children aged 1-9 years is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies are needed to determine the optimal dosage for children aged 1-9 years, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged ³10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable (179 ). # Rimantadine The use of rimantadine among children aged <1 year has not been adequately evaluated. For children aged 1-9 years, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children aged ³10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is recommended (180 ). # Zanamivir Zanamivir is not approved for use in children aged <12 years. The recommended dosage of zanamivir for treatment of influenza in persons aged ³12 years is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days (170 ). # Oseltamivir Oseltamivir is not approved for use in persons aged <18 years (181 ). # Persons Aged ³65 Years Amantadine The daily dose of amantadine for persons aged ³65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For some elderly persons, the dose should be further reduced. # Rimantadine Among elderly persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance (182 ). However, chronically ill elderly persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentrations two to four times higher than in healthy, younger persons when rimantadine has been administered at a dosage of 200 mg/day (135 ). For elderly nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day for prophylaxis or treatment. For other elderly persons, further studies are needed to determine the optimal dosage. However, a reduction in dosage to 100 mg/day should be considered for all persons aged ³65 years who experience side effects when taking a dosage of 200 mg/day. # MMWR April 14, 2000 # Zanamivir and Oseltamivir No reduction in dosage is recommended on the basis of age alone. # Persons with Impaired Renal Function Amantadine A reduction in dosage is recommended for patients with creatinine clearance £50 mL/ min/1.73m 2 . Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. Because recommended dosages based on creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance (183 ). # Rimantadine A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance £10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (184 ). # Zanamivir Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in halflife, and increased systemic exposure to zanamivir were observed (170,185 ). However, a small number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were much higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (186,187 ). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (170 ). # Oseltamivir Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (146,181 ). A reduction of the dose of oseltamivir to 75 mg once daily is recommended for patients with creatinine clearance <30 mL/min (181 ). No data are available concerning the safety or efficacy of oseltamivir in patients with creatinine clearance <10 mL/min. # Persons with Liver Disease Amantadine No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes in patients receiving amantadine have been reported, although a specific relationship between the drug and such changes has not been established (188 ). # MMWR 23 # Rimantadine A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction. # Zanamivir and Oseltamivir Neither of these medications has been studied in persons with hepatic dysfunction. # Persons with Seizure Disorders Amantadine An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (189 ). Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine. # Rimantadine Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine (190 ). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated. # Zanamivir and Oseltamivir No information is available regarding the use of zanamivir or oseltamivir among persons with a history of seizure disorder. # Route Amantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available as a capsule (179)(180)(181). Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of proper use of this device (170 ). # Pharmacokinetics Amantadine More than 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (162,(191)(192)(193)(194). Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency, and dosages might need to be decreased (see Dosage) (Table 2). # Rimantadine Approximately 75% of rimantadine is metabolized by the liver (159 ). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (159,195 ). In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations in liver function were observed after a single dose (159,195 ). However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (180 ). # MMWR April 14, 2000 Rimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (159,184 ). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy persons of the same age (184 ). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (180,196 ). # Zanamivir In studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (197,198 ). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (170,187 ). # Oseltamivir Approximately 80% of orally administered oseltamivir is absorbed systemically (146 ). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (181,199 ). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (199 ). # Side Effects and Adverse Reactions Amantadine and Rimantadine Both amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (200 ). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced at least one CNS symptom, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (200 ). A study of elderly persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (182). Gastrointestinal side effects (e.g., nausea and anorexia) occur in approximately 1%-3% of persons taking either drug, compared with 1% of persons receiving the placebo (200 ). Side effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and sei-zures) (189 ). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (162 ). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 2). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (179 ). Because rimantadine has been marketed for a shorter period than amantadine, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. When considering amantadine or rimantadine (i.e., choice of antiviral drug, dose, and duration of therapy), clinicians must take into account the patient's age, weight, and renal function (Table 2); the presence of other medical conditions; indications for the use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications. # Zanamivir Preliminary results of a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease indicated that more patients receiving zanamivir than placebo experienced a >20% decline in forced expiratory volume in 1 second (FEV1) or peak expiratory flow rates after treatment (170 ). Moreover, in a phase I study of persons with mild or moderate asthma who did not have influenza-like illness, one of 13 patients experienced bronchospasm following administration of zanamivir (170 ). In addition, during postmarketing surveillance, cases of respiratory function deterioration following inhalation of zanamivir have been reported among patients with underlying asthma or chronic obstructive pulmonary disease (155 ). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of proper monitoring and supportive care, including the availability of short-acting bronchodilators (155 ). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to a) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and b) stop using zanamivir and contact their physician if they develop difficulty breathing (170 ). No clear evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (155 ). In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (136)(137)(138)(139)(140)(141)170,197 ). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections (136,137,139,140,170 ). Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (170 ). # Oseltamivir Nausea and vomiting were reported more frequently among persons receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, ap-MMWR April 14, 2000 proximately 6%; vomiting, approximately 3%) (142,143,181,201 ). However, few persons enrolled in the clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (181 ). Nausea and vomiting might be less severe if oseltamivir is taken with food (181,201 ). # Use During Pregnancy No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (68,202 ). However, both amantadine and rimantadine have been shown in animal studies to be teratogenic and embryotoxic when administered at very high doses (179,180 ). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see package inserts ). # Drug Interactions Careful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (135 ). No clinically significant interactions between rimantadine and other drugs have been identified. Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically important drug interactions have been predicted on the basis of in vitro data and data from studies of rats (170,203 ). Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (181,199 ). No published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, the package inserts should be consulted. # Antiviral Drug-Resistant Strains of Influenza Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa (204 ). Drug-resistant viruses can appear in up to approximately one third of patients when either amantadine or rimantadine is used for therapy (161,205 ). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace sensitive strains within 2-3 days of starting therapy (205,206 ). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (207,208 ); however, the frequency with which resistant viruses are transmitted and their impact on efforts to control influenza are unknown. Amantadine-and rimantadine-resistant viruses are not more virulent or transmissible than sensitive viruses (209 ). The screening of epidemic strains of influenza A has rarely detected amantadine-and rimantadine-resistant viruses (205,210,211 ). Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed sensitive viruses early in the course of treatment and later shed drug-resistant viruses, especially after 5-7 days of therapy (161 ). Such persons can benefit from therapy even when resistant viruses emerge. Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (212)(213)(214)(215)(216)(217)(218)(219), but induction of resistance requires several passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (220,221 ). Whether these in vitro findings indicate that clinical drug resistance will occur less frequently with zanamivir and oseltamivir than with amantadine and rimantadine is unknown. Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (138,181,222,223 ). Currently available diagnostic tests are not optimal for detecting clinical resistance, and better tests as well as more testing are needed before firm conclusions can be reached. Postmarketing surveillance for neuraminidase inhibitorresistant influenza viruses is planned. # SOURCES OF INFORMATION ON INFLUENZA AND ITS SURVEILLANCE Information regarding influenza surveillance is available through the CDC Voice Information System (influenza update), (888) 232-3228; CDC Fax Information Service, (888) 232-3299; or website for the Influenza Branch, DVRD, NCID, CDC at . From October through May, the information is updated at least every other week. In addition, periodic updates about influenza are published in the weekly MMWR. State and local health departments should be consulted regarding availability of influenza vaccine, access to vaccination programs, information about state or local influenza activity, and for reporting influenza outbreaks and receiving advice regarding outbreak control. # ADDITIONAL INFORMATION ON INFLUENZA INFECTION CONTROL IN SPECIFIC POPULATIONS Each year, the Advisory Committee on Immunization Practices provides general, annually updated information about the control and prevention of influenza. Other documents on the control and prevention of influenza in specific populations (e.g., immunocompromised persons, health-care workers, hospitals, and travelers) are also available: - Bolyard EA, Tablan OC, Williams WW, et al., Hospital Infection Control Practices Advisory Committee. Guideline for infection control in health care personnel. Am J Infect Control 1998;26:289-354. - Bradley SF, The Long-Term-Care Committee of the Society for Healthcare Epidemiology of America. Prevention of influenza in long-term care facilities. Infect Control Hosp Epidemiol 1999;20:629-37. - American Academy of Pediatrics. 2000 red book: report of the Committee on Infectious Diseases. 25th edition. Elk Grove Village, IL: American Academy of Pediatrics, 2000 (in press). - CDC. 1999 # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.0 hour in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 MMWR April 14, 2000 # GOAL AND OBJECTIVES This MMWR provides recommendations regarding the prevention and control of influenza. These recommendations were developed by CDC staff members and the Influenza Working Group of the ACIP. The goal of this report is to provide guidance for the use of influenza vaccine and influenza antiviral agents in the United States. Upon completion of this educational activity, the reader should be able to a) describe the disease burden of influenza in the United States; b) describe the characteristics of the currently licensed influenza vaccine; c) list the primary target groups for annual influenza vaccination; and d) recognize the most common adverse reactions following administration of influenza vaccine. To receive continuing education credit, please answer all of the following questions. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	This report updates 1999 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use of influenza vaccine and antiviral agents (MMWR 1999;48[No. RR-4]:1-29). These recommendations include five principal changes: a) the age for universal vaccination has been lowered to 50 years from 65 years; b) scheduling of large, organized vaccination campaigns after mid-October may be considered because the availability of vaccine in any location cannot be assured consistently in the early fall; c) 2000-2001 trivalent vaccine virus strains are A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)like, and B/Beijing/184/93-like strains; d) information on neuraminidase-inhibitor antiviral drugs has been added; and e) a list of other influenza-related infection control documents for special populations has been added. This report and other information on influenza can be accessed at the website for the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC at <http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm>.These recommendations include five principal changes: • The age for universal vaccination has been lowered to 50 years from 65 years. • Scheduling of large, organized vaccination campaigns after mid-October may be considered because the availability of vaccine in any location cannot be assured consistently in the early fall.# INTRODUCTION Epidemics of influenza occur during the winter months nearly every year and are responsible for an average of approximately 20,000 deaths per year in the United States (1,2 ). Influenza viruses also can cause global epidemics of disease, known as pandemics, during which rates of illness and death from influenza-related complications can increase dramatically. Influenza viruses cause disease in all age groups (3)(4)(5). Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged ³65 years and persons of any age who have medical conditions that place them at high risk for complications from influenza (3,(6)(7)(8). Influenza vaccine is the primary method for preventing influenza and its more severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target group for influenza vaccination includes persons who are at high risk for serious complications from influenza, including approximately 35 million persons aged ³65 years and approximately 33-39 million persons aged <65 years who have chronic underlying medical conditions (National Immunization Program, CDC, unpublished data, 2000). Beginning with the 2000-2001 influenza season, the ACIP has added persons aged 50-64 years to the primary target group for annual influenza vaccination. This age group was added because a substantial proportion of persons aged 50-64 years (24%-32%) have one or more chronic medical conditions that place them at high risk for influenzarelated hospitalization and death. Rates of influenza-related excess hospitalization among adults aged <65 years with one or more high-risk conditions have been estimated at 56-635 per 100,000 persons compared with 13-60 per 100,000 among those without high-risk conditions (7,9 ). Despite the increased risk of severe illness, only an estimated 40%-41% of persons aged 50-64 years with chronic medical conditions and 28%-29% of those without high-risk conditions were vaccinated against influenza in 1997 (National Immunization Program, CDC, unpublished data, 2000). Age-based strategies have been more successful than patient-selection strategies based on medical conditions; thus, targeting all persons 50-64 years of age will likely increase vaccination rates among persons in this age group with high-risk conditions (10,11 ). In addition, this strategy will also likely help to increase vaccination of persons without high-risk conditions for whom annual vaccination is recommended because they live with or care for persons at increased risk of influenza-related complications. Of the approximately 41 million persons in the United States aged 50-64 years, 28-31 million are without identified chronic underlying medical conditions (National Immunization Program, CDC, unpublished data, 2000). Although healthy adults are at low risk for severe illness, influenza can result in substantial morbidity, health-care provider visits, and lost work days. Vaccination of healthy adults aged <65 years can reduce the number of illnesses and physician visits, work absenteeism, and antibiotic use (12)(13)(14)(15). Further, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (10 ). # Vaccination Coverage Levels Among persons aged ³65 years, influenza vaccination levels increased from 33% in 1989 (16 ) to 63% in 1997 (17 ), surpassing the Healthy People 2000 goal of 60% (18 ). Although influenza vaccination coverage increased in black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind those among whites (17,19 ). Possible reasons for the increase in influenza vaccination levels among persons aged ³65 years include greater acceptance of preventive medical services by practitioners, increased delivery and administration of vaccine by health-care providers and sources other than physicians, and the initiation of Medicare reimbursement for influenza vaccination in 1993 (20 ). The Healthy People 2010 objective is to achieve vaccination coverage for 90% of persons aged ³65 years (21 ). In 1997, the vaccination rate for persons at high risk aged <65 years was <30%, far short of the Healthy People 2000 goal of 60% (17,22 ), despite reported benefits of vaccination. Increasing vaccination coverage among persons at high risk aged <65 years now is the highest priority for expanding influenza vaccine use. Although annual vaccination is recommended for health-care workers, in the 1997 National Health Interview Survey, only 34% of health-care workers reported that they received influenza vaccine (23 ). Vaccination of health-care workers has been associated with reduced work absenteeism (13 ) and decreased deaths among nursing home patients (24,25 ). Efforts should be made to educate health-care workers about the benefits of vaccination and the potential health consequences of influenza illness for themselves and their patients. Measures should be taken to provide all health-care workers convenient access to influenza vaccine at the work site free of charge as part of employee health programs. • Information on neuraminidase-inhibitor antiviral drugs has been added. • A list of other influenza-related infection control documents for special populations has been added. # Influenza and Its Burden # Biology of Influenza Influenza A and B are the two types of influenza viruses that cause epidemic human disease (26 ). Influenza A viruses are further categorized into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B viruses are not categorized into subtypes. Both influenza A and B viruses are further separated into groups based on antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. A person's immunity to the surface antigens, especially hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs (27 ). However, antibody against one influenza virus type or subtype confers little or no protection against another virus type or subtype. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype (28 ). The frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the incorporation of one or more new strains in each year's influenza vaccine. # Clinical Signs and Symptoms of Influenza The incubation period for influenza is 1-4 days with an average of 2 days (29 ). Persons can be infectious starting the day before symptoms begin through approximately 5 days after illness onset; children can be infectious for a longer period. Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis) (30 ). Illness typically resolves after several days for most persons, although cough and malaise can persist for 2 or more weeks. In some persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease) or lead to secondary bacterial pneumonia or primary influenza viral pneumonia (31 ). # MMWR April 14, 2000 # Hospitalizations and Deaths from Influenza The risks for complications, hospitalizations, and deaths from influenza are higher among persons aged ³65 years, very young children, and persons of any age with some underlying health conditions than among healthy older children and younger adults (1,(31)(32)(33)(34). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics: • Among children aged 0-4 years, rates have ranged from approximately 500 per 100,000 population for those with high-risk conditions to 100 per 100,000 population for those without high-risk conditions (35 ). Among children without high-risk conditions, rates differ substantially within the 0-4-year age group: babies aged <6 months have the highest hospitalization rate at approximately 1,040 per 100,000 population, and children aged 2-4 years are hospitalized at a rate of approximately 8-136 per 100,000 population (36,37 ). • Among children aged 5-14 years, rates have ranged from approximately 200 per 100,000 population for those with high-risk conditions to 20-40 per 100,000 population for those without high-risk conditions (35,37 ). • Among persons aged 15-44 years, rates have ranged from approximately 40-60 per 100,000 population for those with high-risk conditions to approximately 20-30 per 100,000 population for those without high-risk conditions (6,7 ). • Among persons aged 45-64 years, rates have ranged from approximately 80-400 per 100,000 population for those with high-risk medical conditions to approximately 20-40 per 100,000 population for those without high-risk conditions (7,35 ). • Among persons aged ³65 years, rates have ranged from approximately 200 to >1,000 per 100,000 population (7,35,38 ). During influenza epidemics from 1969-1970 through 1993-1994, the estimated overall number of influenza-associated hospitalizations in the United States has ranged from approximately 20,000 to >300,000 per epidemic. An analysis of national hospital discharge data indicates an average of approximately 114,000 excess hospitalizations per year are related to influenza. Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A(H3N2) viruses, with an estimated average of 142,000 influenzaassociated hospitalizations per year (39 ). During influenza epidemics, deaths can increase from influenza and pneumonia as well as from exacerbations of cardiopulmonary conditions and other chronic diseases. In studies of influenza epidemics occurring from 1972-1973 through 1994-1995, excess deaths (i.e., the number of influenza-related deaths above a projected baseline of expected deaths) occurred during 19 of 23 influenza epidemics (40 ) (Influenza Branch, Division of Viral and Rickettsial Diseases [DVRD], National Center for Infectious Diseases [NCID], CDC, unpublished data, 1998). During those 19 influenza seasons, estimated rates of influenza-associated deaths ranged from approximately 30 to >150 deaths per 100,000 persons aged ³65 years (Influenza Branch, DVRD, NCID, CDC, unpublished data 1998). These older adults currently account for >90% of the deaths attributed to pneumonia and influenza (41 ). From 1972From -1973From through 1994From -1995, more than 20,000 influenza-associated deaths were estimated to occur during each of 11 different U.S. epidemics, and more than 40,000 influenza-associated deaths were estimated for each of six of these 11 epidemics (40 ) (Influenza Branch, DVRD, NCID, CDC, unpublished data, 1998). In the United States, pneumonia and influenza deaths might be increasing in part because the number of elderly persons is increasing (42 ). # Options for Controlling Influenza In the United States, the main option for reducing the impact of influenza is immunoprophylaxis with inactivated (i.e., killed-virus) vaccine (see Recommendations for the Use of Influenza Vaccine). In addition, the use of influenza-specific antiviral drugs for chemoprophylaxis or treatment of influenza is an important adjunct to vaccine (see Recommendations for the Use of Antiviral Agents for Influenza). Vaccinating persons at high risk for complications before the influenza season each year is the most effective means of reducing the impact of influenza. Vaccination coverage can be increased by administering vaccine to persons during hospitalizations or routine health-care visits before the influenza season, making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains are well matched, achieving high vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing herd immunity (43 ). Vaccination of health-care workers and other persons in close contact with persons in high-risk groups can also help reduce transmission of influenza and subsequent influenza-related complications. # Effectiveness of Inactivated Influenza Vaccine Influenza vaccine contains three strains (two type A and one type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter. The vaccine is made from highly purified, egg-grown viruses that have been made noninfectious (i.e., inactivated) (44 ). Whole-virus, subvirion, and purified-surface-antigen preparations are available. Most vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titers (45,46 ). These antibody titers are protective against illness caused by strains similar to those in the vaccine (46)(47)(48). The effectiveness of influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. When the antigenic match between vaccine and circulating viruses is close, influenza vaccine prevents illness in approximately 70%-90% of healthy persons aged <65 years (49 ). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources when the vaccine and circulating viruses are well matched (13)(14)(15)50 ). Other studies suggest that the use of trivalent inactivated influenza vaccine or live attenuated influenza vaccine decreases the incidence of otitis media and the use of antibiotics among children (51)(52)(53). Elderly persons and persons with certain chronic diseases might develop lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza-related upper respiratory tract infection (54)(55)(56). However, among such persons, the vaccine can be effective in preventing secondary complications and reducing the risk for influenza-related hospitalization and death (43,57,58 ). Among elderly persons living outside of nursing homes or similar chronic-care facilities, influenza vaccine is 30%-70% effective in preventing hospitalization for pneumonia and influenza (12,58 ). Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. In this population, the vaccine can be 50%-60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death, even though the effectiveness in preventing influenza illness often ranges from 30% to 40% (59,60 ). # Composition of the 2000-2001 Influenza Vaccine The trivalent influenza vaccine prepared for the 2000-2001 season will include A/ Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Beijing/184/93like antigens. For the A/Moscow/10/99 (H3N2)-like antigen, U.S. manufacturers will use the antigenically equivalent A/Panama/2007/99 (H3N2) virus and for the B/Beijing/184/ 93-like antigen, they will use the antigenically equivalent B/Yamanashi/166/98 virus; these viruses will be used because of their growth properties and because they are representative of currently circulating A (H3N2) and B viruses. Because the vaccine viruses are initially grown in embryonated hens' eggs, the vaccine might contain small amounts of residual egg protein. Influenza vaccine distributed in the United States might also contain thimerosal, a mercury-containing compound, as the preservative. Manufacturing processes differ by manufacturer. Some manufacturers might use additional compounds to inactivate the influenza viruses, and they might use an antibiotic to prevent bacterial contamination. The package inserts should be consulted for additional information. # RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE Influenza vaccine is strongly recommended for any person aged ³6 months whobecause of age or underlying medical condition -is at increased risk for complications of influenza. In addition, health-care workers and other individuals (including household members) in close contact with persons in high-risk groups should be vaccinated to decrease the risk of transmitting influenza to persons at high risk. Influenza vaccine also can be administered to any person aged ³6 months to reduce the chance of becoming infected with influenza. # Target Groups for Vaccination # Groups at Increased Risk for Complications Vaccination is recommended for the following groups of persons who are at increased risk for complications from influenza or who have a higher prevalence of chronic medical conditions that place them at risk for influenza-related complications: • persons aged ³50 years; • residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions; • adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma; • adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus); • children and teenagers (aged 6 months to 18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza infection; and • women who will be in the second or third trimester of pregnancy during the influenza season. # Persons Who Can Transmit Influenza to Those at High Risk Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from care givers to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies suggests that vaccination of health-care workers is associated with decreased deaths among nursing home patients (24,25 ). Vaccination of health-care workers and others in close contact with persons at high risk is recommended. The following groups should be vaccinated: • physicians, nurses, and other personnel in both hospital and outpatient-care settings, including emergency response workers; • employees of nursing homes and chronic-care facilities who have contact with patients or residents; • employees of assisted living and other residences for persons in high-risk groups; • persons who provide home care to persons in high-risk groups; • household members (including children) of persons in high-risk groups. # Additional Information on Vaccination of Specific Populations Pregnant Women Influenza-associated excess deaths among pregnant women were documented during the pandemics of 1918-1919 and 1957-1958 (61-64 ). Case reports and limited studies also suggest that pregnancy can increase the risk for serious medical complications of influenza as a result of increases in heart rate, stroke volume, and oxygen consumption; decreases in lung capacity; and changes in immunologic function (65)(66)(67)(68). A study of the impact of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42 in comparison with women who were 1-6 months postpartum (69 ). Women in their third trimester of pregnancy were hospitalized at a rate (250 per 100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Using data from this study, researchers estimated that an average of 1-2 hospitalizations could be prevented for every 1,000 pregnant women vaccinated. Women who will be beyond the first trimester of pregnancy (³14 weeks' gestation) during the influenza season should be vaccinated. Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy. Because currently available influenza vaccine is an inactivated vaccine, many experts consider influenza vaccination safe during any stage of pregnancy. A study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (70 ). However, more data are needed to confirm the safety of vaccination during pregnancy. Some experts prefer to administer influenza vaccine during the second trimester to avoid a coincidental association with spontaneous abortion, which is common in the first trimester, and because exposures to vaccines traditionally have been avoided during the first trimester. # Persons Infected with Human Immunodeficiency Virus Limited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with human immunodeficiency virus (HIV) infection (71,72 ). However, a recent retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program found that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than in the peri-influenza periods. The risk of hospitalization for HIV-infected women was higher than the risk for women with other well-recognized high-risk conditions for influenza complications, including chronic heart and lung diseases (9). Other reports suggest that influenza symptoms might be prolonged and the risk for complications from influenza increased for some HIV-infected persons (73,74 ). Influenza vaccination has been shown to produce substantial antibody titers against influenza in vaccinated HIV-infected persons who have minimal acquired immunodeficiency syndrome-related symptoms and high CD4+ T-lymphocyte cell counts (75)(76)(77)(78). A small, randomized, placebo-controlled trial found that influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIVinfected persons with a mean of 400 CD4+ T-lymphocyte cells/mm 3 ; few persons with CD4+ T-lymphocyte cell counts of <200 were included in this study (72 ). In patients who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, influenza vaccine might not induce protective antibody titers (77,78 ); a second dose of vaccine does not improve the immune response in these persons (78,79 ). One study found that HIV RNA levels increased transiently in one HIV-infected patient after influenza infection (80 ). Some studies have demonstrated a transient (i.e., 2-4week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (77,81 ). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (82)(83)(84). Deterioration of CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIV-infected persons following influenza vaccination. The effect of antiretroviral therapy on potential increases in HIV RNA levels following either natural influenza infection or influenza vaccination is unknown (71 ). Because influenza can result in serious illness and complications and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit many HIV-infected patients, including HIV-infected pregnant women. # Breastfeeding Mothers Influenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination. # Travelers The risk of exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, most influenza activity occurs from April through September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups that include persons from areas of the world where influenza viruses are circulating. Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to • travel to the tropics; • travel with large organized tourist groups at any time of year; or • travel to the Southern Hemisphere from April through September. No information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who received the previous season's vaccine before travel should be revaccinated with the current vaccine in the following fall or winter. Persons aged ³50 years and others at high risk might wish to consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks of influenza and the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza. # General Population Physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children as young as 6 months). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics. # Persons Who Should Not Be Vaccinated Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of the antiviral agents amantadine or rimantadine is an option for preventing influenza A among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications of MMWR April 14, 2000 influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information about vaccine components can be found in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate the use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis. # Optimal Timing for Annual Vaccination The optimal time to vaccinate persons in high-risk groups is usually from the beginning of October through mid-November, because influenza activity in the United States generally peaks between late December and early March. Although vaccine generally becomes available in August or September, in some years, vaccine for the upcoming influenza season might not be available in some locations until later in the fall. To minimize the possibility that large organized vaccination campaigns will need to be canceled because vaccine is unavailable, persons planning large organized vaccination campaigns may consider scheduling these events after mid-October because the availability of vaccine in any location cannot be assured consistently in the early fall. Administering vaccine before October should generally be avoided in facilities such as nursing homes, because antibody levels can begin to decline within a few months after vaccination (85,86 ). # Vaccination Outside of Optimal Period To avoid missed opportunities for vaccination, beginning each September, influenza vaccine should be offered to persons at high risk when they are seen by health-care providers for routine care or are hospitalized, provided that vaccine is available. If regional influenza activity is expected to begin earlier than December, vaccination programs also can be undertaken as early as September. Health-care providers should offer vaccine to unvaccinated persons even after influenza virus activity is documented in a community and should continue to offer vaccine throughout the influenza season. (For information on vaccination of travelers, see Travelers.) # Dosage Dosage recommendations vary according to age group (Table 1). Among previously unvaccinated children aged <9 years, two doses administered at least 1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. Among adults, studies have indicated little or no improvement in antibody response when a second dose is administered during the same season (87)(88)(89)(90). Even when the current influenza vaccine contains one or more of the antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year following vaccination (85,86 ). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season. # Route The intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle; a needle length ³1 inch can be considered for these age groups. Infants and young children should be vaccinated in the anterolateral aspect of the thigh (91 ). # Side Effects and Adverse Reactions When educating patients about potential side effects, clinicians should emphasize that a) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and b) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination. # Local Reactions In placebo-controlled blinded studies, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts up to 2 days (92-94 ). These local reactions generally are mild and rarely interfere with the person's ability to conduct usual daily activities. # Systemic Reactions Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children) (95,96 ). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials suggest that among elderly persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (92)(93)(94). Immediate -presumably allergic -reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (97 ). These reactions probably result from hypersensitivity to some vaccine component; most reactions likely are caused by residual egg protein. Although current influenza vaccines contain only a small quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggsincluding those who have had occupational asthma or other allergic responses to egg protein -might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (98,99 ). Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, most patients do not develop reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (100,101 ). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed-type hypersensitivity reactions (100 ). # Guillain-Barré Syndrome The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS) (102,103 ). Among persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was slightly less than 10 cases per million persons vaccinated. Evidence for a causal relationship of GBS with subsequent vaccines prepared from other influenza viruses is less clear. Obtaining strong epidemiologic evidence for a possible small increase in risk is difficult for a rare condition such as GBS, which has an annual incidence of only 10-20 cases per million adults (104 ), and stretches the limits of epidemiologic investigation. More definitive data probably will require the use of other methodologies, such as laboratory studies of the pathophysiology of GBS. During three of four influenza seasons studied from 1977 through 1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (105)(106)(107). However, in a study of the 1992-1993 and 1993-1994 seasons, the overall relative risk for GBS was 1.7 (95% confidence interval = 1.0-2.8; p = 0.04) during the 6 weeks following vaccination, representing an excess of slightly more than one additional case of GBS per million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination (108 ). Thus, investigations to date suggest no large increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976) and that if influenza vaccine does pose a risk, it is probably quite small -slightly more than one additional case per million persons vaccinated. Cases of GBS following influenza infection have been reported, but no epidemiologic studies have documented such an association (109,110 ). Good evidence exists that several infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections in general are associated with GBS (104,(111)(112)(113). Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of slightly more than one additional case per million persons vaccinated is substantially less than the risk for severe influenza, which could be prevented by vaccination in all age groups, especially persons aged ³65 years and those who have medical indications for influenza vaccination. During different epidemics occurring from 1972 through 1981, estimated rates of influenza-associated hospitalization have ranged from approximately 200 to 300 hospitalizations per million population for previously healthy persons aged 5-44 years and from 2,000 to >10,000 hospitalizations per million population for persons aged ³65 years (6,7,35,38 ). During epidemics from 1972-1973 through 1994-1995, estimated rates of influenza-associated death have ranged from approximately 300 to >1,500 per million persons aged ³65 years, who account for more than 90% of all influenza-associated deaths (see Introduction for more information about influenza-associated illness and death). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death greatly outweigh the possible risks for developing vaccine-associated GBS. The average case-fatality ratio for GBS is 6% and increases with age (104,114 ). However, no evidence indicates that the case-fatality ratio for GBS differs among vaccinated persons and those not vaccinated. The incidence of GBS in the general population is very low, but persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history (105,115 ). Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is not known. Therefore, it would seem prudent to avoid vaccinating persons who are not at high risk for severe influenza complications and who are known to have developed GBS within 6 weeks after a previous influenza vaccination. However, many experts believe that for most persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination. # Simultaneous Administration of Other Vaccines, Including Childhood Vaccines The target groups for influenza and pneumococcal vaccination overlap considerably (116 ). For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering pneumococcal and influenza vaccines concurrently. Both vaccines can be administered at the same time at different sites without increasing side effects (117,118 ). However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not. Children at high risk for influenza-related complications can receive influenza vaccine at the same time they receive other routine vaccinations. # MMWR April 14, 2000 # Strategies for Implementing These Recommendations in Health-Care Settings Successful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk (usually by medical record review), use of reminder/recall systems, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine (119 ). Use of standing orders programs are recommended for long-term care facilities (e.g., nursing homes and skilled nursing facilities) under the supervision of a medical director to ensure the administration of recommended vaccinations for adults. Other settings (e.g., inpatient and outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, adult workplaces, and home health care agencies) are encouraged to introduce standing orders programs as well (120 ). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following paragraphs. # Outpatient Facilities Providing Ongoing Care Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccine. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccine and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended who do not have regularly scheduled visits during the fall should be reminded by mail or telephone of the need for vaccination. # Outpatient Facilities Providing Episodic or Acute Care Acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer vaccine to persons for whom vaccination is recommended or provide written information on why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility. # Nursing Homes and Other Residential Long-Term Care Facilities Vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted during the winter months after completion of the vaccination program should be vaccinated at the time of admission. # Acute-Care Hospitals Persons of all ages (including children) with high-risk conditions and persons aged ³50 years who are hospitalized at any time from September through March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. # Visiting Nurses and Others Providing Home Care to Persons at High Risk Nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Care givers and other persons in the household (including children) should be referred for vaccination. # Other Facilities Providing Services to Persons Aged ³50 Years Facilities such as assisted-living facilities, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccine on site before the influenza season. Staff education should emphasize the need for influenza vaccine. # Health-Care Workers Before the influenza season, health-care facilities should offer influenza vaccine to all personnel, including night and weekend staff. Particular emphasis should be placed on persons who care for members of high-risk groups. # Evolving Developments Related to Influenza Vaccine Potential New Vaccines Intranasally administered, cold-adapted, live, attenuated, influenza virus vaccines (LAIVs) are being used in Russia and have been under development in the United States since the 1960s (121)(122)(123)(124)(125). The viruses in these vaccines replicate in the upper respiratory tract and elicit a specific protective immune response. LAIVs have been studied as monovalent, bivalent, and trivalent formulations (124,125 ). LAIVs consist of live viruses that induce minimal symptoms (i.e., attenuated) and that replicate poorly at temperatures found in the lower respiratory tract (i.e., temperature-sensitive). The possible advantages of LAIVs are their potential to induce a broad mucosal and systemic immune response, ease of administration, and the acceptability of an intranasal route of administration compared with injectable vaccines. In a 5-year study that compared trivalent inactivated vaccine and bivalent LAIVs (administered by nose drops) and that used related but different vaccine strains, the two vaccines were found to be approximately equivalent in terms of effectiveness (126 ). In a recent study of children aged 15-71 months, an intranasally administered trivalent LAIV was 93% effective in preventing culture-positive influenza A (H3N2) and B infections, reduced otitis media among vaccinated children by 30%, and reduced otitis media with concomitant antibiotic use by 35% compared with unvaccinated children (51 ). In a follow-up study during the 1997-1998 season, the trivalent LAIV was 86% effective in preventing culture-positive influenza in children, despite a poor match between the vaccine's influenza A (H3N2) component and the predominant circulating influenza A (H3N2) virus (127 ). A study conducted among healthy adults during the same season found a 9%-24% reduction in febrile respiratory illnesses and 13%-28% reduction in lost work days (128 ). No study has directly compared the efficacy or effectiveness of trivalent inactivated vaccine and trivalent LAIV. # Potential Addition of Young Children to Groups Recommended for Vaccination During 1998, the ACIP formed a working group to explore issues related to the potential expansion of recommendations for the use of influenza vaccine. The ACIP influenza working group is considering the impact of influenza in young children as well as the MMWR April 14, 2000 potential safety issues and logistic and economic consequences of recommending routine vaccination of young healthy children. Several studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (35,38,129,130 ). The increased rates of hospitalization are comparable with rates for other high-risk groups. However, the interpretation of these findings has been confounded by cocirculation of respiratory syncytial viruses, which are a major cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (131)(132)(133). Recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children aged <5 years who do not have high-risk conditions (36,37 ). Both studies indicate that otherwise healthy children <2 years of age, and possibly children 2-4 years of age, are at increased risk for influenza-related hospitalization compared with older healthy children. # RECOMMENDATIONS FOR THE USE OF ANTIVIRAL AGENTS FOR INFLUENZA Antiviral drugs for influenza are an important adjunct to influenza vaccine for the control and prevention of influenza. However, they are not a substitute for vaccination. Four currently licensed agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine are chemically related antiviral drugs with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for prophylaxis of influenza A (H2N2) infection and was later approved in 1976 for the treatment and prophylaxis of influenza type A virus infections in adults and children aged ³1 year. Rimantadine was approved in 1993 for treatment and prophylaxis of infection in adults. Although rimantadine was approved only for prophylaxis of infection in children, many experts consider it appropriate for treatment among children. Zanamivir and oseltamivir are neuraminidase inhibitors with activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for the treatment of uncomplicated influenza infections, but neither have yet been approved for prophylaxis. Zanamivir was approved for treatment for persons aged ³12 years, and oseltamivir was approved for treatment for persons aged ³18 years. The four drugs differ in terms of their pharmacokinetics, side effects, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections; however, readers should consult the package inserts for more information. # Role of Laboratory Diagnosis The appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. The early diagnosis of influenza can help reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because some bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated if suspected. In addition, bacterial infections can occur as a complication of influenza. Influenza surveillance information as well as diagnostic testing (e.g., viral culture and rapid tests for influenza) can aid clinical judgment and help guide treatment decisions. Influenza surveillance by state and local health departments and CDC can provide information about the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza. Several commercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (29,134 ). Some of these rapid tests detect only influenza A viruses, whereas other rapid tests detect both influenza A and B viruses but do not distinguish between the two types. Additional commercial diagnostic tests are available for use by laboratories performing tests of high complexity (29 ). Despite the availability of rapid diagnostic tests, the collection of clinical specimens for viral culture is important because only culture isolates can provide specific information on circulating influenza subtypes and strains. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions about influenza treatment and prophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance. # Indications for Use Treatment When administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day (135)(136)(137)(138)(139)(140)(141)(142)(143)(144). More clinical data are available concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (137,145,146 ). However, in vitro data (147)(148)(149)(150)(151)(152) and data from studies of treatment in mice and ferrets (149,150,153,154 ) document that zanamivir and oseltamivir have activity against influenza B viruses. None of the four antiviral agents has been demonstrated to be effective in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is based principally on studies of patients with uncomplicated influenza (155 ). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, and zanamivir for treatment of influenza in persons at high risk for serious complications of influenza (135,137,138,140,(156)(157)(158)(159), and no published data are available concerning the effectiveness of oseltamivir for treatment of influenza in high-risk populations. Studies of the efficacy of any of the four drugs for treatment in children are limited (135,(159)(160)(161). To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days. # Prophylaxis Chemoprophylactic drugs are not a substitute for vaccination, although they are important adjuncts in the prevention and control of influenza. Both amantadine and rimantadine are indicated for the prophylaxis of influenza A infection but are not effective MMWR April 14, 2000 against influenza B. Both drugs are approximately 70%-90% effective in preventing illness from influenza A infection (135,144,159 ). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and the development of protective antibody against circulating influenza viruses. Therefore, some persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (135 ). Both drugs have been studied extensively in nursing home populations as a component of influenza outbreak control programs (135,158,(162)(163)(164). Zanamivir and oseltamivir have not been approved for prophylaxis, but recent community studies suggest that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (165,166 ). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited (167)(168)(169). Use of zanamivir has not been found to impair the immunologic response to influenza vaccine (170,171 ). When determining the timing and duration for administering amantadine or rimantadine for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community (172 ). # Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks (173,174 ). When influenza vaccine is given while influenza A viruses are circulating, chemoprophylaxis with amantadine or rimantadine should be considered for persons at high risk during the time from vaccination until immunity has developed. Children who receive influenza vaccine for the first time can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose). # Persons Who Provide Care to Those at High Risk To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis with amantadine or rimantadine during peak influenza A activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza A that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status. # Persons Who Have Immune Deficiency Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with human immunodeficiency virus (HIV), especially those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered. # Other Persons Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Amantadine or rimantadine also can be administered prophylactically to persons who wish to avoid influenza A illness. Health-care providers and patients should make this decision on an individual basis. # Control of Influenza Outbreaks in Institutions Most published reports on the use of amantadine or rimantadine to control institutional outbreaks of influenza A are based on studies of nursing home populations. When confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice is extremely useful. When institutional outbreaks occur, chemoprophylaxis should be administered to all residents -regardless of whether they received influenza vaccine during the previous fall -and should continue for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not well matched by the vaccine. Chemoprophylaxis has been used successfully to control an influenza A outbreak aboard a large cruise ship (175 ). Chemoprophylaxis also can be considered for controlling influenza A outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). To limit the potential transmission of drug-resistant virus during institutional outbreaks, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis. In addition to using antiviral drugs for treatment and prophylaxis of influenza, other outbreak control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, reoffering influenza vaccine to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (176)(177)(178). (For more information on outbreak control in specific settings, refer to additional references in Additional Information on Influenza Infection Control in Specific Populations.) # Dosage Dosage recommendations vary by age group and medical conditions (Table 2). Oseltamivir is manufactured by Hoffman-LaRoche (Tamiflu® -tablet). * Consult the drug package insert for dosage recommendations for administering amantadine to persons with creatinine clearance £50 mL/min/1.73m 2 . † 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. § Children ³10 years of age who weigh <40 kg should be administered amantadine or rimantadine at a dosage of 5 mg/kg/day. ¶ A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance £10 mL/min. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. NA = Not applicable. † † Elderly nursing home residents should be administered only 100 mg/day of rimantadine. A reduction in dosage to 100 mg/day should be considered for all persons ³65 years of age if they experience possible side effects when taking 200 mg/day. § § Zanamivir is approved for persons ³12 years of age and is administered as two 5-mg inhalations of medicated powder twice a day (i.e., 10 mg twice a day). The medication is administered via inhalation using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of proper use of the device. ¶ ¶ Neither zanamivir nor oseltamivir are approved for prophylaxis. * Oseltamivir is approved for persons ³18 years of age. A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance <30 mL/min. # MMWR 21 # Children Amantadine The use of amantadine among children aged <1 year has not been adequately evaluated. The U.S. Food and Drug Administration-approved dosage for children aged 1-9 years is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies are needed to determine the optimal dosage for children aged 1-9 years, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged ³10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable (179 ). # Rimantadine The use of rimantadine among children aged <1 year has not been adequately evaluated. For children aged 1-9 years, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children aged ³10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is recommended (180 ). # Zanamivir Zanamivir is not approved for use in children aged <12 years. The recommended dosage of zanamivir for treatment of influenza in persons aged ³12 years is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days (170 ). # Oseltamivir Oseltamivir is not approved for use in persons aged <18 years (181 ). # Persons Aged ³65 Years Amantadine The daily dose of amantadine for persons aged ³65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For some elderly persons, the dose should be further reduced. # Rimantadine Among elderly persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance (182 ). However, chronically ill elderly persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentrations two to four times higher than in healthy, younger persons when rimantadine has been administered at a dosage of 200 mg/day (135 ). For elderly nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day for prophylaxis or treatment. For other elderly persons, further studies are needed to determine the optimal dosage. However, a reduction in dosage to 100 mg/day should be considered for all persons aged ³65 years who experience side effects when taking a dosage of 200 mg/day. # MMWR April 14, 2000 # Zanamivir and Oseltamivir No reduction in dosage is recommended on the basis of age alone. # Persons with Impaired Renal Function Amantadine A reduction in dosage is recommended for patients with creatinine clearance £50 mL/ min/1.73m 2 . Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. Because recommended dosages based on creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance (183 ). # Rimantadine A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance £10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (184 ). # Zanamivir Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in halflife, and increased systemic exposure to zanamivir were observed (170,185 ). However, a small number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were much higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (186,187 ). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (170 ). # Oseltamivir Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (146,181 ). A reduction of the dose of oseltamivir to 75 mg once daily is recommended for patients with creatinine clearance <30 mL/min (181 ). No data are available concerning the safety or efficacy of oseltamivir in patients with creatinine clearance <10 mL/min. # Persons with Liver Disease Amantadine No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes in patients receiving amantadine have been reported, although a specific relationship between the drug and such changes has not been established (188 ). # MMWR 23 # Rimantadine A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction. # Zanamivir and Oseltamivir Neither of these medications has been studied in persons with hepatic dysfunction. # Persons with Seizure Disorders Amantadine An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (189 ). Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine. # Rimantadine Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine (190 ). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated. # Zanamivir and Oseltamivir No information is available regarding the use of zanamivir or oseltamivir among persons with a history of seizure disorder. # Route Amantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available as a capsule (179)(180)(181). Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of proper use of this device (170 ). # Pharmacokinetics Amantadine More than 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (162,(191)(192)(193)(194). Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency, and dosages might need to be decreased (see Dosage) (Table 2). # Rimantadine Approximately 75% of rimantadine is metabolized by the liver (159 ). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (159,195 ). In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations in liver function were observed after a single dose (159,195 ). However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (180 ). # MMWR April 14, 2000 Rimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (159,184 ). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy persons of the same age (184 ). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (180,196 ). # Zanamivir In studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (197,198 ). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (170,187 ). # Oseltamivir Approximately 80% of orally administered oseltamivir is absorbed systemically (146 ). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (181,199 ). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (199 ). # Side Effects and Adverse Reactions Amantadine and Rimantadine Both amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (200 ). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced at least one CNS symptom, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (200 ). A study of elderly persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (182). Gastrointestinal side effects (e.g., nausea and anorexia) occur in approximately 1%-3% of persons taking either drug, compared with 1% of persons receiving the placebo (200 ). Side effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and sei-zures) (189 ). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (162 ). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 2). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (179 ). Because rimantadine has been marketed for a shorter period than amantadine, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. When considering amantadine or rimantadine (i.e., choice of antiviral drug, dose, and duration of therapy), clinicians must take into account the patient's age, weight, and renal function (Table 2); the presence of other medical conditions; indications for the use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications. # Zanamivir Preliminary results of a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease indicated that more patients receiving zanamivir than placebo experienced a >20% decline in forced expiratory volume in 1 second (FEV1) or peak expiratory flow rates after treatment (170 ). Moreover, in a phase I study of persons with mild or moderate asthma who did not have influenza-like illness, one of 13 patients experienced bronchospasm following administration of zanamivir (170 ). In addition, during postmarketing surveillance, cases of respiratory function deterioration following inhalation of zanamivir have been reported among patients with underlying asthma or chronic obstructive pulmonary disease (155 ). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of proper monitoring and supportive care, including the availability of short-acting bronchodilators (155 ). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to a) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and b) stop using zanamivir and contact their physician if they develop difficulty breathing (170 ). No clear evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (155 ). In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (136)(137)(138)(139)(140)(141)170,197 ). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections (136,137,139,140,170 ). Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (170 ). # Oseltamivir Nausea and vomiting were reported more frequently among persons receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, ap-MMWR April 14, 2000 proximately 6%; vomiting, approximately 3%) (142,143,181,201 ). However, few persons enrolled in the clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (181 ). Nausea and vomiting might be less severe if oseltamivir is taken with food (181,201 ). # Use During Pregnancy No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (68,202 ). However, both amantadine and rimantadine have been shown in animal studies to be teratogenic and embryotoxic when administered at very high doses (179,180 ). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see package inserts [170,[179][180][181]). # Drug Interactions Careful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (135 ). No clinically significant interactions between rimantadine and other drugs have been identified. Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically important drug interactions have been predicted on the basis of in vitro data and data from studies of rats (170,203 ). Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (181,199 ). No published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, the package inserts should be consulted. # Antiviral Drug-Resistant Strains of Influenza Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa (204 ). Drug-resistant viruses can appear in up to approximately one third of patients when either amantadine or rimantadine is used for therapy (161,205 ). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace sensitive strains within 2-3 days of starting therapy (205,206 ). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (207,208 ); however, the frequency with which resistant viruses are transmitted and their impact on efforts to control influenza are unknown. Amantadine-and rimantadine-resistant viruses are not more virulent or transmissible than sensitive viruses (209 ). The screening of epidemic strains of influenza A has rarely detected amantadine-and rimantadine-resistant viruses (205,210,211 ). Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed sensitive viruses early in the course of treatment and later shed drug-resistant viruses, especially after 5-7 days of therapy (161 ). Such persons can benefit from therapy even when resistant viruses emerge. Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (212)(213)(214)(215)(216)(217)(218)(219), but induction of resistance requires several passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (220,221 ). Whether these in vitro findings indicate that clinical drug resistance will occur less frequently with zanamivir and oseltamivir than with amantadine and rimantadine is unknown. Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (138,181,222,223 ). Currently available diagnostic tests are not optimal for detecting clinical resistance, and better tests as well as more testing are needed before firm conclusions can be reached. Postmarketing surveillance for neuraminidase inhibitorresistant influenza viruses is planned. # SOURCES OF INFORMATION ON INFLUENZA AND ITS SURVEILLANCE Information regarding influenza surveillance is available through the CDC Voice Information System (influenza update), (888) 232-3228; CDC Fax Information Service, (888) 232-3299; or website for the Influenza Branch, DVRD, NCID, CDC at <http://www.cdc.gov/ ncidod/diseases/flu/weekly.htm>. From October through May, the information is updated at least every other week. In addition, periodic updates about influenza are published in the weekly MMWR. State and local health departments should be consulted regarding availability of influenza vaccine, access to vaccination programs, information about state or local influenza activity, and for reporting influenza outbreaks and receiving advice regarding outbreak control. # ADDITIONAL INFORMATION ON INFLUENZA INFECTION CONTROL IN SPECIFIC POPULATIONS Each year, the Advisory Committee on Immunization Practices provides general, annually updated information about the control and prevention of influenza. Other documents on the control and prevention of influenza in specific populations (e.g., immunocompromised persons, health-care workers, hospitals, and travelers) are also available: # • Bolyard EA, Tablan OC, Williams WW, et al., Hospital Infection Control Practices Advisory Committee. Guideline for infection control in health care personnel. Am J Infect Control 1998;26:289-354. • Bradley SF, The Long-Term-Care Committee of the Society for Healthcare Epidemiology of America. Prevention of influenza in long-term care facilities. Infect Control Hosp Epidemiol 1999;20:629-37. • American Academy of Pediatrics. 2000 red book: report of the Committee on Infectious Diseases. 25th edition. Elk Grove Village, IL: American Academy of Pediatrics, 2000 (in press). • CDC. 1999 # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.0 hour in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 MMWR April 14, 2000 # GOAL AND OBJECTIVES This MMWR provides recommendations regarding the prevention and control of influenza. These recommendations were developed by CDC staff members and the Influenza Working Group of the ACIP. The goal of this report is to provide guidance for the use of influenza vaccine and influenza antiviral agents in the United States. Upon completion of this educational activity, the reader should be able to a) describe the disease burden of influenza in the United States; b) describe the characteristics of the currently licensed influenza vaccine; c) list the primary target groups for annual influenza vaccination; and d) recognize the most common adverse reactions following administration of influenza vaccine. To receive continuing education credit, please answer all of the following questions. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	None	None
4f3d3341724acaeb1b16183b4e614a768f2f508c	cdc	None	# INTRODUCTION In late summer 1999, the first domestically acquired human cases of West Nile (WN) encephalitis were documented in the U.S. The discovery of virus-infected, overwintering mosquitoes during the winter of 1999-2000 presaged renewed virus activity for the following spring and precipitated early season vector control and disease surveillance in New York City (NYC) and the surrounding areas. 7,8 These surveillance efforts were focused on identifying and documenting WN virus (WNV) infections in birds, mosquitoes and equines as sentinel animals that could alert health officials to the occurrence of human disease. Surveillance tracked the spread of WNV throughout much of the U.S. between 2000 and 2002. By the end of 2002, WNV activity had been identified in 44 states and the District of Columbia. The 2002 WNV epidemic and epizootic resulted in reports of 4,156 reported human cases of WN disease (including 2,942 meningoencephalitis cases and 284 deaths), 16,741 dead birds, 6,604 infected mosquito pools, and 14,571 equine cases. The 2002 WNV epidemic was the largest recognized arboviral meningoencephalitis epidemic in the Western Hemisphere and the largest WN meningoencephalitis epidemic ever recorded. Significant human disease activity was recorded in Canada for the first time, and WNV activity was also documented in the Caribbean basin and Mexico. In 2002, 4 novel routes of WNV transmission to humans were documented for the first time: 1) blood transfusion, 2) organ transplantation, 3) transplacental transfer, and 4) breast-feeding. WNV is a member of the family Flaviviridae (genus Flavivirus). Serologically, it is a member of the Japanese encephalitis virus antigenic complex, which includes St. Louis, Japanese, Kunjin, and Murray Valley encephalitis viruses. 9,10 WNV was first isolated in the WN province of Uganda in 1937. 11,12 Human and equine outbreaks have been recorded in portions of Africa, southern Europe, North America, and Asia. 13,14 Although it is still not known when or how WNV was introduced into North America, international travel of infected persons to New York, importation of infected birds or mosquitoes, or migration of infected birds are all possibilities. In humans, WNV infection usually produces either asymptomatic infection or mild febrile disease, sometimes accompanied by rash, but it can cause severe and even fatal diseases in a small percentage of patients. The human casefatality rate in the U.S. has been 7% overall, and among patients with neuroinvasive WNV disease, 10%. Unlike WNV within its historical geographic range, or St. Louis encephalitis (SLE) virus in the Western Hemisphere, mortality in a wide variety of bird species has been a hallmark of WNV activity in the U.S. The reasons for this are not known; however, public health officials have been able to use bird mortality (particularly birds from the family Corvidae) to effectively track the movement of WNV. WNV has now been shown to affect 162 species of birds. Previous early-season field studies have determined that areas with bird mortality due to WNV infection were experiencing ongoing enzootic transmission. However, most birds survive WNV infection as indicated by the high seroprevalence in numerous species of resident birds within the regions of most intensive virus transmission. The contribution of migrating birds to natural transmission cycles and dispersal of both WN and SLE viruses is poorly understood. 5 WNV has been transmitted principally by Culex species mosquitoes, the usual vectors of SLE virus. Thirty-six species of mosquitoes have been shown to be infected with WNV. This wide variety of WNV-infected mosquito species has widened this virus' host-range in the U.S.: 27 mammalian species have been shown to be susceptible to WNV infection and disease has been reported in of these (including humans and horses). It must be remembered, however, that the detection of WNV in a mosquito species is necessary but not sufficient to implicate that species as a competent vector of WNV. Since 1999, the Centers for Disease Control and Prevention (CDC) and a variety of other U.S. governmental agencies and partners have sponsored yearly national meetings of arbovirologists, epidemiologists, laboratorians, ecologists, vector-control specialists, wildlife biologists, communication experts, and state and local health and agriculture officials to assess the implications of the WNV introduction into the U.S. and to refine the comprehensive national response plan. Recommendations from these meetings have been used to develop and to update these guidelines. 15,16 This document is available electronically from the CDC Web site at: . To assist guideline implementation in 2000, CDC developed an electronic-based surveillance and reporting system (ArboNet) to track WNV activity in humans, horses, other mammals, birds and mosquitoes. In 2003, the ArboNet surveillance system has been updated to streamline reporting to CDC of WNV activity by the state public health departments. Today=s rapid transport of people, animals, and commodities increase the likelihood that other introductions of exotic pathogens will occur. CDC continues to implement its plan titled APreventing Emerging Infectious Diseases, a Plan for the 21 st Century". 17 # I. SURVEILLANCE A universally applicable arbovirus surveillance system does not exist. In any given jurisdiction, surveillance systems should be tailored according to the probability of arbovirus activity and available resources. In jurisdictions without pre-existing vector-borne disease surveillance and control programs, newly developed avian-based and/or mosquito-based arbovirus surveillance systems will be required. In some, resurrection of previously abandoned systems will be necessary. In others, modification and/or strengthening of existing arbovirus surveillance systems (i.e., those intended to monitor eastern equine encephalitis , western equine encephalitis , and/or St. Louis encephalitis virus activity) will be the most appropriate response. In yet other jurisdictions in which the probability of arbovirus activity is very low and/or resources to support avian-based and/or mosquito-based surveillance are unavailable, laboratory-based surveillance for neurologic disease in humans and equines should be employed at minimum. Seasonality of surveillance activities may vary depending upon geographic region. With the anticipated spread of West Nile virus (WNV) to all of the 48 contiguous United States in 2003, all states should initiate surveillance after mosquitoes become active in the spring. Appropriate and timely response to surveillance data is the key to preventing human and animal disease associated with WNV and other arboviruses. That response must include effective mosquito control and public education without delay, if an increasing intensity of virus activity is detected by bird-or mosquito-based surveillance systems (see Section III.M). For basic information on arbovirus surveillance, see CDC Guidelines for Arbovirus Surveillance Programs in the United States, 18 this document can be obtained from CDC's Division of Vector-Borne Infectious Diseases, Fort Collins, Colorado, and is also available from the CDC Web site at: . # A. Ecologic Surveillance Detection of WNV in bird and mosquito populations helps health officials predict and prevent human and domestic animal infections. Surveillance to detect WNV should focus on the avian and mosquito components of the enzootic transmission cycle. Nonhuman mammals, particularly equines, may also serve as effective sentinels because a high intensity of mosquito exposure makes them more likely to be infected than people. Descriptions of the avian-, mosquito-, and non human mammal-based surveillance strategies follow. # Avian a) Avian morbidity/mortality surveillance Avian morbidity/mortality surveillance appears to be the most sensitive early detection system for WNV activity, and should be a component of every state's arbovirus surveillance program. Its utility for monitoring ongoing transmission in a standardized fashion is currently being investigated, but should include at least two basic elements: the timely reporting and analysis of dead bird sightings and the submission of selected individual birds for WNV testing. GOAL OF AVIAN MORBIDITY/MORTALITY SURVEILLANCE: Utilize bird mortality associated with WNV infection as a means of detecting WNV activity in a location. # 1) Protocols and specimens The level of effort involved in this surveillance activity will depend on a risk assessment in each jurisdiction. Generally, avian surveillance should be initiated when local adult mosquito activity begins in the spring. A database should be established to record and analyze dead bird sightings with the following suggested data: caller identification and call-back number, date observed, location geocoded to the highest feasible resolution, species, and condition. Samples from birds in good condition (unscavenged and without obvious decomposition or maggot infestation) may be submitted for laboratory testing. As with all dead animals, carcasses should be handled carefully, avoiding direct contact with skin. For greatest sensitivity, a variety of bird species should be tested, but corvids should be emphasized. 19 The number of bird specimens tested will be dependent upon resources and whether WNV-infected birds have been found in the area; triage of specimens may be necessary on the basis of sensitive species (such as corvids) and geographic location. Many jurisdictions may limit (or even stop) avian mortality surveillance once WNV is confirmed in their region. It is suggested that avian mortality surveillance be continued in each region as long as it remains necessary to know whether local transmission persists, because dead-bird-based surveillance is the most sensitive method for detection of WNV activity in most regions. A single organ specimen from each bird is sufficient to detect WNV or viral RNA. Kidneys, brains, or hearts are preferable. Oral swabs from corvids have been validated as a sensitive alternative to organ samples, and because fewer resources are necessary to acquire them, oral swabs are the preferred specimen from corvid carcasses. 23 Testing involves isolation of infectious virus, specific RNA detection by reverse transcription-polymerase chain reaction (RT-PCR), 24 or antigen detection, 25,26 and will generally be positive within 1-2 weeks after specimen submission. # 2) Recent experience Analysis of recent avian morbidity and mortality data indicated that (a) The American crow was the most sensitive species for avian morbidity/ mortality surveillance in northern regions. However, some areas did not have WNV-positive American crows, but only WNV-positive birds of other species. In southern regions, blue jays have been more sensitive than crows. (b) Almost all of the positive birds were found singly and not as part of a mass die-off at a single time and place. (c) Approximately one-third of the WNV-positive birds had signs of trauma on necropsy. (d) Many WNV-positive birds did not have pathology indicative of WNV infection on necropsy. No lesions are pathognomonic for WNV infection. (e) WNV-positive dead birds usually provided the earliest indication of viral activity in an area. In 2002, the detection of WNV-infected dead birds was the first positive surveillance event in 1,534 (61%) of 2,531 counties reporting WNV activity. (f) The detection of WNV-positive dead birds preceded reports of human cases (although knowledge of the test result did not necessarily predate the onset of human cases). In 2002, 527 (89%) of 589 counties reporting human WN meningoencephalitis cases first detected WNV transmission in animals. In 327 (72%) of these 527 counties, detection of WNVinfected dead birds was the first positive surveillance event, preceding human illness onset by a median of 38.5 days (range, 2-252 days). (g) Many counties with human cases of WNV infection tended to have high dead bird surveillance indices, both WNV-positive and sightings. Notable exceptions included sparsely populated counties, particularly those in the midwestern states. 27,28 (h) Experimental evidence of direct transmission among corvids and gulls exists, but whether this occurs in nature is unknown. 29 If it does, then in some settings, virus-infected mosquitoes might not be necessary to maintain enzootic transmission cycles. 3) Advantages of avian morbidity/mortality surveillance include the following: (a) Certain species of birds, in particular corvids (e.g., crows and jays) experience high clinical attack rates. (b) The size and coloration of certain dead birds makes them conspicuous (e.g., crows). (c) RT-PCR and antigen-detection assays can be used to rapidly detect WN viral RNA and protein, respectively, in tissues, even if the tissue is partly decomposed. Both assays have now been adapted for field applications. (d) Due to public involvement in reporting dead bird sightings, dead wild birds are readily available over a much wider region than can be sampled by other surveillance methods. (e) Detection of WNV in dead birds likely signifies local transmission. 30 (f) This type of surveillance provides a temporally and spatially sensitive method for the detection of WNV activity. (g) It can be used for early detection and possibly also for ongoing monitoring of WNV transmission. (h) It may be used to estimate risk of human infection with WNV . 27,31,32 4) Disadvantages of avian morbidity/mortality surveillance include the following: (a) Dead bird surveillance data from different jurisdictions are difficult to compare. (b) Birds are highly mobile and often have extensive home ranges, so that the site of death may be distant from the site of infection (especially after the breeding season, when birds are generally less territorial). (c) Collection, handling, shipping, and processing of birds or their clinical specimens is cumbersome. (d) Systems for handling, processing, and testing have at times been overwhelmed by high public response and public expectations. (e) The long-term usefulness of this system is uncertain because natural selection for disease-resistant birds may occur, populations of susceptible species may become very low, or the virus may evolve, resulting in low or no avian mortality. In areas where WNV annually recurs, intense environmental sampling might not be as useful. (f) Success is influenced by public participation, which is highly variable, and depends on the number of public outreach programs, level of public concern, etc. (g) The system may be less sensitive in rural areas, where there are fewer persons to observe dead birds over a wider geographic area. In the western U.S., low observer density is coupled with the presence of a vector (Culex tarsalis) that is less ornithophilic, resulting in fewer reports of dead birds relative to other non-avian surveillance indicators. # b) Live bird surveillance Live-bird surveillance has been used traditionally both to detect and monitor arbovirus transmission (e.g., for SLE, EEE and WEE viruses). Two approaches are captive sentinel surveillance (typically using chickens, but other species have been used as well), and free-ranging bird surveillance. 33 Both depend on serological testing, which generally requires at least 3 weeks to detect and confirm an infection. Successful application of these approaches requires extensive knowledge of local transmission dynamics. It is recommended that further research be done before relying on sentinel birds as a primary means of WNV surveillance. Use of sentinel birds may require institutional animal use and care protocols, and other authorization permits. GOAL OF LIVE-BIRD SURVEILLANCE: Utilize seroconversions in captive or free-ranging bird species as indicators of local WNV activity. # 1) Captive sentinel surveillance Although an ideal captive avian sentinel for WNV --or any other arbovirus -may not exist, such a species would meet the following criteria: 1) is universally susceptible to infection, 2) has a 100% survival rate from infection and universally develops easily detectable antibodies, 3) poses no risk of infection to handlers, and 4) never develops viremia sufficient to infect vector mosquitoes. 18 Captive sentinels have been effectively used to monitor transmission of arboviruses in a standardized fashion, including SLE virus in California and Florida, especially in historical enzootic transmission foci. Captive sentinel flocks should be placed in likely transmission foci (e.g., near vector breeding sites or adult mosquito congregation sites), and presented appropriately to allow feeding by enzootic WNV vectors. Alternatively, pre-existing captive birds (e.g., domestic poultry or pigeons, or zoo birds) may be used as sentinels. (a) Protocols and specimens Whole blood can be collected and centrifuged for serum. Serum is screened by either hemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA) or plaque-reduction neutralization test (PRNT). 34 It is important to note that the extraction of avian serum samples to remove non specific inhibitors of hemagglutination for use in the HI test follows procedures different from those used in tests of human serum samples. 35 Positive tests must be confirmed by neutralization to rule out false positives and cross-reactions due to infection with related flaviviruses (e.g., SLE virus). testing of experimentally infected chickens points to the need for biweekly sampling of sentinels. 36 (iii) Experimental studies have shown that chickens, pigeons, and pheasants (CDC, unpublished data) are candidate sentinels due to their susceptibility to infection, low mortality, and relative incompetence as amplifying hosts. However, small amounts of WNV were detected in cloacal swabs from infected chickens and pigeons. 29,37 (iv) Field studies of avian seroprevalence in Queens in 1999 indicated that captive chickens frequently were infected. 38 In Staten Island in 2000, captive pigeons frequently were infected. 39 (v) Some mortality in chickens was attributed to WNV at various locations in New York State. 40 (c) Advantages of sentinel captive bird surveillance include the following: (i) Chickens have been successfully used in flavivirus surveillance for over 6 decades. (ii) Birds are readily fed upon by Culex mosquitoes. (iii) Captive birds can be serially bled, making the geographic location of infection definite. (iv) The system is flexible and therefore can be expanded and contracted as appropriate. (v) Mosquito-abatement districts can maintain and bleed flocks and submit specimens for testing. (vi) Collection of specimens is inexpensive compared with the costs of free-ranging bird surveillance. (d) Disadvantages of captive sentinel surveillance include the following: (i) Sentinel flocks detect only focal transmission, requiring multiple flocks be positioned in representative geographic areas. This is particularly true when vector mosquitoes have short flight ranges (e.g., Culex pipiens). (ii) Flocks are subject to vandalism and theft. (iii) Flocks must be protected from predators. (iv) Flock set-up and maintenance (i.e., birds, cages, feed, transportation) are expensive. Training is required for proper maintenance and sampling. (v) Pre-existing flocks may already have been exposed due to previous local WNV transmission. # 2) Free-ranging bird surveillance Free-ranging birds provide the opportunity for sampling important reservoir host species and may be used both for early detection and for monitoring virus activity. This type of surveillance has been used effectively for SLE, EEE and WEE virus surveillance in several states. In each geographic area, the optimal free-ranging bird species to be monitored should be determined by serosurveys. The best species for serologic surveillance are those in which infection is rarely, if ever, fatal, and population replacement rates are high, ensuring a high proportion of uninfected individuals. (a) Protocols and specimens The use of free-ranging birds requires differentiation of recent infection from infections acquired in previous years. For most species, assays for detection of IgM antibody will not be available and other tests such as IgG (IgY)-detection ELISAs 41,42 and the PRNT 34 must be used to detect WNV-specific antibody. Antibody-positive birds less than 1 year old may be presumed to have been infected recently (during current transmission season). Weak seropositivity in very young birds (less than 1 month old) may be due to maternal transfer of antibody. Seroconversion in older birds is also evidence of recent transmission, but requires frequent recapture for acquisition of multiple specimens from uniquely banded individuals during the course of the transmission season. WNV seropositivity among afterhatch-year birds, when determined from a single serum specimen, should not be interpreted or reported as evidence of recent infection. State and federal permits are required for capture and banding of federally-protected migratory birds. (b) Recent experience (i) In urban epizootic transmission foci in NYC, several common species (i.e., house sparrows, cardinals, catbirds, mourning doves, rock doves) developed high seroprevalence, making them strong candidate sentinels, although other species may be important in other locations. 38,39 (ii) A comparison of free-ranging bird surveillance in NYC in 2001 found that much greater effort was required for this surveillance system compared with other surveillance systems (Green Street Scientific, LLC, unpublished data). Similar observations have been made in Indiana, Louisiana, New Jersey, Ohio, and Texas. (c) Advantages of free-ranging bird surveillance include the following: (i) It has a long history of successful use in flavivirus surveillance. (ii) Local movement of resident wild birds may increase contact with enzootic transmission foci, thus increasing sensitivity (relative to captive sentinels). (iii) Set-up or maintenance costs may be minimal. (iv) Its sampling capability is highly flexible. (v) It permits evaluation of herd immunity among important amplifying hosts. (vi) Owner confidentiality may be less of an issue. (d) Disadvantages of free-ranging bird surveillance include the following: (i) Interpretation of serologic results is complex. (ii) Handling and venipuncture of birds increases the risk of exposure to pathogens in blood and feces. (iii) Movement of free-ranging wild birds makes it impossible to know where an infection was acquired. (iv) Most birds are protected by federal law, and their collection and sampling requires state and federal permits. Banding permits require complex data reporting. (v) Training is required for live-trapping, blood-sampling, handling, and accurate determination of the species and age of wild birds. (vi) It is generally not feasible to serially bleed individual free-ranging birds because of low recapture rates (although banding can be useful). # Equine Equines appear to be important sentinels of WNV epizootic activity and human risk, at least in some geographic regions. 2) In general, equine WNV disease cases have been scattered. Few case clusters have been documented. 3) In fatal equine WNV disease cases, pathological findings have been nonspecific. Pathognomonic lesions have not been described. A licensed equine WNV vaccine has been available in the U.S. since 2001. No studies of efficacy have been published. c) Advantages of equine disease surveillance include the following: 1) Equines are highly conspicuous, numerous, and widely distributed in some areas. They may be particularly useful sentinels in rural areas, where dead birds may be less likely to be detected. 2) Some equines are routinely bled and tested for other pathogens. 3) Ill equines have been one of the earliest, if not the earliest, sentinels of WNV activity in some geographic areas. d) Disadvantages of equine disease surveillance include the following: 1) In some geographic areas, equines may not be an early sentinel (i.e., human WNV disease cases may occur simultaneously with or soon after equine cases). 2) Necropsies are expensive and logistically difficult. 3) Equines are not present or abundant in many areas of the U.S. (e.g., densely populated metropolitan areas), and proximity of equines to human populations varies. 4) Widespread use of equine WNV vaccines may decrease the incidence of equine WNV disease and therefore the usefulness of equines as sentinels. Because the costs of clinical equine specimen collection and testing are usually borne directly by the owner, economic factors work against the submission and testing of equine specimens for arboviral infections. e) Minimal components of an equine surveillance program 1) All equine neurologic disease cases should be promptly reported; the equines should be tested for infection with WNV and other arboviruses as geographically appropriate, and for rabies. 2) Clusters of equine neurologic disease cases should be promptly investigated. # Mosquito While dead-bird-based surveillance has proven to be the most sensitive method of detecting WNV presence in an area, mosquito-based surveillance remains the primary tool for quantifying the intensity of virus transmission in an area, and should be a mainstay in most surveillance programs for WNV and other arboviruses. # GOALS OF MOSQUITO-BASED SURVEILLANCE: To 1) use data on mosquito populations and virus infection rates to assess the threat of human disease; 2) identify geographic areas of high risk; 3) assess the need for and timing of interventions; 4) identify larval habitats for targeted control; 5) monitor the effectiveness of this type of surveillance and improve prevention and control measures; and 6) develop a better understanding of transmission cycles and potential vector species. a) Protocols and specimens 1) Adult mosquitoes are collected using a variety of trapping techniques and are used to identify the mosquito species and primary vector species present in an area and the relative density of those species. When coupled with virus detection protocols, mosquito collections can be screened for the presence of virus and provide a quantifiable index of WNV activity. Adequate sampling requires trapping regularly at representative sites throughout a community, and rapid testing of collections of sufficient size to detect low infection rates in the vector population. Minimally, adult mosquito density (number collected per trap night) and infection rate (number of individual mosquitoes estimated containing WNV per 1,000 specimens tested) should be recorded for each area to provide a basis for tracking mosquito density and virus incidence. 2) Larval mosquitoes are collected by taking dip samples from a variety of habitats to identify species present in the area and to identify mosquito sources. Thorough mapping of larval habitats will facilitate larval control or source reduction activities. In addition, where larval management is not feasible, quantitative estimates of larval densities will permit anticipation of new adult emergences. Minimally, the number of larvae collected per dip and location where collected should be recorded to provide a basis for tracking larval production and association of larval density with resulting adult mosquito population density. b) Recent experience 1) If mosquito trapping effort is intensive, detection of WNV in mosquitoes might precede detection of virus activity by other surveillance tools. If mosquito trapping effort is inadequate, WNV-positive mosquitoes may not be detected prior to the identification of a virus in dead bird, sentinel animal, or human WNV disease cases. 2) Moderate to high infection rates sustained for several weeks in Cx. pipiens or Cx. quinquefasciatus have been associated with subsequent human outbreaks. Sustained high infection rates early in the year are associated with a higher risk for subsequent outbreaks. 3) Several intense, focal outbreaks during 2002 were associated with relatively low vector densities, but with high infection rates in key vector species (i.e., infection rates in Cx. pipiens or Cx. quinquefasciatus of approximately 10 per 1,000 or greater). 1) It may provide the earliest evidence of transmission in an area. 2) It helps establish information on potential mosquito vector species. 3) It provides an estimate of vector species abundance. 4) It gives quantifiable information on virus infection rates in different mosquito species. 5) It provides quantifiable information on potential risk to humans and animals. 6) It provides baseline data that can be used to guide emergency control operations. 7) It allows evaluation of control methods. d) Disadvantages of mosquito-based surveillance include the following: 1) It is labor-intensive and expensive. 2) Substantial expertise is required for collecting, handling, sorting, species identification, processing, and testing. 3 (iii) Proximity to human population centers and/or recreational areas; and (iv) Flight range of vector species in the area. 2) Laboratory support to identify the mosquitoes' species, and to test the specimens for the presence of WNV. Determine infection rates by species. (a) Make arrangements with a lab for testing. Rapid turnaround is essential. (b) Focus initially on Culex mosquitoes to provide first indication of WNV presence. (c) Once virus is detected in Culex mosquitoes, pool and test all potential vector species with emphasis on incriminated or suspected species. (3) Data management and analysis capabilities to allow tracking of adult mosquito densities and infection rates over time and space. Patterns of virus activity are more likely to be useful than predetermined threshold levels. (4) Development of a plan with descriptions of actions that will be taken in response to indicators of WNV activity. # B. Surveillance for Human Cases Because the primary public health objective of surveillance systems for neurotropic arboviruses is prevention of human infections and disease, human case surveillance alone should not be used for the detection of arbovirus activity, except in jurisdictions where arbovirus activity is rare, or resources to support avian-based and/or mosquitobased arbovirus surveillance are unavailable. e) Using CDC-recommended test methods in public health laboratories, WNVspecific IgM antibody was detected in acute-phase (i.e., those collected 8 or less days after illness onset) serum or CSF specimens, or both, in the large majority of confirmed cases. In contrast, only a small minority of suspected cases were subsequently confirmed in which specific IgM antibody reactivity in acute-phase serum or CSF was in the equivocal or low-positive range. # GOALS OF SURVEILLANCE FOR HUMAN CASES f) Longitudinal studies of WNME cases have shown that WNV-specific IgM antibody can persist in serum for 12 months or longer. 43 Thus, the presence of WNV-specific IgM antibody in a single serum sample is not necessarily diagnostic of acute WN viral infection. For this reason, especially in areas where WNV is known to have circulated previously, suspected, acute WN viral disease cases should be confirmed by observing a fourfold or more change in titer of WNV-specific antibody in serum and the presence of WNV-specific IgM antibody in CSF, when available. i) For suspected WNV disease cases in immunocompromised patients, WNVspecific antibody may not be present. Since longer viremias may be observed in these patients, testing serum and CSF samples for the presence of virus or viral RNA may be useful. # Types of Surveillance a) Clinical syndromes to monitor Monitoring of encephalitis cases is the highest priority. Monitoring milder illnesses (e.g., aseptic meningitis, Guillain-Barré syndrome, acute flaccid paralysis, and brachial plexopathy, and fever or rash illnesses) is resourcedependent and should be of lower priority. # b) Types of human surveillance 1) Enhanced passive surveillance In the absence of known WNV activity in an area, enhanced passive surveillance- for hospitalized cases of encephalitis (and milder clinical syndromes as resources allow), and for patients who have IgM antibodies to either WN or SLE virus in tests conducted in diagnostic or reference laboratories, should be employed. A high clinical suspicion for arboviral encephalitis should be encouraged among health care providers. When the diagnosis is in doubt, appropriate clinical specimens should be submitted to CDC or another laboratory capable of performing reliable serologic testing for antibodies to domestic arboviruses. Testing of CSF and paired acute-and convalescent-phase serum samples should be strongly encouraged to maximize the accuracy of serologic results. # 2) Active surveillance Active surveillance should be strongly considered in areas with known WNV activity. In general, one or both of the following approaches should be taken: (a) Contact physicians in appropriate specialties (i.e., infectious diseases, neurology, and critical care) and hospital infection control personnel on a regular basis to inquire about patients with potential arboviral infections; (b) Implement laboratory-based surveillance to identify CSF specimens - Passive surveillance enhanced by general alerts to key health care personnel such as primary care providers, infectious disease physicians, neurologists, hospital infection control personnel, and diagnostic laboratories. While human infections with neurotropic arboviruses are usually clinically inapparent, most clinically apparent infections are associated with fever, with or without neurologic manifestations, which can range from mild aseptic meningitis to fulminant and fatal encephalitis. Signs and symptoms may include fever, headache, stiff neck, confusion or other mental status changes, nausea, vomiting, meningismus, cranial nerve abnormalities, paresis or paralysis, sensory deficits, altered reflexes, abnormal movements, convulsions, and coma of varying severity. Arboviral meningitis or encephalitis cannot reliably be clinically distinguished from other central nervous system infections. meeting sensitive but nonspecific criteria for arboviral infections (e.g., mild to moderate pleocytosis and negative tests for the presence of nonarboviral agents such as bacteria, fungi, herpesviruses, and enteroviruses) and test them for evidence of WNV infection. # 3) Special surveillance projects Special projects may be used to enhance arboviral disease surveillance. Such projects include the Emerging Infections Network of the Infectious Diseases Society of America (IDSA EIN), Emergency Department Sentinel Network for Emerging Infections (EMERGEncy ID NET), Unexplained Deaths and Critical Illnesses Surveillance of the Emerging Infections Programs (EIP), and the Global Emerging Infections Sentinel Network of the International Society of Travel Medicine (GeoSentinel). In some areas, syndromic surveillance systems may be considered. "Piggy-backing" surveillance for WNME and milder clinical forms of WN viral infection, such as fever with rash or lymphadenopathy, onto existing syndromic surveillance systems, especially those involving large health maintenance organizations, may be considered. Real-time computerized syndromic surveillance in emergency departments, and special surveillance projects to identify WNV disease in pediatric populations, may be useful. # Specimens a) Cerebrospinal fluid (CSF) In WNME cases, WNV-specific IgM antibody commonly can be found in CSF on the day of illness onset using antibody-capture ELISA. Virus also may be isolated (rarely) or detected by RT-PCR (in up to 60% of cases) in acute-phase CSF samples. # b) Serum Paired acute-phase (collected 0-8 days after onset of illness) and convalescentphase (collected 14-21 days after the acute specimen) serum specimens are useful for demonstration of seroconversion to WNV and other arboviruses by ELISA or neutralization tests. Although tests of a single acute-phase serum specimen may provide evidence of a recent WNV infection, a negative acutephase specimen is inadequate for ruling out such an infection, underscoring the importance of collecting paired samples. As mentioned previously, antibody synthesis in immunocompromised individuals might be delayed or absent altogether. # c) Tissues When arboviral encephalitis is suspected in a patient who undergoes a brain biopsy or who dies, tissues (especially brain samples, including samples of cortex, midbrain, and brainstem), heart/venous blood, and buffy coat samples should be submitted to CDC or other specialized laboratories for arbovirus and other testing. Tissue specimens should be divided; half should be frozen at -70°C and the other half fixed in formalin. Available studies include gross pathology, histopathology, RT-PCR tests, virus isolation, and immunohistochemistry. # Surveillance Case Definition The national case definition for arboviral encephalitis (available at www.cdc.gov/epo/dphsi/casedef/encephalitiscurrent.htm) should be used to classify cases as confirmed or probable, once appropriate laboratory results are available (also see Section II). In CDC publications of national arbovirus surveillance data, no distinction is usually made between confirmed and probable human cases for the purposes of case counting. # Minimal Components of a Human Surveillance System Enhanced passive surveillance for hospitalized encephalitis cases of unknown etiology, and for patients who have IgM antibodies to either WN or SLE virus in tests conducted in diagnostic or reference laboratories. # C. Geography and Timing In general, the WNV transmission season in the U.S. is longer than that for other domestic arboviruses and requires longer periods of ecologic and human surveillance. # Northeastern and Midwestern U.S. In the northeastern states in 2001-2002, human illness onset occurred as early as early July and as late as mid-November. During these same years, avian cases occurred as early as the first week of April and as late as the second week of December. Active ecological surveillance and enhanced passive surveillance for human cases should begin in early spring and continue through the fall until mosquito activity ceases because of cold weather. Surveillance in urban and suburban areas should be emphasized. # Southern U.S. In 2001-2002, WNV circulated throughout the year, especially in the Gulf states. Although, in 2001-2002, human illness onset was reported as early as mid-May and June and as late as mid-December, equine and avian infections were reported in all months of the year. Active ecologic surveillance and enhanced passive surveillance for human cases should be conducted year round in these areas. # Western U.S. In 2002, WNV activity was first reported among humans and animals in Rocky Mountain states and among animals in Pacific coast states. These events occurred relatively late in the year (mid-August). Predicting the temporal characteristics of future WNV transmission seasons based on these limited reports is not possible. Despite this limitation, active ecological surveillance and enhanced passive surveillance for human cases beginning in early spring and continuing through the fall until mosquito activity ceases because of cold weather should be encouraged. # Other Areas of the Western Hemisphere In 2002, Canada experienced a WNV epidemic in Ontario and Quebec provinces and an equine/avian epizootic that extended from the maritime provinces to Saskatchewan. Recent serologic evidence supports the conclusion that WNV has now reached Central America. Further spread to South America by migratory birds seems inevitable, if this has not already occurred. Development of surveillance systems capable of detecting WNV activity should be encouraged in the Caribbean and Central and South America. WNV surveillance should be integrated with dengue surveillance in these areas, and with yellow fever surveillance in areas where urban or peri-urban transmission of this virus occurs. # II. LABORATORY DIAGNOSIS The clinical presentation of most patients with viral encephalitis is similar regardless of the cause. Also, infection by many of the arboviruses that cause encephalitis, including West Nile and St. Louis encephalitis viruses, usually is clinically inapparent, or causes a nonspecific viral syndrome in most patients. Definitive diagnosis, therefore, can only be made by laboratory testing using specific reagents. To be successful, active surveillance must have adequate laboratory support. The basic laboratory diagnostic tests-and how they should be used at the national, state, and local level-are outlined below. The initial designation of reference and regional laboratories that can do all testing will be based on the availability of biosafety level 3 (BSL3) containment facilities. Details of the surveillance case definition for human West Nile virus (WNV) disease and of how the laboratory diagnostic tests are used to support surveillance are presented in Appendix B. A. Biocontainment # Laboratory Safety Issues Laboratory-associated infections with WNV have been reported in the literature. The Subcommittee on Arbovirus Laboratory Safety (SALS) in 1980, reported 15 human infections from laboratory accidents. One of these infections was attributed to aerosol exposure. Recently, two parenteral inoculations have been reported during work with animals. a) WNV may be present in blood, serum, tissues and CSF of infected humans, birds, mammals and reptiles. The virus has been found in the oral fluids and feces of birds. Parenteral inoculation with contaminated materials poses the greatest hazard; contact exposure of broken skin is a possible risk. Sharps precautions should be strictly adhered to when handling potentially infectious materials. Workers performing necropsies on infected animals may be at high risk of infection. f) Virus neutralization assays also may be used to differentiate viruses, by using fourfold or greater titer differences as the diagnostic criterion in paired specimens (acute-and convalescent-phase). # Virus Detection in Tissues a) Antigenic analysis 1) Immunohistochemistry (IHC) using virus-specific MAbs on brain tissue has been very useful in identifying both human and avian cases of WNV infection. In suspected fatal cases, IHC should be performed on formalinfixed autopsy, biopsy, and necropsy material, ideally collected from multiple anatomic regions of the brain, including the brainstem, midbrain, and cortex. 24,49 2) Well-characterized antigen-capture ELISAs are now available for detection of SLE 50,51 and WNV antigen in mosquito pools and avian tissues. 25 b) Nucleic acid analysis A number of nucleic acid detection methods have recently been employed for WNV diagnostic and surveillance purposes. An independent antigen or nucleic acid test is required to confirm detection of WNV nucleic acid with any of these methods. 1) RT-PCR of tissues, mosquito pools, and CSF has proven to be a useful surveillance tool. RT-nested PCR has detected WNV nucleic acid in equine brain and spinal cord tissues. Standardized protocols developed by reference laboratories should be disseminated, and primer design information should be included so that other laboratories can prepare primers. A proficiency testing program should be developed by the reference laboratories so that these tests can be CLIA-certified in local laboratories. 2) Fluorogenic 5' nuclease techniques (real-time PCR) and nucleic acid sequence-based amplification (NASBA) methods have been developed and have undergone initial validation in specific diagnostic applications. 24, # D. Training and Infrastructure # State and Local Arbovirus Laboratories Greater numbers of capable state and local laboratories performing screening assays (such as ELISA) should be developed to reduce time demands on reference laboratories. Reference laboratories should be utilized to confirm results of state and local laboratories, particularly for the initial identification of WNV in new locations and in new hosts. # Training Programs Laboratory training programs have been developed and implemented at the federal level. Additional regional training programs may be beneficial. # III. PREVENTION AND CONTROL Prevention and control of arboviral diseases is accomplished most effectively through a comprehensive, integrated mosquito management program using sound integrated pest management (IPM) principles. 55 IPM is based on an understanding of the underlying biology of the transmission system, and utilizes regular monitoring to determine if and when interventions are needed to keep pest numbers below levels at which intolerable levels of damage, annoyance, or disease occur. IPM-based systems employ a variety of physical, mechanical, cultural, biological and educational measures, singly or in appropriate combination, to attain the desired pest population control. Programs consistent with best practices and community needs should be established at the local level and, at a minimum, should be capable of performing surveillance sensitive enough to detect West Nile Virus (WNV) enzootic/epizootic transmission that has been associated with increased risk of disease in humans or domestic animals. Integrated mosquito management programs designed to minimize risk of WNV transmission and prevent infections of humans and domestic animals should optimally include the following components (modified from information provided by the American Mosquito Control Association, the New Jersey Mosquito Control Association, and the Florida Coordinating Council on Mosquito Control) A. Surveillance Effective mosquito control begins with a sustained, consistent surveillance program that targets pest and vector species, identifies and maps their immature habitats by season, and documents the need for control. Records should be kept on the species composition of mosquito populations prior to enacting control of any kind and to allow programs to determine the effectiveness of control operations. All components of the integrated management program must be monitored for efficacy using best practices and standard indices of effectiveness. The following is a list of surveillance methodologies used by mosquito control agencies. # Larval Mosquito Surveillance Larval surveillance involves sampling a wide range of aquatic habitats for the presence of pest and vector species during their developmental stages. Most established programs have a team of trained inspectors to collect larval specimens on a regular basis from known larval habitats, and to perform systematic surveillance for new sources. A mosquito identification specialist normally identifies the larvae's species. Properly trained mosquito identification specialists can separate nuisance and vector mosquito species. Responsible control programs target vector and nuisance populations for control and avoid managing habitats that support benign species. # Adult Mosquito Surveillance Adult mosquito surveillance is used to monitor species presence and relative abundance of adult mosquitoes in an area. Information derived from adult mosquito surveillance programs using standardized and consistent surveillance efforts provide information essential to monitoring potential vector activity, setting action thresholds, and evaluating control efforts. Various methods are available for this purpose and have been demonstrated to be effective in collecting a variety of mosquito species. 59 The New Jersey light trap, CDC's miniature light trap, and other modifications of this design, with or without carbon dioxide bait, have been used extensively for collecting host-seeking adult mosquitoes. 60 Gravid traps frequently are used to monitor the ovipositing segment of Cx. pipiens and Cx. restuans populations. These species have been incriminated as the primary enzootic vectors of WNV in the northeastern states. 61,62 Host-seeking Cx. tarsalis, a species that has been strongly associated with WNV transmission in areas where this species is common, are readily collected in CO 2 -baited CDC miniature light traps. Resting boxes frequently are used to measure populations of Culiseta melanura, a bird-feeding mosquito that is important in the amplification of eastern equine encephalitis (EEE) virus. Pigeon-baited traps may be employed to measure host-seeking Culex mosquitoes that amplify St. Louis encephalitis (SLE) and West Nile viruses. Day-active mosquitoes like Ae. albopictus are difficult to collect, and obtaining a sample representative of the local populations requires extra effort. Where these species are important, sample sizes may be enhanced by using CO 2 -baited CDC miniature light traps during daylight hours or by using alternative trap configurations that may be more effective in collecting these species (e.g., Fay trap or traps using a counterflow geometry). Trap deployment should carefully address species habitat requirements on several spatial scales. # Virus Surveillance The purpose of this component of the vector management program is to determine the prevalence of WNV in the mosquito population. This is often expressed simply as the number of WNV-positive mosquito pools of a given species collected at a defined location and time period. While the number of positive pools provides valuable information, it does not provide an index of virus prevalence in the vector population. Preferably, the proportion of the mosquito population carrying the virus should be expressed as the infection rate (IR, expressed as the estimated number of infected individual mosquitoes per 1,000 specimens tested). This is a more useful index of virus prevalence. The IR can be calculated by dividing the number of positive pools by the total number of specimens tested for that species and collection period, and multiplying the proportion by 1,000. This assumes that a positive pool contains only one infected mosquito, which is a valid assumption in most circumstances. # B. Source Reduction Source reduction is the alteration or elimination of mosquito larval habitat breeding. This remains the most effective and economical method of providing long-term mosquito control in many habitats. Source reduction can include activities as simple as the proper disposal of used tires and the cleaning of rain gutters, bird baths and unused swimming pools by individual property owners, to extensive regional water management projects conducted by mosquito control agencies on state and/or federal lands. All of these activities eliminate or substantially reduce mosquito breeding habitats and the need for repeated applications of insecticides in the affected habitat. Source reduction activities can be separated into the following two general categories: # Sanitation The by-products of human's activities have been a major contributor to the creation of mosquito breeding habitats. An item as small as a bottle cap or as large as the foundation of a demolished building can serve as a mosquito breeding area. Sanitation, such as tire removal, stream restoration, catch-basin cleaning and container removal, is a major part of all integrated vector management programs. Mosquito control agencies in many jurisdictions have statutory powers that allow for due process and summary abatement of mosquito-related public health nuisances created on both public and private property. The sanitation problems most often resolved by agency inspectors are problems of neglect, oversight, or lack of information on the part of property owners. Educational information about the importance of sanitation in the form of videos, slide shows, and fact sheets distributed at press briefings, fairs, schools and other public areas are effective. # Water Management Water management for mosquito control is a form of source reduction that is conducted in fresh and saltwater breeding habitats. Water management programs for vector control generally take two forms, described below. Water management through impoundment and open water management have been very effective in the past. Recently, restrictions on modification of aquatic habitats have limited the implementation of these practices, and in many areas, water management for vector control is no longer routinely employed and may be impractical in many settings. In these situations, alternative methods of mosquito management must be employed. a) Impoundment Management Impoundments are mosquito-producing marshes around which dikes are constructed, thereby allowing water to stand or to be pumped onto the marsh surface from the adjacent estuary. This eliminates mosquito oviposition sites on the impounded marsh and effectively reduces their populations. Rotational Impoundment Management (RIM) is the technique developed to minimally flood the marsh during the summer months and then use flapgated culverts to reintegrate impoundments to the estuary for the remainder of the year, thereby allowing the marsh to provide many of its natural functions. Although impoundments usually achieve adequate control of salt-marsh mosquitoes, there are situations in which impoundments can collect stormwater or rainwater and create freshwater mosquito problems that must be addressed using other techniques. # b) Open Marsh Water Management (OMWM) Ditching as a source-reduction mosquito control technique has been used for many years. Open marsh water management is a technique whereby mosquitoproducing locations on the marsh surface are connected to deep-water habitat (e.g., tidal creeks, deep ditches) with shallow ditches. Mosquito broods are controlled without pesticide use by allowing larvivorous fish access to mosquito-producing depressions. Conversely, the draining of these locations occurs before adult mosquitoes can emerge. OMWM can also include establishing or improving a hydrological connection between the marsh and estuary, providing natural resource enhancement as well as mosquito control benefits. The use of shallow ditching (ditches approximately 3 feet or less in depth rather than the deep ditching used in years past) is considered more environmentally acceptable because than deep ditching because fewer unnatural hydrological impacts occur to the marsh. # c) Management in Stormwater Retention Structures Source reduction and water management practices may also be applied to stormwater retention structures designed to hold runoff before it is discharged into groundwater or surface water. Mosquito control should be considered in the design, construction, and maintenance of these structures, as appropriate. Stormwater retention structures should be designed in consultation with experts in mosquito biology and control to prevent as much mosquito production as possible, and to facilitate proper functioning and maintenance in the future. Regulations associated with stormwater retention and flood control structures should incorporate appropriate operations and maintenance provisions including considerations for routine monitoring and control of mosquito populations. # C. Chemical Control Insecticides can be directed against either the immature or adult stage of the mosquito life cycle when source reduction and water management are not feasible or have failed because of unavoidable or unanticipated problems, or when surveillance indicates the presence of infected adult mosquitoes that pose a health risk. 63 Chemicals used by mosquito control agencies must comply with state and federal requirements. Public health pesticide applicators and operators in most states are required to be licensed or certified by the appropriate state agencies. # Larviciding Larviciding, the application of chemicals to kill mosquito larvae or pupae by ground or aerial treatments, is typically more effective and target-specific than adulticiding, but less permanent than source reduction. An effective larviciding program is an important part of an integrated mosquito control operation. The objective of larviciding is to control the immature stages at the breeding habitat before adult populations have had a chance to disperse and to maintain populations at levels at which the risk of arbovirus transmission is minimal. Larvicides can be applied from the ground or by aerial application if large or inaccessible areas must be treated. Several materials in various formulations are labeled for mosquito larviciding including the organophosphate temephos (Abate); several biological larvicides such as Bacillus thuringiensis israelensis (Bti, a bacterial larvicide), Bacillus sphaericus; methoprene, an insect growth regulator (e.g., Altosid,); several larvicidal oils (e.g., petroleum-based Golden Bear and mineral-based Bonide) and monomolecular surface films (e.g., Agnique, Arosurf); and in some limited habitats diflubenzuron (e.g., Dimilin, a chitin synthesis inhibitor). Applications of larvicides often encompass fewer acres than adulticides because treatments are made to relatively small areas where larvae are concentrated, as opposed to larger regions where adults have dispersed. When applying larvicides, it is important that the material be specific for mosquitoes, minimize impacts on non-target organisms, and, where appropriate, be capable of penetrating dense vegetation canopies. Larvicide formulations (i.e., liquid, granular, solid) must be appropriate to the habitat being treated, accurately applied, and based on surveillance data. Accuracy of application is important because missing even a relatively small area can cause the emergence of a large mosquito brood resulting in the need for broad-scale adulticiding. # Adulticiding Adulticiding is the application of pesticides to kill adult mosquitoes. The ability to control adult mosquitoes is an important component of any integrated mosquito management program, and like the other components of the program, its use should be based on surveillance data. Mosquito adulticiding may be the only practical control technique available in situations where surveillance data indicate that is necessary to reduce the density of adult mosquito populations quickly to lower the risk of WNV transmission to humans. In some situations, source reduction and larvicide applications are not practical, and adulticide application is the only available control strategy. Mosquito adulticides typically are applied as an Ultra-Low-Volume (ULV) spray where small amounts of insecticide are dispersed either by truck-mounted equipment or from fixed-wing or rotary aircraft. Thermal fog applications of adulticides by ground or air are also used in some areas, but to a much lesser degree. Barrier treatments, typically applied as high volume liquids with hand-held spray equipment using compounds with residual characteristics, are common in some U.S. locations. This technique is especially attractive to individual homeowners living near mosquito-producing habitats where residual chemicals applied along property boundaries can provide some control benefits. Mosquito adulticiding differs fundamentally from techniques used to control many other adult insects. For adult mosquito control, insecticide must drift through the habitat in which mosquitoes are flying in order to provide optimal control benefits. The EPA has determined that the insecticides labeled nationally for this type of application do not pose unreasonable health risks to humans, wildlife, or the environment when used according to the label. 56 Adulticides labeled for mosquito control include several organophosphates such as malathion and naled. Some natural pyrethrins and synthetic pyrethroids (permethrin, resmethrin and sumithrin) also hold adulticide labels. Insecticide selection and timing of application should be based on the distribution and behavior of the target mosquito species. Application of adulticides should be timed to coincide with the activity period of the target mosquito species. Many Culex species are nocturnal and are active in the tree canopy level. This should be taken into consideration when planning adulticide applications. Operational experience indicates that Cx. pipiens and Cx. quinquefasciatus may require more frequent adulticide application to achieve desired levels of population reduction during an outbreak. Control of adult day-active species poses additional problems because ULV adulticide effectiveness is greatly reduced during daylight hours. Early-morning use of adulticides, applied before temperatures rise, may provide a measure of control for these species. # D. Resistance Management In order to delay or prevent the development of insecticide resistance in vector populations, integrated vector management programs should include a resistance management component (modified from Florida Coordinating Council on Mosquito Control, 1998). 57 Ideally, this should include annual monitoring of the status of resistance in the target populations to: 1. Provide baseline data for program planning and pesticide selection before the start of control operations. Detect resistance at an early stage so that timely management can be implemented (even detection of resistance at a late stage can be important in elucidating why disease control may fail); however, in such cases, management options other than replacement of the pesticide may not be possible). Continuously monitor the effect of control strategies on resistance. In addition to monitoring resistance in the vector population, the integrated program should include options for managing resistance that are appropriate for the local conditions. The techniques regularly used include the following: a) Management by Moderation -preventing onset of resistance by 1) Using dosages no lower than the lowest label rate to avoid genetic selection. 2) Using less frequent applications. 3) Using chemicals of short environmental persistence. Avoiding slow-release formulations. Avoiding the use of the same class of insecticide to control both adults and immature stages. 6) Applying locally. Currently, most districts treat only hot spots. Area-wide treatments are used only during public health alerts or outbreaks. Leaving certain generations, population segments, or areas untreated. Establishing high pest mosquito densities or action thresholds prior to insecticide application. Alternation of biorational larvicides and insect growth regulators annually or at longer intervals. b) Management by continued suppression -a strategy used in areas of high-value (e.g., heavily touristed areas) or where arthropod vectors of disease must be kept at very low densities. This does not mean saturation of the environment by pesticides, but rather the saturation of the defense mechanisms of the insect by insecticide dosages that can overcome resistance. This is achieved by the application of dosages within label rates but sufficiently high to be lethal to susceptible as well as to heterozygous-resistant individuals. If the heterozygous individuals are killed, resistance (which is a homozygous trait) will be slow to emerge. This method should not be used if any significant portion of the population in question is resistant. Another approach more commonly used is the addition of synergists that inhibit existing detoxification enzymes and thus eliminate the competitive advantage of these individuals. Commonly, the synergist of choice in mosquito control is piperonyl butoxide (PBO). c) Management by multiple attack -achieving control through the action of several different and independent pressures such that selection for any one of them would be below that required for the development of resistance. This strategy involves the use of insecticides with different modes of action in mixtures or in rotations. There are economic problems (e.g., costs of switching chemicals or having storage space for them) associated with this approach, and critical variables in addition to mode of action must be taken into consideration (i.e., mode of resistance inheritance, frequency of mutations, population dynamics of the target species, availability of refuges, and migration). General recommendations are to evaluate resistance patterns at least annually and the need for rotating insecticides at annual or longer intervals. # E. Biological Control Biological control is the use of biological organisms, or their by-products, to control pests. Biocontrol is popular in theory, because of its potential to be host-specific and virtually without non-target effects. Overall, larvivorous fish are the most extensively used biocontrol agent for mosquitoes. Predaceous fish, typically Gambusia or other species which occur naturally in many aquatic habitats, can be placed in permanent or semipermanent water bodies where mosquito larvae occur, providing some measure of control. Other biocontrol agents that have been tested for mosquito control, but that to date generally are not widely used, include the predaceous mosquito Toxorhynchites, predacious copepods, the parasitic nematode Romanomermis, and the fungus Lagenidium giganteum. Biocontrol certainly holds the possibility of becoming a more important tool and playing a larger role in mosquito control in the future, but will likely be effective only as part of an integrated approach. # F. Continuing Education of Mosquito Control Workers Continuing education is directed toward operational workers to instill or refresh knowledge related to practical mosquito control. Training is primarily in safety, applied technology, and requirements for the regulated certification program mandated by most states. # G. Vector Management in Public Health Emergencies A surveillance program adequate to monitor WNV activity levels associated with human risk must be in place. Detection of epizootic transmission of enzootic arboviruses typically precedes detection of human cases by several days to 2 weeks or longer (e.g., as found in SLE epidemics). 71,72 If adequate surveillance is in place, the lead time between detecting significant levels of epizootic transmission and occurrence of human cases can be increased, which will allow for more effective intervention practices. 19,27,31 Early-season detection of enzootic or epizootic WNV activity appears to be correlated with increased risk of human cases later in the season. Control activity should be intensified in response to evidence of virus transmission, as deemed necessary by the local health departments. Such programs should consist of public education emphasizing personal protection and residential source reduction; municipal larval control to prevent repopulation of the area with competent vectors; adult mosquito control to decrease the density of infected, adult mosquitoes in the area; and continued surveillance to monitor virus activity and efficacy of control measures. As evidence of sustained or intensified virus transmission in an area increases, emergency response should be implemented. This is particularly important in areas where vector surveillance indicates that infection rates in Culex mosquitoes are increasing, or that potential accessory vectors (e.g., mammalophilic species) are infected with WNV. Delaying adulticide applications in such areas until human cases occur is illogical and negates the value and purpose of the surveillance system. # H. Adult Mosquito Control Recommendations Ground-based (truck-mounted) application of adult mosquito control agents has several positive attributes. Where road access is adequate, such as in urban and suburban residential areas, good coverage may be achieved. In addition, ground-based application can be done throughout the night, thereby targeting night-active mosquito species. Such applications are prone to skips and patchy coverage in areas where road coverage is not adequate or in which the habitat contains significant barriers to spray dispersal and penetration. Aerial application is capable of covering larger areas in shorter time periods than a ground-based application. This is a critical positive attribute when large residential areas must be treated quickly. In addition, aerial application is less prone to patchy coverage than ground-based application in areas where road coverage is not adequate. One limitation of aerial application is that many applicators will not fly at night, potentially reducing the effectiveness of the applications in Culex species control efforts. Cost benefits of aerial application over ground application may not be realized unless relatively large areas are treated. Several formulations of a variety of active ingredients are available for adulticide applications. Material choice for ground-based or aerially applied mosquito control in public health emergency situations is limited by EPA restrictions on the pesticide label and applicable state and local regulations. Multiple applications will likely be required to appreciably reduce Culex populations and interrupt arbovirus transmission. An emergency SLE virus response plan developed for New Orleans, Louisiana 63 indicates the need for repeated applications to control Cx. quinquefasciatus, and the need to repeatedly apply adulticides in high-risk areas (areas with human cases or positive surveillance events). Two to three adulticide applications spaced 3-4 days apart may be required to significantly reduce Cx. pipiens populations. Effective surveillance must be maintained to determine if and when re-treatment is required to maintain suppression of the vector populations. Urban/suburban population centers with multiple positive surveillance events as described above should be treated first to most efficiently protect the largest number of people from exposure to WNV. Applications should be timed to coincide with the peak activity periods of the target species. For example, applications should be made at night to maximize control of night-active Culex species. Other species such as Oc. sollicitans or Ae. vexans are active shortly after sunset and are effectively controlled with appropriately timed applications. Day-active potential accessory vectors (e.g., Oc. japonicus, Oc. triseriatus, Ae. albopictus) must be addressed separately and are most effectively controlled by residential source reduction efforts, though there is preliminary evidence that early morning ULV applications may be used to control these species. # I. Determining the Scope of Mosquito Adulticiding Operations Once arbovirus activity is detected in a jurisdiction and a decision is made to implement or intensify mosquito control by using adulticides, the size of the area to be treated must be determined. In the broadest context, the underlying program objective (i.e., interruption of the enzootic transmission cycle vs. prevention of transmission to humans and domestic animals) should determine the amount of adulticide coverage that is required. For most jurisdictions the objective is the prevention of transmission to humans and domestic animals. There is no simple formula for determining how large an area to treat around a positive surveillance indicator or a suspected or confirmed human case of WNV. Nor is there adequate information to guide decisions about the degree of vector population suppression that must be attained, or for how long this suppression must be maintained to reduce human disease risk. At a minimum, the following factors must be considered when deciding the scope of the adulticiding effort: 1. The general ecology of the area, e.g., key habitat types and the presence of natural barriers such as large rivers; 2. The population density, distribution, flight range, and age structure (proportion of parous females) of the target mosquito species; 3. The flight range of the avian amplifying host(s); 4. The length of time since birds started dying or became infected in the affected area (typically, there may be a lag of several weeks between recovery of dead birds and confirmation of WNV infection) or since virus-positive mosquito pools were collected; 5. The human population characteristics -spatial distribution and density relative to the positive locality (e.g., urban vs. rural), age demographics; 6. Evidence of persistent WNV activity detected by the surveillance program; and 7. Season of the year and how long WNV activity can be expected to persist until the epizootic/epidemic vector(s) enter diapause. Several of these factors will be unknown or poorly understood. Technical assistance from a mosquito control professional, particularly one experienced in mosquito control in the region, is crucial in this process. Practical experience in conducting mosquito control is required to refine control recommendations. For example, the size of an area selected for control applications may be reduced in response to structures like open areas, bodies of water, major highways, or other barriers that may restrict the distribution of targeted species. Alternatively, adulticide coverage may be expanded to cover large urban or suburban residential neighborhoods with dense human populations. Hypothetically, in some settings where focal early season enzootic WNV activity has been detected, early season adulticiding may be useful in interrupting virus transmission and lead to lower transmission rates later in the season. However, effective larval control of the principal enzootic mosquito vector is probably a more cost-effective way to interrupt early-season virus amplification. # J. Evaluation of Adult Mosquito Control The following parameters should be periodically monitored during control operations: 1. Minimum requirements: a) Pre-and post spray vector mosquito densities inside and outside control area using CO 2 -baited traps and gravid traps; b) Vector mosquito infection rates pre-and post-spray inside and outside the control area; and c) Weather conditions during application (temperature, wind speed, direction). Desirable additions if capacity exists: population age structure of key mosquito species (Cx. pipiens) 3. In addition, both droplet size and flow rate should be documented for each piece of ULV application equipment: 4. During aerial application, GPS monitoring of spray track should be conducted if equipment is available on aircraft. # K. Health Education, Public Information, and Human Behavior Change The goals of health education, public information, and behavior change programs are to inform the public about WNV, promote the adoption of preventive behaviors that reduce disease risk, and gain public support for control measures. Health education/public information includes use of print materials (posters, brochures, fact sheets), electronic information (Web sites), presentations (health experts or peers speaking to community groups), and the media. Information alone is seldom sufficient to encourage people to adopt new behaviors or to change old practices. Programs should include strategies to facilitate protective actions and to address barriers that hinder preventive actions. Examples of programs that go beyond information include developing a community task force, interventions to improve access to window screening materials or repellents, and social marketing to reinforce preventive behaviors. The following section covers key prevention messages, selected best practices, and research/program development priorities for promotion of personal and community measures to decrease risk of WNV infection. Public education and risk communication activities must be ramped up to respond to the degree of WNV risk in a community, as noted in Table 1. # Key WNV Prevention Messages a) Address the multiple levels at which prevention can occur: personal protection (use of repellent on skin and clothing, use of protective clothing, awareness of prime mosquito-biting hours); household protection (eliminating mosquito breeding sites, repairing/installing screens); and community protection (reporting dead birds, advocating for organized mosquito abatement, participating in community mobilization). b) Use of DEET-based repellents on skin and clothing is the backbone of personal protection. (For current recommendations, see www.cdc.gov/ncidod/dvbid/westnile/qa/insect_repellent.htm.) Permethrin-based repellents should be promoted for use on clothing. c) Emphasize the feasibility of actions that can lower an individual's WNV risk through personal protection measures. Messages should acknowledge the seriousness of the disease but should not be fear-driven. Fear-driven messages may heighten the powerlessness many people express in dealing with emerging diseases. d) Recommendations to avoid being outdoors from dusk to dawn may conflict with neighborhood social patterns or practices of persons without air-conditioning or without other health programs seeking to increase physical activity. An alternative is to emphasize that the hours from dusk until dawn are prime mosquito-biting hours, and that protecting oneself through repellent use during these hours is important, with the option of remaining indoors. e) Communication about adulticiding: Public acceptance of emergency adult mosquito control is critical to its success, especially where mosquito control is unfamiliar or unpopular. Questions about the products being used, their safety, and their effects on the environment are common. Improved communication about surveillance and how decisions to adulticide are made may help residents weigh the risks and benefits of control. When possible, provide detailed information regarding the schedule for adulticiding through newspapers, radio, the Internet, or a recorded phone message f) Keep messages clear and consistent with the recommendations of coordinating agencies. Use plain language whenever possible, and adapt materials for lowerliteracy and non-English speaking audiences. # Selected Best Practices a) Targeted prevention Audience members have different disease-related concerns and motivations for action. Proper message targeting permits better use of limited communication and prevention resources. The following are some audience groups that require specific targeting: Develop partnerships with agencies/organizations that have relationships with populations at higher risk (such as persons over 50) or are otherwise recognized as community leaders (e.g., churches, service groups). Working through sources trusted by the target audience can heighten the credibility of and attention to messages. Partnerships with businesses that sell materials to fix or install window screens or that sell insect repellent may be useful in some settings. c) Community mobilization and community outreach Community mobilization can further education and behavior change goals. To counter any idea that health departments/mosquito control programs are able to control WNV alone, develop community ownership for prevention activities. A community task force that includes civic, business, health, and environmental concerns can be valuable in achieving buy-in from various segments of society and in developing a common message. Community mobilization activities can include clean-up days to get rid of mosquito breeding sites. 39 Community outreach involves presenting messages in person, in addition to media and educational materials, and incorporating citizens in prevention activities. Hearing the message of personal prevention from community leaders can validate the importance of the disease. Health promotion events reinforce the importance of prevention in a community setting. # Research and Program Development Priorities a) Audience research Attitudes toward arboviral disease prevention vary considerably by region. Previous experience with nuisance mosquitoes and mosquito control will affect the acceptability of prevention efforts. Audience research can identify local attitudes, motivations, barriers to prevention, and opportunities to promote desired behaviors. Audience research should ideally combine qualitative and quantitative efforts. Surveys assessing knowledge, attitude, and practice levels in the target population can be very helpful, especially in evaluation, though they are a substantial undertaking. Qualitative research techniques, such as interviews and focus groups, can yield valuable data, and are more adaptable to resource levels. Expertise to undertake such efforts may be available from other divisions within a health department (e.g., chronic disease programs, maternal and child health). Pretesting of educational materials is an important step to ensure the usability of materials by the intended audience. Pretesting does not always have to involve considerable time or expense; simply having representatives of the intended audience review materials before printing will be useful. # b) Evaluation Outcome evaluation should be conducted whenever possible to measure the efficacy of the intervention in achieving protective behaviors (e.g., frequency of repellent use, presence of household mosquito breeding sites). Outcome measurement requires extensive effort and must be planned from the outset of a program. # c) Social marketing and risk communication The goal of social marketing is to achieve specific behaviors, using the concepts of product, price, place, and promotion. Use of social marketing approaches can help programs plan to achieve specific behavior change goals. Risk communication is already used by many health departments, and can be useful in refining communication messages for WNV, especially as the disease becomes endemic in new areas, and in discussing community control. Risk communication can help people analyze the choices that are available to them and to their community. # Resources The Other organizations that can provide useful information are the American Mosquito Control Association (www.mosquito.org/) and the National Pesticide Information Center (NPIC) (npic.orst.edu), a program of EPA and Oregon State University concerning pesticides and repellents. They can be contacted at 1-800-858-7378. # L. Legislation In addition to statutes permitting legal action to abate mosquito-related public health nuisances, legislation must be in place to allow creation of and provide funding for municipally-based integrated mosquito management programs. Local jurisdictions can contact state mosquito control associations to provide examples of enabling legislation. # M. Guidelines for a Phased Response to WNV Surveillance Data The principal goal is to minimize the health impact of the WNV in humans, as well as in domestic and zoo animals. Given the limited understanding of the ecology and epidemiology of WNV in the U.S., the low incidence of arboviral encephalitis, and the limitations of prevention methods, prevention and control measures, regardless of intensity, may not prevent all WNV infections in humans. The recommended response levels for the prevention and control of WNV should augment, but not replace, long-standing mosquito control efforts by established programs. These programs often have two objectives: 1) to control nuisance mosquitoes, and 2) to control vector mosquitoes that can transmit pathogenics. Nuisance mosquito control often has different objectives than vector control, and the target mosquito species may also differ. Established mosquito control programs often have long-standing experience with the surveillance and control of indigenous neurotropic arboviruses such as SLE virus. These programs have established thresholds for response based on historical data. Long-standing experience with WNV does not exist in the U.S. These guidelines for the prevention and control of WNV should be interpreted according to the following considerations: 1. All states should prepare for WNV activity. Given the extensive geographic spread of WNV since 1999, its occurrence in many different habitats and ecosystems in the Old World, its expansion into numerous habitat types in the Western Hemisphere, and the fact that SLE virus, a related flavivirus, is widespread in the U.S., there appear to be no barriers to the spread of WNV throughout the U. S. At a minimum, a plan for the surveillance, prevention, and control of WNV should be developed at the state and local levels. indicate that intensity of epizootic WNV activity as measured by avian mortality and mosquito infection rates are good indicators of subsequently increased human infection risk. Data from NYC indicate that human WNV disease cases were more likely to occur in counties that had experienced more than 0.1 dead crow reports per square mile per week. In the Staten Island outbreak of 2000, the density exceeded 1.5 dead crow reports per square mile per week. Also, analysis of 2001 and 2002 surveillance data indicate that counties reporting WNV-infected dead birds early in the transmission season are more likely to report subsequent WNV disease cases in humans than are counties that do not report early WNV-infected dead birds. These observations should be interpreted as a guide rather than an absolute. Levels of epizootic activity that correlate with increased human risk will vary by region. Flexibility is required when implementing the guidelines. Knowledge gained from ongoing surveillance and research could change the phased response recommendations. Specific and detailed recommendations that will fit all possible scenarios are not possible, particularly at a local level. Therefore, public health action should depend on interpreting the best available surveillance data in an area, in light of these general guidelines. In addition, the following factors should be considered when translating these guidelines into a plan of action: The recommended phased response to WNV surveillance data is shown in Table 1. Local and regional characteristics may alter the risk level at which specific actions must be taken. Response as in category 3, plus: Expand public information program to include TV, radio, and newspapers (use of repellents, personal protection, continued source reduction, risk communication about adult mosquito control), Increase visibility of public messages, engage key local partners (e.g., government officials, religious leaders) to speak about WNV ; intensify and expand active surveillance for human cases; intensify adult mosquito control program, repeating applications in areas of high risk or human cases. # Outbreak in progress Multiple confirmed cases in humans; Conditions favoring continued transmission to humans (e.g., persistent high infection rate in mosquitoes, continued avian mortality due to WNV) Response as in category 4, plus: Intensify emergency adult mosquito control program repeating applications as necessary to achieve adequate control. Enhance risk communication about adult mosquito control. Monitor efficacy of spraying on target mosquito populations. If outbreak is widespread and covers multiple jurisdictions, consider a coordinated widespread aerial adulticide application; emphasize urgency of personal protection through community leaders and media, and emphasize use of repellent at visible public events. - Local and regional characteristics may alter the risk level at which specific actions must be taken. # IV. HEALTH DEPARTMENT INFRASTRUCTURE State and Local Health Departments In the 48 contiguous United States, state and local health departments should have a functional arbovirus surveillance and response unit, staffed by well-trained personnel who have adequate data-processing resources, appropriate laboratory facilities, and an adequate operating budget. The size and complexity of these units will vary by jurisdiction, depending on both the risk of arboviral transmission in the area and available resources. A functional arbovirus surveillance unit at the state level should be considered an essential component of any emerging infectious diseases program. Local health department expertise and capabilities should be supported in a manner that complements statewide programmatic goals. # A. Staffing and Personnel Ideally, arboviral surveillance involves epidemiologists, virologists, medical entomologists, vertebrate biologists, veterinarians, laboratory staff, environmental toxicologists, public affairs personnel, and data managers. In a particular jurisdiction, the combination of personnel needed to conduct arboviral surveillance will depend on the importance of arboviral diseases in the area and on resources. Many health departments experience a chronic shortage or complete absence of medical entomologists and expertise in wildlife pathobiology. Addressing these deficiencies should be a high priority. In the event of an arboviral disease outbreak, local health departments will likely require significant surge capacity to ensure an adequate public health response. Contingency planning to identify resources to assist with the enhanced surveillance, laboratory, environmental, and public health needs should be identified ahead of time. # B. Training and Consultation Opportunities exist at federal and state agencies for appropriate training of and consultation with laboratorians, medical entomologists, epidemiologists, vertebrate biologists, and others involved in arbovirus surveillance. # C. Laboratory Capacity The infrastructure of arbovirus laboratories in the U.S. has deteriorated significantly in recent decades, not only in terms of the total number of functional laboratories and overall capacity, but also in terms of the staffing, physical plant, and financial support of many remaining laboratories. This is a problem of national scope and significance, the solution for which will require leadership at all levels of government. # Testing for West Nile Virus (WNV) Infections In the wake of the introduction of WNV into the Western Hemisphere, it is important to distinguish between increasing short-term and long-term laboratory capacity. The latter is preferred and should be emphasized over the former. Laboratories with an existing capability for arbovirus serology should consider adding serologic screening tests for WNV to their repertoire. For serologic screening of patients and mosquito pools, arrangements can be made with CDC to transfer existing technology and reagents, and to obtain appropriate training. Samples giving positive or equivocal screening results should be confirmed by CDC or another laboratory capable of definitive testing. For selected laboratories, similar technology transfer arrangements can be made with regard to RT-PCR primers for use in the testing of tissues and mosquito pools. In the wake of the recent epidemic of WN encephalitis in the Northeast, it is important that programs continue to routinely test for other arboviruses historically active in their area, such as St. Louis encephalitis, eastern equine encephalitis, western encephalitis, and La Crosse viruses, as well as for other causes of acute encephalitis. # D. Developing Local Public Health Agency Infrastructure The function of local public health agencies is assessment, assurance, and policy development to promote and protect the health of the public. As part of this function, local public health agencies are responsible for preventive activities to reduce the risk of WNV infection to individuals in their jurisdictions. This responsibility includes educating communities about reducing mosquito breeding sites and taking personal protective measures. Local public health agencies also must have the capacity to assess human risk by gathering surveillance data or having access to surveillance data gathered on a district, regional, or statewide basis. These local public health agencies are important to formulating local recommendations on the indications and decisions concerning mosquito adulticiding. Education of and communication with the public, and maintenance of local media contacts are generally primary functions of the local public health agency. Included in this responsibility is communicating risk regarding the use of pesticides. The following infrastructure and functional capacities fall within the province of local public health agencies. Where these are not directly provided, access to these capacities is to be ensured). Risk assessment based on surveillance data (including mosquito, bird, and human data). Surveillance data may also include reports from individuals or healthcare providers indicating possible adverse health effects from pesticide use. Health education regarding personal protection, reduction of mosquito breeding sites and minimum health risks posed by approved pesticides applied according to the label. 73,74 3. Communication with the media. Development of a preventive plan including education, mosquito source reduction, and larviciding. Public response capability, particularly when surges of public inquiries arise. This may include the use of telephone hotlines and Internet Web sites. Training of staff. Coordination with state and federal agencies. Local coordination by formulation of a task force with organizations such as departments of public works, offices of public affairs, city/county building management, departments of parks and recreation, departments of planning and zoning, property or building inspection services, police, public schools, colleges and universities, nonprofit and grassroots organizations, businesses, zoos, animal/vector control, local mosquito control districts, emergency medical services, hospitals, poison control centers, departments of game and inland fisheries, departments of environmental quality, emergency, management agencies, etc. because of the relatively large number of species being studied. Specific needs include the following: # Accurate Taxonomic Identification of Specimens Fully understanding the epidemiology and developing effective prevention and control strategies for WNV requires accurate identification of all animal species involved in the virus transmission and maintenance cycles. This is especially true for birds and mosquitoes. # Unique Identifier (UID) Numbering System for Specimens A UID numbering system should be used in each jurisdiction (e.g., state, county, city, surveillance area). Such a system should distinguish readily between each major animal group reported (i.e., humans, birds, and mosquitoes), and encode the location of collection (county or town), date of collection (day/month/year), and a specimenspecific number. # Durable Tagging System for Field-Collected Specimens Use appropriate labels containing complete specimen information on all samples (blood, tissues, or whole animals) so field specimen identification will not be lost during shipment to testing facilities. A very long-term goal is the identification and implementation of new, natural compounds to repel and control mosquito vectors of disease. With efforts to decertify current pesticides, new compounds will be needed in the fight against vector-borne diseases. Much effort has been expended to increase public awareness of the WNV threat and of the actions needed to reduce exposure to infected mosquitoes. These actions include using mosquito repellents, reducing periresidential mosquito breeding sites, and wearing protective clothing when entering mosquito-infested areas. The success of these public information campaigns has not been formally evaluated using scientific instruments such as knowledge and behavior surveys. The cost of such campaigns is high, so formal attempts to assess their success are needed. # G. Laboratory Diagnosis Surveillance for WNV will continue to require accurate laboratory diagnostic tests. Ideally, these tests will be simple and inexpensive, and will distinguish between WNV and other flaviviruses such as the SLE, dengue, and yellow fever viruses. Virus-specific tests for IgM or IgG antibody will be required for humans, various species of birds, horses, and other mammals. Sensitive viral detection methods will be required for both human and animal tissues as well as for mosquito pools. # H. Clinical Spectrum of Disease and Long-Term Prognosis in Humans A better understanding of the spectrum of illness caused by WNV infection in humans is needed, including the long-term consequences of acute infection of the central nervous system. In addition to the severe end of the clinical spectrum (viral encephalitis), it is important to know the degree to which mild viral syndromes occur and whether these patients have any unique clinical presentations that may be characteristic or even pathognomonic. It is also important to know whether they have viremia and, if so, its magnitude and duration. Effective clinical management of severe disease will require detailed clinical studies of confirmed human cases of WNV infection. # I. Risk Factor Studies - "Denominator" data Definition: Weekly totals of dead birds (classified as either corvids or 'others') and mosquito pools (classified by species) collected and/or tested by a jurisdiction's WNV surveillance system, stratified by county within a state. Because recent experience has demonstrated that the following categories of denominator data are of limited use in meeting national surveillance goals, as of 2003, CDC will discontinue the collection of totals of sentinel and free-ranging wild birds, horses, or other non-human mammals tested. - "Numerator" data Definition: Detailed information on individual mosquito pools, sentinel species, dead birds, and ill humans, horses, or other species with confirmed or suspected WNV infections, as determined by laboratory-confirmed or -probable test results. # General Procedures: Reporting "denominator" data: CDC will collect aggregate denominator data via a secure file upload system using a statebased database provided by CDC, continuous data entry into a database stored on a secured CDC web site, or importation of delimited records in a specified format. Denominator data variables are specified in Table 1. An appropriate submission schedule will be arranged by CDC with the jurisdictions submitting surveillance data via file uploading. In addition, - CDC will distribute the necessary software and provide the adequate licenses that will allow regular secured file upload or continuous web-based data entry. - CDC will accommodate state health departments with existing integrated data collection systems, e.g., by arranging for uploads of XML-formatted data. - The data entry screens will be designed as a series of simple forms or tables. - The system will accommodate updates and corrections of previously transmitted data by jurisdictions. - Following the entry of a week's data into the database at the state level, transmission of the data file to CDC will involve a minimal number of keystrokes. Security will be insured by use of the sender's digital certificate. CDC will arrange for those who will be transmitting surveillance data to CDC to obtain digital certificates. - Upon arrival at CDC, records from the specific reporting week of interest will automatically be captured and imported into a master database on the CDC fileserver and also transmitted to USGS in Reston, Virginia. - Using these data, reports will be generated automatically each week. Maps will be generated by CDC and USGS and made available on the USGS web site. A basic set of dynamic maps and corresponding graphs and tables will be made available weekly. The CDC web site and Epi-X (or a similar secured communication network) will contain links to the relevant USGS web pages. # Reporting "numerator" data: CDC strongly encourages prompt ("real-time") reporting of numerator data. CDC will collect such reports in a standardized manner to allow monitoring of regional and national trends, and facilitate prompt confirmatory testing when necessary. As the arbovirus transmission season progresses, the need for immediate reporting of certain data to CDC may diminish. For example, once numerous WNV-positive mosquito pools have been previously documented in a given geographic area, there may not be a compelling need to immediately report further findings. In addition, if at any time the volume of reporting becomes overwhelming, adoption of an alternative system may be necessary. Numerator data variables that will be collected are specified in Table 2. WNV laboratory and surveillance case criteria are specified in Table 3. Specified, line-listed numerator data may be submitted using one of three methods: - Web-based data entry to a CDC server; - Use of state-based, CDC-distributed, Microsoft Access-based data entry/management software (ArboNET) with continuous file upload to a CDC server; or - Data messaging from a unique data collection system to a CDC server (e.g., in XML format). All data entry will be done by the reporting jurisdiction and data is transmitted to a CDC server. After data entry and submission, numerator data will be available on the CDC Secure Data Network (SDN) so that authorized personnel from the reporting jurisdiction may "verify" (proofread, correct, and clear for publication) individual numerator data records in selected surveillance categories. It is essential that each numerator data record include a unique identifier (UID) assigned by the reporting state agency. UIDs will be used by CDC staff to track and update individual numerator data records, and by states to verify records via the CDC SDN. The UID will not appear in output products for public release. Most jurisdictions already have systems in place for generating UIDs, and they should continue to use them. CDC's databases will accommodate numeric or alphanumeric UIDs up to 25 characters long. Jurisdictions are encouraged to begin their UIDs with their state's 2-letter postal code (or "NYC" for New York City). The issue of numerator data records associated with laboratory-probable results deserves special mention. Although CDC encourages confirmation of all laboratory-probable results, it is realized that under some circumstances some states may choose not to do so, depending on the epidemiologic situation, laboratory capacity, and volume. For example, during a known WN viral epizootic, a state may decide that a crow brain associated with a single positive result for WN viral RNA by RT-PCR will undergo no further testing. Although this bird is a laboratoryprobable case (see table below), the jurisdiction may decide to upload that bird's numerator data record to CDC and subsequently authorize CDC to release it publicly. In contrast, a jurisdiction may opt to delay the release of such results to the public until they have been laboratory-confirmed. CDC will rely on individual jurisdictions to decide when to authorize the public release of numerator data records based on laboratory-probable results. CDC will not publicize numerator data records associated with laboratory-equivocal results. In terms of human surveillance, the national surveillance case definition of arboviral encephalitis/meningitis includes two official case-status categories: confirmed and probable (Table 3). For national arboviral encephalitis surveillance, CDC has traditionally combined records in these two categories for its annual summary reports, and will continue this practice within the WNV surveillance system. States are encouraged to promptly report both laboratoryconfirmed and laboratory-probable human WN encephalitis cases as numerator data records. CDC encourages the reporting of human WN viral illnesses other than WNME (e.g., WNF, acute flaccid paralysis, other clinical syndrome, or unspecified). To determine case status (confirmed or probable) for reporting purposes, refer to the national surveillance case definition of arboviral encephalitis/meningitis (Appendix C) and the CDC-recommended surveillance case definition for WNF (Appendix D). A working case definition for WNME in equines is shown in Appendix B. # Arboviruses other than WNV: It is anticipated that enhanced WNV surveillance will result in increased recognition of other domestic arboviral activity, including eastern equine encephalitis (EEE), western equine encephalitis (WEE), SLE, La Crosse (LAC), and Powassan (POW) virus activity. Surveillance numerator (laboratory-positive) data regarding these viruses may be reported to CDC/DVBID via ArboNET, telephone, FAX, or e-mail. # Data Security Issues: General principles: - State and local health authorities will retain control of the timing of data release. - As of 2003, reporting agencies will electronically report to ArboNET all categories of surveillance data, including human numerator data. For non-human data, agencies will verify accuracy and readiness for public release prior to submission. Upon the electronic submission of non-human data to CDC, these reports will be considered verified and publishable. With the 2003 version of ArboNET, human data will be automatically verified upon entry, and the reporting agency has the option to unverify the data via electronic checkbox. CDC will not publicly release unverified human case reports. - Personal identifying or localizing (more specific than county) information will not be released. # Specific issues: - To report data via secure file upload to the CDC fileserver or to enter data directly onto a secured web site, states will utilize the CDC SDN, which provides data encryption for transmission via the Internet. To use the SDN, users must obtain and install a digital certificate from the CDC certificate server. This allows for unique identification of the computer/browser that is accessing a secure web site. - To obtain a digital certificate and be approved to use the SDN, the digital certificate authority at CDC/DVBID must approve the request and forward it to CDC/Atlanta. CDC requests that a maximum of 3 persons from each state be designated to receive digital certification. These should include those who will transmit data to CDC, as well as those who will verify data on the SDN. # Summary Reports to be Produced by CDC and USGS: A working list of basic summary reports is shown in Table 4. The exact list and formats of these reports remain to be determined, and this should be viewed as a dynamic process. Modifications, additions, and deletions may take place over time, as dictated by feedback, experience, technical issues, and events. Using state-approved numerator and denominator data, reports will be generated weekly. Maps and tables will be generated by DVBID and by USGS. Maps and corresponding graphs and tables will be updated at least weekly on the USGS web site (www.USGS.gov). # Communication Issues: - A dedicated telephone line (970-266-3592), electronic mailbox ([email protected]), and fax machine (970-266-3599) will be available at CDC/DVBID (in Fort Collins, Colorado) 24 hours/day for reporting numerator data or other urgent WNV-related business. During nights and weekends, calls to the dedicated phone line will be forwarded to the cellular phone of an on-call CDC/DVBID staff scientist. Because of potential delays in the receipt and reading of email and fax messages, in general please use the telephone for time-sensitive business. - In addition to periodic conference calls between CDC, cooperating states, and other federal agencies, Epi-X and the WNV Information Exchange (WNVIX, part of the Epi-X Forum) will be available to participating jurisdictions and agencies using the CDC SDN. For further information, contact the CDC/DVBID ArboNET staff at 970.221.6400 or send electronic mail to [email protected]. # Submission of Laboratory Specimens to CDC for WNV Testing: See Table 5. Shipping containers: Use only durable containers. Seal specimen containers tightly. Wrap specimen containers in absorbent material and pack them into two different plastic containers to insure that any leakage is contained. Specimens for virus isolation must be sent on enough dry ice to insure that they remain frozen until receipt. Specimens for serologic testing can be shipped on gel-ice and need not remain frozen. Hand-carrying specimens is not recommended but if specimens are hand-carried, the above packing instructions are applicable. # Minimal Information to Accompany Specimens Shipped to CDC: See information in columns 2, 3, and 4 in Table 2. Please read carefully and supply all available information. Use CDC Form 5034 (the ADASH@ form) Form 5034 is available electronically at: Tubes, cryovials, and other specimen containers should be clearly labeled with -at minimumthe specimen's UID, patient's name (human), state, date of onset, date of collection, and specimen type. # Special Collection, Shipping, and Handling Instructions: Mosquitoes: Ship on dry ice. Serum: Store in externally threaded plastic tubes. Ship at least 0.5 mL per specimen. Whenever possible, acute and convalescent specimens should be shipped together. Ship fresh-frozen on dry ice (required for virus isolation) or refrigerated on wet ice (acceptable). CSF: Store in externally threaded plastic tubes. Ship at least 1.0 mL per specimen. Ship freshfrozen on dry ice (required for virus isolation) or refrigerated on wet ice (acceptable). Whole blood: In general, send only if requested for virus isolation attempts in fatal cases (heart blood). Pregnancy-related specimens: In possible cases of intrauterine arboviral infection, tissues collected at the time of delivery can be tested for evidence of infection. The following tissues should be shipped fresh-frozen on dry ice: cross-sections of umbilical cord, placental tissue (approximately 1 cm 3 per sample), cord serum and maternal serum (0.5 ml each), and colostrum or breast milk. For more information, please contact Dr. Dan O'Leary at (970) 266-3525 or [email protected]. # Appendix B B Surveillance Case Definition for WNV Infection in Equines Laboratory criteria for diagnosis Compatible clinical signs plus one or more of the following: ! Isolation of West Nile (WN) virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF) or other body fluid; or ! Detection of IgM antibody against WN virus by IgM-capture ELISA in serum (at 1:400 or greater dilution) or cerebrospinal fluid (CSF) (at dilution 1:2 or greater dilution); or ! An associated 4-fold or greater change in IgG-capture ELISA or plaque-reduction neutralization test (PRNT) antibody titer to WN virus in appropriately timed, paired serum specimens from an equid that is unvaccinated against WN virus; or ! Positive immunohistochemistry (IHC) for WN virus antigen in tissue. # Case classification Probable: compatible clinical signs occurring during a period when arboviral transmission is likely, and with the following supportive serology: 1) a single or stable (less than or equal to two-fold change) but elevated titer of WN virus-specific IgM-capture ELISA or neutralizing serum antibodies without knowledge of prior WN virus vaccination. Confirmed: compatible clinical signs with laboratory-confirmed evidence of WN virus infection. The first serum should be drawn as soon as possible after onset of clinical signs and the second drawn at least 14 days post-onset. _______________________________________________ Assumptions on which case definitions are based: - IgM-capture ELISA testing may give nonspecific results; cross-reactions to closely related flaviviruses (e.g., St. Louis encephalitis virus) may occur. Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to pinpoint the infecting virus by conduction cross-neutralization tests using an appropriate battery of closely related viruses. - Vaccination refers to one or more doses of the current USDA-licensed inactivated WN virus vaccine. - Virus-specific IgM antibodies demonstrated in serum by antibody-capture EIA and confirmed by demonstration of virus-specific serum immunoglobulin G (IgG) antibodies in the same or a later specimen by another serologic assay (e.g., neutralization or hemagglutination inhibition). # Case classification Probable: an encephalitis or meningitis case occurring during a period when arboviral transmission is likely, and with the following supportive serology: 1) a single or stable (less than or equal to twofold change) but elevated titer of virus-specific serum antibodies; or 2) serum IgM antibodies detected by antibody-capture EIA but with no available results of a confirmatory test for virus-specific serum IgG antibodies in the same or a later specimen. Confirmed: an encephalitis or meningitis case that is laboratory confirmed. # Comment Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to pinpoint the infecting virus by conducting cross-neutralization tests using an appropriate battery of closely related viruses. This is essential, for example, in determining that antibodies detected against St. Louis encephalitis virus are not the result of an infection with WN (or dengue) virus, or vice versa, in areas where both of these viruses occur. The seasonality of arboviral transmission is variable and depends on the geographic location of exposure, the specific cycles of viral transmission, and local climatic conditions. # V. INTERJURISDICTIONAL DATA SHARING AND NATIONAL REPORTING OF HUMAN CASES The public and animal health response to West Nile virus (WNV) epidemics/epizootics involves all levels of government, including the federal governments of the U.S. and neighboring countries, and the Pan American Health Organization. In addition, multiple government agencies at each level are often involved. Rapid, efficient, secure, and coordinated systems are needed to allow the sharing of human and ecologic data between these multiple agencies to support long-term surveillance activities, and to support activities that are part of the rapid outbreak response. During an epidemic involving multiple jurisdictions, CDC staff and other authorized persons will use Epi-X, a CDC-sponsored, Web-based system for secured electronic communication, or similar integrated communication systems, for rapid dissemination of information on public health events of public health significance. # A. Human Epidemiological, Clinical, and Laboratory Data Collection Patient confidentiality statutes vary among jurisdictions. Data can be shared between jurisdictions if recipients agree to adhere to the confidentiality statutes of the jurisdiction providing the data. Electronic databases should be appropriately secured by passwords to limit access and minimize opportunities for breaches in confidentiality or security. ArboNET and NETSS will be encouraged. # B. National Reporting of Human WNV # West Nile Fever (WNF) Although WNF is not included in the list of nationally notifiable diseases, states are encouraged to report WNF cases to CDC via ArboNET, using a CDC recommended case definition (see Appendix D). States may also choose to report WNF cases to NETSS using EVENT code 10049. # C. Ecologic Data Many of the issues that apply to the interjurisdictional sharing of human data apply to the sharing of ecologic data as well, although key differences exist. For example, confidentiality is generally not an issue with nonhuman cases, particularly wild animals identified as part of a surveillance program. Maintaining confidentiality may be important for certain owned animals. Data standardization is a far more challenging issue # VI. RESEARCH PRIORITIES The human and animal health implications of the introduction of West Nile virus (WNV) to the U.S. and to the Western Hemisphere continue to emerge. Many questions remain, the answers to which will require considerable research. A research agenda should be supported, with priority given to research questions whose answers can be directly applied to prevention and control. # A. Current and Future Geographic Distribution of WNV To determine the geographic distribution of WNV in the Western Hemisphere, existing laboratory-based surveillance systems for WNV in human, birds, other selected animals, and mosquitoes should be enhanced, or new, active systems should be developed and implemented (see Section I). # B. Bird Migration as a Mechanism of WNV Dispersal Experience in Europe and the Middle East suggests that WNV regularly is introduced to new geographic areas along bird migration routes. A better understanding of this potential is required for the Western Hemisphere. Studies should include the frequency and duration of chronic infections that will allow the long-range transport and recrudescence of viremias necessary to infect mosquitoes. # C. Vector and Vertebrate Host Relationships and Range Relatively little is known about the vertebrate host and mosquito vector relationships of WNV in the U.S. and the Western Hemisphere. Effective prevention and control strategies will require targeting selected species involved in maintenance, epidemic/ epizootic transmission cycles, or both. It is critical that the principal species and the range of these species be determined. # D. Virus Persistence Mechanisms It is not known whether or how WNV will be maintained in the U.S. over the long term. Overwintering mechanisms in Culex and Aedes species should be investigated, as well as persistence and maintenance of the virus in ticks. Other possibilities that should be investigated include the duration of chronic infection and reactivation in birds or other animals, and the introduction of the virus by migratory birds. # E. Mosquito Biology, Behavior, Vector Competence, Surveillance, and Control It is critical that a better understanding is gained of the principal mosquito vectors involved in maintenance, bridge (from enzootic to peridomestic), and epidemic/epizootic transmission. Different vector species may be important in different geographic or ecologic regions. Understanding their biology and behavior will allow for more effective surveillance and development of targeted control methods. # F. Development and Evaluation of Prevention Strategies Effective prevention and control of WNV transmission will require evaluation of the efficacy of current control methods and research on new and innovative control strategies for the principal mosquito vectors. Ultimately, prevention strategies must be integrated and use a variety of approaches to control mosquitoes and reduce the risk of transmission. Research should also be conducted to better define target areas for mosquito control in response to documented WNV activity in an area. Data on the risk factors associated with human and animal infection with WNV are required to develop more effective prevention strategies, particularly when educating the public to take specific prevention measures to reduce exposure to infection. # J. Detailed Clinical Descriptions and Outcome in Human Cases Larger and more detailed case series, as well as studies of short-and long-term outcomes, are needed to better understand the clinical features, clinical course, and public health impact of WNV disease in humans. A suggested framework for collecting standardized "extended" clinical variables is included in Appendix E. # K. Viral Pathogenesis Little is known of the pathogenesis of WNV in humans or other animals. Research is needed to better understand the organ systems affected, the mechanism of central nervous system (CNS) infection, and the role of virus strain in pathogenesis. # L. Genetic Relationships and Molecular Basis of Virulence Only since 1996 has WNV been associated with significant numbers of severe disease cases and fatalities in humans. It is important to better understand whether genetic changes in WN viruses influence their phenotypic expression (i.e., host and vector range, clinical expression in various hosts, and epidemic potential). This will require detailed studies of the genome of WN virus strains isolated from different epidemics in various geographic areas. # M. Vaccine Development for Animals and Humans Ultimately, the most effective prevention strategy may be vaccination. It is important to support research on the development of both human and equine vaccines. # N. Antiviral Therapy for West Nile Virus and Other Flaviviruses To date, none of the available antiviral agents are effective against flaviviruses, including WNV. Research in this area is critical to effective management of severe disease in humans. # O. The Economic Cost of the WNV Epidemic/Epizootic It is important to estimate the total economic cost of the epidemic/epizootic. These data will help set priorities for capacity building and prevention programs. # P. WNV Impact on Wildlife WNV has the potential to greatly impact the wildlife populations in the Western Hemisphere. This is especially true for birds, in many of which the infection appears to have high mortality rates (i.e., Corvidae). Research is needed to analyze and define this impact to determine if the development of new epizootic intervention strategies is needed. Research is also needed to determine what long-term effects WNV infection may have on its animal hosts. # Q. Investigate Alternate Modes of WNV Transmission to Humans Four new modes of WNV transmission to humans were identified in 2002: blood transfusion, tissue transplantation, transplacental transfer, and breast-feeding. New modes of transmission should be investigated to determine the impact they have on human infection and to develop effective approaches for prevention and control of WNV infection by these routes. # Appendix A -National WNV Surveillance System Objectives: The objectives of the national West Nile virus (WNV) surveillance system are to: - Monitor the geographic and temporal spread of WNV in the U.S. - Develop national public health strategies for WNV surveillance, prevention, and control. - Develop a more complete regional picture of the geographic distribution and incidence of the other clinically important arboviruses in the U.S. - Provide national and regional information to public health officials, elected government officials, and the public. - Evaluate the use of cooperative agreement funds and the need for additional resources. # Scope: Coordinated, multi-state surveillance of WNV infections in humans and animals has been repeatedly identified as a high priority by states affected by WNV in 1999-2002. All states conducting surveillance for WNV and other arboviruses are encouraged to participate in ArboNET, a CDC-coordinated program to collect these surveillance data. While the components of WNV surveillance systems employed in individual jurisdictions will vary, national WNV surveillance should, at a minimum, focus on collection of data from: - Mosquito surveillance - Avian (dead bird) surveillance - Equine surveillance - Human surveillance In addition to data from states, data from commercial laboratories will be sought. CDC will 1) formally notify all such laboratories of the need to report any positive laboratory results to the appropriate state or local health department who, in turn, will notify CDC; 2) provide them with a list of state health department contact persons; 3) periodically contact them to encourage reporting; and 4) remind them of the need to have all positive screening tests for arboviral infections confirmed by state public health laboratories. In addition, CDC will provide a list of these commercial laboratories to its cooperative agreement partners, to facilitate their efforts to conduct active laboratory-based surveillance for arboviral infections. # Categories of Data to be Collected: National surveillance will focus on the collection of two general categories of data: # Clinical description Arboviral infections may be asymptomatic or may result in illnesses of variable severity sometimes associated with central nervous system (CNS) involvement. When the CNS is affected, clinical syndromes ranging from febrile headache to aseptic meningitis to encephalitis may occur, and these are usually indistinguishable from similar syndromes caused by other viruses. Arboviral meningitis is characterized by fever, headache, stiff neck, and pleocytosis. Arboviral encephalitis is characterized by fever, headache, and altered mental status ranging from confusion to coma with or without additional signs of brain dysfunction (e.g., paresis or paralysis, cranial nerve palsies, sensory deficits, abnormal reflexes, generalized convulsions, and abnormal movements). # Laboratory criteria for diagnosis - Fourfold or greater change in virus-specific serum antibody titer, or - Isolation of virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF), or other body fluid, or - Virus-specific immunoglobulin M (IgM) antibodies demonstrated in CSF by antibodycapture enzyme immunoassay (EIA), or # Appendix D -CDC-Recommended Surveillance Case Definition for WN Fever What is a CDC-Recommended Case Definition? CDC-recommended surveillance case definitions are prepared for use by U.S. States and Territories interested in conducting public health surveillance for diseases or conditions that have not been designated nationally notifiable and have not been officially approved and sanctioned by the Council of State and Territorial Epidemiologists (CSTE). A CDCrecommended case definition may not be approved by CSTE in the future, unless CSTE and the CDC program with responsibility for prevention and control of the selected disease or condition both wish to seek broader and more formalized approval from both organizations. # CASE DEFINITION # Case Description A non-specific, self-limited, febrile illness caused by infection with WNV, a mosquito-borne flavivirus. Clinical disease generally occurs 2-6 days (range, 2-15 days) following the bite of an infected mosquito. Typical cases are characterized by the acute onset of fever, headache, arthralgias, myalgias, and fatigue. Maculopapular rash and lymphadenopathy generally are observed in less than 20% of cases. Illness typically lasts 2-7 days. # Case Classification A clinically compatible illness, plus: Confirmed: 1) Fourfold or greater change in WNV-specific serum antibody titer; 2) Isolation of WNV from or demonstration of specific WN viral antigen or genomic sequences in tissue, blood, CSF, or other bodily fluid; or 3) WNV-specific IgM antibodies demonstrated in serum by antibody-capture enzyme immunoassay and confirmed by demonstration of WNV-specific serum neutralizing antibodies in the same or a later specimen. Probable: 1) WNV-specific serum IgM antibodies detected by antibody-capture enzyme immunoassay but with no available results of a confirmatory test for WNV-specific serum neutralizing antibodies in the same or a later specimen. (Note: Some WN fever cases progress to WN meningitis or encephalitis. Cases meeting the more restrictive case definition of WN encephalitis/meningitis should be reported as such and only once, using event code 10056 for "WN Encephalitis or Meningitis".) # Comment The seasonality of arboviral transmission is variable and depends on the geographic location of exposure, the specific cycles of viral transmission, and local climatic conditions. Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to identify the infecting virus by conducting crossneutralization tests using an appropriate battery of closely related viruses. This is essential, for example, in determining that antibodies detected against WNV are not the result of an infection with St. Louis encephalitis or dengue virus, or vice versa. Because dengue fever and WN fever can be clinically indistinguishable, the importance of a recent travel history and appropriate serologic testing cannot be overemphasized. In some persons, WNV-specific serum IgM antibody can wane slowly and be detectable for more than one year following infection. Therefore, in areas where WNV has circulated in the recent past, the co-existence of WNVspecific IgM antibody and illness in a given case may be coincidental and unrelated. In those areas, the testing of serially collected serum specimens assumes added importance. Larger and more detailed case series, as well as studies of short-and long-term outcome, are needed to better understand the clinical features, clinical course, and public health impact of WNV disease in humans. A suggested framework for collecting standardized "extended" clinical variables is shown below. During 2003, CDC will work with its partners to populate this framework with specific questions in each category. The use of standardized questions will allow public health officials and other researchers to compare results more readily.	# INTRODUCTION In late summer 1999, the first domestically acquired human cases of West Nile (WN) encephalitis were documented in the U.S. [1][2][3][4][5][6] The discovery of virus-infected, overwintering mosquitoes during the winter of 1999-2000 presaged renewed virus activity for the following spring and precipitated early season vector control and disease surveillance in New York City (NYC) and the surrounding areas. 7,8 These surveillance efforts were focused on identifying and documenting WN virus (WNV) infections in birds, mosquitoes and equines as sentinel animals that could alert health officials to the occurrence of human disease. Surveillance tracked the spread of WNV throughout much of the U.S. between 2000 and 2002. By the end of 2002, WNV activity had been identified in 44 states and the District of Columbia. The 2002 WNV epidemic and epizootic resulted in reports of 4,156 reported human cases of WN disease (including 2,942 meningoencephalitis cases and 284 deaths), 16,741 dead birds, 6,604 infected mosquito pools, and 14,571 equine cases. The 2002 WNV epidemic was the largest recognized arboviral meningoencephalitis epidemic in the Western Hemisphere and the largest WN meningoencephalitis epidemic ever recorded. Significant human disease activity was recorded in Canada for the first time, and WNV activity was also documented in the Caribbean basin and Mexico. In 2002, 4 novel routes of WNV transmission to humans were documented for the first time: 1) blood transfusion, 2) organ transplantation, 3) transplacental transfer, and 4) breast-feeding. WNV is a member of the family Flaviviridae (genus Flavivirus). Serologically, it is a member of the Japanese encephalitis virus antigenic complex, which includes St. Louis, Japanese, Kunjin, and Murray Valley encephalitis viruses. 9,10 WNV was first isolated in the WN province of Uganda in 1937. 11,12 Human and equine outbreaks have been recorded in portions of Africa, southern Europe, North America, and Asia. 13,14 Although it is still not known when or how WNV was introduced into North America, international travel of infected persons to New York, importation of infected birds or mosquitoes, or migration of infected birds are all possibilities. In humans, WNV infection usually produces either asymptomatic infection or mild febrile disease, sometimes accompanied by rash, but it can cause severe and even fatal diseases in a small percentage of patients. The human casefatality rate in the U.S. has been 7% overall, and among patients with neuroinvasive WNV disease, 10%. Unlike WNV within its historical geographic range, or St. Louis encephalitis (SLE) virus in the Western Hemisphere, mortality in a wide variety of bird species has been a hallmark of WNV activity in the U.S. The reasons for this are not known; however, public health officials have been able to use bird mortality (particularly birds from the family Corvidae) to effectively track the movement of WNV. WNV has now been shown to affect 162 species of birds. Previous early-season field studies have determined that areas with bird mortality due to WNV infection were experiencing ongoing enzootic transmission. However, most birds survive WNV infection as indicated by the high seroprevalence in numerous species of resident birds within the regions of most intensive virus transmission. The contribution of migrating birds to natural transmission cycles and dispersal of both WN and SLE viruses is poorly understood. 5 WNV has been transmitted principally by Culex species mosquitoes, the usual vectors of SLE virus. Thirty-six species of mosquitoes have been shown to be infected with WNV. This wide variety of WNV-infected mosquito species has widened this virus' host-range in the U.S.: 27 mammalian species have been shown to be susceptible to WNV infection and disease has been reported in of these (including humans and horses). It must be remembered, however, that the detection of WNV in a mosquito species is necessary but not sufficient to implicate that species as a competent vector of WNV. Since 1999, the Centers for Disease Control and Prevention (CDC) and a variety of other U.S. governmental agencies and partners have sponsored yearly national meetings of arbovirologists, epidemiologists, laboratorians, ecologists, vector-control specialists, wildlife biologists, communication experts, and state and local health and agriculture officials to assess the implications of the WNV introduction into the U.S. and to refine the comprehensive national response plan. Recommendations from these meetings have been used to develop and to update these guidelines. 15,16 This document is available electronically from the CDC Web site at: http://www.cdc.gov/ncidod/dvbid/westnile/publications.htm. To assist guideline implementation in 2000, CDC developed an electronic-based surveillance and reporting system (ArboNet) to track WNV activity in humans, horses, other mammals, birds and mosquitoes. In 2003, the ArboNet surveillance system has been updated to streamline reporting to CDC of WNV activity by the state public health departments. Today=s rapid transport of people, animals, and commodities increase the likelihood that other introductions of exotic pathogens will occur. CDC continues to implement its plan titled APreventing Emerging Infectious Diseases, a Plan for the 21 st Century". 17 # I. SURVEILLANCE A universally applicable arbovirus surveillance system does not exist. In any given jurisdiction, surveillance systems should be tailored according to the probability of arbovirus activity and available resources. In jurisdictions without pre-existing vector-borne disease surveillance and control programs, newly developed avian-based and/or mosquito-based arbovirus surveillance systems will be required. In some, resurrection of previously abandoned systems will be necessary. In others, modification and/or strengthening of existing arbovirus surveillance systems (i.e., those intended to monitor eastern equine encephalitis [EEE], western equine encephalitis [WEE], and/or St. Louis encephalitis [SLE] virus activity) will be the most appropriate response. In yet other jurisdictions in which the probability of arbovirus activity is very low and/or resources to support avian-based and/or mosquito-based surveillance are unavailable, laboratory-based surveillance for neurologic disease in humans and equines should be employed at minimum. Seasonality of surveillance activities may vary depending upon geographic region. With the anticipated spread of West Nile virus (WNV) to all of the 48 contiguous United States in 2003, all states should initiate surveillance after mosquitoes become active in the spring. Appropriate and timely response to surveillance data is the key to preventing human and animal disease associated with WNV and other arboviruses. That response must include effective mosquito control and public education without delay, if an increasing intensity of virus activity is detected by bird-or mosquito-based surveillance systems (see Section III.M). For basic information on arbovirus surveillance, see CDC Guidelines for Arbovirus Surveillance Programs in the United States, 18 this document can be obtained from CDC's Division of Vector-Borne Infectious Diseases, Fort Collins, Colorado, and is also available from the CDC Web site at: http://www.cdc.gov/ncidod/dvbid/arbor/arboguid.htm. # A. Ecologic Surveillance Detection of WNV in bird and mosquito populations helps health officials predict and prevent human and domestic animal infections. Surveillance to detect WNV should focus on the avian and mosquito components of the enzootic transmission cycle. Nonhuman mammals, particularly equines, may also serve as effective sentinels because a high intensity of mosquito exposure makes them more likely to be infected than people. Descriptions of the avian-, mosquito-, and non human mammal-based surveillance strategies follow. # Avian a) Avian morbidity/mortality surveillance Avian morbidity/mortality surveillance appears to be the most sensitive early detection system for WNV activity, and should be a component of every state's arbovirus surveillance program. Its utility for monitoring ongoing transmission in a standardized fashion is currently being investigated, but should include at least two basic elements: the timely reporting and analysis of dead bird sightings and the submission of selected individual birds for WNV testing. GOAL OF AVIAN MORBIDITY/MORTALITY SURVEILLANCE: Utilize bird mortality associated with WNV infection as a means of detecting WNV activity in a location. # 1) Protocols and specimens The level of effort involved in this surveillance activity will depend on a risk assessment in each jurisdiction. Generally, avian surveillance should be initiated when local adult mosquito activity begins in the spring. A database should be established to record and analyze dead bird sightings with the following suggested data: caller identification and call-back number, date observed, location geocoded to the highest feasible resolution, species, and condition. Samples from birds in good condition (unscavenged and without obvious decomposition or maggot infestation) may be submitted for laboratory testing. As with all dead animals, carcasses should be handled carefully, avoiding direct contact with skin. For greatest sensitivity, a variety of bird species should be tested, but corvids should be emphasized. 19 The number of bird specimens tested will be dependent upon resources and whether WNV-infected birds have been found in the area; triage of specimens may be necessary on the basis of sensitive species (such as corvids) and geographic location. Many jurisdictions may limit (or even stop) avian mortality surveillance once WNV is confirmed in their region. It is suggested that avian mortality surveillance be continued in each region as long as it remains necessary to know whether local transmission persists, because dead-bird-based surveillance is the most sensitive method for detection of WNV activity in most regions. A single organ specimen from each bird is sufficient to detect WNV or viral RNA. Kidneys, brains, or hearts are preferable. [20][21][22] Oral swabs from corvids have been validated as a sensitive alternative to organ samples, and because fewer resources are necessary to acquire them, oral swabs are the preferred specimen from corvid carcasses. 23 Testing involves isolation of infectious virus, specific RNA detection by reverse transcription-polymerase chain reaction (RT-PCR), 24 or antigen detection, 25,26 and will generally be positive within 1-2 weeks after specimen submission. # 2) Recent experience Analysis of recent avian morbidity and mortality data indicated that (a) The American crow was the most sensitive species for avian morbidity/ mortality surveillance in northern regions. However, some areas did not have WNV-positive American crows, but only WNV-positive birds of other species. In southern regions, blue jays have been more sensitive than crows. (b) Almost all of the positive birds were found singly and not as part of a mass die-off at a single time and place. (c) Approximately one-third of the WNV-positive birds had signs of trauma on necropsy. (d) Many WNV-positive birds did not have pathology indicative of WNV infection on necropsy. No lesions are pathognomonic for WNV infection. (e) WNV-positive dead birds usually provided the earliest indication of viral activity in an area. In 2002, the detection of WNV-infected dead birds was the first positive surveillance event in 1,534 (61%) of 2,531 counties reporting WNV activity. (f) The detection of WNV-positive dead birds preceded reports of human cases (although knowledge of the test result did not necessarily predate the onset of human cases). In 2002, 527 (89%) of 589 counties reporting human WN meningoencephalitis cases first detected WNV transmission in animals. In 327 (72%) of these 527 counties, detection of WNVinfected dead birds was the first positive surveillance event, preceding human illness onset by a median of 38.5 days (range, 2-252 days). (g) Many counties with human cases of WNV infection tended to have high dead bird surveillance indices, both WNV-positive and sightings. Notable exceptions included sparsely populated counties, particularly those in the midwestern states. 27,28 (h) Experimental evidence of direct transmission among corvids and gulls exists, but whether this occurs in nature is unknown. 29 If it does, then in some settings, virus-infected mosquitoes might not be necessary to maintain enzootic transmission cycles. 3) Advantages of avian morbidity/mortality surveillance include the following: (a) Certain species of birds, in particular corvids (e.g., crows and jays) experience high clinical attack rates. (b) The size and coloration of certain dead birds makes them conspicuous (e.g., crows). (c) RT-PCR and antigen-detection assays can be used to rapidly detect WN viral RNA and protein, respectively, in tissues, even if the tissue is partly decomposed. Both assays have now been adapted for field applications. (d) Due to public involvement in reporting dead bird sightings, dead wild birds are readily available over a much wider region than can be sampled by other surveillance methods. (e) Detection of WNV in dead birds likely signifies local transmission. 30 (f) This type of surveillance provides a temporally and spatially sensitive method for the detection of WNV activity. (g) It can be used for early detection and possibly also for ongoing monitoring of WNV transmission. (h) It may be used to estimate risk of human infection with WNV . 27,31,32 4) Disadvantages of avian morbidity/mortality surveillance include the following: (a) Dead bird surveillance data from different jurisdictions are difficult to compare. (b) Birds are highly mobile and often have extensive home ranges, so that the site of death may be distant from the site of infection (especially after the breeding season, when birds are generally less territorial). # 9 (c) Collection, handling, shipping, and processing of birds or their clinical specimens is cumbersome. (d) Systems for handling, processing, and testing have at times been overwhelmed by high public response and public expectations. (e) The long-term usefulness of this system is uncertain because natural selection for disease-resistant birds may occur, populations of susceptible species may become very low, or the virus may evolve, resulting in low or no avian mortality. In areas where WNV annually recurs, intense environmental sampling might not be as useful. (f) Success is influenced by public participation, which is highly variable, and depends on the number of public outreach programs, level of public concern, etc. (g) The system may be less sensitive in rural areas, where there are fewer persons to observe dead birds over a wider geographic area. In the western U.S., low observer density is coupled with the presence of a vector (Culex tarsalis) that is less ornithophilic, resulting in fewer reports of dead birds relative to other non-avian surveillance indicators. # b) Live bird surveillance Live-bird surveillance has been used traditionally both to detect and monitor arbovirus transmission (e.g., for SLE, EEE and WEE viruses). Two approaches are captive sentinel surveillance (typically using chickens, but other species have been used as well), and free-ranging bird surveillance. 33 Both depend on serological testing, which generally requires at least 3 weeks to detect and confirm an infection. Successful application of these approaches requires extensive knowledge of local transmission dynamics. It is recommended that further research be done before relying on sentinel birds as a primary means of WNV surveillance. Use of sentinel birds may require institutional animal use and care protocols, and other authorization permits. GOAL OF LIVE-BIRD SURVEILLANCE: Utilize seroconversions in captive or free-ranging bird species as indicators of local WNV activity. # 1) Captive sentinel surveillance Although an ideal captive avian sentinel for WNV --or any other arbovirus -may not exist, such a species would meet the following criteria: 1) is universally susceptible to infection, 2) has a 100% survival rate from infection and universally develops easily detectable antibodies, 3) poses no risk of infection to handlers, and 4) never develops viremia sufficient to infect vector mosquitoes. 18 Captive sentinels have been effectively used to monitor transmission of arboviruses in a standardized fashion, including SLE virus in California and Florida, especially in historical enzootic transmission foci. Captive sentinel flocks should be placed in likely transmission foci (e.g., near vector breeding sites or adult mosquito congregation sites), and presented appropriately to allow feeding by enzootic WNV vectors. Alternatively, pre-existing captive birds (e.g., domestic poultry or pigeons, or zoo birds) may be used as sentinels. (a) Protocols and specimens Whole blood can be collected and centrifuged for serum. Serum is screened by either hemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA) or plaque-reduction neutralization test (PRNT). 34 It is important to note that the extraction of avian serum samples to remove non specific inhibitors of hemagglutination for use in the HI test follows procedures different from those used in tests of human serum samples. 35 Positive tests must be confirmed by neutralization to rule out false positives and cross-reactions due to infection with related flaviviruses (e.g., SLE virus). testing of experimentally infected chickens points to the need for biweekly sampling of sentinels. 36 (iii) Experimental studies have shown that chickens, pigeons, and pheasants (CDC, unpublished data) are candidate sentinels due to their susceptibility to infection, low mortality, and relative incompetence as amplifying hosts. However, small amounts of WNV were detected in cloacal swabs from infected chickens and pigeons. 29,37 (iv) Field studies of avian seroprevalence in Queens in 1999 indicated that captive chickens frequently were infected. 38 In Staten Island in 2000, captive pigeons frequently were infected. 39 (v) Some mortality in chickens was attributed to WNV at various locations in New York State. 40 (c) Advantages of sentinel captive bird surveillance include the following: (i) Chickens have been successfully used in flavivirus surveillance for over 6 decades. (ii) Birds are readily fed upon by Culex mosquitoes. (iii) Captive birds can be serially bled, making the geographic location of infection definite. (iv) The system is flexible and therefore can be expanded and contracted as appropriate. (v) Mosquito-abatement districts can maintain and bleed flocks and submit specimens for testing. (vi) Collection of specimens is inexpensive compared with the costs of free-ranging bird surveillance. (d) Disadvantages of captive sentinel surveillance include the following: (i) Sentinel flocks detect only focal transmission, requiring multiple flocks be positioned in representative geographic areas. This is particularly true when vector mosquitoes have short flight ranges (e.g., Culex pipiens). (ii) Flocks are subject to vandalism and theft. (iii) Flocks must be protected from predators. (iv) Flock set-up and maintenance (i.e., birds, cages, feed, transportation) are expensive. Training is required for proper maintenance and sampling. (v) Pre-existing flocks may already have been exposed due to previous local WNV transmission. # 2) Free-ranging bird surveillance Free-ranging birds provide the opportunity for sampling important reservoir host species and may be used both for early detection and for monitoring virus activity. This type of surveillance has been used effectively for SLE, EEE and WEE virus surveillance in several states. In each geographic area, the optimal free-ranging bird species to be monitored should be determined by serosurveys. The best species for serologic surveillance are those in which infection is rarely, if ever, fatal, and population replacement rates are high, ensuring a high proportion of uninfected individuals. (a) Protocols and specimens The use of free-ranging birds requires differentiation of recent infection from infections acquired in previous years. For most species, assays for detection of IgM antibody will not be available and other tests such as IgG (IgY)-detection ELISAs 41,42 and the PRNT 34 must be used to detect WNV-specific antibody. Antibody-positive birds less than 1 year old may be presumed to have been infected recently (during current transmission season). Weak seropositivity in very young birds (less than 1 month old) may be due to maternal transfer of antibody. Seroconversion in older birds is also evidence of recent transmission, but requires frequent recapture for acquisition of multiple specimens from uniquely banded individuals during the course of the transmission season. WNV seropositivity among afterhatch-year birds, when determined from a single serum specimen, should not be interpreted or reported as evidence of recent infection. State and federal permits are required for capture and banding of federally-protected migratory birds. (b) Recent experience (i) In urban epizootic transmission foci in NYC, several common species (i.e., house sparrows, cardinals, catbirds, mourning doves, rock doves) developed high seroprevalence, making them strong candidate sentinels, although other species may be important in other locations. 38,39 (ii) A comparison of free-ranging bird surveillance in NYC in 2001 found that much greater effort was required for this surveillance system compared with other surveillance systems (Green Street Scientific, LLC, unpublished data). Similar observations have been made in Indiana, Louisiana, New Jersey, Ohio, and Texas. (c) Advantages of free-ranging bird surveillance include the following: (i) It has a long history of successful use in flavivirus surveillance. (ii) Local movement of resident wild birds may increase contact with enzootic transmission foci, thus increasing sensitivity (relative to captive sentinels). (iii) Set-up or maintenance costs may be minimal. (iv) Its sampling capability is highly flexible. (v) It permits evaluation of herd immunity among important amplifying hosts. (vi) Owner confidentiality may be less of an issue. (d) Disadvantages of free-ranging bird surveillance include the following: (i) Interpretation of serologic results is complex. (ii) Handling and venipuncture of birds increases the risk of exposure to pathogens in blood and feces. (iii) Movement of free-ranging wild birds makes it impossible to know where an infection was acquired. (iv) Most birds are protected by federal law, and their collection and sampling requires state and federal permits. Banding permits require complex data reporting. (v) Training is required for live-trapping, blood-sampling, handling, and accurate determination of the species and age of wild birds. (vi) It is generally not feasible to serially bleed individual free-ranging birds because of low recapture rates (although banding can be useful). # Equine Equines appear to be important sentinels of WNV epizootic activity and human risk, at least in some geographic regions. 2) In general, equine WNV disease cases have been scattered. Few case clusters have been documented. 3) In fatal equine WNV disease cases, pathological findings have been nonspecific. Pathognomonic lesions have not been described. # 4) A licensed equine WNV vaccine has been available in the U.S. since 2001. No studies of efficacy have been published. c) Advantages of equine disease surveillance include the following: 1) Equines are highly conspicuous, numerous, and widely distributed in some areas. They may be particularly useful sentinels in rural areas, where dead birds may be less likely to be detected. 2) Some equines are routinely bled and tested for other pathogens. 3) Ill equines have been one of the earliest, if not the earliest, sentinels of WNV activity in some geographic areas. d) Disadvantages of equine disease surveillance include the following: 1) In some geographic areas, equines may not be an early sentinel (i.e., human WNV disease cases may occur simultaneously with or soon after equine cases). 2) Necropsies are expensive and logistically difficult. 3) Equines are not present or abundant in many areas of the U.S. (e.g., densely populated metropolitan areas), and proximity of equines to human populations varies. 4) Widespread use of equine WNV vaccines may decrease the incidence of equine WNV disease and therefore the usefulness of equines as sentinels. # 5) Because the costs of clinical equine specimen collection and testing are usually borne directly by the owner, economic factors work against the submission and testing of equine specimens for arboviral infections. e) Minimal components of an equine surveillance program 1) All equine neurologic disease cases should be promptly reported; the equines should be tested for infection with WNV and other arboviruses as geographically appropriate, and for rabies. 2) Clusters of equine neurologic disease cases should be promptly investigated. # Mosquito While dead-bird-based surveillance has proven to be the most sensitive method of detecting WNV presence in an area, mosquito-based surveillance remains the primary tool for quantifying the intensity of virus transmission in an area, and should be a mainstay in most surveillance programs for WNV and other arboviruses. # GOALS OF MOSQUITO-BASED SURVEILLANCE: To 1) use data on mosquito populations and virus infection rates to assess the threat of human disease; 2) identify geographic areas of high risk; 3) assess the need for and timing of interventions; 4) identify larval habitats for targeted control; 5) monitor the effectiveness of this type of surveillance and improve prevention and control measures; and 6) develop a better understanding of transmission cycles and potential vector species. a) Protocols and specimens 1) Adult mosquitoes are collected using a variety of trapping techniques and are used to identify the mosquito species and primary vector species present in an area and the relative density of those species. When coupled with virus detection protocols, mosquito collections can be screened for the presence of virus and provide a quantifiable index of WNV activity. Adequate sampling requires trapping regularly at representative sites throughout a community, and rapid testing of collections of sufficient size to detect low infection rates in the vector population. Minimally, adult mosquito density (number collected per trap night) and infection rate (number of individual mosquitoes estimated containing WNV per 1,000 specimens tested) should be recorded for each area to provide a basis for tracking mosquito density and virus incidence. 15 2) Larval mosquitoes are collected by taking dip samples from a variety of habitats to identify species present in the area and to identify mosquito sources. Thorough mapping of larval habitats will facilitate larval control or source reduction activities. In addition, where larval management is not feasible, quantitative estimates of larval densities will permit anticipation of new adult emergences. Minimally, the number of larvae collected per dip and location where collected should be recorded to provide a basis for tracking larval production and association of larval density with resulting adult mosquito population density. b) Recent experience 1) If mosquito trapping effort is intensive, detection of WNV in mosquitoes might precede detection of virus activity by other surveillance tools. If mosquito trapping effort is inadequate, WNV-positive mosquitoes may not be detected prior to the identification of a virus in dead bird, sentinel animal, or human WNV disease cases. 2) Moderate to high infection rates sustained for several weeks in Cx. pipiens or Cx. quinquefasciatus have been associated with subsequent human outbreaks. Sustained high infection rates early in the year are associated with a higher risk for subsequent outbreaks. 3) Several intense, focal outbreaks during 2002 were associated with relatively low vector densities, but with high infection rates in key vector species (i.e., infection rates in Cx. pipiens or Cx. quinquefasciatus of approximately 10 per 1,000 or greater). 1) It may provide the earliest evidence of transmission in an area. 2) It helps establish information on potential mosquito vector species. 3) It provides an estimate of vector species abundance. 4) It gives quantifiable information on virus infection rates in different mosquito species. 5) It provides quantifiable information on potential risk to humans and animals. 6) It provides baseline data that can be used to guide emergency control operations. 7) It allows evaluation of control methods. d) Disadvantages of mosquito-based surveillance include the following: 1) It is labor-intensive and expensive. 2) Substantial expertise is required for collecting, handling, sorting, species identification, processing, and testing. 3 (iii) Proximity to human population centers and/or recreational areas; and (iv) Flight range of vector species in the area. ) 2) Laboratory support to identify the mosquitoes' species, and to test the specimens for the presence of WNV. Determine infection rates by species. (a) Make arrangements with a lab for testing. Rapid turnaround is essential. (b) Focus initially on Culex mosquitoes to provide first indication of WNV presence. (c) Once virus is detected in Culex mosquitoes, pool and test all potential vector species with emphasis on incriminated or suspected species. (3) Data management and analysis capabilities to allow tracking of adult mosquito densities and infection rates over time and space. Patterns of virus activity are more likely to be useful than predetermined threshold levels. (4) Development of a plan with descriptions of actions that will be taken in response to indicators of WNV activity. # B. Surveillance for Human Cases Because the primary public health objective of surveillance systems for neurotropic arboviruses is prevention of human infections and disease, human case surveillance alone should not be used for the detection of arbovirus activity, except in jurisdictions where arbovirus activity is rare, or resources to support avian-based and/or mosquitobased arbovirus surveillance are unavailable. e) Using CDC-recommended test methods in public health laboratories, WNVspecific IgM antibody was detected in acute-phase (i.e., those collected 8 or less days after illness onset) serum or CSF specimens, or both, in the large majority of confirmed cases. In contrast, only a small minority of suspected cases were subsequently confirmed in which specific IgM antibody reactivity in acute-phase serum or CSF was in the equivocal or low-positive range. # GOALS OF SURVEILLANCE FOR HUMAN CASES f) Longitudinal studies of WNME cases have shown that WNV-specific IgM antibody can persist in serum for 12 months or longer. 43 Thus, the presence of WNV-specific IgM antibody in a single serum sample is not necessarily diagnostic of acute WN viral infection. For this reason, especially in areas where WNV is known to have circulated previously, suspected, acute WN viral disease cases should be confirmed by observing a fourfold or more change in titer of WNV-specific antibody in serum and the presence of WNV-specific IgM antibody in CSF, when available. i) For suspected WNV disease cases in immunocompromised patients, WNVspecific antibody may not be present. Since longer viremias may be observed in these patients, testing serum and CSF samples for the presence of virus or viral RNA may be useful. # Types of Surveillance a) Clinical syndromes to monitor Monitoring of encephalitis cases is the highest priority. Monitoring milder illnesses (e.g., aseptic meningitis, Guillain-Barré syndrome, acute flaccid paralysis, and brachial plexopathy, and fever or rash illnesses) is resourcedependent and should be of lower priority. # b) Types of human surveillance 1) Enhanced passive surveillance In the absence of known WNV activity in an area, enhanced passive surveillance* for hospitalized cases of encephalitis (and milder clinical syndromes as resources allow*), and for patients who have IgM antibodies to either WN or SLE virus in tests conducted in diagnostic or reference laboratories, should be employed. A high clinical suspicion for arboviral encephalitis should be encouraged among health care providers. When the diagnosis is in doubt, appropriate clinical specimens should be submitted to CDC or another laboratory capable of performing reliable serologic testing for antibodies to domestic arboviruses. Testing of CSF and paired acute-and convalescent-phase serum samples should be strongly encouraged to maximize the accuracy of serologic results. # 2) Active surveillance Active surveillance should be strongly considered in areas with known WNV activity. In general, one or both of the following approaches should be taken: (a) Contact physicians in appropriate specialties (i.e., infectious diseases, neurology, and critical care) and hospital infection control personnel on a regular basis to inquire about patients with potential arboviral infections; (b) Implement laboratory-based surveillance to identify CSF specimens Passive surveillance enhanced by general alerts to key health care personnel such as primary care providers, infectious disease physicians, neurologists, hospital infection control personnel, and diagnostic laboratories. # 20 ** While human infections with neurotropic arboviruses are usually clinically inapparent, most clinically apparent infections are associated with fever, with or without neurologic manifestations, which can range from mild aseptic meningitis to fulminant and fatal encephalitis. Signs and symptoms may include fever, headache, stiff neck, confusion or other mental status changes, nausea, vomiting, meningismus, cranial nerve abnormalities, paresis or paralysis, sensory deficits, altered reflexes, abnormal movements, convulsions, and coma of varying severity. Arboviral meningitis or encephalitis cannot reliably be clinically distinguished from other central nervous system infections. meeting sensitive but nonspecific criteria for arboviral infections (e.g., mild to moderate pleocytosis and negative tests for the presence of nonarboviral agents such as bacteria, fungi, herpesviruses, and enteroviruses) and test them for evidence of WNV infection. # 3) Special surveillance projects Special projects may be used to enhance arboviral disease surveillance. Such projects include the Emerging Infections Network of the Infectious Diseases Society of America (IDSA EIN), Emergency Department Sentinel Network for Emerging Infections (EMERGEncy ID NET), Unexplained Deaths and Critical Illnesses Surveillance of the Emerging Infections Programs (EIP), and the Global Emerging Infections Sentinel Network of the International Society of Travel Medicine (GeoSentinel). In some areas, syndromic surveillance systems may be considered. "Piggy-backing" surveillance for WNME and milder clinical forms of WN viral infection, such as fever with rash or lymphadenopathy, onto existing syndromic surveillance systems, especially those involving large health maintenance organizations, may be considered. Real-time computerized syndromic surveillance in emergency departments, and special surveillance projects to identify WNV disease in pediatric populations, may be useful. # Specimens a) Cerebrospinal fluid (CSF) In WNME cases, WNV-specific IgM antibody commonly can be found in CSF on the day of illness onset using antibody-capture ELISA. Virus also may be isolated (rarely) or detected by RT-PCR (in up to 60% of cases) in acute-phase CSF samples. # b) Serum Paired acute-phase (collected 0-8 days after onset of illness) and convalescentphase (collected 14-21 days after the acute specimen) serum specimens are useful for demonstration of seroconversion to WNV and other arboviruses by ELISA or neutralization tests. Although tests of a single acute-phase serum specimen may provide evidence of a recent WNV infection, a negative acutephase specimen is inadequate for ruling out such an infection, underscoring the importance of collecting paired samples. As mentioned previously, antibody synthesis in immunocompromised individuals might be delayed or absent altogether. # c) Tissues When arboviral encephalitis is suspected in a patient who undergoes a brain biopsy or who dies, tissues (especially brain samples, including samples of cortex, midbrain, and brainstem), heart/venous blood, and buffy coat samples should be submitted to CDC or other specialized laboratories for arbovirus and other testing. Tissue specimens should be divided; half should be frozen at -70°C and the other half fixed in formalin. Available studies include gross pathology, histopathology, RT-PCR tests, virus isolation, and immunohistochemistry. # Surveillance Case Definition The national case definition for arboviral encephalitis (available at www.cdc.gov/epo/dphsi/casedef/encephalitiscurrent.htm) should be used to classify cases as confirmed or probable, once appropriate laboratory results are available (also see Section II). In CDC publications of national arbovirus surveillance data, no distinction is usually made between confirmed and probable human cases for the purposes of case counting. # Minimal Components of a Human Surveillance System Enhanced passive surveillance for hospitalized encephalitis cases of unknown etiology, and for patients who have IgM antibodies to either WN or SLE virus in tests conducted in diagnostic or reference laboratories. # C. Geography and Timing In general, the WNV transmission season in the U.S. is longer than that for other domestic arboviruses and requires longer periods of ecologic and human surveillance. # Northeastern and Midwestern U.S. In the northeastern states in 2001-2002, human illness onset occurred as early as early July and as late as mid-November. During these same years, avian cases occurred as early as the first week of April and as late as the second week of December. Active ecological surveillance and enhanced passive surveillance for human cases should begin in early spring and continue through the fall until mosquito activity ceases because of cold weather. Surveillance in urban and suburban areas should be emphasized. # Southern U.S. In 2001-2002, WNV circulated throughout the year, especially in the Gulf states. Although, in 2001-2002, human illness onset was reported as early as mid-May and June and as late as mid-December, equine and avian infections were reported in all months of the year. Active ecologic surveillance and enhanced passive surveillance for human cases should be conducted year round in these areas. # Western U.S. In 2002, WNV activity was first reported among humans and animals in Rocky Mountain states and among animals in Pacific coast states. These events occurred relatively late in the year (mid-August). Predicting the temporal characteristics of future WNV transmission seasons based on these limited reports is not possible. Despite this limitation, active ecological surveillance and enhanced passive surveillance for human cases beginning in early spring and continuing through the fall until mosquito activity ceases because of cold weather should be encouraged. # Other Areas of the Western Hemisphere In 2002, Canada experienced a WNV epidemic in Ontario and Quebec provinces and an equine/avian epizootic that extended from the maritime provinces to Saskatchewan. Recent serologic evidence supports the conclusion that WNV has now reached Central America. Further spread to South America by migratory birds seems inevitable, if this has not already occurred. Development of surveillance systems capable of detecting WNV activity should be encouraged in the Caribbean and Central and South America. WNV surveillance should be integrated with dengue surveillance in these areas, and with yellow fever surveillance in areas where urban or peri-urban transmission of this virus occurs. # II. LABORATORY DIAGNOSIS The clinical presentation of most patients with viral encephalitis is similar regardless of the cause. Also, infection by many of the arboviruses that cause encephalitis, including West Nile and St. Louis encephalitis viruses, usually is clinically inapparent, or causes a nonspecific viral syndrome in most patients. Definitive diagnosis, therefore, can only be made by laboratory testing using specific reagents. To be successful, active surveillance must have adequate laboratory support. The basic laboratory diagnostic tests-and how they should be used at the national, state, and local level-are outlined below. The initial designation of reference and regional laboratories that can do all testing will be based on the availability of biosafety level 3 (BSL3) containment facilities. Details of the surveillance case definition for human West Nile virus (WNV) disease and of how the laboratory diagnostic tests are used to support surveillance are presented in Appendix B. A. Biocontainment # Laboratory Safety Issues Laboratory-associated infections with WNV have been reported in the literature. The Subcommittee on Arbovirus Laboratory Safety (SALS) in 1980, reported 15 human infections from laboratory accidents. One of these infections was attributed to aerosol exposure. Recently, two parenteral inoculations have been reported during work with animals. a) WNV may be present in blood, serum, tissues and CSF of infected humans, birds, mammals and reptiles. The virus has been found in the oral fluids and feces of birds. Parenteral inoculation with contaminated materials poses the greatest hazard; contact exposure of broken skin is a possible risk. Sharps precautions should be strictly adhered to when handling potentially infectious materials. Workers performing necropsies on infected animals may be at high risk of infection. f) Virus neutralization assays also may be used to differentiate viruses, by using fourfold or greater titer differences as the diagnostic criterion in paired specimens (acute-and convalescent-phase). # Virus Detection in Tissues a) Antigenic analysis 1) Immunohistochemistry (IHC) using virus-specific MAbs on brain tissue has been very useful in identifying both human and avian cases of WNV infection. In suspected fatal cases, IHC should be performed on formalinfixed autopsy, biopsy, and necropsy material, ideally collected from multiple anatomic regions of the brain, including the brainstem, midbrain, and cortex. 24,49 2) Well-characterized antigen-capture ELISAs are now available for detection of SLE 50,51 and WNV antigen in mosquito pools and avian tissues. 25 b) Nucleic acid analysis A number of nucleic acid detection methods have recently been employed for WNV diagnostic and surveillance purposes. An independent antigen or nucleic acid test is required to confirm detection of WNV nucleic acid with any of these methods. 1) RT-PCR of tissues, mosquito pools, and CSF has proven to be a useful surveillance tool. RT-nested PCR has detected WNV nucleic acid in equine brain and spinal cord tissues. Standardized protocols developed by reference laboratories should be disseminated, and primer design information should be included so that other laboratories can prepare primers. A proficiency testing program should be developed by the reference laboratories so that these tests can be CLIA-certified in local laboratories. 2) Fluorogenic 5' nuclease techniques (real-time PCR) and nucleic acid sequence-based amplification (NASBA) methods have been developed and have undergone initial validation in specific diagnostic applications. 24,[52][53][54] # D. Training and Infrastructure # State and Local Arbovirus Laboratories Greater numbers of capable state and local laboratories performing screening assays (such as ELISA) should be developed to reduce time demands on reference laboratories. Reference laboratories should be utilized to confirm results of state and local laboratories, particularly for the initial identification of WNV in new locations and in new hosts. # Training Programs Laboratory training programs have been developed and implemented at the federal level. Additional regional training programs may be beneficial. # III. PREVENTION AND CONTROL Prevention and control of arboviral diseases is accomplished most effectively through a comprehensive, integrated mosquito management program using sound integrated pest management (IPM) principles. 55 IPM is based on an understanding of the underlying biology of the transmission system, and utilizes regular monitoring to determine if and when interventions are needed to keep pest numbers below levels at which intolerable levels of damage, annoyance, or disease occur. IPM-based systems employ a variety of physical, mechanical, cultural, biological and educational measures, singly or in appropriate combination, to attain the desired pest population control. Programs consistent with best practices and community needs should be established at the local level and, at a minimum, should be capable of performing surveillance sensitive enough to detect West Nile Virus (WNV) enzootic/epizootic transmission that has been associated with increased risk of disease in humans or domestic animals. Integrated mosquito management programs designed to minimize risk of WNV transmission and prevent infections of humans and domestic animals should optimally include the following components (modified from information provided by the American Mosquito Control Association, the New Jersey Mosquito Control Association, and the Florida Coordinating Council on Mosquito Control) [56][57][58] A. Surveillance Effective mosquito control begins with a sustained, consistent surveillance program that targets pest and vector species, identifies and maps their immature habitats by season, and documents the need for control. Records should be kept on the species composition of mosquito populations prior to enacting control of any kind and to allow programs to determine the effectiveness of control operations. All components of the integrated management program must be monitored for efficacy using best practices and standard indices of effectiveness. The following is a list of surveillance methodologies used by mosquito control agencies. # Larval Mosquito Surveillance Larval surveillance involves sampling a wide range of aquatic habitats for the presence of pest and vector species during their developmental stages. Most established programs have a team of trained inspectors to collect larval specimens on a regular basis from known larval habitats, and to perform systematic surveillance for new sources. A mosquito identification specialist normally identifies the larvae's species. Properly trained mosquito identification specialists can separate nuisance and vector mosquito species. Responsible control programs target vector and nuisance populations for control and avoid managing habitats that support benign species. # Adult Mosquito Surveillance Adult mosquito surveillance is used to monitor species presence and relative abundance of adult mosquitoes in an area. Information derived from adult mosquito surveillance programs using standardized and consistent surveillance efforts provide information essential to monitoring potential vector activity, setting action thresholds, and evaluating control efforts. Various methods are available for this purpose and have been demonstrated to be effective in collecting a variety of mosquito species. 59 The New Jersey light trap, CDC's miniature light trap, and other modifications of this design, with or without carbon dioxide bait, have been used extensively for collecting host-seeking adult mosquitoes. 60 Gravid traps frequently are used to monitor the ovipositing segment of Cx. pipiens and Cx. restuans populations. These species have been incriminated as the primary enzootic vectors of WNV in the northeastern states. 61,62 Host-seeking Cx. tarsalis, a species that has been strongly associated with WNV transmission in areas where this species is common, are readily collected in CO 2 -baited CDC miniature light traps. Resting boxes frequently are used to measure populations of Culiseta melanura, a bird-feeding mosquito that is important in the amplification of eastern equine encephalitis (EEE) virus. Pigeon-baited traps may be employed to measure host-seeking Culex mosquitoes that amplify St. Louis encephalitis (SLE) and West Nile viruses. Day-active mosquitoes like Ae. albopictus are difficult to collect, and obtaining a sample representative of the local populations requires extra effort. Where these species are important, sample sizes may be enhanced by using CO 2 -baited CDC miniature light traps during daylight hours or by using alternative trap configurations that may be more effective in collecting these species (e.g., Fay trap or traps using a counterflow geometry). Trap deployment should carefully address species habitat requirements on several spatial scales. # Virus Surveillance The purpose of this component of the vector management program is to determine the prevalence of WNV in the mosquito population. This is often expressed simply as the number of WNV-positive mosquito pools of a given species collected at a defined location and time period. While the number of positive pools provides valuable information, it does not provide an index of virus prevalence in the vector population. Preferably, the proportion of the mosquito population carrying the virus should be expressed as the infection rate (IR, expressed as the estimated number of infected individual mosquitoes per 1,000 specimens tested). This is a more useful index of virus prevalence. The IR can be calculated by dividing the number of positive pools by the total number of specimens tested for that species and collection period, and multiplying the proportion by 1,000. This assumes that a positive pool contains only one infected mosquito, which is a valid assumption in most circumstances. # B. Source Reduction 29 Source reduction is the alteration or elimination of mosquito larval habitat breeding. This remains the most effective and economical method of providing long-term mosquito control in many habitats. Source reduction can include activities as simple as the proper disposal of used tires and the cleaning of rain gutters, bird baths and unused swimming pools by individual property owners, to extensive regional water management projects conducted by mosquito control agencies on state and/or federal lands. All of these activities eliminate or substantially reduce mosquito breeding habitats and the need for repeated applications of insecticides in the affected habitat. Source reduction activities can be separated into the following two general categories: # Sanitation The by-products of human's activities have been a major contributor to the creation of mosquito breeding habitats. An item as small as a bottle cap or as large as the foundation of a demolished building can serve as a mosquito breeding area. Sanitation, such as tire removal, stream restoration, catch-basin cleaning and container removal, is a major part of all integrated vector management programs. Mosquito control agencies in many jurisdictions have statutory powers that allow for due process and summary abatement of mosquito-related public health nuisances created on both public and private property. The sanitation problems most often resolved by agency inspectors are problems of neglect, oversight, or lack of information on the part of property owners. Educational information about the importance of sanitation in the form of videos, slide shows, and fact sheets distributed at press briefings, fairs, schools and other public areas are effective. # Water Management Water management for mosquito control is a form of source reduction that is conducted in fresh and saltwater breeding habitats. Water management programs for vector control generally take two forms, described below. Water management through impoundment and open water management have been very effective in the past. Recently, restrictions on modification of aquatic habitats have limited the implementation of these practices, and in many areas, water management for vector control is no longer routinely employed and may be impractical in many settings. In these situations, alternative methods of mosquito management must be employed. a) Impoundment Management Impoundments are mosquito-producing marshes around which dikes are constructed, thereby allowing water to stand or to be pumped onto the marsh surface from the adjacent estuary. This eliminates mosquito oviposition sites on the impounded marsh and effectively reduces their populations. Rotational Impoundment Management (RIM) is the technique developed to minimally flood the marsh during the summer months and then use flapgated culverts to reintegrate impoundments to the estuary for the remainder of the year, thereby allowing the marsh to provide many of its natural functions. Although impoundments usually achieve adequate control of salt-marsh mosquitoes, there are situations in which impoundments can collect stormwater or rainwater and create freshwater mosquito problems that must be addressed using other techniques. # b) Open Marsh Water Management (OMWM) Ditching as a source-reduction mosquito control technique has been used for many years. Open marsh water management is a technique whereby mosquitoproducing locations on the marsh surface are connected to deep-water habitat (e.g., tidal creeks, deep ditches) with shallow ditches. Mosquito broods are controlled without pesticide use by allowing larvivorous fish access to mosquito-producing depressions. Conversely, the draining of these locations occurs before adult mosquitoes can emerge. OMWM can also include establishing or improving a hydrological connection between the marsh and estuary, providing natural resource enhancement as well as mosquito control benefits. The use of shallow ditching (ditches approximately 3 feet or less in depth rather than the deep ditching used in years past) is considered more environmentally acceptable because than deep ditching because fewer unnatural hydrological impacts occur to the marsh. # c) Management in Stormwater Retention Structures Source reduction and water management practices may also be applied to stormwater retention structures designed to hold runoff before it is discharged into groundwater or surface water. Mosquito control should be considered in the design, construction, and maintenance of these structures, as appropriate. Stormwater retention structures should be designed in consultation with experts in mosquito biology and control to prevent as much mosquito production as possible, and to facilitate proper functioning and maintenance in the future. Regulations associated with stormwater retention and flood control structures should incorporate appropriate operations and maintenance provisions including considerations for routine monitoring and control of mosquito populations. # C. Chemical Control Insecticides can be directed against either the immature or adult stage of the mosquito life cycle when source reduction and water management are not feasible or have failed because of unavoidable or unanticipated problems, or when surveillance indicates the presence of infected adult mosquitoes that pose a health risk. 63 Chemicals used by mosquito control agencies must comply with state and federal requirements. Public health pesticide applicators and operators in most states are required to be licensed or certified by the appropriate state agencies. # Larviciding # 31 Larviciding, the application of chemicals to kill mosquito larvae or pupae by ground or aerial treatments, is typically more effective and target-specific than adulticiding, but less permanent than source reduction. An effective larviciding program is an important part of an integrated mosquito control operation. The objective of larviciding is to control the immature stages at the breeding habitat before adult populations have had a chance to disperse and to maintain populations at levels at which the risk of arbovirus transmission is minimal. Larvicides can be applied from the ground or by aerial application if large or inaccessible areas must be treated. Several materials in various formulations are labeled for mosquito larviciding including the organophosphate temephos (Abate); several biological larvicides such as Bacillus thuringiensis israelensis (Bti, a bacterial larvicide), Bacillus sphaericus; methoprene, an insect growth regulator (e.g., Altosid,); several larvicidal oils (e.g., petroleum-based Golden Bear and mineral-based Bonide) and monomolecular surface films (e.g., Agnique, Arosurf); and in some limited habitats diflubenzuron (e.g., Dimilin, a chitin synthesis inhibitor). Applications of larvicides often encompass fewer acres than adulticides because treatments are made to relatively small areas where larvae are concentrated, as opposed to larger regions where adults have dispersed. When applying larvicides, it is important that the material be specific for mosquitoes, minimize impacts on non-target organisms, and, where appropriate, be capable of penetrating dense vegetation canopies. Larvicide formulations (i.e., liquid, granular, solid) must be appropriate to the habitat being treated, accurately applied, and based on surveillance data. Accuracy of application is important because missing even a relatively small area can cause the emergence of a large mosquito brood resulting in the need for broad-scale adulticiding. # Adulticiding Adulticiding is the application of pesticides to kill adult mosquitoes. The ability to control adult mosquitoes is an important component of any integrated mosquito management program, and like the other components of the program, its use should be based on surveillance data. Mosquito adulticiding may be the only practical control technique available in situations where surveillance data indicate that is necessary to reduce the density of adult mosquito populations quickly to lower the risk of WNV transmission to humans. In some situations, source reduction and larvicide applications are not practical, and adulticide application is the only available control strategy. Mosquito adulticides typically are applied as an Ultra-Low-Volume (ULV) spray where small amounts of insecticide are dispersed either by truck-mounted equipment or from fixed-wing or rotary aircraft. [64][65][66][67][68] Thermal fog applications of adulticides by ground or air are also used in some areas, but to a much lesser degree. Barrier treatments, typically applied as high volume liquids with hand-held spray equipment using compounds with residual characteristics, are common in some U.S. locations. This technique is especially attractive to individual homeowners living near mosquito-producing habitats where residual chemicals applied along property boundaries can provide some control benefits. Mosquito adulticiding differs fundamentally from techniques used to control many other adult insects. For adult mosquito control, insecticide must drift through the habitat in which mosquitoes are flying in order to provide optimal control benefits. The EPA has determined that the insecticides labeled nationally for this type of application do not pose unreasonable health risks to humans, wildlife, or the environment when used according to the label. 56 Adulticides labeled for mosquito control include several organophosphates such as malathion and naled. Some natural pyrethrins and synthetic pyrethroids (permethrin, resmethrin and sumithrin) also hold adulticide labels. Insecticide selection and timing of application should be based on the distribution and behavior of the target mosquito species. Application of adulticides should be timed to coincide with the activity period of the target mosquito species. Many Culex species are nocturnal and are active in the tree canopy level. This should be taken into consideration when planning adulticide applications. Operational experience indicates that Cx. pipiens and Cx. quinquefasciatus may require more frequent adulticide application to achieve desired levels of population reduction during an outbreak. Control of adult day-active species poses additional problems because ULV adulticide effectiveness is greatly reduced during daylight hours. Early-morning use of adulticides, applied before temperatures rise, may provide a measure of control for these species. # D. Resistance Management In order to delay or prevent the development of insecticide resistance in vector populations, integrated vector management programs should include a resistance management component (modified from Florida Coordinating Council on Mosquito Control, 1998). 57 Ideally, this should include annual monitoring of the status of resistance in the target populations to: 1. Provide baseline data for program planning and pesticide selection before the start of control operations. # 2. Detect resistance at an early stage so that timely management can be implemented (even detection of resistance at a late stage can be important in elucidating why disease control may fail); however, in such cases, management options other than replacement of the pesticide may not be possible). # 3. Continuously monitor the effect of control strategies on resistance. In addition to monitoring resistance in the vector population, the integrated program should include options for managing resistance that are appropriate for the local conditions. [69][70] The techniques regularly used include the following: a) Management by Moderation -preventing onset of resistance by 1) Using dosages no lower than the lowest label rate to avoid genetic selection. 2) Using less frequent applications. 3) Using chemicals of short environmental persistence. # 4) Avoiding slow-release formulations. # 5) Avoiding the use of the same class of insecticide to control both adults and immature stages. 6) Applying locally. Currently, most districts treat only hot spots. Area-wide treatments are used only during public health alerts or outbreaks. # 7) Leaving certain generations, population segments, or areas untreated. # 8) Establishing high pest mosquito densities or action thresholds prior to insecticide application. # 9) Alternation of biorational larvicides and insect growth regulators annually or at longer intervals. b) Management by continued suppression -a strategy used in areas of high-value (e.g., heavily touristed areas) or where arthropod vectors of disease must be kept at very low densities. # 33 This does not mean saturation of the environment by pesticides, but rather the saturation of the defense mechanisms of the insect by insecticide dosages that can overcome resistance. This is achieved by the application of dosages within label rates but sufficiently high to be lethal to susceptible as well as to heterozygous-resistant individuals. If the heterozygous individuals are killed, resistance (which is a homozygous trait) will be slow to emerge. This method should not be used if any significant portion of the population in question is resistant. Another approach more commonly used is the addition of synergists that inhibit existing detoxification enzymes and thus eliminate the competitive advantage of these individuals. Commonly, the synergist of choice in mosquito control is piperonyl butoxide (PBO). c) Management by multiple attack -achieving control through the action of several different and independent pressures such that selection for any one of them would be below that required for the development of resistance. This strategy involves the use of insecticides with different modes of action in mixtures or in rotations. There are economic problems (e.g., costs of switching chemicals or having storage space for them) associated with this approach, and critical variables in addition to mode of action must be taken into consideration (i.e., mode of resistance inheritance, frequency of mutations, population dynamics of the target species, availability of refuges, and migration). General recommendations are to evaluate resistance patterns at least annually and the need for rotating insecticides at annual or longer intervals. # E. Biological Control Biological control is the use of biological organisms, or their by-products, to control pests. Biocontrol is popular in theory, because of its potential to be host-specific and virtually without non-target effects. Overall, larvivorous fish are the most extensively used biocontrol agent for mosquitoes. Predaceous fish, typically Gambusia or other species which occur naturally in many aquatic habitats, can be placed in permanent or semipermanent water bodies where mosquito larvae occur, providing some measure of control. Other biocontrol agents that have been tested for mosquito control, but that to date generally are not widely used, include the predaceous mosquito Toxorhynchites, predacious copepods, the parasitic nematode Romanomermis, and the fungus Lagenidium giganteum. Biocontrol certainly holds the possibility of becoming a more important tool and playing a larger role in mosquito control in the future, but will likely be effective only as part of an integrated approach. # F. Continuing Education of Mosquito Control Workers Continuing education is directed toward operational workers to instill or refresh knowledge related to practical mosquito control. Training is primarily in safety, applied technology, and requirements for the regulated certification program mandated by most states. # G. Vector Management in Public Health Emergencies A surveillance program adequate to monitor WNV activity levels associated with human risk must be in place. Detection of epizootic transmission of enzootic arboviruses typically precedes detection of human cases by several days to 2 weeks or longer (e.g., as found in SLE epidemics). 71,72 If adequate surveillance is in place, the lead time between detecting significant levels of epizootic transmission and occurrence of human cases can be increased, which will allow for more effective intervention practices. 19,27,31 Early-season detection of enzootic or epizootic WNV activity appears to be correlated with increased risk of human cases later in the season. Control activity should be intensified in response to evidence of virus transmission, as deemed necessary by the local health departments. Such programs should consist of public education emphasizing personal protection and residential source reduction; municipal larval control to prevent repopulation of the area with competent vectors; adult mosquito control to decrease the density of infected, adult mosquitoes in the area; and continued surveillance to monitor virus activity and efficacy of control measures. As evidence of sustained or intensified virus transmission in an area increases, emergency response should be implemented. This is particularly important in areas where vector surveillance indicates that infection rates in Culex mosquitoes are increasing, or that potential accessory vectors (e.g., mammalophilic species) are infected with WNV. Delaying adulticide applications in such areas until human cases occur is illogical and negates the value and purpose of the surveillance system. # H. Adult Mosquito Control Recommendations Ground-based (truck-mounted) application of adult mosquito control agents has several positive attributes. Where road access is adequate, such as in urban and suburban residential areas, good coverage may be achieved. In addition, ground-based application can be done throughout the night, thereby targeting night-active mosquito species. Such applications are prone to skips and patchy coverage in areas where road coverage is not adequate or in which the habitat contains significant barriers to spray dispersal and penetration. Aerial application is capable of covering larger areas in shorter time periods than a ground-based application. This is a critical positive attribute when large residential areas must be treated quickly. In addition, aerial application is less prone to patchy coverage than ground-based application in areas where road coverage is not adequate. One limitation of aerial application is that many applicators will not fly at night, potentially reducing the effectiveness of the applications in Culex species control efforts. Cost benefits of aerial application over ground application may not be realized unless relatively large areas are treated. Several formulations of a variety of active ingredients are available for adulticide applications. Material choice for ground-based or aerially applied mosquito control in public health emergency situations is limited by EPA restrictions on the pesticide label and applicable state and local regulations. Multiple applications will likely be required to appreciably reduce Culex populations and interrupt arbovirus transmission. An emergency SLE virus response plan developed for New Orleans, Louisiana 63 indicates the need for repeated applications to control Cx. quinquefasciatus, and the need to repeatedly apply adulticides in high-risk areas (areas with human cases or positive surveillance events). Two to three adulticide applications spaced 3-4 days apart may be required to significantly reduce Cx. pipiens populations. Effective surveillance must be maintained to determine if and when re-treatment is required to maintain suppression of the vector populations. Urban/suburban population centers with multiple positive surveillance events as described above should be treated first to most efficiently protect the largest number of people from exposure to WNV. Applications should be timed to coincide with the peak activity periods of the target species. For example, applications should be made at night to maximize control of night-active Culex species. Other species such as Oc. sollicitans or Ae. vexans are active shortly after sunset and are effectively controlled with appropriately timed applications. Day-active potential accessory vectors (e.g., Oc. japonicus, Oc. triseriatus, Ae. albopictus) must be addressed separately and are most effectively controlled by residential source reduction efforts, though there is preliminary evidence that early morning ULV applications may be used to control these species. # I. Determining the Scope of Mosquito Adulticiding Operations Once arbovirus activity is detected in a jurisdiction and a decision is made to implement or intensify mosquito control by using adulticides, the size of the area to be treated must be determined. In the broadest context, the underlying program objective (i.e., interruption of the enzootic transmission cycle vs. prevention of transmission to humans and domestic animals) should determine the amount of adulticide coverage that is required. For most jurisdictions the objective is the prevention of transmission to humans and domestic animals. There is no simple formula for determining how large an area to treat around a positive surveillance indicator or a suspected or confirmed human case of WNV. Nor is there adequate information to guide decisions about the degree of vector population suppression that must be attained, or for how long this suppression must be maintained to reduce human disease risk. At a minimum, the following factors must be considered when deciding the scope of the adulticiding effort: 1. The general ecology of the area, e.g., key habitat types and the presence of natural barriers such as large rivers; 2. The population density, distribution, flight range, and age structure (proportion of parous females) of the target mosquito species; 3. The flight range of the avian amplifying host(s); 4. The length of time since birds started dying or became infected in the affected area (typically, there may be a lag of several weeks between recovery of dead birds and confirmation of WNV infection) or since virus-positive mosquito pools were collected; 5. The human population characteristics -spatial distribution and density relative to the positive locality (e.g., urban vs. rural), age demographics; 6. Evidence of persistent WNV activity detected by the surveillance program; and 7. Season of the year and how long WNV activity can be expected to persist until the epizootic/epidemic vector(s) enter diapause. Several of these factors will be unknown or poorly understood. Technical assistance from a mosquito control professional, particularly one experienced in mosquito control in the region, is crucial in this process. Practical experience in conducting mosquito control is required to refine control recommendations. For example, the size of an area selected for control applications may be reduced in response to structures like open areas, bodies of water, major highways, or other barriers that may restrict the distribution of targeted species. Alternatively, adulticide coverage may be expanded to cover large urban or suburban residential neighborhoods with dense human populations. Hypothetically, in some settings where focal early season enzootic WNV activity has been detected, early season adulticiding may be useful in interrupting virus transmission and lead to lower transmission rates later in the season. However, effective larval control of the principal enzootic mosquito vector is probably a more cost-effective way to interrupt early-season virus amplification. # J. Evaluation of Adult Mosquito Control The following parameters should be periodically monitored during control operations: 1. Minimum requirements: a) Pre-and post spray vector mosquito densities inside and outside control area using CO 2 -baited traps and gravid traps; b) Vector mosquito infection rates pre-and post-spray inside and outside the control area; and c) Weather conditions during application (temperature, wind speed, direction). # 2. Desirable additions if capacity exists: population age structure of key mosquito species (Cx. pipiens) 3. In addition, both droplet size and flow rate should be documented for each piece of ULV application equipment: 4. During aerial application, GPS monitoring of spray track should be conducted if equipment is available on aircraft. # K. Health Education, Public Information, and Human Behavior Change The goals of health education, public information, and behavior change programs are to inform the public about WNV, promote the adoption of preventive behaviors that reduce disease risk, and gain public support for control measures. Health education/public information includes use of print materials (posters, brochures, fact sheets), electronic information (Web sites), presentations (health experts or peers speaking to community groups), and the media. Information alone is seldom sufficient to encourage people to adopt new behaviors or to change old practices. Programs should include strategies to facilitate protective actions and to address barriers that hinder preventive actions. Examples of programs that go beyond information include developing a community task force, interventions to improve access to window screening materials or repellents, and social marketing to reinforce preventive behaviors. The following section covers key prevention messages, selected best practices, and research/program development priorities for promotion of personal and community measures to decrease risk of WNV infection. Public education and risk communication activities must be ramped up to respond to the degree of WNV risk in a community, as noted in Table 1. # Key WNV Prevention Messages a) Address the multiple levels at which prevention can occur: personal protection (use of repellent on skin and clothing, use of protective clothing, awareness of prime mosquito-biting hours); household protection (eliminating mosquito breeding sites, repairing/installing screens); and community protection (reporting dead birds, advocating for organized mosquito abatement, participating in community mobilization). b) Use of DEET-based repellents on skin and clothing is the backbone of personal protection. (For current recommendations, see www.cdc.gov/ncidod/dvbid/westnile/qa/insect_repellent.htm.) Permethrin-based repellents should be promoted for use on clothing. c) Emphasize the feasibility of actions that can lower an individual's WNV risk through personal protection measures. Messages should acknowledge the seriousness of the disease but should not be fear-driven. Fear-driven messages may heighten the powerlessness many people express in dealing with emerging diseases. d) Recommendations to avoid being outdoors from dusk to dawn may conflict with neighborhood social patterns or practices of persons without air-conditioning or without other health programs seeking to increase physical activity. An alternative is to emphasize that the hours from dusk until dawn are prime mosquito-biting hours, and that protecting oneself through repellent use during these hours is important, with the option of remaining indoors. e) Communication about adulticiding: Public acceptance of emergency adult mosquito control is critical to its success, especially where mosquito control is unfamiliar or unpopular. Questions about the products being used, their safety, and their effects on the environment are common. Improved communication about surveillance and how decisions to adulticide are made may help residents weigh the risks and benefits of control. When possible, provide detailed information regarding the schedule for adulticiding through newspapers, radio, the Internet, or a recorded phone message f) Keep messages clear and consistent with the recommendations of coordinating agencies. Use plain language whenever possible, and adapt materials for lowerliteracy and non-English speaking audiences. # Selected Best Practices a) Targeted prevention Audience members have different disease-related concerns and motivations for action. Proper message targeting permits better use of limited communication and prevention resources. The following are some audience groups that require specific targeting: Develop partnerships with agencies/organizations that have relationships with populations at higher risk (such as persons over 50) or are otherwise recognized as community leaders (e.g., churches, service groups). Working through sources trusted by the target audience can heighten the credibility of and attention to messages. Partnerships with businesses that sell materials to fix or install window screens or that sell insect repellent may be useful in some settings. c) Community mobilization and community outreach Community mobilization can further education and behavior change goals. To counter any idea that health departments/mosquito control programs are able to control WNV alone, develop community ownership for prevention activities. A community task force that includes civic, business, health, and environmental concerns can be valuable in achieving buy-in from various segments of society and in developing a common message. Community mobilization activities can include clean-up days to get rid of mosquito breeding sites. 39 Community outreach involves presenting messages in person, in addition to media and educational materials, and incorporating citizens in prevention activities. Hearing the message of personal prevention from community leaders can validate the importance of the disease. Health promotion events reinforce the importance of prevention in a community setting. # Research and Program Development Priorities a) Audience research Attitudes toward arboviral disease prevention vary considerably by region. Previous experience with nuisance mosquitoes and mosquito control will affect the acceptability of prevention efforts. Audience research can identify local attitudes, motivations, barriers to prevention, and opportunities to promote desired behaviors. Audience research should ideally combine qualitative and quantitative efforts. Surveys assessing knowledge, attitude, and practice levels in the target population can be very helpful, especially in evaluation, though they are a substantial undertaking. Qualitative research techniques, such as interviews and focus groups, can yield valuable data, and are more adaptable to resource levels. Expertise to undertake such efforts may be available from other divisions within a health department (e.g., chronic disease programs, maternal and child health). Pretesting of educational materials is an important step to ensure the usability of materials by the intended audience. Pretesting does not always have to involve considerable time or expense; simply having representatives of the intended audience review materials before printing will be useful. # b) Evaluation Outcome evaluation should be conducted whenever possible to measure the efficacy of the intervention in achieving protective behaviors (e.g., frequency of repellent use, presence of household mosquito breeding sites). Outcome measurement requires extensive effort and must be planned from the outset of a program. # c) Social marketing and risk communication The goal of social marketing is to achieve specific behaviors, using the concepts of product, price, place, and promotion. Use of social marketing approaches can help programs plan to achieve specific behavior change goals. Risk communication is already used by many health departments, and can be useful in refining communication messages for WNV, especially as the disease becomes endemic in new areas, and in discussing community control. Risk communication can help people analyze the choices that are available to them and to their community. # Resources The Other organizations that can provide useful information are the American Mosquito Control Association (www.mosquito.org/) and the National Pesticide Information Center (NPIC) (npic.orst.edu), a program of EPA and Oregon State University concerning pesticides and repellents. They can be contacted at 1-800-858-7378. # L. Legislation In addition to statutes permitting legal action to abate mosquito-related public health nuisances, legislation must be in place to allow creation of and provide funding for municipally-based integrated mosquito management programs. Local jurisdictions can contact state mosquito control associations to provide examples of enabling legislation. # M. Guidelines for a Phased Response to WNV Surveillance Data The principal goal is to minimize the health impact of the WNV in humans, as well as in domestic and zoo animals. Given the limited understanding of the ecology and epidemiology of WNV in the U.S., the low incidence of arboviral encephalitis, and the limitations of prevention methods, prevention and control measures, regardless of intensity, may not prevent all WNV infections in humans. The recommended response levels for the prevention and control of WNV should augment, but not replace, long-standing mosquito control efforts by established programs. These programs often have two objectives: 1) to control nuisance mosquitoes, and 2) to control vector mosquitoes that can transmit pathogenics. Nuisance mosquito control often has different objectives than vector control, and the target mosquito species may also differ. Established mosquito control programs often have long-standing experience with the surveillance and control of indigenous neurotropic arboviruses such as SLE virus. These programs have established thresholds for response based on historical data. Long-standing experience with WNV does not exist in the U.S. These guidelines for the prevention and control of WNV should be interpreted according to the following considerations: 1. All states should prepare for WNV activity. Given the extensive geographic spread of WNV since 1999, its occurrence in many different habitats and ecosystems in the Old World, its expansion into numerous habitat types in the Western Hemisphere, and the fact that SLE virus, a related flavivirus, is widespread in the U.S., there appear to be no barriers to the spread of WNV throughout the U. S. At a minimum, a plan for the surveillance, prevention, and control of WNV should be developed at the state and local levels. indicate that intensity of epizootic WNV activity as measured by avian mortality and mosquito infection rates are good indicators of subsequently increased human infection risk. Data from NYC indicate that human WNV disease cases were more likely to occur in counties that had experienced more than 0.1 dead crow reports per square mile per week. In the Staten Island outbreak of 2000, the density exceeded 1.5 dead crow reports per square mile per week. Also, analysis of 2001 and 2002 surveillance data indicate that counties reporting WNV-infected dead birds early in the transmission season are more likely to report subsequent WNV disease cases in humans than are counties that do not report early WNV-infected dead birds. These observations should be interpreted as a guide rather than an absolute. Levels of epizootic activity that correlate with increased human risk will vary by region. # 3. Flexibility is required when implementing the guidelines. Knowledge gained from ongoing surveillance and research could change the phased response recommendations. Specific and detailed recommendations that will fit all possible scenarios are not possible, particularly at a local level. Therefore, public health action should depend on interpreting the best available surveillance data in an area, in light of these general guidelines. In addition, the following factors should be considered when translating these guidelines into a plan of action: The recommended phased response to WNV surveillance data is shown in Table 1. Local and regional characteristics may alter the risk level at which specific actions must be taken. Response as in category 3, plus: Expand public information program to include TV, radio, and newspapers (use of repellents, personal protection, continued source reduction, risk communication about adult mosquito control), Increase visibility of public messages, engage key local partners (e.g., government officials, religious leaders) to speak about WNV ; intensify and expand active surveillance for human cases; intensify adult mosquito control program, repeating applications in areas of high risk or human cases. # Outbreak in progress Multiple confirmed cases in humans; Conditions favoring continued transmission to humans (e.g., persistent high infection rate in mosquitoes, continued avian mortality due to WNV) Response as in category 4, plus: Intensify emergency adult mosquito control program repeating applications as necessary to achieve adequate control. Enhance risk communication about adult mosquito control. Monitor efficacy of spraying on target mosquito populations. If outbreak is widespread and covers multiple jurisdictions, consider a coordinated widespread aerial adulticide application; emphasize urgency of personal protection through community leaders and media, and emphasize use of repellent at visible public events. • Local and regional characteristics may alter the risk level at which specific actions must be taken. # IV. HEALTH DEPARTMENT INFRASTRUCTURE State and Local Health Departments In the 48 contiguous United States, state and local health departments should have a functional arbovirus surveillance and response unit, staffed by well-trained personnel who have adequate data-processing resources, appropriate laboratory facilities, and an adequate operating budget. The size and complexity of these units will vary by jurisdiction, depending on both the risk of arboviral transmission in the area and available resources. A functional arbovirus surveillance unit at the state level should be considered an essential component of any emerging infectious diseases program. Local health department expertise and capabilities should be supported in a manner that complements statewide programmatic goals. # A. Staffing and Personnel Ideally, arboviral surveillance involves epidemiologists, virologists, medical entomologists, vertebrate biologists, veterinarians, laboratory staff, environmental toxicologists, public affairs personnel, and data managers. In a particular jurisdiction, the combination of personnel needed to conduct arboviral surveillance will depend on the importance of arboviral diseases in the area and on resources. Many health departments experience a chronic shortage or complete absence of medical entomologists and expertise in wildlife pathobiology. Addressing these deficiencies should be a high priority. In the event of an arboviral disease outbreak, local health departments will likely require significant surge capacity to ensure an adequate public health response. Contingency planning to identify resources to assist with the enhanced surveillance, laboratory, environmental, and public health needs should be identified ahead of time. # B. Training and Consultation Opportunities exist at federal and state agencies for appropriate training of and consultation with laboratorians, medical entomologists, epidemiologists, vertebrate biologists, and others involved in arbovirus surveillance. # C. Laboratory Capacity The infrastructure of arbovirus laboratories in the U.S. has deteriorated significantly in recent decades, not only in terms of the total number of functional laboratories and overall capacity, but also in terms of the staffing, physical plant, and financial support of many remaining laboratories. This is a problem of national scope and significance, the solution for which will require leadership at all levels of government. # Testing for West Nile Virus (WNV) Infections 45 In the wake of the introduction of WNV into the Western Hemisphere, it is important to distinguish between increasing short-term and long-term laboratory capacity. The latter is preferred and should be emphasized over the former. Laboratories with an existing capability for arbovirus serology should consider adding serologic screening tests for WNV to their repertoire. For serologic screening of patients and mosquito pools, arrangements can be made with CDC to transfer existing technology and reagents, and to obtain appropriate training. Samples giving positive or equivocal screening results should be confirmed by CDC or another laboratory capable of definitive testing. For selected laboratories, similar technology transfer arrangements can be made with regard to RT-PCR primers for use in the testing of tissues and mosquito pools. In the wake of the recent epidemic of WN encephalitis in the Northeast, it is important that programs continue to routinely test for other arboviruses historically active in their area, such as St. Louis encephalitis, eastern equine encephalitis, western encephalitis, and La Crosse viruses, as well as for other causes of acute encephalitis. # D. Developing Local Public Health Agency Infrastructure The function of local public health agencies is assessment, assurance, and policy development to promote and protect the health of the public. As part of this function, local public health agencies are responsible for preventive activities to reduce the risk of WNV infection to individuals in their jurisdictions. This responsibility includes educating communities about reducing mosquito breeding sites and taking personal protective measures. Local public health agencies also must have the capacity to assess human risk by gathering surveillance data or having access to surveillance data gathered on a district, regional, or statewide basis. These local public health agencies are important to formulating local recommendations on the indications and decisions concerning mosquito adulticiding. Education of and communication with the public, and maintenance of local media contacts are generally primary functions of the local public health agency. Included in this responsibility is communicating risk regarding the use of pesticides. The following infrastructure and functional capacities fall within the province of local public health agencies. Where these are not directly provided, access to these capacities is to be ensured). # 1. Risk assessment based on surveillance data (including mosquito, bird, and human data). Surveillance data may also include reports from individuals or healthcare providers indicating possible adverse health effects from pesticide use. # 2. Health education regarding personal protection, reduction of mosquito breeding sites and minimum health risks posed by approved pesticides applied according to the label. 73,74 3. Communication with the media. # 4. Development of a preventive plan including education, mosquito source reduction, and larviciding. # 5. Public response capability, particularly when surges of public inquiries arise. This may include the use of telephone hotlines and Internet Web sites. # 6. Training of staff. # 7. Coordination with state and federal agencies. # 8. Local coordination by formulation of a task force with organizations such as departments of public works, offices of public affairs, city/county building management, departments of parks and recreation, departments of planning and zoning, property or building inspection services, police, public schools, colleges and universities, nonprofit and grassroots organizations, businesses, zoos, animal/vector control, local mosquito control districts, emergency medical services, hospitals, poison control centers, departments of game and inland fisheries, departments of environmental quality, emergency, management agencies, etc. because of the relatively large number of species being studied. Specific needs include the following: # Accurate Taxonomic Identification of Specimens Fully understanding the epidemiology and developing effective prevention and control strategies for WNV requires accurate identification of all animal species involved in the virus transmission and maintenance cycles. This is especially true for birds and mosquitoes. # Unique Identifier (UID) Numbering System for Specimens A UID numbering system should be used in each jurisdiction (e.g., state, county, city, surveillance area). Such a system should distinguish readily between each major animal group reported (i.e., humans, birds, and mosquitoes), and encode the location of collection (county or town), date of collection (day/month/year), and a specimenspecific number. # Durable Tagging System for Field-Collected Specimens Use appropriate labels containing complete specimen information on all samples (blood, tissues, or whole animals) so field specimen identification will not be lost during shipment to testing facilities. A very long-term goal is the identification and implementation of new, natural compounds to repel and control mosquito vectors of disease. With efforts to decertify current pesticides, new compounds will be needed in the fight against vector-borne diseases. Much effort has been expended to increase public awareness of the WNV threat and of the actions needed to reduce exposure to infected mosquitoes. These actions include using mosquito repellents, reducing periresidential mosquito breeding sites, and wearing protective clothing when entering mosquito-infested areas. The success of these public information campaigns has not been formally evaluated using scientific instruments such as knowledge and behavior surveys. The cost of such campaigns is high, so formal attempts to assess their success are needed. # G. Laboratory Diagnosis Surveillance for WNV will continue to require accurate laboratory diagnostic tests. Ideally, these tests will be simple and inexpensive, and will distinguish between WNV and other flaviviruses such as the SLE, dengue, and yellow fever viruses. Virus-specific tests for IgM or IgG antibody will be required for humans, various species of birds, horses, and other mammals. Sensitive viral detection methods will be required for both human and animal tissues as well as for mosquito pools. # H. Clinical Spectrum of Disease and Long-Term Prognosis in Humans A better understanding of the spectrum of illness caused by WNV infection in humans is needed, including the long-term consequences of acute infection of the central nervous system. In addition to the severe end of the clinical spectrum (viral encephalitis), it is important to know the degree to which mild viral syndromes occur and whether these patients have any unique clinical presentations that may be characteristic or even pathognomonic. It is also important to know whether they have viremia and, if so, its magnitude and duration. Effective clinical management of severe disease will require detailed clinical studies of confirmed human cases of WNV infection. # I. Risk Factor Studies • "Denominator" data Definition: Weekly totals of dead birds (classified as either corvids or 'others') and mosquito pools (classified by species) collected and/or tested by a jurisdiction's WNV surveillance system, stratified by county within a state. Because recent experience has demonstrated that the following categories of denominator data are of limited use in meeting national surveillance goals, as of 2003, CDC will discontinue the collection of totals of sentinel and free-ranging wild birds, horses, or other non-human mammals tested. • "Numerator" data Definition: Detailed information on individual mosquito pools, sentinel species, dead birds, and ill humans, horses, or other species with confirmed or suspected WNV infections, as determined by laboratory-confirmed or -probable test results. # General Procedures: Reporting "denominator" data: CDC will collect aggregate denominator data via a secure file upload system using a statebased database provided by CDC, continuous data entry into a database stored on a secured CDC web site, or importation of delimited records in a specified format. Denominator data variables are specified in Table 1. An appropriate submission schedule will be arranged by CDC with the jurisdictions submitting surveillance data via file uploading. In addition, • CDC will distribute the necessary software and provide the adequate licenses that will allow regular secured file upload or continuous web-based data entry. • CDC will accommodate state health departments with existing integrated data collection systems, e.g., by arranging for uploads of XML-formatted data. • The data entry screens will be designed as a series of simple forms or tables. • The system will accommodate updates and corrections of previously transmitted data by jurisdictions. • Following the entry of a week's data into the database at the state level, transmission of the data file to CDC will involve a minimal number of keystrokes. Security will be insured by use of the sender's digital certificate. CDC will arrange for those who will be transmitting surveillance data to CDC to obtain digital certificates. • Upon arrival at CDC, records from the specific reporting week of interest will automatically be captured and imported into a master database on the CDC fileserver and also transmitted to USGS in Reston, Virginia. # 54 • Using these data, reports will be generated automatically each week. Maps will be generated by CDC and USGS and made available on the USGS web site. A basic set of dynamic maps and corresponding graphs and tables will be made available weekly. The CDC web site and Epi-X (or a similar secured communication network) will contain links to the relevant USGS web pages. # Reporting "numerator" data: CDC strongly encourages prompt ("real-time") reporting of numerator data. CDC will collect such reports in a standardized manner to allow monitoring of regional and national trends, and facilitate prompt confirmatory testing when necessary. As the arbovirus transmission season progresses, the need for immediate reporting of certain data to CDC may diminish. For example, once numerous WNV-positive mosquito pools have been previously documented in a given geographic area, there may not be a compelling need to immediately report further findings. In addition, if at any time the volume of reporting becomes overwhelming, adoption of an alternative system may be necessary. Numerator data variables that will be collected are specified in Table 2. WNV laboratory and surveillance case criteria are specified in Table 3. Specified, line-listed numerator data may be submitted using one of three methods: • Web-based data entry to a CDC server; • Use of state-based, CDC-distributed, Microsoft Access-based data entry/management software (ArboNET) with continuous file upload to a CDC server; or • Data messaging from a unique data collection system to a CDC server (e.g., in XML format). All data entry will be done by the reporting jurisdiction and data is transmitted to a CDC server. After data entry and submission, numerator data will be available on the CDC Secure Data Network (SDN) so that authorized personnel from the reporting jurisdiction may "verify" (proofread, correct, and clear for publication) individual numerator data records in selected surveillance categories. It is essential that each numerator data record include a unique identifier (UID) assigned by the reporting state agency. UIDs will be used by CDC staff to track and update individual numerator data records, and by states to verify records via the CDC SDN. The UID will not appear in output products for public release. Most jurisdictions already have systems in place for generating UIDs, and they should continue to use them. CDC's databases will accommodate numeric or alphanumeric UIDs up to 25 characters long. Jurisdictions are encouraged to begin their UIDs with their state's 2-letter postal code (or "NYC" for New York City). The issue of numerator data records associated with laboratory-probable results deserves special mention. Although CDC encourages confirmation of all laboratory-probable results, it is realized that under some circumstances some states may choose not to do so, depending on the epidemiologic situation, laboratory capacity, and volume. For example, during a known WN viral epizootic, a state may decide that a crow brain associated with a single positive result for WN viral RNA by RT-PCR will undergo no further testing. Although this bird is a laboratoryprobable case (see table below), the jurisdiction may decide to upload that bird's numerator data record to CDC and subsequently authorize CDC to release it publicly. In contrast, a jurisdiction may opt to delay the release of such results to the public until they have been laboratory-confirmed. CDC will rely on individual jurisdictions to decide when to authorize the public release of numerator data records based on laboratory-probable results. CDC will not publicize numerator data records associated with laboratory-equivocal results. In terms of human surveillance, the national surveillance case definition of arboviral encephalitis/meningitis includes two official case-status categories: confirmed and probable (Table 3). For national arboviral encephalitis surveillance, CDC has traditionally combined records in these two categories for its annual summary reports, and will continue this practice within the WNV surveillance system. States are encouraged to promptly report both laboratoryconfirmed and laboratory-probable human WN encephalitis cases as numerator data records. CDC encourages the reporting of human WN viral illnesses other than WNME (e.g., WNF, acute flaccid paralysis, other clinical syndrome, or unspecified). To determine case status (confirmed or probable) for reporting purposes, refer to the national surveillance case definition of arboviral encephalitis/meningitis (Appendix C) and the CDC-recommended surveillance case definition for WNF (Appendix D). A working case definition for WNME in equines is shown in Appendix B. # Arboviruses other than WNV: It is anticipated that enhanced WNV surveillance will result in increased recognition of other domestic arboviral activity, including eastern equine encephalitis (EEE), western equine encephalitis (WEE), SLE, La Crosse (LAC), and Powassan (POW) virus activity. Surveillance numerator (laboratory-positive) data regarding these viruses may be reported to CDC/DVBID via ArboNET, telephone, FAX, or e-mail. # Data Security Issues: General principles: • State and local health authorities will retain control of the timing of data release. • As of 2003, reporting agencies will electronically report to ArboNET all categories of surveillance data, including human numerator data. For non-human data, agencies will verify accuracy and readiness for public release prior to submission. Upon the electronic submission of non-human data to CDC, these reports will be considered verified and publishable. With the 2003 version of ArboNET, human data will be automatically verified upon entry, and the reporting agency has the option to unverify the data via electronic checkbox. CDC will not publicly release unverified human case reports. • Personal identifying or localizing (more specific than county) information will not be released. # Specific issues: • To report data via secure file upload to the CDC fileserver or to enter data directly onto a secured web site, states will utilize the CDC SDN, which provides data encryption for transmission via the Internet. To use the SDN, users must obtain and install a digital certificate from the CDC certificate server. This allows for unique identification of the computer/browser that is accessing a secure web site. • To obtain a digital certificate and be approved to use the SDN, the digital certificate authority at CDC/DVBID must approve the request and forward it to CDC/Atlanta. CDC requests that a maximum of 3 persons from each state be designated to receive digital certification. These should include those who will transmit data to CDC, as well as those who will verify data on the SDN. # Summary Reports to be Produced by CDC and USGS: A working list of basic summary reports is shown in Table 4. The exact list and formats of these reports remain to be determined, and this should be viewed as a dynamic process. Modifications, additions, and deletions may take place over time, as dictated by feedback, experience, technical issues, and events. Using state-approved numerator and denominator data, reports will be generated weekly. Maps and tables will be generated by DVBID and by USGS. Maps and corresponding graphs and tables will be updated at least weekly on the USGS web site (www.USGS.gov). # Communication Issues: • A dedicated telephone line (970-266-3592), electronic mailbox ([email protected]), and fax machine (970-266-3599) will be available at CDC/DVBID (in Fort Collins, Colorado) 24 hours/day for reporting numerator data or other urgent WNV-related business. During nights and weekends, calls to the dedicated phone line will be forwarded to the cellular phone of an on-call CDC/DVBID staff scientist. Because of potential delays in the receipt and reading of email and fax messages, in general please use the telephone for time-sensitive business. • In addition to periodic conference calls between CDC, cooperating states, and other federal agencies, Epi-X and the WNV Information Exchange (WNVIX, part of the Epi-X Forum) will be available to participating jurisdictions and agencies using the CDC SDN. For further information, contact the CDC/DVBID ArboNET staff at 970.221.6400 or send electronic mail to [email protected]. # Submission of Laboratory Specimens to CDC for WNV Testing: See Table 5. Shipping containers: Use only durable containers. Seal specimen containers tightly. Wrap specimen containers in absorbent material and pack them into two different plastic containers to insure that any leakage is contained. Specimens for virus isolation must be sent on enough dry ice to insure that they remain frozen until receipt. Specimens for serologic testing can be shipped on gel-ice and need not remain frozen. Hand-carrying specimens is not recommended but if specimens are hand-carried, the above packing instructions are applicable. # Minimal Information to Accompany Specimens Shipped to CDC: See information in columns 2, 3, and 4 in Table 2. Please read carefully and supply all available information. Use CDC Form 5034 (the ADASH@ form) Form 5034 is available electronically at: http://www.cdc.gov/ncidod/dvbid/CDC_form5034.pdf Tubes, cryovials, and other specimen containers should be clearly labeled with -at minimumthe specimen's UID, patient's name (human), state, date of onset, date of collection, and specimen type. # Special Collection, Shipping, and Handling Instructions: Mosquitoes: Ship on dry ice. Serum: Store in externally threaded plastic tubes. Ship at least 0.5 mL per specimen. Whenever possible, acute and convalescent specimens should be shipped together. Ship fresh-frozen on dry ice (required for virus isolation) or refrigerated on wet ice (acceptable). CSF: Store in externally threaded plastic tubes. Ship at least 1.0 mL per specimen. Ship freshfrozen on dry ice (required for virus isolation) or refrigerated on wet ice (acceptable). Whole blood: In general, send only if requested for virus isolation attempts in fatal cases (heart blood). Pregnancy-related specimens: In possible cases of intrauterine arboviral infection, tissues collected at the time of delivery can be tested for evidence of infection. The following tissues should be shipped fresh-frozen on dry ice: cross-sections of umbilical cord, placental tissue (approximately 1 cm 3 per sample), cord serum and maternal serum (0.5 ml each), and colostrum or breast milk. For more information, please contact Dr. Dan O'Leary at (970) 266-3525 or [email protected]. # Appendix B B Surveillance Case Definition for WNV Infection in Equines Laboratory criteria for diagnosis Compatible clinical signs [1] plus one or more of the following: ! Isolation of West Nile (WN) virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF) or other body fluid; [2] or ! Detection of IgM antibody against WN virus by IgM-capture ELISA in serum (at 1:400 or greater dilution) or cerebrospinal fluid (CSF) (at dilution 1:2 or greater dilution); or ! An associated 4-fold or greater change in IgG-capture ELISA or plaque-reduction neutralization test (PRNT) antibody titer to WN virus in appropriately timed, [3] paired serum specimens from an equid that is unvaccinated against WN virus; or ! Positive immunohistochemistry (IHC) for WN virus antigen in tissue. # Case classification Probable: compatible clinical signs occurring during a period when arboviral transmission is likely, and with the following supportive serology: 1) a single or stable (less than or equal to two-fold change) but elevated titer of WN virus-specific IgM-capture ELISA or neutralizing serum antibodies without knowledge of prior WN virus vaccination. Confirmed: compatible clinical signs with laboratory-confirmed evidence of WN virus infection. The first serum should be drawn as soon as possible after onset of clinical signs and the second drawn at least 14 days post-onset. _______________________________________________ Assumptions on which case definitions are based: • IgM-capture ELISA testing may give nonspecific results; cross-reactions to closely related flaviviruses (e.g., St. Louis encephalitis virus) may occur. Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to pinpoint the infecting virus by conduction cross-neutralization tests using an appropriate battery of closely related viruses. • Vaccination refers to one or more doses of the current USDA-licensed inactivated WN virus vaccine. • Virus-specific IgM antibodies demonstrated in serum by antibody-capture EIA and confirmed by demonstration of virus-specific serum immunoglobulin G (IgG) antibodies in the same or a later specimen by another serologic assay (e.g., neutralization or hemagglutination inhibition). # Case classification Probable: an encephalitis or meningitis case occurring during a period when arboviral transmission is likely, and with the following supportive serology: 1) a single or stable (less than or equal to twofold change) but elevated titer of virus-specific serum antibodies; or 2) serum IgM antibodies detected by antibody-capture EIA but with no available results of a confirmatory test for virus-specific serum IgG antibodies in the same or a later specimen. Confirmed: an encephalitis or meningitis case that is laboratory confirmed. # Comment Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to pinpoint the infecting virus by conducting cross-neutralization tests using an appropriate battery of closely related viruses. This is essential, for example, in determining that antibodies detected against St. Louis encephalitis virus are not the result of an infection with WN (or dengue) virus, or vice versa, in areas where both of these viruses occur. The seasonality of arboviral transmission is variable and depends on the geographic location of exposure, the specific cycles of viral transmission, and local climatic conditions. # V. INTERJURISDICTIONAL DATA SHARING AND NATIONAL REPORTING OF HUMAN CASES The public and animal health response to West Nile virus (WNV) epidemics/epizootics involves all levels of government, including the federal governments of the U.S. and neighboring countries, and the Pan American Health Organization. In addition, multiple government agencies at each level are often involved. Rapid, efficient, secure, and coordinated systems are needed to allow the sharing of human and ecologic data between these multiple agencies to support long-term surveillance activities, and to support activities that are part of the rapid outbreak response. During an epidemic involving multiple jurisdictions, CDC staff and other authorized persons will use Epi-X, a CDC-sponsored, Web-based system for secured electronic communication, or similar integrated communication systems, for rapid dissemination of information on public health events of public health significance. # A. Human Epidemiological, Clinical, and Laboratory Data Collection Patient confidentiality statutes vary among jurisdictions. Data can be shared between jurisdictions if recipients agree to adhere to the confidentiality statutes of the jurisdiction providing the data. Electronic databases should be appropriately secured by passwords to limit access and minimize opportunities for breaches in confidentiality or security. ArboNET and NETSS will be encouraged. # B. National Reporting of Human WNV # West Nile Fever (WNF) Although WNF is not included in the list of nationally notifiable diseases, states are encouraged to report WNF cases to CDC via ArboNET, using a CDC recommended case definition (see Appendix D). States may also choose to report WNF cases to NETSS using EVENT code 10049. # C. Ecologic Data Many of the issues that apply to the interjurisdictional sharing of human data apply to the sharing of ecologic data as well, although key differences exist. For example, confidentiality is generally not an issue with nonhuman cases, particularly wild animals identified as part of a surveillance program. Maintaining confidentiality may be important for certain owned animals. Data standardization is a far more challenging issue # VI. RESEARCH PRIORITIES The human and animal health implications of the introduction of West Nile virus (WNV) to the U.S. and to the Western Hemisphere continue to emerge. Many questions remain, the answers to which will require considerable research. A research agenda should be supported, with priority given to research questions whose answers can be directly applied to prevention and control. # A. Current and Future Geographic Distribution of WNV To determine the geographic distribution of WNV in the Western Hemisphere, existing laboratory-based surveillance systems for WNV in human, birds, other selected animals, and mosquitoes should be enhanced, or new, active systems should be developed and implemented (see Section I). # B. Bird Migration as a Mechanism of WNV Dispersal Experience in Europe and the Middle East suggests that WNV regularly is introduced to new geographic areas along bird migration routes. A better understanding of this potential is required for the Western Hemisphere. Studies should include the frequency and duration of chronic infections that will allow the long-range transport and recrudescence of viremias necessary to infect mosquitoes. # C. Vector and Vertebrate Host Relationships and Range Relatively little is known about the vertebrate host and mosquito vector relationships of WNV in the U.S. and the Western Hemisphere. Effective prevention and control strategies will require targeting selected species involved in maintenance, epidemic/ epizootic transmission cycles, or both. It is critical that the principal species and the range of these species be determined. # D. Virus Persistence Mechanisms It is not known whether or how WNV will be maintained in the U.S. over the long term. Overwintering mechanisms in Culex and Aedes species should be investigated, as well as persistence and maintenance of the virus in ticks. Other possibilities that should be investigated include the duration of chronic infection and reactivation in birds or other animals, and the introduction of the virus by migratory birds. # E. Mosquito Biology, Behavior, Vector Competence, Surveillance, and Control It is critical that a better understanding is gained of the principal mosquito vectors involved in maintenance, bridge (from enzootic to peridomestic), and epidemic/epizootic transmission. Different vector species may be important in different geographic or ecologic regions. Understanding their biology and behavior will allow for more effective surveillance and development of targeted control methods. # F. Development and Evaluation of Prevention Strategies Effective prevention and control of WNV transmission will require evaluation of the efficacy of current control methods and research on new and innovative control strategies for the principal mosquito vectors. Ultimately, prevention strategies must be integrated and use a variety of approaches to control mosquitoes and reduce the risk of transmission. Research should also be conducted to better define target areas for mosquito control in response to documented WNV activity in an area. Data on the risk factors associated with human and animal infection with WNV are required to develop more effective prevention strategies, particularly when educating the public to take specific prevention measures to reduce exposure to infection. # J. Detailed Clinical Descriptions and Outcome in Human Cases Larger and more detailed case series, as well as studies of short-and long-term outcomes, are needed to better understand the clinical features, clinical course, and public health impact of WNV disease in humans. A suggested framework for collecting standardized "extended" clinical variables is included in Appendix E. # K. Viral Pathogenesis Little is known of the pathogenesis of WNV in humans or other animals. Research is needed to better understand the organ systems affected, the mechanism of central nervous system (CNS) infection, and the role of virus strain in pathogenesis. # L. Genetic Relationships and Molecular Basis of Virulence Only since 1996 has WNV been associated with significant numbers of severe disease cases and fatalities in humans. It is important to better understand whether genetic changes in WN viruses influence their phenotypic expression (i.e., host and vector range, clinical expression in various hosts, and epidemic potential). This will require detailed studies of the genome of WN virus strains isolated from different epidemics in various geographic areas. # M. Vaccine Development for Animals and Humans Ultimately, the most effective prevention strategy may be vaccination. It is important to support research on the development of both human and equine vaccines. # N. Antiviral Therapy for West Nile Virus and Other Flaviviruses To date, none of the available antiviral agents are effective against flaviviruses, including WNV. Research in this area is critical to effective management of severe disease in humans. # O. The Economic Cost of the WNV Epidemic/Epizootic It is important to estimate the total economic cost of the epidemic/epizootic. These data will help set priorities for capacity building and prevention programs. # P. WNV Impact on Wildlife WNV has the potential to greatly impact the wildlife populations in the Western Hemisphere. This is especially true for birds, in many of which the infection appears to have high mortality rates (i.e., Corvidae). Research is needed to analyze and define this impact to determine if the development of new epizootic intervention strategies is needed. Research is also needed to determine what long-term effects WNV infection may have on its animal hosts. # Q. Investigate Alternate Modes of WNV Transmission to Humans Four new modes of WNV transmission to humans were identified in 2002: blood transfusion, tissue transplantation, transplacental transfer, and breast-feeding. New modes of transmission should be investigated to determine the impact they have on human infection and to develop effective approaches for prevention and control of WNV infection by these routes. # Appendix A -National WNV Surveillance System Objectives: The objectives of the national West Nile virus (WNV) surveillance system are to: • Monitor the geographic and temporal spread of WNV in the U.S. • Develop national public health strategies for WNV surveillance, prevention, and control. • Develop a more complete regional picture of the geographic distribution and incidence of the other clinically important arboviruses in the U.S. • Provide national and regional information to public health officials, elected government officials, and the public. • Evaluate the use of cooperative agreement funds and the need for additional resources. # Scope: Coordinated, multi-state surveillance of WNV infections in humans and animals has been repeatedly identified as a high priority by states affected by WNV in 1999-2002. All states conducting surveillance for WNV and other arboviruses are encouraged to participate in ArboNET, a CDC-coordinated program to collect these surveillance data. While the components of WNV surveillance systems employed in individual jurisdictions will vary, national WNV surveillance should, at a minimum, focus on collection of data from: • Mosquito surveillance • Avian (dead bird) surveillance • Equine surveillance • Human surveillance In addition to data from states, data from commercial laboratories will be sought. CDC will 1) formally notify all such laboratories of the need to report any positive laboratory results to the appropriate state or local health department who, in turn, will notify CDC; 2) provide them with a list of state health department contact persons; 3) periodically contact them to encourage reporting; and 4) remind them of the need to have all positive screening tests for arboviral infections confirmed by state public health laboratories. In addition, CDC will provide a list of these commercial laboratories to its cooperative agreement partners, to facilitate their efforts to conduct active laboratory-based surveillance for arboviral infections. # Categories of Data to be Collected: National surveillance will focus on the collection of two general categories of data: # Clinical description Arboviral infections may be asymptomatic or may result in illnesses of variable severity sometimes associated with central nervous system (CNS) involvement. When the CNS is affected, clinical syndromes ranging from febrile headache to aseptic meningitis to encephalitis may occur, and these are usually indistinguishable from similar syndromes caused by other viruses. Arboviral meningitis is characterized by fever, headache, stiff neck, and pleocytosis. Arboviral encephalitis is characterized by fever, headache, and altered mental status ranging from confusion to coma with or without additional signs of brain dysfunction (e.g., paresis or paralysis, cranial nerve palsies, sensory deficits, abnormal reflexes, generalized convulsions, and abnormal movements). # Laboratory criteria for diagnosis • Fourfold or greater change in virus-specific serum antibody titer, or • Isolation of virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF), or other body fluid, or • Virus-specific immunoglobulin M (IgM) antibodies demonstrated in CSF by antibodycapture enzyme immunoassay (EIA), or # Appendix D -CDC-Recommended Surveillance Case Definition for WN Fever What is a CDC-Recommended Case Definition? CDC-recommended surveillance case definitions are prepared for use by U.S. States and Territories interested in conducting public health surveillance for diseases or conditions that have not been designated nationally notifiable and have not been officially approved and sanctioned by the Council of State and Territorial Epidemiologists (CSTE). A CDCrecommended case definition may not be approved by CSTE in the future, unless CSTE and the CDC program with responsibility for prevention and control of the selected disease or condition both wish to seek broader and more formalized approval from both organizations. # CASE DEFINITION # Case Description A non-specific, self-limited, febrile illness caused by infection with WNV, a mosquito-borne flavivirus. Clinical disease generally occurs 2-6 days (range, 2-15 days) following the bite of an infected mosquito. Typical cases are characterized by the acute onset of fever, headache, arthralgias, myalgias, and fatigue. Maculopapular rash and lymphadenopathy generally are observed in less than 20% of cases. Illness typically lasts 2-7 days. # Case Classification A clinically compatible illness, plus: Confirmed: 1) Fourfold or greater change in WNV-specific serum antibody titer; 2) Isolation of WNV from or demonstration of specific WN viral antigen or genomic sequences in tissue, blood, CSF, or other bodily fluid; or 3) WNV-specific IgM antibodies demonstrated in serum by antibody-capture enzyme immunoassay and confirmed by demonstration of WNV-specific serum neutralizing antibodies in the same or a later specimen. Probable: 1) WNV-specific serum IgM antibodies detected by antibody-capture enzyme immunoassay but with no available results of a confirmatory test for WNV-specific serum neutralizing antibodies in the same or a later specimen. (Note: Some WN fever cases progress to WN meningitis or encephalitis. Cases meeting the more restrictive case definition of WN encephalitis/meningitis should be reported as such and only once, using event code 10056 for "WN Encephalitis or Meningitis".) # Comment The seasonality of arboviral transmission is variable and depends on the geographic location of exposure, the specific cycles of viral transmission, and local climatic conditions. Because closely related arboviruses exhibit serologic cross-reactivity, positive results of serologic tests using antigens from a single arbovirus can be misleading. In some circumstances (e.g., in areas where two or more closely related arboviruses occur, or in imported arboviral disease cases), it may be epidemiologically important to attempt to identify the infecting virus by conducting crossneutralization tests using an appropriate battery of closely related viruses. This is essential, for example, in determining that antibodies detected against WNV are not the result of an infection with St. Louis encephalitis or dengue virus, or vice versa. Because dengue fever and WN fever can be clinically indistinguishable, the importance of a recent travel history and appropriate serologic testing cannot be overemphasized. In some persons, WNV-specific serum IgM antibody can wane slowly and be detectable for more than one year following infection. Therefore, in areas where WNV has circulated in the recent past, the co-existence of WNVspecific IgM antibody and illness in a given case may be coincidental and unrelated. In those areas, the testing of serially collected serum specimens assumes added importance. Larger and more detailed case series, as well as studies of short-and long-term outcome, are needed to better understand the clinical features, clinical course, and public health impact of WNV disease in humans. A suggested framework for collecting standardized "extended" clinical variables is shown below. During 2003, CDC will work with its partners to populate this framework with specific questions in each category. The use of standardized questions will allow public health officials and other researchers to compare results more readily.	None	None
e0c4a08480d6eb6f2949ed6fccc12e7fae86d607	cdc	None	If you have issues viewing or accessing this file contact us at NCJRS.gov. li.S. Department of Justice National Institute of Justice This document has been reproduced exactly as received from the person or organization originating it, Points of view or opinions stated in this document are those of the authors and do not necessarily represent the official position or policies of the National Institute of Justice. Permission to reproduce this «m a ig iiW J material has been granted by Public Domain/U.5. Dept, of. Health and Human Services to the National Criminal Justice Reference Service (NCJRS). Further reproduction outside of the NCJRS system requires permission of the M M i g M owner.# The people who contributed to this manual are numerous and very dedicated to this field. In particular, we would like to acknowledge the following groups: - Those who gave their time in August 1991 to sit in a crowded room and discuss and debate points of content and advise CDC on the direction of this manual. - Those who provided written and oral comments on drafts of the document. - All who attended the Forum on Youth Violence in Minority Communities in December 1990 at which many of the ideas in this manual were first expressed, and the Minority Health Professions Foundation and the Morehouse School of Medicine, the co-sponsors of that forum. - The staff at Education Development Center, Inc., who prepared the background papers for the Forum on Youth Violence in Minority Communities. Most importantly, we would like to acknowledge the many people in the United States who work to prevent youth violence: people in communities who know the problem first hand, schools, and social service and law enforcement agencies, and the researchers who seek answers to troubling questions. Their work has been hard, but not unnoticed. They have opened the door for the rest of us to enter. # INTRODUCTION BACKGROUND Violence is a large and important health problem in the United States. More than 20,000 people die from homicide every year and more than 2,000,000 people suffer injuries received in violent con flicts. The emotional toll is immense. Violence and violence-related injuries and deaths are particularly common among young people and have escalated in recent years. In December 1990, the Centers for Disease Control (CDC) and the Minority Health Professions Foundation responded to the growing concern of African-American and other minority communities about violence among youth by convening a conference entitled Forum on Youth Violence in Minority Communities: Setting the Agenda for Pre vention. Thepurpose ofthisforum was to review what is known about programs designed to prevent youth violence. This framework for community action originated from the discussions in that forum. It has grown and developed through subsequent discussions and meet ings with many concerned individuals throughout the country. As this manual progressed, the complex distribution of violence across the United States became clear. Some communities of color are severely affected by violence. Others are not. Some white commu nities have high rates of violence while others do not. However, the potential for violence exists everywhere. Therefore, this manual can be used by any community dealing with present or potential problems of violence. Each communitymust assess its own needs and adapt the framework to its own characteristics. The underlying causes of violence vary from community to community. Urban, suburban, and rural commu nities differ; each community is unique. Experts provide no simple explanations of the causes of violent injuries and deaths. Deeply imbedded cultural problems such as racism, sexism, poverty, drug and alcohol abuse, drug trafficking, and frequent exposure to violence are but a few of the important pieces of this complicated puzzle. Efforts to reduce these problems and to increase educational and economic opportunities are needed. How ever, the presence of these large and stubborn problems should not make us forget that vve can do something-we can take action to reduce violence. American society has traditionally looked to the criminal justice system for protection from violence. Criminal justice measures have been useful. However, they have not enabled us to satisfactorily reduce the burden of violence upon society. One important reason is that much of the violence does not begin in a criminal setting but arises instead between companions involved in arguments, some times over trivial matters. In fact, more than 40 percent of all homicides occur between friends and acquaintances. Throughout the country, community organizations are addressing the problem of violence at the local level. These organizations are starting activities based on their understanding of local problems and local conditions. Conflict resolution training is provided in a number of schools. Schools are seeking ways to reduce the number of weap ons brought on campus. In several cities, programs are redirecting the energies of young people in gangs from violent confrontations to more peaceful pursuits. In preparing this manual, we were aware that a great deal of evalu ation needs to be done to determine which of the many activities that have been tried or proposed actually do prevent youth violence. However, the seriousness of the problem of violence demands im mediate action. # THE PURPOSE OF THIS MANUAL Many concerned individuals and community-based organizations want to reduce violence and prevent injuries and deaths from vio lence among youths in their community. This manual is designed to help. It includes a menu of specific activities for communities to undertake plus a framework for putting those activities effectively into place. # Introduction The manual is divided into two major sections. "Activities To Prevent Youth Violence" describes the target groups, settings, and strategies for the prevention of youth violence. The chapter takes into account - What is known about youth violence through scientific research - What has been learned through innovative community efforts - What has been learned from interventions used to prevent other types of health or social problems "Program Management" covers basic principles of effective commu nity-based health promotion programs. This section describes the processes of - Organizing the community - Gathering and analyzing the information needed to describe adequately the problem of youth violence in the community - Setting goals and objectives - Locating resources - Monitoring the progress of the program # ACTIVITIES TO PREVENT YOUTH VIOLENCE To prevent violent injury and death, we need to weaken or break the chain of events that leads to violence. Often we do not know exactly why people behave violently, why one adolescent will react violently in a given situation while another who has a similar background will not. We need to learn much more about the causes of violence in American society. Yet even with imperfect knowledge, helpful action can be taken. We can teach, we can enact and enforce regulations, we can change the environment. Youth can be taught skills to help them deal with violent situations. They can be helped to develop the self-esteem needed to solve differences without violence. Young people can be taught about the situations or actions that are likely to result in violence or violent injuries, such as associating with violent peers, using alcohol or drugs, and possessing a firearm or other weapon. They can be provided with mentors, or special teachers, who can serve as role models. Laws and regulations can be developed specifi cally to reduce injuries and deaths, such as stronger laws governing the use, ownership, and sale of guns. Teenage parents, abused chil dren, or bored or wayward teenagers can be provided with training, support, and recreation. In selecting the activities for any community, you should consider the following general principles: 1. Each activity should have ® an identified target group (e.g., high school students, youths in detention centers) - a setting in which that target group is reached (e.g., schools, detention centers) - a method or strategy to accomplish the objective (e.g., class room instruction, mentors) 2. No single activity in isolation is likely to solve the problem of youth violence. There are too many types and too many causes of violent injury and death to be solved by one strategy. The most effective programs include several types of activities. Most programs will need to begin with one activity and add more activities as they gain expe rience and resources. 3. Activities should complement one another. For example, instruc tion on how to avoid gang membership may be complemented by alternative activities. Instruction on nonviolent conflict resolution maybe accompanied by more monitors in the school hallways. 4. Activities may address different steps in the chain of events that lead to injury and death. For example, activities may address - factors that influence behavior (e.g., knowledge and attitudes) - the behavior itself (e.g., carrying weapons or fighting) - health outcomes (e.g., injury or death) 5. The activities selected should be determined by the unique char acteristics of the community and the goals and objectives of the program. Activities that have worked in other communities maybe a good place to start. They can often be modified to meet the specific needs of your community. However, an activity should not be se lected simply because it is or appears to be working in another community. # TARGET GROUPS A target group is the group of people whom the program or acti vity is designed to influence. Depending on the activity, the target group may be broad or specific. For example, some activities may address adolescents who are out of school or who have a history of violent or criminal behavior. Other activities may address all young children. Still others may address parents, teachers, employers, or others who interact directly or indirectly with youth. Activities suitable for one group may be inappropriate for another because groups and indi viduals vary in terms of culture, values, knowledge, attitudes, skills, behaviors, experience, and other attributes. The selection of target groups should take into account the specific nature of the problem being addressed, the major goals and objec tives of the program, and community characteristics. For example, members of youth gangs would not be an appropriate target group if gangs are not a problem in the community. Successful programs will have activities that address many target groups. However, this takes time, and a decision must be made about which target groups to address first. There are a few broad categories of target groups (Table 1) that are useful to consider. # The General Population of Youth Many activities designed to reduce injuries from youth violence can be applied to all youth (or to the environment that affects them). An example of such an effort is teaching conflict resolution skills to high school students. In this instance, the purpose of the intervention is to affect the manner in which all students resolve conflicts, not just those students who are thought to be most likely to engage in violent behavior. Programs with activities directed toward the general popu-lation of youth, if successful, are likely to produce early and possibly substantial reductions in violent injuries and deaths. However, to be successful they must reach large numbers of youths. # Youth Who Engage in High-Risk Behaviors Youth with high-risk behaviors are those most likely to be injured, those most likely to engage in violent behavior that injures others, or both. These groups include young people who consistently engage in physical fights to resolve problems, those with a criminal record or a history of inflicting or receiving a violent injury, drug users, gang members, or those who have failed or dropped out of school. Other youth who maybe at risk for fighting are relocated youth. This group includes immigrants and migrants, and can also include youth who live in communities that are highly mobile. One other group that may be prone to fighting are those with emotional or mental deficiencies who may not have the personal skills to settle disputes nonviolently. If successful, activities directed toward this group of youth may show early and possibly substantial reductions if these groups account for much of the violent injuries and deaths among youth in the commu nity. Special efforts are often necessary to locate and contact youth with high-risk behaviors. Outreach workers may help. They can meet youths on street corners, parks, fast-food restaurants, or other places where they gather. They work to establish trust. Once trust is estab lished, outreach workers may be able to refer or guide adolescents with high-risk behaviors into helpful activities. Outreach is important in making contact with youth who engage in high-risk behavior, but it is only a part of a program. Other activities are also necessary. The Community Youth Gang Services (CYGS) of Los Angeles, Califor nia, is a good example of a program that has a strong outreach component with a number of other program activities. This program is described on pages 27 and 28. # Young Children (10 Years Old or Less) Violence is a learned behavior. The basic values, attitudes, and interpersonal skills acquired early in life are likely to be pivotal in developing predispositions for violent behavior later in life. There fore, activities for young children that promote nonviolent values, attitudes, and interpersonal skills are important to consider. Also, any long-term strategy to prevent violence may also want to include children who are abused or witness violence and activities that lessen the consequences of exposures to violence. If successful, these inter ventions may show substantial reductions in violent injuries and deaths when these children become adolescents. # Other Target Groups The above three categories of target groups-the general population of youth, youth with high-risk behaviors, and young children-may be considered direct target groups because activities are intended to reduce violent injuries and deaths among those groups or caused by those groups. Programs focusing on these groups will also need activities for indirect target groups-those people who have a par ticular relationship with the primary target f oup. Examples of indirect target groups are family members, adun role models, or the general population. Family members. Family experiences play a critical role in causing, promoting, or reinforcing violent behavior among youth. Conse quently, the family is an important target for activities to prevent youth violence. Activities that target families can focus on parents, siblings, or the entire family unit. Typically, these activities reinforce health promotion or prevention messages, support the parents in raising and managing children and youth, or provide help in coping and responding to family crises. Special groups of adults. Teachers, coaches, clergy, health profes sionals, counselors, athletes, entertainers, and other adults often have special relationships with children and youth. They may be important role models. They may also recognize or decide which children and youth need or receive special services. Adult role models are an important target for youth violence-prevention activi ties because they are very influential in the lives of children and youth, frequently serving as confidants. As such, they can reinforce health promotion and prevention messages, including those pertain ing to violence. General population. The general population is an important target group for several reasons. First, people need to be educated about the role of society as a whole in promoting violent behavior. Second, activities such as modifying or passing gun control legislation may affect wide segments of the population. For such activities to be successful, we must address the entire population. # SETTINGS The setting is the location where a prevention activity occurs. There are four important considerations involved in selecting settings for a prevention activity (Table 2). - First, select a setting where you can reach the target group. Schools, for example, may be an appropriate setting for the general population of youth, but are not an appropriate setting if the target group is youth who are no longer in school. - Second, select a setting appropriate for the strategy. A classroom curriculum probably will not be effective if administered on the playground. - Third, select multiple settings for each target group. The fre quency of violent behavior is more likely to decrease if comple mentary messages or experiences occur in several settings and if the environment is made less conducive to violence. For exam ple, a young boy is less likely to be violent when he is taught alternatives to violent behavior in the school, is exposed less often to violence in the home, and plays in supervised areas where fights are not likely to take place. « Fourth, when appropriate, select one setting suitable for several target groups. Churches, for example, may be an appropriate setting for reaching both youths and parents. Settings in which the general population of youth may be reached include schools, churches, streets, playgrounds, youth activity sites, and homes. Additional settings where certain groups with high-risk behaviors may be found include juvenile justice facilities, mental health facilities, social service facilities, and the medical care facili ties. Young children may also be reached in child care settings (e.g., Head Start locations). # STRATEGIES Activities to prevent youth violence typically employ one of three general prevention strategies: education, legal and regulatory change, and environmental modification. Each of these general strategies has a role in a comprehensive youth violence prevention program (Table 3). # Education Education provides information and teaches skills. New knowledge and new skills change or reinforce a person's attitude and behavior thus reducing the chances that the person will behave violently or become a victim of violence. Educational efforts can be directed toward a wide variety of target groups to help convey knowledge and skills. Face-to-face teaching may occur in the classroom, in worksite or recreational settings, or through special teachers, such as nurses on home visits. Knowledge and skills are a crucial part of the process, but they are often insufficient by themselves. The acquisition of knowledge is usually not followed immediately by the adoption of new behaviors. Behavioral change requires time and repeated effort and is more likely to occur if the physical and social environment support and encourage it. The following are examples of types of educational strategies. With each example are several brief descriptions of the strategy as it is being implemented in a U.S. community. # Adult Mentoring Mentors are special adults who provide a positive, caring influence and standard of conduct for young people. Mentors provide models for young people who have none, or they offer alternatives to negative role models. Mentors may reinforce positive attitudes or behaviors that children are trying to express. Adult role models may be teach ers, counselors, friends, and confidants, or simply members of the community. Mentoring activities can be conducted in almost any setting, such as schools, churches, businesses, or other community locations. The attention and interest bestowed on the youngsters by people who care enhance the youth's self-esteem and strengthen his or her ability to choose nonviolent methods to resolve conflict. # Baltimore, Maryland, Project RAISE (410) 685-8316 In 1988, Project RAISE recruited mentors for more than 400 sixth-grade students. The mentors contact the students at least weekly and meet with them face to face at least every other week. The mentors serve as role models, provide academic support, and strive to boost the youths' self-confi dence. The mentors are recruited from two churches, two businesses, and two colleges that serve as sponsors of the project. A Project RAISE staff member coordinates the project with the schools, matching mentors with students after informal contacts and information exchanges with mentors and students. A private foundation is funding the project.______________________________________ Atlanta, Georgia, Go to High School, Go to College (404) 766-5744 The Atlanta "Go to High School, Go to College" project has paired 100 successful older men with adolescent African-American males at four Atlanta area high schools and one middle school. Each mentor meets twice a week with a student who is struggling academically, has discipline problems, or is at risk of dropping out of school. The mentors are provided with a 40-page curriculum of instructions and ideas. Mentors strive to increase the students' self-esteem and improve their grades. A local fraternity chapter provides scholarships to students who qualify and want to attend college. # Conflict Resolution Education Classes in conflict resolution are designed to provide students with the opportunity to develop empathy with others, learn ways to control impulses, develop problem-solving skills, and manage their anger. Usually this curriculum is delivered in the classroom setting, al though other settings, such as churches, multi-service centers, boys and girls clubs, recreation centers, housing developments, juvenile detention centers, and neighborhood health centers may be appro priate also. Courses in conflict resolution have been developed for students in both elementary and high schools. The methods used to teach conflict resolution usually include role playing conflict situations and analyzing the responses to, and conse quences of, violence. Generally, students are trained for 15 or 20 hours, after which they may work in pairs mediating conflicts that occur in the classroom or cafeteria, on the playground, or elsewhere. These conflicts cover a wide range of situations, including bullying, stealing, and spreading rumors. Teaching materials can be designed to meet individual needs of different groups of students. # Boston, Massachusetts, The Boston Conflict Resolution Program (617) 492-8820 The Boston Conflict Resolution Program (BCRP) is a violence prevention program that helps elementary school teachers and students understand and deal with conflicts frequently encountered in schools. These conflicts often result from prejudice, competition, miscommunication, an inability to constructively express feelings, and a lack of respect and concern for others. The School Initiatives Program in San Francisco grew out of a community program that began in 1977 to train community residents to help their neighbors resolve disputes peacefully. In 1982, this program expanded to the schools because of growing conflict and violence in that setting. This program has two components: classroom curricula and a conflict manager's program. Class room materials are designed for elementary and secondary school students. These materials help students acquire self-esteem and the skills needed to resolve conflict and build a stronger sense of cooperation and community at school. To become conflict managers, students at the middle-and high-school level participate in 15 hours of training over two and one-half days. They learn communication, leadership, problem-solving, and assertiveness. Once trained, these students help their fellow students to express and resolve their conflicts nonvioiently. # Training in Social Skills Teaching young people social skills provides them with the ability to interact with others in positive and friendly ways. Training in social skills includes many things that help students successfully interact with others. Aspects of social-skills training include maintaining self-control, building communication skills, forming friendships, re sisting peer pressure, being appropriately assertive, and forming good relationships with adults. Nonviolent conflict resolution train ing may be included with these other social skills. Acquiring these skills provides students with appropriate standards of behavior, a sense of control over their behavior, and improved self-esteem. They maybe less likely to resort to violence or become victims of violence. These educational activities can be conducted in schools, day-care settings, after-school programs, and youth organizations. # New Haven, Connecticut, The New Haven Social Development Program (203) 432-4530 Since 1983 the Yale University Psychology Department has collaborated with the New Haven public school system to provide training in social skills in the middle schools of the district. The major components of this activity are classroom activities for sixth and seventh graders that teach social development, and modeling of socially competent behavior by school staff. The curriculum empha sizes self-control, stress management, problem-solving, decision-making, and communication skills. Once students have learned a general problem-solving framework, they apply their critical-thinking skills to specific issues, such as substance use. The emphasis is on providing accurate information about the topic and focusing on realistic situations. Finally, school, family, and community resources are identified that are available to help students cope with personal or family difficulties. Methods used are role-playing, videotaping, and live modeling; classroom presentations; smallgroup discussion; and competitive and cooperative games. Classroom teachers undergo training that includes practice modeling and review of techniques for dialogue, discussion of students' reactions to the lessons, and adaptation of the lessons to the special needs of their students. # Activities to.Prevent Youth Violence # Education To Prevent Injuries from Firearms The meaning of education to prevent injuries from firearms varies from community to community. For some, this means avoiding firearms altogether and for others it means the proper handling of firearms. Activities providing education about firearm safety can be conducted in school settings and in the community. A number of educational techniques have been developed, including the use of audiovisual materials and curricula that deal with situations that involve firearms. # Dade County Florida, Kids + Guns = A Deadly Equation (305) 995-1986 A program designed to teach students from kindergarten age through high school about the dangers of playing with or carrying guns was developed jointly by the Dade County Public Schools, the Center to Prevent Handgun Violence, and Youth Crime Watch of Dade. Kids+ Guns= A Deadly Equation includes classroom instruction and schoolwide activities that center on helping students recognize unsafe situations, react appropriately when encountering guns, resist peer pressure to play with or carry guns, and distinguish between real-life and media violence. The curriculum includes a video program for students in grades 7 through 12; a component for parents includes a brochure and video program. # Parenting Centers Improving parenting skills through specially designed classes for parents can improve how the parent and child interact. The improve ment in this relationship may reduce the risk of childhood behavior problems and subsequent antisocial behavior that may predispose an individual to violence in later life. Programs targeted toward parents must address the psychological needs of the parents, especially their sense of being competent parents; the parental behaviors that influ ence the physical and social development of their children; and the stresses and social supports that can either help or hinder parents' ability to adapt to their children's needs. Minneapolis, Minnesota, Project STEEP (612) 624-0210 Project STEEP (Steps Toward Effective, Enjoyable Parenting) serves low-income, first-time parents. Most parents are single and have no more than a high-school education. The program includes both group sessions and home visits. It begins during the second trimester and continues until the baby is at least one year old. Prenatal visits focus on the mother's feelings about pregnancy and preparation for parenting. After the baby is born, transportation to the group sessions is provided by the project. The focus of demonstration and interactive sessions is on child-care skills, infant development, and infant-mother communication. Interactions between mother and infant are vide otaped, reviewed, and discussed with the parent. # State of Missouri, Parents as Teachers (PAT) (314)553-5738 Parents as Teachers is a home/school partnership that serves all parents, including single parents, teenage mothers, and two-parent families. PAT parent educators, trained in child development, go to homes of participating parents to help them understand each stage of their child's development and learn ways to encourage that development. The program also conducts group meetings for parents to get together to gain new insights and to share their experiences, common concerns, and successes. They conduct periodic screening of overall develooment, language, hearing, and vision to detect potential problems, and refer families to special services. # Peer Education Programs that use students to teach their peers about violence pre vention are a powerful force among adolescents and can be used effectively to help shape norms and behaviors in this group. Re search on peer education for other health issues such as alcohol, cigarette, and drug use, has had positive results and shows promise for violence prevention programs. # Ferguson, Missouri, RAPP (Resolve All Problems Peacefully) (314) 521-5792 RAPP was begun to reduce the number of physical fights among students. Students selected by teachers and other students are trained in mediation skills. Students found in conflict are given the choice of going to mediation or going to the office. Those who choose mediation meet with one of the trained mediators who works with them to peacefully resolve the conflict. During the first semester of the project, the number of fights was less than half the average for the same semester over the previous three years. Oakland, California, Teens on Target (510) 635-8600, Ext. 415 Teens on Target is a peer education and mentoring group that was formed by the Oakland Safety Task Force in California after two junior high students were shot in the schools by other students. The task force, made up of a coalition of elected officials, parents, and school and community agency representatives, felt that students would do a better job of dealing with the youth violence problem than adults. Selected high school students are trained in an intensive summer program to be violence prevention advocates, particularly in the areas of guns, drugs (including alcohol), and family violence. These students become peer educators to other high school students and mentors to younger students in the middle and elementary schools. Teachers provide ongoing guidance and supervision to the teen educators. # Public Information and Education Campaigns Public information campaigns reach a broad audience. They draw attention to an issue and help establish acceptable behavior for a community. They also convey a limited amount of information, which by itself is rarely enough to change behaviors. Therefore, activities that provide general information to the public are most effective when combined with other activities in a violence preven tion program. There are a number of ways to inform the public through media. Some examples are public service announcements, educational video programs, appearances on public talk shows, posters, brochures, and other print materials. # Charlotte, North Carolina, The Police Executive Research Forum and the Center to Prevent Handgun Violence (202) 289-7319 The Center to Prevent Handgun Violence in conjunction with Police Executive Research Forum developed and ran a public awareness campaign in Charlotte, North Carolina, that attempted to change people's knowledge, attitudes, and behaviors concerning the protection they believed firearms offered. Together these two groups developed guidelines, produced print and broadcast media messages, distributed brochures, made community presentations, and conducted safety demonstrations. The messages developed through this awareness campaign included safe storage of firearms, instructing children about handgun safety, and checking firearms before cleaning. # Baltimore, Maryland, The Baltimore County Police Department and the Center to Prevent Handgun Violence (202) 289-7319 The Center to Prevent Handgun Violence has also helped the Baltimore County Police Department develop advertisements, public service announcements, pamphlets, brochures, and police presen tations for both gun owners and people who do not own guns. The materials cover the dangers of misusing firearms, how to childproof handguns, legal issues including liability, and the psychological and practical issues of ownership. # The Prevention of Youth Violence # Legal and Regulatory Change Laws or rules may lower the risk of violent behavior or victimization. Some regulations that would help reduce injuries and deaths from violence have already been enacted, but many are neither widely known nor well enforced. In many cases, it is easier to enforce existing laws than it is to enact new laws. In other cases, existing regulations are inadequate and new ones are needed. You can find out your state laws by contacting your state attorney general's office. You can find out your local laws by contacting your local police agency. The success of making or enforcing rules depends on the willingness of the population to support and obey the rules and the ability of regulatory agencies, such as the police, to enforce them. Examples of laws or regulations intended to reduce injuries and deaths from violence include laws prohibiting the carrying of firearms in public and rules prohibiting the wearing of gang colors in schools. # Regulations Concerning the Use of and Access to Weapons Guns, knives, and other dangerous weapons may not actually cause violence, but they can convert an argument with no associated inju ries into one with severe injuries or even death. A variety of strate gies have been used to reduce the likelihood that weapons will be used. Many communities already have existing laws and regulations concerning the sale, ownership, use, or carrying of guns or other weapons. - Most schools prohibit students from bringing weapons into schools. Methods used to help enforce the prohibition include rules requiring students to carry books in see-through bags rather than solid cloth or opaque containers in which weapons can be hidden, random locker searches, rules prohibiting the wearing of clothing in which weapons can be hidden easily, or metal-detector checks at the school entrance, of selected classrooms, or at se lected sites in the school. - Some cities prohibit carrying a firearm within the city limits or carrying a concealed weapon. Recently enacted legislation that increased the penalty for disobeying these laws in Detroit and Massachusetts were apparently effective in reducing the number of homicides and assaults with guns. # Massachusetts Bartley-Fox Act (1975) This law mandated prison terms for anyone carrying an unlicensed firearm. In the two-year period following passage of this law and the accompanying publicity, the incidence of assaults with guns was reduced by 13.5 percent. _ - Some laws ban the possession of particular types of guns, such as handguns or machine guns, except for police or others with a demonstrated need. Individuals who wish to buy these types of guns must obtain special permits. These laws are generally called restrictive licensing laws. # Washington, D.C., Prohibition of Handgun Ownership in 1976, the District of Columbia banned the purchase, sale, transfer, or possession of handguns by civilians. A study that compared homicide rates in the District with rates in the surrounding counties showed that the handgun ban had an effect. The homicide rate in the District dropped about 25 percent in 1977, the first year after the ban went into effect and remained lower than expected until the end of the study in 1988. An estimated 40 homicides per year have been prevented by the ban on handguns. Homicide rates remain high in Washington, D.C., however, indicating other actions besides prohibiting handgun ownership are necessary. - Twenty-six states currently require a waiting period, a police background check, or both before a handgun maybe purchased. For example, in Tennessee, there is a 15-day waiting period to purchase handguns. In Massachusetts, there is no waiting period to purchase any legally sold firearm, but the buyer must have a permit-to-purchase and must wait 40 days after obtaining the permit-to-purchase before purchasing any guns. - Local citizens may be aware of a particular gun dealer who is selling to underage youths or otherwise not obeying the local laws concerning the sale of guns and ammunition. These violations can be brought to the attention of the local police. Local police are generally quite willing to enforce the laws against the illegal sale of weapons. # Regulation of the Use of and Access to Alcohol Alcohol consumption appears to play an important role in many violent situations. Youth who have been drinking are more likely to become involved in physical fights. In all 50 states and the District of Columbia, the minimum drinking age is now 21 years. Laws prohibit the sale or public possession of alcoholic beverages by anyone under the age of 21. - Sale of alcohol to underage youth may be limited by stricter enforcement of laws. As a general rule, regulations are most poorly followed in convenience stores. Establishments that fre quently violate the regulations are often known to the local residents and can be targeted by law enforcement officers. Police are much more likely to take the time to enforce the alcohol laws if they know they have strong community support to do so. - Keg-labeling laws can be established. Liquor stores can be re quired to increase the deposit and to place a numbered band on beer kegs. The numbered band identifies the purchaser, making it possible to trace and arrest people who supply kegs to under aged drinkers. - Clubs, organizations, and those sponsoring entertainment events can prohibit the consumption of alcohol on the premises and refuse admittance to youth who have been drinking. - All states have laws about the liability of alcohol servers for injuries to their patrons or for injuries caused by their patrons because they had too much to drink. These laws can be publi cized, better enforced, and, if necessary, strengthened. - Cooperation between the owners and managers of places that sell or serve alcohol and community organizations concerned about violence could lead to required instruction for servers and man agers. Bartenders and managers of drinking establishments or special events can be taught about their important role in the prevention of irresponsible drinking, how to determine if a cus tomer has had too much to drink, and how to detect underage youth. # Oregon, Alcohol Server Education Program (503) 653-3030 Since 1987, Oregon law has required servers, managers, and owners of establishments that serve alcohol for on-premise consumption to pass a server education course. Participants are taught about the effects of alcohol on the body and its interaction with other drugs. They also learn about their responsibility to prevent irresponsible drinking. They learn to estimate the drinking capacity of customers, to look for signs of intoxication, to cut off people who have had too much to drink without causing an argument, and to identify minors. Courses include a minimum of 4.5 hours of instruction and participation. The Oregon Liquor Control Commission monitors the classes to assure their quality. The servers, managers, and owners must take the course every 5 years. # Other Types of Laws and Regulations In addition to regulations concerning weapons and alcohol, other types of regulations may also reduce youth violence. For example, prohibiting corporal punishment and enforcing some dress codes in schools may be helpful. ® Corporal punishment in schools is now banned in 23 states and in many large cities in other states. Corporal punishment of students by school officials contributes to the perception that fighting and physically injuring another person is acceptable. On occasion, it may actually cause physical injuries. - Dress codes for organizations or schools may reduce the identi fication with gangs or make it more difficult to conceal weapons. # Los Angeles, California, Challengers Boys Club (213) 971-6141 The Prevention of Youth Violence # Environmental Modification Fnvironmental modification includes changes in both the social and the physical environments. # Modification of the Social Environment Methods of changing the social environment of children and adoles cents who may be at risk for being violent or for becoming a victim of violence include such activities as providing preschool education and appropriate or therapeutic day care programs for abused chil dren. For older children and adolescents, this includes providing constructive, alternative activities, such as recreational opportunities and employment. Small, personal after-school programs that offer contact with caring adults, counseling, help with homework, and recreation can create a safe, constructive alternative to violent street cultures. # Home Visitation Home visitation is an activity that provides services in the home either for an individual or the entire family. Home visitation pro grams performed during the prenatal and infancy years of the child focus on preventing health and developmental problems in children born to mothers who are teenagers, unmarried, or of low socioeco nomic status. These activities have been found effective in prevent ing child abuse. Because research shows that abused children are more likely to be violent or be victims of violence as adults, prenatal and infancy home visitation programs maybe an effective long-term strategy for preventing youth violence. These programs are typically designed to meet the needs of parents for information, emotional support, stress management, and other factors that undermine par ents' health habits and the care of their children. # Elmira, New York, The Prenatal/Early Infancy Project (716) 275-3738 This home visitation project was designed to prevent a wide range of health and developmental problems among children born to young, poor, or unmarried women. In this program, nurses visit pregnant women to provide information and support that encourage the mothers to adopt good health habits, learn the skills needed to care for their infant children, get access to needed community services, achieve educational or occupational goals, and prevent unwanted future pregnancies. Home visits begin in the early stages of pregnancy and continue through the second year of life of the child. Evaluation of this project showed that the health and social skills of participants had improved. In addition, there was a substantial reduction in verified cases of child abuse among the children of at-risk women who were visited at home by the nurses. # Preschool Programs Such as Head Start Project Head Start is designed to help children of low-income fami lies develop a greater degree of social competence through develop ing the child's intellectual skills, fostering emotional and social development, meeting the child's health and nutritional needs, and involving parents and the community in these efforts. A 1990 report of the Milton S. Eisenhower Foundation, which grew out of the bipartisan National Commission on the Causes and Pre vention of Violence, reported that preschool programs like Head Start are among the most cost-effective inner-city crime and drug prevention strategies ever developed. (See Other Useful Things To Read on page 54.) # Therapeutic Activities Therapeutic activities provide medical, psychological, or other treat ment for children who have been abused, injured by violence, or witnessed an unusually violent event. The provision of medical, psychological, and nurturing services helps break the cycle of vio lence. In addition to child and family counseling, here are several special types of therapeutic services: - Foster care programs provide basic physical care and safety from abusive parents. They can be very effective if multiple placements are avoided and foster parents are caring and knowledgeable about the needs of the child. » Respite day care and therapeutic day care provide services in a safe, nurturing, stimulating, organized environment without tak ing the child entirely out of the home. Day care programs are often the abused child's first contact with other children besides family members. This interaction helps the child adjust to the separation from parents, attain skills during play, and build self esteem through interaction with peers. - Residential treatment programs target school-age children with special needs, such as emotional disturbances or substance abuse problems. - Crisis management services help groups or individuals deal with the anger, fear, sadness, hopelessness, confusion, and irrational thinking associated with witnessing or being victims of violence. Dallas, Texas, Dallas Independent School District Crisis Management Plan (214) 565-6700 The Dallas Independent School District Crisis Management Plan divides crises into three levels. The most severe level includes terrorist activities or a death at the school. This level also includes severe natural disasters and suicide clusters. For each level, there is a planned coordinated response. The pian includes methods of informing students, families, and the public about the event. It also includes the identification and provision of counseling services to students in need. Each school has a local crisis team. There is also a District crisis team consisting of psychological and social service experts. The District crisis team participates in the most stressful events, such as a death at the school. # Recreational Activities Recreational activities offer young people opportunities to spend time in a structured and purposeful environment. Recreational in terventions cannot be considered a sole answer to youth violence. However, activities that provide outlets for tension, stress, or anger and opportunities for social interactions and constructive problem ' solving are important parts of a program with other violence preven tion components. Many recreational activities are conducted with these goals across the nation in Boys and Girls Clubs, Girl Scouts and Boy Scouts, YMCAs and YWCAs, and local recreation departments. # Modification of the Physical Environment The physical environment does not cause violence, but it may make violent events more or less likely to occur. Some environmental modifications by themselves may appear to merely displace the undesirable behavior to another location. Better lighting on a play ground, for example, may move the undesirable activity to another location in a community. Sometimes, however, the new location is less conducive to violence, more difficult to reach, or easier for potential victims to avoid. In these cases, the overall amount of violence may decrease even though some violence has merely moved to a new location. Protective landscaping, changes in traffic flow, speed bumps, dress codes, visible identification cards, and closed-cir cuit television monitoring are other examples of enviornmental changes. Environmental change maybe particularly effective when combined with educational and regulatory strategies. # Ithaca, New York, Cornell University Blue Light System (607) 255-1111 The Blue Light system on the university campus has three components: an emergency phone system, a bus system, and an escort service. The Blue Light phone system has 61 emergency phones outdoors across the campus, placed so that at least one phone is easily visible to pedestrians. Additionally, there are 158 emergency phones in academic buildings and dormitory entrances. All phones are directly connected to the Public Safety Dispatch Office. When callers pick up the receiver or push a special button, they are automatically connected with the Public Safety office. The location of the phone is displayed and recorded automatically. A patrol unit Is sent to all calls for assistance and to all hang-up calls. The Blue Light bus system is a free transportation system that operates every day from 6:00 p. Crime Prevention Through Environmental Design (CPTED) is a concept that is attracting interest in many police departments. Al though its purpose is to prevent crime, the CPTED principle prob ably will help prevent violence also. CPTED relies primarily on increasing visibility and encouraging a sense of ownership. Undesir able acts are less likely to occur in places where they will be observed, and people naturally use and protect things they own. ® Visibility can be improved by designing areas so that they are more easily observed by people during their normal daily behav ior. For example, parking lots could be placed so they can be clearly seen from the school or office building with which they are associated. - Visibility can be improved by attracting more people to the area. For example, volleyball or basketball courts can be placed in the center of parks or playgrounds. The players will make it more difficult for illicit or violent activity to occur unobserved . - Limiting the ways in which people enter a building also increases visibility. That makes it more difficult for people who do not belong to enter or depart unobserved. Receptionists can be placed at the entryway of schools or offices. The sales desk can be placed near the entrance in stores. - Creating a sense of ownership will increase the use of the envi ronment for desirable-purposes, Cleaning and maintaining an area may give a. sense of ownership. - Changing traffic flow can make a neighborhood belong more to the residents. Limiting the number of through streets, making one-way streets, creating dead-ends, and narrowing the entrances to some streets can reduce traffic by nonresidents. This helps residents feel like the neighborhood is their own. # Los Angeles, California, Community Youth Gang Services (213) 266-4264 Community Youth Gang Services is a program with many components, but some of the most innovative involve reclaiming the community that has been taken by gangs. One aspect of the program carefully plots on maps the physical areas of the community that are affected by gangs. These areas are targeted for reclaiming, and community residents are mobilized to do that through such activities as a Saturday in the Park, in which a particular day is designated for clean-up of the park and family activities. Another activity of this program is the removal of graffiti. Community Youth Gang Services staff have the professional staff and equipment to eradicate graffiti without damaging surfaces. Staff hires and supervises local youth and selected youth on probation to do this task. # Combining Activities for an Effective Program The activities listed in this manual are presented individually so that the reader can investigate the different types of activities available to communities. In reality, activities are rarely conducted inde pendently. Effective programs combine a number of activities to render the maximum impact on the problem and reach as many young people as possible. There are a number of examples of programs that combine three, four, or five strategies that have been discussed. # Philadelphia, Pennsylvania, House of Umoja Boystown (215) 473-5893 The House of Umoja Boystown is a home for African-American boys in Philadelphia, an area with high numbers of youth in gangs. In addition to providing a home with food and shelter, the program offers extensive services that offer emotional and spiritual support. These services cover a number of the types of activities described earlier in these guidelines, such as outreach, educational activities, recreational opportunities, and work/academic opportunities. # Boston, Massachusetts, The Violence Prevention Project (617) 534-5196 The'Violence Prevention Project in Boston, Massachusetts, is a multi-institutional, community-based program designed to reduce the incidence of interpersonal violence among adolescents, along with associated medical and social hazards. The major activity used in this program is a violence prevention curriculum that focuses on conflict resolution. However, in the initial phases of develop ment, it became apparent that a school-based activity was not enough and activities in the community were added to reinforce nonviolent options learned in the classroom. Staff from the program train providers in diverse community settings In the use of the curriculum's strategies. They also help providers find ways to incorporate these strategies into the delivery of services to adolescents and encourage consensus from the community that supports the prevention of violence. As a result, educational materials are available in waiting areas of health centers, and staff at these centers offer violence prevention counseling. This program also includes activities at Boston City Hospital. Adolescents are screened in the emergency room to identify those at high risk of violence, and a special violence prevention clinic at the hospital offers services to these adoles cents. Services include comprehensive assessment, educational interventions, counseling, therapy, and referral to other community services. # Chicago, Illinois, African-American Male Education Network (AMEN) (708) 720-0235 The African-American Male Education Network centers its activities on Rites of Passage programs, which foster self-esteem and pride in one's cultural heritage and provide guidance for youth as they move from one stage of life to another. The program provides the guidance and support to overcome the confusion and frustration that lead to youth choosing destructive alternatives such as violence, gangs, and substance abuse. The program accomplishes these goals through education, teaching life and social skills, and mentoring. # Los Angeles, California, Community Youth Gang Services (213) 266-4264 The Community Youth Gang Services (CYGS) of Los Angeles is a program with many activities. CYGS has crisis intervention teams that negotiate disputes among gangs in the target area and try to convince youth not to join gangs. The program also has activities to reclaim areas of the community from gangs, areas such as parks or playgrounds that were not considered safe because of gang activity. Volunteers work with program staff and local agencies and community groups to develop cultural, recreational, and other activities that are alternatives to gang involvement. Educa tional programs in the schools are complemented with parent education and teacher education. In the job development section of the program, staff work with youth to prepare them for employment and also encourage local employers to hire youth. One other active part of the program is the removal of graffiti from community landmarks. Staff hire youth in the community to do this task under professional supervision. This program has an aggressive outreach effort that works continually In the community to discourage gang membership and direct youth already in gangs to other activities. # PROGRAM MANAGEMENT Certain steps are necessary in building a successful community pro gram to prevent youth violence. These steps, which are essentially the same for all community-action activities, are based on two prin ciples: - Community programs require the input of the entire community. - A problem must be clearly identified before it can be addressed. # COMMUNITY OWNERSHIP A united community can produce powerful changes. Even large and complicated problems like violence can be reduced by the creative energy of a community. One necessary ingredient is the participation of many residents. Community-based health promotion programs in other areas have been effective because they combined the efforts of many different organizations and individuals. In these programs, diverse organizations and individuals recognize their common inter est and work together for a common purpose. A single individual or organization may provide the initial stimulus or the ongoing leader ship, but sustained and effective community-wide action depends upon the coordinated efforts of many individuals and groups. In the process of building a community effort, you should do the following: - Keep leadership and ownership of the program at the community level. Many organizations and government agencies may pro vide support or be involved, but the community should be the leader. Community ownership is the best way to assure that the violence prevention program becomes a permanent program in the com munity. - While keeping leadership of the program at the community level, do not miss opportunities to gain the support and resources that can be provided through the involvement of government agencies or private organizations, such as businesses and churches. Throughout the life of the program, one of the major challenges will be to maintain a productive working relationship among all individuals and organizations interested in working to prevent youth violence. - Include young people of the community in as many parts of the program as possible. They are the most important target group and can be a big help to the program. - Establish a leadership and organizational structure. Initially, both leadership and organizational structure are likely to be informal and flexible. As the program grows, they become more formal. Members of the target population, neighborhood, or community must be part of the leadership group. - Determine the resources available to you. Resources may be divided into three groups: money, ideas, and people. All three types of resources maybe scarce. In addition, the need for each type of resource will vary at different stages of program develop ment. Groups or organizations that may be available to supply some of the necessary resources are listed in Table 4. Not every group on the list is appropriate for every community. Most communities will also have unique organizations and individuals who are not on the list but should be included. - Coordinate efforts. The carefully planned and c-.Vidinated ac tivities of multiple groups, each doing a little bit, accomplish more than the same efforts applied in an uncoordinated fashion. There are several types of information that help describe the nature and extent of the problem in a community. There is factual informa tion from statistical records and opinions about the nature of the problem from people in the community (Table 5). # Factual Information Factual information can describe - The outcome of violent events, such as those that cause injuries and deaths. This information can be obtained from the vital statistics division of the state or local health departments, medical examiner records, hospital or emergency room records, outpa tient records from public or private clinics, emergency medical service (ambulance) records, and school nurse records. Once you have these statistics, it maybe helpful to compare them with state and national data, if possible, to see how your community com pares with other areas. When possible, collect information spe cific to the neighborhood-for example, incident reports from local schools. - The time, place, and circumstances of violent events (e.g., fights over girl-or boyfriends, fights over clothing, fights about drugs, fights between gangs). This information is not routinely assem bled. However, you may find this information byreviewingpolice records, hospital records, or school records. This type of infor mation may help identify times, places, or circumstances that deserve special attention. Because much of this information maybe confidential, you may have to make arrangements to get summary data (e.g., number of firearm injuries) which do not contain information that identifies the people involved. If you are working with a research organi zation or university, they should knowhow to legally have access to records. It is usually best to begin with statistics on the number of violencerelated injuries and deaths. When these are described as well as possible, then look for information about the times, places, and circumstances of the events. # Opinions from Members of the Community You must learn what your community members see as a problem and what they think is causing the problem. You can find this out through surveys of residents and discussions with community leaders, school personnel, legal and police personnel, health workers, and parents. For example, ask school principals and guidance counselors about the violence they see in the schools and listen to their ideas for reducing it. It is also important to talk to children and adolescents themselves, particularly those who might be in trouble or at risk for trouble (for example, those who are expelled from school). Contact youth and their parents in as many community sites as possible, including supermarkets and shopping areas, basketball courts and other recreational areas, churches, schools, and homes. Local schools and universities may be able to help with opinion surveys. - The results of opinion surveys reflect the personal beliefs, view points, and judgments of community members, including victims, offenders, community leaders, and, most importantly, youngpeople. - People who respond to such surveys will give you valuable infor-mation about knowledge, attitudes, and beliefs concerning vio lence in the community. They will also identify what is acceptable in the community and how certain activities may be perceived by community members. - Be sure that workers collecting the information have credibility in the community. # Community Background Information Other types of information on such topics as racism, poverty, unem ployment, and other social, cultural, or economic factors provide helpful background information about the community and the prob lem of violence. Some of this information can be obtained through the U.S. Census (available through your local library), the Depart ment of Labor employment statistics, and from the Department of Housing and Urban Development. When approaching an organiza tion, ask for information specifically related to the institution. For example, ask schools about attendance, truancy, suspensions, expul sions, and failures. The information you acquire from opinion surveys of local leaders and citizens is valuable and may not be available anywhere else. Academic institutions or university research organizations in the community may be able to help you obtain and assemble this type of information. # Data Presentation Statistics from public sources are usually set up for the needs of the particular agency or organization. They may not be tabulated, ex plained, or displayed in ways that you need. You can ask, but do not expect the people or the organizations from whom you get data to modify it for your use. You may find it useful to include people in your effort who have the data or who know how to organize, interpret, and use it. The causes of violent behavior are multiple and complex. The com bination of statistics and opinions is important when you are deciding what you want to do. Statistics will suggest several possible areas for activities. However, the opinions from the community may identify information not provided by the statistics and could indicate the areas that should be addressed first. In addition, information about the community is a powerful tool to convince law-makers and other decision-makers about the importance of the problem and the need to address it. # GOALS AND OBJECTIVES Effective community programs have both goals and objectives. A goal is a broad, general statement about what the program is designed to accomplish. Goals determine the direction of the program. Ob jectives are statements of specific things to be achieved by a specific time, and they determine what activities the community will do. # Example: Goal-Reduce violent behavior in the schools. Objective-In the 1994-95 school year, 100 eighth grade students will study the curriculum on non violent conflict resolution. An objective should tell who should achieve how much of what. where, and by when. . Who means the individuals or groups expected to accomplish a task or change a behavior. - What tells the desired action, such as a change in behavior or health practice. The what should be based on your list of priori ties. At least one of the objectives should be a change in an important health event such as injuries from fights. Other objec tives might relate to the number of fights, the number of students who learn how to avoid a fight, or even the number of students who take a class about avoiding fights. - How much indicates the amount of change you expect. This amount partially depends on available resources. - When means the time by which the desired action or change will be attained. The time will depend on a number of factors-in cluding the resources available to make the change. - Where indicates a geographical area such as a county, city, school system, or neighborhood that has been identified as the target community. As you develop goals and objectives, the following guidelines should be helpful: - Ensure that program members agree upon goals and major ob jectives. The goals and objectives need to be consistent with the overall goals and objectives of each participating group. How ever, they do not need to include all the goals and objectives of each individual organization. Participating groups need to rec ognize their common interests but they cannot be expected to have ah their interests in common. - Create objectives that fit the unique characteristics and resources of the community. « Modify the objectives as new information becomes available, as resources change, or as activities go faster or slower than planned. No program ever goes exactly as planned. - Make objectives detailed enough so you can see what steps need to be taken to successfully implement the activities. - Do not create objectives just to satisfy someone else's research objective. (Be smart, however. Do not miss an opportunity to get resources if it only requires minor additions or modifications to your program.) - If appropriate, divide objectives into categories depending upon whether they pertain to health effects (e.g., injuries), behaviors (e.g., fights), participation (e.g., students in a class), or other aspects of the program (e.g., the number of newspaper articles published on violence). Table 6 shows how objectives flow from a goal. Objectives are important because they clarify the tasks that need to be done, call attention to areas of needed effort, and document the progress of the program and its activities. Example: By 1996, the number of visits by high school students to the school nurse for injuries re lated to weapons violence in Ajax County will be reduced from an average of 2 per month to an av erage of 1 per month. Who: High school students What: Injuries related to weapons violence How much: Reduce from an average of 2 visits per month to 1 visit per month When: By 1996 Where: Ajax County The above example is a possible final objective. Often several intermediate objectives (steps) must be achieved first to ultimately meet the final objective. # Objectives: 1. By 1993, principals will have placed posters about the policy forbidding weapons in schools in all classrooms and on all public announcement boards in all Ajax County high schools. As you can see from this example, an objective: - Is specific and quantitative. It specifies the group involved, a single result, and a target date. « Tells what will happen and when, not why or how this should be done. - Is readily understandable to those involved. - Is realistic, attainable, yet a challenge. ® Identifies criteria for evaluating achievement. # LOCATING RESOURCES FOR YOUR PROGRAM You will need many resources to run a community violence preven tion program. The greatest resource you can have is the time and efforts of community people. There are also a number of resources, such as office space, equipment, and supplies, that m aybe donated by organizations that cannot contribute money to a program. All these resources cost real dollars if they are not donated. Therefore, their contribution is very important. Although having funds will allow you to conduct more activities and reach more people, money does not assure success. There are two major sources of funds for community programs: public and private (Table 7). Public funds come from federal, state, or local governments. Particularly in tight financial times, govern ment funds often go to support existing programs. In addition, because people administering public funds are held accountable to the public for their management, government agencies usually retain a great deal of control over how the money is spent. Private funds come from a number of private organizations, such as foundations, corporations and other businesses, voluntary organiza tions, charitable institutions, churches, and a wide variety of local concerns. Usually private organizations are more flexible than pub lic agencies in the types of programs they fund and in the manage ment of the program. Your own program can also raise funds by sponsoring events that bring attention to the program and also raise money. For example, you can conduct walk-a-thons or community road races, solicit pledges through media programs, conduct bake sales, or conduct contests or raffles with prizes donated by local businesses. Although the amount of money raised in this manner varies, the community's willingness to participate and to take on responsibility provides your program a good record when you approach private or public organi zations to request funding. In fact, some granting organizations require that a percentage of the program's costs be provided by the community or other sources. # Private Organizations # Community Organizations Many organizations within local communities want to help worthy causes, often because of their sense of "corporate citizenship." You should consider the following types of organization's as possible sources of funding: - Businesses (including banks) - Civic organizations, such as the Kiwanis and Lions Clubs - Religious organizations - Local divisions of state or national voluntary organizations (such as the American Heart Association and the American Cancer Society) - Hospitals and other health care facilities - Local television and radio stations and newspapers (Community media often contribute publicity and the help of local media personalities for community efforts.) - Schools, including local colleges and universities with programs aimed at violence prevention (Educational organizations often provide volunteers as well as conduct fund-raising activities through student organizations.) - Community service organizations, such as sororities, fraternities, and associations of retired teachers Some organizations may not have funds to contribute, but may donate facilities, equipment, or labor. Because these resources would probably cost a program real dollars to acquire, their donation is as good as money. Community organizations may not require formal grant proposals or extensive written requests. However, you must convince the person making decisions that the project is good for the community. Also, these organizations are not easily located. One of the best ways to find them is to talk with people who are likely to know about different kinds of community organizations and their leaders. You can also contact people with authority in organizations that have donated to local activities in the past. # Foundations The sole purpose of foundations is philanthropic giving. One major advantage to grants from foundations is that it is usually easier to request money from foundations than from public agencies. Foun dations also have the reputation for funding programs with good ideas but little experience. They are more likely to take a chance on a new organization. Because foundations may support only specific types of projects or projects in certain geographic areas, it is important to find out what foundations support violence prevention projects. The Foundation Center is an authoritative guide to foundations and provides detailed information on the interests and restrictions of individual founda tions and on the money they have granted. The Foundation Center has four main offices as well as libraries in all 50 states. To locate the nearest library, call 1-800-424-9836. You can also find listings of foundations and information on what they support in your local library. After identifying a potential foundation funding source, write a letter to the foundation that briefly states what you want to do in the community and ask whether the foundation is interested in this type of project. Through this inquiry, you will also find ou t how to submit a grant proposal. # Corporations Large business and nonprofit organizations in the United States donate a great deal of money each year. You may find a large company with facilities in your community, such as a factory or major distribution office, that is interested in donating money to your program. In addition, each state receives Federal funds in the form of block grants. These block grants are divided into four areas: preventive health; maternal and child health; alcohol, drug abuse, and mental health; and primary care. For information about these block grants, you can contact the appropriate administrative agency: Preventive Health Other Federal agencies and organizations that have an interest in violence programs are listed here. These programs may not provide grant money or may have very restrictive qualifications for grantees. You should write the agency or talk with someone there to determine whether they are interested in your program. # CENTERS FOR DISEASE CONTROL AND PREVENTION # MONITORING THE PROGRESS OF YOUR PROGRAM Program monitoring or evaluation is essential. It helps you adjust your program to meet unanticipated circumstances. Monitoring things daily is how we improve things. Monitoring also enables the workers, the funding agencies, and, most importantly, the community members to know whether the program is making progress. Moni toring includes the collection of both objective data (e.g., the number of children who took a conflict resolution class) and subjective data (e.g., the number of students who say they are less likely to get into a fight). Monitoring should indicate v aether your activities are on track and whether the intended outcomes are being achieved. Here are some of the questions that should be answered: - Have the activities or interventions been implemented? For example: Has the conflict resolution curriculum actually been used? - Has the activity been properly implemented? For example: Were teaching materials provided? Were the teachers trained? Were the classes given in all the schools? Did all eighth grade students take the classes? - Did the activity achieve its intermediate objectives? For exam ple: Did the students pass the test at the end of the course? - Did the activity achieve its long-term objectives? For example: Were there fewer fights in school and on the school grounds? One of the major difficulties in violence prevention is that very few activities have been proven to work. Although some appear promis ing, thorough scientific evaluations of these programs are badly needed. However, such evaluations are complicated, expensive, and often too difficult for a community to do alone. Communities with a local university have a good opportunity to develop a community/academic partnership. In this type of relationship, the university could help design and carry out detailed evaluation of the community's violence prevention program. Even communities with limited resources must monitor and evaluate their progress. The specific evaluation activities undertaken and data collected are determined by the goals and objectives of the program. At the very least, community-based programs should do the following to monitor their progress: 1. Examine the objectives. Properly prepared objectives will help identify the information necessary to determine whether the pro gram is on track. Keep records and collect data to see whether the objectives are being achieved. # CONCLUSION Effective community programs must do two general things: 1) Include activities that are appropriate for the community and the problem. 2) Create the organization to carry out the activities effectively. The descriptions of the strategies (pp. 11-28) provide a "menu" of violence prevention activities that maybe appropriate for your com munity. Few of these activities are scientifically proven, but they appear promising. Many can be adapted to the specific needs of most communities. The chapter on 'Program Management" (pp. 29-49) provides suggestions about how to define the problem, select activi ties, get them started, and see them through to success. In general, one should strive to do the following: - Empower the community to take active leadership, responsibil ity, and control of the program. - Enlist and coordinate multiple community organizations and groups. - Include many activities targeted at specific risk groups in a variety of settings. - Support individual behavioral change through policy and envi ronmental change. » Provide necessary training for all community people, both volun teers and professionals, who are working in the program. To be successful, a program also requires attention day by day. Here are a few suggestions: « Be flexible. Nothing goes exactly as planned. Make adjustments but do not lose sight of the long-term goal. « Seek new individuals and organizations to broaden the scope of the program and enhance the probability of its success. - Search for ways to provide special training and specific experi ence for the workers. Violence prevention is a new area and few experienced and trained people are available. The natural talents of many of the workers often can be rapidly improved with training. In particular, staff members might receive conflict reso lution training. - Listen to your co workers. Theyknow the community. They often have original and practical ideas. - Be alert for and seek new resources. Do not lose sight of the long-term goal, but be willing to bend a little or add a little in order to get the resources to move the whole program ahead. - Set up numerous milestones so that workers can appreciate their progress. Violence is a big problem. For a community effort to work, the problem needs to be divided into pieces that are small enough to be realistically addressed with goals that have a chance of being reached. Success builds enthusiasm and commitment. - Continually evaluate the progress of the program. Note whether the objectives are being reached. - Be persistent. However, do not set impossible goals and objec tives. - Design activities for hard-to-reach groups who are also the groups most at risk of violence. Outreach activities are necessary to help youth in gangs or those who are separated from the mainstream: the homeless, runaways, or youth who are out of school. - When you do not know what to do, ask someone for help. If you do not know who to ask, call one of the projects mentioned in this manual or listed in the appendix.	If you have issues viewing or accessing this file contact us at NCJRS.gov. li.S. Department of Justice National Institute of Justice This document has been reproduced exactly as received from the person or organization originating it, Points of view or opinions stated in this document are those of the authors and do not necessarily represent the official position or policies of the National Institute of Justice. Permission to reproduce this «m a ig iiW J material has been granted by Public Domain/U.5. Dept, of. Health and Human Services to the National Criminal Justice Reference Service (NCJRS). Further reproduction outside of the NCJRS system requires permission of the M M i g M owner.# The people who contributed to this manual are numerous and very dedicated to this field. In particular, we would like to acknowledge the following groups: • Those who gave their time in August 1991 to sit in a crowded room and discuss and debate points of content and advise CDC on the direction of this manual. • Those who provided written and oral comments on drafts of the document. • All who attended the Forum on Youth Violence in Minority Communities in December 1990 at which many of the ideas in this manual were first expressed, and the Minority Health Professions Foundation and the Morehouse School of Medicine, the co-sponsors of that forum. • The staff at Education Development Center, Inc., who prepared the background papers for the Forum on Youth Violence in Minority Communities. Most importantly, we would like to acknowledge the many people in the United States who work to prevent youth violence: people in communities who know the problem first hand, schools, and social service and law enforcement agencies, and the researchers who seek answers to troubling questions. Their work has been hard, but not unnoticed. They have opened the door for the rest of us to enter. # INTRODUCTION BACKGROUND Violence is a large and important health problem in the United States. More than 20,000 people die from homicide every year and more than 2,000,000 people suffer injuries received in violent con flicts. The emotional toll is immense. Violence and violence-related injuries and deaths are particularly common among young people and have escalated in recent years. In December 1990, the Centers for Disease Control (CDC) and the Minority Health Professions Foundation responded to the growing concern of African-American and other minority communities about violence among youth by convening a conference entitled Forum on Youth Violence in Minority Communities: Setting the Agenda for Pre vention. Thepurpose ofthisforum was to review what is known about programs designed to prevent youth violence. This framework for community action originated from the discussions in that forum. It has grown and developed through subsequent discussions and meet ings with many concerned individuals throughout the country. As this manual progressed, the complex distribution of violence across the United States became clear. Some communities of color are severely affected by violence. Others are not. Some white commu nities have high rates of violence while others do not. However, the potential for violence exists everywhere. Therefore, this manual can be used by any community dealing with present or potential problems of violence. Each communitymust assess its own needs and adapt the framework to its own characteristics. The underlying causes of violence vary from community to community. Urban, suburban, and rural commu nities differ; each community is unique. Experts provide no simple explanations of the causes of violent injuries and deaths. Deeply imbedded cultural problems such as racism, sexism, poverty, drug and alcohol abuse, drug trafficking, and frequent exposure to violence are but a few of the important pieces of this complicated puzzle. Efforts to reduce these problems and to increase educational and economic opportunities are needed. How ever, the presence of these large and stubborn problems should not make us forget that vve can do something-we can take action to reduce violence. American society has traditionally looked to the criminal justice system for protection from violence. Criminal justice measures have been useful. However, they have not enabled us to satisfactorily reduce the burden of violence upon society. One important reason is that much of the violence does not begin in a criminal setting but arises instead between companions involved in arguments, some times over trivial matters. In fact, more than 40 percent of all homicides occur between friends and acquaintances. Throughout the country, community organizations are addressing the problem of violence at the local level. These organizations are starting activities based on their understanding of local problems and local conditions. Conflict resolution training is provided in a number of schools. Schools are seeking ways to reduce the number of weap ons brought on campus. In several cities, programs are redirecting the energies of young people in gangs from violent confrontations to more peaceful pursuits. In preparing this manual, we were aware that a great deal of evalu ation needs to be done to determine which of the many activities that have been tried or proposed actually do prevent youth violence. However, the seriousness of the problem of violence demands im mediate action. # THE PURPOSE OF THIS MANUAL Many concerned individuals and community-based organizations want to reduce violence and prevent injuries and deaths from vio lence among youths in their community. This manual is designed to help. It includes a menu of specific activities for communities to undertake plus a framework for putting those activities effectively into place. # Introduction The manual is divided into two major sections. "Activities To Prevent Youth Violence" describes the target groups, settings, and strategies for the prevention of youth violence. The chapter takes into account • What is known about youth violence through scientific research • What has been learned through innovative community efforts • What has been learned from interventions used to prevent other types of health or social problems "Program Management" covers basic principles of effective commu nity-based health promotion programs. This section describes the processes of • Organizing the community • Gathering and analyzing the information needed to describe adequately the problem of youth violence in the community • Setting goals and objectives • Locating resources • Monitoring the progress of the program # ACTIVITIES TO PREVENT YOUTH VIOLENCE To prevent violent injury and death, we need to weaken or break the chain of events that leads to violence. Often we do not know exactly why people behave violently, why one adolescent will react violently in a given situation while another who has a similar background will not. We need to learn much more about the causes of violence in American society. Yet even with imperfect knowledge, helpful action can be taken. We can teach, we can enact and enforce regulations, we can change the environment. Youth can be taught skills to help them deal with violent situations. They can be helped to develop the self-esteem needed to solve differences without violence. Young people can be taught about the situations or actions that are likely to result in violence or violent injuries, such as associating with violent peers, using alcohol or drugs, and possessing a firearm or other weapon. They can be provided with mentors, or special teachers, who can serve as role models. Laws and regulations can be developed specifi cally to reduce injuries and deaths, such as stronger laws governing the use, ownership, and sale of guns. Teenage parents, abused chil dren, or bored or wayward teenagers can be provided with training, support, and recreation. In selecting the activities for any community, you should consider the following general principles: 1. Each activity should have ® an identified target group (e.g., high school students, youths in detention centers) • a setting in which that target group is reached (e.g., schools, detention centers) • a method or strategy to accomplish the objective (e.g., class room instruction, mentors) 2. No single activity in isolation is likely to solve the problem of youth violence. There are too many types and too many causes of violent injury and death to be solved by one strategy. The most effective programs include several types of activities. Most programs will need to begin with one activity and add more activities as they gain expe rience and resources. 3. Activities should complement one another. For example, instruc tion on how to avoid gang membership may be complemented by alternative activities. Instruction on nonviolent conflict resolution maybe accompanied by more monitors in the school hallways. 4. Activities may address different steps in the chain of events that lead to injury and death. For example, activities may address • factors that influence behavior (e.g., knowledge and attitudes) • the behavior itself (e.g., carrying weapons or fighting) • health outcomes (e.g., injury or death) 5. The activities selected should be determined by the unique char acteristics of the community and the goals and objectives of the program. Activities that have worked in other communities maybe a good place to start. They can often be modified to meet the specific needs of your community. However, an activity should not be se lected simply because it is or appears to be working in another community. # TARGET GROUPS A target group is the group of people whom the program or acti vity is designed to influence. Depending on the activity, the target group may be broad or specific. For example, some activities may address adolescents who are out of school or who have a history of violent or criminal behavior. Other activities may address all young children. Still others may address parents, teachers, employers, or others who interact directly or indirectly with youth. Activities suitable for one group may be inappropriate for another because groups and indi viduals vary in terms of culture, values, knowledge, attitudes, skills, behaviors, experience, and other attributes. The selection of target groups should take into account the specific nature of the problem being addressed, the major goals and objec tives of the program, and community characteristics. For example, members of youth gangs would not be an appropriate target group if gangs are not a problem in the community. Successful programs will have activities that address many target groups. However, this takes time, and a decision must be made about which target groups to address first. There are a few broad categories of target groups (Table 1) that are useful to consider. # The General Population of Youth Many activities designed to reduce injuries from youth violence can be applied to all youth (or to the environment that affects them). An example of such an effort is teaching conflict resolution skills to high school students. In this instance, the purpose of the intervention is to affect the manner in which all students resolve conflicts, not just those students who are thought to be most likely to engage in violent behavior. Programs with activities directed toward the general popu-lation of youth, if successful, are likely to produce early and possibly substantial reductions in violent injuries and deaths. However, to be successful they must reach large numbers of youths. # Youth Who Engage in High-Risk Behaviors Youth with high-risk behaviors are those most likely to be injured, those most likely to engage in violent behavior that injures others, or both. These groups include young people who consistently engage in physical fights to resolve problems, those with a criminal record or a history of inflicting or receiving a violent injury, drug users, gang members, or those who have failed or dropped out of school. Other youth who maybe at risk for fighting are relocated youth. This group includes immigrants and migrants, and can also include youth who live in communities that are highly mobile. One other group that may be prone to fighting are those with emotional or mental deficiencies who may not have the personal skills to settle disputes nonviolently. If successful, activities directed toward this group of youth may show early and possibly substantial reductions if these groups account for much of the violent injuries and deaths among youth in the commu nity. Special efforts are often necessary to locate and contact youth with high-risk behaviors. Outreach workers may help. They can meet youths on street corners, parks, fast-food restaurants, or other places where they gather. They work to establish trust. Once trust is estab lished, outreach workers may be able to refer or guide adolescents with high-risk behaviors into helpful activities. Outreach is important in making contact with youth who engage in high-risk behavior, but it is only a part of a program. Other activities are also necessary. The Community Youth Gang Services (CYGS) of Los Angeles, Califor nia, is a good example of a program that has a strong outreach component with a number of other program activities. This program is described on pages 27 and 28. # Young Children (10 Years Old or Less) Violence is a learned behavior. The basic values, attitudes, and interpersonal skills acquired early in life are likely to be pivotal in developing predispositions for violent behavior later in life. There fore, activities for young children that promote nonviolent values, attitudes, and interpersonal skills are important to consider. Also, any long-term strategy to prevent violence may also want to include children who are abused or witness violence and activities that lessen the consequences of exposures to violence. If successful, these inter ventions may show substantial reductions in violent injuries and deaths when these children become adolescents. # Other Target Groups The above three categories of target groups-the general population of youth, youth with high-risk behaviors, and young children-may be considered direct target groups because activities are intended to reduce violent injuries and deaths among those groups or caused by those groups. Programs focusing on these groups will also need activities for indirect target groups-those people who have a par ticular relationship with the primary target f oup. Examples of indirect target groups are family members, adun role models, or the general population. Family members. Family experiences play a critical role in causing, promoting, or reinforcing violent behavior among youth. Conse quently, the family is an important target for activities to prevent youth violence. Activities that target families can focus on parents, siblings, or the entire family unit. Typically, these activities reinforce health promotion or prevention messages, support the parents in raising and managing children and youth, or provide help in coping and responding to family crises. Special groups of adults. Teachers, coaches, clergy, health profes sionals, counselors, athletes, entertainers, and other adults often have special relationships with children and youth. They may be important role models. They may also recognize or decide which children and youth need or receive special services. Adult role models are an important target for youth violence-prevention activi ties because they are very influential in the lives of children and youth, frequently serving as confidants. As such, they can reinforce health promotion and prevention messages, including those pertain ing to violence. General population. The general population is an important target group for several reasons. First, people need to be educated about the role of society as a whole in promoting violent behavior. Second, activities such as modifying or passing gun control legislation may affect wide segments of the population. For such activities to be successful, we must address the entire population. # SETTINGS The setting is the location where a prevention activity occurs. There are four important considerations involved in selecting settings for a prevention activity (Table 2). • First, select a setting where you can reach the target group. Schools, for example, may be an appropriate setting for the general population of youth, but are not an appropriate setting if the target group is youth who are no longer in school. • Second, select a setting appropriate for the strategy. A classroom curriculum probably will not be effective if administered on the playground. • Third, select multiple settings for each target group. The fre quency of violent behavior is more likely to decrease if comple mentary messages or experiences occur in several settings and if the environment is made less conducive to violence. For exam ple, a young boy is less likely to be violent when he is taught alternatives to violent behavior in the school, is exposed less often to violence in the home, and plays in supervised areas where fights are not likely to take place. « Fourth, when appropriate, select one setting suitable for several target groups. Churches, for example, may be an appropriate setting for reaching both youths and parents. Settings in which the general population of youth may be reached include schools, churches, streets, playgrounds, youth activity sites, and homes. Additional settings where certain groups with high-risk behaviors may be found include juvenile justice facilities, mental health facilities, social service facilities, and the medical care facili ties. Young children may also be reached in child care settings (e.g., Head Start locations). # STRATEGIES Activities to prevent youth violence typically employ one of three general prevention strategies: education, legal and regulatory change, and environmental modification. Each of these general strategies has a role in a comprehensive youth violence prevention program (Table 3). # Education Education provides information and teaches skills. New knowledge and new skills change or reinforce a person's attitude and behavior thus reducing the chances that the person will behave violently or become a victim of violence. Educational efforts can be directed toward a wide variety of target groups to help convey knowledge and skills. Face-to-face teaching may occur in the classroom, in worksite or recreational settings, or through special teachers, such as nurses on home visits. Knowledge and skills are a crucial part of the process, but they are often insufficient by themselves. The acquisition of knowledge is usually not followed immediately by the adoption of new behaviors. Behavioral change requires time and repeated effort and is more likely to occur if the physical and social environment support and encourage it. The following are examples of types of educational strategies. With each example are several brief descriptions of the strategy as it is being implemented in a U.S. community. # Adult Mentoring Mentors are special adults who provide a positive, caring influence and standard of conduct for young people. Mentors provide models for young people who have none, or they offer alternatives to negative role models. Mentors may reinforce positive attitudes or behaviors that children are trying to express. Adult role models may be teach ers, counselors, friends, and confidants, or simply members of the community. Mentoring activities can be conducted in almost any setting, such as schools, churches, businesses, or other community locations. The attention and interest bestowed on the youngsters by people who care enhance the youth's self-esteem and strengthen his or her ability to choose nonviolent methods to resolve conflict. # Baltimore, Maryland, Project RAISE (410) 685-8316 In 1988, Project RAISE recruited mentors for more than 400 sixth-grade students. The mentors contact the students at least weekly and meet with them face to face at least every other week. The mentors serve as role models, provide academic support, and strive to boost the youths' self-confi dence. The mentors are recruited from two churches, two businesses, and two colleges that serve as sponsors of the project. A Project RAISE staff member coordinates the project with the schools, matching mentors with students after informal contacts and information exchanges with mentors and students. A private foundation is funding the project.______________________________________ Atlanta, Georgia, Go to High School, Go to College (404) 766-5744 The Atlanta "Go to High School, Go to College" project has paired 100 successful older men with adolescent African-American males at four Atlanta area high schools and one middle school. Each mentor meets twice a week with a student who is struggling academically, has discipline problems, or is at risk of dropping out of school. The mentors are provided with a 40-page curriculum of instructions and ideas. Mentors strive to increase the students' self-esteem and improve their grades. A local fraternity chapter provides scholarships to students who qualify and want to attend college. # Conflict Resolution Education Classes in conflict resolution are designed to provide students with the opportunity to develop empathy with others, learn ways to control impulses, develop problem-solving skills, and manage their anger. Usually this curriculum is delivered in the classroom setting, al though other settings, such as churches, multi-service centers, boys and girls clubs, recreation centers, housing developments, juvenile detention centers, and neighborhood health centers may be appro priate also. Courses in conflict resolution have been developed for students in both elementary and high schools. The methods used to teach conflict resolution usually include role playing conflict situations and analyzing the responses to, and conse quences of, violence. Generally, students are trained for 15 or 20 hours, after which they may work in pairs mediating conflicts that occur in the classroom or cafeteria, on the playground, or elsewhere. These conflicts cover a wide range of situations, including bullying, stealing, and spreading rumors. Teaching materials can be designed to meet individual needs of different groups of students. # Boston, Massachusetts, The Boston Conflict Resolution Program (617) 492-8820 The Boston Conflict Resolution Program (BCRP) is a violence prevention program that helps elementary school teachers and students understand and deal with conflicts frequently encountered in schools. These conflicts often result from prejudice, competition, miscommunication, an inability to constructively express feelings, and a lack of respect and concern for others. The School Initiatives Program in San Francisco grew out of a community program that began in 1977 to train community residents to help their neighbors resolve disputes peacefully. In 1982, this program expanded to the schools because of growing conflict and violence in that setting. This program has two components: classroom curricula and a conflict manager's program. Class room materials are designed for elementary and secondary school students. These materials help students acquire self-esteem and the skills needed to resolve conflict and build a stronger sense of cooperation and community at school. To become conflict managers, students at the middle-and high-school level participate in 15 hours of training over two and one-half days. They learn communication, leadership, problem-solving, and assertiveness. Once trained, these students help their fellow students to express and resolve their conflicts nonvioiently. # Training in Social Skills Teaching young people social skills provides them with the ability to interact with others in positive and friendly ways. Training in social skills includes many things that help students successfully interact with others. Aspects of social-skills training include maintaining self-control, building communication skills, forming friendships, re sisting peer pressure, being appropriately assertive, and forming good relationships with adults. Nonviolent conflict resolution train ing may be included with these other social skills. Acquiring these skills provides students with appropriate standards of behavior, a sense of control over their behavior, and improved self-esteem. They maybe less likely to resort to violence or become victims of violence. These educational activities can be conducted in schools, day-care settings, after-school programs, and youth organizations. # New Haven, Connecticut, The New Haven Social Development Program (203) 432-4530 Since 1983 the Yale University Psychology Department has collaborated with the New Haven public school system to provide training in social skills in the middle schools of the district. The major components of this activity are classroom activities for sixth and seventh graders that teach social development, and modeling of socially competent behavior by school staff. The curriculum empha sizes self-control, stress management, problem-solving, decision-making, and communication skills. Once students have learned a general problem-solving framework, they apply their critical-thinking skills to specific issues, such as substance use. The emphasis is on providing accurate information about the topic and focusing on realistic situations. Finally, school, family, and community resources are identified that are available to help students cope with personal or family difficulties. Methods used are role-playing, videotaping, and live modeling; classroom presentations; smallgroup discussion; and competitive and cooperative games. Classroom teachers undergo training that includes practice modeling and review of techniques for dialogue, discussion of students' reactions to the lessons, and adaptation of the lessons to the special needs of their students. # Activities to.Prevent Youth Violence # Education To Prevent Injuries from Firearms The meaning of education to prevent injuries from firearms varies from community to community. For some, this means avoiding firearms altogether and for others it means the proper handling of firearms. Activities providing education about firearm safety can be conducted in school settings and in the community. A number of educational techniques have been developed, including the use of audiovisual materials and curricula that deal with situations that involve firearms. # Dade County Florida, Kids + Guns = A Deadly Equation (305) 995-1986 A program designed to teach students from kindergarten age through high school about the dangers of playing with or carrying guns was developed jointly by the Dade County Public Schools, the Center to Prevent Handgun Violence, and Youth Crime Watch of Dade. Kids+ Guns= A Deadly Equation includes classroom instruction and schoolwide activities that center on helping students recognize unsafe situations, react appropriately when encountering guns, resist peer pressure to play with or carry guns, and distinguish between real-life and media violence. The curriculum includes a video program for students in grades 7 through 12; a component for parents includes a brochure and video program. # Parenting Centers Improving parenting skills through specially designed classes for parents can improve how the parent and child interact. The improve ment in this relationship may reduce the risk of childhood behavior problems and subsequent antisocial behavior that may predispose an individual to violence in later life. Programs targeted toward parents must address the psychological needs of the parents, especially their sense of being competent parents; the parental behaviors that influ ence the physical and social development of their children; and the stresses and social supports that can either help or hinder parents' ability to adapt to their children's needs. Minneapolis, Minnesota, Project STEEP (612) 624-0210 Project STEEP (Steps Toward Effective, Enjoyable Parenting) serves low-income, first-time parents. Most parents are single and have no more than a high-school education. The program includes both group sessions and home visits. It begins during the second trimester and continues until the baby is at least one year old. Prenatal visits focus on the mother's feelings about pregnancy and preparation for parenting. After the baby is born, transportation to the group sessions is provided by the project. The focus of demonstration and interactive sessions is on child-care skills, infant development, and infant-mother communication. Interactions between mother and infant are vide otaped, reviewed, and discussed with the parent. # State of Missouri, Parents as Teachers (PAT) (314)553-5738 Parents as Teachers is a home/school partnership that serves all parents, including single parents, teenage mothers, and two-parent families. PAT parent educators, trained in child development, go to homes of participating parents to help them understand each stage of their child's development and learn ways to encourage that development. The program also conducts group meetings for parents to get together to gain new insights and to share their experiences, common concerns, and successes. They conduct periodic screening of overall develooment, language, hearing, and vision to detect potential problems, and refer families to special services. # Peer Education Programs that use students to teach their peers about violence pre vention are a powerful force among adolescents and can be used effectively to help shape norms and behaviors in this group. Re search on peer education for other health issues such as alcohol, cigarette, and drug use, has had positive results and shows promise for violence prevention programs. # Ferguson, Missouri, RAPP (Resolve All Problems Peacefully) (314) 521-5792 RAPP was begun to reduce the number of physical fights among students. Students selected by teachers and other students are trained in mediation skills. Students found in conflict are given the choice of going to mediation or going to the office. Those who choose mediation meet with one of the trained mediators who works with them to peacefully resolve the conflict. During the first semester of the project, the number of fights was less than half the average for the same semester over the previous three years. Oakland, California, Teens on Target (510) 635-8600, Ext. 415 Teens on Target is a peer education and mentoring group that was formed by the Oakland Safety Task Force in California after two junior high students were shot in the schools by other students. The task force, made up of a coalition of elected officials, parents, and school and community agency representatives, felt that students would do a better job of dealing with the youth violence problem than adults. Selected high school students are trained in an intensive summer program to be violence prevention advocates, particularly in the areas of guns, drugs (including alcohol), and family violence. These students become peer educators to other high school students and mentors to younger students in the middle and elementary schools. Teachers provide ongoing guidance and supervision to the teen educators. # Public Information and Education Campaigns Public information campaigns reach a broad audience. They draw attention to an issue and help establish acceptable behavior for a community. They also convey a limited amount of information, which by itself is rarely enough to change behaviors. Therefore, activities that provide general information to the public are most effective when combined with other activities in a violence preven tion program. There are a number of ways to inform the public through media. Some examples are public service announcements, educational video programs, appearances on public talk shows, posters, brochures, and other print materials. # Charlotte, North Carolina, The Police Executive Research Forum and the Center to Prevent Handgun Violence (202) 289-7319 The Center to Prevent Handgun Violence in conjunction with Police Executive Research Forum developed and ran a public awareness campaign in Charlotte, North Carolina, that attempted to change people's knowledge, attitudes, and behaviors concerning the protection they believed firearms offered. Together these two groups developed guidelines, produced print and broadcast media messages, distributed brochures, made community presentations, and conducted safety demonstrations. The messages developed through this awareness campaign included safe storage of firearms, instructing children about handgun safety, and checking firearms before cleaning. # Baltimore, Maryland, The Baltimore County Police Department and the Center to Prevent Handgun Violence (202) 289-7319 The Center to Prevent Handgun Violence has also helped the Baltimore County Police Department develop advertisements, public service announcements, pamphlets, brochures, and police presen tations for both gun owners and people who do not own guns. The materials cover the dangers of misusing firearms, how to childproof handguns, legal issues including liability, and the psychological and practical issues of ownership. # The Prevention of Youth Violence # Legal and Regulatory Change Laws or rules may lower the risk of violent behavior or victimization. Some regulations that would help reduce injuries and deaths from violence have already been enacted, but many are neither widely known nor well enforced. In many cases, it is easier to enforce existing laws than it is to enact new laws. In other cases, existing regulations are inadequate and new ones are needed. You can find out your state laws by contacting your state attorney general's office. You can find out your local laws by contacting your local police agency. The success of making or enforcing rules depends on the willingness of the population to support and obey the rules and the ability of regulatory agencies, such as the police, to enforce them. Examples of laws or regulations intended to reduce injuries and deaths from violence include laws prohibiting the carrying of firearms in public and rules prohibiting the wearing of gang colors in schools. # Regulations Concerning the Use of and Access to Weapons Guns, knives, and other dangerous weapons may not actually cause violence, but they can convert an argument with no associated inju ries into one with severe injuries or even death. A variety of strate gies have been used to reduce the likelihood that weapons will be used. Many communities already have existing laws and regulations concerning the sale, ownership, use, or carrying of guns or other weapons. • Most schools prohibit students from bringing weapons into schools. Methods used to help enforce the prohibition include rules requiring students to carry books in see-through bags rather than solid cloth or opaque containers in which weapons can be hidden, random locker searches, rules prohibiting the wearing of clothing in which weapons can be hidden easily, or metal-detector checks at the school entrance, of selected classrooms, or at se lected sites in the school. • Some cities prohibit carrying a firearm within the city limits or carrying a concealed weapon. Recently enacted legislation that increased the penalty for disobeying these laws in Detroit and Massachusetts were apparently effective in reducing the number of homicides and assaults with guns. # Massachusetts Bartley-Fox Act (1975) This law mandated prison terms for anyone carrying an unlicensed firearm. In the two-year period following passage of this law and the accompanying publicity, the incidence of assaults with guns was reduced by 13.5 percent. _ • Some laws ban the possession of particular types of guns, such as handguns or machine guns, except for police or others with a demonstrated need. Individuals who wish to buy these types of guns must obtain special permits. These laws are generally called restrictive licensing laws. # Washington, D.C., Prohibition of Handgun Ownership in 1976, the District of Columbia banned the purchase, sale, transfer, or possession of handguns by civilians. A study that compared homicide rates in the District with rates in the surrounding counties showed that the handgun ban had an effect. The homicide rate in the District dropped about 25 percent in 1977, the first year after the ban went into effect and remained lower than expected until the end of the study in 1988. An estimated 40 homicides per year have been prevented by the ban on handguns. Homicide rates remain high in Washington, D.C., however, indicating other actions besides prohibiting handgun ownership are necessary. • Twenty-six states currently require a waiting period, a police background check, or both before a handgun maybe purchased. For example, in Tennessee, there is a 15-day waiting period to purchase handguns. In Massachusetts, there is no waiting period to purchase any legally sold firearm, but the buyer must have a permit-to-purchase and must wait 40 days after obtaining the permit-to-purchase before purchasing any guns. • Local citizens may be aware of a particular gun dealer who is selling to underage youths or otherwise not obeying the local laws concerning the sale of guns and ammunition. These violations can be brought to the attention of the local police. Local police are generally quite willing to enforce the laws against the illegal sale of weapons. # Regulation of the Use of and Access to Alcohol Alcohol consumption appears to play an important role in many violent situations. Youth who have been drinking are more likely to become involved in physical fights. In all 50 states and the District of Columbia, the minimum drinking age is now 21 years. Laws prohibit the sale or public possession of alcoholic beverages by anyone under the age of 21. • Sale of alcohol to underage youth may be limited by stricter enforcement of laws. As a general rule, regulations are most poorly followed in convenience stores. Establishments that fre quently violate the regulations are often known to the local residents and can be targeted by law enforcement officers. Police are much more likely to take the time to enforce the alcohol laws if they know they have strong community support to do so. • Keg-labeling laws can be established. Liquor stores can be re quired to increase the deposit and to place a numbered band on beer kegs. The numbered band identifies the purchaser, making it possible to trace and arrest people who supply kegs to under aged drinkers. • Clubs, organizations, and those sponsoring entertainment events can prohibit the consumption of alcohol on the premises and refuse admittance to youth who have been drinking. • All states have laws about the liability of alcohol servers for injuries to their patrons or for injuries caused by their patrons because they had too much to drink. These laws can be publi cized, better enforced, and, if necessary, strengthened. • Cooperation between the owners and managers of places that sell or serve alcohol and community organizations concerned about violence could lead to required instruction for servers and man agers. Bartenders and managers of drinking establishments or special events can be taught about their important role in the prevention of irresponsible drinking, how to determine if a cus tomer has had too much to drink, and how to detect underage youth. # Oregon, Alcohol Server Education Program (503) 653-3030 Since 1987, Oregon law has required servers, managers, and owners of establishments that serve alcohol for on-premise consumption to pass a server education course. Participants are taught about the effects of alcohol on the body and its interaction with other drugs. They also learn about their responsibility to prevent irresponsible drinking. They learn to estimate the drinking capacity of customers, to look for signs of intoxication, to cut off people who have had too much to drink without causing an argument, and to identify minors. Courses include a minimum of 4.5 hours of instruction and participation. The Oregon Liquor Control Commission monitors the classes to assure their quality. The servers, managers, and owners must take the course every 5 years. # Other Types of Laws and Regulations In addition to regulations concerning weapons and alcohol, other types of regulations may also reduce youth violence. For example, prohibiting corporal punishment and enforcing some dress codes in schools may be helpful. ® Corporal punishment in schools is now banned in 23 states and in many large cities in other states. Corporal punishment of students by school officials contributes to the perception that fighting and physically injuring another person is acceptable. On occasion, it may actually cause physical injuries. • Dress codes for organizations or schools may reduce the identi fication with gangs or make it more difficult to conceal weapons. # Los Angeles, California, Challengers Boys Club (213) 971-6141 The Prevention of Youth Violence # Environmental Modification Fnvironmental modification includes changes in both the social and the physical environments. # Modification of the Social Environment Methods of changing the social environment of children and adoles cents who may be at risk for being violent or for becoming a victim of violence include such activities as providing preschool education and appropriate or therapeutic day care programs for abused chil dren. For older children and adolescents, this includes providing constructive, alternative activities, such as recreational opportunities and employment. Small, personal after-school programs that offer contact with caring adults, counseling, help with homework, and recreation can create a safe, constructive alternative to violent street cultures. # Home Visitation Home visitation is an activity that provides services in the home either for an individual or the entire family. Home visitation pro grams performed during the prenatal and infancy years of the child focus on preventing health and developmental problems in children born to mothers who are teenagers, unmarried, or of low socioeco nomic status. These activities have been found effective in prevent ing child abuse. Because research shows that abused children are more likely to be violent or be victims of violence as adults, prenatal and infancy home visitation programs maybe an effective long-term strategy for preventing youth violence. These programs are typically designed to meet the needs of parents for information, emotional support, stress management, and other factors that undermine par ents' health habits and the care of their children. # Elmira, New York, The Prenatal/Early Infancy Project (716) 275-3738 This home visitation project was designed to prevent a wide range of health and developmental problems among children born to young, poor, or unmarried women. In this program, nurses visit pregnant women to provide information and support that encourage the mothers to adopt good health habits, learn the skills needed to care for their infant children, get access to needed community services, achieve educational or occupational goals, and prevent unwanted future pregnancies. Home visits begin in the early stages of pregnancy and continue through the second year of life of the child. Evaluation of this project showed that the health and social skills of participants had improved. In addition, there was a substantial reduction in verified cases of child abuse among the children of at-risk women who were visited at home by the nurses. # Preschool Programs Such as Head Start Project Head Start is designed to help children of low-income fami lies develop a greater degree of social competence through develop ing the child's intellectual skills, fostering emotional and social development, meeting the child's health and nutritional needs, and involving parents and the community in these efforts. A 1990 report of the Milton S. Eisenhower Foundation, which grew out of the bipartisan National Commission on the Causes and Pre vention of Violence, reported that preschool programs like Head Start are among the most cost-effective inner-city crime and drug prevention strategies ever developed. (See Other Useful Things To Read on page 54.) # Therapeutic Activities Therapeutic activities provide medical, psychological, or other treat ment for children who have been abused, injured by violence, or witnessed an unusually violent event. The provision of medical, psychological, and nurturing services helps break the cycle of vio lence. In addition to child and family counseling, here are several special types of therapeutic services: • Foster care programs provide basic physical care and safety from abusive parents. They can be very effective if multiple placements are avoided and foster parents are caring and knowledgeable about the needs of the child. » Respite day care and therapeutic day care provide services in a safe, nurturing, stimulating, organized environment without tak ing the child entirely out of the home. Day care programs are often the abused child's first contact with other children besides family members. This interaction helps the child adjust to the separation from parents, attain skills during play, and build self esteem through interaction with peers. • Residential treatment programs target school-age children with special needs, such as emotional disturbances or substance abuse problems. • Crisis management services help groups or individuals deal with the anger, fear, sadness, hopelessness, confusion, and irrational thinking associated with witnessing or being victims of violence. Dallas, Texas, Dallas Independent School District Crisis Management Plan (214) 565-6700 The Dallas Independent School District Crisis Management Plan divides crises into three levels. The most severe level includes terrorist activities or a death at the school. This level also includes severe natural disasters and suicide clusters. For each level, there is a planned coordinated response. The pian includes methods of informing students, families, and the public about the event. It also includes the identification and provision of counseling services to students in need. Each school has a local crisis team. There is also a District crisis team consisting of psychological and social service experts. The District crisis team participates in the most stressful events, such as a death at the school. # Recreational Activities Recreational activities offer young people opportunities to spend time in a structured and purposeful environment. Recreational in terventions cannot be considered a sole answer to youth violence. However, activities that provide outlets for tension, stress, or anger and opportunities for social interactions and constructive problem ' solving are important parts of a program with other violence preven tion components. Many recreational activities are conducted with these goals across the nation in Boys and Girls Clubs, Girl Scouts and Boy Scouts, YMCAs and YWCAs, and local recreation departments. # Modification of the Physical Environment The physical environment does not cause violence, but it may make violent events more or less likely to occur. Some environmental modifications by themselves may appear to merely displace the undesirable behavior to another location. Better lighting on a play ground, for example, may move the undesirable activity to another location in a community. Sometimes, however, the new location is less conducive to violence, more difficult to reach, or easier for potential victims to avoid. In these cases, the overall amount of violence may decrease even though some violence has merely moved to a new location. Protective landscaping, changes in traffic flow, speed bumps, dress codes, visible identification cards, and closed-cir cuit television monitoring are other examples of enviornmental changes. Environmental change maybe particularly effective when combined with educational and regulatory strategies. # Ithaca, New York, Cornell University Blue Light System (607) 255-1111 The Blue Light system on the university campus has three components: an emergency phone system, a bus system, and an escort service. The Blue Light phone system has 61 emergency phones outdoors across the campus, placed so that at least one phone is easily visible to pedestrians. Additionally, there are 158 emergency phones in academic buildings and dormitory entrances. All phones are directly connected to the Public Safety Dispatch Office. When callers pick up the receiver or push a special button, they are automatically connected with the Public Safety office. The location of the phone is displayed and recorded automatically. A patrol unit Is sent to all calls for assistance and to all hang-up calls. The Blue Light bus system is a free transportation system that operates every day from 6:00 p. Crime Prevention Through Environmental Design (CPTED) is a concept that is attracting interest in many police departments. Al though its purpose is to prevent crime, the CPTED principle prob ably will help prevent violence also. CPTED relies primarily on increasing visibility and encouraging a sense of ownership. Undesir able acts are less likely to occur in places where they will be observed, and people naturally use and protect things they own. ® Visibility can be improved by designing areas so that they are more easily observed by people during their normal daily behav ior. For example, parking lots could be placed so they can be clearly seen from the school or office building with which they are associated. • Visibility can be improved by attracting more people to the area. For example, volleyball or basketball courts can be placed in the center of parks or playgrounds. The players will make it more difficult for illicit or violent activity to occur unobserved . • Limiting the ways in which people enter a building also increases visibility. That makes it more difficult for people who do not belong to enter or depart unobserved. Receptionists can be placed at the entryway of schools or offices. The sales desk can be placed near the entrance in stores. • Creating a sense of ownership will increase the use of the envi ronment for desirable-purposes, Cleaning and maintaining an area may give a. sense of ownership. • Changing traffic flow can make a neighborhood belong more to the residents. Limiting the number of through streets, making one-way streets, creating dead-ends, and narrowing the entrances to some streets can reduce traffic by nonresidents. This helps residents feel like the neighborhood is their own. # Los Angeles, California, Community Youth Gang Services (213) 266-4264 Community Youth Gang Services is a program with many components, but some of the most innovative involve reclaiming the community that has been taken by gangs. One aspect of the program carefully plots on maps the physical areas of the community that are affected by gangs. These areas are targeted for reclaiming, and community residents are mobilized to do that through such activities as a Saturday in the Park, in which a particular day is designated for clean-up of the park and family activities. Another activity of this program is the removal of graffiti. Community Youth Gang Services staff have the professional staff and equipment to eradicate graffiti without damaging surfaces. Staff hires and supervises local youth and selected youth on probation to do this task. # Combining Activities for an Effective Program The activities listed in this manual are presented individually so that the reader can investigate the different types of activities available to communities. In reality, activities are rarely conducted inde pendently. Effective programs combine a number of activities to render the maximum impact on the problem and reach as many young people as possible. There are a number of examples of programs that combine three, four, or five strategies that have been discussed. # Philadelphia, Pennsylvania, House of Umoja Boystown (215) 473-5893 The House of Umoja Boystown is a home for African-American boys in Philadelphia, an area with high numbers of youth in gangs. In addition to providing a home with food and shelter, the program offers extensive services that offer emotional and spiritual support. These services cover a number of the types of activities described earlier in these guidelines, such as outreach, educational activities, recreational opportunities, and work/academic opportunities. # Boston, Massachusetts, The Violence Prevention Project (617) 534-5196 The'Violence Prevention Project in Boston, Massachusetts, is a multi-institutional, community-based program designed to reduce the incidence of interpersonal violence among adolescents, along with associated medical and social hazards. The major activity used in this program is a violence prevention curriculum that focuses on conflict resolution. However, in the initial phases of develop ment, it became apparent that a school-based activity was not enough and activities in the community were added to reinforce nonviolent options learned in the classroom. Staff from the program train providers in diverse community settings In the use of the curriculum's strategies. They also help providers find ways to incorporate these strategies into the delivery of services to adolescents and encourage consensus from the community that supports the prevention of violence. As a result, educational materials are available in waiting areas of health centers, and staff at these centers offer violence prevention counseling. This program also includes activities at Boston City Hospital. Adolescents are screened in the emergency room to identify those at high risk of violence, and a special violence prevention clinic at the hospital offers services to these adoles cents. Services include comprehensive assessment, educational interventions, counseling, therapy, and referral to other community services. # Chicago, Illinois, African-American Male Education Network (AMEN) (708) 720-0235 The African-American Male Education Network centers its activities on Rites of Passage programs, which foster self-esteem and pride in one's cultural heritage and provide guidance for youth as they move from one stage of life to another. The program provides the guidance and support to overcome the confusion and frustration that lead to youth choosing destructive alternatives such as violence, gangs, and substance abuse. The program accomplishes these goals through education, teaching life and social skills, and mentoring. # Los Angeles, California, Community Youth Gang Services (213) 266-4264 The Community Youth Gang Services (CYGS) of Los Angeles is a program with many activities. CYGS has crisis intervention teams that negotiate disputes among gangs in the target area and try to convince youth not to join gangs. The program also has activities to reclaim areas of the community from gangs, areas such as parks or playgrounds that were not considered safe because of gang activity. Volunteers work with program staff and local agencies and community groups to develop cultural, recreational, and other activities that are alternatives to gang involvement. Educa tional programs in the schools are complemented with parent education and teacher education. In the job development section of the program, staff work with youth to prepare them for employment and also encourage local employers to hire youth. One other active part of the program is the removal of graffiti from community landmarks. Staff hire youth in the community to do this task under professional supervision. This program has an aggressive outreach effort that works continually In the community to discourage gang membership and direct youth already in gangs to other activities. # PROGRAM MANAGEMENT Certain steps are necessary in building a successful community pro gram to prevent youth violence. These steps, which are essentially the same for all community-action activities, are based on two prin ciples: • Community programs require the input of the entire community. • A problem must be clearly identified before it can be addressed. # COMMUNITY OWNERSHIP A united community can produce powerful changes. Even large and complicated problems like violence can be reduced by the creative energy of a community. One necessary ingredient is the participation of many residents. Community-based health promotion programs in other areas have been effective because they combined the efforts of many different organizations and individuals. In these programs, diverse organizations and individuals recognize their common inter est and work together for a common purpose. A single individual or organization may provide the initial stimulus or the ongoing leader ship, but sustained and effective community-wide action depends upon the coordinated efforts of many individuals and groups. In the process of building a community effort, you should do the following: • Keep leadership and ownership of the program at the community level. Many organizations and government agencies may pro vide support or be involved, but the community should be the leader. Community ownership is the best way to assure that the violence prevention program becomes a permanent program in the com munity. * While keeping leadership of the program at the community level, do not miss opportunities to gain the support and resources that can be provided through the involvement of government agencies or private organizations, such as businesses and churches. Throughout the life of the program, one of the major challenges will be to maintain a productive working relationship among all individuals and organizations interested in working to prevent youth violence. • Include young people of the community in as many parts of the program as possible. They are the most important target group and can be a big help to the program. • Establish a leadership and organizational structure. Initially, both leadership and organizational structure are likely to be informal and flexible. As the program grows, they become more formal. Members of the target population, neighborhood, or community must be part of the leadership group. • Determine the resources available to you. Resources may be divided into three groups: money, ideas, and people. All three types of resources maybe scarce. In addition, the need for each type of resource will vary at different stages of program develop ment. Groups or organizations that may be available to supply some of the necessary resources are listed in Table 4. Not every group on the list is appropriate for every community. Most communities will also have unique organizations and individuals who are not on the list but should be included. • Coordinate efforts. The carefully planned and c-.Vidinated ac tivities of multiple groups, each doing a little bit, accomplish more than the same efforts applied in an uncoordinated fashion. There are several types of information that help describe the nature and extent of the problem in a community. There is factual informa tion from statistical records and opinions about the nature of the problem from people in the community (Table 5). # Factual Information Factual information can describe • The outcome of violent events, such as those that cause injuries and deaths. This information can be obtained from the vital statistics division of the state or local health departments, medical examiner records, hospital or emergency room records, outpa tient records from public or private clinics, emergency medical service (ambulance) records, and school nurse records. Once you have these statistics, it maybe helpful to compare them with state and national data, if possible, to see how your community com pares with other areas. When possible, collect information spe cific to the neighborhood-for example, incident reports from local schools. • The time, place, and circumstances of violent events (e.g., fights over girl-or boyfriends, fights over clothing, fights about drugs, fights between gangs). This information is not routinely assem bled. However, you may find this information byreviewingpolice records, hospital records, or school records. This type of infor mation may help identify times, places, or circumstances that deserve special attention. Because much of this information maybe confidential, you may have to make arrangements to get summary data (e.g., number of firearm injuries) which do not contain information that identifies the people involved. If you are working with a research organi zation or university, they should knowhow to legally have access to records. It is usually best to begin with statistics on the number of violencerelated injuries and deaths. When these are described as well as possible, then look for information about the times, places, and circumstances of the events. # Opinions from Members of the Community You must learn what your community members see as a problem and what they think is causing the problem. You can find this out through surveys of residents and discussions with community leaders, school personnel, legal and police personnel, health workers, and parents. For example, ask school principals and guidance counselors about the violence they see in the schools and listen to their ideas for reducing it. It is also important to talk to children and adolescents themselves, particularly those who might be in trouble or at risk for trouble (for example, those who are expelled from school). Contact youth and their parents in as many community sites as possible, including supermarkets and shopping areas, basketball courts and other recreational areas, churches, schools, and homes. Local schools and universities may be able to help with opinion surveys. • The results of opinion surveys reflect the personal beliefs, view points, and judgments of community members, including victims, offenders, community leaders, and, most importantly, youngpeople. • People who respond to such surveys will give you valuable infor-mation about knowledge, attitudes, and beliefs concerning vio lence in the community. They will also identify what is acceptable in the community and how certain activities may be perceived by community members. • Be sure that workers collecting the information have credibility in the community. # Community Background Information Other types of information on such topics as racism, poverty, unem ployment, and other social, cultural, or economic factors provide helpful background information about the community and the prob lem of violence. Some of this information can be obtained through the U.S. Census (available through your local library), the Depart ment of Labor employment statistics, and from the Department of Housing and Urban Development. When approaching an organiza tion, ask for information specifically related to the institution. For example, ask schools about attendance, truancy, suspensions, expul sions, and failures. The information you acquire from opinion surveys of local leaders and citizens is valuable and may not be available anywhere else. Academic institutions or university research organizations in the community may be able to help you obtain and assemble this type of information. # Data Presentation Statistics from public sources are usually set up for the needs of the particular agency or organization. They may not be tabulated, ex plained, or displayed in ways that you need. You can ask, but do not expect the people or the organizations from whom you get data to modify it for your use. You may find it useful to include people in your effort who have the data or who know how to organize, interpret, and use it. The causes of violent behavior are multiple and complex. The com bination of statistics and opinions is important when you are deciding what you want to do. Statistics will suggest several possible areas for activities. However, the opinions from the community may identify information not provided by the statistics and could indicate the areas that should be addressed first. In addition, information about the community is a powerful tool to convince law-makers and other decision-makers about the importance of the problem and the need to address it. # GOALS AND OBJECTIVES Effective community programs have both goals and objectives. A goal is a broad, general statement about what the program is designed to accomplish. Goals determine the direction of the program. Ob jectives are statements of specific things to be achieved by a specific time, and they determine what activities the community will do. # Example: Goal-Reduce violent behavior in the schools. Objective-In the 1994-95 school year, 100 eighth grade students will study the curriculum on non violent conflict resolution. An objective should tell who should achieve how much of what. where, and by when. . Who means the individuals or groups expected to accomplish a task or change a behavior. • What tells the desired action, such as a change in behavior or health practice. The what should be based on your list of priori ties. At least one of the objectives should be a change in an important health event such as injuries from fights. Other objec tives might relate to the number of fights, the number of students who learn how to avoid a fight, or even the number of students who take a class about avoiding fights. • How much indicates the amount of change you expect. This amount partially depends on available resources. • When means the time by which the desired action or change will be attained. The time will depend on a number of factors-in cluding the resources available to make the change. • Where indicates a geographical area such as a county, city, school system, or neighborhood that has been identified as the target community. As you develop goals and objectives, the following guidelines should be helpful: • Ensure that program members agree upon goals and major ob jectives. The goals and objectives need to be consistent with the overall goals and objectives of each participating group. How ever, they do not need to include all the goals and objectives of each individual organization. Participating groups need to rec ognize their common interests but they cannot be expected to have ah their interests in common. • Create objectives that fit the unique characteristics and resources of the community. « Modify the objectives as new information becomes available, as resources change, or as activities go faster or slower than planned. No program ever goes exactly as planned. • Make objectives detailed enough so you can see what steps need to be taken to successfully implement the activities. • Do not create objectives just to satisfy someone else's research objective. (Be smart, however. Do not miss an opportunity to get resources if it only requires minor additions or modifications to your program.) • If appropriate, divide objectives into categories depending upon whether they pertain to health effects (e.g., injuries), behaviors (e.g., fights), participation (e.g., students in a class), or other aspects of the program (e.g., the number of newspaper articles published on violence). Table 6 shows how objectives flow from a goal. Objectives are important because they clarify the tasks that need to be done, call attention to areas of needed effort, and document the progress of the program and its activities. Example: By 1996, the number of visits by high school students to the school nurse for injuries re lated to weapons violence in Ajax County will be reduced from an average of 2 per month to an av erage of 1 per month. Who: High school students What: Injuries related to weapons violence How much: Reduce from an average of 2 visits per month to 1 visit per month When: By 1996 Where: Ajax County The above example is a possible final objective. Often several intermediate objectives (steps) must be achieved first to ultimately meet the final objective. # Objectives: 1. By 1993, principals will have placed posters about the policy forbidding weapons in schools in all classrooms and on all public announcement boards in all Ajax County high schools. As you can see from this example, an objective: • Is specific and quantitative. It specifies the group involved, a single result, and a target date. « Tells what will happen and when, not why or how this should be done. • Is readily understandable to those involved. • Is realistic, attainable, yet a challenge. ® Identifies criteria for evaluating achievement. # LOCATING RESOURCES FOR YOUR PROGRAM You will need many resources to run a community violence preven tion program. The greatest resource you can have is the time and efforts of community people. There are also a number of resources, such as office space, equipment, and supplies, that m aybe donated by organizations that cannot contribute money to a program. All these resources cost real dollars if they are not donated. Therefore, their contribution is very important. Although having funds will allow you to conduct more activities and reach more people, money does not assure success. There are two major sources of funds for community programs: public and private (Table 7). Public funds come from federal, state, or local governments. Particularly in tight financial times, govern ment funds often go to support existing programs. In addition, because people administering public funds are held accountable to the public for their management, government agencies usually retain a great deal of control over how the money is spent. Private funds come from a number of private organizations, such as foundations, corporations and other businesses, voluntary organiza tions, charitable institutions, churches, and a wide variety of local concerns. Usually private organizations are more flexible than pub lic agencies in the types of programs they fund and in the manage ment of the program. Your own program can also raise funds by sponsoring events that bring attention to the program and also raise money. For example, you can conduct walk-a-thons or community road races, solicit pledges through media programs, conduct bake sales, or conduct contests or raffles with prizes donated by local businesses. Although the amount of money raised in this manner varies, the community's willingness to participate and to take on responsibility provides your program a good record when you approach private or public organi zations to request funding. In fact, some granting organizations require that a percentage of the program's costs be provided by the community or other sources. # Private Organizations # Community Organizations Many organizations within local communities want to help worthy causes, often because of their sense of "corporate citizenship." You should consider the following types of organization's as possible sources of funding: ■ • Businesses (including banks) • Civic organizations, such as the Kiwanis and Lions Clubs • Religious organizations • Local divisions of state or national voluntary organizations (such as the American Heart Association and the American Cancer Society) • Hospitals and other health care facilities • Local television and radio stations and newspapers (Community media often contribute publicity and the help of local media personalities for community efforts.) • Schools, including local colleges and universities with programs aimed at violence prevention (Educational organizations often provide volunteers as well as conduct fund-raising activities through student organizations.) • Community service organizations, such as sororities, fraternities, and associations of retired teachers Some organizations may not have funds to contribute, but may donate facilities, equipment, or labor. Because these resources would probably cost a program real dollars to acquire, their donation is as good as money. Community organizations may not require formal grant proposals or extensive written requests. However, you must convince the person making decisions that the project is good for the community. Also, these organizations are not easily located. One of the best ways to find them is to talk with people who are likely to know about different kinds of community organizations and their leaders. You can also contact people with authority in organizations that have donated to local activities in the past. # Foundations The sole purpose of foundations is philanthropic giving. One major advantage to grants from foundations is that it is usually easier to request money from foundations than from public agencies. Foun dations also have the reputation for funding programs with good ideas but little experience. They are more likely to take a chance on a new organization. Because foundations may support only specific types of projects or projects in certain geographic areas, it is important to find out what foundations support violence prevention projects. The Foundation Center is an authoritative guide to foundations and provides detailed information on the interests and restrictions of individual founda tions and on the money they have granted. The Foundation Center has four main offices as well as libraries in all 50 states. To locate the nearest library, call 1-800-424-9836. You can also find listings of foundations and information on what they support in your local library. After identifying a potential foundation funding source, write a letter to the foundation that briefly states what you want to do in the community and ask whether the foundation is interested in this type of project. Through this inquiry, you will also find ou t how to submit a grant proposal. # Corporations Large business and nonprofit organizations in the United States donate a great deal of money each year. You may find a large company with facilities in your community, such as a factory or major distribution office, that is interested in donating money to your program. In addition, each state receives Federal funds in the form of block grants. These block grants are divided into four areas: preventive health; maternal and child health; alcohol, drug abuse, and mental health; and primary care. For information about these block grants, you can contact the appropriate administrative agency: Preventive Health Other Federal agencies and organizations that have an interest in violence programs are listed here. These programs may not provide grant money or may have very restrictive qualifications for grantees. You should write the agency or talk with someone there to determine whether they are interested in your program. # CENTERS FOR DISEASE CONTROL AND PREVENTION # MONITORING THE PROGRESS OF YOUR PROGRAM Program monitoring or evaluation is essential. It helps you adjust your program to meet unanticipated circumstances. Monitoring things daily is how we improve things. Monitoring also enables the workers, the funding agencies, and, most importantly, the community members to know whether the program is making progress. Moni toring includes the collection of both objective data (e.g., the number of children who took a conflict resolution class) and subjective data (e.g., the number of students who say they are less likely to get into a fight). Monitoring should indicate v aether your activities are on track and whether the intended outcomes are being achieved. Here are some of the questions that should be answered: • Have the activities or interventions been implemented? For example: Has the conflict resolution curriculum actually been used? • Has the activity been properly implemented? For example: Were teaching materials provided? Were the teachers trained? Were the classes given in all the schools? Did all eighth grade students take the classes? • Did the activity achieve its intermediate objectives? For exam ple: Did the students pass the test at the end of the course? • Did the activity achieve its long-term objectives? For example: Were there fewer fights in school and on the school grounds? One of the major difficulties in violence prevention is that very few activities have been proven to work. Although some appear promis ing, thorough scientific evaluations of these programs are badly needed. However, such evaluations are complicated, expensive, and often too difficult for a community to do alone. Communities with a local university have a good opportunity to develop a community/academic partnership. In this type of relationship, the university could help design and carry out detailed evaluation of the community's violence prevention program. Even communities with limited resources must monitor and evaluate their progress. The specific evaluation activities undertaken and data collected are determined by the goals and objectives of the program. At the very least, community-based programs should do the following to monitor their progress: 1. Examine the objectives. Properly prepared objectives will help identify the information necessary to determine whether the pro gram is on track. Keep records and collect data to see whether the objectives are being achieved. # CONCLUSION Effective community programs must do two general things: 1) Include activities that are appropriate for the community and the problem. 2) Create the organization to carry out the activities effectively. The descriptions of the strategies (pp. 11-28) provide a "menu" of violence prevention activities that maybe appropriate for your com munity. Few of these activities are scientifically proven, but they appear promising. Many can be adapted to the specific needs of most communities. The chapter on 'Program Management" (pp. 29-49) provides suggestions about how to define the problem, select activi ties, get them started, and see them through to success. In general, one should strive to do the following: • Empower the community to take active leadership, responsibil ity, and control of the program. • Enlist and coordinate multiple community organizations and groups. • Include many activities targeted at specific risk groups in a variety of settings. • Support individual behavioral change through policy and envi ronmental change. » Provide necessary training for all community people, both volun teers and professionals, who are working in the program. To be successful, a program also requires attention day by day. Here are a few suggestions: « Be flexible. Nothing goes exactly as planned. Make adjustments but do not lose sight of the long-term goal. « Seek new individuals and organizations to broaden the scope of the program and enhance the probability of its success. • Search for ways to provide special training and specific experi ence for the workers. Violence prevention is a new area and few experienced and trained people are available. The natural talents of many of the workers often can be rapidly improved with training. In particular, staff members might receive conflict reso lution training. • Listen to your co workers. Theyknow the community. They often have original and practical ideas. • Be alert for and seek new resources. Do not lose sight of the long-term goal, but be willing to bend a little or add a little in order to get the resources to move the whole program ahead. • Set up numerous milestones so that workers can appreciate their progress. Violence is a big problem. For a community effort to work, the problem needs to be divided into pieces that are small enough to be realistically addressed with goals that have a chance of being reached. Success builds enthusiasm and commitment. • Continually evaluate the progress of the program. Note whether the objectives are being reached. • Be persistent. However, do not set impossible goals and objec tives. • Design activities for hard-to-reach groups who are also the groups most at risk of violence. Outreach activities are necessary to help youth in gangs or those who are separated from the mainstream: the homeless, runaways, or youth who are out of school. • When you do not know what to do, ask someone for help. If you do not know who to ask, call one of the projects mentioned in this manual or listed in the appendix. # Acknowledgments # Appendix # Activities in the United States To Prevent Youth Violence The following lists of community programs designed to prevent youth violence will help other communities that want to start activities locate programs that are of interest and talk to the people involved. Several points to keep in mind: • Programs included are not promoted by the Public Health Service or the Centers for Disease Control as the answer to any one community's problems. Very few violence prevention programs have been evaluated. In addition, programs that work in one com munity may need to be tailored to fit another community's needs. ® Programs are listed by the strategies discussed in these guidelines. Because many programs have more than one strategy, some programs will be listed in a number of places. • The programs listed are those that CDC has been involved in or that have been reported to CDC by various organizations across the country. The list is by no means complete. If you have a program that you would like listed, please fill in the form at the end of this appendix and send to the address given. Please feel free to duplicate this form and pass along to other interested organizations. # We would appreciate your helping us improve subsequent versions o f this manual by taking a few minutes to answer the following questions: What did you find about the manual that was most helpful? What did you find least helpful? How would you improve this manual?	None	None
ac7803c45c6482a1bc631f7f762e6c086965b664	cdc	None	An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States. During 1985-1992, the United States was confronted with an unprecedented TB resurgence. This resurgence was accompanied by a rise in multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin. In addition, virtually untreatable strains of M. tuberculosis are emerging globally. Extensively drug-resistant (XDR) TB is defined as MDR TB that also is resistant to the most effective second-line therapeutic drugs used commonly to treat MDR TB: fluoroquinolones and at least one of three injectable second-line drugs used to treat TB (amikacin, kanamycin, or capreomycin). XDR TB has been identified in all regions of the world, including the United States. In the United States, the cost of hospitalization for one XDR TB patient is estimated to average $483,000, approximately twice the cost for MDR TB patients. Because of the limited responsiveness of XDR TB to available antibiotics, mortality rates among patients with XDR TB are similar to those of TB patients in the preantibiotic era. In January 1992, CDC convened a Federal TB Task Force to draft an action plan to improve prevention and control of drugresistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41(). In November 2006, CDC reconvened the Task Force to draft an updated action plan to address the issue of MDR TB and XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing problems, identifying barriers to improvement, and recommending specific action steps to improve prevention and control of XDR TB within their respective areas. Although the first priority of the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to address MDR TB and XDR TB domestically, members recognized the necessity for TB experts in the United States to work with the international community to help strengthen TB control efforts globally. TB represents a substantial public health problem in low-and middle-income countries, many of which might benefit from assistance by the United States. In addition, the global TB epidemic directly affects the United States because the majority of all cases of TB and 80% of cases of MDR TB reported in the United States occur among foreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agencies can take to help solve global XDR TB problems. Unless the fundamental causes of MDR TB and XDR TB are addressed in the United States and internationally, the United States is likely to experience a growing number of cases of MDR TB and XDR TB that will be difficult, if not impossible, to treat or prevent. The recommendations provided in this report include specific action steps and new activities that will require additional funding and a renewed commitment by government and nongovernment organizations involved in domestic and international TB control efforts to be implemented effectively. The Federal TB Task Force will coordinate activities of various federal agencies and partner with state and local health departments, nonprofit and TB advocacy organizations in implementing this plan to control and prevent XDR TB in the United States and to contribute to global efforts in the fight against this emerging public health crisis.# Introduction Global Health Burden of Tuberculosis Tuberculosis (TB) is among the most common infectious diseases and frequent causes of death worldwide (1). TB is caused by Mycobacterium tuberculosis and is spread most commonly by airborne transmission. M. tuberculosis can affect any part of the body but is found most often in the lungs. Persons with pulmonary TB generally have a cough that produces small airborne droplet nuclei containing tubercle bacilli that can remain in the air for hours. Vulnerable persons exposed to tubercle bacilli in airborne droplets might become infected. The majority of persons who become infected remain noncontagious and without a cough or other symptoms. These persons have latent M. tuberculosis infection (LTBI) and can be treated with a single drug (isoniazid) for 9 months to prevent disease. Infected persons who do not have underlying medical problems and do not receive LTBI treatment have a 5%-10% lifetime risk for progressing to TB disease (2). However, the risk for disease progression increases substantially in the presence of immunosuppression, such as that caused by the human immunodeficiency virus (HIV) and immunosuppressive medications (2). Persons with pulmonary TB can be cured with a 6-month course of antibiotics that includes isoniazid, rifampin, pyrazinamide, and ethambutol during the first 2 months. In the United States, diagnosis and treatment for TB is accessible and effective (3). However, many developing countries have limited resources to diagnose TB illness and treat persons with TB. Worldwide, 2 billion persons (one third of the world's population) are thought to have LTBI. Nearly 9 million persons develop TB disease each year, and close to 2 million TB-related deaths occur annually (1). In the United States, approximately 13,000 new cases of TB are reported annually, and 650 persons die from TB each year (4). TB is the leading cause of mortality among persons infected with HIV (5). # Emergence of Drug-Resistant Tuberculosis During 1985-1992, the United States experienced an unprecedented TB resurgence marked by a substantial number of patients with TB who did not respond to treatment and who eventually died (6). Physicians and epidemiologists quickly determined that these persons had multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to both isoniazid and rifampin (7). Although persons with MDR TB usually can be treated effectively by relying on second-line drugs (amikacin, kanamycin, or capreomycin), these have more side effects and are more expensive and less effective than first-line drugs and require regimens lasting 18-24 months (3). In addition, the cure rate for persons with MDR TB is 50%-60%, compared with 95%-97% for persons with drug-susceptible TB (3). In response to several MDR TB outbreaks in hospitals and correctional facilities in New York and Florida during 1988-1991 (8,9), CDC convened a Federal TB Task Force- with representatives from multiple U.S. agencies † to produce recommendations for a nationwide response to the MDR TB outbreaks. In June 1992, the Federal TB Task Force published an action plan that provided a framework for response and specific action steps for state and local health departments and federal agencies (7). These action steps were grouped into nine categories: 1) surveillance and epidemiology, 2) laboratory diagnosis, 3) patient management, 4) screening and preventive therapy, 5) infection control, 6) outbreak control, 7) program evaluation, 8) information dissemination/training and education, and 9) research. Emergency federal funding was appropriated to CDC in 1993 and again in 1994 to allow the Federal TB Task Force and state and local health departments to implement certain parts of the plan. For example, CDC investigative teams were deployed to assist local programs in defining and organizing appropriate response to MDR TB outbreaks (CDC, personal communication, 2007). State and local health departments enhanced diagnostic laboratory capacity, increased the sensitivity of their surveillance systems, improved infection-control practices, and reemphasized the need for optimal treatment of all forms of TB to prevent the development and further transmission of MDR TB. Other federal agencies that are members of the task force also contributed substantially to implementation of the plan; a description of their activities follows. The need for increased biomedical research and product development for TB was recognized by the National Institutes of Health (NIH) as part of the implementation of the 1992 Action Plan. The National Institute for Allergy and Infectious Diseases (NIAID) established extramural and intramural research programs in all areas of fundamental, translational, and clinical research in TB to create a platform of knowledge and the research tools needed to study M. tuberculosis and its interaction with the host and to characterize TB in animal models and humans. In June 2007, NIAID released a research agenda describing the specific biomedical research challenges and priorities that should be addressed in response to the emergence of drug-resistant TB (10). The National Heart, Lung, and Blood Institute (NHLBI) supported studies with a strong emphasis on pulmonary TB, including complications through coinfection with HIV, and developed a training curriculum in TB for health professionals at medical institutions through the National Tuberculosis Curriculum Consortium (NTCC) (11,12). The Fogarty International Center (FIC) supported TB research and research training for developing country scientists through collaborative grants with U.S. institutions (13). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) focused on international clinical research for optimizing TB treatment in children and women coinfected with HIV (14). The more recently created National Institute of Biomedical Imaging and Bioengineering (NIBIB) has a substantial investment in diagnostic platform technologies (point-of-care and imaging) that can help improve TB diagnosis through advances in medical imaging methods (15). In May 1994, the Food and Drug Administration (FDA) approved Rifater (a fixed-dose combination of rifampin, isoniazid, and pyrazinamide) to facilitate patient adherence with lengthy and complex multidrug therapy (16). In addition, FDA granted a priority new drug application review for the drug rifapentine, which was approved in July 1998 for the treatment of TB (17). In 1993, the United States Marshals Service (USMS) established a formal medical program for prisoners with TB (USMS, personal communication, 2007). As part of this activity, USMS drafted a series of advisory memoranda to provide education information and guidance to USMS field offices to support TB screening for staff and prisoners. USMS also collaborated with the Texas Department of Health to conduct presentations on TB control in correctional facilities highlighting patient tracking and follow-up issues that arise when transferring prisoners between and outside jurisdictions. The Department of Housing and Urban Development (HUD) developed web-based information and training activities on acquired immune deficiency syndrome (AIDS) and TB (HUD, personal communication, 2007). Since 1998, with the creation of specific international TB programs (e.g., directly observed treatment, short-course expansion; research; training; and TB/HIV coinfection), the U.S. Agency for International Development (USAID) has provided technical and financial support to strengthen TB control programs worldwide (18). USAID also has supported drug-resistance surveys with biannual global reports and pilot programs to optimize MDR TB treatment and the Green Light Committee (GLC), which helps countries gain access to high-quality second-line TB drugs so they can provide treatment for persons with MDR TB (19). More recently, the Division of Immigration Health Services (DIHS) of the Health Resources and Services Administration (HRSA) implemented a national TB Continuity of Care Program for persons who are detained by U.S. Immigration and Customs Enforcement (ICE) agents in the Department of Homeland Security (DHS) and who are to be deported before completing TB therapy (20); in October 2007, DIHS was transferred from HRSA to ICE. In addition, U.S. government agencies have worked with their counterparts in Mexico and in U.S. state agencies to develop initiatives (e.g., Ten Against TB) to address TB, including drug-resistant TB, along the U.S.-Mexico border (21). During 1993-2007, as a result of implementation of the 1992 Action Plan, the reported annual incidence of MDR TB in the United States declined 75%, from 485 cases in 1993 to 119 cases in 2007 (4). # Emergence of Extensively Drug-Resistant Tuberculosis Since 1993, both incidence of TB and the total number of TB cases in the United States have decreased, although the rate of decline has slowed since 2000. Worldwide, the number of TB cases has continued to increase, but the incidence rate has decreased since 2003. Recently, highly drug-resistant forms of TB have emerged worldwide. In 2006, CDC, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) reported the results of a survey regarding drug-resistant TB conducted by 25 reference laboratories comprising the Global Supranational TB Reference Laboratory Network (2000)(2001)(2002)(2003)(2004), the National TB Surveillance System in the United States (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), the national reference laboratory of South Korea (2004), and the national MDR TB patient registry in Latvia (2000-2002) (22). The findings indicated that 20% of M. tuberculosis isolates were MDR, and 2% also were resistant to multiple second-line drugs. This highly resistant form of TB was identified in every region of the world, including the United States, where 4% of MDR TB isolates also were resistant to multiple second-line drugs. In a report published in 2006, this highly resistant form of TB was named extensively drug-resistant TB (XDR TB) (22). XDR TB is a subset of MDR TB that is resistant both to isoniazid and rifampin and to any fluoroquinolone drug and at least one of three second-line injectable drugs (amikacin, kanamycin, or capreomycin) (23). The emergence of XDR TB raises concerns about the possibility of epidemics of virtually untreatable TB. Such epidemics could result in excessive mortality and substantial financial and infrastructure burden for public health and TB control programs. XDR TB is much more expensive to treat, with hospitalization costs in the United States estimated to average $483,000 per case. A major outbreak of XDR TB in the United States would constitute a substantial drain on public health resources and could quickly deplete the existing state and local TB budgets and have a negative impact on progress toward TB elimination. This is especially true in an era of diminishing resources for TB control at the national, state, and local levels (6). Treatment failures and subsequent death are more common among patients with XDR TB, and the drugs available to treat XDR TB are associated with serious adverse effects. Because persons who are infected with HIV or who have other immune-compromising conditions (e.g., diabetes) are more vulnerable to progressing to active TB disease, infection with XDR TB is of particular concern among these persons. In countries with high rates of HIV and limited health-care resources, substantial numbers of XDR TB cases are likely present. As of April 2007, South Africa (where HIV prevalence was estimated at 10.8% in 2005) had reported 352 cases of XDR TB, with the actual prevalence likely being much higher (24) because cultures and susceptibility testing are performed on only a small fraction of TB patients, and many drug-resistant cases will go undetected. # Methodology After an outbreak of XDR TB among HIV-infected persons in Kwazulu Natal, South Africa, reported in August 2006, urgent expert consultations were organized by the South African Medical Research Council (SAMRC) and WHO in September and October 2006 (25). The result of these consultations was the 2007 publication of a global MDR TB and XDR TB response plan with eight overarching objectives (26). Several U.S. government agencies, including CDC, participated in the expert consultations. The U.S. Federal TB Task Force was recognized as the appropriate venue to coordinate U.S. involvement in the global response to XDR TB. In November 2006, following participation in the SAMRC and WHO XDR TB consultations, CDC convened members of the Federal TB Task Force to discuss the emergence of XDR TB and coordinate U.S. government agency involvement in the domestic and international response to this problem. After several teleconferences, the Task Force agreed that a U.S. government agency action plan should be written. The action plan that had been published in 1992 to respond to MDR TB was selected as a basis for drafting the XDR TB response plan (7). Several members of the 2006 Task Force also had contributed to the 1992 Action Plan to combat MDR TB. This MDR TB expertise contributed substantially to a well-informed and effective discussion and the creation of an Action Plan to Combat Extensively Drug-Resistant TB. As had occurred in the process to create the 1992 Action Plan, members of the Federal TB Task Force were divided into sections to address critical areas of response. The 1992 action plan distributed the objectives and implementation steps needed to address 38 problems among nine response areas (surveillance and epidemiology, laboratory diagnosis, patient management, screening and preventive therapy, infection control, outbreak control, program evaluation, information dissemination/training and education, and research). Although largely overlapping with the 1992 action plan, the response areas for the XDR TB plan were reorganized as follows: 1) diagnostic laboratory; 2) surveillance, epidemiology, and outbreak investigations; 3) infection control; 4) clinical and programmatic interventions; 5) ethical and legal issues; 6) communication and education; 7) research; 8) partnerships; and 9) cost analysis. These response areas also are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug-sensitivity testing, 3) improve the technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities. In addition, the implementation steps were renamed "action steps." In January 2007, each subgroup of the Federal TB Task Force that was responsible for addressing a critical response area began by reviewing the relevant sections of the 1992 action plan to determine which problems, objectives, and action (formerly implementation) steps needed to be deleted or updated and revised. The subgroups also determined if gaps existed requiring the identification of additional problems, objectives and action steps. In particular, because the 1992 plan had focused primarily on domestic MDR TB, the subgroups were instructed to expand the scope of the new plan to address the role of U.S. government agencies in the international response to XDR TB. To reflect this distinction, the new plan labels objectives as domestic, international, or both. The expanded scope and a greater emphasis on detail resulted in a substantial increase in the number of problems, objectives, and action steps identified compared with the 1992 plan. For example, the number of problems increased from 38 in 1992 to 67 in the current plan. An emphasis also was placed on being as inclusive as possible when designating lead federal agencies and potential external partners. To provide a basis for revisions, the subgroup members reviewed pertinent literature published since 1992, which is substantially more voluminous, especially for drug-resistant TB, compared with that available before 1992, and available unpublished data. After drafts of the sections were completed, the sections were compiled into a single document that was distributed to the entire Federal TB Task Force for review and comment. In June 2007, the Federal TB Task Force met in Rockville, Maryland, to make additional revisions, especially to eliminate redundancies between sections. These revisions were incorporated into a final draft that was submitted for multiple agency clearance in September 2007. # Recommendations to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory The diagnosis of XDR TB is established by laboratory methods. Accurate, reliable, and prompt TB laboratory services should be coordinated fully with provider and public health practitioners caring for persons with TB. Test results must be available in a time frame that allows clinicians to make prompt and informed patient management decisions. For this goal to be met, laboratory capacity for the diagnosis of TB and the detection of drug resistance must be rapidly enhanced, both in the United States and worldwide. Adequate infrastructure must be built where it does not exist, a stable and well-trained work force must be developed and maintained, and a systems approach (27) must be implemented to maximize efficiency and proficiency. Laboratory methods and reporting, especially for susceptibility to second-line drugs, should be standardized through expert consensus. Rapid tests for TB diagnosis and drug-susceptibility testing on the basis of newer molecular methods must be evaluated promptly to determine their feasibility, especially for low-resource settings, and, if appropriately validated, their use should be promoted and facilitated. Internationally, competent, high-quality reference laboratory services with capacity to perform required testing of samples and to report results in a prompt fashion to providers and health officials must be available to jurisdictions in need. # Surveillance, Epidemiology, and outbreak Investigation Domestic XDR TB surveillance must include accurate and complete reporting of second-line drug-susceptibility testing, real-time reporting, and active case finding. Central notification of MDR TB and XDR TB is essential to identify cross-jurisdictional issues and to provide potential for rapid emergency federal support, when needed. Internationally, rapid drug-susceptibility test (DST) surveys and more sustained systematic capture of DST information are highlighted as areas to be addressed as part of a comprehensive response to XDR TB. Epidemiologic studies that make use of genotyping tools are recommended to elucidate XDR TB risk factors and transmission dynamics. Strategies also are needed to rapidly identify and respond to domestic and international XDR TB outbreaks. # Infection Control Effective infection-control practices are critical to prevent the transmission and further spread of MDR and XDR TB in health-care settings and other congregate settings (e.g., correctional facilities and homeless shelters). CDC infectioncontrol guidelines were updated in December 2005 and should continue to be updated as needed (28). Further studies are needed to assess the effectiveness and feasibility of various infection-control strategies in different institutional settings. Testing workers for TB in various institutional settings is an important strategy for identifying workers infected with TB and detecting unsuspected transmission. # Clinical and Programmatic Interventions Prevention and control of TB in the United States require a robust public health infrastructure that includes a workforce trained in TB prevention, diagnosis, treatment, and case management. Because some patients fail to recognize TB symptoms, health care often is not sought during early stages of disease. In addition, providers who are unfamiliar with signs and symptoms of TB and with diagnostic standards might not suspect TB, delaying the start of effective treatment. Access to comprehensive and affordable clinical TB services (i.e., preventive, diagnostic, and treatment/case management) should be provided to all persons with TB or those suspected to have TB. Health-care providers who screen persons for TB should use up-to-date diagnostic and treatment guidelines. More health-care workers are needed to provide directly observed therapy (DOT) for TB patients to ensure successful treatment and help prevent development of disease attributable to drug-resistant TB. # Ethical and Legal Issues Strict infection-control measures are necessary to prevent the spread of XDR TB. Patients with XDR TB might need to be placed in airborne infectious isolation while initial treatment response is monitored in order to prevent disease transmission to others. Guidance is needed regarding the ethical and legal issues involved in identifying and treating persons with XDR TB. The adequacy of current public health laws in the United States to address drug-resistant TB has not been studied comprehensively since 1993 (29). All states have laws to compel isolation for persons with certain infectious diseases (including TB); however, these laws vary by state, and those for TB might be contingent on patient nonadherence and failure of voluntary measures. Public health authorities must balance the interests of the public with individual rights. Legal and ethical issues become even more complicated when persons have XDR TB because prolonged isolation might be necessary even when a patient is adherent. In addition, for some patients, no effective treatment is available that would allow for release from isolation on completion. Additional complexity also exists regarding non-U.S. citizens with infectious XDR TB who are scheduled to be repatriated to their native countries. U.S. public health officials might not be familiar with public health laws of other countries. # Communication and Education As a result of TB incidence rates decreasing in the United States, health-care providers have received little training regarding TB and consequently might not recognize the signs and symptoms of TB, which can lead to incorrect diagnosis and treatment, creation of drug resistance, and continued spread of TB in the community (30,31). Health-care providers should be educated about the signs and symptoms of TB, diagnostic methods, prevention, and treatment. In addition, education materials on MDR TB and XDR TB should be developed for the general public, populations at high-risk for TB on the basis of demographic and clinical characteristics, TB patients, TB prevention advocacy organizations, and policy makers, including legislators. Education materials should include informational pamphlets, instructions for therapy, behaviors to prevent transmission, medical alerts, and descriptions of TB programs. Distribution of these materials should be coordinated across federal and state agencies and updated as necessary. Advocacy is critical to make the public aware of the importance of TB control to the public's health, and to educate policy makers on the magnitude of the problems that will result if resources to state and local TB control programs continue to decline. # Research The biomedical research challenges represented by drugresistant TB in the context of overall TB research activities have been described previously (10). Knowledge gaps remain regarding the genetics and growth characteristics of M. tuberculosis, the physiology and biochemistry of both the host and pathogen during infection, and the disease and genotypic and biologic markers that facilitate surveillance and indicate infection, disease, and drug resistance. Basic research needs to be supported to advance understanding of these issues and to help design new approaches to diagnosis and treatment. The emergence of drug-resistant TB illustrates the pressing need to develop new and effective drug regimens for the treatment of TB, including drugs to cure MDR TB and XDR TB and to prevent development of active disease among persons who are infected latently with drug-resistant M. tuberculosis. Because poor patient adherence to therapy is one factor that can lead to development of MDR TB and XDR TB, research of associated behavioral and social factors should be conducted to identify ways to improve patient adherence and treatment completion. New, rapid, and cost-effective diagnostic methods are needed, particularly for use in rural areas and developing countries. Ultimately, an effective vaccine is needed to eliminate TB. # Partnerships To coordinate efforts to control XDR TB, existing partnerships must be strengthened, and new partnerships are needed between countries and within both the public and private sectors, including government and nongovernment organizations. Partnerships are necessary to focus existing resources on the most affected geographic areas, increase current public and private resources (both financial and human resources), coordinate the efforts (including research, education, laboratory, and programmatic), and raise awareness of the problem and consequences. # Cost Analysis Comprehensive information is not available on the cost of treating and implementing programs and interventions to prevent XDR TB. Research on the cost of treating and preventing XDR TB is needed to calculate the cost-effectiveness and benefits of interventions and strategies to combat XDR TB. # Action Plan to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory The laboratory plays a critical role in the diagnosis and management of drug-resistant TB. Test results must be available in a time frame that allows clinicians to make prompt patient management decisions. Many laboratory techniques used to confirm a TB diagnosis and to identify drug resistance were developed in the 1950s, 1960s, and 1970s. Substantial improvements have been made in culture techniques and in rapid methods in the past decade. However, these more accurate, rapid, and sophisticated methods have not been implemented widely, particularly in regions of the world where MDR TB and XDR TB are common and optimized algorithms for providing rapid point-of-care laboratory confirmation of TB and detection of drug resistance have not been established. To combat the growing problem of resistance to TB drugs, the most current methods need to be applied to their fullest capacity while better diagnostic tests are developed. The needs of the TB laboratory must be addressed to make laboratory services for TB, MDR TB, and XDR TB more rapid, sensitive, reliable, and more responsive to the needs for patient management, infection control, and TB control efforts. Although the challenges and potential solutions vary by setting, domestic and international TB laboratories face many of the same challenges. # Problem 1 Many clinicians, laboratorians, health-care professionals, public health officials, and policy makers do not possess upto-date knowledge of what constitutes appropriate laboratory capabilities and capacities or the appropriate use of tests to arrive at a prompt and accurate diagnosis of TB. Increase awareness of the need to develop necessary capacity and capabilities for the laboratory diagnosis of TB. This includes proper use of diagnostic tests, prompt reporting of results, and appropriate interpretation of test results for establishing a definite diagnosis and for guiding management of TB (domestic and international). # Problem 4 The quality of and proficiency in TB laboratory diagnosis varies within the United States and internationally because a well-trained and stable laboratory workforce is not universally available. # Problem 5 TB laboratory services at certain local public health laboratories are limited and might depend on access to networks of other public and private laboratories with better diagnostic capabilities, which often leads to substantial delays in diagnosis and treatment of TB. Develop a systems approach to improving TB laboratory services at the local level (domestic). # Action Steps 5.1.1. Assess available TB laboratory services in a jurisdiction to determine the status and capacity of services and to identify unmet needs, obstacles to obtaining services, and opportunities for improvement. 5.1.2. Assess the actual costs of providing TB laboratory services through existing programs and develop a business plan for providing these services through an integrated system of laboratory services in the United States. 5.1.3. Develop a strategic plan for implementing and maintaining a systems approach to TB laboratory services. 5.1.4. Develop outcome measures to assess performance of and improvements in laboratory services and overall TB control programs. Lead federal agencies: HHS (CDC). 5.2.4. Develop program-specific plans and phased approaches to improving laboratory services in national, country-level regional and peripheral (local) laboratories. 5.2.5. Develop local, district, regional, and national laboratories, including referral laboratories, that provide reliable services through conventional and rapid methods for TB diagnosis, drug-susceptibility testing and patient care. 5.2.6. Develop or ensure access to effective external quality assessment programs for laboratory services (e.g., acid fast bacillus -smear microscopy, culture, and drug-susceptibility testing) provided at each level. 5.2.7. Support development of laboratory standards and accreditation programs with an emphasis on culture and drug-susceptibility testing to facilitate assessment and quality improvement of national and regional laboratories. 5.2.8. Explore options to increase TB laboratory capacity as part of efforts to improve general diagnostic laboratory service capacity and overall health sector reform. 5.2.9. Identify interim laboratory support services until local and regional capacity is developed. 5.2.10. Support research to develop inexpensive, high-quality diagnostic tools that can be used in resource-limited settings. Lead federal agencies: HHS (CDC and NIH), and USAID. Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD. Culture-based laboratory tests to identify persons with XDR TB are slow, lack sensitivity, and have poor reliability, resulting in delayed diagnosis, treatment, and public health control efforts. objective 6.1 Improve the ability of TB laboratories to identify and report drug-resistant M. tuberculosis (domestic). # Action Steps 6.1.1. Develop local, district, state, regional, or referral laboratories that are able to rapidly identify M. tuberculosis bacteria in patient specimens and determine drug susceptibilities to first-and second-line agents using state-of-the-art conventional or rapid methods. 6.1.2. Encourage the use of state-of-the-art rapid tests for detection of M. tuberculosis and drug-susceptibility testing through focused laboratory funding. 6.1.3. Develop a bank of M. tuberculosis isolates for use in proficiency testing and research. 6.1.4. Implement proficiency testing programs and external quality assessment programs for new drug-susceptibility tests and rapid methods. 6.1.5. Assist laboratories in developing and implementing an integrated information management system for inventory, specimen tracking, reporting, and information sharing. 6.1.6. Identify interim laboratory support services until local and regional capacities are developed. Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: APHL and NTCA. # Problem 7 The lack of guidelines for the use of conventional and rapid culture-based or molecular methods for detection of M. tuberculosis and drug resistance impedes the widespread use of these tests. Develop consensus guidelines to address TB laboratory testing in the United States, in high-burden and in focus countries (domestic and international). Action Steps 7.1.1. Develop consensus guidelines for culture, drug-susceptibility, and rapid diagnostic testing to be used in local, district, state, national, and country-level regional laboratories. 7.1.2. Develop consensus guidelines for the use of rapid methods (e.g., nucleic acid amplification tests) to detect M. tuberculosis directly from patient specimens. 7.1.3. Develop consensus guidelines for the use of rapid, molecular methods for drug-susceptibility testing. 7.1.4. Develop consensus guidelines for culture-based methods to determine resistance to second-line TB drugs. 7.1.5. Conduct operational and implementation research to develop guidelines for optimal algorithms for TB laboratory testing, specimen referral, and reporting. Lead federal agencies: HHS (CDC and NIH) and USAID. Suggested collaborators: APHL, ATS, IDSA, CLSI, WHO, IUATLD, and academia. # Problem 8 The current process for evaluating newly developed diagnostic tests can be time consuming and delay implementation for routine clinical use. Develop strategies for expedited evaluation and implementation of new rapid methods for laboratory confirmation of TB and identification of drug-resistance patterns (domestic and international). 8.1.10. Determine and promote the most effective pointof-care drug-susceptibility testing methods and diagnostic algorithms and strategies, including molecular testing at the local level followed by transport of positive specimens to fullservice laboratories for further evaluation. 8.1.11. Provide access to or conduct clinical trials in partnership with high-burden countries to validate new microbiologic drug-susceptibility tests as part of local diagnostic procedures/ algorithms. 8.1.12. Discuss with FDA criteria that will be required for approval of new tests for identification of drug-resistant TB and to perform rapid drug-susceptibility testing. Lead federal agencies: HHS (CDC, FDA, and NIH), and USAID. Suggested collaborators: DoD, Foundation for Innovative New Diagnostics (FIND), WHO Special Programme for Research and Training in Tropical Diseases ), academia, public health laboratories, and IUATLD. # Problem 9 The laboratory confirmation of TB in HIV-infected persons is difficult and time consuming because of the need for highly sensitive, sophisticated and technically challenging diagnostic tests that are not universally available in all settings with a high burden of HIV and TB. Suggested collaborators: DOS, DoD, FIND, WHO (TDR), ASM, APHL, academia, IUATLD, and public health laboratories. # Problem 10 Current technical assistance for laboratory capacity building is sporadic and not well coordinated or integrated often leading to unclear and inconsistent guidance. # Develop consistent and well-coordinated approaches to technical assistance and consultation for TB laboratories in high-burden and focus countries (international). Action Steps 10.1.1. Develop technical assistance approaches and practices that are coordinated, consistent, and compatible with the efforts of international partners such as WHO and IUATLD. 10.1.2. Establish a cadre of well-trained consultants to help guide coordinated approaches to building TB laboratory capacity in high-burden and focus countries. 10.1.3. Contribute to the coordinated development of standardized checklists and templates for laboratory evaluation and training materials for laboratory capacity building efforts. 10.1.4. Contribute to the coordinated development of external quality assessment guidance and documents for microscopic and culture identification of M. tuberculosis and drug-susceptibility testing. 10.1.5. Contribute to the coordinated development of widely compatible laboratory information systems to facilitate transfer of information within and between TB control programs. 10.1.6. Promote expansion of the Supranational Laboratory Network through inclusion of reference laboratories that can assist in capacity building and external quality assessment. 10.1.7. Promote expansion of the Supranational Laboratory Network proficiency testing to include second-line drugsusceptibility testing. 10.1.8. Promote and coordinate partnering of public health laboratories in the United States with public health laboratories in high-burden and focus countries. Lead federal agencies: HHS (CDC and NIH), and USAID. Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD. # Problem 11 Providing technical assistance is logistically difficult. objective 11.1 Establish international regional centers of excellence to facilitate implementation of technical assistance provided by the United States to TB endemic or TB-focus countries (international). # Action Steps 11.1.1. Build expertise for technical assistance to TB laboratories at selected centers of excellence in high-burden countries. February 13, 2009 11.1.2. Provide opportunities for peer-to-peer training and exchange of laboratory personnel in resource limited settings. 11.1.3. Assist centers of excellence in developing training programs for program staff, laboratory managers and bench workers on establishing methods for external quality assessment processes through site visits and monitoring. 11.1.4. Assist centers of excellence in establishing reference laboratory services for identification of M. tuberculosis and susceptibility testing for first-and second-line drugs that would qualify them as Supranational Reference Laboratories and that could be made available to partner programs. Lead federal agencies: HHS (CDC and NIH) and USAID. Suggested collaborators: DOS, DoD, WHO, IUATLD, APHL, ASM, KNCV, RIT, academia, and public health laboratories. # Problem 12 Resources available to TB laboratories are often inadequate for building and maintaining the necessary infrastructure and competencies to provide consistently high-quality diagnostic services. Mobilize resources and support international efforts to strengthen and sustain TB laboratory capacity (international). # Action Steps 12.1.1. Identify funding opportunities through the President's Emergency Plan for AIDS Relief, USAID, and the Global Fund to contribute to strengthening international laboratory efforts. 12.1.2. Support global efforts (e.g., WHO's strategic approach to the strengthening of laboratory services for TB control). 12.1.3. Support the Stop TB Partnership's Global Laboratory Initiative and the DOTS (directly observed therapy, short course) Expansion Working Group. Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: DOS, WHO, the Bill & Melinda Gates Foundation, APHL, and the American Lung Association (ALA). # Problem 13 The role of public and private TB laboratories in the diagnosis of persons latently infected with XDR M. tuberculosis has not been defined clearly. # Develop laboratory services to identify persons with drug-resistant latent M. tuberculosis infection (DR LTBI) (domestic). # Action Steps 13.1.1. Assess the capacity of public and private TB laboratories to support DR LTBI diagnostic testing by determining the status and capacity of currently available services and identifying gaps, obstacles and opportunities for improvement. 13.1.2. Develop materials and programs to train laboratory personnel in DR LTBI diagnostic testing. 13.1.3. Develop consensus laboratory guidelines for DR LTBI testing methods. 13.1.4. Conduct operational research to optimize testing and referral algorithms. 13.1.5. Develop proficiency testing and external quality assessment modules for DR LTBI diagnosis. 13.1.6. Conduct Phase 4 clinical studies of new technologies for DR LTBI diagnosis and management. Lead federal agencies: HHS (CDC, FDA, NIH). Suggested collaborators: DoD, NTCA, APHL, CLSI, ATS, and IDSA. # Problem 14 International laboratory services used by physicians under provisions of the United States Immigration and Nationality Act often are not equipped to the standards of U.S. TB programs and might not be able to reliably identify persons with drug-susceptible or MDR TB and XDR TB. Evaluate and improve the ability of international laboratories employed to identify M. tuberculosis and perform drug-susceptibility testing for potential U.S. immigrants (international). Suggested collaborators: DoD, FIND, and academia. # Surveillance, Epidemiology, and outbreak Investigations Identifying outbreaks of XDR TB to prevent further transmission requires a rapid, accurate, and adaptable surveillance system and coordinated response strategies. In the United States, individual states require reporting of TB cases by health-care providers and facilities to public health authorities. By mutual agreement, state health authorities report TB cases to CDC. Substantial delays can occur in reporting to CDC because many states report on a quarterly basis or at the end of the year. Key domestic surveillance needs include immediate case reporting, accurate and complete reporting of second-line drug susceptibility and genotyping results, and active case finding among contacts and other high risk groups. Central notification of MDR and XDR TB is essential to identify crossjurisdictional issues and to outline specific areas that should be targeted for rapid emergency (federal) support. Improved, unambiguous technical guidance (including outcome standards) is needed for collection, reporting, and data-quality procedures at the local, state, and federal levels. Internationally, areas that require increased attention and improvement include capacity for rapid DST surveys and more sustained, systematic capture of DST information. Epidemiologic studies, including genetic analyses of host and pathogen, are recommended to elucidate risk factors for acquiring XDR TB, transmission dynamics and determinants of host survival. # Problem 16 No requirement exists for rapid reporting of TB cases to the National TB Surveillance System (NTSS), and many state and city TB programs report to NTSS only quarterly or at the end of the year, thus substantially limiting the ability to identify rapidly and respond promptly to outbreaks of MDR TB and XDR TB. # Problem 23 In areas where XDR TB has been identified, the actual prevalence of resistance to first-and second-line drugs among TB cases is unknown. # Problem 24 The risk factors for and transmission dynamics of XDR TB in domestic and international settings are not completely understood. # Problem 25 The survival rates among patients with TB that is resistant to first-and second-line therapeutics have not been adequately analyzed, and host/pathogen determinants of survival, including the effect of co-morbidities, remain to be elucidated. # Infection Control Because TB is spread by the airborne route, anyone who breathes air containing viable tubercle bacilli is at risk for acquiring M. tuberculosis infection. This includes persons caring for and exposed to infectious TB patients, especially patients without an established diagnosis. To prevent the spread of disease and maintain the best possible care for patients, special infection-control practices and procedures must be available. Effective infection control depends on early detection and diagnosis of TB disease, prompt initiation of effective therapy, and airborne infection isolation to prevent further disease transmission. Each institutional setting that might house persons with undiagnosed TB disease or in which TB patients are treated should have infection-control programs available that minimize the risk for TB transmission, including MDR TB and XDR TB, to patients, workers, and others within the institutional setting. Various infection-control strategies are available depending on whether a setting will provide primary care or triage and refer patients with suspected or confirmed TB disease. All infection-control strategies should be on the basis of a three-level hierarchy: administrative controls, environmental controls, and personal respiratory protection. Combinations of these infection-control strategies have been demonstrated to be effective at preventing TB transmission. However, these strategies are not implemented consistently, and their individual effectiveness and feasibility are not well-characterized. # Problem 27 Although administrative controls, environmental controls, and respiratory protection have been effective when used in combination, ethical issues have prevented assessment of their individual effectiveness in settings in which TB transmission occurs. Resulting knowledge gaps hamper efforts to prioritize interventions for optimal cost-benefit in resource-limited settings. -bjective 27.1 Ensure dissemination and implementation of currently recommended infection-control strategies across a range of highrisk institutional settings (e.g., health-care facilities, substance abuse clinics, residential treatment centers, homeless shelters, and correctional and detention facilities) through education and regulatory programs (domestic and international). 28.1.2. Recommend considering positive tuberculin skin test (TST) or blood assay (BAMT) for identification of M. tuberculosis infection among health-care workers as an outcome measure of the effectiveness of TB infection-control programs in health-care facilities that are in the medium risk category or have been classified as having potential ongoing transmission. 28.1.3. Provide health departments with support in recruitment of and assistance to health-care centers, correctional facilities, homeless shelters, and substance-abuse treatment centers to implement and assess the effectiveness of programs for systematic TB screening of workers employed in mediumor high-risk settings. Lead federal agencies: HHS (CDC). Suggested collaborators: OSHA, JCAHO, and state and local health departments. # Clinical and Programmatic Interventions The fundamental principles and practices of TB control have been described previously (3,33). These principles and practices underlie the clinical and programmatic components of diagnosis, reporting, treatment and prevention of drugresistant TB addressed in this Task Force Plan Persons at risk for TB disease often fail to access health-care systems for a variety of complex reasons. A lack of understanding of TB and its symptoms, lack of financial resources (e.g., health insurance or transportation to the clinic), lack of awareness of free clinical services for TB, concerns of deportation and stigmatization, and existence of competing priorities (e.g., shelter and food) all contribute to delays in TB diagnosis and result in prolonged TB transmission in the community. Clinical and programmatic services must be integrated with and closely coordinated with TB laboratory services through a systems approach to ensure successful diagnosis and case management. Once patients access care, lack of familiarity with TB by health-care providers might result in misdiagnosis and inappropriate treatment, which in turn can lead to development of drug resistance and continued transmission of M. tuberculosis. Once a TB diagnosis has been established, providing clinical TB services (preventive, diagnostic, and treatment/ case-management) that are culturally acceptable, affordable and logistically accessible to patients is a prerequisite for successful TB management and treatment completion. Throughout the process of clinical care of TB patients, infection-control practices must be implemented properly, and health-care providers (physicians, nurses, pharmacists, dentists, laboratorians, other allied health professionals, traditional healers) must be educated thoroughly and trained in all principles and practices of TB care. To sustain consistent high quality and prompt care of TB patients, monitoring and evaluation programs must be established to identify rapidly systems failures and implement corrective measures. The elements of the health system that are necessary to prevent the development and transmission of MDR TB and XDR TB have been identified (Figure). Failures at any of the necessary steps related to proper TB diagnosis, treatment and infectioncontrol measures can lead to the development or transmission of drug-resistant TB. # Figure. Prevention of development and transmission of drug-resistant tuberculosis (TB) The United States needs to assist international TB control programs in the development of clinical and programmatic practices that follow international standards for TB diagnosis and care, laboratory services, and infection control. Support should be provided to ensure that TB patients receive services free of charge and have access to DOT through the completion of treatment. The implementation of international informa-tion sharing mechanisms is critical for the prevention of drug resistance and the successful control of TB worldwide. # Problem 30 Initial point-of-contact (POC) providers (e.g., emergency, urgent, primary, and correctional care providers; university health service and occupational medicine clinicians; health department clinicians; civil surgeons † † ; and traditional healers) might not suspect TB or have current or complete information about the diagnosis and/or treatment of TB (see Problem 44). Provide POC providers who serve at-risk persons with education and guidance to increase their knowledge of TB and increase their access to resources to avoid misdiagnosis, prolonged transmission, and inappropriate treatment (domestic). # Action Steps 30.1.1. Promote general knowledge of TB among providers through specific TB curricula and self-study modules. Educate providers about the critical importance of patient-centered case management and how to deliver high-quality services needed to ensure patient adherence and treatment completion. Explain the risks associated with undiagnosed, misdiagnosed, and inappropriately or inadequately treated TB. 30.1.2. Promote practices such as use of treatment regimens on the basis of national guidelines, DOT, prompt adjustment of treatment in response to DST results, patient incentives and enablers to maintain adherence, monitoring of response to treatment, and comprehensive case management in close collaboration with the local TB control program and treatment experts to prevent development and amplification of drug resistance among all TB patients. 30.1.3. Conduct a national media campaign to raise awareness of TB for the general public and health-care providers. 30.1.4. Engage medical professional associations to raise awareness of TB and TB guidelines. 30.1.5. Review TB screening procedures and protocols for institutional facilities and primary care providers to assure competency and develop links between POC providers, local and state health departments and RTMCCs for diagnosis and referral of suspects. 30.1.6. Develop and distribute current regional, national and international MDR/XDR surveillance charts to healthcare providers and public health programs to inform them of high-prevalence areas for MDR TB and XDR TB. 30.1.7. Address health-care provider fears about MDR TB and XDR TB through discussions with medical societies, formal and informal presentations with health-care professionals at meetings, and through targeted mailings. 30 31.1.3. Educate health-care providers on the need for expedited drug-susceptibility testing immediately after an initial TB diagnosis, especially in high-risk congregate settings and in immunocompromised persons, to reduce morbidity and mortality in persons with drug-resistant TB. 31.1.4. Update TB care guidelines to recommend routine HIV testing during initial patient evaluation for TB on the basis of opt-out testing § § recommended by CDC. 31.1.5. Develop and distribute regularly updated regional, national and international MDR TB and XDR TB surveillance charts to health-care providers and public health programs to increase awareness of the extent of drug-resistant disease in patients who do not respond to first-line therapy. 31.1.6. Develop a system of consultation and patient referral between primary care physicians (including HRSA Community Health Centers, primary care HIV clinics, and homeless programs), physicians in correctional or detention settings, departments of health, and RTMCCs to improve diagnosis and management of TB patients, especially those with MDR TB and XDR TB. 31.1.7. Discuss with FDA requirements for review and approval of rapid tests to detect rifampin resistance (RIF) as a primary/surrogate indicator for MDR TB and XDR TB and define special situation where use of rapid RIF assays and other molecular tests to diagnose drug resistance would be appropriate. Lead federal agencies: HHS (CDC, FDA, and HRSA). Suggested collaborators: NTCA, RTMCCs, state and local health departments, and health-care provider professional societies. # Problem 32 Existing diagnostic protocols used for screening foreign-born persons entering, or already residing in the United States, are not sufficient to detect XDR reliably. # Problem 34 The quality of currently available services and treatment for XDR TB patients has not been monitored or evaluated sufficiently. Improve the quality and effectiveness of free clinical services, medications and treatment regimens as part of patient-centered management for patients with XDR TB (domestic). # Action Steps 34.1.1. Develop and implement fully supported, improved patient-centered clinical services for outpatient management of persons with XDR TB that ensure full cooperation and maximum chance of success. 34.1.2. Develop and implement procedures and due process and recommendations for legal recourse for management of § § Defined as performing HIV testing after notifying the patient that the test will be performed and consent is inferred unless the patient specifically declines. XDR TB patients refusing treatment or care to minimize risk to communities (see Problems 39, 41, and 42). 34.1.3. Identify centers of excellence for in-patient treatment of MDR TB and XDR TB that are available for consultation on and referral of XDR TB patients to optimize care and increase likelihood of cure. 34.1.4. Evaluate whether XDR TB centers of excellence might be developed as national referral centers for all patients with XDR TB to provide the best possible care, increase treatment success and reduce transmission to others. 34.1.5. Develop procedures for transfer of patients to referral centers and identify funding to support the cost of treating and managing XDR TB patients. 34.1.6. Establish programs to facilitate collaboration between XDR TB centers of excellence and the RTMCCs for ongoing medical education, consultation, and technical assistance to community providers on all aspects of care of MDR TB and XDR TB patients. 34.1.7. Develop processes and procedures for referral and care of patients who are in legal custody during inpatient or outpatient treatment to ensure appropriate discharge and continuity of care when released from custody or transferred to a different detention facility or law enforcement agency. 34.1.8. Develop processes to request a stay of removal for patients slated for deportation to a country where treatment is not likely to be available and establish procedures and resources to complete TB treatment in the United States, including provision of secure environments, if appropriate. Lead 38.1.5. Review the technical instructions for panel physicians ¶ ¶ who conduct TB screening as part of immigration procedures with regard to XDR TB diagnosis and contact management and develop a process to certify panel physicians. 38.1.6. Support and recommend the use of fixed-dose drug combinations when appropriate and provide training and technical assistance to improve TB drug management. 38.1.7. Provide technical assistance through full-time consultants to ministries of health in countries that are sources of large numbers of U.S. immigrants and countries with a high burden of drug-resistant TB to support completion of ongoing drug-resistance surveys and the establishment of drug-resistance surveillance systems. 38.1.8. Provide resources and support to establish U.S.transnational TB case management programs such as international referral programs and information-sharing system. Lead federal agencies: USAID, HHS (CDC, HRSA), and DHS (ICE). Suggested collaborators: DOS, WHO, IUATLD, Green Light Committee (GLC), Medicins Sans Frontieres (MSF), and KNCV. # Ethical and Legal Issues TB is a reportable infectious disease, and public health protection and TB control activities are described in specific state laws. Many existing laws were established before the contemporary public health recommendations for the prevention and control of TB became available (6,35). As a result, the Advisory Committee for the Elimination of Tuberculosis (ACET) and CDC conducted a survey of state TB control laws and regulations and developed recommendations that addressed legal issues of TB control in the United States. Since these recommendations were published (29), no systematic follow up has been conducted to determine the extent to which these recommendations were implemented. # Problem 39 Laws and regulations permitting authorities to compel treatment and isolation of patients with tuberculosis vary by state. Suggested collaborators: state and local health departments, law schools, and national justice and health ministries. # Problem 41 The effectiveness of mandated isolation or quarantine to compel treatment for TB patients as compared to less restrictive measures, and the ethical issues associated with these measures, have not been evaluated closely. Develop guidelines and a research agenda to determine the effectiveness of and ethical issues associated with compelling treatment and isolation for TB patients who are considered a threat to public health (domestic). # Action Steps 41.1.1. Conduct research to determine the impact and effectiveness of mandatory isolation to compel treatment for tuberculosis as compared with less restrictive measures. 41.1.2. Conduct research on ethical issues of mandated isolation (or quarantine) and less restrictive measures to compel treatment for tuberculosis. 41.1.3. Convene a workshop for bioethicists and TB control, care, and research professionals to identify and catalog key ethical issues likely to be confronted as part of the XDR TB response. Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ. Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists). # Problem 42 Patients with XDR TB could require prolonged isolation measures regardless of the patient's adherence to treatment, which might present an ethical dilemma in balancing the interests of public health with those of the patient. Develop guidance on ethical issues pertaining to prolonged isolation of patients with XDR TB who are fully adherent to treatment (domestic). # Action Steps 42.1.1. Conduct research on ethical considerations of prolonged, mandated isolation including contexts of fully adherent patients and those who are in the terminal stages of disease. Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ. Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists). # Problem 43 Obstacles to compassionate use of experimental chemotherapeutic agents for patients with XDR TB limit critically important therapeutic options. # Communication and Education Comprehensive and tailored information on TB and drugresistant TB including XDR is needed for many different audiences. In the United States, private health-care providers (i.e., those not in public health departments) receive little education or training on detection and appropriate treatment of TB (11,30,31,(36)(37)(38). As a consequence, infectious TB often goes unrecognized, even if a patient presents to a physician with apparent signs and symptoms of active disease. This has led to incorrect treatment, prolonged transmission of TB in the community, and creation of drug-resistant organisms. Education and communication must be appropriately targeted to health-care providers and patients to improve awareness and guide access to competent clinical services. Community leaders and health policy makers, including public health officials, must be well informed about the need to communicate and address issues that can fuel the development and spread of drug-resistant TB in their communities. Education efforts should clearly outline the critical elements that must be applied to prevent and control TB in various settings and risk populations (34). Clear, concise messages, easy to understand yet comprehensive education materials and medical alerts should be developed and disseminated to the general public, TB patients, physicians and other health-care workers, health advocacy organizations, and decision makers, including legislators. These communications should be coordinated across Federal agencies and updated as necessary. Increasing awareness of the signs and symptoms of TB and the appropriate treatment and control strategies, must become a priority in the United States to ensure TB is recognized and treated as a public health threat with the potential to result in virtually untreatable forms of disease, such as XDR TB. In TB-endemic countries where cases of drug-resistant TB are increasing, health authorities must also remain informed about the risk for and incidence of XDR TB. There, provider education initiatives must also focus on the need for appropri-ate case management, including knowledge regarding locally and regionally available specialty resources and medications and the consequences of inappropriate or inadequate treatment of drug-resistant TB. # Problem 44 Health-care providers and the general public are not wellinformed about the symptoms, appropriate, diagnosis, treatment, and prevention of drug-susceptible and drug-resistant TB including XDR TB. Develop education mechanisms and materials, targeted to public and private health-care providers and other workers who might come into contact with populations with a high prevalence of TB infection and disease in settings such as health-care facilities, homeless shelters and correctional facilities, about drug-susceptible and drug-resistant TB including XDR, heighten awareness and encourage appropriate prevention, diagnosis, treatment, and referral (domestic). # Action Steps 44.1.1. Review and update existing education materials and communication products on TB to include relevant information about drug-resistant forms of disease. 44.1.2. Identify communication gaps and special needs for education and communication products regarding drugsusceptible and drug-resistant TB and develop new materials as needed. 44.1.3. Communicate to health-care providers appropriate measures to prevent MDR TB and XDR TB, including the importance of detecting and treating LTBI and TB disease and the importance of prompt reporting of TB cases to proper health authorities. 44.1.4. Communicate to health-care providers the importance of consulting and engaging TB experts in the medical management of MDR TB patients to avoid the development of XDR TB and to ensure that appropriate specialized resources for treatment of drug-resistant TB are optimally used. 44.1.5. Familiarize health-care providers serving high-risk patients with TB training and medical consultation resources that are available through the RTMCCs. 44.1.6. Contribute to the dissemination and promotion of infection-control guidelines and supporting education materials in the United States (28) and globally (39). 44.1.7. Develop strategies and materials on TB and MDR TB and XDR TB diagnosis, treatment, and reporting for dissemination at national medical and laboratory meetings. 44.1.8. Develop education materials for digital mass media, such as the Internet, personal digital assistants, and podcasts to reach and inform health-care providers about control of all forms of TB. 44.1.9. Develop and distribute targeted education material to health-care providers and nontraditional partners who are not usually engaged in TB control activities such as primary care and nurse practitioners, physician assistants, emergency care and urgent care specialists, health-care providers in correctional facilities, civil surgeons, pharmacists, foreign-trained clinicians, non-U.S. health-care providers, university health service, occupational medicine specialists, rheumatologists, oncologists, radiologists, laboratories, traditional healers, NGOs, and CBOs. 44.1.10. Present specialty-specific information about care and control of all forms of TB at professional conferences. 44.1.11. Develop targeted TB training and education for other workers who might be exposed to TB in settings such as health-care facilities, homeless shelters and correctional facilities. Lead federal agencies: HHS (CDC, NIH, and HRSA). Suggested collaborators: RTMCCs, NTCA, ATS, American College of Chest Physicians (ACCP), IDSA, American Medical Association (AMA), American Association of Family Practitioners (AAFP), and APHL. Develop education mechanisms and materials to inform decision makers in the public and private sectors about priorities and strategies for the prevention and control of TB and MDR TB and XDR TB (domestic). Establish and maintain mechanisms to facilitate regular communication among federal agencies, and with state and local TB control programs (domestic). # MMWR February 13, 2009 Action Steps 44.4.1. Regularly update and disseminate information by the CDC, WHO, and other agencies on MDR TB and XDR TB to federal staff, TB control programs, HIV/AIDS programs, and other public health agencies and interested organizations to ensure that U.S. public health programs are well informed about the incidence and prevalence of drug-resistant TB in the United States and globally. 44.4.2. Identify federal TB Task Force members to serve as key spokespersons for issues related to MDR TB and XDR TB while ensuring that all Task Force members are well informed to contribute to the ongoing dissemination of information on all forms of TB. 44.4.3. Communicate on a regular basis efforts and relevant results and outcomes related to prevention and control of MDR TB and XDR TB by federal agencies. Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: NTCA and state and local health departments. # Research Biomedical research in TB creates a foundation of knowledge that informs the development of new health-care interventions as well as control and prevention strategies for drug-resistant TB. While U.S. federal agencies have substantially contributed to research in TB and the identification of drugs, vaccines and diagnostics, the emergence of more difficult to treat forms of drug-resistant TB will require renewed and more targeted efforts to help control and prevent the development and transmission of drug-resistant forms of TB. One compilation of biomedical research priorities related to MDR TB and XDR TB has been published (7). TB therapy was revolutionized in the 1940s by the development of antibiotics by academic and for-profit organizations, and the demonstration of their efficacy and safety in randomized clinical trials largely conducted by the public sector. These therapies became the basis for the global DOTS strategy for TB control. Although initially highly effective in reducing the incidence and prevalence of TB in endemic countries, the continued success of the DOTS strategy is now seriously threatened by the emergence of highly drug-resistant strains of M. tuberculosis. Furthermore, interactions between TB and HIV medications and drugs used in the treatment of specialized problems such as diabetes, drug addiction and mental disorders (conditions that are encountered in populations at risk for TB) might substantially complicate the development of effective new TB drugs. To ensure the continued availability of effective therapeutics against all forms of TB, the development of new, safe, and effective TB drugs must remain a high priority. Success in TB drug development will also heavily rely on the establishment and continued support of competent, experienced trial sites in TB and TB/HIV endemic countries for all phases of clinical testing. # Problem 45 Few new TB drugs are in preclinical and clinical development. Increase the number of candidates in all stages of the TB drug development pipeline to increase the likelihood that new agents will become available for clinical use within the next 5-10 years (domestic and international). # Action Steps 45.1.1. Increase communication between private not-forprofit and commercial organizations and relevant public sector agencies to identify opportunities for public/private collaborations in TB drug development. 45.1.2. Reevaluate, refine, and optimize support for drug discovery and preclinical studies for pharmaceutical companies and academic/not-for profit organizations (in vitro and animal models). 45.1.3. Encourage pharmaceutical companies, academic researchers and nonprofit organizations to engage in TB drug development research and development efforts. Lead federal agencies: HHS (CDC, FDA, and NIH) and USAID. Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, and academia. # Problem 46 The global capacity to conduct clinical trials for new drugs that treat TB and MDR TB and XDR TB is limited. # Problem 47 Well-validated surrogate markers do not exist to rapidly assess clinical efficacy of new chemotherapeutic agents and regimens against drug-susceptible and MDR TB and XDR TB. Lead federal agencies: HHS (CDC, FDA, and NIH). Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia. # Problem 49 The types of clinical data needed to support registration of new chemotherapeutic agents against TB have not been clearly defined making it difficult to design effective clinical development plans and timelines. Establish a forum for discussion between U.S. and international regulatory agencies to define specific guidance for clinical development and approval of chemotherapeutic agents indicated for use in MDR TB and XDR TB (domestic and international). # Fundamental Science The foundation for development of new health-care interventions in TB is a solid understanding of the interaction between M. tuberculosis and the host and how infection transitions to active disease. Knowledge acquired through basic research in these areas must be effectively leveraged in translational science (i.e., research that translates basic scientific discoveries into clinical applications). As a consequence of the sequencing of the genome of both the host and pathogen, the development of molecular tools to manipulate the pathogen, the establishment of genomic and postgenomic technologies and tools, and the expansion of animal models available to study TB, many important questions in the pathogenicity of TB now can be addressed. Although considerable progress in fundamental science (basic and translational) of TB has been made over the past decade, the availability of more tools, technologies and advanced methodologies has made it possible to create new hypotheses and revisit earlier observations to contribute to a more detailed understanding of the best points of intervention in TB treatment, necessary characteristics of potential new TB vaccines, and what host/pathogen factors might be early indicators of infection, disease, drug resistance, and transmission. In addition, the effectiveness of current and new infection-control measures, such as negative pressure, high-efficiency particulate air filters, laminar flow, ventilation design on the basis of modeling approaches (e.g., computational fluid dynamics, ultraviolet germicidal irradiation, room air cleaners, and alternative air disinfection methodologies) should be evaluated in appropriate research settings. # Problem 52 The characteristics of M. tuberculosis (e.g., growth, physiology, biochemistry, genetics, and molecular biology) are incompletely understood. 52.1.6. Continue to provide high quality research reagents to facilitate TB research. 52.1.7. Expand efforts to identify and validate novel drug targets, vaccine strategies, diagnostic markers and research tools. 52.1.8. Encourage and support research on genomics of both M. tuberculosis and human/animal hosts, linking to genetic epidemiologic research to direct studies in transmission, pathogenicity, microbial host interactions, and disease progression. 52.1.9. Support studies to characterize manifestations of TB in pediatric and immunocompromised populations. Lead federal agencies: HHS (CDC and NIH) Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia. # Problem 53 The effectiveness of various individual strategies for preventing TB transmission has not been sufficiently evaluated in domestic and international health-care settings. 53.1.3. Support research and efforts to develop effective, affordable methods for expedient isolation of contagious patients that do not require major facility modifications. 53.1.4. Encourage and support cost analyses for modifying existing health-care settings, correctional and detention facilities, homeless shelters, community residences for special needs populations and other high-risk institutional settings to achieve compliance with current and future infection-control requirements. 53.1.5. Support research to characterize dose-infection relationships for airborne M. tuberculosis to inform risk assessment of infection in relation to reductions in exposure. 53.1.6. Develop protocols and support studies to evaluate the effectiveness of various administrative controls on the reduction of TB transmission. 53.1.7. Support research to objectively document and improve the ability of various environmental controls to reduce exposure to airborne M. tuberculosis. 53.1.8. Support research to develop objective measures to document and compare the ability of various respiratory protective devices to reduce exposure to M. tuberculosis and to establish evidence-based recommendations for use of nationally certified respirators providing the appropriate level of protection. Lead federal agencies: HHS (CDC and NIH), DHS (ICE), and DOJ (USMS and BOP). Suggested collaborators: OSHA, WHO, health-care facilities, academia, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai) # Diagnostics The prompt and correct diagnosis of drug-susceptible and drug-resistant TB is one of the cornerstones of effective TB control. Current diagnosis of pulmonary TB in endemic countries is limited to clinical evaluation combined with low sensitivity microbiologic tests. Available diagnostics do not offer the speed and sophistication needed to provide physicians in the field in high-burden countries with the information required to accurately diagnose drug-susceptible and drugresistant TB and to prescribe the most appropriate treatment regimens. Although certain diagnostics platforms might be technologically too advanced for field use in resource limited countries, these tests might nevertheless provide a substantial contribution to the advancement of new therapeutics for TB by allowing rapid assessment of response to therapy in clinical trials. Such measures are critical in settings with patients with extrapulmonary TB and those where drug-susceptibility testing is not possible or delayed. Furthermore, rapid assessment of response to therapy will help determine whether adequate regimens have been prescribed and might contribute to limiting the development of drug resistance. # Problem 54 Rapid, point-of-care identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB among HIV-negative and HIV-positive adults and pediatric populations ands reliable early identification of latent M. tuberculosis infection are not yet possible (see Problem 15). Develop rapid, point-of-care diagnostics for the reliable identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB disease and latent infection including in HIV infected patients and pediatric populations (domestic and international). # Vaccines Long-term control and ultimate elimination of TB likely will require an effective vaccine (40). Research to characterize needs for an effective vaccine, on the basis of immunological responses of persons infected with M. tuberculosis who do not become ill and animal models and comparisons with the currently used vaccine M. bovis Bacille Calmette-Guerin (BCG) have been supported for over a decade. BCG vaccine, usually administered once in infancy in countries with a moderate and high incidence of TB, is effective in preventing TB meningitis and disseminated TB in children but has highly variable efficacy in preventing other forms of TB, especially in adults (41). Strategic plans for a TB vaccine have been developed, and support for biomedical research for the development of new, more effective vaccines and vaccinations strategies has resulted in progress to the point where several new vaccine candidates are now being evaluated in clinical trials. Nevertheless, a highly effective vaccine has remained elusive. Increased capacity to allow entry of novel vaccine candidates into Phase I clinical studies and comparative studies of vaccine platforms in human trials will contribute substantially to understanding development needs for effective TB vaccines. However, assays and methodologies for preclinical validation and clinical characterization need to be standardized globally. Clinical trial protocols for the assessment of vaccination strategies and the development of expertise to conduct clinical trials and immunological assays in TB endemic countries are needed to establish a robust infrastructure for TB vaccine research and development (R&D). # Problem 56 Current preclinical and clinical efforts in TB vaccine development are not optimally coordinated. # Behavioral, Social, Clinical, and operational Science Current TB therapy is complex and lengthy, and it can be associated with adverse reactions to medications. Patient adherence often is difficult, leading to discontinuation of therapy; this results in relapse, continued transmission of disease, and, in some cases, the development of drug-resistant TB. Adherence is influenced by patient characteristics, differences in healthcare seeking behavior, assumptions about disease, the healthcare environment, the availability of adherence-enhancing interventions, the quality of communication between patients and providers, the availability and use of education materials to inform patients and families about TB, treatment and consequences of defaulting, the convenience of access to drugs for supervised treatment, and the quality of drugs available through TB control programs. The complexity of factors underlying patient adherence and the importance of completing treatment for TB necessitates increased emphasis on patient-centered treatment options and a thorough understanding of behavioral and social interventions that have to be in place to augment traditional TB control approaches. Operational research to improve care programs must include studies to characterize TB health services, case and data management practices, staff selection, training and retention incentives, physician training, management and organizational structure, relationships with the community, community perceptions of services, community resistance to public health services, and clinic policies and practices to provide the best possible environment for ensuring patient trust and treatment completion. # Problem 57 Patient adherence to TB chemotherapy is not optimal, and alternative methods for ensuring completion of therapy are not fully developed. Identify alternatives and adjuncts to currently used treatment protocols through behavioral research to improve adherence to therapy (domestic and international). # Problem 58 Operational and clinical questions related to patient adherence and optimal organization and structure of health services to ensure effective TB care remain unanswered. # Partnerships Because XDR TB presents a worldwide threat, a coordinated international response will rely on effective partnerships between all organizations and governments that are involved in TB control programs, TB biomedical research and product development (Box). In addition, the establishment of new alliances is needed to fill the critical gaps in the global response identified in this report. Currently, government agencies at all levels, international organizations, nongovernment organizations (NGOs), academic institutions, and the private sector are coordinating their efforts as members of the STOP TB Partnership. Furthermore, cross-disciplinary research and product development efforts are brought together through various nonprofit organizations focused on developing affordable and effective drugs, vaccines and diagnostics. Representatives from United States government agencies are actively involved in these partnerships and contribute their knowledge and expertise to help address the national and global aspects of XDR TB. The U.S. Federal Tuberculosis Task Force serves as a mechanism to coordinate activities of various federal agencies that are involved in domestic and international TB prevention and elimination programs. Domestically, U.S. government agencies work closely with local and state TB control programs, academic institutions, professional associations, and pharmaceutical companies to assure the most effective use of available resources and to minimize duplication of effort. The expansion of existing partnerships to include management and prevention of XDR TB and other forms of drug-resistant TB will be important if TB is to be eliminated in the United States and worldwide. # Problem 59 Differing jurisdictions among public health agencies, scopes of work among nongovernment organizations, and varying country-specific public health policies, economic conditions, and political commitments pose a substantial barrier to launching and focusing a coordinated response to TB (MDR TB and XDR TB and HIV/TB) in high-burden settings with the greatest needs. Optimize integration, coordination and synergy between U.S. government agencies, international organizations, and national TB/HIV programs to achieve reduction in disease rates through more focused prevention/intervention activities for MDR TB and XDR TB and HIV/TB and nonduplicative allocation of funding, staff and resources (international). # Action Steps 59.1.1. Develop programs or working groups to maximize cooperation between international organizations and to align resources for an efficient, resource sparing response in highburden countries. 59.1.2. Establish additional interagency agreements to formalize existing cooperative efforts, where feasible. Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: WHO, STOP TB, IUATLD, KNCV, ministries of health, and national and local National TB Program (NTP) staff. # Problem 60 Currently available global funds are insufficient to mount a comprehensive response to XDR TB, particularly in settings with high rates of HIV/TB co-infection. Resources need to be focused on this emerging threat, on the basis of identification of specific needs. # Problem 61 Globally, human resources at all levels in national TB programs are insufficient and maintaining a well qualified workforce has been difficult due to the continuous exodus of qualified, experienced TB and/or HIV staff. Domestically, the number of medical professionals with experience in managing TB patients, much less MDR TB and XDR TB patients, has declined in parallel with TB cases. A critical need is to strengthen human resources at the local and state/provincial/ district level. # Problem 63 Biomedical and product development activities and regulatory activities are not coordinated optimally between U.S. and international governmental and private agencies. Insufficient coordination of research activities exists among the various international entities with commitments to support TB research, or with involvement in related activities such as medical regulation. Establish and maintain partnerships with appropriate organizations within and outside the public health community to increase awareness of XDR TB among policy makers and the general public (domestic and international). # Action Steps 64.1.1. In collaboration with appropriate partners, develop coordinated and consistent education material to promote informed awareness of XDR TB in the U.S. and internationally. Lead federal agencies: HHS (CDC, NIH, and HRSA), USAID, and HUD. Suggested collaborators: WHO, IUATLD, Results International, American Lung Association, Treatment Action Group, local and state health departments, academia, and national ministries of health. # Problem 65 Current public health partnerships are not sufficient to ensure continuity of care for TB patients and their contacts who either reside temporarily in the United States or frequently February 13, 2009 cross its borders. More than half the TB cases in the United States occur among immigrants who become infected before their arrival in the United States. Lack of continuity of care contributes to treatment default, ongoing transmission, and prolonged illness. Partnerships are needed for effective transnational case management. Identify appropriate partners and programs to contribute to projects and strategies that ensure continuity of TB care for patients traveling or migrating into or out of the United States (domestic and international). # Action Steps 65.1.1. Identify domestic and international partners to participate in an assessment of barriers to continuity of care for migrants or traveling TB patients. 65.1.2. Develop and implement transnational partnerships that allow establishment of cross-border TB care and management programs, such as the Bi-National TB Card and transnational referral programs for continuity of TB therapy. 65.1.3. Strengthen partnerships between ICE and TB Programs in countries to which patients are deported while on TB treatment that was initiated in the United States. Lead federal agencies: HHS (CDC and HRSA), USAID, DHS (ICE, CBP), federal courts, and USMS. Suggested collaborators: foreign NTPs and ministries of health, local and state TB programs in the United States and other countries, Cure TB, and TB Net. # Cost Analysis A realistic national estimate of the costs of diagnosing, treating, and managing XDR TB will be an important prerequisite for measuring the benefit and savings to the United States that would be realized through prevention of XDR TB. CDC has estimated the costs for hospitalization of one XDR TB patient at approximately $483,000 (CDC, unpublished data 2007) whereas outpatient treatment costs, productivity losses, patient out-of-pocket expenses, and quality of life changes attributable to XDR TB are unknown. Some of the existing interventions and strategies for TB care and management, such as the use of DOT, already have been demonstrated to be cost effective in preventing the development of MDR TB, but information about additional strategies is currently not available. Analysis of such cost-benefit and cost-effectiveness data will be critical to prioritize programs and advocate for resources to implement specific interventions to help prevent XDR TB. # Problem 66 A comprehensive and up-to-date estimate of the costs of diagnosing, treating, and managing XDR TB in the United States in not available. Conduct a study on the basis of health-care system and societal perspectives to calculate the costs of diagnosing, treating, and managing all cases of XDR TB identified through surveillance for patients and their contacts (domestic). # Action Steps 66.1.1. Identify representative samples or cohorts of XDR TB patients during 2004-2007 (verified and reported, unreported incident and prevalent cases), and their contacts for estimating costs associated with health care and personal productivity. 66.1.2. Estimate from representative samples or cohorts of XDR TB patients the average medical costs incurred on the basis of the extent and pattern of drug resistance, medically indicated procedures and examinations needed to diagnose drug-resistant TB, the length of inpatient and outpatient treatment, management of adverse events and treatment and disease associated chronic sequelae, and the cost of case management of contacts. 66.1.3. Estimate from representative samples or cohorts of XDR TB patients that were employed prior or during XDR TB diagnosis associated losses in personal productivity and salary losses on the basis of the extent and pattern of drug resistance, chronic disease, and the impact of patient mortality (age at death and time to death). 66.1.4. From a survey of XDR TB survivors and their family members, estimate loss of quality-adjusted life years on the basis of extent and patterns of drug-resistant TB disease. 66.1.5. Conduct patient interviews to estimate out-of-pocket medical expenses associated with XDR TB disease. Lead federal agencies: HHS (CDC). Suggested collaborators: state/local Departments of Health, public and private outpatient providers and hospitals, laboratories, former patients, and family members. # Problem 67 Cost-effective strategies to prevent XDR TB remain to be established. 67.1.4. Determine the cost benefit for each prevention strategy in relation to cost that would have been incurred to treat XDR TB. Lead federal agencies: HHS (CDC). Suggested collaborators: state and local health departments, and academia. # Conclusion The nine response areas addressed in this report are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug sensitivity testing, 3) improve technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities. The Federal TB Task Force Plan and the Global Action Plan will require a renewed commitment by all public health workers as well as new resources from both the public and private sectors. In the United States, federal funding has remained relatively level since 2000, and state and local funding has declined in many states since 2000. As a result, TB prevention and control capacity in the United States has eroded. For example, many states have decided to implement selective rather than universal patient-centered DOT to ensure adherence to treatment until complete. These decisions are made on the basis of financial constraints but place the patient at high risk for treatment failure and subsequently the potential creation of MDR TB or XDR TB. In the absence of shorter treatment regimens, and without adherence-promoting measures such as DOT, the TB patient is more likely to experience drug resistance that could result from interruptions in treatment. These choices place the public and the nation in a vulnerable position, risking outbreaks of MDR or XDR TB if conditions facilitate rapid spread and possibly causing public health crises. (42,43) The Federal TB Task Force Plan provides an effective framework to detect, prevent, and control XDR TB, but it also highlights the existence of substantial unmet needs. There is concern that progress in TB prevention and control is waning as manifested by the decrease in the rate of decline in TB incidence since 2000. The United States responded successfully to the MDR TB problem in the 1990s and is capable of preventing and controlling XDR TB; however, this will require a united commitment and effort similar to that which occurred in 1992.	An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States. During 1985-1992, the United States was confronted with an unprecedented TB resurgence. This resurgence was accompanied by a rise in multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin. In addition, virtually untreatable strains of M. tuberculosis are emerging globally. Extensively drug-resistant (XDR) TB is defined as MDR TB that also is resistant to the most effective second-line therapeutic drugs used commonly to treat MDR TB: fluoroquinolones and at least one of three injectable second-line drugs used to treat TB (amikacin, kanamycin, or capreomycin). XDR TB has been identified in all regions of the world, including the United States. In the United States, the cost of hospitalization for one XDR TB patient is estimated to average $483,000, approximately twice the cost for MDR TB patients. Because of the limited responsiveness of XDR TB to available antibiotics, mortality rates among patients with XDR TB are similar to those of TB patients in the preantibiotic era. In January 1992, CDC convened a Federal TB Task Force to draft an action plan to improve prevention and control of drugresistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41([No. RR-11]). In November 2006, CDC reconvened the Task Force to draft an updated action plan to address the issue of MDR TB and XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing problems, identifying barriers to improvement, and recommending specific action steps to improve prevention and control of XDR TB within their respective areas. Although the first priority of the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to address MDR TB and XDR TB domestically, members recognized the necessity for TB experts in the United States to work with the international community to help strengthen TB control efforts globally. TB represents a substantial public health problem in low-and middle-income countries, many of which might benefit from assistance by the United States. In addition, the global TB epidemic directly affects the United States because the majority of all cases of TB and 80% of cases of MDR TB reported in the United States occur among foreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agencies can take to help solve global XDR TB problems. Unless the fundamental causes of MDR TB and XDR TB are addressed in the United States and internationally, the United States is likely to experience a growing number of cases of MDR TB and XDR TB that will be difficult, if not impossible, to treat or prevent. The recommendations provided in this report include specific action steps and new activities that will require additional funding and a renewed commitment by government and nongovernment organizations involved in domestic and international TB control efforts to be implemented effectively. The Federal TB Task Force will coordinate activities of various federal agencies and partner with state and local health departments, nonprofit and TB advocacy organizations in implementing this plan to control and prevent XDR TB in the United States and to contribute to global efforts in the fight against this emerging public health crisis.# Introduction Global Health Burden of Tuberculosis Tuberculosis (TB) is among the most common infectious diseases and frequent causes of death worldwide (1). TB is caused by Mycobacterium tuberculosis and is spread most commonly by airborne transmission. M. tuberculosis can affect any part of the body but is found most often in the lungs. Persons with pulmonary TB generally have a cough that produces small airborne droplet nuclei containing tubercle bacilli that can remain in the air for hours. Vulnerable persons exposed to tubercle bacilli in airborne droplets might become infected. The majority of persons who become infected remain noncontagious and without a cough or other symptoms. These persons have latent M. tuberculosis infection (LTBI) and can be treated with a single drug (isoniazid) for 9 months to prevent disease. Infected persons who do not have underlying medical problems and do not receive LTBI treatment have a 5%-10% lifetime risk for progressing to TB disease (2). However, the risk for disease progression increases substantially in the presence of immunosuppression, such as that caused by the human immunodeficiency virus (HIV) and immunosuppressive medications (2). Persons with pulmonary TB can be cured with a 6-month course of antibiotics that includes isoniazid, rifampin, pyrazinamide, and ethambutol during the first 2 months. In the United States, diagnosis and treatment for TB is accessible and effective (3). However, many developing countries have limited resources to diagnose TB illness and treat persons with TB. Worldwide, 2 billion persons (one third of the world's population) are thought to have LTBI. Nearly 9 million persons develop TB disease each year, and close to 2 million TB-related deaths occur annually (1). In the United States, approximately 13,000 new cases of TB are reported annually, and 650 persons die from TB each year (4). TB is the leading cause of mortality among persons infected with HIV (5). # Emergence of Drug-Resistant Tuberculosis During 1985-1992, the United States experienced an unprecedented TB resurgence marked by a substantial number of patients with TB who did not respond to treatment and who eventually died (6). Physicians and epidemiologists quickly determined that these persons had multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to both isoniazid and rifampin (7). Although persons with MDR TB usually can be treated effectively by relying on second-line drugs (amikacin, kanamycin, or capreomycin), these have more side effects and are more expensive and less effective than first-line drugs and require regimens lasting 18-24 months (3). In addition, the cure rate for persons with MDR TB is 50%-60%, compared with 95%-97% for persons with drug-susceptible TB (3). In response to several MDR TB outbreaks in hospitals and correctional facilities in New York and Florida during 1988-1991 (8,9), CDC convened a Federal TB Task Force* with representatives from multiple U.S. agencies † to produce recommendations for a nationwide response to the MDR TB outbreaks. In June 1992, the Federal TB Task Force published an action plan that provided a framework for response and specific action steps for state and local health departments and federal agencies (7). These action steps were grouped into nine categories: 1) surveillance and epidemiology, 2) laboratory diagnosis, 3) patient management, 4) screening and preventive therapy, 5) infection control, 6) outbreak control, 7) program evaluation, 8) information dissemination/training and education, and 9) research. Emergency federal funding was appropriated to CDC in 1993 and again in 1994 to allow the Federal TB Task Force and state and local health departments to implement certain parts of the plan. For example, CDC investigative teams were deployed to assist local programs in defining and organizing appropriate response to MDR TB outbreaks (CDC, personal communication, 2007). State and local health departments enhanced diagnostic laboratory capacity, increased the sensitivity of their surveillance systems, improved infection-control practices, and reemphasized the need for optimal treatment of all forms of TB to prevent the development and further transmission of MDR TB. Other federal agencies that are members of the task force also contributed substantially to implementation of the plan; a description of their activities follows. The need for increased biomedical research and product development for TB was recognized by the National Institutes of Health (NIH) as part of the implementation of the 1992 Action Plan. The National Institute for Allergy and Infectious Diseases (NIAID) established extramural and intramural research programs in all areas of fundamental, translational, and clinical research in TB to create a platform of knowledge and the research tools needed to study M. tuberculosis and its interaction with the host and to characterize TB in animal models and humans. In June 2007, NIAID released a research agenda describing the specific biomedical research challenges and priorities that should be addressed in response to the emergence of drug-resistant TB (10). The National Heart, Lung, and Blood Institute (NHLBI) supported studies with a strong emphasis on pulmonary TB, including complications through coinfection with HIV, and developed a training curriculum in TB for health professionals at medical institutions through the National Tuberculosis Curriculum Consortium (NTCC) (11,12). The Fogarty International Center (FIC) supported TB research and research training for developing country scientists through collaborative grants with U.S. institutions (13). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) focused on international clinical research for optimizing TB treatment in children and women coinfected with HIV (14). The more recently created National Institute of Biomedical Imaging and Bioengineering (NIBIB) has a substantial investment in diagnostic platform technologies (point-of-care and imaging) that can help improve TB diagnosis through advances in medical imaging methods (15). In May 1994, the Food and Drug Administration (FDA) approved Rifater (a fixed-dose combination of rifampin, isoniazid, and pyrazinamide) to facilitate patient adherence with lengthy and complex multidrug therapy (16). In addition, FDA granted a priority new drug application review for the drug rifapentine, which was approved in July 1998 for the treatment of TB (17). In 1993, the United States Marshals Service (USMS) established a formal medical program for prisoners with TB (USMS, personal communication, 2007). As part of this activity, USMS drafted a series of advisory memoranda to provide education information and guidance to USMS field offices to support TB screening for staff and prisoners. USMS also collaborated with the Texas Department of Health to conduct presentations on TB control in correctional facilities highlighting patient tracking and follow-up issues that arise when transferring prisoners between and outside jurisdictions. The Department of Housing and Urban Development (HUD) developed web-based information and training activities on acquired immune deficiency syndrome (AIDS) and TB (HUD, personal communication, 2007). Since 1998, with the creation of specific international TB programs (e.g., directly observed treatment, short-course [DOTS] expansion; research; training; and TB/HIV coinfection), the U.S. Agency for International Development (USAID) has provided technical and financial support to strengthen TB control programs worldwide (18). USAID also has supported drug-resistance surveys with biannual global reports and pilot programs to optimize MDR TB treatment and the Green Light Committee (GLC), which helps countries gain access to high-quality second-line TB drugs so they can provide treatment for persons with MDR TB (19). More recently, the Division of Immigration Health Services (DIHS) of the Health Resources and Services Administration (HRSA) implemented a national TB Continuity of Care Program for persons who are detained by U.S. Immigration and Customs Enforcement (ICE) agents in the Department of Homeland Security (DHS) and who are to be deported before completing TB therapy (20); in October 2007, DIHS was transferred from HRSA to ICE. In addition, U.S. government agencies have worked with their counterparts in Mexico and in U.S. state agencies to develop initiatives (e.g., Ten Against TB) to address TB, including drug-resistant TB, along the U.S.-Mexico border (21). During 1993-2007, as a result of implementation of the 1992 Action Plan, the reported annual incidence of MDR TB in the United States declined 75%, from 485 cases in 1993 to 119 cases in 2007 (4). # Emergence of Extensively Drug-Resistant Tuberculosis Since 1993, both incidence of TB and the total number of TB cases in the United States have decreased, although the rate of decline has slowed since 2000. Worldwide, the number of TB cases has continued to increase, but the incidence rate has decreased since 2003. Recently, highly drug-resistant forms of TB have emerged worldwide. In 2006, CDC, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) reported the results of a survey regarding drug-resistant TB conducted by 25 reference laboratories comprising the Global Supranational TB Reference Laboratory Network (2000)(2001)(2002)(2003)(2004), the National TB Surveillance System in the United States (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), the national reference laboratory of South Korea (2004), and the national MDR TB patient registry in Latvia (2000-2002) (22). The findings indicated that 20% of M. tuberculosis isolates were MDR, and 2% also were resistant to multiple second-line drugs. This highly resistant form of TB was identified in every region of the world, including the United States, where 4% of MDR TB isolates also were resistant to multiple second-line drugs. In a report published in 2006, this highly resistant form of TB was named extensively drug-resistant TB (XDR TB) (22). XDR TB is a subset of MDR TB that is resistant both to isoniazid and rifampin and to any fluoroquinolone drug and at least one of three second-line injectable drugs (amikacin, kanamycin, or capreomycin) (23). The emergence of XDR TB raises concerns about the possibility of epidemics of virtually untreatable TB. Such epidemics could result in excessive mortality and substantial financial and infrastructure burden for public health and TB control programs. XDR TB is much more expensive to treat, with hospitalization costs in the United States estimated to average $483,000 per case. A major outbreak of XDR TB in the United States would constitute a substantial drain on public health resources and could quickly deplete the existing state and local TB budgets and have a negative impact on progress toward TB elimination. This is especially true in an era of diminishing resources for TB control at the national, state, and local levels (6). Treatment failures and subsequent death are more common among patients with XDR TB, and the drugs available to treat XDR TB are associated with serious adverse effects. Because persons who are infected with HIV or who have other immune-compromising conditions (e.g., diabetes) are more vulnerable to progressing to active TB disease, infection with XDR TB is of particular concern among these persons. In countries with high rates of HIV and limited health-care resources, substantial numbers of XDR TB cases are likely present. As of April 2007, South Africa (where HIV prevalence was estimated at 10.8% in 2005) had reported 352 cases of XDR TB, with the actual prevalence likely being much higher (24) because cultures and susceptibility testing are performed on only a small fraction of TB patients, and many drug-resistant cases will go undetected. # Methodology After an outbreak of XDR TB among HIV-infected persons in Kwazulu Natal, South Africa, reported in August 2006, urgent expert consultations were organized by the South African Medical Research Council (SAMRC) and WHO in September and October 2006 (25). The result of these consultations was the 2007 publication of a global MDR TB and XDR TB response plan with eight overarching objectives (26). Several U.S. government agencies, including CDC, participated in the expert consultations. The U.S. Federal TB Task Force was recognized as the appropriate venue to coordinate U.S. involvement in the global response to XDR TB. In November 2006, following participation in the SAMRC and WHO XDR TB consultations, CDC convened members of the Federal TB Task Force to discuss the emergence of XDR TB and coordinate U.S. government agency involvement in the domestic and international response to this problem. After several teleconferences, the Task Force agreed that a U.S. government agency action plan should be written. The action plan that had been published in 1992 to respond to MDR TB was selected as a basis for drafting the XDR TB response plan (7). Several members of the 2006 Task Force also had contributed to the 1992 Action Plan to combat MDR TB. This MDR TB expertise contributed substantially to a well-informed and effective discussion and the creation of an Action Plan to Combat Extensively Drug-Resistant TB. As had occurred in the process to create the 1992 Action Plan, members of the Federal TB Task Force were divided into sections to address critical areas of response. The 1992 action plan distributed the objectives and implementation steps needed to address 38 problems among nine response areas (surveillance and epidemiology, laboratory diagnosis, patient management, screening and preventive therapy, infection control, outbreak control, program evaluation, information dissemination/training and education, and research). Although largely overlapping with the 1992 action plan, the response areas for the XDR TB plan were reorganized as follows: 1) diagnostic laboratory; 2) surveillance, epidemiology, and outbreak investigations; 3) infection control; 4) clinical and programmatic interventions; 5) ethical and legal issues; 6) communication and education; 7) research; 8) partnerships; and 9) cost analysis. These response areas also are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug-sensitivity testing, 3) improve the technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities. In addition, the implementation steps were renamed "action steps." In January 2007, each subgroup of the Federal TB Task Force that was responsible for addressing a critical response area began by reviewing the relevant sections of the 1992 action plan to determine which problems, objectives, and action (formerly implementation) steps needed to be deleted or updated and revised. The subgroups also determined if gaps existed requiring the identification of additional problems, objectives and action steps. In particular, because the 1992 plan had focused primarily on domestic MDR TB, the subgroups were instructed to expand the scope of the new plan to address the role of U.S. government agencies in the international response to XDR TB. To reflect this distinction, the new plan labels objectives as domestic, international, or both. The expanded scope and a greater emphasis on detail resulted in a substantial increase in the number of problems, objectives, and action steps identified compared with the 1992 plan. For example, the number of problems increased from 38 in 1992 to 67 in the current plan. An emphasis also was placed on being as inclusive as possible when designating lead federal agencies and potential external partners. To provide a basis for revisions, the subgroup members reviewed pertinent literature published since 1992, which is substantially more voluminous, especially for drug-resistant TB, compared with that available before 1992, and available unpublished data. After drafts of the sections were completed, the sections were compiled into a single document that was distributed to the entire Federal TB Task Force for review and comment. In June 2007, the Federal TB Task Force met in Rockville, Maryland, to make additional revisions, especially to eliminate redundancies between sections. These revisions were incorporated into a final draft that was submitted for multiple agency clearance in September 2007. # Recommendations to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory The diagnosis of XDR TB is established by laboratory methods. Accurate, reliable, and prompt TB laboratory services should be coordinated fully with provider and public health practitioners caring for persons with TB. Test results must be available in a time frame that allows clinicians to make prompt and informed patient management decisions. For this goal to be met, laboratory capacity for the diagnosis of TB and the detection of drug resistance must be rapidly enhanced, both in the United States and worldwide. Adequate infrastructure must be built where it does not exist, a stable and well-trained work force must be developed and maintained, and a systems approach (27) must be implemented to maximize efficiency and proficiency. Laboratory methods and reporting, especially for susceptibility to second-line drugs, should be standardized through expert consensus. Rapid tests for TB diagnosis and drug-susceptibility testing on the basis of newer molecular methods must be evaluated promptly to determine their feasibility, especially for low-resource settings, and, if appropriately validated, their use should be promoted and facilitated. Internationally, competent, high-quality reference laboratory services with capacity to perform required testing of samples and to report results in a prompt fashion to providers and health officials must be available to jurisdictions in need. # Surveillance, Epidemiology, and outbreak Investigation Domestic XDR TB surveillance must include accurate and complete reporting of second-line drug-susceptibility testing, real-time reporting, and active case finding. Central notification of MDR TB and XDR TB is essential to identify cross-jurisdictional issues and to provide potential for rapid emergency federal support, when needed. Internationally, rapid drug-susceptibility test (DST) surveys and more sustained systematic capture of DST information are highlighted as areas to be addressed as part of a comprehensive response to XDR TB. Epidemiologic studies that make use of genotyping tools are recommended to elucidate XDR TB risk factors and transmission dynamics. Strategies also are needed to rapidly identify and respond to domestic and international XDR TB outbreaks. # Infection Control Effective infection-control practices are critical to prevent the transmission and further spread of MDR and XDR TB in health-care settings and other congregate settings (e.g., correctional facilities and homeless shelters). CDC infectioncontrol guidelines were updated in December 2005 and should continue to be updated as needed (28). Further studies are needed to assess the effectiveness and feasibility of various infection-control strategies in different institutional settings. Testing workers for TB in various institutional settings is an important strategy for identifying workers infected with TB and detecting unsuspected transmission. # Clinical and Programmatic Interventions Prevention and control of TB in the United States require a robust public health infrastructure that includes a workforce trained in TB prevention, diagnosis, treatment, and case management. Because some patients fail to recognize TB symptoms, health care often is not sought during early stages of disease. In addition, providers who are unfamiliar with signs and symptoms of TB and with diagnostic standards might not suspect TB, delaying the start of effective treatment. Access to comprehensive and affordable clinical TB services (i.e., preventive, diagnostic, and treatment/case management) should be provided to all persons with TB or those suspected to have TB. Health-care providers who screen persons for TB should use up-to-date diagnostic and treatment guidelines. More health-care workers are needed to provide directly observed therapy (DOT) for TB patients to ensure successful treatment and help prevent development of disease attributable to drug-resistant TB. # Ethical and Legal Issues Strict infection-control measures are necessary to prevent the spread of XDR TB. Patients with XDR TB might need to be placed in airborne infectious isolation while initial treatment response is monitored in order to prevent disease transmission to others. Guidance is needed regarding the ethical and legal issues involved in identifying and treating persons with XDR TB. The adequacy of current public health laws in the United States to address drug-resistant TB has not been studied comprehensively since 1993 (29). All states have laws to compel isolation for persons with certain infectious diseases (including TB); however, these laws vary by state, and those for TB might be contingent on patient nonadherence and failure of voluntary measures. Public health authorities must balance the interests of the public with individual rights. Legal and ethical issues become even more complicated when persons have XDR TB because prolonged isolation might be necessary even when a patient is adherent. In addition, for some patients, no effective treatment is available that would allow for release from isolation on completion. Additional complexity also exists regarding non-U.S. citizens with infectious XDR TB who are scheduled to be repatriated to their native countries. U.S. public health officials might not be familiar with public health laws of other countries. # Communication and Education As a result of TB incidence rates decreasing in the United States, health-care providers have received little training regarding TB and consequently might not recognize the signs and symptoms of TB, which can lead to incorrect diagnosis and treatment, creation of drug resistance, and continued spread of TB in the community (30,31). Health-care providers should be educated about the signs and symptoms of TB, diagnostic methods, prevention, and treatment. In addition, education materials on MDR TB and XDR TB should be developed for the general public, populations at high-risk for TB on the basis of demographic and clinical characteristics, TB patients, TB prevention advocacy organizations, and policy makers, including legislators. Education materials should include informational pamphlets, instructions for therapy, behaviors to prevent transmission, medical alerts, and descriptions of TB programs. Distribution of these materials should be coordinated across federal and state agencies and updated as necessary. Advocacy is critical to make the public aware of the importance of TB control to the public's health, and to educate policy makers on the magnitude of the problems that will result if resources to state and local TB control programs continue to decline. # Research The biomedical research challenges represented by drugresistant TB in the context of overall TB research activities have been described previously (10). Knowledge gaps remain regarding the genetics and growth characteristics of M. tuberculosis, the physiology and biochemistry of both the host and pathogen during infection, and the disease and genotypic and biologic markers that facilitate surveillance and indicate infection, disease, and drug resistance. Basic research needs to be supported to advance understanding of these issues and to help design new approaches to diagnosis and treatment. The emergence of drug-resistant TB illustrates the pressing need to develop new and effective drug regimens for the treatment of TB, including drugs to cure MDR TB and XDR TB and to prevent development of active disease among persons who are infected latently with drug-resistant M. tuberculosis. Because poor patient adherence to therapy is one factor that can lead to development of MDR TB and XDR TB, research of associated behavioral and social factors should be conducted to identify ways to improve patient adherence and treatment completion. New, rapid, and cost-effective diagnostic methods are needed, particularly for use in rural areas and developing countries. Ultimately, an effective vaccine is needed to eliminate TB. # Partnerships To coordinate efforts to control XDR TB, existing partnerships must be strengthened, and new partnerships are needed between countries and within both the public and private sectors, including government and nongovernment organizations. Partnerships are necessary to focus existing resources on the most affected geographic areas, increase current public and private resources (both financial and human resources), coordinate the efforts (including research, education, laboratory, and programmatic), and raise awareness of the problem and consequences. # Cost Analysis Comprehensive information is not available on the cost of treating and implementing programs and interventions to prevent XDR TB. Research on the cost of treating and preventing XDR TB is needed to calculate the cost-effectiveness and benefits of interventions and strategies to combat XDR TB. # Action Plan to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory The laboratory plays a critical role in the diagnosis and management of drug-resistant TB. Test results must be available in a time frame that allows clinicians to make prompt patient management decisions. Many laboratory techniques used to confirm a TB diagnosis and to identify drug resistance were developed in the 1950s, 1960s, and 1970s. Substantial improvements have been made in culture techniques and in rapid methods in the past decade. However, these more accurate, rapid, and sophisticated methods have not been implemented widely, particularly in regions of the world where MDR TB and XDR TB are common and optimized algorithms for providing rapid point-of-care laboratory confirmation of TB and detection of drug resistance have not been established. To combat the growing problem of resistance to TB drugs, the most current methods need to be applied to their fullest capacity while better diagnostic tests are developed. The needs of the TB laboratory must be addressed to make laboratory services for TB, MDR TB, and XDR TB more rapid, sensitive, reliable, and more responsive to the needs for patient management, infection control, and TB control efforts. Although the challenges and potential solutions vary by setting, domestic and international TB laboratories face many of the same challenges. # Problem 1 Many clinicians, laboratorians, health-care professionals, public health officials, and policy makers do not possess upto-date knowledge of what constitutes appropriate laboratory capabilities and capacities or the appropriate use of tests to arrive at a prompt and accurate diagnosis of TB. Increase awareness of the need to develop necessary capacity and capabilities for the laboratory diagnosis of TB. This includes proper use of diagnostic tests, prompt reporting of results, and appropriate interpretation of test results for establishing a definite diagnosis and for guiding management of TB (domestic and international). # Problem 4 The quality of and proficiency in TB laboratory diagnosis varies within the United States and internationally because a well-trained and stable laboratory workforce is not universally available. # Problem 5 TB laboratory services at certain local public health laboratories are limited and might depend on access to networks of other public and private laboratories with better diagnostic capabilities, which often leads to substantial delays in diagnosis and treatment of TB. Develop a systems approach to improving TB laboratory services at the local level (domestic). # Action Steps 5.1.1. Assess available TB laboratory services in a jurisdiction to determine the status and capacity of services and to identify unmet needs, obstacles to obtaining services, and opportunities for improvement. 5.1.2. Assess the actual costs of providing TB laboratory services through existing programs and develop a business plan for providing these services through an integrated system of laboratory services in the United States. 5.1.3. Develop a strategic plan for implementing and maintaining a systems approach to TB laboratory services. 5.1.4. Develop outcome measures to assess performance of and improvements in laboratory services and overall TB control programs. Lead federal agencies: HHS (CDC). 5.2.4. Develop program-specific plans and phased approaches to improving laboratory services in national, country-level regional and peripheral (local) laboratories. 5.2.5. Develop local, district, regional, and national laboratories, including referral laboratories, that provide reliable services through conventional and rapid methods for TB diagnosis, drug-susceptibility testing and patient care. 5.2.6. Develop or ensure access to effective external quality assessment programs for laboratory services (e.g., acid fast bacillus [AFB]-smear microscopy, culture, and drug-susceptibility testing) provided at each level. 5.2.7. Support development of laboratory standards and accreditation programs with an emphasis on culture and drug-susceptibility testing to facilitate assessment and quality improvement of national and regional laboratories. 5.2.8. Explore options to increase TB laboratory capacity as part of efforts to improve general diagnostic laboratory service capacity and overall health sector reform. 5.2.9. Identify interim laboratory support services until local and regional capacity is developed. 5.2.10. Support research to develop inexpensive, high-quality diagnostic tools that can be used in resource-limited settings. Lead federal agencies: HHS (CDC and NIH), and USAID. Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD. Culture-based laboratory tests to identify persons with XDR TB are slow, lack sensitivity, and have poor reliability, resulting in delayed diagnosis, treatment, and public health control efforts. objective 6.1 Improve the ability of TB laboratories to identify and report drug-resistant M. tuberculosis (domestic). # Action Steps 6.1.1. Develop local, district, state, regional, or referral laboratories that are able to rapidly identify M. tuberculosis bacteria in patient specimens and determine drug susceptibilities to first-and second-line agents using state-of-the-art conventional or rapid methods. 6.1.2. Encourage the use of state-of-the-art rapid tests for detection of M. tuberculosis and drug-susceptibility testing through focused laboratory funding. 6.1.3. Develop a bank of M. tuberculosis isolates for use in proficiency testing and research. 6.1.4. Implement proficiency testing programs and external quality assessment programs for new drug-susceptibility tests and rapid methods. 6.1.5. Assist laboratories in developing and implementing an integrated information management system for inventory, specimen tracking, reporting, and information sharing. 6.1.6. Identify interim laboratory support services until local and regional capacities are developed. Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: APHL and NTCA. # Problem 7 The lack of guidelines for the use of conventional and rapid culture-based or molecular methods for detection of M. tuberculosis and drug resistance impedes the widespread use of these tests. Develop consensus guidelines to address TB laboratory testing in the United States, in high-burden and in focus countries (domestic and international). Action Steps 7.1.1. Develop consensus guidelines for culture, drug-susceptibility, and rapid diagnostic testing to be used in local, district, state, national, and country-level regional laboratories. 7.1.2. Develop consensus guidelines for the use of rapid methods (e.g., nucleic acid amplification tests) to detect M. tuberculosis directly from patient specimens. 7.1.3. Develop consensus guidelines for the use of rapid, molecular methods for drug-susceptibility testing. 7.1.4. Develop consensus guidelines for culture-based methods to determine resistance to second-line TB drugs. 7.1.5. Conduct operational and implementation research to develop guidelines for optimal algorithms for TB laboratory testing, specimen referral, and reporting. Lead federal agencies: HHS (CDC and NIH) and USAID. Suggested collaborators: APHL, ATS, IDSA, CLSI, WHO, IUATLD, and academia. # Problem 8 The current process for evaluating newly developed diagnostic tests can be time consuming and delay implementation for routine clinical use. Develop strategies for expedited evaluation and implementation of new rapid methods for laboratory confirmation of TB and identification of drug-resistance patterns (domestic and international). 8.1.10. Determine and promote the most effective pointof-care drug-susceptibility testing methods and diagnostic algorithms and strategies, including molecular testing at the local level followed by transport of positive specimens to fullservice laboratories for further evaluation. 8.1.11. Provide access to or conduct clinical trials in partnership with high-burden countries to validate new microbiologic drug-susceptibility tests as part of local diagnostic procedures/ algorithms. 8.1.12. Discuss with FDA criteria that will be required for approval of new tests for identification of drug-resistant TB and to perform rapid drug-susceptibility testing. Lead federal agencies: HHS (CDC, FDA, and NIH), and USAID. Suggested collaborators: DoD, Foundation for Innovative New Diagnostics (FIND), WHO Special Programme for Research and Training in Tropical Diseases [TDR]), academia, public health laboratories, and IUATLD. # Problem 9 The laboratory confirmation of TB in HIV-infected persons is difficult and time consuming because of the need for highly sensitive, sophisticated and technically challenging diagnostic tests that are not universally available in all settings with a high burden of HIV and TB. Suggested collaborators: DOS, DoD, FIND, WHO (TDR), ASM, APHL, academia, IUATLD, and public health laboratories. # Problem 10 Current technical assistance for laboratory capacity building is sporadic and not well coordinated or integrated often leading to unclear and inconsistent guidance. # Develop consistent and well-coordinated approaches to technical assistance and consultation for TB laboratories in high-burden and focus countries (international). Action Steps 10.1.1. Develop technical assistance approaches and practices that are coordinated, consistent, and compatible with the efforts of international partners such as WHO and IUATLD. 10.1.2. Establish a cadre of well-trained consultants to help guide coordinated approaches to building TB laboratory capacity in high-burden and focus countries. 10.1.3. Contribute to the coordinated development of standardized checklists and templates for laboratory evaluation and training materials for laboratory capacity building efforts. 10.1.4. Contribute to the coordinated development of external quality assessment guidance and documents for microscopic and culture identification of M. tuberculosis and drug-susceptibility testing. 10.1.5. Contribute to the coordinated development of widely compatible laboratory information systems to facilitate transfer of information within and between TB control programs. 10.1.6. Promote expansion of the Supranational Laboratory Network through inclusion of reference laboratories that can assist in capacity building and external quality assessment. 10.1.7. Promote expansion of the Supranational Laboratory Network proficiency testing to include second-line drugsusceptibility testing. 10.1.8. Promote and coordinate partnering of public health laboratories in the United States with public health laboratories in high-burden and focus countries. Lead federal agencies: HHS (CDC and NIH), and USAID. Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD. # Problem 11 Providing technical assistance is logistically difficult. objective 11.1 Establish international regional centers of excellence to facilitate implementation of technical assistance provided by the United States to TB endemic or TB-focus countries (international). # Action Steps 11.1.1. Build expertise for technical assistance to TB laboratories at selected centers of excellence in high-burden countries. February 13, 2009 11.1.2. Provide opportunities for peer-to-peer training and exchange of laboratory personnel in resource limited settings. 11.1.3. Assist centers of excellence in developing training programs for program staff, laboratory managers and bench workers on establishing methods for external quality assessment processes through site visits and monitoring. 11.1.4. Assist centers of excellence in establishing reference laboratory services for identification of M. tuberculosis and susceptibility testing for first-and second-line drugs that would qualify them as Supranational Reference Laboratories and that could be made available to partner programs. Lead federal agencies: HHS (CDC and NIH) and USAID. Suggested collaborators: DOS, DoD, WHO, IUATLD, APHL, ASM, KNCV, RIT, academia, and public health laboratories. # Problem 12 Resources available to TB laboratories are often inadequate for building and maintaining the necessary infrastructure and competencies to provide consistently high-quality diagnostic services. Mobilize resources and support international efforts to strengthen and sustain TB laboratory capacity (international). # Action Steps 12.1.1. Identify funding opportunities through the President's Emergency Plan for AIDS Relief, USAID, and the Global Fund to contribute to strengthening international laboratory efforts. 12.1.2. Support global efforts (e.g., WHO's strategic approach to the strengthening of laboratory services for TB control). 12.1.3. Support the Stop TB Partnership's Global Laboratory Initiative and the DOTS (directly observed therapy, short course) Expansion Working Group. Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: DOS, WHO, the Bill & Melinda Gates Foundation, APHL, and the American Lung Association (ALA). # Problem 13 The role of public and private TB laboratories in the diagnosis of persons latently infected with XDR M. tuberculosis has not been defined clearly. # Develop laboratory services to identify persons with drug-resistant latent M. tuberculosis infection (DR LTBI) (domestic). # Action Steps 13.1.1. Assess the capacity of public and private TB laboratories to support DR LTBI diagnostic testing by determining the status and capacity of currently available services and identifying gaps, obstacles and opportunities for improvement. 13.1.2. Develop materials and programs to train laboratory personnel in DR LTBI diagnostic testing. 13.1.3. Develop consensus laboratory guidelines for DR LTBI testing methods. 13.1.4. Conduct operational research to optimize testing and referral algorithms. 13.1.5. Develop proficiency testing and external quality assessment modules for DR LTBI diagnosis. 13.1.6. Conduct Phase 4 clinical studies of new technologies for DR LTBI diagnosis and management. Lead federal agencies: HHS (CDC, FDA, NIH). Suggested collaborators: DoD, NTCA, APHL, CLSI, ATS, and IDSA. # Problem 14 International laboratory services used by physicians under provisions of the United States Immigration and Nationality Act often are not equipped to the standards of U.S. TB programs and might not be able to reliably identify persons with drug-susceptible or MDR TB and XDR TB. Evaluate and improve the ability of international laboratories employed to identify M. tuberculosis and perform drug-susceptibility testing for potential U.S. immigrants (international). Suggested collaborators: DoD, FIND, and academia. # Surveillance, Epidemiology, and outbreak Investigations Identifying outbreaks of XDR TB to prevent further transmission requires a rapid, accurate, and adaptable surveillance system and coordinated response strategies. In the United States, individual states require reporting of TB cases by health-care providers and facilities to public health authorities. By mutual agreement, state health authorities report TB cases to CDC. Substantial delays can occur in reporting to CDC because many states report on a quarterly basis or at the end of the year. Key domestic surveillance needs include immediate case reporting, accurate and complete reporting of second-line drug susceptibility and genotyping results, and active case finding among contacts and other high risk groups. Central notification of MDR and XDR TB is essential to identify crossjurisdictional issues and to outline specific areas that should be targeted for rapid emergency (federal) support. Improved, unambiguous technical guidance (including outcome standards) is needed for collection, reporting, and data-quality procedures at the local, state, and federal levels. Internationally, areas that require increased attention and improvement include capacity for rapid DST surveys and more sustained, systematic capture of DST information. Epidemiologic studies, including genetic analyses of host and pathogen, are recommended to elucidate risk factors for acquiring XDR TB, transmission dynamics and determinants of host survival. # Problem 16 No requirement exists for rapid reporting of TB cases to the National TB Surveillance System (NTSS), and many state and city TB programs report to NTSS only quarterly or at the end of the year, thus substantially limiting the ability to identify rapidly and respond promptly to outbreaks of MDR TB and XDR TB. # Problem 23 In areas where XDR TB has been identified, the actual prevalence of resistance to first-and second-line drugs among TB cases is unknown. # Problem 24 The risk factors for and transmission dynamics of XDR TB in domestic and international settings are not completely understood. # Problem 25 The survival rates among patients with TB that is resistant to first-and second-line therapeutics have not been adequately analyzed, and host/pathogen determinants of survival, including the effect of co-morbidities, remain to be elucidated. # Infection Control Because TB is spread by the airborne route, anyone who breathes air containing viable tubercle bacilli is at risk for acquiring M. tuberculosis infection. This includes persons caring for and exposed to infectious TB patients, especially patients without an established diagnosis. To prevent the spread of disease and maintain the best possible care for patients, special infection-control practices and procedures must be available. Effective infection control depends on early detection and diagnosis of TB disease, prompt initiation of effective therapy, and airborne infection isolation to prevent further disease transmission. Each institutional setting that might house persons with undiagnosed TB disease or in which TB patients are treated should have infection-control programs available that minimize the risk for TB transmission, including MDR TB and XDR TB, to patients, workers, and others within the institutional setting. Various infection-control strategies are available depending on whether a setting will provide primary care or triage and refer patients with suspected or confirmed TB disease. All infection-control strategies should be on the basis of a three-level hierarchy: administrative controls, environmental controls, and personal respiratory protection. Combinations of these infection-control strategies have been demonstrated to be effective at preventing TB transmission. However, these strategies are not implemented consistently, and their individual effectiveness and feasibility are not well-characterized. # Problem 27 Although administrative controls, environmental controls, and respiratory protection have been effective when used in combination, ethical issues have prevented assessment of their individual effectiveness in settings in which TB transmission occurs. Resulting knowledge gaps hamper efforts to prioritize interventions for optimal cost-benefit in resource-limited settings. objective 27.1 Ensure dissemination and implementation of currently recommended infection-control strategies across a range of highrisk institutional settings (e.g., health-care facilities, substance abuse clinics, residential treatment centers, homeless shelters, and correctional and detention facilities) through education and regulatory programs (domestic and international). 28.1.2. Recommend considering positive tuberculin skin test (TST) or blood assay (BAMT) for identification of M. tuberculosis infection among health-care workers as an outcome measure of the effectiveness of TB infection-control programs in health-care facilities that are in the medium risk category or have been classified as having potential ongoing transmission. 28.1.3. Provide health departments with support in recruitment of and assistance to health-care centers, correctional facilities, homeless shelters, and substance-abuse treatment centers to implement and assess the effectiveness of programs for systematic TB screening of workers employed in mediumor high-risk settings. Lead federal agencies: HHS (CDC). Suggested collaborators: OSHA, JCAHO, and state and local health departments. # Clinical and Programmatic Interventions The fundamental principles and practices of TB control have been described previously (3,33). These principles and practices underlie the clinical and programmatic components of diagnosis, reporting, treatment and prevention of drugresistant TB addressed in this Task Force Plan Persons at risk for TB disease often fail to access health-care systems for a variety of complex reasons. A lack of understanding of TB and its symptoms, lack of financial resources (e.g., health insurance or transportation to the clinic), lack of awareness of free clinical services for TB, concerns of deportation and stigmatization, and existence of competing priorities (e.g., shelter and food) all contribute to delays in TB diagnosis and result in prolonged TB transmission in the community. Clinical and programmatic services must be integrated with and closely coordinated with TB laboratory services through a systems approach to ensure successful diagnosis and case management. Once patients access care, lack of familiarity with TB by health-care providers might result in misdiagnosis and inappropriate treatment, which in turn can lead to development of drug resistance and continued transmission of M. tuberculosis. Once a TB diagnosis has been established, providing clinical TB services (preventive, diagnostic, and treatment/ case-management) that are culturally acceptable, affordable and logistically accessible to patients is a prerequisite for successful TB management and treatment completion. Throughout the process of clinical care of TB patients, infection-control practices must be implemented properly, and health-care providers (physicians, nurses, pharmacists, dentists, laboratorians, other allied health professionals, traditional healers) must be educated thoroughly and trained in all principles and practices of TB care. To sustain consistent high quality and prompt care of TB patients, monitoring and evaluation programs must be established to identify rapidly systems failures and implement corrective measures. The elements of the health system that are necessary to prevent the development and transmission of MDR TB and XDR TB have been identified (Figure). Failures at any of the necessary steps related to proper TB diagnosis, treatment and infectioncontrol measures can lead to the development or transmission of drug-resistant TB. # Figure. Prevention of development and transmission of drug-resistant tuberculosis (TB) * The United States needs to assist international TB control programs in the development of clinical and programmatic practices that follow international standards for TB diagnosis and care, laboratory services, and infection control. Support should be provided to ensure that TB patients receive services free of charge and have access to DOT through the completion of treatment. The implementation of international informa-tion sharing mechanisms is critical for the prevention of drug resistance and the successful control of TB worldwide. # Problem 30 Initial point-of-contact (POC) providers (e.g., emergency, urgent, primary, and correctional care providers; university health service and occupational medicine clinicians; health department clinicians; civil surgeons † † ; and traditional healers) might not suspect TB or have current or complete information about the diagnosis and/or treatment of TB (see Problem 44). Provide POC providers who serve at-risk persons with education and guidance to increase their knowledge of TB and increase their access to resources to avoid misdiagnosis, prolonged transmission, and inappropriate treatment (domestic). # Action Steps 30.1.1. Promote general knowledge of TB among providers through specific TB curricula and self-study modules. Educate providers about the critical importance of patient-centered case management and how to deliver high-quality services needed to ensure patient adherence and treatment completion. Explain the risks associated with undiagnosed, misdiagnosed, and inappropriately or inadequately treated TB. 30.1.2. Promote practices such as use of treatment regimens on the basis of national guidelines, DOT, prompt adjustment of treatment in response to DST results, patient incentives and enablers to maintain adherence, monitoring of response to treatment, and comprehensive case management in close collaboration with the local TB control program and treatment experts to prevent development and amplification of drug resistance among all TB patients. 30.1.3. Conduct a national media campaign to raise awareness of TB for the general public and health-care providers. 30.1.4. Engage medical professional associations to raise awareness of TB and TB guidelines. 30.1.5. Review TB screening procedures and protocols for institutional facilities and primary care providers to assure competency and develop links between POC providers, local and state health departments and RTMCCs for diagnosis and referral of suspects. 30.1.6. Develop and distribute current regional, national and international MDR/XDR surveillance charts to healthcare providers and public health programs to inform them of high-prevalence areas for MDR TB and XDR TB. 30.1.7. Address health-care provider fears about MDR TB and XDR TB through discussions with medical societies, formal and informal presentations with health-care professionals at meetings, and through targeted mailings. 30 31.1.3. Educate health-care providers on the need for expedited drug-susceptibility testing immediately after an initial TB diagnosis, especially in high-risk congregate settings and in immunocompromised persons, to reduce morbidity and mortality in persons with drug-resistant TB. 31.1.4. Update TB care guidelines to recommend routine HIV testing during initial patient evaluation for TB on the basis of opt-out testing § § recommended by CDC. 31.1.5. Develop and distribute regularly updated regional, national and international MDR TB and XDR TB surveillance charts to health-care providers and public health programs to increase awareness of the extent of drug-resistant disease in patients who do not respond to first-line therapy. 31.1.6. Develop a system of consultation and patient referral between primary care physicians (including HRSA Community Health Centers, primary care HIV clinics, and homeless programs), physicians in correctional or detention settings, departments of health, and RTMCCs to improve diagnosis and management of TB patients, especially those with MDR TB and XDR TB. 31.1.7. Discuss with FDA requirements for review and approval of rapid tests to detect rifampin resistance (RIF) as a primary/surrogate indicator for MDR TB and XDR TB and define special situation where use of rapid RIF assays and other molecular tests to diagnose drug resistance would be appropriate. Lead federal agencies: HHS (CDC, FDA, and HRSA). Suggested collaborators: NTCA, RTMCCs, state and local health departments, and health-care provider professional societies. # Problem 32 Existing diagnostic protocols used for screening foreign-born persons entering, or already residing in the United States, are not sufficient to detect XDR reliably. # Problem 34 The quality of currently available services and treatment for XDR TB patients has not been monitored or evaluated sufficiently. Improve the quality and effectiveness of free clinical services, medications and treatment regimens as part of patient-centered management for patients with XDR TB (domestic). # Action Steps 34.1.1. Develop and implement fully supported, improved patient-centered clinical services for outpatient management of persons with XDR TB that ensure full cooperation and maximum chance of success. 34.1.2. Develop and implement procedures and due process and recommendations for legal recourse for management of § § Defined as performing HIV testing after notifying the patient that the test will be performed and consent is inferred unless the patient specifically declines. XDR TB patients refusing treatment or care to minimize risk to communities (see Problems 39, 41, and 42). 34.1.3. Identify centers of excellence for in-patient treatment of MDR TB and XDR TB that are available for consultation on and referral of XDR TB patients to optimize care and increase likelihood of cure. 34.1.4. Evaluate whether XDR TB centers of excellence might be developed as national referral centers for all patients with XDR TB to provide the best possible care, increase treatment success and reduce transmission to others. 34.1.5. Develop procedures for transfer of patients to referral centers and identify funding to support the cost of treating and managing XDR TB patients. 34.1.6. Establish programs to facilitate collaboration between XDR TB centers of excellence and the RTMCCs for ongoing medical education, consultation, and technical assistance to community providers on all aspects of care of MDR TB and XDR TB patients. 34.1.7. Develop processes and procedures for referral and care of patients who are in legal custody during inpatient or outpatient treatment to ensure appropriate discharge and continuity of care when released from custody or transferred to a different detention facility or law enforcement agency. 34.1.8. Develop processes to request a stay of removal for patients slated for deportation to a country where treatment is not likely to be available and establish procedures and resources to complete TB treatment in the United States, including provision of secure environments, if appropriate. Lead 38.1.5. Review the technical instructions for panel physicians ¶ ¶ who conduct TB screening as part of immigration procedures with regard to XDR TB diagnosis and contact management and develop a process to certify panel physicians. 38.1.6. Support and recommend the use of fixed-dose drug combinations when appropriate and provide training and technical assistance to improve TB drug management. 38.1.7. Provide technical assistance through full-time consultants to ministries of health in countries that are sources of large numbers of U.S. immigrants and countries with a high burden of drug-resistant TB to support completion of ongoing drug-resistance surveys and the establishment of drug-resistance surveillance systems. 38.1.8. Provide resources and support to establish U.S.transnational TB case management programs such as international referral programs and information-sharing system. Lead federal agencies: USAID, HHS (CDC, HRSA), and DHS (ICE). Suggested collaborators: DOS, WHO, IUATLD, Green Light Committee (GLC), Medicins Sans Frontieres (MSF), and KNCV. # Ethical and Legal Issues TB is a reportable infectious disease, and public health protection and TB control activities are described in specific state laws. Many existing laws were established before the contemporary public health recommendations for the prevention and control of TB became available (6,35). As a result, the Advisory Committee for the Elimination of Tuberculosis (ACET) and CDC conducted a survey of state TB control laws and regulations and developed recommendations that addressed legal issues of TB control in the United States. Since these recommendations were published (29), no systematic follow up has been conducted to determine the extent to which these recommendations were implemented. # Problem 39 Laws and regulations permitting authorities to compel treatment and isolation of patients with tuberculosis vary by state. Suggested collaborators: state and local health departments, law schools, and national justice and health ministries. # Problem 41 The effectiveness of mandated isolation or quarantine to compel treatment for TB patients as compared to less restrictive measures, and the ethical issues associated with these measures, have not been evaluated closely. Develop guidelines and a research agenda to determine the effectiveness of and ethical issues associated with compelling treatment and isolation for TB patients who are considered a threat to public health (domestic). # Action Steps 41.1.1. Conduct research to determine the impact and effectiveness of mandatory isolation to compel treatment for tuberculosis as compared with less restrictive measures. 41.1.2. Conduct research on ethical issues of mandated isolation (or quarantine) and less restrictive measures to compel treatment for tuberculosis. 41.1.3. Convene a workshop for bioethicists and TB control, care, and research professionals to identify and catalog key ethical issues likely to be confronted as part of the XDR TB response. Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ. Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists). # Problem 42 Patients with XDR TB could require prolonged isolation measures regardless of the patient's adherence to treatment, which might present an ethical dilemma in balancing the interests of public health with those of the patient. Develop guidance on ethical issues pertaining to prolonged isolation of patients with XDR TB who are fully adherent to treatment (domestic). # Action Steps 42.1.1. Conduct research on ethical considerations of prolonged, mandated isolation including contexts of fully adherent patients and those who are in the terminal stages of disease. Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ. Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists). # Problem 43 Obstacles to compassionate use of experimental chemotherapeutic agents for patients with XDR TB limit critically important therapeutic options. # Communication and Education Comprehensive and tailored information on TB and drugresistant TB including XDR is needed for many different audiences. In the United States, private health-care providers (i.e., those not in public health departments) receive little education or training on detection and appropriate treatment of TB (11,30,31,(36)(37)(38). As a consequence, infectious TB often goes unrecognized, even if a patient presents to a physician with apparent signs and symptoms of active disease. This has led to incorrect treatment, prolonged transmission of TB in the community, and creation of drug-resistant organisms. Education and communication must be appropriately targeted to health-care providers and patients to improve awareness and guide access to competent clinical services. Community leaders and health policy makers, including public health officials, must be well informed about the need to communicate and address issues that can fuel the development and spread of drug-resistant TB in their communities. Education efforts should clearly outline the critical elements that must be applied to prevent and control TB in various settings and risk populations (34). Clear, concise messages, easy to understand yet comprehensive education materials and medical alerts should be developed and disseminated to the general public, TB patients, physicians and other health-care workers, health advocacy organizations, and decision makers, including legislators. These communications should be coordinated across Federal agencies and updated as necessary. Increasing awareness of the signs and symptoms of TB and the appropriate treatment and control strategies, must become a priority in the United States to ensure TB is recognized and treated as a public health threat with the potential to result in virtually untreatable forms of disease, such as XDR TB. In TB-endemic countries where cases of drug-resistant TB are increasing, health authorities must also remain informed about the risk for and incidence of XDR TB. There, provider education initiatives must also focus on the need for appropri-ate case management, including knowledge regarding locally and regionally available specialty resources and medications and the consequences of inappropriate or inadequate treatment of drug-resistant TB. # Problem 44 Health-care providers and the general public are not wellinformed about the symptoms, appropriate, diagnosis, treatment, and prevention of drug-susceptible and drug-resistant TB including XDR TB. Develop education mechanisms and materials, targeted to public and private health-care providers and other workers who might come into contact with populations with a high prevalence of TB infection and disease in settings such as health-care facilities, homeless shelters and correctional facilities, about drug-susceptible and drug-resistant TB including XDR, heighten awareness and encourage appropriate prevention, diagnosis, treatment, and referral (domestic). # Action Steps 44.1.1. Review and update existing education materials and communication products on TB to include relevant information about drug-resistant forms of disease. 44.1.2. Identify communication gaps and special needs for education and communication products regarding drugsusceptible and drug-resistant TB and develop new materials as needed. 44.1.3. Communicate to health-care providers appropriate measures to prevent MDR TB and XDR TB, including the importance of detecting and treating LTBI and TB disease and the importance of prompt reporting of TB cases to proper health authorities. 44.1.4. Communicate to health-care providers the importance of consulting and engaging TB experts in the medical management of MDR TB patients to avoid the development of XDR TB and to ensure that appropriate specialized resources for treatment of drug-resistant TB are optimally used. 44.1.5. Familiarize health-care providers serving high-risk patients with TB training and medical consultation resources that are available through the RTMCCs. 44.1.6. Contribute to the dissemination and promotion of infection-control guidelines and supporting education materials in the United States (28) and globally (39). 44.1.7. Develop strategies and materials on TB and MDR TB and XDR TB diagnosis, treatment, and reporting for dissemination at national medical and laboratory meetings. 44.1.8. Develop education materials for digital mass media, such as the Internet, personal digital assistants, and podcasts to reach and inform health-care providers about control of all forms of TB. 44.1.9. Develop and distribute targeted education material to health-care providers and nontraditional partners who are not usually engaged in TB control activities such as primary care and nurse practitioners, physician assistants, emergency care and urgent care specialists, health-care providers in correctional facilities, civil surgeons, pharmacists, foreign-trained clinicians, non-U.S. health-care providers, university health service, occupational medicine specialists, rheumatologists, oncologists, radiologists, laboratories, traditional healers, NGOs, and CBOs. 44.1.10. Present specialty-specific information about care and control of all forms of TB at professional conferences. 44.1.11. Develop targeted TB training and education for other workers who might be exposed to TB in settings such as health-care facilities, homeless shelters and correctional facilities. Lead federal agencies: HHS (CDC, NIH, and HRSA). Suggested collaborators: RTMCCs, NTCA, ATS, American College of Chest Physicians (ACCP), IDSA, American Medical Association (AMA), American Association of Family Practitioners (AAFP), and APHL. Develop education mechanisms and materials to inform decision makers in the public and private sectors about priorities and strategies for the prevention and control of TB and MDR TB and XDR TB (domestic). Establish and maintain mechanisms to facilitate regular communication among federal agencies, and with state and local TB control programs (domestic). # MMWR February 13, 2009 Action Steps 44.4.1. Regularly update and disseminate information by the CDC, WHO, and other agencies on MDR TB and XDR TB to federal staff, TB control programs, HIV/AIDS programs, and other public health agencies and interested organizations to ensure that U.S. public health programs are well informed about the incidence and prevalence of drug-resistant TB in the United States and globally. 44.4.2. Identify federal TB Task Force members to serve as key spokespersons for issues related to MDR TB and XDR TB while ensuring that all Task Force members are well informed to contribute to the ongoing dissemination of information on all forms of TB. 44.4.3. Communicate on a regular basis efforts and relevant results and outcomes related to prevention and control of MDR TB and XDR TB by federal agencies. Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: NTCA and state and local health departments. # Research Biomedical research in TB creates a foundation of knowledge that informs the development of new health-care interventions as well as control and prevention strategies for drug-resistant TB. While U.S. federal agencies have substantially contributed to research in TB and the identification of drugs, vaccines and diagnostics, the emergence of more difficult to treat forms of drug-resistant TB will require renewed and more targeted efforts to help control and prevent the development and transmission of drug-resistant forms of TB. One compilation of biomedical research priorities related to MDR TB and XDR TB has been published (7). TB therapy was revolutionized in the 1940s by the development of antibiotics by academic and for-profit organizations, and the demonstration of their efficacy and safety in randomized clinical trials largely conducted by the public sector. These therapies became the basis for the global DOTS strategy for TB control. Although initially highly effective in reducing the incidence and prevalence of TB in endemic countries, the continued success of the DOTS strategy is now seriously threatened by the emergence of highly drug-resistant strains of M. tuberculosis. Furthermore, interactions between TB and HIV medications and drugs used in the treatment of specialized problems such as diabetes, drug addiction and mental disorders (conditions that are encountered in populations at risk for TB) might substantially complicate the development of effective new TB drugs. To ensure the continued availability of effective therapeutics against all forms of TB, the development of new, safe, and effective TB drugs must remain a high priority. Success in TB drug development will also heavily rely on the establishment and continued support of competent, experienced trial sites in TB and TB/HIV endemic countries for all phases of clinical testing. # Problem 45 Few new TB drugs are in preclinical and clinical development. Increase the number of candidates in all stages of the TB drug development pipeline to increase the likelihood that new agents will become available for clinical use within the next 5-10 years (domestic and international). # Action Steps 45.1.1. Increase communication between private not-forprofit and commercial organizations and relevant public sector agencies to identify opportunities for public/private collaborations in TB drug development. 45.1.2. Reevaluate, refine, and optimize support for drug discovery and preclinical studies for pharmaceutical companies and academic/not-for profit organizations (in vitro and animal models). 45.1.3. Encourage pharmaceutical companies, academic researchers and nonprofit organizations to engage in TB drug development research and development efforts. Lead federal agencies: HHS (CDC, FDA, and NIH) and USAID. Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, and academia. # Problem 46 The global capacity to conduct clinical trials for new drugs that treat TB and MDR TB and XDR TB is limited. # Problem 47 Well-validated surrogate markers do not exist to rapidly assess clinical efficacy of new chemotherapeutic agents and regimens against drug-susceptible and MDR TB and XDR TB. Lead federal agencies: HHS (CDC, FDA, and NIH). Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia. # Problem 49 The types of clinical data needed to support registration of new chemotherapeutic agents against TB have not been clearly defined making it difficult to design effective clinical development plans and timelines. Establish a forum for discussion between U.S. and international regulatory agencies to define specific guidance for clinical development and approval of chemotherapeutic agents indicated for use in MDR TB and XDR TB (domestic and international). # Fundamental Science The foundation for development of new health-care interventions in TB is a solid understanding of the interaction between M. tuberculosis and the host and how infection transitions to active disease. Knowledge acquired through basic research in these areas must be effectively leveraged in translational science (i.e., research that translates basic scientific discoveries into clinical applications). As a consequence of the sequencing of the genome of both the host and pathogen, the development of molecular tools to manipulate the pathogen, the establishment of genomic and postgenomic technologies and tools, and the expansion of animal models available to study TB, many important questions in the pathogenicity of TB now can be addressed. Although considerable progress in fundamental science (basic and translational) of TB has been made over the past decade, the availability of more tools, technologies and advanced methodologies has made it possible to create new hypotheses and revisit earlier observations to contribute to a more detailed understanding of the best points of intervention in TB treatment, necessary characteristics of potential new TB vaccines, and what host/pathogen factors might be early indicators of infection, disease, drug resistance, and transmission. In addition, the effectiveness of current and new infection-control measures, such as negative pressure, high-efficiency particulate air filters, laminar flow, ventilation design on the basis of modeling approaches (e.g., computational fluid dynamics, ultraviolet germicidal irradiation, room air cleaners, and alternative air disinfection methodologies) should be evaluated in appropriate research settings. # Problem 52 The characteristics of M. tuberculosis (e.g., growth, physiology, biochemistry, genetics, and molecular biology) are incompletely understood. 52.1.6. Continue to provide high quality research reagents to facilitate TB research. 52.1.7. Expand efforts to identify and validate novel drug targets, vaccine strategies, diagnostic markers and research tools. 52.1.8. Encourage and support research on genomics of both M. tuberculosis and human/animal hosts, linking to genetic epidemiologic research to direct studies in transmission, pathogenicity, microbial host interactions, and disease progression. 52.1.9. Support studies to characterize manifestations of TB in pediatric and immunocompromised populations. Lead federal agencies: HHS (CDC and NIH) Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia. # Problem 53 The effectiveness of various individual strategies for preventing TB transmission has not been sufficiently evaluated in domestic and international health-care settings. 53.1.3. Support research and efforts to develop effective, affordable methods for expedient isolation of contagious patients that do not require major facility modifications. 53.1.4. Encourage and support cost analyses for modifying existing health-care settings, correctional and detention facilities, homeless shelters, community residences for special needs populations and other high-risk institutional settings to achieve compliance with current and future infection-control requirements. 53.1.5. Support research to characterize dose-infection relationships for airborne M. tuberculosis to inform risk assessment of infection in relation to reductions in exposure. 53.1.6. Develop protocols and support studies to evaluate the effectiveness of various administrative controls on the reduction of TB transmission. 53.1.7. Support research to objectively document and improve the ability of various environmental controls to reduce exposure to airborne M. tuberculosis. 53.1.8. Support research to develop objective measures to document and compare the ability of various respiratory protective devices to reduce exposure to M. tuberculosis and to establish evidence-based recommendations for use of nationally certified respirators providing the appropriate level of protection. Lead federal agencies: HHS (CDC and NIH), DHS (ICE), and DOJ (USMS and BOP). Suggested collaborators: OSHA, WHO, health-care facilities, academia, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai) # Diagnostics The prompt and correct diagnosis of drug-susceptible and drug-resistant TB is one of the cornerstones of effective TB control. Current diagnosis of pulmonary TB in endemic countries is limited to clinical evaluation combined with low sensitivity microbiologic tests. Available diagnostics do not offer the speed and sophistication needed to provide physicians in the field in high-burden countries with the information required to accurately diagnose drug-susceptible and drugresistant TB and to prescribe the most appropriate treatment regimens. Although certain diagnostics platforms might be technologically too advanced for field use in resource limited countries, these tests might nevertheless provide a substantial contribution to the advancement of new therapeutics for TB by allowing rapid assessment of response to therapy in clinical trials. Such measures are critical in settings with patients with extrapulmonary TB and those where drug-susceptibility testing is not possible or delayed. Furthermore, rapid assessment of response to therapy will help determine whether adequate regimens have been prescribed and might contribute to limiting the development of drug resistance. # Problem 54 Rapid, point-of-care identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB among HIV-negative and HIV-positive adults and pediatric populations ands reliable early identification of latent M. tuberculosis infection are not yet possible (see Problem 15). Develop rapid, point-of-care diagnostics for the reliable identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB disease and latent infection including in HIV infected patients and pediatric populations (domestic and international). # Vaccines Long-term control and ultimate elimination of TB likely will require an effective vaccine (40). Research to characterize needs for an effective vaccine, on the basis of immunological responses of persons infected with M. tuberculosis who do not become ill and animal models and comparisons with the currently used vaccine M. bovis Bacille Calmette-Guerin (BCG) have been supported for over a decade. BCG vaccine, usually administered once in infancy in countries with a moderate and high incidence of TB, is effective in preventing TB meningitis and disseminated TB in children but has highly variable efficacy in preventing other forms of TB, especially in adults (41). Strategic plans for a TB vaccine have been developed, and support for biomedical research for the development of new, more effective vaccines and vaccinations strategies has resulted in progress to the point where several new vaccine candidates are now being evaluated in clinical trials. Nevertheless, a highly effective vaccine has remained elusive. Increased capacity to allow entry of novel vaccine candidates into Phase I clinical studies and comparative studies of vaccine platforms in human trials will contribute substantially to understanding development needs for effective TB vaccines. However, assays and methodologies for preclinical validation and clinical characterization need to be standardized globally. Clinical trial protocols for the assessment of vaccination strategies and the development of expertise to conduct clinical trials and immunological assays in TB endemic countries are needed to establish a robust infrastructure for TB vaccine research and development (R&D). # Problem 56 Current preclinical and clinical efforts in TB vaccine development are not optimally coordinated. # Behavioral, Social, Clinical, and operational Science Current TB therapy is complex and lengthy, and it can be associated with adverse reactions to medications. Patient adherence often is difficult, leading to discontinuation of therapy; this results in relapse, continued transmission of disease, and, in some cases, the development of drug-resistant TB. Adherence is influenced by patient characteristics, differences in healthcare seeking behavior, assumptions about disease, the healthcare environment, the availability of adherence-enhancing interventions, the quality of communication between patients and providers, the availability and use of education materials to inform patients and families about TB, treatment and consequences of defaulting, the convenience of access to drugs for supervised treatment, and the quality of drugs available through TB control programs. The complexity of factors underlying patient adherence and the importance of completing treatment for TB necessitates increased emphasis on patient-centered treatment options and a thorough understanding of behavioral and social interventions that have to be in place to augment traditional TB control approaches. Operational research to improve care programs must include studies to characterize TB health services, case and data management practices, staff selection, training and retention incentives, physician training, management and organizational structure, relationships with the community, community perceptions of services, community resistance to public health services, and clinic policies and practices to provide the best possible environment for ensuring patient trust and treatment completion. # Problem 57 Patient adherence to TB chemotherapy is not optimal, and alternative methods for ensuring completion of therapy are not fully developed. Identify alternatives and adjuncts to currently used treatment protocols through behavioral research to improve adherence to therapy (domestic and international). # Problem 58 Operational and clinical questions related to patient adherence and optimal organization and structure of health services to ensure effective TB care remain unanswered. # Partnerships Because XDR TB presents a worldwide threat, a coordinated international response will rely on effective partnerships between all organizations and governments that are involved in TB control programs, TB biomedical research and product development (Box). In addition, the establishment of new alliances is needed to fill the critical gaps in the global response identified in this report. Currently, government agencies at all levels, international organizations, nongovernment organizations (NGOs), academic institutions, and the private sector are coordinating their efforts as members of the STOP TB Partnership. Furthermore, cross-disciplinary research and product development efforts are brought together through various nonprofit organizations focused on developing affordable and effective drugs, vaccines and diagnostics. Representatives from United States government agencies are actively involved in these partnerships and contribute their knowledge and expertise to help address the national and global aspects of XDR TB. The U.S. Federal Tuberculosis Task Force serves as a mechanism to coordinate activities of various federal agencies that are involved in domestic and international TB prevention and elimination programs. Domestically, U.S. government agencies work closely with local and state TB control programs, academic institutions, professional associations, and pharmaceutical companies to assure the most effective use of available resources and to minimize duplication of effort. The expansion of existing partnerships to include management and prevention of XDR TB and other forms of drug-resistant TB will be important if TB is to be eliminated in the United States and worldwide. # Problem 59 Differing jurisdictions among public health agencies, scopes of work among nongovernment organizations, and varying country-specific public health policies, economic conditions, and political commitments pose a substantial barrier to launching and focusing a coordinated response to TB (MDR TB and XDR TB and HIV/TB) in high-burden settings with the greatest needs. Optimize integration, coordination and synergy between U.S. government agencies, international organizations, and national TB/HIV programs to achieve reduction in disease rates through more focused prevention/intervention activities for MDR TB and XDR TB and HIV/TB and nonduplicative allocation of funding, staff and resources (international). # Action Steps 59.1.1. Develop programs or working groups to maximize cooperation between international organizations and to align resources for an efficient, resource sparing response in highburden countries. 59.1.2. Establish additional interagency agreements to formalize existing cooperative efforts, where feasible. Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: WHO, STOP TB, IUATLD, KNCV, ministries of health, and national and local National TB Program (NTP) staff. # Problem 60 Currently available global funds are insufficient to mount a comprehensive response to XDR TB, particularly in settings with high rates of HIV/TB co-infection. Resources need to be focused on this emerging threat, on the basis of identification of specific needs. # Problem 61 Globally, human resources at all levels in national TB programs are insufficient and maintaining a well qualified workforce has been difficult due to the continuous exodus of qualified, experienced TB and/or HIV staff. Domestically, the number of medical professionals with experience in managing TB patients, much less MDR TB and XDR TB patients, has declined in parallel with TB cases. A critical need is to strengthen human resources at the local and state/provincial/ district level. # Problem 63 Biomedical and product development activities and regulatory activities are not coordinated optimally between U.S. and international governmental and private agencies. Insufficient coordination of research activities exists among the various international entities with commitments to support TB research, or with involvement in related activities such as medical regulation. Establish and maintain partnerships with appropriate organizations within and outside the public health community to increase awareness of XDR TB among policy makers and the general public (domestic and international). # Action Steps 64.1.1. In collaboration with appropriate partners, develop coordinated and consistent education material to promote informed awareness of XDR TB in the U.S. and internationally. Lead federal agencies: HHS (CDC, NIH, and HRSA), USAID, and HUD. Suggested collaborators: WHO, IUATLD, Results International, American Lung Association, Treatment Action Group, local and state health departments, academia, and national ministries of health. # Problem 65 Current public health partnerships are not sufficient to ensure continuity of care for TB patients and their contacts who either reside temporarily in the United States or frequently February 13, 2009 cross its borders. More than half the TB cases in the United States occur among immigrants who become infected before their arrival in the United States. Lack of continuity of care contributes to treatment default, ongoing transmission, and prolonged illness. Partnerships are needed for effective transnational case management. Identify appropriate partners and programs to contribute to projects and strategies that ensure continuity of TB care for patients traveling or migrating into or out of the United States (domestic and international). # Action Steps 65.1.1. Identify domestic and international partners to participate in an assessment of barriers to continuity of care for migrants or traveling TB patients. 65.1.2. Develop and implement transnational partnerships that allow establishment of cross-border TB care and management programs, such as the Bi-National TB Card and transnational referral programs for continuity of TB therapy. 65.1.3. Strengthen partnerships between ICE and TB Programs in countries to which patients are deported while on TB treatment that was initiated in the United States. Lead federal agencies: HHS (CDC and HRSA), USAID, DHS (ICE, CBP), federal courts, and USMS. Suggested collaborators: foreign NTPs and ministries of health, local and state TB programs in the United States and other countries, Cure TB, and TB Net. # Cost Analysis A realistic national estimate of the costs of diagnosing, treating, and managing XDR TB will be an important prerequisite for measuring the benefit and savings to the United States that would be realized through prevention of XDR TB. CDC has estimated the costs for hospitalization of one XDR TB patient at approximately $483,000 (CDC, unpublished data 2007) whereas outpatient treatment costs, productivity losses, patient out-of-pocket expenses, and quality of life changes attributable to XDR TB are unknown. Some of the existing interventions and strategies for TB care and management, such as the use of DOT, already have been demonstrated to be cost effective in preventing the development of MDR TB, but information about additional strategies is currently not available. Analysis of such cost-benefit and cost-effectiveness data will be critical to prioritize programs and advocate for resources to implement specific interventions to help prevent XDR TB. # Problem 66 A comprehensive and up-to-date estimate of the costs of diagnosing, treating, and managing XDR TB in the United States in not available. Conduct a study on the basis of health-care system and societal perspectives to calculate the costs of diagnosing, treating, and managing all cases of XDR TB identified through surveillance for patients and their contacts (domestic). # Action Steps 66.1.1. Identify representative samples or cohorts of XDR TB patients during 2004-2007 (verified and reported, unreported incident and prevalent cases), and their contacts for estimating costs associated with health care and personal productivity. 66.1.2. Estimate from representative samples or cohorts of XDR TB patients the average medical costs incurred on the basis of the extent and pattern of drug resistance, medically indicated procedures and examinations needed to diagnose drug-resistant TB, the length of inpatient and outpatient treatment, management of adverse events and treatment and disease associated chronic sequelae, and the cost of case management of contacts. 66.1.3. Estimate from representative samples or cohorts of XDR TB patients that were employed prior or during XDR TB diagnosis associated losses in personal productivity and salary losses on the basis of the extent and pattern of drug resistance, chronic disease, and the impact of patient mortality (age at death and time to death). 66.1.4. From a survey of XDR TB survivors and their family members, estimate loss of quality-adjusted life years on the basis of extent and patterns of drug-resistant TB disease. 66.1.5. Conduct patient interviews to estimate out-of-pocket medical expenses associated with XDR TB disease. Lead federal agencies: HHS (CDC). Suggested collaborators: state/local Departments of Health, public and private outpatient providers and hospitals, laboratories, former patients, and family members. # Problem 67 Cost-effective strategies to prevent XDR TB remain to be established. 67.1.4. Determine the cost benefit for each prevention strategy in relation to cost that would have been incurred to treat XDR TB. Lead federal agencies: HHS (CDC). Suggested collaborators: state and local health departments, and academia. # Conclusion The nine response areas addressed in this report are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug sensitivity testing, 3) improve technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities. The Federal TB Task Force Plan and the Global Action Plan will require a renewed commitment by all public health workers as well as new resources from both the public and private sectors. In the United States, federal funding has remained relatively level since 2000, and state and local funding has declined in many states since 2000. As a result, TB prevention and control capacity in the United States has eroded. For example, many states have decided to implement selective rather than universal patient-centered DOT to ensure adherence to treatment until complete. These decisions are made on the basis of financial constraints but place the patient at high risk for treatment failure and subsequently the potential creation of MDR TB or XDR TB. In the absence of shorter treatment regimens, and without adherence-promoting measures such as DOT, the TB patient is more likely to experience drug resistance that could result from interruptions in treatment. These choices place the public and the nation in a vulnerable position, risking outbreaks of MDR or XDR TB if conditions facilitate rapid spread and possibly causing public health crises. (42,43) The Federal TB Task Force Plan provides an effective framework to detect, prevent, and control XDR TB, but it also highlights the existence of substantial unmet needs. There is concern that progress in TB prevention and control is waning as manifested by the decrease in the rate of decline in TB incidence since 2000. The United States responded successfully to the MDR TB problem in the 1990s and is capable of preventing and controlling XDR TB; however, this will require a united commitment and effort similar to that which occurred in 1992.	None	None
f10f8bdc4772dd4daba3b6934a9a06ae757e546f	cdc	None	Cleaning and disinfecting are part of a broad approach to preventing infectious diseases in schools. To help slow the spread of influenza (flu), the first line of defense is getting vaccinated. Other measures include covering coughs and sneezes, washing hands, and keeping sick people away from others. Below are tips on how to slow the spread of flu specifically through cleaning and disinfecting.# 1. Know the difference between cleaning, disinfecting, and sanitizing. Cleaning removes germs, dirt, and impurities from surfaces or objects. Cleaning works by using soap (or detergent) and water to physically remove germs from surfaces. This process does not necessarily kill germs, but by removing them, it lowers their numbers and the risk of spreading infection. Disinfecting kills germs on surfaces or objects. Disinfecting works by using chemicals to kill germs on surfaces or objects. This process does not necessarily clean dirty surfaces or remove germs, but by killing germs on a surface after cleaning, it can further lower the risk of spreading infection. Sanitizing lowers the number of germs on surfaces or objects to a safe level, as judged by public health standards or requirements. This process works by either cleaning or disinfecting surfaces or objects to lower the risk of spreading infection. 2. Clean and disinfect surfaces and objects that are touched often. Follow your school's standard procedures for routine cleaning and disinfecting. Typically, this means daily sanitizing surfaces and objects that are touched often, such as desks, countertops, doorknobs, computer keyboards, hands-on learning items, faucet handles, phones, and toys. Some schools may also require daily disinfecting these items. Standard procedures often call for disinfecting specific areas of the school, like bathrooms. Immediately clean surfaces and objects that are visibly soiled. If surfaces or objects are soiled with body fluids or blood, use gloves and other standard precautions to avoid coming into contact with the fluid. Remove the spill, and then clean and disinfect the surface. # Simply do routine cleaning and disinfecting. It's important to match your cleaning and disinfecting activities to the types of germs you want to remove or kill. Most studies have shown that the flu virus can live and potentially infect a person for only 2 to 8 hours after being deposited on a surface. Therefore, it is not necessary to close schools to clean or disinfect every surface in the building to slow the spread of flu. Also, if students and staff are dismissed because the school cannot function normally (e.g., high absenteeism during a flu outbreak), it is not necessary to do extra cleaning and disinfecting. Flu viruses are relatively fragile, so standard cleaning and disinfecting practices are sufficient to remove or kill them. Special cleaning and disinfecting processes, including wiping down walls and ceilings, frequently using room air deodorizers, and fumigating, are not necessary or recommended. These processes can irritate eyes, noses, throats, and skin; aggravate asthma; and cause other serious side effects. # Clean and disinfect correctly. Always follow label directions on cleaning products and disinfectants. Wash surfaces with a general household cleaner to remove germs. Rinse with water, and follow with an EPA-registered disinfectant to kill germs. Read the label to make sure it states that EPA has approved the product for effectiveness against influenza A virus. If an EPA-registered disinfectant is not available, use a fresh chlorine bleach solution. To make and use the solution: - Add 1 tablespoon of bleach to 1 quart (4 cups) of water. For a larger supply of disinfectant, add ¼ cup of bleach to 1 gallon (16 cups) of water. - Apply the solution to the surface with a cloth. - Let it stand for 3 to 5 minutes. - Rinse the surface with clean water. If a surface is not visibly dirty, you can clean it with an EPAregistered product that both cleans (removes germs) and disinfects (kills germs) instead. Be sure to read the label directions carefully, as there may be a separate procedure for using the product as a cleaner or as a disinfectant. Disinfection usually requires the product to remain on the surface for a certain period of time. Use disinfecting wipes on electronic items that are touched often, such as phones and computers. Pay close attention to the directions for using disinfecting wipes. It may be necessary to use more than one wipe to keep the surface wet for the stated length of contact time. Make sure that the electronics can withstand the use of liquids for cleaning and disinfecting. Routinely wash eating utensils in a dishwasher or by hand with soap and water. Wash and dry bed sheets, towels, and other linens as you normally do with household laundry soap, according to the fabric labels. Eating utensils, dishes, and linens used by sick persons do not need to be cleaned separately, but they should not be shared unless they've been washed thoroughly. Wash your hands with soap and water after handling soiled dishes and laundry items. # Use products safely. Pay close attention to hazard warnings and directions on product labels. Cleaning products and disinfectants often call for the use of gloves or eye protection. For example, gloves should always be worn to protect your hands when working with bleach solutions. Do not mix cleaners and disinfectants unless the labels indicate it is safe to do so. Combining certain products (such as chlorine bleach and ammonia cleaners) can result in serious injury or death. Ensure that custodial staff, teachers, and others who use cleaners and disinfectants read and understand all instruction labels and understand safe and appropriate use. This might require that instructional materials and training be provided in other languages. # Handle waste properly. Follow your school's standard procedures for handling waste, which may include wearing gloves. Place no-touch waste baskets where they are easy to use. Throw disposable items used to clean surfaces and items in the trash immediately after use. Avoid touching used tissues and other waste when emptying waste baskets. Wash your hands with soap and water after emptying waste baskets and touching used tissues and similar waste.	Cleaning and disinfecting are part of a broad approach to preventing infectious diseases in schools. To help slow the spread of influenza (flu), the first line of defense is getting vaccinated. Other measures include covering coughs and sneezes, washing hands, and keeping sick people away from others. Below are tips on how to slow the spread of flu specifically through cleaning and disinfecting.# 1. Know the difference between cleaning, disinfecting, and sanitizing. Cleaning removes germs, dirt, and impurities from surfaces or objects. Cleaning works by using soap (or detergent) and water to physically remove germs from surfaces. This process does not necessarily kill germs, but by removing them, it lowers their numbers and the risk of spreading infection. Disinfecting kills germs on surfaces or objects. Disinfecting works by using chemicals to kill germs on surfaces or objects. This process does not necessarily clean dirty surfaces or remove germs, but by killing germs on a surface after cleaning, it can further lower the risk of spreading infection. Sanitizing lowers the number of germs on surfaces or objects to a safe level, as judged by public health standards or requirements. This process works by either cleaning or disinfecting surfaces or objects to lower the risk of spreading infection. 2. Clean and disinfect surfaces and objects that are touched often. Follow your school's standard procedures for routine cleaning and disinfecting. Typically, this means daily sanitizing surfaces and objects that are touched often, such as desks, countertops, doorknobs, computer keyboards, hands-on learning items, faucet handles, phones, and toys. Some schools may also require daily disinfecting these items. Standard procedures often call for disinfecting specific areas of the school, like bathrooms. Immediately clean surfaces and objects that are visibly soiled. If surfaces or objects are soiled with body fluids or blood, use gloves and other standard precautions to avoid coming into contact with the fluid. Remove the spill, and then clean and disinfect the surface. # Simply do routine cleaning and disinfecting. It's important to match your cleaning and disinfecting activities to the types of germs you want to remove or kill. Most studies have shown that the flu virus can live and potentially infect a person for only 2 to 8 hours after being deposited on a surface. Therefore, it is not necessary to close schools to clean or disinfect every surface in the building to slow the spread of flu. Also, if students and staff are dismissed because the school cannot function normally (e.g., high absenteeism during a flu outbreak), it is not necessary to do extra cleaning and disinfecting. Flu viruses are relatively fragile, so standard cleaning and disinfecting practices are sufficient to remove or kill them. Special cleaning and disinfecting processes, including wiping down walls and ceilings, frequently using room air deodorizers, and fumigating, are not necessary or recommended. These processes can irritate eyes, noses, throats, and skin; aggravate asthma; and cause other serious side effects. # Clean and disinfect correctly. Always follow label directions on cleaning products and disinfectants. Wash surfaces with a general household cleaner to remove germs. Rinse with water, and follow with an EPA-registered disinfectant to kill germs. Read the label to make sure it states that EPA has approved the product for effectiveness against influenza A virus. If an EPA-registered disinfectant is not available, use a fresh chlorine bleach solution. To make and use the solution: • Add 1 tablespoon of bleach to 1 quart (4 cups) of water. For a larger supply of disinfectant, add ¼ cup of bleach to 1 gallon (16 cups) of water. • Apply the solution to the surface with a cloth. • Let it stand for 3 to 5 minutes. • Rinse the surface with clean water. If a surface is not visibly dirty, you can clean it with an EPAregistered product that both cleans (removes germs) and disinfects (kills germs) instead. Be sure to read the label directions carefully, as there may be a separate procedure for using the product as a cleaner or as a disinfectant. Disinfection usually requires the product to remain on the surface for a certain period of time. Use disinfecting wipes on electronic items that are touched often, such as phones and computers. Pay close attention to the directions for using disinfecting wipes. It may be necessary to use more than one wipe to keep the surface wet for the stated length of contact time. Make sure that the electronics can withstand the use of liquids for cleaning and disinfecting. Routinely wash eating utensils in a dishwasher or by hand with soap and water. Wash and dry bed sheets, towels, and other linens as you normally do with household laundry soap, according to the fabric labels. Eating utensils, dishes, and linens used by sick persons do not need to be cleaned separately, but they should not be shared unless they've been washed thoroughly. Wash your hands with soap and water after handling soiled dishes and laundry items. # Use products safely. Pay close attention to hazard warnings and directions on product labels. Cleaning products and disinfectants often call for the use of gloves or eye protection. For example, gloves should always be worn to protect your hands when working with bleach solutions. Do not mix cleaners and disinfectants unless the labels indicate it is safe to do so. Combining certain products (such as chlorine bleach and ammonia cleaners) can result in serious injury or death. Ensure that custodial staff, teachers, and others who use cleaners and disinfectants read and understand all instruction labels and understand safe and appropriate use. This might require that instructional materials and training be provided in other languages. # Handle waste properly. Follow your school's standard procedures for handling waste, which may include wearing gloves. Place no-touch waste baskets where they are easy to use. Throw disposable items used to clean surfaces and items in the trash immediately after use. Avoid touching used tissues and other waste when emptying waste baskets. Wash your hands with soap and water after emptying waste baskets and touching used tissues and similar waste.	None	None
71474dec8fc94c122380386c86ec4da6f76fc44b	cdc	None	Surveillance of dead birds for WNV has proven useful for the early detection of WNV in the United States. In recent months, it has also proven useful for the early detection of highly pathogenic H5N1 avian influenza A (HPAI H5N1, hereafter referred to as H5N1 virus) in Europe. Given the potential for H5N1 to infect wild birds in North America in the future, the following interim guidance is offered to support the efforts of states conducting avian mortality surveillance.# General Considerations for States Conducting Avian Mortality Surveillance - If different agencies within a state are separately responsible for conducting surveillance for WNV or H5N1 among wild birds, the sharing of resources, including dead birds submitted for testing, may increase the efficiency of both systems. - Any dead bird might be infected with any one of a number of zoonotic diseases currently present in the United States (US), such as WNV. However, in countries where H5N1 has been found in captive and wild birds, it frequently has resulted in multiple deaths within and across species, and if H5N1 enters the US, it is likely to result in the death of wild birds. If wild birds in the US are exposed to the virus, both single and groups of dead birds should be considered potentially infected. - Avian mortality due to the introduction of H5N1 could occur at any time of the year, whereas WNV is more often detected when mosquitoes are active. - To date, no human infections of WNV have been confirmed due to contact with live or dead wild birds in outdoor settings. - Most human H5N1 cases overseas have been associated with close contact with infected poultry or their environment; however, a very small number of cases appear to be related to the handling of infected wild birds or their feathers or feces without the use of proper personal protective equipment (PPE). There is no evidence of H5N1 transmission to humans from exposure to H5N1 virus-contaminated water during swimming; however this may be theoretically possible. # Infection Control and Health and Safety Precautions These guidelines are intended for any person handling dead birds. The risk of infection with WNV from such contact is small. The risk of infection with H5N1 from handling dead birds is difficult to quantify and is likely to vary with each situation. Risk is related to the nature of the work environment, the number of birds to be collected, and the potential for aerosolization of bird feces, body fluids, or other tissues. The most important factor that will influence the degree of infection risk from handling wild birds is whether H5N1 has been reported in the area. Local public health officials can be consulted to help in selecting the most appropriate PPE for the situation. General Precautions for Collection of Single Dead Birds (These precautions are applicable to employees as well as the general public) When collecting dead birds, the risk of infection from WNV, H5N1, or any other pathogen may be eliminated by avoiding contamination of mucous membranes, eyes, and skin by material from the birds. This can be accomplished by eliminating any direct contact with dead birds via use of the following safety precautions: - When picking up any dead bird, wear disposable impermeable gloves and place it directly into a plastic bag. Gloves should be changed if torn or otherwise damaged. If gloves are not available, use an inverted double-plastic bag technique for picking up carcasses or use a shovel to scoop the carcass into a plastic bag. - In situations in which the bird carcass is in a wet environment or in other situations in which splashing or aerosolization of viral particles is likely to occur during disposal, safety goggles or glasses and a surgical mask may be worn to protect mucous membranes against splashed droplets or particles. - Bird carcasses should be double bagged and placed in a trash receptacle that is secured from access by children and animals. If the carcass will be submitted for testing, hold it a cool location until it pickup or delivery to authorities. Carcasses should not be held in close contact with food (e.g., not in a household refrigerator or picnic cooler). - After handling any dead bird, avoid touching the face with gloved or unwashed hands. - Any PPE that was used (e.g. gloves, safety glasses, mask) should be discarded or disinfected- when done, and hands should then be washed with soap and water (or use an alcohol-based hand gel when soap and water are not available). / - If possible, before disposing of the bird, members of the public may wish to consult with their local animal control, health, wildlife or agricultural agency or other such entity to inquire whether dead bird reports are being tallied and if the dead bird in question might be a candidate for WNV or H5N1 testing. Additional Precautions for Personnel Tasked with Collecting Dead Birds in Higher-Risk Settings (e.g., when collecting large numbers or in confined indoor spaces, particularly once H5N1 has been confirmed in an area) - Minimize any work activities that generate airborne particles. For example, during the cleanup phase of the bird removal, avoid washing surfaces with pressurized water or cleaner (i.e., pressure washing), which could theoretically aerosolize H5N1 viral particles that could then be inhaled. If aerosolization is unavoidable, the use of a filtering face-piece respirator (e.g., N95) would be prudent, particularly while handling large quantities of dead birds repeatedly as part of regular work requirements. - If using safety glasses, a mask, or a respirator, do not remove until after gloves have been removed and hands have been washed with soap and water (or use an alcohol-based hand gel when soap and water are not available). After PPE has been removed, hands should immediately be cleaned again. / Personal protective equipment worn (e.g., gloves, mask, or clothing) should be disinfected- or discarded. - Discuss appropriate biosafety practices and PPE use with your employer. # *Recommendations for PPE Disinfection For machine-washable, reusable PPE: Disinfect PPE in a washing machine with detergent in a normal wash cycle. Adding bleach will increase the speed of viral inactivation as will hot water but detergent alone in cold water will be effective. Follow manufacturer recommendations for drying the PPE. Non machine-washable, reusable PPE should be cleaned following the manufacturer's recommendations for cleaning. # Laboratory Biosafety Recommendations Laboratory handling of routine diagnostic specimens of avian carcasses requires a minimum of BSL-2 laboratory safety precautions. However, if either WNV or H5N1 infection of the specimens is suspected on the basis of previous surveillance findings, at a minimum BSL-3 precautions are advisable. Consult your institutional biosafety officer for specific recommendations. Biosafety levels are described at www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4s3.htm. # Additional Information Sources	Surveillance of dead birds for WNV has proven useful for the early detection of WNV in the United States. In recent months, it has also proven useful for the early detection of highly pathogenic H5N1 avian influenza A (HPAI H5N1, hereafter referred to as H5N1 virus) in Europe. Given the potential for H5N1 to infect wild birds in North America in the future, the following interim guidance is offered to support the efforts of states conducting avian mortality surveillance.# General Considerations for States Conducting Avian Mortality Surveillance • If different agencies within a state are separately responsible for conducting surveillance for WNV or H5N1 among wild birds, the sharing of resources, including dead birds submitted for testing, may increase the efficiency of both systems. • Any dead bird might be infected with any one of a number of zoonotic diseases currently present in the United States (US), such as WNV. However, in countries where H5N1 has been found in captive and wild birds, it frequently has resulted in multiple deaths within and across species, and if H5N1 enters the US, it is likely to result in the death of wild birds. If wild birds in the US are exposed to the virus, both single and groups of dead birds should be considered potentially infected. • Avian mortality due to the introduction of H5N1 could occur at any time of the year, whereas WNV is more often detected when mosquitoes are active. • To date, no human infections of WNV have been confirmed due to contact with live or dead wild birds in outdoor settings. • Most human H5N1 cases overseas have been associated with close contact with infected poultry or their environment; however, a very small number of cases appear to be related to the handling of infected wild birds or their feathers or feces without the use of proper personal protective equipment (PPE). There is no evidence of H5N1 transmission to humans from exposure to H5N1 virus-contaminated water during swimming; however this may be theoretically possible. # Infection Control and Health and Safety Precautions These guidelines are intended for any person handling dead birds. The risk of infection with WNV from such contact is small. The risk of infection with H5N1 from handling dead birds is difficult to quantify and is likely to vary with each situation. Risk is related to the nature of the work environment, the number of birds to be collected, and the potential for aerosolization of bird feces, body fluids, or other tissues. The most important factor that will influence the degree of infection risk from handling wild birds is whether H5N1 has been reported in the area. Local public health officials can be consulted to help in selecting the most appropriate PPE for the situation. General Precautions for Collection of Single Dead Birds (These precautions are applicable to employees as well as the general public) When collecting dead birds, the risk of infection from WNV, H5N1, or any other pathogen may be eliminated by avoiding contamination of mucous membranes, eyes, and skin by material from the birds. This can be accomplished by eliminating any direct contact with dead birds via use of the following safety precautions: • When picking up any dead bird, wear disposable impermeable gloves and place it directly into a plastic bag. Gloves should be changed if torn or otherwise damaged. If gloves are not available, use an inverted double-plastic bag technique for picking up carcasses or use a shovel to scoop the carcass into a plastic bag. • In situations in which the bird carcass is in a wet environment or in other situations in which splashing or aerosolization of viral particles is likely to occur during disposal, safety goggles or glasses and a surgical mask may be worn to protect mucous membranes against splashed droplets or particles. • Bird carcasses should be double bagged and placed in a trash receptacle that is secured from access by children and animals. If the carcass will be submitted for testing, hold it a cool location until it pickup or delivery to authorities. Carcasses should not be held in close contact with food (e.g., not in a household refrigerator or picnic cooler). • After handling any dead bird, avoid touching the face with gloved or unwashed hands. • Any PPE that was used (e.g. gloves, safety glasses, mask) should be discarded or disinfected* when done, and hands should then be washed with soap and water (or use an alcohol-based hand gel when soap and water are not available). http://www.cdc.gov/cleanhands/ • If possible, before disposing of the bird, members of the public may wish to consult with their local animal control, health, wildlife or agricultural agency or other such entity to inquire whether dead bird reports are being tallied and if the dead bird in question might be a candidate for WNV or H5N1 testing. Additional Precautions for Personnel Tasked with Collecting Dead Birds in Higher-Risk Settings (e.g., when collecting large numbers or in confined indoor spaces, particularly once H5N1 has been confirmed in an area) • Minimize any work activities that generate airborne particles. For example, during the cleanup phase of the bird removal, avoid washing surfaces with pressurized water or cleaner (i.e., pressure washing), which could theoretically aerosolize H5N1 viral particles that could then be inhaled. If aerosolization is unavoidable, the use of a filtering face-piece respirator (e.g., N95) would be prudent, particularly while handling large quantities of dead birds repeatedly as part of regular work requirements. • If using safety glasses, a mask, or a respirator, do not remove until after gloves have been removed and hands have been washed with soap and water (or use an alcohol-based hand gel when soap and water are not available). After PPE has been removed, hands should immediately be cleaned again. http://www.cdc.gov/cleanhands/ Personal protective equipment worn (e.g., gloves, mask, or clothing) should be disinfected* or discarded. • Discuss appropriate biosafety practices and PPE use with your employer. # *Recommendations for PPE Disinfection For machine-washable, reusable PPE: Disinfect PPE in a washing machine with detergent in a normal wash cycle. Adding bleach will increase the speed of viral inactivation as will hot water but detergent alone in cold water will be effective. Follow manufacturer recommendations for drying the PPE. Non machine-washable, reusable PPE should be cleaned following the manufacturer's recommendations for cleaning. # Laboratory Biosafety Recommendations Laboratory handling of routine diagnostic specimens of avian carcasses requires a minimum of BSL-2 laboratory safety precautions. However, if either WNV or H5N1 infection of the specimens is suspected on the basis of previous surveillance findings, at a minimum BSL-3 precautions are advisable. Consult your institutional biosafety officer for specific recommendations. Biosafety levels are described at www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4s3.htm. # Additional Information Sources	None	None
b6c5e996b275f53c5ba1b786cf986d2952e0a4d7	cdc	None	Because case management of children with elevated blood lead levels varies markedly among states, cities, and other jurisdictions, the Advisory Committee on Childhood Lead Poisoning Prevention developed these nationally applicable recommendations. Based on recently published studies and augmented with opinions of experts, this report defines the elements of case management and offers assessment and management guidelines for health departments, case managers, primary care physicians, and other professionals. Not all recommendations are appropriate for any individual child because of variations in age, blood lead level, housing status, and-most important-the ability of caregivers to respond to recommendations without being overwhelmed. The report contains five chapters in addition to the introduction: home environment investigation and interventions, medical evaluation and treatment, nutritional assessment and dietary modification, developmental surveillance and interventions, and education for caregivers. At the beginning of each chapter is a summary table of specific management recommendations. (The remainder of the tables, the figures, and the references are at the end of each chapter.) The text of the chapters provides the detailed information and references upon which most recommendations are based. Each chapter concludes with suggestions for further research. This report, in addition to addressing the case management of individual children, also discusses the importance of state laws, regulations, and financing related to lead abatement efforts and the provision of appropriate services for affected children. Finally, the authors of this report recognize that case management is involved with the secondary prevention of elevated blood lead levels and that primary prevention by the removal of ongoing lead exposure sources should be promoted as the ideal and most effective means of preventing elevated blood lead levels.# Table of Contents # List of Tables # Managing Elevated Blood Lead Levels Among Young Children vii # Foreword The overall reduction in childhood lead levels over the last three decades has been one of the great environmental health success stories in this country. However, our goal has not yet been reached. There are still far too many lower-income children living in older housing who are being hurt by elevated blood lead levels. The public health, housing, and environmental communities must continue to work together to eliminate the threat of lead poisoning for our future generations. An important factor in the battle against lead poisoning is the proper management of children who have been identified as having elevated blood lead levels. In this publication, the Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) and other public health practitioners have developed guidelines for assessment and interventions in the areas of medicine, nutrition, environmental exposure, childhood development, and education. Implementation of these "Best Practices" will greatly assist case managers, medical care providers, and others in delivering the most effective services to the lead poisoned child and the child's caregiver. I congratulate the ACCLPP and all the authors of these guidelines and thank them for their efforts. This report is a critical piece in the nation's effort to eliminate childhood lead poisoning in America by the year 2010. # Richard Joseph Jackson, MD, MPH Director, National Center for Environmental Health Managing Elevated Blood Lead Levels Among Young Children ix # Development of the Case Management Recommendations This report from the Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) is intended to facilitate the management of children with elevated blood lead levels (EBLLs) by providing case managers with information and guidance. Some of the assessments and interventions recommended herein will be the primary responsibility not of case managers, but of other individuals or groups-primary care providers (PCPs), public health agencies, nutritionists, managed care organizations, and environmental inspectors-for whom this document should be considered as only a supplementary, not primary, source of information. Through this document, however, case managers can become familiar with the activities and responsibilities of others, and thus be better prepared to offer them guidance, assistance, and support. Many studies published since the 1991 Centers for Disease Control and Prevention (CDC) report Preventing Lead Poisoning in Young Children (1) have provided updated or new information that can assist case managers of affected children and their families. In response, some states and localities have implemented a variety of changes in case management procedures. The plethora of new information and the marked variation in assessment and management policies among various jurisdictions were the main stimuli for the development of these guidelines. This report is divided into five chapters other than this introduction: four that present assessment and intervention guidelines from environmental, medical, nutritional, and developmental viewpoints plus one that presents caregiver education guidelines. Experts in each subject area were asked to summarize recommended case management actions; to provide a detailed, referenced basis for their recommendations; and to suggest the most important areas for future research to support, modify, or eliminate poorly justified or empirically based recommendations. Recommendations in each chapter are based on the results of evidence-based studies wherever possible. The most convincing basis for a specific recommendation is data from prospective, randomized, controlled trials. Unfortunately, such data are scarce; therefore, experts who developed each chapter had to rely primarily on softer data from cross-sectional studies, cohort or case controlled studies, uncontrolled studies, epidemiologic data, and-if appropriate-case reports or animal studies. They were also asked to note whether studies of interventions used to support their recommendations were efficacy studies (studies performed under ideal conditions) or effectiveness studies (studies performed in ordinary settings). In the absence of sufficient study data, the opinions of respected authorities were considered in the formulation of these recommendations. Recommendations, particularly those not based on controlled studies, were often modified by the ACCLPP working group and subsequently by the full committee. Thus, in their final form, the recommendations in this report represent the consensus of the ACCLPP rather than individual opinions of the authors of each chapter. # Chapter 1. Introduction This report is written primarily for those who will provide case management for children with EBLLs and for health department personnel who oversee case management follow-up. Because there is unavoidable overlap among chapters, interested professionals may gain insight from chapters covering areas outside their own expertise. For example, a nutritionist or a PCP will find iron stores and anemia discussed in both the medical and the nutritional sections. Although the primary cause of EBLLs in children is exposure to deteriorated paint in housing built before 1950, other sources of lead are found in some states and localities. Consequently, users of these guidelines may need to modify them to meet the needs unique to specific communities. Further, because the prevalence of EBLLs among children will vary markedly among and within states, the number of children managed will show corresponding variation. Because there is no apparent threshold below which adverse effects of lead do not occur, "EBLL" must be defined arbitrarily. This report uses the definition given in the 1997 CDC report Screening Young Children for Lead Poisoning (2), which defined child blood lead levels (BLLs) $10 Fg/dL as elevated. Although the BLL at which particular elements of case management will be initiated is variable, education and follow-up BLL monitoring should be available for any child who has a confirmed BLL $10 Fg/dL. More intense management, including home visiting and environmental investigation, should be available to any child with a BLL $ 20 Fg/dL, or persistent levels in the 15 to 19 Fg/dL range. Another variable, the duration of management, will depend on the effects of lead on the child being treated. As noted in Chapter 5, "Developmental Assessment and Interventions," the effect of lead on a child may not be demonstrable until the child is well into the elementary school years, meaning that some children will need continued tracking by PCPs or others long after their case management ends. The interventions recommended in this report are for the secondary prevention of EBLLs-which is to prevent further lead exposure and to reduce BLLs in children who have been identified as having EBLLs-and involve a number of scientific, technical, and implementation issues. The ultimate goal, primary prevention-the removal of harmful lead exposure sources (especially older, deteriorated housing) and the elimination of lead from products with which children may come in direct or indirect contact-involves other, sometimes overlapping, issues. The importance of primary prevention should not be overlooked, since the behavioral and cognitive effects of EBLLs in young children are apparently irreversible. # Overview of Comprehensive Case Management # What Is Case Management? Case management of children with EBLLs involves coordinating, providing, and overseeing the services required to reduce their BLLs below the level of concern (i.e., 10 Fg/dL). It is based on the efforts of an organized team that includes the child's caregivers. A hallmark of effective case management is ongoing communication with the caregivers and other service providers, and a cooperative approach to solving any problems that may arise during efforts to decrease the child's BLL and eliminate lead hazards in the child's environment. Case management is not simply referring a child to other service providers, contacting caregivers by telephone, or other minimal activities. The current model of case management has eight components: client identification and outreach; individual assessment and diagnosis; service planning and resource identification; the linking of clients to needed services; service implementation and coordination; the monitoring of service delivery; advocacy; and evaluation (3). Once an eligible child is identified, the case manager should do the following: Visit the child's residence (and other sites where the child spends significant amounts of time) a minimum of two times. - Assess factors that may impact the child's BLL (including sources of lead, nutrition, access to services, family interaction, and caregiver understanding). Oversee the activities of the case management team. - Develop a written plan for intervention. Coordinate the implementation of the plan. Evaluate compliance with the plan and the success of the plan. An environmental inspector should also visit the child's residence, with the case manager if possible, to conduct a thorough investigation of the site and identify sources of environmental lead exposure. The case management team can then use the results of this investigation to develop a plan to protect the child and correct hazardous conditions. Although environmental services may be provided by the case manager, the environmental inspector, or other program staff, the case manager is responsible for ensuring that a child receives services in a timely fashion. # Funding Nationally, an estimated 83% of children with BLLs $ 20 Fg/dL are eligible for Medicaid (4). Both the case management of eligible children and the environmental investigation of their surroundings are reimbursable according to federal Medicaid policy, with each state responsible for setting reimbursement rates for eligible services. Despite this, funding for services remains a critical resource issue for most states. Fewer than half of all states provide Medicaid reimbursement for lead follow-up services, with the level of reimbursement varying widely. In addition, most state programs do not know how many children with BLLs $ 20 Fg/dL also receive Medicaid. As of 2000, only 10 state lead programs Chapter 1. Introduction were able to successfully identify Medicaid children by linking their Medicaid and lead screening data bases (5). # Who Provides Case Management? Ninety percent of programs use professionals (nurses or social workers) to deliver case management services (6). The case manager is usually a member of the local health department staff, although nearly half of all states also use other providers to deliver case management services. In most cases, a management team can best meet the needs of an individual child. The team may include the case manager, the child's caregiver, the child's PCP, an environmental inspector, a health educator, a nutritionist, and the local public health agency. # Time Frames for Initiating Case Management Services A case manager should schedule an appointment with the child's caregiver as soon as possible after being assigned to the case. Where feasible, public health agencies providing case management services should give priority to children with the highest BLLs and those less than 2 years of age. If the caregiver does not have a telephone, the case manager should visit the child's home and leave information at the door if no one is there. For children with BLLs $ 45 Fg/dL, the case manager should contact the child's PCP immediately to determine whether the child is being chelated at home or in the hospital. If the child is hospitalized, the initial visit may take place at the hospital. However, it is critical that team members conduct a hazard assessment in the child's home as quickly as possible. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," and Chapter 3, "Medical Assessment and Interventions.") Blood # The Case Management Plan The case manager is responsible for developing and implementing a written management plan based on a needs assessment done at visits to the child's home and other sites where the child spends significant amounts of time. Although all cases require a Chapter 1. Introduction minimum of two home visits, additional visits are often necessary. The caregivers also should be involved in developing the plan to ensure that it is realistic and meets their perceived needs. Areas the plan should cover are detailed in Table 1.1 and in specific sections of this report. # Coordination of Care by the Case Manager The case manager is responsible for coordinating care and ensuring that all team members, including the caregiver, stay in communication and work together. Such communication includes verbal consultations with and written summaries of progress for team members. Case managers need not directly provide all follow-up care, but they are responsible for seeing that needed care is provided, including medical follow-up. In most jurisdictions, the environmental inspector or program issues and enforces lead hazard remediation orders. The case manager must be sufficiently knowledgeable about environmental investigation and follow-up, however, to ensure that inspection and remediation take place in a timely fashion and that short-term efforts are made to decrease an affected child's exposure to lead hazards. Similarly, the case manager is responsible for ensuring that someone follows up on referrals for other problems identified during case management. # Case Closure It often takes an extended period of time to complete all the elements in a case management plan. When the environmental lead hazards have been eliminated, the child's BLL has declined to below 15 Fg/dL for at least 6 months, and other objectives of the plan have been achieved, the case should be closed. However, the case manager should discuss with the PCP and caregiver provisions for appropriate long-term developmental follow-up. (See Chapter 5, "Developmental Assessment and Interventions".) Case closure criteria should also include provisions for administrative closeout if at least three documented attempts to locate or gain access to the child and caregiver have failed. # Public Health Agency Role Although the recommended public health agency activities are not part of case management per se, they are necessary to achieve optimum results. With their focus on the core public health functions of assessment, policy development, and quality assurance, public health agencies play a broad role in coordinating care at the state and local level. They also are responsible for initiating and implementing laws and regulations that will help to eliminate childhood lead poisoning. Local jurisdictions must have the political will Chapter 1. Introduction to take enforcement actions, where needed, to protect the health of children. The identification of affected children and exposure sources will have little impact unless lead hazards are eliminated in a timely manner. Public health agencies should take the following steps to coordinate care in six areas: Screening and surveillance: Ensure that screening of at-risk children is conducted in accordance with the state or local plan. Develop and maintain communication and good working relationships with PCPs and public and private health delivery organizations (including Medicaid). - Laboratory testing and reporting: Require that EBLL test results (and, ideally, all blood lead test results) be reported in a timely and accurate manner, and provide oversight to ensure such reporting. Implement quality control measures for both environmental and blood specimens to ensure the validity and reliability of results. # General Considerations There are several guiding principles to consider when making recommendations for children with EBLLs. First, interventions should be directed at children whose risk for lead exposure is high. Second, where possible, interventions should be targeted at children less than 2 years old because neurotoxicity is greater and lead exposure is more likely to result in a rapid increase in BLLs in very young children. Finally, when intervention recommendations are based on tenuous data or on expert opinion, as are some in this document, case managers and other involved professionals should more than ever remember primum non nocere (first, do no harm). Most children with EBLLs come from economically disadvantaged families who may have difficulty meeting the daily challenges of life and who may be overwhelmed if presented with a long list of interventions. Further, as has been found in many studies of interventions to combat other childhood problems (injury prevention, dietary counseling), behavioral change recommendations usually have only a modest effect at best. Thus, better results may be achieved by focusing on the most important recommendations (usually those designed to eliminate environmental lead hazards) and assisting caregivers in implementing them. Encouraging and supporting families without making them feel guilty for their child's EBLL or making unrealistic demands on them may offer the greatest benefit to the child. # Introduction Recent research concerning lead exposure from leaded paint in the residential environment has shown that some of the recommendations on managing lead hazards in the child's environment made in the 1991 Centers for Disease Control and Prevention (CDC) guidance, Preventing Lead Poisoning in Young Children, need updating (1). In addition, a regulation to control lead exposure from public drinking water (2), implemented during the 1990s, makes possible a more focused approach to assessing that source than was previously recommended. This chapter summarizes current knowledge concerning children's lead exposure in the residential environment, recommends interventions directed at reducing or eliminating lead exposure, and provides information to guide state and local officials in developing and updating policies and procedures for identifying and managing lead hazards in the residential environment of children with elevated blood lead levels (EBLLs). Detailed technical protocols for assessing and correcting lead hazards in a variety of situations can be found in guidance developed by the Department of Housing and Urban Development (HUD) for property owners, private contractors, and government housing agencies (3). These are cited where appropriate. # Sources and pathways of residential lead exposure Lead can be found in high concentrations in three media to which children may be directly or indirectly exposed: paint, interior dust, and exterior soil or dust. This section discusses the distribution of lead in these media and their relationships to one another and to blood lead levels (BLLs) in children (Figure 2.1). Lead in tap water, generally a lower dose source of exposure, is also addressed. # Paint Although the addition of lead to residential paint and similar surface-coating materials, such as varnishes and stains, was banned in 1978 (4), 74% of dwellings constructed prior to 1980 contain some leaded paint. - The amount of lead in paint is much greater in homes built before 1950 than in homes built later but prior to the ban on leaded house paint. For example, 90% of - Throughout this document, the term "paint" will be used to refer to paint and, where appropriate, similar surface-coating materials such as varnishes and stains. Paints and coatings manufactured since 1978 must contain < 0.06% lead by weight. For testing of lead content in existing structures, the regulatory threshold for defining "lead based paint" is $ 1 milligram of lead per square centimeter of paint film or $ 0.5 % lead by weight. These standards, however, were based on the limitations of measurement techniques available when they were formulated rather than on health considerations. dwellings built before 1940 have paint containing more than 1 mg/cm 2 of lead, compared with 62% of dwellings built from 1960 through 1979. The relative contrast is much greater for paint containing more than 2 mg/cm 2 : 75% versus 18%, respectively (5). Direct and indirect exposure of children to leaded paint that has deteriorated because of deferred maintenance is likely the major factor in the increased risk for EBLL associated with poverty and living in older housing. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that the prevalence of EBLLs among children living in homes built before 1946 is five times higher than that among children living in homes built after 1973 (most of which do not have leaded paint) (6). Furthermore, for low-income children living in pre-1946 dwellings, the prevalence of EBLLs is 16%, compared with 4% for middle-income children living in such dwellings (6). Although children may be exposed to lead from paint directly by ingesting paint chips (7), they are more commonly exposed by ingesting house dust or soil contaminated by leaded paint (8,9). Federal law defines a leaded paint hazard as a condition in which exposure to lead from lead-contaminated dust, lead-contaminated soil, or deteriorated leaded paint would have an adverse effect on human health (10). Lead contamination of dust or soil occurs when leaded paint deteriorates or is subject to friction or abrasion (as on window sashes). In addition, lead can be dispersed when paint is disturbed during demolition, remodeling, paint removal, or preparation of painted surfaces for repainting. In a population-based study in Wisconsin, about two-thirds of children who had a blood lead test lived in a home that had undergone some type of renovation, repair, or remodeling work in the prior year. These children were at 1.3 times greater risk of having an EBLL than were children not exposed to such activities (11). The risk was even higher among children living in homes where certain practices, such as the removal of paint with heat guns, had been used. # Interior dust Interior house dust can become contaminated with lead as the result of the deterioration or disturbance of leaded paint, the tracking or blowing in of contaminated soil, and the fallout of airborne lead particulate from industrial or vehicular sources. A simple visual inspection of older homes can identify those in poor condition. The condition of leaded paint more accurately predicts lead exposure than the lead content of paint by itself (12,13). Older homes in poor condition have much higher dust lead levels than older homes in good condition (Figure 2.2) (14). The amount of lead in house dust, in turn, has a strong correlation with the BLLs of young children (12,13,15,16) and is more predictive of BLLs in children than is the amount of lead in house paint (13). Lead levels in house dust can be measured either as a mass concentration (mass of lead/mass of dust) or as surface loading (mass of lead per surface area sampled). The most widely used sampling technique, in which a wipe sample is collected with commercially available baby wipes (3), can determine only lead surface loading. However, this measure Chapter 2. Assessment and Remediation of Residential Lead Exposure predicts BLLs as well as or better than mass concentration (17). Lead loadings vary considerably among the types of surfaces commonly tested, with levels on interior window sills and window "wells" (the part of the window that receives the lower sash when closed) often being, respectively, 1 and 2 orders of magnitude higher than those found on floors. Higher levels on window components may reflect a combination of lead dust derived from friction and the deterioration of leaded paint on the windows themselves and from the settling of airborne dust from outside of the dwelling. Dust lead loading on all three surfaces (floors, windowsills, and window wells) correlates with BLLs in children (12). A recent statistical analysis of data from 12 studies relating lead in dust to BLLs in children between 6 and 36 months of age found a strong direct association between dust lead loading and the risk of having an EBLL (13). The association extended well below the 40 Fg/ft 2 threshold for a lead hazard in dust samples collected from floors as defined by HUD (18) and the Environmental Protection Agency (EPA) (19). For example, the estimated probability of a child having an EBLL increases from 7% to 18% with an increase in floor dust lead loading from 10 to 40 Fg/ft 2 (Figure 2.3) (13). For dust samples collected from window sills, lead levels $ 250 Fg/ft 2 are defined as hazardous (18,19). # Soil and Exterior Dust Contamination of soil and exterior dust has been linked to point source emissions, such as lead smelters, fall-out from past use of leaded gasoline, and weathering of exterior leaded paint (20). Soil located next to dwellings typically has higher lead content than that sampled from other locations in a yard. Potentially hazardous levels of lead in soil are not uncommon. Results of a national survey in which soil samples were collected from both bare and covered soil showed that residences with intact exterior leaded paint are more than three times as likely to have soil lead levels exceeding 500 ppm than are dwellings without lead in exterior paint (21% vs. 6%). Results also showed that soil contamination is eight times more common at residences with non-intact leaded exterior paint than at residences without exterior leaded paint (48% vs. 6%) (5). In urban neighborhoods, high levels of lead have also been found in exterior dust collected from paved surfaces, such as sidewalks (21). Soil lead content is an important predictor of children's risk for an EBLL, though less important than the lead content of interior floor dust (13). Soil samples taken from play areas in a yard have a stronger relationship to children's BLLs than samples from other locations. The EPA defines a soil lead hazard as bare soil that contains 400 ppm of lead in a play area or 1200 ppm in other parts of a yard (19). # Chapter 2. Assessment and Remediation of Residential Lead Exposure # Tap water Lead found in tap water usually is from the corrosion of lead-containing materials found in water distribution systems and household plumbing (22). Exposure to lead in tap water has been reduced by measures taken during the last two decades under the requirements of the 1986 and 1996 amendments to the Safe Drinking Water Act and a subsequent EPA regulation (the Lead and Copper Rule) (2). The latter regulation, which only applies to public water systems, requires those systems to monitor tap water for lead and to implement public education and other measures to reduce lead levels in drinking water if they exceed 15 Fg/L in more than 10% of household samples (2). Lead levels are reduced by treating the supplied water to make it less corrosive and, in some cases, by replacing lead water-service lines. These regulations do not apply to the more than 40 million households supplied by private well water that can have elevated levels of lead if the water is corrosive and lead is present in the well pump or household plumbing system (23). In most jurisdictions, there is no monitoring for lead in the drinking water supplied by private wells. A number of studies, mostly of adults, have attempted to characterize the relationship between lead levels in drinking water and BLLs (24)(25)(26). Data from these studies indicate that exposure to water with a lead content close to the EPA action level would not, by itself, be expected to produce an EBLL. However, the individual risk will vary depending upon the circumstances and amount of water consumed. For example, infants consuming formula prepared with lead-contaminated water may be at particular risk because of the large amount of water they consume relative to their body size (27). # Effectiveness and Safety of Lead Hazard Control Measures Interventions to reduce exposure to lead in the residential environment include measures focused on immediate hazards to current occupants, such as removing or covering nonintact leaded paint, repairing or replacing windows to prevent abrasion of leaded paint on moving surfaces, sealing floors to create smooth and cleanable surfaces, using professional cleaners to control household dust, and covering bare, contaminated soil. Additional interventions may be carried out to prevent lead hazards from developing in the future, such as replacing building components that have leaded paint (whether intact or not) and removing (stripping) leaded paint from components left in the dwelling. Most studies evaluating the effectiveness of lead hazard control measures for reducing EBLLs have lacked controls. In addition, many studies evaluated interventions prior to the institution of stringent procedures for limiting the contamination of residences with leaded dust. In general, these earlier studies showed that among children with baseline BLLs greater than about 25 Fg/dL, measures to remove or repair nonintact leaded paint were followed by declines Chapter 2. Assessment and Remediation of Residential Lead Exposure in BLLs of 20% to 30% over the following year (28). In one controlled study, the decline in BLLs for children in treated dwellings was about twice that of children in untreated dwellings (29). In homes of children with EBLLs, extensive removal of leaded paint without measures to prevent the children's exposure to abatement dust and debris has also been associated with increases in the children's BLLs (30)(31)(32). These increases were apparently the result of corresponding increases in house dust lead levels. Consequently, regulations in many jurisdictions now prohibit certain hazardous paint removal methods, such as uncontained power sanding, and require safe work practices, cleaning, and dust lead testing to protect occupants from lead exposure associated with the disturbance of leaded paint. Most jurisdictions require that post-intervention dust lead levels be below clearance standards-the maximum allowable levels of lead. If the dust lead levels in a particular dwelling exceed the clearance standard, that dwelling cannot be reoccupied until additional cleaning or other measures reduce dust lead contamination to less than the clearance threshold. Clearance standards for public and federally assisted housing are 40 Fg/ft 2 for floors, 250 Fg/ft 2 for windowsills, and 400 Fg/ft 2 for window wells. Some state and local jurisdictions have established other clearance standards (20). Recent longitudinal studies have evaluated leaded paint abatement programs that combined multiple lead hazard control methods (33)(34)(35). Interventions used in these programs included measures to prevent the generation of leaded paint chips and dust (treatments to eliminate nonintact leaded paint and windows containing leaded paint subject to friction), leaded dust removal (specialized cleaning), and measures to make floors smooth and cleanable (by sealing or using durable floor coverings). The elimination of leaded paint hazards in the programs relied primarily on component replacement, enclosure, and paint stabilization, with limited on-site paint removal. Although these studies did not include randomly assigned control homes that received no treatment, their results strongly suggest that these treatments resulted in substantial, sustained reductions in interior dust lead loading and little if any risk of children having substantial shortterm increases in BLLs. While average BLLs in children occupying treated dwellings fell by approximately 20% to 25% over the following year (from baseline averages in the 5-15 Fg/dL range) (35), no data on children in untreated dwellings are available to directly estimate the proportion of decline attributable to the hazard-reduction treatments. In one of these studies, greater initial and sustained reductions in interior dust lead loadings were achieved with more intensive treatments, including window replacement (rather than repair) and the use of durable floor coverings (rather than paints and sealants) (34). However, among children living in the more intensively treated dwellings, average BLL declines following the intervention were not significantly greater than those among children whose dwellings had more limited interventions. These studies generally involved interventions that left some intact leaded paint in place. The only certain way to prevent future exposure to lead from paint in a dwelling is to remove all leaded paint from the dwelling. However, no studies are available that compare changes in children's BLLs following the total "deleading" of their dwelling with changes following interventions that leave some leaded paint intact. If many components in a dwelling contain leaded paint, complete deleading may be impractical unless performed as part of a substantial or "gut" renovation. One study of children with baseline BLLs of 10 to 24 Fg/dL found that leaded paint hazardcontrol measures, including extensive on-site paint removal, resulted in increases in children's BLLs after abatement (36). These increases occurred despite a protocol for safe work practices, cleaning, and clearance testing. However, the clearance standard used for floors was 200 Fg/ft 2 , which may have been too high to prevent continued or increased exposure to leaded dust when compared with pre-intervention levels. The previously cited impact of relatively "low" levels of lead in house dust on children's BLLs could explain the increases. Interventions focused on reducing exposure to leaded dust have been evaluated in several studies (37)(38)(39). Household dust control performed repeatedly by professional cleaners was associated with decreases in children's mean BLL with the greatest benefits seen among children whose dwellings were cleaned at least 20 times during a 1-year follow-up period (38). To be effective, dust control should be conducted every 2-3 weeks. However, simply educating parents about the need to perform dust control as a preventive measure has not proven effective in preventing increases in children's mean BLLs (39). See Chapter 6, "Educational Interventions for Caregivers," for a detailed discussion of the effects of such education. In a controlled study, soil removal and replacement with uncontaminated soil was associated with a 15% reduction in BLLs among children whose average baseline BLL was from 10 to 24 Fg/dL and who were exposed to high levels of lead in soil (40). Two other studies of the lead abatement of soil with lower baseline contamination showed no reduction in children's BLLs following such abatement (21,41). In the studies noted above and reviewed in detail in Chapter 6, the benefits of environmental interventions have generally been modest-BLL reductions in the range of 10% to 30%. A number of factors might explain the limited effectiveness of these interventions. One such factor is that the interventions were limited in scope: lead hazard control often involved the interior but not the exterior of homes. Another factor is that most interventions were performed in scattered rather than contiguous blocks of homes. Thus, children's continued exposure to lead from sources in the neighborhood might limit the effectiveness of the interventions. In the Baltimore repair and maintenance study, for example, one comparison group consisted of modern urban homes located in contiguous blocks of such dwellings that were built where older row homes with leaded paint once stood. The geometric mean level of lead contamination in the floor dust of the modern urban homes was less than one-tenth that of older homes that had previously undergone complete lead paint abatement but which were still surrounded by other homes with leaded paint. The geometric mean BLL for children living in the modern homes was one-fourth that of the children living in the older homes (34). A final factor is that the release of lead from bone might also reduce the impact of environmental interventions. By one estimate, an Chapter 2. Assessment and Remediation of Residential Lead Exposure intervention reducing total lead exposure by half for a 5-year-old child would, because of mobilized bone lead stores, cause the child's BLL to decline by only 25% after 1 year (42). # Recommendations for Assessment and Remediation # General Recommendations Conduct prompt and effective environmental management. The identification and control of ongoing sources of lead exposure for children with EBLLs should be the highest priority. In addition, identifying children with EBLLs may help officials identify and control potential sources of lead exposure for other children. Because the main objective of environmental management is to reduce lead exposure quickly, investigations should be initiated as soon as possible after a case is identified. Priority should be placed on responding to children with the highest BLLs and to infants and children less than 2 years of age with any EBLL, because their BLLs are more likely to increase and they are more sensitive to lead's neurotoxic effects. Table 2.2 shows the recommended maximum time frames for initiating environmental investigations and interventions according to a child's BLL. Obtain an exposure history. Investigations to identify sources of a child's lead exposure should begin with an interview with the child's caregiver. Whenever possible, the interview should take place at the child's residence. The interviewer should question the caregiver concerning a range of possible exposure sources. (See Table 2.3 and Appendix I.) It is also important to collect information concerning locations outside the home, such as childcare sites, where the child spends significant amounts of time. The interview should be guided by a checklist tailored to sources of lead exposure found in a given jurisdiction. Checklists facilitate data collection and ensure that potential sources are not overlooked. A sample checklist is provided in Chapter 3, "Medical Assessment and Interventions," and in the 1995 HUD guidelines (3). Visually inspect the residential environment. A visual inspection can quickly identify areas where deteriorating paint may be contributing to lead exposure and should include windows, porches, bare soil, and common areas in multifamily dwellings, as well as any other locations where the child spends time. Measure lead in environmental media. Selection of the media to be tested should be guided by the visual inspection and the child's exposure history. Depending on the inspector's training, the equipment available, and the media to be tested, environmental analysis may be done either on-site with portable instruments or at an environmental laboratory. Personnel performing environmental sampling and on-site testing should be appropriately trained and be certified as risk assessors (43) or have equivalent qualifications. # Chapter 2. Assessment and Remediation of Residential Lead Exposure Communicate results. Results of investigations, including recommended actions to protect the child from further exposure, should be communicated promptly to caregivers, to primary care providers (PCPs), and, where relevant, to property owners and housing code enforcement authorities. Environmental management activities should be coordinated with other health professionals, including those providing clinical care, case management, and social services. # Specific Recommendations Since leaded paint and associated lead in house dust and soil are the most common sources of exposure, they should be the focus of environmental investigations and control efforts. State and local health officials should review current policies concerning childhood lead poisoning prevention and revise them as needed to be consistent with the following recommendations. Measure lead levels in house dust, paint, and bare soil. Investigations of the residential environment of children with EBLLs should focus on immediate lead hazards. At a minimum, testing should include house dust, paints, and similar surface coatings that are not intact or that are located on surfaces subject to friction, and bare soil, especially in play areas. Detailed protocols for sampling and measuring lead in these media can be found in the 1995 HUD guidelines (3). There is no evidence that complete testing of all building components for leaded paint, regardless of the condition or location of the paint, is helpful in identifying ongoing exposure. Such testing may serve other purposes, however, such as educating occupants about the health hazards of leaded paints, planning the abatement of potential future leaded paint hazards, planning renovation work that may involve disturbance of intact paint, or complying with state and local regulations. Test for lead in tap water. For homes served by public water systems, data on lead in drinking water should be obtained from the water supplier. Many public water systems post data on the Internet on the quality of drinking water, including results of lead testing. Links to such data can be found at the following EPA Web site: . If prior testing of a public water system shows that lead contamination is not a problem in homes served by that system, no additional testing is necessary, unless no other source of a child's EBLL can be found. For all other children with EBLLs, including children living in homes served by private wells, water that the child may consume should be tested. If necessary, measures should be implemented to prevent the child's further exposure to lead (e.g., the use of bottled water or appropriate water filters). If bottled water is used, fluoride supplementation should be discussed with the PCP and the caregiver. More information on lead in drinking water can be found at or by contacting the Safe Drinking Water hotline at (800) 426-4791 or [email protected]. Additional sources of information Lead hazard control work must be performed in accordance with safe practices by trained workers to avoid exposing workers to unsafe lead levels or increasing the level of lead exposure to occupants. Detailed guidelines for residential lead hazard control work have been published by HUD (3). On-site removal of intact leaded paint should be kept to a minimum, and safer alternatives, such as component replacement, enclosure, encapsulation, off-site paint removal, and paint-film stabilization should be used when possible. Replacing building components that have intact leaded paint reduces the potential for future lead exposure as the leaded paint deteriorates or is disturbed during renovation. However, such work can generate leaded dust, and workers should follow the precautions described in HUD guidelines. As discussed previously, there is no evidence that environmental interventions that include complete removal of all leaded paint are more effective at reducing residents' BLLs than interventions focused on current lead hazards. Furthermore, some evidence suggests that extensive on-site paint removal increases the potential for lead exposure, at least in the short run. The amount of lead in 1 ft 2 of paint containing 1 mg/cm 2 of lead (approximately 1 g or 1 million Fg) is very large relative to the amount of lead in dust associated with an increased risk for EBLLs (approximately 10 Fg/ft 2 ). Thus, performing extensive on-site removal of leaded paint in a dwelling without increasing the occupants' lead exposure requires a degree of caution that may be difficult to achieve and monitor in the routine, large-scale implementation of health codes. Long-term control of residential hazards from leaded paint may involve considerable time and expense. Obtaining the compliance of property owners may cause additional delays in reducing residents' lead exposure. Therefore, interim measures to rapidly reduce lead exposure, including specialized cleaning to reduce exposure to leaded dust, are often required. # Chapter 2. Assessment and Remediation of Residential Lead Exposure Perform clearance testing. Following lead hazard reduction work, repeat testing for lead in house dust is essential to see whether the work has resulted in levels of lead low enough for safe re-occupancy. Post-intervention tests showing increased or persistently high dust lead levels indicate the need for further cleaning or other additional work. Available evidence indicates that current and proposed guidelines for levels of lead in dust on floors may not adequately protect young children and that levels well below these guidelines are achievable and are often present even before intervention. Therefore, the goal should be to attain post-intervention dust lead levels that are as low as is feasible, which is generally less than 10 Fg/ft 2 on floors (44), and that are at or below baseline levels. Where leaded paint is left in place, periodic monitoring with visual inspection and dust testing should be performed. Relocate occupants. Temporary occupant relocation is generally required to safely conduct lead hazard control activities that may increase dust lead levels. In some cases, it may be feasible to protect occupants during lead control activities by creating barriers, monitoring the work site daily, and, where appropriate, obtaining serial dust lead measurements. In other cases, permanently relocating occupants to lead-safe housing may be the best way of quickly reducing their lead exposure. Examples of situations that might require relocation include a child living in a dwelling that is structurally unsound or a child living in a dwelling where temporary measures to reduce exposure cannot be taken or are ineffective. Case managers and social workers with experience in assisting families with housing difficulties can play a vital role in assessing the needs and desires of the family and arranging such relocation. A registry of lead-safe housing units in a community can also be helpful. When families permanently relocate from a dwelling where lead hazards are identified, measures should be taken to ensure that the hazards are corrected before any other families with young children occupy the dwelling. # Enforcement of Laws and Regulations Although enforcing laws and regulations pertaining to lead hazards is not part of case management per se, it is essential to realizing the long-range goal of reducing those hazards. Individual states should provide health and housing officials with the necessary legal authority to require that timely and effective actions are taken to eliminate lead hazards at properties where children with EBLLs have been identified. Health and housing officials should take all steps necessary to prevent additional or repeated cases of children with EBLLs at one property. In a recent national survey, only 18 states indicated that they have legal authority to order remediation at properties where children with EBLLs reside, with only 14 states reporting that their authority was based on lead-specific state laws or regulations (45). State and local governments should examine their laws, ordinances, and housing codes and their enforcement structure to determine whether they are effective in dealing with identified lead hazards and make changes to ensure that children are protected. At a minimum, legislation or ordinances should include the action level at which the law applies, procedures for investigation and re-inspection, standards for leadsafe housing, requirements for completing lead hazard control work (including permits, time frames, permissible methods, waste disposal methods, and clearance standards) and enforcement provisions for noncompliance. In addition, states and localities should be encouraged to develop lead-safe housing standards to protect children from exposure and to ensure that older rental housing is safe for children with EBLLs. Finally, state and local governments should also ensure that they have the ability and necessary resources to take emergency actions (including cleaning the rental units, stabilizing the paint in them, and relocating the occupants) to protect children from identified lead hazards. # Financial Resources for Lead Hazard Control Many of the homes in which children with EBLLs live are poorly maintained, deteriorated, low-income rental properties. For some economically distressed housing, subsidies and other financial assistance for lead hazard control are required to enable owners to make timely corrections of residential lead hazards. Because resources for addressing lead hazards, particularly in low-income housing, are inadequate in most areas of the country, an increase in resources at the federal, state, and local level should be strongly supported. In addition, state and local health agencies should develop strong partnerships with local housing and community development organizations, investigate currently available resources for improving low-income housing, and establish mechanisms to apply such resources to lead hazard control in homes of children with EBLLs. A detailed discussion and recommendations concerning financing of lead hazard control work can be found in a HUD publication (46). Some examples of current programs providing resources for this purpose are provided in the following paragraphs. HUD's Lead Hazard Control Grant Program (47) enables state or local agencies to provide grants or loans to property owners for conducting lead hazard control measures in low-income housing. Federal regulations require the timely identification and remediation of lead hazards in federally assisted housing, including rental property, whose owners receive tenant-based assistance (Section 8 housing) (19). This program should create a growing pool of lead-safe housing in the future. Decisions on specific priorities for tenant selection under Section 8 and for public housing have been devolved to state and local public-housing agencies. This local flexibility gives health departments in jurisdictions where lead exposure is a major problem an opportunity to urge that priority for assistance be given to families of children with the highest BLLs who are unable to find or afford lead-safe housing. State and local governments can use HUD's Community Development Block Grant (CDBG) and HOME Investment Partnership block grant funds to make housing lead-safe. The resources available for state and local block grants under these programs ($6.4 billion in FY 2000) dwarf the $60 million available under the Lead Hazard Control Grant Program. Both the CDBG and Chapter 2. Assessment and Remediation of Residential Lead Exposure HOME programs provide a high degree of flexibility in the use of funds. Indeed, CDBG funds are used by some jurisdictions to support emergency programs dealing with problems such as the breakdown of plumbing or heating systems. A similar approach would be desirable for controlling lead hazards. State and local governments receiving these block grants must submit a consolidated plan (ConPlan) containing a 5-year strategic plan and a 1-year action plan for their use of these and other available funds. The strategic plan must include actions to evaluate and reduce leaded paint hazards and describe how hazard reduction will be integrated into other housing activities. Evaluating and reducing leaded paint hazards is also a required component of the annual action plan. HUD regulations require that eligible jurisdictions consult with state or local health and child welfare agencies as well as health and social service providers as part of the planning process. State and local health departments with identified lead problems should involve themselves in this planning process to ensure that lead hazard control is a priority for federal CDBG and HOME funding. # Recommendations for Future Research Technical knowledge concerning the identification and control of lead hazards in homes has advanced greatly over the past several years, resulting in more efficient, safe, and effective environmental management for children with EBLLs. Still, prevention efforts could be improved with further work in several areas. Additional studies are needed to assess the long-term impact of current lead hazard control methods on children's EBLLs, especially on levels from 10 to 20 Fg/dL. Available data indicate that these methods are safe and effective (i.e., they do not increase children's BLLs in the short run and they decrease children's exposure to leaded dust). Because BLL changes over time may be influenced by a child's age, the season, and secular trends, as well as by regression to the mean, controlled studies are needed to determine how much of the observed decline in BLLs among children living in these dwellings can be attributed to the interventions. Future research should also evaluate the cost effectiveness of interventions. Until recently, most residential lead hazard control work and studies have involved children who already had EBLLs and presumably relatively high body stores of lead from chronic exposure. The effectiveness of residential lead hazard control in preventing future increases in BLLs among infants and toddlers needs further study. The level of neighborhood lead exposures appears to make an important contribution to the risk for EBLLs among children. Research is needed to examine how community-level lead sources, such as lead from building demolitions, contribute to children's exposure. Finally, the effectiveness of community-level interventions to reduce children's exposure to lead in dwellings and in exterior dust and soil should be further studied. The ACCLPP encourages programs to develop methods to deliver environmental assessment services to caregivers for children living in high-risk dwellings regardless of the children's blood lead levels. b Micrograms per deciliter of whole blood measured in a venous sample collected following an elevated screening measurement. c The recommended clinical evaluation is described in Chapter 3, "Medical Assessment and Interventions." # Chapter 3. Medical Assessment and Interventions Prepared by James R. Roberts, MD, MPH, and J. Routt Reigart, MD # Introduction Case management of children with elevated blood lead levels (EBLLs) requires a different approach from that used in the past. Prior to the development of programs aimed at screening children for EBLLs, lead exposure was generally not detected until a child presented with symptoms of lead toxicity. Neurological findings associated with acute encephalopathy (lethargy, ataxia, seizures, papilledema, and coma) were often the first signs of an EBLL, and children with these symptoms required immediate hospitalization and treatment. Encephalopathy could result from a blood lead level (BLL) $70 Fg/dL and could develop without prior symptoms. Among children with BLLs exceeding 150 Fg/dL, laboratory abnormalities often included phosphaturia, proteinuria, aminoaciduria, glucosuria, and hypophosphatemia (1)(2)(3). Today such presentations are rare. Children with EBLLs usually have BLLs below 30 Fg/dL, and few BLLs exceed 50 Fg/dL. Most children with EBLLs have no symptoms. Case management now focuses on reducing children's exposure to lead and decreasing their BLLs, whether they have symptoms of lead toxicity or not. What follows is a guide to the basic standards and principles of medical case management. It is not intended for use as a complete protocol but rather as a tool for adapting management to local needs and conditions. # General Principles of Medical Case Management # Coordinating Care Coordination of care is critical to successful case management. For each child, an individualized plan of follow-up must be devised and implemented. Members of the case management team need to maintain open lines of communication and work together. Case managers and primary care providers (PCPs), in particular, must work collaboratively to ensure proper medical management and follow-up. # Conducting Medical Case Management Medical case management for children with EBLLs is largely predicated on a secondary prevention model (i.e., intervention after an EBLL has been detected, usually prior to the onset of symptoms). By interrupting the process of lead poisoning through early detection and intervention, case managers working with PCPs can prevent children from dying or suffering severe permanent sequelae of lead toxicity such as persistent seizures and mental retardation (4,5). The detrimental effects of EBLLs in the range of 10 to 45 Fg/dL are usually subclinical and may include neurodevelopmental impairment often apparent only at a later age. (See Chapter 4, "Developmental Assessment and Intervention.") Figure 3.1 illustrates the lowest reported BLLs for some of the effects associated with EBLLs. If a child presents without symptoms, the child's PCP and case manager may have trouble convincing the child's caregiver of the importance of suggested interventions. Case managers should manage each child individually, taking into consideration the child's BLL and the ability of caregivers to cooperate and implement interventions. # Identifying Children with EBLLs Screening programs are the main vehicle for identifying children with EBLLs. Those found in this manner typically have BLLs from 10 to 30 Fg/dL and present with no abnormalities on routine medical history, physical examination, or laboratory tests (other than their EBLL). It is critical that case managers as well as PCPs not equate the absence of clinical symptoms, physical abnormalities, or abnormal laboratory results with an absence of toxicity. # Identifying Sources of Lead Exposure When evaluating a child with an EBLL, case managers must identify the sources of a child's lead exposure. The most common source of lead in children with EBLLs is leaded paint. Housing built before 1950 has been shown to be routinely contaminated with lead and to represent a risk for children (6,7). Contamination of dust or soil occurs when leaded paint chalks or chips, or is subject to friction. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure.") Other less common sources include lead in water, lead in substances used in caregiver hobbies or occupations, lead in culturally specific substances such as folk remedies, and lead in imported cookware or cosmetics (Appendix 1). # Medical History # General Considerations Although abdominal pain, vomiting, constipation, change in appetite, and irritability have been described in association with EBLLs, they are seldom caused by BLLs less than 40 Fg/dL, and other causes for such symptoms should be sought. Case managers, caregivers, and PCPs may note increased activity among children with BLLs < 45 Fg/dL. However, they should not assume that increased activity is related to the EBLL (5,8). # History Taking to Determine Lead Sources A child's environmental history can provide information about the child's possible exposure to residential and other sources of lead. It should: Taking a history in the child's home allows for direct observation and further in-depth questioning. If a child's BLL remains elevated despite lead hazard reduction, less common sources should be considered. Because a child may be exposed to lead from multiple sources, identifying one source may not be sufficient to eliminate all lead exposure. Repeated history taking by different members of the management team is often required. Because knowledge about the lead sources in a community and the prevalence of EBLLs in specific geographic areas of the community can be useful in determining sources of exposure, the interpretation of a child's environmental history may require consultation with lead experts. Case managers play a crucial role in treating children's EBLLs by fostering a multi-disciplinary approach to the environmental evaluation and by coordinating communication among public health officials, PCPs, and caregivers. Table 3.2 outlines suggested questions to ask in determining a child's environmental history. This is only intended to be a guide, and case managers and PCPs are encouraged to tailor this list to local needs. # Miscellaneous questions Does the home contain vinyl mini-blinds made overseas and purchased before 1997? Does the child receive or have access to imported food, cosmetics, or folk remedies? Is food prepared or stored in imported pottery or metal vessels? # Chapter 3. Medical Assessment and Interventions # Paint and soil exposure * Case managers should consider the following elements in assessing a child's exposure to lead in paint or soil: Age and condition of housing: Pre-1950 housing that is in poor condition poses the greatest risk for children (6,7). Housing built from 1950 through 1978 may also contain leaded paint, although the concentration of lead in paint was lower during this period than previously. The condition of the home is important: deterioration of lead-painted surfaces markedly increases the risk to children ( (13). At present, there is no evidence that routine house cleaning by family members or frequent and thorough hand washing decreases BLLs. However, because leaded dust is a primary contributor to EBLLs (14-17), strict attention to *See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," for a detailed discussion of paint and soil exposure. # Relevant child behaviors While pica has long been a known risk factor for EBLLs, typical hand-to-mouth activity during the toddler years is a more frequent cause of lead ingestion (18,19). Although no supporting data are available, frequent hand washing may help lower EBLLs of young children. # Caregiver exposures and at-risk behaviors Household members who work in lead-contaminated environments or participate in certain hobbies can bring lead into the home on their clothing or shoes (20). It is important to ask such household members whether they regularly shower and change clothes and shoes after these activities. Caregivers may also introduce airborne lead into the home by burning leadcontaminated materials in an indoor fireplace. (See Appendix I for a detailed discussion of caregiver exposures.) # Miscellaneous Water: When no other source of lead is found, the water supply should be considered. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure.") While public water systems must monitor, and, if necessary, treat tap water for elevated lead levels, regulations governing lead in drinking water do not apply to households supplied by private wells. Municipal water companies and private industrial laboratories can advise case managers and caregivers on how to collect and process water. In areas where there are no known hazardous water-supply lines, lead contamination of the water may occur within the home from lead solder in plumbing fixtures or from fixtures made of lead-containing alloys. Contamination is increased when the water is relatively acidic (pH 8.5. He also found that low mineral content increased lead contamination in water, but not as greatly as acidity (21). Water that is hot or has been stationary in pipes overnight contains more lead than freely running cold water. Lead contamination decreases with the aging of home plumbing, particularly if the water supply is alkaline or contains significant calcium or other mineral deposits (22,23). Mini-blinds: Imported vinyl mini-blinds may contain lead and result in exposure. (See Appendix I.) Cultural practices: Specific ethnic groups may use imported folk remedies, cosmetics, food, or cookware contaminated with lead. Practices resulting in lead exposure from these sources are often localized, and determining children's risk from such practices requires knowledge about a specific group's cultural habits. Caregivers may be reluctant to admit using some of these items, and it is important not to put them on the defensive when taking the history. (See Appendix I.) Newly identified sources: In the past, various items have emerged as lead hazards, often first presented through the news media. Case managers and PCPs should be cognizant of recent media and Consumer Product Safety Commission reports that may be relevant to children with whom they have contact (see ). # Physical Examination Children evaluated as a consequence of an EBLL found by screening most often have no physical findings specific for lead toxicity. Gingival lead lines, although often stressed during medical training, are rarely seen in clinical practice and are of no use in the diagnosis and management of children with EBLLs. Pallor, papilledema, and other neurologic findings suggestive of acute encephalopathy would not be expected. A thorough evaluation of all children with BLLs $20 Fg/dL is recommended for three reasons. First, it will allow PCPs to ascertain whether children with such EBLLs have any findings suggestive of encephalopathy. The BLL threshold for encephalopathic findings is believed to be 70 Fg/dL, although encephalopathy is usually associated with much higher BLLs (1,3). Second, it will allow PCPs to assess whether children with EBLLs are engaging in at-risk behaviors such as pica and hand-to-mouth activity. Finally, it will allow PCPs to identify behavioral and neurodevelopmental disorders, such as distractibility, aggression, or speech delay. If a child has any of these findings, regardless of their etiology, the case manager or PCP should, when appropriate, refer the child for a further evaluation. (See Chapter 5, "Developmental Assessment and Interventions.") # Laboratory and Imaging Evaluation Among asymptomatic children, most clinical laboratory results other than BLLs will be normal and therefore will not be of assistance in case management. However, all children should have a hemoglobin or hematocrit test performed, as anemia is associated with EBLLs. That iron deficiency rather than lead is the cause of such anemia does not diminish the need for follow-up (24,25). PCPs may wish to assess children's iron stores by one or more of a variety of laboratory tests. Iron deficiency may delay children's neurodevelopment independently of the effects of lead (26). Because basophilic stippling is not specific for lead toxicity, a peripheral blood smear is of no use in the hematologic evaluation. The inhibition of heme synthesis leads to the accumulation of excess porphyrins, particularly protoporphyrin IX in red cells. The fluorescence of these porphyrins has led to the development of methods to detect extracted porphyrins-free erythrocyte protoporphyrin (FEP) or erythrocyte porphyrin (EP) testing-and to the observation of zinc protoporphyrin (ZPP) in red cells. Because the relationship between the results of these tests and BLLs is log-linear, these tests can be used to evaluate and follow children with very high BLLs. However, the results are confounded by concomitant iron deficiency and show poor correlation with BLLs <25 Fg/dL (27). Therefore, EP tests should be used infrequently except in evaluating children with BLLs well above 25 Fg/dL whose BLLs do not show a steady decline in response to medical and environmental interventions. In such situations, these measures may assist PCPs in differentiating BLL rebound after treatment from the effects of re-exposure. While very high BLLs have been associated with serious to severe renal tubular dysfunction (2,28), there is no evidence to support routinely evaluating the renal status of children with presymptomatic BLLs. However, if potentially nephrotoxic chelating agents such as EDTA are to be used in treatment, renal function testing is appropriate prior to and during therapy. Abdominal radiographs may be useful in determining whether children are currently ingesting lead-contaminated non-food items, including paint chips. They are particularly useful when children have an unexpected acute rise in BLL or are not responding to case management as expected. Long-bone films for the presence of growth arrest lines ("lead lines") may be of interest but rarely provide information useful for a child's case management (29). Lead lines are not present unless BLLs exceed 50 Fg/dL and are indicative of chronic exposure (30). Also of no documented utility in the management of children with EBLLs are hair (31), fingernail, and tooth (dentin) lead measurements. Hair and fingernails are subject to external contamination, which makes the results of lead tests on them uninterpretable. A few studies have demonstrated alteration of neurophysiologic function (e.g., postural sway, auditory evoked potentials, nerve conduction) with BLLs observed today (32)(33)(34)(35). However, further research is needed to define normative standards and determine inter-individual variation and clinical significance. Until then, such measures are of little use in the diagnosis or management of an individual child. X-ray fluorescence of long bones uses a radioactive source to provide noninvasive estimation of lead in bone (36). At the present time, it should be considered a research tool to be used only to characterize groups of children in epidemiological studies. As with the neurophysiologic methods discussed previously, it is insufficiently standardized, and results show significant inter-laboratory variation. # Chelation Therapy While chelation therapy is considered a mainstay in the medical management of children with BLLs > 45 Fg/dL, it should be used with caution. Primary care providers should consult with an expert in the management of lead chemotherapy prior to using chelation agents. If unaware of a center with such expertise, PCPs should contact their local or state lead poisoning prevention program, local poison control center, or the Lead Poisoning Prevention Branch at CDC (404-498-1420) for the names of accessible experts. A child with an EBLL and signs or symptoms consistent with encephalopathy should be chelated in a center capable of providing appropriate intensive care services! Controversy exists as to the appropriate level at which to initiate chelation therapy, and which drugs are most appropriate. Succimer treatment of young children with BLLs < 45 Fg/dL lowered their BLLs but failed to improve their neurodevelopmental test scores (37). (See Chapter 5, "Developmental Assessment and Interventions.") Chelation therapy with succimer is addressed in a document on pharmaceutical agents in the treatment of lead poisoning (38). If oral outpatient chelation therapy is undertaken, the case manager should ensure that caregivers adhere to the prescribed dosing schedule and should serve as the liaison between the medical community and the child's caregiver. Treatment should occur in a lead-safe environment. # Monitoring Blood Lead Levels Measurement of BLLs is the main method of determining whether significant absorption of lead has occurred, how urgently intervention is needed, and how successful case management has been. When a child's BLL does not fall within a reasonable amount of time, it is the responsibility of the case manager and other team members to determine the cause of failure. The rate of BLL decrease can depend on both the amount of lead in the child's body and the duration of the BLL elevation. A course of chelation therapy with succimer results in a rapid fall in BLL after 1 week of treatment. However, BLLs of those treated rebound after treatment ends, and by approximately 7 weeks after an initial course of therapy, BLLs of treated patients may reach almost 75% of prechelation levels (39). CDC recommends rechecking children's BLLs 7 to 21 days after completion of chelation therapy (40). A continuing increase in children's BLLs above the rebound level during the follow-up period may indicate continuing or possibly increased exposure to lead and definitely indicates a need for further environmental investigation. Common causes of rising BLLs include failure to address hazards in the child's environment, improper environmental lead abatement techniques, and continued use of imported pottery, cosmetics, or folk medicines that are contaminated with lead. However, medical conditions resulting in bed rest or similar immobilization (41), or in acidosis (42), can cause children's BLLs to rise unexpectedly, or fail to fall. # Confirmation of BLL by Venous Sample Any screening BLL above 10 Fg/dL must be confirmed with a venous sample. The time frame for confirmation depends upon the initial BLL (Table 3.3). In general, the higher the screening BLL, the sooner the confirmatory test. However, if a child is less than 12 months old, # Chapter 3. Medical Assessment and Interventions -r if there is reason to believe that the BLL is rising rapidly, an earlier diagnostic confirmation may be indicated. The higher the BLL on the screening test, the more urgent the need for confirmatory testing. # Follow-Up Venous Blood Lead Testing Medical management includes follow-up blood lead testing. Table 3.4 presents the suggested frequency of follow-up tests. This table is to be used as guidance. Case managers and PCPs should consider individual patient characteristics and caregiver capabilities and adjust the frequency of follow-up tests accordingly. # Educating Caregivers Educating caregivers is an important part of case management. Caregivers need to understand EBLLs and the risks that an EBLL poses to their child, what they can do to eliminate their child's exposure to lead, and the importance of follow-up. It is important to not overburden caregivers and to provide them with understandable information and manageable interventions. (See Chapter 6, "Educational Interventions for Caregivers," for a detailed discussion.) # Monitoring a Child's Developmental Progress Follow-up also requires attention to the behavioral sequelae of EBLLs. Neurodevelopmental monitoring should continue long after a case meets BLL closure criteria, as many deficits will not manifest themselves until after a child starts school. Because developmental history and testing at the time of an EBLL usually will not identify lead-caused problems, a child's EBLL history should be part of his or her permanent medical record. A referral for testing of intellectual and behavioral performance, whether or not related to EBLLs, should be made if indicated. (See Chapter 5, "Developmental Assessment and Interventions," for details.) The PCP and case manager should be intimately involved with any educational and behavioral interventions, in consultation with developmental and behavioral experts. # Chapter 3. Medical Assessment and Interventions # Monitoring Caregiver Compliance with Follow-Up Measures For many reasons, caregivers may have trouble adhering to follow-up measures. Case managers, PCPs, and other members of the case management team must be careful not to blame the caregivers but should continue to make them aware that follow-up is for the benefit of the child. Caregivers may have trouble appreciating the importance of follow-up for asymptomatic children. Many caregivers have problems with basic needs such as transportation, food, or paying monthly bills. Therefore, it is important to limit interventions to those most likely to benefit the child while being within the capabilities of the caregiver. Punitive interventions, such as referring children to protective services, should be done as a last resort, when all more constructive approaches have been exhausted. Members of the case management team should always remember that virtually all caregivers are doing the best they can for their children and should be assisted in their efforts. # Recommendations for # Chapter 4. Nutritional Assessment and Interventions Prepared by James Sargent, MD # Introduction While the assessment and remediation of lead sources should be the top priority for the management of children with EBLLs, nutritional interventions may also be beneficial (1)(2)(3)(4). This chapter evaluates the evidence supporting commonly used nutritional interventions, makes recommendations, and suggests an agenda for future clinical research. In evaluation studies on the effects of various nutritional interventions on EBLLs, we considered both the design of the studies and the effectiveness of the interventions. Because of a lack of randomized, controlled clinical trials of nutritional interventions among children with EBLLs, most recommendations are based on generally accepted nutritional principles, as well as on the results of adult human, animal, or cross-sectional studies, with greater weight being given to those studies with designs that are less subject to bias and inferential error. # Nutritional Interventions: Summary of the Evidence # Iron Are children at higher risk for EBLLs also at higher risk for iron deficiency? Despite declines in the prevalence of iron deficiency over the past 30 years with the routine supplementation of infant foods with iron, iron deficiency remains the most common nutritional deficiency in infants and young children (5). Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that in 1988-94, 9% of toddlers aged 1 to 2 years were iron deficient (6). As with EBLLs, young age, poor nutrition, and low socioeconomic status are associated with iron deficiency. In addition, some reports suggest that iron deficiency in young children is associated with pica, a risk factor for lead ingestion (7-10). In short, many nutritional and behavioral factors associated with iron deficiency may also be found in children with EBLLs. # Is iron deficiency associated with EBLLs? Because animal studies and other evidence suggest that iron deficiency and EBLLs are associated, the Centers for Disease Control and Prevention (CDC) in the past has recommended providing an iron-rich diet for all children with EBLLs, evaluating children with blood lead levels (BLLs) > 20 Fg/dL for iron deficiency, and treating iron deficiency if present (11). However, the association between EBLLs and iron deficiency in children is not well defined. It is unknown whether this relationship is causal and operating through a nutritional or physiological mechanism or whether it is merely the result of shared risk factors. Prospective studies of children with and without iron deficiency living in lead-contaminated environments are difficult to conduct since treatment is indicated for both iron deficiency and EBLLs. Therefore, most studies that address this question are case series, case-control studies, or cross-sectional surveys. Though the results of most early studies suggested that iron deficiency is more common among children with EBLLs, these studies can be criticized for one or more of the following reasons: 1) they lacked an appropriate comparison group; 2) they screened for EBLLs with erythrocyte protoporphyrin, an indicator of both lead and iron status; or 3) they failed to adjust results for factors associated with both EBLLs and iron deficiency, including age and socioeconomic status. Of the four studies we found that avoided these methodological problems, two reported a positive association between iron deficiency and BLLs in children and two suggested no association. Each study used different definitions of iron status and EBLL. Of the studies finding a positive association, one suggested iron deficiency in children was associated with a 60% increased risk for a BLL > 10 Fg/dL after adjustments for children's age, hemoglobin level, and insurance status (12). The second, a study on dietary iron, found that children in the highest quartile for iron intake were at a significantly lower risk of having a BLL > 15 Fg/dL, after adjustments for maternal education, children's lead exposure, age, and total caloric intake (odds ratio 0.4, 95% confidence interval, 0.2-0.9) (13). Of the studies that indicated no association, one was conducted among black children 11 to 33 months of age who resided in urban areas, and the results may not be applicable to other groups (14). In that study, the prevalence of iron deficiency was 7% among children with BLLs 20 to 44 Fg/dL and 5% among children with BLLs 10 Fg/dL after adjusting for age of housing; education of household head; and children's age, race, and poverty status, and intake of fat, calcium, and vitamin C (15). During the 1980s, some prospective studies of children's BLLs and development gathered data on the children's iron status as well; most of the data from these studies are unpublished. Bornshein (personal communication, University of Cincinnati Medical Center, November 1988) found that Cincinnati children who became more iron deficient (as evidenced by increased total iron-binding capacity) had greater increases in BLLs, but McMichael et al. (16) and Bellinger (personal communication, Harvard Medical School, March 1989) found no association between BLLs or changes in BLLs and initially low serum ferritin levels. Neither study, however, adjusted for children's use of iron supplements or for other factors. If children with initially low serum ferritin levels received iron supplements, this could have affected the association between initial low serum ferritin levels and changes in BLLs. # Does iron deficiency increase absorption of lead? Some animal studies suggest mechanisms by which iron levels could affect lead retention. For example, one study of rats indicates that iron and lead absorption may be mediated by common carriers and that ingested iron decreases the absorption of lead in a dose-related manner, presumably by competitive inhibition of the carrier protein (17). Moreover, iron-deficient animals have significantly higher rates of lead absorption than iron-replete ones (18). However, the effect of iron levels and iron supplementation on radiolabeled lead retention in humans is controversial, with at least one study finding an effect (19) and at least one not (20). In their latest study, Watson and colleagues (19) found a correlation between lead and iron absorption; however, the mean lead-absorption value for iron-deficient subjects was not significantly different from the value for those who were not iron deficient. No data are available for children. # Does iron deficiency enhance the adverse effect of lead on development? Although iron deficiency may not modify children's risk for lead exposure or retention, iron deficiency and EBLLs have similar toxicity profiles. Both result in a lower production in heme; this is manifested clinically by higher erythrocyte protoporphyrin levels in children with EBLLs and iron deficiency than in those children with either condition alone (21). More importantly, both iron deficiency and EBLLs have a deleterious effect on cognitive development. This raises the possibility that the neurodevelopmental effects of lead may be more severe when iron deficiency is also present. However, there is no evidence to suggest that iron deficiency modifies the neurodevelopmental effect of EBLLs. Instead, in one study comparing the cognitive development of children living near a lead smelter with that of those in a nearby town in Yugoslavia, researchers found the neurodevelopmental effects of iron deficiency and EBLLs to be independent of one another (22). # Does iron supplementation have an effect on BLLs? There is evidence to suggest that iron-sufficient children excrete more urinary lead when chelated with EDTA, although the increase is small and probably not clinically significant. In addition, after iron administration, chelation-induced lead excretion increased among patients with iron deficiency. The study in which this occurred, however, did not address the effect of iron deficiency on BLLs and lead excretion in the absence of chelation (23). In a study conducted by Ruff and colleagues (24), children with EBLLs and iron deficiency were given iron supplements, whereas children with EBLLs but no iron deficiency were not. The children who were iron deficient and received supplements had only half the reduction in BLLs of the children who were iron sufficient and did not. However, it is not clear whether this was due to the effect of iron supplementation on hemoglobin concentration or to another factor affecting lead biokinetics. The problem with using BLL as an indicator of body burden of lead in iron studies is that, because 99% of lead in blood is intraerythrocytic, any intervention that causes a significant increase in the hemoglobin concentration will similarly affect the BLL. # Summary Although iron may help prevent lead absorption in animals, studies of the association between iron deficiency and BLLs in children have produced inconsistent results. There is little evidence that iron promotes a clinically important increase in lead excretion. However, the use of iron supplements among children with EBLLs and iron deficiency has been shown to improve their developmental scores, suggesting that the effects of iron deficiency on cognition can be partially reversed among children with EBLLs (24). This finding is consistent with a wealth of data indicating that neurodevelopmental impairment among children with iron-deficiency anemia can be partially resolved by treatment with iron supplements (25)(26)(27)(28). However, treatment with succimer (dimercaptosuccinic acid) to lower EBLLs (20 to 44 Fg/dL) in toddlers has not been shown to improve their cognition (29). Since the effects of iron deficiency on children's development appear to be independent of the effects of lead, there is no compelling reason to screen and treat children with lead exposure differently from children of similar age on the basis of their risk for iron deficiency, assessed independently of their lead exposure. Detailed recommendations for the prevention of iron deficiency can be found in a recent CDC report (30). Several of these recommendations are summarized later in this chapter. # Vitamin C Could increasing children's vitamin C intake decrease their BLLs? Decreased lead retention has been shown in rats fed vitamin C and exposed to lead (31)(32)(33). Clinical studies in humans actually predate these and other animal studies, as case reports of lead-poisoned workers' response to ascorbate began to appear in the literature as early as 1939 (34). Later, clinical trials were conducted among workers and other adults. An uncontrolled experiment involving 39 workers showed that their BLLs had declined 24 weeks after they began treatment with vitamin C (35). Results of a single-blind clinical trial of vitamin C (1 g daily) among lead smelter workers with BLLs of 28 to 76 Fg/dL did not show vitamin C to affect their urinary excretion of lead (36). In a double-blind randomized clinical trial, however, adult male smokers given a daily dose of vitamin C (1 g) experienced a statistically significant 80% decline in BLLs (from 36 to 20 Fg/dL) after 1 week of treatment that persisted through the 4-week period of the study (37). Much less is known about the effect of vitamin C on BLLs in children. One correlative cross-sectional study using NHANES III data showed high levels of serum vitamin C to be associated with a low prevalence of EBLLs for both children and adults. Results of this study also showed an association between serum vitamin C levels and log BLLs among adults but not among children (38).This study, however, did not control for environmental lead risk or include children below the age of 4 years who are the usual subjects for case management (39). In summary, although there is fairly strong evidence to support giving vitamin C to adults with EBLLs, there is insufficient evidence to recommend for or against vitamin C supplementation for children with EBLLs. It is important to note that CDC recommends giving all children 6 months and older at least two servings of foods rich in vitamin C per day for the prevention of iron deficiency (30). # Chapter 4. Nutritional Assessment and Interventions # Calcium Are children at higher risk for EBLLs also at higher risk for inadequate calcium intake? Recommended daily allowance values for calcium intake have been replaced by "adequate intake"(AI) levels (40). AIs for young children are age-specific: 0-6 months, 210 mg/day; 7 12 months, 270 mg/day; 1-3 years, 500 mg/day; and 4-8 years, 800 mg/day. Actual mean calcium intake levels may be estimated from NHANES III data. Figure 4.1 depicts the median, 75 th percentile, and 25 th percentile levels for daily calcium intake among children aged 1 to 4 years by race. Calcium intake is below the AI level for more than 25% of Mexican American and non-Hispanic black 1-to 3-year-olds, and approaches 25% for non-Hispanic white 1-to 3-year-olds. Similarly, there is little variation in calcium intake across income groups (results not shown). Although these data do not specifically reflect the calcium intake of children with EBLLs, groups that typically have higher risk for EBLLs in this nationally representative sample of children have only a slightly higher risk for calcium intake below AI levels. One research group assessed the calcium intake of 314 mostly African-American children using a food frequency questionnaire (41). The results for children aged 1 to 3 years were similar to those of NHANES III, with about 30% of children having calcium intakes below the AI level of 500 mg per day. Because calcium intakes were not much higher for 4-to 8-year-old children in this sample, a substantially higher proportion of them (almost 60%) had calcium intakes below the AI level of 800 mg for their age group. # Does inadequate calcium intake confer a higher risk for EBLLs? Animal studies have shown higher lead retention in animals fed low-calcium diets, raising the possibility that low-calcium diets could affect the BLLs of humans (42)(43)(44)(45). Furthermore, studies of radiolabeled lead absorption in human adults show lower absorption of lead when lead is co-administered with calcium (46,47). In 89 metabolic balance studies of 12 infants, dietary calcium intake was found to be inversely associated with lead retention (48). As the authors noted, however, dietary calcium intake closely paralleled the intake of phosphorus and other unmeasured components of milk and formula, so it is difficult to attribute this effect solely to calcium. In NHANES II (1976 -1980), calcium intake was inversely associated with BLLs in a nationally representative sample of children aged 3 to 11 years (49). The analysis included good controls for children's socioeconomic status, region of the country, and urban vs. rural residence. Results of this analysis showed that children's calcium intake had a small, inverse correlation with their BLL, with children's BLLs declining by only about 0.2% for each 100 mg increase in dietary calcium. The study was subject to the following limitations. First, it included no direct controls for environmental lead exposure. Second, because the backward selection procedure used for the regression analysis removed confounding nutritional variables from the final model, and the p-value for the calcium effect was close to 0.05, statistical significance would probably be lost with the inclusion of only one nutritional confounder. Results of other smaller published cross-sectional studies generally support an inverse association between children's calcium intake and BLLs, but these studies also did not control for confounding (50,51). Calcium supplementation above the AI level Meredith et al. showed that increases in dietary calcium of up to 5 mmol decreased lead retention in rats with no pre-existing calcium deficiency; however, they found no further decrease with oral doses of calcium above 5 mmol (100-fold molar excess of calcium) ( 52). This finding is consistent with those from the studies of radiolabeled lead absorption in human adults mentioned above (46,47). In an unpublished balance study of the effect of calcium glubionate syrup supplementation (50 mg calcium/kg/day) on lead retention in six children, neither lead absorption nor lead retention was found to be affected by calcium supplementation (personal communication, Ekhard E. Ziegler, University of Iowa College of Medicine, May 14, 1990). Similarly, no effect of calcium supplementation was found in a randomized clinical trial of calcium glycerophosphate supplementation of infant formula involving 105 infants (53). In this study, infants in the treatment group received, on average, 1600 mg of calcium per day. Change in BLL over time was small for all of the infants in the prevention trial (only 1 Fg/dL), limiting the power of the study to examine a treatment effect. # Summary There is little evidence that a child typically considered at high risk for lead exposure is at greater risk for low calcium intake than children without EBLLs. However, because of the frequency of inadequate calcium intake among all children, it is important to verify that a child with an EBLL is receiving enough calcium. The results of both animal studies and human laboratory studies provide good evidence that dietary calcium competitively inhibits lead absorption. The results of one cross-sectional study of older children with controls for socioeconomic status show an inverse association between dietary calcium intake and BLLs. There are few data on young children in the high-risk age range, and no clinical trials have evaluated the efficacy of supplementation among children with low calcium intakes who are at risk for lead exposure. The results of studies among older children and adults, animal studies, and cross-sectional studies all reinforce the importance of adequate calcium intake (i.e., two servings per day of dairy products or other calcium-rich foods). However, there is no clinical evidence that supplementation of calcium beyond the recommended AI level in children with EBLLs has a clinical effect on the BLLs; therefore, we do not recommend giving calcium supplements to children with EBLLs. # Chapter 4. Nutritional Assessment and Interventions # Total fat intake The link between fat intake and BLLs comes primarily from animal experiments (54). In one cross-sectional experimental study, researchers found a direct association between dietary fat and BLLs (55); however, no such relationship between dietary fat and BLL was found in NHANES II (47). Thus, no strong case can be made for decreasing children's total fat intake. In addition, dietary fat is an important constituent in the diets of children under 2 years of age because calories from fat support high calorie requirements for growth during this period. Thus, we do not recommend low-fat diets for the treatment of younger children with EBLLs. # Zinc supplementation Some evidence from animal studies suggests that high levels of dietary zinc inhibit the absorption and retention of lead in animals (56). However, in one small clinical study in which zinc was given with and without vitamin C to lead-exposed workers, the zinc had no demonstrable effect on their BLLs (36). As with calcium, we do not recommend adding zinc supplements to the diet of children with EBLLs. # Other factors Many other factors have been evaluated as mediators of lead absorption and excretion in adults or animals. These factors include vitamins (thiamin, pyridoxine, vitamin D), minerals (phosphorus), dietary chelators (phytatic acid, alginates, oral EDTA), and frequency of meals. These were not included in this review because of a lack of evidence to determine their efficacy in children. # General Recommendations # WIC referral Because children with EBLLs are at risk for poor diet, refer children with EBLLs to supplemental food programs that provide nutritional counseling and access to healthy foods. - Determine whether children with EBLLs are eligible for WIC and ensure their access to this program if they are eligible. An EBLL is a condition that should qualify age-eligible older children who might otherwise not be candidates for participation in the program. # Iron deficiency - Low-income or minority children with EBLLs are usually at high risk for iron-deficiency anemia. Detailed recommendations for the prevention of iron deficiency can be found in a recent CDC report (30). Several of these recommendations are included below. - Test those at risk for anemia (e.g., those from low-income, migrant, or recently arrived refugee families or those qualifying for WIC). These children should be tested at the following ages: S Initially between ages 9 and 12 months S Six months later S Annually from ages 2 to 5 years Vitamin C intake - Advise caregivers to provide children with an adequate intake of vitamin C. For children approximately age 6 months and older, encourage caregivers to provide two feedings per day of foods rich in vitamin C (e.g., fruits, vegetables, or juice), preferably with meals, as a way of improving their iron absorption. # Iron intake - Encourage caregivers to provide children with an adequate intake of iron by: S Introducing them to iron-fortified cereals and pureed meats at their appropriate developmental stages. S Providing one serving of lean red meat per day to older children. S Do not recommend giving children iron supplements except under the supervision of a physician or nutritionist and only when iron deficiency or anemia is documented. # Calcium intake - Encourage caregivers to see that children with EBLLs receive an adequate amount of calcium (500 mg/day @ 1 to 3 years; 800 mg/day @ 4 to 8 years), by: S Providing them with two servings of dairy products per day, unless they are lactase deficient. S Providing lactase-deficient children with sufficient dietary calcium from other sources (e.g., broccoli, greens, kidney beans, and calcium-fortified juices). S Do not recommend giving children calcium supplements except under the supervision of a physician or nutritionist. - Do not recommend supplementation in children with EBLLs beyond the recommended AI levels. # Fat intake - Do not encourage a low-fat diet as a means of lowering children's EBLLs. Not only is there no clinical evidence to support the implementation of such a diet, but dietary fat is an important constituent in the diets of children, especially those under 2 years of age. # Chapter 4. Nutritional Assessment and Interventions Zinc supplementation - Do not recommend zinc supplementation. # Recommendations for Future Research Evidence suggests that some population-based nutritional measures may reduce lead absorption in children. However, we do not yet know enough about the relationship between children's EBLLs and many specific nutrients to make recommendations. The literature is replete with animal studies that have not been adequately followed up in the human population. When they are, the epidemiologic work consists mostly of correlative cross-sectional studies without adequate controls for environmental lead exposure. Because of the sparse evidence for the efficacy of various nutritional interventions for children with EBLLs, it is premature to call for the implementation of population-based nutritional interventions. Instead, promising interventions should be evaluated in randomized clinical trials. Such clinical trials are especially important for several reasons. First, correlative nutrition studies are hampered by our limited ability to measure dietary intake. In addition, many nutrient intakes correlate with each other, so only large observational studies can separate the effects of, for example, dietary fat from iron. An association between a nutritional factor and BLL, however, does not mean that manipulating the nutritional factor will have a clinically meaningful effect on an EBLL. Some of the randomized trials of dust control among children illustrate this (57,58). Only clinical trials employing randomized designs can determine whether modifying children's intake of specific nutrients will actually influence their BLLs. Furthermore, many patient-compliance and side-effects issues need to be resolved before nutritional interventions can be studied clinically. For example: Which vitamin C supplements will children reliably take? Which ones will caregivers reliably give? Does it matter when the dose is given? Should the supplement be given as a medication or through a frequently eaten food item? What is the level of supplementation that could result in side effects? Finally, many nutritional interventions will involve behavioral change for families. Results of clinical studies of behavioral change (e.g., parental smoking cessation and environmental tobacco exposure reduction ), suggest that only modest behavioral changes can be expected from limited-contact counseling interventions. In addition, injury research shows that passive interventions (e.g., using childproof medicine caps) are much more effective in preventing injuries than are active interventions (e.g., asking parents to keep medicines out of reach). Therefore, controlled randomized studies should identify and evaluate actions and interventions that may result in improved compliance with recommendations. - Also consider developmental surveillance for a child who has a BLL that does not exceed 20 Fg/dL but who has other significant developmental risk factors. - Do not base decisions regarding developmental assessment or intervention on a child's age at the time the child is found to have an elevated blood lead level (EBLL). - If you wish to refer a child with an EBLL for intervention services, consider referring that child to early intervention/stimulation programs. - Include a history of a child's EBLL in the problem list maintained in the child's medical record. - Do not stop developmental surveillance when a child with an EBLL reaches age 6 or when the child's blood lead level is reduced. A responsible party (e.g., the child's PCP) should provide ongoing developmental surveillance of that child after the EBLL case is closed. - In the developmental surveillance of children with EBLLs: -Watch for emerging difficulties at critical transition points in childhood: first, fourth, and sixth/seventh grades. -Watch for behaviors that interfere with learning, such as inattention and distractibility. - Refer children experiencing neurodevelopmental problems for a thorough diagnostic evaluation. - Be advocates for the child. # Introduction Since Preventing Lead Poisoning in Young Children was published in 1991 by the Centers for Disease Control and Prevention (CDC) (1), considerable new data have become available on the developmental and neurobehavioral effects of lead, including late results of a number of prospective longitudinal studies begun around 1980. These new data generally bolster the conclusion, reached in the 1991 statement, that lead adversely affects children's performance on tests of cognition at blood lead levels (BLLs) below 10 Fg/dL (2,3). New insights have been generated as well regarding both the most sensitive functional endpoints and the range of endpoints affected. Specifically, recent data suggest that lead toxicity may contribute to neurobehavioral, as well as cognitive, morbidities of childhood. Because of the consistency of these associations and the relatively high prevalence of BLLs in the range associated with these increased risks, it is important to address the issues involved in the identification and treatment of lead-related cognitive and neurobehavioral effects. Any recommendations regarding neurodevelopmental assessments and interventions for children with elevated blood lead levels (EBLLs) must rest on a firm empirical foundation. Therefore, this chapter presents an overview of numerous studies of the association between children's BLLs and their neurodevelopment and behavior, as well as the recommendations based on the studies. # Detailed Bases for Recommendations # BLLs and IQ Several older case series clearly demonstrate that children presenting with symptoms and findings of severe lead intoxication are at substantially increased risk for serious neurological sequelae (4)(5)(6). Asymptomatic children with BLLs in the 30-to 60-Fg/dL range also may suffer a variety of neurologic and neurobehavioral adversities (7)(8)(9). Recent epidemiological studies provide a wealth of data on the nature of the dose-effect relationship for children with BLLs below 35 Fg/dL. The relationship between children's BLL and IQ appears to be linear, even at BLLs below 10 Fg/dL (2,3). Some data suggest, however, that the slope for the dose-effect relationship is steeper for BLLs below 15 Fg/dL than it is for levels above 15 Fg/dL (3). Meta-analyses of the results of several studies indicate that an increase in average postnatal BLL from 10 to 20 Fg/dL is associated with a decrease of 1 to 3 points in the child's IQ measured at age 5 or older (3,10,11). The point estimates for the IQ change associated with a doubling of BLL from 10 to 20 Fg/dL were 2.57 points (standard error 0.41) in Schwartz' analysis of a mixed set of prospective and cross-sectional studies (3) and 2.53 points (standard error 0.41) in the analysis of cross-sectional studies by Pocock et al. (10). # Chapter 5. Developmental Assessment and Interventions The study cohorts were quite diverse ethnically, culturally, and sociodemographically. Children in some cohorts experienced chronic exposure by virtue of living near a smelter (12,13), while children in other cohorts were impoverished and living in inner-city areas in old housing with leaded paint in poor repair (14,15). Yet other cohorts consisted largely of children from relatively well-to-do families (16,17). The likelihood that these interstudy differences were accompanied by differences in the nature and extent of confounding bias makes the overall consistency in the findings of the different studies even more impressive, and increases the plausibility of the conclusion that lead plays a causal role in a child's neurodevelopment. As in most areas of epidemiological research, however, interstudy variability is apparent in the strength of the association, with some investigators reporting that the association between children's BLLs and IQ scores was not statistically significant (15,(17)(18)(19). Nevertheless, the overall weight of evidence clearly supports the existence of an inverse association between children's BLLs and their IQ scores. # Other Neurodevelopmental Deficits Associated with EBLLs Children presenting with severe symptomatic lead intoxication are known to suffer from neurobehavioral problems such as impulsivity, aggression, and short attention span (4). Results of a number of studies support the hypothesis that the spectrum of low-level lead effects on children includes neurobehavioral problems (20)(21)(22)(23). At present, there is no compelling evidence that an EBLL increases a child's risk for attention deficit hyperactivity disorder (ADHD) (24). However, because the studies mounted to address this question have been cross-sectional or retrospective, children's lead exposure status at earlier developmental periods may have been misclassified. It is noteworthy that elevated blood or tooth lead levels have been repeatedly linked to the types of behavioral problems pertinent to the diagnosis of attention deficit disorder inattentive subtype, a diagnosis included for the first time in the fourth (and most recent) edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (25). These behaviors include distractibility, poor organization, a lack of persistence, and daydreaming (26)(27)(28)(29). Elevated bone lead levels have also been linked to an increased risk of engaging in antisocial behaviors in middle childhood (29). Efforts to identify a "neurobehavioral signature" for children with EBLLs have generally been unsuccessful (30), although several studies have found that among preschool children, EBLLs were most strongly associated with deficits in nonverbal functions, particularly visualmotor skills (13,(31)(32)(33). However, the nature of the deficits identified when children reach school age are less consistent. It is likely that the manner in which lead toxicity is expressed depends on many factors, including the timing and chronicity of exposure, the child's age when outcomes are assessed, and the context of the assessment (30). Given the absence of specificity in the findings associated with an EBLL, a child's specific deficits are of little use in making a diagnosis of past or present EBLL. # Chapter 5. Developmental Assessment and Interventions # Interchild Variability The BLLs at which individual children show signs of clinical lead intoxication vary widely, and despite the consistent inverse association between children's BLL and IQ noted above, children have varying sensitivity to the more subtle functional impairments associated with EBLLs (30). Although, on average, children with higher BLLs tend to score lower on IQ tests than do children with lower BLLs, some children seem to be more affected than others by a given lead dose (34). This suggests that not all children with a given BLL should be considered at equivalent neurodevelopmental risk. In other words, an EBLL should be viewed as a risk factor for neurodevelopmental problems, not a diagnosis. # Importance of Age Identifying the age at which children are most sensitive to the neurodevelopmental effects of lead is complicated by the relatively high degree of stability in children's BLLs and the frequent confounding of age and peak BLL (32,35). However, data from cohorts in which these obstacles to inference are less severe indicate that children's IQs may be particularly sensitive to leadassociated effects when the children are about 2 years old (16). Pocock et al. for example, found that EBLLs in children from 1 to 3 years of age appear to be the most predictive of children's later development (10). On the other hand, data from several of the prospective studies suggest that recent or concurrent BLLs are among the strongest predictors of children's neurodevelopmental function at school-age (12,32). Furthermore, primate studies indicate that the period of greatest susceptibility to EBLLs may depend upon the specific deficit being evaluated (36). There is some limited evidence for this from human studies as well (37). # Time Lag Associated with the Effects of EBLLs For the most part, the evidence from prospective studies regarding the time course of the association between a child's BLL and neurodevelopment is consistent with a lag effect (16,31). It is much more common to find a significant association between children's previous BLLs and their current neurodevelopmental status than between their current BLLs and current developmental status. This pattern is less clear under circumstances in which children's BLLs remain elevated for extended periods of time, such as when they live near smelters or in hazardous housing; under such conditions, children's current and past BLLs tend to be strongly correlated. The lag may be the result of a toxicological process in which some period of time is required for past lead exposure to affect the central nervous system function. Another explanation is that lead may primarily affect higher-order neurodevelopmental processes that are best tested at later ages when children's response modalities are more highly differentiated. One implication of this lag is that neurodevelopmental assessments conducted when a child has an EBLL may produce many false-negative results and fail to identify a child who is at risk for later neurodevelopmental dysfunction. Careful long-term surveillance of behavior and neurodevelopment is thus needed to ensure that such children are identified. The effects of EBLLs on the skills required for academic success may not be appreciated until a child reaches critical transition points in school: 1) first grade, when children are expected to begin acquiring basic academic skills such as reading words or performing arithmetic operations; 2) fourth grade, where the emphasis begins to shift from acquiring basic skills to using those skills to learn new material ("reading to learn" as opposed to "learning to read"); and 3) sixth or seventh grade, when students are expected to use higher-order planning and organizational skills in order to complete long-term projects. Increased BLLs have been associated with difficulties with all three types of skills (20,26,38). # Persistence of Neurodevelopmental Effects Results from a variety of studies indicate that neurodevelopmental problems associated with elevated postnatal BLLs are persistent (8,16,(38)(39)(40)(41)(42)(43). The natural history of these problems appears to correspond to a "constant decrement" model, with the deficits associated with higher BLLs neither increasing nor decreasing over time (44), although few data are available on the persistence of effects. In contrast, the findings from most of the prospective studies are consistent with the hypothesis that neurodevelopmental effects associated with elevations in biomarkers of prenatal lead exposure attenuate during a child's early years of life (10). # Factors Affecting a Child's Risk for Neurological Sequelae Increased exposure to lead frequently occurs in the context of other factors that also place a child at increased neurodevelopmental risk (e.g., poverty, single-parent household, teen-age mother, child abuse, poor nutrition). From this perspective, lead represents an additional "hit," adding to a child's cumulative neurodevelopmental risk (45). In multivariate statistical models, children's BLLs tend to account for a relatively small amount of the variance in their neurodevelopmental status. The amount varies across outcomes measured and across studies, ranging from 0% (i.e., accounting for no variance in neurodevelopmental measurements) to as much as 11% (46), although usually on the order of 1% to 3%. For instance, in the set of crosssectional studies included in the meta-analysis of Needleman and Gatsonis (47), children's BLLs accounted for 2.3% of the variance in their IQ scores (based on a weighted partial correlation of -0.152). Other factors, particularly social class and parental intelligence, typically account for much larger percentages of outcome variance. Some evidence suggests that certain characteristics of children and their families are associated with the children's increased risk for neurodevelopmental impairments from a given level of lead exposure. Several studies, although not all, have identified family social class as one such characteristic, with children from lower social strata appearing to express the neurodevelopmental effects of lead at a lower BLL (48)(49)(50)(51). A sex difference is also sometimes found, although in some studies it is girls (52,53) and in others it is boys (10,50,54) who are found to be at greater risk. One implication of these findings is that lead's association with children's neurodevelopment cannot be accurately expressed as a single number because the magnitude of the association may vary depending on the characteristics of a particular child and his or her environment. A more promising implication, however, is that the effects of lead on a child might be reduced by modifying critical aspects of the environment. For example, indirect observational evidence indicates that the persistence of the link between an EBLL and reduced function varies with factors such as family social class, maternal IQ, and quality of the home environment (54). Specifically, if two children with the same early BLL achieve the same developmental score at time 1, but one child's environment offers greater cognitive stimulation, that child's developmental status at time 2 is likely to be better than that of the child from the less stimulating environment. Thus certain factors might help children to weather the developmental insult of early lead exposure, either preventing neurodevelopmental effects from being expressed or facilitating subsequent recovery of function. Social class is often found to be such an effect modifier, although higher social class is presumably a surrogate for the more proximal influences that confer this greater resilience (e.g., better nutrition, greater access to academic supports, more varied experiences). # Effectiveness of Reducing BLLs It has not been shown that lowering a BLL after it has been elevated prevents lead-induced cognitive defects. In one study, children with BLLs between 25 and 55 Fg/dL were chelated if a test dose of EDTA increased their urinary lead excretion. Chelation did not change their neurodevelopmental test scores or BLLs at 6 months of follow-up. However, the children whose BLLs fell the most, whether they had chelation or not, had the greatest improvement in test scores at their 6-month follow-up evaluation (55). It is noteworthy that children's test scores increased one point for each decline of 3 Fg/dL in their BLL, a slope that is consistent with the slope for the dose-effect relationship from several observational studies that did not involve any intervention. However, the only large-scale randomized trial assessing the effects of chelation induced BLL reductions on neurotoxicity showed that oral chelation with succimer (dimercaptosuccinic acid) lowered children's BLLs but did not improve their scores on a range of cognitive, neuropsychological, and neurobehavioral tests. Conducted among children living in deteriorating housing in four inner-city areas, this study involved 780 children (12 to 23 months of age) with BLLs from 20 to 44 Fg/dL who were randomly assigned to receive either a placebo or up to three courses of succimer. While the mean BLL of the treated group was 4.5 Fg/dL lower than that of the control group 6 months after treatment, there were no significant differences between them in any of the mean test scores 3 years after treatment began, when the children were, on average, 5 years old (56). # Effects of Early Enrichment on Children with EBLLs No studies have been published on the effectiveness of non-medical interventions, such as early enrichment programs, in ameliorating the effects of EBLLs on children's neurodevelopment. In the absence of such data, it is reasonable to hypothesize that children with neurodevelopmental problems associated with an EBLL would benefit from the types of interventions shown to be effective in facilitating the neurodevelopment of other groups of children with idiopathic neurodevelopmental problems or those known to be at increased risk for such problems, such as low birth weight infants. Evaluations of interventions to foster the development of preschool children at risk for neurodevelopmental problems because of socioeconomic disadvantage, nonorganic failure to thrive, or low birth weight indicate that such programs can produce IQ increases on the order of 8 points (57). Although the magnitude of these IQ effects might attenuate after children complete the programs, participation in such programs is associated with lower rates of grade retention and need for special education (58). Some evidence suggests that programs in which participation begins prior to age 3 are more effective than those in which participation begins later (59). Programs that include procedures to foster both child development and parenting skills tend to be more effective than programs that are solely child-focused or parent-focused (57). Examples of such programs are the Mother-Infant Transaction Program (60)(61)(62)(63)(64) and the Infant Health and Development Program (65)(66)(67). # General Recommendations Make long-term developmental surveillance a component of the management plan for any child with a BLL $ 20 Fg/dL. The precise BLL that one identifies as a "trigger" for neurodevelopmental surveillance will depend on the type and magnitude of deficit that one considers sufficiently large to warrant concern. Current CDC guidelines recommend that a child whose BLL is 20 Fg/dL or above receive environmental and medical evaluations. It makes both clinical and logistical sense to integrate neurodevelopmental surveillance and possible referral for diagnostic assessment or intervention into the overall management plan of such a child. The PCP and case manager, working in close collaboration, are best positioned to organize and oversee these processes. A BLL that exceeds 20 Fg/dL should not necessarily result in a referral for diagnostic assessment or intervention. This clinical decision should be made on a case-by-case basis, taking into account whether other neurodevelopmental risk factors are present (e.g., teen-age mother, poor parenting skills, inadequate cognitive or emotional stimulation, child abuse, poverty, genetic disorder, poor nutrition, other medical issues). Under some circumstances, such as persistent BLLs of 15 to 19 Fg/dL or the presence of other significant neurodevelopmental risk factors, it would be appropriate to place a child with a lower BLL under increased neurodevelopmental surveillance. The case manager is in a unique position to assist the PCP in this regard by virtue of his or her knowledge of a child's risk factors gleaned from visits to the home or other contacts. Thus, the case manager can serve as a critical information resource to the PCP regarding contextual factors germane to the PCP's decisions about a child's neurodevelopmental needs. Furthermore, a case manager with training in neurodevelopmental assessment can conduct screening evaluations and bring potential problems to the PCP's attention. The usual absence of associations between concurrent BLLs and risk for neurobehavioral deficits among children aged 0 to 3 years suggests that neurodevelopmental assessment of children while they have an EBLL might not identify children who will later experience cognitive problems (false-negatives). If a child currently has or has ever had an EBLL, however, the PCP and case manager should take a more aggressive approach in assessing that child's neurodevelopment and referring that child for follow-up. Under ordinary circumstances, the PCP is in the best position to follow up with long-term monitoring of a child with an EBLL. The developmental and behavioral screening that PCPs conduct at well-child visits, including taking a clinical history and administering brief instruments such as the Denver Developmental Screening Test, may be sufficient to identify children who are failing to make age-appropriate progress and transitions and who thus require additional diagnostic evaluation. Kindergartenreadiness evaluations generally are not designed to identify vulnerabilities that may be expressed as serious academic problems once children enter school. Because they produce many false negatives, kindergarten evaluations are not sufficiently sensitive to identify potential leadassociated learning difficulties. # Do not base decisions regarding developmental assessment or intervention on a child's age at the time of the EBLL. Age is an inappropriate criterion for determining which children with EBLLs need referral for developmental evaluation. The neurodevelopmental effects of EBLLs are persistent and may be delayed. Also, there is no way of knowing how long a child may have had an EBLL. A child first identified as having an EBLL at age 4 might well have also had an EBLL at age 2 or 3 and, on the basis of a presumed chronic exposure, could be regarded as being in greater need of developmental assessment than a child with an EBLL at age 2. Because detailed information about children's blood lead history is often not available, a child of any age who is found to have a BLL of 20 Fg/dL or greater should be placed under increased surveillance in order to identify any emerging neurodevelopmental problems as early as possible. If you wish to refer a child with an EBLL for intervention services, consider referring that child for early intervention/stimulation programs that are available for children at increased developmental risk. Although there is no empirical basis for recommending interventions with specific characteristics for children with neurodevelopmental problems resulting from an EBLL, it is reasonable to hypothesize that such children would benefit from the types of interventions shown to be effective in facilitating the neurodevelopment of other groups of children with idiopathic neurodevelopmental problems. Programs in which participation begins prior to age 3 or those that include procedures to foster both child development and parenting skills may be most effective. Examples of such programs are the Mother-Infant Transaction Program and the Infant Health and Development Program. # Include a history of a child's EBLL in the problem list maintained in the child's medical record. If a child changes his or her PCP, ensure that this information, along with other pertinent aspects of the child's medical history, is transmitted to the next provider. The PCP should work with the case manager to ensure appropriate follow-through. For the purposes of developmental surveillance, do not consider a child's case "closed" when the child reaches age 6 or when his or her BLLs are reduced. The period of increased risk for the expression of lead-associated neurodevelopmental problems continues after lead exposure has been remediated and BLLs reduced. Closure of a child's case by the case manager does not mean that the need for neurodevelopmental monitoring has ended. # Be especially vigilant for emerging difficulties at critical transition points in childhood. There are three periods when different types of learning difficulties are typically expressed: 1. First grade: Children begin acquiring basic academic skills. 2. Fourth grade: They use these basic skills to learn new material. 3. Sixth or seventh grade: They need higher order planning and organizational skills. A child with a history of EBLLs who experienced difficulties making earlier transitions should be viewed as being at increased risk of experiencing difficulties with later transitions. Even children who made early transitions smoothly should be under increased surveillance at later transition points, as they may have problems when new educational demands are placed on them. # Chapter 5. Developmental Assessment and Interventions Be alert for behaviors that might interfere with learning. An EBLL in early childhood is associated with an increased risk for behaviors such as inattention, distractibility, and impulsivity that can interfere with learning. These behaviors are characteristic of the recently recognized inattentive subtype of ADHD. Even if the behaviors a child presents are not sufficient to warrant the diagnosis of ADHD, the child may be helped by the types of classroom and work accommodations routinely made for children with an attention disorder. If you suspect that a child might be experiencing neurodevelopmental problems, consider arranging a thorough diagnostic (as opposed to screening) evaluation. The procedures used for assessment and intervention for a child with a history of EBLL and neurodevelopmental problems should be the same as those for a child with neurodevelopmental problems due to known and unknown causes. Ideally, assessments should be conducted by multidisciplinary teams, which might include developmental-behavioral pediatricians, educators, neuropsychologists, neurologists, speech/language pathologists, and child psychiatrists. # Be advocates for the child. This might involve assisting the family in arranging diagnostic evaluations, interpreting the results, and petitioning third parties to pay for the evaluation on the grounds that the evaluation might reduce special education or specialized therapy costs in future years. In regions where access to specialized neurodevelopmental clinics is limited, diagnosis and treatment planning can also be achieved by means of school-based evaluations or private practitioners. It is important to recognize the complexities of school-system involvement in this process. Some school systems may be unwilling to commit resources to evaluate a child in the absence of a complaint that includes reduced academic progress. Furthermore, expecting schools to conduct such evaluations places them in a position of possible conflict of interest insofar as they would have to pay for remedial services deemed necessary as a result of the evaluations. # Recommendations for Future Research 1. Conduct studies to characterize in greater detail the neurodevelopmental presentation associated with an EBLL, including analyses of the degree to which the presentation varies with factors such as the child's age at exposure and the magnitude and chronicity of the exposure. 2. Conduct studies to characterize the associations between EBLLs and learning disabilities. 3. Conduct studies to evaluate the role of EBLLs in causing or exacerbating behaviors associated with ADHD, conduct disorder, and other psychiatric diagnoses. 4. Conduct studies to evaluate the potential psychosocial vulnerabilities of children with EBLLs (e.g., self-esteem, self-concept, social competencies, aggression). 5. Conduct randomized trials to evaluate the efficacy of specific interventions in ameliorating lead-associated neurodevelopmental problems. # Introduction The 1990s witnessed dramatic declines in children's mean blood lead levels (BLLs) and in the percent of children with elevated blood lead levels (EBLLs) (1). During that decade, we learned a lot about children's exposure to lead in and around their homes, and about how to reduce that exposure through environmental interventions and caregiver education and counseling. In this chapter, we provide current recommendations for educational interventions, review the quality of evidence that supports these recommendations, and identify research needed to improve the effectiveness of caregiver education. Much of the relevant research is discussed in more detail in Chapter 2, "Assessment and Remediation of Residential Lead Exposure." The efficacy of most interventions has not been studied in isolation. Studies usually involved multiple interventions, thus limiting our understanding of the utility of individual recommendations. # Sources and Pathways of Residential Lead Exposure Leaded paint is the most common high-concentration source of lead for children and is typically seen in homes built prior to 1950. Poorly maintained older homes with deteriorating paint or those undergoing renovation, whether they are the children's primary residences or secondary sites where children spend much time, pose the highest risk of lead exposure. The usual sites of deteriorating leaded paint are interior painted surfaces, particularly those subject to abrasion such as window components, and exterior surfaces like siding and porches. The paint chalks or chips off from normal wear-and-tear and deteriorates into dust. Leaded dust can also be created by improperly conducted abatement (2). Soil is another significant source of lead for some children (3). Exterior soil can become very contaminated with lead from deteriorating overlying leaded paint, driplines, or lingering fall-out from previously used leaded gasoline, especially along heavily traveled roads. Children typically ingest leaded dust as a consequence of age-appropriate hand-to-mouth activity. Studies consistently show an association between the amount of lead on children's hands and their BLLs (4,5). Children are also exposed by intentionally ingesting paint chips, dust, or soil. Housing and soil sources are the most common cause of EBLLs in children. Additional significant sources of lead in certain communities include water, industrial contamination, folk medicines, and imported cosmetics or pottery (6)(7)(8). In addition, as shown in Appendix I, numerous less common lead sources may be the cause of individual cases of EBLLs. # General Principles Educational interventions are directed at helping caregivers reduce the exposure of children to residential and other sources of lead. While most children are exposed through the deterioration of leaded paint, they may also be exposed to lead from other sources; some of these exposures are a consequence of cultural practices or caregiver occupations or hobbies. Case managers should therefore select the information and interventions that are most appropriate to each child, family, and community and avoid overwhelming caregivers with interventions that may be of little or no benefit. Although there is no risk-perception or risk-communication research specific to childhood lead poisoning, general principles of these fields can be applied to improve the effectiveness of educational interventions to reduce children's BLLs. Case managers must recognize that caregivers understand the "risk" of EBLLs in ways different from the ways that experts in lead poisoning understand them, and case managers should tailor their recommended interventions to caregivers' conceptions of risks. If interventions are not tailored to caregivers' conceptions of risks, then caregivers are less likely to act on the information they receive (9, 10). In addition to educating caregivers about childhood lead poisoning, case managers may also need to provide detailed instructions on intervention techniques, actually demonstrate the techniques, and then ask caregivers to perform the techniques themselves. Such actions should increase caregivers' understanding of the interventions and consequently increase the chances that the interventions will be successful. # Studies of Various Interventions # Interventions to reduce children's lead exposure from residential deteriorating paint Interventions to reduce children's exposure to deteriorating paint in their homes include the safe repair of non-intact leaded paint, the safe repair or replacement of windows or other building components to prevent abrasion of leaded paint, and the safe removal (stripping) of leaded paint from components left in the home. In a review of uncontrolled studies involving children with baseline BLLs greater than 25 Fg/dL, the EPA found that BLLs of children in homes where non-intact leaded paint was safely removed or repaired declined 20% to 30% over the following year (11). In one controlled study, the mean BLL of children in treated dwellings declined twice as much as that of children in untreated dwellings (12). # Interventions to reduce children's lead exposure from residential dust Four clinical trials assessed the efficacy of household dust control by professional cleaners (13)(14)(15)(16)(17). Three trials assessed the effectiveness of household dust control done by the families of children with EBLLs: two randomized clinical trials (18)(19)(20), and one nonrandomized, retrospective analysis with a comparison group (21,22). Among the studies of professional house dust control, two (13,17) found that children in homes that underwent intensive dust-control (i.e., two trained cleaners wet mopping floors and wet wiping horizontal surfaces for 2 hours every 2-3 weeks) had a 17% -18% decrease in their mean BLL 1 year after the initial test. In one of these studies (17), a subgroup of children whose homes were cleaned 20 or more times over the year (a mean of once every 2.6 weeks) had a 34% decrease in their BLLs. Since trained cleaners conducted the interventions, this effect size is probably the optimum that can be achieved. The remaining studies (14)(15)(16) failed to show that dust control is associated with a decrease in children's BLL. Two of these studies were of a one time intervention (14,15), and the other was of cleaning done every 6 weeks (16). However, one time or infrequent interventions would most likely not prevent EBLLs, because household dust builds up again after a short time. This is suggested by Hilts et al., who found that children's lead loading returned to baseline levels 3 weeks after high-efficiency particulate air (HEPA) vacuuming (16). Similarly, Rhoads et al. found no change in the mean BLL of children whose homes were cleaned fewer than 10 times over the year (at most every 5.6 weeks) (17). Lanphear et al. conducted two trials in which the cleaning was done by the caregivers (18)(19)(20). In the first, 104 children (aged 12 to 31 months; BLLs 1.7 to 30.6 Fg/dL) were randomly assigned to an intervention group (in which caregivers received cleaning supplies, were educated about areas likely to be contaminated with lead, and were instructed to clean monthly) or to a control group (in which caregivers received only a brochure about preventing EBLLs) (18). Seven months after enrollment, the median change in children's BLL was -0.05 Fg/dL in the intervention group and -0.60 Fg/dL in the control group (p=0.50). However, in this study, the researchers could not ensure that the families adhered to the recommended cleaning regimen. The second trial involved 275 children with a mean baseline BLL of 2.8 Fg/dL (19,20). These children were randomly assigned to either an intervention group that received education, cleaning supplies, and up to eight home visits by an advisor, or to a control group that did not receive any of these interventions. Again, researchers found no significant differences in the geometric mean BLLs of children in the two groups at 12, 18, 24 and 48 months of age. But again, they could not ensure that the families adhered to the recommended regimen. Schultz et al. conducted a retrospective analysis of an in-home educational intervention (21,22). Health department staff visited the homes of children (mean age 3.4 years) with BLLs 20 to 24 Fg/dL and conducted an educational session for caregivers regarding lead sources, methods to reduce children's exposure to these sources, and appropriate nutrition for children. The children in visited homes made up the study group. A reference group was made up of children (comparable with the study group by age, sex, race, and BLL) who did not receive the educational intervention. Follow-up BLLs were obtained about 6 months after the intervention. The study group children had a significantly greater mean decline in BLL (4.2 Fg/dL) than the reference group children (1.2 Fg/dL, P<0.001). The authors concluded that home educational visits may have helped lower children's BLLs (22). However, they also noted that "he validity of this conclusion depends upon whether children who received the visits were comparable to reference group children whose families were often unavailable for outreach visits. Families that were unavailable…may have been more likely to exhibit behavior patterns responsible for the continued elevation of their children's blood lead levels" (22). Thus, with no randomization of subjects, the reference group may not have been comparable in at least one important way. In a meta-analysis, the findings of several studies were combined to determine the effect of dust control on children's BLL (23). To be eligible for analysis, the studies had to be randomized controlled trials, cost less than $2,500, and be conducted in a community without a continual lead emission source, such as a lead smelter. Five studies were eligible (15,(17)(18)(19)(20). Results of the meta-analysis showed no significant post-intervention differences in mean BLLs between children in the intervention and control groups. However, the intervention groups contained significantly fewer children with BLLs $ 15 Fg/dL and $ 20 Fg/dL than did the control groups. For example, only 1.8% of children in the intervention groups had BLLs $ 20 Fg/dL, whereas 5.3% of those in the control group did (OR=0.29, CI 0.01 -0.85, p=0.024). This finding persisted even after the single study involving professional dust control (17) was removed from the analysis. The aforementioned studies largely focused on cleaning dust on uncarpeted floors. Although the dust lead loading on uncarpeted floors has a higher correlation with children's BLLs than the dust lead loading on carpets, dust lead loading on carpets does correlate with children's BLLs (24). However, neither HEPA vacuums nor common household vacuums reduced carpet dust lead levels by clinically relevant amounts (16,25,26). Furthermore, in one study, children whose homes were HEPA vacuumed actually had higher levels of lead on their hands after the interventions although their BLLs did not change (16). The authors speculate this may have occurred because families who received the vacuuming "…may have relaxed their hygiene efforts…because of a perceived reduction in exposure risk" (16). A report that HEPA vacuuming increased the lead loading on the surface of the carpet by bringing lead from deep in the carpet to the surface (25) offers an alternative explanation for the increase in hand lead levels. In summary, studies indicate that household dust control performed by professional cleaners is associated with decreases in children's mean BLL, although it appears that to be effective, such dust control must be conducted at least every 2 to 3 weeks. However, simply educating parents of the need to perform dust control has not proven effective in reducing children's mean BLL. # Interventions to reduce children's lead exposure by improving personal hygiene practices We found no controlled studies that examined the effect of personal hygiene on BLLs of children, although studies of the correlation between the level of lead on children's hands and their BLLs have consistently found an association between the two (6,7,27,28). Although the frequency of self-reported hand washing has not been associated with children's BLLs (27,28), the validity of study results based on such self-reported hygiene measures is clouded by the possible effects of social desirability bias. reductions in children's BLLs do not appear to be clinically relevant. Further, an economic analysis concluded that soil lead abatement was not cost-effective (33). Therefore, we do not recommend residential soil lead abatement in the secondary prevention of children's EBLLs. Nevertheless, because some children may experience significant lead exposure from soil either because they play in or ingest soil or because their soil has high levels of lead, we do recommend simple, safe measures such as providing sandboxes with covers or covering open soil with grass or mulch. # Nutritional Interventions Although the effects of various nutritional interventions on children's BLLs are either limited or have not been studied, certain interventions are of value to the children's general health, because many children with EBLLs are at risk for poor nutrition. See Chapter 4, "Nutritional Assessment and Interventions," for a detailed discussion. # Recommendations # General Recommendations Tailor educational interventions to each child and caregiver. Select the interventions and information that are most appropriate to the child. Devise a written plan with specific recommendations to reduce the child's exposure to identified sources of lead in consultation with the caregivers and give a copy of the plan to them. # Continue educational efforts beyond a one-time intervention. Monitor children's follow-up BLLs. If a child's BLL is not decreasing, discuss the case with the primary care provider (PCP) and, if appropriate, an environmental health specialist, to determine whether lead sources are being overlooked. Case managers may need to make further home visits to assess new lead sources and ensure that caregivers understand and are carrying out recommended interventions. # Environmental Recommendations Prompt and effective control of the sources of children's lead exposure is the highest priority. Ensure that all sites lived in or regularly visited by a child with an EBLL are inspected jointly with the caregiver to identify potential sources of lead exposure. surfaces every 2-3 weeks until all of their child's hand-to-mouth behaviors cease. Since windowsills and wells can contain high levels of leaded dust, they should be kept clean and, if feasible, shut to prevent abrasion of painted surfaces. Advise caregivers to use disposable cleaning materials or reusable materials used only for cleaning. The EPA recommends the use of a general-purpose, nonphosphate cleaner (36). In studies that found house dust control to be associated with a decrease in children's mean BLL, professional house cleaners used a powdered detergent rather than bleach or ammonia (13,17 Water sources can become contaminated with lead from household pipes made of lead or harboring leaded solder (37). The local health authority will know if this is a prevalent community-wide problem. See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," for a detailed discussion of contamination in municipal or well water. If household water is a suspected source of lead exposure, advise caregivers to implement the following interventions pending the results of water testing: - Do not drink or cook with hot tap water. Lead is more soluble in warm water. Run the tap water cold for 1-2 minutes in the morning, and then fill a pitcher with the water. The water is then available that day for drinking, cooking, and formula preparation. Although the benefit of regularly running the tap before consuming water has not been studied in isolation, this is a simple intervention that poses no risk. If drinking water in a child's home is contaminated with lead, advise caregivers to use only bottled water until household water lead levels have been corrected. However, since most bottled water does not contain fluoride, fluoride supplementation may be necessary. For more information on bottled water, contact the United States Food and Drug Administration (301-443-4166); NSF International, an organization that certifies bottled water and water filters (313-769-5106); or the International Bottled Water Association (703-683-5213). # Nutritional Recommendations # Discuss dietary interventions. Recommend that caregivers provide children with foods rich in absorbable iron, vitamin C, and calcium. Foods such as red meat and iron-enriched cereals are good sources of absorbable iron. Adding foods to a meal that are rich in vitamin C (e.g., fruit juice) can dramatically increase iron absorption. Two servings per day of dairy products are recommended. Unless the child does not ingest dairy products because of lactase deficiency, do not suggest calcium supplements, as they can be contaminated with lead (38). Both iron deficiency and EBLLs are common among children of low-income families (39,40), so providing iron-rich foods to children with EBLLs would contribute to the treatment of iron deficiency. (See Chapter 4, "Nutritional Assessment and Interventions," for details.) - Recommend that caregivers provide regular meals and snacks. In one study of five adults, a higher proportion of lead was absorbed when it was given to people when they were fasting (41). Therefore, encourage caregivers to provide three meals and two snacks (during midafternoon and at bedtime) a day. Refer eligible families to food supplementation programs such as the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). # Medical Recommendations Discuss the importance of regular medical follow-up. Follow-up blood tests are the best way to determine the success of environmental and other interventions. Therefore, remind caregivers to: - Make and keep follow-up appointments for blood tests. When making appointments, follow the schedule in Table 3.4 of Chapter 3, "Medical Assessment and Interventions." - Notify the case manager if the child moves to a new residence. - Advise caregivers not to use containers, cookware, or tableware purchased abroad to store or cook foods or liquids unless they are shown to be lead-free. Advise caregivers not to use folk remedies and cosmetics purchased abroad unless they are shown to be lead-free. # Recommendations for Future Research Although dust control performed by trained cleaners has been shown to reduce children's mean BLLs (13,17), simply educating families on the need to perform dust control does not attain the same results. Further research on how to motivate families to perform regular and effective cleaning is important. Reports indicate that, in the absence of interventions to reduce ongoing contamination of dust from disintegrating paint, the effect of dust control on children's BLLs is modest (17,18,20,44). However, randomized trials examining the effects of a multifactor intervention involving dust control, nutritional supplementation, and behavioral modification on children's BLLs would be of value. In other areas of environmental health, a great deal has been learned about ways in which different people view risks, methods of risk reduction, and barriers to addressing risks. Despite this increased understanding of the scientific basis of risk perception and communication in the past 20 years (45), no studies of risk perception or communication have been conducted among caregivers of children with EBLLs. In order to develop more effective educational and riskreduction strategies to combat EBLLs in children, health officials need better information about what people think about lead hazards and why they think that way. Methods such as mental modeling (46) and value integration (47) would be very valuable approaches to obtaining such information. Soil lead abatement is costly and has not been associated with clinically significant reductions in BLLs. However, studies are needed to assess the effectiveness and costs of using barriers such as grass, shrubbery, or cement to protect children with high soil lead exposures. Research is also needed on the efficacy of various barriers, such as wallpaper or paneling, in protecting children from exposure inside their homes. Since the half-life of lead in the blood can be up to 38 months (48), children must be followed for prolonged periods to determine whether their BLLs are decreasing and whether interventions have been effective. Decreases in dust lead levels or hand lead levels might be used as intermediate, proxy measures of children's lead exposure if we could develop practical, inexpensive, and reliable methods of using such assays in a clinical setting. manufacturing process, the candied jam is packaged in stoneware or terra cotta ceramic jars that can leach lead. # Food and Beverage Containers # Bulk-water storage tank Lead leached from soldered seams and brass fittings in bulkwater storage tanks. # CR Report of three children aged 6, 12, and 14 months. # Ceramic glaze Lead in ceramic glaze can leach into stored beverages, especially juices since they are acidic. The risk is highest for improperly fired containers. # CR Multiple reports. 7, 12, 49 Cocktail glass Lead leached from cocktail glass. CR Report of a family with one adult and children aged 4, 5, and 14 years. # Iranian urn (samovar) Lead spot solder from the original manufacturing process leached into water used to make baby formula. # CR Reports of a 10-week-old child with seizures and of a 4-month-old child. Managing Elevated Blood Lead Levels Among Young Children	Because case management of children with elevated blood lead levels varies markedly among states, cities, and other jurisdictions, the Advisory Committee on Childhood Lead Poisoning Prevention developed these nationally applicable recommendations. Based on recently published studies and augmented with opinions of experts, this report defines the elements of case management and offers assessment and management guidelines for health departments, case managers, primary care physicians, and other professionals. Not all recommendations are appropriate for any individual child because of variations in age, blood lead level, housing status, and-most important-the ability of caregivers to respond to recommendations without being overwhelmed. The report contains five chapters in addition to the introduction: home environment investigation and interventions, medical evaluation and treatment, nutritional assessment and dietary modification, developmental surveillance and interventions, and education for caregivers. At the beginning of each chapter is a summary table of specific management recommendations. (The remainder of the tables, the figures, and the references are at the end of each chapter.) The text of the chapters provides the detailed information and references upon which most recommendations are based. Each chapter concludes with suggestions for further research. This report, in addition to addressing the case management of individual children, also discusses the importance of state laws, regulations, and financing related to lead abatement efforts and the provision of appropriate services for affected children. Finally, the authors of this report recognize that case management is involved with the secondary prevention of elevated blood lead levels and that primary prevention by the removal of ongoing lead exposure sources should be promoted as the ideal and most effective means of preventing elevated blood lead levels.# Table of Contents # List of Tables # Managing Elevated Blood Lead Levels Among Young Children vii # Foreword The overall reduction in childhood lead levels over the last three decades has been one of the great environmental health success stories in this country. However, our goal has not yet been reached. There are still far too many lower-income children living in older housing who are being hurt by elevated blood lead levels. The public health, housing, and environmental communities must continue to work together to eliminate the threat of lead poisoning for our future generations. An important factor in the battle against lead poisoning is the proper management of children who have been identified as having elevated blood lead levels. In this publication, the Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) and other public health practitioners have developed guidelines for assessment and interventions in the areas of medicine, nutrition, environmental exposure, childhood development, and education. Implementation of these "Best Practices" will greatly assist case managers, medical care providers, and others in delivering the most effective services to the lead poisoned child and the child's caregiver. I congratulate the ACCLPP and all the authors of these guidelines and thank them for their efforts. This report is a critical piece in the nation's effort to eliminate childhood lead poisoning in America by the year 2010. # Richard Joseph Jackson, MD, MPH Director, National Center for Environmental Health Managing Elevated Blood Lead Levels Among Young Children ix # Development of the Case Management Recommendations This report from the Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) is intended to facilitate the management of children with elevated blood lead levels (EBLLs) by providing case managers with information and guidance. Some of the assessments and interventions recommended herein will be the primary responsibility not of case managers, but of other individuals or groups-primary care providers (PCPs), public health agencies, nutritionists, managed care organizations, and environmental inspectors-for whom this document should be considered as only a supplementary, not primary, source of information. Through this document, however, case managers can become familiar with the activities and responsibilities of others, and thus be better prepared to offer them guidance, assistance, and support. Many studies published since the 1991 Centers for Disease Control and Prevention (CDC) report Preventing Lead Poisoning in Young Children (1) have provided updated or new information that can assist case managers of affected children and their families. In response, some states and localities have implemented a variety of changes in case management procedures. The plethora of new information and the marked variation in assessment and management policies among various jurisdictions were the main stimuli for the development of these guidelines. This report is divided into five chapters other than this introduction: four that present assessment and intervention guidelines from environmental, medical, nutritional, and developmental viewpoints plus one that presents caregiver education guidelines. Experts in each subject area were asked to summarize recommended case management actions; to provide a detailed, referenced basis for their recommendations; and to suggest the most important areas for future research to support, modify, or eliminate poorly justified or empirically based recommendations. Recommendations in each chapter are based on the results of evidence-based studies wherever possible. The most convincing basis for a specific recommendation is data from prospective, randomized, controlled trials. Unfortunately, such data are scarce; therefore, experts who developed each chapter had to rely primarily on softer data from cross-sectional studies, cohort or case controlled studies, uncontrolled studies, epidemiologic data, and-if appropriate-case reports or animal studies. They were also asked to note whether studies of interventions used to support their recommendations were efficacy studies (studies performed under ideal conditions) or effectiveness studies (studies performed in ordinary settings). In the absence of sufficient study data, the opinions of respected authorities were considered in the formulation of these recommendations. Recommendations, particularly those not based on controlled studies, were often modified by the ACCLPP working group and subsequently by the full committee. Thus, in their final form, the recommendations in this report represent the consensus of the ACCLPP rather than individual opinions of the authors of each chapter. # Chapter 1. Introduction This report is written primarily for those who will provide case management for children with EBLLs and for health department personnel who oversee case management follow-up. Because there is unavoidable overlap among chapters, interested professionals may gain insight from chapters covering areas outside their own expertise. For example, a nutritionist or a PCP will find iron stores and anemia discussed in both the medical and the nutritional sections. Although the primary cause of EBLLs in children is exposure to deteriorated paint in housing built before 1950, other sources of lead are found in some states and localities. Consequently, users of these guidelines may need to modify them to meet the needs unique to specific communities. Further, because the prevalence of EBLLs among children will vary markedly among and within states, the number of children managed will show corresponding variation. Because there is no apparent threshold below which adverse effects of lead do not occur, "EBLL" must be defined arbitrarily. This report uses the definition given in the 1997 CDC report Screening Young Children for Lead Poisoning (2), which defined child blood lead levels (BLLs) $10 Fg/dL as elevated. Although the BLL at which particular elements of case management will be initiated is variable, education and follow-up BLL monitoring should be available for any child who has a confirmed BLL $10 Fg/dL. More intense management, including home visiting and environmental investigation, should be available to any child with a BLL $ 20 Fg/dL, or persistent levels in the 15 to 19 Fg/dL range. Another variable, the duration of management, will depend on the effects of lead on the child being treated. As noted in Chapter 5, "Developmental Assessment and Interventions," the effect of lead on a child may not be demonstrable until the child is well into the elementary school years, meaning that some children will need continued tracking by PCPs or others long after their case management ends. The interventions recommended in this report are for the secondary prevention of EBLLs-which is to prevent further lead exposure and to reduce BLLs in children who have been identified as having EBLLs-and involve a number of scientific, technical, and implementation issues. The ultimate goal, primary prevention-the removal of harmful lead exposure sources (especially older, deteriorated housing) and the elimination of lead from products with which children may come in direct or indirect contact-involves other, sometimes overlapping, issues. The importance of primary prevention should not be overlooked, since the behavioral and cognitive effects of EBLLs in young children are apparently irreversible. # Overview of Comprehensive Case Management # What Is Case Management? Case management of children with EBLLs involves coordinating, providing, and overseeing the services required to reduce their BLLs below the level of concern (i.e., 10 Fg/dL). It is based on the efforts of an organized team that includes the child's caregivers. A hallmark of effective case management is ongoing communication with the caregivers and other service providers, and a cooperative approach to solving any problems that may arise during efforts to decrease the child's BLL and eliminate lead hazards in the child's environment. Case management is not simply referring a child to other service providers, contacting caregivers by telephone, or other minimal activities. The current model of case management has eight components: client identification and outreach; individual assessment and diagnosis; service planning and resource identification; the linking of clients to needed services; service implementation and coordination; the monitoring of service delivery; advocacy; and evaluation (3). Once an eligible child is identified, the case manager should do the following: • Visit the child's residence (and other sites where the child spends significant amounts of time) a minimum of two times. • Assess factors that may impact the child's BLL (including sources of lead, nutrition, access to services, family interaction, and caregiver understanding). # • Oversee the activities of the case management team. • Develop a written plan for intervention. # • Coordinate the implementation of the plan. # • Evaluate compliance with the plan and the success of the plan. An environmental inspector should also visit the child's residence, with the case manager if possible, to conduct a thorough investigation of the site and identify sources of environmental lead exposure. The case management team can then use the results of this investigation to develop a plan to protect the child and correct hazardous conditions. Although environmental services may be provided by the case manager, the environmental inspector, or other program staff, the case manager is responsible for ensuring that a child receives services in a timely fashion. # Funding Nationally, an estimated 83% of children with BLLs $ 20 Fg/dL are eligible for Medicaid (4). Both the case management of eligible children and the environmental investigation of their surroundings are reimbursable according to federal Medicaid policy, with each state responsible for setting reimbursement rates for eligible services. Despite this, funding for services remains a critical resource issue for most states. Fewer than half of all states provide Medicaid reimbursement for lead follow-up services, with the level of reimbursement varying widely. In addition, most state programs do not know how many children with BLLs $ 20 Fg/dL also receive Medicaid. As of 2000, only 10 state lead programs Chapter 1. Introduction were able to successfully identify Medicaid children by linking their Medicaid and lead screening data bases (5). # Who Provides Case Management? Ninety percent of programs use professionals (nurses or social workers) to deliver case management services (6). The case manager is usually a member of the local health department staff, although nearly half of all states also use other providers to deliver case management services. In most cases, a management team can best meet the needs of an individual child. The team may include the case manager, the child's caregiver, the child's PCP, an environmental inspector, a health educator, a nutritionist, and the local public health agency. # Time Frames for Initiating Case Management Services A case manager should schedule an appointment with the child's caregiver as soon as possible after being assigned to the case. Where feasible, public health agencies providing case management services should give priority to children with the highest BLLs and those less than 2 years of age. If the caregiver does not have a telephone, the case manager should visit the child's home and leave information at the door if no one is there. For children with BLLs $ 45 Fg/dL, the case manager should contact the child's PCP immediately to determine whether the child is being chelated at home or in the hospital. If the child is hospitalized, the initial visit may take place at the hospital. However, it is critical that team members conduct a hazard assessment in the child's home as quickly as possible. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," and Chapter 3, "Medical Assessment and Interventions.") Blood # The Case Management Plan The case manager is responsible for developing and implementing a written management plan based on a needs assessment done at visits to the child's home and other sites where the child spends significant amounts of time. Although all cases require a Chapter 1. Introduction minimum of two home visits, additional visits are often necessary. The caregivers also should be involved in developing the plan to ensure that it is realistic and meets their perceived needs. Areas the plan should cover are detailed in Table 1.1 and in specific sections of this report. # Coordination of Care by the Case Manager The case manager is responsible for coordinating care and ensuring that all team members, including the caregiver, stay in communication and work together. Such communication includes verbal consultations with and written summaries of progress for team members. Case managers need not directly provide all follow-up care, but they are responsible for seeing that needed care is provided, including medical follow-up. In most jurisdictions, the environmental inspector or program issues and enforces lead hazard remediation orders. The case manager must be sufficiently knowledgeable about environmental investigation and follow-up, however, to ensure that inspection and remediation take place in a timely fashion and that short-term efforts are made to decrease an affected child's exposure to lead hazards. Similarly, the case manager is responsible for ensuring that someone follows up on referrals for other problems identified during case management. # Case Closure It often takes an extended period of time to complete all the elements in a case management plan. When the environmental lead hazards have been eliminated, the child's BLL has declined to below 15 Fg/dL for at least 6 months, and other objectives of the plan have been achieved, the case should be closed. However, the case manager should discuss with the PCP and caregiver provisions for appropriate long-term developmental follow-up. (See Chapter 5, "Developmental Assessment and Interventions".) Case closure criteria should also include provisions for administrative closeout if at least three documented attempts to locate or gain access to the child and caregiver have failed. # Public Health Agency Role Although the recommended public health agency activities are not part of case management per se, they are necessary to achieve optimum results. With their focus on the core public health functions of assessment, policy development, and quality assurance, public health agencies play a broad role in coordinating care at the state and local level. They also are responsible for initiating and implementing laws and regulations that will help to eliminate childhood lead poisoning. Local jurisdictions must have the political will Chapter 1. Introduction to take enforcement actions, where needed, to protect the health of children. The identification of affected children and exposure sources will have little impact unless lead hazards are eliminated in a timely manner. Public health agencies should take the following steps to coordinate care in six areas: # • Screening and surveillance: Ensure that screening of at-risk children is conducted in accordance with the state or local plan. Develop and maintain communication and good working relationships with PCPs and public and private health delivery organizations (including Medicaid). • Laboratory testing and reporting: Require that EBLL test results (and, ideally, all blood lead test results) be reported in a timely and accurate manner, and provide oversight to ensure such reporting. Implement quality control measures for both environmental and blood specimens to ensure the validity and reliability of results. # General Considerations There are several guiding principles to consider when making recommendations for children with EBLLs. First, interventions should be directed at children whose risk for lead exposure is high. Second, where possible, interventions should be targeted at children less than 2 years old because neurotoxicity is greater and lead exposure is more likely to result in a rapid increase in BLLs in very young children. Finally, when intervention recommendations are based on tenuous data or on expert opinion, as are some in this document, case managers and other involved professionals should more than ever remember primum non nocere (first, do no harm). Most children with EBLLs come from economically disadvantaged families who may have difficulty meeting the daily challenges of life and who may be overwhelmed if presented with a long list of interventions. Further, as has been found in many studies of interventions to combat other childhood problems (injury prevention, dietary counseling), behavioral change recommendations usually have only a modest effect at best. Thus, better results may be achieved by focusing on the most important recommendations (usually those designed to eliminate environmental lead hazards) and assisting caregivers in implementing them. Encouraging and supporting families without making them feel guilty for their child's EBLL or making unrealistic demands on them may offer the greatest benefit to the child. # Introduction Recent research concerning lead exposure from leaded paint in the residential environment has shown that some of the recommendations on managing lead hazards in the child's environment made in the 1991 Centers for Disease Control and Prevention (CDC) guidance, Preventing Lead Poisoning in Young Children, need updating (1). In addition, a regulation to control lead exposure from public drinking water (2), implemented during the 1990s, makes possible a more focused approach to assessing that source than was previously recommended. This chapter summarizes current knowledge concerning children's lead exposure in the residential environment, recommends interventions directed at reducing or eliminating lead exposure, and provides information to guide state and local officials in developing and updating policies and procedures for identifying and managing lead hazards in the residential environment of children with elevated blood lead levels (EBLLs). Detailed technical protocols for assessing and correcting lead hazards in a variety of situations can be found in guidance developed by the Department of Housing and Urban Development (HUD) for property owners, private contractors, and government housing agencies (3). These are cited where appropriate. # Sources and pathways of residential lead exposure Lead can be found in high concentrations in three media to which children may be directly or indirectly exposed: paint, interior dust, and exterior soil or dust. This section discusses the distribution of lead in these media and their relationships to one another and to blood lead levels (BLLs) in children (Figure 2.1). Lead in tap water, generally a lower dose source of exposure, is also addressed. # Paint Although the addition of lead to residential paint and similar surface-coating materials, such as varnishes and stains, was banned in 1978 (4), 74% of dwellings constructed prior to 1980 contain some leaded paint. * The amount of lead in paint is much greater in homes built before 1950 than in homes built later but prior to the ban on leaded house paint. For example, 90% of * Throughout this document, the term "paint" will be used to refer to paint and, where appropriate, similar surface-coating materials such as varnishes and stains. Paints and coatings manufactured since 1978 must contain < 0.06% lead by weight. For testing of lead content in existing structures, the regulatory threshold for defining "lead based paint" is $ 1 milligram of lead per square centimeter of paint film or $ 0.5 % lead by weight. These standards, however, were based on the limitations of measurement techniques available when they were formulated rather than on health considerations. dwellings built before 1940 have paint containing more than 1 mg/cm 2 of lead, compared with 62% of dwellings built from 1960 through 1979. The relative contrast is much greater for paint containing more than 2 mg/cm 2 : 75% versus 18%, respectively (5). Direct and indirect exposure of children to leaded paint that has deteriorated because of deferred maintenance is likely the major factor in the increased risk for EBLL associated with poverty and living in older housing. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that the prevalence of EBLLs among children living in homes built before 1946 is five times higher than that among children living in homes built after 1973 (most of which do not have leaded paint) (6). Furthermore, for low-income children living in pre-1946 dwellings, the prevalence of EBLLs is 16%, compared with 4% for middle-income children living in such dwellings (6). Although children may be exposed to lead from paint directly by ingesting paint chips (7), they are more commonly exposed by ingesting house dust or soil contaminated by leaded paint (8,9). Federal law defines a leaded paint hazard as a condition in which exposure to lead from lead-contaminated dust, lead-contaminated soil, or deteriorated leaded paint would have an adverse effect on human health (10). Lead contamination of dust or soil occurs when leaded paint deteriorates or is subject to friction or abrasion (as on window sashes). In addition, lead can be dispersed when paint is disturbed during demolition, remodeling, paint removal, or preparation of painted surfaces for repainting. In a population-based study in Wisconsin, about two-thirds of children who had a blood lead test lived in a home that had undergone some type of renovation, repair, or remodeling work in the prior year. These children were at 1.3 times greater risk of having an EBLL than were children not exposed to such activities (11). The risk was even higher among children living in homes where certain practices, such as the removal of paint with heat guns, had been used. # Interior dust Interior house dust can become contaminated with lead as the result of the deterioration or disturbance of leaded paint, the tracking or blowing in of contaminated soil, and the fallout of airborne lead particulate from industrial or vehicular sources. A simple visual inspection of older homes can identify those in poor condition. The condition of leaded paint more accurately predicts lead exposure than the lead content of paint by itself (12,13). Older homes in poor condition have much higher dust lead levels than older homes in good condition (Figure 2.2) (14). The amount of lead in house dust, in turn, has a strong correlation with the BLLs of young children (12,13,15,16) and is more predictive of BLLs in children than is the amount of lead in house paint (13). Lead levels in house dust can be measured either as a mass concentration (mass of lead/mass of dust) or as surface loading (mass of lead per surface area sampled). The most widely used sampling technique, in which a wipe sample is collected with commercially available baby wipes (3), can determine only lead surface loading. However, this measure Chapter 2. Assessment and Remediation of Residential Lead Exposure predicts BLLs as well as or better than mass concentration (17). Lead loadings vary considerably among the types of surfaces commonly tested, with levels on interior window sills and window "wells" (the part of the window that receives the lower sash when closed) often being, respectively, 1 and 2 orders of magnitude higher than those found on floors. Higher levels on window components may reflect a combination of lead dust derived from friction and the deterioration of leaded paint on the windows themselves and from the settling of airborne dust from outside of the dwelling. Dust lead loading on all three surfaces (floors, windowsills, and window wells) correlates with BLLs in children (12). A recent statistical analysis of data from 12 studies relating lead in dust to BLLs in children between 6 and 36 months of age found a strong direct association between dust lead loading and the risk of having an EBLL (13). The association extended well below the 40 Fg/ft 2 threshold for a lead hazard in dust samples collected from floors as defined by HUD (18) and the Environmental Protection Agency (EPA) (19). For example, the estimated probability of a child having an EBLL increases from 7% to 18% with an increase in floor dust lead loading from 10 to 40 Fg/ft 2 (Figure 2.3) (13). For dust samples collected from window sills, lead levels $ 250 Fg/ft 2 are defined as hazardous (18,19). # Soil and Exterior Dust Contamination of soil and exterior dust has been linked to point source emissions, such as lead smelters, fall-out from past use of leaded gasoline, and weathering of exterior leaded paint (20). Soil located next to dwellings typically has higher lead content than that sampled from other locations in a yard. Potentially hazardous levels of lead in soil are not uncommon. Results of a national survey in which soil samples were collected from both bare and covered soil showed that residences with intact exterior leaded paint are more than three times as likely to have soil lead levels exceeding 500 ppm than are dwellings without lead in exterior paint (21% vs. 6%). Results also showed that soil contamination is eight times more common at residences with non-intact leaded exterior paint than at residences without exterior leaded paint (48% vs. 6%) (5). In urban neighborhoods, high levels of lead have also been found in exterior dust collected from paved surfaces, such as sidewalks (21). Soil lead content is an important predictor of children's risk for an EBLL, though less important than the lead content of interior floor dust (13). Soil samples taken from play areas in a yard have a stronger relationship to children's BLLs than samples from other locations. The EPA defines a soil lead hazard as bare soil that contains 400 ppm of lead in a play area or 1200 ppm in other parts of a yard (19). # Chapter 2. Assessment and Remediation of Residential Lead Exposure # Tap water Lead found in tap water usually is from the corrosion of lead-containing materials found in water distribution systems and household plumbing (22). Exposure to lead in tap water has been reduced by measures taken during the last two decades under the requirements of the 1986 and 1996 amendments to the Safe Drinking Water Act and a subsequent EPA regulation (the Lead and Copper Rule) (2). The latter regulation, which only applies to public water systems, requires those systems to monitor tap water for lead and to implement public education and other measures to reduce lead levels in drinking water if they exceed 15 Fg/L in more than 10% of household samples (2). Lead levels are reduced by treating the supplied water to make it less corrosive and, in some cases, by replacing lead water-service lines. These regulations do not apply to the more than 40 million households supplied by private well water that can have elevated levels of lead if the water is corrosive and lead is present in the well pump or household plumbing system (23). In most jurisdictions, there is no monitoring for lead in the drinking water supplied by private wells. A number of studies, mostly of adults, have attempted to characterize the relationship between lead levels in drinking water and BLLs (24)(25)(26). Data from these studies indicate that exposure to water with a lead content close to the EPA action level would not, by itself, be expected to produce an EBLL. However, the individual risk will vary depending upon the circumstances and amount of water consumed. For example, infants consuming formula prepared with lead-contaminated water may be at particular risk because of the large amount of water they consume relative to their body size (27). # Effectiveness and Safety of Lead Hazard Control Measures Interventions to reduce exposure to lead in the residential environment include measures focused on immediate hazards to current occupants, such as removing or covering nonintact leaded paint, repairing or replacing windows to prevent abrasion of leaded paint on moving surfaces, sealing floors to create smooth and cleanable surfaces, using professional cleaners to control household dust, and covering bare, contaminated soil. Additional interventions may be carried out to prevent lead hazards from developing in the future, such as replacing building components that have leaded paint (whether intact or not) and removing (stripping) leaded paint from components left in the dwelling. Most studies evaluating the effectiveness of lead hazard control measures for reducing EBLLs have lacked controls. In addition, many studies evaluated interventions prior to the institution of stringent procedures for limiting the contamination of residences with leaded dust. In general, these earlier studies showed that among children with baseline BLLs greater than about 25 Fg/dL, measures to remove or repair nonintact leaded paint were followed by declines Chapter 2. Assessment and Remediation of Residential Lead Exposure in BLLs of 20% to 30% over the following year (28). In one controlled study, the decline in BLLs for children in treated dwellings was about twice that of children in untreated dwellings (29). In homes of children with EBLLs, extensive removal of leaded paint without measures to prevent the children's exposure to abatement dust and debris has also been associated with increases in the children's BLLs (30)(31)(32). These increases were apparently the result of corresponding increases in house dust lead levels. Consequently, regulations in many jurisdictions now prohibit certain hazardous paint removal methods, such as uncontained power sanding, and require safe work practices, cleaning, and dust lead testing to protect occupants from lead exposure associated with the disturbance of leaded paint. Most jurisdictions require that post-intervention dust lead levels be below clearance standards-the maximum allowable levels of lead. If the dust lead levels in a particular dwelling exceed the clearance standard, that dwelling cannot be reoccupied until additional cleaning or other measures reduce dust lead contamination to less than the clearance threshold. Clearance standards for public and federally assisted housing are 40 Fg/ft 2 for floors, 250 Fg/ft 2 for windowsills, and 400 Fg/ft 2 for window wells. Some state and local jurisdictions have established other clearance standards (20). Recent longitudinal studies have evaluated leaded paint abatement programs that combined multiple lead hazard control methods (33)(34)(35). Interventions used in these programs included measures to prevent the generation of leaded paint chips and dust (treatments to eliminate nonintact leaded paint and windows containing leaded paint subject to friction), leaded dust removal (specialized cleaning), and measures to make floors smooth and cleanable (by sealing or using durable floor coverings). The elimination of leaded paint hazards in the programs relied primarily on component replacement, enclosure, and paint stabilization, with limited on-site paint removal. Although these studies did not include randomly assigned control homes that received no treatment, their results strongly suggest that these treatments resulted in substantial, sustained reductions in interior dust lead loading and little if any risk of children having substantial shortterm increases in BLLs. While average BLLs in children occupying treated dwellings fell by approximately 20% to 25% over the following year (from baseline averages in the 5-15 Fg/dL range) (35), no data on children in untreated dwellings are available to directly estimate the proportion of decline attributable to the hazard-reduction treatments. In one of these studies, greater initial and sustained reductions in interior dust lead loadings were achieved with more intensive treatments, including window replacement (rather than repair) and the use of durable floor coverings (rather than paints and sealants) (34). However, among children living in the more intensively treated dwellings, average BLL declines following the intervention were not significantly greater than those among children whose dwellings had more limited interventions. These studies generally involved interventions that left some intact leaded paint in place. The only certain way to prevent future exposure to lead from paint in a dwelling is to remove all leaded paint from the dwelling. However, no studies are available that compare changes in children's BLLs following the total "deleading" of their dwelling with changes following interventions that leave some leaded paint intact. If many components in a dwelling contain leaded paint, complete deleading may be impractical unless performed as part of a substantial or "gut" renovation. One study of children with baseline BLLs of 10 to 24 Fg/dL found that leaded paint hazardcontrol measures, including extensive on-site paint removal, resulted in increases in children's BLLs after abatement (36). These increases occurred despite a protocol for safe work practices, cleaning, and clearance testing. However, the clearance standard used for floors was 200 Fg/ft 2 , which may have been too high to prevent continued or increased exposure to leaded dust when compared with pre-intervention levels. The previously cited impact of relatively "low" levels of lead in house dust on children's BLLs could explain the increases. Interventions focused on reducing exposure to leaded dust have been evaluated in several studies (37)(38)(39). Household dust control performed repeatedly by professional cleaners was associated with decreases in children's mean BLL with the greatest benefits seen among children whose dwellings were cleaned at least 20 times during a 1-year follow-up period (38). To be effective, dust control should be conducted every 2-3 weeks. However, simply educating parents about the need to perform dust control as a preventive measure has not proven effective in preventing increases in children's mean BLLs (39). See Chapter 6, "Educational Interventions for Caregivers," for a detailed discussion of the effects of such education. In a controlled study, soil removal and replacement with uncontaminated soil was associated with a 15% reduction in BLLs among children whose average baseline BLL was from 10 to 24 Fg/dL and who were exposed to high levels of lead in soil (40). Two other studies of the lead abatement of soil with lower baseline contamination showed no reduction in children's BLLs following such abatement (21,41). In the studies noted above and reviewed in detail in Chapter 6, the benefits of environmental interventions have generally been modest-BLL reductions in the range of 10% to 30%. A number of factors might explain the limited effectiveness of these interventions. One such factor is that the interventions were limited in scope: lead hazard control often involved the interior but not the exterior of homes. Another factor is that most interventions were performed in scattered rather than contiguous blocks of homes. Thus, children's continued exposure to lead from sources in the neighborhood might limit the effectiveness of the interventions. In the Baltimore repair and maintenance study, for example, one comparison group consisted of modern urban homes located in contiguous blocks of such dwellings that were built where older row homes with leaded paint once stood. The geometric mean level of lead contamination in the floor dust of the modern urban homes was less than one-tenth that of older homes that had previously undergone complete lead paint abatement but which were still surrounded by other homes with leaded paint. The geometric mean BLL for children living in the modern homes was one-fourth that of the children living in the older homes (34). A final factor is that the release of lead from bone might also reduce the impact of environmental interventions. By one estimate, an Chapter 2. Assessment and Remediation of Residential Lead Exposure intervention reducing total lead exposure by half for a 5-year-old child would, because of mobilized bone lead stores, cause the child's BLL to decline by only 25% after 1 year (42). # Recommendations for Assessment and Remediation # General Recommendations Conduct prompt and effective environmental management. The identification and control of ongoing sources of lead exposure for children with EBLLs should be the highest priority. In addition, identifying children with EBLLs may help officials identify and control potential sources of lead exposure for other children. Because the main objective of environmental management is to reduce lead exposure quickly, investigations should be initiated as soon as possible after a case is identified. Priority should be placed on responding to children with the highest BLLs and to infants and children less than 2 years of age with any EBLL, because their BLLs are more likely to increase and they are more sensitive to lead's neurotoxic effects. Table 2.2 shows the recommended maximum time frames for initiating environmental investigations and interventions according to a child's BLL. Obtain an exposure history. Investigations to identify sources of a child's lead exposure should begin with an interview with the child's caregiver. Whenever possible, the interview should take place at the child's residence. The interviewer should question the caregiver concerning a range of possible exposure sources. (See Table 2.3 and Appendix I.) It is also important to collect information concerning locations outside the home, such as childcare sites, where the child spends significant amounts of time. The interview should be guided by a checklist tailored to sources of lead exposure found in a given jurisdiction. Checklists facilitate data collection and ensure that potential sources are not overlooked. A sample checklist is provided in Chapter 3, "Medical Assessment and Interventions," and in the 1995 HUD guidelines (3). Visually inspect the residential environment. A visual inspection can quickly identify areas where deteriorating paint may be contributing to lead exposure and should include windows, porches, bare soil, and common areas in multifamily dwellings, as well as any other locations where the child spends time. Measure lead in environmental media. Selection of the media to be tested should be guided by the visual inspection and the child's exposure history. Depending on the inspector's training, the equipment available, and the media to be tested, environmental analysis may be done either on-site with portable instruments or at an environmental laboratory. Personnel performing environmental sampling and on-site testing should be appropriately trained and be certified as risk assessors (43) or have equivalent qualifications. # Chapter 2. Assessment and Remediation of Residential Lead Exposure Communicate results. Results of investigations, including recommended actions to protect the child from further exposure, should be communicated promptly to caregivers, to primary care providers (PCPs), and, where relevant, to property owners and housing code enforcement authorities. Environmental management activities should be coordinated with other health professionals, including those providing clinical care, case management, and social services. # Specific Recommendations Since leaded paint and associated lead in house dust and soil are the most common sources of exposure, they should be the focus of environmental investigations and control efforts. State and local health officials should review current policies concerning childhood lead poisoning prevention and revise them as needed to be consistent with the following recommendations. Measure lead levels in house dust, paint, and bare soil. Investigations of the residential environment of children with EBLLs should focus on immediate lead hazards. At a minimum, testing should include house dust, paints, and similar surface coatings that are not intact or that are located on surfaces subject to friction, and bare soil, especially in play areas. Detailed protocols for sampling and measuring lead in these media can be found in the 1995 HUD guidelines (3). There is no evidence that complete testing of all building components for leaded paint, regardless of the condition or location of the paint, is helpful in identifying ongoing exposure. Such testing may serve other purposes, however, such as educating occupants about the health hazards of leaded paints, planning the abatement of potential future leaded paint hazards, planning renovation work that may involve disturbance of intact paint, or complying with state and local regulations. Test for lead in tap water. For homes served by public water systems, data on lead in drinking water should be obtained from the water supplier. Many public water systems post data on the Internet on the quality of drinking water, including results of lead testing. Links to such data can be found at the following EPA Web site: http://yosemite.epa.gov/ogwdw/ccr.nsf/America?OpenView. If prior testing of a public water system shows that lead contamination is not a problem in homes served by that system, no additional testing is necessary, unless no other source of a child's EBLL can be found. For all other children with EBLLs, including children living in homes served by private wells, water that the child may consume should be tested. If necessary, measures should be implemented to prevent the child's further exposure to lead (e.g., the use of bottled water or appropriate water filters). If bottled water is used, fluoride supplementation should be discussed with the PCP and the caregiver. More information on lead in drinking water can be found at http://www.epa.gov/ogwdw/dwh/o-ioc/lead.html or by contacting the Safe Drinking Water hotline at (800) 426-4791 or [email protected]. Additional sources of information Lead hazard control work must be performed in accordance with safe practices by trained workers to avoid exposing workers to unsafe lead levels or increasing the level of lead exposure to occupants. Detailed guidelines for residential lead hazard control work have been published by HUD (3). On-site removal of intact leaded paint should be kept to a minimum, and safer alternatives, such as component replacement, enclosure, encapsulation, off-site paint removal, and paint-film stabilization should be used when possible. Replacing building components that have intact leaded paint reduces the potential for future lead exposure as the leaded paint deteriorates or is disturbed during renovation. However, such work can generate leaded dust, and workers should follow the precautions described in HUD guidelines. As discussed previously, there is no evidence that environmental interventions that include complete removal of all leaded paint are more effective at reducing residents' BLLs than interventions focused on current lead hazards. Furthermore, some evidence suggests that extensive on-site paint removal increases the potential for lead exposure, at least in the short run. The amount of lead in 1 ft 2 of paint containing 1 mg/cm 2 of lead (approximately 1 g or 1 million Fg) is very large relative to the amount of lead in dust associated with an increased risk for EBLLs (approximately 10 Fg/ft 2 ). Thus, performing extensive on-site removal of leaded paint in a dwelling without increasing the occupants' lead exposure requires a degree of caution that may be difficult to achieve and monitor in the routine, large-scale implementation of health codes. Long-term control of residential hazards from leaded paint may involve considerable time and expense. Obtaining the compliance of property owners may cause additional delays in reducing residents' lead exposure. Therefore, interim measures to rapidly reduce lead exposure, including specialized cleaning to reduce exposure to leaded dust, are often required. # Chapter 2. Assessment and Remediation of Residential Lead Exposure Perform clearance testing. Following lead hazard reduction work, repeat testing for lead in house dust is essential to see whether the work has resulted in levels of lead low enough for safe re-occupancy. Post-intervention tests showing increased or persistently high dust lead levels indicate the need for further cleaning or other additional work. Available evidence indicates that current and proposed guidelines for levels of lead in dust on floors may not adequately protect young children and that levels well below these guidelines are achievable and are often present even before intervention. Therefore, the goal should be to attain post-intervention dust lead levels that are as low as is feasible, which is generally less than 10 Fg/ft 2 on floors (44), and that are at or below baseline levels. Where leaded paint is left in place, periodic monitoring with visual inspection and dust testing should be performed. Relocate occupants. Temporary occupant relocation is generally required to safely conduct lead hazard control activities that may increase dust lead levels. In some cases, it may be feasible to protect occupants during lead control activities by creating barriers, monitoring the work site daily, and, where appropriate, obtaining serial dust lead measurements. In other cases, permanently relocating occupants to lead-safe housing may be the best way of quickly reducing their lead exposure. Examples of situations that might require relocation include a child living in a dwelling that is structurally unsound or a child living in a dwelling where temporary measures to reduce exposure cannot be taken or are ineffective. Case managers and social workers with experience in assisting families with housing difficulties can play a vital role in assessing the needs and desires of the family and arranging such relocation. A registry of lead-safe housing units in a community can also be helpful. When families permanently relocate from a dwelling where lead hazards are identified, measures should be taken to ensure that the hazards are corrected before any other families with young children occupy the dwelling. # Enforcement of Laws and Regulations Although enforcing laws and regulations pertaining to lead hazards is not part of case management per se, it is essential to realizing the long-range goal of reducing those hazards. Individual states should provide health and housing officials with the necessary legal authority to require that timely and effective actions are taken to eliminate lead hazards at properties where children with EBLLs have been identified. Health and housing officials should take all steps necessary to prevent additional or repeated cases of children with EBLLs at one property. In a recent national survey, only 18 states indicated that they have legal authority to order remediation at properties where children with EBLLs reside, with only 14 states reporting that their authority was based on lead-specific state laws or regulations (45). State and local governments should examine their laws, ordinances, and housing codes and their enforcement structure to determine whether they are effective in dealing with identified lead hazards and make changes to ensure that children are protected. At a minimum, legislation or ordinances should include the action level at which the law applies, procedures for investigation and re-inspection, standards for leadsafe housing, requirements for completing lead hazard control work (including permits, time frames, permissible methods, waste disposal methods, and clearance standards) and enforcement provisions for noncompliance. In addition, states and localities should be encouraged to develop lead-safe housing standards to protect children from exposure and to ensure that older rental housing is safe for children with EBLLs. Finally, state and local governments should also ensure that they have the ability and necessary resources to take emergency actions (including cleaning the rental units, stabilizing the paint in them, and relocating the occupants) to protect children from identified lead hazards. # Financial Resources for Lead Hazard Control Many of the homes in which children with EBLLs live are poorly maintained, deteriorated, low-income rental properties. For some economically distressed housing, subsidies and other financial assistance for lead hazard control are required to enable owners to make timely corrections of residential lead hazards. Because resources for addressing lead hazards, particularly in low-income housing, are inadequate in most areas of the country, an increase in resources at the federal, state, and local level should be strongly supported. In addition, state and local health agencies should develop strong partnerships with local housing and community development organizations, investigate currently available resources for improving low-income housing, and establish mechanisms to apply such resources to lead hazard control in homes of children with EBLLs. A detailed discussion and recommendations concerning financing of lead hazard control work can be found in a HUD publication (46). Some examples of current programs providing resources for this purpose are provided in the following paragraphs. HUD's Lead Hazard Control Grant Program (47) enables state or local agencies to provide grants or loans to property owners for conducting lead hazard control measures in low-income housing. Federal regulations require the timely identification and remediation of lead hazards in federally assisted housing, including rental property, whose owners receive tenant-based assistance (Section 8 housing) (19). This program should create a growing pool of lead-safe housing in the future. Decisions on specific priorities for tenant selection under Section 8 and for public housing have been devolved to state and local public-housing agencies. This local flexibility gives health departments in jurisdictions where lead exposure is a major problem an opportunity to urge that priority for assistance be given to families of children with the highest BLLs who are unable to find or afford lead-safe housing. State and local governments can use HUD's Community Development Block Grant (CDBG) and HOME Investment Partnership block grant funds to make housing lead-safe. The resources available for state and local block grants under these programs ($6.4 billion in FY 2000) dwarf the $60 million available under the Lead Hazard Control Grant Program. Both the CDBG and Chapter 2. Assessment and Remediation of Residential Lead Exposure HOME programs provide a high degree of flexibility in the use of funds. Indeed, CDBG funds are used by some jurisdictions to support emergency programs dealing with problems such as the breakdown of plumbing or heating systems. A similar approach would be desirable for controlling lead hazards. State and local governments receiving these block grants must submit a consolidated plan (ConPlan) containing a 5-year strategic plan and a 1-year action plan for their use of these and other available funds. The strategic plan must include actions to evaluate and reduce leaded paint hazards and describe how hazard reduction will be integrated into other housing activities. Evaluating and reducing leaded paint hazards is also a required component of the annual action plan. HUD regulations require that eligible jurisdictions consult with state or local health and child welfare agencies as well as health and social service providers as part of the planning process. State and local health departments with identified lead problems should involve themselves in this planning process to ensure that lead hazard control is a priority for federal CDBG and HOME funding. # Recommendations for Future Research Technical knowledge concerning the identification and control of lead hazards in homes has advanced greatly over the past several years, resulting in more efficient, safe, and effective environmental management for children with EBLLs. Still, prevention efforts could be improved with further work in several areas. Additional studies are needed to assess the long-term impact of current lead hazard control methods on children's EBLLs, especially on levels from 10 to 20 Fg/dL. Available data indicate that these methods are safe and effective (i.e., they do not increase children's BLLs in the short run and they decrease children's exposure to leaded dust). Because BLL changes over time may be influenced by a child's age, the season, and secular trends, as well as by regression to the mean, controlled studies are needed to determine how much of the observed decline in BLLs among children living in these dwellings can be attributed to the interventions. Future research should also evaluate the cost effectiveness of interventions. Until recently, most residential lead hazard control work and studies have involved children who already had EBLLs and presumably relatively high body stores of lead from chronic exposure. The effectiveness of residential lead hazard control in preventing future increases in BLLs among infants and toddlers needs further study. The level of neighborhood lead exposures appears to make an important contribution to the risk for EBLLs among children. Research is needed to examine how community-level lead sources, such as lead from building demolitions, contribute to children's exposure. Finally, the effectiveness of community-level interventions to reduce children's exposure to lead in dwellings and in exterior dust and soil should be further studied. The ACCLPP encourages programs to develop methods to deliver environmental assessment services to caregivers for children living in high-risk dwellings regardless of the children's blood lead levels. b Micrograms per deciliter of whole blood measured in a venous sample collected following an elevated screening measurement. c The recommended clinical evaluation is described in Chapter 3, "Medical Assessment and Interventions." # Chapter 3. Medical Assessment and Interventions Prepared by James R. Roberts, MD, MPH, and J. Routt Reigart, MD # Introduction Case management of children with elevated blood lead levels (EBLLs) requires a different approach from that used in the past. Prior to the development of programs aimed at screening children for EBLLs, lead exposure was generally not detected until a child presented with symptoms of lead toxicity. Neurological findings associated with acute encephalopathy (lethargy, ataxia, seizures, papilledema, and coma) were often the first signs of an EBLL, and children with these symptoms required immediate hospitalization and treatment. Encephalopathy could result from a blood lead level (BLL) $70 Fg/dL and could develop without prior symptoms. Among children with BLLs exceeding 150 Fg/dL, laboratory abnormalities often included phosphaturia, proteinuria, aminoaciduria, glucosuria, and hypophosphatemia (1)(2)(3). Today such presentations are rare. Children with EBLLs usually have BLLs below 30 Fg/dL, and few BLLs exceed 50 Fg/dL. Most children with EBLLs have no symptoms. Case management now focuses on reducing children's exposure to lead and decreasing their BLLs, whether they have symptoms of lead toxicity or not. What follows is a guide to the basic standards and principles of medical case management. It is not intended for use as a complete protocol but rather as a tool for adapting management to local needs and conditions. # General Principles of Medical Case Management # Coordinating Care Coordination of care is critical to successful case management. For each child, an individualized plan of follow-up must be devised and implemented. Members of the case management team need to maintain open lines of communication and work together. Case managers and primary care providers (PCPs), in particular, must work collaboratively to ensure proper medical management and follow-up. # Conducting Medical Case Management Medical case management for children with EBLLs is largely predicated on a secondary prevention model (i.e., intervention after an EBLL has been detected, usually prior to the onset of symptoms). By interrupting the process of lead poisoning through early detection and intervention, case managers working with PCPs can prevent children from dying or suffering severe permanent sequelae of lead toxicity such as persistent seizures and mental retardation (4,5). The detrimental effects of EBLLs in the range of 10 to 45 Fg/dL are usually subclinical and may include neurodevelopmental impairment often apparent only at a later age. (See Chapter 4, "Developmental Assessment and Intervention.") Figure 3.1 illustrates the lowest reported BLLs for some of the effects associated with EBLLs. If a child presents without symptoms, the child's PCP and case manager may have trouble convincing the child's caregiver of the importance of suggested interventions. Case managers should manage each child individually, taking into consideration the child's BLL and the ability of caregivers to cooperate and implement interventions. # Identifying Children with EBLLs Screening programs are the main vehicle for identifying children with EBLLs. Those found in this manner typically have BLLs from 10 to 30 Fg/dL and present with no abnormalities on routine medical history, physical examination, or laboratory tests (other than their EBLL). It is critical that case managers as well as PCPs not equate the absence of clinical symptoms, physical abnormalities, or abnormal laboratory results with an absence of toxicity. # Identifying Sources of Lead Exposure When evaluating a child with an EBLL, case managers must identify the sources of a child's lead exposure. The most common source of lead in children with EBLLs is leaded paint. Housing built before 1950 has been shown to be routinely contaminated with lead and to represent a risk for children (6,7). Contamination of dust or soil occurs when leaded paint chalks or chips, or is subject to friction. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure.") Other less common sources include lead in water, lead in substances used in caregiver hobbies or occupations, lead in culturally specific substances such as folk remedies, and lead in imported cookware or cosmetics (Appendix 1). # Medical History # General Considerations Although abdominal pain, vomiting, constipation, change in appetite, and irritability have been described in association with EBLLs, they are seldom caused by BLLs less than 40 Fg/dL, and other causes for such symptoms should be sought. Case managers, caregivers, and PCPs may note increased activity among children with BLLs < 45 Fg/dL. However, they should not assume that increased activity is related to the EBLL (5,8). # History Taking to Determine Lead Sources A child's environmental history can provide information about the child's possible exposure to residential and other sources of lead. It should: Taking a history in the child's home allows for direct observation and further in-depth questioning. If a child's BLL remains elevated despite lead hazard reduction, less common sources should be considered. Because a child may be exposed to lead from multiple sources, identifying one source may not be sufficient to eliminate all lead exposure. Repeated history taking by different members of the management team is often required. Because knowledge about the lead sources in a community and the prevalence of EBLLs in specific geographic areas of the community can be useful in determining sources of exposure, the interpretation of a child's environmental history may require consultation with lead experts. Case managers play a crucial role in treating children's EBLLs by fostering a multi-disciplinary approach to the environmental evaluation and by coordinating communication among public health officials, PCPs, and caregivers. Table 3.2 outlines suggested questions to ask in determining a child's environmental history. This is only intended to be a guide, and case managers and PCPs are encouraged to tailor this list to local needs. # Miscellaneous questions Does the home contain vinyl mini-blinds made overseas and purchased before 1997? Does the child receive or have access to imported food, cosmetics, or folk remedies? Is food prepared or stored in imported pottery or metal vessels? # Chapter 3. Medical Assessment and Interventions # Paint and soil exposure * Case managers should consider the following elements in assessing a child's exposure to lead in paint or soil: • Age and condition of housing: Pre-1950 housing that is in poor condition poses the greatest risk for children (6,7). Housing built from 1950 through 1978 may also contain leaded paint, although the concentration of lead in paint was lower during this period than previously. The condition of the home is important: deterioration of lead-painted surfaces markedly increases the risk to children ( (13). At present, there is no evidence that routine house cleaning by family members or frequent and thorough hand washing decreases BLLs. However, because leaded dust is a primary contributor to EBLLs (14-17), strict attention to *See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," for a detailed discussion of paint and soil exposure. # Relevant child behaviors While pica has long been a known risk factor for EBLLs, typical hand-to-mouth activity during the toddler years is a more frequent cause of lead ingestion (18,19). Although no supporting data are available, frequent hand washing may help lower EBLLs of young children. # Caregiver exposures and at-risk behaviors Household members who work in lead-contaminated environments or participate in certain hobbies can bring lead into the home on their clothing or shoes (20). It is important to ask such household members whether they regularly shower and change clothes and shoes after these activities. Caregivers may also introduce airborne lead into the home by burning leadcontaminated materials in an indoor fireplace. (See Appendix I for a detailed discussion of caregiver exposures.) # Miscellaneous Water: When no other source of lead is found, the water supply should be considered. (See Chapter 2, "Assessment and Remediation of Residential Lead Exposure.") While public water systems must monitor, and, if necessary, treat tap water for elevated lead levels, regulations governing lead in drinking water do not apply to households supplied by private wells. Municipal water companies and private industrial laboratories can advise case managers and caregivers on how to collect and process water. In areas where there are no known hazardous water-supply lines, lead contamination of the water may occur within the home from lead solder in plumbing fixtures or from fixtures made of lead-containing alloys. Contamination is increased when the water is relatively acidic (pH < 6.5). Moore found that water lead levels and the subsequent BLLs of children drinking such water substantially decreased when the pH of drinking water was raised to > 8.5. He also found that low mineral content increased lead contamination in water, but not as greatly as acidity (21). Water that is hot or has been stationary in pipes overnight contains more lead than freely running cold water. Lead contamination decreases with the aging of home plumbing, particularly if the water supply is alkaline or contains significant calcium or other mineral deposits (22,23). Mini-blinds: Imported vinyl mini-blinds may contain lead and result in exposure. (See Appendix I.) Cultural practices: Specific ethnic groups may use imported folk remedies, cosmetics, food, or cookware contaminated with lead. Practices resulting in lead exposure from these sources are often localized, and determining children's risk from such practices requires knowledge about a specific group's cultural habits. Caregivers may be reluctant to admit using some of these items, and it is important not to put them on the defensive when taking the history. (See Appendix I.) Newly identified sources: In the past, various items have emerged as lead hazards, often first presented through the news media. Case managers and PCPs should be cognizant of recent media and Consumer Product Safety Commission reports that may be relevant to children with whom they have contact (see http://www.cpsc.gov). # Physical Examination Children evaluated as a consequence of an EBLL found by screening most often have no physical findings specific for lead toxicity. Gingival lead lines, although often stressed during medical training, are rarely seen in clinical practice and are of no use in the diagnosis and management of children with EBLLs. Pallor, papilledema, and other neurologic findings suggestive of acute encephalopathy would not be expected. A thorough evaluation of all children with BLLs $20 Fg/dL is recommended for three reasons. First, it will allow PCPs to ascertain whether children with such EBLLs have any findings suggestive of encephalopathy. The BLL threshold for encephalopathic findings is believed to be 70 Fg/dL, although encephalopathy is usually associated with much higher BLLs (1,3). Second, it will allow PCPs to assess whether children with EBLLs are engaging in at-risk behaviors such as pica and hand-to-mouth activity. Finally, it will allow PCPs to identify behavioral and neurodevelopmental disorders, such as distractibility, aggression, or speech delay. If a child has any of these findings, regardless of their etiology, the case manager or PCP should, when appropriate, refer the child for a further evaluation. (See Chapter 5, "Developmental Assessment and Interventions.") # Laboratory and Imaging Evaluation Among asymptomatic children, most clinical laboratory results other than BLLs will be normal and therefore will not be of assistance in case management. However, all children should have a hemoglobin or hematocrit test performed, as anemia is associated with EBLLs. That iron deficiency rather than lead is the cause of such anemia does not diminish the need for follow-up (24,25). PCPs may wish to assess children's iron stores by one or more of a variety of laboratory tests. Iron deficiency may delay children's neurodevelopment independently of the effects of lead (26). Because basophilic stippling is not specific for lead toxicity, a peripheral blood smear is of no use in the hematologic evaluation. The inhibition of heme synthesis leads to the accumulation of excess porphyrins, particularly protoporphyrin IX in red cells. The fluorescence of these porphyrins has led to the development of methods to detect extracted porphyrins-free erythrocyte protoporphyrin (FEP) or erythrocyte porphyrin (EP) testing-and to the observation of zinc protoporphyrin (ZPP) in red cells. Because the relationship between the results of these tests and BLLs is log-linear, these tests can be used to evaluate and follow children with very high BLLs. However, the results are confounded by concomitant iron deficiency and show poor correlation with BLLs <25 Fg/dL (27). Therefore, EP tests should be used infrequently except in evaluating children with BLLs well above 25 Fg/dL whose BLLs do not show a steady decline in response to medical and environmental interventions. In such situations, these measures may assist PCPs in differentiating BLL rebound after treatment from the effects of re-exposure. While very high BLLs have been associated with serious to severe renal tubular dysfunction (2,28), there is no evidence to support routinely evaluating the renal status of children with presymptomatic BLLs. However, if potentially nephrotoxic chelating agents such as EDTA are to be used in treatment, renal function testing is appropriate prior to and during therapy. Abdominal radiographs may be useful in determining whether children are currently ingesting lead-contaminated non-food items, including paint chips. They are particularly useful when children have an unexpected acute rise in BLL or are not responding to case management as expected. Long-bone films for the presence of growth arrest lines ("lead lines") may be of interest but rarely provide information useful for a child's case management (29). Lead lines are not present unless BLLs exceed 50 Fg/dL and are indicative of chronic exposure (30). Also of no documented utility in the management of children with EBLLs are hair (31), fingernail, and tooth (dentin) lead measurements. Hair and fingernails are subject to external contamination, which makes the results of lead tests on them uninterpretable. A few studies have demonstrated alteration of neurophysiologic function (e.g., postural sway, auditory evoked potentials, nerve conduction) with BLLs observed today (32)(33)(34)(35). However, further research is needed to define normative standards and determine inter-individual variation and clinical significance. Until then, such measures are of little use in the diagnosis or management of an individual child. X-ray fluorescence of long bones uses a radioactive source to provide noninvasive estimation of lead in bone (36). At the present time, it should be considered a research tool to be used only to characterize groups of children in epidemiological studies. As with the neurophysiologic methods discussed previously, it is insufficiently standardized, and results show significant inter-laboratory variation. # Chelation Therapy While chelation therapy is considered a mainstay in the medical management of children with BLLs > 45 Fg/dL, it should be used with caution. Primary care providers should consult with an expert in the management of lead chemotherapy prior to using chelation agents. If unaware of a center with such expertise, PCPs should contact their local or state lead poisoning prevention program, local poison control center, or the Lead Poisoning Prevention Branch at CDC (404-498-1420) for the names of accessible experts. A child with an EBLL and signs or symptoms consistent with encephalopathy should be chelated in a center capable of providing appropriate intensive care services! Controversy exists as to the appropriate level at which to initiate chelation therapy, and which drugs are most appropriate. Succimer treatment of young children with BLLs < 45 Fg/dL lowered their BLLs but failed to improve their neurodevelopmental test scores (37). (See Chapter 5, "Developmental Assessment and Interventions.") Chelation therapy with succimer is addressed in a document on pharmaceutical agents in the treatment of lead poisoning (38). If oral outpatient chelation therapy is undertaken, the case manager should ensure that caregivers adhere to the prescribed dosing schedule and should serve as the liaison between the medical community and the child's caregiver. Treatment should occur in a lead-safe environment. # Monitoring Blood Lead Levels Measurement of BLLs is the main method of determining whether significant absorption of lead has occurred, how urgently intervention is needed, and how successful case management has been. When a child's BLL does not fall within a reasonable amount of time, it is the responsibility of the case manager and other team members to determine the cause of failure. The rate of BLL decrease can depend on both the amount of lead in the child's body and the duration of the BLL elevation. A course of chelation therapy with succimer results in a rapid fall in BLL after 1 week of treatment. However, BLLs of those treated rebound after treatment ends, and by approximately 7 weeks after an initial course of therapy, BLLs of treated patients may reach almost 75% of prechelation levels (39). CDC recommends rechecking children's BLLs 7 to 21 days after completion of chelation therapy (40). A continuing increase in children's BLLs above the rebound level during the follow-up period may indicate continuing or possibly increased exposure to lead and definitely indicates a need for further environmental investigation. Common causes of rising BLLs include failure to address hazards in the child's environment, improper environmental lead abatement techniques, and continued use of imported pottery, cosmetics, or folk medicines that are contaminated with lead. However, medical conditions resulting in bed rest or similar immobilization (41), or in acidosis (42), can cause children's BLLs to rise unexpectedly, or fail to fall. # Confirmation of BLL by Venous Sample Any screening BLL above 10 Fg/dL must be confirmed with a venous sample. The time frame for confirmation depends upon the initial BLL (Table 3.3). In general, the higher the screening BLL, the sooner the confirmatory test. However, if a child is less than 12 months old, # Chapter 3. Medical Assessment and Interventions or if there is reason to believe that the BLL is rising rapidly, an earlier diagnostic confirmation may be indicated. The higher the BLL on the screening test, the more urgent the need for confirmatory testing. # Follow-Up Venous Blood Lead Testing Medical management includes follow-up blood lead testing. Table 3.4 presents the suggested frequency of follow-up tests. This table is to be used as guidance. Case managers and PCPs should consider individual patient characteristics and caregiver capabilities and adjust the frequency of follow-up tests accordingly. # Educating Caregivers Educating caregivers is an important part of case management. Caregivers need to understand EBLLs and the risks that an EBLL poses to their child, what they can do to eliminate their child's exposure to lead, and the importance of follow-up. It is important to not overburden caregivers and to provide them with understandable information and manageable interventions. (See Chapter 6, "Educational Interventions for Caregivers," for a detailed discussion.) # Monitoring a Child's Developmental Progress Follow-up also requires attention to the behavioral sequelae of EBLLs. Neurodevelopmental monitoring should continue long after a case meets BLL closure criteria, as many deficits will not manifest themselves until after a child starts school. Because developmental history and testing at the time of an EBLL usually will not identify lead-caused problems, a child's EBLL history should be part of his or her permanent medical record. A referral for testing of intellectual and behavioral performance, whether or not related to EBLLs, should be made if indicated. (See Chapter 5, "Developmental Assessment and Interventions," for details.) The PCP and case manager should be intimately involved with any educational and behavioral interventions, in consultation with developmental and behavioral experts. # Chapter 3. Medical Assessment and Interventions # Monitoring Caregiver Compliance with Follow-Up Measures For many reasons, caregivers may have trouble adhering to follow-up measures. Case managers, PCPs, and other members of the case management team must be careful not to blame the caregivers but should continue to make them aware that follow-up is for the benefit of the child. Caregivers may have trouble appreciating the importance of follow-up for asymptomatic children. Many caregivers have problems with basic needs such as transportation, food, or paying monthly bills. Therefore, it is important to limit interventions to those most likely to benefit the child while being within the capabilities of the caregiver. Punitive interventions, such as referring children to protective services, should be done as a last resort, when all more constructive approaches have been exhausted. Members of the case management team should always remember that virtually all caregivers are doing the best they can for their children and should be assisted in their efforts. # Recommendations for # Chapter 4. Nutritional Assessment and Interventions Prepared by James Sargent, MD # Introduction While the assessment and remediation of lead sources should be the top priority for the management of children with EBLLs, nutritional interventions may also be beneficial (1)(2)(3)(4). This chapter evaluates the evidence supporting commonly used nutritional interventions, makes recommendations, and suggests an agenda for future clinical research. In evaluation studies on the effects of various nutritional interventions on EBLLs, we considered both the design of the studies and the effectiveness of the interventions. Because of a lack of randomized, controlled clinical trials of nutritional interventions among children with EBLLs, most recommendations are based on generally accepted nutritional principles, as well as on the results of adult human, animal, or cross-sectional studies, with greater weight being given to those studies with designs that are less subject to bias and inferential error. # Nutritional Interventions: Summary of the Evidence # Iron Are children at higher risk for EBLLs also at higher risk for iron deficiency? Despite declines in the prevalence of iron deficiency over the past 30 years with the routine supplementation of infant foods with iron, iron deficiency remains the most common nutritional deficiency in infants and young children (5). Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that in 1988-94, 9% of toddlers aged 1 to 2 years were iron deficient (6). As with EBLLs, young age, poor nutrition, and low socioeconomic status are associated with iron deficiency. In addition, some reports suggest that iron deficiency in young children is associated with pica, a risk factor for lead ingestion (7-10). In short, many nutritional and behavioral factors associated with iron deficiency may also be found in children with EBLLs. # Is iron deficiency associated with EBLLs? Because animal studies and other evidence suggest that iron deficiency and EBLLs are associated, the Centers for Disease Control and Prevention (CDC) in the past has recommended providing an iron-rich diet for all children with EBLLs, evaluating children with blood lead levels (BLLs) > 20 Fg/dL for iron deficiency, and treating iron deficiency if present (11). However, the association between EBLLs and iron deficiency in children is not well defined. It is unknown whether this relationship is causal and operating through a nutritional or physiological mechanism or whether it is merely the result of shared risk factors. Prospective studies of children with and without iron deficiency living in lead-contaminated environments are difficult to conduct since treatment is indicated for both iron deficiency and EBLLs. Therefore, most studies that address this question are case series, case-control studies, or cross-sectional surveys. Though the results of most early studies suggested that iron deficiency is more common among children with EBLLs, these studies can be criticized for one or more of the following reasons: 1) they lacked an appropriate comparison group; 2) they screened for EBLLs with erythrocyte protoporphyrin, an indicator of both lead and iron status; or 3) they failed to adjust results for factors associated with both EBLLs and iron deficiency, including age and socioeconomic status. Of the four studies we found that avoided these methodological problems, two reported a positive association between iron deficiency and BLLs in children and two suggested no association. Each study used different definitions of iron status and EBLL. Of the studies finding a positive association, one suggested iron deficiency in children was associated with a 60% increased risk for a BLL > 10 Fg/dL after adjustments for children's age, hemoglobin level, and insurance status (12). The second, a study on dietary iron, found that children in the highest quartile for iron intake were at a significantly lower risk of having a BLL > 15 Fg/dL, after adjustments for maternal education, children's lead exposure, age, and total caloric intake (odds ratio 0.4, 95% confidence interval, 0.2-0.9) (13). Of the studies that indicated no association, one was conducted among black children 11 to 33 months of age who resided in urban areas, and the results may not be applicable to other groups (14). In that study, the prevalence of iron deficiency was 7% among children with BLLs 20 to 44 Fg/dL and 5% among children with BLLs < 10 Fg/dL. The other study, using NHANES III data and published only in abstract form, reported no association between iron deficiency (with or without anemia) and BLLs > 10 Fg/dL after adjusting for age of housing; education of household head; and children's age, race, and poverty status, and intake of fat, calcium, and vitamin C (15). During the 1980s, some prospective studies of children's BLLs and development gathered data on the children's iron status as well; most of the data from these studies are unpublished. Bornshein (personal communication, University of Cincinnati Medical Center, November 1988) found that Cincinnati children who became more iron deficient (as evidenced by increased total iron-binding capacity) had greater increases in BLLs, but McMichael et al. (16) and Bellinger (personal communication, Harvard Medical School, March 1989) found no association between BLLs or changes in BLLs and initially low serum ferritin levels. Neither study, however, adjusted for children's use of iron supplements or for other factors. If children with initially low serum ferritin levels received iron supplements, this could have affected the association between initial low serum ferritin levels and changes in BLLs. # Does iron deficiency increase absorption of lead? Some animal studies suggest mechanisms by which iron levels could affect lead retention. For example, one study of rats indicates that iron and lead absorption may be mediated by common carriers and that ingested iron decreases the absorption of lead in a dose-related manner, presumably by competitive inhibition of the carrier protein (17). Moreover, iron-deficient animals have significantly higher rates of lead absorption than iron-replete ones (18). However, the effect of iron levels and iron supplementation on radiolabeled lead retention in humans is controversial, with at least one study finding an effect (19) and at least one not (20). In their latest study, Watson and colleagues (19) found a correlation between lead and iron absorption; however, the mean lead-absorption value for iron-deficient subjects was not significantly different from the value for those who were not iron deficient. No data are available for children. # Does iron deficiency enhance the adverse effect of lead on development? Although iron deficiency may not modify children's risk for lead exposure or retention, iron deficiency and EBLLs have similar toxicity profiles. Both result in a lower production in heme; this is manifested clinically by higher erythrocyte protoporphyrin levels in children with EBLLs and iron deficiency than in those children with either condition alone (21). More importantly, both iron deficiency and EBLLs have a deleterious effect on cognitive development. This raises the possibility that the neurodevelopmental effects of lead may be more severe when iron deficiency is also present. However, there is no evidence to suggest that iron deficiency modifies the neurodevelopmental effect of EBLLs. Instead, in one study comparing the cognitive development of children living near a lead smelter with that of those in a nearby town in Yugoslavia, researchers found the neurodevelopmental effects of iron deficiency and EBLLs to be independent of one another (22). # Does iron supplementation have an effect on BLLs? There is evidence to suggest that iron-sufficient children excrete more urinary lead when chelated with EDTA, although the increase is small and probably not clinically significant. In addition, after iron administration, chelation-induced lead excretion increased among patients with iron deficiency. The study in which this occurred, however, did not address the effect of iron deficiency on BLLs and lead excretion in the absence of chelation (23). In a study conducted by Ruff and colleagues (24), children with EBLLs and iron deficiency were given iron supplements, whereas children with EBLLs but no iron deficiency were not. The children who were iron deficient and received supplements had only half the reduction in BLLs of the children who were iron sufficient and did not. However, it is not clear whether this was due to the effect of iron supplementation on hemoglobin concentration or to another factor affecting lead biokinetics. The problem with using BLL as an indicator of body burden of lead in iron studies is that, because 99% of lead in blood is intraerythrocytic, any intervention that causes a significant increase in the hemoglobin concentration will similarly affect the BLL. # Summary Although iron may help prevent lead absorption in animals, studies of the association between iron deficiency and BLLs in children have produced inconsistent results. There is little evidence that iron promotes a clinically important increase in lead excretion. However, the use of iron supplements among children with EBLLs and iron deficiency has been shown to improve their developmental scores, suggesting that the effects of iron deficiency on cognition can be partially reversed among children with EBLLs (24). This finding is consistent with a wealth of data indicating that neurodevelopmental impairment among children with iron-deficiency anemia can be partially resolved by treatment with iron supplements (25)(26)(27)(28). However, treatment with succimer (dimercaptosuccinic acid) to lower EBLLs (20 to 44 Fg/dL) in toddlers has not been shown to improve their cognition (29). Since the effects of iron deficiency on children's development appear to be independent of the effects of lead, there is no compelling reason to screen and treat children with lead exposure differently from children of similar age on the basis of their risk for iron deficiency, assessed independently of their lead exposure. Detailed recommendations for the prevention of iron deficiency can be found in a recent CDC report (30). Several of these recommendations are summarized later in this chapter. # Vitamin C Could increasing children's vitamin C intake decrease their BLLs? Decreased lead retention has been shown in rats fed vitamin C and exposed to lead (31)(32)(33). Clinical studies in humans actually predate these and other animal studies, as case reports of lead-poisoned workers' response to ascorbate began to appear in the literature as early as 1939 (34). Later, clinical trials were conducted among workers and other adults. An uncontrolled experiment involving 39 workers showed that their BLLs had declined 24 weeks after they began treatment with vitamin C (35). Results of a single-blind clinical trial of vitamin C (1 g daily) among lead smelter workers with BLLs of 28 to 76 Fg/dL did not show vitamin C to affect their urinary excretion of lead (36). In a double-blind randomized clinical trial, however, adult male smokers given a daily dose of vitamin C (1 g) experienced a statistically significant 80% decline in BLLs (from 36 to 20 Fg/dL) after 1 week of treatment that persisted through the 4-week period of the study (37). Much less is known about the effect of vitamin C on BLLs in children. One correlative cross-sectional study using NHANES III data showed high levels of serum vitamin C to be associated with a low prevalence of EBLLs for both children and adults. Results of this study also showed an association between serum vitamin C levels and log BLLs among adults but not among children (38).This study, however, did not control for environmental lead risk or include children below the age of 4 years who are the usual subjects for case management (39). In summary, although there is fairly strong evidence to support giving vitamin C to adults with EBLLs, there is insufficient evidence to recommend for or against vitamin C supplementation for children with EBLLs. It is important to note that CDC recommends giving all children 6 months and older at least two servings of foods rich in vitamin C per day for the prevention of iron deficiency (30). # Chapter 4. Nutritional Assessment and Interventions # Calcium Are children at higher risk for EBLLs also at higher risk for inadequate calcium intake? Recommended daily allowance values for calcium intake have been replaced by "adequate intake"(AI) levels (40). AIs for young children are age-specific: 0-6 months, 210 mg/day; 7 12 months, 270 mg/day; 1-3 years, 500 mg/day; and 4-8 years, 800 mg/day. Actual mean calcium intake levels may be estimated from NHANES III data. Figure 4.1 depicts the median, 75 th percentile, and 25 th percentile levels for daily calcium intake among children aged 1 to 4 years by race. Calcium intake is below the AI level for more than 25% of Mexican American and non-Hispanic black 1-to 3-year-olds, and approaches 25% for non-Hispanic white 1-to 3-year-olds. Similarly, there is little variation in calcium intake across income groups (results not shown). Although these data do not specifically reflect the calcium intake of children with EBLLs, groups that typically have higher risk for EBLLs in this nationally representative sample of children have only a slightly higher risk for calcium intake below AI levels. One research group assessed the calcium intake of 314 mostly African-American children using a food frequency questionnaire (41). The results for children aged 1 to 3 years were similar to those of NHANES III, with about 30% of children having calcium intakes below the AI level of 500 mg per day. Because calcium intakes were not much higher for 4-to 8-year-old children in this sample, a substantially higher proportion of them (almost 60%) had calcium intakes below the AI level of 800 mg for their age group. # Does inadequate calcium intake confer a higher risk for EBLLs? Animal studies have shown higher lead retention in animals fed low-calcium diets, raising the possibility that low-calcium diets could affect the BLLs of humans (42)(43)(44)(45). Furthermore, studies of radiolabeled lead absorption in human adults show lower absorption of lead when lead is co-administered with calcium (46,47). In 89 metabolic balance studies of 12 infants, dietary calcium intake was found to be inversely associated with lead retention (48). As the authors noted, however, dietary calcium intake closely paralleled the intake of phosphorus and other unmeasured components of milk and formula, so it is difficult to attribute this effect solely to calcium. In NHANES II (1976 -1980), calcium intake was inversely associated with BLLs in a nationally representative sample of children aged 3 to 11 years (49). The analysis included good controls for children's socioeconomic status, region of the country, and urban vs. rural residence. Results of this analysis showed that children's calcium intake had a small, inverse correlation with their BLL, with children's BLLs declining by only about 0.2% for each 100 mg increase in dietary calcium. The study was subject to the following limitations. First, it included no direct controls for environmental lead exposure. Second, because the backward selection procedure used for the regression analysis removed confounding nutritional variables from the final model, and the p-value for the calcium effect was close to 0.05, statistical significance would probably be lost with the inclusion of only one nutritional confounder. Results of other smaller published cross-sectional studies generally support an inverse association between children's calcium intake and BLLs, but these studies also did not control for confounding (50,51). Calcium supplementation above the AI level Meredith et al. showed that increases in dietary calcium of up to 5 mmol decreased lead retention in rats with no pre-existing calcium deficiency; however, they found no further decrease with oral doses of calcium above 5 mmol (100-fold molar excess of calcium) ( 52). This finding is consistent with those from the studies of radiolabeled lead absorption in human adults mentioned above (46,47). In an unpublished balance study of the effect of calcium glubionate syrup supplementation (50 mg calcium/kg/day) on lead retention in six children, neither lead absorption nor lead retention was found to be affected by calcium supplementation (personal communication, Ekhard E. Ziegler, University of Iowa College of Medicine, May 14, 1990). Similarly, no effect of calcium supplementation was found in a randomized clinical trial of calcium glycerophosphate supplementation of infant formula involving 105 infants (53). In this study, infants in the treatment group received, on average, 1600 mg of calcium per day. Change in BLL over time was small for all of the infants in the prevention trial (only 1 Fg/dL), limiting the power of the study to examine a treatment effect. # Summary There is little evidence that a child typically considered at high risk for lead exposure is at greater risk for low calcium intake than children without EBLLs. However, because of the frequency of inadequate calcium intake among all children, it is important to verify that a child with an EBLL is receiving enough calcium. The results of both animal studies and human laboratory studies provide good evidence that dietary calcium competitively inhibits lead absorption. The results of one cross-sectional study of older children with controls for socioeconomic status show an inverse association between dietary calcium intake and BLLs. There are few data on young children in the high-risk age range, and no clinical trials have evaluated the efficacy of supplementation among children with low calcium intakes who are at risk for lead exposure. The results of studies among older children and adults, animal studies, and cross-sectional studies all reinforce the importance of adequate calcium intake (i.e., two servings per day of dairy products or other calcium-rich foods). However, there is no clinical evidence that supplementation of calcium beyond the recommended AI level in children with EBLLs has a clinical effect on the BLLs; therefore, we do not recommend giving calcium supplements to children with EBLLs. # Chapter 4. Nutritional Assessment and Interventions # Total fat intake The link between fat intake and BLLs comes primarily from animal experiments (54). In one cross-sectional experimental study, researchers found a direct association between dietary fat and BLLs (55); however, no such relationship between dietary fat and BLL was found in NHANES II (47). Thus, no strong case can be made for decreasing children's total fat intake. In addition, dietary fat is an important constituent in the diets of children under 2 years of age because calories from fat support high calorie requirements for growth during this period. Thus, we do not recommend low-fat diets for the treatment of younger children with EBLLs. # Zinc supplementation Some evidence from animal studies suggests that high levels of dietary zinc inhibit the absorption and retention of lead in animals (56). However, in one small clinical study in which zinc was given with and without vitamin C to lead-exposed workers, the zinc had no demonstrable effect on their BLLs (36). As with calcium, we do not recommend adding zinc supplements to the diet of children with EBLLs. # Other factors Many other factors have been evaluated as mediators of lead absorption and excretion in adults or animals. These factors include vitamins (thiamin, pyridoxine, vitamin D), minerals (phosphorus), dietary chelators (phytatic acid, alginates, oral EDTA), and frequency of meals. These were not included in this review because of a lack of evidence to determine their efficacy in children. # General Recommendations # WIC referral • Because children with EBLLs are at risk for poor diet, refer children with EBLLs to supplemental food programs that provide nutritional counseling and access to healthy foods. • Determine whether children with EBLLs are eligible for WIC and ensure their access to this program if they are eligible. An EBLL is a condition that should qualify age-eligible older children who might otherwise not be candidates for participation in the program. # Iron deficiency • Low-income or minority children with EBLLs are usually at high risk for iron-deficiency anemia. Detailed recommendations for the prevention of iron deficiency can be found in a recent CDC report (30). Several of these recommendations are included below. • Test those at risk for anemia (e.g., those from low-income, migrant, or recently arrived refugee families or those qualifying for WIC). These children should be tested at the following ages: S Initially between ages 9 and 12 months S Six months later S Annually from ages 2 to 5 years Vitamin C intake • Advise caregivers to provide children with an adequate intake of vitamin C. For children approximately age 6 months and older, encourage caregivers to provide two feedings per day of foods rich in vitamin C (e.g., fruits, vegetables, or juice), preferably with meals, as a way of improving their iron absorption. # Iron intake • Encourage caregivers to provide children with an adequate intake of iron by: S Introducing them to iron-fortified cereals and pureed meats at their appropriate developmental stages. S Providing one serving of lean red meat per day to older children. S Do not recommend giving children iron supplements except under the supervision of a physician or nutritionist and only when iron deficiency or anemia is documented. # Calcium intake • Encourage caregivers to see that children with EBLLs receive an adequate amount of calcium (500 mg/day @ 1 to 3 years; 800 mg/day @ 4 to 8 years), by: S Providing them with two servings of dairy products per day, unless they are lactase deficient. S Providing lactase-deficient children with sufficient dietary calcium from other sources (e.g., broccoli, greens, kidney beans, and calcium-fortified juices). S Do not recommend giving children calcium supplements except under the supervision of a physician or nutritionist. • Do not recommend supplementation in children with EBLLs beyond the recommended AI levels. # Fat intake • Do not encourage a low-fat diet as a means of lowering children's EBLLs. Not only is there no clinical evidence to support the implementation of such a diet, but dietary fat is an important constituent in the diets of children, especially those under 2 years of age. # Chapter 4. Nutritional Assessment and Interventions Zinc supplementation • Do not recommend zinc supplementation. # Recommendations for Future Research Evidence suggests that some population-based nutritional measures may reduce lead absorption in children. However, we do not yet know enough about the relationship between children's EBLLs and many specific nutrients to make recommendations. The literature is replete with animal studies that have not been adequately followed up in the human population. When they are, the epidemiologic work consists mostly of correlative cross-sectional studies without adequate controls for environmental lead exposure. Because of the sparse evidence for the efficacy of various nutritional interventions for children with EBLLs, it is premature to call for the implementation of population-based nutritional interventions. Instead, promising interventions should be evaluated in randomized clinical trials. Such clinical trials are especially important for several reasons. First, correlative nutrition studies are hampered by our limited ability to measure dietary intake. In addition, many nutrient intakes correlate with each other, so only large observational studies can separate the effects of, for example, dietary fat from iron. An association between a nutritional factor and BLL, however, does not mean that manipulating the nutritional factor will have a clinically meaningful effect on an EBLL. Some of the randomized trials of dust control among children illustrate this (57,58). Only clinical trials employing randomized designs can determine whether modifying children's intake of specific nutrients will actually influence their BLLs. Furthermore, many patient-compliance and side-effects issues need to be resolved before nutritional interventions can be studied clinically. For example: Which vitamin C supplements will children reliably take? Which ones will caregivers reliably give? Does it matter when the dose is given? Should the supplement be given as a medication or through a frequently eaten food item? What is the level of supplementation that could result in side effects? Finally, many nutritional interventions will involve behavioral change for families. Results of clinical studies of behavioral change (e.g., parental smoking cessation [59,60] and environmental tobacco exposure reduction [61]), suggest that only modest behavioral changes can be expected from limited-contact counseling interventions. In addition, injury research shows that passive interventions (e.g., using childproof medicine caps) are much more effective in preventing injuries than are active interventions (e.g., asking parents to keep medicines out of reach). Therefore, controlled randomized studies should identify and evaluate actions and interventions that may result in improved compliance with recommendations. • Also consider developmental surveillance for a child who has a BLL that does not exceed 20 Fg/dL but who has other significant developmental risk factors. • Do not base decisions regarding developmental assessment or intervention on a child's age at the time the child is found to have an elevated blood lead level (EBLL). • If you wish to refer a child with an EBLL for intervention services, consider referring that child to early intervention/stimulation programs. • Include a history of a child's EBLL in the problem list maintained in the child's medical record. • Do not stop developmental surveillance when a child with an EBLL reaches age 6 or when the child's blood lead level is reduced. A responsible party (e.g., the child's PCP) should provide ongoing developmental surveillance of that child after the EBLL case is closed. • In the developmental surveillance of children with EBLLs: -Watch for emerging difficulties at critical transition points in childhood: first, fourth, and sixth/seventh grades. -Watch for behaviors that interfere with learning, such as inattention and distractibility. • Refer children experiencing neurodevelopmental problems for a thorough diagnostic evaluation. • Be advocates for the child. # Introduction Since Preventing Lead Poisoning in Young Children was published in 1991 by the Centers for Disease Control and Prevention (CDC) (1), considerable new data have become available on the developmental and neurobehavioral effects of lead, including late results of a number of prospective longitudinal studies begun around 1980. These new data generally bolster the conclusion, reached in the 1991 statement, that lead adversely affects children's performance on tests of cognition at blood lead levels (BLLs) below 10 Fg/dL (2,3). New insights have been generated as well regarding both the most sensitive functional endpoints and the range of endpoints affected. Specifically, recent data suggest that lead toxicity may contribute to neurobehavioral, as well as cognitive, morbidities of childhood. Because of the consistency of these associations and the relatively high prevalence of BLLs in the range associated with these increased risks, it is important to address the issues involved in the identification and treatment of lead-related cognitive and neurobehavioral effects. Any recommendations regarding neurodevelopmental assessments and interventions for children with elevated blood lead levels (EBLLs) must rest on a firm empirical foundation. Therefore, this chapter presents an overview of numerous studies of the association between children's BLLs and their neurodevelopment and behavior, as well as the recommendations based on the studies. # Detailed Bases for Recommendations # BLLs and IQ Several older case series clearly demonstrate that children presenting with symptoms and findings of severe lead intoxication are at substantially increased risk for serious neurological sequelae (4)(5)(6). Asymptomatic children with BLLs in the 30-to 60-Fg/dL range also may suffer a variety of neurologic and neurobehavioral adversities (7)(8)(9). Recent epidemiological studies provide a wealth of data on the nature of the dose-effect relationship for children with BLLs below 35 Fg/dL. The relationship between children's BLL and IQ appears to be linear, even at BLLs below 10 Fg/dL (2,3). Some data suggest, however, that the slope for the dose-effect relationship is steeper for BLLs below 15 Fg/dL than it is for levels above 15 Fg/dL (3). Meta-analyses of the results of several studies indicate that an increase in average postnatal BLL from 10 to 20 Fg/dL is associated with a decrease of 1 to 3 points in the child's IQ measured at age 5 or older (3,10,11). The point estimates for the IQ change associated with a doubling of BLL from 10 to 20 Fg/dL were 2.57 points (standard error 0.41) in Schwartz' analysis of a mixed set of prospective and cross-sectional studies (3) and 2.53 points (standard error 0.41) in the analysis of cross-sectional studies by Pocock et al. (10). # Chapter 5. Developmental Assessment and Interventions The study cohorts were quite diverse ethnically, culturally, and sociodemographically. Children in some cohorts experienced chronic exposure by virtue of living near a smelter (12,13), while children in other cohorts were impoverished and living in inner-city areas in old housing with leaded paint in poor repair (14,15). Yet other cohorts consisted largely of children from relatively well-to-do families (16,17). The likelihood that these interstudy differences were accompanied by differences in the nature and extent of confounding bias makes the overall consistency in the findings of the different studies even more impressive, and increases the plausibility of the conclusion that lead plays a causal role in a child's neurodevelopment. As in most areas of epidemiological research, however, interstudy variability is apparent in the strength of the association, with some investigators reporting that the association between children's BLLs and IQ scores was not statistically significant (15,(17)(18)(19). Nevertheless, the overall weight of evidence clearly supports the existence of an inverse association between children's BLLs and their IQ scores. # Other Neurodevelopmental Deficits Associated with EBLLs Children presenting with severe symptomatic lead intoxication are known to suffer from neurobehavioral problems such as impulsivity, aggression, and short attention span (4). Results of a number of studies support the hypothesis that the spectrum of low-level lead effects on children includes neurobehavioral problems (20)(21)(22)(23). At present, there is no compelling evidence that an EBLL increases a child's risk for attention deficit hyperactivity disorder (ADHD) (24). However, because the studies mounted to address this question have been cross-sectional or retrospective, children's lead exposure status at earlier developmental periods may have been misclassified. It is noteworthy that elevated blood or tooth lead levels have been repeatedly linked to the types of behavioral problems pertinent to the diagnosis of attention deficit disorder inattentive subtype, a diagnosis included for the first time in the fourth (and most recent) edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (25). These behaviors include distractibility, poor organization, a lack of persistence, and daydreaming (26)(27)(28)(29). Elevated bone lead levels have also been linked to an increased risk of engaging in antisocial behaviors in middle childhood (29). Efforts to identify a "neurobehavioral signature" for children with EBLLs have generally been unsuccessful (30), although several studies have found that among preschool children, EBLLs were most strongly associated with deficits in nonverbal functions, particularly visualmotor skills (13,(31)(32)(33). However, the nature of the deficits identified when children reach school age are less consistent. It is likely that the manner in which lead toxicity is expressed depends on many factors, including the timing and chronicity of exposure, the child's age when outcomes are assessed, and the context of the assessment (30). Given the absence of specificity in the findings associated with an EBLL, a child's specific deficits are of little use in making a diagnosis of past or present EBLL. # Chapter 5. Developmental Assessment and Interventions # Interchild Variability The BLLs at which individual children show signs of clinical lead intoxication vary widely, and despite the consistent inverse association between children's BLL and IQ noted above, children have varying sensitivity to the more subtle functional impairments associated with EBLLs (30). Although, on average, children with higher BLLs tend to score lower on IQ tests than do children with lower BLLs, some children seem to be more affected than others by a given lead dose (34). This suggests that not all children with a given BLL should be considered at equivalent neurodevelopmental risk. In other words, an EBLL should be viewed as a risk factor for neurodevelopmental problems, not a diagnosis. # Importance of Age Identifying the age at which children are most sensitive to the neurodevelopmental effects of lead is complicated by the relatively high degree of stability in children's BLLs and the frequent confounding of age and peak BLL (32,35). However, data from cohorts in which these obstacles to inference are less severe indicate that children's IQs may be particularly sensitive to leadassociated effects when the children are about 2 years old (16). Pocock et al. for example, found that EBLLs in children from 1 to 3 years of age appear to be the most predictive of children's later development (10). On the other hand, data from several of the prospective studies suggest that recent or concurrent BLLs are among the strongest predictors of children's neurodevelopmental function at school-age (12,32). Furthermore, primate studies indicate that the period of greatest susceptibility to EBLLs may depend upon the specific deficit being evaluated (36). There is some limited evidence for this from human studies as well (37). # Time Lag Associated with the Effects of EBLLs For the most part, the evidence from prospective studies regarding the time course of the association between a child's BLL and neurodevelopment is consistent with a lag effect (16,31). It is much more common to find a significant association between children's previous BLLs and their current neurodevelopmental status than between their current BLLs and current developmental status. This pattern is less clear under circumstances in which children's BLLs remain elevated for extended periods of time, such as when they live near smelters or in hazardous housing; under such conditions, children's current and past BLLs tend to be strongly correlated. The lag may be the result of a toxicological process in which some period of time is required for past lead exposure to affect the central nervous system function. Another explanation is that lead may primarily affect higher-order neurodevelopmental processes that are best tested at later ages when children's response modalities are more highly differentiated. One implication of this lag is that neurodevelopmental assessments conducted when a child has an EBLL may produce many false-negative results and fail to identify a child who is at risk for later neurodevelopmental dysfunction. Careful long-term surveillance of behavior and neurodevelopment is thus needed to ensure that such children are identified. The effects of EBLLs on the skills required for academic success may not be appreciated until a child reaches critical transition points in school: 1) first grade, when children are expected to begin acquiring basic academic skills such as reading words or performing arithmetic operations; 2) fourth grade, where the emphasis begins to shift from acquiring basic skills to using those skills to learn new material ("reading to learn" as opposed to "learning to read"); and 3) sixth or seventh grade, when students are expected to use higher-order planning and organizational skills in order to complete long-term projects. Increased BLLs have been associated with difficulties with all three types of skills (20,26,38). # Persistence of Neurodevelopmental Effects Results from a variety of studies indicate that neurodevelopmental problems associated with elevated postnatal BLLs are persistent (8,16,(38)(39)(40)(41)(42)(43). The natural history of these problems appears to correspond to a "constant decrement" model, with the deficits associated with higher BLLs neither increasing nor decreasing over time (44), although few data are available on the persistence of effects. In contrast, the findings from most of the prospective studies are consistent with the hypothesis that neurodevelopmental effects associated with elevations in biomarkers of prenatal lead exposure attenuate during a child's early years of life (10). # Factors Affecting a Child's Risk for Neurological Sequelae Increased exposure to lead frequently occurs in the context of other factors that also place a child at increased neurodevelopmental risk (e.g., poverty, single-parent household, teen-age mother, child abuse, poor nutrition). From this perspective, lead represents an additional "hit," adding to a child's cumulative neurodevelopmental risk (45). In multivariate statistical models, children's BLLs tend to account for a relatively small amount of the variance in their neurodevelopmental status. The amount varies across outcomes measured and across studies, ranging from 0% (i.e., accounting for no variance in neurodevelopmental measurements) to as much as 11% (46), although usually on the order of 1% to 3%. For instance, in the set of crosssectional studies included in the meta-analysis of Needleman and Gatsonis (47), children's BLLs accounted for 2.3% of the variance in their IQ scores (based on a weighted partial correlation of -0.152). Other factors, particularly social class and parental intelligence, typically account for much larger percentages of outcome variance. Some evidence suggests that certain characteristics of children and their families are associated with the children's increased risk for neurodevelopmental impairments from a given level of lead exposure. Several studies, although not all, have identified family social class as one such characteristic, with children from lower social strata appearing to express the neurodevelopmental effects of lead at a lower BLL (48)(49)(50)(51). A sex difference is also sometimes found, although in some studies it is girls (52,53) and in others it is boys (10,50,54) who are found to be at greater risk. One implication of these findings is that lead's association with children's neurodevelopment cannot be accurately expressed as a single number because the magnitude of the association may vary depending on the characteristics of a particular child and his or her environment. A more promising implication, however, is that the effects of lead on a child might be reduced by modifying critical aspects of the environment. For example, indirect observational evidence indicates that the persistence of the link between an EBLL and reduced function varies with factors such as family social class, maternal IQ, and quality of the home environment (54). Specifically, if two children with the same early BLL achieve the same developmental score at time 1, but one child's environment offers greater cognitive stimulation, that child's developmental status at time 2 is likely to be better than that of the child from the less stimulating environment. Thus certain factors might help children to weather the developmental insult of early lead exposure, either preventing neurodevelopmental effects from being expressed or facilitating subsequent recovery of function. Social class is often found to be such an effect modifier, although higher social class is presumably a surrogate for the more proximal influences that confer this greater resilience (e.g., better nutrition, greater access to academic supports, more varied experiences). # Effectiveness of Reducing BLLs It has not been shown that lowering a BLL after it has been elevated prevents lead-induced cognitive defects. In one study, children with BLLs between 25 and 55 Fg/dL were chelated if a test dose of EDTA increased their urinary lead excretion. Chelation did not change their neurodevelopmental test scores or BLLs at 6 months of follow-up. However, the children whose BLLs fell the most, whether they had chelation or not, had the greatest improvement in test scores at their 6-month follow-up evaluation (55). It is noteworthy that children's test scores increased one point for each decline of 3 Fg/dL in their BLL, a slope that is consistent with the slope for the dose-effect relationship from several observational studies that did not involve any intervention. However, the only large-scale randomized trial assessing the effects of chelation induced BLL reductions on neurotoxicity showed that oral chelation with succimer (dimercaptosuccinic acid) lowered children's BLLs but did not improve their scores on a range of cognitive, neuropsychological, and neurobehavioral tests. Conducted among children living in deteriorating housing in four inner-city areas, this study involved 780 children (12 to 23 months of age) with BLLs from 20 to 44 Fg/dL who were randomly assigned to receive either a placebo or up to three courses of succimer. While the mean BLL of the treated group was 4.5 Fg/dL lower than that of the control group 6 months after treatment, there were no significant differences between them in any of the mean test scores 3 years after treatment began, when the children were, on average, 5 years old (56). # Effects of Early Enrichment on Children with EBLLs No studies have been published on the effectiveness of non-medical interventions, such as early enrichment programs, in ameliorating the effects of EBLLs on children's neurodevelopment. In the absence of such data, it is reasonable to hypothesize that children with neurodevelopmental problems associated with an EBLL would benefit from the types of interventions shown to be effective in facilitating the neurodevelopment of other groups of children with idiopathic neurodevelopmental problems or those known to be at increased risk for such problems, such as low birth weight infants. Evaluations of interventions to foster the development of preschool children at risk for neurodevelopmental problems because of socioeconomic disadvantage, nonorganic failure to thrive, or low birth weight indicate that such programs can produce IQ increases on the order of 8 points (57). Although the magnitude of these IQ effects might attenuate after children complete the programs, participation in such programs is associated with lower rates of grade retention and need for special education (58). Some evidence suggests that programs in which participation begins prior to age 3 are more effective than those in which participation begins later (59). Programs that include procedures to foster both child development and parenting skills tend to be more effective than programs that are solely child-focused or parent-focused (57). Examples of such programs are the Mother-Infant Transaction Program (60)(61)(62)(63)(64) and the Infant Health and Development Program (65)(66)(67). # General Recommendations Make long-term developmental surveillance a component of the management plan for any child with a BLL $ 20 Fg/dL. The precise BLL that one identifies as a "trigger" for neurodevelopmental surveillance will depend on the type and magnitude of deficit that one considers sufficiently large to warrant concern. Current CDC guidelines recommend that a child whose BLL is 20 Fg/dL or above receive environmental and medical evaluations. It makes both clinical and logistical sense to integrate neurodevelopmental surveillance and possible referral for diagnostic assessment or intervention into the overall management plan of such a child. The PCP and case manager, working in close collaboration, are best positioned to organize and oversee these processes. A BLL that exceeds 20 Fg/dL should not necessarily result in a referral for diagnostic assessment or intervention. This clinical decision should be made on a case-by-case basis, taking into account whether other neurodevelopmental risk factors are present (e.g., teen-age mother, poor parenting skills, inadequate cognitive or emotional stimulation, child abuse, poverty, genetic disorder, poor nutrition, other medical issues). Under some circumstances, such as persistent BLLs of 15 to 19 Fg/dL or the presence of other significant neurodevelopmental risk factors, it would be appropriate to place a child with a lower BLL under increased neurodevelopmental surveillance. The case manager is in a unique position to assist the PCP in this regard by virtue of his or her knowledge of a child's risk factors gleaned from visits to the home or other contacts. Thus, the case manager can serve as a critical information resource to the PCP regarding contextual factors germane to the PCP's decisions about a child's neurodevelopmental needs. Furthermore, a case manager with training in neurodevelopmental assessment can conduct screening evaluations and bring potential problems to the PCP's attention. The usual absence of associations between concurrent BLLs and risk for neurobehavioral deficits among children aged 0 to 3 years suggests that neurodevelopmental assessment of children while they have an EBLL might not identify children who will later experience cognitive problems (false-negatives). If a child currently has or has ever had an EBLL, however, the PCP and case manager should take a more aggressive approach in assessing that child's neurodevelopment and referring that child for follow-up. Under ordinary circumstances, the PCP is in the best position to follow up with long-term monitoring of a child with an EBLL. The developmental and behavioral screening that PCPs conduct at well-child visits, including taking a clinical history and administering brief instruments such as the Denver Developmental Screening Test, may be sufficient to identify children who are failing to make age-appropriate progress and transitions and who thus require additional diagnostic evaluation. Kindergartenreadiness evaluations generally are not designed to identify vulnerabilities that may be expressed as serious academic problems once children enter school. Because they produce many false negatives, kindergarten evaluations are not sufficiently sensitive to identify potential leadassociated learning difficulties. # Do not base decisions regarding developmental assessment or intervention on a child's age at the time of the EBLL. Age is an inappropriate criterion for determining which children with EBLLs need referral for developmental evaluation. The neurodevelopmental effects of EBLLs are persistent and may be delayed. Also, there is no way of knowing how long a child may have had an EBLL. A child first identified as having an EBLL at age 4 might well have also had an EBLL at age 2 or 3 and, on the basis of a presumed chronic exposure, could be regarded as being in greater need of developmental assessment than a child with an EBLL at age 2. Because detailed information about children's blood lead history is often not available, a child of any age who is found to have a BLL of 20 Fg/dL or greater should be placed under increased surveillance in order to identify any emerging neurodevelopmental problems as early as possible. If you wish to refer a child with an EBLL for intervention services, consider referring that child for early intervention/stimulation programs that are available for children at increased developmental risk. Although there is no empirical basis for recommending interventions with specific characteristics for children with neurodevelopmental problems resulting from an EBLL, it is reasonable to hypothesize that such children would benefit from the types of interventions shown to be effective in facilitating the neurodevelopment of other groups of children with idiopathic neurodevelopmental problems. Programs in which participation begins prior to age 3 or those that include procedures to foster both child development and parenting skills may be most effective. Examples of such programs are the Mother-Infant Transaction Program and the Infant Health and Development Program. # Include a history of a child's EBLL in the problem list maintained in the child's medical record. If a child changes his or her PCP, ensure that this information, along with other pertinent aspects of the child's medical history, is transmitted to the next provider. The PCP should work with the case manager to ensure appropriate follow-through. For the purposes of developmental surveillance, do not consider a child's case "closed" when the child reaches age 6 or when his or her BLLs are reduced. The period of increased risk for the expression of lead-associated neurodevelopmental problems continues after lead exposure has been remediated and BLLs reduced. Closure of a child's case by the case manager does not mean that the need for neurodevelopmental monitoring has ended. # Be especially vigilant for emerging difficulties at critical transition points in childhood. There are three periods when different types of learning difficulties are typically expressed: 1. First grade: Children begin acquiring basic academic skills. 2. Fourth grade: They use these basic skills to learn new material. 3. Sixth or seventh grade: They need higher order planning and organizational skills. A child with a history of EBLLs who experienced difficulties making earlier transitions should be viewed as being at increased risk of experiencing difficulties with later transitions. Even children who made early transitions smoothly should be under increased surveillance at later transition points, as they may have problems when new educational demands are placed on them. # Chapter 5. Developmental Assessment and Interventions Be alert for behaviors that might interfere with learning. An EBLL in early childhood is associated with an increased risk for behaviors such as inattention, distractibility, and impulsivity that can interfere with learning. These behaviors are characteristic of the recently recognized inattentive subtype of ADHD. Even if the behaviors a child presents are not sufficient to warrant the diagnosis of ADHD, the child may be helped by the types of classroom and work accommodations routinely made for children with an attention disorder. If you suspect that a child might be experiencing neurodevelopmental problems, consider arranging a thorough diagnostic (as opposed to screening) evaluation. The procedures used for assessment and intervention for a child with a history of EBLL and neurodevelopmental problems should be the same as those for a child with neurodevelopmental problems due to known and unknown causes. Ideally, assessments should be conducted by multidisciplinary teams, which might include developmental-behavioral pediatricians, educators, neuropsychologists, neurologists, speech/language pathologists, and child psychiatrists. # Be advocates for the child. This might involve assisting the family in arranging diagnostic evaluations, interpreting the results, and petitioning third parties to pay for the evaluation on the grounds that the evaluation might reduce special education or specialized therapy costs in future years. In regions where access to specialized neurodevelopmental clinics is limited, diagnosis and treatment planning can also be achieved by means of school-based evaluations or private practitioners. It is important to recognize the complexities of school-system involvement in this process. Some school systems may be unwilling to commit resources to evaluate a child in the absence of a complaint that includes reduced academic progress. Furthermore, expecting schools to conduct such evaluations places them in a position of possible conflict of interest insofar as they would have to pay for remedial services deemed necessary as a result of the evaluations. # Recommendations for Future Research 1. Conduct studies to characterize in greater detail the neurodevelopmental presentation associated with an EBLL, including analyses of the degree to which the presentation varies with factors such as the child's age at exposure and the magnitude and chronicity of the exposure. 2. Conduct studies to characterize the associations between EBLLs and learning disabilities. 3. Conduct studies to evaluate the role of EBLLs in causing or exacerbating behaviors associated with ADHD, conduct disorder, and other psychiatric diagnoses. 4. Conduct studies to evaluate the potential psychosocial vulnerabilities of children with EBLLs (e.g., self-esteem, self-concept, social competencies, aggression). 5. Conduct randomized trials to evaluate the efficacy of specific interventions in ameliorating lead-associated neurodevelopmental problems. # Introduction The 1990s witnessed dramatic declines in children's mean blood lead levels (BLLs) and in the percent of children with elevated blood lead levels (EBLLs) (1). During that decade, we learned a lot about children's exposure to lead in and around their homes, and about how to reduce that exposure through environmental interventions and caregiver education and counseling. In this chapter, we provide current recommendations for educational interventions, review the quality of evidence that supports these recommendations, and identify research needed to improve the effectiveness of caregiver education. Much of the relevant research is discussed in more detail in Chapter 2, "Assessment and Remediation of Residential Lead Exposure." The efficacy of most interventions has not been studied in isolation. Studies usually involved multiple interventions, thus limiting our understanding of the utility of individual recommendations. # Sources and Pathways of Residential Lead Exposure Leaded paint is the most common high-concentration source of lead for children and is typically seen in homes built prior to 1950. Poorly maintained older homes with deteriorating paint or those undergoing renovation, whether they are the children's primary residences or secondary sites where children spend much time, pose the highest risk of lead exposure. The usual sites of deteriorating leaded paint are interior painted surfaces, particularly those subject to abrasion such as window components, and exterior surfaces like siding and porches. The paint chalks or chips off from normal wear-and-tear and deteriorates into dust. Leaded dust can also be created by improperly conducted abatement (2). Soil is another significant source of lead for some children (3). Exterior soil can become very contaminated with lead from deteriorating overlying leaded paint, driplines, or lingering fall-out from previously used leaded gasoline, especially along heavily traveled roads. Children typically ingest leaded dust as a consequence of age-appropriate hand-to-mouth activity. Studies consistently show an association between the amount of lead on children's hands and their BLLs (4,5). Children are also exposed by intentionally ingesting paint chips, dust, or soil. Housing and soil sources are the most common cause of EBLLs in children. Additional significant sources of lead in certain communities include water, industrial contamination, folk medicines, and imported cosmetics or pottery (6)(7)(8). In addition, as shown in Appendix I, numerous less common lead sources may be the cause of individual cases of EBLLs. # General Principles Educational interventions are directed at helping caregivers reduce the exposure of children to residential and other sources of lead. While most children are exposed through the deterioration of leaded paint, they may also be exposed to lead from other sources; some of these exposures are a consequence of cultural practices or caregiver occupations or hobbies. Case managers should therefore select the information and interventions that are most appropriate to each child, family, and community and avoid overwhelming caregivers with interventions that may be of little or no benefit. Although there is no risk-perception or risk-communication research specific to childhood lead poisoning, general principles of these fields can be applied to improve the effectiveness of educational interventions to reduce children's BLLs. Case managers must recognize that caregivers understand the "risk" of EBLLs in ways different from the ways that experts in lead poisoning understand them, and case managers should tailor their recommended interventions to caregivers' conceptions of risks. If interventions are not tailored to caregivers' conceptions of risks, then caregivers are less likely to act on the information they receive (9, 10). In addition to educating caregivers about childhood lead poisoning, case managers may also need to provide detailed instructions on intervention techniques, actually demonstrate the techniques, and then ask caregivers to perform the techniques themselves. Such actions should increase caregivers' understanding of the interventions and consequently increase the chances that the interventions will be successful. # Studies of Various Interventions # Interventions to reduce children's lead exposure from residential deteriorating paint Interventions to reduce children's exposure to deteriorating paint in their homes include the safe repair of non-intact leaded paint, the safe repair or replacement of windows or other building components to prevent abrasion of leaded paint, and the safe removal (stripping) of leaded paint from components left in the home. In a review of uncontrolled studies involving children with baseline BLLs greater than 25 Fg/dL, the EPA found that BLLs of children in homes where non-intact leaded paint was safely removed or repaired declined 20% to 30% over the following year (11). In one controlled study, the mean BLL of children in treated dwellings declined twice as much as that of children in untreated dwellings (12). # Interventions to reduce children's lead exposure from residential dust Four clinical trials assessed the efficacy of household dust control by professional cleaners (13)(14)(15)(16)(17). Three trials assessed the effectiveness of household dust control done by the families of children with EBLLs: two randomized clinical trials (18)(19)(20), and one nonrandomized, retrospective analysis with a comparison group (21,22). Among the studies of professional house dust control, two (13,17) found that children in homes that underwent intensive dust-control (i.e., two trained cleaners wet mopping floors and wet wiping horizontal surfaces for 2 hours every 2-3 weeks) had a 17% -18% decrease in their mean BLL 1 year after the initial test. In one of these studies (17), a subgroup of children whose homes were cleaned 20 or more times over the year (a mean of once every 2.6 weeks) had a 34% decrease in their BLLs. Since trained cleaners conducted the interventions, this effect size is probably the optimum that can be achieved. The remaining studies (14)(15)(16) failed to show that dust control is associated with a decrease in children's BLL. Two of these studies were of a one time intervention (14,15), and the other was of cleaning done every 6 weeks (16). However, one time or infrequent interventions would most likely not prevent EBLLs, because household dust builds up again after a short time. This is suggested by Hilts et al., who found that children's lead loading returned to baseline levels 3 weeks after high-efficiency particulate air (HEPA) vacuuming (16). Similarly, Rhoads et al. found no change in the mean BLL of children whose homes were cleaned fewer than 10 times over the year (at most every 5.6 weeks) (17). Lanphear et al. conducted two trials in which the cleaning was done by the caregivers (18)(19)(20). In the first, 104 children (aged 12 to 31 months; BLLs 1.7 to 30.6 Fg/dL) were randomly assigned to an intervention group (in which caregivers received cleaning supplies, were educated about areas likely to be contaminated with lead, and were instructed to clean monthly) or to a control group (in which caregivers received only a brochure about preventing EBLLs) (18). Seven months after enrollment, the median change in children's BLL was -0.05 Fg/dL in the intervention group and -0.60 Fg/dL in the control group (p=0.50). However, in this study, the researchers could not ensure that the families adhered to the recommended cleaning regimen. The second trial involved 275 children with a mean baseline BLL of 2.8 Fg/dL (19,20). These children were randomly assigned to either an intervention group that received education, cleaning supplies, and up to eight home visits by an advisor, or to a control group that did not receive any of these interventions. Again, researchers found no significant differences in the geometric mean BLLs of children in the two groups at 12, 18, 24 and 48 months of age. But again, they could not ensure that the families adhered to the recommended regimen. Schultz et al. conducted a retrospective analysis of an in-home educational intervention (21,22). Health department staff visited the homes of children (mean age 3.4 years) with BLLs 20 to 24 Fg/dL and conducted an educational session for caregivers regarding lead sources, methods to reduce children's exposure to these sources, and appropriate nutrition for children. The children in visited homes made up the study group. A reference group was made up of children (comparable with the study group by age, sex, race, and BLL) who did not receive the educational intervention. Follow-up BLLs were obtained about 6 months after the intervention. The study group children had a significantly greater mean decline in BLL (4.2 Fg/dL) than the reference group children (1.2 Fg/dL, P<0.001). The authors concluded that home educational visits may have helped lower children's BLLs (22). However, they also noted that "[t]he validity of this conclusion depends upon whether children who received the visits were comparable to reference group children whose families were often unavailable for outreach visits. Families that were unavailable…may have been more likely to exhibit behavior patterns responsible for the continued elevation of their children's blood lead levels" (22). Thus, with no randomization of subjects, the reference group may not have been comparable in at least one important way. In a meta-analysis, the findings of several studies were combined to determine the effect of dust control on children's BLL (23). To be eligible for analysis, the studies had to be randomized controlled trials, cost less than $2,500, and be conducted in a community without a continual lead emission source, such as a lead smelter. Five studies were eligible (15,(17)(18)(19)(20). Results of the meta-analysis showed no significant post-intervention differences in mean BLLs between children in the intervention and control groups. However, the intervention groups contained significantly fewer children with BLLs $ 15 Fg/dL and $ 20 Fg/dL than did the control groups. For example, only 1.8% of children in the intervention groups had BLLs $ 20 Fg/dL, whereas 5.3% of those in the control group did (OR=0.29, CI 0.01 -0.85, p=0.024). This finding persisted even after the single study involving professional dust control (17) was removed from the analysis. The aforementioned studies largely focused on cleaning dust on uncarpeted floors. Although the dust lead loading on uncarpeted floors has a higher correlation with children's BLLs than the dust lead loading on carpets, dust lead loading on carpets does correlate with children's BLLs (24). However, neither HEPA vacuums nor common household vacuums reduced carpet dust lead levels by clinically relevant amounts (16,25,26). Furthermore, in one study, children whose homes were HEPA vacuumed actually had higher levels of lead on their hands after the interventions although their BLLs did not change (16). The authors speculate this may have occurred because families who received the vacuuming "…may have relaxed their hygiene efforts…because of a perceived reduction in exposure risk" (16). A report that HEPA vacuuming increased the lead loading on the surface of the carpet by bringing lead from deep in the carpet to the surface (25) offers an alternative explanation for the increase in hand lead levels. In summary, studies indicate that household dust control performed by professional cleaners is associated with decreases in children's mean BLL, although it appears that to be effective, such dust control must be conducted at least every 2 to 3 weeks. However, simply educating parents of the need to perform dust control has not proven effective in reducing children's mean BLL. # Interventions to reduce children's lead exposure by improving personal hygiene practices We found no controlled studies that examined the effect of personal hygiene on BLLs of children, although studies of the correlation between the level of lead on children's hands and their BLLs have consistently found an association between the two (6,7,27,28). Although the frequency of self-reported hand washing has not been associated with children's BLLs (27,28), the validity of study results based on such self-reported hygiene measures is clouded by the possible effects of social desirability bias. reductions in children's BLLs do not appear to be clinically relevant. Further, an economic analysis concluded that soil lead abatement was not cost-effective (33). Therefore, we do not recommend residential soil lead abatement in the secondary prevention of children's EBLLs. Nevertheless, because some children may experience significant lead exposure from soil either because they play in or ingest soil or because their soil has high levels of lead, we do recommend simple, safe measures such as providing sandboxes with covers or covering open soil with grass or mulch. # Nutritional Interventions Although the effects of various nutritional interventions on children's BLLs are either limited or have not been studied, certain interventions are of value to the children's general health, because many children with EBLLs are at risk for poor nutrition. See Chapter 4, "Nutritional Assessment and Interventions," for a detailed discussion. # Recommendations # General Recommendations Tailor educational interventions to each child and caregiver. Select the interventions and information that are most appropriate to the child. Devise a written plan with specific recommendations to reduce the child's exposure to identified sources of lead in consultation with the caregivers and give a copy of the plan to them. # Continue educational efforts beyond a one-time intervention. Monitor children's follow-up BLLs. If a child's BLL is not decreasing, discuss the case with the primary care provider (PCP) and, if appropriate, an environmental health specialist, to determine whether lead sources are being overlooked. Case managers may need to make further home visits to assess new lead sources and ensure that caregivers understand and are carrying out recommended interventions. # Environmental Recommendations Prompt and effective control of the sources of children's lead exposure is the highest priority. Ensure that all sites lived in or regularly visited by a child with an EBLL are inspected jointly with the caregiver to identify potential sources of lead exposure. surfaces every 2-3 weeks until all of their child's hand-to-mouth behaviors cease. Since windowsills and wells can contain high levels of leaded dust, they should be kept clean and, if feasible, shut to prevent abrasion of painted surfaces. Advise caregivers to use disposable cleaning materials or reusable materials used only for cleaning. The EPA recommends the use of a general-purpose, nonphosphate cleaner (36). In studies that found house dust control to be associated with a decrease in children's mean BLL, professional house cleaners used a powdered detergent rather than bleach or ammonia (13,17 Water sources can become contaminated with lead from household pipes made of lead or harboring leaded solder (37). The local health authority will know if this is a prevalent community-wide problem. See Chapter 2, "Assessment and Remediation of Residential Lead Exposure," for a detailed discussion of contamination in municipal or well water. If household water is a suspected source of lead exposure, advise caregivers to implement the following interventions pending the results of water testing: • Do not drink or cook with hot tap water. Lead is more soluble in warm water. # • Run the tap water cold for 1-2 minutes in the morning, and then fill a pitcher with the water. The water is then available that day for drinking, cooking, and formula preparation. Although the benefit of regularly running the tap before consuming water has not been studied in isolation, this is a simple intervention that poses no risk. # • If drinking water in a child's home is contaminated with lead, advise caregivers to use only bottled water until household water lead levels have been corrected. However, since most bottled water does not contain fluoride, fluoride supplementation may be necessary. For more information on bottled water, contact the United States Food and Drug Administration (301-443-4166); NSF International, an organization that certifies bottled water and water filters (313-769-5106); or the International Bottled Water Association (703-683-5213). # Nutritional Recommendations # Discuss dietary interventions. • Recommend that caregivers provide children with foods rich in absorbable iron, vitamin C, and calcium. Foods such as red meat and iron-enriched cereals are good sources of absorbable iron. Adding foods to a meal that are rich in vitamin C (e.g., fruit juice) can dramatically increase iron absorption. Two servings per day of dairy products are recommended. Unless the child does not ingest dairy products because of lactase deficiency, do not suggest calcium supplements, as they can be contaminated with lead (38). Both iron deficiency and EBLLs are common among children of low-income families (39,40), so providing iron-rich foods to children with EBLLs would contribute to the treatment of iron deficiency. (See Chapter 4, "Nutritional Assessment and Interventions," for details.) • Recommend that caregivers provide regular meals and snacks. In one study of five adults, a higher proportion of lead was absorbed when it was given to people when they were fasting (41). Therefore, encourage caregivers to provide three meals and two snacks (during midafternoon and at bedtime) a day. Refer eligible families to food supplementation programs such as the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). # Medical Recommendations Discuss the importance of regular medical follow-up. Follow-up blood tests are the best way to determine the success of environmental and other interventions. Therefore, remind caregivers to: • Make and keep follow-up appointments for blood tests. When making appointments, follow the schedule in Table 3.4 of Chapter 3, "Medical Assessment and Interventions." • Notify the case manager if the child moves to a new residence. • Advise caregivers not to use containers, cookware, or tableware purchased abroad to store or cook foods or liquids unless they are shown to be lead-free. # • Advise caregivers not to use folk remedies and cosmetics purchased abroad unless they are shown to be lead-free. # Recommendations for Future Research Although dust control performed by trained cleaners has been shown to reduce children's mean BLLs (13,17), simply educating families on the need to perform dust control does not attain the same results. Further research on how to motivate families to perform regular and effective cleaning is important. Reports indicate that, in the absence of interventions to reduce ongoing contamination of dust from disintegrating paint, the effect of dust control on children's BLLs is modest (17,18,20,44). However, randomized trials examining the effects of a multifactor intervention involving dust control, nutritional supplementation, and behavioral modification on children's BLLs would be of value. In other areas of environmental health, a great deal has been learned about ways in which different people view risks, methods of risk reduction, and barriers to addressing risks. Despite this increased understanding of the scientific basis of risk perception and communication in the past 20 years (45), no studies of risk perception or communication have been conducted among caregivers of children with EBLLs. In order to develop more effective educational and riskreduction strategies to combat EBLLs in children, health officials need better information about what people think about lead hazards and why they think that way. Methods such as mental modeling (46) and value integration (47) would be very valuable approaches to obtaining such information. Soil lead abatement is costly and has not been associated with clinically significant reductions in BLLs. However, studies are needed to assess the effectiveness and costs of using barriers such as grass, shrubbery, or cement to protect children with high soil lead exposures. Research is also needed on the efficacy of various barriers, such as wallpaper or paneling, in protecting children from exposure inside their homes. Since the half-life of lead in the blood can be up to 38 months (48), children must be followed for prolonged periods to determine whether their BLLs are decreasing and whether interventions have been effective. Decreases in dust lead levels or hand lead levels might be used as intermediate, proxy measures of children's lead exposure if we could develop practical, inexpensive, and reliable methods of using such assays in a clinical setting. manufacturing process, the candied jam is packaged in stoneware or terra cotta ceramic jars that can leach lead. # Food and Beverage Containers # Bulk-water storage tank Lead leached from soldered seams and brass fittings in bulkwater storage tanks. # CR Report of three children aged 6, 12, and 14 months. # 11 # Ceramic glaze Lead in ceramic glaze can leach into stored beverages, especially juices since they are acidic. The risk is highest for improperly fired containers. # CR Multiple reports. 7, 12, 49 Cocktail glass Lead leached from cocktail glass. CR Report of a family with one adult and children aged 4, 5, and 14 years. # 22 # Iranian urn (samovar) Lead spot solder from the original manufacturing process leached into water used to make baby formula. # CR Reports of a 10-week-old child with seizures and of a 4-month-old child. # 33, 48 Managing Elevated Blood Lead Levels Among Young Children # Acknowledgments I am indebted to many people for their input into this document. The Working Group decided on the format and appropriate individuals to develop each chapter, reviewed with those authorities # While there is no evidence that hand washing is associated with a decrease in children's BLLs, it is a simple intervention that poses no risks. # Interventions to reduce children's lead exposure from residential soil The major study examining whether soil abatement is efficacious at reducing children's BLLs, the Urban Soil Lead Abatement Demonstration Project (29), was conducted in three cities: Boston, Baltimore, and Cincinnati. In Boston, Weitzman et al. studied the effects of paint, dust, and soil lead abatement on the BLLs of 152 children (mean age: 31.6 months; mean baseline BLL: 12.5 Fg/dL; and median surface soil lead level: 2075 ppm) (14). Eleven months after soil lead abatement, the adjusted mean BLL of children in homes having the abatement dropped to 10.26 Fg/dL, and that of control children dropped to 11.54 Fg/dL (p=0.02). However, despite the statistical significance, the authors concluded that these differences were clinically irrelevant. In a follow-up of these children for an additional year, they found that soil lead abatement was associated with a 2.25 to 2.70 Fg/dL decline in the children's BLL, but that children who lived in dwellings with consistently elevated floor levels of leaded dust derived no benefit from the soil abatement (30). In Baltimore, Farrell et al. randomly assigned 408 children (aged 6 to 72 months) to either an intervention group (whose homes underwent exterior paint stabilization followed by soil abatement) or a control group (whose homes underwent exterior paint stabilization but no soil abatement) (31). The children's mean BLL was about 11 Fg/dL. At baseline, only 54% of properties had soil samples with a lead concentration above 1000 ppm. Ten to 13 months after the intervention, the geometric mean BLL of the treatment group was unchanged, while that of the control group had fallen 0.7 Fg/dL (29). Results of multivariate analysis showed no significant difference in the mean BLL of the groups at follow-up. In the Cincinnati trial, researchers studied the effects of soil lead abatement on the BLLs of 206 children (aged 9 to 72 months; median BLL 10 Fg/dL) by assessing changes in the children's median BLLs 9 to 10 months after the interventions. Through multivariate analysis, they found no significant difference in the mean BLL of children in households receiving and households not receiving soil lead abatement. There are a number of possible explanations for why these studies of soil abatement showed no effect. First, most of the interventions were performed in scattered homes rather than contiguous blocks of homes, so continued exposure to lead from nearby properties may have limited the effectiveness of the interventions. Second, the studies enrolled children whose sources of lead exposure were primarily from their homes rather than children whose sources were primarily from soil (i.e., those who avidly played in or ingested soil). Finally, the release of lead from children's bones may have attenuated the impact of the interventions (32). The EPA concluded that when soil is a significant source of lead for a child, the lead abatement of that soil is associated with a reduction in that child's BLL (29). However, the mean # Chapter 6. Educational Interventions for Caregivers Provide information about potential sources of lead. If caregivers are informed of lead sources identified during the environmental inspection, as well as other potential sources (Appendix I), they may change their attitudes and behaviors in ways that result in secondary prevention. Therefore, encourage caregivers to examine their yards and homes for chipping paint, especially areas where their child spends a good deal of time, and to alert lead inspectors to areas that may be potential sources of exposure. Explain that lead abatement should be conducted by trained workers. Improperly conducted lead abatement (e.g., grinding or sanding lead-based paint and thus producing lead dust, or allowing children access to areas of abatement) may actually increase children's lead exposure (34,35). Therefore, recommend that abatement be conducted by certified professionals. However, if caregivers choose to conduct lead abatement themselves, direct them to resources that will at least give them guidance in how to conduct lead abatement safely (Appendix II). # Discuss and demonstrate methods that caregivers can implement to reduce their children's lead exposure. While verbal instructions and written materials are useful, it is important to demonstrate methods of reducing children's lead exposure whenever possible. Demonstrating these methods at the child's home can help in overcoming language and cultural barriers. Encouraging caregivers to practice the methods demonstrated and provide corrective feedback if necessary should help them better understand and adhere to the recommended interventions. Although many of these interventions have not been studied in isolation or shown to be effective, most are simple interventions that pose no risk and should help reduce children's risk for lead exposure. Have anyone engaging in "lead hobbies" change clothes either before entering the home or in an area that is inaccessible to children. • Wash contaminated clothing separately from the rest of the family laundry. • Properly store and dispose of toxic substances. # Discuss the hazards of food containers, folk remedies, or cosmetics contaminated with lead. Items that may be associated with lead exposure are listed in Appendix I. A gray or black eye cosmetic applied to the conjunctival margins of the eyes. Can contain up to 83% lead. It is believed to strengthen and protect the eyes against disease. Also known as Al Kohl. # Appendixes # Appendix I. Published Reports of Less Common Causes of Elevated Blood Lead Levels (EBLLs) in Children. # E A study of 538 girls aged 6 to 12 years demonstrated that the application of kohl was associated with higher BLLs (p=0.0461). # 3, 37 # Pakistani eye cosmetics Eye cosmetics are often applied to the eyes of children. # E Retrospective chart review of 175 children aged 8 months to 6 years showed an average BLL of 4.3 µg/dL for Pakistani/Indian children not using eye cosmetics and 12.9 µg/dL for those using eye cosmetics (p=0.03). # 50, 52 Surma (India) A black fine powder applied to the eyes for medicinal and cosmetic reasons. # E A case-control study of 62 children demonstrated higher BLLs in children using surma (p<.001). # 2, 15 # Contaminated Foods # Apple cider Cider was made in a maple syrup evaporator that had lead solder joining the interior seams. An herbal medicine used to relieve pain. # CR Report of three children aged 13 and 23 months and 2.5 years. 10 # Pay-loo-ah (Vietnam) A red powder given to children to cure fever or rash. CR Report of a 6-month-old child. # 13, 15 Po Ying Tan (China) An herbal medicine used to treat minor ailments in children. # CR Report of a 4-month-old child. 20 # Santrinj (Saudi Arabia) An amorphous red powder containing 98% lead oxide used principally as a primer for paint for metallic surfaces, but also as a home remedy for "gum boils" and "teething." # Fishing sinkers Ingestion of a lead-containing fishing sinker. # CR Report of an 8-year-old. 39 # Gasoline sniffing Lead in gasoline absorbed through gasoline sniffing. CR Report of six of seven siblings aged 10 to 17 years. # 9, 24 # Lead bullet Lead absorbed from a retained bullet. # CR Report of one adult and review of 18 other cases including seven children under 2 years old. # 23, 32 Lead pellets Ingestion of lead pellets from pellet gun. CR Report of a 6-year-old child. 45 # Lead shot and toy (boat keel) Lead shot used in a toy boat keel that was eaten by a child. # CR Report of a 4-year-old child. 28 # Newsprint fireplace log Lead inhaled during burning of a log made from old newsprint.	None	None
4d037350a7cfdbe418604ce89aba1c906ecd8961	cdc	None	# Changes in the Schedule for October 2006-September 2007 The 2006-2007 schedule differs from the previous schedule as follows: - The broken red line has been deleted on the age-based schedule (Figure 1). Vaccination of persons with specific risk factors is now shown only with purple bars. - Human papillomavirus (HPV) vaccine has been added to the age-based schedule, with a yellow bar indicating that the vaccine is recommended for women 60 years. - A new column has been added to the medical/other indications schedule (Figure 2) to clarify indications for hepatitis A and B vaccines. The indications "chronic liver disease" and "recipients of clotting factor concentrates" have been removed from the previous schedule's third and fifth columns, respectively, and combined into a new column. The column has a yellow bar for hepatitis A and B vaccines, clarifying that these vaccines are recommended for all persons with these medical indications. - HPV vaccine has been added to the medical/other indications schedule, with a yellow bar to indicate the vaccine is recommended for women aged <26 years with all indications except pregnancy. - Tdap was added to the medical/other indications schedule, with a hatched yellow bar to indicate that Tdap is a one-time, 1-dose recommendation for all indications except pregnancy. - The tetanus and diphtheria footnote (#1) has been reworded to reflect ACIP recommendations for use of Tdap. - A footnote (#2) has been added to reflect ACIP recommendations for HPV vaccination for all women aged <26 years. - The measles, mumps, and rubella (MMR) footnote (#3) has been reworded to reflect ACIP recommendations to administer a second dose of mumps vaccine to adults in certain age groups and with certain risk factors. - The varicella footnote (#4) has been reworded in accordance with ACIP recommendations for administering a routine second dose for all adults without evidence of immunity. The footnote also has been revised to reflect the new definition of immunity to varicella. - The influenza footnote (#5) has been revised to reflect recent ACIP recommendations to vaccinate close contacts of children aged 0-59 months rather than 0-23 months (1). Recommended if some other risk factor is (e.g., on the basis of medical, occupational, lifestyle, or other indications) present who are sexually active should still be vaccinated. Sexually active women who have not been infected with any of the HPV vaccine types receive the full benefit of the vaccination. Vaccination is less beneficial for women who have already been infected with one or more of the four HPV vaccine types. A complete series consists of 3 doses. The second dose should be administered 2 months after the first dose; the third dose should be administered 6 months after the first dose. Vaccination is not recommended during pregnancy. If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. # Measles, mumps, rubella (MMR) vaccination. Measles component: adults born before 1957 can be considered immune to measles. Adults born during or after 1957 should receive >1 dose of MMR unless they have a medical contraindication, documentation of >1 dose, history of measles based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) have been recently exposed to measles or in an outbreak setting; 2) have been previously vaccinated with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963-1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Withhold MMR or other measles-containing vaccines from HIV-infected persons with severe immunosuppression. Mumps component: adults born before 1957 can generally be considered immune to mumps. Adults born during or after 1957 should receive 1 dose of MMR unless they have a medical contraindication, history of mumps based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) are in an age group that is affected during a mumps outbreak; 2) are students in postsecondary educational institutions; 3) work in a healthcare facility; or 4) plan to travel internationally. For unvaccinated healthcare workers born before 1957 who do not have other evidence of Q-3 mumps immunity, consider giving 1 dose on a routine basis and strongly consider giving a second dose during an outbreak. Rubella component: administer 1 dose of MMR vaccine to women whose rubella vaccination history is unreliable or who lack laboratory evidence of immunity. For women of childbearing age, regardless of birth year, routinely determine rubella immunity and counsel women regarding congenital rubella syndrome. Do not vaccinate women who are pregnant or who might become pregnant within 4 weeks of receiving vaccine. Women who do not have evidence of immunity should receive MMR vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. 4. Varicella vaccination. All adults without evidence of immunity to varicella should receive 2 doses of varicella vaccine. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care workers and family contacts of immunocompromised persons) or 2) are at high risk for exposure or transmission (e.g., teachers of young children; child care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; non-pregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care workers and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or presenting with an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on health-care provider diagnosis; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Do not vaccinate women who are pregnant or might become pregnant within 4 weeks of receiving the vaccine. Assess pregnant women for evidence of varicella immunity. Women who do not have evidence of immunity should receive dose 1 of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. Dose 2 should be administered 4-8 weeks after dose 1. ). 10. Meningococcal vaccination. Medical indications: adults with anatomic or functional asplenia, or terminal complement component deficiencies. Other indications: first-year college students living in dormitories; microbiologists who are routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season ), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Meningococcal conjugate vaccine is preferred for adults with any of the preceding indications who are aged <55 years, although meningococcal polysaccharide vaccine (MPSV4) is an acceptable alternative. Revaccination after 5 years might be indicated for adults previously vaccinated with MPSV4 who remain at high risk for infection (e.g., persons residing in areas in which disease is epidemic). 11. Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used. Hib conjugate vaccines are licensed for children aged 6 weeks-71 months. No efficacy data are available on which to base a recommendation concerning use of Hib vaccine for older children and adults with the chronic conditions associated with an increased risk for Hib disease. However, studies suggest good immunogenicity in patients who have sickle cell disease, leukemia, or HIV infection or who have had splenectomies; administering vaccine to these patients is not contraindicated. # FIGURE 2. Recommended adult immunization schedule, by vaccine and medical and other indications - This schedule indicates the recommended age groups and medical indications for routine administration of currently licensed vaccines for persons aged >19 years, as of October 1, 2006. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or that are issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (). Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at or by telephone, 800-822-7967. Information on how to file a Vaccine Injury Compensation Program claim is available at or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005; telephone, 202-357-6400. Additional information about the vaccines in this schedule and contraindications for vaccination is also available at or from the CDC-INFO Contact Center at 800-CDC-INFO (800-232-4636) in English and Spanish, 24 hours a day, 7 days a week.	# Changes in the Schedule for October 2006-September 2007 The 2006-2007 schedule differs from the previous schedule as follows: • The broken red line has been deleted on the age-based schedule (Figure 1). Vaccination of persons with specific risk factors is now shown only with purple bars. • Human papillomavirus (HPV) vaccine has been added to the age-based schedule, with a yellow bar indicating that the vaccine is recommended for women <26 years. • Tetanus, diphtheria, and acellular pertussis (Tdap) vaccine has been added to the age-based schedule, with a hatched yellow bar indicating that Tdap is a one-time, 1-dose recommendation for persons <64 years. • The purple bar for varicella vaccine has been shortened in anticipation of the recommendation for the use of zoster vaccine in persons aged >60 years. • A new column has been added to the medical/other indications schedule (Figure 2) to clarify indications for hepatitis A and B vaccines. The indications "chronic liver disease" and "recipients of clotting factor concentrates" have been removed from the previous schedule's third and fifth columns, respectively, and combined into a new column. The column has a yellow bar for hepatitis A and B vaccines, clarifying that these vaccines are recommended for all persons with these medical indications. • HPV vaccine has been added to the medical/other indications schedule, with a yellow bar to indicate the vaccine is recommended for women aged <26 years with all indications except pregnancy. • Tdap was added to the medical/other indications schedule, with a hatched yellow bar to indicate that Tdap is a one-time, 1-dose recommendation for all indications except pregnancy. • The tetanus and diphtheria footnote (#1) has been reworded to reflect ACIP recommendations for use of Tdap. • A footnote (#2) has been added to reflect ACIP recommendations for HPV vaccination for all women aged <26 years. • The measles, mumps, and rubella (MMR) footnote (#3) has been reworded to reflect ACIP recommendations to administer a second dose of mumps vaccine to adults in certain age groups and with certain risk factors. • The varicella footnote (#4) has been reworded in accordance with ACIP recommendations for administering a routine second dose for all adults without evidence of immunity. The footnote also has been revised to reflect the new definition of immunity to varicella. • The influenza footnote (#5) has been revised to reflect recent ACIP recommendations to vaccinate close contacts of children aged 0-59 months rather than 0-23 months (1). Recommended if some other risk factor is (e.g., on the basis of medical, occupational, lifestyle, or other indications) present who are sexually active should still be vaccinated. Sexually active women who have not been infected with any of the HPV vaccine types receive the full benefit of the vaccination. Vaccination is less beneficial for women who have already been infected with one or more of the four HPV vaccine types. A complete series consists of 3 doses. The second dose should be administered 2 months after the first dose; the third dose should be administered 6 months after the first dose. Vaccination is not recommended during pregnancy. If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. # Measles, mumps, rubella (MMR) vaccination. Measles component: adults born before 1957 can be considered immune to measles. Adults born during or after 1957 should receive >1 dose of MMR unless they have a medical contraindication, documentation of >1 dose, history of measles based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) have been recently exposed to measles or in an outbreak setting; 2) have been previously vaccinated with killed measles vaccine; 3) have been vaccinated with an unknown type of measles vaccine during 1963-1967; 4) are students in postsecondary educational institutions; 5) work in a health-care facility; or 6) plan to travel internationally. Withhold MMR or other measles-containing vaccines from HIV-infected persons with severe immunosuppression. Mumps component: adults born before 1957 can generally be considered immune to mumps. Adults born during or after 1957 should receive 1 dose of MMR unless they have a medical contraindication, history of mumps based on health-care provider diagnosis, or laboratory evidence of immunity. A second dose of MMR is recommended for adults who 1) are in an age group that is affected during a mumps outbreak; 2) are students in postsecondary educational institutions; 3) work in a healthcare facility; or 4) plan to travel internationally. For unvaccinated healthcare workers born before 1957 who do not have other evidence of Q-3 mumps immunity, consider giving 1 dose on a routine basis and strongly consider giving a second dose during an outbreak. Rubella component: administer 1 dose of MMR vaccine to women whose rubella vaccination history is unreliable or who lack laboratory evidence of immunity. For women of childbearing age, regardless of birth year, routinely determine rubella immunity and counsel women regarding congenital rubella syndrome. Do not vaccinate women who are pregnant or who might become pregnant within 4 weeks of receiving vaccine. Women who do not have evidence of immunity should receive MMR vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. 4. Varicella vaccination. All adults without evidence of immunity to varicella should receive 2 doses of varicella vaccine. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care workers and family contacts of immunocompromised persons) or 2) are at high risk for exposure or transmission (e.g., teachers of young children; child care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; non-pregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care workers and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or presenting with an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on health-care provider diagnosis; or 5) laboratory evidence of immunity or laboratory confirmation of disease. Do not vaccinate women who are pregnant or might become pregnant within 4 weeks of receiving the vaccine. Assess pregnant women for evidence of varicella immunity. Women who do not have evidence of immunity should receive dose 1 of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. Dose 2 should be administered 4-8 weeks after dose 1. ). 10. Meningococcal vaccination. Medical indications: adults with anatomic or functional asplenia, or terminal complement component deficiencies. Other indications: first-year college students living in dormitories; microbiologists who are routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the "meningitis belt" of sub-Saharan Africa during the dry season [December-June]), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Meningococcal conjugate vaccine is preferred for adults with any of the preceding indications who are aged <55 years, although meningococcal polysaccharide vaccine (MPSV4) is an acceptable alternative. Revaccination after 5 years might be indicated for adults previously vaccinated with MPSV4 who remain at high risk for infection (e.g., persons residing in areas in which disease is epidemic). 11. Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used. Hib conjugate vaccines are licensed for children aged 6 weeks-71 months. No efficacy data are available on which to base a recommendation concerning use of Hib vaccine for older children and adults with the chronic conditions associated with an increased risk for Hib disease. However, studies suggest good immunogenicity in patients who have sickle cell disease, leukemia, or HIV infection or who have had splenectomies; administering vaccine to these patients is not contraindicated. # FIGURE 2. Recommended adult immunization schedule, by vaccine and medical and other indications - This schedule indicates the recommended age groups and medical indications for routine administration of currently licensed vaccines for persons aged >19 years, as of October 1, 2006. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or that are issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (http://www.cdc.gov/nip/publications/acip-list.htm). Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at http://www.vaers.hhs.gov or by telephone, 800-822-7967. Information on how to file a Vaccine Injury Compensation Program claim is available at http://www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005; telephone, 202-357-6400. Additional information about the vaccines in this schedule and contraindications for vaccination is also available at http://www.cdc.gov/nip or from the CDC-INFO Contact Center at 800-CDC-INFO (800-232-4636) in English and Spanish, 24 hours a day, 7 days a week.	None	None
7597ce2af1828847cf2118f0c73b1f539d90d280	cdc	None	Suspected cases of reportable vaccine-preventable diseases or outbreaks to the local or state health department y Clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System at www.vaers.hhs.gov or 800-822-7967 Download the CDC Vaccine Schedules App for providers at www.cdc.gov/vaccines/schedules/hcp/schedule-app.html.# Injury claims All vaccines included in the adult immunization schedule except pneumococcal 23-valent polysaccharide and zoster vaccines are covered by the Vaccine Injury Compensation Program. Information on how to file a vaccine injury claim is available at www.hrsa.gov/vaccinecompensation or 800-338-2382. # Questions or comments Contact www.cdc.gov/cdc-info or 800-CDC- , in English or Spanish, 8 a.m.-8 p.m. ET, Monday through Friday, excluding holidays. # Helpful information	Suspected cases of reportable vaccine-preventable diseases or outbreaks to the local or state health department y Clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System at www.vaers.hhs.gov or 800-822-7967 Download the CDC Vaccine Schedules App for providers at www.cdc.gov/vaccines/schedules/hcp/schedule-app.html.# Injury claims All vaccines included in the adult immunization schedule except pneumococcal 23-valent polysaccharide and zoster vaccines are covered by the Vaccine Injury Compensation Program. Information on how to file a vaccine injury claim is available at www.hrsa.gov/vaccinecompensation or 800-338-2382. # Questions or comments Contact www.cdc.gov/cdc-info or 800-CDC- , in English or Spanish, 8 a.m.-8 p.m. ET, Monday through Friday, excluding holidays. # Helpful information	None	None
a784ade11e3291a8f405d4ba2571f4dd64117c61	cdc	None	Much of the data on occupational exposure to cobalt have come from the tungsten carbide industry. McDermott , in 1971, found the average concentration of cobalt in 40 general air samples of seven tungsten carbide facilities to be below 0.1 mg/cu m (range, 0.005-0.15). About 70% of the 133 breathing zone samples were also less than 0.1 mg/cu m. Based on the data provided, however, mean concentrations in breathing zones of press operators and machine tool operators averaged 0.16 and 0.21 mg/cu m, respectively. A tungsten carbide facility reported that during 1977-78 the concentration of cobalt in worker breathing zones averaged 0.048 mg/cu m in the powder area, 0.033 mg/cu m in the pressing area, 0.019 mg/cu m in grinding, and 0.025 for general maintenance . The highest concentration measured was 0.17 mg/cu m and the lowest was 0.004 mg/cu m. A study of eight cemented carbide plants in Sweden revealed that exposure to cobalt varies considerably with job classification . Groups handling powder were most exposed, while press operators, shapers, dry grinders, wet grinders, face grinders, and inspection personnel received decreasing levels of exposure to cobalt (in that order). Some workers handling powder probably received short-term exposures in excess of 0.1 mg cobalt/cu m.# B ack grou nd R e s p i r a t o r y E f f e c t s E f f e c t s on t h e S k in C a r d ia c E f f e c t s E f f e c t s on B lo o d E f f e c t s on t h e T h y r o id C a r c i n o g e n i c i t y and M u t a g e n ic it y E f f e c t s on R e p r o d u c tio n O th er E f f e c t s D i s t r i b u t i o n and R e t e n t i o n EXTENT AND MEASUREMENT OF EXPOSURE # Work C lo t h in g and P r o t e c t i v e E qu ip m en t The u s e and p r o p e r c l e a n i n g o f a p p r o p r ia t e w ork c l o t h i n g i s r e q u ir e d t o p r e v e n t s k i n e f f e c t s and s e n s i t i z a t i o n . P r o t e c t i v e e q u ip m e n t t h a t i s a p p r o p r ia t e t o t h e i r p o t e n t i # S p ir o m e t r ic e x a m in a tio n t o d e t e c t r e s t r i c t i v e v e n t i l a t o r y im p a ir m e n t i s o n e p o s s i b i l i t y , b u t t h e r e s u l t s do n o t a g r e e t o t a l l y on t h e s e n s i t i v i t y o f t h i s t e s t . P e r h a p s much o f t h e c o n f l i c t i n g e v i d e n c e i s t h e r e s u l t o f t h e l e s s s o p h i s t i c a t e d eq u ip m e n t a v a i l a b l e t o t h e e a r l i e r i n v e s t i A recent study at a Swedish hard metal plant attributed four cases of allergic alveolitis to exposure to soluble cobalt dissolved in the coolant used for wet grinding . One worker showed only signs and symptoms of asthma, but the other three showed evidence of mild pulmonary fibrosis as well. All four had contact eczema and were sensitive to cobalt. Even though they ceased all exposure to cobalt, the four persons have continued to show abnormalities on their chest radiographs. # (c) Other Reports of Respiratory Disease in Workers Exposed to Cobalt Studies of the effects of cobalt exposure on workers not employed in the manufacture or use of hard metal are rare, but some indicate pulmonary disease in these workers. # At a Finnish metal refinery, one or two new cases of bronchial asthma had been diagnosed annually in a group of 230-240 cobalt workers . A cross-sectional study demonstrated a highly significant correlation between exposure to cobalt sulfate and asthma. In contrast, nonasthmatic cobalt workers at the same plant had no evidence of any excess of chronic bronchitis. Kochetkova described the death of a woman with a history of 7 years of exposure to metallic cobalt dust. The cause of death was cardiopulmonary insufficiency resulting from massive fibrosis. Levels of cobalt in the lung, liver, heart, ««id kidney tissue were described as markedly elevated. Her heart was enlarged, the liver and spleen were congested, and the cortical layer of the kidneys was swollen. In contrast, Cau et al did not find radiographic evidence of fibrotic damage to the lungs of seven workers employed as sifters of cobalt powder. The workers had been exposed from 2 to 5 years, and they complained of cough, exertional dyspnea, nasopharyngeal irritation, and digestive disorders; two subjects had polycythemia. The authors concluded that exposure to finely divided cobalt metal dust did not induce pulmonary damage. In light of the toxic signs described by the workers and the short duration of exposure, this conclusion seems inappropriate. # An extensive study of workers exposed to cobalt was reported by Verhamme in 1973. Medical examinations had been given to workers at a plant where cobalt oxides, powders, and salts were produced. Measurements of airborne cobalt were not reported, but the author believed that workers in the hydrometallurgic area had little or no dust exposure and that workers in the salts, oxides, and finished powders production areas were the most exposed groups. The finished powders had an average diameter of less than 1.4 jum, and To investigate the suggestion of Bruckner that pulmonary reactions to cobalt may be mediated through a hypersensitivity mechanism, Kerfoot et al first exposed the experimental animals 6 hours a day for 5 days. After a 10-day lapse, the animals were reexposed 6 hours daily, 5 days a week for 3 months. All animals appeared normal until the 4th week of exposure, after which time the animals from both cobalt groups became lethargic. Some animals appeared to be wheezing during exposure; this was confirmed by auscultation. Postexposure pulmonary function tests showed a significant reduction in mean tidal volume, mean total compliance, and mean specific compliance in both cobalt-exposed groups . The authors interpreted change in compliance as demonstrating functional lung impairment. This change was reversed in animals examined 2 months after the cobalt exposure ended. Serial radiographs conducted on all animals showed no evidence of diffuse pulmonary disease . The animals were examined grossly and by light microscopy at necropsy, and the lungs, heart, liver, and kidneys did not show any persistent or significant abnormalities. There was no evidence of cobalt in any lung tissue examined. Electron microscopic examination of lung biopsy tissue taken at the end of exposure revealed masses of collagen, elastic tissue, and fibroblasts in some of the tissues. However, no quantitative analysis was presented, nor was there mention of the methodology used in selecting tissue sites for examinations. The greatest changes were observed in the high-concentration cobalt exposure group, with the fewest changes being observed in controls. In a Soviet study, male albino rats received exposures to aerosols of metallic cobalt continuously (24 hours a day, 7 days a week) for 3 months . There apparently was a concurrent control group, but the reports did not contain important details such as the number of animals exposed or tables of results presenting actual data. Chronic inhalation of cobalt at 0.5 mg/cu m was said to be irritating to the lungs . The animals exposed to cobalt at 0.05 and 0.005 mg/cu m were described as having changes similar to, but less pronounced than, the changes in animals exposed at 0.5 mg/cu m. The lowest concentration (0.001 mg/cu m) produced what was described only as a weak general toxic effect. # Microscopic examination of lung tissue from animals exposed at the highest concentration of 0.5 mg/cu m revealed accumulations of macrophages in the alveoli . Interalveolar septa were consolidated in several areas of the lung. The severity of these changes reportedly was related to the exposure concentration. The lungs of animals exposed at 0.001 mg/cu m were described as similar to those of controls. While information in this report is not completely satisfactory, effects such as consolidation of the alveolar septa are indicative of a prefibrotic condition. Wehner et al exposed 2-month-old Syrian golden hamsters to cobaltous oxide aerosols at 10 mg/cu m for their lifespans. The animals were exposed for 7 hours daily for 5 days a week to aerosols with a median diameter of 0.45 (an. Particulate material accumulated in alveolar macrophages and became denser as exposure continued. Emphysema became apparent. The extent of the changes became more severe as exposure time increased, and hyperplasia and hypertrophy of alveolar lining cells also appeared. Macrophages, frequently containing particulate matter, increased in number throughout the lung, and numerous focal accumulations of these cells could be found. Proliferative changes involving the epithelial components of bronchi and bronchioles became detectable early during exposure and increased in severity with exposure time. # Laryngeal lesions occurred in five animals (10%) during the study. The lifetime exposure of hamsters to cobaltous oxide clearly resulted in pneumoconiosis, but it did not significantly shorten their lives. From the experimental studies in animals, the ability of some cobalt compounds to cause pulmonary fibrosis is evident. However, the information is insufficient to determine what effect, if any, exposure to other substances often present in cemented tungsten carbide may have on the development of hard metal disease. Thus, the possibility must be considered that adverse effects in workers exposed to cobalt at the 0.06-0.2 mg/cu m range were aggravated by exposure to mixtures. However, the degree of worker exposure to cobalt is clearly related to the number of signs and symptoms observed in workers. Thus, decreasing exposure to cobalt should reduce the risk of adverse health effects. For cobalt metal, results in animals indicate that worker exposure should be limited as much as possible, and that in no case should the present Federal limit be exceeded. Similar information is not available for any other cobalt compound, including those in commercial use. # Effects on the Skin The incidence of sensitivity to cobalt in the general population appears to be low; in a small group ( 41 When all available data are combined, approximately 5% of the persons studied were cobalt-sensitive; 82% of these had combined metal sensitivities. All three metals are prevalent in the general environment, which suggests that individuals with cobalt sensitivity also have had contact with nickel and chromium. Their responses thus could represent independent sensitization reactions, so that cross-sensitivity is not necessarily implied. The mechanism of the allergic response to cobalt after dermal contact is unknown. Haxthausen contended that about 90% of the cobalt is absorbed from the skin following intradermal administration before any allergic reaction becomes visible. Norgaard , however, reported that cobalt is not absorbed through intact skin when applied to the forearm as a 0.3% or 5% solution. This same study reported systemic absorption of cobalt in solutions applied to the depilated skin of rabbits and guinea pigs . Another investigative group also observed systemic absorption when solutions of cobaltous chloride were placed on the clipped backs of guinea pigs . From this Information, NIOSH concludes that the risk of systemic poisoning from dermal absorption of soluble salts of cobalt is minimal for skin contact under normal working conditions. Abraded skin should be adequately protected to prevent contamination with cobalt compounds so that systemic absorption will not occur. # Very few reports on skin diseases in workers who No information is available to judge the effects of many cobalt compounds. Some organocobalt complexes are uncharged and relatively apolar, which would indicate that they probably can be absorbed dermally at least as effectively as the inorganic salts. At least some of these complexes may be stable compounds in body fluids, so that their toxic effects could differ from the simple salts. The authors considered the disease to be of occupational origin and attributable to cobalt. However, data to support this conclusion were not provided in the report. # Cardiac Effects Alexandersson and Atterhog examined dry and wet grinders exposed to cobalt at 0.01 mg/cu m and powder handlers exposed at 0.06 mg/cu m. No ECG changes were observed in dry grinders or powder handlers, even though the powder handlers showed evidence of impaired pulmonary function. The ECG's of wet grinders were abnormal and showed a high incidence of ectopic (premature) heartbeats. However, the authors believed that the ECG changes were related to exposure to cutting oils rather than cobalt. Only one study in animals has examined the effects on the heart of cobalt exposure similar to that encountered in the workplace. In the study on miniature swine exposed to cobalt metal dust at 0.1 or 1 mg/cu m, Kerfoot and coworkers observed abnormalities in ECG's taken at the end of the 3-month exposure period. These alterations were interpreted by the authors to indicate a decrease in the strength of ventricular contraction and repolarization abnormalities. Sufficient evidence exists to suggest that both cobalt metal and cobalt salts can produce cardiac changes, but apparently only at high doses. It should be noted that the amount of cobalt ingested daily by persons who consumed 6 liters a day of beer was about 5-10 mg, much higher than the amount inhaled by a worker breathing 10-15 cu m of air in a day at the current Federal limit of 0.1 mg/cu m. The question of whether changes such as those seen in the miniature swine could result in significant problems over a long period of exposure in especially susceptible individuals, such as those with existing heart disease and, possibly, persons who consume alcohol on a regular basis, needs to be examined. # Effects on Blood Cobalt-induced polycythemia is a well known effect. This property of cobalt has been exploited therapeutically in the treatment of refractory anemia . The information collected for this review, however, revealed that other lesser known effects may occur at concentrations below those needed to produce polycythemia. The information available, although often incomplete, is presented below. # The polycythemic effects of cobalt have been observed not only in patients but also in controlled experiments in persons with normal blood counts and in animals. Volunteers receiving oral doses of cobaltous chloride ranging from 100 to 1,200 mg daily for 1-12 weeks or 120-150 mg daily for 1-3 weeks experienced an increase in RBC and Hb levels. Numerous studies in animals administered cobaltous chloride at high dosage levels for as long as 16 weeks either orally, or by subcutaneous (sc) or ip injection, also reported slight to substantial increases in RBC or Hb. One study in mice demonstrated an increase in RBC's subsequent to ip injection of cobaltous nitrate . However, inhalation studies in animals exposed to cobalt metal provide little evidence to support the contention that polycythemia would be expected in workers exposed to cobalt at low concentrations. Similar studies on cobalt salts have not been conducted. Since the effects of cobalt on the blood would be expected to depend on its ability to concentrate at certain critical sites, cobalt salts might demonstrate effects at levels differing from cobalt metal. However, the mechanisms responsible for the changes in blood that are induced by cobalt are not known. The information available suggests to NIOSH that the effects of cobalt on the blood are multiple and poorly understood. # While a polycythemic effect is clearly demonstrated in the reports Polycythemia is clearly one manifestation of exposure to cobalt metal or cobalt salts, and increases in erythropoietin could be a factor in producing this effect. The airborne concentrations of cobalt at which this polycythemic effect would be significant are poorly documented, but they appear to be well above the Federal standard for cobalt metal. Information is not adequate to judge whether this airborne concentration, 0.1 mg/cu m, would be adequate to prevent polycythemia from other cobalt compounds. Because RBC's have been found to decrease in exposed workers only at very high airborne concentrations of cobalt, this effect is judged insignificant if exposure is through inhalation. The role of cobalt in retarding blood clot formation is not well documented, but preliminary evidence suggests that it could be highly significant. # Effects on the Thyroid The Placebo tablets were substituted for the cobalt preparation, and thyroid function returned to normal by 12 weeks. Numerous additional reports that followed now show that 2-10 mg cobalt (as chloride)/kg given orally each day for 2-4 months will induce goiter formation in a small percentage of persons . In all cases, the thyroid hyperplasi^ has been reduced or reversed after cobalt administration was stopped. Controlled clinical studies have also examined the effects of cobalt on the thyroid gland. In one study, 12 adults with normal thyroids were given 50 mg of cobaltous chloride orally three times a day for 2 weeks . # Radioactive iodine uptake was reduced in all but one person after the 1st week; by 2 weeks all uptake levels were near zero. The effect was reversible after cobalt administration ceased. In a separate study, the majority of individuals given cobaltous chloride either orally or by iv infusion also had decreased iodine uptake in the thyroid . In fact, cobaltous chloride has been tested as a treatment for hyperthyroidism. Pimentel-Malaussena et al observed that four of eight patients receiving 150-600 mg a day for up to 117 days responded with clinical improvement as manifested by reductions in tachycardia, metabolic rate, and uptake of radioactive iodine. Three of four, however, had thyroids of increased size, and the authors concluded that the action of cobalt was unpredictable. mg/cu m. This value is near the permissible exposure limit for cobalt metal fume and dust, and long-term effects at low levels have not been studied in humans for any cobalt compounds. This information suggests that alterations of thyroid function should be considered as a possible effect of workplace exposure to cobalt. # The results of studies in guinea pi # Carcinogenicity and Mutagenicity Fibrosis, and not carcinogenicity, has received most of the attention of the occupational health community concerned with cobalt. The many reports available concerning fibrosis would not be adequate to demonstrate any carcinogenic effect, because none are epidemiologic studies concerned with incidence rates. The three case reports describing the development of benign or malignant tumors in hard metal workers and two epidemiologic studies describing an increased risk of lung cancer in cobalt recovery areas of nickel refineries are not useful in demonstrating a possible carcinogenic effect of cobalt. Arsenic was also present in the air of some plants examined in the epidemiologic studies. Mixed exposures to substances known to be or suspected of carcinogenicity were involved in all cases. The case reports cannot distinguish between the role of occupational exposure and other factors, including normal incidence. Thus, information from human studies does not provide any answers about the possible carcinogenic potential of cobalt. The two studies conducted in animals by routes of administration most applicable to workplace exposure did not demonstrate a carcinogenic effect for cobalt . The incidence of tumor development was low and did not differ significantly from controls in male Syrian golden hamsters exposed for their life spans to aerosols of cobaltous oxide at 10 mg/cu m, 7 hours daily, 5 days a week . Many of these animals did develop fibrotic changes. Hamsters injected intratracheally once a week for 30 weeks with 4 mg of cobaltous cobaltic oxide (Co304) failed to develop a statistically significant excess of tumors compared with control animals . It should be noted, however, that the two tumors that developed in the 50 animals exposed to cobalt were alveolar in origin while the four tumors in controls were at sites unrelated to exposure. These studies provide little evidence to suggest that cobalt oxides are carcinogens, but no similar studies have been conducted in animals other than hamsters. The results of studies of the carcinogenic potential of cobaltous chloride are conflicting. Gunn et al reported that no tumors were observed for 10-16 months in Wistar rats given four simultaneous injections of cobaltous chloride (0.18 mg cobalt/site) into a vital organ (liver or kidney), a gland (salivary or ventral prostate), and two mesenchymal mesodermal structures (chest, interscapular area, thigh, or femur). Similarly, Shelley reported that no tumors were observed in 10 ICR mice given cobaltous chloride (3.5 mg cobalt) in the dorsal earlobe, although the 2-to 5-month observation period was relatively short. On the other hand, Shabaan et al found subcutaneous fibrosarcomas in 14 of 27 rats surviving 8-12 months following 10 injections of cobaltous chloride at 40 mg/kg into the central abdominal wall. Two tumors were at the injection site, and the remainder were at various distances from the abdominal region. Metastases were not found in any tumorbearing animal. This study provides evidence that cobaltous chloride could be a carcinogen, and it argues for the need to perform chronic testing of cobalt salts in animals by routes of exposure more applicable to the workplace. Information on cobalt is inadequate to conclude that cobalt is a carcinogen. The information is also Inadequate to conclude that cobalt is noncarcinogenic. # Several investigators have In fact, limited data provide suggestive evidence that at least some cobalt compounds may prove carcinogenic when subjected to long-term testing by currently accepted protocols. Until such testing is performed, no definitive guidelines can be given. Tumor induction at the injection site, however, would argue for the need to adequately clean any wound contaminated with cobalt. # Effects on Reproduction Whether exposure to a substance in the workplace can result in adverse effects on reproductive capacity or harm to the developing fetus is of grave concern to workers and to all persons responsible for the health of workers. The information available on cobalt is conflicting and insufficient to draw definite conclusions on the effects of cobalt on reproduction. Although this information dees not substantiate any effects, it is presented below. Studies in humans and animals This experiment is of questionable relevance because of the nonmammalian test system used. The literature describing the effects of cobalt on testicular function is characterized by disagreement among investigators. Hoey reported marked but reversible changes (including suppression of spermatogenesis, abnormal sperm, deformation of the epididymal tubules, and necrosis of the duct system) in rats administered cobaltous chloride by sc injection. Kamboj and Kar injected cobaltous nitrate sc in mice or intratesticularly in rats, and they found no microscopic damage to the testes or effects on spermatozoa. Niebroj injected cobaltous chloride ip, and considered the effects on the testes of these mice to be generally positive. # Other Effects There are numerous studies of additional toxic effects attributed to cobalt. Some, such as the acute lethality studies in animals, have little impact on the occupational environment since such exposure conditions are rarely, if ever, encountered. Some effects, such as increased levels of plasma lipids, have been observed in humans, but only rarely in anemic patients receiving cobalt . Some, such as experimental induction of epilepsy by implantation of cobalt in the brain of animals, appear irrelevant. Other effects, such as kidney and liver changes, may be relevant; but information on occupational exposure is quite limited. also described its long-term accumulation in bone. Considering these sites of deposition, it is not at all surprising that a fraction of the administered dose is retained for a long time. # Retention of cobalt oxides after inhalation has been examined in animals. Wehner and Craig reported that hamsters eliminated 90% of the total dose of cobaltous oxide, inhaled at 15.6 mg/cu m 7 hours a day for 2 days, within the subsequent 3 days (day 5 of experiment); however, the remainder was retained tenaciously in the body of the animal. Barnes et al administered respirable-sized particles of cobalt oxides by inhalation to dogs. In 10 days, only 10% of the cobaltous oxide was retained, compared with 60% of the cobaltous cobaltic oxide. Cobaltous cobaltic oxide showed accumulation in the lymph nodes of the lung, a typical reaction of tissueinsoluble substances, while substantially more cobaltous oxide was found in the tissues and blood. The information on distribution and retention of cobalt is typical of substances showing moderate to substantial tissue solubility. Information on the chloride salt is particularly revealing. It appears that enough of the salts can be absorbed through the gastrointestinal tract to warrant good sanitation and personal hygiene by workers so that they can avoid absorbing significant amounts of cobalt through ingestion. The long-term accumulation of cobalt in the liver may also be relevant. # I I I . EXTENT AND MEASUREMENT OF EXPOSURE # Uses of Cobalt Cobalt (atomic number 27, atomic weight 58.93) Is a transition element located between iron and nickel in group VIII of the periodic table. The metallic form is silver gray to bluish white and is magnetic. There are three oxides of cobalt: cobaltous oxide, CoO; cobaltic oxide, Co203; and cobaltous cobaltic oxide, Co304. Ionic cobalt can exist in either a divalent or a trivalent form. The cobaltous ion can form numerous inorganic and organic salts , and cobalt can form complexes with amines, nitrites, and cyanides Cobalt alloyed with chromium and nickel is used in heat-resistant gas turbine blades and jet engine parts. Hard metal is found in high-speed cutting tools, armaments, masonry drills and cutters, high-speed dental drills, and tire studs. This property also leads to its somewhat unusual use as "invisible" ink. Cobalt pigments are very important in the ceramic and pottery industry. A wide variety of pigments in differing shades and colors contain cobalt, often as mixtures with other metal salts. Black cobalt oxide paint is of particular value because of its heat and wear resistance. A mixture of cobalt oxide and cobalt aluminate forms a blue color. Cobalt blue is sometimes added to glass to detint the yellowish color that occurs if iron is present. Small amounts of cobalt salts are also used as boiler water scavengers, in magnetic tapes, and in steel-belted tires. # Table III-l lists some occupations in which there is potential exposure to cobalt compounds . The amount of exposure to cobalt that workers actually receive in these occupations probably varies widely. Large amounts of cobalt are used in some industries, such as cobalt salts manufacturing, the cemented carbide industry, and the manufacture of cobalt-containing alloys. Many users of these products handle extremely small quantities of cobalt. Others perform cutting, grinding, or welding operations on products, and the potential for worker exposure to cobalt is significant. Exposure of painters to cobalt driers is probably minimal; exposure of spray painters to cobalt pigments is not. Also, Janssens et al reported that air samples collected in Belgium, apparently near a cobalt-manufacturing plant, showed levels of 0.4-7.3 ng/cu m (mean, 2.8). All of these levels in ambient air are far below the Federal standard of 0.1 mg/cu m for cobalt metal fume and dust. # Environmental Data # Cobalt is present in low concentrations # TABLE I I I -l At an operation where tungsten carbide tools containing 6 .0-8.5% cobalt were sharpened by wet grinding, general air samples were well below 0.1 # mg/cu m . Two-thirds of the breathing zone samples, however, were above 0.1 mg/cu m of cobalt (range, 0.04-0.93 mg/cu m ) . Full-shift TWA exposures were measured on a number of the grinders. Two-thirds of those values were above 0.1 mg/cu m with a range of 0.03-0.56 mg/cu m and a mean of 0.24 mg/cu m. A US nickel refinery provided cobalt dust exposure data collected in June 1978 (B Roy, written communication, September 1978). Average concentrations of cobalt were generally low, ranging from less than 0.002 to 0.099 mg/cu m, except for two tower cleanup workers whose exposures averaged 0.156 mg/cu m. Within the occupational groups, the concentration ranges were sometimes quite variable; for example, the exposure of one cobalt operator was 0.313 mg/cu m, and for a supervisor it was 0.148 mg/cu m, even though averages for all 13 workers in these groups were substantially lower. Where the dried cakes were broken into fine powders, cobalt concentrations varied, ranging from not detectable to 0.2 mg/cu m. On the average, the drum-loading operations were the dustiest, but the cobalt concentrations, 0.04-0.5 mg/cu m, varied widely. Other operations in the plant were contained and well ventilated so that the concentration of cobalt in those areas would be expected to be low. III-2 These data covered 1970 to 1974. Exposures to cobalt on the average were substantially less than 0.1 mg/cu m, but they were quite variable, even for the same areas. For example, exposure to cobalt in the breathing zones of workers in the melt shops were 0 .001-1.43 mg/cu m. # An environmental survey conducted in May 1978 at a US jet aircraft engine assembly plant provided exposure data for three occupational groups (Table In the powder products area, six samples ranged from 0.09 to 9.7 mg/cu m. General area samples tended to show a lower cobalt concentration than breathing zone samples. Almost no published data on exposure to cobalt in welding and thermal cutting operations were found. Hewitt measured cobalt and other metallic contaminants in a number of welding operations in well ventilated areas. Airborne cobalt concentrations were all 0.1-0.4 jug/cu m. Cobaltcontaining welding rods can contain other metals such as nickel or chromium that can also be hazardous if they become airborne. Eight plant site visits were conducted to collect information for this report . The number of production workers ranged from less than 50 to 25,000. The three largest plants (at least 800 production workers) all had formal plans for sampling and inhouse capabilities for analysis. Two other plants sampled for cobalt on an irregular basis, and one other sampled for nuisance dust only. The two plants with less than 50 production workers had no program for air monitoring. These plants had relied on corporate headquarters, insurance carriers, and contractors for air monitoring where in-house capability was unavailable. One disadvantage of electrostatic precipitators is that actual worker exposure may not be estimated as closely as is possible with personal sampling. # S am pling M ethods # Analytical Methods Many methods have been developed for the analysis of cobalt samples collected from air. Among these, colorimetric procedures can be satisfactory provided that other metals do not interfere with the results. Color reagents that have been used include nitroso R salt (sodium nitroso-2-naphthol-3,6disulfonate) and sodium thiocyanate . Although these methods are tedious and require skill, they can give satisfactory results. # Emission spectrometric methods have been used frequently to analyze airborne particulate material. Because of its sensitivity, the emission spectrograph has been used to measure pollutants in the community atmosphere , but this technique is also useful to determine concentrations of airborne cobalt in the workplace. One investigator, using a specialized electrode for air sampling, was able to perform direct analysis of samples using the Although this method is sensitive and does not destroy the sample, the requirements for elaborate equipment, the safety precautions necessary for use of an irradiating beam or radioactive sources, and the relatively small thermal neutron cross section of cobalt make NAA less practical than AAS for routine use. # Another technique for analysis of airborne cobalt use is the x-ray fluorescence method . The fluorescence method resembles the neutron activation procedure in specificity, sensitivity, and ability to analyze a single sample for a number of elements. It is nondestructive and requires a minimum of sample handling. Results can be obtained quite rapidly for cobalt as well as for a number of other metals , and the x-ray fluorescence method can be an acceptable alternative to M S when analyzing cobalt. In summary, the collection of air samples on membrane filters and the analysis of those samples by AAS, as described in the NIOSH P&CAM 173, are the methods of choice for monitoring of workers' exposure to cobalt (see the Appendix). Other methods, at least as sensitive and precise, are also acceptable. # IV. CONTROL OF EXPOSURE Over a million workers have some potential for exposure to at least one cobalt-containing compound in the course of their employment. Many receive little exposure because they work with very small amounts of cobalt on an intermittent basis. Others, however, work with large amounts of cobalt regularly. These workers can become exposed through inhalation, dermal contact, or ingestion. In some operations, exposure to cobalt is limited because of the use of extensive engineering controls. Other operations, however, require manual handling of materials containing cobalt. Local exhaust ventilation and good work practices can minimize exposure to cobalt in such circumstances. In all cases, ingestion of cobalt is easily prevented by the use of good personal hygiene in combination with the maintenance of a clean worksite. Workers who maintain or repair equipment, enter confined spaces such as tanks or vessels, or are involved in emergencies or other nonroutine situations have an especially high risk of exposure to cobalt. These workers should be trained to recognize hazards, and in some circumstances they may require special protective equipment or clothing to decrease exposure. # Information on typical industrial practices for the control of cobalt came from several site visits to plants manufacturing or using cobalt-containing products. These plants included a refinery, an alloy producer, cemented tungsten carbide producers, and cobalt salt manufacturers. Other sites visited included a welding-rod maker and an aircraft engine manufacturing facility. There is some published information on control of cobalt , but much of the following information came from plant visits . # Engineering Controls Well-maintained closed systems and the prevention of dust generation, when compatible with the operation involved, are the most effective methods of limiting worker exposure. When a closed system is used, it must prevent or minimize the release of materials. When closed systems are not practical, worker exposure can often be reduced by process equipment modification, the use of control rooms, or local exhaust ventilation. # Properly designed and maintained ventilation systems, including local exhaust systems, can prevent the accumulation of airborne cobalt-containing dusts and fumes. Local exhaust systems were in frequent use in the plants visited. Examples include the use of glove boxes for welding, exhaust hoods provided to individuals using hand-held buffers and grinders, local exhaust on the other grinding machines and on press machines, and dust-collecting hoses for packaging operations . In addition, a ventilation system is desirable as a standby, should a closed system fail. Where exhaust ventilation is required, adequate makeup air, conditioned as necessary for worker comfort, must be provided. Ventilation requirements for grinding, buffing, and polishing operations were described in a NIOSH research report . Dry grinding equipment was classified as pedestal type, abrasive cutoff tools, surface-type disc grinders, portable grinders and cutoff machines, and other grinding machines according to ventilation system design requirements. Polishing (coated abrasive) equipment was classified as wheel and drum type, disc type, belt polishers, and complex machines. Buffing (loose abrasive) equipment was classified as pedestal type, portable, or multiple buffer machines. For grinding and abrasive polishing, most of the equipment-generated particulate material was thought to be from the workplace. This would be so even for hard metal if a diamond wheel is used. Much more dust was contributed by the abrasive and the abrasive support materials in buffing. The report, in noting that the TLV for cobalt is very much less than for nuisance dust, considered that adequate control of cobalt is not likely to be possible with standard ventilation systems. Totally enclosed ventilation systems and respiratory protection for personnel within the enclosure were recommended. However, many alloys containing only a small percentage of cobalt are used, and restrictions could be less severe in such cases. Engineering controls for most buffing and grinding machines are built to conform to the configuration of the equipment and the materials being handled. Specific guidelines, therefore, are difficult to propose. This can be exceedingly dusty, especially with fine powders. Hoods that prevent the powder from dispersing into the work area and do not interfere with the weighing procedure are difficult, but not impossible, to design. Design requirements, however, are quite dependent on the size and shape of the container. In most of the plants visited, engineering controls in use were generally not specific to cobalt alone, but rather to the entire process . For example, emissions from furnaces preparing specialty steels must be controlled for all the metals in the melt. Cobalt may not be the limiting factor in control of exposure in such situations. Ball mills used in the cemented carbide industry use solvents, such as acetone, and these emissions must be controlled. Several plants used cobalt in foundry operations where silica and other substances used in the molds dictated many of the control measures used. In milling, hot and cold rolling, and other operations, noise was often a factor in the use of control booths and of other means of control that often helped to lower exposure to cobalt. In buffing, exposure to the abrasive support material must be controlled as must oil mists generated in wet grinding. In manufacture of salts, extensive use of strong acids led to requirements for emission control and cleanup procedures that also limited exposure to cobalt. These overall requirements must be considered in designing engineering controls for cobalt. To ensure effective operation of ventilation systems, trained personnel should conduct a regular monitoring program. Routine inspection should include face velocity measurements of the collecting hood, examination of the air mover and collection or dispersion system, and measurements of atmospheric concentrations of cobalt in the work environment. Where appropriate, the use of continuous airflow indicators, such as water or oil manometers properly mounted at strategic locations and marked to indicate acceptable air flow, should be considered. Any changes in the work operation, process, or equipment that may affect the ventilation system must be evaluated promptly to ensure that control measures adequately protect workers. All exhaust emissions from ventilation systems should be passed through a system designed to minimize the release or recirculation of raw materials, cobalt, and wastes into the occupational and community environments. # Work Practices Ultimately, any program of worker protection must consider the prevention of pulmonary fibrosis, which has been clearly demonstrated to result from excessive exposure to cobalt metal and oxides. Dermatitis and an occasional case of extreme pulmonary hypersensitivity to cobalt, however, are much more frequently encountered problems in the day-to-day operation of health care for cobalt workers. These problems cannot be neglected in establishing an effective program for worker protection. Employers should institute programs that emphasize good personal hygiene to prevent skin and respiratory irritation caused by cobalt-containing dusts. After working with cobalt products, workers should thoroughly wash their hands and face before drinking, eating, or smoking. If skin contact with cobalt solutions occurs, the worker should wash the affected skin promptly. The employer should provide showers if workers have substantial contact with cobalt. These workers should be encouraged to wash or shower after each workshift. Employers should prohibit smoking or carrying of tobacco products in work areas because of possible cobalt contamination. For the same reason, employers should prohibit eating, food handling, or food storage within the work area. To maintain a safe workplace, employers must identify the many physical hazards involved in handling cobalt and take measures to eliminate them. In particular, several potentially hazardous situations were observed in plant site visits . These included sharp edges on some rolled alloys and rolled-alloy scraps, the need to lift heavy containers of cobalt, and press operators who placed their fingers under moving machinery to remove parts. Rolled alloy workers can avoid finger cuts by wearing gloves. Trained workers who follow proper lifting techniques could avoid back injuries when they lift dense material such as cobalt metal. Protective clothing must not increase the potential for injury of workers who handle cobalt when working with machinery with moving parts. In storage, cleanup of spills, and emergencies involving fires, employers must be aware of the properties of individual cobalt compounds to ensure proper planning. Finely divided cobalt will ignite, but its fire and explosion hazard is very weak [ # General plant maintenance must be conducted regularly to prevent cobaltcontaining dusts from accumulating in work areas. Cleaning should be performed with vacuum pickup or wet mopping to minimize the amount of dust dispersed into the air. A decontamination room should be available for cleaning equipment that is to receive major overhaul or maintenance. Spills of cobalt-containing material should be promptly cleaned up to minimize inhalation or dermal contact. Liquid material spills can be copiously flushed with water and channeled to a treatment system or holding tank for reclamation or proper disposal. Spills of dry material can be removed by vacuuming or wet mopping. Some spills can be removed by hosing, first with a mist of water to dampen the spilled material and then with a more forceful stream that flushes it into a holding tank or other facility for handling contaminated water. Work surfaces or contaminated clothing should never be cleaned by dry sweeping or blowing with pressurized hoses. Recovery systems used to reclaim waste metals should comply with Federal, state, and local regulations. All waste material generated in the handling of cobalt-containing substances should be disposed of in compliance with Federal, state, and local regulations. Maintenance and repair workers face special problems regarding their potential exposure. The very circumstances that require the maintenance or repair work and dictate the work conditions will often preclude use of some control procedures. Consequently, very careful supervisory control must be exercised over such activities. These workers must wear appropriate protective equipment and clothing, and they must be trained to recognize and control the hazards they face. Special precautions are necessary when workers must enter tanks or vessels, such as reaction vessels containing cobalt catalysts or vessels used to prepare cobalt salts . Before any worker enters a vessel, all sources for transferring cobalt and other materials into or out ot the vessel must be blanked to prevent their entry. The vessel interior must then be washed with water and purged with air. After purging the vessel's interior, trained personnel should test the vessel's atmosphere with suitable instruments to ensure that no hazards from fire, explosion, oxygen deficiency, or dust inhalation exist. No one should enter a tank or vessel without first being equipped with an appropriate respirator and a secured lifeline or harness. Mechanical ventilation should be provided continuously when workers are inside the tank. At least one other worker similarly equipped with respiratory protection, lifeline, and harness should watch at all times from outside the vessel. Workers inside the tank must be able to communicate with those persons outside. Other workers must be available to assist in an emergency. Flame-or spark-generating operations, such as welding or cutting, should be performed only when an authorized representative of the employer has signed a permit based on a finding that all necessary safety precautions have been taken. Gloves and protective sleeves should be used in manual transfer operations, together with a face shield (if respiratory protection is not needed) to keep soiled fingers from touching the face. Employers should provide change rooms and dual lockers so workers can remove soiled coveralls during breaks. # Work Clothing and Protective Work clothing should be worn for only a single day work period, then collected directly into a designated and labeled container, and laundered by a management-selected laundry service. This is encouraged to prevent the spread of contamination into the homes of workers. Eye irritation has apparently not been a problem for workers handling cobalt products; however, in operations that do scatter fine particles in the air, such as grinding, eye protection must be used that complies with 29 CFR 1910.133. Workers who are especially sensitive to cobalt or who handle solutions of cobalt in such a manner that cobalt can splash on the skin or into the eyes must wear protective suits, or face shields with goggles as appropriate, to prevent appreciable skin and eye contact. Emergency eyewashing facilities, where needed, must be readily available to affected workers. Workers experiencing skin irritation should see a physician promptly. # Respirators are not a substitute for proper engineering controls. Respirators may be needed, however, for nonroutine maintenance work, entry into confined spaces, pending installation of adequate controls, and in emergencies where the concentration of cobalt could be unknown or excessive. In these situations, employers must provide workers with respirators, and establish a respiratory protective program meeting the requirements of 29 CFR 1910.134. These programs should emphasize the importance of having clean, well-maintained, well-fitted respirators for use in unusual circumstances and emergencies. Workers must be aware of the need to guard against contamination of the interior of the facepiece. Table IV- # Effective Planning No program to minimize worker exposure to cobalt can be effective unless adequate attention has been given to problems before they arise. When a new facility is to be constructed, persons knowledgeable in occupational safety and health and industrial hygiene engineering should review plans both in the design phase and during construction. They should ensure that working areas and engineering controls are designed so that spills and airborne cobalt will be minimized when the plant is in operation. # For plants already in operation, management should review materialhandling operations, maintenance and repair procedures, and process operations periodically. This review should identify areas and job locations where workers might be exposed to cobalt or cobalt-containing waste products, either through inhalation or direct contact with the skin or eyes. If work practices or engineering controls in any area are no longer adequate, management should modify them promptly. Contingency planning for emergencies, inadvertent release of materials, and breakdown of facilities is vital. These plans should be developed for each department as well as plantwide. They should outline where appropriate equipment and trained personnel are located, and should be written, well understood by workers, and updated as required. Each plant should also be prepared to assess the impact or hazards of a specific spill or release of material should it reach a waterway or create a cloud. Supervisors should have information available, including lists of appropriate names and telephone numbers, for reporting emergencies. In addition to internal reporting procedures, plant management should clearly understand what situations require recordkeeping or external reporting to OSHA, the Environmental Protection Agency (EPA), and any appropriate state agencies. # Worker Education and Monitoring A fundamental part of any program designed to provide a more healthful workplace involves education and monitoring of workers. Workers who understand the reasons for rules concerning hygiene and work practices are more likely to help keep their work area clean. For cobalt, medical and environmental monitoring are especially important since the potential effects of exposure are poorly understood. Employers must follow the results of medical examinations and correlate them with exposure measurements to ensure that workers are adequately protected. Workers should understand the importance of the medical and environmental monitoring to ensure that they will cooperate and report any possible adverse reaction to cobalt promptly. For workers in areas where the concentration of airborne cobalt is likely to exceed 0.05 mg cobalt/cu m (one-half the Federal limit), the employer should establish the following program. Personal monitoring should be conducted to identify and measure, or permit calculation of, the exposure of each worker. Appropriate methods for sampling and analysis are listed in the Appendix. 2. Samples should be representative of the breathing zone air of workers, but source and area monitoring can be a useful supplement for identifying leaks or other sources of emissions. While all workers do not have to be monitored, sufficient samples should be collected to characterize the exposure of all workers. Variations in exposure during different shifts, because of location or job function and of changes in production schedule, should be considered in deciding the number of samples to be collected. If a worker is exposed to cobalt at concentrations exceeding the Federal standard, improved measures to control exposure should be taken immediately. Once the control measures are in effect, exposure monitoring should be repeated. If two consecutive measurements, taken at least 1 week apart, are below the Federal standard, the worker's exposure may be considered no longer excessive. Personal monitoring records should be kept for 30 years to ensure compliance with new OSHA regulations concerning worker rights to information about their exposure (29 CFR 1910.20). (c) Medical Surveillance N10SH encourages the provision of medical surveillance programs for workers. Some companies already maintain high-quality programs that allow absorption of hazardous chemicals to be detected at the earliest possible time. This allows early intervention by surveying the workplace and initiating work practice and engineering changes necessary to protect workers. # Medical surveillance programs should ideally include preplacement examinations and periodic réévaluations that will, based on the characteristics of the individual substance or agent, allow detection of absorption before onset of perceptible damage. In most programs, periodic examinations should be carried out on an annual basis. Since cobalt has been implicated to lesser or greater degrees with many effects on the body, these examinations should include not only the points discussed below but also be thorough enough to give reasonable assurance that effects have not occurred elsewhere in the body. The circumstances of each workplace and the types of cobalt compounds present will of course influence the program chosen by the responsible physician. The most dramatic effect of cobalt is on the lungs, Involving development of pulmonary fibrosis. As a result, a medical history is important to determine the presence of factors that would argue against placement in a job requiring exposure to cobalt. The physical examination should give special attention to the chest and lungs. Because pulmonary function studies are sensitive indicators of early changes in lung tissues, NIOSH recommends that they be conducted yearly. The forced expiratory volume in 1 second (FEV 1) and forced vital capacity (FVC) tests are sensitive and easy to administer. Chest x-rays can be useful but are somewhat less able to detect early changes as compared to pulmonary function tests, so 3 years is probably a suitable time between radiologic examinations. The skin should receive attention because cobalt compounds can cause allergic responses and sensitization. Once sensitized, a worker can probably not tolerate any additional exposure. As a result, any worker with a previous history of allergic skin disease should be carefully counselled and schooled in techniques that will minimize contact with cobalt. In addition, skin protection should be stressed in the workplace to keep the number of new cases of skin sensitization at a minimum. Cobalt affects the thyroid gland, and results in production of goiter. While the strength of this association is not clear, it seems that palpation of the thyroid for enlargement would be a prudent and simple step to include. This standard is based on the TLV adopted by the AC6IH in 1968. Workers in industries other than those manufacturing or using cemented carbide should be examined for adverse lung effects. # V. BASIS FOR STANDARDS CONCERNING OCCUPATIONAL EXPOSURE TO COBALT For both animals and humans, an attempt should be made to obtain dose-response data if fibrosis or prefibrotic changes are found. The possibility that certain specialty steels cannot release cobalt in the lung following inhalation should be examined. Some of these substances are used because of their extreme heat and corrosion resistance. It is possible that their toxic effects are unrelated to their cobalt content. An effort should be made to determine the prevalence of dermatitis caused by sensitization to cobalt in various US industries. Information should be collected for different types of cobalt and should Include cobalt metal, cemented carbide, and cobalt salts. Work practices and types of protective clothing should be considered in order to determine the protection needed by workers to minimize their chances of becoming sensitized. The issue of the possible carcinogenicity of cobalt is very much unresolved. Inhalation studies need to be conducted in animals, and such studies could be performed in conjunction with examination of possible fibrotic effects. In humans, epidemiologic studies should be conducted. The cemented carbide Industry, In particular, should be examined since the process is sufficiently old that an appropriate cohort should be available. Any epidemiologic study should also collect information on heart disease. The possibility that cobalt exposure at fairly low levels over a considerable period of time could lead to heart disease cannot be ruled out from information now available. Finally, many cobalt compounds in commercial use have not been examined for toxicity, or very little information of limited use is reported. For example, some cobalt pigments and cobalt driers for oil-based paints have widespread use. Compounds such as these should be subjected to thorough testing for toxicity. (f) V arious c l i p s , tu b in g , s p rin g co n n ecto rs, or b e l t s u f f i c i e n t to connect sampling apparatus to worker being sampled. # C a l i b r a t i o n o f E quipm ent Since th e accuracy of an a n a ly s is can be no g r e a te r than th e accuracy w ith which th e volume of a i r i s m easured, a c c u ra te c a l i b r a t i o n of th e sampling pump i s e s s e n t i a l . The frequency of c a li b r a t io n re q u ire d depends on th e u se , c a re , and handling th a t the pump r e c e iv e s . Pumps should be r e c a l i b r a t e d i f they have been abused or i f they have j u s t been re p a ire d or receiv ed from th e m anufacturer. M aintenance and c a li b r a t io n should be performed on a r o u tin e sch ed u le, and re co rd s of th e se should be m aintained. (f) Check th e w ater manometer to ensure t h a t th e p re ssu re drop ac ro ss th e sampling t r a i n does not exceed 33 cm of w ater (approxim ately 2.54 cm of m ercu ry ). L ig h t-s c a tte r in g problems may be encountered when s o lu tio n s of high s a l t co n ten t a re being analyzed. L ig h t-s c a tte r in g problems a re most sev ere when measurements a re made a t th e lower w avelengths, i e , below about 250 nm. Background a b so rp tio n may a lso occur as th e r e s u l t of the form ation of v ario u s m olecular sp ec ie s th a t can absorb l i g h t . The ( 1) 125-ml P h i l l i p s or G r i f f i n beakers w ith w atchglass covers. (2) 15-ml graduated c e n tr ifu g e tubes. # Reagents (a) P u rity : ACS a n a l y t i c a l re ag en t grade chem icals or eq u iv a le n t should be used in a l l t e s t s . R eferences to w ater s h a l l be understood to mean double d i s t i l l e d w ater or e q u iv a le n t. Care i n s e l e c t io n of re a g e n ts and in follow ing th e l i s t e d p re cau tio n s i s e s s e n t i a l i f low blank v alu es a r e to be o b tain ed . # ( (d) P e rc h lo ric a c id , re a g e n t grade. # ml. A sp ira te w ater a f t e r each sample. As a minimum, a m idrange standard must be a s p ira te d w ith s u f f i c i e n t frequency, i e , once every f iv e sam ples, to ensure th e accuracy of th e sample d e te rm in a tio n s. I t i s b e s t to run a stan d ard w ith a c o n c e n tra tio n c lo se to th a t of a sample a f t e r each sample i s ru n . To th e e x te n t p o s s ib le , base a l l d eterm in a tio n s on r e p l i c a t e an a ly se s. Cobaltous n i t r a t e 8,600 Cobaltous o x a la te 1,700 Cobaltous s u l f a t e 8,300 C obalt cyanide 7,200 C obalt hydroxide 2,500 C obalt 2-eth y lh ex o ate 3,900 *Many of th ese workers would be p o t e n t i a l l y exposed to only sm all amounts of c o b a lt through i n h a la tio n , in g e s tio n , o r dermal c o n ta c t. The exposure e stim a te s are not a d d itiv e , sin ce some workers would be exposed to more than one compound. Substance(s) com prising the d r i e r were no t i d e n t i f i e d . Thyroid function studies do not seem necessary unless enlargement or some other sign or symptom of thyroid dysfunction la present. Present information suggests the possibility of polycythemia in the blood and electrocardiographic changes in the heart being produced by exposure to cobalt. The information is very unclear and appears to show effects only at a very high dosage. Therefore, no specific tests are suggested for these organ systems unless there is a potential for exposute to high levels of cobalt in the workplace. The medical surveillance program should be reevaluated frequently and changed to reflect current working conditions and knowledge of health effects. Medical records should be kept for 30 years after the worker's last exposure to cobalt. This will ensure compliance with OSHA's (29 CFR 1910.20) standard concerning worker's rights to his or her own medical records. # V I I . REFERENCES Morral FR: Cobalt and cobalt alloys, in Standen A (ed.): Kirk-Othmer Encyclopedia of Chemical Technology, ed 2 rev. New York, Interscience Publishers, 1970, vol 5, pp 716-48 2. Hawley GG (ed.): The Condensed Chemical Dictionary, ed 9. New York, Van Nostrand Reinhold Co, 1977, pp The effects of cobalt injections on total circulating red cell volume and bone marrow cytology in normal and adrenalectomized dogs. , 1970, pp 197,210,223,231,278,287,303,343,347 Once th e ashing i s com plete, remove th e w atch g lass, and allow th e sample to evaporate to near dryness (approxim ately 0 .5 m l). I f c h a rrin g o c c u rs, add HN03 (1 ml) and evaporate to near dryness (0 .5 ml) again. R epeat, i f n ecessary . Remove th e beaker from th e h o t p la t e , c o o l, and add 1 ml HN03 and 2-3 ml of d i s t i l l e d w ater. T ra n sfer th e s o lu tio n q u a n t i t a t i v e l y w ith d i s t i l l e d w ater to a 10-ml volum etric f l a s k , and then d i l u t e th e samples to volume (10 ml) w ith w ater.	Much of the data on occupational exposure to cobalt have come from the tungsten carbide industry. McDermott [261], in 1971, found the average concentration of cobalt in 40 general air samples of seven tungsten carbide facilities to be below 0.1 mg/cu m (range, 0.005-0.15). About 70% of the 133 breathing zone samples were also less than 0.1 mg/cu m. Based on the data provided, however, mean concentrations in breathing zones of press operators and machine tool operators averaged 0.16 and 0.21 mg/cu m, respectively. A tungsten carbide facility reported that during 1977-78 the concentration of cobalt in worker breathing zones averaged 0.048 mg/cu m in the powder area, 0.033 mg/cu m in the pressing area, 0.019 mg/cu m in grinding, and 0.025 for general maintenance [255]. The highest concentration measured was 0.17 mg/cu m and the lowest was 0.004 mg/cu m. A study of eight cemented carbide plants in Sweden revealed that exposure to cobalt varies considerably with job classification [262]. Groups handling powder were most exposed, while press operators, shapers, dry grinders, wet grinders, face grinders, and inspection personnel received decreasing levels of exposure to cobalt (in that order). Some workers handling powder probably received short-term exposures in excess of 0.1 mg cobalt/cu m.# B ack grou nd R e s p i r a t o r y E f f e c t s E f f e c t s on t h e S k in C a r d ia c E f f e c t s E f f e c t s on B lo o d E f f e c t s on t h e T h y r o id C a r c i n o g e n i c i t y and M u t a g e n ic it y E f f e c t s on R e p r o d u c tio n O th er E f f e c t s D i s t r i b u t i o n and R e t e n t i o n EXTENT AND MEASUREMENT OF EXPOSURE # Work C lo t h in g and P r o t e c t i v e E qu ip m en t The u s e and p r o p e r c l e a n i n g o f a p p r o p r ia t e w ork c l o t h i n g i s r e q u ir e d t o p r e v e n t s k i n e f f e c t s and s e n s i t i z a t i o n . P r o t e c t i v e e q u ip m e n t t h a t i s a p p r o p r ia t e t o t h e i r p o t e n t i # S p ir o m e t r ic e x a m in a tio n t o d e t e c t r e s t r i c t i v e v e n t i l a t o r y im p a ir m e n t i s o n e p o s s i b i l i t y , b u t t h e r e s u l t s do n o t a g r e e t o t a l l y on t h e s e n s i t i v i t y o f t h i s t e s t . P e r h a p s much o f t h e c o n f l i c t i n g e v i d e n c e i s t h e r e s u l t o f t h e l e s s s o p h i s t i c a t e d eq u ip m e n t a v a i l a b l e t o t h e e a r l i e r i n v e s t i A recent study at a Swedish hard metal plant attributed four cases of allergic alveolitis to exposure to soluble cobalt dissolved in the coolant used for wet grinding [48]. One worker showed only signs and symptoms of asthma, but the other three showed evidence of mild pulmonary fibrosis as well. All four had contact eczema and were sensitive to cobalt. Even though they ceased all exposure to cobalt, the four persons have continued to show abnormalities on their chest radiographs. # (c) Other Reports of Respiratory Disease in Workers Exposed to Cobalt Studies of the effects of cobalt exposure on workers not employed in the manufacture or use of hard metal are rare, but some indicate pulmonary disease in these workers. # At a Finnish metal refinery, one or two new cases of bronchial asthma had been diagnosed annually in a group of 230-240 cobalt workers [49]. A cross-sectional study demonstrated a highly significant correlation between exposure to cobalt sulfate and asthma. In contrast, nonasthmatic cobalt workers at the same plant had no evidence of any excess of chronic bronchitis. Kochetkova [50] described the death of a woman with a history of 7 years of exposure to metallic cobalt dust. The cause of death was cardiopulmonary insufficiency resulting from massive fibrosis. Levels of cobalt in the lung, liver, heart, ««id kidney tissue were described as markedly elevated. Her heart was enlarged, the liver and spleen were congested, and the cortical layer of the kidneys was swollen. In contrast, Cau et al [51] did not find radiographic evidence of fibrotic damage to the lungs of seven workers employed as sifters of cobalt powder. The workers had been exposed from 2 to 5 years, and they complained of cough, exertional dyspnea, nasopharyngeal irritation, and digestive disorders; two subjects had polycythemia. The authors concluded that exposure to finely divided cobalt metal dust did not induce pulmonary damage. In light of the toxic signs described by the workers and the short duration of exposure, this conclusion seems inappropriate. # An extensive study of workers exposed to cobalt was reported by Verhamme [52] in 1973. Medical examinations had been given to workers at a plant where cobalt oxides, powders, and salts were produced. Measurements of airborne cobalt were not reported, but the author believed that workers in the hydrometallurgic area had little or no dust exposure and that workers in the salts, oxides, and finished powders production areas were the most exposed groups. The finished powders had an average diameter of less than 1.4 jum, and To investigate the suggestion of Bruckner [58] that pulmonary reactions to cobalt may be mediated through a hypersensitivity mechanism, Kerfoot et al first exposed the experimental animals 6 hours a day for 5 days. After a 10-day lapse, the animals were reexposed 6 hours daily, 5 days a week for 3 months. All animals appeared normal until the 4th week of exposure, after which time the animals from both cobalt groups became lethargic. Some animals appeared to be wheezing during exposure; this was confirmed by auscultation. Postexposure pulmonary function tests showed a significant reduction in mean tidal volume, mean total compliance, and mean specific compliance in both cobalt-exposed groups [44]. The authors interpreted change in compliance as demonstrating functional lung impairment. This change was reversed in animals examined 2 months after the cobalt exposure ended. Serial radiographs conducted on all animals showed no evidence of diffuse pulmonary disease [44]. The animals were examined grossly and by light microscopy at necropsy, and the lungs, heart, liver, and kidneys did not show any persistent or significant abnormalities. There was no evidence of cobalt in any lung tissue examined. Electron microscopic examination of lung biopsy tissue taken at the end of exposure revealed masses of collagen, elastic tissue, and fibroblasts in some of the tissues. However, no quantitative analysis was presented, nor was there mention of the methodology used in selecting tissue sites for examinations. The greatest changes were observed in the high-concentration cobalt exposure group, with the fewest changes being observed in controls. In a Soviet study, male albino rats received exposures to aerosols of metallic cobalt continuously (24 hours a day, 7 days a week) for 3 months [59,60]. There apparently was a concurrent control group, but the reports did not contain important details such as the number of animals exposed or tables of results presenting actual data. Chronic inhalation of cobalt at 0.5 mg/cu m was said to be irritating to the lungs [59]. The animals exposed to cobalt at 0.05 and 0.005 mg/cu m were described as having changes similar to, but less pronounced than, the changes in animals exposed at 0.5 mg/cu m. The lowest concentration (0.001 mg/cu m) produced what was described only as a weak general toxic effect. # Microscopic examination of lung tissue from animals exposed at the highest concentration of 0.5 mg/cu m revealed accumulations of macrophages in the alveoli [60]. Interalveolar septa were consolidated in several areas of the lung. The severity of these changes reportedly was related to the exposure concentration. The lungs of animals exposed at 0.001 mg/cu m were described as similar to those of controls. While information in this report is not completely satisfactory, effects such as consolidation of the alveolar septa are indicative of a prefibrotic condition. Wehner et al [45] exposed 2-month-old Syrian golden hamsters to cobaltous oxide aerosols at 10 mg/cu m for their lifespans. The animals were exposed for 7 hours daily for 5 days a week to aerosols with a median diameter of 0.45 (an. Particulate material accumulated in alveolar macrophages and became denser as exposure continued. Emphysema became apparent. The extent of the changes became more severe as exposure time increased, and hyperplasia and hypertrophy of alveolar lining cells also appeared. Macrophages, frequently containing particulate matter, increased in number throughout the lung, and numerous focal accumulations of these cells could be found. Proliferative changes involving the epithelial components of bronchi and bronchioles became detectable early during exposure and increased in severity with exposure time. # Laryngeal lesions occurred in five animals (10%) during the study. The lifetime exposure of hamsters to cobaltous oxide clearly resulted in pneumoconiosis, but it did not significantly shorten their lives. From the experimental studies in animals, the ability of some cobalt compounds to cause pulmonary fibrosis is evident. However, the information is insufficient to determine what effect, if any, exposure to other substances often present in cemented tungsten carbide may have on the development of hard metal disease. Thus, the possibility must be considered that adverse effects in workers exposed to cobalt at the 0.06-0.2 mg/cu m range were aggravated by exposure to mixtures. However, the degree of worker exposure to cobalt is clearly related to the number of signs and symptoms observed in workers. Thus, decreasing exposure to cobalt should reduce the risk of adverse health effects. For cobalt metal, results in animals indicate that worker exposure should be limited as much as possible, and that in no case should the present Federal limit be exceeded. Similar information is not available for any other cobalt compound, including those in commercial use. # Effects on the Skin The incidence of sensitivity to cobalt in the general population appears to be low; in a small group ( 41 When all available data are combined, approximately 5% of the persons studied were cobalt-sensitive; 82% of these had combined metal sensitivities. All three metals are prevalent in the general environment, which suggests that individuals with cobalt sensitivity also have had contact with nickel and chromium. Their responses thus could represent independent sensitization reactions, so that cross-sensitivity is not necessarily implied. The mechanism of the allergic response to cobalt after dermal contact is unknown. Haxthausen [84] contended that about 90% of the cobalt is absorbed from the skin following intradermal administration before any allergic reaction becomes visible. Norgaard [85], however, reported that cobalt is not absorbed through intact skin when applied to the forearm as a 0.3% or 5% solution. This same study reported systemic absorption of cobalt in solutions applied to the depilated skin of rabbits and guinea pigs [85]. Another investigative group also observed systemic absorption when solutions of cobaltous chloride were placed on the clipped backs of guinea pigs [86]. From this Information, NIOSH concludes that the risk of systemic poisoning from dermal absorption of soluble salts of cobalt is minimal for skin contact under normal working conditions. Abraded skin should be adequately protected to prevent contamination with cobalt compounds so that systemic absorption will not occur. # Very few reports on skin diseases in workers who No information is available to judge the effects of many cobalt compounds. Some organocobalt complexes are uncharged and relatively apolar, which would indicate that they probably can be absorbed dermally at least as effectively as the inorganic salts. At least some of these complexes may be stable compounds in body fluids, so that their toxic effects could differ from the simple salts. The authors considered the disease to be of occupational origin and attributable to cobalt. However, data to support this conclusion were not provided in the report. # Cardiac Effects Alexandersson and Atterhog [106] examined dry and wet grinders exposed to cobalt at 0.01 mg/cu m and powder handlers exposed at 0.06 mg/cu m. No ECG changes were observed in dry grinders or powder handlers, even though the powder handlers showed evidence of impaired pulmonary function. The ECG's of wet grinders were abnormal and showed a high incidence of ectopic (premature) heartbeats. However, the authors believed that the ECG changes were related to exposure to cutting oils rather than cobalt. Only one study in animals has examined the effects on the heart of cobalt exposure similar to that encountered in the workplace. In the study on miniature swine exposed to cobalt metal dust at 0.1 or 1 mg/cu m, Kerfoot and coworkers [44] observed abnormalities in ECG's taken at the end of the 3-month exposure period. These alterations were interpreted by the authors to indicate a decrease in the strength of ventricular contraction and repolarization abnormalities. Sufficient evidence exists to suggest that both cobalt metal and cobalt salts can produce cardiac changes, but apparently only at high doses. It should be noted that the amount of cobalt ingested daily by persons who consumed 6 liters a day of beer was about 5-10 mg, much higher than the amount inhaled by a worker breathing 10-15 cu m of air in a day at the current Federal limit of 0.1 mg/cu m. The question of whether changes such as those seen in the miniature swine could result in significant problems over a long period of exposure in especially susceptible individuals, such as those with existing heart disease and, possibly, persons who consume alcohol on a regular basis, needs to be examined. # Effects on Blood Cobalt-induced polycythemia is a well known effect. This property of cobalt has been exploited therapeutically in the treatment of refractory anemia [107-115]. The information collected for this review, however, revealed that other lesser known effects may occur at concentrations below those needed to produce polycythemia. The information available, although often incomplete, is presented below. # The polycythemic effects of cobalt have been observed not only in patients but also in controlled experiments in persons with normal blood counts and in animals. Volunteers receiving oral doses of cobaltous chloride ranging from 100 to 1,200 mg daily for 1-12 weeks [107] or 120-150 mg daily for 1-3 weeks [116] experienced an increase in RBC and Hb levels. Numerous studies [117-125] in animals administered cobaltous chloride at high dosage levels for as long as 16 weeks either orally, or by subcutaneous (sc) or ip injection, also reported slight to substantial increases in RBC or Hb. One study in mice demonstrated an increase in RBC's subsequent to ip injection of cobaltous nitrate [126]. However, inhalation studies in animals exposed to cobalt metal [44,59] provide little evidence to support the contention that polycythemia would be expected in workers exposed to cobalt at low concentrations. Similar studies on cobalt salts have not been conducted. Since the effects of cobalt on the blood would be expected to depend on its ability to concentrate at certain critical sites, cobalt salts might demonstrate effects at levels differing from cobalt metal. However, the mechanisms responsible for the changes in blood that are induced by cobalt are not known. The information available suggests to NIOSH that the effects of cobalt on the blood are multiple and poorly understood. # While a polycythemic effect is clearly demonstrated in the reports Polycythemia is clearly one manifestation of exposure to cobalt metal or cobalt salts, and increases in erythropoietin could be a factor in producing this effect. The airborne concentrations of cobalt at which this polycythemic effect would be significant are poorly documented, but they appear to be well above the Federal standard for cobalt metal. Information is not adequate to judge whether this airborne concentration, 0.1 mg/cu m, would be adequate to prevent polycythemia from other cobalt compounds. Because RBC's have been found to decrease in exposed workers only at very high airborne concentrations of cobalt, this effect is judged insignificant if exposure is through inhalation. The role of cobalt in retarding blood clot formation is not well documented, but preliminary evidence suggests that it could be highly significant. # Effects on the Thyroid The Placebo tablets were substituted for the cobalt preparation, and thyroid function returned to normal by 12 weeks. Numerous additional reports that followed now show that 2-10 mg cobalt (as chloride)/kg given orally each day for 2-4 months will induce goiter formation in a small percentage of persons [147][148][149][150][151][152][153][154]. In all cases, the thyroid hyperplasi^ has been reduced or reversed after cobalt administration was stopped. Controlled clinical studies have also examined the effects of cobalt on the thyroid gland. In one study, 12 adults with normal thyroids were given 50 mg of cobaltous chloride orally three times a day for 2 weeks [155]. # Radioactive iodine uptake was reduced in all but one person after the 1st week; by 2 weeks all uptake levels were near zero. The effect was reversible after cobalt administration ceased. In a separate study, the majority of individuals given cobaltous chloride either orally or by iv infusion also had decreased iodine uptake in the thyroid [156]. In fact, cobaltous chloride has been tested as a treatment for hyperthyroidism. Pimentel-Malaussena et al [157] observed that four of eight patients receiving 150-600 mg a day for up to 117 days responded with clinical improvement as manifested by reductions in tachycardia, metabolic rate, and uptake of radioactive iodine. Three of four, however, had thyroids of increased size, and the authors concluded that the action of cobalt was unpredictable. mg/cu m. This value is near the permissible exposure limit for cobalt metal fume and dust, and long-term effects at low levels have not been studied in humans for any cobalt compounds. This information suggests that alterations of thyroid function should be considered as a possible effect of workplace exposure to cobalt. # The results of studies in guinea pi # Carcinogenicity and Mutagenicity Fibrosis, and not carcinogenicity, has received most of the attention of the occupational health community concerned with cobalt. The many reports available concerning fibrosis would not be adequate to demonstrate any carcinogenic effect, because none are epidemiologic studies concerned with incidence rates. The three case reports describing the development of benign or malignant tumors in hard metal workers [17,32,38] and two epidemiologic studies describing an increased risk of lung cancer in cobalt recovery areas of nickel refineries [162,163] are not useful in demonstrating a possible carcinogenic effect of cobalt. Arsenic was also present in the air of some plants examined in the epidemiologic studies. Mixed exposures to substances known to be or suspected of carcinogenicity were involved in all cases. The case reports cannot distinguish between the role of occupational exposure and other factors, including normal incidence. Thus, information from human studies does not provide any answers about the possible carcinogenic potential of cobalt. The two studies conducted in animals by routes of administration most applicable to workplace exposure did not demonstrate a carcinogenic effect for cobalt [45,164]. The incidence of tumor development was low and did not differ significantly from controls in male Syrian golden hamsters exposed for their life spans to aerosols of cobaltous oxide at 10 mg/cu m, 7 hours daily, 5 days a week [45]. Many of these animals did develop fibrotic changes. Hamsters injected intratracheally once a week for 30 weeks with 4 mg of cobaltous cobaltic oxide (Co304) failed to develop a statistically significant excess of tumors compared with control animals [164]. It should be noted, however, that the two tumors that developed in the 50 animals exposed to cobalt were alveolar in origin while the four tumors in controls were at sites unrelated to exposure. These studies provide little evidence to suggest that cobalt oxides are carcinogens, but no similar studies have been conducted in animals other than hamsters. The results of studies of the carcinogenic potential of cobaltous chloride are conflicting. Gunn et al [165] reported that no tumors were observed for 10-16 months in Wistar rats given four simultaneous injections of cobaltous chloride (0.18 mg cobalt/site) into a vital organ (liver or kidney), a gland (salivary or ventral prostate), and two mesenchymal mesodermal structures (chest, interscapular area, thigh, or femur). Similarly, Shelley [166] reported that no tumors were observed in 10 ICR mice given cobaltous chloride (3.5 mg cobalt) in the dorsal earlobe, although the 2-to 5-month observation period was relatively short. On the other hand, Shabaan et al [167] found subcutaneous fibrosarcomas in 14 of 27 rats surviving 8-12 months following 10 injections of cobaltous chloride at 40 mg/kg into the central abdominal wall. Two tumors were at the injection site, and the remainder were at various distances from the abdominal region. Metastases were not found in any tumorbearing animal. This study provides evidence that cobaltous chloride could be a carcinogen, and it argues for the need to perform chronic testing of cobalt salts in animals by routes of exposure more applicable to the workplace. Information on cobalt is inadequate to conclude that cobalt is a carcinogen. The information is also Inadequate to conclude that cobalt is noncarcinogenic. # Several investigators have In fact, limited data [167,175,176] provide suggestive evidence that at least some cobalt compounds may prove carcinogenic when subjected to long-term testing by currently accepted protocols. Until such testing is performed, no definitive guidelines can be given. Tumor induction at the injection site, however, would argue for the need to adequately clean any wound contaminated with cobalt. # Effects on Reproduction Whether exposure to a substance in the workplace can result in adverse effects on reproductive capacity or harm to the developing fetus is of grave concern to workers and to all persons responsible for the health of workers. The information available on cobalt is conflicting and insufficient to draw definite conclusions on the effects of cobalt on reproduction. Although this information dees not substantiate any effects, it is presented below. Studies in humans [190][191][192] and animals [193,194] This experiment is of questionable relevance because of the nonmammalian test system used. The literature describing the effects of cobalt on testicular function is characterized by disagreement among investigators. Hoey [197] reported marked but reversible changes (including suppression of spermatogenesis, abnormal sperm, deformation of the epididymal tubules, and necrosis of the duct system) in rats administered cobaltous chloride by sc injection. Kamboj and Kar [198] injected cobaltous nitrate sc in mice or intratesticularly in rats, and they found no microscopic damage to the testes or effects on spermatozoa. Niebroj [199] injected cobaltous chloride ip, and considered the effects on the testes of these mice to be generally positive. # Other Effects There are numerous studies of additional toxic effects attributed to cobalt. Some, such as the acute lethality studies in animals, have little impact on the occupational environment since such exposure conditions are rarely, if ever, encountered. Some effects, such as increased levels of plasma lipids, have been observed in humans, but only rarely in anemic patients receiving cobalt [145,150,200]. Some, such as experimental induction of epilepsy by implantation of cobalt in the brain of animals, appear irrelevant. Other effects, such as kidney and liver changes, may be relevant; but information on occupational exposure is quite limited. also described its long-term accumulation in bone. Considering these sites of deposition, it is not at all surprising that a fraction of the administered dose is retained for a long time. # Retention of cobalt oxides after inhalation has been examined in animals. Wehner and Craig [244] reported that hamsters eliminated 90% of the total dose of cobaltous oxide, inhaled at 15.6 mg/cu m 7 hours a day for 2 days, within the subsequent 3 days (day 5 of experiment); however, the remainder was retained tenaciously in the body of the animal. Barnes et al [246] administered respirable-sized particles of cobalt oxides by inhalation to dogs. In 10 days, only 10% of the cobaltous oxide was retained, compared with 60% of the cobaltous cobaltic oxide. Cobaltous cobaltic oxide showed accumulation in the lymph nodes of the lung, a typical reaction of tissueinsoluble substances, while substantially more cobaltous oxide was found in the tissues and blood. The information on distribution and retention of cobalt is typical of substances showing moderate to substantial tissue solubility. Information on the chloride salt is particularly revealing. It appears that enough of the salts can be absorbed through the gastrointestinal tract to warrant good sanitation and personal hygiene by workers so that they can avoid absorbing significant amounts of cobalt through ingestion. The long-term accumulation of cobalt in the liver may also be relevant. # I I I . EXTENT AND MEASUREMENT OF EXPOSURE # Uses of Cobalt Cobalt (atomic number 27, atomic weight 58.93) Is a transition element located between iron and nickel in group VIII of the periodic table. The metallic form is silver gray to bluish white and is magnetic. There are three oxides of cobalt: cobaltous oxide, CoO; cobaltic oxide, Co203; and cobaltous cobaltic oxide, Co304. Ionic cobalt can exist in either a divalent or a trivalent form. The cobaltous ion can form numerous inorganic and organic salts [247], and cobalt can form complexes with amines, nitrites, and cyanides Cobalt alloyed with chromium and nickel is used in heat-resistant gas turbine blades and jet engine parts. Hard metal is found in high-speed cutting tools, armaments, masonry drills and cutters, high-speed dental drills, and tire studs. This property also leads to its somewhat unusual use as "invisible" ink. Cobalt pigments are very important in the ceramic and pottery industry. A wide variety of pigments in differing shades and colors contain cobalt, often as mixtures with other metal salts. Black cobalt oxide paint is of particular value because of its heat and wear resistance. A mixture of cobalt oxide and cobalt aluminate forms a blue color. Cobalt blue is sometimes added to glass to detint the yellowish color that occurs if iron is present. Small amounts of cobalt salts are also used as boiler water scavengers, in magnetic tapes, and in steel-belted tires. # Table III-l lists some occupations in which there is potential exposure to cobalt compounds [256]. The amount of exposure to cobalt that workers actually receive in these occupations probably varies widely. Large amounts of cobalt are used in some industries, such as cobalt salts manufacturing, the cemented carbide industry, and the manufacture of cobalt-containing alloys. Many users of these products handle extremely small quantities of cobalt. Others perform cutting, grinding, or welding operations on products, and the potential for worker exposure to cobalt is significant. Exposure of painters to cobalt driers is probably minimal; exposure of spray painters to cobalt pigments is not. Also, Janssens et al [260] reported that air samples collected in Belgium, apparently near a cobalt-manufacturing plant, showed levels of 0.4-7.3 ng/cu m (mean, 2.8). All of these levels in ambient air are far below the Federal standard of 0.1 mg/cu m for cobalt metal fume and dust. # Environmental Data # Cobalt is present in low concentrations # TABLE I I I -l At an operation where tungsten carbide tools containing 6 .0-8.5% cobalt were sharpened by wet grinding, general air samples were well below 0.1 # mg/cu m [40]. Two-thirds of the breathing zone samples, however, were above 0.1 mg/cu m of cobalt (range, 0.04-0.93 mg/cu m ) . Full-shift TWA exposures were measured on a number of the grinders. Two-thirds of those values were above 0.1 mg/cu m with a range of 0.03-0.56 mg/cu m and a mean of 0.24 mg/cu m. A US nickel refinery provided cobalt dust exposure data collected in June 1978 (B Roy, written communication, September 1978). Average concentrations of cobalt were generally low, ranging from less than 0.002 to 0.099 mg/cu m, except for two tower cleanup workers whose exposures averaged 0.156 mg/cu m. Within the occupational groups, the concentration ranges were sometimes quite variable; for example, the exposure of one cobalt operator was 0.313 mg/cu m, and for a supervisor it was 0.148 mg/cu m, even though averages for all 13 workers in these groups were substantially lower. Where the dried cakes were broken into fine powders, cobalt concentrations varied, ranging from not detectable to 0.2 mg/cu m. On the average, the drum-loading operations were the dustiest, but the cobalt concentrations, 0.04-0.5 mg/cu m, varied widely. Other operations in the plant were contained and well ventilated so that the concentration of cobalt in those areas would be expected to be low. III-2 These data covered 1970 to 1974. Exposures to cobalt on the average were substantially less than 0.1 mg/cu m, but they were quite variable, even for the same areas. For example, exposure to cobalt in the breathing zones of workers in the melt shops were 0 .001-1.43 mg/cu m. # An environmental survey conducted in May 1978 at a US jet aircraft engine assembly plant provided exposure data for three occupational groups (Table In the powder products area, six samples ranged from 0.09 to 9.7 mg/cu m. General area samples tended to show a lower cobalt concentration than breathing zone samples. Almost no published data on exposure to cobalt in welding and thermal cutting operations were found. Hewitt [259] measured cobalt and other metallic contaminants in a number of welding operations in well ventilated areas. Airborne cobalt concentrations were all 0.1-0.4 jug/cu m. Cobaltcontaining welding rods can contain other metals such as nickel or chromium that can also be hazardous if they become airborne. Eight plant site visits were conducted to collect information for this report [255]. The number of production workers ranged from less than 50 to 25,000. The three largest plants (at least 800 production workers) all had formal plans for sampling and inhouse capabilities for analysis. Two other plants sampled for cobalt on an irregular basis, and one other sampled for nuisance dust only. The two plants with less than 50 production workers had no program for air monitoring. These plants had relied on corporate headquarters, insurance carriers, and contractors for air monitoring where in-house capability was unavailable. One disadvantage of electrostatic precipitators is that actual worker exposure may not be estimated as closely as is possible with personal sampling. # S am pling M ethods # Analytical Methods Many methods have been developed for the analysis of cobalt samples collected from air. Among these, colorimetric procedures can be satisfactory provided that other metals do not interfere with the results. Color reagents that have been used include nitroso R salt (sodium nitroso-2-naphthol-3,6disulfonate) and sodium thiocyanate [273][274][275]. Although these methods are tedious and require skill, they can give satisfactory results. # Emission spectrometric methods have been used frequently to analyze airborne particulate material. Because of its sensitivity, the emission spectrograph has been used to measure pollutants in the community atmosphere [276], but this technique is also useful to determine concentrations of airborne cobalt in the workplace. One investigator, using a specialized electrode for air sampling, was able to perform direct analysis of samples using the Although this method is sensitive and does not destroy the sample, the requirements for elaborate equipment, the safety precautions necessary for use of an irradiating beam or radioactive sources, and the relatively small thermal neutron cross section of cobalt make NAA less practical than AAS for routine use. # Another technique for analysis of airborne cobalt use is the x-ray fluorescence method [258,266,272]. The fluorescence method resembles the neutron activation procedure in specificity, sensitivity, and ability to analyze a single sample for a number of elements. It is nondestructive and requires a minimum of sample handling. Results can be obtained quite rapidly for cobalt as well as for a number of other metals [266,272], and the x-ray fluorescence method can be an acceptable alternative to M S when analyzing cobalt. In summary, the collection of air samples on membrane filters and the analysis of those samples by AAS, as described in the NIOSH P&CAM 173, are the methods of choice for monitoring of workers' exposure to cobalt (see the Appendix). Other methods, at least as sensitive and precise, are also acceptable. # IV. CONTROL OF EXPOSURE Over a million workers have some potential for exposure to at least one cobalt-containing compound in the course of their employment. Many receive little exposure because they work with very small amounts of cobalt on an intermittent basis. Others, however, work with large amounts of cobalt regularly. These workers can become exposed through inhalation, dermal contact, or ingestion. In some operations, exposure to cobalt is limited because of the use of extensive engineering controls. Other operations, however, require manual handling of materials containing cobalt. Local exhaust ventilation [261,285] and good work practices can minimize exposure to cobalt in such circumstances. In all cases, ingestion of cobalt is easily prevented by the use of good personal hygiene in combination with the maintenance of a clean worksite. Workers who maintain or repair equipment, enter confined spaces such as tanks or vessels, or are involved in emergencies or other nonroutine situations have an especially high risk of exposure to cobalt. These workers should be trained to recognize hazards, and in some circumstances they may require special protective equipment or clothing to decrease exposure. # Information on typical industrial practices for the control of cobalt came from several site visits to plants manufacturing or using cobalt-containing products. These plants included a refinery, an alloy producer, cemented tungsten carbide producers, and cobalt salt manufacturers. Other sites visited included a welding-rod maker and an aircraft engine manufacturing facility. There is some published information on control of cobalt [261,285], but much of the following information came from plant visits [255]. # Engineering Controls Well-maintained closed systems and the prevention of dust generation, when compatible with the operation involved, are the most effective methods of limiting worker exposure. When a closed system is used, it must prevent or minimize the release of materials. When closed systems are not practical, worker exposure can often be reduced by process equipment modification, the use of control rooms, or local exhaust ventilation. # Properly designed and maintained ventilation systems, including local exhaust systems, can prevent the accumulation of airborne cobalt-containing dusts and fumes. Local exhaust systems were in frequent use in the plants visited. Examples include the use of glove boxes for welding, exhaust hoods provided to individuals using hand-held buffers and grinders, local exhaust on the other grinding machines and on press machines, and dust-collecting hoses for packaging operations [255]. In addition, a ventilation system is desirable as a standby, should a closed system fail. Where exhaust ventilation is required, adequate makeup air, conditioned as necessary for worker comfort, must be provided. Ventilation requirements for grinding, buffing, and polishing operations were described in a NIOSH research report [286]. Dry grinding equipment was classified as pedestal type, abrasive cutoff tools, surface-type disc grinders, portable grinders and cutoff machines, and other grinding machines according to ventilation system design requirements. Polishing (coated abrasive) equipment was classified as wheel and drum type, disc type, belt polishers, and complex machines. Buffing (loose abrasive) equipment was classified as pedestal type, portable, or multiple buffer machines. For grinding and abrasive polishing, most of the equipment-generated particulate material was thought to be from the workplace. This would be so even for hard metal if a diamond wheel is used. Much more dust was contributed by the abrasive and the abrasive support materials in buffing. The report, in noting that the TLV for cobalt is very much less than for nuisance dust, considered that adequate control of cobalt is not likely to be possible with standard ventilation systems. Totally enclosed ventilation systems and respiratory protection for personnel within the enclosure were recommended. However, many alloys containing only a small percentage of cobalt are used, and restrictions could be less severe in such cases. Engineering controls for most buffing and grinding machines are built to conform to the configuration of the equipment and the materials being handled. Specific guidelines, therefore, are difficult to propose. This can be exceedingly dusty, especially with fine powders. Hoods that prevent the powder from dispersing into the work area and do not interfere with the weighing procedure are difficult, but not impossible, to design. Design requirements, however, are quite dependent on the size and shape of the container. In most of the plants visited, engineering controls in use were generally not specific to cobalt alone, but rather to the entire process [255]. For example, emissions from furnaces preparing specialty steels must be controlled for all the metals in the melt. Cobalt may not be the limiting factor in control of exposure in such situations. Ball mills used in the cemented carbide industry use solvents, such as acetone, and these emissions must be controlled. Several plants used cobalt in foundry operations where silica and other substances used in the molds dictated many of the control measures used. In milling, hot and cold rolling, and other operations, noise was often a factor in the use of control booths and of other means of control that often helped to lower exposure to cobalt. In buffing, exposure to the abrasive support material must be controlled as must oil mists generated in wet grinding. In manufacture of salts, extensive use of strong acids led to requirements for emission control and cleanup procedures that also limited exposure to cobalt. These overall requirements must be considered in designing engineering controls for cobalt. To ensure effective operation of ventilation systems, trained personnel should conduct a regular monitoring program. Routine inspection should include face velocity measurements of the collecting hood, examination of the air mover and collection or dispersion system, and measurements of atmospheric concentrations of cobalt in the work environment. Where appropriate, the use of continuous airflow indicators, such as water or oil manometers properly mounted at strategic locations and marked to indicate acceptable air flow, should be considered. Any changes in the work operation, process, or equipment that may affect the ventilation system must be evaluated promptly to ensure that control measures adequately protect workers. All exhaust emissions from ventilation systems should be passed through a system designed to minimize the release or recirculation of raw materials, cobalt, and wastes into the occupational and community environments. # Work Practices Ultimately, any program of worker protection must consider the prevention of pulmonary fibrosis, which has been clearly demonstrated to result from excessive exposure to cobalt metal and oxides. Dermatitis and an occasional case of extreme pulmonary hypersensitivity to cobalt, however, are much more frequently encountered problems in the day-to-day operation of health care for cobalt workers. These problems cannot be neglected in establishing an effective program for worker protection. Employers should institute programs that emphasize good personal hygiene to prevent skin and respiratory irritation caused by cobalt-containing dusts. After working with cobalt products, workers should thoroughly wash their hands and face before drinking, eating, or smoking. If skin contact with cobalt solutions occurs, the worker should wash the affected skin promptly. The employer should provide showers if workers have substantial contact with cobalt. These workers should be encouraged to wash or shower after each workshift. Employers should prohibit smoking or carrying of tobacco products in work areas because of possible cobalt contamination. For the same reason, employers should prohibit eating, food handling, or food storage within the work area. To maintain a safe workplace, employers must identify the many physical hazards involved in handling cobalt and take measures to eliminate them. In particular, several potentially hazardous situations were observed in plant site visits [255]. These included sharp edges on some rolled alloys and rolled-alloy scraps, the need to lift heavy containers of cobalt, and press operators who placed their fingers under moving machinery to remove parts. Rolled alloy workers can avoid finger cuts by wearing gloves. Trained workers who follow proper lifting techniques could avoid back injuries when they lift dense material such as cobalt metal. Protective clothing must not increase the potential for injury of workers who handle cobalt when working with machinery with moving parts. In storage, cleanup of spills, and emergencies involving fires, employers must be aware of the properties of individual cobalt compounds to ensure proper planning. Finely divided cobalt will ignite, but its fire and explosion hazard is very weak [ # General plant maintenance must be conducted regularly to prevent cobaltcontaining dusts from accumulating in work areas. Cleaning should be performed with vacuum pickup or wet mopping to minimize the amount of dust dispersed into the air. A decontamination room should be available for cleaning equipment that is to receive major overhaul or maintenance. Spills of cobalt-containing material should be promptly cleaned up to minimize inhalation or dermal contact. Liquid material spills can be copiously flushed with water and channeled to a treatment system or holding tank for reclamation or proper disposal. Spills of dry material can be removed by vacuuming or wet mopping. Some spills can be removed by hosing, first with a mist of water to dampen the spilled material and then with a more forceful stream that flushes it into a holding tank or other facility for handling contaminated water. Work surfaces or contaminated clothing should never be cleaned by dry sweeping or blowing with pressurized hoses. Recovery systems used to reclaim waste metals should comply with Federal, state, and local regulations. All waste material generated in the handling of cobalt-containing substances should be disposed of in compliance with Federal, state, and local regulations. Maintenance and repair workers face special problems regarding their potential exposure. The very circumstances that require the maintenance or repair work and dictate the work conditions will often preclude use of some control procedures. Consequently, very careful supervisory control must be exercised over such activities. These workers must wear appropriate protective equipment and clothing, and they must be trained to recognize and control the hazards they face. Special precautions are necessary when workers must enter tanks or vessels, such as reaction vessels containing cobalt catalysts or vessels used to prepare cobalt salts [290]. Before any worker enters a vessel, all sources for transferring cobalt and other materials into or out ot the vessel must be blanked to prevent their entry. The vessel interior must then be washed with water and purged with air. After purging the vessel's interior, trained personnel should test the vessel's atmosphere with suitable instruments to ensure that no hazards from fire, explosion, oxygen deficiency, or dust inhalation exist. No one should enter a tank or vessel without first being equipped with an appropriate respirator and a secured lifeline or harness. Mechanical ventilation should be provided continuously when workers are inside the tank. At least one other worker similarly equipped with respiratory protection, lifeline, and harness should watch at all times from outside the vessel. Workers inside the tank must be able to communicate with those persons outside. Other workers must be available to assist in an emergency. Flame-or spark-generating operations, such as welding or cutting, should be performed only when an authorized representative of the employer has signed a permit based on a finding that all necessary safety precautions have been taken. Gloves and protective sleeves should be used in manual transfer operations, together with a face shield (if respiratory protection is not needed) to keep soiled fingers from touching the face. Employers should provide change rooms and dual lockers so workers can remove soiled coveralls during breaks. # Work Clothing and Protective Work clothing should be worn for only a single day work period, then collected directly into a designated and labeled container, and laundered by a management-selected laundry service. This is encouraged to prevent the spread of contamination into the homes of workers. Eye irritation has apparently not been a problem for workers handling cobalt products; however, in operations that do scatter fine particles in the air, such as grinding, eye protection must be used that complies with 29 CFR 1910.133. Workers who are especially sensitive to cobalt or who handle solutions of cobalt in such a manner that cobalt can splash on the skin or into the eyes must wear protective suits, or face shields with goggles as appropriate, to prevent appreciable skin and eye contact. Emergency eyewashing facilities, where needed, must be readily available to affected workers. Workers experiencing skin irritation should see a physician promptly. # Respirators are not a substitute for proper engineering controls. Respirators may be needed, however, for nonroutine maintenance work, entry into confined spaces, pending installation of adequate controls, and in emergencies where the concentration of cobalt could be unknown or excessive. In these situations, employers must provide workers with respirators, and establish a respiratory protective program meeting the requirements of 29 CFR 1910.134. These programs should emphasize the importance of having clean, well-maintained, well-fitted respirators for use in unusual circumstances and emergencies. Workers must be aware of the need to guard against contamination of the interior of the facepiece. Table IV- # Effective Planning No program to minimize worker exposure to cobalt can be effective unless adequate attention has been given to problems before they arise. When a new facility is to be constructed, persons knowledgeable in occupational safety and health and industrial hygiene engineering should review plans both in the design phase and during construction. They should ensure that working areas and engineering controls are designed so that spills and airborne cobalt will be minimized when the plant is in operation. # For plants already in operation, management should review materialhandling operations, maintenance and repair procedures, and process operations periodically. This review should identify areas and job locations where workers might be exposed to cobalt or cobalt-containing waste products, either through inhalation or direct contact with the skin or eyes. If work practices or engineering controls in any area are no longer adequate, management should modify them promptly. Contingency planning for emergencies, inadvertent release of materials, and breakdown of facilities is vital. These plans should be developed for each department as well as plantwide. They should outline where appropriate equipment and trained personnel are located, and should be written, well understood by workers, and updated as required. Each plant should also be prepared to assess the impact or hazards of a specific spill or release of material should it reach a waterway or create a cloud. Supervisors should have information available, including lists of appropriate names and telephone numbers, for reporting emergencies. In addition to internal reporting procedures, plant management should clearly understand what situations require recordkeeping or external reporting to OSHA, the Environmental Protection Agency (EPA), and any appropriate state agencies. # Worker Education and Monitoring A fundamental part of any program designed to provide a more healthful workplace involves education and monitoring of workers. Workers who understand the reasons for rules concerning hygiene and work practices are more likely to help keep their work area clean. For cobalt, medical and environmental monitoring are especially important since the potential effects of exposure are poorly understood. Employers must follow the results of medical examinations and correlate them with exposure measurements to ensure that workers are adequately protected. Workers should understand the importance of the medical and environmental monitoring to ensure that they will cooperate and report any possible adverse reaction to cobalt promptly. For workers in areas where the concentration of airborne cobalt is likely to exceed 0.05 mg cobalt/cu m (one-half the Federal limit), the employer should establish the following program. # 1. Personal monitoring should be conducted to identify and measure, or permit calculation of, the exposure of each worker. Appropriate methods for sampling and analysis are listed in the Appendix. 2. Samples should be representative of the breathing zone air of workers, but source and area monitoring can be a useful supplement for identifying leaks or other sources of emissions. # 3. While all workers do not have to be monitored, sufficient samples should be collected to characterize the exposure of all workers. Variations in exposure during different shifts, because of location or job function and of changes in production schedule, should be considered in deciding the number of samples to be collected. # 4. If a worker is exposed to cobalt at concentrations exceeding the Federal standard, improved measures to control exposure should be taken immediately. Once the control measures are in effect, exposure monitoring should be repeated. If two consecutive measurements, taken at least 1 week apart, are below the Federal standard, the worker's exposure may be considered no longer excessive. Personal monitoring records should be kept for 30 years to ensure compliance with new OSHA regulations concerning worker rights to information about their exposure (29 CFR 1910.20). (c) Medical Surveillance N10SH encourages the provision of medical surveillance programs for workers. Some companies already maintain high-quality programs that allow absorption of hazardous chemicals to be detected at the earliest possible time. This allows early intervention by surveying the workplace and initiating work practice and engineering changes necessary to protect workers. # Medical surveillance programs should ideally include preplacement examinations and periodic réévaluations that will, based on the characteristics of the individual substance or agent, allow detection of absorption before onset of perceptible damage. In most programs, periodic examinations should be carried out on an annual basis. Since cobalt has been implicated to lesser or greater degrees with many effects on the body, these examinations should include not only the points discussed below but also be thorough enough to give reasonable assurance that effects have not occurred elsewhere in the body. The circumstances of each workplace and the types of cobalt compounds present will of course influence the program chosen by the responsible physician. The most dramatic effect of cobalt is on the lungs, Involving development of pulmonary fibrosis. As a result, a medical history is important to determine the presence of factors that would argue against placement in a job requiring exposure to cobalt. The physical examination should give special attention to the chest and lungs. Because pulmonary function studies are sensitive indicators of early changes in lung tissues, NIOSH recommends that they be conducted yearly. The forced expiratory volume in 1 second (FEV 1) and forced vital capacity (FVC) tests are sensitive and easy to administer. Chest x-rays can be useful but are somewhat less able to detect early changes as compared to pulmonary function tests, so 3 years is probably a suitable time between radiologic examinations. The skin should receive attention because cobalt compounds can cause allergic responses and sensitization. Once sensitized, a worker can probably not tolerate any additional exposure. As a result, any worker with a previous history of allergic skin disease should be carefully counselled and schooled in techniques that will minimize contact with cobalt. In addition, skin protection should be stressed in the workplace to keep the number of new cases of skin sensitization at a minimum. Cobalt affects the thyroid gland, and results in production of goiter. While the strength of this association is not clear, it seems that palpation of the thyroid for enlargement would be a prudent and simple step to include. This standard is based on the TLV adopted by the AC6IH in 1968. Workers in industries other than those manufacturing or using cemented carbide should be examined for adverse lung effects. # V. BASIS FOR STANDARDS CONCERNING OCCUPATIONAL EXPOSURE TO COBALT For both animals and humans, an attempt should be made to obtain dose-response data if fibrosis or prefibrotic changes are found. The possibility that certain specialty steels cannot release cobalt in the lung following inhalation should be examined. Some of these substances are used because of their extreme heat and corrosion resistance. It is possible that their toxic effects are unrelated to their cobalt content. An effort should be made to determine the prevalence of dermatitis caused by sensitization to cobalt in various US industries. Information should be collected for different types of cobalt and should Include cobalt metal, cemented carbide, and cobalt salts. Work practices and types of protective clothing should be considered in order to determine the protection needed by workers to minimize their chances of becoming sensitized. The issue of the possible carcinogenicity of cobalt is very much unresolved. Inhalation studies need to be conducted in animals, and such studies could be performed in conjunction with examination of possible fibrotic effects. In humans, epidemiologic studies should be conducted. The cemented carbide Industry, In particular, should be examined since the process is sufficiently old that an appropriate cohort should be available. Any epidemiologic study should also collect information on heart disease. The possibility that cobalt exposure at fairly low levels over a considerable period of time could lead to heart disease cannot be ruled out from information now available. Finally, many cobalt compounds in commercial use have not been examined for toxicity, or very little information of limited use is reported. For example, some cobalt pigments and cobalt driers for oil-based paints have widespread use. Compounds such as these should be subjected to thorough testing for toxicity. (f) V arious c l i p s , tu b in g , s p rin g co n n ecto rs, or b e l t s u f f i c i e n t to connect sampling apparatus to worker being sampled. # C a l i b r a t i o n o f E quipm ent Since th e accuracy of an a n a ly s is can be no g r e a te r than th e accuracy w ith which th e volume of a i r i s m easured, a c c u ra te c a l i b r a t i o n of th e sampling pump i s e s s e n t i a l . The frequency of c a li b r a t io n re q u ire d depends on th e u se , c a re , and handling th a t the pump r e c e iv e s . Pumps should be r e c a l i b r a t e d i f they have been abused or i f they have j u s t been re p a ire d or receiv ed from th e m anufacturer. M aintenance and c a li b r a t io n should be performed on a r o u tin e sch ed u le, and re co rd s of th e se should be m aintained. (f) Check th e w ater manometer to ensure t h a t th e p re ssu re drop ac ro ss th e sampling t r a i n does not exceed 33 cm of w ater (approxim ately 2.54 cm of m ercu ry ). L ig h t-s c a tte r in g problems may be encountered when s o lu tio n s of high s a l t co n ten t a re being analyzed. L ig h t-s c a tte r in g problems a re most sev ere when measurements a re made a t th e lower w avelengths, i e , below about 250 nm. Background a b so rp tio n may a lso occur as th e r e s u l t of the form ation of v ario u s m olecular sp ec ie s th a t can absorb l i g h t . The ( 1) 125-ml P h i l l i p s or G r i f f i n beakers w ith w atchglass covers. (2) 15-ml graduated c e n tr ifu g e tubes. ( # Reagents (a) P u rity : ACS a n a l y t i c a l re ag en t grade chem icals or eq u iv a le n t should be used in a l l t e s t s . R eferences to w ater s h a l l be understood to mean double d i s t i l l e d w ater or e q u iv a le n t. Care i n s e l e c t io n of re a g e n ts and in follow ing th e l i s t e d p re cau tio n s i s e s s e n t i a l i f low blank v alu es a r e to be o b tain ed . # ( (d) P e rc h lo ric a c id , re a g e n t grade. # ml. A sp ira te w ater a f t e r each sample. As a minimum, a m idrange standard must be a s p ira te d w ith s u f f i c i e n t frequency, i e , once every f iv e sam ples, to ensure th e accuracy of th e sample d e te rm in a tio n s. I t i s b e s t to run a stan d ard w ith a c o n c e n tra tio n c lo se to th a t of a sample a f t e r each sample i s ru n . To th e e x te n t p o s s ib le , base a l l d eterm in a tio n s on r e p l i c a t e an a ly se s. # 10,000 Cobaltous n i t r a t e 8,600 Cobaltous o x a la te 1,700 Cobaltous s u l f a t e 8,300 C obalt cyanide 7,200 C obalt hydroxide 2,500 C obalt 2-eth y lh ex o ate 3,900 Many of th ese workers would be p o t e n t i a l l y exposed to only sm all amounts of c o b a lt through i n h a la tio n , in g e s tio n , o r dermal c o n ta c t. The exposure e stim a te s are not a d d itiv e , sin ce some workers would be exposed to more than one compound. *Substance(s) com prising the d r i e r were no t i d e n t i f i e d . # Thyroid function studies do not seem necessary unless enlargement or some other sign or symptom of thyroid dysfunction la present. Present information suggests the possibility of polycythemia in the blood and electrocardiographic changes in the heart being produced by exposure to cobalt. The information is very unclear and appears to show effects only at a very high dosage. Therefore, no specific tests are suggested for these organ systems unless there is a potential for exposute to high levels of cobalt in the workplace. The medical surveillance program should be reevaluated frequently and changed to reflect current working conditions and knowledge of health effects. Medical records should be kept for 30 years after the worker's last exposure to cobalt. This will ensure compliance with OSHA's (29 CFR 1910.20) standard concerning worker's rights to his or her own medical records. # V I I . REFERENCES # 1. Morral FR: Cobalt and cobalt alloys, in Standen A (ed.): Kirk-Othmer Encyclopedia of Chemical Technology, ed 2 rev. New York, Interscience Publishers, 1970, vol 5, pp 716-48 2. Hawley GG (ed.): The Condensed Chemical Dictionary, ed 9. New York, Van Nostrand Reinhold Co, 1977, pp The effects of cobalt injections on total circulating red cell volume and bone marrow cytology in normal and adrenalectomized dogs. , 1970, pp 197,210,223,231,278,287,303,343,347 Once th e ashing i s com plete, remove th e w atch g lass, and allow th e sample to evaporate to near dryness (approxim ately 0 .5 m l). I f c h a rrin g o c c u rs, add HN03 (1 ml) and evaporate to near dryness (0 .5 ml) again. R epeat, i f n ecessary . Remove th e beaker from th e h o t p la t e , c o o l, and add 1 ml HN03 and 2-3 ml of d i s t i l l e d w ater. T ra n sfer th e s o lu tio n q u a n t i t a t i v e l y w ith d i s t i l l e d w ater to a 10-ml volum etric f l a s k , and then d i l u t e th e samples to volume (10 ml) w ith w ater.	None	None
2498baa2c9ab5c47907c82c4c231f261eea1cd35	cdc	None	and is being reprinted as a courtesy to the American Thoracic Society, the Infectious Diseases Society of America, and the MMWR readership.# What's New In This Document - The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient. - It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy. - Recommended treatment regimens are rated according to the strength of the evidence supporting their use. Where possible, other interventions are also rated. - Emphasis is placed on the importance of obtaining sputum cultures at the time of completion of the initial phase of treatment in order to identify patients at increased risk of relapse. - Extended treatment is recommended for patients with drug-susceptible pulmonary tuberculosis who have cavitation noted on the initial chest film and who have positive sputum cultures at the time 2 months of treatment is completed. - The roles of rifabutin, rifapentine, and the fluoroquinolones are discussed and a regimen with rifapentine in a once-a-week continuation phase for selected patients is described. - Practical aspects of therapy, including drug administration, use of fixed-dose combination preparations, monitoring and management of adverse effects, and drug interactions are discussed. - Treatment completion is defined by number of doses ingested, as well as the duration of treatment administration. - Special treatment situations, including human immunodeficiency virus infection, tuberculosis in children, extrapulmonary tuberculosis, culture-negative tuberculosis, pregnancy and breastfeeding, hepatic disease and renal disease are discussed in detail. - The management of tuberculosis caused by drug-resistant organisms is updated. - These recommendations are compared with those of the WHO and the IUATLD and the DOTS strategy is described. - The current status of research to improve treatment is reviewed. # Summary Responsibility for Successful Treatment The overall goals for treatment of tuberculosis are 1) to cure the individual patient, and 2) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy. Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control. However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician. # Organization and Supervision of Treatment Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. It is essential that treatment be tailored and supervision be based on each patient's clinical and social circumstances (patient-centered care). Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate diagnostic and treatment services are available, and for monitoring the results of therapy. It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision. This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy. Programs utilizing DOT as the central element in a comprehensive, patient-centered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies. Each patient's management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen. Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers. # Recommended Treatment Regimens The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA). The rating system includes a letter (A, B, C, D, or E) that indicates the strength of the recommendation and a roman numeral (I, II, or III) that indicates the quality of evidence supporting the recommendation (Table 1). There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms. Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances, described subsequently. Each regimen has an initial phase of 2 months followed by a choice of several options for the continuation phase of either 4 or 7 months. The recommended regimens together with the number of doses specified by the regimen are described in Table 2. The initial phases are denoted by a number (1, 2, 3, or 4) and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c). Drug doses are shown in Tables 3, 4, and 5. The general approach to treatment is summarized in Figure 1. Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2, Regimens 1-3). If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms (Table 6) or when the child has "adult-type" (upper lobe infiltration, cavity formation) tuberculosis. If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for 2 months (Regimen 4). Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy. EMB should be included in the initial phase of Regimen 4 until drug susceptibility is determined. The initial phase may be given daily throughout (Regimens 1 and 4), daily for 2 weeks and then twice weekly for 6 weeks (Regimen 2), or three times weekly throughout (Regimen 3). For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than 2 months (i.e., when susceptibility test results are known), but there is no evidence to support this approach. Although clinical trials have shown that the efficacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful. Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely. The continuation phase (Table 2) of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in the large majority of patients. The 7-month - Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given. † Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion. ‡ When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. § Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses or 62 doses ) continuation phase. ¶ Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. # Not recommended for HIV-infected patients with CD4 + cell counts <100 cells/µl. Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months. continuation phase is recommended only for three groups: patients with cavitary pulmonary tuberculosis caused by drugsusceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; patients whose initial phase of treatment did not include PZA; and patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the initial phase is positive. The continuation phase may be given daily (Regimens 1a and 4a), two times weekly by DOT (Regimens 1b, 2a, and 4b), or three times weekly by DOT (Regimen 3a). For human immunodeficiency virus (HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as determined by standard chest radiography), and negative sputum smears at completion of 2 months of treatment, the continuation phase may consist of rifapentine and INH given once weekly for 4 months by DOT (Regimens 1c and 2b) (Figure 1). If the culture at completion of the initial phase of treatment is positive, the once weekly INH and rifapentine continuation phase should be extended to 7 months. All of the 6-month regimens, except the INH-rifapentine once weekly continuation phase for persons with HIV infection (Rating EI), are rated as AI or AII, or BI or BII, in both HIV-infected and uninfected patients. The once-weekly continuation phase is contraindicated (Rating EI) in patients with HIV infection because of an unacceptable rate of failure/relapse, often with rifamycinresistant organisms. For the same reason twice weekly treatment, either as part of the initial phase (Regimen 2) or continuation phase (Regimens 1b and 2a), is not recommended for HIV-infected patients with CD4 + cell counts <100 cells/ µl. These patients should receive either daily (initial phase) or three times weekly (continuation phase) treatment. Regimen 4 (and 4a/4b), a 9-month regimen, is rated CI for patients without HIV infection and CII for those with HIV infection. # Deciding To Initiate Treatment The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPDtuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test Levofloxacin Tablets (50 mg, 100 mg, 300 mg); elixir (50 mg/5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection Capsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection Capsule (150 mg) Tablet (150 mg, film coated) Tablet (500 mg, scored) Tablet (100 mg, 400 mg) Capsule (250 mg) Tablet (250 mg) Aqueous solution (1-g vials) for intravenous or intramuscular administration Aqueous solution (500-mg and 1-g vials) for intravenous or intramuscular administration Aqueous solution (1-g vials) for intravenous or intramuscular administration Granules (4-g packets) can be mixed with food; tablets (500 mg) are still available in some countries, but not in the United States; a solution for intravenous administration is available in Europe Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500mg vials) for intravenous injection Adults (max.) Children (max.) Adults ‡ (max.) Children (max.) There are no data to support intermittent administration † † 15 mg/kg (900 mg) 20-30 mg/kg (900 mg) 10 mg/kg (600 mg) 10-20 mg/kg (600 mg) 5 mg/kg (300 mg) Appropriate dosing for children is unknown -The drug is not approved for use in children Adults See supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis (see below). If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic # TABLE 6. Epidemiological circumstances in which an exposed person is at increased risk of infection with drug-resistant Mycobacterium tuberculosis* - Exposure to a person who has known drug-resistant tuberculosis - Exposure to a person with active tuberculosis who has had prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known - Exposure to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance - Exposure to persons who continue to have positive sputum smears after 2 months of combination chemotherapy - Travel in an area of high prevalence of drug resistance # MMWR June 20,2003 acid amplification test, treatment can be continued to complete a standard course of therapy (Figure 1). When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPDtuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tubercu-losis (Figure 2). If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered. If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months) (Figure 2). In lowsuspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, one of the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include (1) INH for a total of 9 months, (2) RIF with or without INH for a total of 4 months, or (3) RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIF-PZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this egimen. # Baseline and Follow-Up Evaluations Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances. Susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Secondline drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drugresistant tuberculosis, who have demonstrated resistance to Patients in whom tuberculosis is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at the time of completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4 + cell count is <100/ µl, the continuation phase should consist of daily or three times weekly isoniazid and rifampin. In HIVuninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly isoniazid and rifapentine, or daily or twice weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). - EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. † PZA may be discontinued after it has been taken for 2 months (56 doses). ‡ RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. § Therapy should be extended to 9 months if 2-month culture is positive. CXR = chest radiograph; EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine. rifampin or to other first-line drugs, or who have positive cultures after more than 3 months of treatment. It is recommended that all patients with tuberculosis have counseling and testing for HIV infection, at least by the time treatment is initiated, if not earlier. For patients with HIV infection, a CD4 + lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses. For all adult patients baseline measurements of serum amino transferases (aspartate aminotransferase , alanine aminotransferase ), bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when EMB is to be used. During treatment of patients with pulmonary tuberculosis, a sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture. More frequent AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved. In addition, it is critical that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur. Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse). At each monthly visit patients taking EMB should be questioned regarding possible visual disturbances including blurred vision or scotomata; monthly testing of visual acuity and color discrimination is recommended for patients taking doses that on a milligram per kilogram basis are greater than those listed in Table 5 and for patients receiving the drug for longer than 2 months. # Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase of treatment is completed has been shown in clinical trials to identify patients at high risk for adverse outcomes (treatment failure, usually defined by positive cultures after 4 months of treatment, or relapse, defined by recurrent tuberculosis at any time after completion of treatment and apparent cure). For this reason it is particularly important to conduct a microbiological evaluation 2 months after initiation of treatment (Figure 1). Approximately 80% of patients # FIGURE 2. Treatment algorithm for active, culture-negative pulmonary tuberculosis and inactive tuberculosis The decision to begin treatment for a patient with sputum smears that are negative depends on the degree of suspicion that the patient has tuberculosis. The considerations in choosing among the treatment options are discussed in text. If the clinical suspicion is high (bottom), then multidrug therapy should be initiated before acid-fast smear and culture results are known. If the diagnosis is confirmed by a positive culture, treatment can be continued to complete a standard course of therapy (see Figure 1). If initial cultures remain negative and treatment has consisted of multiple drugs for 2 months, then there are two options depending on repeat evaluation at 2 months (bottom): 1) if the patient demonstrates symptomatic or radiographic improvement without another apparent diagnosis, then a diagnosis of culture-negative tuberculosis can be inferred. Treatment should be continued with isoniazid and rifampin alone for an additional 2 months; 2) if the patient demonstrates neither symptomatic nor radiographic improvement, then prior tuberculosis is unlikely and treatment is complete once treatment including at least 2 months of rifampin and pyrazinamide has been administered. In low-suspicion patients not initially receiving treatment (top), if cultures remain negative, the patient has no symptoms, and the chest radiograph is unchanged at 2-3 months, there are three treatment options: these are 1) isoniazid for 9 months, 2) rifampin with or without isoniazid for 4 months, or 3) rifampin and pyrazinamide for 2 months. CXR = chest X-ray; EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; Sx = signs/symptoms. (It should be noted that the RIF/PZA 2-month regimen should be used only for patients who are not likely to complete a longer course of treatment and can be monitored closely.) # MMWR June 20,2003 with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause. For patients who have positive cultures after 2 months of treatment and have not been receiving DOT, the most common reason is nonadherence to the regimen. Other possibilities, especially for patients receiving DOT, include extensive cavitary disease at the time of diagnosis, drug resistance, malabsorption of drugs, laboratory error, and biological variation in response. In USPHS Study 22, nearly 21% of patients in the control arm of the study (a continuation phase of twice weekly INH and RIF) who had both cavitation on the initial chest radiograph and a positive culture at the 2-month juncture relapsed. Patients who had only one of these factors (either cavitation or a positive 2-month culture) had relapse rates of 5-6% compared with 2% for patients who had neither risk factor. In view of this evidence, it is recommended that, for patients who have cavitation on the initial chest radiograph and whose 2-month culture is positive, the minimum duration of treatment should be 9 months (a total of 84-273 doses depending on whether the drugs are given daily or intermittently) (Figure 1 and Table 2). The recommendation to lengthen the continuation phase of treatment is based on expert opinion and on the results of a study of the optimal treatment duration for patients with silicotuberculosis showing that extending treatment from 6 to 8 months greatly reduced the rate of relapse (Rating AIII). The recommendation is also supported by the results of a trial in which the once weekly INHrifapentine continuation phase was extended to 7 months for patients at high risk of relapse. The rate of relapse was reduced significantly compared with historical control subjects from another trial in which the continuation phase was 4 months. For patients who have either cavitation on the initial film or a positive culture after completing the initial phase of treatment (i.e., at 2 months), the rates of relapse were 5-6%. In this group decisions to prolong the continuation phase should be made on an individual basis. # Completion of Treatment A full course of therapy (completion of treatment) is determined more accurately by the total number of doses taken, not solely by the duration of therapy. For example, the "6-month" daily regimen (given 7 days/week; see below) should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of treatment and accurately indicates the amount of time the drugs are given only if there are no interruptions in drug administration. In some cases, either because of drug toxicity or nonadherence to the treatment regimen, the specified number of doses cannot be administered within the targeted period. In such cases the goal is to deliver the specified number of doses within a recommended maximum time. For example, for a 6-month daily regimen the 182 doses should be administered within 9 months of beginning treatment. If treatment is not completed within this period, the patient should be assessed to determine the appropriate action to take-continuing treatment for a longer duration or restarting treatment from the beginning, either of which may require more restrictive measures to be used to ensure completion. Clinical experience suggests that patients being managed by DOT administered 5 days/week have a rate of successful therapy equivalent to those being given drugs 7 days/week. Thus, "daily therapy" may be interpreted to mean DOT given 5 days/week and the required number of doses adjusted accordingly. For example, for the 6-month "daily" regimen given 5 days/week the planned total number of doses is 130. (Direct observation of treatment given 5 days/week has been used in a number of clinical trials, including USPHS Study 22, but has not been evaluated in a controlled trial; thus, this modification should be rated AIII.) As an option, patients might be given the medications to take without DOT on weekends. Interruptions in treatment may have a significant effect on the duration of therapy. Reinstitution of treatment must take into account the bacillary load of the patient, the point in time when the interruption occurred, and the duration of the interruption. In general, the earlier in treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning. # Practical Aspects of Patient Management During Treatment The first-line antituberculosis medications should be administered together; split dosing should be avoided. Fixeddose combination preparations may be administered more easily than single drug tablets and may decrease the risk of acquired drug resistance and medication errors. Fixed-dose combinations may be used when DOT is given daily and are especially useful when DOT is not possible, but they are not formulated for use with intermittent dosing. It should be noted that for patients weighing more than 90 kg the dose of PZA in the three-drug combination is insufficient and additional PZA tablets are necessary. There are two combination formulations approved for use in the United States: INH and RIF (Rifamate ® ) and INH, RIF, and PZA (Rifater ® ). Providers treating patients with tuberculosis must be especially vigilant for drug interactions. Given the frequency of comorbid conditions, it is quite common for patients with tuberculosis to be taking a variety of other medications, the effects of which may be altered by the antituberculosis medications, especially the rifamycins. These interactions are described in Section 7, Drug Interactions. Adverse effects, especially gastrointestinal upset, are relatively common in the first few weeks of antituberculosis therapy; however, first-line antituberculosis drugs, particularly RIF, must not be discontinued because of minor side effects. Although ingestion with food delays or moderately decreases the absorption of antituberculosis drugs, the effects of food are of little clinical significance. Thus, if patients have epigastric distress or nausea with the first-line drugs, dosing with meals or changing the hour of dosing is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. Drug-induced hepatitis, the most serious common adverse effect, is defined as a serum AST level more than three times the upper limit of normal in the presence of symptoms, or more than five times the upper limit of normal in the absence of symptoms. If hepatitis occurs INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more antituberculosis medications without hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), may be used until the cause of the hepatitis is identified. Once the AST level decreases to less than two times the upper limit of normal and symptoms have significantly improved, the first-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients. # Treatment in Special Situations # HIV infection Recommendations for the treatment of tuberculosis in HIVinfected adults are, with a few exceptions, the same as those for HIV-uninfected adults (Table 2). The INH-rifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin-or rifabutin-based regimens. Consequently, patients with CD4 + cell counts <100/µl should receive daily or three times weekly treatment (Regimen 1/1a or Regimen 3/ 3a). DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis. Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified. On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic findings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinflammatory agents may be useful for symptomatic relief. For severe paradoxical reactions, prednisone (1-2 mg/kg per day for 1-2 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach (Rating CIII). # Children Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop "adult-type" tuberculosis with upper lobe infiltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances (Table 6) suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15-20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary. Most studies of treatment in children have used 6 months of INH and RIF supplemented during the first 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Most treatment studies of intermittent dosing in children have used daily drug administration for the first 2 weeks to 2 months. DOT should always be used in treating children. Because it is difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 9-12 months of treatment is recommended. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation. # Extrapulmonary tuberculosis The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although relatively few studies have examined treatment of extrapulmonary tuberculosis, increasing evidence suggests that 6-to 9-month regimens that include INH and RIF are effective. Thus, a 6-month course of therapy is recommended for treating tuberculosis involving any site with the exception of the meninges, for which a 9-12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis. # Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months. Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely) (Figure 2). # Renal insufficiency and end-stage renal disease Specific dosing guidelines for patients with renal insufficiency and end-stage renal disease are provided in Table 15. For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs. # Liver disease INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation. In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury. # Pregnancy and breastfeeding Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount. # Management of Relapse, Treatment Failure, and Drug Resistance Relapse refers to the circumstance in which a patient becomes and remains culture negative while receiving therapy but, at some point after completion of therapy, either becomes culture positive again or has clinical or radiographic deterioration that is consistent with active tuberculosis. In the latter situation rigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. Most relapses occur within the first 6-12 months after completion of therapy. In nearly all patients with tuberculosis caused by drugsusceptible organisms and who were treated with rifamycincontaining regimens using DOT, relapses occur with susceptible organisms. However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycincontaining regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. The selection of empirical treatment for patients with relapse should be based on the prior treatment scheme and severity of disease. For patients with tuberculosis that was caused by drug-susceptible organisms and who were treated under DOT, initiation of the standard four-drug regimen is appropriate until the results of drug susceptibility tests are available. However, for patients who have life-threatening forms of tuberculosis, at least three additional agents to which the organisms are likely to be susceptible should be included. For patients with relapse who did not receive DOT, who were not treated with a rifamycin-based regimen, or who are known or presumed to have had irregular treatment, it is prudent to infer that drug resistance is present and to begin an expanded regimen with INH, RIF, and PZA plus an additional two or three agents based on the probability of in vitro susceptibility. Usual agents to be employed would include a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), an injectable agent such as SM (if not used previously and susceptibility to SM had been established), amikacin, kanamycin, or capreomycin, with or without an additional oral drug. Treatment failure is defined as continued or recurrently positive cultures during the course of antituberculosis therapy. After 3 months of multidrug therapy for pulmonary tuberculosis caused by drug-susceptible organisms, 90 Possible reasons for treatment failure in patients receiving appropriate regimens include nonadherence to the drug regimen (the most common reason), drug resistance, malabsorption of drugs, laboratory error, and extreme biological variation in response. If treatment failure occurs, early consultation with a specialty center is strongly advised. If failure is likely due to drug resistance and the patient is not seriously ill, an empirical retreatment regimen could be started or administration of an altered regimen could be deferred until results of drug susceptibility testing from a recent isolate are available. If the patient is seriously ill or sputum AFB smears are positive, an empirical regimen should be started immediately and continued until susceptibility tests are available. For patients who have treatment failure, M. tuberculosis isolates should be sent promptly to a reference laboratory for drug susceptibility testing to both first-and second-line agents. A fundamental principle in managing patients with treatment failure is never to add a single drug to a failing regimen; so doing leads to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs to which susceptibility could logically be inferred should be added to lessen the probability of further acquired resistance. Empirical retreatment regimens might include a fluoroquinolone, an injectable agent such as SM (if not used previously and the patient is not from an area of the world having high rates of SM resistance), amikacin, kanamycin, or capreomycin, and an additional oral agent such as p-aminosalicylic acid (PAS), cycloserine, or ethionamide. Once drug-susceptibility test results are available, the regimen should be adjusted according to the results. Patients having tuberculosis caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug-resistant ) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or consultation obtained from specialized treatment centers as identified by the local or state health departments or CDC. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert. Definitive randomized or controlled studies have not been performed to establish optimum regimens for treating patients with the various patterns of drug-resistant tuberculosis; thus, treatment recommendations are based on expert opinion, guided by a set of general principles specified in Section 9, Management of Relapse, Treatment Failure, and Drug Resistance. Table 16 contains treatment regimens suggested for use in patients with various patterns of drug-resistant tuberculosis (all are rated AIII). The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies and results have been mixed. Surgery should be performed by surgeons with experience in these situations and only after the patient has received several months of intensive chemotherapy. Expert opinion suggests that chemotherapy should be continued for 1-2 years postoperatively to prevent relapse. # Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/ CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in highincidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin. The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field. The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS," the acronym for "directly observed therapy, short course," in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data. New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection. A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of "protective" cytokines such as interferon-γ and interleukin-2, and nutritional supplements, especially vitamin A and zinc. Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT. # Introduction and Background Since 1971 the American Thoracic Society (ATS) and CDC have regularly collaborated to develop joint guidelines for the diagnosis, treatment, prevention, and control of tuberculosis (1). These documents have been intended to guide both public health programs and health care providers in all aspects of the clinical and public health management of tuberculosis in low-incidence countries, with a particular focus on the United States. The most recent version of guidelines for the treatment of tuberculosis was published in 1994 (2). The current document differs from its predecessor in a number of important areas that are summarized above. The process by which this revision of the recommendations for treatment was developed was modified substantially from the previous versions. For the first time the Infectious Diseases Society of America (IDSA) has become a cosponsor of the statement, together with the ATS and CDC. The IDSA has had representation on prior statement committees but has not previously been a cosponsor of the document. Practice guidelines that serve to complement the current statement have been developed by the IDSA (3). In addition to the IDSA, representatives of the American Academy of Pediatrics (AAP), the (United States) National Tuberculosis Controllers Association (NTCA), the Canadian Thoracic Society (CTS), the IUATLD, and the WHO participated in the revision. By virtue of their different perspectives these committee members served to provide broader input and to help ensure that the guidelines are sputum smear microscopy among symptomatic patients selfreporting to health services, 3) a standardized treatment regimen of 6-8 months for at least all confirmed sputum smear-positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall. A number of other differences exist as well: # A Research Agenda for Tuberculosis Treatment New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the placed in an appropriate context. It should be emphasized that the current guidelines are intended for areas in which mycobacterial cultures, drug susceptibility tests, radiographic facilities, and second-line drugs are available, either immediately or by referral, on a routine basis. For this revision of the recommendations essentially all clinical trials of antituberculosis treatment in the English language literature were reviewed and the strength of the evidence they presented was rated according to the IDSA/USPHS rating scale (4). This revision of the recommendations for treatment of tuberculosis presents a significant philosophic departure from previous versions. In this document the responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse. For these reasons, antituberculosis chemotherapy is both a personal and a public health measure that cannot be equated with the treatment of, for example, hypertension or diabetes mellitus, wherein the benefits largely accrue to the patient. Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. All reasonable attempts should be made to accommodate the patient so that a successful outcome is achieved. However, interventions such as detention may be necessary for patients who are persistently nonadherent. The recommendations in this statement are not applicable under all epidemiologic circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. Although the basic principles of therapy described in this document apply regardless of conditions, the diagnostic approach, methods of patient supervision, and monitoring for response and for adverse drug effects, and in some instances the regimens recommended, are quite different in highincidence, low-income areas compared with low-incidence, high-income areas of the world. A summary of the important differences between the recommendations in this document and those of the IUATLD and the WHO is found in Section 10,Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUTLD. In the United States there has been a call for the elimination of tuberculosis, and a committee constituted by the Institute of Medicine (IOM) issued a set of recommendations for reaching this goal (5). The IOM committee had two main recommendations related to treatment of tuberculosis; first, that all U.S jurisdictions have health regulations that mandate completion of therapy (treatment until the patient is cured); and second, that all treatment be administered in the context of patient-centered programs that are based on individual patient characteristics and needs. The IOM recommendations emphasize the importance of the structure and organization of treatment services, as well as the drugs that are used, to treat patients effectively. This philosophy is the core of the DOTS strategy (described in Section 10 Treatment of Tuberculosis in Low-Income Countries: Recommendations oof the WHO and the IUTLD), developed by the IUATLD and implemented globally by the WHO. Thus, although there are superficial differences in the approach to tuberculosis treatment between high-and low-incidence countries, the fundamental concern, regardless of where treatment is given, is ensuring patient adherence to the drug regimen and successful completion of therapy (6). # Provider Responsibility Treatment of tuberculosis benefits both the community as a whole and the individual patient; thus, any public health program or private provider (or both in a defined arrangement by which management is shared) undertaking to treat a patient with tuberculosis is assuming a public health function that includes not only prescribing an appropriate regimen but also ensuring adherence to the regimen until treatment is completed. # Organization and Supervision of Treatment Successful treatment of tuberculosis depends on more than the science of chemotherapy. To have the highest likelihood of success, chemotherapy must be provided within a clinical and social framework based on an individual patient's circumstances. Optimal organization of treatment programs requires an effective network of primary and referral services and cooperation between clinicians and public health officials, between health care facilities and community outreach programs, and between the private and public sectors of medical care. This section describes the approaches to organization of treatment that serve to ensure that treatment has a high likelihood of being successful. As noted previously, antituberculosis chemotherapy is both a personal health measure intended to cure the sick patient and a basic public health strategy intended to reduce the transmission of Mycobacterium tuberculosis. Typically, tuberculosis treatment is provided by public health departments, often working in collaboration with other providers and organizations including private physicians, community health centers, migrant health centers, correctional facilities, hospitals, hospices, long-term care facilities, and homeless shelters. Private providers and public health departments may cosupervise patients, assuring that the patient completes therapy in a setting that is not only mutually agreeable but also enables access to tuberculosis expertise and resources that might otherwise not be available. In managed care settings delivery of tuberculosis treatment may require a more structured public/private partnership, often defined by a contract, to assure completion of therapy. Regardless of the means by which treatment is provided, the ultimate legal authority for assuring that patients complete therapy rests with the public health system. # Role of the Health Department The responsibility of the health department in the control of tuberculosis is to ensure that all persons who are suspected of having tuberculosis are identified and evaluated promptly and that an appropriate course of treatment is prescribed and completed successfully (1,2). A critical component of the evaluation scheme is access to proficient microbiological laboratory services, for which the health department is responsible. The responsibilities of the health department may be accomplished indirectly by epidemiologic surveillance and monitoring of treatment decisions and outcome, applying generally agreed-on standards and guidelines, or more directly by provision of diagnostic and treatment services, as well as by conducting epidemiologic investigations. Given the diverse sociodemographic characteristics of patients with tuberculosis and the many mechanisms by which health care is delivered, the means by which the goals of the health department are accomplished may be quite varied. In dealing with individual patients, approaches that focus on each person's needs and characteristics should be used to determine a tailored treatment plan that is designed to ensure completion of therapy (3). Such treatment plans are developed with the patient as an active participant together with the physician and/or nurse, outreach workers, social worker (when needed), and others as appropriate. Given that onehalf the current incident cases of tuberculosis in the United States were born outside the United States (similar circumstances prevail in most other low-incidence countries), translation of materials into the patient's primary language is often necessary to ensure his/her participation in developing the treatment plan. Ideally, a specific case manager is assigned individual responsibility for assuring that the patient completes therapy. The treatment plan is reviewed periodically and revised as needed. These reviews may be accomplished in meetings between the patient and the assigned provider, as well as more formally through case and cohort evaluations. The treatment plan is based on the principle of using the least restrictive measures that are likely to achieve success. The full spectrum of measures that may be employed ranges from, at an absolute minimum, monthly monitoring of the patient in the outpatient setting to legally mandated hospitalization (4). Directly observed therapy (DOT) is the preferred initial means to assure adherence. For nonadherent patients more restrictive measures are implemented in a stepwise fashion. Any approach must be balanced, ensuring that the needs and rights of the patient, as well as those of the public, are met. Care plans for patients being managed in the private sector should be developed jointly by the health department and the private provider, and must address identified and anticipated barriers to adherence. # Promoting Adherence Louis Pasteur once said, "The microbe is nothing...the terrain everything" (5). Assuming appropriate drugs are prescribed, the terrain (the circumstances surrounding each patient that may affect his or her ability to complete treatment) # What's DOT? Direct observation of therapy (DOT) involves providing the antituberculosis drugs directly to the patient and watching as he/she swallows the medications. It is the preferred core management strategy for all patients with tuberculosis. becomes the most important consideration in completion of tuberculosis treatment. Many factors may be part of this terrain. Factors that interfere with adherence to the treatment regimen include cultural and linguistic barriers to cooperation, lifestyle differences, homelessness, substance abuse, and a large number of other conditions and circumstances that, for the patient, are priorities that compete with taking treatment for tuberculosis (6). Barriers may be patient related, such as conflicting health beliefs, alcohol or drug dependence, or mental illness, or they may be system related, such as lack of transportation, inconvenient clinic hours, and lack of interpreters (7). Effective tuberculosis case management identifies and characterizes the terrain and determines an appropriate care plan based on each of the identified factors. Additional advantages of the patient-centered approach are that, by increasing communication with the patient, it provides opportunities for further education concerning tuberculosis and enables elicitation of additional information concerning contacts. To maximize completion of therapy, patient-centered programs identify and utilize a broad range of approaches based on the needs and circumstances of individual patients. Among these approaches, DOT is the preferred initial strategy and deserves special emphasis. Although DOT itself has not been subjected to controlled trials in low-incidence areas (and, thus, is rated AII), observational studies and a meta-analysis in the United States strongly suggest that DOT, coupled with individualized case management, leads to the best treatment results (8-10). To date there have been three published studies of DOT in high-incidence areas, two of which (11,12) showed no benefit and one (13) in which there was a significant advantage for DOT. What is clear from these studies is that DOT cannot be limited merely to passive observation of medication ingestion; there must be aggressive interventions when patients miss doses. Using DOT in this manner can only improve results. DOT can be provided daily or intermittently in the office, clinic, or in the "field" (patient's home, place of employment, school, street corner, bar, or any other site that is mutually agreeable) by appropriately trained personnel. DOT should be used for all patients residing in institutional settings such as hospitals, nursing homes, or correctional facilities, or in other settings, such as methadone treatment sites, that are conducive to observation of therapy (14). However, even in such supervised settings careful attention must be paid to ensuring that ingestion of the medication is, in fact, observed. It is essential that all patients being treated with regimens that use intermittent drug administration have all doses administered under DOT because of the potentially serious consequences of missed doses. DOT also enables early identification of nonadherence, adverse drug reactions, and clinical worsening of tuberculosis. DOT provides a close connection to the health care system for a group of patients at high risk of other adverse health events and, thus, should facilitate identification and management of other conditions. The use of DOT does not guarantee ingestion of all doses of every medication (15). Patients may miss appointments, may not actually swallow the pills, or may deliberately regurgitate the medications. Consequently, all patients, including those who are being treated by DOT, should continue to be monitored for signs of treatment failure. DOT is only one aspect of a comprehensive patient-centered program that, in addition, includes incentives and enablers described subsequently (16)(17)(18)(19)(20). Patients who are more likely to present a transmission risk to others or are more likely to have problems with adherence (Table 7) should be prioritized for DOT when resources are limited. When DOT is not being used, fixeddose combination preparations (see Section 6.2, Fixed-Dose Combination Preparations) containing INH and RIF or INH, RIF, and PZA reduce the risk of the patient taking only one drug and may help prevent the development of drug resistance. Combination formulations are easier to administer and also may reduce medication errors. Depending on the identified obstacles to completion of therapy, the treatment plan may also include enablers and incentives such as those listed in Table 8. Studies have examined the use of a patient-centered approach that utilizes DOT in addition to other adherence-promoting tools (9,21,22). These studies demonstrate, as shown in Figure 3, that "enhanced DOT" (DOT together with incentives and enablers) produces the highest treatment completion rates (in excess of 90% across a range of geographic and socioeconomic settings), and reinforces the importance of patient-related factors in designing and implementing case management (9,23). Intensive educational efforts should be initiated as soon as the patient is suspected of having tuberculosis. The instruction should be at an educational level appropriate for the patient and should include information about tuberculosis, expected outcomes of treatment, the benefits and possible adverse effects of the drug regimen, methods of supervision, assessment of response, and a discussion of infectiousness and infection control. The medication regimen must be explained in clear, understandable language and the verbal explanation followed with written instructions. An interpreter is necessary when the patient and health care provider do not speak the same language. Materials should be appropriate for the culture, language, age, and reading level of the patient. Relevant information should be reinforced at each visit. The patient's clinical progress and the treatment plan must be reviewed at least monthly to evaluate the response to therapy and to identify adherence problems. Use of a record system (Figure 4) either manual or computer-based, that quantifies the dosage and frequency of medication administered, indicates AFB smear and culture status, and notes symptom improvement as well as any adverse effects of treatment serves to facilitate the regular reviews and also provides data for cohort analyses. In addition, adherence monitoring by direct methods, such as the detection of drugs or drug metabolites in the patient's urine, or indirect methods, such as pill counts or a medication monitor, should be a part of routine management, especially if the patient is not being given DOT. Tracking patients is also a critical concern for those charged with assuring completion of treatment. It has been shown that patients who move from one jurisdiction to another before completion of therapy are much more likely to default than patients who do not move (24). Factors that have been shown to be associated with moving/defaulting include diagnosis of tuberculosis in a state correctional facility, drug and alcohol # Tracking Tuberculosis Inter-and intrastate notifications constitute the key patient-tracking systems for patients moving within the United States. International notifications can also be made, although specific tracking programs vary by country. Currently there are two formal patienttracking systems in operation for patients moving across the United States-Mexico border: TB Net, operated by the Migrant Clinician Network based in Austin, Texas (; telephone, 512-327-2017) and Cure TB, managed by the San Diego County, California, Division of Tuberculosis Control (http:// www.curetb.org; telephone, 619-692-5719). abuse, and homelessness. Communication and coordination of services among different sources of care and different health departments are especially important for patients in these groups as well as for migrant workers and other patients with no permanent home. Such communication may also be necessary across national boundaries, especially the United States-Mexico border, and there are systems in place to facilitate such communication and tracking. Some patients, for example those with tuberculosis caused by drug-resistant organisms, or who have comorbid conditions, such as HIV infection, alcoholism, or other significant underlying disorders, may need to be hospitalized in a facility where tuberculosis expertise is available and where there are appropriate infection control measures in place. Hospitalization may be necessary for nonadherent patients for whom less restrictive measures have failed (25)(26)(27). Public health laws exist in most states that allow the use of detainment under these circumstances, at least for patients who remain infectious (28). Court-ordered DOT has been used successfully in some states as a less costly alternative. The use of these interventions depends on the existence of appropriate laws, cooperative courts, and law enforcement officials, and the availability of appropriate facilities. Health departments must be consulted to initiate legal action when it is necessary. # Drugs in Current Use Currently, there are 10 drugs approved by the United States Food and Drug Administration (FDA) for treating tuberculosis (Table 9). In addition, the fluoroquinolones, although not approved by the FDA for tuberculosis, are used relatively commonly to treat tuberculosis caused by drug-resistant organisms or for patients who are intolerant of some of the first-line drugs. Rifabutin, approved for use in preventing Mycobacterium avium complex disease in patients with HIV infection but not approved for tuberculosis, is useful for treating tuberculosis in patients concurrently taking drugs that have unacceptable interactions with other rifamycins. Amikacin and kanamycin, nearly identical aminoglycoside drugs used in treating patients with tuberculosis caused by drug-resistant organisms, are not approved by the FDA for tuberculosis. Of the approved drugs isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) are considered first-line antituberculosis agents and form the core of initial treatment regimens. Rifabutin and rifapentine may also be considered first-line agents under the specific situations described below. Streptomycin (SM) was formerly considered to be a first-line agent and, in some instances, is still used in initial treatment; however, an increasing prevalence of resistance to SM in many parts of the world has decreased its overall usefulness. The remaining drugs are reserved for special situations such as drug intolerance or resistance. The drug preparations available currently and the recommended doses are shown in Tables 3, 4, and 5. # First-Line Drugs # Isoniazid Role in treatment regimen. Isoniazid (INH) is a first-line agent for treatment of all forms of tuberculosis caused by organisms known or presumed to be susceptible to the drug. It has profound early bactericidal activity against rapidly dividing cells (1,2). Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily; 15 mg/kg (900 mg) once, twice, or three times weekly. Children (maximum): 10-15 mg/kg (300 mg) daily; 20-30 mg/kg (900 mg) twice weekly (3). Preparations. Tablets (50 mg, 100 mg, 300 mg); syrup (50 mg/5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection. Adverse effects. Asymptomatic elevation of aminotransferases: Aminotransferase elevations up to five times the upper limit of normal occur in 10-20% of persons receiving INH alone for treatment of latent tuberculosis infection (4). The enzyme levels usually return to normal even with continued administration of the drug. Clinical hepatitis: (see Table 10.) Data indicate that the incidence of clinical hepatitis is lower than was previously thought. Hepatitis occurred in only 0.1-0.15% of 11,141 persons receiving INH alone as treatment for latent tuberculosis infection in an urban tuberculosis control program (5). Prior studies suggested a higher rate, and a meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH alone to be 0.6% (6)(7)(8). In the meta-analysis the rate of clinical hepatitis was 1.6% when INH was given with other agents, not including RIF. The risk was higher when the drug was combined with RIF, an average of 2.7% in 19 reports (8). For INH alone the risk increases with increasing age; it is uncommon in persons less than 20 years of age but is nearly 2% in persons aged 50-64 years (6). The risk also may be increased in persons with underlying liver disease, in those with a history of heavy alcohol consumption, and, data suggest, in the postpartum period, particularly among Hispanic women (9). Fatal hepatitis: A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower (10,11). The risk may be increased in women. Death has been associated with continued administration of INH despite onset of symptoms of hepatitis (12). Peripheral neurotoxicity (13,14): This adverse effect is dose related and is uncommon (less than 0.2%) at conventional doses (15)(16)(17). The risk is increased in persons with other conditions that may be associated with neuropathy such as nutritional deficiency, diabetes, HIV infection, renal failure, and alcoholism, as well as for pregnant and breastfeeding women. Pyridoxine supplementation (25 mg/day) is recommended for patients with these conditions to help prevent this neuropathy (18). Central nervous system effects: Effects such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate have been reported but have not been quantified. Lupus-like syndrome (19): Approximately 20% of patients receiving INH develop anti-nuclear antibodies. Less than 1% develop clinical lupus erythematosis, necessitating drug discontinuation. Hypersensitivity reactions: Reactions, such as fever, rash, Stevens-Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare. Monoamine (histamine/tyramine) poisoning: This has been reported to occur after ingestion of foods and beverages with high monoamine content but is rare (20)(21)(22). If flushing occurs, patients should be instructed to avoid foods and drinks, such as certain cheeses and wine, having high concentrations of monoamines. Diarrhea: Use of the commercial liquid preparation of INH, because it contains sorbitol, is associated with diarrhea. Use in pregnancy. INH is considered safe in pregnancy, but the risk of hepatitis may be increased in the peripartum period (9,23). Pyridoxine supplementation (25 mg/day) is recommended if INH is administered during pregnancy (18). It should be noted that multivitamin preparations have variable amounts of pyridoxine but generally less than 25 mg/day and, thus, do not provide adequate supplementation. CNS penetration. Penetration is excellent. Cerebrospinal fluid (CSF) concentrations are similar to concentrations achieved in serum (24). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) INH can be used safely without dose adjustment in patients with renal insufficiency (25) and with end-stage renal isease who require chronic hemodialysis (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The risk of drug accumulation and drug-induced hepatitis may be increased in the presence of hepatic disease; however, INH may be used in patients with stable hepatic disease. Laboratory and clinical monitoring should be more frequent in such situations. Monitoring. Routine monitoring is not necessary. However, for patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of the drug, liver function tests should be measured monthly and when symptoms occur. Serum concentrations of phenytoin and carbamazepine may be increased in persons taking INH. However, in combination therapy with RIF the effects of INH on serum concentrations of the anticonvulsants are limited by the decrease caused by RIF. Thus, it is important to measure serum concentrations of these drugs in patients receiving INH with or without RIF and adjust the dose if necessary. # Rifampin Role in treatment regimen. Rifampin (RIF) is a first-line agent for treatment of all forms of tuberculosis caused by organisms with known or presumed sensitivity to the drug. It has activity against organisms that are dividing rapidly (early bactericidal activity) (1) and against semidormant bacterial populations, thus accounting for its sterilizing activity (27). Rifampin is an essential component of all short-course regimens. Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg) once daily, twice weekly, or three times weekly. Children (maximum): 10-20 mg/kg (600 mg) once daily or twice weekly. Preparations. Capsules (150 mg, 300 mg); contents of capsule may also be mixed in an appropriate diluent to prepare an oral suspension; aqueous solution for parenteral administration. # Adverse effects (28). Cutaneous reactions (29): Pruritis with or without rash may occur in as many as 6% of patients but is generally selflimited (30). This reaction may not represent true hypersensitivity and continued treatment with the drug may be possible. More severe, true hypersensitivity reactions are uncommon, occurring in 0.07-0.3% of patients (17,31,32). Gastrointestinal reactions (nausea, anorexia, abdominal pain): The incidence is variable, but symptoms are rarely severe enough to necessitate discontinuation of the drug (28)(29)(30). Flulike syndrome: This may occur in 0.4-0.7% of patients receiving 600 mg twice weekly but not with daily administration of the same dose (31)(32)(33)(34). Symptoms are more likely to occur with intermittent administration of a higher dose (29,35). Hepatotoxicity: Transient asymptomatic hyperbilirubinemia may occur in as many as 0.6% of patients receiving the drug. More severe clinical hepatitis that, typically, has a cholestatic pattern may also occur (8,36). Hepatitis is more common when the drug is given in combination with INH (2.7%) than when given alone (nearly 0%) or in combination with drugs other than INH (1.1%) (8). Severe immunologic reactions: In addition to cutaneous reactions and flulike syndrome, other reactions thought to be immune mediated include the following: thrombocytopenia, hemolytic anemia, acute renal failure, and thrombotic thrombocytopenic purpura. These reactions are rare, each occurring in less than 0.1% of patients (31,32,37). Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. # Rifabutin and Rifapentine The newer rifamycins, rifabutin and rifapentine, should be considered first-line drugs in special situations: rifabutin for patients who are receiving medications, especially antiretroviral drugs, that have unacceptable interactions with rifampin or who have experienced intolerance to rifampin; and rifapentine, together with INH, in a once-a-week continuation phase for certain selected patients who meet specified criteria. # Drug interactions due to induction of hepatic microsomal enzymes: There are a number of drug interactions (described in Section 7, Drug Interactions, and Table 12) with potentially serious consequences. Of particular concern are reductions, often to ineffective levels, in serum concentrations of common drugs, such as oral contraceptives, methadone, and warfarin. In addition there are important bidirectional interactions between rifamycins and antiretroviral agents. Because information regarding rifamycin drug interactions is evolving rapidly, readers are advised to consult the CDC web site www.cdc.gov/nchstp/tb/ to obtain the most up-to-date information. Use in pregnancy. RIF is considered safe in pregnancy (38). CNS penetration. Concentrations in the CSF may be only 10-20% of serum levels, but this is sufficient for clinical efficacy. Penetration may be improved in the setting of meningitis (39). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) RIF can be used safely without dose adjustment in patients with renal insufficiency and endstage renal disease (26,40). Use in hepatic disease. (see Section 8.8: Hepatic Disease.) Clearance of the drug may be impaired in the presence of liver disease, causing increased serum levels (40). However, because of the critical importance of rifampin in all short-course regimens, it generally should be included, but the frequency of clinical and laboratory monitoring should be increased. Monitoring. No routine monitoring tests are required. However, rifampin causes many drug interactions described in Section 7, Drug Interactions, that may necessitate regular measurements of the serum concentrations of the drugs in question. # Rifabutin Role in treatment regimen. Rifabutin is used as a substitute for RIF in the treatment of all forms of tuberculosis caused by organisms that are known or presumed to be susceptible to this agent. The drug is generally reserved for patients who are receiving any medication having unacceptable interactions with rifampin (41) or have experienced intolerance to rifampin. Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily, twice, or three times weekly. The dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. When rifabutin is used with efavirenz the dose of rifabutin should be increased to 450-600 mg either daily or intermittently. Because information regarding rifamycin drug interactions is evolving rapidly readers are advised to consult the CDC web site, / nchstp/tb/, to obtain the most up-to-date information. # Children (maximum): Appropriate dosing for children is unknown. Preparations: Capsules (150 mg) for oral administration. # Adverse effects. Hematologic toxicity: In a placebo-controlled, double-blind trial involving patients with advanced acquired immunodeficiency syndrome (AIDS) (CD4+ cell counts <200 cells/µl), neutropenia occurred in 25% compared with 20% in patients receiving placebo (p = 0.03). Neutropenia severe enough to necessitate discontinuation of the drug occurred in 2% of patients receiving the drug (product insert B; Adria Laboratories, Columbus, OH). The effect is dose related, occurring more frequently with daily than with intermittent administration of the same dose (42). In several studies of patients with and without HIV infection, neither neutropenia nor thrombocytopenia was associated with rifabutin (43)(44)(45)(46)(47). Uveitis: This is a rare (less than 0.01%) complication when the drug is given alone at a standard (300 mg daily) dose. The occurrence is higher (8%) with higher doses or when rifabutin is used in combination with macrolide antimicrobial agents that reduce its clearance (48). Uveitis may also occur with other drugs that reduce clearance such as protease inhibitors and azole antifungal agents. Gastrointestinal symptoms: These symptoms occurred in 3% of patients with advanced HIV infection given 300 mg/day (package insert). In subsequent studies no increased incidence of gastrointestinal symptoms was noted among patients taking rifabutin (43,44,(46)(47)(48). Polyarthralgias: This symptom occurred in 1-2% of persons receiving a standard 300-mg dose (package insert). It is more common at higher doses (48). Polyarthralgias have not been noted in more recent studies involving both HIV-infected and uninfected patients (43,44,46,47). Hepatotoxity: Asymptomatic elevation of liver enzymes has been reported at a frequency similar to that of RIF (48). Clinical hepatitis occurs in less than 1% of patients receiving the drug. Pseudojaundice (skin discoloration with normal bilirubin): This is usually self-limited and resolves with discontinuation of the drug (49). Rash: Although initially reported to occur in as many as 4% of patients with advanced HIV infection, subsequent studies suggest that rash is only rarely (less than 0.1%) associated with rifabutin (46). Flulike syndrome: Flulike syndrome is rare (less than 0.1%) in patients taking rifabutin. Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. # Use in pregnancy. There are insufficient data to recommend the use of rifabutin in pregnant women; thus, the drug should be used with caution in pregnancy. CNS penetration. The drug penetrates inflamed meninges (50). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Rifabutin may be used without dosage adjustment in patients with renal insufficiency and end-stage renal disease (50). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The drug should be used with increased clinical and laboratory monitoring in patients with underlying liver disease. Dose reduction may be necessary in patients with severe liver dysfunction (50). Monitoring. Monitoring is similar to that recommended for rifampin. Although drug interactions are less problematic with rifabutin, they still occur and close monitoring is required. # Rifapentine Role in treatment regimen. Rifapentine may be used once weekly with INH in the continuation phase of treatment for HIV-seronegative patients with noncavitary, drug-susceptible pulmonary tuberculosis who have negative sputum smears at completion of the initial phase of treatment (51). Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg), once weekly during the continuation phase of treatment. Data have suggested that a dose of 900 mg is well tolerated but the clinical efficacy of this dose has not been established (52). Children: The drug is not approved for use in children. Preparation. Tablet (150 mg, film coated). # Adverse effects. The adverse effects of rifapentine are similar to those associated with RIF. Rifapentine is an inducer of multiple hepatic enzymes and therefore may increase metabolism of coadministered drugs that are metabolized by these enzymes (see Section 7: Drug Interactions). Use in pregnancy. There is not sufficient information to recommend the use of rifapentine for pregnant women. CNS penetration. There are no data on CSF concentrations of rifapentine. Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease .) The pharmacokinetics of rifapentine have not been evaluated in patients with renal impairment. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function in the disposition of rifapentine is not known. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The pharmacokinetics of rifapentine and its 25-desacetyl metabolite were similar among patients with various degrees of hepatic impairment and not different from those in healthy volunteers, even though the elimination of these compounds is primarily via the liver (53). The clinical significance of impaired hepatic function in the disposition of rifapentine and its 25-desacetyl metabolite is not known. Monitoring. Monitoring is similar to that for RIF. Drug interactions involving rifapentine are being investigated and are likely to be similar to those of RIF. # Pyrazinamide Role in treatment regimen. Pyrazinamide (PZA) is a firstline agent for the treatment of all forms of tuberculosis caused by organisms with known or presumed susceptibility to the drug. The drug is believed to exert greatest activity against the population of dormant or semidormant organisms contained within macrophages or the acidic environment of caseous foci (54). Dose. See Tables 3 and 4. Adults: 20-25 mg/kg per day. Recommended adult dosages by weight, using whole tablets, are listed in Table 4. Children (maximum): 15-30 mg/kg (2.0 g) daily; 50 mg/kg twice weekly (2.0 g). Preparations. Tablets (500 mg, scored). # Adverse effects. Hepatotoxicity: Early studies (55,56) using doses of 40-70 mg/kg per day reported high rates of hepatotoxicity. However, in treatment trials with multiple other drugs, including INH, liver toxicity has been rare at doses of 25 mg/kg per day or less (15,34,57). In one study, however, hepatotoxicity attributable to PZA used in standard doses occurred at a rate of about 1% (58). Gastrointestinal symptoms (nausea, vomiting): Mild anorexia and nausea are common at standard doses. Vomiting and severe nausea are rare except at high doses (59). Nongouty polyarthralgia: Polyarthralgias may occur in up to 40% of patients receiving daily doses of PZA. This rarely requires dosage adjustment or discontinuation of the drug (60). The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents. In clinical trials of PZA in the initial intensive phase of treatment, athralgias were not noted to be a significant problem (15,61). Asymptomatic hyperuricemia: This is an expected effect of the drug and is generally without adverse consequence (15,62). Acute gouty arthritis: Acute gout is rare except in patients with preexisting gout (63), generally a contraindication to the use of the drug. Transient morbilliform rash: This is usually self-limited and is not an indication for discontinuation of the drug. Dermatitis: PZA may cause photosensitive dermatitis (59). # Use in pregnancy. There is little information about the safety of PZA in pregnancy. However, when there are sound reasons to utilize a 6-month course of treatment, the benefits of PZA may outweigh the possible (but unquantified) risk. The WHO and the IUATLD recommend this drug for use in pregnant women with tuberculosis (see Section 10: Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUATLD). CNS penetration. The drug passes freely into the CSF, achieving concentrations equivalent to those in serum (64). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) PZA is cleared primarily by the liver, but its metabolites are excreted in the urine and may accumulate in patients with renal insufficiency (65). The dose may, therefore, need to be reduced in patients with renal insufficiency. It should be administered at a reduced dose (25-35 mg/kg) three times a week after dialysis in patients with end-stage renal disease (Table 15) (26). The risk of hyperuricemia caused by PZA is increased in patients with renal insufficiency. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Although the frequency is slightly lower than with INH or RIF, the drug can cause liver injury that may be severe and prolonged. If the drug is used in patients with underlying liver disease, laboratory and clinical monitoring should be increased. Monitoring. Serum uric acid measurements are not recommended as a routine but may serve as a surrogate marker for compliance. Liver chemistry monitoring should be performed when the drug is used in patients with underlying liver disease or when it is used with rifampin in treating latent tuberculosis infection. # Ethambutol Role in treatment regimen. Ethambutol (EMB) is a firstline drug for treating all forms of tuberculosis. It is included in initial treatment regimens primarily to prevent emergence of RIF resistance when primary resistance to INH may be present. Ethambutol is generally not recommended for routine use in children whose visual acuity cannot be monitored. However, if a child has adult-type tuberculosis or disease that is suspected or proven to be caused by organisms that are resistant to either INH or RIF, EMB should be used (see Section 8.2: Children and Adolescents, and Table 6). Dose. See Tables 3 and 5. Adults: 15-20 mg/kg per day: Table 5 lists recommended dosages for adults, using whole tablets. Children (maximum): 15-20 mg/kg per day (2.5 g); 50 mg/ kg twice weekly (2.5 g). The drug can be used safely in older children but should be used with caution in children in whom visual acuity cannot be monitored (generally less than 5 years of age) (66). In younger children EMB can be used if there is concern with resistance to INH or RIF (Table 6). Preparations. Tablets (100 mg, 400 mg) for oral administration. Adverse effects. Retrobulbar neuritis: This is manifested as decreased visual acuity or decreased red-green color discrimination that may affect one or both eyes. The effect is dose related, with minimal risk at a daily dose of 15 mg/kg (67). No difference was found in the prevalence of decreased visual acuity between regimens that contained EMB at 15 mg/kg and those not containing the drug (68). The risk of optic toxicity is higher at higher doses given daily (18% of patients receiving more than 30 mg/kg per day) and in patients with renal insufficiency. Higher doses can be given safely twice or three times weekly. Peripheral neuritis: This is a rare adverse effect (69). Cutaneous reactions: Skin reactions requiring discontinuation of the drug occur in 0.2-0.7% of patients (68). Use in pregnancy. EMB is considered safe for use in pregnancy (70)(71)(72). CNS penetration. The agent penetrates the meninges in the presence of inflammation but does not have demonstrated efficacy in tuberculous meningitis (73). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) EMB is cleared primarily by the kidneys. The dose or dosing interval should be adjusted when the creatinine clearance is less than 70 ml/minute (74). EMB should be administered at a dose of 15-20 mg/kg three times a week by DOT after dialysis in patients with end-stage renal disease (Table 15) (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) EMB can be used safely in patients with hepatic disease. Monitoring. Patients should have baseline visual acuity testing (Snellen chart) and testing of color discrimination (Ishihara tests). At each monthly visit patients should be questioned regarding possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses greater than 15-25 mg/kg, patients receiving the drug for longer than 2 months, and any patient with renal insufficiency. Patients should be instructed to contact their physician or public health clinic immediately if they experience a change in vision. EMB should be discontinued immediately and permanently if there are any signs of visual toxicity. # Fixed-dose combination preparations Role in treatment regimen. Two combined preparations, INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®), are available in the United States. These formulations are a means of minimizing inadvertent monotherapy, particularly when DOT is not possible, and, therefore, may decrease the risk of acquired drug resistance (75). The use of fixed-dose formulations may reduce the number of pills that must be taken daily. Constituent drugs are combined in proportions compatible with daily treatment regimens. Formulations for intermittent administration are not available in the United States. Preparations and dose. Rifamate®: As sold in North America, each capsule contains RIF (300 mg) and INH (150 mg); thus, the daily dose is two capsules (600 mg of RIF and 300 mg of INH). Two capsules of Rifamate® plus two 300-mg tablets of INH are used by some programs for intermittent therapy given twice weekly as DOT. Rifater® Use in hepatic disease. (See Section 8.8: Hepatic Disease.) In patients with underlying hepatic disease it is advisable to treat with single-drug formulations until safety in an individual patient can be determined and a stable regimen established. # Second-Line Drugs # Cycloserine Role in treatment regimen. Cycloserine (76,77) is a second-line drug that is used for treating patients with drug-resistant tuberculosis caused by organisms with known or presumed susceptibility to the agent. It may also be used on a temporary basis for patients with acute hepatitis in combination with other nonhepatotoxic drugs. Dose. See Table 3. Adults (maximum): 10-15 mg/kg per day (1,000 mg), usually 500-750 mg/day given in two doses. Clinicians with experience with cycloserine indicate that toxicity is more common at doses over 500 mg/day. Serum concentration measurements aiming for a peak concentration of 20-35 mg/ml are often useful in determining the optimum dose for a given patient. There are no data to support intermittent administration. Children (maximum): 10-15 mg/kg per day (1.0 g/day). Preparations. Capsules (250 mg). Adverse effects. Central nervous system effects: The central nervous system effects range from mild reactions, such as headache or restlessness, to severe reactions, such as psychosis and seizures. The drug may exacerbate underlying seizure disorders or mental illness. Seizures have been reported to occur in up to 16% of patients receiving 500 mg twice daily but in only 3% when receiving 500 mg once daily (78). Pyridoxine may help prevent and treat neurotoxic side effects and is usually given in a dosage of 100-200 mg/day (79). Rarely, cycloserine may cause peripheral neuritis. Use in pregnancy. Cycloserine crosses the placenta. There are limited data on safety in pregnancy; thus, it should be used in pregnant women only when there are no suitable alternatives (77). CNS penetration. Concentrations in CSF approach those in serum (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) The drug can accumulate in patients with impaired renal function and should be used cautiously in such patients. Generally, the dose should be reduced and serum concentrations measured. Cycloserine should not be used in patients having a creatinine clearance of less than 50 ml/minute unless the patient is receiving hemodialysis. For patients being hemodialyzed the dose should be 500 mg three times a week or 250 mg daily (Table 15). Serum concentrations of the drug should be measured and the dose adjusted accordingly. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) There are no precautions except for patients with alcoholrelated hepatitis in whom there is an increased risk of seizures (77). Monitoring. Neuropsychiatric status should be assessed at least at monthly intervals and more frequently if symptoms # Role of Fixed-Dose Combination Preparations Fixed-dose combination preparations minimize inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors. These preparations should generally be used when therapy cannot be administered under DOT. develop. As noted above, measurements of serum concentrations may be necessary until an appropriate dose is established. For patients taking phenytoin, serum concentrations of phenytoin should be measured. # Ethionamide Role in treatment. Ethionamide (76,77) is a second-line drug that is used for patients with drug-resistant tuberculosis disease caused by organisms that have demonstrated or presumed susceptibility to the drug. Dose: See Table 3. Adults (maximum): 15-20 mg/kg per day (1.0 g/day), usually 500-750 mg/day in a single daily dose or two divided doses. The single daily dose can be given at bedtime or with the main meal. There are no data to support intermittent dosing. Children (maximum): 15-20 mg/kg per day (1.0 g/day). Preparations: Tablets (250 mg). # Adverse reactions. Gastrointestinal effects: Ethionamide commonly causes profound gastrointestinal side effects, including a metallic taste, nausea, vomiting (that is often severe), loss of appetite, and abdominal pain (80). Symptoms may improve if doses are taken with food or at bedtime. Hepatotoxicity: Ethionamide is similar in structure to INH and may cause similar side effects. Hepatotoxicity occurs in about 2% of patients taking the drug (81,82). Neurotoxicity: Neurotoxicity, including peripheral neuritis, optic neuritis, anxiety, depression, and psychosis, has been reported in 1-2% of patients taking shorter courses of the drug with higher rates reported with prolonged treatment (83,84). Endocrine effects: Endocrine disturbances, including gynecomastia, alopecia, hypothyroidism, and impotence, have been described (85,86). Diabetes may be more difficult to manage in patients taking ethionamide (77). Use in pregnancy. Ethionamide crosses the placenta and is teratogenic in laboratory animals. It should not be used in pregnancy. CNS penetration. CSF concentrations are equal to those in serum (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-stage Renal Disease.) For patients having a creatinine clearance of less than 30 ml/minute or who are receiving hemodialysis the dose should be reduced to 250-500 mg/day (Table 15). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Ethionamide should be used with caution in patients with underlying liver disease. Monitoring. Liver function tests should be obtained at baseline and, if there is underlying liver disease, at monthly intervals. The studies should be repeated if symptoms occur. Thyroid-stimulating hormone should be measured at baseline and at monthly intervals. # Streptomycin Role in treatment regimen. Streptomycin (SM) (76,77,(87)(88)(89) and EMB have been shown to be approximately equivalent when used in the initial phase of treatment with 6-month regimens. However, among patients likely to have acquired M. tuberculosis in a high-incidence country, the relatively high rate of resistance to SM limits its usefulness. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1 g/day) parenterally, usually given as a single daily dose (5-7 days/week) initially, and then reducing to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons over 59 years of age, the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 12-15 mg/kg per dose two or three times per week) in persons with renal insufficiency (see below: Use in Renal Disease) (91,92). Children (maximum): 20-40 mg/kg per day (1 g/day). Preparations. Aqueous solution in vials of 1 g (93). # Adverse effects. Ototoxicity: The most important adverse reaction caused by SM is ototoxicity, including vestibular and hearing disturbances. The risk is increased with age (94) or concomitant use of loop-inhibiting diuretics (furosemide, ethacrynic acid). The risk of ototoxicity increases with increasing single doses and with the cumulative dose, especially above 100-120 g. Neurotoxicity: SM relatively commonly causes circumoral parasthesias immediately after injection. Rarely, it may interact with muscle relaxants to cause postoperative respiratory muscle weakness. Nephrotoxicity: Nephrotoxicity occurs less commonly with SM than with amikacin, kanamycin, or capreomycin (95). Renal insufficiency requiring discontinuation occurs in about 2% of patients (96). Use in pregnancy. SM is contraindicated in pregnancy because of the risk of fetal hearing loss (77,97,98). CNS penetration. There is only slight diffusion of SM into CSF, even in patients with meningitis (77,99) Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) SM should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufficiency, including the elderly and those undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 12-15 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. An audiogram, vestibular testing, Romberg testing, and serum creatinine measurement should be performed at baseline. Assessments of renal function, and questioning regarding auditory or vestibular symptoms, should be performed monthly. An audiogram and vestibular testing should be repeated if there are symptoms of eighth nerve toxicity. # Amikacin and kanamycin Role in treatment regimen. Amikacin and kanamycin (76,77,101) are two closely related injectable second-line drugs that are used for patients with drug-resistant tuberculosis whose isolate has demonstrated or presumed susceptibility to the agents. There is nearly always complete cross-resistance between the two drugs, but most SM-resistant strains are susceptible to both (102). Because it is used to treat a number of other types of infections, amikacin may be more easily obtained, and serum drug concentration measurements are readily available. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), intramuscular or intravenous, usually given as a single daily dose (5-7 days/week) initially, and then reducing to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 12-15 mg/kg per dose, two or three times per week) in persons with renal insufficiency (see below: Use in Renal Disease) (91,92). Children (maximum): 15-30 mg/kg per day (1 g/day) intramuscular or intravenous as a single daily dose. Preparations. Aqueous solution for intramuscular or intravenous injection in vials of 500 mg and 1 g. # Adverse effects. Ototoxicity: Amikacin and kanamycin may cause deafness, but they cause less vestibular dysfunction than SM (103,104). Ototoxicity is more common with concurrent use of diuretics. In one report high-frequency hearing loss occurred in 24% of patients receiving amikacin, with higher rates occurring among those receiving longer treatment and/or higher doses (105), whereas a review of the literature found only 1.5% hearing loss (106). Nephrotoxicity: Amikacin and kanamycin may be more nephrotoxic than SM (95). Renal impairment was seen in 8.7% of patients receiving amikacin, with a higher frequency in patients with initially increased creatinine levels, patients receiving larger total doses, and patients receiving other nephrotoxic agents. A frequency of 3.4% was reported in patients with no risk factors (106,107). Use in pregnancy. Both amikacin and kanamycin are contraindicated in pregnant women because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Only low concentrations of the drugs are found in CSF, although slightly higher concentrations have been found in the presence of meningitis (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Amikacin and kanamycin should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufficiency, including the elderly and those receiving hemodialysis. In such patients, the dosing frequency should be reduced to two or three times per week, but the dose should be maintained at 12-15 mg/kg to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. An advantage of amikacin is that serum concentration measurements can be obtained routinely. Patients with severe hepatic disease, because of predisposition to hepatorenal syndrome, may be at greater risk for nephrotoxicity from amikacin/kanamycin and should have renal function monitored closely. # Capreomycin # Role in treatment. Capreomycin is a second-line injectable drug that is used for patients with drug-resistant tuberculosis caused by organisms that have known or presumed susceptibility to the drug (108). Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), usually given as a single daily dose five to seven times a week, and reduced to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced to 12-15 mg/kg two or three times per week in persons with renal insufficiency (see below: Use In Renal Disease) (91,92). Children (maximum): 15-30 mg/kg per day (1 g/day) as a single daily or twice weekly dose. Preparations. Capreomycin is available in vials of 1 g for both intramuscular and intravenous administration. Adverse effects. Nephrotoxicity: Nephrotoxic effects may result in reduced creatinine clearance or potassium and magnesium depletion. Proteinuria is common (109). Significant renal toxicity requiring discontinuation of the drug has been reported to occur in 20-25% of patients (110,111). Ototoxicity: Vestibular disturbances, tinnitus, and deafness appear to occur more often in elderly persons or those with preexisting renal impairment (111). Use in pregnancy. Capreomycin should be avoided in pregnancy because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Capreomycin does not penetrate into the CSF (77). Use in renal disease. (see Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Capreomycin should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity (112). Because capreomycin is nearly entirely cleared by the kidneys, dosing adjustments are essential in patients with underlying renal insufficiency and end-stage renal disease, including patients undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 12-15 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (100,113). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. In addition, serum potassium and magnesium concentrations should be measured at baseline and at least at monthly intervals. # p-Aminosalicylic acid Role in treatment. p-Aminosalicylic acid (PAS) is an oral agent used in treatment of drug-resistant tuberculosis caused by organisms that are susceptible to the drug. Dose. See Table 3. Adults: 8-12 g/day in two or three doses. For PAS granules, 4 g three times daily has been the usual dosage (114,115). However, it has been shown that administration of 4 g twice daily is adequate to achieve the target serum concentration (116). Children: 200-300 mg/kg per day in two to four divided doses (117). Preparations. The only available formulation in the United States is granules in 4-g packets (Paser Granules®) (118). It was previously thought that the granules needed to be taken with acidic food (115); however, more recent data suggest that this is not necessary (C. Peloquin, personal communication). Tablets (500 mg) are still available in some countries. A solution for intravenous administration is available in Europe (119,120). Adverse effects. Hepatotoxicity: In a review of 7,492 patients being treated for tuberculosis, 38 (0.5%) developed hepatitis, of which 28 cases (0.3%) were attributed at least in part to PAS (121). Gastrointestinal distress: This is the most common side effect of PAS (122). In a large study of INH and PAS 11% of patients had drug toxicity, mainly gastrointestinal intolerance to PAS (114). The incidence of gastrointestinal side effects is less with lower doses (8 g daily) and with the granular formulation of the drug. Malabsorption syndrome: This is characterized by steatorrhea and low serum folate levels (123). Hypothyroidism: This is a common side effect, especially with prolonged administration or concomitant use of ethionamide. It may be accompanied by goiter formation. Thyroid hormone replacement may be required. Thyroid function returns to normal after discontinuation of the drug (124). Coagulopathy: A doubling of the prothrombin time that seemed to be lessened by coadministration of streptomycin has been reported (125). Use in pregnancy. No studies have been done in humans; however, PAS has been used safely in pregnancy. The drug should be used only if there are no alternatives (see below) for a pregnant woman who has multidrug-resistant tuberculosis. CNS penetration. In the presence of inflamed meninges, PAS concentrations are between 10-50% of those achieved in serum (119). The drug has marginal efficacy in meningitis. Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Approximately 80% of the drug is excreted in the urine (118). Unless there is no alternative, PAS is contraindicated in severe renal insufficiency because of the accumulation of the acetylated form (123,126,127). Because both PAS and acetyl-PAS are removed by dialysis, the drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (126). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The clearance of PAS is not substantially altered in liver disease, suggesting that the drug may be used in usual doses but with increased laboratory and clinical monitoring (127). Monitoring. Hepatic enzymes and thyroid function should be measured at baseline. With prolonged therapy (i.e., more than 3 months) thyroid function should be checked every 3 months. # Fluoroquinolones Role in treatment regimen. Of the fluoroquinolones (128)(129)(130)(131), levofloxacin, moxifloxacin, and gatifloxacin have the most activity against M. tuberculosis. On the basis of cumulative experience suggesting a good safety profile with long-term use of levofloxacin, this drug is the preferred oral agent for treating drug-resistant tuberculosis caused by organisms known or presumed to be sensitive to this class of drugs, or when first-line agents cannot be used because of intolerance. Data on long-term safety and tolerability of moxifloxacin and gatifloxacin, especially at doses above 400 mg/day, are limited. Cross-resistance has been demonstrated among ciprofloxacin, ofloxacin, and levofloxacin and presumably is a class effect (132). Fluoroquinolones should not be considered first-line agents for the treatment of drug-susceptible tuberculosis except in patients who are intolerant of first-line drugs. Dose. (See Table 3.) The doses given are for levofloxacin. Adults: 500-1,000 mg daily. Children: The long-term (more than several weeks) use of fluoroquinolones in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with MDR tuberculosis. The optimal dose is not known. Preparations (Levofloxacin). Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500 mg) for intravenous administration. Adverse effects. The adverse effects (133) cited are for levofloxacin. Gastrointestinal disturbance: Nausea and bloating occur in 0.5-1.8% of patients taking the drug. Neurologic effects: Dizziness, insomnia, tremulousness, and headache occur in 0.5% of patients. Cutaneous reactions: Rash, pruritis, and photosensitivity occur in 0.2-0.4% of patients. Use in pregnancy. This class of drugs should be avoided in pregnancy because of teratogenic effects (119,134). # CNS penetration. The concentration in CSF after administration of a standard dose of levofloxacin is 16-20% of that in serum (135). Interference with absorption. Because antacids and other medications containing divalent cations markedly decrease absorption of fluoroquinolones, it is critical that any fluoroquinolone not be administered within 2 hours of such medications (see Section 7.1: Interactions Affecting Antituberculosis Drugs). Use in renal disease. (See Section 8.7: Renal Insufficiency and End Stage Renal Disease.) The drug is cleared primarily (80%) by the kidney (135). Dosage adjustment (750-1,000 mg three times a week) is recommended if creatinine clearance is less than 50 ml/minute (Table 15) (136). It is not cleared by hemodialysis; supplemental doses after dialysis are not necessary (135). Use in hepatic disease. Drug levels are not affected by hepatic disease (135). It is presumed to be safe for use in the setting of severe liver disease, but as with all drugs, should be used with caution. # Principles of Antituberculosis Chemotherapy # Combination Chemotherapy The primary goals of antituberculosis chemotherapy are to kill tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the host's tissues to prevent relapse (1). To accomplish these goals, multiple antituberculosis drugs must be taken for a sufficiently long time. The theoretical model of chemotherapy for tuberculosis is founded on current understanding of the biology of M. tuberculosis in the host and on the specific activities of antituberculosis drugs. This model is supported by data from numerous in vivo and in vitro studies. It is theorized that there are three separate subpopulations of M. tuberculosis within the host. These populations are defined by their growth characteristics and the milieu in which they are located (1). The largest of the subpopulations consists of rapidly growing extracellular bacilli that reside mainly in cavities. This subpopulation, because of its size, is most likely to harbor organisms with random mutations that confer drug resistance. The frequency of these mutations that confer resistance is about 10 -6 for INH and SM, 10 -8 for RIF, and 10 -5 for EMB; thus, the frequency of concurrent mutations to both INH and RIF, for example, would be 10 -14 , making simultaneous resistance to both drugs in an untreated patient a highly unlikely event (2). INH has been shown to possess the most potent ability to kill rapidly multiplying M. tuberculosis during the initial part of therapy (early bactericidal activity), thereby rapidly decreasing infectiousness (3-5). It is followed in this regard by EMB, RIF, and SM. PZA has weak early bactericidal activity during the first 2 weeks of treatment (3,6). Drugs that have potent early bactericidal activity reduce the chance of resistance developing within the bacillary population. Early experience in clinical trials demonstrated that multiple agents are necessary to prevent the emergence of a drugresistant population as a consequence of the selection pressure from administration of a single agent. Shortly after the discovery of SM, it was demonstrated that treatment with this agent alone resulted in treatment failure and drug resistance (7). Subsequently, it was shown that the combination of PAS and SM substantially lessened the likelihood of acquired resistance and treatment failure (8). In modern regimens both INH and RIF have considerable ability to prevent the emergence of drug resistance when given with another drug. EMB and SM are also effective in preventing the emergence of drug resistance, whereas the activity of PZA in this regard is poor (9,10). For this reason PZA should not be used with only one other agent when treating active tuberculosis. The rapidly dividing population of bacilli is eliminated early in effective therapy as shown by the early clinical responses and clearing of live bacilli from sputum within 2 months in about 80% of patients. The remaining subpopulations of M. tuberculosis account for treatment failures and relapses, especially when the duration of therapy is inadequate. These residual populations include organisms that are growing more slowly, often in the acidic environment provided by areas of necrosis, and a group that is characterized by having spurts of growth interspersed with periods of dormancy. The sterilizing activity of a drug is defined by its ability to kill bacilli, mainly in these two subpopulations that persist beyond the early months of therapy, thus decreasing the risk of relapse (1). The use of drugs that have good sterilizing properties is essential for regimens as short as 6 months. RIF and PZA have the greatest sterilizing activity followed by INH and SM (11,12). The sterilizing activity of RIF persists throughout the course of therapy, but this does not appear to be true for PZA. When given in RIF-containing regimens, PZA provides additive sterilizing activity only during the initial 2 months of therapy. The sterilizing activity of PZA may not be so limited in regimens where RIF cannot be used or is not effective, so regimens for MDR tuberculosis may include PZA for the full course of treatment if the isolate is susceptible to this agent. # Optimum Duration of Treatment Truly effective chemotherapy for tuberculosis became available with the introduction of INH in the early 1950s. Adding INH to SM and PAS increased cure rates from about 70 to 95% but required treatment for 18-24 months (13). Eventually, EMB replaced PAS as the companion agent for INH (14). Subsequent investigations of combination chemotherapy sought to identify regimens that were shorter and that could be given intermittently. The British Medical Research Council (BMRC) in East Africa (15) conducted the first large-scale multicenter study of short-course (6-month) regimens. This study demonstrated that the addition of RIF or PZA to a base regimen of daily SM and INH increased the proportion of patients whose sputum cultures were negative by 2 months after the initiation of treatment and significantly reduced the relapse rate. Moreover, the relapse rate of the short-course regimens was no greater than that of the standard 18-month regimen containing SM, INH, and thiacetazone (a drug used in many countries in place of PAS or EMB). In Hong Kong, administration of a 9-month regimen of SM, INH, and PZA daily, twice weekly, or three times weekly was associated with a relapse rate of only 5-6% (16). Unfortunately, all short-course regimens that did not include RIF required fully supervised therapy and SM had to be used for the entire 9 months. Subsequent investigations conducted by the British Thoracic Association demonstrated that SM (or EMB) was necessary only for the first 2 months # Effects of Antituberculosis Chemotherapy Antituberculosis chemotherapy is designed to kill tubercle bacilli rapidly, minimize the potential for the organisms to develop drug resistance, and sterilize the host's tissues. The achievement of these effects requires that a combination of agents with specific activities be administered for a sufficiently long period of time. As a consequence of these effects, the patient is cured and has only a small likelihood of relapse. # MMWR June 20, 2003 to achieve excellent results with a 9-month treatment duration, using INH and RIF throughout (17,18). The BMRC conducted studies in Hong Kong proving that EMB was roughly as effective as SM in the initial phase of therapy, thereby demonstrating that an all-oral regimen was effective (19). The addition of PZA to a regimen containing INH and RIF enabled further shortening of the duration of therapy to 6 months. The British Thoracic Association demonstrated that a regimen of INH and RIF for 6 months, supplemented during the first 2 months with PZA and either EMB or SM, was as effective as a 9-month regimen of INH and RIF with EMB in the first 2 months (18). Administration of PZA beyond the initial 2 months in an RIF-containing regimen had no additional benefit. The efficacy of the treatment regimens was similar regardless of whether PZA was given for 2, 4, or 6 months (20). Subsequent studies of 6-month regimens have served to refine the approach used currently. USPHS Trial 21 compared self-administered INH and RIF for 6 months plus PZA given during the initial 2 months with INH and RIF for 9 months (21). EMB was added only if INH resistance was suspected. Patients taking the 6-month PZA-containing regimen had negative sputum cultures sooner after treatment was started than those treated for 9 months without PZA and relapse rates were similar for the two regimens (3.5 versus 2.8%). Investigators in Denver reported a low relapse rate (1.6%) when using a 62-dose, directly observed, 6-month regimen that consisted of 2 weeks of daily INH, RIF, PZA, and SM, 6 weeks of the same four drugs given twice weekly, and 18 weeks of twice weekly INH and RIF (22). Regimens less than 6 months in duration have been shown to have unacceptably high relapse rates among patients with smear-positive pulmonary tuberculosis (23,24). However, in a study in Hong Kong among patients with smear-negative, culture-positive tuberculosis, the relapse rate was about 2% when using a 4-month regimen of daily SM, INH, RIF, and PZA (25); among smear-negative, culture-negative cases, the relapse rate was only 1%. In Arkansas, patients with tuberculosis who had negative smears and cultures were treated with INH and RIF given daily for 1 month followed by 3 months of twice weekly INH and RIF (26). Only 3 of 126 (2.4%) patients developed active tuberculosis during 3.5 years of follow-up. Thus, it appears that a 4-month, INH-and RIF-containing regimen is effective in culture-negative tuberculosis (see Section 8.4: Culture-Negative Pulmonary Tuberculosis in Adults). # Intermittent Drug Administration Nonadherence to the antituberculosis treatment regimen is well known to be the most common cause of treatment failure, relapse, and the emergence of drug resistance. Administration of therapy on an intermittent basis, as opposed to daily dosing, facilitates supervision of therapy, thereby improving the outcome. The concept of intermittent administration of antituberculosis drugs developed from early clinical observations and was supported by subsequent laboratory investigations. First, it was noted that a single daily dose of 400 mg of INH was more effective than the same total dose given in two divided doses (27). Second, in an early study from Madras, investigators demonstrated that fully supervised twice weekly therapy could be delivered to nonhospitalized patients and that the results were better than with a conventional selfadministered daily regimen (28). These findings, plus the laboratory results noted below, led to a series of clinical trials that compared daily and intermittent dosing of antituberculosis medications. In all of these studies, intermittent regimens were demonstrated to be as effective as daily regimens and no more toxic (20). In the laboratory it was noted that in vitro exposure of tubercle bacilli to drugs was followed by a lag period of several days before growth began again (postantibiotic effect) (29)(30)(31). Thus, it was concluded that maintaining continuous inhibitory drug concentrations was not necessary to kill or inhibit growth of M. tuberculosis. Studies in guinea pigs substantiated that INH could be given at intervals as long as 4 days without loss of efficacy; however, there was a significant decrease in activity with an 8-day dosing interval (30,31). The concept of intermittent drug administration continues to evolve. Studies have demonstrated that the frequency of drug administration in the continuation phase of treatment may be decreased to once a week when using INH and rifapentine for certain highly selected patients (32)(33)(34). Because of the newness of these findings the data are presented in some detail. The results from three open-label, randomized clinical trials indicate that rifapentine given with INH once a week is safe and effective when used for the treatment of selected, HIVnegative patients with pulmonary tuberculosis. In a study performed in Hong Kong, patients with pulmonary tuberculosis were allocated at random to receive 600 mg of rifapentine and 900 mg of INH given either once every week or once every 2 of 3 weeks for 4 months after completion of a standard 2-month initial phase (32). Overall, about 11% of patients in the two rifapentine arms failed or relapsed during a 5-year follow-up period, compared with 4% of the patients who received three times weekly INH-RIF (control arm) in the continuation phase of treatment. Omitting every third dose of INH-rifapentine did not appreciably increase the relapse rate, indicating that modest nonadherence may have a negligible effect. Multivariate analyses showed that the significant prognostic factors were treatment arm, radiographic extent of disease (all three regimens), and sex (women fared better than men). The frequency of failures and relapses was also greater in all three arms if the 2-month culture was positive. The pivotal study for drug registration was conducted in North America and South Africa among HIV-negative patients with pulmonary tuberculosis (33). Patients in the experimental arm received directly observed twice weekly rifapentine together with daily self-administered INH, PZA, and EMB in the initial 2 months, followed by 4 months of once weekly directly observed rifapentine and INH. Patients in the control arm received a standard four-drug initial phase, followed by twice weekly INH-RIF. Relapse rates during 2 years of follow-up were similar to those seen in the Hong Kong study (8.2% relapse in the experimental arm versus 4.4% in the control arm), and cavitary disease, sputum culture positivity at the end of the initial phase, and nonadherence with INH, EMB, and PZA in the experimental arm were significantly associated with an increased probability of relapse. The third study was conducted by the CDC Tuberculosis Trials Consortium, and employed a design similar to the Hong Kong trial, in which HIV-negative patients were allocated at random after successful completion of standard 2-month initial phase therapy (34). Again, results, as measured by rates of failure/relapse, were remarkably similar to the first two trials, 9.2% in the experimental (INH-rifapentine once weekly) arm compared with 5.6% in the control (INH-RIF twice weekly) arm. However, as in the South Africa study, relapse was significantly associated with the presence of cavitary lesions seen on the initial chest film and sputum culture positivity at 2 months, both of which were more common in the rifapentine arm. With adjustment for these factors, the difference in outcome in the two arms was not statistically significant. Relapse rates among patients who did not have cavitary disease and had negative sputum cultures at 2 months were low in both treatment arms. However, in patients who had both cavitation and a positive culture at 2 months the relapse rate in the rifapentine arm was 22% and in the twice weekly INH-RIF arm was 21% (Table 11). In all of the cited studies, rifapentine was well tolerated, with the adverse events being similar to those occurring with RIF. A small number of HIV-positive patients were enrolled in the CDC study, but this arm was closed after the development of acquired rifampin resistance among relapse cases in the rifapentine arm (35). # Recommended Treatment Regimens # Evidence-based Rating System To assist in making informed treatment decisions based on the most credible research results, evidence-based ratings have been assigned to the treatment recommendations (Table 1). The ratings system is the same as that used in the recommendations for treating latent tuberculosis infection, in which a letter indicating the strength of the recommendation, and a roman numeral indicating the quality of the evidence supporting the recommendation, are assigned to each regimen (1). Thus, clinicians can use the ratings to differentiate among recommendations based on data from clinical trials and those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice when clinical trial data are not available. # Recommended Regimens There are four basic regimens recommended for treating adults with tuberculosis caused by organisms that are known or presumed to be susceptible to INH, RIF, PZA, and EMB (Table 2). As noted below, children, depending on the circumstances, may not receive EMB in the initial phase of a 6-month regimen, but the regimens are otherwise identical. Each regimen has an initial phase of 2 months, followed by a choice of several options for the continuation phase of either 4 or 7 months. In Table 2 the initial phase is denoted by a number (1, 2, 3, or 4) and the options for the continuation phase are denoted by the respective number and a letter designation (a, b, or c). DOT is the preferred initial management strategy for all regimens and should be used whenever feasible. All patients being given drugs less than 7 days per week (5, 3, or 2 days/week) must receive DOT. # Six-month regimens The current minimal acceptable duration of treatment for all children and adults with culture-positive tuberculosis is 6 months (26 weeks). The initial phase of a 6-month regimen for adults should consist of a 2-month period of INH, RIF, PZA, and EMB given daily throughout (Regimen 1), daily for 2 weeks followed by two times weekly for 6 weeks (Regimen 2), or three times a week (Regimen 3). The minimum number of doses is specified in Table 2. On the basis of substantial clinical experience, 5 day-a-week drug administration by DOT is considered to be equivalent to 7 day-a-week administration; thus, either may be considered "daily." Although administration of antituberculosis drugs by DOT at 5 days/week, rather than 7 days, has been reported in a large number of studies it has not been compared with 7-day administration in a clinical trial and therefore is rated AIII. The recommendation that a four-drug regimen be used initially for all patients is based on the current proportion of new tuberculosis cases caused by organisms that are resistant to INH (2). This recommendation is supported by a retrospective analysis of data from various BMRC studies indicating that in the presence of INH resistance there were fewer treatment failures and relapses if a regimen containing four drugs, INH, RIF, PZA, and EMB, was used in the initial phase (3). However, if therapy is being initiated after drug susceptibility test results are known and the organisms are susceptible to INH and RIF, EMB is not necessary. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to the first-line agents. In most situations these results are not available before 6-8 weeks after treatment is begun. The continuation phase of treatment should consist of INH and RIF given for a minimum of 4 months (18 weeks). Patients should be treated until they have received the specified total number of doses for the treatment regimen (Table 2). The continuation phase can be given daily (Regimen 1a), twice weekly (Regimens 1b and 2a), or three times weekly (Regimen 3a). The continuation phase should be extended for an additional 3 months for patients who have cavitation on the initial or follow-up chest radiograph and are culture-positive at the time of completion of the initial phase of treatment (2 months). Patients who are HIV negative, who do not have cavities on the chest radiograph, and who have negative sputum AFB smears at completion of the initial phase of treatment may be treated with once weekly INH and rifapentine in the continuation phase for 4 months. If the culture of the sputum obtained at 2 months is positive, observational data and expert opinion suggest that the continuation phase of once weekly INH and rifapentine should be 7 months (4). # Nine-month regimen If PZA cannot be included in the initial regimen, or if the isolate is determined to be resistant to PZA (an unusual circumstance, except for Mycobacterium bovis and M. bovis var. BCG), a regimen consisting of INH, RIF, and EMB should be given for the initial 2 months (Regimen 4) followed by INH and RIF for 7 months given either daily or twice weekly (Regimens 4a and 4b). # Alternative regimens In some cases, either because of intolerance or drug resistance, the above-described regimens cannot be used. In these instances, an alternative regimen may be required. In a retrospective analysis of the combined results of clinical trials conducted by the BMRC it was concluded that, in the presence of initial resistance to INH, if a four-drug regimen containing RIF and PZA was used in the initial phase and RIF was used throughout a 4-month continuation phase there were no treatment failures and 7% relapses compared with 4% relapses among patients with fully susceptible strains (3). Data from a Hong Kong BMRC study suggest that in the presence of INH resistance results are better when PZA is used throughout (5). On the basis of these data, when INH cannot be used or the organisms are resistant to INH, a 6-month regimen of RIF, PZA, and EMB is nearly as efficacious as an INH-containing regimen (Rating BI) (3). Alternatively, RIF and EMB for 12 months may be used, preferably with PZA during at least the initial 2 months (Rating BII) (5,6). If RIF is not used, INH, EMB, and FQN should be given for a minimum of 12-18 months supplemented with PZA during at least the initial 2 months (Rating BIII). An injectable agent may also be included for the initial 2-3 months for patients with more extensive disease or to shorten the duration (e.g., to 12 months), (7,8). Levofloxacin, moxifloxacin, or gatifloxacin may be useful in alternative regimens, but the potential role of a fluoroquinolone and optimal length of therapy have not been defined (9,10). In situations in which several of the first-line agents cannot be used because of intolerance, regimens based on the principles described for treating multiple drugresistant tuberculosis (Section 9.3: Management of Tuberculosis Caused by Drug-Resistant Organisms) should be used. # Deciding to Initiate Treatment The decision to initiate combination chemotherapy for tuberculosis should be based on epidemiologic information, clinical and radiographic features of the patient, and the results of the initial series of AFB smears (preferably three) and, subsequently, cultures for mycobacteria. Rapid amplification tests, if used, can also confirm the diagnosis of tuberculosis more quickly than cultures. On the basis of this information, the likelihood that a given patient has tuberculosis can be estimated. For example, a patient who has emigrated recently from a high-incidence country, has a history of cough and weight loss, and has characteristic findings on chest radiograph should be considered highly likely to have tuberculosis. In such situations combination drug therapy should be initiated, even before AFB smear and mycobacterial culture results are known. Empirical treatment with a fourdrug regimen should be initiated promptly when a patient is seriously ill with a disorder that is thought possibly to be tuberculosis. Initiation of treatment should not be delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. Disseminated (miliary) tuberculosis, for example, is often associated with negative sputum AFB smears. Likewise, for a patient with suspected tuberculosis and a high risk of transmitting M. tuberculosis if, in fact, she or he had the disease, combination chemotherapy should be initiated in advance of microbiological confirmation of the diagnosis to minimize potential transmission. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, or is strongly inferred from clinical or radiographic improvement consistent with a response to treatment, the regimen can be continued to complete a standard course of therapy (Figure 1). A PPD-tuberculin skin test may be done at the time of initial evaluation, but a negative test does not exclude the diagnosis of active tuberculosis. However, a positive skin test supports the diagnosis of culture-negative pulmonary tuberculosis or, in persons with stable abnormal chest radiographs consistent with inactive tuberculosis, a diagnosis of latent tuberculosis infection (see below). If the cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and there is no response to treatment, the options are as follows: 1) stop treatment if RIF and PZA have been given for at least 2 months; 2) continue treatment with RIF, with or without INH, for a total of 4 months; or 3) continue treatment with INH for a total of 9 months (11). All three of these options provide adequate therapy for persons with prior tuberculosis once active disease has been excluded. If clinical suspicion for active tuberculosis is low, the options are to begin treatment with combination chemotherapy or to defer treatment until additional data have been obtained to clarify the situation (usually within 2 months) (Figure 2, top). Even when the suspicion of active tuberculosis is low, treatment for latent tuberculosis infection with a single drug should not be initiated until active tuberculosis has been excluded. In low-suspicion patients not initially treated, if cultures remain negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, there are three treatment options (Figure 2, top) (11). The preferred options are INH for 9 months or RIF, with or without INH, for 4 months. RIF and PZA for a total of 2 months can be used for patients not likely to complete a longer regimen and who can be monitored closely. However, this last regimen has been associated with an increased risk of hepatotoxicity and should be used only in the limited circumstances described (12,13). An advantage of the early use of combination chemotherapy is that, once active disease is excluded by negative cultures and lack of clinical or radiographic response to treatment, the patient will have completed 2 months of combination treatment that can be applied to the total duration of treatment recommended for latent tuberculosis infection (Figure 2, bottom). # Baseline and Follow-Up Evaluations Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained 8-24 hours apart. In patients who are not producing sputum spontaneously, induction of sputum using aerosolized hypertonic saline or bronchoscopy (performed under appropriate infection control procedures) may be necessary to obtain specimens. Susceptibility testing for INH, RIF, and EMB should be performed on an initial positive culture, regardless of the source. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, have been in contact of a patient with known drug resistance, have demonstrated resistance to rifampin or two other first-line drugs, or who have positive cultures after more than 3 months of treatment. At the time treatment is initiated, in addition to the microbiologic examinations, it is recommended that all patients with tuberculosis have counseling and testing for HIV infection (14). Patients with epidemiologic factors suggesting a risk for hepatitis B or C, for example, injection drug use, birth in Asia or Africa, or HIV infection, should have serologic tests for these viruses (15,16). HIV-infected patients should also undergo CD4 + lymphocyte count measurement. Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all adults. Testing of visual acuity (Snellen chart) and color vision (Ishihara tests) should be performed when EMB is to be used. During treatment of patients with pulmonary tuberculosis, at a minimum, a sputum specimen for AFB smear and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture. As described subsequently, important decisions concerning the continuation-phase regimen hinge on the microbiological status at the end of the initial phase of treatment, thus, obtaining sputum specimens at this juncture is critical, if sputum conversion to negative has not already been documented. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations in which the risk of transmission is high. On occasion, AFB-positive sputa are culture negative; this occurs most frequently among patients with far advanced cavitary tuberculosis after the first months of treatment. It is thought that these organisms are dead and that their presence is not a sign of treatment failure, even if noted later in treatment. However, repeat cultures should be obtained to confirm that the earlier culture result was correct and not a false negative. Drug susceptibility tests should be repeated on isolates from patients who have positive cultures after 3 months of treatment. As described in Section 9.2 (Treatment Failure), patients who have positive cultures after 4 months of treatment should be considered as having failed treatment and managed accordingly. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained. In addition to the microbiological evaluations, it is essential that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. For patients with positive cultures at diagnosis, a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential. A chest radiograph at completion of therapy provides a baseline against which subsequent examinations can be compared, but, as with the 2-month examination, it is not essential. When the initial sputum cultures are negative, a presumptive diagnosis can be made if radiographic improvement is noted, generally by the time 2 months of treatment has been completed. Thus, in patients with negative initial cultures, a chest radiograph is necessary after 2 months of treatment and a radiograph at completion of treatment is desirable. Generally, follow-up after completion of therapy is not necessary. As a routine, it is not necessary to monitor liver or renal function or platelet count for patients being treated with firstline drugs unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements. Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening. Patients receiving EMB should be questioned regarding visual disturbances at monthly intervals; monthly repeat testing of visual acuity and color vision is recommended for patients receiving an EMB dose exceeding 15-20 mg/kg (the recommended range) and for patients receiving the drug for more than 2 months. Monitoring tests for the individual second-line drugs are listed in Section 3: Drugs in Current Use. # Identification and Management of Patients at Increased Risk of Relapse The result of a sputum culture at the conclusion of the initial phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis. In seven clinical trials performed by the BMRC, the regimens that had the highest proportion of patients with a positive sputum culture at 2 months after treatment was initiated were associated with a higher likelihood of relapse within 2 years (17). Of greater relevance to the current recommendations, data from USPHS Trial 22 comparing once weekly rifapentine and INH with twice weekly RIF and INH, showed an increased rate of relapse in patients who had a positive culture at 2 months in both study arms (18). Cavitation on the initial chest radiograph was also an independent risk factor for relapse. In patients in the control arm (twice weekly INH-RIF) the presence of both cavitation and a positive culture at completion of 2 months of therapy # Patients At Increased Risk of Relapse Patients who have cavitation on initial chest radiograph and who have a positive culture at completion of 2 months of therapy are at substantially increased risk of relapse. For these patients it is recommended that the continuation phase of treatment be prolonged to 7 months, making a total treatment period of 9 months. was associated with a 21% rate of relapse, compared with 2% for patients who had neither risk factor (Table 11). Similar findings were reported in a retrospective analysis of data from BMRC trials (17) and from a USPHS trial conducted in Poland (19). The most effective means of decreasing the likelihood of relapse for patients at increased risk has not yet been determined by clinical trials. However, in a controlled trial of treatment for silicotuberculosis in Hong Kong, prolongation of the continuation phase from 4 to 6 months decreased the rate of relapse from 22 to 7% (p <0.025) (20). Also in studies from Hong Kong, it was found that increasing the duration of PZA beyond the 2-month initial phase did not improve the efficacy of RIF-containing regimens (21). It has been reported that for patients at high risk of relapse, prolongation of the once weekly INH-rifapentine continuation phase from 4 to 7 months resulted in significantly better results compared with patients in an earlier trial (4). In view of this evidence and on the basis of expert opinion, it is recommended that treatment for patients who have cavitation noted on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy should be extended with INH and RIF for an additional 3 months for a total of 9 months (Rating AIII). In USPHS Study 22 patients treated with INH and RIF twice weekly in the continuation phase who had either cavitation on the initial chest radiograph or a positive culture at 2 months had approximately a 5-6% rate of relapse (Table 11) (18). This rate of adverse outcomes is not deemed to be sufficient to recommend prolongation of the continuation phase; however, patients with one or the other of these risk factors should be monitored more closely and consideration given to lengthening treatment if there are suggestions of a poor response. Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being more than 10% underweight at diagnosis, having HIV infection, or having extensive involvement on chest radiograph. Patients with noncavitary pulmonary tuberculosis and a negative AFB smear at 2 months who are started on the once weekly rifapentine-INH continuation phase and are subsequently found to be culture positive at 2 months should have treatment extended by an additional 3 months for a total of 9 months. # Definition of Completion of Therapy Treatment for a defined duration without accounting for the number of doses taken can result in undertreatment. Therefore, the determination of whether or not treatment has been completed is based on the total number of doses taken-not solely on the duration of therapy (Table 2). For example, the 6-month daily (given 7 days/week) regimen should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. If the drugs are administered by DOT at 5 days/week, the minimum number of doses is 130. A similar reduction in the target number of doses for 5-day-a-week administration applies to any of the regimens with a daily component. In some cases, either because of drug toxicity or nonadherence to the regimen, the specified number of doses cannot be administered within the targeted time period. In such cases, it is recommended that all of the specified number of doses for the initial phase be delivered within 3 months and those for the 4-month continuation phase be delivered within 6 months, so that the 6-month regimen should be completed within 9 months. If these targets are not met the patient must be considered to have interrupted therapy and be managed as described below. # Interruptions in Therapy Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. This decision depends in part on whether the interruption occurred during the initial or the continuation phase of therapy. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart the treatment from the beginning. Continuous treatment is more important in the initial phase of therapy, when there is the highest bacillary population and the chance of developing drug resistance is greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriological status of the patient before and after the interruption are also important considerations. There is no evidence on which to base detailed recommendations for managing interruptions in treatment, and no recommendations will cover all of the situations that may arise. The following approach (summarized in Figure 5), modified from the New York City Bureau of Tuberculosis Control Clinical Policies and Protocols (22), is presented as an example. If the interruption occurs during the initial phase of treatment and the lapse is 14 days or more in duration, treatment should be restarted from the beginning. However, if the lapse is less than 14 days, the treatment regimen should be continued. In either instance the total number of doses targeted for the initial phase should be given. If the interruption in treatment occurs during the continuation phase after the patient has received more than 80% of the planned total continuation phase doses given by DOT, further treatment may not be necessary if the patient's sputum was AFB smear negative on initial presentation. However, for patients who were smear positive initially, continued treatment to complete the planned total number of doses is warranted. If the patient has received less than 80% of the planned total doses and the lapse is 3 months or more in duration, treatment should be restarted from the beginning. If the lapse is less than 3 months in duration, treatment should be continued to complete a full course. At the time the patient is returned to treatment sputum cultures should be obtained and repeat drug susceptibility testing performed. If the cultures are still positive, the treatment regimen should be restarted. If sputum cultures are negative the patient could be treated as having culture-negative tuberculosis and given an additional 4 months of combination chemotherapy. Regardless of the timing and duration of the interruption, DOT should be used. If the patient was already being managed with DOT, additional measures will be necessary to ensure completion of therapy. Consultation with an expert is recommended to assist in managing treatment interruptions. # Practical Aspects of Treatment # Drug Administration The first-line antituberculosis medications should be administered together as single dose rather than in divided doses. A single dose leads to higher, and potentially more effective, peak serum concentrations. Administering a single daily dose also facilitates using DOT. Ingestion with food delays or moderately decreases the absorption of antituberculosis drugs (1). However, given the wide therapeutic margin of the first-line agents, the effects of food are of little clinical significance. Thus, if patients have epigastric distress or nausea with the first-line drugs, dosing with food is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. The absorption of INH can be substantially decreased when the drug is ingested with glucose or lactose. Because of this effect, the commercial preparation of INH elixir uses sorbitol for flavor, rather than glucose or lactose. However, sorbitol can cause diarrhea, limiting the acceptability of the commercial INH elixir. Administration of crushed INH tablets in a food with relatively low concentrations of glucose, such as applesauce, has not been formally evaluated, but has been used successfully by many providers. Antacids have minimal effects on the absorption of the first-line antituberculosis drugs. With the exception of fluoroquinolones, there is little information regarding the effect of food and antacids on the second-line antituberculosis drugs. In the absence of data, it is preferable to administer the drugs on an empty stomach if they are tolerated. However, antacids and other medications containing divalent cations markedly decrease the absorption of the fluoroquinolones, an interaction that has been associated with failure of antibiotic therapy (2,3). Therefore, it is critical that any fluoroquinolone not be administered within 2 hours of a dose of antacids, the chewable tablet form of didanosine, sucralfate, iron, magnesium, calcium, zinc, or vitamins or dietary supplements (e.g., Ensure ® , Sustical ® ) containing a significant amount of these cations. Parenteral therapy is indicated for severely ill patients who cannot take oral therapy and may be useful for the uncommon patient for whom poor absorption has been documented. Preparations of INH, RIF, the aminoglycosides, capreomycin, and most fluoroquinolones are available for intravenous administration. # Fixed-Dose Combination Preparations There are two fixed-dose combination preparations currently available for use in the United States, a combination of INH and RIF (Rifamate ® ) and a combination of INH, RIF, and PZA (Rifater ® ) (see Section 3: Drugs in Current Use). (A fourdrug combination of INH, RIF, EMB, and PZA is available in some countries.) Two tablets of Rifamate ® provide conventional daily doses of both INH (300 mg) and RIF (600 mg). The Rifater ® tablet that is available in the United States contains INH (50 mg), RIF (120 mg), and PZA (300 mg). Six tablets of Rifater ® would provide INH (300 mg) RIF (720 mg), and PZA (1,800 mg). The RIF dose is higher than is used typically in the United States because the RIF is less bioavailable in this formulation. These fixed-dose combinations have been formulated for use in daily therapy, although some programs use Rifamate ® plus INH tablets for twice weekly treatment. It should be noted that the dose of PZA in Rifater ® is such that additional PZA tablets will be required to provide an adequate dose for persons weighing more than 90 kg. Although there is no evidence indicating that fixed-dose combination medications are superior to individual drugs, expert opinion suggests that these formulations should be used when DOT is given daily and when DOT is not possible. Moreover, they are strongly recommended in international recommendations of the WHO and IUATLD. The theoretical advantage of reducing the risk of inadvertent monotherapy, the ease of administration, and the potential for reducing medication errors make them preferable to individual medications in many instances. When prescribing a fixed-dose combination preparation, care must be taken because of the similarity of the trade names of RIF (Rifadin ® ) and the fixeddose combinations (Rifamate ® , Rifater ® ). # Management of Common Adverse Effects As is true with all medications, combination chemotherapy for tuberculosis is associated with a predictable incidence of adverse effects, some mild, some serious. A comprehensive list of reported adverse reactions and their frequency is described in Section 3: Drugs in Current Use. Mild adverse effects can generally be managed with symptomatic therapy, whereas with more severe effects the offending drug or drugs must be discontinued. Although it is important to be attuned to the potential for adverse effects it is at least equally important that first-line drugs not be stopped without adequate justification. The following is a summary, based largely on clinical experience and expert opinion, of the approaches that should be taken in managing the common adverse effects of tuberculosis treatment. Proper management of more serious adverse reactions often requires expert consultation. # Gastrointestinal upset: nausea, vomiting, poor appetite, abdominal pain Gastrointestinal reactions are common, particularly in the first few weeks of therapy. Many of the antituberculosis drugs can cause gastrointestinal upset (4). In the presence of gastrointestinal symptoms serum AST and bilirubin should be measured. If the AST level is less than three times the upper limit of normal, the symptoms are assumed not to be due to hepatic toxicity. However, if the AST level is three or more times the upper limit of normal the symptoms should be assumed to represent hepatic toxicity, and the patient should be evaluated as described below. The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity, is to change the hour of drug administration and/or to administer the drugs with food. If patients are taking daily DOT, the timing of the drug administration should be altered, preferably to be closer to mealtime. Alternatively, food can be taken at the time of DOT administration. (In many programs food is offered as an incentive with DOT.) Patients receiving self-administered therapy can take the medications at bedtime. If gastrointestinal intolerance persists it may be best for all medications to be taken with meals. # Rash All drugs used in treating tuberculosis can cause a rash. The response to a patient with a rash depends on its severity. The rash may be minor, affecting a limited area or being predominantly manifested as itching, in which case antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued. A petechial rash may suggest thrombocytopenia in patients taking RIF (5). The platelet count should be checked and, if low, RIF hypersensitivity should be presumed to be the cause. RIF should be stopped and the platelet count monitored until it returns to baseline; RIF should not be restarted. If there is a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement, all drugs should be stopped immediately. If the patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral agents) should be started. When the rash is substantially improved the medications can be restarted one by one, at intervals of 2-3 days. RIF should be restarted first (because it is the least likely to cause rash, and it is the most important agent), followed by INH, and then EMB or PZA. If the rash recurs the last drug added should be stopped. If no rash appears after the first three drugs have been restarted, the fourth drug should not be restarted unless the rash was relatively mild and the fourth drug is considered essential for therapy. # Drug fever Recurrence of fever in a patient who has been receiving therapy for several weeks should suggest drug fever, especially if the patient is showing microbiological and radiographic improvement. It should be noted, however, that fever from tuberculosis may persist for as long as 2 months after therapy has been initiated (6). Fever may also be a manifestation of a paradoxical reaction, especially in patients with HIV infection (see Section 8.1: HIV Infection) (7). The clinical hallmark of drug fever is that the patient looks and feels well despite having a high fever (often greater than 39 º C). There is no specific pattern to the fever. Eosinophilia may or may not be present. The first step in management of a possible drug fever is to ensure that there is no superinfection or worsening of tuberculosis. If these potential causes are excluded all drugs should be stopped. Drug-related fever usually will resolve within 24 hours. Patients with severe tuberculosis should be given at least three new drugs in the interim. Once the fever has resolved, the same protocol as described above for restarting drugs in the presence of a rash should be followed. # Hepatitis (Management of patients with baseline abnormal liver function is described in Section 8.8: Hepatic Disease.) Three of the first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury (AST level three or more times the upper limit of normal in the presence of symptoms, or five or more times the upper limit of normal in the absence of symptoms) (8). If the AST level is less than 5 times the upper limit of normal, toxicity can be considered mild, an AST level 5-10 times normal defines moderate toxicity, and an AST level greater than 10 times normal (i.e., greater than 500 IU) is severe (9). In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase. This pattern is more consistent with rifampin hepatotoxicity It is important to note that an asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen (10). In the absence of symptoms therapy should not be altered because of modest asymptomatic elevations of AST, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic aminotransferase elevations resolve spontaneously. However, if AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms, hepatotoxic drugs should be stopped immediately and the patient evaluated carefully. Similarly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation. Serologic testing for hepatitis A, B, and C should be performed and the patient questioned carefully regarding symptoms suggestive of biliary tract disease and exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications. Drug-induced hepatitis is usually a diagnosis of exclusion but in view of the frequency with which other possible causes are present in any given patient, determining the cause may be difficult. Because the schedule for restarting antituberculosis medications is slower with hepatitis than for rash or drug fever it is generally prudent to give at least three nonhepatotoxic antituberculosis drugs until the specific cause of hepatotoxicity can be determined and an appropriate longer term regimen begun. The suspect antituberculosis medications should be restarted one at a time after the AST concentration returns to less than two times the upper limit of normal. (In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels.) Because RIF is much less likely to cause hepatotoxicity than is INH or PZA (Table 10) (10) and is the most effective agent, it should be restarted first. If there is no increase in AST after about 1 week, INH may be restarted. PZA can be started 1 week after INH if AST does not increase. If symptoms recur or AST increases the last drug added should be stopped. If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months. # Serum Drug Concentration Measurements The first-line drugs (INH, RIF, PZA, and EMB) have relatively predictable pharmacokinetics (11,12) and are highly efficacious when given in standard doses as DOT (13,14). Rarely, patients may have poor absorption or altered metabolism of the first-line drugs, resulting in failure of therapy (15,16) Second-line agents have a much narrower therapeutic window (the range of concentrations having reliable activity against M. tuberculosis but rarely causing toxicity) than the first-line drugs, and the consequences of treatment failure of drugresistant tuberculosis may be difficult to manage. These considerations suggest several clinical situations in which therapeutic drug monitoring may be helpful: 1) patients with treatment failure that is not explained by nonadherence or drug resistance, 2) persons with medical conditions that may result in abnormal pharmacokinetics of the first-line drugs, and 3) the management of multidrug-resistant tuberculosis with second-line drugs. Be aware, however, that there are many uncertainties about the use of therapeutic drug monitoring in tuberculosis treatment. An important limitation is the lack of sufficient data to formulate clinically validated therapeutic ranges for antituberculosis agents. One response to the lack of clinically derived therapeutic ranges for the rifamycins is to use the distribution of concentrations achieved in healthy volunteers as the therapeutic range. However, in practice this approach has been quite problematic. For example, serum concentrations of the first-line drugs among HIV-infected patients with active tuberculosis are frequently lower than those in healthy volunteers (17,18), but HIV-related tuberculosis responds well to standard tuberculosis treatment regimens (19,20). The disadvantages of therapeutic drug monitoring are as follows: 1) the time necessary, from both patients and providers, to obtain and ship blood samples, and 2) the relatively high cost of measuring serum drug concentrations. Until more data are available, it seems prudent to restrict therapeutic drug monitoring for the first-line drugs to patients who are having an inadequate response to DOT (that is not due to nonadherence or drug resistance) or evidence of severe gastrointestinal or metabolic abnormalities. Examples of such circumstances include severe gastroparesis, short-bowel syndrome, chronic diarrhea with malabsorption, and renal insufficiency. As described above, patients with HIV-related tuberculosis may have an increased incidence of malabsorption of antituberculosis drugs (although some studies have contrary findings) (21,22). Even if true, this tendency for lower drug concentrations among patients with HIV-related tuberculosis is not sufficient to warrant routine therapeutic drug monitoring in this population. # Drug Interactions # Interactions Affecting Antituberculosis Drugs Drug-drug interactions can result in changes in the concentrations of one or both of the drugs involved. In the case of the antituberculosis drugs, there are relatively few interactions that substantially change the concentrations of the antituberculosis drugs; much more often the antituberculosis drugs cause clinically relevant changes in the concentrations of other drugs. The exceptions to this general rule are rifabutin and the fluoroquinolones. Rifabutin is partially metabolized by cytochrome P450 (CYP) 3A. Inhibitors of CYP3A increase serum concentrations of rifabutin and one of its metabolites (25-O-desacetyl-rifabutin), sometimes to toxic levels. For example, administration of ritonavir, a potent CYP3A inhibitor, with the standard daily dose of rifabutin (300 mg) increases the serum concentrations of rifabutin (4-fold increase) and 25-O-desacetyl-rifabutin (35-fold increase) (1) and is associated with increased rates of leukopenia, arthralgias, skin discoloration, and uveitis (2), all recognized to be toxic effects of rifabutin or one of its metabolites (3,4). Conversely, administering rifabutin with a CYP3A inducer decreases its concentrations, perhaps to ineffective levels. For example, efavirenz, a potent antiretroviral drug, decreases rifabutin serum concentrations by approximately one-third (5). Recommendations for making dose adjustments of rifabutin when it is given with commonly used CYP3A inhibitors and inducers are available (6,7). However, the complexity of these interactions and the rapidly changing nature of antiretroviral therapy strongly suggest that the management of cases of HIVrelated tuberculosis should involve a physician with experience in this field. Absorption of the fluoroquinolones is markedly decreased by ingestion with medications containing divalent cations (calcium, iron, zinc), including antacids (8,9); supplements or vitamins containing calcium, iron or zinc (10), sucralfate (11); and the chewable tablet formulation of didanosine (12). These drug interactions can be avoided by assuring that medications containing divalent cations are ingested at least 2 hours apart from doses of fluoroquinolones (13). # Effects of Antituberculosis Drugs on Other Drugs # Drug interactions due to rifamycins The drugs used to treat tuberculosis affect the metabolism of many other drugs, and can result in a lack of efficacy (interactions with the rifamycins) or toxicity (interactions with isoniazid and the fluoroquinolones). Most of the clinically relevant drug-drug interactions involving the antituberculosis drugs are due to the effect of the rifamycins (rifampin, rifabutin, and rifapentine) on the metabolism of other drugs. All of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 system (14)(15)(16)(17)(18). By inducing the activity of metabolic enzymes, rifamycin therapy results in a decrease in the serum concentrations of many drugs, sometimes to levels that are subtherapeutic. The rifamycins differ substantially in their potency as enzyme inducers; rifampin is the most potent, rifapentine is intermediate, and rifabutin is the least potent enzyme inducer (19). The well-described, clinically relevant drug-drug interactions involving the rifamycins are presented in Table 12 (1,5,15,. However, it is important to note that many possible interactions involving the rifamycins have not been investigated fully and additional clinically relevant interactions undoubtedly will be described. Therefore, it is important to check all concomitant medications for possible, as well as confirmed, drug-drug interactions with rifamycins. Some of these drug-drug interactions can be managed with close clinical or laboratory monitoring and dose increases of the medication(s) affected by the rifamycins (Table 12). In other cases, the magnitude of the decrease in concentrations of a concomitant medication may be such that serum concentrations cannot be restored by a dose increase. If the dose of a medication is increased to compensate for the effect of a rifamycin, it is critical to remember that the dose of this drug will probably need to be decreased within the 2 weeks after the rifamycin is discontinued and its inductive effect resolves. In some situations, rifabutin can sometimes be used in place of rifampin, if there is an unacceptable drug-drug interaction between rifampin and another drug, such as cyclosporine (51) and most of the HIV-1 protease inhibitors (89). All the rifamycins may cause unacceptable decreases in the serum concentrations of certain drugs, such as delavirdine (26,27,90), ketoconazole and itraconazole (34,91). # Drug interactions due to isoniazid Isoniazid is a relatively potent inhibitor of several cytochrome P450 isozymes (CYP2C9, CYP2C19, and CYP2E1) ( 92), but has minimal effect on CYP3A (20). As an inhibitor, isoniazid can increase concentrations of some drugs to the point of toxicity. The clearest examples of toxicity due to the inhibitory activity of isoniazid are the anticonvulsants, phenytoin (93,94) and carbamazepine (95,96). Isoniazid also increases concentrations of benzodiazepines metabolized by oxidation, such as diazepam (85) and triazolam (97), but not those metabolized by conjugation, such as oxazepam (97). It is worth noting that rifampin has the opposite effect on the serum concentrations of many of these drugs. The available data demonstrate that the inductive effect of rifampin outweighs the inhibitory effect of isoniazid, so that the overall effect of combined therapy with rifampin and isoniazid is a decrease in the concentrations of drugs such as phenytoin (59) and diazepam (85). Isoniazid may increase toxicity of other drugsacetaminophen (98), valproate (99), serotonergic antidepressants (100), disulfiram (101), warfarin (102), and theophylline (103)-but these potential interactions have not been well studied. # Drug interactions due to fluoroquinolones Ciprofloxacin (104) inhibits the metabolism of theophylline and can cause clinical theophylline toxicity (105). However, levofloxacin (106), gatifloxacin (107), and moxifloxacin (108) do not affect theophylline metabolism. Benzodiazepines (e.g., diazepam , triazolam ), zolpidem (87), buspirone (88) # Comments Can be used with rifabutin. Ritonavir, 400-600 mg twice daily, probably can be used with rifampin. The combination of saquinavir and ritonavir can also be used with rifampin. Delavirdine should not be used with any rifamycin. Doses of nevirapine (28) and efavirenz (29) need to be increased if given with rifampin, no dose increase needed if given with rifabutin (5). Azithromycin has no significant interaction with rifamycins. May require use of a drug other than doxycycline. Itraconazole, ketoconazole, and voriconazole concentrations may be subtherapeutic with any of the rifamycins. Fluconazole can be used with rifamycins, but the dose of fluconazole may have to be increased. Consider alternate form of Pneumocystis carinii treatment or prophylaxis. Consider an alternative antibiotic. Consider alternate form of malaria prophylaxis. Women of reproductive potential on oral contraceptives should be advised to add a barrier method of contraception when taking a rifamycin. May require alternate therapy or use of a nonrifamycin-containing regimen. Monitoring of serum TSH recommended; may require increased dose of levothyroxine. Rifampin and rifapentine use may require methadone dose increase; rifabutin infrequently causes methadone withdrawal. Monitor prothrombin time; may require two-to threefold dose increase. Rifabutin may allow concomitant use of cyclosporine and a rifamycin; monitoring of cyclosporine serum concentrations may assist with dosing. Monitor clinically; may require two-to threefold increase in corticosteroid dose (58). Therapeutic drug monitoring recommended; may require anticonvulsant dose increase. Clinical monitoring recommended; may require change to an alternate cardiovascular agent. Clinical monitoring recommended; may require dose increase or change to an alternate cardiovascular drug. Monitor clinically; may require a dose increase or use of an alternate cardiovascular drug. Therapeutic drug monitoring recommended; may require digoxin or digitoxin dose increase. Therapeutic drug monitoring recommended; may require quinidine dose increase. Clinical monitoring recommended; may require change to an alternate cardiovascular drug. Therapeutic drug monitoring recommended; may require theophylline dose increase. Monitor blood glucose; may require dose increase or change to an alternate hypoglycemic drug. Monitor hypolipidemic effect; may require use of an alternate hypolipidemic drug. Therapeutic drug monitoring recommended; may require dose increase or change to alternate psychotropic drug. Monitor clinically; may require a dose increase or use of an alternate psychotropic drug. Monitor clinically; may require a dose increase or use of an alternate psychotropic drug. # Treatment in Special Situations # HIV Infection Treatment of tuberculosis in patients with HIV infection follows the same principles as treatment of HIV-uninfected patients. However, there are several important differences between patients with and without HIV infection. These differences include the potential for drug interactions, especially between the rifamycins and antiretroviral agents, paradoxical reactions that may be interpreted as clinical worsening, and the potential for the development of acquired resistance to rifamycins when treated with highly intermittent therapy. # Clinical trials of treatment for tuberculosis in HIV-infected patients There have been seven prospective studies of 6-month regimens for the treatment of pulmonary tuberculosis in patients with HIV infection for which recurrence data were reported. Four of the studies were randomized, controlled trials (1-4), and three were observational in nature (5,6). These studies differed somewhat in design, patient population, eligibility criteria, frequency of dosing, treatment supervision, and outcome definitions; therefore, it is difficult to provide meaningful cross-study comparisons. All of the studies reported a good early clinical response to therapy and the time required for sputum culture conversion from positive to negative and treatment failure rates were similar to these indices of treatment efficacy in patients without HIV infection. Recurrence rates have varied among studies, with most reporting rates of 5% or less (2,3,5,6). In one study from the Democratic Republic of Congo (formerly Zaire), in which the recurrence rate in the 6-month arm was 9% compared with 3% in the 12-month arm, nonadherence in the continuation phase and/or exogenous reinfection may have contributed to the higher recurrence rate (1). In a randomized trial of once weekly INH-rifapentine versus twice weekly INH-RIF in the continuation phase of therapy, 5 of 30 (17%) HIVinfected patients receiving treatment in the once weekly arm relapsed compared with 3 of 31 (10%) patients in the twice weekly INH-RIF arm (4). Four of the five relapsed patients in the once weekly group had resistance to rifampin alone compared with none in the standard treatment arm. Because of the small sample size in the standard treatment arm, it is difficult to interpret the relapse rate of 10%. In an observational study of twice weekly INH-rifabutin among HIV-infected tuberculosis patients also receiving antiretroviral therapy, 7 of 156 patients failed treatment or relapsed (7). Although the life table rate of failure/relapse was low (4.6%), M. tuberculosis isolated from all five of these patients was resistant to RIF alone. The phenomenon of acquired rifampin monoresistance was also seen in a trial of largely twice weekly INH-RIF therapy, albeit at a lower rate (3). In all of these studies, acquired RIF resistance occurred only among patients with CD4 + cell counts <100 cells/µl. Acquired rifampin resistance has not been seen in trials where RIF was given daily. A consistent finding in the treatment studies has been a high mortality rate among HIV-seropositive patients. In most studies the cause of death is difficult to ascertain. Early mortality may be related to advanced tuberculosis, but deaths during the continuation phase of therapy are usually due to other AIDS-related conditions. Mortality during treatment among HIV-infected patients with tuberculosis has been associated with advanced HIV disease (1,3,6,8). However, the use of effective antiretroviral therapy during the treatment of tuberculosis in persons with HIV infection may improve treatment outcomes and, thus, is recommended, as described subsequently (9). A major concern in treating tuberculosis in the setting of HIV infection is the interaction of RIF with antiretroviral agents (see Section 7: Drug Interactions, and Table 12). As described previously, rifabutin is highly active against M. tuberculosis but has less of an effect in inducing hepatic microsomal enzymes than RIF. Data from clinical trials suggest that rifabutin and RIF-based regimens are equally efficacious. Gonzalez-Montaner and colleagues (10) reported the first randomized clinical trial comparing rifabutin (150 and 300 mg) with RIF in a 6-month regimen in persons without HIV infection. The outcomes were highly favorable in both groups and there were few adverse reactions. Investigators from South Africa reported a randomized, open-label trial comparing rifabutin with RIF in a standard four-drug regimen administered with DOT (11). Although patients did not have HIV testing performed, the HIV seroprevalence was reportedly low at the time of the study. In the continuation phase, the medications were given twice weekly. By 2 months after treatment was begun, 88% of the patients in the RIF arm and 92% of those given rifabutin had negative sputum cultures. The relapse rate was 3.8% in the RIF group versus 5.1% in the rifabutin group (p = NS). Only one study examining the effectiveness of rifabutin included HIV-infected patients (12). A single blind randomized study of 50 HIV-infected patients in Uganda compared a fully supervised regimen of RIF versus rifabutin together with INH, EMB, and PZA. Time to sputum conversion was similar between groups when controlling for baseline characteristics. Relapse data were not available. Investigators in Uganda have reported a higher mortality rate among HIV-infected patients treated with regimens that did not contain RIF. Wallis and associates (13) reported that a # Tuberculosis and HIV Infection The treatment of tuberculosis in persons with HIV infection is essentially the same as for patients without HIV infection. There are two important exceptions to this generalization: 1) Once weekly INH-rifapentine in the continuation phase should not be used in any HIV-infected patient; and 2) twice weekly INH-RIF or rifabutin should not be used for patients with CD4 + lymphocyte counts less than 100/µl. Providers must be alert to the potential for interactions among many of the antiretroviral drugs and the rifamycins. Paradoxical reactions that mimic worsening of tuberculosis are more common in patients with HIV infection and may complicate therapy. non-RIF-containing regimen was associated with shortened survival compared with an RIF-based regimen. In addition to the higher mortality associated with non-RIF-based regimens, other studies have demonstrated unacceptably high recurrence rates in the setting of HIV infection (14,15). Thus, every effort should be made to use a rifamycin-based regimen for the entire course of therapy in persons with HIV infection. # Treatment recommendations Recommendations for the treatment of tuberculosis in HIVinfected adults are, with two exceptions, identical to those for HIV-uninfected adults: a 6-month regimen consisting of an initial phase of INH, RIF, PZA, and EMB given for 2 months followed by INH and RIF for 4 months when the disease is caused by organisms that are known or presumed to be susceptible to the first-line agents. This regimen may be given by daily or intermittent administration as listed in Table 1 and described in Section 5.2: Recommended Regimens. However, on the basis of data showing an increased frequency of rifamycin resistance among patients having CD4 + cell counts 100/µl). Once weekly administration of INH-rifapentine in the continuation phase should not be used in any patient with HIV infection. Six months should be considered the minimum duration of treatment for adults, even for patients with culture-negative tuberculosis. If there is evidence of a slow or suboptimal response (e.g., cultures are still positive after 2 months of therapy), prolongation of the continuation phase to 7 months (a total of 9 months treatment) should be strongly considered. DOT and other adherence-promoting strategies should be used in all patients with HIV-related tuberculosis. Although there are no data on which to base recommendations, the American Academy of Pediatrics recommends that for HIVinfected children the minimum duration of therapy be 9 months (17). All patients with tuberculosis should be advised to undergo voluntary counseling and HIV testing. Efforts should be made to engage all patients with a new diagnosis of HIV infection in HIV care during their treatment for tuberculosis. Ideally, patients should be managed by physicians who are expert in the treatment of tuberculosis/HIV coinfection. If the HIV care provider and tuberculosis care provider are not the same person, communication between them is essential and should occur frequently throughout the course of treatment. # Safety and tolerability The frequency of antituberculosis drug-related toxicity in patients with HIV infection has varied from study to study. In a retrospective study from San Francisco, 18% of HIVseropositive patients with tuberculosis had a change of regimen because of adverse drug reactions (18). RIF was the drug implicated most commonly, producing an adverse reaction in 12% of the patients. In the Democratic Republic of Congo, 11% of the seropositive patients developed a rash but in none was the treatment interrupted (1). Paresthesia developed in 21% of the cases, suggesting the need for pyridoxine when treating tuberculosis in persons with HIV infection. Other investigators have reported low rates of significant adverse reactions (3,5,6,19). In the three times weekly regimen studied in Haiti, there were no differences in adverse events between HIV-infected and uninfected patients (6). In HIV-infected patients it is often difficult to distinguish an adverse reaction to antituberculosis drugs from the effects of associated conditions or reactions to any of the many medications that are often being taken concurrently. Because of the difficulties in diagnosing a drug reaction and in determining the responsible agent, the first-line antituberculosis drugs (especially INH or RIF) should not be stopped permanently without strong evidence that the antituberculosis drug was the cause of the reaction. In such situations consultation with an expert in treating tuberculosis in persons with HIV infection is recommended. In a study reported by Ungo and associates (20), it was demonstrated that the relative risk of developing drug-induced hepatoxicity in tuberculosis patients with hepatitis C virus or HIV infection was 5-and 4-fold, respectively, compared with a 14-fold relative risk in patients with both hepatitis C virus and HIV infections. This finding was not confirmed in a study from Baltimore, in which rates of transaminase elevation were not greater in patients with HIV and hepatitis C virus who were given INH (21). Current IDSA and USPHS guidelines recommend screening all HIV-infected patients for hepatitis C virus (22). Until more data are available it is probably prudent to provide more frequent clinical and laboratory monitoring, as described for patients with preexisting liver disease, for patients with HIV infection or hepatitis C virus infection who are being treated for tuberculosis. # Concurrent administration of antiretroviral agents and rifamycins Most patients with tuberculosis have relatively advanced HIV disease and, thus, antiretroviral therapy is indicated (23). Antiretroviral therapy should not be withheld simply because the patient is being treated for tuberculosis, if it is otherwise indicated. Nevertheless, it is not advisable to begin both antiretroviral therapy and combination chemotherapy for tuberculosis at nearly the same time. So doing may involve as many as eight new drugs with interactions and overlapping toxicities that would be difficult to evaluate. Although there are few data on which to base recommendations, expert opinion suggests that treatment for tuberculosis should be initiated first. Although antiretroviral therapy has a dramatic effect in decreasing progression of HIV disease (decreasing CD4 + cell counts, new opportunistic infections, or death), among patients with HIV-related tuberculosis, the use of antiretroviral therapy in the setting of tuberculosis therapy is complex. In those patients not already receiving antiretroviral therapy, early initiation of antiretroviral therapy may decrease HIV disease progression, but is also associated with a high incidence of side effects and paradoxical reactions, some severe enough to warrant discontinuation of both antiretroviral and antituberculosis drugs (9). In addition, starting so many new medications in a short time period may present a tremendous adherence challenge for patients adjusting to the diagnoses of both tuberculosis and AIDS. Delaying the initiation of antiretroviral therapy until 4-8 weeks after starting antituberculosis therapy has the potential advantages of being better able to ascribe a specific cause for a drug side effect, decreasing the severity of paradoxical reactions, and decreasing the adherence difficulties for the patient. Until there have been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with HIV infection and tuberculosis, this decision should be individualized, based on the patient's initial response to treatment for tuberculosis, occurrence of side effects, and ready availability of multidrug antiretroviral therapy. For patients with CD4 + cell counts >350 cells/µl, the antiretroviral regimen could be initiated at any time after tuberculosis treatment was begun, based on current recommendations (23). For patients who are already receiving an antiretroviral regimen, treatment should generally be continued, although the regimen may need to be modified on the basis of the risk of drug-drug interactions, as described in Section 7: Drug Interactions. Even though drug interactions are common, a rifamycin should not be excluded from the tuberculosis treatment regimen for fear of interactions with some antiretroviral agents. The exclusion of a rifamycin from the treatment regimen is likely to delay sputum conversion, will prolong the duration of therapy, and possibly result in a poorer outcome (24). As noted in Section 7, Drug Interactions, rifabutin has fewer interactions than RIF and should be used if these categories of antiretroviral agents are being administered. The categories of antiretroviral agents available currently are nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The NRTIs and NtRTIs do not have clinically significant drug interactions with the standard antituberculosis medications; thus, drugs in these categories can be used together with rifamycins without any dose adjustment being necessary. However, the PIs and NNRTIs, depending on the specific drug, may either inhibit or induce cytochrome P450 isoenzymes (CYP450). Thus, these drugs may alter the serum concentration of rifabutin, as described in Section 7.1: Interactions Affecting Antituberculosis Drugs. When rifabutin is combined with antiretroviral agents, its dose and the dose of the antiretroviral agents may require adjustment. A report described the successful use of rifabutin with an antiretroviral regimen containing PIs (25). All 25 patients became culture negative by 2 months and no relapses were reported after a median follow-up of 13 months. Moreover, the circulating HIV RNA levels decreased significantly, with 20 of 25 patients achieving viral loads of less than 500 copies/ml. Thus, it appears that both tuberculosis and HIV can be treated successfully with concurrent use of a rifabutinbased regimen and potent combinations of antiretroviral agents. Previous guidelines from CDC specifically stated that RIF was contraindicated in patients who were taking any PI or NNRTI (26). However, new data indicate that RIF can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents (27,28). As recommended by CDC (27), rifampin can be used with a regimen of efavirenz and two NRTIs, with ritonavir and one or more NRTIs, with ritonavir and saquinavir (either hard-gel or soft-gel capsule), and with a triple nucleoside regimen. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified. Because these recommendations are frequently revised, obtaining the most up-to-date information from the CDC website, http:// www.cdc.gov/nchstp/tb/, is advised. Updated information on antiretroviral drugs and drug interactions, compiled by Medscape, can be found at / updates/quickguide. When starting NNRTIs or PIs for tuberculosis patients receiving RIF, a 2-week "washout" period is generally recommended between the last dose of RIF and the first dose of PIs or NNRTIs to allow for reduction of the enzyme-inducing activity of RIF. During this time, rifabutin may be started to ensure that the tuberculosis treatment regimen is adequate. For patients already receiving antiretroviral agents at the time treatment for tuberculosis is begun, an assessment of the antiretroviral regimen should be undertaken and, if necessary, changes made to ensure optimum treatment of the HIV infection during tuberculosis therapy. Conversely, the determination of whether to use RIF and the dose of the rifamycin must take into account the antiretroviral regimen. # Paradoxical reaction On occasion, patients have a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis (paradoxical reaction) after beginning antituberculosis treatment. Worsening of this sort occurs in patients without HIV infection, especially with lymphadenitis, but it is more common among HIV-infected patients. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by antiretroviral therapy or, perhaps, by treatment of the tuberculosis itself. Narita and colleagues (29) reported that among HIV-infected patients who were taking antiretroviral agents, 36% developed paradoxical worsening after beginning treatment for tuberculosis compared with 7% of those who were not taking antiretroviral drugs. In contrast, Wendel and colleagues (30) reported that only 7% of HIV-infected patients with tuberculosis developed paradoxical worsening and the reactions were not associated with antiretroviral therapy. Signs of a paradoxical reaction may include high fevers, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially tuberculosis treatment failure. A paradoxical reaction that is not severe should be treated symptomatically without a change in antituberculosis or antiretroviral therapy. Although approaches to the management of severe reactions, such as high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, and sepsis syndrome, have not been studied, expert opinion suggests that prednisone or methylprednisolone be started at a dose of about 1 mg/kg and gradually reduced after 1 to 2 weeks. # Children and Adolescents Children most commonly develop tuberculosis as a complication of the initial infection with M. tuberculosis (primary tuberculosis). Radiographically, primary tuberculosis is characterized by intrathoracic adenopathy, mid-and lower lung zone infiltrates, and the absence of cavitation. However, children, occasionally, and adolescents, more frequently, develop adult-type tuberculosis (upper lobe infiltration and cavitation associated with sputum production). The lesions of primary tuberculosis have a smaller number of M. tuberculosis organisms than those of adult-type pulmonary tuberculosis; thus, treatment failure, relapse, and development of secondary resistance are rare phenomena among children. Because it is more difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis than from an adult, it is frequently necessary to rely on the results of culture and susceptibility tests of specimens from the person presumed to be the source of the infection in the child to guide the choice of drugs for the child. In children in whom drug resistance is suspected or for whom no source case isolate is available, attempts to isolate organisms via three early morning gastric aspirations (optimally during hospitalization), bronchoalveolar lavage, or tissue biopsy must be considered. Because tuberculosis in infants and children younger than 4 years of age is more likely to disseminate, treatment should be started as soon as the diagnosis is suspected. Asymptomatic children with a positive PPD-tuberculin skin test and an abnormal chest radiograph (atelectasis, parenchymal infiltrate, or hilar adenopathy) should receive combination chemotherapy, usually with INH, RIF, and PZA as initial therapy. Several controlled and observational trials of 6-month therapy in children with pulmonary tuberculosis caused by organisms known or presumed to be susceptible to the firstline drugs have been published (1)(2)(3)(4)(5)(6)(7)(8)(9). Six months of therapy with INH and RIF has been shown to be effective for hilar adenopathy and pulmonary disease caused by drugsusceptible organisms (5,6). However, most studies used 6 months of daily treatment with INH and RIF, supplemented during the first 2 weeks to 2 months with PZA. This threedrug combination has a success rate of greater than 95% and a rate of adverse effects of less than 2%. Two studies used twice or three times weekly therapy from the beginning with good results (1,7). Many experts prefer to treat children with three (rather than four) drugs in the initial phase because the bacillary population is low, because many infants and children cannot tolerate the pill burden required with four oral drugs, and because of the difficulty in performing visual acuity tests in young children who are being treated with EMB. In children suspected or known to have been infected with an M. tuberculosis strain that is fully susceptible, the initial phase should consist of INH, RIF, and PZA. If the susceptibility of the presumed infecting strain is not known and the likelihood of failure is low (primary tuberculosis), some experts prefer to use three drugs. However, children and adolescents with adult-type pulmonary tuberculosis, as defined above, should be treated with the four-drug initial phase regimen, unless the infecting strain is known to be susceptible (10). When epidemiologic circumstances (Table 6) suggest an increased risk of drug-resistant organisms being present, EMB can be used safely in a dose of about 15-20 mg/kg per day, even in children too young for routine eye testing. Older children should have monthly evaluations of visual acuity and color discrimination while taking EMB. SM, kanamycin, or amikacin can be used as the fourth drug, when necessary. The usual doses for daily and twice weekly treatment in children are listed in Section 3, Drugs in Current Use, and shown in Table 3. Three times weekly therapy is not recommended for children. Pyridoxine is recommended for infants, children, and adolescents who are being treated with INH and who have nutritional deficiencies, symptomatic HIV infection, or who are breastfeeding. DOT should be used for all children with tuberculosis. The lack of pediatric dosage forms of most antituberculosis medications necessitates using crushed pills and suspensions. Even when drugs are given under DOT, tolerance of the medications must be monitored closely. Parents should not be relied on to supervise DOT. Because of the difficulties in isolating M. tuberculosis from children, bacteriological examinations are less useful in evaluating the response to treatment and clinical and radiographic examinations are of relatively greater importance. However, hilar adenopathy and resultant atelectasis may require 2-3 years to resolve. Thus, a persisting abnormality on chest radiographs is not necessarily a criterion for extending continuing therapy. Recognition of treatment failure or relapse in a child is subject to the same difficulties as making a diagnosis. Thus, clinical and radiographic worsening may not be accompanied by positive AFB smears or mycobacterial cultures. A decision to modify the drug regimen should not be made lightly, but often must be made on clinical grounds only. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions may be disseminated disease, and meningitis, for which there are inadequate data to support 6-month therapy. A fourth drug is recommended in the initial phase when there is disseminated tuberculosis. The recommended duration is 9-12 months. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs (INH and RIF, plus PZA for the first 2 months), and the total duration of therapy should be at least 9 months (11). # Extrapulmonary Tuberculosis Tuberculosis can involve virtually any organ or tissue in the body. Nonpulmonary sites tend to be more common among children and persons with impaired immunity. To establish the diagnosis of extrapulmonary tuberculosis, appropriate specimens including pleural fluid; pericardial or peritoneal fluid; pleural, pericardial, and peritoneal biopsy specimens; lymph node tissue; and bone marrow, bone, blood, urine, brain, or cerebrospinal fluid should be obtained for AFB staining, mycobacterial culture, and drug susceptibility testing (1). Tissue specimens should also be examined microscopically, after routine and AFB staining, but the absence of AFB and of granulomas or even failure to culture M. tuberculosis does not exclude the diagnosis of tuberculosis. Bacteriological evaluation of the response to treatment in extrapulmonary tuberculosis is often limited by the difficulty in obtaining follow-up specimens. Thus, response often must be judged on the basis of clinical and radiographic findings. The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although many fewer treatment studies have examined treatment of extrapulmonary tuberculosis, compared with pulmonary disease, increasing evidence, including some randomized controlled trials, suggests that 6-to 9-month regimens that include INH and RIF are effective (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Therefore, among patients with extrapulmonary tuberculosis, a 6-to 9-month regimen (2 months of INH, RIF, PZA, and EMB followed by 4-7 months of INH and RIF) is recommended as initial therapy unless the organisms are known or strongly suspected of being resistant to the first-line drugs. If PZA cannot be used in the initial phase, the continuation phase must be increased to 7 months, as described for pulmonary tuberculosis. The exception to the recommendation for a 6-to 9-month regimen is tuberculous meningitis, for which the optimal length of therapy has not been established, but some experts recommend 9-12 months. Although in extrapulmonary tuberculosis there have not been controlled trials of the various patterns of intermittent drug administration listed in Table 2, expert opinion suggests that all could be used, with the exception of INH-rifapentine once weekly in the continuation phase. Given the lack of experience with this regimen, it is not recommended currently for treating extrapulmonary tuberculosis. Corticosteroid treatment is a useful adjunct in treating some forms of extrapulmonary tuberculosis, specifically meningitis and pericarditis caused by drug-susceptible organisms. Evidence-based recommendations on the duration of treatment for extrapulmonary tuberculosis and the use of corticosteriods are shown in Table 13. # Lymph node tuberculosis A 6-month regimen as described in Section 5, Recommended Treatment Regimens, and Table 2 is recommended for initial treatment of all patients with tuberculous lymphadenitis caused by drug-susceptible organisms (2)(3)(4)(5)(6). Affected lymph nodes may enlarge while patients are receiving appropriate therapy or after the end of treatment without any evidence of bacteriological relapse (3,5,17,18). On occasion, new nodes can appear during or after treatment as well. Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration or incision and drainage appears to be beneficial, although this approach has not been examined systematically (Rating BIII). It should be noted that the majority of cases of lymphatic mycobacterial disease in children born in the United States are caused by nontuberculous mycobacteria. # Bone and joint tuberculosis Several studies have examined treatment of bone and joint tuberculosis and have shown that 6-to 9-month regimens containing RIF are at least as effective as 18-month regimens that do not contain RIF (13)(14)(15) Because of the difficulties in assessing response, however, some experts tend to favor the 9-month duration. A randomized trial performed primarily among ambulatory patients by the Medical Research Council Working Party on Tuberculosis of the Spine (13) demonstrated no additional benefit of surgical debridement or radical operation (resection of the spinal focus and bone grafting) in combination with chemotherapy compared with chemotherapy alone. Myelopathy with or without functional impairment most often responds to chemotherapy. In two Medical Research Council studies conducted in Korea, 24 of 30 patients in one study (14) and 74 of 85 patients in an earlier study (19) had complete resolution of myelopathy or complete functional recovery when treated medically. In some circumstances, however, surgery appears to be beneficial and may be indicated. Such situations include failure to respond to chemotherapy with evidence of ongoing infection, the relief of cord compression in patients with persistence or recurrence of neurologic deficits, or instability of the spine. # Pericardial tuberculosis For patients with pericardial tuberculosis, a 6-month regimen is recommended. Corticosteroids are recommended as adjunctive therapy for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. In a randomized, double-blind, controlled trial, patients in the later effusiveconstrictive phase who received prednisolone had a (9). As before, there was no statistically significant impact on progression to constriction or in the need for pericardiectomy. An additional small randomized trial by Hakim and associates (20) performed in HIV-infected patients with tuberculous pericarditis also demonstrated that prednisolone therapy was associated with a reduced risk of mortality. On the basis of these studies, it is recommended that daily adjunctive prednisolone or prednisone treatment be given to adults and children with tuberculous pericarditis. For adults the prednisone dose is 60 mg/day (or the equivalent dose of prednisolone) given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and finally 5 mg/day for week 11 (the final week). Children should be treated with doses proportionate to their weight, beginning with about 1 mg/kg body weight and decreasing the dose as described for adults. # Pleural tuberculosis A 6-month regimen is also recommended for treating pleural tuberculosis. A number of studies have examined the role of corticosteroid therapy for tuberculous pleural effusions (21), but only two have been prospective, double blind, and randomized (7,22). In both of these studies, prednisone (or prednisolone) administration did not reduce the development of residual pleural thickening. Lee and associates (22) found that patients with pleural tuberculosis who received prednisone had a significantly more rapid resolution of symptoms such as fever, chest pain, and dyspnea than patients given placebo. Patients who received prednisone had a more rapid radiographic resolution of the effusions. In the study by Wyser and colleagues (7), all patients had complete drainage of the effusion performed at the time of the diagnostic procedure; patients were then allocated at random to receive adjunctive oral prednisone or placebo for 6 weeks. The complete drainage led to a rapid resolution of symptoms, and the added benefit of corticosteroids on symptoms was minimal. Tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy. Surgery, when needed, should be undertaken by experienced thoracic surgeons (23). The optimum duration of treatment for this unusual form of tuberculosis has not been established. # Tuberculous meningitis Before the advent of effective antituberculosis chemotherapy, tuberculous meningitis was uniformly fatal. Tuberculous meningitis remains a potentially devastating disease that is associated with a high morbidity and mortality, despite prompt initiation of adequate chemotherapy (24)(25)(26)(27)(28)(29). HIV-infected patients appear to be at increased risk for developing tuberculous meningitis but the clinical features and outcomes of the disease are similar to those in patients without HIV infection (24)(25)(26)29). Patients presenting with more severe neurologic impairment such as drowsiness, obtundation, or coma have a greater risk of neurologic sequelae and a higher mortality. Chemotherapy should be initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. INH and RIF, as well as the aminoglycosides, capreomycin, and the fluoroquinolones are available in parenteral forms for patients with altered mental status who may not be able to take oral medications. After 2 months of four-drug therapy for meningitis caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined, and there are no data from randomized, controlled trials to serve as the basis of recommendations. Repeated lumbar punctures should be considered to monitor changes in CSF cell count, glucose, and protein, especially in the early course of therapy. Differences in regimens among patient groups and in the use of corticosteroid therapy have made meta-analysis of published treatment trials impossible (30). Some authors have advocated longer courses of therapy, up to 2 years (28,31), whereas others have suggested that short-course RIF-based regimens for 6 to 9 months may be adequate therapy (10,32,33). It has been reported that some patients being treated for tuberculous meningitis develop tuberculomas during therapy, perhaps as a form of paradoxical reaction; however, this does not necessarily indicate treatment failure. A number of investigators have examined the role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis (21,(34)(35)(36)(37)(38)(39)(40)(41), but many of these are limited by small sample size or use of a regimen that did not include RIF. There are no large, prospective, randomized, controlled trials of adjunctive corticosteroid use for tuberculous meningitis in which an RIF-based regimen has been used. Six of eight controlled trials noted a benefit of corticosteroid therapy in terms of survival, frequency of sequelae, or both. In the study conducted by Girgis and coworkers (34), the greatest benefit was for patients with Stage II disease (lethargic) on presentation (4 of 27 of those who received dexamethasone died versus 14 of 35 in the control group; p <0.02). For patients presenting with coma (Stage III), there was no significant difference in survival between those who received dexamethasone and control patients (28 of 44 mortality for the dexamethasone group versus 35 of 46 for control subjects). However, the small sample size may have precluded finding an effect. Likewise, there were too few patients with Stage I disease (alert) on entry to determine the effectiveness of dexamethasone for this less severely ill group. On the basis of the available data, albeit limited, adjunctive corticosteroid therapy with dexamethasone is recommended for all patients, particularly those with a decreased level of consciousness, with tuberculous meningitis. The recommended regimen is dexamethasone in an initial dose of 8 mg/ day for children weighing less than 25 kg and 12 mg/day for children weighing 25 kg or more and for adults. The initial dose is given for 3 weeks and then decreased gradually during the following 3 weeks. # Disseminated tuberculosis A 6-month regimen is recommended for tuberculosis at multiple sites and for miliary tuberculosis, although there are limited data from controlled clinical trials addressing this issue. (The AAP recommends 9 months of treatment for children with disseminated tuberculosis.) Expert opinion suggests that corticosteroid therapy may be useful for treating respiratory failure caused by disseminated tuberculosis but there are no data to support its use. # Genitourinary tuberculosis Renal tuberculosis is treated primarily with medical therapy (12,(42)(43)(44)(45)(46), and a 6-month regimen is recommended. If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal drainage by stenting or nephrostomy is recommended (42). The use of corticosteriods in addition to stenting for the treatment of ureteric stenosis is discussed in the urologic literature but the efficacy of steroids in this setting is unclear. Nephrectomy is not usually indicated for the treatment of uncomplicated renal tuberculosis but should be considered when there is a nonfunctioning or poorly functioning kidney, particularly if hypertension or continuous flank pain is present. Tuberculosis of either the female or male genital tract responds well to standard chemotherapy, and surgery is needed only for residual large tubo-ovarian abscesses. A positive urine culture for M. tuberculosis occurs relatively commonly as an incidental finding among patients with pulmonary or disseminated disease, especially those with HIV infection. The positive culture may occur in the absence of any abnormalities on urinalysis and does not necessarily represent genitourinary tract involvement. # Abdominal tuberculosis A 6-month regimen is recommended for patients with peritoneal or intestinal tuberculosis (47,48). There are insufficient data to recommend adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis (21). In a small study of peritoneal tuberculosis alternate patients received adjunctive corticosteroid therapy for 4 months (total of 23 steroid recipients) (49). Fibrotic complications were noted in 4 of 24 in the control group and in none of those in the steroid group (23 patients), but the difference was not statistically significant. # Other sites of involvement As noted above, tuberculosis can involve any organ or tissue. In treating tuberculosis in sites other than those mentioned, the basic principles of therapy apply, but experts should be consulted for specific advice concerning individual patients. 49. Singh MM, Bhargava AN, Jain KP. Tuberculous peritonitis: an evaluation of pathogenetic mechanisms, diagnostic procedures and therapeutic measures. N Engl J Med 1969;281:1091-1094. # Culture-Negative Pulmonary Tuberculosis in Adults Failure to isolate M. tuberculosis from appropriately collected specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active tuberculosis. For the United States as a whole, about 17% of the reported new cases of pulmonary tuberculosis have negative cultures (1). Low bacillary populations, temporal variations in the number of bacilli being expelled, and errors in specimen processing all may result in failure to isolate organisms from patients who have active tuberculosis. It should be emphasized that alternative diagnoses must be considered carefully and appropriate diagnostic studies undertaken in patients who have what appears to be culture-negative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis should have three sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria as part of the diagnostic evaluation. Depending on the clinical features and differential diagnosis, other diagnostic testing, such as bronchoscopy with bronchoalveolar lavage and biopsy, should be considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture, treatment for active disease should be continued. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have a thorough follow-up clinical and radiographic evaluation at the time 2 months of therapy has been completed to determine whether there has been a response that can be attributed to antituberculosis treatment. If there is either clinical or radiographic improvement and no other etiology is identified, treatment should be continued for active tuberculosis. A 4-month, INH and RIF regimen for culture-negative tuberculosis has been demonstrated to be successful with only 1.2% relapses during an average follow-up of 44 months (2). However, because the results of cultures may not be known for 3-8 weeks and because of the possibility of drug resistance, initiation of two-drug therapy with INH and RIF alone is not recommended, but the continuation phase can be shortened to 2 months using INH and RIF (Figure 2). On occasion, patients who are being evaluated for pulmonary tuberculosis will be found to have positive AFB smears but negative cultures. There are several potential explanations for this occurrence, including the possibilities that the acidfast organisms are nontuberculous and difficult to culture, that they are nonviable tubercle bacilli, and that they are the result of laboratory error. The approach taken in such cases should be individualized on the basis of clinical and radiographic findings. If suspicion of tuberculosis is high and the patient has positive AFB smears, even with negative cultures, he/she should be treated as if the culture is positive, using one of the recommended regimens. # Radiographic Evidence of Prior Tuberculosis: Inactive Tuberculosis Persons with a positive tuberculin PPD skin test who have radiographic findings consistent with prior pulmonary tuberculosis (ATS/CDC Class 4) (1) and who have not been treated are at increased risk for the subsequent development of active tuberculosis (2)(3)(4). The radiographic findings that constitute evidence of prior tuberculosis are apical fibronodular infiltrations, often with volume loss. Case rates among such persons in one study were about 2.5 times those of persons infected with M. tuberculosis who did not have chest radiographic abnormalities (3). Persons with radiographic findings of healed primary tuberculosis (e.g., calcified solitary pulmonary nodules, calcified hilar lymph nodes, and pleural thickening) are not at increased risk for tuberculosis compared with other persons with latent tuberculosis infection. Patients should not be classified as having radiographic evidence of prior tuberculosis if another disease is found to account for the radiographic findings. The activity of tuberculosis cannot be determined from a single chest radiograph, and unless there are previous radiographs showing that the abnormality has not changed, it is recommended that sputum examination, using sputum induction if necessary, be performed to assess the possibility of active tuberculosis. Once active tuberculosis has been excluded by sputum culture, these persons are high-priority candidates for treatment of latent tuberculosis infection (5). The optimum treatment for patients with latent tuberculosis infection and abnormal chest radiographs consistent with prior tuberculosis has been examined in several studies. A placebo-controlled trial conducted by the IUATLD (2) compared the efficacy of 3, 6, and 12 months of INH in preventing # Pregnancy and Breastfeeding Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. Infants born to women with untreated tuberculosis may be of lower birth weight than those born to women without tuberculosis and, rarely, the infant may acquire congenital tuberculosis (1)(2)(3). Thus, treatment of a pregnant woman with suspected tuberculosis should be started if the probability of tuberculosis is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. SM should not be substituted for EMB. Although PZA is recommended for routine use in pregnant women by the WHO (4) and the IUATLD (5), the drug has not been recommended for general use in pregnant women in the United States because of insufficient data to determine safety. However, some public health jurisdictions in the United States have used PZA in pregnant women without reported adverse events (1). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Pyridoxine, 25 mg/ day, should be given to pregnant women who are receiving INH. INH, RIF, and EMB cross the placenta, but none has been shown to have teratogenic effects (6). SM, the only antituberculosis drug documented to have harmful effects on the human fetus, interferes with development of the ear and may cause congenital deafness. In 40 pregnancies among women being treated with SM, 17% of the babies had eighth nerve damage with deficits ranging from mild hearing loss to bilateral deafness (6,7). Kanamycin, amikacin, and capreomycin presumably share this toxic potential; however, there is little specific information on the fetal effects of these three drugs. PAS was used commonly with INH in the past and there was no indication of teratogenicity among babies whose mothers had received these two drugs (2). There are not enough data to determine the risk of cycloserine or ethionamide, although one report described nonspecific teratogenic effects attributed to ethionamide (8). The fluoroquinolones have been associated with arthropathies in young animals; therefore, they should be avoided if possible in pregnant women (6). In general, administration of antituberculosis drugs is not an indication for termination of pregnancy (2). However, in women who are being treated for drug-resistant tuberculosis, counseling concerning the risk to the fetus should be provided because of the known and unknown risks of the second-line agents. Breastfeeding should not be discouraged for women being treated with first-line agents, because the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant (9). Conversely, drugs in breast milk should not be considered to serve as effective treatment for active tuberculosis or latent tuberculosis infection in a nursing infant. Supplementary pyridoxine is recommended for the nursing mother receiving INH. The administration of the fluoroquinolones during breastfeeding is not recommended, although, as of 1998, there have been no reported cases of adverse reactions in infants breast fed by women taking these drugs (6). # Renal Insufficiency and End-stage Renal Disease Renal insufficiency complicates the management of tuberculosis because some antituberculosis medications are cleared by the kidneys. Management may be further complicated by the removal of some antituberculosis agents via hemodialysis. Thus, some alteration in dosing antituberculosis medications is commonly necessary in patients with renal insufficiency and endstage renal disease (ESRD) receiving hemodialysis (Table 15). Decreasing the dose of selected antituberculosis drugs may not be the best method of treating tuberculosis because, although toxicity may be avoided, the peak serum concentrations may be too low. Therefore, instead of decreasing the dose of the antituberculosis agent, increasing the dosing interval is recommended (1). The general approach described in Table 15 involves either estimating or measuring creatinine clearance. Administration of drugs that are cleared by the kidneys to patients having a creatinine clearance of less than 30 ml/ minute and those receiving hemodialysis are managed in the same manner, with an increase in dosing interval (C. Peloquin, personal communication). There are insufficient data to guide dosing recommendations for patients having a reduced creatinine clearance but not less than 30 ml/minute. In such patients standard doses should be used, but measurement of serum concentrations should be considered to avoid toxicity. RIF and INH are metabolized by the liver, so conventional dosing may be used in the setting of renal insufficiency (1)(2)(3)(4)(5). PZA is also metabolized by the liver but its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) may accumulate in patients with renal insufficiency (3,6). EMB is about 80% cleared by the kidneys and may accumulate in patients with renal insufficiency (7). A longer interval between doses with three times a week administration is recommended for PZA and EMB (3,7). INH, EMB, and PZA (as well as its metabolites) are cleared by hemodialysis to some degree, but only PZA and presumably its metabolites are dialyzed to a significant degree (3). RIF is not cleared by hemodialysis because of its high molecular weight, wide distribution into tissues, high degree of protein binding, and rapid hepatic metabolism (3). Therefore, supplemental dosing is not necessary for INH, RIF, or EMB. If PZA is given after hemodialysis, supplemental dosing is not required. In general, antituberculosis drugs should be given after hemodialysis to avoid any loss of the drugs during hemodialysis, and to facilitate DOT. Doses of streptomycin, kanamycin, amikacin, and capreomycin must be adjusted in patients with renal failure because the kidneys excrete essentially all of these drugs. Approximately 40% of the dose is removed with hemodialysis when these drugs are given just before hemodialysis (8). Far less drug is likely to be removed once the drugs have had time to distribute throughout the body, and some accumulation of the drugs should be anticipated. As with EMB and PZA, the dosing interval should be increased. In general, the dose should not be reduced because the drugs exhibit concentrationdependent bactericidal action (9), and smaller doses may reduce drug efficacy. Ethionamide is not cleared by the kidneys, nor is the drug removed with hemodialysis, so no dose adjustment is necessary (10). PAS is modestly cleared by hemodialysis (6.3%) but its metabolite, acetyl-PAS, is substantially removed by hemodialysis; twice daily dosing (4 g) should be adequate if the granule formulation is used (Jacobus Pharmaceuticals) (10). Cycloserine is excreted primarily by the kidney, and is cleared by hemodialysis (56%). Thus, an increase in the dosing interval is necessary to avoid accumulation between hemodialysis sessions, and the drug should be given after hemodialysis to avoid underdosing (10). The fluoroquinolones undergo some degree of renal clearance that varies from drug to drug. For example, levofloxacin undergoes greater renal clearance than moxifloxacin (11). It should be noted that the fluoroquinolone dosing recommendations for end-stage renal disease provided by the manufacturers were developed for treating pyogenic bacterial infections. These recommendations may not be applicable to the treatment of tuberculosis in patients with end-stage renal disease. As noted above, administration of all antituberculosis drugs immediately after hemodialysis will facilitate DOT (three times per week) and avoid premature removal of the drugs (2). It is important to monitor serum drug concentrations in persons with renal insufficiency who are taking cycloserine, EMB, or any of the injectable agents to minimize dose-related toxicity, while providing effective doses. Clinicians also should be aware that patients with end-stage renal disease may have additional clinical conditions, such as diabetes mellitus with gastroparesis, that may affect the absorption of the antituberculosis drugs, or they may be taking concurrent medications that interact with these drugs. Under these circumstances a careful clinical and pharmacologic assessment is necessary, and, in selected cases, serum drug concentration measurements may be used to assist in determining the optimum dose of the antituberculosis drugs (9). Finally, data currently do not exist for patients receiving peritoneal dialysis. Because the drug removal mechanisms differ between hemodialysis and peritoneal dialysis, it cannot be assumed that all of the recommendations in Table 15 will apply to peritoneal dialysis. Such patients may require close monitoring, including measurements of the serum concentrations of the antituberculosis drugs. # Hepatic Disease The treatment of tuberculosis in patients with unstable or advanced liver disease is problematic for several reasons. First, the likelihood of drug-induced hepatitis may be greater. Second, the implications of drug-induced hepatitis for patients with marginal hepatic reserve are potentially serious, even lifethreatening. Finally, fluctuations in the biochemical indicators of liver function (with/without symptoms) related to the preexisting liver disease confound monitoring for drug-induced hepatitis. Thus, clinicians may consider regimens with fewer potentially hepatotoxic agents in patients with advanced or unstable liver disease, and expert consultation is advisable in treating such patients. It should be noted that tuberculosis itself may involve the liver, causing abnormal liver function; thus, not all abnormalities in liver function tests noted at baseline should be attributed to causes other than tuberculosis. The hepatic abnormalities caused by tuberculosis will improve with effective treatment. Possible treatment regimens in the setting of liver disease include the following. # Treatment without INH As described in Section 5.2, Alternative Regimens, analysis of data from several studies conducted by the BMRC in patients with smear-positive pulmonary tuberculosis demonstrated high levels of efficacy with 6-month regimens despite in vitro resistance to INH so long as the initial phase contained four drugs and RIF was used throughout the 6 months (1). Subsequent studies by the Hong Kong Chest Service and the BMRC suggested that results were improved when PZA was used throughout the 6 months (2). Thus, it is reasonable to employ an initial phase regimen of RIF, PZA, and EMB followed by a continuation phase of RIF, EMB, and PZA (Rating BII). Although this regimen has two potentially hepatotoxic medications, it has the advantage of retaining the 6-month duration. # Treatment without PZA Although the frequency of PZA-induced hepatitis is slightly less than occurs with INH or RIF, the liver injury induced by this drug may be severe and prolonged (3). Therefore, one might elect to employ a regimen with an initial phase of INH, RIF, and EMB for 2 months followed by a continuation phase of INH and RIF for 7 months, for a total of 9 months (Table 2, Regimen 4). # Regimens with only one potentially hepatotoxic drug For patients with advanced liver disease, a regimen with only one potential hepatotoxic drug might be selected. Generally, RIF should be retained. Additional agents in such regimens could include EMB, a fluoroquinolone, cycloserine, and injectable agents. The duration of treatment with such regimens should be 12-18 months, depending on the extent of the disease and the response (Rating CIII). Consultation is advised in such situations. # Regimens with no potentially hepatotoxic drugs In the setting of severe unstable liver disease, a regimen with no hepatotoxic agents might be necessary. Such a regimen might include SM, EMB, a fluoroquinolone, and another second-line oral drug. There are no data that provide guidance as to the choice of agents or the duration of treatment or that indicate the effectiveness of such a regimen. Expert opinion suggests that a regimen of this sort should be given for 18-24 months (Rating CIII). Consultation should always be obtained before embarking on such a treatment plan. # Microbiological Confirmation of Relapse Should be Pursued Vigorously. Relapses may occur with either drug-resistant or drug-susceptible strains of M. tuberculosis. To confirm that a true relapse has occurred and to obtain drug susceptibility tests, microbiological confirmation of relapse should be pursued vigorously. # Other Associated Disorders Tuberculosis commonly occurs in association with other diseases or conditions. An associated disorder may alter immune responsiveness, thereby causing a predisposition to tuberculosis, or simply may be a disorder that occurs frequently in the same social and cultural milieu as tuberculosis. Examples of the former class of disorders include HIV infection, hematologic or reticuloendothelial malignancies, immunosuppressive therapy, chronic renal failure, poorly controlled, insulin-dependent diabetes mellitus, and malnutrition. Silicosis, by impairing pulmonary macrophage function, is a unique example of local immune dysfunction. The latter group of disorders includes chronic alcoholism and its secondary effects, other substance abuse, and psychiatric illnesses, among others. All of these conditions may influence the organization, supervision, and outcome of therapy (discussed in Section 2: Organization and Supervision of Treatment). The response of immunocompromised patients to treatment may not be as good as would be expected in a person with normal immunity, although in patients with HIV infection the response to treatment is not impaired Nevertheless, therapeutic decisions for the immunocompromised host should be more individualized, taking into account the severity of tuberculosis and the response to treatment. When possible, steps should be taken to correct the immune deficiency. In patients with silicotuberculosis there are data demonstrating that the rate of cure is improved if the continuation phase is extended for at least 2 months (1,2). # Management of Relapse, Treatment Failure, and Drug Resistance # Relapse Relapse refers to the circumstance in which a patient becomes and remains culture-negative while receiving antituberculosis drugs but, at some point after completion of therapy, either becomes culture-positive again or experiences clinical or radiographic deterioration consistent with active tuberculosis. In such patients vigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. True relapses are due to failure of chemotherapy to sterilize the host tissues, thereby enabling endogenous recrudescence of the original infection. In some hyperendemic settings, however, exogenous reinfection with a new strain of M. tuberculosis may be responsible for the apparent relapse (1). Patients who are most likely to have true relapses are those with extensive tuberculosis whose sputum cultures remain positive after 2 months of chemotherapy (2)(3)(4). Most patients relapse within the first 6-12 months after completion of therapy. In nearly all patients with tuberculosis caused by drug-susceptible organisms who were treated with rifamycincontaining regimens using DOT, relapses occur with susceptible organisms (5,6). However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycincontaining regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. Among patients who received self-administered therapy, the risk of erratic drug administration leading to relapse with resistant organisms is greater. In view of these considerations, the selection of empirical treatment regimens for patients with relapses should be based on the prior treatment scheme. For patients with tuberculosis that was caused by drug-susceptible organisms, who were treated by DOT, and who have relapses, retreatment using the standard four-drug initial phase regimen may be appropriate, at least until the results of susceptibility tests are known. For patients who did not receive DOT or are known to have had irregular treatment in the past, it is prudent to infer a higher risk of acquired drug resistance and begin an expanded regimen (see below). The expanded regimen is indicated especially in patients with impaired immunity, limited respiratory reserve, central nervous system involvement, or other life-threatening circumstances, that is, cases in which treatment with an inadequate regimen could have severe consequences. For the relatively few patients in whom epidemiologic circumstances provide a strong suspicion of exogenous reinfection as the cause of apparent relapse, the choice of a regimen is influenced by the drug susceptibility pattern of the presumed source case. If the presumed source case is known to have tuberculosis caused by drug-susceptible organisms, resumption of a standard four-drug initial phase may be indicated. However, if the likely source case is known to have drugresistant organisms, an empirically expanded regimen based on the resistance profile of the putative source case may be suitable. There are no clinical trials to guide the choice of agents to include in expanded empirical regimens for presumed drug resistance; however, expert opinion indicates that such regimens should generally employ INH, RIF, and PZA plus an additional three agents, based on the probability of in vitro susceptibility. Usual agents would include EMB, a fluoroquinolone, and an injectable agent such as SM (if not used previously, and the initial isolate was susceptible) amikacin, kanamycin or capreomycin, with or without other drugs. # Treatment Failure Treatment failure is defined as continued or recurrently positive cultures in a patient receiving appropriate chemotherapy. Among patients with drug-susceptible pulmonary tuberculosis, even with extensive lung cavitation, 90-95% will be culture-negative after 3 months of treatment with a regimen that contains INH and RIF. During this time the vast majority of patients show clinical improvement, including defervescence, reduced cough, and weight gain. Thus, patients with persistently positive cultures after 3 months of chemotherapy, with or without on-going symptoms, should be evaluated carefully to attempt to identify the cause of the delayed response. Patients whose sputum cultures remain positive after 4 months of treatment are considered to have failed treatment. There are multiple potential reasons for treatment failure. If the patient is not receiving DOT, the most likely explanation for persistently positive cultures is nonadherence to the drug regimen. Among patients receiving DOT, cryptic nonadherence (spitting out or deliberately regurgitating pills) or failure of the health care system to reliably deliver the drugs may be the cause. Other potential reasons include unrecognized drug resistance (Was initial drug-susceptibility testing done? Was it reported accurately?), malabsorption (prior resectional surgery of the stomach or small intestine, taking tuberculosis medication with antacids or other drugs/substances that might bind or interfere with drug absorption (see Section 6.1: Drug Administration, and Section 7.1: Interactions Affecting Antituberculosis Drugs), or simply an extreme biologic variation (For unclear reasons, rare "normal" patients may experience very protracted disease including persistently positive cultures or prolonged symptoms in the face of chemotherapy that would be expected to be effective). Laboratory error should also be considered as a possible reason for a positive culture in a patient who is doing well. Recent reports document cross contamination or mislabeling of specimens as a source for some of these unexpectedly positive cultures (7,8). Clinicians should be alert, as well, to the possibility of transient clinical or radiographic worsening (paradoxical reactions), despite appropriate therapy that would eventually result in cure. Examples of this include ongoing inflammation at sites of lymphadenitis, worsened abnormalities on chest radiographs after several months of treatment, or the new appearance of pleural effusions during therapy for pulmonary tuberculosis (9)(10)(11). Such paradoxical worsening during treatment occurs more commonly but not exclusively in persons with HIV infection (12)(13)(14) (see Section 8.1: HIV Infection). For patients who meet criteria for treatment failure, the possible reasons listed above should be addressed promptly. If clinicians are not familiar with the management of drug-resistant tuberculosis, prompt referral to, or consultation with a specialty center is indicated. If treatment failure is presumed to be due to drug resistance and the patient does not have severe tuberculosis, one may either initiate an empirical retreatment regimen or wait for drug susceptibility results from a recent isolate. If the patient is seriously ill or has a positive sputum AFB smear, an empirical regimen that would be anticipated to be effective should be started immediately and continued until susceptibility tests are available to guide therapy. For patients who have failed treatment, mycobacterial isolates should be sent promptly to a reference laboratory for susceptibility testing for both first-and second-line drugs. A fundamental principle in managing patients who have failed treatment is that a single new drug should never be added to a failing regimen; so doing may lead to acquired resistance to the added drug. In such cases, it is generally prudent to add at least three new drugs to which susceptibility could logically # Never Add a Single Drug To a Failing Regimen Treatment failure is defined by continued or recurrent positive cultures after 4 months of treatment in patients in whom medication ingestion was assured. Patients with treatment failure should be assumed, until proven otherwise, to have drug-resistant organisms and be treated with multiple agents that they have not received before. A single drug should never be added to a failing regimen. So doing risks development of resistance to the new drug, further complicating management. be inferred to lessen the probability of further acquired resistance. As noted previously there are no clinical trials to guide the choice of an empirical regimen; however, expert opinion indicates that empirical retreatment regimens might include a fluoroquinolone such as levofloxacin, an injectable agent such as SM (if not used previously and the isolate was susceptible initially), amikacin, kanamycin, or capreomycin, and an oral agent such as PAS, cycloserine, or ethionamide (Rating AIII). When drug susceptibility results are available, the regimen should be adjusted according to the results. # Management of Tuberculosis Caused by Drug-Resistant Organisms Tubercle bacilli are continually undergoing spontaneous mutations that create resistance to individual antituberculosis drugs. However, the frequency of these single mutations is sufficiently low that with appropriate combination chemotherapy that is reliably ingested, clinically significant resistance will not develop (see Section 4.1: Combination Chemotherapy) (15). Most commonly the development of acquired drug resistance occurs when there is a large bacillary population, such as in pulmonary cavities, when an inadequate drug regimen is prescribed (inappropriate drugs, insufficient dosage) or when there is a combined failure of both the patient and the provider to ensure that an adequate regimen is taken (16). Rarely, malabsorption of one or more antituberculosis drugs may account for acquired resistance. Drug resistance is much more likely to occur in cavitary pulmonary tuberculosis because of the immense number of rapidly multiplying bacilli in the cavity(ies) (17). During extended or repeated treatment, resistance to multiple agents may evolve. Patients with acquired drug resistance may transmit their strains to others who, if they develop tuberculosis, will have primary drug resistance. Drug resistance in a patient with newly diagnosed tuberculosis may be suspected on the basis of historical (previous treatment) or epidemiologic information (contact with a known drug-resistant case or coming from a region in which drug resistance is common) (18,19). In such situations it is prudent to employ an empirically expanded regimen, as described previously, especially if the patient is seriously ill (Table 16). Drug resistance can be proven only by drug-susceptibility testing performed in a competent laboratory (Table17). The steps taken when resistance is shown to be present are of critical importance. Patients harboring strains of M. tuberculosis resistant to both INH and RIF (MDR) are at high risk for treatment failure and further acquired resistance; they must be referred immediately to a specialist or consultation obtained from specialized treatment centers. Patients with strains resistant to RIF alone have a better prognosis than MDR cases, but also are at increased risk for failure and additional resistance. Thus, their management should also be subject to special scrutiny. Definitive randomized or controlled studies have not been performed among patients with the various patterns of drug resistance. In the absence of ideal evidence, practices in the treatment of patients are based on a mixture of general principles, extrapolations and expert opinion. The WHO and IUATLD have formulated standard algorithmic regimens for the management of treatment failure or chronic cases, largely based on the principles listed below, as well as on expert opinion (20,21). This approach is best suited to regions without in vitro susceptibility testing capacity and access to the full array of retreatment medications, but it is not appropriate for industrialized nations with more ample resources (22,23). Guidelines for management of patients with tuberculosis caused by drug-resistant organisms are based on the following guidelines, all of which are rated A III: - A single new drug should never be added to a failing regimen. - When initiating or revising therapy, always attempt to employ at least three previously unused drugs to which there is in vitro susceptibility. One of these should be an injectable agent. - Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. In patients with MDR organisms in whom there is resistance to first-line agents in addition to INH and RIF, regimens employing four to six medications appear to be associated with better results (24)(25)(26). - Patients should receive either hospital-based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT. - Intermittent therapy should not be used in treating tuberculosis caused by drug-resistant organisms, except perhaps for injectable agents after an initial period (usually 2-3 months) of daily therapy. # Request Consultation Treatment of tuberculosis caused by drug-resistant organisms should be done by or in close consultation with an expert in the management of these difficult situations. Second-line regimens often represent the patient's last best hope for being cured. Inappropriate management can, thus, have life-threatening consequences. - The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs (assuming the test results are accurate), and usually, alternative medications are available. (28). - There is no cross-resistance between SM and the other injectable agents: amikacin, kanamycin, and capreomycin (although resistance to all may occur as independent events); however, cross-resistance between amikacin and kanamycin is universal (24). Simultaneous use of two injectable agents is not recommended due to the absence of proof of efficacy and potential amplification of drug toxicity. - Determination of resistance to PZA is technically problematic and, thus, is not made in many laboratories. However, resistance to PZA is uncommon in the absence of resistance to other first-line drugs (30). If monoresistance to PZA is observed, consideration must be given to the possibility that the etiologic agent is M. bovis, not M. tuberculosis (M. bovis is genotypically resistant to PZA In such cases, extended treatment is needed to lessen the risk of relapse. In cases with extensive disease, the use of an additional agent (alternative agents) may be prudent to lessen the risk of failure and additional acquired drug resistance. Resectional surgery may be appropriate (see text). Use the first-line agents to which there is susceptibility. Add two or more alternative agents in case of extensive disease. Surgery should be considered (see text). Daily and three times weekly regimens of INH, PZA, and SM given for 9 mo were effective in a BMRC trial ‡ (Rating BI). However, extended use of an injectable agent may not be feasible. It is not known if EMB would be as effective as SM in these regimens. An all-oral regimen for 12-18 mo should be effective (Rating BIII). But for more extensive disease and/or to shorten duration (e.g., to 12 months), an injectable agent may be added in the initial 2 mo of therapy (Rating BIII). and is not distinguished from M. tuberculosis by nucleic acid hybridization-probe assays that are commonly used for identification). Table 16 contains regimens suggested for use in patients with various patterns of drug-resistant tuberculosis. # Role of Surgery in MDR Tuberculosis The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies. In one series, patients with severe drug resistance (on average, having resistance to more than 5 drugs) appeared to benefit from the resection of cavitary or badly damaged lung tissue when compared with historical controls (31). In contrast, other clinicians have reported patients with drug resistance having similar cure rates without surgery (25,32). The disparity in these reports may be due to long-standing disease with extensive fibrosis in the former group. If surgery is to be done, it should be performed by an experienced surgeon after the patient has received several months of intensive chemotherapy. Even with successful resection, 12-24 additional months of chemotherapy, using drugs to which there is demonstrated susceptibility, should be given. # Laboratory Considerations in Determining Drug Resistance Susceptibility testing of M. tuberculosis is critical for appropriate patient management and should be performed on an initial isolate from all patients from whom M. tuberculosis is recovered (1). Public health laboratories routinely will perform susceptibility testing on initial isolates but, often, private laboratories do not perform such testing unless specifically requested to do so by the physician. As noted previously, susceptibility testing should be repeated if the patient still has a positive culture result after 3 months of therapy or again develops positive cultures after a period of negative cultures (2). Antimicrobial susceptibility testing should be performed using a standard methodology, such as that recommended by the National Committee for Clinical Laboratory Standards (3). The second edition of a tentative standard (M24-T2) for sus- # Obtaining Drug Susceptibility Tests Drug susceptibility testing for INH, RIF and EMB should be performed on an initial isolate of M. tuberculosis from all patients. Susceptibility testing for firstline and second line drugs should be performed for all patients with possible treatment failure or relapse. Most public health laboratories will perform initial susceptibility tests without a specific request, but this may not be true for private laboratories. Testing for susceptibility to the second-line drugs should be performed only in reference laboratories. ceptibility testing of mycobacteria was published by the National Committee for Clinical Laboratory Standards in 2000 (3). Susceptibility of M. tuberculosis is determined by evaluating the ability of an isolate to grow on agar or in broth containing a single "critical" concentration of a drug (2). The agar proportion method has been proposed as the reference method for all antituberculosis drugs except pyrazinamide, in which case the BACTEC broth-based methodology is the reference method (3). With the agar proportion method, resistance is defined as growth on the drug-containing plate that is more than 1% of the growth on the non-drug-containing plate (4). Because the agar method requires up to 6 weeks to yield results, it is recommended that initial susceptibility testing of M. tuberculosis isolates to first-line antituberculosis drugs be performed using more rapid broth-based methods (e.g., BACTEC and others). The goal, as stated by CDC, is to have culture and susceptibility results (to first-line drugs) available within 28 days of receipt of a clinical specimen (5). The critical concentrations recommended by the National Committee for Clinical Laboratory Standards for agar proportion method and "equivalent" concentrations for broth-based testing methods are shown in Table 17 (2,3). The National Committee for Clinical Laboratory Standards recommends that susceptibility testing be performed for INH (two concentrations) and RIF and EMB (one concentration each) using a broth-based method on all initial M. tuberculosis isolates. Pyrazinamide testing may be done if there is a sufficiently high prevalence of PZA resistance. It is also recommended that the full panel of drugs (including second-line drugs) be tested when there is resistance to RIF alone or to two or more drugs. Testing of second-line drugs is performed using the agar proportion method, generally by public health laboratories. Secondary antituberculous drugs used for testing are capreomycin, ethionamide, kanamycin (which also predicts amikacin susceptibility), ofloxacin (used to assess fluoroquinolone activity), PAS, rifabutin, and SM (3). For second-line drug testing, a second concentration of EMB is also recommended. Susceptibility testing for cycloserine is not recommended because of the technical problems associated with the test. # Treatment Of Tuberculosis in Low-Income Countries: Recommendations and Guidelines of the WHO and the IUATLD This brief summary of the differences between the recommendations for treatment of tuberculosis in high-income, lowincidence countries and low-income, high incidence countries is presented to provide an international context for the ATS/ CDC/IDSA guidelines. As tuberculosis in low-incidence countries, such as the United States, becomes more and more a reflection of the situation in high-incidence countries, it is important that health care providers in low-incidence countries have an understanding of the differences in the approaches used and the reasons for these differences so as to be better equipped to treat the increasing proportion of patients from high-incidence countries (1). As noted at the outset of this document, the ATS/CDC/IDSA recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront it to an important extent determine the approaches used. A number of differences exist between these new ATS/CDC/ IDSA recommendations, and the current tuberculosis treatment recommendations of WHO (2) and IUATLD (3), the two major sets of international guidelines. Rather than being recommendations per se, the IUATLD document presents a distillation of IUATLD practice, validated in the field. The WHO and the IUATLD documents target, in general, countries in which mycobacterial culture and susceptibility testing and radiographic examinations are not widely available. These organizations recommend a tuberculosis control strategy called "DOTS" (Directly Observed Treatment, Short-Course) in which direct observation of therapy ("DOT" in the current statement) is only one of five key elements (4). The boxed insert lists the elements of DOTS strategy. Selected important differences among the recommendations are summarized below. Some of the differences arise from variations in strategies, based on availability of resources, whereas others, such as the use of twice weekly regimens, arise from different interpretations of common elements, for example, whether DOT is used throughout the entire course of therapy or is limited to the initial phase. # Microbiological Tests for Diagnosis and Evaluation of Response The WHO and the IUATLD recommend diagnosis and classification of cases and assessment of response based on sputum AFB smears. The AFB smear is emphasized because access to reliable culture facilities is limited in many countries. In addition, the AFB smear identifies patients who are most likely to transmit the organism. Susceptibility testing for new patients is not recommended because of cost, limited applicability and lack of facilities. However, susceptibility testing is recommended by the WHO for patients who fail (sputum smear-positive in month 5 of treatment or later during the course of treatment) the initial treatment regimen, and for those who fail a supervised retreatment regimen. Regarding follow-up, it is recommended by the WHO and the IUATLD that patients who have initial positive smears have repeat smears examined at 2 months, 5 months, and at completion of treatment (either 6 or 8 months). The IUATLD recommends that for patients who have positive smears at 2 months, the initial phase should be extended for 1 month. # Use of Chest Radiographs in Diagnosis and Follow-Up of Patients Being Treated In many parts of the world radiographs are not readily available. Moreover, because the highest priority for treatment is the highly infectious sputum smear-positive patient, there is concern that treatment based on radiographic findings alone is an inefficient use of resources. Thus, chest radiography is recommended by both the WHO and the IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. # Initial Treatment Regimens The WHO recommends a single initial phase of daily INH, RIF, PZA, and EMB (or SM) for 2 months followed by a continuation phase of either daily or three times a week INH and RIF, all given by DOT, for 4 months or daily INH and EMB for 6 months (self-administered). The WHO specifically discourages programs from using twice weekly regimens, the reason being that there is a lesser margin of safety if a dose or doses are missed. The IUATLD recommends a 2-month initial phase of INH, RIF, PZA, and EMB given by DOT, followed by a 6-month continuation phase of daily INH and thiacetazone, selfadministered. For patients with HIV infection the IUATLD recommends EMB in place of thiaocetazone. The IUATLD also recommends a 12-month regimen with a 2-month initial phase of INH, SM, and thioacetazone given daily and a 10-month continuation phase of daily INH and thioacetazone. This regimen is intended to be used for patients who have negative smears or when the 8-month regimen is not available. The rationale for the 8-month regimen recommendation is that it is felt that RIF should always be given by DOT; yet, many programs cannot afford to provide the supervision required by DOT for the full 6 months of treatment. The 8-month regimen is less efficacious in patients with drugsusceptible tuberculosis, but use of this regimen will likely preserve RIF for use in retreatment regimens. In addition to the issue of supervision, the 8-month regimen's continuation phase of INH and EMB costs about 27% less than a 4-month continuation phase of daily INH and RIF. # Approach to Previously Treated Patients The WHO and the IUATLD recommend a standardized regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. (The approach to this last group of patients is currently under discussion at the WHO.) The regimen consists of an initial phase of INH, RIF, PZA, EMB, and SM given daily for 2 months and then 1 month of daily INH, RIF, PZA, and EMB. The continuation phase consists of 5 months of daily INH, RIF, and EMB. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and secondline drugs are available (5). The IUATLD recommendations do not address the issue. The issue of chronic cases is an area of considerable controversy (6). In countries with sufficient resources, such as the Five Components of the DOTS Strategy - Government commitment to sustained TB control activities. - Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services. - Standardized treatment regimen of 6-8 months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial 2 months. - A regular, uninterrupted supply of all essential antituberculosis drugs. - A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control program overall. # Research Agenda for Tuberculosis Treatment # New Antituberculosis Drugs New antituberculosis drugs are needed for three reasons: to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, to improve the treatment of patients with MDR tuberculosis, and to provide more effective and efficient treatment of latent tuberculosis infection (LTBI) (1). Although treatment regimens for drug-susceptible tuberculosis are effective, they must be administered for a minimum of 6 months to achieve optimal results. Nonadherence to this relatively lengthy course of treatment remains a major problem. To address the problem of nonadherence, DOT (as a component of the DOTS strategy) is recommended as a standard of care worldwide. However, the administrative and financial burden of providing DOT for all patients is considerable. Thus, new drugs that would permit significant shortening of treatment are urgently needed, as are drugs that could enable effective treatment to be given at dosing intervals of 1 week or more. Rates of multidrug-resistant tuberculosis are alarmingly high in several countries (2), and even in countries, such as the United States, where the rates are low and decreasing, the occasional case presents an often extremely difficult treatment problem (see Section 9: Management of Relapse, Treatment Failure, and Drug Resistance). Current treatment regimens for drug-resistant tuberculosis utilize drugs that are less effective, more toxic, and more expensive than those used for standard treatment. Moreover, these treatment regimens often have to be given for 18-24 months. Although new drugs that are effective against resistant organisms would alone not solve the problem of drug resistance, their judicious use would greatly improve the treatment for many patients. Finally, the United States and several other low-incidence countries have embarked on plans to eliminate tuberculosis. An important component of an elimination strategy is the identification and treatment of persons with LTBI who are at high risk of developing tuberculosis (3). In the United States the most commonly used LTBI treatment regimen is INH given for 9 months; however, poor adherence to this regimen imposes a major limitation on its effectiveness. A shorter LTBI treatment regimen with RIF and PZA appears to be effective, but reports have indicated that toxicity may be unacceptably high (4). Thus, new drugs to provide for safe and effective "short-course" LTBI treatment are a major need. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are presently available for clinical study. However, further work to optimize the effectiveness of once weekly rifapentine regimens and investigate the role of newer fluoroquinolones in the treatment of drug-susceptible tuberculosis is warranted. As noted above, once weekly rifapentine-INH is recommended only in the continuation phase for HIV-negative patients with noncavitary pulmonary tuberculosis who have negative sputum smears at completion of 2 months of treatment. Two approaches to improve intermittent rifapentine regimens have been suggested by experimental studies: increasing the rifapentine dosage (5), and adding moxifloxacin as a companion drug to provide better protection against the development of drug resistance and enhance the sterilizing activity of the regimen (6). Other data from a clinical trial of ofloxacin suggest that fluoroquinolones have the potential to significantly shorten treatment (7). Of the newer fluoroquinolones with more potent activity against M. tuberculosis, moxifloxacin appears to be the most promising. Other compounds that might become available for clinical evaluation in the future include the nitroimidazopyrans that are chemically related to metronidazole, for which activity against dormant M. tuberculosis has been suggested; oxazolidinones such as linezolid; and drugs that target isocitrate lyase, an enzyme that may be necessary for the establishment of latent tuberculosis infection (8). The nitroimidazopyran compound PA-824 has bactericidal activity comparable to that of INH and appears to act as well on bacilli maintained in an anaerobic environment (9). However, additional preclinical evaluation of PA-824 is needed before clinical studies could begin. Although linezolid, a drug that is marketed for the treatment of selected acute bacterial infections, does have demonstrated activity against M. tuberculosis, other compounds in that class may be more suited for the treatment of tuberculosis (10). # Other Interventions To Improve the Efficacy of Treatment A number of other approaches have been suggested that might lead to improved treatment outcome, including alternative drug delivery systems and a variety of methods of immunomodulation and immunotherapy. Experimental studies have demonstrated that effective serum concentrations of INH and PZA can be provided through incorporation of drug into slow-release, biodegradable polymers that are implanted subcutaneously (11). However, there has been little apparent commercial interest in pursuing this approach. Liposomal encapsulation of antituberculosis drugs has been suggested as an approach to direct drug to the proposed site of infection (i.e., the macrophage) providing for more effective and better tolerated therapy, as well as for more widely spaced treatment. Similarly, incorporation of drug into inhalable microparticles may reduce dose requirements, minimize toxicity, and deliver drug to infected alveolar macrophages. Although experimental studies have suggested that these approaches might be effective, little clinical work has been done in these areas (11,12). Because of possible detrimental effects of the cytokine, tumor necrosis factor-α, in HIV-associated tuberculosis, there has been some interest in the use of drugs, such as thalidomide and pentoxifylline, that block tumor necrosis factor-α production. Studies have shown that administration of thalidomide improves weight gain in both HIV-positive and HIVnegative tuberculosis patients (13). Pentoxifylline has been associated with reductions in circulating HIV viral load in patients with tuberculosis (14). However, the potential side effects of these drugs may outweigh possible benefits. A more promising intervention is the administration of "protective" cytokines, such as aerosolized interferon-γ and subcutaneous interleukin-2, that have shown activity as adjuncts to chemotherapy in patients with multidrug-resistant tuberculosis (15,16). Another method of immunomodulation, the use of heat-killed preparations of M. vaccae as a therapeutic vaccine, has not shown clinically significant benefits when carefully evaluated in randomized clinical trials (17). Nonetheless, there continues to be interest in this approach, especially for patients with advanced drug-resistant tuberculosis. Other vaccines that have been shown to lead to expression of protective cytokines have shown more promise in experimental studies (18). Finally, a study suggested that the administration of Vitamin A and zinc to patients with pulmonary tuberculosis is associated with an increased rate of sputum conversion and improvement in chest radiographs (19). Further assessment of nutritional supplements in tuberculosis treatment may be indicated. # Better methods to identify and manage high-and low-risk patients As noted above, sputum culture positivity at 2 months appears to be a marker for an increased risk of relapse for patients with pulmonary tuberculosis. Surrogate markers that could be measured earlier in therapy and have a greater sensitivity and specificity for a poor outcome could better select high risk patients for more intensive or longer therapy, thus minimizing the likelihood of relapse. Studies of several molecular markers in the sputum have shown promise and deserve further evaluation (20). Conversely, markers that reliably identify patients at lower risk of an adverse treatment outcome would be helpful to select patients for less intense or shorter treatment. Whether or not low-risk patients can be treated with shorter regimens using currently available drugs is a topic of considerable importance. # Health services research to facilitate treatment administration and improve treatment outcome Although DOT (as a component of DOTS) is widely advocated as a universal standard of care for tuberculosis treatment, many tuberculosis control programs do not have the resources to provide DOT for all patients. Moreover, some programs have achieved excellent results by targeting DOT to patients known or suspected of being at increased risk for nonadherence. Further evaluation of alternatives to universal DOT is needed. Finally, although limited work has been done in the area of behavioral studies of tuberculosis patients and providers, an ambitious research agenda established in the mid-1990s has not been implemented and should be revisited (21).	and is being reprinted as a courtesy to the American Thoracic Society, the Infectious Diseases Society of America, and the MMWR readership.# What's New In This Document • The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient. • It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy. • Recommended treatment regimens are rated according to the strength of the evidence supporting their use. Where possible, other interventions are also rated. • Emphasis is placed on the importance of obtaining sputum cultures at the time of completion of the initial phase of treatment in order to identify patients at increased risk of relapse. • Extended treatment is recommended for patients with drug-susceptible pulmonary tuberculosis who have cavitation noted on the initial chest film and who have positive sputum cultures at the time 2 months of treatment is completed. • The roles of rifabutin, rifapentine, and the fluoroquinolones are discussed and a regimen with rifapentine in a once-a-week continuation phase for selected patients is described. • Practical aspects of therapy, including drug administration, use of fixed-dose combination preparations, monitoring and management of adverse effects, and drug interactions are discussed. • Treatment completion is defined by number of doses ingested, as well as the duration of treatment administration. • Special treatment situations, including human immunodeficiency virus infection, tuberculosis in children, extrapulmonary tuberculosis, culture-negative tuberculosis, pregnancy and breastfeeding, hepatic disease and renal disease are discussed in detail. • The management of tuberculosis caused by drug-resistant organisms is updated. • These recommendations are compared with those of the WHO and the IUATLD and the DOTS strategy is described. • The current status of research to improve treatment is reviewed. # Summary Responsibility for Successful Treatment The overall goals for treatment of tuberculosis are 1) to cure the individual patient, and 2) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy. Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control. However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician. # Organization and Supervision of Treatment Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. It is essential that treatment be tailored and supervision be based on each patient's clinical and social circumstances (patient-centered care). Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate diagnostic and treatment services are available, and for monitoring the results of therapy. It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision. This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy. Programs utilizing DOT as the central element in a comprehensive, patient-centered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies. Each patient's management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen. Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers. # Recommended Treatment Regimens The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA). The rating system includes a letter (A, B, C, D, or E) that indicates the strength of the recommendation and a roman numeral (I, II, or III) that indicates the quality of evidence supporting the recommendation (Table 1). There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms. Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances, described subsequently. Each regimen has an initial phase of 2 months followed by a choice of several options for the continuation phase of either 4 or 7 months. The recommended regimens together with the number of doses specified by the regimen are described in Table 2. The initial phases are denoted by a number (1, 2, 3, or 4) and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c). Drug doses are shown in Tables 3, 4, and 5. The general approach to treatment is summarized in Figure 1. Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2, Regimens 1-3). If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms (Table 6) or when the child has "adult-type" (upper lobe infiltration, cavity formation) tuberculosis. If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for 2 months (Regimen 4). Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy. EMB should be included in the initial phase of Regimen 4 until drug susceptibility is determined. The initial phase may be given daily throughout (Regimens 1 and 4), daily for 2 weeks and then twice weekly for 6 weeks (Regimen 2), or three times weekly throughout (Regimen 3). For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than 2 months (i.e., when susceptibility test results are known), but there is no evidence to support this approach. Although clinical trials have shown that the efficacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful. Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely. The continuation phase (Table 2) of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in the large majority of patients. The 7-month * Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given. † Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion. ‡ When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. § Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. ¶ Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. # Not recommended for HIV-infected patients with CD4 + cell counts <100 cells/µl. ** Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months. continuation phase is recommended only for three groups: patients with cavitary pulmonary tuberculosis caused by drugsusceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; patients whose initial phase of treatment did not include PZA; and patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the initial phase is positive. The continuation phase may be given daily (Regimens 1a and 4a), two times weekly by DOT (Regimens 1b, 2a, and 4b), or three times weekly by DOT (Regimen 3a). For human immunodeficiency virus (HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as determined by standard chest radiography), and negative sputum smears at completion of 2 months of treatment, the continuation phase may consist of rifapentine and INH given once weekly for 4 months by DOT (Regimens 1c and 2b) (Figure 1). If the culture at completion of the initial phase of treatment is positive, the once weekly INH and rifapentine continuation phase should be extended to 7 months. All of the 6-month regimens, except the INH-rifapentine once weekly continuation phase for persons with HIV infection (Rating EI), are rated as AI or AII, or BI or BII, in both HIV-infected and uninfected patients. The once-weekly continuation phase is contraindicated (Rating EI) in patients with HIV infection because of an unacceptable rate of failure/relapse, often with rifamycinresistant organisms. For the same reason twice weekly treatment, either as part of the initial phase (Regimen 2) or continuation phase (Regimens 1b and 2a), is not recommended for HIV-infected patients with CD4 + cell counts <100 cells/ µl. These patients should receive either daily (initial phase) or three times weekly (continuation phase) treatment. Regimen 4 (and 4a/4b), a 9-month regimen, is rated CI for patients without HIV infection and CII for those with HIV infection. # Deciding To Initiate Treatment The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPDtuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test Levofloxacin Tablets (50 mg, 100 mg, 300 mg); elixir (50 mg/5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection Capsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection Capsule (150 mg) Tablet (150 mg, film coated) Tablet (500 mg, scored) Tablet (100 mg, 400 mg) Capsule (250 mg) Tablet (250 mg) Aqueous solution (1-g vials) for intravenous or intramuscular administration Aqueous solution (500-mg and 1-g vials) for intravenous or intramuscular administration Aqueous solution (1-g vials) for intravenous or intramuscular administration Granules (4-g packets) can be mixed with food; tablets (500 mg) are still available in some countries, but not in the United States; a solution for intravenous administration is available in Europe Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500mg vials) for intravenous injection Adults (max.) Children (max.) Adults ‡ (max.) Children (max.) There are no data to support intermittent administration † † 15 mg/kg (900 mg) 20-30 mg/kg (900 mg) 10 mg/kg (600 mg) 10-20 mg/kg (600 mg) 5 mg/kg (300 mg) Appropriate dosing for children is unknown -The drug is not approved for use in children Adults See supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis (see below). If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic # TABLE 6. Epidemiological circumstances in which an exposed person is at increased risk of infection with drug-resistant Mycobacterium tuberculosis* • Exposure to a person who has known drug-resistant tuberculosis • Exposure to a person with active tuberculosis who has had prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known • Exposure to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance • Exposure to persons who continue to have positive sputum smears after 2 months of combination chemotherapy • Travel in an area of high prevalence of drug resistance # MMWR June 20,2003 acid amplification test, treatment can be continued to complete a standard course of therapy (Figure 1). When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPDtuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tubercu-losis (Figure 2). If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered. If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months) (Figure 2). In lowsuspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, one of the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include (1) INH for a total of 9 months, (2) RIF with or without INH for a total of 4 months, or (3) RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIF-PZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this egimen. # Baseline and Follow-Up Evaluations Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances. Susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Secondline drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drugresistant tuberculosis, who have demonstrated resistance to Patients in whom tuberculosis is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at the time of completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4 + cell count is <100/ µl, the continuation phase should consist of daily or three times weekly isoniazid and rifampin. In HIVuninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly isoniazid and rifapentine, or daily or twice weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). * EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. † PZA may be discontinued after it has been taken for 2 months (56 doses). ‡ RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. § Therapy should be extended to 9 months if 2-month culture is positive. CXR = chest radiograph; EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine. rifampin or to other first-line drugs, or who have positive cultures after more than 3 months of treatment. It is recommended that all patients with tuberculosis have counseling and testing for HIV infection, at least by the time treatment is initiated, if not earlier. For patients with HIV infection, a CD4 + lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses. For all adult patients baseline measurements of serum amino transferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when EMB is to be used. During treatment of patients with pulmonary tuberculosis, a sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture. More frequent AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved. In addition, it is critical that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur. Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse). At each monthly visit patients taking EMB should be questioned regarding possible visual disturbances including blurred vision or scotomata; monthly testing of visual acuity and color discrimination is recommended for patients taking doses that on a milligram per kilogram basis are greater than those listed in Table 5 and for patients receiving the drug for longer than 2 months. # Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase of treatment is completed has been shown in clinical trials to identify patients at high risk for adverse outcomes (treatment failure, usually defined by positive cultures after 4 months of treatment, or relapse, defined by recurrent tuberculosis at any time after completion of treatment and apparent cure). For this reason it is particularly important to conduct a microbiological evaluation 2 months after initiation of treatment (Figure 1). Approximately 80% of patients # FIGURE 2. Treatment algorithm for active, culture-negative pulmonary tuberculosis and inactive tuberculosis The decision to begin treatment for a patient with sputum smears that are negative depends on the degree of suspicion that the patient has tuberculosis. The considerations in choosing among the treatment options are discussed in text. If the clinical suspicion is high (bottom), then multidrug therapy should be initiated before acid-fast smear and culture results are known. If the diagnosis is confirmed by a positive culture, treatment can be continued to complete a standard course of therapy (see Figure 1). If initial cultures remain negative and treatment has consisted of multiple drugs for 2 months, then there are two options depending on repeat evaluation at 2 months (bottom): 1) if the patient demonstrates symptomatic or radiographic improvement without another apparent diagnosis, then a diagnosis of culture-negative tuberculosis can be inferred. Treatment should be continued with isoniazid and rifampin alone for an additional 2 months; 2) if the patient demonstrates neither symptomatic nor radiographic improvement, then prior tuberculosis is unlikely and treatment is complete once treatment including at least 2 months of rifampin and pyrazinamide has been administered. In low-suspicion patients not initially receiving treatment (top), if cultures remain negative, the patient has no symptoms, and the chest radiograph is unchanged at 2-3 months, there are three treatment options: these are 1) isoniazid for 9 months, 2) rifampin with or without isoniazid for 4 months, or 3) rifampin and pyrazinamide for 2 months. CXR = chest X-ray; EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; Sx = signs/symptoms. (It should be noted that the RIF/PZA 2-month regimen should be used only for patients who are not likely to complete a longer course of treatment and can be monitored closely.) # MMWR June 20,2003 with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause. For patients who have positive cultures after 2 months of treatment and have not been receiving DOT, the most common reason is nonadherence to the regimen. Other possibilities, especially for patients receiving DOT, include extensive cavitary disease at the time of diagnosis, drug resistance, malabsorption of drugs, laboratory error, and biological variation in response. In USPHS Study 22, nearly 21% of patients in the control arm of the study (a continuation phase of twice weekly INH and RIF) who had both cavitation on the initial chest radiograph and a positive culture at the 2-month juncture relapsed. Patients who had only one of these factors (either cavitation or a positive 2-month culture) had relapse rates of 5-6% compared with 2% for patients who had neither risk factor. In view of this evidence, it is recommended that, for patients who have cavitation on the initial chest radiograph and whose 2-month culture is positive, the minimum duration of treatment should be 9 months (a total of 84-273 doses depending on whether the drugs are given daily or intermittently) (Figure 1 and Table 2). The recommendation to lengthen the continuation phase of treatment is based on expert opinion and on the results of a study of the optimal treatment duration for patients with silicotuberculosis showing that extending treatment from 6 to 8 months greatly reduced the rate of relapse (Rating AIII). The recommendation is also supported by the results of a trial in which the once weekly INHrifapentine continuation phase was extended to 7 months for patients at high risk of relapse. The rate of relapse was reduced significantly compared with historical control subjects from another trial in which the continuation phase was 4 months. For patients who have either cavitation on the initial film or a positive culture after completing the initial phase of treatment (i.e., at 2 months), the rates of relapse were 5-6%. In this group decisions to prolong the continuation phase should be made on an individual basis. # Completion of Treatment A full course of therapy (completion of treatment) is determined more accurately by the total number of doses taken, not solely by the duration of therapy. For example, the "6-month" daily regimen (given 7 days/week; see below) should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of treatment and accurately indicates the amount of time the drugs are given only if there are no interruptions in drug administration. In some cases, either because of drug toxicity or nonadherence to the treatment regimen, the specified number of doses cannot be administered within the targeted period. In such cases the goal is to deliver the specified number of doses within a recommended maximum time. For example, for a 6-month daily regimen the 182 doses should be administered within 9 months of beginning treatment. If treatment is not completed within this period, the patient should be assessed to determine the appropriate action to take-continuing treatment for a longer duration or restarting treatment from the beginning, either of which may require more restrictive measures to be used to ensure completion. Clinical experience suggests that patients being managed by DOT administered 5 days/week have a rate of successful therapy equivalent to those being given drugs 7 days/week. Thus, "daily therapy" may be interpreted to mean DOT given 5 days/week and the required number of doses adjusted accordingly. For example, for the 6-month "daily" regimen given 5 days/week the planned total number of doses is 130. (Direct observation of treatment given 5 days/week has been used in a number of clinical trials, including USPHS Study 22, but has not been evaluated in a controlled trial; thus, this modification should be rated AIII.) As an option, patients might be given the medications to take without DOT on weekends. Interruptions in treatment may have a significant effect on the duration of therapy. Reinstitution of treatment must take into account the bacillary load of the patient, the point in time when the interruption occurred, and the duration of the interruption. In general, the earlier in treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning. # Practical Aspects of Patient Management During Treatment The first-line antituberculosis medications should be administered together; split dosing should be avoided. Fixeddose combination preparations may be administered more easily than single drug tablets and may decrease the risk of acquired drug resistance and medication errors. Fixed-dose combinations may be used when DOT is given daily and are especially useful when DOT is not possible, but they are not formulated for use with intermittent dosing. It should be noted that for patients weighing more than 90 kg the dose of PZA in the three-drug combination is insufficient and additional PZA tablets are necessary. There are two combination formulations approved for use in the United States: INH and RIF (Rifamate ® ) and INH, RIF, and PZA (Rifater ® ). Providers treating patients with tuberculosis must be especially vigilant for drug interactions. Given the frequency of comorbid conditions, it is quite common for patients with tuberculosis to be taking a variety of other medications, the effects of which may be altered by the antituberculosis medications, especially the rifamycins. These interactions are described in Section 7, Drug Interactions. Adverse effects, especially gastrointestinal upset, are relatively common in the first few weeks of antituberculosis therapy; however, first-line antituberculosis drugs, particularly RIF, must not be discontinued because of minor side effects. Although ingestion with food delays or moderately decreases the absorption of antituberculosis drugs, the effects of food are of little clinical significance. Thus, if patients have epigastric distress or nausea with the first-line drugs, dosing with meals or changing the hour of dosing is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. Drug-induced hepatitis, the most serious common adverse effect, is defined as a serum AST level more than three times the upper limit of normal in the presence of symptoms, or more than five times the upper limit of normal in the absence of symptoms. If hepatitis occurs INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more antituberculosis medications without hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), may be used until the cause of the hepatitis is identified. Once the AST level decreases to less than two times the upper limit of normal and symptoms have significantly improved, the first-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients. # Treatment in Special Situations # HIV infection Recommendations for the treatment of tuberculosis in HIVinfected adults are, with a few exceptions, the same as those for HIV-uninfected adults (Table 2). The INH-rifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin-or rifabutin-based regimens. Consequently, patients with CD4 + cell counts <100/µl should receive daily or three times weekly treatment (Regimen 1/1a or Regimen 3/ 3a). DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis. Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified. On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic findings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinflammatory agents may be useful for symptomatic relief. For severe paradoxical reactions, prednisone (1-2 mg/kg per day for 1-2 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach (Rating CIII). # Children Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop "adult-type" tuberculosis with upper lobe infiltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances (Table 6) suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15-20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary. Most studies of treatment in children have used 6 months of INH and RIF supplemented during the first 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Most treatment studies of intermittent dosing in children have used daily drug administration for the first 2 weeks to 2 months. DOT should always be used in treating children. Because it is difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 9-12 months of treatment is recommended. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation. # Extrapulmonary tuberculosis The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although relatively few studies have examined treatment of extrapulmonary tuberculosis, increasing evidence suggests that 6-to 9-month regimens that include INH and RIF are effective. Thus, a 6-month course of therapy is recommended for treating tuberculosis involving any site with the exception of the meninges, for which a 9-12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis. # Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months. Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely) (Figure 2). # Renal insufficiency and end-stage renal disease Specific dosing guidelines for patients with renal insufficiency and end-stage renal disease are provided in Table 15. For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs. # Liver disease INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation. In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury. # Pregnancy and breastfeeding Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount. # Management of Relapse, Treatment Failure, and Drug Resistance Relapse refers to the circumstance in which a patient becomes and remains culture negative while receiving therapy but, at some point after completion of therapy, either becomes culture positive again or has clinical or radiographic deterioration that is consistent with active tuberculosis. In the latter situation rigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. Most relapses occur within the first 6-12 months after completion of therapy. In nearly all patients with tuberculosis caused by drugsusceptible organisms and who were treated with rifamycincontaining regimens using DOT, relapses occur with susceptible organisms. However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycincontaining regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. The selection of empirical treatment for patients with relapse should be based on the prior treatment scheme and severity of disease. For patients with tuberculosis that was caused by drug-susceptible organisms and who were treated under DOT, initiation of the standard four-drug regimen is appropriate until the results of drug susceptibility tests are available. However, for patients who have life-threatening forms of tuberculosis, at least three additional agents to which the organisms are likely to be susceptible should be included. For patients with relapse who did not receive DOT, who were not treated with a rifamycin-based regimen, or who are known or presumed to have had irregular treatment, it is prudent to infer that drug resistance is present and to begin an expanded regimen with INH, RIF, and PZA plus an additional two or three agents based on the probability of in vitro susceptibility. Usual agents to be employed would include a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), an injectable agent such as SM (if not used previously and susceptibility to SM had been established), amikacin, kanamycin, or capreomycin, with or without an additional oral drug. Treatment failure is defined as continued or recurrently positive cultures during the course of antituberculosis therapy. After 3 months of multidrug therapy for pulmonary tuberculosis caused by drug-susceptible organisms, 90 Possible reasons for treatment failure in patients receiving appropriate regimens include nonadherence to the drug regimen (the most common reason), drug resistance, malabsorption of drugs, laboratory error, and extreme biological variation in response. If treatment failure occurs, early consultation with a specialty center is strongly advised. If failure is likely due to drug resistance and the patient is not seriously ill, an empirical retreatment regimen could be started or administration of an altered regimen could be deferred until results of drug susceptibility testing from a recent isolate are available. If the patient is seriously ill or sputum AFB smears are positive, an empirical regimen should be started immediately and continued until susceptibility tests are available. For patients who have treatment failure, M. tuberculosis isolates should be sent promptly to a reference laboratory for drug susceptibility testing to both first-and second-line agents. A fundamental principle in managing patients with treatment failure is never to add a single drug to a failing regimen; so doing leads to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs to which susceptibility could logically be inferred should be added to lessen the probability of further acquired resistance. Empirical retreatment regimens might include a fluoroquinolone, an injectable agent such as SM (if not used previously and the patient is not from an area of the world having high rates of SM resistance), amikacin, kanamycin, or capreomycin, and an additional oral agent such as p-aminosalicylic acid (PAS), cycloserine, or ethionamide. Once drug-susceptibility test results are available, the regimen should be adjusted according to the results. Patients having tuberculosis caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug-resistant [MDR]) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or consultation obtained from specialized treatment centers as identified by the local or state health departments or CDC. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert. Definitive randomized or controlled studies have not been performed to establish optimum regimens for treating patients with the various patterns of drug-resistant tuberculosis; thus, treatment recommendations are based on expert opinion, guided by a set of general principles specified in Section 9, Management of Relapse, Treatment Failure, and Drug Resistance. Table 16 contains treatment regimens suggested for use in patients with various patterns of drug-resistant tuberculosis (all are rated AIII). The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies and results have been mixed. Surgery should be performed by surgeons with experience in these situations and only after the patient has received several months of intensive chemotherapy. Expert opinion suggests that chemotherapy should be continued for 1-2 years postoperatively to prevent relapse. # Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/ CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in highincidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin. The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field. The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS," the acronym for "directly observed therapy, short course," in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data. New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection. A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of "protective" cytokines such as interferon-γ and interleukin-2, and nutritional supplements, especially vitamin A and zinc. Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT. # Introduction and Background Since 1971 the American Thoracic Society (ATS) and CDC have regularly collaborated to develop joint guidelines for the diagnosis, treatment, prevention, and control of tuberculosis (1). These documents have been intended to guide both public health programs and health care providers in all aspects of the clinical and public health management of tuberculosis in low-incidence countries, with a particular focus on the United States. The most recent version of guidelines for the treatment of tuberculosis was published in 1994 (2). The current document differs from its predecessor in a number of important areas that are summarized above. The process by which this revision of the recommendations for treatment was developed was modified substantially from the previous versions. For the first time the Infectious Diseases Society of America (IDSA) has become a cosponsor of the statement, together with the ATS and CDC. The IDSA has had representation on prior statement committees but has not previously been a cosponsor of the document. Practice guidelines that serve to complement the current statement have been developed by the IDSA (3). In addition to the IDSA, representatives of the American Academy of Pediatrics (AAP), the (United States) National Tuberculosis Controllers Association (NTCA), the Canadian Thoracic Society (CTS), the IUATLD, and the WHO participated in the revision. By virtue of their different perspectives these committee members served to provide broader input and to help ensure that the guidelines are sputum smear microscopy among symptomatic patients selfreporting to health services, 3) a standardized treatment regimen of 6-8 months for at least all confirmed sputum smear-positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall. A number of other differences exist as well: • # A Research Agenda for Tuberculosis Treatment New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the placed in an appropriate context. It should be emphasized that the current guidelines are intended for areas in which mycobacterial cultures, drug susceptibility tests, radiographic facilities, and second-line drugs are available, either immediately or by referral, on a routine basis. For this revision of the recommendations essentially all clinical trials of antituberculosis treatment in the English language literature were reviewed and the strength of the evidence they presented was rated according to the IDSA/USPHS rating scale (4). This revision of the recommendations for treatment of tuberculosis presents a significant philosophic departure from previous versions. In this document the responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse. For these reasons, antituberculosis chemotherapy is both a personal and a public health measure that cannot be equated with the treatment of, for example, hypertension or diabetes mellitus, wherein the benefits largely accrue to the patient. Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. All reasonable attempts should be made to accommodate the patient so that a successful outcome is achieved. However, interventions such as detention may be necessary for patients who are persistently nonadherent. The recommendations in this statement are not applicable under all epidemiologic circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. Although the basic principles of therapy described in this document apply regardless of conditions, the diagnostic approach, methods of patient supervision, and monitoring for response and for adverse drug effects, and in some instances the regimens recommended, are quite different in highincidence, low-income areas compared with low-incidence, high-income areas of the world. A summary of the important differences between the recommendations in this document and those of the IUATLD and the WHO is found in Section 10,Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUTLD. In the United States there has been a call for the elimination of tuberculosis, and a committee constituted by the Institute of Medicine (IOM) issued a set of recommendations for reaching this goal (5). The IOM committee had two main recommendations related to treatment of tuberculosis; first, that all U.S jurisdictions have health regulations that mandate completion of therapy (treatment until the patient is cured); and second, that all treatment be administered in the context of patient-centered programs that are based on individual patient characteristics and needs. The IOM recommendations emphasize the importance of the structure and organization of treatment services, as well as the drugs that are used, to treat patients effectively. This philosophy is the core of the DOTS strategy (described in Section 10 Treatment of Tuberculosis in Low-Income Countries: Recommendations oof the WHO and the IUTLD), developed by the IUATLD and implemented globally by the WHO. Thus, although there are superficial differences in the approach to tuberculosis treatment between high-and low-incidence countries, the fundamental concern, regardless of where treatment is given, is ensuring patient adherence to the drug regimen and successful completion of therapy (6). # Provider Responsibility Treatment of tuberculosis benefits both the community as a whole and the individual patient; thus, any public health program or private provider (or both in a defined arrangement by which management is shared) undertaking to treat a patient with tuberculosis is assuming a public health function that includes not only prescribing an appropriate regimen but also ensuring adherence to the regimen until treatment is completed. # Organization and Supervision of Treatment Successful treatment of tuberculosis depends on more than the science of chemotherapy. To have the highest likelihood of success, chemotherapy must be provided within a clinical and social framework based on an individual patient's circumstances. Optimal organization of treatment programs requires an effective network of primary and referral services and cooperation between clinicians and public health officials, between health care facilities and community outreach programs, and between the private and public sectors of medical care. This section describes the approaches to organization of treatment that serve to ensure that treatment has a high likelihood of being successful. As noted previously, antituberculosis chemotherapy is both a personal health measure intended to cure the sick patient and a basic public health strategy intended to reduce the transmission of Mycobacterium tuberculosis. Typically, tuberculosis treatment is provided by public health departments, often working in collaboration with other providers and organizations including private physicians, community health centers, migrant health centers, correctional facilities, hospitals, hospices, long-term care facilities, and homeless shelters. Private providers and public health departments may cosupervise patients, assuring that the patient completes therapy in a setting that is not only mutually agreeable but also enables access to tuberculosis expertise and resources that might otherwise not be available. In managed care settings delivery of tuberculosis treatment may require a more structured public/private partnership, often defined by a contract, to assure completion of therapy. Regardless of the means by which treatment is provided, the ultimate legal authority for assuring that patients complete therapy rests with the public health system. # Role of the Health Department The responsibility of the health department in the control of tuberculosis is to ensure that all persons who are suspected of having tuberculosis are identified and evaluated promptly and that an appropriate course of treatment is prescribed and completed successfully (1,2). A critical component of the evaluation scheme is access to proficient microbiological laboratory services, for which the health department is responsible. The responsibilities of the health department may be accomplished indirectly by epidemiologic surveillance and monitoring of treatment decisions and outcome, applying generally agreed-on standards and guidelines, or more directly by provision of diagnostic and treatment services, as well as by conducting epidemiologic investigations. Given the diverse sociodemographic characteristics of patients with tuberculosis and the many mechanisms by which health care is delivered, the means by which the goals of the health department are accomplished may be quite varied. In dealing with individual patients, approaches that focus on each person's needs and characteristics should be used to determine a tailored treatment plan that is designed to ensure completion of therapy (3). Such treatment plans are developed with the patient as an active participant together with the physician and/or nurse, outreach workers, social worker (when needed), and others as appropriate. Given that onehalf the current incident cases of tuberculosis in the United States were born outside the United States (similar circumstances prevail in most other low-incidence countries), translation of materials into the patient's primary language is often necessary to ensure his/her participation in developing the treatment plan. Ideally, a specific case manager is assigned individual responsibility for assuring that the patient completes therapy. The treatment plan is reviewed periodically and revised as needed. These reviews may be accomplished in meetings between the patient and the assigned provider, as well as more formally through case and cohort evaluations. The treatment plan is based on the principle of using the least restrictive measures that are likely to achieve success. The full spectrum of measures that may be employed ranges from, at an absolute minimum, monthly monitoring of the patient in the outpatient setting to legally mandated hospitalization (4). Directly observed therapy (DOT) is the preferred initial means to assure adherence. For nonadherent patients more restrictive measures are implemented in a stepwise fashion. Any approach must be balanced, ensuring that the needs and rights of the patient, as well as those of the public, are met. Care plans for patients being managed in the private sector should be developed jointly by the health department and the private provider, and must address identified and anticipated barriers to adherence. # Promoting Adherence Louis Pasteur once said, "The microbe is nothing...the terrain everything" (5). Assuming appropriate drugs are prescribed, the terrain (the circumstances surrounding each patient that may affect his or her ability to complete treatment) # What's DOT? Direct observation of therapy (DOT) involves providing the antituberculosis drugs directly to the patient and watching as he/she swallows the medications. It is the preferred core management strategy for all patients with tuberculosis. becomes the most important consideration in completion of tuberculosis treatment. Many factors may be part of this terrain. Factors that interfere with adherence to the treatment regimen include cultural and linguistic barriers to cooperation, lifestyle differences, homelessness, substance abuse, and a large number of other conditions and circumstances that, for the patient, are priorities that compete with taking treatment for tuberculosis (6). Barriers may be patient related, such as conflicting health beliefs, alcohol or drug dependence, or mental illness, or they may be system related, such as lack of transportation, inconvenient clinic hours, and lack of interpreters (7). Effective tuberculosis case management identifies and characterizes the terrain and determines an appropriate care plan based on each of the identified factors. Additional advantages of the patient-centered approach are that, by increasing communication with the patient, it provides opportunities for further education concerning tuberculosis and enables elicitation of additional information concerning contacts. To maximize completion of therapy, patient-centered programs identify and utilize a broad range of approaches based on the needs and circumstances of individual patients. Among these approaches, DOT is the preferred initial strategy and deserves special emphasis. Although DOT itself has not been subjected to controlled trials in low-incidence areas (and, thus, is rated AII), observational studies and a meta-analysis in the United States strongly suggest that DOT, coupled with individualized case management, leads to the best treatment results (8-10). To date there have been three published studies of DOT in high-incidence areas, two of which (11,12) showed no benefit and one (13) in which there was a significant advantage for DOT. What is clear from these studies is that DOT cannot be limited merely to passive observation of medication ingestion; there must be aggressive interventions when patients miss doses. Using DOT in this manner can only improve results. DOT can be provided daily or intermittently in the office, clinic, or in the "field" (patient's home, place of employment, school, street corner, bar, or any other site that is mutually agreeable) by appropriately trained personnel. DOT should be used for all patients residing in institutional settings such as hospitals, nursing homes, or correctional facilities, or in other settings, such as methadone treatment sites, that are conducive to observation of therapy (14). However, even in such supervised settings careful attention must be paid to ensuring that ingestion of the medication is, in fact, observed. It is essential that all patients being treated with regimens that use intermittent drug administration have all doses administered under DOT because of the potentially serious consequences of missed doses. DOT also enables early identification of nonadherence, adverse drug reactions, and clinical worsening of tuberculosis. DOT provides a close connection to the health care system for a group of patients at high risk of other adverse health events and, thus, should facilitate identification and management of other conditions. The use of DOT does not guarantee ingestion of all doses of every medication (15). Patients may miss appointments, may not actually swallow the pills, or may deliberately regurgitate the medications. Consequently, all patients, including those who are being treated by DOT, should continue to be monitored for signs of treatment failure. DOT is only one aspect of a comprehensive patient-centered program that, in addition, includes incentives and enablers described subsequently (16)(17)(18)(19)(20). Patients who are more likely to present a transmission risk to others or are more likely to have problems with adherence (Table 7) should be prioritized for DOT when resources are limited. When DOT is not being used, fixeddose combination preparations (see Section 6.2, Fixed-Dose Combination Preparations) containing INH and RIF or INH, RIF, and PZA reduce the risk of the patient taking only one drug and may help prevent the development of drug resistance. Combination formulations are easier to administer and also may reduce medication errors. Depending on the identified obstacles to completion of therapy, the treatment plan may also include enablers and incentives such as those listed in Table 8. Studies have examined the use of a patient-centered approach that utilizes DOT in addition to other adherence-promoting tools (9,21,22). These studies demonstrate, as shown in Figure 3, that "enhanced DOT" (DOT together with incentives and enablers) produces the highest treatment completion rates (in excess of 90% across a range of geographic and socioeconomic settings), and reinforces the importance of patient-related factors in designing and implementing case management (9,23). Intensive educational efforts should be initiated as soon as the patient is suspected of having tuberculosis. The instruction should be at an educational level appropriate for the patient and should include information about tuberculosis, expected outcomes of treatment, the benefits and possible adverse effects of the drug regimen, methods of supervision, assessment of response, and a discussion of infectiousness and infection control. The medication regimen must be explained in clear, understandable language and the verbal explanation followed with written instructions. An interpreter is necessary when the patient and health care provider do not speak the same language. Materials should be appropriate for the culture, language, age, and reading level of the patient. Relevant information should be reinforced at each visit. The patient's clinical progress and the treatment plan must be reviewed at least monthly to evaluate the response to therapy and to identify adherence problems. Use of a record system (Figure 4) either manual or computer-based, that quantifies the dosage and frequency of medication administered, indicates AFB smear and culture status, and notes symptom improvement as well as any adverse effects of treatment serves to facilitate the regular reviews and also provides data for cohort analyses. In addition, adherence monitoring by direct methods, such as the detection of drugs or drug metabolites in the patient's urine, or indirect methods, such as pill counts or a medication monitor, should be a part of routine management, especially if the patient is not being given DOT. Tracking patients is also a critical concern for those charged with assuring completion of treatment. It has been shown that patients who move from one jurisdiction to another before completion of therapy are much more likely to default than patients who do not move (24). Factors that have been shown to be associated with moving/defaulting include diagnosis of tuberculosis in a state correctional facility, drug and alcohol # Tracking Tuberculosis Inter-and intrastate notifications constitute the key patient-tracking systems for patients moving within the United States. International notifications can also be made, although specific tracking programs vary by country. Currently there are two formal patienttracking systems in operation for patients moving across the United States-Mexico border: TB Net, operated by the Migrant Clinician Network based in Austin, Texas (http://www.migrantclinician.org; telephone, 512-327-2017) and Cure TB, managed by the San Diego County, California, Division of Tuberculosis Control (http:// www.curetb.org; telephone, 619-692-5719). abuse, and homelessness. Communication and coordination of services among different sources of care and different health departments are especially important for patients in these groups as well as for migrant workers and other patients with no permanent home. Such communication may also be necessary across national boundaries, especially the United States-Mexico border, and there are systems in place to facilitate such communication and tracking. Some patients, for example those with tuberculosis caused by drug-resistant organisms, or who have comorbid conditions, such as HIV infection, alcoholism, or other significant underlying disorders, may need to be hospitalized in a facility where tuberculosis expertise is available and where there are appropriate infection control measures in place. Hospitalization may be necessary for nonadherent patients for whom less restrictive measures have failed (25)(26)(27). Public health laws exist in most states that allow the use of detainment under these circumstances, at least for patients who remain infectious (28). Court-ordered DOT has been used successfully in some states as a less costly alternative. The use of these interventions depends on the existence of appropriate laws, cooperative courts, and law enforcement officials, and the availability of appropriate facilities. Health departments must be consulted to initiate legal action when it is necessary. # Drugs in Current Use Currently, there are 10 drugs approved by the United States Food and Drug Administration (FDA) for treating tuberculosis (Table 9). In addition, the fluoroquinolones, although not approved by the FDA for tuberculosis, are used relatively commonly to treat tuberculosis caused by drug-resistant organisms or for patients who are intolerant of some of the first-line drugs. Rifabutin, approved for use in preventing Mycobacterium avium complex disease in patients with HIV infection but not approved for tuberculosis, is useful for treating tuberculosis in patients concurrently taking drugs that have unacceptable interactions with other rifamycins. Amikacin and kanamycin, nearly identical aminoglycoside drugs used in treating patients with tuberculosis caused by drug-resistant organisms, are not approved by the FDA for tuberculosis. Of the approved drugs isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) are considered first-line antituberculosis agents and form the core of initial treatment regimens. Rifabutin and rifapentine may also be considered first-line agents under the specific situations described below. Streptomycin (SM) was formerly considered to be a first-line agent and, in some instances, is still used in initial treatment; however, an increasing prevalence of resistance to SM in many parts of the world has decreased its overall usefulness. The remaining drugs are reserved for special situations such as drug intolerance or resistance. The drug preparations available currently and the recommended doses are shown in Tables 3, 4, and 5. # First-Line Drugs # Isoniazid Role in treatment regimen. Isoniazid (INH) is a first-line agent for treatment of all forms of tuberculosis caused by organisms known or presumed to be susceptible to the drug. It has profound early bactericidal activity against rapidly dividing cells (1,2). Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily; 15 mg/kg (900 mg) once, twice, or three times weekly. Children (maximum): 10-15 mg/kg (300 mg) daily; 20-30 mg/kg (900 mg) twice weekly (3). Preparations. Tablets (50 mg, 100 mg, 300 mg); syrup (50 mg/5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection. Adverse effects. Asymptomatic elevation of aminotransferases: Aminotransferase elevations up to five times the upper limit of normal occur in 10-20% of persons receiving INH alone for treatment of latent tuberculosis infection (4). The enzyme levels usually return to normal even with continued administration of the drug. Clinical hepatitis: (see Table 10.) Data indicate that the incidence of clinical hepatitis is lower than was previously thought. Hepatitis occurred in only 0.1-0.15% of 11,141 persons receiving INH alone as treatment for latent tuberculosis infection in an urban tuberculosis control program (5). Prior studies suggested a higher rate, and a meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH alone to be 0.6% (6)(7)(8). In the meta-analysis the rate of clinical hepatitis was 1.6% when INH was given with other agents, not including RIF. The risk was higher when the drug was combined with RIF, an average of 2.7% in 19 reports (8). For INH alone the risk increases with increasing age; it is uncommon in persons less than 20 years of age but is nearly 2% in persons aged 50-64 years (6). The risk also may be increased in persons with underlying liver disease, in those with a history of heavy alcohol consumption, and, data suggest, in the postpartum period, particularly among Hispanic women (9). Fatal hepatitis: A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower (10,11). The risk may be increased in women. Death has been associated with continued administration of INH despite onset of symptoms of hepatitis (12). Peripheral neurotoxicity (13,14): This adverse effect is dose related and is uncommon (less than 0.2%) at conventional doses (15)(16)(17). The risk is increased in persons with other conditions that may be associated with neuropathy such as nutritional deficiency, diabetes, HIV infection, renal failure, and alcoholism, as well as for pregnant and breastfeeding women. Pyridoxine supplementation (25 mg/day) is recommended for patients with these conditions to help prevent this neuropathy (18). Central nervous system effects: Effects such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate have been reported but have not been quantified. Lupus-like syndrome (19): Approximately 20% of patients receiving INH develop anti-nuclear antibodies. Less than 1% develop clinical lupus erythematosis, necessitating drug discontinuation. Hypersensitivity reactions: Reactions, such as fever, rash, Stevens-Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare. Monoamine (histamine/tyramine) poisoning: This has been reported to occur after ingestion of foods and beverages with high monoamine content but is rare (20)(21)(22). If flushing occurs, patients should be instructed to avoid foods and drinks, such as certain cheeses and wine, having high concentrations of monoamines. Diarrhea: Use of the commercial liquid preparation of INH, because it contains sorbitol, is associated with diarrhea. Use in pregnancy. INH is considered safe in pregnancy, but the risk of hepatitis may be increased in the peripartum period (9,23). Pyridoxine supplementation (25 mg/day) is recommended if INH is administered during pregnancy (18). It should be noted that multivitamin preparations have variable amounts of pyridoxine but generally less than 25 mg/day and, thus, do not provide adequate supplementation. CNS penetration. Penetration is excellent. Cerebrospinal fluid (CSF) concentrations are similar to concentrations achieved in serum (24). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) INH can be used safely without dose adjustment in patients with renal insufficiency (25) and with end-stage renal isease who require chronic hemodialysis (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The risk of drug accumulation and drug-induced hepatitis may be increased in the presence of hepatic disease; however, INH may be used in patients with stable hepatic disease. Laboratory and clinical monitoring should be more frequent in such situations. Monitoring. Routine monitoring is not necessary. However, for patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of the drug, liver function tests should be measured monthly and when symptoms occur. Serum concentrations of phenytoin and carbamazepine may be increased in persons taking INH. However, in combination therapy with RIF the effects of INH on serum concentrations of the anticonvulsants are limited by the decrease caused by RIF. Thus, it is important to measure serum concentrations of these drugs in patients receiving INH with or without RIF and adjust the dose if necessary. # Rifampin Role in treatment regimen. Rifampin (RIF) is a first-line agent for treatment of all forms of tuberculosis caused by organisms with known or presumed sensitivity to the drug. It has activity against organisms that are dividing rapidly (early bactericidal activity) (1) and against semidormant bacterial populations, thus accounting for its sterilizing activity (27). Rifampin is an essential component of all short-course regimens. Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg) once daily, twice weekly, or three times weekly. Children (maximum): 10-20 mg/kg (600 mg) once daily or twice weekly. Preparations. Capsules (150 mg, 300 mg); contents of capsule may also be mixed in an appropriate diluent to prepare an oral suspension; aqueous solution for parenteral administration. # Adverse effects (28). Cutaneous reactions (29): Pruritis with or without rash may occur in as many as 6% of patients but is generally selflimited (30). This reaction may not represent true hypersensitivity and continued treatment with the drug may be possible. More severe, true hypersensitivity reactions are uncommon, occurring in 0.07-0.3% of patients (17,31,32). Gastrointestinal reactions (nausea, anorexia, abdominal pain): The incidence is variable, but symptoms are rarely severe enough to necessitate discontinuation of the drug (28)(29)(30). Flulike syndrome: This may occur in 0.4-0.7% of patients receiving 600 mg twice weekly but not with daily administration of the same dose (31)(32)(33)(34). Symptoms are more likely to occur with intermittent administration of a higher dose (29,35). Hepatotoxicity: Transient asymptomatic hyperbilirubinemia may occur in as many as 0.6% of patients receiving the drug. More severe clinical hepatitis that, typically, has a cholestatic pattern may also occur (8,36). Hepatitis is more common when the drug is given in combination with INH (2.7%) than when given alone (nearly 0%) or in combination with drugs other than INH (1.1%) (8). Severe immunologic reactions: In addition to cutaneous reactions and flulike syndrome, other reactions thought to be immune mediated include the following: thrombocytopenia, hemolytic anemia, acute renal failure, and thrombotic thrombocytopenic purpura. These reactions are rare, each occurring in less than 0.1% of patients (31,32,37). Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. # Rifabutin and Rifapentine The newer rifamycins, rifabutin and rifapentine, should be considered first-line drugs in special situations: rifabutin for patients who are receiving medications, especially antiretroviral drugs, that have unacceptable interactions with rifampin or who have experienced intolerance to rifampin; and rifapentine, together with INH, in a once-a-week continuation phase for certain selected patients who meet specified criteria. # Drug interactions due to induction of hepatic microsomal enzymes: There are a number of drug interactions (described in Section 7, Drug Interactions, and Table 12) with potentially serious consequences. Of particular concern are reductions, often to ineffective levels, in serum concentrations of common drugs, such as oral contraceptives, methadone, and warfarin. In addition there are important bidirectional interactions between rifamycins and antiretroviral agents. Because information regarding rifamycin drug interactions is evolving rapidly, readers are advised to consult the CDC web site www.cdc.gov/nchstp/tb/ to obtain the most up-to-date information. Use in pregnancy. RIF is considered safe in pregnancy (38). CNS penetration. Concentrations in the CSF may be only 10-20% of serum levels, but this is sufficient for clinical efficacy. Penetration may be improved in the setting of meningitis (39). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) RIF can be used safely without dose adjustment in patients with renal insufficiency and endstage renal disease (26,40). Use in hepatic disease. (see Section 8.8: Hepatic Disease.) Clearance of the drug may be impaired in the presence of liver disease, causing increased serum levels (40). However, because of the critical importance of rifampin in all short-course regimens, it generally should be included, but the frequency of clinical and laboratory monitoring should be increased. Monitoring. No routine monitoring tests are required. However, rifampin causes many drug interactions described in Section 7, Drug Interactions, that may necessitate regular measurements of the serum concentrations of the drugs in question. # Rifabutin Role in treatment regimen. Rifabutin is used as a substitute for RIF in the treatment of all forms of tuberculosis caused by organisms that are known or presumed to be susceptible to this agent. The drug is generally reserved for patients who are receiving any medication having unacceptable interactions with rifampin (41) or have experienced intolerance to rifampin. Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily, twice, or three times weekly. The dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. When rifabutin is used with efavirenz the dose of rifabutin should be increased to 450-600 mg either daily or intermittently. Because information regarding rifamycin drug interactions is evolving rapidly readers are advised to consult the CDC web site, http://www.cdc.gov/ nchstp/tb/, to obtain the most up-to-date information. # Children (maximum): Appropriate dosing for children is unknown. Preparations: Capsules (150 mg) for oral administration. # Adverse effects. Hematologic toxicity: In a placebo-controlled, double-blind trial involving patients with advanced acquired immunodeficiency syndrome (AIDS) (CD4+ cell counts <200 cells/µl), neutropenia occurred in 25% compared with 20% in patients receiving placebo (p = 0.03). Neutropenia severe enough to necessitate discontinuation of the drug occurred in 2% of patients receiving the drug (product insert B; Adria Laboratories, Columbus, OH). The effect is dose related, occurring more frequently with daily than with intermittent administration of the same dose (42). In several studies of patients with and without HIV infection, neither neutropenia nor thrombocytopenia was associated with rifabutin (43)(44)(45)(46)(47). Uveitis: This is a rare (less than 0.01%) complication when the drug is given alone at a standard (300 mg daily) dose. The occurrence is higher (8%) with higher doses or when rifabutin is used in combination with macrolide antimicrobial agents that reduce its clearance (48). Uveitis may also occur with other drugs that reduce clearance such as protease inhibitors and azole antifungal agents. Gastrointestinal symptoms: These symptoms occurred in 3% of patients with advanced HIV infection given 300 mg/day (package insert). In subsequent studies no increased incidence of gastrointestinal symptoms was noted among patients taking rifabutin (43,44,(46)(47)(48). Polyarthralgias: This symptom occurred in 1-2% of persons receiving a standard 300-mg dose (package insert). It is more common at higher doses (48). Polyarthralgias have not been noted in more recent studies involving both HIV-infected and uninfected patients (43,44,46,47). Hepatotoxity: Asymptomatic elevation of liver enzymes has been reported at a frequency similar to that of RIF (48). Clinical hepatitis occurs in less than 1% of patients receiving the drug. Pseudojaundice (skin discoloration with normal bilirubin): This is usually self-limited and resolves with discontinuation of the drug (49). Rash: Although initially reported to occur in as many as 4% of patients with advanced HIV infection, subsequent studies suggest that rash is only rarely (less than 0.1%) associated with rifabutin (46). Flulike syndrome: Flulike syndrome is rare (less than 0.1%) in patients taking rifabutin. Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. # Use in pregnancy. There are insufficient data to recommend the use of rifabutin in pregnant women; thus, the drug should be used with caution in pregnancy. CNS penetration. The drug penetrates inflamed meninges (50). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Rifabutin may be used without dosage adjustment in patients with renal insufficiency and end-stage renal disease (50). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The drug should be used with increased clinical and laboratory monitoring in patients with underlying liver disease. Dose reduction may be necessary in patients with severe liver dysfunction (50). Monitoring. Monitoring is similar to that recommended for rifampin. Although drug interactions are less problematic with rifabutin, they still occur and close monitoring is required. # Rifapentine Role in treatment regimen. Rifapentine may be used once weekly with INH in the continuation phase of treatment for HIV-seronegative patients with noncavitary, drug-susceptible pulmonary tuberculosis who have negative sputum smears at completion of the initial phase of treatment (51). Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg), once weekly during the continuation phase of treatment. Data have suggested that a dose of 900 mg is well tolerated but the clinical efficacy of this dose has not been established (52). Children: The drug is not approved for use in children. Preparation. Tablet (150 mg, film coated). # Adverse effects. The adverse effects of rifapentine are similar to those associated with RIF. Rifapentine is an inducer of multiple hepatic enzymes and therefore may increase metabolism of coadministered drugs that are metabolized by these enzymes (see Section 7: Drug Interactions). Use in pregnancy. There is not sufficient information to recommend the use of rifapentine for pregnant women. CNS penetration. There are no data on CSF concentrations of rifapentine. Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease .) The pharmacokinetics of rifapentine have not been evaluated in patients with renal impairment. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function in the disposition of rifapentine is not known. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The pharmacokinetics of rifapentine and its 25-desacetyl metabolite were similar among patients with various degrees of hepatic impairment and not different from those in healthy volunteers, even though the elimination of these compounds is primarily via the liver (53). The clinical significance of impaired hepatic function in the disposition of rifapentine and its 25-desacetyl metabolite is not known. Monitoring. Monitoring is similar to that for RIF. Drug interactions involving rifapentine are being investigated and are likely to be similar to those of RIF. # Pyrazinamide Role in treatment regimen. Pyrazinamide (PZA) is a firstline agent for the treatment of all forms of tuberculosis caused by organisms with known or presumed susceptibility to the drug. The drug is believed to exert greatest activity against the population of dormant or semidormant organisms contained within macrophages or the acidic environment of caseous foci (54). Dose. See Tables 3 and 4. Adults: 20-25 mg/kg per day. Recommended adult dosages by weight, using whole tablets, are listed in Table 4. Children (maximum): 15-30 mg/kg (2.0 g) daily; 50 mg/kg twice weekly (2.0 g). Preparations. Tablets (500 mg, scored). # Adverse effects. Hepatotoxicity: Early studies (55,56) using doses of 40-70 mg/kg per day reported high rates of hepatotoxicity. However, in treatment trials with multiple other drugs, including INH, liver toxicity has been rare at doses of 25 mg/kg per day or less (15,34,57). In one study, however, hepatotoxicity attributable to PZA used in standard doses occurred at a rate of about 1% (58). Gastrointestinal symptoms (nausea, vomiting): Mild anorexia and nausea are common at standard doses. Vomiting and severe nausea are rare except at high doses (59). Nongouty polyarthralgia: Polyarthralgias may occur in up to 40% of patients receiving daily doses of PZA. This rarely requires dosage adjustment or discontinuation of the drug (60). The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents. In clinical trials of PZA in the initial intensive phase of treatment, athralgias were not noted to be a significant problem (15,61). Asymptomatic hyperuricemia: This is an expected effect of the drug and is generally without adverse consequence (15,62). Acute gouty arthritis: Acute gout is rare except in patients with preexisting gout (63), generally a contraindication to the use of the drug. Transient morbilliform rash: This is usually self-limited and is not an indication for discontinuation of the drug. Dermatitis: PZA may cause photosensitive dermatitis (59). # Use in pregnancy. There is little information about the safety of PZA in pregnancy. However, when there are sound reasons to utilize a 6-month course of treatment, the benefits of PZA may outweigh the possible (but unquantified) risk. The WHO and the IUATLD recommend this drug for use in pregnant women with tuberculosis (see Section 10: Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUATLD). CNS penetration. The drug passes freely into the CSF, achieving concentrations equivalent to those in serum (64). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) PZA is cleared primarily by the liver, but its metabolites are excreted in the urine and may accumulate in patients with renal insufficiency (65). The dose may, therefore, need to be reduced in patients with renal insufficiency. It should be administered at a reduced dose (25-35 mg/kg) three times a week after dialysis in patients with end-stage renal disease (Table 15) (26). The risk of hyperuricemia caused by PZA is increased in patients with renal insufficiency. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Although the frequency is slightly lower than with INH or RIF, the drug can cause liver injury that may be severe and prolonged. If the drug is used in patients with underlying liver disease, laboratory and clinical monitoring should be increased. Monitoring. Serum uric acid measurements are not recommended as a routine but may serve as a surrogate marker for compliance. Liver chemistry monitoring should be performed when the drug is used in patients with underlying liver disease or when it is used with rifampin in treating latent tuberculosis infection. # Ethambutol Role in treatment regimen. Ethambutol (EMB) is a firstline drug for treating all forms of tuberculosis. It is included in initial treatment regimens primarily to prevent emergence of RIF resistance when primary resistance to INH may be present. Ethambutol is generally not recommended for routine use in children whose visual acuity cannot be monitored. However, if a child has adult-type tuberculosis or disease that is suspected or proven to be caused by organisms that are resistant to either INH or RIF, EMB should be used (see Section 8.2: Children and Adolescents, and Table 6). Dose. See Tables 3 and 5. Adults: 15-20 mg/kg per day: Table 5 lists recommended dosages for adults, using whole tablets. Children (maximum): 15-20 mg/kg per day (2.5 g); 50 mg/ kg twice weekly (2.5 g). The drug can be used safely in older children but should be used with caution in children in whom visual acuity cannot be monitored (generally less than 5 years of age) (66). In younger children EMB can be used if there is concern with resistance to INH or RIF (Table 6). Preparations. Tablets (100 mg, 400 mg) for oral administration. Adverse effects. Retrobulbar neuritis: This is manifested as decreased visual acuity or decreased red-green color discrimination that may affect one or both eyes. The effect is dose related, with minimal risk at a daily dose of 15 mg/kg (67). No difference was found in the prevalence of decreased visual acuity between regimens that contained EMB at 15 mg/kg and those not containing the drug (68). The risk of optic toxicity is higher at higher doses given daily (18% of patients receiving more than 30 mg/kg per day) and in patients with renal insufficiency. Higher doses can be given safely twice or three times weekly. Peripheral neuritis: This is a rare adverse effect (69). Cutaneous reactions: Skin reactions requiring discontinuation of the drug occur in 0.2-0.7% of patients (68). Use in pregnancy. EMB is considered safe for use in pregnancy (70)(71)(72). CNS penetration. The agent penetrates the meninges in the presence of inflammation but does not have demonstrated efficacy in tuberculous meningitis (73). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) EMB is cleared primarily by the kidneys. The dose or dosing interval should be adjusted when the creatinine clearance is less than 70 ml/minute (74). EMB should be administered at a dose of 15-20 mg/kg three times a week by DOT after dialysis in patients with end-stage renal disease (Table 15) (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) EMB can be used safely in patients with hepatic disease. Monitoring. Patients should have baseline visual acuity testing (Snellen chart) and testing of color discrimination (Ishihara tests). At each monthly visit patients should be questioned regarding possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses greater than 15-25 mg/kg, patients receiving the drug for longer than 2 months, and any patient with renal insufficiency. Patients should be instructed to contact their physician or public health clinic immediately if they experience a change in vision. EMB should be discontinued immediately and permanently if there are any signs of visual toxicity. # Fixed-dose combination preparations Role in treatment regimen. Two combined preparations, INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®), are available in the United States. These formulations are a means of minimizing inadvertent monotherapy, particularly when DOT is not possible, and, therefore, may decrease the risk of acquired drug resistance (75). The use of fixed-dose formulations may reduce the number of pills that must be taken daily. Constituent drugs are combined in proportions compatible with daily treatment regimens. Formulations for intermittent administration are not available in the United States. Preparations and dose. Rifamate®: As sold in North America, each capsule contains RIF (300 mg) and INH (150 mg); thus, the daily dose is two capsules (600 mg of RIF and 300 mg of INH). Two capsules of Rifamate® plus two 300-mg tablets of INH are used by some programs for intermittent therapy given twice weekly as DOT. Rifater® Use in hepatic disease. (See Section 8.8: Hepatic Disease.) In patients with underlying hepatic disease it is advisable to treat with single-drug formulations until safety in an individual patient can be determined and a stable regimen established. # Second-Line Drugs # Cycloserine Role in treatment regimen. Cycloserine (76,77) is a second-line drug that is used for treating patients with drug-resistant tuberculosis caused by organisms with known or presumed susceptibility to the agent. It may also be used on a temporary basis for patients with acute hepatitis in combination with other nonhepatotoxic drugs. Dose. See Table 3. Adults (maximum): 10-15 mg/kg per day (1,000 mg), usually 500-750 mg/day given in two doses. Clinicians with experience with cycloserine indicate that toxicity is more common at doses over 500 mg/day. Serum concentration measurements aiming for a peak concentration of 20-35 mg/ml are often useful in determining the optimum dose for a given patient. There are no data to support intermittent administration. Children (maximum): 10-15 mg/kg per day (1.0 g/day). Preparations. Capsules (250 mg). Adverse effects. Central nervous system effects: The central nervous system effects range from mild reactions, such as headache or restlessness, to severe reactions, such as psychosis and seizures. The drug may exacerbate underlying seizure disorders or mental illness. Seizures have been reported to occur in up to 16% of patients receiving 500 mg twice daily but in only 3% when receiving 500 mg once daily (78). Pyridoxine may help prevent and treat neurotoxic side effects and is usually given in a dosage of 100-200 mg/day (79). Rarely, cycloserine may cause peripheral neuritis. Use in pregnancy. Cycloserine crosses the placenta. There are limited data on safety in pregnancy; thus, it should be used in pregnant women only when there are no suitable alternatives (77). CNS penetration. Concentrations in CSF approach those in serum (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) The drug can accumulate in patients with impaired renal function and should be used cautiously in such patients. Generally, the dose should be reduced and serum concentrations measured. Cycloserine should not be used in patients having a creatinine clearance of less than 50 ml/minute unless the patient is receiving hemodialysis. For patients being hemodialyzed the dose should be 500 mg three times a week or 250 mg daily (Table 15). Serum concentrations of the drug should be measured and the dose adjusted accordingly. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) There are no precautions except for patients with alcoholrelated hepatitis in whom there is an increased risk of seizures (77). Monitoring. Neuropsychiatric status should be assessed at least at monthly intervals and more frequently if symptoms # Role of Fixed-Dose Combination Preparations Fixed-dose combination preparations minimize inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors. These preparations should generally be used when therapy cannot be administered under DOT. develop. As noted above, measurements of serum concentrations may be necessary until an appropriate dose is established. For patients taking phenytoin, serum concentrations of phenytoin should be measured. # Ethionamide Role in treatment. Ethionamide (76,77) is a second-line drug that is used for patients with drug-resistant tuberculosis disease caused by organisms that have demonstrated or presumed susceptibility to the drug. Dose: See Table 3. Adults (maximum): 15-20 mg/kg per day (1.0 g/day), usually 500-750 mg/day in a single daily dose or two divided doses. The single daily dose can be given at bedtime or with the main meal. There are no data to support intermittent dosing. Children (maximum): 15-20 mg/kg per day (1.0 g/day). Preparations: Tablets (250 mg). # Adverse reactions. Gastrointestinal effects: Ethionamide commonly causes profound gastrointestinal side effects, including a metallic taste, nausea, vomiting (that is often severe), loss of appetite, and abdominal pain (80). Symptoms may improve if doses are taken with food or at bedtime. Hepatotoxicity: Ethionamide is similar in structure to INH and may cause similar side effects. Hepatotoxicity occurs in about 2% of patients taking the drug (81,82). Neurotoxicity: Neurotoxicity, including peripheral neuritis, optic neuritis, anxiety, depression, and psychosis, has been reported in 1-2% of patients taking shorter courses of the drug with higher rates reported with prolonged treatment (83,84). Endocrine effects: Endocrine disturbances, including gynecomastia, alopecia, hypothyroidism, and impotence, have been described (85,86). Diabetes may be more difficult to manage in patients taking ethionamide (77). Use in pregnancy. Ethionamide crosses the placenta and is teratogenic in laboratory animals. It should not be used in pregnancy. CNS penetration. CSF concentrations are equal to those in serum (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-stage Renal Disease.) For patients having a creatinine clearance of less than 30 ml/minute or who are receiving hemodialysis the dose should be reduced to 250-500 mg/day (Table 15). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Ethionamide should be used with caution in patients with underlying liver disease. Monitoring. Liver function tests should be obtained at baseline and, if there is underlying liver disease, at monthly intervals. The studies should be repeated if symptoms occur. Thyroid-stimulating hormone should be measured at baseline and at monthly intervals. # Streptomycin Role in treatment regimen. Streptomycin (SM) (76,77,(87)(88)(89) and EMB have been shown to be approximately equivalent when used in the initial phase of treatment with 6-month regimens. However, among patients likely to have acquired M. tuberculosis in a high-incidence country, the relatively high rate of resistance to SM limits its usefulness. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1 g/day) parenterally, usually given as a single daily dose (5-7 days/week) initially, and then reducing to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons over 59 years of age, the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 12-15 mg/kg per dose two or three times per week) in persons with renal insufficiency (see below: Use in Renal Disease) (91,92). Children (maximum): 20-40 mg/kg per day (1 g/day). Preparations. Aqueous solution in vials of 1 g (93). # Adverse effects. Ototoxicity: The most important adverse reaction caused by SM is ototoxicity, including vestibular and hearing disturbances. The risk is increased with age (94) or concomitant use of loop-inhibiting diuretics (furosemide, ethacrynic acid). The risk of ototoxicity increases with increasing single doses and with the cumulative dose, especially above 100-120 g. Neurotoxicity: SM relatively commonly causes circumoral parasthesias immediately after injection. Rarely, it may interact with muscle relaxants to cause postoperative respiratory muscle weakness. Nephrotoxicity: Nephrotoxicity occurs less commonly with SM than with amikacin, kanamycin, or capreomycin (95). Renal insufficiency requiring discontinuation occurs in about 2% of patients (96). Use in pregnancy. SM is contraindicated in pregnancy because of the risk of fetal hearing loss (77,97,98). CNS penetration. There is only slight diffusion of SM into CSF, even in patients with meningitis (77,99) Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) SM should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufficiency, including the elderly and those undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 12-15 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. An audiogram, vestibular testing, Romberg testing, and serum creatinine measurement should be performed at baseline. Assessments of renal function, and questioning regarding auditory or vestibular symptoms, should be performed monthly. An audiogram and vestibular testing should be repeated if there are symptoms of eighth nerve toxicity. # Amikacin and kanamycin Role in treatment regimen. Amikacin and kanamycin (76,77,101) are two closely related injectable second-line drugs that are used for patients with drug-resistant tuberculosis whose isolate has demonstrated or presumed susceptibility to the agents. There is nearly always complete cross-resistance between the two drugs, but most SM-resistant strains are susceptible to both (102). Because it is used to treat a number of other types of infections, amikacin may be more easily obtained, and serum drug concentration measurements are readily available. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), intramuscular or intravenous, usually given as a single daily dose (5-7 days/week) initially, and then reducing to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 12-15 mg/kg per dose, two or three times per week) in persons with renal insufficiency (see below: Use in Renal Disease) (91,92). Children (maximum): 15-30 mg/kg per day (1 g/day) intramuscular or intravenous as a single daily dose. Preparations. Aqueous solution for intramuscular or intravenous injection in vials of 500 mg and 1 g. # Adverse effects. Ototoxicity: Amikacin and kanamycin may cause deafness, but they cause less vestibular dysfunction than SM (103,104). Ototoxicity is more common with concurrent use of diuretics. In one report high-frequency hearing loss occurred in 24% of patients receiving amikacin, with higher rates occurring among those receiving longer treatment and/or higher doses (105), whereas a review of the literature found only 1.5% hearing loss (106). Nephrotoxicity: Amikacin and kanamycin may be more nephrotoxic than SM (95). Renal impairment was seen in 8.7% of patients receiving amikacin, with a higher frequency in patients with initially increased creatinine levels, patients receiving larger total doses, and patients receiving other nephrotoxic agents. A frequency of 3.4% was reported in patients with no risk factors (106,107). Use in pregnancy. Both amikacin and kanamycin are contraindicated in pregnant women because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Only low concentrations of the drugs are found in CSF, although slightly higher concentrations have been found in the presence of meningitis (77). Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Amikacin and kanamycin should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufficiency, including the elderly and those receiving hemodialysis. In such patients, the dosing frequency should be reduced to two or three times per week, but the dose should be maintained at 12-15 mg/kg to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. An advantage of amikacin is that serum concentration measurements can be obtained routinely. Patients with severe hepatic disease, because of predisposition to hepatorenal syndrome, may be at greater risk for nephrotoxicity from amikacin/kanamycin and should have renal function monitored closely. # Capreomycin # Role in treatment. Capreomycin is a second-line injectable drug that is used for patients with drug-resistant tuberculosis caused by organisms that have known or presumed susceptibility to the drug (108). Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), usually given as a single daily dose five to seven times a week, and reduced to two or three times a week after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced to 12-15 mg/kg two or three times per week in persons with renal insufficiency (see below: Use In Renal Disease) (91,92). Children (maximum): 15-30 mg/kg per day (1 g/day) as a single daily or twice weekly dose. Preparations. Capreomycin is available in vials of 1 g for both intramuscular and intravenous administration. Adverse effects. Nephrotoxicity: Nephrotoxic effects may result in reduced creatinine clearance or potassium and magnesium depletion. Proteinuria is common (109). Significant renal toxicity requiring discontinuation of the drug has been reported to occur in 20-25% of patients (110,111). Ototoxicity: Vestibular disturbances, tinnitus, and deafness appear to occur more often in elderly persons or those with preexisting renal impairment (111). Use in pregnancy. Capreomycin should be avoided in pregnancy because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Capreomycin does not penetrate into the CSF (77). Use in renal disease. (see Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Capreomycin should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity (112). Because capreomycin is nearly entirely cleared by the kidneys, dosing adjustments are essential in patients with underlying renal insufficiency and end-stage renal disease, including patients undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 12-15 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (Table 15) (91,92). Smaller doses may reduce the efficacy of this drug. The drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (100,113). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. In addition, serum potassium and magnesium concentrations should be measured at baseline and at least at monthly intervals. # p-Aminosalicylic acid Role in treatment. p-Aminosalicylic acid (PAS) is an oral agent used in treatment of drug-resistant tuberculosis caused by organisms that are susceptible to the drug. Dose. See Table 3. Adults: 8-12 g/day in two or three doses. For PAS granules, 4 g three times daily has been the usual dosage (114,115). However, it has been shown that administration of 4 g twice daily is adequate to achieve the target serum concentration (116). Children: 200-300 mg/kg per day in two to four divided doses (117). Preparations. The only available formulation in the United States is granules in 4-g packets (Paser Granules®) (118). It was previously thought that the granules needed to be taken with acidic food (115); however, more recent data suggest that this is not necessary (C. Peloquin, personal communication). Tablets (500 mg) are still available in some countries. A solution for intravenous administration is available in Europe (119,120). Adverse effects. Hepatotoxicity: In a review of 7,492 patients being treated for tuberculosis, 38 (0.5%) developed hepatitis, of which 28 cases (0.3%) were attributed at least in part to PAS (121). Gastrointestinal distress: This is the most common side effect of PAS (122). In a large study of INH and PAS 11% of patients had drug toxicity, mainly gastrointestinal intolerance to PAS (114). The incidence of gastrointestinal side effects is less with lower doses (8 g daily) and with the granular formulation of the drug. Malabsorption syndrome: This is characterized by steatorrhea and low serum folate levels (123). Hypothyroidism: This is a common side effect, especially with prolonged administration or concomitant use of ethionamide. It may be accompanied by goiter formation. Thyroid hormone replacement may be required. Thyroid function returns to normal after discontinuation of the drug (124). Coagulopathy: A doubling of the prothrombin time that seemed to be lessened by coadministration of streptomycin has been reported (125). Use in pregnancy. No studies have been done in humans; however, PAS has been used safely in pregnancy. The drug should be used only if there are no alternatives (see below) for a pregnant woman who has multidrug-resistant tuberculosis. CNS penetration. In the presence of inflamed meninges, PAS concentrations are between 10-50% of those achieved in serum (119). The drug has marginal efficacy in meningitis. Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Approximately 80% of the drug is excreted in the urine (118). Unless there is no alternative, PAS is contraindicated in severe renal insufficiency because of the accumulation of the acetylated form (123,126,127). Because both PAS and acetyl-PAS are removed by dialysis, the drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (126). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The clearance of PAS is not substantially altered in liver disease, suggesting that the drug may be used in usual doses but with increased laboratory and clinical monitoring (127). Monitoring. Hepatic enzymes and thyroid function should be measured at baseline. With prolonged therapy (i.e., more than 3 months) thyroid function should be checked every 3 months. # Fluoroquinolones Role in treatment regimen. Of the fluoroquinolones (128)(129)(130)(131), levofloxacin, moxifloxacin, and gatifloxacin have the most activity against M. tuberculosis. On the basis of cumulative experience suggesting a good safety profile with long-term use of levofloxacin, this drug is the preferred oral agent for treating drug-resistant tuberculosis caused by organisms known or presumed to be sensitive to this class of drugs, or when first-line agents cannot be used because of intolerance. Data on long-term safety and tolerability of moxifloxacin and gatifloxacin, especially at doses above 400 mg/day, are limited. Cross-resistance has been demonstrated among ciprofloxacin, ofloxacin, and levofloxacin and presumably is a class effect (132). Fluoroquinolones should not be considered first-line agents for the treatment of drug-susceptible tuberculosis except in patients who are intolerant of first-line drugs. Dose. (See Table 3.) The doses given are for levofloxacin. Adults: 500-1,000 mg daily. Children: The long-term (more than several weeks) use of fluoroquinolones in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with MDR tuberculosis. The optimal dose is not known. Preparations (Levofloxacin). Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500 mg) for intravenous administration. Adverse effects. The adverse effects (133) cited are for levofloxacin. Gastrointestinal disturbance: Nausea and bloating occur in 0.5-1.8% of patients taking the drug. Neurologic effects: Dizziness, insomnia, tremulousness, and headache occur in 0.5% of patients. Cutaneous reactions: Rash, pruritis, and photosensitivity occur in 0.2-0.4% of patients. Use in pregnancy. This class of drugs should be avoided in pregnancy because of teratogenic effects (119,134). # CNS penetration. The concentration in CSF after administration of a standard dose of levofloxacin is 16-20% of that in serum (135). Interference with absorption. Because antacids and other medications containing divalent cations markedly decrease absorption of fluoroquinolones, it is critical that any fluoroquinolone not be administered within 2 hours of such medications (see Section 7.1: Interactions Affecting Antituberculosis Drugs). Use in renal disease. (See Section 8.7: Renal Insufficiency and End Stage Renal Disease.) The drug is cleared primarily (80%) by the kidney (135). Dosage adjustment (750-1,000 mg three times a week) is recommended if creatinine clearance is less than 50 ml/minute (Table 15) (136). It is not cleared by hemodialysis; supplemental doses after dialysis are not necessary (135). Use in hepatic disease. Drug levels are not affected by hepatic disease (135). It is presumed to be safe for use in the setting of severe liver disease, but as with all drugs, should be used with caution. # Principles of Antituberculosis Chemotherapy # Combination Chemotherapy The primary goals of antituberculosis chemotherapy are to kill tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the host's tissues to prevent relapse (1). To accomplish these goals, multiple antituberculosis drugs must be taken for a sufficiently long time. The theoretical model of chemotherapy for tuberculosis is founded on current understanding of the biology of M. tuberculosis in the host and on the specific activities of antituberculosis drugs. This model is supported by data from numerous in vivo and in vitro studies. It is theorized that there are three separate subpopulations of M. tuberculosis within the host. These populations are defined by their growth characteristics and the milieu in which they are located (1). The largest of the subpopulations consists of rapidly growing extracellular bacilli that reside mainly in cavities. This subpopulation, because of its size, is most likely to harbor organisms with random mutations that confer drug resistance. The frequency of these mutations that confer resistance is about 10 -6 for INH and SM, 10 -8 for RIF, and 10 -5 for EMB; thus, the frequency of concurrent mutations to both INH and RIF, for example, would be 10 -14 , making simultaneous resistance to both drugs in an untreated patient a highly unlikely event (2). INH has been shown to possess the most potent ability to kill rapidly multiplying M. tuberculosis during the initial part of therapy (early bactericidal activity), thereby rapidly decreasing infectiousness (3-5). It is followed in this regard by EMB, RIF, and SM. PZA has weak early bactericidal activity during the first 2 weeks of treatment (3,6). Drugs that have potent early bactericidal activity reduce the chance of resistance developing within the bacillary population. Early experience in clinical trials demonstrated that multiple agents are necessary to prevent the emergence of a drugresistant population as a consequence of the selection pressure from administration of a single agent. Shortly after the discovery of SM, it was demonstrated that treatment with this agent alone resulted in treatment failure and drug resistance (7). Subsequently, it was shown that the combination of PAS and SM substantially lessened the likelihood of acquired resistance and treatment failure (8). In modern regimens both INH and RIF have considerable ability to prevent the emergence of drug resistance when given with another drug. EMB and SM are also effective in preventing the emergence of drug resistance, whereas the activity of PZA in this regard is poor (9,10). For this reason PZA should not be used with only one other agent when treating active tuberculosis. The rapidly dividing population of bacilli is eliminated early in effective therapy as shown by the early clinical responses and clearing of live bacilli from sputum within 2 months in about 80% of patients. The remaining subpopulations of M. tuberculosis account for treatment failures and relapses, especially when the duration of therapy is inadequate. These residual populations include organisms that are growing more slowly, often in the acidic environment provided by areas of necrosis, and a group that is characterized by having spurts of growth interspersed with periods of dormancy. The sterilizing activity of a drug is defined by its ability to kill bacilli, mainly in these two subpopulations that persist beyond the early months of therapy, thus decreasing the risk of relapse (1). The use of drugs that have good sterilizing properties is essential for regimens as short as 6 months. RIF and PZA have the greatest sterilizing activity followed by INH and SM (11,12). The sterilizing activity of RIF persists throughout the course of therapy, but this does not appear to be true for PZA. When given in RIF-containing regimens, PZA provides additive sterilizing activity only during the initial 2 months of therapy. The sterilizing activity of PZA may not be so limited in regimens where RIF cannot be used or is not effective, so regimens for MDR tuberculosis may include PZA for the full course of treatment if the isolate is susceptible to this agent. # Optimum Duration of Treatment Truly effective chemotherapy for tuberculosis became available with the introduction of INH in the early 1950s. Adding INH to SM and PAS increased cure rates from about 70 to 95% but required treatment for 18-24 months (13). Eventually, EMB replaced PAS as the companion agent for INH (14). Subsequent investigations of combination chemotherapy sought to identify regimens that were shorter and that could be given intermittently. The British Medical Research Council (BMRC) in East Africa (15) conducted the first large-scale multicenter study of short-course (6-month) regimens. This study demonstrated that the addition of RIF or PZA to a base regimen of daily SM and INH increased the proportion of patients whose sputum cultures were negative by 2 months after the initiation of treatment and significantly reduced the relapse rate. Moreover, the relapse rate of the short-course regimens was no greater than that of the standard 18-month regimen containing SM, INH, and thiacetazone (a drug used in many countries in place of PAS or EMB). In Hong Kong, administration of a 9-month regimen of SM, INH, and PZA daily, twice weekly, or three times weekly was associated with a relapse rate of only 5-6% (16). Unfortunately, all short-course regimens that did not include RIF required fully supervised therapy and SM had to be used for the entire 9 months. Subsequent investigations conducted by the British Thoracic Association demonstrated that SM (or EMB) was necessary only for the first 2 months # Effects of Antituberculosis Chemotherapy Antituberculosis chemotherapy is designed to kill tubercle bacilli rapidly, minimize the potential for the organisms to develop drug resistance, and sterilize the host's tissues. The achievement of these effects requires that a combination of agents with specific activities be administered for a sufficiently long period of time. As a consequence of these effects, the patient is cured and has only a small likelihood of relapse. # MMWR June 20, 2003 to achieve excellent results with a 9-month treatment duration, using INH and RIF throughout (17,18). The BMRC conducted studies in Hong Kong proving that EMB was roughly as effective as SM in the initial phase of therapy, thereby demonstrating that an all-oral regimen was effective (19). The addition of PZA to a regimen containing INH and RIF enabled further shortening of the duration of therapy to 6 months. The British Thoracic Association demonstrated that a regimen of INH and RIF for 6 months, supplemented during the first 2 months with PZA and either EMB or SM, was as effective as a 9-month regimen of INH and RIF with EMB in the first 2 months (18). Administration of PZA beyond the initial 2 months in an RIF-containing regimen had no additional benefit. The efficacy of the treatment regimens was similar regardless of whether PZA was given for 2, 4, or 6 months (20). Subsequent studies of 6-month regimens have served to refine the approach used currently. USPHS Trial 21 compared self-administered INH and RIF for 6 months plus PZA given during the initial 2 months with INH and RIF for 9 months (21). EMB was added only if INH resistance was suspected. Patients taking the 6-month PZA-containing regimen had negative sputum cultures sooner after treatment was started than those treated for 9 months without PZA and relapse rates were similar for the two regimens (3.5 versus 2.8%). Investigators in Denver reported a low relapse rate (1.6%) when using a 62-dose, directly observed, 6-month regimen that consisted of 2 weeks of daily INH, RIF, PZA, and SM, 6 weeks of the same four drugs given twice weekly, and 18 weeks of twice weekly INH and RIF (22). Regimens less than 6 months in duration have been shown to have unacceptably high relapse rates among patients with smear-positive pulmonary tuberculosis (23,24). However, in a study in Hong Kong among patients with smear-negative, culture-positive tuberculosis, the relapse rate was about 2% when using a 4-month regimen of daily SM, INH, RIF, and PZA (25); among smear-negative, culture-negative cases, the relapse rate was only 1%. In Arkansas, patients with tuberculosis who had negative smears and cultures were treated with INH and RIF given daily for 1 month followed by 3 months of twice weekly INH and RIF (26). Only 3 of 126 (2.4%) patients developed active tuberculosis during 3.5 years of follow-up. Thus, it appears that a 4-month, INH-and RIF-containing regimen is effective in culture-negative tuberculosis (see Section 8.4: Culture-Negative Pulmonary Tuberculosis in Adults). # Intermittent Drug Administration Nonadherence to the antituberculosis treatment regimen is well known to be the most common cause of treatment failure, relapse, and the emergence of drug resistance. Administration of therapy on an intermittent basis, as opposed to daily dosing, facilitates supervision of therapy, thereby improving the outcome. The concept of intermittent administration of antituberculosis drugs developed from early clinical observations and was supported by subsequent laboratory investigations. First, it was noted that a single daily dose of 400 mg of INH was more effective than the same total dose given in two divided doses (27). Second, in an early study from Madras, investigators demonstrated that fully supervised twice weekly therapy could be delivered to nonhospitalized patients and that the results were better than with a conventional selfadministered daily regimen (28). These findings, plus the laboratory results noted below, led to a series of clinical trials that compared daily and intermittent dosing of antituberculosis medications. In all of these studies, intermittent regimens were demonstrated to be as effective as daily regimens and no more toxic (20). In the laboratory it was noted that in vitro exposure of tubercle bacilli to drugs was followed by a lag period of several days before growth began again (postantibiotic effect) (29)(30)(31). Thus, it was concluded that maintaining continuous inhibitory drug concentrations was not necessary to kill or inhibit growth of M. tuberculosis. Studies in guinea pigs substantiated that INH could be given at intervals as long as 4 days without loss of efficacy; however, there was a significant decrease in activity with an 8-day dosing interval (30,31). The concept of intermittent drug administration continues to evolve. Studies have demonstrated that the frequency of drug administration in the continuation phase of treatment may be decreased to once a week when using INH and rifapentine for certain highly selected patients (32)(33)(34). Because of the newness of these findings the data are presented in some detail. The results from three open-label, randomized clinical trials indicate that rifapentine given with INH once a week is safe and effective when used for the treatment of selected, HIVnegative patients with pulmonary tuberculosis. In a study performed in Hong Kong, patients with pulmonary tuberculosis were allocated at random to receive 600 mg of rifapentine and 900 mg of INH given either once every week or once every 2 of 3 weeks for 4 months after completion of a standard 2-month initial phase (32). Overall, about 11% of patients in the two rifapentine arms failed or relapsed during a 5-year follow-up period, compared with 4% of the patients who received three times weekly INH-RIF (control arm) in the continuation phase of treatment. Omitting every third dose of INH-rifapentine did not appreciably increase the relapse rate, indicating that modest nonadherence may have a negligible effect. Multivariate analyses showed that the significant prognostic factors were treatment arm, radiographic extent of disease (all three regimens), and sex (women fared better than men). The frequency of failures and relapses was also greater in all three arms if the 2-month culture was positive. The pivotal study for drug registration was conducted in North America and South Africa among HIV-negative patients with pulmonary tuberculosis (33). Patients in the experimental arm received directly observed twice weekly rifapentine together with daily self-administered INH, PZA, and EMB in the initial 2 months, followed by 4 months of once weekly directly observed rifapentine and INH. Patients in the control arm received a standard four-drug initial phase, followed by twice weekly INH-RIF. Relapse rates during 2 years of follow-up were similar to those seen in the Hong Kong study (8.2% relapse in the experimental arm versus 4.4% in the control arm), and cavitary disease, sputum culture positivity at the end of the initial phase, and nonadherence with INH, EMB, and PZA in the experimental arm were significantly associated with an increased probability of relapse. The third study was conducted by the CDC Tuberculosis Trials Consortium, and employed a design similar to the Hong Kong trial, in which HIV-negative patients were allocated at random after successful completion of standard 2-month initial phase therapy (34). Again, results, as measured by rates of failure/relapse, were remarkably similar to the first two trials, 9.2% in the experimental (INH-rifapentine once weekly) arm compared with 5.6% in the control (INH-RIF twice weekly) arm. However, as in the South Africa study, relapse was significantly associated with the presence of cavitary lesions seen on the initial chest film and sputum culture positivity at 2 months, both of which were more common in the rifapentine arm. With adjustment for these factors, the difference in outcome in the two arms was not statistically significant. Relapse rates among patients who did not have cavitary disease and had negative sputum cultures at 2 months were low in both treatment arms. However, in patients who had both cavitation and a positive culture at 2 months the relapse rate in the rifapentine arm was 22% and in the twice weekly INH-RIF arm was 21% (Table 11). In all of the cited studies, rifapentine was well tolerated, with the adverse events being similar to those occurring with RIF. A small number of HIV-positive patients were enrolled in the CDC study, but this arm was closed after the development of acquired rifampin resistance among relapse cases in the rifapentine arm (35). # Recommended Treatment Regimens # Evidence-based Rating System To assist in making informed treatment decisions based on the most credible research results, evidence-based ratings have been assigned to the treatment recommendations (Table 1). The ratings system is the same as that used in the recommendations for treating latent tuberculosis infection, in which a letter indicating the strength of the recommendation, and a roman numeral indicating the quality of the evidence supporting the recommendation, are assigned to each regimen (1). Thus, clinicians can use the ratings to differentiate among recommendations based on data from clinical trials and those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice when clinical trial data are not available. # Recommended Regimens There are four basic regimens recommended for treating adults with tuberculosis caused by organisms that are known or presumed to be susceptible to INH, RIF, PZA, and EMB (Table 2). As noted below, children, depending on the circumstances, may not receive EMB in the initial phase of a 6-month regimen, but the regimens are otherwise identical. Each regimen has an initial phase of 2 months, followed by a choice of several options for the continuation phase of either 4 or 7 months. In Table 2 the initial phase is denoted by a number (1, 2, 3, or 4) and the options for the continuation phase are denoted by the respective number and a letter designation (a, b, or c). DOT is the preferred initial management strategy for all regimens and should be used whenever feasible. All patients being given drugs less than 7 days per week (5, 3, or 2 days/week) must receive DOT. # Six-month regimens The current minimal acceptable duration of treatment for all children and adults with culture-positive tuberculosis is 6 months (26 weeks). The initial phase of a 6-month regimen for adults should consist of a 2-month period of INH, RIF, PZA, and EMB given daily throughout (Regimen 1), daily for 2 weeks followed by two times weekly for 6 weeks (Regimen 2), or three times a week (Regimen 3). The minimum number of doses is specified in Table 2. On the basis of substantial clinical experience, 5 day-a-week drug administration by DOT is considered to be equivalent to 7 day-a-week administration; thus, either may be considered "daily." Although administration of antituberculosis drugs by DOT at 5 days/week, rather than 7 days, has been reported in a large number of studies it has not been compared with 7-day administration in a clinical trial and therefore is rated AIII. The recommendation that a four-drug regimen be used initially for all patients is based on the current proportion of new tuberculosis cases caused by organisms that are resistant to INH (2). This recommendation is supported by a retrospective analysis of data from various BMRC studies indicating that in the presence of INH resistance there were fewer treatment failures and relapses if a regimen containing four drugs, INH, RIF, PZA, and EMB, was used in the initial phase (3). However, if therapy is being initiated after drug susceptibility test results are known and the organisms are susceptible to INH and RIF, EMB is not necessary. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to the first-line agents. In most situations these results are not available before 6-8 weeks after treatment is begun. The continuation phase of treatment should consist of INH and RIF given for a minimum of 4 months (18 weeks). Patients should be treated until they have received the specified total number of doses for the treatment regimen (Table 2). The continuation phase can be given daily (Regimen 1a), twice weekly (Regimens 1b and 2a), or three times weekly (Regimen 3a). The continuation phase should be extended for an additional 3 months for patients who have cavitation on the initial or follow-up chest radiograph and are culture-positive at the time of completion of the initial phase of treatment (2 months). Patients who are HIV negative, who do not have cavities on the chest radiograph, and who have negative sputum AFB smears at completion of the initial phase of treatment may be treated with once weekly INH and rifapentine in the continuation phase for 4 months. If the culture of the sputum obtained at 2 months is positive, observational data and expert opinion suggest that the continuation phase of once weekly INH and rifapentine should be 7 months (4). # Nine-month regimen If PZA cannot be included in the initial regimen, or if the isolate is determined to be resistant to PZA (an unusual circumstance, except for Mycobacterium bovis and M. bovis var. BCG), a regimen consisting of INH, RIF, and EMB should be given for the initial 2 months (Regimen 4) followed by INH and RIF for 7 months given either daily or twice weekly (Regimens 4a and 4b). # Alternative regimens In some cases, either because of intolerance or drug resistance, the above-described regimens cannot be used. In these instances, an alternative regimen may be required. In a retrospective analysis of the combined results of clinical trials conducted by the BMRC it was concluded that, in the presence of initial resistance to INH, if a four-drug regimen containing RIF and PZA was used in the initial phase and RIF was used throughout a 4-month continuation phase there were no treatment failures and 7% relapses compared with 4% relapses among patients with fully susceptible strains (3). Data from a Hong Kong BMRC study suggest that in the presence of INH resistance results are better when PZA is used throughout (5). On the basis of these data, when INH cannot be used or the organisms are resistant to INH, a 6-month regimen of RIF, PZA, and EMB is nearly as efficacious as an INH-containing regimen (Rating BI) (3). Alternatively, RIF and EMB for 12 months may be used, preferably with PZA during at least the initial 2 months (Rating BII) (5,6). If RIF is not used, INH, EMB, and FQN should be given for a minimum of 12-18 months supplemented with PZA during at least the initial 2 months (Rating BIII). An injectable agent may also be included for the initial 2-3 months for patients with more extensive disease or to shorten the duration (e.g., to 12 months), (7,8). Levofloxacin, moxifloxacin, or gatifloxacin may be useful in alternative regimens, but the potential role of a fluoroquinolone and optimal length of therapy have not been defined (9,10). In situations in which several of the first-line agents cannot be used because of intolerance, regimens based on the principles described for treating multiple drugresistant tuberculosis (Section 9.3: Management of Tuberculosis Caused by Drug-Resistant Organisms) should be used. # Deciding to Initiate Treatment The decision to initiate combination chemotherapy for tuberculosis should be based on epidemiologic information, clinical and radiographic features of the patient, and the results of the initial series of AFB smears (preferably three) and, subsequently, cultures for mycobacteria. Rapid amplification tests, if used, can also confirm the diagnosis of tuberculosis more quickly than cultures. On the basis of this information, the likelihood that a given patient has tuberculosis can be estimated. For example, a patient who has emigrated recently from a high-incidence country, has a history of cough and weight loss, and has characteristic findings on chest radiograph should be considered highly likely to have tuberculosis. In such situations combination drug therapy should be initiated, even before AFB smear and mycobacterial culture results are known. Empirical treatment with a fourdrug regimen should be initiated promptly when a patient is seriously ill with a disorder that is thought possibly to be tuberculosis. Initiation of treatment should not be delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. Disseminated (miliary) tuberculosis, for example, is often associated with negative sputum AFB smears. Likewise, for a patient with suspected tuberculosis and a high risk of transmitting M. tuberculosis if, in fact, she or he had the disease, combination chemotherapy should be initiated in advance of microbiological confirmation of the diagnosis to minimize potential transmission. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, or is strongly inferred from clinical or radiographic improvement consistent with a response to treatment, the regimen can be continued to complete a standard course of therapy (Figure 1). A PPD-tuberculin skin test may be done at the time of initial evaluation, but a negative test does not exclude the diagnosis of active tuberculosis. However, a positive skin test supports the diagnosis of culture-negative pulmonary tuberculosis or, in persons with stable abnormal chest radiographs consistent with inactive tuberculosis, a diagnosis of latent tuberculosis infection (see below). If the cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and there is no response to treatment, the options are as follows: 1) stop treatment if RIF and PZA have been given for at least 2 months; 2) continue treatment with RIF, with or without INH, for a total of 4 months; or 3) continue treatment with INH for a total of 9 months (11). All three of these options provide adequate therapy for persons with prior tuberculosis once active disease has been excluded. If clinical suspicion for active tuberculosis is low, the options are to begin treatment with combination chemotherapy or to defer treatment until additional data have been obtained to clarify the situation (usually within 2 months) (Figure 2, top). Even when the suspicion of active tuberculosis is low, treatment for latent tuberculosis infection with a single drug should not be initiated until active tuberculosis has been excluded. In low-suspicion patients not initially treated, if cultures remain negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, there are three treatment options (Figure 2, top) (11). The preferred options are INH for 9 months or RIF, with or without INH, for 4 months. RIF and PZA for a total of 2 months can be used for patients not likely to complete a longer regimen and who can be monitored closely. However, this last regimen has been associated with an increased risk of hepatotoxicity and should be used only in the limited circumstances described (12,13). An advantage of the early use of combination chemotherapy is that, once active disease is excluded by negative cultures and lack of clinical or radiographic response to treatment, the patient will have completed 2 months of combination treatment that can be applied to the total duration of treatment recommended for latent tuberculosis infection (Figure 2, bottom). # Baseline and Follow-Up Evaluations Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained 8-24 hours apart. In patients who are not producing sputum spontaneously, induction of sputum using aerosolized hypertonic saline or bronchoscopy (performed under appropriate infection control procedures) may be necessary to obtain specimens. Susceptibility testing for INH, RIF, and EMB should be performed on an initial positive culture, regardless of the source. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, have been in contact of a patient with known drug resistance, have demonstrated resistance to rifampin or two other first-line drugs, or who have positive cultures after more than 3 months of treatment. At the time treatment is initiated, in addition to the microbiologic examinations, it is recommended that all patients with tuberculosis have counseling and testing for HIV infection (14). Patients with epidemiologic factors suggesting a risk for hepatitis B or C, for example, injection drug use, birth in Asia or Africa, or HIV infection, should have serologic tests for these viruses (15,16). HIV-infected patients should also undergo CD4 + lymphocyte count measurement. Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all adults. Testing of visual acuity (Snellen chart) and color vision (Ishihara tests) should be performed when EMB is to be used. During treatment of patients with pulmonary tuberculosis, at a minimum, a sputum specimen for AFB smear and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture. As described subsequently, important decisions concerning the continuation-phase regimen hinge on the microbiological status at the end of the initial phase of treatment, thus, obtaining sputum specimens at this juncture is critical, if sputum conversion to negative has not already been documented. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations in which the risk of transmission is high. On occasion, AFB-positive sputa are culture negative; this occurs most frequently among patients with far advanced cavitary tuberculosis after the first months of treatment. It is thought that these organisms are dead and that their presence is not a sign of treatment failure, even if noted later in treatment. However, repeat cultures should be obtained to confirm that the earlier culture result was correct and not a false negative. Drug susceptibility tests should be repeated on isolates from patients who have positive cultures after 3 months of treatment. As described in Section 9.2 (Treatment Failure), patients who have positive cultures after 4 months of treatment should be considered as having failed treatment and managed accordingly. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained. In addition to the microbiological evaluations, it is essential that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. For patients with positive cultures at diagnosis, a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential. A chest radiograph at completion of therapy provides a baseline against which subsequent examinations can be compared, but, as with the 2-month examination, it is not essential. When the initial sputum cultures are negative, a presumptive diagnosis can be made if radiographic improvement is noted, generally by the time 2 months of treatment has been completed. Thus, in patients with negative initial cultures, a chest radiograph is necessary after 2 months of treatment and a radiograph at completion of treatment is desirable. Generally, follow-up after completion of therapy is not necessary. As a routine, it is not necessary to monitor liver or renal function or platelet count for patients being treated with firstline drugs unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements. Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening. Patients receiving EMB should be questioned regarding visual disturbances at monthly intervals; monthly repeat testing of visual acuity and color vision is recommended for patients receiving an EMB dose exceeding 15-20 mg/kg (the recommended range) and for patients receiving the drug for more than 2 months. Monitoring tests for the individual second-line drugs are listed in Section 3: Drugs in Current Use. # Identification and Management of Patients at Increased Risk of Relapse The result of a sputum culture at the conclusion of the initial phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis. In seven clinical trials performed by the BMRC, the regimens that had the highest proportion of patients with a positive sputum culture at 2 months after treatment was initiated were associated with a higher likelihood of relapse within 2 years (17). Of greater relevance to the current recommendations, data from USPHS Trial 22 comparing once weekly rifapentine and INH with twice weekly RIF and INH, showed an increased rate of relapse in patients who had a positive culture at 2 months in both study arms (18). Cavitation on the initial chest radiograph was also an independent risk factor for relapse. In patients in the control arm (twice weekly INH-RIF) the presence of both cavitation and a positive culture at completion of 2 months of therapy # Patients At Increased Risk of Relapse Patients who have cavitation on initial chest radiograph and who have a positive culture at completion of 2 months of therapy are at substantially increased risk of relapse. For these patients it is recommended that the continuation phase of treatment be prolonged to 7 months, making a total treatment period of 9 months. was associated with a 21% rate of relapse, compared with 2% for patients who had neither risk factor (Table 11). Similar findings were reported in a retrospective analysis of data from BMRC trials (17) and from a USPHS trial conducted in Poland (19). The most effective means of decreasing the likelihood of relapse for patients at increased risk has not yet been determined by clinical trials. However, in a controlled trial of treatment for silicotuberculosis in Hong Kong, prolongation of the continuation phase from 4 to 6 months decreased the rate of relapse from 22 to 7% (p <0.025) (20). Also in studies from Hong Kong, it was found that increasing the duration of PZA beyond the 2-month initial phase did not improve the efficacy of RIF-containing regimens (21). It has been reported that for patients at high risk of relapse, prolongation of the once weekly INH-rifapentine continuation phase from 4 to 7 months resulted in significantly better results compared with patients in an earlier trial (4). In view of this evidence and on the basis of expert opinion, it is recommended that treatment for patients who have cavitation noted on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy should be extended with INH and RIF for an additional 3 months for a total of 9 months (Rating AIII). In USPHS Study 22 patients treated with INH and RIF twice weekly in the continuation phase who had either cavitation on the initial chest radiograph or a positive culture at 2 months had approximately a 5-6% rate of relapse (Table 11) (18). This rate of adverse outcomes is not deemed to be sufficient to recommend prolongation of the continuation phase; however, patients with one or the other of these risk factors should be monitored more closely and consideration given to lengthening treatment if there are suggestions of a poor response. Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being more than 10% underweight at diagnosis, having HIV infection, or having extensive involvement on chest radiograph. Patients with noncavitary pulmonary tuberculosis and a negative AFB smear at 2 months who are started on the once weekly rifapentine-INH continuation phase and are subsequently found to be culture positive at 2 months should have treatment extended by an additional 3 months for a total of 9 months. # Definition of Completion of Therapy Treatment for a defined duration without accounting for the number of doses taken can result in undertreatment. Therefore, the determination of whether or not treatment has been completed is based on the total number of doses taken-not solely on the duration of therapy (Table 2). For example, the 6-month daily (given 7 days/week) regimen should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. If the drugs are administered by DOT at 5 days/week, the minimum number of doses is 130. A similar reduction in the target number of doses for 5-day-a-week administration applies to any of the regimens with a daily component. In some cases, either because of drug toxicity or nonadherence to the regimen, the specified number of doses cannot be administered within the targeted time period. In such cases, it is recommended that all of the specified number of doses for the initial phase be delivered within 3 months and those for the 4-month continuation phase be delivered within 6 months, so that the 6-month regimen should be completed within 9 months. If these targets are not met the patient must be considered to have interrupted therapy and be managed as described below. # Interruptions in Therapy Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. This decision depends in part on whether the interruption occurred during the initial or the continuation phase of therapy. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart the treatment from the beginning. Continuous treatment is more important in the initial phase of therapy, when there is the highest bacillary population and the chance of developing drug resistance is greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriological status of the patient before and after the interruption are also important considerations. There is no evidence on which to base detailed recommendations for managing interruptions in treatment, and no recommendations will cover all of the situations that may arise. The following approach (summarized in Figure 5), modified from the New York City Bureau of Tuberculosis Control Clinical Policies and Protocols (22), is presented as an example. If the interruption occurs during the initial phase of treatment and the lapse is 14 days or more in duration, treatment should be restarted from the beginning. However, if the lapse is less than 14 days, the treatment regimen should be continued. In either instance the total number of doses targeted for the initial phase should be given. If the interruption in treatment occurs during the continuation phase after the patient has received more than 80% of the planned total continuation phase doses given by DOT, further treatment may not be necessary if the patient's sputum was AFB smear negative on initial presentation. However, for patients who were smear positive initially, continued treatment to complete the planned total number of doses is warranted. If the patient has received less than 80% of the planned total doses and the lapse is 3 months or more in duration, treatment should be restarted from the beginning. If the lapse is less than 3 months in duration, treatment should be continued to complete a full course. At the time the patient is returned to treatment sputum cultures should be obtained and repeat drug susceptibility testing performed. If the cultures are still positive, the treatment regimen should be restarted. If sputum cultures are negative the patient could be treated as having culture-negative tuberculosis and given an additional 4 months of combination chemotherapy. Regardless of the timing and duration of the interruption, DOT should be used. If the patient was already being managed with DOT, additional measures will be necessary to ensure completion of therapy. Consultation with an expert is recommended to assist in managing treatment interruptions. # Practical Aspects of Treatment # Drug Administration The first-line antituberculosis medications should be administered together as single dose rather than in divided doses. A single dose leads to higher, and potentially more effective, peak serum concentrations. Administering a single daily dose also facilitates using DOT. Ingestion with food delays or moderately decreases the absorption of antituberculosis drugs (1). However, given the wide therapeutic margin of the first-line agents, the effects of food are of little clinical significance. Thus, if patients have epigastric distress or nausea with the first-line drugs, dosing with food is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. The absorption of INH can be substantially decreased when the drug is ingested with glucose or lactose. Because of this effect, the commercial preparation of INH elixir uses sorbitol for flavor, rather than glucose or lactose. However, sorbitol can cause diarrhea, limiting the acceptability of the commercial INH elixir. Administration of crushed INH tablets in a food with relatively low concentrations of glucose, such as applesauce, has not been formally evaluated, but has been used successfully by many providers. Antacids have minimal effects on the absorption of the first-line antituberculosis drugs. With the exception of fluoroquinolones, there is little information regarding the effect of food and antacids on the second-line antituberculosis drugs. In the absence of data, it is preferable to administer the drugs on an empty stomach if they are tolerated. However, antacids and other medications containing divalent cations markedly decrease the absorption of the fluoroquinolones, an interaction that has been associated with failure of antibiotic therapy (2,3). Therefore, it is critical that any fluoroquinolone not be administered within 2 hours of a dose of antacids, the chewable tablet form of didanosine, sucralfate, iron, magnesium, calcium, zinc, or vitamins or dietary supplements (e.g., Ensure ® , Sustical ® ) containing a significant amount of these cations. Parenteral therapy is indicated for severely ill patients who cannot take oral therapy and may be useful for the uncommon patient for whom poor absorption has been documented. Preparations of INH, RIF, the aminoglycosides, capreomycin, and most fluoroquinolones are available for intravenous administration. # Fixed-Dose Combination Preparations There are two fixed-dose combination preparations currently available for use in the United States, a combination of INH and RIF (Rifamate ® ) and a combination of INH, RIF, and PZA (Rifater ® ) (see Section 3: Drugs in Current Use). (A fourdrug combination of INH, RIF, EMB, and PZA is available in some countries.) Two tablets of Rifamate ® provide conventional daily doses of both INH (300 mg) and RIF (600 mg). The Rifater ® tablet that is available in the United States contains INH (50 mg), RIF (120 mg), and PZA (300 mg). Six tablets of Rifater ® would provide INH (300 mg) RIF (720 mg), and PZA (1,800 mg). The RIF dose is higher than is used typically in the United States because the RIF is less bioavailable in this formulation. These fixed-dose combinations have been formulated for use in daily therapy, although some programs use Rifamate ® plus INH tablets for twice weekly treatment. It should be noted that the dose of PZA in Rifater ® is such that additional PZA tablets will be required to provide an adequate dose for persons weighing more than 90 kg. Although there is no evidence indicating that fixed-dose combination medications are superior to individual drugs, expert opinion suggests that these formulations should be used when DOT is given daily and when DOT is not possible. Moreover, they are strongly recommended in international recommendations of the WHO and IUATLD. The theoretical advantage of reducing the risk of inadvertent monotherapy, the ease of administration, and the potential for reducing medication errors make them preferable to individual medications in many instances. When prescribing a fixed-dose combination preparation, care must be taken because of the similarity of the trade names of RIF (Rifadin ® ) and the fixeddose combinations (Rifamate ® , Rifater ® ). # Management of Common Adverse Effects As is true with all medications, combination chemotherapy for tuberculosis is associated with a predictable incidence of adverse effects, some mild, some serious. A comprehensive list of reported adverse reactions and their frequency is described in Section 3: Drugs in Current Use. Mild adverse effects can generally be managed with symptomatic therapy, whereas with more severe effects the offending drug or drugs must be discontinued. Although it is important to be attuned to the potential for adverse effects it is at least equally important that first-line drugs not be stopped without adequate justification. The following is a summary, based largely on clinical experience and expert opinion, of the approaches that should be taken in managing the common adverse effects of tuberculosis treatment. Proper management of more serious adverse reactions often requires expert consultation. # Gastrointestinal upset: nausea, vomiting, poor appetite, abdominal pain Gastrointestinal reactions are common, particularly in the first few weeks of therapy. Many of the antituberculosis drugs can cause gastrointestinal upset (4). In the presence of gastrointestinal symptoms serum AST and bilirubin should be measured. If the AST level is less than three times the upper limit of normal, the symptoms are assumed not to be due to hepatic toxicity. However, if the AST level is three or more times the upper limit of normal the symptoms should be assumed to represent hepatic toxicity, and the patient should be evaluated as described below. The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity, is to change the hour of drug administration and/or to administer the drugs with food. If patients are taking daily DOT, the timing of the drug administration should be altered, preferably to be closer to mealtime. Alternatively, food can be taken at the time of DOT administration. (In many programs food is offered as an incentive with DOT.) Patients receiving self-administered therapy can take the medications at bedtime. If gastrointestinal intolerance persists it may be best for all medications to be taken with meals. # Rash All drugs used in treating tuberculosis can cause a rash. The response to a patient with a rash depends on its severity. The rash may be minor, affecting a limited area or being predominantly manifested as itching, in which case antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued. A petechial rash may suggest thrombocytopenia in patients taking RIF (5). The platelet count should be checked and, if low, RIF hypersensitivity should be presumed to be the cause. RIF should be stopped and the platelet count monitored until it returns to baseline; RIF should not be restarted. If there is a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement, all drugs should be stopped immediately. If the patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral agents) should be started. When the rash is substantially improved the medications can be restarted one by one, at intervals of 2-3 days. RIF should be restarted first (because it is the least likely to cause rash, and it is the most important agent), followed by INH, and then EMB or PZA. If the rash recurs the last drug added should be stopped. If no rash appears after the first three drugs have been restarted, the fourth drug should not be restarted unless the rash was relatively mild and the fourth drug is considered essential for therapy. # Drug fever Recurrence of fever in a patient who has been receiving therapy for several weeks should suggest drug fever, especially if the patient is showing microbiological and radiographic improvement. It should be noted, however, that fever from tuberculosis may persist for as long as 2 months after therapy has been initiated (6). Fever may also be a manifestation of a paradoxical reaction, especially in patients with HIV infection (see Section 8.1: HIV Infection) (7). The clinical hallmark of drug fever is that the patient looks and feels well despite having a high fever (often greater than 39 º C). There is no specific pattern to the fever. Eosinophilia may or may not be present. The first step in management of a possible drug fever is to ensure that there is no superinfection or worsening of tuberculosis. If these potential causes are excluded all drugs should be stopped. Drug-related fever usually will resolve within 24 hours. Patients with severe tuberculosis should be given at least three new drugs in the interim. Once the fever has resolved, the same protocol as described above for restarting drugs in the presence of a rash should be followed. # Hepatitis (Management of patients with baseline abnormal liver function is described in Section 8.8: Hepatic Disease.) Three of the first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury (AST level three or more times the upper limit of normal in the presence of symptoms, or five or more times the upper limit of normal in the absence of symptoms) (8). If the AST level is less than 5 times the upper limit of normal, toxicity can be considered mild, an AST level 5-10 times normal defines moderate toxicity, and an AST level greater than 10 times normal (i.e., greater than 500 IU) is severe (9). In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase. This pattern is more consistent with rifampin hepatotoxicity It is important to note that an asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen (10). In the absence of symptoms therapy should not be altered because of modest asymptomatic elevations of AST, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic aminotransferase elevations resolve spontaneously. However, if AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms, hepatotoxic drugs should be stopped immediately and the patient evaluated carefully. Similarly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation. Serologic testing for hepatitis A, B, and C should be performed and the patient questioned carefully regarding symptoms suggestive of biliary tract disease and exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications. Drug-induced hepatitis is usually a diagnosis of exclusion but in view of the frequency with which other possible causes are present in any given patient, determining the cause may be difficult. Because the schedule for restarting antituberculosis medications is slower with hepatitis than for rash or drug fever it is generally prudent to give at least three nonhepatotoxic antituberculosis drugs until the specific cause of hepatotoxicity can be determined and an appropriate longer term regimen begun. The suspect antituberculosis medications should be restarted one at a time after the AST concentration returns to less than two times the upper limit of normal. (In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels.) Because RIF is much less likely to cause hepatotoxicity than is INH or PZA (Table 10) (10) and is the most effective agent, it should be restarted first. If there is no increase in AST after about 1 week, INH may be restarted. PZA can be started 1 week after INH if AST does not increase. If symptoms recur or AST increases the last drug added should be stopped. If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months. # Serum Drug Concentration Measurements The first-line drugs (INH, RIF, PZA, and EMB) have relatively predictable pharmacokinetics (11,12) and are highly efficacious when given in standard doses as DOT (13,14). Rarely, patients may have poor absorption or altered metabolism of the first-line drugs, resulting in failure of therapy (15,16) Second-line agents have a much narrower therapeutic window (the range of concentrations having reliable activity against M. tuberculosis but rarely causing toxicity) than the first-line drugs, and the consequences of treatment failure of drugresistant tuberculosis may be difficult to manage. These considerations suggest several clinical situations in which therapeutic drug monitoring may be helpful: 1) patients with treatment failure that is not explained by nonadherence or drug resistance, 2) persons with medical conditions that may result in abnormal pharmacokinetics of the first-line drugs, and 3) the management of multidrug-resistant tuberculosis with second-line drugs. Be aware, however, that there are many uncertainties about the use of therapeutic drug monitoring in tuberculosis treatment. An important limitation is the lack of sufficient data to formulate clinically validated therapeutic ranges for antituberculosis agents. One response to the lack of clinically derived therapeutic ranges for the rifamycins is to use the distribution of concentrations achieved in healthy volunteers as the therapeutic range. However, in practice this approach has been quite problematic. For example, serum concentrations of the first-line drugs among HIV-infected patients with active tuberculosis are frequently lower than those in healthy volunteers (17,18), but HIV-related tuberculosis responds well to standard tuberculosis treatment regimens (19,20). The disadvantages of therapeutic drug monitoring are as follows: 1) the time necessary, from both patients and providers, to obtain and ship blood samples, and 2) the relatively high cost of measuring serum drug concentrations. Until more data are available, it seems prudent to restrict therapeutic drug monitoring for the first-line drugs to patients who are having an inadequate response to DOT (that is not due to nonadherence or drug resistance) or evidence of severe gastrointestinal or metabolic abnormalities. Examples of such circumstances include severe gastroparesis, short-bowel syndrome, chronic diarrhea with malabsorption, and renal insufficiency. As described above, patients with HIV-related tuberculosis may have an increased incidence of malabsorption of antituberculosis drugs (although some studies have contrary findings) (21,22). Even if true, this tendency for lower drug concentrations among patients with HIV-related tuberculosis is not sufficient to warrant routine therapeutic drug monitoring in this population. # Drug Interactions # Interactions Affecting Antituberculosis Drugs Drug-drug interactions can result in changes in the concentrations of one or both of the drugs involved. In the case of the antituberculosis drugs, there are relatively few interactions that substantially change the concentrations of the antituberculosis drugs; much more often the antituberculosis drugs cause clinically relevant changes in the concentrations of other drugs. The exceptions to this general rule are rifabutin and the fluoroquinolones. Rifabutin is partially metabolized by cytochrome P450 (CYP) 3A. Inhibitors of CYP3A increase serum concentrations of rifabutin and one of its metabolites (25-O-desacetyl-rifabutin), sometimes to toxic levels. For example, administration of ritonavir, a potent CYP3A inhibitor, with the standard daily dose of rifabutin (300 mg) increases the serum concentrations of rifabutin (4-fold increase) and 25-O-desacetyl-rifabutin (35-fold increase) (1) and is associated with increased rates of leukopenia, arthralgias, skin discoloration, and uveitis (2), all recognized to be toxic effects of rifabutin or one of its metabolites (3,4). Conversely, administering rifabutin with a CYP3A inducer decreases its concentrations, perhaps to ineffective levels. For example, efavirenz, a potent antiretroviral drug, decreases rifabutin serum concentrations by approximately one-third (5). Recommendations for making dose adjustments of rifabutin when it is given with commonly used CYP3A inhibitors and inducers are available (6,7). However, the complexity of these interactions and the rapidly changing nature of antiretroviral therapy strongly suggest that the management of cases of HIVrelated tuberculosis should involve a physician with experience in this field. Absorption of the fluoroquinolones is markedly decreased by ingestion with medications containing divalent cations (calcium, iron, zinc), including antacids (8,9); supplements or vitamins containing calcium, iron or zinc (10), sucralfate (11); and the chewable tablet formulation of didanosine (12). These drug interactions can be avoided by assuring that medications containing divalent cations are ingested at least 2 hours apart from doses of fluoroquinolones (13). # Effects of Antituberculosis Drugs on Other Drugs # Drug interactions due to rifamycins The drugs used to treat tuberculosis affect the metabolism of many other drugs, and can result in a lack of efficacy (interactions with the rifamycins) or toxicity (interactions with isoniazid and the fluoroquinolones). Most of the clinically relevant drug-drug interactions involving the antituberculosis drugs are due to the effect of the rifamycins (rifampin, rifabutin, and rifapentine) on the metabolism of other drugs. All of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 system (14)(15)(16)(17)(18). By inducing the activity of metabolic enzymes, rifamycin therapy results in a decrease in the serum concentrations of many drugs, sometimes to levels that are subtherapeutic. The rifamycins differ substantially in their potency as enzyme inducers; rifampin is the most potent, rifapentine is intermediate, and rifabutin is the least potent enzyme inducer (19). The well-described, clinically relevant drug-drug interactions involving the rifamycins are presented in Table 12 (1,5,15,. However, it is important to note that many possible interactions involving the rifamycins have not been investigated fully and additional clinically relevant interactions undoubtedly will be described. Therefore, it is important to check all concomitant medications for possible, as well as confirmed, drug-drug interactions with rifamycins. Some of these drug-drug interactions can be managed with close clinical or laboratory monitoring and dose increases of the medication(s) affected by the rifamycins (Table 12). In other cases, the magnitude of the decrease in concentrations of a concomitant medication may be such that serum concentrations cannot be restored by a dose increase. If the dose of a medication is increased to compensate for the effect of a rifamycin, it is critical to remember that the dose of this drug will probably need to be decreased within the 2 weeks after the rifamycin is discontinued and its inductive effect resolves. In some situations, rifabutin can sometimes be used in place of rifampin, if there is an unacceptable drug-drug interaction between rifampin and another drug, such as cyclosporine (51) and most of the HIV-1 protease inhibitors (89). All the rifamycins may cause unacceptable decreases in the serum concentrations of certain drugs, such as delavirdine (26,27,90), ketoconazole and itraconazole (34,91). # Drug interactions due to isoniazid Isoniazid is a relatively potent inhibitor of several cytochrome P450 isozymes (CYP2C9, CYP2C19, and CYP2E1) ( 92), but has minimal effect on CYP3A (20). As an inhibitor, isoniazid can increase concentrations of some drugs to the point of toxicity. The clearest examples of toxicity due to the inhibitory activity of isoniazid are the anticonvulsants, phenytoin (93,94) and carbamazepine (95,96). Isoniazid also increases concentrations of benzodiazepines metabolized by oxidation, such as diazepam (85) and triazolam (97), but not those metabolized by conjugation, such as oxazepam (97). It is worth noting that rifampin has the opposite effect on the serum concentrations of many of these drugs. The available data demonstrate that the inductive effect of rifampin outweighs the inhibitory effect of isoniazid, so that the overall effect of combined therapy with rifampin and isoniazid is a decrease in the concentrations of drugs such as phenytoin (59) and diazepam (85). Isoniazid may increase toxicity of other drugsacetaminophen (98), valproate (99), serotonergic antidepressants (100), disulfiram (101), warfarin (102), and theophylline (103)-but these potential interactions have not been well studied. # Drug interactions due to fluoroquinolones Ciprofloxacin (104) inhibits the metabolism of theophylline and can cause clinical theophylline toxicity (105). However, levofloxacin (106), gatifloxacin (107), and moxifloxacin (108) do not affect theophylline metabolism. Benzodiazepines (e.g., diazepam [85], triazolam [86]), zolpidem (87), buspirone (88) # Comments Can be used with rifabutin. Ritonavir, 400-600 mg twice daily, probably can be used with rifampin. The combination of saquinavir and ritonavir can also be used with rifampin. Delavirdine should not be used with any rifamycin. Doses of nevirapine (28) and efavirenz (29) need to be increased if given with rifampin, no dose increase needed if given with rifabutin (5). Azithromycin has no significant interaction with rifamycins. May require use of a drug other than doxycycline. Itraconazole, ketoconazole, and voriconazole concentrations may be subtherapeutic with any of the rifamycins. Fluconazole can be used with rifamycins, but the dose of fluconazole may have to be increased. Consider alternate form of Pneumocystis carinii treatment or prophylaxis. Consider an alternative antibiotic. Consider alternate form of malaria prophylaxis. Women of reproductive potential on oral contraceptives should be advised to add a barrier method of contraception when taking a rifamycin. May require alternate therapy or use of a nonrifamycin-containing regimen. Monitoring of serum TSH recommended; may require increased dose of levothyroxine. Rifampin and rifapentine use may require methadone dose increase; rifabutin infrequently causes methadone withdrawal. Monitor prothrombin time; may require two-to threefold dose increase. Rifabutin may allow concomitant use of cyclosporine and a rifamycin; monitoring of cyclosporine serum concentrations may assist with dosing. Monitor clinically; may require two-to threefold increase in corticosteroid dose (58). Therapeutic drug monitoring recommended; may require anticonvulsant dose increase. Clinical monitoring recommended; may require change to an alternate cardiovascular agent. Clinical monitoring recommended; may require dose increase or change to an alternate cardiovascular drug. Monitor clinically; may require a dose increase or use of an alternate cardiovascular drug. Therapeutic drug monitoring recommended; may require digoxin or digitoxin dose increase. Therapeutic drug monitoring recommended; may require quinidine dose increase. Clinical monitoring recommended; may require change to an alternate cardiovascular drug. Therapeutic drug monitoring recommended; may require theophylline dose increase. Monitor blood glucose; may require dose increase or change to an alternate hypoglycemic drug. Monitor hypolipidemic effect; may require use of an alternate hypolipidemic drug. Therapeutic drug monitoring recommended; may require dose increase or change to alternate psychotropic drug. Monitor clinically; may require a dose increase or use of an alternate psychotropic drug. Monitor clinically; may require a dose increase or use of an alternate psychotropic drug. # Treatment in Special Situations # HIV Infection Treatment of tuberculosis in patients with HIV infection follows the same principles as treatment of HIV-uninfected patients. However, there are several important differences between patients with and without HIV infection. These differences include the potential for drug interactions, especially between the rifamycins and antiretroviral agents, paradoxical reactions that may be interpreted as clinical worsening, and the potential for the development of acquired resistance to rifamycins when treated with highly intermittent therapy. # Clinical trials of treatment for tuberculosis in HIV-infected patients There have been seven prospective studies of 6-month regimens for the treatment of pulmonary tuberculosis in patients with HIV infection for which recurrence data were reported. Four of the studies were randomized, controlled trials (1-4), and three were observational in nature (5,6). These studies differed somewhat in design, patient population, eligibility criteria, frequency of dosing, treatment supervision, and outcome definitions; therefore, it is difficult to provide meaningful cross-study comparisons. All of the studies reported a good early clinical response to therapy and the time required for sputum culture conversion from positive to negative and treatment failure rates were similar to these indices of treatment efficacy in patients without HIV infection. Recurrence rates have varied among studies, with most reporting rates of 5% or less (2,3,5,6). In one study from the Democratic Republic of Congo (formerly Zaire), in which the recurrence rate in the 6-month arm was 9% compared with 3% in the 12-month arm, nonadherence in the continuation phase and/or exogenous reinfection may have contributed to the higher recurrence rate (1). In a randomized trial of once weekly INH-rifapentine versus twice weekly INH-RIF in the continuation phase of therapy, 5 of 30 (17%) HIVinfected patients receiving treatment in the once weekly arm relapsed compared with 3 of 31 (10%) patients in the twice weekly INH-RIF arm (4). Four of the five relapsed patients in the once weekly group had resistance to rifampin alone compared with none in the standard treatment arm. Because of the small sample size in the standard treatment arm, it is difficult to interpret the relapse rate of 10%. In an observational study of twice weekly INH-rifabutin among HIV-infected tuberculosis patients also receiving antiretroviral therapy, 7 of 156 patients failed treatment or relapsed (7). Although the life table rate of failure/relapse was low (4.6%), M. tuberculosis isolated from all five of these patients was resistant to RIF alone. The phenomenon of acquired rifampin monoresistance was also seen in a trial of largely twice weekly INH-RIF therapy, albeit at a lower rate (3). In all of these studies, acquired RIF resistance occurred only among patients with CD4 + cell counts <100 cells/µl. Acquired rifampin resistance has not been seen in trials where RIF was given daily. A consistent finding in the treatment studies has been a high mortality rate among HIV-seropositive patients. In most studies the cause of death is difficult to ascertain. Early mortality may be related to advanced tuberculosis, but deaths during the continuation phase of therapy are usually due to other AIDS-related conditions. Mortality during treatment among HIV-infected patients with tuberculosis has been associated with advanced HIV disease (1,3,6,8). However, the use of effective antiretroviral therapy during the treatment of tuberculosis in persons with HIV infection may improve treatment outcomes and, thus, is recommended, as described subsequently (9). A major concern in treating tuberculosis in the setting of HIV infection is the interaction of RIF with antiretroviral agents (see Section 7: Drug Interactions, and Table 12). As described previously, rifabutin is highly active against M. tuberculosis but has less of an effect in inducing hepatic microsomal enzymes than RIF. Data from clinical trials suggest that rifabutin and RIF-based regimens are equally efficacious. Gonzalez-Montaner and colleagues (10) reported the first randomized clinical trial comparing rifabutin (150 and 300 mg) with RIF in a 6-month regimen in persons without HIV infection. The outcomes were highly favorable in both groups and there were few adverse reactions. Investigators from South Africa reported a randomized, open-label trial comparing rifabutin with RIF in a standard four-drug regimen administered with DOT (11). Although patients did not have HIV testing performed, the HIV seroprevalence was reportedly low at the time of the study. In the continuation phase, the medications were given twice weekly. By 2 months after treatment was begun, 88% of the patients in the RIF arm and 92% of those given rifabutin had negative sputum cultures. The relapse rate was 3.8% in the RIF group versus 5.1% in the rifabutin group (p = NS). Only one study examining the effectiveness of rifabutin included HIV-infected patients (12). A single blind randomized study of 50 HIV-infected patients in Uganda compared a fully supervised regimen of RIF versus rifabutin together with INH, EMB, and PZA. Time to sputum conversion was similar between groups when controlling for baseline characteristics. Relapse data were not available. Investigators in Uganda have reported a higher mortality rate among HIV-infected patients treated with regimens that did not contain RIF. Wallis and associates (13) reported that a # Tuberculosis and HIV Infection The treatment of tuberculosis in persons with HIV infection is essentially the same as for patients without HIV infection. There are two important exceptions to this generalization: 1) Once weekly INH-rifapentine in the continuation phase should not be used in any HIV-infected patient; and 2) twice weekly INH-RIF or rifabutin should not be used for patients with CD4 + lymphocyte counts less than 100/µl. Providers must be alert to the potential for interactions among many of the antiretroviral drugs and the rifamycins. Paradoxical reactions that mimic worsening of tuberculosis are more common in patients with HIV infection and may complicate therapy. non-RIF-containing regimen was associated with shortened survival compared with an RIF-based regimen. In addition to the higher mortality associated with non-RIF-based regimens, other studies have demonstrated unacceptably high recurrence rates in the setting of HIV infection (14,15). Thus, every effort should be made to use a rifamycin-based regimen for the entire course of therapy in persons with HIV infection. # Treatment recommendations Recommendations for the treatment of tuberculosis in HIVinfected adults are, with two exceptions, identical to those for HIV-uninfected adults: a 6-month regimen consisting of an initial phase of INH, RIF, PZA, and EMB given for 2 months followed by INH and RIF for 4 months when the disease is caused by organisms that are known or presumed to be susceptible to the first-line agents. This regimen may be given by daily or intermittent administration as listed in Table 1 and described in Section 5.2: Recommended Regimens. However, on the basis of data showing an increased frequency of rifamycin resistance among patients having CD4 + cell counts <100/ µl, it is recommended that patients with advanced HIV disease be treated with daily or three times weekly therapy in the continuation phase (Rating AIII) (16). Twice weekly drug administration in the continuation phase should not be used in patients with CD4 + cell counts <100/µl. Twice weekly therapy may be considered in patients with less advanced immunosuppression (CD4 + cell counts >100/µl). Once weekly administration of INH-rifapentine in the continuation phase should not be used in any patient with HIV infection. Six months should be considered the minimum duration of treatment for adults, even for patients with culture-negative tuberculosis. If there is evidence of a slow or suboptimal response (e.g., cultures are still positive after 2 months of therapy), prolongation of the continuation phase to 7 months (a total of 9 months treatment) should be strongly considered. DOT and other adherence-promoting strategies should be used in all patients with HIV-related tuberculosis. Although there are no data on which to base recommendations, the American Academy of Pediatrics recommends that for HIVinfected children the minimum duration of therapy be 9 months (17). All patients with tuberculosis should be advised to undergo voluntary counseling and HIV testing. Efforts should be made to engage all patients with a new diagnosis of HIV infection in HIV care during their treatment for tuberculosis. Ideally, patients should be managed by physicians who are expert in the treatment of tuberculosis/HIV coinfection. If the HIV care provider and tuberculosis care provider are not the same person, communication between them is essential and should occur frequently throughout the course of treatment. # Safety and tolerability The frequency of antituberculosis drug-related toxicity in patients with HIV infection has varied from study to study. In a retrospective study from San Francisco, 18% of HIVseropositive patients with tuberculosis had a change of regimen because of adverse drug reactions (18). RIF was the drug implicated most commonly, producing an adverse reaction in 12% of the patients. In the Democratic Republic of Congo, 11% of the seropositive patients developed a rash but in none was the treatment interrupted (1). Paresthesia developed in 21% of the cases, suggesting the need for pyridoxine when treating tuberculosis in persons with HIV infection. Other investigators have reported low rates of significant adverse reactions (3,5,6,19). In the three times weekly regimen studied in Haiti, there were no differences in adverse events between HIV-infected and uninfected patients (6). In HIV-infected patients it is often difficult to distinguish an adverse reaction to antituberculosis drugs from the effects of associated conditions or reactions to any of the many medications that are often being taken concurrently. Because of the difficulties in diagnosing a drug reaction and in determining the responsible agent, the first-line antituberculosis drugs (especially INH or RIF) should not be stopped permanently without strong evidence that the antituberculosis drug was the cause of the reaction. In such situations consultation with an expert in treating tuberculosis in persons with HIV infection is recommended. In a study reported by Ungo and associates (20), it was demonstrated that the relative risk of developing drug-induced hepatoxicity in tuberculosis patients with hepatitis C virus or HIV infection was 5-and 4-fold, respectively, compared with a 14-fold relative risk in patients with both hepatitis C virus and HIV infections. This finding was not confirmed in a study from Baltimore, in which rates of transaminase elevation were not greater in patients with HIV and hepatitis C virus who were given INH (21). Current IDSA and USPHS guidelines recommend screening all HIV-infected patients for hepatitis C virus (22). Until more data are available it is probably prudent to provide more frequent clinical and laboratory monitoring, as described for patients with preexisting liver disease, for patients with HIV infection or hepatitis C virus infection who are being treated for tuberculosis. # Concurrent administration of antiretroviral agents and rifamycins Most patients with tuberculosis have relatively advanced HIV disease and, thus, antiretroviral therapy is indicated (23). Antiretroviral therapy should not be withheld simply because the patient is being treated for tuberculosis, if it is otherwise indicated. Nevertheless, it is not advisable to begin both antiretroviral therapy and combination chemotherapy for tuberculosis at nearly the same time. So doing may involve as many as eight new drugs with interactions and overlapping toxicities that would be difficult to evaluate. Although there are few data on which to base recommendations, expert opinion suggests that treatment for tuberculosis should be initiated first. Although antiretroviral therapy has a dramatic effect in decreasing progression of HIV disease (decreasing CD4 + cell counts, new opportunistic infections, or death), among patients with HIV-related tuberculosis, the use of antiretroviral therapy in the setting of tuberculosis therapy is complex. In those patients not already receiving antiretroviral therapy, early initiation of antiretroviral therapy may decrease HIV disease progression, but is also associated with a high incidence of side effects and paradoxical reactions, some severe enough to warrant discontinuation of both antiretroviral and antituberculosis drugs (9). In addition, starting so many new medications in a short time period may present a tremendous adherence challenge for patients adjusting to the diagnoses of both tuberculosis and AIDS. Delaying the initiation of antiretroviral therapy until 4-8 weeks after starting antituberculosis therapy has the potential advantages of being better able to ascribe a specific cause for a drug side effect, decreasing the severity of paradoxical reactions, and decreasing the adherence difficulties for the patient. Until there have been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with HIV infection and tuberculosis, this decision should be individualized, based on the patient's initial response to treatment for tuberculosis, occurrence of side effects, and ready availability of multidrug antiretroviral therapy. For patients with CD4 + cell counts >350 cells/µl, the antiretroviral regimen could be initiated at any time after tuberculosis treatment was begun, based on current recommendations (23). For patients who are already receiving an antiretroviral regimen, treatment should generally be continued, although the regimen may need to be modified on the basis of the risk of drug-drug interactions, as described in Section 7: Drug Interactions. Even though drug interactions are common, a rifamycin should not be excluded from the tuberculosis treatment regimen for fear of interactions with some antiretroviral agents. The exclusion of a rifamycin from the treatment regimen is likely to delay sputum conversion, will prolong the duration of therapy, and possibly result in a poorer outcome (24). As noted in Section 7, Drug Interactions, rifabutin has fewer interactions than RIF and should be used if these categories of antiretroviral agents are being administered. The categories of antiretroviral agents available currently are nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The NRTIs and NtRTIs do not have clinically significant drug interactions with the standard antituberculosis medications; thus, drugs in these categories can be used together with rifamycins without any dose adjustment being necessary. However, the PIs and NNRTIs, depending on the specific drug, may either inhibit or induce cytochrome P450 isoenzymes (CYP450). Thus, these drugs may alter the serum concentration of rifabutin, as described in Section 7.1: Interactions Affecting Antituberculosis Drugs. When rifabutin is combined with antiretroviral agents, its dose and the dose of the antiretroviral agents may require adjustment. A report described the successful use of rifabutin with an antiretroviral regimen containing PIs (25). All 25 patients became culture negative by 2 months and no relapses were reported after a median follow-up of 13 months. Moreover, the circulating HIV RNA levels decreased significantly, with 20 of 25 patients achieving viral loads of less than 500 copies/ml. Thus, it appears that both tuberculosis and HIV can be treated successfully with concurrent use of a rifabutinbased regimen and potent combinations of antiretroviral agents. Previous guidelines from CDC specifically stated that RIF was contraindicated in patients who were taking any PI or NNRTI (26). However, new data indicate that RIF can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents (27,28). As recommended by CDC (27), rifampin can be used with a regimen of efavirenz and two NRTIs, with ritonavir and one or more NRTIs, with ritonavir and saquinavir (either hard-gel or soft-gel capsule), and with a triple nucleoside regimen. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified. Because these recommendations are frequently revised, obtaining the most up-to-date information from the CDC website, http:// www.cdc.gov/nchstp/tb/, is advised. Updated information on antiretroviral drugs and drug interactions, compiled by Medscape, can be found at http://www.medscape.com/ updates/quickguide. When starting NNRTIs or PIs for tuberculosis patients receiving RIF, a 2-week "washout" period is generally recommended between the last dose of RIF and the first dose of PIs or NNRTIs to allow for reduction of the enzyme-inducing activity of RIF. During this time, rifabutin may be started to ensure that the tuberculosis treatment regimen is adequate. For patients already receiving antiretroviral agents at the time treatment for tuberculosis is begun, an assessment of the antiretroviral regimen should be undertaken and, if necessary, changes made to ensure optimum treatment of the HIV infection during tuberculosis therapy. Conversely, the determination of whether to use RIF and the dose of the rifamycin must take into account the antiretroviral regimen. # Paradoxical reaction On occasion, patients have a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis (paradoxical reaction) after beginning antituberculosis treatment. Worsening of this sort occurs in patients without HIV infection, especially with lymphadenitis, but it is more common among HIV-infected patients. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by antiretroviral therapy or, perhaps, by treatment of the tuberculosis itself. Narita and colleagues (29) reported that among HIV-infected patients who were taking antiretroviral agents, 36% developed paradoxical worsening after beginning treatment for tuberculosis compared with 7% of those who were not taking antiretroviral drugs. In contrast, Wendel and colleagues (30) reported that only 7% of HIV-infected patients with tuberculosis developed paradoxical worsening and the reactions were not associated with antiretroviral therapy. Signs of a paradoxical reaction may include high fevers, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially tuberculosis treatment failure. A paradoxical reaction that is not severe should be treated symptomatically without a change in antituberculosis or antiretroviral therapy. Although approaches to the management of severe reactions, such as high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, and sepsis syndrome, have not been studied, expert opinion suggests that prednisone or methylprednisolone be started at a dose of about 1 mg/kg and gradually reduced after 1 to 2 weeks. # Children and Adolescents Children most commonly develop tuberculosis as a complication of the initial infection with M. tuberculosis (primary tuberculosis). Radiographically, primary tuberculosis is characterized by intrathoracic adenopathy, mid-and lower lung zone infiltrates, and the absence of cavitation. However, children, occasionally, and adolescents, more frequently, develop adult-type tuberculosis (upper lobe infiltration and cavitation associated with sputum production). The lesions of primary tuberculosis have a smaller number of M. tuberculosis organisms than those of adult-type pulmonary tuberculosis; thus, treatment failure, relapse, and development of secondary resistance are rare phenomena among children. Because it is more difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis than from an adult, it is frequently necessary to rely on the results of culture and susceptibility tests of specimens from the person presumed to be the source of the infection in the child to guide the choice of drugs for the child. In children in whom drug resistance is suspected or for whom no source case isolate is available, attempts to isolate organisms via three early morning gastric aspirations (optimally during hospitalization), bronchoalveolar lavage, or tissue biopsy must be considered. Because tuberculosis in infants and children younger than 4 years of age is more likely to disseminate, treatment should be started as soon as the diagnosis is suspected. Asymptomatic children with a positive PPD-tuberculin skin test and an abnormal chest radiograph (atelectasis, parenchymal infiltrate, or hilar adenopathy) should receive combination chemotherapy, usually with INH, RIF, and PZA as initial therapy. Several controlled and observational trials of 6-month therapy in children with pulmonary tuberculosis caused by organisms known or presumed to be susceptible to the firstline drugs have been published (1)(2)(3)(4)(5)(6)(7)(8)(9). Six months of therapy with INH and RIF has been shown to be effective for hilar adenopathy and pulmonary disease caused by drugsusceptible organisms (5,6). However, most studies used 6 months of daily treatment with INH and RIF, supplemented during the first 2 weeks to 2 months with PZA. This threedrug combination has a success rate of greater than 95% and a rate of adverse effects of less than 2%. Two studies used twice or three times weekly therapy from the beginning with good results (1,7). Many experts prefer to treat children with three (rather than four) drugs in the initial phase because the bacillary population is low, because many infants and children cannot tolerate the pill burden required with four oral drugs, and because of the difficulty in performing visual acuity tests in young children who are being treated with EMB. In children suspected or known to have been infected with an M. tuberculosis strain that is fully susceptible, the initial phase should consist of INH, RIF, and PZA. If the susceptibility of the presumed infecting strain is not known and the likelihood of failure is low (primary tuberculosis), some experts prefer to use three drugs. However, children and adolescents with adult-type pulmonary tuberculosis, as defined above, should be treated with the four-drug initial phase regimen, unless the infecting strain is known to be susceptible (10). When epidemiologic circumstances (Table 6) suggest an increased risk of drug-resistant organisms being present, EMB can be used safely in a dose of about 15-20 mg/kg per day, even in children too young for routine eye testing. Older children should have monthly evaluations of visual acuity and color discrimination while taking EMB. SM, kanamycin, or amikacin can be used as the fourth drug, when necessary. The usual doses for daily and twice weekly treatment in children are listed in Section 3, Drugs in Current Use, and shown in Table 3. Three times weekly therapy is not recommended for children. Pyridoxine is recommended for infants, children, and adolescents who are being treated with INH and who have nutritional deficiencies, symptomatic HIV infection, or who are breastfeeding. DOT should be used for all children with tuberculosis. The lack of pediatric dosage forms of most antituberculosis medications necessitates using crushed pills and suspensions. Even when drugs are given under DOT, tolerance of the medications must be monitored closely. Parents should not be relied on to supervise DOT. Because of the difficulties in isolating M. tuberculosis from children, bacteriological examinations are less useful in evaluating the response to treatment and clinical and radiographic examinations are of relatively greater importance. However, hilar adenopathy and resultant atelectasis may require 2-3 years to resolve. Thus, a persisting abnormality on chest radiographs is not necessarily a criterion for extending continuing therapy. Recognition of treatment failure or relapse in a child is subject to the same difficulties as making a diagnosis. Thus, clinical and radiographic worsening may not be accompanied by positive AFB smears or mycobacterial cultures. A decision to modify the drug regimen should not be made lightly, but often must be made on clinical grounds only. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions may be disseminated disease, and meningitis, for which there are inadequate data to support 6-month therapy. A fourth drug is recommended in the initial phase when there is disseminated tuberculosis. The recommended duration is 9-12 months. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs (INH and RIF, plus PZA for the first 2 months), and the total duration of therapy should be at least 9 months (11). # Extrapulmonary Tuberculosis Tuberculosis can involve virtually any organ or tissue in the body. Nonpulmonary sites tend to be more common among children and persons with impaired immunity. To establish the diagnosis of extrapulmonary tuberculosis, appropriate specimens including pleural fluid; pericardial or peritoneal fluid; pleural, pericardial, and peritoneal biopsy specimens; lymph node tissue; and bone marrow, bone, blood, urine, brain, or cerebrospinal fluid should be obtained for AFB staining, mycobacterial culture, and drug susceptibility testing (1). Tissue specimens should also be examined microscopically, after routine and AFB staining, but the absence of AFB and of granulomas or even failure to culture M. tuberculosis does not exclude the diagnosis of tuberculosis. Bacteriological evaluation of the response to treatment in extrapulmonary tuberculosis is often limited by the difficulty in obtaining follow-up specimens. Thus, response often must be judged on the basis of clinical and radiographic findings. The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although many fewer treatment studies have examined treatment of extrapulmonary tuberculosis, compared with pulmonary disease, increasing evidence, including some randomized controlled trials, suggests that 6-to 9-month regimens that include INH and RIF are effective (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Therefore, among patients with extrapulmonary tuberculosis, a 6-to 9-month regimen (2 months of INH, RIF, PZA, and EMB followed by 4-7 months of INH and RIF) is recommended as initial therapy unless the organisms are known or strongly suspected of being resistant to the first-line drugs. If PZA cannot be used in the initial phase, the continuation phase must be increased to 7 months, as described for pulmonary tuberculosis. The exception to the recommendation for a 6-to 9-month regimen is tuberculous meningitis, for which the optimal length of therapy has not been established, but some experts recommend 9-12 months. Although in extrapulmonary tuberculosis there have not been controlled trials of the various patterns of intermittent drug administration listed in Table 2, expert opinion suggests that all could be used, with the exception of INH-rifapentine once weekly in the continuation phase. Given the lack of experience with this regimen, it is not recommended currently for treating extrapulmonary tuberculosis. Corticosteroid treatment is a useful adjunct in treating some forms of extrapulmonary tuberculosis, specifically meningitis and pericarditis caused by drug-susceptible organisms. Evidence-based recommendations on the duration of treatment for extrapulmonary tuberculosis and the use of corticosteriods are shown in Table 13. # Lymph node tuberculosis A 6-month regimen as described in Section 5, Recommended Treatment Regimens, and Table 2 is recommended for initial treatment of all patients with tuberculous lymphadenitis caused by drug-susceptible organisms (2)(3)(4)(5)(6). Affected lymph nodes may enlarge while patients are receiving appropriate therapy or after the end of treatment without any evidence of bacteriological relapse (3,5,17,18). On occasion, new nodes can appear during or after treatment as well. Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration or incision and drainage appears to be beneficial, although this approach has not been examined systematically (Rating BIII). It should be noted that the majority of cases of lymphatic mycobacterial disease in children born in the United States are caused by nontuberculous mycobacteria. # Bone and joint tuberculosis Several studies have examined treatment of bone and joint tuberculosis and have shown that 6-to 9-month regimens containing RIF are at least as effective as 18-month regimens that do not contain RIF (13)(14)(15) Because of the difficulties in assessing response, however, some experts tend to favor the 9-month duration. A randomized trial performed primarily among ambulatory patients by the Medical Research Council Working Party on Tuberculosis of the Spine (13) demonstrated no additional benefit of surgical debridement or radical operation (resection of the spinal focus and bone grafting) in combination with chemotherapy compared with chemotherapy alone. Myelopathy with or without functional impairment most often responds to chemotherapy. In two Medical Research Council studies conducted in Korea, 24 of 30 patients in one study (14) and 74 of 85 patients in an earlier study (19) had complete resolution of myelopathy or complete functional recovery when treated medically. In some circumstances, however, surgery appears to be beneficial and may be indicated. Such situations include failure to respond to chemotherapy with evidence of ongoing infection, the relief of cord compression in patients with persistence or recurrence of neurologic deficits, or instability of the spine. # Pericardial tuberculosis For patients with pericardial tuberculosis, a 6-month regimen is recommended. Corticosteroids are recommended as adjunctive therapy for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. In a randomized, double-blind, controlled trial, patients in the later effusiveconstrictive phase who received prednisolone had a (9). As before, there was no statistically significant impact on progression to constriction or in the need for pericardiectomy. An additional small randomized trial by Hakim and associates (20) performed in HIV-infected patients with tuberculous pericarditis also demonstrated that prednisolone therapy was associated with a reduced risk of mortality. On the basis of these studies, it is recommended that daily adjunctive prednisolone or prednisone treatment be given to adults and children with tuberculous pericarditis. For adults the prednisone dose is 60 mg/day (or the equivalent dose of prednisolone) given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and finally 5 mg/day for week 11 (the final week). Children should be treated with doses proportionate to their weight, beginning with about 1 mg/kg body weight and decreasing the dose as described for adults. # Pleural tuberculosis A 6-month regimen is also recommended for treating pleural tuberculosis. A number of studies have examined the role of corticosteroid therapy for tuberculous pleural effusions (21), but only two have been prospective, double blind, and randomized (7,22). In both of these studies, prednisone (or prednisolone) administration did not reduce the development of residual pleural thickening. Lee and associates (22) found that patients with pleural tuberculosis who received prednisone had a significantly more rapid resolution of symptoms such as fever, chest pain, and dyspnea than patients given placebo. Patients who received prednisone had a more rapid radiographic resolution of the effusions. In the study by Wyser and colleagues (7), all patients had complete drainage of the effusion performed at the time of the diagnostic procedure; patients were then allocated at random to receive adjunctive oral prednisone or placebo for 6 weeks. The complete drainage led to a rapid resolution of symptoms, and the added benefit of corticosteroids on symptoms was minimal. Tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy. Surgery, when needed, should be undertaken by experienced thoracic surgeons (23). The optimum duration of treatment for this unusual form of tuberculosis has not been established. # Tuberculous meningitis Before the advent of effective antituberculosis chemotherapy, tuberculous meningitis was uniformly fatal. Tuberculous meningitis remains a potentially devastating disease that is associated with a high morbidity and mortality, despite prompt initiation of adequate chemotherapy (24)(25)(26)(27)(28)(29). HIV-infected patients appear to be at increased risk for developing tuberculous meningitis but the clinical features and outcomes of the disease are similar to those in patients without HIV infection (24)(25)(26)29). Patients presenting with more severe neurologic impairment such as drowsiness, obtundation, or coma have a greater risk of neurologic sequelae and a higher mortality. Chemotherapy should be initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. INH and RIF, as well as the aminoglycosides, capreomycin, and the fluoroquinolones are available in parenteral forms for patients with altered mental status who may not be able to take oral medications. After 2 months of four-drug therapy for meningitis caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined, and there are no data from randomized, controlled trials to serve as the basis of recommendations. Repeated lumbar punctures should be considered to monitor changes in CSF cell count, glucose, and protein, especially in the early course of therapy. Differences in regimens among patient groups and in the use of corticosteroid therapy have made meta-analysis of published treatment trials impossible (30). Some authors have advocated longer courses of therapy, up to 2 years (28,31), whereas others have suggested that short-course RIF-based regimens for 6 to 9 months may be adequate therapy (10,32,33). It has been reported that some patients being treated for tuberculous meningitis develop tuberculomas during therapy, perhaps as a form of paradoxical reaction; however, this does not necessarily indicate treatment failure. A number of investigators have examined the role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis (21,(34)(35)(36)(37)(38)(39)(40)(41), but many of these are limited by small sample size or use of a regimen that did not include RIF. There are no large, prospective, randomized, controlled trials of adjunctive corticosteroid use for tuberculous meningitis in which an RIF-based regimen has been used. Six of eight controlled trials noted a benefit of corticosteroid therapy in terms of survival, frequency of sequelae, or both. In the study conducted by Girgis and coworkers (34), the greatest benefit was for patients with Stage II disease (lethargic) on presentation (4 of 27 [15%] of those who received dexamethasone died versus 14 of 35 [40%] in the control group; p <0.02). For patients presenting with coma (Stage III), there was no significant difference in survival between those who received dexamethasone and control patients (28 of 44 [64%] mortality for the dexamethasone group versus 35 of 46 [76%] for control subjects). However, the small sample size may have precluded finding an effect. Likewise, there were too few patients with Stage I disease (alert) on entry to determine the effectiveness of dexamethasone for this less severely ill group. On the basis of the available data, albeit limited, adjunctive corticosteroid therapy with dexamethasone is recommended for all patients, particularly those with a decreased level of consciousness, with tuberculous meningitis. The recommended regimen is dexamethasone in an initial dose of 8 mg/ day for children weighing less than 25 kg and 12 mg/day for children weighing 25 kg or more and for adults. The initial dose is given for 3 weeks and then decreased gradually during the following 3 weeks. # Disseminated tuberculosis A 6-month regimen is recommended for tuberculosis at multiple sites and for miliary tuberculosis, although there are limited data from controlled clinical trials addressing this issue. (The AAP recommends 9 months of treatment for children with disseminated tuberculosis.) Expert opinion suggests that corticosteroid therapy may be useful for treating respiratory failure caused by disseminated tuberculosis but there are no data to support its use. # Genitourinary tuberculosis Renal tuberculosis is treated primarily with medical therapy (12,(42)(43)(44)(45)(46), and a 6-month regimen is recommended. If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal drainage by stenting or nephrostomy is recommended (42). The use of corticosteriods in addition to stenting for the treatment of ureteric stenosis is discussed in the urologic literature but the efficacy of steroids in this setting is unclear. Nephrectomy is not usually indicated for the treatment of uncomplicated renal tuberculosis but should be considered when there is a nonfunctioning or poorly functioning kidney, particularly if hypertension or continuous flank pain is present. Tuberculosis of either the female or male genital tract responds well to standard chemotherapy, and surgery is needed only for residual large tubo-ovarian abscesses. A positive urine culture for M. tuberculosis occurs relatively commonly as an incidental finding among patients with pulmonary or disseminated disease, especially those with HIV infection. The positive culture may occur in the absence of any abnormalities on urinalysis and does not necessarily represent genitourinary tract involvement. # Abdominal tuberculosis A 6-month regimen is recommended for patients with peritoneal or intestinal tuberculosis (47,48). There are insufficient data to recommend adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis (21). In a small study of peritoneal tuberculosis alternate patients received adjunctive corticosteroid therapy for 4 months (total of 23 steroid recipients) (49). Fibrotic complications were noted in 4 of 24 in the control group and in none of those in the steroid group (23 patients), but the difference was not statistically significant. # Other sites of involvement As noted above, tuberculosis can involve any organ or tissue. In treating tuberculosis in sites other than those mentioned, the basic principles of therapy apply, but experts should be consulted for specific advice concerning individual patients. 49. Singh MM, Bhargava AN, Jain KP. Tuberculous peritonitis: an evaluation of pathogenetic mechanisms, diagnostic procedures and therapeutic measures. N Engl J Med 1969;281:1091-1094. # Culture-Negative Pulmonary Tuberculosis in Adults Failure to isolate M. tuberculosis from appropriately collected specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active tuberculosis. For the United States as a whole, about 17% of the reported new cases of pulmonary tuberculosis have negative cultures (1). Low bacillary populations, temporal variations in the number of bacilli being expelled, and errors in specimen processing all may result in failure to isolate organisms from patients who have active tuberculosis. It should be emphasized that alternative diagnoses must be considered carefully and appropriate diagnostic studies undertaken in patients who have what appears to be culture-negative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis should have three sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria as part of the diagnostic evaluation. Depending on the clinical features and differential diagnosis, other diagnostic testing, such as bronchoscopy with bronchoalveolar lavage and biopsy, should be considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture, treatment for active disease should be continued. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have a thorough follow-up clinical and radiographic evaluation at the time 2 months of therapy has been completed to determine whether there has been a response that can be attributed to antituberculosis treatment. If there is either clinical or radiographic improvement and no other etiology is identified, treatment should be continued for active tuberculosis. A 4-month, INH and RIF regimen for culture-negative tuberculosis has been demonstrated to be successful with only 1.2% relapses during an average follow-up of 44 months (2). However, because the results of cultures may not be known for 3-8 weeks and because of the possibility of drug resistance, initiation of two-drug therapy with INH and RIF alone is not recommended, but the continuation phase can be shortened to 2 months using INH and RIF (Figure 2). On occasion, patients who are being evaluated for pulmonary tuberculosis will be found to have positive AFB smears but negative cultures. There are several potential explanations for this occurrence, including the possibilities that the acidfast organisms are nontuberculous and difficult to culture, that they are nonviable tubercle bacilli, and that they are the result of laboratory error. The approach taken in such cases should be individualized on the basis of clinical and radiographic findings. If suspicion of tuberculosis is high and the patient has positive AFB smears, even with negative cultures, he/she should be treated as if the culture is positive, using one of the recommended regimens. # Radiographic Evidence of Prior Tuberculosis: Inactive Tuberculosis Persons with a positive tuberculin PPD skin test who have radiographic findings consistent with prior pulmonary tuberculosis (ATS/CDC Class 4) (1) and who have not been treated are at increased risk for the subsequent development of active tuberculosis (2)(3)(4). The radiographic findings that constitute evidence of prior tuberculosis are apical fibronodular infiltrations, often with volume loss. Case rates among such persons in one study were about 2.5 times those of persons infected with M. tuberculosis who did not have chest radiographic abnormalities (3). Persons with radiographic findings of healed primary tuberculosis (e.g., calcified solitary pulmonary nodules, calcified hilar lymph nodes, and pleural thickening) are not at increased risk for tuberculosis compared with other persons with latent tuberculosis infection. Patients should not be classified as having radiographic evidence of prior tuberculosis if another disease is found to account for the radiographic findings. The activity of tuberculosis cannot be determined from a single chest radiograph, and unless there are previous radiographs showing that the abnormality has not changed, it is recommended that sputum examination, using sputum induction if necessary, be performed to assess the possibility of active tuberculosis. Once active tuberculosis has been excluded by sputum culture, these persons are high-priority candidates for treatment of latent tuberculosis infection (5). The optimum treatment for patients with latent tuberculosis infection and abnormal chest radiographs consistent with prior tuberculosis has been examined in several studies. A placebo-controlled trial conducted by the IUATLD (2) compared the efficacy of 3, 6, and 12 months of INH in preventing # Pregnancy and Breastfeeding Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. Infants born to women with untreated tuberculosis may be of lower birth weight than those born to women without tuberculosis and, rarely, the infant may acquire congenital tuberculosis (1)(2)(3). Thus, treatment of a pregnant woman with suspected tuberculosis should be started if the probability of tuberculosis is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. SM should not be substituted for EMB. Although PZA is recommended for routine use in pregnant women by the WHO (4) and the IUATLD (5), the drug has not been recommended for general use in pregnant women in the United States because of insufficient data to determine safety. However, some public health jurisdictions in the United States have used PZA in pregnant women without reported adverse events (1). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Pyridoxine, 25 mg/ day, should be given to pregnant women who are receiving INH. INH, RIF, and EMB cross the placenta, but none has been shown to have teratogenic effects (6). SM, the only antituberculosis drug documented to have harmful effects on the human fetus, interferes with development of the ear and may cause congenital deafness. In 40 pregnancies among women being treated with SM, 17% of the babies had eighth nerve damage with deficits ranging from mild hearing loss to bilateral deafness (6,7). Kanamycin, amikacin, and capreomycin presumably share this toxic potential; however, there is little specific information on the fetal effects of these three drugs. PAS was used commonly with INH in the past and there was no indication of teratogenicity among babies whose mothers had received these two drugs (2). There are not enough data to determine the risk of cycloserine or ethionamide, although one report described nonspecific teratogenic effects attributed to ethionamide (8). The fluoroquinolones have been associated with arthropathies in young animals; therefore, they should be avoided if possible in pregnant women (6). In general, administration of antituberculosis drugs is not an indication for termination of pregnancy (2). However, in women who are being treated for drug-resistant tuberculosis, counseling concerning the risk to the fetus should be provided because of the known and unknown risks of the second-line agents. Breastfeeding should not be discouraged for women being treated with first-line agents, because the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant (9). Conversely, drugs in breast milk should not be considered to serve as effective treatment for active tuberculosis or latent tuberculosis infection in a nursing infant. Supplementary pyridoxine is recommended for the nursing mother receiving INH. The administration of the fluoroquinolones during breastfeeding is not recommended, although, as of 1998, there have been no reported cases of adverse reactions in infants breast fed by women taking these drugs (6). # Renal Insufficiency and End-stage Renal Disease Renal insufficiency complicates the management of tuberculosis because some antituberculosis medications are cleared by the kidneys. Management may be further complicated by the removal of some antituberculosis agents via hemodialysis. Thus, some alteration in dosing antituberculosis medications is commonly necessary in patients with renal insufficiency and endstage renal disease (ESRD) receiving hemodialysis (Table 15). Decreasing the dose of selected antituberculosis drugs may not be the best method of treating tuberculosis because, although toxicity may be avoided, the peak serum concentrations may be too low. Therefore, instead of decreasing the dose of the antituberculosis agent, increasing the dosing interval is recommended (1). The general approach described in Table 15 involves either estimating or measuring creatinine clearance. Administration of drugs that are cleared by the kidneys to patients having a creatinine clearance of less than 30 ml/ minute and those receiving hemodialysis are managed in the same manner, with an increase in dosing interval (C. Peloquin, personal communication). There are insufficient data to guide dosing recommendations for patients having a reduced creatinine clearance but not less than 30 ml/minute. In such patients standard doses should be used, but measurement of serum concentrations should be considered to avoid toxicity. RIF and INH are metabolized by the liver, so conventional dosing may be used in the setting of renal insufficiency (1)(2)(3)(4)(5). PZA is also metabolized by the liver but its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) may accumulate in patients with renal insufficiency (3,6). EMB is about 80% cleared by the kidneys and may accumulate in patients with renal insufficiency (7). A longer interval between doses with three times a week administration is recommended for PZA and EMB (3,7). INH, EMB, and PZA (as well as its metabolites) are cleared by hemodialysis to some degree, but only PZA and presumably its metabolites are dialyzed to a significant degree (3). RIF is not cleared by hemodialysis because of its high molecular weight, wide distribution into tissues, high degree of protein binding, and rapid hepatic metabolism (3). Therefore, supplemental dosing is not necessary for INH, RIF, or EMB. If PZA is given after hemodialysis, supplemental dosing is not required. In general, antituberculosis drugs should be given after hemodialysis to avoid any loss of the drugs during hemodialysis, and to facilitate DOT. Doses of streptomycin, kanamycin, amikacin, and capreomycin must be adjusted in patients with renal failure because the kidneys excrete essentially all of these drugs. Approximately 40% of the dose is removed with hemodialysis when these drugs are given just before hemodialysis (8). Far less drug is likely to be removed once the drugs have had time to distribute throughout the body, and some accumulation of the drugs should be anticipated. As with EMB and PZA, the dosing interval should be increased. In general, the dose should not be reduced because the drugs exhibit concentrationdependent bactericidal action (9), and smaller doses may reduce drug efficacy. Ethionamide is not cleared by the kidneys, nor is the drug removed with hemodialysis, so no dose adjustment is necessary (10). PAS is modestly cleared by hemodialysis (6.3%) but its metabolite, acetyl-PAS, is substantially removed by hemodialysis; twice daily dosing (4 g) should be adequate if the granule formulation is used (Jacobus Pharmaceuticals) (10). Cycloserine is excreted primarily by the kidney, and is cleared by hemodialysis (56%). Thus, an increase in the dosing interval is necessary to avoid accumulation between hemodialysis sessions, and the drug should be given after hemodialysis to avoid underdosing (10). The fluoroquinolones undergo some degree of renal clearance that varies from drug to drug. For example, levofloxacin undergoes greater renal clearance than moxifloxacin (11). It should be noted that the fluoroquinolone dosing recommendations for end-stage renal disease provided by the manufacturers were developed for treating pyogenic bacterial infections. These recommendations may not be applicable to the treatment of tuberculosis in patients with end-stage renal disease. As noted above, administration of all antituberculosis drugs immediately after hemodialysis will facilitate DOT (three times per week) and avoid premature removal of the drugs (2). It is important to monitor serum drug concentrations in persons with renal insufficiency who are taking cycloserine, EMB, or any of the injectable agents to minimize dose-related toxicity, while providing effective doses. Clinicians also should be aware that patients with end-stage renal disease may have additional clinical conditions, such as diabetes mellitus with gastroparesis, that may affect the absorption of the antituberculosis drugs, or they may be taking concurrent medications that interact with these drugs. Under these circumstances a careful clinical and pharmacologic assessment is necessary, and, in selected cases, serum drug concentration measurements may be used to assist in determining the optimum dose of the antituberculosis drugs (9). Finally, data currently do not exist for patients receiving peritoneal dialysis. Because the drug removal mechanisms differ between hemodialysis and peritoneal dialysis, it cannot be assumed that all of the recommendations in Table 15 will apply to peritoneal dialysis. Such patients may require close monitoring, including measurements of the serum concentrations of the antituberculosis drugs. # Hepatic Disease The treatment of tuberculosis in patients with unstable or advanced liver disease is problematic for several reasons. First, the likelihood of drug-induced hepatitis may be greater. Second, the implications of drug-induced hepatitis for patients with marginal hepatic reserve are potentially serious, even lifethreatening. Finally, fluctuations in the biochemical indicators of liver function (with/without symptoms) related to the preexisting liver disease confound monitoring for drug-induced hepatitis. Thus, clinicians may consider regimens with fewer potentially hepatotoxic agents in patients with advanced or unstable liver disease, and expert consultation is advisable in treating such patients. It should be noted that tuberculosis itself may involve the liver, causing abnormal liver function; thus, not all abnormalities in liver function tests noted at baseline should be attributed to causes other than tuberculosis. The hepatic abnormalities caused by tuberculosis will improve with effective treatment. Possible treatment regimens in the setting of liver disease include the following. # Treatment without INH As described in Section 5.2, Alternative Regimens, analysis of data from several studies conducted by the BMRC in patients with smear-positive pulmonary tuberculosis demonstrated high levels of efficacy with 6-month regimens despite in vitro resistance to INH so long as the initial phase contained four drugs and RIF was used throughout the 6 months (1). Subsequent studies by the Hong Kong Chest Service and the BMRC suggested that results were improved when PZA was used throughout the 6 months (2). Thus, it is reasonable to employ an initial phase regimen of RIF, PZA, and EMB followed by a continuation phase of RIF, EMB, and PZA (Rating BII). Although this regimen has two potentially hepatotoxic medications, it has the advantage of retaining the 6-month duration. # Treatment without PZA Although the frequency of PZA-induced hepatitis is slightly less than occurs with INH or RIF, the liver injury induced by this drug may be severe and prolonged (3). Therefore, one might elect to employ a regimen with an initial phase of INH, RIF, and EMB for 2 months followed by a continuation phase of INH and RIF for 7 months, for a total of 9 months (Table 2, Regimen 4). # Regimens with only one potentially hepatotoxic drug For patients with advanced liver disease, a regimen with only one potential hepatotoxic drug might be selected. Generally, RIF should be retained. Additional agents in such regimens could include EMB, a fluoroquinolone, cycloserine, and injectable agents. The duration of treatment with such regimens should be 12-18 months, depending on the extent of the disease and the response (Rating CIII). Consultation is advised in such situations. # Regimens with no potentially hepatotoxic drugs In the setting of severe unstable liver disease, a regimen with no hepatotoxic agents might be necessary. Such a regimen might include SM, EMB, a fluoroquinolone, and another second-line oral drug. There are no data that provide guidance as to the choice of agents or the duration of treatment or that indicate the effectiveness of such a regimen. Expert opinion suggests that a regimen of this sort should be given for 18-24 months (Rating CIII). Consultation should always be obtained before embarking on such a treatment plan. # Microbiological Confirmation of Relapse Should be Pursued Vigorously. Relapses may occur with either drug-resistant or drug-susceptible strains of M. tuberculosis. To confirm that a true relapse has occurred and to obtain drug susceptibility tests, microbiological confirmation of relapse should be pursued vigorously. # Other Associated Disorders Tuberculosis commonly occurs in association with other diseases or conditions. An associated disorder may alter immune responsiveness, thereby causing a predisposition to tuberculosis, or simply may be a disorder that occurs frequently in the same social and cultural milieu as tuberculosis. Examples of the former class of disorders include HIV infection, hematologic or reticuloendothelial malignancies, immunosuppressive therapy, chronic renal failure, poorly controlled, insulin-dependent diabetes mellitus, and malnutrition. Silicosis, by impairing pulmonary macrophage function, is a unique example of local immune dysfunction. The latter group of disorders includes chronic alcoholism and its secondary effects, other substance abuse, and psychiatric illnesses, among others. All of these conditions may influence the organization, supervision, and outcome of therapy (discussed in Section 2: Organization and Supervision of Treatment). The response of immunocompromised patients to treatment may not be as good as would be expected in a person with normal immunity, although in patients with HIV infection the response to treatment is not impaired Nevertheless, therapeutic decisions for the immunocompromised host should be more individualized, taking into account the severity of tuberculosis and the response to treatment. When possible, steps should be taken to correct the immune deficiency. In patients with silicotuberculosis there are data demonstrating that the rate of cure is improved if the continuation phase is extended for at least 2 months (1,2). # Management of Relapse, Treatment Failure, and Drug Resistance # Relapse Relapse refers to the circumstance in which a patient becomes and remains culture-negative while receiving antituberculosis drugs but, at some point after completion of therapy, either becomes culture-positive again or experiences clinical or radiographic deterioration consistent with active tuberculosis. In such patients vigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. True relapses are due to failure of chemotherapy to sterilize the host tissues, thereby enabling endogenous recrudescence of the original infection. In some hyperendemic settings, however, exogenous reinfection with a new strain of M. tuberculosis may be responsible for the apparent relapse (1). Patients who are most likely to have true relapses are those with extensive tuberculosis whose sputum cultures remain positive after 2 months of chemotherapy (2)(3)(4). Most patients relapse within the first 6-12 months after completion of therapy. In nearly all patients with tuberculosis caused by drug-susceptible organisms who were treated with rifamycincontaining regimens using DOT, relapses occur with susceptible organisms (5,6). However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycincontaining regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. Among patients who received self-administered therapy, the risk of erratic drug administration leading to relapse with resistant organisms is greater. In view of these considerations, the selection of empirical treatment regimens for patients with relapses should be based on the prior treatment scheme. For patients with tuberculosis that was caused by drug-susceptible organisms, who were treated by DOT, and who have relapses, retreatment using the standard four-drug initial phase regimen may be appropriate, at least until the results of susceptibility tests are known. For patients who did not receive DOT or are known to have had irregular treatment in the past, it is prudent to infer a higher risk of acquired drug resistance and begin an expanded regimen (see below). The expanded regimen is indicated especially in patients with impaired immunity, limited respiratory reserve, central nervous system involvement, or other life-threatening circumstances, that is, cases in which treatment with an inadequate regimen could have severe consequences. For the relatively few patients in whom epidemiologic circumstances provide a strong suspicion of exogenous reinfection as the cause of apparent relapse, the choice of a regimen is influenced by the drug susceptibility pattern of the presumed source case. If the presumed source case is known to have tuberculosis caused by drug-susceptible organisms, resumption of a standard four-drug initial phase may be indicated. However, if the likely source case is known to have drugresistant organisms, an empirically expanded regimen based on the resistance profile of the putative source case may be suitable. There are no clinical trials to guide the choice of agents to include in expanded empirical regimens for presumed drug resistance; however, expert opinion indicates that such regimens should generally employ INH, RIF, and PZA plus an additional three agents, based on the probability of in vitro susceptibility. Usual agents would include EMB, a fluoroquinolone, and an injectable agent such as SM (if not used previously, and the initial isolate was susceptible) amikacin, kanamycin or capreomycin, with or without other drugs. # Treatment Failure Treatment failure is defined as continued or recurrently positive cultures in a patient receiving appropriate chemotherapy. Among patients with drug-susceptible pulmonary tuberculosis, even with extensive lung cavitation, 90-95% will be culture-negative after 3 months of treatment with a regimen that contains INH and RIF. During this time the vast majority of patients show clinical improvement, including defervescence, reduced cough, and weight gain. Thus, patients with persistently positive cultures after 3 months of chemotherapy, with or without on-going symptoms, should be evaluated carefully to attempt to identify the cause of the delayed response. Patients whose sputum cultures remain positive after 4 months of treatment are considered to have failed treatment. There are multiple potential reasons for treatment failure. If the patient is not receiving DOT, the most likely explanation for persistently positive cultures is nonadherence to the drug regimen. Among patients receiving DOT, cryptic nonadherence (spitting out or deliberately regurgitating pills) or failure of the health care system to reliably deliver the drugs may be the cause. Other potential reasons include unrecognized drug resistance (Was initial drug-susceptibility testing done? Was it reported accurately?), malabsorption (prior resectional surgery of the stomach or small intestine, taking tuberculosis medication with antacids or other drugs/substances that might bind or interfere with drug absorption (see Section 6.1: Drug Administration, and Section 7.1: Interactions Affecting Antituberculosis Drugs), or simply an extreme biologic variation (For unclear reasons, rare "normal" patients may experience very protracted disease including persistently positive cultures or prolonged symptoms in the face of chemotherapy that would be expected to be effective). Laboratory error should also be considered as a possible reason for a positive culture in a patient who is doing well. Recent reports document cross contamination or mislabeling of specimens as a source for some of these unexpectedly positive cultures (7,8). Clinicians should be alert, as well, to the possibility of transient clinical or radiographic worsening (paradoxical reactions), despite appropriate therapy that would eventually result in cure. Examples of this include ongoing inflammation at sites of lymphadenitis, worsened abnormalities on chest radiographs after several months of treatment, or the new appearance of pleural effusions during therapy for pulmonary tuberculosis (9)(10)(11). Such paradoxical worsening during treatment occurs more commonly but not exclusively in persons with HIV infection (12)(13)(14) (see Section 8.1: HIV Infection). For patients who meet criteria for treatment failure, the possible reasons listed above should be addressed promptly. If clinicians are not familiar with the management of drug-resistant tuberculosis, prompt referral to, or consultation with a specialty center is indicated. If treatment failure is presumed to be due to drug resistance and the patient does not have severe tuberculosis, one may either initiate an empirical retreatment regimen or wait for drug susceptibility results from a recent isolate. If the patient is seriously ill or has a positive sputum AFB smear, an empirical regimen that would be anticipated to be effective should be started immediately and continued until susceptibility tests are available to guide therapy. For patients who have failed treatment, mycobacterial isolates should be sent promptly to a reference laboratory for susceptibility testing for both first-and second-line drugs. A fundamental principle in managing patients who have failed treatment is that a single new drug should never be added to a failing regimen; so doing may lead to acquired resistance to the added drug. In such cases, it is generally prudent to add at least three new drugs to which susceptibility could logically # Never Add a Single Drug To a Failing Regimen Treatment failure is defined by continued or recurrent positive cultures after 4 months of treatment in patients in whom medication ingestion was assured. Patients with treatment failure should be assumed, until proven otherwise, to have drug-resistant organisms and be treated with multiple agents that they have not received before. A single drug should never be added to a failing regimen. So doing risks development of resistance to the new drug, further complicating management. be inferred to lessen the probability of further acquired resistance. As noted previously there are no clinical trials to guide the choice of an empirical regimen; however, expert opinion indicates that empirical retreatment regimens might include a fluoroquinolone such as levofloxacin, an injectable agent such as SM (if not used previously and the isolate was susceptible initially), amikacin, kanamycin, or capreomycin, and an oral agent such as PAS, cycloserine, or ethionamide (Rating AIII). When drug susceptibility results are available, the regimen should be adjusted according to the results. # Management of Tuberculosis Caused by Drug-Resistant Organisms Tubercle bacilli are continually undergoing spontaneous mutations that create resistance to individual antituberculosis drugs. However, the frequency of these single mutations is sufficiently low that with appropriate combination chemotherapy that is reliably ingested, clinically significant resistance will not develop (see Section 4.1: Combination Chemotherapy) (15). Most commonly the development of acquired drug resistance occurs when there is a large bacillary population, such as in pulmonary cavities, when an inadequate drug regimen is prescribed (inappropriate drugs, insufficient dosage) or when there is a combined failure of both the patient and the provider to ensure that an adequate regimen is taken (16). Rarely, malabsorption of one or more antituberculosis drugs may account for acquired resistance. Drug resistance is much more likely to occur in cavitary pulmonary tuberculosis because of the immense number of rapidly multiplying bacilli in the cavity(ies) (17). During extended or repeated treatment, resistance to multiple agents may evolve. Patients with acquired drug resistance may transmit their strains to others who, if they develop tuberculosis, will have primary drug resistance. Drug resistance in a patient with newly diagnosed tuberculosis may be suspected on the basis of historical (previous treatment) or epidemiologic information (contact with a known drug-resistant case or coming from a region in which drug resistance is common) (18,19). In such situations it is prudent to employ an empirically expanded regimen, as described previously, especially if the patient is seriously ill (Table 16). Drug resistance can be proven only by drug-susceptibility testing performed in a competent laboratory (Table17). The steps taken when resistance is shown to be present are of critical importance. Patients harboring strains of M. tuberculosis resistant to both INH and RIF (MDR) are at high risk for treatment failure and further acquired resistance; they must be referred immediately to a specialist or consultation obtained from specialized treatment centers. Patients with strains resistant to RIF alone have a better prognosis than MDR cases, but also are at increased risk for failure and additional resistance. Thus, their management should also be subject to special scrutiny. Definitive randomized or controlled studies have not been performed among patients with the various patterns of drug resistance. In the absence of ideal evidence, practices in the treatment of patients are based on a mixture of general principles, extrapolations and expert opinion. The WHO and IUATLD have formulated standard algorithmic regimens for the management of treatment failure or chronic cases, largely based on the principles listed below, as well as on expert opinion (20,21). This approach is best suited to regions without in vitro susceptibility testing capacity and access to the full array of retreatment medications, but it is not appropriate for industrialized nations with more ample resources (22,23). Guidelines for management of patients with tuberculosis caused by drug-resistant organisms are based on the following guidelines, all of which are rated A III: • A single new drug should never be added to a failing regimen. • When initiating or revising therapy, always attempt to employ at least three previously unused drugs to which there is in vitro susceptibility. One of these should be an injectable agent. • Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. In patients with MDR organisms in whom there is resistance to first-line agents in addition to INH and RIF, regimens employing four to six medications appear to be associated with better results (24)(25)(26). • Patients should receive either hospital-based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT. • Intermittent therapy should not be used in treating tuberculosis caused by drug-resistant organisms, except perhaps for injectable agents after an initial period (usually 2-3 months) of daily therapy. # Request Consultation Treatment of tuberculosis caused by drug-resistant organisms should be done by or in close consultation with an expert in the management of these difficult situations. Second-line regimens often represent the patient's last best hope for being cured. Inappropriate management can, thus, have life-threatening consequences. • The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs (assuming the test results are accurate), and usually, alternative medications are available. (28). • There is no cross-resistance between SM and the other injectable agents: amikacin, kanamycin, and capreomycin (although resistance to all may occur as independent events); however, cross-resistance between amikacin and kanamycin is universal (24). Simultaneous use of two injectable agents is not recommended due to the absence of proof of efficacy and potential amplification of drug toxicity. • Determination of resistance to PZA is technically problematic and, thus, is not made in many laboratories. However, resistance to PZA is uncommon in the absence of resistance to other first-line drugs (30). If monoresistance to PZA is observed, consideration must be given to the possibility that the etiologic agent is M. bovis, not M. tuberculosis (M. bovis is genotypically resistant to PZA In such cases, extended treatment is needed to lessen the risk of relapse. In cases with extensive disease, the use of an additional agent (alternative agents) may be prudent to lessen the risk of failure and additional acquired drug resistance. Resectional surgery may be appropriate (see text). Use the first-line agents to which there is susceptibility. Add two or more alternative agents in case of extensive disease. Surgery should be considered (see text). Daily and three times weekly regimens of INH, PZA, and SM given for 9 mo were effective in a BMRC trial ‡ (Rating BI). However, extended use of an injectable agent may not be feasible. It is not known if EMB would be as effective as SM in these regimens. An all-oral regimen for 12-18 mo should be effective (Rating BIII). But for more extensive disease and/or to shorten duration (e.g., to 12 months), an injectable agent may be added in the initial 2 mo of therapy (Rating BIII). and is not distinguished from M. tuberculosis by nucleic acid hybridization-probe assays that are commonly used for identification). Table 16 contains regimens suggested for use in patients with various patterns of drug-resistant tuberculosis. # Role of Surgery in MDR Tuberculosis The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies. In one series, patients with severe drug resistance (on average, having resistance to more than 5 drugs) appeared to benefit from the resection of cavitary or badly damaged lung tissue when compared with historical controls (31). In contrast, other clinicians have reported patients with drug resistance having similar cure rates without surgery (25,32). The disparity in these reports may be due to long-standing disease with extensive fibrosis in the former group. If surgery is to be done, it should be performed by an experienced surgeon after the patient has received several months of intensive chemotherapy. Even with successful resection, 12-24 additional months of chemotherapy, using drugs to which there is demonstrated susceptibility, should be given. # Laboratory Considerations in Determining Drug Resistance Susceptibility testing of M. tuberculosis is critical for appropriate patient management and should be performed on an initial isolate from all patients from whom M. tuberculosis is recovered (1). Public health laboratories routinely will perform susceptibility testing on initial isolates but, often, private laboratories do not perform such testing unless specifically requested to do so by the physician. As noted previously, susceptibility testing should be repeated if the patient still has a positive culture result after 3 months of therapy or again develops positive cultures after a period of negative cultures (2). Antimicrobial susceptibility testing should be performed using a standard methodology, such as that recommended by the National Committee for Clinical Laboratory Standards (3). The second edition of a tentative standard (M24-T2) for sus- # Obtaining Drug Susceptibility Tests Drug susceptibility testing for INH, RIF and EMB should be performed on an initial isolate of M. tuberculosis from all patients. Susceptibility testing for firstline and second line drugs should be performed for all patients with possible treatment failure or relapse. Most public health laboratories will perform initial susceptibility tests without a specific request, but this may not be true for private laboratories. Testing for susceptibility to the second-line drugs should be performed only in reference laboratories. ceptibility testing of mycobacteria was published by the National Committee for Clinical Laboratory Standards in 2000 (3). Susceptibility of M. tuberculosis is determined by evaluating the ability of an isolate to grow on agar or in broth containing a single "critical" concentration of a drug (2). The agar proportion method has been proposed as the reference method for all antituberculosis drugs except pyrazinamide, in which case the BACTEC broth-based methodology is the reference method (3). With the agar proportion method, resistance is defined as growth on the drug-containing plate that is more than 1% of the growth on the non-drug-containing plate (4). Because the agar method requires up to 6 weeks to yield results, it is recommended that initial susceptibility testing of M. tuberculosis isolates to first-line antituberculosis drugs be performed using more rapid broth-based methods (e.g., BACTEC and others). The goal, as stated by CDC, is to have culture and susceptibility results (to first-line drugs) available within 28 days of receipt of a clinical specimen (5). The critical concentrations recommended by the National Committee for Clinical Laboratory Standards for agar proportion method and "equivalent" concentrations for broth-based testing methods are shown in Table 17 (2,3). The National Committee for Clinical Laboratory Standards recommends that susceptibility testing be performed for INH (two concentrations) and RIF and EMB (one concentration each) using a broth-based method on all initial M. tuberculosis isolates. Pyrazinamide testing may be done if there is a sufficiently high prevalence of PZA resistance. It is also recommended that the full panel of drugs (including second-line drugs) be tested when there is resistance to RIF alone or to two or more drugs. Testing of second-line drugs is performed using the agar proportion method, generally by public health laboratories. Secondary antituberculous drugs used for testing are capreomycin, ethionamide, kanamycin (which also predicts amikacin susceptibility), ofloxacin (used to assess fluoroquinolone activity), PAS, rifabutin, and SM (3). For second-line drug testing, a second concentration of EMB is also recommended. Susceptibility testing for cycloserine is not recommended because of the technical problems associated with the test. # Treatment Of Tuberculosis in Low-Income Countries: Recommendations and Guidelines of the WHO and the IUATLD This brief summary of the differences between the recommendations for treatment of tuberculosis in high-income, lowincidence countries and low-income, high incidence countries is presented to provide an international context for the ATS/ CDC/IDSA guidelines. As tuberculosis in low-incidence countries, such as the United States, becomes more and more a reflection of the situation in high-incidence countries, it is important that health care providers in low-incidence countries have an understanding of the differences in the approaches used and the reasons for these differences so as to be better equipped to treat the increasing proportion of patients from high-incidence countries (1). As noted at the outset of this document, the ATS/CDC/IDSA recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront it to an important extent determine the approaches used. A number of differences exist between these new ATS/CDC/ IDSA recommendations, and the current tuberculosis treatment recommendations of WHO (2) and IUATLD (3), the two major sets of international guidelines. Rather than being recommendations per se, the IUATLD document presents a distillation of IUATLD practice, validated in the field. The WHO and the IUATLD documents target, in general, countries in which mycobacterial culture and susceptibility testing and radiographic examinations are not widely available. These organizations recommend a tuberculosis control strategy called "DOTS" (Directly Observed Treatment, Short-Course) in which direct observation of therapy ("DOT" in the current statement) is only one of five key elements (4). The boxed insert lists the elements of DOTS strategy. Selected important differences among the recommendations are summarized below. Some of the differences arise from variations in strategies, based on availability of resources, whereas others, such as the use of twice weekly regimens, arise from different interpretations of common elements, for example, whether DOT is used throughout the entire course of therapy or is limited to the initial phase. # Microbiological Tests for Diagnosis and Evaluation of Response The WHO and the IUATLD recommend diagnosis and classification of cases and assessment of response based on sputum AFB smears. The AFB smear is emphasized because access to reliable culture facilities is limited in many countries. In addition, the AFB smear identifies patients who are most likely to transmit the organism. Susceptibility testing for new patients is not recommended because of cost, limited applicability and lack of facilities. However, susceptibility testing is recommended by the WHO for patients who fail (sputum smear-positive in month 5 of treatment or later during the course of treatment) the initial treatment regimen, and for those who fail a supervised retreatment regimen. Regarding follow-up, it is recommended by the WHO and the IUATLD that patients who have initial positive smears have repeat smears examined at 2 months, 5 months, and at completion of treatment (either 6 or 8 months). The IUATLD recommends that for patients who have positive smears at 2 months, the initial phase should be extended for 1 month. # Use of Chest Radiographs in Diagnosis and Follow-Up of Patients Being Treated In many parts of the world radiographs are not readily available. Moreover, because the highest priority for treatment is the highly infectious sputum smear-positive patient, there is concern that treatment based on radiographic findings alone is an inefficient use of resources. Thus, chest radiography is recommended by both the WHO and the IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. # Initial Treatment Regimens The WHO recommends a single initial phase of daily INH, RIF, PZA, and EMB (or SM) for 2 months followed by a continuation phase of either daily or three times a week INH and RIF, all given by DOT, for 4 months or daily INH and EMB for 6 months (self-administered). The WHO specifically discourages programs from using twice weekly regimens, the reason being that there is a lesser margin of safety if a dose or doses are missed. The IUATLD recommends a 2-month initial phase of INH, RIF, PZA, and EMB given by DOT, followed by a 6-month continuation phase of daily INH and thiacetazone, selfadministered. For patients with HIV infection the IUATLD recommends EMB in place of thiaocetazone. The IUATLD also recommends a 12-month regimen with a 2-month initial phase of INH, SM, and thioacetazone given daily and a 10-month continuation phase of daily INH and thioacetazone. This regimen is intended to be used for patients who have negative smears or when the 8-month regimen is not available. The rationale for the 8-month regimen recommendation is that it is felt that RIF should always be given by DOT; yet, many programs cannot afford to provide the supervision required by DOT for the full 6 months of treatment. The 8-month regimen is less efficacious in patients with drugsusceptible tuberculosis, but use of this regimen will likely preserve RIF for use in retreatment regimens. In addition to the issue of supervision, the 8-month regimen's continuation phase of INH and EMB costs about 27% less than a 4-month continuation phase of daily INH and RIF. # Approach to Previously Treated Patients The WHO and the IUATLD recommend a standardized regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. (The approach to this last group of patients is currently under discussion at the WHO.) The regimen consists of an initial phase of INH, RIF, PZA, EMB, and SM given daily for 2 months and then 1 month of daily INH, RIF, PZA, and EMB. The continuation phase consists of 5 months of daily INH, RIF, and EMB. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and secondline drugs are available (5). The IUATLD recommendations do not address the issue. The issue of chronic cases is an area of considerable controversy (6). In countries with sufficient resources, such as the Five Components of the DOTS Strategy • Government commitment to sustained TB control activities. • Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services. • Standardized treatment regimen of 6-8 months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial 2 months. • A regular, uninterrupted supply of all essential antituberculosis drugs. • A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control program overall. # Research Agenda for Tuberculosis Treatment # New Antituberculosis Drugs New antituberculosis drugs are needed for three reasons: to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, to improve the treatment of patients with MDR tuberculosis, and to provide more effective and efficient treatment of latent tuberculosis infection (LTBI) (1). Although treatment regimens for drug-susceptible tuberculosis are effective, they must be administered for a minimum of 6 months to achieve optimal results. Nonadherence to this relatively lengthy course of treatment remains a major problem. To address the problem of nonadherence, DOT (as a component of the DOTS strategy) is recommended as a standard of care worldwide. However, the administrative and financial burden of providing DOT for all patients is considerable. Thus, new drugs that would permit significant shortening of treatment are urgently needed, as are drugs that could enable effective treatment to be given at dosing intervals of 1 week or more. Rates of multidrug-resistant tuberculosis are alarmingly high in several countries (2), and even in countries, such as the United States, where the rates are low and decreasing, the occasional case presents an often extremely difficult treatment problem (see Section 9: Management of Relapse, Treatment Failure, and Drug Resistance). Current treatment regimens for drug-resistant tuberculosis utilize drugs that are less effective, more toxic, and more expensive than those used for standard treatment. Moreover, these treatment regimens often have to be given for 18-24 months. Although new drugs that are effective against resistant organisms would alone not solve the problem of drug resistance, their judicious use would greatly improve the treatment for many patients. Finally, the United States and several other low-incidence countries have embarked on plans to eliminate tuberculosis. An important component of an elimination strategy is the identification and treatment of persons with LTBI who are at high risk of developing tuberculosis (3). In the United States the most commonly used LTBI treatment regimen is INH given for 9 months; however, poor adherence to this regimen imposes a major limitation on its effectiveness. A shorter LTBI treatment regimen with RIF and PZA appears to be effective, but reports have indicated that toxicity may be unacceptably high (4). Thus, new drugs to provide for safe and effective "short-course" LTBI treatment are a major need. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are presently available for clinical study. However, further work to optimize the effectiveness of once weekly rifapentine regimens and investigate the role of newer fluoroquinolones in the treatment of drug-susceptible tuberculosis is warranted. As noted above, once weekly rifapentine-INH is recommended only in the continuation phase for HIV-negative patients with noncavitary pulmonary tuberculosis who have negative sputum smears at completion of 2 months of treatment. Two approaches to improve intermittent rifapentine regimens have been suggested by experimental studies: increasing the rifapentine dosage (5), and adding moxifloxacin as a companion drug to provide better protection against the development of drug resistance and enhance the sterilizing activity of the regimen (6). Other data from a clinical trial of ofloxacin suggest that fluoroquinolones have the potential to significantly shorten treatment (7). Of the newer fluoroquinolones with more potent activity against M. tuberculosis, moxifloxacin appears to be the most promising. Other compounds that might become available for clinical evaluation in the future include the nitroimidazopyrans that are chemically related to metronidazole, for which activity against dormant M. tuberculosis has been suggested; oxazolidinones such as linezolid; and drugs that target isocitrate lyase, an enzyme that may be necessary for the establishment of latent tuberculosis infection (8). The nitroimidazopyran compound PA-824 has bactericidal activity comparable to that of INH and appears to act as well on bacilli maintained in an anaerobic environment (9). However, additional preclinical evaluation of PA-824 is needed before clinical studies could begin. Although linezolid, a drug that is marketed for the treatment of selected acute bacterial infections, does have demonstrated activity against M. tuberculosis, other compounds in that class may be more suited for the treatment of tuberculosis (10). # Other Interventions To Improve the Efficacy of Treatment A number of other approaches have been suggested that might lead to improved treatment outcome, including alternative drug delivery systems and a variety of methods of immunomodulation and immunotherapy. Experimental studies have demonstrated that effective serum concentrations of INH and PZA can be provided through incorporation of drug into slow-release, biodegradable polymers that are implanted subcutaneously (11). However, there has been little apparent commercial interest in pursuing this approach. Liposomal encapsulation of antituberculosis drugs has been suggested as an approach to direct drug to the proposed site of infection (i.e., the macrophage) providing for more effective and better tolerated therapy, as well as for more widely spaced treatment. Similarly, incorporation of drug into inhalable microparticles may reduce dose requirements, minimize toxicity, and deliver drug to infected alveolar macrophages. Although experimental studies have suggested that these approaches might be effective, little clinical work has been done in these areas (11,12). Because of possible detrimental effects of the cytokine, tumor necrosis factor-α, in HIV-associated tuberculosis, there has been some interest in the use of drugs, such as thalidomide and pentoxifylline, that block tumor necrosis factor-α production. Studies have shown that administration of thalidomide improves weight gain in both HIV-positive and HIVnegative tuberculosis patients (13). Pentoxifylline has been associated with reductions in circulating HIV viral load in patients with tuberculosis (14). However, the potential side effects of these drugs may outweigh possible benefits. A more promising intervention is the administration of "protective" cytokines, such as aerosolized interferon-γ and subcutaneous interleukin-2, that have shown activity as adjuncts to chemotherapy in patients with multidrug-resistant tuberculosis (15,16). Another method of immunomodulation, the use of heat-killed preparations of M. vaccae as a therapeutic vaccine, has not shown clinically significant benefits when carefully evaluated in randomized clinical trials (17). Nonetheless, there continues to be interest in this approach, especially for patients with advanced drug-resistant tuberculosis. Other vaccines that have been shown to lead to expression of protective cytokines have shown more promise in experimental studies (18). Finally, a study suggested that the administration of Vitamin A and zinc to patients with pulmonary tuberculosis is associated with an increased rate of sputum conversion and improvement in chest radiographs (19). Further assessment of nutritional supplements in tuberculosis treatment may be indicated. # Better methods to identify and manage high-and low-risk patients As noted above, sputum culture positivity at 2 months appears to be a marker for an increased risk of relapse for patients with pulmonary tuberculosis. Surrogate markers that could be measured earlier in therapy and have a greater sensitivity and specificity for a poor outcome could better select high risk patients for more intensive or longer therapy, thus minimizing the likelihood of relapse. Studies of several molecular markers in the sputum have shown promise and deserve further evaluation (20). Conversely, markers that reliably identify patients at lower risk of an adverse treatment outcome would be helpful to select patients for less intense or shorter treatment. Whether or not low-risk patients can be treated with shorter regimens using currently available drugs is a topic of considerable importance. # Health services research to facilitate treatment administration and improve treatment outcome Although DOT (as a component of DOTS) is widely advocated as a universal standard of care for tuberculosis treatment, many tuberculosis control programs do not have the resources to provide DOT for all patients. Moreover, some programs have achieved excellent results by targeting DOT to patients known or suspected of being at increased risk for nonadherence. Further evaluation of alternatives to universal DOT is needed. Finally, although limited work has been done in the area of behavioral studies of tuberculosis patients and providers, an ambitious research agenda established in the mid-1990s has not been implemented and should be revisited (21). # Acknowledgment The Committee thanks Elisha Malanga of the American Thoracic Society for excellent administrative support. The Committee also thanks the members of an ad hoc review panel convened by the Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC, for their thorough review and helpful comments. The members of this panel were as follows # active tuberculosis for persons with latent tuberculosis infection who had chest radiographs showing fibrotic lesions consistent with inactive tuberculosis. Among those receiving INH for at least 6 months, the incidence of tuberculosis was significantly reduced compared with those given placebo. In patients with fibrotic lesions greater than 2 cm in diameter INH given for 12 months was significantly better than 6 months (89 versus 67% reduction). A reanalysis of data from a community-based study of persons with abnormal radiographs felt to represent inactive tuberculosis showed that the efficacy of INH decreased significantly if less than 9 months of the drug was taken, but that further protection was not conferred if the duration was extended from 9 to 12 months (6). On the basis of these data, guidelines for treatment of latent tuberculosis infection recommend 9 months of INH for persons with abnormal chest radiographs consistent with prior tuberculosis (5). (7). Instances of severe and fatal liver disease have been reported in patients taking RIF and PZA for treatment of latent tuberculosis infection (8). In addition, the frequency of hepatotoxicity has been shown to be greater with RIF-PZA than with INH alone (7.7% Grade 3 or 4 hepatotoxicity with RIF-PZA compared with 1% for INH; p = 0.001) (9). In view of these data, the regimen should be used with caution and with careful monitoring, measuring serum AST and bilirubin at baseline and after 2, 4, and 6 weeks of treatment. RIF-PZA is not recommended for patients with underlying liver disease or a history of alcoholism, or for those who have had hepatotoxicity from INH. The regimen should be reserved for patients who are not likely to complete a longer course of treatment and who can be monitored carefully. ¶ Isolates of M. tuberculosis that are resistant to rifampin or resistant to any two primary drugs should be tested for susceptibility to the secondary drugs. In addition, the NCCLS recommends a higher concentration of ethambutol (i.e., 10 mg/ml in both 7H10 and 7H11 agar) should be tested. # Kanamycin is the class agent for amikacin. ** Some investigators also test a higher concentration (usually 1.0 or 2.0 mg/ml) of rifabutin. United States, individualized retreatment regimens, based on drug susceptibility patterns, as described in Section 9, Management of Relapse, Treatment Failure, and Drug Resistance, are recommended. However, in countries without the capacity to obtain susceptibility tests, individualized regimens cannot be prescribed. Nevertheless, at least one group has demonstrated that in a high-incidence, low-income country (Peru) treatment with individualized regimens is feasible and effective (7). # Monitoring of Outcomes of Therapy Both the WHO and the IUATLD recommend a formal system for monitoring outcomes of treatment that classifies all cases into one of six categories (cured, completed without proof of cure, failed, died, defaulted, or transferred out). The assessment of cure is based on clinical response and on sputum AFB smear (or culture when available) at completion of treatment. The analysis of these outcomes is by temporal cohorts and enables identification of programmatic shortcomings. # Recommended Doses of Antituberculosis Drugs The WHO recommends 10 mg/kg as the dose for three times weekly INH, whereas the ATS/CDC/IDSA recommend 15 mg/kg (Table 3). There is no difference in the daily doses recommended for adults (5 mg/kg per day to a maximum of 300 mg/day), but the ATS/CDC/IDSA recommend a higher dose for children (10-15 mg/kg per day), based primarily on the expert opinion of pediatricians. The IUATLD recommendations are based on the number of pills required for three weight ranges resulting in a dose of about 5 mg/kg up to 300 mg/day. The clinical trials of the BMRC that established the efficacy of three times weekly regimens all used an INH dose of 15 mg/kg. The 10-mg/kg INH dose for thrice-weekly regimens was extrapolated by the WHO and the IUATLD (with assistance from global experts), and was chosen to maintain the weekly amount of INH approximately equal to that of the daily or twice weekly regimens. # Drugs/Preparations Not Available in the United States Thioacetazone, which formerly was commonly used, is still available in most parts of the world, but is used less frequently. However, thioacetazone remains listed as an "essential" firstline drug by the WHO and is a component of the recommended IUATLD first-line regimen. Combination preparations not available in the United States but listed by the WHO include the following: INH (150 mg) and EMB (400 mg); INH (100 mg) and thioacetazone (50 mg); and INH (75 mg), RIF (150 mg), PZA (400 mg), and EMB (275 mg). The IUATLD recommends using only combination preparations of INH and RIF or INH and thiacetazone. # Treating Pregnant Women Both the WHO and the IUATLD include PZA in the regimen for treating pregnant women, in the absence of data indicating that there are adverse consequences. # Management of Common Adverse Reactions Neither baseline nor follow-up testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly. # Goal and Objectives This MMWR provides recommendations regarding treatment for tuberculosis (TB) infection in the United States. These recommendations were developed by the American Thoracic Society, CDC staff, and the Infectious Disease Society of America. The goal of this report is to provide guidance for health-care providers and public health professionals regarding the treatment for active TB among adults and children in the United States. Upon completion of this educational activity, the reader should be able to 1) describe the principles of antituberculosis chemotherapy; 2) describe the current recommendations for treating tuberculosis; 3) describe how to treat TB in special situations; 4) describe precautions regarding treatment regimens for TB; and 5) describe how to manage disease relapse, treatment failure, and drug resistance. To receive continuing education credit, please answer all of the following questions. # Which of the following groups should be given high priority for directly observed therapy (DOT)? A. Persons with current or prior substance abuse. B. Persons with memory impairment. C. Persons having pulmonary TB with positive sputum smears. D. Persons who have been previously treated for latent TB infection. E. All of the above groups. # Which of the following statements is false concerning sputum cultures? A. Sputum cultures should be obtained at the end of the initial treatment phase. B. Patients with positive cultures at diagnosis must have a repeat chest radiograph at 2 months. C. If a positive culture is obtained at 2 months in a patient with initial chest cavitation, the total treatment regimen should be extended to 9 months. D. Cultures that are initially positive should undergo susceptibility testing for isoniazid, rifampin, and ethambutol. # Which of the following is the preferred treatment regimen for TB among HIV-positive persons? A. Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by once weekly isoniazid and rifapentine for 4 months. B. Daily isoniazid, rifampin, and ethambutol for 2 months, followed by daily isoniazid and rifampin for 4 months. C. Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by daily isoniazid and rifampin for 4 months. D. Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by thrice weekly isoniazid and rifampin for 4 months. # Which of the following is the preferred treatment regimen for TB among children? A. Thrice weekly isoniazid, ethambutol, and rifapentine for 2 months, followed by thrice weekly isoniazid and rifapentine for 4 months. B. Daily isoniazid and rifampin supplemented with pyrazinamide for 2 months, followed by daily isoniazid and rifampin for 4 months. C. Daily isoniazid, rifampin, and ethambutol for 2 months, followed by daily isoniazid and rifapentine for 4 months. D. Daily isoniazid, rifampin, streptomycin, and ethambutol for 2 months, followed by thrice weekly isoniazid and rifampin for 4 months. # Which of the following statements is true concerning management of adverse effects? A. If a patient with severe TB experiences a rash or fever, three new drugs should be administered in the interim before medications are restarted one by one. B. Rifampin should be excluded from the treatment regimen for patients who experience drug-induced hepatitis. C. Patients experiencing adverse effects from first-line drugs should switch to second-line drugs. D. Modest asymptomatic elevations of aspartate aminotransferase (AST) require changing the treatment regimen. # Which of the following is a clinically relevant drug-drug interaction? A. Rifabutin and CYP3A inducers. B. Isoniazid and certain anticonvulsants. C. Rifampin and the majority of human immunodeficiency virus type 1(HIV-1) protease-inhibitors. D. Ciprofloxacin and theophylline. E. All of the above. # Which of the following statements is true concerning interruptions in treatment? A. The duration of interruptions in treatment alone determines whether the regimen should be restarted. B. Continuous treatment is more important in the continuation phase of therapy. C. DOT is not necessary for brief interruptions in treatment. D. Patients who complete >80% of the planned total doses in the continuation phase may not need additional treatment. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy each week, send an e-mail message to [email protected]. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/mmwr or from CDC's file transfer protocol server at ftp://ftp.cdc.gov/pub/publications/mmwr. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone 202-512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone 888-232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. All MMWR references are available on the Internet at http://www.cdc.gov/mmwr. Use the search function to find specific articles. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.	None	None
769e680a09b96b81f7651d601c7ac8f0a25a916d	cdc	None	These revised recom m endations o f the Im mumzafioh Practices A dvisory Comrhittee (ACIP) on measles prevention update the previous recom m endations f MMWR 1982,31:217-224,229-231) to include current inform ation about vaccine effectiveness and m easles e lim ination efforts. A lthough there are no basic changes in approach, the statem ent includes an a dditional option fo r outbreak control (revaccination o f persons in itia lly vaccinated at 12-14 m onths o f age) and new recom m endations fo r in tern a tio n a l travelers and m edical personnel.July 10, 1987 ACIP: Measles -Continued in 1965 (Schwarz strain), and a similar vaccine (Moraten strain) was licensed in 1968. These further-attenuated vaccines cause fewer reactions than the Edmonston B vaccine yet are equally effective. The Moraten vaccine is the vaccine currently used in the United States. Because of evidence of increased vaccine efficacy at older ages, the recommended age for vaccination, originally set at 9 months in 1963, was changed to 12 months in 1965 and to 15 months in 1976. Although vaccination is currently recommended at 15 months of age for optimal efficacy, vaccination as early as 12 months of age (on or after the first birthday) is considered appropriate evidence of measles immunity, and children vaccinated at 12-14 months of age are not routinely revaccinated. Vaccina tion as early as 6 months of age is recommended in settings of increased risk of disease.Since licensure of vaccine in 1963, the collaborative efforts of professional and voluntary medical and public health organizations in vaccination programs have resulted in a 98%-99% reduction in the reported incidence of measles in the United States. The number of reported measles cases decreased during the late 1960s and early 1970s to between 22,000 and 75,000 cases annually, with incidence rates falling dramatically in all age groups. Children <10 years old had the greatest decline in incidence, whereas older children had a slightly less dramatic decrease. As a result, the proportion of total cases occurring in different age groups changed so that by the period 1976-1980,46% of cases occurred in children ^10 years of age, compared with the period 1960-1964, when only 9.9% of cases occurred in this age group. A Measles Elimination Program was announced in 1978, with a goal to eliminate indigenous measles from the United States by October 1, 1982. There are three components of this program: 1) achievement and maintenance of high levels of immunity, 2) effective surveillance of disease, and 3) aggressive outbreak control. As a result of these efforts, the number of cases of measles reported annually dropped from 26,# INTRODUCTION Measles (rubeola) is often a severe disease, frequently complicated by middle ear infection or bronchopneumonia. Encephalitis occurs in approximately one of every 2,000 reported cases; survivors often have permanent brain damage and mental retardation. Death, predominantly from respiratory and neurologic causes, occurs in one of every 3,000 reported measles cases. The risk of death is greater for infants and adults than for children and adolescents. Subacute sclerosing panencephalitis (SSPE) is a "slow virus" infection of the central nervous system associated with measles virus. Widespread use of measles vaccine has led to the virtual disappearance of SSPE from the United States. Contracting measles during pregnancy increases fetal risk. Most commonly, this risk involves premature labor and moderately increased rates of spontaneous abortion and of low birth weight. One study has suggested that measles infection in the first trimester may induce congenital malformations; confirmatory reports have not been published. Before measles vaccine was available, more than 400,000 measles cases were reported each year in the United States. However, since virtually all children acquired measles, the true number of cases was probably more than 4 million per year (i.e., the entire birth cohort). Both the type of measles vaccine and the recommended age for measles vaccination have changed several times since 1963, when both an inacti vated and a live, attenuated vaccine (Edmonston B strain) were licensed for use in the United States. The inactivated vaccine was used until 1967, andEdmonston B vaccine, until 1972. A live, further-attenuated Edmonston vaccine was first introduced # Impediments to Measles Elimination Despite the great success achieved to date in reducing the occurrence of measles in the United States, the goal of eliminating indigenous measles has not yet been reached. Part of the problem is failure to implement the current strategy. Preventable cases (i.e., those in unvaccinated persons) account for approximately one-third of all cases. The age group with the largest proportion of preventable cases is the preschool group. Children at this age may not yet be enrolled in institutions covered by day-care or school-entry immunization requirements. A substantial proportion of cases occur among persons who have previously received vaccine. Theoretically, vaccine failures may be primary (the person never developed an adequate immune response to vaccination) or secondary (the person initially developed an adequate response but lost immunity over time). Some of the reported vaccine failures may be among persons whose records incorrectly indicate that they were properly vaccinated. Measles vaccine is at least 95% effective in children vaccinated at ^15 months of age. However, efficacy may be slightly lower in persons vaccinated between 12 and 14 months of age, presumably because transpla cental maternal antibody may persist beyond the first birthday in some children and Another problem is importation of measles from outside the United States. Although importations account for a small proportion of cases (2%), they have initiated several outbreaks and, in some parts of the United States, may be respon sible for more measles cases than the number indicated by available surveillance data. # Augmentation of Measles Elimination Activities The Committee considered, in detail, current measles epidemiology and the measles elimination strategy, as well as potential modifications. It concluded that the current strategy needed more complete implementation to ensure that vaccination takes place at 15 months of age rather than being delayed, for example, until it is required for school entry. After consideration of possible modifications of the measles elimination strategy, including administering two doses, lowering the age for vaccination, and routinely revaccinating those vaccinated between 12 and 14 months of age, the Committee determined that no change in the routine policy is indicated at present. Continued careful observation and analysis of measles epidemiology is indicated so that any necessary change in strategy can be implemented. # MEASLES VIRUS VACCINE Live measles virus vaccine,- available in the United States, is prepared in chick embryo cell culture. It is available in monovalent (measles only) form and in combinations: measles-rubella (MR) and measles-mumps-rubella (MMR) vaccines. All vaccines containing measles virus are recommended for use at 15 months of age under routine conditions. MMR is the vaccine of choice for routine vaccination programs. In all situations in which measles vaccine is to be used, a combination vaccine should be given if recipients are likely to be susceptible to rubella and/or mumps as well as to measles. There is no harm in revaccinating persons already immune to any of the components of MMR vaccine. Measles vaccine produces a mild or inapparent noncommunicable infection. Measles antibodies develop in at least 95% of susceptible children vaccinated at ^15 months of age. Both serologic and epidemiologic evidence extending through 23 years indicates that, although the titers of vaccine-induced antibody are lower than those following natural disease, the protection conferred appears to be durable. # Vaccine Shipment and Storage Vaccine that has been improperly stored may not provide protection against measles. Although data indicate that current measles vaccine may be more thermo stable than vaccine produced in the past, it should be kept at 2 C-8 C (35.6 F-46.4 F) or colder during storage. It must also be protected from light, which may inactivate the virus. Vaccine must be shipped at 10 C (50 F) or colder and may be shipped on dry ice. # VACCINE USAGE General Recommendations Persons are considered immune to measles only if they have documentation of 1) adequate immunization with live measles vaccine on or after the first birthday, 2) physician-diagnosed measles, or 3) laboratory evidence of measles immunity. Most persons born before 1957 are likely to have been naturally infected and generally need not be considered susceptible. All other children, adolescents, and The most commonly used laboratory test for assessing immunity to measles has been the hemagglutination-inhibition (HI) test. Other sensitive assays, such as the enzyme immunoassay (EIA), are now being used by many laboratories. Probably most, if not all, persons with detectable antibody are immune. Routine serologic screening to determine measles immunity is not recommended. # Dosage A single dose of live measles vaccine (as a monovalent or combination product) should be given subcutaneously in the volume specified by the manufacturer. There is no need for a "booster" dose of vaccine if vaccine is given on or after the first birthday. # Age at Vaccination Measles vaccine is indicated for persons susceptible to measles, regardless of age, unless otherwise contraindicated (see below). Current evidence indicates that for a maximum seroconversion rate, measles vaccine should be given when children are >15 months of age. Because cases continue to occur in preschool children, increased emphasis must be placed on vaccinating children promptly at 15 months of age. It is particularly important to vaccinate young children >15 months of age before they might encounter measles in day-care centers or other environments where young children cluster. The risk of complications from measles is high among infants <1 year of age. Therefore, considering the benefits and risks, the Committee recommends that infants as young as 6 months of age should be vaccinated with monovalent measles vaccine when exposure to natural measles is considered likely. Because infants vaccinated before the first birthday have a significantly lower rate of seroconversion, they should be revaccinated when they are 15 months old to ensure protection. # Revaccination of Persons Vaccinated According to Earlier Recommendations Previous vaccination with live vaccine: Persons vaccinated with live measles vaccine before their first birthday should be identified and revaccinated. Some serologic studies show lower seroconversion and seroprevalence rates in children vaccinated between 12 and 14 months of age (80%-95%) than in those vaccinated at >15 months (>95%). Many outbreak investigations have also found higher attack rates in persons vaccinated between 12 and 14 months of age than in those vaccinated at >15 months of age. However, a few other studies have not found a difference. Between 1965 and 1976, the recommended age for vaccination in the United States was 12 months; therefore, a large proportion of persons who are between 10 and 21 years of age in 1987 are likely to have been vaccinated when they were between 12 and 14 months of age. Because the vast majority of persons vaccinated between 12 and 14 months of age are fully protected against measles, routine revaccination of such persons is not warranted. However, if revaccination is requested, there is no immunologic or safety reason to deny the request. In an outbreak setting, such revaccination may be useful. (See Outbreak Control.) Edmonston B vaccine was effectively administered with immune globulin (IG). However, the immune response to further-attenuated measles vaccine strains may be impeded by IG. Therefore, the Committee recommends that persons who received measles vaccine of unknown type or further-attenuated measles vaccine accompa nied by IG should be revaccinated. Previous vaccination with killed vaccine or vaccine of unknown type: Some persons who have received inactivated vaccine are at risk of contracting a severe atypical measles syndrome when exposed to the natural virus. Consequently, persons vaccinated at any age with inactivated vaccine (available in the United States from 1963 to 1967) and persons vaccinated with inactivated vaccine followed by live vaccine within 3 months should be revaccinated. Revaccination is particularly important when the risk of exposure to natural measles virus is increased, for example, during foreign travel. A wide range (4%-55%) of prior recipients of killed measles vaccine who were revaccinated with live measles vaccine have reportedly had adverse reactions to the live vaccine. Most of these reactions have been mild, consisting of local swelling and erythema, with or without low-grade fever lasting 1-2 days. Rarely, more severe reactions, including prolonged high fevers and extensive local reactions requiring hospitalization, have been reported. However, prior recipients of killed measles vaccine are more likely to have serious illness when exposed to natural measles than when given live measles virus vaccine. These same recommendations for revaccination apply to persons vaccinated between 1963 and 1967 with a vaccine of unknown type, since their only vaccination may have been with inactivated vaccine. Because killed measles vaccine was not distributed in the United States after 1967, persons vaccinated after 1967 with a vaccine of unknown type need not be revaccinated if the original vaccination occurred on or after the first birthday and was not accompanied by IG. # Individuals Exposed to Disease Use of vaccine: Exposure to measles is not a contraindication to vaccination. Available data suggest that live measles vaccine, if given within 72 hours of measles exposure, may provide protection and is preferable to the use of IG in persons at least 12 months of age if there is no contraindication. If the exposure does not result in infection, the vaccine should induce protection against subsequent measles infection. Use of IG: IG can be given to prevent or modify measles in a susceptible person within 6 days after exposure. The recommended dose of IG is 0.25 ml/kg (0.11 ml/lb) of body weight (maximum dose = 15 ml). IG may be especially indicated for suscep tible household contacts of measles patients, particularly contacts under 1 year of age, pregnant women, or immunocompromised persons, for whom the risk of complications is highest. The recommended dose of IG for immunocompromised persons is 0.5 ml/kg of body weight (maximum dose = 15 ml). If the individual is at least 15 months old and there is no contraindication to vaccination, live measles vaccine should be given 3 months later, by which time the passively acquired measles antibodies should have disappeared. IG should not be used to control measles outbreaks. # SIDE EFFECTS AND ADVERSE REACTIONS Experience with more than 160 million doses of measles vaccine distributed in the United States through 1986 indicates an excellent record of safety. From 5% to 15% of vaccinees may develop a temperature of 5103 F (239.4 C) beginning about the fifth ACIP: Measles -Continued day after vaccination and usually lasting several days. Most persons with fever are otherwise asymptomatic. Transient rashes in approximately 5% of vaccinees have been reported. Central nervous system conditions including encephalitis and enceph alopathy have been reported with a frequency of less than one case per million doses administered. The incidence rate of encephalitis or encephalopathy following mea sles vaccination is lower than the observed incidence rate of encephalitis of unknown etiology, suggesting that some or most of the reported severe neurologic disorders may be only temporally related to measles vaccination rather than due to vaccination. Limited data indicate that reactions to the vaccine are not age related. # Personal and Family History of Convulsions As with the administration of any agent that may produce fever, some children may have a febrile seizure following measles vaccination. Although children with a personal or family history of seizures are at increased risk for developing idiopathic epilepsy, febrile seizures -including those following vaccinations-do not, in and of themselves, increase the probability of subsequent epilepsy or other neurologic disorders. Most convulsions following measles-containing vaccines are simple febrile seizures, and they occur in children without known risk factors. Recent data suggest that there is an increased risk of these convulsions among children with a prior history of convulsions or those with a history of convulsions in first-degree family members (i.e., siblings or parents). Although the precise risk cannot bedetermined, it appears to be low. In developing vaccination recommendations concerning these children, the Com mittee considered a number of factors including risks from measles disease, the large number (5%-7%) of children with a personal or family history of convulsions, and the fact that convulsions following measles vaccine are uncommon and have not been associated with permanent brain damage. The Committee concluded that the benefits of immunizing children with a personal history of convulsions or a family history of convulsions in first-degree relatives greatly outweigh the risks. These children should be vaccinated in the same way that children without such histories are vaccinated. Because the period for contracting vaccine-induced fever begins approximately 5 days after vaccination and lasts approximately 1 week, effective reduction of the risk of a febrile seizure is difficult. Prophylaxis with antipyretics is one alternative, but these agents probably would be ineffective if given after the onset of fever. To be effective, they would have to be given before the expected onset of fever and continued for another 5-7 days. Nevertheless, parents should closely observe children for fever during this period, and if fever occurs, the child should be treated appropriately. Children who are receiving anticonvulsants should continue to take them after measles vaccination. Because protective levels of most currently available anticon vulsant drugs (e.g., phenobarbitol) are not achieved for some time after the initiation of therapy, prophylactic use of these drugs does not seem feasible. The parents of children who have either a personal or family history of seizures should be advised that such children have a small increased risk of seizures following vaccination. In particular, they should be told in advance of measles vaccination what to do in the unlikely event that the child has a seizure. The permanent medical record July 10, 1987 ACIP: Measles -Continued should document that the small risk of postvaccination seizures and the benefits of vaccination for these children have been discussed. # Revaccination Risks There is no evidence of enhanced risk from receiving live measles vaccine to persons who are already immune to measles, either from vaccination or natural disease. (See Previous vaccination with killed vaccine or vaccine of unknown type.) # PRECAUTIONS AND CONTRAINDICATIONS Pregnancy Live measles vaccine should not be given to women known to be pregnant or who are considering becoming pregnant within 3 months after vaccination. This precau tion is based on the theoretical risk of fetal infection, which applies to the adminis tration of any live virus vaccine to women who might be pregnant or who might become pregnant shortly after vaccination. No evidence exists to substantiate this theoretical risk from measles vaccine. Considering the importance of protecting adolescents and young adults against measles with its known serious risks, asking women if they are pregnant, excluding those who are, and explaining the theoretical risks to the others before vaccination are the recommended precautions in a measles immunization program. # Febrile Illness Vaccine administration should not be postponed because of minor illnesses, such as mild upper-respiratory infections. However, vaccination of persons with severe febrile illnesses should generally be deferred until they have recovered. Considering the importance of measles protection, medical personnel should use every opportu nity to vaccinate susceptible children. # Allergies Hypersensitivity reactions following the administration of live measles vaccine are rare. Most of these reactions are minor and consist of wheal and flare or urticaria at the injection site. With more than 160 million doses of measles vaccine distributed in the United States, there have been at least five reported cases of immediate allergic reactions in children who had histories of anaphylactic reactions to egg ingestion. These reactions to vaccine could potentially have been life threatening. Four children experienced difficulty in breathing; one of these had hypotension. Persons with a history of anaphylactic reactions following egg ingestion (hives, swelling of the mouth and throat, difficulty in breathing, hypotension, or shock) should be vaccinated only with extreme caution. Protocols have been developed for vaccinating such persons ( 1 ). Evidence indicates that persons are not at increased risk if they have egg allergies that are not anaphylactic in nature. Such persons should be vaccinated in the usual manner. There is no evidence that persons with allergies to chickens or feathers are at increased risk of reaction to the vaccine. Since measles vaccine contains trace amounts of neomycin (25\|xg), persons who have had anaphylactic reactions to topically or systemically administered neomycin should not receive measles vaccine. Most often, neomycin allergy is manifested as a contact dermatitis that is a delayed-type (cell-mediated) immune response rather than anaphylaxis. In such individuals the adverse reaction, if any, to 25\|xg of neomycin in the vaccine would be an erythematous, pruritic nodule or papule at 48-96 hours. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine. Live measles virus vaccine does not contain penicillin. MMWR 417 # ACIP: Measles -Continued Recent Administration of IG Vaccination should be deferred for 3 months after a person has received IG, whole blood, or other antibody-containing blood products because passively acquired antibodies might interfere with the response to the vaccine. If vaccine is given to a person who has received such products within the preceding 3 months, the person should be revaccinated. If IG is to be administered in preparation for international travel, administration of vaccine should precede IG by at least 2 weeks. # Tuberculosis Tuberculosis may be exacerbated by natural measles infection. There is no evidence that the live measles virus vaccine has such an effect. Tuberculin skin testing is not a prerequisite for measles vaccination. If tuberculin testing is needed, it can be done the day of vaccination. Otherwise, it is prudent to wait 4-6 weeks after measles immunization before administering a tuberculin skin test, since measles vaccination may temporarily suppress tuberculin reactivity. # Altered Immunity Replication of the measles vaccine virus may be potentiated in patients with immune deficiency diseases and by the suppressed immune responses that occur with leukemia, lymphoma, generalized malignancy, acquired immunodeficiency syndrome (AIDS), or with certain therapies (corticosteroids, alkylating drugs, antime tabolites, or radiation). Patients with such conditions should not be given live measles virus vaccine. Since vaccinated persons do not transmit vaccine virus, the risk to these patients of being exposed to measles may be reduced by vaccinating their close susceptible contacts. Management of such persons, should they be exposed to measles, can be facilitated by prior knowledge of their immune status. If susceptible, they should receive IG following exposure (see below). Patients with leukemia in remission whose chemotherapy has been terminated for at least 3 months may receive live virus vaccines. Persons infected with the human immunodeficiency virus (HIV) who are asymptomatic also can receive measles vaccine (2 ). Short-term corticosteroid therapy (<2 weeks), topical steroid therapy (e.g., nasal, skin), and intraarticular, bursal, or tendon injection with corticosteroids should not be immunosuppressive and do not contraindicate measles vaccine administration. However, measles vaccine should be avoided if systemic immuno suppressive levels are reached by prolonged, extensive, topical application. # Management of Patients with Contraindications to Measles Vaccine If immediate protection against measles is required for persons for whom measles vaccine is contraindicated, passive immunization with IG, 0.25 ml/kg (0.11 ml/lb) of body weight, should be given as soon as possible after known exposure (maximum dose = 15 ml). It is important to note, however, that IG in usual doses may not be effective in children with acute leukemia or other conditions associated with altered immunity. Consequently, for immunocompromised persons, the recommended dose of IG is 0.5 ml/kg of body weight (maximum dose = 15 ml). # SIMULTANEOUS ADMINISTRATION OF VACCINES Simultaneous administration of MMR, oral poliovirus vaccine (OPV), and diphthe ria and tetanus toxoids and pertussis (DTP) vaccines results in seroconversion rates and rates of side effects similar to those observed when the vaccines are adminis tered separately. On the basis of these results, the Committee recommends routine administration of MMR, OPV, and DTP simultaneously to susceptible persons at 15 months of age (3 ). Some health-care providers may prefer to continue administering MMR at 15 months of age, followed by DTP and OPV at 18 months of age, especially for patients who are known to be compliant with health-care recommendations. # ONGOING PROGRAMS The best means of reducing the incidence of measles is by having an immune population. Programs aimed at vaccinating children against measles at 15 months of age should be established and maintained in all communities. In addition, all other persons thought to be susceptible, regardless of age, should be vaccinated when they are identified, unless vaccine is otherwise contraindicated. Official health agencies should take whatever steps are necessary, including development and enforcement of school immunization requirements, to achieve and maintain high immunization levels. Most states currently require evidence of immu nity to measles for children enrolled in day-care centers. Enforcement of such requirements has been correlated with reduced measles incidence rates. (Continued on page 423) # Vaccination for College Entry Measles outbreaks continue to be reported from settings where young adults are concentrated, such as colleges. Measles control in these places requires careful evaluation of susceptibility and vaccination of those who are susceptible. The Committee recommends that colleges and universities require proof of measles immunity as a condition for matriculation. # Vaccination for Medical Personnel Medical personnel are at higher risk for acquiring measles than the general population. Medical facilities should ensure that all employees born after 1956 have proof of immunity (See Vaccine Usage). Since a substantial proportion of medical personnel who have acquired measles were born before 1957, medical facilities may also consider requiring proof of measles immunity for older employees who may have occupational exposure to measles. # Outbreak Control All reports of suspected measles cases should be investigated rapidly. A measles outbreak exists in a community whenever one case of measles is confirmed. Once an outbreak occurs, preventing dissemination of measles depends on promptly vacci nating susceptible persons. Control activities should not be delayed until laboratory results on suspected cases are received. All persons who cannot readily provide proof of immunity should be vaccinated or excluded from the setting (e.g., school). Documentation of vaccination should be considered adequate only if the date of vaccination is provided. An effective means of terminating school outbreaks and quickly increasing rates of immunization is to exclude all children or adolescents from the outbreak area who cannot present valid evidence of immunity. Students can be readmitted immediately after vaccination. Experience with outbreak control indicates that almost all students who are excluded from the outbreak area because they lack evidence of immunity to measles quickly comply with requirements and can be readmitted to school. Pupils who have been exempted from measles vaccination because of medical, religious, or other reasons should be excluded until at least 2 weeks after the onset of rash in the last person with measles in the outbreak area. Persons vaccinated between 12 and 14 months of age have been shown in some serologic and epidemic investigations to be at increased risk of acquiring measles compared with those vaccinated at 215 months of age.However, the increased risk of acquiring measles is small. Nevertheless, in many outbreaks, particularly in junior and senior high schools, persons vaccinated at 12-14 months of age appear to have played a substantial role in perpetuating transmission. Therefore, although the effectiveness of such a strategy in terminating outbreaks has not been demonstrated conclusively, the Committee recommends that revaccination of persons vaccinated at 12-14 months of age should be considered in outbreak settings, particularly in junior and senior high schools. If revaccination is recommended, local officials should establish a geographic zone of risk and lim it revaccination to persons in this area. In the absence of an outbreak, routine revaccination of persons vaccinated at 12-14 months of age is not recommended. # Importations Measles importations are a continuing source of reported measles cases in the United States. Although most importations result in limited transmission, several large outbreaks have occurred. If susceptible persons are exposed to a patient on a common carrier, such as an airplane, rapid reporting of such imported cases to state and local health departments is important. Other state health departments should be notified to identify exposed contacts as well as to initiate surveillance and control measures. # SURVEILLANCE As the incidence rate of measles declines in the United States, aggressive surveillance becomes increasingly important. Known or suspected measles cases should be reported immediately to local health departments. Serologic confirmation should be attempted for every suspected case of measles that cannot be linked to a confirmed case. Reporting of suspected cases and implementation of outbreakcontrol activities should not be delayed while awaiting laboratory results. Effective surveillance of measles and its complications can delineate inadequate levels of protection, further define groups needing special attention, and assess the effective ness of control activities. Continuous and careful review of adverse events following measles vaccination is also important. All adverse events following vaccination should be evaluated and reported in detail to local and state health officials as well as to the vaccine manufacturer. # Laboratory Diagnosis The traditional serologic diagnosis of measles requires a significant rise in antibody titer between the acute-phase and convalescent-phase serum specimen. However, a single specimen can be used to detect the presence of immunoglobulin M (IgM) antibody. Correct interpretation of serologic data depends on the proper timing of specimen collection in relation to onset of rash. This is especially important for interpreting negative IgM results, since IgM antibody peaks 10 days after rash onset and is usually undetectable 30 days after rash onset. Asymptomatic reinfection with measles virus can occur in persons who have previously developed antibody, whether from vaccination or from natural disease. Symptomatic reinfections have been reported rarely. These infections have been accompanied by fourfold or greater rises in measles HI antibody titers, but measlesspecific IgM antibodies have not been detected in appropriately timed serum specimens. # INTERNATIONAL TRAVEL Persons traveling abroad should be immune to measles. Since the risk of serious complications and death is greater for adults than for children, it is especially important to protect young adults who have escaped measles and have not been vaccinated. Also, because measles vaccine is not 100% effective and because the risk of exposure to measles abroad may be substantially greater than in the United States, consideration should be given to providing a one-time dose of measles vaccine to persons born after 1956 who travel abroad regardless of their previous vaccination status, unless there is a contraindication. Persons born before 1957 need not be considered susceptible. MMR is preferred for persons likely to be susceptible to mumps and rubella. If single-antigen measles vaccine is not readily available, travelers should receive MMR regardless of their immune status to mumps and rubella. The age for measles vaccination should be lowered for children traveling to areas where measles is endemic or epidemic. Children 12-14 months of age should receive MMR vaccine before their departure (without need for revaccination). Children 6-11 ACIP: Measles -Continued ACIP: Measles -Continued months of age should receive a dose of single-antigen measles vaccine before departure and subsequently should receive MMR vaccine. Whereas the optimal age for revaccination is 15 months, the age for revaccination may be as low as 12 months if the child remains in a high-risk area. Since virtually all infants <6 months of age will be protected by maternally derived antibodies, no additional protection against measles in this age group is generally necessary.	These revised recom m endations o f the Im mumzafioh Practices A dvisory Comrhittee (ACIP) on measles prevention update the previous recom m endations f MMWR 1982,31:217-224,229-231) to include current inform ation about vaccine effectiveness and m easles e lim ination efforts. A lthough there are no basic changes in approach, the statem ent includes an a dditional option fo r outbreak control (revaccination o f persons in itia lly vaccinated at 12-14 m onths o f age) and new recom m endations fo r in tern a tio n a l travelers and m edical personnel.July 10, 1987 ACIP: Measles -Continued in 1965 (Schwarz strain), and a similar vaccine (Moraten strain) was licensed in 1968. These further-attenuated vaccines cause fewer reactions than the Edmonston B vaccine yet are equally effective. The Moraten vaccine is the vaccine currently used in the United States. Because of evidence of increased vaccine efficacy at older ages, the recommended age for vaccination, originally set at 9 months in 1963, was changed to 12 months in 1965 and to 15 months in 1976. Although vaccination is currently recommended at 15 months of age for optimal efficacy, vaccination as early as 12 months of age (on or after the first birthday) is considered appropriate evidence of measles immunity, and children vaccinated at 12-14 months of age are not routinely revaccinated. Vaccina tion as early as 6 months of age is recommended in settings of increased risk of disease.Since licensure of vaccine in 1963, the collaborative efforts of professional and voluntary medical and public health organizations in vaccination programs have resulted in a 98%-99% reduction in the reported incidence of measles in the United States. The number of reported measles cases decreased during the late 1960s and early 1970s to between 22,000 and 75,000 cases annually, with incidence rates falling dramatically in all age groups. Children <10 years old had the greatest decline in incidence, whereas older children had a slightly less dramatic decrease. As a result, the proportion of total cases occurring in different age groups changed so that by the period 1976-1980,46% of cases occurred in children ^10 years of age, compared with the period 1960-1964, when only 9.9% of cases occurred in this age group. A Measles Elimination Program was announced in 1978, with a goal to eliminate indigenous measles from the United States by October 1, 1982. There are three components of this program: 1) achievement and maintenance of high levels of immunity, 2) effective surveillance of disease, and 3) aggressive outbreak control. As a result of these efforts, the number of cases of measles reported annually dropped from 26,# INTRODUCTION Measles (rubeola) is often a severe disease, frequently complicated by middle ear infection or bronchopneumonia. Encephalitis occurs in approximately one of every 2,000 reported cases; survivors often have permanent brain damage and mental retardation. Death, predominantly from respiratory and neurologic causes, occurs in one of every 3,000 reported measles cases. The risk of death is greater for infants and adults than for children and adolescents. Subacute sclerosing panencephalitis (SSPE) is a "slow virus" infection of the central nervous system associated with measles virus. Widespread use of measles vaccine has led to the virtual disappearance of SSPE from the United States. Contracting measles during pregnancy increases fetal risk. Most commonly, this risk involves premature labor and moderately increased rates of spontaneous abortion and of low birth weight. One study has suggested that measles infection in the first trimester may induce congenital malformations; confirmatory reports have not been published. Before measles vaccine was available, more than 400,000 measles cases were reported each year in the United States. However, since virtually all children acquired measles, the true number of cases was probably more than 4 million per year (i.e., the entire birth cohort). Both the type of measles vaccine and the recommended age for measles vaccination have changed several times since 1963, when both an inacti vated and a live, attenuated vaccine (Edmonston B strain) were licensed for use in the United States. The inactivated vaccine was used until 1967, andEdmonston B vaccine, until 1972. A live, further-attenuated Edmonston vaccine was first introduced # Impediments to Measles Elimination Despite the great success achieved to date in reducing the occurrence of measles in the United States, the goal of eliminating indigenous measles has not yet been reached. Part of the problem is failure to implement the current strategy. Preventable cases (i.e., those in unvaccinated persons) account for approximately one-third of all cases. The age group with the largest proportion of preventable cases is the preschool group. Children at this age may not yet be enrolled in institutions covered by day-care or school-entry immunization requirements. A substantial proportion of cases occur among persons who have previously received vaccine. Theoretically, vaccine failures may be primary (the person never developed an adequate immune response to vaccination) or secondary (the person initially developed an adequate response but lost immunity over time). Some of the reported vaccine failures may be among persons whose records incorrectly indicate that they were properly vaccinated. Measles vaccine is at least 95% effective in children vaccinated at ^15 months of age. However, efficacy may be slightly lower in persons vaccinated between 12 and 14 months of age, presumably because transpla cental maternal antibody may persist beyond the first birthday in some children and Another problem is importation of measles from outside the United States. Although importations account for a small proportion of cases (2%), they have initiated several outbreaks and, in some parts of the United States, may be respon sible for more measles cases than the number indicated by available surveillance data. # Augmentation of Measles Elimination Activities The Committee considered, in detail, current measles epidemiology and the measles elimination strategy, as well as potential modifications. It concluded that the current strategy needed more complete implementation to ensure that vaccination takes place at 15 months of age rather than being delayed, for example, until it is required for school entry. After consideration of possible modifications of the measles elimination strategy, including administering two doses, lowering the age for vaccination, and routinely revaccinating those vaccinated between 12 and 14 months of age, the Committee determined that no change in the routine policy is indicated at present. Continued careful observation and analysis of measles epidemiology is indicated so that any necessary change in strategy can be implemented. # MEASLES VIRUS VACCINE Live measles virus vaccine,* available in the United States, is prepared in chick embryo cell culture. It is available in monovalent (measles only) form and in combinations: measles-rubella (MR) and measles-mumps-rubella (MMR) vaccines. All vaccines containing measles virus are recommended for use at 15 months of age under routine conditions. MMR is the vaccine of choice for routine vaccination programs. In all situations in which measles vaccine is to be used, a combination vaccine should be given if recipients are likely to be susceptible to rubella and/or mumps as well as to measles. There is no harm in revaccinating persons already immune to any of the components of MMR vaccine. Measles vaccine produces a mild or inapparent noncommunicable infection. Measles antibodies develop in at least 95% of susceptible children vaccinated at ^15 months of age. Both serologic and epidemiologic evidence extending through 23 years indicates that, although the titers of vaccine-induced antibody are lower than those following natural disease, the protection conferred appears to be durable. # Vaccine Shipment and Storage Vaccine that has been improperly stored may not provide protection against measles. Although data indicate that current measles vaccine may be more thermo stable than vaccine produced in the past, it should be kept at 2 C-8 C (35.6 F-46.4 F) or colder during storage. It must also be protected from light, which may inactivate the virus. Vaccine must be shipped at 10 C (50 F) or colder and may be shipped on dry ice. # VACCINE USAGE General Recommendations Persons are considered immune to measles only if they have documentation of 1) adequate immunization with live measles vaccine on or after the first birthday, 2) physician-diagnosed measles, or 3) laboratory evidence of measles immunity. Most persons born before 1957 are likely to have been naturally infected and generally need not be considered susceptible. All other children, adolescents, and The most commonly used laboratory test for assessing immunity to measles has been the hemagglutination-inhibition (HI) test. Other sensitive assays, such as the enzyme immunoassay (EIA), are now being used by many laboratories. Probably most, if not all, persons with detectable antibody are immune. Routine serologic screening to determine measles immunity is not recommended. # Dosage A single dose of live measles vaccine (as a monovalent or combination product) should be given subcutaneously in the volume specified by the manufacturer. There is no need for a "booster" dose of vaccine if vaccine is given on or after the first birthday. # Age at Vaccination Measles vaccine is indicated for persons susceptible to measles, regardless of age, unless otherwise contraindicated (see below). Current evidence indicates that for a maximum seroconversion rate, measles vaccine should be given when children are >15 months of age. Because cases continue to occur in preschool children, increased emphasis must be placed on vaccinating children promptly at 15 months of age. It is particularly important to vaccinate young children >15 months of age before they might encounter measles in day-care centers or other environments where young children cluster. The risk of complications from measles is high among infants <1 year of age. Therefore, considering the benefits and risks, the Committee recommends that infants as young as 6 months of age should be vaccinated with monovalent measles vaccine when exposure to natural measles is considered likely. Because infants vaccinated before the first birthday have a significantly lower rate of seroconversion, they should be revaccinated when they are 15 months old to ensure protection. # Revaccination of Persons Vaccinated According to Earlier Recommendations Previous vaccination with live vaccine: Persons vaccinated with live measles vaccine before their first birthday should be identified and revaccinated. Some serologic studies show lower seroconversion and seroprevalence rates in children vaccinated between 12 and 14 months of age (80%-95%) than in those vaccinated at >15 months (>95%). Many outbreak investigations have also found higher attack rates in persons vaccinated between 12 and 14 months of age than in those vaccinated at >15 months of age. However, a few other studies have not found a difference. Between 1965 and 1976, the recommended age for vaccination in the United States was 12 months; therefore, a large proportion of persons who are between 10 and 21 years of age in 1987 are likely to have been vaccinated when they were between 12 and 14 months of age. Because the vast majority of persons vaccinated between 12 and 14 months of age are fully protected against measles, routine revaccination of such persons is not warranted. However, if revaccination is requested, there is no immunologic or safety reason to deny the request. In an outbreak setting, such revaccination may be useful. (See Outbreak Control.) Edmonston B vaccine was effectively administered with immune globulin (IG). However, the immune response to further-attenuated measles vaccine strains may be impeded by IG. Therefore, the Committee recommends that persons who received measles vaccine of unknown type or further-attenuated measles vaccine accompa nied by IG should be revaccinated. Previous vaccination with killed vaccine or vaccine of unknown type: Some persons who have received inactivated vaccine are at risk of contracting a severe atypical measles syndrome when exposed to the natural virus. Consequently, persons vaccinated at any age with inactivated vaccine (available in the United States from 1963 to 1967) and persons vaccinated with inactivated vaccine followed by live vaccine within 3 months should be revaccinated. Revaccination is particularly important when the risk of exposure to natural measles virus is increased, for example, during foreign travel. A wide range (4%-55%) of prior recipients of killed measles vaccine who were revaccinated with live measles vaccine have reportedly had adverse reactions to the live vaccine. Most of these reactions have been mild, consisting of local swelling and erythema, with or without low-grade fever lasting 1-2 days. Rarely, more severe reactions, including prolonged high fevers and extensive local reactions requiring hospitalization, have been reported. However, prior recipients of killed measles vaccine are more likely to have serious illness when exposed to natural measles than when given live measles virus vaccine. These same recommendations for revaccination apply to persons vaccinated between 1963 and 1967 with a vaccine of unknown type, since their only vaccination may have been with inactivated vaccine. Because killed measles vaccine was not distributed in the United States after 1967, persons vaccinated after 1967 with a vaccine of unknown type need not be revaccinated if the original vaccination occurred on or after the first birthday and was not accompanied by IG. # Individuals Exposed to Disease Use of vaccine: Exposure to measles is not a contraindication to vaccination. Available data suggest that live measles vaccine, if given within 72 hours of measles exposure, may provide protection and is preferable to the use of IG in persons at least 12 months of age if there is no contraindication. If the exposure does not result in infection, the vaccine should induce protection against subsequent measles infection. Use of IG: IG can be given to prevent or modify measles in a susceptible person within 6 days after exposure. The recommended dose of IG is 0.25 ml/kg (0.11 ml/lb) of body weight (maximum dose = 15 ml). IG may be especially indicated for suscep tible household contacts of measles patients, particularly contacts under 1 year of age, pregnant women, or immunocompromised persons, for whom the risk of complications is highest. The recommended dose of IG for immunocompromised persons is 0.5 ml/kg of body weight (maximum dose = 15 ml). If the individual is at least 15 months old and there is no contraindication to vaccination, live measles vaccine should be given 3 months later, by which time the passively acquired measles antibodies should have disappeared. IG should not be used to control measles outbreaks. # SIDE EFFECTS AND ADVERSE REACTIONS Experience with more than 160 million doses of measles vaccine distributed in the United States through 1986 indicates an excellent record of safety. From 5% to 15% of vaccinees may develop a temperature of 5103 F (239.4 C) beginning about the fifth ACIP: Measles -Continued day after vaccination and usually lasting several days. Most persons with fever are otherwise asymptomatic. Transient rashes in approximately 5% of vaccinees have been reported. Central nervous system conditions including encephalitis and enceph alopathy have been reported with a frequency of less than one case per million doses administered. The incidence rate of encephalitis or encephalopathy following mea sles vaccination is lower than the observed incidence rate of encephalitis of unknown etiology, suggesting that some or most of the reported severe neurologic disorders may be only temporally related to measles vaccination rather than due to vaccination. Limited data indicate that reactions to the vaccine are not age related. # Personal and Family History of Convulsions As with the administration of any agent that may produce fever, some children may have a febrile seizure following measles vaccination. Although children with a personal or family history of seizures are at increased risk for developing idiopathic epilepsy, febrile seizures -including those following vaccinations-do not, in and of themselves, increase the probability of subsequent epilepsy or other neurologic disorders. Most convulsions following measles-containing vaccines are simple febrile seizures, and they occur in children without known risk factors. Recent data suggest that there is an increased risk of these convulsions among children with a prior history of convulsions or those with a history of convulsions in first-degree family members (i.e., siblings or parents). Although the precise risk cannot bedetermined, it appears to be low. In developing vaccination recommendations concerning these children, the Com mittee considered a number of factors including risks from measles disease, the large number (5%-7%) of children with a personal or family history of convulsions, and the fact that convulsions following measles vaccine are uncommon and have not been associated with permanent brain damage. The Committee concluded that the benefits of immunizing children with a personal history of convulsions or a family history of convulsions in first-degree relatives greatly outweigh the risks. These children should be vaccinated in the same way that children without such histories are vaccinated. Because the period for contracting vaccine-induced fever begins approximately 5 days after vaccination and lasts approximately 1 week, effective reduction of the risk of a febrile seizure is difficult. Prophylaxis with antipyretics is one alternative, but these agents probably would be ineffective if given after the onset of fever. To be effective, they would have to be given before the expected onset of fever and continued for another 5-7 days. Nevertheless, parents should closely observe children for fever during this period, and if fever occurs, the child should be treated appropriately. Children who are receiving anticonvulsants should continue to take them after measles vaccination. Because protective levels of most currently available anticon vulsant drugs (e.g., phenobarbitol) are not achieved for some time after the initiation of therapy, prophylactic use of these drugs does not seem feasible. The parents of children who have either a personal or family history of seizures should be advised that such children have a small increased risk of seizures following vaccination. In particular, they should be told in advance of measles vaccination what to do in the unlikely event that the child has a seizure. The permanent medical record July 10, 1987 ACIP: Measles -Continued should document that the small risk of postvaccination seizures and the benefits of vaccination for these children have been discussed. # Revaccination Risks There is no evidence of enhanced risk from receiving live measles vaccine to persons who are already immune to measles, either from vaccination or natural disease. (See Previous vaccination with killed vaccine or vaccine of unknown type.) # PRECAUTIONS AND CONTRAINDICATIONS Pregnancy Live measles vaccine should not be given to women known to be pregnant or who are considering becoming pregnant within 3 months after vaccination. This precau tion is based on the theoretical risk of fetal infection, which applies to the adminis tration of any live virus vaccine to women who might be pregnant or who might become pregnant shortly after vaccination. No evidence exists to substantiate this theoretical risk from measles vaccine. Considering the importance of protecting adolescents and young adults against measles with its known serious risks, asking women if they are pregnant, excluding those who are, and explaining the theoretical risks to the others before vaccination are the recommended precautions in a measles immunization program. # Febrile Illness Vaccine administration should not be postponed because of minor illnesses, such as mild upper-respiratory infections. However, vaccination of persons with severe febrile illnesses should generally be deferred until they have recovered. Considering the importance of measles protection, medical personnel should use every opportu nity to vaccinate susceptible children. # Allergies Hypersensitivity reactions following the administration of live measles vaccine are rare. Most of these reactions are minor and consist of wheal and flare or urticaria at the injection site. With more than 160 million doses of measles vaccine distributed in the United States, there have been at least five reported cases of immediate allergic reactions in children who had histories of anaphylactic reactions to egg ingestion. These reactions to vaccine could potentially have been life threatening. Four children experienced difficulty in breathing; one of these had hypotension. Persons with a history of anaphylactic reactions following egg ingestion (hives, swelling of the mouth and throat, difficulty in breathing, hypotension, or shock) should be vaccinated only with extreme caution. Protocols have been developed for vaccinating such persons ( 1 ). Evidence indicates that persons are not at increased risk if they have egg allergies that are not anaphylactic in nature. Such persons should be vaccinated in the usual manner. There is no evidence that persons with allergies to chickens or feathers are at increased risk of reaction to the vaccine. Since measles vaccine contains trace amounts of neomycin (25\|xg), persons who have had anaphylactic reactions to topically or systemically administered neomycin should not receive measles vaccine. Most often, neomycin allergy is manifested as a contact dermatitis that is a delayed-type (cell-mediated) immune response rather than anaphylaxis. In such individuals the adverse reaction, if any, to 25\|xg of neomycin in the vaccine would be an erythematous, pruritic nodule or papule at 48-96 hours. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine. Live measles virus vaccine does not contain penicillin. MMWR 417 # ACIP: Measles -Continued Recent Administration of IG Vaccination should be deferred for 3 months after a person has received IG, whole blood, or other antibody-containing blood products because passively acquired antibodies might interfere with the response to the vaccine. If vaccine is given to a person who has received such products within the preceding 3 months, the person should be revaccinated. If IG is to be administered in preparation for international travel, administration of vaccine should precede IG by at least 2 weeks. # Tuberculosis Tuberculosis may be exacerbated by natural measles infection. There is no evidence that the live measles virus vaccine has such an effect. Tuberculin skin testing is not a prerequisite for measles vaccination. If tuberculin testing is needed, it can be done the day of vaccination. Otherwise, it is prudent to wait 4-6 weeks after measles immunization before administering a tuberculin skin test, since measles vaccination may temporarily suppress tuberculin reactivity. # Altered Immunity Replication of the measles vaccine virus may be potentiated in patients with immune deficiency diseases and by the suppressed immune responses that occur with leukemia, lymphoma, generalized malignancy, acquired immunodeficiency syndrome (AIDS), or with certain therapies (corticosteroids, alkylating drugs, antime tabolites, or radiation). Patients with such conditions should not be given live measles virus vaccine. Since vaccinated persons do not transmit vaccine virus, the risk to these patients of being exposed to measles may be reduced by vaccinating their close susceptible contacts. Management of such persons, should they be exposed to measles, can be facilitated by prior knowledge of their immune status. If susceptible, they should receive IG following exposure (see below). Patients with leukemia in remission whose chemotherapy has been terminated for at least 3 months may receive live virus vaccines. Persons infected with the human immunodeficiency virus (HIV) who are asymptomatic also can receive measles vaccine (2 ). Short-term corticosteroid therapy (<2 weeks), topical steroid therapy (e.g., nasal, skin), and intraarticular, bursal, or tendon injection with corticosteroids should not be immunosuppressive and do not contraindicate measles vaccine administration. However, measles vaccine should be avoided if systemic immuno suppressive levels are reached by prolonged, extensive, topical application. # Management of Patients with Contraindications to Measles Vaccine If immediate protection against measles is required for persons for whom measles vaccine is contraindicated, passive immunization with IG, 0.25 ml/kg (0.11 ml/lb) of body weight, should be given as soon as possible after known exposure (maximum dose = 15 ml). It is important to note, however, that IG in usual doses may not be effective in children with acute leukemia or other conditions associated with altered immunity. Consequently, for immunocompromised persons, the recommended dose of IG is 0.5 ml/kg of body weight (maximum dose = 15 ml). # SIMULTANEOUS ADMINISTRATION OF VACCINES Simultaneous administration of MMR, oral poliovirus vaccine (OPV), and diphthe ria and tetanus toxoids and pertussis (DTP) vaccines results in seroconversion rates and rates of side effects similar to those observed when the vaccines are adminis tered separately. On the basis of these results, the Committee recommends routine administration of MMR, OPV, and DTP simultaneously to susceptible persons at 15 months of age (3 ). Some health-care providers may prefer to continue administering MMR at 15 months of age, followed by DTP and OPV at 18 months of age, especially for patients who are known to be compliant with health-care recommendations. # ONGOING PROGRAMS The best means of reducing the incidence of measles is by having an immune population. Programs aimed at vaccinating children against measles at 15 months of age should be established and maintained in all communities. In addition, all other persons thought to be susceptible, regardless of age, should be vaccinated when they are identified, unless vaccine is otherwise contraindicated. Official health agencies should take whatever steps are necessary, including development and enforcement of school immunization requirements, to achieve and maintain high immunization levels. Most states currently require evidence of immu nity to measles for children enrolled in day-care centers. Enforcement of such requirements has been correlated with reduced measles incidence rates. (Continued on page 423) # Vaccination for College Entry Measles outbreaks continue to be reported from settings where young adults are concentrated, such as colleges. Measles control in these places requires careful evaluation of susceptibility and vaccination of those who are susceptible. The Committee recommends that colleges and universities require proof of measles immunity as a condition for matriculation. # Vaccination for Medical Personnel Medical personnel are at higher risk for acquiring measles than the general population. Medical facilities should ensure that all employees born after 1956 have proof of immunity (See Vaccine Usage). Since a substantial proportion of medical personnel who have acquired measles were born before 1957, medical facilities may also consider requiring proof of measles immunity for older employees who may have occupational exposure to measles. # Outbreak Control All reports of suspected measles cases should be investigated rapidly. A measles outbreak exists in a community whenever one case of measles is confirmed. Once an outbreak occurs, preventing dissemination of measles depends on promptly vacci nating susceptible persons. Control activities should not be delayed until laboratory results on suspected cases are received. All persons who cannot readily provide proof of immunity should be vaccinated or excluded from the setting (e.g., school). Documentation of vaccination should be considered adequate only if the date of vaccination is provided. An effective means of terminating school outbreaks and quickly increasing rates of immunization is to exclude all children or adolescents from the outbreak area who cannot present valid evidence of immunity. Students can be readmitted immediately after vaccination. Experience with outbreak control indicates that almost all students who are excluded from the outbreak area because they lack evidence of immunity to measles quickly comply with requirements and can be readmitted to school. Pupils who have been exempted from measles vaccination because of medical, religious, or other reasons should be excluded until at least 2 weeks after the onset of rash in the last person with measles in the outbreak area. Persons vaccinated between 12 and 14 months of age have been shown in some serologic and epidemic investigations to be at increased risk of acquiring measles compared with those vaccinated at 215 months of age.However, the increased risk of acquiring measles is small. Nevertheless, in many outbreaks, particularly in junior and senior high schools, persons vaccinated at 12-14 months of age appear to have played a substantial role in perpetuating transmission. Therefore, although the effectiveness of such a strategy in terminating outbreaks has not been demonstrated conclusively, the Committee recommends that revaccination of persons vaccinated at 12-14 months of age should be considered in outbreak settings, particularly in junior and senior high schools. If revaccination is recommended, local officials should establish a geographic zone of risk and lim it revaccination to persons in this area. In the absence of an outbreak, routine revaccination of persons vaccinated at 12-14 months of age is not recommended. # Importations Measles importations are a continuing source of reported measles cases in the United States. Although most importations result in limited transmission, several large outbreaks have occurred. If susceptible persons are exposed to a patient on a common carrier, such as an airplane, rapid reporting of such imported cases to state and local health departments is important. Other state health departments should be notified to identify exposed contacts as well as to initiate surveillance and control measures. # SURVEILLANCE As the incidence rate of measles declines in the United States, aggressive surveillance becomes increasingly important. Known or suspected measles cases should be reported immediately to local health departments. Serologic confirmation should be attempted for every suspected case of measles that cannot be linked to a confirmed case. Reporting of suspected cases and implementation of outbreakcontrol activities should not be delayed while awaiting laboratory results. Effective surveillance of measles and its complications can delineate inadequate levels of protection, further define groups needing special attention, and assess the effective ness of control activities. Continuous and careful review of adverse events following measles vaccination is also important. All adverse events following vaccination should be evaluated and reported in detail to local and state health officials as well as to the vaccine manufacturer. # Laboratory Diagnosis The traditional serologic diagnosis of measles requires a significant rise in antibody titer between the acute-phase and convalescent-phase serum specimen. However, a single specimen can be used to detect the presence of immunoglobulin M (IgM) antibody. Correct interpretation of serologic data depends on the proper timing of specimen collection in relation to onset of rash. This is especially important for interpreting negative IgM results, since IgM antibody peaks 10 days after rash onset and is usually undetectable 30 days after rash onset. Asymptomatic reinfection with measles virus can occur in persons who have previously developed antibody, whether from vaccination or from natural disease. Symptomatic reinfections have been reported rarely. These infections have been accompanied by fourfold or greater rises in measles HI antibody titers, but measlesspecific IgM antibodies have not been detected in appropriately timed serum specimens. # INTERNATIONAL TRAVEL Persons traveling abroad should be immune to measles. Since the risk of serious complications and death is greater for adults than for children, it is especially important to protect young adults who have escaped measles and have not been vaccinated. Also, because measles vaccine is not 100% effective and because the risk of exposure to measles abroad may be substantially greater than in the United States, consideration should be given to providing a one-time dose of measles vaccine to persons born after 1956 who travel abroad regardless of their previous vaccination status, unless there is a contraindication. Persons born before 1957 need not be considered susceptible. MMR is preferred for persons likely to be susceptible to mumps and rubella. If single-antigen measles vaccine is not readily available, travelers should receive MMR regardless of their immune status to mumps and rubella. The age for measles vaccination should be lowered for children traveling to areas where measles is endemic or epidemic. Children 12-14 months of age should receive MMR vaccine before their departure (without need for revaccination). Children 6-11 ACIP: Measles -Continued ACIP: Measles -Continued months of age should receive a dose of single-antigen measles vaccine before departure and subsequently should receive MMR vaccine. Whereas the optimal age for revaccination is 15 months, the age for revaccination may be as low as 12 months if the child remains in a high-risk area. Since virtually all infants <6 months of age will be protected by maternally derived antibodies, no additional protection against measles in this age group is generally necessary. # -------------------------------------------------------------------------------------------------------------------------------------- .	None	None
dbbf74466f1873da2d5f8e4f4f9d04680c04e9bd	cdc	None	Front cover photo: An illustration of human papillomavirus (HPV) virions constructed with 3D animation software, using Protein Data Bank entry 1L0T.# Introduction Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 14 million persons are newly infected every year (1). Although most infections cause no symptoms and are self-limited, persistent HPV infection can cause cervical cancer in women as well as other anogenital cancers, oropharyngeal cancer, and genital warts in men and women. More than 150 HPV types have been identified, including approximately 40 that infect the genital area (2,3). Genital HPV types are categorized according to their epidemiologic association with cervical cancer. High-risk types have the potential to act as carcinogens. Low-risk types (e.g., types 6 and 11) can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis (4). High-risk types (e.g., types 16 and 18) can cause lowgrade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and cancers (5)(6)(7). Essentially all cervical cancers are attributable to high-risk HPV types (8), and approximately 70% of cervical cancer cases worldwide are caused by types 16 and 18 (9). In addition to cervical cancer, HPV infection also is the cause of some other anogenital cancers such as cancer of the vulva, vagina, penis, and anus, as well as cancer of the oropharynx (6). Two HPV vaccines, bivalent HPV vaccine (HPV2) and quadrivalent HPV vaccine (HPV4) are licensed for use in the United States (10,11). Both vaccines protect against HPV types 16 and 18, which cause 70% of cervical cancers. HPV type 16 also causes the majority of other cancers attributable to HPV. HPV4 also protects against HPV types 6 and 11, which cause >90% of genital warts and recurrent respiratory papillomatosis (4). This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccines, provides updated information on vaccines from clinical trials and postlicensure safety studies and monitoring, and compiles recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) for use of HPV vaccines (12)(13)(14)(15). # Methods The Advisory Committee on Immunization Practices (ACIP) HPV Vaccine Work Group- first met in February 2004 to begin reviewing data related to HPV4. Since February 2004, the Work Group has held multiple teleconferences and periodic meetings to review published and unpublished data from HPV2 and HPV4 clinical trials including data on safety, immunogenicity, and efficacy (12)(13)(14)(15). Data on epidemiology and natural history of HPV, sexual behavior, vaccine acceptability, and cost-effectiveness of HPV vaccination also were considered. Presentations were made to ACIP during multiple meetings before ACIP votes (16). The first vote for routine use of HPV4 in females was held in June 2006 (Table 1). The second vote occurred in October 2009 after HPV2 was licensed for use in females; ACIP updated the recommendation to state that either vaccine could be used in females (13). At the same meeting, ACIP provided guidance that HPV4 may be given to males aged 9 through 26 years, but vaccination of males was not included in the routine schedule (14). In October 2011, ACIP recommended routine vaccination of males (15). Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was adopted by ACIP in 2011 (14) and the routine recommendation for males was considered using GRADE (15). Factors considered in determining the recommendation for males included benefits and harms, evidence type, values and preferences, and health economic analysis (17). The Work Group continues to review data as they become available and considers any needed policy changes. # Background Biology and Immunology of HPV HPVs are nonenveloped, double-stranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as "types" in most commonly used nomenclature, with International Committee on Taxonomy of Viruses (ICTV) proposing use of "strains." The types (or strains) are assigned numbers in order of their discovery (2). Types are designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8-kb circular genome enclosed in a capsid shell comprising the major and minor capsid proteins L1 and L2, respectively. Purified L1 protein will self-assemble to form empty shells that resemble a virus, called virus-like particles (VLPs). In addition to the structural genes (L1 and L2), the genome encodes several early genes (E1, E2, E4, E5, E6, and E7) that enable viral transcription and replication and interact with the host genome. Immortalization and transformation functions are associated with the E6 and E7 genes of high-risk HPV types. E6 and E7 proteins from highrisk types are the primary oncoproteins; they manipulate cell cycle regulators, induce chromosomal abnormalities, and block apoptosis (3). Papillomaviruses initiate infection in the basal layer of the epithelium, and viral genome amplification occurs in differentiating cells using the cellular replication machinery. After infection, differentiating epithelial cells that are normally nondividing remain in an active cell cycle. This can result in a thickened, sometimes exophytic, epithelial lesion. The virus is released as cells exfoliate from the epithelium. With neoplastic progression, the virus might integrate into the host chromosomes, and little virion production will occur. HPV infections are largely shielded from the host immune response because they are nonlytic and restricted to the epithelium (3,18). Humoral and cellular immune responses have been documented, but correlates of immunity have not been established (18). Serum antibodies against many different viral products have been demonstrated. The best characterized antibodies are those directed against conformational epitopes of the L1 capsid protein assembled as VLPs. Not all infected persons develop detectable antibody; in one study, 54%-69% of women with incident HPV 6, 16, or 18 infections had type-specific antibody (19). Among newly infected men, 4%-36% developed type-specific antibody to one of seven types (20). Only 13% developed antibody after infection with HPV 16. # Laboratory Testing for HPV Because HPV infections are not treated, the clinical indications for HPV testing are to identify women at risk for HPV-associated cervical disease and to guide follow-up decisions for those with disease. HPV cannot be cultured directly from patient specimens, so tests require detecting HPV genetic information. Most commercially available assays detect DNA. Because HPV is cell-associated, cellular samples are required. The Food and Drug Administration (FDA) has approved clinical HPV tests for detecting clinically significant levels of any of 14 high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) from cervical specimens (see Cervical Cancer Screening). HPV tests are approved either for use with the Papanicolaou (Pap) test for routine screening in women aged >30 years or for following up certain abnormal Pap test results. One HPV test has been approved for primary cervical cancer screening but is not currently part of national recommendations (21). There are no other approved indications for clinical HPV testing. HPV tests are not recommended or approved for use in men or adolescents, for detection of HPV in partners, or at anatomic sites other than the cervix. Epidemiologic and basic research studies of HPV typically use nucleic acid amplification methods that generate typespecific and, in certain formats, quantitative results. Polymerase chain reaction (PCR) assays targeting genetically conserved regions of the L1 gene are designed to amplify essentially all HPV, and types are then determined by type-specific hybridization. However, a wide variety of HPV detection and typing methods exist (22). Although HPV DNA tests detect current HPV infection at specific sites, HPV serology can be used as a measure of current or past infection (or vaccination) in research settings. As noted previously, the host immune response to HPV infection is weak, and not all infected persons develop detectable antibody. Nonetheless, in unvaccinated populations, the age-specific seroprevalence reflects the overall age of first exposure, and seroprevalence data were used to help guide the ages targeted for preventive HPV vaccines. Serologic testing was conducted in the HPV vaccine clinical trials (see Evaluation of Serologic Response to Vaccination). The most frequently used HPV serologic assays are VLP-based enzyme-linked immunoassays, which are designed to detect antibodies to the L1 viral protein. The type-specificity of the assay depends on preparation of conformationally intact VLPs in recombinant baculovirus or (24). Prevalence of HPV was highest among those aged 20-24 years (53.8%). In this age group, prevalence of HPV types 6, 11, 16, or 18 was 18.5% (25). Other information on HPV prevalence among females and males has been obtained primarily from clinic-based populations (e.g., family planning and sexually transmitted disease or university health clinic patients). These evaluations found prevalence of HPV ranging from 14% to 90%, with similar peak prevalence in young adults (26,27). Although most information on HPV epidemiology is derived from studies of cervical infection in women, there are also studies on anogenital HPV infection in males (28,29). A study among men aged 18-70 years seeking information about sexually transmitted disease testing from Brazil, Mexico, and the United States determined that genital HPV prevalence ranged from 52% to 69% by country, with no consistent variation by age (28). Studies of incident infections demonstrate that first HPV infection occurs within a few years of becoming sexually active. In a prospective study of women attending university in the United States, the cumulative probability of incident infection was 38.9% by 24 months after first sexual intercourse (30). Of all HPV types, new detection of HPV 16 was highest (10.4%); new detection of HPV 18 was 4.1% (30). Detection of HPV DNA is the best indication of infection but does not provide information on persons who were infected but cleared the HPV infection. Seroprevalence data provide an estimate of cumulative exposure but also will be an underestimate because not all persons with natural HPV infection develop or maintain detectable antibodies. NHANES 2003NHANES -2004 data indicate that seroprevalence of HPV 6, 11, 16, or 18 among females reached 42% by age 30-39 years (31). The cumulative incidence of HPV infection among men also is high. In a prospective study of men attending university in the United States, the cumulative probability of incident infection at 24 months after study enrollment was 62.4% (32). In contrast to women, for whom the risk for HPV acquisition increases with age through the early 20s and then decreases, studies have demonstrated that incidence among men is relatively constant over a wide age range (33). # Transmission and Natural History Genital HPV infection is transmitted primarily by genital contact, usually through sexual intercourse but also through other intimate contact (e.g., oral-genital or genital-genital) (30,(34)(35)(36)(37). Nonsexual routes of genital HPV transmission are less common and can include intrapartum transmission from mother to infant (38). Most data on natural history of HPV are obtained from studies of cervical infection. In virtually all studies of HPV prevalence and incidence, the most consistent predictors of infection have been measures of sexual activity, most importantly the number of sex partners (lifetime and recent) (39)(40)(41)(42)(43)(44). However, even persons with one lifetime sex partner are at risk for infection. One study found that HPV prevalence among women aged 18-25 years was 14.3% for those with one lifetime sex partner, 22.3% for those with two lifetime partners, and 31.5% for those with three or more lifetime partners (44). Additional risk factors include sexual behavior of the partner (30) and immune status (45,46). Transmission is very common between sex partners, and likely more frequent from females to males than from males to females (36). Most HPV infections are transient and asymptomatic and cause no clinical problems; 70% of persons with new cervical HPV infection will clear the infection within 1 year, and approximately 90% within 2 years (39,(47)(48)(49). The median duration of new infections is about 8 months for genital infection among both females and males (33,39,48,(50)(51)(52). Oral HPV infection is much less common than genital infection (53), but time to clearance appears to be similar (54). Immunocompromised persons, such as those with human immunodeficiency virus (HIV), have higher rates of HPV acquisition and progression to disease (55). The risk for persistence and progression to cancer precursor lesions varies by HPV type as well as host factors. HPV 16 is more likely to persist and progress to cancer than other high-risk HPV types (52,56). The usual time between initial HPV infection and development of cervical cancer is decades but more rapid progression has occurred. Many aspects of the natural history of HPV are poorly understood, including the role and duration of naturally acquired immunity after HPV infection. # Clinical Sequelae of HPV Infection # Cancers Associated with HPV Persistent infection with oncogenic HPV types has a causal role in nearly all cervical cancers and in many vulvar, vaginal, penile, anal, and oropharyngeal cancers (57). On the basis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and CDC's National Program of Cancer Registries (NPCR), the burden of HPV-associated cancers in the United States has been estimated (58). Because cancer registries typically do not capture information on HPV, the number of HPV-attributable cancers was estimated by multiplying the number of cancers at each body site (HPV-associated) by the percentage attributable to HPV, based on genotyping studies (59)(60)(61)(62)(63)(64). From 2006 to 2010, on average, 33,160 HPV-associated cancers were diagnosed in the United States, including 20,589 (62%) among females and 12,571 (38%) among males. Approximately 26,900 new cancers at these body sites were attributable to HPV, including 17,600 (65%) among females and 9,300 (35%) among males. Cervical and oropharyngeal cancers were the most common with an estimated 10,400 cervical cancers and 9,000 oropharyngeal cancers (7,200 among men and 1,800 among women). Among these six cancers, approximately 17,500 were attributable to HPV16/18 (5,900 among men and 11,600 among women) (Table 2). Data from nine cancer registries in the SEER program have been analyzed to obtain long-term trends of invasive HPV-associated cancers and their precursors from 1978 through 2007 (65), and data from 42 NPCR/SEER cancer registries that cover a larger percentage of the U.S. population have been analyzed to obtain trends of invasive HPV-associated cancers from 2000 through 2009 (66). # Cervical Precancers and Cancer The only HPV-associated cancer for which screening is recommended is cervical cancer (67,68). Cervical cancer screening is based on exfoliated cytology (Pap test) with clinical HPV testing in appropriate settings (see Cervical Cancer Screening). Abnormalities detected in screening require follow-up, and diagnosis is based on histology of the tissue sample. Terminology for histologic outcomes of squamous precursor lesions is changing from grades 1-3 of cervical intraepithelial neoplasia (CIN) to the same terminology that is used for cytological abnormalities: low-or high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively) (69). HSIL is considered a cancer precursor that requires treatment whereas LSIL generally clears without treatment. Precursors of glandular or adenocarcinomas are designated adenocarcinoma in situ (AIS). These lesions are detected less readily by Pap test because of their endocervical location. AIS also is considered a cancer precursor that requires treatment. The CIN terminology continues to be used widely and conveys the spectrum of changes from those that are clearly low grade (CIN1) to those that are clearly high grade (CIN3). The CIN2 lesions represent an intermediate group that includes lesions that could be grouped into either low-or high-grade lesions (69). Most LSIL, HSIL, and AIS lesions are HPV-associated, but the type distribution changes with severity of the abnormality; high-risk types, particularly HPV 16, increase in frequency with severity of lesion. In meta-analyses, HPV prevalence was 12% (HPV 16 accounting for 20%) in women with normal cytology, 52% (HPV 16 accounting for 23%) in those with equivocal cytology, and 76% and 85%, respectively, in those with LSIL and HSIL cytology. Among histological specimens, HPV prevalence increased from 73% among CIN1 lesions to 93% among CIN3 lesions (70). On the basis of a combination of natural history studies and HPV molecular analyses, essentially all cervical cancers are thought to be attributable to HPV (57). A 2011 meta-analysis of studies using sensitive PCR methods reported HPV detection in 90% of cervical cancers worldwide (71). HPV 16 and 18 were the most common types, detected in approximately 70% of cervical cancers (9,71). The prevalence of other types varies somewhat worldwide, but the next-most-frequent types detected were HPV 31, 33, 45, 52, and 58. A U.S. study found that HPV was detected in 91% of cervical cancers (51% HPV 16, 16% HPV 18, and 24% other oncogenic and rare types) (62). Beyond high-risk HPV persistence, additional independent risk factors for cervical precancer and cancer include cigarette smoking, oral contraceptive use, and higher parity (72)(73)(74). In the United States, cervical cancer cases and deaths have decreased substantially since the 1950s (75). Racial/ethnic and geographic disparities remain, with non-Hispanic black and Hispanic women having higher cervical cancer incidence and mortality; rates of cervical cancer also are higher in the southern states. Most disparities are thought to be attributable to differential access to both screening and follow-up after an abnormal cervical cancer screening result (76). # Vulvar and Vaginal Precancers and Cancer Worldwide studies report detection of HPV in 85% of vulvar intraepithelial neoplasia grade 2 or 3 (VIN2/3), and 40% of invasive vulvar cancer (77). HPV 16 is the most frequent type detected. In the United States, HPV was detected in 69% of invasive vulvar cancer and 97% of VIN3, with HPV 16 detected in 49% of invasive cancers and 81% of VIN3 (61). Since the 1970s, the incidence of pre-invasive vulvar cancer in the United States has increased at a faster rate than has invasive vulvar cancer (65). Recent data indicate that rates of invasive vulvar cancer are increasing among both white and black women (66). Worldwide, 90% of vaginal intraepithelial neoplasia grade 2 or 3 (VaIN2/3) and 70% of invasive vaginal cancers have been demonstrated to be HPV DNA-positive (77). In a U.S. study, 75% of invasive vaginal cancer cases were positive for HPV; HPV 16 was the most common type detected (55%) (64). The incidence of vaginal cancer has remained stable in the United States. Vaginal cancer rates have been highest among non-Hispanic black women; the most recent data show the rate declining among this group (65,66). # Anal Precancers and Cancer Anal intraepithelial neoplasia (AIN) grade 2/3 is recognized as a precursor of anal cancer, although the natural history of these lesions (i.e., rate of progression and regression) is less clear than for cervical disease (51). Worldwide, a meta-analysis reported HPV in 84% of anal cancers, but HPV prevalence was higher in AIN2/3 (94%) (77). In the United States, 91% of anal cancers have been found to be positive for HPV, with HPV 16 being the most common type detected (77%) (59). Men who have sex with men (MSM) and persons who have HIV infection are at higher risk for anal precancer and cancer (29,78,79). Although the burden of anal cancer and precancers is substantial, data are insufficient to recommend routine anal cancer screening with anal cytology in HIV-infected persons or HIV-negative MSM (29,80). More evidence is needed concerning the natural history of anal intraepithelial neoplasia, the best screening methods and target populations, and safety and response to treatments before routine screening can be recommended (80). Some clinical centers perform anal cytology to screen for anal cancer among high-risk populations (e.g., HIV-infected persons and MSM), followed by highresolution anoscopy for those with abnormal cytologic results. Rates of AIN3 have risen more rapidly among men than among women (65). This increase could be attributable to true increases or more aggressive screening among MSM in certain areas of the country, facilitating diagnosis (81). Both long-and short-term trends indicate that invasive anal cancer has increased at a steady rate among both males and females and among persons in almost every racial/ethnic group (65,66). # Oropharyngeal Cancer Some oropharyngeal cancers are attributable to HPV. Although tobacco smoking, tobacco chewing, and alcohol are strongly associated with cancers of the oropharynx, substantial evidence indicates a causal association between HPV infection and oropharyngeal cancers (57,82). Previous studies reported that worldwide, HPV DNA detection in oropharyngeal cancers varies substantially (range: 13%-56%) (57,83). HPV 16 is detected in the majority of HPV-attributable cancers (57,83). A recent U.S. study reported that approximately 72% of oropharyngeal cancers were positive for HPV; 61% had HPV 16 (63). By anatomic oropharyngeal location, 80% of tonsillar and 70% of base of tongue cancers were positive for one of 14 high-risk HPV types. Prevalence of HPV 16/18 in these cancers was higher in males than females, and lower in non-Hispanic blacks than in other racial/ethnic groups. Trends for oropharyngeal cancer are limited to invasive cancer because no pre-invasive lesion has been established for oropharyngeal . Estimates rounded to the nearest 100. § Although HPV is accepted to be a necessary factor in the causal pathway to invasive cervical cancer, HPV is not always detected in tumor specimens from women who receive a diagnosis of invasive cervical cancer due to a variety of reasons: including misclassification of tissue specimens as cervix, quality of tissue specimens, assay sensitivity, and a small proportion of HPV-negative, cervical cancers. cancer. In the United States, oropharyngeal cancer rates have increased for males since the 1970s (65) and for females from 2000 through 2009 (66). # Penile Cancer Penile cancer is extremely rare. Worldwide, HPV has been associated with 40%-50% of penile squamous cell cancers (57,84). Among HPV-positive penile cancers, HPV 16 has been detected in a large portion (57,84). A U.S. study reported HPV prevalence of 63%, with HPV 16 detected in 46% of all cases (60). Differences in detection found among studies have been attributed to geographic variations or differences in sampling and testing (84). Besides HPV, independent risk factors for penile cancer include cigarette smoking and lack of circumcision (85). In the United States, rates of invasive penile cancer have declined since the late 1970s (85) with stable rates from 2000 through 2009 (66). # Anogenital Warts All anogenital warts are caused by HPV, and >90% are associated with HPV 6 and 11 (4,86). The average time to development of new anogenital warts following HPV infection has ranged in studies from a few months to years (86)(87)(88)(89). Anogenital warts might regress, grow larger, or remain the same. Recurrence of anogenital warts is common (approximately 30%), whether clearance occurs spontaneously or following treatment (90). Genital warts occurring among HIV-infected persons often require longer courses of treatment (80). Anogenital warts are not reported routinely in the United States. On the basis of 2004 health claims data in the United States, the annual incidence of genital warts was 1.2/1000 females and 1.1/1000 males, and highest in females aged 20-24 years and males aged 25-29 years (91). Anogenital warts are associated with psychosocial reactions, including increased anxiety and depression, and can have a substantial negative impact on personal relationships (92,93). # Recurrent Respiratory Papillomatosis Infection with low-risk HPV types, primarily types 6 or 11, can cause recurrent respiratory papillomatosis, a rare disease that is characterized by recurrent warts or papillomas in the upper respiratory tract, particularly the larynx. Recurrent respiratory papillomavirus (RRP) is divided into juvenile onset (JORRP) and adult onset forms based on age at presentation. JORRP, generally defined as onset before age 18 years, is believed to result from vertical transmission of HPV from mother to infant during delivery, although the median age of diagnosis is 3.1 years (94). A multicenter registry of JORRP in the United States, including 22 centers, collected data during 1996-2002 and demonstrated that although the clinical course of JORRP is variable, it is associated with extensive morbidity, requiring a median of 4.3 annual surgeries to remove warts and maintain an open airway (94). Estimates of the incidence of JORRP are relatively imprecise but range from 0.12-2.1 cases per 100,000 children aged <18 years in two U.S. cities (95). The prevalence, incidence, and disease course of adult onset RRP are less clear. # Prevention (Other Than Vaccine), Cervical Cancer Screening, and Treatment # Prevention of Sexual Transmission Abstaining from sexual activity (i.e., refraining from any genital contact with another person) is the surest way to prevent genital HPV infection. Persons also can lower their chances of becoming infected with HPV by being in a monogamous relationship with one partner, limiting their number of sex partners, and choosing a partner who has had no or few previous sex partners. However, even persons with only one lifetime sex partner can be infected with HPV. Consistent and correct condom use can reduce the risk for HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). A limited number of prospective studies have been conducted evaluating male condom use and HPV; one prospective study among newly sexually active women attending university demonstrated a 70% reduction in HPV infection when their partners used condoms consistently and correctly (96). Randomized clinical trials of male circumcision demonstrate a lower risk of HPV infection among circumcised males as well as among their female partners (97)(98)(99). Neither routine surveillance for HPV infection nor partner notification is useful for HPV prevention. Genital HPV infection is so prevalent that most partners of HPV-infected persons have already acquired HPV themselves (80). # Cervical Cancer Screening Cervical cancer screening does not prevent HPV infection, but can secondarily prevent most cervical cancer cases and deaths if women with abnormal screening results receive appropriate follow-up and treatment. In the United States, cervical cancer screening recommendations were revised in 2012 after the U.S. Preventive Services Task Force (USPSTF) and a multidisciplinary group that included representatives of the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), and the American College of Obstetrics and Gynecology (ACOG) reviewed new evidence (67,68,100). Since 2012, all of these organizations recommend that screening with cervical cytology (Pap test; conventional or liquid-based) should begin at age 21 years. Women aged 21-65 years should be screened with a Pap test every 3 years. For women aged 30-65 years who want to lengthen the screening interval, screening can be performed with a combination of cytology and HPV testing ("co-testing") every 5 years. "Co-testing" in this age group every 5 years is preferred by ACS, ASCCP, and ASCP. In 2014, FDA approved one clinical HPV test for primary screening, but there are no national recommendations for use of this test for primary screening (21). In the United States, cervical cancer screening programs have reduced the number of cervical cancer cases and deaths (67,68,75). The availability and use of HPV4 and HPV2 does not eliminate the need for cervical cancer screening in the United States because not all HPV types that cause cervical cancer are prevented by either vaccine. Screening strategies in the United States will continue to be reviewed and evaluated as vaccination coverage increases and further postlicensure monitoring data become available (67). # Treatment There is no treatment for HPV infections. Only HPV-associated lesions including genital warts, RRP, precancers, and cancers are treated (101)(102)(103). Recommended treatments vary depending on the diagnosis, size, and location of the lesion. Local treatment of lesions might not eradicate all HPV containing cells fully; whether available therapies for HPV-associated lesions reduce infectiousness is unclear. # Health-Care and Research Laboratory Workers For this report, data were reviewed on potential risks to health-care and research laboratory workers. Some HPVassociated conditions (including anogenital and oral warts, anogenital intraepithelial neoplasias , and recurrent respiratory papillomatosis) are treated with laser or electrosurgical procedures. These procedures should be performed in an appropriately ventilated room using standard precautions (104) and local exhaust ventilation (e.g., smoke evacuator) (105). Workers in HPV research laboratories handling wild-type virus or "quasi virions" might be at risk of acquiring HPV from occupational exposures (106). In the laboratory setting, proper infection control should be instituted including, at minimum, biosafety level 2 (BSL-2). Whether HPV vaccination would be of benefit in these settings is unclear because no data exist on transmission risk or vaccine efficacy. # HPV Vaccines and Evaluation # HPV Vaccine Composition Two HPV vaccines are licensed for use in the United States (10,11) (Table 3). Quadrivalent HPV vaccine (Gardasil, produced by Merck and Co, Inc., Whitehouse Station, New Jersey) is licensed for use in females and males aged 9 through 26 years. Bivalent HPV vaccine (Cervarix, produced by GlaxoSmithKline, Rixensart, Belgium) is licensed for use in females aged 9 through 25 years. Both vaccines are composed of type-specific HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein using recombinant DNA technology produces VLPs. The vaccines are noninfectious. Quadrivalent vaccine (HPV4) contains HPV 6, 11, 16, and 18 L1 VLPs. The L1 protein is expressed in Saccharomyces cerevisiae (baker's yeast) and self-assembles into conformationally intact, noninfectious VLPs. Each 0. # Evaluation of Efficacy of HPV Vaccines The efficacy of HPV vaccines has been evaluated by using a variety of endpoints; these include HPV-associated disease and persistent infection. The primary endpoint in the phase III trials, and the basis for licensure in females for both vaccines, was incident HPV 16-and 18-related CIN2/3 or AIS (CIN2+) (10,11). These endpoints served as a surrogate marker for cervical cancer. Studies using invasive cervical cancer as an endpoint are not feasible because the standard of care is to screen for and treat CIN2+ lesions to prevent invasive cervical cancer. Furthermore, the time from acquisition of infection to the development of cancer can exceed 20 years. VaIN2/3, VIN2/3 and AIN2/3 were used as endpoints and surrogate markers in some trials for vaginal, vulvar and anal cancers. In the phase III efficacy trials, participants were enrolled without regard to HPV DNA or antibody status (10,11). Participants were tested for HPV DNA by PCR to determine current infection and for antibody to vaccine types to evaluate past infection but were not excluded from the trials. Several different analyses have been conducted. The main analyses were restricted to participants who received all 3 doses, had no evidence of current or past infection with the relevant vaccine HPV type through 1 month after the third dose (month 7), and did not deviate from protocol. In these according-to-protocol (ATP) or per-protocol analyses, cases were counted starting 1 month after the third dose. The intention-to-treat population (ITT) or total vaccinated cohort (TVC) included all participants regardless of baseline HPV status, and cases were counted starting 1 day after the first dose. Efficacy was lower in the ITT compared with the ATP or per-protocol analyses because some participants had prevalent infection with a vaccine type HPV at the time of study enrollment and the vaccines do not prevent progression of infection to disease among those already infected. Other populations analyzed included the unrestricted susceptible population (or total vaccinated-naive population) which included only participants who were negative to all HPV types evaluated and received at least 1 dose. Protection against oncogenic types other than HPV 16 and 18 (cross protection) also has been evaluated in post hoc analyses (107)(108)(109). Types evaluated include those related to HPV 16 (types in the alpha 9 species) and HPV 18 (types in the alpha 7 species). Both infection and disease endpoints have been assessed. Evaluation of cross-protection against disease endpoints is complicated because more than one type can be detected in a lesion, making it difficult to determine the causal HPV type. # Evaluation of Serologic Response to Vaccination Serologic assays used in the HPV4 and HPV2 vaccine trials differed. The competitive Luminex immunoassay (cLIA) was used in the HPV4 trials, and an enzyme linked immunosorbant assay (ELISA) was used in the HPV2 trials (107,110,111). These assays measure different subsets of antibody induced by vaccination, making comparison across vaccine trials difficult. The cLIA measures all antibody classes but detects antibodies against a single neutralizing epitope for each HPV type. The ELISA measures only IgG but detects antibodies against all conformational epitopes for each HPV type. Antibody titers cannot be compared directly between assays, or across HPV types for a given assay. Some studies that compared the two vaccines directly by using the same serologic assay found higher HPV 16 and 18 antibody titers among vaccinees who received HPV2 compared with HPV4 (112). There is no known serologic correlative of immunity or minimum titer determined to be protective. The high efficacy found in the clinical trials to date has precluded identification of a minimum protective antibody titer. # Quadrivalent HPV Vaccine (HPV4) HPV4 Efficacy Females Aged 16-26 years Three randomized, double-blind, placebo-controlled clinical trials evaluated the efficacy of HPV4 for prevention of HPV-associated disease: a phase II trial (protocol 007) among females aged 16-23 years (113) and two phase III trials (protocols 013 and 015) among females aged 16-24 and 15-26 years, respectively (114,115). Data from these trials and data from a randomized, placebo-controlled phase II trial of monovalent HPV 16 vaccine (116,117) were included in the FDA Biologics License Application (11). More than 20,000 females were enrolled in these four studies and received either vaccine or placebo. Interim analysis of the phase III trials showed high efficacy (114,115 Efficacy for prevention of persistent infection was evaluated in phase II efficacy trials. HPV 16 persistent infection was the primary endpoint for the phase II monovalent HPV vaccine trial; efficacy for prevention of persistent infection (defined as a vaccine type detected by PCR at 2 or more visits at least 4 months apart) was 100% (116,117). In the phase II HPV4 trial, efficacy for prevention of persistent HPV 6, 11, 16, and 18 infection was 89% (95% CI = 70-97); three of four cases in the vaccine group were detected at last study visit with no documented persistence (113). In the phase III trials, among females aged 16-26 years who had HPV vaccine type DNA detected at study enrollment (either seropositive or seronegative), there was no efficacy against progression to disease or impact on clearance of infection of that type (114,120). However, HPV4 had 100% efficacy for prevention of CIN2+ attributable to types not already acquired (120). Among persons seropositive to the relevant HPV type but HPV DNA-negative, too few cases were detected to evaluate efficacy, but disease incidence was low and all cases occurred in the placebo group. # Males Aged 16-26 Years Efficacy of HPV4 among males was evaluated in one phase III trial, including 4,065 males aged 16-26 years (121). In the end-of-study analysis (median follow-up time of 35 months after the first dose), per-protocol efficacy for prevention of HPV 6-, 11-, 16-, and 18-related genital warts was 89.4% (Table 5). In the ITT analysis, efficacy was 67.2% (95% CI = 47.3-80.3). As in females, no efficacy was observed among males who were infected with the respective HPV type at baseline. Although grade 1, 2, and 3 penile/perineal/perianal intraepithelial neoplasias were evaluated, too few cases were observed to evaluate efficacy. A substudy of the phase III efficacy trial included 602 MSM; outcomes were AIN grades 1, 2, or 3 (AIN1/2/3), AIN2/3 and anal warts (Table 5) (122). Per-protocol efficacy for prevention of HPV 6-, 11-, 16-, and 18-related AIN2/3 was 74.9% (95% CI = 8.8-95.4) and for prevention of HPV 6-, 11-, 16-, and 18-related anal warts was 100% (95% CI = 8.2-100). In the ITT analyses, efficacy for prevention of vaccine type AIN2/3 was 54.2% (95% CI = 18.0-75.3) and for anal warts was 57.2% (95% CI = 15.9-79.5). Efficacy for prevention of 6-month persistent HPV 6, 11, 16, or 18 infection was a prespecified secondary endpoint for the phase III trials among males and for the substudy in MSM. Per-protocol efficacy for prevention of 6-month persistent vaccine type genital or perianal HPV infection was 85.6% (97.5% CI = 73.4-92.9). In the MSM substudy, per-protocol efficacy for prevention of anal 6-month persistent vaccine type HPV infection was 94.9% (95% CI = 80.4-99.4). # Duration of Protection In the phase III trials, females aged 16-26 years were followed for a mean of 42 months after dose one (118). The longest follow-up for HPV4 is from the phase II trial (protocol 007): a subset of participants (n = 241) were followed for 60 months after dose one. Efficacy against vaccine type persistent infection or disease was 95.8% (95% CI = 83.8-99.5) and efficacy against vaccine type-related CIN or external genital lesions was 100% (95% CI = 12.4-100) (123). Follow-up through 8.5 years in the monovalent HPV 16 vaccine trial showed high efficacy and no decline in protection (124). Additional data on duration of protection will be available from follow-up of approximately 5,500 females enrolled in one of the phase III HPV4 trials in the Nordic countries. Half of the females had received vaccine while the other half had received placebo in the randomized clinical trial and were then vaccinated after the first 4 years of the study. These females will be followed for at least 10-14 years after vaccination; serologic testing will be conducted 9 and 14 years after vaccination among the original group of vaccine recipients, and Pap testing results will be linked to pathology specimens for sectioning and HPV DNA testing by PCR. Data from follow-up through 7 to 8 years showed no evidence of waning protection (125). Males in the phase III trial will be followed for 10 years after vaccination. In addition, adolescent girls and boys who were vaccinated at age 10-15 years in an immunogenicity study (see HPV4 Immunogenicity) are being followed as they become sexually active. Through 8 years of follow-up, no cases of disease in females or infection in males related to HPV 6, 11, 16, or 18 were observed (126). This study will continue to follow participants through at least 10 years after vaccination. # Evaluation of Protection Against Nonvaccine Types Protection against infection and CIN2+ attributable to nonvaccine types was evaluated for HPV4. In prespecified analyses among females without evidence of current or previous infection with 14 HPV types at baseline in the phase III trials (protocols 013 and 015), efficacy against CIN2+ associated with any of five nonvaccine types in the alpha 9 (109). No protection was demonstrated against any other individual nonvaccine HPV type. Analyses did not exclude lesions in which HPV 16 or 18 were also detected, making results difficult to interpret (107,109). Among males, no efficacy was observed against external genital lesions or AIN associated with any of the 10 nonvaccine types evaluated (127). # HPV4 Immunogenicity Females and Males Aged 9-26 Years Data on immunogenicity in females are available from phase II and III efficacy trials conducted among females aged 16-26 years and immunogenicity trials conducted among children and adolescents aged 9-15 years. In all studies conducted to date, more than 99% of females had an antibody response to all four HPV vaccine types 1 month after the third dose (123,128). High seropositivity rates were observed after vaccination regardless of sex, race/ethnicity, country of origin, smoking status, or body mass index (129). Vaccination produced antibody titers higher than those after natural infection: among females aged 16-23 years, anti-HPV 6, 11, 16, and 18 geometric mean titers (GMTs) 1 month after the third dose were higher than those observed in participants who were HPV seropositive and PCR negative at enrollment in the placebo group (123). Antibody titers declined over time after the third dose but plateaued by 24 months. At 36 months, HPV 16 GMTs among vaccinees remained higher than those in participants in the placebo group who were seropositive at baseline; HPV 6, 11, and 18 GMTs were similar to those seropositive in the placebo group (113). At 36 months, seropositivity rates in vaccinees were 94%, 96%, 100%, and 76% to HPV 6, 11, 16, and 18, respectively (113). In the follow-up of females in the phase II or phase III efficacy trials, there was no evidence of waning efficacy among participants who became seronegative (130). This suggests that loss of detectable antibody by the cLIA, seen particularly for HPV 18, is not associated with loss of protection. Data from a revaccination study in which vaccinated females were given a challenge dose of vaccine 5 years after enrollment demonstrated an augmented rise in antibody titer, consistent with immune memory (131). Vaccination of females who were seropositive to a specific vaccine HPV type at enrollment resulted in higher antibody titers to that type, particularly after the first dose, compared with those seronegative at enrollment, suggesting a boosting of naturally acquired antibody by vaccination (131). Data on immunogenicity among males are available from the phase III trial in males aged 16-26 years and immunogenicity trials among males aged 9-15 years (128,132). Among males in the efficacy trial, seroconversion rates were 97%-99% 1 month after the third dose (132). High seropositivity rates were observed after vaccination regardless of demographic group, but blacks had higher GMTs than whites, and heterosexual males had higher GMTs than MSM. By month 36, 89%, 94%, 98%, and 57% of males remained seropositive to HPV 6, 11, 16, and 18, respectively (132). Immunogenicity trials allowed comparison of seroconversion rates and GMTs among females and males aged 9-15 years with participants in the efficacy trials (11,128). Seroconversion rates for both females and males aged 9-15 years exceeded 99% for all four vaccine types (Table 6). Among those vaccinated at age 9-15 years, GMTs 1 month after the third dose were noninferior (and 1.7-to 2.7-fold higher) to those vaccinated at age 16-26 years. At 24-36 months after vaccination, GMTs among those vaccinated at 9-15 years remained higher than among those vaccinated at age 16-26 years (11). # Spacing of Vaccine Doses In prelicensure trials among females aged 16-26 years, vaccine was administered according to a 0-, 2-, and 6-month schedule. The interval between the first and second dose ranged from 6-12 weeks and the interval between the second and third dose ranged from 12-23 weeks. Variation in the interval did not diminish GMTs postvaccination. Postlicensure studies have also evaluated GMTs after longer intervals between doses including: 0, 2, and 12 months; 0, 3, and 9 months; 0, 6, and 12 months; and 0, 12, and 24 months (133,134). GMTs in schedules with longer intervals between doses were noninferior and for some schedules were higher than with the standard schedule (0, 2, 6 months). # Concomitant Administration with Other Vaccines Seroconversion rates and GMTs after concomitant administration of HPV4 with other vaccines (including meningococcal conjugate vaccine, tetanus, diphtheria, and acellular pertussis vaccine; inactivated polio vaccine; and hepatitis B vaccine) have been evaluated (135). In all studies conducted to date, HPV GMTs in the co-administered group were noninferior to GMTs after administration of HPV vaccine alone. Rates of solicited and unsolicited symptoms and adverse events were similar in all study groups. # HIV-Infected Persons Several immunogenicity studies of HPV4 in HIV-infected persons have been published, and others are ongoing (46). A randomized clinical trial of HPV4 found the vaccine to be safe and immunogenic in 126 HIV-infected children aged 7-12 years. Antibody titers were lower for HPV 6 and 18 compared with historic age-matched immunocompetent controls (136). At 18 months after the third dose, 94%-99% had antibody to HPV 6, 11 and 16; 76% had antibody to HPV 18. After a fourth dose, all children demonstrated an anamnestic response for all HPV vaccine types (137). A study in 109 HIV-infected males and another in 99 HIV-infected females found the vaccine to be immunogenic and well tolerated (138,139). GMTs were higher among persons on antiretroviral therapy compared with those not receiving therapy. # Efficacy and Immunogenicity Among Persons Aged >26 years HPV4 is not licensed in the United States for use in persons aged >26 years. One randomized, double-blind, placebocontrolled trial of HPV4 was conducted in 3,819 females aged 24-45 years (140). In the end-of-study analysis, perprotocol efficacy against HPV 6, 11, 16, and 18 persistent infection, related CIN, or external genital lesions was 88.7% (95% CI = 78.1-94.8) (141). There were few CIN2+ events (one case in the vaccine arm and six cases in the placebo arm of the trial). In the ITT analysis, efficacy against vaccine type-related persistent infection or disease was 47.2% (95% CI = 33.5-58.2), but efficacy was not demonstrated against CIN2+: 22.4% (95% CI = -42.5-58.3). One month after the third dose, seropositivity to HPV 6, 11, 16 and 18 was 98%, 98%, 99%, and 97%, respectively. At month 48, seropositivity was 92%, 92%, 97%, and 48%, respectively. GMTs were lower than those among females aged 16-23 years. There are no data from efficacy trials in males aged >26 years. # HPV4 Safety Prelicensure Trials In prelicensure trials, HPV4 was evaluated for injection-site and systemic adverse events, new medical conditions reported during the follow-up period, and safety during pregnancy and lactation. Safety data on HPV4 are available from seven clinical trials and included 18,083 persons who received HPV4, aluminum-containing control (AAHS), or saline placebo (11). In both the female and male study populations aged 9-26 years with detailed safety data, a larger proportion reported injection-site adverse events in the group that received HPV4 compared with AAHS control or saline placebo groups. In all three groups, pain was the most common injection site adverse event (Table 7). Systemic clinical adverse events were reported by a similar proportion of vaccine and control/placebo groups among both females and males. Headache was most common, reported by 28.2% of females who received HPV4 and 28.4% of those who received AAHS or saline placebo; among males, 12.3% of those who received HPV4 and 11.2% of those who received AAHS or saline placebo reported headache. Overall, 4.0%-4.9% of females and 2.8%-3.0% of males who received HPV4 reported a temperature ≥100°F (≥38°C) after the first, second, or third dose. The proportions of persons reporting a serious adverse event were similar in the vaccine and placebo groups, as were the types of serious adverse event reported. Vaccine-related serious adverse events occurred in <0.1% of persons. Across all clinical studies (29,323 participants), during the course of the trials, 21 deaths (0.1%) occurred among persons in HPV4 groups and 19 (0.1%) among persons in the control or placebo groups. None of the deaths was considered to be vaccine related (11). Information was collected on new medical conditions that occurred during follow-up of up to 4 years for females and 3 years for males. Overall, among females aged 9-26 years, 2.3% in the HPV4 group and 2.3% in the AAHS control or placebo groups had conditions potentially indicative of autoimmune disorders. Among males aged 9-26 years, 1.5% in the HPV4 group and 1.5% in the AAHS control or placebo groups had conditions potentially indicative of autoimmune disorders. No statistically significant differences were found between vaccine and AAHS control/placebo recipients for the incidence of the conditions (11). Although HPV4 is not licensed by FDA for use among persons aged >26 years, studies among females aged 27-45 years indicate that the adverse events profile is comparable to the profile observed in those aged 9-26 years (11). - The per-protocol immunogenicity population included all subjects who were not general protocol violators, received all three vaccinations within acceptable day ranges, were seronegative at day 1 and (for all subjects except those aged <16 years in the immunogenicity studies who were not tested) DNA negative day 1 through month 7 for the relevant HPV type(s), and had a month 7 serum sample collected within an acceptable day range. # Pregnancy The HPV4 trial protocols excluded women who were pregnant; however, 3,819 females in the trials reported at least one pregnancy (11). Adverse outcomes (defined as the combined numbers of spontaneous abortions, late fetal deaths, and congenital anomaly cases out of the total number of known pregnancy outcomes, excluding elective terminations), were 22.6% (446/1973) in the HPV4 group and 23.1% (460/1994) in the AAHS control or saline placebo group. A total of 45 cases of congenital anomaly in pregnancies occurred in females who received HPV4, and 34 cases occurred in females who received AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, five anomalies (all different) occurred in the vaccine group, and one occurred in the placebo group. In pregnancies with onset >30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received HPV4 and 33 cases in the group that received AAHS control or saline placebo. Rates of congenital anomalies were consistent with those in surveillance registries. HPV4 has been classified as Pregnancy Category B on the basis of studies in rats showing no evidence of impaired fertility or harm to the fetus (11). A registry for females inadvertently vaccinated during pregnancy was established by the manufacturer as part of its postlicensure commitment to FDA (142,143). More than 2,800 females who received vaccine within 1 month before their last menstrual period or anytime during pregnancy were enrolled in the registry (144). Rates of spontaneous abortions and major birth defects were not greater than those of a comparison unexposed population. The registry was terminated at the end of December 2012 with concurrence from FDA and other regulatory agencies. However, the manufacturer is still collecting information on persons inadvertently vaccinated during pregnancy. CDC will continue to monitor pregnancy outcomes through reports to the Vaccine Adverse Event Reporting System (VAERS) and through studies in the Vaccine Safety Datalink (VSD) (see Postlicensure Safety Data). # Postlicensure Safety Data In the United States, federal agencies and vaccine manufacturers conduct independent postlicensure vaccine safety and monitoring activities. CDC monitors vaccine safety through several systems, including VAERS and VSD (145). CDC and FDA established VAERS in 1990 (146). VAERS is a national spontaneous reporting system that accepts reports from providers and the public regarding adverse events that occur after vaccination. The system is not designed to determine whether a reported adverse event was caused by vaccination, but it does identify signals or trends that warrant further study. From June 2006 through March 2014, approximately 67 million doses of HPV4 were distributed in the United States. VAERS received a total of 25,063 adverse event reports (22,867 in females and 2,196 males) after receipt of HPV4 (147). Reporting among females peaked in 2008 and decreased each year thereafter (148). The proportion of reports to VAERS that were classified as serious (i.e., those resulting in permanent disability, hospitalization, life-threatening illnesses, or death) peaked in 2009 at 12.8% and then decreased to 7.4% in 2013 (the last full year of reporting). † Of the total HPV4 reports, 92.4% were classified as nonserious. Among the nonserious adverse events, the most commonly reported generalized symptoms in females were syncope (fainting), dizziness, nausea, headache, and fever; in males, the most commonly reported generalized symptoms were dizziness, syncope, pallor, headache, and loss of consciousness. Overall, the most commonly reported local symptoms were injectionsite pain and redness. Among the 7.6% of total reports classified as serious, headache, nausea, vomiting, and fever were the most frequently reported symptoms for both males and females (CDC, unpublished data, 2014). Overall reporting of adverse events to VAERS is consistent with prelicensure clinical trial data and with the 2009 published summary of the first 2.5 years of postlicensure reporting to VAERS (147,149). During the postlicensure period from June 2006 to March 2014, a total of 96 reports of death after receiving HPV4 were submitted to VAERS. CDC and FDA review all available information on reports of death following any vaccine, including HPV4. Among the 96 reports of death, 47 deaths were considered confirmed in that the reports included a certificate of death, autopsy report, or other medical documentation of death (150). Causes of the confirmed death reports included bacterial meningitis, viral myocarditis, pulmonary embolism, diabetic ketoacidosis, and seizure disorder. Detailed review of every report of death following HPV4 alone or in combination with other vaccines by medical officers from CDC and FDA identified no pattern of occurrence of death with respect to time after vaccination, vaccine dose number, combination of vaccines administered, or diagnosis at death that would suggest a causal association with HPV4. VSD is a collaboration between CDC and nine integrated health-care organizations that allows for active surveillance and research. VSD conducts evaluations of specific events that might be associated with vaccination (151). Data were analyzed after 600,558 doses of HPV4 had been administered to females. No statistically significant increased risks were observed for any of the prespecified endpoints including Guillain-Barré syndrome (GBS), stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis (151) (Table 8). Studies in males are ongoing. Postlicensure studies also have been conducted by the manufacturer (152,153). In a general safety assessment evaluating outcomes diagnosed in emergency departments visits and hospitalizations among 189,000 females receiving at least 1 dose of HPV4, same-day syncope and skin infections in the 2 weeks after vaccination were found to be associated with HPV4. No other safety concerns were identified (152). In another study, rates of 16 autoimmune disorders in the vaccinated population were not increased compared with a matched population of nonvaccinated females (153). Postlicensure safety data for HPV4 available from other countries show a good safety profile (154)(155)(156). A large population-based cohort study conducted in Denmark and Sweden analyzed data on >696,000 doses of HPV4 among females. No consistent evidence supporting causal associations between exposure to HPV4 and autoimmune, neurologic conditions, and venous thromboembolism was observed (155). In France, a case-control study was conducted to evaluate autoimmune disorders following HPV4. Among 211 cases and 875 controls, no increased risk was observed for idiopathic thrombocytopenic purpura, central demyelination/multiple sclerosis, GBS, connective tissue disorders (including systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus, and autoimmune thyroiditis after receipt of HPV4 (156). # Bivalent HPV Vaccine (HPV2) HPV2 Efficacy Females Aged 15-25 Years HPV2 efficacy against CIN2+ was evaluated in two randomized, double-blind, controlled clinical trials in females aged 15-25 years, including a phase II study and a phase III trial (157,158). The phase III trial included 18,644 females (158,159). Interim analysis of the phase III trial showed high efficacy (158). In the end-of-study ATP analysis, efficacy against HPV 16-and 18-related CIN2+ was 94.9% (95% CI = 87.7-98.4) (Table 4) (160). Statistically significant efficacy was demonstrated individually against HPV 16-and HPV 18-related lesions. In the ITT analysis, efficacy against HPV 16-and 18-related CIN2+ was 60.7% (95% CI = 49.6-69.5). The end-of-study analysis also found high efficacy against CIN3 regardless of HPV type in the TVC-naïve population (160). HPV2 efficacy against persistent HPV infection was evaluated. In the phase III trial, efficacy against 6-month and 12-month persistent HPV 16 or HPV 18 cervical infection in the ATP cohort was 94.3% (96.1% CI = 91.5-96.3) and 91.4% (96.1% CI = 86.1-95.0), respectively (159). Data on persistent infection endpoints are also available from a trial conducted in Costa Rica (161), a randomized, double-blind, controlled trial in 7,466 women aged 18-25 years. (Efficacy data from the Costa Rica trial were not included in the FDA Biologics License Application.) The primary endpoint was 12-month persistent HPV 16 or HPV 18 cervical infection (161). In the ATP analysis, efficacy against HPV 16 or HPV 18 persistent infection was 90.9% (95% CI = 82.0-95.9) and in the ITT analysis was 49.0% (95% CI = 38.1-58.1). Among women who were HPV 16 or 18 DNA positive at enrollment into the clinical trials, either seropositive or seronegative, the vaccine had no efficacy against progression of infection to disease (159) or impact on clearance of infection of that HPV type (162). However, among participants DNA positive to one vaccine HPV type, HPV2 was found to have high efficacy (90%) for prevention of CIN2+ associated with the type for which a female was DNA negative at enrollment (163). Among persons seropositive to the relevant HPV type but HPV DNA negative, there were fewer cases, but efficacy was observed against CIN1 or higher grade lesions (163). Efficacy against prevalent anal and oral HPV infection was evaluated in the Costa Rica trial. Although this trial was not designed to assess efficacy against oral or anal infection, and baseline infection at these anatomic sites was not determined, prevalent infection was determined at the 4-year exit study visit. There were 15 prevalent HPV 16 or 18 oral infections among the 2,924 females in the control group and one among the 2,910 females in the vaccine group; estimated efficacy was 93.3% (95% CI = 62.5-99.7) (164). Among females who were HPV 16/18 seronegative and DNA negative at the cervix at the time of enrollment, efficacy against anal HPV 16 or HPV 18 prevalent infection was 83.6% (95% CI = 66.7-92.8) (165). # Duration of Protection In the phase III efficacy trial, females were followed for a median of 47 months after the first vaccine dose (160). The longest follow-up from the HPV2 clinical trials is from the phase II trial; a subset of participants has been followed for up to 9.4 years after the first dose (166). Among the 437 participants evaluated, efficacy for prevention of HPV 16/18 12-month persistent infection was 100% (95% CI = 61.4-100). Further data on duration of protection will be available from follow-up of females in the phase III trial. In addition, adolescents who were vaccinated at age 10-15 years in an immunogenicity trial (see HPV2 Immunogenicity) are being followed as they become sexually active. # Evaluation of Protection Against Nonvaccine Types Protection against persistent infection and CIN2+ endpoints attributable to nonvaccine types was evaluated using a variety of different analytic populations (107,108). The most consistent # HPV2 Immunogenicity Females Aged 9-25 Years Data on immunogenicity are available from the phase II and phase efficacy III trials conducted in females aged 15-25 years and immunogenicity trials conducted in females aged 9-14 years (10,158,167). In all trials, >99% of study participants developed antibody to both HPV 16 and HPV 18 1 month after completing the 3-dose series. Among females aged 15-25 years, antibody titers were more than 100-fold higher than those after natural infection (158). Follow-up data from females who received HPV2 at ages 15-25 years are available through 9.4 years (166). Peak GMTs occur at 1 month after the third dose and then plateau about 2 years later. At 9.4 years after vaccination, all females had detectable antibody; GMTs were at least 10-fold higher by ELISA and fourfold higher by a neutralizing assay than GMTs after clearance of natural infection. Immunogenicity trials including 1,275 females aged 9-14 years provided data allowing comparison of seroconversion and GMTs with those in females aged 15-25 years who were enrolled in the phase III efficacy trial (10). A direct comparison between females aged 10-14 years and 15-25 years was made in one study (Table 9) (167). In all trials, seropositivity 1 month after the third dose among females aged 10-14 years was 100% for HPV 16 and HPV 18; GMTs were noninferior (and approximately twofold higher) to those vaccinated at age 15-25 years. At month 48, GMTs in females vaccinated at ages 10-14 years remained twofold higher than those in females vaccinated at ages 15-25 years (168). # Spacing of Vaccine Doses In prelicensure efficacy and immunogenicity trials, HPV2 was administered according to a 0, 1, and 6 month schedule. Postlicensure trials have evaluated GMTs after longer intervals between doses, including 6 months between the first and second dose and 12 months between the first and third dose (169,170). GMTs after schedules with longer intervals between doses were noninferior to those after the standard dosing schedule. # Concomitant Administration with Other Vaccines Seroconversion rates and GMTs after concomitant administration of HPV2 with other vaccines, including meningococcal conjugate vaccine, tetanus, diphtheria and acellular pertussis vaccine, inactivated poliovirus vaccine, hepatitis B vaccine, and combined hepatitis A and B vaccine have been evaluated (135). GMTs were noninferior in the co-administered group compared with GMTs after administration of HPV2 alone in all studies. Rates of solicited and unsolicited symptoms and events were similar in all study groups. # HIV-Infected Persons One HPV2 immunogenicity study has been conducted comparing antibody response in HIV-infected and uninfected females aged 18-25 years. All subjects seroconverted to HPV 16 and HPV 18 and the vaccine was well tolerated; GMTs were lower in the HIV-infected females compared with those not infected (171). However, HPV 16 and HPV 18 GMTs in HIV-infected females 1 month after the third dose were 124-and 90-fold higher, respectively than those reported in healthy females aged 15-25 years after natural infection. # Immunogenicity in Females Aged >25 Years HPV2 is not licensed in the United States for use among females aged >25 years. No published data are available on HPV2 efficacy in females aged >25 years. One trial compared HPV2 immunogenicity among females aged 26-55 years and those aged 15-25 years (172). All participants were seropositive to HPV 16 and HPV 18 at 1 month after the third dose, and >99% were seropositive at month 48 (173). GMTs were lower than those among females aged 15-25 years and decreased with increasing age. However, even in the oldest age group (age 46-55 years), GMTs 1 month after the third dose were 57-and 84-fold higher than GMTs after natural infection for HPV 16 and HPV 18 (172). # HPV2 Safety In prelicensure trials, HPV2 vaccinees were evaluated for injection-site and systemic adverse events, medically significant conditions, new onset autoimmune disorders, new onset chronic diseases, deaths, serious adverse events, and pregnancy outcomes. Safety was evaluated by pooling data from 11 clinical trials of HPV2 in females aged 9 through 25 years and by a meta-analysis of safety databases of HPV2 as well as other vaccines that have the same adjuvant (10,174,175). The pooled safety analysis included 23,952 females aged 9-25 years; approximately 13,000 females received at least 1 dose of HPV2 (10). In an analysis of local and systemic adverse events, a larger proportion of persons reported at least one injection-site symptom in the HPV2 group compared with controls (who received hepatitis A vaccine). In the HPV2 group, 92% reported injection-site pain, 48% redness, and 44% swelling compared with 64%-87%, 24%-28%, and 17%-21%, respectively, in the control groups (Table 10). Fatigue, headache, and myalgia were the most common systemic symptoms. No differences were observed in unsolicited symptoms within 30 days of vaccination between the vaccine group and control groups. Serious adverse events were evaluated in a pooled safety analysis that included 30,192 females aged 9-72 years (16,381 received HPV2). Proportions of persons reporting a serious adverse event were similar in vaccine and control groups (5.3% and 5.9%, respectively), as were the types of serious adverse events reported (10). In the pooled safety analysis, including 12,772 females who received HPV2 and 10,730 in the control groups, incidence of potential new autoimmune disorders did not differ (0.8% in both groups). Overall, among completed and ongoing studies that enrolled 57,323 females aged 9-72 years, 37 deaths were reported during 7.4 years of follow-up: 20 among those who received bivalent vaccine (0.06%) and 17 among those in the control groups (0.07%). None of the deaths was considered to be vaccine-related. # Vaccination During Pregnancy Clinical protocols excluded females who were pregnant, and participants were instructed to avoid pregnancy until 2 months after the last vaccination. However, 3,696 pregnancies occurred in the HPV2 group and 3,580 in the pooled control groups (10). Overall, no differences were observed in rates of any specific pregnancy outcomes between groups. Among 761 pregnancies around the time of vaccination (defined as last menstrual period 30 days before to 45 days after vaccination), 13.6% of pregnancies ended in spontaneous abortion in the HPV2 group compared with 9.6% in the control group. Abnormal infant outcomes (other than congenital anomalies) were reported in 5.1% of the HPV2 group and 4.7% of the control group. Other outcomes (congenital anomalies, still birth, ectopic pregnancy, and therapeutic abortion) were reported in 0.3% to 1.8% of the HPV2 group and 0.3% to 1.4% of the control group. HPV2 has been classified as Pregnancy Category B on the basis of animal studies that revealed no evidence of impaired fertility or harm to the fetus (10). A registry for females inadvertently vaccinated during pregnancy was established by the manufacturer as part of its postlicensure commitment to FDA. To date, the rate of major congenital anomalies and spontaneous abortions has been within the reported background rates (176). In addition, a postmarketing required study is being conducted to assess the risk of spontaneous abortions in females who receive HPV2 during pregnancy in an observational database cohort study in the United Kingdom (177). No data are available on use of HPV2 in lactating females. # Postlicensure Safety Data From October 2009 through March 2014, approximately 719,000 doses of HPV2 were distributed in the United States. Because of the smaller number of doses distributed compared with HPV4, formal evaluations of the passive surveillance data from VAERS or data from VSD have not been conducted. During this time period, VAERS has received a total of 113 adverse event reports occurring in females after receipt of HPV2; 93.8% were classified as nonserious (CDC, unpublished data, 2014). Among nonserious adverse events, the most commonly reported generalized symptoms were nausea, dizziness, headache, and urticaria; the most commonly reported local symptoms were injection-site redness, swelling, and induration. Postlicensure safety data are available from other countries that have implemented vaccination programs using HPV2 (154,176). In a review of passive reports from countries that have implemented HPV2 vaccination programs, the distribution of adverse events was consistent with prelicensure trials. Passive reports revealed no concerns about potentially immune mediated diseases (176). In addition, a postmarketing observational database cohort study will assess the risk of autoimmune diseases in adolescent and young adult women who received HPV2 in the United Kingdom (177). # Economic Burden of HPV and Cost-Effectiveness of Vaccination in the United States Before HPV vaccine introduction, the prevention and treatment of HPV-related disease imposed an estimated burden of $8 billion or more in direct costs in the United States each year (178). Of this, approximately $1 billion was for treatment of cancer, including $400 million for invasive cervical cancer and $300 million for oropharyngeal cancer. Approximately $200 million was for treatment of recurrent respiratory papillomatosis and $300 million was for treatment of genital warts. The remainder ($6.6 billion) was for cervical cancer screening and follow-up. Modeling studies have shown consistently that the routine vaccination of 12-year-old girls with either HPV2 or HPV4 is a cost-effective use of public health resources, as long as vaccine duration of protection is sufficient (e.g., 30 years) (179,180). Estimates of the incremental cost per quality-adjusted life year (QALY) gained by adding HPV vaccination of girls aged 12 years to existing cervical cancer screening programs vary (approximate range: $3,000-$45,000) (181)(182)(183)(184)(185)(186). Although cost-effectiveness estimates for vaccination of girls aged 12 years are quite consistent across published models, cost-effectiveness estimates for vaccination of females aged >12 years and for vaccination of males are more uncertain and less precise. The published models generally suggest that the cost-effectiveness of vaccination of females becomes less favorable as the age at vaccination increases beyond the early teenage years. However, there is no consensus on the exact age at which catch-up vaccination of females might no longer be considered cost-effective. Models suggest that catch-up vaccination of females could be cost-effective through the mid-20s, particularly if all potential benefits of vaccination are included (185,187). Numerous published models have found that the costeffectiveness of adding males to a female-only vaccination program depends on the vaccination coverage in females and the cost of vaccine (180). As vaccination coverage of females increases, the health burden of HPV can be reduced in both females and males (through herd immunity), thereby reducing the potential benefits of male vaccination. Male vaccination at age 12 years, when added to a female-only vaccination program, costs about $20,000 to $40,000 per QALY gained in the most favorable scenarios for male vaccination and about $75,000 to more than $250,000 per QALY gained in the least favorable scenarios (187)(188)(189). Scenarios for male vaccination are more favorable when female vaccination coverage is low (e.g., 20%) and when all potential health benefits are included in the analysis (179,188). Scenarios for male vaccination are less favorable when female vaccination coverage is high (e.g., 75%), when including only the health outcomes for which evidence of vaccine efficacy is available, if vaccinated males have mostly vaccinated female sex partners, and when male vaccination is compared with an alternative strategy of increased vaccination coverage among females (179,188). Vaccination of adult males becomes less cost-effective as age at vaccination increases, particularly for age >21 years (15). Vaccination of MSM through age 26 years potentially could be cost-effective across many scenarios, according to the only study available of the cost-effectiveness of HPV vaccination of MSM in the United States (190). # HPV Vaccination Program in the United States Recommendations for HPV vaccination have evolved since HPV4 was first licensed in 2006. In June 2006, HPV4 was licensed for use in females and recommended for routine vaccination of females aged 11 or 12 years and for those aged 13 through 26 years not previously vaccinated (12). In 2009, HPV2 was licensed for use in females and ACIP updated recommendations to state that either HPV vaccine is recommended for females (13). In 2009, HPV4 was licensed for use in males (14) and in late 2011, HPV4 was recommended for routine vaccination of males aged 11 or 12 years and for those aged 13 through 21 years not previously vaccinated (15). The recommendations for females and males state that the vaccination series can be started beginning at age 9 years. Most HPV vaccine administered in the United States has been HPV4 (147). Almost all HPV vaccinations are delivered by primary care providers or health clinics (191). In the United States, there is both public and private financing for vaccines. The Vaccines for Children Program (VFC) supplies enrolled private and public health-care providers with federally purchased vaccines for use among uninsured, Medicaid-eligible and other entitled children through age 18 years (192,193). Under the Patient Protection and Affordable Care Act of 2010, nongrandfathered private health plans must offer, at no cost to beneficiaries, vaccines that are recommended by ACIP. Similarly, qualified health plans on the new health insurance exchanges that went into effect starting in 2014 must offer ACIP-recommended vaccines at no cost to beneficiaries (194). HPV vaccination coverage with at least 1 dose among girls aged 13-17 years increased from 25.1% in 2007 to 53.0% in 2011 (148). However, the annual increase lagged behind that of other vaccines recommended for adolescents, and in 2012 there was no increase. In 2013, at least 1 dose coverage and 3 dose coverage increased slightly; among girls aged 13-17 years 57.3% had received at least 1 dose and 37.6% had received all 3 doses (147). Variation by state remains wide, with at least 1 dose vaccine coverage ranging from 39.9% to 76.6% (195). The main reasons parents reported for not intending or being unsure about vaccinating their daughters in the next 12 months were a lack of knowledge, a belief that the vaccine was not needed, concerns about vaccine safety or side effects, and the vaccine not being recommended by their provider (147). These responses indicate gaps in understanding, including the reasons vaccination is recommended at age 11 or 12 years and the need to strengthen provider recommendations. Updated educational materials that address these issues are available from CDC at http:// www.cdc.gov/vaccines/who/teens/index.html. Data from 2012 were the first since the October 2011 ACIP recommendation for routine vaccination of males. At least 1 dose coverage among boys aged 13-17 years increased from 8.3% in 2011 to 20.8% in 2012 and further increased to 34.6% in 2013 (147). # Summary of Rationale for HPV Vaccination Recommendations The availability of HPV vaccines provides an opportunity to decrease the burden of cervical cancer precursors, cervical cancer, other anogenital cancer precursors and cancers, and genital warts in the United States (10,11). Although data on efficacy against oropharyngeal disease endpoints are not available from clinical trials, HPV vaccination is also likely to be effective for prevention of HPV-attributable oropharyngeal cancer (63,164). Two vaccines are licensed for use in females in the United States; HPV4 (directed against HPV 6, 11, 16, and 18) and HPV2 (directed against HPV 16 and 18). One vaccine (HPV4) is licensed for use in males in the United States. HPV 16 and 18 are the cause of approximately 70% of cervical cancers and most other HPV-attributable cancers; HPV 6 and 11 are the cause of approximately 90% of genital warts. HPV vaccines are most effective when administered before exposure to HPV (107,118,160). The recommendation for routine vaccination at age 11 or 12 years is based on several considerations including studies indicating that HPV vaccines are safe and immunogenic in this age group, the higher antibody titers achieved after vaccination at age 11 or 12 years compared with older age groups, data on HPV epidemiology, and age of sexual debut in the United States (128,167,196). The recommendation also considered cost-effectiveness evaluations and the established young adolescent health-care visit at age 11 or 12 years recommended by several professional organizations, when receipt of other vaccines also is recommended (197). Data suggest that protection after vaccination will be long lasting (124)(125)(126)166); long-term follow-up studies are underway to determine the duration of protection. Although routine vaccination is recommended at age 11 or 12 years, older adolescents and young adults through the recommended ages can benefit from vaccination. Adolescents and young adults who are not yet sexually active can be expected to receive the full benefit of vaccination. Although sexually active persons in this age group might have been infected with one or more vaccine HPV types, studies suggest that only a small percentage have been infected with both HPV 16 and 18 or all four vaccine types (31,198). The vaccines can protect against types not already acquired. Neither vaccine protects against persistent infection, precancer lesions, or anogenital warts caused by an HPV type that persons are infected with at the time of vaccination. Although vaccine effectiveness would be lower when administered to those who are sexually active, and would decrease with older age and likelihood of previous HPV exposure, the majority of persons in the recommended age groups will derive at least partial benefit from vaccination. HPV vaccines are not licensed in the United States for use in persons aged >26 years. Among women, the expected population-level impact of HPV vaccination in this age group is lower than that for younger women because of the higher likelihood that women have already had vaccine type infection, because fewer would have incident infection that could be prevented and the risk for development of disease from incident infection is less (199). # Recommendations for Use of HPV Vaccines Routine Recommendations ACIP recommends routine vaccination at age 11 or 12 years with HPV4 or HPV2 for females and with HPV4 for males (male GRADE recommendation category: A, evidence type: 2 ). The vaccination series can be started beginning at age 9 years. HPV4 and HPV2 are each administered in a 3-dose schedule. The second dose should be administered 1-2 months after the first dose and the third dose 6 months after the first dose. # Recommendations for Those Not Vaccinated at the Routine Age Vaccination also is recommended for females aged 13 through 26 years and for males aged 13 through 21 years, who have not been vaccinated previously or who have not completed the 3-dose series. Males aged 22 through 26 years may be vaccinated. If females or males reach age 27 years before the vaccination series is complete, the second and/or third doses of vaccine can be administered after age 26 years to complete the vaccination series. Prevaccination assessments (e.g., Pap testing or screening for high-risk HPV DNA, type-specific HPV DNA tests, or HPV antibody tests) to establish the appropriateness of HPV vaccination are not recommended. # Administration HPV vaccine (either HPV4 or HPV2) should be shaken well before administration. The dose for either vaccine is 0.5 ml, administered intramuscularly (IM), preferably in the deltoid muscle. # Minimum Dosing Intervals and Interrupted Schedules The minimum interval between the first and second doses of HPV vaccine (either HPV4 or HPV2) is 4 weeks. The minimum recommended interval between the second and third dose of vaccine is 12 weeks. The minimum interval between the first and third dose is 24 weeks. Inadequate doses or vaccine doses received after a shorter-than-recommended dosing interval should be re-administered. If the vaccine schedule is interrupted for either HPV4 or HPV2, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered, and the second and third doses should be separated by an interval of at least 12 weeks. # Concomitant Administration with Other Vaccines HPV vaccine (either HPV4 or HPV2) can be administered at the same visit as other age-appropriate vaccines, such as tetanus, diphtheria, and acellular pertussis and quadrivalent meningococcal conjugate vaccines. Administering all indicated vaccines together at a single visit increases the likelihood that adolescents will receive each of the vaccines on schedule. Each vaccine should be administered by using a separate syringe at a different anatomic site. # Interchangeability of HPV Vaccine Products ACIP recommends that the HPV vaccination series for females be completed with the same HPV vaccine product, whenever possible. However, if vaccination providers do not know or have available the HPV vaccine product previously administered, either HPV vaccine product may be used to continue or complete the series for females to provide protection against HPV 16 and HPV 18. Only HPV4 is licensed for use in males. No studies address the interchangeability of the two HPV vaccines. However, there is no theoretic reason to expect that the risk for adverse events would be increased if the series included more than one product. The effectiveness of a series that contained both products might be reduced compared with a complete series with one product for protection against HPV 16/18-related cancers and precancers. A series with <3 doses of HPV4 might provide less protection against genital warts than a complete 3-dose series of HPV4. # Special Populations Abnormal Pap Test, Known HPV Infection, Anogenital Warts, or HPV-Associated Lesions HPV vaccination can provide protection against infection with HPV vaccine types not already acquired. Therefore, vaccination is recommended through the recommended age for females regardless of whether they have an abnormal Pap test result, and for females or males regardless of known HPV infection, HPV-associated precancer lesions, or anogenital warts. Females who have abnormalities on cervical cancer screening are likely to be infected with one or more genital HPV types. With increasing severity of Pap test findings, the likelihood of infection with HPV 16 or HPV 18 increases (70), and the expected benefit of vaccination decreases. Females who have had HPV testing as part of cervical cancer screening might have information about their HPV status. Males or females with AIN are likely infected with HPV. The presence of anogenital warts or a history of anogenital warts indicates present or past infection with HPV, most often HPV 6 or HPV 11. Although vaccination is still recommended, patients should be advised that vaccination will not have any therapeutic effect on an existing HPV infection, HPV-associated precancer lesion, cancer, or anogenital warts. # Immunocompromised Persons Persons who are immunocompromised because of transplant, medications, or HIV have a higher burden of HPV-associated disease and cancer (46). Although studies have found the vaccines to be well tolerated and immunogenic in HIV-infected persons, some studies found that GMTs were lower among HIV-infected persons compared with those who are uninfected (136)(137)(138)(139)171). Whether there will be any differences in HPV vaccine efficacy between immunocompromised and immunocompetent persons is unclear. ACIP recommends routine vaccination at age 11 or 12 years with HPV2 or HPV4 for females and with HPV4 for males. Vaccination is recommended through age 26 years for immunocompromised persons who have not been vaccinated previously or who have not completed the 3-dose series. # Men Who Have Sex with Men MSM are at high risk for infection with HPV and associated conditions, including anogenital warts and anal cancer (29). For MSM, ACIP recommends routine vaccination with HPV4, as for all males, and vaccination through age 26 years for those who have not been vaccinated previously or who have not completed the 3-dose series. # Lactating Women Lactating women can receive HPV vaccine. # History of Sexual Abuse or Assault Health-care providers who evaluate and treat children and youth who are suspected or confirmed victims of sexual abuse or assault should be aware of the need for HPV vaccination. Sexual abuse and assault raise the risk of HPV infection attributable to the abuse itself, potential future victimization, and subsequent engagement in at-risk behaviors. Children who are victims of sexual abuse or assault are recognized to be more likely to engage in subsequent unsafe and unprotected intercourse and to engage in these behaviors at an earlier age than nonabused children (200). Although HPV vaccination will not promote viral clearance or protect against disease progression attributable to types already acquired, vaccination would protect against vaccine-preventable types not yet acquired. ACIP recommends HPV vaccination beginning at age 9 years for children and youth with any history of sexual abuse or assault who have not initiated or completed the 3-dose series. Females and males who are victims of sexual abuse or assault should receive HPV vaccine through the recommended ages if they have not already been vaccinated. # Precautions and Contraindications # Hypersensitivity or Allergy to Vaccine Components HPV vaccines are contraindicated for persons with a history of immediate hypersensitivity to any vaccine component. HPV4 is produced in Saccharomyces cerevisiae (baker's yeast) and is contraindicated for persons with a history of immediate hypersensitivity to yeast. The tip cap of prefilled syringes of HPV2 might contain latex. HPV2 should not be used in persons with anaphylactic allergy to latex. # Acute Illnesses HPV vaccines can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infections with or without fever). Vaccination of persons with moderate or severe acute illnesses should be deferred until after the patient improves. # Preventing Syncope After Vaccination Syncope (vasovagal or vasodepressor reaction) can occur after vaccination, most commonly among adolescents and young adults (201). One of the most frequent reports to VAERS for HPV4 since licensure has been syncope (148). Although syncopal episodes are uncommon, vaccine providers should consider observing patients (with patients seated or lying down to decrease the risk for injury should they faint) for 15 minutes after they receive any vaccine, including HPV vaccine (202). # Vaccination During Pregnancy HPV vaccines are not recommended for use in pregnant women. The vaccines have not been associated causally with adverse outcomes of pregnancy or adverse events in the developing fetus. However, if a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose series should be delayed until completion of pregnancy. Pregnancy testing is not needed before vaccination. If a vaccine dose has been administered during pregnancy, no intervention is needed. Patients and health-care providers can report an exposure to HPV vaccine during pregnancy to VAERS. FDA considered Merck's regulatory commitment for a pregnancy registry fulfilled in April 2013 and the registry was terminated (see HPV4 Safety). Although the registry has been terminated, HPV4 exposure during pregnancy can continue to be reported to Merck at telephone 1-877-888-4231. HPV2 exposure during pregnancy should be reported to the GlaxoSmithKline Pregnancy Registry at telephone 1-888-452-9622. # Monitoring Impact of HPV Vaccination in the United States Most cancers that could be prevented by HPV vaccine occur years after infection; therefore, it might be decades before an impact of vaccination is observed on these outcomes. The United States has cancer registries that monitor the incidence of cervical and other HPV-associated cancers (203). To determine earlier impact of vaccination, several more proximal outcomes are being monitored, including HPV prevalence, genital warts, and cervical precancers (204)(205)(206)(207)(208). Challenges to establishing a unified monitoring system for precancer outcomes as well as other outcomes include incomplete immunization information systems, lack of unique identifiers to link medical records, and lack of population-based cervical cancer screening registries. Despite 3-dose coverage in 2010 of only 32% in girls aged 13-17 years (148), data obtained within 4 years of introduction of HPV vaccination in the United States show a reduction of HPV vaccine type prevalence and genital warts in adolescent girls. In a national survey, HPV 6, 11, 16, and 18 type prevalence among girls aged 14-19 years decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010 (207). An analysis of health claims data found that genital warts decreased among girls aged 15-19 years from a prevalence per 1,000 person-years of 2.9 in 2006 to 1.8 in 2010 (208). Data from other studies in the United States also show vaccine impact (209). Dramatic decreases in genital warts and vaccine type prevalence have been demonstrated in countries that have achieved high coverage (209,210). # Areas of Ongoing Research and Future Priority Activities Since HPV vaccine was first introduced in the United States, substantial additional data have been provided by clinical trials and postlicensure evaluations. Ongoing research and other activities will provide additional data in the future. - Efficacy and duration of protection: Available data show no loss of protection through 8 to 10 years (124,125,166). Ongoing evaluations will continue to provide information on duration of protection for both vaccines. - Reduced dose schedules: There is broad interest in reduced dose schedules; immunogenicity trials show noninferior antibody response after 2 doses in females aged 9-14 years compared with 3 doses in females aged 15-26 years (170,211,212). Available data as well as data from ongoing studies will provide important information for policy considerations (170,212,213 # ISSN: 1057-5987 The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format. To receive an electronic copy each week, visit MMWR's free subscription page at . html. Paper copy subscriptions are available through the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone 202-512-1800.	Front cover photo: An illustration of human papillomavirus (HPV) virions constructed with 3D animation software, using Protein Data Bank entry 1L0T.# Introduction Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 14 million persons are newly infected every year (1). Although most infections cause no symptoms and are self-limited, persistent HPV infection can cause cervical cancer in women as well as other anogenital cancers, oropharyngeal cancer, and genital warts in men and women. More than 150 HPV types have been identified, including approximately 40 that infect the genital area (2,3). Genital HPV types are categorized according to their epidemiologic association with cervical cancer. High-risk types have the potential to act as carcinogens. Low-risk types (e.g., types 6 and 11) can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis (4). High-risk types (e.g., types 16 and 18) can cause lowgrade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and cancers (5)(6)(7). Essentially all cervical cancers are attributable to high-risk HPV types (8), and approximately 70% of cervical cancer cases worldwide are caused by types 16 and 18 (9). In addition to cervical cancer, HPV infection also is the cause of some other anogenital cancers such as cancer of the vulva, vagina, penis, and anus, as well as cancer of the oropharynx (6). Two HPV vaccines, bivalent HPV vaccine (HPV2) and quadrivalent HPV vaccine (HPV4) are licensed for use in the United States (10,11). Both vaccines protect against HPV types 16 and 18, which cause 70% of cervical cancers. HPV type 16 also causes the majority of other cancers attributable to HPV. HPV4 also protects against HPV types 6 and 11, which cause >90% of genital warts and recurrent respiratory papillomatosis (4). This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccines, provides updated information on vaccines from clinical trials and postlicensure safety studies and monitoring, and compiles recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) for use of HPV vaccines (12)(13)(14)(15). # Methods The Advisory Committee on Immunization Practices (ACIP) HPV Vaccine Work Group* first met in February 2004 to begin reviewing data related to HPV4. Since February 2004, the Work Group has held multiple teleconferences and periodic meetings to review published and unpublished data from HPV2 and HPV4 clinical trials including data on safety, immunogenicity, and efficacy (12)(13)(14)(15). Data on epidemiology and natural history of HPV, sexual behavior, vaccine acceptability, and cost-effectiveness of HPV vaccination also were considered. Presentations were made to ACIP during multiple meetings before ACIP votes (16). The first vote for routine use of HPV4 in females was held in June 2006 (Table 1). The second vote occurred in October 2009 after HPV2 was licensed for use in females; ACIP updated the recommendation to state that either vaccine could be used in females (13). At the same meeting, ACIP provided guidance that HPV4 may be given to males aged 9 through 26 years, but vaccination of males was not included in the routine schedule (14). In October 2011, ACIP recommended routine vaccination of males (15). Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was adopted by ACIP in 2011 (14) and the routine recommendation for males was considered using GRADE (15). Factors considered in determining the recommendation for males included benefits and harms, evidence type, values and preferences, and health economic analysis (17). The Work Group continues to review data as they become available and considers any needed policy changes. # Background Biology and Immunology of HPV HPVs are nonenveloped, double-stranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as "types" in most commonly used nomenclature, with International Committee on Taxonomy of Viruses (ICTV) proposing use of "strains." The types (or strains) are assigned numbers in order of their discovery (2). Types are designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8-kb circular genome enclosed in a capsid shell comprising the major and minor capsid proteins L1 and L2, respectively. Purified L1 protein will self-assemble to form empty shells that resemble a virus, called virus-like particles (VLPs). In addition to the structural genes (L1 and L2), the genome encodes several early genes (E1, E2, E4, E5, E6, and E7) that enable viral transcription and replication and interact with the host genome. Immortalization and transformation functions are associated with the E6 and E7 genes of high-risk HPV types. E6 and E7 proteins from highrisk types are the primary oncoproteins; they manipulate cell cycle regulators, induce chromosomal abnormalities, and block apoptosis (3). Papillomaviruses initiate infection in the basal layer of the epithelium, and viral genome amplification occurs in differentiating cells using the cellular replication machinery. After infection, differentiating epithelial cells that are normally nondividing remain in an active cell cycle. This can result in a thickened, sometimes exophytic, epithelial lesion. The virus is released as cells exfoliate from the epithelium. With neoplastic progression, the virus might integrate into the host chromosomes, and little virion production will occur. HPV infections are largely shielded from the host immune response because they are nonlytic and restricted to the epithelium (3,18). Humoral and cellular immune responses have been documented, but correlates of immunity have not been established (18). Serum antibodies against many different viral products have been demonstrated. The best characterized antibodies are those directed against conformational epitopes of the L1 capsid protein assembled as VLPs. Not all infected persons develop detectable antibody; in one study, 54%-69% of women with incident HPV 6, 16, or 18 infections had type-specific antibody (19). Among newly infected men, 4%-36% developed type-specific antibody to one of seven types (20). Only 13% developed antibody after infection with HPV 16. # Laboratory Testing for HPV Because HPV infections are not treated, the clinical indications for HPV testing are to identify women at risk for HPV-associated cervical disease and to guide follow-up decisions for those with disease. HPV cannot be cultured directly from patient specimens, so tests require detecting HPV genetic information. Most commercially available assays detect DNA. Because HPV is cell-associated, cellular samples are required. The Food and Drug Administration (FDA) has approved clinical HPV tests for detecting clinically significant levels of any of 14 high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) from cervical specimens (see Cervical Cancer Screening). HPV tests are approved either for use with the Papanicolaou (Pap) test for routine screening in women aged >30 years or for following up certain abnormal Pap test results. One HPV test has been approved for primary cervical cancer screening but is not currently part of national recommendations (21). There are no other approved indications for clinical HPV testing. HPV tests are not recommended or approved for use in men or adolescents, for detection of HPV in partners, or at anatomic sites other than the cervix. Epidemiologic and basic research studies of HPV typically use nucleic acid amplification methods that generate typespecific and, in certain formats, quantitative results. Polymerase chain reaction (PCR) assays targeting genetically conserved regions of the L1 gene are designed to amplify essentially all HPV, and types are then determined by type-specific hybridization. However, a wide variety of HPV detection and typing methods exist (22). Although HPV DNA tests detect current HPV infection at specific sites, HPV serology can be used as a measure of current or past infection (or vaccination) in research settings. As noted previously, the host immune response to HPV infection is weak, and not all infected persons develop detectable antibody. Nonetheless, in unvaccinated populations, the age-specific seroprevalence reflects the overall age of first exposure, and seroprevalence data were used to help guide the ages targeted for preventive HPV vaccines. Serologic testing was conducted in the HPV vaccine clinical trials (see Evaluation of Serologic Response to Vaccination). The most frequently used HPV serologic assays are VLP-based enzyme-linked immunoassays, which are designed to detect antibodies to the L1 viral protein. The type-specificity of the assay depends on preparation of conformationally intact VLPs in recombinant baculovirus or (24). Prevalence of HPV was highest among those aged 20-24 years (53.8%). In this age group, prevalence of HPV types 6, 11, 16, or 18 was 18.5% (25). Other information on HPV prevalence among females and males has been obtained primarily from clinic-based populations (e.g., family planning and sexually transmitted disease or university health clinic patients). These evaluations found prevalence of HPV ranging from 14% to 90%, with similar peak prevalence in young adults (26,27). Although most information on HPV epidemiology is derived from studies of cervical infection in women, there are also studies on anogenital HPV infection in males (28,29). A study among men aged 18-70 years seeking information about sexually transmitted disease testing from Brazil, Mexico, and the United States determined that genital HPV prevalence ranged from 52% to 69% by country, with no consistent variation by age (28). Studies of incident infections demonstrate that first HPV infection occurs within a few years of becoming sexually active. In a prospective study of women attending university in the United States, the cumulative probability of incident infection was 38.9% by 24 months after first sexual intercourse (30). Of all HPV types, new detection of HPV 16 was highest (10.4%); new detection of HPV 18 was 4.1% (30). Detection of HPV DNA is the best indication of infection but does not provide information on persons who were infected but cleared the HPV infection. Seroprevalence data provide an estimate of cumulative exposure but also will be an underestimate because not all persons with natural HPV infection develop or maintain detectable antibodies. NHANES 2003NHANES -2004 data indicate that seroprevalence of HPV 6, 11, 16, or 18 among females reached 42% by age 30-39 years (31). The cumulative incidence of HPV infection among men also is high. In a prospective study of men attending university in the United States, the cumulative probability of incident infection at 24 months after study enrollment was 62.4% (32). In contrast to women, for whom the risk for HPV acquisition increases with age through the early 20s and then decreases, studies have demonstrated that incidence among men is relatively constant over a wide age range (33). # Transmission and Natural History Genital HPV infection is transmitted primarily by genital contact, usually through sexual intercourse but also through other intimate contact (e.g., oral-genital or genital-genital) (30,(34)(35)(36)(37). Nonsexual routes of genital HPV transmission are less common and can include intrapartum transmission from mother to infant (38). Most data on natural history of HPV are obtained from studies of cervical infection. In virtually all studies of HPV prevalence and incidence, the most consistent predictors of infection have been measures of sexual activity, most importantly the number of sex partners (lifetime and recent) (39)(40)(41)(42)(43)(44). However, even persons with one lifetime sex partner are at risk for infection. One study found that HPV prevalence among women aged 18-25 years was 14.3% for those with one lifetime sex partner, 22.3% for those with two lifetime partners, and 31.5% for those with three or more lifetime partners (44). Additional risk factors include sexual behavior of the partner (30) and immune status (45,46). Transmission is very common between sex partners, and likely more frequent from females to males than from males to females (36). Most HPV infections are transient and asymptomatic and cause no clinical problems; 70% of persons with new cervical HPV infection will clear the infection within 1 year, and approximately 90% within 2 years (39,(47)(48)(49). The median duration of new infections is about 8 months for genital infection among both females and males (33,39,48,(50)(51)(52). Oral HPV infection is much less common than genital infection (53), but time to clearance appears to be similar (54). Immunocompromised persons, such as those with human immunodeficiency virus (HIV), have higher rates of HPV acquisition and progression to disease (55). The risk for persistence and progression to cancer precursor lesions varies by HPV type as well as host factors. HPV 16 is more likely to persist and progress to cancer than other high-risk HPV types (52,56). The usual time between initial HPV infection and development of cervical cancer is decades but more rapid progression has occurred. Many aspects of the natural history of HPV are poorly understood, including the role and duration of naturally acquired immunity after HPV infection. # Clinical Sequelae of HPV Infection # Cancers Associated with HPV Persistent infection with oncogenic HPV types has a causal role in nearly all cervical cancers and in many vulvar, vaginal, penile, anal, and oropharyngeal cancers (57). On the basis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and CDC's National Program of Cancer Registries (NPCR), the burden of HPV-associated cancers in the United States has been estimated (58). Because cancer registries typically do not capture information on HPV, the number of HPV-attributable cancers was estimated by multiplying the number of cancers at each body site (HPV-associated) by the percentage attributable to HPV, based on genotyping studies (59)(60)(61)(62)(63)(64). From 2006 to 2010, on average, 33,160 HPV-associated cancers were diagnosed in the United States, including 20,589 (62%) among females and 12,571 (38%) among males. Approximately 26,900 new cancers at these body sites were attributable to HPV, including 17,600 (65%) among females and 9,300 (35%) among males. Cervical and oropharyngeal cancers were the most common with an estimated 10,400 cervical cancers and 9,000 oropharyngeal cancers (7,200 [80%] among men and 1,800 [20%] among women). Among these six cancers, approximately 17,500 were attributable to HPV16/18 (5,900 [34%] among men and 11,600 [66%] among women) (Table 2). Data from nine cancer registries in the SEER program have been analyzed to obtain long-term trends of invasive HPV-associated cancers and their precursors from 1978 through 2007 (65), and data from 42 NPCR/SEER cancer registries that cover a larger percentage of the U.S. population have been analyzed to obtain trends of invasive HPV-associated cancers from 2000 through 2009 (66). # Cervical Precancers and Cancer The only HPV-associated cancer for which screening is recommended is cervical cancer (67,68). Cervical cancer screening is based on exfoliated cytology (Pap test) with clinical HPV testing in appropriate settings (see Cervical Cancer Screening). Abnormalities detected in screening require follow-up, and diagnosis is based on histology of the tissue sample. Terminology for histologic outcomes of squamous precursor lesions is changing from grades 1-3 of cervical intraepithelial neoplasia (CIN) to the same terminology that is used for cytological abnormalities: low-or high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively) (69). HSIL is considered a cancer precursor that requires treatment whereas LSIL generally clears without treatment. Precursors of glandular or adenocarcinomas are designated adenocarcinoma in situ (AIS). These lesions are detected less readily by Pap test because of their endocervical location. AIS also is considered a cancer precursor that requires treatment. The CIN terminology continues to be used widely and conveys the spectrum of changes from those that are clearly low grade (CIN1) to those that are clearly high grade (CIN3). The CIN2 lesions represent an intermediate group that includes lesions that could be grouped into either low-or high-grade lesions (69). Most LSIL, HSIL, and AIS lesions are HPV-associated, but the type distribution changes with severity of the abnormality; high-risk types, particularly HPV 16, increase in frequency with severity of lesion. In meta-analyses, HPV prevalence was 12% (HPV 16 accounting for 20%) in women with normal cytology, 52% (HPV 16 accounting for 23%) in those with equivocal cytology, and 76% and 85%, respectively, in those with LSIL and HSIL cytology. Among histological specimens, HPV prevalence increased from 73% among CIN1 lesions to 93% among CIN3 lesions (70). On the basis of a combination of natural history studies and HPV molecular analyses, essentially all cervical cancers are thought to be attributable to HPV (57). A 2011 meta-analysis of studies using sensitive PCR methods reported HPV detection in 90% of cervical cancers worldwide (71). HPV 16 and 18 were the most common types, detected in approximately 70% of cervical cancers (9,71). The prevalence of other types varies somewhat worldwide, but the next-most-frequent types detected were HPV 31, 33, 45, 52, and 58. A U.S. study found that HPV was detected in 91% of cervical cancers (51% HPV 16, 16% HPV 18, and 24% other oncogenic and rare types) (62). Beyond high-risk HPV persistence, additional independent risk factors for cervical precancer and cancer include cigarette smoking, oral contraceptive use, and higher parity (72)(73)(74). In the United States, cervical cancer cases and deaths have decreased substantially since the 1950s (75). Racial/ethnic and geographic disparities remain, with non-Hispanic black and Hispanic women having higher cervical cancer incidence and mortality; rates of cervical cancer also are higher in the southern states. Most disparities are thought to be attributable to differential access to both screening and follow-up after an abnormal cervical cancer screening result (76). # Vulvar and Vaginal Precancers and Cancer Worldwide studies report detection of HPV in 85% of vulvar intraepithelial neoplasia grade 2 or 3 (VIN2/3), and 40% of invasive vulvar cancer (77). HPV 16 is the most frequent type detected. In the United States, HPV was detected in 69% of invasive vulvar cancer and 97% of VIN3, with HPV 16 detected in 49% of invasive cancers and 81% of VIN3 (61). Since the 1970s, the incidence of pre-invasive vulvar cancer in the United States has increased at a faster rate than has invasive vulvar cancer (65). Recent data indicate that rates of invasive vulvar cancer are increasing among both white and black women (66). Worldwide, 90% of vaginal intraepithelial neoplasia grade 2 or 3 (VaIN2/3) and 70% of invasive vaginal cancers have been demonstrated to be HPV DNA-positive (77). In a U.S. study, 75% of invasive vaginal cancer cases were positive for HPV; HPV 16 was the most common type detected (55%) (64). The incidence of vaginal cancer has remained stable in the United States. Vaginal cancer rates have been highest among non-Hispanic black women; the most recent data show the rate declining among this group (65,66). # Anal Precancers and Cancer Anal intraepithelial neoplasia (AIN) grade 2/3 is recognized as a precursor of anal cancer, although the natural history of these lesions (i.e., rate of progression and regression) is less clear than for cervical disease (51). Worldwide, a meta-analysis reported HPV in 84% of anal cancers, but HPV prevalence was higher in AIN2/3 (94%) (77). In the United States, 91% of anal cancers have been found to be positive for HPV, with HPV 16 being the most common type detected (77%) (59). Men who have sex with men (MSM) and persons who have HIV infection are at higher risk for anal precancer and cancer (29,78,79). Although the burden of anal cancer and precancers is substantial, data are insufficient to recommend routine anal cancer screening with anal cytology in HIV-infected persons or HIV-negative MSM (29,80). More evidence is needed concerning the natural history of anal intraepithelial neoplasia, the best screening methods and target populations, and safety and response to treatments before routine screening can be recommended (80). Some clinical centers perform anal cytology to screen for anal cancer among high-risk populations (e.g., HIV-infected persons and MSM), followed by highresolution anoscopy for those with abnormal cytologic results. Rates of AIN3 have risen more rapidly among men than among women (65). This increase could be attributable to true increases or more aggressive screening among MSM in certain areas of the country, facilitating diagnosis (81). Both long-and short-term trends indicate that invasive anal cancer has increased at a steady rate among both males and females and among persons in almost every racial/ethnic group (65,66). # Oropharyngeal Cancer Some oropharyngeal cancers are attributable to HPV. Although tobacco smoking, tobacco chewing, and alcohol are strongly associated with cancers of the oropharynx, substantial evidence indicates a causal association between HPV infection and oropharyngeal cancers (57,82). Previous studies reported that worldwide, HPV DNA detection in oropharyngeal cancers varies substantially (range: 13%-56%) (57,83). HPV 16 is detected in the majority of HPV-attributable cancers (57,83). A recent U.S. study reported that approximately 72% of oropharyngeal cancers were positive for HPV; 61% had HPV 16 (63). By anatomic oropharyngeal location, 80% of tonsillar and 70% of base of tongue cancers were positive for one of 14 high-risk HPV types. Prevalence of HPV 16/18 in these cancers was higher in males than females, and lower in non-Hispanic blacks than in other racial/ethnic groups. Trends for oropharyngeal cancer are limited to invasive cancer because no pre-invasive lesion has been established for oropharyngeal . Estimates rounded to the nearest 100. § Although HPV is accepted to be a necessary factor in the causal pathway to invasive cervical cancer, HPV is not always detected in tumor specimens from women who receive a diagnosis of invasive cervical cancer due to a variety of reasons: including misclassification of tissue specimens as cervix, quality of tissue specimens, assay sensitivity, and a small proportion of HPV-negative, cervical cancers. cancer. In the United States, oropharyngeal cancer rates have increased for males since the 1970s (65) and for females from 2000 through 2009 (66). # Penile Cancer Penile cancer is extremely rare. Worldwide, HPV has been associated with 40%-50% of penile squamous cell cancers (57,84). Among HPV-positive penile cancers, HPV 16 has been detected in a large portion (57,84). A U.S. study reported HPV prevalence of 63%, with HPV 16 detected in 46% of all cases (60). Differences in detection found among studies have been attributed to geographic variations or differences in sampling and testing (84). Besides HPV, independent risk factors for penile cancer include cigarette smoking and lack of circumcision (85). In the United States, rates of invasive penile cancer have declined since the late 1970s (85) with stable rates from 2000 through 2009 (66). # Anogenital Warts All anogenital warts are caused by HPV, and >90% are associated with HPV 6 and 11 (4,86). The average time to development of new anogenital warts following HPV infection has ranged in studies from a few months to years (86)(87)(88)(89). Anogenital warts might regress, grow larger, or remain the same. Recurrence of anogenital warts is common (approximately 30%), whether clearance occurs spontaneously or following treatment (90). Genital warts occurring among HIV-infected persons often require longer courses of treatment (80). Anogenital warts are not reported routinely in the United States. On the basis of 2004 health claims data in the United States, the annual incidence of genital warts was 1.2/1000 females and 1.1/1000 males, and highest in females aged 20-24 years and males aged 25-29 years (91). Anogenital warts are associated with psychosocial reactions, including increased anxiety and depression, and can have a substantial negative impact on personal relationships (92,93). # Recurrent Respiratory Papillomatosis Infection with low-risk HPV types, primarily types 6 or 11, can cause recurrent respiratory papillomatosis, a rare disease that is characterized by recurrent warts or papillomas in the upper respiratory tract, particularly the larynx. Recurrent respiratory papillomavirus (RRP) is divided into juvenile onset (JORRP) and adult onset forms based on age at presentation. JORRP, generally defined as onset before age 18 years, is believed to result from vertical transmission of HPV from mother to infant during delivery, although the median age of diagnosis is 3.1 years (94). A multicenter registry of JORRP in the United States, including 22 centers, collected data during 1996-2002 and demonstrated that although the clinical course of JORRP is variable, it is associated with extensive morbidity, requiring a median of 4.3 annual surgeries to remove warts and maintain an open airway (94). Estimates of the incidence of JORRP are relatively imprecise but range from 0.12-2.1 cases per 100,000 children aged <18 years in two U.S. cities (95). The prevalence, incidence, and disease course of adult onset RRP are less clear. # Prevention (Other Than Vaccine), Cervical Cancer Screening, and Treatment # Prevention of Sexual Transmission Abstaining from sexual activity (i.e., refraining from any genital contact with another person) is the surest way to prevent genital HPV infection. Persons also can lower their chances of becoming infected with HPV by being in a monogamous relationship with one partner, limiting their number of sex partners, and choosing a partner who has had no or few previous sex partners. However, even persons with only one lifetime sex partner can be infected with HPV. Consistent and correct condom use can reduce the risk for HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). A limited number of prospective studies have been conducted evaluating male condom use and HPV; one prospective study among newly sexually active women attending university demonstrated a 70% reduction in HPV infection when their partners used condoms consistently and correctly (96). Randomized clinical trials of male circumcision demonstrate a lower risk of HPV infection among circumcised males as well as among their female partners (97)(98)(99). Neither routine surveillance for HPV infection nor partner notification is useful for HPV prevention. Genital HPV infection is so prevalent that most partners of HPV-infected persons have already acquired HPV themselves (80). # Cervical Cancer Screening Cervical cancer screening does not prevent HPV infection, but can secondarily prevent most cervical cancer cases and deaths if women with abnormal screening results receive appropriate follow-up and treatment. In the United States, cervical cancer screening recommendations were revised in 2012 after the U.S. Preventive Services Task Force (USPSTF) and a multidisciplinary group that included representatives of the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), and the American College of Obstetrics and Gynecology (ACOG) reviewed new evidence (67,68,100). Since 2012, all of these organizations recommend that screening with cervical cytology (Pap test; conventional or liquid-based) should begin at age 21 years. Women aged 21-65 years should be screened with a Pap test every 3 years. For women aged 30-65 years who want to lengthen the screening interval, screening can be performed with a combination of cytology and HPV testing ("co-testing") every 5 years. "Co-testing" in this age group every 5 years is preferred by ACS, ASCCP, and ASCP. In 2014, FDA approved one clinical HPV test for primary screening, but there are no national recommendations for use of this test for primary screening (21). In the United States, cervical cancer screening programs have reduced the number of cervical cancer cases and deaths (67,68,75). The availability and use of HPV4 and HPV2 does not eliminate the need for cervical cancer screening in the United States because not all HPV types that cause cervical cancer are prevented by either vaccine. Screening strategies in the United States will continue to be reviewed and evaluated as vaccination coverage increases and further postlicensure monitoring data become available (67). # Treatment There is no treatment for HPV infections. Only HPV-associated lesions including genital warts, RRP, precancers, and cancers are treated (101)(102)(103). Recommended treatments vary depending on the diagnosis, size, and location of the lesion. Local treatment of lesions might not eradicate all HPV containing cells fully; whether available therapies for HPV-associated lesions reduce infectiousness is unclear. # Health-Care and Research Laboratory Workers For this report, data were reviewed on potential risks to health-care and research laboratory workers. Some HPVassociated conditions (including anogenital and oral warts, anogenital intraepithelial neoplasias [e.g., CIN], and recurrent respiratory papillomatosis) are treated with laser or electrosurgical procedures. These procedures should be performed in an appropriately ventilated room using standard precautions (104) and local exhaust ventilation (e.g., smoke evacuator) (105). Workers in HPV research laboratories handling wild-type virus or "quasi virions" might be at risk of acquiring HPV from occupational exposures (106). In the laboratory setting, proper infection control should be instituted including, at minimum, biosafety level 2 (BSL-2). Whether HPV vaccination would be of benefit in these settings is unclear because no data exist on transmission risk or vaccine efficacy. # HPV Vaccines and Evaluation # HPV Vaccine Composition Two HPV vaccines are licensed for use in the United States (10,11) (Table 3). Quadrivalent HPV vaccine (Gardasil, produced by Merck and Co, Inc., Whitehouse Station, New Jersey) is licensed for use in females and males aged 9 through 26 years. Bivalent HPV vaccine (Cervarix, produced by GlaxoSmithKline, Rixensart, Belgium) is licensed for use in females aged 9 through 25 years. Both vaccines are composed of type-specific HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein using recombinant DNA technology produces VLPs. The vaccines are noninfectious. Quadrivalent vaccine (HPV4) contains HPV 6, 11, 16, and 18 L1 VLPs. The L1 protein is expressed in Saccharomyces cerevisiae (baker's yeast) and self-assembles into conformationally intact, noninfectious VLPs. Each 0. # Evaluation of Efficacy of HPV Vaccines The efficacy of HPV vaccines has been evaluated by using a variety of endpoints; these include HPV-associated disease and persistent infection. The primary endpoint in the phase III trials, and the basis for licensure in females for both vaccines, was incident HPV 16-and 18-related CIN2/3 or AIS (CIN2+) (10,11). These endpoints served as a surrogate marker for cervical cancer. Studies using invasive cervical cancer as an endpoint are not feasible because the standard of care is to screen for and treat CIN2+ lesions to prevent invasive cervical cancer. Furthermore, the time from acquisition of infection to the development of cancer can exceed 20 years. VaIN2/3, VIN2/3 and AIN2/3 were used as endpoints and surrogate markers in some trials for vaginal, vulvar and anal cancers. In the phase III efficacy trials, participants were enrolled without regard to HPV DNA or antibody status (10,11). Participants were tested for HPV DNA by PCR to determine current infection and for antibody to vaccine types to evaluate past infection but were not excluded from the trials. Several different analyses have been conducted. The main analyses were restricted to participants who received all 3 doses, had no evidence of current or past infection with the relevant vaccine HPV type through 1 month after the third dose (month 7), and did not deviate from protocol. In these according-to-protocol (ATP) or per-protocol analyses, cases were counted starting 1 month after the third dose. The intention-to-treat population (ITT) or total vaccinated cohort (TVC) included all participants regardless of baseline HPV status, and cases were counted starting 1 day after the first dose. Efficacy was lower in the ITT compared with the ATP or per-protocol analyses because some participants had prevalent infection with a vaccine type HPV at the time of study enrollment and the vaccines do not prevent progression of infection to disease among those already infected. Other populations analyzed included the unrestricted susceptible population (or total vaccinated-naive population) which included only participants who were negative to all HPV types evaluated and received at least 1 dose. Protection against oncogenic types other than HPV 16 and 18 (cross protection) also has been evaluated in post hoc analyses (107)(108)(109). Types evaluated include those related to HPV 16 (types in the alpha 9 species) and HPV 18 (types in the alpha 7 species). Both infection and disease endpoints have been assessed. Evaluation of cross-protection against disease endpoints is complicated because more than one type can be detected in a lesion, making it difficult to determine the causal HPV type. # Evaluation of Serologic Response to Vaccination Serologic assays used in the HPV4 and HPV2 vaccine trials differed. The competitive Luminex immunoassay (cLIA) was used in the HPV4 trials, and an enzyme linked immunosorbant assay (ELISA) was used in the HPV2 trials (107,110,111). These assays measure different subsets of antibody induced by vaccination, making comparison across vaccine trials difficult. The cLIA measures all antibody classes but detects antibodies against a single neutralizing epitope for each HPV type. The ELISA measures only IgG but detects antibodies against all conformational epitopes for each HPV type. Antibody titers cannot be compared directly between assays, or across HPV types for a given assay. Some studies that compared the two vaccines directly by using the same serologic assay found higher HPV 16 and 18 antibody titers among vaccinees who received HPV2 compared with HPV4 (112). There is no known serologic correlative of immunity or minimum titer determined to be protective. The high efficacy found in the clinical trials to date has precluded identification of a minimum protective antibody titer. # Quadrivalent HPV Vaccine (HPV4) HPV4 Efficacy Females Aged 16-26 years Three randomized, double-blind, placebo-controlled clinical trials evaluated the efficacy of HPV4 for prevention of HPV-associated disease: a phase II trial (protocol 007) among females aged 16-23 years (113) and two phase III trials (protocols 013 and 015) among females aged 16-24 and 15-26 years, respectively (114,115). Data from these trials and data from a randomized, placebo-controlled phase II trial of monovalent HPV 16 vaccine (116,117) were included in the FDA Biologics License Application (11). More than 20,000 females were enrolled in these four studies and received either vaccine or placebo. Interim analysis of the phase III trials showed high efficacy (114,115 Efficacy for prevention of persistent infection was evaluated in phase II efficacy trials. HPV 16 persistent infection was the primary endpoint for the phase II monovalent HPV vaccine trial; efficacy for prevention of persistent infection (defined as a vaccine type detected by PCR at 2 or more visits at least 4 months apart) was 100% (116,117). In the phase II HPV4 trial, efficacy for prevention of persistent HPV 6, 11, 16, and 18 infection was 89% (95% CI = 70-97); three of four cases in the vaccine group were detected at last study visit with no documented persistence (113). In the phase III trials, among females aged 16-26 years who had HPV vaccine type DNA detected at study enrollment (either seropositive or seronegative), there was no efficacy against progression to disease or impact on clearance of infection of that type (114,120). However, HPV4 had 100% efficacy for prevention of CIN2+ attributable to types not already acquired (120). Among persons seropositive to the relevant HPV type but HPV DNA-negative, too few cases were detected to evaluate efficacy, but disease incidence was low and all cases occurred in the placebo group. # Males Aged 16-26 Years Efficacy of HPV4 among males was evaluated in one phase III trial, including 4,065 males aged 16-26 years (121). In the end-of-study analysis (median follow-up time of 35 months after the first dose), per-protocol efficacy for prevention of HPV 6-, 11-, 16-, and 18-related genital warts was 89.4% (Table 5). In the ITT analysis, efficacy was 67.2% (95% CI = 47.3-80.3). As in females, no efficacy was observed among males who were infected with the respective HPV type at baseline. Although grade 1, 2, and 3 penile/perineal/perianal intraepithelial neoplasias were evaluated, too few cases were observed to evaluate efficacy. A substudy of the phase III efficacy trial included 602 MSM; outcomes were AIN grades 1, 2, or 3 (AIN1/2/3), AIN2/3 and anal warts (Table 5) (122). Per-protocol efficacy for prevention of HPV 6-, 11-, 16-, and 18-related AIN2/3 was 74.9% (95% CI = 8.8-95.4) and for prevention of HPV 6-, 11-, 16-, and 18-related anal warts was 100% (95% CI = 8.2-100). In the ITT analyses, efficacy for prevention of vaccine type AIN2/3 was 54.2% (95% CI = 18.0-75.3) and for anal warts was 57.2% (95% CI = 15.9-79.5). Efficacy for prevention of 6-month persistent HPV 6, 11, 16, or 18 infection was a prespecified secondary endpoint for the phase III trials among males and for the substudy in MSM. Per-protocol efficacy for prevention of 6-month persistent vaccine type genital or perianal HPV infection was 85.6% (97.5% CI = 73.4-92.9). In the MSM substudy, per-protocol efficacy for prevention of anal 6-month persistent vaccine type HPV infection was 94.9% (95% CI = 80.4-99.4). # Duration of Protection In the phase III trials, females aged 16-26 years were followed for a mean of 42 months after dose one (118). The longest follow-up for HPV4 is from the phase II trial (protocol 007): a subset of participants (n = 241) were followed for 60 months after dose one. Efficacy against vaccine type persistent infection or disease was 95.8% (95% CI = 83.8-99.5) and efficacy against vaccine type-related CIN or external genital lesions was 100% (95% CI = 12.4-100) (123). Follow-up through 8.5 years in the monovalent HPV 16 vaccine trial showed high efficacy and no decline in protection (124). Additional data on duration of protection will be available from follow-up of approximately 5,500 females enrolled in one of the phase III HPV4 trials in the Nordic countries. Half of the females had received vaccine while the other half had received placebo in the randomized clinical trial and were then vaccinated after the first 4 years of the study. These females will be followed for at least 10-14 years after vaccination; serologic testing will be conducted 9 and 14 years after vaccination among the original group of vaccine recipients, and Pap testing results will be linked to pathology specimens for sectioning and HPV DNA testing by PCR. Data from follow-up through 7 to 8 years showed no evidence of waning protection (125). Males in the phase III trial will be followed for 10 years after vaccination. In addition, adolescent girls and boys who were vaccinated at age 10-15 years in an immunogenicity study (see HPV4 Immunogenicity) are being followed as they become sexually active. Through 8 years of follow-up, no cases of disease in females or infection in males related to HPV 6, 11, 16, or 18 were observed (126). This study will continue to follow participants through at least 10 years after vaccination. # Evaluation of Protection Against Nonvaccine Types Protection against infection and CIN2+ attributable to nonvaccine types was evaluated for HPV4. In prespecified analyses among females without evidence of current or previous infection with 14 HPV types at baseline in the phase III trials (protocols 013 and 015), efficacy against CIN2+ associated with any of five nonvaccine types in the alpha 9 (109). No protection was demonstrated against any other individual nonvaccine HPV type. Analyses did not exclude lesions in which HPV 16 or 18 were also detected, making results difficult to interpret (107,109). Among males, no efficacy was observed against external genital lesions or AIN associated with any of the 10 nonvaccine types evaluated (127). # HPV4 Immunogenicity Females and Males Aged 9-26 Years Data on immunogenicity in females are available from phase II and III efficacy trials conducted among females aged 16-26 years and immunogenicity trials conducted among children and adolescents aged 9-15 years. In all studies conducted to date, more than 99% of females had an antibody response to all four HPV vaccine types 1 month after the third dose (123,128). High seropositivity rates were observed after vaccination regardless of sex, race/ethnicity, country of origin, smoking status, or body mass index (129). Vaccination produced antibody titers higher than those after natural infection: among females aged 16-23 years, anti-HPV 6, 11, 16, and 18 geometric mean titers (GMTs) 1 month after the third dose were higher than those observed in participants who were HPV seropositive and PCR negative at enrollment in the placebo group (123). Antibody titers declined over time after the third dose but plateaued by 24 months. At 36 months, HPV 16 GMTs among vaccinees remained higher than those in participants in the placebo group who were seropositive at baseline; HPV 6, 11, and 18 GMTs were similar to those seropositive in the placebo group (113). At 36 months, seropositivity rates in vaccinees were 94%, 96%, 100%, and 76% to HPV 6, 11, 16, and 18, respectively (113). In the follow-up of females in the phase II or phase III efficacy trials, there was no evidence of waning efficacy among participants who became seronegative (130). This suggests that loss of detectable antibody by the cLIA, seen particularly for HPV 18, is not associated with loss of protection. Data from a revaccination study in which vaccinated females were given a challenge dose of vaccine 5 years after enrollment demonstrated an augmented rise in antibody titer, consistent with immune memory (131). Vaccination of females who were seropositive to a specific vaccine HPV type at enrollment resulted in higher antibody titers to that type, particularly after the first dose, compared with those seronegative at enrollment, suggesting a boosting of naturally acquired antibody by vaccination (131). Data on immunogenicity among males are available from the phase III trial in males aged 16-26 years and immunogenicity trials among males aged 9-15 years (128,132). Among males in the efficacy trial, seroconversion rates were 97%-99% 1 month after the third dose (132). High seropositivity rates were observed after vaccination regardless of demographic group, but blacks had higher GMTs than whites, and heterosexual males had higher GMTs than MSM. By month 36, 89%, 94%, 98%, and 57% of males remained seropositive to HPV 6, 11, 16, and 18, respectively (132). Immunogenicity trials allowed comparison of seroconversion rates and GMTs among females and males aged 9-15 years with participants in the efficacy trials (11,128). Seroconversion rates for both females and males aged 9-15 years exceeded 99% for all four vaccine types (Table 6). Among those vaccinated at age 9-15 years, GMTs 1 month after the third dose were noninferior (and 1.7-to 2.7-fold higher) to those vaccinated at age 16-26 years. At 24-36 months after vaccination, GMTs among those vaccinated at 9-15 years remained higher than among those vaccinated at age 16-26 years (11). # Spacing of Vaccine Doses In prelicensure trials among females aged 16-26 years, vaccine was administered according to a 0-, 2-, and 6-month schedule. The interval between the first and second dose ranged from 6-12 weeks and the interval between the second and third dose ranged from 12-23 weeks. Variation in the interval did not diminish GMTs postvaccination. Postlicensure studies have also evaluated GMTs after longer intervals between doses including: 0, 2, and 12 months; 0, 3, and 9 months; 0, 6, and 12 months; and 0, 12, and 24 months (133,134). GMTs in schedules with longer intervals between doses were noninferior and for some schedules were higher than with the standard schedule (0, 2, 6 months). # Concomitant Administration with Other Vaccines Seroconversion rates and GMTs after concomitant administration of HPV4 with other vaccines (including meningococcal conjugate vaccine, tetanus, diphtheria, and acellular pertussis vaccine; inactivated polio vaccine; and hepatitis B vaccine) have been evaluated (135). In all studies conducted to date, HPV GMTs in the co-administered group were noninferior to GMTs after administration of HPV vaccine alone. Rates of solicited and unsolicited symptoms and adverse events were similar in all study groups. # HIV-Infected Persons Several immunogenicity studies of HPV4 in HIV-infected persons have been published, and others are ongoing (46). A randomized clinical trial of HPV4 found the vaccine to be safe and immunogenic in 126 HIV-infected children aged 7-12 years. Antibody titers were lower for HPV 6 and 18 compared with historic age-matched immunocompetent controls (136). At 18 months after the third dose, 94%-99% had antibody to HPV 6, 11 and 16; 76% had antibody to HPV 18. After a fourth dose, all children demonstrated an anamnestic response for all HPV vaccine types (137). A study in 109 HIV-infected males and another in 99 HIV-infected females found the vaccine to be immunogenic and well tolerated (138,139). GMTs were higher among persons on antiretroviral therapy compared with those not receiving therapy. # Efficacy and Immunogenicity Among Persons Aged >26 years HPV4 is not licensed in the United States for use in persons aged >26 years. One randomized, double-blind, placebocontrolled trial of HPV4 was conducted in 3,819 females aged 24-45 years (140). In the end-of-study analysis, perprotocol efficacy against HPV 6, 11, 16, and 18 persistent infection, related CIN, or external genital lesions was 88.7% (95% CI = 78.1-94.8) (141). There were few CIN2+ events (one case in the vaccine arm and six cases in the placebo arm of the trial). In the ITT analysis, efficacy against vaccine type-related persistent infection or disease was 47.2% (95% CI = 33.5-58.2), but efficacy was not demonstrated against CIN2+: 22.4% (95% CI = -42.5-58.3). One month after the third dose, seropositivity to HPV 6, 11, 16 and 18 was 98%, 98%, 99%, and 97%, respectively. At month 48, seropositivity was 92%, 92%, 97%, and 48%, respectively. GMTs were lower than those among females aged 16-23 years. There are no data from efficacy trials in males aged >26 years. # HPV4 Safety Prelicensure Trials In prelicensure trials, HPV4 was evaluated for injection-site and systemic adverse events, new medical conditions reported during the follow-up period, and safety during pregnancy and lactation. Safety data on HPV4 are available from seven clinical trials and included 18,083 persons who received HPV4, aluminum-containing control (AAHS), or saline placebo (11). In both the female and male study populations aged 9-26 years with detailed safety data, a larger proportion reported injection-site adverse events in the group that received HPV4 compared with AAHS control or saline placebo groups. In all three groups, pain was the most common injection site adverse event (Table 7). Systemic clinical adverse events were reported by a similar proportion of vaccine and control/placebo groups among both females and males. Headache was most common, reported by 28.2% of females who received HPV4 and 28.4% of those who received AAHS or saline placebo; among males, 12.3% of those who received HPV4 and 11.2% of those who received AAHS or saline placebo reported headache. Overall, 4.0%-4.9% of females and 2.8%-3.0% of males who received HPV4 reported a temperature ≥100°F (≥38°C) after the first, second, or third dose. The proportions of persons reporting a serious adverse event were similar in the vaccine and placebo groups, as were the types of serious adverse event reported. Vaccine-related serious adverse events occurred in <0.1% of persons. Across all clinical studies (29,323 participants), during the course of the trials, 21 deaths (0.1%) occurred among persons in HPV4 groups and 19 (0.1%) among persons in the control or placebo groups. None of the deaths was considered to be vaccine related (11). Information was collected on new medical conditions that occurred during follow-up of up to 4 years for females and 3 years for males. Overall, among females aged 9-26 years, 2.3% in the HPV4 group and 2.3% in the AAHS control or placebo groups had conditions potentially indicative of autoimmune disorders. Among males aged 9-26 years, 1.5% in the HPV4 group and 1.5% in the AAHS control or placebo groups had conditions potentially indicative of autoimmune disorders. No statistically significant differences were found between vaccine and AAHS control/placebo recipients for the incidence of the conditions (11). Although HPV4 is not licensed by FDA for use among persons aged >26 years, studies among females aged 27-45 years indicate that the adverse events profile is comparable to the profile observed in those aged 9-26 years (11). * The per-protocol immunogenicity population included all subjects who were not general protocol violators, received all three vaccinations within acceptable day ranges, were seronegative at day 1 and (for all subjects except those aged <16 years in the immunogenicity studies who were not tested) DNA negative day 1 through month 7 for the relevant HPV type(s), and had a month 7 serum sample collected within an acceptable day range. # Pregnancy The HPV4 trial protocols excluded women who were pregnant; however, 3,819 females in the trials reported at least one pregnancy (11). Adverse outcomes (defined as the combined numbers of spontaneous abortions, late fetal deaths, and congenital anomaly cases out of the total number of known pregnancy outcomes, excluding elective terminations), were 22.6% (446/1973) in the HPV4 group and 23.1% (460/1994) in the AAHS control or saline placebo group. A total of 45 cases of congenital anomaly in pregnancies occurred in females who received HPV4, and 34 cases occurred in females who received AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, five anomalies (all different) occurred in the vaccine group, and one occurred in the placebo group. In pregnancies with onset >30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received HPV4 and 33 cases in the group that received AAHS control or saline placebo. Rates of congenital anomalies were consistent with those in surveillance registries. HPV4 has been classified as Pregnancy Category B on the basis of studies in rats showing no evidence of impaired fertility or harm to the fetus (11). A registry for females inadvertently vaccinated during pregnancy was established by the manufacturer as part of its postlicensure commitment to FDA (142,143). More than 2,800 females who received vaccine within 1 month before their last menstrual period or anytime during pregnancy were enrolled in the registry (144). Rates of spontaneous abortions and major birth defects were not greater than those of a comparison unexposed population. The registry was terminated at the end of December 2012 with concurrence from FDA and other regulatory agencies. However, the manufacturer is still collecting information on persons inadvertently vaccinated during pregnancy. CDC will continue to monitor pregnancy outcomes through reports to the Vaccine Adverse Event Reporting System (VAERS) and through studies in the Vaccine Safety Datalink (VSD) (see Postlicensure Safety Data). # Postlicensure Safety Data In the United States, federal agencies and vaccine manufacturers conduct independent postlicensure vaccine safety and monitoring activities. CDC monitors vaccine safety through several systems, including VAERS and VSD (145). CDC and FDA established VAERS in 1990 (146). VAERS is a national spontaneous reporting system that accepts reports from providers and the public regarding adverse events that occur after vaccination. The system is not designed to determine whether a reported adverse event was caused by vaccination, but it does identify signals or trends that warrant further study. From June 2006 through March 2014, approximately 67 million doses of HPV4 were distributed in the United States. VAERS received a total of 25,063 adverse event reports (22,867 in females and 2,196 males) after receipt of HPV4 (147). Reporting among females peaked in 2008 and decreased each year thereafter (148). The proportion of reports to VAERS that were classified as serious (i.e., those resulting in permanent disability, hospitalization, life-threatening illnesses, or death) peaked in 2009 at 12.8% and then decreased to 7.4% in 2013 (the last full year of reporting). † Of the total HPV4 reports, 92.4% were classified as nonserious. Among the nonserious adverse events, the most commonly reported generalized symptoms in females were syncope (fainting), dizziness, nausea, headache, and fever; in males, the most commonly reported generalized symptoms were dizziness, syncope, pallor, headache, and loss of consciousness. Overall, the most commonly reported local symptoms were injectionsite pain and redness. Among the 7.6% of total reports classified as serious, headache, nausea, vomiting, and fever were the most frequently reported symptoms for both males and females (CDC, unpublished data, 2014). Overall reporting of adverse events to VAERS is consistent with prelicensure clinical trial data and with the 2009 published summary of the first 2.5 years of postlicensure reporting to VAERS (147,149). During the postlicensure period from June 2006 to March 2014, a total of 96 reports of death after receiving HPV4 were submitted to VAERS. CDC and FDA review all available information on reports of death following any vaccine, including HPV4. Among the 96 reports of death, 47 deaths were considered confirmed in that the reports included a certificate of death, autopsy report, or other medical documentation of death (150). Causes of the confirmed death reports included bacterial meningitis, viral myocarditis, pulmonary embolism, diabetic ketoacidosis, and seizure disorder. Detailed review of every report of death following HPV4 alone or in combination with other vaccines by medical officers from CDC and FDA identified no pattern of occurrence of death with respect to time after vaccination, vaccine dose number, combination of vaccines administered, or diagnosis at death that would suggest a causal association with HPV4. VSD is a collaboration between CDC and nine integrated health-care organizations that allows for active surveillance and research. VSD conducts evaluations of specific events that might be associated with vaccination (151). Data were analyzed after 600,558 doses of HPV4 had been administered to females. No statistically significant increased risks were observed for any of the prespecified endpoints including Guillain-Barré syndrome (GBS), stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis (151) (Table 8). Studies in males are ongoing. Postlicensure studies also have been conducted by the manufacturer (152,153). In a general safety assessment evaluating outcomes diagnosed in emergency departments visits and hospitalizations among 189,000 females receiving at least 1 dose of HPV4, same-day syncope and skin infections in the 2 weeks after vaccination were found to be associated with HPV4. No other safety concerns were identified (152). In another study, rates of 16 autoimmune disorders in the vaccinated population were not increased compared with a matched population of nonvaccinated females (153). Postlicensure safety data for HPV4 available from other countries show a good safety profile (154)(155)(156). A large population-based cohort study conducted in Denmark and Sweden analyzed data on >696,000 doses of HPV4 among females. No consistent evidence supporting causal associations between exposure to HPV4 and autoimmune, neurologic conditions, and venous thromboembolism was observed (155). In France, a case-control study was conducted to evaluate autoimmune disorders following HPV4. Among 211 cases and 875 controls, no increased risk was observed for idiopathic thrombocytopenic purpura, central demyelination/multiple sclerosis, GBS, connective tissue disorders (including systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus, and autoimmune thyroiditis after receipt of HPV4 (156). # Bivalent HPV Vaccine (HPV2) HPV2 Efficacy Females Aged 15-25 Years HPV2 efficacy against CIN2+ was evaluated in two randomized, double-blind, controlled clinical trials in females aged 15-25 years, including a phase II study and a phase III trial (157,158). The phase III trial included 18,644 females (158,159). Interim analysis of the phase III trial showed high efficacy (158). In the end-of-study ATP analysis, efficacy against HPV 16-and 18-related CIN2+ was 94.9% (95% CI = 87.7-98.4) (Table 4) (160). Statistically significant efficacy was demonstrated individually against HPV 16-and HPV 18-related lesions. In the ITT analysis, efficacy against HPV 16-and 18-related CIN2+ was 60.7% (95% CI = 49.6-69.5). The end-of-study analysis also found high efficacy against CIN3 regardless of HPV type in the TVC-naïve population (160). HPV2 efficacy against persistent HPV infection was evaluated. In the phase III trial, efficacy against 6-month and 12-month persistent HPV 16 or HPV 18 cervical infection in the ATP cohort was 94.3% (96.1% CI = 91.5-96.3) and 91.4% (96.1% CI = 86.1-95.0), respectively (159). Data on persistent infection endpoints are also available from a trial conducted in Costa Rica (161), a randomized, double-blind, controlled trial in 7,466 women aged 18-25 years. (Efficacy data from the Costa Rica trial were not included in the FDA Biologics License Application.) The primary endpoint was 12-month persistent HPV 16 or HPV 18 cervical infection (161). In the ATP analysis, efficacy against HPV 16 or HPV 18 persistent infection was 90.9% (95% CI = 82.0-95.9) and in the ITT analysis was 49.0% (95% CI = 38.1-58.1). Among women who were HPV 16 or 18 DNA positive at enrollment into the clinical trials, either seropositive or seronegative, the vaccine had no efficacy against progression of infection to disease (159) or impact on clearance of infection of that HPV type (162). However, among participants DNA positive to one vaccine HPV type, HPV2 was found to have high efficacy (90%) for prevention of CIN2+ associated with the type for which a female was DNA negative at enrollment (163). Among persons seropositive to the relevant HPV type but HPV DNA negative, there were fewer cases, but efficacy was observed against CIN1 or higher grade lesions (163). Efficacy against prevalent anal and oral HPV infection was evaluated in the Costa Rica trial. Although this trial was not designed to assess efficacy against oral or anal infection, and baseline infection at these anatomic sites was not determined, prevalent infection was determined at the 4-year exit study visit. There were 15 prevalent HPV 16 or 18 oral infections among the 2,924 females in the control group and one among the 2,910 females in the vaccine group; estimated efficacy was 93.3% (95% CI = 62.5-99.7) (164). Among females who were HPV 16/18 seronegative and DNA negative at the cervix at the time of enrollment, efficacy against anal HPV 16 or HPV 18 prevalent infection was 83.6% (95% CI = 66.7-92.8) (165). # Duration of Protection In the phase III efficacy trial, females were followed for a median of 47 months after the first vaccine dose (160). The longest follow-up from the HPV2 clinical trials is from the phase II trial; a subset of participants has been followed for up to 9.4 years after the first dose (166). Among the 437 participants evaluated, efficacy for prevention of HPV 16/18 12-month persistent infection was 100% (95% CI = 61.4-100). Further data on duration of protection will be available from follow-up of females in the phase III trial. In addition, adolescents who were vaccinated at age 10-15 years in an immunogenicity trial (see HPV2 Immunogenicity) are being followed as they become sexually active. # Evaluation of Protection Against Nonvaccine Types Protection against persistent infection and CIN2+ endpoints attributable to nonvaccine types was evaluated using a variety of different analytic populations (107,108). The most consistent # HPV2 Immunogenicity Females Aged 9-25 Years Data on immunogenicity are available from the phase II and phase efficacy III trials conducted in females aged 15-25 years and immunogenicity trials conducted in females aged 9-14 years (10,158,167). In all trials, >99% of study participants developed antibody to both HPV 16 and HPV 18 1 month after completing the 3-dose series. Among females aged 15-25 years, antibody titers were more than 100-fold higher than those after natural infection (158). Follow-up data from females who received HPV2 at ages 15-25 years are available through 9.4 years (166). Peak GMTs occur at 1 month after the third dose and then plateau about 2 years later. At 9.4 years after vaccination, all females had detectable antibody; GMTs were at least 10-fold higher by ELISA and fourfold higher by a neutralizing assay than GMTs after clearance of natural infection. Immunogenicity trials including 1,275 females aged 9-14 years provided data allowing comparison of seroconversion and GMTs with those in females aged 15-25 years who were enrolled in the phase III efficacy trial (10). A direct comparison between females aged 10-14 years and 15-25 years was made in one study (Table 9) (167). In all trials, seropositivity 1 month after the third dose among females aged 10-14 years was 100% for HPV 16 and HPV 18; GMTs were noninferior (and approximately twofold higher) to those vaccinated at age 15-25 years. At month 48, GMTs in females vaccinated at ages 10-14 years remained twofold higher than those in females vaccinated at ages 15-25 years (168). # Spacing of Vaccine Doses In prelicensure efficacy and immunogenicity trials, HPV2 was administered according to a 0, 1, and 6 month schedule. Postlicensure trials have evaluated GMTs after longer intervals between doses, including 6 months between the first and second dose and 12 months between the first and third dose (169,170). GMTs after schedules with longer intervals between doses were noninferior to those after the standard dosing schedule. # Concomitant Administration with Other Vaccines Seroconversion rates and GMTs after concomitant administration of HPV2 with other vaccines, including meningococcal conjugate vaccine, tetanus, diphtheria and acellular pertussis vaccine, inactivated poliovirus vaccine, hepatitis B vaccine, and combined hepatitis A and B vaccine have been evaluated (135). GMTs were noninferior in the co-administered group compared with GMTs after administration of HPV2 alone in all studies. Rates of solicited and unsolicited symptoms and events were similar in all study groups. # HIV-Infected Persons One HPV2 immunogenicity study has been conducted comparing antibody response in HIV-infected and uninfected females aged 18-25 years. All subjects seroconverted to HPV 16 and HPV 18 and the vaccine was well tolerated; GMTs were lower in the HIV-infected females compared with those not infected (171). However, HPV 16 and HPV 18 GMTs in HIV-infected females 1 month after the third dose were 124-and 90-fold higher, respectively than those reported in healthy females aged 15-25 years after natural infection. # Immunogenicity in Females Aged >25 Years HPV2 is not licensed in the United States for use among females aged >25 years. No published data are available on HPV2 efficacy in females aged >25 years. One trial compared HPV2 immunogenicity among females aged 26-55 years and those aged 15-25 years (172). All participants were seropositive to HPV 16 and HPV 18 at 1 month after the third dose, and >99% were seropositive at month 48 (173). GMTs were lower than those among females aged 15-25 years and decreased with increasing age. However, even in the oldest age group (age 46-55 years), GMTs 1 month after the third dose were 57-and 84-fold higher than GMTs after natural infection for HPV 16 and HPV 18 (172). # HPV2 Safety In prelicensure trials, HPV2 vaccinees were evaluated for injection-site and systemic adverse events, medically significant conditions, new onset autoimmune disorders, new onset chronic diseases, deaths, serious adverse events, and pregnancy outcomes. Safety was evaluated by pooling data from 11 clinical trials of HPV2 in females aged 9 through 25 years and by a meta-analysis of safety databases of HPV2 as well as other vaccines that have the same adjuvant (10,174,175). The pooled safety analysis included 23,952 females aged 9-25 years; approximately 13,000 females received at least 1 dose of HPV2 (10). In an analysis of local and systemic adverse events, a larger proportion of persons reported at least one injection-site symptom in the HPV2 group compared with controls (who received hepatitis A vaccine). In the HPV2 group, 92% reported injection-site pain, 48% redness, and 44% swelling compared with 64%-87%, 24%-28%, and 17%-21%, respectively, in the control groups (Table 10). Fatigue, headache, and myalgia were the most common systemic symptoms. No differences were observed in unsolicited symptoms within 30 days of vaccination between the vaccine group and control groups. Serious adverse events were evaluated in a pooled safety analysis that included 30,192 females aged 9-72 years (16,381 received HPV2). Proportions of persons reporting a serious adverse event were similar in vaccine and control groups (5.3% and 5.9%, respectively), as were the types of serious adverse events reported (10). In the pooled safety analysis, including 12,772 females who received HPV2 and 10,730 in the control groups, incidence of potential new autoimmune disorders did not differ (0.8% in both groups). Overall, among completed and ongoing studies that enrolled 57,323 females aged 9-72 years, 37 deaths were reported during 7.4 years of follow-up: 20 among those who received bivalent vaccine (0.06%) and 17 among those in the control groups (0.07%). None of the deaths was considered to be vaccine-related. # Vaccination During Pregnancy Clinical protocols excluded females who were pregnant, and participants were instructed to avoid pregnancy until 2 months after the last vaccination. However, 3,696 pregnancies occurred in the HPV2 group and 3,580 in the pooled control groups (10). Overall, no differences were observed in rates of any specific pregnancy outcomes between groups. Among 761 pregnancies around the time of vaccination (defined as last menstrual period 30 days before to 45 days after vaccination), 13.6% of pregnancies ended in spontaneous abortion in the HPV2 group compared with 9.6% in the control group. Abnormal infant outcomes (other than congenital anomalies) were reported in 5.1% of the HPV2 group and 4.7% of the control group. Other outcomes (congenital anomalies, still birth, ectopic pregnancy, and therapeutic abortion) were reported in 0.3% to 1.8% of the HPV2 group and 0.3% to 1.4% of the control group. HPV2 has been classified as Pregnancy Category B on the basis of animal studies that revealed no evidence of impaired fertility or harm to the fetus (10). A registry for females inadvertently vaccinated during pregnancy was established by the manufacturer as part of its postlicensure commitment to FDA. To date, the rate of major congenital anomalies and spontaneous abortions has been within the reported background rates (176). In addition, a postmarketing required study is being conducted to assess the risk of spontaneous abortions in females who receive HPV2 during pregnancy in an observational database cohort study in the United Kingdom (177). No data are available on use of HPV2 in lactating females. # Postlicensure Safety Data From October 2009 through March 2014, approximately 719,000 doses of HPV2 were distributed in the United States. Because of the smaller number of doses distributed compared with HPV4, formal evaluations of the passive surveillance data from VAERS or data from VSD have not been conducted. During this time period, VAERS has received a total of 113 adverse event reports occurring in females after receipt of HPV2; 93.8% were classified as nonserious (CDC, unpublished data, 2014). Among nonserious adverse events, the most commonly reported generalized symptoms were nausea, dizziness, headache, and urticaria; the most commonly reported local symptoms were injection-site redness, swelling, and induration. Postlicensure safety data are available from other countries that have implemented vaccination programs using HPV2 (154,176). In a review of passive reports from countries that have implemented HPV2 vaccination programs, the distribution of adverse events was consistent with prelicensure trials. Passive reports revealed no concerns about potentially immune mediated diseases (176). In addition, a postmarketing observational database cohort study will assess the risk of autoimmune diseases in adolescent and young adult women who received HPV2 in the United Kingdom (177). # Economic Burden of HPV and Cost-Effectiveness of Vaccination in the United States Before HPV vaccine introduction, the prevention and treatment of HPV-related disease imposed an estimated burden of $8 billion or more in direct costs in the United States each year (178). Of this, approximately $1 billion was for treatment of cancer, including $400 million for invasive cervical cancer and $300 million for oropharyngeal cancer. Approximately $200 million was for treatment of recurrent respiratory papillomatosis and $300 million was for treatment of genital warts. The remainder ($6.6 billion) was for cervical cancer screening and follow-up. Modeling studies have shown consistently that the routine vaccination of 12-year-old girls with either HPV2 or HPV4 is a cost-effective use of public health resources, as long as vaccine duration of protection is sufficient (e.g., 30 years) (179,180). Estimates of the incremental cost per quality-adjusted life year (QALY) gained by adding HPV vaccination of girls aged 12 years to existing cervical cancer screening programs vary (approximate range: $3,000-$45,000) (181)(182)(183)(184)(185)(186). Although cost-effectiveness estimates for vaccination of girls aged 12 years are quite consistent across published models, cost-effectiveness estimates for vaccination of females aged >12 years and for vaccination of males are more uncertain and less precise. The published models generally suggest that the cost-effectiveness of vaccination of females becomes less favorable as the age at vaccination increases beyond the early teenage years. However, there is no consensus on the exact age at which catch-up vaccination of females might no longer be considered cost-effective. Models suggest that catch-up vaccination of females could be cost-effective through the mid-20s, particularly if all potential benefits of vaccination are included (185,187). Numerous published models have found that the costeffectiveness of adding males to a female-only vaccination program depends on the vaccination coverage in females and the cost of vaccine (180). As vaccination coverage of females increases, the health burden of HPV can be reduced in both females and males (through herd immunity), thereby reducing the potential benefits of male vaccination. Male vaccination at age 12 years, when added to a female-only vaccination program, costs about $20,000 to $40,000 per QALY gained in the most favorable scenarios for male vaccination and about $75,000 to more than $250,000 per QALY gained in the least favorable scenarios (187)(188)(189). Scenarios for male vaccination are more favorable when female vaccination coverage is low (e.g., 20%) and when all potential health benefits are included in the analysis (179,188). Scenarios for male vaccination are less favorable when female vaccination coverage is high (e.g., 75%), when including only the health outcomes for which evidence of vaccine efficacy is available, if vaccinated males have mostly vaccinated female sex partners, and when male vaccination is compared with an alternative strategy of increased vaccination coverage among females (179,188). Vaccination of adult males becomes less cost-effective as age at vaccination increases, particularly for age >21 years (15). Vaccination of MSM through age 26 years potentially could be cost-effective across many scenarios, according to the only study available of the cost-effectiveness of HPV vaccination of MSM in the United States (190). # HPV Vaccination Program in the United States Recommendations for HPV vaccination have evolved since HPV4 was first licensed in 2006. In June 2006, HPV4 was licensed for use in females and recommended for routine vaccination of females aged 11 or 12 years and for those aged 13 through 26 years not previously vaccinated (12). In 2009, HPV2 was licensed for use in females and ACIP updated recommendations to state that either HPV vaccine is recommended for females (13). In 2009, HPV4 was licensed for use in males (14) and in late 2011, HPV4 was recommended for routine vaccination of males aged 11 or 12 years and for those aged 13 through 21 years not previously vaccinated (15). The recommendations for females and males state that the vaccination series can be started beginning at age 9 years. Most HPV vaccine administered in the United States has been HPV4 (147). Almost all HPV vaccinations are delivered by primary care providers or health clinics (191). In the United States, there is both public and private financing for vaccines. The Vaccines for Children Program (VFC) supplies enrolled private and public health-care providers with federally purchased vaccines for use among uninsured, Medicaid-eligible and other entitled children through age 18 years (192,193). Under the Patient Protection and Affordable Care Act of 2010, nongrandfathered private health plans must offer, at no cost to beneficiaries, vaccines that are recommended by ACIP. Similarly, qualified health plans on the new health insurance exchanges that went into effect starting in 2014 must offer ACIP-recommended vaccines at no cost to beneficiaries (194). HPV vaccination coverage with at least 1 dose among girls aged 13-17 years increased from 25.1% in 2007 to 53.0% in 2011 (148). However, the annual increase lagged behind that of other vaccines recommended for adolescents, and in 2012 there was no increase. In 2013, at least 1 dose coverage and 3 dose coverage increased slightly; among girls aged 13-17 years 57.3% had received at least 1 dose and 37.6% had received all 3 doses (147). Variation by state remains wide, with at least 1 dose vaccine coverage ranging from 39.9% to 76.6% (195). The main reasons parents reported for not intending or being unsure about vaccinating their daughters in the next 12 months were a lack of knowledge, a belief that the vaccine was not needed, concerns about vaccine safety or side effects, and the vaccine not being recommended by their provider (147). These responses indicate gaps in understanding, including the reasons vaccination is recommended at age 11 or 12 years and the need to strengthen provider recommendations. Updated educational materials that address these issues are available from CDC at http:// www.cdc.gov/vaccines/who/teens/index.html. Data from 2012 were the first since the October 2011 ACIP recommendation for routine vaccination of males. At least 1 dose coverage among boys aged 13-17 years increased from 8.3% in 2011 to 20.8% in 2012 and further increased to 34.6% in 2013 (147). # Summary of Rationale for HPV Vaccination Recommendations The availability of HPV vaccines provides an opportunity to decrease the burden of cervical cancer precursors, cervical cancer, other anogenital cancer precursors and cancers, and genital warts in the United States (10,11). Although data on efficacy against oropharyngeal disease endpoints are not available from clinical trials, HPV vaccination is also likely to be effective for prevention of HPV-attributable oropharyngeal cancer (63,164). Two vaccines are licensed for use in females in the United States; HPV4 (directed against HPV 6, 11, 16, and 18) and HPV2 (directed against HPV 16 and 18). One vaccine (HPV4) is licensed for use in males in the United States. HPV 16 and 18 are the cause of approximately 70% of cervical cancers and most other HPV-attributable cancers; HPV 6 and 11 are the cause of approximately 90% of genital warts. HPV vaccines are most effective when administered before exposure to HPV (107,118,160). The recommendation for routine vaccination at age 11 or 12 years is based on several considerations including studies indicating that HPV vaccines are safe and immunogenic in this age group, the higher antibody titers achieved after vaccination at age 11 or 12 years compared with older age groups, data on HPV epidemiology, and age of sexual debut in the United States (128,167,196). The recommendation also considered cost-effectiveness evaluations and the established young adolescent health-care visit at age 11 or 12 years recommended by several professional organizations, when receipt of other vaccines also is recommended (197). Data suggest that protection after vaccination will be long lasting (124)(125)(126)166); long-term follow-up studies are underway to determine the duration of protection. Although routine vaccination is recommended at age 11 or 12 years, older adolescents and young adults through the recommended ages can benefit from vaccination. Adolescents and young adults who are not yet sexually active can be expected to receive the full benefit of vaccination. Although sexually active persons in this age group might have been infected with one or more vaccine HPV types, studies suggest that only a small percentage have been infected with both HPV 16 and 18 or all four vaccine types (31,198). The vaccines can protect against types not already acquired. Neither vaccine protects against persistent infection, precancer lesions, or anogenital warts caused by an HPV type that persons are infected with at the time of vaccination. Although vaccine effectiveness would be lower when administered to those who are sexually active, and would decrease with older age and likelihood of previous HPV exposure, the majority of persons in the recommended age groups will derive at least partial benefit from vaccination. HPV vaccines are not licensed in the United States for use in persons aged >26 years. Among women, the expected population-level impact of HPV vaccination in this age group is lower than that for younger women because of the higher likelihood that women have already had vaccine type infection, because fewer would have incident infection that could be prevented and the risk for development of disease from incident infection is less (199). # Recommendations for Use of HPV Vaccines Routine Recommendations ACIP recommends routine vaccination at age 11 or 12 years with HPV4 or HPV2 for females and with HPV4 for males (male GRADE recommendation category: A, evidence type: 2 [15,17]). The vaccination series can be started beginning at age 9 years. HPV4 and HPV2 are each administered in a 3-dose schedule. The second dose should be administered 1-2 months after the first dose and the third dose 6 months after the first dose. # Recommendations for Those Not Vaccinated at the Routine Age Vaccination also is recommended for females aged 13 through 26 years and for males aged 13 through 21 years, who have not been vaccinated previously or who have not completed the 3-dose series. Males aged 22 through 26 years may be vaccinated. If females or males reach age 27 years before the vaccination series is complete, the second and/or third doses of vaccine can be administered after age 26 years to complete the vaccination series. Prevaccination assessments (e.g., Pap testing or screening for high-risk HPV DNA, type-specific HPV DNA tests, or HPV antibody tests) to establish the appropriateness of HPV vaccination are not recommended. # Administration HPV vaccine (either HPV4 or HPV2) should be shaken well before administration. The dose for either vaccine is 0.5 ml, administered intramuscularly (IM), preferably in the deltoid muscle. # Minimum Dosing Intervals and Interrupted Schedules The minimum interval between the first and second doses of HPV vaccine (either HPV4 or HPV2) is 4 weeks. The minimum recommended interval between the second and third dose of vaccine is 12 weeks. The minimum interval between the first and third dose is 24 weeks. Inadequate doses or vaccine doses received after a shorter-than-recommended dosing interval should be re-administered. If the vaccine schedule is interrupted for either HPV4 or HPV2, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered, and the second and third doses should be separated by an interval of at least 12 weeks. # Concomitant Administration with Other Vaccines HPV vaccine (either HPV4 or HPV2) can be administered at the same visit as other age-appropriate vaccines, such as tetanus, diphtheria, and acellular pertussis and quadrivalent meningococcal conjugate vaccines. Administering all indicated vaccines together at a single visit increases the likelihood that adolescents will receive each of the vaccines on schedule. Each vaccine should be administered by using a separate syringe at a different anatomic site. # Interchangeability of HPV Vaccine Products ACIP recommends that the HPV vaccination series for females be completed with the same HPV vaccine product, whenever possible. However, if vaccination providers do not know or have available the HPV vaccine product previously administered, either HPV vaccine product may be used to continue or complete the series for females to provide protection against HPV 16 and HPV 18. Only HPV4 is licensed for use in males. No studies address the interchangeability of the two HPV vaccines. However, there is no theoretic reason to expect that the risk for adverse events would be increased if the series included more than one product. The effectiveness of a series that contained both products might be reduced compared with a complete series with one product for protection against HPV 16/18-related cancers and precancers. A series with <3 doses of HPV4 might provide less protection against genital warts than a complete 3-dose series of HPV4. # Special Populations Abnormal Pap Test, Known HPV Infection, Anogenital Warts, or HPV-Associated Lesions HPV vaccination can provide protection against infection with HPV vaccine types not already acquired. Therefore, vaccination is recommended through the recommended age for females regardless of whether they have an abnormal Pap test result, and for females or males regardless of known HPV infection, HPV-associated precancer lesions, or anogenital warts. Females who have abnormalities on cervical cancer screening are likely to be infected with one or more genital HPV types. With increasing severity of Pap test findings, the likelihood of infection with HPV 16 or HPV 18 increases (70), and the expected benefit of vaccination decreases. Females who have had HPV testing as part of cervical cancer screening might have information about their HPV status. Males or females with AIN are likely infected with HPV. The presence of anogenital warts or a history of anogenital warts indicates present or past infection with HPV, most often HPV 6 or HPV 11. Although vaccination is still recommended, patients should be advised that vaccination will not have any therapeutic effect on an existing HPV infection, HPV-associated precancer lesion, cancer, or anogenital warts. # Immunocompromised Persons Persons who are immunocompromised because of transplant, medications, or HIV have a higher burden of HPV-associated disease and cancer (46). Although studies have found the vaccines to be well tolerated and immunogenic in HIV-infected persons, some studies found that GMTs were lower among HIV-infected persons compared with those who are uninfected (136)(137)(138)(139)171). Whether there will be any differences in HPV vaccine efficacy between immunocompromised and immunocompetent persons is unclear. ACIP recommends routine vaccination at age 11 or 12 years with HPV2 or HPV4 for females and with HPV4 for males. Vaccination is recommended through age 26 years for immunocompromised persons who have not been vaccinated previously or who have not completed the 3-dose series. # Men Who Have Sex with Men MSM are at high risk for infection with HPV and associated conditions, including anogenital warts and anal cancer (29). For MSM, ACIP recommends routine vaccination with HPV4, as for all males, and vaccination through age 26 years for those who have not been vaccinated previously or who have not completed the 3-dose series. # Lactating Women Lactating women can receive HPV vaccine. # History of Sexual Abuse or Assault Health-care providers who evaluate and treat children and youth who are suspected or confirmed victims of sexual abuse or assault should be aware of the need for HPV vaccination. Sexual abuse and assault raise the risk of HPV infection attributable to the abuse itself, potential future victimization, and subsequent engagement in at-risk behaviors. Children who are victims of sexual abuse or assault are recognized to be more likely to engage in subsequent unsafe and unprotected intercourse and to engage in these behaviors at an earlier age than nonabused children (200). Although HPV vaccination will not promote viral clearance or protect against disease progression attributable to types already acquired, vaccination would protect against vaccine-preventable types not yet acquired. ACIP recommends HPV vaccination beginning at age 9 years for children and youth with any history of sexual abuse or assault who have not initiated or completed the 3-dose series. Females and males who are victims of sexual abuse or assault should receive HPV vaccine through the recommended ages if they have not already been vaccinated. # Precautions and Contraindications # Hypersensitivity or Allergy to Vaccine Components HPV vaccines are contraindicated for persons with a history of immediate hypersensitivity to any vaccine component. HPV4 is produced in Saccharomyces cerevisiae (baker's yeast) and is contraindicated for persons with a history of immediate hypersensitivity to yeast. The tip cap of prefilled syringes of HPV2 might contain latex. HPV2 should not be used in persons with anaphylactic allergy to latex. # Acute Illnesses HPV vaccines can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infections with or without fever). Vaccination of persons with moderate or severe acute illnesses should be deferred until after the patient improves. # Preventing Syncope After Vaccination Syncope (vasovagal or vasodepressor reaction) can occur after vaccination, most commonly among adolescents and young adults (201). One of the most frequent reports to VAERS for HPV4 since licensure has been syncope (148). Although syncopal episodes are uncommon, vaccine providers should consider observing patients (with patients seated or lying down to decrease the risk for injury should they faint) for 15 minutes after they receive any vaccine, including HPV vaccine (202). # Vaccination During Pregnancy HPV vaccines are not recommended for use in pregnant women. The vaccines have not been associated causally with adverse outcomes of pregnancy or adverse events in the developing fetus. However, if a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose series should be delayed until completion of pregnancy. Pregnancy testing is not needed before vaccination. If a vaccine dose has been administered during pregnancy, no intervention is needed. Patients and health-care providers can report an exposure to HPV vaccine during pregnancy to VAERS. FDA considered Merck's regulatory commitment for a pregnancy registry fulfilled in April 2013 and the registry was terminated (see HPV4 Safety). Although the registry has been terminated, HPV4 exposure during pregnancy can continue to be reported to Merck at telephone 1-877-888-4231. HPV2 exposure during pregnancy should be reported to the GlaxoSmithKline Pregnancy Registry at telephone 1-888-452-9622. # Monitoring Impact of HPV Vaccination in the United States Most cancers that could be prevented by HPV vaccine occur years after infection; therefore, it might be decades before an impact of vaccination is observed on these outcomes. The United States has cancer registries that monitor the incidence of cervical and other HPV-associated cancers (203). To determine earlier impact of vaccination, several more proximal outcomes are being monitored, including HPV prevalence, genital warts, and cervical precancers (204)(205)(206)(207)(208). Challenges to establishing a unified monitoring system for precancer outcomes as well as other outcomes include incomplete immunization information systems, lack of unique identifiers to link medical records, and lack of population-based cervical cancer screening registries. Despite 3-dose coverage in 2010 of only 32% in girls aged 13-17 years (148), data obtained within 4 years of introduction of HPV vaccination in the United States show a reduction of HPV vaccine type prevalence and genital warts in adolescent girls. In a national survey, HPV 6, 11, 16, and 18 type prevalence among girls aged 14-19 years decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010 (207). An analysis of health claims data found that genital warts decreased among girls aged 15-19 years from a prevalence per 1,000 person-years of 2.9 in 2006 to 1.8 in 2010 (208). Data from other studies in the United States also show vaccine impact (209). Dramatic decreases in genital warts and vaccine type prevalence have been demonstrated in countries that have achieved high coverage (209,210). # Areas of Ongoing Research and Future Priority Activities Since HPV vaccine was first introduced in the United States, substantial additional data have been provided by clinical trials and postlicensure evaluations. Ongoing research and other activities will provide additional data in the future. • Efficacy and duration of protection: Available data show no loss of protection through 8 to 10 years (124,125,166). Ongoing evaluations will continue to provide information on duration of protection for both vaccines. • Reduced dose schedules: There is broad interest in reduced dose schedules; immunogenicity trials show noninferior antibody response after 2 doses in females aged 9-14 years compared with 3 doses in females aged 15-26 years (170,211,212). Available data as well as data from ongoing studies will provide important information for policy considerations (170,212,213 # ISSN: 1057-5987 The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format. To receive an electronic copy each week, visit MMWR's free subscription page at http://www.cdc.gov/mmwr/mmwrsubscribe. html. Paper copy subscriptions are available through the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone 202-512-1800.	None	None
67e590e658cdf103cba2ecd0ec819c4b9023fca4	cdc	None	Pursuant to the fulfillment of this need, the National Institute for Occupational Safety and Health (NIOSH) has developed a reporting strategy intended to assist employers In providing personal protection for employees from exposure to carcinogenic, mutagenic, and teratogenic substances. This strategy involves the development of Special Occupational Hazard Reviews which serve to support and complement the other major criteria documentation activities of the Institute. It is the intent of a Special Occupational Hazard Review to document, from a health standpoint, the problems associated with a given industrial chemical or process. While Special Occupational Hazard Reviews are not intended to supplant the more comprehensive NIOSH Criteria Documents nor the less comprehensive NIOSH Current Intelligence Bulletins, they are nevertheless prepared in such a way as to be amenable to full regulatory usage if so desired. Dissemination of Special Occupational Hazard Reviews may be accomplished through appropriate trade associations, unions, industries, and members of the scientific community.# The acute toxicity ofDDT is relatively low, the estimated oral LD50 in humans being 250 mg/kg. Documented chronic toxicity in humans, clearly related to DDT, is non-existent, and, therefore, the results of experiments with animals must be used to predict chronic effects that may occur in humans. Most notahle of these chronic effects is DDT's potential for producing cancer in animals. DDT has produced an increased incidence of tumors in mice in at least eleven experiments. Most tumors involved the liver but tumors of the lungs and lymphatic system have also been reported. In one experiment with mice, DDT induced an increased incidence of tumors at dietary levels as low as 2 and 10 ppm. In two of three experiments involving rats, increased occurrences of liver tumors of varying degrees of malignancy have been reported. Based on the demonstrated potential of DDT for inducing tumors in both rats and mice, NIOSH recommends that DDT be controlled and handled in the workplace as a suspected occupational carcinogen and that exposure to DDT be minimized to the greatest extent possible. With regard to airborne exposure, NIOSH recommends that the workplace environmental limit be no higher than 0.5 mg/cu m, which is the lowest concentration detectable by the current NIOSH validated sampling and analytical method (NIOSH method S274). Workers should also avoid skin contact with DDT, as the pesticide can be absorbed through the skin. Percutaneous absorption is substantially increased when DDT is dissolved in organic solvents. The physical and chemical properties of DDT as well as synonyms and trade names are summarized in Table 5.2, and synonyms and trade names are given in the Table 5.3. The structures of DDT, other compounds that occur in technical DDT, and their metabolites are presented in Table 5.1 (WHO 1977). The structure of the o,p' and m,p' compounds can be inferred from those of the p,p' isomers. # Discovery and Introduction Technical DDT is synthesized by condensing chloral hydrate with chlorobenzene in the presence of sulfuric acid, a process first discovered by Zeidler in 1874. However, it was 1939 before the insecticidal applications of DDT were identified, by Muller and his coworkers (IARC 1974). By 1943, low-cost production methods had been developed, and commercial production had begun (IARC 1974). # Changing Patterns of Use and Production Before 1945, all of the DDT produced in the USA was used or allocated by the military services for various medical and public health uses. Early in 1945 it became available for experimental work in agriculture, and it was commercially available in limited quantitites early in the autumn of the same year. The results were so spectacular that use in the United States increased until 1959, and in response to a demand for exports production continued to increase until about 1963. Even before 1963 some restrictions were placed on its use in the United States, mainly to minimize residues in food and in the feed of animals that produce milk and meat. Another important factor reducing the use of DDT was the increasing resistance of pests. After a peak in 1959, the use of DDT in the United States declined steadily, except for its major remaining use on cotton (Table 1.3 Outside the United States, DDT is still used extensively for agriculture and vector control in many tropical countries (WHO 1977). Although many pests of public health importance have become resistant to DDT in some or all of their range, resistance in vectors of malaria has been less widespread (WHO 1977). Accordingly the use of DDT for The demand for DDT as a residual spray against adult mosquitos in antimalarial programs for the decade 1971-81 has been predicted to be 470,000 metric tons or an average of 47,000 metric tons/year, a figure similar to that predicted for agricultural uses. The estimated requirements for six regions of the world (Africa, America, Southeast Asia, Europe, the Eastern Mediterranean, and the Western Pacific) are given in Table 1.3.4. The estimated annual demands tend to increase toward a maximum in 1977, with a subsequent decrease until 1981, the last year of the forecast, when the pre dicted requirement is 29,000 metric tons (Goldberg 1975 (1). However, as of 1972, there were reportedly only two major producers left in Europe. DDT is also known to be produced in: Brazil, where production was 3 million kg in 1969 and is believed to be increasing; Israel, where the total capacity in 1970 was 350 thousand kg; and India, where production for 1971-72 was 4 million kg and was expected to increase. Japan produced 4.6 million kg in 1970 (IARC 1974). # Exposure Generally, exposure to DDT is greatest for manufacturers and formulators, moderate for agricultural applicators, less for the general population, and least for special groups whose location or practices minimize their exposure. However, for brief intervals the exposure of agricultural applicators may exceed anything that good industrial practice would permit (WHO 1977). Occupational exposure to DDT is reflected quantitatively by the concentration of DDT and DDE in blood and fat and by the con centration of DDA in urine (See Section 1.5.4). Urinary excretion of DDA may be increased for several days after a single exposure to DDT by inhalation or percutaneous absorption (Wolfe et al 1970). In a study of formulators, urinary excretion of DDA was increased for only 1 day after exposure (Table 1. (Wolfe andArmstrong 1971, IARC 1974). Estimates of potential respiratory exposure ranged from 0.11 mg/hr for outdoor spraying to 7.1 mg/hr for indoor spraying ( Similarly, blood levels of DDT and DDE and urinary levels of DDA were 2-10 times higher in aircraft sprayers than those in the general population and increased with the duration of exposure ( (Moriarty 1974(Moriarty , 1975. Thus the data in the literature should be interpreted as describing "quasi-steady" states reached after long-term exposure, and they may underestimate the potential for storage after exposure of more than 1-2 years. Data for a number of species suggest that residues in tissues increase with increasing dietary concentrations but not in direct proportion to rates of intake (Figures 1.5.7-1.5.9, USDHEW 1969, Hayes 1975, Moriarty 1975). These data have been evaluated and summarized by Hayes (1975) . Additional data for mice are summarized in Table 1.5.4. Storage factors for three species at medium exposure rates (about 1 mg/kg/day or 10 ppm in the diet) are shown in Table 1.5.5. A "storage factor" is defined as the concentration of DDT in the fat of an animal after long-term exposure divided by the concentration in the diet. These storage factors range between 2 and 24. Although data for other species refer only to higher dose ranges, storage factors for dogs, cattle, and hamsters appear to be lower than those for rats and mice in comparable conditions (Figure (Hayes 1964(Hayes , 1975IARC 1974). Female rats given DDT at 32 m g A g / d a y secreted about 25% of the # Mode of Action The The author suggested that the uncoupling of oxidative phosphorylation in brain mitochondria may be responsible for some phenomena of DDT intoxi cation in mammals. # Long-Term Feeding Experiments A number of experiments involving long-term dietary exposure of rats, mice, hamsters, dogs, and other mammals to DDT are summarized in histopathologic changes in the liver, impaired reproduction, and increased incidence of tumors of the liver, lungs, and lympathic system. These effects are summarized in the following sections. Organ-Specific Toxicity # Liver and Kidney Effects In addtion to the effects on the CNS and reproductive organs, chlorinated # Morphologic changes (outlined in Table 2.2.1), including an increase in SER and atypical mitochondria, were observed in all exposed groups and were more pronounced in rats given both DDT and dieldrin. # Liver Enzyme and Other Biochemical Effects Numerous studies have been conducted in which DDT has been identified as an inducer of hepatic microsomal enzymes and hence as an effector of the # Effects on the Cardiovascular System Most dogs killed by a single dose of DDT die of ventricular fibril lation, and the same is true of some cats, monkeys, and rabbits. Monkeys differ from dogs in that the DDT-sensitized heart is able to recover from fibrillation and resume a normal rhythm (Philips and Gilman 1946). DDT not only sensitizes the myocardium in a way similar to that of halogenated hydrocarbon solvents but, through its action on the central nervous system, produces the stimulus that increases the likelihood of fibrillation. There is no evidence that repeated, tolerated doses of DDT sensitize the heart. Rats were fed DDT at a dietary level of 200 ppm (about 10 mg/ kg/day) for 8 months, during which they received weekly, intraperitoneal doses of vasopressin, a compound that causes a temporary myocardial ischemia. Electrocardiograms showed no significant increase in cardiac arrhythmias in the DDT-fed rats as compared with controls. The same results were obtained in rabbits treated in essentially the same way (Jeyaratnam and Forshaw 1974). Male mice exposed to p,p'-DDE at dietary levels of 125 or 250 ppm throughout life suffered a high incidence of myocardial necrosis (Tomatis et al 1974a). # Adrenal # Central Nervous System Effects The # In Dogs In Depending upon the dose regimen of DDT and the particular days injections were given during gestation, the number of implantation sites in the DDT-treated mice was decreased. Subsequent studies by Lundberg (1974) confirmed that DDT caused a decreased in the frequency of implanted embryos. # In Mice # Interactions with Steroid # In Rats Fifteen male and 15 female Fischer rats were each given 15 mg of DDT (unspecified composition) by stomach tube, 5 times/week, starting at weaning. Exposure lasted 1 year, and survivors were observed for a further 6 months, the average survival being 14 months. No liver tumors were found, and no data were provided on the occurrence of other tumors (Weisburger and Weisburger 1968). Males: controls, 50%; DDT at 250 ppm, 23%; DDT at 500 ppm, 13%; # Rossi et al (1977) reported that DDT induced liver tumors in DDT at 1,000 ppm, 0; Females: controls, 41%; DDT at 250 ppm, 17%; DDT at 500 ppm,0; DDT at 1,000 ppm, 0. The occurence of other types of tumors was not reported. # In Dogs A total of 22 animals, approximately equally divided by sex, were fed diets containing DDT at 0 (2 dogs), 400 ppm (2 dogs), 2,000 ppm (4 dogs), or 3,200 ppm (14 dogs). Only the control dogs, the two dogs given 400 ppm, and two of the dogs receiving 2,000 ppm survived to the time of sacrifice (39-49 months). Liver damage was reported (Lehman 1965, IARC 1974), but the study was too short to serve as an adequate carinogenicity test. # Carcinogenic Interactions As noted in the preceding sections, the actions of DDT and Fischer rats were given daily doses of either 1 mg of 2-AAF or 1 mg of 2-AAF plus 10 mg of DDT, 5 days/week, for 52 weeks, followed by an average of 60 days without exposure. Hepatomas were observed in 90% of the males and 33% of the females in the DDT-exposed groups, versus 67% and 7%, respectively, in the groups exposed to 2-AAF alone. dieldrin # Mutagenicity and Related Cytotoxic Effects Kelly-Garvert and Legator (1973) Buselmaier et al (1972,1973) (1956,1971). The first study involved 51 men. Of these, three completed 1 year of dosage at 3.5 mg/man/day, and seven completed 1 year at 35 mg/man/day. Onset in 30-60 min in those most severely affected; men first seen 2-3 hr after ingestion; in spite of severe early vomiting that reduced the effective dose, severity of illness and especially intensity of numbness and paralysis of extremities proportional to amount of DDT ingested; recovery in all but 8 men in 48 hr; 5 others fully recovered in 2 wk, but some weakness and ataxia of the hands in 3 5 weeks after ingestion exposed to DDT and lindane. However, the workers' exposure to lindane was the only one that was clearly significant, as indicated by its concentration in plasma (Kolmodin-Hedman 1973 ). In a previous study (Kolmodin et al 1969) In addition to the reported effects listed in # Effects on Experimental Animals DOT i n 11. # STORAGE OF DDT'IN THE' TISSUES OF RATS FED DIETS CONTAINING DDT AT DIFFERENT CONCENTRATIONS FIGURE 1.5.7 (USDHEW 1969).	Pursuant to the fulfillment of this need, the National Institute for Occupational Safety and Health (NIOSH) has developed a reporting strategy intended to assist employers In providing personal protection for employees from exposure to carcinogenic, mutagenic, and teratogenic substances. This strategy involves the development of Special Occupational Hazard Reviews which serve to support and complement the other major criteria documentation activities of the Institute. It is the intent of a Special Occupational Hazard Review to document, from a health standpoint, the problems associated with a given industrial chemical or process. While Special Occupational Hazard Reviews are not intended to supplant the more comprehensive NIOSH Criteria Documents nor the less comprehensive NIOSH Current Intelligence Bulletins, they are nevertheless prepared in such a way as to be amenable to full regulatory usage if so desired. Dissemination of Special Occupational Hazard Reviews may be accomplished through appropriate trade associations, unions, industries, and members of the scientific community.# The acute toxicity ofDDT is relatively low, the estimated oral LD50 in humans being 250 mg/kg. Documented chronic toxicity in humans, clearly related to DDT, is non-existent, and, therefore, the results of experiments with animals must be used to predict chronic effects that may occur in humans. Most notahle of these chronic effects is DDT's potential for producing cancer in animals. DDT has produced an increased incidence of tumors in mice in at least eleven experiments. Most tumors involved the liver but tumors of the lungs and lymphatic system have also been reported. In one experiment with mice, DDT induced an increased incidence of tumors at dietary levels as low as 2 and 10 ppm. In two of three experiments involving rats, increased occurrences of liver tumors of varying degrees of malignancy have been reported. Based on the demonstrated potential of DDT for inducing tumors in both rats and mice, NIOSH recommends that DDT be controlled and handled in the workplace as a suspected occupational carcinogen and that exposure to DDT be minimized to the greatest extent possible. With regard to airborne exposure, NIOSH recommends that the workplace environmental limit be no higher than 0.5 mg/cu m, which is the lowest concentration detectable by the current NIOSH validated sampling and analytical method (NIOSH method S274). Workers should also avoid skin contact with DDT, as the pesticide can be absorbed through the skin. Percutaneous absorption is substantially increased when DDT is dissolved in organic solvents. The physical and chemical properties of DDT as well as synonyms and trade names are summarized in Table 5.2, and synonyms and trade names are given in the Table 5.3. The structures of DDT, other compounds that occur in technical DDT, and their metabolites are presented in Table 5.1 (WHO 1977). The structure of the o,p' and m,p' compounds can be inferred from those of the p,p' isomers. # Discovery and Introduction Technical DDT is synthesized by condensing chloral hydrate with chlorobenzene in the presence of sulfuric acid, a process first discovered by Zeidler in 1874. However, it was 1939 before the insecticidal applications of DDT were identified, by Muller and his coworkers (IARC 1974). By 1943, low-cost production methods had been developed, and commercial production had begun (IARC 1974). # Changing Patterns of Use and Production Before 1945, all of the DDT produced in the USA was used or allocated by the military services for various medical and public health uses. Early in 1945 it became available for experimental work in agriculture, and it was commercially available in limited quantitites early in the autumn of the same year. The results were so spectacular that use in the United States increased until 1959, and in response to a demand for exports production continued to increase until about 1963. Even before 1963 some restrictions were placed on its use in the United States, mainly to minimize residues in food and in the feed of animals that produce milk and meat. Another important factor reducing the use of DDT was the increasing resistance of pests. After a peak in 1959, the use of DDT in the United States declined steadily, except for its major remaining use on cotton (Table 1.3 Outside the United States, DDT is still used extensively for agriculture and vector control in many tropical countries (WHO 1977). Although many pests of public health importance have become resistant to DDT in some or all of their range, resistance in vectors of malaria has been less widespread (WHO 1977). Accordingly the use of DDT for The demand for DDT as a residual spray against adult mosquitos in antimalarial programs for the decade 1971-81 has been predicted to be 470,000 metric tons or an average of 47,000 metric tons/year, a figure similar to that predicted for agricultural uses. The estimated requirements for six regions of the world (Africa, America, Southeast Asia, Europe, the Eastern Mediterranean, and the Western Pacific) are given in Table 1.3.4. The estimated annual demands tend to increase toward a maximum in 1977, with a subsequent decrease until 1981, the last year of the forecast, when the pre dicted requirement is 29,000 metric tons (Goldberg 1975 (1). However, as of 1972, there were reportedly only two major producers left in Europe. DDT is also known to be produced in: Brazil, where production was 3 million kg in 1969 and is believed to be increasing; Israel, where the total capacity in 1970 was 350 thousand kg; and India, where production for 1971-72 was 4 million kg and was expected to increase. Japan produced 4.6 million kg in 1970 (IARC 1974). # Exposure Generally, exposure to DDT is greatest for manufacturers and formulators, moderate for agricultural applicators, less for the general population, and least for special groups whose location or practices minimize their exposure. However, for brief intervals the exposure of agricultural applicators may exceed anything that good industrial practice would permit (WHO 1977). Occupational exposure to DDT is reflected quantitatively by the concentration of DDT and DDE in blood and fat and by the con centration of DDA in urine (See Section 1.5.4). Urinary excretion of DDA may be increased for several days after a single exposure to DDT by inhalation or percutaneous absorption (Wolfe et al 1970). In a study of formulators, urinary excretion of DDA was increased for only 1 day after exposure (Table 1. (Wolfe andArmstrong 1971, IARC 1974). Estimates of potential respiratory exposure ranged from 0.11 mg/hr for outdoor spraying to 7.1 mg/hr for indoor spraying ( Similarly, blood levels of DDT and DDE and urinary levels of DDA were 2-10 times higher in aircraft sprayers than those in the general population and increased with the duration of exposure ( (Moriarty 1974(Moriarty , 1975. Thus the data in the literature should be interpreted as describing "quasi-steady" states reached after long-term exposure, and they may underestimate the potential for storage after exposure of more than 1-2 years. Data for a number of species suggest that residues in tissues increase with increasing dietary concentrations but not in direct proportion to rates of intake (Figures 1.5.7-1.5.9, USDHEW 1969, Hayes 1975, Moriarty 1975). These data have been evaluated and summarized by Hayes (1975) . Additional data for mice are summarized in Table 1.5.4. Storage factors for three species at medium exposure rates (about 1 mg/kg/day or 10 ppm in the diet) are shown in Table 1.5.5. A "storage factor" is defined as the concentration of DDT in the fat of an animal after long-term exposure divided by the concentration in the diet. These storage factors range between 2 and 24. Although data for other species refer only to higher dose ranges, storage factors for dogs, cattle, and hamsters appear to be lower than those for rats and mice in comparable conditions (Figure (Hayes 1964(Hayes , 1975IARC 1974). Female rats given DDT at 32 m g A g / d a y secreted about 25% of the # Mode of Action The The author suggested that the uncoupling of oxidative phosphorylation in brain mitochondria may be responsible for some phenomena of DDT intoxi cation in mammals. # Long-Term Feeding Experiments A number of experiments involving long-term dietary exposure of rats, mice, hamsters, dogs, and other mammals to DDT are summarized in histopathologic changes in the liver, impaired reproduction, and increased incidence of tumors of the liver, lungs, and lympathic system. These effects are summarized in the following sections. # 2.2 Organ-Specific Toxicity # Liver and Kidney Effects In addtion to the effects on the CNS and reproductive organs, chlorinated # Morphologic changes (outlined in Table 2.2.1), including an increase in SER and atypical mitochondria, were observed in all exposed groups and were more pronounced in rats given both DDT and dieldrin. # Liver Enzyme and Other Biochemical Effects Numerous studies have been conducted in which DDT has been identified as an inducer of hepatic microsomal enzymes and hence as an effector of the # Effects on the Cardiovascular System Most dogs killed by a single dose of DDT die of ventricular fibril lation, and the same is true of some cats, monkeys, and rabbits. Monkeys differ from dogs in that the DDT-sensitized heart is able to recover from fibrillation and resume a normal rhythm (Philips and Gilman 1946). DDT not only sensitizes the myocardium in a way similar to that of halogenated hydrocarbon solvents but, through its action on the central nervous system, produces the stimulus that increases the likelihood of fibrillation. There is no evidence that repeated, tolerated doses of DDT sensitize the heart. Rats were fed DDT at a dietary level of 200 ppm (about 10 mg/ kg/day) for 8 months, during which they received weekly, intraperitoneal doses of vasopressin, a compound that causes a temporary myocardial ischemia. Electrocardiograms showed no significant increase in cardiac arrhythmias in the DDT-fed rats as compared with controls. The same results were obtained in rabbits treated in essentially the same way (Jeyaratnam and Forshaw 1974). Male mice exposed to p,p'-DDE at dietary levels of 125 or 250 ppm throughout life suffered a high incidence of myocardial necrosis (Tomatis et al 1974a). # Adrenal # Central Nervous System Effects The # In Dogs In Depending upon the dose regimen of DDT and the particular days injections were given during gestation, the number of implantation sites in the DDT-treated mice was decreased. Subsequent studies by Lundberg (1974) confirmed that DDT caused a decreased in the frequency of implanted embryos. # In Mice # Interactions with Steroid # In Rats Fifteen male and 15 female Fischer rats were each given 15 mg of DDT (unspecified composition) by stomach tube, 5 times/week, starting at weaning. Exposure lasted 1 year, and survivors were observed for a further 6 months, the average survival being 14 months. No liver tumors were found, and no data were provided on the occurrence of other tumors (Weisburger and Weisburger 1968). Males: controls, 50%; DDT at 250 ppm, 23%; DDT at 500 ppm, 13%; # Rossi et al (1977) reported that DDT induced liver tumors in DDT at 1,000 ppm, 0; Females: controls, 41%; DDT at 250 ppm, 17%; DDT at 500 ppm,0; DDT at 1,000 ppm, 0. The occurence of other types of tumors was not reported. # In Dogs A total of 22 animals, approximately equally divided by sex, were fed diets containing DDT at 0 (2 dogs), 400 ppm (2 dogs), 2,000 ppm (4 dogs), or 3,200 ppm (14 dogs). Only the control dogs, the two dogs given 400 ppm, and two of the dogs receiving 2,000 ppm survived to the time of sacrifice (39-49 months). Liver damage was reported (Lehman 1965, IARC 1974), but the study was too short to serve as an adequate carinogenicity test. # Carcinogenic Interactions As noted in the preceding sections, the actions of DDT and Fischer rats were given daily doses of either 1 mg of 2-AAF or 1 mg of 2-AAF plus 10 mg of DDT, 5 days/week, for 52 weeks, followed by an average of 60 days without exposure. Hepatomas were observed in 90% of the males and 33% of the females in the DDT-exposed groups, versus 67% and 7%, respectively, in the groups exposed to 2-AAF alone. dieldrin # 2.6 # Mutagenicity and Related Cytotoxic Effects Kelly-Garvert and Legator (1973) Buselmaier et al (1972,1973) (1956,1971). The first study involved 51 men. Of these, three completed 1 year of dosage at 3.5 mg/man/day, and seven completed 1 year at 35 mg/man/day. Onset in 30-60 min in those most severely affected; men first seen 2-3 hr after ingestion; in spite of severe early vomiting that reduced the effective dose, severity of illness and especially intensity of numbness and paralysis of extremities proportional to amount of DDT ingested; recovery in all but 8 men in 48 hr; 5 others fully recovered in 2 wk, but some weakness and ataxia of the hands in 3 5 weeks after ingestion exposed to DDT and lindane. However, the workers' exposure to lindane was the only one that was clearly significant, as indicated by its concentration in plasma (Kolmodin-Hedman 1973 ). In a previous study (Kolmodin et al 1969) In addition to the reported effects listed in # Effects on Experimental Animals # DOT i n 11. # STORAGE OF DDT'IN THE' TISSUES OF RATS FED DIETS CONTAINING DDT AT DIFFERENT CONCENTRATIONS FIGURE 1.5.7 (USDHEW 1969).	None	None
ab5dee91c786ac037ba6029aff5b14ab244baedf	cdc	None	Prevention of pneumococcal disease among infants and children---use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(No. RR-11). 4. CDC. Prevention and control of influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59(No. RR-8). 5. CDC. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR 2011;60:13--5. 6. CDC. Updated recommendations for use of meningococcal conjugate vaccines---Advisory Committee on Immunization Practices (# ) Alternate Text: The figure above shows the recommended immunization schedule for 2011 for persons aged 0 through 6 years in the United States This schedule includes recommendations in effect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment, patient preference, and the potential for adverse events. Providers should consult the relevant Advisory Committee on Immunization Practices statement for detailed recommendations: . Clinically significant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at or by telephone, 800-822-7967. # Hepatitis B vaccine (HepB). (Minimum age: birth) # At birth: Administer monovalent HepB to all newborns before hospital discharge. If mother is hepatitis B surface antigen (HBsAg)-positive, administer HepB and 0.5 mL of hepatitis B immune globulin (HBIG) within 12 hours of birth. If mother's HBsAg status is unknown, administer HepB within 12 hours of birth. Determine mother's HBsAg status as soon as possible and, if HBsAg-positive, administer HBIG (no later than age 1 week). # Doses following the birth dose: The second dose should be administered at age 1 or 2 months. Monovalent HepB should be used for doses administered before age 6 weeks. Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg 1 to 2 months after completion of at least 3 doses of the HepB series, at age 9 through 18 months (generally at the next well-child visit). Administration of 4 doses of HepB to infants is permissible when a combination vaccine containing HepB is administered after the birth dose. Infants who did not receive a birth dose should receive 3 doses of HepB on a schedule of 0, 1, and 6 months. The final (3rd or 4th) dose in the HepB series should be administered no earlier than age 24 weeks. # Rotavirus vaccine (RV). (Minimum age: 6 weeks) Administer the first dose at age 6 through 14 weeks (maximum age: 14 weeks 6 days). Vaccination should not be initiated for infants aged 15 weeks 0 days or older. The maximum age for the final dose in the series is 8 months 0 days If Rotarix is administered at ages 2 and 4 months, a dose at 6 months is not indicated. # Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). (Minimum age: 6 weeks) The fourth dose may be administered as early as age 12 months, provided at least 6 months have elapsed since the third dose. # Haemophilus influenzae type b conjugate vaccine (Hib). (Minimum age: 6 weeks) If PRP-OMP (PedvaxHIB or Comvax ) is administered at ages 2 and 4 months, a dose at age 6 months is not indicated. Hiberix should not be used for doses at ages 2, 4, or 6 months for the primary series but can be used as the final dose in children aged 12 months through 4 years. PCV is recommended for all children aged younger than 5 years. Administer 1 dose of PCV to all healthy children aged 24 through 59 months who are not completely vaccinated for their age. A PCV series begun with 7-valent PCV (PCV7) should be completed with 13-valent PCV (PCV13). A single supplemental dose of PCV13 is recommended for all children aged 14 through 59 months who have received an age-appropriate series of PCV7. A single supplemental dose of PCV13 is recommended for all children aged 60 through 71 months with underlying medical conditions who have received an age-appropriate series of PCV7. The supplemental dose of PCV13 should be administered at least 8 weeks after the previous dose of PCV7. See MMWR 2010:59(No. RR-11). Administer PPSV at least 8 weeks after last dose of PCV to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant. # Inactivated poliovirus vaccine (IPV). (Minimum age: 6 weeks) If 4 or more doses are administered prior to age 4 years an additional dose should be administered at age 4 through 6 years. The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. # Influenza vaccine (seasonal). (Minimum age: 6 months for trivalent inactivated influenza vaccine ; 2 years for live, attenuated influenza vaccine ) For healthy children aged 2 years and older (i.e., those who do not have underlying medical conditions that predispose them to influenza complications), either LAIV or TIV may be used, except LAIV should not be given to children aged 2 through 4 years who have had wheezing in the past 12 months. Administer 2 doses (separated by at least 4 weeks) to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but only received 1 dose. Children aged 6 months through 8 years who received no doses of monovalent 2009 H1N1 vaccine should receive 2 doses of 2010--2011 seasonal influenza vaccine. See MMWR 2010;59(No. RR-8):33--34. # Measles, mumps, and rubella vaccine (MMR). (Minimum age: 12 months) The second dose may be administered before age 4 years, provided at least 4 weeks have elapsed since the first dose. # Varicella vaccine. (Minimum age: 12 months) The second dose may be administered before age 4 years, provided at least 3 months have elapsed since the first dose. For children aged 12 months through 12 years the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. # Hepatitis A vaccine (HepA). (Minimum age: 12 months) Administer 2 doses at least 6 months apart. HepA is recommended for children aged older than 23 months who live in areas where vaccination programs target older children, who are at increased risk for infection, or for whom immunity against hepatitis A is desired. # Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age: 2 years) Administer 2 doses of MCV4 at least 8 weeks apart to children aged 2 through 10 years with persistent complement component deficiency and anatomic or functional asplenia, and 1 dose every 5 years thereafter. Persons with human immunodeficiency virus (HIV) infection who are vaccinated with MCV4 should receive 2 doses at least 8 weeks apart. Administer 1 dose of MCV4 to children aged 2 through 10 years who travel to countries with highly endemic or epidemic disease and during outbreaks caused by a vaccine serogroup. Administer MCV4 to children at continued risk for meningococcal disease who were previously vaccinated with MCV4 or meningococcal polysaccharide vaccine after 3 years if the first dose was administered at age 2 through 6 years. The Recommended Immunization Schedules for Persons Aged 0 Through 18 Years are approved by the Advisory Committee on Immunization Practices (), the American Academy of Pediatrics ( ), and the American Academy of Family Physicians ( ). U.S. Department of Health and Human Services - Centers for Disease Control and Prevention ]) Alternate Text: The figure above shows the recommended immunization schedule for 2011 for persons aged 7 through 18 years in the United States This schedule includes recommendations in effect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment, patient preference, and the potential for adverse events. Providers should consult the relevant Advisory Committee on Immunization Practices statement for detailed recommendations: . Clinically significant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at or by telephone, 800-822-7967. # Tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap). (Minimum age: 10 years for Boostrix and 11 years for Adacel) Persons aged 11 through 18 years who have not received Tdap should receive a dose followed by Td booster doses every 10 years thereafter. Persons aged 7 through 10 years who are not fully immunized against pertussis (including those never vaccinated or with unknown pertussis vaccination status) should receive a single dose of Tdap. Refer to the catch-up schedule if additional doses of tetanus and diphtheria toxoid--containing vaccine are needed. Tdap can be administered regardless of the interval since the last tetanus and diphtheria toxoid-containing vaccine. # Human papillomavirus vaccine (HPV). (Minimum age: 9 years) Quadrivalent HPV vaccine (HPV4) or bivalent HPV vaccine (HPV2) is recommended for the prevention of cervical precancers and cancers in females. HPV4 is recommended for prevention of cervical precancers, cancers, and genital warts in females. HPV4 may be administered in a 3-dose series to males aged 9 through 18 years to reduce their likelihood of genital warts. Administer the second dose 1 to 2 months after the first dose and the third dose 6 months after the first dose (at least 24 weeks after the first dose). # Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age: 2 years) Administer MCV4 at age 11 through 12 years with a booster dose at age 16 years. Administer 1 dose at age 13 through 18 years if not previously vaccinated. Persons who received their first dose at age 13 through 15 years should receive a booster dose at age 16 through 18 years. Administer 1 dose to previously unvaccinated college freshmen living in a dormitory. Administer 2 doses at least 8 weeks apart to children aged 2 through 10 years with persistent complement component deficiency and anatomic or functional asplenia, and 1 dose every 5 years thereafter. Persons with HIV infection who are vaccinated with MCV4 should receive 2 doses at least 8 weeks apart. Administer 1 dose of MCV4 to children aged 2 through 10 years who travel to countries with highly endemic or epidemic disease and during outbreaks caused by a vaccine serogroup. Administer MCV4 to children at continued risk for meningococcal disease who were previously vaccinated with MCV4 or meningococcal polysaccharide vaccine after 3 years (if first dose administered at age 2 through 6 years) or after 5 years (if first dose administered at age 7 years or older). # Influenza vaccine (seasonal). For healthy nonpregnant persons aged 7 through 18 years (i.e., those who do not have underlying medical conditions that predispose them to influenza complications), either LAIV or TIV may be used. Administer 2 doses (separated by at least 4 weeks) to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but only received 1 dose. Children 6 months through 8 years of age who received no doses of monovalent 2009 H1N1 vaccine should receive 2 doses of 2010-2011 seasonal influenza vaccine. See MMWR 2010;59(No. RR-8):33--34. # Pneumococcal vaccines. A single dose of 13-valent pneumococcal conjugate vaccine (PCV13) may be administered to children aged 6 through 18 years who have functional or anatomic asplenia, HIV infection or other immunocompromising condition, cochlear implant or CSF leak. See MMWR 2010;59(No. RR-11). The dose of PCV13 should be administered at least 8 weeks after the previous dose of PCV7. Administer pneumococcal polysaccharide vaccine at least 8 weeks after the last dose of PCV to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant. A single revaccination should be administered after 5 years to children with functional or anatomic asplenia or an immunocompromising condition. # Hepatitis A vaccine (HepA). Administer 2 doses at least 6 months apart. HepA is recommended for children aged older than 23 months who live in areas where vaccination programs target older children, or who are at increased risk for infection, or for whom immunity against hepatitis A is desired. # Hepatitis B vaccine (HepB). Administer the 3-dose series to those not previously vaccinated. For those with incomplete vaccination, follow the catch-up recommendations (Table ). A 2-dose series (separated by at least 4 months) of adult formulation Recombivax HB is licensed for children aged 11 through 15 years. # Inactivated poliovirus vaccine (IPV). The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. If both OPV and IPV were administered as part of a series, a total of 4 doses should be administered, regardless of the child's current age. # Measles, mumps, and rubella vaccine (MMR). The minimum interval between the 2 doses of MMR is 4 weeks. # Varicella vaccine. For persons aged 7 through 18 years without evidence of immunity (see MMWR 2007;56), administer 2 doses if not previously vaccinated or the second dose if only 1 dose has been administered. For persons aged 7 through 12 years, the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. For persons aged 13 years and older, the minimum interval between doses is 4 weeks. The table below provides catch-up schedules and minimum intervals between doses for children whose vaccinations have been delayed. A vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Use the section appropriate for the child's age. # PERSONS AGED 4 MONTHS THROUGH 6 YEARS # Vaccine # Minimum # Hepatitis B vaccine (HepB). Administer the 3-dose series to those not previously vaccinated. The minimum age for the third dose of HepB is 24 weeks. A 2-dose series (separated by at least 4 months) of adult formulation Recombivax HB is licensed for children aged 11 through 15 years. # Rotavirus vaccine (RV). The maximum age for the first dose is 14 weeks 6 days. Vaccination should not be initiated for infants aged 15 weeks 0 days or older. The maximum age for the final dose in the series is 8 months 0 days. If Rotarix was administered for the first and second doses, a third dose is not indicated. # Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). The fifth dose is not necessary if the fourth dose was administered at age 4 years or older. # Haemophilus influenzae type b conjugate vaccine (Hib). 1 dose of Hib vaccine should be considered for unvaccinated persons aged 5 years or older who have sickle cell disease, leukemia, or HIV infection, or who have had a splenectomy. If the first 2 doses were PRP-OMP (PedvaxHIB or Comvax), and administered at age 11 months or younger, the third (and final) dose should be administered at age 12 through 15 months and at least 8 weeks after the second dose. If the first dose was administered at age 7 through 11 months, administer the second dose at least 4 weeks later and a final dose at age 12 through 15 months. # Pneumococcal vaccine. Administer 1 dose of 13-valent pneumococcal conjugate vaccine (PCV13) to all healthy children aged 24 through 59 months with any incomplete PCV schedule (PCV7 or PCV13). For children aged 24 through 71 months with underlying medical conditions, administer 1 dose of PCV13 if 3 doses of PCV were received previously or administer 2 doses of PCV13 at least 8 weeks apart if fewer than 3 doses of PCV were received previously. A single dose of PCV13 is recommended for certain children with underlying medical conditions through 18 years of age. See age-specific schedules for details. Administer pneumococcal polysaccharide vaccine (PPSV) to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant, at least 8 weeks after the last dose of PCV. A single revaccination should be administered after 5 years to children with functional or anatomic asplenia or an immunocompromising condition. See MMWR 2010;59(No. RR-11). # Inactivated poliovirus vaccine (IPV). The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. A fourth dose is not necessary if the third dose was administered at age 4 years or older and at least 6 months following the previous dose. In the first 6 months of life, minimum age and minimum intervals are only recommended if the person is at risk for imminent exposure to circulating poliovirus (i.e., travel to a polio-endemic region or during an outbreak). # Measles, mumps, and rubella vaccine (MMR). Administer the second dose routinely at age 4 through 6 years. The minimum interval between the 2 doses of MMR is 4 weeks. # Varicella vaccine. Administer the second dose routinely at age 4 through 6 years. If the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. # Hepatitis A vaccine (HepA). HepA is recommended for children aged older than age 23 months who live in areas where vaccination programs target older children, or who are at increased risk for infection, or for whom immunity against hepatitis A is desired.	Prevention of pneumococcal disease among infants and children---use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(No. RR-11). 4. CDC. Prevention and control of influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59(No. RR-8). 5. CDC. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR 2011;60:13--5. 6. CDC. Updated recommendations for use of meningococcal conjugate vaccines---Advisory Committee on Immunization Practices (# ] ) Alternate Text: The figure above shows the recommended immunization schedule for 2011 for persons aged 0 through 6 years in the United States This schedule includes recommendations in effect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment, patient preference, and the potential for adverse events. Providers should consult the relevant Advisory Committee on Immunization Practices statement for detailed recommendations: http://www.cdc.gov/vaccines/pubs/acip-list.htm. Clinically significant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at http://www.vaers.hhs.gov or by telephone, 800-822-7967. # Hepatitis B vaccine (HepB). (Minimum age: birth) # At birth: Administer monovalent HepB to all newborns before hospital discharge. If mother is hepatitis B surface antigen (HBsAg)-positive, administer HepB and 0.5 mL of hepatitis B immune globulin (HBIG) within 12 hours of birth. If mother's HBsAg status is unknown, administer HepB within 12 hours of birth. Determine mother's HBsAg status as soon as possible and, if HBsAg-positive, administer HBIG (no later than age 1 week). # Doses following the birth dose: The second dose should be administered at age 1 or 2 months. Monovalent HepB should be used for doses administered before age 6 weeks. Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg 1 to 2 months after completion of at least 3 doses of the HepB series, at age 9 through 18 months (generally at the next well-child visit). Administration of 4 doses of HepB to infants is permissible when a combination vaccine containing HepB is administered after the birth dose. Infants who did not receive a birth dose should receive 3 doses of HepB on a schedule of 0, 1, and 6 months. The final (3rd or 4th) dose in the HepB series should be administered no earlier than age 24 weeks. # Rotavirus vaccine (RV). (Minimum age: 6 weeks) Administer the first dose at age 6 through 14 weeks (maximum age: 14 weeks 6 days). Vaccination should not be initiated for infants aged 15 weeks 0 days or older. The maximum age for the final dose in the series is 8 months 0 days If Rotarix is administered at ages 2 and 4 months, a dose at 6 months is not indicated. # Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). (Minimum age: 6 weeks) The fourth dose may be administered as early as age 12 months, provided at least 6 months have elapsed since the third dose. # Haemophilus influenzae type b conjugate vaccine (Hib). (Minimum age: 6 weeks) If PRP-OMP (PedvaxHIB or Comvax [HepB-Hib]) is administered at ages 2 and 4 months, a dose at age 6 months is not indicated. Hiberix should not be used for doses at ages 2, 4, or 6 months for the primary series but can be used as the final dose in children aged 12 months through 4 years. PCV is recommended for all children aged younger than 5 years. Administer 1 dose of PCV to all healthy children aged 24 through 59 months who are not completely vaccinated for their age. A PCV series begun with 7-valent PCV (PCV7) should be completed with 13-valent PCV (PCV13). A single supplemental dose of PCV13 is recommended for all children aged 14 through 59 months who have received an age-appropriate series of PCV7. A single supplemental dose of PCV13 is recommended for all children aged 60 through 71 months with underlying medical conditions who have received an age-appropriate series of PCV7. The supplemental dose of PCV13 should be administered at least 8 weeks after the previous dose of PCV7. See MMWR 2010:59(No. RR-11). Administer PPSV at least 8 weeks after last dose of PCV to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant. # Inactivated poliovirus vaccine (IPV). (Minimum age: 6 weeks) If 4 or more doses are administered prior to age 4 years an additional dose should be administered at age 4 through 6 years. The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. # Influenza vaccine (seasonal). (Minimum age: 6 months for trivalent inactivated influenza vaccine [TIV]; 2 years for live, attenuated influenza vaccine [LAIV]) For healthy children aged 2 years and older (i.e., those who do not have underlying medical conditions that predispose them to influenza complications), either LAIV or TIV may be used, except LAIV should not be given to children aged 2 through 4 years who have had wheezing in the past 12 months. Administer 2 doses (separated by at least 4 weeks) to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but only received 1 dose. Children aged 6 months through 8 years who received no doses of monovalent 2009 H1N1 vaccine should receive 2 doses of 2010--2011 seasonal influenza vaccine. See MMWR 2010;59(No. RR-8):33--34. # Measles, mumps, and rubella vaccine (MMR). (Minimum age: 12 months) The second dose may be administered before age 4 years, provided at least 4 weeks have elapsed since the first dose. # Varicella vaccine. (Minimum age: 12 months) The second dose may be administered before age 4 years, provided at least 3 months have elapsed since the first dose. For children aged 12 months through 12 years the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. # Hepatitis A vaccine (HepA). (Minimum age: 12 months) Administer 2 doses at least 6 months apart. HepA is recommended for children aged older than 23 months who live in areas where vaccination programs target older children, who are at increased risk for infection, or for whom immunity against hepatitis A is desired. # Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age: 2 years) Administer 2 doses of MCV4 at least 8 weeks apart to children aged 2 through 10 years with persistent complement component deficiency and anatomic or functional asplenia, and 1 dose every 5 years thereafter. Persons with human immunodeficiency virus (HIV) infection who are vaccinated with MCV4 should receive 2 doses at least 8 weeks apart. Administer 1 dose of MCV4 to children aged 2 through 10 years who travel to countries with highly endemic or epidemic disease and during outbreaks caused by a vaccine serogroup. Administer MCV4 to children at continued risk for meningococcal disease who were previously vaccinated with MCV4 or meningococcal polysaccharide vaccine after 3 years if the first dose was administered at age 2 through 6 years. The Recommended Immunization Schedules for Persons Aged 0 Through 18 Years are approved by the Advisory Committee on Immunization Practices (http://www.cdc.gov/vaccines/recs/acip), the American Academy of Pediatrics (http://www.aap.org ), and the American Academy of Family Physicians (http://www.aafp.org ). U.S. Department of Health and Human Services • Centers for Disease Control and Prevention ]) Alternate Text: The figure above shows the recommended immunization schedule for 2011 for persons aged 7 through 18 years in the United States This schedule includes recommendations in effect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment, patient preference, and the potential for adverse events. Providers should consult the relevant Advisory Committee on Immunization Practices statement for detailed recommendations: http://www.cdc.gov/vaccines/pubs/acip-list.htm. Clinically significant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at http://www.vaers.hhs.gov or by telephone, 800-822-7967. # Tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap). (Minimum age: 10 years for Boostrix and 11 years for Adacel) Persons aged 11 through 18 years who have not received Tdap should receive a dose followed by Td booster doses every 10 years thereafter. Persons aged 7 through 10 years who are not fully immunized against pertussis (including those never vaccinated or with unknown pertussis vaccination status) should receive a single dose of Tdap. Refer to the catch-up schedule if additional doses of tetanus and diphtheria toxoid--containing vaccine are needed. Tdap can be administered regardless of the interval since the last tetanus and diphtheria toxoid-containing vaccine. # Human papillomavirus vaccine (HPV). (Minimum age: 9 years) Quadrivalent HPV vaccine (HPV4) or bivalent HPV vaccine (HPV2) is recommended for the prevention of cervical precancers and cancers in females. HPV4 is recommended for prevention of cervical precancers, cancers, and genital warts in females. HPV4 may be administered in a 3-dose series to males aged 9 through 18 years to reduce their likelihood of genital warts. Administer the second dose 1 to 2 months after the first dose and the third dose 6 months after the first dose (at least 24 weeks after the first dose). # Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age: 2 years) Administer MCV4 at age 11 through 12 years with a booster dose at age 16 years. Administer 1 dose at age 13 through 18 years if not previously vaccinated. Persons who received their first dose at age 13 through 15 years should receive a booster dose at age 16 through 18 years. Administer 1 dose to previously unvaccinated college freshmen living in a dormitory. Administer 2 doses at least 8 weeks apart to children aged 2 through 10 years with persistent complement component deficiency and anatomic or functional asplenia, and 1 dose every 5 years thereafter. Persons with HIV infection who are vaccinated with MCV4 should receive 2 doses at least 8 weeks apart. Administer 1 dose of MCV4 to children aged 2 through 10 years who travel to countries with highly endemic or epidemic disease and during outbreaks caused by a vaccine serogroup. Administer MCV4 to children at continued risk for meningococcal disease who were previously vaccinated with MCV4 or meningococcal polysaccharide vaccine after 3 years (if first dose administered at age 2 through 6 years) or after 5 years (if first dose administered at age 7 years or older). # Influenza vaccine (seasonal). For healthy nonpregnant persons aged 7 through 18 years (i.e., those who do not have underlying medical conditions that predispose them to influenza complications), either LAIV or TIV may be used. Administer 2 doses (separated by at least 4 weeks) to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but only received 1 dose. Children 6 months through 8 years of age who received no doses of monovalent 2009 H1N1 vaccine should receive 2 doses of 2010-2011 seasonal influenza vaccine. See MMWR 2010;59(No. RR-8):33--34. # Pneumococcal vaccines. A single dose of 13-valent pneumococcal conjugate vaccine (PCV13) may be administered to children aged 6 through 18 years who have functional or anatomic asplenia, HIV infection or other immunocompromising condition, cochlear implant or CSF leak. See MMWR 2010;59(No. RR-11). The dose of PCV13 should be administered at least 8 weeks after the previous dose of PCV7. Administer pneumococcal polysaccharide vaccine at least 8 weeks after the last dose of PCV to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant. A single revaccination should be administered after 5 years to children with functional or anatomic asplenia or an immunocompromising condition. # Hepatitis A vaccine (HepA). Administer 2 doses at least 6 months apart. HepA is recommended for children aged older than 23 months who live in areas where vaccination programs target older children, or who are at increased risk for infection, or for whom immunity against hepatitis A is desired. # Hepatitis B vaccine (HepB). Administer the 3-dose series to those not previously vaccinated. For those with incomplete vaccination, follow the catch-up recommendations (Table ). A 2-dose series (separated by at least 4 months) of adult formulation Recombivax HB is licensed for children aged 11 through 15 years. # Inactivated poliovirus vaccine (IPV). The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. If both OPV and IPV were administered as part of a series, a total of 4 doses should be administered, regardless of the child's current age. # Measles, mumps, and rubella vaccine (MMR). The minimum interval between the 2 doses of MMR is 4 weeks. # Varicella vaccine. For persons aged 7 through 18 years without evidence of immunity (see MMWR 2007;56[No. RR-4]), administer 2 doses if not previously vaccinated or the second dose if only 1 dose has been administered. For persons aged 7 through 12 years, the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. For persons aged 13 years and older, the minimum interval between doses is 4 weeks. The table below provides catch-up schedules and minimum intervals between doses for children whose vaccinations have been delayed. A vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Use the section appropriate for the child's age. # PERSONS AGED 4 MONTHS THROUGH 6 YEARS # Vaccine # Minimum # Hepatitis B vaccine (HepB). Administer the 3-dose series to those not previously vaccinated. The minimum age for the third dose of HepB is 24 weeks. A 2-dose series (separated by at least 4 months) of adult formulation Recombivax HB is licensed for children aged 11 through 15 years. # Rotavirus vaccine (RV). The maximum age for the first dose is 14 weeks 6 days. Vaccination should not be initiated for infants aged 15 weeks 0 days or older. The maximum age for the final dose in the series is 8 months 0 days. If Rotarix was administered for the first and second doses, a third dose is not indicated. # Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). The fifth dose is not necessary if the fourth dose was administered at age 4 years or older. # Haemophilus influenzae type b conjugate vaccine (Hib). 1 dose of Hib vaccine should be considered for unvaccinated persons aged 5 years or older who have sickle cell disease, leukemia, or HIV infection, or who have had a splenectomy. If the first 2 doses were PRP-OMP (PedvaxHIB or Comvax), and administered at age 11 months or younger, the third (and final) dose should be administered at age 12 through 15 months and at least 8 weeks after the second dose. If the first dose was administered at age 7 through 11 months, administer the second dose at least 4 weeks later and a final dose at age 12 through 15 months. # Pneumococcal vaccine. Administer 1 dose of 13-valent pneumococcal conjugate vaccine (PCV13) to all healthy children aged 24 through 59 months with any incomplete PCV schedule (PCV7 or PCV13). For children aged 24 through 71 months with underlying medical conditions, administer 1 dose of PCV13 if 3 doses of PCV were received previously or administer 2 doses of PCV13 at least 8 weeks apart if fewer than 3 doses of PCV were received previously. A single dose of PCV13 is recommended for certain children with underlying medical conditions through 18 years of age. See age-specific schedules for details. Administer pneumococcal polysaccharide vaccine (PPSV) to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant, at least 8 weeks after the last dose of PCV. A single revaccination should be administered after 5 years to children with functional or anatomic asplenia or an immunocompromising condition. See MMWR 2010;59(No. RR-11). # Inactivated poliovirus vaccine (IPV). The final dose in the series should be administered on or after the fourth birthday and at least 6 months following the previous dose. A fourth dose is not necessary if the third dose was administered at age 4 years or older and at least 6 months following the previous dose. In the first 6 months of life, minimum age and minimum intervals are only recommended if the person is at risk for imminent exposure to circulating poliovirus (i.e., travel to a polio-endemic region or during an outbreak). # Measles, mumps, and rubella vaccine (MMR). Administer the second dose routinely at age 4 through 6 years. The minimum interval between the 2 doses of MMR is 4 weeks. # Varicella vaccine. Administer the second dose routinely at age 4 through 6 years. If the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. # Hepatitis A vaccine (HepA). HepA is recommended for children aged older than age 23 months who live in areas where vaccination programs target older children, or who are at increased risk for infection, or for whom immunity against hepatitis A is desired.	None	None
6b7776376281b61cfbeb78de672842574c4182d0	cdc	None	The CDC Guideline Development and Reporting Checklist (GDRC) will help you develop guidelines that comply with well-known standards used by most recognized guideline authorities in the world. The World Health Organization (WHO) defines a guideline as: "A guideline is a document that contains recommendations about health interventions, whether they be clinical, public health, or policy interventions. A recommendation provides information about what policy makers, health care providers, or patients should do. It implies a choice between different interventions that have an impact on health and that have ramifications for the use of resources." 1 CDC's guidelines and recommendations vary in content, scope, audience, and development methods. The style will also vary depending on how the document is distributed and accessed. Venues for CDC guidelines include Morbidity and Mortality Weekly Report (and Recommendations and Reports), peerreviewed journals, and CDC-branded and partner publications. CDC's Office of the Associate Director for Science (OADS) recognizes that one reporting template for all CDC guidelines is neither practical nor sufficient. Yet by identifying key elements that each report should contain, we enhance transparency, clarity, and credibility. These key elements are indicated in the checklist that follows. The elements were adapted from the CDC Primer, developed by the CDC Guidelines and Recommendations Work Group in 2012. 2 CDC-OADS clearance officials also use the checklist when reviewing and clearing guidelines and recommendations. Each element includes an example from a published guideline, followed by a text box titled "Type description here." This allows guideline developers to use the checklist as a working document. Guideline developers should determine the appropriate process for developing the guidelines, such as creating an internal working group or involving subject matter experts outside CDC to develop material or to review and approve the guideline. This may be done ad hoc by creating a larger working group and steering committee or by using a committee already chartered under the Federal Advisory Committee Act (FACA). Guideline developers should first determine whether their proposed guidelines is subject to the Federal Advisory Committee Act (FACA). To find out if FACA applies, contact the MASO Federal Advisory Committee Policy and Oversight Team (CDC) at facmp&[email protected] or by calling (770) 488-4707. Regardless of whether FACA rules apply, guideline developers should follow this checklist to improve the quality of the guidelines and to ensure CDC OADS clearance is obtained. When reporting guidelines, the style you select will depend on the audience, publication venue, and intended use. Guideline developers must use their best judgment in deciding how to report key You may contact the Guidelines and Recommendation Activity Team located in the OADS, Office of Science Quality for a consultation at any stage of the guideline development process. For more information about the Guidelines and Recommendations Activity, resources and tools, and training, visit the Office of the Associate Director for Science Guidelines and Recommendations Activity site.# information. Some information will require detailed description, and presentation format may vary. For example, detailed technical material may be put in appendices. A short-version document may be used to report the recommendations and summarize the methods used, whereas a longer, technical document may be used to report detailed descriptions of searches and evidence tables. Short versions need to provide enough detail so that readers can understand the rationale behind the development process and can locate supplemental information reported in electronic or printed documents. --------------------------------------- Type description here. 10. ☐ Describe questions related to guideline topic for systematic literature review. 11. ☒ Describe the literature search protocol; cover at least 10 years of most recent published literature and databases used. # Example of questions related to guideline topic for systematic literature review # Example of search criteria and sources: "The scientific literature was searched through December 2000 by using the MEDLINE database of the National Library of Medicine (started in 1966), the Educational Resources Information Center database (ERIC, 1966), the Cumulative Index to Nursing and Allied Health database (CINAHL, 1982), andHealthstar (1975). The medical subject headings (MeSH) searched were diabetes, case management, and disease management, including all subheadings. Text word searches were performed on multiple additional terms, including care model, shared care, primary health care, medical specialties, primary, or specialist. Abstracts were not included because they generally had insufficient information to assess the validity of the study using Community Guide criteria. A total of 22 dissertations were excluded either because the abstracts contained insufficient information for evaluation or the full text was unavailable. Extracted articles and abstracts were reviewed for relevance; and if deemed relevant, the full-text article was retrieved. We also reviewed the reference lists of included articles, and our consultants provided additional relevant citations." Type description here. 12. ☒ Provide criteria used to select studies extracted from the literature review. # Example of criteria of select studies - English language - Peer-reviewed, full-length publication with original data - Multiple publications of the same study were treated as a single study to avoid double-counting patients The study included at least one of the following bloodborne pathogens: HIV, HBV, and HCV. The presence or absence of HIV/HBV/HCV was based on laboratory test(s), not on subjective estimates, physician interviews, or patient interviews. - Additional criteria were applied on a per-question basis, as depicted in Table 1 on the next page. For many questions, an insufficient number of studies were identified to support the development of the guideline. Consequently, in an effort to provide a sufficient amount of relevant information to support the development of the guideline, committee members expanded the inclusion criteria in multiple iterations over several months." 13. ☒ Provide a table of findings that summarizes the body of evidence or a link to websites containing evidence tables. 14. ☒ Describe methods used to assess evidence quality, whether they be GRADE, Cochrane, USPSTF, Community Guide, or other methods. # (Continued on the next page) # Example of summary of findings table: # Example of description of methods used to assess evidence quality: "We used the GRADE evidence rating methodology, which has been developed for treatment comparisons (Questions 6, 7 and 8) 1 6.3. The details of the application of the GRADE system for each question are described in those sections. GRADE methodology has not been developed for the questions on epidemiology (Question 1), transmission (Question 2), risk factors (Questions 3 and 4), and the impact of exclusions on the donor pool (Questions 9 and 10). For these, we created GRADE methodology as follows. For Questions 1 and 2, no randomized trials are necessary to address the questions, therefore the starting evidence grade was high and we applied the other components of the GRADE system as appropriate. For Questions 3 and 4, we used a starting evidence grade of Low because risk factor studies are by nature observational. Portions of Questions 3 and 4 involve the prevalence of risk factors; these were graded similarly as Question 1 (epidemiology). For Questions 9 and 10, it was not necessary to develop new GRADE methodology, because for Question 9 there was only one study and it had already been graded in Question 8, and for Question 10 there were no included studies." Type description here. 16. ☐ Describe methods used to obtain and assess economic data. # Example of methods to obtain and assess economic data: To examine the cost-effectiveness of various strategies for assessing HCP protection from hepatitis B, two economic models that yielded calculations of the incremental cost per quality-adjusted life-year (QALY) saved were developed. One model represented an approach in which anti-HBs is measured on a preexposure basis, and HCP with anti-HBs <10 mIU/mL receive an additional dose of HepB vaccine, followed by repeat anti-HBs measurement. If anti-HBs remains <10 mIU/mL after the first revaccination dose, the HCP receives two additional revaccination doses of HepB vaccine followed by repeat anti-HBs measurement. Another model represented a postexposure management approach; at the time of exposure, the HCP is tested for anti-HBs and the source patient is tested simultaneously for HBsAg, and postexposure prophylaxis would be administered on the basis of these results. Results from the two models were compared. A decision-tree analysis was used to combine all parameters and calculate the total intervention costs and probability of infection. In addition, HBV infection-related costs and QALY loss (accounting for acute and asymptomatic infections and a 6% probability of chronic infection) were determined from an existing model ( 89 17. ☐ Summarize the evidence of economic efficiency for proposed recommendations. # Example of narrative of economic efficiency: "For pre-exposure anti-HBs testing followed by revaccination and retesting, if necessary, compared with doing nothing, the incremental cost per QALY saved was $4,542,467 for trainees and $3,149,183 for nontrainees at year one,and decreased to $893,619 and $796,140, respectively, over 10 years. This approach is expected to result in 3.7 and 1.6 visits to occupational health for trainees and nontrainees, respectively. The expected number of infections is 0.7 per 100,000 and 0.4 per 100,000 for trainees and nontrainees, respectively. For an approach relying upon postexposure management, compared with doing nothing, the incremental cost per QALY saved was $2,270,801 for trainees and $1,610,998 for nontrainees at year one, and decreased to $917,859 and $1,114,364 respectively, over 10 years. The expected number of infections is 3.0 per 100,000 and 1.7 per 100,000 for trainees and nontrainees, respectively. Although an approach relying upon postexposure management might be less costly per QALY saved initially for many institutions, pre-exposure anti-HBs testing with possible revaccination becomes more cost-effective compared with a postexposure approach over time. Sensitivity analyses demonstrated that costeffectiveness improves in settings where a greater proportion of source patients are HBsAg-positive and among HCP with higher risk for exposure (e.g., surgeons Example of linking the recommendation to the evidence: Recommendations: - Amenorrhea does not require any medical treatment. Provide reassurance. If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive Evidence Summary: During contraceptive counseling and before insertion of the implant, information about common side effects such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use, should be discussed. A pooled analysis of data from 11 clinical trials indicate that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (121). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). A systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily LNG contraceptive implants (122)(123)(124)(125)(126). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (124,125). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (126,127). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (126). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (128). Evidence also suggests that estrogen (129)(130)(131) 19. ☒ Describe methods used to formulate recommendations (e.g., group discussion, consensus). # Example of methods used to formulate the recommendations: "During October 4-7, 2011, CDC convened a meeting in Atlanta, Georgia, of 36 experts who were invited to assist in guideline development and provide their perspective on the scientific evidence presented and the discussions on potential recommendations that followed. The group included obstetrician/ gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with research and clinical practice expertise in contraceptive safety, effectiveness, and management. Participants received all of the systematic reviews before the meeting. During the meeting, the evidence from the systematic review for each topic was presented, and participants discussed the evidence and the translation of the scientific evidence into recommendations that would meet the needs of U.S. health care providers. In particular, participants discussed whether and how the U.S. context might be different from the global context and whether these differences suggested any need for modifications to the global guidance. CDC gathered the input from the experts during the meeting and finalized the recommendations in this report. The document was peer reviewed by meeting participants, who were asked to comment on specific issues that were raised during the meeting. Feedback also was received from an external review panel, composed of health care providers who had not participated in the meetings. These providers were asked to comments on the accuracy, feasibility, and clarity of the recommendations, as well as to provide other comments. Areas of research that need additional investigation also were considered during the meeting (31)." 20. ☒ Describe factors that influenced the strength of the recommendations including how expert opinion, values, and preferences supported the recommendations. # Examples of factors influencing the strength of the recommendations: "To evaluate the evidence on reducing transmission of HIV, HBV, and HCV, we examined data addressing 10 key questions within five major topic areas (Figure 1). A sixth topic area includes questions addressed by expert opinion (Figure 2). We drew upon subject-matter experts to draft summaries related to these questions, as a preliminary scan of the literature showed that a systematic review would likely yield insufficient data. Recommendations related to the 10 key questions were based on a targeted systematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish this review, we used a modified Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for evaluating quality of evidence and determining strength of recommendations. If weighing the critical outcomes for a key question resulted in a net benefit or a net harm, then a Category I recommendation was formulated to recommend strongly for or against the given intervention, respectively. If weighing the critical outcomes for a key question resulted in a trade-off between benefits and harms, then a Category II recommendation was formulated to recommend that providers or institutions consider the intervention when deemed appropriate. In addition to a category rating, recommendations were also assigned a level rating (A through D) 21. ☐ Describe other considerations that informed the recommendations (e.g., applicability, feasibility, barriers to implementation). # Example of assessment of applicability of the recommendation: "The same body of evidence used to assess effectiveness was used to assess the applicability of smoking bans and restrictions to different settings and populations. Smoking bans and restrictions were evaluated in a variety of settings, including hospitals and medical centers, 28,57,72 offices of health care providers, 57 workplaces in the government or public sector, 35,47,55 and a university. 42 Studies on representative samples of employed people in California 31,61,79,80 and in Missouri 36 demonstrated that smoking bans and restrictions reduced self-reported exposure to ETS in workplaces community-wide. Studies included representative samples of indoor workers in the states of California 31,61,79,80 and Missouri, 36 large, diverse samples of government employees in Texas, 47 and health maintenance organization (HMO) employees in Oregon. 57 The evidence of effectiveness in these studies should extend to most indoor workers in the United States." ----------------------------------------------------------------------------------- # Example of barriers to implementation of the intervention: "A major barrier to efforts by local governments to adopt smoking bans is pre-emption, which is the passage or presence of a state law with weaker smoking restrictions that prevents implementation and enforcement of stronger local laws. 91,92 # Example of description of areas for future research "The systematic review for this guideline revealed numerous gaps in the evidence that affected the guideline's ability to adequately address many of the key questions reviewed. Additional gaps in evidence were identified from other sources, such as comments submitted during the public comment period or in review following public comment. The following are 20 specific areas recommended for further study. These recommendations are arranged to correspond to the order of the 10 key questions followed by the three expert opinion questions; they are not listed in priority order. # Task Force for Community Preventive Services Community Guide Reviews-Topic Index Community Guide Reviews-Systematic Review Methods # US Preventive Services Task Force USPSTF Procedure Manual # Cochrane Collaboration Cochrane Handbook for Systematic Reviews of Interventions Cochrane Systematic Reviews # GRADE Working Group List of GRADE Working Group publications and presentations Type description here. # Review and Vetting 24. ☒ Describe who (people and organizations) reviewed and commented on the recommendations, if the comments influenced and resulted in a revision of the recommendations. # Example of how individuals and organizations review the recommendations "After a draft of the tables, narrative summaries, and recommendations was completed, the guideline authors shared the draft guideline with the Expert Panel and Review Committee and made revisions to the guideline based in part on their feedback. Explain when guidelines and recommendations will be updated here. # Additional Resources CDC Resources CDC, Office of the Associate Director for Science. Guidelines and Recommendations: A CDC Primer, 2012. # Conference on Guideline Standardization Shiffman	The CDC Guideline Development and Reporting Checklist (GDRC) will help you develop guidelines that comply with well-known standards used by most recognized guideline authorities in the world. The World Health Organization (WHO) defines a guideline as: "A guideline is a document that contains recommendations about health interventions, whether they be clinical, public health, or policy interventions. A recommendation provides information about what policy makers, health care providers, or patients should do. It implies a choice between different interventions that have an impact on health and that have ramifications for the use of resources." 1 CDC's guidelines and recommendations vary in content, scope, audience, and development methods. The style will also vary depending on how the document is distributed and accessed. Venues for CDC guidelines include Morbidity and Mortality Weekly Report (and Recommendations and Reports), peerreviewed journals, and CDC-branded and partner publications. CDC's Office of the Associate Director for Science (OADS) recognizes that one reporting template for all CDC guidelines is neither practical nor sufficient. Yet by identifying key elements that each report should contain, we enhance transparency, clarity, and credibility. These key elements are indicated in the checklist that follows. The elements were adapted from the CDC Primer, developed by the CDC Guidelines and Recommendations Work Group in 2012. 2 CDC-OADS clearance officials also use the checklist when reviewing and clearing guidelines and recommendations. Each element includes an example from a published guideline, followed by a text box titled "Type description here." This allows guideline developers to use the checklist as a working document. Guideline developers should determine the appropriate process for developing the guidelines, such as creating an internal working group or involving subject matter experts outside CDC to develop material or to review and approve the guideline. This may be done ad hoc by creating a larger working group and steering committee or by using a committee already chartered under the Federal Advisory Committee Act (FACA). Guideline developers should first determine whether their proposed guidelines is subject to the Federal Advisory Committee Act (FACA). To find out if FACA applies, contact the MASO Federal Advisory Committee Policy and Oversight Team (CDC) at facmp&[email protected] or by calling (770) 488-4707. Regardless of whether FACA rules apply, guideline developers should follow this checklist to improve the quality of the guidelines and to ensure CDC OADS clearance is obtained. When reporting guidelines, the style you select will depend on the audience, publication venue, and intended use. Guideline developers must use their best judgment in deciding how to report key You may contact the Guidelines and Recommendation Activity Team located in the OADS, Office of Science Quality for a consultation at any stage of the guideline development process. For more information about the Guidelines and Recommendations Activity, resources and tools, and training, visit the Office of the Associate Director for Science Guidelines and Recommendations Activity site.# information. Some information will require detailed description, and presentation format may vary. For example, detailed technical material may be put in appendices. A short-version document may be used to report the recommendations and summarize the methods used, whereas a longer, technical document may be used to report detailed descriptions of searches and evidence tables. Short versions need to provide enough detail so that readers can understand the rationale behind the development process and can locate supplemental information reported in electronic or printed documents. --------------------------------------- Type description here. 10. ☐ Describe questions related to guideline topic for systematic literature review. 11. ☒ Describe the literature search protocol; cover at least 10 years of most recent published literature and databases used. # Example of questions related to guideline topic for systematic literature review # Example of search criteria and sources: "The scientific literature was searched through December 2000 by using the MEDLINE database of the National Library of Medicine (started in 1966), the Educational Resources Information Center database (ERIC, 1966), the Cumulative Index to Nursing and Allied Health database (CINAHL, 1982), andHealthstar (1975). The medical subject headings (MeSH) searched were diabetes, case management, and disease management, including all subheadings. Text word searches were performed on multiple additional terms, including care model, shared care, primary health care, medical specialties, primary, or specialist. Abstracts were not included because they generally had insufficient information to assess the validity of the study using Community Guide criteria. A total of 22 dissertations were excluded either because the abstracts contained insufficient information for evaluation or the full text was unavailable. Extracted articles and abstracts were reviewed for relevance; and if deemed relevant, the full-text article was retrieved. We also reviewed the reference lists of included articles, and our consultants provided additional relevant citations." Type description here. 12. ☒ Provide criteria used to select studies extracted from the literature review. # Example of criteria of select studies • English language • Peer-reviewed, full-length publication with original data • Multiple publications of the same study were treated as a single study to avoid double-counting patients • The study included at least one of the following bloodborne pathogens: HIV, HBV, and HCV. # • The presence or absence of HIV/HBV/HCV was based on laboratory test(s), not on subjective estimates, physician interviews, or patient interviews. • Additional criteria were applied on a per-question basis, as depicted in Table 1 on the next page. For many questions, an insufficient number of studies were identified to support the development of the guideline. Consequently, in an effort to provide a sufficient amount of relevant information to support the development of the guideline, committee members expanded the inclusion criteria in multiple iterations over several months." 13. ☒ Provide a table of findings that summarizes the body of evidence or a link to websites containing evidence tables. 14. ☒ Describe methods used to assess evidence quality, whether they be GRADE, Cochrane, USPSTF, Community Guide, or other methods. # (Continued on the next page) # Example of summary of findings table: # Example of description of methods used to assess evidence quality: "We used the GRADE evidence rating methodology, which has been developed for treatment comparisons (Questions 6, 7 and 8) 1 6.3. The details of the application of the GRADE system for each question are described in those sections. GRADE methodology has not been developed for the questions on epidemiology (Question 1), transmission (Question 2), risk factors (Questions 3 and 4), and the impact of exclusions on the donor pool (Questions 9 and 10). For these, we created GRADE methodology as follows. For Questions 1 and 2, no randomized trials are necessary to address the questions, therefore the starting evidence grade was high and we applied the other components of the GRADE system as appropriate. For Questions 3 and 4, we used a starting evidence grade of Low because risk factor studies are by nature observational. Portions of Questions 3 and 4 involve the prevalence of risk factors; these were graded similarly as Question 1 (epidemiology). For Questions 9 and 10, it was not necessary to develop new GRADE methodology, because for Question 9 there was only one study and it had already been graded in Question 8, and for Question 10 there were no included studies." Type description here. 16. ☐ Describe methods used to obtain and assess economic data. # Example of methods to obtain and assess economic data: To examine the cost-effectiveness of various strategies for assessing HCP protection from hepatitis B, two economic models that yielded calculations of the incremental cost per quality-adjusted life-year (QALY) saved were developed. One model represented an approach in which anti-HBs is measured on a preexposure basis, and HCP with anti-HBs <10 mIU/mL receive an additional dose of HepB vaccine, followed by repeat anti-HBs measurement. If anti-HBs remains <10 mIU/mL after the first revaccination dose, the HCP receives two additional revaccination doses of HepB vaccine followed by repeat anti-HBs measurement. Another model represented a postexposure management approach; at the time of exposure, the HCP is tested for anti-HBs and the source patient is tested simultaneously for HBsAg, and postexposure prophylaxis would be administered on the basis of these results. Results from the two models were compared. A decision-tree analysis was used to combine all parameters and calculate the total intervention costs and probability of infection. In addition, HBV infection-related costs and QALY loss (accounting for acute and asymptomatic infections and a 6% probability of chronic infection) were determined from an existing model ( 89 17. ☐ Summarize the evidence of economic efficiency for proposed recommendations. # Example of narrative of economic efficiency: "For pre-exposure anti-HBs testing followed by revaccination and retesting, if necessary, compared with doing nothing, the incremental cost per QALY saved was $4,542,467 for trainees and $3,149,183 for nontrainees at year one,and decreased to $893,619 and $796,140, respectively, over 10 years. This approach is expected to result in 3.7 and 1.6 visits to occupational health for trainees and nontrainees, respectively. The expected number of infections is 0.7 per 100,000 and 0.4 per 100,000 for trainees and nontrainees, respectively. For an approach relying upon postexposure management, compared with doing nothing, the incremental cost per QALY saved was $2,270,801 for trainees and $1,610,998 for nontrainees at year one, and decreased to $917,859 and $1,114,364 respectively, over 10 years. The expected number of infections is 3.0 per 100,000 and 1.7 per 100,000 for trainees and nontrainees, respectively. Although an approach relying upon postexposure management might be less costly per QALY saved initially for many institutions, pre-exposure anti-HBs testing with possible revaccination becomes more cost-effective compared with a postexposure approach over time. Sensitivity analyses demonstrated that costeffectiveness improves in settings where a greater proportion of source patients are HBsAg-positive and among HCP with higher risk for exposure (e.g., surgeons Example of linking the recommendation to the evidence: Recommendations: • Amenorrhea does not require any medical treatment. Provide reassurance. If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive Evidence Summary: During contraceptive counseling and before insertion of the implant, information about common side effects such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use, should be discussed. A pooled analysis of data from 11 clinical trials indicate that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (121). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). A systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily LNG contraceptive implants (122)(123)(124)(125)(126). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (124,125). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (126,127). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (126). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (128). Evidence also suggests that estrogen (129)(130)(131) 19. ☒ Describe methods used to formulate recommendations (e.g., group discussion, consensus). # Example of methods used to formulate the recommendations: "During October 4-7, 2011, CDC convened a meeting in Atlanta, Georgia, of 36 experts who were invited to assist in guideline development and provide their perspective on the scientific evidence presented and the discussions on potential recommendations that followed. The group included obstetrician/ gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with research and clinical practice expertise in contraceptive safety, effectiveness, and management. Participants received all of the systematic reviews before the meeting. During the meeting, the evidence from the systematic review for each topic was presented, and participants discussed the evidence and the translation of the scientific evidence into recommendations that would meet the needs of U.S. health care providers. In particular, participants discussed whether and how the U.S. context might be different from the global context and whether these differences suggested any need for modifications to the global guidance. CDC gathered the input from the experts during the meeting and finalized the recommendations in this report. The document was peer reviewed by meeting participants, who were asked to comment on specific issues that were raised during the meeting. Feedback also was received from an external review panel, composed of health care providers who had not participated in the meetings. These providers were asked to comments on the accuracy, feasibility, and clarity of the recommendations, as well as to provide other comments. Areas of research that need additional investigation also were considered during the meeting (31)." 20. ☒ Describe factors that influenced the strength of the recommendations including how expert opinion, values, and preferences supported the recommendations. # Examples of factors influencing the strength of the recommendations: "To evaluate the evidence on reducing transmission of HIV, HBV, and HCV, we examined data addressing 10 key questions within five major topic areas (Figure 1). A sixth topic area includes questions addressed by expert opinion (Figure 2). We drew upon subject-matter experts to draft summaries related to these questions, as a preliminary scan of the literature showed that a systematic review would likely yield insufficient data. Recommendations related to the 10 key questions were based on a targeted systematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish this review, we used a modified Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for evaluating quality of evidence and determining strength of recommendations. [14][15][16][17][18] If weighing the critical outcomes for a key question resulted in a net benefit or a net harm, then a Category I recommendation was formulated to recommend strongly for or against the given intervention, respectively. If weighing the critical outcomes for a key question resulted in a trade-off between benefits and harms, then a Category II recommendation was formulated to recommend that providers or institutions consider the intervention when deemed appropriate. In addition to a category rating, recommendations were also assigned a level rating (A through D) 21. ☐ Describe other considerations that informed the recommendations (e.g., applicability, feasibility, barriers to implementation). # Example of assessment of applicability of the recommendation: "The same body of evidence used to assess effectiveness was used to assess the applicability of smoking bans and restrictions to different settings and populations. Smoking bans and restrictions were evaluated in a variety of settings, including hospitals and medical centers, 28,57,72 offices of health care providers, 57 workplaces in the government or public sector, 35,47,55 and a university. 42 Studies on representative samples of employed people in California 31,61,79,80 and in Missouri 36 demonstrated that smoking bans and restrictions reduced self-reported exposure to ETS in workplaces community-wide. Studies included representative samples of indoor workers in the states of California 31,61,79,80 and Missouri, 36 large, diverse samples of government employees in Texas, 47 and health maintenance organization (HMO) employees in Oregon. 57 The evidence of effectiveness in these studies should extend to most indoor workers in the United States." ----------------------------------------------------------------------------------- # Example of barriers to implementation of the intervention: "A major barrier to efforts by local governments to adopt smoking bans is pre-emption, which is the passage or presence of a state law with weaker smoking restrictions that prevents implementation and enforcement of stronger local laws. 91,92 # Example of description of areas for future research "The systematic review for this guideline revealed numerous gaps in the evidence that affected the guideline's ability to adequately address many of the key questions reviewed. Additional gaps in evidence were identified from other sources, such as comments submitted during the public comment period or in review following public comment. The following are 20 specific areas recommended for further study. These recommendations are arranged to correspond to the order of the 10 key questions followed by the three expert opinion questions; they are not listed in priority order. # Task Force for Community Preventive Services Community Guide Reviews-Topic Index Community Guide Reviews-Systematic Review Methods # US Preventive Services Task Force USPSTF Procedure Manual # Cochrane Collaboration Cochrane Handbook for Systematic Reviews of Interventions Cochrane Systematic Reviews # GRADE Working Group List of GRADE Working Group publications and presentations # Type description here. # Review and Vetting 24. ☒ Describe who (people and organizations) reviewed and commented on the recommendations, if the comments influenced and resulted in a revision of the recommendations. # Example of how individuals and organizations review the recommendations "After a draft of the tables, narrative summaries, and recommendations was completed, the guideline authors shared the draft guideline with the Expert Panel and Review Committee and made revisions to the guideline based in part on their feedback. Explain when guidelines and recommendations will be updated here. # Additional Resources CDC Resources CDC, Office of the Associate Director for Science. Guidelines and Recommendations: A CDC Primer, 2012. # Conference on Guideline Standardization Shiffman	None	None
03de94098168d8a4782309372af4dd61a77e882a	cdc	None	The contributors to this report (Appendix C) declared no interests regarding the commercial products discussed herein. The report describes the use of certain drugs, tests, and procedures for some indications that do not reflect labeling approved by the U.S. Food and Drug Administration (FDA) at the time of publication. Information about such drugs, tests, or procedures is noted in the relevant sections.# This report updates and expands recommendations on the four topics covered by the 2003 Recommendations:  Screening for behaviors that could transmit HIV and behavioral interventions to reduce the risk of transmission  STD screening, treatment, and other sexual health services that may reduce the risk of HIV transmission  Services for sex partners and drug-injection partners of persons with HIV (known as HIV partner services † )  Referral ‡ for other medical and social services that influence HIV transmission or use of HIV prevention and care services The 2003 Recommendations were directed to health care providers who serve persons with HIV. In contrast, the recommendations in this report are directed to a broader audience of clinical providers and nonclinical providers who serve persons with HIV and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. The recommendations may also be of interest to persons with HIV; partners of persons with HIV; specialists in HIV planning and service delivery who work for medical assistance programs, health insurance plans, or health systems; and specialists in HIV policy who develop HIV-related programs, legislation, and regulations. ‡ Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). In this report, clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. A specially convened Project Workgroup comprised of HIV experts from CDC and HRSA consolidated longstanding recommendations from current federal guidance that were based on scientific evidence, program experience, and/or expert opinion published through July 2014. The Workgroup also developed new recommendations which were based on scientific evidence, program experience, laws, regulations, and expert opinion. Some highlights of the recommendations include the following:  Engaging clinical providers, nonclinical providers, health departments, and HIV planning groups to use their expertise, professional authorities, and collaborative relationships to serve individuals or populations of persons with HIV  Creating a spirit of partnership among persons with HIV and the providers who serve them in order to achieve both individual HIV prevention and care goals and public health benefits  Using evidence-based strategies † † to promptly link persons with newly diagnosed HIV infection to HIV medical care and promote their long-term retention in care  Using HIV clinical and surveillance data to promote linkage to and retention in care of individuals or populations with HIV, if allowed by the laws or regulations of the jurisdiction  Informing all persons with HIV (regardless of their CD4 cell count) about the role of effective ART in promoting their health and reducing HIV transmission and offering ART regimens recommended by the U.S. Department of Health and Human Services  Supporting sustained high adherence to ART using evidence-based interventions  Using both biomedical factors, such as HIV viral load and recently diagnosed STDs, and HIV risk behaviors ‡ ‡ to assess a person's risk of HIV transmission  Supporting safer sexual and drug-use behaviors using effective, evidence-based interventions  Supporting persons with HIV to selectively disclose their HIV infection status and notify partners of possible HIV exposure using methods that minimize the risk of stigma, discrimination, prosecution, and other negative consequences  Expediting HIV partner services to persons with acute HIV infection § § or high viral load who are most infectious  Informing persons with HIV about the availability of preexposure prophylaxis (PrEP)* or nonoccupational postexposure prophylaxis (nPEP) † † † for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  Screening persons with HIV with the most sensitive STD tests, including tests for rectal and oropharyngeal specimens from gay, bisexual, and other men who have sex with men (MSM), and treating infected persons with the most effective STD treatment, as recommended by the latest CDC guidance † † Evidence-based interventions, strategies, guidelines, and recommendations are based on sound scientific research, testing, or program evaluation. ‡ ‡ Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). § § Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. * PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 9 † † † nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 10  Providing women and men with HIV who are of reproductive age with contraceptive services, reproductive health counseling, and information and access to special conception methods that can reduce the risk of HIV transmission, as recommended by the latest federal guidance  Providing women with HIV who are pregnant and HIV-uninfected pregnant women with HIVinfected partners various biomedical and behavioral interventions that prevent sexual or perinatal HIV transmission during pregnancy, as recommended by the latest federal guidance  Helping persons with HIV obtain other medical and social services that support long-term HIV care and high adherence to ART, encourage safer behaviors, and prevent HIV transmission, such as mental health and substance use treatment, stable housing, and transportation to health-related visits  Applying quality improvement ‡ ‡ ‡ strategies and program monitoring and evaluation § § § to improve the effectiveness and efficiency of HIV prevention and care services This report is published with 3 shorter summaries that list the subset of recommendations pertaining to a specific audience: clinical providers, 11 nonclinical providers, 12 and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. 13 A companion Web site includes dozens of practical decision-support tools and training aids and is regularly updated as new materials become available: Because these recommendations are both numerous and ambitious, health professionals and organizations must focus on the interventions that are most feasible given their professional authority, skills, and resources and are most important for their clients, patients, and communities. This report's broad audience highlights both the unique and shared roles of different provider types who offer interventions as well as opportunities for collaboration across clinical, nonclinical, and public health organizations. Collaboration is important at a time when the number and longevity of persons with HIV in the United States is increasing, more effective interventions are available, and shortages of trained HIV care and prevention providers persist. 14,15 Finally, these recommendations can help mobilize support, policies, resources, and quality improvement for HIV prevention activities in communities and health systems that will ensure that "prevention with persons with HIV" is a cornerstone of HIV prevention in the United States. # Section 1. Introduction More than 1 million people are living with HIV in the United States, an increase of 60% over the previous 15 years. 1 The number of newly infected persons exceeds the number of deaths among HIV-infected persons, which results in a net increase of about 30,000 persons with HIV each year. 2,3 In 2012, about 64% of infections in adults and adolescents were diagnosed among gay, bisexual, and other men who have sex with men (MSM) and about 10% in persons who inject drugs. Nearly 26% of infections were diagnosed in heterosexual persons, of whom about 67% were women. 2 Persons diagnosed with HIV are disproportionately black/African-American and Hispanic/Latino and residents of selected states of the Southeast and Mid-Atlantic regions, Puerto Rico, the U.S. Virgin Islands, and about a dozen of the largest U.S. cities. The growing number of persons living with HIV challenges delivery of prevention and care services and demands more effective methods to prevent HIV transmission to others. 4 Some persons with HIV have taken steps to reduce the risk of transmitting HIV by starting HIV care shortly after diagnosis, using ART to reduce infectiousness, or undergoing STD screening and treatment. Many practice safer sexual and drug-use behaviors, notify partners of possible HIV exposure, or use reproductive health services and substance use treatment to lower their transmission risk. Nevertheless, national data indicate that many persons with HIV do not benefit from the full range of biomedical, behavioral, and structural interventions that can reduce infectiousness and the risk of exposing others to HIV. 9 Of the more than 1 million HIV-infected individuals living in the United States in 2009, only about  82% of persons with HIV were aware of their HIV infection status  66% of persons with diagnosed HIV were linked to care  37% of those who entered care were retained in care  33% were prescribed antiretroviral treatment (ART)  25% had a suppressed viral load, which reduces infectiousness 9 (see Figure 1-1) Nationally representative data also indicate that only about 45% of persons receiving outpatient HIV medical care reported receiving HIV prevention counseling- from a health care provider during the preceding year. 10 This may be due to time constraints, competing clinical priorities, lack of training in sexual health or injection-drug use, uncertainty that counseling will motivate behavior change, and other factors. 11,12 Many persons with HIV do not receive routine screening for sexually transmitted diseases (STDs) that may facilitate HIV transmission or services to notify partners of possible HIV exposure. 6,13 Personal choice to defer safer behaviors also contributes to HIV transmission. Studies conducted in the United States when ART was routinely initiated at CD4 cell counts below 350 per mm^3 of blood show that some adolescents and adults with HIV who are aware of their infection status did not practice safe sex and drug-injection behaviors. 14 In 2011, an estimated 13% of MSM with HIV reported engaging in sex without a condom with male partners who were HIV-uninfected or whose infection status was unknown. 15 A review of several U.S. studies of condom use in female adolescents infected with HIV through perinatal exposure, sexual activity, or drug use found that about 40%-60% of adolescents reported engaging in unprotected sex. 16 One 2001 study found that adolescent girls who disclosed their HIV infection to partners were more likely to report consistent condom use than adolescent girls who did not disclose their infection. 17 The 2010 National HIV/AIDS Strategy highlighted the need to accelerate HIV prevention and to increase health equity through several approaches. These include reducing the HIV transmission rate; increasing the percentage of persons with HIV who know their infection status, are promptly linked to HIV care, and remain in continuous care; and increasing the proportion of persons in priority populations (MSM, black/African-American, and Hispanic/Latino) with undetectable HIV viral loads. 18 A prevention strategy that aims to increase access to effective biomedical, behavioral, and structural interventions for the more than 1 million persons with HIV is more likely to decrease HIV transmission than a strategy that attempts to change sexual and drug-injection behaviors of the many millions of persons at risk for infection. 19,20 Also, many prevention interventions for persons with HIV can capitalize on existing clinical systems and resources because most receive care for HIV or other medical conditions sometime after their HIV diagnosis. This report updates and expands earlier recommendations about HIV prevention for persons with HIV published by the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America in 2003: Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. 21 Several factors prompted this update, including advances in behavioral, biomedical, and structural interventions, new national HIV prevention goals, 18 and recent changes in public-and private-sector health care delivery and financing in the United States. 22,23 These recommendations also incorporated perspectives of additional stakeholders, including persons with HIV, HIV medical care providers, nonclinical HIV prevention providers, health department HIV/AIDS program managers, and experts in HIV policy and legal issues (see Section 2,Methods). This report consolidates a large number of federal recommendations about effective biomedical, behavioral, and structural interventions that can reduce the infectiousness of adults and adolescents with HIV and behaviors that can transmit HIV. The recommendations relate to 11 topics, which correspond to the 11 main sections of this report:  Individual, social, structural, ethical, legal, policy, and programmatic factors that influence HIV transmission and use of prevention services † (referred to as the Context of HIV prevention)  Linkage ‡ to and retention in HIV medical care  Use of ART for improving health and for preventing HIV transmission  Methods to achieve sustained, high adherence to ART to reduce infectiousness  Screening for behavioral, biomedical, and structural factors that increase risk of HIV transmission and risk-reduction interventions that promote health and reduce the risk of HIV transmission  Services for sex partners and drug-injection partners of persons with HIV (referred to as HIV partner services § )  STD screening, treatment, and other sexual health services that may reduce the risk of HIV transmission † Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. ‡ Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). § Partner services include an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services.  Reproductive health care for women and men to reduce the risk of sexual HIV transmission when attempting conception or unintended pregnancy (thereby reducing the risk of perinatal HIV transmission)  Pregnancy-related services to reduce the risk of sexual or perinatal transmission during recognized pregnancy  Other medical and social services that influence HIV transmission or use of HIV prevention and care services  Methods to monitor, evaluate, and improve the quality of HIV prevention and care services and programs for persons with HIV The vast majority of recommendations in this report pertain to persons with HIV, but a few relate to interventions for HIV-uninfected, sex or drug-injection partners of persons with HIV, and these interventions may be used by the partners to reduce their risk of acquiring HIV. # The recommendations consolidate  the latest guidance from several federal agencies published through May 2014  new evidence that supports this federal guidance  several entirely new recommendations and their supporting rationale Section 2, Methods, describes the methods used to consolidate this federal guidance, to identify new evidence supporting this guidance, and to develop new recommendations based on scientific evidence, program experience, and expert opinion. # This report does not include recommendations about  comprehensive primary care for persons with HIV 24  the prevention, diagnosis, and treatment of infections that are relatively common in persons with HIV but are not known to facilitate HIV transmission, such as viral hepatitis, some STDs, and most opportunistic infections 24,25  prevention of HIV transmission from infants or young children The primary audiences for this report include the following:  Clinical providers working in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments.  Nonclinical providers working in community-based organizations or health departments outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These providers include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, † † partner services specialists, ‡ ‡ case managers, and social workers.  Staff of health departments and HIV planning groups who provide population-level HIV prevention and care services, such as HIV surveillance or coordination of state and local HIV prevention and care resources. Secondary audiences for this report include persons with HIV, partners of persons with HIV, specialists in HIV/AIDS policy and law, funding, and service coverage and reimbursement for public and private sector health systems and community-based programs. These also include developers of HIV-related policies, government regulations, and legislation and managers of health insurance plans, medical assistance programs, and private and public health care systems that serve persons with HIV. By directing these recommendations to a wide range of health professionals and organizations, this report highlights both their unique and shared roles in carrying out individual-and population-level HIV prevention and care strategies. It also underscores opportunities for collaboration across clinical, nonclinical, and public health organizations. Collaboration and task sharing are especially needed as the number and lifespans of persons with HIV increases, more effective interventions are available, and shortages of trained HIV care and prevention providers persist. 1,29 Linkage to HIV medical care provides an example: health department HIV surveillance programs can identify populations or individuals with newly diagnosed HIV who may warrant help linking to HIV medical care, nonclinical HIV testing providers can help newly diagnosed clients schedule their first HIV care appointments, health care providers can request expedited scheduling, and HIV planning groups can promote HIV training for primary care physicians, physician assistants, and nurses. Sections 4 through 12 summarize each intervention topic using a similar format: background that defines the intervention and how it is delivered; a list of recommendations that are specific to provider type; examples of operational strategies, methods, or best practices to implement the recommendations; a summary of how the recommendations differ from previous federal guidance on this topic; methods used to assess federal guidance, published literature, or other sources of evidence used when developing the recommendations; a summary of evidence supporting the recommendations; a summary of issues that influence implementation of the recommendations; a link to a Web site that includes decision-support tools and other implementation resources (/ resources.html); and references. Section 13 describes quality improvement § § and program monitoring and evaluation * methods that can determine if interventions are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods. This report is published with 3 shorter summary documents that list the subset of recommendations for clinical providers, 30 nonclinical † † Linkage facilitators assist persons with HIV to access HIV medical care and other medical and social services through active methods (e.g., help with making appointments, providing transportation to appointments). ‡ ‡ Partner services specialists include specially trained disease investigation specialists, public health investigators, or communicable disease investigators who work in health departments and staff of other agencies who are trained and authorized to provide partner services. § § Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. * Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. providers, 31 and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. 32 Together these recommendations and implementation resources provide a national action plan to promote HIV prevention with persons with HIV. They can guide the daily work of clinical providers, nonclinical providers, and staff of health departments and HIV planning groups. They can inform HIV prevention policies, quality improvement initiatives, and resource allocation decisions. By galvanizing support and collaboration for HIV prevention activities across health systems, community organizations, and government agencies, these recommendations can reaffirm that prevention with persons with HIV is a cornerstone of HIV prevention in the United States. # Section 2. Methods These Writing groups had expertise in HIV-related public health; epidemiology; clinical medicine; behavioral and social science; health education; statistics; laboratory science; health policy; health equity; clinical quality improvement; † clinical and nonclinical interventions; program implementation, evaluation, and monitoring; and guideline development. Each member was required to be free of financial or intellectual interests that might pose a conflict regarding federal guidance about commercial products. Each writing group used a slightly different approach in evaluating federal government guidance (hereafter called "source guidance") or other evidence that might support recommendations because the extent of source guidance and primary scientific evidence varied by topic. Three CDC HIV specialists and two HIV information specialists conducted searches of published literature for nine of the eleven topics (all except the topics on context of HIV prevention and quality improvement and program monitoring). The searches were expanded to include guidance from federal agencies (CDC, HRSA, NIH, and the U.S. Department of Health and Human Services ) and two federally-sponsored organizations: the U.S. Preventive Services Task Force and the Community Preventive Services Task Force. The above systematic reviews were published in English from 2000 to 2011 and were included in the CDC HIV/AIDS Prevention Research Synthesis (PRS) Project's cumulative HIV/AIDS/STD prevention database. This database includes articles without language restriction that are indexed in EMBASE, MEDLINE, PsycINFO, Sociological Abstracts, and CINAHL. The information specialists searched articles indexed by MeSH terms or keywords related to three domains: disease (HIV, AIDS, or STD); study type (prevention, intervention, education, or evaluation); and outcome (behavior or other outcomes); details on the search terms are described in other documents. 1,2 The information specialists also searched systematic reviews published through 2009 that were cited in the Cochrane Database of Systematic Reviews and indexed with the following terms found in the title, abstract or keywords: (HIV infection OR Acquired Immunodeficiency Syndrome OR Sexually Transmitted Diseases) AND (Prevention OR Intervention). 3 The information specialists classified each identified article by one of the nine intervention topics. Each writing group sought additional information through narrative literature reviews that yielded guidelines from nongovernmental organizations in the United States, peer-reviewed journal articles, abstracts from HIV conferences, program evaluation reports, unpublished data from CDC, and policy and legal documents that had been published from 2000 to as late as July 2014. The Methods topic of each section describes these sources. Fourth, all 11 writing groups drafted recommendations that were based on the latest federal source guidance, recommendations, laws, regulations, or policies published through May 2014 and/or sources of scientific evidence, program experience, and/or expert opinion that were available through July 2014. Most recommendations simply restated the latest relevant source guidance that was based on scientific evidence, program experience, and/or expert opinion. Although some writing groups did not reexamine the evidence supporting recommendations in the source guidance, all groups evaluated evidence that had accumulated since publication of the source guidance to determine if the latest published recommendations warranted reconsideration. The writing groups consolidated and restated the recommendations from the source guidance instead of excerpting them verbatim. This rephrasing enabled use of a standard format that explicitly defined the recommendation's audiences and beneficiaries (that some source guidance had only implied). For example, "Recommendations for clinical providers: Advise patients to take antiretroviral treatment (ART) as prescribed." Roman numerals indicate the source guidance for each recommendation. Some writing groups also drafted new recommendations that extended a recommendation in the source guidance that was directed to one provider type to another provider type; this occurred when published evidence, program experience, or expert opinion indicated that another provider type could become authorized for and proficient at providing this service. For example, the section writing group on ART extended to nonclinical providers the current federal recommendation for clinical providers to inform patients that ART can reduce the risk of transmitting HIV because several experts and programs have found that nonclinical providers in community-based HIV service organizations and health departments can become proficient at providing this information. All recommendations that were extended from one provider type to another provider type are labeled with alphabetic superscripts. Some writing groups drafted new recommendations (which did not simply restate or extend recommendations from source guidance) when they identified scientific evidence with generally consistent findings, statistically significant differences between intervention groups and comparison groups; appreciable effect size; and/or consistent or extensive program experience. The writing groups did not combine primary data from more than one study using meta-analyses, direct comparison of effect sizes, or other quantitative methods, and they did not formally rate the quality of evidence. Some groups also considered information on the cost-effectiveness of interventions and expert opinions expressed in published literature or during the April 2011 consultation (described below). Writing groups used an informal consensus process without voting when developing new recommendations. 4 In general, recommendations about biomedical interventions (e.g., ART, STD screening), behavioral interventions (e.g., adherence, risk-reduction interventions), and structural interventions (e.g., referral ‡ to supportive housing services) were more likely to be based on evidence from controlled or observational studies, clinical case reports or series, or program evaluation data. Recommendations about program design, operations, or infrastructure (e.g., use of appointment reminders, collaboration agreements) were often based on program evaluations or expert opinion. Writing groups did not grade the strength of recommendations for two reasons: 1) many recommendations derived from source guidance had not been rated for strength or did not specify the supporting evidence; and 2) no single system was well-suited to rate a diverse set of recommendations pertaining to medical evaluation, drugs, devices, counseling messages, and program operations that were based on highly varied types of supporting evidence. All recommendations are listed in boxes with titles that include "recommendations" or "recommended." Some recommendations are linked to supplemental boxes that list operational strategies, implementation methods, or discussion topics. For example, the recommendation to screen for HIV risk behaviors is linked to a supplemental box that lists possible screening topics. Each section also includes information from systematic or narrative reviews regarding 1) progress, challenges, and opportunities in implementing the recommendations; 2) policy, legal, and ethical considerations; 3) implementation issues for special populations; and 4) a link to a Web site that includes decision-support tools and other resources to facilitate implementation of the recommendations (/ pwp/resources.html). The report does not include recommendations about future research needs because NIH's national HIV research agenda recently addressed many HIV prevention topics. 5 Fifth, the Project Workgroup solicited oral and written input on the draft recommendations and supporting evidence on many occasions from 2011 through September 2014. Reviewers included 1) participants at a 3-day consultation in April 2011 attended by 103 This report will be revised periodically as needed. # Section 3. The Context of Prevention with Persons with HIV: Essential Considerations for Providers Background Several broad, contextual issues shape the lives of persons with HIV and their ability to use HIV prevention and care services and adopt HIV prevention strategies. These include individual, social, structural, ethical, legal, and policy issues that influence access to, use of, and delivery of HIV prevention and care services. 1 Service providers who understand these contextual issues are better prepared to  share responsibility and decision making for HIV prevention with persons with HIV  communicate in a sensitive, respectful, and culturally appropriate manner  motivate persons with HIV to adopt realistic, evidence-based- prevention strategies  help persons with HIV obtain essential medical and social services  endorse the strategy of "treatment as prevention," in which services for persons with HIV contribute to community well-being  recognize how contextual factors influence HIV transmission in their communities  promote the development of community resources that offer prevention and care services This section makes general recommendations about these contextual issues. In Sections 4 through 12, the Issues that Influence Implementation of the Recommendations topic describes contextual issues related to specific interventions. Quality improvement † and program monitoring and evaluation ‡ can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). # Recommendations BOX 3. RECOMMENDATIONS-CONTEXTUAL ISSUES For nonclinical providers, clinical providers, and health department staff who serve clients, patients, or populations with HIV  Become familiar with  social and structural determinants of health that influence use of HIV prevention and care services (i, ii, iii, iv) (see Table 3-1)  federal, state, and local laws and policies that regulate the following issues (ii, iii, iv, v, vi, vii, viii): - rights, responsibilities, and protections of persons with HIV regarding disclosure of their HIV-infection status and the unintentional or intentional exposure of others to HIV - provider responsibilities regarding HIV case reporting, protecting confidentiality, obtaining informed consent for HIV services, avoiding discrimination, and any requirements to inform persons about possible HIV exposure  governmental and nongovernmental agencies that serve persons with HIV with various insurance and income characteristics and coverage and reimbursement policies (iii, v, ix) (see Table 3-2)  Support  partnerships between persons with HIV and their service providers that foster collaboration, communication, and a spirit of shared responsibility for HIV prevention and care that benefits individuals and the community (iii, v)  enrollment of persons with HIV in long-term health care coverage to hasten access to HIV treatment and prevention services a and to reduce health disparities (i, iii, x, xi)  the development of a skilled workforce and organization infrastructure to deliver, coordinate, and finance HIV prevention and care services (i, iii, v) (see Box 3-A)  strategies that reduce HIV health disparities and improve access to HIV prevention and care services (i, iii, ix) (see Box 3-A)  protection of confidential health information (i, ii, iii, iv, vi, vii, xii) (see Box 3-B)  Encourage  communication that does not stigmatize or negatively judge persons with HIV or their gender identity, sexual orientation, sexual and drug-use behaviors, and medical or social characteristics (i, ii, iii, iv, v, vi)  provision of information about rights and responsibilities of persons with HIV regarding confidentiality, privacy, protection from discrimination, and partner notification b (i, ii, iii, iv, xii)  planning by persons with HIV to notify exposed sex and drug-injection partners through partner notification assistance or self-disclosure that reflects an understanding of the benefits and risks of HIV disclosure in the jurisdiction (vi)  access to services and devices that improve the knowledge, ability, and motivation of persons with HIV to improve their health, protect the health of partners, and reduce transmission of HIV (i, ii, iii, vi) # BOX 3. RECOMMENDATIONS-CONTEXTUAL ISSUES (cont) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These persons include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the federal guidelines cited in the Recommendation boxes of each chapter may have been updated. For current federal recommendations, please refer to /. a Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. b Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. # Methods The section writing group based these recommendations on a narrative literature review of two sources: 1) reports in peer-reviewed journals published in English from December 2000-March 2014 that pertained to the United States and were indexed by using combinations of these terms: HIV, disclosure, privacy, confidentiality, Health Insurance Portability and Accountability Act (HIPAA), workforce, capacity, prevention, stigma, discrimination, barriers, structural issues, gender, poverty, social issues, ethics, collaboration, coordination, uninsured, and underinsured; and 2) reports, policy statements, and legal information about the above topics published on the Web sites of governmental and nongovernmental health organizations during this same period. This review included recent reports and recommendations of the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and the Institute of Medicine (IOM) about contextual issues influencing persons with HIV; laws and policies that affect the delivery of HIV prevention and care services; and shortages of HIV prevention and care providers. The writing group also obtained information on state laws, statutes, and regulations (hereafter referred to as "laws"), and legal review articles by searching 1) WestlawNext™ using the terms HIV; human immunodeficiency virus; AIDS; acquired immunodeficiency syndrome; sexual transmit disease; sexual transmit infection; communicable disease; venereal disease; CD4; T-lymphocyte; viral load; and nucleic acid; 2) the public Web site of a national HIV legal advocacy organization; 12 and 3) a 2014 systematic search of state HIV-specific criminal laws. 13 # Individual, Social, and Structural Issues that Influence Access to and Use of HIV Prevention and Care Services # The central role of persons with HIV Since the HIV epidemic was first recognized in the United States more than 30 years ago, persons with HIV have played an unprecedented role in drawing attention to the health and social burden of HIV, advocating for HIV prevention and care services, and mobilizing social and legal reforms. This commitment has served as a role model for personal empowerment and shared decision making that has improved access to and quality of services for HIV and other diseases. 14 Persons with HIV and the providers and public health organizations that serve them can create mutually beneficial partnerships that foster shared responsibility for HIV prevention and a common understanding that high quality patient care promotes both individual health and community well-being. 15,16 At the individual level, the concept of "prevention with persons with HIV" recognizes the rights and responsibilities of persons with HIV to make informed decisions about personal behaviors, to use HIV prevention and care services, and to set prevention goals that incorporate attitudes about infectiousness that do not imply blame. This concept encourages providers to listen to and respect the knowledge, beliefs, values, and cultural background of persons with HIV, to share information that is affirming and practical, and to engage in shared decision making. For example, providers serving persons with HIV who desire complete viral suppression prescribe the most effective ART adherence strategies, while providers may refer persons who inject drugs (PWID) but decline substance use treatment to legal syringe services programs § (SSPs). "Prevention with persons with HIV" may also focus on couples who jointly set HIV prevention goals, such as using condoms or supporting high adherence to ART. At the community level, "prevention with persons with HIV" encourages persons with HIV, health systems, health departments, community-based organizations (CBOs), and HIV planning groups to jointly design, implement, and evaluate HIV prevention and care services. 17 In recent years, persons with HIV have led many health, legal, financial, and social reforms that promote HIV prevention and care. These include developing a "patient bill of rights" that describes essential HIV prevention and care services for local health systems and education campaigns that champion "treatment as prevention," the use of ART to reduce the risk of transmission. 18 Working with health and social justice advocates, persons with HIV § Programs that provide free, new, sterile syringes and needles in exchange for used syringes and needles to reduce transmission of bloodborne pathogens among people who inject drugs. May be called syringe exchange programs or needle exchange programs. have mobilized supportive housing and peer education programs for persons with HIV; advocated for protection of confidential health information; and promoted legal unions of same-sex couples. # Individual, social, and structural factors In the United States, several populations bear a disproportionate burden of HIV infection:  Gay, bisexual and other men who have sex with men (MSM)  Black and Hispanic/Latino males and females  Adolescents and young adults, including those leaving foster care  Males and females using drugs, especially PWID  Males and females living in communities with high HIV prevalence  People who live in poverty or lack stable housing  Transgender females (persons whose assigned sex at birth was male but whose gender expression or identity is female) 22,23 The social and structural determinants of HIV infection are complex. They include poverty; unemployment; inadequate health care and health literacy; lack of affordable permanent housing; and stigma, inequality, and discrimination related to race, ethnicity, and sexual orientation. 24 These factors drive disparities in the burden of HIV and other health conditions and in the access, utilization, and quality of many prevention, care, and social services (see Table 3 -1). For instance,  some persons who are poor or suffer from mental illness cannot find stable, affordable housing that fosters high adherence to ART  some transgender persons fear being stigmatized by their health care providers  some minors are not aware they can receive services for HIV, sexually transmitted diseases (STDs), family planning, or substance use treatment without parental consent  some inmates who do not receive pre-release transition planning return to the community without an established HIV health care provider or adequate ART supply  some rural residents cannot find nearby health care providers who are skilled in treating HIV or substance use The 2010 National HIV/AIDS Strategy stressed the need for HIV prevention and care services for populations that bear the highest burden of HIV infection and for individuals with comorbidities and unique social needs. 23 Many governmental health and welfare agencies, health systems, and individual providers have developed programs and services that are directed to populations heavily affected by HIV. 25 Section 12, Other Medical and Social Services, describes services that can mitigate individual, social, and structural factors that impair use of HIV prevention and care services. # Ethical and legal issues that influence access to and use of HIV prevention and care services Since the early 1980s, federal and state governments have enacted several laws intended to protect the confidentiality, rights, and autonomy of persons with HIV; promote access to HIV prevention and care services; or prevent HIV transmission. Many relate to  authorized and unauthorized disclosure of HIV status  discrimination protections  autonomy in health decisions and rights to access prevention and care services Providers who are aware of these issues are better equipped to affirm the rights and responsibilities of persons with HIV, encourage safer sexual and drug-use behaviors, and fulfill their own legal and ethical obligations. These providers are also more likely to direct patients and clients to appropriate services, support public health practice, and foster mutual respect and cooperation between persons with HIV, their service providers, and their communities. # Authorized and unauthorized disclosure of HIV status by providers of prevention and care services Several federal and state laws protect the privacy and confidentiality of persons with HIV. These laws have taken on greater importance as health information and delivery of care have become more collaborative, integrated, and networked and as teams are more frequently used to manage the care of a person with HIV or other complex, chronic conditions. All 50 states and the District of Columbia require name-based reporting of HIV cases and laboratory test results that confirm HIV infection to health departments for HIV surveillance purposes. Most persons with HIV are legitimately sensitive about case reporting because of the risk of stigma, discrimination, and other adverse consequences of unintended HIV disclosure as well as reported cases of inadvertent and intended breaches of confidentiality. To protect confidentiality, all jurisdictions require health departments to collect, store, use, and transmit identifiable HIV-related information in a secure manner consistent with HIPAA and state laws. 26,27 CDC has issued standards for handling HIV surveillance data that minimize uses that might reveal the identity of persons with HIV (see Box 3-B). 5 This includes situations in which health departments use surveillance data to identify populations or individuals with HIV who have unmet HIV prevention needs. For example, HIV surveillance programs that track cases of HIV infection that are not followed by reported CD4 cell count test results (a marker of receiving HIV medical care) can identify populations that may warrant being offered assistance with linkage to HIV care, if allowed by the jurisdiction. 28,29 In jurisdictions in which surveillance data are used to support an individual's health care, case reports may prompt health department disease investigation specialists to help HIV testing providers link casepersons to HIV medical care. Also, in states that require reporting of a person's sequential CD4 cell count and viral load test results, health departments can identify persons who have declining CD4 cell Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). counts or increasing viral load levels and may warrant being offered more effective treatment or adherence support. 32 (See Sections 4, 6, 8, and 11 for recommendations about using HIV surveillance data to assess unmet HIV prevention needs.) A CDC toolkit describes strategies that HIV surveillance programs and health departments can use to promote HIV prevention and care, including ethical considerations when using confidential surveillance data. 33,34 HIPAA specifies standards to protect the confidentiality of individual-level, identifiable health information for electronic transactions initiated by health care providers, health plans, and health care clearinghouses. 35 These protections are especially important for persons with HIV because they  enable informed choices about how health information is used and shared  set boundaries on the use and release of health records  impose civil and criminal penalties on persons who violate patient confidentiality Since widespread implementation of HIPAA in 2003, many persons with HIV and their providers have reported greater trust in and acceptance of the security protections for HIV-related health information. 36 In some jurisdictions, health care providers, health plans, and health care clearinghouses covered by HIPAA may be required to disclose some confidential health information without an individual's authorization for a few specific purposes, including 35  conducting HIV-related surveillance, investigations, or interventions reporting abuse, neglect, or domestic violence that may involve HIV exposure  enforcing federal, tribal, state, or local laws and judicial and administrative proceedings related to HIV exposure In many states, additional regulations govern the transfer of HIV-related information from the patient's treating health care provider to another health care provider serving that patient; some state regulations are more stringent than those prescribed by HIPAA. 35 Additional federal laws also govern privacy protection of mental health and drug and alcohol treatment records. If state law and federal law conflict on matters of confidentiality, the law that best protects confidentiality applies. Use of confidential electronic medical records (EMRs) † † for managing patients with HIV has grown as a result of the Patient Protection and Affordable Care Act (ACA) and technology innovations. Once stripped of confidential information, data from these record systems can also be used for legitimate quality improvement and monitoring purposes, such as revealing gaps in the continuum of HIV care within medical practices and health systems. However, some providers who are not familiar with regulations that protect the confidentiality of paper-based and electronic records may be overly cautious about sharing or withholding information. In some cases, this may delay important care and prevention services, ‡ ‡ including initiation of ART. 37 For example, in some states, results of HIV tests conducted in 2 health care facilities that share EMRs are not accessible to patients' providers unless they work inside the facility that ordered the test. In other states, a quality improvement program in one health system † † An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. ‡ ‡ Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. cannot access HIV viral load results from one of its clinics, thereby precluding using viral load to estimate treatment effectiveness. 38 Some states have "duty-to-inform" laws that obligate or permit providers who know that a person has exposed another person to HIV to notify the exposed person. 39,40 Providers may also be required or permitted to disclose HIV-related information to law enforcement authorities when required for legal proceedings. # Voluntary disclosure by persons with HIV State laws about HIV disclosure vary in scope and degree of enforcement. Many require that persons with HIV notify their sex or drug-injection partners, including spouses, after they have received an HIV diagnosis. Partner services specialists in many health departments offer voluntary, confidential assistance to persons who want help notifying their partners. 41 Voluntary disclosure of HIV infection status to providers has many potential benefits. It can foster open communication and well-informed, shared decision making about HIV prevention and care goals, and facilitate access to medical and social services that can improve health and reduce HIV transmission. 16 Disclosure to partners may enhance intimacy and psychosocial well-being and prompt frank discussion about using condoms, contraception, or sterile drug-injection equipment. Disclosure to family and friends can engage support for ART adherence or managing psychosocial problems. 42 Disclosure can also empower persons with HIV to openly collaborate with organizations that seek input from persons with HIV 17 (see Section 7, Risk Screening and Risk Reduction, and Section 8, Partner Services, for recommendations about HIV disclosure to partners.) However, disclosure can also lead to negative outcomes, such as physical or verbal abuse, dissolution of relationships, criminal or civil sanctions for HIV exposure, or job discrimination for health care providers with HIV. 43 Providers can take several steps to help patients and clients support safe, selective disclosure. They can review the health and psychosocial benefits of self-disclosure and describe effective disclosure strategies, such as choosing a safe, secure place to make the disclosure; offering partners information about where to obtain HIV testing; and anticipating and managing negative reactions. 37 They can also help persons engage partner notification § § assistance from health department specialists who are trained to assess risk of partner physical or verbal abuse. They can also provide information about local laws on voluntary disclosure and make referrals* to legal professionals who can understand specific legal consequences of disclosure in the jurisdiction 44 (see Section 8, Partner Services). # Discrimination protections for persons with HIV The Americans with Disabilities Act (ADA) protects HIV-infected persons, including those without AIDS-defining conditions, from discrimination in employment, housing, education, health care, and other settings. 45 By guarding against discrimination in housing and employment, the ADA can foster more § § Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. stable housing, income, and lifestyles that encourage safe behaviors and sustained access to HIV medical care and ART. 45 Despite the privacy, confidentiality, and discrimination protections promised by ADA, HIPAA, and other regulations, many persons with HIV choose not to disclose their infection to others or forbid others to disclose this information because they fear stigma, abuse, prejudice, discrimination, deportation or criminal prosecution. 42,46 Although experts have long known that HIV cannot be transmitted through casual contact, concerns that persist even among health care personnel can provoke negative reactions. 47 HIV-related stigma can compound stigma related to sexuality ("homophobia" or "transphobia"), substance abuse, race, ethnicity, and other characteristics that many populations heavily affected by HIV already face. Prejudice may manifest as anger, physical or verbal abuse, offensive nonverbal cues, or social marginalization that devalues or discredits persons with HIV. 47 This may cause psychological distress, depression, and other mental health problems that may erode safe behaviors, encourage substance abuse, or lead to immunosuppression. 48,49 Social isolation may make it difficult to engage friends and family in supporting risk-reduction or ART adherence goals. Some persons who wish to avoid real or perceived stigma or discrimination may defer HIV testing, care, and prevention services. 49,50 Other persons with HIV may be denied medical or dental care, experience indifferent or substandard health care, or face housing or employment discrimination. 47 Yet others may decline to carry sterile drug-using equipment or condoms in public settings if they fear that possession may increase the risk of charges of illegal drug use or commercial sex work. 51,52 # Implications of not disclosing HIV infection status Between 1986 and 2011, 33 states enacted HIV-specific laws that could be used to impose criminal penalties on persons who knowingly expose others to HIV. 13,53 These laws are controversial and have been subject to intense public debate. Most were passed before 2000, a period when the use of ART to reduce HIV-related disease and HIV transmission was less prevalent. Of these 33 states, 27 specifically criminalize behaviors that pose a high risk of HIV transmission, including anal or vaginal sex, prostitution, and donating blood, tissue, or body fluids. Additionally, 25 states have laws that criminalize behaviors that pose negligible or no risk of HIV transmission, such as spitting or biting. Many of the 33 states specifically criminalize behaviors when persons have not disclosed their HIV infection to sex partners (24 states) or drug-injection partners (14 states). Few of these laws allow defendants to claim use of ART, condoms, or other prevention measures in their defense against criminal liability. 13 In 28 of these 33 states, violations of HIV-specific criminal laws are classified as felonies and prison sentences can range from 1 to 20 years. 13 In 3 states that do not impose criminal sanctions for HIV exposure, a person's infection status may increase the severity of sentencing or be considered an aggravating factor if the person is prosecuted for a related crime. 13 Some states have also used general criminal laws (e.g., assault, battery, reckless endangerment, or communicable disease laws) to prosecute persons accused of exposing others to HIV. 53,54 National databases cannot readily estimate the number of state-level prosecution, arrests, or plea agreements related to these HIV-specific criminal laws. However, one evaluation of 186 arrests or prosecutions related to HIV from 2008 to January 2014 found that about 80% occurred under such laws. 55 Many HIV criminalization laws were enacted with the expectation that awareness of these laws would encourage persons with HIV to disclose their infection status and avoid behaviors that would result in HIV exposure. 13 However, studies have shown that many persons with HIV are unaware of HIV disclosure requirements and exposure laws until they are notified by a provider and that 25%-50% of persons with HIV served by community-based organizations may not be aware of HIV criminalization laws in their state. 57,58 Health professionals and staff of health departments can play a valuable role in informing persons with HIV about legal requirements about disclosure and referring clients and patients to legal resources if prosecution is possible; however, they cannot provide legal counsel. 26 These professionals can also help persons to engage health department partner notification assistance (especially if physical or verbal abuse is possible) and to prevent exposing others to HIV in the future. The impact of HIV criminalization laws on HIV disclosure, use of health department partner services, † † † or HIV transmission is not known. However, several studies have concluded that these laws may not deter HIV risk behaviors ‡ ‡ ‡ and may cause significant or unintended harms. Harms may include resistance to HIV testing and self-disclosure or forcing persons to choose between the risk of prosecution for undisclosed sexual HIV exposure and the risk of intimate partner violence after disclosing their HIV infection. For these reasons, the 2010 National HIV/AIDS Strategy (NHAS) stated that it may be appropriate for legislators to consider if existing criminalization laws in their jurisdictions advance the public's interest and health. 23 Some health policy experts have proposed revising these laws to limit prosecution to persons in whom intent to harm (e.g., sexual assault) or high risk of intentional transmission has been demonstrated (e.g., practicing prostitution without using condoms). 53,54,61,62 Autonomy in health decisions and rights to access prevention and care services The principles of autonomy in health care decisions and informed consent are fundamental to providing HIV prevention and care. Persons with HIV have the right to accept and decline prevention and care services, even if these services might lower their risk of exposing others to HIV or their infectiousness. For example, the U.S. Department of Health and Human Services (HHS) recommends that ART be offered to all persons with HIV to treat and prevent HIV-related disease and to reduce the risk of HIV transmission but only be prescribed to those who are ready and willing to adhere to the regimen on a long-term basis. 63 Health department partner notification services are also strictly voluntary. 3 In most states, minors may consent to HIV-related services, STD testing, and reproductive health services without parental consent. 41,64 Many low income persons with HIV obtain free or subsidized care through Medicare, Medicaid, and the Ryan White HIV/AIDS Program based on income, disability, or other characteristics. Increases in insurance coverage prompted by the ACA, increased eligibility for Medicaid for low-income persons in many states, and continued funding of flagship HIV care programs, such as the Ryan White HIV/AIDS Program (described below), are expected to improve access to HIV prevention and care services. 65 However, demand for government-funded services may outstrip available resources in the short-term as the number of persons living with HIV increases, more effective treatment increases their lifespans, and † † † Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. ‡ ‡ ‡ Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). socioeconomic disparities in the burden of HIV persist. This situation raises ethical questions about rights to health care if persons with HIV do not receive basic prevention and care services or receive them only after harmful delays. For example, until 2014, many states were unable to provide subsidized ART to all eligible persons due to long waiting lists for the AIDS Drug Assistance Program (ADAP). 66 Some clinical settings § § § are unable to promptly offer HIV medical care to all recently diagnosed persons because of appointment backlogs, lack of qualified health care providers, or delays in patient enrollment in health insurance or medical assistance programs. Some health departments that handle a high volume of HIV case reports cannot promptly offer partner services to all newly diagnosed persons when staffing for this core public health service declines. 71 # Laws, Regulations, Policies, and Programs that Promote Delivery of HIV Prevention and Care Services Several federal and state laws, regulations, policies, and programs promote delivery of prevention, care, or social services to persons with HIV. Providers who are familiar with these issues are better equipped to help their clients and patients navigate a complex patchwork of service providers and leverage resources to secure needed services. # Governmental and nongovernmental policies and programs that provide or fund prevention and care services for persons with HIV Many governmental and nongovernmental policies and programs determine the funding or infrastructure for delivering HIV prevention and care services. The NHAS described several essential elements of HIV prevention and care that favor more holistic, comprehensive care, reduce gaps in the continuum of HIV care, and reduce the burden of HIV in the communities where the infection is most prevalent. 23 The NHAS encourages HIV prevention and care providers to use evidence-based strategies to provide services, including the following: 77 The ACA encourages states to enroll persons with HIV and other chronic conditions who are eligible for Medicaid into "medical homes" that use teams of providers to coordinate comprehensive care and engage patient support services. 73,78,79 This approach is intended to increase attention to primary care and prevention, communication and service coordination between providers, financial efficiencies, adoption of standards of care, and use of integrated EMRs. 73, HRSA is seeking to expand the successful "HIV medical home" used in Ryan White-funded clinics by offering training in HIV care, treatment, prevention, HIV-related mental health, and cultural competency to health centers without this expertise. 81 Several states have recently specifically expanded opportunities for "medical homes" for persons with HIV. 82 Many state and local health agencies and HIV planning groups are monitoring HIV service delivery, health outcomes, and coverage policies in their jurisdictions to identify coverage gaps during this transition and advocating for relevant coverage expansion. 80 Despite anticipated improvements in HIV services due to ACA implementation, several troubling gaps in access to HIV prevention and care services persist and may delay implementation of recommendations in this report. 73,78,83 73,85 Immigrants who are not citizens and do not meet these residency requirements can receive care through other federal and state HIV assistance programs that do not specify eligibility requirements related to immigration status if they can provide required enrollment documentation. 86 Until these many gaps are closed, the Ryan White HIV/AIDS Program, ADAP, and other "safety net" programs will continue to provide essential HIV services and cover the cost of copays, deductibles, and other noncovered expenses for many persons with HIV.  Early # Strategies to expand the HIV prevention and care workforce The demand for skilled HIV prevention and care providers in clinical settings and nonclinical settings † † † † will grow over the next decade as the number and lifespan of persons with HIV increase, persons with HIV seek services in new settings, and options for prevention and care services expand. 23 The IOM recently cautioned about the national shortage of skilled HIV prevention providers and called for 10  training primary care medical providers, including those who will provide HIV services under ACA-related Medicaid expansion, in HIV prevention and care services  developing a new cadre of HIV medical specialists who can replace retiring specialists  aligning health department resources to maximize HIV prevention and care services after recent budget cuts In the face of these challenges, the IOM recommended that health departments, primary care providers, and others advocate to increase the number of HIV providers and to train non-HIV specialists in HIV care and treatment. IOM also recommended shifting some tasks across provider levels, e.g., physicians could share some ART adherence support functions with physician assistants, advance practice nurses, registered nurses, pharmacists, and health educators. 87 Multidisciplinary clinical teams can form within a single practice or health system or within networks of service providers who practice locally or through remote, telemedicine services. ‡ ‡ ‡ ‡88 The Ryan White HIV/AIDS Program's experience with comprehensive HIV services through "medical homes" provides valuable lessons about provider networks that other prevention and care providers could apply. Use of effective and cost-effective interventions and evaluation processes that monitor intervention delivery and outcomes may also encourage more judicious use of providers' time. To build the capacity of health care providers serving persons with HIV, HRSA and CDC support regional training centers across the U.S. that offer training in the prevention, diagnosis, and management of HIV and STD. 89,90 Nonclinical HIV prevention providers in community-based organizations and health departments will continue to lead crucial HIV prevention and care programs. These organizations have provided HIV testing, risk-reduction interventions, and partner services for decades; many are now helping persons with HIV to engage in HIV medical care and support ART adherence with funding from CDC and other sources. 6 For example, one state health department is tracking case-specific CD4 cell counts and viral load measures reported to HIV surveillance as a means to identify persons who have had lapses in HIV medical care and may warrant help to resume care. 31 HIV planning groups can foster the development of a skilled HIV prevention and care workforce by supporting training programs, adequate provider reimbursement for HIV services, and use of the most effective and cost-effective interventions. 91 # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at . † † † † Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. ‡ ‡ ‡ ‡ Telemedicine services involve the use of telecommunications technology to provide, enhance, or expedite health care services or to provide consultation, training, and mentoring to health care professionals. # Section 4. Linkage to and Retention in HIV Medical Care Background A growing body of evidence indicates that early initiation of HIV medical care and antiretroviral treatment (ART) and sustained high adherence to ART improve health outcomes and survival rates and can prevent HIV transmission (see Section 5,Treatment). Starting HIV medical care shortly after diagnosis and sustaining long-term care also provides opportunities to offer risk-reduction interventions, partner services,- sexually transmitted disease (STD) services, and other services to prevent HIV transmission. Some studies show that persons who stay in care during their first year of outpatient HIV medical care are more likely to start ART than persons with early lapses in care, have high adherence to ART, achieve virologic suppression, and practice safer sexual behaviors. 3,7,20,21 A meta-analysis of studies published from 1996-2009 found that about 25% of persons who tested positive for HIV did not start HIV medical care within 6 months after their first positive test result. This analysis also revealed limited retention in care: only 69% of persons who tested positive had two or more visits during the 6 months after diagnosis; only 61% had at least one visit every 6 months during the 18-24 months after diagnosis; and only 26% had at least one visit per year during the 3-5 years after diagnosis. 22 and often involve tracking outcomes, such as completion of scheduled visits. 24 Linkage strategies can operate at the patient, facility, or system level and often require formal coordination* and collaboration † † † among nonclinical providers, clinical providers, health systems, and health departments that provide HIV testing or other HIV services. 25,26 Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § § § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 4. RECOMMENDATIONS-LINKAGE TO AND RETENTION IN HIV MEDICAL CARE For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Establish infrastructure to support starting HIV care (within 3 months after diagnosis), long-term retention in care, and resuming care after a lapse a,b (i, ii, iii, iv, v, vi) (see Box 4-A)  Inform persons about the benefits of starting HIV care and antiretroviral treatment (ART) early (even when feeling well) and staying in care for personal health and to prevent HIV transmission, before HIV testing is offered and when providing preliminary or confirmatory HIV positive test results (v, vi, The Methods topic in this section describes the sources of evidence that identified these barriers and intervention components. a Case management is a service generally provided through an ongoing relationship with a client or patient that includes comprehensive assessment of medical and psychosocial support needs, development of a formal plan to address needs, provision of assistance and advocacy in accessing services, and monitoring of service delivery. b Navigation assistance is the process of helping persons obtain timely and appropriate medical or social services given their preferences about providers, insurance status, scheduling issues, and other factors that may complicate access to or utilization of services. Note. This box includes only selected steps and strategies among many that may be available. See the Evidence topic in this section for more information. # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with guidance from the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and the U.S. Department of Health and Human Services (HHS) that recommend that persons be linked to services shortly after a positive HIV test. 6,11,26, However, the recommendations in this section provide  greater emphasis on proactive linkage and retention strategies instead of passive referral methods  greater emphasis on starting care within 3 months after diagnosis because of the benefits of starting ART regardless of CD4 cell count  strategies for health departments to establish infrastructure and services that support linkage to and retention in care, if allowed by their jurisdictions (e.g., use of surveillance data)  more detailed guidance on evidence-based methods to support linkage to, retention in, and reengagement in HIV medical care The recommendations are also generally consistent with the latest comparable recommendations about linkage to and retention in care of these nongovernmental organizations: the International Association of Physicians in AIDS Care; 38 the HIV Medicine Association of the Infectious Diseases Society of America; 39 and the International Antiviral Society-USA Panel. 4,15 # Methods The section writing group based these recommendations on several sources of federal guidance, scientific evidence, and programmatic experience:  Previously # Evidence Supporting the Recommendations # Linkage to HIV medical care # Barriers to linkage to care The systematic review 40 and other studies identified several barriers to linkage to care (see Box 4-B). # Interventions to promote linkage to care # Evidence from the systematic literature review This review identified 6 studies that reported linkage to care outcomes. 40 Five studies evaluated linkage assistance for persons diagnosed with HIV during the previous 12 months in health departments, clinics, and community-based programs in large cities. 43, All 5 found that 78%-92% of participants had their first HIV care visit within 3-6 months after receiving linkage assistance. Four intervention components significantly improved linkage to care (as compared with the reference group) or were likely to result in initiation of care (for observational studies). These components included: 1) motivational and strengthsbased counseling tailored to a person's strengths, barriers, and needs; 2) assistance in navigating the health care system; 3) linkage to an HIV care site at the same location where the HIV diagnosis was made or transportation assistance to the care site; and 4) other medical or social services, such as substance use treatment, mental health services, child care, food vouchers, or emergency financial assistance. 40  One of these 5 studies was ARTAS, an RCT conducted in 4 cities from 2001-2003. 43 Participants recruited from health department testing sites, STD clinics, hospitals, and community-based organizations were randomized to receive 1) one to five motivational, strengths-based case management sessions over 90 days that allowed time to build rapport and that focused on identifying personal motivations for starting HIV care (e.g., desire to protect health) and overcoming barriers to starting care (e.g., helping to make appointments, accompanying at the first visit, providing transportation assistance, or helping to enroll in health insurance); or 2) information about local sources of HIV medical care. Participants who received the case management sessions were significantly more likely to attend at least 1 visit within 6 months after enrollment than participants who received information only (78% vs. 60%; adjusted relative risk 1.36, p=0.0005). 43  Four observational studies evaluated the outcomes of various types of linkage assistance. Most newly diagnosed persons started HIV care within 3-6 months after receiving assistance:  79% of persons who received motivational, strengths-based case management sessions (as described by ARTAS study above) in clinical, nonclinical, or health department settings. 58  87% of African American or Hispanic gay, bisexual, or other men who reported sex with men (MSM) aged 13-24 years and who received the following services from staff of health departments, community-based organizations, or universities: counseling and psychosocial support, appointment reminders, and transportation to visits. 59  90% of persons who received the following services from peer and nonpeer outreach workers, case managers, or nurses: counseling tailored to their individual barriers; riskreduction information; rapport-building phone calls and meetings; coordinating and accompanying at visits; and coordinating and making referrals for other medical and social services. 57  92% of persons who received brief sessions led by linkage facilitators that addressed psychosocial, financial and structural barriers to starting HIV care, and provided information on HIV, HIV-related stigmatization, and how to obtain health insurance and housing. 60  The sixth study in the systematic review evaluated linkage services at community-based, HIV education and testing sites in California where outreach workers encountered persons with HIV who did not report receiving HIV medical care. 61 On average, clients were offered linkage assistance 18 months after HIV diagnosis. Only 29% started HIV care within 15 months after receiving linkage assistance. Of those who started HIV care, clients had their first visit an average of 33 months after diagnosis. The low linkage rates in this study contrast with the high linkage rates in the 5 studies described above that offered linkage assistance within 6-12 months after diagnosis. # Evidence from the Best Practices Compendium Two studies met criteria for "best practices": the ARTAS study 43 described above and Project Connect from Birmingham, Alabama 54 (the study was published in 2008 in a journal that was not included in the systematic review). In Project Connect, linkage facilitators invited persons with newly diagnosed HIV to an orientation visit at an HIV outpatient clinic. Facilitators aimed to build rapport with patients, gathered information about patients through semi-structured interviews and psychosocial assessments, collected laboratory test specimens, and initiated referrals for conditions that might deter HIV care (e.g., substance abuse and mental health services). A significantly higher proportion of patients attended a comprehensive HIV care visit within the next 6 months compared with the period before the clinic had implemented this program (81% vs. 69%, p<0.01). # Evidence from modeling study A cost-effectiveness study compared the effectiveness of linkage interventions with the prevailing standard of providing contact information for local HIV clinics using data on per-client costs from the ARTAS intervention. 43 It found that the linkage interventions to prevent HIV transmission were costsaving compared with the prevailing standard 44 and that the intervention cost per new case of HIV averted (~$270,000) was substantially lower than the lifetime cost of HIV treatment (>$400,000). 62 # Retention and reengagement in HIV medical care # Barriers to retention in care The systematic review 41 and other studies identified several barriers to retention (see Box 4-B). # Interventions to promote retention in care # Evidence from the systematic literature review This review qualitatively examined 13 multifaceted interventions. 41 Four studies were RCTs, 7 compared retention before and after receipt of retention assistance, and 2 observed retention in care after assistance was offered. The review found that persons who received multifaceted interventions were more likely to stay in care than those not receiving assistance, but none of the studies assessed the independent effect of specific intervention components. 41 Ten of the 13 studies identified intervention components that were associated with increased retention in care: strengths-based case management, navigation assistance (e.g., appointment coordination), accompanying persons at visits, transportation assistance, colocating HIV medical care and social services in the same facility, bilingual/bicultural health care teams (for Hispanic/Latino patients), messages about the importance of retention in care during medical visits, HIV-related posters and brochures in clinics, regular reminder calls, and tailored HIV education and support through phone calls, home visits, or other outreach methods. Of the 4 RCTs in this systematic review, only the one that used strengths-based case management showed a strong effect on retention. 58 One RCT found that motivational interviewing provided by peer outreach workers (who had similar demographic characteristics to their clients) working in community sites or clinics yielded similar retention outcomes as motivational interviewing provided by health care providers. 63 However, an RCT that evaluated rental housing assistance for persons without stable Colocating is the provision of more than one type of HIV service in the same physical space, such as providing substance use treatment in an HIV medical clinic or providing HIV partner services in an HIV testing site. housing 64 and an RCT that evaluated peer mentoring for persons who inject drugs (PWID) through group discussion and video presentations did not appreciably improve retention in care. 65 # Evidence from the Best Practices Compendium Eight intervention studies met criteria for "best practices" for improving retention in care: four were RCTs and four compared retention outcomes before and after the intervention was implemented. Five of these studies were included in the systematic review of retention interventions, 41 of which one was an RCT (ARTAS, 43 described above) and four used "before-after" comparison designs. The 4 RCTs were the following:  An RCT evaluated retention outcomes in 4 clinics during 2001-2003. Participants who received motivational, strengths-based counseling from a case manager were significantly more likely to continue HIV care (defined as at least 2 visits over 12 months) than participants who only received information about where to obtain HIV care (64% vs. 49%, adjusted relative risk 1.41, p=0.006). 43  An RCT in 6 HIV clinics evaluated retention of patients who received 1 of 3 interventions: 1) enhanced contact (brief face-to-face meeting with clinic staff when returning for care, appointment reminders, phone calls between scheduled visits, and calls about missed visits); 2) enhanced contact (as described above) plus skills building in organization (e.g., appointment calendars), problem solving, and communicating with health care providers; or 3) the clinic's prevailing standard of appointment reminders provided by staff or audio recordings. Patients who received enhanced contact or enhanced contact plus skills building had a 22% higher number of visits attended and 6%-8% relative improvement in visits attended over 12 months, when compared with patients who received only appointment reminders. 70  An RCT evaluated a clinical decision-support system in a large HIV clinic practice that generated alerts in electronic medical records (EMRs) † † † † that notified HIV care providers of gaps in follow up visits, laboratory evidence of virologic failure, and adverse events. Alerts on the EMR home page, patient-specific EMR, and biweekly emails included key clinical information and expedited ordering of lab tests and scheduling follow-up visits. Over the 12 month follow-up period, patients of providers who received alerts had a lower rate of suboptimal retention in care over 6 months than patients of providers who did not receive alerts (20.6 vs. 30.1 events per 100 patient-years, p=0.022). 71  A buprenorphine treatment study evaluated opioid-dependent patients in an HIV primary care clinic. Intervention patients received directly observed buprenorphine treatment (BUP) 3 times a week and supplies to last until their next visit, individual counseling, and urine drug testing. Control patients were referred for community-based opioid replacement therapy and intensive case management services. Over the 12-month follow-up period, patients who received directly observed BUP had significantly more HIV care visits than control patients (median, 3.5 vs. 3 visits, p=0.047). 72 † † † † An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. # Evidence from a modeling study A cost-effectiveness study compared the effectiveness of retention interventions with the prevailing standard of scheduling follow-up appointments, using data on per-client costs from the ARTAS trial. 43 It found that retention interventions to prevent HIV transmission had a cost per quality-adjusted life-year gained of $13,460 when compared with scheduling follow-up appointments. 44 It also estimated that the intervention cost per new case of HIV averted (~$478,000) was similar to the lifetime cost of HIV treatment (>$400,000). 62 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Data on linkage to and retention in care collected through 2009 (described in the Background topic above) may not reflect patterns of care since 2012, the year HHS recommended starting ART regardless of CD4 cell count and when the Patient Protection and Affordable Care Act (ACA) expanded health insurance options for persons for HIV. 73 Linkage and retention rates are likely to improve as more persons with HIV become aware of the health and prevention benefits of early ART and become enrolled in health insurance or medical assistance programs. Improving linkage and retention will also require a cadre of trained professionals and peers to provide linkage and retention assistance; this assistance can be particularly beneficial for populations that are uninsured or live in communities with limited or fragmented HIV medical services (see Box 4-A and Section 3, Context of Prevention). Enabling billing and reimbursement for linkage and retention services can encourage providers to offer these services. Some health systems and health departments are exploring strategies for third-party reimbursement for these services. 74 # Policy, legal, and ethical considerations Providing linkage and retention services usually requires sharing HIV test results and other identifiable health information between agencies; this process must protect the confidentiality of persons with HIV and comply with health information security standards, including the Health Insurance Portability and Accountability Act (see Section 3, Context of Prevention). CDC provides guidance on how health departments might use HIV surveillance data (e.g., dates of HIV diagnosis, first and follow-up CD4 cell count test results and viral load test results) to identify persons who might benefit from linkage or retention assistance, if allowed in their jurisdictions. 23,27,75,76,78 # Special populations Many individual and contextual factors may impair the use of HIV medical care (see barriers noted in Box 4-B). Interventions to promote linkage may have less impact for persons who use drugs or suffer from depression 79 and retention interventions may be less effective for patients who are young, lack health insurance, 50,83 are homeless, 84 or use drugs. 85 Linkage and retention services that are tailored to such special circumstances may be more acceptable and effective. Examples include the following:  Adolescents concerned about stigma, inability to access confidential HIV care if uninsured or insured by parents, or unwanted disclosure of HIV infection status to parents can benefit from linkage to providers who do not require parental consent and who provide free or low cost services and reassurance about the confidentiality of HIV services 48  Transgender persons can benefit from linkage to providers who are familiar with the unique medical and psychosocial concerns of these individuals 49,86,87  Substance users can benefit from enrolling in treatment programs that encourage structured lifestyles that foster attendance at scheduled visits 88-93  Immigrants can benefit from help to secure documents needed to start care (e.g., employment verification, Social Security number); linkage to providers who serve immigrants under ACAapproved insurance plans, the Ryan White HIV/AIDS Program, medical assistance programs, or specialty clinics; 73,94 and information about whether seeking HIV care may threaten job security or prompt deportation or legal actions  Inmates can benefit from reentry planning to enable continuous HIV care after release  Women of reproductive age can benefit from information and reproductive health counseling about ART regimens that are safe and tolerable during and after pregnancy, and options for free, subsidized, or otherwise affordable ART # Implementation Resources Examples of best practices for linkage, retention, and reengagement and materials to support implementation of these recommendations are found at . # Section 5. Antiretroviral Treatment for Care and Prevention Background Antiretroviral treatment (ART) refers to treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication. Current federal HIV treatment guidelines and other studies recommend ART for all persons with HIV, regardless of CD4 cell count, - to improve their health, prolong their lives, and reduce their risk of transmitting HIV to others. The initial and regular follow-up clinical visits that are required to prescribe and manage ART also provide opportunities to reinforce risk-reduction messages and to provide other care and prevention services. † To maximize the individual and public health benefits of ART, sustained high adherence is essential. 3 This section covers several aspects of use of ART for personal health benefits and preventing HIV transmission; however, it does not provide comprehensive recommendations on managing patients who are eligible for or who are using ART found in other federal guidance. 3,4 This section also addresses informing persons with HIV about antiretroviral medications that HIV-uninfected partners may take to reduce their risk of HIV acquisition, if clinically indicated; it does not provide comprehensive recommendations on prophylaxis for HIV-uninfected persons found in other federal guidance. 5,6 Quality improvement ‡ Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 5. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT FOR CARE AND PREVENTION For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Inform all persons with HIV about the following issues regarding antiretroviral treatment (ART) (i.e., treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication) a (i, ii) (see Box 5-A):  The health benefits of early initiation of ART, including - improving or maintaining health when compared with later initiation of ART - prolonging lifespan - reducing risk of HIV transmission to others b  The limitations of ART, including - the need for lifelong treatment - the need for high adherence - potential medication side effects - the use of ART substantially reduces, but may not eliminate, the risk of HIV transmission  Inform all persons with HIV (and any of their HIV-uninfected partners referred for evaluation) about the following HIV prophylaxis issues c,d (iii, iv) (see Box 5-B):  The availability of preexposure prophylaxis e (PrEP) and nonoccupational postexposure prophylaxis f (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  Names and locations of health care facilities where HIV-uninfected partners can be evaluated for prophylaxis indications, and assisting with accessing these services, when feasible  Use of these regimens may reduce, but may not eliminate, the risk of HIV acquisition # Specific to clinical providers (in addition to above recommendations)  Offer ART (according to U.S. Department of Health and Human Services recommendations), regardless of patient's CD4 cell count, for the following purposes (i, ii):  To treat and prevent HIV-related disease  To reduce the risk of transmitting HIV  When prescribing ART, provide information to ensure that patients understand the following (i, ii):  Expected benefits and risks to personal health  Expected reduction in HIV transmission risk  Need for sustained high adherence to ART, long-term follow-up, and retention in care  Importance of committing to initiating or resuming lifelong, uninterrupted ART  Hazards of sharing their ART with others (e.g., HIV-uninfected partners seeking antiretroviral medication for prophylaxis) g  Use of ART is voluntary and patients can decline ART without risk of being denied medical and social services  For patients who choose to postpone or discontinue treatment, periodically reoffer ART after informing them of the benefits and risks of currently recommended regimens based on experiences of other patients with similar viral load and immune status (i,ii) # BOX 5. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT FOR CARE AND PREVENTION (cont) For staff of health departments and HIV planning groups who provide population-level HIV prevention and care services  Support efforts to increase access to HIV medical care and affordable ART through the following (v, vi, vii, viii, ix) (see Box 5-C):  Direct interventions with staff, contractors, and programs  Partnerships with public and private sector health systems # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to . a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup and recent program experience, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b The U.S. Food and Drug Administration (FDA) had approved the use of antiretroviral medication for treating HIV-infected persons. The cited source guidance recommends use of ART for HIV treatment and for reducing the risk of HIV transmission. c In July 2012, FDA approved one PrEP regimen (tenofovir/emtricitabine) for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. d The cited source guidance advises health care providers to inform HIV-uninfected persons about these interventions, but does not address the role of health care providers in informing HIV-infected persons about the use of PrEP or nPEP for their uninfected partners. e PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 f nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 5 g Information described in the Implementation topic in this section supports this statement. # Sources i. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with the most recent federal guidance on ART and the prophylactic use of antiretroviral medications to reduce the risk of HIV acquisition by partners of persons with HIV. They are also consistent with nearly all of the latest comparable recommendations about using ART for treatment and prevention from the HIV Medicine Association of the Infectious Diseases Society of America; 7 and the International Antiviral Society-USA Panel. 8,9 However, these recommendations differ in several ways from those in the 2003 Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. 10 This report recommends that  clinical providers offer ART to all persons with HIV, regardless of CD4 cell count, for both their own health and for reducing the risk of HIV transmission, according to the most recent U.S. Department of Health and Human Services (HHS) treatment recommendations 3  clinical providers and nonclinical providers inform persons with HIV about  the benefits of ART for their own health, prolonging lifespan, and reducing the risk of HIV transmission  the limitations and risks of ART, including that use of effective ART substantially reduces, but may not eliminate, the risk of HIV transmission  options to obtain ART and cover and minimize costs of ART  the availability of two different prophylactic regimens of antiretroviral medications, preexposure prophylaxis (PrEP) † † and nonoccupational postexposure prophylaxis (nPEP), ‡ ‡ for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition § § # Methods The section writing group based these recommendations on current guidance from HHS 3 and the Health Resources and Services Administration (HRSA) on the use of ART 3,4 and current guidance from HHS on the use of nPEP and PrEP for HIV-uninfected partners of persons with HIV. 5,6 This federal guidance was based on a large body of scientific evidence, including randomized controlled trials (RCTs) (see the Evidence topic). The writing group also reviewed a systematic review and meta-analysis of the relation of viral load and sexual HIV transmission, 1 a meta-analysis of the influence of ART on sexual behavior, 11 and the latest nongovernmental recommendations of the International Antiviral Society-USA Panel 9 and the HIV Medicine Association of the Infectious Diseases Society of America. 7 The writing group also considered information about the role of ART on HIV transmission, acute HIV infection, and ART resistance identified during a narrative literature review of peer-reviewed studies and abstracts of HIV conferences published in English from January 1996 through May 2014. The recommendations to health departments and HIV planning groups were based on recent federal guidance about population-level strategies to increase access to HIV medical care and ART. Evidence Supporting the Recommendations Several sources of evidence support the use of ART to reduce the risk of HIV transmission. In untreated adults, the risk of sexual HIV transmission increases with the amount of HIV RNA present in the plasma 17 and genital secretions. 18,19 ART reduces HIV plasma viral load 20 and also reduces quantities of HIV RNA detectable in potentially infectious body fluids, including semen, 21,22 cervicovaginal secretions, 23,24 and anorectal secretions. 25 Plasma HIV RNA viral load usually correlates with levels of HIV RNA detected in semen, cervicovaginal secretions, 23,30,31 and anorectal secretions. 28,32 Although use of effective ART with high adherence can suppress plasma and genital viral load, its use may not † † PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 ‡ ‡ nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 5 This recommendation supplements-and does not replace-federal recommendations to provide information about PrEP and nPEP to HIVuninfected persons at risk of HIV exposure. 5,6 eliminate transmission risk. Some persons with suppressed plasma viral loads may have detectable HIV in semen, 21,22,26, in cervicovaginal secretions, 23,30,37 and possibly in rectal secretions. 28,32 Some sexually transmitted diseases (STDs) that cause genital inflammation may also increase shedding of HIV into semen 34,38 and into cervicovaginal secretions, 30,39,40 even in persons with low or undetectable plasma viral loads (see Section 9, STD Services). At least one case of HIV transmission from a patient with suppressed plasma viral load to a monogamous, uninfected sex partner has been reported. 41 Observational studies of heterosexual couples have found that effective ART substantially reduces the risk of sexual transmission. A meta-analysis of these and other studies determined that ART decreased the risk of HIV transmission to uninfected heterosexual partners from 5.64 to 0.46 per 100 person-years, a reduction of 92%. 1 A subsequent RCT of 1,763 HIV-1 discordant couples enrolled mostly in Africa and Asia, 97% of whom were heterosexual, confirmed a 96% reduction in sexual HIV transmission associated with treating the HIV-infected partner (hazard ratio 0.04, 95% confidence interval 0.01-0.27, p<0.001). 2 In this study, infected partners with CD4 cell counts in the range of 350-550 cells/mm^3 were randomized to receive either ART immediately or when their CD4 cell counts declined to <250 cells/mm^3. This study concluded that sustained viral suppression in genital secretions resulting from sustained high adherence to ART explained this protective effect. To date, no published RCT or cohort studies have demonstrated the influence of ART in preventing HIV transmission among MSM and persons who inject drugs (PWID). However, a priori biological plausibility and ecological analyses suggest that ART reduces HIV transmission from all persons with HIV, including MSM 47 and PWID. 48 An ongoing prospective observational study in 14 European countries is assessing sexual transmission among HIV-discordant couples in which the infected partners have plasma HIV RNA viral loads <200 copies/mL, the uninfected partners use neither PrEP nor nPEP, and the couples do not use condoms. 49 In preliminary analysis of data from 767 couples (282 MSM, 445 heterosexual) who contributed 894 couple-years of follow-up (CYFU) and engaged in an estimated 30,400 sex acts without condoms, no HIV transmissions were observed. Study enrollment and follow up continue to ensure the statistical power needed to refine the upper confidence limits associated with the risk of transmission; preliminary analysis yielded confidence limits from 4.0 infections per 100 CYFU for receptive anal sex with ejaculation in MSM couples to 1.5 infections per 100 CYFU for insertive anal sex in MSM couples and penile-vaginal sex in heterosexual couples. Mathematical models also indicate that ART could substantially reduce HIV transmission in MSM and other risk groups in the United States. This body of evidence suggests that ART is likely to reduce the risk of HIV transmission regardless of a person's age, race, ethnicity, sex, gender identity, sexual orientation, or HIV transmission risk category. 17,47,48, Limited theoretical evidence suggests that perceptions about using ART for preventing HIV transmission may influence attitudes about sexual behaviors. A meta-analysis that included 25 studies found that persons with HIV were more likely to report that they might have unprotected sex * if they agreed that taking ART or having an undetectable viral load protects against transmitting HIV or that the availability of ART reduced their anxiety about having unsafe sex. 11 Despite these findings, this study found that * Unprotected sex or unprotected sexual contact is sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginaldigital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). persons with undetectable viral loads were no more likely to engage in unprotected sex than persons with detectable viral loads. A compelling body of evidence supports early initiation of ART at progressively higher CD4 cell counts to improve health outcomes, reduce mortality due to AIDS and other conditions, and prevent HIV transmission. Observational data on health outcomes after early treatment served as the basis for HHS and international recommendations to initiate ART regardless of CD4 cell count. 3,9 An ongoing RCT is directly comparing the benefits and risks of starting newly recommended ART regimens at >350 cells/mm^3 versus >500 cells/mm^3, 58 including chronic diseases that are relatively common in persons with longstanding HIV infection but are not typically associated with immunosuppression. Two other factors support early ART initiation for health or prevention purposes: 1) contemporary initial ART regimens are more convenient, potent, and tolerable than earlier regimens; 3 and 2) drug resistance occurs less frequently in persons who start ART early in the course of their infection, 59 partly because early initiation prolongs the period in which adherent persons can suppress their viral loads. Comparisons of the lifetime costs of health care for persons starting ART with CD4 cell counts at 350 to 500 cells/mm^3 and persons starting ART with CD4 cell counts >500 cells/mm^3 have not yet been reported. However, studies and federal guidelines evaluating ART regimens used over the last two decades have shown that 1) starting ART soon after diagnosis is more cost-effective than delaying ART until CD4 cell counts have declined substantially (e.g., <350 cells per mm^3) and 2) early treatment reduces the costs of AIDS-and non-AIDS-related care even though it increases the lifetime cost of antiretroviral medications. 3,60 Other sources describe the evidence supporting recommendations about the use of PrEP and nPEP. 5,6 Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Among all persons living with HIV in 2009, an estimated 82% had been diagnosed with HIV infection, 66% were linked to HIV medical care, 37% were retained in care, 33% were prescribed ART, and 25% had a suppressed viral load. 61 However, among adults diagnosed with HIV who received ongoing HIV medical care between 2008 and 2010 (when HHS routinely recommended starting ART for persons with CD4 cell counts 350 cells/mm^3 expressed interest in starting ART to decrease transmission risk. 65 Surveys of health care providers prescribing ART in Washington, DC, and the Bronx, NY found that 95% agreed or strongly agreed that ART can decrease HIV transmission and 75% would offer ART earlier to patients at high risk of transmitting HIV (defined as persons who have HIVuninfected partners or report sex without condoms with a partner of unknown HIV status). 66 People may delay initiating ART for health or prevention purposes for several reasons: denial that they are HIVinfected or that HIV is a serious medical condition; lack of understanding of the benefits of early treatment; lack of trusted relationships with health care providers; and lack of health insurance or access to federal and state medical assistance programs, such as Medicaid. 61,67 Access to affordable ART (and PrEP and nPEP for uninfected partners of persons with HIV) is a continuing challenge in the United States. Long-term use of ART is expensive because it requires multiple medications, most of which are not yet available in generic form. The annual, unsubsidized cost of ART regimens recommended by HHS as of 2014 exceeds $10,000. 3 Studies conducted before 2014 found that some persons declined or postponed ART because they were unaware of free or low cost ART sources, anticipated difficulty obtaining affordable ART, did not access subsidized ART through AIDS Drug Assistance Programs (ADAP), or were deterred by ADAP waiting lists. As of 2014, many options can substantially reduce out-of-pocket costs of ART, including Medicaid and Medicare, state ADAP, private sector health insurance, health care exchange plans initiated under the Patient Protection and Affordable Care Act (ACA), and pharmaceutical company drug assistance programs. 14,16,72,73 Increased enrollment in health plans with pharmacy benefits and near elimination of state ADAP waiting lists (as of April 2014) has improved access to subsidized ART. 74 Nevertheless, it has been estimated that under the ACA's health care exchange plans, coinsurance for ART may be substantial, with up to 55% of plans requiring enrollees to pay an average of 35% of their total ART cost. 73 In states that have not yet expanded the populations of low-income or disabled persons that are eligible for Medicaid, the Ryan White HIV/AIDS Program and ADAP will remain crucial sources of affordable HIV care and ART. In states that have expanded Medicaid, the Ryan White HIV/AIDS Program will continue to cover copays and deductibles for many persons with HIV. Disparities in access to ART are compounded by longstanding geographic, economic, social, racial, and ethnic disparities in the burden of HIV. This convergence of disparities reinforces ethical imperatives to increase access to HIV care and treatment. 75 Selecting appropriate ART regimens may be complex for persons who use other prescription, nonprescription, or recreational drugs, alcohol, or dietary supplements that may interact with ART or for women who are pregnant or attempting conception in whom fetal safety must be considered. Other federal guidance describes potential interactions between ART and other substances and preferred regimens during pregnancy and additional clinical evaluation needed in these situations. 3,76 providers, and their uninfected partners are not familiar with the use of nPEP after isolated, inadvertent exposures after voluntary behaviors (e.g., condom failure) and involuntary behaviors (e.g., sexual assault). 78,79 Two reviews of studies on nPEP use published from 2001-2008 found that less than half of U.S. health care providers working in emergency departments had ever offered nPEP to patients after sexual assault. 80,81 Some persons with HIV may consider sharing their ART medications with HIV-uninfected partners seeking PrEP or nPEP. This practice should be discouraged because 1) it may impair ART adherence; 2) medications used for ART may not be suitable for prophylaxis; 3) partners' perceived or reported HIVnegative status may be inaccurate, and 4) ART medications that are shared with partners seeking prophylaxis who are in fact HIV-infected may not provide optimal HIV treatment or may promote viral drug resistance. 3,5,6,82,83 # Policy, legal, and ethical considerations Use of ART for health or prevention benefits should be voluntary. The principal consideration in decisions about using ART is personal health, not reducing risk of HIV transmission. Clinical providers can help patients make informed choices about ART use by stressing that ART is the single most important intervention they can choose to maintain their health, prolong their lives, and reduce the risk of infecting others; noting potential harms, such as side effects; and reassuring patients who decline ART that they will not be denied medical or social services. This principle of autonomy also applies to HIVuninfected persons offered PrEP or nPEP. Clinical providers can caution their patients that sustained high adherence to ART substantially reduces the risk of transmission, but it may not eliminate the risk. Clinical providers can also discourage risk compensation, ‡ ‡ ‡ which may lead to deferral of condom use or of other safer sex or drug-injection behaviors (see the Evidence topic in this section). Patients who alert their partners to the limitations of ART may reduce partner distress and disputes if transmission should occur (see Section 3, Context of Prevention, for information on HIV disclosure). HIV-uninfected persons who use nPEP or PrEP also can benefit from knowing that these regimens may reduce, but may not eliminate, their risk of HIV acquisition. # Special populations Several vulnerable or marginalized populations warrant specialized attention when offering, starting, and continuing ART. These populations include adolescents who are taking more responsibility for health decisions and leaving parental homes or foster care; persons entering or leaving correctional facilities; and immigrants who lack the documentation needed to receive HIV care through private insurance or medical assistance programs. The presence of mental health or substance use disorders does not make a person ineligible for ART. If these conditions raise questions about a person's ability to effectively use ART, referral for appropriate mental health and substance abuse treatment is indicated. 3 (Section 6, ART Adherence, addresses ART ‡ ‡ ‡ Risk compensation is modifying sex or drug-injection behaviors in way that increases risk of HIV transmission or acquisition when other safeguards are introduced (e.g., when persons with HIV who believe that ART use reduces their infectiousness no longer use condoms to prevent HIV transmission). for special populations. Section 12, Other Medical and Social Services, addresses specialty services that can facilitate initiation of HIV medical care and ART.) # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at /. A list of wholesale costs of regimens that HHS recommends for persons starting ART is also available. 3 Section 6, ART Adherence, includes a link for adherence assessment and support materials. # Section 6. Antiretroviral Treatment Adherence Background Antiretroviral treatment (ART) adherence describes the extent to which a person takes ART according to the prescribed doses, dosing intervals, and other medication instructions. Sustained high adherence is essential to maximize the effectiveness of ART, which suppresses viral load and, in turn, preserves CD4 cells counts, prevents progression to AIDS, and prolongs lifespan. Inconsistent or low adherence can lead to virologic failure- or the emergence of drug-resistant virus, both of which may limit future treatment options. Sustained high adherence is also critical for maximizing the benefits of ART in reducing the risk of sexual and perinatal HIV transmission. Studies of early combination ART regimens found that adherence levels greater than 95% were needed to maximally suppress viral load. 16 However, more recent studies indicate that viral suppression can be achieved with lower adherence levels, particularly when newer regimens are used. 10,12,17 Because the level of adherence necessary for viral suppression may vary by regimen and adherence has been described in different ways in the scientific literature, there is no standard definition of high adherence. † The literature suggests that the levels of adherence needed to maximize treatment benefits may range from at least 80% to at least 95% of doses taken as prescribed. 10,12,17 Given the uncertainty, persons with HIV should try to achieve and sustain the highest possible adherence to ART. 17 To help persons with HIV reach their adherence goals, clinical providers, nonclinical providers, and selected health department staff can offer a variety of support strategies when needed. This section addresses methods to assess adherence, factors that influence adherence and interventions that promote sustained high adherence. Quality improvement ‡ and program monitoring and evaluation § can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 5, Antiretroviral Treatment, describes the benefits of ART use with sustained high adherence and factors other than adherence that influence treatment effectiveness, including concurrent medical conditions, drug-resistant virus, and the use of other drugs, alcohol, or dietary supplements that may alter ART absorption or metabolism. Other federal guidance provides additional information about ART adherence, including clinical criteria for selecting initial and changing regimens that may influence adherence. 1,22 Section 4, Linkage to and Retention in HIV Medical Care, addresses issues affecting retention in HIV care, which is essential for sustained access to ART and adherence support. The inability to achieve or maintain suppression of viral replication (to an HIV RNA level <200 copies/mL). 1 † Studies published over the last decade have measured adherence using different methods, cut offs, and recall periods. Most studies classified high adherence as a patient report of having taken at least 90% of medications as prescribed over the previous 7-30 days. 20,21 ‡ Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 6. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT ADHERENCE For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV), if allowed by professional authority and jurisdiction  Participate in multidisciplinary teams with health educators, service linkage facilitators, community health workers, a case managers, nurses, pharmacists, and physicians to assess and support adherence to antiretroviral treatment (ART) b,c (i, ii, iii)  Inform persons with HIV about the benefits of sustained high adherence, even if they are feeling well, and the risks of low adherence (e.g., illness, drug resistance, transmitting HIV to others) b,d (i, ii)  Provide adherence support tailored to each person's regimen and characteristics, according to provider role, authority, and setting b (i, ii) (see Box 6-A)  Provide or make referrals for services to address factors that may impair adherence (e.g., demographic, comorbidity, psychosocial, and structural issues) b (i, ii) (see Table 6-1)  Offer advice on how to obtain sustained coverage or subsidies for ART through private-or public-sector sources b (i, iv, v, vi) # Specific to clinical providers (in addition to above recommendations)  Before prescribing ART, assess patient readiness to start ART, sources of pharmacy coverage, and possible barriers to sustained high adherence (e.g., anticipated changes in health insurance, disruptive life events, mental illness) (i, ii)  Offer highly effective ART regimens, preferably those that minimize pill burden, dosing frequency, and dietary restrictions (i, ii)  Involve patient in decisions about treatment regimens (i, ii)  Advise patients to take ART as prescribed; provide information about the regimen, and check for understanding in the following areas (i, ii):  Details of the regimen, including dosing method and schedule, dietary restrictions, and what to do when drinking alcohol or when missing doses  Consequences of missing doses, such as increased risk of HIV-related illness, developing drug resistance, and transmitting HIV  Potential side effects and what to do if side effects occur  Potential interactions with other prescription, nonprescription, and recreational drugs; alcohol; and dietary supplements that may impair ART effectiveness or cause toxicity that could impair adherence  The possibility of HIV transmission even when virus is not detectable in the blood because blood measurements may not reflect viral load in genital and anal fluids or may have increased since last measurement  Routinely assess patient's questions, concerns, or challenges regarding ART use to identify potential problems before virologic failure e occurs (i, ii)  Remind patients to report current or planned use of prescription, nonprescription, or recreational drugs; alcohol; and dietary supplements because these may impair ART effectiveness or cause toxicity that could impair ART adherence (ii)  Assess self-reported adherence at each visit using a nonjudgmental manner f (i, ii)  Assess and manage side effects at each visit (i, ii)  Routinely use HIV viral load to monitor ART effectiveness that may be affected by adherence (i, ii)  Consider assessing ART prescription refills or pill counts, if feasible, when needed to supplement routine assessment of self-reported adherence (e.g., when treatment response is not consistent with self-reported adherence) (i, ii)  Do not directly administer ART to patients on a routine basis, except in settings where other medications are directly administered on a routine basis (e.g., young adolescents living with parents, prisons, residential substance use treatment centers, opioid replacement programs, mental health hospitals) (i) BOX 6. # RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT ADHERENCE (cont) For staff of health departments who provide population-level HIV prevention and care services  Use HIV surveillance data to identify populations or individuals who have CD4 cell counts or viral load test results that indicate suboptimal treatment that may be related to low adherence and who may warrant being offered ART adherence support, if allowed by the jurisdiction (vii, viii)  Engage health department disease investigation specialists or other community health workers, if allowed by the jurisdiction, in collaborating with health care providers to offer adherence support to their patients a,g  Support other population-level strategies to promote sustained high adherence (vii) (see Box 6-B) # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to . a Linkage facilitators assist persons with HIV to access HIV medical care and other medical and social services through active methods (e.g., help making appointments, providing transportation to appointments).Community health workers might include community-based HIV prevention specialists contracted by health departments or employees of community-based HIV service organizations. b The cited federal government guidance that supports this recommendation was intended for health care providers. Based on program experience and opinions of the Project Workgroup, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. c In some jurisdictions, collaboration may involve communicating with HIV surveillance programs that monitor HIV viral load levels of reported HIV cases to identify persons with suboptimal treatment response that may be due to low adherence. d The source guidance only addresses the personal health benefits of high adherence, not the benefits of high adherence in reducing the risk of transmission to others. e Virologic failure is the inability to achieve or maintain suppression of HIV replication to an HIV RNA level of <200 copies/mL. f Some experts recommend asking patients to answer the question, "In the last 30 days, how good a job did you do at taking HIV medicines in the way you were supposed to?" using a multistep scale ranging from very poor to excellent. 23 g See the Background topic in this section for information supporting this statement. # Sources # How These Recommendations Differ from Previous Recommendations The 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care 24 did not address adherence to ART as a means to suppress viral load or prevent HIV transmission. However, the recommendations in this section are consistent with the latest federal guidance for clinical providers regarding adherence assessment and support. 1,22,25 They are also consistent with the latest federal guidance for health departments regarding collection and use of HIV surveillance data (as a measure of ART effectiveness, which may be affected by adherence) in populations or individuals, if allowed by their jurisdictions. These recommendations are also consistent with nearly all of the latest comparable recommendations about ART adherence of these nongovernmental organizations: the International Association of Physicians in AIDS Care Panel; 29 the HIV Medicine Association of the Infectious Diseases Society of America; 30 and the International Antiviral Society-USA Panel. 31,32 This report also makes new recommendations based on recent studies, programmatic experience, and/or expert opinion. These include recommendations for  nonclinical providers (including community health workers employed by health departments or community-based organizations) to provide selected educational, counseling, and referral services to support adherence, if allowed by their professional authority and jurisdiction (see Box 6 and Box 6-A)  nonclinical and clinical providers to apply motivational interviewing techniques to help persons taking ART identify strategies for maintaining or improving their adherence (see Box 6-A) Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information.  health departments to engage health department disease investigation specialists or other community health workers in collaborating with health care providers to offer their patients adherence support, if allowed by the jurisdiction (see Box 6) # Methods The section writing group based these recommendations on several sources of scientific information including federal guidance, published systematic reviews, and published primary studies. adherence that were conducted in the United States and other countries and were published from 2000-2012. 36,43,45, These reviews varied regarding the number of studies included, eligibility for inclusion (e.g., published versus unpublished literature, inclusion of randomized controlled trials , one-group designs, or other designs), methods for assessing adherence, and methods for summarizing evidence. The reviews examined several types of adherence interventions; many combined education, adherence tools, and long-term support strategies.  An electronically published systematic review, the PRS Compendium of Evidence-based HIV Behavioral Interventions (PRS Compendium) that is updated annually as new published studies that meet inclusion criteria are identified. 65 The 2014 compendium included 10 evidence-based behavioral interventions † † (EBIs) for improving adherence (described in 9 studies) that were determined to be efficacious based on PRS efficacy criteria (hereafter termed "adherence EBIs"). Each study met pre-established criteria for rigorous evaluation design (i.e., used a comparison group), reported significant findings (i.e., statistically significant positive intervention effects on adherence or viral load), and was published in a peer-reviewed journal. 75  Six cost-effectiveness analyses of adherence interventions in the United States. # Evidence Supporting the Recommendations # Methods to regularly assess adherence Adherence can be measured using various methods, including self-reported medication use or pill counts, pill counts assessed by providers, electronic drug-monitoring data, pharmacy records, and drug levels in the blood. Each method has good correlation with one or more other measurement methods and with HIV viral load. 14,15,21, There is no consensus on the most accurate, simple, and feasible method because each method has strengths and weaknesses. 82 Self-reported adherence is commonly used in daily practice and is recommended for routine adherence assessment because it is inexpensive and easy to † † Evidence-based interventions are individual-, group-, or population-level interventions that have been shown to promote safer behaviors or reduce HIV or STD transmission in research studies, program evaluations, or theory-based intervention experience. implement. 1,22 Most other methods are less practical in clinical settings ‡ ‡ because of high cost, patient or provider burden, or require medical or pharmaceutical information systems that were not designed for routine adherence assessment. Although self-reported adherence tends to over-estimate adherence by up to 20%, certain response options and recall methods may improve accuracy. 1,22,85 For example, some experts recommend asking patients to answer the question, "In the last 30 days, how good a job did you do at taking HIV medicines in the way you were supposed to?" using a multistep scale from very poor to excellent. 23 In addition, providers who use a positive, nonjudgmental manner with patients and acknowledge the challenges of adherence can encourage more accurate self-reporting. 1,22 Current federal recommendations advise using pharmacy refill information and pill counts to supplement, but not replace, self-reported adherence measures only in clinical settings that can routinely collect this information and recognize biases when refill data are incomplete or patients discard pills before they are counted. 1,22 Federal recommendations for clinical settings do not advise measuring antiretroviral drug concentrations in biologic specimens (which is costly and biased by short, drug half-lives) or recording data from electronic drug monitoring devices (which is often impractical). 1,22 # Assessing factors that influence adherence Achieving consistently high adherence over the span of chronic HIV infection is often challenging. Even persons who have maintained high adherence for long periods may have lapses in adherence due to medical or psychosocial issues or life events. While the most common reason for low adherence that patients cite is forgetting to take the medication, 13,18,43, a complex set of personal, social, cultural, and structural factors can influence adherence. Table 6-1 summarizes the most common factors related to low adherence described in 18 published reviews on correlates and HHS guidelines on ART use. 1,8,20, Low adherence was most often associated with patient factors-particularly alcohol or substance abuse and depression, anxiety, or other psychological conditions-and regimen factors, such as frequent or severe treatment side effects, high pill burden, and frequent dosing. Other common patient-level factors affecting adherence included negative attitudes or beliefs about HIV disease, fear of stigma, lack of social support, negative attitudes or beliefs about treatment, and lack of a daily routine. Several structural factors-such as homelessness or lack of insurance or financial assistance-were also associated with low adherence. The 3 reviews that focused on adolescents found that characteristics of parents or caregivers were associated with their adolescent's adherence; these included knowledge (e.g., education level, understanding about ART), perceptions (e.g., belief of treatment efficacy, self-efficacy), and well-being (e.g., stress). 43,45,46 ‡ ‡ Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. # Structural factors  Inability to afford or obtain a continuous supply of ART due to lack of health insurance or enrollment in medical assistance programs 35,36,39,41  Unstable housing, incarceration, and recent release from imprisonment 35,36,38,40,41,43,45 # Strategies that increase adherence The 19 systematic reviews that evaluated the impact of behavioral interventions on improving adherence included formal meta-analyses (n=6) and qualitative or semi-quantitative analyses (n=13). Many reviews concluded that adherence interventions resulted in statistically significant improvements in adherence (as measured by self-reported adherence, pill counts, or electronic medication monitoring devices), but that the magnitude of differences in adherence levels between intervention and comparison groups was moderate. 49,54, Many reviews showed that persons who received adherence interventions also had reduced HIV viral loads, although effect sizes were weaker than those related to adherence measures. 49,53,54,60,62,63 Several reviews found that adherence increased during the intervention period but declined thereafter or that ongoing support was needed to sustain high adherence. 49,54, Overall, the most effective interventions focused on educating and motivating patients, addressing concerns or negative beliefs about treatment, building patients' skills and providing tools for managing medications, and offering ongoing support. Several reviews suggested that to be effective, adherence interventions must use a multifaceted, long-term approach; engage members of multidisciplinary teams; and consider a variety of strategies tailored to the individual. Details on specific strategies that improved adherence when used alone or in combination with other strategies are summarized below. # Providers of adherence support Several systematic reviews of intervention evaluations found that various types of providers who provide adherence support can improve adherence. A meta-analysis of 10 adherence interventions (7 of which specifically addressed ART) found that interventions in which nurses provided adherence counseling and other support significantly improved both short-and long-term adherence. 64 Another review found that engaging pharmacists to provide education, counseling, and training on adherence management tools was often associated with improved adherence and viral suppression. 60 In addition, interventions that used peer educators, community health workers, or outreach workers to educate patients about medication management and to provide repeated, long-term adherence support could improve adherence. 55 # Simplified ART regimens Several of the 18 systematic reviews that assessed factors associated with adherence found that greater pill burden and more frequent dosing were associated with lower adherence. 8,33,35,36, One review described a meta-analysis of 11 RCTs that found that adherence to once-daily regimens was slightly better than adherence to twice-daily regimens in all patients (a difference of 2.9%) and in the subset of patients who had recently started treatment (a difference of 4.4%). 42 In 6 of these studies, patients prescribed once-daily regimens had significantly higher adherence (a difference of 4.5%) and lower viral load levels (defined as <50 copies/ml, a difference of 5.7%) as compared with patients prescribed twicedaily regimens. 42 All of these modest differences were statistically significant. # Management of side effects Several of the 18 systematic reviews that assessed factors associated with adherence found that adverse side effects impair adherence. 8,33,35,36,41,43,44,47,48 One meta-analysis found that patients reporting side effects were about 40% less likely to report high adherence than were patients reporting no adverse effects, although the magnitude of difference varied slightly by type of adverse effect. 48 None of the 19 systematic reviews of intervention evaluations reported the impact of strategies to manage side effects. However, 3 adherence EBIs in the PRS Compendium informed patients about ART side effects or provided tailored advice if patients reported that side effects impaired adherence. 68,69,72 Although newer ART regimens cause milder and less frequent side effects as compared with many older regimens, side effects continue to impair adherence in some persons. # Adherence education and counseling Three systematic reviews of intervention evaluations found that education and counseling that address cognitive and behavioral aspects of taking ART can improve adherence. These strategies included providing information about treatment; addressing negative beliefs about medication, lack of motivation to take medication, or unrealistic expectations about adherence; providing individually tailored approaches to build self-confidence and medication management skills; and encouraging seeking support for adherence from providers, fellow patients, friends, or family. A systematic review of 5 interventions that involved motivational interviewing found that 3 significantly improved adherence and 2 significantly reduced viral load. 63 In addition, 8 of the 10 adherence EBIs in the PRS Compendium focused primarily on educational or cognitive-behavioral approaches to improving adherence. Strategies included providing education about ART use and the health benefits of adherence, addressing barriers to adherence, assisting with problem solving and decision making, setting adherence and treatment goals, building adherence skills, and engaging support for adherence from peers. # Adherence tools Two systematic reviews of intervention evaluations studies found that technology-based methods, such as mobile phones that generate auto alarms or text messages and other electronic reminder devices (e.g., pagers, alarms, and electronic pill boxes), do not improve adherence when used alone. However, they are effective when combined with other strategies, such as education and individually tailored counseling. 59,61 A more recent systematic review examining 2 Kenyan trials found that weekly mobile text messages with adherence reminders significantly improved adherence and suppressed viral load. 62 Of the 10 adherence EBIs in the PRS Compendium, 1 study sent daily pager messages that included reminders to take ART as the sole adherence support strategy. 72 Persons who received messages were more likely to achieve undetectable viral load levels than were persons who did not receive messages. # Directly administered antiretroviral treatment or therapy § § (DAART) Two of the 19 systematic reviews of intervention evaluations compared DAART to self-administered treatment in various populations: HIV clinic patients, substance users (including those receiving and those deferring substance use treatment), persons who inject drugs (PWID), homeless persons, prisoners, and hospice patients. The reviews found limited evidence that DAART improved adherence or viral suppression. 53,54 The first review found that DAART only significantly improved adherence or viral suppression in PWID and homeless persons. 53 The second review found that DAART improved adherence and viral suppression only during the intervention period but not thereafter. 54 Two of the 10 adherence EBIs in the PRS Compendium found that DAART for substance users resulted in significant reductions in viral load. 66,70 One multifaceted intervention involved sending pager reminders to receive daytime doses (in a mobile van) and to take evening doses over a period of 6 months; it also included case management, social support, and medication management education to help transition clients after DAART ceased. 66 Persons who received this intervention were significantly more likely than persons who managed their own ART to achieve an undetectable viral load or a large reduction in viral load (70% vs 55%, p=0.017). 66 The other study provided DAART to clients of a methadone maintenance clinic who had started a new ART regimen. 70 Persons who received the intervention were more likely to have § § Directly administered antiretroviral treatment or therapy (DAART) is a form of drug administration in which a provider directly observes a person with HIV taking oral ART on a daily or nearly daily basis. undetectable viral loads 6 months after starting DAART as compared with persons who managed their own ART (74% vs 41%, p<0.001). The studies raise questions about the general applicability of DAART, however, because the interventions were restricted to substance users, did not show a sustained effect after DAART ceased, and were fairly labor-intensive. # Multifaceted interventions with several components Several adherence EBIs in the PRS Compendium 75 were found to improve adherence (n=7) or to reduce viral load (n=4). 66,69,70,72 Seven evidence-based interventions were multifaceted and included several strategies for improving adherence, such as cognitive-behavioral approaches, social support, treatment delivery methods, and adherence tools. 71,73,74 The interventions were directed to adults with varied characteristics and ART experience, including substance users, clinic patients, couples with discordant HIV status, persons starting ART, experienced users, persons switching regimens, and persons experiencing adherence problems. All interventions focused on populations comprising mainly racial/ethnic minorities, and most were implemented in clinics or directed to established clinic patients. The interventions also varied regarding delivery mode (individual, couples, group) and provider type (physician, nurse, peer counselor, outreach worker, other facilitators). Two of the 7 multifaceted EBIs were associated with significant decreases in viral load. 66,69 One brief, clinic-based intervention consisted of brief (~3-5 minutes) counseling sessions by physicians at each HIV care visit along with clinic posters and patient education materials reinforcing ART adherence. 69 Patients who received this intervention were nearly 3 times more likely than patients who did not receive the intervention to report high adherence (>95% of prescribed pills taken over the previous 7 days) (OR=2.9, p=0.001) and were less likely to have detectable viral load levels (>500 copies/mL) (OR=0.60, p=0.04). 69 In the other multifaceted intervention (described in the DAART topic above) persons who received DAART, pager reminders, case management, and other supportive services through a mobile van were more likely than persons who did not receive these services to achieve undetectable viral loads or large reductions in viral load 6 months after DAART started (70% vs 55%, p=0.017). 66 # Cost-effectiveness of adherence interventions Five cost-effectiveness studies published from 2000-2010 evaluated different adherence interventions, including individual counseling for gay, bisexual, or other men who have sex with men (MSM) provided by health professionals, home visits by nurses, and provision of DAART in the clinic or the home. The studies considered different comparison groups (i.e., persons taking placebos or persons receiving verbal reminders to take medications as prescribed), different populations (e.g., treatment naïve, specific CD4 cell count or viral load, demographic group), and different intervention providers (e.g., nurses, pharmacists). Two studies estimated intervention efficacy and cost from data collected during adherence trials, 76,79 and 3 studies estimated cost data using data from other published reports. 77,78,80 The studies found that adherence interventions cost from $1,300 to $90,000 per quality-adjusted life year gained (mean=$43,970). In addition, modeling analysis estimating the cost effectiveness of adherence interventions (in which per-patient costs were based on 2 clinic-based interventions that appreciably improved adherence) 76,95 found that providing adherence interventions to prevent HIV transmission was cost-saving compared with not providing interventions. 81 It also concluded that the intervention cost per new case of HIV averted was ~$339,000, 81 slightly less costly than the lifetime cost of HIV treatment (>$400,000). 96 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Studies over the last decade have shown that average rates of adherence (estimated at various times after ART initiation) range from 30% to 89% 5,6,11,13,14,16,18, and tend to decline over time. 5,70, A recent meta-analysis estimated that, on average, only 59% (95% CI: 53%-65%) of persons with HIV in North America reported ≥90% adherence to ART. 20 A 2011 evaluation of 128 HIV clinics funded by the Ryan White HIV/AIDS Program found that 15% of patients had a documented problem with adherence. 109 However, levels of adherence among persons with HIV may improve in the future for several reasons: 1) HHS now recommends use of ART for preventing HIV transmission; 2) newer medications require less frequent doses and cause fewer side effects; 3) access to pharmacy benefits from health insurance and expanded state Medicaid programs has increased under the Patient Protection and Affordable Care Act (ACA); 4) funding of the AIDS Drug Assistance Program and other programs that subsidize ART continues; and 5) cost of some ART medications will decline as patents expire. As more persons with HIV start ART for the dual purpose of treatment and preventing transmission, future studies can evaluate the impact of adherence support for persons who have high CD4 cell counts and feel well. 1 Two studies suggest that patients who start or use ART when they have high CD4 cell counts are less likely to have sustained high adherence than persons with low CD4 cell counts. 113,114 Nevertheless, theoretical considerations suggest that when comparing the potential risk of low adherence in some persons starting ART at high CD4 levels to the potential benefit of decreasing the population viral load, large increases in the numbers of persons starting ART are likely to result in a net benefit in preventing HIV transmission. 1 Although many studies show the benefits of regular adherence assessment and support, many health care providers do not regularly assess adherence, address adherence barriers, or provide adherence support because of competing priorities or lack of experience. 115,116 When time is limited, many providers prioritize support to patients who are starting or restarting ART, changing regimens, or reporting low adherence and adherence challenges. Use of multidisciplinary care teams, task sharing, and "medical homes" encouraged by the ACA can expand the range of providers who can support adherence. 110,112 Electronic medical records* that can track viral load levels over time and generate reminders for health care providers when viral loads increase may prompt adherence assessment in some clinical settings. 117 Anecdotal reports suggest that some persons with HIV may consider sharing their ART medications with other persons with HIV or with HIV-uninfected partners seeking antiretroviral medications for * An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. preexposure prophylaxis (PrEP) † † † and nonoccupational postexposure prophylaxis. ‡ ‡ ‡ Providers should discourage sharing ART because it may impair adherence and pose other problems (see Section 5, Antiretroviral Treatment). 1, # Policy, legal, and ethical considerations Concerns about confidentiality, stigma, and social disapproval and nondisclosure of HIV infection status are associated with low adherence 36,41,47,91 (see Section 3, Context of Prevention). Some persons may be reluctant to carry or display their ART in public or to seek adherence support from others if they fear legal consequences or deportation. A study of more than 1,800 persons with HIV in North America found that those living in areas where transmitting or exposing others to HIV was a crime reported lower adherence compared with persons living in other areas. 122 Providers can assess adherence in a nonjudgmental manner, stress that adherence information is confidential, explain the relation between adherence and viral load, and help persons with HIV find practical adherence strategies. These strategies may encourage patients to honestly disclose their adherence levels, to admit adherence challenges, and to set realistic adherence goals. Several studies have also shown that persons who share decision making about ART adherence goals with their clinical providers have higher adherence. 8,36,44 This approach respects the patient's autonomy while using clinical input about the levels of adherence needed to achieve treatment goals. Other factors that influence adherence are described elsewhere: retention in HIV medical care (Section 4, Linkage to and Retention in HIV Medical Care); and sustained access to affordable ART (Section 5, Antiretroviral Treatment). # Special populations Persons who have substance use problems, unstable housing, or other characteristics associated with low adherence can achieve high adherence when given adequate support. 2,11,39,40,86,89, For example, providers who regularly monitor drug and alcohol use that signal life stressors may preempt lapses in adherence that lead to virologic failure. 103,126 Clinical providers who serve younger adolescents who rely on parents or caregivers to manage medicines can refer to adherence strategies for children recommended by HHS. 127 Providers serving older adolescents can honor confidentiality by asking which adults sponsor their health insurance, are aware of their HIV infection, and have the knowledge and attitudes about ART that enable them to provide adherence support. 43,45,46,128 ART adherence can be challenging for some older persons, particularly those taking many medications for other conditions or experiencing cognitive impairment. 47,129,130 Several strategies may be helpful: avoiding prescribing drugs that may cause adverse interactions, managing drug interactions, and offering tools and training to organize medications. Patients who cannot read pill bottles or understand package † † † PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 118 ‡ ‡ ‡ The use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational or occupational exposures to body fluids potentially containing HIV-such as after unprotected sexual intercourse, condom breakage, or needlesticks-in order to reduce the risk of HIV acquisition. inserts because of low literacy or language barriers may benefit from visual aids or simplified medication instructions in the appropriate language. Section 12 describes assessment, linkage, and referral to other medical and social services for populations that face unique barriers to adherence. # Implementation Resources Practical resources to support implementation of these recommendations, including a list of interventions shown to be efficacious in supporting adherence, can be found at . A list of wholesale costs of ART regimens recommended by HHS is also available. 1 # Section 7. Risk Screening and Risk-reduction Interventions Background Risk screening is the collection of information to determine a person's risk of transmitting HIV to others. In this report, risk screening is defined as a brief evaluation of behavioral factors that may affect the risk of exposing others to HIV (e.g., unprotected- sex or sharing drug-injection equipment) and biomedical or biologic factors that influence HIV viral load, viral shedding, and infectiousness (e.g., antiretroviral treatment use, ART adherence, sexually transmitted disease , and pregnancy). Risk screening † is used to identify behavioral or biomedical risk-reduction interventions suited to a specific individual. Behavioral risk-reduction interventions include various services provided in clinical settings ‡ and nonclinical settings § that have been shown to promote safer behaviors and reduce the risk of exposing others to HIV. Many interventions address psychological, social, or structural factors that influence sexual, drug-injection, and reproductive behaviors. Some aim to provide information, build knowledge, and improve skills that lead to safer behaviors. Others increase motivation to adopt safer behaviors or modify social norms. Some interventions involve a structural component, such as increasing access to condoms. Behavioral risk-reduction interventions can be offered to individuals or groups through counseling, discussion, role plays, or exercises; through print media, such as brochures and posters; and through interactive media, such as computers, telephones, and mobile devices. 5 This section addresses risk screening and behavioral risk-reduction interventions that can promote safer sexual and drug-injection behavior over a lifetime. Quality improvement and program monitoring and evaluation † † methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Because risk screening and risk-reduction interventions are central to HIV prevention with persons with HIV, other sections also describe behavioral and biomedical strategies to reduce the risk of HIV transmission: linkage to and retention in care (Section 4), antiretroviral treatment (Section 5), ART - Unprotected sex or unprotected sexual contact is sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginaldigital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). † Risk screening is the collection of information to determine a person's risk of transmitting HIV to others. In this report, risk screening is defined as a brief evaluation of behavioral factors that may affect the risk of exposing others to HIV (e.g., unprotected sex or sharing druginjection equipment) and biomedical factors that influence HIV viral load, viral shedding, and infectiousness (e.g., antiretroviral treatment use, ART adherence, sexually transmitted disease , and pregnancy). Information gathered during this screening can be used to identify suitable behavioral or biomedical risk-reduction interventions. ‡ Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. § Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. † † Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness.  Behavioral characteristics that affect their risk of exposing others to HIV (e.g., unprotected sex, sharing drug-injection equipment) b,c,d  Biologic or biomedical characteristics that affect their level of infectiousness, (e.g., use of and adherence to antiretroviral treatment (ART), viral load level, sexually transmitted disease diagnoses, pregnancy) b,c,d,e,f,g,h  Characteristics of partners that affect the partner's risk of acquiring HIV or STD, when information available (e.g., use of preexposure prophylaxis i or nonoccupational postexposure prophylaxis j ) b,c,d,e,f,g,h  Offer positive reinforcement to persons who report safer behaviors and use of biomedical strategies that reduce their level of infectiousness to motivate their continued use (ii, iv, vii) ‡ ‡ Partner services include an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. # BOX 7. RECOMMENDATIONS-RISK SCREENING AND RISK-REDUCTION INTERVENTIONS (cont) Individual-level risk-reduction services i PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. j nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 7 Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. k Common misconceptions relate to perceptions of the relative, per-act risk of HIV transmission for various types of sexual contact; how behavioral, biologic, and viral factors influence transmission risk; whether ART use can reduce the risk of HIV transmission; and whether use of PrEP or nPEP with antiretroviral medications can reduce the risk of HIV acquisition by HIV-uninfected partners. a The practice of limiting unprotected sex (i.e., sexual activity without using a physical barrier) to partners believed to have the same HIV infection status (e.g., persons with HIV only have unprotected sex with persons believed to be HIV-infected). b The practice of modifying sexual activity based on beliefs about the partner's HIV infection status and the per-act risk of HIV transmission for a given type of contact (e.g., persons with HIV practice receptive fellatio with HIV-uninfected partners because they believe this type of contact is less likely to transmit HIV than insertive fellatio , anal sex, or vaginal sex). c Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. d A recent diagnosis may be based HIV test result indicative of acute infection (i.e., positive HIV antigen or nucleic acid amplification test or HIV antibody result indicative of recent seroconversion) and/or clinical evaluation of symptoms or signs of acute retroviral syndrome (e.g., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, headache, lymphadenopathy). e See Section 5, Antiretroviral Treatment, for recommendations on the use of ART to reduce the infectiousness of persons with HIV and to reduce the risk of their HIV-uninfected partners' acquiring HIV. f See Section 9, STD Services, for recommendations on STD screening and treatment to reduce the infectiousness of persons with HIV and the role of STD in facilitating HIV transmission. g See Section 10, Reproductive Health Care, for recommendations on family planning to prevent unintended pregnancy and special conception methods that reduce the risk of HIV transmission or acquisition. h See Section 11, Pregnancy, for recommendations on reducing the risk of sexual and perinatal transmission or acquiring HIV during pregnancy and the postpartum period. i See Section 8, Partner Services, for recommendations on reducing the risk of acquiring HIV by HIV-uninfected partners, including STD screening and treatment, PrEP and nPEP, and reproductive and pregnancy services. # Box 7-C. Important topics when informing persons with HIV about how to prevent transmission of HIV to others # General topics  How HIV is spread (e.g., exchange of body fluid) and not spread (e.g., handshake)  How sustained high adherence to ART suppresses viral load and reduces the risk of transmitting HIV  How preventing or treating symptomatic and asymptomatic STDs can improve health and decrease the risk of transmitting HIV  How avoiding drugs and alcohol can improve health and may promote safer drug-use or sexual behaviors  Benefits of support from family, friends, or partners to encourage safer behaviors  Benefits and risks of selectively disclosing HIV infection to others (e.g., those at a heightened risk of HIV exposure, health care providers) and methods that minimize the risk of negative consequences of disclosure a  Benefits of knowing the HIV-infection status of sex and drug-injection partners  How serosorting may result in HIV transmission if assumptions about partners' HIV status are incorrect or may result in acquiring STDs and, more rarely, new HIV strains from infected partners  Characteristics of HIV-uninfected sex and drug-injection partners that increase their risk of HIV acquisition (e.g., sharing nonsterile drug-injection equipment, STDs)  Availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to prevent HIV acquisition b,c  Availability of voluntary, confidential, and usually free health department services to notify sex or drug-injection partners of possible HIV exposure d # Box 7-C. Important topics when informing persons with HIV about how to prevent transmission of HIV to others (cont) # Topics related to sexual transmission (or perinatal transmission if pregnant woman becomes HIV infected through sexual contact) e,f  Communicating with partners to foster healthy sexuality (e.g., noncoercive sexual contact, negotiating safer behaviors)  Methods that HIV-discordant couples can use to reduce the risk of sexual HIV transmission, including the following:  Using latex and polyurethane male and female condoms: negotiating with partner to use; reminders to use; correct and consistent use  Using dental dams or other physical barriers while having oral-vaginal or oral-rectal sex  Using sexual positioning that lowers a partner's risk of acquiring HIV (order from lowest to highest risk: insertive fellatio, receptive fellatio, insertive penile-vaginal sex, receptive penile-vaginal sex, insertive anal sex, receptive anal sex) g  Practicing mutual masturbation and digital penetration and using clean sex toys that do not cause anal or genital bleeding or trauma h  Avoiding exposing partner to blood, semen, vaginal secretions, and other body fluids that are visibly contaminated with blood  Avoiding sexual intercourse with HIV-infected persons after invasive anal or genital procedures until healing is complete, i or when anal or genital bleeding, inflammation, or trauma may be present (e.g., if infected with STD or when using irritating sexual aids) h  Using only water-based spermicides and lubricants that do not contain nonoxynol-9  Avoiding contact with body fluids of HIV-infected persons after invasive oral or dental procedures  Reducing the number of sex partners  Risk of acquiring STDs in genital and nongenital sites if having genital, anal, or oral sexual contact e  Presence of symptomatic or asymptomatic STD in persons with HIV e  Presence of symptomatic or asymptomatic STD in HIV-uninfected partners, which may increase their risk of acquiring HIV and may indicate a substantial risk for HIV that is a clinical indication for PrEP c  Methods to prevent unintended pregnancy e  Conception options that reduce the risk of HIV transmission f  Interventions to reduce the risk of perinatal transmission f  Evidence that male circumcision may reduce a man's risk of acquiring HIV from a female partner with HIV j Box 7-C. # Important topics when informing persons with HIV about how to prevent transmission of HIV to others (cont) # Topics related to transmission resulting from substance use and sharing drug-injection equipment k  Health benefits of abstaining from or reducing substance use  The relation between use of some recreational drugs and higher risk sexual practices (e.g., methamphetamines)  Risk of transmitting HIV when sharing drug-injection equipment  Benefits of completing substance use treatment (that may include relapse prevention and opioid substitution programs)  Methods to reduce the risk of transmitting HIV if drug injection continues, including the following:  Reducing the number of drug-injection partners  Using new, sterile equipment from reliable sources (pharmacies, SSPs)  Using sterile needles, syringes, fluids, cookers, and cotton each time to prepare and inject drugs  Using sterile water (preferable) or fresh tap water when preparing drugs  Never sharing or reusing drug-injection or preparation equipment  Cleaning injection sites with alcohol swabs before injection  Disposing needles and syringes in safe places after each use # Note. Providers can address topics relevant to each person with HIV using print, audiovisual materials, or discussion over one or more encounters. The Implementation Resources topic in this section includes a link to print, audiovisual, and online risk-reduction interventions and materials that can be used in nonclinical and clinical settings. a See Section 3, Context of Prevention. b Preexposure prophylaxis (PrEP) is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. c See Section 5, Antiretroviral Treatment, for more information regarding the use of PrEP and nPEP. 6,7 d See Section 8, Partner Services, for more information. e See Section 10, Reproductive Health Care, for more information on contraception and conception options. f See Section 11, Pregnancy, for more information on interventions to reduce the risk of perinatal HIV transmission. g Estimated risk of acquiring HIV from an HIV-infected partner (in order of lowest to highest risk): insertive fellatio, receptive fellatio, insertive vaginal sex, receptive vaginal sex, insertive anal sex, receptive anal sex. 8,9 h Including penile piercing devices, constrictive penile rings, or other sex aids, devices, or toys that have touched the blood or genital secretions of HIV-infected persons (see the Evidence topic in this section for additional information). i Examples include tubal ligation; vasectomy; dilatation and curettage; and removal of vaginal, cervical, and penile warts, polyps, and precancerous lesions. j CDC has disseminated information from African trials showing that adult male circumcision may reduce a man's risk of acquiring HIV from an infected female partner. 1,10 k More detailed CDC guidance on methods to reduce the risk of injection-related HIV transmission is found in other sources. 11 # Box 7-D. Examples of population-level strategies for health departments to support risk screening and risk-reduction services  Monitor prevalence of HIV risk behaviors in jurisdiction through behavioral surveillance or special projects  Support programs that increase access to risk-reduction information, condoms, and legal, sterile syringes, if allowed in the jurisdiction  Make available directories of:  risk-reduction services sites  condom distribution sites  legal sources of sterile syringes  substance abuse treatment programs  Provide technical assistance to clinical and nonclinical providers about these topics:  how to access and strengthen risk-reduction services networks  financial and reimbursement issues  protecting confidentiality and data  security during the referral process # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with other current federal guidance that advises conducting routine, periodic risk screening; providing accurate information about HIV transmission risk; offering behavioral risk-reduction information; providing risk-reduction interventions tailored to an individual's risks onsite or through referrals; § § encouraging safe and voluntary disclosure of HIV-positive status to partners; and informing partners about biomedical and behavioral methods to reduce their risk of acquiring HIV. 1,6,7, These recommendations are also generally consistent with the latest guidance about these topics from several nongovernmental organizations. However To describe the prevalence of sexual and drug-injection risk behaviors in persons with HIV in the United States, the writing group also conducted a narrative review of articles published in PubMed database between 2010 and March 2014 that were indexed with these terms: HIV, risk behavior, and HIV transmission. # Evidence Supporting the Recommendations This topic summarizes evidence that supports recommendations on risk screening, several behavioral interventions, and one biomedical intervention (male circumcision). Other sections summarize the evidence that support recommendations about other biomedical interventions: antiretroviral treatment (Section 5), ART adherence (Section 6), partner services (Section 8), STD services (Section 9), reproductive health care (Section 10), pregnancy services (Section 11), and services for other medical conditions and social factors that influence HIV transmission (Section 12). # The role of risk screening for behavioral and biomedical factors that influence HIV transmission in guiding the content of risk-reduction interventions Accurate information on behavioral and biologic risks of HIV transmission is needed to identify the most appropriate risk-reduction interventions. However, it can be difficult to accurately estimate a person's risk of HIV transmission because risk varies depending on the type and frequency of sexual and drug-injection behaviors, ART use and adherence, HIV viral load, concurrent STDs, pregnancy, partners' HIV status, and other factors over time. Moreover, the results of risk screening may be inaccurate due to 31  poor recall  misunderstanding about risks associated with specific behaviors  previous negative experience with disclosing risk behaviors  fear of or experience with negative judgments, criticism, or stigmatization  desire for social approval  concerns about legal consequences of reporting risk behaviors  doubts about confidentiality protections  poor rapport with providers Studies show that some persons who have been diagnosed with an acute bacterial STD-an objective marker of unprotected sexual activity-deny having unprotected sex. 1 However, providers who conduct risk screening using a nonjudgmental approach that stresses confidentiality may encourage trust and elicit more honest responses. 32,33 Most clinical providers and some nonclinical providers can access biomedical information, such as a recent STD diagnosis, that can help to validate the accuracy of reported risk behaviors. 1 Three controlled clinical studies found that information elicited during risk screening guided the content of motivational interviews and led to statistically significant reductions in the amount or frequency of unprotected anal or vaginal sex. By periodically screening for both behavioral and biologic factors that influence HIV transmission, providers can identify a wider range of risk-reduction options that are acceptable to persons with HIV and their partners. 34 For example, some persons with HIV may prefer lifelong ART use with high adherence rather than lifelong condom use. Other persons with HIV may urge partners to reduce their risk of exposure or biologic susceptibility to HIV by using condoms, taking PrEP, or seeking screening and treatment for STDs. # The role of behavioral risk-reduction interventions in promoting safer sexual behavior or reducing HIV or STD transmission # Characteristics of behavioral risk-reduction interventions associated with unprotected sex and STD acquisition in persons with HIV Two 2006 meta-analyses evaluated a total of 18 different controlled trials of behavioral risk-reduction interventions conducted in the United States, Puerto Rico, and Canada after ART became available in 1996. 26,27 The interventions involved single or multiple sessions in clinical or nonclinical settings. Both meta-analyses concluded that behavioral risk-reduction interventions were effective in reducing the frequency or number of unprotected sex acts and/or the risk of acquisition of STDs by persons with HIV. 26,27 Several intervention characteristics were significantly associated with a lower frequency of unprotected sex (i.e., 95% confidence intervals did not include 1.0). These characteristics included the following:  based on cognitive behavioral theory 26 (OR=0.52)  used motivational enhancement 27 (OR=0.32)  offered skills building (e.g., correct use of male and female condoms, role play for negotiating condom use) 26 (OR=0.59)  focused on HIV transmission behaviors in more than two-thirds of sessions 26 # Behavioral risk-reduction interventions in clinical or nonclinical settings Several studies have shown that persons with HIV tend to report safer sexual activity after having received behavioral risk-reduction interventions in clinical or nonclinical settings. These studies include a demonstration project in public-sector HIV clinics 35 # and 14 interventions that CDC classified as EBIs ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Fifteen EBIs have met the established criteria as of April 2016, but the current version of this guideline has not been updated to reflect that number. (see the Methods topic in this section). 5,29 These EBIs were conducted in clinical (n=8) or nonclinical (n=6) settings and involved single or multiple sessions of varied duration. 5,29 Each intervention included at least one of the characteristics associated with intervention effectiveness listed above. # Brief prevention counseling messages during routine medical visits Three interventions classified as EBIs found that adults who received brief prevention counseling messages from clinical providers (or from actors portraying physicians in a video) during all routine HIV medical visits were significantly less likely to report unprotected sex than adults who did not receive these repeated messages. 2,3,36 These prevention messages were tailored to the patient's reported risk and/or focused on self-protection, partner protection, and HIV disclosure. All 3 interventions also included posters and/or patient brochures that reinforced the prevention messages provided by clinical providers. Additionally, findings of an evaluation 35 of observational data from 13 clinics funded by the Health Resources and Services Administration (HRSA) were consistent with the 3 EBIs. Brief risk-reduction counseling sessions (lasting about 3-5 minutes) during all routine HIV care visits were associated with a significant reduction in the number of reported acts of unprotected vaginal and anal sex. 35 # Intensive risk-reduction interventions during routine HIV care visits Five randomized control trials classified as EBIs found that patients who participated in a series of several interactive prevention sessions, each lasting 40 to 120 minutes, had a significant reduction in the reported number of unprotected sex acts with partners at risk for acquiring HIV when compared with patients who received standard of care (e.g., basic HIV information) or non-HIV health promotion interventions (e.g., advice about nutrition or cancer prevention). The interventions used various approaches:  MSM with HIV serving as peer advocates offered MSM 4 individual counseling sessions and 2 follow-up sessions that focused on reducing unprotected sex with partners with negative or unknown infection status. 40  Trained facilitators offered 2 individual and 5 group sessions that focused on ART, adherence to ART, and sexual decision making under various hypothetical conditions related to substance use, HIV status disclosure, treatment status, viral load, social relationships, and mood. The intervention was also associated with improved adherence to ART. 39  Trained counselors offered individual, monthly sessions over 4 consecutive months. Sessions included motivational interviewing, CDs, and booklets that contained information about safer sex tailored to patients' risks, and 4 follow-up letters that reinforced the content of the preceding session. 37,38  Trained female peer educators with HIV and professional health educators offered 4 group sessions to women with HIV. Sessions focused on gender pride, social support, healthy sexual relationships, and skills to negotiate safer sex. 41  Trained male and female facilitators offered 23 sessions (two sessions per week over 6 months) to groups of adolescents with HIV. Sessions focused on coping with an HIV diagnosis, HIV disclosure, participating in health care decisions, identifying factors that triggered risk behaviors, skills to negotiate safer sex, implementing daily routines to stay healthy, and reducing substance use and unprotected sex. 42 # Intensive behavioral risk-reduction interventions in nonclinical settings In 6 EBIs, 5 peer educators or health educators led a series of interactive intervention sessions for individuals, small groups, or heterosexual HIV-discordant couples with varied demographic characteristics. 29, Sessions focused on coping with an HIV diagnosis, building condom-use skills, negotiating safer sex behaviors, avoiding drug use that might increase the risk of HIV transmission, and other topics. Compared with groups who did not receive the interventions, participants of all 6 interventions were significantly less likely to report unprotected sex acts during the 3 to 12 months after sessions ended. The magnitude of reductions varied by intervention. 29 # Condom distribution in clinical and nonclinical settings A meta-analysis of 21 studies found that programs that increased the acceptability and accessibility of condoms in several sites used by persons with HIV and persons at high risk for HIV. 51 These sites included: publicly-funded health care facilities (e.g., health clinics, mental health centers, substance abuse treatment centers), local businesses (e.g., hotels, bars, bathhouses, brothels), schools (e.g., outside classrooms and nurses' offices), and organized public events. The analysis of 20 studies reported significantly increased condom use among persons who access these sites (OR=1.81, 95% CI: 1.51, 2.17). An analysis of 5 studies found that condom distribution programs were associated with a reduced incidence of HIV and STD among persons who access these sites (OR=0.69, 95% CI: 0.53, 0.91). 51 # The cost-effectiveness of behavioral risk-reduction interventions A recent cost-effectiveness analysis evaluated 5 individual-and group-level interventions shown to reduce unprotected sex in 3 hypothetical populations of persons with HIV (MSM, heterosexual persons, and PWID). 30 The evaluation found that providing these interventions to prevent HIV transmission was cost-saving compared with not providing the interventions and that the intervention cost per new case of HIV averted for a hypothetical population of MSM (~$150,000) 30 was substantially lower than the lifetime cost of HIV treatment (>$400,000). 52 When these same estimates of intervention cost and intervention effectiveness were applied to hypothetical populations of heterosexual persons with HIV and PWID, these interventions were cost-effective in preventing HIV transmission (with a cost per qualityadjusted life year gained of ~$550 for heterosexual persons and ~$16,000 for PWID) compared with not providing the interventions. However, the intervention cost per new case of HIV averted was slightly greater than the lifetime cost of HIV treatment for both populations. 30 # The relation between sexual practices and risk of sexual transmission # Type of sexual activity Seropositioning is the practice of modifying sexual activity based on beliefs about the partner's HIV infection status and the per-act risk of HIV transmission for a given type of contact. A recent study found the estimated relative risk of acquiring HIV varies by the type of sexual activity. 8 The risk is highest for receptive anal sex, and decreases in the following order: insertive anal sex, receptive vaginal sex, insertive vaginal sex, receptive fellatio, § § § § and insertive fellatio. * (The risk associated with § § § § The practice of receiving a partner's penis in one's mouth. * The practice of inserting one's penis into a partner's mouth. cunnilingus † † † † † was not examined.) By extension, persons with HIV are most likely to transmit HIV to their uninfected partners when practicing insertive anal sex (person with HIV inserts his penis into partner's anus), followed in order by receptive anal sex (person with HIV receives partner's penis in his/her anus), insertive penile-vaginal sex (person with HIV inserts penis into partner's vagina), receptive penile-vaginal sex (person with HIV receives partner's penis in her vagina), insertive fellatio (person with HIV receives oral stimulation of his penis by partner), and receptive fellatio (person with HIV orally stimulates penis of partner). 8 Serosorting is the practice of having unprotected sex only with partners believed to have the same HIV infection status. Persons with HIV who have sex only with infected partners cannot transmit HIV to uninfected persons only if assumptions about partner infection status are correct. Serosorting among persons with HIV may rarely cause HIV superinfection, 53 the acquisition of another HIV strain that may reduce the effectiveness of HIV treatment if new, drug-resistant HIV strains are acquired. 54 Serosorting does not protect persons with HIV from acquiring hepatitis C virus infection or STDs, including STDs that may facilitate HIV transmission. 1,13,55 Practices that result in anal or genital trauma, inflammation, or bleeding Some sex toys and products that contain nonoxynol-9 (lubricants and spermicides) may occasionally cause anal or genital trauma, bleeding, irritation, or inflammation that may increase the risk of HIV transmission, especially if these products are used frequently or for long duration. 1,24,25, Longstanding recommendations to inform women with HIV that unprotected sex during menses poses a potential risk of HIV transmission were based on evidence that menstrual fluid and female genital secretions may contain HIV. The HIV viral load in menstrual fluids of women who have high adherence to effective ART is substantially lower than the viral load in menstrual fluids of women not taking ART. 60,61 However, plasma viral load may not reflect the HIV viral load in female genital secretions and women with HIV can shed HIV even if their plasma viral load is undetectable. 62 One nested case-control study of risk factors for prevalent HIV infection among uncircumcised Kenyan men, found that having sex with a partner during menses increased the odds of becoming HIV-infected about two-fold (OR 2.1, 95% CI: 1.1-3.7) after controlling for all other factors that were associated with prevalent HIV infection. 63 However, a longitudinal study of European HIV-discordant couples (in which either the man or woman was infected) who inconsistently used condoms did not report an association between sex during menses and HIV transmission. 64 # Use of recreational drugs before or during sex A 2012 systematic review of 61 studies among MSM with HIV found that those who used methamphetamine were more likely to engage in higher-risk sexual behaviors (e.g., having unprotected anal intercourse, group sex, sex with multiple partners, sex with casual partners, sex with PWID, sex with HIV-uninfected partners) than MSM with HIV who do not use this drug. 65 One U.S. study found that use of inhaled nitrites ("poppers") was associated with engaging in unprotected anal intercourse. 66 Several studies have shown that use of erectile dysfunction medications was associated with unprotected anal sex among MSM, including MSM with HIV. # Male circumcision Three well-designed clinical trials in African countries found that circumcision of HIV-uninfected men reduced their risk of acquiring HIV from women by 50% to 60%. Observational studies in heterosexual, HIV-uninfected persons have found that male circumcision reduced a man's risk of acquiring STDs that facilitate HIV transmission or acquisition (e.g., syphilis, HSV-2) and reduced a female sex partner's risk of acquiring STDs that facilitate HIV transmission or acquisition (i.e., female genital ulceration, bacterial vaginosis, and trichomoniasis) (see Section 9, STD Services). A metaanalysis of the 7 well-designed studies conducted in African countries (1 randomized controlled trial and 6 longitudinal analyses) found that female partners of circumcised men did not have a lower risk of acquiring HIV (RR 0.80, 95% CI 0.53-1.36). 79 Most HIV transmission in the United States occurs among MSM, most of whom practice both insertive and receptive anal sex. 70,80,81 A recent Cochrane Review conducted pooled analyses of data from 20 observational studies of MSM that included more than 65,000 participants from low-, middle-, and high-income countries, most of whom were circumcised as infants. 82 Pooled analyses of data from all MSM and the subset of MSM reporting receptive anal sex found that circumcision had no protective effect. The authors concluded that this evidence was insufficient to support a recommendation that adolescent or adult MSM undergo circumcision as an HIV prevention strategy. 82 The American Academy of Pediatrics (with endorsement by the American College of Obstetricians and Gynecologists ), the American Academy of Family Physicians (AAFP), and the American Urological Association (AUA) stated that neonatal circumcision has potential health benefits, such as prevention of urinary tract infections, penile cancer, and some sexually transmitted infections, including HIV. Although the AAP, ACOG, and AAFP concluded that these health benefits were not sufficient to recommend routine neonatal circumcision for health reasons, they stated that the benefits of neonatal circumcision are sufficient to justify access to this procedure, including third-party payment, for families that choose it. The AAFP and AUA have cautioned that African studies showing that circumcision substantially reduces the risk of men acquiring HIV from women with HIV may not necessarily be extrapolated to men in the U.S. The AAFP list of recommended clinical indications for adult circumcision (penile abnormalities and diseases) does not include preventing HIV acquisition. 87 The AUA recommends presenting circumcision to men in the U.S. as one possible strategy to prevent HIV acquisition that should be used with other prevention methods such as safe sexual practices. 86,87 # The role of risk-reduction interventions in promoting safer druginjection behaviors # Behavioral interventions Studies are too few to determine if behavioral interventions can promote safer drug-injection behaviors (e.g., needle cleaning) in persons with HIV who continue to inject drugs. 26 However, several studies have shown that many PWID with HIV stop injecting drugs or inject less frequently after they obtain substance use treatment. # Syringe services programs Using nonfederal funds, many U.S. communities distribute sterile drug-injection equipment and/or information about the benefits of sterile syringes to PWID through syringe services programs (SSPs), ‡ ‡ ‡ ‡ ‡ outreach workers, or vending machines. 91,92 Several reviews of evidence from North America, including one systematic review conducted in the United States in 1997, found that SSPs lead to safer injecting behaviors and can be effective in reducing HIV transmission among PWID when part of comprehensive HIV prevention programs. The Institute of Medicine's evaluation of SSPs in the United States and other countries found that SSPs were associated with reductions in drug-use and injection-related risk behaviors (such as sharing injection equipment). However, it concluded that evidence of the effect of SSPs on HIV incidence was inconclusive. 93 A study from San Francisco that included about 100 PWID, including persons with HIV, found that many PWID relied on syringes from SSPs or pharmacies that sold sterile syringes, and that PWID were more likely to share injection equipment when access to these syringe sources was limited. 99 # Legal access to syringes through physicians and pharmacists Sterile syringes are sold in pharmacies in some states to reduce the risk of transmitting HIV and other bloodborne pathogens; § § § § § some states require a physician's prescription to purchase syringes. 100,101 A CDC report concluded that physician prescribing authority may not have a large-scale, population-level impact on HIV incidence, but this method offers PWID with HIV a safe means to obtain sterile syringes. 102 A 2006 national physician survey found that fewer than 1% of participants reported prescribing syringes for PWID, including persons with HIV, but 60% reported a willingness to prescribe syringes for PWID. 100 Physicians with certain characteristics were more likely to report being willing to prescribe syringes: they served PWID, asked PWID about syringe sharing, believed that PWID share syringes because of lack of access to sterile syringes, knew that syringes were legally available in their community, and knew other physicians who prescribed syringes. 100 The effectiveness of physician prescribing authority as a strategy to promote safer injection behaviors and reduce HIV incidence has not been evaluated at a population level. # Oral opioid maintenance programs A 2011 Cochrane systematic review assessed the influence of opioid substitution programs on injection and sexual behaviors. The review evaluated 38 studies, including many from the United States, involving more than 12,000 participants. The studies consistently found that oral methadone or buprenorphine maintenance treatment by opioid-dependent PWID was associated with statistically significant reductions (i.e., 95% confidence intervals did not include 1.0) in subgroups with these characteristics 103 :  used opioids (relative risk ranged from 0.37 to 0.81)  used drug-injection equipment (relative risk ranged from 0.45 to 0.87) ‡ ‡ ‡ ‡ ‡Syringe services programs provide free, new, sterile syringes and needles in exchange for used syringes and needles to reduce transmission of bloodborne pathogens among people who inject drugs. They may be called syringe exchange programs or needle exchange programs. § § § § § At the time of the review, these activities were not supported by federal funds. Check with your state health department for latest information on funding opportunities.  shared drug-injection equipment (relative risk ranged from 0.37 to 0.49)  had multiple sex partners (relative risk = 0.37)  exchanged sex for drugs or money (relative risk ranged from 0.62 to 0.65) # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Abstinence from penetrative sexual intercourse is the most effective method to reduce the risk of sexual HIV transmission. However, many persons with HIV remain sexually active and use other methods to reduce their risk of HIV transmission after their diagnosis. An analysis of 2009 surveillance data found that among about 600,000 persons with HIV with unsuppressed viral load, 20% engaged in unprotected, HIV-discordant risk behavior, resulting in an estimated transmission rate of 23.13%. A meta-analysis of 30 U.S. studies that included more than 18,000 MSM with HIV estimated that the prevalence of unprotected anal sex was considerably higher with partners with HIV (30%, 95% CI: 25%-36%) than with partners of unknown HIV infection status (16%, 95% CI: 13%-21%) or HIV-uninfected partners (13%, 95% CI: 10%-16%). 80 Abstinence from sharing drug-injection equipment with HIV-uninfected persons is the most effective method to reduce injection-related HIV transmission but many persons who are addicted to injected drugs continue to share injection equipment after their HIV diagnosis. In 2012, an estimated 3,456 reported cases of HIV were related to injection drug use, not including cases among MSM who injected drugs. 110 Many cases occurred in areas where substance use treatment and legal sources of sterile syringes are available to PWID. Baseline data from an ongoing RCT that enrolled 1,100 HIV-infected PWID found that 39.7% engaged in both sharing drug-injection equipment and unprotected sex. 109 In 2009, 25% of the estimated 165,900 PWID with HIV had unsuppressed viral load and reported unprotected sex with persons of different HIV infection status. 109 Of the 179 cases of perinatally infected infants diagnosed in 15 areas during 2005-2008, several were born to women who became infected after having sex or sharing drug-injection equipment late in pregnancy with a person with HIV. 111 Whenever possible, most persons with HIV should receive some risk-reduction counseling from their health care providers when they start HIV medical care. Nationally representative data indicate that only about 45% of persons receiving outpatient HIV medical care reported receiving HIV prevention counseling † † † † † † from a health care provider during the preceding year. 112 Evaluations of patients receiving HIV primary care through the Ryan White HIV/AIDS Program in 9 states found that 53% of all patients and 65% of PWID reported having discussed safer sex and HIV prevention methods with their providers during their last visit. 113,114 Some clinical providers who provide HIV risk-reduction counseling at initial visits do not provide it at later visits. In one study, 60% of providers reported providing risk-reduction counseling to more than 90% of their newly diagnosed patients, but only 14% of providers reported such counseling to more than 90% of their returning patients. 115 A study of patients with HIV in 15 Ryan HIV-discordant risk behavior is engaging in unprotected sex or sharing drug-injection equipment with a person with a different HIV infection status. † † † † † † HIV prevention counseling is an interactive process between client or patient and counselor aimed at reducing sexual, drug-use, and reproductive behaviors that pose a risk of HIV transmission or acquisition. White-funded clinics in 12 states and Washington, DC, showed that providers reported counseling 69% of new patients but only 52% of returning patients. 116 Lack of time and staff and competing priorities are common barriers to providing risk screening and riskreduction interventions in clinical settings, community-based organizations, and health departments. 117,118 Intensive, multisession interventions are generally more effective in promoting safer behaviors among persons with HIV than brief interventions (see the Evidence topic in this section). However, intensive interventions are impractical without trained staff and dedicated space and they may appeal only to persons who will commit to attending several sessions. Some clinical providers may defer risk screening and risk-reduction interventions because they do not 1) have the needed skills or comfort, 2) believe that interventions will change behaviors, or 3) provide periodic STD screening that might identify patients with objective markers of unprotected sex. 113,115, A qualitative systematic review of 30 behavioral risk-reduction interventions found that several factors enabled provision of brief or intensive risk-reduction interventions in clinical settings 28 :  Securing buy-in from clinical providers before introducing the intervention  Addressing provider attitudes and beliefs about risk reduction  Overcoming resistance from providers who are uncomfortable with risk-reduction counseling  Providing training in selected risk-reduction counseling techniques  Anticipating changes in clinic flow due to the intervention  Clarifying responsibilities of all members of the care team to provide or reinforce risk-reduction messages At least three studies found that training and decision-support tools can enhance providers' comfort, skill, efficiency, and motivation to provide risk screening and risk-reduction interventions. 120,122,124 Brief provider-or patient-administered risk-screening tools and computer-based and video-based risk-reduction interventions may be practical alternatives for both clinical and nonclinical providers when time is limited (see the Implementation Resources topic below). 26,29 By offering accurate, self-collected STD screening tests that do not require provider time for specimen collection, providers can routinely use positive test results as markers of unprotected sex (see Section 9, STD Services). Clear billing procedures, adequate reimbursement, and formal referral agreements with other providers of risk-reduction interventions also promote delivery of risk-reduction interventions. 113 The Patient Protection and Affordable Care Act (ACA) enables clinical and nonclinical providers to bill risk screening and risk-reduction services. 125 Some health departments are exploring third-party reimbursement for risk-reduction services. 126,127 # Policy, legal, and ethical considerations Laws about HIV confidentiality protections, HIV disclosure, and duty to inform others about possible HIV exposure vary by jurisdiction. Providers who are aware of these laws are better equipped to fulfill their own obligations to notify persons of possible HIV exposure and to inform persons with HIV about their rights and responsibilities regarding HIV disclosure. (See Section 3, Context of Prevention, and Section 8, Partner Services, for details on the legal and ethical issues related to HIV exposure.) In some jurisdictions, persons with HIV may hesitate to carry condoms or sterile drug-injection equipment in public settings if possessing these devices could result in charges of illegal sex work or drug use. 128,129 Laws about the distribution and prescription authority for sterile drug-injection equipment vary by jurisdiction; some states do not authorize legal access to sterile equipment through medical care providers, pharmacists, or SSPs. 130 # Implementation Resources Resources to support implementation of these recommendations are available at . These include risk-screening tools, training materials, and packaged information on evidence-based risk-reduction interventions. 5 # Section 8. HIV Partner Services Background HIV partner services comprise an array of voluntary services intended to reduce HIV transmission. They are provided to 1) persons with HIV (described as index patients) who have been newly diagnosed in clinical settings † or nonclinical settings; ‡ represent a case of infection that is reported to health departments; or have been previously diagnosed and also pose a high risk of exposing others to HIV (e.g., a recently diagnosed STD that indicates unprotected sex § or may facilitate HIV transmission or sharing drug-injection equipment); and 2) their sex and drug-injection partners. The core components include interviewing persons with HIV to obtain information to contact or locate their sex and druginjection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted disease (STD), and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. 1 This proactive approach can hasten the diagnosis of HIV and other infections; can prompt treatment before symptoms appear; and can reduce the transmission, burden, and costs of these communicable diseases in communities. Reporting of cases of HIV, syphilis, gonorrhea, and chlamydial infection † † is required in all states, the District of Columbia, and U.S. territories. 2 In many jurisdictions, receipt of a laboratory or clinical case report of HIV or STD by a health department or its HIV or STD surveillance program will activate a health department's legal authority to provide partner services. 1 Cases of HIV identified at anonymous testing sites cannot be reported by name to health departments. Most health departments initiate HIV partner services after receiving reports of confirmed cases of HIV. However, some may initiate contact with "presumptive" index patients upon receiving reports of positive preliminary test results 3,4 but defer notifying partners until additional testing of the index patient confirms HIV infection. Health departments can adopt this practice if they apply the 2014 Centers for Disease Control and Prevention (CDC) revised HIV surveillance case definition that allows routine reporting of positive preliminary HIV test results before confirmatory test results are available. 5 CDC's revised surveillance case definition also recommends routine reporting of cases of acute infection diagnosed by HIV antigen or nucleic acid amplification tests. 5 In states that adopt this case definition, health departments can rapidly identify acutely infected persons who are likely to be highly infectious and who warrant being offered expedited partner services. Some clinical and nonclinical providers contact health department partner services - A person with diagnosed HIV or STD and whose diagnosis prompts an investigation to identify other persons (known as partners) who may have become infected through sexual contact or exposure to blood or other body fluids of the index patient. † Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginal-digital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). Drug-injection equipment includes needles and syringes; drug preparation equipment, such as cookers, mixing containers, spoons, and filters; swabs; and water or some other liquid used for preparing a drug solution or for rinsing drug equipment. † † Another document describes partner services that are prompted by the diagnosis of bacterial STD in index patients who are not infected with HIV. 1 specialists immediately after they identify persons with positive HIV tests-particularly persons with acute infection-rather than wait for receipt of a surveillance case report to activate partner services. 1,3,4,6 In the United States, most HIV partner services are provided by health department partner services specialists who are highly trained in providing voluntary, confidential partner services and can be engaged through routine case reporting, provider referral, and requests by persons with HIV. 1 Nevertheless, methods of delivering partner services may vary by jurisdiction. Partner elicitation ‡ ‡ can be done by health department specialists, HIV testing providers, and other clinical or nonclinical providers who are trained and authorized to conduct partner elicitation. 1,6 Partner notification § § can be performed by health department specialists; physicians; nurse practitioners, and physician assistants who work under the authority of a physician; other clinical and nonclinical providers who are trained and authorized to provide partner notification; and index patients. 1 Some jurisdictions use hybrid methods in which 1) trained clinical providers or nonclinical HIV testing providers elicit partner information from index patients, but defer partner notification to health department specialists; 2) index patients give partner contact information to health department specialists, who in turn notify the partners; 3) index patients and health department specialists or other providers jointly notify the partners; and 4) index patients make verbal contracts with health department specialists to notify partners within a specific time frame, and if this fails, the specialists attempt to notify partners. Health department partner services are voluntary and confidential and usually involve no cost to index patients or partners; specialists notify partners of possible HIV exposure without revealing the index patient's name or other potentially identifying information. 1 These specialists contact index patients and partners by phone, letter, email, or text message or in person at HIV testing sites, HIV clinical settings, STD clinics, homes, or other community settings where private communication is possible. In some health departments, specialists also use "screen names" or other information provided by index patients to contact partners who were found through Internet dating sites, "chat rooms," mobile device applications, or social networking tools. 1,3,10 Specialists may also help index patients use Internet † † † or social media sites to directly notify partners about possible HIV exposure. 11 In a national survey of 57 state or local health departments, two-thirds reported using Internet-based partner notification. 9 Because partner services specialists routinely offer HIV testing to partners, they offer a form of targeted, community-based HIV screening for persons at high risk for HIV. Some partner services programs offer venue-based HIV testing in sites frequented by index patients or partners. 1 They also use social network ‡ ‡ ‡ or "cluster" approaches in which health department specialists encourage index patients or partners to recruit friends, family members, or others for HIV testing. 1 In some cases, specialists will actively link ‡ ‡ Partner elicitation is an early step of voluntary, confidential partner services in which a health department partner services specialist or other provider interviews or reinterviews a person with HIV or STD to collect names, descriptions, and locating and contact information of persons who are sex or drug-injection partners so the partners can be notified of possible HIV or STD exposure. § § Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. * Social networking is a strategy to recruit persons for HIV testing or prevention services in which high-risk individuals use their personal influence to recruit peers they believe are at high risk for HIV infection. index patients or partners with HIV to HIV medical care. 12,13 In addition, some health care providers provide HIV testing to partners who are referred by their patients with HIV. 6 This section addresses partner services prompted by a diagnosis of HIV or the diagnosis of an STD in a person previously diagnosed with HIV. Other federal guidance describes partner services for HIVuninfected persons diagnosed with STDs. 1 Quality improvement § § § and program monitoring and evaluation can determine if the services described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 9, STD Services, provides more information about STD screening, treatment, and counseling of index patients and management of partners. Section 5, Antiretroviral Treatment, describes the use of nonoccupational postexposure prophylaxis (nPEP) † † † † for HIV-uninfected partners with very recent HIV exposure, and preexposure prophylaxis (PrEP) ‡ ‡ ‡ ‡ for HIV-uninfected partners at substantial risk for acquiring HIV infection. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. # Recommendations Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. † † † † nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposure to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. ‡ ‡ ‡ ‡ PrEP is the daily, continuous use of a specific regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 14 # BOX 8. RECOMMENDATIONS-HIV PARTNER SERVICES (cont)  Newly diagnosed sexually transmitted diseases (STDs) that indicate recent unprotected sex (i.e., sexual activity without using a physical barrier) and facilitate HIV transmission-primary and secondary syphilis; gonorrhea and chlamydial infection (including rectal infection); herpes simplex virus type 2 (HSV-2); and trichomoniasis (in women) c  Increased risk of HIV transmission due to pregnancy d  Behaviors that pose a high risk of exposing others to HIV (e.g., multiple, anonymous partners; having unprotected sex with persons with negative or unknown HIV-infection status; sharing drug-injection equipment) e  A specific request for partner services  Ask index patients if they have disclosed their HIV infection to all sex and drug-injection partners and if selfnotification would pose any risks (i, ii, v)  Promptly refer index patients to health department partner services directly or through HIV case reporting according to the methods of the jurisdiction (i, ii, iii, iv, v, In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. In this section, recommendations for health department partner services specialists are listed separately from recommendations for other nonclinical providers because state and local laws and regulations influence their roles and responsibilities. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education and counseling; disease screening, diagnosis, and treatment; and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Most states authorize physicians to provide partner services as part of their duty to inform persons of possible exposure to HIV or STD. Some jurisdictions authorize other clinical providers to provide partner services because they work under the authority of a physician (e.g., nurse practitioners and physician assistants) or have been trained and authorized by health departments to provide partner services. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to . # BOX 8. RECOMMENDATIONS-HIV PARTNER SERVICES (cont) a See Section 3, Context of Prevention, for more information on HIV disclosure. b Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. c See Section 9, STD Services, for more information on STDs that may facilitate HIV transmission. d See Section 11, Pregnancy, for more information on how pregnancy influences HIV transmission. e See Section 7, Risk Screening and Risk Reduction, for more information on risk behaviors. f See Section 13, Quality Improvement, for more information. # Sources # General principles (i, ii)  Inform index patients and partners referred by index patients that partner services  have potential benefits and risks  are voluntary and confidential  can be provided in several ways, including through health department specialists  Consider various methods to notify partners based on the preferences of index patients and their partners' characteristics (e.g., found through the Internet, risk of adverse reaction), including self-notification and assistance from health departments and providers  Protect the confidentiality of the index patient and partners and the privacy of their health information a  Communicate in a nonjudgmental, culturally appropriate, and sensitive manner  Monitor and adhere to changes in jurisdiction regulations that may affect partner services, especially these issues:  Any duty of index patients or providers to inform spouses or other persons of possible HIV exposure a  Intimate partner violence, sexual assault, or child or elder abuse when index patients or partners report abuse or when abuse is suspected a  Rights of minors a # Services for index patients  Offer voluntary, confidential partner notification assistance through health department partner services specialists and explain the notification process, the role of health department specialists, and confidentiality protections (i, iii, iv, v, vi)  If the index patient accepts health department partner notification assistance, the health department specialist should take the following steps (i, iii):  Explain the rationale for notifying partners of possible HIV exposure (i.e., partners who had contact with the index patient in the 12 months before HIV diagnoses), with priority given to partners who had contact during the 3 months before HIV diagnosis or during the previous month if the index patient has acute HIV infection or high viral load  Ask the index patient which sex and drug-injection partners have already been notified of possible HIV exposure  Collect contact and other information, using CDC-recommended methods, about sex and drug-injection partners who have not been notified b  Collect information about physical venues and Internet sites frequented by the index patient or members of his or her social network if using venue-based or social network HIV testing methods  Assess barriers and risks to partner notification for each named partner (e.g., physical or verbal abuse), offer advice and services to reduce this risk (e.g., describe measures to prevent partner violence), and defer notification if a risk is apparent  Notify the index patient's partners using CDC-recommended methods b  Recognize that some index patients prefer to self-notify some partners but request assistance to notify other partners  If the index patient declines referral to health department partner services by a nonclinical or nonclinical, the provider should take the following steps (i, iii, iv, vi):  Help the index patient develop a plan to notify partners directly or with provider assistance, as allowed by the jurisdiction  Offer assistance in testing partners for HIV, STDs, and viral hepatitis c,d,e # Box 8-B. Essential elements of HIV partner services (cont)  If the index patient seeks partner notification assistance from a nonclinical or clinical provider who is trained and authorized to provide partner services, the provider should take these steps (i, iii, iv):  Explain the rationale for notifying partners of possible HIV exposure (i.e., partners who had contact with the index patient in the 12 months before HIV diagnoses), with priority given to partners who had contact during the 3 months before HIV diagnosis or during the previous month if the index patient has acute HIV infection or high viral load  Ask the index patient which sex and drug-injection partners have already been notified of possible HIV exposure  Collect contact and other information, using CDC-recommended methods, about sex and drug-injection partners who have not been notified  Assess barriers and risks to partner notification for each named partner (e.g., physical or verbal abuse), offer advice and services to reduce this risk (e.g., describe measures to prevent partner violence), and defer notification if a risk is apparent  Notify the index patient's partners using CDC-recommended methods as appropriate to legal authority and skills b  Recognize that some index patients prefer to self-notify some partners but request assistance to notify other partners  If the index patient chooses to self-notify any partner without assistance, the provider should describe (i, iii, iv, vii):  Possible challenges of self-notification, such as partner violence, and discourage self-notification if a risk is apparent  Self-notification methods for known partners (e.g., in person) and anonymous partners (e.g., established Internet notification programs)  Methods to improve the effectiveness of self-notification (e.g., focus on partners over the previous 3 months or, if diagnosed with acute HIV infection or high viral load, focus on partners over the previous month; use a private, safe setting; anticipate and respond to negative partner reactions; seek provider assistance if questions arise)  Key messages for partners (e.g., how to obtain HIV, STD, and viral hepatitis testing and evaluation in facilities that link partners with positive tests to health care providers or to home HIV testing if the partners decline other testing options) c,d,e  If the index patient declines any partner services through the health department, provider or self-notification, re-offer partner services at the next encounter and/or notify the HIV care provider serving the index patient that partner services should be offered at the HIV care visit, when appropriate (i)  Regardless of the partner notification method, the provider should promptly offer index patients the following prevention and care services onsite or through linkage, if not recently provided:  HIV medical care c (i, iii, iv, vi, viii, ix)  STD and viral hepatitis testing, evaluation, treatment, vaccination, and counseling c,d,e (i, iii, vi)  Risk-reduction services and devices (e.g., behavioral information, counseling, risk-reduction interventions, latex or polyurethane condoms) f,g (i, iii, iv, vi, ix)  Information about the availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition h,i (i, x, xi)  Other medical or social services that influence HIV transmission (e.g., substance use treatment, mental health services) j (i, iii, iv, vi, ix) # Box 8-B. Essential elements of HIV partner services (cont) Services for sex and drug-injection partners  Notify the partner about possible HIV exposure (and STD exposure if the index patient is coinfected with STD) without disclosing the identity of the index patient, using CDC-recommended methods (i, vi, viii)  Provide information about HIV, STD, and viral hepatitis infections (i, vi)  Promptly offer the following services onsite or through linkage:  HIV testing if the partner is not known to be HIV-infected (followed by verification of test results) k (i, iii, iv, ix) 16,17 The updated recommendations in this section are consistent with 2008 CDC recommendations for partner services 1 and other current federal guidance about partner services. 6,14, They are also consistent with the latest comparable guidance about notifying partners of patients with HIV from the International Antiviral Society-USA Panel. 23 They are also generally consistent with guidance about 1) social network, cluster, and Internet-based partner notification methods; 2) integrating and matching HIV and STD surveillance data to identify index patients eligible for partner services; and 3) collaborations among health departments, community-based organizations, and health care providers from the National Network of STD/HIV Prevention Training Centers, 9 the National Coalition of STD Directors, 10 and the National Alliance of State and Territorial AIDS Directors. 24 Compared with the 2003 Recommendations, 15 these updated recommendations  advise that health department specialists provide partner services whenever possible because of evidence that these specialists provide more efficient, effective, and cost-effective services than other providers  stress building relationships between health departments and HIV testing, prevention, and health care providers (especially those serving a large number of persons with HIV) to expedite partner services to index patients who have been newly diagnosed with HIV or are at high risk of exposing others to HIV  advise expediting interviews of index patients with laboratory or clinical evidence of acute HIV infection § § § § who may be highly infectious  stress actively helping index patients and partners with positive HIV tests to start or resume HIV medical care  advise informing index patients about the availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  encourage health departments to consider using innovative methods to locate and notify partners (e.g., Internet) # Methods The section writing group based most of these recommendations on the 2008 CDC recommendations for partner services that were based on a systematic literature review and expert opinion (that the writing group did not reexamine). 1,25 26 a review of Internet-based partner notification, 27 evidence-based guidance on partner services from an expert panel on community-based preventive services in the United States, 28 and 2 studies of the cost-effectiveness of HIV partner services. 29,30 # Evidence Supporting the Recommendations The literature review yielded new evidence about the relative effectiveness of health department partner services, the benefits of timely partner services, new methods to notify partners, and the costeffectiveness of partner services. Several studies confirmed earlier findings that health department partner services specialists contacted more partners with unrecognized HIV infection per index patient than other types of partner services providers. Specialized training and field experience may enable health department specialists to elicit more accurate information about partners from index patients 35 and to identify more partners per index patient. 31 In contrast, several studies indicate that many health care providers or HIV testing providers § § § § Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. may not 1) understand health department partner services procedures; 2) routinely advise patients to notify their partners about possible HIV exposure; 3) routinely refer patients for health department assistance; or 4) have the skills or time to elicit, notify, or manage partners. 31, Some providers do not inform persons newly diagnosed with HIV that case reporting required by health care providers and laboratories may activate health departments to offer partner services. 1 Several recent studies found that assigning health department specialists to work in clinics, hospitals, and private medical practices that provide a high-volume of HIV testing were more effective than traditional, offsite partner services. 3,12,37,39,40 Assigning health department specialists to work in testing sites can also increase the proportion of index patients who receive partner services and shorten the interval between diagnosis and interview. This approach can also increase the proportion of partners who were located, were newly diagnosed with HIV infection, and obtained treatment. 3,12,39,40 Some health departments routinely use HIV surveillance data to identify persons with acute infection or routinely integrate or match HIV and STD surveillance systems to identify HIV-infected persons who have new STD diagnoses and warrant being offered expedited interviews. Surveys of state and city health departments indicate that partner services programs that routinely access name-based HIV case reports and surveillance data can serve a higher proportion of index patients than health departments without such access. 9,46 Several studies found that partner services were more productive when they were offered to persons shortly after their HIV diagnoses or to persons diagnosed with acute HIV infection. 34, A small study in San Francisco evaluated the effort to find 1 newly identified HIV-infected partner; health department partner services specialists had to interview only 8 HIV-infected index patients if their interviews occurred within 2 weeks after diagnosis, but had to interview 21 HIV-infected index patients if their interviews occurred more than 2 weeks after diagnosis (p=0.008). 48 A study in North Carolina compared interview outcomes of persons with acute HIV infection and persons with established infection: persons with acute infection named 2.5 times more partners (95% confidence interval: 2.1 to 3.0) and named 1.9 times more partners who were newly diagnosed with HIV infection (95% confidence interval: 1.1 to 3.5). 34 A study in 2 large cities evaluated partner notification services for 48 persons with acute HIV infection; 23 of the 72 named partners underwent HIV testing and 5 (21.7%) had positive test results. 49 A study in New York City found that after health department partner services specialists began to offer rapid, point-of-service HIV testing to partners, the proportion of partners who underwent testing rose from 52% to 76% (p<0.001) and the program identified more than twice the number of partners with newly diagnosed HIV infection than it had before rapid testing started. 50 At least 5 recent evaluations examined partner notification using electronic technologies. Three evaluations assessed ecards (using inSPOT software) sent by index patients to notify partners as a means to supplement traditional partner notification. Although most evaluations used indirect methods to estimate partners' receipt of ecards or to estimate follow-up HIV testing (because they did not know the identity of ecard recipients), these evaluations found that awareness and use of inSPOT was limited and resulted in few partners obtaining HIV testing. 27,51,52 A few studies evaluated the acceptability of Internetbased partner notification. One found that gay, bisexual, or other men who have sex with men (MSM) were willing to receive or initiate emails about partner notification, regardless of their HIV infection status. 53 The investigators concluded that health departments considering Internet methods should use culturally sensitive social marketing campaigns to increase awareness and acceptability of these methods. A study of MSM found that responders would be less likely to seek care and to notify partners if notified by anonymous ecards than if notified directly by their partner. 54 Studies in 2 states evaluated the cost and effectiveness of partner services programs that included counseling and rapid HIV testing. 30 When fixed program costs were excluded, the estimated cost per partner notified of a new HIV diagnosis was $11,626 in Colorado and $2,545 in Louisiana. A costeffectiveness analysis assessed a set of partner services provided by health department specialists to 3 different hypothetical populations: MSM, persons who inject drugs (PWID), and heterosexuals. The services included HIV testing, referring HIV-infected partners to HIV care, and behavioral risk-reduction information. 29 These partner services were cost-saving compared with no intervention. Moreover, the intervention cost per new case of HIV averted in a partner (ranging from ~$116,000 for MSM, ~$263,000 for PWID, and ~$349,000 for heterosexuals) was lower than the lifetime cost of HIV treatment (>$400,000). 55 Other sections of this report cite evidence that supports recommendations about PrEP and nPEP (Section 5, Antiretroviral Treatment) and STD screening and treatment (Section 9, STD Services). # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities A 2006 survey of more than 51 health departments in the United States found that 43% of persons with newly reported HIV infection received health department partner services; this was a significant increase from the proportion reported in a 2001 health department survey (32%). 46 According to a survey and interviews of staff of health departments from 51 states/territories and 6 large cities published in 2008, * health departments offered partner services to 47% to 79% of index patients with HIV. 9 Health department partner services programs serving jurisdictions with low HIV morbidity and name-based HIV reporting were more likely than programs serving jurisdictions with high HIV morbidity without namebased reporting to report routinely use HIV surveillance to activate partner services, serve index patients diagnosed in private health systems, and notify a high proportion of partners. Many survey respondents reported that high caseloads in high-morbidity areas and unlinked or incompatible HIV surveillance and partner services information systems hindered partner services. In general, persons diagnosed with HIV in public-sector clinics and HIV testing sites affiliated with health departments are more likely to receive health department partner services than persons diagnosed elsewhere. 56 These public-sector sites are more likely to routinely refer index patients to health department partner services specialists or to invite these specialists to work onsite. To increase use of partner services, some health departments have marketed their services to private-sector HIV testing providers or assigned partner services specialists to work in large HIV care practices. 1,9,12,39,57 Since the passage of the Patient Protection and Affordable Care Act, some health departments are exploring thirdparty reimbursement to enhance program capacity. 9,58 * Most recent nationally reported data is available at . Although partner services can benefit all persons with HIV, high caseloads or staffing shortages force most health departments to prioritize the order of interviewing index patients and partners. 1 Most health departments expedite interviewing of index patients who have newly reported and newly diagnosed HIV infection. The 2014 CDC revised HIV surveillance case definition recommends that laboratories and HIV testing providers report cases of acute HIV infection or preliminary positive HIV test results to expedite partner services. 5,59 Some health departments also expedite interviewing of index patients with established HIV infection who have been recently diagnosed with STD (particularly infectious primary or secondary syphilis and rectal gonorrhea among MSM). Patients who are coinfected with HIV and STD are easier to identify if HIV surveillance and STD surveillance systems are integrated or routinely matched. 3,42 # Policy, legal, and ethical considerations Well-implemented partner services balance the interests of infected persons, their partners, and the community. Because partner services are voluntary and confidential, it is unethical to coerce, deceive, or withhold information from index patients when attempting to elicit partner information or notify partners. Index patients who feel pressured to provide partner information may not provide accurate partner information. Several studies show that most persons with HIV, their partners, and their health care providers accept partner services, including the involvement of health departments and Internet-based partner notification, and consider partner services a valuable service rather than an imposition. 53, Developing standard referral procedures and interagency agreements that protect confidentiality may improve the acceptability of partner services and improve communication and collaboration between HIV testing providers and health departments 1,9,10 (see the Implementation Resources topic below). State and local laws and public health regulations generally protect the confidentiality of all HIV and STD information, including information obtained from or about index patients. 1 Persons who fear that partner notification might cause stigma; provoke physical or verbal abuse; harm relationships; or expose illegal activity may choose confidential partner notification (that does not reveal the identity of the index patient) over self-notification. Confidentiality is subject to practical limits when a person has a single, identifiable partner and when couples seek joint HIV testing and post-test counseling. Although there is growing interest in couple-based HIV testing and counseling after joint consent, some providers hesitate to offer this service because of concerns about violating HIV-related confidentiality protections. 67,68 Despite the longstanding practice of confidential health department partner services, some clinicians, HIV testing providers, and persons with HIV may be unaware of or doubt these confidentiality protections. Some individuals and communities do not favor health department access to personal health information for public health purposes because they distrust public health authorities or fear the information might be stigmatizing, provoke negative partner reactions, or have legal ramifications. 1,62,69,70 Nevertheless, real or perceived breaches of confidentiality during provision of partner services appear to be rare. Several studies conducted from the late 1990s to 2011, most of which involved heterosexual partners, found that the risk of violence due to partner notification was low and that partner notification itself did not increase rates of partnership dissolution. 62,71,75 Some jurisdictions have laws that require or allow public health officials or health care providers to notify partners who may have been exposed to HIV infection, even when index patients object. 1 Persons who misunderstand these laws may believe that all partner notification is mandatory or nonconfidential. To minimize negative attitudes about partner services, providers can reassure index patients that partner services are strictly voluntary and confidential, are usually provided at no cost to index patients and partners, and are deferred if there is a risk of partner retribution. Section 3, Context of Prevention, and Section 9, STD Services, provide further information on policy, legal, and ethical aspects of partner services. # Special populations Some adolescents, undocumented immigrants, sexual assault survivors, prisoners, and other vulnerable or medically marginalized persons with HIV may resist health department partner services. Adolescents who do not know that these services are confidential, voluntary, and do not require parental consent in many states may appreciate careful explanations of consent and confidentiality procedures. Immigrants may believe that partner services conflict with their cultural norms or may prompt deportation or other legal action. Some immigrants may require partner services information in their own language. 1 Rapid, pointof-care HIV testing is useful when screening transient partners, such as migrant workers 1 (see Section 12, Other Medical and Social Services). # Section 9. Sexually Transmitted Disease (STD) Preventive Services Background Sexually transmitted diseases (STDs), also known as sexually transmitted infections (STIs), are infections transmitted through penile, vaginal, oral, or anal sexual contact, regardless of the presence of symptoms or signs. 1 In this section, STD preventive services for persons with HIV are defined as the following: assessment of behavioral and biological factors that may increase the risk of transmitting HIV or STD; sexual risk-reduction interventions; screening asymptomatic persons for STD pathogens; clinical evaluation (including physical examination and diagnostic testing- of persons with STD signs or symptoms); treatment; and partner services. † STD preventive services are an essential component of HIV prevention because 1) the diagnosis of an STD is an objective biologic marker of unprotected sexual activity that may result in HIV transmission; 2) certain STDs may increase plasma HIV viral load and genital HIV shedding, which may increase the risk of sexual and perinatal HIV transmission; and 3) STD treatment may reduce STD-related morbidity and lower the risk of HIV transmission. 1 The vast majority of STD preventive services are provided in health care facilities. However, some nonclinical settings, ‡ such as intake units of correctional facilities and residential job-training sites, schools, and community-based organizations, offer risk assessments, risk-reduction interventions, screening, and subsequent linkage § to treatment and partner services. 2 STD preventive services in nonclinical settings may be more convenient for populations who have limited or irregular access to health care. To be effective, nonclinical STD services must ensure prompt linkage of persons who have had STD symptoms, positive screening tests, or sexual contact with a partner treated for an STD to health care providers for examination and treatment and to health departments for voluntary, confidential partner services. 2 Self-collected specimens can be used to screen for some pathogens (i.e., chlamydial infection or gonorrhea using nucleic acid amplification tests tests) when requested by a physician or a nonclinical provider working under a physician's order. These specimens can be obtained at "express visits" in STD clinics, community-based organizations that offer HIV testing or risk-reduction services, or at home. Self-collected specimens collected in nonclinical - Testing that is initiated for a person with clinical signs or symptoms to obtain objective evidence of the presence or absence of diseases or infections. † Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). settings must be tested in laboratories that have validated procedures specified by the Clinical Laboratory Improvement Act (CLIA) for testing specimens obtained in nonclinical settings. Health departments are responsible for population-level STD prevention and control programs. These programs include STD case reporting and surveillance, outbreak detection and control, prevention services for persons with STD and their sex partners to stem onward transmission, assurance of STD preventive services in clinical settings, screening programs in nonclinical settings, antimicrobial drug resistance monitoring, provider and community education, and health promotion activities. This section focuses on preventive services for 5 STDs that may increase the risk of transmitting HIV: syphilis, gonorrhea, chlamydial infection, and herpes simplex virus type 2 (HSV-2) in men and women and trichomoniasis in women. 1 This section does not provide comprehensive recommendations about STD preventive services for persons with HIV. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont) # Specific to clinical providers (in addition to above recommendations)  At initiation of HIV medical care, provide all persons with HIV the following services:  Detailed sexual history, including number and gender of sex partners; types of sexual practices; anatomic sites of sexual contact; condom use; previous STD screening, testing, diagnoses, and treatment; and recent sex partners who have had STD symptoms or treatment b (i, iii)  Detailed history of alcohol and substance use b (i, iii)  Detailed history of recent STD-related symptoms (e.g., urethral, vaginal, or anal discharge; dysuria; abnormal vaginal or rectal pain or bleeding; genital, perianal, or oropharyngeal exudate, sores or bumps; skin rash) (i, iii)  STD screening tests d,f (i, iii) (see Box 9-A)  Physical examination for signs of STDs, including skin, oral, anal, genital, and gynecologic examinations for women and skin, oral, anal, and genital examinations for men (i, iii)  Diagnostic testing for STD if persons have STD signs or symptoms f (i, iii)  For persons with HIV who report sexual or drug-injection risk behaviors, provide the following services: - Provide or refer to brief or intensive behavioral risk-reduction interventions b (i, ii, iii, v, vi) - Refer to voluntary health department HIV partner services or other trained partner services provider if persons are newly diagnosed with HIV; have evidence of acute HIV infection or high HIV viral load; or report new sex partners h (i, ii, iii, iv, v)  For persons with HIV who have a clinical evaluation indicative of STD or positive screening or diagnostic STD tests, or recent sex partners who have had STD symptoms or treatment for syphilis, gonorrhea, or chlamydial infection, provide the following services: - Provide oral or injectable STD treatment onsite, including presumptive treatment i (while awaiting STD test results) when indicated, according to the latest CDC STD Treatment Guidelines (i, iii, vi, vii) - Advise to return 3 months after treatment for gonorrhea, chlamydial infection, or trichomoniasis to obtain retesting for the relevant infection at the anatomic site of infection k (i, iii) (see Box 9-A) - Advise persons diagnosed with syphilis to return for follow up serologic testing according to latest CDC recommendations k (i) (see Box 9-A) - Provide or refer for brief or intensive behavioral risk-reduction interventions b (i, iii, vi) - Refer to voluntary health department HIV/STD partner services or other trained partner services provider h (i, iii, iv) - Report cases of STD according to jurisdiction requirements and inform persons diagnosed with STD that case reporting may prompt health departments to offer voluntary, confidential partner services in some jurisdictions j (i, iii) # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont)  At follow-up HIV care visits, provide all persons with HIV the following services:  Review of sexual, alcohol, and substance use histories since last visit to determine if behavioral riskreduction interventions are warranted b (i, iii)  Review of STD symptoms since last visit and recent sex partners who have had STD symptoms or treatment to determine if STD testing, physical examination, or treatment is warranted (as described above at initiation of HIV care) (i, iii)  STD screening at least annually or more often if indicated by sexual risk behaviors d,f (i, iii) (see Box 9-A)  Review of sex partners who were not notified of possible HIV or STD exposure to determine if offering HIV partner services is warranted h (i, iii)  For persons with a positive STD test; STD symptoms or signs; or recent sex partners who have had STD symptoms or treatment for syphilis, gonorrhea, chlamydial infection, or trichomoniasis or experiencing STD symptoms, provide the following services: - Provide oral or injectable treatment onsite according to the latest CDC STD Treatment Guidelines (including presumptive treatment (while awaiting STD test results) if indicated because of STD symptoms, or recent sex partners who have had STD symptoms or treatment) i (i, iii, vi, vii) - Advise to return 3 months after treatment for gonorrhea, chlamydial infection, or trichomoniasis to obtain retesting for the relevant infection at the anatomic site of infection k (i, iii) (see Box 9-A) - Advise persons diagnosed with syphilis to return for follow up serologic testing according to latest CDC recommendations k (i) (see Box 9-A) - Provide or refer to brief or intensive behavioral risk-reduction interventions b (i, iii, vi) - Refer to voluntary HIV/STD partner services at health department or other trained partner services provider h (i, iii, iv) - Report cases of STD according to jurisdiction requirements and inform persons diagnosed with STD that case reporting may prompt health departments to offer voluntary, confidential partner services in some jurisdictions j (i, iii) For staff of health departments who provide population-level HIV prevention and care services  Develop methods to integrate or routinely match HIV and STD surveillance case reports and use these surveillance data to routinely identify populations or individuals with HIV who have new STD infections and may warrant being offered HIV and STD preventive services, including voluntary partner services (iv, viii)  Support efforts to promote STD and HIV prevention for persons with HIV in community (i, iv, viii) (see Box 9-B) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to /. # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont) a Some of the cited source guidance that supports this recommendation was intended for clinical providers and partner services specialists. Based on program experience in the United States, the section writing group concluded that it would be beneficial and feasible for some nonclinical HIV prevention providers to implement this recommendation. b See Section 7, Risk Screening and Risk Reduction, for information on assessing behavioral and biologic factors that may influence risk of HIV transmission and risk-reduction interventions. Assessment of behavioral and biologic risks factors is recommended at initial and subsequent visits in clinical settings providing continuing care. In clinical or nonclinical settings that provide one-time or episodic STD services, assessment is recommended at initial encounter and when clients seek follow-up services; recalling clients specifically for risk assessment may not be feasible. c In this section, the term "assess" means eliciting information about behavioral and biologic risk factors for HIV transmission, including history of STD and STD symptoms, and the term "screen" means testing for STD pathogens in persons without symptoms. In other sections, the term "screen" means a brief assessment of behavioral and biologic risk factors for HIV, including history of STD, and STD symptoms that differs from an intensive, individually tailored assessment of these factors; and the phrase "STD screening tests" means testing to assess the presence of infection. d This section does not address screening persons with HIV for other conditions that have not been shown to facilitate HIV transmission to others, such as viral hepatitis and human papillomavirus infection. e See Section 4, Linkage to and Retention in Care. According to the latest CDC STD Treatment Guidelines, 1 immediate presumptive treatment (or immediate linkage to such treatment) is recommended for persons who report sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis or have STD syndromes in order to reduce the risk of onward STD transmission. STD syndromes are conditions that can be caused by sexually transmitted pathogens and that cause symptoms or abnormal findings (signs) on physical examination, such as genital ulcer disease, urethritis, cervicitis, pelvic inflammatory disease, epididymitis, and proctitis. j Information in the Policy, Legal, and Ethical Considerations topic in this section supports this recommendation. k The cited source guidance describes the rationale for retesting for syphilis, gonorrhea, chlamydial infection; the Evidence topic describes the rationale for retesting for trichomoniasis.  Urogenital N. gonorrhoeae (using nucleic acid amplification tests on urine specimen) a,b (i, ii, iii)  Urogenital C. trachomatis (using NAAT on urine specimen) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv) For gay, bisexual and other males who have sex with men (MSM), regardless of condom use  Provide these additional screening tests at initial visit (or encounters in nonclinical settings that offer STD screening tests) and at least annually- thereafter a,d  Rectal N. gonorrhoeae (using NAAT) if person reports receptive anal sex (i, ii, iii)  Rectal C. trachomatis (using NAAT) if person reports receptive anal sex (i, ii, iii)  Oropharyngeal N. gonorrhoeae (using NAAT) if person reports receptive oral sex (i, ii, iii) - More frequent screening at anatomic sites of exposure (i.e., every 3-6 months) is indicated for MSM whose risk behaviors persist or have multiple or anonymous sex partners. (i, iii) For males diagnosed with syphilis or treated for gonorrhea or chlamydial infection  Retest persons diagnosed with syphilis using serologic tests recommended by CDC c (i)  Retest persons treated for gonorrhea or chlamydial infection for the relevant infection at the anatomic site of infection 3 months after treatment a,b,d (i, iii) # For all females  Provide the following tests at initial visit (or encounters in nonclinical settings that offer STD screening tests) and at least annually thereafter:  Urogenital N. gonorrhoeae (using NAAT) a,b (i, ii, iii)  Urogenital C. trachomatis (using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv)  Vaginal trichomoniasis test e,f (i, iii) For all pregnant females f  Provide the following tests at the first prenatal visit:  Urogenital C. trachomatis (using NAAT) a,b (i, ii, iii)  Urogenital N. gonorrhoeae (using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv)  Provide the following tests at the beginning of the third trimester for women at risk for STD g :  Urogenital C. trachomatis (preferably using NAAT) a,b (i, ii, iii)  Urogenital N. gonorrhoeae (preferably using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv) For females diagnosed with syphilis or treated for gonorrhea, chlamydial infection, or trichomoniasis  Retest persons diagnosed with syphilis using serologic tests recommended by CDC c (i)  Retest persons treated for gonorrhea or chlamydial infection for relevant infection at the anatomic site of infection 3 months after treatment a,b,e,h (i, iii)  the local burden of STDs  characteristics of persons with HIV at greatest risk for STD infection and HIV-uninfected partners at risk for HIV (e.g., MSM diagnosed with STD, especially infectious syphilis and rectal gonorrhea or chlamydial infection; young men of color; transgender persons)  the role of STD preventive services in clinical and nonclinical settings for HIV prevention  Increase access to routine behavioral risk-reduction services, STD screening services, and latex or polyurethane condoms in clinical and nonclinical settings  Increase the capacity of laboratories to screen rectal and oropharyngeal specimens for N. gonorrhoeae and C. trachomatis using NAATs and to monitor gonococcal antimicrobial drug resistance trends using culture tests # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with current federal guidance about STD risk assessment, screening, and treatment, and HIV and STD partner services for persons with HIV published through April 2014. 1,4,7, They are also consistent with most of the latest comparable recommendations about STD services for persons with HIV of the HIV Medicine Association of the Infectious Diseases Society of America 15 and the International Antiviral Society-USA Panel. 16 This report updates recommendations about assessing behavioral and biologic risks for HIV and STD and STD screening from the 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care in several ways. 17 These updated recommendations advise the following:  Screening for gonorrhea and chlamydial infection in genital and extra-genital sites using nucleic acid amplification tests (NAATs)  Screening for women for trichomoniasis with more sensitive tests: NAAT or culture  Informing persons with HIV that reporting of cases of HIV, infectious syphilis, gonorrhea, and chlamydial infection by laboratories and health care providers as required by state laws may prompt health departments to offer voluntary, confidential HIV partner services in some jurisdictions  Retesting persons diagnosed with gonorrhea, chlamydial infection, or trichomoniasis 3 months after treatment  Using the STD treatment regimens that have been most recently recommended by the Centers for Disease Control and Prevention (CDC) that include administration of two different antimicrobial drugs for gonorrhea, one of which requires injection 1,14  Providing persons with HIV who have STD symptoms or report recent sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis with access to presumptive STD treatment (while awaiting STD test results) through onsite treatment at a health care facility or immediate linkage to a health care facility that offers clinical evaluation and onsite presumptive STD treatment  Engaging nonclinical providers to  inform sexually active persons with HIV that some STDs may increase the risk of HIV transmission and that screening for these STDs at least annually is beneficial  offer recommended STD screening tests using venous blood specimens or provider-initiated self-collected specimens, if feasible in the nonclinical setting, or refer clients to clinical settings that offer STD screening  promptly link persons with HIV who report symptoms of STD or sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis to health care providers who can provide clinical evaluation (including physical examination and diagnostic testing) and presumptive treatment ‡ ‡ ‡ with recommended injectable or oral antimicrobial drugs  Engaging health departments to integrate or routinely match STD and HIV surveillance data to identify populations or individuals with HIV with STD coinfection who may warrant being offered HIV and STD preventive services, including voluntary HIV partner services # Methods The section writing group compiled recommendations on STD services and STD laboratory testing for persons with HIV from CDC, the Health Resources and Services Administration (HRSA), and the U.S. Department of Health and Human Services (HHS) published through April 2014, and these recommendations will be revised periodically. All of this federal guidance was based on systematic reviews of evidence and, when evidence was sparse or absent, expert opinion. 1,4,7, The group also reviewed recommendations about STD screening from the 2013 guidelines of the nongovernmental HIV Medical Association of the Infectious Diseases Society of America. 15 In addition, the group reviewed the following sources on the role of STD screening and treatment in preventing HIV transmission that were published from January 2010 to March 2014: 2 published systematic reviews, 18,19 1 published narrative review, 20 recent CDC programmatic guidance to state and local health departments, 21 and the 2015 CDC STD Treatment Guidelines. # Evidence Supporting the Recommendations Certain STDs have been found to increase HIV-1 DNA or RNA in persons with HIV, which may increase the risk of HIV transmission. 18,20 A meta-analysis conducted in 2007 found that persons with HIV who had been diagnosed with urethritis, cervicitis, gonorrhea, and chlamydial infection had a 2-to 3-fold increase in the frequency of HIV shedding in the genital tract. 22 Trichomoniasis in women has been associated with increased vaginal HIV shedding 23 and increased risk of perinatal HIV transmission in pregnant women with symptomatic T. vaginalis infection. 24 Studies conducted outside the United States have shown statistically significant declines in the HIV concentration in semen of men who were treated ‡ ‡ ‡ Presumptive treatment involves providing treatment for syphilis, gonorrhea, chlamydial infection or trichomoniasis before the results of STD testing or clinical evaluation are available. This treatment approach is recommended for persons who report symptoms suggestive of these STDs or recent sex partners who were treated for these STDs, or have clinical signs of these STDs. for urethritis associated with N. gonorrhoeae or trichomonas and in the vaginal fluid of women who were treated for cervicitis associated with N. gonorrhoeae, C. trachomatis, and trichomonas. Because a high proportion of persons infected with these 3 STDs may lack symptoms or signs, periodic screening with sensitive laboratory tests is needed to detect infection. 1,4 Men and women diagnosed with gonorrhea and chlamydial infection and women diagnosed with trichomoniasis can benefit from rescreening 3 months after treatment due to high rates of reinfection or persistent infection. 1,14,29 A meta-analysis of 11 studies conducted in 2010 showed that HSV-2 coinfection increased plasma HIV viral load by almost a quarter log (difference in mean VL 0.22 log10 copies/mL, 95% CI: 0.04-0.40). 18 However, 2 randomized controlled trials conducted from 2004-2007 did not find that acyclovir treatment of persons coinfected with HIV and HSV-2 significantly reduced the risk of HIV transmission among HIV-discordant couples. 30 Reviews of trials and observational studies conducted in low-income countries have concluded that treatment of STDs detected through screening is associated with lower rates of HIV transmission in selected populations that have high STD burden; limited access to routine screening and prompt, effective treatment; and rising HIV prevalence. 19,20 However, no controlled clinical trials of U.S. populations have evaluated the role of STD screening and treatment in preventing onward HIV transmission from persons with HIV. This section's recommendations about STD screening tests, screening frequency, and STD treatment are therefore based on biologic plausibility, epidemiologic risk factor studies, prospective studies of populations that differ epidemiologically from the United States, ecologic associations in the United States, and expert opinion. Voluntary, confidential partner services can benefit many persons with HIV and STDs and their partners. 10 Nevertheless, many providers do not explain the benefits of partner services, the role of trained health department specialists, or that reporting of cases of HIV or STD by laboratories and providers can activate voluntary, confidential health department partner services. 10 Persons with HIV who are aware of the benefits of partner services may be more likely to accept these services. See Section 8, Partner Services, for additional evidence supporting recommendations about partner services. # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities STD screening is an underused prevention strategy despite the high incidence of STDs in some persons with HIV, particularly men who have sex with multiple male partners. A study of 8 large HIV clinics in 6 cities from 2006-2008 found that more than 65% of HIV-infected gay, bisexual, and other men who have sex with men (MSM) were annually screened for syphilis, but only 2.3% to 8.5% were annually screened for rectal chlamydial infection and rectal and oropharyngeal gonorrhea despite moderate to high positivity rates in specimens from asymptomatic patients (3.0% to 9.8%). Rates of annual urogenital chlamydial infection or gonorrhea screening were only modestly higher (13.8% to 18.3%). 31 Several factors may contribute to low screening rates: reluctance to collect anal and genital specimens (in contrast to syphilis serology can use venous blood collected for CD4 cell count and HIV viral load testing 32 ); incomplete sexual behavior assessments that fail to identify the need for testing rectal and oropharyngeal specimens; limited knowledge of NAAT tests for rectal and pharyngeal specimens (including how to access tests, seek insurance coverage, and apply billing codes); and competing clinical priorities. 31 The performance of STD screening and diagnostic tests, like that of all clinical tests, may vary by test type, specimen collection and handling, prevalence of infection in a given population, and other factors; false positive and false negative results are rare. 1,4 These recommendations advise use of sensitive, specific commercially available NAATs to detect gonorrhea in rectal and oropharyngeal specimens and chlamydial infection in rectal specimens, although use of these tests with rectal or oropharyngeal specimens is not cleared by the U.S. Food and Drug Administration (FDA). However, several state public health and national commercial laboratories have met all CLIA regulatory requirements for off-label procedures for testing rectal and oropharyngeal specimens and billing codes have been assigned. 1,3,33 STD treatment is generally safe and effective and rarely results in adverse reactions. 1 Emergence of antimicrobial-resistant pathogens may impair the effectiveness of some treatments over time. For example, in 2012 CDC recommended treating N. gonorrhoeae with two antimicrobial drugs (at least one requiring injection) that are more effective against antimicrobial-resistant strains. 14 Poor adherence to STD treatment can impair effectiveness. 1 Persons with HIV can become reinfected with STD if any partners diagnosed with STD are not treated or they do not take their treatment as prescribed. 1 It is therefore important to offer partner services to persons with HIV who are diagnosed with STDs so that their partners can be notified and offered testing and presumptive treatment (see Section 8, Partner Services). Some health departments integrate or routinely match HIV and STD surveillance data to identify persons with HIV who warrant being offered HIV and STD preventive services. 21 Innovations in information technology and increased use of electronic medical information under the Affordable Care Act may expedite confidential, electronic reporting of surveillance data and support the assessment and assurance functions of public health programs. 34 # Policy, legal, and ethical considerations State laws generally protect the confidentiality of HIV and STD information reported to health department surveillance programs that may activate voluntary, confidential health department partner services. Nevertheless, some persons with HIV who are diagnosed with an STD may feel anxious about providers reporting cases to public health authorities or notifying sex partners because an STD diagnosis in a person with HIV is an objective marker of unprotected sexual activity that may result in HIV or STD transmission. 10 In some jurisdictions, duty-to-inform regulations require or allow providers to inform sex and drug-infection partners of possible HIV or STD exposure, particularly if the person with HIV was aware of their infection before the activity or the activity was not consensual. 10,35 Some persons with HIV worry that HIV or STD case reporting by laboratories or providers or partner notification might breach confidentiality or, in the case of minors, prompt unwanted parental notification (see Section 8, Partner Services). Health departments use methods similar to health care providers to rigorously protect personal health information and maintain the confidentiality of surveillance case reports that can activate voluntary, confidential health department partner services; however, they may release personal health information if subpoenaed or if required to enforce duty-to-inform statutes. 36 Providers who are aware of and adhere to laws and regulations about minors' rights to access and consent to confidential STD preventive services are better equipped to serve and protect the privacy rights of minors. 1 See Section 3, Context of Prevention, and Section 8, Partner Services, for related information. # Special populations Persons with HIV who continue to practice HIV risk behaviors, § § § particularly unprotected sex with multiple or anonymous partners, are highly likely to be exposed to STD and may benefit from screening every 3 to 6 months instead of annually (see Box 9-A). These persons may include some MSM and substance users as well as persons who are aware that their sex partners have multiple sex partners. 1 # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at /. # Section 10. Reproductive Health Care for Women and Men Background Reproductive health care involves several services for adults and adolescents with HIV who are of reproductive age and wish to avoid unplanned pregnancies or reduce the risk of sexual HIV transmission. 1 These services are essential because most women and men with HIV in the United States acquired HIV through sexual exposure during their reproductive years and they remain sexually active after their diagnosis. Once aware of their infection, many persons with HIV engage in safer sex practices or use contraception to prevent unintended pregnancy, but some do not. Also, members of many HIV-discordant couples want to have children 8,9 and therefore may benefit from conception methods that reduce the risk of sexual HIV transmission and perinatal transmission, if pregnancy occurs. Providing reproductive health services therefore supports the rights of persons with HIV to be sexually active, to prevent or attempt conception, and to have children. This section addresses services for persons with HIV, HIV-concordant couples (in which both members are HIV-infected), or HIV-discordant couples (in which only one member is infected):  Assessment of reproductive plans of women and men with HIV  Assessment of pregnancy status of women with HIV  Reproductive health counseling- for persons with HIV and their partners regardless of their pregnancy intentions  Information and services related to contraception  Use of effective antiretroviral treatment (ART) before attempting to conceive  Information and services related to conception methods that reduce the risk of sexual and perinatal HIV transmission  Information on unique aspects of antiretroviral prophylaxis for HIV-uninfected members of discordant couples who are not consistently and correctly using condoms or are attempting conception This section does not provide a comprehensive summary of all reproductive services for women and men with HIV, such as counseling or screening related to smoking, alcohol, substance use, and viral hepatitis. Quality improvement † and program monitoring and evaluation ‡ methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 11, Pregnancy, - Reproductive health counseling for persons with HIV includes information and counseling for HIV-infected women and HIV-infected men of reproductive age and their uninfected partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks. † Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. ‡ Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. describes methods-including use of ART-to prevent sexual or perinatal transmission of HIV during recognized pregnancies of HIV-infected women or HIV-uninfected women who have partners with HIV. Other sections cover linkage to HIV medical care § (Section 4, Linkage to and Retention in Care), general aspects of ART use and use of antiretroviral prophylaxis by HIV-uninfected partners (Section 5, Antiretroviral Treatment), methods to reduce sexual transmission of HIV (Section 7, Risk Screening and Risk Reduction), and services for sex partners of persons with HIV (Section 8, Partner Services). # Recommendations BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Assess pregnancy status of HIV-infected women and reproductive plans of women and men with HIV, with methods and frequency as appropriate to provider role and setting (e.g., self-reported pregnancy or referral for pregnancy testing) a (i, ii, iii)  Provide education, reproductive health counseling b , and/or referral for contraceptive services as appropriate to provider role and setting a , to women and men who wish to prevent or delay future pregnancy a (i, ii, iii)  Advise women and men with HIV (and HIV-uninfected partners referred by them) to use latex or polyurethane male or female condoms to reduce the risk of HIV transmission and unintended pregnancy even if using medical or surgical contraception a (i, ii, iv)  Inform persons with HIV about the role of antiretroviral treatment (ART) in reducing sexual HIV transmission and in preventing perinatal HIV transmission a (i, ii, iii, iv) (see Box 10-A)  Inform persons with HIV (and HIV-uninfected partners referred by them) about  the availability of preexposure prophylaxis (PrEP) c for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition when attempting conception using penile-vaginal intercourse without a condom a (i, v, vi)  the availability of nonoccupational postexposure prophylaxis (nPEP) d for HIV-uninfected partners when clinically indicated on a one-time or infrequent basis to reduce the risk of HIV acquisition in the event of inadvertent sexual or parenteral HIV exposure within the past 72 hours (e.g., unprotected intercourse, condom breakage, shared drug-injection equipment) a (i, vi, vii)  Refer persons with HIV who wish to conceive to health care providers skilled in reproductive health counseling b for persons with HIV a (i, ii) (see Box 10-A)  Offer periodic HIV testing to HIV-uninfected members of HIV-discordant couples, particularly those who are attempting conception or who report unprotected intercourse a (i)  Become familiar with state and local laws and regulations in the jurisdiction that affect access to contraceptive services, pregnancy termination, and other reproductive health services, including access for minors without parental consent a (viii) § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). # BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN (cont) # Specific to clinical providers (in addition to above recommendations)  Assist persons with HIV who do not wish to conceive in making informed decisions about contraception that consider  the benefits of dual contraceptive methods (condoms plus other contraception) (i, iii, ix, x)  the high efficacy and safety profile of hormonal contraception and IUDs for women with HIV e (i, iii, ix, x)  the benefits of using water-based spermicides and condom lubricants that do not contain nonoxynol-9 (xi, xii)  Inform women with HIV who are considering medically attended pregnancy termination that available evidence indicates that HIV infection does not increase the risk of complications after the procedure f  Offer ART and adherence support according to U.S. Department of Health and Human Services (HHS) treatment guidelines to prevent sexual transmission of HIV and, should pregnancy occur, to prevent perinatal HIV transmission g (i, iv, vi)  Inform women with HIV who are using or considering using ART and hormonal contraception at the same time about possible drug interactions that might influence the efficacy of the ART or the hormonal contraception (ix, x)  Provide (in consultation with HIV care experts) or make referral for h (see Box 10-A)  additional preconception information and counseling for persons with HIV who are considering conception (preferably with their partner's participation) (i, ii, iv, vi)  information about conception methods for members of HIV-discordant couples that reduce the risk of sexual transmission of HIV or, should pregnancy occur, perinatal HIV transmission (i, iv, vi)  Offer PrEP or nPEP to HIV-uninfected partners referred by persons with HIV when clinically indicated after considering factors specific to women who may be or intend to become pregnant c,d (v, vii) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines that offer reproductive health services to adults and adolescents with HIV (xiii)  Provide information to clinical providers about state and local laws regarding minors' access to and consent for reproductive health services i (xiv)  Prioritize health department partner services for persons with HIV or partners who may be at risk for unintended pregnancy (e.g., adolescents) j (xv)  Support efforts and partnerships that increase access to reproductive health services for persons with HIV, including enrollment in private or public sector health plans and use of public sector clinics that serve uninsured persons (e.g., federally funded clinics) (xvi, xvii, xviii) Note. Section 11, Pregnancy, contains recommendations specific to women with recognized pregnancy and their partners. # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessment, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to . # BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN (cont) a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b Reproductive health counseling includes information and counseling for HIV-infected women and HIV-infected men of reproductive age and their partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks. c PrEP is the daily, continuous use of a specific regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. See Section 5, Antiretroviral Treatment, for more information regarding the use of PrEP. d nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. See Section 5, Antiretroviral Treatment, for more information regarding the use of nPEP. e The Contraceptive Services topic in this section describes special considerations for the use of hormonal contraception, intrauterine devices, and spermicides by women with HIV.  delivery methods that reduce perinatal transmission risk  Benefits of initiating ART before attempting conception to maximally suppress viral load  Availability of PrEP for HIV-uninfected persons who are attempting conception using unprotected intercourse with an HIV-infected partner c  Availability of nPEP for HIV-uninfected persons to reduce the risk of HIV acquisition through unprotected intercourse within the past 72 hours with an HIV-infected partner c  Availability of special conception methods that lower, but do not eliminate, HIV transmission risk (compared with unprotected penile-vaginal intercourse), including  specifically timed, periovulatory unprotected intercourse d  intravaginal or intrauterine artificial insemination, e in vitro fertilization, or intracytoplasmic sperm injection f using semen of an HIV-uninfected donor or specially processed ("washed") sperm of an HIV-infected man g,h Note. Some topics may only be suited for providers with appropriate skills and training. # Box 10-A. Specific topics for counseling adults and adolescents with HIV who are considering conception a See Section 7, Risk Screening and Risk Reduction, for more information on strategies to reduce the risk of sexual transmission of HIV. b Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. c See Section 5, Antiretroviral Treatment, for more information on ART, nPEP, and PrEP. HHS does not recommend repeated courses of nPEP 10 (e.g., for discordant couples who rarely use condoms) as a long-term means to prevent HIV acquisition. Recent HHS guidance recommends consideration of PrEP as one of several options to protect HIV-uninfected partners in HIV-discordant couples from acquiring HIV infection when attempting to conceive. 11,12 d Timed, periovulatory intercourse is a conception method intended to reduce the risk of HIV transmission in HIV-discordant couples in which unprotected intercourse occurs only when infected partners have achieved maximal viral suppression, the woman is in the periovulatory period of her menstrual cycle, and condoms are used at all other times. e Artificial insemination (intravaginal and intrauterine) is a conception method in which semen is collected and instilled into the uterus (by a physician) or into the upper vagina (by a physician, person with HIV, or partner). f Intracytoplasmic sperm injection is an in vitro fertilization procedure in which specially prepared ("washed") sperm of a man with HIV is injected directly into an egg retrieved from an ovarian follicle to achieve fertilization while minimizing the risk of HIV transmission to the female partner. g Sperm washing is a procedure that removes components (including seminal fluid that may contain HIV) other than sperm from a semen sample before it is used for artificial insemination. As of April 2013, the U.S. Food and Drug Administration has not reviewed sperm preparation procedures of HIV-infected men. h The Evidence topic in this section describes special conception methods to reduce the risk of HIV transmission that are recommended by HHS. # How These Recommendations Differ from Previous Recommendations The recommendations in this section greatly expand on the only recommendation about reproductive health in the 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care: referring women with HIV for contraception and reproductive health services. 13 These recommendations are consistent with current HIV-related federal guidelines about assessment of pregnancy status and reproduction plans of women and men, provision of or referral for contraceptive services and other reproductive health services, 14 avoidance of nonoxynol-9-containing spermicides, 15 behavioral methods to prevent HIV transmission, ART use to prevent sexual and perinatal HIV transmission, 14, reproductive health counseling, 11,14,18 and conception methods that reduce the risk of HIV transmission. 11,14,17,20 The recommendations in this section are also consistent with the latest comparable recommendations of these nongovernmental organizations: the American College of Obstetricians and Gynecologists; 21 the HIV Medicine Association of the Infectious Diseases Society of America; 22 and the International Antiviral Society-USA Panel. 23,24 However, these updated recommendations provide new guidance for  nonclinical providers to ask about pregnancy status and reproductive health plans and to refer clients to reproductive health counseling, contraceptive services, and other reproductive health care  nonclinical and clinical providers to inform persons with HIV about  the benefits of ART for preventing HIV transmission in HIV-discordant couples who have unprotected sex or are attempting conception Sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginal-digital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot).  the availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition  health department staff to provide information to clinical providers about state laws regarding minors' access to and consent for reproductive health services # Methods The section writing group based these recommendations on the latest guidance from the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and other federal agencies through May 2014. Those recommendations were based on a large body of scientific evidence and extensive experience of clinical experts. 17,18,25 The writing group that compiled these recommendations did not reexamine the evidence supporting this federal guidance, but examined additional evidence from three other sources:  Systematic reviews and meta-analyses from the CDC HIV/AIDS Prevention Research Synthesis (PRS) project's cumulative HIV/AIDS/STD prevention database identified using these search terms: HIV infection and reproductive health, women, contraception, family planning, birth control, and reproductive health counseling (see Section 2, Methods)  Reviews of the publications referenced in the search results  Narrative reviews of selected topics not addressed by federal guidelines listed above that were based on searches in PubMed, in OVID, and of scientific meeting abstracts published from 2000-2013 using these terms: HIV infection, family planning, reproductive health, nonoxynol-9, lubricants, sperm washing, artificial insemination, contraception, and birth control # Evidence Supporting the Recommendations This topic summarizes key evidence that supports the federal guidance on which the recommendations in this section are based or that was identified from the 3 additional sources described above. # Assessing pregnancy status, reproductive plans, and reproductive health service needs Providers who routinely assess pregnancy status and the reproductive plans of persons with HIV are able to offer them reproductive health information, counseling, and services that enable them to make wellinformed reproductive decisions that may reduce the risk of sexual and perinatal transmission of HIV. 11 This information and counseling also provides the opportunity to correct misperceptions about HIV transmission risks and options for contraception and conception. 11,16 Federal guidance recommends including both members of the couple when possible to encourage shared decision making and cooperation. # Use of antiretroviral medication for sexually active persons of reproductive age # Use of ART by persons with HIV Current HHS recommendations and subject matter experts advise that health care providers offer ART to all persons with HIV to prevent sexual HIV transmission regardless of the use of condoms or other contraception. 11,26 These recommendations also advise prescribing ART before persons with HIV attempt to conceive to provide time to maximally suppress viral load. 11,14 The recommendations also state that women attempting conception should avoid starting agents with a potential increased risk of maternal complications should pregnancy occur (e.g., hepatotoxicity associated with initiation of nevirapine in women with CD4 cell counts of >250 cells/mm^3) or a potential increased risk of teratogenicity (e.g., efavirenz). However, women who present for prenatal care in the first trimester and are virologically suppressed while taking efavirenz can continue this medication. 11 In addition, HIV-infected members of HIV-discordant couples should not share their ART medication with uninfected partners who are seeking nPEP or PrEP. Sharing may impair adherence of the person with HIV, and regimens suitable for treating persons with HIV may not be suitable for HIV-uninfected partners (see Section 5, Antiretroviral Treatment). 11,14 Nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners of persons with HIV An isolated, inadvertent episode of condom failure during intercourse within the past 72 hours with an HIV-infected partner may be an indication for nPEP. 10 Current HHS recommendations state that isolated nPEP use is not contraindicated in women with suspected or confirmed pregnancy, but potentially teratogenic regimens should be avoided. 10 However, these recommendations do not support repeated use of nPEP while an HIV-discordant couple is attempting conception through repeated acts of unprotected intercourse. Rather, HIV-discordant couples attempting to conceive should consider other conception † † Risk screening is a brief assessment of behavioral factors that may affect the risk of exposing others to HIV, such as inconsistent condom use or sharing drug-injection equipment, and biomedical factors that influence HIV transmission, such as viral load, antiretroviral treatment and adherence, sexually transmitted disease, and pregnancy. Risk screening is used to identify behavioral or biomedical risk-reduction interventions suited to a specific individual. ‡ ‡ Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. § § Clinician Consultation Center staff includes OB/GYNs, infectious disease specialists, internists, family practitioners, and clinical pharmacists at the University of California, San Francisco (1-888-448-8765 or /). methods that do not require unprotected intercourse (e.g., intrauterine insemination and in vitro fertilization) or the use of PrEP to prevent HIV acquisition (see Section 5, Antiretroviral Treatment). 11,12 Preexposure prophylaxis (PrEP) for HIV-uninfected partners of persons with HIV The use of PrEP can reduce the risk of HIV acquisition by HIV-uninfected sex partners when attempting to conceive with a person with HIV. 11,12 Current federal guidance recommends that providers address the use of PrEP with HIV-uninfected members of HIV-discordant couples who are attempting conception because of their risk of HIV acquisition (see Section 5,Antiretroviral Treatment). Current federal guidance and additional expert opinion also recommend that health care providers inform persons using PrEP that the effects of fetal exposure to PrEP are not yet fully assessed but that no harm has been reported to date. 12,27 # Contraceptive services Offering contraceptive services to sexually active persons with HIV who want to avoid, delay, or space pregnancies is essential, especially given the high proportion of women with HIV who report unintended pregnancies. 28 Current HHS recommendations and other evidence reviewed by the writing group indicate that contraceptive methods available in the United States are generally safe in women with HIV. 17,18, Evidence-based* criteria regarding medical eligibility for contraception for women with HIV are detailed in other documents. 17,20 In brief, condoms, when used consistently and correctly, are effective 1) for contraception, 2) in preventing HIV transmission to HIV-uninfected partners, 3) in preventing HIV superinfection † † † of persons already infected with other HIV strains, 21,34 and 4) in preventing other STDs. Current HHS recommendations conclude that concurrent use of barrier contraception, such as male or female condoms, and nonbarrier contraception, such as hormonal contraception and IUDs, is more effective in preventing pregnancy than using a single contraceptive method and reduces the risk of sexual transmission of HIV. 11,14 Several methods are more than 99% effective in preventing pregnancy when used correctly with all acts of intercourse, but no contraceptive method, including male and female condoms, hormonal contraception, or IUDs, is 100% effective in preventing pregnancy. 33,35 Many persons with HIV rely on ART to reduce the risk of transmitting HIV to others, especially when not routinely using condoms or when attempting conception using unprotected intercourse. # Hormonal contraception Research studies identified through the systematic and narrative reviews and clinical experience (including postmarketing drug safety surveillance) indicate that hormonal contraception (including pills, injectables, rings, patches, implants, and emergency postcoital contraception ‡ ‡ ‡ ) is generally safe, effective, and suitable for HIV-infected women. 36,37 Oral contraceptives are generally not contraindicated in HIV-infected women because they have not been shown to increase HIV progression or transmission, increase viral load, or reduce absolute CD4 cell count levels. 17,38 However, a few oral contraceptives and some antiretroviral medications may interact with each other. 14,16, Emergency postcoital contraception is a type of oral hormonal contraception used within a few days after intercourse that is intended to prevent pregnancy by disrupting ovulation or fertilization. women taking certain classes of antiretroviral medication (protease inhibitors or nonnucleoside reverse transcriptase inhibitors) may experience changes in levels of ethinyl estradiol and norethindrone found in some oral contraceptives. Decreased levels may reduce contraceptive effectiveness, while increased levels may increase adverse effects of oral contraception. HHS recommendations also note that some oral contraceptives may decrease levels of some antiretroviral medications and that potential pharmacokinetic interactions should guide ART and contraception choices. 16 However, the recommendations state that concerns about possible drug interactions should not deter health care providers from recommending hormonal contraception to women taking ART. These recommendations highlight the benefits of informing women about 1) potential interactions between ART and hormonal contraception and 2) the use of hormonal contraception that may be used with condoms as a dual contraception strategy to avoid unintended pregnancy and perinatal HIV transmission. 17 Little is known about how ART interacts with non-oral hormonal contraceptives. 17,37,44 The fact that some non-oral contraceptives have lower systemic absorption than oral contraceptives, act locally, and in some cases do not depend on first-pass metabolism suggests that interactions with ART may be less likely than with oral contraceptives. Recent studies have raised questions about whether the use of depot medroxyprogesterone acetate, the injectable progesterone-only contraceptive agent available in the United States, may increase the risk of transmitting HIV to male sex partners or the risk of women acquiring HIV infection. 37,45 Because the evidence remains inconclusive, CDC and the World Health Organization recently recommended that women with HIV who use this injectable contraceptive should ensure that male or female condoms are consistently used during intercourse. 17,44 Intrauterine devices (IUDs) Two studies have shown that IUDs available in the United States (copper-releasing IUDs and levonorgestrel-releasing IUDs) are safe for HIV-infected women without AIDS who can regularly access providers to monitor for IUD-related complications, including possible infection. 32,46 Clinical trials indicate these IUDs do not influence cervicovaginal shedding of HIV or increase risk of HIV transmission to sex partners. 47,48 Current CDC recommendations state that IUD insertion and use are generally safe for women with HIV and that HIV-infected IUD users have no higher risk of IUD-related complications than HIV-uninfected IUD users. However, women with AIDS who are taking ART and not clinically well should generally not undergo IUD insertion, because the risk of pelvic infection outweighs the benefits of effective contraception. 20 # Other contraceptive methods HHS recommendations advise against use of spermicides and anal and genital lubricants containing nonoxynol-9 because when used frequently, long-term, or in high doses they can cause genital irritation and inflammation, which may increase the risk of HIV transmission. 15,18,25 HHS recommendations and studies identified through the narrative review indicate that voluntary tubal sterilization and vasectomy are safe, effective contraceptive methods for HIV-infected women and men, respectively. 17,29,49 # Pregnancy termination One study identified in the narrative review found that HIV-infected women do not have a higher prevalence of postabortion complications after medically attended surgical abortion than HIV-uninfected women; this finding supports the recommendation to inform HIV-infected women who are considering medically attended pregnancy termination that available evidence indicates that HIV infection does not increase the risk of complications after the procedure. 50 Women with HIV who undergo termination procedures should defer vaginal sexual contact until bleeding has ceased and healing is complete to lower the risk of HIV transmission to others. # Conception methods that reduce the risk of sexual and perinatal transmission in HIV-discordant couples Current HHS guidelines recommend consideration of special conception options (preferably after expert consultation) that have been shown to reduce the risk of HIV transmission in HIV-discordant couples attempting conception. 11  For couples who prefer natural conception after having received information and counseling about the risks of sexual transmission and perinatal transmission (should pregnancy occur) and assisted conception methods, these options include  timed, periovulatory unprotected intercourse after the partner with HIV has achieved maximal viral suppression through ART and the use of male or female condoms with all other acts of intercourse 11  the use of PrEP to further reduce the risk of HIV acquisition by the HIV-uninfected male or female partner during unprotected intercourse. 12  For couples in which the man is HIV-infected and can access assisted conception methods, these options include  preconception semen analysis to determine semen volume and any abnormal sperm characteristics that may influence conception decisions (because repeated semen exposure could result in HIV infection but not lead to conception or a viable fetus) 11  intrauterine artificial insemination, § § § in vitro fertilization, or intracytoplasmic sperm injection, using semen or sperm from an HIV-uninfected donor, or if donor semen or sperm is an unacceptable option, sperm from the HIV-infected man that has undergone procedures † † † † that remove seminal fluid that may contain HIV ("sperm washing") 11,51-54  For couples who use natural or assisted conception methods that involve exposure to potentially HIV-infected semen or other genital secretions, periodic HIV testing of HIV-uninfected partners to identify early infection and to hasten linkage to HIV medical care is warranted. 11 The availability, insurance coverage, and affordability of these methods may vary by the individual's area of residence and health insurance status. § § § Intrauterine artificial insemination is a conception method in which semen is collected and instilled into the uterus by a clinician. Intracytoplasmic sperm injection is an in vitro fertilization procedure in which specially prepared ("washed") sperm of a man with HIV is injected directly into an egg retrieved from an ovarian follicle to achieve fertilization while minimizing the risk of HIV transmission to the female partner. † † † † As of April 2013, the U.S. Food and Drug Administration has not reviewed preparation procedures of semen from men with HIV. # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Recent surveys indicate that 57% to 84% of all women with HIV report consistent condom use, depending on the HIV status of the sex partner. 55 However, less than 30% of women with HIV currently use condoms or other contraception; and use of ART does not influence prevalence of current contraceptive use. 49,55,56 Also, about half of sexually active adolescents with HIV report engaging in unprotected sex after learning they are infected. 56 As with American women overall (in whom about half of pregnancies are unintended), unplanned pregnancies are common among women with HIV. 28,57,58 These findings underscore the benefits of expanding reproductive health care services to persons with HIV. Implementation of the Patient Protection and Affordable Care Act and continued support for federally funded family planning programs are expected to improve access to family planning and reproductive health services, including some assisted conception methods. 59,60 However, access to health care providers with experience in reproductive health counseling, contraceptive methods, and assisted conception methods may continue to be limited for persons who do not have health insurance or who live in rural or other medically underserved areas. 61,62 Primary care providers seeking information about reproductive considerations for persons with HIV can consult the Clinician Consultation Center (1-888-448-8765 or /). 63 # Policy, legal, and ethical considerations Laws and regulations about consent, confidentiality, parental disclosure, and disease reporting for minors who seek family planning, pregnancy termination, or other sexual and reproductive health services vary by jurisdiction. Some states permit minors to receive a wide variety of sexual and reproductive health services without parental consent. 64 Providers who discuss sexuality, sexual behavior, and reproductive choices using a neutral, nonjudgmental style may elicit accurate information and foster autonomy in health decisions. Motivating persons with HIV to use sexual risk-reduction methods decreases the risk of exposing partners to HIV and the negative reactions, conflict, and legal disputes that may follow. See Section 3, Context of Prevention, and Section 8, Partner Services, for more information about legal and ethical issues related to HIV disclosure and notification of partners. # Special populations Adolescents with HIV have high rates of unintended pregnancy. Navigating multiple health care providers is difficult, but these adolescents can benefit from linkage to HIV medical care providers who also provide reproductive health services. 57,65 Expediting access to reproductive health services is also important for transgender persons, migrants, women at risk for sexual violence, sex workers, and others who may use contraception inconsistently or have trouble finding confidential or affordable health care. 56,66 Integrating reproductive and HIV services within the same health care facility and cross-training HIV providers and reproductive health care providers may increase capacity for reproductive services and more comprehensive "medical homes" for persons with HIV. # Section 11. HIV Prevention Related to Pregnancy Background Specific prevention considerations are relevant for women who become infected with HIV during pregnancy or the postpartum period. Several interventions can reduce the risk of 1) sexual HIV transmission from pregnant women with HIV or to uninfected pregnant women and 2) perinatal transmission during pregnancy, labor, delivery, and the postpartum period, as well as during breastfeeding. Unprotected sexual activity may occur during pregnancy, especially when partners are no longer using condoms for contraception purposes. 1 Furthermore, the physiologic state of pregnancy may increase the risk of sexual HIV transmission both from HIV-infected pregnant women to uninfected male partners 2 and from HIV-infected male partners to uninfected pregnant women. 2 This increased risk may be due to changes in systemic or genital mucosal immunity, HIV shedding or virulence, HIV coreceptors, or other factors. 2 The initiation of prenatal care, here defined as health care for women with a recognized pregnancy, also provides opportunities for informing pregnant women and their sex partners about methods to avoid sexual transmission of HIV during pregnancy. This care also enables offering HIV testing and retesting to sex partners of persons with HIV who are uninfected or have an unknown infection status. This section addresses methods to reduce 1) HIV transmission from women with HIV and recognized pregnancies and 2) HIV acquisition by HIV-uninfected women with recognized pregnancies. However, this section does not provide a comprehensive summary of all prevention and care services for pregnant women with HIV and their partners. Quality improvement- and program monitoring and evaluation † methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Other sections describe  General aspects of antiretroviral treatment (ART) and prophylaxis by HIV-uninfected partners (Section 5, Antiretroviral Treatment);  General aspects of adherence to ART (Section 6, ART Adherence)  Contraception services and reproductive health counseling ‡ that can be provided in the postpartum period (Section 10, Reproductive Health Care)  Behavioral risk-reduction interventions, including those for HIV-infected partners of pregnant women (Section 7, Risk Screening and Risk Reduction)  Sexually transmitted disease (STD) services, including screening pregnant women for STD pathogens (Section 9, STD Services) - Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. † Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. ‡ Information and counseling for HIV-infected women and HIV-infected men of reproductive age and their partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks.  Promptly link women to HIV medical care, preferably to settings where providers have expertise in managing pregnancy in women with HIV a,b (i, ii, iii, iv)  Inform women (and their sex partners who are aware of the woman's infection status) about risks of perinatal and sexual HIV transmission a,c,d (i, ii, iii, v) (see Box 11-D)  Support adherence to antiretroviral treatment (ART) during the prenatal and postnatal periods for optimal maternal health and prevention of perinatal and sexual transmission a (ii, v, vi)  Inform women and HIV-uninfected partners they refer about  the availability of preexposure prophylaxis (PrEP) e for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition during unprotected sexual intercourse a,c,f (ii)  the availability of nonoccupational postexposure prophylaxis (nPEP) g for HIV-uninfected partners to reduce the risk of HIV acquisition in the event of inadvertent sexual or parenteral HIV exposure within the past 72 hours (e.g., unprotected intercourse, condom breakage, shared drug-injection equipment) a,c,f (vii) § Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). # Box 11-A. Recommended services for pregnant women with HIV (cont)  Offer women support, information, and assistance to notify their sex and drug-injection partners about their HIV status a,c,h (iii)  Advise women to urge sex partners and drug-injection partners to get HIV testing and to use condoms to prevent HIV acquisition a,c (ii, v)  Offer latex or polyurethane male and/or female condoms a (i)  Inform women and their partners that breastfeeding by HIV-infected women is not recommended in the United States and that formula feeding is recommended for the infants of these women a (i, ii)  Provide education, counseling and/or referral for postpartum contraception services for women who wish to prevent or delay future pregnancy, as appropriate to the setting a (ii, v) # Specific to clinical providers (in addition to above recommendations)  Offer an ART regimen during the prenatal, intrapartum, and postpartum periods, regardless of maternal CD4 cell count, to prevent perinatal transmission and thereafter for the woman's health and to prevent HIV transmission to others, according to U.S. Department of Health and Human Services (HHS) recommendations (i, ii, v, vi) (see Box 11-D)  Inform women about options for free or subsidized ART, such as AIDS Drug Assistance Program (ADAP) or pharmaceutical drug assistance programs to help address financial concerns that may deter ART use (i)  Screen and treat women for STDs that may increase risk of HIV transmission during pregnancy i (iii, v, vii)  Do not use invasive prenatal and intrapartum procedures (e.g., amniocentesis, chorionic villous sampling, amniotomy, and transvaginal instrumentation) unless women have started an effective ART regimen and are, ideally, virally suppressed at the time of the procedure as these procedures may increase fetal exposure to maternal blood thereby increasing the risk of perinatal transmission (i, ii)  Inform women of delivery options that can reduce the risk of perinatal transmission (ii)  Discuss risks and benefits of cesarean delivery and recommend scheduled cesarean delivery at 38 weeks gestation for women with suboptimal viral suppression near the time of delivery (i.e., HIV RNA levels >1000 copies/mL) (i, ii)  Notify infant health care providers of impending birth of HIV-exposed infants and any anticipated complications (ii) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines that offer pregnancy services to women with HIV (iv)  Provide information to clinical providers about state laws regarding consent for HIV testing during the perinatal period and minors' access to and consent for pregnancy services j  Prioritize health department partner services for pregnant women with HIV k (iii)  Support efforts and partnerships that increase access to pregnancy and perinatal services for persons with HIV, including enrollment in private insurance or medical assistance programs and use of public sector clinics (e.g., federally funded clinics) (ix, x, xi) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, disease screening, diagnosis, and treatment; and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated as of present. For current federal recommendations, please refer to . # Box 11-B. Recommended postnatal services for women with HIV and their infants to reduce the risk of perinatal HIV transmission For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV) serving postpartum women with HIV or their HIV-exposed infants  Assist women to obtain regular HIV care and in adhering to their prescribed ART regimen to maximize their health a (i, ii)  Advise women with HIV not to breastfeed (even if taking ART) and provide information about how to obtain formula a (i, ii)  Advise women with HIV not to donate their breast milk to breast milk banks a (iii)  Advise caregivers with HIV not to prechew food for infants and children a (ii, iv, v)  Provide education, counseling, and/or referral for postpartum contraceptive services to women who wish to prevent or delay future pregnancy, as appropriate to the setting a (ii) # Specific to clinical providers (in addition to above recommendations)  Offer a 6-week, postnatal infant prophylaxis with antiretroviral medications according to HHS guidelines within 12 hours of birth to all HIV-exposed infants b (ii)  Provide infant caregivers information about the importance of adherence to postnatal infant prophylaxis and about services to support adherence c (ii)  Consider virologic testing d of HIV-exposed infants within 24 hours at birth to monitor infant's infection status, especially when maternal virologic control during pregnancy was poor or if adequate follow-up of the infant may not be assured (i, ii)  Assist parent or guardian in obtaining health care for the HIV-exposed newborn to monitor newborn's infection status (i, ii)  Offer repeated virologic tests to the infant at ages 14 to 21 days, 1 to 2 months, and 4 to 6 months to assess the presence of HIV infection before 18 months of age (ii)  Report cases of perinatally exposed or HIV-infected infants to health departments according to local requirements for HIV disclosure, confidentiality, and case reporting e (vi) For staff of health departments who provide population-level HIV prevention and care services  Conduct surveillance for HIV-exposed infants (vi)  If allowed in jurisdiction, use surveillance data for public health purposes (e.g., contacting health care providers who report cases of HIV-exposed infants) to ensure that (vii)  the infant's infection status is later ascertained and, if infected, ensure that the infant receives clinical care (including the offer of treatment) and the confirmed case is reported to the health department  the mother's HIV infection status is documented and the mother is offered help with starting HIV medical care f a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the writing group for this section concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. HHS guidelines describe specific regimens. 7 c The source guidance addresses initiation of postnatal infant prophylaxis and use of a 6-week regimen, but does not address infant adherence support. d Such as nucleic acid amplification test for HIV RNA or DNA, according to HHS guidelines. 7 e For state and territorial case reporting requirements, see guidance of CDC and the Council of State and Territorial Epidemiologists. 8,9 f Authorized uses of perinatal surveillance data vary by jurisdiction. 9 Box 11-C. Recommended services for pregnant women who are HIV-uninfected or have unknown infection status and have sex or drug-injection partners with HIV (cont) # Specific to clinical providers (in addition to above recommendations)  Include HIV testing early in pregnancy as part of routine prenatal screening panel; use opt-out approaches when allowed in the jurisdiction (ii, iii, vii)  Conduct repeat testing during the third trimester (using a test that detects recent HIV infection e ) for women whose earlier HIV test was negative. When a woman reports a possible, recent HIV exposure that might result in a new infection that would not be detected by antibody test alone (i.e., during the window period f ) or has signs or symptoms of acute HIV infection, use both an HIV antibody test and a plasma RNA test to enable diagnosis of acute HIV infection (ii, iii)  Screen and treat for STDs that may increase risk of HIV acquisition during pregnancy or thereafter g (vii)  For women who first present for pregnancy care during labor with unknown HIV status offer  expedited HIV testing (using opt-out testing strategy when allowed by the jurisdiction) and provide information about perinatal HIV transmission (ii, iii)  IV zidovudine immediately if preliminary test result is positive to prevent perinatal transmission (ii)  For women who decline testing and whose HIV status remains unknown at delivery, take these steps (i, ii, iii):  provide expedited antibody testing of the newborn as soon as possible after birth using consent procedures consistent with state laws  inform the woman that identifying HIV antibodies in the newborn would indicate maternal HIV infection  If the newborn HIV antibody test is positive, promptly inform the mother  that the newborn needs virologic testing and immediate initiation of postnatal prophylaxis (i, ii, iii)  that she may obtain these services (ii, iii): - voluntary HIV testing and HIV medical care during the postpartum period or later - other medical and social services that may guide future decisions about HIV testing or medical care for herself and her infant  Offer PrEP during or after pregnancy when clinically indicated and manage women who are using PrEP during or after pregnancy according to HHS recommendations c (ii, vi)  Assess women with possible HIV exposure within the past 72 hours for indications for nPEP, and offer women with nPEP indications regimens that are suitable during pregnancy, based on HHS recommendations c (v) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines in jurisdictions that offer pregnancy services, including PrEP to HIV-uninfected, pregnant women at substantial risk of HIV infection h (x)  Make available information about state laws regarding consent for HIV testing during the perinatal period and minors' access to and consent for pregnancy services i  Prioritize health department partner services for HIV-uninfected pregnant women who have HIV-infected partners (iv)  Support efforts and partnerships that increase access to pregnancy and perinatal services for persons with HIV and their partners, including enrollment in public or private-sector health plans and use of public sector clinics (e.g., federally funded clinics) (xi, xii, xiii) # Box 11-D. Important messages regarding HIV prevention and pregnancy # For pregnant women with HIV who have HIV-uninfected partners  Approximately 25% of HIV-infected women who are not treated with ART during pregnancy will transmit the virus to their infant during pregnancy, labor, or delivery, in nonbreastfeeding populations  HIV can be transmitted through breast milk of a woman with HIV  Use of ART by pregnant women with HIV is highly effective in protecting the infant from HIV infection and may improve the mother's health and prevent HIV transmission to their uninfected partners  Other interventions that may further reduce the risk of transmission from HIV-infected women to their infant, including  nonemergent cesarean delivery at 38 weeks gestation that is initiated within 4 hours after the start of labor for women who do not have a suppressed viral load (<1000 copies/mL) at 34 to 36 weeks gestation  use of infant formula instead of breast milk from a woman with HIV to prevent HIV transmission through breast milk  not feeding infants food that has been prechewed by a person with HIV # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with current federal guidelines for HIV-infected pregnant women, HIV-exposed newborns, and HIV-uninfected pregnant women with HIV-infected partners. 3,7,8, They are also consistent with the Centers for Disease Control and Prevention (CDC) recommendations that HIV-infected caregivers not prechew food for infants. 16 These recommendations are also consistent with the latest comparable recommendations of these nongovernmental organizations: the American College of Obstetrics and Gynecology; 17 the HIV Medicine Association of the Infectious Diseases Society of America; 18 and the International Antiviral Society-USA Panel. 19,20 This section compiles existing federal recommendations, provides new evidence for their support, and makes one new recommendation for nonclinical and clinical providers to inform pregnant women with HIV (and sex partners referred by them) about the availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition. # Methods The section writing group compiled the most recent recommendations about HIV prevention related to pregnancy as of May 2014 from CDC, the Health Resources and Services Administration (HRSA), National Institutes of Health, and other federal agencies. 7,8, Those recommendations were based on extensive clinical experience and a large body of scientific evidence that was not reexamined by the writing group. When existing guidelines contained no or limited evidence about a topic, the writing group examined evidence on the topic from three sources: 1) Systematic reviews and meta-analyses that were identified by searching the CDC HIV/AIDS Prevention Research Synthesis (PRS) project's cumulative HIV/AIDS/STD prevention database using the following terms: HIV infection and pregnant women, newborn, infant feeding, and cesarean delivery (see Section 2, Methods); 21 2) a narrative review of PubMed for articles indexed with the following terms: HIV infection and prevention of mother-to-child transmission, pregnant women, newborn, and cesarean delivery; and 3) relevant articles identified after manual review of the publications referenced in the search results. # Evidence Supporting the Recommendations This section briefly summarizes evidence supporting these recommendations that has been described in other documents. 7,8, See other sections for evidence related to STD services (Section 9, STD Services), risk screening † † and behavioral risk-reduction interventions (Section 7, Risk Screening and Risk Reduction), and linkage to HIV medical care ‡ ‡ (Section 4, Linkage to and Retention in Care). # HIV testing for pregnant women and their partners The start of prenatal care enables routine HIV testing of pregnant women and their partners. Use of an opt-out consent approach (whereby a woman is tested unless she specifically declines testing) that is consistent with state laws has been shown to yield higher testing acceptance. This approach also hastens HIV diagnosis and management and use of interventions to prevent sexual or perinatal transmission. 11 Because pregnancy can increase the risk of HIV transmission and acquisition 2 and new infection induces a rapid rise in viral load, repeated testing of pregnant women and their partners can identify persons at high risk of transmitting or acquiring HIV during pregnancy. 11 Testing of HIV-uninfected male partners of HIV-infected pregnant women and repeat testing of HIV-uninfected pregnant women during the third trimester are particularly important because of the increased risk of HIV transmission during pregnancy (both from man to woman, and from woman to man). 2,7,11 HIV-uninfected pregnant women and their partners who are HIV infected or at high risk of HIV infection can benefit from knowing about symptoms of acute retroviral syndrome (e.g., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, and headache) and the increase in viral load during acute infection. This information may motivate them to seek testing for acute infection, to seek HIV medical care if infection is confirmed, and to make informed reproductive decisions. 14,22 HIV testing also offers opportunities to provide sexual risk-reduction information and interventions, as well as condoms. 11 Providing partner services to HIV-infected pregnant women or HIV-infected partners is important to prevent onward HIV transmission. Engaging voluntary, confidential health department partner services can be especially helpful for notifying multiple partners, estranged partners, or partners who do not attend prenatal care visits (see Section 7, Risk Screening and Risk Reduction, and Section 8, Partner Services). Promptly referring HIV-infected pregnant women or uninfected pregnant women with HIV-infected partners for contraception services immediately after delivery can reduce the risk of future, unintended pregnancies (see Section 10, Reproductive Health Care). Prompt linkage of women who receive a preliminary or confirmed HIV diagnosis during pregnancy or the postpartum period can improve the health of both the woman and her infant and minimize transmission risks (see Section 4, Linkage to and Retention in Care). # Antiretroviral treatment and prophylaxis for pregnant women with HIV The goal of ART during pregnancy is to maximally suppress viral load, restore or preserve immune function, improve quality of life, and prevent perinatal and sexual transmission. Maternal ART use that suppresses viral load to undetectable levels or to levels <50 copies/ml decreases the risk of HIV transmission from mother to infant from 25% to <1%. Regardless of their CD4 cell count, pregnant women who adhere to appropriate combination ART have a substantially lower risk of perinatal transmission than untreated women. 7,26 Starting ART before conception provides more time to maximally suppress viral load before pregnancy and reduce the risk of perinatal transmission to the greatest degree (see Section 10, Reproductive Health Care). Choice of regimens may be affected by several factors, including the potential to maximize viral suppression, the risk of maternal and fetal toxicity, the need for dosing adjustments due to pharmacokinetic and physiologic changes during pregnancy, the presence of drug resistance, the degree of side effects, and patient preferences (see . # Invasive prenatal and intrapartum procedures Invasive procedures in pregnant women with known or undiagnosed HIV infection can increase the risk of fetal HIV exposure. These procedures include amniocentesis, chorionic villous sampling, percutaneous umbilical blood sampling during the prenatal period, intrapartum amniotomy, placement of fetal scalp electrodes, episiotomy, and use of forceps or vacuum extraction delivery during labor. 7 When these procedures are indicated, women who use effective antiretroviral treatment (ART) regimen before the procedure to maximally suppress viral load can reduce the risk of fetal exposure. If membranes rupture spontaneously before labor starts or early in labor, women in labor should be managed on an individual basis depending on how long since membranes ruptured, the plasma viral load, the current ART regimen, and the planned mode of delivery based on obstetrical indications. Data are limited regarding the influence of cesarean delivery after rupture of membranes in decreasing the risk of perinatal HIV transmission. 7 # Cesarean delivery The risk of perinatal transmission among women with suppressed viral load during labor who undergo a vaginal delivery is low, but increases as maternal viral load increases. Studies have shown that the risk of HIV transmission to the infant is less than 2% in women with varied levels of viral suppression who undergo cesarean delivery for obstetric indications after the start of labor and membrane rupture and in women who undergo vaginal delivery while taking prenatal ART. 7 Assessing HIV viral load at approximately 34 to 36 weeks gestation can determine the extent of viral suppression and the safest mode of delivery. 7 Because cesarean delivery reduces exposure to blood and vaginal secretions in the birth canal, current federal guidance recommends this procedure for women with viral load levels >1000 copies/mL at the time of delivery or for women who deliver 4 hours after membranes rupture. 7,27,28 The presence of genital herpetic lesions during the intrapartum period (which may prompt some health care providers to offer cesarean delivery to reduce the risk of neonatal herpes § § ) also increases genital HIV shedding, which may increase risk of perinatal HIV transmission. 29,30 # Interventions for newborns with known or suspected HIV exposure Infant HIV testing and linkage to HIV care HIV testing of the infants of women known to be infected during pregnancy is needed to determine if the infant is infected. 7 Virologic tests (RNA or DNA nucleic acid amplification tests ) are used to diagnose infant infection because infant HIV antibody tests during the first 18 months of life cannot distinguish passively acquired maternal antibody from antibody expressed due to infant infection. When maternal virologic control was poor during pregnancy or adequate follow-up of the infant is uncertain, some experts recommend virologic testing of the infant at birth using NAAT tests. Newborns with positive NAAT tests immediately after birth warrant being offered ART, whereas newborns with negative NAAT tests immediately after birth warrant being offered postnatal infant prophylaxis* with antiretroviral medications (see next topic). Infants born to women whose HIV infection status is unknown at delivery can benefit from expedited antibody tests. 7 A positive test identifies HIV-exposed infants who warrant being offered prophylaxis and later virologic testing to assess infant HIV infection. Positive infant antibody tests also identify infected mothers due to detection of maternal antibody. Notifying a mother that a positive infant antibody test indicates maternal infection may prompt her to seek HIV care for herself and follow up care for the infant. Reporting of cases of HIV-exposed infants to health departments by health care providers or through hospital and birthing center surveillance programs may activate communication with health care providers who can engage care for the infant or mother 8 (see Section 4, Linkage to and Retention in § § The American College of Obstetrics and Gynecology also recommends cesarean delivery for women with herpetic lesions or prodromal symptoms of genital herpes at the time of labor or after membrane rupture to reduce the risk of neonatal herpes. * Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. Care). During follow-up visits for HIV-exposed or HIV-infected newborns and their parents or caregivers, providers can offer support for adherence to infant prophylaxis, ART, and maternal ART; reinforce the need to feed infants with formula instead of breast milk; and discuss postpartum contraception services. # Antiretroviral prophylaxis for newborns of women with HIV All infants born to women with HIV warrant a postnatal regimen of prophylactic antiretroviral medications because this regimen can reduce their risk of HIV acquisition. 7 Infant antiretroviral prophylaxis is most effective when started within 12 hours of birth and when adherence is high. 7 Close clinical follow-up of these infants allows for sustained adherence support and HIV testing to confirm or exclude the infant's HIV diagnosis. 31 Social workers, case managers, and home health personnel can help parents and caregivers support high adherence to infant prophylaxis. Detailed recommendations about treating HIV in infants are found in other documents. 7 # Infant feeding Breastfeeding by women with HIV, even those taking effective ART, is not recommended in the United States because formula is a safe, affordable, available, and acceptable alternative. 7 Breastfeeding increases risk of perinatal HIV transmission by 5%-20%. 7 Some women face cultural or familial pressure to breastfeed and may need additional education and counseling to avoid breastfeeding. 32 Because expressed breast milk may contain HIV and could expose recipients to HIV, it is not safe for women with HIV, regardless of their viral load or ART treatment status, to donate breast milk to human milk banks. 33 Infants may also acquire HIV by eating food that has been prechewed by a person with HIV. This may be due to obvious or inadvertent contamination of the food with blood from HIV-infected persons who have bleeding gums or other sources of oral bleeding or have had recent dental work. 16 # Interventions for HIV-uninfected pregnant women with partners with HIV Methods that discordant couples can use to reduce the risk of HIV transmission during pregnancy are also described in other sections. Federal guidance notes that pregnancy is not a contraindication for PrEP. Information on the safety of maternal PrEP use for the fetus and newborn is limited, but no harm has been reported to date. 3,7 PrEP may be clinically indicated for HIV-uninfected women with HIV-infected partners who are attempting conception or who are pregnant and have received counseling about the risks and benefits of PrEP use. 3,7 Also, some HIV-uninfected women started taking PrEP before they became pregnant because of their substantial risk of acquiring HIV. Women who wish to sustain this protection during pregnancy may continue to use PrEP. Federal guidance recommends that health care providers prescribing PrEP for women during pregnancy notify other maternal or infant care providers about this PrEP use and submit reports about pregnant women using PrEP (with no identifying information about the pregnant women) to the Antiretroviral Use in Pregnancy Registry. 3 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Over the last 3 decades, cases of perinatal transmission in the United States have declined due to many factors. These include widespread use of opt-out prenatal HIV testing of pregnant women, maternal ART, maternal and infant prophylaxis, scheduled cesarean delivery, avoidance of breastfeeding, and other maternal and infant interventions. 34 In 2012, an estimated 161 persons under the age of 13 years were diagnosed with perinatally acquired HIV infection in the United States. 35 An HIV diagnosis in a pregnant woman may be missed if prenatal HIV testing is not routine and is only directed to women classified as having high risk of HIV, or if repeat HIV testing is not offered to women who tested negative earlier in pregnancy. Women with HIV who are uninsured or who live in communities that are rural or have a low prevalence of HIV may have trouble finding or gaining access to affordable prenatal and postpartum care or health care providers skilled in managing pregnant women with HIV. 36 Implementation of the Patient Protection and Affordable Care Act and continued support for federally funded reproductive health programs may improve access to prenatal and postpartum care services. Providers who need information about reproductive issues for persons with HIV can consult the Clinicians Consultation Center (see the Implementation Resources topic below). 40 Community-based HIV testing programs for sex workers, drug users, and survivors of rape or intimate partner violence can also identify women at high risk of acquiring HIV infection before or during pregnancy. 36,41,42 State and local health departments vary regarding their capacity to conduct active surveillance for cases of maternal HIV infection, HIV-exposed infants, and HIV-infected infants and to follow up with providers who reported these cases, particularly since some jurisdictions do not require reporting of HIV-exposed infants 43 (see Section 4, Linkage to and Retention in Care). # Policy, legal, and ethical considerations State laws about HIV testing during pregnancy vary and are guided by principles of voluntary testing. Most states allow an opt-out approach. Others require written informed consent, special patient education, and medical record documentation before HIV testing. Regardless of the consent method, all states require that pregnant women should be aware when HIV testing is being performed, receive information about the test, and understand that they can decline testing without the risk of being denied medical care. 5 Routine use of opt-out testing during prenatal care has increased the number of women who receive prenatal HIV testing and gain access to perinatal HIV prevention strategies. The number of adolescents using HIV testing services also increased in several states after they suspended parental consent requirements. 47,48 Nevertheless, cases of perinatal transmission continue to occur in the United States, primarily in women who are exposed to HIV or diagnosed with HIV infection after pregnancy is recognized or who decline services that prevent perinatal transmission. Some women may defer HIV testing or prenatal care if they believe that information about maternal HIV infection, sex work, or substance use may influence child custody decisions or provoke partner abuse. 49 When providers notify pregnant women who have declined prenatal HIV testing that their newborn's HIV positive test results indicate maternal infection, they should offer these women voluntary HIV prevention and care services but respect their right to decline them. These services include HIV testing, HIV medical care, and social services that may influence future decisions about HIV testing or infant care (e.g., counseling about how to avoid abuse by a partner who may become violent after learning of the infant's HIV infection status). Providers who are familiar with state laws about maternal and infant testing, case reporting, HIV disclosure, and protocols for confidential exchange of health information are in the best position to address these concerns while respecting patient autonomy about HIV testing. Section 3, Context of Prevention, Section 8, Partner Services, and Section 9, STD Services, address duty-to-inform laws that may prompt providers to notify pregnant sex partners of possible HIV or STD exposure. A woman's decision to use antiretroviral medications during pregnancy is voluntary and must honor her autonomy. This decision may weigh considerations of fetal or newborn safety; pregnancy-related conditions, such as nausea; medication costs; and other factors. ART adherence may be especially challenging for pregnant women who face the many physical and psychological changes of pregnancy and newborn care. Providers can encourage pregnant women to stand and maintain high adherence to ART regimens that are safe during pregnancy by offering information about how to manage side effects and how to obtain affordable ART through insurance, the AIDS Drug Assistance Program (ADAP), or other drug assistance programs. Section 5, Antiretroviral Treatment, and Section 6, ART Adherence, describe other ART issues relevant to pregnant women. # Special populations Some pregnant women and adolescents with HIV may practice sex work, be heavy alcohol and substance users, be incarcerated, experience mental illness or sexual violence, or lack regular health care. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. ‡ Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Evidence Supporting the Recommendations # Poverty, unemployment, and lack of affordable health care Surveillance data in geographic areas with the highest prevalence of HIV infection demonstrate that poverty, unemployment, and lack of job opportunities are common among persons with HIV. Nationally representative data indicate that nearly 44% of persons who received outpatient HIV medical care in 2010 reported household incomes at or below the federal poverty threshold. 22 A study evaluating low-income, urban areas with high HIV prevalence found that the HIV prevalence of persons living below the federal poverty line was twice as high as that of persons living above the poverty line (2.4% prevalence vs. 1.2%, respectively). 23 Poverty and unemployment pose barriers to obtaining health insurance, HIV medical care, specialty services, and sustained access to costly ART. Poverty may also lead to unstable housing and lack of food that may force people to pay for basic necessities instead of ART medications. 24,25 Compared with employed persons with HIV, unemployed persons with HIV report a lower quality of life and greater suffering from depression, suicidal thoughts, low self-esteem, and impaired memory. Steady employment is associated with higher adherence to ART and better health outcomes partly because it fosters regular schedules that serve as reminders to take ART and to keep HIV care appointments. 27,29,30 Malnutrition related to poverty may exacerbate the immunosuppression associated with HIV; it may also impair ART tolerability, absorption, effectiveness, and adherence. 25,31 Case management and navigation assistance have been shown to help persons with HIV obtain income assistance and health insurance 11 (see . Studies have also shown that many HIV service providers who recognize the psychological and structural benefits of employment refer persons with HIV to employment support services. 26,28 # Unstable housing and homelessness Persons who have unstable housing or are homeless have HIV/AIDS infection rates that are 3 to 9 times the rates of persons with stable housing. 32 Unstable housing can cause psychological distress and lifestyles that lead to risk behaviors, such as having multiple sex partners, engaging in sex work, and abusing drugs or alcohol. One multicenter study published in 2008 found that homeless persons were 3 to 4 times more likely than persons with stable housing to use drugs or exchange sex for drugs or money and were significantly more likely to have elevated HIV viral load levels. 33 The lack of a consistent, secure place to store ART and lack of regular daily routines associated with stable housing can also impair adherence to ART. Residents of temporary housing who fear revealing their HIV infection status may hesitate to take ART in front of others or openly engage in HIV care and prevention services † † . Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). † † Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. Unstable housing may prompt some persons with HIV to have sex or inject drugs outdoors or in transient settings where condoms and sterile injection equipment are not available. 33,37 A variety of housing services have been developed specifically for adults and adolescents with HIV, 33,38,39 and some have resulted in beneficial outcomes 33 (see Table 12-1). A study published in 2009 evaluated "supportive housing" for persons with HIV, a multifaceted strategy that provides stable housing, case management, risk-reduction counseling, ART adherence support, and psychosocial support. Provision of supportive housing to 678 homeless persons with HIV in San Francisco was associated with an 80% lower mortality rate over 5 years than persons who did not receive this intervention and was found to be cost-effective. 39 Studies published in 2008 and 2010 found that persons with HIV who received rental assistance were more likely than those who did not receive this aid to refrain from high-risk sexual behaviors and substance abuse and had better physical and mental health outcomes, including lower HIV viral load levels. 33,40 # Substance use, including illicit drug injection Alcohol and drug use are more common among persons with HIV; in 2012, about 7 percent of new HIV infections were among people who inject drugs. 41 Substance use can promote HIV transmission through sharing nonsterile drug-injection equipment or through cognitive and emotional changes that cause disinhibition and poor judgment, which can result in high-risk sexual and drug-injection behaviors. The unstable, unstructured lifestyles and social isolation associated with substance abuse can also impair regular HIV care, high adherence to ART, and the ability to recruit family and friends to support safe behaviors and adherence to ART. Treatment for substance use and alcohol abuse, including oral substitution therapy for persons who inject opioids, can reduce drug and alcohol dependency and enable access to risk-reduction interventions that encourage safer sexual or drug-injection risk behaviors. Several studies have shown that persons receiving substance use treatment are more likely than those not receiving such treatment to start and remain in HIV medical care, to adopt safer behaviors, and to adhere to ART 1,44, (see Table 12-1). # Mental illness Estimates of the prevalence of HIV infection among Americans with mental illness vary between 3% and 23%, with a mean of about 7%. 64 Depression and other mental illness are common among persons with HIV. A recent study of 1,061 persons receiving mental health services in 2 large U.S. cities found that their HIV prevalence was more than 4 times the prevalence of the cities' general populations. 65 A nationally representative, population-based study of 3,643 persons with HIV receiving outpatient HIV medical care found that 33% needed mental health counseling. 66 Psychosocial distress and mental illness may stem from the strain of coping with a difficult chronic disease, social isolation, limited social support, discrimination, abuse, or violence. Stigma and discrimination related to HIV, sexual orientation or gender identity (e.g., homophobia, transphobia), ‡ ‡ poverty, race, substance use, and unstable housing may lead to psychological distress, depression, and other mental health problems that, in turn, can erode safe behaviors and cause immunosuppression. Persons who anticipate being stigmatized when seeking HIV prevention and care services may also forego valuable services. 68,69, Transphobia is an aversion to individuals who do not conform to the traditional or cultural norm of gender identity. Mental illness can also hinder the use of safe sex and drug-using behaviors, the willingness or ability to use prevention and care services, and the use of and adherence to ART. Stress; depression; difficulty coping with a complex, potentially fatal chronic disease; and a lack of social support have also been associated with increases in viral load levels. Several studies have shown that receiving mental health services improves engagement and retention in HIV care and quality of life 1,61,62,77,84 (see Table 12-1). # Legal detention and incarceration In some jurisdictions, person with HIV who carry HIV prevention devices in public, such as condoms or sterile drug-injection equipment, may be vulnerable to prosecution for commercial sex work or drug use, respectively. 85,86 HIV incidence is about 3 times higher in prisoners than in the general population. 87,88 At the end of 2008, an estimated 1.5% of state and federal prisoners were infected with HIV. 88 Adults and adolescents with HIV in jails, halfway houses, and parole programs may have unique HIV prevention and care needs. 89 Detainees with HIV may not disclose substance use, sex work, or other illegal activities that caused their infection because of concerns about prosecution, discrimination, or breach of confidentiality. 90 When persons with HIV move to or from correctional facilities, they may lose access to their usual source of HIV medical care and ART. Some prisons that provide substance abuse and mental health treatment and other specialty services onsite or through referral § § cannot continue their services after an inmate is released. After release from detention, persons with HIV also face changes in housing, food supplies, employment, transportation, income, and health insurance. This forces many to focus on meeting basic needs of food and shelter and to delay seeking HIV medical care or specialty services. 89 For this reason, correctional facilities that provide reentry transition planning or case management can increase the proportion of persons with HIV who obtain HIV prevention and care services after their release 89,91,92 (see Table 12-1). # Immigration Many undocumented immigrants with HIV are ineligible for public-or private-sector HIV prevention, care, and specialty services, including services covered by health plans regulated by the Patient Protection and Affordable Care Act (ACA). Many low-income immigrants also lack health insurance or cannot afford to pay for services out of pocket. 93,94 Some immigrants with HIV who are unaware of their infection may defer HIV testing and unknowingly transmit HIV to others. Those who are aware of their infection may delay HIV medical care or not disclose their infection to service providers if they fear arrest, deportation, or discrimination. 95 Recent immigrants may retain health care beliefs and practices from their country of origin and may hesitate to engage in mainstream medical care and use unfamiliar medications. 96 Immigrants who must rely on emergency departments, migrant health clinics, or other safety net providers often receive only sporadic care for acute conditions rather than continuous, longterm HIV medical care that is most effective. 93 Many communities have local providers, federally-funded clinics, and other medical assistance programs that provide medical and social services to immigrants (see Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. # Adolescence and legal minor status Many adolescents and young adults with HIV experience age-related or legal circumstances that pose barriers to obtaining HIV prevention and care services. Some adolescents with HIV do not have established health care providers or do not know how to find HIV medical care. Several surveys demonstrate that adolescents may forgo health care if they believe information about rendered services (bills or explanations of benefits) can be disclosed without their consent to parents or guardians who sponsor their insurance. Even when minors have rights to confidential HIV services, their doubts about confidentiality protections may deter them from seeking services (see Section 3, Context of Prevention). For example, some minors who must provide family income records to confirm eligibility for Ryan White HIV/AIDS Program benefits or other HIV services may forego these services if their parents do not know their infection status. 122 They may also defer contraception, other reproductive health services, and employment support that might influence the risk of HIV transmission. Some adolescents with HIV may fear, or have experienced, that disclosing their HIV infection to their parents prompts unwanted questions about sexual activity, sexual orientation, or substance use, or leads to accusations, abuse, or loss of parental financial support or housing. Youth with HIV who have not disclosed their diagnosis may find it difficult to adhere to ART if they must covertly take or store pills. Also, adolescents with perinatally acquired HIV often take more responsibility for managing their HIV care, ART supplies, and adherence than they did as children. 123 Providers can encourage youth to access HIV services by describing their rights to confidential health care (which may differ by state), parental disclosure requirements, and billing procedures. When confidentiality of billing information may be a problem, providers can refer adolescents to providers who do not charge for their services or do not bill parents. Some HIV prevention and care programs have created welcoming, "youth-friendly" environments that offer flexible service hours and age-appropriate education and skill-building about coping, communication, and adherence to ART. 124 Some of these orient adolescents who are transitioning from pediatric to adult health care providers about differences in patient support services. 125,126 Other valuable services include patient navigation support by peer educators, case managers, and multidisciplinary teams that address the developmental, medical, legal, and educational needs of youth 38,124,127,128 (see Table 12-1). With support from CDC, HRSA, and the National Institute of Child Health and Human Development, urban adolescent care centers, local health departments, and adolescent outreach experts are collaborating in a program that supports identification of youth with undiagnosed HIV and prompt linkage to providers of HIV medical care who practice in "youth-friendly" settings. 129 New guidance for adolescent health care providers who serve gay, bisexual, and transgender youth at risk of HIV is also available. 106 # Advanced age As persons with HIV in the United States live longer, the number of older persons with HIV is rapidly increasing. By 2020, an estimated one-half of all persons with HIV will be aged 50 years or older. 130 Many older persons with HIV have or will develop physical, mental health, or social needs related to chronic HIV infection and the normal aging process that may warrant special assessment, support, or services. 131,132 For example, age-related changes in immune function may impair response to ART. Older patients with suppressed viral load consistently experience less robust CD4 cell count responses, possibly because CD4-cell-mediated immune reconstitution related to thymic function declines with age. 130 Cognitive decline, comorbid health conditions, social isolation, and "regimen fatigue" may also erode adherence to ART. 133 Aging may also change sexual practices. Persons who lose longstanding partners may seek new or casual sex partners. Persons may use sexual performance aids (e.g., penile rings) that may cause genital trauma or erectile dysfunction medications that have been associated with higher levels of unprotected anal sex † † † . Providers who routinely assess adherence to ART and risk behaviors of older persons with HIV can tailor services, risk-reduction messages, and HIV prevention and care services to any unique needs 9 (see Section 7, Risk Screening and Risk Reduction, Section 6, ART Adherence, and Unprotected anal sex is sexual activity without using a physical barrier (i.e., without using a male condom; oral-anal contact without using a dental dam or other barrier device; or rectal-digital contact without using a latex glove or finger cot). # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities The capacity to provide specialty services to persons with HIV varies greatly by jurisdiction and is limited in many communities. For example, a study published in 2012 found substantial gaps in mental health services; substance use treatment; and support for food, housing, and transportation for persons with HIV. The study cautioned that this gap in infrastructure would increase if service capacity did not keep pace with the growing number of persons with HIV. 110 Several factors impair the delivery of specialty services: lack of understanding that other medical and social issues influence HIV transmission; lack of established infrastructure, standard procedures, trained staff, and tracking methods; lack of time; and competing priorities. Case managers and coordinated case management systems for persons with HIV with complex navigation needs are scarce in many areas. 11,66 Specialty services serving youth, rural residents, undocumented immigrants, and persons lacking health insurance are particularly overstretched. 141,142 Fortunately, implementation of the ACA promises to improve access to and use of specialty services by the growing number of persons with HIV who have enrolled in private insurance, Medicaid, or other medical assistance programs. The ACA will also enable health care providers working in Ryan White-funded clinics to bill Medicaid, other medical assistance programs, or private health insurance for specialty services related to HIV prevention and care. 146 Use of multidisciplinary teams, collaboration, and task-sharing can also facilitate access to specialty services 8,10-12 (see Boxes 12-A and 12-B). For example, clinical providers can engage mental health care, substance use treatment, or other special medical services that are provided onsite or through referral to other health care providers, while nonclinical providers can help persons with HIV find stable housing, transportation to medical visits, and condom supplies. Nonclinical HIV testing sites can assess specialty service needs as part of their routine risk screening ‡ ‡ ‡ or post-test services for persons who test positive. Health care facilities that cannot hire onsite case managers may contract with community-based organizations that offer navigation assistance to persons with HIV. # Policy, legal, and ethical considerations Referrals to specialty services usually require the exchange of confidential health information. Persons with HIV may be more willing to respond to a referral recommendation when providers seek explicit informed consent and describe measures to maintain confidentiality during the referral process, such as the Health Insurance Portability and Accountability Act and state or federal confidentiality standards specific to HIV 147 (see Section 3, Context of Prevention, for additional information on confidentiality). # Implementation Resources Resources to support implementation of these recommendations are found at . They include referral assessment tools, sample memoranda of agreement with referral agencies, and online directories of specialty service providers. QI relies on the routine, repeated use of demographic, administrative, and health data to improve clinical and public health systems, processes, and outcomes. QI has traditionally been the domain of health care administrators who are seeking better health outcomes, higher standards of care, more efficient operation, or greater patient satisfaction. Recently, health departments and nonclinical organizations have engaged in QI efforts. 1 QI is driven by 3 fundamental questions:  "What change in health status or other outcomes do we want to achieve?"  "What kinds of changes can we make that may result in an improvement?"  "How will we know that a change led to an improvement (i.e., how is change measured)?" QI usually involves small, incremental changes in practice and rapid feedback of results. It is often an iterative process of repeated cycles of change and feedback that can be integrated into practices and programs as a continuous, routine performance improvement strategy and can be led by internal staff (see Table 13-1). The process relies on collecting and analyzing "real-time" data that reflect current practice. In HIV medical settings, QI often focuses on guideline adherence; evidence-based § clinical decision making; or measures to increase efficiency, lower costs, strategically use staff and health information, or improve care coordination and patient flow. For example, staff in one HIV outpatient clinic compared 2 types of computer alerts in electronic medical records (EMRs) used by physicians serving patients with high HIV viral load or suboptimal retention in care. 2 Use of "interactive alerts" that facilitated appointment scheduling and laboratory testing were associated with greater improvements in CD4 cell counts and follow-up visits than "static alerts" that only listed these patients. - Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. † Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Evidence-based interventions, strategies, guidelines, and recommendations are based on sound scientific research, testing, or program evaluation. An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. Program monitoring involves the ongoing, repeated collection and review of information about the activities and operation of a program. Program evaluation involves periodic collection of information about program activities, characteristics, and outcomes in order to assess causal attribution, improve effectiveness, or identify lessons learned. 3 M&E efforts usually focus on questions of program design, implementation, effectiveness, acceptability, coverage, and cost. They attempt to answer questions, such as the following:  "What are we trying to accomplish?"  "Are we doing it right?"  "Are we implementing the program as planned and on a large enough scale?"  "What assumptions or potential risks relate to this program?"  "Are the interventions making a difference?" Because M&E can assess program coverage, impact, and costs, M&E is an essential accountability function of many health departments, HIV planning groups, and publicly funded community-based organizations. Recent federal M&E efforts have focused on monitoring linkage † † to (and retention in) HIV medical care, antiretroviral treatment (ART) use, and viral suppression, and the collected data and performance measurements are now used by several federal agencies (see Table 13-2). Some state health departments have analyzed population-level data about continuum of HIV care, such as the proportion of persons in the jurisdiction without laboratory reports indicating continued care and suppressed viral load. These analyses can identify populations that would benefit from being offered interventions to improve retention in care. 4 The recommendations and examples of best practices for QI and M&E in this section were based on a review of federal and state recommendations for QI and M&E that are relevant to HIV clinical settings and nonclinical programs, national HIV indicators and performance measures, and opinions of experts on QI and M&E for HIV clinical care and community programs (see Box 13-A and Figure 13-1). These practices can be applied to many interventions (see and used by government agencies, public and private payers, accreditation entities, health departments, community-based organizations, large health systems, and small clinical practices. † † Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). For staff of health departments and HIV planning groups who provide population-level HIV prevention and care services  Regularly monitor program implementation and periodically evaluate program outcomes according to best practices (i, iii, iv) Note. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to . a In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. b The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup and program experience, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. opportunities, and challenges of the service or program and priorities for improvement  Develop a program improvement plan that describes the service or program purpose, defines QI goals and strategies, establishes accountability for the plan, and describes resources for QI activities  Develop a "conceptual map" that depicts the relation between program inputs, outputs, and outcomes to pinpoint where to target improvement activities  Design QI intervention cycles after reviewing past experience from literature, colleagues, technical assistance providers, and stakeholders  Establish benchmarks, baseline measures, and performance goals based on national or local standards, clinical guidance, or accreditation standards  Develop data collection methods that adhere to confidentiality and data security regulations  Identify, test, refine, and use new or existing indicators to track service delivery, quality, satisfaction, and outcomes (see Table 13-2)  Implement interventions by testing feasibility and evaluating results (e.g., "Plan-Do-Study-Act" approach) (see Table 13-1)  Develop and execute a plan to interpret and communicate data after consulting with stakeholders  Scale up successful, feasible interventions and identify lessons from interventions that did or did not result in desired change  Repeat QI cycles to determine if interventions achieve desired outcomes Note. Many programs use additional, program-specific indicators. # Methods The recommendations in this section were based on guidance from CDC and HRSA that were supported by scientific evidence, program experience, and expert opinion. 5,10,17,18 Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Many federal, state, and local programs routinely implement QI and program evaluation methods that address HIV prevention with persons with HIV. Quality management programs that develop and encourage reporting of performance measures are more likely to motivate programs to participate in QI and M&E. 21 For example, the Health Resources and Services Administration's HIV/AIDS Bureau engages in many quality initiatives for HIV services provided through the Ryan White HIV/AIDS Program that are guided by a set of clinical performance measures. 21 This focus on QI and program evaluation has expanded the range of clinical and social services for persons with HIV, improved documentation and billing of rendered services, and introduced more versatile electronic medical information systems and novel uses of surveillance and administrative data. 19,22,23 QI and M&E are intended to improve service access, quality, cost, overall impact, and/or satisfaction for clients and other program stakeholders, but can sometimes disrupt service delivery priorities and require substantial resources. Developing or amending data collection processes and electronic information systems to collect or calculate performance data can be costly, complex, time-consuming, and require hiring of specialized staff. 21 Burdensome data collection to meet internal demands or external accountability requirements can become an end in itself and is wasteful if it is not used to guide program improvement. If QI and M&E results are used to create incentives for improvement or change rather than to highlight failures, they are more likely to be acceptable to an organization's employees and leadership. # Policy, legal, and ethical considerations Several organizations have issued guidance about policy, legal, and ethical factors that influence HIVrelated QI and M&E. This guidance addresses sharing health information, protecting patient confidentiality, using HIV-related surveillance and clinical data for QI and M&E, balancing data collection burdens with program benefit, maintaining integrity when evaluating publicly funded programs, and respecting staff and client time and privacy. Section 3, Context of Prevention, provides additional information on confidentiality issues. # Client. A person receiving prevention, testing, or social services from a health department or communitybased service providers, not including health facilities. This term is preferred over 'patient' in settings that provide healthy persons prevention and health maintenance services. Clinical providers. Persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other services to prevent, diagnose, treat, or manage health conditions. They include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Clinical setting. A health care facility in which medical diagnostic, treatment, and disease prevention services are routinely provided. Collaboration. Working with another person, organization, or group for mutual benefit by exchanging information, sharing resources, or enhancing the other's capacity, often to achieve a common goal or purpose. Colocating. The provision of more than one type of HIV service in the same physical space, such as providing substance use treatment in an HIV medical clinic or providing HIV partner services in an HIV testing facility. Community-based HIV service organizations. Organizations that offer and deliver community-based HIV services, not including diagnostic and treatment services. Many collaborate with health departments to provide services to specific populations. Confidentiality. Ensuring that information is accessible only to persons authorized to have access in order to maintain client and patient privacy. # Coordination. A process of creating more client-centered, streamlined, and nonduplicative systems that clarify communication methods, staff roles, use of health information, and reimbursement policies and procedures. Culturally appropriate. Conforming to a culture's acceptable expressions and standards of behavior and thoughts. Interventions and educational materials are more likely to be culturally appropriate when representatives of the intended audience are involved in planning, development, and pilot testing. Cunnilingus. Oral stimulation of the female genitals. # Diagnostic testing. Testing that is initiated for a person with clinical signs or symptoms to obtain objective evidence of the presence or absence of diseases or infections, including HIV and STDs. # Directly administered antiretroviral treatment or therapy (DAART). A method to promote ART adherence in which a clinical or nonclinical provider observes persons with HIV take all or most doses of prescribed ART. Also referred to as directly observed therapy (DOT). # Disclosure (of HIV infection status). A process in which a person with HIV reveals his or her HIV infection to others, or when an HIV prevention or care provider shares information about a person's HIV infection status with another HIV prevention or care provider. # Drug-injection partner. A person who has shared nonsterile or previously used needles, syringes, or other drug-injection equipment with another person. exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. Partner services specialists. Persons who provide partner services, including specially trained disease investigation specialists, public health investigators, or communicable disease investigators who work in health departments and staff of other agencies who are trained and authorized to provide these services. Person at high risk of HIV infection. A person who has behaviors that place him/her at high risk of contracting HIV infection (e.g., having unprotected sex or sharing drug-injection equipment with a person known to be HIV-infected or with persons from communities with a high prevalence of HIV infection). # Persons who inject drugs (PWID). Persons who inject illicit drugs using equipment that may facilitate HIV transmission, such as nonsterile syringes, needles, cookers, or spoons. Population-level intervention. An intervention intended to improve the risk conditions and behaviors in a population or community by focusing on the population or community as a whole, rather than on individuals or small groups. Examples include community mobilization, social marketing campaigns, community events, policy interventions, and housing programs meant to alter social norms, policies, or environmental characteristics. Postnatal infant prophylaxis. The use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. Preexposure prophylaxis (PrEP). The daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. Presumptive treatment. The provision of treatment for syphilis, gonorrhea, chlamydial infection or trichomoniasis before the results of STD testing or clinical evaluation are available. This treatment approach is recommended for persons who report symptoms suggestive of these STDs or recent sex partners who were treated for these STDs, or have clinical signs of these STDs. Prevalence. The total number of cases of a disease in a given population at a particular point in time. HIV/AIDS prevalence refers to persons infected with HIV, regardless of time of infection or diagnosis date. Prevention services (or program). Interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. Examples of HIV prevention services include risk-reduction information and interventions, condom distribution, use of antiretroviral therapy to reduce HIV viral load, and STD screening and treatment to control infections that can facilitate HIV transmission. A prevention program is an organized effort to implement one or more interventions. Privacy. The right and power to control information about oneself. Quality improvement. An approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. Receptive anal sex. The practice of receiving a partner's penis in one's anus. Also known as receptive penile-anal sex. assess the risk of disease progression, to monitor virologic response to ART, and to estimate the degree of infectiousness. Virologic failure. The inability to achieve or maintain suppression of HIV replication to an HIV RNA level of <200 copies/mL. Virologic testing. The process of using tests that detect HIV antigens or nucleic acids such as RNA or DNA Window period. Interval between a person's infection with HIV and the production of HIV antibodies that can be detected by an HIV test.	The contributors to this report (Appendix C) declared no interests regarding the commercial products discussed herein. The report describes the use of certain drugs, tests, and procedures for some indications that do not reflect labeling approved by the U.S. Food and Drug Administration (FDA) at the time of publication. Information about such drugs, tests, or procedures is noted in the relevant sections.# This report updates and expands recommendations on the four topics covered by the 2003 Recommendations:  Screening for behaviors that could transmit HIV and behavioral interventions to reduce the risk of transmission  STD screening, treatment, and other sexual health services that may reduce the risk of HIV transmission  Services for sex partners and drug-injection partners of persons with HIV (known as HIV partner services † )  Referral ‡ for other medical and social services that influence HIV transmission or use of HIV prevention and care services The 2003 Recommendations were directed to health care providers who serve persons with HIV. In contrast, the recommendations in this report are directed to a broader audience of clinical providers and nonclinical providers who serve persons with HIV and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. The recommendations may also be of interest to persons with HIV; partners of persons with HIV; specialists in HIV planning and service delivery who work for medical assistance programs, health insurance plans, or health systems; and specialists in HIV policy who develop HIV-related programs, legislation, and regulations. ‡ Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). In this report, clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. A specially convened Project Workgroup comprised of HIV experts from CDC and HRSA consolidated longstanding recommendations from current federal guidance that were based on scientific evidence, program experience, and/or expert opinion published through July 2014. The Workgroup also developed new recommendations which were based on scientific evidence, program experience, laws, regulations, and expert opinion. Some highlights of the recommendations include the following:  Engaging clinical providers, nonclinical providers, health departments, and HIV planning groups to use their expertise, professional authorities, and collaborative relationships to serve individuals or populations of persons with HIV  Creating a spirit of partnership among persons with HIV and the providers who serve them in order to achieve both individual HIV prevention and care goals and public health benefits  Using evidence-based strategies † † to promptly link persons with newly diagnosed HIV infection to HIV medical care and promote their long-term retention in care  Using HIV clinical and surveillance data to promote linkage to and retention in care of individuals or populations with HIV, if allowed by the laws or regulations of the jurisdiction  Informing all persons with HIV (regardless of their CD4 cell count) about the role of effective ART in promoting their health and reducing HIV transmission and offering ART regimens recommended by the U.S. Department of Health and Human Services  Supporting sustained high adherence to ART using evidence-based interventions  Using both biomedical factors, such as HIV viral load and recently diagnosed STDs, and HIV risk behaviors ‡ ‡ to assess a person's risk of HIV transmission  Supporting safer sexual and drug-use behaviors using effective, evidence-based interventions  Supporting persons with HIV to selectively disclose their HIV infection status and notify partners of possible HIV exposure using methods that minimize the risk of stigma, discrimination, prosecution, and other negative consequences  Expediting HIV partner services to persons with acute HIV infection § § or high viral load who are most infectious  Informing persons with HIV about the availability of preexposure prophylaxis (PrEP)* or nonoccupational postexposure prophylaxis (nPEP) † † † for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  Screening persons with HIV with the most sensitive STD tests, including tests for rectal and oropharyngeal specimens from gay, bisexual, and other men who have sex with men (MSM), and treating infected persons with the most effective STD treatment, as recommended by the latest CDC guidance † † Evidence-based interventions, strategies, guidelines, and recommendations are based on sound scientific research, testing, or program evaluation. ‡ ‡ Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). § § Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. * PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 9 † † † nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 10  Providing women and men with HIV who are of reproductive age with contraceptive services, reproductive health counseling, and information and access to special conception methods that can reduce the risk of HIV transmission, as recommended by the latest federal guidance  Providing women with HIV who are pregnant and HIV-uninfected pregnant women with HIVinfected partners various biomedical and behavioral interventions that prevent sexual or perinatal HIV transmission during pregnancy, as recommended by the latest federal guidance  Helping persons with HIV obtain other medical and social services that support long-term HIV care and high adherence to ART, encourage safer behaviors, and prevent HIV transmission, such as mental health and substance use treatment, stable housing, and transportation to health-related visits  Applying quality improvement ‡ ‡ ‡ strategies and program monitoring and evaluation § § § to improve the effectiveness and efficiency of HIV prevention and care services This report is published with 3 shorter summaries that list the subset of recommendations pertaining to a specific audience: clinical providers, 11 nonclinical providers, 12 and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. 13 A companion Web site includes dozens of practical decision-support tools and training aids and is regularly updated as new materials become available: http://www.cdc.gov/hiv/prevention/programs/pwp/resources.html Because these recommendations are both numerous and ambitious, health professionals and organizations must focus on the interventions that are most feasible given their professional authority, skills, and resources and are most important for their clients, patients, and communities. This report's broad audience highlights both the unique and shared roles of different provider types who offer interventions as well as opportunities for collaboration across clinical, nonclinical, and public health organizations. Collaboration is important at a time when the number and longevity of persons with HIV in the United States is increasing, more effective interventions are available, and shortages of trained HIV care and prevention providers persist. 14,15 Finally, these recommendations can help mobilize support, policies, resources, and quality improvement for HIV prevention activities in communities and health systems that will ensure that "prevention with persons with HIV" is a cornerstone of HIV prevention in the United States. # Section 1. Introduction More than 1 million people are living with HIV in the United States, an increase of 60% over the previous 15 years. 1 The number of newly infected persons exceeds the number of deaths among HIV-infected persons, which results in a net increase of about 30,000 persons with HIV each year. 2,3 In 2012, about 64% of infections in adults and adolescents were diagnosed among gay, bisexual, and other men who have sex with men (MSM) and about 10% in persons who inject drugs. Nearly 26% of infections were diagnosed in heterosexual persons, of whom about 67% were women. 2 Persons diagnosed with HIV are disproportionately black/African-American and Hispanic/Latino and residents of selected states of the Southeast and Mid-Atlantic regions, Puerto Rico, the U.S. Virgin Islands, and about a dozen of the largest U.S. cities. The growing number of persons living with HIV challenges delivery of prevention and care services and demands more effective methods to prevent HIV transmission to others. 4 Some persons with HIV have taken steps to reduce the risk of transmitting HIV by starting HIV care shortly after diagnosis, using ART to reduce infectiousness, or undergoing STD screening and treatment. Many practice safer sexual and drug-use behaviors, notify partners of possible HIV exposure, or use reproductive health services and substance use treatment to lower their transmission risk. [5][6][7][8] Nevertheless, national data indicate that many persons with HIV do not benefit from the full range of biomedical, behavioral, and structural interventions that can reduce infectiousness and the risk of exposing others to HIV. 9 Of the more than 1 million HIV-infected individuals living in the United States in 2009, only about  82% of persons with HIV were aware of their HIV infection status  66% of persons with diagnosed HIV were linked to care  37% of those who entered care were retained in care  33% were prescribed antiretroviral treatment (ART)  25% had a suppressed viral load, which reduces infectiousness 9 (see Figure 1-1) Nationally representative data also indicate that only about 45% of persons receiving outpatient HIV medical care reported receiving HIV prevention counseling* from a health care provider during the preceding year. 10 This may be due to time constraints, competing clinical priorities, lack of training in sexual health or injection-drug use, uncertainty that counseling will motivate behavior change, and other factors. 11,12 Many persons with HIV do not receive routine screening for sexually transmitted diseases (STDs) that may facilitate HIV transmission or services to notify partners of possible HIV exposure. 6,13 Personal choice to defer safer behaviors also contributes to HIV transmission. Studies conducted in the United States when ART was routinely initiated at CD4 cell counts below 350 per mm^3 of blood show that some adolescents and adults with HIV who are aware of their infection status did not practice safe sex and drug-injection behaviors. 14 In 2011, an estimated 13% of MSM with HIV reported engaging in sex without a condom with male partners who were HIV-uninfected or whose infection status was unknown. 15 A review of several U.S. studies of condom use in female adolescents infected with HIV through perinatal exposure, sexual activity, or drug use found that about 40%-60% of adolescents reported engaging in unprotected sex. 16 One 2001 study found that adolescent girls who disclosed their HIV infection to partners were more likely to report consistent condom use than adolescent girls who did not disclose their infection. 17 The 2010 National HIV/AIDS Strategy highlighted the need to accelerate HIV prevention and to increase health equity through several approaches. These include reducing the HIV transmission rate; increasing the percentage of persons with HIV who know their infection status, are promptly linked to HIV care, and remain in continuous care; and increasing the proportion of persons in priority populations (MSM, black/African-American, and Hispanic/Latino) with undetectable HIV viral loads. 18 A prevention strategy that aims to increase access to effective biomedical, behavioral, and structural interventions for the more than 1 million persons with HIV is more likely to decrease HIV transmission than a strategy that attempts to change sexual and drug-injection behaviors of the many millions of persons at risk for infection. 19,20 Also, many prevention interventions for persons with HIV can capitalize on existing clinical systems and resources because most receive care for HIV or other medical conditions sometime after their HIV diagnosis. This report updates and expands earlier recommendations about HIV prevention for persons with HIV published by the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America in 2003: Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. 21 Several factors prompted this update, including advances in behavioral, biomedical, and structural interventions, new national HIV prevention goals, 18 and recent changes in public-and private-sector health care delivery and financing in the United States. 22,23 These recommendations also incorporated perspectives of additional stakeholders, including persons with HIV, HIV medical care providers, nonclinical HIV prevention providers, health department HIV/AIDS program managers, and experts in HIV policy and legal issues (see Section 2,Methods). This report consolidates a large number of federal recommendations about effective biomedical, behavioral, and structural interventions that can reduce the infectiousness of adults and adolescents with HIV and behaviors that can transmit HIV. The recommendations relate to 11 topics, which correspond to the 11 main sections of this report:  Individual, social, structural, ethical, legal, policy, and programmatic factors that influence HIV transmission and use of prevention services † (referred to as the Context of HIV prevention)  Linkage ‡ to and retention in HIV medical care  Use of ART for improving health and for preventing HIV transmission  Methods to achieve sustained, high adherence to ART to reduce infectiousness  Screening for behavioral, biomedical, and structural factors that increase risk of HIV transmission and risk-reduction interventions that promote health and reduce the risk of HIV transmission  Services for sex partners and drug-injection partners of persons with HIV (referred to as HIV partner services § )  STD screening, treatment, and other sexual health services that may reduce the risk of HIV transmission † Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. ‡ Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). § Partner services include an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services.  Reproductive health care for women and men to reduce the risk of sexual HIV transmission when attempting conception or unintended pregnancy (thereby reducing the risk of perinatal HIV transmission)  Pregnancy-related services to reduce the risk of sexual or perinatal transmission during recognized pregnancy  Other medical and social services that influence HIV transmission or use of HIV prevention and care services  Methods to monitor, evaluate, and improve the quality of HIV prevention and care services and programs for persons with HIV The vast majority of recommendations in this report pertain to persons with HIV, but a few relate to interventions for HIV-uninfected, sex or drug-injection partners of persons with HIV, and these interventions may be used by the partners to reduce their risk of acquiring HIV. # The recommendations consolidate  the latest guidance from several federal agencies published through May 2014  new evidence that supports this federal guidance  several entirely new recommendations and their supporting rationale Section 2, Methods, describes the methods used to consolidate this federal guidance, to identify new evidence supporting this guidance, and to develop new recommendations based on scientific evidence, program experience, and expert opinion. # This report does not include recommendations about  comprehensive primary care for persons with HIV 24  the prevention, diagnosis, and treatment of infections that are relatively common in persons with HIV but are not known to facilitate HIV transmission, such as viral hepatitis, some STDs, and most opportunistic infections 24,25  prevention of HIV transmission from infants or young children [26][27][28] The primary audiences for this report include the following:  Clinical providers working in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments.  Nonclinical providers working in community-based organizations or health departments outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These providers include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, † † partner services specialists, ‡ ‡ case managers, and social workers.  Staff of health departments and HIV planning groups who provide population-level HIV prevention and care services, such as HIV surveillance or coordination of state and local HIV prevention and care resources. Secondary audiences for this report include persons with HIV, partners of persons with HIV, specialists in HIV/AIDS policy and law, funding, and service coverage and reimbursement for public and private sector health systems and community-based programs. These also include developers of HIV-related policies, government regulations, and legislation and managers of health insurance plans, medical assistance programs, and private and public health care systems that serve persons with HIV. By directing these recommendations to a wide range of health professionals and organizations, this report highlights both their unique and shared roles in carrying out individual-and population-level HIV prevention and care strategies. It also underscores opportunities for collaboration across clinical, nonclinical, and public health organizations. Collaboration and task sharing are especially needed as the number and lifespans of persons with HIV increases, more effective interventions are available, and shortages of trained HIV care and prevention providers persist. 1,29 Linkage to HIV medical care provides an example: health department HIV surveillance programs can identify populations or individuals with newly diagnosed HIV who may warrant help linking to HIV medical care, nonclinical HIV testing providers can help newly diagnosed clients schedule their first HIV care appointments, health care providers can request expedited scheduling, and HIV planning groups can promote HIV training for primary care physicians, physician assistants, and nurses. Sections 4 through 12 summarize each intervention topic using a similar format: background that defines the intervention and how it is delivered; a list of recommendations that are specific to provider type; examples of operational strategies, methods, or best practices to implement the recommendations; a summary of how the recommendations differ from previous federal guidance on this topic; methods used to assess federal guidance, published literature, or other sources of evidence used when developing the recommendations; a summary of evidence supporting the recommendations; a summary of issues that influence implementation of the recommendations; a link to a Web site that includes decision-support tools and other implementation resources (http://www.cdc.gov/hiv/prevention/programs/pwp/ resources.html); and references. Section 13 describes quality improvement § § and program monitoring and evaluation * methods that can determine if interventions are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods. This report is published with 3 shorter summary documents that list the subset of recommendations for clinical providers, 30 nonclinical † † Linkage facilitators assist persons with HIV to access HIV medical care and other medical and social services through active methods (e.g., help with making appointments, providing transportation to appointments). ‡ ‡ Partner services specialists include specially trained disease investigation specialists, public health investigators, or communicable disease investigators who work in health departments and staff of other agencies who are trained and authorized to provide partner services. § § Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. *** Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. providers, 31 and staff of health departments and HIV planning groups who provide population-level HIV prevention and care services. 32 Together these recommendations and implementation resources provide a national action plan to promote HIV prevention with persons with HIV. They can guide the daily work of clinical providers, nonclinical providers, and staff of health departments and HIV planning groups. They can inform HIV prevention policies, quality improvement initiatives, and resource allocation decisions. By galvanizing support and collaboration for HIV prevention activities across health systems, community organizations, and government agencies, these recommendations can reaffirm that prevention with persons with HIV is a cornerstone of HIV prevention in the United States. # Section 2. Methods These Writing groups had expertise in HIV-related public health; epidemiology; clinical medicine; behavioral and social science; health education; statistics; laboratory science; health policy; health equity; clinical quality improvement; † clinical and nonclinical interventions; program implementation, evaluation, and monitoring; and guideline development. Each member was required to be free of financial or intellectual interests that might pose a conflict regarding federal guidance about commercial products. Each writing group used a slightly different approach in evaluating federal government guidance (hereafter called "source guidance") or other evidence that might support recommendations because the extent of source guidance and primary scientific evidence varied by topic. Three CDC HIV specialists and two HIV information specialists conducted searches of published literature for nine of the eleven topics (all except the topics on context of HIV prevention and quality improvement and program monitoring). The searches were expanded to include guidance from federal agencies (CDC, HRSA, NIH, and the U.S. Department of Health and Human Services [HHS]) and two federally-sponsored organizations: the U.S. Preventive Services Task Force and the Community Preventive Services Task Force. The above systematic reviews were published in English from 2000 to 2011 and were included in the CDC HIV/AIDS Prevention Research Synthesis (PRS) Project's cumulative HIV/AIDS/STD prevention database. This database includes articles without language restriction that are indexed in EMBASE, MEDLINE, PsycINFO, Sociological Abstracts, and CINAHL. The information specialists searched articles indexed by MeSH terms or keywords related to three domains: disease (HIV, AIDS, or STD); study type (prevention, intervention, education, or evaluation); and outcome (behavior or other outcomes); details on the search terms are described in other documents. 1,2 The information specialists also searched systematic reviews published through 2009 that were cited in the Cochrane Database of Systematic Reviews and indexed with the following terms found in the title, abstract or keywords: (HIV infection OR Acquired Immunodeficiency Syndrome OR Sexually Transmitted Diseases) AND (Prevention OR Intervention). 3 The information specialists classified each identified article by one of the nine intervention topics. Each writing group sought additional information through narrative literature reviews that yielded guidelines from nongovernmental organizations in the United States, peer-reviewed journal articles, abstracts from HIV conferences, program evaluation reports, unpublished data from CDC, and policy and legal documents that had been published from 2000 to as late as July 2014. The Methods topic of each section describes these sources. Fourth, all 11 writing groups drafted recommendations that were based on the latest federal source guidance, recommendations, laws, regulations, or policies published through May 2014 and/or sources of scientific evidence, program experience, and/or expert opinion that were available through July 2014. Most recommendations simply restated the latest relevant source guidance that was based on scientific evidence, program experience, and/or expert opinion. Although some writing groups did not reexamine the evidence supporting recommendations in the source guidance, all groups evaluated evidence that had accumulated since publication of the source guidance to determine if the latest published recommendations warranted reconsideration. The writing groups consolidated and restated the recommendations from the source guidance instead of excerpting them verbatim. This rephrasing enabled use of a standard format that explicitly defined the recommendation's audiences and beneficiaries (that some source guidance had only implied). For example, "Recommendations for clinical providers: Advise patients to take antiretroviral treatment (ART) as prescribed." Roman numerals indicate the source guidance for each recommendation. Some writing groups also drafted new recommendations that extended a recommendation in the source guidance that was directed to one provider type to another provider type; this occurred when published evidence, program experience, or expert opinion indicated that another provider type could become authorized for and proficient at providing this service. For example, the section writing group on ART extended to nonclinical providers the current federal recommendation for clinical providers to inform patients that ART can reduce the risk of transmitting HIV because several experts and programs have found that nonclinical providers in community-based HIV service organizations and health departments can become proficient at providing this information. All recommendations that were extended from one provider type to another provider type are labeled with alphabetic superscripts. Some writing groups drafted new recommendations (which did not simply restate or extend recommendations from source guidance) when they identified scientific evidence with generally consistent findings, statistically significant differences between intervention groups and comparison groups; appreciable effect size; and/or consistent or extensive program experience. The writing groups did not combine primary data from more than one study using meta-analyses, direct comparison of effect sizes, or other quantitative methods, and they did not formally rate the quality of evidence. Some groups also considered information on the cost-effectiveness of interventions and expert opinions expressed in published literature or during the April 2011 consultation (described below). Writing groups used an informal consensus process without voting when developing new recommendations. 4 In general, recommendations about biomedical interventions (e.g., ART, STD screening), behavioral interventions (e.g., adherence, risk-reduction interventions), and structural interventions (e.g., referral ‡ to supportive housing services) were more likely to be based on evidence from controlled or observational studies, clinical case reports or series, or program evaluation data. Recommendations about program design, operations, or infrastructure (e.g., use of appointment reminders, collaboration agreements) were often based on program evaluations or expert opinion. Writing groups did not grade the strength of recommendations for two reasons: 1) many recommendations derived from source guidance had not been rated for strength or did not specify the supporting evidence; and 2) no single system was well-suited to rate a diverse set of recommendations pertaining to medical evaluation, drugs, devices, counseling messages, and program operations that were based on highly varied types of supporting evidence. All recommendations are listed in boxes with titles that include "recommendations" or "recommended." Some recommendations are linked to supplemental boxes that list operational strategies, implementation methods, or discussion topics. For example, the recommendation to screen for HIV risk behaviors is linked to a supplemental box that lists possible screening topics. Each section also includes information from systematic or narrative reviews regarding 1) progress, challenges, and opportunities in implementing the recommendations; 2) policy, legal, and ethical considerations; 3) implementation issues for special populations; and 4) a link to a Web site that includes decision-support tools and other resources to facilitate implementation of the recommendations (http://www.cdc.gov/hiv/prevention/programs/ pwp/resources.html). The report does not include recommendations about future research needs because NIH's national HIV research agenda recently addressed many HIV prevention topics. 5 Fifth, the Project Workgroup solicited oral and written input on the draft recommendations and supporting evidence on many occasions from 2011 through September 2014. Reviewers included 1) participants at a 3-day consultation in April 2011 attended by 103 This report will be revised periodically as needed. # Section 3. The Context of Prevention with Persons with HIV: Essential Considerations for Providers Background Several broad, contextual issues shape the lives of persons with HIV and their ability to use HIV prevention and care services and adopt HIV prevention strategies. These include individual, social, structural, ethical, legal, and policy issues that influence access to, use of, and delivery of HIV prevention and care services. 1 Service providers who understand these contextual issues are better prepared to  share responsibility and decision making for HIV prevention with persons with HIV  communicate in a sensitive, respectful, and culturally appropriate manner  motivate persons with HIV to adopt realistic, evidence-based* prevention strategies  help persons with HIV obtain essential medical and social services  endorse the strategy of "treatment as prevention," in which services for persons with HIV contribute to community well-being  recognize how contextual factors influence HIV transmission in their communities  promote the development of community resources that offer prevention and care services This section makes general recommendations about these contextual issues. In Sections 4 through 12, the Issues that Influence Implementation of the Recommendations topic describes contextual issues related to specific interventions. Quality improvement † and program monitoring and evaluation ‡ can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). # Recommendations BOX 3. RECOMMENDATIONS-CONTEXTUAL ISSUES For nonclinical providers, clinical providers, and health department staff who serve clients, patients, or populations with HIV  Become familiar with  social and structural determinants of health that influence use of HIV prevention and care services (i, ii, iii, iv) (see Table 3-1)  federal, state, and local laws and policies that regulate the following issues (ii, iii, iv, v, vi, vii, viii): • rights, responsibilities, and protections of persons with HIV regarding disclosure of their HIV-infection status and the unintentional or intentional exposure of others to HIV • provider responsibilities regarding HIV case reporting, protecting confidentiality, obtaining informed consent for HIV services, avoiding discrimination, and any requirements to inform persons about possible HIV exposure  governmental and nongovernmental agencies that serve persons with HIV with various insurance and income characteristics and coverage and reimbursement policies (iii, v, ix) (see Table 3-2)  Support  partnerships between persons with HIV and their service providers that foster collaboration, communication, and a spirit of shared responsibility for HIV prevention and care that benefits individuals and the community (iii, v)  enrollment of persons with HIV in long-term health care coverage to hasten access to HIV treatment and prevention services a and to reduce health disparities (i, iii, x, xi)  the development of a skilled workforce and organization infrastructure to deliver, coordinate, and finance HIV prevention and care services (i, iii, v) (see Box 3-A)  strategies that reduce HIV health disparities and improve access to HIV prevention and care services (i, iii, ix) (see Box 3-A)  protection of confidential health information (i, ii, iii, iv, vi, vii, xii) (see Box 3-B)  Encourage  communication that does not stigmatize or negatively judge persons with HIV or their gender identity, sexual orientation, sexual and drug-use behaviors, and medical or social characteristics (i, ii, iii, iv, v, vi)  provision of information about rights and responsibilities of persons with HIV regarding confidentiality, privacy, protection from discrimination, and partner notification b (i, ii, iii, iv, xii)  planning by persons with HIV to notify exposed sex and drug-injection partners through partner notification assistance or self-disclosure that reflects an understanding of the benefits and risks of HIV disclosure in the jurisdiction (vi)  access to services and devices that improve the knowledge, ability, and motivation of persons with HIV to improve their health, protect the health of partners, and reduce transmission of HIV (i, ii, iii, vi) # BOX 3. RECOMMENDATIONS-CONTEXTUAL ISSUES (cont) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These persons include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the federal guidelines cited in the Recommendation boxes of each chapter may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/. a Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. b Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. # Methods The section writing group based these recommendations on a narrative literature review of two sources: 1) reports in peer-reviewed journals published in English from December 2000-March 2014 that pertained to the United States and were indexed by using combinations of these terms: HIV, disclosure, privacy, confidentiality, Health Insurance Portability and Accountability Act (HIPAA), workforce, capacity, prevention, stigma, discrimination, barriers, structural issues, gender, poverty, social issues, ethics, collaboration, coordination, uninsured, and underinsured; and 2) reports, policy statements, and legal information about the above topics published on the Web sites of governmental and nongovernmental health organizations during this same period. This review included recent reports and recommendations of the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and the Institute of Medicine (IOM) about contextual issues influencing persons with HIV; laws and policies that affect the delivery of HIV prevention and care services; and shortages of HIV prevention and care providers. [2][3][4][5][6][7][8][9][10][11] The writing group also obtained information on state laws, statutes, and regulations (hereafter referred to as "laws"), and legal review articles by searching 1) WestlawNext™ using the terms HIV; human immunodeficiency virus; AIDS; acquired immunodeficiency syndrome; sexual transmit disease; sexual transmit infection; communicable disease; venereal disease; CD4; T-lymphocyte; viral load; and nucleic acid; 2) the public Web site of a national HIV legal advocacy organization; 12 and 3) a 2014 systematic search of state HIV-specific criminal laws. 13 # Individual, Social, and Structural Issues that Influence Access to and Use of HIV Prevention and Care Services # The central role of persons with HIV Since the HIV epidemic was first recognized in the United States more than 30 years ago, persons with HIV have played an unprecedented role in drawing attention to the health and social burden of HIV, advocating for HIV prevention and care services, and mobilizing social and legal reforms. This commitment has served as a role model for personal empowerment and shared decision making that has improved access to and quality of services for HIV and other diseases. 14 Persons with HIV and the providers and public health organizations that serve them can create mutually beneficial partnerships that foster shared responsibility for HIV prevention and a common understanding that high quality patient care promotes both individual health and community well-being. 15,16 At the individual level, the concept of "prevention with persons with HIV" recognizes the rights and responsibilities of persons with HIV to make informed decisions about personal behaviors, to use HIV prevention and care services, and to set prevention goals that incorporate attitudes about infectiousness that do not imply blame. This concept encourages providers to listen to and respect the knowledge, beliefs, values, and cultural background of persons with HIV, to share information that is affirming and practical, and to engage in shared decision making. For example, providers serving persons with HIV who desire complete viral suppression prescribe the most effective ART adherence strategies, while providers may refer persons who inject drugs (PWID) but decline substance use treatment to legal syringe services programs § (SSPs). "Prevention with persons with HIV" may also focus on couples who jointly set HIV prevention goals, such as using condoms or supporting high adherence to ART. At the community level, "prevention with persons with HIV" encourages persons with HIV, health systems, health departments, community-based organizations (CBOs), and HIV planning groups to jointly design, implement, and evaluate HIV prevention and care services. 17 In recent years, persons with HIV have led many health, legal, financial, and social reforms that promote HIV prevention and care. These include developing a "patient bill of rights" that describes essential HIV prevention and care services for local health systems and education campaigns that champion "treatment as prevention," the use of ART to reduce the risk of transmission. 18 Working with health and social justice advocates, persons with HIV § Programs that provide free, new, sterile syringes and needles in exchange for used syringes and needles to reduce transmission of bloodborne pathogens among people who inject drugs. May be called syringe exchange programs or needle exchange programs. have mobilized supportive housing and peer education programs for persons with HIV; advocated for protection of confidential health information; and promoted legal unions of same-sex couples. [18][19][20][21] # Individual, social, and structural factors In the United States, several populations bear a disproportionate burden of HIV infection:  Gay, bisexual and other men who have sex with men (MSM)  Black and Hispanic/Latino males and females  Adolescents and young adults, including those leaving foster care  Males and females using drugs, especially PWID  Males and females living in communities with high HIV prevalence  People who live in poverty or lack stable housing  Transgender females (persons whose assigned sex at birth was male but whose gender expression or identity is female) 22,23 The social and structural determinants of HIV infection are complex. They include poverty; unemployment; inadequate health care and health literacy; lack of affordable permanent housing; and stigma, inequality, and discrimination related to race, ethnicity, and sexual orientation. 24 These factors drive disparities in the burden of HIV and other health conditions and in the access, utilization, and quality of many prevention, care, and social services (see Table 3 -1). For instance,  some persons who are poor or suffer from mental illness cannot find stable, affordable housing that fosters high adherence to ART  some transgender persons fear being stigmatized by their health care providers  some minors are not aware they can receive services for HIV, sexually transmitted diseases (STDs), family planning, or substance use treatment without parental consent  some inmates who do not receive pre-release transition planning return to the community without an established HIV health care provider or adequate ART supply  some rural residents cannot find nearby health care providers who are skilled in treating HIV or substance use The 2010 National HIV/AIDS Strategy stressed the need for HIV prevention and care services for populations that bear the highest burden of HIV infection and for individuals with comorbidities and unique social needs. 23 Many governmental health and welfare agencies, health systems, and individual providers have developed programs and services that are directed to populations heavily affected by HIV. 25 Section 12, Other Medical and Social Services, describes services that can mitigate individual, social, and structural factors that impair use of HIV prevention and care services. # Ethical and legal issues that influence access to and use of HIV prevention and care services Since the early 1980s, federal and state governments have enacted several laws intended to protect the confidentiality, rights, and autonomy of persons with HIV; promote access to HIV prevention and care services; or prevent HIV transmission. Many relate to  authorized and unauthorized disclosure of HIV status  discrimination protections  autonomy in health decisions and rights to access prevention and care services Providers who are aware of these issues are better equipped to affirm the rights and responsibilities of persons with HIV, encourage safer sexual and drug-use behaviors, and fulfill their own legal and ethical obligations. These providers are also more likely to direct patients and clients to appropriate services, support public health practice, and foster mutual respect and cooperation between persons with HIV, their service providers, and their communities. # Authorized and unauthorized disclosure of HIV status by providers of prevention and care services Several federal and state laws protect the privacy and confidentiality of persons with HIV. These laws have taken on greater importance as health information and delivery of care have become more collaborative, integrated, and networked and as teams are more frequently used to manage the care of a person with HIV or other complex, chronic conditions. All 50 states and the District of Columbia require name-based reporting of HIV cases and laboratory test results that confirm HIV infection to health departments for HIV surveillance purposes. Most persons with HIV are legitimately sensitive about case reporting because of the risk of stigma, discrimination, and other adverse consequences of unintended HIV disclosure as well as reported cases of inadvertent and intended breaches of confidentiality. To protect confidentiality, all jurisdictions require health departments to collect, store, use, and transmit identifiable HIV-related information in a secure manner consistent with HIPAA and state laws. 26,27 CDC has issued standards for handling HIV surveillance data that minimize uses that might reveal the identity of persons with HIV (see Box 3-B). 5 This includes situations in which health departments use surveillance data to identify populations or individuals with HIV who have unmet HIV prevention needs. For example, HIV surveillance programs that track cases of HIV infection that are not followed by reported CD4 cell count test results (a marker of receiving HIV medical care) can identify populations that may warrant being offered assistance with linkage to HIV care, if allowed by the jurisdiction. 28,29 In jurisdictions in which surveillance data are used to support an individual's health care, case reports may prompt health department disease investigation specialists to help HIV testing providers link casepersons to HIV medical care. [29][30][31] Also, in states that require reporting of a person's sequential CD4 cell count and viral load test results, health departments can identify persons who have declining CD4 cell Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). counts or increasing viral load levels and may warrant being offered more effective treatment or adherence support. 32 (See Sections 4, 6, 8, and 11 for recommendations about using HIV surveillance data to assess unmet HIV prevention needs.) A CDC toolkit describes strategies that HIV surveillance programs and health departments can use to promote HIV prevention and care, including ethical considerations when using confidential surveillance data. 33,34 HIPAA specifies standards to protect the confidentiality of individual-level, identifiable health information for electronic transactions initiated by health care providers, health plans, and health care clearinghouses. 35 These protections are especially important for persons with HIV because they  enable informed choices about how health information is used and shared  set boundaries on the use and release of health records  impose civil and criminal penalties on persons who violate patient confidentiality Since widespread implementation of HIPAA in 2003, many persons with HIV and their providers have reported greater trust in and acceptance of the security protections for HIV-related health information. 36 In some jurisdictions, health care providers, health plans, and health care clearinghouses covered by HIPAA may be required to disclose some confidential health information without an individual's authorization for a few specific purposes, including 35  conducting HIV-related surveillance, investigations, or interventions reporting abuse, neglect, or domestic violence that may involve HIV exposure  enforcing federal, tribal, state, or local laws and judicial and administrative proceedings related to HIV exposure In many states, additional regulations govern the transfer of HIV-related information from the patient's treating health care provider to another health care provider serving that patient; some state regulations are more stringent than those prescribed by HIPAA. 35 Additional federal laws also govern privacy protection of mental health and drug and alcohol treatment records. If state law and federal law conflict on matters of confidentiality, the law that best protects confidentiality applies. Use of confidential electronic medical records (EMRs) † † for managing patients with HIV has grown as a result of the Patient Protection and Affordable Care Act (ACA) and technology innovations. Once stripped of confidential information, data from these record systems can also be used for legitimate quality improvement and monitoring purposes, such as revealing gaps in the continuum of HIV care within medical practices and health systems. However, some providers who are not familiar with regulations that protect the confidentiality of paper-based and electronic records may be overly cautious about sharing or withholding information. In some cases, this may delay important care and prevention services, ‡ ‡ including initiation of ART. 37 For example, in some states, results of HIV tests conducted in 2 health care facilities that share EMRs are not accessible to patients' providers unless they work inside the facility that ordered the test. In other states, a quality improvement program in one health system † † An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. ‡ ‡ Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. cannot access HIV viral load results from one of its clinics, thereby precluding using viral load to estimate treatment effectiveness. 38 Some states have "duty-to-inform" laws that obligate or permit providers who know that a person has exposed another person to HIV to notify the exposed person. 39,40 Providers may also be required or permitted to disclose HIV-related information to law enforcement authorities when required for legal proceedings. # Voluntary disclosure by persons with HIV State laws about HIV disclosure vary in scope and degree of enforcement. Many require that persons with HIV notify their sex or drug-injection partners, including spouses, after they have received an HIV diagnosis. Partner services specialists in many health departments offer voluntary, confidential assistance to persons who want help notifying their partners. 41 Voluntary disclosure of HIV infection status to providers has many potential benefits. It can foster open communication and well-informed, shared decision making about HIV prevention and care goals, and facilitate access to medical and social services that can improve health and reduce HIV transmission. 16 Disclosure to partners may enhance intimacy and psychosocial well-being and prompt frank discussion about using condoms, contraception, or sterile drug-injection equipment. Disclosure to family and friends can engage support for ART adherence or managing psychosocial problems. 42 Disclosure can also empower persons with HIV to openly collaborate with organizations that seek input from persons with HIV 17 (see Section 7, Risk Screening and Risk Reduction, and Section 8, Partner Services, for recommendations about HIV disclosure to partners.) However, disclosure can also lead to negative outcomes, such as physical or verbal abuse, dissolution of relationships, criminal or civil sanctions for HIV exposure, or job discrimination for health care providers with HIV. 43 Providers can take several steps to help patients and clients support safe, selective disclosure. They can review the health and psychosocial benefits of self-disclosure and describe effective disclosure strategies, such as choosing a safe, secure place to make the disclosure; offering partners information about where to obtain HIV testing; and anticipating and managing negative reactions. 37 They can also help persons engage partner notification § § assistance from health department specialists who are trained to assess risk of partner physical or verbal abuse. They can also provide information about local laws on voluntary disclosure and make referrals* to legal professionals who can understand specific legal consequences of disclosure in the jurisdiction 44 (see Section 8, Partner Services). # Discrimination protections for persons with HIV The Americans with Disabilities Act (ADA) protects HIV-infected persons, including those without AIDS-defining conditions, from discrimination in employment, housing, education, health care, and other settings. 45 By guarding against discrimination in housing and employment, the ADA can foster more § § Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. # * Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. stable housing, income, and lifestyles that encourage safe behaviors and sustained access to HIV medical care and ART. 45 Despite the privacy, confidentiality, and discrimination protections promised by ADA, HIPAA, and other regulations, many persons with HIV choose not to disclose their infection to others or forbid others to disclose this information because they fear stigma, abuse, prejudice, discrimination, deportation or criminal prosecution. 42,46 Although experts have long known that HIV cannot be transmitted through casual contact, concerns that persist even among health care personnel can provoke negative reactions. 47 HIV-related stigma can compound stigma related to sexuality ("homophobia" or "transphobia"), substance abuse, race, ethnicity, and other characteristics that many populations heavily affected by HIV already face. Prejudice may manifest as anger, physical or verbal abuse, offensive nonverbal cues, or social marginalization that devalues or discredits persons with HIV. 47 This may cause psychological distress, depression, and other mental health problems that may erode safe behaviors, encourage substance abuse, or lead to immunosuppression. 48,49 Social isolation may make it difficult to engage friends and family in supporting risk-reduction or ART adherence goals. Some persons who wish to avoid real or perceived stigma or discrimination may defer HIV testing, care, and prevention services. 49,50 Other persons with HIV may be denied medical or dental care, experience indifferent or substandard health care, or face housing or employment discrimination. 47 Yet others may decline to carry sterile drug-using equipment or condoms in public settings if they fear that possession may increase the risk of charges of illegal drug use or commercial sex work. 51,52 # Implications of not disclosing HIV infection status Between 1986 and 2011, 33 states enacted HIV-specific laws that could be used to impose criminal penalties on persons who knowingly expose others to HIV. 13,53 These laws are controversial and have been subject to intense public debate. Most were passed before 2000, a period when the use of ART to reduce HIV-related disease and HIV transmission was less prevalent. Of these 33 states, 27 specifically criminalize behaviors that pose a high risk of HIV transmission, including anal or vaginal sex, prostitution, and donating blood, tissue, or body fluids. Additionally, 25 states have laws that criminalize behaviors that pose negligible or no risk of HIV transmission, such as spitting or biting. Many of the 33 states specifically criminalize behaviors when persons have not disclosed their HIV infection to sex partners (24 states) or drug-injection partners (14 states). Few of these laws allow defendants to claim use of ART, condoms, or other prevention measures in their defense against criminal liability. 13 In 28 of these 33 states, violations of HIV-specific criminal laws are classified as felonies and prison sentences can range from 1 to 20 years. 13 In 3 states that do not impose criminal sanctions for HIV exposure, a person's infection status may increase the severity of sentencing or be considered an aggravating factor if the person is prosecuted for a related crime. 13 Some states have also used general criminal laws (e.g., assault, battery, reckless endangerment, or communicable disease laws) to prosecute persons accused of exposing others to HIV. 53,54 National databases cannot readily estimate the number of state-level prosecution, arrests, or plea agreements related to these HIV-specific criminal laws. However, one evaluation of 186 arrests or prosecutions related to HIV from 2008 to January 2014 found that about 80% occurred under such laws. 55 Many HIV criminalization laws were enacted with the expectation that awareness of these laws would encourage persons with HIV to disclose their infection status and avoid behaviors that would result in HIV exposure. 13 However, studies have shown that many persons with HIV are unaware of HIV disclosure requirements and exposure laws until they are notified by a provider and that 25%-50% of persons with HIV served by community-based organizations may not be aware of HIV criminalization laws in their state. 57,58 Health professionals and staff of health departments can play a valuable role in informing persons with HIV about legal requirements about disclosure and referring clients and patients to legal resources if prosecution is possible; however, they cannot provide legal counsel. 26 These professionals can also help persons to engage health department partner notification assistance (especially if physical or verbal abuse is possible) and to prevent exposing others to HIV in the future. The impact of HIV criminalization laws on HIV disclosure, use of health department partner services, † † † or HIV transmission is not known. However, several studies have concluded that these laws may not deter HIV risk behaviors ‡ ‡ ‡ and may cause significant or unintended harms. Harms may include resistance to HIV testing and self-disclosure or forcing persons to choose between the risk of prosecution for undisclosed sexual HIV exposure and the risk of intimate partner violence after disclosing their HIV infection. [59][60][61] For these reasons, the 2010 National HIV/AIDS Strategy (NHAS) stated that it may be appropriate for legislators to consider if existing criminalization laws in their jurisdictions advance the public's interest and health. 23 Some health policy experts have proposed revising these laws to limit prosecution to persons in whom intent to harm (e.g., sexual assault) or high risk of intentional transmission has been demonstrated (e.g., practicing prostitution without using condoms). 53,54,61,62 Autonomy in health decisions and rights to access prevention and care services The principles of autonomy in health care decisions and informed consent are fundamental to providing HIV prevention and care. Persons with HIV have the right to accept and decline prevention and care services, even if these services might lower their risk of exposing others to HIV or their infectiousness. For example, the U.S. Department of Health and Human Services (HHS) recommends that ART be offered to all persons with HIV to treat and prevent HIV-related disease and to reduce the risk of HIV transmission but only be prescribed to those who are ready and willing to adhere to the regimen on a long-term basis. 63 Health department partner notification services are also strictly voluntary. 3 In most states, minors may consent to HIV-related services, STD testing, and reproductive health services without parental consent. 41,64 Many low income persons with HIV obtain free or subsidized care through Medicare, Medicaid, and the Ryan White HIV/AIDS Program based on income, disability, or other characteristics. Increases in insurance coverage prompted by the ACA, increased eligibility for Medicaid for low-income persons in many states, and continued funding of flagship HIV care programs, such as the Ryan White HIV/AIDS Program (described below), are expected to improve access to HIV prevention and care services. 65 However, demand for government-funded services may outstrip available resources in the short-term as the number of persons living with HIV increases, more effective treatment increases their lifespans, and † † † Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. ‡ ‡ ‡ Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). socioeconomic disparities in the burden of HIV persist. This situation raises ethical questions about rights to health care if persons with HIV do not receive basic prevention and care services or receive them only after harmful delays. For example, until 2014, many states were unable to provide subsidized ART to all eligible persons due to long waiting lists for the AIDS Drug Assistance Program (ADAP). 66 Some clinical settings § § § are unable to promptly offer HIV medical care to all recently diagnosed persons because of appointment backlogs, lack of qualified health care providers, or delays in patient enrollment in health insurance or medical assistance programs. [67][68][69][70] Some health departments that handle a high volume of HIV case reports cannot promptly offer partner services to all newly diagnosed persons when staffing for this core public health service declines. 71 # Laws, Regulations, Policies, and Programs that Promote Delivery of HIV Prevention and Care Services Several federal and state laws, regulations, policies, and programs promote delivery of prevention, care, or social services to persons with HIV. Providers who are familiar with these issues are better equipped to help their clients and patients navigate a complex patchwork of service providers and leverage resources to secure needed services. # Governmental and nongovernmental policies and programs that provide or fund prevention and care services for persons with HIV Many governmental and nongovernmental policies and programs determine the funding or infrastructure for delivering HIV prevention and care services. The NHAS described several essential elements of HIV prevention and care that favor more holistic, comprehensive care, reduce gaps in the continuum of HIV care, and reduce the burden of HIV in the communities where the infection is most prevalent. 23 The NHAS encourages HIV prevention and care providers to use evidence-based strategies to provide services, including the following: 77 The ACA encourages states to enroll persons with HIV and other chronic conditions who are eligible for Medicaid into "medical homes" that use teams of providers to coordinate comprehensive care and engage patient support services. 73,78,79 This approach is intended to increase attention to primary care and prevention, communication and service coordination between providers, financial efficiencies, adoption of standards of care, and use of integrated EMRs. 73,[78][79][80] HRSA is seeking to expand the successful "HIV medical home" used in Ryan White-funded clinics by offering training in HIV care, treatment, prevention, HIV-related mental health, and cultural competency to health centers without this expertise. 81 Several states have recently specifically expanded opportunities for "medical homes" for persons with HIV. 82 Many state and local health agencies and HIV planning groups are monitoring HIV service delivery, health outcomes, and coverage policies in their jurisdictions to identify coverage gaps during this transition and advocating for relevant coverage expansion. 80 Despite anticipated improvements in HIV services due to ACA implementation, several troubling gaps in access to HIV prevention and care services persist and may delay implementation of recommendations in this report. 73,78,83 73,85 Immigrants who are not citizens and do not meet these residency requirements can receive care through other federal and state HIV assistance programs that do not specify eligibility requirements related to immigration status if they can provide required enrollment documentation. 86 Until these many gaps are closed, the Ryan White HIV/AIDS Program, ADAP, and other "safety net" programs will continue to provide essential HIV services and cover the cost of copays, deductibles, and other noncovered expenses for many persons with HIV.  Early # Strategies to expand the HIV prevention and care workforce The demand for skilled HIV prevention and care providers in clinical settings and nonclinical settings † † † † will grow over the next decade as the number and lifespan of persons with HIV increase, persons with HIV seek services in new settings, and options for prevention and care services expand. 23 The IOM recently cautioned about the national shortage of skilled HIV prevention providers and called for 10  training primary care medical providers, including those who will provide HIV services under ACA-related Medicaid expansion, in HIV prevention and care services  developing a new cadre of HIV medical specialists who can replace retiring specialists  aligning health department resources to maximize HIV prevention and care services after recent budget cuts In the face of these challenges, the IOM recommended that health departments, primary care providers, and others advocate to increase the number of HIV providers and to train non-HIV specialists in HIV care and treatment. IOM also recommended shifting some tasks across provider levels, e.g., physicians could share some ART adherence support functions with physician assistants, advance practice nurses, registered nurses, pharmacists, and health educators. 87 Multidisciplinary clinical teams can form within a single practice or health system or within networks of service providers who practice locally or through remote, telemedicine services. ‡ ‡ ‡ ‡88 The Ryan White HIV/AIDS Program's experience with comprehensive HIV services through "medical homes" provides valuable lessons about provider networks that other prevention and care providers could apply. Use of effective and cost-effective interventions and evaluation processes that monitor intervention delivery and outcomes may also encourage more judicious use of providers' time. To build the capacity of health care providers serving persons with HIV, HRSA and CDC support regional training centers across the U.S. that offer training in the prevention, diagnosis, and management of HIV and STD. 89,90 Nonclinical HIV prevention providers in community-based organizations and health departments will continue to lead crucial HIV prevention and care programs. These organizations have provided HIV testing, risk-reduction interventions, and partner services for decades; many are now helping persons with HIV to engage in HIV medical care and support ART adherence with funding from CDC and other sources. 6 For example, one state health department is tracking case-specific CD4 cell counts and viral load measures reported to HIV surveillance as a means to identify persons who have had lapses in HIV medical care and may warrant help to resume care. 31 HIV planning groups can foster the development of a skilled HIV prevention and care workforce by supporting training programs, adequate provider reimbursement for HIV services, and use of the most effective and cost-effective interventions. 91 # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at http://www.cdc.gov/hiv/guidelines/implementationresources.html. † † † † Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. ‡ ‡ ‡ ‡ Telemedicine services involve the use of telecommunications technology to provide, enhance, or expedite health care services or to provide consultation, training, and mentoring to health care professionals. # Section 4. Linkage to and Retention in HIV Medical Care Background A growing body of evidence indicates that early initiation of HIV medical care and antiretroviral treatment (ART) and sustained high adherence to ART improve health outcomes and survival rates and can prevent HIV transmission [1][2][3][4][5][6][7][8] (see Section 5,Treatment). Starting HIV medical care shortly after diagnosis and sustaining long-term care also provides opportunities to offer risk-reduction interventions, partner services,* sexually transmitted disease (STD) services, and other services to prevent HIV transmission. [9][10][11][12][13][14][15][16][17][18][19] Some studies show that persons who stay in care during their first year of outpatient HIV medical care are more likely to start ART than persons with early lapses in care, have high adherence to ART, achieve virologic suppression, and practice safer sexual behaviors. 3,7,20,21 A meta-analysis of studies published from 1996-2009 found that about 25% of persons who tested positive for HIV did not start HIV medical care within 6 months after their first positive test result. This analysis also revealed limited retention in care: only 69% of persons who tested positive had two or more visits during the 6 months after diagnosis; only 61% had at least one visit every 6 months during the 18-24 months after diagnosis; and only 26% had at least one visit per year during the 3-5 years after diagnosis. 22 and often involve tracking outcomes, such as completion of scheduled visits. 24 Linkage strategies can operate at the patient, facility, or system level and often require formal coordination* and collaboration † † † among nonclinical providers, clinical providers, health systems, and health departments that provide HIV testing or other HIV services. 25,26 Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § § § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 4. RECOMMENDATIONS-LINKAGE TO AND RETENTION IN HIV MEDICAL CARE For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Establish infrastructure to support starting HIV care (within 3 months after diagnosis), long-term retention in care, and resuming care after a lapse a,b (i, ii, iii, iv, v, vi) (see Box 4-A)  Inform persons about the benefits of starting HIV care and antiretroviral treatment (ART) early (even when feeling well) and staying in care for personal health and to prevent HIV transmission, before HIV testing is offered and when providing preliminary or confirmatory HIV positive test results (v, vi, The Methods topic in this section describes the sources of evidence that identified these barriers and intervention components. a Case management is a service generally provided through an ongoing relationship with a client or patient that includes comprehensive assessment of medical and psychosocial support needs, development of a formal plan to address needs, provision of assistance and advocacy in accessing services, and monitoring of service delivery. b Navigation assistance is the process of helping persons obtain timely and appropriate medical or social services given their preferences about providers, insurance status, scheduling issues, and other factors that may complicate access to or utilization of services. Note. This box includes only selected steps and strategies among many that may be available. See the Evidence topic in this section for more information. # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with guidance from the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and the U.S. Department of Health and Human Services (HHS) that recommend that persons be linked to services shortly after a positive HIV test. 6,11,26,[28][29][30][31][32][33][34][35][36][37] However, the recommendations in this section provide  greater emphasis on proactive linkage and retention strategies instead of passive referral methods  greater emphasis on starting care within 3 months after diagnosis because of the benefits of starting ART regardless of CD4 cell count  strategies for health departments to establish infrastructure and services that support linkage to and retention in care, if allowed by their jurisdictions (e.g., use of surveillance data)  more detailed guidance on evidence-based methods to support linkage to, retention in, and reengagement in HIV medical care The recommendations are also generally consistent with the latest comparable recommendations about linkage to and retention in care of these nongovernmental organizations: the International Association of Physicians in AIDS Care; 38 the HIV Medicine Association of the Infectious Diseases Society of America; 39 and the International Antiviral Society-USA Panel. 4,15 # Methods The section writing group based these recommendations on several sources of federal guidance, scientific evidence, and programmatic experience:  Previously # Evidence Supporting the Recommendations # Linkage to HIV medical care # Barriers to linkage to care The systematic review 40 and other studies [45][46][47][48][49][50][51][52][53][54][55][56] identified several barriers to linkage to care (see Box 4-B). # Interventions to promote linkage to care # Evidence from the systematic literature review This review identified 6 studies that reported linkage to care outcomes. 40 Five studies evaluated linkage assistance for persons diagnosed with HIV during the previous 12 months in health departments, clinics, and community-based programs in large cities. 43,[57][58][59][60] All 5 found that 78%-92% of participants had their first HIV care visit within 3-6 months after receiving linkage assistance. Four intervention components significantly improved linkage to care (as compared with the reference group) or were likely to result in initiation of care (for observational studies). These components included: 1) motivational and strengthsbased counseling tailored to a person's strengths, barriers, and needs; 2) assistance in navigating the health care system; 3) linkage to an HIV care site at the same location where the HIV diagnosis was made or transportation assistance to the care site; and 4) other medical or social services, such as substance use treatment, mental health services, child care, food vouchers, or emergency financial assistance. 40  One of these 5 studies was ARTAS, an RCT conducted in 4 cities from 2001-2003. 43 Participants recruited from health department testing sites, STD clinics, hospitals, and community-based organizations were randomized to receive 1) one to five motivational, strengths-based case management sessions over 90 days that allowed time to build rapport and that focused on identifying personal motivations for starting HIV care (e.g., desire to protect health) and overcoming barriers to starting care (e.g., helping to make appointments, accompanying at the first visit, providing transportation assistance, or helping to enroll in health insurance); or 2) information about local sources of HIV medical care. Participants who received the case management sessions were significantly more likely to attend at least 1 visit within 6 months after enrollment than participants who received information only (78% vs. 60%; adjusted relative risk 1.36, p=0.0005). 43  Four observational studies evaluated the outcomes of various types of linkage assistance. [57][58][59][60] Most newly diagnosed persons started HIV care within 3-6 months after receiving assistance:  79% of persons who received motivational, strengths-based case management sessions (as described by ARTAS study above) in clinical, nonclinical, or health department settings. 58  87% of African American or Hispanic gay, bisexual, or other men who reported sex with men (MSM) aged 13-24 years and who received the following services from staff of health departments, community-based organizations, or universities: counseling and psychosocial support, appointment reminders, and transportation to visits. 59  90% of persons who received the following services from peer and nonpeer outreach workers, case managers, or nurses: counseling tailored to their individual barriers; riskreduction information; rapport-building phone calls and meetings; coordinating and accompanying at visits; and coordinating and making referrals for other medical and social services. 57  92% of persons who received brief sessions led by linkage facilitators that addressed psychosocial, financial and structural barriers to starting HIV care, and provided information on HIV, HIV-related stigmatization, and how to obtain health insurance and housing. 60  The sixth study in the systematic review evaluated linkage services at community-based, HIV education and testing sites in California where outreach workers encountered persons with HIV who did not report receiving HIV medical care. 61 On average, clients were offered linkage assistance 18 months after HIV diagnosis. Only 29% started HIV care within 15 months after receiving linkage assistance. Of those who started HIV care, clients had their first visit an average of 33 months after diagnosis. The low linkage rates in this study contrast with the high linkage rates in the 5 studies described above that offered linkage assistance within 6-12 months after diagnosis. # Evidence from the Best Practices Compendium Two studies met criteria for "best practices": the ARTAS study 43 described above and Project Connect from Birmingham, Alabama 54 (the study was published in 2008 in a journal that was not included in the systematic review). In Project Connect, linkage facilitators invited persons with newly diagnosed HIV to an orientation visit at an HIV outpatient clinic. Facilitators aimed to build rapport with patients, gathered information about patients through semi-structured interviews and psychosocial assessments, collected laboratory test specimens, and initiated referrals for conditions that might deter HIV care (e.g., substance abuse and mental health services). A significantly higher proportion of patients attended a comprehensive HIV care visit within the next 6 months compared with the period before the clinic had implemented this program (81% vs. 69%, p<0.01). # Evidence from modeling study A cost-effectiveness study compared the effectiveness of linkage interventions with the prevailing standard of providing contact information for local HIV clinics using data on per-client costs from the ARTAS intervention. 43 It found that the linkage interventions to prevent HIV transmission were costsaving compared with the prevailing standard 44 and that the intervention cost per new case of HIV averted (~$270,000) was substantially lower than the lifetime cost of HIV treatment (>$400,000). 62 # Retention and reengagement in HIV medical care # Barriers to retention in care The systematic review 41 and other studies [45][46][47][48][49][50] identified several barriers to retention (see Box 4-B). # Interventions to promote retention in care # Evidence from the systematic literature review This review qualitatively examined 13 multifaceted interventions. 41 Four studies were RCTs, 7 compared retention before and after receipt of retention assistance, and 2 observed retention in care after assistance was offered. The review found that persons who received multifaceted interventions were more likely to stay in care than those not receiving assistance, but none of the studies assessed the independent effect of specific intervention components. 41 Ten of the 13 studies identified intervention components that were associated with increased retention in care: strengths-based case management, navigation assistance (e.g., appointment coordination), accompanying persons at visits, transportation assistance, colocating HIV medical care and social services in the same facility, bilingual/bicultural health care teams (for Hispanic/Latino patients), messages about the importance of retention in care during medical visits, HIV-related posters and brochures in clinics, regular reminder calls, and tailored HIV education and support through phone calls, home visits, or other outreach methods. Of the 4 RCTs in this systematic review, only the one that used strengths-based case management showed a strong effect on retention. 58 One RCT found that motivational interviewing provided by peer outreach workers (who had similar demographic characteristics to their clients) working in community sites or clinics yielded similar retention outcomes as motivational interviewing provided by health care providers. 63 However, an RCT that evaluated rental housing assistance for persons without stable ** Colocating is the provision of more than one type of HIV service in the same physical space, such as providing substance use treatment in an HIV medical clinic or providing HIV partner services in an HIV testing site. housing 64 and an RCT that evaluated peer mentoring for persons who inject drugs (PWID) through group discussion and video presentations did not appreciably improve retention in care. 65 # Evidence from the Best Practices Compendium Eight intervention studies met criteria for "best practices" for improving retention in care: four were RCTs and four compared retention outcomes before and after the intervention was implemented. Five of these studies were included in the systematic review of retention interventions, 41 of which one was an RCT (ARTAS, 43 described above) and four used "before-after" comparison designs. [66][67][68][69] The 4 RCTs were the following:  An RCT evaluated retention outcomes in 4 clinics during 2001-2003. Participants who received motivational, strengths-based counseling from a case manager were significantly more likely to continue HIV care (defined as at least 2 visits over 12 months) than participants who only received information about where to obtain HIV care (64% vs. 49%, adjusted relative risk 1.41, p=0.006). 43  An RCT in 6 HIV clinics evaluated retention of patients who received 1 of 3 interventions: 1) enhanced contact (brief face-to-face meeting with clinic staff when returning for care, appointment reminders, phone calls between scheduled visits, and calls about missed visits); 2) enhanced contact (as described above) plus skills building in organization (e.g., appointment calendars), problem solving, and communicating with health care providers; or 3) the clinic's prevailing standard of appointment reminders provided by staff or audio recordings. Patients who received enhanced contact or enhanced contact plus skills building had a 22% higher number of visits attended and 6%-8% relative improvement in visits attended over 12 months, when compared with patients who received only appointment reminders. 70  An RCT evaluated a clinical decision-support system in a large HIV clinic practice that generated alerts in electronic medical records (EMRs) † † † † that notified HIV care providers of gaps in follow up visits, laboratory evidence of virologic failure, and adverse events. Alerts on the EMR home page, patient-specific EMR, and biweekly emails included key clinical information and expedited ordering of lab tests and scheduling follow-up visits. Over the 12 month follow-up period, patients of providers who received alerts had a lower rate of suboptimal retention in care over 6 months than patients of providers who did not receive alerts (20.6 vs. 30.1 events per 100 patient-years, p=0.022). 71  A buprenorphine treatment study evaluated opioid-dependent patients in an HIV primary care clinic. Intervention patients received directly observed buprenorphine treatment (BUP) 3 times a week and supplies to last until their next visit, individual counseling, and urine drug testing. Control patients were referred for community-based opioid replacement therapy and intensive case management services. Over the 12-month follow-up period, patients who received directly observed BUP had significantly more HIV care visits than control patients (median, 3.5 vs. 3 visits, p=0.047). 72 † † † † An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. # Evidence from a modeling study A cost-effectiveness study compared the effectiveness of retention interventions with the prevailing standard of scheduling follow-up appointments, using data on per-client costs from the ARTAS trial. 43 It found that retention interventions to prevent HIV transmission had a cost per quality-adjusted life-year gained of $13,460 when compared with scheduling follow-up appointments. 44 It also estimated that the intervention cost per new case of HIV averted (~$478,000) was similar to the lifetime cost of HIV treatment (>$400,000). 62 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Data on linkage to and retention in care collected through 2009 (described in the Background topic above) may not reflect patterns of care since 2012, the year HHS recommended starting ART regardless of CD4 cell count and when the Patient Protection and Affordable Care Act (ACA) expanded health insurance options for persons for HIV. 73 Linkage and retention rates are likely to improve as more persons with HIV become aware of the health and prevention benefits of early ART and become enrolled in health insurance or medical assistance programs. Improving linkage and retention will also require a cadre of trained professionals and peers to provide linkage and retention assistance; this assistance can be particularly beneficial for populations that are uninsured or live in communities with limited or fragmented HIV medical services (see Box 4-A and Section 3, Context of Prevention). Enabling billing and reimbursement for linkage and retention services can encourage providers to offer these services. Some health systems and health departments are exploring strategies for third-party reimbursement for these services. 74 # Policy, legal, and ethical considerations Providing linkage and retention services usually requires sharing HIV test results and other identifiable health information between agencies; this process must protect the confidentiality of persons with HIV and comply with health information security standards, including the Health Insurance Portability and Accountability Act [75][76][77] (see Section 3, Context of Prevention). CDC provides guidance on how health departments might use HIV surveillance data (e.g., dates of HIV diagnosis, first and follow-up CD4 cell count test results and viral load test results) to identify persons who might benefit from linkage or retention assistance, if allowed in their jurisdictions. 23,27,75,76,78 # Special populations Many individual and contextual factors may impair the use of HIV medical care (see barriers noted in Box 4-B). Interventions to promote linkage may have less impact for persons who use drugs or suffer from depression 79 and retention interventions may be less effective for patients who are young, [80][81][82] lack health insurance, 50,83 are homeless, 84 or use drugs. 85 Linkage and retention services that are tailored to such special circumstances may be more acceptable and effective. Examples include the following:  Adolescents concerned about stigma, inability to access confidential HIV care if uninsured or insured by parents, or unwanted disclosure of HIV infection status to parents can benefit from linkage to providers who do not require parental consent and who provide free or low cost services and reassurance about the confidentiality of HIV services 48  Transgender persons can benefit from linkage to providers who are familiar with the unique medical and psychosocial concerns of these individuals 49,86,87  Substance users can benefit from enrolling in treatment programs that encourage structured lifestyles that foster attendance at scheduled visits 88-93  Immigrants can benefit from help to secure documents needed to start care (e.g., employment verification, Social Security number); linkage to providers who serve immigrants under ACAapproved insurance plans, the Ryan White HIV/AIDS Program, medical assistance programs, or specialty clinics; 73,94 and information about whether seeking HIV care may threaten job security or prompt deportation or legal actions  Inmates can benefit from reentry planning to enable continuous HIV care after release [95][96][97]  Women of reproductive age can benefit from information and reproductive health counseling about ART regimens that are safe and tolerable during and after pregnancy, and options for free, subsidized, or otherwise affordable ART [45][46][47] # Implementation Resources Examples of best practices for linkage, retention, and reengagement and materials to support implementation of these recommendations are found at http://www.cdc.gov/hiv/guidelines/implementationresources.html. # Section 5. Antiretroviral Treatment for Care and Prevention Background Antiretroviral treatment (ART) refers to treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication. Current federal HIV treatment guidelines and other studies recommend ART for all persons with HIV, regardless of CD4 cell count, * to improve their health, prolong their lives, and reduce their risk of transmitting HIV to others. [1][2][3] The initial and regular follow-up clinical visits that are required to prescribe and manage ART also provide opportunities to reinforce risk-reduction messages and to provide other care and prevention services. † To maximize the individual and public health benefits of ART, sustained high adherence is essential. 3 This section covers several aspects of use of ART for personal health benefits and preventing HIV transmission; however, it does not provide comprehensive recommendations on managing patients who are eligible for or who are using ART found in other federal guidance. 3,4 This section also addresses informing persons with HIV about antiretroviral medications that HIV-uninfected partners may take to reduce their risk of HIV acquisition, if clinically indicated; it does not provide comprehensive recommendations on prophylaxis for HIV-uninfected persons found in other federal guidance. 5,6 Quality improvement ‡ Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 5. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT FOR CARE AND PREVENTION For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Inform all persons with HIV about the following issues regarding antiretroviral treatment (ART) (i.e., treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication) a (i, ii) (see Box 5-A):  The health benefits of early initiation of ART, including • improving or maintaining health when compared with later initiation of ART • prolonging lifespan • reducing risk of HIV transmission to others b  The limitations of ART, including • the need for lifelong treatment • the need for high adherence • potential medication side effects • the use of ART substantially reduces, but may not eliminate, the risk of HIV transmission  Inform all persons with HIV (and any of their HIV-uninfected partners referred for evaluation) about the following HIV prophylaxis issues c,d (iii, iv) (see Box 5-B):  The availability of preexposure prophylaxis e (PrEP) and nonoccupational postexposure prophylaxis f (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  Names and locations of health care facilities where HIV-uninfected partners can be evaluated for prophylaxis indications, and assisting with accessing these services, when feasible  Use of these regimens may reduce, but may not eliminate, the risk of HIV acquisition # Specific to clinical providers (in addition to above recommendations)  Offer ART (according to U.S. Department of Health and Human Services [HHS] recommendations), regardless of patient's CD4 cell count, for the following purposes (i, ii):  To treat and prevent HIV-related disease  To reduce the risk of transmitting HIV  When prescribing ART, provide information to ensure that patients understand the following (i, ii):  Expected benefits and risks to personal health  Expected reduction in HIV transmission risk  Need for sustained high adherence to ART, long-term follow-up, and retention in care  Importance of committing to initiating or resuming lifelong, uninterrupted ART  Hazards of sharing their ART with others (e.g., HIV-uninfected partners seeking antiretroviral medication for prophylaxis) g  Use of ART is voluntary and patients can decline ART without risk of being denied medical and social services  For patients who choose to postpone or discontinue treatment, periodically reoffer ART after informing them of the benefits and risks of currently recommended regimens based on experiences of other patients with similar viral load and immune status (i,ii) # BOX 5. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT FOR CARE AND PREVENTION (cont) For staff of health departments and HIV planning groups who provide population-level HIV prevention and care services  Support efforts to increase access to HIV medical care and affordable ART through the following (v, vi, vii, viii, ix) (see Box 5-C):  Direct interventions with staff, contractors, and programs  Partnerships with public and private sector health systems # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup and recent program experience, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b The U.S. Food and Drug Administration (FDA) had approved the use of antiretroviral medication for treating HIV-infected persons. The cited source guidance recommends use of ART for HIV treatment and for reducing the risk of HIV transmission. c In July 2012, FDA approved one PrEP regimen (tenofovir/emtricitabine) for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. d The cited source guidance advises health care providers to inform HIV-uninfected persons about these interventions, but does not address the role of health care providers in informing HIV-infected persons about the use of PrEP or nPEP for their uninfected partners. e PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 f nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 5 g Information described in the Implementation topic in this section supports this statement. # Sources i. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with the most recent federal guidance on ART and the prophylactic use of antiretroviral medications to reduce the risk of HIV acquisition by partners of persons with HIV. [3][4][5][6] They are also consistent with nearly all of the latest comparable recommendations about using ART for treatment and prevention from the HIV Medicine Association of the Infectious Diseases Society of America; 7 and the International Antiviral Society-USA Panel. 8,9 However, these recommendations differ in several ways from those in the 2003 Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. 10 This report recommends that  clinical providers offer ART to all persons with HIV, regardless of CD4 cell count, for both their own health and for reducing the risk of HIV transmission, according to the most recent U.S. Department of Health and Human Services (HHS) treatment recommendations 3  clinical providers and nonclinical providers inform persons with HIV about  the benefits of ART for their own health, prolonging lifespan, and reducing the risk of HIV transmission  the limitations and risks of ART, including that use of effective ART substantially reduces, but may not eliminate, the risk of HIV transmission  options to obtain ART and cover and minimize costs of ART  the availability of two different prophylactic regimens of antiretroviral medications, preexposure prophylaxis (PrEP) † † and nonoccupational postexposure prophylaxis (nPEP), ‡ ‡ for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition § § # Methods The section writing group based these recommendations on current guidance from HHS 3 and the Health Resources and Services Administration (HRSA) on the use of ART 3,4 and current guidance from HHS on the use of nPEP and PrEP for HIV-uninfected partners of persons with HIV. 5,6 This federal guidance was based on a large body of scientific evidence, including randomized controlled trials (RCTs) (see the Evidence topic). The writing group also reviewed a systematic review and meta-analysis of the relation of viral load and sexual HIV transmission, 1 a meta-analysis of the influence of ART on sexual behavior, 11 and the latest nongovernmental recommendations of the International Antiviral Society-USA Panel 9 and the HIV Medicine Association of the Infectious Diseases Society of America. 7 The writing group also considered information about the role of ART on HIV transmission, acute HIV infection, and ART resistance identified during a narrative literature review of peer-reviewed studies and abstracts of HIV conferences published in English from January 1996 through May 2014. The recommendations to health departments and HIV planning groups were based on recent federal guidance about population-level strategies to increase access to HIV medical care and ART. [12][13][14][15][16] Evidence Supporting the Recommendations Several sources of evidence support the use of ART to reduce the risk of HIV transmission. In untreated adults, the risk of sexual HIV transmission increases with the amount of HIV RNA present in the plasma 17 and genital secretions. 18,19 ART reduces HIV plasma viral load 20 and also reduces quantities of HIV RNA detectable in potentially infectious body fluids, including semen, 21,22 cervicovaginal secretions, 23,24 and anorectal secretions. 25 Plasma HIV RNA viral load usually correlates with levels of HIV RNA detected in semen, [26][27][28][29] cervicovaginal secretions, 23,30,31 and anorectal secretions. 28,32 Although use of effective ART with high adherence can suppress plasma and genital viral load, its use may not † † PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 ‡ ‡ nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 5 # § § This recommendation supplements-and does not replace-federal recommendations to provide information about PrEP and nPEP to HIVuninfected persons at risk of HIV exposure. 5,6 eliminate transmission risk. Some persons with suppressed plasma viral loads may have detectable HIV in semen, 21,22,26,[33][34][35][36] in cervicovaginal secretions, 23,30,37 and possibly in rectal secretions. 28,32 Some sexually transmitted diseases (STDs) that cause genital inflammation may also increase shedding of HIV into semen 34,38 and into cervicovaginal secretions, 30,39,40 even in persons with low or undetectable plasma viral loads (see Section 9, STD Services). At least one case of HIV transmission from a patient with suppressed plasma viral load to a monogamous, uninfected sex partner has been reported. 41 Observational studies of heterosexual couples [42][43][44][45][46] have found that effective ART substantially reduces the risk of sexual transmission. A meta-analysis of these and other studies determined that ART decreased the risk of HIV transmission to uninfected heterosexual partners from 5.64 to 0.46 per 100 person-years, a reduction of 92%. 1 A subsequent RCT of 1,763 HIV-1 discordant couples enrolled mostly in Africa and Asia, 97% of whom were heterosexual, confirmed a 96% reduction in sexual HIV transmission associated with treating the HIV-infected partner (hazard ratio 0.04, 95% confidence interval 0.01-0.27, p<0.001). 2 In this study, infected partners with CD4 cell counts in the range of 350-550 cells/mm^3 were randomized to receive either ART immediately or when their CD4 cell counts declined to <250 cells/mm^3. This study concluded that sustained viral suppression in genital secretions resulting from sustained high adherence to ART explained this protective effect. To date, no published RCT or cohort studies have demonstrated the influence of ART in preventing HIV transmission among MSM and persons who inject drugs (PWID). However, a priori biological plausibility and ecological analyses suggest that ART reduces HIV transmission from all persons with HIV, including MSM 47 and PWID. 48 An ongoing prospective observational study in 14 European countries is assessing sexual transmission among HIV-discordant couples in which the infected partners have plasma HIV RNA viral loads <200 copies/mL, the uninfected partners use neither PrEP nor nPEP, and the couples do not use condoms. 49 In preliminary analysis of data from 767 couples (282 MSM, 445 heterosexual) who contributed 894 couple-years of follow-up (CYFU) and engaged in an estimated 30,400 sex acts without condoms, no HIV transmissions were observed. Study enrollment and follow up continue to ensure the statistical power needed to refine the upper confidence limits associated with the risk of transmission; preliminary analysis yielded confidence limits from 4.0 infections per 100 CYFU for receptive anal sex with ejaculation in MSM couples to 1.5 infections per 100 CYFU for insertive anal sex in MSM couples and penile-vaginal sex in heterosexual couples. Mathematical models also indicate that ART could substantially reduce HIV transmission in MSM and other risk groups in the United States. [50][51][52][53] This body of evidence suggests that ART is likely to reduce the risk of HIV transmission regardless of a person's age, race, ethnicity, sex, gender identity, sexual orientation, or HIV transmission risk category. 17,47,48,[54][55][56][57] Limited theoretical evidence suggests that perceptions about using ART for preventing HIV transmission may influence attitudes about sexual behaviors. A meta-analysis that included 25 studies found that persons with HIV were more likely to report that they might have unprotected sex * if they agreed that taking ART or having an undetectable viral load protects against transmitting HIV or that the availability of ART reduced their anxiety about having unsafe sex. 11 Despite these findings, this study found that * Unprotected sex or unprotected sexual contact is sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginaldigital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). persons with undetectable viral loads were no more likely to engage in unprotected sex than persons with detectable viral loads. A compelling body of evidence supports early initiation of ART at progressively higher CD4 cell counts to improve health outcomes, reduce mortality due to AIDS and other conditions, and prevent HIV transmission. Observational data on health outcomes after early treatment served as the basis for HHS and international recommendations to initiate ART regardless of CD4 cell count. 3,9 An ongoing RCT is directly comparing the benefits and risks of starting newly recommended ART regimens at >350 cells/mm^3 versus >500 cells/mm^3, 58 including chronic diseases that are relatively common in persons with longstanding HIV infection but are not typically associated with immunosuppression. Two other factors support early ART initiation for health or prevention purposes: 1) contemporary initial ART regimens are more convenient, potent, and tolerable than earlier regimens; 3 and 2) drug resistance occurs less frequently in persons who start ART early in the course of their infection, 59 partly because early initiation prolongs the period in which adherent persons can suppress their viral loads. Comparisons of the lifetime costs of health care for persons starting ART with CD4 cell counts at 350 to 500 cells/mm^3 and persons starting ART with CD4 cell counts >500 cells/mm^3 have not yet been reported. However, studies and federal guidelines evaluating ART regimens used over the last two decades have shown that 1) starting ART soon after diagnosis is more cost-effective than delaying ART until CD4 cell counts have declined substantially (e.g., <350 cells per mm^3) and 2) early treatment reduces the costs of AIDS-and non-AIDS-related care even though it increases the lifetime cost of antiretroviral medications. 3,60 Other sources describe the evidence supporting recommendations about the use of PrEP and nPEP. 5,6 Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Among all persons living with HIV in 2009, an estimated 82% had been diagnosed with HIV infection, 66% were linked to HIV medical care, 37% were retained in care, 33% were prescribed ART, and 25% had a suppressed viral load. 61 However, among adults diagnosed with HIV who received ongoing HIV medical care between 2008 and 2010 (when HHS routinely recommended starting ART for persons with CD4 cell counts <350 cells/mm^3), an estimated 89% were prescribed ART, of whom 77% had suppressed viral load. 61,62 However, among adults diagnosed with HIV who received ongoing HIV medical care as of the end of 2010 (when HHS routinely recommended starting ART for persons with CD4 cell counts <350 cells/mm^3), an estimated 90% reported taking ART, of whom 74% reported suppressed viral load at their last measurement. 63 Use of ART is expected to rise after 2012, the year HHS first recommended initiating ART, regardless of CD4 cell count, for both health and prevention benefits. Moreover, the newer ART regimens recommended by HHS are likely to be more acceptable than earlier regimens that were less effective, tolerable, and convenient. 64 Interest in using ART for prevention purposes is not well characterized. In one study, 50% of HIVinfected patients with CD4 cell counts >350 cells/mm^3 expressed interest in starting ART to decrease transmission risk. 65 Surveys of health care providers prescribing ART in Washington, DC, and the Bronx, NY found that 95% agreed or strongly agreed that ART can decrease HIV transmission and 75% would offer ART earlier to patients at high risk of transmitting HIV (defined as persons who have HIVuninfected partners or report sex without condoms with a partner of unknown HIV status). 66 People may delay initiating ART for health or prevention purposes for several reasons: denial that they are HIVinfected or that HIV is a serious medical condition; lack of understanding of the benefits of early treatment; lack of trusted relationships with health care providers; and lack of health insurance or access to federal and state medical assistance programs, such as Medicaid. 61,67 Access to affordable ART (and PrEP and nPEP for uninfected partners of persons with HIV) is a continuing challenge in the United States. Long-term use of ART is expensive because it requires multiple medications, most of which are not yet available in generic form. The annual, unsubsidized cost of ART regimens recommended by HHS as of 2014 exceeds $10,000. 3 Studies conducted before 2014 found that some persons declined or postponed ART because they were unaware of free or low cost ART sources, anticipated difficulty obtaining affordable ART, did not access subsidized ART through AIDS Drug Assistance Programs (ADAP), or were deterred by ADAP waiting lists. [68][69][70][71] As of 2014, many options can substantially reduce out-of-pocket costs of ART, including Medicaid and Medicare, state ADAP, private sector health insurance, health care exchange plans initiated under the Patient Protection and Affordable Care Act (ACA), and pharmaceutical company drug assistance programs. 14,16,72,73 Increased enrollment in health plans with pharmacy benefits and near elimination of state ADAP waiting lists (as of April 2014) has improved access to subsidized ART. 74 Nevertheless, it has been estimated that under the ACA's health care exchange plans, coinsurance for ART may be substantial, with up to 55% of plans requiring enrollees to pay an average of 35% of their total ART cost. 73 In states that have not yet expanded the populations of low-income or disabled persons that are eligible for Medicaid, the Ryan White HIV/AIDS Program and ADAP will remain crucial sources of affordable HIV care and ART. In states that have expanded Medicaid, the Ryan White HIV/AIDS Program will continue to cover copays and deductibles for many persons with HIV. Disparities in access to ART are compounded by longstanding geographic, economic, social, racial, and ethnic disparities in the burden of HIV. This convergence of disparities reinforces ethical imperatives to increase access to HIV care and treatment. 75 Selecting appropriate ART regimens may be complex for persons who use other prescription, nonprescription, or recreational drugs, alcohol, or dietary supplements that may interact with ART or for women who are pregnant or attempting conception in whom fetal safety must be considered. Other federal guidance describes potential interactions between ART and other substances and preferred regimens during pregnancy and additional clinical evaluation needed in these situations. 3,76 providers, and their uninfected partners are not familiar with the use of nPEP after isolated, inadvertent exposures after voluntary behaviors (e.g., condom failure) and involuntary behaviors (e.g., sexual assault). 78,79 Two reviews of studies on nPEP use published from 2001-2008 found that less than half of U.S. health care providers working in emergency departments had ever offered nPEP to patients after sexual assault. 80,81 Some persons with HIV may consider sharing their ART medications with HIV-uninfected partners seeking PrEP or nPEP. This practice should be discouraged because 1) it may impair ART adherence; 2) medications used for ART may not be suitable for prophylaxis; 3) partners' perceived or reported HIVnegative status may be inaccurate, and 4) ART medications that are shared with partners seeking prophylaxis who are in fact HIV-infected may not provide optimal HIV treatment or may promote viral drug resistance. 3,5,6,82,83 # Policy, legal, and ethical considerations Use of ART for health or prevention benefits should be voluntary. The principal consideration in decisions about using ART is personal health, not reducing risk of HIV transmission. Clinical providers can help patients make informed choices about ART use by stressing that ART is the single most important intervention they can choose to maintain their health, prolong their lives, and reduce the risk of infecting others; noting potential harms, such as side effects; and reassuring patients who decline ART that they will not be denied medical or social services. This principle of autonomy also applies to HIVuninfected persons offered PrEP or nPEP. Clinical providers can caution their patients that sustained high adherence to ART substantially reduces the risk of transmission, but it may not eliminate the risk. Clinical providers can also discourage risk compensation, ‡ ‡ ‡ which may lead to deferral of condom use or of other safer sex or drug-injection behaviors (see the Evidence topic in this section). Patients who alert their partners to the limitations of ART may reduce partner distress and disputes if transmission should occur (see Section 3, Context of Prevention, for information on HIV disclosure). HIV-uninfected persons who use nPEP or PrEP also can benefit from knowing that these regimens may reduce, but may not eliminate, their risk of HIV acquisition. # Special populations Several vulnerable or marginalized populations warrant specialized attention when offering, starting, and continuing ART. These populations include adolescents who are taking more responsibility for health decisions and leaving parental homes or foster care; persons entering or leaving correctional facilities; and immigrants who lack the documentation needed to receive HIV care through private insurance or medical assistance programs. The presence of mental health or substance use disorders does not make a person ineligible for ART. If these conditions raise questions about a person's ability to effectively use ART, referral for appropriate mental health and substance abuse treatment is indicated. 3 (Section 6, ART Adherence, addresses ART ‡ ‡ ‡ Risk compensation is modifying sex or drug-injection behaviors in way that increases risk of HIV transmission or acquisition when other safeguards are introduced (e.g., when persons with HIV who believe that ART use reduces their infectiousness no longer use condoms to prevent HIV transmission). for special populations. Section 12, Other Medical and Social Services, addresses specialty services that can facilitate initiation of HIV medical care and ART.) # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at http://www.cdc.gov/hiv/guidelines/. A list of wholesale costs of regimens that HHS recommends for persons starting ART is also available. 3 Section 6, ART Adherence, includes a link for adherence assessment and support materials. # Section 6. Antiretroviral Treatment Adherence Background Antiretroviral treatment (ART) adherence describes the extent to which a person takes ART according to the prescribed doses, dosing intervals, and other medication instructions. Sustained high adherence is essential to maximize the effectiveness of ART, which suppresses viral load and, in turn, preserves CD4 cells counts, prevents progression to AIDS, and prolongs lifespan. Inconsistent or low adherence can lead to virologic failure* or the emergence of drug-resistant virus, both of which may limit future treatment options. [2][3][4][5][6][7] Sustained high adherence is also critical for maximizing the benefits of ART in reducing the risk of sexual and perinatal HIV transmission. [1][2][3][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Studies of early combination ART regimens found that adherence levels greater than 95% were needed to maximally suppress viral load. 16 However, more recent studies indicate that viral suppression can be achieved with lower adherence levels, particularly when newer regimens are used. 10,12,17 Because the level of adherence necessary for viral suppression may vary by regimen and adherence has been described in different ways in the scientific literature, there is no standard definition of high adherence. † The literature suggests that the levels of adherence needed to maximize treatment benefits may range from at least 80% to at least 95% of doses taken as prescribed. 10,12,17 Given the uncertainty, persons with HIV should try to achieve and sustain the highest possible adherence to ART. 17 To help persons with HIV reach their adherence goals, clinical providers, nonclinical providers, and selected health department staff can offer a variety of support strategies when needed. This section addresses methods to assess adherence, factors that influence adherence and interventions that promote sustained high adherence. Quality improvement ‡ and program monitoring and evaluation § can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 5, Antiretroviral Treatment, describes the benefits of ART use with sustained high adherence and factors other than adherence that influence treatment effectiveness, including concurrent medical conditions, drug-resistant virus, and the use of other drugs, alcohol, or dietary supplements that may alter ART absorption or metabolism. Other federal guidance provides additional information about ART adherence, including clinical criteria for selecting initial and changing regimens that may influence adherence. 1,22 Section 4, Linkage to and Retention in HIV Medical Care, addresses issues affecting retention in HIV care, which is essential for sustained access to ART and adherence support. # * The inability to achieve or maintain suppression of viral replication (to an HIV RNA level <200 copies/mL). 1 † Studies published over the last decade have measured adherence using different methods, cut offs, and recall periods. Most studies classified high adherence as a patient report of having taken at least 90% of medications as prescribed over the previous 7-30 days. 20,21 ‡ Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Recommendations BOX 6. RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT ADHERENCE For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV), if allowed by professional authority and jurisdiction  Participate in multidisciplinary teams with health educators, service linkage facilitators, community health workers, a case managers, nurses, pharmacists, and physicians to assess and support adherence to antiretroviral treatment (ART) b,c (i, ii, iii)  Inform persons with HIV about the benefits of sustained high adherence, even if they are feeling well, and the risks of low adherence (e.g., illness, drug resistance, transmitting HIV to others) b,d (i, ii)  Provide adherence support tailored to each person's regimen and characteristics, according to provider role, authority, and setting b (i, ii) (see Box 6-A)  Provide or make referrals for services to address factors that may impair adherence (e.g., demographic, comorbidity, psychosocial, and structural issues) b (i, ii) (see Table 6-1)  Offer advice on how to obtain sustained coverage or subsidies for ART through private-or public-sector sources b (i, iv, v, vi) # Specific to clinical providers (in addition to above recommendations)  Before prescribing ART, assess patient readiness to start ART, sources of pharmacy coverage, and possible barriers to sustained high adherence (e.g., anticipated changes in health insurance, disruptive life events, mental illness) (i, ii)  Offer highly effective ART regimens, preferably those that minimize pill burden, dosing frequency, and dietary restrictions (i, ii)  Involve patient in decisions about treatment regimens (i, ii)  Advise patients to take ART as prescribed; provide information about the regimen, and check for understanding in the following areas (i, ii):  Details of the regimen, including dosing method and schedule, dietary restrictions, and what to do when drinking alcohol or when missing doses  Consequences of missing doses, such as increased risk of HIV-related illness, developing drug resistance, and transmitting HIV  Potential side effects and what to do if side effects occur  Potential interactions with other prescription, nonprescription, and recreational drugs; alcohol; and dietary supplements that may impair ART effectiveness or cause toxicity that could impair adherence  The possibility of HIV transmission even when virus is not detectable in the blood because blood measurements may not reflect viral load in genital and anal fluids or may have increased since last measurement  Routinely assess patient's questions, concerns, or challenges regarding ART use to identify potential problems before virologic failure e occurs (i, ii)  Remind patients to report current or planned use of prescription, nonprescription, or recreational drugs; alcohol; and dietary supplements because these may impair ART effectiveness or cause toxicity that could impair ART adherence (ii)  Assess self-reported adherence at each visit using a nonjudgmental manner f (i, ii)  Assess and manage side effects at each visit (i, ii)  Routinely use HIV viral load to monitor ART effectiveness that may be affected by adherence (i, ii)  Consider assessing ART prescription refills or pill counts, if feasible, when needed to supplement routine assessment of self-reported adherence (e.g., when treatment response is not consistent with self-reported adherence) (i, ii)  Do not directly administer ART to patients on a routine basis, except in settings where other medications are directly administered on a routine basis (e.g., young adolescents living with parents, prisons, residential substance use treatment centers, opioid replacement programs, mental health hospitals) (i) BOX 6. # RECOMMENDATIONS-ANTIRETROVIRAL TREATMENT ADHERENCE (cont) For staff of health departments who provide population-level HIV prevention and care services  Use HIV surveillance data to identify populations or individuals who have CD4 cell counts or viral load test results that indicate suboptimal treatment that may be related to low adherence and who may warrant being offered ART adherence support, if allowed by the jurisdiction (vii, viii)  Engage health department disease investigation specialists or other community health workers, if allowed by the jurisdiction, in collaborating with health care providers to offer adherence support to their patients a,g  Support other population-level strategies to promote sustained high adherence (vii) (see Box 6-B) # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. a Linkage facilitators assist persons with HIV to access HIV medical care and other medical and social services through active methods (e.g., help making appointments, providing transportation to appointments).Community health workers might include community-based HIV prevention specialists contracted by health departments or employees of community-based HIV service organizations. b The cited federal government guidance that supports this recommendation was intended for health care providers. Based on program experience and opinions of the Project Workgroup, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. c In some jurisdictions, collaboration may involve communicating with HIV surveillance programs that monitor HIV viral load levels of reported HIV cases to identify persons with suboptimal treatment response that may be due to low adherence. d The source guidance only addresses the personal health benefits of high adherence, not the benefits of high adherence in reducing the risk of transmission to others. e Virologic failure is the inability to achieve or maintain suppression of HIV replication to an HIV RNA level of <200 copies/mL. f Some experts recommend asking patients to answer the question, "In the last 30 days, how good a job did you do at taking HIV medicines in the way you were supposed to?" using a multistep scale ranging from very poor to excellent. 23 g See the Background topic in this section for information supporting this statement. # Sources # How These Recommendations Differ from Previous Recommendations The 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care 24 did not address adherence to ART as a means to suppress viral load or prevent HIV transmission. However, the recommendations in this section are consistent with the latest federal guidance for clinical providers regarding adherence assessment and support. 1,22,25 They are also consistent with the latest federal guidance for health departments regarding collection and use of HIV surveillance data (as a measure of ART effectiveness, which may be affected by adherence) in populations or individuals, if allowed by their jurisdictions. [26][27][28] These recommendations are also consistent with nearly all of the latest comparable recommendations about ART adherence of these nongovernmental organizations: the International Association of Physicians in AIDS Care Panel; 29 the HIV Medicine Association of the Infectious Diseases Society of America; 30 and the International Antiviral Society-USA Panel. 31,32 This report also makes new recommendations based on recent studies, programmatic experience, and/or expert opinion. These include recommendations for  nonclinical providers (including community health workers employed by health departments or community-based organizations) to provide selected educational, counseling, and referral services to support adherence, if allowed by their professional authority and jurisdiction (see Box 6 and Box 6-A)  nonclinical and clinical providers to apply motivational interviewing techniques to help persons taking ART identify strategies for maintaining or improving their adherence (see Box 6-A) Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information.  health departments to engage health department disease investigation specialists or other community health workers in collaborating with health care providers to offer their patients adherence support, if allowed by the jurisdiction (see Box 6) # Methods The section writing group based these recommendations on several sources of scientific information including federal guidance, published systematic reviews, and published primary studies. adherence that were conducted in the United States and other countries and were published from 2000-2012. 36,43,45,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] These reviews varied regarding the number of studies included, eligibility for inclusion (e.g., published versus unpublished literature, inclusion of randomized controlled trials [RCTs], one-group designs, or other designs), methods for assessing adherence, and methods for summarizing evidence. The reviews examined several types of adherence interventions; many combined education, adherence tools, and long-term support strategies.  An electronically published systematic review, the PRS Compendium of Evidence-based HIV Behavioral Interventions (PRS Compendium) that is updated annually as new published studies that meet inclusion criteria are identified. 65 The 2014 compendium included 10 evidence-based behavioral interventions † † (EBIs) for improving adherence (described in 9 studies) that were determined to be efficacious based on PRS efficacy criteria (hereafter termed "adherence EBIs"). [66][67][68][69][70][71][72][73][74] Each study met pre-established criteria for rigorous evaluation design (i.e., used a comparison group), reported significant findings (i.e., statistically significant positive intervention effects on adherence or viral load), and was published in a peer-reviewed journal. 75  Six cost-effectiveness analyses of adherence interventions in the United States. [76][77][78][79][80][81] # Evidence Supporting the Recommendations # Methods to regularly assess adherence Adherence can be measured using various methods, including self-reported medication use or pill counts, pill counts assessed by providers, electronic drug-monitoring data, pharmacy records, and drug levels in the blood. Each method has good correlation with one or more other measurement methods and with HIV viral load. 14,15,21,[82][83][84] There is no consensus on the most accurate, simple, and feasible method because each method has strengths and weaknesses. 82 Self-reported adherence is commonly used in daily practice and is recommended for routine adherence assessment because it is inexpensive and easy to † † Evidence-based interventions are individual-, group-, or population-level interventions that have been shown to promote safer behaviors or reduce HIV or STD transmission in research studies, program evaluations, or theory-based intervention experience. implement. 1,22 Most other methods are less practical in clinical settings ‡ ‡ because of high cost, patient or provider burden, or require medical or pharmaceutical information systems that were not designed for routine adherence assessment. Although self-reported adherence tends to over-estimate adherence by up to 20%, certain response options and recall methods may improve accuracy. 1,22,85 For example, some experts recommend asking patients to answer the question, "In the last 30 days, how good a job did you do at taking HIV medicines in the way you were supposed to?" using a multistep scale from very poor to excellent. 23 In addition, providers who use a positive, nonjudgmental manner with patients and acknowledge the challenges of adherence can encourage more accurate self-reporting. 1,22 Current federal recommendations advise using pharmacy refill information and pill counts to supplement, but not replace, self-reported adherence measures only in clinical settings that can routinely collect this information and recognize biases when refill data are incomplete or patients discard pills before they are counted. 1,22 Federal recommendations for clinical settings do not advise measuring antiretroviral drug concentrations in biologic specimens (which is costly and biased by short, drug half-lives) or recording data from electronic drug monitoring devices (which is often impractical). 1,22 # Assessing factors that influence adherence Achieving consistently high adherence over the span of chronic HIV infection is often challenging. Even persons who have maintained high adherence for long periods may have lapses in adherence due to medical or psychosocial issues or life events. While the most common reason for low adherence that patients cite is forgetting to take the medication, 13,18,43,[86][87][88][89] a complex set of personal, social, cultural, and structural factors can influence adherence. Table 6-1 summarizes the most common factors related to low adherence described in 18 published reviews on correlates and HHS guidelines on ART use. 1,8,20,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Low adherence was most often associated with patient factors-particularly alcohol or substance abuse and depression, anxiety, or other psychological conditions-and regimen factors, such as frequent or severe treatment side effects, high pill burden, and frequent dosing. Other common patient-level factors affecting adherence included negative attitudes or beliefs about HIV disease, fear of stigma, lack of social support, negative attitudes or beliefs about treatment, and lack of a daily routine. Several structural factors-such as homelessness or lack of insurance or financial assistance-were also associated with low adherence. The 3 reviews that focused on adolescents found that characteristics of parents or caregivers were associated with their adolescent's adherence; these included knowledge (e.g., education level, understanding about ART), perceptions (e.g., belief of treatment efficacy, self-efficacy), and well-being (e.g., stress). 43,45,46 ‡ ‡ Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. # Structural factors  Inability to afford or obtain a continuous supply of ART due to lack of health insurance or enrollment in medical assistance programs 35,36,39,41  Unstable housing, incarceration, and recent release from imprisonment 35,36,38,40,41,43,45 # Strategies that increase adherence The 19 systematic reviews that evaluated the impact of behavioral interventions on improving adherence included formal meta-analyses (n=6) and qualitative or semi-quantitative analyses (n=13). Many reviews concluded that adherence interventions resulted in statistically significant improvements in adherence (as measured by self-reported adherence, pill counts, or electronic medication monitoring devices), but that the magnitude of differences in adherence levels between intervention and comparison groups was moderate. 49,54,[56][57][58][60][61][62][63][64] Many reviews showed that persons who received adherence interventions also had reduced HIV viral loads, although effect sizes were weaker than those related to adherence measures. 49,53,54,[56][57][58]60,62,63 Several reviews found that adherence increased during the intervention period but declined thereafter or that ongoing support was needed to sustain high adherence. 49,54,[56][57][58] Overall, the most effective interventions focused on educating and motivating patients, addressing concerns or negative beliefs about treatment, building patients' skills and providing tools for managing medications, and offering ongoing support. [56][57][58] Several reviews suggested that to be effective, adherence interventions must use a multifaceted, long-term approach; engage members of multidisciplinary teams; and consider a variety of strategies tailored to the individual. [56][57][58][59] Details on specific strategies that improved adherence when used alone or in combination with other strategies are summarized below. # Providers of adherence support Several systematic reviews of intervention evaluations found that various types of providers who provide adherence support can improve adherence. A meta-analysis of 10 adherence interventions (7 of which specifically addressed ART) found that interventions in which nurses provided adherence counseling and other support significantly improved both short-and long-term adherence. 64 Another review found that engaging pharmacists to provide education, counseling, and training on adherence management tools was often associated with improved adherence and viral suppression. 60 In addition, interventions that used peer educators, community health workers, or outreach workers to educate patients about medication management and to provide repeated, long-term adherence support could improve adherence. 55 # Simplified ART regimens Several of the 18 systematic reviews that assessed factors associated with adherence found that greater pill burden and more frequent dosing were associated with lower adherence. 8,33,35,36,[41][42][43][44][45] One review described a meta-analysis of 11 RCTs that found that adherence to once-daily regimens was slightly better than adherence to twice-daily regimens in all patients (a difference of 2.9%) and in the subset of patients who had recently started treatment (a difference of 4.4%). 42 In 6 of these studies, patients prescribed once-daily regimens had significantly higher adherence (a difference of 4.5%) and lower viral load levels (defined as <50 copies/ml, a difference of 5.7%) as compared with patients prescribed twicedaily regimens. 42 All of these modest differences were statistically significant. # Management of side effects Several of the 18 systematic reviews that assessed factors associated with adherence found that adverse side effects impair adherence. 8,33,35,36,41,43,44,47,48 One meta-analysis found that patients reporting side effects were about 40% less likely to report high adherence than were patients reporting no adverse effects, although the magnitude of difference varied slightly by type of adverse effect. 48 None of the 19 systematic reviews of intervention evaluations reported the impact of strategies to manage side effects. However, 3 adherence EBIs in the PRS Compendium informed patients about ART side effects or provided tailored advice if patients reported that side effects impaired adherence. 68,69,72 Although newer ART regimens cause milder and less frequent side effects as compared with many older regimens, side effects continue to impair adherence in some persons. # Adherence education and counseling Three systematic reviews of intervention evaluations found that education and counseling that address cognitive and behavioral aspects of taking ART can improve adherence. These strategies included providing information about treatment; addressing negative beliefs about medication, lack of motivation to take medication, or unrealistic expectations about adherence; providing individually tailored approaches to build self-confidence and medication management skills; and encouraging seeking support for adherence from providers, fellow patients, friends, or family. [56][57][58] A systematic review of 5 interventions that involved motivational interviewing found that 3 significantly improved adherence and 2 significantly reduced viral load. 63 In addition, 8 of the 10 adherence EBIs in the PRS Compendium focused primarily on educational or cognitive-behavioral approaches to improving adherence. Strategies included providing education about ART use and the health benefits of adherence, addressing barriers to adherence, assisting with problem solving and decision making, setting adherence and treatment goals, building adherence skills, and engaging support for adherence from peers. [67][68][69][71][72][73][74] # Adherence tools Two systematic reviews of intervention evaluations studies found that technology-based methods, such as mobile phones that generate auto alarms or text messages and other electronic reminder devices (e.g., pagers, alarms, and electronic pill boxes), do not improve adherence when used alone. However, they are effective when combined with other strategies, such as education and individually tailored counseling. 59,61 A more recent systematic review examining 2 Kenyan trials found that weekly mobile text messages with adherence reminders significantly improved adherence and suppressed viral load. 62 Of the 10 adherence EBIs in the PRS Compendium, 1 study sent daily pager messages that included reminders to take ART as the sole adherence support strategy. 72 Persons who received messages were more likely to achieve undetectable viral load levels than were persons who did not receive messages. # Directly administered antiretroviral treatment or therapy § § (DAART) Two of the 19 systematic reviews of intervention evaluations compared DAART to self-administered treatment in various populations: HIV clinic patients, substance users (including those receiving and those deferring substance use treatment), persons who inject drugs (PWID), homeless persons, prisoners, and hospice patients. The reviews found limited evidence that DAART improved adherence or viral suppression. 53,54 The first review found that DAART only significantly improved adherence or viral suppression in PWID and homeless persons. 53 The second review found that DAART improved adherence and viral suppression only during the intervention period but not thereafter. 54 Two of the 10 adherence EBIs in the PRS Compendium found that DAART for substance users resulted in significant reductions in viral load. 66,70 One multifaceted intervention involved sending pager reminders to receive daytime doses (in a mobile van) and to take evening doses over a period of 6 months; it also included case management, social support, and medication management education to help transition clients after DAART ceased. 66 Persons who received this intervention were significantly more likely than persons who managed their own ART to achieve an undetectable viral load or a large reduction in viral load (70% vs 55%, p=0.017). 66 The other study provided DAART to clients of a methadone maintenance clinic who had started a new ART regimen. 70 Persons who received the intervention were more likely to have § § Directly administered antiretroviral treatment or therapy (DAART) is a form of drug administration in which a provider directly observes a person with HIV taking oral ART on a daily or nearly daily basis. undetectable viral loads 6 months after starting DAART as compared with persons who managed their own ART (74% vs 41%, p<0.001). The studies raise questions about the general applicability of DAART, however, because the interventions were restricted to substance users, did not show a sustained effect after DAART ceased, and were fairly labor-intensive. # Multifaceted interventions with several components Several adherence EBIs in the PRS Compendium 75 were found to improve adherence (n=7) [67][68][69][71][72][73][74] or to reduce viral load (n=4). 66,69,70,72 Seven evidence-based interventions were multifaceted and included several strategies for improving adherence, such as cognitive-behavioral approaches, social support, treatment delivery methods, and adherence tools. [66][67][68][69]71,73,74 The interventions were directed to adults with varied characteristics and ART experience, including substance users, clinic patients, couples with discordant HIV status, persons starting ART, experienced users, persons switching regimens, and persons experiencing adherence problems. All interventions focused on populations comprising mainly racial/ethnic minorities, and most were implemented in clinics or directed to established clinic patients. The interventions also varied regarding delivery mode (individual, couples, group) and provider type (physician, nurse, peer counselor, outreach worker, other facilitators). Two of the 7 multifaceted EBIs were associated with significant decreases in viral load. 66,69 One brief, clinic-based intervention consisted of brief (~3-5 minutes) counseling sessions by physicians at each HIV care visit along with clinic posters and patient education materials reinforcing ART adherence. 69 Patients who received this intervention were nearly 3 times more likely than patients who did not receive the intervention to report high adherence (>95% of prescribed pills taken over the previous 7 days) (OR=2.9, p=0.001) and were less likely to have detectable viral load levels (>500 copies/mL) (OR=0.60, p=0.04). 69 In the other multifaceted intervention (described in the DAART topic above) persons who received DAART, pager reminders, case management, and other supportive services through a mobile van were more likely than persons who did not receive these services to achieve undetectable viral loads or large reductions in viral load 6 months after DAART started (70% vs 55%, p=0.017). 66 # Cost-effectiveness of adherence interventions Five cost-effectiveness studies published from 2000-2010 evaluated different adherence interventions, including individual counseling for gay, bisexual, or other men who have sex with men (MSM) provided by health professionals, home visits by nurses, and provision of DAART in the clinic or the home. [76][77][78][79][80] The studies considered different comparison groups (i.e., persons taking placebos or persons receiving verbal reminders to take medications as prescribed), different populations (e.g., treatment naïve, specific CD4 cell count or viral load, demographic group), and different intervention providers (e.g., nurses, pharmacists). Two studies estimated intervention efficacy and cost from data collected during adherence trials, 76,79 and 3 studies estimated cost data using data from other published reports. 77,78,80 The studies found that adherence interventions cost from $1,300 to $90,000 per quality-adjusted life year gained (mean=$43,970). In addition, modeling analysis estimating the cost effectiveness of adherence interventions (in which per-patient costs were based on 2 clinic-based interventions that appreciably improved adherence) 76,95 found that providing adherence interventions to prevent HIV transmission was cost-saving compared with not providing interventions. 81 It also concluded that the intervention cost per new case of HIV averted was ~$339,000, 81 slightly less costly than the lifetime cost of HIV treatment (>$400,000). 96 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Studies over the last decade have shown that average rates of adherence (estimated at various times after ART initiation) range from 30% to 89% 5,6,11,13,14,16,18,[86][87][88][97][98][99][100][101][102][103] and tend to decline over time. 5,70,[104][105][106][107][108] A recent meta-analysis estimated that, on average, only 59% (95% CI: 53%-65%) of persons with HIV in North America reported ≥90% adherence to ART. 20 A 2011 evaluation of 128 HIV clinics funded by the Ryan White HIV/AIDS Program found that 15% of patients had a documented problem with adherence. 109 However, levels of adherence among persons with HIV may improve in the future for several reasons: 1) HHS now recommends use of ART for preventing HIV transmission; 2) newer medications require less frequent doses and cause fewer side effects; 3) access to pharmacy benefits from health insurance and expanded state Medicaid programs has increased under the Patient Protection and Affordable Care Act (ACA); 4) funding of the AIDS Drug Assistance Program and other programs that subsidize ART continues; and 5) cost of some ART medications will decline as patents expire. [110][111][112] As more persons with HIV start ART for the dual purpose of treatment and preventing transmission, future studies can evaluate the impact of adherence support for persons who have high CD4 cell counts and feel well. 1 Two studies suggest that patients who start or use ART when they have high CD4 cell counts are less likely to have sustained high adherence than persons with low CD4 cell counts. 113,114 Nevertheless, theoretical considerations suggest that when comparing the potential risk of low adherence in some persons starting ART at high CD4 levels to the potential benefit of decreasing the population viral load, large increases in the numbers of persons starting ART are likely to result in a net benefit in preventing HIV transmission. 1 Although many studies show the benefits of regular adherence assessment and support, many health care providers do not regularly assess adherence, address adherence barriers, or provide adherence support because of competing priorities or lack of experience. 115,116 When time is limited, many providers prioritize support to patients who are starting or restarting ART, changing regimens, or reporting low adherence and adherence challenges. Use of multidisciplinary care teams, task sharing, and "medical homes" encouraged by the ACA can expand the range of providers who can support adherence. 110,112 Electronic medical records* that can track viral load levels over time and generate reminders for health care providers when viral loads increase may prompt adherence assessment in some clinical settings. 117 Anecdotal reports suggest that some persons with HIV may consider sharing their ART medications with other persons with HIV or with HIV-uninfected partners seeking antiretroviral medications for * An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. preexposure prophylaxis (PrEP) † † † and nonoccupational postexposure prophylaxis. ‡ ‡ ‡ Providers should discourage sharing ART because it may impair adherence and pose other problems (see Section 5, Antiretroviral Treatment). 1,[118][119][120][121] # Policy, legal, and ethical considerations Concerns about confidentiality, stigma, and social disapproval and nondisclosure of HIV infection status are associated with low adherence 36,41,[43][44][45]47,91 (see Section 3, Context of Prevention). Some persons may be reluctant to carry or display their ART in public or to seek adherence support from others if they fear legal consequences or deportation. A study of more than 1,800 persons with HIV in North America found that those living in areas where transmitting or exposing others to HIV was a crime reported lower adherence compared with persons living in other areas. 122 Providers can assess adherence in a nonjudgmental manner, stress that adherence information is confidential, explain the relation between adherence and viral load, and help persons with HIV find practical adherence strategies. These strategies may encourage patients to honestly disclose their adherence levels, to admit adherence challenges, and to set realistic adherence goals. Several studies have also shown that persons who share decision making about ART adherence goals with their clinical providers have higher adherence. 8,36,44 This approach respects the patient's autonomy while using clinical input about the levels of adherence needed to achieve treatment goals. Other factors that influence adherence are described elsewhere: retention in HIV medical care (Section 4, Linkage to and Retention in HIV Medical Care); and sustained access to affordable ART (Section 5, Antiretroviral Treatment). # Special populations Persons who have substance use problems, unstable housing, or other characteristics associated with low adherence can achieve high adherence when given adequate support. 2,11,39,40,86,89,[123][124][125] For example, providers who regularly monitor drug and alcohol use that signal life stressors may preempt lapses in adherence that lead to virologic failure. 103,126 Clinical providers who serve younger adolescents who rely on parents or caregivers to manage medicines can refer to adherence strategies for children recommended by HHS. 127 Providers serving older adolescents can honor confidentiality by asking which adults sponsor their health insurance, are aware of their HIV infection, and have the knowledge and attitudes about ART that enable them to provide adherence support. 43,45,46,128 ART adherence can be challenging for some older persons, particularly those taking many medications for other conditions or experiencing cognitive impairment. 47,129,130 Several strategies may be helpful: avoiding prescribing drugs that may cause adverse interactions, managing drug interactions, and offering tools and training to organize medications. Patients who cannot read pill bottles or understand package † † † PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 118 ‡ ‡ ‡ The use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational or occupational exposures to body fluids potentially containing HIV-such as after unprotected sexual intercourse, condom breakage, or needlesticks-in order to reduce the risk of HIV acquisition. inserts because of low literacy or language barriers may benefit from visual aids or simplified medication instructions in the appropriate language. Section 12 describes assessment, linkage, and referral to other medical and social services for populations that face unique barriers to adherence. # Implementation Resources Practical resources to support implementation of these recommendations, including a list of interventions shown to be efficacious in supporting adherence, can be found at http://www.cdc.gov/hiv/guidelines/implementationresources.html. A list of wholesale costs of ART regimens recommended by HHS is also available. 1 # Section 7. Risk Screening and Risk-reduction Interventions Background Risk screening is the collection of information to determine a person's risk of transmitting HIV to others. In this report, risk screening is defined as a brief evaluation of behavioral factors that may affect the risk of exposing others to HIV (e.g., unprotected* sex or sharing drug-injection equipment) and biomedical or biologic factors that influence HIV viral load, viral shedding, and infectiousness (e.g., antiretroviral treatment [ART] use, ART adherence, sexually transmitted disease [STD], and pregnancy). Risk screening † is used to identify behavioral or biomedical risk-reduction interventions suited to a specific individual. [1][2][3][4] Behavioral risk-reduction interventions include various services provided in clinical settings ‡ and nonclinical settings § that have been shown to promote safer behaviors and reduce the risk of exposing others to HIV. Many interventions address psychological, social, or structural factors that influence sexual, drug-injection, and reproductive behaviors. Some aim to provide information, build knowledge, and improve skills that lead to safer behaviors. Others increase motivation to adopt safer behaviors or modify social norms. Some interventions involve a structural component, such as increasing access to condoms. Behavioral risk-reduction interventions can be offered to individuals or groups through counseling, discussion, role plays, or exercises; through print media, such as brochures and posters; and through interactive media, such as computers, telephones, and mobile devices. 5 This section addresses risk screening and behavioral risk-reduction interventions that can promote safer sexual and drug-injection behavior over a lifetime. Quality improvement** and program monitoring and evaluation † † methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Because risk screening and risk-reduction interventions are central to HIV prevention with persons with HIV, other sections also describe behavioral and biomedical strategies to reduce the risk of HIV transmission: linkage to and retention in care (Section 4), antiretroviral treatment (Section 5), ART * Unprotected sex or unprotected sexual contact is sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginaldigital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). † Risk screening is the collection of information to determine a person's risk of transmitting HIV to others. In this report, risk screening is defined as a brief evaluation of behavioral factors that may affect the risk of exposing others to HIV (e.g., unprotected sex or sharing druginjection equipment) and biomedical factors that influence HIV viral load, viral shedding, and infectiousness (e.g., antiretroviral treatment [ART] use, ART adherence, sexually transmitted disease [STD], and pregnancy). Information gathered during this screening can be used to identify suitable behavioral or biomedical risk-reduction interventions. ‡ Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. § Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. † † Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness.  Behavioral characteristics that affect their risk of exposing others to HIV (e.g., unprotected sex, sharing drug-injection equipment) b,c,d  Biologic or biomedical characteristics that affect their level of infectiousness, (e.g., use of and adherence to antiretroviral treatment (ART), viral load level, sexually transmitted disease [STD] diagnoses, pregnancy) b,c,d,e,f,g,h  Characteristics of partners that affect the partner's risk of acquiring HIV or STD, when information available (e.g., use of preexposure prophylaxis [PrEP] i or nonoccupational postexposure prophylaxis [nPEP] j ) b,c,d,e,f,g,h  Offer positive reinforcement to persons who report safer behaviors and use of biomedical strategies that reduce their level of infectiousness to motivate their continued use (ii, iv, vii) ‡ ‡ Partner services include an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. # BOX 7. RECOMMENDATIONS-RISK SCREENING AND RISK-REDUCTION INTERVENTIONS (cont) Individual-level risk-reduction services i PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. j nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 7 Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. k Common misconceptions relate to perceptions of the relative, per-act risk of HIV transmission for various types of sexual contact; how behavioral, biologic, and viral factors influence transmission risk; whether ART use can reduce the risk of HIV transmission; and whether use of PrEP or nPEP with antiretroviral medications can reduce the risk of HIV acquisition by HIV-uninfected partners. a The practice of limiting unprotected sex (i.e., sexual activity without using a physical barrier) to partners believed to have the same HIV infection status (e.g., persons with HIV only have unprotected sex with persons believed to be HIV-infected). b The practice of modifying sexual activity based on beliefs about the partner's HIV infection status and the per-act risk of HIV transmission for a given type of contact (e.g., persons with HIV practice receptive fellatio [i.e., the practice of receiving a partner's penis in one's mouth] with HIV-uninfected partners because they believe this type of contact is less likely to transmit HIV than insertive fellatio [i.e., the practice of inserting one's penis into a partner's mouth], anal sex, or vaginal sex). c Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. d A recent diagnosis may be based HIV test result indicative of acute infection (i.e., positive HIV antigen or nucleic acid amplification test or HIV antibody result indicative of recent seroconversion) and/or clinical evaluation of symptoms or signs of acute retroviral syndrome (e.g., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, headache, lymphadenopathy). e See Section 5, Antiretroviral Treatment, for recommendations on the use of ART to reduce the infectiousness of persons with HIV and to reduce the risk of their HIV-uninfected partners' acquiring HIV. f See Section 9, STD Services, for recommendations on STD screening and treatment to reduce the infectiousness of persons with HIV and the role of STD in facilitating HIV transmission. g See Section 10, Reproductive Health Care, for recommendations on family planning to prevent unintended pregnancy and special conception methods that reduce the risk of HIV transmission or acquisition. h See Section 11, Pregnancy, for recommendations on reducing the risk of sexual and perinatal transmission or acquiring HIV during pregnancy and the postpartum period. i See Section 8, Partner Services, for recommendations on reducing the risk of acquiring HIV by HIV-uninfected partners, including STD screening and treatment, PrEP and nPEP, and reproductive and pregnancy services. # Box 7-C. Important topics when informing persons with HIV about how to prevent transmission of HIV to others # General topics  How HIV is spread (e.g., exchange of body fluid) and not spread (e.g., handshake)  How sustained high adherence to ART suppresses viral load and reduces the risk of transmitting HIV  How preventing or treating symptomatic and asymptomatic STDs can improve health and decrease the risk of transmitting HIV  How avoiding drugs and alcohol can improve health and may promote safer drug-use or sexual behaviors  Benefits of support from family, friends, or partners to encourage safer behaviors  Benefits and risks of selectively disclosing HIV infection to others (e.g., those at a heightened risk of HIV exposure, health care providers) and methods that minimize the risk of negative consequences of disclosure a  Benefits of knowing the HIV-infection status of sex and drug-injection partners  How serosorting may result in HIV transmission if assumptions about partners' HIV status are incorrect or may result in acquiring STDs and, more rarely, new HIV strains from infected partners  Characteristics of HIV-uninfected sex and drug-injection partners that increase their risk of HIV acquisition (e.g., sharing nonsterile drug-injection equipment, STDs)  Availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to prevent HIV acquisition b,c  Availability of voluntary, confidential, and usually free health department services to notify sex or drug-injection partners of possible HIV exposure d # Box 7-C. Important topics when informing persons with HIV about how to prevent transmission of HIV to others (cont) # Topics related to sexual transmission (or perinatal transmission if pregnant woman becomes HIV infected through sexual contact) e,f  Communicating with partners to foster healthy sexuality (e.g., noncoercive sexual contact, negotiating safer behaviors)  Methods that HIV-discordant couples can use to reduce the risk of sexual HIV transmission, including the following:  Using latex and polyurethane male and female condoms: negotiating with partner to use; reminders to use; correct and consistent use  Using dental dams or other physical barriers while having oral-vaginal or oral-rectal sex  Using sexual positioning that lowers a partner's risk of acquiring HIV (order from lowest to highest risk: insertive fellatio, receptive fellatio, insertive penile-vaginal sex, receptive penile-vaginal sex, insertive anal sex, receptive anal sex) g  Practicing mutual masturbation and digital penetration and using clean sex toys that do not cause anal or genital bleeding or trauma h  Avoiding exposing partner to blood, semen, vaginal secretions, and other body fluids that are visibly contaminated with blood  Avoiding sexual intercourse with HIV-infected persons after invasive anal or genital procedures until healing is complete, i or when anal or genital bleeding, inflammation, or trauma may be present (e.g., if infected with STD or when using irritating sexual aids) h  Using only water-based spermicides and lubricants that do not contain nonoxynol-9  Avoiding contact with body fluids of HIV-infected persons after invasive oral or dental procedures  Reducing the number of sex partners  Risk of acquiring STDs in genital and nongenital sites if having genital, anal, or oral sexual contact e  Presence of symptomatic or asymptomatic STD in persons with HIV e  Presence of symptomatic or asymptomatic STD in HIV-uninfected partners, which may increase their risk of acquiring HIV and may indicate a substantial risk for HIV that is a clinical indication for PrEP c  Methods to prevent unintended pregnancy e  Conception options that reduce the risk of HIV transmission f  Interventions to reduce the risk of perinatal transmission f  Evidence that male circumcision may reduce a man's risk of acquiring HIV from a female partner with HIV j Box 7-C. # Important topics when informing persons with HIV about how to prevent transmission of HIV to others (cont) # Topics related to transmission resulting from substance use and sharing drug-injection equipment k  Health benefits of abstaining from or reducing substance use  The relation between use of some recreational drugs and higher risk sexual practices (e.g., methamphetamines)  Risk of transmitting HIV when sharing drug-injection equipment  Benefits of completing substance use treatment (that may include relapse prevention and opioid substitution programs)  Methods to reduce the risk of transmitting HIV if drug injection continues, including the following:  Reducing the number of drug-injection partners  Using new, sterile equipment from reliable sources (pharmacies, SSPs)  Using sterile needles, syringes, fluids, cookers, and cotton each time to prepare and inject drugs  Using sterile water (preferable) or fresh tap water when preparing drugs  Never sharing or reusing drug-injection or preparation equipment  Cleaning injection sites with alcohol swabs before injection  Disposing needles and syringes in safe places after each use # Note. Providers can address topics relevant to each person with HIV using print, audiovisual materials, or discussion over one or more encounters. The Implementation Resources topic in this section includes a link to print, audiovisual, and online risk-reduction interventions and materials that can be used in nonclinical and clinical settings. a See Section 3, Context of Prevention. b Preexposure prophylaxis (PrEP) is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 6 In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. c See Section 5, Antiretroviral Treatment, for more information regarding the use of PrEP and nPEP. 6,7 d See Section 8, Partner Services, for more information. e See Section 10, Reproductive Health Care, for more information on contraception and conception options. f See Section 11, Pregnancy, for more information on interventions to reduce the risk of perinatal HIV transmission. g Estimated risk of acquiring HIV from an HIV-infected partner (in order of lowest to highest risk): insertive fellatio, receptive fellatio, insertive vaginal sex, receptive vaginal sex, insertive anal sex, receptive anal sex. 8,9 h Including penile piercing devices, constrictive penile rings, or other sex aids, devices, or toys that have touched the blood or genital secretions of HIV-infected persons (see the Evidence topic in this section for additional information). i Examples include tubal ligation; vasectomy; dilatation and curettage; and removal of vaginal, cervical, and penile warts, polyps, and precancerous lesions. j CDC has disseminated information from African trials showing that adult male circumcision may reduce a man's risk of acquiring HIV from an infected female partner. 1,10 k More detailed CDC guidance on methods to reduce the risk of injection-related HIV transmission is found in other sources. 11 # Box 7-D. Examples of population-level strategies for health departments to support risk screening and risk-reduction services  Monitor prevalence of HIV risk behaviors in jurisdiction through behavioral surveillance or special projects  Support programs that increase access to risk-reduction information, condoms, and legal, sterile syringes, if allowed in the jurisdiction  Make available directories of:  risk-reduction services sites  condom distribution sites  legal sources of sterile syringes  substance abuse treatment programs  Provide technical assistance to clinical and nonclinical providers about these topics:  how to access and strengthen risk-reduction services networks  financial and reimbursement issues  protecting confidentiality and data  security during the referral process # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with other current federal guidance that advises conducting routine, periodic risk screening; providing accurate information about HIV transmission risk; offering behavioral risk-reduction information; providing risk-reduction interventions tailored to an individual's risks onsite or through referrals; § § encouraging safe and voluntary disclosure of HIV-positive status to partners; and informing partners about biomedical and behavioral methods to reduce their risk of acquiring HIV. 1,6,7,[12][13][14][15][16][17] These recommendations are also generally consistent with the latest guidance about these topics from several nongovernmental organizations. [18][19][20][21][22][23] However To describe the prevalence of sexual and drug-injection risk behaviors in persons with HIV in the United States, the writing group also conducted a narrative review of articles published in PubMed database between 2010 and March 2014 that were indexed with these terms: HIV, risk behavior, and HIV transmission. # Evidence Supporting the Recommendations This topic summarizes evidence that supports recommendations on risk screening, several behavioral interventions, and one biomedical intervention (male circumcision). Other sections summarize the evidence that support recommendations about other biomedical interventions: antiretroviral treatment (Section 5), ART adherence (Section 6), partner services (Section 8), STD services (Section 9), reproductive health care (Section 10), pregnancy services (Section 11), and services for other medical conditions and social factors that influence HIV transmission (Section 12). # The role of risk screening for behavioral and biomedical factors that influence HIV transmission in guiding the content of risk-reduction interventions Accurate information on behavioral and biologic risks of HIV transmission is needed to identify the most appropriate risk-reduction interventions. However, it can be difficult to accurately estimate a person's risk of HIV transmission because risk varies depending on the type and frequency of sexual and drug-injection behaviors, ART use and adherence, HIV viral load, concurrent STDs, pregnancy, partners' HIV status, and other factors over time. Moreover, the results of risk screening may be inaccurate due to 31  poor recall  misunderstanding about risks associated with specific behaviors  previous negative experience with disclosing risk behaviors  fear of or experience with negative judgments, criticism, or stigmatization  desire for social approval  concerns about legal consequences of reporting risk behaviors  doubts about confidentiality protections  poor rapport with providers Studies show that some persons who have been diagnosed with an acute bacterial STD-an objective marker of unprotected sexual activity-deny having unprotected sex. 1 However, providers who conduct risk screening using a nonjudgmental approach that stresses confidentiality may encourage trust and elicit more honest responses. 32,33 Most clinical providers and some nonclinical providers can access biomedical information, such as a recent STD diagnosis, that can help to validate the accuracy of reported risk behaviors. 1 Three controlled clinical studies [2][3][4] found that information elicited during risk screening guided the content of motivational interviews and led to statistically significant reductions in the amount or frequency of unprotected anal or vaginal sex. By periodically screening for both behavioral and biologic factors that influence HIV transmission, providers can identify a wider range of risk-reduction options that are acceptable to persons with HIV and their partners. 34 For example, some persons with HIV may prefer lifelong ART use with high adherence rather than lifelong condom use. Other persons with HIV may urge partners to reduce their risk of exposure or biologic susceptibility to HIV by using condoms, taking PrEP, or seeking screening and treatment for STDs. # The role of behavioral risk-reduction interventions in promoting safer sexual behavior or reducing HIV or STD transmission # Characteristics of behavioral risk-reduction interventions associated with unprotected sex and STD acquisition in persons with HIV Two 2006 meta-analyses evaluated a total of 18 different controlled trials of behavioral risk-reduction interventions conducted in the United States, Puerto Rico, and Canada after ART became available in 1996. 26,27 The interventions involved single or multiple sessions in clinical or nonclinical settings. Both meta-analyses concluded that behavioral risk-reduction interventions were effective in reducing the frequency or number of unprotected sex acts and/or the risk of acquisition of STDs by persons with HIV. 26,27 Several intervention characteristics were significantly associated with a lower frequency of unprotected sex (i.e., 95% confidence intervals did not include 1.0). These characteristics included the following:  based on cognitive behavioral theory 26 (OR=0.52)  used motivational enhancement 27 (OR=0.32)  offered skills building (e.g., correct use of male and female condoms, role play for negotiating condom use) 26 (OR=0.59)  focused on HIV transmission behaviors in more than two-thirds of sessions 26 # Behavioral risk-reduction interventions in clinical or nonclinical settings Several studies have shown that persons with HIV tend to report safer sexual activity after having received behavioral risk-reduction interventions in clinical or nonclinical settings. These studies include a demonstration project in public-sector HIV clinics 35 # and 14 interventions that CDC classified as EBIs ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Fifteen EBIs have met the established criteria as of April 2016, but the current version of this guideline has not been updated to reflect that number. (see the Methods topic in this section). 5,29 These EBIs were conducted in clinical (n=8) or nonclinical (n=6) settings and involved single or multiple sessions of varied duration. 5,29 Each intervention included at least one of the characteristics associated with intervention effectiveness listed above. # Brief prevention counseling messages during routine medical visits Three interventions classified as EBIs found that adults who received brief prevention counseling messages from clinical providers (or from actors portraying physicians in a video) during all routine HIV medical visits were significantly less likely to report unprotected sex than adults who did not receive these repeated messages. 2,3,36 These prevention messages were tailored to the patient's reported risk and/or focused on self-protection, partner protection, and HIV disclosure. All 3 interventions also included posters and/or patient brochures that reinforced the prevention messages provided by clinical providers. Additionally, findings of an evaluation 35 of observational data from 13 clinics funded by the Health Resources and Services Administration (HRSA) were consistent with the 3 EBIs. Brief risk-reduction counseling sessions (lasting about 3-5 minutes) during all routine HIV care visits were associated with a significant reduction in the number of reported acts of unprotected vaginal and anal sex. 35 # Intensive risk-reduction interventions during routine HIV care visits Five randomized control trials classified as EBIs found that patients who participated in a series of several interactive prevention sessions, each lasting 40 to 120 minutes, had a significant reduction in the reported number of unprotected sex acts with partners at risk for acquiring HIV when compared with patients who received standard of care (e.g., basic HIV information) or non-HIV health promotion interventions (e.g., advice about nutrition or cancer prevention). [37][38][39][40][41][42] The interventions used various approaches:  MSM with HIV serving as peer advocates offered MSM 4 individual counseling sessions and 2 follow-up sessions that focused on reducing unprotected sex with partners with negative or unknown infection status. 40  Trained facilitators offered 2 individual and 5 group sessions that focused on ART, adherence to ART, and sexual decision making under various hypothetical conditions related to substance use, HIV status disclosure, treatment status, viral load, social relationships, and mood. The intervention was also associated with improved adherence to ART. 39  Trained counselors offered individual, monthly sessions over 4 consecutive months. Sessions included motivational interviewing, CDs, and booklets that contained information about safer sex tailored to patients' risks, and 4 follow-up letters that reinforced the content of the preceding session. 37,38  Trained female peer educators with HIV and professional health educators offered 4 group sessions to women with HIV. Sessions focused on gender pride, social support, healthy sexual relationships, and skills to negotiate safer sex. 41  Trained male and female facilitators offered 23 sessions (two sessions per week over 6 months) to groups of adolescents with HIV. Sessions focused on coping with an HIV diagnosis, HIV disclosure, participating in health care decisions, identifying factors that triggered risk behaviors, skills to negotiate safer sex, implementing daily routines to stay healthy, and reducing substance use and unprotected sex. 42 # Intensive behavioral risk-reduction interventions in nonclinical settings In 6 EBIs, 5 peer educators or health educators led a series of interactive intervention sessions for individuals, small groups, or heterosexual HIV-discordant couples with varied demographic characteristics. 29,[43][44][45][46][47][48][49][50] Sessions focused on coping with an HIV diagnosis, building condom-use skills, negotiating safer sex behaviors, avoiding drug use that might increase the risk of HIV transmission, and other topics. Compared with groups who did not receive the interventions, participants of all 6 interventions were significantly less likely to report unprotected sex acts during the 3 to 12 months after sessions ended. The magnitude of reductions varied by intervention. 29 # Condom distribution in clinical and nonclinical settings A meta-analysis of 21 studies found that programs that increased the acceptability and accessibility of condoms in several sites used by persons with HIV and persons at high risk for HIV. 51 These sites included: publicly-funded health care facilities (e.g., health clinics, mental health centers, substance abuse treatment centers), local businesses (e.g., hotels, bars, bathhouses, brothels), schools (e.g., outside classrooms and nurses' offices), and organized public events. The analysis of 20 studies reported significantly increased condom use among persons who access these sites (OR=1.81, 95% CI: 1.51, 2.17). An analysis of 5 studies found that condom distribution programs were associated with a reduced incidence of HIV and STD among persons who access these sites (OR=0.69, 95% CI: 0.53, 0.91). 51 # The cost-effectiveness of behavioral risk-reduction interventions A recent cost-effectiveness analysis evaluated 5 individual-and group-level interventions shown to reduce unprotected sex in 3 hypothetical populations of persons with HIV (MSM, heterosexual persons, and PWID). 30 The evaluation found that providing these interventions to prevent HIV transmission was cost-saving compared with not providing the interventions and that the intervention cost per new case of HIV averted for a hypothetical population of MSM (~$150,000) 30 was substantially lower than the lifetime cost of HIV treatment (>$400,000). 52 When these same estimates of intervention cost and intervention effectiveness were applied to hypothetical populations of heterosexual persons with HIV and PWID, these interventions were cost-effective in preventing HIV transmission (with a cost per qualityadjusted life year gained of ~$550 for heterosexual persons and ~$16,000 for PWID) compared with not providing the interventions. However, the intervention cost per new case of HIV averted was slightly greater than the lifetime cost of HIV treatment for both populations. 30 # The relation between sexual practices and risk of sexual transmission # Type of sexual activity Seropositioning is the practice of modifying sexual activity based on beliefs about the partner's HIV infection status and the per-act risk of HIV transmission for a given type of contact. A recent study found the estimated relative risk of acquiring HIV varies by the type of sexual activity. 8 The risk is highest for receptive anal sex, and decreases in the following order: insertive anal sex, receptive vaginal sex, insertive vaginal sex, receptive fellatio, § § § § and insertive fellatio. * (The risk associated with § § § § The practice of receiving a partner's penis in one's mouth. * The practice of inserting one's penis into a partner's mouth. cunnilingus † † † † † was not examined.) By extension, persons with HIV are most likely to transmit HIV to their uninfected partners when practicing insertive anal sex (person with HIV inserts his penis into partner's anus), followed in order by receptive anal sex (person with HIV receives partner's penis in his/her anus), insertive penile-vaginal sex (person with HIV inserts penis into partner's vagina), receptive penile-vaginal sex (person with HIV receives partner's penis in her vagina), insertive fellatio (person with HIV receives oral stimulation of his penis by partner), and receptive fellatio (person with HIV orally stimulates penis of partner). 8 Serosorting is the practice of having unprotected sex only with partners believed to have the same HIV infection status. Persons with HIV who have sex only with infected partners cannot transmit HIV to uninfected persons only if assumptions about partner infection status are correct. Serosorting among persons with HIV may rarely cause HIV superinfection, 53 the acquisition of another HIV strain that may reduce the effectiveness of HIV treatment if new, drug-resistant HIV strains are acquired. 54 Serosorting does not protect persons with HIV from acquiring hepatitis C virus infection or STDs, including STDs that may facilitate HIV transmission. 1,13,55 Practices that result in anal or genital trauma, inflammation, or bleeding Some sex toys and products that contain nonoxynol-9 (lubricants and spermicides) may occasionally cause anal or genital trauma, bleeding, irritation, or inflammation that may increase the risk of HIV transmission, especially if these products are used frequently or for long duration. 1,24,25,[56][57][58] Longstanding recommendations to inform women with HIV that unprotected sex during menses poses a potential risk of HIV transmission were based on evidence that menstrual fluid and female genital secretions may contain HIV. [59][60][61] The HIV viral load in menstrual fluids of women who have high adherence to effective ART is substantially lower than the viral load in menstrual fluids of women not taking ART. 60,61 However, plasma viral load may not reflect the HIV viral load in female genital secretions and women with HIV can shed HIV even if their plasma viral load is undetectable. 62 One nested case-control study of risk factors for prevalent HIV infection among uncircumcised Kenyan men, found that having sex with a partner during menses increased the odds of becoming HIV-infected about two-fold (OR 2.1, 95% CI: 1.1-3.7) after controlling for all other factors that were associated with prevalent HIV infection. 63 However, a longitudinal study of European HIV-discordant couples (in which either the man or woman was infected) who inconsistently used condoms did not report an association between sex during menses and HIV transmission. 64 # Use of recreational drugs before or during sex A 2012 systematic review of 61 studies among MSM with HIV found that those who used methamphetamine were more likely to engage in higher-risk sexual behaviors (e.g., having unprotected anal intercourse, group sex, sex with multiple partners, sex with casual partners, sex with PWID, sex with HIV-uninfected partners) than MSM with HIV who do not use this drug. 65 One U.S. study found that use of inhaled nitrites ("poppers") was associated with engaging in unprotected anal intercourse. 66 Several studies have shown that use of erectile dysfunction medications was associated with unprotected anal sex among MSM, including MSM with HIV. [67][68][69][70] # Male circumcision Three well-designed clinical trials in African countries found that circumcision of HIV-uninfected men reduced their risk of acquiring HIV from women by 50% to 60%. [71][72][73][74] Observational studies in heterosexual, HIV-uninfected persons have found that male circumcision reduced a man's risk of acquiring STDs that facilitate HIV transmission or acquisition (e.g., syphilis, HSV-2) and reduced a female sex partner's risk of acquiring STDs that facilitate HIV transmission or acquisition (i.e., female genital ulceration, bacterial vaginosis, and trichomoniasis) [75][76][77][78] (see Section 9, STD Services). A metaanalysis of the 7 well-designed studies conducted in African countries (1 randomized controlled trial [RCT] and 6 longitudinal analyses) found that female partners of circumcised men did not have a lower risk of acquiring HIV (RR 0.80, 95% CI 0.53-1.36). 79 Most HIV transmission in the United States occurs among MSM, most of whom practice both insertive and receptive anal sex. 70,80,81 A recent Cochrane Review conducted pooled analyses of data from 20 observational studies of MSM that included more than 65,000 participants from low-, middle-, and high-income countries, most of whom were circumcised as infants. 82 Pooled analyses of data from all MSM and the subset of MSM reporting receptive anal sex found that circumcision had no protective effect. The authors concluded that this evidence was insufficient to support a recommendation that adolescent or adult MSM undergo circumcision as an HIV prevention strategy. 82 The American Academy of Pediatrics (with endorsement by the American College of Obstetricians and Gynecologists [ACOG]), the American Academy of Family Physicians (AAFP), and the American Urological Association (AUA) stated that neonatal circumcision has potential health benefits, such as prevention of urinary tract infections, penile cancer, and some sexually transmitted infections, including HIV. [83][84][85][86] Although the AAP, ACOG, and AAFP concluded that these health benefits were not sufficient to recommend routine neonatal circumcision for health reasons, they stated that the benefits of neonatal circumcision are sufficient to justify access to this procedure, including third-party payment, for families that choose it. The AAFP and AUA have cautioned that African studies showing that circumcision substantially reduces the risk of men acquiring HIV from women with HIV may not necessarily be extrapolated to men in the U.S. The AAFP list of recommended clinical indications for adult circumcision (penile abnormalities and diseases) does not include preventing HIV acquisition. 87 The AUA recommends presenting circumcision to men in the U.S. as one possible strategy to prevent HIV acquisition that should be used with other prevention methods such as safe sexual practices. 86,87 # The role of risk-reduction interventions in promoting safer druginjection behaviors # Behavioral interventions Studies are too few to determine if behavioral interventions can promote safer drug-injection behaviors (e.g., needle cleaning) in persons with HIV who continue to inject drugs. 26 However, several studies have shown that many PWID with HIV stop injecting drugs or inject less frequently after they obtain substance use treatment. [88][89][90] # Syringe services programs Using nonfederal funds, many U.S. communities distribute sterile drug-injection equipment and/or information about the benefits of sterile syringes to PWID through syringe services programs (SSPs), ‡ ‡ ‡ ‡ ‡ outreach workers, or vending machines. 91,92 Several reviews of evidence from North America, including one systematic review conducted in the United States in 1997, found that SSPs lead to safer injecting behaviors and can be effective in reducing HIV transmission among PWID when part of comprehensive HIV prevention programs. [93][94][95][96][97][98] The Institute of Medicine's evaluation of SSPs in the United States and other countries found that SSPs were associated with reductions in drug-use and injection-related risk behaviors (such as sharing injection equipment). However, it concluded that evidence of the effect of SSPs on HIV incidence was inconclusive. 93 A study from San Francisco that included about 100 PWID, including persons with HIV, found that many PWID relied on syringes from SSPs or pharmacies that sold sterile syringes, and that PWID were more likely to share injection equipment when access to these syringe sources was limited. 99 # Legal access to syringes through physicians and pharmacists Sterile syringes are sold in pharmacies in some states to reduce the risk of transmitting HIV and other bloodborne pathogens; § § § § § some states require a physician's prescription to purchase syringes. 100,101 A CDC report concluded that physician prescribing authority may not have a large-scale, population-level impact on HIV incidence, but this method offers PWID with HIV a safe means to obtain sterile syringes. 102 A 2006 national physician survey found that fewer than 1% of participants reported prescribing syringes for PWID, including persons with HIV, but 60% reported a willingness to prescribe syringes for PWID. 100 Physicians with certain characteristics were more likely to report being willing to prescribe syringes: they served PWID, asked PWID about syringe sharing, believed that PWID share syringes because of lack of access to sterile syringes, knew that syringes were legally available in their community, and knew other physicians who prescribed syringes. 100 The effectiveness of physician prescribing authority as a strategy to promote safer injection behaviors and reduce HIV incidence has not been evaluated at a population level. # Oral opioid maintenance programs A 2011 Cochrane systematic review assessed the influence of opioid substitution programs on injection and sexual behaviors. The review evaluated 38 studies, including many from the United States, involving more than 12,000 participants. The studies consistently found that oral methadone or buprenorphine maintenance treatment by opioid-dependent PWID was associated with statistically significant reductions (i.e., 95% confidence intervals did not include 1.0) in subgroups with these characteristics 103 :  used opioids (relative risk ranged from 0.37 to 0.81)  used drug-injection equipment (relative risk ranged from 0.45 to 0.87) ‡ ‡ ‡ ‡ ‡Syringe services programs provide free, new, sterile syringes and needles in exchange for used syringes and needles to reduce transmission of bloodborne pathogens among people who inject drugs. They may be called syringe exchange programs or needle exchange programs. § § § § § At the time of the review, these activities were not supported by federal funds. Check with your state health department for latest information on funding opportunities.  shared drug-injection equipment (relative risk ranged from 0.37 to 0.49)  had multiple sex partners (relative risk = 0.37)  exchanged sex for drugs or money (relative risk ranged from 0.62 to 0.65) # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Abstinence from penetrative sexual intercourse is the most effective method to reduce the risk of sexual HIV transmission. However, many persons with HIV remain sexually active and use other methods to reduce their risk of HIV transmission after their diagnosis. [104][105][106] An analysis of 2009 surveillance data found that among about 600,000 persons with HIV with unsuppressed viral load, 20% engaged in unprotected, HIV-discordant risk behavior, ** resulting in an estimated transmission rate of 23.13%. [107][108][109] A meta-analysis of 30 U.S. studies that included more than 18,000 MSM with HIV estimated that the prevalence of unprotected anal sex was considerably higher with partners with HIV (30%, 95% CI: 25%-36%) than with partners of unknown HIV infection status (16%, 95% CI: 13%-21%) or HIV-uninfected partners (13%, 95% CI: 10%-16%). 80 Abstinence from sharing drug-injection equipment with HIV-uninfected persons is the most effective method to reduce injection-related HIV transmission but many persons who are addicted to injected drugs continue to share injection equipment after their HIV diagnosis. In 2012, an estimated 3,456 reported cases of HIV were related to injection drug use, not including cases among MSM who injected drugs. 110 Many cases occurred in areas where substance use treatment and legal sources of sterile syringes are available to PWID. Baseline data from an ongoing RCT that enrolled 1,100 HIV-infected PWID found that 39.7% engaged in both sharing drug-injection equipment and unprotected sex. 109 In 2009, 25% of the estimated 165,900 PWID with HIV had unsuppressed viral load and reported unprotected sex with persons of different HIV infection status. 109 Of the 179 cases of perinatally infected infants diagnosed in 15 areas during 2005-2008, several were born to women who became infected after having sex or sharing drug-injection equipment late in pregnancy with a person with HIV. 111 Whenever possible, most persons with HIV should receive some risk-reduction counseling from their health care providers when they start HIV medical care. Nationally representative data indicate that only about 45% of persons receiving outpatient HIV medical care reported receiving HIV prevention counseling † † † † † † from a health care provider during the preceding year. 112 Evaluations of patients receiving HIV primary care through the Ryan White HIV/AIDS Program in 9 states found that 53% of all patients and 65% of PWID reported having discussed safer sex and HIV prevention methods with their providers during their last visit. 113,114 Some clinical providers who provide HIV risk-reduction counseling at initial visits do not provide it at later visits. In one study, 60% of providers reported providing risk-reduction counseling to more than 90% of their newly diagnosed patients, but only 14% of providers reported such counseling to more than 90% of their returning patients. 115 A study of patients with HIV in 15 Ryan **** HIV-discordant risk behavior is engaging in unprotected sex or sharing drug-injection equipment with a person with a different HIV infection status. † † † † † † HIV prevention counseling is an interactive process between client or patient and counselor aimed at reducing sexual, drug-use, and reproductive behaviors that pose a risk of HIV transmission or acquisition. White-funded clinics in 12 states and Washington, DC, showed that providers reported counseling 69% of new patients but only 52% of returning patients. 116 Lack of time and staff and competing priorities are common barriers to providing risk screening and riskreduction interventions in clinical settings, community-based organizations, and health departments. 117,118 Intensive, multisession interventions are generally more effective in promoting safer behaviors among persons with HIV than brief interventions (see the Evidence topic in this section). However, intensive interventions are impractical without trained staff and dedicated space and they may appeal only to persons who will commit to attending several sessions. Some clinical providers may defer risk screening and risk-reduction interventions because they do not 1) have the needed skills or comfort, 2) believe that interventions will change behaviors, or 3) provide periodic STD screening that might identify patients with objective markers of unprotected sex. 113,115,[119][120][121][122][123] A qualitative systematic review of 30 behavioral risk-reduction interventions found that several factors enabled provision of brief or intensive risk-reduction interventions in clinical settings 28 :  Securing buy-in from clinical providers before introducing the intervention  Addressing provider attitudes and beliefs about risk reduction  Overcoming resistance from providers who are uncomfortable with risk-reduction counseling  Providing training in selected risk-reduction counseling techniques  Anticipating changes in clinic flow due to the intervention  Clarifying responsibilities of all members of the care team to provide or reinforce risk-reduction messages At least three studies found that training and decision-support tools can enhance providers' comfort, skill, efficiency, and motivation to provide risk screening and risk-reduction interventions. 120,122,124 Brief provider-or patient-administered risk-screening tools and computer-based and video-based risk-reduction interventions may be practical alternatives for both clinical and nonclinical providers when time is limited (see the Implementation Resources topic below). 26,29 By offering accurate, self-collected STD screening tests that do not require provider time for specimen collection, providers can routinely use positive test results as markers of unprotected sex (see Section 9, STD Services). Clear billing procedures, adequate reimbursement, and formal referral agreements with other providers of risk-reduction interventions also promote delivery of risk-reduction interventions. 113 The Patient Protection and Affordable Care Act (ACA) enables clinical and nonclinical providers to bill risk screening and risk-reduction services. 125 Some health departments are exploring third-party reimbursement for risk-reduction services. 126,127 # Policy, legal, and ethical considerations Laws about HIV confidentiality protections, HIV disclosure, and duty to inform others about possible HIV exposure vary by jurisdiction. Providers who are aware of these laws are better equipped to fulfill their own obligations to notify persons of possible HIV exposure and to inform persons with HIV about their rights and responsibilities regarding HIV disclosure. (See Section 3, Context of Prevention, and Section 8, Partner Services, for details on the legal and ethical issues related to HIV exposure.) In some jurisdictions, persons with HIV may hesitate to carry condoms or sterile drug-injection equipment in public settings if possessing these devices could result in charges of illegal sex work or drug use. 128,129 Laws about the distribution and prescription authority for sterile drug-injection equipment vary by jurisdiction; some states do not authorize legal access to sterile equipment through medical care providers, pharmacists, or SSPs. 130 # Implementation Resources Resources to support implementation of these recommendations are available at http://www.cdc.gov/hiv/guidelines/implementationresources.html. These include risk-screening tools, training materials, and packaged information on evidence-based risk-reduction interventions. 5 # Section 8. HIV Partner Services Background HIV partner services comprise an array of voluntary services intended to reduce HIV transmission. They are provided to 1) persons with HIV (described as index patients) who have been newly diagnosed in clinical settings † or nonclinical settings; ‡ represent a case of infection that is reported to health departments; or have been previously diagnosed and also pose a high risk of exposing others to HIV (e.g., a recently diagnosed STD that indicates unprotected sex § or may facilitate HIV transmission or sharing drug-injection equipment); and 2) their sex and drug-injection partners. The core components include interviewing persons with HIV to obtain information to contact or locate their sex and druginjection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted disease (STD), and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. 1 This proactive approach can hasten the diagnosis of HIV and other infections; can prompt treatment before symptoms appear; and can reduce the transmission, burden, and costs of these communicable diseases in communities. Reporting of cases of HIV, syphilis, gonorrhea, and chlamydial infection † † is required in all states, the District of Columbia, and U.S. territories. 2 In many jurisdictions, receipt of a laboratory or clinical case report of HIV or STD by a health department or its HIV or STD surveillance program will activate a health department's legal authority to provide partner services. 1 Cases of HIV identified at anonymous testing sites cannot be reported by name to health departments. Most health departments initiate HIV partner services after receiving reports of confirmed cases of HIV. However, some may initiate contact with "presumptive" index patients upon receiving reports of positive preliminary test results 3,4 but defer notifying partners until additional testing of the index patient confirms HIV infection. Health departments can adopt this practice if they apply the 2014 Centers for Disease Control and Prevention (CDC) revised HIV surveillance case definition that allows routine reporting of positive preliminary HIV test results before confirmatory test results are available. 5 CDC's revised surveillance case definition also recommends routine reporting of cases of acute infection diagnosed by HIV antigen or nucleic acid amplification tests. 5 In states that adopt this case definition, health departments can rapidly identify acutely infected persons who are likely to be highly infectious and who warrant being offered expedited partner services. Some clinical and nonclinical providers contact health department partner services A person with diagnosed HIV or STD and whose diagnosis prompts an investigation to identify other persons (known as partners) who may have become infected through sexual contact or exposure to blood or other body fluids of the index patient. † Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginal-digital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). Drug-injection equipment includes needles and syringes; drug preparation equipment, such as cookers, mixing containers, spoons, and filters; swabs; and water or some other liquid used for preparing a drug solution or for rinsing drug equipment. † † Another document describes partner services that are prompted by the diagnosis of bacterial STD in index patients who are not infected with HIV. 1 specialists immediately after they identify persons with positive HIV tests-particularly persons with acute infection-rather than wait for receipt of a surveillance case report to activate partner services. 1,3,4,6 In the United States, most HIV partner services are provided by health department partner services specialists who are highly trained in providing voluntary, confidential partner services and can be engaged through routine case reporting, provider referral, and requests by persons with HIV. 1 Nevertheless, methods of delivering partner services may vary by jurisdiction. Partner elicitation ‡ ‡ can be done by health department specialists, HIV testing providers, and other clinical or nonclinical providers who are trained and authorized to conduct partner elicitation. 1,6 Partner notification § § can be performed by health department specialists; physicians; nurse practitioners, and physician assistants who work under the authority of a physician; other clinical and nonclinical providers who are trained and authorized to provide partner notification; and index patients. 1 Some jurisdictions use hybrid methods in which 1) trained clinical providers or nonclinical HIV testing providers elicit partner information from index patients, but defer partner notification to health department specialists; 2) index patients give partner contact information to health department specialists, who in turn notify the partners; 3) index patients and health department specialists or other providers jointly notify the partners; and 4) index patients make verbal contracts with health department specialists to notify partners within a specific time frame, and if this fails, the specialists attempt to notify partners. [7][8][9] Health department partner services are voluntary and confidential and usually involve no cost to index patients or partners; specialists notify partners of possible HIV exposure without revealing the index patient's name or other potentially identifying information. 1 These specialists contact index patients and partners by phone, letter, email, or text message or in person at HIV testing sites, HIV clinical settings, STD clinics, homes, or other community settings where private communication is possible. In some health departments, specialists also use "screen names" or other information provided by index patients to contact partners who were found through Internet dating sites, "chat rooms," mobile device applications, or social networking* tools. 1,3,10 Specialists may also help index patients use Internet † † † or social media sites to directly notify partners about possible HIV exposure. 11 In a national survey of 57 state or local health departments, two-thirds reported using Internet-based partner notification. 9 Because partner services specialists routinely offer HIV testing to partners, they offer a form of targeted, community-based HIV screening for persons at high risk for HIV. Some partner services programs offer venue-based HIV testing in sites frequented by index patients or partners. 1 They also use social network ‡ ‡ ‡ or "cluster" approaches in which health department specialists encourage index patients or partners to recruit friends, family members, or others for HIV testing. 1 In some cases, specialists will actively link ‡ ‡ Partner elicitation is an early step of voluntary, confidential partner services in which a health department partner services specialist or other provider interviews or reinterviews a person with HIV or STD to collect names, descriptions, and locating and contact information of persons who are sex or drug-injection partners so the partners can be notified of possible HIV or STD exposure. § § Partner notification is a step of voluntary, confidential partner services that involves locating and confidentially notifying sex and druginjection partners of persons infected with HIV or STD of possible exposure to HIV or STD. * Social networking is a strategy to recruit persons for HIV testing or prevention services in which high-risk individuals use their personal influence to recruit peers they believe are at high risk for HIV infection. index patients or partners with HIV to HIV medical care. 12,13 In addition, some health care providers provide HIV testing to partners who are referred by their patients with HIV. 6 This section addresses partner services prompted by a diagnosis of HIV or the diagnosis of an STD in a person previously diagnosed with HIV. Other federal guidance describes partner services for HIVuninfected persons diagnosed with STDs. 1 Quality improvement § § § and program monitoring and evaluation can determine if the services described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 9, STD Services, provides more information about STD screening, treatment, and counseling of index patients and management of partners. Section 5, Antiretroviral Treatment, describes the use of nonoccupational postexposure prophylaxis (nPEP) † † † † for HIV-uninfected partners with very recent HIV exposure, and preexposure prophylaxis (PrEP) ‡ ‡ ‡ ‡ for HIV-uninfected partners at substantial risk for acquiring HIV infection. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. # Recommendations Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. † † † † nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposure to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. ‡ ‡ ‡ ‡ PrEP is the daily, continuous use of a specific regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 14 # BOX 8. RECOMMENDATIONS-HIV PARTNER SERVICES (cont)  Newly diagnosed sexually transmitted diseases (STDs) that indicate recent unprotected sex (i.e., sexual activity without using a physical barrier) and facilitate HIV transmission-primary and secondary syphilis; gonorrhea and chlamydial infection (including rectal infection); herpes simplex virus type 2 (HSV-2); and trichomoniasis (in women) c  Increased risk of HIV transmission due to pregnancy d  Behaviors that pose a high risk of exposing others to HIV (e.g., multiple, anonymous partners; having unprotected sex with persons with negative or unknown HIV-infection status; sharing drug-injection equipment) e  A specific request for partner services  Ask index patients if they have disclosed their HIV infection to all sex and drug-injection partners and if selfnotification would pose any risks (i, ii, v)  Promptly refer index patients to health department partner services directly or through HIV case reporting according to the methods of the jurisdiction (i, ii, iii, iv, v, In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. In this section, recommendations for health department partner services specialists are listed separately from recommendations for other nonclinical providers because state and local laws and regulations influence their roles and responsibilities. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education and counseling; disease screening, diagnosis, and treatment; and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Most states authorize physicians to provide partner services as part of their duty to inform persons of possible exposure to HIV or STD. Some jurisdictions authorize other clinical providers to provide partner services because they work under the authority of a physician (e.g., nurse practitioners and physician assistants) or have been trained and authorized by health departments to provide partner services. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. # BOX 8. RECOMMENDATIONS-HIV PARTNER SERVICES (cont) a See Section 3, Context of Prevention, for more information on HIV disclosure. b Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. c See Section 9, STD Services, for more information on STDs that may facilitate HIV transmission. d See Section 11, Pregnancy, for more information on how pregnancy influences HIV transmission. e See Section 7, Risk Screening and Risk Reduction, for more information on risk behaviors. f See Section 13, Quality Improvement, for more information. # Sources # General principles (i, ii)  Inform index patients and partners referred by index patients that partner services  have potential benefits and risks  are voluntary and confidential  can be provided in several ways, including through health department specialists  Consider various methods to notify partners based on the preferences of index patients and their partners' characteristics (e.g., found through the Internet, risk of adverse reaction), including self-notification and assistance from health departments and providers  Protect the confidentiality of the index patient and partners and the privacy of their health information a  Communicate in a nonjudgmental, culturally appropriate, and sensitive manner  Monitor and adhere to changes in jurisdiction regulations that may affect partner services, especially these issues:  Any duty of index patients or providers to inform spouses or other persons of possible HIV exposure a  Intimate partner violence, sexual assault, or child or elder abuse when index patients or partners report abuse or when abuse is suspected a  Rights of minors a # Services for index patients  Offer voluntary, confidential partner notification assistance through health department partner services specialists and explain the notification process, the role of health department specialists, and confidentiality protections (i, iii, iv, v, vi)  If the index patient accepts health department partner notification assistance, the health department specialist should take the following steps (i, iii):  Explain the rationale for notifying partners of possible HIV exposure (i.e., partners who had contact with the index patient in the 12 months before HIV diagnoses), with priority given to partners who had contact during the 3 months before HIV diagnosis or during the previous month if the index patient has acute HIV infection or high viral load  Ask the index patient which sex and drug-injection partners have already been notified of possible HIV exposure  Collect contact and other information, using CDC-recommended methods, about sex and drug-injection partners who have not been notified b  Collect information about physical venues and Internet sites frequented by the index patient or members of his or her social network if using venue-based or social network HIV testing methods  Assess barriers and risks to partner notification for each named partner (e.g., physical or verbal abuse), offer advice and services to reduce this risk (e.g., describe measures to prevent partner violence), and defer notification if a risk is apparent  Notify the index patient's partners using CDC-recommended methods b  Recognize that some index patients prefer to self-notify some partners but request assistance to notify other partners  If the index patient declines referral to health department partner services by a nonclinical or nonclinical, the provider should take the following steps (i, iii, iv, vi):  Help the index patient develop a plan to notify partners directly or with provider assistance, as allowed by the jurisdiction  Offer assistance in testing partners for HIV, STDs, and viral hepatitis c,d,e # Box 8-B. Essential elements of HIV partner services (cont)  If the index patient seeks partner notification assistance from a nonclinical or clinical provider who is trained and authorized to provide partner services, the provider should take these steps (i, iii, iv):  Explain the rationale for notifying partners of possible HIV exposure (i.e., partners who had contact with the index patient in the 12 months before HIV diagnoses), with priority given to partners who had contact during the 3 months before HIV diagnosis or during the previous month if the index patient has acute HIV infection or high viral load  Ask the index patient which sex and drug-injection partners have already been notified of possible HIV exposure  Collect contact and other information, using CDC-recommended methods, about sex and drug-injection partners who have not been notified  Assess barriers and risks to partner notification for each named partner (e.g., physical or verbal abuse), offer advice and services to reduce this risk (e.g., describe measures to prevent partner violence), and defer notification if a risk is apparent  Notify the index patient's partners using CDC-recommended methods as appropriate to legal authority and skills b  Recognize that some index patients prefer to self-notify some partners but request assistance to notify other partners  If the index patient chooses to self-notify any partner without assistance, the provider should describe (i, iii, iv, vii):  Possible challenges of self-notification, such as partner violence, and discourage self-notification if a risk is apparent  Self-notification methods for known partners (e.g., in person) and anonymous partners (e.g., established Internet notification programs)  Methods to improve the effectiveness of self-notification (e.g., focus on partners over the previous 3 months or, if diagnosed with acute HIV infection or high viral load, focus on partners over the previous month; use a private, safe setting; anticipate and respond to negative partner reactions; seek provider assistance if questions arise)  Key messages for partners (e.g., how to obtain HIV, STD, and viral hepatitis testing and evaluation in facilities that link partners with positive tests to health care providers or to home HIV testing if the partners decline other testing options) c,d,e  If the index patient declines any partner services through the health department, provider or self-notification, re-offer partner services at the next encounter and/or notify the HIV care provider serving the index patient that partner services should be offered at the HIV care visit, when appropriate (i)  Regardless of the partner notification method, the provider should promptly offer index patients the following prevention and care services onsite or through linkage, if not recently provided:  HIV medical care c (i, iii, iv, vi, viii, ix)  STD and viral hepatitis testing, evaluation, treatment, vaccination, and counseling c,d,e (i, iii, vi)  Risk-reduction services and devices (e.g., behavioral information, counseling, risk-reduction interventions, latex or polyurethane condoms) f,g (i, iii, iv, vi, ix)  Information about the availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition h,i (i, x, xi)  Other medical or social services that influence HIV transmission (e.g., substance use treatment, mental health services) j (i, iii, iv, vi, ix) # Box 8-B. Essential elements of HIV partner services (cont) Services for sex and drug-injection partners  Notify the partner about possible HIV exposure (and STD exposure if the index patient is coinfected with STD) without disclosing the identity of the index patient, using CDC-recommended methods (i, vi, viii)  Provide information about HIV, STD, and viral hepatitis infections (i, vi)  Promptly offer the following services onsite or through linkage:  HIV testing if the partner is not known to be HIV-infected (followed by verification of test results) k (i, iii, iv, ix) 16,17 The updated recommendations in this section are consistent with 2008 CDC recommendations for partner services 1 and other current federal guidance about partner services. 6,14,[18][19][20][21][22] They are also consistent with the latest comparable guidance about notifying partners of patients with HIV from the International Antiviral Society-USA Panel. 23 They are also generally consistent with guidance about 1) social network, cluster, and Internet-based partner notification methods; 2) integrating and matching HIV and STD surveillance data to identify index patients eligible for partner services; and 3) collaborations among health departments, community-based organizations, and health care providers from the National Network of STD/HIV Prevention Training Centers, 9 the National Coalition of STD Directors, 10 and the National Alliance of State and Territorial AIDS Directors. 24 Compared with the 2003 Recommendations, 15 these updated recommendations  advise that health department specialists provide partner services whenever possible because of evidence that these specialists provide more efficient, effective, and cost-effective services than other providers  stress building relationships between health departments and HIV testing, prevention, and health care providers (especially those serving a large number of persons with HIV) to expedite partner services to index patients who have been newly diagnosed with HIV or are at high risk of exposing others to HIV  advise expediting interviews of index patients with laboratory or clinical evidence of acute HIV infection § § § § who may be highly infectious  stress actively helping index patients and partners with positive HIV tests to start or resume HIV medical care  advise informing index patients about the availability of PrEP and nPEP for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition  encourage health departments to consider using innovative methods to locate and notify partners (e.g., Internet)  # Methods The section writing group based most of these recommendations on the 2008 CDC recommendations for partner services that were based on a systematic literature review and expert opinion (that the writing group did not reexamine). 1,25 26 a review of Internet-based partner notification, 27 evidence-based guidance on partner services from an expert panel on community-based preventive services in the United States, 28 and 2 studies of the cost-effectiveness of HIV partner services. 29,30 # Evidence Supporting the Recommendations The literature review yielded new evidence about the relative effectiveness of health department partner services, the benefits of timely partner services, new methods to notify partners, and the costeffectiveness of partner services. Several studies confirmed earlier findings that health department partner services specialists contacted more partners with unrecognized HIV infection per index patient than other types of partner services providers. [31][32][33][34] Specialized training and field experience may enable health department specialists to elicit more accurate information about partners from index patients 35 and to identify more partners per index patient. 31 In contrast, several studies indicate that many health care providers or HIV testing providers § § § § Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. may not 1) understand health department partner services procedures; 2) routinely advise patients to notify their partners about possible HIV exposure; 3) routinely refer patients for health department assistance; or 4) have the skills or time to elicit, notify, or manage partners. 31,[36][37][38] Some providers do not inform persons newly diagnosed with HIV that case reporting required by health care providers and laboratories may activate health departments to offer partner services. 1 Several recent studies found that assigning health department specialists to work in clinics, hospitals, and private medical practices that provide a high-volume of HIV testing were more effective than traditional, offsite partner services. 3,12,37,39,40 Assigning health department specialists to work in testing sites can also increase the proportion of index patients who receive partner services and shorten the interval between diagnosis and interview. This approach can also increase the proportion of partners who were located, were newly diagnosed with HIV infection, and obtained treatment. 3,12,39,40 Some health departments routinely use HIV surveillance data to identify persons with acute infection or routinely integrate or match HIV and STD surveillance systems to identify HIV-infected persons who have new STD diagnoses and warrant being offered expedited interviews. [41][42][43][44][45] Surveys of state and city health departments indicate that partner services programs that routinely access name-based HIV case reports and surveillance data can serve a higher proportion of index patients than health departments without such access. 9,46 Several studies found that partner services were more productive when they were offered to persons shortly after their HIV diagnoses or to persons diagnosed with acute HIV infection. 34,[47][48][49] A small study in San Francisco evaluated the effort to find 1 newly identified HIV-infected partner; health department partner services specialists had to interview only 8 HIV-infected index patients if their interviews occurred within 2 weeks after diagnosis, but had to interview 21 HIV-infected index patients if their interviews occurred more than 2 weeks after diagnosis (p=0.008). 48 A study in North Carolina compared interview outcomes of persons with acute HIV infection and persons with established infection: persons with acute infection named 2.5 times more partners (95% confidence interval: 2.1 to 3.0) and named 1.9 times more partners who were newly diagnosed with HIV infection (95% confidence interval: 1.1 to 3.5). 34 A study in 2 large cities evaluated partner notification services for 48 persons with acute HIV infection; 23 of the 72 named partners underwent HIV testing and 5 (21.7%) had positive test results. 49 A study in New York City found that after health department partner services specialists began to offer rapid, point-of-service HIV testing to partners, the proportion of partners who underwent testing rose from 52% to 76% (p<0.001) and the program identified more than twice the number of partners with newly diagnosed HIV infection than it had before rapid testing started. 50 At least 5 recent evaluations examined partner notification using electronic technologies. Three evaluations assessed ecards (using inSPOT software) sent by index patients to notify partners as a means to supplement traditional partner notification. Although most evaluations used indirect methods to estimate partners' receipt of ecards or to estimate follow-up HIV testing (because they did not know the identity of ecard recipients), these evaluations found that awareness and use of inSPOT was limited and resulted in few partners obtaining HIV testing. 27,51,52 A few studies evaluated the acceptability of Internetbased partner notification. One found that gay, bisexual, or other men who have sex with men (MSM) were willing to receive or initiate emails about partner notification, regardless of their HIV infection status. 53 The investigators concluded that health departments considering Internet methods should use culturally sensitive social marketing campaigns to increase awareness and acceptability of these methods. A study of MSM found that responders would be less likely to seek care and to notify partners if notified by anonymous ecards than if notified directly by their partner. 54 Studies in 2 states evaluated the cost and effectiveness of partner services programs that included counseling and rapid HIV testing. 30 When fixed program costs were excluded, the estimated cost per partner notified of a new HIV diagnosis was $11,626 in Colorado and $2,545 in Louisiana. A costeffectiveness analysis assessed a set of partner services provided by health department specialists to 3 different hypothetical populations: MSM, persons who inject drugs (PWID), and heterosexuals. The services included HIV testing, referring HIV-infected partners to HIV care, and behavioral risk-reduction information. 29 These partner services were cost-saving compared with no intervention. Moreover, the intervention cost per new case of HIV averted in a partner (ranging from ~$116,000 for MSM, ~$263,000 for PWID, and ~$349,000 for heterosexuals) was lower than the lifetime cost of HIV treatment (>$400,000). 55 Other sections of this report cite evidence that supports recommendations about PrEP and nPEP (Section 5, Antiretroviral Treatment) and STD screening and treatment (Section 9, STD Services). # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities A 2006 survey of more than 51 health departments in the United States found that 43% of persons with newly reported HIV infection received health department partner services; this was a significant increase from the proportion reported in a 2001 health department survey (32%). 46 According to a survey and interviews of staff of health departments from 51 states/territories and 6 large cities published in 2008, * health departments offered partner services to 47% to 79% of index patients with HIV. 9 Health department partner services programs serving jurisdictions with low HIV morbidity and name-based HIV reporting were more likely than programs serving jurisdictions with high HIV morbidity without namebased reporting to report routinely use HIV surveillance to activate partner services, serve index patients diagnosed in private health systems, and notify a high proportion of partners. Many survey respondents reported that high caseloads in high-morbidity areas and unlinked or incompatible HIV surveillance and partner services information systems hindered partner services. In general, persons diagnosed with HIV in public-sector clinics and HIV testing sites affiliated with health departments are more likely to receive health department partner services than persons diagnosed elsewhere. 56 These public-sector sites are more likely to routinely refer index patients to health department partner services specialists or to invite these specialists to work onsite. To increase use of partner services, some health departments have marketed their services to private-sector HIV testing providers or assigned partner services specialists to work in large HIV care practices. 1,9,12,39,57 Since the passage of the Patient Protection and Affordable Care Act, some health departments are exploring thirdparty reimbursement to enhance program capacity. 9,58 *** Most recent nationally reported data is available at http://www.cdc.gov/hiv/library/reports/evaluation.html. Although partner services can benefit all persons with HIV, high caseloads or staffing shortages force most health departments to prioritize the order of interviewing index patients and partners. 1 Most health departments expedite interviewing of index patients who have newly reported and newly diagnosed HIV infection. The 2014 CDC revised HIV surveillance case definition recommends that laboratories and HIV testing providers report cases of acute HIV infection or preliminary positive HIV test results to expedite partner services. 5,59 Some health departments also expedite interviewing of index patients with established HIV infection who have been recently diagnosed with STD (particularly infectious primary or secondary syphilis and rectal gonorrhea among MSM). Patients who are coinfected with HIV and STD are easier to identify if HIV surveillance and STD surveillance systems are integrated or routinely matched. 3,42 # Policy, legal, and ethical considerations Well-implemented partner services balance the interests of infected persons, their partners, and the community. Because partner services are voluntary and confidential, it is unethical to coerce, deceive, or withhold information from index patients when attempting to elicit partner information or notify partners. Index patients who feel pressured to provide partner information may not provide accurate partner information. Several studies show that most persons with HIV, their partners, and their health care providers accept partner services, including the involvement of health departments and Internet-based partner notification, and consider partner services a valuable service rather than an imposition. 53,[60][61][62] Developing standard referral procedures and interagency agreements that protect confidentiality may improve the acceptability of partner services and improve communication and collaboration between HIV testing providers and health departments 1,9,10 (see the Implementation Resources topic below). State and local laws and public health regulations generally protect the confidentiality of all HIV and STD information, including information obtained from or about index patients. 1 Persons who fear that partner notification might cause stigma; provoke physical or verbal abuse; harm relationships; or expose illegal activity may choose confidential partner notification (that does not reveal the identity of the index patient) over self-notification. [63][64][65][66] Confidentiality is subject to practical limits when a person has a single, identifiable partner and when couples seek joint HIV testing and post-test counseling. Although there is growing interest in couple-based HIV testing and counseling after joint consent, some providers hesitate to offer this service because of concerns about violating HIV-related confidentiality protections. 67,68 Despite the longstanding practice of confidential health department partner services, some clinicians, HIV testing providers, and persons with HIV may be unaware of or doubt these confidentiality protections. Some individuals and communities do not favor health department access to personal health information for public health purposes because they distrust public health authorities or fear the information might be stigmatizing, provoke negative partner reactions, or have legal ramifications. 1,62,69,70 Nevertheless, real or perceived breaches of confidentiality during provision of partner services appear to be rare. Several studies conducted from the late 1990s to 2011, most of which involved heterosexual partners, found that the risk of violence due to partner notification was low [71][72][73][74] and that partner notification itself did not increase rates of partnership dissolution. 62,71,75 Some jurisdictions have laws that require or allow public health officials or health care providers to notify partners who may have been exposed to HIV infection, even when index patients object. 1 Persons who misunderstand these laws may believe that all partner notification is mandatory or nonconfidential. To minimize negative attitudes about partner services, providers can reassure index patients that partner services are strictly voluntary and confidential, are usually provided at no cost to index patients and partners, and are deferred if there is a risk of partner retribution. Section 3, Context of Prevention, and Section 9, STD Services, provide further information on policy, legal, and ethical aspects of partner services. # Special populations Some adolescents, undocumented immigrants, sexual assault survivors, prisoners, and other vulnerable or medically marginalized persons with HIV may resist health department partner services. Adolescents who do not know that these services are confidential, voluntary, and do not require parental consent in many states may appreciate careful explanations of consent and confidentiality procedures. Immigrants may believe that partner services conflict with their cultural norms or may prompt deportation or other legal action. Some immigrants may require partner services information in their own language. 1 Rapid, pointof-care HIV testing is useful when screening transient partners, such as migrant workers 1 (see Section 12, Other Medical and Social Services). # Section 9. Sexually Transmitted Disease (STD) Preventive Services Background Sexually transmitted diseases (STDs), also known as sexually transmitted infections (STIs), are infections transmitted through penile, vaginal, oral, or anal sexual contact, regardless of the presence of symptoms or signs. 1 In this section, STD preventive services for persons with HIV are defined as the following: assessment of behavioral and biological factors that may increase the risk of transmitting HIV or STD; sexual risk-reduction interventions; screening asymptomatic persons for STD pathogens; clinical evaluation (including physical examination and diagnostic testing* of persons with STD signs or symptoms); treatment; and partner services. † STD preventive services are an essential component of HIV prevention because 1) the diagnosis of an STD is an objective biologic marker of unprotected sexual activity that may result in HIV transmission; 2) certain STDs may increase plasma HIV viral load and genital HIV shedding, which may increase the risk of sexual and perinatal HIV transmission; and 3) STD treatment may reduce STD-related morbidity and lower the risk of HIV transmission. 1 The vast majority of STD preventive services are provided in health care facilities. However, some nonclinical settings, ‡ such as intake units of correctional facilities and residential job-training sites, schools, and community-based organizations, offer risk assessments, risk-reduction interventions, screening, and subsequent linkage § to treatment and partner services. 2 STD preventive services in nonclinical settings may be more convenient for populations who have limited or irregular access to health care. To be effective, nonclinical STD services must ensure prompt linkage of persons who have had STD symptoms, positive screening tests, or sexual contact with a partner treated for an STD to health care providers for examination and treatment and to health departments for voluntary, confidential partner services. 2 Self-collected specimens can be used to screen for some pathogens (i.e., chlamydial infection or gonorrhea using nucleic acid amplification tests [NAAT] tests) when requested by a physician or a nonclinical provider working under a physician's order. These specimens can be obtained at "express visits" in STD clinics, community-based organizations that offer HIV testing or risk-reduction services, or at home. Self-collected specimens collected in nonclinical * Testing that is initiated for a person with clinical signs or symptoms to obtain objective evidence of the presence or absence of diseases or infections. † Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). settings must be tested in laboratories that have validated procedures specified by the Clinical Laboratory Improvement Act (CLIA) for testing specimens obtained in nonclinical settings. [3][4][5] Health departments are responsible for population-level STD prevention and control programs. These programs include STD case reporting and surveillance, outbreak detection and control, prevention services for persons with STD and their sex partners to stem onward transmission, assurance of STD preventive services in clinical settings,** screening programs in nonclinical settings, antimicrobial drug resistance monitoring, provider and community education, and health promotion activities. This section focuses on preventive services for 5 STDs that may increase the risk of transmitting HIV: syphilis, gonorrhea, chlamydial infection, and herpes simplex virus type 2 (HSV-2) in men and women and trichomoniasis in women. 1 This section does not provide comprehensive recommendations about STD preventive services for persons with HIV. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. § § Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont) # Specific to clinical providers (in addition to above recommendations)  At initiation of HIV medical care, provide all persons with HIV the following services:  Detailed sexual history, including number and gender of sex partners; types of sexual practices; anatomic sites of sexual contact; condom use; previous STD screening, testing, diagnoses, and treatment; and recent sex partners who have had STD symptoms or treatment b (i, iii)  Detailed history of alcohol and substance use b (i, iii)  Detailed history of recent STD-related symptoms (e.g., urethral, vaginal, or anal discharge; dysuria; abnormal vaginal or rectal pain or bleeding; genital, perianal, or oropharyngeal exudate, sores or bumps; skin rash) (i, iii)  STD screening tests d,f (i, iii) (see Box 9-A)  Physical examination for signs of STDs, including skin, oral, anal, genital, and gynecologic examinations for women and skin, oral, anal, and genital examinations for men (i, iii)  Diagnostic testing for STD if persons have STD signs or symptoms f (i, iii)  For persons with HIV who report sexual or drug-injection risk behaviors, provide the following services: • Provide or refer to brief or intensive behavioral risk-reduction interventions b (i, ii, iii, v, vi) • Refer to voluntary health department HIV partner services or other trained partner services provider if persons are newly diagnosed with HIV; have evidence of acute HIV infection or high HIV viral load; or report new sex partners h (i, ii, iii, iv, v)  For persons with HIV who have a clinical evaluation indicative of STD or positive screening or diagnostic STD tests, or recent sex partners who have had STD symptoms or treatment for syphilis, gonorrhea, or chlamydial infection, provide the following services: • Provide oral or injectable STD treatment onsite, including presumptive treatment i (while awaiting STD test results) when indicated, according to the latest CDC STD Treatment Guidelines (i, iii, vi, vii) • Advise to return 3 months after treatment for gonorrhea, chlamydial infection, or trichomoniasis to obtain retesting for the relevant infection at the anatomic site of infection k (i, iii) (see Box 9-A) • Advise persons diagnosed with syphilis to return for follow up serologic testing according to latest CDC recommendations k (i) (see Box 9-A) • Provide or refer for brief or intensive behavioral risk-reduction interventions b (i, iii, vi) • Refer to voluntary health department HIV/STD partner services or other trained partner services provider h (i, iii, iv) • Report cases of STD according to jurisdiction requirements and inform persons diagnosed with STD that case reporting may prompt health departments to offer voluntary, confidential partner services in some jurisdictions j (i, iii) # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont)  At follow-up HIV care visits, provide all persons with HIV the following services:  Review of sexual, alcohol, and substance use histories since last visit to determine if behavioral riskreduction interventions are warranted b (i, iii)  Review of STD symptoms since last visit and recent sex partners who have had STD symptoms or treatment to determine if STD testing, physical examination, or treatment is warranted (as described above at initiation of HIV care) (i, iii)  STD screening at least annually or more often if indicated by sexual risk behaviors d,f (i, iii) (see Box 9-A)  Review of sex partners who were not notified of possible HIV or STD exposure to determine if offering HIV partner services is warranted h (i, iii)  For persons with a positive STD test; STD symptoms or signs; or recent sex partners who have had STD symptoms or treatment for syphilis, gonorrhea, chlamydial infection, or trichomoniasis or experiencing STD symptoms, provide the following services: • Provide oral or injectable treatment onsite according to the latest CDC STD Treatment Guidelines (including presumptive treatment (while awaiting STD test results) if indicated because of STD symptoms, or recent sex partners who have had STD symptoms or treatment) i (i, iii, vi, vii) • Advise to return 3 months after treatment for gonorrhea, chlamydial infection, or trichomoniasis to obtain retesting for the relevant infection at the anatomic site of infection k (i, iii) (see Box 9-A) • Advise persons diagnosed with syphilis to return for follow up serologic testing according to latest CDC recommendations k (i) (see Box 9-A) • Provide or refer to brief or intensive behavioral risk-reduction interventions b (i, iii, vi) • Refer to voluntary HIV/STD partner services at health department or other trained partner services provider h (i, iii, iv) • Report cases of STD according to jurisdiction requirements and inform persons diagnosed with STD that case reporting may prompt health departments to offer voluntary, confidential partner services in some jurisdictions j (i, iii) For staff of health departments who provide population-level HIV prevention and care services  Develop methods to integrate or routinely match HIV and STD surveillance case reports and use these surveillance data to routinely identify populations or individuals with HIV who have new STD infections and may warrant being offered HIV and STD preventive services, including voluntary partner services (iv, viii)  Support efforts to promote STD and HIV prevention for persons with HIV in community (i, iv, viii) (see Box 9-B) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/. # BOX 9. RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES (cont) a Some of the cited source guidance that supports this recommendation was intended for clinical providers and partner services specialists. Based on program experience in the United States, the section writing group concluded that it would be beneficial and feasible for some nonclinical HIV prevention providers to implement this recommendation. b See Section 7, Risk Screening and Risk Reduction, for information on assessing behavioral and biologic factors that may influence risk of HIV transmission and risk-reduction interventions. Assessment of behavioral and biologic risks factors is recommended at initial and subsequent visits in clinical settings providing continuing care. In clinical or nonclinical settings that provide one-time or episodic STD services, assessment is recommended at initial encounter and when clients seek follow-up services; recalling clients specifically for risk assessment may not be feasible. c In this section, the term "assess" means eliciting information about behavioral and biologic risk factors for HIV transmission, including history of STD and STD symptoms, and the term "screen" means testing for STD pathogens in persons without symptoms. In other sections, the term "screen" means a brief assessment of behavioral and biologic risk factors for HIV, including history of STD, and STD symptoms that differs from an intensive, individually tailored assessment of these factors; and the phrase "STD screening tests" means testing to assess the presence of infection. d This section does not address screening persons with HIV for other conditions that have not been shown to facilitate HIV transmission to others, such as viral hepatitis and human papillomavirus infection. e See Section 4, Linkage to and Retention in Care. According to the latest CDC STD Treatment Guidelines, 1 immediate presumptive treatment (or immediate linkage to such treatment) is recommended for persons who report sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis or have STD syndromes in order to reduce the risk of onward STD transmission. STD syndromes are conditions that can be caused by sexually transmitted pathogens and that cause symptoms or abnormal findings (signs) on physical examination, such as genital ulcer disease, urethritis, cervicitis, pelvic inflammatory disease, epididymitis, and proctitis. j Information in the Policy, Legal, and Ethical Considerations topic in this section supports this recommendation. k The cited source guidance describes the rationale for retesting for syphilis, gonorrhea, chlamydial infection; the Evidence topic describes the rationale for retesting for trichomoniasis.  Urogenital N. gonorrhoeae (using nucleic acid amplification tests [NAATs] on urine specimen) a,b (i, ii, iii)  Urogenital C. trachomatis (using NAAT on urine specimen) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv) For gay, bisexual and other males who have sex with men (MSM), regardless of condom use  Provide these additional screening tests at initial visit (or encounters in nonclinical settings that offer STD screening tests) and at least annually* thereafter a,d  Rectal N. gonorrhoeae (using NAAT) if person reports receptive anal sex (i, ii, iii)  Rectal C. trachomatis (using NAAT) if person reports receptive anal sex (i, ii, iii)  Oropharyngeal N. gonorrhoeae (using NAAT) if person reports receptive oral sex (i, ii, iii) * More frequent screening at anatomic sites of exposure (i.e., every 3-6 months) is indicated for MSM whose risk behaviors persist or have multiple or anonymous sex partners. (i, iii) For males diagnosed with syphilis or treated for gonorrhea or chlamydial infection  Retest persons diagnosed with syphilis using serologic tests recommended by CDC c (i)  Retest persons treated for gonorrhea or chlamydial infection for the relevant infection at the anatomic site of infection 3 months after treatment a,b,d (i, iii) # For all females  Provide the following tests at initial visit (or encounters in nonclinical settings that offer STD screening tests) and at least annually thereafter:  Urogenital N. gonorrhoeae (using NAAT) a,b (i, ii, iii)  Urogenital C. trachomatis (using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv)  Vaginal trichomoniasis test e,f (i, iii) For all pregnant females f  Provide the following tests at the first prenatal visit:  Urogenital C. trachomatis (using NAAT) a,b (i, ii, iii)  Urogenital N. gonorrhoeae (using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv)  Provide the following tests at the beginning of the third trimester for women at risk for STD g :  Urogenital C. trachomatis (preferably using NAAT) a,b (i, ii, iii)  Urogenital N. gonorrhoeae (preferably using NAAT) a,b (i, ii, iii)  Syphilis serology c (i, iii, iv) For females diagnosed with syphilis or treated for gonorrhea, chlamydial infection, or trichomoniasis  Retest persons diagnosed with syphilis using serologic tests recommended by CDC c (i)  Retest persons treated for gonorrhea or chlamydial infection for relevant infection at the anatomic site of infection 3 months after treatment a,b,e,h (i, iii)  the local burden of STDs  characteristics of persons with HIV at greatest risk for STD infection and HIV-uninfected partners at risk for HIV (e.g., MSM diagnosed with STD, especially infectious syphilis and rectal gonorrhea or chlamydial infection; young men of color; transgender persons)  the role of STD preventive services in clinical and nonclinical settings for HIV prevention  Increase access to routine behavioral risk-reduction services, STD screening services, and latex or polyurethane condoms in clinical and nonclinical settings  Increase the capacity of laboratories to screen rectal and oropharyngeal specimens for N. gonorrhoeae and C. trachomatis using NAATs and to monitor gonococcal antimicrobial drug resistance trends using culture tests # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with current federal guidance about STD risk assessment, screening, and treatment, and HIV and STD partner services for persons with HIV published through April 2014. 1,4,7,[10][11][12][13][14] They are also consistent with most of the latest comparable recommendations about STD services for persons with HIV of the HIV Medicine Association of the Infectious Diseases Society of America 15 and the International Antiviral Society-USA Panel. 16 This report updates recommendations about assessing behavioral and biologic risks for HIV and STD and STD screening from the 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care in several ways. 17 These updated recommendations advise the following:  Screening for gonorrhea and chlamydial infection in genital and extra-genital sites using nucleic acid amplification tests (NAATs)  Screening for women for trichomoniasis with more sensitive tests: NAAT or culture  Informing persons with HIV that reporting of cases of HIV, infectious syphilis, gonorrhea, and chlamydial infection by laboratories and health care providers as required by state laws may prompt health departments to offer voluntary, confidential HIV partner services in some jurisdictions  Retesting persons diagnosed with gonorrhea, chlamydial infection, or trichomoniasis 3 months after treatment  Using the STD treatment regimens that have been most recently recommended by the Centers for Disease Control and Prevention (CDC) that include administration of two different antimicrobial drugs for gonorrhea, one of which requires injection 1,14  Providing persons with HIV who have STD symptoms or report recent sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis with access to presumptive STD treatment (while awaiting STD test results) through onsite treatment at a health care facility or immediate linkage to a health care facility that offers clinical evaluation and onsite presumptive STD treatment  Engaging nonclinical providers to  inform sexually active persons with HIV that some STDs may increase the risk of HIV transmission and that screening for these STDs at least annually is beneficial  offer recommended STD screening tests using venous blood specimens or provider-initiated self-collected specimens, if feasible in the nonclinical setting, or refer clients to clinical settings that offer STD screening  promptly link persons with HIV who report symptoms of STD or sexual contact with partners treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis to health care providers who can provide clinical evaluation (including physical examination and diagnostic testing) and presumptive treatment ‡ ‡ ‡ with recommended injectable or oral antimicrobial drugs  Engaging health departments to integrate or routinely match STD and HIV surveillance data to identify populations or individuals with HIV with STD coinfection who may warrant being offered HIV and STD preventive services, including voluntary HIV partner services # Methods The section writing group compiled recommendations on STD services and STD laboratory testing for persons with HIV from CDC, the Health Resources and Services Administration (HRSA), and the U.S. Department of Health and Human Services (HHS) published through April 2014, and these recommendations will be revised periodically. All of this federal guidance was based on systematic reviews of evidence and, when evidence was sparse or absent, expert opinion. 1,4,7,[10][11][12][13][14] The group also reviewed recommendations about STD screening from the 2013 guidelines of the nongovernmental HIV Medical Association of the Infectious Diseases Society of America. 15 In addition, the group reviewed the following sources on the role of STD screening and treatment in preventing HIV transmission that were published from January 2010 to March 2014: 2 published systematic reviews, 18,19 1 published narrative review, 20 recent CDC programmatic guidance to state and local health departments, 21 and the 2015 CDC STD Treatment Guidelines. # Evidence Supporting the Recommendations Certain STDs have been found to increase HIV-1 DNA or RNA in persons with HIV, which may increase the risk of HIV transmission. 18,20 A meta-analysis conducted in 2007 found that persons with HIV who had been diagnosed with urethritis, cervicitis, gonorrhea, and chlamydial infection had a 2-to 3-fold increase in the frequency of HIV shedding in the genital tract. 22 Trichomoniasis in women has been associated with increased vaginal HIV shedding 23 and increased risk of perinatal HIV transmission in pregnant women with symptomatic T. vaginalis infection. 24 Studies conducted outside the United States have shown statistically significant declines in the HIV concentration in semen of men who were treated ‡ ‡ ‡ Presumptive treatment involves providing treatment for syphilis, gonorrhea, chlamydial infection or trichomoniasis before the results of STD testing or clinical evaluation are available. This treatment approach is recommended for persons who report symptoms suggestive of these STDs or recent sex partners who were treated for these STDs, or have clinical signs of these STDs. for urethritis associated with N. gonorrhoeae or trichomonas and in the vaginal fluid of women who were treated for cervicitis associated with N. gonorrhoeae, C. trachomatis, and trichomonas. [25][26][27][28] Because a high proportion of persons infected with these 3 STDs may lack symptoms or signs, periodic screening with sensitive laboratory tests is needed to detect infection. 1,4 Men and women diagnosed with gonorrhea and chlamydial infection and women diagnosed with trichomoniasis can benefit from rescreening 3 months after treatment due to high rates of reinfection or persistent infection. 1,14,29 A meta-analysis of 11 studies conducted in 2010 showed that HSV-2 coinfection increased plasma HIV viral load by almost a quarter log (difference in mean VL 0.22 log10 copies/mL, 95% CI: 0.04-0.40). 18 However, 2 randomized controlled trials conducted from 2004-2007 did not find that acyclovir treatment of persons coinfected with HIV and HSV-2 significantly reduced the risk of HIV transmission among HIV-discordant couples. 30 Reviews of trials and observational studies conducted in low-income countries have concluded that treatment of STDs detected through screening is associated with lower rates of HIV transmission in selected populations that have high STD burden; limited access to routine screening and prompt, effective treatment; and rising HIV prevalence. 19,20 However, no controlled clinical trials of U.S. populations have evaluated the role of STD screening and treatment in preventing onward HIV transmission from persons with HIV. This section's recommendations about STD screening tests, screening frequency, and STD treatment are therefore based on biologic plausibility, epidemiologic risk factor studies, prospective studies of populations that differ epidemiologically from the United States, ecologic associations in the United States, and expert opinion. Voluntary, confidential partner services can benefit many persons with HIV and STDs and their partners. 10 Nevertheless, many providers do not explain the benefits of partner services, the role of trained health department specialists, or that reporting of cases of HIV or STD by laboratories and providers can activate voluntary, confidential health department partner services. 10 Persons with HIV who are aware of the benefits of partner services may be more likely to accept these services. See Section 8, Partner Services, for additional evidence supporting recommendations about partner services. # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities STD screening is an underused prevention strategy despite the high incidence of STDs in some persons with HIV, particularly men who have sex with multiple male partners. A study of 8 large HIV clinics in 6 cities from 2006-2008 found that more than 65% of HIV-infected gay, bisexual, and other men who have sex with men (MSM) were annually screened for syphilis, but only 2.3% to 8.5% were annually screened for rectal chlamydial infection and rectal and oropharyngeal gonorrhea despite moderate to high positivity rates in specimens from asymptomatic patients (3.0% to 9.8%). Rates of annual urogenital chlamydial infection or gonorrhea screening were only modestly higher (13.8% to 18.3%). 31 Several factors may contribute to low screening rates: reluctance to collect anal and genital specimens (in contrast to syphilis serology can use venous blood collected for CD4 cell count and HIV viral load testing 32 ); incomplete sexual behavior assessments that fail to identify the need for testing rectal and oropharyngeal specimens; limited knowledge of NAAT tests for rectal and pharyngeal specimens (including how to access tests, seek insurance coverage, and apply billing codes); and competing clinical priorities. 31 The performance of STD screening and diagnostic tests, like that of all clinical tests, may vary by test type, specimen collection and handling, prevalence of infection in a given population, and other factors; false positive and false negative results are rare. 1,4 These recommendations advise use of sensitive, specific commercially available NAATs to detect gonorrhea in rectal and oropharyngeal specimens and chlamydial infection in rectal specimens, although use of these tests with rectal or oropharyngeal specimens is not cleared by the U.S. Food and Drug Administration (FDA). However, several state public health and national commercial laboratories have met all CLIA regulatory requirements for off-label procedures for testing rectal and oropharyngeal specimens and billing codes have been assigned. 1,3,33 STD treatment is generally safe and effective and rarely results in adverse reactions. 1 Emergence of antimicrobial-resistant pathogens may impair the effectiveness of some treatments over time. For example, in 2012 CDC recommended treating N. gonorrhoeae with two antimicrobial drugs (at least one requiring injection) that are more effective against antimicrobial-resistant strains. 14 Poor adherence to STD treatment can impair effectiveness. 1 Persons with HIV can become reinfected with STD if any partners diagnosed with STD are not treated or they do not take their treatment as prescribed. 1 It is therefore important to offer partner services to persons with HIV who are diagnosed with STDs so that their partners can be notified and offered testing and presumptive treatment (see Section 8, Partner Services). Some health departments integrate or routinely match HIV and STD surveillance data to identify persons with HIV who warrant being offered HIV and STD preventive services. 21 Innovations in information technology and increased use of electronic medical information under the Affordable Care Act may expedite confidential, electronic reporting of surveillance data and support the assessment and assurance functions of public health programs. 34 # Policy, legal, and ethical considerations State laws generally protect the confidentiality of HIV and STD information reported to health department surveillance programs that may activate voluntary, confidential health department partner services. Nevertheless, some persons with HIV who are diagnosed with an STD may feel anxious about providers reporting cases to public health authorities or notifying sex partners because an STD diagnosis in a person with HIV is an objective marker of unprotected sexual activity that may result in HIV or STD transmission. 10 In some jurisdictions, duty-to-inform regulations require or allow providers to inform sex and drug-infection partners of possible HIV or STD exposure, particularly if the person with HIV was aware of their infection before the activity or the activity was not consensual. 10,35 Some persons with HIV worry that HIV or STD case reporting by laboratories or providers or partner notification might breach confidentiality or, in the case of minors, prompt unwanted parental notification (see Section 8, Partner Services). Health departments use methods similar to health care providers to rigorously protect personal health information and maintain the confidentiality of surveillance case reports that can activate voluntary, confidential health department partner services; however, they may release personal health information if subpoenaed or if required to enforce duty-to-inform statutes. 36 Providers who are aware of and adhere to laws and regulations about minors' rights to access and consent to confidential STD preventive services are better equipped to serve and protect the privacy rights of minors. 1 See Section 3, Context of Prevention, and Section 8, Partner Services, for related information. # Special populations Persons with HIV who continue to practice HIV risk behaviors, § § § particularly unprotected sex with multiple or anonymous partners, are highly likely to be exposed to STD and may benefit from screening every 3 to 6 months instead of annually (see Box 9-A). These persons may include some MSM and substance users as well as persons who are aware that their sex partners have multiple sex partners. 1 # Implementation Resources Additional information and practical resources to support implementation of these recommendations can be found at http://www.cdc.gov/hiv/guidelines/. # Section 10. Reproductive Health Care for Women and Men Background Reproductive health care involves several services for adults and adolescents with HIV who are of reproductive age and wish to avoid unplanned pregnancies or reduce the risk of sexual HIV transmission. 1 These services are essential because most women and men with HIV in the United States acquired HIV through sexual exposure during their reproductive years and they remain sexually active after their diagnosis. [2][3][4][5][6][7] Once aware of their infection, many persons with HIV engage in safer sex practices or use contraception to prevent unintended pregnancy, but some do not. Also, members of many HIV-discordant couples want to have children 8,9 and therefore may benefit from conception methods that reduce the risk of sexual HIV transmission and perinatal transmission, if pregnancy occurs. Providing reproductive health services therefore supports the rights of persons with HIV to be sexually active, to prevent or attempt conception, and to have children. This section addresses services for persons with HIV, HIV-concordant couples (in which both members are HIV-infected), or HIV-discordant couples (in which only one member is infected):  Assessment of reproductive plans of women and men with HIV  Assessment of pregnancy status of women with HIV  Reproductive health counseling* for persons with HIV and their partners regardless of their pregnancy intentions  Information and services related to contraception  Use of effective antiretroviral treatment (ART) before attempting to conceive  Information and services related to conception methods that reduce the risk of sexual and perinatal HIV transmission  Information on unique aspects of antiretroviral prophylaxis for HIV-uninfected members of discordant couples who are not consistently and correctly using condoms or are attempting conception This section does not provide a comprehensive summary of all reproductive services for women and men with HIV, such as counseling or screening related to smoking, alcohol, substance use, and viral hepatitis. Quality improvement † and program monitoring and evaluation ‡ methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Section 11, Pregnancy, * Reproductive health counseling for persons with HIV includes information and counseling for HIV-infected women and HIV-infected men of reproductive age and their uninfected partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks. † Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. ‡ Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. describes methods-including use of ART-to prevent sexual or perinatal transmission of HIV during recognized pregnancies of HIV-infected women or HIV-uninfected women who have partners with HIV. Other sections cover linkage to HIV medical care § (Section 4, Linkage to and Retention in Care), general aspects of ART use and use of antiretroviral prophylaxis by HIV-uninfected partners (Section 5, Antiretroviral Treatment), methods to reduce sexual transmission of HIV (Section 7, Risk Screening and Risk Reduction), and services for sex partners of persons with HIV (Section 8, Partner Services). # Recommendations BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  Assess pregnancy status of HIV-infected women and reproductive plans of women and men with HIV, with methods and frequency as appropriate to provider role and setting (e.g., self-reported pregnancy or referral for pregnancy testing) a (i, ii, iii)  Provide education, reproductive health counseling b , and/or referral for contraceptive services as appropriate to provider role and setting a , to women and men who wish to prevent or delay future pregnancy a (i, ii, iii)  Advise women and men with HIV (and HIV-uninfected partners referred by them) to use latex or polyurethane male or female condoms to reduce the risk of HIV transmission and unintended pregnancy even if using medical or surgical contraception a (i, ii, iv)  Inform persons with HIV about the role of antiretroviral treatment (ART) in reducing sexual HIV transmission and in preventing perinatal HIV transmission a (i, ii, iii, iv) (see Box 10-A)  Inform persons with HIV (and HIV-uninfected partners referred by them) about  the availability of preexposure prophylaxis (PrEP) c for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition when attempting conception using penile-vaginal intercourse without a condom a (i, v, vi)  the availability of nonoccupational postexposure prophylaxis (nPEP) d for HIV-uninfected partners when clinically indicated on a one-time or infrequent basis to reduce the risk of HIV acquisition in the event of inadvertent sexual or parenteral HIV exposure within the past 72 hours (e.g., unprotected intercourse, condom breakage, shared drug-injection equipment) a (i, vi, vii)  Refer persons with HIV who wish to conceive to health care providers skilled in reproductive health counseling b for persons with HIV a (i, ii) (see Box 10-A)  Offer periodic HIV testing to HIV-uninfected members of HIV-discordant couples, particularly those who are attempting conception or who report unprotected intercourse a (i)  Become familiar with state and local laws and regulations in the jurisdiction that affect access to contraceptive services, pregnancy termination, and other reproductive health services, including access for minors without parental consent a (viii) § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). # BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN (cont) # Specific to clinical providers (in addition to above recommendations)  Assist persons with HIV who do not wish to conceive in making informed decisions about contraception that consider  the benefits of dual contraceptive methods (condoms plus other contraception) (i, iii, ix, x)  the high efficacy and safety profile of hormonal contraception and IUDs for women with HIV e (i, iii, ix, x)  the benefits of using water-based spermicides and condom lubricants that do not contain nonoxynol-9 (xi, xii)  Inform women with HIV who are considering medically attended pregnancy termination that available evidence indicates that HIV infection does not increase the risk of complications after the procedure f  Offer ART and adherence support according to U.S. Department of Health and Human Services (HHS) treatment guidelines to prevent sexual transmission of HIV and, should pregnancy occur, to prevent perinatal HIV transmission g (i, iv, vi)  Inform women with HIV who are using or considering using ART and hormonal contraception at the same time about possible drug interactions that might influence the efficacy of the ART or the hormonal contraception (ix, x)  Provide (in consultation with HIV care experts) or make referral for h (see Box 10-A)  additional preconception information and counseling for persons with HIV who are considering conception (preferably with their partner's participation) (i, ii, iv, vi)  information about conception methods for members of HIV-discordant couples that reduce the risk of sexual transmission of HIV or, should pregnancy occur, perinatal HIV transmission (i, iv, vi)  Offer PrEP or nPEP to HIV-uninfected partners referred by persons with HIV when clinically indicated after considering factors specific to women who may be or intend to become pregnant c,d (v, vii) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines that offer reproductive health services to adults and adolescents with HIV (xiii)  Provide information to clinical providers about state and local laws regarding minors' access to and consent for reproductive health services i (xiv)  Prioritize health department partner services for persons with HIV or partners who may be at risk for unintended pregnancy (e.g., adolescents) j (xv)  Support efforts and partnerships that increase access to reproductive health services for persons with HIV, including enrollment in private or public sector health plans and use of public sector clinics that serve uninsured persons (e.g., federally funded clinics) (xvi, xvii, xviii) Note. Section 11, Pregnancy, contains recommendations specific to women with recognized pregnancy and their partners. # Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessment, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. # BOX 10. RECOMMENDATIONS-REPRODUCTIVE HEALTH CARE FOR WOMEN AND MEN (cont) a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b Reproductive health counseling includes information and counseling for HIV-infected women and HIV-infected men of reproductive age and their partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks. c PrEP is the daily, continuous use of a specific regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. See Section 5, Antiretroviral Treatment, for more information regarding the use of PrEP. d nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. See Section 5, Antiretroviral Treatment, for more information regarding the use of nPEP. e The Contraceptive Services topic in this section describes special considerations for the use of hormonal contraception, intrauterine devices, and spermicides by women with HIV.  delivery methods that reduce perinatal transmission risk  Benefits of initiating ART before attempting conception to maximally suppress viral load  Availability of PrEP for HIV-uninfected persons who are attempting conception using unprotected intercourse with an HIV-infected partner c  Availability of nPEP for HIV-uninfected persons to reduce the risk of HIV acquisition through unprotected intercourse within the past 72 hours with an HIV-infected partner c  Availability of special conception methods that lower, but do not eliminate, HIV transmission risk (compared with unprotected penile-vaginal intercourse), including  specifically timed, periovulatory unprotected intercourse d  intravaginal or intrauterine artificial insemination, e in vitro fertilization, or intracytoplasmic sperm injection f using semen of an HIV-uninfected donor or specially processed ("washed") sperm of an HIV-infected man g,h Note. Some topics may only be suited for providers with appropriate skills and training. # Box 10-A. Specific topics for counseling adults and adolescents with HIV who are considering conception a See Section 7, Risk Screening and Risk Reduction, for more information on strategies to reduce the risk of sexual transmission of HIV. b Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. c See Section 5, Antiretroviral Treatment, for more information on ART, nPEP, and PrEP. HHS does not recommend repeated courses of nPEP 10 (e.g., for discordant couples who rarely use condoms) as a long-term means to prevent HIV acquisition. Recent HHS guidance recommends consideration of PrEP as one of several options to protect HIV-uninfected partners in HIV-discordant couples from acquiring HIV infection when attempting to conceive. 11,12 d Timed, periovulatory intercourse is a conception method intended to reduce the risk of HIV transmission in HIV-discordant couples in which unprotected intercourse occurs only when infected partners have achieved maximal viral suppression, the woman is in the periovulatory period of her menstrual cycle, and condoms are used at all other times. e Artificial insemination (intravaginal and intrauterine) is a conception method in which semen is collected and instilled into the uterus (by a physician) or into the upper vagina (by a physician, person with HIV, or partner). f Intracytoplasmic sperm injection is an in vitro fertilization procedure in which specially prepared ("washed") sperm of a man with HIV is injected directly into an egg retrieved from an ovarian follicle to achieve fertilization while minimizing the risk of HIV transmission to the female partner. g Sperm washing is a procedure that removes components (including seminal fluid that may contain HIV) other than sperm from a semen sample before it is used for artificial insemination. As of April 2013, the U.S. Food and Drug Administration has not reviewed sperm preparation procedures of HIV-infected men. h The Evidence topic in this section describes special conception methods to reduce the risk of HIV transmission that are recommended by HHS. # How These Recommendations Differ from Previous Recommendations The recommendations in this section greatly expand on the only recommendation about reproductive health in the 2003 Recommendations for Incorporating HIV Prevention into HIV Medical Care: referring women with HIV for contraception and reproductive health services. 13 These recommendations are consistent with current HIV-related federal guidelines about assessment of pregnancy status and reproduction plans of women and men, provision of or referral for contraceptive services and other reproductive health services, 14 avoidance of nonoxynol-9-containing spermicides, 15 behavioral methods to prevent HIV transmission, ART use to prevent sexual and perinatal HIV transmission, [10][11][12]14,[16][17][18][19] reproductive health counseling, 11,14,18 and conception methods that reduce the risk of HIV transmission. 11,14,17,20 The recommendations in this section are also consistent with the latest comparable recommendations of these nongovernmental organizations: the American College of Obstetricians and Gynecologists; 21 the HIV Medicine Association of the Infectious Diseases Society of America; 22 and the International Antiviral Society-USA Panel. 23,24 However, these updated recommendations provide new guidance for  nonclinical providers to ask about pregnancy status and reproductive health plans and to refer clients to reproductive health counseling, contraceptive services, and other reproductive health care  nonclinical and clinical providers to inform persons with HIV about  the benefits of ART for preventing HIV transmission in HIV-discordant couples who have unprotected sex or are attempting conception Sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginal-digital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot).  the availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition  health department staff to provide information to clinical providers about state laws regarding minors' access to and consent for reproductive health services # Methods The section writing group based these recommendations on the latest guidance from the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and other federal agencies through May 2014. Those recommendations were based on a large body of scientific evidence and extensive experience of clinical experts. [10][11][12][13][14][15]17,18,25 The writing group that compiled these recommendations did not reexamine the evidence supporting this federal guidance, but examined additional evidence from three other sources:  Systematic reviews and meta-analyses from the CDC HIV/AIDS Prevention Research Synthesis (PRS) project's cumulative HIV/AIDS/STD prevention database identified using these search terms: HIV infection and reproductive health, women, contraception, family planning, birth control, and reproductive health counseling (see Section 2, Methods)  Reviews of the publications referenced in the search results  Narrative reviews of selected topics not addressed by federal guidelines listed above that were based on searches in PubMed, in OVID, and of scientific meeting abstracts published from 2000-2013 using these terms: HIV infection, family planning, reproductive health, nonoxynol-9, lubricants, sperm washing, artificial insemination, contraception, and birth control # Evidence Supporting the Recommendations This topic summarizes key evidence that supports the federal guidance on which the recommendations in this section are based or that was identified from the 3 additional sources described above. # Assessing pregnancy status, reproductive plans, and reproductive health service needs Providers who routinely assess pregnancy status and the reproductive plans of persons with HIV are able to offer them reproductive health information, counseling, and services that enable them to make wellinformed reproductive decisions that may reduce the risk of sexual and perinatal transmission of HIV. 11 This information and counseling also provides the opportunity to correct misperceptions about HIV transmission risks and options for contraception and conception. 11,16 Federal guidance recommends including both members of the couple when possible to encourage shared decision making and cooperation. # Use of antiretroviral medication for sexually active persons of reproductive age # Use of ART by persons with HIV Current HHS recommendations and subject matter experts advise that health care providers offer ART to all persons with HIV to prevent sexual HIV transmission regardless of the use of condoms or other contraception. 11,26 These recommendations also advise prescribing ART before persons with HIV attempt to conceive to provide time to maximally suppress viral load. 11,14 The recommendations also state that women attempting conception should avoid starting agents with a potential increased risk of maternal complications should pregnancy occur (e.g., hepatotoxicity associated with initiation of nevirapine in women with CD4 cell counts of >250 cells/mm^3) or a potential increased risk of teratogenicity (e.g., efavirenz). However, women who present for prenatal care in the first trimester and are virologically suppressed while taking efavirenz can continue this medication. 11 In addition, HIV-infected members of HIV-discordant couples should not share their ART medication with uninfected partners who are seeking nPEP or PrEP. Sharing may impair adherence of the person with HIV, and regimens suitable for treating persons with HIV may not be suitable for HIV-uninfected partners (see Section 5, Antiretroviral Treatment). 11,14 Nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners of persons with HIV An isolated, inadvertent episode of condom failure during intercourse within the past 72 hours with an HIV-infected partner may be an indication for nPEP. 10 Current HHS recommendations state that isolated nPEP use is not contraindicated in women with suspected or confirmed pregnancy, but potentially teratogenic regimens should be avoided. 10 However, these recommendations do not support repeated use of nPEP while an HIV-discordant couple is attempting conception through repeated acts of unprotected intercourse. Rather, HIV-discordant couples attempting to conceive should consider other conception † † Risk screening is a brief assessment of behavioral factors that may affect the risk of exposing others to HIV, such as inconsistent condom use or sharing drug-injection equipment, and biomedical factors that influence HIV transmission, such as viral load, antiretroviral treatment and adherence, sexually transmitted disease, and pregnancy. Risk screening is used to identify behavioral or biomedical risk-reduction interventions suited to a specific individual. ‡ ‡ Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. § § Clinician Consultation Center staff includes OB/GYNs, infectious disease specialists, internists, family practitioners, and clinical pharmacists at the University of California, San Francisco (1-888-448-8765 or http://nccc.ucsf.edu/clinician-consultation/perinatal-hivaids/). methods that do not require unprotected intercourse (e.g., intrauterine insemination and in vitro fertilization) or the use of PrEP to prevent HIV acquisition (see Section 5, Antiretroviral Treatment). 11,12 Preexposure prophylaxis (PrEP) for HIV-uninfected partners of persons with HIV The use of PrEP can reduce the risk of HIV acquisition by HIV-uninfected sex partners when attempting to conceive with a person with HIV. 11,12 Current federal guidance recommends that providers address the use of PrEP with HIV-uninfected members of HIV-discordant couples who are attempting conception because of their risk of HIV acquisition (see Section 5,Antiretroviral Treatment). Current federal guidance and additional expert opinion also recommend that health care providers inform persons using PrEP that the effects of fetal exposure to PrEP are not yet fully assessed but that no harm has been reported to date. 12,27 # Contraceptive services Offering contraceptive services to sexually active persons with HIV who want to avoid, delay, or space pregnancies is essential, especially given the high proportion of women with HIV who report unintended pregnancies. 28 Current HHS recommendations and other evidence reviewed by the writing group indicate that contraceptive methods available in the United States are generally safe in women with HIV. 17,18,[29][30][31][32][33] Evidence-based* criteria regarding medical eligibility for contraception for women with HIV are detailed in other documents. 17,20 In brief, condoms, when used consistently and correctly, are effective 1) for contraception, 2) in preventing HIV transmission to HIV-uninfected partners, 3) in preventing HIV superinfection † † † of persons already infected with other HIV strains, 21,34 and 4) in preventing other STDs. Current HHS recommendations conclude that concurrent use of barrier contraception, such as male or female condoms, and nonbarrier contraception, such as hormonal contraception and IUDs, is more effective in preventing pregnancy than using a single contraceptive method and reduces the risk of sexual transmission of HIV. 11,14 Several methods are more than 99% effective in preventing pregnancy when used correctly with all acts of intercourse, but no contraceptive method, including male and female condoms, hormonal contraception, or IUDs, is 100% effective in preventing pregnancy. 33,35 Many persons with HIV rely on ART to reduce the risk of transmitting HIV to others, especially when not routinely using condoms or when attempting conception using unprotected intercourse. # Hormonal contraception Research studies identified through the systematic and narrative reviews and clinical experience (including postmarketing drug safety surveillance) indicate that hormonal contraception (including pills, injectables, rings, patches, implants, and emergency postcoital contraception ‡ ‡ ‡ ) is generally safe, effective, and suitable for HIV-infected women. [30][31][32]36,37 Oral contraceptives are generally not contraindicated in HIV-infected women because they have not been shown to increase HIV progression or transmission, increase viral load, or reduce absolute CD4 cell count levels. 17,[29][30][31]38 However, a few oral contraceptives and some antiretroviral medications may interact with each other. 14,16,[39][40][41][42][43] Emergency postcoital contraception is a type of oral hormonal contraception used within a few days after intercourse that is intended to prevent pregnancy by disrupting ovulation or fertilization. women taking certain classes of antiretroviral medication (protease inhibitors or nonnucleoside reverse transcriptase inhibitors) may experience changes in levels of ethinyl estradiol and norethindrone found in some oral contraceptives. Decreased levels may reduce contraceptive effectiveness, while increased levels may increase adverse effects of oral contraception. HHS recommendations also note that some oral contraceptives may decrease levels of some antiretroviral medications and that potential pharmacokinetic interactions should guide ART and contraception choices. 16 However, the recommendations state that concerns about possible drug interactions should not deter health care providers from recommending hormonal contraception to women taking ART. These recommendations highlight the benefits of informing women about 1) potential interactions between ART and hormonal contraception and 2) the use of hormonal contraception that may be used with condoms as a dual contraception strategy to avoid unintended pregnancy and perinatal HIV transmission. 17 Little is known about how ART interacts with non-oral hormonal contraceptives. 17,37,44 The fact that some non-oral contraceptives have lower systemic absorption than oral contraceptives, act locally, and in some cases do not depend on first-pass metabolism suggests that interactions with ART may be less likely than with oral contraceptives. Recent studies have raised questions about whether the use of depot medroxyprogesterone acetate, the injectable progesterone-only contraceptive agent available in the United States, may increase the risk of transmitting HIV to male sex partners or the risk of women acquiring HIV infection. 37,45 Because the evidence remains inconclusive, CDC and the World Health Organization recently recommended that women with HIV who use this injectable contraceptive should ensure that male or female condoms are consistently used during intercourse. 17,44 Intrauterine devices (IUDs) Two studies have shown that IUDs available in the United States (copper-releasing IUDs and levonorgestrel-releasing IUDs) are safe for HIV-infected women without AIDS who can regularly access providers to monitor for IUD-related complications, including possible infection. 32,46 Clinical trials indicate these IUDs do not influence cervicovaginal shedding of HIV or increase risk of HIV transmission to sex partners. 47,48 Current CDC recommendations state that IUD insertion and use are generally safe for women with HIV and that HIV-infected IUD users have no higher risk of IUD-related complications than HIV-uninfected IUD users. However, women with AIDS who are taking ART and not clinically well should generally not undergo IUD insertion, because the risk of pelvic infection outweighs the benefits of effective contraception. 20 # Other contraceptive methods HHS recommendations advise against use of spermicides and anal and genital lubricants containing nonoxynol-9 because when used frequently, long-term, or in high doses they can cause genital irritation and inflammation, which may increase the risk of HIV transmission. 15,18,25 HHS recommendations and studies identified through the narrative review indicate that voluntary tubal sterilization and vasectomy are safe, effective contraceptive methods for HIV-infected women and men, respectively. 17,29,49 # Pregnancy termination One study identified in the narrative review found that HIV-infected women do not have a higher prevalence of postabortion complications after medically attended surgical abortion than HIV-uninfected women; this finding supports the recommendation to inform HIV-infected women who are considering medically attended pregnancy termination that available evidence indicates that HIV infection does not increase the risk of complications after the procedure. 50 Women with HIV who undergo termination procedures should defer vaginal sexual contact until bleeding has ceased and healing is complete to lower the risk of HIV transmission to others. # Conception methods that reduce the risk of sexual and perinatal transmission in HIV-discordant couples Current HHS guidelines recommend consideration of special conception options (preferably after expert consultation) that have been shown to reduce the risk of HIV transmission in HIV-discordant couples attempting conception. 11  For couples who prefer natural conception after having received information and counseling about the risks of sexual transmission and perinatal transmission (should pregnancy occur) and assisted conception methods, these options include  timed, periovulatory unprotected intercourse after the partner with HIV has achieved maximal viral suppression through ART and the use of male or female condoms with all other acts of intercourse 11  the use of PrEP to further reduce the risk of HIV acquisition by the HIV-uninfected male or female partner during unprotected intercourse. 12  For couples in which the man is HIV-infected and can access assisted conception methods, these options include  preconception semen analysis to determine semen volume and any abnormal sperm characteristics that may influence conception decisions (because repeated semen exposure could result in HIV infection but not lead to conception or a viable fetus) 11  intrauterine artificial insemination, § § § in vitro fertilization, or intracytoplasmic sperm injection, using semen or sperm from an HIV-uninfected donor, or if donor semen or sperm is an unacceptable option, sperm from the HIV-infected man that has undergone procedures † † † † that remove seminal fluid that may contain HIV ("sperm washing") 11,51-54  For couples who use natural or assisted conception methods that involve exposure to potentially HIV-infected semen or other genital secretions, periodic HIV testing of HIV-uninfected partners to identify early infection and to hasten linkage to HIV medical care is warranted. 11 The availability, insurance coverage, and affordability of these methods may vary by the individual's area of residence and health insurance status. § § § Intrauterine artificial insemination is a conception method in which semen is collected and instilled into the uterus by a clinician. ** Intracytoplasmic sperm injection is an in vitro fertilization procedure in which specially prepared ("washed") sperm of a man with HIV is injected directly into an egg retrieved from an ovarian follicle to achieve fertilization while minimizing the risk of HIV transmission to the female partner. † † † † As of April 2013, the U.S. Food and Drug Administration has not reviewed preparation procedures of semen from men with HIV. # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Recent surveys indicate that 57% to 84% of all women with HIV report consistent condom use, depending on the HIV status of the sex partner. 55 However, less than 30% of women with HIV currently use condoms or other contraception; and use of ART does not influence prevalence of current contraceptive use. 49,55,56 Also, about half of sexually active adolescents with HIV report engaging in unprotected sex after learning they are infected. 56 As with American women overall (in whom about half of pregnancies are unintended), unplanned pregnancies are common among women with HIV. 28,57,58 These findings underscore the benefits of expanding reproductive health care services to persons with HIV. Implementation of the Patient Protection and Affordable Care Act and continued support for federally funded family planning programs are expected to improve access to family planning and reproductive health services, including some assisted conception methods. 59,60 However, access to health care providers with experience in reproductive health counseling, contraceptive methods, and assisted conception methods may continue to be limited for persons who do not have health insurance or who live in rural or other medically underserved areas. 61,62 Primary care providers seeking information about reproductive considerations for persons with HIV can consult the Clinician Consultation Center (1-888-448-8765 or http://nccc.ucsf.edu/clinician-consultation/perinatal-hiv-aids/). 63 # Policy, legal, and ethical considerations Laws and regulations about consent, confidentiality, parental disclosure, and disease reporting for minors who seek family planning, pregnancy termination, or other sexual and reproductive health services vary by jurisdiction. Some states permit minors to receive a wide variety of sexual and reproductive health services without parental consent. 64 Providers who discuss sexuality, sexual behavior, and reproductive choices using a neutral, nonjudgmental style may elicit accurate information and foster autonomy in health decisions. Motivating persons with HIV to use sexual risk-reduction methods decreases the risk of exposing partners to HIV and the negative reactions, conflict, and legal disputes that may follow. See Section 3, Context of Prevention, and Section 8, Partner Services, for more information about legal and ethical issues related to HIV disclosure and notification of partners. # Special populations Adolescents with HIV have high rates of unintended pregnancy. Navigating multiple health care providers is difficult, but these adolescents can benefit from linkage to HIV medical care providers who also provide reproductive health services. 57,65 Expediting access to reproductive health services is also important for transgender persons, migrants, women at risk for sexual violence, sex workers, and others who may use contraception inconsistently or have trouble finding confidential or affordable health care. 56,66 Integrating reproductive and HIV services within the same health care facility and cross-training HIV providers and reproductive health care providers may increase capacity for reproductive services and more comprehensive "medical homes" for persons with HIV. # Section 11. HIV Prevention Related to Pregnancy Background Specific prevention considerations are relevant for women who become infected with HIV during pregnancy or the postpartum period. Several interventions can reduce the risk of 1) sexual HIV transmission from pregnant women with HIV or to uninfected pregnant women and 2) perinatal transmission during pregnancy, labor, delivery, and the postpartum period, as well as during breastfeeding. Unprotected sexual activity may occur during pregnancy, especially when partners are no longer using condoms for contraception purposes. 1 Furthermore, the physiologic state of pregnancy may increase the risk of sexual HIV transmission both from HIV-infected pregnant women to uninfected male partners 2 and from HIV-infected male partners to uninfected pregnant women. 2 This increased risk may be due to changes in systemic or genital mucosal immunity, HIV shedding or virulence, HIV coreceptors, or other factors. 2 The initiation of prenatal care, here defined as health care for women with a recognized pregnancy, also provides opportunities for informing pregnant women and their sex partners about methods to avoid sexual transmission of HIV during pregnancy. This care also enables offering HIV testing and retesting to sex partners of persons with HIV who are uninfected or have an unknown infection status. This section addresses methods to reduce 1) HIV transmission from women with HIV and recognized pregnancies and 2) HIV acquisition by HIV-uninfected women with recognized pregnancies. However, this section does not provide a comprehensive summary of all prevention and care services for pregnant women with HIV and their partners. Quality improvement* and program monitoring and evaluation † methods can determine if the interventions described in this section are implemented as intended, yield the expected outcomes, or warrant changes in delivery methods (see Section 13, Quality Improvement). Other sections describe  General aspects of antiretroviral treatment (ART) and prophylaxis by HIV-uninfected partners (Section 5, Antiretroviral Treatment);  General aspects of adherence to ART (Section 6, ART Adherence)  Contraception services and reproductive health counseling ‡ that can be provided in the postpartum period (Section 10, Reproductive Health Care)  Behavioral risk-reduction interventions, including those for HIV-infected partners of pregnant women (Section 7, Risk Screening and Risk Reduction)  Sexually transmitted disease (STD) services, including screening pregnant women for STD pathogens (Section 9, STD Services) * Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. † Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. ‡ Information and counseling for HIV-infected women and HIV-infected men of reproductive age and their partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks.  Promptly link women to HIV medical care, preferably to settings where providers have expertise in managing pregnancy in women with HIV a,b (i, ii, iii, iv)  Inform women (and their sex partners who are aware of the woman's infection status) about risks of perinatal and sexual HIV transmission a,c,d (i, ii, iii, v) (see Box 11-D)  Support adherence to antiretroviral treatment (ART) during the prenatal and postnatal periods for optimal maternal health and prevention of perinatal and sexual transmission a (ii, v, vi)  Inform women and HIV-uninfected partners they refer about  the availability of preexposure prophylaxis (PrEP) e for HIV-uninfected partners when clinically indicated to reduce the risk of HIV acquisition during unprotected sexual intercourse a,c,f (ii)  the availability of nonoccupational postexposure prophylaxis (nPEP) g for HIV-uninfected partners to reduce the risk of HIV acquisition in the event of inadvertent sexual or parenteral HIV exposure within the past 72 hours (e.g., unprotected intercourse, condom breakage, shared drug-injection equipment) a,c,f (vii) § Partner services includes an array of voluntary services for persons with HIV or STD and their sex and drug-injection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). # Box 11-A. Recommended services for pregnant women with HIV (cont)  Offer women support, information, and assistance to notify their sex and drug-injection partners about their HIV status a,c,h (iii)  Advise women to urge sex partners and drug-injection partners to get HIV testing and to use condoms to prevent HIV acquisition a,c (ii, v)  Offer latex or polyurethane male and/or female condoms a (i)  Inform women and their partners that breastfeeding by HIV-infected women is not recommended in the United States and that formula feeding is recommended for the infants of these women a (i, ii)  Provide education, counseling and/or referral for postpartum contraception services for women who wish to prevent or delay future pregnancy, as appropriate to the setting a (ii, v) # Specific to clinical providers (in addition to above recommendations)  Offer an ART regimen during the prenatal, intrapartum, and postpartum periods, regardless of maternal CD4 cell count, to prevent perinatal transmission and thereafter for the woman's health and to prevent HIV transmission to others, according to U.S. Department of Health and Human Services (HHS) recommendations (i, ii, v, vi) (see Box 11-D)  Inform women about options for free or subsidized ART, such as AIDS Drug Assistance Program (ADAP) or pharmaceutical drug assistance programs to help address financial concerns that may deter ART use (i)  Screen and treat women for STDs that may increase risk of HIV transmission during pregnancy i (iii, v, vii)  Do not use invasive prenatal and intrapartum procedures (e.g., amniocentesis, chorionic villous sampling, amniotomy, and transvaginal instrumentation) unless women have started an effective ART regimen and are, ideally, virally suppressed at the time of the procedure as these procedures may increase fetal exposure to maternal blood thereby increasing the risk of perinatal transmission (i, ii)  Inform women of delivery options that can reduce the risk of perinatal transmission (ii)  Discuss risks and benefits of cesarean delivery and recommend scheduled cesarean delivery at 38 weeks gestation for women with suboptimal viral suppression near the time of delivery (i.e., HIV RNA levels >1000 copies/mL) (i, ii)  Notify infant health care providers of impending birth of HIV-exposed infants and any anticipated complications (ii) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines that offer pregnancy services to women with HIV (iv)  Provide information to clinical providers about state laws regarding consent for HIV testing during the perinatal period and minors' access to and consent for pregnancy services j  Prioritize health department partner services for pregnant women with HIV k (iii)  Support efforts and partnerships that increase access to pregnancy and perinatal services for persons with HIV, including enrollment in private insurance or medical assistance programs and use of public sector clinics (e.g., federally funded clinics) (ix, x, xi) Note. In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, disease screening, diagnosis, and treatment; and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Some of the recommendations specific to clinical providers apply only to clinical providers with authority for clinical evaluation and examinations, diagnosis, treatment, and prescribing. Some of the federal guidelines cited in the Recommendation boxes may have been updated as of present. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. # Box 11-B. Recommended postnatal services for women with HIV and their infants to reduce the risk of perinatal HIV transmission For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV) serving postpartum women with HIV or their HIV-exposed infants  Assist women to obtain regular HIV care and in adhering to their prescribed ART regimen to maximize their health a (i, ii)  Advise women with HIV not to breastfeed (even if taking ART) and provide information about how to obtain formula a (i, ii)  Advise women with HIV not to donate their breast milk to breast milk banks a (iii)  Advise caregivers with HIV not to prechew food for infants and children a (ii, iv, v)  Provide education, counseling, and/or referral for postpartum contraceptive services to women who wish to prevent or delay future pregnancy, as appropriate to the setting a (ii) # Specific to clinical providers (in addition to above recommendations)  Offer a 6-week, postnatal infant prophylaxis with antiretroviral medications according to HHS guidelines within 12 hours of birth to all HIV-exposed infants b (ii)  Provide infant caregivers information about the importance of adherence to postnatal infant prophylaxis and about services to support adherence c (ii)  Consider virologic testing d of HIV-exposed infants within 24 hours at birth to monitor infant's infection status, especially when maternal virologic control during pregnancy was poor or if adequate follow-up of the infant may not be assured (i, ii)  Assist parent or guardian in obtaining health care for the HIV-exposed newborn to monitor newborn's infection status (i, ii)  Offer repeated virologic tests to the infant at ages 14 to 21 days, 1 to 2 months, and 4 to 6 months to assess the presence of HIV infection before 18 months of age (ii)  Report cases of perinatally exposed or HIV-infected infants to health departments according to local requirements for HIV disclosure, confidentiality, and case reporting e (vi) For staff of health departments who provide population-level HIV prevention and care services  Conduct surveillance for HIV-exposed infants (vi)  If allowed in jurisdiction, use surveillance data for public health purposes (e.g., contacting health care providers who report cases of HIV-exposed infants) to ensure that (vii)  the infant's infection status is later ascertained and, if infected, ensure that the infant receives clinical care (including the offer of treatment) and the confirmed case is reported to the health department  the mother's HIV infection status is documented and the mother is offered help with starting HIV medical care f a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the writing group for this section concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. HHS guidelines describe specific regimens. 7 c The source guidance addresses initiation of postnatal infant prophylaxis and use of a 6-week regimen, but does not address infant adherence support. d Such as nucleic acid amplification test for HIV RNA or DNA, according to HHS guidelines. 7 e For state and territorial case reporting requirements, see guidance of CDC and the Council of State and Territorial Epidemiologists. 8,9 f Authorized uses of perinatal surveillance data vary by jurisdiction. 9 Box 11-C. Recommended services for pregnant women who are HIV-uninfected or have unknown infection status and have sex or drug-injection partners with HIV (cont) # Specific to clinical providers (in addition to above recommendations)  Include HIV testing early in pregnancy as part of routine prenatal screening panel; use opt-out approaches when allowed in the jurisdiction (ii, iii, vii)  Conduct repeat testing during the third trimester (using a test that detects recent HIV infection e ) for women whose earlier HIV test was negative. When a woman reports a possible, recent HIV exposure that might result in a new infection that would not be detected by antibody test alone (i.e., during the window period f ) or has signs or symptoms of acute HIV infection, use both an HIV antibody test and a plasma RNA test to enable diagnosis of acute HIV infection (ii, iii)  Screen and treat for STDs that may increase risk of HIV acquisition during pregnancy or thereafter g (vii)  For women who first present for pregnancy care during labor with unknown HIV status offer  expedited HIV testing (using opt-out testing strategy when allowed by the jurisdiction) and provide information about perinatal HIV transmission (ii, iii)  IV zidovudine immediately if preliminary test result is positive to prevent perinatal transmission (ii)  For women who decline testing and whose HIV status remains unknown at delivery, take these steps (i, ii, iii):  provide expedited antibody testing of the newborn as soon as possible after birth using consent procedures consistent with state laws  inform the woman that identifying HIV antibodies in the newborn would indicate maternal HIV infection  If the newborn HIV antibody test is positive, promptly inform the mother  that the newborn needs virologic testing and immediate initiation of postnatal prophylaxis (i, ii, iii)  that she may obtain these services (ii, iii): • voluntary HIV testing and HIV medical care during the postpartum period or later • other medical and social services that may guide future decisions about HIV testing or medical care for herself and her infant  Offer PrEP during or after pregnancy when clinically indicated and manage women who are using PrEP during or after pregnancy according to HHS recommendations c (ii, vi)  Assess women with possible HIV exposure within the past 72 hours for indications for nPEP, and offer women with nPEP indications regimens that are suitable during pregnancy, based on HHS recommendations c (v) For staff of health departments who provide population-level HIV prevention and care services  Make available online directories of health care providers and professional advice hotlines in jurisdictions that offer pregnancy services, including PrEP to HIV-uninfected, pregnant women at substantial risk of HIV infection h (x)  Make available information about state laws regarding consent for HIV testing during the perinatal period and minors' access to and consent for pregnancy services i  Prioritize health department partner services for HIV-uninfected pregnant women who have HIV-infected partners (iv)  Support efforts and partnerships that increase access to pregnancy and perinatal services for persons with HIV and their partners, including enrollment in public or private-sector health plans and use of public sector clinics (e.g., federally funded clinics) (xi, xii, xiii) # Box 11-D. Important messages regarding HIV prevention and pregnancy # For pregnant women with HIV who have HIV-uninfected partners  Approximately 25% of HIV-infected women who are not treated with ART during pregnancy will transmit the virus to their infant during pregnancy, labor, or delivery, in nonbreastfeeding populations  HIV can be transmitted through breast milk of a woman with HIV  Use of ART by pregnant women with HIV is highly effective in protecting the infant from HIV infection and may improve the mother's health and prevent HIV transmission to their uninfected partners  Other interventions that may further reduce the risk of transmission from HIV-infected women to their infant, including  nonemergent cesarean delivery at 38 weeks gestation that is initiated within 4 hours after the start of labor for women who do not have a suppressed viral load (<1000 copies/mL) at 34 to 36 weeks gestation  use of infant formula instead of breast milk from a woman with HIV to prevent HIV transmission through breast milk  not feeding infants food that has been prechewed by a person with HIV # How These Recommendations Differ from Previous Recommendations These recommendations are consistent with current federal guidelines for HIV-infected pregnant women, HIV-exposed newborns, and HIV-uninfected pregnant women with HIV-infected partners. 3,7,8,[11][12][13][14][15] They are also consistent with the Centers for Disease Control and Prevention (CDC) recommendations that HIV-infected caregivers not prechew food for infants. 16 These recommendations are also consistent with the latest comparable recommendations of these nongovernmental organizations: the American College of Obstetrics and Gynecology; 17 the HIV Medicine Association of the Infectious Diseases Society of America; 18 and the International Antiviral Society-USA Panel. 19,20 This section compiles existing federal recommendations, provides new evidence for their support, and makes one new recommendation for nonclinical and clinical providers to inform pregnant women with HIV (and sex partners referred by them) about the availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition. # Methods The section writing group compiled the most recent recommendations about HIV prevention related to pregnancy as of May 2014 from CDC, the Health Resources and Services Administration (HRSA), National Institutes of Health, and other federal agencies. 7,8,[11][12][13][14] Those recommendations were based on extensive clinical experience and a large body of scientific evidence that was not reexamined by the writing group. When existing guidelines contained no or limited evidence about a topic, the writing group examined evidence on the topic from three sources: 1) Systematic reviews and meta-analyses that were identified by searching the CDC HIV/AIDS Prevention Research Synthesis (PRS) project's cumulative HIV/AIDS/STD prevention database using the following terms: HIV infection and pregnant women, newborn, infant feeding, and cesarean delivery (see Section 2, Methods); 21 2) a narrative review of PubMed for articles indexed with the following terms: HIV infection and prevention of mother-to-child transmission, pregnant women, newborn, and cesarean delivery; and 3) relevant articles identified after manual review of the publications referenced in the search results. # Evidence Supporting the Recommendations This section briefly summarizes evidence supporting these recommendations that has been described in other documents. 7,8,[11][12][13][14] See other sections for evidence related to STD services (Section 9, STD Services), risk screening † † and behavioral risk-reduction interventions (Section 7, Risk Screening and Risk Reduction), and linkage to HIV medical care ‡ ‡ (Section 4, Linkage to and Retention in Care). # HIV testing for pregnant women and their partners The start of prenatal care enables routine HIV testing of pregnant women and their partners. Use of an opt-out consent approach (whereby a woman is tested unless she specifically declines testing) that is consistent with state laws has been shown to yield higher testing acceptance. This approach also hastens HIV diagnosis and management and use of interventions to prevent sexual or perinatal transmission. 11 Because pregnancy can increase the risk of HIV transmission and acquisition 2 and new infection induces a rapid rise in viral load, repeated testing of pregnant women and their partners can identify persons at high risk of transmitting or acquiring HIV during pregnancy. 11 Testing of HIV-uninfected male partners of HIV-infected pregnant women and repeat testing of HIV-uninfected pregnant women during the third trimester are particularly important because of the increased risk of HIV transmission during pregnancy (both from man to woman, and from woman to man). 2,7,11 HIV-uninfected pregnant women and their partners who are HIV infected or at high risk of HIV infection can benefit from knowing about symptoms of acute retroviral syndrome (e.g., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, and headache) and the increase in viral load during acute infection. This information may motivate them to seek testing for acute infection, to seek HIV medical care if infection is confirmed, and to make informed reproductive decisions. 14,22 HIV testing also offers opportunities to provide sexual risk-reduction information and interventions, as well as condoms. 11 Providing partner services to HIV-infected pregnant women or HIV-infected partners is important to prevent onward HIV transmission. Engaging voluntary, confidential health department partner services can be especially helpful for notifying multiple partners, estranged partners, or partners who do not attend prenatal care visits (see Section 7, Risk Screening and Risk Reduction, and Section 8, Partner Services). Promptly referring HIV-infected pregnant women or uninfected pregnant women with HIV-infected partners for contraception services immediately after delivery can reduce the risk of future, unintended pregnancies (see Section 10, Reproductive Health Care). Prompt linkage of women who receive a preliminary or confirmed HIV diagnosis during pregnancy or the postpartum period can improve the health of both the woman and her infant and minimize transmission risks (see Section 4, Linkage to and Retention in Care). # Antiretroviral treatment and prophylaxis for pregnant women with HIV The goal of ART during pregnancy is to maximally suppress viral load, restore or preserve immune function, improve quality of life, and prevent perinatal and sexual transmission. Maternal ART use that suppresses viral load to undetectable levels or to levels <50 copies/ml decreases the risk of HIV transmission from mother to infant from 25% to <1%. [23][24][25] Regardless of their CD4 cell count, pregnant women who adhere to appropriate combination ART have a substantially lower risk of perinatal transmission than untreated women. 7,26 Starting ART before conception provides more time to maximally suppress viral load before pregnancy and reduce the risk of perinatal transmission to the greatest degree (see Section 10, Reproductive Health Care). Choice of regimens may be affected by several factors, including the potential to maximize viral suppression, the risk of maternal and fetal toxicity, the need for dosing adjustments due to pharmacokinetic and physiologic changes during pregnancy, the presence of drug resistance, the degree of side effects, and patient preferences (see . # Invasive prenatal and intrapartum procedures Invasive procedures in pregnant women with known or undiagnosed HIV infection can increase the risk of fetal HIV exposure. These procedures include amniocentesis, chorionic villous sampling, percutaneous umbilical blood sampling during the prenatal period, intrapartum amniotomy, placement of fetal scalp electrodes, episiotomy, and use of forceps or vacuum extraction delivery during labor. 7 When these procedures are indicated, women who use effective antiretroviral treatment (ART) regimen before the procedure to maximally suppress viral load can reduce the risk of fetal exposure. If membranes rupture spontaneously before labor starts or early in labor, women in labor should be managed on an individual basis depending on how long since membranes ruptured, the plasma viral load, the current ART regimen, and the planned mode of delivery based on obstetrical indications. Data are limited regarding the influence of cesarean delivery after rupture of membranes in decreasing the risk of perinatal HIV transmission. 7 # Cesarean delivery The risk of perinatal transmission among women with suppressed viral load during labor who undergo a vaginal delivery is low, but increases as maternal viral load increases. Studies have shown that the risk of HIV transmission to the infant is less than 2% in women with varied levels of viral suppression who undergo cesarean delivery for obstetric indications after the start of labor and membrane rupture and in women who undergo vaginal delivery while taking prenatal ART. 7 Assessing HIV viral load at approximately 34 to 36 weeks gestation can determine the extent of viral suppression and the safest mode of delivery. 7 Because cesarean delivery reduces exposure to blood and vaginal secretions in the birth canal, current federal guidance recommends this procedure for women with viral load levels >1000 copies/mL at the time of delivery or for women who deliver 4 hours after membranes rupture. 7,27,28 The presence of genital herpetic lesions during the intrapartum period (which may prompt some health care providers to offer cesarean delivery to reduce the risk of neonatal herpes § § ) also increases genital HIV shedding, which may increase risk of perinatal HIV transmission. 29,30 # Interventions for newborns with known or suspected HIV exposure Infant HIV testing and linkage to HIV care HIV testing of the infants of women known to be infected during pregnancy is needed to determine if the infant is infected. 7 Virologic tests (RNA or DNA nucleic acid amplification tests [NAAT]) are used to diagnose infant infection because infant HIV antibody tests during the first 18 months of life cannot distinguish passively acquired maternal antibody from antibody expressed due to infant infection. When maternal virologic control was poor during pregnancy or adequate follow-up of the infant is uncertain, some experts recommend virologic testing of the infant at birth using NAAT tests. Newborns with positive NAAT tests immediately after birth warrant being offered ART, whereas newborns with negative NAAT tests immediately after birth warrant being offered postnatal infant prophylaxis* with antiretroviral medications (see next topic). Infants born to women whose HIV infection status is unknown at delivery can benefit from expedited antibody tests. 7 A positive test identifies HIV-exposed infants who warrant being offered prophylaxis and later virologic testing to assess infant HIV infection. Positive infant antibody tests also identify infected mothers due to detection of maternal antibody. Notifying a mother that a positive infant antibody test indicates maternal infection may prompt her to seek HIV care for herself and follow up care for the infant. Reporting of cases of HIV-exposed infants to health departments by health care providers or through hospital and birthing center surveillance programs may activate communication with health care providers who can engage care for the infant or mother 8 (see Section 4, Linkage to and Retention in § § The American College of Obstetrics and Gynecology also recommends cesarean delivery for women with herpetic lesions or prodromal symptoms of genital herpes at the time of labor or after membrane rupture to reduce the risk of neonatal herpes. * Postnatal infant prophylaxis is the use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. Care). During follow-up visits for HIV-exposed or HIV-infected newborns and their parents or caregivers, providers can offer support for adherence to infant prophylaxis, ART, and maternal ART; reinforce the need to feed infants with formula instead of breast milk; and discuss postpartum contraception services. # Antiretroviral prophylaxis for newborns of women with HIV All infants born to women with HIV warrant a postnatal regimen of prophylactic antiretroviral medications because this regimen can reduce their risk of HIV acquisition. 7 Infant antiretroviral prophylaxis is most effective when started within 12 hours of birth and when adherence is high. 7 Close clinical follow-up of these infants allows for sustained adherence support and HIV testing to confirm or exclude the infant's HIV diagnosis. 31 Social workers, case managers, and home health personnel can help parents and caregivers support high adherence to infant prophylaxis. Detailed recommendations about treating HIV in infants are found in other documents. 7 # Infant feeding Breastfeeding by women with HIV, even those taking effective ART, is not recommended in the United States because formula is a safe, affordable, available, and acceptable alternative. 7 Breastfeeding increases risk of perinatal HIV transmission by 5%-20%. 7 Some women face cultural or familial pressure to breastfeed and may need additional education and counseling to avoid breastfeeding. 32 Because expressed breast milk may contain HIV and could expose recipients to HIV, it is not safe for women with HIV, regardless of their viral load or ART treatment status, to donate breast milk to human milk banks. 33 Infants may also acquire HIV by eating food that has been prechewed by a person with HIV. This may be due to obvious or inadvertent contamination of the food with blood from HIV-infected persons who have bleeding gums or other sources of oral bleeding or have had recent dental work. 16 # Interventions for HIV-uninfected pregnant women with partners with HIV Methods that discordant couples can use to reduce the risk of HIV transmission during pregnancy are also described in other sections. Federal guidance notes that pregnancy is not a contraindication for PrEP. Information on the safety of maternal PrEP use for the fetus and newborn is limited, but no harm has been reported to date. 3,7 PrEP may be clinically indicated for HIV-uninfected women with HIV-infected partners who are attempting conception or who are pregnant and have received counseling about the risks and benefits of PrEP use. 3,7 Also, some HIV-uninfected women started taking PrEP before they became pregnant because of their substantial risk of acquiring HIV. Women who wish to sustain this protection during pregnancy may continue to use PrEP. Federal guidance recommends that health care providers prescribing PrEP for women during pregnancy notify other maternal or infant care providers about this PrEP use and submit reports about pregnant women using PrEP (with no identifying information about the pregnant women) to the Antiretroviral Use in Pregnancy Registry. 3 # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Over the last 3 decades, cases of perinatal transmission in the United States have declined due to many factors. These include widespread use of opt-out prenatal HIV testing of pregnant women, maternal ART, maternal and infant prophylaxis, scheduled cesarean delivery, avoidance of breastfeeding, and other maternal and infant interventions. 34 In 2012, an estimated 161 persons under the age of 13 years were diagnosed with perinatally acquired HIV infection in the United States. 35 An HIV diagnosis in a pregnant woman may be missed if prenatal HIV testing is not routine and is only directed to women classified as having high risk of HIV, or if repeat HIV testing is not offered to women who tested negative earlier in pregnancy. Women with HIV who are uninsured or who live in communities that are rural or have a low prevalence of HIV may have trouble finding or gaining access to affordable prenatal and postpartum care or health care providers skilled in managing pregnant women with HIV. 36 Implementation of the Patient Protection and Affordable Care Act and continued support for federally funded reproductive health programs may improve access to prenatal and postpartum care services. [37][38][39] Providers who need information about reproductive issues for persons with HIV can consult the Clinicians Consultation Center (see the Implementation Resources topic below). 40 Community-based HIV testing programs for sex workers, drug users, and survivors of rape or intimate partner violence can also identify women at high risk of acquiring HIV infection before or during pregnancy. 36,41,42 State and local health departments vary regarding their capacity to conduct active surveillance for cases of maternal HIV infection, HIV-exposed infants, and HIV-infected infants and to follow up with providers who reported these cases, particularly since some jurisdictions do not require reporting of HIV-exposed infants 43 (see Section 4, Linkage to and Retention in Care). # Policy, legal, and ethical considerations State laws about HIV testing during pregnancy vary and are guided by principles of voluntary testing. Most states allow an opt-out approach. Others require written informed consent, special patient education, and medical record documentation before HIV testing. Regardless of the consent method, all states require that pregnant women should be aware when HIV testing is being performed, receive information about the test, and understand that they can decline testing without the risk of being denied medical care. 5 Routine use of opt-out testing during prenatal care has increased the number of women who receive prenatal HIV testing and gain access to perinatal HIV prevention strategies. [44][45][46] The number of adolescents using HIV testing services also increased in several states after they suspended parental consent requirements. 47,48 Nevertheless, cases of perinatal transmission continue to occur in the United States, primarily in women who are exposed to HIV or diagnosed with HIV infection after pregnancy is recognized or who decline services that prevent perinatal transmission. Some women may defer HIV testing or prenatal care if they believe that information about maternal HIV infection, sex work, or substance use may influence child custody decisions or provoke partner abuse. 49 When providers notify pregnant women who have declined prenatal HIV testing that their newborn's HIV positive test results indicate maternal infection, they should offer these women voluntary HIV prevention and care services but respect their right to decline them. These services include HIV testing, HIV medical care, and social services that may influence future decisions about HIV testing or infant care (e.g., counseling about how to avoid abuse by a partner who may become violent after learning of the infant's HIV infection status). Providers who are familiar with state laws about maternal and infant testing, case reporting, HIV disclosure, and protocols for confidential exchange of health information are in the best position to address these concerns while respecting patient autonomy about HIV testing. Section 3, Context of Prevention, Section 8, Partner Services, and Section 9, STD Services, address duty-to-inform laws that may prompt providers to notify pregnant sex partners of possible HIV or STD exposure. A woman's decision to use antiretroviral medications during pregnancy is voluntary and must honor her autonomy. This decision may weigh considerations of fetal or newborn safety; pregnancy-related conditions, such as nausea; medication costs; and other factors. ART adherence may be especially challenging for pregnant women who face the many physical and psychological changes of pregnancy and newborn care. Providers can encourage pregnant women to stand and maintain high adherence to ART regimens that are safe during pregnancy by offering information about how to manage side effects and how to obtain affordable ART through insurance, the AIDS Drug Assistance Program (ADAP), or other drug assistance programs. Section 5, Antiretroviral Treatment, and Section 6, ART Adherence, describe other ART issues relevant to pregnant women. # Special populations Some pregnant women and adolescents with HIV may practice sex work, be heavy alcohol and substance users, be incarcerated, experience mental illness or sexual violence, or lack regular health care. Quality improvement is an approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. ‡ Monitoring and evaluation is a process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. # Evidence Supporting the Recommendations # Poverty, unemployment, and lack of affordable health care Surveillance data in geographic areas with the highest prevalence of HIV infection demonstrate that poverty, unemployment, and lack of job opportunities are common among persons with HIV. [19][20][21] Nationally representative data indicate that nearly 44% of persons who received outpatient HIV medical care in 2010 reported household incomes at or below the federal poverty threshold. 22 A study evaluating low-income, urban areas with high HIV prevalence found that the HIV prevalence of persons living below the federal poverty line was twice as high as that of persons living above the poverty line (2.4% prevalence vs. 1.2%, respectively). 23 Poverty and unemployment pose barriers to obtaining health insurance, HIV medical care, specialty services, and sustained access to costly ART. Poverty may also lead to unstable housing and lack of food that may force people to pay for basic necessities instead of ART medications. 24,25 Compared with employed persons with HIV, unemployed persons with HIV report a lower quality of life and greater suffering from depression, suicidal thoughts, low self-esteem, and impaired memory. [26][27][28] Steady employment is associated with higher adherence to ART and better health outcomes partly because it fosters regular schedules that serve as reminders to take ART and to keep HIV care appointments. 27,29,30 Malnutrition related to poverty may exacerbate the immunosuppression associated with HIV; it may also impair ART tolerability, absorption, effectiveness, and adherence. 25,31 Case management and navigation assistance have been shown to help persons with HIV obtain income assistance and health insurance 11 (see . Studies have also shown that many HIV service providers who recognize the psychological and structural benefits of employment refer persons with HIV to employment support services. 26,28 # Unstable housing and homelessness Persons who have unstable housing or are homeless have HIV/AIDS infection rates that are 3 to 9 times the rates of persons with stable housing. 32 Unstable housing can cause psychological distress and lifestyles that lead to risk behaviors, such as having multiple sex partners, engaging in sex work, and abusing drugs or alcohol. One multicenter study published in 2008 found that homeless persons were 3 to 4 times more likely than persons with stable housing to use drugs or exchange sex for drugs or money and were significantly more likely to have elevated HIV viral load levels. 33 The lack of a consistent, secure place to store ART and lack of regular daily routines associated with stable housing can also impair adherence to ART. Residents of temporary housing who fear revealing their HIV infection status may hesitate to take ART in front of others or openly engage in HIV care and prevention services † † . [34][35][36] Risk behaviors are behaviors that can result in transmitting HIV to others or acquiring HIV through sexual contact, drug use, or during pregnancy (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). † † Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. Unstable housing may prompt some persons with HIV to have sex or inject drugs outdoors or in transient settings where condoms and sterile injection equipment are not available. 33,37 A variety of housing services have been developed specifically for adults and adolescents with HIV, 33,38,39 and some have resulted in beneficial outcomes 33 (see Table 12-1). A study published in 2009 evaluated "supportive housing" for persons with HIV, a multifaceted strategy that provides stable housing, case management, risk-reduction counseling, ART adherence support, and psychosocial support. Provision of supportive housing to 678 homeless persons with HIV in San Francisco was associated with an 80% lower mortality rate over 5 years than persons who did not receive this intervention and was found to be cost-effective. 39 Studies published in 2008 and 2010 found that persons with HIV who received rental assistance were more likely than those who did not receive this aid to refrain from high-risk sexual behaviors and substance abuse and had better physical and mental health outcomes, including lower HIV viral load levels. 33,40 # Substance use, including illicit drug injection Alcohol and drug use are more common among persons with HIV; in 2012, about 7 percent of new HIV infections were among people who inject drugs. 41 Substance use can promote HIV transmission through sharing nonsterile drug-injection equipment or through cognitive and emotional changes that cause disinhibition and poor judgment, which can result in high-risk sexual and drug-injection behaviors. [42][43][44][45][46][47][48][49][50][51][52][53][54] The unstable, unstructured lifestyles and social isolation associated with substance abuse can also impair regular HIV care, high adherence to ART, and the ability to recruit family and friends to support safe behaviors and adherence to ART. [43][44][45][46][47][48][49][50][51][52][53][54][55] Treatment for substance use and alcohol abuse, including oral substitution therapy for persons who inject opioids, can reduce drug and alcohol dependency and enable access to risk-reduction interventions that encourage safer sexual or drug-injection risk behaviors. [56][57][58][59] Several studies have shown that persons receiving substance use treatment are more likely than those not receiving such treatment to start and remain in HIV medical care, to adopt safer behaviors, and to adhere to ART 1,44,[60][61][62][63] (see Table 12-1). # Mental illness Estimates of the prevalence of HIV infection among Americans with mental illness vary between 3% and 23%, with a mean of about 7%. 64 Depression and other mental illness are common among persons with HIV. A recent study of 1,061 persons receiving mental health services in 2 large U.S. cities found that their HIV prevalence was more than 4 times the prevalence of the cities' general populations. 65 A nationally representative, population-based study of 3,643 persons with HIV receiving outpatient HIV medical care found that 33% needed mental health counseling. 66 Psychosocial distress and mental illness may stem from the strain of coping with a difficult chronic disease, social isolation, limited social support, discrimination, abuse, or violence. Stigma and discrimination related to HIV, sexual orientation or gender identity (e.g., homophobia, transphobia), ‡ ‡ poverty, race, substance use, and unstable housing may lead to psychological distress, depression, and other mental health problems that, in turn, can erode safe behaviors and cause immunosuppression. [67][68][69][70][71][72] Persons who anticipate being stigmatized when seeking HIV prevention and care services may also forego valuable services. 68,69,[73][74][75] ‡ ‡ Transphobia is an aversion to individuals who do not conform to the traditional or cultural norm of gender identity. Mental illness can also hinder the use of safe sex and drug-using behaviors, the willingness or ability to use prevention and care services, and the use of and adherence to ART. [76][77][78] Stress; depression; difficulty coping with a complex, potentially fatal chronic disease; and a lack of social support have also been associated with increases in viral load levels. [79][80][81][82][83] Several studies have shown that receiving mental health services improves engagement and retention in HIV care and quality of life 1,61,62,77,84 (see Table 12-1). # Legal detention and incarceration In some jurisdictions, person with HIV who carry HIV prevention devices in public, such as condoms or sterile drug-injection equipment, may be vulnerable to prosecution for commercial sex work or drug use, respectively. 85,86 HIV incidence is about 3 times higher in prisoners than in the general population. 87,88 At the end of 2008, an estimated 1.5% of state and federal prisoners were infected with HIV. 88 Adults and adolescents with HIV in jails, halfway houses, and parole programs may have unique HIV prevention and care needs. 89 Detainees with HIV may not disclose substance use, sex work, or other illegal activities that caused their infection because of concerns about prosecution, discrimination, or breach of confidentiality. 90 When persons with HIV move to or from correctional facilities, they may lose access to their usual source of HIV medical care and ART. Some prisons that provide substance abuse and mental health treatment and other specialty services onsite or through referral § § cannot continue their services after an inmate is released. After release from detention, persons with HIV also face changes in housing, food supplies, employment, transportation, income, and health insurance. This forces many to focus on meeting basic needs of food and shelter and to delay seeking HIV medical care or specialty services. 89 For this reason, correctional facilities that provide reentry transition planning or case management can increase the proportion of persons with HIV who obtain HIV prevention and care services after their release 89,91,92 (see Table 12-1). # Immigration Many undocumented immigrants with HIV are ineligible for public-or private-sector HIV prevention, care, and specialty services, including services covered by health plans regulated by the Patient Protection and Affordable Care Act (ACA). Many low-income immigrants also lack health insurance or cannot afford to pay for services out of pocket. 93,94 Some immigrants with HIV who are unaware of their infection may defer HIV testing and unknowingly transmit HIV to others. Those who are aware of their infection may delay HIV medical care or not disclose their infection to service providers if they fear arrest, deportation, or discrimination. 95 Recent immigrants may retain health care beliefs and practices from their country of origin and may hesitate to engage in mainstream medical care and use unfamiliar medications. 96 Immigrants who must rely on emergency departments, migrant health clinics, or other safety net providers often receive only sporadic care for acute conditions rather than continuous, longterm HIV medical care that is most effective. 93 Many communities have local providers, federally-funded clinics, and other medical assistance programs that provide medical and social services to immigrants (see Referral is a process to help persons identify and access needed services by offering the service provider's address, phone number, directions, hours of operation, and other basic information. # Adolescence and legal minor status Many adolescents and young adults with HIV experience age-related or legal circumstances that pose barriers to obtaining HIV prevention and care services. Some adolescents with HIV do not have established health care providers or do not know how to find HIV medical care. Several surveys demonstrate that adolescents may forgo health care if they believe information about rendered services (bills or explanations of benefits) can be disclosed without their consent to parents or guardians who sponsor their insurance. [116][117][118][119][120][121] Even when minors have rights to confidential HIV services, their doubts about confidentiality protections may deter them from seeking services (see Section 3, Context of Prevention). For example, some minors who must provide family income records to confirm eligibility for Ryan White HIV/AIDS Program benefits or other HIV services may forego these services if their parents do not know their infection status. 122 They may also defer contraception, other reproductive health services, and employment support that might influence the risk of HIV transmission. Some adolescents with HIV may fear, or have experienced, that disclosing their HIV infection to their parents prompts unwanted questions about sexual activity, sexual orientation, or substance use, or leads to accusations, abuse, or loss of parental financial support or housing. Youth with HIV who have not disclosed their diagnosis may find it difficult to adhere to ART if they must covertly take or store pills. Also, adolescents with perinatally acquired HIV often take more responsibility for managing their HIV care, ART supplies, and adherence than they did as children. 123 Providers can encourage youth to access HIV services by describing their rights to confidential health care (which may differ by state), parental disclosure requirements, and billing procedures. When confidentiality of billing information may be a problem, providers can refer adolescents to providers who do not charge for their services or do not bill parents. Some HIV prevention and care programs have created welcoming, "youth-friendly" environments that offer flexible service hours and age-appropriate education and skill-building about coping, communication, and adherence to ART. 124 Some of these orient adolescents who are transitioning from pediatric to adult health care providers about differences in patient support services. 125,126 Other valuable services include patient navigation support by peer educators, case managers, and multidisciplinary teams that address the developmental, medical, legal, and educational needs of youth 38,124,127,128 (see Table 12-1). With support from CDC, HRSA, and the National Institute of Child Health and Human Development, urban adolescent care centers, local health departments, and adolescent outreach experts are collaborating in a program that supports identification of youth with undiagnosed HIV and prompt linkage to providers of HIV medical care who practice in "youth-friendly" settings. 129 New guidance for adolescent health care providers who serve gay, bisexual, and transgender youth at risk of HIV is also available. 106 # Advanced age As persons with HIV in the United States live longer, the number of older persons with HIV is rapidly increasing. By 2020, an estimated one-half of all persons with HIV will be aged 50 years or older. 130 Many older persons with HIV have or will develop physical, mental health, or social needs related to chronic HIV infection and the normal aging process that may warrant special assessment, support, or services. 131,132 For example, age-related changes in immune function may impair response to ART. Older patients with suppressed viral load consistently experience less robust CD4 cell count responses, possibly because CD4-cell-mediated immune reconstitution related to thymic function declines with age. 130 Cognitive decline, comorbid health conditions, social isolation, and "regimen fatigue" may also erode adherence to ART. 133 Aging may also change sexual practices. Persons who lose longstanding partners may seek new or casual sex partners. Persons may use sexual performance aids (e.g., penile rings) that may cause genital trauma or erectile dysfunction medications that have been associated with higher levels of unprotected anal sex † † † . [134][135][136][137] Providers who routinely assess adherence to ART and risk behaviors of older persons with HIV can tailor services, risk-reduction messages, and HIV prevention and care services to any unique needs 9 (see Section 7, Risk Screening and Risk Reduction, Section 6, ART Adherence, and Unprotected anal sex is sexual activity without using a physical barrier (i.e., without using a male condom; oral-anal contact without using a dental dam or other barrier device; or rectal-digital contact without using a latex glove or finger cot). # Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities The capacity to provide specialty services to persons with HIV varies greatly by jurisdiction and is limited in many communities. For example, a study published in 2012 found substantial gaps in mental health services; substance use treatment; and support for food, housing, and transportation for persons with HIV. The study cautioned that this gap in infrastructure would increase if service capacity did not keep pace with the growing number of persons with HIV. 110 Several factors impair the delivery of specialty services: lack of understanding that other medical and social issues influence HIV transmission; lack of established infrastructure, standard procedures, trained staff, and tracking methods; lack of time; and competing priorities. [138][139][140] Case managers and coordinated case management systems for persons with HIV with complex navigation needs are scarce in many areas. 11,66 Specialty services serving youth, rural residents, undocumented immigrants, and persons lacking health insurance are particularly overstretched. 141,142 Fortunately, implementation of the ACA promises to improve access to and use of specialty services by the growing number of persons with HIV who have enrolled in private insurance, Medicaid, or other medical assistance programs. [143][144][145] The ACA will also enable health care providers working in Ryan White-funded clinics to bill Medicaid, other medical assistance programs, or private health insurance for specialty services related to HIV prevention and care. 146 Use of multidisciplinary teams, collaboration, and task-sharing can also facilitate access to specialty services 8,10-12 (see Boxes 12-A and 12-B). For example, clinical providers can engage mental health care, substance use treatment, or other special medical services that are provided onsite or through referral to other health care providers, while nonclinical providers can help persons with HIV find stable housing, transportation to medical visits, and condom supplies. Nonclinical HIV testing sites can assess specialty service needs as part of their routine risk screening ‡ ‡ ‡ or post-test services for persons who test positive. Health care facilities that cannot hire onsite case managers may contract with community-based organizations that offer navigation assistance to persons with HIV. # Policy, legal, and ethical considerations Referrals to specialty services usually require the exchange of confidential health information. Persons with HIV may be more willing to respond to a referral recommendation when providers seek explicit informed consent and describe measures to maintain confidentiality during the referral process, such as the Health Insurance Portability and Accountability Act and state or federal confidentiality standards specific to HIV 147 (see Section 3, Context of Prevention, for additional information on confidentiality). # Implementation Resources Resources to support implementation of these recommendations are found at http://www.cdc.gov/hiv/guidelines/implementationresources.html. They include referral assessment tools, sample memoranda of agreement with referral agencies, and online directories of specialty service providers. QI relies on the routine, repeated use of demographic, administrative, and health data to improve clinical and public health systems, processes, and outcomes. QI has traditionally been the domain of health care administrators who are seeking better health outcomes, higher standards of care, more efficient operation, or greater patient satisfaction. Recently, health departments and nonclinical organizations have engaged in QI efforts. 1 QI is driven by 3 fundamental questions:  "What change in health status or other outcomes do we want to achieve?"  "What kinds of changes can we make that may result in an improvement?"  "How will we know that a change led to an improvement (i.e., how is change measured)?" QI usually involves small, incremental changes in practice and rapid feedback of results. It is often an iterative process of repeated cycles of change and feedback that can be integrated into practices and programs as a continuous, routine performance improvement strategy and can be led by internal staff (see Table 13-1). The process relies on collecting and analyzing "real-time" data that reflect current practice. In HIV medical settings, QI often focuses on guideline adherence; evidence-based § clinical decision making; or measures to increase efficiency, lower costs, strategically use staff and health information, or improve care coordination and patient flow. For example, staff in one HIV outpatient clinic compared 2 types of computer alerts in electronic medical records (EMRs) used by physicians serving patients with high HIV viral load or suboptimal retention in care. 2 Use of "interactive alerts" that facilitated appointment scheduling and laboratory testing were associated with greater improvements in CD4 cell counts and follow-up visits than "static alerts" that only listed these patients. * Prevention services include interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. † Clinical settings are health care facilities in which medical diagnostic, treatment, and disease prevention services are routinely provided. ‡ Nonclinical settings are facilities that provide prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. § Evidence-based interventions, strategies, guidelines, and recommendations are based on sound scientific research, testing, or program evaluation. ** An electronic medical record (EMR) is a patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. Program monitoring involves the ongoing, repeated collection and review of information about the activities and operation of a program. Program evaluation involves periodic collection of information about program activities, characteristics, and outcomes in order to assess causal attribution, improve effectiveness, or identify lessons learned. 3 M&E efforts usually focus on questions of program design, implementation, effectiveness, acceptability, coverage, and cost. They attempt to answer questions, such as the following:  "What are we trying to accomplish?"  "Are we doing it right?"  "Are we implementing the program as planned and on a large enough scale?"  "What assumptions or potential risks relate to this program?"  "Are the interventions making a difference?" Because M&E can assess program coverage, impact, and costs, M&E is an essential accountability function of many health departments, HIV planning groups, and publicly funded community-based organizations. Recent federal M&E efforts have focused on monitoring linkage † † to (and retention in) HIV medical care, antiretroviral treatment (ART) use, and viral suppression, and the collected data and performance measurements are now used by several federal agencies (see Table 13-2). Some state health departments have analyzed population-level data about continuum of HIV care, such as the proportion of persons in the jurisdiction without laboratory reports indicating continued care and suppressed viral load. These analyses can identify populations that would benefit from being offered interventions to improve retention in care. 4 The recommendations and examples of best practices for QI and M&E in this section were based on a review of federal and state recommendations for QI and M&E that are relevant to HIV clinical settings and nonclinical programs, national HIV indicators and performance measures, and opinions of experts on QI and M&E for HIV clinical care and community programs (see Box 13-A and Figure 13-1). [5][6][7][8][9][10][11][12] These practices can be applied to many interventions (see and used by government agencies, public and private payers, accreditation entities, health departments, community-based organizations, large health systems, and small clinical practices. † † Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). For staff of health departments and HIV planning groups who provide population-level HIV prevention and care services  Regularly monitor program implementation and periodically evaluate program outcomes according to best practices (i, iii, iv) Note. Some of the federal guidelines cited in the Recommendation boxes may have been updated. For current federal recommendations, please refer to http://www.cdc.gov/hiv/guidelines/personswithhiv.html. a In this report, nonclinical providers are defined as persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. Clinical providers are defined as persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other health-related services. These providers include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. b The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup and program experience, the section writing group concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. opportunities, and challenges of the service or program and priorities for improvement  Develop a program improvement plan that describes the service or program purpose, defines QI goals and strategies, establishes accountability for the plan, and describes resources for QI activities  Develop a "conceptual map" that depicts the relation between program inputs, outputs, and outcomes to pinpoint where to target improvement activities  Design QI intervention cycles after reviewing past experience from literature, colleagues, technical assistance providers, and stakeholders  Establish benchmarks, baseline measures, and performance goals based on national or local standards, clinical guidance, or accreditation standards  Develop data collection methods that adhere to confidentiality and data security regulations  Identify, test, refine, and use new or existing indicators to track service delivery, quality, satisfaction, and outcomes (see Table 13-2)  Implement interventions by testing feasibility and evaluating results (e.g., "Plan-Do-Study-Act" approach) (see Table 13-1)  Develop and execute a plan to interpret and communicate data after consulting with stakeholders  Scale up successful, feasible interventions and identify lessons from interventions that did or did not result in desired change  Repeat QI cycles to determine if interventions achieve desired outcomes Note. Many programs use additional, program-specific indicators. # Methods The recommendations in this section were based on guidance from CDC and HRSA that were supported by scientific evidence, program experience, and expert opinion. 5,10,17,18 Issues that Influence Implementation of the Recommendations # Implementation progress, challenges, and opportunities Many federal, state, and local programs routinely implement QI and program evaluation methods that address HIV prevention with persons with HIV. [18][19][20] Quality management programs that develop and encourage reporting of performance measures are more likely to motivate programs to participate in QI and M&E. 21 For example, the Health Resources and Services Administration's HIV/AIDS Bureau engages in many quality initiatives for HIV services provided through the Ryan White HIV/AIDS Program that are guided by a set of clinical performance measures. 21 This focus on QI and program evaluation has expanded the range of clinical and social services for persons with HIV, improved documentation and billing of rendered services, and introduced more versatile electronic medical information systems and novel uses of surveillance and administrative data. 19,22,23 QI and M&E are intended to improve service access, quality, cost, overall impact, and/or satisfaction for clients and other program stakeholders, but can sometimes disrupt service delivery priorities and require substantial resources. Developing or amending data collection processes and electronic information systems to collect or calculate performance data can be costly, complex, time-consuming, and require hiring of specialized staff. 21 Burdensome data collection to meet internal demands or external accountability requirements can become an end in itself and is wasteful if it is not used to guide program improvement. If QI and M&E results are used to create incentives for improvement or change rather than to highlight failures, they are more likely to be acceptable to an organization's employees and leadership. # Policy, legal, and ethical considerations Several organizations have issued guidance about policy, legal, and ethical factors that influence HIVrelated QI and M&E. This guidance addresses sharing health information, protecting patient confidentiality, using HIV-related surveillance and clinical data for QI and M&E, balancing data collection burdens with program benefit, maintaining integrity when evaluating publicly funded programs, and respecting staff and client time and privacy. [24][25][26][27][28] Section 3, Context of Prevention, provides additional information on confidentiality issues. # Client. A person receiving prevention, testing, or social services from a health department or communitybased service providers, not including health facilities. This term is preferred over 'patient' in settings that provide healthy persons prevention and health maintenance services. Clinical providers. Persons who work in health care facilities and who provide risk assessments, health education, counseling, screening, diagnosis, treatment, and other services to prevent, diagnose, treat, or manage health conditions. They include physicians, registered nurses, advance practice nurses, physician assistants, dentists, mental health providers, pharmacists, health educators, case managers, social workers, and counselors. Some may be employees or contractors of health departments. Clinical setting. A health care facility in which medical diagnostic, treatment, and disease prevention services are routinely provided. Collaboration. Working with another person, organization, or group for mutual benefit by exchanging information, sharing resources, or enhancing the other's capacity, often to achieve a common goal or purpose. Colocating. The provision of more than one type of HIV service in the same physical space, such as providing substance use treatment in an HIV medical clinic or providing HIV partner services in an HIV testing facility. Community-based HIV service organizations. Organizations that offer and deliver community-based HIV services, not including diagnostic and treatment services. Many collaborate with health departments to provide services to specific populations. Confidentiality. Ensuring that information is accessible only to persons authorized to have access in order to maintain client and patient privacy. # Coordination. A process of creating more client-centered, streamlined, and nonduplicative systems that clarify communication methods, staff roles, use of health information, and reimbursement policies and procedures. Culturally appropriate. Conforming to a culture's acceptable expressions and standards of behavior and thoughts. Interventions and educational materials are more likely to be culturally appropriate when representatives of the intended audience are involved in planning, development, and pilot testing. Cunnilingus. Oral stimulation of the female genitals. # Diagnostic testing. Testing that is initiated for a person with clinical signs or symptoms to obtain objective evidence of the presence or absence of diseases or infections, including HIV and STDs. # Directly administered antiretroviral treatment or therapy (DAART). A method to promote ART adherence in which a clinical or nonclinical provider observes persons with HIV take all or most doses of prescribed ART. Also referred to as directly observed therapy (DOT). # Disclosure (of HIV infection status). A process in which a person with HIV reveals his or her HIV infection to others, or when an HIV prevention or care provider shares information about a person's HIV infection status with another HIV prevention or care provider. # Drug-injection partner. A person who has shared nonsterile or previously used needles, syringes, or other drug-injection equipment with another person. exposure; offering testing for HIV, sexually transmitted diseases, and other infections; providing condoms, prevention information, and counseling; and providing help in obtaining risk-reduction services, HIV medical care, and other medical and social services. Partner services specialists. Persons who provide partner services, including specially trained disease investigation specialists, public health investigators, or communicable disease investigators who work in health departments and staff of other agencies who are trained and authorized to provide these services. Person at high risk of HIV infection. A person who has behaviors that place him/her at high risk of contracting HIV infection (e.g., having unprotected sex or sharing drug-injection equipment with a person known to be HIV-infected or with persons from communities with a high prevalence of HIV infection). # Persons who inject drugs (PWID). Persons who inject illicit drugs using equipment that may facilitate HIV transmission, such as nonsterile syringes, needles, cookers, or spoons. Population-level intervention. An intervention intended to improve the risk conditions and behaviors in a population or community by focusing on the population or community as a whole, rather than on individuals or small groups. Examples include community mobilization, social marketing campaigns, community events, policy interventions, and housing programs meant to alter social norms, policies, or environmental characteristics. Postnatal infant prophylaxis. The use of selected antiretroviral medications for several weeks by newborns born to women with HIV to prevent HIV acquisition. Preexposure prophylaxis (PrEP). The daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. Presumptive treatment. The provision of treatment for syphilis, gonorrhea, chlamydial infection or trichomoniasis before the results of STD testing or clinical evaluation are available. This treatment approach is recommended for persons who report symptoms suggestive of these STDs or recent sex partners who were treated for these STDs, or have clinical signs of these STDs. Prevalence. The total number of cases of a disease in a given population at a particular point in time. HIV/AIDS prevalence refers to persons infected with HIV, regardless of time of infection or diagnosis date. Prevention services (or program). Interventions, strategies, policies, and structures designed to reduce the transmission of HIV infection. Examples of HIV prevention services include risk-reduction information and interventions, condom distribution, use of antiretroviral therapy to reduce HIV viral load, and STD screening and treatment to control infections that can facilitate HIV transmission. A prevention program is an organized effort to implement one or more interventions. Privacy. The right and power to control information about oneself. Quality improvement. An approach to the continuous study and improvement of the processes of providing services that meet or exceed established professional standards and user expectations. Receptive anal sex. The practice of receiving a partner's penis in one's anus. Also known as receptive penile-anal sex. assess the risk of disease progression, to monitor virologic response to ART, and to estimate the degree of infectiousness. Virologic failure. The inability to achieve or maintain suppression of HIV replication to an HIV RNA level of <200 copies/mL. Virologic testing. The process of using tests that detect HIV antigens or nucleic acids such as RNA or DNA Window period. Interval between a person's infection with HIV and the production of HIV antibodies that can be detected by an HIV test. # Acknowledgments The Project Workgroup thanks staff and members of the HIV Medicine Association of the Infectious Diseases Society of America, Arlington, Virginia, for their invaluable comments on several drafts. # Abbreviations AAHIVM-American Academy of HIV Medicine Box 8-A. Recommended strategies to establish infrastructure for HIV partner services (cont)  Establish criteria for partners who warrant expedited notification with the following characteristics (i, ii):  Likely to be infected with HIV or STD but unaware of their infection  Had contact with index patients in the 3 months before their HIV diagnoses  Warrant STD testing and presumptive STD treatment because the index patients are coinfected with STD  Spouses, long-term partners, and other partners who had contact with index patient in the past 12 months  Establish protocols regarding methods and preferred timeframes to expedite the following partner services (i):  Communicating with index patients (preferably within 2-3 working days of identifying the index patient) and follow-up communication if the index patient did not provide partner information at the initial encounter (preferably within 2 weeks of the initial encounter)  Notifying partners in person or by phone, letter, email, or other means (preferably within 2-3 working days of obtaining partner locating information)  Providing index patients STD and viral hepatitis screening, reproductive health services, and relevant support services onsite or by linking to another provider (preferably within 2 weeks of initial encounter) f  Providing partners screening for HIV, STD, and viral hepatitis, evaluation for HIV prophylaxis, and other medical and social services onsite or by linking to another provider f  Periodically evaluate the partner services program to guide quality improvement e (i) # Note. Another document describes additional recommendations on infrastructure. 1 a Acute HIV infection is the period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. b PrEP is the daily, continuous use of a specific regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. In July 2012, FDA approved one PrEP regimen (tenofovir/emtricitabine) for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. c nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. d See Section 5, Antiretroviral Treatment, for more information about HIV prophylaxis for HIV-uninfected partners of persons with HIV. e See Section 13, Quality Improvement, for more information. f Viral hepatitis testing (and treatment of infected persons) has not been shown to influence HIV transmission but is included here because it is often offered in combination with HIV and STD testing for individual and public health benefits. This section does not address services for partners exposed to viral hepatitis by persons with HIV who are coinfected with viral hepatitis. g See Section 9, STD Services, for more information on STDs that may facilitate HIV transmission. h See Section 11, Pregnancy, for more information on how pregnancy influences HIV transmission. # Sources Implementation Resources Additional information and resources to support implementation of these recommendations can be found at http://www.cdc.gov/hiv/guidelines/. # Recommendations RECOMMENDATIONS-SEXUALLY TRANSMITTED DISEASE (STD) PREVENTIVE SERVICES For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV)  At the initial HIV-related encounter and thereafter with a frequency appropriate to setting and risk assessment results, provide the following services:  Inform persons with HIV about: • methods to reduce the risk of HIV and STD transmission a (i, ii, iii, iv, v) • STDs that can increase HIV viral load and may facilitate HIV transmission a (i, iii, iv) • the benefits of screening for STDs (that are often asymptomatic) and STD treatment a (i, iii, iv)  Assess these behavioral and biologic risk factors for HIV and STD transmission c : • Sexual, alcohol, and drug-use behaviors that may lead to HIV or STD transmission a,b (i, ii, iii, iv) • Recent sex partners who were treated for STD a,b (i, iii, iv) • Past and recent STD diagnosis, screening, and symptoms a,b (i, ii, iii, iv) • Concurrent STD infection by providing STD screening tests onsite (if allowed by professional authority) or linking to a health care facility that provides STD screening tests a,d,e,f (i, iii, vi) (see Box 9-A)  Offer latex or polyurethane male and/or female condoms g (i, ii, iii)  For persons with HIV who report sexual risk behaviors, provide the following services: • Provide or refer for brief or intensive behavioral risk-reduction interventions b (i, ii, iii, v, vi) • Refer to voluntary health department HIV partner services or other trained partner services provider if persons are newly diagnosed with HIV or report new sex partners h (i, ii, iii, iv, v)  For persons with HIV who report symptoms suggestive of an STD or recent sex partners who were treated for syphilis, gonorrhea, chlamydial infection, or trichomoniasis, provide access to presumptive STD treatment according to the latest Centers for Disease Control and Prevention (CDC) STD Treatment Guidelines through i • onsite clinical evaluation (including physical examination and diagnostic testing) followed by immediate presumptive treatment, if allowed by professional authority (i, iii, iv) or • immediate linkage to a health care facility that offers clinical evaluation and onsite presumptive STD treatment a,e (i)  For persons with HIV who have positive STD screening tests, provide the following services: • Provide access to treatment according to the latest CDC STD Treatment Guidelines through onsite treatment or linkage within 24 hours to a health care facility that offers onsite STD treatment (including recommended injectable medications), a,e as allowed by professional authority (i, iii, vi, vii) • Refer to voluntary health department HIV/STD partner services or other trained partner services provider h (i, iii, iv) • Provide or refer to brief or intensive behavioral risk-reduction interventions a,b (i, iii, vi) • Report cases of STD according to jurisdiction requirements and inform persons diagnosed with STD that case reporting may prompt health departments to offer voluntary, confidential partner services in some jurisdictions j (i, iii) Box 9-A. # Recommended STD screening for persons with HIV who are sexually active (cont) Note. Source guidance that supports these recommendations also indicates that type-specific serologic testing for herpes simplex virus type 2 (HSV-2) infection can be considered in persons with HIV with unknown herpes infection status. 1,7 Note. This section does not address screening for other conditions that may affect persons with HIV but have not been shown to facilitate HIV transmission to others, such as viral hepatitis, bacterial vaginosis, and human papillomavirus infection. Note. Most STD screening occurs in clinical settings. However, some nonclinical settings have the capacity to screen for gonorrhea and chlamydia (using self-collected urine, vaginal, rectal, and oropharyngeal specimens) or syphilis (using venous blood drawn by phlebotomy). a Using tests recommended by CDC for laboratory detection of Chlamydia trachomatis and Neisseria gonorrhoeae. 4 b For gonorrhea and chlamydia screening, optimal specimen types for NAATs are first-catch urine from men and vaginal swabs from women that are collected in clinical settings. 4 In women with cervicitis, endocervical specimens and vaginal specimens yield comparable results when tested with NAATs. Commercially available NAATs for C. trachomatis and N. gonorrhoeae are not cleared by the U.S. Food and Drug Administration (FDA) for urine, vaginal, or rectal specimens collected outside clinical settings. However, some laboratories have established performance specifications for testing specimens collected outside clinical settings to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. 1,4,8 c Using tests recommended by the most recent CDC STD Treatment Guidelines. 1 d The FDA has not cleared commercially available NAATs to test rectal specimens for gonorrhea and chlamydial infection or oropharyngeal specimens for gonorrhea. However, some laboratories have established performance specifications for testing these types of specimens to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. 1,4,8 e NAATs are the most sensitive and specific tests to detect Trichomonas vaginalis. 9 f Pregnant women should be screened for vaginal trichomoniasis at the same frequency as nonpregnant women (i.e., at their initial HIV care visit and annually thereafter). g Characteristics of women at high risk are defined by the most recent CDC STD Treatment Guidelines. 1 h The cited source guidance describes the rationale for retesting for gonorrhea and chlamydial infection; the Evidence topic describes the rationale for retesting for trichomoniasis. # Implementation Resources More information on implementation, including training materials and decision-support tools, can be found at http://www.cdc.gov/hiv/guidelines/. # Box 11-A. Recommended services for pregnant women with HIV (cont) a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the writing group for this section concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b This includes women with preliminary or confirmed HIV positive test results. c A woman with HIV must explicitly grant her provider permission to discuss her HIV infection status with her partners. d See Section 5, Antiretroviral Treatment; Section 7, Risk Screening and Risk Reduction; and Section 8, Partner Services. e PrEP is the daily, continuous use of a select regimen of antiretroviral medications for a period of time by an HIV-uninfected person to achieve levels of drug in the blood and anal and genital mucosa sufficient to reduce the risk of HIV acquisition. 3 In July 2012, FDA approved one PrEP drug regimen for preventing sexual transmission. Although HHS recommendations in May 2014 advised use of this same regimen for persons who inject drugs, the product label only addresses use for preventing sexual transmission. f See Section 5, Antiretroviral Treatment, for information about notifying HIV-uninfected partners about PrEP and nPEP. The cited source guidance advises health care providers to inform HIV-uninfected persons about these interventions, but does not address the role of health care providers in informing HIV-infected persons about the use of PrEP or nPEP by their uninfected partners. g nPEP is the use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. 4 Use of antiretroviral medication for nPEP does not reflect labeling approved by FDA. h See Section 3, Context of Prevention, and Section 8, Partner Services. i See Section 9, STD Services. j The Policy, Legal, and Ethical Considerations topic describes the benefits of awareness of testing laws. For a summary of state HIV testing regulations, see "Compendium of state HIV testing laws" (http://nccc.ucsf.edu/clinical-resources/hiv-aids-resources/state-hiv-testinglaws/). 5 For a summary of minors' access to reproductive health services, see "An Overview of Minors' Consent Law" (http://www.guttmacher.org/statecenter/spibs/spib_OMCL.pdf). 6 k See Section 8, Partner Services, for information about expediting services for persons with HIV and their partners. # Box 11-B. Recommended postnatal services for women with HIV and their infants to reduce the risk of perinatal HIV transmission (cont) # Box 11-C. Recommended services for pregnant women who are HIV-uninfected or have unknown infection status and have sex or drug-injection partners with HIV # For nonclinical and clinical providers (including health department staff who provide individual-level services to persons with HIV) serving pregnant women or their HIV-infected partners  Inform women and their partners about risks of sexual acquisition of HIV and, should infection occur, the risk of perinatal transmission, including transmission during breastfeeding a (i, ii) (see Box 11-D)  Encourage consistent, correct condom use throughout pregnancy and breastfeeding to prevent sexual and/or perinatal transmission a (i, ii)  Inform women that HIV testing is recommended for all pregnant women and provide information about the test (ii, iii).  Conduct HIV testing using consent procedures consistent with state laws (e.g., inform women in states that allow opt-out testing that testing is done as part of the routine panel of prenatal tests unless they decline; obtain prior written consent if required by state law b ) (ii, iii)  Address reasons for declining an HIV test (e.g., lack of perceived risk, fear of the disease, and concerns regarding partner violence, stigma, or discrimination) (ii, iii)  Inform women about the symptoms of acute retroviral syndrome and the availability of tests for acute HIV infection if these symptoms occur or if a woman suspects recent HIV exposure a (ii, iii)  If serving HIV-infected partners of pregnant women, link partners who are not engaged in HIV medical care to health care providers who can recommend ART to reduce the risk of HIV transmission and support ART adherence a (iv)  Inform HIV-uninfected women who are considering starting or continuing use of PrEP during pregnancy or breastfeeding that pregnancy is not a contraindication for PrEP and provide information about known benefits and risks of PrEP to the woman and fetus to enable informed decision making c (ii, v, vi)  Inform women about the availability of nPEP to reduce the risk of HIV acquisition in the event of inadvertent sexual or parenteral HIV exposure within the past 72 hours (e.g., unprotected intercourse, condom breakage, shared drug-injection equipment) c (v)  Provide education, counseling, and/or referral for postpartum contraceptive services to women who wish to prevent or delay future pregnancy, as appropriate to the setting a,d (vii, viii, ix)  Offer latex or polyurethane male and/or female condoms (i) Box 11-C. # Recommended services for pregnant women who are HIV-uninfected or have unknown infection status and have sex or drug-injection partners with HIV (cont) a The cited source guidance that supports this recommendation was intended for health care providers. Based on opinions of the Project Workgroup, the writing group for this section concluded that it would be beneficial and feasible for other types of providers to implement this recommendation. b As of 2014, all but 2 states allow opt-out testing of pregnant women without prior written consent. c See Section 5, Antiretroviral Treatment, for more information regarding use of PrEP and nPEP. d See Section 10, Reproductive Health Care, for reproductive health services. e For additional information on FDA-approved tests to detect recent HIV infection, see "Complete list of donor screening assays for infectious agents and HIV diagnostic assays" (http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/Infec tiousDisease/UCM080466). 10 f The window period is the interval between a person's infection with HIV and the production of HIV antibodies that can be detected by an HIV test. g See Section 8, Partner Services, for additional information about services for sex and drug-injection partners (including pregnant women) of persons with HIV and Section 9, STD Services, for information about STD that increase a woman's risk of acquiring HIV. h The source guidance does not address distributing information about PrEP providers or hotlines. i For a summary of state HIV testing laws, see "Compendium of state HIV testing laws" (http://nccc.ucsf.edu/clinical-resources/hiv-aidsresources/state-hiv-testing-laws/), 5 and for a summary of minors' access to reproductive health services, see "An overview of minors' consent law" (http://www.guttmacher.org/statecenter/spibs/spib_OMCL.pdf). 6 # Implementation Resources The Clinician Consultation Center provides telephone or online consultation from health care providers with expertise in managing pregnancies in women with HIV and preventing HIV transmission during labor and delivery and the postpartum period (1-888-448-8765 or http://nccc.ucsf.edu/clinicianconsultation/perinatal-hiv-aids/). For resources to support implementation of these recommendations, including decision-support tools and a compendium of state HIV testing laws, see http://www.cdc.gov/hiv/guidelines/. 2 these updated recommendations advise providers to first offer specialty services that help persons with HIV to start or resume HIV medical care (e.g., providing transportation to the first visit), and then later provide specialty services that might reduce the risk of HIV transmission (e.g., substance use treatment). # BOX 12. RECOMMENDATIONS-SERVICES FOR OTHER MEDICAL CONDITIONS AND SOCIAL FACTORS THAT INFLUENCE HIV TRANSMISSION # Methods The section writing group compiled these recommendations from several CDC, HRSA, and HHS guidance documents that were based on scientific evidence and expert opinion through May 2014. [5][6][7]11,13,15,16 The writing group did not reexamine the evidence supporting these federal guidelines. The writing group conducted a narrative literature review about specialty services that are commonly needed or used by persons with HIV. The review involved searching PubMed for English-language articles § Linkage to care is the process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). # Cultural and linguistic background, gender identification, and sexual orientation Persons with HIV who are racial or ethnic minorities or are not proficient in English may feel marginalized by their communities and may be unable to access HIV prevention and care information. They may also have trouble finding HIV service providers who speak their language or offer prevention and care services that reflect their cultural norms. 93,96 Evaluations of health care systems in the United States suggest that providers who offer non-English language services and are trained in cultural competency are better equipped to serve culturally diverse persons with HIV. 100 The federal government has developed voluntary standards for language services, cultural competency training, and other means to improve access and quality of care. 101 These standards also provide guidelines for federal, state, and national agencies that accredit health care organizations. 101 HIV prevalence in the United States is very high among sexual minorities, particularly gay, bisexual and other men who have sex with men (MSM) and transgender women who practice high-risk sexual and drug-use behaviors. 41,102 National surveys and focused studies have shown that many MSM and transgender women struggle to find health care providers who are experienced in serving sexual minorities. Many also anticipate stigma or discrimination when seeking health care. [103][104][105] Some medical and social service organizations have issued guidance on professional competencies that foster more welcoming, effective services for sexual minorities. 106,107 Specialized peer support, group counseling, legal services, and health navigation assistance can also help persons who feel medically marginalized, socially isolated, or vulnerable to stigma or discrimination (see Table 12-1). # Transportation and childcare barriers Many persons with HIV lack transportation to HIV prevention and care services because their communities do not offer affordable public transportation or care services can only be accessed by car. 22,61,100,108,109 A nationally representative, population-based HIV surveillance study of persons with HIV receiving outpatient HIV care through the end of 2010 found that 9% reported needing transportation assistance. 22 Transportation is a challenge for both urban residents and rural residents who must travel great distances to obtain these services. 22,108 Case management that includes arranging transportation assistance has been shown to hasten the initiation of HIV medical care, improve retention in care, and improve adherence to ART 61,100,110,111 (see # Acquired immunodeficiency syndrome (AIDS). A disease of the human immune system caused by infection with human immunodeficiency virus (HIV). It is characterized by a reduction in the numbers of CD-4 bearing helper T cells that may result in opportunistic infections and illnesses that may be potentially life-threatening. Acute HIV infection. The period between initial HIV infection and the expression of HIV antibodies that can be detected by HIV antibody tests. This period is characterized by high levels of HIV in the blood and a vigorous immune response. Also referred to as primary HIV infection. # Acute retroviral syndrome. A symptomatic phase of acute HIV infection experienced by many, but not all, persons with HIV that is characterized by fever, lymphadenopathy, and other symptoms. Adherence. The extent to which a person takes medication in the way it was prescribed by a health care provider. Adherence interventions focus on educating and motivating patients, building patients' skills, providing support and tools for medication management, and addressing barriers to adherence. # Antiretroviral treatment or therapy (ART). Medications used by persons with HIV to inhibit HIV replication in the body or, when used for preexposure prophylaxis or postexposure prophylaxis by HIVuninfected persons, to prevent acquisition of HIV. # Artificial insemination (intravaginal and intrauterine). Conception methods in which semen is collected and instilled into the uterus (by a physician) or into the upper vagina (by a physician, person with HIV, or a partner). For HIV-discordant couples attempting to conceive, these methods pose a lower risk of HIV exposure because they avoid penile-vaginal intercourse. Behavioral intervention. Specific activity (or set of related activities) intended to promote safe behaviors and reduce the risk of an individual spreading or becoming infected with the human immunodeficiency virus. # Behavioral risk-reduction interventions. Wide range of services intended to promote safe behaviors and reduce exposing others to HIV. # Biomedical intervention. The use of approaches designed to moderate biological and physiological factors to reduce the infectiousness of a person with HIV or to reduce a person's susceptibility to contracting HIV. Case management. A service generally provided through an ongoing relationship with a client or patient that includes comprehensive assessment of medical and psychosocial support needs, development of a formal plan to address needs, provision of assistance and advocacy in accessing services, and monitoring of service delivery. # CD4 cell count. The number of CD4+ T-lymphocyte cells per millimeter cubed (mm^3) of blood. CD4 cell count is a marker of the immune system's capacity to fight infection, CD4 cell count is used to assign stage of HIV disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about the need for treatment to prevent HIV-related diseases. # Electronic medical record (EMR). A patient record that is maintained using computer software. The record should include patient history, including diagnoses, treatments, prescribed medications, drug allergies, and self-reported problems; patient demographics; physician clinical notes; and laboratory and imaging results. # Emergency postcoital contraception. A type of oral hormonal contraception used within a few days after intercourse that is intended to prevent pregnancy by disrupting ovulation or fertilization. It is most effective when taken as soon as possible after unprotected intercourse, but within 72 hours. Enrollment. The process by which individuals are identified and invited to participant in HIV care and prevention services or interventions, such as HIV medical care or risk-reduction interventions. Ethnicity. The cultural characteristics that connect a particular group or groups of people to each other, such as people of Hispanic/Latino origin. # Evaluation. A formal process to identify program strengths and areas for improvement. # Evidence-based. A characteristic of interventions, strategies, guidelines, and recommendations that are based on sound scientific research, testing, or program evaluation. # Evidence-based HIV behavioral intervention (EBI). Individual-, group-, or population-level interventions that have been shown to promote safer behaviors or reduce HIV or STD transmission in research studies, program evaluations, or theory-based intervention experience. Gender identity. A person's private sense or personal experience of her/his own gender, or sense of being a man or a woman. Gender identity is not necessarily consistent with biological sex. # Health insurance marketplaces (previously known as "exchanges"). Competitive marketplaces created by the Patient Protection and Affordable Care Act (ACA) for individuals and small employers to directly compare available private health insurance options on the basis of price, quality, and other factors. The intent of marketplaces is to provide transparent, consumer education that enables persons to enroll in suitable, affordable health insurance. The Health Insurance Portability and Accountability Act (HIPAA). HIPAA provides standards for protecting the privacy of individual-level, identifiable health information for certain electronic transactions initiated by health care providers, health plans, and health care clearinghouses. HIPAA is especially important for persons with HIV and other diseases that may result in stigma or discrimination. HIV-discordant couple. An HIV-discordant couple consists of one HIV-infected person and one HIVuninfected person. HIV-discordant risk behavior. Engaging in unprotected sex or sharing drug-injection equipment with a person with a different HIV infection status. HIV medical care. Medical services that address HIV infection and HIV-related diseases. These include evaluation of CD4 cell count and HIV viral load, prescribing antiretroviral treatment (ART), providing ART adherence support, prevention and treatment of HIV-related diseases, behavioral health education and interventions, and provision or referrals for other medical and social services, such as STD screening, partner services, reproductive and pregnancy services, substance use treatment, and mental health services. HIV planning group. An official organization or committee that develops, advocates for, and implements a comprehensive plan for HIV prevention and care for a given jurisdiction. HIV prevention counseling. An interactive process between client or patient and counselor aimed at reducing sexual, drug-use, and reproductive behaviors that pose a risk of HIV transmission or acquisition. HIV superinfection. The acquisition of another HIV strain that may reduce the effectiveness of HIV treatment if new, drug-resistant HIV strains are acquired. # Human immunodeficiency virus (HIV). HIV is a retrovirus that causes immune deficiency and may eventually lead to AIDS, especially if appropriate treatment is not used. Incidence. The number of new cases of a disease diagnosed in a defined population in a specified period, often a year. # Index patient. A person with diagnosed HIV or STD and whose diagnosis prompts an investigation to identify other persons (known as partners) who may have become infected through sexual contact or exposure to blood or other body fluids of the index patient Indicator. A measure used to determine implementation over time of prevention or care services and the functions, processes, or outcomes of those services. Informed consent. Communication between a person and a provider of prevention, testing, treatment or other health services, such as starting HIV treatment or referral to mental health services. It includes an oral or written summary of 1) the risks and benefits of the service, 2) documentation of services rendered and their outcomes, 3) the opportunity to ask questions, and 4) reassurance that declining a service will not result in denial of other clinical or nonclinical services. Insertive anal sex. The practice of inserting one's penis into a partner's anus. Also known as insertive penile-anal sex. Insertive fellatio. The practice of inserting one's penis into a partner's mouth. Also known as insertive penile-oral sex. Insertive vaginal sex. The practice of inserting one's penis into a partner's vagina. Also known as insertive penile-vaginal sex. # Intracytoplasmic sperm injection. An in vitro fertilization procedure in which specially prepared ("washed") sperm of a man with HIV is injected directly into an egg retrieved from an ovarian follicle to achieve fertilization while minimizing the risk of HIV transmission to the female partner. Linkage facilitator. Individual who assists persons with HIV to access HIV medical care and other medical and social services through active methods (e.g., help making appointments, providing transportation to appointments). May be called service linkage facilitator. Linkage to care. The process of helping persons with HIV to obtain HIV medical care and prevention or social services through active methods (e.g., appointment scheduling, reminders, transportation to appointments). It is more active and immediate than referral and often includes navigation assistance and verification of rendered services. # Monitoring and evaluation (M&E). A process that involves the repeated, ongoing collection and review of information about program activities, characteristics, and outcomes in order to assess program implementation, coverage, acceptability, cost, and effectiveness. Navigation assistance. The process of helping persons obtain timely and appropriate medical or social services given their preferences about providers, insurance status, scheduling issues, and other factors that may complicate access or utilization of services. Newly reported HIV infection. A case of HIV infection that has been newly reported to a health department's surveillance registry. Nonclinical providers. Persons who work in community-based organizations or health departments operating outside of health care facilities and who provide HIV testing, health education, risk-reduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. # Nonclinical setting. A setting that provides prevention, education, screening and interventions for risk behaviors, and referrals for medical and social services. Some nonclinical settings may also provide health promotion services and screening for HIV and some STD. Nonclinical settings do not routinely provide medical diagnostic and treatment services. Nonoccupational postexposure prophylaxis (nPEP). The use of selected antiretroviral medications by HIV-uninfected persons within 72 hours after isolated, nonoccupational exposures to body fluids potentially containing HIV, such as after unprotected sexual intercourse or condom breakage, in order to reduce the risk of HIV acquisition. Nonoxynol-9. An organic compound with spermicidal properties that is used in vaginal spermicides and anogenital lubricants. # Nucleic acid amplification test (NAAT). A type of sensitive laboratory test that detects genetic material of a pathogen, such as HIV or Neisseria gonorrhoeae. Outreach. A systematic attempt to improve uptake of services by seeking persons who may benefit from services in community settings (e.g., parks, churches, bars). Partner. A person with whom 1) a person with HIV (known as an index patient) has either had sex or shared drug-injection equipment at least once, or 2) a person with an STD has had sex at least once. Partner elicitation. An early step of voluntary, confidential partner services in which a health department partner services specialist or other provider interviews or reinterviews a person with HIV or STD to collect names, descriptions, and locating and contact information of persons who are sex or drug-injection partners so the partners can be notified of possible HIV or STD exposure. Partner notification. A step of voluntary, confidential partner services that involves locating and confidentially notifying sex and drug-injection partners of persons infected with HIV or STD of possible exposure to HIV or STD. Partner services. An array of voluntary services for persons with HIV or STD and their sex and druginjection partners that are intended to reduce HIV transmission: interviewing persons with HIV to obtain information to contact or locate their sex and drug-injection partners; notifying partners of possible HIV Receptive fellatio. The practice of receiving a partner's penis in one's mouth. Also known as receptive penile-oral sex. Receptive vaginal sex. The practice of receiving a partner's penis in one's vagina. Also known as receptive penile-vaginal sex. # Reengagement. A process to help persons with HIV resume HIV medical care and attend scheduled HIV medical appointments after a lapse in care. # Referral. A process by which nonclinical or clinical providers assess a person's needs for prevention, care, and supportive services and help him or her identify and access services (e.g., providing directions and phone numbers of nearby facilities, providing information about how to enroll in health insurance). It is less intensive than active linkage assistance and may not include ongoing support or case management. Reproductive health counseling. Information and counseling for HIV-infected women and HIV-infected men of reproductive age and their partners about preventing unintended pregnancy; pregnancy planning and spacing; the risks of HIV transmission when attempting conception; the risk of adverse maternal or fetal outcomes should transmission occur when attempting conception or during pregnancy; and methods to reduce these risks. # Retention in care. A process to help persons with HIV continue to attend scheduled HIV medical appointments after their initial HIV medical appointment. # Risk behaviors. Behaviors that can result in transmitting HIV to others or acquiring HIV (e.g., anal or vaginal intercourse without a barrier, sharing nonsterile drug-injection equipment). # Risk compensation. Modifying sex or drug-injection behaviors in way that increases risk of HIV transmission or acquisition when other safeguards are introduced (e.g., when persons with HIV who believe that ART use reduces their infectiousness no longer use condoms to prevent HIV transmission). # Risk screening. A brief assessment of behavioral factors that may affect the risk of exposing others to HIV, such as inconsistent condom use or sharing drug-injection equipment, and biomedical factors that influence HIV transmission, such as viral load, antiretroviral treatment and adherence, sexually transmitted disease, and pregnancy. Risk screening is used to identify behavioral or biomedical riskreduction interventions suited to a specific individual. Seropositioning. The practice of modifying sexual activity based on beliefs about the partner's HIV infection status and the per-act risk of HIV transmission for a given type of contact (e.g., persons with HIV practice receptive fellatio with HIV-uninfected partners because they believe this type of contact is less likely to transmit HIV than insertive fellatio, anal sex, or vaginal sex). Serosorting. The practice of limiting unprotected sex to partners believed to have the same HIV infection status. For example, persons with HIV only have unprotected sex with persons believed to be HIVinfected. Sexual orientation. A person's physical or emotional attraction to persons of the same and/or opposite gender, (e.g., heterosexual, bisexual, or homosexual). # Sexually transmitted diseases (STD). Diseases that are spread primarily through person-to-person sexual contact. Also referred to as sexually transmitted infections (STI). # Social network. A group of persons connected by social relationships, such as friends, family, sex and drug-injection partners, or persons who frequent the same physical or virtual venues. # Social networking. A strategy to recruit persons for HIV testing or prevention services in which highrisk individuals use their personal influence to recruit peers they believe are at high risk for HIV infection. # Sperm washing. A procedure that removes components (including seminal fluid that may contain HIV) other than sperm from a semen sample before it is used for artificial insemination. State and local health departments. Governmental organizations in states, locales, territories, and tribes that provide planning, policy development, surveillance, partner services, and other services to promote the health of communities and control communicable and chronic diseases. STD syndromes. Conditions caused by sexually transmitted pathogens that cause symptoms and/or abnormal findings on physical examination (signs). May include genital ulcer disease, urethritis, cervicitis, pelvic inflammatory disease, epididymitis, and proctitis. Substance use or abuse. Recreational use of alcohol, legal or illicit drugs, and other substances that may impair judgment, influence HIV risk behaviors, hinder seeking of HIV prevention services, or cause other problems. In some cases, it is associated with dependence or addiction to the substance. Surveillance. The ongoing and systematic collection, analysis, interpretation, and dissemination of data about occurrences of a disease or health condition. # Syringe services programs (SSPs). Programs that provide free, new, sterile syringes and needles in exchange for used syringes and needles to reduce transmission of bloodborne pathogens among people who inject drugs. May be called syringe exchange programs or needle exchange programs. Telemedicine services. The use of telecommunications technology to provide, enhance, or expedite health care services or to provide consultation, training, and mentoring to health care professionals. Timed, periovulatory intercourse. A conception method intended to reduce the risk of HIV transmission in HIV-discordant couples in which unprotected intercourse occurs only when infected partners have achieved maximal viral suppression, the woman is in the periovulatory period of her menstrual cycle, and condoms are used at all other times. Transgender man. An individual whose assigned sex at birth is female but whose gender expression and/or gender identity is male. Transgender woman. An individual whose assigned sex at birth is male but whose gender expression and/or gender identity is female. Transmission risk. Factors identified as potential modes of HIV transmission (e.g., unprotected sexual contact, sharing drug-injection equipment). Unprotected sex or unprotected sexual contact. Sexual activity without using a physical barrier (i.e., penile sex without using a male condom; vaginal sex without using a male or female condom; oral-anal contact without using a dental dam or other barrier device; vaginal-digital contact without using a female condom, latex glove, or finger cot; or rectal-digital contact without using a latex glove or finger cot). Viral load. The HIV-1 viral load measurement indicates the number of copies of HIV-1 RNA per milliliter of plasma. It reflects the burden of infection and the magnitude of viral replication and is used to # Appendix C. Organizations and Persons Contributing to this Report Project Workgroup	None	None
72d5b30c70e44de66f7150430b2dbcec25cf53fc	cdc	None	On June 19, 2013, the Advisory Committee on Immunization Practices (ACIP) voted to extend existing recommendations for use of inactivated Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC) (Ixiaro, Intercell Biomedical) to include children aged 2 months through 16 years (1). The ACIP JE Vaccine Workgroup reviewed the epidemiology of JE in travelers and evaluated published and unpublished data on JE-VC immunogenicity and safety in adults and children. The evidence for benefits and risks associated with JE-VC vaccination of children was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (2,3). This report summarizes the evidence considered by ACIP and outlines the recommendations for use of JE-VC in children traveling to JE-endemic countries.JE virus, a mosquito-borne flavivirus, is an important cause of encephalitis in Asia (4). JE is a severe disease with a case fatality rate of 20%-30% and neurologic or psychiatric sequelae in 30%-50% of survivors (4). Although no specific treatment is available, the disease is vaccine-preventable. The risk for JE for most travelers to Asia is very low, but varies based on destination, duration, season, and activities (4,5). The overall incidence of JE among persons from nonendemic countries traveling to Asia is estimated to be less than one case per 1 million travelers. However, the risk for JE among expatriates and travelers who stay for prolonged periods in rural areas with active JE virus transmission might be similar to the risk among the susceptible resident population (5-50 cases per 100,000 children per year) (4). Recurrent travelers or travelers on brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Short-term travelers whose visits are restricted to major urban areas are at minimal risk for JE.JE-VC is the only JE vaccine licensed and available in the United States. An inactivated mouse brain-derived vaccine (JE-MB ) previously was available and recommended for use in adults and children aged ≥1 year but is no longer being produced. In 2009, JE-VC was licensed and recommended for use in persons aged ≥17 years (4). In May 2013, the Food and Drug Administration (FDA) licensed JE-VC for use in children aged 2 months through 16 years (6).# Dosage, Administration, and Schedule The primary series for JE-VC is 2 intramuscular doses administered 28 days apart. For children aged 2 months through 2 years, each dose is 0.25 mL, and for adults and children aged ≥3 years, each dose is 0.5 mL. For persons aged ≥17 years, ACIP recommends that if the primary series of JE-VC was administered >1 year previously, a booster dose may be given before potential JE virus exposure (7). Although studies are being conducted on the need for a booster dose following a primary series of JE-VC in children, data are not yet available. # JE-VC Licensure and Usage in Adults No efficacy data are available for JE-VC. However, a JE virus 50% plaque reduction neutralization test (PRNT 50 ) titer of ≥10 is an accepted immunologic correlate of protection (8,9). JE-VC was licensed based on its ability to induce seroprotective JE virus neutralizing antibody titers, a noninferiority comparison of safety and immunogenicity with JE-MB, and safety evaluations in approximately 5,000 adults (10)(11)(12). Since JE-VC was licensed in 2009, approximately 375,000 doses have been distributed in the United States for use in adults and no safety concerns have been identified (13,14). # JE-VC Immunogenicity in Children The pivotal pediatric clinical trial of JE-VC was conducted in children aged 2 months through 17 years in the Philippines (3,15,16). Among children randomly assigned to receive 2 age-appropriate doses of JE-VC, 384 (100%) of 385 were seroprotected at 28 days after the second dose (95% confidence interval = 96%-100%) (Table ). At 6 months after completing the primary series, 134 (88%; CI = 82%-92%) of 152 children aged 2 months through 2 years and 224 (95%; CI = 91%-97%) of 237 children aged 3-17 years had protective neutralizing antibodies. In a randomized, controlled trial conducted in India among children aged 1 and 2 years, 22 (96%; CI = 87%-100%) of 23 children were seroprotected at 28 days after receiving two 0.25 mL doses of JE-VC (3,(15)(16)(17). No statistically significant differences were detected in the seroprotection rates between this group and children who received two 0.5 mL doses of JE-VC (20/21; 95%) (CI = 86%-100%) or 3 doses of an inactivated mouse brain-derived JE vaccine produced by the Korean Green Cross (10/11, 91%) (CI = 74%-100%). In an observational study of children from nonendemic countries, all 51 children in the interim analysis had protective neutralizing antibodies at 28 days after the second dose of JE-VC (Table) (3,15,16). All 18 children evaluated remained seroprotected at 6 months after completing the primary series. # JE-VC Safety Data for Children In the open-label trial in the Philippines, 195 infants aged 2-11 months were randomly assigned to receive JE-VC (N = 131) or 7-valent pneumococcal conjugate vaccine (N = 64). An additional 1,674 children, aged 1-17 years, were randomly assigned to receive JE-VC (N = 1,280) or hepatitis A vaccine (N = 394) (3,15,16). The incidences of local, systemic, medically attended, and FDA-defined serious adverse events were similar between children who received JE-VC or the comparison vaccines. Overall, 9% (122/1,411) of JE-VC recipients had fever (≥100.4°F ) within 7 days after the first dose and 6% (84/1,405) had fever within 7 days after the second dose. Within 1 month after either dose, four (<1%) recipients had urticaria or hypersensitivity reactions, and five (<1%) had neurologic adverse events, including febrile seizures (N = 3), drooling (N = 1), and dizziness (N = 1); all were similar to rates for recipients of the comparison vaccines. Among the 1,411 children who received JE-VC, 23 (2%) reported a serious adverse event within 7 months of the first dose. The most common serious adverse events were pneumonia (N = 6) and febrile seizures (N = 5). Only three serious adverse events were reported within 2 weeks after a dose of JE-VC, including one report each of a febrile convulsion, cellulitis, and gastroenteritis. One death resulted from suspected bacterial meningitis and pneumonia in a male aged 12 years at 4 months after the second dose of JE-VC. No other neurologic or hypersensitivity events were reported as serious adverse events. Among the 48 children aged 1 and 2 years who were randomly assigned to receive JE-VC in India, five (10%) reported injection site tenderness, and one (2%) reported fever within 7 days after either dose (3,(15)(16)(17). The only unsolicited adverse events were one report each of skin lesion and skin rash. No serious adverse events or deaths were reported. In the observational study of children aged 2 months through 17 years from nonendemic countries, among 60 children included in the interim analysis, four (7%) had fever, 22 (37%) had injection site tenderness, and 15 (25%) had muscle pain in the 7 days after either JE-VC dose (3,15,16). Two serious adverse events were reported, one child each with diabetes mellitus (3 months after dose 2) and dizziness (4 months after dose 2). No other neurologic or hypersensitivity adverse events were reported. # Rationale for JE Vaccine Recommendations Considerations in providing recommendations for use of JE-VC in travelers include 1) the overall low risk for travel-associated JE, which varies based on itinerary and activities, 2) the lack of available treatment and high rates of morbidity and mortality when the disease does occur, and 3) the high rates of seroprotection and low probability of serious adverse events following vaccination (3,4,14). Travel vaccines are usually paid for by the travelers themselves; they are not covered under the Vaccines for Children (VFC) program or by most private insurance plans. A cost-effectiveness study of JE vaccine for U.S. children traveling to JE-endemic countries was not performed. However, given the large numbers of travelers to Asia (>5.5 million U.S. travelers entered JE-endemic countries in 2004), the low risk for JE for most travelers to Asia, and the high cost of JE-VC ($400-$500 per 2-dose primary series), providing JE vaccine to all travelers to Asia likely would not be cost-effective. In addition, for some travelers with lower risk itineraries, even a low probability of vaccine-related serious adverse events might be higher than the risk for disease. Therefore, JE vaccine should be targeted to travelers who, on the basis of their planned travel itinerary and activities, are at higher risk for disease (Box) (4). # ACIP Recommendations for Use of JE-VC in Children ACIP recommendations for use of JE-VC for the primary series in children aged 2 months through 16 years are the same as for persons aged ≥17 years (Box) (4). Travelers to JE-endemic Abbreviation: PRNT 50 = 50% plaque reduction neutralization test. - For children aged 2 months-2 years, two 0.25 mL doses administered 28 days apart; for children aged 3-17 years, two 0.5 mL doses administered 28 days apart. † Of an additional 98 children aged 3-11 years who received two 0.25 mL doses, 94 (96%) were seroprotected at 1 month after the second dose. § Of 21 children aged 1-2 years who received two 0.5 mL doses, 20 (95%) were seroprotected at 1 month after the second dose; the FDA-approved dose for children aged 1-2 years is 0.25 mL. countries should be advised of the risks for JE disease and the importance of personal protective measures to reduce the risk for mosquito bites. For some travelers who will be in a higherrisk setting based on season, location, duration, and activities, JE vaccine can further reduce the risk for infection. JE vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JE virus transmission season. JE vaccine should be considered for short-term (<1 month) travelers whose itinerary or activities might increase their risk for exposure to JE virus. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas. -Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or periods outside of a well-defined JE virus transmission season.	On June 19, 2013, the Advisory Committee on Immunization Practices (ACIP) voted to extend existing recommendations for use of inactivated Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC) (Ixiaro, Intercell Biomedical) to include children aged 2 months through 16 years (1). The ACIP JE Vaccine Workgroup reviewed the epidemiology of JE in travelers and evaluated published and unpublished data on JE-VC immunogenicity and safety in adults and children. The evidence for benefits and risks associated with JE-VC vaccination of children was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (2,3). This report summarizes the evidence considered by ACIP and outlines the recommendations for use of JE-VC in children traveling to JE-endemic countries.JE virus, a mosquito-borne flavivirus, is an important cause of encephalitis in Asia (4). JE is a severe disease with a case fatality rate of 20%-30% and neurologic or psychiatric sequelae in 30%-50% of survivors (4). Although no specific treatment is available, the disease is vaccine-preventable. The risk for JE for most travelers to Asia is very low, but varies based on destination, duration, season, and activities (4,5). The overall incidence of JE among persons from nonendemic countries traveling to Asia is estimated to be less than one case per 1 million travelers. However, the risk for JE among expatriates and travelers who stay for prolonged periods in rural areas with active JE virus transmission might be similar to the risk among the susceptible resident population (5-50 cases per 100,000 children per year) (4). Recurrent travelers or travelers on brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Short-term travelers whose visits are restricted to major urban areas are at minimal risk for JE.JE-VC is the only JE vaccine licensed and available in the United States. An inactivated mouse brain-derived vaccine (JE-MB [JE-VAX]) previously was available and recommended for use in adults and children aged ≥1 year but is no longer being produced. In 2009, JE-VC was licensed and recommended for use in persons aged ≥17 years (4). In May 2013, the Food and Drug Administration (FDA) licensed JE-VC for use in children aged 2 months through 16 years (6).# Dosage, Administration, and Schedule The primary series for JE-VC is 2 intramuscular doses administered 28 days apart. For children aged 2 months through 2 years, each dose is 0.25 mL, and for adults and children aged ≥3 years, each dose is 0.5 mL. For persons aged ≥17 years, ACIP recommends that if the primary series of JE-VC was administered >1 year previously, a booster dose may be given before potential JE virus exposure (7). Although studies are being conducted on the need for a booster dose following a primary series of JE-VC in children, data are not yet available. # JE-VC Licensure and Usage in Adults No efficacy data are available for JE-VC. However, a JE virus 50% plaque reduction neutralization test (PRNT 50 ) titer of ≥10 is an accepted immunologic correlate of protection (8,9). JE-VC was licensed based on its ability to induce seroprotective JE virus neutralizing antibody titers, a noninferiority comparison of safety and immunogenicity with JE-MB, and safety evaluations in approximately 5,000 adults (10)(11)(12). Since JE-VC was licensed in 2009, approximately 375,000 doses have been distributed in the United States for use in adults and no safety concerns have been identified (13,14). # JE-VC Immunogenicity in Children The pivotal pediatric clinical trial of JE-VC was conducted in children aged 2 months through 17 years in the Philippines (3,15,16). Among children randomly assigned to receive 2 age-appropriate doses of JE-VC, 384 (100%) of 385 were seroprotected at 28 days after the second dose (95% confidence interval [CI] = 96%-100%) (Table ). At 6 months after completing the primary series, 134 (88%; CI = 82%-92%) of 152 children aged 2 months through 2 years and 224 (95%; CI = 91%-97%) of 237 children aged 3-17 years had protective neutralizing antibodies. In a randomized, controlled trial conducted in India among children aged 1 and 2 years, 22 (96%; CI = 87%-100%) of 23 children were seroprotected at 28 days after receiving two 0.25 mL doses of JE-VC (3,(15)(16)(17). No statistically significant differences were detected in the seroprotection rates between this group and children who received two 0.5 mL doses of JE-VC (20/21; 95%) (CI = 86%-100%) or 3 doses of an inactivated mouse brain-derived JE vaccine produced by the Korean Green Cross (10/11, 91%) (CI = 74%-100%). In an observational study of children from nonendemic countries, all 51 children in the interim analysis had protective neutralizing antibodies at 28 days after the second dose of JE-VC (Table) (3,15,16). All 18 children evaluated remained seroprotected at 6 months after completing the primary series. # JE-VC Safety Data for Children In the open-label trial in the Philippines, 195 infants aged 2-11 months were randomly assigned to receive JE-VC (N = 131) or 7-valent pneumococcal conjugate vaccine (N = 64). An additional 1,674 children, aged 1-17 years, were randomly assigned to receive JE-VC (N = 1,280) or hepatitis A vaccine (N = 394) (3,15,16). The incidences of local, systemic, medically attended, and FDA-defined serious adverse events were similar between children who received JE-VC or the comparison vaccines. Overall, 9% (122/1,411) of JE-VC recipients had fever (≥100.4°F [≥38.0°C]) within 7 days after the first dose and 6% (84/1,405) had fever within 7 days after the second dose. Within 1 month after either dose, four (<1%) recipients had urticaria or hypersensitivity reactions, and five (<1%) had neurologic adverse events, including febrile seizures (N = 3), drooling (N = 1), and dizziness (N = 1); all were similar to rates for recipients of the comparison vaccines. Among the 1,411 children who received JE-VC, 23 (2%) reported a serious adverse event within 7 months of the first dose. The most common serious adverse events were pneumonia (N = 6) and febrile seizures (N = 5). Only three serious adverse events were reported within 2 weeks after a dose of JE-VC, including one report each of a febrile convulsion, cellulitis, and gastroenteritis. One death resulted from suspected bacterial meningitis and pneumonia in a male aged 12 years at 4 months after the second dose of JE-VC. No other neurologic or hypersensitivity events were reported as serious adverse events. Among the 48 children aged 1 and 2 years who were randomly assigned to receive JE-VC in India, five (10%) reported injection site tenderness, and one (2%) reported fever within 7 days after either dose (3,(15)(16)(17). The only unsolicited adverse events were one report each of skin lesion and skin rash. No serious adverse events or deaths were reported. In the observational study of children aged 2 months through 17 years from nonendemic countries, among 60 children included in the interim analysis, four (7%) had fever, 22 (37%) had injection site tenderness, and 15 (25%) had muscle pain in the 7 days after either JE-VC dose (3,15,16). Two serious adverse events were reported, one child each with diabetes mellitus (3 months after dose 2) and dizziness (4 months after dose 2). No other neurologic or hypersensitivity adverse events were reported. # Rationale for JE Vaccine Recommendations Considerations in providing recommendations for use of JE-VC in travelers include 1) the overall low risk for travel-associated JE, which varies based on itinerary and activities, 2) the lack of available treatment and high rates of morbidity and mortality when the disease does occur, and 3) the high rates of seroprotection and low probability of serious adverse events following vaccination (3,4,14). Travel vaccines are usually paid for by the travelers themselves; they are not covered under the Vaccines for Children (VFC) program or by most private insurance plans. A cost-effectiveness study of JE vaccine for U.S. children traveling to JE-endemic countries was not performed. However, given the large numbers of travelers to Asia (>5.5 million U.S. travelers entered JE-endemic countries in 2004), the low risk for JE for most travelers to Asia, and the high cost of JE-VC ($400-$500 per 2-dose primary series), providing JE vaccine to all travelers to Asia likely would not be cost-effective. In addition, for some travelers with lower risk itineraries, even a low probability of vaccine-related serious adverse events might be higher than the risk for disease. Therefore, JE vaccine should be targeted to travelers who, on the basis of their planned travel itinerary and activities, are at higher risk for disease (Box) (4). # ACIP Recommendations for Use of JE-VC in Children ACIP recommendations for use of JE-VC for the primary series in children aged 2 months through 16 years are the same as for persons aged ≥17 years (Box) (4). Travelers to JE-endemic Abbreviation: PRNT 50 = 50% plaque reduction neutralization test. * For children aged 2 months-2 years, two 0.25 mL doses administered 28 days apart; for children aged 3-17 years, two 0.5 mL doses administered 28 days apart. † Of an additional 98 children aged 3-11 years who received two 0.25 mL doses, 94 (96%) were seroprotected at 1 month after the second dose. § Of 21 children aged 1-2 years who received two 0.5 mL doses, 20 (95%) were seroprotected at 1 month after the second dose; the FDA-approved dose for children aged 1-2 years is 0.25 mL. countries should be advised of the risks for JE disease and the importance of personal protective measures to reduce the risk for mosquito bites. For some travelers who will be in a higherrisk setting based on season, location, duration, and activities, JE vaccine can further reduce the risk for infection. JE vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JE virus transmission season. JE vaccine should be considered for short-term (<1 month) travelers whose itinerary or activities might increase their risk for exposure to JE virus. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas. -Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or periods outside of a well-defined JE virus transmission season. # Acknowledgments Members of the Advisory Committee on Immunization Practices (ACIP); ACIP Japanese Encephalitis Vaccines Workgroup. ACIP member roster for July 2012-June 2013 available at http://www.cdc.gov/vaccines/acip/committee/members-archive/ members-07-2012-06-2013.html.	None	None
776da412d18343f25d76be8b00d110d9a2ede14d	cdc	None	Japanese encephalitis (JE) vaccine was available in the United States from 1983 through 1987 on an investigational basis, through travel clinics in collaboration with CDC (1). JE vaccine manufactured by Biken and distributed by Connaught Laboratories, Inc. (Japanese encephalitis virus vaccine, inactivated, JE-VAX), was licensed on December 10, 1992, to meet the needs of increasing numbers of U.S. residents traveling to Asia and to accommodate the needs of the U.S. military.# INTRODUCTION Japanese encephalitis (JE), a mosquito-borne arboviral infection, is the leading cause of viral encephalitis in Asia (2)(3)(4). Approximately 50,000 sporadic and epidemic cases of JE are reported annually from the People's Republic of China (PRC), Korea, Japan, Southeast Asia, the Indian subcontinent, and parts of Oceania. Viral transmission occurs across a much broader area of the region than is recognized by epidemiologic surveillance (Figure 1). JE virus is related antigenically to the flaviviruses of St. Louis encephalitis and Murray Valley encephalitis, and to West Nile virus (5 ). Infection leads to overt encephalitis in only 1 of 20 to 1,000 cases. Encephalitis usually is severe, resulting in a fatal outcome in 25% of cases and residual neuropsychiatric sequelae in 30% of cases (2,6 ). Limited data indicate that JE acquired during the first or second trimesters of pregnancy causes intrauterine infection and miscarriage (7,8 ). Infections that occur during the third trimester of pregnancy have not been associated with adverse outcomes in newborns. The virus is transmitted in an enzootic cycle among mosquitoes and vertebrateamplifying hosts, chiefly domestic pigs and Ardeid (wading) birds (2 ). Culex mosquitoes, primarily Cx. tritaeniorhynchus , are the principal vectors. Viral infection rates in the mosquitoes range from <1% to 3%. These species are prolific in rural areas where their larvae breed in ground pools and especially in flooded rice fields. All elements of the transmission cycle are prevalent in rural areas of Asia, and human infections occur principally in this setting. Because vertebrate-amplifying hosts and agricultural activities may be situated within and at the periphery of cities, JE cases occasionally are reported from urban locations. JE virus is transmitted seasonally in most areas of Asia (Table 1). In temperate regions, JE virus is transmitted during the summer and early fall, approximately from May to September (2)(3)(4)(5)(6). In subtropical and tropical areas, seasonal patterns of viral transmission are correlated with the abundance of vector mosquitoes and of vertebrate-amplifying hosts. These, in turn, fluctuate with rainfall, with the rainy season, and with migratory patterns of avian-amplifying hosts. In some tropical locations, however, irrigation associated with agricultural practices is a more important factor affecting vector abundance, and transmission may occur year-round (9)(10)(11)(12). Patterns of JE viral transmission vary regionally, within individual countries, and from year to year. In areas where JE is endemic, annual incidence ranges from 1 to 10 per 10,000 (13 ). Children <15 years of age are principally affected. Seroprevalence studies indicate nearly universal exposure by adulthood (calculating from a ratio of asymptomatic to symptomatic infections of 200 to 1, approximately 10% of the susceptible population is infected per year). In developed countries of Asia and in areas where children are -Continued protected by immunization, a secondary increase in JE incidence has been observed in the elderly (14 ). These observations suggest a biological basis for increased JE risk with age because of waning immunity or other factors. # RISK FOR ACQUIRING JAPANESE ENCEPHALITIS AMONG TRAVELERS Risk for acquiring JE among most travelers to Asia is extremely low; however, the risk for an individual traveler is highly variable and depends on factors such as the season, locations and duration of travel, and activities of the person. Travel during the transmission season and exposure in rural areas, especially for extended periods of time, are the principal factors contributing to risk. The extent and nature of outdoor activity, use of protective clothing, bed nets and repellents, and lodging in air-conditioned or well-screened rooms are additional factors that affect exposure. Residents of developed countries usually have no natural immunity to JE virus and travelers of all ages are equally susceptible to infection with JE virus; however, the elderly may be more susceptible to developing neuroinvasive disease. Although the probability of exposure to JE viral infection and illness increases with the duration of stay in rural endemic areas, one case occurred in a traveler who made only a few excursions into rural areas while on a 2-week vacation (15 ). Since 1981, 11 U.S. residents have been infected with JE virus; eight were military personnel or their dependents (Table 2 (1,17 ). For travelers to rural areas where JE is endemic, risk per month of exposure can be extrapolated from incidence rates in the resident population. Assuming an annual incidence rate of 10 per 10,000, and recognizing that nearly all cases occur within a 5-month period, the estimated risk for JE during a 1-month period (the transmission season) is 1 per 5,000 or 1 per 20,000 per week. Similar rates (<0.1-2.1 per 10,000 per week) have been observed in non-immunized Western military personnel in Asia (data from 1945 through 1991) (18)(19)(20)(21)(22)(23). The risk for developing JE after a mosquito bite can be factored into a series of probabilities. Only bites of vector mosquitoes pose a risk and fewer than 3% of vector mosquitoes are likely to be infected. Only one of approximately 200 infections leads to neuroinvasive disease. The use of bed nets, insect repellents and protective clothing, and avoidance of outdoor activity, especially during twilight periods and in the evening, will reduce risk even further. # INACTIVATED JAPANESE ENCEPHALITIS VIRUS VACCINE An inactivated JE vaccine derived from infected mouse brain has been licensed in Japan since 1954 (24 ). JE vaccine licensed in the United States is produced by the Research Institute of Osaka University (Biken) and is distributed by Connaught Laboratories Inc. The Biken vaccine is the most widely used JE vaccine of its type. Similar mouse brain derived JE vaccines are produced by other manufacturers in India, Japan, Korea, Taiwan, Thailand, and Vietnam (25,26 ). In the PRC, inactivated and attenuated JE vaccines are produced in primary hamster kidney cells (27,28 ). The Biken vaccine is prepared with the Nakayama-NIH strain of JE virus, originally isolated in 1935 from an infected human. The vaccine is produced from infected mouse brains by a sequence of protamine sulfate treatment, formalin inactivation, ultra-filtration, and ammonium sulfate precipitation. The vaccine is purified further by ultracentrifugation through a sucrose cushion. Gelatin is added as a stabilizer during several steps of the process. No myelin basic protein (MBP) can be detected in the vaccine at a level of 2 ng/mL, the detection threshold of the MBP assay. Thimerosal is added as a preservative. Vaccine potency is determined in comparison with a reference vaccine of known clinical efficacy. # VACCINE EFFICACY Efficacy was demonstrated in a single placebo-controlled trial conducted in Thailand (13 ). The study compared the efficacy of two doses of monovalent JE vaccine prepared with the Nakayama-NIH strain (21,628 children) with two doses of a bivalent vaccine also containing the Beijing strain (22,080 children); 21,516 children were ad-ministered tetanus toxoid (TT) as a placebo. After 2 years, two JE cases were reported among recipients of either JE vaccine and 11 cases were observed in the placebo cohort, for an overall vaccine efficacy of 91% (95% confidence interval of 70%-97%). The monovalent and bivalent vaccines did not differ in their efficacy. A prototype of the currently licensed vaccine, which was a less refined mouse brain-derived product, was field tested in Taiwan in 1965 (29 ). Two doses of JE vaccine or TT were administered under masked protocol to 111,749 and 131,865 children, respectively; 22,194 children were administered a single dose of JE vaccine and 140,514 unvaccinated children also were observed. Observations during a single year showed rates of 4 per 100,000 in recipients of two JE vaccine doses and 18 per 100,000 in recipients of TT for a vaccine efficacy of 80%. A single vaccine dose had no demonstrable efficacy. # IMMUNOGENICITY Levels of neutralizing antibody that are considered protective have been defined by animal challenge experiments (24 ). A neutralizing antibody titer of ≥1:10 in passively immunized mice protected against challenge with 10 5 LD50 of JE virus, a viral dose that might be transmitted by an infected mosquito. Thus neutralizing antibody titers ≥ 1:10 (as determined by the technique used at Biken) have been presumed to protect against natural infection. The dosage regimen shown to be efficacious in the trials cited previously, which is used for primary vaccination in many areas of Asia, consists of two doses administered 1-4 weeks apart. However, immunogenicity studies in the United States and among British subjects indicate that three doses are needed to provide protective levels of neutralizing antibody in a suitable proportion of vaccinees (Table 3) (17,30 ). Fewer than 80% of vaccinees receiving two doses seroconverted (reciprocal neutralizing antibody titer of ≥8-10). Moreover, after 6-12 months, only 29% of vaccinees still had adequate antibody levels (17 ). The vaccine's efficacy and immunogenicity after two doses in Asian subjects may reflect the effects of prior immunity or subsequent exposures to JE, West Nile, dengue, and other flaviviruses circulating in Asia (31 ). Although exposure to flaviviruses is almost universal at an early age in developing areas of Asia, flaviviral infections are rare in North America and in most areas of Europe. Immunogenicity studies with another flaviviral vaccine (inactivated tick-borne encephalitis vaccine) showed that previous flaviviral infections or yellow fever immunization augmented and accelerated the antibody response to TBE vaccine (32 ). Preliminary studies do not indicate such an effect among JE vaccine recipients (De-Fraites R, unpublished data ). The vaccine was more immunogenic when administered in three doses during a 30-day period (days 0, 7, and 30) than during a shorter period of 2 weeks (days 0, 7, and 14) (Table 3). Although all subjects seroconverted with either regimen, at 6 months geometric mean titers (GMT) were higher with the longer schedule (p<.0001) (DeFraites R, unpublished data ). The longevity of neutralizing antibody after primary vaccination is not known. The GMT of vaccinees receiving three doses was unchanged between 6 months and 1 year (1:76) after the primary series. After a booster dose was administered at 1 year, neutralizing antibody titers increased sharply 3 months later to a mean titer of 1:1,117 (DeFraites R, unpublished data ). Twenty-one subjects who did not receive a booster retained elevated antibody titers for 2 years after primary vaccination (GMT 1:105). Additional data on the persistence of antibody are pending. In one Japanese study, antibody titers above 1:10 persisted for 3 years after a booster dose (33 ). # ADVERSE REACTIONS JE vaccination is associated with a moderate frequency of local and mild systemic side effects (13,17,25,26,34,35) (DeFraites R, unpublished data ). Tenderness, redness, swelling, and other local effects have been reported in about 20% of vaccinees (<1%-31%). Systemic side effects -fever, headache, malaise, rash, and other reactions such as chills, dizziness, myalgia, nausea, vomiting, and abdominal pain -have been reported in about 10% of vaccinees. The neural tissue substrate of the vaccine has raised concerns about the possibility of vaccine-related neurologic side effects (36 ). The amount of mouse MBP in the vaccine, if any, is well below levels associated with an encephalitogenic effect in a guinea pig model. Surveillance of JE vaccine-related complications in Japan during the years 1965-1973, disclosed neurologic events (principally, encephalitis, encephalopathy, seizures, and peripheral neuropathy) among 1 to 2.3 per million vaccinees (37) (Biken, foundation for vaccination research, unpublished data ). One case of Guillain Barré syndrome temporally related to JE vaccination has been reported in the United States since 1984; however, this patient also had pharyngitis 3 weeks before the onset of weakness and had a positive monospot test (DeFraites R, unpublished data ). A causal relation between JE vaccination and temporally related neurologic events has not been established in this or other cases. Since 1989, an apparently new pattern of adverse reactions has been reported, principally among travelers vaccinated in Australia, Europe, and North America (35,(38)(39) )(Navy Environmental Health Center, unpublished data; Cambridge Self Diagnostic Services, unpublished data; and Andersen MM, Rone T, personal communication ) (Table 4). The reactions have been characterized by urticaria, often in a generalized distribution, and/or angioedema of the extremities, face, and oro-pharynx, especially of the lips. Three vaccine recipients developed respiratory distress. Distress or collapse because of hypotension or other causes led to hospitalization for several persons. Most reactions were treated successfully with antihistamines or oral steroids; however some patients were hospitalized for parenteral steroid therapy. Three patients developed associated erythema multiforme or erythema nodosum, and some patients have had joint swelling. Some vaccinees have complained of generalized itching without objective evidence of a rash. The immunologic mechanism of these adverse events has not been defined. Additional immunologic studies are pending. An important feature of these reactions has been the interval between vaccination and onset of symptoms. Reactions after a first vaccine dose occurred after a median of 12 hours following vaccination (88% of reactions occurred within 3 days). The interval between administration of a second dose and onset of symptoms generally was longer (median 3 days) and possibly as long as 2 weeks. Reactions have occurred after a second or third dose, when preceding doses were received uneventfully. Although some observers have reported that reactions occur chiefly after a second or third dose, one prospective study found similar reaction rates after first and second doses (Navy Environmental Health Center, unpublished data ). A case-control study among U.S. military personnel found an association between reactions to JE vaccine and a past history of urticaria (after hymenoptera envenomation, medications, physical or other provocations or of idiopathic cause ) (Navy Environmental Health Center, unpublished data ). Surveillance of adverse reactions during a mass immunization campaign of 35,000 active duty U.S. military personnel and their dependents on Okinawa disclosed the sudden death of a 21-year-old man who had received a first dose of JE vaccine 60 hours earlier. He also had received a third dose of plague vaccine on the day of death. The man had a medical history of recurrent hypersensitivity phenomena and an episode of possible anaphylaxis. He reported no antecedent symptoms before he was found dead, and the cause of death was not established at autopsy. The incidence of these adverse reactions has varied widely depending on the circumstances of vaccine administration and surveillance (Table 4). In two reports from travelers' clinics in Australia and Canada, rates of 50-104 per 10,000 vaccinees were reported. National surveillance estimates in Denmark, Australia, the United Kingdom, and Sweden are about 10-fold lower and range from 0.7 to 12 per 10,000. Studies among U.S. citizens have disclosed rates of 15-62 per 10,000 (Table 4). Whether this pattern of adverse reactions is new for JE vaccine is unclear. Data from Denmark and Australia suggest that this may be the case. From 1983 to November 1989, no such adverse reactions were reported to the Danish State Serum Institute among recipients of 161,000 doses. From November, 1989 to June 1991, 19 cases were reported among 62,000 vaccine recipients (p <10 -6 , Poisson) (38 ). Although JE vaccine had been distributed to 4,000 persons in Australia since 1987, the seven adverse reactions meeting the above description were reported only after June 1990 (38 ). Other patients with similar clinical features were reported from the United Kingdom in 1991, from Canada in 1990, and Sweden in the period from 1989-1990. However, in retrospect, similar adverse events were observed in a JE vaccine trial conducted from 1983 to 1987 in the United States (17 ). One patient had an anaphylactic reaction occurring within 5 minutes of vaccination; the other subject developed generalized urticaria 7 hours after vaccination. Although the latter case initially was diagnosed as exercise-induced urticaria, a relation of the reaction to JE vaccine cannot be excluded. The vaccine constituent(s) responsible for these adverse events has (have) not been identified. Twelve of 45 vaccine lots produced from April 1988 to January 1991 have been associated with this pattern of adverse reactions. However, 26 of the remaining 33 lots were distributed exclusively to Asian countries. The absence of similar reports associated with these lots may be related to differences in the sensitivity of surveillance for adverse reactions, variations in susceptibility of vaccinees in Asia, or other lot variations. Therefore, whether the reactogenicity of JE vaccine produced recently is associated only with certain lots, or whether a uniform pattern of reactogenicity has gone undetected, is uncertain. Post-marketing surveillance for adverse reactions occurring in the United States will be established by the manufacturer. # Booster Doses Protective levels of neutralizing antibody persist for at least 2 years in vaccinees who have completed a three-dose primary series. The full duration of protection is unknown, therefore, definitive recommendations cannot be given on the timing of booster doses. Booster doses of 1.0 mL (0.5 mL for children <3 years of age) may be administered after 2 years. # PRECAUTIONS AND CONTRAINDICATIONS Adverse Reactions and Hypersensitivity Adverse reactions to JE vaccine manifesting as generalized urticaria and angioedema have occurred within minutes to as long as 2 weeks after vaccination. Epinephrine and other medications and equipment to treat anaphylaxis should be available. Vaccinees should be observed for 30 minutes after vaccination and warned about the possibility of delayed urticaria and angioedema of the head and airway. Vaccinees should be advised to remain in areas with ready access to medical care in the 10 days after receiving a dose of JE vaccine. Persons with a history of certain allergic disorders (see ADVERSE REACTIONS) appear to have a greater risk for developing adverse reactions to JE vaccine. This history should be considered when weighing the risks and benefits of the vaccine for an individual patient. When patients with such a history are offered JE vaccine, they should be alerted to their increased risk for reaction and monitored appropriately. There are no data supporting the efficacy of prophylactic antihistamines or steroids in preventing JE vaccine-related allergic reactions. JE vaccine is produced in mouse brains and should not be administered to persons with a proven or suspected hypersensitivity to proteins of rodent or neural origin (other vaccines produced in rodent neural tissue include experimental hantaviral vaccines produced in Korea and the PRC and the previously used French neurotropic strain yellow fever vaccine ). Hypersensitivity to thimerosal is a contraindication to vaccination. The vaccine should not be administered to persons who have had a previous adverse reaction after receiving JE vaccine. Patients who develop allergic or unusual adverse reactions after vaccination should be reported through the Vaccine Adverse Event Reporting System (1-800-822-7967). # Age No data are available on the safety and efficacy of JE vaccine among infants <1 year of age. Whenever possible vaccination of infants should be deferred until they are ≥1 year of age. # Pregnancy No specific information is available on the safety of JE vaccine in pregnancy. Vaccination poses an unknown but theoretical risk to the developing fetus, and the vaccine should not be routinely administered during pregnancy. Pregnant women who must travel to an area where risk of JE is high should be vaccinated when the theoretical risks of immunization are outweighed by the risk of infection to the mother and developing fetus. # Altered Immune States The only data on the use of inactivated JE vaccine in patients with altered immune states come from a small study among children. These data did not suggest a changed pattern of adverse reactions or immune response after vaccination (45 ). # Simultaneous Administration of Other Vaccines or Drugs Limited data suggest that the immunogenicity and safety of JE vaccination is not compromised by simultaneous administration with DTP vaccine (Nisalak A, unpublished data ). No data exist on the effect of concurrent administration of other vaccines, drugs (e.g., chloroquine, mefloquine), or biologicals on the safety and immunogenicity of JE vaccine. # VACCINATION OF RESEARCH LABORATORY WORKERS Twenty-two cases of laboratory-acquired JE have been reported (46 ). Although work with JE virus is restricted to facilities with BL-3 capabilities, JE virus may be transmitted in a laboratory setting through needlesticks and other accidental exposures. Vaccine-derived immunity presumably protects against exposure through these percutaneous routes. Exposure to aerosolized JE virus, and particularly to high concentrations of virus, that may occur during viral purification, potentially could lead to infection through mucous membranes and possibly directly into the central nervous system through the olfactory epithelium. Whether vaccine-derived immunity protects against such exposures is unknown, but vaccination is recommended for all laboratory workers with a potential for exposure to infectious JE virus. # VACCINE USAGE U.S. Expatriates JE vaccine is recommended for persons who plan to reside in areas where JE is endemic or epidemic (residence during a transmission season) (40)(41)(42)(43)(44). Risk for acquiring JE is highly variable within the endemic regions (Table 1, Figure 1). The incidence of JE in the location of intended residence, the conditions of housing, nature of activities, and the possibility of unexpected travel to high-risk areas are factors that should be considered in the decision to seek vaccination. # Travelers JE vaccine is NOT recommended for all travelers to Asia. In general, vaccine should be offered to persons spending a month or longer in endemic areas during the transmission season, especially if travel will include rural areas. Under specific circumstances, vaccine should be considered for persons spending <30 days in endemic areas, e.g., travelers to areas experiencing epidemic transmission and persons whose activities, such as extensive outdoor activities in rural areas, place them at high risk for exposure. In all instances, travelers should be advised to take personal precautions; e.g., to reduce exposure to mosquito bites. The decision to use JE vaccine should balance the risks for exposure to the virus (Table 1, Figure 1) and for developing illness, the availability and acceptability of repellents and other alternative protective measures (44 ), and the side effects of vaccination. Risk assessments should be interpreted cautiously (Table 1, Figure 1) since risk can vary within areas and from year to year and available data are incomplete. Estimates suggest that risk of JE in highly endemic areas during the transmission season can reach 1 per 5,000 per month of exposure; risk for most shortterm travelers may be ≤1 per million. Although JE vaccine is reactogenic, rates of serious allergic reactions (generalized urticaria or angioedema) are low (1 to 104 per 10,000). Advanced age may be a risk factor for developing symptomatic illness after infection. JE acquired during pregnancy carries the potential for intrauterine infection and fetal death. These special factors should be considered when advising elderly persons and pregnant women who plan visits to areas where JE is endemic. # Primary Immunization Schedule The recommended primary immunization series is three doses of 1.0 mL each, administered subcutaneously on days 0, 7, and 30. An abbreviated schedule of days 0, 7, and 14 can be used when the longer schedule is impractical or inconvenient because of time constraints. Two doses administered a week apart will confer short-term immunity among 80% of vaccinees (Table 3). However, this schedule should be used only under unusual circumstances and is not routinely recommended. The last dose should be administered at least 10 days before the commencement of travel to ensure an adequate immune response and access to medical care in the event of delayed adverse reactions. The immunization schedule for children 1-3 years of age is identical except that the manufacturer recommends 0.5 mL administered subcutaneously. No data are available on vaccine safety and efficacy in infants <1 year of age.	Japanese encephalitis (JE) vaccine was available in the United States from 1983 through 1987 on an investigational basis, through travel clinics in collaboration with CDC (1). JE vaccine manufactured by Biken and distributed by Connaught Laboratories, Inc. (Japanese encephalitis virus vaccine, inactivated, JE-VAX), was licensed on December 10, 1992, to meet the needs of increasing numbers of U.S. residents traveling to Asia and to accommodate the needs of the U.S. military.# INTRODUCTION Japanese encephalitis (JE), a mosquito-borne arboviral infection, is the leading cause of viral encephalitis in Asia (2)(3)(4). Approximately 50,000 sporadic and epidemic cases of JE are reported annually from the People's Republic of China (PRC), Korea, Japan, Southeast Asia, the Indian subcontinent, and parts of Oceania. Viral transmission occurs across a much broader area of the region than is recognized by epidemiologic surveillance (Figure 1). JE virus is related antigenically to the flaviviruses of St. Louis encephalitis and Murray Valley encephalitis, and to West Nile virus (5 ). Infection leads to overt encephalitis in only 1 of 20 to 1,000 cases. Encephalitis usually is severe, resulting in a fatal outcome in 25% of cases and residual neuropsychiatric sequelae in 30% of cases (2,6 ). Limited data indicate that JE acquired during the first or second trimesters of pregnancy causes intrauterine infection and miscarriage (7,8 ). Infections that occur during the third trimester of pregnancy have not been associated with adverse outcomes in newborns. The virus is transmitted in an enzootic cycle among mosquitoes and vertebrateamplifying hosts, chiefly domestic pigs and Ardeid (wading) birds (2 ). Culex mosquitoes, primarily Cx. tritaeniorhynchus , are the principal vectors. Viral infection rates in the mosquitoes range from <1% to 3%. These species are prolific in rural areas where their larvae breed in ground pools and especially in flooded rice fields. All elements of the transmission cycle are prevalent in rural areas of Asia, and human infections occur principally in this setting. Because vertebrate-amplifying hosts and agricultural activities may be situated within and at the periphery of cities, JE cases occasionally are reported from urban locations. JE virus is transmitted seasonally in most areas of Asia (Table 1). In temperate regions, JE virus is transmitted during the summer and early fall, approximately from May to September (2)(3)(4)(5)(6). In subtropical and tropical areas, seasonal patterns of viral transmission are correlated with the abundance of vector mosquitoes and of vertebrate-amplifying hosts. These, in turn, fluctuate with rainfall, with the rainy season, and with migratory patterns of avian-amplifying hosts. In some tropical locations, however, irrigation associated with agricultural practices is a more important factor affecting vector abundance, and transmission may occur year-round (9)(10)(11)(12). Patterns of JE viral transmission vary regionally, within individual countries, and from year to year. In areas where JE is endemic, annual incidence ranges from 1 to 10 per 10,000 (13 ). Children <15 years of age are principally affected. Seroprevalence studies indicate nearly universal exposure by adulthood (calculating from a ratio of asymptomatic to symptomatic infections of 200 to 1, approximately 10% of the susceptible population is infected per year). In developed countries of Asia and in areas where children are -Continued protected by immunization, a secondary increase in JE incidence has been observed in the elderly (14 ). These observations suggest a biological basis for increased JE risk with age because of waning immunity or other factors. # RISK FOR ACQUIRING JAPANESE ENCEPHALITIS AMONG TRAVELERS Risk for acquiring JE among most travelers to Asia is extremely low; however, the risk for an individual traveler is highly variable and depends on factors such as the season, locations and duration of travel, and activities of the person. Travel during the transmission season and exposure in rural areas, especially for extended periods of time, are the principal factors contributing to risk. The extent and nature of outdoor activity, use of protective clothing, bed nets and repellents, and lodging in air-conditioned or well-screened rooms are additional factors that affect exposure. Residents of developed countries usually have no natural immunity to JE virus and travelers of all ages are equally susceptible to infection with JE virus; however, the elderly may be more susceptible to developing neuroinvasive disease. Although the probability of exposure to JE viral infection and illness increases with the duration of stay in rural endemic areas, one case occurred in a traveler who made only a few excursions into rural areas while on a 2-week vacation (15 ). Since 1981, 11 U.S. residents have been infected with JE virus; eight were military personnel or their dependents (Table 2 (1,17 ). For travelers to rural areas where JE is endemic, risk per month of exposure can be extrapolated from incidence rates in the resident population. Assuming an annual incidence rate of 10 per 10,000, and recognizing that nearly all cases occur within a 5-month period, the estimated risk for JE during a 1-month period (the transmission season) is 1 per 5,000 or 1 per 20,000 per week. Similar rates (<0.1-2.1 per 10,000 per week) have been observed in non-immunized Western military personnel in Asia (data from 1945 through 1991) (18)(19)(20)(21)(22)(23). The risk for developing JE after a mosquito bite can be factored into a series of probabilities. Only bites of vector mosquitoes pose a risk and fewer than 3% of vector mosquitoes are likely to be infected. Only one of approximately 200 infections leads to neuroinvasive disease. The use of bed nets, insect repellents and protective clothing, and avoidance of outdoor activity, especially during twilight periods and in the evening, will reduce risk even further. # INACTIVATED JAPANESE ENCEPHALITIS VIRUS VACCINE An inactivated JE vaccine derived from infected mouse brain has been licensed in Japan since 1954 (24 ). JE vaccine licensed in the United States is produced by the Research Institute of Osaka University (Biken) and is distributed by Connaught Laboratories Inc. The Biken vaccine is the most widely used JE vaccine of its type. Similar mouse brain derived JE vaccines are produced by other manufacturers in India, Japan, Korea, Taiwan, Thailand, and Vietnam (25,26 ). In the PRC, inactivated and attenuated JE vaccines are produced in primary hamster kidney cells (27,28 ). The Biken vaccine is prepared with the Nakayama-NIH strain of JE virus, originally isolated in 1935 from an infected human. The vaccine is produced from infected mouse brains by a sequence of protamine sulfate treatment, formalin inactivation, ultra-filtration, and ammonium sulfate precipitation. The vaccine is purified further by ultracentrifugation through a sucrose cushion. Gelatin is added as a stabilizer during several steps of the process. No myelin basic protein (MBP) can be detected in the vaccine at a level of 2 ng/mL, the detection threshold of the MBP assay. Thimerosal is added as a preservative. Vaccine potency is determined in comparison with a reference vaccine of known clinical efficacy. # VACCINE EFFICACY Efficacy was demonstrated in a single placebo-controlled trial conducted in Thailand (13 ). The study compared the efficacy of two doses of monovalent JE vaccine prepared with the Nakayama-NIH strain (21,628 children) with two doses of a bivalent vaccine also containing the Beijing strain (22,080 children); 21,516 children were ad-ministered tetanus toxoid (TT) as a placebo. After 2 years, two JE cases were reported among recipients of either JE vaccine and 11 cases were observed in the placebo cohort, for an overall vaccine efficacy of 91% (95% confidence interval [CI] of 70%-97%). The monovalent and bivalent vaccines did not differ in their efficacy. A prototype of the currently licensed vaccine, which was a less refined mouse brain-derived product, was field tested in Taiwan in 1965 (29 ). Two doses of JE vaccine or TT were administered under masked protocol to 111,749 and 131,865 children, respectively; 22,194 children were administered a single dose of JE vaccine and 140,514 unvaccinated children also were observed. Observations during a single year showed rates of 4 per 100,000 in recipients of two JE vaccine doses and 18 per 100,000 in recipients of TT for a vaccine efficacy of 80%. A single vaccine dose had no demonstrable efficacy. # IMMUNOGENICITY Levels of neutralizing antibody that are considered protective have been defined by animal challenge experiments (24 ). A neutralizing antibody titer of ≥1:10 in passively immunized mice protected against challenge with 10 5 LD50 of JE virus, a viral dose that might be transmitted by an infected mosquito. Thus neutralizing antibody titers ≥ 1:10 (as determined by the technique used at Biken) have been presumed to protect against natural infection. The dosage regimen shown to be efficacious in the trials cited previously, which is used for primary vaccination in many areas of Asia, consists of two doses administered 1-4 weeks apart. However, immunogenicity studies in the United States and among British subjects indicate that three doses are needed to provide protective levels of neutralizing antibody in a suitable proportion of vaccinees (Table 3) (17,30 ). Fewer than 80% of vaccinees receiving two doses seroconverted (reciprocal neutralizing antibody titer of ≥8-10). Moreover, after 6-12 months, only 29% of vaccinees still had adequate antibody levels (17 ). The vaccine's efficacy and immunogenicity after two doses in Asian subjects may reflect the effects of prior immunity or subsequent exposures to JE, West Nile, dengue, and other flaviviruses circulating in Asia (31 ). Although exposure to flaviviruses is almost universal at an early age in developing areas of Asia, flaviviral infections are rare in North America and in most areas of Europe. Immunogenicity studies with another flaviviral vaccine (inactivated tick-borne encephalitis [TBE] vaccine) showed that previous flaviviral infections or yellow fever immunization augmented and accelerated the antibody response to TBE vaccine (32 ). Preliminary studies do not indicate such an effect among JE vaccine recipients (De-Fraites R, unpublished data ). The vaccine was more immunogenic when administered in three doses during a 30-day period (days 0, 7, and 30) than during a shorter period of 2 weeks (days 0, 7, and 14) (Table 3). Although all subjects seroconverted with either regimen, at 6 months geometric mean titers (GMT) were higher with the longer schedule (p<.0001) (DeFraites R, unpublished data ). The longevity of neutralizing antibody after primary vaccination is not known. The GMT of vaccinees receiving three doses was unchanged between 6 months and 1 year (1:76) after the primary series. After a booster dose was administered at 1 year, neutralizing antibody titers increased sharply 3 months later to a mean titer of 1:1,117 (DeFraites R, unpublished data ). Twenty-one subjects who did not receive a booster retained elevated antibody titers for 2 years after primary vaccination (GMT 1:105). Additional data on the persistence of antibody are pending. In one Japanese study, antibody titers above 1:10 persisted for 3 years after a booster dose (33 ). # ADVERSE REACTIONS JE vaccination is associated with a moderate frequency of local and mild systemic side effects (13,17,25,26,34,35) (DeFraites R, unpublished data ). Tenderness, redness, swelling, and other local effects have been reported in about 20% of vaccinees (<1%-31%). Systemic side effects -fever, headache, malaise, rash, and other reactions such as chills, dizziness, myalgia, nausea, vomiting, and abdominal pain -have been reported in about 10% of vaccinees. The neural tissue substrate of the vaccine has raised concerns about the possibility of vaccine-related neurologic side effects (36 ). The amount of mouse MBP in the vaccine, if any, is well below levels associated with an encephalitogenic effect in a guinea pig model. Surveillance of JE vaccine-related complications in Japan during the years 1965-1973, disclosed neurologic events (principally, encephalitis, encephalopathy, seizures, and peripheral neuropathy) among 1 to 2.3 per million vaccinees (37) (Biken, foundation for vaccination research, unpublished data ). One case of Guillain Barré syndrome temporally related to JE vaccination has been reported in the United States since 1984; however, this patient also had pharyngitis 3 weeks before the onset of weakness and had a positive monospot test (DeFraites R, unpublished data ). A causal relation between JE vaccination and temporally related neurologic events has not been established in this or other cases. Since 1989, an apparently new pattern of adverse reactions has been reported, principally among travelers vaccinated in Australia, Europe, and North America (35,(38)(39) )(Navy Environmental Health Center, unpublished data; Cambridge Self Diagnostic Services, unpublished data; and Andersen MM, Rone T, personal communication ) (Table 4). The reactions have been characterized by urticaria, often in a generalized distribution, and/or angioedema of the extremities, face, and oro-pharynx, especially of the lips. Three vaccine recipients developed respiratory distress. Distress or collapse because of hypotension or other causes led to hospitalization for several persons. Most reactions were treated successfully with antihistamines or oral steroids; however some patients were hospitalized for parenteral steroid therapy. Three patients developed associated erythema multiforme or erythema nodosum, and some patients have had joint swelling. Some vaccinees have complained of generalized itching without objective evidence of a rash. The immunologic mechanism of these adverse events has not been defined. Additional immunologic studies are pending. An important feature of these reactions has been the interval between vaccination and onset of symptoms. Reactions after a first vaccine dose occurred after a median of 12 hours following vaccination (88% of reactions occurred within 3 days). The interval between administration of a second dose and onset of symptoms generally was longer (median 3 days) and possibly as long as 2 weeks. Reactions have occurred after a second or third dose, when preceding doses were received uneventfully. Although some observers have reported that reactions occur chiefly after a second or third dose, one prospective study found similar reaction rates after first and second doses (Navy Environmental Health Center, unpublished data ). A case-control study among U.S. military personnel found an association between reactions to JE vaccine and a past history of urticaria (after hymenoptera envenomation, medications, physical or other provocations or of idiopathic cause [relative risk 9.1, 95% CI 1.8-50.9]) (Navy Environmental Health Center, unpublished data ). Surveillance of adverse reactions during a mass immunization campaign of 35,000 active duty U.S. military personnel and their dependents on Okinawa disclosed the sudden death of a 21-year-old man who had received a first dose of JE vaccine 60 hours earlier. He also had received a third dose of plague vaccine on the day of death. The man had a medical history of recurrent hypersensitivity phenomena and an episode of possible anaphylaxis. He reported no antecedent symptoms before he was found dead, and the cause of death was not established at autopsy. The incidence of these adverse reactions has varied widely depending on the circumstances of vaccine administration and surveillance (Table 4). In two reports from travelers' clinics in Australia and Canada, rates of 50-104 per 10,000 vaccinees were reported. National surveillance estimates in Denmark, Australia, the United Kingdom, and Sweden are about 10-fold lower and range from 0.7 to 12 per 10,000. Studies among U.S. citizens have disclosed rates of 15-62 per 10,000 (Table 4). Whether this pattern of adverse reactions is new for JE vaccine is unclear. Data from Denmark and Australia suggest that this may be the case. From 1983 to November 1989, no such adverse reactions were reported to the Danish State Serum Institute among recipients of 161,000 doses. From November, 1989 to June 1991, 19 cases were reported among 62,000 vaccine recipients (p <10 -6 , Poisson) (38 ). Although JE vaccine had been distributed to 4,000 persons in Australia since 1987, the seven adverse reactions meeting the above description were reported only after June 1990 (38 ). Other patients with similar clinical features were reported from the United Kingdom in 1991, from Canada in 1990, and Sweden in the period from 1989-1990. However, in retrospect, similar adverse events were observed in a JE vaccine trial conducted from 1983 to 1987 in the United States (17 ). One patient had an anaphylactic reaction occurring within 5 minutes of vaccination; the other subject developed generalized urticaria 7 hours after vaccination. Although the latter case initially was diagnosed as exercise-induced urticaria, a relation of the reaction to JE vaccine cannot be excluded. The vaccine constituent(s) responsible for these adverse events has (have) not been identified. Twelve of 45 vaccine lots produced from April 1988 to January 1991 have been associated with this pattern of adverse reactions. However, 26 of the remaining 33 lots were distributed exclusively to Asian countries. The absence of similar reports associated with these lots may be related to differences in the sensitivity of surveillance for adverse reactions, variations in susceptibility of vaccinees in Asia, or other lot variations. Therefore, whether the reactogenicity of JE vaccine produced recently is associated only with certain lots, or whether a uniform pattern of reactogenicity has gone undetected, is uncertain. Post-marketing surveillance for adverse reactions occurring in the United States will be established by the manufacturer. # Booster Doses Protective levels of neutralizing antibody persist for at least 2 years in vaccinees who have completed a three-dose primary series. The full duration of protection is unknown, therefore, definitive recommendations cannot be given on the timing of booster doses. Booster doses of 1.0 mL (0.5 mL for children <3 years of age) may be administered after 2 years. # PRECAUTIONS AND CONTRAINDICATIONS Adverse Reactions and Hypersensitivity Adverse reactions to JE vaccine manifesting as generalized urticaria and angioedema have occurred within minutes to as long as 2 weeks after vaccination. Epinephrine and other medications and equipment to treat anaphylaxis should be available. Vaccinees should be observed for 30 minutes after vaccination and warned about the possibility of delayed urticaria and angioedema of the head and airway. Vaccinees should be advised to remain in areas with ready access to medical care in the 10 days after receiving a dose of JE vaccine. Persons with a history of certain allergic disorders (see ADVERSE REACTIONS) appear to have a greater risk for developing adverse reactions to JE vaccine. This history should be considered when weighing the risks and benefits of the vaccine for an individual patient. When patients with such a history are offered JE vaccine, they should be alerted to their increased risk for reaction and monitored appropriately. There are no data supporting the efficacy of prophylactic antihistamines or steroids in preventing JE vaccine-related allergic reactions. JE vaccine is produced in mouse brains and should not be administered to persons with a proven or suspected hypersensitivity to proteins of rodent or neural origin (other vaccines produced in rodent neural tissue include experimental hantaviral vaccines produced in Korea and the PRC and the previously used French neurotropic strain yellow fever vaccine [discontinued in 1982]). Hypersensitivity to thimerosal is a contraindication to vaccination. The vaccine should not be administered to persons who have had a previous adverse reaction after receiving JE vaccine. Patients who develop allergic or unusual adverse reactions after vaccination should be reported through the Vaccine Adverse Event Reporting System (1-800-822-7967). # Age No data are available on the safety and efficacy of JE vaccine among infants <1 year of age. Whenever possible vaccination of infants should be deferred until they are ≥1 year of age. # Pregnancy No specific information is available on the safety of JE vaccine in pregnancy. Vaccination poses an unknown but theoretical risk to the developing fetus, and the vaccine should not be routinely administered during pregnancy. Pregnant women who must travel to an area where risk of JE is high should be vaccinated when the theoretical risks of immunization are outweighed by the risk of infection to the mother and developing fetus. # Altered Immune States The only data on the use of inactivated JE vaccine in patients with altered immune states come from a small study among children. These data did not suggest a changed pattern of adverse reactions or immune response after vaccination (45 ). # Simultaneous Administration of Other Vaccines or Drugs Limited data suggest that the immunogenicity and safety of JE vaccination is not compromised by simultaneous administration with DTP vaccine (Nisalak A, unpublished data ). No data exist on the effect of concurrent administration of other vaccines, drugs (e.g., chloroquine, mefloquine), or biologicals on the safety and immunogenicity of JE vaccine. # VACCINATION OF RESEARCH LABORATORY WORKERS Twenty-two cases of laboratory-acquired JE have been reported (46 ). Although work with JE virus is restricted to facilities with BL-3 capabilities, JE virus may be transmitted in a laboratory setting through needlesticks and other accidental exposures. Vaccine-derived immunity presumably protects against exposure through these percutaneous routes. Exposure to aerosolized JE virus, and particularly to high concentrations of virus, that may occur during viral purification, potentially could lead to infection through mucous membranes and possibly directly into the central nervous system through the olfactory epithelium. Whether vaccine-derived immunity protects against such exposures is unknown, but vaccination is recommended for all laboratory workers with a potential for exposure to infectious JE virus. # VACCINE USAGE U.S. Expatriates JE vaccine is recommended for persons who plan to reside in areas where JE is endemic or epidemic (residence during a transmission season) (40)(41)(42)(43)(44). Risk for acquiring JE is highly variable within the endemic regions (Table 1, Figure 1). The incidence of JE in the location of intended residence, the conditions of housing, nature of activities, and the possibility of unexpected travel to high-risk areas are factors that should be considered in the decision to seek vaccination. # Travelers JE vaccine is NOT recommended for all travelers to Asia. In general, vaccine should be offered to persons spending a month or longer in endemic areas during the transmission season, especially if travel will include rural areas. Under specific circumstances, vaccine should be considered for persons spending <30 days in endemic areas, e.g., travelers to areas experiencing epidemic transmission and persons whose activities, such as extensive outdoor activities in rural areas, place them at high risk for exposure. In all instances, travelers should be advised to take personal precautions; e.g., to reduce exposure to mosquito bites. The decision to use JE vaccine should balance the risks for exposure to the virus (Table 1, Figure 1) and for developing illness, the availability and acceptability of repellents and other alternative protective measures (44 ), and the side effects of vaccination. Risk assessments should be interpreted cautiously (Table 1, Figure 1) since risk can vary within areas and from year to year and available data are incomplete. Estimates suggest that risk of JE in highly endemic areas during the transmission season can reach 1 per 5,000 per month of exposure; risk for most shortterm travelers may be ≤1 per million. Although JE vaccine is reactogenic, rates of serious allergic reactions (generalized urticaria or angioedema) are low (1 to 104 per 10,000). Advanced age may be a risk factor for developing symptomatic illness after infection. JE acquired during pregnancy carries the potential for intrauterine infection and fetal death. These special factors should be considered when advising elderly persons and pregnant women who plan visits to areas where JE is endemic. # Primary Immunization Schedule The recommended primary immunization series is three doses of 1.0 mL each, administered subcutaneously on days 0, 7, and 30. An abbreviated schedule of days 0, 7, and 14 can be used when the longer schedule is impractical or inconvenient because of time constraints. Two doses administered a week apart will confer short-term immunity among 80% of vaccinees (Table 3). However, this schedule should be used only under unusual circumstances and is not routinely recommended. The last dose should be administered at least 10 days before the commencement of travel to ensure an adequate immune response and access to medical care in the event of delayed adverse reactions. The immunization schedule for children 1-3 years of age is identical except that the manufacturer recommends 0.5 mL administered subcutaneously. No data are available on vaccine safety and efficacy in infants <1 year of age.	None	None
43d6613bdc6b0b195aeb380da81f6d211ba47543	cdc	None	The recommendations outline how to provide quality family planning services, which include contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, and sexually transmitted disease services. The primary audience for this report is all current or potential providers of family planning services, including those working in service sites that are dedicated to family planning service delivery as well as private and public providers of more comprehensive primary care. The United States continues to face substantial challenges to improving the reproductive health of the U.S. population. Nearly one half of all pregnancies are unintended, with more than 700,000 adolescents aged 15-19 years becoming pregnant each year and more than 300,000 giving birth. One of eight pregnancies in the United States results in preterm birth, and infant mortality rates remain high compared with those of other developed countries. This report can assist primary care providers in offering family planning services that will help women, men, and couples achieve their desired number and spacing of children and increase the likelihood that those children are born healthy. The report provides recommendations for how to help prevent and achieve pregnancy, emphasizes offering a full range of contraceptive methods for persons seeking to prevent pregnancy, highlights the special needs of adolescent clients, and encourages the use of the family planning visit to provide selected preventive health services for women, in accordance with the recommendations for women issued by the Institute of Medicine and adopted by HHS.# Introduction The United States continues to face challenges to improving the reproductive health of the U.S. population. Nearly half (49%) of all pregnancies are unintended (1). Although adolescent birth rates declined by more than 61% during 1991-2012, the United States has one of the highest adolescent pregnancy rates in the developed world, with >700,000 adolescents aged 15-19 years becoming pregnant each year and >300,000 giving birth (2,3). Approximately one of eight pregnancies in the United States results in a preterm birth, and infant mortality rates remain high compared with other developed countries (3,4). Moreover, all of these outcomes affect racial and ethnic minority populations disproportionately (1)(2)(3)(4). Family planning services can help address these and other public health challenges by providing education, counseling, and medical services (5). Family planning services include the following: - providing contraception to help women and men plan and space births, prevent unintended pregnancies, and reduce the number of abortions; - offering pregnancy testing and counseling; - helping clients who want to conceive; - providing basic infertility services; - providing preconception health services to improve infant and maternal outcomes and improve women's and men's health; and - providing sexually transmitted disease (STD) screening and treatment services to prevent tubal infertility and improve the health of women, men, and infants. This report provides recommendations developed collaboratively by CDC and the Office of Population Affairs (OPA) of the U.S. Department of Health and Human Services (HHS). The recommendations outline how to provide family planning services by: - defining a core set of family planning services for women and men, - describing how to provide contraceptive and other clinical services, serve adolescents, and perform quality improvements, and - encouraging the use of the family planning visit to provide selected preventive health services for women, in accordance with the recommendations for women issued by the Institute of Medicine (IOM) and adopted by HHS (6). The collaboration between CDC and OPA drew on the strengths of both agencies. CDC has a long-standing history of developing evidence-based recommendations for clinical care, and OPA's Title X Family Planning Program (7) has served as the national leader in direct family planning service delivery since the Title X program was established in 1970. This report provides recommendations for providing care to clients of reproductive age who are in need of family planning services. These recommendations are intended for all current or potential providers of family planning services, including those funded by the Title X program. # Current Context of Family Planning Services Women of reproductive age often report that their family planning provider is also their usual source of health care (8). As the U.S. health-care system evolves in response to increased efforts to expand health insurance coverage, contain costs, and emphasize preventive care (9), providers of family planning services will face new challenges and opportunities in care delivery. For example, they will have increased opportunities to serve new clients and to serve as gateways for their clients to other essential health-care services. In addition, primary care and other providers who provide a range of health-care services will be expected to integrate family planning services for all persons of reproductive age, including those whose primary reason for their health-care visit might not be family planning. Strengthened, multidirectional care coordination also will be needed to improve health outcomes. For example, this type of care coordination will be needed with clients referred to specialist care after initial screening at a family planning visit, as well as with specialists referring clients with family planning needs to family planning providers. # Defining Quality in Family Planning Service Delivery The central premise underpinning these recommendations is that improving the quality of family planning services will lead to improved reproductive health outcomes (10)(11)(12). IOM defines health-care quality as the extent to which health-care services improve health outcomes in a manner that is consistent with current professional knowledge (10,13). According to IOM, quality health care has the following attributes: - Safety. These recommendations integrate other CDC recommendations about which contraceptive methods can be provided safely to women with various medical conditions, and integrate CDC and U.S. Preventive Services Task Force (USPSTF) recommendations on STD, preconception, and related preventive health services. - Effectiveness. These recommendations support offering a full range of Food and Drug Administration (FDA)-approved contraceptive methods as well as counseling that highlights the effectiveness of contraceptive methods overall and, in specific patient situations, draws attention to the effectiveness of specific clinical preventive health services and identifies clinical preventive health services for which the potential harms outweigh the benefits (i.e., USPSTF "D" recommendations). - Client-centered approach. These recommendations encourage taking a client-centered approach by 1) highlighting that the client's primary purpose for visiting the service site must be respected, 2) noting the importance of confidential services and suggesting ways to provide them, 3) encouraging the availability of a broad range of contraceptive methods so that clients can make a selection based on their individual needs and preferences, and 4) reinforcing the need to deliver services in a culturally competent manner so as to meet the needs of all clients, including adolescents, those with limited English proficiency, those with disabilities, and those who are lesbian, gay, bisexual, transgender, or questioning their sexual identity (LGBTQ). Organizational policies, governance structures, and individual attitudes and practices all contribute to the cultural competence of a health-care entity and its staff. Cultural competency within a health-care setting refers to attitudes, practices, and policies that enable professionals to work effectively in cross-cultural situations (14-16). - Timeliness. These recommendations highlight the importance of ensuring that services are provided to clients in a timely manner. - Efficiency. These recommendations identify a core set of services that providers can focus on delivering, as well as ways to maximize the use of resources. - Accessibility. These recommendations address how to remove barriers to contraceptive use, use the family planning visit to provide access to a broader range of primary care and behavioral health services, use the primary care visit to provide access to contraceptive and other family planning services, and strengthen links to other sources of care. - Equity. These recommendations highlight the need for providers of family planning services to deliver highquality care to all clients, including adolescents, LGBTQ persons, racial and ethnic minorities, clients with limited English proficiency, and persons living with disabilities. - Value. These recommendations highlight services (i.e., contraception and other clinical preventive services) that have been shown to be very cost-effective (17)(18)(19). # Methods # Recommendations Development Process The recommendations were developed jointly under the auspices of CDC's Division of Reproductive Health and OPA, in consultation with a wide range of experts and key stakeholders. More information about the processes used to conduct systematic reviews, the role of technical experts in reviewing the evidence, and the process of using the evidence to develop recommendations is provided (Appendix A). A multistage process was used to develop the recommendations that drew on established procedures for developing clinical guidelines (20,21). First, an Expert Work Group- was formed comprising family planning clinical providers, program administrators, and representatives from relevant federal agencies and professional medical associations to help define the scope of the recommendations. Next, literature about three priority topics (i.e., counseling and education, serving adolescents, and quality improvement) was reviewed by using the USPSTF methodology for conducting systematic reviews (22). The results were presented to three technical panels † comprising subject matter experts (one panel for each priority topic) who considered the quality of the evidence and made suggestions for what recommendations might be supported on the basis of the evidence. In a separate process, existing clinical recommendations on women's and men's preventive services were compiled from more than 35 federal and professional medical associations, and these results were presented to two technical panels of subject matter experts, one that addressed women's clinical services and one that addressed men's clinical services. The panels provided individual feedback about which clinical preventive services should be offered in a family planning setting and which clinical recommendations should receive the highest consideration. CDC and OPA used the input from the subject matter experts to develop a set of core recommendations and asked the Expert Work Group to review them. The members of the Expert Work Group were more familiar with the family planning service delivery context than the members of the Technical Panel and thus could better comment on the feasibility and appropriateness of the recommendations, as well as the supporting evidence. The Expert Work Group considered the core recommendations by using the following criteria: 1) the quality of the evidence; 2) the positive and negative consequences of implementing the recommendations on health outcomes, costs or cost-savings, and implementation challenges; and 3) the relative importance of these consequences, (e.g., the likelihood that implementation of the recommendation will have a substantial effect on health outcomes might be considered more than the logistical challenges of implementing it) (20). In certain cases, when the evidence from the literature reviews was inconclusive or incomplete, recommendations were made on the basis of expert opinion. Finally, CDC and OPA staff considered the individual feedback from Expert Work Group members when finalizing the core recommendations and writing the recommendations document. A description of how the recommendations link to the evidence is provided together with the rationale for the inclusion of each recommendation in this report (Appendix B). The evidence used to prepare these recommendations will appear in background papers that will be published separately. Resources that will help providers implement the recommendations will be provided through a web-based tool kit that will be available at . # Audience for the Recommendations The primary audience for this report is all providers or potential providers of family planning services to clients of reproductive age, including providers working in clinics that are dedicated to family planning service delivery, as well as private and public providers of more comprehensive primary care. Providers of dedicated family planning services might be less familiar with the specific recommendations for the delivery of preconception services. Providers of more comprehensive primary care might be less familiar with the delivery of contraceptive services, pregnancy testing and counseling, and services to help clients achieve pregnancy. This report can be used by medical directors to write clinical protocols that describe how care should be provided. Job aids and other resources for use in service sites are being developed and will be made available when ready through OPA's website (). In this report, the term "provider" refers to any staff member who is involved in providing family planning services to a client. This includes physicians, physician assistants, nurse practitioners, nurse-midwives, nursing staff, and health educators. The term "service site" represents the numerous settings in which family planning services are delivered, which include freestanding service sites, community health centers, private medical facilities, and hospitals. A list of special terms used in this report is provided (Box 1). The recommendations are designed to guide general clinical practice; however, health-care providers always should consider the individual clinical circumstances of each person seeking family planning services. Similarly, these recommendations might need to be adapted to meet the needs of particular populations, such as clients who are HIV-positive or who are substance users. # Organization of the Recommendations This report is divided into nine sections. An initial section provides an overview of steps to assess the needs of a client and decide what family planning services to offer. Subsequent sections describe how to provide each of the following services: contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, STD services and related preventive health services. A final section on quality improvement describes actions that all providers of family planning services should consider to ensure that services are of high quality. More detailed information about selected topics addressed in the recommendations is provided (Appendices A-F). These recommendations focus on the direct delivery of care to individual clients. However, parallel steps might need to be taken to maintain the systems required to support the provision of quality services for all clients (e.g., record-keeping procedures that preserve client confidentiality, procedures that improve efficiency and reduce clients' wait time, staff training to ensure that all clients are treated with respect, and the establishment and maintenance of a strong system of care coordination and referrals). # Client Care Family planning services are embedded within a broader framework of preventive health services (Figure 1). In this report, health services are divided into three main categories: - Family planning services. These include contraceptive services for clients who want to prevent pregnancy and space births, pregnancy testing and counseling, assistance to achieve pregnancy, basic infertility services, STD services (including HIV/AIDS), and other preconception health services (e.g., screening for obesity, smoking, and mental health). STD/HIV and other preconception health services are considered family planning services because they improve women's and men's health and can influence a person's ability to conceive or to have a healthy birth outcome. - Related preventive health services. These include services that are considered to be beneficial to reproductive health, # BOX 1. Definitions of quality terms used in this report Accessible. The timely use of personal health services to achieve the best possible health outcomes.- Client-centered. Care is respectful of, and responsive to, individual client preferences, needs, and values; client values guide all clinical decisions. † Effective. Services are based on scientific knowledge and provided to all who could benefit and are not provided to those not likely to benefit. † Efficient. Waste is avoided, including waste of equipment, supplies, ideas, and energy. † Equitable. Care does not vary in quality because of the personal characteristics of clients (e.g., sex, race/ethnicity, geographic location, insurance status, or socioeconomic status). † Evidence-based. The process of integrating sciencebased interventions with community preferences to improve the health of populations. § Health-care quality. The degree to which health-care services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge. † Process. Whether services are provided correctly and completely and how clients perceive the care they receive. ¶ Safe. Avoids injuries to clients from the care that is intended to help them. † Structure. The characteristics of the settings in which providers deliver health care, including material resources, human resources, and organizational structure. ¶ Timely. Waits and sometimes harmful delays for both those who receive and those who provide care are reduced. † Value. The care provides good return relative to the costs involved, such as a return on investment or a reduction in the per capita cost of health care.- are closely linked to family planning services, and are appropriate to deliver in the context of a family planning visit but that do not contribute directly to achieving or preventing pregnancy (e.g., breast and cervical cancer screening). - Other preventive health services. These include preventive health services for women that were not included above (6), as well as preventive services for men. Screening for lipid disorders, skin cancer, colorectal cancer, or osteoporosis are examples of this type of service. Although important in the context of primary care, these have no direct link to family planning services. Providers of family planning services should be trained and equipped to offer all family planning and related preventive health services so that they can provide optimal care to clients, with referral for specialist care, as needed. Other preventive health services should be available either on-site or by referral, but these recommendations do not address this category of services. Information about preventive services that are beyond the scope of this report is available at . uspreventiveservicestaskforce.org. # Determining the Client's Need for Services These recommendations apply to two types of encounters with women and men of reproductive age. In the first type of encounter, the primary reason for a client's visit to a healthcare provider is related to preventing or achieving pregnancy, (i.e., contraceptive services, pregnancy testing and counseling, or becoming pregnant). Other aspects of managing pregnancy (e.g., prenatal and delivery care ) are not addressed in these recommendations. For clients seeking to prevent or achieve pregnancy, providers should assess whether the client needs other related services and offer them to the client. In the second type of encounter, the primary reason for a client's visit to a health-care provider is not related to preventing or achieving pregnancy. For example, the client might come in for acute care (e.g., a male client coming in for STD symptoms or as a contact of a person with an STD), for chronic care, or for another preventive service. In this situation, providers not only should address the client's primary reason for the visit but also assess the client's need for services related to preventing or achieving pregnancy. A clinical pathway of family planning services for women and men of reproductive age is provided (Figure 2). The following questions can help providers determine what family planning services are most appropriate for a given visit. - -If the client wants to have a child and is experiencing difficulty conceiving, then provide basic infertility services. # Does the client need preconception health services? Preconception health services (such as screening for obesity, smoking, and mental health) are a subset of all preventive services for women and men. Preconception health care is intended to promote the health of women and men of reproductive age before conception, with the goal of improving pregnancy-related outcomes (24). Preconception health services are also important because they improve the health of women and men, even if they choose not to become pregnant. The federal and professional medical recommendations cited in this report should be followed when determining which preconception health services a client might need. The individual client's needs should be considered when determining what services to offer at a given visit. It might not be feasible to deliver all the needed services in a single visit, and they might need to be delivered over the course of several visits. Providers should tailor services to meet the specific needs of the population they serve. For example, clients who are trying to achieve pregnancy and those at high risk of unintended pregnancy should be given higher priority for preconception health services. In some cases, the provider will deliver the initial screening service but then refer to another provider for further diagnosis or follow-up care. The delivery of preconception, STD, and related preventive health services should not become a barrier to a client's ability to receive services related to preventing or achieving pregnancy. For these clients, receiving services related to preventing or achieving pregnancy is the priority; if other family planning services cannot be delivered at the initial visit, then follow-up visits should be scheduled. In addition, professional recommendations for how to address the needs of diverse clients, such as LGBTQ persons (26)(27)(28)(29)(30)(31)(32) or persons with disabilities (33), should be consulted and integrated into procedures, as appropriate. For example, as noted before, providers should avoid making assumptions about a client's gender identity, sexual orientation, race, or ethnicity; all requests for services should be treated without regard to these characteristics. Similarly, services for adolescents should be provided in a "youth-friendly" manner, which means that they are accessible, equitable, acceptable, appropriate, comprehensive, effective, and efficient for youth, as recommended by the World Health Organization (34). # Contraceptive Services Providers should offer contraceptive services to clients who wish to delay or prevent pregnancy. Contraceptive services should include consideration of a full range of FDA-approved contraceptive methods, a brief assessment to identify the contraceptive methods that are safe for the client, contraceptive counseling to help a client choose a method of contraception and use it correctly and consistently, and provision of one or more selected contraceptive method(s), preferably on site, but by referral if necessary. Contraceptive counseling is defined as a process that enables clients to make and follow through on decisions about their contraceptive use. Education is an integral component of the contraceptive counseling process that helps clients to make informed decisions and obtain the information they need to use contraceptive methods correctly. Key steps in providing contraceptive services, including contraceptive counseling and education, have been outlined (Box 3). These key steps are in accordance with the five principles of quality counseling (Appendix C). To help a client who is initiating or switching to a new method of contraception, providers should follow these steps. These steps most likely will be implemented iteratively when working with a client and should help clients adopt, change, or maintain contraceptive use. Step 1. Establish and maintain rapport with the client. Providers should strive to establish and maintain rapport. Strategies to achieve these goals include the following: - using open-ended questions; - demonstrating expertise, trustworthiness, and accessibility; - ensuring privacy and confidentiality; - explaining how personal information will be used; - encouraging the client to ask questions and share information; - listening to and observing the client; and - being encouraging and demonstrating empathy and acceptance. Step 2. Obtain clinical and social information from the client. Providers should ask clients about their medical history to identify methods that are safe. In addition, to learn more about factors that might influence a client's choice of a contraceptive method, providers should confirm the client's pregnancy intentions or reproductive life plan, ask about the client's contraceptive experiences and preferences, and conduct a sexual health assessment. When available, standardized tools should be used. - (35). Clients considering combined hormonal contraception should be asked about smoking tobacco, in accordance with CDC guidelines on contraceptive use (35). Additional details about the methods of contraception that are safe to use for female clients with specific medical conditions and characteristics (e.g., hypertension) are addressed in previously published guidelines (35). For a male client, a medical history should include use of condoms, known allergies to condoms, partner use of contraception, recent intercourse, whether his partner is currently pregnant or has had a child, miscarriage, or termination, and the presence of any infectious or chronic health condition. However, the taking of a medical history should not be a barrier to making condoms available in the clinical setting (i.e., a formal visit should not be a prerequisite for a client to obtain condoms). about contraceptive methods that the client can safely use, and help the client consider potential barriers to using the method(s) under consideration. Use of decision aids (e.g., computerized programs that help a client to identify a range of methods that might be appropriate for the client based on her physical characteristics such as health conditions or preferences about side effects) before or while waiting for the appointment can facilitate and maximize the utility of the time spent on this step. Providers should inform clients about all contraceptive methods that can be used safely. Before the health-care visit, clients might have only limited information about all or specific methods of contraception (37). A broad range of methods, including long-acting reversible contraception (i.e., intrauterine devices and implants), should be discussed with all women and adolescents, if medically appropriate. Providers are encouraged to present information on potential reversible methods of contraception by using a tiered approach (i.e., presenting information on the most effective methods first, before presenting information on less effective methods) (38,39). This information should include an explanation that longacting reversible contraceptive methods are safe and effective for most women, including those who have never given birth and adolescents (35). Information should be tailored and presented to ensure a client-centered approach. It is not appropriate to omit presenting information on a method solely because the method is not available at the service site. If not all methods are available at the service site, it is important to have strong referral links in place to other providers to maximize opportunities for clients to obtain their preferred method that is medically appropriate. # BOX 3. Steps in providing contraceptive services, including contraceptive counseling- and education - Establish and maintain rapport with the client. - Obtain clinical and social information from the client. - Work with the client interactively to select the most effective and appropriate contraceptive method. - Conduct a physical assessment related to contraceptive use, only when warranted. - Provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow up, and confirm client understanding. For clients who have completed childbearing or do not plan to have children, permanent sterilization (female or male) is an option that may be discussed. Both female and male sterilization are safe, are highly effective, and can be performed in an office or outpatient surgery setting (40,41). Women and men should be counseled that these procedures are not intended to be reversible and that other highly effective, reversible methods of contraception (e.g., implants or IUDs) might be an alternative if they are unsure about future childbearing. Clients interested in sterilization should be referred to an appropriate source of care if the provider does not perform the procedure. When educating clients about contraceptive methods that the clients can use safely, providers should ensure that clients understand the following: - Method effectiveness. A contraceptive method's rate of typical effectiveness, or the percentage of women experiencing an unintended pregnancy during the first year of typical use, is an important consideration (Figure 3; Appendix D) (38,42). - Correct use of the method. The mode of administration and understanding how to use the method correctly might be important considerations for the client when choosing a method. For example, receiving a contraceptive injection every 3 months might not be acceptable to a woman who fears injections. Similarly, oral contraceptives might not be acceptable to a woman who is concerned that she might not be able to remember to take a pill every day. - Noncontraceptive benefits. Many contraceptives have noncontraceptive benefits, in addition to preventing pregnancy, such as reducing heavy menstrual bleeding. Although the noncontraceptive benefits are not generally the major determinant for selecting a method, awareness of these benefits can help clients decide between two or more suitable methods and might enhance the client's motivation to use the method correctly and consistently. - Side effects. Providers should inform the client about risks and side effects of the method(s) under consideration, help the client understand that certain side effects of contraceptive methods might disappear over time, and encourage the client to weigh the experience of coping with side effects against the experience and consequences of an unintended pregnancy. The provider should be prepared to discuss and correct misperceptions about side effects. Clients also should be informed about warning signs for rare, but serious, adverse events with specific contraceptive methods, such as stroke and venous thromboembolism with use of combined hormonal methods. - Protection from STDs, including HIV. Clients should be informed that contraceptive methods other than condoms offer no protection against STDs, including HIV. Condoms, when used correctly and consistently, help reduce the risk of STDs, including HIV, and provide protection against pregnancy. Dual protection (i.e., protection from both pregnancy and STDs) is important for clients at risk of contracting an STD, such as those with multiple or potentially infected partner(s). Dual protection can be achieved through correct and consistent use of condoms with every act of sexual intercourse, or correct and consistent use of a condom to prevent infection plus another form of contraception to prevent pregnancy. (For more information about preventing and treating STDs, see STD Services.) When educating clients about the range of contraceptive methods, providers should ensure that clients have information that is medically accurate, balanced, and provided in a nonjudgmental manner. To assist clients in making informed decisions, providers should educate clients in a manner that can be readily understood and retained. The content, format, method, and medium for delivering education should be evidence-based (see Appendix E). When working with male clients, when appropriate, providers should discuss information about female-controlled methods - Practices: Explore the types of sexual activity in which the patient engages (e.g., vaginal, anal, or oral sex). - Pregnancy prevention: Discuss current and future contraceptive options. Ask about current and previous use of methods, use of contraception at last sex, difficulties with contraception, and whether the client has a particular method in mind. - Partners: Ask questions to determine the number, gender (men, women, or both), and concurrency of the patient's sex partners (if partner had sex with another partner while still in a sexual relationship with the patient). It might be necessary to define the term "partner" to the patient or use other, relevant terminology. - Protection from sexually transmitted diseases (STDs): Ask about condom use, with whom they do or do not use condoms, and situations that make it harder or easier to use condoms. Topics such as monogamy and abstinence also can be discussed. - Past STD history: Ask about any history of STDs, including whether their partners have ever had an STD. Explain that the likelihood of an STD is higher with a past history of an STD. (including emergency contraception) encourage discussion of contraception with partners, and provide information about how partners can access contraceptive services. Male clients should also be reminded that condoms should be used correctly and consistently to reduce risk of STDs, including HIV. When working with any client, encourage partner communication about contraception, as well as understanding partner barriers (e.g., misperceptions about side effects) and facilitators (e.g., general support) of contraceptive use (43)(44)(45)(46). The provider should help the client consider potential barriers to using the method(s) under consideration. This includes consideration of the following factors: - Social-behavioral factors. Social-behavioral factors might influence the likelihood of correct and consistent use of contraception (47). Providers should help the client consider the advantages and disadvantages of the method(s) being considered, the client's feelings about using the method(s), how her or his partner is likely to respond, the client's peers' perceptions of the method(s), and the client's confidence in being able to use the method correctly and consistently (e.g., using a condom during every act of intercourse or remembering to take a pill every day) (37). - Intimate partner violence and sexual violence. Current and past intimate partner sexual or domestic violence might impede the correct and consistent use of contraception, and might be a consideration when choosing a method (47)(48)(49). For example, an IUD might (42). A list of assessments that need to be conducted when providing reversible contraceptive services to a female client seeking to initiate or switch to a new method of reversible contraception is provided (Table 1) (42). Clinical evaluation of a client electing permanent sterilization should be guided by the clinician who performs the procedure. Recommendations for contraceptive use are available (42). Key points include the following: - Blood pressure should be taken before initiating the use of combined hormonal contraception. - Providers should assess the current pregnancy status of clients receiving contraception (42), which provides guidance on how to be reasonably certain that a woman is not pregnant at the time of contraception initiation. In most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman about to start using a contraceptive method. Routine pregnancy testing for every woman is not necessary. - Weight measurement is not needed to determine medical eligibility for any method of contraception because all methods generally can be used among obese women. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. - Unnecessary medical procedures and tests might create logistical, emotional, or economic barriers to contraceptive access for some women, particularly adolescents and lowincome women, who have high rates of unintended pregnancies (1,51,52). For both adolescent and adult female clients, the following examinations and tests are not needed routinely to provide contraception safely to a healthy client (although they might be needed to address other non-contraceptive health needs) ( 42): -pelvic examinations, unless inserting an intrauterine device (IUD) or fitting a diaphragm; -cervical cytology or other cancer screening, including clinical breast exam; -human immunodeficiency virus (HIV) screening; and -laboratory tests for lipid, glucose, liver enzyme, and hemoglobin levels or thrombogenic mutations. For male clients, no physical examination needs to be performed before distributing condoms. Step 5. Provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow-up, and confirm client understanding. - A broad range of FDA-approved contraceptive methods should be available onsite. Referrals for methods not available onsite should be provided for clients who indicate they prefer those methods. When providing contraception, providers should instruct the client about correct and consistent use and employ the following strategies to facilitate a client's use of contraception: -Provide onsite dispensing; -Begin contraception at the time of the visit rather than waiting for next menses (also known as "quick start") if the provider can reasonably be certain that the client is not pregnant (42). A provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria (42,53): ˏ is ≤7 days after the start of normal menses, ˏ has not had sexual intercourse since the start of last normal menses, ˏ has been using a reliable method of contraception correctly and consistently, ˏ is ≤7 days after spontaneous or induced abortion, ˏ is within 4 weeks postpartum, ˏ is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority of feeds are breastfeeds), amenorrheic, and <6 months postpartum; -Provide or prescribe multiple cycles (ideally a full year's supply) of oral contraceptive pills, the patch, or the ring to minimize the number of times a client has to return to the service site; -Make condoms easily and inexpensively available; and -If a client chooses a method that is not available on-site or the same day, provide the client another method to use until she or he can start the chosen method. - Help the client develop a plan for using the selected method. Using a method incorrectly or inconsistently and having gaps in contraceptive protection because of method switching both increase the likelihood of an unintended pregnancy (37). After the method has been provided, or a plan put into place to obtain the chosen method, providers should help the client develop an action plan for using the selected method. Providers should encourage clients to anticipate reasons why they might not use their chosen method(s) correctly or consistently, and help them develop strategies to deal with these possibilities. For example, for a client selecting oral contraceptive pills who might forget to take a pill, the provider can work with the client to identify ways to routinize daily pill taking (e.g., use of reminder systems such as daily text messages or cell phone alarms). Providers also may inform clients about the availability of emergency contraceptive pills and may provide clients an advance supply of emergency contraceptive pills on-site or by prescription, if requested. Side effects (e.g., irregular vaginal bleeding) are a primary reason for method discontinuation (54), so providers should discuss ways the client might deal with potential side effects to increase satisfaction with the method and improve continuation (42). - Develop a plan for follow-up. Providers should discuss an appropriate follow-up plan with the client to meet their individual needs, considering the client's risk for discontinuation. Follow-up provides an opportunity to inquire about any initial difficulties the client might be experiencing, and might reinforce the perceived accessibility of the provider and increase rapport. Alternative modes of follow-up other than visits to the service site, such as telephone, e-mail, or text messaging, should be considered (assuming confidentiality can be assured), as needed. As noted previously, if a client chooses a method that is not available on-site or during the visit, the provider # TABLE 1. Assessments to conduct when a female client is initiating a new method of reversible contraception # Cu-IUD and LNG-IUD Implant Injectable # Combined hormonal contraception # Progestinonly pills Condom Diaphragm or cervical cap Spermicide Abbreviations: A = Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method; B = Class B: contributes substantially to safe and effective use, but implementation might be considered within the public health and/or service context (the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available); C = Class C: does not contribute substantially to safe and effective use of the contraceptive method; Cu-IUD = copper-containing intrauterine device; LNG-IUD = levonorgestrel releasing intrauterine device. - In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. should schedule a follow-up visit with the client or provide a referral for her or him to receive the method. The client should be provided another method to use until she or he can start the chosen method. - Confirm the client's understanding. Providers should assess whether the client understands the information that was presented. The client's understanding of the most important information about her or his chosen contraceptive method should be documented in the medical record (e.g., by a checkbox or written statement). The teach-back method may be used to confirm the client's understanding by asking the client to repeat back messages about risks and benefits and appropriate method use and follow-up. If providers assess the client's understanding, then the check box or written statement can be used in place of a written method-specific informed consent form. Topics that providers may consider having the client repeat back include the following: typical method effectiveness; how to use the method correctly; protection from STDs; warning signs for rare, but serious, adverse events and what to do if they experience a warning sign; and when to return for follow-up. Examination Blood pressure C C C A- C C C C Weight (BMI) (weight /height 2 ) - † - † - † - † - † C C C Clinical breast examination C C C C C C C C Bimanual examination and cervical inspection A C C C C C A § C Laboratory test Glucose C C C C C C C C Lipids C C C C C C C C Liver enzymes C C C C C C C C Hemoglobin C C C C C C C C Thrombogenic mutations C C C C C C C C Cervical cytology (Papanicolaou smear) C C C C C C C C STD # Provide Counseling for Returning Clients When serving contraceptive clients who return for ongoing care related to contraception, providers should ask if the client has any concerns with the method and assess its use. The provider should assess any changes in the client's medical history, including changes in risk factors and medications that might affect safe use of the contraceptive method. If the client is using the method correctly and consistently and there are no concerns about continued use, an appropriate follow-up plan should be discussed and more contraceptive supplies given (42). If the client or provider has concerns about the client's correct or consistent use of the method, the provider should ask if the client would be interested in considering a different method of contraception. If the client is interested, the steps described above should be followed. # Counseling Adolescent Clients Providers should give comprehensive information to adolescent clients about how to prevent pregnancy (55)(56)(57). This information should clarify that avoiding sex (i.e., abstinence) is an effective way to prevent pregnancy and STDs. If the adolescent indicates that she or he will be sexually active, providers should give information about contraception and help her or him to choose a method that best meets her or his individual needs, including the use of condoms to reduce the risk of STDs. Long-acting reversible contraception is a safe and effective option for many adolescents, including those who have not been pregnant or given birth (35). Providers of family planning services should offer confidential services to adolescents and observe all relevant state laws and any legal obligations, such as notification or reporting of child abuse, child molestation, sexual abuse, rape, or incest, as well as human trafficking (58,59). Confidentiality is critical for adolescents and can greatly influence their willingness to access and use services (60)(61)(62)(63)(64)(65)(66)(67). As a result, multiple professional medical associations have emphasized the importance of providing confidential services to adolescents (68)(69)(70). Providers should encourage and promote communication between the adolescent and his or her parent(s) or guardian(s) about sexual and reproductive health (71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86). Adolescents who come to the service site alone should be encouraged to talk to their parents or guardians. Educational materials and programs can be provided to parents or guardians that help them talk about sex and share their values with their child (72,87). When both parent or guardian and child have agreed, joint discussions can address family values and expectations about dating, relationships, and sexual behavior. In a given year, approximately 20% of adolescent births represent repeat births (88), so in addition to providing postpartum contraception, providers should refer pregnant and parenting adolescents to home visiting and other programs that have been demonstrated to provide needed support and reduce rates of repeat teen pregnancy (89)(90)(91)(92)(93)(94). Services for adolescents should be provided in a "youthfriendly" manner, which means that they are accessible, equitable, acceptable, appropriate, comprehensive, effective, and efficient for youth as recommended by the World Health Organization (34). # Pregnancy Testing and Counseling Providers of family planning services should offer pregnancy testing and counseling services as part of core family planning services, in accordance with recommendations of major professional medical organizations, such as the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) (95)(96)(97). Pregnancy testing is a common reason for a client to visit a provider of family planning services. Approximately 65% of pregnancies result in live births, 18% in induced abortion, and 17% spontaneous fetal loss (98). Among live births, only 1% of infants are placed for adoption within their first month of life (99). The visit should include a discussion about her reproductive life plan and a medical history that includes asking about any coexisting conditions (e.g., chronic medical illnesses, physical disability, psychiatric illness) (95,96). In most cases, a qualitative urine pregnancy test will be sufficient; however, in certain cases, the provider may consider performing a quantitative serum pregnancy test, if exact hCG levels would be helpful for diagnosis and management. The test results should be presented to the client, followed by a discussion of options and appropriate referrals. Options counseling should be provided in accordance with recommendations from professional medical associations, such as ACOG and AAP (95)(96)(97). A female client might wish to include her partner in the discussion; however, if a client chooses not to involve her partner, confidentiality must be assured. # Positive Pregnancy Test If the pregnancy test is positive, the clinical visit should include an estimation of gestational age so that appropriate counseling can be provided. If a woman is uncertain about the date of her last normal menstrual period, a pelvic examination might be needed to help assess gestational age. In addition, clients should receive information about the normal signs and symptoms of early pregnancy, and should be instructed to report any concerns to a provider for further evaluation. If ectopic pregnancy or other pregnancy abnormalities or problems are suspected, the provider should either manage the condition or refer the client for immediate diagnosis and management. Referral to appropriate providers of follow-up care should be made at the request of the client, as needed. Every effort should be made to expedite and follow through on all referrals. For example, providers might provide a resource listing or directory of providers to help the client identify options for care. Depending upon a client's needs, the provider may make an appointment for the client, or call the referral site to let them know the client was referred. Providers also should assess the client's social support and refer her to appropriate counseling or other supportive services, as needed. For clients who are considering or choose to continue the pregnancy, initial prenatal counseling should be provided in accordance with the recommendations of professional medical associations, such as ACOG (97). The client should be informed that some medications might be contraindicated in pregnancy, and any current medications taken during pregnancy need to be reviewed by a prenatal care provider (e.g., an obstetrician or midwife). In addition, the client should be encouraged to take a daily prenatal vitamin that includes folic acid; to avoid smoking, alcohol, and other drugs; and not to eat fish that might have high levels of mercury (97). If there might be delays in obtaining prenantal care, the client should be provided or referred for any needed STD screening (including HIV) and vaccinations (36). # Negative Pregnancy Test Women who are not pregnant and who do not want to become pregnant at this time should be offered contraceptive services, as described previously. The contraceptive counseling session should explore why the client thought that she was pregnant and sought pregnancy testing services, and whether she has difficulties using her current method of contraception. A negative pregnancy test also provides an opportunity to discuss the value of making a reproductive life plan. Ideally, these services will be offered in the same visit as the pregnancy test because clients might not return at a later time for contraceptive services. Women who are not pregnant and who are trying to become pregnant should be offered services to help achieve pregnancy or basic infertility services, as appropriate (see "Clients Who Want to Become Pregnant" and "Basic Infertility Services"). They also should be offered preconception health and STD services (see "Preconception Health Services" and "STD services"). # Clients Who Want to Become Pregnant Providers should advise clients who wish to become pregnant in accordance with the recommendations of professional medical organizations, such as the American Society for Reproductive Medicine (ASRM) (100). Providers should ask the client (or couple) how long she or they have been trying to get pregnant and when she or they hope to become pregnant. If the client's situation does not meet one of the standard definitions of infertility (see "Basic Infertility Services"), then she or he may be counseled about how to maximize fertility. Key points are as follows: - The client should be educated about peak days and signs of fertility, including the 6-day interval ending on the day of ovulation that is characterized by slippery, stretchy cervical mucus and other possible signs of ovulation. - Women with regular menstrual cycles should be advised that vaginal intercourse every 1-2 days beginning soon after the menstrual period ends can increase the likelihood of becoming pregnant. - Methods or devices designed to determine or predict the time of ovulation (e.g., over-the-counter ovulation kits, digital telephone applications, or cycle beads) should be discussed. - It should be noted that fertility rates are lower among women who are very thin or obese, and those who consume high levels of caffeine (e.g., more than five cups per day). - Smoking, consuming alcohol, using recreational drugs, and using most commercially available vaginal lubricants should be discouraged as these might reduce fertility. # Basic Infertility Services Providers should offer basic infertility care as part of core family planning services in accordance with the recommendations of professional medical organizations, such as ACOG, ASRM, and the American Urological Association (AUA) (96,101,102). Infertility commonly is defined as the failure of a couple to achieve pregnancy after 12 months or longer of regular unprotected intercourse (101). Earlier assessment (such as 6 months of regular unprotected intercourse) is justified for women aged >35 years, those with a history of oligoamenorrhea (infrequent menstruation), those with known or suspected uterine or tubal disease or endometriosis, or those with a partner known to be subfertile (the condition of being less than normally fertile though still capable of effecting fertilization) ( 101). An early evaluation also might be warranted if risk factors of male infertility are known to be present or if there are questions regarding the male partner's fertility potential (102). Infertility visits to a family planning provider are focused on determining potential causes of the inability to achieve pregnancy and making any needed referrals to specialist care (101,102). ASRM recommends that evaluation of both partners should begin at the same time (101). # Basic Infertility Care for Women The clinical visit should focus on understanding the client's reproductive life plan (24) and her difficulty in achieving pregnancy through a medical history, sexual health assessment and physical exam, in accordance with recommendations developed by professional medical associations such as ASRM (101) and ACOG (96). The medical history should include past surgery, including indications and outcome(s), previous hospitalizations, serious illnesses or injuries, medical conditions associated with reproductive failure (e.g., thyroid disorders, hirsutism, or other endocrine disorders), and childhood disorders; results of cervical cancer screening and any follow-up treatment; current medication use and allergies; and family history of reproductive failure. In addition, a reproductive history should include how long the client has been trying to achieve pregnancy; coital frequency and timing, level of fertility awareness, and results of any previous evaluation and treatment; gravidity, parity, pregnancy outcome(s), and associated complications; age at menarche, cycle length and characteristics, and onset/severity of dysmenorrhea; and sexual history, including pelvic inflammatory disease, history of STDs, or exposure to STDs. A review of systems should emphasize symptoms of thyroid disease, pelvic or abdominal pain, dyspareunia, galactorrhea, and hirsutism (101). The physical examination should include: height, weight, and body mass index (BMI) calculation; thyroid examination to identify any enlargement, nodule, or tenderness; clinical breast examination; and assessment for any signs of androgen excess. A pelvic examination should assess for: pelvic or abdominal tenderness, organ enlargement or mass; vaginal or cervical abnormality, secretions, or discharge; uterine size, shape, position, and mobility; adnexal mass or tenderness; and cul-de-sac mass, tenderness, or nodularity. If needed, clients should be referred for further diagnosis and treatment (e.g., serum progesterone levels, follicle-stimulating hormone/luteinizing hormone levels, thyroid function tests, prolactin levels, endometrial biopsy, transvaginal ultrasound, hysterosalpingography, laparoscopy, and clomiphene citrate). # Basic Infertility Care for Men Infertility services should be provided for the male partner of an infertile couple in accordance with recommendations developed by professional medical associations such as AUA (102). Providers should discuss the client's reproductive life plan, take a medical history, and conduct a sexual health assessment. AUA recommends that the medical history include a reproductive history (102). The medical history should include systemic medical illnesses (e.g., diabetes mellitus), prior surgeries and past infections; medications (prescription and nonprescription) and allergies; and lifestyle exposures. The reproductive history should include methods of contraception, coital frequency and timing; duration of infertility and prior fertility; sexual history; and gonadal toxin exposure, including heat. Patients also should be asked about their female partners' history of pelvic inflammatory disease, their partners' histories of STDs, and problems with sexual dysfunction. In addition, a physical examination should be conducted with particular focus given to 1) examination of the penis, including the location of the urethral meatus; 2) palpation of the testes and measurement of their size; 3) presence and consistency of both the vas deferens and epididymis; 4) presence of a varicocele; 5) secondary sex characteristics; and 6) a digital rectal exam (102). Male clients concerned about their fertility should have a semen analysis. If this test is abnormal, they should be referred for further diagnosis (i.e., second semen analysis, endocrine evaluation, post-ejaculate urinalysis, or others deemed necessary) and treatment. The semen analysis is the first and most simple screen for male fertility. # Infertility Counseling Counseling provided during the clinical visit should be guided by information elicited from the client during the medical and reproductive history and the findings of the physical exam. If there is no apparent cause of infertility and the client does not meet the definition above, providers should educate the client about how to maximize fertility (see "Clients Who Want to Become Pregnant"). ACOG notes the importance of addressing the emotional and educational needs of clients with infertility and recommends that providers consider referring clients for psychological support, infertility support groups, or family counseling (96). # Preconception Health Services Providers of family planning services should offer preconception health services to female and male clients in accordance with CDC's recommendations to improve preconception health and health care (24). Preconception health services are beneficial because of their effect on pregnancy and birth outcomes and their role in improving the health of women and men. The term preconception describes any time that a woman of reproductive potential is not pregnant but at risk of becoming pregnant, or when a man is at risk for impregnating his female partner. Preconception health-care services for women aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcomes through prevention and management. It promotes the health of women of reproductive age before conception, and thereby helps to reduce pregnancyrelated adverse outcomes, such as low birthweight, premature birth, and infant mortality (24). Moreover, the preconception health services recommended here are equally important because they contribute to the improvement of women's health and well-being, regardless of her childbearing intentions. CDC recommends that preconception health services be integrated into primary care visits made by women of reproductive age, such as family planning visits (24). In the family planning setting, providers may prioritize screening and counseling about preconception health for couples that are trying to achieve pregnancy and couples seeking basic infertility services. Women who are using contraception to prevent or delay pregnancy might also benefit from preconception health services, especially those at high risk of unintended pregnancy. A woman is at high risk of unintended pregnancy if she is using no method or a less effective method of contraception (e.g., barrier methods, rhythm, or withdrawal), or has a history of contraceptive discontinuation or incorrect use (38,39). A woman is at lower risk of unintended pregnancy if she is using a highly effective method, such as an IUD or implant, or has an established history of using methods of contraception, such as injections, pills, patch, or ring correctly and consistently (38,39). Clients who do not want to become pregnant should also be provided preconception health services, since they are recommended by USPSTF for the purpose of improving the health of adults. Recommendations for improving the preconception health of men also have been identified, although the evidence base for many of the recommendations for men is less than that for women (103). This report includes preconception health services that address men as partners in family planning (i.e., both preventing and achieving pregnancy), their direct contributions to infant health (e.g., genetics), and their role in improving the health of women (e.g., through reduced STD/HIV transmission). Moreover, these services are important for improving the health of men regardless of their pregnancy intention. In a family planning setting, all women planning or capable of pregnancy should be counseled about the need to take a daily supplement containing 0.4 to 0.8 mg of folic acid, in accordance with the USPSTF recommendation (Grade A) (104). Other preconception health services for women and men should include discussion of a reproductive life plan and sexual health assessment (Boxes 2 and 4), as well as the screening services described below (24,103,105). Services should be provided in accordance with the cited clinical recommendations, and any needed follow up (further diagnosis, treatment) should be provided either on-site or through referral. # Medical History For female clients, the medical history should include the reproductive history, history of poor birth outcomes (i.e., preterm, cesarean delivery, miscarriage, and stillbirth), environmental exposures, hazards and toxins (e.g., smoking, alcohol, other drugs), medications that are known teratogens, genetic conditions, and family history (24,105). For male clients, the medical history should include asking about the client's past medical and surgical history that might impair his reproductive health (e.g., genetic conditions, history of reproductive failures, or conditions that can reduce sperm quality, such as obesity, diabetes mellitus, and varicocele) and environmental exposures, hazards and toxins (e.g., smoking) (103). # Intimate Partner Violence Providers should screen women of childbearing age for intimate partner violence and provide or refer women who screen positive to intervention services, in accordance with USPSTF (Grade B) recommendations (106). # Alcohol and Other Drug Use For female and male adult clients, providers should screen for alcohol use in accordance with the USPSTF recommendation (Grade B) for how to do so, and provide behavioral counseling interventions, as indicated (107). Screening adults for other drug use and screening adolescents for alcohol and other drug use has the potential to reduce misuse of alcohol and other drugs, and can be recommended (105,108,109). However, the USPSTF recommendation for screening for other drugs in adults, and for alcohol and other drugs in adolescents, is an "I," and patients should be informed that there is insufficient evidence to assess the balance of benefits and harms of this screening (107,110). # Tobacco Use For female and male clients, providers should screen for tobacco use in accordance with the USPSTF recommendation (111,112) for how to do so. Adults (Grade A) who use tobacco products should be provided or referred for tobacco cessation interventions, including brief behavioral counseling sessions (<10 minutes) and pharmacotherapy delivered in primary care settings (111). Adolescents (Grade B) should be provided intervention to prevent initiation of tobacco use (112). # Immunizations For female and male clients, providers should screen for immunization status in accordance with recommendations of CDC's Advisory Committee on Immunization Practices (113) and offer vaccination, as indicated, or provide referrals to community providers for immunization. Female and male clients should be screened for age-appropriate vaccinations, such as influenza and tetanus-diphtheria-pertussis (Tdap), measles, mumps, and rubella (MMR), varicella, pneumococcal, and meningococcal. In addition, ACOG recommends that rubella titer be performed in women who are uncertain about MMR immunization (108). (For vaccines for reproductive health-related conditions, i.e., human papillomavirus and hepatitis B, see "Sexually Transmitted Disease Services.") # Depression For all clients, providers should screen for depression when staff-assisted depression care supports are in place to ensure accurate diagnosis, effective treatment, and follow-up (114,115). Staff-assisted care supports are defined as clinical staff members who assist the primary care clinician by providing some direct depression care, such as care support or coordination, case management, or mental health treatment. The lowest effective staff supports consist of a screening nurse who advises primary care clinicians of a positive screen and provides a protocol facilitating referral to behavioral therapy. Providers also may follow American Psychiatric Association (116) and American Academy of Child and Adolescent Psychiatry (117) recommendations to assess risk for suicide among persons experiencing depression and other risk factors. # Height, Weight, and Body Mass Index For all clients, providers should screen adult (Grade B) and adolescent (Grade B) clients for obesity in accordance with the USPSTF recommendation, and obese adults should be referred for intensive counseling and behavioral interventions to promote sustained weight loss (118,119). Clients likely will need to be referred for this service. These interventions typically comprise 12 to 26 sessions in a year and include multiple behavioral management activities, such as group sessions, individual sessions, setting weight-loss goals, improving diet or nutrition, physical activity sessions, addressing barriers to change, active use of self-monitoring, and strategizing how to maintain lifestyle changes. # Blood Pressure For female and male clients, providers should screen for hypertension in accordance with the USPSTF's recommendation (Grade A) that blood pressure be measured routinely among adults (120) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure's recommendation that persons with blood pressure less than 120/80 be screened every 2 years, and every year if prehypertensive (i.e., blood pressure 120-139/80-89) (121). Providers also may follow AAP's recommendation that adolescents receive annual blood pressure screening (109). # Diabetes For female and male clients, providers should follow the USPSTF recommendation (Grade B) to screen for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) >135/80 mmHg (122). # Sexually Transmitted Disease Services Providers should offer STD services in accordance with CDC's STD treatment and HIV testing guidelines (36,123,124). It is important to test for chlamydia annually among young sexually active females and for gonorrhea routinely among all sexually active females at risk for infection because they can cause tubal infertility in women if left untreated. Testing for syphilis, HIV/AIDS, and hepatitis C should be conducted as recommended (36,123,124). Vaccination for human papillomavirus (HPV) and hepatitis B are also important parts of STD services and preconception care (113). STD services should be provided for persons with no signs or symptoms suggestive of an STD. STD diagnostic management recommendations are not included in these guidelines, so providers should refer to CDC's STD treatment guidelines (36) when caring for clients with STD symptoms. STD services include the following steps, which should be provided at the initial visit and at least annually thereafter: Step 1. Assess: The provider should discuss the client's reproductive life plan, conduct a standard medical history and sexual health assessment (see text box above), and check immunization status. A pelvic exam is not indicated in patients with no symptoms suggestive of an STD. Step 2. Screen: A client who is at risk of an STD (i.e., sexually active and not involved in a mutually monogamous relationship with an uninfected partner) should be screened for HIV and the other STDs listed below, in accordance with CDC's STD treatment guidelines (36) and recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings (123). Clients also should follow CDC's recommendations for testing for hepatitis C (124), and the Advisory Committee on Immunization Practice's recommendations on reproductive health-related immunizations (113). It is important to follow these guidelines both to ensure that clients receive needed services and to avoid unnecessary screening. # Chlamydia For female clients, providers should screen all sexually active women aged ≤25 years for chlamydia annually, in addition to sexually active women aged >25 years with risk factors for chlamydia infection (36). Women aged >25 years at higher risk include sexually active women who have a new or more than one sex partner or who have a partner who has other concurrent partners. Females with chlamydia infection should be rescreened for re-infection at 3 months after treatment. Pregnant women should be screened for chlamydia at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). For male clients, chlamydia screening can be considered for males seen at sites with a high prevalence of chlamydia, such as adolescent clinics, correctional facilities, and STD clinics (36,125,126). Providers should screen men who have sex with men (MSM) for chlamydia at anatomic sites of exposure, in accordance with CDC's STD treatment guidelines (36). Males with symptoms suggestive of chlamydia (urethral discharge or dysuria or whose partner has chlamydia) should be tested and empirically treated at the initial visit. Males with chlamydia infection should be re-screened for reinfection at 3 months (36). # Gonorrhea For female clients, providers should screen clients for gonorrhea, in accordance with CDC's STD treatment guidelines (36). Routine screening for N. gonorrhoeae in all sexually active women at risk for infection is recommended annually (36). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors that place women at increased risk include a previous gonorrhea infection, the presence of other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. Females with gonnorrhea infection should be re-screened for re-infection at 3 months after treatment. Pregnant women should be screened for gonorrhea at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). For male clients, providers should screen MSM for gonorrhea at anatomic sites of exposure, in accordance with CDC's STD treatment guidelines (36). Males with symptoms suggestive of gonorrhea (urethral discharge or dysuria or whose partner has gonorrhea) should be tested and empirically treated at the initial visit. Males with gonorrhea infection should be re-screened for reinfection at 3 months after treatment (36,(126)(127)(128). # Syphilis For female and male clients, providers should screen clients for syphilis, in accordance with CDC's STD treatment guidelines (36). CDC recommends that persons at risk for syphilis infection should be screened. Populations at risk include MSM, commercial sex workers, persons who exchange sex for drugs, those in adult correctional facilities and those living in communities with high prevalence of syphilis (36). Pregnant women should be screened for syphilis at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). # HIV/AIDS For female and male clients, providers should screen clients for HIV/AIDS, in accordance with CDC HIV testing guidelines (123). Providers should follow CDC recommendations that all clients aged 13-64 years be screened routinely for HIV infection and that all persons likely to be at high risk for HIV be rescreened at least annually (123). Persons likely to be at high risk include injection-drug users and their sex partners, persons who exchange sex for money or drugs, sex partners of HIV-infected persons, and MSM or heterosexual persons who themselves or whose sex partners have had more than one sex partner since their most recent HIV test. CDC further recommends that screening be provided after the patient is notified that testing will be performed as part of general medical consent unless the patient declines (opt-out screening) or otherwise prohibited by state law. The USPSTF also recommends screening for HIV (Grade A) (129). # Hepatitis C For female and male clients, CDC recommends one-time testing for hepatitis C (HCV) without prior ascertainment of HCV risk for persons born during 1945-1965, a population with a disproportionately high prevalence of HCV infection and related disease. Persons identified as having HCV infection should receive a brief screening for alcohol use and intervention as clinically indicated, followed by referral to appropriate care for HCV infection and related conditions. These recommendations do not replace previous guidelines for HCV testing that are based on known risk factors and clinical indications. Rather, they define an additional target population for testing: persons born during 1945-1965 (124). USPSTF also recommends screening persons at high risk for infection for hepatitis C and one-time screening for HCV infection for persons in the 1945-1965 birth cohort (Grade B) (130). # Immunizations Related to Reproductive Health Female clients aged 11-26 years should be offered either human papillomavirus (HPV) 2 or HPV4 vaccine for the prevention of HPV and cervical cancer if not previously vaccinated, although the series can be started in persons as young as age 9 years (113); recommendations include starting at age 11-12 years and catch up vaccine among females aged 13-26 who have not been vaccinated previously or have not completed the 3-dose series through age 26. Routine hepatitis B vaccination should be offered to all unvaccinated children and adolescents aged <19 years and all adults who are unvaccinated and do not have any documented history of hepatitis B infection (113). Male clients aged 11-21 years (minimum age: 9 years) should be offered HPV4 vaccine, if not vaccinated previously; recommendations include starting at age 11-12 years and catch up vaccine among males aged 13-21 years who have not been vaccinated previously or have not completed the 3-dose series through age 21 years; vaccination is recommended among at-risk males, including MSM and immune-compromised males through age 26 years if not vaccinated previously or males who have not completed the 3-dose series through age 26 years. Heterosexual males aged 22-26 years may be vaccinated (131). Routine hepatitis B vaccination should be offered to all unvaccinated children and adolescents aged <19 years, and all unvaccinated adults who do not have a documented history of hepatitis B infection (113). Step 3. Treat: A client with an STD and her or his partner(s) should be treated in a timely fashion to prevent complications, re-infection and further spread of the infection in the community in accordance with CDC's STD treatment guidelines; clients with HIV infection should be linked to HIV care and treatment (36,123). Clients should be counseled about the need for partner evaluation and treatment to avoid reinfection at the time the client receives the positive test results. For partners of clients with chlamydia or gonorrhea, one option is to schedule them to come in with the client; another option for partners who cannot come in with the client is expedited partner therapy (EPT), as permissible by state laws, in which medication or a prescription is provided to the patient to give to the partner to ensure treatment. EPT is a partner treatment strategy for partners who are unable to access care and treatment in a timely fashion. Because of concerns related to resistant gonorrhea, efforts to bring in for treatment partners of patients with gonorrhea infection are recommended; EPT for gonorrhea should be reserved for situations in which efforts to treat partners in a clinical setting are unsuccessful and EPT is a gonorrhea treatment of last resort. All clients treated for chlamydia or gonorrhea should be rescreened 3 months after treatment; HIV-infected females with Trichomonas vaginalis should be linked to HIV care and rescreened for T. vaginalis at 3 months. If needed, the client also should be vaccinated for hepatitis B and HPV (113). Ideally, STD treatment should be directly observed in the facility rather than a prescription given or called in to a pharmacy. If a referral is made to a service site that has the necessary medication available on-site, such as the recommended injectable antimicrobials for gonorrhea and syphilis, then the referring provider must document that treatment was given. Step 4. Provide risk counseling: If the client is at risk for or has an STD, high-intensity behavioral counseling for sexual behavioral risk reduction should be provided in accordance with the USPSTF recommendation (Grade B) (132). One high-intensity behavioral counseling model that is similar to the contraceptive counseling model is Project Respect (133), which could be implemented in family planning settings. All sexually active adolescents are at risk, and adults are at increased risk if they have current STDs, had an STD in the past year, have multiple sexual partners, are in nonmonogamous relationships, or are sexually active and live in a community with a high rate of STDs. Other key messages to give infected clients before they leave the service site include the following: a) refrain from unprotected sexual intercourse during the period of STD treatment, 2) encourage partner(s) to be screened or to get treatment as quickly as possible in accordance with CDC's STD treatment guidelines (partners in the past 60 days for chlamydia and gonorrhea, 3 to 6 months plus the duration of lesions or signs for primary and secondary syphilis, respectively) if the partner did not accompany the client to the service site for treatment, and 3) return for retesting in 3 months. If the partner is unlikely to access treatment quickly, then EPT for chlamydia or gonorrhea should be considered, if permissible by state law. A client using or considering contraceptive methods other than condoms should be advised that these methods do not protect against STDs. Providers should encourage a client who is not in a mutually monogamous relationship with an uninfected partner to use condoms. Patients who do not know their partners' infection status should be encouraged to get tested and use condoms or avoid sexual intercourse until their infection status is known. # Related Preventive Health Services For many women and men of reproductive age, a family planning service site is their only source of health care; therefore, visits should include provision of or referral to other preventive health services. Providers of family planning services that do not have the capacity to offer comprehensive primary care services should have strong links to other community providers to ensure that clients have access to primary care. If a client does not have another source of primary care, priority should be given to providing related reproductive health services or providing referrals, as needed. For clients without a primary care provider, the following screening services should be provided, with appropriate follow-up, if needed, while linking the client to a primary care provider. These services should be provided in accordance with federal and professional medical recommendations cited below regarding the frequency of screening, the characteristics of the clients that should be screened, and the screening procedures to be used. # Medical History USPSTF recommends that women be asked about family history that would be suggestive of an increased risk for deleterious mutations in BRCA1 or BRCA2 genes (e.g., receiving a breast cancer diagnosis at an early age, bilateral breast cancer, history of both breast and ovarian cancer, presence of breast cancer in one or more female family members, multiple cases of breast cancer in the family, both breast and ovarian cancer in the family, one or more family members with two primary cases of cancer, and Ashkenazi background). Women with identified risk(s) should be referred for genetic counseling and evaluation for BRCA testing (Grade B) (134). The USPSTF also recommends that women at increased risk for breast cancer should be counseled about risk-reducing medications (Grade B) (135). # Cervical Cytology Providers should provide cervical cancer screening to clients receiving related preventive health services. Providers should follow USPSTF recommendations to screen women aged 21-65 years with cervical cytology (Pap smear) every 3 years, or for women aged 30-65 years, screening with a combination of cytology and HPV testing every 5 years (Grade A) (136). Cervical cytology no longer is recommended on an annual basis. Further, it is not recommended (Grade D) for women aged <21 years (136). Women with abnormal test results should be treated in accordance with professional standards of care, which may include colposcopy (96,137). The need for cervical cytology should not delay initiation or hinder continuation of a contraceptive method (42). Providers should also follow ACOG and AAP recommendations that a genital exam should accompany a cervical cancer screening to inspect for any suspicious lesions or other signs that might indicate an undiagnosed STD (96,97,138). # Clinical Breast Examamination Despite a lack of definitive data for or against, clinical breast examination has the potential to detect palpable breast cancer and can be recommended. ACOG recommends annual examination for all women aged >19 years (108). ACS recommends screening every 3 years for women aged 20-39 years, and annually for women aged ≥40 years (139). However, the USPSTF recommendation for clinical breast exam is an I, and patients should be informed that there is insufficient evidence to assess the balance of benefits and harms of the service (140). # Mammography Providers should follow USPSTF recommendations (Grade B) to screen women aged 50-74 years on a biennial basis; they should screen women aged <50 years if other conditions support providing the service to an individual patient (140). # Genital Examination For adolescent males, examination of the genitals should be conducted. This includes documentation of normal growth and development and other common genital findings, including hydrocele, varicocele, and signs of STDs (141). Components of this examination include inspecting skin and hair, palpating inguinal nodes, scrotal contents and penis, and inspecting the perinanal region (as indicated). # Summary of Recommendations for Providing Family Planning and Related Preventive Health Services The screening components for each family planning and related preventive health service are provided in summary checklists for women (Table 2) and men (Table 3). When considering how to provide the services listed in these recommendations (e.g., the screening components for each service, risk groups that should be screened, the periodicity of screening, what follow-up steps should be taken if screening reveals the presence of a health condition), providers should follow CDC and USPSTF recommendations cited above, or, in the absence of CDC and USPSTF recommendations, the recommendations of professional medical associations. Following these recommendations is important both to ensure clients receive needed care and to avoid unnecessary screening of clients who do not need the services. The summary tables describe multiple screening steps, which refer to the following: 1) the process of asking questions about a client's history, including a determination of whether risk factors for a disease or health condition exist; 2) performing a physical exam; and 3) performing laboratory tests in at-risk asymptomatic persons to help detect the presence of a specific disease, infection, or condition. Many screening recommendations apply only to certain subpopulations (e.g., specific age groups, persons who engage in specific risk behaviors or who have specific health conditions), or some screening recommendations apply to a particular frequency (e.g., a cervical cancer screening is generally recommended every 3 years rather than annually). Providers should be aware that the USPSTF also has recommended that certain screening services not be provided because the harm outweighs the benefit (see Appendix F). When screening results indicate the potential or actual presence of a health condition, the provider should either provide or refer the client for the appropriate further diagnostic testing or treatment in a manner that is consistent with the relevant federal or professional medical associations' clinical recommendations. # Conducting Quality Improvement Service sites that offer family planning services should have a system for conducting quality improvement, which is designed to review and strengthen the quality of services on an ongoing basis. Quality improvement is the use of a deliberate and continuous effort to achieve measurable improvements in the identified indicators of quality of care, which improve the health of the community (142). By improving the quality of care, family planning outcomes, such as reduced rates of unintended pregnancy, improved patient experiences, and reduced costs, are more likely to be achieved (10,12,143,144). Several frameworks for conducting quality improvement have been developed (144)(145)(146). This section presents a general overview of three key steps that providers should take when conducting quality improvement of family planning services: 1) determine which measures are needed to monitor quality; 2) collect the information needed; and 3) use the findings to make changes to improve quality (147). Ideally, these steps will be conducted on a frequent (optimally, quarterly) and ongoing basis. However, since quality cuts across all aspects of a program, not all domains of quality can necessarily be considered at all times. Within a sustainable system of quality improvement, programs can opt to focus on a subset of quality dimensions and their respective measures. # Determining Which Measures Are Needed Performance measures provide information about how well the service site is meeting pre-established goals (148). The following questions should be considered when selecting performance measures ( 143): - Is the topic important to measure and report? For example, does it address a priority aspect of health care, and is there opportunity for improvement? - What is the level of evidence for the measure (e.g., that a change in the measure is likely to represent a true change in health outcomes)? Does the measure produce consistent (reliable) and credible (valid) results about the quality of care? - Are the results meaningful and understandable and useful for informing quality improvement? - Is the measure feasible? Can it be implemented without undue burden (e.g., captured with electronic data or electronic health records)? Performance measures should consider the quality of the structure of services (e.g., the characteristics of the settings in which providers deliver health care, including material resources, human resources, and organizational structure), the process by which care is provided (whether services are provided correctly and completely, and how clients perceive the care they receive), and the outcomes of that care (e.g., client behaviors or health conditions that result) (149). They also may assess each dimension of quality services (10,13). Examples of measures that can be used for monitoring the quality of family planning services (150) and suggested measures that might help providers monitor quality of care have been listed (Table 6). However, other measures have been developed that also might be useful (151)(152)(153). Service sites that offer family planning services should select, measure, and assess at least one intermediate or outcome measure on an ongoing basis, for which the service site can be accountable. Structure-and process-based measures that assess the eight dimensions of quality services may be used to better determine how to improve quality (154). # Collecting Information Once providers have determined what information is needed, the next steps are to collect and use that information to improve the quality of care. Commonly used methods of data collection include the following: -4]). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § § Indicates that screening is suggested only for those persons at highest risk or for a specific subpopulation with high prevalence of an infection or condition. ¶ ¶ Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD treatment guidelines (Sources: CDC. STD Abbreviations: HBV = hepatitis B virus; HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome; HPV = human papillomavirus virus; STD = sexually transmitted disease. - No special evaluation needs to be done prior to making condoms available to males. However, when a male client requests advice on pregnancy prevention, he should be provided contraceptive services as described in the section "Provide Contraceptive Services. " † The services listed here represent a sub-set of recommended preconception health services for men that were recommended and for which there was a direct link to fertility or infant health outcomes (Source: Frey K, Navarro S, Kotelchuck M, Lu M. The clinical content of preconception care: preconception care for men. Am J Obstet Gynecol 2008;199:S389-95). § STD services also promote preconception health, but are listed separately here to highlight their importance in the context of all types of family planning visit. The services listed in this column are for men without symptoms suggestive of an STD. ¶ CDC recommendation. U.S. Preventive Services Task Force recommendation. † † Professional medical association recommendation. § § Indicates that screening is suggested only for those persons at highest risk or for a specific subpopulation with high prevalence of infection or other condition. provider's behavior might be influenced if she or he knows clients are being interviewed. - Facility audit. Questions about a service site's structure (e.g., on-site availability of a broad range of FDA-approved methods) and processes (e.g., skills and technical competence of staff, referral mechanisms) can be used to determine the readiness of the facility to serve clients. - Direct observation. A provider's behavior is observed during an actual encounter with a client. Evaluation of a full range of competencies, including communication skills, can be carried out. A main limitation is that the observer's presence might influence the provider's performance. - Interview with the health-care provider. Providers are interviewed about how specific conditions are managed. Both closed-and open-ended questions can be used, although it is important to frame the question so that the 'correct' answer is not suggested. A limitation is that providers tend to over-report their performance. # Consideration and Use of the Findings After data are collected, they should be tabulated, analyzed, and used to improve care. Staff whose performance was assessed should be involved in the development of the data collection tools and analysis of results. Analysis should address the following questions (155): - What is the performance level of the facility? - Is there a consistent pattern of performance among providers? - What is the trend in performance? - What are the causes of poor performance? - How can performance gaps be minimized? Given the findings, service site staff should use a systematic approach to identifying ways to improve the quality of care. One example of a systematic approach to improving the quality of care is the "Plan, Do, Study, and Act" (PDSA) model (147,156), in which staff first develop a plan for improving quality, then execute the plan on a small scale, evaluate feedback to confirm or adjust the plan, and finally, make the plan permanent. Examples of steps that may be taken to improve the quality of care include developing job aids, providing task-specific training for providers, conducting more patient education, or strengthening relationships with referral sites through formal memoranda of understanding (146). # Conclusion The United States continues to face substantial challenges to improving the reproductive health of the U.S. population. The recommendations in this report can contribute to improved reproductive health by defining a core set of family planning services for women and men, describing how to provide contraceptive and other family planning services to both adult and adolescent clients, and encouraging the use of the family planning visit to provide selected preventive health services for women and men. This guidance is intended to assist primary care providers to offer the family planning services that will help persons and couples achieve their desired number and spacing of children and increase the likelihood that those children are born healthy. Recommendations are updated periodically. The most recent versions are available at . The recommendations were developed jointly under the auspices of CDC's Division of Reproductive Health (DRH) and the Office of Population Affairs (OPA), in consultation with a wide range of experts and key stakeholders. A multistage process that drew on established procedures for developing clinical guidelines (1,2) was used to develop the recommendations. In April 2010, an Expert Work Group (EWG) comprising family planning clinical providers, program administrators, representatives from relevant federal agencies, and representatives from professional medical organizations was created to advise OPA and CDC on the structure and content of the revised recommendations and to help make the recommendations more feasible and relevant to the needs of the field. This group made two key initial recommendations: 1) to examine the scientific evidence for three priority areas of focus identified as key components of family planning service delivery, (i.e., counseling and education, serving adolescents, and quality improvement); and 2) to guide providers of family planning services in the use of various recommendations for how to provide clinical care to women and men. # Developing Recommendations on Counseling, Adolescent Services, and Quality Improvement Systematic reviews of the published literature from January 1985 through December 2010 were conducted for each priority topic to identify evidence-based and evidence-informed approaches to family planning service delivery. Standard methods for conducting the reviews were used, including the development of key questions and analytic frameworks, the identification of the evidence base through a search of the published as well as "gray literature" (i.e., studies published somewhere other than in a peer-reviewed journal), and a synthesis of the evidence in which findings were summarized and the quality of individual studies was considered, using the methodology of the U.S. Preventive Services Task Force (USPSTF) (3). Eight databases were searched (i.e., MEDLINE, PsychInfo, PubMed, CINAHL, Cochrane, EMBASE, POPLINE, and the U.K. National Clearinghouse Service Economic Evaluation Database) and were restricted to literature from the United States and other developed countries. Summaries of the evidence used to prepare these recommendations will appear in background papers that will be published separately. In May 2011, three technical panels (one for each priority topic) comprising subject matter experts were convened to consider the quality of the evidence and suggest what recommendations might be justified on the basis of the evidence. CDC and OPA used this feedback to develop core recommendations for counseling, serving adolescents, and quality improvement. EWG members subsequently reviewed these core recommendations; EWG members differed from the subject matter experts in that they were more familiar with the family planning service delivery context and could comment on the feasibility and appropriateness of the recommendations as well as on their scientific justification. EWG members met to consider the core recommendations using 1) the quality of the evidence; 2) the positive and negative consequences of implementing the recommendations on health outcomes, costs or cost-savings, and implementation challenges; and 3) the relative importance of these consequences (e.g., the ability of the recommendations to have a substantial effect on health outcomes may be weighed more than the logistical challenges of implementing them) (1). In certain cases, when the evidence was inconclusive or incomplete, recommendations were made on the basis of expert opinion (see Appendix B). Finally, CDC and OPA staff considered the feedback from EWG members when finalizing the core recommendations and writing this report. # Developing Recommendations on Clinical Services DRH and OPA staff members synthesized recommendations for clinical care for women and for men that were developed by >35 federal and professional medical organizations. They were assisted in this effort by staff from OPA's Office of Family Planning Male Training Center and from CDC's Division of STD Prevention, Division of Violence Prevention, Division of Immunization Services, and Division of Cancer Prevention and Control. The synthesis was needed because clinical recommendations are sometimes inconsistent with each other and can vary by the extent to which they are evidence-based. The clinical recommendations addressed contraceptive services, achieving pregnancy, basic infertility services, preconception health services, sexually transmitted disease services, and related health-care services. An attempt was made to apply the Institute of Medicine's criteria for clinical practice guidelines when deciding which professional medical organizations to include in the review (2). However, many organizations did not articulate the process used to develop the recommendations fully, and many did not conduct comprehensive and systematic reviews of the literature. In the end, to be included in the synthesis, the recommending organization had to be a federal agency or major professional medical organization that represents established medical disciplines. In addition, a recommendation had to be made on the basis of an independent review of the evidence or expert opinion and be considered a primary source that was developed for the United States. In July 2011, two technical panels comprising subject matter experts on clinical services for women and men were convened to review the synthesis of federal and professional medical recommendations, reconcile inconsistent recommendations, and provide individual feedback to CDC and OPA about the implications for family planning service delivery. CDC and OPA used this individual feedback to develop core recommendations for clinical services. The core recommendations were subsequently reviewed by EWG members, and feedback was used to finalize the core recommendations and write this report. Members of the technical panels recommended that contraceptive services, pregnancy testing and counseling, services to achieve pregnancy, basic infertility care, STD services, and other preconception health services should be considered family planning services. This feedback considered federal statute and regulation, CDC and USPSTF recommendations for clinical care, and EWG members' opinion. Because CDC's preconception health recommendations include many services, the panel narrowed the range of preconception services that were included by using the following criteria: 1) the Select Panel on Preconception Care (4) had assigned an A or B recommendation to that service for women, which means that there was either good or fair evidence to support the recommendation that the condition be considered in a preconception care evaluation (Table 1), or 2) the service was included among recommendations made by experts in preconception health for males (5). Services for men that addressed health conditions that affect reproductive capacity or pregnancy outcomes directly were included as preconception health; services that addressed men's health but that were not related directly to pregnancy outcomes were considered to be related preventive health services. The Expert Work Group noted that more preventive services are recommended than can be offered feasibly in some settings. However, a primary purpose of this report is to set a broad framework within which individual clinics will tailor services to meet the specific needs of the populations that they serve. In addition, EWG members identified specific subgroups that should have the greatest priority for preconception health services (i.e., those trying to achieve pregnancy and those at high risk of unintended pregnancy). Future operational research should provide more information about how to deliver these services most efficiently during multiple visits to clients with diverse needs. # Determining How Clinical Services Should Be Provided Various federal agencies and professional medical associations have made recommendations for how to provide family planning services. When considering these recommendations, the Expert Work Group used the following hierarchy: - Highest priority was given to CDC guidelines because they are developed after a rigorous review of scientific evidence. CDC guidelines tailor recommendations for higher risk individuals, (whereas USPSTF focuses on average risk individuals), who are more representative of the clients seeking family planning services. - When no CDC guideline existed to guide the recommendations, the relevant USPSTF A or B recommendations (which indicate a high or moderate certainty that the benefit is moderate to substantial) were used. USPSTF recommendations are made on the basis of a thorough review of the available evidence. - If neither a CDC nor a USPSTF A or B recommendation existed, the recommendations of selected major professional medical associations were considered as resources. The American Academy of Pediatrics' (AAP) Bright Futures guidelines (6) were used as the primary source of recommendations for adolescents when no CDC or USPSTF recommendations existed. - For a limited number of recommendations, there were no federal or major professional medical recommendations, but the service was recommended by EWG members on the basis of expert opinion for family planning clients. In some cases, a service was graded as an I recommendation by USPSTF for the general population (an I recommendation means that the current evidence is insufficient to assess the balance of benefits and harms of the service, so if the service is offered, patients should be informed of this fact), but either CDC, EWG members, or another organization recommended the service for women or men seeking family planning services. The situations in which this occurred and the reasons why the service was recommended despite its receiving an I recommendation by USPSTF have been summarized (Table 2). The approach used to consider the evidence and make recommendations that are used by USPSTF have been summarized (Tables 3 and 4) (7). # TABLE 1. Select Panel on Preconception Care grading system Quality of the evidence- I-a Evidence was obtained from at least one properly conducted, randomized, controlled trial that was performed with subjects who were not pregnant. # I-b Evidence was obtained from at least one properly conducted, randomized, controlled trial that was done not necessarily before pregnancy. II-1 Evidence was obtained from well-designed, controlled trials without randomization. II-2 Evidence was obtained from well-designed cohort or case-control analytic studies, preferably conducted by more than one center or research group. II-3 Evidence was obtained from multiple-time series with or without the intervention, or dramatic results in uncontrolled experiments. III Opinions were gathered from respected authorities on the basis of clinical experience, descriptive studies and case reports, or reports of expert committees. # Strength of the recommendation A There is good evidence to support the recommendation that the condition be considered specifically in a preconception care evaluation. B There is fair evidence to support the recommendation that the condition be considered specifically in a preconception care evaluation. C There is insufficient evidence to recommend for or against the inclusion of the condition in a preconception care evaluation, but recommendation to include or exclude may be made on other grounds. D There is fair evidence to support the recommendation that the condition be excluded in a preconception care evaluation. E There is good evidence to support the recommendation that the condition be excluded in a preconception care evaluation. This service should be offered or provided. B USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. This service should be offered or provided. # C Clinicians may provide this service to selected patients depending on individual circumstances. However, for a majority of persons without signs or symptoms there is likely to be only a limited benefit from this service. This service should be offered or provided only if other considerations support the offering or providing the service in an individual patient. D USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Use of this service should be discouraged. I Statement USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. The clinical considerations section of USPSTF recommendation statement should be consulted. If the service is offered, patients should be educated about the uncertainty of the balance of benefits and harms. Source: US Preventive Services Task Force. USPSTF: methods and processes. Available at . # TABLE 4. Levels of certainty regarding net benefit # Level of certainty- Description # High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. # Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as - the number, size, or quality of individual studies; - inconsistency of findings across individual studies; - limited generalizability of findings to routine primary care practice; and - lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. # Low The available evidence is insufficient to assess effects on health outcomes is insufficient because of - the limited number or size of studies, - important flaws in study design or methods, - inconsistency of findings across individual studies, - gaps in the chain of evidence, - findings not generalizable to routine primary care practice, - lack of information on important health outcomes, or - more information required to allow estimation of effects on health outcomes. Source: US Preventive Services Task Force. USPSTF: methods and processes. Available at . - The US Preventive Services Task Force (USPSTF) defines certainty as the likelihood that the USPSTF assessment of the net benefit of a preventive service is correct. The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. USPSTF assigns a certainty level on the basis of the nature of the overall evidence available to assess the net benefit of a preventive service. Sixteen core recommendations that were considered by the Expert Work Group (EWG) are presented below. Each recommendation is accompanied by a summary of the relevant evidence (full summaries of which will be published separately), a list of potential consequences of implementing the recommendation, and its rationale. When considering the recommendations, the Expert Work Group was divided into two groups (one comprising seven members and the other five members), and each group considered separate recommendations. # Definition of Family Planning Services Recommendation: Primary care providers should offer the following family planning services: contraceptive services for women and men who want to prevent pregnancy and space births, pregnancy testing and counseling, help for clients who wish to achieve pregnancy, basic infertility services, sexually transmitted disease (STD) services and preconception health services to improve the health of women, men, and infants. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of federal statute and regulation (1,2), CDC clinical recommendations (3)(4)(5), and expert opinion. Potential consequences: Adding preconception health services means that more women and men will receive preconception health services. The recommended services also will promote the health of women and men even if they do not have children. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered in some settings. Rationale: Services to prevent and achieve pregnancy are core to the federal government's efforts to promote reproductive health. Adding preconception health as a family planning service is consistent with this mission; it emphasizes achieving a healthy pregnancy and also promotes adult health. Adding preconception health is also consistent with CDC recommendations to integrate preconception health services into primary care platforms (3). All seven EWG members agreed to this recommendation. # Preconception Health -Women Recommendation: Preconception health services for women include the following screening services: reproductive # Appendix B The Evidence, Potential Consequences, and Rationales for Core Recommendations life plan; medical history; sexual health assessment; intimate partner violence, alcohol, and other drug use; tobacco use; immunizations; depression; body mass index (BMI); blood pressure; chlamydia, gonorrhea, syphilis, and HIV/AIDS; and diabetes. All female clients also should be counseled about the need to take a daily supplement of folic acid. When screening results indicate the presence of a health condition, the provider should take steps either to provide or to refer the client for the appropriate further diagnostic testing and or treatment. Services should be provided in a manner that is consistent with established federal and professional medical associations' recommendations to enable clients who need services to receive them and to avoid over-screening. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of CDC's recommendations to improve preconception health and health care (3) and a review of preconception health services by an expert panel on preconception care for women (6). Potential consequences: More women will receive specified preconception health services, which will improve the health of infants and women. The evidence base for preconception health is not fully established. There is a potential risk that a client with a positive screen will not be able to afford treatment if the client is uninsured and not eligible for public programs. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered. Rationale: The potential benefits to the health of women and infants were thought by the panel to be greater than the costs, potential harms, and opportunity costs of providing these services. Implementation (e.g., training and monitoring of providers) can address the issues related to providers over-screening and not following the federal and professional medical recommendations. CDC will continue to monitor related research and modify these recommendations, as needed. Health-care reform might make follow-up care more available to low-income clients. All seven EWG members agreed to this recommendation. # Preconception Health -Men Recommendation: Preconception health services for men include the following screening services: reproductive life plan; medical history; sexual health assessment; alcohol and other drug use; tobacco use; immunizations; depression; BMI; blood pressure; chlamydia, gonorrhea, syphilis, and HIV/AIDS; and diabetes. When screening results indicate the presence of a health condition, the provider should take steps either to provide or to refer the client for the appropriate further diagnostic testing and or treatment. Services should be provided in a manner that is consistent with established federal and professional medical associations' recommendations to ensure that clients who need services receive them and to avoid over-screening. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of CDC's recommendations to improve preconception health and health care (3) and a review of preconception health services for men (7). Potential consequences: More men will receive preconception health services, which might improve infant and men's health. The evidence base for preconception health is not well established and is less than that for women's preconception health. There is a risk of over-screening if recommendations are not followed. There is a potential risk that a client with a positive screen might not be able to afford treatment if the client is uninsured and not eligible for public programs. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered. Rationale: The potential benefits to men and infant health were thought by the panel to be greater than the costs, potential harms, and opportunity costs of not providing these services. Implementation (e.g., training and monitoring of providers) can address the issues related to providers over-screening and not following the federal and professional medical recommendations. CDC will continue to monitor related research and modify these recommendations, as needed. Health-care reform might make follow-up care more available to low-income clients. All seven EWG members agreed to this recommendation. # Contraceptive Services -Contraceptive Counseling Steps Recommendation: To help a client who is initiating or switching to a new method of contraception, providers should follow these steps, which are in accordance with the key principles for providing quality counseling: 1) establish and maintain rapport with the client; 2) obtain clinical and social information from the client; 3) work with the client interactively to select the most effective and appropriate contraceptive method for her or him; 4) provide a physical assessment related to contraceptive use, when warranted; and 5) provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow-up, and confirm understanding. Quality of evidence: Twenty-two studies were identified that examined the impact of contraceptive counseling in clinical settings and met the inclusion criteria. Of the 16 studies that focused on adults or mixed populations (adolescents and adults) (8-23), 11 found a statistically significant positive impact of counseling interventions with low (11,12,(14)(15)(16)(18)(19)(20)(21), moderate (8), or unrated ( 22) intensity on at least one outcome of interest; study designs included two cross-sectional surveys (14,22), one pre-post study (21), one prospective cohort study (8), one controlled trial (15), and six randomized controlled trials (RCTs) (11,12,16,(18)(19)(20). Six studies examined the impact of contraceptive counseling among adolescents (24)(25)(26)(27)(28)(29), with four finding a statistically significant positive impact of low-intensity (27) or moderateintensity (24,25,29) counseling interventions on at least one outcome of interest; study designs included two pre-post studies (24,30), one controlled trial (29), and one RCT (27). In addition, five studies were identified that examined the impact of reminder system interventions in clinical settings on family planning outcomes and met the inclusion criteria (31)(32)(33)(34)(35); of these, two found a statistically significant positive impact of reminder systems on perfect oral contraceptive compliance, a retrospective historical nonrandomized controlled trial that examined daily reminder email messages (31) and a cohort study that examined use of a small reminder device that emitted a daily audible beep (34). In addition, two studies examined the impact of reminder systems among depot medroxyprogesterone acetate users (DMPA) (33,35) with one, a retrospective cohort study, finding a statistically significant positive impact of receiving a wallet-sized reminder card with the date of the next DMPA injection and a reminder postcard shortly before the next injection appointment on timely DMPA injections. Statements about safety and unnecessary medical examinations and tests are made on the basis of CDC guidelines on contraceptive use (36,37). Potential consequences: Fewer clients will use methods that are not safe for them, there will be increased contraceptive use, increased use of more effective methods, increased continuation of method use, increased use of dual methods, increased knowledge, increased satisfaction with services, and increased use of repeat or follow-up services. Rationale: Making sure that a contraceptive method is safe for an individual client is a fundamental responsibility of all providers of family planning services. Removing medical barriers to contraceptive use is key to increasing access to contraception and helping clients prevent unintended pregnancy. Consistent use of contraceptives is needed to prevent unintended pregnancies, so appropriate counseling is critical to ensure clients make the best possible choice of methods for their unique circumstances, and are supported in continued use of the chosen method. The principles of quality counseling, from which the steps listed in the recommendations are based, are supported by a substantial body of evidence and expert opinion. Future research to evaluate the five principles will be monitored and the recommendations modified, as needed. All seven EWG members agreed to this recommendation. # Contraceptive Services -Tiered Approach to Counseling Recommendation: For clients who might want to get pregnant in the future and prefer reversible methods of contraception, providers should use a tiered approach to presenting a broad range of contraceptive methods (including long-acting reversible contraception such as intrauterine devices and contraceptive implants), in which the most effective methods are presented before less effective methods. Quality of evidence: National surveys have demonstrated low rates of LARC use overall (38,39). However, Project CHOICE has demonstrated high uptake of long-acting reversible contraception (approximately two thirds of clients when financial barriers are removed) and a very substantial reduction in rates of unintended pregnancy (40). Further, a recent study of postpartum contraceptive use shows that 50% of teen mothers with a recent live birth are using long-acting reversible contraception postpartum in Colorado, which demonstrates high levels of acceptance in the context of a statewide program to remove financial barriers (41). Potential consequences: Use of long-acting reversible contraception has the potential to help many more persons prevent unintended pregnancy because of its ease of use, safety, and effectiveness. Several questions were raised about ethical issues in using a tiered approach to counseling. First, is it ethical to educate about long-acting reversible contraception when the methods are not all available on-site? Second, conversely, is it ethical not to inform clients about the most effective methods? In other health service areas, the standard of care is to inform the client about the most effective treatment (e.g., blood pressure medications), so the client can make a fully informed decision, and this standard should apply in this instance as well. On the basis of historic experiences, there is a need to ensure that methods always are offered on a completely voluntary and noncoercive basis. Health-care reform might make contraceptive services more available to the majority of clients. Rationale: Providers have an obligation to inform clients about the most effective methods available, even if they cannot provide them. Further, health-care reform will reduce the financial barriers to long-acting reversible contraception for many persons. The potential increase in use of long-acting reversible contraception and other more effective methods is likely to help reduce rates of unintended pregnancy. All seven EWG members agreed to this recommendation. # Contraceptive Services -Broad Range of Methods Recommendation: A broad range of methods should be available on-site or through referral. Quality of evidence: Three descriptive studies from the review of quality improvement literature identified contraceptive choice as an important aspect of quality care (42)(43)(44). Potential consequences: Clients will be more likely to select a method that they will use consistently and correctly. Rationale: A central tenet of quality health care is that it be client-centered. Being able to provide a client with a method that best fits her or his unique circumstances is essential for that reason. All seven EWG members agreed to this recommendation. # Contraceptive Services -Education Recommendation: The content, format, method, and medium for delivering education should be evidence-based. Quality of evidence: Seventeen studies were identified that met the inclusion criteria for this systematic review. Of these, 15 studies looked at knowledge of correct method use or contraceptive risks and benefits, including side effects and method effectiveness (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). All but one study (56) found a statistically significant positive impact of educational interventions on increased knowledge. These studies included six randomized controlled trials with low risk for bias. Potential consequences: Clients will make more informed decisions when choosing a contraceptive method. More clients will be satisfied with the process of selecting a contraceptive method. Rationale: Knowledge obtained through educational activities, as integrated into the larger counseling model, is a critically important precondition for the client's ability to make informed decisions. The techniques described in the recommendations have a well-established evidence base for increasing knowledge and satisfaction with services. This knowledge lays the foundation for further counseling steps that will increase the likelihood of correct and consistent use, and increased satisfaction will increase return visits to the service site, as needed. Four of seven EWG members agreed to this recommendation; three members did not express an opinion. # Contraceptive Services -Confirm Understanding Recommendation: A check box or written statement should be available in the medical record that can be used to document that the client expressed understanding of the most important information about her/his chosen contraceptive method. The teach-back method may be used to get clients to express the most important points by repeating back messages about risks and benefits and appropriate method use and follow-up. Documentation of understanding using the teach-back method and a check box or written statement can be used in place of a written method-specific informed consent. Quality of evidence: Two studies from outside the family planning literature (one cohort study and one controlled trial with unclear randomization) (60,61) and a strong recommendation by members of the Technical Panel on Counseling and Education were considered. Potential consequences: More clients will make informed decisions, adherence to contraceptive and treatment plans will improve, and reproductive and other health conditions will be better controlled. Rationale: Asking providers to document in the record that the client is making an informed decision will increase providers' attention to this task. This recommendation will replace a previous requirement that providers obtain methodspecific informed consent from each client (in addition to a general consent form). Six of seven EWG members agreed to this recommendation. # Adolescent Services -Comprehensive Information Recommendation: Providers should provide comprehensive information to adolescent clients about how to prevent pregnancy and STDs. This should include information about contraception and that avoiding sex (abstinence) is an effective way to prevent pregnancy and STDs. Quality of evidence: A systematic review was not conducted because other recent reviews were available that have shown a substantial impact of comprehensive sexual health education on reduced adolescent risk behavior (62)(63)(64)(65)(66). The evidence for abstinence-only education was more limited: CDC's Community Guide concluded that there was insufficient evidence (67), but the Department of Health and Human Services' Office of Adolescent Health has identified two abstinence-based programs as having evidence of effectiveness (68). Potential consequences: Teens will make more informed decisions and will delay initiation of sexual intercourse. The absence of harmful effects from comprehensive sexual health education was noted. Rationale: The benefits of informing adolescents about all ways to prevent pregnancy are substantial. Ultimately, each adolescent should make an informed decision that meets her or his unique circumstances, based on the counseling provided by the provider. Six of seven EWG members agreed to this recommendation. # Adolescent Services -Use of Long-Acting Reversible Contraception Recommendation: Education about contraceptive methods should include an explanation that long-acting reversible contraception is safe and effective for nulliparous women (women who have not been pregnant or given birth), including adolescents. Quality of evidence: CDC guidelines on contraceptive use (37) provide evidence that long-acting reversible contraception is safe and effective for adolescents and nulliparous women. Potential consequences: More providers will encourage adolescents to consider long-acting reversible contraception; more adolescents will choose long-acting reversible contraception, resulting in reduced rates of teen pregnancy, including rapid repeat pregnancy. Rationale: Long-acting reversible contraception is safe for adolescents (37). As noted above, providers should inform clients about the most effective methods available. The potential increase in use of long-acting reversible contraception and other more effective methods by adolescents is substantial and is likely to lead to further reductions in teen pregnancy. Three EWG members agreed to this recommendation; two EWG members abstained. # Adolescent Services -Confidential Services Recommendation: Confidential family planning services should be made available to adolescents, while observing state laws and any legal obligations for reporting. Quality of evidence: Six descriptive studies documented one or more of the following: that confidentiality is important to adolescents; that many adolescents reported they will not use reproductive health services if confidentiality cannot be assured; and that adolescents might not be honest in discussing reproductive health with providers if confidentiality cannot be assured (69)(70)(71)(72)(73)(74). One RCT showed a slight reduction in use of services after receiving conditional confidentiality, compared with complete confidentiality (75). One study showed a positive association between confidentiality and intention to use services (73). Potential consequences: Consequences might include an increased intention to use services, increased use of services, and reduced rates of teen pregnancy. However, explaining the need to report under certain circumstances (rape, child abuse) might deter some adolescent clients from using services. Further, some parents/guardians might not agree that adolescents should have access to confidential services. Rationale: Minors' rights to confidential reproductive health services are consistent with state and federal law. The risks of not providing confidential services to adolescents are great and likely to result in an increased rate of teen pregnancies. Finally, this recommendation is consistent with the recommendations of three professional medical associations that endorse provision of confidential services to adolescents (76)(77)(78). All seven EWG members agreed to this recommendation. # Adolescent Services -Family-Child Communication Recommendation: Providers should encourage and promote family-child communication about sexual and reproductive health. Quality of evidence: From the family planning literature, 16 parental involvement programs (most using an RCT study design) were found to be positively associated with at least one short-term (13 of 16 studies) or medium-term (four of seven studies) outcome (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94). However, only one of these studies was linked to clinical services (80); others were implemented in community settings. Potential consequences: Consequences might include increased parental/guardian involvement and communication, improved knowledge/awareness, increased intentions to use contraceptives, and the adoption of more pro-social norms that support parent-child communication about sexual health. Rationale: The literature provides strong evidence that increased communication between a child and her/his parent/ guardian will lead to safer sexual behavior among teens, and numerous community-based programs have created an evidence base for how to strengthen parents/guardians' ability to hold those conversations. Although less is known about how to do so in a clinical setting, providers can refer their clients to programs in the community, and principles from the community-based approaches can be used to help providers develop appropriate approaches in the clinical setting. Research in this area will be monitored, and the recommendations will be revised, as needed. Four of five EWG members who provided input agreed to this recommendation; one member abstained. # Adolescent Services -Repeat Teen Pregnancy Recommendation: Providers should refer pregnant and parenting adolescents to home visiting and other programs that have been shown to provide needed support and reduce rates of repeat teen pregnancy. Quality of evidence: Three of four studies of clinic-based programs (using retrospective case-control cohort, ecological evaluation, and prospective cohort study designs) showed that comprehensive teen pregnancy prevention programs (programs with clinical, school, case management, and community components) were associated with both medium-and longterm outcomes (95)(96)(97)(98). In addition, several randomized trials of community-based home visiting programs, and an existing systematic review of the home visiting literature, demonstrated a protective impact of these programs on preventing repeat teen pregnancy and other relevant outcomes (99)(100)(101)(102)(103). Potential consequences: Consequences might include decreased rapid repeat pregnancy and abortion rates, and increased use of contraceptives. Rationale: There is sufficient evidence to recommend that providers link pregnant and parenting teens to community and social services that might reduce rates of rapid repeat pregnancy. Three of seven EWG members agreed to an earlier version of this recommendation. Other members wanted to remove a clause about prioritizing the contraceptive needs of pregnant/ parenting teens because they felt that all clients should be treated as priority clients. This suggestion was adopted, but the EWG did not have a chance to vote again on the modified recommendation. # Contraceptive Method Availability Recommendation: Family planning programs should stock and offer a broad a range of FDA-approved contraceptive methods so that the needs of individual clients can be met. These methods are optimally available on-site, but strong referrals can serve to make methods not available on-site real options for clients. Quality of evidence: No research was identified that explicitly addressed the question of whether having a broad range of methods was associated with short-, medium-, or long-term reproductive health outcomes. However, as noted above, three descriptive studies from the review of quality improvement literature identified contraceptive choice as an important aspect of quality care (42)(43)(44). Potential consequences: Consequences might include increased use of contraception and increased use of reproductive health services. It also was noted that there are sometimes high costs to stocking certain methods (e.g., intrauterine devices and contraceptive implants). Rationale: Having a broad range of contraceptive methods is central to client-centered care, a core aspect of providing quality services. Individual clients need to have a choice so they can select a method that best fits their particular circumstances. This is likely to result in more correct and consistent use of the chosen methods. The benefits of this recommendation were weighed more heavily than the negative outcomes (e.g., additional cost). All five EWG members agreed to this recommendation. # Youth-Friendly Services Recommendation: Family planning programs should take steps to make services "youth-friendly." Quality of evidence: Of 20 studies that were identified, six looked at short-, medium-, or long-term outcomes with mixed designs (one group time series, one cross-sectional, three prospective cohort, and one nonrandomized trial); protective effects were found on long-term (two of three studies), medium-term (three of three), and short-term (three of three) outcomes (29,30,(104)(105)(106)(107). One of these six studies (29), plus 13 other descriptive studies (for a total of 14 studies), presented adolescents' or providers' views on facilitators for adolescent clients in using youth-friendly family planning services. Key factors described were confidentiality (13 of 14), accessibility (11 of 14), peer involvement (three of 14), parental or familial involvement (four of 14), and quality of provider interaction (11 of 14) (105-121). Four of these studies (111,112,114,121) plus one other descriptive study (108) described barriers to clinics adopting and implementing youth-friendly family planning services. Potential consequences: Consequences might include increased use of reproductive health services by adolescents, improved contraceptive use, use of more effective methods, more consistent use of contraception, and reduced rates of teen pregnancy. It is also likely to lead to improved satisfaction with services and greater knowledge about pregnancy prevention among adolescents. It is possible that there will be higher costs, and some uncertainty regarding the benefits due to a relatively weak evidence base. Rationale: Existing evidence has demonstrated the importance of specific characteristics to adolescents' attitudes and use of clinical services. The potential benefits of providing youth-friendly services outweigh the potential costs and weak evidence base. All five EWG members agreed to this recommendation. Some thought that it should be cast as an example of comprehensively client-centered care, rather than an end of its own. # Quality Improvement Recommendation: Family planning programs should have a system for quality improvement, which is designed to review and strengthen the quality of services on an ongoing basis. Family planning programs should select, measure, and assess at least one outcome measure on an ongoing basis, for which the service site can be accountable. Quality of evidence: A recent systematic review ( 122) was supplemented with 10 articles that provided information related to client and/or provider perspectives regarding what constitutes quality family planning services (42)(43)(44)113,(123)(124)(125)(126)(127)(128). These studies used a qualitative (k = 4) or cross-sectional (k = 6) study design. Ten descriptive studies identified client and provider perspectives on what constitutes quality family planning services, which include stigma and embarrassment reduction (n = 9), client access and convenience (n = 8); confidentiality (n = 3); efficiency and tailoring of services (n = 6); client autonomy and confidence (n = 5); contraceptive access and choice (n = 4); increased time of patient-provider interaction (n = 3); communication and relationship (n = 3); structure and facilities (n = 2); continuity of care (n = 2). Well-established frameworks for guiding quality improvement efforts were referenced (122,(129)(130)(131)(132). Potential consequences: Consequences might include increased use by clients of more effective contraceptive methods, clients might be more likely to return for care, client satisfaction might improve, and there might be reduced rates of teen and unintended pregnancy, and improved spacing of births. Rationale: Research, albeit limited, has demonstrated that quality services are associated with improved client experience with care and adoption of more protective contraceptive behavior. Further, these recommendations on quality improvement are consistent with those made by national leaders in the quality improvement field. Research is either under way or planned to validate a core set of performance measures, and the recommendations will be updated as new findings emerge. All five EWG members agreed to these recommendations. Counseling is a process that enables clients to make and follow through on decisions. Education is an integral component of the counseling process that helps clients to make informed decisions. Providing quality counseling is an essential component of client-centered care. Key principles of providing quality counseling are listed below and may be used when providing family planning services. The model was developed in consultation with the Technical Panel on Contraceptive Counseling and Education and reviewed by the Expert Work Group. Although developed specifically for providing contraceptive counseling, the principles are broad and can be applied to health counseling on other topics. Although the principles are listed here in a particular sequence, counseling is an iterative process, and at every point in the client encounter it is necessary to determine whether it is important to readdress and emphasize a given principle. # Principles of Quality Counseling Principle 1. Establish and Maintain Rapport with the Client Establishing and maintaining rapport with a client is vital to the encounter and achieving positive outcomes (1). This can begin by creating a welcoming environment and should continue through every stage of the client encounter, including follow-up. The contraceptive counseling literature indicates that counseling models that emphasized the quality of the interaction between client and provider have been associated with decreased teen pregnancy, increased contraceptive use, increased use of more effective methods, increased use of repeat or follow-up services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (2)(3)(4)(5) . # Principle 2. Assess the Client's Needs and Personalize Discussions Accordingly Each visit should be tailored to the client's individual circumstances and needs. Clients come to family planning providers for various services and with varying needs. Standardized questions and assessment tools can help providers determine what services are most appropriate for a given visit (6). Contraceptive counseling studies that have incorporated standardized assessment tools during the counseling process have resulted in increased contraceptive use, increased correct # Appendix C Principles for Providing Quality Counseling use of contraceptives, and increased use of more effective methods (2,7,8). Contraceptive counseling studies that have personalized discussions to meet the individual needs of clients have been associated with increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, increased use of dual-method contraceptives to prevent both sexually transmitted diseases (STDs) and pregnancy, increased quality and satisfaction with services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (4,7,(9)(10)(11)(12). # Principle 3. Work with the Client Interactively to Establish a Plan Working with a client interactively to establish a plan, including a plan for follow-up, is important. Establishing a plan should include setting goals, discussing possible difficulties with achieving goals, and developing action plans to deal with potential difficulties. The amount of time spent establishing a plan will differ depending on the client's purpose for the visit and health-care needs. A client plan that requires behavioral change should be made on the basis of the client's own goals, interests, and readiness for change (13)(14)(15). Use of computerized decision aids before the appointment can facilitate this process by providing a structured yet interactive framework for clients to analyze their available options systematically and to consider the personal importance of perceived advantages and disadvantages (16,17). The contraceptive counseling literature indicates that counseling models that incorporated goal setting and development of action plans have been associated with increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, and increased knowledge (2,9,(18)(19)(20). Furthermore, contraceptive counseling models that incorporated follow-up contacts resulted in decreased teen pregnancy, increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, increased continuation of method use, increased use of dual-method contraceptives to prevent both STDs and pregnancy, increased use of repeat or follow-up services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (2,3,7,11,21,22) . From the family planning education literature, computerized decision aids have helped clients formulate questions and have been associated with increased knowledge, selection of more effective methods, and increased continuation and compliance (23)(24)(25). # Principle 4. Provide Information That Can Be Understood and Retained by the Client Clients need information that is medically accurate, balanced, and nonjudgmental to make informed decisions and follow through on developed plans. When speaking with clients or providing educational materials through any medium (e.g., written, audio/visual, or computer/web-based), the provider must present information in a manner that can be readily understood and retained by the client. Strategies for making information accessible to clients are provided (see Appendix D). # Principle 5. Confirm Client Understanding It is important to ensure that clients have processed the information provided and discussed. One technique for confirming understanding is to have the client restate the most important messages in her or his own words. This teach-back method can increase the likelihood of the client and provider reaching a shared understanding, and has improved compliance with treatment plans and health outcomes (26,27). Using the teach-back method early in the decision-making process will help ensure that a client has the opportunity to understand her or his options and is making informed choices (28). The client should receive and understand the information she or he needs to make informed decisions and follow treatment plans. This requires careful attention to how information is communicated. The following strategies can make information more readily comprehensible to clients: # Strategies for Providing Information to Clients Educational materials should be provided that are clear and easy to understand. Educational materials delivered through any one of a variety of media (for example, written, audio/ visual, computer/web-based) need to be presented in a format that is clear and easy to interpret by clients with a 4th to 6th grade reading level (1)(2)(3). Many adults have only a basic ability to obtain, process, and understand health information necessary to make decisions about their health (4). Making easy-to-access materials enhances informed decision-making (1)(2)(3). Test all educational materials with the intended audiences for clarity and comprehension before wide-scale use. The following evidence-based tools provide recommendations for increasing the accessibility of materials through careful consideration of content, organization, formatting, and writing style: - Prevention and Health Promotion (available at http:// www.health.gov/healthliteracyonline). Information should be delivered in a manner that is culturally and linguistically appropriate. In presenting information it is important to be sensitive to the client's cultural and linguistic preferences (5,6). Ideally information should be presented in the client's primary language, but translations and interpretation services should be available when necessary. Information presented must also be culturally appropriate, reflecting the client's beliefs, ethnic background, and cultural practices. Tools for addressing cultural and linguistic differences and preferences include - Health Literacy Universal Precautions Toolkit, provided by the Agency for Healthcare Research and Quality (available at ), and # Appendix E Strategies for Providing Information to Clients - Toolkit for Making Written Material Clear and Effective, Part 11; Understanding and using the "Toolkit Guidelines for Culturally Appropriate Translation," provided by the Centers for Medicare and Medicaid Services (available at / writtenmaterialstoolkit/downloads/toolkitpart11.pdf ). The amount of information presented should be limited and emphasize essential points. Providers should focus on needs and knowledge gaps identified during the assessment. Many clients immediately forget or remember incorrectly much of the information provided. This problem is exacerbated as more information is presented (7)(8)(9). Limiting the amount of information presented and highlighting important facts by presenting them first improves comprehension (10)(11)(12)(13)(14). Numeric quantities should be communicated in a way that is easily understood. Whenever possible, providers should use natural frequencies and common denominators (for example, 85 of 100 sexually active women are likely to get pregnant within 1 year using no contraceptive, as compared with 1 in 100 using an IUD or implant), and display quantities in graphs and visuals. Providers also should avoid using verbal descriptors without numeric quantities (for example, sexually active women using an IUD or implant almost never become pregnant). Finally, they should quantify risk in absolute rather than relative terms (for example, "the chance of unintended pregnancy is reduced from 8 in 100 to 1 in 100 by switching from oral contraceptives to an IUD" versus the chance of unintended pregnancy is reduced by 87%). Numeracy is more highly correlated with health outcomes than the ability to read or listen effectively (15). The strategies listed above can help clients interpret numeric quantities correctly (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Balanced information on risks and benefits should be presented and messages framed positively. In addition to discussing risks, contraindications, and warnings, providers should discuss the advantages and benefits of contraception. In presenting this information, providers should express risks and benefits in a common format (for example, do not present risks in relative terms and benefits in absolute terms), and frame messages in positive terms (for example "99 out of 100 women find this a safe method with no side effects," versus "1 out of 100 women experience noticeable side effects"). Many clients prefer to receive a balance of information on risks and benefits (29), and using a common format avoids bias in presentation of information (18,22,26,30). Framing messages positively increases acceptance and comprehension (18,22,31,32). Active client engagement should be encouraged. Providers should use educational materials that encourage active information processing (e.g., questions, quizzes, fill-in-theblank, web-based games, and activities). In addition, they should be sure the client has an opportunity to discuss the information provided, and when speaking with a client, providers should engage her or him actively. Research has indicated that interactive materials improve knowledge of contraceptive risks, benefits, and correct method use (33)(34)(35). Clients also value spoken information (29,36); and educational materials, when delivered by a provider, more effectively increase knowledge (10,37). In particular, presenting information in a question and answer format is more effective than simply presenting the information (10,15,(37)(38)(39)(40)(41). - Among typical couples who initiate use of a method (not necessarily for the first time), the percentage of couples who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Estimates of the probability of pregnancy during the first year of typical use for spermicides and the diaphragm are taken from the 1995 National Survey of Family Growth corrected for underreporting of abortion; estimates for fertility awareness-based methods, withdrawal, the male condom, the pill, and Depo-Provera are taken from the 1995 and 2002 National Survey of Family Growth corrected for underreporting of abortion. See the text for the derivation of estimates for the other methods. † Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage of couples who experience an accidental pregnancy during the first year if they do not stop use for any other reason. See the text for the derivation of the estimate for each method. § Among couples attempting to avoid pregnancy, the percentage of couples who continue to use a method for 1 year. ¶ The percentages becoming pregnant in columns labeled "typical use" and "perfect use" are based on data from populations in which contraception is not used and from women who cease using contraception to become pregnant. Among such populations, approximately 89% become pregnant within 1 year. This estimate was lowered slightly (to 85%) to represent the percentage of women who would become pregnant within 1 year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. † † The Ovulation and 2-day methods are based on evaluation of cervical mucus. The Standard Days method avoids intercourse on cycle days 8 through 19. The Symptothermal method is a double-check method based on evaluation of cervical mucus to determine the first fertile day and evaluation of cervical mucus and temperature to determine the last fertile day. § § Without spermicides. ¶ ¶ With spermicidal cream or jelly. * Ella, Plan B One-Step, and Next Choice are the only dedicated products specifically marketed for emergency contraception. The label for Plan B One-Step (1 dose is 1 white pill) says to take the pill within 72 hours after unprotected intercourse. Research has indicated that all of the brands listed here are effective when used within 120 hours after unprotected intercourse. The label for Next Choice (1 dose is 1 peach pill) says to take one pill within 72 hours after unprotected intercourse and another pill 12 hours later. Research has indicated that that both pills can be taken at the same time with no decrease in efficacy or increase in side effects and that they are effective when used within 120 hours after unprotected intercourse. The Food and Drug Administration has in addition declared the following 19 brands of oral contraceptives to be safe and effective for emergency contraception: Ogestrel (1 dose is 2 white pills), Nordette (1 dose is 4 light-orange pills), Cryselle, Levora, Low-Ogestrel, Lo/Ovral, or Quasence (1 dose is 4 white pills), Jolessa, Portia, Seasonale or Trivora (1 dose is 4 pink pills), Seasonique (1 dose is 4 light-blue-green pills), Enpresse (1 dose is 4 orange pills), Lessina (1 dose is 5 pink pills), Aviane or LoSeasonique (one dose is 5 orange pills), Lutera or Sronyx (1 dose is 5 white pills), and Lybrel (1 dose is 6 yellow pills). † † † However, for effective protection against pregnancy to be maintained, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches age 6 months. unintended pregnancy during the first year of use, and is estimated for both typical and perfect use (Table ). The following services have been given a D recommendation from the U.S. Preventive Services Task Force (USPSTF), which indicates that the potential harms of routine screening outweigh the benefits. Providers should not perform these screening services. The USPSTF has recommended against offering the following services to women and men: - Asymptomatic bacteriuria: USPSTF recommends against screening for asymptomatic bacteriuria in men and nonpregnant women (1). - Gonorrhea: USPSTF recommends against routine screening for gonorrhea infection in men and women who are at low risk of infection (2). - Hepatitis B: USPSTF recommends against routinely screening the general asymptomatic population for chronic hepatitis B virus infection (3). - Herpes simplex virus (HSV): USPSTF recommends against routine serological screening for HSV in asymptomatic adolescents and adults (4). - Syphilis: USPSTF recommends against screening of asymptomatic persons who are not at increased risk of syphilis infection (5). The USPSTF has recommended against offering the following services to women: - BRCA mutation testing for breast and ovarian cancer susceptibility: USPSTF recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk of deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) (6). However, USPSTF continues to recommend that women whose family history is associated with an increased risk of deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. - Breast self-examination: USPSTF recommends against teaching breast self-examination (7). - Cervical cytology: USPSTF recommends against routine screening for cervical cancer with cytology (Pap smear) in the following groups: women aged 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (i.e., cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer. USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women aged <30 years (8). # Appendix F Screening Services For Which Evidence Does Not Support Screening - Ovarian cancer: USPSTF recommends against routine screening for ovarian cancer (9). The USPSTF has recommended against offering the following services to men: - Prostate cancer: USPSTF recommends against prostatespecific antigen (PSA)-based screening for prostate cancer (10). - Testicular cancer: USPSTF recommends against screening for testicular cancer in adolescent or adult males (11). # Technical on Men's Clinical Services	The recommendations outline how to provide quality family planning services, which include contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, and sexually transmitted disease services. The primary audience for this report is all current or potential providers of family planning services, including those working in service sites that are dedicated to family planning service delivery as well as private and public providers of more comprehensive primary care. The United States continues to face substantial challenges to improving the reproductive health of the U.S. population. Nearly one half of all pregnancies are unintended, with more than 700,000 adolescents aged 15-19 years becoming pregnant each year and more than 300,000 giving birth. One of eight pregnancies in the United States results in preterm birth, and infant mortality rates remain high compared with those of other developed countries. This report can assist primary care providers in offering family planning services that will help women, men, and couples achieve their desired number and spacing of children and increase the likelihood that those children are born healthy. The report provides recommendations for how to help prevent and achieve pregnancy, emphasizes offering a full range of contraceptive methods for persons seeking to prevent pregnancy, highlights the special needs of adolescent clients, and encourages the use of the family planning visit to provide selected preventive health services for women, in accordance with the recommendations for women issued by the Institute of Medicine and adopted by HHS.# Introduction The United States continues to face challenges to improving the reproductive health of the U.S. population. Nearly half (49%) of all pregnancies are unintended (1). Although adolescent birth rates declined by more than 61% during 1991-2012, the United States has one of the highest adolescent pregnancy rates in the developed world, with >700,000 adolescents aged 15-19 years becoming pregnant each year and >300,000 giving birth (2,3). Approximately one of eight pregnancies in the United States results in a preterm birth, and infant mortality rates remain high compared with other developed countries (3,4). Moreover, all of these outcomes affect racial and ethnic minority populations disproportionately (1)(2)(3)(4). Family planning services can help address these and other public health challenges by providing education, counseling, and medical services (5). Family planning services include the following: • providing contraception to help women and men plan and space births, prevent unintended pregnancies, and reduce the number of abortions; • offering pregnancy testing and counseling; • helping clients who want to conceive; • providing basic infertility services; • providing preconception health services to improve infant and maternal outcomes and improve women's and men's health; and • providing sexually transmitted disease (STD) screening and treatment services to prevent tubal infertility and improve the health of women, men, and infants. This report provides recommendations developed collaboratively by CDC and the Office of Population Affairs (OPA) of the U.S. Department of Health and Human Services (HHS). The recommendations outline how to provide family planning services by: • defining a core set of family planning services for women and men, • describing how to provide contraceptive and other clinical services, serve adolescents, and perform quality improvements, and • encouraging the use of the family planning visit to provide selected preventive health services for women, in accordance with the recommendations for women issued by the Institute of Medicine (IOM) and adopted by HHS (6). The collaboration between CDC and OPA drew on the strengths of both agencies. CDC has a long-standing history of developing evidence-based recommendations for clinical care, and OPA's Title X Family Planning Program (7) has served as the national leader in direct family planning service delivery since the Title X program was established in 1970. This report provides recommendations for providing care to clients of reproductive age who are in need of family planning services. These recommendations are intended for all current or potential providers of family planning services, including those funded by the Title X program. # Current Context of Family Planning Services Women of reproductive age often report that their family planning provider is also their usual source of health care (8). As the U.S. health-care system evolves in response to increased efforts to expand health insurance coverage, contain costs, and emphasize preventive care (9), providers of family planning services will face new challenges and opportunities in care delivery. For example, they will have increased opportunities to serve new clients and to serve as gateways for their clients to other essential health-care services. In addition, primary care and other providers who provide a range of health-care services will be expected to integrate family planning services for all persons of reproductive age, including those whose primary reason for their health-care visit might not be family planning. Strengthened, multidirectional care coordination also will be needed to improve health outcomes. For example, this type of care coordination will be needed with clients referred to specialist care after initial screening at a family planning visit, as well as with specialists referring clients with family planning needs to family planning providers. # Defining Quality in Family Planning Service Delivery The central premise underpinning these recommendations is that improving the quality of family planning services will lead to improved reproductive health outcomes (10)(11)(12). IOM defines health-care quality as the extent to which health-care services improve health outcomes in a manner that is consistent with current professional knowledge (10,13). According to IOM, quality health care has the following attributes: • Safety. These recommendations integrate other CDC recommendations about which contraceptive methods can be provided safely to women with various medical conditions, and integrate CDC and U.S. Preventive Services Task Force (USPSTF) recommendations on STD, preconception, and related preventive health services. • Effectiveness. These recommendations support offering a full range of Food and Drug Administration (FDA)-approved contraceptive methods as well as counseling that highlights the effectiveness of contraceptive methods overall and, in specific patient situations, draws attention to the effectiveness of specific clinical preventive health services and identifies clinical preventive health services for which the potential harms outweigh the benefits (i.e., USPSTF "D" recommendations). • Client-centered approach. These recommendations encourage taking a client-centered approach by 1) highlighting that the client's primary purpose for visiting the service site must be respected, 2) noting the importance of confidential services and suggesting ways to provide them, 3) encouraging the availability of a broad range of contraceptive methods so that clients can make a selection based on their individual needs and preferences, and 4) reinforcing the need to deliver services in a culturally competent manner so as to meet the needs of all clients, including adolescents, those with limited English proficiency, those with disabilities, and those who are lesbian, gay, bisexual, transgender, or questioning their sexual identity (LGBTQ). Organizational policies, governance structures, and individual attitudes and practices all contribute to the cultural competence of a health-care entity and its staff. Cultural competency within a health-care setting refers to attitudes, practices, and policies that enable professionals to work effectively in cross-cultural situations (14-16). • Timeliness. These recommendations highlight the importance of ensuring that services are provided to clients in a timely manner. • Efficiency. These recommendations identify a core set of services that providers can focus on delivering, as well as ways to maximize the use of resources. • Accessibility. These recommendations address how to remove barriers to contraceptive use, use the family planning visit to provide access to a broader range of primary care and behavioral health services, use the primary care visit to provide access to contraceptive and other family planning services, and strengthen links to other sources of care. • Equity. These recommendations highlight the need for providers of family planning services to deliver highquality care to all clients, including adolescents, LGBTQ persons, racial and ethnic minorities, clients with limited English proficiency, and persons living with disabilities. • Value. These recommendations highlight services (i.e., contraception and other clinical preventive services) that have been shown to be very cost-effective (17)(18)(19). # Methods # Recommendations Development Process The recommendations were developed jointly under the auspices of CDC's Division of Reproductive Health and OPA, in consultation with a wide range of experts and key stakeholders. More information about the processes used to conduct systematic reviews, the role of technical experts in reviewing the evidence, and the process of using the evidence to develop recommendations is provided (Appendix A). A multistage process was used to develop the recommendations that drew on established procedures for developing clinical guidelines (20,21). First, an Expert Work Group* was formed comprising family planning clinical providers, program administrators, and representatives from relevant federal agencies and professional medical associations to help define the scope of the recommendations. Next, literature about three priority topics (i.e., counseling and education, serving adolescents, and quality improvement) was reviewed by using the USPSTF methodology for conducting systematic reviews (22). The results were presented to three technical panels † comprising subject matter experts (one panel for each priority topic) who considered the quality of the evidence and made suggestions for what recommendations might be supported on the basis of the evidence. In a separate process, existing clinical recommendations on women's and men's preventive services were compiled from more than 35 federal and professional medical associations, and these results were presented to two technical panels of subject matter experts, one that addressed women's clinical services and one that addressed men's clinical services. The panels provided individual feedback about which clinical preventive services should be offered in a family planning setting and which clinical recommendations should receive the highest consideration. CDC and OPA used the input from the subject matter experts to develop a set of core recommendations and asked the Expert Work Group to review them. The members of the Expert Work Group were more familiar with the family planning service delivery context than the members of the Technical Panel and thus could better comment on the feasibility and appropriateness of the recommendations, as well as the supporting evidence. The Expert Work Group considered the core recommendations by using the following criteria: 1) the quality of the evidence; 2) the positive and negative consequences of implementing the recommendations on health outcomes, costs or cost-savings, and implementation challenges; and 3) the relative importance of these consequences, (e.g., the likelihood that implementation of the recommendation will have a substantial effect on health outcomes might be considered more than the logistical challenges of implementing it) (20). In certain cases, when the evidence from the literature reviews was inconclusive or incomplete, recommendations were made on the basis of expert opinion. Finally, CDC and OPA staff considered the individual feedback from Expert Work Group members when finalizing the core recommendations and writing the recommendations document. A description of how the recommendations link to the evidence is provided together with the rationale for the inclusion of each recommendation in this report (Appendix B). The evidence used to prepare these recommendations will appear in background papers that will be published separately. Resources that will help providers implement the recommendations will be provided through a web-based tool kit that will be available at http://www.hhs.gov/opa. # Audience for the Recommendations The primary audience for this report is all providers or potential providers of family planning services to clients of reproductive age, including providers working in clinics that are dedicated to family planning service delivery, as well as private and public providers of more comprehensive primary care. Providers of dedicated family planning services might be less familiar with the specific recommendations for the delivery of preconception services. Providers of more comprehensive primary care might be less familiar with the delivery of contraceptive services, pregnancy testing and counseling, and services to help clients achieve pregnancy. This report can be used by medical directors to write clinical protocols that describe how care should be provided. Job aids and other resources for use in service sites are being developed and will be made available when ready through OPA's website (http://www.hhs.gov/opa). In this report, the term "provider" refers to any staff member who is involved in providing family planning services to a client. This includes physicians, physician assistants, nurse practitioners, nurse-midwives, nursing staff, and health educators. The term "service site" represents the numerous settings in which family planning services are delivered, which include freestanding service sites, community health centers, private medical facilities, and hospitals. A list of special terms used in this report is provided (Box 1). The recommendations are designed to guide general clinical practice; however, health-care providers always should consider the individual clinical circumstances of each person seeking family planning services. Similarly, these recommendations might need to be adapted to meet the needs of particular populations, such as clients who are HIV-positive or who are substance users. # Organization of the Recommendations This report is divided into nine sections. An initial section provides an overview of steps to assess the needs of a client and decide what family planning services to offer. Subsequent sections describe how to provide each of the following services: contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, STD services and related preventive health services. A final section on quality improvement describes actions that all providers of family planning services should consider to ensure that services are of high quality. More detailed information about selected topics addressed in the recommendations is provided (Appendices A-F). These recommendations focus on the direct delivery of care to individual clients. However, parallel steps might need to be taken to maintain the systems required to support the provision of quality services for all clients (e.g., record-keeping procedures that preserve client confidentiality, procedures that improve efficiency and reduce clients' wait time, staff training to ensure that all clients are treated with respect, and the establishment and maintenance of a strong system of care coordination and referrals). # Client Care Family planning services are embedded within a broader framework of preventive health services (Figure 1). In this report, health services are divided into three main categories: • Family planning services. These include contraceptive services for clients who want to prevent pregnancy and space births, pregnancy testing and counseling, assistance to achieve pregnancy, basic infertility services, STD services (including HIV/AIDS), and other preconception health services (e.g., screening for obesity, smoking, and mental health). STD/HIV and other preconception health services are considered family planning services because they improve women's and men's health and can influence a person's ability to conceive or to have a healthy birth outcome. • Related preventive health services. These include services that are considered to be beneficial to reproductive health, # BOX 1. Definitions of quality terms used in this report Accessible. The timely use of personal health services to achieve the best possible health outcomes.* Client-centered. Care is respectful of, and responsive to, individual client preferences, needs, and values; client values guide all clinical decisions. † Effective. Services are based on scientific knowledge and provided to all who could benefit and are not provided to those not likely to benefit. † Efficient. Waste is avoided, including waste of equipment, supplies, ideas, and energy. † Equitable. Care does not vary in quality because of the personal characteristics of clients (e.g., sex, race/ethnicity, geographic location, insurance status, or socioeconomic status). † Evidence-based. The process of integrating sciencebased interventions with community preferences to improve the health of populations. § Health-care quality. The degree to which health-care services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge. † Process. Whether services are provided correctly and completely and how clients perceive the care they receive. ¶ Safe. Avoids injuries to clients from the care that is intended to help them. † Structure. The characteristics of the settings in which providers deliver health care, including material resources, human resources, and organizational structure. ¶ Timely. Waits and sometimes harmful delays for both those who receive and those who provide care are reduced. † Value. The care provides good return relative to the costs involved, such as a return on investment or a reduction in the per capita cost of health care.* are closely linked to family planning services, and are appropriate to deliver in the context of a family planning visit but that do not contribute directly to achieving or preventing pregnancy (e.g., breast and cervical cancer screening). • Other preventive health services. These include preventive health services for women that were not included above (6), as well as preventive services for men. Screening for lipid disorders, skin cancer, colorectal cancer, or osteoporosis are examples of this type of service. Although important in the context of primary care, these have no direct link to family planning services. Providers of family planning services should be trained and equipped to offer all family planning and related preventive health services so that they can provide optimal care to clients, with referral for specialist care, as needed. Other preventive health services should be available either on-site or by referral, but these recommendations do not address this category of services. Information about preventive services that are beyond the scope of this report is available at http://www. uspreventiveservicestaskforce.org. # Determining the Client's Need for Services These recommendations apply to two types of encounters with women and men of reproductive age. In the first type of encounter, the primary reason for a client's visit to a healthcare provider is related to preventing or achieving pregnancy, (i.e., contraceptive services, pregnancy testing and counseling, or becoming pregnant). Other aspects of managing pregnancy (e.g., prenatal and delivery care ) are not addressed in these recommendations. For clients seeking to prevent or achieve pregnancy, providers should assess whether the client needs other related services and offer them to the client. In the second type of encounter, the primary reason for a client's visit to a health-care provider is not related to preventing or achieving pregnancy. For example, the client might come in for acute care (e.g., a male client coming in for STD symptoms or as a contact of a person with an STD), for chronic care, or for another preventive service. In this situation, providers not only should address the client's primary reason for the visit but also assess the client's need for services related to preventing or achieving pregnancy. A clinical pathway of family planning services for women and men of reproductive age is provided (Figure 2). The following questions can help providers determine what family planning services are most appropriate for a given visit. • -If the client wants to have a child and is experiencing difficulty conceiving, then provide basic infertility services. # • Does the client need preconception health services? Preconception health services (such as screening for obesity, smoking, and mental health) are a subset of all preventive services for women and men. Preconception health care is intended to promote the health of women and men of reproductive age before conception, with the goal of improving pregnancy-related outcomes (24). Preconception health services are also important because they improve the health of women and men, even if they choose not to become pregnant. The federal and professional medical recommendations cited in this report should be followed when determining which preconception health services a client might need. The individual client's needs should be considered when determining what services to offer at a given visit. It might not be feasible to deliver all the needed services in a single visit, and they might need to be delivered over the course of several visits. Providers should tailor services to meet the specific needs of the population they serve. For example, clients who are trying to achieve pregnancy and those at high risk of unintended pregnancy should be given higher priority for preconception health services. In some cases, the provider will deliver the initial screening service but then refer to another provider for further diagnosis or follow-up care. The delivery of preconception, STD, and related preventive health services should not become a barrier to a client's ability to receive services related to preventing or achieving pregnancy. For these clients, receiving services related to preventing or achieving pregnancy is the priority; if other family planning services cannot be delivered at the initial visit, then follow-up visits should be scheduled. In addition, professional recommendations for how to address the needs of diverse clients, such as LGBTQ persons (26)(27)(28)(29)(30)(31)(32) or persons with disabilities (33), should be consulted and integrated into procedures, as appropriate. For example, as noted before, providers should avoid making assumptions about a client's gender identity, sexual orientation, race, or ethnicity; all requests for services should be treated without regard to these characteristics. Similarly, services for adolescents should be provided in a "youth-friendly" manner, which means that they are accessible, equitable, acceptable, appropriate, comprehensive, effective, and efficient for youth, as recommended by the World Health Organization (34). # Contraceptive Services Providers should offer contraceptive services to clients who wish to delay or prevent pregnancy. Contraceptive services should include consideration of a full range of FDA-approved contraceptive methods, a brief assessment to identify the contraceptive methods that are safe for the client, contraceptive counseling to help a client choose a method of contraception and use it correctly and consistently, and provision of one or more selected contraceptive method(s), preferably on site, but by referral if necessary. Contraceptive counseling is defined as a process that enables clients to make and follow through on decisions about their contraceptive use. Education is an integral component of the contraceptive counseling process that helps clients to make informed decisions and obtain the information they need to use contraceptive methods correctly. Key steps in providing contraceptive services, including contraceptive counseling and education, have been outlined (Box 3). These key steps are in accordance with the five principles of quality counseling (Appendix C). To help a client who is initiating or switching to a new method of contraception, providers should follow these steps. These steps most likely will be implemented iteratively when working with a client and should help clients adopt, change, or maintain contraceptive use. Step 1. Establish and maintain rapport with the client. Providers should strive to establish and maintain rapport. Strategies to achieve these goals include the following: • using open-ended questions; • demonstrating expertise, trustworthiness, and accessibility; • ensuring privacy and confidentiality; • explaining how personal information will be used; • encouraging the client to ask questions and share information; • listening to and observing the client; and • being encouraging and demonstrating empathy and acceptance. Step 2. Obtain clinical and social information from the client. Providers should ask clients about their medical history to identify methods that are safe. In addition, to learn more about factors that might influence a client's choice of a contraceptive method, providers should confirm the client's pregnancy intentions or reproductive life plan, ask about the client's contraceptive experiences and preferences, and conduct a sexual health assessment. When available, standardized tools should be used. • (35). Clients considering combined hormonal contraception should be asked about smoking tobacco, in accordance with CDC guidelines on contraceptive use (35). Additional details about the methods of contraception that are safe to use for female clients with specific medical conditions and characteristics (e.g., hypertension) are addressed in previously published guidelines (35). For a male client, a medical history should include use of condoms, known allergies to condoms, partner use of contraception, recent intercourse, whether his partner is currently pregnant or has had a child, miscarriage, or termination, and the presence of any infectious or chronic health condition. However, the taking of a medical history should not be a barrier to making condoms available in the clinical setting (i.e., a formal visit should not be a prerequisite for a client to obtain condoms). about contraceptive methods that the client can safely use, and help the client consider potential barriers to using the method(s) under consideration. Use of decision aids (e.g., computerized programs that help a client to identify a range of methods that might be appropriate for the client based on her physical characteristics such as health conditions or preferences about side effects) before or while waiting for the appointment can facilitate and maximize the utility of the time spent on this step. Providers should inform clients about all contraceptive methods that can be used safely. Before the health-care visit, clients might have only limited information about all or specific methods of contraception (37). A broad range of methods, including long-acting reversible contraception (i.e., intrauterine devices [IUDs] and implants), should be discussed with all women and adolescents, if medically appropriate. Providers are encouraged to present information on potential reversible methods of contraception by using a tiered approach (i.e., presenting information on the most effective methods first, before presenting information on less effective methods) (38,39). This information should include an explanation that longacting reversible contraceptive methods are safe and effective for most women, including those who have never given birth and adolescents (35). Information should be tailored and presented to ensure a client-centered approach. It is not appropriate to omit presenting information on a method solely because the method is not available at the service site. If not all methods are available at the service site, it is important to have strong referral links in place to other providers to maximize opportunities for clients to obtain their preferred method that is medically appropriate. # BOX 3. Steps in providing contraceptive services, including contraceptive counseling* and education • Establish and maintain rapport with the client. • Obtain clinical and social information from the client. • Work with the client interactively to select the most effective and appropriate contraceptive method. • Conduct a physical assessment related to contraceptive use, only when warranted. • Provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow up, and confirm client understanding. For clients who have completed childbearing or do not plan to have children, permanent sterilization (female or male) is an option that may be discussed. Both female and male sterilization are safe, are highly effective, and can be performed in an office or outpatient surgery setting (40,41). Women and men should be counseled that these procedures are not intended to be reversible and that other highly effective, reversible methods of contraception (e.g., implants or IUDs) might be an alternative if they are unsure about future childbearing. Clients interested in sterilization should be referred to an appropriate source of care if the provider does not perform the procedure. When educating clients about contraceptive methods that the clients can use safely, providers should ensure that clients understand the following: • Method effectiveness. A contraceptive method's rate of typical effectiveness, or the percentage of women experiencing an unintended pregnancy during the first year of typical use, is an important consideration (Figure 3; Appendix D) (38,42). • Correct use of the method. The mode of administration and understanding how to use the method correctly might be important considerations for the client when choosing a method. For example, receiving a contraceptive injection every 3 months might not be acceptable to a woman who fears injections. Similarly, oral contraceptives might not be acceptable to a woman who is concerned that she might not be able to remember to take a pill every day. • Noncontraceptive benefits. Many contraceptives have noncontraceptive benefits, in addition to preventing pregnancy, such as reducing heavy menstrual bleeding. Although the noncontraceptive benefits are not generally the major determinant for selecting a method, awareness of these benefits can help clients decide between two or more suitable methods and might enhance the client's motivation to use the method correctly and consistently. • Side effects. Providers should inform the client about risks and side effects of the method(s) under consideration, help the client understand that certain side effects of contraceptive methods might disappear over time, and encourage the client to weigh the experience of coping with side effects against the experience and consequences of an unintended pregnancy. The provider should be prepared to discuss and correct misperceptions about side effects. Clients also should be informed about warning signs for rare, but serious, adverse events with specific contraceptive methods, such as stroke and venous thromboembolism with use of combined hormonal methods. • Protection from STDs, including HIV. Clients should be informed that contraceptive methods other than condoms offer no protection against STDs, including HIV. Condoms, when used correctly and consistently, help reduce the risk of STDs, including HIV, and provide protection against pregnancy. Dual protection (i.e., protection from both pregnancy and STDs) is important for clients at risk of contracting an STD, such as those with multiple or potentially infected partner(s). Dual protection can be achieved through correct and consistent use of condoms with every act of sexual intercourse, or correct and consistent use of a condom to prevent infection plus another form of contraception to prevent pregnancy. (For more information about preventing and treating STDs, see STD Services.) When educating clients about the range of contraceptive methods, providers should ensure that clients have information that is medically accurate, balanced, and provided in a nonjudgmental manner. To assist clients in making informed decisions, providers should educate clients in a manner that can be readily understood and retained. The content, format, method, and medium for delivering education should be evidence-based (see Appendix E). When working with male clients, when appropriate, providers should discuss information about female-controlled methods • Practices: Explore the types of sexual activity in which the patient engages (e.g., vaginal, anal, or oral sex). • Pregnancy prevention: Discuss current and future contraceptive options. Ask about current and previous use of methods, use of contraception at last sex, difficulties with contraception, and whether the client has a particular method in mind. • Partners: Ask questions to determine the number, gender (men, women, or both), and concurrency of the patient's sex partners (if partner had sex with another partner while still in a sexual relationship with the patient). It might be necessary to define the term "partner" to the patient or use other, relevant terminology. • Protection from sexually transmitted diseases (STDs): Ask about condom use, with whom they do or do not use condoms, and situations that make it harder or easier to use condoms. Topics such as monogamy and abstinence also can be discussed. • Past STD history: Ask about any history of STDs, including whether their partners have ever had an STD. Explain that the likelihood of an STD is higher with a past history of an STD. (including emergency contraception) encourage discussion of contraception with partners, and provide information about how partners can access contraceptive services. Male clients should also be reminded that condoms should be used correctly and consistently to reduce risk of STDs, including HIV. When working with any client, encourage partner communication about contraception, as well as understanding partner barriers (e.g., misperceptions about side effects) and facilitators (e.g., general support) of contraceptive use (43)(44)(45)(46). The provider should help the client consider potential barriers to using the method(s) under consideration. This includes consideration of the following factors: • Social-behavioral factors. Social-behavioral factors might influence the likelihood of correct and consistent use of contraception (47). Providers should help the client consider the advantages and disadvantages of the method(s) being considered, the client's feelings about using the method(s), how her or his partner is likely to respond, the client's peers' perceptions of the method(s), and the client's confidence in being able to use the method correctly and consistently (e.g., using a condom during every act of intercourse or remembering to take a pill every day) (37). • Intimate partner violence and sexual violence. Current and past intimate partner sexual or domestic violence might impede the correct and consistent use of contraception, and might be a consideration when choosing a method (47)(48)(49). For example, an IUD might (42). A list of assessments that need to be conducted when providing reversible contraceptive services to a female client seeking to initiate or switch to a new method of reversible contraception is provided (Table 1) (42). Clinical evaluation of a client electing permanent sterilization should be guided by the clinician who performs the procedure. Recommendations for contraceptive use are available (42). Key points include the following: • Blood pressure should be taken before initiating the use of combined hormonal contraception. • Providers should assess the current pregnancy status of clients receiving contraception (42), which provides guidance on how to be reasonably certain that a woman is not pregnant at the time of contraception initiation. In most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman about to start using a contraceptive method. Routine pregnancy testing for every woman is not necessary. • Weight measurement is not needed to determine medical eligibility for any method of contraception because all methods generally can be used among obese women. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. • Unnecessary medical procedures and tests might create logistical, emotional, or economic barriers to contraceptive access for some women, particularly adolescents and lowincome women, who have high rates of unintended pregnancies (1,51,52). For both adolescent and adult female clients, the following examinations and tests are not needed routinely to provide contraception safely to a healthy client (although they might be needed to address other non-contraceptive health needs) ( 42): -pelvic examinations, unless inserting an intrauterine device (IUD) or fitting a diaphragm; -cervical cytology or other cancer screening, including clinical breast exam; -human immunodeficiency virus (HIV) screening; and -laboratory tests for lipid, glucose, liver enzyme, and hemoglobin levels or thrombogenic mutations. For male clients, no physical examination needs to be performed before distributing condoms. Step 5. Provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow-up, and confirm client understanding. • A broad range of FDA-approved contraceptive methods should be available onsite. Referrals for methods not available onsite should be provided for clients who indicate they prefer those methods. When providing contraception, providers should instruct the client about correct and consistent use and employ the following strategies to facilitate a client's use of contraception: -Provide onsite dispensing; -Begin contraception at the time of the visit rather than waiting for next menses (also known as "quick start") if the provider can reasonably be certain that the client is not pregnant (42). A provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria (42,53): ˏ is ≤7 days after the start of normal menses, ˏ has not had sexual intercourse since the start of last normal menses, ˏ has been using a reliable method of contraception correctly and consistently, ˏ is ≤7 days after spontaneous or induced abortion, ˏ is within 4 weeks postpartum, ˏ is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority [≥85%] of feeds are breastfeeds), amenorrheic, and <6 months postpartum; -Provide or prescribe multiple cycles (ideally a full year's supply) of oral contraceptive pills, the patch, or the ring to minimize the number of times a client has to return to the service site; -Make condoms easily and inexpensively available; and -If a client chooses a method that is not available on-site or the same day, provide the client another method to use until she or he can start the chosen method. • Help the client develop a plan for using the selected method. Using a method incorrectly or inconsistently and having gaps in contraceptive protection because of method switching both increase the likelihood of an unintended pregnancy (37). After the method has been provided, or a plan put into place to obtain the chosen method, providers should help the client develop an action plan for using the selected method. Providers should encourage clients to anticipate reasons why they might not use their chosen method(s) correctly or consistently, and help them develop strategies to deal with these possibilities. For example, for a client selecting oral contraceptive pills who might forget to take a pill, the provider can work with the client to identify ways to routinize daily pill taking (e.g., use of reminder systems such as daily text messages or cell phone alarms). Providers also may inform clients about the availability of emergency contraceptive pills and may provide clients an advance supply of emergency contraceptive pills on-site or by prescription, if requested. Side effects (e.g., irregular vaginal bleeding) are a primary reason for method discontinuation (54), so providers should discuss ways the client might deal with potential side effects to increase satisfaction with the method and improve continuation (42). • Develop a plan for follow-up. Providers should discuss an appropriate follow-up plan with the client to meet their individual needs, considering the client's risk for discontinuation. Follow-up provides an opportunity to inquire about any initial difficulties the client might be experiencing, and might reinforce the perceived accessibility of the provider and increase rapport. Alternative modes of follow-up other than visits to the service site, such as telephone, e-mail, or text messaging, should be considered (assuming confidentiality can be assured), as needed. As noted previously, if a client chooses a method that is not available on-site or during the visit, the provider # TABLE 1. Assessments to conduct when a female client is initiating a new method of reversible contraception # Cu-IUD and LNG-IUD Implant Injectable # Combined hormonal contraception # Progestinonly pills Condom Diaphragm or cervical cap Spermicide Abbreviations: A = Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method; B = Class B: contributes substantially to safe and effective use, but implementation might be considered within the public health and/or service context (the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available); C = Class C: does not contribute substantially to safe and effective use of the contraceptive method; Cu-IUD = copper-containing intrauterine device; LNG-IUD = levonorgestrel releasing intrauterine device. * In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. should schedule a follow-up visit with the client or provide a referral for her or him to receive the method. The client should be provided another method to use until she or he can start the chosen method. • Confirm the client's understanding. Providers should assess whether the client understands the information that was presented. The client's understanding of the most important information about her or his chosen contraceptive method should be documented in the medical record (e.g., by a checkbox or written statement). The teach-back method may be used to confirm the client's understanding by asking the client to repeat back messages about risks and benefits and appropriate method use and follow-up. If providers assess the client's understanding, then the check box or written statement can be used in place of a written method-specific informed consent form. Topics that providers may consider having the client repeat back include the following: typical method effectiveness; how to use the method correctly; protection from STDs; warning signs for rare, but serious, adverse events and what to do if they experience a warning sign; and when to return for follow-up. Examination Blood pressure C C C A* C C C C Weight (BMI) (weight [kg]/height [m] 2 ) - † - † - † - † - † C C C Clinical breast examination C C C C C C C C Bimanual examination and cervical inspection A C C C C C A § C Laboratory test Glucose C C C C C C C C Lipids C C C C C C C C Liver enzymes C C C C C C C C Hemoglobin C C C C C C C C Thrombogenic mutations C C C C C C C C Cervical cytology (Papanicolaou smear) C C C C C C C C STD # Provide Counseling for Returning Clients When serving contraceptive clients who return for ongoing care related to contraception, providers should ask if the client has any concerns with the method and assess its use. The provider should assess any changes in the client's medical history, including changes in risk factors and medications that might affect safe use of the contraceptive method. If the client is using the method correctly and consistently and there are no concerns about continued use, an appropriate follow-up plan should be discussed and more contraceptive supplies given (42). If the client or provider has concerns about the client's correct or consistent use of the method, the provider should ask if the client would be interested in considering a different method of contraception. If the client is interested, the steps described above should be followed. # Counseling Adolescent Clients Providers should give comprehensive information to adolescent clients about how to prevent pregnancy (55)(56)(57). This information should clarify that avoiding sex (i.e., abstinence) is an effective way to prevent pregnancy and STDs. If the adolescent indicates that she or he will be sexually active, providers should give information about contraception and help her or him to choose a method that best meets her or his individual needs, including the use of condoms to reduce the risk of STDs. Long-acting reversible contraception is a safe and effective option for many adolescents, including those who have not been pregnant or given birth (35). Providers of family planning services should offer confidential services to adolescents and observe all relevant state laws and any legal obligations, such as notification or reporting of child abuse, child molestation, sexual abuse, rape, or incest, as well as human trafficking (58,59). Confidentiality is critical for adolescents and can greatly influence their willingness to access and use services (60)(61)(62)(63)(64)(65)(66)(67). As a result, multiple professional medical associations have emphasized the importance of providing confidential services to adolescents (68)(69)(70). Providers should encourage and promote communication between the adolescent and his or her parent(s) or guardian(s) about sexual and reproductive health (71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86). Adolescents who come to the service site alone should be encouraged to talk to their parents or guardians. Educational materials and programs can be provided to parents or guardians that help them talk about sex and share their values with their child (72,87). When both parent or guardian and child have agreed, joint discussions can address family values and expectations about dating, relationships, and sexual behavior. In a given year, approximately 20% of adolescent births represent repeat births (88), so in addition to providing postpartum contraception, providers should refer pregnant and parenting adolescents to home visiting and other programs that have been demonstrated to provide needed support and reduce rates of repeat teen pregnancy (89)(90)(91)(92)(93)(94). Services for adolescents should be provided in a "youthfriendly" manner, which means that they are accessible, equitable, acceptable, appropriate, comprehensive, effective, and efficient for youth as recommended by the World Health Organization (34). # Pregnancy Testing and Counseling Providers of family planning services should offer pregnancy testing and counseling services as part of core family planning services, in accordance with recommendations of major professional medical organizations, such as the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) (95)(96)(97). Pregnancy testing is a common reason for a client to visit a provider of family planning services. Approximately 65% of pregnancies result in live births, 18% in induced abortion, and 17% spontaneous fetal loss (98). Among live births, only 1% of infants are placed for adoption within their first month of life (99). The visit should include a discussion about her reproductive life plan and a medical history that includes asking about any coexisting conditions (e.g., chronic medical illnesses, physical disability, psychiatric illness) (95,96). In most cases, a qualitative urine pregnancy test will be sufficient; however, in certain cases, the provider may consider performing a quantitative serum pregnancy test, if exact hCG levels would be helpful for diagnosis and management. The test results should be presented to the client, followed by a discussion of options and appropriate referrals. Options counseling should be provided in accordance with recommendations from professional medical associations, such as ACOG and AAP (95)(96)(97). A female client might wish to include her partner in the discussion; however, if a client chooses not to involve her partner, confidentiality must be assured. # Positive Pregnancy Test If the pregnancy test is positive, the clinical visit should include an estimation of gestational age so that appropriate counseling can be provided. If a woman is uncertain about the date of her last normal menstrual period, a pelvic examination might be needed to help assess gestational age. In addition, clients should receive information about the normal signs and symptoms of early pregnancy, and should be instructed to report any concerns to a provider for further evaluation. If ectopic pregnancy or other pregnancy abnormalities or problems are suspected, the provider should either manage the condition or refer the client for immediate diagnosis and management. Referral to appropriate providers of follow-up care should be made at the request of the client, as needed. Every effort should be made to expedite and follow through on all referrals. For example, providers might provide a resource listing or directory of providers to help the client identify options for care. Depending upon a client's needs, the provider may make an appointment for the client, or call the referral site to let them know the client was referred. Providers also should assess the client's social support and refer her to appropriate counseling or other supportive services, as needed. For clients who are considering or choose to continue the pregnancy, initial prenatal counseling should be provided in accordance with the recommendations of professional medical associations, such as ACOG (97). The client should be informed that some medications might be contraindicated in pregnancy, and any current medications taken during pregnancy need to be reviewed by a prenatal care provider (e.g., an obstetrician or midwife). In addition, the client should be encouraged to take a daily prenatal vitamin that includes folic acid; to avoid smoking, alcohol, and other drugs; and not to eat fish that might have high levels of mercury (97). If there might be delays in obtaining prenantal care, the client should be provided or referred for any needed STD screening (including HIV) and vaccinations (36). # Negative Pregnancy Test Women who are not pregnant and who do not want to become pregnant at this time should be offered contraceptive services, as described previously. The contraceptive counseling session should explore why the client thought that she was pregnant and sought pregnancy testing services, and whether she has difficulties using her current method of contraception. A negative pregnancy test also provides an opportunity to discuss the value of making a reproductive life plan. Ideally, these services will be offered in the same visit as the pregnancy test because clients might not return at a later time for contraceptive services. Women who are not pregnant and who are trying to become pregnant should be offered services to help achieve pregnancy or basic infertility services, as appropriate (see "Clients Who Want to Become Pregnant" and "Basic Infertility Services"). They also should be offered preconception health and STD services (see "Preconception Health Services" and "STD services"). # Clients Who Want to Become Pregnant Providers should advise clients who wish to become pregnant in accordance with the recommendations of professional medical organizations, such as the American Society for Reproductive Medicine (ASRM) (100). Providers should ask the client (or couple) how long she or they have been trying to get pregnant and when she or they hope to become pregnant. If the client's situation does not meet one of the standard definitions of infertility (see "Basic Infertility Services"), then she or he may be counseled about how to maximize fertility. Key points are as follows: • The client should be educated about peak days and signs of fertility, including the 6-day interval ending on the day of ovulation that is characterized by slippery, stretchy cervical mucus and other possible signs of ovulation. • Women with regular menstrual cycles should be advised that vaginal intercourse every 1-2 days beginning soon after the menstrual period ends can increase the likelihood of becoming pregnant. • Methods or devices designed to determine or predict the time of ovulation (e.g., over-the-counter ovulation kits, digital telephone applications, or cycle beads) should be discussed. • It should be noted that fertility rates are lower among women who are very thin or obese, and those who consume high levels of caffeine (e.g., more than five cups per day). • Smoking, consuming alcohol, using recreational drugs, and using most commercially available vaginal lubricants should be discouraged as these might reduce fertility. # Basic Infertility Services Providers should offer basic infertility care as part of core family planning services in accordance with the recommendations of professional medical organizations, such as ACOG, ASRM, and the American Urological Association (AUA) (96,101,102). Infertility commonly is defined as the failure of a couple to achieve pregnancy after 12 months or longer of regular unprotected intercourse (101). Earlier assessment (such as 6 months of regular unprotected intercourse) is justified for women aged >35 years, those with a history of oligoamenorrhea (infrequent menstruation), those with known or suspected uterine or tubal disease or endometriosis, or those with a partner known to be subfertile (the condition of being less than normally fertile though still capable of effecting fertilization) ( 101). An early evaluation also might be warranted if risk factors of male infertility are known to be present or if there are questions regarding the male partner's fertility potential (102). Infertility visits to a family planning provider are focused on determining potential causes of the inability to achieve pregnancy and making any needed referrals to specialist care (101,102). ASRM recommends that evaluation of both partners should begin at the same time (101). # Basic Infertility Care for Women The clinical visit should focus on understanding the client's reproductive life plan (24) and her difficulty in achieving pregnancy through a medical history, sexual health assessment and physical exam, in accordance with recommendations developed by professional medical associations such as ASRM (101) and ACOG (96). The medical history should include past surgery, including indications and outcome(s), previous hospitalizations, serious illnesses or injuries, medical conditions associated with reproductive failure (e.g., thyroid disorders, hirsutism, or other endocrine disorders), and childhood disorders; results of cervical cancer screening and any follow-up treatment; current medication use and allergies; and family history of reproductive failure. In addition, a reproductive history should include how long the client has been trying to achieve pregnancy; coital frequency and timing, level of fertility awareness, and results of any previous evaluation and treatment; gravidity, parity, pregnancy outcome(s), and associated complications; age at menarche, cycle length and characteristics, and onset/severity of dysmenorrhea; and sexual history, including pelvic inflammatory disease, history of STDs, or exposure to STDs. A review of systems should emphasize symptoms of thyroid disease, pelvic or abdominal pain, dyspareunia, galactorrhea, and hirsutism (101). The physical examination should include: height, weight, and body mass index (BMI) calculation; thyroid examination to identify any enlargement, nodule, or tenderness; clinical breast examination; and assessment for any signs of androgen excess. A pelvic examination should assess for: pelvic or abdominal tenderness, organ enlargement or mass; vaginal or cervical abnormality, secretions, or discharge; uterine size, shape, position, and mobility; adnexal mass or tenderness; and cul-de-sac mass, tenderness, or nodularity. If needed, clients should be referred for further diagnosis and treatment (e.g., serum progesterone levels, follicle-stimulating hormone/luteinizing hormone levels, thyroid function tests, prolactin levels, endometrial biopsy, transvaginal ultrasound, hysterosalpingography, laparoscopy, and clomiphene citrate). # Basic Infertility Care for Men Infertility services should be provided for the male partner of an infertile couple in accordance with recommendations developed by professional medical associations such as AUA (102). Providers should discuss the client's reproductive life plan, take a medical history, and conduct a sexual health assessment. AUA recommends that the medical history include a reproductive history (102). The medical history should include systemic medical illnesses (e.g., diabetes mellitus), prior surgeries and past infections; medications (prescription and nonprescription) and allergies; and lifestyle exposures. The reproductive history should include methods of contraception, coital frequency and timing; duration of infertility and prior fertility; sexual history; and gonadal toxin exposure, including heat. Patients also should be asked about their female partners' history of pelvic inflammatory disease, their partners' histories of STDs, and problems with sexual dysfunction. In addition, a physical examination should be conducted with particular focus given to 1) examination of the penis, including the location of the urethral meatus; 2) palpation of the testes and measurement of their size; 3) presence and consistency of both the vas deferens and epididymis; 4) presence of a varicocele; 5) secondary sex characteristics; and 6) a digital rectal exam (102). Male clients concerned about their fertility should have a semen analysis. If this test is abnormal, they should be referred for further diagnosis (i.e., second semen analysis, endocrine evaluation, post-ejaculate urinalysis, or others deemed necessary) and treatment. The semen analysis is the first and most simple screen for male fertility. # Infertility Counseling Counseling provided during the clinical visit should be guided by information elicited from the client during the medical and reproductive history and the findings of the physical exam. If there is no apparent cause of infertility and the client does not meet the definition above, providers should educate the client about how to maximize fertility (see "Clients Who Want to Become Pregnant"). ACOG notes the importance of addressing the emotional and educational needs of clients with infertility and recommends that providers consider referring clients for psychological support, infertility support groups, or family counseling (96). # Preconception Health Services Providers of family planning services should offer preconception health services to female and male clients in accordance with CDC's recommendations to improve preconception health and health care (24). Preconception health services are beneficial because of their effect on pregnancy and birth outcomes and their role in improving the health of women and men. The term preconception describes any time that a woman of reproductive potential is not pregnant but at risk of becoming pregnant, or when a man is at risk for impregnating his female partner. Preconception health-care services for women aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcomes through prevention and management. It promotes the health of women of reproductive age before conception, and thereby helps to reduce pregnancyrelated adverse outcomes, such as low birthweight, premature birth, and infant mortality (24). Moreover, the preconception health services recommended here are equally important because they contribute to the improvement of women's health and well-being, regardless of her childbearing intentions. CDC recommends that preconception health services be integrated into primary care visits made by women of reproductive age, such as family planning visits (24). In the family planning setting, providers may prioritize screening and counseling about preconception health for couples that are trying to achieve pregnancy and couples seeking basic infertility services. Women who are using contraception to prevent or delay pregnancy might also benefit from preconception health services, especially those at high risk of unintended pregnancy. A woman is at high risk of unintended pregnancy if she is using no method or a less effective method of contraception (e.g., barrier methods, rhythm, or withdrawal), or has a history of contraceptive discontinuation or incorrect use (38,39). A woman is at lower risk of unintended pregnancy if she is using a highly effective method, such as an IUD or implant, or has an established history of using methods of contraception, such as injections, pills, patch, or ring correctly and consistently (38,39). Clients who do not want to become pregnant should also be provided preconception health services, since they are recommended by USPSTF for the purpose of improving the health of adults. Recommendations for improving the preconception health of men also have been identified, although the evidence base for many of the recommendations for men is less than that for women (103). This report includes preconception health services that address men as partners in family planning (i.e., both preventing and achieving pregnancy), their direct contributions to infant health (e.g., genetics), and their role in improving the health of women (e.g., through reduced STD/HIV transmission). Moreover, these services are important for improving the health of men regardless of their pregnancy intention. In a family planning setting, all women planning or capable of pregnancy should be counseled about the need to take a daily supplement containing 0.4 to 0.8 mg of folic acid, in accordance with the USPSTF recommendation (Grade A) (104). Other preconception health services for women and men should include discussion of a reproductive life plan and sexual health assessment (Boxes 2 and 4), as well as the screening services described below (24,103,105). Services should be provided in accordance with the cited clinical recommendations, and any needed follow up (further diagnosis, treatment) should be provided either on-site or through referral. # Medical History For female clients, the medical history should include the reproductive history, history of poor birth outcomes (i.e., preterm, cesarean delivery, miscarriage, and stillbirth), environmental exposures, hazards and toxins (e.g., smoking, alcohol, other drugs), medications that are known teratogens, genetic conditions, and family history (24,105). For male clients, the medical history should include asking about the client's past medical and surgical history that might impair his reproductive health (e.g., genetic conditions, history of reproductive failures, or conditions that can reduce sperm quality, such as obesity, diabetes mellitus, and varicocele) and environmental exposures, hazards and toxins (e.g., smoking) (103). # Intimate Partner Violence Providers should screen women of childbearing age for intimate partner violence and provide or refer women who screen positive to intervention services, in accordance with USPSTF (Grade B) recommendations (106). # Alcohol and Other Drug Use For female and male adult clients, providers should screen for alcohol use in accordance with the USPSTF recommendation (Grade B) for how to do so, and provide behavioral counseling interventions, as indicated (107). Screening adults for other drug use and screening adolescents for alcohol and other drug use has the potential to reduce misuse of alcohol and other drugs, and can be recommended (105,108,109). However, the USPSTF recommendation for screening for other drugs in adults, and for alcohol and other drugs in adolescents, is an "I," and patients should be informed that there is insufficient evidence to assess the balance of benefits and harms of this screening (107,110). # Tobacco Use For female and male clients, providers should screen for tobacco use in accordance with the USPSTF recommendation (111,112) for how to do so. Adults (Grade A) who use tobacco products should be provided or referred for tobacco cessation interventions, including brief behavioral counseling sessions (<10 minutes) and pharmacotherapy delivered in primary care settings (111). Adolescents (Grade B) should be provided intervention to prevent initiation of tobacco use (112). # Immunizations For female and male clients, providers should screen for immunization status in accordance with recommendations of CDC's Advisory Committee on Immunization Practices (113) and offer vaccination, as indicated, or provide referrals to community providers for immunization. Female and male clients should be screened for age-appropriate vaccinations, such as influenza and tetanus-diphtheria-pertussis (Tdap), measles, mumps, and rubella (MMR), varicella, pneumococcal, and meningococcal. In addition, ACOG recommends that rubella titer be performed in women who are uncertain about MMR immunization (108). (For vaccines for reproductive health-related conditions, i.e., human papillomavirus and hepatitis B, see "Sexually Transmitted Disease Services.") # Depression For all clients, providers should screen for depression when staff-assisted depression care supports are in place to ensure accurate diagnosis, effective treatment, and follow-up (114,115). Staff-assisted care supports are defined as clinical staff members who assist the primary care clinician by providing some direct depression care, such as care support or coordination, case management, or mental health treatment. The lowest effective staff supports consist of a screening nurse who advises primary care clinicians of a positive screen and provides a protocol facilitating referral to behavioral therapy. Providers also may follow American Psychiatric Association (116) and American Academy of Child and Adolescent Psychiatry (117) recommendations to assess risk for suicide among persons experiencing depression and other risk factors. # Height, Weight, and Body Mass Index For all clients, providers should screen adult (Grade B) and adolescent (Grade B) clients for obesity in accordance with the USPSTF recommendation, and obese adults should be referred for intensive counseling and behavioral interventions to promote sustained weight loss (118,119). Clients likely will need to be referred for this service. These interventions typically comprise 12 to 26 sessions in a year and include multiple behavioral management activities, such as group sessions, individual sessions, setting weight-loss goals, improving diet or nutrition, physical activity sessions, addressing barriers to change, active use of self-monitoring, and strategizing how to maintain lifestyle changes. # Blood Pressure For female and male clients, providers should screen for hypertension in accordance with the USPSTF's recommendation (Grade A) that blood pressure be measured routinely among adults (120) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure's recommendation that persons with blood pressure less than 120/80 be screened every 2 years, and every year if prehypertensive (i.e., blood pressure 120-139/80-89) (121). Providers also may follow AAP's recommendation that adolescents receive annual blood pressure screening (109). # Diabetes For female and male clients, providers should follow the USPSTF recommendation (Grade B) to screen for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) >135/80 mmHg (122). # Sexually Transmitted Disease Services Providers should offer STD services in accordance with CDC's STD treatment and HIV testing guidelines (36,123,124). It is important to test for chlamydia annually among young sexually active females and for gonorrhea routinely among all sexually active females at risk for infection because they can cause tubal infertility in women if left untreated. Testing for syphilis, HIV/AIDS, and hepatitis C should be conducted as recommended (36,123,124). Vaccination for human papillomavirus (HPV) and hepatitis B are also important parts of STD services and preconception care (113). STD services should be provided for persons with no signs or symptoms suggestive of an STD. STD diagnostic management recommendations are not included in these guidelines, so providers should refer to CDC's STD treatment guidelines (36) when caring for clients with STD symptoms. STD services include the following steps, which should be provided at the initial visit and at least annually thereafter: Step 1. Assess: The provider should discuss the client's reproductive life plan, conduct a standard medical history and sexual health assessment (see text box above), and check immunization status. A pelvic exam is not indicated in patients with no symptoms suggestive of an STD. Step 2. Screen: A client who is at risk of an STD (i.e., sexually active and not involved in a mutually monogamous relationship with an uninfected partner) should be screened for HIV and the other STDs listed below, in accordance with CDC's STD treatment guidelines (36) and recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings (123). Clients also should follow CDC's recommendations for testing for hepatitis C (124), and the Advisory Committee on Immunization Practice's recommendations on reproductive health-related immunizations (113). It is important to follow these guidelines both to ensure that clients receive needed services and to avoid unnecessary screening. # Chlamydia For female clients, providers should screen all sexually active women aged ≤25 years for chlamydia annually, in addition to sexually active women aged >25 years with risk factors for chlamydia infection (36). Women aged >25 years at higher risk include sexually active women who have a new or more than one sex partner or who have a partner who has other concurrent partners. Females with chlamydia infection should be rescreened for re-infection at 3 months after treatment. Pregnant women should be screened for chlamydia at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). For male clients, chlamydia screening can be considered for males seen at sites with a high prevalence of chlamydia, such as adolescent clinics, correctional facilities, and STD clinics (36,125,126). Providers should screen men who have sex with men (MSM) for chlamydia at anatomic sites of exposure, in accordance with CDC's STD treatment guidelines (36). Males with symptoms suggestive of chlamydia (urethral discharge or dysuria or whose partner has chlamydia) should be tested and empirically treated at the initial visit. Males with chlamydia infection should be re-screened for reinfection at 3 months (36). # Gonorrhea For female clients, providers should screen clients for gonorrhea, in accordance with CDC's STD treatment guidelines (36). Routine screening for N. gonorrhoeae in all sexually active women at risk for infection is recommended annually (36). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors that place women at increased risk include a previous gonorrhea infection, the presence of other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. Females with gonnorrhea infection should be re-screened for re-infection at 3 months after treatment. Pregnant women should be screened for gonorrhea at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). For male clients, providers should screen MSM for gonorrhea at anatomic sites of exposure, in accordance with CDC's STD treatment guidelines (36). Males with symptoms suggestive of gonorrhea (urethral discharge or dysuria or whose partner has gonorrhea) should be tested and empirically treated at the initial visit. Males with gonorrhea infection should be re-screened for reinfection at 3 months after treatment (36,(126)(127)(128). # Syphilis For female and male clients, providers should screen clients for syphilis, in accordance with CDC's STD treatment guidelines (36). CDC recommends that persons at risk for syphilis infection should be screened. Populations at risk include MSM, commercial sex workers, persons who exchange sex for drugs, those in adult correctional facilities and those living in communities with high prevalence of syphilis (36). Pregnant women should be screened for syphilis at the time of their pregnancy test if there might be delays in obtaining prenatal care (36). # HIV/AIDS For female and male clients, providers should screen clients for HIV/AIDS, in accordance with CDC HIV testing guidelines (123). Providers should follow CDC recommendations that all clients aged 13-64 years be screened routinely for HIV infection and that all persons likely to be at high risk for HIV be rescreened at least annually (123). Persons likely to be at high risk include injection-drug users and their sex partners, persons who exchange sex for money or drugs, sex partners of HIV-infected persons, and MSM or heterosexual persons who themselves or whose sex partners have had more than one sex partner since their most recent HIV test. CDC further recommends that screening be provided after the patient is notified that testing will be performed as part of general medical consent unless the patient declines (opt-out screening) or otherwise prohibited by state law. The USPSTF also recommends screening for HIV (Grade A) (129). # Hepatitis C For female and male clients, CDC recommends one-time testing for hepatitis C (HCV) without prior ascertainment of HCV risk for persons born during 1945-1965, a population with a disproportionately high prevalence of HCV infection and related disease. Persons identified as having HCV infection should receive a brief screening for alcohol use and intervention as clinically indicated, followed by referral to appropriate care for HCV infection and related conditions. These recommendations do not replace previous guidelines for HCV testing that are based on known risk factors and clinical indications. Rather, they define an additional target population for testing: persons born during 1945-1965 (124). USPSTF also recommends screening persons at high risk for infection for hepatitis C and one-time screening for HCV infection for persons in the 1945-1965 birth cohort (Grade B) (130). # Immunizations Related to Reproductive Health Female clients aged 11-26 years should be offered either human papillomavirus (HPV) 2 or HPV4 vaccine for the prevention of HPV and cervical cancer if not previously vaccinated, although the series can be started in persons as young as age 9 years (113); recommendations include starting at age 11-12 years and catch up vaccine among females aged 13-26 who have not been vaccinated previously or have not completed the 3-dose series through age 26. Routine hepatitis B vaccination should be offered to all unvaccinated children and adolescents aged <19 years and all adults who are unvaccinated and do not have any documented history of hepatitis B infection (113). Male clients aged 11-21 years (minimum age: 9 years) should be offered HPV4 vaccine, if not vaccinated previously; recommendations include starting at age 11-12 years and catch up vaccine among males aged 13-21 years who have not been vaccinated previously or have not completed the 3-dose series through age 21 years; vaccination is recommended among at-risk males, including MSM and immune-compromised males through age 26 years if not vaccinated previously or males who have not completed the 3-dose series through age 26 years. Heterosexual males aged 22-26 years may be vaccinated (131). Routine hepatitis B vaccination should be offered to all unvaccinated children and adolescents aged <19 years, and all unvaccinated adults who do not have a documented history of hepatitis B infection (113). Step 3. Treat: A client with an STD and her or his partner(s) should be treated in a timely fashion to prevent complications, re-infection and further spread of the infection in the community in accordance with CDC's STD treatment guidelines; clients with HIV infection should be linked to HIV care and treatment (36,123). Clients should be counseled about the need for partner evaluation and treatment to avoid reinfection at the time the client receives the positive test results. For partners of clients with chlamydia or gonorrhea, one option is to schedule them to come in with the client; another option for partners who cannot come in with the client is expedited partner therapy (EPT), as permissible by state laws, in which medication or a prescription is provided to the patient to give to the partner to ensure treatment. EPT is a partner treatment strategy for partners who are unable to access care and treatment in a timely fashion. Because of concerns related to resistant gonorrhea, efforts to bring in for treatment partners of patients with gonorrhea infection are recommended; EPT for gonorrhea should be reserved for situations in which efforts to treat partners in a clinical setting are unsuccessful and EPT is a gonorrhea treatment of last resort. All clients treated for chlamydia or gonorrhea should be rescreened 3 months after treatment; HIV-infected females with Trichomonas vaginalis should be linked to HIV care and rescreened for T. vaginalis at 3 months. If needed, the client also should be vaccinated for hepatitis B and HPV (113). Ideally, STD treatment should be directly observed in the facility rather than a prescription given or called in to a pharmacy. If a referral is made to a service site that has the necessary medication available on-site, such as the recommended injectable antimicrobials for gonorrhea and syphilis, then the referring provider must document that treatment was given. Step 4. Provide risk counseling: If the client is at risk for or has an STD, high-intensity behavioral counseling for sexual behavioral risk reduction should be provided in accordance with the USPSTF recommendation (Grade B) (132). One high-intensity behavioral counseling model that is similar to the contraceptive counseling model is Project Respect (133), which could be implemented in family planning settings. All sexually active adolescents are at risk, and adults are at increased risk if they have current STDs, had an STD in the past year, have multiple sexual partners, are in nonmonogamous relationships, or are sexually active and live in a community with a high rate of STDs. Other key messages to give infected clients before they leave the service site include the following: a) refrain from unprotected sexual intercourse during the period of STD treatment, 2) encourage partner(s) to be screened or to get treatment as quickly as possible in accordance with CDC's STD treatment guidelines (partners in the past 60 days for chlamydia and gonorrhea, 3 to 6 months plus the duration of lesions or signs for primary and secondary syphilis, respectively) if the partner did not accompany the client to the service site for treatment, and 3) return for retesting in 3 months. If the partner is unlikely to access treatment quickly, then EPT for chlamydia or gonorrhea should be considered, if permissible by state law. A client using or considering contraceptive methods other than condoms should be advised that these methods do not protect against STDs. Providers should encourage a client who is not in a mutually monogamous relationship with an uninfected partner to use condoms. Patients who do not know their partners' infection status should be encouraged to get tested and use condoms or avoid sexual intercourse until their infection status is known. # Related Preventive Health Services For many women and men of reproductive age, a family planning service site is their only source of health care; therefore, visits should include provision of or referral to other preventive health services. Providers of family planning services that do not have the capacity to offer comprehensive primary care services should have strong links to other community providers to ensure that clients have access to primary care. If a client does not have another source of primary care, priority should be given to providing related reproductive health services or providing referrals, as needed. For clients without a primary care provider, the following screening services should be provided, with appropriate follow-up, if needed, while linking the client to a primary care provider. These services should be provided in accordance with federal and professional medical recommendations cited below regarding the frequency of screening, the characteristics of the clients that should be screened, and the screening procedures to be used. # Medical History USPSTF recommends that women be asked about family history that would be suggestive of an increased risk for deleterious mutations in BRCA1 or BRCA2 genes (e.g., receiving a breast cancer diagnosis at an early age, bilateral breast cancer, history of both breast and ovarian cancer, presence of breast cancer in one or more female family members, multiple cases of breast cancer in the family, both breast and ovarian cancer in the family, one or more family members with two primary cases of cancer, and Ashkenazi background). Women with identified risk(s) should be referred for genetic counseling and evaluation for BRCA testing (Grade B) (134). The USPSTF also recommends that women at increased risk for breast cancer should be counseled about risk-reducing medications (Grade B) (135). # Cervical Cytology Providers should provide cervical cancer screening to clients receiving related preventive health services. Providers should follow USPSTF recommendations to screen women aged 21-65 years with cervical cytology (Pap smear) every 3 years, or for women aged 30-65 years, screening with a combination of cytology and HPV testing every 5 years (Grade A) (136). Cervical cytology no longer is recommended on an annual basis. Further, it is not recommended (Grade D) for women aged <21 years (136). Women with abnormal test results should be treated in accordance with professional standards of care, which may include colposcopy (96,137). The need for cervical cytology should not delay initiation or hinder continuation of a contraceptive method (42). Providers should also follow ACOG and AAP recommendations that a genital exam should accompany a cervical cancer screening to inspect for any suspicious lesions or other signs that might indicate an undiagnosed STD (96,97,138). # Clinical Breast Examamination Despite a lack of definitive data for or against, clinical breast examination has the potential to detect palpable breast cancer and can be recommended. ACOG recommends annual examination for all women aged >19 years (108). ACS recommends screening every 3 years for women aged 20-39 years, and annually for women aged ≥40 years (139). However, the USPSTF recommendation for clinical breast exam is an I, and patients should be informed that there is insufficient evidence to assess the balance of benefits and harms of the service (140). # Mammography Providers should follow USPSTF recommendations (Grade B) to screen women aged 50-74 years on a biennial basis; they should screen women aged <50 years if other conditions support providing the service to an individual patient (140). # Genital Examination For adolescent males, examination of the genitals should be conducted. This includes documentation of normal growth and development and other common genital findings, including hydrocele, varicocele, and signs of STDs (141). Components of this examination include inspecting skin and hair, palpating inguinal nodes, scrotal contents and penis, and inspecting the perinanal region (as indicated). # Summary of Recommendations for Providing Family Planning and Related Preventive Health Services The screening components for each family planning and related preventive health service are provided in summary checklists for women (Table 2) and men (Table 3). When considering how to provide the services listed in these recommendations (e.g., the screening components for each service, risk groups that should be screened, the periodicity of screening, what follow-up steps should be taken if screening reveals the presence of a health condition), providers should follow CDC and USPSTF recommendations cited above, or, in the absence of CDC and USPSTF recommendations, the recommendations of professional medical associations. Following these recommendations is important both to ensure clients receive needed care and to avoid unnecessary screening of clients who do not need the services. The summary tables describe multiple screening steps, which refer to the following: 1) the process of asking questions about a client's history, including a determination of whether risk factors for a disease or health condition exist; 2) performing a physical exam; and 3) performing laboratory tests in at-risk asymptomatic persons to help detect the presence of a specific disease, infection, or condition. Many screening recommendations apply only to certain subpopulations (e.g., specific age groups, persons who engage in specific risk behaviors or who have specific health conditions), or some screening recommendations apply to a particular frequency (e.g., a cervical cancer screening is generally recommended every 3 years rather than annually). Providers should be aware that the USPSTF also has recommended that certain screening services not be provided because the harm outweighs the benefit (see Appendix F). When screening results indicate the potential or actual presence of a health condition, the provider should either provide or refer the client for the appropriate further diagnostic testing or treatment in a manner that is consistent with the relevant federal or professional medical associations' clinical recommendations. # Conducting Quality Improvement Service sites that offer family planning services should have a system for conducting quality improvement, which is designed to review and strengthen the quality of services on an ongoing basis. Quality improvement is the use of a deliberate and continuous effort to achieve measurable improvements in the identified indicators of quality of care, which improve the health of the community (142). By improving the quality of care, family planning outcomes, such as reduced rates of unintended pregnancy, improved patient experiences, and reduced costs, are more likely to be achieved (10,12,143,144). Several frameworks for conducting quality improvement have been developed (144)(145)(146). This section presents a general overview of three key steps that providers should take when conducting quality improvement of family planning services: 1) determine which measures are needed to monitor quality; 2) collect the information needed; and 3) use the findings to make changes to improve quality (147). Ideally, these steps will be conducted on a frequent (optimally, quarterly) and ongoing basis. However, since quality cuts across all aspects of a program, not all domains of quality can necessarily be considered at all times. Within a sustainable system of quality improvement, programs can opt to focus on a subset of quality dimensions and their respective measures. # Determining Which Measures Are Needed Performance measures provide information about how well the service site is meeting pre-established goals (148). The following questions should be considered when selecting performance measures ( 143): • Is the topic important to measure and report? For example, does it address a priority aspect of health care, and is there opportunity for improvement? • What is the level of evidence for the measure (e.g., that a change in the measure is likely to represent a true change in health outcomes)? Does the measure produce consistent (reliable) and credible (valid) results about the quality of care? • Are the results meaningful and understandable and useful for informing quality improvement? • Is the measure feasible? Can it be implemented without undue burden (e.g., captured with electronic data or electronic health records)? Performance measures should consider the quality of the structure of services (e.g., the characteristics of the settings in which providers deliver health care, including material resources, human resources, and organizational structure), the process by which care is provided (whether services are provided correctly and completely, and how clients perceive the care they receive), and the outcomes of that care (e.g., client behaviors or health conditions that result) (149). They also may assess each dimension of quality services (10,13). Examples of measures that can be used for monitoring the quality of family planning services (150) and suggested measures that might help providers monitor quality of care have been listed (Table 6). However, other measures have been developed that also might be useful (151)(152)(153). Service sites that offer family planning services should select, measure, and assess at least one intermediate or outcome measure on an ongoing basis, for which the service site can be accountable. Structure-and process-based measures that assess the eight dimensions of quality services may be used to better determine how to improve quality (154). # Collecting Information Once providers have determined what information is needed, the next steps are to collect and use that information to improve the quality of care. Commonly used methods of data collection include the following: -4]). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § § Indicates that screening is suggested only for those persons at highest risk or for a specific subpopulation with high prevalence of an infection or condition. ¶ ¶ Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD treatment guidelines (Sources: CDC. STD Abbreviations: HBV = hepatitis B virus; HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome; HPV = human papillomavirus virus; STD = sexually transmitted disease. * No special evaluation needs to be done prior to making condoms available to males. However, when a male client requests advice on pregnancy prevention, he should be provided contraceptive services as described in the section "Provide Contraceptive Services. " † The services listed here represent a sub-set of recommended preconception health services for men that were recommended and for which there was a direct link to fertility or infant health outcomes (Source: Frey K, Navarro S, Kotelchuck M, Lu M. The clinical content of preconception care: preconception care for men. Am J Obstet Gynecol 2008;199[6 Suppl 2]:S389-95). § STD services also promote preconception health, but are listed separately here to highlight their importance in the context of all types of family planning visit. The services listed in this column are for men without symptoms suggestive of an STD. ¶ CDC recommendation. ** U.S. Preventive Services Task Force recommendation. † † Professional medical association recommendation. § § Indicates that screening is suggested only for those persons at highest risk or for a specific subpopulation with high prevalence of infection or other condition. provider's behavior might be influenced if she or he knows clients are being interviewed. • Facility audit. Questions about a service site's structure (e.g., on-site availability of a broad range of FDA-approved methods) and processes (e.g., skills and technical competence of staff, referral mechanisms) can be used to determine the readiness of the facility to serve clients. • Direct observation. A provider's behavior is observed during an actual encounter with a client. Evaluation of a full range of competencies, including communication skills, can be carried out. A main limitation is that the observer's presence might influence the provider's performance. • Interview with the health-care provider. Providers are interviewed about how specific conditions are managed. Both closed-and open-ended questions can be used, although it is important to frame the question so that the 'correct' answer is not suggested. A limitation is that providers tend to over-report their performance. # Consideration and Use of the Findings After data are collected, they should be tabulated, analyzed, and used to improve care. Staff whose performance was assessed should be involved in the development of the data collection tools and analysis of results. Analysis should address the following questions (155): • What is the performance level of the facility? • Is there a consistent pattern of performance among providers? • What is the trend in performance? • What are the causes of poor performance? • How can performance gaps be minimized? Given the findings, service site staff should use a systematic approach to identifying ways to improve the quality of care. One example of a systematic approach to improving the quality of care is the "Plan, Do, Study, and Act" (PDSA) model (147,156), in which staff first develop a plan for improving quality, then execute the plan on a small scale, evaluate feedback to confirm or adjust the plan, and finally, make the plan permanent. Examples of steps that may be taken to improve the quality of care include developing job aids, providing task-specific training for providers, conducting more patient education, or strengthening relationships with referral sites through formal memoranda of understanding (146). # Conclusion The United States continues to face substantial challenges to improving the reproductive health of the U.S. population. The recommendations in this report can contribute to improved reproductive health by defining a core set of family planning services for women and men, describing how to provide contraceptive and other family planning services to both adult and adolescent clients, and encouraging the use of the family planning visit to provide selected preventive health services for women and men. This guidance is intended to assist primary care providers to offer the family planning services that will help persons and couples achieve their desired number and spacing of children and increase the likelihood that those children are born healthy. Recommendations are updated periodically. The most recent versions are available at http://www.hhs.gov/opa. The recommendations were developed jointly under the auspices of CDC's Division of Reproductive Health (DRH) and the Office of Population Affairs (OPA), in consultation with a wide range of experts and key stakeholders. A multistage process that drew on established procedures for developing clinical guidelines (1,2) was used to develop the recommendations. In April 2010, an Expert Work Group (EWG) comprising family planning clinical providers, program administrators, representatives from relevant federal agencies, and representatives from professional medical organizations was created to advise OPA and CDC on the structure and content of the revised recommendations and to help make the recommendations more feasible and relevant to the needs of the field. This group made two key initial recommendations: 1) to examine the scientific evidence for three priority areas of focus identified as key components of family planning service delivery, (i.e., counseling and education, serving adolescents, and quality improvement); and 2) to guide providers of family planning services in the use of various recommendations for how to provide clinical care to women and men. # Developing Recommendations on Counseling, Adolescent Services, and Quality Improvement Systematic reviews of the published literature from January 1985 through December 2010 were conducted for each priority topic to identify evidence-based and evidence-informed approaches to family planning service delivery. Standard methods for conducting the reviews were used, including the development of key questions and analytic frameworks, the identification of the evidence base through a search of the published as well as "gray literature" (i.e., studies published somewhere other than in a peer-reviewed journal), and a synthesis of the evidence in which findings were summarized and the quality of individual studies was considered, using the methodology of the U.S. Preventive Services Task Force (USPSTF) (3). Eight databases were searched (i.e., MEDLINE, PsychInfo, PubMed, CINAHL, Cochrane, EMBASE, POPLINE, and the U.K. National Clearinghouse Service Economic Evaluation Database) and were restricted to literature from the United States and other developed countries. Summaries of the evidence used to prepare these recommendations will appear in background papers that will be published separately. In May 2011, three technical panels (one for each priority topic) comprising subject matter experts were convened to consider the quality of the evidence and suggest what recommendations might be justified on the basis of the evidence. CDC and OPA used this feedback to develop core recommendations for counseling, serving adolescents, and quality improvement. EWG members subsequently reviewed these core recommendations; EWG members differed from the subject matter experts in that they were more familiar with the family planning service delivery context and could comment on the feasibility and appropriateness of the recommendations as well as on their scientific justification. EWG members met to consider the core recommendations using 1) the quality of the evidence; 2) the positive and negative consequences of implementing the recommendations on health outcomes, costs or cost-savings, and implementation challenges; and 3) the relative importance of these consequences (e.g., the ability of the recommendations to have a substantial effect on health outcomes may be weighed more than the logistical challenges of implementing them) (1). In certain cases, when the evidence was inconclusive or incomplete, recommendations were made on the basis of expert opinion (see Appendix B). Finally, CDC and OPA staff considered the feedback from EWG members when finalizing the core recommendations and writing this report. # Developing Recommendations on Clinical Services DRH and OPA staff members synthesized recommendations for clinical care for women and for men that were developed by >35 federal and professional medical organizations. They were assisted in this effort by staff from OPA's Office of Family Planning Male Training Center and from CDC's Division of STD Prevention, Division of Violence Prevention, Division of Immunization Services, and Division of Cancer Prevention and Control. The synthesis was needed because clinical recommendations are sometimes inconsistent with each other and can vary by the extent to which they are evidence-based. The clinical recommendations addressed contraceptive services, achieving pregnancy, basic infertility services, preconception health services, sexually transmitted disease services, and related health-care services. An attempt was made to apply the Institute of Medicine's criteria for clinical practice guidelines when deciding which professional medical organizations to include in the review (2). However, many organizations did not articulate the process used to develop the recommendations fully, and many did not conduct comprehensive and systematic reviews of the literature. In the end, to be included in the synthesis, the recommending organization had to be a federal agency or major professional medical organization that represents established medical disciplines. In addition, a recommendation had to be made on the basis of an independent review of the evidence or expert opinion and be considered a primary source that was developed for the United States. In July 2011, two technical panels comprising subject matter experts on clinical services for women and men were convened to review the synthesis of federal and professional medical recommendations, reconcile inconsistent recommendations, and provide individual feedback to CDC and OPA about the implications for family planning service delivery. CDC and OPA used this individual feedback to develop core recommendations for clinical services. The core recommendations were subsequently reviewed by EWG members, and feedback was used to finalize the core recommendations and write this report. Members of the technical panels recommended that contraceptive services, pregnancy testing and counseling, services to achieve pregnancy, basic infertility care, STD services, and other preconception health services should be considered family planning services. This feedback considered federal statute and regulation, CDC and USPSTF recommendations for clinical care, and EWG members' opinion. Because CDC's preconception health recommendations include many services, the panel narrowed the range of preconception services that were included by using the following criteria: 1) the Select Panel on Preconception Care (4) had assigned an A or B recommendation to that service for women, which means that there was either good or fair evidence to support the recommendation that the condition be considered in a preconception care evaluation (Table 1), or 2) the service was included among recommendations made by experts in preconception health for males (5). Services for men that addressed health conditions that affect reproductive capacity or pregnancy outcomes directly were included as preconception health; services that addressed men's health but that were not related directly to pregnancy outcomes were considered to be related preventive health services. The Expert Work Group noted that more preventive services are recommended than can be offered feasibly in some settings. However, a primary purpose of this report is to set a broad framework within which individual clinics will tailor services to meet the specific needs of the populations that they serve. In addition, EWG members identified specific subgroups that should have the greatest priority for preconception health services (i.e., those trying to achieve pregnancy and those at high risk of unintended pregnancy). Future operational research should provide more information about how to deliver these services most efficiently during multiple visits to clients with diverse needs. # Determining How Clinical Services Should Be Provided Various federal agencies and professional medical associations have made recommendations for how to provide family planning services. When considering these recommendations, the Expert Work Group used the following hierarchy: • Highest priority was given to CDC guidelines because they are developed after a rigorous review of scientific evidence. CDC guidelines tailor recommendations for higher risk individuals, (whereas USPSTF focuses on average risk individuals), who are more representative of the clients seeking family planning services. • When no CDC guideline existed to guide the recommendations, the relevant USPSTF A or B recommendations (which indicate a high or moderate certainty that the benefit is moderate to substantial) were used. USPSTF recommendations are made on the basis of a thorough review of the available evidence. • If neither a CDC nor a USPSTF A or B recommendation existed, the recommendations of selected major professional medical associations were considered as resources. The American Academy of Pediatrics' (AAP) Bright Futures guidelines (6) were used as the primary source of recommendations for adolescents when no CDC or USPSTF recommendations existed. • For a limited number of recommendations, there were no federal or major professional medical recommendations, but the service was recommended by EWG members on the basis of expert opinion for family planning clients. In some cases, a service was graded as an I recommendation by USPSTF for the general population (an I recommendation means that the current evidence is insufficient to assess the balance of benefits and harms of the service, so if the service is offered, patients should be informed of this fact), but either CDC, EWG members, or another organization recommended the service for women or men seeking family planning services. The situations in which this occurred and the reasons why the service was recommended despite its receiving an I recommendation by USPSTF have been summarized (Table 2). The approach used to consider the evidence and make recommendations that are used by USPSTF have been summarized (Tables 3 and 4) (7). # TABLE 1. Select Panel on Preconception Care grading system Quality of the evidence* I-a Evidence was obtained from at least one properly conducted, randomized, controlled trial that was performed with subjects who were not pregnant. # I-b Evidence was obtained from at least one properly conducted, randomized, controlled trial that was done not necessarily before pregnancy. II-1 Evidence was obtained from well-designed, controlled trials without randomization. II-2 Evidence was obtained from well-designed cohort or case-control analytic studies, preferably conducted by more than one center or research group. II-3 Evidence was obtained from multiple-time series with or without the intervention, or dramatic results in uncontrolled experiments. III Opinions were gathered from respected authorities on the basis of clinical experience, descriptive studies and case reports, or reports of expert committees. # Strength of the recommendation A There is good evidence to support the recommendation that the condition be considered specifically in a preconception care evaluation. B There is fair evidence to support the recommendation that the condition be considered specifically in a preconception care evaluation. C There is insufficient evidence to recommend for or against the inclusion of the condition in a preconception care evaluation, but recommendation to include or exclude may be made on other grounds. D There is fair evidence to support the recommendation that the condition be excluded in a preconception care evaluation. E There is good evidence to support the recommendation that the condition be excluded in a preconception care evaluation. This service should be offered or provided. B USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. This service should be offered or provided. # C Clinicians may provide this service to selected patients depending on individual circumstances. However, for a majority of persons without signs or symptoms there is likely to be only a limited benefit from this service. This service should be offered or provided only if other considerations support the offering or providing the service in an individual patient. D USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Use of this service should be discouraged. I Statement USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. The clinical considerations section of USPSTF recommendation statement should be consulted. If the service is offered, patients should be educated about the uncertainty of the balance of benefits and harms. Source: US Preventive Services Task Force. USPSTF: methods and processes. Available at http://www.uspreventiveservicestaskforce.org/methods.htm. # TABLE 4. Levels of certainty regarding net benefit # Level of certainty* Description # High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. # Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as • the number, size, or quality of individual studies; • inconsistency of findings across individual studies; • limited generalizability of findings to routine primary care practice; and • lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. # Low The available evidence is insufficient to assess effects on health outcomes is insufficient because of • the limited number or size of studies, • important flaws in study design or methods, • inconsistency of findings across individual studies, • gaps in the chain of evidence, • findings not generalizable to routine primary care practice, • lack of information on important health outcomes, or • more information required to allow estimation of effects on health outcomes. Source: US Preventive Services Task Force. USPSTF: methods and processes. Available at http://www.uspreventiveservicestaskforce.org/methods.htm. * The US Preventive Services Task Force (USPSTF) defines certainty as the likelihood that the USPSTF assessment of the net benefit of a preventive service is correct. The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. USPSTF assigns a certainty level on the basis of the nature of the overall evidence available to assess the net benefit of a preventive service. Sixteen core recommendations that were considered by the Expert Work Group (EWG) are presented below. Each recommendation is accompanied by a summary of the relevant evidence (full summaries of which will be published separately), a list of potential consequences of implementing the recommendation, and its rationale. When considering the recommendations, the Expert Work Group was divided into two groups (one comprising seven members and the other five members), and each group considered separate recommendations. # Definition of Family Planning Services Recommendation: Primary care providers should offer the following family planning services: contraceptive services for women and men who want to prevent pregnancy and space births, pregnancy testing and counseling, help for clients who wish to achieve pregnancy, basic infertility services, sexually transmitted disease (STD) services and preconception health services to improve the health of women, men, and infants. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of federal statute and regulation (1,2), CDC clinical recommendations (3)(4)(5), and expert opinion. Potential consequences: Adding preconception health services means that more women and men will receive preconception health services. The recommended services also will promote the health of women and men even if they do not have children. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered in some settings. Rationale: Services to prevent and achieve pregnancy are core to the federal government's efforts to promote reproductive health. Adding preconception health as a family planning service is consistent with this mission; it emphasizes achieving a healthy pregnancy and also promotes adult health. Adding preconception health is also consistent with CDC recommendations to integrate preconception health services into primary care platforms (3). All seven EWG members agreed to this recommendation. # Preconception Health -Women Recommendation: Preconception health services for women include the following screening services: reproductive # Appendix B The Evidence, Potential Consequences, and Rationales for Core Recommendations life plan; medical history; sexual health assessment; intimate partner violence, alcohol, and other drug use; tobacco use; immunizations; depression; body mass index (BMI); blood pressure; chlamydia, gonorrhea, syphilis, and HIV/AIDS; and diabetes. All female clients also should be counseled about the need to take a daily supplement of folic acid. When screening results indicate the presence of a health condition, the provider should take steps either to provide or to refer the client for the appropriate further diagnostic testing and or treatment. Services should be provided in a manner that is consistent with established federal and professional medical associations' recommendations to enable clients who need services to receive them and to avoid over-screening. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of CDC's recommendations to improve preconception health and health care (3) and a review of preconception health services by an expert panel on preconception care for women (6). Potential consequences: More women will receive specified preconception health services, which will improve the health of infants and women. The evidence base for preconception health is not fully established. There is a potential risk that a client with a positive screen will not be able to afford treatment if the client is uninsured and not eligible for public programs. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered. Rationale: The potential benefits to the health of women and infants were thought by the panel to be greater than the costs, potential harms, and opportunity costs of providing these services. Implementation (e.g., training and monitoring of providers) can address the issues related to providers over-screening and not following the federal and professional medical recommendations. CDC will continue to monitor related research and modify these recommendations, as needed. Health-care reform might make follow-up care more available to low-income clients. All seven EWG members agreed to this recommendation. # Preconception Health -Men Recommendation: Preconception health services for men include the following screening services: reproductive life plan; medical history; sexual health assessment; alcohol and other drug use; tobacco use; immunizations; depression; BMI; blood pressure; chlamydia, gonorrhea, syphilis, and HIV/AIDS; and diabetes. When screening results indicate the presence of a health condition, the provider should take steps either to provide or to refer the client for the appropriate further diagnostic testing and or treatment. Services should be provided in a manner that is consistent with established federal and professional medical associations' recommendations to ensure that clients who need services receive them and to avoid over-screening. Quality of evidence: A systematic review was not conducted; the recommendation was made on the basis of CDC's recommendations to improve preconception health and health care (3) and a review of preconception health services for men (7). Potential consequences: More men will receive preconception health services, which might improve infant and men's health. The evidence base for preconception health is not well established and is less than that for women's preconception health. There is a risk of over-screening if recommendations are not followed. There is a potential risk that a client with a positive screen might not be able to afford treatment if the client is uninsured and not eligible for public programs. The human and financial cost of providing preconception health services might mean that fewer contraceptive and other services can be offered. Rationale: The potential benefits to men and infant health were thought by the panel to be greater than the costs, potential harms, and opportunity costs of not providing these services. Implementation (e.g., training and monitoring of providers) can address the issues related to providers over-screening and not following the federal and professional medical recommendations. CDC will continue to monitor related research and modify these recommendations, as needed. Health-care reform might make follow-up care more available to low-income clients. All seven EWG members agreed to this recommendation. # Contraceptive Services -Contraceptive Counseling Steps Recommendation: To help a client who is initiating or switching to a new method of contraception, providers should follow these steps, which are in accordance with the key principles for providing quality counseling: 1) establish and maintain rapport with the client; 2) obtain clinical and social information from the client; 3) work with the client interactively to select the most effective and appropriate contraceptive method for her or him; 4) provide a physical assessment related to contraceptive use, when warranted; and 5) provide the contraceptive method along with instructions about correct and consistent use, help the client develop a plan for using the selected method and for follow-up, and confirm understanding. Quality of evidence: Twenty-two studies were identified that examined the impact of contraceptive counseling in clinical settings and met the inclusion criteria. Of the 16 studies that focused on adults or mixed populations (adolescents and adults) (8-23), 11 found a statistically significant positive impact of counseling interventions with low (11,12,(14)(15)(16)(18)(19)(20)(21), moderate (8), or unrated ( 22) intensity on at least one outcome of interest; study designs included two cross-sectional surveys (14,22), one pre-post study (21), one prospective cohort study (8), one controlled trial (15), and six randomized controlled trials (RCTs) (11,12,16,(18)(19)(20). Six studies examined the impact of contraceptive counseling among adolescents (24)(25)(26)(27)(28)(29), with four finding a statistically significant positive impact of low-intensity (27) or moderateintensity (24,25,29) counseling interventions on at least one outcome of interest; study designs included two pre-post studies (24,30), one controlled trial (29), and one RCT (27). In addition, five studies were identified that examined the impact of reminder system interventions in clinical settings on family planning outcomes and met the inclusion criteria (31)(32)(33)(34)(35); of these, two found a statistically significant positive impact of reminder systems on perfect oral contraceptive compliance, a retrospective historical nonrandomized controlled trial that examined daily reminder email messages (31) and a cohort study that examined use of a small reminder device that emitted a daily audible beep (34). In addition, two studies examined the impact of reminder systems among depot medroxyprogesterone acetate users (DMPA) (33,35) with one, a retrospective cohort study, finding a statistically significant positive impact of receiving a wallet-sized reminder card with the date of the next DMPA injection and a reminder postcard shortly before the next injection appointment on timely DMPA injections. Statements about safety and unnecessary medical examinations and tests are made on the basis of CDC guidelines on contraceptive use (36,37). Potential consequences: Fewer clients will use methods that are not safe for them, there will be increased contraceptive use, increased use of more effective methods, increased continuation of method use, increased use of dual methods, increased knowledge, increased satisfaction with services, and increased use of repeat or follow-up services. Rationale: Making sure that a contraceptive method is safe for an individual client is a fundamental responsibility of all providers of family planning services. Removing medical barriers to contraceptive use is key to increasing access to contraception and helping clients prevent unintended pregnancy. Consistent use of contraceptives is needed to prevent unintended pregnancies, so appropriate counseling is critical to ensure clients make the best possible choice of methods for their unique circumstances, and are supported in continued use of the chosen method. The principles of quality counseling, from which the steps listed in the recommendations are based, are supported by a substantial body of evidence and expert opinion. Future research to evaluate the five principles will be monitored and the recommendations modified, as needed. All seven EWG members agreed to this recommendation. # Contraceptive Services -Tiered Approach to Counseling Recommendation: For clients who might want to get pregnant in the future and prefer reversible methods of contraception, providers should use a tiered approach to presenting a broad range of contraceptive methods (including long-acting reversible contraception such as intrauterine devices and contraceptive implants), in which the most effective methods are presented before less effective methods. Quality of evidence: National surveys have demonstrated low rates of LARC use overall (38,39). However, Project CHOICE has demonstrated high uptake of long-acting reversible contraception (approximately two thirds of clients when financial barriers are removed) and a very substantial reduction in rates of unintended pregnancy (40). Further, a recent study of postpartum contraceptive use shows that 50% of teen mothers with a recent live birth are using long-acting reversible contraception postpartum in Colorado, which demonstrates high levels of acceptance in the context of a statewide program to remove financial barriers (41). Potential consequences: Use of long-acting reversible contraception has the potential to help many more persons prevent unintended pregnancy because of its ease of use, safety, and effectiveness. Several questions were raised about ethical issues in using a tiered approach to counseling. First, is it ethical to educate about long-acting reversible contraception when the methods are not all available on-site? Second, conversely, is it ethical not to inform clients about the most effective methods? In other health service areas, the standard of care is to inform the client about the most effective treatment (e.g., blood pressure medications), so the client can make a fully informed decision, and this standard should apply in this instance as well. On the basis of historic experiences, there is a need to ensure that methods always are offered on a completely voluntary and noncoercive basis. Health-care reform might make contraceptive services more available to the majority of clients. Rationale: Providers have an obligation to inform clients about the most effective methods available, even if they cannot provide them. Further, health-care reform will reduce the financial barriers to long-acting reversible contraception for many persons. The potential increase in use of long-acting reversible contraception and other more effective methods is likely to help reduce rates of unintended pregnancy. All seven EWG members agreed to this recommendation. # Contraceptive Services -Broad Range of Methods Recommendation: A broad range of methods should be available on-site or through referral. Quality of evidence: Three descriptive studies from the review of quality improvement literature identified contraceptive choice as an important aspect of quality care (42)(43)(44). Potential consequences: Clients will be more likely to select a method that they will use consistently and correctly. Rationale: A central tenet of quality health care is that it be client-centered. Being able to provide a client with a method that best fits her or his unique circumstances is essential for that reason. All seven EWG members agreed to this recommendation. # Contraceptive Services -Education Recommendation: The content, format, method, and medium for delivering education should be evidence-based. Quality of evidence: Seventeen studies were identified that met the inclusion criteria for this systematic review. Of these, 15 studies looked at knowledge of correct method use or contraceptive risks and benefits, including side effects and method effectiveness (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). All but one study (56) found a statistically significant positive impact of educational interventions on increased knowledge. These studies included six randomized controlled trials with low risk for bias. Potential consequences: Clients will make more informed decisions when choosing a contraceptive method. More clients will be satisfied with the process of selecting a contraceptive method. Rationale: Knowledge obtained through educational activities, as integrated into the larger counseling model, is a critically important precondition for the client's ability to make informed decisions. The techniques described in the recommendations have a well-established evidence base for increasing knowledge and satisfaction with services. This knowledge lays the foundation for further counseling steps that will increase the likelihood of correct and consistent use, and increased satisfaction will increase return visits to the service site, as needed. Four of seven EWG members agreed to this recommendation; three members did not express an opinion. # Contraceptive Services -Confirm Understanding Recommendation: A check box or written statement should be available in the medical record that can be used to document that the client expressed understanding of the most important information about her/his chosen contraceptive method. The teach-back method may be used to get clients to express the most important points by repeating back messages about risks and benefits and appropriate method use and follow-up. Documentation of understanding using the teach-back method and a check box or written statement can be used in place of a written method-specific informed consent. Quality of evidence: Two studies from outside the family planning literature (one cohort study and one controlled trial with unclear randomization) (60,61) and a strong recommendation by members of the Technical Panel on Counseling and Education were considered. Potential consequences: More clients will make informed decisions, adherence to contraceptive and treatment plans will improve, and reproductive and other health conditions will be better controlled. Rationale: Asking providers to document in the record that the client is making an informed decision will increase providers' attention to this task. This recommendation will replace a previous requirement that providers obtain methodspecific informed consent from each client (in addition to a general consent form). Six of seven EWG members agreed to this recommendation. # Adolescent Services -Comprehensive Information Recommendation: Providers should provide comprehensive information to adolescent clients about how to prevent pregnancy and STDs. This should include information about contraception and that avoiding sex (abstinence) is an effective way to prevent pregnancy and STDs. Quality of evidence: A systematic review was not conducted because other recent reviews were available that have shown a substantial impact of comprehensive sexual health education on reduced adolescent risk behavior (62)(63)(64)(65)(66). The evidence for abstinence-only education was more limited: CDC's Community Guide concluded that there was insufficient evidence (67), but the Department of Health and Human Services' Office of Adolescent Health has identified two abstinence-based programs as having evidence of effectiveness (68). Potential consequences: Teens will make more informed decisions and will delay initiation of sexual intercourse. The absence of harmful effects from comprehensive sexual health education was noted. Rationale: The benefits of informing adolescents about all ways to prevent pregnancy are substantial. Ultimately, each adolescent should make an informed decision that meets her or his unique circumstances, based on the counseling provided by the provider. Six of seven EWG members agreed to this recommendation. # Adolescent Services -Use of Long-Acting Reversible Contraception Recommendation: Education about contraceptive methods should include an explanation that long-acting reversible contraception is safe and effective for nulliparous women (women who have not been pregnant or given birth), including adolescents. Quality of evidence: CDC guidelines on contraceptive use (37) provide evidence that long-acting reversible contraception is safe and effective for adolescents and nulliparous women. Potential consequences: More providers will encourage adolescents to consider long-acting reversible contraception; more adolescents will choose long-acting reversible contraception, resulting in reduced rates of teen pregnancy, including rapid repeat pregnancy. Rationale: Long-acting reversible contraception is safe for adolescents (37). As noted above, providers should inform clients about the most effective methods available. The potential increase in use of long-acting reversible contraception and other more effective methods by adolescents is substantial and is likely to lead to further reductions in teen pregnancy. Three EWG members agreed to this recommendation; two EWG members abstained. # Adolescent Services -Confidential Services Recommendation: Confidential family planning services should be made available to adolescents, while observing state laws and any legal obligations for reporting. Quality of evidence: Six descriptive studies documented one or more of the following: that confidentiality is important to adolescents; that many adolescents reported they will not use reproductive health services if confidentiality cannot be assured; and that adolescents might not be honest in discussing reproductive health with providers if confidentiality cannot be assured (69)(70)(71)(72)(73)(74). One RCT showed a slight reduction in use of services after receiving conditional confidentiality, compared with complete confidentiality (75). One study showed a positive association between confidentiality and intention to use services (73). Potential consequences: Consequences might include an increased intention to use services, increased use of services, and reduced rates of teen pregnancy. However, explaining the need to report under certain circumstances (rape, child abuse) might deter some adolescent clients from using services. Further, some parents/guardians might not agree that adolescents should have access to confidential services. Rationale: Minors' rights to confidential reproductive health services are consistent with state and federal law. The risks of not providing confidential services to adolescents are great and likely to result in an increased rate of teen pregnancies. Finally, this recommendation is consistent with the recommendations of three professional medical associations that endorse provision of confidential services to adolescents (76)(77)(78). All seven EWG members agreed to this recommendation. # Adolescent Services -Family-Child Communication Recommendation: Providers should encourage and promote family-child communication about sexual and reproductive health. Quality of evidence: From the family planning literature, 16 parental involvement programs (most using an RCT study design) were found to be positively associated with at least one short-term (13 of 16 studies) or medium-term (four of seven studies) outcome (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94). However, only one of these studies was linked to clinical services (80); others were implemented in community settings. Potential consequences: Consequences might include increased parental/guardian involvement and communication, improved knowledge/awareness, increased intentions to use contraceptives, and the adoption of more pro-social norms that support parent-child communication about sexual health. Rationale: The literature provides strong evidence that increased communication between a child and her/his parent/ guardian will lead to safer sexual behavior among teens, and numerous community-based programs have created an evidence base for how to strengthen parents/guardians' ability to hold those conversations. Although less is known about how to do so in a clinical setting, providers can refer their clients to programs in the community, and principles from the community-based approaches can be used to help providers develop appropriate approaches in the clinical setting. Research in this area will be monitored, and the recommendations will be revised, as needed. Four of five EWG members who provided input agreed to this recommendation; one member abstained. # Adolescent Services -Repeat Teen Pregnancy Recommendation: Providers should refer pregnant and parenting adolescents to home visiting and other programs that have been shown to provide needed support and reduce rates of repeat teen pregnancy. Quality of evidence: Three of four studies of clinic-based programs (using retrospective case-control cohort, ecological evaluation, and prospective cohort study designs) showed that comprehensive teen pregnancy prevention programs (programs with clinical, school, case management, and community components) were associated with both medium-and longterm outcomes (95)(96)(97)(98). In addition, several randomized trials of community-based home visiting programs, and an existing systematic review of the home visiting literature, demonstrated a protective impact of these programs on preventing repeat teen pregnancy and other relevant outcomes (99)(100)(101)(102)(103). Potential consequences: Consequences might include decreased rapid repeat pregnancy and abortion rates, and increased use of contraceptives. Rationale: There is sufficient evidence to recommend that providers link pregnant and parenting teens to community and social services that might reduce rates of rapid repeat pregnancy. Three of seven EWG members agreed to an earlier version of this recommendation. Other members wanted to remove a clause about prioritizing the contraceptive needs of pregnant/ parenting teens because they felt that all clients should be treated as priority clients. This suggestion was adopted, but the EWG did not have a chance to vote again on the modified recommendation. # Contraceptive Method Availability Recommendation: Family planning programs should stock and offer a broad a range of FDA-approved contraceptive methods so that the needs of individual clients can be met. These methods are optimally available on-site, but strong referrals can serve to make methods not available on-site real options for clients. Quality of evidence: No research was identified that explicitly addressed the question of whether having a broad range of methods was associated with short-, medium-, or long-term reproductive health outcomes. However, as noted above, three descriptive studies from the review of quality improvement literature identified contraceptive choice as an important aspect of quality care (42)(43)(44). Potential consequences: Consequences might include increased use of contraception and increased use of reproductive health services. It also was noted that there are sometimes high costs to stocking certain methods (e.g., intrauterine devices and contraceptive implants). Rationale: Having a broad range of contraceptive methods is central to client-centered care, a core aspect of providing quality services. Individual clients need to have a choice so they can select a method that best fits their particular circumstances. This is likely to result in more correct and consistent use of the chosen methods. The benefits of this recommendation were weighed more heavily than the negative outcomes (e.g., additional cost). All five EWG members agreed to this recommendation. # Youth-Friendly Services Recommendation: Family planning programs should take steps to make services "youth-friendly." Quality of evidence: Of 20 studies that were identified, six looked at short-, medium-, or long-term outcomes with mixed designs (one group time series, one cross-sectional, three prospective cohort, and one nonrandomized trial); protective effects were found on long-term (two of three studies), medium-term (three of three), and short-term (three of three) outcomes (29,30,(104)(105)(106)(107). One of these six studies (29), plus 13 other descriptive studies (for a total of 14 studies), presented adolescents' or providers' views on facilitators for adolescent clients in using youth-friendly family planning services. Key factors described were confidentiality (13 of 14), accessibility (11 of 14), peer involvement (three of 14), parental or familial involvement (four of 14), and quality of provider interaction (11 of 14) (105-121). Four of these studies (111,112,114,121) plus one other descriptive study (108) described barriers to clinics adopting and implementing youth-friendly family planning services. Potential consequences: Consequences might include increased use of reproductive health services by adolescents, improved contraceptive use, use of more effective methods, more consistent use of contraception, and reduced rates of teen pregnancy. It is also likely to lead to improved satisfaction with services and greater knowledge about pregnancy prevention among adolescents. It is possible that there will be higher costs, and some uncertainty regarding the benefits due to a relatively weak evidence base. Rationale: Existing evidence has demonstrated the importance of specific characteristics to adolescents' attitudes and use of clinical services. The potential benefits of providing youth-friendly services outweigh the potential costs and weak evidence base. All five EWG members agreed to this recommendation. Some thought that it should be cast as an example of comprehensively client-centered care, rather than an end of its own. # Quality Improvement Recommendation: Family planning programs should have a system for quality improvement, which is designed to review and strengthen the quality of services on an ongoing basis. Family planning programs should select, measure, and assess at least one outcome measure on an ongoing basis, for which the service site can be accountable. Quality of evidence: A recent systematic review ( 122) was supplemented with 10 articles that provided information related to client and/or provider perspectives regarding what constitutes quality family planning services (42)(43)(44)113,(123)(124)(125)(126)(127)(128). These studies used a qualitative (k = 4) or cross-sectional (k = 6) study design. Ten descriptive studies identified client and provider perspectives on what constitutes quality family planning services, which include stigma and embarrassment reduction (n = 9), client access and convenience (n = 8); confidentiality (n = 3); efficiency and tailoring of services (n = 6); client autonomy and confidence (n = 5); contraceptive access and choice (n = 4); increased time of patient-provider interaction (n = 3); communication and relationship (n = 3); structure and facilities (n = 2); continuity of care (n = 2). Well-established frameworks for guiding quality improvement efforts were referenced (122,(129)(130)(131)(132). Potential consequences: Consequences might include increased use by clients of more effective contraceptive methods, clients might be more likely to return for care, client satisfaction might improve, and there might be reduced rates of teen and unintended pregnancy, and improved spacing of births. Rationale: Research, albeit limited, has demonstrated that quality services are associated with improved client experience with care and adoption of more protective contraceptive behavior. Further, these recommendations on quality improvement are consistent with those made by national leaders in the quality improvement field. Research is either under way or planned to validate a core set of performance measures, and the recommendations will be updated as new findings emerge. All five EWG members agreed to these recommendations. Counseling is a process that enables clients to make and follow through on decisions. Education is an integral component of the counseling process that helps clients to make informed decisions. Providing quality counseling is an essential component of client-centered care. Key principles of providing quality counseling are listed below and may be used when providing family planning services. The model was developed in consultation with the Technical Panel on Contraceptive Counseling and Education and reviewed by the Expert Work Group. Although developed specifically for providing contraceptive counseling, the principles are broad and can be applied to health counseling on other topics. Although the principles are listed here in a particular sequence, counseling is an iterative process, and at every point in the client encounter it is necessary to determine whether it is important to readdress and emphasize a given principle. # Principles of Quality Counseling Principle 1. Establish and Maintain Rapport with the Client Establishing and maintaining rapport with a client is vital to the encounter and achieving positive outcomes (1). This can begin by creating a welcoming environment and should continue through every stage of the client encounter, including follow-up. The contraceptive counseling literature indicates that counseling models that emphasized the quality of the interaction between client and provider have been associated with decreased teen pregnancy, increased contraceptive use, increased use of more effective methods, increased use of repeat or follow-up services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (2)(3)(4)(5) . # Principle 2. Assess the Client's Needs and Personalize Discussions Accordingly Each visit should be tailored to the client's individual circumstances and needs. Clients come to family planning providers for various services and with varying needs. Standardized questions and assessment tools can help providers determine what services are most appropriate for a given visit (6). Contraceptive counseling studies that have incorporated standardized assessment tools during the counseling process have resulted in increased contraceptive use, increased correct # Appendix C Principles for Providing Quality Counseling use of contraceptives, and increased use of more effective methods (2,7,8). Contraceptive counseling studies that have personalized discussions to meet the individual needs of clients have been associated with increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, increased use of dual-method contraceptives to prevent both sexually transmitted diseases (STDs) and pregnancy, increased quality and satisfaction with services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (4,7,(9)(10)(11)(12). # Principle 3. Work with the Client Interactively to Establish a Plan Working with a client interactively to establish a plan, including a plan for follow-up, is important. Establishing a plan should include setting goals, discussing possible difficulties with achieving goals, and developing action plans to deal with potential difficulties. The amount of time spent establishing a plan will differ depending on the client's purpose for the visit and health-care needs. A client plan that requires behavioral change should be made on the basis of the client's own goals, interests, and readiness for change (13)(14)(15). Use of computerized decision aids before the appointment can facilitate this process by providing a structured yet interactive framework for clients to analyze their available options systematically and to consider the personal importance of perceived advantages and disadvantages (16,17). The contraceptive counseling literature indicates that counseling models that incorporated goal setting and development of action plans have been associated with increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, and increased knowledge (2,9,(18)(19)(20). Furthermore, contraceptive counseling models that incorporated follow-up contacts resulted in decreased teen pregnancy, increased contraceptive use, increased correct use of contraceptives, increased use of more effective methods, increased continuation of method use, increased use of dual-method contraceptives to prevent both STDs and pregnancy, increased use of repeat or follow-up services, increased knowledge, and enhanced psychosocial determinants of contraceptive use (2,3,7,11,21,22) . From the family planning education literature, computerized decision aids have helped clients formulate questions and have been associated with increased knowledge, selection of more effective methods, and increased continuation and compliance (23)(24)(25). # Principle 4. Provide Information That Can Be Understood and Retained by the Client Clients need information that is medically accurate, balanced, and nonjudgmental to make informed decisions and follow through on developed plans. When speaking with clients or providing educational materials through any medium (e.g., written, audio/visual, or computer/web-based), the provider must present information in a manner that can be readily understood and retained by the client. Strategies for making information accessible to clients are provided (see Appendix D). # Principle 5. Confirm Client Understanding It is important to ensure that clients have processed the information provided and discussed. One technique for confirming understanding is to have the client restate the most important messages in her or his own words. This teach-back method can increase the likelihood of the client and provider reaching a shared understanding, and has improved compliance with treatment plans and health outcomes (26,27). Using the teach-back method early in the decision-making process will help ensure that a client has the opportunity to understand her or his options and is making informed choices (28). The client should receive and understand the information she or he needs to make informed decisions and follow treatment plans. This requires careful attention to how information is communicated. The following strategies can make information more readily comprehensible to clients: # Strategies for Providing Information to Clients Educational materials should be provided that are clear and easy to understand. Educational materials delivered through any one of a variety of media (for example, written, audio/ visual, computer/web-based) need to be presented in a format that is clear and easy to interpret by clients with a 4th to 6th grade reading level (1)(2)(3). Many adults have only a basic ability to obtain, process, and understand health information necessary to make decisions about their health (4). Making easy-to-access materials enhances informed decision-making (1)(2)(3). Test all educational materials with the intended audiences for clarity and comprehension before wide-scale use. The following evidence-based tools provide recommendations for increasing the accessibility of materials through careful consideration of content, organization, formatting, and writing style: • Prevention and Health Promotion (available at http:// www.health.gov/healthliteracyonline). Information should be delivered in a manner that is culturally and linguistically appropriate. In presenting information it is important to be sensitive to the client's cultural and linguistic preferences (5,6). Ideally information should be presented in the client's primary language, but translations and interpretation services should be available when necessary. Information presented must also be culturally appropriate, reflecting the client's beliefs, ethnic background, and cultural practices. Tools for addressing cultural and linguistic differences and preferences include • Health Literacy Universal Precautions Toolkit, provided by the Agency for Healthcare Research and Quality (available at http://www.ahrq.gov/qual/literacy), and # Appendix E Strategies for Providing Information to Clients • Toolkit for Making Written Material Clear and Effective, Part 11; Understanding and using the "Toolkit Guidelines for Culturally Appropriate Translation," provided by the Centers for Medicare and Medicaid Services (available at http://www.cms.gov/outreach-and-education/outreach/ writtenmaterialstoolkit/downloads/toolkitpart11.pdf ). The amount of information presented should be limited and emphasize essential points. Providers should focus on needs and knowledge gaps identified during the assessment. Many clients immediately forget or remember incorrectly much of the information provided. This problem is exacerbated as more information is presented (7)(8)(9). Limiting the amount of information presented and highlighting important facts by presenting them first improves comprehension (10)(11)(12)(13)(14). Numeric quantities should be communicated in a way that is easily understood. Whenever possible, providers should use natural frequencies and common denominators (for example, 85 of 100 sexually active women are likely to get pregnant within 1 year using no contraceptive, as compared with 1 in 100 using an IUD or implant), and display quantities in graphs and visuals. Providers also should avoid using verbal descriptors without numeric quantities (for example, sexually active women using an IUD or implant almost never become pregnant). Finally, they should quantify risk in absolute rather than relative terms (for example, "the chance of unintended pregnancy is reduced from 8 in 100 to 1 in 100 by switching from oral contraceptives to an IUD" versus the chance of unintended pregnancy is reduced by 87%). Numeracy is more highly correlated with health outcomes than the ability to read or listen effectively (15). The strategies listed above can help clients interpret numeric quantities correctly (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Balanced information on risks and benefits should be presented and messages framed positively. In addition to discussing risks, contraindications, and warnings, providers should discuss the advantages and benefits of contraception. In presenting this information, providers should express risks and benefits in a common format (for example, do not present risks in relative terms and benefits in absolute terms), and frame messages in positive terms (for example "99 out of 100 women find this a safe method with no side effects," versus "1 out of 100 women experience noticeable side effects"). Many clients prefer to receive a balance of information on risks and benefits (29), and using a common format avoids bias in presentation of information (18,22,26,30). Framing messages positively increases acceptance and comprehension (18,22,31,32). Active client engagement should be encouraged. Providers should use educational materials that encourage active information processing (e.g., questions, quizzes, fill-in-theblank, web-based games, and activities). In addition, they should be sure the client has an opportunity to discuss the information provided, and when speaking with a client, providers should engage her or him actively. Research has indicated that interactive materials improve knowledge of contraceptive risks, benefits, and correct method use (33)(34)(35). Clients also value spoken information (29,36); and educational materials, when delivered by a provider, more effectively increase knowledge (10,37). In particular, presenting information in a question and answer format is more effective than simply presenting the information (10,15,(37)(38)(39)(40)(41). # * Among typical couples who initiate use of a method (not necessarily for the first time), the percentage of couples who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Estimates of the probability of pregnancy during the first year of typical use for spermicides and the diaphragm are taken from the 1995 National Survey of Family Growth corrected for underreporting of abortion; estimates for fertility awareness-based methods, withdrawal, the male condom, the pill, and Depo-Provera are taken from the 1995 and 2002 National Survey of Family Growth corrected for underreporting of abortion. See the text for the derivation of estimates for the other methods. † Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage of couples who experience an accidental pregnancy during the first year if they do not stop use for any other reason. See the text for the derivation of the estimate for each method. § Among couples attempting to avoid pregnancy, the percentage of couples who continue to use a method for 1 year. ¶ The percentages becoming pregnant in columns labeled "typical use" and "perfect use" are based on data from populations in which contraception is not used and from women who cease using contraception to become pregnant. Among such populations, approximately 89% become pregnant within 1 year. This estimate was lowered slightly (to 85%) to represent the percentage of women who would become pregnant within 1 year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. † † The Ovulation and 2-day methods are based on evaluation of cervical mucus. The Standard Days method avoids intercourse on cycle days 8 through 19. The Symptothermal method is a double-check method based on evaluation of cervical mucus to determine the first fertile day and evaluation of cervical mucus and temperature to determine the last fertile day. § § Without spermicides. ¶ ¶ With spermicidal cream or jelly. * Ella, Plan B One-Step, and Next Choice are the only dedicated products specifically marketed for emergency contraception. The label for Plan B One-Step (1 dose is 1 white pill) says to take the pill within 72 hours after unprotected intercourse. Research has indicated that all of the brands listed here are effective when used within 120 hours after unprotected intercourse. The label for Next Choice (1 dose is 1 peach pill) says to take one pill within 72 hours after unprotected intercourse and another pill 12 hours later. Research has indicated that that both pills can be taken at the same time with no decrease in efficacy or increase in side effects and that they are effective when used within 120 hours after unprotected intercourse. The Food and Drug Administration has in addition declared the following 19 brands of oral contraceptives to be safe and effective for emergency contraception: Ogestrel (1 dose is 2 white pills), Nordette (1 dose is 4 light-orange pills), Cryselle, Levora, Low-Ogestrel, Lo/Ovral, or Quasence (1 dose is 4 white pills), Jolessa, Portia, Seasonale or Trivora (1 dose is 4 pink pills), Seasonique (1 dose is 4 light-blue-green pills), Enpresse (1 dose is 4 orange pills), Lessina (1 dose is 5 pink pills), Aviane or LoSeasonique (one dose is 5 orange pills), Lutera or Sronyx (1 dose is 5 white pills), and Lybrel (1 dose is 6 yellow pills). † † † However, for effective protection against pregnancy to be maintained, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches age 6 months. unintended pregnancy during the first year of use, and is estimated for both typical and perfect use (Table ). The following services have been given a D recommendation from the U.S. Preventive Services Task Force (USPSTF), which indicates that the potential harms of routine screening outweigh the benefits. Providers should not perform these screening services. The USPSTF has recommended against offering the following services to women and men: • Asymptomatic bacteriuria: USPSTF recommends against screening for asymptomatic bacteriuria in men and nonpregnant women (1). • Gonorrhea: USPSTF recommends against routine screening for gonorrhea infection in men and women who are at low risk of infection (2). • Hepatitis B: USPSTF recommends against routinely screening the general asymptomatic population for chronic hepatitis B virus infection (3). • Herpes simplex virus (HSV): USPSTF recommends against routine serological screening for HSV in asymptomatic adolescents and adults (4). • Syphilis: USPSTF recommends against screening of asymptomatic persons who are not at increased risk of syphilis infection (5). The USPSTF has recommended against offering the following services to women: • BRCA mutation testing for breast and ovarian cancer susceptibility: USPSTF recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk of deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) (6). However, USPSTF continues to recommend that women whose family history is associated with an increased risk of deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. • Breast self-examination: USPSTF recommends against teaching breast self-examination (7). • Cervical cytology: USPSTF recommends against routine screening for cervical cancer with cytology (Pap smear) in the following groups: women aged <21 years, women aged >65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (i.e., cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer. USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women aged <30 years (8). # Appendix F Screening Services For Which Evidence Does Not Support Screening • Ovarian cancer: USPSTF recommends against routine screening for ovarian cancer (9). The USPSTF has recommended against offering the following services to men: • Prostate cancer: USPSTF recommends against prostatespecific antigen (PSA)-based screening for prostate cancer (10). • Testicular cancer: USPSTF recommends against screening for testicular cancer in adolescent or adult males (11). # Technical on Men's Clinical Services	None	None
b87c3f3fe151976e1762bfcddd264b63eca6b5a5	cdc	None	These revised recommendations by the Advisory Committee on Immunization Practices concerning prevention of plague update previous recommendations ( MMWR 1982;31:301-4). This report includes information and recommendations on vaccination, public health practices, and medical treatment to prevent plague among humans.# INTRODUCTION Plague is an acute, often fatal, and potentially epidemic disease caused by infection with Yersinia pestis. Plague exists in natural enzootic cycles involving wild rodents and their fleas in certain regions of Asia, Africa, the Americas, and extreme southeastern Europe near the Caspian Sea (Figure 1). These natural cycles may be inapparent, with no transmission to humans, or associated with sporadic transmission to humans. Epidemics of plague occasionally occur when the disease spreads from wild rodents into populations of rats (genus Rattus) that live near human habitation. Because of the high case-fatality rate and the epidemic potential of this disease, plague is designated a Class I notifiable disease and thus is subject to International Health Regulations. These regulations require that all suspected cases be reported to and investigated by public health authorities and that confirmed cases be reported to the World Health Organization (WHO) in Geneva, Switzerland. In the United States, suspected cases of plague should be reported to state health departments, which in turn notify CDC. All cases subsequently confirmed by laboratory analysis are reported by CDC to WHO. # CHARACTERISTICS OF PLAGUE # Etiologic Agent Y. pestis is a gram-negative coccobacillus belonging to the Enterobacteriaceae. This bacterium has several chromosomal and plasmid-associated factors that are essential to its virulence and survival in mammalian hosts and flea vectors (1,2 ). # Modes of Transmission and Description of Disease The most common mode of transmission of Y. pestis to humans is by the bite of infectious fleas. Less frequently, infection is caused by a) direct contact with infectious body fluids or tissues while handling an infected animal or b) inhaling infectious respiratory droplets or other infectious materials (e.g., laboratory-generated aerosols containing Y. pestis ). Infection causes a severe febrile illness characterized by headache, myalgia, malaise, shaking chills, prostration, and gastrointestinal symptoms. The three principal clinical presentations of plague are bubonic, septicemic, and pneumonic. Bubonic plague, characterized by development of an acute regional lymphadenopathy, or bubo, is the most common clinical form of disease, accounting for 80%-90% of cases in the United States. Buboes typically involve lymph nodes that drain the site of initial infection and are most often located in the inguinal, axillary, or cervical regions (3,4 ). The incubation period for bubonic plague usually ranges from and rarely exceeds 2 to 6 days. The case-fatality rate for infected persons who are not treated is 50%-60% (3 ). Septicemic plague, which occurs when Y. pestis invades and continues to multiply in the bloodstream, can occur secondarily to bubonic plague or can develop without detectable lymphadenopathy (i.e., primary septicemic plague) (3)(4)(5). In the United States during 1947-1977, approximately 10% of plague patients presented with septicemic plague; approximately 50% of these persons died as a result of disease (3 ). Complications of this form of plague include septic shock, consumptive coagulopathy, meningitis, and coma (3 ). Pneumonic plague is the least common but most dangerous and fatal form of the disease. It can develop as a secondary complication of septicemic plague or result from inhalation of infectious respiratory droplets expelled from a human or animal that has plague pneumonia. Signs of pneumonic plague include severe pneumonia accompanied by high fever, dyspnea, and often hemoptysis. The incubation period for primary pneumonic plague is 1-3 days. Patients who do not receive adequate treatment within 18 hours after onset of respiratory symptoms are unlikely to survive (3 ). # Ecology Y. pestis is maintained in complex enzootic and epizootic transmission cycles involving susceptible wild rodents and their fleas (3,6 ). Risk for plague in humans is greatest when epizootics cause high mortality in commensal rat populations, thereby forcing infected rat fleas (Xenopsylla cheopis ) to seek alternative hosts, including humans. These episodes of high mortality among rats do not contribute to maintenance of Y. pestis in nature (3 ). Other animals, including carnivores and rabbits, occasionally become infected with Y. pestis but are only incidental hosts. However, carnivores may contribute to the transfer of infected fleas from one geographic area to another (7 ). # Epidemiology During 1980-1994, a total of 18,739 cases of plague in humans were reported to WHO from 20 countries (average: 1,087 cases per year) (Table 1) (8 ). Plague is underreported in many countries, particularly those in which surveillance and laboratory capabilities are inadequate. Epidemics are most likely to occur in areas that have poor sanitary conditions and large populations of rats. Isolated cases in humans also can result from exposure to infected wild or domestic animals or their fleas. Outbreaks of plague have been reported recently from Africa, Asia, and South America (8 ). In the United States, 341 cases of plague in humans were reported to CDC during 1970-1995 (average: 13 cases per year) (Figure 2). Of these cases, 80% occurred in the southwestern states of New Mexico, Arizona, and Colorado (9,10 ; CDC, unpublished data). Another 9% of cases were reported from California. Nine other western states reported limited numbers of cases. Modes of transmission were determined for 284 of these case-patients and included flea bite- (n=222; 78%); direct contact with infected animals (n=56; 20%); and inhalation of infectious respiratory droplets or other airborne materials from infected animals (n=7; 2%). Five of the seven persons who were infected by inhalation were exposed to infected domestic cats, and a sixth person (a veterinarian) also may have had such an exposure. In the United States, most cases of plague in humans occur in the summer months, when risk for exposure to infected fleas is greatest. The majority of these cases, especially those in the Southwest, are acquired in or near the patient's residence (9,10 ). Risks for acquiring the disease are associated with conditions that provide food and shelter for plague-susceptible rodents near human dwellings (6,(9)(10)(11)(12). Less often, plague is acquired while working or while participating in recreational activities, the latter having occurred most often among patients from California (13 ). # PLAGUE VACCINE # History of Plague Vaccines Killed bacteria have been used in plague vaccines since 1896. However, only one vaccine-a formalin-inactivated preparation-is currently licensed for use in the United States. This vaccine (plague vaccine, USP) was manufactured by Cutter Biologicals (a division of Miles Laboratories, Inc.) but is now available only from Greer Laboratories, Inc. The killed or inactivated plague vaccine is prepared from Y. pestis organisms grown in artificial media and then inactivated in formaldehyde. The inactivated bacteria are suspended in a 0.9% sodium chloride solution at a concentration of 1.8 to 2.2 x 10 9 bacteria per mL of vaccine. The vaccine also contains trace amounts of media components (e.g., beef-heart infusion, soytone , casamino acids, sodium sulfite , L-cysteine hydrochloride, and yeast extract) and 0.5% phenol as a preservative. Live Y. pestis vaccines composed of presumably avirulent strains also have been developed (14 ). However, none of these vaccines is commercially available, and their safety and efficacy have not been adequately tested. # Immunogenicity and Efficacy The efficacy of the inactivated plague vaccine in humans has not been measured in controlled studies. Completion of such studies in the United States is unlikely because of the low incidence of plague in this country. A retrospective study of U.S. military personnel who served in Vietnam provides some indirect evidence for the efficacy of the inactivated vaccine (manufactured by Cutter Laboratories) in preventing *Persons who develop inguinal buboes or recall being bitten by fleas are considered to have been infected via flea bite. flea-borne plague (15 ). During 1961-1971, only eight cases of plague were diagnosed among U.S. personnel in Vietnam who had received plague vaccine (i.e., one case per 10 6 person-years of exposure). U.S. military personnel in Vietnam were considered to be at risk for exposure to Y. pestis-infected fleas because a) many military personnel developed murine typhus, which is a rickettsial disease transmitted by the same rat flea (X. cheopis ) that is the primary vector of plague in Vietnam; b) thousands of cases of plague occurred among Vietnamese civilians during 1961-1971 (333 cases per 10 6 person-years of exposure ); c) plague was commonly identified in rodent populations on or near U.S. military installations; and d) fourfold rises in antibody titer to Y. pestis were identified in four murine typhus patients who previously had had low passive-hemagglutination (PHA) titers as a result of vaccination and in another three persons who had had no detectable levels of antibody in acute-phase serum samples. Such evidence suggests exposure to both Rickettsia typhi (formerly Rickettsia mooseri ) and Y. pestis. Researchers have not determined whether vaccination protects against infectious droplets or aerosols generated in laboratories or against exposure to infectious respiratory droplets from patients who have pneumonic plague. At least two persons vaccinated with a previous formulation of the inactivated vaccine contracted pneumonic plague following exposure to Y. pestis (17,18 ). Whether these cases developed after the patients inhaled infectious droplets or as complications of septicemic plague was not reported. Persons potentially exposed to patients who have pneumonic plague or to Y. pestis aerosols in the laboratory should be administered a 7-day course of antimicrobial therapy, regardless of vaccination history. Antimicrobials recommended for prophylaxis include tetracycline, doxycycline, or trimethoprimsulfamethoxazole (19 ). Laboratory studies involving animals suggest that induction of antibodies to the fraction 1 capsular antigen (F1) of Y. pestis following vaccination is a strong indicator of protection (18,(20)(21)(22)(23)(24)(25). Data from one study indicated that 90% of rats that had anti-F1 titers ≥128 by PHA survived injection with 1 x 10 3 to 5 x 10 5 virulent Y. pestis, compared with 46% of rats with titers of 32-64 and 6% of rats with titers of ≤16 (24 ). Data from other studies reveal that 11 of 14 Hanuman langurs and six of seven African green vervets that had anti-F1 titers ≥128 survived similar challenges (18,24,26,27 ). Mice vaccinated with F1 antigen expressed by a recombinant Escherichia coli clone containing the F1 gene of Y. pestis also were protected against challenge by virulent Y. pestis (28 ). Although data from previous studies have correlated the induction of adequate anti-F1 antibody titers with protection against plague, recent data indicate that immune responses to other Y. pestis antigens (e.g., V antigen) also might provide protection in laboratory animals (29 ). The extent to which plague vaccine induces such immune responses, however, has not been adequately determined. Studies of passively immunized animals also suggest that an anti-F1 titer ≥128 is protective (18 ). For these indirect potency tests, sera (0.5 mL) from immunized mice, guinea pigs, monkeys, or humans are injected into 10 test mice. The object of this indirect mouse potency test is to determine whether anti-F1 antibodies present in the sera of the immunized animals protects the recipient mice from a subcutaneous challenge with virulent Y. pestis (20,30,31 ). Results are expressed as a mouse protection index (MPI), which is calculated by dividing the percentage of mortality among the 10 test mice by the average day of death (20,30 ). The lower the index, the greater the level of protection; MPIs ≤10 are considered protective (18 ). Data concerning protective antibodies in humans are limited. Data from one study indicated that 15 of 23 persons vaccinated with two doses of inactivated plague vaccine (manufactured by Cutter Biologicals) developed antibodies that were protective for mice (i.e., MPI ≤10) (18 ). A second study examined serum antibody levels among 29 persons who were administered three injections of the same vaccine (1.0 mL for the initial vaccination and 0.2 mL for vaccination 90 and 270 days later); 90% of vaccinees had detectable PHA titers within 15 days after the second injection, and 93% had such titers within 4 days after the third injection (20 ). The titers for each of the 29 vaccinees were not reported, but serum samples from five vaccine recipients who had titers ≥128 yielded MPI values ≤10. Serum samples from five subjects who had PHA titers <128 did not protect mice in potency tests (20 ). Data from another study of 117 military personnel who received multiple doses of the inactivated plague vaccine (manufactured by Cutter Biologicals) indicated that 84 (72%) developed PHA titers ranging from 1,024 to 16,382, a total of 23 (20%) had titers from 64 to 512, and nine (8%) did not develop a titer in response to vaccine (32 ). Each of these 117 persons had received an initial series of three injections, followed by repeated booster injections at about 6-month intervals (average: five booster doses per person). Serum samples from 16 of these persons were tested in indirect mouse potency tests. All six vaccinees with PHA titers 10, and four of the 10 subjects with titers ≥128 had MPIs ≤10. A recent study conducted among U.S. military personnel compared MPI values in serum samples from four groups: persons vaccinated with one of three different lots of the inactivated vaccine manufactured by Greer Laboratories and a fourth group of persons administered the vaccine formerly marketed by Cutter Biologicals (Table 2) (Greer Laboratories, Inc., unpublished data). Subjects were vaccinated with two doses approximately 30 days apart. Humoral immune responses were measured in serum samples obtained 4 weeks after the second dose. Indirect potency tests demonstrated protective levels of antibody (MPI values ≤10) in sera of only 55%-58% of vaccinees. MPI values did not differ significantly by vaccine lot or manufacturer. # Vaccine Administration Indications Persons should be vaccinated only if they are at high risk for exposure. Thus, vaccine is recommended for persons in the following high-risk groups: - laboratory personnel who routinely perform procedures that involve viable Y. pestis; and - persons (e.g., mammalogists, ecologists, and other field workers) who have regular contact with wild rodents or their fleas in areas in which plague is enzootic or epizootic. All vaccinated persons should follow the preventive measures discussed in this report because of uncertainties about the efficacy of the vaccine (see Alternatives to Vaccination and Supplemental Protection). If vaccinees are believed to have been exposed to plague or if their risk for exposure is exceptionally high, prophylactic antibiotic use should be considered as a supplement to vaccination. Vaccination is not intended as a method of controlling plague epidemics because several months are required to complete the primary vaccination series and to develop adequate levels of protective antibodies. Routine vaccination is not necessary for persons living in areas in which plague is enzootic (e.g., the western United States). Vaccination is not indicated for hospital staff or other medical personnel in such areas, nor for most travelers to countries in which cases of plague have been reported,- particularly if their itineraries are limited to urban areas and modern hotel accommodations. # Supply and Storage Plague vaccine is manufactured by Greer Laboratories, Inc., P.O. Box 800, Lenoir, N.C. 28645-0800. The vaccine is shipped refrigerated in 20-mL vials and should be stored at 35-46 F (2-8 C). The vaccine should not be frozen. # Primary Vaccination All injections should be administered intramuscularly, preferably in a deltoid muscle. Primary vaccination consists of a series of three injections (Table 3). Recommended dosages are available only for persons 18-61 years of age; dosage recommendations for other age groups have not been formulated because data are insufficient. No published data are available concerning the interactions of plague vaccine with drugs or other biologics administered concurrently. The simultaneous administration of plague vaccine with other vaccines that are likely to be reactogenic should be avoided. # Booster Doses and Monitoring Antibody Levels The proportion of vaccinees whose serum produces an MPI ≤10 in the indirect mouse potency test after three doses of vaccine is unknown. PHA antibody titers decrease soon after vaccination and could drop below the presumably protective level of 128 within a few months (20 ). Booster doses of 0.2 mL each can be administered three times at approximately 6-month intervals when vaccinees have continuing high risk for exposure, especially for those persons who have PHA titers of <128. Additional booster doses can be administered at 1-to 2-year intervals to persons who remain at risk for infection. Persons considering being vaccinated should be advised that they may have difficulty having their PHA titers evaluated because only a few public health and research laboratories routinely perform this test. # Adverse Reactions Adverse reactions following injection of the first dose of plague vaccine generally are mild, but the frequency and severity of such events can increase with repeated doses (33 ). Common adverse reactions include local erythema and induration at the site of injection, malaise, headache, fever, and lymphadenopathy (14 ). These reactions usually do not persist for >48 hours. Severe reactions to plague vaccine occur in a limited number of recipients, most often in persons who receive repeated doses (33 ). Data regarding adverse reactions have been obtained largely from a study conducted during 1950-1971 that examined 1,219 persons who received a total of 18,751 injections (including primary-series and booster doses) of one or more of three different formalin-inactivated vaccine preparations (manufactured by Cutter Biologicals) (33 ). These preparations differed primarily in the growth media, strains of Y. pestis, and methods of standardization used in their preparation. The most recent of these three vaccine preparations, used during 1967-1971, was produced using essentially the same methods as the current Greer Laboratories vaccine. Although some local reactions (i.e., edema, induration at the site of injection, or both) were observed in 29% of the study population, moderately severe to severe local reactions were rare (occurring after 0.15% of injections). Severe local reactions included various combinations of a) >12-cm edema and/or induration; b) inflammatory involvement of elbow, forearm, and/or clavicular fossa; and c) inflammation causing >50% limitation of use of the arm. Seven (0.04%) additional injections resulted in immediate reactions characterized by transient swelling and redness radiating from the injection site. Six of these seven reactions occurred in the same person. Twenty percent of vaccine recipients had some systemic reactions (e.g., malaise, mild headache, generalized myalgia and arthralgia, fever, chills, and nausea). Of the 18,751 individual injections administered during the study, 68 resulted in severe systemic reactions (0.4% of total injections) that were characterized by one or more of the following manifestations: severe headache, generalized myalgia and arthralgia, malaise, nausea and vomiting, diarrhea, shaking chills, and oral temperatures ≥101 F (≥38 C). Fourteen instances of anaphylaxis (0.07% of total injections) also were reported and were characterized by urticaria, bronchospasm, and hypotension. Anaphylaxis occurred within 30 minutes of inoculation and was of short duration because patients received prompt medical treatment. Fifty-three persons received only the more recently manufactured vaccine preparation, which is similar to the current Greer Laboratories vaccine. Local reactions occurred in 3% of persons who received this vaccine; 1% of persons had systemic reactions. Information regarding the severity of the local and systematic reactions occurring in this group was not reported. Although a few reports of sterile abscesses occurring following administration of plague vaccine were received by the former manufacturer (Cutter Biologicals), no such abscesses were identified in this study (Greer Laboratories, Inc., plague vaccine package insert). Plague vaccine has not been reported to cause death; however, one person who had a history of idiopathic anaphylaxis died several hours after receiving a third dose of plague vaccine (34 ). This person also had received Japanese encephalitis vaccine 2 days before death. The cause of death was not identified at autopsy. The frequency and severity of adverse reactions among military personnel 18-61 years of age who were administered the current Greer Laboratories vaccine are comparable to those previously reported for the Cutter Biologicals vaccine (Greer Laboratories, Inc., unpublished data). Persons who were administered vaccine manufactured by Greer Laboratories were initially injected with a 1.0-mL dose and then were administered a second, 0.2-mL dose 30 days later (Table 4). Adverse reactions generally were mild and transient and occurred less frequently after the second 0.2-mL injection than after the initial 1.0-mL dose (Table 4). No data concerning adverse events are available for the third primary dose or for booster injections of the Greer Laboratories vaccine. Adverse reactions should be reported to the Vaccine Adverse Event Reporting System (VAERS). VAERS reporting forms and information can be obtained by calling (800) 822-7967. # Precautions and Contraindications Precautions to prevent adverse reactions should include review of the vaccinee's history of hypersensitivity to plague vaccine and its components. Epinephrine should be available for immediate use in the event of anaphylaxis or other allergic reactions to the vaccine. The safety and immunogenicity of the vaccine for persons <18 years of age have not been evaluated. The effects of plague vaccine on the developing fetus also are unknown. Pregnant women who cannot avoid high-risk situations should be advised of risk-reduction practices and should be vaccinated only if the potential benefits of vaccination outweigh potential risks to the fetus. Persons who are immunocompromised or who are receiving immunosuppressive therapy may not develop protective levels of antibody following vaccination. Whenever possible, antibody levels determined by PHA should be obtained to determine whether additional doses beyond the primary series should be administered. Plague vaccine should not be administered to persons who have a history of hypersensitivity to the vaccine or its components. Persons who have an acute febrile illness (e.g., influenza) should not be vaccinated until they have recovered fully. # Persons Who Work with Potentially Infected Animals These workers should be informed on how to minimize their exposure to the tissues and fleas of potentially infective animals. Precautionary measures include a) avoiding areas where high mortality in commensal rat populations has been observed, b) wearing gloves when handling animals, c) applying insect repellents containing DEET to clothes and skin, and d) treating clothes with appropriate insecticides. # Persons Who Work in Veterinary Clinics Persons working in veterinary practices in areas where plague is enzootic should be educated on the risks of handling cats infected with Y. pestis. Such persons should wear gloves and eye protection and take appropriate respiratory precautions when examining cats that have fever and obvious acute lymphadenopathy, oral lesions, or pneumonia (9 ). # Persons Living, Working, or Traveling in Other Countries In most countries of Africa, Asia, and South America in which plague is enzootic, the risk for acquiring plague is greatest in semiarid grassland or mountainous areas. The likelihood of plague spreading from wild-rodent foci into village or urban centers is greatest when a) environmental conditions precipitate an increase in or movement of rodent populations, thus leading to increased population densities of plaguesusceptible rodents and their fleas or b) natural disasters or other events interrupt routine sanitary practices. Whenever possible, persons living in regions where plague is enzootic should avoid rodent-infested locations, especially if unusually high numbers of dead rodents have been reported. Persons who must work in such areas should avoid handling sick and dead rodents and use repellents and appropriate insecticides to reduce their risk for being bitten by fleas. Travelers to plague-endemic areas generally are at low risk for infection with Y. pestis. Persons who travel to these areas should avoid rat-infested sites with recently reported cases of plague among humans, especially those sites at which dead rats have been observed. To reduce the likelihood of being bitten by fleas, travelers can apply insect repellents to skin and repellents and insecticides to clothing and outer bedding. Short-term prophylactic use of antibiotics should be considered only for circumstances of exceptionally high risk of exposure to plague. # CONCLUSION Plague is an acute bacterial illness that is typically transmitted to humans by the bites of infectious fleas, direct contact with infected animals, or inhalation of infectious respiratory droplets. In most instances, plague can be prevented by using an appropriate combination of a) personal protective measures; b) applications of insecticides to home, recreational, and work environments when plague has been detected in local animal or flea populations; c) insecticidal treatment of pets; d) avoidance of sick or dead animals; e) environmental modifications to reduce the amount of food and shelter available to rodents; and f) prophylactic antibiotic therapy for persons who are presumed to have been exposed to infection. Although various modifications of killed plague vaccine have been available since World War II, its efficacy in protecting humans has not been adequately demonstrated. Pneumonic plague has developed in at least two persons despite vaccination, indicating that the vaccine may not be effective in the prevention of infection via inhalation of infectious respiratory droplets or other airborne materials. However, indirect evidence indicates that plague vaccine is effective for preventing flea-borne transmission of disease. Thus, plague vaccine is recommended for laboratory personnel who routinely are exposed to viable Y. pestis. Vaccine also should be considered for persons who regularly have contact with the wild-rodent hosts of plague or their fleas in areas where plague is enzootic or epizootic. # ALTERNATIVES TO VACCINATION AND SUPPLEMENTAL PROTECTION Vaccination is usually unnecessary when appropriate preventive measures are taken. Vaccinated persons should follow the preventive measures discussed in the following sections because of uncertainties about the efficacy of plague vaccine. # Residents of Areas in Which Plague Is Enzootic In the western United States, most persons with plague become infected when rodent plague epizootics occur near their residences. Recommended means of reducing the risk for acquiring plague in and around homes include a) eliminating sources of food and shelter for rodents near homes, b) modifying homes to prevent rodent access, c) treating domestic dogs and cats weekly with appropriate insecticides, d) avoiding direct contact with sick or dead rodents, and e) handling severely ill cats with extreme caution (these animals should be examined by a veterinarian). # Persons Who Participate in Outdoor Activities Hikers, campers, and other persons who participate in outdoor recreational activities in areas where plague is enzootic should a) avoid handling sick or dead animals, b) avoid rodent nests and burrows, c) use insect repellents containing N, N-diethyl-mtoluamide (DEET) on skin and repellents or appropriate insecticidal sprays on clothing, and d) treat accompanying pets with appropriate insecticides. Hunters should always wear gloves when handling dead animals. # Medical Personnel and Persons Having Close Contact with Infected Persons Persons suspected of having pneumonic plague should be maintained under respiratory droplet precautions for 48 hours after antibiotic treatment begins (35 ). Persons who have confirmed cases of pneumonic plague should be kept under droplet precautions until sputum cultures are negative (35,36 ). Patients in whom pneumonic plague has been excluded warrant standard precautions only (35 ). Prophylactic antibiotics should be administered to persons who have had close exposure (i.e., within 6.5 feet ) to persons suspected of having pneumonic plague (Table 5) (19,36 ). Persons who have not had such exposure are unlikely to become infected but should be monitored closely. # Laboratory Workers Routine bacteriologic work involving plague can be performed in biosafety level 2 laboratories. Standard precautions (e.g., the use of a biological safety cabinet to contain aerosols that are generated unintentionally) are sufficient to prevent clinical laboratory workers from being infected with Y. pestis. Few laboratoryassociated cases have been reported; these cases have involved unusual exposures in clinical diagnostic laboratories or in laboratories that conduct research involving live Y. pestis (37 ). # The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	These revised recommendations by the Advisory Committee on Immunization Practices concerning prevention of plague update previous recommendations ( MMWR 1982;31:301-4). This report includes information and recommendations on vaccination, public health practices, and medical treatment to prevent plague among humans.# INTRODUCTION Plague is an acute, often fatal, and potentially epidemic disease caused by infection with Yersinia pestis. Plague exists in natural enzootic cycles involving wild rodents and their fleas in certain regions of Asia, Africa, the Americas, and extreme southeastern Europe near the Caspian Sea (Figure 1). These natural cycles may be inapparent, with no transmission to humans, or associated with sporadic transmission to humans. Epidemics of plague occasionally occur when the disease spreads from wild rodents into populations of rats (genus Rattus) that live near human habitation. Because of the high case-fatality rate and the epidemic potential of this disease, plague is designated a Class I notifiable disease and thus is subject to International Health Regulations. These regulations require that all suspected cases be reported to and investigated by public health authorities and that confirmed cases be reported to the World Health Organization (WHO) in Geneva, Switzerland. In the United States, suspected cases of plague should be reported to state health departments, which in turn notify CDC. All cases subsequently confirmed by laboratory analysis are reported by CDC to WHO. # CHARACTERISTICS OF PLAGUE # Etiologic Agent Y. pestis is a gram-negative coccobacillus belonging to the Enterobacteriaceae. This bacterium has several chromosomal and plasmid-associated factors that are essential to its virulence and survival in mammalian hosts and flea vectors (1,2 ). # Modes of Transmission and Description of Disease The most common mode of transmission of Y. pestis to humans is by the bite of infectious fleas. Less frequently, infection is caused by a) direct contact with infectious body fluids or tissues while handling an infected animal or b) inhaling infectious respiratory droplets or other infectious materials (e.g., laboratory-generated aerosols containing Y. pestis ). Infection causes a severe febrile illness characterized by headache, myalgia, malaise, shaking chills, prostration, and gastrointestinal symptoms. The three principal clinical presentations of plague are bubonic, septicemic, and pneumonic. Bubonic plague, characterized by development of an acute regional lymphadenopathy, or bubo, is the most common clinical form of disease, accounting for 80%-90% of cases in the United States. Buboes typically involve lymph nodes that drain the site of initial infection and are most often located in the inguinal, axillary, or cervical regions (3,4 ). The incubation period for bubonic plague usually ranges from and rarely exceeds 2 to 6 days. The case-fatality rate for infected persons who are not treated is 50%-60% (3 ). Septicemic plague, which occurs when Y. pestis invades and continues to multiply in the bloodstream, can occur secondarily to bubonic plague or can develop without detectable lymphadenopathy (i.e., primary septicemic plague) (3)(4)(5). In the United States during 1947-1977, approximately 10% of plague patients presented with septicemic plague; approximately 50% of these persons died as a result of disease (3 ). Complications of this form of plague include septic shock, consumptive coagulopathy, meningitis, and coma (3 ). Pneumonic plague is the least common but most dangerous and fatal form of the disease. It can develop as a secondary complication of septicemic plague or result from inhalation of infectious respiratory droplets expelled from a human or animal that has plague pneumonia. Signs of pneumonic plague include severe pneumonia accompanied by high fever, dyspnea, and often hemoptysis. The incubation period for primary pneumonic plague is 1-3 days. Patients who do not receive adequate treatment within 18 hours after onset of respiratory symptoms are unlikely to survive (3 ). # Ecology Y. pestis is maintained in complex enzootic and epizootic transmission cycles involving susceptible wild rodents and their fleas (3,6 ). Risk for plague in humans is greatest when epizootics cause high mortality in commensal rat populations, thereby forcing infected rat fleas (Xenopsylla cheopis ) to seek alternative hosts, including humans. These episodes of high mortality among rats do not contribute to maintenance of Y. pestis in nature (3 ). Other animals, including carnivores and rabbits, occasionally become infected with Y. pestis but are only incidental hosts. However, carnivores may contribute to the transfer of infected fleas from one geographic area to another (7 ). # Epidemiology During 1980-1994, a total of 18,739 cases of plague in humans were reported to WHO from 20 countries (average: 1,087 cases per year) (Table 1) (8 ). Plague is underreported in many countries, particularly those in which surveillance and laboratory capabilities are inadequate. Epidemics are most likely to occur in areas that have poor sanitary conditions and large populations of rats. Isolated cases in humans also can result from exposure to infected wild or domestic animals or their fleas. Outbreaks of plague have been reported recently from Africa, Asia, and South America (8 ). In the United States, 341 cases of plague in humans were reported to CDC during 1970-1995 (average: 13 cases per year) (Figure 2). Of these cases, 80% occurred in the southwestern states of New Mexico, Arizona, and Colorado (9,10 ; CDC, unpublished data). Another 9% of cases were reported from California. Nine other western states reported limited numbers of cases. Modes of transmission were determined for 284 of these case-patients and included flea bite* (n=222; 78%); direct contact with infected animals (n=56; 20%); and inhalation of infectious respiratory droplets or other airborne materials from infected animals (n=7; 2%). Five of the seven persons who were infected by inhalation were exposed to infected domestic cats, and a sixth person (a veterinarian) also may have had such an exposure. In the United States, most cases of plague in humans occur in the summer months, when risk for exposure to infected fleas is greatest. The majority of these cases, especially those in the Southwest, are acquired in or near the patient's residence (9,10 ). Risks for acquiring the disease are associated with conditions that provide food and shelter for plague-susceptible rodents near human dwellings (6,(9)(10)(11)(12). Less often, plague is acquired while working or while participating in recreational activities, the latter having occurred most often among patients from California (13 ). # PLAGUE VACCINE # History of Plague Vaccines Killed bacteria have been used in plague vaccines since 1896. However, only one vaccine-a formalin-inactivated preparation-is currently licensed for use in the United States. This vaccine (plague vaccine, USP) was manufactured by Cutter Biologicals (a division of Miles Laboratories, Inc.) but is now available only from Greer Laboratories, Inc. The killed or inactivated plague vaccine is prepared from Y. pestis organisms grown in artificial media and then inactivated in formaldehyde. The inactivated bacteria are suspended in a 0.9% sodium chloride solution at a concentration of 1.8 to 2.2 x 10 9 bacteria per mL of vaccine. The vaccine also contains trace amounts of media components (e.g., beef-heart infusion, soytone [or phytone], casamino acids, sodium sulfite [Na 2 SO 3 ], L-cysteine hydrochloride, and yeast extract) and 0.5% phenol as a preservative. Live Y. pestis vaccines composed of presumably avirulent strains also have been developed (14 ). However, none of these vaccines is commercially available, and their safety and efficacy have not been adequately tested. # Immunogenicity and Efficacy The efficacy of the inactivated plague vaccine in humans has not been measured in controlled studies. Completion of such studies in the United States is unlikely because of the low incidence of plague in this country. A retrospective study of U.S. military personnel who served in Vietnam provides some indirect evidence for the efficacy of the inactivated vaccine (manufactured by Cutter Laboratories) in preventing Persons who develop inguinal buboes or recall being bitten by fleas are considered to have been infected via flea bite. flea-borne plague (15 ). During 1961-1971, only eight cases of plague were diagnosed among U.S. personnel in Vietnam who had received plague vaccine (i.e., one case per 10 6 person-years of exposure). U.S. military personnel in Vietnam were considered to be at risk for exposure to Y. pestis-infected fleas because a) many military personnel developed murine typhus, which is a rickettsial disease transmitted by the same rat flea (X. cheopis ) that is the primary vector of plague in Vietnam; b) thousands of cases of plague occurred among Vietnamese civilians during 1961-1971 (333 cases per 10 6 person-years of exposure [16 ]); c) plague was commonly identified in rodent populations on or near U.S. military installations; and d) fourfold rises in antibody titer to Y. pestis were identified in four murine typhus patients who previously had had low passive-hemagglutination (PHA) titers as a result of vaccination and in another three persons who had had no detectable levels of antibody in acute-phase serum samples. Such evidence suggests exposure to both Rickettsia typhi (formerly Rickettsia mooseri ) and Y. pestis. Researchers have not determined whether vaccination protects against infectious droplets or aerosols generated in laboratories or against exposure to infectious respiratory droplets from patients who have pneumonic plague. At least two persons vaccinated with a previous formulation of the inactivated vaccine contracted pneumonic plague following exposure to Y. pestis (17,18 ). Whether these cases developed after the patients inhaled infectious droplets or as complications of septicemic plague was not reported. Persons potentially exposed to patients who have pneumonic plague or to Y. pestis aerosols in the laboratory should be administered a 7-day course of antimicrobial therapy, regardless of vaccination history. Antimicrobials recommended for prophylaxis include tetracycline, doxycycline, or trimethoprimsulfamethoxazole (19 ). Laboratory studies involving animals suggest that induction of antibodies to the fraction 1 capsular antigen (F1) of Y. pestis following vaccination is a strong indicator of protection (18,(20)(21)(22)(23)(24)(25). Data from one study indicated that 90% of rats that had anti-F1 titers ≥128 by PHA survived injection with 1 x 10 3 to 5 x 10 5 virulent Y. pestis, compared with 46% of rats with titers of 32-64 and 6% of rats with titers of ≤16 (24 ). Data from other studies reveal that 11 of 14 Hanuman langurs and six of seven African green vervets that had anti-F1 titers ≥128 survived similar challenges (18,24,26,27 ). Mice vaccinated with F1 antigen expressed by a recombinant Escherichia coli clone containing the F1 gene of Y. pestis also were protected against challenge by virulent Y. pestis (28 ). Although data from previous studies have correlated the induction of adequate anti-F1 antibody titers with protection against plague, recent data indicate that immune responses to other Y. pestis antigens (e.g., V antigen) also might provide protection in laboratory animals (29 ). The extent to which plague vaccine induces such immune responses, however, has not been adequately determined. Studies of passively immunized animals also suggest that an anti-F1 titer ≥128 is protective (18 ). For these indirect potency tests, sera (0.5 mL) from immunized mice, guinea pigs, monkeys, or humans are injected into 10 test mice. The object of this indirect mouse potency test is to determine whether anti-F1 antibodies present in the sera of the immunized animals protects the recipient mice from a subcutaneous challenge with virulent Y. pestis (20,30,31 ). Results are expressed as a mouse protection index (MPI), which is calculated by dividing the percentage of mortality among the 10 test mice by the average day of death (20,30 ). The lower the index, the greater the level of protection; MPIs ≤10 are considered protective (18 ). Data concerning protective antibodies in humans are limited. Data from one study indicated that 15 of 23 persons vaccinated with two doses of inactivated plague vaccine (manufactured by Cutter Biologicals) developed antibodies that were protective for mice (i.e., MPI ≤10) (18 ). A second study examined serum antibody levels among 29 persons who were administered three injections of the same vaccine (1.0 mL for the initial vaccination and 0.2 mL for vaccination 90 and 270 days later); 90% of vaccinees had detectable PHA titers within 15 days after the second injection, and 93% had such titers within 4 days after the third injection (20 ). The titers for each of the 29 vaccinees were not reported, but serum samples from five vaccine recipients who had titers ≥128 yielded MPI values ≤10. Serum samples from five subjects who had PHA titers <128 did not protect mice in potency tests (20 ). Data from another study of 117 military personnel who received multiple doses of the inactivated plague vaccine (manufactured by Cutter Biologicals) indicated that 84 (72%) developed PHA titers ranging from 1,024 to 16,382, a total of 23 (20%) had titers from 64 to 512, and nine (8%) did not develop a titer in response to vaccine (32 ). Each of these 117 persons had received an initial series of three injections, followed by repeated booster injections at about 6-month intervals (average: five booster doses per person). Serum samples from 16 of these persons were tested in indirect mouse potency tests. All six vaccinees with PHA titers <128 had MPI values >10, and four of the 10 subjects with titers ≥128 had MPIs ≤10. A recent study conducted among U.S. military personnel compared MPI values in serum samples from four groups: persons vaccinated with one of three different lots of the inactivated vaccine manufactured by Greer Laboratories and a fourth group of persons administered the vaccine formerly marketed by Cutter Biologicals (Table 2) (Greer Laboratories, Inc., unpublished data). Subjects were vaccinated with two doses approximately 30 days apart. Humoral immune responses were measured in serum samples obtained 4 weeks after the second dose. Indirect potency tests demonstrated protective levels of antibody (MPI values ≤10) in sera of only 55%-58% of vaccinees. MPI values did not differ significantly by vaccine lot or manufacturer. # Vaccine Administration Indications Persons should be vaccinated only if they are at high risk for exposure. Thus, vaccine is recommended for persons in the following high-risk groups: • laboratory personnel who routinely perform procedures that involve viable Y. pestis; and • persons (e.g., mammalogists, ecologists, and other field workers) who have regular contact with wild rodents or their fleas in areas in which plague is enzootic or epizootic. All vaccinated persons should follow the preventive measures discussed in this report because of uncertainties about the efficacy of the vaccine (see Alternatives to Vaccination and Supplemental Protection). If vaccinees are believed to have been exposed to plague or if their risk for exposure is exceptionally high, prophylactic antibiotic use should be considered as a supplement to vaccination. Vaccination is not intended as a method of controlling plague epidemics because several months are required to complete the primary vaccination series and to develop adequate levels of protective antibodies. Routine vaccination is not necessary for persons living in areas in which plague is enzootic (e.g., the western United States). Vaccination is not indicated for hospital staff or other medical personnel in such areas, nor for most travelers to countries in which cases of plague have been reported, particularly if their itineraries are limited to urban areas and modern hotel accommodations. # Supply and Storage Plague vaccine is manufactured by Greer Laboratories, Inc., P.O. Box 800, Lenoir, N.C. 28645-0800. The vaccine is shipped refrigerated in 20-mL vials and should be stored at 35-46 F (2-8 C). The vaccine should not be frozen. # Primary Vaccination All injections should be administered intramuscularly, preferably in a deltoid muscle. Primary vaccination consists of a series of three injections (Table 3). Recommended dosages are available only for persons 18-61 years of age; dosage recommendations for other age groups have not been formulated because data are insufficient. No published data are available concerning the interactions of plague vaccine with drugs or other biologics administered concurrently. The simultaneous administration of plague vaccine with other vaccines that are likely to be reactogenic should be avoided. # Booster Doses and Monitoring Antibody Levels The proportion of vaccinees whose serum produces an MPI ≤10 in the indirect mouse potency test after three doses of vaccine is unknown. PHA antibody titers decrease soon after vaccination and could drop below the presumably protective level of 128 within a few months (20 ). Booster doses of 0.2 mL each can be administered three times at approximately 6-month intervals when vaccinees have continuing high risk for exposure, especially for those persons who have PHA titers of <128. Additional booster doses can be administered at 1-to 2-year intervals to persons who remain at risk for infection. Persons considering being vaccinated should be advised that they may have difficulty having their PHA titers evaluated because only a few public health and research laboratories routinely perform this test. # Adverse Reactions Adverse reactions following injection of the first dose of plague vaccine generally are mild, but the frequency and severity of such events can increase with repeated doses (33 ). Common adverse reactions include local erythema and induration at the site of injection, malaise, headache, fever, and lymphadenopathy (14 ). These reactions usually do not persist for >48 hours. Severe reactions to plague vaccine occur in a limited number of recipients, most often in persons who receive repeated doses (33 ). Data regarding adverse reactions have been obtained largely from a study conducted during 1950-1971 that examined 1,219 persons who received a total of 18,751 injections (including primary-series and booster doses) of one or more of three different formalin-inactivated vaccine preparations (manufactured by Cutter Biologicals) (33 ). These preparations differed primarily in the growth media, strains of Y. pestis, and methods of standardization used in their preparation. The most recent of these three vaccine preparations, used during 1967-1971, was produced using essentially the same methods as the current Greer Laboratories vaccine. Although some local reactions (i.e., edema, induration at the site of injection, or both) were observed in 29% of the study population, moderately severe to severe local reactions were rare (occurring after 0.15% of injections). Severe local reactions included various combinations of a) >12-cm edema and/or induration; b) inflammatory involvement of elbow, forearm, and/or clavicular fossa; and c) inflammation causing >50% limitation of use of the arm. Seven (0.04%) additional injections resulted in immediate reactions characterized by transient swelling and redness radiating from the injection site. Six of these seven reactions occurred in the same person. Twenty percent of vaccine recipients had some systemic reactions (e.g., malaise, mild headache, generalized myalgia and arthralgia, fever, chills, and nausea). Of the 18,751 individual injections administered during the study, 68 resulted in severe systemic reactions (0.4% of total injections) that were characterized by one or more of the following manifestations: severe headache, generalized myalgia and arthralgia, malaise, nausea and vomiting, diarrhea, shaking chills, and oral temperatures ≥101 F (≥38 C). Fourteen instances of anaphylaxis (0.07% of total injections) also were reported and were characterized by urticaria, bronchospasm, and hypotension. Anaphylaxis occurred within 30 minutes of inoculation and was of short duration because patients received prompt medical treatment. Fifty-three persons received only the more recently manufactured vaccine preparation, which is similar to the current Greer Laboratories vaccine. Local reactions occurred in 3% of persons who received this vaccine; 1% of persons had systemic reactions. Information regarding the severity of the local and systematic reactions occurring in this group was not reported. Although a few reports of sterile abscesses occurring following administration of plague vaccine were received by the former manufacturer (Cutter Biologicals), no such abscesses were identified in this study (Greer Laboratories, Inc., plague vaccine package insert). Plague vaccine has not been reported to cause death; however, one person who had a history of idiopathic anaphylaxis died several hours after receiving a third dose of plague vaccine (34 ). This person also had received Japanese encephalitis vaccine 2 days before death. The cause of death was not identified at autopsy. The frequency and severity of adverse reactions among military personnel 18-61 years of age who were administered the current Greer Laboratories vaccine are comparable to those previously reported for the Cutter Biologicals vaccine (Greer Laboratories, Inc., unpublished data). Persons who were administered vaccine manufactured by Greer Laboratories were initially injected with a 1.0-mL dose and then were administered a second, 0.2-mL dose 30 days later (Table 4). Adverse reactions generally were mild and transient and occurred less frequently after the second 0.2-mL injection than after the initial 1.0-mL dose (Table 4). No data concerning adverse events are available for the third primary dose or for booster injections of the Greer Laboratories vaccine. Adverse reactions should be reported to the Vaccine Adverse Event Reporting System (VAERS). VAERS reporting forms and information can be obtained by calling (800) 822-7967. # Precautions and Contraindications Precautions to prevent adverse reactions should include review of the vaccinee's history of hypersensitivity to plague vaccine and its components. Epinephrine should be available for immediate use in the event of anaphylaxis or other allergic reactions to the vaccine. The safety and immunogenicity of the vaccine for persons <18 years of age have not been evaluated. The effects of plague vaccine on the developing fetus also are unknown. Pregnant women who cannot avoid high-risk situations should be advised of risk-reduction practices and should be vaccinated only if the potential benefits of vaccination outweigh potential risks to the fetus. Persons who are immunocompromised or who are receiving immunosuppressive therapy may not develop protective levels of antibody following vaccination. Whenever possible, antibody levels determined by PHA should be obtained to determine whether additional doses beyond the primary series should be administered. Plague vaccine should not be administered to persons who have a history of hypersensitivity to the vaccine or its components. Persons who have an acute febrile illness (e.g., influenza) should not be vaccinated until they have recovered fully. # Persons Who Work with Potentially Infected Animals These workers should be informed on how to minimize their exposure to the tissues and fleas of potentially infective animals. Precautionary measures include a) avoiding areas where high mortality in commensal rat populations has been observed, b) wearing gloves when handling animals, c) applying insect repellents containing DEET to clothes and skin, and d) treating clothes with appropriate insecticides. # Persons Who Work in Veterinary Clinics Persons working in veterinary practices in areas where plague is enzootic should be educated on the risks of handling cats infected with Y. pestis. Such persons should wear gloves and eye protection and take appropriate respiratory precautions when examining cats that have fever and obvious acute lymphadenopathy, oral lesions, or pneumonia (9 ). # Persons Living, Working, or Traveling in Other Countries In most countries of Africa, Asia, and South America in which plague is enzootic, the risk for acquiring plague is greatest in semiarid grassland or mountainous areas. The likelihood of plague spreading from wild-rodent foci into village or urban centers is greatest when a) environmental conditions precipitate an increase in or movement of rodent populations, thus leading to increased population densities of plaguesusceptible rodents and their fleas or b) natural disasters or other events interrupt routine sanitary practices. Whenever possible, persons living in regions where plague is enzootic should avoid rodent-infested locations, especially if unusually high numbers of dead rodents have been reported. Persons who must work in such areas should avoid handling sick and dead rodents and use repellents and appropriate insecticides to reduce their risk for being bitten by fleas. Travelers to plague-endemic areas generally are at low risk for infection with Y. pestis. Persons who travel to these areas should avoid rat-infested sites with recently reported cases of plague among humans, especially those sites at which dead rats have been observed. To reduce the likelihood of being bitten by fleas, travelers can apply insect repellents to skin and repellents and insecticides to clothing and outer bedding. Short-term prophylactic use of antibiotics should be considered only for circumstances of exceptionally high risk of exposure to plague. # CONCLUSION Plague is an acute bacterial illness that is typically transmitted to humans by the bites of infectious fleas, direct contact with infected animals, or inhalation of infectious respiratory droplets. In most instances, plague can be prevented by using an appropriate combination of a) personal protective measures; b) applications of insecticides to home, recreational, and work environments when plague has been detected in local animal or flea populations; c) insecticidal treatment of pets; d) avoidance of sick or dead animals; e) environmental modifications to reduce the amount of food and shelter available to rodents; and f) prophylactic antibiotic therapy for persons who are presumed to have been exposed to infection. Although various modifications of killed plague vaccine have been available since World War II, its efficacy in protecting humans has not been adequately demonstrated. Pneumonic plague has developed in at least two persons despite vaccination, indicating that the vaccine may not be effective in the prevention of infection via inhalation of infectious respiratory droplets or other airborne materials. However, indirect evidence indicates that plague vaccine is effective for preventing flea-borne transmission of disease. Thus, plague vaccine is recommended for laboratory personnel who routinely are exposed to viable Y. pestis. Vaccine also should be considered for persons who regularly have contact with the wild-rodent hosts of plague or their fleas in areas where plague is enzootic or epizootic. # ALTERNATIVES TO VACCINATION AND SUPPLEMENTAL PROTECTION Vaccination is usually unnecessary when appropriate preventive measures are taken. Vaccinated persons should follow the preventive measures discussed in the following sections because of uncertainties about the efficacy of plague vaccine. # Residents of Areas in Which Plague Is Enzootic In the western United States, most persons with plague become infected when rodent plague epizootics occur near their residences. Recommended means of reducing the risk for acquiring plague in and around homes include a) eliminating sources of food and shelter for rodents near homes, b) modifying homes to prevent rodent access, c) treating domestic dogs and cats weekly with appropriate insecticides, d) avoiding direct contact with sick or dead rodents, and e) handling severely ill cats with extreme caution (these animals should be examined by a veterinarian). # Persons Who Participate in Outdoor Activities Hikers, campers, and other persons who participate in outdoor recreational activities in areas where plague is enzootic should a) avoid handling sick or dead animals, b) avoid rodent nests and burrows, c) use insect repellents containing N, N-diethyl-mtoluamide (DEET) on skin and repellents or appropriate insecticidal sprays on clothing, and d) treat accompanying pets with appropriate insecticides. Hunters should always wear gloves when handling dead animals. # Medical Personnel and Persons Having Close Contact with Infected Persons Persons suspected of having pneumonic plague should be maintained under respiratory droplet precautions for 48 hours after antibiotic treatment begins (35 ). Persons who have confirmed cases of pneumonic plague should be kept under droplet precautions until sputum cultures are negative (35,36 ). Patients in whom pneumonic plague has been excluded warrant standard precautions only (35 ). Prophylactic antibiotics should be administered to persons who have had close exposure (i.e., within 6.5 feet [2 meters]) to persons suspected of having pneumonic plague (Table 5) (19,36 ). Persons who have not had such exposure are unlikely to become infected but should be monitored closely. # Laboratory Workers Routine bacteriologic work involving plague can be performed in biosafety level 2 laboratories. Standard precautions (e.g., the use of a biological safety cabinet to contain aerosols that are generated unintentionally) are sufficient to prevent clinical laboratory workers from being infected with Y. pestis. Few laboratoryassociated cases have been reported; these cases have involved unusual exposures in clinical diagnostic laboratories or in laboratories that conduct research involving live Y. pestis (37 ). # The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	None	None
fe11285b8e6c1aa08fb44a25019425ac026d4dbf	cdc	None	The human T-lymphotropic viruses, type I (HTLV-I) and type II (HTLV-II), are closely related but distinct retroviruses that can infect humans. They are different from the human immunodeficiency viruses that cause acquired immunodeficiency syndrome. Screening of the U.S. blood supply for HTLV-I/II, which began in 1988, identifies HTLV-I-and HTLV-II-infected persons who should be counseled regarding their infections. This document summarizes current information about HTLV, types I and II, and presents recommendations developed by CDC and a U.S. Public Health Service working group for counseling HTLV-Iand HTLV-II-infected persons.# INTRODUCTION Human T-lymphotropic viruses, type I (HTLV-I) and type II (HTLV-II), were the first human retroviruses discovered (1,2 ). Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro. They are only distantly related to the human immunodeficiency viruses (HIV-1 and HIV-2), which belong to the lentivirus subfamily of retroviruses and which cause acquired immunodeficiency syndrome (AIDS). Infections with HTLV-I and HTLV-II are most easily detected serologically. The presence of antibodies to HTLV-I or HTLV-II indicates that a person is infected with the virus. In November 1988, the Food and Drug Administration (FDA) recommended that blood donation centers screen the U.S. blood supply for HTLV-I (3 ). Since then, all donations of whole blood and blood components in the United States have been screened for antibodies to HTLV-I. The screening tests that were licensed, as well as the investigational supplementary tests used to confirm seroreactivity (Western immunoblot and radioimmunoprecipitation assay), do not reliably differentiate between antibodies to HTLV-I and the closely related HTLV-II. In addition, the licensed screening tests, which use HTLV-I antigens, vary in their sensitivity to detect antibodies to HTLV-II (4,5 ). Approximately 2,000 HTLV-I/II-infected volunteer blood donors were identified in the first year of screening in the United States; testing, after amplification by polymerase chain reaction, indicated that approximately half were infected with HTLV-I and half with HTLV-II (6 ). Such donors are counseled and permanently deferred from donating blood. Because the polymerase chain-reaction test is not routinely available, many donors and other persons positive by serologic assays have been told that they are infected with HTLV-I/II. The uncertainty regarding the identity of the infecting virus and the differing epidemiologic and clinical correlates of HTLV-I and HTLV-II infections have complicated counseling of HTLV-I/II-infected persons. Until recently, the only reliable way to differentiate HTLV-I from HTLV-II infection was by polymerase chain reaction (7 ). Within the past 2 years, investigational peptide-and recombinant protein-based serologic assays that can more easily differentiate the antibodies to HTLV-I and HTLV-II have been developed (8,9 ). Preliminary data suggest that these investigational tests are potentially useful for typing serum samples (8,9 ). The recommendations for counseling HTLV-I-, HTLV-II-, and HTLV-I/II-infected persons included in this document are intended for use by health-care workers and public health officials in the United States. They may not be applicable in developing countries, where the need for breast-feeding may outweigh concerns about transmission of these viruses. # HTLV-I Prevalence HTLV-I infection is endemic in southwestern Japan (10 ), the Caribbean basin (11 ), Melanesia (12 ), and in parts of Africa (13)(14)(15). In some areas where HTLV-I infection is endemic, prevalence rates as high as 15% have been reported in the general population. Seroprevalence increases with age; in older age groups, rates are usually higher among women than men. In the United States, HTLV-I/II seroprevalence rates among volunteer blood donors average 0.016% (6 ). Approximately half of HTLV-I/II-seropositive blood donors nationwide are infected with HTLV-I. HTLV-I-infected donors most often report a history of birth in HTLV-I-endemic countries or sexual contact with persons from the Caribbean or Japan. Smaller percentages report a history of either injecting drug use or blood transfusion. Clusters of HTLV-I infections have also been reported in blacks from the southeastern United States (16 ) and in immigrants from HTLV-I-endemic areas residing in Brooklyn, New York (17 ). # Transmission Transmission of HTLV-I occurs from mother to child (18 ), by sexual contact (19 ), by blood transfusion (20 ), and by sharing contaminated needles. Mother-to-child transmission occurs primarily through breast-feeding (21 ); in HTLV-I-endemic areas, approximately 25% of breast-fed infants born to HTLV-I-seropositive mothers acquire infection. Recent studies suggest that transmission of HTLV-I by breast-feeding may be associated with the presence of maternal antibodies to the HTLV-I transactivating # TABLE 1. Clinical features of adult T-cell leukemia/lymphoma Leukemia with circulating abnormal lymphocytes (flower cells) Generalized peripheral lymphadenopathy Hepatomegaly and abnormal liver function tests Splenomegaly Skin lesions Bone lesions and hypercalcemia protein, tax (22 ), or with elevated maternal titers of total antibodies to HTLV-I (23 ). However, the clinical usefulness of these markers has not been established. Intrauterine or perinatal transmission of HTLV-I does occur, but it appears to be less frequent than transmission by breast-feeding; approximately 5% of children born to infected mothers but not breast-fed acquire infection (24 ). Sexual transmission of HTLV-I appears to be more efficient from males to females than from females to males. In one study of married couples in Japan, the efficiency of sexual transmission from males to females was estimated to be 60.8% over a 10year period, compared with <1% from females to males (25 ). In another study, the presence of antibody to tax in the male partner was associated with sexual transmission to the female partner (26 ). In one study in Jamaica, genital ulcer disease in the male was identified as a risk for female-to-male sexual transmission (27 ). In the United States, approximately 25%-30% of sex partners of HTLV-I/II-seropositive blood donors are also seropositive (28,29 ). Transmission of HTLV-I by blood transfusion occurs with transfusion of cellular blood products (whole blood, red blood cells, and platelets) but not with the plasma fraction or plasma derivatives from HTLV-I-infected blood. Seroconversion rates of 44% to 63% have been reported in recipients of HTLV-I-infected cellular components in HTLV-I endemic areas (20,30 ). Lower rates (approximately 20%) have been reported in recipients of contaminated cellular components in the United States (31 ). The probability of transmission by whole blood or packed red blood cells appears to diminish with greater duration of product storage; this finding has been ascribed to depletion of infected cells, presumably T-lymphocytes (30,32 ). Sharing blood-contaminated needles is the likely mode of transmission among injecting drug users. HTLV-I is not transmitted by casual contact. Health-care workers caring for HTLV-Iinfected persons need only be concerned about percutaneous exposure to HTLV-I-contaminated blood. One health-care worker who unintentionally inoculated himself with blood from an adult T-cell leukemia/lymphoma patient in Japan is reported to have seroconverted (33 ). However, no seroconversions occurred among 31 other laboratory and health-care workers exposed to HTLV-I via puncture wounds (34 ). Universal precautions, recommended for contact with all patients, are adequate to guard against HTLV-I transmission to health-care workers (35 ). # TABLE 2. Clinical features of HTLV-I-associated myelopathy/tropical spastic paraparesis Slowly progressive chronic spastic paraparesis Lower limb weakness Urinary incontinence and impotence Sensory disturbances such as tingling, pins and needles, and burning Low back pain Lower-extremity hyperreflexia with clonus and Babinski's sign Impaired vibration sense # Diseases Two diseases have been definitively associated with HTLV-I: adult T-cell leukemia/lymphoma (ATL) and a chronic degenerative neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). ATL is a malignancy of HTLV-I-infected CD4+ T-lymphocytes. The HTLV-I provirus is monoclonally integrated in the abnormal cell population. A spectrum of clinical and pathologic features has been described, including acute, chronic, lymphomatous, and smoldering forms (36,37 ). The acute form of ATL is characterized by infiltration of lymph nodes, viscera, and skin with malignant cells, resulting in a constellation of clinical features (Table 1). Circulating abnormal lymphocytes, called flower cells, are generally seen. Hypercalcemia, abnormal liver function values, and lytic bone lesions are common. Median survival is 11 months from diagnosis. Conventional chemotherapy is not curative, and relapses often occur quickly, although prolonged survival has been reported. ATL has been estimated to occur in 2%-4% of persons infected with HTLV-I in regions where HTLV-I is endemic and where early childhood infection is common (38,39 ). ATL occurs most frequently among persons 40-60 years of age, suggesting that a latent period as long as a few decades may be required for the disease to develop. One case of ATL in an immunocompromised patient has been reported in which the infection appears to have been transfusion acquired (40 ). HAM/TSP is characterized by progressive, permanent lower-extremity weakness, spasticity, hyperreflexia, sensory disturbances, and urinary incontinence (Table 2). In patients with HAM/TSP, unlike those with multiple sclerosis, the signs and symptoms do not wax and wane, cranial nerves are not involved, and cognitive function is not affected. Antibodies to HTLV-I are characteristically found in the cerebrospinal fluid (41 ). Treatment with corticosteroids has been reported to be useful in some cases (42 ). Danazol, a synthetic androgen, reportedly improves symptoms, including bladder dysfunction (43,44 ). HAM/TSP develops in <1% of HTLV-I-infected persons (45 ), is believed to be immunologically mediated, and affects women more frequently than men. The latency period for HAM/TSP is shorter than that for ATL; cases of HAM/TSP have been associated with blood transfusion, with a median interval of 3.3 years between transfusion and development of HAM/TSP (46 ). Recently, infective dermatitis, a chronic eczema associated with Staphylococcus aureus and beta-hemolytic streptococcus, has been reported in Jamaican children infected with HTLV-I (47 ). The full spectrum of HTLV-I-associated diseases may include other disorders. Cases of polymyositis (48 ), chronic arthropathy (49 ), panbronchiolitis (50 ), and uveitis (51 ) have been reported in HTLV-I-infected patients. # HTLV-II Prevalence Until recently, partly because of the lack of serologic tests to differentiate HTLV-II from HTLV-I, no information was available regarding the seroepidemiology or modes of transmission of HTLV-II. HTLV-II is prevalent among injecting drug users in the United States and in Europe (52,53 ); more than 80% of HTLV-I/II seropositivity in drug users in the United States is due to HTLV-II infection (54 ). HTLV-II also appears to be endemic in American Indian populations, including the Guaymi Indians in Panama (55 ) and North American Indians in Florida (56 ) and New Mexico (57 ). Approximately half of U.S. volunteer blood donors seropositive for HTLV-I/II are infected with HTLV-II. HTLV-II-infected blood donors most often report either a history of injecting drug use or a history of sexual contact with an injecting drug user (6,58 ). A smaller percentage report a history of blood transfusion. # Transmission HTLV-II is presumed to be transmitted similarly to HTLV-I, but much less is known about the specific modes and efficiency of transmission of HTLV-II. One study of 20 non-breast-fed children born to HTLV-II-infected women in New York City failed to show evidence of transmission to the newborns (59 ). The HTLV-II provirus has been detected in breast milk from HTLV-II-infected mothers ( 60), but no data are available regarding transmission to breast-fed infants. HTLV-II can be transmitted sexually (61 ); the most commonly reported risk factor among HTLV-II-infected female U.S. blood donors is sexual contact with an injecting drug user (6,58 ). HTLV-II can be transmitted by transfusion of cellular blood products (whole blood, red blood cells, and platelets) (31,32 ). The probability of transmission from red blood cells appears to diminish with greater duration of product storage (31 ). The high prevalence of HTLV-II among injecting drug users is likely due to sharing blood-contaminated needles or other injection paraphernalia (62 ). # Diseases HTLV-II infection has not been clearly associated with any diseases. The virus was first isolated from two patients with hairy-cell leukemia (2,63 ), but no evidence of HTLV-II infection was found in 21 additional patients with hairy-cell leukemia (64 ). In one study, rates of lymphoproliferative illnesses were not found to be increased in New Mexico, where HTLV-II is present in American Indians (65 ). Rare cases of HAM/TSP-like neurologic illnesses (66 ) and of mycosis fungoides (67 ) and large granular lymphocyte leukemia (68 ) have been reported in HTLV-II-infected persons. Cases of erythrodermatitis and bacterial skin infections have been reported in HIV-1and HTLV-II-coinfected persons (69 ). # SEROLOGIC TESTS FOR HTLV-I AND HTLV-II Serum specimens are screened for antibody to HTLV-I by using licensed enzyme immunoassays prepared from HTLV-I whole-virus lysate antigens. These assays vary in their sensitivity to detect antibodies to HTLV-II (4,5 ). Initially reactive specimens are retested in duplicate to minimize the chance that reactivity is due to technical error. Specimens that are reactive in either of the duplicate tests are considered repeatably reactive. Specimens that do not react in either of the duplicate repeat tests are considered nonreactive (3 ). Additional tests, such as the Western immunoblot and the radioimmunoprecipitation assay, are needed to correctly interpret repeatably reactive specimens. Such supplementary tests must be inherently capable of identifying antibodies to the core (gag ) and the envelope (env ) proteins of HTLV-I/II. Indirect fluorescent antibody test-ing for HTLV-I/II has been used in some laboratories, but it does not distinguish antibodies to specific HTLV gene products. None of the supplementary tests have been licensed by the Food and Drug Administration, but they are available in research institutions, blood banks, some public health laboratories, and industrial laboratories, and as in-house tests in some diagnostic laboratories. The following criteria for HTLV-I/II seropositivity were adopted by a U.S. Public Health Service (USPHS) working group in 1988 (3 ): a specimen that is repeatably reactive by enzyme immunoassay must demonstrate immunoreactivity to both the gag gene product p24 and to an env gene product (gp46 and/or gp61/68) to be considered seropositive for HTLV-I/II. Reactive serum specimens that do not satisfy these criteria but do show immunoreactivity to at least one suspected HTLV gene product are designated "indeterminate." Both Western immunoblot and radioimmunoprecipitation may be required to determine whether a specimen is positive or indeterminate. Serum specimens with no immunoreactivity to any HTLV gene product in additional, more specific tests are considered false positive. Several studies involving provirus amplification have supported the accuracy of these diagnostic criteria; persons whose specimens satisfy the criteria for positivity are virtually always infected with HTLV-I or HTLV-II (7,70 ). In contrast, persons whose specimens are "indeterminate" are rarely infected with either virus; for those who are found to be infected, repeat serologic testing frequently demonstrates seropositivity (70,71 ). In rare instances, persons with reactivity to p19 and to an env gene product (gp46 and/or gp61/68) but without reactivity to p24 have been found to be infected with HTLV-I/II (72 ). An important advance in HTLV serologic testing has been the development of a recombinant env protein, p21e. Reactivity to p21e (in either enzyme immunoassay or "spiked" Western immunoblot) has been found to be highly sensitive for HTLV-I/II infection, being observed in virtually 100% of infected persons (73 ). However, the specificity of the p21e reactivity has been questioned (74,75 ). For purposes of notification and counseling, the positivity of samples showing p21e serologically should be confirmed by tests that detect env reactivity, such as radioimmunoprecipitation or recombinant protein-based assays (76 ), or by polymerase chain reaction until further information is available concerning this test. The supplementary serologic tests discussed thus far are incapable of differentiating antibodies to HTLV-I and HTLV-II. The relative intensity of the reactivity to the gag proteins p19 and p24 on the "spiked" Western immunoblot has been used to differentiate HTLV-I from HTLV-II (77 ), but such differentiation may be unreliable (78 ). Recently, several synthetic peptides and recombinant proteins have been developed for this purpose (8,9,79 ). As with the previously discussed supplementary tests, all these tests are available for research only. Preliminary data indicate that such assays can be highly specific in differentiating antibodies to HTLV-I and HTLV-II (8,9,79 ). Not all HTLV-I/II-positive serum specimens, however, can be typed as HTLV-I or HTLV-II by using these tests. In these cases, more sophisticated methods, such as provirus amplification or virus isolation, may be needed to differentiate HTLV-I from HTLV-II infection. # NOTIFICATION AND DEFERRAL OF BLOOD DONORS In the United States, blood donors whose serum specimens are repeatably reactive by the HTLV-I enzyme immunoassay and confirmed as seropositive for HTLV-I/II by the additional specific tests discussed above are notified and permanently deferred from donating blood. This deferral policy includes donors confirmed positive with antibodies to HTLV-I, HTLV-II, or HTLV-I/II (if differentiation between the infections is not attempted or is unsuccessful). Blood donors with serum specimens repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II (a category that includes false-positive specimens and those indeterminate for HTLV) should also be notified and deferred if the same result is obtained on two separate donations. In some blood centers, such donors are deferred after the first such donation. Persons who are repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II should not be told that they are infected with HTLV-I or HTLV-II. The above policies for donor deferral are based on FDA recommendations. In addition, FDA recommendations regarding the use of blood components should be followed. # RECOMMENDATIONS FOR COUNSELING In consideration of the information presented above, the following recommendations for counseling HTLV-seropositive persons have been issued. In instances in which viral typing is possible, counseling should be virus specific. As noted above, HTLV-I and HTLV-II are two different retroviruses with differing epidemiologies and disease associations. The specific recommendations for persons infected with HTLV-I or HTLV-II should therefore take these differences into account. # HTLV-I Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-I by additional testing should be informed that they are infected with HTLV-I. They should be told that HTLV-I is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-I is a lifelong infection. They should be given information regarding modes and efficiency of transmission, disease associations, and the probability of developing disease. In particular, persons infected with HTLV-I should be advised to: - Share the information with their physician - Refrain from donating blood, semen, body organs, or other tissues - Refrain from sharing needles or syringes with anyone - Refrain from breast-feeding infants # Consider the use of latex condoms to prevent sexual transmission If the HTLV-I-positive person is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-I to the negative partner, male or female. Male-infected, female-non-infected couples desiring pregnancy should be made aware of the finite risk of sexual transmission of HTLV-I during attempts at pregnancy and of the small risk for vertical transmission from mother to infant unrelated to breast-feeding. Such couples might be advised to use latex condoms at all times except during the fertile period while they are attempting pregnancy. The use of latex condoms is strongly recommended for HTLV-I-positive persons with multiple sex partners or otherwise engaging in non-mutually monogamous sexual relationships. These persons should be reminded of the risk of acquiring other sexually transmitted infections, including HIV. # HTLV-II Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-II by additional testing should be informed that they are infected with HTLV-II. They should be told that HTLV-II is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-II is a lifelong infection. They should be given information regarding possible modes of transmission and the lack of firm disease associations. In particular, they should be advised to: - Share the information with their physician - Refrain from donating blood, semen, body organs, or other tissues - Refrain from sharing drug needles or syringes with anyone # Refrain from breast-feeding infants Although the risks of transmission of HTLV-II by breast-feeding and of disease from HTLV-II are unknown, the theoretical risk of transmission and disease, as for HTLV-I, makes it prudent to recommend that HTLV-II-infected mothers refrain from breast-feeding when and where safe nutritional alternatives exist. - Consider the use of barrier precautions to prevent sexual transmission HTLV-II can be sexually transmitted, but the risks of disease are unknown. If the HTLV-II-positive person is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-II to the negative partner, male or female. The use of latex condoms is strongly recommended for HTLV-II-positive persons with multiple sex partners or otherwise engaging in non-mutually monogamous sexual relationships. These persons should be reminded of the risk of acquiring other sexually transmitted infections, including HIV. # HTLV-I/II Persons found to be seropositive for HTLV-I/II according to the USPHS criteria but without differentiation of their infection should be informed they are positive for HTLV-I/II and that they are likely infected with either HTLV-I or HTLV-II. Because of the differences in the epidemiologic and clinical correlates of HTLV-I and HTLV-II, an effort to type the infection should be made. If such efforts are unsuccessful, these HTLV-I/II seropositive persons should be given information regarding possible modes and effi-ciency of transmission of HTLV-I and HTLV-II, disease associations of HTLV-I, and the probability of developing disease. Specific counseling advice should be the same as for HTLV-I-infected persons (refer to HTLV-I section). # HTLV Indeterminate Blood donors with serum specimens that are HTLV-indeterminate on two occasions at least 3 months apart should be advised that their specimens were reactive in a screening test for HTLV-I but that the results could not be confirmed by a second, more specific test. They should be reassured that "indeterminate" test results are only rarely caused by HTLV-I or HTLV-II infection. Persons testing "indeterminate" for HTLV-I/II on one occasion should be offered retesting to make sure they are not recently infected with HTLV-I or HTLV-II and in the process of seroconverting. If subsequent test results are the same, they should be reassured that they are unlikely to be infected with HTLV-I or HTLV-II. # HTLV False Positive Blood donors with serum specimens that are repeatably reactive by HTLV-I enzyme immunoassay but negative by Western immunoblot on two occasions should be advised that their HTLV-I screening test is falsely positive and that it could not be confirmed by a second, more specific test. They should be reassured that they are not infected with HTLV-I or HTLV-II. # Medical Follow-up A periodic medical evaluation of HTLV-I-or HTLV-I/II-infected persons by a physician knowlegeable about these viruses is recommended. This evaluation might include a physical examination, including a neurologic examination, and a complete blood count with peripheral smear examination. Medical evaluation of HTLV-II-infected persons should be considered optional. # Recommendations on Prophylaxis and # INTRODUCTION Mycobacterium avium complex (MAC) causes disseminated disease in up to 40% of patients with human immunodeficiency virus (HIV) in the United States, producing fever, sweats, weight loss, and anemia (1-3 ). Disseminated MAC characteristically affects patients with advanced HIV disease and peripheral CD4+ T-lymphocyte counts <100 cells/µL. Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons. Two randomized, placebo-controlled, multicenter studies were recently conducted to study the use of rifabutin for the prevention of disseminated MAC, as defined by positive blood culture. In these studies, rifabutin was shown to reduce the frequency of MAC bacteremia by approximately 50% (48 of 566 patients receiving rifabutin developed MAC, compared with 102 of 580 patients receiving placebo, p<0.001) (4,5 ). On December 23, 1992, the Food and Drug Administration issued the first approval for a prophylactic drug targeted against MAC. Data collected in published and unpublished studies (1-3 ) suggest that health-care providers may utilize and their patients may benefit from recommendations for prevention and management provided by a panel of experts drawn from government agencies, universities, practicing clinicians, and the community. The U.S. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex was convened in Bethesda, Maryland, on December 7-8, 1992, and issued the recommendations in this report. # Indications for Prophylaxis Patients with HIV infection and <100 CD4+ T-lymphocytes/µL should be administered prophylaxis against MAC. Prophylaxis should be continued for the patient's lifetime unless multiple drug therapy for MAC becomes necessary because of the development of MAC disease. Clinicians must weigh the potential benefits of MAC prophylaxis against the potential for toxicities and drug interactions, the cost, the potential to produce resistance in a community with a high rate of tuberculosis, and the possibility that the addition of another drug to the medical regimen may adversely affect patients' compliance with treatment. Because of these concerns, therefore, in some situations rifabutin prophylaxis should not be administered. # Evaluation before Beginning Prophylaxis Before prophylaxis is administered, patients should be assessed to ensure that they do not have active disease due to MAC, M. tuberculosis, or any other mycobacterial species. This assessment may include a chest radiograph and tuberculin skin test. # Prophylactic Regimens Rifabutin, 300 mg by mouth daily, is recommended for the patient's lifetime unless disseminated MAC develops, which would then require multiple drug therapy (4,5 ). Although other drugs, such as azithromycin and clarithromycin, have laboratory and clinical activity against MAC, none has been shown in a prospective, controlled trial to be effective and safe for prophylaxis. Thus, in the absence of data, no other regimen can be recommended at this time. The 300-mg dose of rifabutin has been well tolerated (4,5 ). Adverse effects included neutropenia, thrombocytopenia, rash, and gastrointestinal disturbances. # Diagnosis of MAC Disseminated MAC is most readily diagnosed by one positive blood culture (6 ). Blood cultures should be performed in patients with symptoms, signs, or laboratory abnormalities compatible with mycobacterium infection. Blood cultures are not routinely recommended for asymptomatic persons, even for those who have CD4+ T-lymphocyte counts <100 cells/µL. # Therapy of Disseminated MAC Although studies have not yet identified an optimal regimen or confirmed that any therapeutic regimen produces sustained clinical benefit for patients with disseminated MAC, the Task Force concluded that the available information indicated the need for treatment of disseminated MAC (7)(8)(9)(10)(11)(12)(13)(14). The Public Health Service therefore recommends that regimens be based on the following principles: - Treatment regimens outside a clinical trial should include at least two agents. - Every regimen should contain either azithromycin or clarithromycin; many experts prefer ethambutol as a second drug. Many clinicians have added one or more of the following as second, third, or fourth agents: clofazimine, rifabutin, rifampin, ciprofloxacin, and in some situations amikacin. Isoniazid and pyrazinamide are not effective for the therapy of MAC. to address the prophylaxis and therapy of MAC recommends that patients with HIV infection and <100 CD4+ T-lymphocytes/µL be administered prophylaxis against MAC. The recommended regimen is rifabutin, 300 mg by mouth daily, for the patient's lifetime. If disseminated MAC develops, a treatment regimen containing clarithromycin or azithromycin and at least one other agent is recommended. Diagnosis, therapy, and prophylaxis for HIV-infected children follow similar guidelines. - Therapy should continue for the lifetime of the patient if clinical and microbiologic improvement is observed. # Monitoring Patients Receiving Therapy for Disseminated MAC - Clinical manifestations of disseminated MAC-such as fever, weight loss, and night sweats-should be monitored several times during the initial weeks of therapy. Microbiologic response, as assessed by blood culture every 4 weeks during initial therapy, can also be helpful in interpreting the efficacy of a therapeutic regimen. - Most patients who ultimately respond show substantial clinical improvement in the first 4-6 weeks of therapy. Elimination of the organisms from blood cultures may take somewhat longer, often requiring 4-12 weeks. # Recommendations for HIV-Infected Children HIV-infected children <12 years of age also develop disseminated MAC. Some age adjustment is necessary when clinicians interpret CD4+ T-lymphocyte counts in children <2 years of age. Diagnosis, therapy, and prophylaxis should follow recommendations similar to those for adolescents and adults.	The human T-lymphotropic viruses, type I (HTLV-I) and type II (HTLV-II), are closely related but distinct retroviruses that can infect humans. They are different from the human immunodeficiency viruses that cause acquired immunodeficiency syndrome. Screening of the U.S. blood supply for HTLV-I/II, which began in 1988, identifies HTLV-I-and HTLV-II-infected persons who should be counseled regarding their infections. This document summarizes current information about HTLV, types I and II, and presents recommendations developed by CDC and a U.S. Public Health Service working group for counseling HTLV-Iand HTLV-II-infected persons.# INTRODUCTION Human T-lymphotropic viruses, type I (HTLV-I) and type II (HTLV-II), were the first human retroviruses discovered (1,2 ). Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro. They are only distantly related to the human immunodeficiency viruses (HIV-1 and HIV-2), which belong to the lentivirus subfamily of retroviruses and which cause acquired immunodeficiency syndrome (AIDS). Infections with HTLV-I and HTLV-II are most easily detected serologically. The presence of antibodies to HTLV-I or HTLV-II indicates that a person is infected with the virus. In November 1988, the Food and Drug Administration (FDA) recommended that blood donation centers screen the U.S. blood supply for HTLV-I (3 ). Since then, all donations of whole blood and blood components in the United States have been screened for antibodies to HTLV-I. The screening tests that were licensed, as well as the investigational supplementary tests used to confirm seroreactivity (Western immunoblot and radioimmunoprecipitation assay), do not reliably differentiate between antibodies to HTLV-I and the closely related HTLV-II. In addition, the licensed screening tests, which use HTLV-I antigens, vary in their sensitivity to detect antibodies to HTLV-II (4,5 ). Approximately 2,000 HTLV-I/II-infected volunteer blood donors were identified in the first year of screening in the United States; testing, after amplification by polymerase chain reaction, indicated that approximately half were infected with HTLV-I and half with HTLV-II (6 ). Such donors are counseled and permanently deferred from donating blood. Because the polymerase chain-reaction test is not routinely available, many donors and other persons positive by serologic assays have been told that they are infected with HTLV-I/II. The uncertainty regarding the identity of the infecting virus and the differing epidemiologic and clinical correlates of HTLV-I and HTLV-II infections have complicated counseling of HTLV-I/II-infected persons. Until recently, the only reliable way to differentiate HTLV-I from HTLV-II infection was by polymerase chain reaction (7 ). Within the past 2 years, investigational peptide-and recombinant protein-based serologic assays that can more easily differentiate the antibodies to HTLV-I and HTLV-II have been developed (8,9 ). Preliminary data suggest that these investigational tests are potentially useful for typing serum samples (8,9 ). The recommendations for counseling HTLV-I-, HTLV-II-, and HTLV-I/II-infected persons included in this document are intended for use by health-care workers and public health officials in the United States. They may not be applicable in developing countries, where the need for breast-feeding may outweigh concerns about transmission of these viruses. # HTLV-I Prevalence HTLV-I infection is endemic in southwestern Japan (10 ), the Caribbean basin (11 ), Melanesia (12 ), and in parts of Africa (13)(14)(15). In some areas where HTLV-I infection is endemic, prevalence rates as high as 15% have been reported in the general population. Seroprevalence increases with age; in older age groups, rates are usually higher among women than men. In the United States, HTLV-I/II seroprevalence rates among volunteer blood donors average 0.016% (6 ). Approximately half of HTLV-I/II-seropositive blood donors nationwide are infected with HTLV-I. HTLV-I-infected donors most often report a history of birth in HTLV-I-endemic countries or sexual contact with persons from the Caribbean or Japan. Smaller percentages report a history of either injecting drug use or blood transfusion. Clusters of HTLV-I infections have also been reported in blacks from the southeastern United States (16 ) and in immigrants from HTLV-I-endemic areas residing in Brooklyn, New York (17 ). # Transmission Transmission of HTLV-I occurs from mother to child (18 ), by sexual contact (19 ), by blood transfusion (20 ), and by sharing contaminated needles. Mother-to-child transmission occurs primarily through breast-feeding (21 ); in HTLV-I-endemic areas, approximately 25% of breast-fed infants born to HTLV-I-seropositive mothers acquire infection. Recent studies suggest that transmission of HTLV-I by breast-feeding may be associated with the presence of maternal antibodies to the HTLV-I transactivating # TABLE 1. Clinical features of adult T-cell leukemia/lymphoma Leukemia with circulating abnormal lymphocytes (flower cells) Generalized peripheral lymphadenopathy Hepatomegaly and abnormal liver function tests Splenomegaly Skin lesions Bone lesions and hypercalcemia protein, tax (22 ), or with elevated maternal titers of total antibodies to HTLV-I (23 ). However, the clinical usefulness of these markers has not been established. Intrauterine or perinatal transmission of HTLV-I does occur, but it appears to be less frequent than transmission by breast-feeding; approximately 5% of children born to infected mothers but not breast-fed acquire infection (24 ). Sexual transmission of HTLV-I appears to be more efficient from males to females than from females to males. In one study of married couples in Japan, the efficiency of sexual transmission from males to females was estimated to be 60.8% over a 10year period, compared with <1% from females to males (25 ). In another study, the presence of antibody to tax in the male partner was associated with sexual transmission to the female partner (26 ). In one study in Jamaica, genital ulcer disease in the male was identified as a risk for female-to-male sexual transmission (27 ). In the United States, approximately 25%-30% of sex partners of HTLV-I/II-seropositive blood donors are also seropositive (28,29 ). Transmission of HTLV-I by blood transfusion occurs with transfusion of cellular blood products (whole blood, red blood cells, and platelets) but not with the plasma fraction or plasma derivatives from HTLV-I-infected blood. Seroconversion rates of 44% to 63% have been reported in recipients of HTLV-I-infected cellular components in HTLV-I endemic areas (20,30 ). Lower rates (approximately 20%) have been reported in recipients of contaminated cellular components in the United States (31 ). The probability of transmission by whole blood or packed red blood cells appears to diminish with greater duration of product storage; this finding has been ascribed to depletion of infected cells, presumably T-lymphocytes (30,32 ). Sharing blood-contaminated needles is the likely mode of transmission among injecting drug users. HTLV-I is not transmitted by casual contact. Health-care workers caring for HTLV-Iinfected persons need only be concerned about percutaneous exposure to HTLV-I-contaminated blood. One health-care worker who unintentionally inoculated himself with blood from an adult T-cell leukemia/lymphoma patient in Japan is reported to have seroconverted (33 ). However, no seroconversions occurred among 31 other laboratory and health-care workers exposed to HTLV-I via puncture wounds (34 ). Universal precautions, recommended for contact with all patients, are adequate to guard against HTLV-I transmission to health-care workers (35 ). # TABLE 2. Clinical features of HTLV-I-associated myelopathy/tropical spastic paraparesis Slowly progressive chronic spastic paraparesis Lower limb weakness Urinary incontinence and impotence Sensory disturbances such as tingling, pins and needles, and burning Low back pain Lower-extremity hyperreflexia with clonus and Babinski's sign Impaired vibration sense # Diseases Two diseases have been definitively associated with HTLV-I: adult T-cell leukemia/lymphoma (ATL) and a chronic degenerative neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). ATL is a malignancy of HTLV-I-infected CD4+ T-lymphocytes. The HTLV-I provirus is monoclonally integrated in the abnormal cell population. A spectrum of clinical and pathologic features has been described, including acute, chronic, lymphomatous, and smoldering forms (36,37 ). The acute form of ATL is characterized by infiltration of lymph nodes, viscera, and skin with malignant cells, resulting in a constellation of clinical features (Table 1). Circulating abnormal lymphocytes, called flower cells, are generally seen. Hypercalcemia, abnormal liver function values, and lytic bone lesions are common. Median survival is 11 months from diagnosis. Conventional chemotherapy is not curative, and relapses often occur quickly, although prolonged survival has been reported. ATL has been estimated to occur in 2%-4% of persons infected with HTLV-I in regions where HTLV-I is endemic and where early childhood infection is common (38,39 ). ATL occurs most frequently among persons 40-60 years of age, suggesting that a latent period as long as a few decades may be required for the disease to develop. One case of ATL in an immunocompromised patient has been reported in which the infection appears to have been transfusion acquired (40 ). HAM/TSP is characterized by progressive, permanent lower-extremity weakness, spasticity, hyperreflexia, sensory disturbances, and urinary incontinence (Table 2). In patients with HAM/TSP, unlike those with multiple sclerosis, the signs and symptoms do not wax and wane, cranial nerves are not involved, and cognitive function is not affected. Antibodies to HTLV-I are characteristically found in the cerebrospinal fluid (41 ). Treatment with corticosteroids has been reported to be useful in some cases (42 ). Danazol, a synthetic androgen, reportedly improves symptoms, including bladder dysfunction (43,44 ). HAM/TSP develops in <1% of HTLV-I-infected persons (45 ), is believed to be immunologically mediated, and affects women more frequently than men. The latency period for HAM/TSP is shorter than that for ATL; cases of HAM/TSP have been associated with blood transfusion, with a median interval of 3.3 years between transfusion and development of HAM/TSP (46 ). Recently, infective dermatitis, a chronic eczema associated with Staphylococcus aureus and beta-hemolytic streptococcus, has been reported in Jamaican children infected with HTLV-I (47 ). The full spectrum of HTLV-I-associated diseases may include other disorders. Cases of polymyositis (48 ), chronic arthropathy (49 ), panbronchiolitis (50 ), and uveitis (51 ) have been reported in HTLV-I-infected patients. # HTLV-II Prevalence Until recently, partly because of the lack of serologic tests to differentiate HTLV-II from HTLV-I, no information was available regarding the seroepidemiology or modes of transmission of HTLV-II. HTLV-II is prevalent among injecting drug users in the United States and in Europe (52,53 ); more than 80% of HTLV-I/II seropositivity in drug users in the United States is due to HTLV-II infection (54 ). HTLV-II also appears to be endemic in American Indian populations, including the Guaymi Indians in Panama (55 ) and North American Indians in Florida (56 ) and New Mexico (57 ). Approximately half of U.S. volunteer blood donors seropositive for HTLV-I/II are infected with HTLV-II. HTLV-II-infected blood donors most often report either a history of injecting drug use or a history of sexual contact with an injecting drug user (6,58 ). A smaller percentage report a history of blood transfusion. # Transmission HTLV-II is presumed to be transmitted similarly to HTLV-I, but much less is known about the specific modes and efficiency of transmission of HTLV-II. One study of 20 non-breast-fed children born to HTLV-II-infected women in New York City failed to show evidence of transmission to the newborns (59 ). The HTLV-II provirus has been detected in breast milk from HTLV-II-infected mothers ( 60), but no data are available regarding transmission to breast-fed infants. HTLV-II can be transmitted sexually (61 ); the most commonly reported risk factor among HTLV-II-infected female U.S. blood donors is sexual contact with an injecting drug user (6,58 ). HTLV-II can be transmitted by transfusion of cellular blood products (whole blood, red blood cells, and platelets) (31,32 ). The probability of transmission from red blood cells appears to diminish with greater duration of product storage (31 ). The high prevalence of HTLV-II among injecting drug users is likely due to sharing blood-contaminated needles or other injection paraphernalia (62 ). # Diseases HTLV-II infection has not been clearly associated with any diseases. The virus was first isolated from two patients with hairy-cell leukemia (2,63 ), but no evidence of HTLV-II infection was found in 21 additional patients with hairy-cell leukemia (64 ). In one study, rates of lymphoproliferative illnesses were not found to be increased in New Mexico, where HTLV-II is present in American Indians (65 ). Rare cases of HAM/TSP-like neurologic illnesses (66 ) and of mycosis fungoides (67 ) and large granular lymphocyte leukemia (68 ) have been reported in HTLV-II-infected persons. Cases of erythrodermatitis and bacterial skin infections have been reported in HIV-1and HTLV-II-coinfected persons (69 ). # SEROLOGIC TESTS FOR HTLV-I AND HTLV-II Serum specimens are screened for antibody to HTLV-I by using licensed enzyme immunoassays prepared from HTLV-I whole-virus lysate antigens. These assays vary in their sensitivity to detect antibodies to HTLV-II (4,5 ). Initially reactive specimens are retested in duplicate to minimize the chance that reactivity is due to technical error. Specimens that are reactive in either of the duplicate tests are considered repeatably reactive. Specimens that do not react in either of the duplicate repeat tests are considered nonreactive (3 ). Additional tests, such as the Western immunoblot and the radioimmunoprecipitation assay, are needed to correctly interpret repeatably reactive specimens. Such supplementary tests must be inherently capable of identifying antibodies to the core (gag ) and the envelope (env ) proteins of HTLV-I/II. Indirect fluorescent antibody test-ing for HTLV-I/II has been used in some laboratories, but it does not distinguish antibodies to specific HTLV gene products. None of the supplementary tests have been licensed by the Food and Drug Administration, but they are available in research institutions, blood banks, some public health laboratories, and industrial laboratories, and as in-house tests in some diagnostic laboratories. The following criteria for HTLV-I/II seropositivity were adopted by a U.S. Public Health Service (USPHS) working group in 1988 (3 ): a specimen that is repeatably reactive by enzyme immunoassay must demonstrate immunoreactivity to both the gag gene product p24 and to an env gene product (gp46 and/or gp61/68) to be considered seropositive for HTLV-I/II. Reactive serum specimens that do not satisfy these criteria but do show immunoreactivity to at least one suspected HTLV gene product are designated "indeterminate." Both Western immunoblot and radioimmunoprecipitation may be required to determine whether a specimen is positive or indeterminate. Serum specimens with no immunoreactivity to any HTLV gene product in additional, more specific tests are considered false positive. Several studies involving provirus amplification have supported the accuracy of these diagnostic criteria; persons whose specimens satisfy the criteria for positivity are virtually always infected with HTLV-I or HTLV-II (7,70 ). In contrast, persons whose specimens are "indeterminate" are rarely infected with either virus; for those who are found to be infected, repeat serologic testing frequently demonstrates seropositivity (70,71 ). In rare instances, persons with reactivity to p19 and to an env gene product (gp46 and/or gp61/68) but without reactivity to p24 have been found to be infected with HTLV-I/II (72 ). An important advance in HTLV serologic testing has been the development of a recombinant env protein, p21e. Reactivity to p21e (in either enzyme immunoassay or "spiked" Western immunoblot) has been found to be highly sensitive for HTLV-I/II infection, being observed in virtually 100% of infected persons (73 ). However, the specificity of the p21e reactivity has been questioned (74,75 ). For purposes of notification and counseling, the positivity of samples showing p21e serologically should be confirmed by tests that detect env reactivity, such as radioimmunoprecipitation or recombinant protein-based assays (76 ), or by polymerase chain reaction until further information is available concerning this test. The supplementary serologic tests discussed thus far are incapable of differentiating antibodies to HTLV-I and HTLV-II. The relative intensity of the reactivity to the gag proteins p19 and p24 on the "spiked" Western immunoblot has been used to differentiate HTLV-I from HTLV-II (77 ), but such differentiation may be unreliable (78 ). Recently, several synthetic peptides and recombinant proteins have been developed for this purpose (8,9,79 ). As with the previously discussed supplementary tests, all these tests are available for research only. Preliminary data indicate that such assays can be highly specific in differentiating antibodies to HTLV-I and HTLV-II (8,9,79 ). Not all HTLV-I/II-positive serum specimens, however, can be typed as HTLV-I or HTLV-II by using these tests. In these cases, more sophisticated methods, such as provirus amplification or virus isolation, may be needed to differentiate HTLV-I from HTLV-II infection. # NOTIFICATION AND DEFERRAL OF BLOOD DONORS In the United States, blood donors whose serum specimens are repeatably reactive by the HTLV-I enzyme immunoassay and confirmed as seropositive for HTLV-I/II by the additional specific tests discussed above are notified and permanently deferred from donating blood. This deferral policy includes donors confirmed positive with antibodies to HTLV-I, HTLV-II, or HTLV-I/II (if differentiation between the infections is not attempted or is unsuccessful). Blood donors with serum specimens repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II (a category that includes false-positive specimens and those indeterminate for HTLV) should also be notified and deferred if the same result is obtained on two separate donations. In some blood centers, such donors are deferred after the first such donation. Persons who are repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II should not be told that they are infected with HTLV-I or HTLV-II. The above policies for donor deferral are based on FDA recommendations. In addition, FDA recommendations regarding the use of blood components should be followed. # RECOMMENDATIONS FOR COUNSELING In consideration of the information presented above, the following recommendations for counseling HTLV-seropositive persons have been issued. In instances in which viral typing is possible, counseling should be virus specific. As noted above, HTLV-I and HTLV-II are two different retroviruses with differing epidemiologies and disease associations. The specific recommendations for persons infected with HTLV-I or HTLV-II should therefore take these differences into account. # HTLV-I Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-I by additional testing should be informed that they are infected with HTLV-I. They should be told that HTLV-I is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-I is a lifelong infection. They should be given information regarding modes and efficiency of transmission, disease associations, and the probability of developing disease. In particular, persons infected with HTLV-I should be advised to: • Share the information with their physician • Refrain from donating blood, semen, body organs, or other tissues • Refrain from sharing needles or syringes with anyone • Refrain from breast-feeding infants # • Consider the use of latex condoms to prevent sexual transmission If the HTLV-I-positive person is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-I to the negative partner, male or female. Male-infected, female-non-infected couples desiring pregnancy should be made aware of the finite risk of sexual transmission of HTLV-I during attempts at pregnancy and of the small risk for vertical transmission from mother to infant unrelated to breast-feeding. Such couples might be advised to use latex condoms at all times except during the fertile period while they are attempting pregnancy. The use of latex condoms is strongly recommended for HTLV-I-positive persons with multiple sex partners or otherwise engaging in non-mutually monogamous sexual relationships. These persons should be reminded of the risk of acquiring other sexually transmitted infections, including HIV. # HTLV-II Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-II by additional testing should be informed that they are infected with HTLV-II. They should be told that HTLV-II is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-II is a lifelong infection. They should be given information regarding possible modes of transmission and the lack of firm disease associations. In particular, they should be advised to: • Share the information with their physician • Refrain from donating blood, semen, body organs, or other tissues • Refrain from sharing drug needles or syringes with anyone # • Refrain from breast-feeding infants Although the risks of transmission of HTLV-II by breast-feeding and of disease from HTLV-II are unknown, the theoretical risk of transmission and disease, as for HTLV-I, makes it prudent to recommend that HTLV-II-infected mothers refrain from breast-feeding when and where safe nutritional alternatives exist. • Consider the use of barrier precautions to prevent sexual transmission HTLV-II can be sexually transmitted, but the risks of disease are unknown. If the HTLV-II-positive person is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-II to the negative partner, male or female. The use of latex condoms is strongly recommended for HTLV-II-positive persons with multiple sex partners or otherwise engaging in non-mutually monogamous sexual relationships. These persons should be reminded of the risk of acquiring other sexually transmitted infections, including HIV. # HTLV-I/II Persons found to be seropositive for HTLV-I/II according to the USPHS criteria but without differentiation of their infection should be informed they are positive for HTLV-I/II and that they are likely infected with either HTLV-I or HTLV-II. Because of the differences in the epidemiologic and clinical correlates of HTLV-I and HTLV-II, an effort to type the infection should be made. If such efforts are unsuccessful, these HTLV-I/II seropositive persons should be given information regarding possible modes and effi-ciency of transmission of HTLV-I and HTLV-II, disease associations of HTLV-I, and the probability of developing disease. Specific counseling advice should be the same as for HTLV-I-infected persons (refer to HTLV-I section). # HTLV Indeterminate Blood donors with serum specimens that are HTLV-indeterminate on two occasions at least 3 months apart should be advised that their specimens were reactive in a screening test for HTLV-I but that the results could not be confirmed by a second, more specific test. They should be reassured that "indeterminate" test results are only rarely caused by HTLV-I or HTLV-II infection. Persons testing "indeterminate" for HTLV-I/II on one occasion should be offered retesting to make sure they are not recently infected with HTLV-I or HTLV-II and in the process of seroconverting. If subsequent test results are the same, they should be reassured that they are unlikely to be infected with HTLV-I or HTLV-II. # HTLV False Positive Blood donors with serum specimens that are repeatably reactive by HTLV-I enzyme immunoassay but negative by Western immunoblot on two occasions should be advised that their HTLV-I screening test is falsely positive and that it could not be confirmed by a second, more specific test. They should be reassured that they are not infected with HTLV-I or HTLV-II. # Medical Follow-up A periodic medical evaluation of HTLV-I-or HTLV-I/II-infected persons by a physician knowlegeable about these viruses is recommended. This evaluation might include a physical examination, including a neurologic examination, and a complete blood count with peripheral smear examination. Medical evaluation of HTLV-II-infected persons should be considered optional. # Recommendations on Prophylaxis and # INTRODUCTION Mycobacterium avium complex (MAC) causes disseminated disease in up to 40% of patients with human immunodeficiency virus (HIV) in the United States, producing fever, sweats, weight loss, and anemia (1-3 ). Disseminated MAC characteristically affects patients with advanced HIV disease and peripheral CD4+ T-lymphocyte counts <100 cells/µL. Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons. Two randomized, placebo-controlled, multicenter studies were recently conducted to study the use of rifabutin for the prevention of disseminated MAC, as defined by positive blood culture. In these studies, rifabutin was shown to reduce the frequency of MAC bacteremia by approximately 50% (48 of 566 patients receiving rifabutin developed MAC, compared with 102 of 580 patients receiving placebo, p<0.001) (4,5 ). On December 23, 1992, the Food and Drug Administration issued the first approval for a prophylactic drug targeted against MAC. Data collected in published and unpublished studies (1-3 ) suggest that health-care providers may utilize and their patients may benefit from recommendations for prevention and management provided by a panel of experts drawn from government agencies, universities, practicing clinicians, and the community. The U.S. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex was convened in Bethesda, Maryland, on December 7-8, 1992, and issued the recommendations in this report. # Indications for Prophylaxis Patients with HIV infection and <100 CD4+ T-lymphocytes/µL should be administered prophylaxis against MAC. Prophylaxis should be continued for the patient's lifetime unless multiple drug therapy for MAC becomes necessary because of the development of MAC disease. Clinicians must weigh the potential benefits of MAC prophylaxis against the potential for toxicities and drug interactions, the cost, the potential to produce resistance in a community with a high rate of tuberculosis, and the possibility that the addition of another drug to the medical regimen may adversely affect patients' compliance with treatment. Because of these concerns, therefore, in some situations rifabutin prophylaxis should not be administered. # Evaluation before Beginning Prophylaxis Before prophylaxis is administered, patients should be assessed to ensure that they do not have active disease due to MAC, M. tuberculosis, or any other mycobacterial species. This assessment may include a chest radiograph and tuberculin skin test. # Prophylactic Regimens Rifabutin, 300 mg by mouth daily, is recommended for the patient's lifetime unless disseminated MAC develops, which would then require multiple drug therapy (4,5 ). Although other drugs, such as azithromycin and clarithromycin, have laboratory and clinical activity against MAC, none has been shown in a prospective, controlled trial to be effective and safe for prophylaxis. Thus, in the absence of data, no other regimen can be recommended at this time. The 300-mg dose of rifabutin has been well tolerated (4,5 ). Adverse effects included neutropenia, thrombocytopenia, rash, and gastrointestinal disturbances. # Diagnosis of MAC Disseminated MAC is most readily diagnosed by one positive blood culture (6 ). Blood cultures should be performed in patients with symptoms, signs, or laboratory abnormalities compatible with mycobacterium infection. Blood cultures are not routinely recommended for asymptomatic persons, even for those who have CD4+ T-lymphocyte counts <100 cells/µL. # Therapy of Disseminated MAC Although studies have not yet identified an optimal regimen or confirmed that any therapeutic regimen produces sustained clinical benefit for patients with disseminated MAC, the Task Force concluded that the available information indicated the need for treatment of disseminated MAC (7)(8)(9)(10)(11)(12)(13)(14). The Public Health Service therefore recommends that regimens be based on the following principles: • Treatment regimens outside a clinical trial should include at least two agents. • Every regimen should contain either azithromycin or clarithromycin; many experts prefer ethambutol as a second drug. Many clinicians have added one or more of the following as second, third, or fourth agents: clofazimine, rifabutin, rifampin, ciprofloxacin, and in some situations amikacin. Isoniazid and pyrazinamide are not effective for the therapy of MAC. # to address the prophylaxis and therapy of MAC recommends that patients with HIV infection and <100 CD4+ T-lymphocytes/µL be administered prophylaxis against MAC. The recommended regimen is rifabutin, 300 mg by mouth daily, for the patient's lifetime. If disseminated MAC develops, a treatment regimen containing clarithromycin or azithromycin and at least one other agent is recommended. Diagnosis, therapy, and prophylaxis for HIV-infected children follow similar guidelines. • Therapy should continue for the lifetime of the patient if clinical and microbiologic improvement is observed. # Monitoring Patients Receiving Therapy for Disseminated MAC • Clinical manifestations of disseminated MAC-such as fever, weight loss, and night sweats-should be monitored several times during the initial weeks of therapy. Microbiologic response, as assessed by blood culture every 4 weeks during initial therapy, can also be helpful in interpreting the efficacy of a therapeutic regimen. • Most patients who ultimately respond show substantial clinical improvement in the first 4-6 weeks of therapy. Elimination of the organisms from blood cultures may take somewhat longer, often requiring 4-12 weeks. # Recommendations for HIV-Infected Children HIV-infected children <12 years of age also develop disseminated MAC. Some age adjustment is necessary when clinicians interpret CD4+ T-lymphocyte counts in children <2 years of age. Diagnosis, therapy, and prophylaxis should follow recommendations similar to those for adolescents and adults.	None	None
8b70617989022eb9772b6f618cae552c82b5e73a	cdc	None	General recommendations on pertussis prevention were issued August 8, 1991, in the ACIP statement on diphtheria, tetanus, and pertussis (1). A supplementary statement on the use of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) was issued February 7, 1992 (2) after the licensure of ACEL-IMUNE (Registered), prepared by Lederle Laboratories. With the recent licensure of a second DTaP product, - Tripedia(Trademark), this statement updates the supplement. Tripedia(Trademark) has a formulation that differs from that of ACEL-IMUNE(Registered). Both DTaP vaccines are licensed for use only as the fourth and/or fifth doses of diphtheria, tetanus, and pertussis vaccination; they are not licensed for the initial three-dose series for infants and children, regardless of age. Whole-cell DTP should continue to be used for the initial three-dose series and remains an acceptable alternative for the fourth and fifth doses. For details on the background, indications, use, and precautions and contraindications of DTaP, refer to the earlier supplementary statement (2). Corporation (Osaka, Japan), and is combined with diphtheria and tetanus toxoids manufactured by Connaught Laboratories.Disclaimer All MMWR HTML documents published before January 1993 are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.# INTRODUCTION Simultaneous vaccination against diphtheria, tetanus, and pertussis during infancy and childhood has been a recommended routine practice in the United States since the late 1940s. Whole-cell pertussis vaccines in the United States have been and continue to be prepared from suspensions of killed Bordetella pertussis whole bacterial cells. Routine vaccination with whole-cell vaccines has been highly effective in reducing the burden of disease and deaths due to pertussis (3). Whole-cell pertussis vaccines, although safe, are associated with a variety of expected adverse events; these concerns have led to attempts to develop safer pertussis vaccines that have high efficacy. Several antigenic components of Bordetella pertussis have been identified. Candidate acellular pertussis vaccines, produced by multinational manufacturers, are now available due to advances in the methods of purifying and preparing these components. In general, these vaccines are immunogenic and are less likely to cause common adverse reactions than the current whole-cell preparations. Several clinical trials, which compare relative protective efficacy of primary vaccination utilizing diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines with that of whole-cell vaccines administered to infants, are in progress or development. A lack of adequate evidence, until recently, to demonstrate the effectiveness of any single preparation has delayed U.S. licensure for any indication of a candidate acellular pertussis vaccine. On December 17, 1991, the Food and Drug Administration (FDA) licensed the DTaP vaccine ACEL-IMUNE (Registered) for use as the fourth and/or fifth doses of the recommended DTP series. The FDA has now licensed a second DTaP vaccine, Tripedia(Trademark). # Tripedia(Trademark) Information On August 21, 1992, the FDA licensed Tripedia(Trademark) for use as the fourth and/or fifth doses of the recommended DTP series. The acellular pertussis vaccine components are purified from Bordetella pertussis by salt precipitation, ultracentrifugation, and ultrafiltration. After purification, filamentous hemagglutinin (FHA) and pertussis toxin (PT) are combined to obtain a 1:1 ratio and are then treated with formaldehyde to inactivate PT. Each dose of Tripedia(Trademark) contains 23.4 mcg protein of FHA and 23.4 mcg protein of inactivated PT (toxoid), as well as 6.7 Lf of diphtheria toxoid and 5.0 Lf of tetanus toxoid. The combined components are adsorbed to aluminum potassium sulfate and preserved with 1:10,000 thimerosal. Household exposure and ecologic studies among Japanese children vaccinated at greater than or equal to 2 years of age, have suggested efficacy of the BIKEN and other acellular pertussis vaccines when combined with diphtheria and tetanus toxoids as DTaP (4-7). In addition, a randomized, placebo-controlled clinical efficacy trial in Sweden during the period 1985-1987 demonstrated efficacy when two doses of a BIKEN pertussis vaccine --similar to the formulation in Tripedia(Trademark) --were given to children starting at ages 5-11 months old, an age older than that recommended for initiating whole-cell DTP vaccination in the United States (1,8). However, the experiences in Sweden and Japan do not satisfactorily define whether acellular pertussis vaccines confer clinical protection when administered early in infancy (i.e., 2, 4, and 6 months of age) and whether protection induced at any age is equivalent to that of whole-cell pertussis vaccine preparations. The following evidence supports the use of Tripedia(Trademark) after the initial three-dose series of whole-cell DTP vaccine in infants: Immunogenicity Antibody responses to PT and FHA following administration of Tripedia(Trademark) as the fourth and fifth doses of the vaccination series are similar to or higher than those following whole-cell DTP vaccine (Table_1). Data are available to demonstrate the immunogenicity of Tripedia(Trademark) among children ages 15-16 months. The standard, single-dose volume of Tripedia(Trademark) is 0.5 mL and should be administered intramuscularly (IM). # Clinical efficacy The efficacy of two acellular pertussis vaccines developed by the Japan National Institute of Health (JNIH) and prepared by BIKEN was studied in 1985-1987 in a randomized, placebo-controlled clinical trial in Sweden (2,8). One of the vaccines (JNIH-6) contained 23.4 mcg protein/dose each of formaldehyde-treated PT and FHA. The first dose of vaccine or placebo was administered at 5-11 months of age; the second dose was administered 8-12 weeks later. For culture-confirmed disease with cough of any duration, the observed efficacy for JNIH-6 was 69% (95% confidence interval (CI), 47%-82%); for culture-confirmed pertussis with cough lasting greater than 30 days, the observed efficacy was 79% (95% CI, 57%-90%) (8). Non-blinded follow-up studies conducted over a 42-month interval after the trial had ended support the efficacy estimates obtained from the clinical trial (9). # Safety Local reactions, fever, and other common systemic symptoms occur less frequently after receipt of Tripedia(Trademark) vaccine than after whole-cell DTP vaccine. In general, the frequency of local and common systemic events is approximately one-fifth to one-half the frequency of these events after wholecell DTP vaccination (Table_2). # VACCINE USAGE See the general ACIP statement on diphtheria, tetanus, and pertussis (1) and the supplementary statement on DTaP for more details (2). DTaP preparations are currently licensed only for use as the fourth and/or fifth doses of the DTP series among children ages 15 months through 6 years (before the seventh birthday). Any of the licensed whole-cell DTP or DTaP preparations can be used interchangeably for the fourth and fifth doses of the routine series of vaccination against diphtheria, tetanus, and pertussis among children greater than or equal to 15 months of age. The ACIP Committee recommends the use of DTaP, if readily available, because it substantially reduces local reactions, fever, and other common systemic events that often follow receipt of whole-cell DTP. There are no specific data to support the use of one particular DTaP vaccine product over the other. No data exist regarding the intermixed use of the two DTaP products at the fourth and fifth doses of the series with respect to safety, immunogenicity, or efficacy. Tripedia(Trademark) can be administered to children as part of the recommended schedule of routine simultaneous vaccination with DTP; oral poliovirus vaccine (OPV); measles, mumps, and rubella vaccine (MMR); and, when appropriate, Haemophilus b conjugate vaccine (HbCV) at 15-18 months of age (9). # SIDE EFFECTS AND ADVERSE REACTIONS For a complete discussion, see the general ACIP statement on diphtheria, tetanus, and pertussis and the supplementary statement on DTaP (1,2). Refer to the earlier supplementary statement for details on the precautions and contraindications to DTaP use (2). Although mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia occur frequently after both whole-cell DTP vaccination and Tripedia(Trademark) vaccination, they are less common after Tripedia(Trademark) (Table_2). These reactions are self-limited and can be safely managed with symptomatic treatment. Moderate-to-severe systemic events, including fever greater than or equal to 40.5 C (105 F); persistent, inconsolable crying lasting greater than or equal to 3 hours; and collapse (hypotonic-hyporesponsive episode) have rarely been reported after vaccination with DTaP (8,(10)(11)(12). Each of these events appears to occur less often than with whole-cell DTP. When these events occur after the administration of whole-cell DTP, they appear to be without sequelae; the limited experience with DTaP suggests a similar outcome. Other more severe neurologic events, such as prolonged convulsions or encephalopathy, have not been reported in temporal association after administration of approximately 11,000 doses of Tripedia(Trademark) in U.S. studies. This limited experience does not allow conclusions to be drawn as to whether any rare serious adverse events will occur after administration of DTaP. Because DTaP causes fever less frequently than whole-cell DTP, it is anticipated that events such as febrile convulsions will be less common after receipt of DTaP. # Table_1 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. ------------------------------- -------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------- # Table_2 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. --------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------	General recommendations on pertussis prevention were issued August 8, 1991, in the ACIP statement on diphtheria, tetanus, and pertussis (1). A supplementary statement on the use of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) was issued February 7, 1992 (2) after the licensure of ACEL-IMUNE (Registered), prepared by Lederle Laboratories. With the recent licensure of a second DTaP product, * Tripedia(Trademark), this statement updates the supplement. Tripedia(Trademark) has a formulation that differs from that of ACEL-IMUNE(Registered). Both DTaP vaccines are licensed for use only as the fourth and/or fifth doses of diphtheria, tetanus, and pertussis vaccination; they are not licensed for the initial three-dose series for infants and children, regardless of age. Whole-cell DTP should continue to be used for the initial three-dose series and remains an acceptable alternative for the fourth and fifth doses. For details on the background, indications, use, and precautions and contraindications of DTaP, refer to the earlier supplementary statement (2). Corporation (Osaka, Japan), and is combined with diphtheria and tetanus toxoids manufactured by Connaught Laboratories.Disclaimer All MMWR HTML documents published before January 1993 are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.# INTRODUCTION Simultaneous vaccination against diphtheria, tetanus, and pertussis during infancy and childhood has been a recommended routine practice in the United States since the late 1940s. Whole-cell pertussis vaccines in the United States have been and continue to be prepared from suspensions of killed Bordetella pertussis whole bacterial cells. Routine vaccination with whole-cell vaccines has been highly effective in reducing the burden of disease and deaths due to pertussis (3). Whole-cell pertussis vaccines, although safe, are associated with a variety of expected adverse events; these concerns have led to attempts to develop safer pertussis vaccines that have high efficacy. Several antigenic components of Bordetella pertussis have been identified. Candidate acellular pertussis vaccines, produced by multinational manufacturers, are now available due to advances in the methods of purifying and preparing these components. In general, these vaccines are immunogenic and are less likely to cause common adverse reactions than the current whole-cell preparations. Several clinical trials, which compare relative protective efficacy of primary vaccination utilizing diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines with that of whole-cell vaccines administered to infants, are in progress or development. A lack of adequate evidence, until recently, to demonstrate the effectiveness of any single preparation has delayed U.S. licensure for any indication of a candidate acellular pertussis vaccine. On December 17, 1991, the Food and Drug Administration (FDA) licensed the DTaP vaccine ACEL-IMUNE (Registered) for use as the fourth and/or fifth doses of the recommended DTP series. The FDA has now licensed a second DTaP vaccine, Tripedia(Trademark). # Tripedia(Trademark) Information On August 21, 1992, the FDA licensed Tripedia(Trademark) for use as the fourth and/or fifth doses of the recommended DTP series. The acellular pertussis vaccine components are purified from Bordetella pertussis by salt precipitation, ultracentrifugation, and ultrafiltration. After purification, filamentous hemagglutinin (FHA) and pertussis toxin (PT) are combined to obtain a 1:1 ratio and are then treated with formaldehyde to inactivate PT. Each dose of Tripedia(Trademark) contains 23.4 mcg protein of FHA and 23.4 mcg protein of inactivated PT (toxoid), as well as 6.7 Lf of diphtheria toxoid and 5.0 Lf of tetanus toxoid. The combined components are adsorbed to aluminum potassium sulfate and preserved with 1:10,000 thimerosal. Household exposure and ecologic studies among Japanese children vaccinated at greater than or equal to 2 years of age, have suggested efficacy of the BIKEN and other acellular pertussis vaccines when combined with diphtheria and tetanus toxoids as DTaP (4-7). In addition, a randomized, placebo-controlled clinical efficacy trial in Sweden during the period 1985-1987 demonstrated efficacy when two doses of a BIKEN pertussis vaccine --similar to the formulation in Tripedia(Trademark) --were given to children starting at ages 5-11 months old, an age older than that recommended for initiating whole-cell DTP vaccination in the United States (1,8). However, the experiences in Sweden and Japan do not satisfactorily define whether acellular pertussis vaccines confer clinical protection when administered early in infancy (i.e., 2, 4, and 6 months of age) and whether protection induced at any age is equivalent to that of whole-cell pertussis vaccine preparations. The following evidence supports the use of Tripedia(Trademark) after the initial three-dose series of whole-cell DTP vaccine in infants: Immunogenicity Antibody responses to PT and FHA following administration of Tripedia(Trademark) as the fourth and fifth doses of the vaccination series are similar to or higher than those following whole-cell DTP vaccine (Table_1). Data are available to demonstrate the immunogenicity of Tripedia(Trademark) among children ages 15-16 months. The standard, single-dose volume of Tripedia(Trademark) is 0.5 mL and should be administered intramuscularly (IM). # Clinical efficacy The efficacy of two acellular pertussis vaccines developed by the Japan National Institute of Health (JNIH) and prepared by BIKEN was studied in 1985-1987 in a randomized, placebo-controlled clinical trial in Sweden (2,8). One of the vaccines (JNIH-6) contained 23.4 mcg protein/dose each of formaldehyde-treated PT and FHA. The first dose of vaccine or placebo was administered at 5-11 months of age; the second dose was administered 8-12 weeks later. For culture-confirmed disease with cough of any duration, the observed efficacy for JNIH-6 was 69% (95% confidence interval (CI), 47%-82%); for culture-confirmed pertussis with cough lasting greater than 30 days, the observed efficacy was 79% (95% CI, 57%-90%) (8). Non-blinded follow-up studies conducted over a 42-month interval after the trial had ended support the efficacy estimates obtained from the clinical trial (9). # Safety Local reactions, fever, and other common systemic symptoms occur less frequently after receipt of Tripedia(Trademark) vaccine than after whole-cell DTP vaccine. In general, the frequency of local and common systemic events is approximately one-fifth to one-half the frequency of these events after wholecell DTP vaccination (Table_2). # VACCINE USAGE See the general ACIP statement on diphtheria, tetanus, and pertussis (1) and the supplementary statement on DTaP for more details (2). DTaP preparations are currently licensed only for use as the fourth and/or fifth doses of the DTP series among children ages 15 months through 6 years (before the seventh birthday). Any of the licensed whole-cell DTP or DTaP preparations can be used interchangeably for the fourth and fifth doses of the routine series of vaccination against diphtheria, tetanus, and pertussis among children greater than or equal to 15 months of age. The ACIP Committee recommends the use of DTaP, if readily available, because it substantially reduces local reactions, fever, and other common systemic events that often follow receipt of whole-cell DTP. There are no specific data to support the use of one particular DTaP vaccine product over the other. No data exist regarding the intermixed use of the two DTaP products at the fourth and fifth doses of the series with respect to safety, immunogenicity, or efficacy. Tripedia(Trademark) can be administered to children as part of the recommended schedule of routine simultaneous vaccination with DTP; oral poliovirus vaccine (OPV); measles, mumps, and rubella vaccine (MMR); and, when appropriate, Haemophilus b conjugate vaccine (HbCV) at 15-18 months of age (9). # SIDE EFFECTS AND ADVERSE REACTIONS For a complete discussion, see the general ACIP statement on diphtheria, tetanus, and pertussis and the supplementary statement on DTaP (1,2). Refer to the earlier supplementary statement for details on the precautions and contraindications to DTaP use (2). Although mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia occur frequently after both whole-cell DTP vaccination and Tripedia(Trademark) vaccination, they are less common after Tripedia(Trademark) (Table_2). These reactions are self-limited and can be safely managed with symptomatic treatment. Moderate-to-severe systemic events, including fever greater than or equal to 40.5 C (105 F); persistent, inconsolable crying lasting greater than or equal to 3 hours; and collapse (hypotonic-hyporesponsive episode) have rarely been reported after vaccination with DTaP (8,(10)(11)(12). Each of these events appears to occur less often than with whole-cell DTP. When these events occur after the administration of whole-cell DTP, they appear to be without sequelae; the limited experience with DTaP suggests a similar outcome. Other more severe neurologic events, such as prolonged convulsions or encephalopathy, have not been reported in temporal association after administration of approximately 11,000 doses of Tripedia(Trademark) in U.S. studies. This limited experience does not allow conclusions to be drawn as to whether any rare serious adverse events will occur after administration of DTaP. Because DTaP causes fever less frequently than whole-cell DTP, it is anticipated that events such as febrile convulsions will be less common after receipt of DTaP. # Table_1 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. ------------------------------- -------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------- # Table_2 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. --------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------	None	None
99f7cf71fa1cb563ed8c01b9863511a2ccd9c173	cdc	None	Farm workers are approximately six times more likely to develop tuberculosis (TB) than the general population of employed adults. These recommendations are presented to assist health-care providers serving migrant and seasonal farm workers. The following services, listed by priority, that should be available for migrant and seasonal farm workers and their family members are: a) detection and diagnosis of those with current symptoms of active TB; b) appropriate treatment and monitoring for those who have current disease; c) contact investigation and appropriate preventive therapy for those exposed to infectious persons; d) screening and appropriate preventive therapy for asymptomatically infected workers who may be immunosuppressed, such as those with human immunodeficiency virus (HIV) infection; e) screening and appropriate preventive therapy for children of migrant and seasonal farm workers; and f) widespread tuberculin test screening for workers and families with preventive therapy prescribed, as appropriate. Health-care providers should immediately perform appropriate diagnostic studies for persons with a productive, prolonged cough, or other symptoms suggestive of tuberculosis. Health departments should be immediately notified when TB is suspected or diagnosed to enable examination of contacts and initiation of other health department diagnostic, preventive, or patient management services. Workers and family members with uncomplicated pulmonary TB should be treated with a regimen that includes isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). Drug-resistant TB is an important consideration since it requires altered treatment regimes and because higher rates of resistance have been found in ethnic and social groups comprising much of the migrant farm worker-force. Patients should be monitored carefully for compliance, treatment response, and toxicity. Ideally, patients should be placed on directly observed therapy given by a well-trained, outreach worker from the same cultural/language background as the patients.# INTRODUCTION The Department of Health and Human Services (DHHS) Advisory Council for the Elimination of Tuberculosis (ACET) has published a plan for the elimination of tuberculosis (TB) from the United States by the Year 2010 (1). The plan gives top priority to implementation of strategies to prevent TB in identifiable high-incidence population groups, including migrant and seasonal farm workers. In this document, a "migrant farm worker" is defined as a laborer whose principal employment is in agriculture on a seasonal basis and who establishes for the purposes of such employment a temporary abode. The term "seasonal farm worker" means a person whose principal employment is in agriculture on a seasonal basis, but who does not move from area to area for work. These recommendations are intended for health-care providers serving migrant and seasonal farm workers --providers who can contribute to the elimination of TB in this population through improved screening, prevention, and control activities. The recommendations are also directed to health departments because of their important role in assisting migrant health-care providers in the prevention and control of TB among migrant and seasonal farm workers. Finally, these recommendations are directed to public policy and decision makers because many health departments and migrant health-care providers do not now have the resources and staff to fully implement these recommendations. # MIGRANT FARM WORKERS AND MIGRANT PATTERNS Information provided by the Office of Migrant Health, DHHS, indicates that there are an estimated 4.2 million migrant and seasonal farm workers in the United States. Approximately 500,000 (12%) are served by federally supported migrant health centers (2). Compared with the general population, these workers often have numerous and complex health problems (e.g., TB, parasitic diseases, other communicable diseases, diabetes, hypertension, high-risk pregnancy, and neonatal problems), and they often live in substandard housing and in very crowded conditions. Continuity of medical care is difficult for migrant farm workers because they move often. Migrant and seasonal farm workers and their families often face linguistic, cultural, financial, immigration, educational, and other barriers that also make it difficult for them to obtain needed health-care services. These barriers must be addressed by migrant health and public health officials when designing and carrying out strategies for implementing the recommendations in this report. Migrant farm workers in the United States traditionally follow one of three geographic migratory streams (travel patterns: East Coast, Midwest, and West Coast). The race, ethnicity, and cultural background of migrant farm workers vary somewhat from stream to stream. Living and working conditions, as well as access to transportation, also vary. These differing characteristics may affect access to health-care and the formulation of strategies for TB prevention and control. In all three streams, families often migrate together to maximize family income. Some settle in a town to pursue better educational or work opportunities, but often remain tied to local agricultural activities. The primary residence or homebase areas (e.g., California, Texas, Puerto Rico, and Florida) for all three streams are economically disadvantaged areas. # East Coast Migrant Stream In the East Coast stream, most workers have their primary homebase, or winter home, in southern Florida. The largest cultural groups in this stream are Hispanic, primarily Mexican Americans and Mexicans, Central American refugees, and Puerto Ricans; other groups in this stream are American blacks, Haitians and Appalachian whites. Migrants in the East Coast stream most often reside in ethnically homogeneous labor camps, characterized by family unit housing or single-sex barracks. A primary contractor or crew leader usually contracts directly with a grower to supply farm workers. The crew leader also provides meals and transportation, the cost of which is usually deducted from workers' pay. Farm workers, during the harvest season, may change camps or move to a new location with a crew or group. Thus, outreach is a very important factor in delivering health care to this migrant population. # Midwest Migrant Stream In the Midwest stream, most farm workers use south Texas as their homebase and work winter crops there before moving up into the midwestern states. South Texas is the largest migrant homebase area in the nation. Migrant farm workers from there also may move into the East and West Coast migrant streams. Mexican Americans constitute the majority of migrant farm workers in this stream, but recently the number of Southeast Asian migrant farm workers has been increasing in this stream. The basic Midwest migrant family unit travels "upstream" from the homebase community in groups with children and other relatives, sometimes also accompanied by friends, including single males. The migrant groups generally travel in cars with the crew leader or "truckero" transporting personal possessions in a truck for the crew. The crew leader's truck also may be used to haul produce during harvesting. Migrants in southern Texas live as part of the community in "colonias" or unincorporated areas. These areas are not required to have water, sewage, or electric services, and some colonias have none. Three to six families may live under one roof on a 20' by 40' plot of land. Family members cross the border to visit or stay with relatives in Mexico during the winter months. When not in the homebase area, migrants in the Midwest stream live primarily in labor camps. # West Coast Migrant Stream Most migrant farm workers in the West Coast stream use southern California as homebase. This stream runs north through Idaho, Oregon, and Washington. The West Coast stream consists mostly of Mexican Americans from the southwest, primarily California and Texas. American blacks, non-Hispanic whites, and increasing numbers of Southeast Asians and Central Americans comprise a smaller percentage of the migrant farm workers in this stream. Southeast Asians, however, quickly settle in the area, leaving the migrant stream. The primary migrant units in the West Coast Stream are individual families. Some single males come from Mexico to work the crops and then return home. Many of these workers own their own cars and have more mobility and better access to medical care. Generally, there are better housing conditions in the West Coast stream than in the other streams. However, migrants are living under bridges and along river banks in Southern California. As in other migrant streams, these migrant families live in labor camps when they leave their homebase. # TUBERCULOSIS IN MIGRANT FARM WORKERS Although the magnitude of the problem of TB among migrant and seasonal farm workers is not clearly established, a survey conducted by CDC during the period 1985-1989 assessed the occupational and residential characteristics of TB cases reported in 29 states; overall farm workers accounted for more than 5% of all employed cases. Based on data from that survey, the risk of TB among farm workers was estimated to be six times greater than the general population of employed adults (CDC, unpublished data). The first population-based study of TB in a random sample of migrant farm workers, conducted in 1988 in North Carolina, indicated a prevalence of active TB in 0.47% of Hispanics and 3.5% of American blacks (3). Migrant farm workers also have high rates of asymptomatic TB infection (positive skin tests). A 1987 study showed a skin-test positivity rate of 29% among U.S.-born blacks and 55% among Haitian migrant farm workers in the Delmarva Peninsula (4). Tuberculin testing of migrant farm workers employed in Virginia's Eastern Shore showed overall skin-test positivity rates of 39% and 48% in 1984 and 1985, respectively (5). In a separate study conducted in 1988, Hispanic migrant farm workers in North Carolina had a tuberculin skin-test positivity rate of 31% (6). A 1988 study demonstrated a 47% prevalence rate of TB infection among migrant farm workers 15-34 years of age and a 68% prevalence rate among those greater than 34 years of age (7). In the population-based study (3), tuberculin positivity rates ranged from 33% (Hispanics) to 62% (blacks) to 76% (Haitians). These high rates of asymptomatic TB infection suggest that screening and prevention activities should be directed to migrant farm workers. # INFECTION AND TRANSMISSION The TB organism M. tuberculosis, also known as the tubercle bacillus, is transmitted primarily through the air from persons with TB of the lung who are coughing. Persons who share the same air with an infectious person for long periods of time are at risk of becoming infected. This includes persons living in the same household with the infectious person and those who travel in the same vehicle. Most persons who become infected usually develop a positive TB skin test, but remain asymptomatic and are not infectious. The lifetime risk of acquiring clinically active TB disease is about 10%; it is greatest in the first 2 years after infection, but disease can also occur many years later. Impairment of the immune system, such as by HIV infection, increases the risk of clinically active TB. # RECOMMENDATIONS ACET developed these recommendations for the Public Health Service, public health departments, and for health-care providers serving migrant and seasonal farm workers. # Prevention and Control The following prevention and control activities should be undertaken for all migrant and seasonal farm workers and their families. The services of highest priority that should be available to all workers and their families, are: Detection and diagnosis of those persons with current symptoms of active TB. Appropriate treatment for those persons with disease. Contact investigation and appropriate preventive therapy for those persons exposed to infectious (sputum positive) TB. Screening and appropriate preventive therapy for workers who may be immunosuppressed, including those with HIV infection. The second priority is screening and appropriate preventive therapy for children of migrant and seasonal farm workers. The third priority is widespread tuberculin skin-test screening of workers and families, followed by appropriate preventive therapy. Providing the above services will require a commitment of resources from the national, state, and local levels. # Diagnosis Pulmonary TB should be suspected in persons with a productive, prolonged cough ( greater than 2 weeks in duration). Other common symptoms of TB include fever, chills, night sweats, fatigue, loss of appetite, weight loss, and, occasionally, hemoptysis (coughing up blood). Persons with suspected pulmonary TB should receive an immediate evaluation that includes: a medical history and physical examination, chest x-ray, Mantoux tuberculin test, at least three sputum specimens (collected on separate days) for acid fast bacilli (AFB) smear, culture and drug susceptibility testing, and HIV-antibody counseling and testing. If the clinician confirms or suspects TB as a result of this examination, the local health department should be notified so that appropriate examination of contacts can be initiated. Migrant health-care providers should seek, and health departments should provide, no-cost TB medical consultation, medication and laboratory services for migrant farm workers. # Hospitalization and Isolation Health departments should ensure that inpatient care (e.g., hospitalization) is available at no cost to migrant farm workers or family members. Persons hospitalized with infectious TB should be placed in AFB isolation until they become noninfectious (8). Health department TB control staff should be consulted on issues regarding hospitalization, housing, and return to work. The restriction of normal activities and the duration of such restrictions depends upon: the degree of infectiousness, the response to treatment, the nature of activities, and the likelihood that others might be exposed. Some patients are never infectious and have no need for restrictions. Care must be taken in housing TB patients to ensure that those who may be infectious do not expose uninfected farm workers or family members. Patients who feel well may be able to continue normal work activities, particularly in an open-air work setting where there is little risk of exposure for new or highly susceptible contacts. Treatment (Tables 1 and 2) Migrant and seasonal farm workers and family members with uncomplicated pulmonary TB can be treated with the following 6-month regimen: isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) given for 2 months (initial phase), followed by isoniazid and rifampin for 4 months (second phase). Ethambutol (or streptomycin) should be included in the initial regimen until drug susceptibility studies are available. Among migrant workers, higher rates of resistance to isoniazid and streptomycin are known to occur. Drug resistance is also more common in patients with a history of previous treatment and in contacts to drug-resistant patients. Medication does not have to be given on a daily basis throughout the entire course of treatment. Several options exist for administering directly observed therapy. Intermittent (e.g., twice weekly) therapy may be administered during the second phase after daily therapy during the initial phase. For those for whom prolonged supervision of daily therapy during the initial phase is impractical, a regimen of daily isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) for 2 weeks, followed by twice weekly administration of the same drugs for 6 weeks, and subsequently twice weekly isoniazid and rifampin for 16 weeks has been shown to be highly effective (9). Alternatively, three times weekly administration of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) for 6 months yields equivalent results (10). (When isoniazid, ethambutol, and pyrazinamide are administered 2 or 3 times weekly instead of every day, the dosage must be increased; the rifampin dose is the same for daily or intermittent therapy.) In cases of smear and culture negative pulmonary TB, when drug resistance is unlikely, reducing the 6-month regimen to 4 months is acceptable. The same regimen should be used to treat sputum-culture-negative, tuberculin-positive persons with radiographic evidence of healed TB or silicosis. All persons with confirmed or suspected TB should be offered HIV testing and counseling. For HIV seropositive patients, treatment should be continued for a minimum of 9 months and for at least 6 months beyond documented culture conversion as evidenced by three negative cultures. Patients treated with rifampin who are on methadone should have the methadone dosage increased to avoid withdrawal symptoms resulting from the interaction between the two drugs (11). The treatment regimen should be appropriately revised if resistance to any of the drugs in the regimen is found. Treatment of extrapulmonary TB and TB related to drug resistance or HIV infection may be complicated. For this reason, a health department or another qualified TB and infectious disease medical expert should be consulted. # Monitoring Response (Table 3) Patients should be medically assessed at least twice monthly for symptoms and by smear until they become asymptomatic and smear negative. Cultures should be obtained at least monthly until negative. Frequent smears and cultures are the most reliable means for detecting treatment failure. Treatment failure is often due to patient noncompliance with therapy, but also may be due to an ineffective regimen (e.g., when the organisms are resistant to the drugs). Patients should demonstrate sputum conversion within 3 months. Appropriate medical consultation should be sought for patients whose sputum does not convert within this time. Such patients must be evaluated for noncompliance and drug-resistant organisms. Toxicity monitoring must be individualized and based on the drugs used in a given regimen and patient factors related to toxicity (e.g., age and alcohol use). Patients should be evaluated at least monthly during therapy and questioned about reactions to determine toxicity, even if no problems are apparent. Patients should be specifically instructed to look for symptoms associated with the most common reactions to the medications they are receiving. If symptoms suggesting drug toxicity occur, appropriate laboratory testing and medical evaluation should be performed immediately. All patients receiving isoniazid, rifampin, and/or pyrazinamide should be instructed to report immediately any symptoms suggesting hepatitis (loss of appetite, nausea, vomiting, jaundice, malaise, unexplained elevated temperature of greater than 3 days duration, or abdominal tenderness). Peripheral neuropathy associated with isoniazid administration is uncommon at doses of 5 mg/kg. Among persons with conditions in which neuropathy is common (diabetes, uremia, alcoholism, malnutrition), pyridoxine (50 mg day) may be given with isoniazid. It is also advisable to give pyridoxine with isoniazid to pregnant women or persons who have a seizure disorder. Hyperuricemia may occur in patients receiving pyrazinamide, but acute gout is uncommon. The interaction of isoniazid and phenytoin increases the serum concentration of both drugs. When these drugs are given concomitantly, the serum level of phenytoin should be monitored. Rifampin may accelerate clearance of drugs metabolized by the liver. These include methadone, coumadin derivatives, glucocorticoids, estrogens, oral hypoglycemic agents, digitalis, anticonvulsants, ketoconazole, and cyclosporin. By accelerating estrogen metabolism, rifampin may interfere with the effectiveness of oral contraceptives. Outreach workers responsible for directly observed therapy should be trained to identify symptoms related to reactions and toxicity. They should also be trained to obtain sputum specimens. # Monitoring Compliance Treatment must be continuous to be effective. Identify noncompliance early, before drug resistance, treatment failure, or relapse occurs, or before the patient is lost to follow-up. A number of techniques have been developed to assist in identifying the noncompliant patient. The majority of noncompliant patients is determined by their failure to return for follow-up clinic visits. Thus, having an accurate appointment and delinquent referral system is paramount. An effective communication system is also needed to assure that the discovery of missed appointments immediately comes to the attention of the responsible public health officials. Monthly pill counts are also helpful in early identification of noncompliance. The best way to ensure compliance is to place patients on directly observed therapy given by a well-trained outreach worker from the same cultural/language background as the patient population. Health departments should provide staff for this purpose. As an alternative, a concerned and interested person may be identified to directly observe the patient's therapy (e.g., family member). Incentives and enablers should be considered to encourage patient compliance. These might include such items as food or food vouchers and transportation vouchers or tokens. Long-term institutionalization is sometimes necessary for the management of seriously uncooperative patients. If, despite the best efforts of migrant health-care and health department staff, an infectious patient refuses treatment, temporary involuntary isolation may be mecessary in accordance with state and local public health laws and regulations. This option should be used only in rare instances and only after due process. # Contact Investigation Contact investigation should begin as soon as a migrant or seasonal farm worker or family member is suspected to have infectious TB. The health department assumes this responsibility. The investigation normally involves a visit to the patient's work and housing site to observe transmission possibilities, identify contacts, and to note factors that might affect compliance with treatment or preventive therapy. The investigation should begin with close contacts who are most likely to be infected, usually the persons living with and sharing the same air space as the patient. Close contacts include family members of workers traveling and working alone, if they have lived in the household during the preceding year. (The health department can make arrangements to ensure that out-of-area family members and other remote contacts receive appropriate examinations.) High priority should be given to rapid examination of close contacts who are children. Newly infected children can develop life threatening meningitis within weeks of infection unless preventive therapy is administered. Contacts should be interviewed for symptoms and given a tuberculin skin-test using the Mantoux technique. Those with symptoms of respiratory disease or skin-test reactions of greater than or equal to 5mm should be given chest radiograph examinations. All contacts with reactions of greater than or equal to 5mm should be considered for preventive therapy. Close contacts of highly infectious persons, especially young children, should be considered for preventive therapy even if the initial tuberculin test after exposure is negative. The preventive therapy can be halted if contact with the infectious person(s) is discontinued and a repeat tuberculin test, 3 months after exposure, remains negative. # Screening Screening should be carried out by migrant health-care providers in cooperation with employers and local health departments. In the absence of definitive data, screening of migrant farm workers should be considered annually. Emphasis should be placed on screening and preventive therapy conducted in the homebase sites. However, since access to health care is sometimes better in non-homebase areas, TB screening and preventive therapy programs should be encouraged wherever resources and access to migrant farm workers permit. This is particularly important for "settled out" workers who choose not to return to homebase areas. The Mantoux tuberculin skin test should be used to identify persons who have been infected with M. tuberculosis. Multiple puncture tests should not be used. Migrant and seasonal farm workers, as well as members of their families, should be considered tuberculin positive according to the following criteria. Outside the United States, many countries use Bacille Calmette-Guerin (BCG) vaccination as part of their TB control activities, especially for infants. The degree of sensitivity to tuberculin that is acquired after BCG vaccination is highly variable. No reliable method exists for distinguishing tuberculin reactions caused by previous BCG vaccination from those caused by natural mycobacterial infections. Positive tuberculin reactions in BCG-vaccinated persons from high prevalence areas usually indicate infection with M. tuberculosis. Such persons should be evaluated for preventive therapy. Persons who have tuberculous infection should receive a chest radiograph. If the radiograph does not show TB, preventive therapy should be considered. Persons with abnormal radiographs and/or other symptoms suggesting TB should be referred for further evaluation. # Preventive Therapy The use of preventive therapy can substantially reduce the risk of TB (by more than 90%) in infected persons who comply with therapy (12). A minimum of 6 months of preventive therapy is recommended. However, a 12-month course is recommended for tuberculin-positive persons with HIV infection. Whenever necessary, preventive therapy should be directly observed and should be administered twice weekly to facilitate the supervision of treatment (INH 15mg/kg up to 900mg). Before migrant farm workers and their family members are placed on preventive therapy, ensure that they are likely to complete at least 6 months of the regimen. The rationale for this policy is to ensure that persons receive the benefits from 6 months of preventive therapy and not just the early risk of toxicity. Persons with a positive tuberculin reaction who are not placed on preventive therapy should be counseled about the meaning of the skin-test reaction and instructed to seek medical attention if they develop symptoms suggesting TB. The following list defines those migrant and seasonal farm workers and their family members with positive tuberculin reactions (who have not been previously treated) who should be considered candidates for preventive therapy regardless of age: Persons with known or suspected HIV infection, including injecting drug users. # Close contacts of infectious persons. Recent tuberculin skin test converters (defined as a greater than or equal to 10 mm increase for those less than 35 years old; or a greater than or equal to 15 mm increase for those greater than or equal to 35 years old). Persons with medical conditions that increase the risk of TB (e.g., diabetes, being 10% or more below ideal body weight, or prolonged adrenocorticosteroid therapy). Persons with a positive tuberculin test should be considered for preventive therapy even if they have no other medical risk factor when they are less than 35 years of age. Before therapy is initiated, baseline liver function studies should be done for all persons greater than or equal to 35 years of age. Persons on preventive therapy should be monitored at least monthly, by questioning, for: compliance with prescribed regimen, symptoms of neurotoxicity (such as paresthesia of hands or feet), and signs consistent with hepatotoxicity (e.g., loss of appetite, nausea, vomiting, persistent dark urine, jaundice, malaise, or unexplained elevated temperature of greater than 3 days duration, or abdominal tenderness especially in the upper right quadrant). Patients should be advised to report immediately to their health-care provider if any of these signs or symptoms occur. Pill counts should be done each month for all persons on preventive therapy. # Follow-Up When a migrant farm worker is departing and requires treatment for active TB, preventive treatment, or diagnostic services, health providers should contact their state health department TB control officers to apprise them of the need for follow-up and of the next possible destination of the farm worker. Out-of-state communications regarding TB care should be routed through state health departments to ensure that the information is transmitted appropriately and that necessary follow-up is initiated. Often the health-care provider or health department will receive a TB laboratory report after the person departs for another area. The report should be immediately telephoned or expeditiously mailed to the health department or health-care provider in the next area. Although sharing necessary information between health-care providers and health departments is encouraged to protect the health of the worker and the public, information should be shared only on a need-to-know basis. Measures must be taken to ensure confidentiality. Migrants who are placed on antituberculosis treatment or preventive therapy should be given records they can take with them to indicate their current treatment and diagnostic status. Special care should be taken to instruct such persons on how to take their medications and how and where to get additional medication and medical care at the destination sites. Different areas have different protocols for the treatment of active TB and for the preventive treatment of infected persons. However, once a patient starts treatment or a preventive treatment regimen, the same regimen should be continued in the migrant's next location (unless medically contraindicated). # Role of Public Health Departments Health departments should ensure the provision of TB services for migrant and seasonal farm workers regardless of ability to pay. These services should include diagnostic services, antituberculosis medication, laboratory services, contact follow-up and inpatient and outpatient clinical services. Making medical care accessible to the migrant farm workers and their families often means providing services in migrant health-care centers or near the work site. Health departments should make outreach services available for directly observed therapy. Health departments should ensure that expert TB medical consultation is available to the clinicians and nurses providing health-care services to migrant farm workers. # Role of the Public Health Service The Public Health Service (PHS) should promote collaboration between health departments and migrant health centers in the homebase states and elsewhere to plan and carry out TB screening and preventive therapy programs. The PHS should require documentation of such collaboration as part of applications for federally funded migrant health and TB grants and cooperative agreements. In addition, as part of routine site visits, PHS staff should review related activities and make proposals for more effective implementation of the recommendations in this document. The CDC and the Health Resources and Services Administration, with the assistance of the Migrant Clinicians Network, should jointly develop a prototype TB medical history card to be given to migrant workers. The card should indicate results of the worker's latest tuberculin test, history of preventive therapy, and appropriate current and past treatment and diagnostic status. This card can serve as a supplement to, but cannot substitute for, complete medical records Full implementation will require the commitment of additional resources at the national, state and local levels. Implementation of these recommendations is an important step in the TB elimination effort. Most importantly, implementation of these recommendations will be of great benefit to individual migrant farm workers and their families whose economic and social progress is being impeded by the occurrence of TB. 12. IUAT. Efficacy of various duration of isoniazid preventive therapy for tuberculosis: five years of follow-up in IUAT trials. Bull WHO 1982;60:(4):555-64. The Advisory Council for the Elimination of Tuberculosis recognizes that a variety of terms are used and preferred by different groups to describe race and ethnicity. Racial and ethnic terms used throughout this document reflect the way data are collected and reported by official health agencies. All MMWR HTML documents published before January 1993 electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices. # Return To: MMWR MMWR Home Page CDC Home Page Questions or messages regarding errors in formatting should be addressed to [email protected].	Farm workers are approximately six times more likely to develop tuberculosis (TB) than the general population of employed adults. These recommendations are presented to assist health-care providers serving migrant and seasonal farm workers. The following services, listed by priority, that should be available for migrant and seasonal farm workers and their family members are: a) detection and diagnosis of those with current symptoms of active TB; b) appropriate treatment and monitoring for those who have current disease; c) contact investigation and appropriate preventive therapy for those exposed to infectious persons; d) screening and appropriate preventive therapy for asymptomatically infected workers who may be immunosuppressed, such as those with human immunodeficiency virus (HIV) infection; e) screening and appropriate preventive therapy for children of migrant and seasonal farm workers; and f) widespread tuberculin test screening for workers and families with preventive therapy prescribed, as appropriate. Health-care providers should immediately perform appropriate diagnostic studies for persons with a productive, prolonged cough, or other symptoms suggestive of tuberculosis. Health departments should be immediately notified when TB is suspected or diagnosed to enable examination of contacts and initiation of other health department diagnostic, preventive, or patient management services. Workers and family members with uncomplicated pulmonary TB should be treated with a regimen that includes isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). Drug-resistant TB is an important consideration since it requires altered treatment regimes and because higher rates of resistance have been found in ethnic and social groups comprising much of the migrant farm worker-force. Patients should be monitored carefully for compliance, treatment response, and toxicity. Ideally, patients should be placed on directly observed therapy given by a well-trained, outreach worker from the same cultural/language background as the patients.# INTRODUCTION The Department of Health and Human Services (DHHS) Advisory Council for the Elimination of Tuberculosis (ACET) has published a plan for the elimination of tuberculosis (TB) from the United States by the Year 2010 (1). The plan gives top priority to implementation of strategies to prevent TB in identifiable high-incidence population groups, including migrant and seasonal farm workers. In this document, a "migrant farm worker" is defined as a laborer whose principal employment is in agriculture on a seasonal basis and who establishes for the purposes of such employment a temporary abode. The term "seasonal farm worker" means a person whose principal employment is in agriculture on a seasonal basis, but who does not move from area to area for work. These recommendations are intended for health-care providers serving migrant and seasonal farm workers --providers who can contribute to the elimination of TB in this population through improved screening, prevention, and control activities. The recommendations are also directed to health departments because of their important role in assisting migrant health-care providers in the prevention and control of TB among migrant and seasonal farm workers. Finally, these recommendations are directed to public policy and decision makers because many health departments and migrant health-care providers do not now have the resources and staff to fully implement these recommendations. # MIGRANT FARM WORKERS AND MIGRANT PATTERNS Information provided by the Office of Migrant Health, DHHS, indicates that there are an estimated 4.2 million migrant and seasonal farm workers in the United States. Approximately 500,000 (12%) are served by federally supported migrant health centers (2). Compared with the general population, these workers often have numerous and complex health problems (e.g., TB, parasitic diseases, other communicable diseases, diabetes, hypertension, high-risk pregnancy, and neonatal problems), and they often live in substandard housing and in very crowded conditions. Continuity of medical care is difficult for migrant farm workers because they move often. Migrant and seasonal farm workers and their families often face linguistic, cultural, financial, immigration, educational, and other barriers that also make it difficult for them to obtain needed health-care services. These barriers must be addressed by migrant health and public health officials when designing and carrying out strategies for implementing the recommendations in this report. Migrant farm workers in the United States traditionally follow one of three geographic migratory streams (travel patterns: East Coast, Midwest, and West Coast). The race, ethnicity, and cultural background of migrant farm workers vary somewhat from stream to stream. Living and working conditions, as well as access to transportation, also vary. These differing characteristics may affect access to health-care and the formulation of strategies for TB prevention and control. In all three streams, families often migrate together to maximize family income. Some settle in a town to pursue better educational or work opportunities, but often remain tied to local agricultural activities. The primary residence or homebase areas (e.g., California, Texas, Puerto Rico, and Florida) for all three streams are economically disadvantaged areas. # East Coast Migrant Stream In the East Coast stream, most workers have their primary homebase, or winter home, in southern Florida. The largest cultural groups in this stream are Hispanic, primarily Mexican Americans and Mexicans, Central American refugees, and Puerto Ricans; other groups in this stream are American blacks, Haitians and Appalachian whites. Migrants in the East Coast stream most often reside in ethnically homogeneous labor camps, characterized by family unit housing or single-sex barracks. A primary contractor or crew leader usually contracts directly with a grower to supply farm workers. The crew leader also provides meals and transportation, the cost of which is usually deducted from workers' pay. Farm workers, during the harvest season, may change camps or move to a new location with a crew or group. Thus, outreach is a very important factor in delivering health care to this migrant population. # Midwest Migrant Stream In the Midwest stream, most farm workers use south Texas as their homebase and work winter crops there before moving up into the midwestern states. South Texas is the largest migrant homebase area in the nation. Migrant farm workers from there also may move into the East and West Coast migrant streams. Mexican Americans constitute the majority of migrant farm workers in this stream, but recently the number of Southeast Asian migrant farm workers has been increasing in this stream. The basic Midwest migrant family unit travels "upstream" from the homebase community in groups with children and other relatives, sometimes also accompanied by friends, including single males. The migrant groups generally travel in cars with the crew leader or "truckero" transporting personal possessions in a truck for the crew. The crew leader's truck also may be used to haul produce during harvesting. Migrants in southern Texas live as part of the community in "colonias" or unincorporated areas. These areas are not required to have water, sewage, or electric services, and some colonias have none. Three to six families may live under one roof on a 20' by 40' plot of land. Family members cross the border to visit or stay with relatives in Mexico during the winter months. When not in the homebase area, migrants in the Midwest stream live primarily in labor camps. # West Coast Migrant Stream Most migrant farm workers in the West Coast stream use southern California as homebase. This stream runs north through Idaho, Oregon, and Washington. The West Coast stream consists mostly of Mexican Americans from the southwest, primarily California and Texas. American blacks, non-Hispanic whites, and increasing numbers of Southeast Asians and Central Americans comprise a smaller percentage of the migrant farm workers in this stream. Southeast Asians, however, quickly settle in the area, leaving the migrant stream. The primary migrant units in the West Coast Stream are individual families. Some single males come from Mexico to work the crops and then return home. Many of these workers own their own cars and have more mobility and better access to medical care. Generally, there are better housing conditions in the West Coast stream than in the other streams. However, migrants are living under bridges and along river banks in Southern California. As in other migrant streams, these migrant families live in labor camps when they leave their homebase. # TUBERCULOSIS IN MIGRANT FARM WORKERS Although the magnitude of the problem of TB among migrant and seasonal farm workers is not clearly established, a survey conducted by CDC during the period 1985-1989 assessed the occupational and residential characteristics of TB cases reported in 29 states; overall farm workers accounted for more than 5% of all employed cases. Based on data from that survey, the risk of TB among farm workers was estimated to be six times greater than the general population of employed adults (CDC, unpublished data). The first population-based study of TB in a random sample of migrant farm workers, conducted in 1988 in North Carolina, indicated a prevalence of active TB in 0.47% of Hispanics and 3.5% of American blacks (3). Migrant farm workers also have high rates of asymptomatic TB infection (positive skin tests). A 1987 study showed a skin-test positivity rate of 29% among U.S.-born blacks and 55% among Haitian migrant farm workers in the Delmarva Peninsula (4). Tuberculin testing of migrant farm workers employed in Virginia's Eastern Shore showed overall skin-test positivity rates of 39% and 48% in 1984 and 1985, respectively (5). In a separate study conducted in 1988, Hispanic migrant farm workers in North Carolina had a tuberculin skin-test positivity rate of 31% (6). A 1988 study demonstrated a 47% prevalence rate of TB infection among migrant farm workers 15-34 years of age and a 68% prevalence rate among those greater than 34 years of age (7). In the population-based study (3), tuberculin positivity rates ranged from 33% (Hispanics) to 62% (blacks) to 76% (Haitians). These high rates of asymptomatic TB infection suggest that screening and prevention activities should be directed to migrant farm workers. # INFECTION AND TRANSMISSION The TB organism M. tuberculosis, also known as the tubercle bacillus, is transmitted primarily through the air from persons with TB of the lung who are coughing. Persons who share the same air with an infectious person for long periods of time are at risk of becoming infected. This includes persons living in the same household with the infectious person and those who travel in the same vehicle. Most persons who become infected usually develop a positive TB skin test, but remain asymptomatic and are not infectious. The lifetime risk of acquiring clinically active TB disease is about 10%; it is greatest in the first 2 years after infection, but disease can also occur many years later. Impairment of the immune system, such as by HIV infection, increases the risk of clinically active TB. # RECOMMENDATIONS ACET developed these recommendations for the Public Health Service, public health departments, and for health-care providers serving migrant and seasonal farm workers. # Prevention and Control The following prevention and control activities should be undertaken for all migrant and seasonal farm workers and their families. The services of highest priority that should be available to all workers and their families, are: Detection and diagnosis of those persons with current symptoms of active TB. Appropriate treatment for those persons with disease. Contact investigation and appropriate preventive therapy for those persons exposed to infectious (sputum positive) TB. Screening and appropriate preventive therapy for workers who may be immunosuppressed, including those with HIV infection. The second priority is screening and appropriate preventive therapy for children of migrant and seasonal farm workers. The third priority is widespread tuberculin skin-test screening of workers and families, followed by appropriate preventive therapy. Providing the above services will require a commitment of resources from the national, state, and local levels. # Diagnosis Pulmonary TB should be suspected in persons with a productive, prolonged cough ( greater than 2 weeks in duration). Other common symptoms of TB include fever, chills, night sweats, fatigue, loss of appetite, weight loss, and, occasionally, hemoptysis (coughing up blood). Persons with suspected pulmonary TB should receive an immediate evaluation that includes: a medical history and physical examination, chest x-ray, Mantoux tuberculin test, at least three sputum specimens (collected on separate days) for acid fast bacilli (AFB) smear, culture and drug susceptibility testing, and HIV-antibody counseling and testing. If the clinician confirms or suspects TB as a result of this examination, the local health department should be notified so that appropriate examination of contacts can be initiated. Migrant health-care providers should seek, and health departments should provide, no-cost TB medical consultation, medication and laboratory services for migrant farm workers. # Hospitalization and Isolation Health departments should ensure that inpatient care (e.g., hospitalization) is available at no cost to migrant farm workers or family members. Persons hospitalized with infectious TB should be placed in AFB isolation until they become noninfectious (8). Health department TB control staff should be consulted on issues regarding hospitalization, housing, and return to work. The restriction of normal activities and the duration of such restrictions depends upon: the degree of infectiousness, the response to treatment, the nature of activities, and the likelihood that others might be exposed. Some patients are never infectious and have no need for restrictions. Care must be taken in housing TB patients to ensure that those who may be infectious do not expose uninfected farm workers or family members. Patients who feel well may be able to continue normal work activities, particularly in an open-air work setting where there is little risk of exposure for new or highly susceptible contacts. Treatment (Tables 1 and 2) Migrant and seasonal farm workers and family members with uncomplicated pulmonary TB can be treated with the following 6-month regimen: isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) given for 2 months (initial phase), followed by isoniazid and rifampin for 4 months (second phase). Ethambutol (or streptomycin) should be included in the initial regimen until drug susceptibility studies are available. Among migrant workers, higher rates of resistance to isoniazid and streptomycin are known to occur. Drug resistance is also more common in patients with a history of previous treatment and in contacts to drug-resistant patients. Medication does not have to be given on a daily basis throughout the entire course of treatment. Several options exist for administering directly observed therapy. Intermittent (e.g., twice weekly) therapy may be administered during the second phase after daily therapy during the initial phase. For those for whom prolonged supervision of daily therapy during the initial phase is impractical, a regimen of daily isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) for 2 weeks, followed by twice weekly administration of the same drugs for 6 weeks, and subsequently twice weekly isoniazid and rifampin for 16 weeks has been shown to be highly effective (9). Alternatively, three times weekly administration of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) for 6 months yields equivalent results (10). (When isoniazid, ethambutol, and pyrazinamide are administered 2 or 3 times weekly instead of every day, the dosage must be increased; the rifampin dose is the same for daily or intermittent therapy.) In cases of smear and culture negative pulmonary TB, when drug resistance is unlikely, reducing the 6-month regimen to 4 months is acceptable. The same regimen should be used to treat sputum-culture-negative, tuberculin-positive persons with radiographic evidence of healed TB or silicosis. All persons with confirmed or suspected TB should be offered HIV testing and counseling. For HIV seropositive patients, treatment should be continued for a minimum of 9 months and for at least 6 months beyond documented culture conversion as evidenced by three negative cultures. Patients treated with rifampin who are on methadone should have the methadone dosage increased to avoid withdrawal symptoms resulting from the interaction between the two drugs (11). The treatment regimen should be appropriately revised if resistance to any of the drugs in the regimen is found. Treatment of extrapulmonary TB and TB related to drug resistance or HIV infection may be complicated. For this reason, a health department or another qualified TB and infectious disease medical expert should be consulted. # Monitoring Response (Table 3) Patients should be medically assessed at least twice monthly for symptoms and by smear until they become asymptomatic and smear negative. Cultures should be obtained at least monthly until negative. Frequent smears and cultures are the most reliable means for detecting treatment failure. Treatment failure is often due to patient noncompliance with therapy, but also may be due to an ineffective regimen (e.g., when the organisms are resistant to the drugs). Patients should demonstrate sputum conversion within 3 months. Appropriate medical consultation should be sought for patients whose sputum does not convert within this time. Such patients must be evaluated for noncompliance and drug-resistant organisms. Toxicity monitoring must be individualized and based on the drugs used in a given regimen and patient factors related to toxicity (e.g., age and alcohol use). Patients should be evaluated at least monthly during therapy and questioned about reactions to determine toxicity, even if no problems are apparent. Patients should be specifically instructed to look for symptoms associated with the most common reactions to the medications they are receiving. If symptoms suggesting drug toxicity occur, appropriate laboratory testing and medical evaluation should be performed immediately. All patients receiving isoniazid, rifampin, and/or pyrazinamide should be instructed to report immediately any symptoms suggesting hepatitis (loss of appetite, nausea, vomiting, jaundice, malaise, unexplained elevated temperature of greater than 3 days duration, or abdominal tenderness). Peripheral neuropathy associated with isoniazid administration is uncommon at doses of 5 mg/kg. Among persons with conditions in which neuropathy is common (diabetes, uremia, alcoholism, malnutrition), pyridoxine (50 mg day) may be given with isoniazid. It is also advisable to give pyridoxine with isoniazid to pregnant women or persons who have a seizure disorder. Hyperuricemia may occur in patients receiving pyrazinamide, but acute gout is uncommon. The interaction of isoniazid and phenytoin increases the serum concentration of both drugs. When these drugs are given concomitantly, the serum level of phenytoin should be monitored. Rifampin may accelerate clearance of drugs metabolized by the liver. These include methadone, coumadin derivatives, glucocorticoids, estrogens, oral hypoglycemic agents, digitalis, anticonvulsants, ketoconazole, and cyclosporin. By accelerating estrogen metabolism, rifampin may interfere with the effectiveness of oral contraceptives. Outreach workers responsible for directly observed therapy should be trained to identify symptoms related to reactions and toxicity. They should also be trained to obtain sputum specimens. # Monitoring Compliance Treatment must be continuous to be effective. Identify noncompliance early, before drug resistance, treatment failure, or relapse occurs, or before the patient is lost to follow-up. A number of techniques have been developed to assist in identifying the noncompliant patient. The majority of noncompliant patients is determined by their failure to return for follow-up clinic visits. Thus, having an accurate appointment and delinquent referral system is paramount. An effective communication system is also needed to assure that the discovery of missed appointments immediately comes to the attention of the responsible public health officials. Monthly pill counts are also helpful in early identification of noncompliance. The best way to ensure compliance is to place patients on directly observed therapy given by a well-trained outreach worker from the same cultural/language background as the patient population. Health departments should provide staff for this purpose. As an alternative, a concerned and interested person may be identified to directly observe the patient's therapy (e.g., family member). Incentives and enablers should be considered to encourage patient compliance. These might include such items as food or food vouchers and transportation vouchers or tokens. Long-term institutionalization is sometimes necessary for the management of seriously uncooperative patients. If, despite the best efforts of migrant health-care and health department staff, an infectious patient refuses treatment, temporary involuntary isolation may be mecessary in accordance with state and local public health laws and regulations. This option should be used only in rare instances and only after due process. # Contact Investigation Contact investigation should begin as soon as a migrant or seasonal farm worker or family member is suspected to have infectious TB. The health department assumes this responsibility. The investigation normally involves a visit to the patient's work and housing site to observe transmission possibilities, identify contacts, and to note factors that might affect compliance with treatment or preventive therapy. The investigation should begin with close contacts who are most likely to be infected, usually the persons living with and sharing the same air space as the patient. Close contacts include family members of workers traveling and working alone, if they have lived in the household during the preceding year. (The health department can make arrangements to ensure that out-of-area family members and other remote contacts receive appropriate examinations.) High priority should be given to rapid examination of close contacts who are children. Newly infected children can develop life threatening meningitis within weeks of infection unless preventive therapy is administered. Contacts should be interviewed for symptoms and given a tuberculin skin-test using the Mantoux technique. Those with symptoms of respiratory disease or skin-test reactions of greater than or equal to 5mm should be given chest radiograph examinations. All contacts with reactions of greater than or equal to 5mm should be considered for preventive therapy. Close contacts of highly infectious persons, especially young children, should be considered for preventive therapy even if the initial tuberculin test after exposure is negative. The preventive therapy can be halted if contact with the infectious person(s) is discontinued and a repeat tuberculin test, 3 months after exposure, remains negative. # Screening Screening should be carried out by migrant health-care providers in cooperation with employers and local health departments. In the absence of definitive data, screening of migrant farm workers should be considered annually. Emphasis should be placed on screening and preventive therapy conducted in the homebase sites. However, since access to health care is sometimes better in non-homebase areas, TB screening and preventive therapy programs should be encouraged wherever resources and access to migrant farm workers permit. This is particularly important for "settled out" workers who choose not to return to homebase areas. The Mantoux tuberculin skin test should be used to identify persons who have been infected with M. tuberculosis. Multiple puncture tests should not be used. Migrant and seasonal farm workers, as well as members of their families, should be considered tuberculin positive according to the following criteria. Outside the United States, many countries use Bacille Calmette-Guerin (BCG) vaccination as part of their TB control activities, especially for infants. The degree of sensitivity to tuberculin that is acquired after BCG vaccination is highly variable. No reliable method exists for distinguishing tuberculin reactions caused by previous BCG vaccination from those caused by natural mycobacterial infections. Positive tuberculin reactions in BCG-vaccinated persons from high prevalence areas usually indicate infection with M. tuberculosis. Such persons should be evaluated for preventive therapy. Persons who have tuberculous infection should receive a chest radiograph. If the radiograph does not show TB, preventive therapy should be considered. Persons with abnormal radiographs and/or other symptoms suggesting TB should be referred for further evaluation. # Preventive Therapy The use of preventive therapy can substantially reduce the risk of TB (by more than 90%) in infected persons who comply with therapy (12). A minimum of 6 months of preventive therapy is recommended. However, a 12-month course is recommended for tuberculin-positive persons with HIV infection. Whenever necessary, preventive therapy should be directly observed and should be administered twice weekly to facilitate the supervision of treatment (INH 15mg/kg up to 900mg). Before migrant farm workers and their family members are placed on preventive therapy, ensure that they are likely to complete at least 6 months of the regimen. The rationale for this policy is to ensure that persons receive the benefits from 6 months of preventive therapy and not just the early risk of toxicity. Persons with a positive tuberculin reaction who are not placed on preventive therapy should be counseled about the meaning of the skin-test reaction and instructed to seek medical attention if they develop symptoms suggesting TB. The following list defines those migrant and seasonal farm workers and their family members with positive tuberculin reactions (who have not been previously treated) who should be considered candidates for preventive therapy regardless of age: Persons with known or suspected HIV infection, including injecting drug users. # Close contacts of infectious persons. Recent tuberculin skin test converters (defined as a greater than or equal to 10 mm increase for those less than 35 years old; or a greater than or equal to 15 mm increase for those greater than or equal to 35 years old). Persons with medical conditions that increase the risk of TB (e.g., diabetes, being 10% or more below ideal body weight, or prolonged adrenocorticosteroid therapy). Persons with a positive tuberculin test should be considered for preventive therapy even if they have no other medical risk factor when they are less than 35 years of age. Before therapy is initiated, baseline liver function studies should be done for all persons greater than or equal to 35 years of age. Persons on preventive therapy should be monitored at least monthly, by questioning, for: compliance with prescribed regimen, symptoms of neurotoxicity (such as paresthesia of hands or feet), and signs consistent with hepatotoxicity (e.g., loss of appetite, nausea, vomiting, persistent dark urine, jaundice, malaise, or unexplained elevated temperature of greater than 3 days duration, or abdominal tenderness especially in the upper right quadrant). Patients should be advised to report immediately to their health-care provider if any of these signs or symptoms occur. Pill counts should be done each month for all persons on preventive therapy. # Follow-Up When a migrant farm worker is departing and requires treatment for active TB, preventive treatment, or diagnostic services, health providers should contact their state health department TB control officers to apprise them of the need for follow-up and of the next possible destination of the farm worker. Out-of-state communications regarding TB care should be routed through state health departments to ensure that the information is transmitted appropriately and that necessary follow-up is initiated. Often the health-care provider or health department will receive a TB laboratory report after the person departs for another area. The report should be immediately telephoned or expeditiously mailed to the health department or health-care provider in the next area. Although sharing necessary information between health-care providers and health departments is encouraged to protect the health of the worker and the public, information should be shared only on a need-to-know basis. Measures must be taken to ensure confidentiality. Migrants who are placed on antituberculosis treatment or preventive therapy should be given records they can take with them to indicate their current treatment and diagnostic status. Special care should be taken to instruct such persons on how to take their medications and how and where to get additional medication and medical care at the destination sites. Different areas have different protocols for the treatment of active TB and for the preventive treatment of infected persons. However, once a patient starts treatment or a preventive treatment regimen, the same regimen should be continued in the migrant's next location (unless medically contraindicated). # Role of Public Health Departments Health departments should ensure the provision of TB services for migrant and seasonal farm workers regardless of ability to pay. These services should include diagnostic services, antituberculosis medication, laboratory services, contact follow-up and inpatient and outpatient clinical services. Making medical care accessible to the migrant farm workers and their families often means providing services in migrant health-care centers or near the work site. Health departments should make outreach services available for directly observed therapy. Health departments should ensure that expert TB medical consultation is available to the clinicians and nurses providing health-care services to migrant farm workers. # Role of the Public Health Service The Public Health Service (PHS) should promote collaboration between health departments and migrant health centers in the homebase states and elsewhere to plan and carry out TB screening and preventive therapy programs. The PHS should require documentation of such collaboration as part of applications for federally funded migrant health and TB grants and cooperative agreements. In addition, as part of routine site visits, PHS staff should review related activities and make proposals for more effective implementation of the recommendations in this document. The CDC and the Health Resources and Services Administration, with the assistance of the Migrant Clinicians Network, should jointly develop a prototype TB medical history card to be given to migrant workers. The card should indicate results of the worker's latest tuberculin test, history of preventive therapy, and appropriate current and past treatment and diagnostic status. This card can serve as a supplement to, but cannot substitute for, complete medical records Full implementation will require the commitment of additional resources at the national, state and local levels. Implementation of these recommendations is an important step in the TB elimination effort. Most importantly, implementation of these recommendations will be of great benefit to individual migrant farm workers and their families whose economic and social progress is being impeded by the occurrence of TB. 12. IUAT. Efficacy of various duration of isoniazid preventive therapy for tuberculosis: five years of follow-up in IUAT trials. Bull WHO 1982;60:(4):555-64. The Advisory Council for the Elimination of Tuberculosis recognizes that a variety of terms are used and preferred by different groups to describe race and ethnicity. Racial and ethnic terms used throughout this document reflect the way data are collected and reported by official health agencies. All MMWR HTML documents published before January 1993 electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices. # Return To: MMWR MMWR Home Page CDC Home Page **Questions or messages regarding errors in formatting should be addressed to [email protected].	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07302f882239f6e7bf806ae9da9924bd8b1dbd7b	cdc	None	This report provides updated, integrated recommendations for services provided to partners of persons with human immunodeficiency virus (HIV) infection and three other sexually transmitted diseases (STDs) (i.e., syphilis, gonorrhea, and chlamydial infection) and replaces the CDC 2001 Program Operations Guidelines for STD Prevention-Partner Services and the 1998 HIV Partner Counseling and Referral Services Guidance (1,2). These recommendations are intended for health department program managers responsible for overseeing partner services programs for HIV infection and the three other STDs at the state and local levels. The recommendations also might be beneficial for HIV prevention community planning groups, STD program advisory bodies, technical assistance providers, community-based organizations, and clinical care providers. The value of partner services in the control of syphilis and gonorrhea is widely accepted. However, such services are underused among partners of persons with HIV infection. On the basis of evidence of effectiveness and cost-effectiveness of these services, CDC strongly recommends that all persons with newly diagnosed or reported HIV infection or early syphilis receive partner services with active health department involvement. Persons with a diagnosis of, or who are reported with, gonorrhea or chlamydial infection also are suitable candidates for partner services; however, resource limitations and the numerous cases of these infections might preclude direct health department involvement in certain instances. Health departments might need to limit direct involvement in partner services for gonorrhea and chlamydial infection to selected high-priority cases and use other strategies for the remainder (e.g., expedited partner therapy). These recommendations highlight the importance of program collaboration and service integration in the provision of partner services. Because coinfection with HIV and one or more other STDs is common, all persons with a diagnosis of HIV should be tested for other types of STDs, and vice versa; rates of coinfection with HIV and syphilis have been particularly high in recent years. Many persons at risk for these infections also are at risk for other infectious diseases, such as tuberculosis and viral hepatitis, as well as various other health conditions. STD and HIV partner services offer STD, HIV, and other public health programs an opportunity for collaboration to deliver comprehensive services to clients, improve program efficiency, and maximize the positive effects on public health.# Introduction determining the role of expedited partner therapy for partners of patients with gonorrhea or chlamydial infection. To reduce Inconsistencies in the partner services module of the CDC duplication and discrepancies, incorporate new information, 2001 Program Operations Guidelines for STD Prevention and and address emerging challenges, this report integrates the 1998 HIV Partner Counseling and Referral Services Guidance guidelines for partner services for HIV infection, syphilis, (1,2) have been confusing for providers of partner services for gonorrhea, and chlamydial infection into a single set of human immunodeficiency virus (HIV) infection and three recommendations. These updated, integrated recommendations other sexually transmitted (STDs) for which partner services are often provided: syphilis, gonorrhea, and chlamydial serve as a basis for delivery of partner services and related infection. In addition, new information has become available training and technical assistance. through research and program experience, new technologies These recommendations are intended for health department are available (e.g., rapid HIV tests), and new challenges have program managers responsible for overseeing partner services emerged, such as finding sex partners via the Internet and programs for HIV infection, syphilis, gonorrhea, and chlamydial infection at the state and local levels and were developed to help program managers plan, implement, and # Methods CDC led a work group that planned and coordinated the process of revising and combining the two existing guideline documents into a single set of recommendations. Simultaneously, numerous organizations and experts with potential interest in partner services were notified that the guidelines were being revised and invited to provide input; approximately 70 stakeholder groups were included in this process. In addition, an extensive review was conducted to identify relevant published research. During 2005-2006, CDC sought input from attendees at five national HIV and STD conferences. Detailed reviews of HIV partner services programs were conducted at eight health departments (six state health departments and two city health departments) to identify current program practices and challenges and to obtain input from persons directly involved in delivering partner services. Discussions with focus groups of potential and actual recipients of HIV partner services were held in five cities to elicit information about experiences with and perceptions of these services. In addition, discussions with focus groups of private clinicians were held in seven cities to assess their level of awareness and understanding of partner services and their perceptions of the importance and effectiveness of such services. Finally, a detailed review was conducted of state laws related to HIV partner services to identify legal concerns and provide a framework of the legal and regulatory environment in which partner services are delivered. A draft of recommendations was developed and in November 2006, a meeting was convened in Atlanta, Georgia, to obtain input. The meeting was attended by approximately 70 participants from 23 states and the District of Columbia (DC). Participants included representatives of other federal agencies; state and local HIV and STD health department directors, program managers, and staff members; academic research experts; ethicists; representatives from legal, medical, and other professional organizations; and representatives from CBOs, correctional facility health organizations, community advocacy groups, and training centers with expertise in partner services. After the meeting, CDC convened seven workgroups, which included CDC staff members and non-CDC participants recruited from the meeting, to revise the draft of the recommendations based on input from meeting participants. In January 2008, a revised draft was distributed for review to federal agencies, health departments, academic and research centers, professional organizations, CBOs, and community advocacy groups. In compliance with requirements of the Office of Management and Budget for influential scientific assessments, CDC also solicited reviews from nonfederal subject-matter experts. The recommendations were revised after reviewer comments were received. # How These Recommendations Differ from Previous Partner Services Guidelines These recommendations integrate previously separate guidelines for partner services for HIV infection, syphilis, gonorrhea, and chlamydial infection into a single set of recommendations; a complete summary of these new recommendations is provided (Appendix A). These recommendations have increased emphasis on the following: - integration of services at the client level; - linkage between surveillance and program activities to help ensure that partner services are offered to all persons who test positive for HIV and early syphilis; - direct public health program involvement in partner ser vices as quickly as possible after diagnosis; - rationale for selection of the preferred notification strat egy for each disease; - active linkage to medical and prevention services for per sons identified as infected with HIV; - collaboration with internal and external partners involved in all aspects of partner services, including ensuring that partner services are available for all HIV-infected persons throughout the prevention and care continuum; - program monitoring and evaluation and quality improve ment; and - a focus on which types of activities HIV and STD pro grams should be performing rather than precisely how they should be performing them The 1998 HIV Partner Counseling and Referral Services Guidance used the term partner counseling and referral services rather than contact tracing or partner notification to describe the type and range of public health services recommended for sex and drug-injection partners of HIV-infected persons (2). The 2001 Program Operations Guidelines for STD Prevention used the term partner services to describe similar activities (1). This report uses the term partner services to describe services offered to persons with HIV or other STDs. The term partner services is broad and encompasses services typically included in partner counseling and referral services and other services (e.g., screening for other STDs, screening for chronic infection with hepatitis B virus and hepatitis C virus , and vaccination for hepatitis A virus and HBV). In addition, the principles of notifying an exposed person do not differ substantially among diseases, and persons with STDs other than HIV often need the same array of services as persons with HIV infection. Using the same term for partner services for HIV and other STDs emphasizes these points. # Terminology Many terms used in this report are familiar to persons with experience in partner services for HIV and other STDs; however, certain terms might be used differently than they were in previous guidelines, and certain new terms are used. Following are terms used frequently in this report; a glossary and list of abbreviations also are provided (Appendices B and C). - Client, patient. These recommendations include both terms, depending on context. In certain instances, the term patient best describes a person receiving a service (e.g., a person being treated for an infection), whereas in other situations, the term client is a better descriptor of a person receiving services (e.g., a person receiving referral services). - Index patient. Person with newly diagnosed or reported STDs/HIV infection. - Partner. For persons with syphilis, gonorrhea, or chlamydial infection: refers to sex partners (i.e., persons with whom an index patient has had sex at least once); for persons with HIV infection: refers to sex and druginjection partners (i.e., persons with whom an index patient has had sex or shared drug-injection equipment at least once). - Drug-injection partner. A person with whom an index patient shares drug-injection equipment (e.g., needles, syringes, cottons, cookers, or rinse water). - Disease intervention specialists (DISs). Health department personnel who are specifically trained to provide partner services. Some health departments use different titles for persons providing partner services. In addition, in certain jurisdictions, other persons (e.g., HIV counselors or clinicians) either inside or outside of the health department provide certain or all elements of partner services. - Provider referral. Partner notification carried out by health department staff members. - Third-party referral. Partner notification carried out by professionals other than health department staff members (e.g., HIV counselors or clinicians who are not part of a health department). - Social contacts. Persons who are named by index patients as part of their social network but who are not sex or drug-injection partners. Social contacts were referred to as suspects in previous STD partner services guidelines. # Definition and Overview of Partner Services Partner services are a broad array of services that should be offered to persons with HIV infection, syphilis, gonorrhea, or chlamydial infection and their partners. A critical function of partner services is partner notification, a process through which infected persons are interviewed to elicit information about their partners, who can then be confidentially notified of their possible exposure or potential risk. Other functions of partner services include prevention counseling, testing for HIV and other types of STDs (not necessarily limited to syphilis, gonorrhea, and chlamydial infection), hepatitis screening and vaccination, treatment or linkage to medical care, linkage or referral to other prevention services, and linkage or referral to other services (e.g., reproductive health services, prenatal care, substance abuse treatment, social support, housing assistance, legal services, and mental health services). The rationale for use of partner services is that appropriate use of public health resources to identify infected persons, notify their partners of their possible exposure, and provide infected persons and their partners a range of medical, prevention, and psychosocial services can have positive results including 1) positive behavior changes and reduced infectiousness; 2) decreased STD/HIV transmission; and 3) reduced STD/HIV incidence and improved public health (Figure 1). The value of partner notification in the control of syphilis and gonorrhea is widely accepted (3). In recent times, syphilis prevalence peaked in approximately 1990, resulting in a concerted national attempt to apply public health resources, including partner services, toward its reduction and, later, elimination (4). Subsequently, syphilis prevalence decreased to historic lows (approximately 6,000 primary and secondary cases in 2000). Cost data from the early 1990s on syphilis partner services suggest costs per partner treated are commensurate with current costs of other syphilis-elimination strategies in the United States (5). However, recent increases in primary and secondary syphilis cases to approximately 10,000 cases in 2007 indicate that continued vigilance in syphilis control is needed. In New York, notification and referral services for gonor rhea have targeted specific geographic areas with notification services rather than attempting to interview all index patients and notify all partners in person. Evaluation of 10 years of data from the New York program, as well as of other program data, has shown a reduction in gonorrhea prevalence (6,7). Treatment of partners is valuable for control of chlamydial infection and cost-effective in averting sequelae. When used, partner services via provider referral seems to identify enough infected partners to decrease transmission and therefore pro mote infection-control measures, and more partners are treated through partner services than through other strategies (8)(9)(10). However, provider referral coverage for chlamydial infection is low and not a significant contributor to controlling this infec tion (8,11,12). For example, one survey indicated that only 12% of patients with chlamydial infection were interviewed by health department staff members about their partners (13). Partner services can play an essential role in preventing and controlling HIV in the United States. Of approximately 1-1.2 million persons living with HIV infection in the United States, approximately 25% are not aware of their infection; transmission from persons not aware of their infection accounts for 54%-70% of new infections (14,15). Partner notification, a critical component of partner services, effectively identifies persons with previously undiagnosed HIV infection. A review of the case-finding effectiveness of partner notification found that among partners for whom notification was initiated, the median percentage with newly diagnosed cases was 8%, approximately the same as for syphilis (8); in the reports included in this review, eight index patients were interviewed for partner notification to discover one newly diagnosed case of HIV, on average. A systematic literature review conducted for the Task Force on Community Preventive Services found that among the nine studies included, a range of one to eight partners was identified per index patient with HIV infection, a mean of 67% of partners were notified of their exposure to HIV, a mean of 63% of persons notified of exposure were tested, and a mean of 20% of those tested were newly diagnosed as infected with HIV (range: 14%-26%). On the basis of this review, the task force concluded that sufficient evidence exists to demonstrate that partner services, with partner notification by a public health professional, increases identification of a high-prevalence population for HIV testing and increases the identification of HIV-infected persons (16,17). Although limited, additional data also suggest that HIV partner services are cost-effective (18)(19)(20)(21)(22). Despite the potential benefits, HIV partner services are highly underused (23). The services are more frequently provided to persons who receive diagnoses in publicly funded HIV testing sites than outside of public health sites (23). On the basis of evidence of the effectiveness and costeffectiveness of partner services, CDC strongly recommends that all persons with newly diagnosed or reported HIV infection or early syphilis receive partner services with active health department involvement. All persons who receive a diagnosis of or who are reported with gonorrhea or chlamydial infection also are suitable candidates for partner services; however, high numbers of cases and resource limitations might preclude direct health department involvement in all instances. Health departments might need to limit their direct involvement in partner services for gonorrhea and chlamydial infection to selected high-priority cases and use other strategies for the remainder. # Principles of Partner Services The following principles serve as the foundation for providing partner services to persons with HIV infection or other STDs and their partners: - Client centered. All steps of the partner services process should be tailored to the behaviors, circumstances, and specific needs of each client. - Confidential. Confidentiality should be maintained and is essential to the success of partner services. Confidentiality also applies to data collected as part of the partner services process. When notifying partners of exposure, the identity of the index patient must never be revealed, and no information about partners should be conveyed back to the index patient. - Voluntary and noncoercive. Participating in partner services should be voluntary for both infected persons and their partners; they should not be coerced into participation. - Free. Partner services should be free of charge for infected persons and their partners. - Evidence based. Partner services should be as evidence based as possible. - Culturally, linguistically, and developmentally appropriate. Partner services should be provided in a nonjudgmental way and be appropriate for the cultural, linguistic, and developmental characteristics of each client. - Accessible and available to all. Partner services should be accessible and available to all infected persons regardless of where they are tested or receive a diagnosis and whether they are tested confidentially or anonymously. Because of the chronic nature of HIV infection, partner services for HIV should not be a one-time event. They should be offered as soon as HIV-infected persons learn their serostatus and should be available throughout their counseling and treatment. HIV-infected persons should have the ability to access partner services whenever needed. - Comprehensive and integrative. Partner services should be part of an array of services that are integrated to the greatest extent possible for persons with HIV infection or other STDs and their partners. # Goals of Partner Services The goals of partner services for infected persons, their partners, and the community are as follows: - Infected persons -Maximize access to partner services by providing all infected persons with support to ensure that the partners are confidentially informed of their exposure. -Maximize effective linkage to medical care, treatment, prevention interventions to reduce the risk for transmission to others, and other services. - Partners of infected persons -Maximize the proportion of partners who are notified of their exposure. -Maximize early linkage of partners to testing, medical care, prevention interventions, and other services. - Community -Reduce future rates of transmission by aiding in early diagnosis and treatment (or linkage to treatment, for those with HIV infection) and provision of preven tion services to infected persons. # Benefits of Partner Services Partner services programs offer substantial benefits to three principal groups: persons infected with HIV infection or other STDs, their partners, and the community (Figure 1). A primary benefit for index patients is that DISs can help them ensure that partners are notified of their possible exposure to the infection, while protecting the confidentiality of the patients. For index patients who expect to notify partners themselves, DISs can provide coaching and assistance with this process and provide support if the index patient is unable to complete the notification successfully. In addition, when interviewing index patients, DISs can assess whether they have been adequately treated or linked to appropriate medical and prevention services and, for those who have not, facilitate access to these services. DISs also can assess whether index patients need other services (e.g., reproductive health services or substance abuse treatment) and make appropriate referrals for such services. Finally, when persons are repeatedly reported as index patients for syphilis or gonorrhea or have been previously reported with HIV infection, DISs can provide additional prevention counseling or help them access more intensive riskreduction interventions. For persons having difficulty achieving and maintaining behavior changes, these services can help develop skills to reduce their risk for repeatedly acquiring new STDs or transmitting HIV to current or future partners. Partners of persons with HIV infection or other types of STDs are at high risk for infection, as indicated by the high prevalence of infection among notified partners (8,16). In the case of HIV, many partners are not aware of their risk and have never been tested for HIV (24). Partner services provide a confidential process for these persons to become aware of their risk and access appropriate diagnostic, treatment, and prevention services. Recently exposed partners of persons with early syphilis and gonorrhea who do not yet have evidence of infection can be treated preventively, and partners with evidence of infection can be treated for cure. All partners can be assessed to determine whether they need other services (e.g., reproductive health services or substance abuse treatment) and receive appropriate referrals. Partner services might also benefit the community by helping reduce transmission rates, reducing effects of disease, and facilitating earlier identification and treatment of previously undiagnosed STDs/HIV infection among its members. Demonstrating that a specific prevention intervention (e.g., comprehensive risk counseling and services) reduces transmission rates at the community level is difficult. Nevertheless, studies have demonstrated that 1) quality prevention counseling can reduce risk for acquiring a new STD, 2) behavioral interventions can reduce transmission risk behaviors, and 3) persons with HIV infection who are aware of their infection have substantially lower levels of transmission risk behaviors than those who are not aware (15,(25)(26)(27)(28)(29)(30)(31). Thus, by increasing access to prevention counseling and other prevention interventions and by providing counseling and testing to persons at very high risk for infection (i.e., known partners of infected persons), partner services should result in lower transmission rates. In addition, by reducing the viral load in HIV-infected persons to undetectable levels, antiretroviral therapy (ART) likely reduces (but does not eliminate) infectiousness and risk for sex-and injection-related transmission (32)(33)(34)(35)(36)(37). Therefore, identifying persons with previously undiagnosed HIV infection and linking them to medical care services, and possibly to ART, also might reduce transmission within the community. Finally, partner services can improve disease surveillance and identify sex and druginjection networks at high risk for infection that can then be targeted for screening and prevention services (38). # Challenges for Partner Services Challenges for partner services include whether the services will be accepted by patients, the potential for abuse resulting from partner notification, and potential negative effects on relationships after partner notification. DIS training includes methods to maximize acceptability of partner services among patients. A recent systematic review of the acceptability of HIV partner counseling and referral services found that among participants in the studies reviewed, 1) the majority of surveyed potential clients (i.e., HIV-positive or HIV-negative persons who had no direct experience with HIV partner counseling and referral services) indicated that they would be willing to participate in client referral (i.e., notify a partner themselves); 2) most potential clients would be willing for health department personnel to notify their partners; 3) the majority of HIV-positive clients receiving partner counseling and referral services used provider referral to notify one or more partners; 4) the majority of partners either wanted to be notified or were comfortable with a health-care provider notifying them; and 5) the majority of providers were in favor of partner notification (39). The high level of acceptability of HIV partner services among diverse groups suggests that, when provided appropriately, they are considered a service rather than an imposition by those for whom they are intended. A second challenge is the potential for emotional or physical abuse by or against the index patient as a result of partner notification. Available data suggest that the rate of violence attributable to partner notification is likely low; however, data are limited, and additional study is needed (40)(41)(42)(43). A third frequently cited challenge is the potential negative effect of partner notification on relationships (e.g., dissolution of a long-standing relationship) (39,40,44). In one study, the rate of partnership dissolution was 46.8% among partnerships involving syphilis or HIV cases, with no significant difference between the two infections; however, the rate was lower in partnerships for which partner notification was completed than in those for which notification was not completed (24.3% and 75.7%, respectively) (40). A similar study addressing the effect of HIV partner notification on partnership dissolution MMWR November 7, 2008 found that although the rate of partnership dissolution was high (65% at 6 months postinterview), the rate was not increased by partner notification (44). Study design and low enrollment make drawing firm conclusions from these studies difficult; however, the studies suggest that partner notification itself does not increase rates of partnership dissolution. # Legal and Ethical Concerns Well-implemented partner services balance the interests of infected persons, their partners, and the community. Describing a single plan for successfully balancing the interests of all involved parties is difficult because the legal context within which partner services programs operate varies among states and jurisdictions. Nonetheless, recognition of and adherence to certain principles is essential for all partner services programs. This report does not include a comprehensive discussion of all areas of law relevant to partner services. Program managers should consult with the legal counsel of their agency to gain a thorough understanding of the legal framework in which their specific programs operate, including their own legal authorities and those of other agencies (e.g., law enforcement) with whom they might interact. These CDC recommendations should not be taken as legal advice or as CDC interpretation of the laws of any jurisdiction. # Legal Authorities States hold the legal authority for the notification and referral of partners of persons with HIV infection and other types of STDs. One federal law specifically addresses HIV partner notification services for spouses: the Ryan White CARE Act Amendments of 1996 (Pub. L. No. 104-146 ) require that states receiving funds under part B of title XXVI of the Public Health Service Act (42 U.S.C. Sect. 300ff-27a ) take "administrative or legislative action to require that a good faith effort be made to notify a spouse of a known HIV-infected patient that such spouse might have been exposed to the human immunodeficiency virus and should seek testing." A spouse is defined as any person who is the marriage partner of an HIV-infected patient or has been the marriage partner of that patient at any time within the 10-year period before the diagnosis of HIV infection. # Voluntary and Informed Nature of Participation in Partner Services Participation in partner services is voluntary only if it is informed and not coerced. The effectiveness of partner services as a public health intervention relies on the voluntary cooperation and participation of index patients, partners, social contacts, and associates. These persons voluntarily choose to 1) provide information about themselves and others in response to questions and requests from a DIS; 2) notify others of their possible exposure to HIV, syphilis, gonorrhea, or chlamydia; 3) accept STD/HIV testing and treatment; and 4) engage in behaviors that promote health and reduce risk for transmission or acquisition of HIV infection and all other types of STDs. Ethically, for a public health official or health-care provider to coerce, deceive, or withhold information from persons to influence them to take any of these actions is inappropriate. In addition, persons who believe that they are being coerced might lie or withhold information. These considerations do not preclude use of persuasive reasoning to gain the cooperation of index patients and others and to motivate them to participate actively in partner services. However, for partner services to be truly voluntary, all persons should be clearly informed of the known benefits and risks for themselves and others that might result from their participation. # Confidentiality In the context of partner services, confidentiality refers to keeping information obtained from or about index patients, partners, social contacts, and associates in confidence; information is not divulged to others or obtained or maintained in a way that makes it accessible to others. The concept of confidentiality is related to privacy, which might be a legal right in certain instances. That is, laws might prohibit forcing persons to reveal certain types of information, and persons who decline to provide certain types of information are not prevented from receiving services. When a person agrees to disclose private information, especially in the context of a service aimed at helping others, such information should be held in strict confidence, both because of its private nature and as a sign of respect for the person who is volunteering to share the information. Research has demonstrated that the degree to which confidentiality is maintained by partner services programs is an important determinant of the acceptability of those services to clients and client willingness to participate in partner services (39,(45)(46)(47). Real or perceived breaches of confidentiality can endanger persons being served, who might face stereotyping; social isolation; loss of social or financial support; barriers to accessing housing, employment, and various social and medical services; and physical or emotional abuse (48,49). Such breaches also can undermine community trust in and access to essential public health programs and services. For these reasons, policies and procedures for protecting confidentiality are critical. State laws generally protect the confidentiality of all STD information, including information related to HIV and acquired immunodeficiency syndrome (AIDS). In certain states, specific laws or regulations prescribe the parameters of information to be kept confidential and establish penalties for confidentiality breaches. Although confidentiality is a central principle of partner services, it is subject to legal exceptions such as those stipulated in certain duty-to-warn laws, which in certain situations require medical or public health officials to notify known partners who are at risk for infection, even against the specific wishes of the index patient. Confidentiality also is subject to practical limits, including the possibility that partners might guess the identity of the index patient at any point during the process. Because partner services programs cannot absolutely guarantee patient or partner anonymity, health officials must make all reasonable attempts to ensure that the confidential nature of communication with a DIS is respected and protected to the fullest extent allowed by law. # Duty and Privilege to Warn The legal duty to warn has its foundation in a 1976 case, Tarasoff v. Regents of the University of California, in which the family of a murdered woman sued because the killer's therapist did not warn their daughter that his patient planned to kill her (49). The Tarasoff decision indicates that a patient's intention to seriously harm another person could result in a provider's duty to warn. The Tarasoff decision does not overshadow the importance of confidentiality and trust in a therapeutic relationship but emphasizes that the threatened harm must be serious, imminent, targeted at an identified (or identifiable) person, and articulated in the context of an existing therapeutic relationship. At the state level, the legal concept of the duty to warn is complex; consultation with legal counsel is necessary. Certain states have laws requiring practitioners (directly or with the assistance of public health authorities) to warn persons they know to be at risk for infection with a communicable disease, an STD, or HIV by their patients. Many other states have laws permitting but not requiring practitioners to warn persons that they are at risk (i.e., privilege to warn). DISs generally must avoid disclosing the name of an index patient. However, because cases involving duty to warn require the health-care providers to provide sufficient information for partners to protect themselves, situations involving a duty to warn might require a provider to reveal the name of an index patient to at-risk partners, thereby breaching the confidential relationship between the provider and the patient (50). Programs that too readily assume that the duty to warn is applicable in a specific case and alert partners against the will of or without the knowledge of an index patient might find future patients reluctant to be honest about sexual or drugsharing activities or unwilling to accept testing or medical care. In such situations, important opportunities for counseling, support for disclosure, and prevention education might be lost. Accordingly, health-care providers and public health program managers should proceed cautiously and seek legal counsel before assuming that a duty to warn has been triggered or that they have a privilege to warn. # Criminal Transmission and Exposure Despite extensive education and counseling to prevent transmission and acquisition of HIV infection and other types of STDs, certain persons persistently engage in behaviors that put themselves and others at risk for infection. Certain criminal laws of general application, such as assault, battery, or reckless endangerment laws, might be used to prosecute a person who intentionally exposes another person to infection. However, many states have enacted criminal laws focusing either specifically on HIV transmission or generally on transmission of sexually transmitted infections. These laws vary according to several factors, including 1) which types of conduct are considered criminal (e.g., with HIV, most states proscribe engaging in conduct that exposes someone else to HIV rather than limiting liability to situations in which transmission has occurred) (51); 2) the specificity with which the proscribed conduct is described (e.g., most statutes that consider exposing someone to HIV to be a criminal act do not define exposure, although certain statutes specifically proscribe exposure by transfer of body fluids or tissues, engaging in sexual activities, or needle sharing) (51); and 3) the knowledge required (e.g., for exposure to be considered criminal, almost all states require that infected persons who expose another person to HIV must have had knowledge of being infected with HIV) (51). Laws might also vary depending on whether disclosure of HIV status before engaging in the conduct 1) means that no crime has been committed, 2) is an affirmative defense that can be raised by a person charged with criminal transmission or exposure, or 3) means that the person is not legally liable. Depending on the unique circumstances of each case, options available to partner services program managers in cases involving persons who persistently engage in behaviors that put themselves and others at risk might include 1) initiating increasingly intensive prevention interventions (e.g., comprehensive risk counseling and services); 2) facilitating access to HIV primary care; 3) arranging linkage to substance abuse treatment, mental health services, or other relevant services; 4) initiating epidemiologic investigation of situations involving possible exposure of persons to infection; and 5) seeking legal advice when public health interventions are not sufficient or appropriate. Determining the most appropriate course of action requires consideration of the details of the specific situation; every case must be managed carefully and confidentially. # Recommendations for Legal and Ethical Concerns - Public health agencies responsible for partner services should conduct a thorough review of all laws relevant to their provision of these services. This review should serve as a basis for developing policies and procedures for partner services programs. Program managers should also ensure that program staff members understand the implications these laws have for conducting partner services. Laws relevant to provision of these services include the following: -the legal authority for the public health agencies for partner services; -provisions related to privacy and confidentiality (e.g., requirements of the federal Health Insurance Portability and Accountability Act ); -provisions related to duty or privilege to warn and criminal transmission and exposure; and -the ability of the public health agencies to coordinate with other agencies (e.g., law enforcement). - Program managers should ensure that their staff members understand the legal basis for their work, legal restrictions on their practice (e.g., duty or privilege to warn), the extent to which they are protected from civil litigation, and how to coordinate with law enforcement officials in ways that protect the civil and procedural rights of the persons involved. - To ensure that program staff members invoke their duty or privilege to warn appropriately, partner services programs should have written policies and procedures to guide staff members in handling complex cases. Guidelines and protocols should be based on the jurisdiction's statutory and case law and developed in consultation with legal counsel. Legal counsel should also be consulted regarding specific cases in which duty to warn or privilege to warn might apply. - Program managers should be aware of the applicable laws regarding criminal transmission and exposure in their jurisdictions and should coordinate with legal counsel regarding specific cases in which allegations of criminal transmission or exposure are made. # Elements of Partner Services Partner services include several essential elements (Figure 1). In general, these elements are relevant for partner services for HIV, early syphilis, gonorrhea, and chlamydial infection, although differences in how they are implemented vary by infection. Program managers should ensure that policies and procedures adequately address each of these elements. # Index Patients - identifying index patients (i.e., infected persons who are candidates for partner services) and prioritizing them for partner services; - introducing partner services to index patients and conducting interviews to elicit information about their partners; - counseling index patients about reducing their risk for acquiring or transmitting infection to others and referring them for additional prevention services, if needed; - treating index patients or linking them to medical care and treatment; and - referring index patients to other services. # Partners - notifying partners of their exposure; - counseling partners about reducing their risk for acquiring HIV infection and other types of STDs and referring them for additional prevention services, if needed; - offering partners STD/HIV testing; - treating partners or linking them to medical care and treatment; and - referring partners to other services. # Identifying Index Patients Identifying persons who are candidates for partner services (i.e., index patients) is a critical step in the partner services process. For early syphilis and, in certain instances, gonorrhea, standard identification of index patients occurs 1) when persons seek care with no prompting (i.e., volunteers) and 2) when persons receive screening or testing and their case reports are provided to STD programs for treatment, case management, and partner services. For early syphilis, public health records indicate that since the 1940s, index patients routinely have been interviewed and their partners followed. In modern times, a survey of partner notification for STDs/ HIV found that 89% of syphilis-infected persons in highmorbidity geographic areas were interviewed (13). The same survey found that a markedly lower proportion (17%) of persons with gonorrhea were interviewed, although certain jurisdictions still attempt to interview all patients with gonorrhea. Other jurisdictions that lack resources to interview all patients with gonorrhea have focused their interviews on patients in high-morbidity areas (i.e., core areas) (7). Interview strategies for chlamydial infection tend to be similar to those for gonorrhea, although interviews are generally considered lower priority than interviews for gonorrhea. Among highmorbidity jurisdictions in a survey of STD/HIV partner services, only 12% of persons with chlamydial infection were interviewed (13). The workload for health departments is related to the number of cases reported, which is an essential factor affecting approaches to partner services for early syphilis, gonorrhea, and chlamydial infection. During 2000-2007, fewer than 50,000 cases of early syphilis (i.e., primary, secondary, and early latent) were diagnosed each year. In contrast, estimates of annual prevalence of gonorrhea and chlamydial infection are one to two orders of magnitude higher (52,53), far too many patients for public health staff members, at the current staffing level, to interview directly. Available evidence suggests that the majority of HIV-infected persons are not interviewed for HIV partner services. A survey found that in 22 jurisdictions with HIV reporting, health departments interviewed 32% of 20,353 persons with newly reported HIV infection (23). Active strategies for identifying more candidates for partner services are needed. Because an extensive literature search did not identify any published studies or program evaluations that examined this topic, recommendations in this report for identifying HIV index patients were based on input from consultants with partner services expertise. For HIV, although the main emphasis of partner services programs should be on persons with newly diagnosed or reported infection, partner services also might be appropriate for persons with previously diagnosed infection on an as-needed basis (54). some or all HIV partner services might be provided exclusively by HIV program staff members. In these situations, managers of both programs should establish policies and procedures to ensure that persons with a diagnosis of HIV infection, syphilis, gonorrhea, or chlamydial infection by either program receive appropriate partner services. Systems also are needed to ensure that persons with a diagnosis of HIV infection or any of these three other STDs in other health department clinics (e.g., tuberculosis or reproductive health clinics) are linked to the partner services program. Certain patients receive a diagnosis of HIV infection and of another STD simultaneously. Policies and procedures are needed to ensure that these patients and their partners receive partner services for both infections from only one DIS to improve services for the patients and partners and maximize program resources. Identification of syphilis cases can be complicated because treated and noninfectious persons can have reactive syphilis tests indefinitely. Titration of the rapid plasma reagin (RPR) test can yield elevated RPR titers for persons who have already been treated and clinically cured of syphilis. Therefore, CDC encourages programs to use syphilis treatment registries and algorithms for prioritizing follow-up investigations of persons with reactive syphilis tests (i.e., reactors). A syphilis reactor grid is constructed from a combination of quantitative test results, age, and sex to identify which persons with reactive tests are most likely to be both untreated and infectious. Individual programs vary in precisely how they use a reactor grid but generally investigate all persons with RPR titers higher than a specified level, all persons younger than a certain age, and persons most at risk for negative outcomes (e.g., pregnant women). A recent evaluation of syphilis reactor grids suggested that most missed cases of early syphilis were among men aged 30-50 years and women aged 20-40 years with low RPR titers (55). # Diagnoses Received in Settings Other than Health Department Clinics Most types of STDs are frequently diagnosed in settings other than health departments (56), such as public hospitals and clinics, private hospitals and medical practices, community health centers, Veterans Administration health-care facilities, Indian Health Service and tribal health-care facilities, correctional facilities, CBOs, reproductive health service organizations, substance abuse treatment centers, and student health centers. In particular, chlamydial infection and gonorrhea are more frequently diagnosed in private care settings. Reporting delays, especially for cases diagnosed when patients are the most infectious, diminish the effectiveness of partner services in infection control. Approximately 90% of all HIV tests and 70% of positive HIV tests are performed in settings other than health department clinics (57). # MMWR November 7, 2008 Persons diagnosed in settings other than health department clinics might not be directly linked to partner services if the provider does not notify the partner services program; therefore, program managers should establish strategies for rapidly identifying these persons and offering them partner services. This can be accomplished by linking disease reporting systems and partner services programs, conducting active outreach to service providers (e.g., physicians and health-care facilities that frequently diagnose STDs/HIV infection, HIV counseling and testing providers, and case managers) and diagnostic laboratories, or using a combination of these strategies. Each strategy has potential advantages and disadvantages. For example, linking disease reporting activities and partner services programs might maximize the number of newly diagnosed persons identified for partner services, but reporting delays might reduce the timeliness with which partner services are initiated. In contrast, active outreach to health-care providers might improve the timeliness of partner services but result in more missed cases because reaching all providers is difficult. For most programs, a combination of these two strategies will likely be most effective. Program managers might also develop other strategies for identifying persons with newly diagnosed infection. Strategies should be monitored for how effectively they identify index patients and the timeliness with which they provide services. Linkage with Disease Reporting. For surveillance purposes, cases of HIV/AIDS and other STDs might be reported to health departments by service providers (e.g., clinicians or CBOs providing testing services), diagnostic laboratories, or both. Data collected through HIV/AIDS and STD surveil lance systems are used for many complementary public health purposes at the national, state, and local levels. Examples of such uses include disease monitoring, estimating incidence of infection, identifying changing trends in transmission, tar geting and evaluating prevention interventions, and allocat ing funds for care and prevention services. Certain states and territories also use case reports to initiate partner services for infected persons and offer referrals for prevention, medical care, and supportive services. In 2007, the Council of State and Territorial Epidemiologists (CSTE) conducted a national assessment of HIV/AIDS surveillance capacity and training by surveying HIV surveillance coordinators in 65 state, large city, and territorial health departments. Several questions as sessed current practices regarding use of HIV surveillance data to support partner services. Seventy-one percent of respon dents (30 of 42 respondents to the question) reported sharing data in some form with partner services programs; 43% (24 of 56 respondents to the question) reported sharing individuallevel data that included personal identifiers with partner ser vices (CSTE, unpublished data, 2007). Sharing information between HIV/AIDS and STD surveil lance programs and partner services programs is important for comprehensive disease intervention and offers many po tential mutual benefits, including the following: - Surveillance data can provide information about demographic and behavioral characteristics of persons newly diagnosed with HIV, leading to a more complete understanding of the population of persons in need of partner services in both the public and private sectors. - Using surveillance data to initiate partner services can help ensure that partner services are offered to the greatest possible number of newly identified or reported infected persons for whom services are appropriate, thereby supporting the public health goal of maximizing access to partner services. - Linking surveillance and partner services can help ensure that patients who test positive receive and understand their test results, that they receive appropriate treatment or are linked to medical care services, and that they receive appropriate prevention counseling. - Surveillance data can supplement client-level program information regarding demographic and risk characteristics and testing history and inform DISs before initial contact with clients. - Partner services programs can supplement surveillance data by obtaining more complete and accurate demographic and risk information and identifying duplicate reporting. - Sharing information might help streamline surveillance and partner services activities and increase efficiency (e.g., might limit the number of times the same medical record is reviewed or a medical provider is contacted about the same person). - Partner services programs can use surveillance data to identify health-care providers who diagnose and treat persons with HIV infection and other STDs; DISs can then contact these providers and ensure that they are well informed about the benefits of partner services. - Through collaborative relationships with health-care providers, partner services can encourage complete and timely reporting of HIV/AIDS and other STDs. Before using surveillance data to identify candidates for partner services, health departments should consider staffing and resources, relevant state and local laws and regulations, and level of community awareness and acceptance. The organizational structure of the health department also affects the way surveillance and partner services programs interact. For example, health departments in which surveillance and partner services programs are integrated often share staff members, have similar missions, have programmatic and administrative commonalities, and receive oversight from a shared overall responsible party (ORP, an official who has overall responsibility for implementing and enforcing HIV/ AIDS and STD surveillance security standards), all of which might facilitate information sharing for partner services purposes. Potential barriers to sharing surveillance data include a negative impact on provider reporting because of concerns about confidentiality of information, increased workload for surveillance staff members, and, for HIV, perceived negative effects on HIV-testing behaviors of providers or persons at risk for infection. For most STDs, data from a physician survey suggest that although physicians might be reluctant to collect partner services data themselves, they are willing to report cases to health departments to ensure that their patients receive partner services (58). Although the data from this survey do not include HIV, other surveys have found that the majority of health-care providers favor HIV partner notification (39). To facilitate information sharing between partner services and surveillance programs, health departments should review state and local laws and regulations that might apply to data sharing. Engaging key stakeholders such as medical providers, community advocates, and CPGs in the design and implementation of surveillance and partner services data linkage processes can result in support of and success in these measures. Clear, well-defined security and confidentiality policies and procedures that are followed by both surveillance and partner services program staff members increase the likelihood that surveillance data will be kept secure and patient information confidential, leading to patient and medical provider trust and cooperation with partner services programs. Historically, certain programs have limited the sharing of HIV/AIDS surveillance data with partner services programs. In certain situations, programs imposed these limits after collaboration with communities and medical providers on implementation of named-based HIV reporting, which resulted in use of reporting methods that separate surveillance and partner services. When considering changes in data-sharing policies, programs should use the same careful collaboration and deliberation with medical providers and affected communities to prevent erosion of the public trust and of the integrity of the systems already in place. Levels of Surveillance Information. Three levels of sur veillance data can support partner services: 1) individual, 2) provider, and 3) aggregate. These range from very sensitive data requiring high levels of security and confidentiality (in dividual level) to substantially less sensitive data (aggregate level). Individual-level data are the most valuable for immedi ate provision of partner services, although provider-and ag gregate-level data also can be useful. # Security and Confidentiality. Partner services data for HIV infection and other types of STDs, with or without data ob tained from disease reporting systems, are among the most sensitive public health data routinely collected and should re ceive careful protection. HIV and STD partner services pro grams have an excellent record of maintaining confidentiality, and continued vigilance is critical to future success. Programs considering operational and policy changes, should carefully review the proposed changes to ensure that they will not de crease security or confidentiality. CDC and CSTE have published technical guidance describ ing minimum standards for HIV/AIDS data security and con fidentiality that should be met by surveillance programs; these standards reflect best practices for protecting HIV/AIDS sur veillance data (59). With minor adjustments to accommo date practical realities encountered in many health departments, the same standards should be upheld by any partner services program with which HIV/AIDS surveillance programs share individual-level data (Appendix D). To en sure that appropriate policies and procedures are developed and followed, HIV/AIDS surveillance programs designate an ORP, who is responsible for security of the program's infor mation collection and management systems, including pro cesses, data, information, software, and hardware. Although this guidance was developed specifically for HIV/AIDS sur veillance activities, it might be useful for data and informa tion collected and used by all programs conducting partner services. Outreach to Service Providers and Diagnostic Labora tories. Persons might receive a diagnosis of HIV or other STDs from various service providers outside of health department clinics. In addition to using disease reporting systems to iden tify potential candidates for partner services, programs can collaborate with service providers and diagnostic laboratories to help ensure that persons who receive a diagnosis of STDs/ HIV are linked rapidly to health department partner services programs. Although reaching all service providers is unlikely to be feasible, a small number of providers or laboratories might account for a large proportion of new diagnoses. In this case, health department partner services program managers can collaborate with surveillance coordinators to identify these providers and laboratories to establish procedures for partner services referrals. Certain partner services programs have iden tified health-care facilities that diagnose large numbers of cases and have placed DISs in those facilities to meet with persons with new diagnoses. This strategy might reduce the need for extensive field work to locate individual index patients. How ever, such strategies should be monitored closely to assess their effectiveness and cost-effectiveness; no systematic evaluations of these strategies have been published. CDC recommends that in all health-care settings, volun tary screening for HIV infection should be performed rou tinely for all patients aged 13-64 years unless a patient declines HIV testing or has been tested recently (60). These recom mendations might produce a substantial increase in new HIV diagnoses. Therefore, program managers responsible for HIV partner services should work with health-care providers who implement the screening recommendations and diagnose nu merous HIV-infected persons to help ensure that those per sons are linked to partner services. # Anonymous HIV Testing Anonymous testing accounts for a small but significant pro portion of all HIV tests and might reach a subset of persons who might not otherwise be tested (61,62). Persons who test positive for HIV anonymously should be strongly encouraged to transfer to a confidential system; however, if they decline, HIV partner services can still be offered and performed. Part ner services might be more difficult to provide for persons using anonymous testing than for those using confidential testing. A study in Colorado assessed provider-referral part ner notification for persons who tested HIV positive during October 1990-March 1992 at a single anonymous test site in Denver and 13 confidential test sites throughout the state (63). The average number of named, notified, and counseled part ners was 30%-50% greater among index patients tested at sites offering confidential testing than among those tested at sites offering anonymous testing. A North Carolina study found that the number of partners notified and counseled per index patient interviewed was 2.7 times greater for index pa tients tested confidentially compared with those tested anony mously (64). A literature review of this topic indicated that two to three times more partners are notified when persons are tested confidentially than when they are tested anony mously (8). However, one study, conducted by the Multistate Evaluation of Surveillance for HIV Study Group in five states with name-based HIV reporting, found no difference in the number of notified partners between persons who were tested anonymously and those tested confidentially (65). Therefore, program managers who are responsible for HIV partner ser vices should work with providers who offer anonymous HIV testing to develop strategies for offering and providing part ner services to persons who test positive anonymously and elect not to enter a confidential system. (54). These recommendations urge HIV clinical care providers to 1) ask patients at the initial visit whether all their partners have been informed of their exposure to HIV; 2) regularly screen patients for HIV transmission risk behaviors, STDs, and pregnancy; 3) inquire at routine follow-up visits whether patients have had any new sex or drug-injection partners who have not been informed of their exposure; and 4) refer patients to the appropriate health department to discuss partners who have not been informed of their exposure and arrange for their notification and referral for HIV counseling and testing. Program managers responsible for HIV partner services can work actively with HIV clinical care providers and case managers to engage them in identifying patients who need partner services, offering them these services, and linking them to health department DISs when indicated. Persons who previously received a diagnosis of HIV also might be named as partners in the course of conducting partner services with other index patients. These persons should be interviewed to assess behavioral risk, provided partner services, and referred for more intensive prevention interventions, when indicated. # Recommendations for # IV Infection - HIV partner services programs should collaborate with health-care providers who provide HIV screening or testing, other HIV counseling and testing providers, HIV care providers, and HIV case managers to ensure that their clients and patients are offered HIV partner services as soon as possible after diagnosis and on an ongoing basis, as needed. # H - HIV partner services programs should work with providers of anonymous HIV testing services to develop strategies for providing partner services to persons who test positive, even if the person decides not to enter a confidential system. These providers should be trained on how to offer partner services and elicit partner information from persons with newly diagnosed HIV infection. # Prioritizing Index Patients All persons with newly diagnosed or reported HIV infection or early syphilis should be offered partner services and prioritized for interview, although some of these patients have a higher priority than others. Because of the high incidence of gonorrhea and chlamydial infection in many jurisdictions, attempts to reach and interview all patients might be hampered by various factors, including insufficient funds and staffing. Therefore, for these infections, programs might need to use partner services strategies that do not require interviews by DISs, focusing their interviewing on specific subsets of patients. To maximize available resources, programs should establish criteria for determining which index patients are prioritized for interview. In general, these criteria should include behavioral and clinical factors that affect the likelihood of additional transmission and, thus, increase the epidemiologic consequences of delayed receipt of partner services. This information might not be known until the index patient is interviewed; however, it might be available from the diagnosing clinician or counselor or through record review. Criteria for prioritizing index patients vary somewhat according to the infection involved. Program effectiveness and efficiency can be improved by periodically reviewing and adjusting criteria for prioritizing index patients for partner services. The following categories of persons are considered highpriority index patients for partner services, regardless of the infection involved: - Pregnant women and male index patients with pregnant partners. Pregnant women are at risk for transmitting HIV and other types of STDs to their fetus both in utero and during delivery. Newborns also are at risk for becoming infected with HIV through breastfeeding. Prioritizing pregnant women for interview gives DISs an opportunity to verify that the women have received appropriate treatment or, for those with HIV infection, have been successfully linked to medical services so that they can be treated with ART to reduce the risk for mother to-child transmission. - Index patients suspected of or known to be engaging in behaviors that substantially increase risk for # Syphilis, Gonorrhea, and Chlamydial Infection The following categories of persons also are considered high-priority index patients for partner services for syphilis, gonorrhea, and chlamydial infection. - Persons with clinical signs or symptoms suggestive of infection. Symptomatic persons have a high risk for disease transmission (68,69). Presence of clinical symptoms suggests recent sexual exposure and risk behavior, so partner services programs might have an opportunity for a primary disease intervention. - Infected persons from core areas. Prioritizing gonorrheainfected persons from core areas might offer an opportunity to reduce transmission at the community level. # HIV Infection The following categories of persons also are considered highpriority index patients for partner services for HIV. # Interviewing Index Patients With the exception of interview period and timing of interviews, the following information is applicable to partner services for HIV infection, early syphilis, gonorrhea, and chlamydial infection. The success of partner services depends on the cooperation of index patients. If index patients do not provide complete, accurate information about partners, partner services are not effective. Obtaining accurate information largely depends on treating index patients with respect and gaining their trust. Withholding relevant information is likely to generate mistrust. When offering partner services, public health personnel should delicately balance the need to provide these important services with the knowledge that index patients can choose whether to participate. Index patients should have the following types of information explained to them: - the purpose of partner services; - what partners services entail; - benefits and potential risks of partner services for index patients and their partners and steps taken to minimize risks; - how and to what extent privacy and confidentiality can be protected; - the right to decline participation in partner services without being denied other services; and - available options for notifying partners. The amount of information an index patient needs about each of these topics varies. Regardless, all patients should be offered ample opportunities to ask questions and voice concerns. # Types of Interviews Interviewing index patients to elicit partner information is a cornerstone of partner services. Two types of interviews are used: the original interview and the reinterview. A supplementary approach, clustering, also is used by certain programs to obtain information about the index patient's social network. # Original Interviews and Reinterviews The purpose of the original interview is to gather information from index patients about partners they have had within a defined period (i.e., the interview period). In addition to eliciting as many partner names as possible, the interviewer attempts to obtain enough information about the partners so that they can be located and notified of their possible exposure. Most programs conduct a subsequent interview, the reinterview. The reinterview has several purposes: 1) to gather additional location information on partners identified by index patients in the original interview, if sufficient information was not initially obtained; 2) to follow up on the status of partners that index patients initially elected to notify themselves; 3) to elicit additional partners index patients might not have recalled in the original interview; and 4) to verify that index patients have received adequate treatment or additional tests. Frequently, more than one reinterview is conducted. Few studies have been conducted regarding the yield of reinterviewing or the relative yield of the original interview compared with the reinterview. Second interviews of 1,000 persons with STDs in a clinic in Berlin, Germany, in 1976 resulted in elicitation of 9% more partner names (D Brewer, unpublished manuscript, 2003). A subsequent sample of 110 persons from the same clinic were interviewed before diagnosis with gonorrhea then reinterviewed twice after diagnosis. The second and third interviews together elicited 12% more partner names compared with the first interview, resulting in an 11% increase in the total number of partners located and a 13% increase in the number of infected partners identified. In a study of forgetfulness as a cause of incomplete reporting of partner names, patients recalled roughly equal numbers of partners in the first and second interview; however, the sets of partners recalled in the two interviews tended to differ (71). Finally, in a randomized trial of supplementary techniques used during contact interviews for chlamydial infection, gonorrhea, and early syphilis, use of a combination of five sets of recall cues increased the number of partner names elicited by approximately 23% and the number of partners notified by approximately 11% per index patient. This approach was approximately two to three times as effective in eliciting additional partners as a second interview (72). Reinterviews are recommended for all early syphilis investigations and are standard practice in most partner services programs. Persons who have just been informed that they are infected with HIV are often willing to provide partner information and might address the topic of partners without being prompted. Other patients might be too overwhelmed by the new diagnosis to focus on identifying partners effectively or to hear and understand messages regarding prevention or linkage to care during the original interview. In these instances, using the first interaction with an index patient to help with various challenges arising from the HIV diagnosis and addressing partner elicitation in a subsequent interview might increase the likelihood that the index patient will identify partners. This approach must be weighed against the possibility that the index patient might not be available for a second interview. # Clustering A technique known as clustering has been recommended for use when interviewing index patients (1). Clustering involves eliciting information from index patients about persons in their social networks, other than partners, who might benefit from counseling, testing, and other services. These persons, referred to as social contacts (and referred to as suspects in previous guidelines), might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination (e.g., pregnant females). Clustering also might include eliciting information about venues in which the index patients and their social contacts interact socially (e.g., bars or clubs). Clustering differs from cluster interviewing, which involves asking uninfected partners or social contacts of index patients about their own social networks. Cluster interviewing is addressed in more detail in the section on partners. Data on the effectiveness of clustering for case finding are limited. A 6-month pilot project was conducted in which a network approach was used for routine syphilis partner notification in an Atlanta, Georgia, zip code with a high rate of early syphilis (260 cases per 100,000 population) (73). Among sex partners of syphilis index patients, 23.1% were infected with syphilis, whereas 5.9% of nonsexual contacts were infected. Another study included an analysis of 1993-1996 partner notification data for 12,927 patients with syphilis throughout Louisiana (74). Of 19,188 partners located and examined, 19% were newly identified as having syphilis; of 3,121 social contacts of index patients, 11% were newly identified as infected. A review of the effectiveness of partner notification and cluster investigations for identifying HIV and other STD cases indicated that, based on a small number of studies from the previous 20 years, the yield of cluster investigation for cases early syphilis was substantially less than the yield from partner notification for early syphilis (mean number of newly diagnosed cases found from interviewing one index patient was 0.002-0.11 for cluster investigation compared with 0.05-0.46 for partner notification) (8). Furthermore, the same review found that, compared with a few reports from previous years of syphilis control, the yield of cluster investigation has declined considerably, possibly related to the marked decline in early syphilis prevalence. In summary, data from a small number of reported studies suggest that the case-finding yield of clustering for early syphilis is substantially lower than that of partner notification. However, the yield is highly variable, and clustering might be more productive in areas with relatively high early syphilis case rates. Clustering and cluster investigation might be particularly useful during an outbreak. Published data on the case-finding yield of clustering for HIV are not available. Although data regarding the effectiveness of clustering for case finding are limited, information obtained through clustering has potential epidemiologic value. By obtaining and analyzing information about social contacts and venues of index patients, programs can gain insight into how and where infection is being transmitted in the community and develop strategies for conducting screening or other prevention interventions (e.g., social marketing campaigns) at the community level. # Interview Environments Because of confidentiality concerns, interviews generally should be conducted in environments that are private and comfortable enough that clients do not feel afraid or coerced. Public health clinics provide a safer environment for partner services staff members and a more confidential setting for interviewing and counseling than field settings. However, interviews conducted in settings other than the clinic might allow index patients to feel more comfortable discussing highly personal information. Interviews have traditionally been conducted in person; however, this approach is time and labor intensive and not always possible. The next most common method (and the most common in certain settings) is interview by telephone. Other interview methods, such as use of self-administered questionnaires and audio computer-assisted self-interviews have been suggested as alternatives or supplements to in-person interviews; however, little research has been done on this topic (D Brewer, unpublished manuscript, 2003). Although selfadministered questionnaires are frequently used in medical care settings to obtain information from patients before they are seen by a clinician, no studies of this approach for partner services have been published. Likewise, little data are available on telephone interviews and partner services. Previous CDC recommendations for STD partner services suggested that a telephone interview might be considered if attempts to meet with an index patient in person are unsuccessful or the index patient is in a different geographic location than the interviewer. One study, in which STD and community clinic attendees responded to varying hypothetical partner services providers and interview and notification conditions, showed that interview settings that were not in clinics were less favorably viewed than clinic interviews (75); telephone notification and letters by partner services providers were also less favorably viewed, although not significantly so. Although the available evidence suggests that audio computer-assisted self-interviews might effectively elicit partner information from index patients, no studies examining this particular use were found (76)(77)(78)(79)(80)(81)(82)(83)(84)(85). # Interview Techniques Incomplete reporting of partner names might stem from various factors, such as concern about potential negative consequences (e.g., fear of partner violence), perceived social undesirability of acknowledging participation in stigmatized or illegal activities, and forgetting or memory errors (71). However, although partner elicitation can be challenging, its effectiveness can be improved through systematic use of simple techniques. In a study of forgetting as a cause of incomplete reporting of partner names, using simple and nonspecific prompting (e.g., "Who else have you had sex with in the last 12 months?") and reading back the list of partners already named improved recall substantially (71). On average, these methods accounted for 10% of all partners recalled during an interview. In a randomized trial of interviewing techniques for persons at high risk for HIV infection, administering a set of five types of cues to participants, after they had freely recalled their partners, increased the number of sex and drug-injection partners elicited by an average of 40% and 123%, respectively (86). Eliciting partners in reverse chronological order, as suggested in previous CDC recommendations, was no more effective than using free recall. In a subsequent study of supplementary interview techniques for eliciting partners from index patients with chlamydial infection, gonorrhea, and early syphilis, patients were asked to freely recall partners, were prompted nonspecifically, and had the list of elicited partners read back (72). They were then administered three sets of cues, which increased the number of new cases found by 12% and identified network branches not previously recognized. Using supplementary interview techniques might be an efficient strategy for increasing the number of partners elicited and located. This approach seems to be effective for persons at risk for HIV as well as those with other STDs, suggesting that comprehensive, systematic use of such techniques during the original interview might enhance the yield of new partners identified. # Interview Period The interview period is the time interval for which index patients are asked to recall their partners. Ideally, the interview period covers the time from the earliest date an index patient could have been infected up to the date of treatment (i.e., the time period during which the patient could have become infected or transmitted the infection to others). Anyone who had sex with or, for those with HIV infection, shared druginjection paraphernalia with the index patient during this interval is at high risk for infection. Because of differences in biological factors and natural history, the interview periods for HIV, early syphilis, gonorrhea, and chlamydial infection differ (Table 1). # Syphilis, Gonorrhea, and Chlamydial Infection The interview period for early syphilis varies according to the stage of disease (primary, secondary, or early latent) because stages develop within well-defined timelines. Thus, the interview is used not only to find early syphilis cases but also to estimate which partners are most likely to have infected the index patient (i.e., the source) and which partners the index patient is most likely to have infected (i.e., spread). Source and spread information aid in defining the epidemiology of the infection and can be used to identify networks of infection. To some extent, source and spread can be estimated for gonorrhea and chlamydial infection but almost exclusively on the basis of interview results and generally not on the basis of stage of disease. The interview period for syphilis is based on the disease stage at the time of diagnosis and incorporates all maximum time periods for incubation and stage of disease. The interview period for a person with a diagnosis of primary syphilis is 4 months and 1 week, based on a 90-day maximum incubation plus 5 weeks (35-day maximum duration of lesion). The interview period for a person with a diagnosis of secondary syphilis is 8 months (34 weeks), based on a maximum 90-day incubation period and 5-week duration of primary syphilis, 10-week primary-secondary latency, and 6-week maximum duration of secondary symptoms. The maximum interview period is 12 months for early latent cases unless a credible primary or secondary history can be established and for cases of unknown duration. Unlike syphilis, which has multiple increases and decreases in level of infectivity, infectivity for gonorrhea and chlamydial infection increases to a single peak and then decreases. The standard interview period is 60 days before the date of specimen collection and should be extended through the date of treatment if the patient was not treated at the time the specimen was collected. For persons who seek treatment at a clinic because of signs or symptoms of gonorrhea and chlamydial infection, incubation is almost entirely covered within this 60-day period (although a few programs use 90 days). For asymptomatic cases of either STD (e.g., cases discovered during screening), the number of cases identified from partner notification can decrease substantially. This is especially relevant for chlamydial infection, which is most likely to be asymptomatic and for which widespread screening is most likely. In such instances, attempts to ascertain source and spread would have to be established on behavioral reports during interviews. However, data are useful for describing networks and the epidemiology of infection. # HIV Infection Determining when an index patient was infected with HIV often is difficult. Therefore, HIV programs frequently establish an interview period based on the estimated likelihood of being able to locate and contact the partners (e.g., 1-2 years before HIV diagnosis). The recommended interview period in a particular jurisdiction might subsequently be modified based on analysis of local data or availability of resources. Additional considerations might influence the interview period for specific index patients. Previous Negative HIV Test. A confirmed history of a nega tive HIV antibody test might be useful for defining the ap propriate interview period for a specific index patient. Knowing the date of the patient's most recent negative test and consid ering the window period (i.e., the time interval following in fection during which an HIV test might be negative because antibodies have not yet developed to a detectable level), the interviewer can establish how far back in time the interview period should extend. An estimated 95% of persons infected with HIV develop detectable HIV antibody within 6 months of infection, suggesting 6 months might be an appropriate interval to use as a window period; however, these estimates were developed using previous, less sensitive versions of the 1 year before start of treatment - The time interval for which an index patient is asked to recall sex or drug-injection partners. † The interview period is based on patient diagnosis and incorporates all maximum time periods. The interview period is not shortened, regardless of patient symptoms, serological history, or incidental treatment. If the patient claims having had no partners during the interview period, then the most recent partner before the interview period should be identified and notified. HIV enzyme immunosorbent assay (EIA) (87,88). More recent EIA tests (e.g., second-generation immunoglobulin G tests and third-generation IgG/immunoglobulin M tests) are considerably more sensitive than the previ ous tests and might allow the estimated window period to be shortened to 3 months (89,90). Evidence of Recent Infection. For certain patients, recent infection might be suggested by a clear history of an acute retroviral syndrome, which might result in the interview pe riod being shortened for these specific patients (91). Recently, HIV RNA testing has been used to screen pooled, HIV anti body-negative specimens to identify persons with acute or very recent infections (i.e., HIV RNA-positive and HIV an tibody-negative) (70,90,(92)(93)(94)(95)(96)(97)(98). For these index patients, the likely period of the date of infection can be narrowed consid erably, and the interview period can be adjusted accordingly. Spouses. As noted previously, the Ryan White CARE Act Amendments of 1996 require that states receiving funds un der part B of title XXVI of the Public Health Service Act en sure that a good-faith effort is made to notify the current spouse of an HIV-infected person or persons who have been legal spouses of that person during the 10 years before the diagno sis that such spouse might have been exposed to HIV and should seek testing. The 10-year interview period might be modified if a confirmed history of a negative HIV test or other laboratory testing indicates that the index patient was infected more recently; however, states should consult with their legal counsel to determine whether their laws allow them to make this modification. # Timing of Interviews The time in which partner services should be offered to reduce the disease transmission rate and the likelihood of reinfection might vary somewhat by disease. However, in general, partner services should be offered as soon as possible. # Syphilis, Gonorrhea, and Chlamydial Infection The pattern of infectiousness for early syphilis requires rapid notification and treatment of sex partners to have an effect on subsequent disease progression or transmission; therefore, partners should be notified quickly. For gonorrhea and chlamydial infection, the vast majority of additional transmission (i.e., by infected and untreated partners of the index patient) occurs quickly, and a delay in the interview is inadvisable. The morbidity for these two infections, especially chlamydial infection, have led to investigation of various notification and treatment options that are not widely advocated for syphilis (e.g., contact slips for patients to deliver to partners or patient delivery of oral medications). # HIV Infection Persons who test positive for HIV should be contacted and offered partner services as soon as possible after being identified by the partner services program, ideally within a few days. Rapid identification, notification, and testing of partners can reduce risk for additional transmission. A rapid interview allows partners to be identified and notified of possible exposure as soon as possible so that they can 1) obtain HIV counseling and testing; 2) take steps to avoid becoming infected or, if already infected, to avoid infecting others; and 3) access medical care and other services as soon after infection as possible. Patient reactions to learning about their HIV MMWR November 7, 2008 infection vary, and personal circumstances differ among patients. Partner services providers should recognize and, within reason, accommodate index patients who need particular concerns resolved before feeling ready to participate fully in partner services. For index patients who decline or are not ready to participate in an initial partner services interview at the time of first contact, a follow-up appointment should be arranged to discuss partner services concerns more thoroughly, preferably no later than 2 weeks after the initial contact. No studies are available related to introducing partner services to persons with reactive rapid HIV tests and interviewing them to elicit partner information. Partner services providers might consider conducting an initial interview and eliciting partner information when the reactive rapid test result is obtained and before results of confirmatory testing are available if the index patient accepts partner services at that time. However, persons with considerable partner services experience have suggested that partners not be contacted and notified until a positive confirmatory test is obtained. If a confirmatory test is not performed at the time the rapid test is found to be reactive, attempts can be made to locate the patient and obtain confirmatory testing. If the patient cannot be located or declines confirmatory testing, and the rapid test was performed on a blood specimen, the DIS can then contact the partners and notify them about their possible exposure to HIV through someone who had a reactive rapid test result. This suggestion is based on the high predictive value of a reactive rapid test, in most circumstances, when performed on a blood specimen. Local policies might preclude use of this approach. # Interviewers Traditionally, index patients have been interviewed by health department DISs. Certain evidence indicates that health department specialists might elicit more partner names from index patients with gonorrhea or chlamydial infection than other, presumably untrained, interviewers (99). A cohort study of the efficacy of partner notification for HIV infection found that although patients counseled by health department specialists reported more locatable partners than those counseled by physicians, the number of partners per index patient interviewed who were then identified as having a new diagnosis of HIV infection was similar for both groups of health-care providers (100). No such comparative data exist for gonorrhea or chlamydial infection, although the frequency with which both STDs are diagnosed outside public settings (especially STD clinics) suggests that collaboration with physicians is appropriate. Health departments might be able to expand access to and coverage of partner services by developing agreements with providers who are not in health departments to elicit information about partners and provide that information to a health department DIS. The DIS can then notify the partners. Existing relationships and rapport between these providers and their patients might facilitate partner elicitation; providers must inform patients that the information will be shared with health department DISs. Documented experience with this strategy is scarce; however, such approaches have been used by health departments in several jurisdictions, with anecdotal reports of success. Other than DISs, types of providers who might elicit partner information from index patients on behalf of partner services programs include the following: - other health department personnel (e.g., physicians, nurses, counselors, or case managers); - health care or service providers who are not in health departments (e.g., primary care providers) who provide STD screening and HIV counseling and testing to their patients; - counselors in publicly funded HIV counseling and testing sites; - counselors in other HIV counseling and testing sites; and - health care or service providers who are not in health departments (e.g., physicians, physician assistants, nurse practitioners, nurses, CBO staff members, or HIV case managers) who provide services, including screening for other STDs, to persons with HIV infection. These providers, who often have ongoing relationships with HIV-infected persons, might be particularly useful in providing ongoing partner services to their clients (i.e., periodically inquiring about new partners who might be at risk and initiating partner services as needed). If other types of providers participate in this way, roles and responsibilities should be clearly defined. # Unique Circumstances of Index Patients Unique characteristics of index patients and their individual circumstances might affect the partner services process. In certain instances, the mental health status and decision-making capabilities of an index patient might affect the approach to providing partner services. Guardians or others might be charged with making legal and health-care decisions for such persons. Local laws, regulations, and policies might address these concerns. Programs should develop policies and procedures that describe how to work with index patients who might have limited comprehension or other mitigating circumstances; this might require consultation with persons who have expertise in these areas. Examples of concerns that should be considered when developing protocols include age and developmental level, literacy level, language barriers, cultural concerns, hearing or visual impairments, alcoholism or abuse of other substances, mental health concerns, or potential violence (either on the part of index patients or their partners). # Recommendations for Interviewing Index Patients # General - In general, partner names should be elicited (partner elicitation) during the original interview. If this is not possible, a reinterview should be scheduled. - Programs should establish clear policies and procedures for the timing of interviews relative to date of diagnosis or report. - Index patients should be provided information about the following: -the purpose of partner services; -what partner services entail; -benefits and potential risks of partner services for index patients and their partners, and steps taken to minimize any risks; -how and to what extent privacy and confidentiality can be protected; -the right to decline participation in partner services without being denied other services; and -options available for notifying partners. - Program managers should ensure that policies and protocols are in place to safeguard the confidentiality of information shared with health department staff members during the partner notification process. Specifically, staff members must be trained to maintain confidentiality in both their professional and private lives. Confidentiality is particularly salient in rural areas, where a DIS might have substantial contact with clients outside of the professional environment (e.g., because they are neighbors, parents of children's classmates, or members of the same church) (101). - To ensure confidentiality, interviews should not be conducted with other persons present, except for quality assurance or for interpreting. - In general, partner-elicitation interviews should be conducted by trained health department specialists. However, to expand partner services coverage, health departments should consider enlisting other types of providers to conduct interviews on their behalf. Successfully eliciting information about partners requires skilled counseling and interviewing; therefore, all providers conducting interviews on behalf of the health department should receive appropriate training. The yield of interviews conducted by other providers should be carefully monitored. - In general, interviews should be conducted in person. Telephone interviews might be conducted if no reasonable alternative exists, with strict safeguards in place to verify the identity of the person being spoken with and ensure that privacy and confidentiality are protected. - Programs should use interview techniques that maximize the amount of information gathered in the original interview about the index patient's partners. Policies, procedures, and protocols should establish criteria for instances in which reinterviews should be done, how soon they should be done, and when they are unnecessary. The yield of original interviews and reinterviews should be monitored closely and policies, procedures, and protocols adjusted accordingly. - In addition to information about partners, interviewers also can elicit information about the index patient's social network, including venues frequented, for use in planning additional prevention activities. - Policies, procedures, and protocols should address circumstances that might require specific consideration in interviews with index patients (e.g., age and developmental level, literacy, language barriers, hearing or visual impairment, alcoholism or abuse of other substances, mental health concerns, or potential violence). # Syphilis, Gonorrhea, and Chlamydial Infection - For early stages of syphilis, policies, procedures, and protocols should specify that all index patients receive an original interview as close to the time of diagnosis and treatment as possible. Every reasonable effort should be made to ensure the partner notification process begins on the date of the original interview. - For cases of gonorrhea and chlamydial infections that partner services staff members will follow up, policies, procedures, and protocols should specify that all index patients receive an original interview as close as possible to the time of diagnosis and treatment. Unless the index patient has evidence of recent infection, notification primarily serves case-finding goals and might be briefly delayed, if necessary. - For cases of gonorrhea and chlamydial infection that partner services staff members will not follow up, patient referral instructions should be provided as close as possible to the time of diagnosis and treatment. - For STDs other than HIV, partner services programs should follow established recommendations for interview periods (Table 1). # HIV Infection - Policies, procedures, and protocols should specify that all index patients receive an original interview as soon as possible after diagnosis, ideally within a few days. For index patients who are not willing or able to provide partner information during the original interview, a reinterview should be scheduled, preferably no later than 2 weeks after contact was first made (and sooner, if possible, for index patients with acute infections). - Programs should develop criteria for establishing the interview period for index patients with HIV infection (Table 1). Criteria for prioritizing partners should be developed in consultation with persons who have expertise in clinical and laboratory aspects of HIV (e.g., viral and serologic markers of HIV infection). - Program managers should ensure that policies and procedures regarding notification of spouses adhere to requirements of the Ryan White CARE Act Amendments of 1996 and any other applicable laws. - Policies, procedures, and protocols should address interviews for persons with reactive rapid HIV tests, including when partner names should be elicited, when partners should be notified, and policies about notifying partners when a confirmatory test is not available. # Risk-Reduction Interventions for Index Patients Many HIV-infected persons are knowledgeable about STD/ HIV transmission and prevention; however, misconceptions and inadequate information about transmission and methods for reducing transmission risk are common (102)(103)(104)(105). All index patients likely can benefit from receiving information and brief prevention messages about adopting and maintaining safer behaviors to protect their own health and that of their partners (25,106). In the case of HIV infection, this includes discussing the index patients' responsibility for disclosing their HIV serostatus to current and future partners. These messages can be integrated easily into the activities of DISs. In addition to provision of information and brief prevention messages, prevention counseling can be relevant for all infected persons, regardless of the STD diagnosis. Project RESPECT, a risk-reduction intervention trial conducted during the mid 1990s, was aimed at preventing HIV and other STDs in HIVnegative, heterosexual STD clinic patients (25). Approximately one third of participants had an STD at the time of enrollment. Participants were randomly assigned into three groups and received either two sessions of interactive risk-reduction counseling; four sessions of enhanced interactive, theory-based counseling; or two brief sessions of didactic information. Compared with baseline, participants in all three groups reported higher levels of condom use at 3, 6, 9, and 12 months follow-up. At 3 and 6 months, participants receiving either of the two counseling interventions reported significantly higher levels of condom use than those receiving only didactic information. At 9 and 12 months, participants in all three groups continued to report higher levels of condom use than at baseline, but the differences between those in the two counseling groups and those in the didactic information group were no longer significant. In addition, compared with participants in the didactic information group, 30% fewer participants in the two counseling groups had new STDs after 6 months, and 20% fewer participants in either counseling group had new STDs through the 12-month interval. The relative effectiveness of counseling was greater among participants who had an STD diagnosis at enrollment than among those with no STD. Interactive and individually tailored counseling is likely similar to the communication between many DISs and patients regarding partner services and future behavior. However, use of the intervention in STD clinics, with at least two sessions, has been limited (107). Another study of counseling to prevent STDs and HIV infection in STD clinic patients compared the effectiveness of two 20-minute individual counseling sessions with four 1-hour group sessions with a follow-up session 2 months later. After 12 months, both groups had similar and significant increases in condom use, decreases in number of partners, and decreases in numbers of new infections with gonorrhea (14%), chlamydia (10%), or syphilis (2%) (108). # Syphilis, Gonorrhea, and Chlamydial Infection Although prevention counseling is relevant for persons with early syphilis, gonorrhea, or chlamydial infection, prevention counseling other than individualized attempts during an interview is typically composed of brief prevention messages delivered once. With early syphilis patients, repeated contact with DISs during the course of an investigation is common enough that they can establish a record of behavioral change or reinforce previous counseling. Except for repeat cases, health department-mediated prevention counseling with gonorrhea or chlamydial infection is almost certain to be a one-time session. The gap between demonstrated efficacy and implementation merits additional examination. Certain aspects of counseling for patients with syphilis, gonorrhea, and chlamydial infections are devoted to promoting rescreening at 3 months, which CDC recommends, given frequently high rates of reinfection among STD clinic attendees (3,109). In one study of STD clinics in Los Angeles County, California, and Maryland, telephone reminders and pointof-care interviews (approximately 20 minutes) to reinforce the importance of rescreening to the patient were both associated with increased rates of return at 3 months (110). Subsequent efficacy and cost-effectiveness analyses suggested the telephone reminder alone would be most efficient and most cost-effective, although the point-of-care interviews should be used in situations in which telephone contact is unlikely (110,111). Another condition tested in the study, a $20 incentive with brief instructions, was associated with higher return rates for men but not women. Although programs might consider incentives to improve return rates, offering them only to men would have ethical implications. Data on interventions to promote follow-up testing for syphilis recurrence would broaden the scope of evidence available for making program decisions about this disease. # HIV Infection Many persons substantially reduce HIV transmission risk behaviors after learning they are infected (28,30,(112)(113)(114). A metaanalysis of high-risk sexual behavior in HIV-infected persons aware and not aware of their infection found that the prevalence of unprotected anal or vaginal intercourse with any partner was an average of 53% lower for HIV-infected persons aware of their infection compared with HIV-infected persons not aware of their infection and 68% lower after adjusting data to focus on unprotected anal or vaginal intercourse with partners who were not already HIV infected (29). However, a considerable percentage (range: 10%-60%) do not consistently practice safer behaviors and might transmit infection to others or put themselves at risk for acquiring other STDs (26). Thus, although certain HIV-infected index patients might already have reduced their level of risky behaviors by the time they are interviewed for partner services, others are continuing risky behaviors and require additional prevention counseling or other more intensive prevention intervention. Index patients who need additional counseling or other riskreduction interventions can be identified through brief behavioral risk screening that can be integrated easily into the interview process (54). Questions used for behavioral risk screening need to be broad enough to identify most index patients engaging in risky behaviors. This includes index patients currently or recently engaging in risky sex or druginjection practices, those who have a current or recently diagnosed STD, those who might be pregnant or at risk for unintended pregnancy, those with other characteristics associated with risky behaviors (e.g., alcohol or other noninjection drug use), and those who were previously identified and are now named as partners by other index patients, which suggests ongoing risky sex or drug-injection behavior. Index patients whose risk screening indicates continuing risky behavior should be informed of the risks involved in continuing the behavior. They should also be provided prevention counseling or referred for counseling or more intensive prevention services. Several risk-reduction interventions designed specifically for HIV-infected persons have been demonstrated to be effective. Most of these interventions involve multiple sessions provided over time, usually in a group format (26,27,31). Most do not focus only on reducing transmission risk; rather, they address multiple life concerns faced by HIV-infected persons, which might increase the likelihood that patients can make and sustain behavioral changes. These interventions are not feasible to provide through partner services but might be available through CBOs in the area or as part of ongoing prevention activities incorporated into the medical care of persons living with HIV infection (54). Certain partner services programs might have adequate resources to assess and provide prevention counseling to index patients whose screenings indicate continued risky behaviors. However, health department DISs often have limited numbers of interactions with index patients. Furthermore, the time available for DISs to provide prevention counseling to index patients might be limited, especially if health departments expand their partner services activities to ensure that all persons with newly diagnosed or reported HIV infection receive adequate partner services. Consequently, in certain programs, health department DISs might have difficulty providing prevention counseling to all index patients for whom it is indicated. In these situations, and for index patients requiring more intensive prevention interventions, referral or linkage to agencies that provide these services or to case managers who can arrange them is appropriate. # Recommendations for Risk-Reduction Interventions for Index Patients - Program managers should develop protocols that establish the minimum amount of information and prevention messages that should be provided to all index patients. For patients with HIV infection, the information should include the index patients' responsibility for disclosing their HIV serostatus to current and future partners. # Treatment for Index Patients Syphilis, Gonorrhea, and Chlamydial Infection The CDC 2006 STD treatment guidelines provide preferred and alternative treatments for syphilis, gonorrhea, and chlamydial infection (3). DISs should verify that index patients have been treated appropriately. Because each of these STDs is curable, linkage to additional medical care (in the absence of coinfection with HIV) generally is not needed, although recommendations for follow-up testing are appropriate. # HIV Infection Effective and timely medical evaluation, initiation of currently recommended combination ART, and provision of appropriate vaccinations and other preventive health interventions have led to substantial reductions in HIV-related morbidity and mortality (115,116). HIV-infected persons who begin receiving (or reestablishing) medical care not only can benefit from ART but also can receive screening for other STDs and bloodborne infections (e.g., HBV and HCV), appropriate vaccinations for vaccine-preventable infections, and other medical services. In addition, through medical care and HIV case management, patients can be evaluated and receive referrals for a wide range of other medical and psychosocial services, and the medical care setting offers an opportunity for patients to be more completely assessed for HIV transmission risk and provided or referred for appropriate HIV prevention services (54). Furthermore, ART might decrease infectiousness and reduce risk for transmission to others by reducing the patient's viral load (32,117,118). However, delays in accessing medical care and inadequate use of care are common among persons who receive an HIV diagnosis (14,119,120). Linking HIV-infected persons to medical care and ongoing HIV case management as soon as possible after diagnosis is essential. Brief HIV case management for persons with newly diagnosed HIV infection increased attendance at HIV care facilities. The Antiretroviral Treatment Access Study, a multisite, randomized control intervention for persons with newly diagnosed HIV infection, directly compared passive referral (i.e., giving patients a list of medical providers) with brief HIV case management and found that those who received HIV case management were significantly more likely to be linked to and attend clinic visits over a 12-month period (121,122). In certain situations, these brief HIV casemanagement services were provided by DISs. This underscores the importance of DISs actively helping index patients with newly diagnosed or newly reported HIV infection to access medical care either directly or by linking them to HIV case managers. DISs also might be able to facilitate reestablishment of reentry into HIV case management and medical care for HIV-infected persons who are not currently receiving medical care but have in the past. # Recommendations for Treatment for Index Patients Syphilis, Gonorrhea, and Chlamydial Infection - Program managers should ensure that patients are treated according to CDC treatment guidelines for timely and efficacious treatment with appropriate instructions and attention to recommendations regarding the importance of follow-up testing. # HIV Infection - Program managers should create strong referral linkages with HIV care providers and case managers to help ensure that the medical needs of index patients are addressed. - HIV-infected index patients who are not receiving medical care should be referred or directly linked to medical care or to case managers who can then link them to care services. # Referring Index Patients to Other Services Many index patients have underlying problems that impede their ability to access medical care or adopt and maintain safer behaviors and would benefit from referrals to various psychosocial services. Because of the numerous U.S. cases of gonorrhea and chlamydial infection, and because medical management of syphilis, gonorrhea, and chlamydial infection does not generally require an ongoing care relationship with partners, the process of referral to other services for index patients with these STDs is less intense than it is for index patients with HIV infection. Nevertheless, many jurisdictions offer referrals for care on request or if the need for other services is ascertained during the course of interviewing the index patient. For index patients whose infections are likely related to their living conditions (e.g., homelessness or partner violence), attention to need for supportive services might reduce the likelihood of reinfection and contribute to infection control. Program collaboration and service integration facilitate this process. Index patients might need a range of services, such as the following: # Notifying Partners of Exposure Notification Strategies After index patients have identified partners, the partners should be notified of the exposure as soon as possible. Traditionally, four strategies have been used to accomplish this: provider referral, self-referral, contract referral, and dual referral. Provider referral notification involves a partner being notified of their possible exposure by a health department specialist who has been specifically trained to locate and notify partners. The specialists then link the partners to medical, prevention, and support services while protecting the confidentiality of the index patient. The term provider referral has sometimes led to confusion, because health-care providers other than health department specialists might conduct some or all steps in the partner services process, especially for index patients who receive a diagnosis in a setting other than the health department. Therefore, these recommendations use the term provider referral to specifically describe notification carried out by health department staff members and the term third-party referral to describe partner notification carried out by other professionals (e.g., HIV counselors and clinicians who are not in health departments). Self-referral notification (also called client or patient referral notification) gives the index patient full responsibility for informing partners of exposure and referring them to appropriate services. Contract referral notification involves index patients selecting specific partners they prefer to notify themselves and agreeing to a specific time frame in which they will do so. Patients agree that if they do not notify the selected partners within the established time frame, the DIS will notify the partners. Dual referral notification involves an index patient and a provider (a DIS or third party) jointly notifying a partner of exposure. The notification strategies primarily differ in the degree of responsibility assumed by the DISs. Variations in the extent of DIS involvement, in turn, contribute to differences among the strategies in terms of effectiveness, intensity of resource use, and acceptability to index patients and partners (Table 2). The limited available data suggest the following: - Provider referral is the most effective single method for notifying partners. - Self-referral is the least effective single method for notifying partners. - Maximum notification rates for HIV are achieved when the provider and index patient share the responsibility for notification. - No data are available on the relative timeliness of the various partner notification strategies. # Provider Referral Notification STDs Other than HIV. A 1977 study comparing provider referral with self-referral for gonorrhea found that similar pro portions of partners were evaluated and treated, although pro vider referral follow-up was required for a small number of partners who originally had been randomly assigned to the self-referral group (123). In a study of partner notification for syphilis, for which provider referral is most strongly empha sized of all the STDs, a comparison of three referral approaches (two groups with provider referral, one with contract referral) revealed no clear evidence of increased effectiveness or costeffectiveness for any strategy compared with another (5). Be cause the majority of spread of infection of primary and secondary syphilis is likely to occur near the same time as the interview, infection control requires almost immediate part ner notification and referral. Such swift notification is most reliably accomplished through provider referral (although notification of Internet partners might be an exception). The effectiveness of provider referral (or third-party refer ral) depends on the ability and willingness of index patients to provide sufficient identifying and locating information. Index patients often cannot provide sufficient information to conduct provider referral for all partners, and other strategies might be needed. For example, during syphilis outbreaks in several U.S. cities during 2002-2005 among men who have sex with men (MSM) (124,125), program staff members con sidered using Internet-based notification when index patients could provide only e-mail addresses or chat-room nicknames as identifiers. Gonorrhea and chlamydial cases are frequently too numer ous to permit provider referral. The basis for notification in such instances should be self-referral, although basic instruc tions can be supplemented with brief oral counseling, written instructions, and contact information for patients to give to partners (most commonly known as contact slips or referral cards) (126,127). Circumstances in which index patients also are provided with medications or prescriptions to deliver to partners are known as patient-delivered partner therapy, a form of expedited partner therapy. HIV Infection. Provider referral has been found to be an effective means of identifying new cases of HIV. In nine stud ies that qualified for inclusion in the Guide to Community Preventive Services review, a range of one to eight partners were identified per index case. A mean of 67% of named partners were found and notified of their exposure to HIV (range: 44%-89%), a mean of 63% of those notified were tested, and of those tested, a mean of 20% were newly identified as HIV infected (range: 14%-26%) (16). Only two U.S. studies comparing provider referral with other referral strategies for HIV partner notification have been pub lished; both were included in the Guide to Community Pre ventive Services review. In one study comparing the effectiveness of provider referral and self-referral (i.e., patient referral) notification in three health departments in North Carolina, index patients were randomly assigned to provider referral or patient referral groups (128). In the provider refer ral group, index patients were given the option of selecting between provider referral conducted by a health department counselor and contract referral. With contract referral, they were given 2 weeks to notify a partner themselves, after which time a counselor attempted to notify any partners who had not been notified by the index patient. In the patient referral group, index patients were asked notify all of their partners themselves and were not given the option of requesting pro vider referral for any partners. Patients were given 1 month for notification, after which time the counselors attempted to notify any partners who had not been notified by the index patient. In the provider referral group, counselors notified 70 (45%) of 157 partners. In the patient referral group, index patients notified only 10 (7%) of 153 partners. Thus, in this study, provider referral was approximately 6.5 times more ef fective than patient referral. Of the 143 partners who were not notified by index patients in the patient referral group, counselors were able to notify only 40 (28%) partners. A sec ond study analyzed results of HIV partner notification ser vices provided by the Colorado Department of Health in 1988 (129). Of 84 partners for whom provider referral was intended, 71 (85%) were notified by providers. Of 30 partners for whom patient referral was intended, 17 (57%) were notified by in dex patients. Thus, in this analysis, provider referral was ap proximately 1.5 times more effective than patient referral. # Self-Referral Notification Syphilis, Gonorrhea, and Chlamydial Infection. Although provider referral is favored and generally expected for notify ing partners of persons with syphilis, self-referral is the typical form of partner notification for persons with chlamydial in fection. Successful public health involvement with partner no tification for chlamydial infection is likely to be limited to improving self-referral effectiveness through interventions provided at the time of diagnosis or treatment (e.g., brief counseling) and possibly through increased monitoring of the proportion of those seeking care who have been referred by a partner (11). Gonorrhea is somewhat more likely than chlamy dial infection to be targeted for provider referral in public clinic settings; nonetheless, strategies for chlamydial infection often are applicable for gonorrhea (especially outside public clinic settings); basic instructions can be supplemented with brief verbal counseling. A randomized, controlled trial in Brooklyn, New York, showed male notification rates of part ners could be improved with a brief counseling session (ap proximately 20 minutes) aimed at identifying and reducing barriers (130). Index patients' intentions, skills, and belief in their ability to notify (i.e., self-efficacy) have been associated with more successful referrals, including among adolescents, and interventions to increase the effectiveness of self-referral typically have incorporated approaches aimed at improving self-efficacy (131). Written instructions for index patients to deliver to part ners are known as contact slips or referral cards. Referral cards are used to add legitimacy to the index patient's notification of the partner, provide information to the partner, and pro vide information and a short history of exposure to any clini cian from whom the partner seeks evaluation. This ensures that the clinician has sufficient, accurate information to guide appropriate evaluation and management of the partner. In ideal circumstances, the referral card with treatment notes from the evaluating clinician is returned to a public health pro gram, but this situation rarely occurs. A referral card can in clude the specific type of exposure, where to go for timely evaluation, what to expect in an evaluation, the recommended treatment, and what to do until treatment begins (e.g., ab stain from sexual activity). For confidentiality reasons, no ju risdictions permit names on a referral card, and many jurisdictions have policies prohibiting naming the type of in fection. One British study showed that partners of index pa tients with chlamydial infection were much more likely to seek evaluation if their referral card specifically referred to chlamydial infection (84% versus 33%, p<0.01) (132). Among program evaluations in the United States and other industri alized nations, use of referral cards typically has been associ ated with improved notification and treatment rates. In one trial, their use was associated with reduction in reinfection of index patients but not improved notification (11,126). HIV Infection. As noted previously, a randomized, con trolled trial in North Carolina and an analysis of program data in Colorado both found self-referral notification strate gies to be less effective than provider referral for notifying partners of exposure, especially when index patients were re quired to notify their own partners and given no other op tions (128,129). However, in the North Carolina study, patients notified 14% of all partners who were eventually notified, and in the Colorado report, patients notified 20% of all partners who were eventually notified. Research of HIV disclosure practices and attitudes toward partner notification might offer insight into index patient and partner characteristics associated with higher likelihood of disclosure or self-referral. Disclosure or self-referral is more likely for partners described by the patient as primary, regu lar, or main partners than for partners described as nonmain, casual, or one-time partners, regardless of patient age or risk behaviors (133)(134)(135)(136)(137). Intention to notify also is associated with a higher likelihood of disclosure. In turn, intention is related to factors such as sense of duty or responsibility to the partner and an HIV-infected person's perceived self-efficacy for disclosing serostatus (138)(139)(140)(141)(142)(143). Increasing number of partners is inversely related to likelihood of disclosure; as the number of partners increases, the likelihood that the index patient will notify any of them decreases (134,(144)(145)(146)(147). # Contract Referral Notification Syphilis, Gonorrhea, and Chlamydial Infection. Con tract referral has not been widely evaluated for syphilis, gon orrhea, or chlamydial infection. A trial including provider and contract referral notification for syphilis infection revealed no clear advantages to either method (5). DISs must balance the efficiency gained by having to notify fewer partners in the short term (i.e., partners who are notified by the index pa tient and also seek evaluation) with the efficiency lost by con ducting additional interviews with index patients who did not notify partners as intended and with the potential for addi tional transmission because of delayed notification. HIV Infection. No published study has assessed directly the notification and case-finding effectiveness of contract re ferral for HIV partner notification. However, some insight might be gained from the previously discussed North Caro lina and Colorado studies (128,129). In the North Carolina study, 128 (41%) of 310 partners were notified by a combi nation of providers and patients, whereas of the 292 partners who providers attempted to notify alone, 110 (38%) were notified. In the Colorado study, 104 (91%) of 114 partners were notified by a combination of providers and patient, whereas of the 91 partners who providers attempted to notify alone, 81 (89%) were notified. These findings suggest that including index patients in the notification process might be as effective as relying solely on providers to carry out all noti fications and that the strategy certainly is efficient. # Dual Referral Notification Dual referral notification involves an index patient and provider, together, notifying a partner of exposure. Dual referral provides the index patient direct support in the notification process and might decrease the possibility of negative consequences such as violence or severe emotional reactions. The DIS is available to offer immediate counseling, provide accurate information, answer questions, address concerns, and provide referrals to other services. At the same time, participation by index patients might help patients begin to think about their infection status, increase the likelihood that partners are located and notified, and increase the acceptability of the partner services process to partners. In theory, dual referral has substantial advantages over other approaches; however, the frequency with which this approach is used and its effectiveness (either absolute or relative to other notification methods) are not known. # Third-Party Referral Notification Third-party referral notification involves partners being notified by providers who are not with health departments (e.g., private physicians). The frequency with which this strategy is used, its feasibility and effectiveness, and its acceptability to index patients, providers, and partners are not known. In general, the most appropriate roles for third parties in partner services are likely interviewing index patients to elicit partner information and possibly participating in partner notification when dual referral strategies are used. Because no data are available on the effectiveness and safety of third parties conducting field notification, the level of training and skill needed for third-party referral is unclear. State and local laws might have specific requirements related to duty to warn for third-party providers. # Prioritizing Partners for Notification All identified partners should be notified of their possible exposure as soon as possible, unless partner violence resulting from the notification is a concern. However, prioritizing certain partners for the most immediate notification is appropriate. In general, criteria for prioritizing partners for more immediate notification include behavioral and clinical factors that increase the likelihood of the partner having been infected as a result of exposure or of transmitting infection to others if the partners are infected. Criteria vary somewhat according to the infection involved. Program effectiveness can be improved by periodically reviewing and adjusting prioritization criteria. # HIV Infection, Syphilis, Gonorrhea, and Chlamydial Infection Following are categories of partners who are considered to have the highest priority for notification of exposure, regardless of the infection involved: - Female partners who are known or likely to be pregnant - Partners suspected of or known to be engaging in behaviors that substantially increase the risk for transmission to multiple other persons (e.g., those who have multiple partners) - Partners with whom the index patient reports having had unprotected anal or vaginal sex # HIV Infection Following are examples of other categories of partners who are considered to have the highest priority for notification of exposure to HIV: - -Partners whose earliest known exposure has been within the past 3 months. Studies suggest that the incubation period for HIV infection (time from infection to acute retroviral syndrome) ranges from 5 to 75 days, that serum viral load is likely to be highest in the month after infection, and that viral load in seminal and cervicovaginal fluid is likely to be highest in the first 2 months after infection (148)(149)(150). Therefore, partners who are likely to have been infected within the previous 3 months might be more likely to spread HIV to others. # Confidentiality When notifying partners of exposure, the identity of the index patient must never be revealed. Partners might correctly guess the identity of the index patient and pressure health department staff members to confirm their suspicions, but well-trained DISs avoid such confirmations, either orally or through body language. In addition, information about partners should not be reported back to the index patient. Steps can be taken to reduce the likelihood that neighbors, family, friends, or others are able to discern the purpose of health department staff members in the field looking for index patients or named partners, such as not wearing identification badges, not using marked vehicles, and not explaining to others the reason a particular person is being sought. # Screening for Potential Partner Violence The potential for violence initiated either by a partner or by an index patient during the process of partner notification is an important concern. Published data on violence associated with partner notification are limited. A study conducted in New Orleans, Louisiana, examining the effect of HIV and syphilis partner notification on partnerships found that, at baseline, 42.3% of index patients reported having experienced emotional abuse from a partner in the 3 months before interview and 23.6% reported having experienced physical violence from a partner during the same interval (40). No difference between HIV and syphilis partnerships was found in terms of the proportion of participants reporting either emotional abuse or physical abuse at baseline; during the 6 months after partner notification, emotional abuse and physical abuse decreased significantly among both HIV and syphilis partnerships, with no difference between the two. However, this study did not determine whether any of the abuse or violence was directly related to partner notification. A study of Mexican-American and African-American women with nonviral STDs examined factors related to whether the women had notified their male partners or intended to do so (43). Of 775 women in the study, 63% reported having ever been physically or sexually abused, but history of abuse was not associated with notification status. The women reported having experienced abusive behavior in relationships with 19% of the male partners; however, this also was not associated with notification status, and only 4% of the women cited concern about violence as a reason for not notifying a partner. Additional insight into the topic of notification-associated violence might be gained through studies of partner violence associated with disclosure of positive HIV serostatus, although the findings are less likely to apply to other STDs. A small number of surveys of HIV-infected women have indicated that rates of disclosure-associated partner violence might range from 0.5% to 4% (41). Interviews with 336 HIV-positive and 298 HIV-negative pregnant women in Brooklyn, New York; Connecticut; Miami, Florida; and North Carolina found that the proportion of women reporting violence was not higher among 142 HIV-positive women who received the HIV diagnosis during the current pregnancy (5.8%) than among seronegative women (10.7%) or HIV-positive women who previously received the diagnosis (9.4%) (42). Of 260 HIVpositive women with main male partners, 206 (79.2%) said their partner knew their serostatus; of these, one (0.5%) reported being physically assaulted when her partner found out she was infected. Thus, this study indicates that disclosureassociated partner violence was rare. However, 21% of the women had not disclosed their serostatus to their partners; the estimated risk for violence might have been higher had all these women disclosed their status Although the rate of violence directly attributable to partner notification is likely low, the available data are limited, and additional study is needed. The prevalence of partner violence among the populations studied in the few published reports is of substantial concern, regardless of whether the violence was precipitated by partner notification or was coincidental. Therefore, screening for potential risk for partner violence before notifying partners is important. # Recommendations for Notifying Partners of Exposure # Partners - All identified partners should be notified of their possible exposure as soon as possible, typically within 2-3 working days of identification, unless a potential for partner violence exists. - Program managers should ensure that protocols include screening for potential violence with each partner named before notification. If the provider considers a violent situation possible, the provider should seek expert advice before proceeding with notification. DISs should follow up on referrals for partner violence services to verify that referred persons are safe and have accessed these services. - Programs should establish criteria for prioritizing the order in which partners are notified. Criteria should be based on behavioral and clinical factors that confer a higher likelihood of the partner having been infected as a result of exposure or, if already infected, of transmitting infection to others. In addition, the Ryan White CARE Act Amendments of 1996 require that states receiving funds under part B of title XXVI of the Public Health Service Act should ensure that a good-faith effort is made to identify spouses of HIV-infected patients. Criteria should be reviewed at regular intervals (at least annually). - Programs should accommodate various notification strategies that allow the DIS and index patient to collaborate on the best approach for notifying each partner of exposure and ensure that the partner receives appropriate counseling and testing. Regardless of which strategy is used, the DIS and index patient should plan for potential unanticipated outcomes. - For partners for whom the index patient has provided a name (or other identifying information, such as an alias) and locating information, programs should strongly encourage provider referral but be supportive of index patients who choose contract referral for selected partners. - When contract referral is chosen, the DIS should establish an agreement with the index patient specifying when partners should be notified (typically within 24-48 hours), how the provider will confirm that partners were notified, and which follow-up services will be required for situations in which the index patient does not notify the partner within the allotted time frame. - Programs should allow for self-referral as permitted by state and local laws and regulations. Index patients who choose self-referral for certain or all partners should be informed of its disadvantages and informed about methods for accomplishing the notification safely and successfully. Self-referral should be discouraged if screening indicates a potentially violent situation. - Protocols for self-referral should, when possible, incorporate interventions that enhance its effectiveness and include instructing the index patient about the following: -when to notify the partner (e.g., within 24-48 hours); -where to notify the partner (e.g., private and safe setting); -how to tell the partner; -how to anticipate potential problems and respond to the partner's reactions; -how and where the partner can access counseling and testing for HIV and other types of STDs; -for persons with HIV infection, how to address the psychological and social impact of disclosing infection status to others; and -how to contact the DIS with any questions or concerns that might arise. - To the extent possible, programs should develop methods of monitoring whether partners who are to be notified by the index patient (i.e., via contract or self-referral) are actually notified and receive appropriate counseling and testing. - Dual referral should be an option for index patients who prefer to be directly involved in the notification but express a need for assistance and support from the DIS. When dual referral is chosen, the DIS and index patient should plan in advance how the session will be conducted. - Program managers should ensure that policies and procedures, consistent with applicable laws, are in place to protect the identities of index patients when informing partners of their exposure and to ensure that information about partners is not reported back to index patients. - Local reporting laws relating to domestic violence, including child abuse and abuse of older adults, must be followed when clients report risk or history of abuse. - Program managers should ensure that DISs are the following: -knowledgeable about HIV and STD infections, transmission, and prevention; -well informed about relevant laws and regulations; -familiar with HIV and STD program standards, objectives, and performance guidelines; -culturally competent in providing partner services; -skilled at problem solving and dealing with situations that might be encountered in the field (e.g., personal safety, intimate partner violence, and violence to others); and -trained how to screen for and address partner violence concerns. # Social Contacts General. In general, notification of partners should have a higher priority than notification of individual social contacts identified through clustering. Routine follow-up of social con tacts should be carried out only after the program is success fully interviewing most new patients with cases and locating and notifying most partners and only after carefully consider ing the potential case-finding yield and resource implications. If this strategy is used, the number of cases identified should be carefully monitored, and the approach should be contin ued only if its effectiveness and cost-effectiveness equal or ex ceed those of other case-finding strategies. Notification of social contacts might be given higher priority during an outbreak. HIV Infection. For persons with HIV infection, informa tion about social contacts should be used as an aid to under standing transmission dynamics in the community and to help guide additional prevention interventions at the community level (e.g., screening and social marketing). In general, if indi vidual social contacts are to be recruited for HIV testing, a self-referral approach rather than provider referral should be used. A provider referral approach should be used only after careful consideration of potential individual and community concerns about privacy and confidentiality. Provider referral might be appropriate during an outbreak. # Risk-Reduction Interventions for Partners Providing Information, Brief Prevention Messages, or Interactive Prevention Counseling Misconceptions and inadequate information about STD/ HIV transmission and methods for reducing transmission risk are common; all partners likely can benefit from receiving information and brief prevention messages about adopting and maintaining safer behaviors to reduce their risk for acquiring or transmitting STDs/HIV (25,106). These messages can be integrated easily into DIS activities. Previous CDC guidelines for HIV partner counseling and referral services and STD partner services have recommended interactive, client-centered prevention counseling for partners (1,2). No published studies are available regarding the effectiveness of prevention counseling specifically in the context of partner services. Some reduction in risk behavior after partner notification has been reported; however, overall, data are too limited to allow any conclusions to be drawn (44,151). A metaanalysis of HIV counseling and testing research published during 1985-1997 concluded that HIV counseling and testing did not seem to reduce risk behaviors among HIVnegative persons (112). However, the studies included generally provided little or no detail about the type of counseling used. Subsequently, the previously mentioned Project RESPECT trial (25) demonstrated that heterosexual STD clinic patients who tested negative for HIV and received either two sessions of brief, interactive, client-centered prevention counseling intervention or four sessions of enhanced, interactive, theorybased prevention counseling reported higher levels of condom use at 3-and 6-month follow-up than those who received two sessions of didactic information only; all three groups continued to report higher levels of condom use at 9 and 12 months than at baseline, but the difference between the two counseling groups and the didactic information group was no longer significant. Compared with participants in the didactic information group, 30% fewer participants in the two counseling groups had new STDs during the first 6 months following enrollment, and 20% fewer had new STDs during the entire 12-month follow-up period. A later study examined the effect of adding a follow-up counseling session 6 months after the initial 2-session counseling intervention (152). Participants who received the follow-up counseling session and those who did not had similar rates of new STDs during the subsequent 6 months. At the 9-month follow-up visit (3 months after the follow-up counseling session), participants who received the follow-up counseling session reported significantly less sexual risk behavior than those who did not receive the follow-up counseling; however, at the 12-month follow-up, this difference was no longer significant. Another study examined the relative efficacy of a single prevention counseling session in conjunction with rapid HIV testing compared with two prevention counseling sessions in conjunction with standard HIV testing (153). The incidence of new STDs among participants in the two groups during the subsequent 12 months was not significantly different (19.1% among rapid testers vs. 17.1% among standard testers). Brief group-level counseling of STD clinic patients also has been found to be effective (154)(155)(156). The possibility that prevention counseling might be more effective for notified partners than for persons in a more general population, given that the exposure risk for partners is personal and certain rather than hypothetical, has not been studied. As previously mentioned, many persons testing positive for HIV reduce transmission risk behaviors after learning they are infected (30,112,114). # Other Prevention Interventions For certain partners, more intensive prevention interventions might be appropriate. Behavioral risk screening might be useful for identifying these persons. Several more intensive riskreduction interventions have been demonstrated to be effective (26,27,31,157). As mentioned previously, these interventions cannot reasonably be delivered through partner services activities but might be available through other service providers in the area (e.g., CBOs) or as part of ongoing prevention activities incorporated into the medical care of persons living with HIV infection (54). DISs can play an important role in referring partners to these services. Many partners who are notified of exposure to HIV do not receive counseling and testing. In one review, only 63% of notified partners were known to have been counseled and tested (16). One reason for this might be that partner services programs are unaware when partners are counseled and tested by another provider or receive counseling and testing at a later date. # Recommendations for Risk-Reduction Interventions for Partners - Program managers should develop protocols that describe the minimum amount of general information and prevention messages that should be provided to all partners at the time of notification. # Cluster Interviewing Partners Previous CDC guidelines for STD partner services have recommended the use of cluster interviews with partners (1). Cluster interviews involve eliciting information from uninfected partners about their own partners and other persons in their social networks who might benefit from counseling and testing. These persons, referred to as associates, might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination (e.g., pregnant females). Cluster interviewing might also include eliciting information about venues in which partners and their associates interact socially (e.g., bars or clubs). As with clustering of index patients, cluster interviews of partners can be used for identifying additional cases or for epidemiologic purposes. Data on the effectiveness of cluster interviewing for case finding are limited. In one study, a network approach was used to notify partners of persons with syphilis in an Atlanta, Georgia, zip code with a high syphilis rate. Among sex partners of uninfected partners, social contacts, and associates, 5.7% were infected with syphilis, whereas 5.3% of nonsexual contacts were infected (73). Another study analyzed partner notification for syphilis in Louisiana and found that a total of 29 (6%) of 503 associates who were located and examined had newly diagnosed cases of syphilis (74). As previously mentioned, a review of the case-finding effectiveness of cluster investigation for HIV and other STDs found that the number of cases identified through cluster investigations for syphilis is substantially less than the number identified from syphilis partner notification (8). Finally, during an outbreak of syphilis in a suburban Atlanta, Georgia, community, interview of social contacts and associates facilitated identification of an extensive sexual network that might otherwise have gone undetected (158). Data from a small number of reported studies suggest that the case-finding yield of cluster interviews for syphilis is substantially lower than that of partner notification, that this approach might be more productive in areas with relatively high syphilis case rates, and that it might be particularly useful during an outbreak. Published data on the case-finding yield of cluster interviews for HIV are not available. As with clustering of index patients, information obtained through cluster interviews has potential value for providing insight into how and where infection is being propagated in the community and might help guide screening or other prevention interventions (e.g., social marketing campaigns) at the community level. # Recommendations for Cluster Interviewing Partners # General - When notifying partners of their possible exposure, DISs might also elicit information about the partners' social networks, including venues frequented, for use in planning additional prevention activities. - In general, notification of partners should be prioritized over follow-up of individual associates identified through cluster interviews. Routine follow-up of associates should be done only after the program is successfully interviewing most new patients with cases and locating and notifying most partners, and only after carefully considering the potential case-finding yield and resource implications. If this strategy is used, its case-finding yield should be carefully monitored, and the strategy should be continued only if its effectiveness and cost-effectiveness equal or exceed those of other case-finding strategies. Follow-up of associates might be given higher priority during an outbreak. # HIV Infection - For persons with HIV infection, information about associates should be used as an aid to understanding transmission dynamics in the community and to help guide additional prevention interventions at the community level (e.g., screening and social marketing). In general, if individual associates are to be recruited for HIV testing, a self-referral approach rather than provider referral should be used. A provider referral approach should be used only after careful consideration of potential individual and community concerns about privacy and confidentiality. A provider referral approach might be appropriate during an outbreak. # Testing Partners After partners are notified of possible exposure to STDs/ HIV, they must have access to appropriate diagnostic testing and treatment as soon as possible. Many partners who are notified of possible exposure to HIV do not receive counseling and testing. The number of partners who are examined and receive counseling and testing might be increased if testing is performed at the time of notification, whether this occurs at the clinic or another health-care facility or in the field. # Syphilis Serologic testing remains the standard for syphilis testing and requires a blood sample (159). Blood can be drawn easily in a clinical setting; certain DISs are trained in phlebotomy and can draw blood in the field. Rapid tests have been developed but are not yet approved by the Food and Drug Administration for use. Moreover, rapid tests do not indicate stage of disease like reagin-based tests (i.e., through measuring titers). Whether partners are interviewed or have blood drawn in the field, they should be referred for evaluation and possible treatment. # Gonorrhea and Chlamydial Infection Gonorrhea and chlamydial infection both can be detected via culture; however, chlamydia cultures are demanding and lack sensitivity, and transport of both types of organisms require careful attention to ambient conditions. However, nucleic acid hybridization tests, and, increasingly, nucleic acid amplification tests (NAATs) have been used more frequently in recent years. Non-NAATs are less sensitive than NAATs, and NAATs can be used with urine samples as well as urethral (men) and endocervical (women) samples (160,161). Testing of samples in the field is not feasible; therefore, partners tested at the point of notification can only be referred for evaluation or dispensed medication on a prophylactic basis (i.e., via fielddelivered therapy). For those who are notified via telephone, follow-up evaluation can be conducted by obtaining urine samples via mailed kits; kits can be mailed to the partners and returned in person or by mail. No data are available on the application of mailed kits for testing, but use of this option for programlevel rescreening was moderately successful (i.e., a 22% response rate and 3% positivity) in one study with women (162). Although 22% is not a strong response rate in many settings, public health agents who are rescreening per CDC guidelines have 22% fewer patients (3). A similar approach was used for chlamydial screening (not rescreening) of men in a managed care organization; 7.8% of men who received a kit were tested, although this rate was higher than the rate achieved by a letter alone (3.6%) (163). However, testing rates might rise if tests were conducted in conjunction with notification, because partners might be more concerned about being infected. # HIV Infection Testing in clinic settings can be conducted with conventional test procedures or with rapid tests using oral fluid or blood. If notification is carried out in the field, a rapid test can be performed, an oral fluid specimen can be obtained or blood drawn for conventional testing, or the partner can be escorted or referred to a public health clinic or other test provider. Ensuring that partners who are tested, especially those who test positive, receive their test results is critical. At publicly funded counseling and testing sites in 2004, only 84% of persons testing positive and 78% of those testing negative received their test results (61). Research has shown that rapid testing is acceptable and feasible in various settings and that more persons might get tested and learn their results if they are tested with rapid rather than conventional tests (164)(165)(166)(167)(168)(169)(170). Rapid testing has also been found to promote earlier initiation of care compared with conventional testing (167). Although the use of rapid testing in partner services has not been well studied, in one survey of health departments, 16 (37.2%) of 43 departments that responded reported using rapid tests in their partner services programs (171). Partners might be infected with HIV but test negative because of the window period between infection and development of detectable levels of HIV antibodies. With recent EIA tests (e.g., second-generation IgG-sensitive tests and third-generation IgG/IgM-sensitive tests), most infected persons develop detectable antibody within 3 months of infection (89,90). Therefore, partners who test negative but whose last date of exposure is unknown might ordinarily be advised to be retested 3 months later; those known to have been exposed recently might be advised to be retested 3 months after the date of last known exposure. In partner services, suggestions for retesting are complicated because reference to any date might compromise the index patient's identity. For this reason, routinely suggesting that partners be tested at the time of notification and retested 3 months later might be the best course of action. Persons with acute or recent HIV infection might test negative because of the window period. HIV RNA testing has been used to screen pooled, HIV antibody-negative specimens to identify persons with acute or very recent infection (i.e., HIV RNA positive and HIV antibody negative) (70,90,(92)(93)(94)(95)(96)(97)(98). Given the high prevalence of previously undiagnosed HIV infection among partners and the possibility that partner notification might lead to earlier detection of HIV than other strategies, HIV RNA testing might also be useful in this context. However, prospective use of testing for acute or recent infection in the context of partner services has not been reported. # Screening for Concomitant Infections Although rates of coinfection vary considerably in different areas and settings, partners who are notified about exposure to one STD often are at risk for other STDs, including HBV. Drug-injection partners are at risk for both HBV and HCV (172). Consequently, partners being notified of exposure to any STD, including HIV, might benefit from 1) screening and treatment for other STDs and 2) HBV vaccination (and HAV vaccination for MSM) (3). Those with a history of injection drug use should be screened for both HBV and HCV. Screening for HIV, syphilis, chronic HBV, and chlamydial infection is currently recommended for all pregnant women, as is screening for gonorrhea and HCV in pregnant women at risk (3). For sexually active MSM, current screening recommendations include serologic tests for HIV and syphilis, tests for urethral gonorrhea and chlamydial infection in men who have had insertive intercourse in the preceding year, tests for rectal gonorrhea and chlamydial infection in men who have had receptive anal intercourse in the preceding year, and a test for pharyngeal gonorrhea in men who have had receptive oral intercourse in the preceding year (3). HBV vaccine is recommended for all nonvaccinated, uninfected persons being evaluated for an STD (3,173,174). HAV vaccine is recommended for MSM and users of illicit drugs (both injection and noninjection) (3,175). Specific details about hepatitis vaccination, including prevaccination serologic testing, are available at . Partner services provide an opportunity to integrate these services at the client level. Although integration might be difficult for logistical reasons (e.g., testing being done in the field by a person not authorized to administer vaccines) or because of limited resources, partner services and other health department program managers might be able to collaborate to make these services available to partners. # Recommendations for Testing Partners # General - To the extent possible, testing for HIV and other types of STDs should be done at the time of notification. Partners who are not tested at the time of notification should be escorted or referred to the health department for testing or linked to other health-care providers who can provide these services. - DISs should follow up on partners not tested at the time of notification to verify that testing has occurred, test results were received and understood, and other referral services were accessed. If another health jurisdiction has been asked to contact a partner, follow up should be conducted by the initiating health department to determine whether services have been received. - Program managers should explore ways in which screening for HIV, screening and treatment for other types of STDs, screening for HBV and HCV, and vaccination for HAV and HBV might be integrated in partner services programs. # Syphilis - Blood should be drawn in the field when DISs are trained to do so and when specimen maintenance conditions can be met. Partners should be referred for evaluation regardless of whether a specimen has been collected. # Gonorrhea and Chlamydial Infection - If provider referral is used, programs should consider protocols for collecting specimens in the field. # HIV Infection - Partner services programs should consider using rapid HIV tests to maximize the number of partners who are tested and receive test results. - When notification is done in the field, rapid tests should be used or a blood or an oral fluid specimen should be collected for conventional testing. If neither of these is possible, the partner should be escorted or referred to the clinic for testing. - Partners who test negative for HIV antibody should be advised to be retested in 3 months. # Treatment for Partners Syphilis, Gonorrhea, and Chlamydial Infection The principal goal for syphilis, gonorrhea, and chlamydial infection is immediate treatment, whether curative for infected partners or preventive if a partner tests negative or has an unknown status. Timely treatment of partners serves as a primary means of minimizing subsequent transmission. Expedited partner therapy (EPT) is a process through which treatment for partners of persons with a diagnosis of gonorrhea or chlamydial infection is administered before the clinical evaluation occurs. Most uses of EPT involve patient-delivered partner therapy (PDPT), or delivery of medications or prescriptions via the index patient. EPT is recommended as a clinical option for heterosexual men and women, especially for partners who are not likely to seek evaluation (3,176). On an individual basis, clinicians and patients decide whether to use EPT; at the program level, no evidence suggests that partners of persons with either gonorrhea or chlamydial infection seek care in sufficient proportions to stem transmission. Randomized, controlled trials of single-dose oral therapy for both STDs have shown reduced rates of reinfection among index patients exposed to EPT compared with controls; approximately 20% for chlamydial infection and 50% for gonorrhea (126,177,178). A 2007 metaanalysis of trials revealed that these were statistically significant overall reductions (179). Use of EPT also was associated with increased rates of index patient notification of partners and of partner treatment. However, EPT was not associated with reduced reinfections among women with trichomoniasis; in addition, EPT with MSM should be used cautiously because of lack of data showing efficacy of EPT for MSM, and because the risk of potential comorbidity with HIV is higher among MSM with STDs than among heterosexual males or females (3,127). Ensuring that EPT is accompanied by written instructions is important, including instructions for the medication, for the length of time to avoid sexual activity, and advice to seek evaluation. Essentially, instructions are equivalent to a referral card. Single-dose therapy with EPT is the most likely to result in treatment being administered appropriately and completely, just as with therapy prescribed to a patient. EPT with multidose regimens has not been evaluated (e.g., doxycycline for chlamydial infection). Other general treatment recommendations relevant to EPT include cotreatment for chlamydial infection in persons with a diagnosis of gonorrhea, but not vice versa. Although the high caseload of gonorrhea and chlamydial infections have inhibited provider referral, a few programs have used EPT through DIS delivery of medications, or fielddelivered therapy (FDT). The DIS (or public health nurse) delivering FDT should be licensed to do so under a protocol for standing orders or another similar arrangement. In 1999, the San Francisco Department of Public Health used FDT for partners of patients with gonorrhea and chlamydial infection (180). By 2000, the proportion of partners completing treatment increased from 62% to 81%. The advantage of FDT over PDPT is that DISs can be trained to watch for immediate adverse reactions (e.g., allergic reactions) and can verify treatment and deliver prevention messages directly, an approach similar to directly observed therapy for TB infections. The disadvantage of FDT is that a public health staff person is required to trace and notify partners; therefore, resources remain a vital consideration. Although unevaluated, FDT is a possible strategy for treating syphilis if 1) a person licensed to administer injections and monitor and respond to adverse reactions accompanies the DIS and 2) the partner's stage of disease and coinfection can be adequately addressed during the contact interview. Although treatment on the basis of exposure is a well-known public health strategy, the absence of a clear physician-patient relationship places EPT (especially in the form of PDPT) in an uncertain legal status in many jurisdictions. To aid programs in establishing formal programs that are clinically useful and legally defensible, CDC has a website (available at / std/ept) with CDC guidance, guidance models from states in which EPT is specifically permitted, and a state-by-state analysis of the legal landscape of EPT, based on a recent survey of laws, regulations, court decisions, and policies (181). # HIV Infection As mentioned previously, effective and timely medical evaluation, initiation of currently recommended combination ART, provision of appropriate vaccinations and other preventive health interventions, and referrals for a wide range of other medical and psychosocial services are critical for persons with a new diagnosis of HIV infection. Linking partners who test positive for HIV to medical care and HIV case management is essential as soon after diagnosis as possible. The importance of linking HIV-infected partners to medical care and verifying that they have had a medical evaluation or received HIV case management at least once cannot be overemphasized. Accumulated data from animal and human clinical and observational studies suggest that PEP for sexual, injectiondrug use, and other substantial nonoccupational HIV exposure might prevent HIV infection and that potential risks from PEP (e.g., increase of risky sexual behavior, adverse reactions to medications, and selection of resistant virus) might be minimal (182). PEP is intended to be initiated within 72 hours of exposure to HIV, and antiretroviral medications must be taken for 28 days. Partners who have been exposed and can be notified within this time frame might be candidates for PEP (3). Because PEP is only intended for persons who are HIV negative and because partners might not be aware of their HIV status, access to rapid testing is necessary for this option to be offered. Incorporating PEP into partner services programs poses substantial logistical and resource challenges; however, certain health departments have developed program recommendations for PEP that might be useful for jurisdictions considering implementing such a program (183). Although PEP might be useful in certain partner services contexts (e.g., with new partners of the index patient), health departments will ultimately need to evaluate whether integrating PEP into their partner services programs is feasible and consistent with program objectives. # Recommendations for Treatment for Partners # Syphilis, Gonorrhea, and Chlamydial Infection - Program managers should ensure that partners are treated according to CDC treatment guidelines as soon as possible after notification. - Programs should consider FDT for gonorrhea and chlamydial infection when partners are notified via provider referral. - Because single-dose oral therapy is used for gonorrhea and chlamydial infection, programs should consider PDPT for partners who will not be notified via provider referral. - Programs should be sure that all appropriate parties are consulted to ensure that any EPT strategy in the jurisdiction is medically and legally sound. Appropriate parties vary by jurisdiction but might include state health commissioners or legislative bodies. HIV Infection # Referring Partners to Other Services Whether partners test positive or negative for a particular disease, underlying factors might impede their ability to access medical care effectively or adopt and maintain safer behaviors, and they might benefit from referral to various psychosocial services. Considerations regarding referrals for partners are essentially the same as those for referrals for index patients. # Recommendations for Referring Partners to Other Services - Because of the diverse needs of partners, program managers should identify referral resources for psychosocial and other support services. DISs routinely should be provided updated information about referral resources. - Many referral needs of partners testing positive for HIV will be addressed through linkage to early intervention, medical care, and HIV case management; however, DISs should screen for immediate needs and make appropriate referrals. - Partners testing negative for HIV should be screened and referred for other medical and psychosocial needs and prevention services. # Specific Populations The recommendations in this report generally apply to all lients with HIV infection or other STDs regardless of setting, opulation, or disease. However, certain populations such as ouths, migrant and immigrant populations, and persons in orrectional facilities have unique characteristics and ircumstances. (184). ouths are at higher risk for HIV infection and other types of TDs because they frequently have unprotected intercourse, re biologically more susceptible to infection (especially emales), are engaged in sexual partnerships of limited uration, and face multiple obstacles to using health care . The unique biologic and cognitive developmental oncerns associated with youths require that services for them e developmentally appropriate and as comprehensive and eamless as possible. # artner Elicitation Approaching youths who have received a recent diagnosis f HIV or any other type of STD can be challenging. Before roaching the subject of partner elicitation with a young index atient, assessing immediate needs is important, especially for atients in need of housing or food. Youths might have many isperceptions and information gaps about partner services hat need to be addressed, such as understanding that partner ervices are voluntary and that they have the right to decline articipation. They also should understand the concept of confidentiality and that it includes not reporting to their parents unless the youth requests parent or guardian involvement. In addition, specific counseling skills might be necessary, especially for youths with a recent diagnosis of HIV, to ensure that they understand the ramifications of the diagnosis and how to prevent future acquisition of HIV and other types of STDs and transmission to others (190). Youths who fear losing partners and friends might find it especially difficult disclosing information about sexual or injection-drug partners and other social contacts (191). In addition, youths might be reluctant to provide information about adult partners because of fear of legal repercussions related to sex between an adult and a youth. In addition, fear of partner violence might prevent partner identification; therefore, assessing the potential for partner violence is essential for each partner identified. Assessing other potential violence or maltreatment situations that might occur involving parents, guardians, or friends also is critical. Finally, DISs providing services to youths should be sure to discuss the topic of sexual abuse with their clients; if sexual abuse is suspected, they should notify the appropriate authorities (e.g., child protective services agency) in accordance with applicable laws and regulations. # Notifying, Counseling, and Testing Partners Although the process of notifying partners named by youths and named by adults is the same, legal concerns might exist in situations with youths, especially when an adult partner is named. Knowledge of state laws is essential; if sexual abuse or statutory rape is suspected, staff members must be prepared to report to the appropriate agency. Counseling skills of partner services providers are especially important when partners are very young or immature. Developing simple and clear messages regarding the STD and HIV notification process is needed to ensure that youths are able to understand the purpose of notification and the urgency of getting tested if testing is not provided in the field (190). Being able to assess the maturity of the partner is a fundamental skill for DISs so that they can ensure that an appropriate plan of action is developed. Young partners might also require specific types of assistance to obtain testing. For example, partner services staff members should be prepared to call previously identified testing sites, make an appointment for testing, and then follow up with the youths to verify that they received the test. Youths might be reluctant to access services because of financial and transportation limitations and because of fears that parents must give permission or be informed. Youths must understand that, with a few exceptions, all adolescents in the United States can legally consent to receiving a confidential diagnosis and treatment of STDs (3) In all 50 states and DC, medical care for STDs can be provided to adolescents without parental consent or knowledge. In addition, in the majority of states, adolescents can consent to HIV counseling and testing. Consent laws for vaccination of adolescents differ by state. Several states consider provision of vaccine similar to treatment of STDs and provide vaccination services without parental consent. Because confidentiality is crucial, health-care providers should follow policies that provide confidentiality and comply with state laws for STD services. Partner services staff members should remain knowledgeable and updated on related state and local laws and regulations. # Treatment for Partners Because youths often are a medically underserved population compared with persons in other age groups, they might be less likely to receive office-based medical care or to use primary care services (192,193). Reasons for this include concerns about confidentiality, lack of health insurance, lack of adolescent-specific services including health-care providers with adolescent health experience, and appointment times that conflict with school schedules (185,(194)(195)(196)(197)(198). HIV-infected youths might face additional challenges, and health care providers serving HIV-infected youths report that acceptance of HIV diagnosis and return for care and treatment can take many months. Programs might be able to increase the likelihood of successfully linking adolescents to care and treatment by developing relationships with medical facilities that are sensitive to youth concerns and that have a strong case-management component (199,200). # Confidentiality and Privacy Although confidentiality is a basic principle for all steps of the partner services process, careful attention must be paid to providing a private and safe place for the interview and notification process for young index patients and their partners. However, ensuring confidentiality in cases involving suspected child or sexual abuse is not always possible. Local laws, statutes, and regulations define the limits of confidentiality in these cases. # Recommendations for Youths - Programs should have specific protocols in place to guide partner services for youths. Protocols should address assessment of maturity and extent of social support, use of age-appropriate counseling and communication models, provision of services in youth-friendly environments, and assessment for physical and sexual abuse. These protocols should be developed in collaboration with legal counsel to ensure that they are consistent with all applicable laws and regulations. # Immigrants and Migrants Data on the prevalence of HIV infection or other STDs among immigrant and migrant populations in the United States are limited. However, certain immigrant and migrant populations in the United States might be particularly vulnerable to HIV and other STDs because of inadequate knowledge about the infections, lack of information about and access to prevention and related health-care services, and delays in accessing HIV and other STD testing, treatment, and care (201,202). Immigrant and migrant women also might experience concerns related to power and economic disparities between men and women that make women more vulnerable to sexual abuse or domestic violence and decrease their ability to protect themselves from sexual exposures to infection (203). All of these concerns might contribute to HIV and other STD acquisition and transmission among these populations. Partner services programs can be an effective way to identify and reach members of immigrant and migrant populations who might not otherwise access HIV and other STD testing services. # Partner Elicitation Concerns affecting partner elicitation among migrants and immigrants might include difficulty in locating such persons because of their transient movement within the United States or across international borders (e.g., U.S.-Mexico border) (204). Interviews might be difficult because of language and cultural barriers. Index patients might be reluctant to provide information if translators are family members or are from their own communities. A lack of understanding about the voluntary and confidential nature of partner services makes it essential that simple and clear messages are provided to encourage participation and gain the trust of index patients. Partner elicitation might be hindered by concerns that named partners could be deported (205). Concern about individual stigma related to STDs or HIV infection and activities related to transmission (e.g., male-to-male sex or injection drug use) also might be a barrier to full participation in partner services. Because of fears of partner violence, which might be substantial among immigrant and migrant women, DISs must be able to adequately assess the potential of partner violence before initiating partner notification (206). # Notifying, Counseling, and Testing Partners Locating and notifying partners among immigrants and migrants might be difficult for the same reasons that partner elicitation is challenging. In addition, the usual counseling models might not be culturally appropriate because of cultural norms regarding discussion of sex and sexual behaviors. These concerns can make risk assessments or HIV and STD prevention counseling especially difficult. # Treatment for Partners Treatment and care services might not be available or easily accessible to immigrant and migrant populations because of a lack of financial resources, transportation, and child care resources. Concerns about confidentiality, loss of employment, and fear of deportation or other legal consequences also might make immigrant and migrant populations reluctant to access care. If they do access care, medical care providers might lack linguistically and culturally appropriate services. # Recommendations for Immigrants and Migrants - Program managers should review epidemiologic and other data to identify potential immigrant and migrant populations at high risk for infection in their jurisdictions and be prepared to provide partner services that are linguistically and culturally appropriate. # Incarcerated Populations The majority of the 2.2 million adults and juveniles residing in jails, detention centers, and state and federal prisons eventually will be released and rejoin the larger community. Persons in prisons are generally housed for longer periods of time than persons in other correctional facilities, such as jails. Certain persons in city and county jails and juvenile facilities are released in less than 24 hours, with the majority (93%) of jail inmates staying less than 1 year (207). Multiple studies and surveillance projects have demonstrated high rates of sexual risk and STD prevalence among persons entering prisons, jails, and juvenile correctional facilities (208)(209)(210). Data from the Bureau of Justice Statistics indicate that, as of December 31, 2005, a total of 22,480 (1.8%) state and federal prison inmates were infected with HIV or had confirmed AIDS. The prevalence was higher in state prisons (20,888 inmates, 1.8%) than in federal prisons (1,592 inmates, 1.0%) and was higher among female than male inmates (2.3% and 1.7%, respectively) (211). A study of syphilis cases during 1997-2002 in Indianapolis, Indiana, and Nashville, Tennessee, found that 19% of cases in women and 27% of cases in men were identified through jail screening; in certain situations, the casefinding yield of jail screening approached that for STD clinics (212). Many persons who are arrested are at high risk for STD and HIV infection because of high-risk behaviors (e.g., multiple sex partners or injection and other drug use) and poor health-care-seeking behaviors while in the community. Therefore, providing routine screening for HIV and other types of STDs during the correctional facility intake process offers an opportunity to identify infections, prevent complications, and reduce further transmission by improving access to treatment, care, and prevention. Many correctional facilities provide screening for HIV and other types of STDs. Conducting partner services for persons in correctional facilities who test positive presents a unique opportunity to access possibly hard-to-reach partners at high risk for infection both in the facility and in the community. Conducting partner services might lead to a better understanding of risk behaviors and prevention needs of inmates, help programs better target resources and evaluate prevention program performance, and possibly lead to a better understanding of disease transmission dynamics in the broader community. The extent to which partner services are conducted in correctional facilities varies with program resources and individual facilities. When public health staff members conduct these services in correctional facilities, formal collaboration mechanisms between the health department and the correctional facility are essential to help coordinate activities and ensure that all parties understand what is needed to conduct services within the facilities. Following are factors to consider when developing partner services programs for incarcerated populations. # Partner Elicitation Inmates who receive a diagnosis of HIV infection or another STD while incarcerated might not want to identify sex or injection-drug partners that reside in the community or the facility. Partner services providers should be aware that partners might include other inmates, correctional facility staff members, or visitors. Reasons for not wanting to identify partners might include fears of partnership dissolution, loss of privileges within the facility, and concerns about revealing possible illegal activities. Before partner services providers ask inmates for information about partners, the providers should ensure that the inmates understand the confidential and voluntary nature of partner services and the limits of confidentiality related to disclosing information about sex partners who reside within the facility. In all states, sex with another inmate or with correctional facility staff members is prohibited and might be required to be reported (213). Therefore, partner services programs should have a full understanding of these laws and regulations as well as of individual facility policies before initiating any partner services activities. Inmates have a right to privacy and confidentiality of their medical information, and DISs have a duty to protect all confidential information. However, maintaining the confidentiality of inmate health information might be challenging in correctional facilities. Partner services programs should work with medical staff members within the facilities to ensure that procedures are in place to reduce possible breaches of confidentiality. Breaches of confidentiality for inmates with HIV infection or other STDs might result in increased discrimination, stigmatization, and violence. Because incarcerated populations often are moved about within correctional systems, locating or accessing an index patient might be difficult. Partner services providers should work with correctional facility staff members to determine how best to locate and access inmates. In addition, other challenges might arise if a particular inmate has already been released, because released inmates are often transient, use aliases, or do not have a permanent address. If the inmate has already been released, DISs should obtain contact information from the correctional system to assist with partner services activities. Having a private space to conduct partner elicitation in correctional facilities might be a challenge. Correctional healthcare clinics often are busy, and space is not always available. In addition, security concerns often require that custodial staff members are able to see staff members and inmates at all times to ensure safety. Thus, clinic layout and proximity of nonhealth-care staff members can create an impression of lack of privacy or confidentiality. Partner services staff members must work with correctional facility staff members to identify a private area, whether in the clinic or in the housing area, to elicit partner names without compromising safety. The # Notifying, Counseling, and Testing Partners For named partners who are located in the community (i.e., not in the correctional facility), the notification process is no different than for partners named by persons outside correctional facilities. However, legal concerns might exist related to named partners who are located within the correctional system (e.g., other inmates or correctional facility staff members). Knowledge of state laws and possible reporting requirements are essential, and partner services staff members must be prepared to adhere to these regulations and should consult with program managers or legal counsel when questions arise regarding specific situation. # Treatment for Partners Ensuring medical care for partners who are inmates is the responsibility of the correctional facility. Facilities that release inmates before adequate care or treatment can be provided should provide referrals before the release. However, when program resources are available, partner services staff members can provide follow-up for recently released persons to verify that they are adequately treated or are linked to care. Correctional facilities or the health department also should consider partnering with local service providers, including CBOs, that provide transitional services. These agencies might be able to provide follow-up and possibly HIV case-management services especially for those who are HIV infected. # Recommendations for Incarcerated Populations - Program managers should become familiar with the federal, state, or county jail and correctional facilities in their jurisdictions. They should meet with key personnel in correctional facilities to discuss the services offered and goals of partner services as a public health intervention, the need for public health staff members to have access to facilities and adequate private space to meet with clients, and ways that partner services activities can be integrated into the facility response plans that are required by PREA. Follow-up meetings to facilitate communications and coordination should be held periodically. - Program managers and key correctional facility personnel should establish a formal written agreement to clearly outline roles and responsibilities for both public health and correctional facility staff members. - Program managers should collaborate with correctional facility staff members to develop protocols for partner services staff members to follow while in the facility, especially during emergencies. Ensuring that partner services staff members know and adhere to facility rules and regulations also is essential. Not adhering to the rules and regulations of a correctional facility will jeopardize implementation and continuation of the partner services program. - Program managers should collaborate with correctional facility staff members to develop protocols regarding administration of partner services for named partners within a correctional facility. # MMWR November 7, 2008 # Strategies to Enhance Case Finding and Partner Notification Core Areas A core area is a specific, typically geographically defined area, such as a neighborhood or census tract, that has a relatively high concentration of STDs and likely accounts for a large proportion of disease transmission in a community. Infected persons in a core area might not have any social or sexual connections; their only relationship might be geographic. An example of a core area is a zip code in which >50% of the gonorrhea cases in the county are identified. Core areas are different from core groups, which are socially defined groups of persons who are likely to be a source of continued disease transmission (i.e., core transmitters). In certain circumstances, programs might maximize resource use and prevention effectiveness by concentrating on specific core areas. For example, in New York state, targeting 100% of provider-referral partner-notification measures for gonorrhea in core areas (as defined by endemic prevalence, or census tracts containing 50% of reported annual gonorrhea cases) was associated with a substantial decline in incidence, even compared with a control area in which a larger proportion (60%-70%) of gonorrhea-infected persons were actually interviewed (7). In Colorado, partner notification services for gonorrhea that focused on a military base (the putative core area) and the surrounding civilian community produced a 13% decrease in overall gonorrhea cases and a 20% decrease in the civilian community (214). Military incidence was largely unchanged. Similar large-scale measures in the United Kingdom (i.e., the Tyneside scheme) have been associated with reductions in gonorrhea morbidity (215). Similar data for chlamydial infection are lacking, and whether core areas play a substantial role in chlamydial infections is uncertain (216). In general, syphilis is so geographically concentrated that syphilis infection-control measures, by definition, involve a core-area approach. # Recommendation for Core Areas - Health departments should assess the geographic concentration of gonorrhea and consider focusing providerreferral partner notification in core areas. # Social Networks A social network is a group of persons connected by various types of social relationships, such as family, work, and recreational relationships; sexual partnerships; and drug-use relationships. A social network also can include the venues in which interactions among the members of a social network occur. The persons in a social network might share social, economic, cultural, or behavioral characteristics that influence their risk for various health conditions, including HIV and other STDs (217). Consequently, members of the social network of a person with HIV infection or other STDs might also be at increased risk for these infections, even though they might not have a sexual or drug-injection relationship specifically with the infected person. By exploring the social, sexual, and drug-use connections among persons and places and diagramming these links, HIV/STD prevention programs might uncover more cases than by relying on partner notification and testing alone. This approach also can provide helpful information about a disease in a core area by integrating epidemiologic, geographic, and sociodemographic information. Using social network methods to identify persons with HIV infection can help bring previously undiagnosed HIVinfected persons into the partner services process and might also be used to identify persons who previously tested positive and left care or never received care. A program that uses this approach can track networks at several levels, first assessing persons and places and then possibly going further to look at geographically defined sociodemographic data. Although this approach can seem intimidating and labor intensive, DISs often collect much of these data during patient interviews and from field records, and certain programs use network approaches on a de facto basis. Other data can be added as resources permit. An established and periodically updated network diagram might aid in the investigation of outbreaks as they occur (rather than as a retrospective tool to explain why they occurred). Programs might also conduct more formal network analyses, which involve calculating various statistics that describe characteristics of a network (e.g., components, degree, betweenness, information centrality, and k-core) (158). However, the capacity to perform these analyses is not available in many health departments and might not be performed quickly enough to affect outbreaks as they occur. Nevertheless, analyses of outbreaks and endemicity can reveal details not otherwise identified and can therefore inform program needs and future actions (218,219). Peer referral is one type of social-network approach that has been used to identify HIV cases; clients are enlisted as recruiters and coached to refer persons from their social networks (peer referral) for counseling and testing. Those referred also can be enlisted to recruit others, creating a peer-driven cluster approach. With the peer-referral approach, virtually all contact with program staff members is at the point of care, and extensive field work is not needed. The approach can be refined by assessing which persons are more effective at referring infected persons or those at high risk for infection and concentrating on the persons who are the most effective. In a demonstration project conducted in seven U.S. cities, nine CBOs enrolled HIV-positive persons and HIV-negative persons at high risk for infection to serve as peer recruiters. These persons agreed to refer persons in their networks who they thought to be at risk for HIV infection for counseling, testing, and referral services (220). The 6% prevalence of newly identified HIV infection found among social network associates tested in this project was five times the average prevalence reported by publicly funded HIV counseling and testing sites. An evaluation project conducted in King County, Washington, enlisted and trained MSM who had received a diagnosis of HIV or other STDs to become peer recruiters and yielded similar results (221). Of the 438 recruited peers who had not previously received a diagnosis of HIV, 22 received a new diagnosis of HIV, an 8% increase in the health department's total HIV case-finding yield. The approach was particularly useful for identifying non-white MSM with HIV infection, increasing the health department's total case-finding yield for this group by 19%. This peer-referral approach was a more cost-effective strategy for identifying HIV cases among MSM in this area than other outreach approaches. (Additional information on implementing a social networks strategy for HIV case is available at / guidelines/snt.) Use of a network approach should not replace partner notification; instead, the approach should be used to enhance existing partner services practices. Initiation of a network approach can be labor intensive, and a full-scale network approach to describing disease in a given program area requires analytic capacity that not all programs possess. Nevertheless, basic network data are often already collected by DISs and other program staff members, and a program could link these data to produce a more complete representation of STDs/ HIV than previously possible. Additional research on the use of social networks for disease prevention is needed. Studies analyzing the use of social networks to enhance partner services and assess disease transmission for a particular area or population have produced encouraging results, but these results might not be generalizable. Peer-driven cluster referral has been most effective for finding cases of both HIV and HCV. As with cluster interviewing and clustering, the effectiveness of the approach in detecting cases is affected by the prevalence of the disease. For example, in Seattle, where the prevalences of gonorrhea and chlamydial infection are relatively low, peerdriven referral among MSM detected minimal numbers of cases of gonorrhea and chlamydial infections (221). The approach needs to be tested among groups with higher prevalence of bacterial STDs. # Recommendations for Social Networks - Programs should assess the social networks that influence disease transmission in the area as a strategy for finding persons who are at risk for disease but have not been identified by an index patient or partner. - This strategy should be used to enhance case finding, considering relevant epidemiological and behavioral information. # The Internet The Internet is used to facilitate formation of sexual partnerships and is a potential contributing factor in situations involving high-risk behaviors and transmission of HIV and other STDs (222)(223)(224)(225). Although most of the published research evaluating links between sexual risk behaviors and Internet use has focused on MSM, findings from studies of heterosexual male and female groups indicate trends that are similar to those identified among MSM; seeking sex partners online is associated with high-risk behaviors and acquisition of HIV and other types of STDs (222,(226)(227)(228)(229)(230). Certain partner services programs have used the Internet for partner notification when the only contact information available for a partner is an e-mail address or Internet screen name. Two studies have documented outcomes for HIV Internet partner notification, and the rate of response (i.e., number of partners who responded to contact attempts) differed substantially between the two studies. Public health staff members who conducted a cluster investigation among MSM in Minnesota used the Internet to contact 50 persons who had been exposed to HIV or other STDs but for whom the only available contact information was an e-mail address or screen name; responses were received from 30 (60%) (231). In Los Angeles, California, an HIV-infected index patient had 111 sex partners for whom he could provide only an e-mail address; of these, 29 (26%) responded to e-mails sent by staff members at the Los Angeles County Department of Health Services (LACDHS) (232). None of these partners would have been notified without Internet partner notification. In a survey of 1,848 U.S. MSM recruited by a banner advertisement on an MSM-targeted website for meeting sexual partners, acceptance of Internet partner notification was high: >92% of respondents indicated that they would use Internet partner notification in some way (i.e., use the health department to notify sex partners via e-mail, notify sex partners themselves via e-mail, or do both) to inform their sex partners if infected with an STD in the future (233). Available data regarding use of the Internet to notify partners exposed to other STDs such as syphilis are sparse but encouraging. In 1999, the San Francisco Department of Public Health (SFDPH) conducted a case-control study of seven early syphilis cases in persons that were associated with an online chat room (234). The mean number of partners per index patients was 5.9, and the only locating information for the sex partners was online screen names. Using the Internet to notify the partners of exposure resulted in 42% of the named partners being notified and confirmed as having been tested. In a review of early syphilis cases among MSM interviewed for partner management during January-April 2003, SFDPH identified 67 men who reported meeting sex partners through the Internet; 14 of these men provided information about 44 sex partners for whom the only locating information was an Internet e-mail address (235). Health department staff members were able to locate 15 (34%) of the Internet partners and ensure that they were evaluated and treated appropriately. In addition, LACDHS reported a case of recently diagnosed syphilis in an index patient who reported having met 16 sex partners through the Internet during his infectious period (232). The patient contacted 13 of these partners via e-mail; seven replied and made arrangements for evaluation. Finally, the Austin/Travis County Health Department sent e-mail messages to sex partners of persons infected with syphilis or HIV when e-mail contact was all that was available to DISs (236). Fifty percent of partners responded, and 81% of those (40% of all partners e-mailed) were evaluated. Thus, although response rates and overall proportion of partners evaluated were substantially lower than for in-person provider referral from the same health department, e-mail provider referral resulted in numerous partner notifications and evaluations when in-person notification was not possible. Internet-based partner notification services are available online for several U.S. cities and states (). Website users can learn the individual-and community-level rationales for partner notification, find locations for testing resources, and send a notification card via e-mail (an e-card) to each partner exposed to an STD (of any type) through sexual contact. E-cards come in several designs and may be sent anonymously or with sender information attached; senders can tailor personal messages. All cards provide information on how to get tested. Both the site and cards provide the basic information that should be shared through any other form of patient-led referral: 1) that the recipient has been exposed to an STD; 2) to seek medical evaluation and where to do so; and 3) the importance of seeking medical evaluation. Use of Internet-based partner services programs is not necessarily restricted to health departments; health departments in areas where these services are available on the Internet generally facilitate access to them (e.g., by providing an index patient access to an on-site computer). The nature of the program makes the effectiveness difficult to evaluate, and no effectiveness data are available. Partner notification programs recognize that the Internet is a potential route for partner notification in certain situations and the only route in others. Nevertheless, certain programs face specific challenges when conducting partner notification using the Internet. Certain challenges are structural or bureaucratic, such as lack of access to computers in clinics or computer firewalls on agency computers meant to bar employees from visiting websites with sexual content (237). Other challenges include program staff members who need training regarding appropriate use of Internet partner notification or health department staff members who have difficulty reaching index patients' partners who rarely enter chat rooms during typical business hours. Compared with in-person notification, e-mail contact presents certain unique challenges for DISs. Ensuring that an e-mailed notification or a chat request is received only by the person for whom it is intended can be difficult. In addition, as with letters and telephone messages, confidentiality constraints often lead to nonspecific initial contacts; this nonspecific contact might increase the likelihood of a recipient deleting the notification e-mail or ignoring a chat request, especially when the sender is unknown. One study aimed at assessing the acceptability of various forms of electronically mediated interventions found that only 45% of 4,601 interviewed persons indicated that they would open an e-mail providing information on HIV and other STDs, and even fewer (30%) indicated that they would chat about the topic (226). Although the study was not directly related to online partner notification, the reasons provided by those surveyed are likely relevant. A substantial proportion of study respondents indicated that they were generally unwilling to open e-mail from unknown senders (40%); a smaller proportion (10%) also considered health department attempts to reach them through e-mail or chat venues to be an invasion of privacy. Strategies to increase the likelihood of a response have not been formally evaluated. However, e-mails that contain the name, occupation, and, particularly, contact numbers of DISs provide a channel for communication and might increase the likelihood of a response. Similar techniques might be used with persons contacted in chat rooms through instant messaging. Patient-led Internet-based partner notification mitigates certain structural and confidentiality concerns related to provider referral, although the approach has some drawbacks. First, malicious notification is a concern (i.e., using the notification process inappropriately, such as to frighten a partner who has not actually been exposed). However, the likelihood might decrease if the website posts injunctions against such use and incorporates protection against automated programs that attempt to use the site for mass e-mailing. Massachusetts offers a verification step that allows the e-mail recipient to contact the customer service department of the website and confirm the validity of the public health account used for partner notification. Second, because Internet-based approaches are easy to use and require less time and resources than the provider referral approach, DISs might use them instead of provider referral; however, verifying that the partner has actually been notified is easier with provider referral. # Recommendations for the Internet - When an index patient indicates having Internet partners, the DIS should attempt to obtain identifying and locating information about the partners (e.g., e-mail addresses, chat room handles, and names of chat rooms or websites where the partner might be located). - Internet partner notification is recommended for partners who cannot be contacted by other means or can be more efficiently contacted and notified through the Internet. This type of notification includes ensuring policies and protocols are in place to 1) ensure that confidentiality or anonymity of the index patient and partners are maintained on the Internet and 2) eliminate structural and bureaucratic barriers to staff member use of the Internet for partner notification. - Partner services programs should collaborate with community partners to develop strategies for addressing structural challenges to health department-mediated Internet partner notification. # Program Collaboration and Service Integration HIV and other STDs often occur simultaneously, and many populations at risk for these diseases are at risk for other infections (e.g., TB and viral hepatitis). Program collaboration and service integration is a method of organizing related health concerns, activities, and services to maximize the public health impact and facilitate comprehensive delivery of services. Improving collaboration, coordination, and communication can increase program efficiency, reduce duplication of services, and result in fewer missed opportunities for providing comprehensive prevention services to individual clients. Through linkages with other programs, greater flexibility and responsiveness to changes in the epidemics of HIV infection and other STDs can occur. Finally, by using local information from surveillance and essential monitoring and evaluation data among multiple programs, prevention services can be more comprehensive. The extent to which a state or local program can effectively coordinate and integrate STD/HIV partner services activities could substantially influence the success of the services. Service integration might best be achieved through program integration; however, program collaboration, if effective, can achieve the same goal. At a minimum, addressing all elements of partner services, especially for persons with more than one STD, requires collaboration among health department units responsible for conducting HIV and other STD reporting and surveillance, as well as among HIV and STD prevention programs (if any of these programs operate separately from one another). Ideally, program collaboration and service integration includes TB and hepatitis. Regardless of the way a health department is organized, the HIV and STD programs should be functionally arranged to ensure that the following occur: - resources (human and financial) are used efficiently; - all persons who receive a diagnosis of HIV or syphilis are offered partner services; - coinfected index patients are not interviewed separately (i.e., by different DISs) for HIV and other STDs; - partners of coinfected index patients are not notified of exposure to HIV and other STDs separately (i.e., by different DISs); - partners receive appropriate and comprehensive clinical services, including testing for HIV and other STDs, treatment or linkage to medical care or HIV case management, and prevention counseling; and - information needed to conduct and evaluate partner services is readily accessible to partner services providers and designated evaluators, respectively. Barriers to program collaboration and service integration exist. Separate funding mechanisms for HIV prevention, HIV care, STD services, substance abuse treatment, mental health care, hepatitis prevention, and TB prevention and treatment can present challenges to service integration. Other challenges include ideological differences in approaches to service delivery; distrust among the various entities involved; concern about loss of program identity; political, legislative, or regulatory obstacles; staff member resistance; and lack of staff member training. Despite these challenges, the potential benefits of program collaboration and service integration are substantial enough that program managers should attempt to align partner services programs with other health department units and service entities. Service alignment can lead to increased efficiency in program administration, service delivery, and use of resources and to more knowledgeable staff members (i.e., through training), increased flexibility in providing interventions for both HIV infection and other STDs, and more efficient data collection and analysis. # Coordination and Collaboration Within Health Departments The organization of HIV and STD prevention programs determine the mechanisms used to ensure a coordinated approach to partner services. To facilitate this process within HIV and STD programs, including disease reporting, surveillance, and other health department units (e.g., TB, hepatitis, vaccination, and reproductive health), programs might need to develop shared policies, memoranda of agreement, shared information systems, shared staffing plans and cross-training of staff. For example, staff members who conduct surveillance and staff members who conduct partner services might each have or develop information important to the other person's function. Having information-sharing agreements that encourage timely, accurate, and secure exchange of information can ensure early identification of potential index patients and more complete surveillance data. For STD programs that provide all partner services, defining how the STD program and the HIV program coordinate services for index patients, partners, social contacts, and associates is important. The level of coordination needed with other health department programs depends partly on local epidemiologic factors and needs of populations at high risk for infection. # Coordination and Collaboration Among Jurisdictions Secure and confidential sharing of information on patients, partners, and other social contacts among jurisdictions facilitates disease prevention. Index patients often name partners who live in a location other than the state or jurisdiction where the diagnosis was made. In addition, a person who tests positive for HIV or other STDs might move to another state or jurisdiction before the test result can be delivered or an interview conducted. Both situations require communication of confidential information from one state or jurisdiction to another; success depends on the willingness of each program manager to take the steps necessary to ensure that security and confidentiality standards are upheld and to hold others accountable when breaches occur. Trust, mutual cooperation, and shared professional ethics are essential. # Coordination and Collaboration with Medical Providers Organizations and agencies that are not part of a health department but are involved in particular aspects of partner services must collaborate to maximize results. HIV partner services program managers should work actively with healthcare providers who provide testing for HIV and other STDs, HIV care providers and case managers, and other social service agencies who provide services to HIV-infected persons to identify patients who have not received HIV partner services or who need additional services. In addition, educating private medical providers about the public health benefits of partner services might lead to increased referrals for partner services. Following are important topics to consider when conducting outreach and education activities with medical providers: - the potential benefits of partner services for medical care providers and their patients; - the role of medical providers in partner services (e.g., timely and accurate reporting of HIV/AIDS and other STD cases to the health department, encouraging clients to use health department partner services, and use of EPT and reporting that use); - health department goals and principles in the provision of partner services; - the importance of evaluating and treating partners of clients; and - the benefits of obtaining assistance from the health department (rather than medical care providers attempting to notify partners themselves), which include the following: 1) trained professionals contact clients and discreetly inform partners of risk, 2) client confidentiality is maintained, 3) clients can be coached on ways to notify partners, 4) patients can be linked to counseling and other prevention and social services support not readily available from medical providers, and 5) partner services are voluntary and free of charge. When medical providers want to provide any aspects of partner services themselves (e.g., partner elicitation, partner notification via dual referral, or EPT), the health department should collaborate with them to provide training and support. However, evidence suggests such collaboration is rare (238). For example, certain providers might be willing and able to elicit partner information that can then be provided to the health department, but most do not have the time or training needed to perform partner notification services for clients. These medical providers should be encouraged to use partner services provided by local health departments. In addition, program managers should consider any applicable legal or regulatory limits on medical care providers being involved in partner services. # Coordination and Collaboration with Other Agencies and Organizations Many CBOs and other health and human services organizations (e.g., community health centers) provide HIV prevention services, including HIV counseling and testing, to populations that are hard to reach and at high risk for transmitting or acquiring HIV. Therefore, CBOs can act as a partner services entry point for clients who might not otherwise be offered these services, and staff members can promote partner services to the communities. CBOs also might be adept at gaining trust and establishing rapport with wary, untrusting, and fearful clients and their partners. CBO staff members might effectively elicit partner information from HIV-infected clients and provide counseling and testing to partners who come to the CBOs for services. (Additional information is available from CDC's Provisional Procedural Guidance for Community Based Organizations ). Before partner services program managers determine how best to use CBOs in the partner services process, they should consider local laws and regulations. In certain jurisdictions, health departments and medical providers are the only entities with legal authority to notify persons of their exposure to HIV and other types of STDs. Because many index patients and their partners have multiple referral needs that cannot be solely addressed by the health department or CBOs, partner services program managers should coordinate and collaborate with other service organizations. Such needs include violence prevention programs, drug treatment programs, mental health agencies, reproductive health programs, community health centers, parole and probation agencies, faith-based organizations, agencies funded by the Ryan White CARE Act, homeless shelters, legal services, and homeless support services. Collaboration can be used to promote partner services, identify referral resources, establish formalized referral mechanisms, and minimize duplication of effort in the jurisdiction. # Communication with Communities and Community Planning Groups Although data indicate that clients are generally accepting of partner services, misperceptions still exist, especially regarding concerns about breaches in confidentiality (39). Program managers should consider developing educational campaigns directed to members of affected communities, advocacy groups, and medical care providers to address concerns and misperceptions about the partner services process. In addition, partner services programs should keep their respective HIV community planning groups (CPGs) informed of partner services activities and ensure that CPGs have access to analyses of current data, including potential implications for HIV prevention in the jurisdiction. Given the comorbidity of HIV and other STDs, as well as relationships among these conditions and various social behavioral risk factors, communication also is warranted among health departments, CPGs, and CBOs about early syphilis, gonorrhea, and chlamydial infection, even if the community groups are primarily focused on HIV. # Recommendations for Program Collaboration and Service Integration - To the extent possible, partner services program managers should ensure that persons receive coordinated HIV and STD prevention and related social services, particularly when the persons are affected by more than one disease. - Partner services program managers should assess and eliminate barriers to programmatic collaboration and service integration within the jurisdiction so that, at a minimum, services are well integrated at the client (i.e., service delivery) level. - Partner services program managers should ensure that shared protocols and policies are developed to help coordinate partner services for persons identified through HIV or STD clinics or other health department clinics. - Partner services program managers should encourage private medical care providers to support partner services through active communication mechanisms (e.g., by visiting key medical providers, making presentations about partner services at local and state meetings of providers of HIV care, mailing educational brochures, or providing a summary of these recommendations). - Partner services program managers should establish systems of communication and information to ensure widespread distribution of these recommendations to health department partners, medical providers, and CBOs. - HIV program managers should ensure that communica tion and information about the partner services recommen dations are shared with HIV prevention CPGs. - Partner services programs should ensure that clearly defined, written protocols and procedures that address confidentiality and data security are in place to address incoming and outgoing requests for intrastate and interstate transmission of information. # Program Monitoring, Evaluation, and Quality Improvement Partner services programs should be monitored to assess program performance and identify areas that need improvement. Additional information is available from the CDC's Practical Use of Program Evaluation Among Sexually Transmitted Disease (STD) Programs and CDC's Framework for Program Evaluation in Public Health (240,241). Specific performance measures for CDC-funded HIV and STD programs are published in CDC funding opportunity announcements. Recommendations in this section are intended for assessment of programs and not of individual staff members. Program monitoring includes the following: - tracking program productivity, including number of partners identified, initiated for follow-up, located and notified, examined, tested, treated or linked to care services, and, for HIV, newly identified as infected; - assessing essential steps in the partner services process to identify areas in which program performance can be improved; - gathering information that can be used to guide resource allocation and improve accountability to funders and stakeholders; - identifying demographic, geographic, and behavioral characteristics of index patients and partners to improve services to clients and better target screening and prevention activities to ensure that they are focused on subpopulations at most risk; - tracking temporal trends in demographic, geographic, and behavioral characteristics of index patients and partners to identify initial indications of shifts in the epidemic and identify potential outbreaks at early stages, when they are easier to control; and - identifying social, sexual, and drug-using networks that might be facilitating transmission in the community so that appropriate screening and preventive measures can be developed and implemented. # Monitoring Program Processes and Outcomes Program monitoring should be designed to address specific questions about program performance, both processes and outcomes; all data collected should be clearly related to answering these questions. Program monitoring data should be accessible to and used by program staff members and all levels of management to improve program effectiveness and efficiency. Program managers should review the data at least quarterly, and more frequently (e.g., monthly) for 1) new programs; 2) programs that are introducing substantial changes in policies, procedures, or program design; and 3) programs that have identified potential problems with any of their processes or outcomes. # Essential Questions The following four questions and measures that can be used to assess them must be addressed by managers of partner services programs. These questions were developed by identifying the steps involved in conducting partner services programs and then identifying essential processes and outcomes that can provide measures of program performance (Figure 2). For curable STDs such as syphilis, chlamydial infection, and gonorrhea, the term index case (question number 1) refers to individual episodes of infection. If an individual patient has recurrent episodes of an infection during the defined time period, each episode is counted as a separate index case; an index case does not represent an individual person. For example, a person who has three reported episodes of gonorrhea over a 1-year time period represents three index cases during that year. In contrast, once a person is infected with HIV, the person remains infected. Therefore, once identified as having an index case of HIV infection, the person does not count as another index case in the future (i.e., each index case of HIV infection represents a unique person). Named partners (question number 2) are partners for whom the index patient provides sufficient identifying and other information that the partner can reasonably be considered locatable. Identifying information includes an actual name, an alias, a specific e-mail address or chat-room screen name, or enough other descriptive information that the person can reasonably be considered identifiable. # How completely is the program identifying newly reported cases and interviewing patients for partner services? Assess cases of HIV infection, syphilis, gonorrhea, and chlamydial infection separately, for a defined time period ): - Number of new cases reported to the health department, including cases identified through surveillance activities - Of new cases reported to the health department, the number and proportion of patients who were eligible for partner services (i.e., not deceased or out of jurisdiction at the time of report ) - Of new patients eligible for partner services (i.e., index patients), the number and proportion who were interviewed to elicit partner information Assess cases of syphilis, gonorrhea, and chlamydial infection separately, for a defined time period ): - Of partners examined or tested, the number and proportion found to be infected - Of all named partners, the number and proportion found to be infected - Of all named partners, the number and proportion treated preventively - Of all named partners, the number and proportion treated for cure (i.e., infected and brought to treatment) # Additional Assessments In addition to addressing the previous four questions, most programs benefit from more detailed monitoring. For example, by considering how successfully the program is performing each step throughout the partner services process, program managers can identify specific steps that need improvement to enhance overall program performance. Qualitative information can be collected to identify factors contributing to areas of concern and aid in improvement. Stratifying the analysis by demographic and behavioral risk characteristics might provide information that allows services to be tailored to the needs of particular subpopulations. The timeliness with which various steps of the process are completed also can be examined. Following is an example: - the number of partners preventively treated within 7, 14, and 30 calendar days from day of interview of index patient per index case of primary and secondary syphilis and - the number of partners with new syphilis cases brought to treatment within 7, 14, and 30 calendar days from day of interview of index patient per index case of primary and secondary syphilis. Following are examples of stepwise process monitoring ques tions that programs should address for index patients, based on the detailed steps in the partner services process (Figure 2 2) can be used to create a similar series of stepwise questions for locatable partners that are identified from index patient interviews, such as, "Among identified partners of HIV index patients, how many are already known via record review to be HIV infected? Of these, what proportion is contacted and provided HIV prevention counseling?" Another important consideration for program managers is how the success of provider referral compares with that of self-referral (or third-party referral) for notifying partners of their risk. Outcomes for partners designated to be notified through self-referral usually are challenging to measure, because verifying that the partners have been notified and tested, what their test results are, and whether they have been linked to medical services, HIV case management, or prevention services are difficult. Several strategies have been used in attempts to obtain this information, but none have been adequately tested for reliability. Examples of such strategies include the following: - requesting that, after notification has occurred, the index patient ask the partner to contact the DIS to verify that the notification has occurred; - providing coded referral cards to the index patient, who then gives a card to each partner to be turned in when the partner arrives for counseling and testing; and - requesting that the index patient accompany the partner to the counseling and testing site, rather than simply referring the partner, which allows the index patient to validate that the partner has been notified. Finally, similar monitoring can be conducted to assess outcomes of clustering and cluster interviewing (e.g., assessing the relative number of new cases of syphilis and gonorrhea identified or of newly identified HIV-positive partners, social contacts, and associates). # Monitoring Program Objectives In addition to monitoring program processes and outcomes, program managers should monitor achievement of program objectives. Annually, programs should establish clear, specific, realistic, time-phased, measurable objectives for each key step or process in the program, as well as expected program outcomes. Progress toward achieving these objectives should be tracked continuously. If progress on one or more processes is unsatisfactory, possible reasons should be considered and processes modified accordingly. Certain originally established objectives might later be determined to be unrealistic and also can be modified. # Monitoring Use of Staff Members and Other Resources Program managers also should monitor program staff members and resource use to identify and quantify activities being performed by staff members, the number of staff members and amount of time required to perform each activity, the types and level of other resources required to implement and maintain the program, and the overall cost of the program. Using a combination of qualitative and quantitative data, this information can be used to adjust use of staff members and resources and plan future program activities. # Program Evaluation In general, evaluations require more rigorous design, analysis, and interpretation than monitoring and frequently require more resources. In certain situations, programs might need to consult with experts in evaluation. Following are examples of questions that might be addressed through evaluation: - Compared with other strategies (e.g., outreach counseling and testing), how effective are partner services as a casefinding method? - What are the most effective strategies for linking infected partners to medical services, HIV case management, and other prevention services? - Who more effectively elicits information regarding spouses and other partners and notifies them of their exposure to HIV: health department specialists, clinicians, counseling and testing providers, or others? - What are the most effective strategies for recruiting persons at high risk for infection into counseling and testing and ensuring that they receive their results? - How cost-effective are partner services compared with other strategies for identifying and testing persons at high risk for infection? - Do certain staff members seem to provide partner services more successfully than others? If so, what are some possible explanations? - Are partner services more effective with certain subpopu lations (e.g., men, women, youths, or racial/ethnic minority groups) or behavioral risk groups (e.g., MSM, injection-drug users, or heterosexuals at high risk for infection) than with others? # Support of Staff Members Staff Development and Assessment Staff assessment and staff development, training, and support have an important association: staff members who are not adequately prepared for and supported while performing their jobs have difficulty performing satisfactorily. Staff development and support begins with a clear description of staff roles and responsibilities, as well as of the knowledge and skills required for the job. This information is used to recruit staff members and identify an appropriate training curriculum to follow initially and at periodic intervals. In addition, assessment of individual strengths and weaknesses of staff members allows supervisors to help them design specific training plans for building their skills. All staff members conducting partner services activities need in-depth training on partner services goals and principles, methods of partner services, and any specific concerns related to specific infections. Training can be obtained through the CDC-supported Prevention Training Centers. After the initial training, updates should occur periodically; close supervision, observation, and mentoring of staff members is critical, especially for those new to the job. In addition, staff members should have easy access to all materials, tools (e.g., cellular telephones), and resources needed to perform the job efficiently and effectively; this is not the responsibility of individual staff members. Staff assessments should include both qualitative and quantitative outcome measures that are constructive and not punitive. These types of assessments are more likely to result in improvement of staff skills and performance than using a single, quantitative outcome measure. For example, the number of partners tested per index patient interviewed can be used as a single measure of staff proficiency; however, an assessment of each essential step in the process (e.g., proportion of index patients located and interviewed, number of partners elicited per index patient interviewed, proportion of partners located and notified, and proportion of located partners counseled, examined, and tested), supplemented with qualitative information, would provide a better assessment of the staff. Qualitative assessments can begin with supervisors routinely meeting with individual DISs to review the timeliness and completeness of specific cases, with a focus on barriers encountered in managing the case and strategies for overcoming these barriers. These one-on-one meetings provide supervisors an opportunity to review the quantitative measures of important steps with the staff member, discuss the validity of the measures, consider potential factors contributing to the performance of the staff member, and discuss strategies for improving certain skills. These meetings also provide an opportunity to assess staff member awareness of and adherence to program guidelines, protocols, and performance standards. Routine, periodic supervisor observation of DISs in all aspects of activities, with immediate feedback, can be very useful. Direct observation can be an important tool in assessing whether staff members have the necessary skills and knowledge to conduct interviews, provide referrals, and satisfy other client needs (242). For example, successful staff-client interactions, in which staff members demonstrate sensitivity to and interest in the client, as well as adherence to current policies and procedures, are essential for effective partner services. Observation and feedback should be structured and constructive and not punitive. Supervisors should reinforce positive performance and provide specific, constructive comments regarding areas that need improvement. A reasonable initial time frame for supervisor observation of DISs is twice monthly for the first 6 months, monthly for the second 6 months, and quarterly for staff members with more than 1 year of experience, depending on individual performance. This schedule might need to be modified depending on program experience. Case conferences also can be very useful for staff support as well as for quality improvement. Regularly scheduled group DIS meetings allow supervisors to understand the skills and areas that need improvement among staff members and provide an opportunity for staff members to learn from one another. Case conferences are a valuable forum for staff members to discuss specific concerns, address difficult situations, and share resources. Case conferences also give supervisors an opportunity to emphasize that conducting partner services is a team effort and that competitive behavior interferes with collaboration and sharing of valuable information and resources. Frequency of case conferences should be balanced with workload, with attempts to conduct such conferences at least monthly. Finally, although staff member assessments often focus on DISs, ensuring that supervisors and program managers themselves are adequately trained, supported, and assessed is equally if not more important. # Staff Safety Certain field activities can include unsafe situations for DISs. Program managers should develop and maintain detailed guidelines for ensuring staff safety. Examples of safety procedures that are often used by partner services programs include the following: - training that includes a common-sense approach to field work, such as appropriate dress, including not wearing jewelry that appears expensive; locking purses and other valuables out of sight; locking car doors and keeping windows rolled up; remaining aware of surroundings; and relying on instincts; - ensuring that program staff members carry photo identification when in the field; - maintaining an employee file, including name, address, physical description, emergency locating information, a recent photo of the employee, and a description of the employee's vehicle and vehicle license number, that can be shared with authorities in case of emergency; - encouraging field workers to work in pairs if needed; - providing cellular telephones, pagers, or electronic navigation systems and requiring staff members to call in when changing plans or when an investigation becomes problematic; - requiring field staff members to submit a daily route sheet of intended stops to the supervisor so that the route can be traced if an emergency arises; - having immediate supervisors or other experienced staff members accompany new field staff members to point out community locations that could be risky (e.g., drug houses, parks, bars, prostitution stroll areas, or areas controlled by gangs) and to model desired behavior; and - routinely discussing safety concerns and emerging problem areas during staff meetings and daily debriefings. The primary way staff members can avoid unsafe situations is to have knowledge of the community; consequently, spending time establishing personal rapport with members of the community is important. This can be accomplished while performing health department outreach activities, organizing field screenings, and participating with CBOs in outreach activities. Other safety concerns involve occupational infections in the workplace, particularly for programs that use DISs to draw blood or collect other specimens in the field. These programs should review all relevant state and local health and safety codes and local public health protocols to determine required training and certification procedures before performing these activities. They also must have in place an Occupational Infections in the Workplace policy that is at least as restrictive as applicable Occupational Safety and Health Administration (OSHA) policies in their areas. Policies and procedures should specifically address management of occupational exposure to HBV, HCV, and HIV, including PEP (243). DISs who might be collecting specimens in the field are strongly encouraged to receive an orientation to state or local Occupational Infections in the Workplace policies and supporting procedural manuals. - Public health agencies responsible for partner services should conduct a thorough review of all laws relevant to their provision of these services. This review should serve as a basis for developing policies and procedures for partner services programs. Program managers should also ensure that program staff members understand the implications these laws have for conducting partner services. Laws relevant to provision of these services include the following: # Recommendations for Support for Staff Members -the legal authority for the public health agencies for partner services; -provisions related to privacy and confidentiality (e.g., requirements of the Health Insurance Portability and Accountability Act ); -provisions related to duty or privilege to warn and criminal transmission and exposure; -the ability of the public health agencies to coordinate with other agencies (e.g., law enforcement). - Program managers should ensure that their staff members understand the legal basis for their work, legal restrictions on their practice (e.g., duty or privilege to warn), the extent to which they are protected from civil litigation, and how to coordinate with law enforcement officials in ways that protect the civil and procedural rights of the persons involved. - To ensure that program staff members invoke their duty or privilege to warn appropriately, partner services programs should have written policies and procedures to guide staff members in handling complex cases. Guidelines and protocols should be based on the jurisdiction's statutory and case law and developed in consultation with legal counsel. Legal counsel should also be consulted regarding specific cases in which duty to warn or privilege to warn might apply. - Program managers should be aware of the applicable laws regarding criminal transmission and exposure in their jurisdictions and should coordinate with legal counsel regarding specific cases in which allegations of criminal transmission or exposure are made. # HIV Infection - HIV partner services programs should collaborate with health-care providers who provide HIV screening or testing, other HIV counseling and testing providers, HIV care providers, and HIV case managers to ensure that their clients and patients are offered HIV partner services as soon as possible after diagnosis and on an ongoing basis, as needed. - HIV partner services programs should work with providers of anonymous HIV testing services to develop strategies for providing partner services to persons who test positive, even if the person decides not to enter a confidential system. These providers should be trained on how to offer partner services and elicit partner information from persons with newly diagnosed HIV infection. # Prioritizing Index Patients General - Program managers should establish criteria for prioritizing index patients to determine which patients will be interviewed first. In general, these criteria should include behavioral and clinical factors that affect the likelihood of additional transmission. Pregnant women should always be considered a high priority, regardless of behavioral or other clinical factors. - Persons with evidence of ongoing risk behaviors for transmission (e.g., recurrent sexually transmitted diseases or being repeatedly named as a partner of other infected persons) might be playing an important role in transmission in the overall community and should be prioritized for partner services. # Syphilis - Many program areas use a reactor grid to assist with determining investigative priorities for syphilis reactors. The reactor grid is based on age and syphilis serology laboratory results (titers). Programs that use a reactor grid are strongly encouraged to validate its performance annually and during suspected outbreaks. # Interviewing Index Patients # yphilis, Gonorrhea, and Chlamydial nfection - For early stages of syphilis, policies, procedures, and protocols should specify that all index patients receive an original interview as close to the time of diagnosis and treatment as possible. Every reasonable effort should be made to ensure the partner notification process begins on the date of the original interview. - For cases of gonorrhea and chlamydial infections that partner services staff members will follow up, policies, procedures, and protocols should specify that all index patients receive an original interview as close as possible to the time of diagnosis and treatment. Unless the index patient has evidence of recent infection, notification primarily serves case-finding goals and might be briefly delayed, if necessary. - For cases of gonorrhea and chlamydial infection that partner services staff members will not follow up, patient referral instructions should be provided as close as possible to the time of diagnosis and treatment. - For STDs other than HIV, partner services programs should follow established recommendations for interview periods (Table 1). # IV Infection - Policies, procedures, and protocols should specify that all index patients receive an original interview as soon as possible after diagnosis, ideally within a few days. For index patients who are not willing or able to provide partner information during the original interview, a reinterview should be scheduled, preferably no later than 2 weeks after contact was first made (and sooner, if possible, for index patients with acute infections). - Programs should develop criteria for establishing the interview period for index patients with HIV infection ( # Syphilis - Blood should be drawn in the field when DISs are trained to do so and when specimen maintenance conditions can be met. Partners should be referred for evaluation regardless of whether a specimen has been collected. # Gonorrhea and Chlamydial Infection - If provider referral is used, programs should consider protocols for collecting specimens in the field. # HIV Infection - Partner services programs should consider using rapid HIV tests to maximize the number of partners who are tested and receive test results. - When notification is done in the field, rapid tests should be used or a blood or an oral fluid specimen should be collected for conventional testing. If neither of these is possible, the partner should be escorted or referred to the clinic for testing. - Partners who test negative for HIV antibody should be advised to be retested in 3 months. # Treatment for Partners # Syphilis, Gonorrhea, and Chlamydial Infection - Program managers should ensure that partners are treated according to CDC treatment guidelines as soon as possible after notification. - Programs should consider field-delivered therapy for gonorrhea and chlamydial infection when partners are notified via provider referral. - For STDs for which single-dose oral therapy is feasible (i.e., gonorrhea and chlamydial infection), programs should consider patient-delivered partner therapy for partners who will not be notified via provider referral. - Programs should be sure that all appropriate parties are consulted to ensure that any EPT strategy in the jurisdiction is medically and legally sound. Appropriate parties vary by jurisdiction but might include state health commissioners or legislative bodies. HIV Infection # Immigrants and Migrants - Program managers should review epidemiologic and other data to identify potential immigrant and migrant populations at high risk for infection in their jurisdictions and be prepared to provide partner services that are linguistically and culturally appropriate. # Strategies to Enhance Case Finding and Partner Notification Core Areas - Health departments should assess the geographic concentration of gonorrhea and consider focusing provider-referral partner notification in core areas. # Social Networks - Programs should assess the social networks that influence disease transmission in the area as a strategy for finding persons who are at risk for disease but have not been identified by an index patient or partner. - This strategy should be used to enhance case finding, considering relevant epidemiological and behavioral information. # The Internet - When an index patient indicates having Internet partners, the DIS should attempt to obtain identifying and locating information about the partners (e.g., e-mail addresses, chat room handles, and names of chat rooms or websites where the partner might be located). - Internet partner notification is recommended for partners who cannot be contacted by other means or can be more efficiently contacted and notified through the Internet. This type of notification includes ensuring policies and protocols are in place to 1) ensure that confidentiality or anonymity of the index patient and partners are maintained on the Internet and 2) eliminate structural and bureaucratic barriers to staff member use of the Internet for partner notification. - Partner services programs should collaborate with community partners to develop strategies for addressing structural challenges to health department-mediated Internet partner notification. # Program Collaboration and Service Integration - To the extent possible, partner services program managers should ensure that persons receive coordinated HIV and STD prevention and related social services, particularly when the persons are affected by more than one disease. - Partner services program managers should assess and eliminate barriers to programmatic collaboration and service integration within the jurisdiction so that, at a minimum, services are well integrated at the client (i.e., service delivery) level. # Program Monitoring, Evaluation, and Quality Improvement - Partner services programs should be monitored closely to assess program performance and identify areas that need improvement. - Monitoring should be designed to answer specific questions about program performance; all data collected should be clearly related to answering these questions. - Data should be analyzed and reviewed regularly and used to improve program effectiveness and efficiency. - At a minimum, the following questions should be addressed through monitoring: -How completely is the program identifying newly reported cases and intervewing patients for partner services? -How effectively is the program identifying partners, notifying them of their risk, and examining or testing them for infection? -How effectively is the program identifying new cases of syphilis, gonorrhea, and chlamydial infection Comprehensive risk counseling and services (CRCS). An intensive, client-centered counseling process aimed at ensuring the adoption and maintenance of HIV risk-reduction behaviors designed for HIV-infected persons who continue demonstrating risk behaviors and for HIV-negative persons who are at high risk for acquiring HIV infection and other types of STDs. Confidentiality. The ethical principle associated with the health profession (or the legal right of a client receiving healthcare services) in which health professionals do not disclose information relating to a patient unless the patient gives consent permitting disclosure or disclosure is necessary to protect public health. # Contract referral. A partner notification strategy in which an index patient identifies a specific partner to notify the partner of possible exposure and agrees to do so within a specific time frame, with the understanding that if notification does not occur within the designated time frame, the disease intervention specialist (DIS) will notify the partner. Core area. A specific, typically geographically defined area, such as a neighborhood or census tract, in which a relatively high concentration of disease exists and which likely accounts for a large proportion of transmission in a community. Core groups. Socially defined groups of persons who, as a consequence of continuing risky sexual or drug-injecting behavior, are likely to be sources of continued disease transmission in a network or community (i.e., are core transmitters). Core transmitter. A person who, as a consequence of continuing risky sexual or drug-injecting behavior, is likely to be a source of continued disease transmission in a network or community. Disease intervention. The process of stopping the spread of a disease and the complications of disease. # Disease intervention specialist (DIS). A health department staff member who is specially trained to interview persons infected with HIV or another STD (i.e., index patients); elicit information about their partners and associates; notify the partners of their possible exposure; ensure that the partners are offered appropriate services, including examination, treatment, and referrals; and provide prevention counseling to index patients, partners, social contacts, and associates. # Drug-injection partner. A person with whom a patient shares drug-injection equipment (e.g., needles, syringes, cottons, cookers, or rinse water). These persons have been traditionally referred to as needle-sharing partners or syringe-sharing partners. Dual referral. A notification strategy in which an index patient, together with a health-care provider (typically a disease intervention specialist) notifies a partner of the partner's possible exposure. The strategy allows the provider to provide direct support to the index patient during the notification process and provide the partner with immediate access to counseling, testing, and other information resources (e.g., referrals). # Duty to warn. A legal concept that a health-care provider who learns that an HIV-infected client is likely to transmit the virus to another identifiable person must take steps to warn that person. State laws determine which circumstances constitute a duty to warn. Early syphilis. Primary, secondary, and early latent syphilis. # Expedited partner therapy (EPT). The process by which treatment for partners of persons diagnosed with gonorrhea or chlamydial infection is administered before clinical evaluation. Medications or prescriptions are delivered through either 1) the index patient (i.e., patient-delivered partner therapy) or 2) a disease intervention specialist (i.e., field-delivered therapy). # HIV prevention community planning group (CPG). A planning group consisting of local health officials, representatives from affected communities, and technical experts who share responsibility for developing a comprehensive HIV prevention plan for their community. The intent of the process is to increase meaningful community involvement in prevention planning, to improve the scientific basis of program decisions, and to target resources to those communities at highest risk for HIV transmission and acquisition. HIV prevention counseling. An interactive process between client and counselor aimed at reducing risky sex and druginjection behaviors related to HIV acquisition or transmission. Index case. The first case recognized or reported during an outbreak or epidemic. In epidemiology, the term case generally refers to an episode of infection or disease, not to a unique person. An index case is not necessarily the source of an outbreak or epidemic; it is simply the first case identified. In the context of HIV/STD partner services, an index case is a newly reported case that prompts the initiation of an investigation to identify other possibly related cases. For curable STDs, the term index case refers to discrete episodes of infection. A person who has recurrent episodes of a curable STD during a defined time period is counted as a separate index case for each episode. For example, a person who has three reported episodes of gonorrhea during 1 year would represent three index cases during that year. In contrast, once a person is infected with HIV, the person remains infected; therefore, once a person with HIV infection is identified, the person will not be counted as an index case again in the future. Index patient. The person in whom an index case occurs and who prompts the initiation of an investigation to identify other possibly related cases. Index patients also are sometimes referred to as "original patients" (i.e., the original patient identified in an investigation, not necessarily the original patient in a chain of transmission). Indicator. A measure used to determine an organization's performance of a particular element of care over time. The indicator might measure a particular function, process, or outcome Interview period. The period of time for which an index patient is asked to recall sex or drug-injection partners. Because of differences in biological factors and progression of various diseases, the recommended interview period varies by disease. Ongoing partner services. The concept that partner services should be available to persons with HIV infection at any time needed throughout the course of their life. Original interview. The first interview conducted with an infected patient. The primary purpose of the original interview is to gather information from index patients about partners they have had during the relevant interview period. Original patient. See index patient. Outcomes. Benefits or other results (positive or negative) for clients that might occur during or after their participation in a program. Outcomes can be client level or system level. # Overall responsible party (ORP). The person who accepts overall responsibility for implementing and enforcing HIV/ AIDS and STD data security standards and who might be liable for any breaches of confidentiality. Partner. For persons with syphilis, gonorrhea, or chlamydial infection: refers to sex partners (i.e., persons with whom an index patient has had sex at least once, not just regular or main partners); for persons with HIV infection: refers to sex and drug-injection partners (i.e., persons with whom an index patient has had sex or shared drug-injection equipment at least once, not just regular or main partners). Partner elicitation. The process of obtaining the names, descriptions, and locating information of persons who are partners (or social contacts) of an index patient. Partner elicitation is one step in the process of partner referral Partner notification. The process of locating and confidentially notifying partners that they have been exposed to an infection. Partner notification is one step in the process of partner referral. Partner referral. The process in which partner names are elicited (i.e., partner elicitation), partners are located and notified of their exposure (i.e., partner notification), and notified partners receive a combination of counseling and referrals for testing (or in some cases, testing in the field) and other social support services. Partner services. A broad array of services that should be offered to persons with HIV infection, syphilis, gonorrhea, or chlamydial infection and their partners. Identifying partners and notifying them of their exposure (i.e., partner notification) are two critical elements of these services. Other elements include prevention counseling, testing for HIV and other types of STDs, linkage to medical evaluation and treatment, and linkage or referral to other services, such as reproductive health, prenatal care, substance abuse treatment, social support, housing, legal services and mental health services. # Patient. A client who is diagnosed with HIV infection or another STD. Patient referral. See self-referral. Performance measure. A quantitative tool that provides an indication of an organization's performance in relation to a specified process or outcome. # Personal identifier. A datum or collection of data that allows the identity of a single person to be determined with a specified degree of certainty. Postexposure prophylaxis (PEP). Administration of antiretroviral drugs to HIV-negative persons who have been exposed to HIV in an effort to prevent establishment of infection. The treatment is initiated within 72 hours of exposure and generally continues over the course of a 28-day period. Prevention counseling. An interactive process between client and counselor aimed at reducing risky sex and drug-injection behaviors related to acquisition or transmission of HIV and other types of STDs. # Prison Rape Elimination Act of 2003 (PREA). A public law that provides for analysis of the incidence and effects of prison rape in federal, state, and local institutions and for information, resources, recommendations, and funding to protect persons in prison from rape. Privilege to warn. The legal concept that a health-care worker is legally permitted to warn the partners of an HIV-infected person of the risk of past or future exposure to HIV. # Program collaboration and service integration. A mechanism of organizing and blending interrelated health concerns, separate activities, and services to maximize public health impact through new and established linkages among programs to facilitate delivery of services. Provider referral. A notification strategy in which a health department specialist (e.g., disease intervention specialist) confidentially notifies a partner of possible exposure. # Quality. The degree to which a health or social service meets or exceeds established professional standards and user expectations. Quality improvement. An approach to the continuous study and improvement of the processes of providing services to meet the needs of the person and others. Reactor grid. The use of quantitative test results, age, and sex criteria to identify which persons with reactive syphilis tests are most likely to be untreated and infectious cases. Reinterview. An interview that follows the original interview with an index patient. The reinterview is used to gather additional locating information about partners identified by index patients during the original interview, monitor the status of partners index patients initially decided to notify themselves, elicit names of additional partners index patients might not have recalled in the original interview, and verify that index patients have received adequate treatment or additional tests. Ryan White CARE Act Amendments of 1996. The law reauthorizing the Ryan White HIV/AIDS Program, a program administered by the Health Resources and Services Administration that provides for grants to support the medical care needs of low-income, uninsured, and underinsured persons living with acquired immunodeficiency syndrome (AIDS) and HIV infection. # Self-referral. A notification strategy in which an index patient accepts full responsibility for informing a partner of possible exposure and referring the partner to appropriate services. A health-care provider helps the index patient determine when, where, and how to notify the partner as well as how to cope with potential reactions. This process is also known as client referral and patient referral. # Social contact. A person named by the index patient during an interview as part of the social network who is not a sex or drug-injection partner of the index patient. Social contacts (referred to as suspects in previous STD partner services guidelines) might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination. # Social network. A group of persons connected by various types of social relationships, such as family, work and recreational relationships, sexual partnerships, and drug-using relationships. The social network might also include venues in which interactions among members of a social network occur. Persons in a social network might share social, economic, cultural, or behavioral characteristics that influence their risk for various health conditions, including HIV infection and other STDs. Standards. Elements or procedures that must be followed by CDC grantees in virtually all instances in which CDC funds are used to support services. # Suspect. A social contact. This term has historically been used to describe a person named by an index patient as part of the social network who is not a sex or drug-injection partner of the index patient. These persons might have symptoms suggestive of disease, might be partners of other persons known to be infected, or might be other persons who might benefit from examination. System. A group of related processes. Third-party provider. A health or social services professional not affiliated with a health department (e.g., physicians, nurses, or counselors) who might participate in certain aspects of partner services, such as partner elicitation or partner notification via dual referral Third-party referral. A notification strategy by which a partner is notified of exposure to HIV or another STD by a professional other than a health department staff member (e.g., a private physician). Window period. The time interval after infection during which a serologic test might be negative because antibodies have not reached a detectable level. Guiding Principle 5. Security practices and written policies will be reviewed and assessed continuously and, as necessary, changed to improve the protection of confidential partner services case information and data. Partner services programs should adhere to the following program standards when developing area-specific guidelines, policies, and procedures for individual-level record keeping and data collection, management, and security: Standard 1. All policies and procedures must be written and reviewed at least annually and revised as needed. # Standard 2. A policy must name the persons who act as the overall responsible party (ORP) for the security of the data that might be stored in various data systems. # Standard 3. A policy must describe the methods for review of security practices for data. Included in the policy should be a requirement for an ongoing review of evolving technology to ensure that information and data remain secure. # Standard 4. The ORP must certify annually that these standards are met. # Standard 5. Access to and use of individual-level information must be defined in a data-release policy. Standard 6. Policies must be readily accessible to any staff members having access to confidential, individual-level data. # Standard 7. A policy must define the roles and access level for all persons with authorized access and describe which standard procedures or methods will be used when accessed. Standard 8. All authorized staff members must sign a confidentiality statement annually. Newly hired staff members must sign a confidentiality statement before access to individual-level information and data is authorized. # Standard 9. A policy must outline procedures for handling incoming mail and faxes to the programs and outgoing mail and faxes from the programs. The amount and sensitivity of information contained in any piece of correspondence must remain minimal. Standard 10. All persons who are authorized to access individual-level information must be knowledgeable about the organization's information security policies and procedures. Standard 11. All staff members authorized to access individual-level information must be responsible for questioning persons who attempt to access this information but who are not authorized to do so. # Standard 12. All staff members who are authorized to access individual-level information are responsible for protecting their own computer workstation, laptop computer, or other devices with confidential, individuallevel information or data. This responsibility includes protecting keys, passwords, and codes that would allow access to confidential information or data. Staff members must be careful not to infect program software with computer viruses and not to damage hardware through exposure to extreme heat or cold. Standard 17. Partner services analysis data sets must be stored securely with protective software (i.e., software that controls the storage, removal, and use of the data), and personal identifiers should be removed when possible. Standard 18. Partner services information and data transfers and methods for data collection must be approved by the ORP and incorporate the use of access controls. Individual-level information and data must be encrypted before electronic transfer. When possible, databases and files with individual-level data must be encrypted when not in use. # Standard 19. When individual-level partner services information and data are electronically transmitted, any transmission that does not incorporate the use of an encryption package meeting the encryption standards of the National Institute of Standards and Technology (available at / standards.html) and approved by the ORP must not contain identifying information or use terms easily associated with HIV, AIDS, or any other type of STD. The terms HIV and AIDS, terms that specifically identify other STDs, or specific behavioral information must not appear anywhere in the context of the transmission, including the sender and recipient address and label. Standard 20. When partner services information with personal identifiers or data are taken from secured areas and included in line lists or supporting notes, in either electronic or paper format, the documents must contain the least amount of information needed for completing a given task and, if possible, coded to disguise any information that could easily be associated with HIV, AIDS, or any other type of STD. # Standard 21. Individual-level information or data with personal identifiers must not be taken to private staff members' residences unless specific, documented permission is granted or the transfer is permitted according to a written policy established by the program manager or ORP. # Standard 22. Prior approval must be obtained from the program manager or approved procedures must be followed when planned business travel precludes the return of information with personal identifiers to the secured area by the close of business on the same day. Standard 23. Access to any partner services program information or data containing names for research purposes (i.e., for other than routine program purposes) must be contingent on a demonstrated need for the names, institutional review board (IRB) approval, and the signing of a confidentiality statement regarding rules of access and final disposition of the information. Access to partner services program information or data without names for research purposes beyond routine program activities might still require IRB approval, depending on the numbers and types of variables requested in accordance with local data release policies. # Standard 24. Access to any secured areas where individuallevel partner services information are stored must be limited to authorized persons as documented within policies and procedures (e.g., cleaning or maintenance staff members). # Standard 25. Access to confidential partner services information and data by personnel outside the partner services program must be limited to those authorized based on an expressed and justifiable public health need, must not compromise or impede program activities, must not affect the public perception of confidentiality of the data system, and should be approved by the ORP. # Standard 26. Access to partner services information and data with identifiers by those who maintain other disease data stores should be limited to those for whom the ORP has weighed the benefits and risks of allowing access and can certify that the level of security established is equivalent to these standards. Standard 27. Access to partner services information or data for purposes unrelated to public health (e.g., litigation, discovery, or court order) can only be granted to the extent required by law. Standard 28. All staff members who are authorized to access partner services information and data must be responsible for reporting suspected security breaches. Nonprogram staff members also must be informed of this directive. Standard 29. Any breach of protocol or procedures, regardless of whether personal information was released, must be investigated immediately to assess causes and implement remedies. Standard 30. A breach of confidentiality (i.e., a security infraction that results in the release of private information with or without harm to one or more persons) must be reported immediately to the ORP. In consultation with appropriate legal counsel, partner services staff members should determine whether a breach warrants reporting to law enforcement agencies. Standard 31. Laptop computers and other portable devices (e.g., personal digital assistants , other handheld devices, and tablet personal computers ) that receive or store partner services program information or data with personal identifiers must have encryption software. Program information with identifiers must be encrypted and stored on an external storage device or on the laptop removable hard drive. The external storage device or hard drive containing the information must be separated from the laptop and held securely when not in use. The decryption key cannot be on the laptop. Other portable devices without removable or external storage components must use encryption software that meets federal standards. Standard 32. All removable or external storage devices containing partner services information or data that contains personal identifiers must 1) include only the minimum amount of information necessary to accomplish assigned tasks as determined by the program manager; 2) be encrypted or stored under lock and key when not in use; and 3) be sanitized immediately after a given task (excludes devices used for backups). Before any device containing sensitive data is taken out of a secured area, the information or data must be encrypted. Methods for sanitizing a storage device must ensure that the information cannot be retrievable using "undelete" or other data-retrieval software. Hard drives that contain identifying information must be sanitized or destroyed before computers are labeled as excess or surplus, reassigned to non-program staff members, or sent off site for repair. # Quality Improvement Program managers should implement quality improvement systems to help ensure that services are delivered as intended, programs are responsive and accountable to the funders and consumers of the services, and program performance and quality of care are continuously improved. Quality improvement activities typically focus on the following areas: - awareness of services among all potential consumers and easy accessibility to such services; consumers include clinicians and counseling and testing providers who are diagnosing STD/HIV infections; persons with newly diagnosed STD/HIV infections; and persons with a previous STD/HIV diagnosis who might not have received partner services at the time of diagnosis or might need subsequent partner services; - appropriateness of services for client needs, including availability of services and materials appropriate for the culture, language, sex, sexual orientation, age, and developmental level of the clients; - continuity, availability, and accessibility of referral services appropriate for the clients, especially medical evaluation and management for persons with a new HIV diagnosis; - development, implementation, and accessibility of written program guidelines, protocols for provision of services, and performance standards; - adherence to program guidelines, protocols, and performance standards by all program staff members; - performance and proficiency (e.g., initial and ongoing competence and skill and appropriate training and credentialing) of staff members; and - supervision and support of staff members, including routine, timely feedback and record-keeping procedures that support efficiency and ensure client confidentiality and data security. Various methods can be used to help improve program quality, including the following: - regular, direct supervisor observation of staff performance and demonstration of appropriate skills and behavior; - case-management sessions that facilitate discussion of specific cases, safety concerns, social network analysis, All program standards and security considerations should be based on the following five guiding principles: Guiding Principle 1. Partner services information and data should be maintained in a physically secure environment. Guiding Principle 2. Electronic partner services data should be held in a technically secure environment, with the number of data repositories and persons permitted access kept to a minimum. Operational security procedures should be implemented and documented to minimize the number of staff members who have access to personal identifiers and to minimize the number of locations where personal identifiers are stored. Guiding Principle 3. Individual program staff members and persons authorized to access case-specific information are responsible for protecting confidential partner services case information and data; these persons will face legal action for confidentiality violations. Guiding Principle 4. Security breaches of partner services information or data will be investigated thoroughly and sanctions imposed as appropriate. # ACCREDITATION # Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 3.5 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been reviewed and approved as an # Continuing Nursing Education (CNE). CDC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. CDC will award 3.5 contact hour(s) in CNE credit. # Certified Health Education Specialist (CHES). CDC is a designated provider of continuing education contact hours (CECH) in health education by the National Commission for Health Education Credentialing, Inc. This program is a designated event for CHESs to receive 3.0 category I contact hour(s) in health education. The CDC provider number is GA0082. depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices # Goals and Objectives This report describes recommendations for conducting partner services for persons with human immunodeficiency virus (HIV) infection, syphilis, gonorrhea, or chlamydial infection. Upon completion of this educational activity, the reader should be able to 1) describe the goals and functions of partner services; 2) describe ways to identify and prioritize index patient for partner services; 3) identify ways to notify partners of their exposure to HIV, syphilis, gonorrhea, or chlamydia; 4) describe options for treating partners; and 5) identify ways to address the needs of specific populations with regard to partner services. To receive continuing education credit, please answer all of the following questions. # Expedited partner therapy is… A. the process of moving partners through the clinic faster than regular patients. B. the process of notifying partners of their exposure within 24 hours of diagnosis. C. the practice of treating partners before treating the index patient. D. the practice of treating partners before clinical evaluation. E. the practice of decreasing notification times within a partner services program. # Advantages of field delivered therapy are… A. requires index patients to take responsibility for their infection. B. allows the disease intervention specialist to monitor any adverse reactions to medication. C. reduces the amount of time disease intervention specialists spend in the field. D. all of these. E. none of these. # Which of the following statements is true about partner services for incarcerated populations? A. Privacy is not recommended for safety reasons. B. Because inmates are confined, protecting their confidentiality is not required. C. Inmates might not want to identify partners while they are incarcerated. D. Identified partners should be informed that the index patient is incarcerated. E. Ensuring medical care for partners is the responsibility of the health department. Failure to complete these items can result in a delay or rejection of your application for continuing education credit.	This report provides updated, integrated recommendations for services provided to partners of persons with human immunodeficiency virus (HIV) infection and three other sexually transmitted diseases (STDs) (i.e., syphilis, gonorrhea, and chlamydial infection) and replaces the CDC 2001 Program Operations Guidelines for STD Prevention-Partner Services and the 1998 HIV Partner Counseling and Referral Services Guidance (1,2). These recommendations are intended for health department program managers responsible for overseeing partner services programs for HIV infection and the three other STDs at the state and local levels. The recommendations also might be beneficial for HIV prevention community planning groups, STD program advisory bodies, technical assistance providers, community-based organizations, and clinical care providers. The value of partner services in the control of syphilis and gonorrhea is widely accepted. However, such services are underused among partners of persons with HIV infection. On the basis of evidence of effectiveness and cost-effectiveness of these services, CDC strongly recommends that all persons with newly diagnosed or reported HIV infection or early syphilis receive partner services with active health department involvement. Persons with a diagnosis of, or who are reported with, gonorrhea or chlamydial infection also are suitable candidates for partner services; however, resource limitations and the numerous cases of these infections might preclude direct health department involvement in certain instances. Health departments might need to limit direct involvement in partner services for gonorrhea and chlamydial infection to selected high-priority cases and use other strategies for the remainder (e.g., expedited partner therapy). These recommendations highlight the importance of program collaboration and service integration in the provision of partner services. Because coinfection with HIV and one or more other STDs is common, all persons with a diagnosis of HIV should be tested for other types of STDs, and vice versa; rates of coinfection with HIV and syphilis have been particularly high in recent years. Many persons at risk for these infections also are at risk for other infectious diseases, such as tuberculosis and viral hepatitis, as well as various other health conditions. STD and HIV partner services offer STD, HIV, and other public health programs an opportunity for collaboration to deliver comprehensive services to clients, improve program efficiency, and maximize the positive effects on public health.# Introduction determining the role of expedited partner therapy for partners of patients with gonorrhea or chlamydial infection. To reduce Inconsistencies in the partner services module of the CDC duplication and discrepancies, incorporate new information, 2001 Program Operations Guidelines for STD Prevention and and address emerging challenges, this report integrates the 1998 HIV Partner Counseling and Referral Services Guidance guidelines for partner services for HIV infection, syphilis, (1,2) have been confusing for providers of partner services for gonorrhea, and chlamydial infection into a single set of human immunodeficiency virus (HIV) infection and three recommendations. These updated, integrated recommendations other sexually transmitted (STDs) for which partner services are often provided: syphilis, gonorrhea, and chlamydial serve as a basis for delivery of partner services and related infection. In addition, new information has become available training and technical assistance. through research and program experience, new technologies These recommendations are intended for health department are available (e.g., rapid HIV tests), and new challenges have program managers responsible for overseeing partner services emerged, such as finding sex partners via the Internet and programs for HIV infection, syphilis, gonorrhea, and chlamydial infection at the state and local levels and were developed to help program managers plan, implement, and # Methods CDC led a work group that planned and coordinated the process of revising and combining the two existing guideline documents into a single set of recommendations. Simultaneously, numerous organizations and experts with potential interest in partner services were notified that the guidelines were being revised and invited to provide input; approximately 70 stakeholder groups were included in this process. In addition, an extensive review was conducted to identify relevant published research. During 2005-2006, CDC sought input from attendees at five national HIV and STD conferences. Detailed reviews of HIV partner services programs were conducted at eight health departments (six state health departments and two city health departments) to identify current program practices and challenges and to obtain input from persons directly involved in delivering partner services. Discussions with focus groups of potential and actual recipients of HIV partner services were held in five cities to elicit information about experiences with and perceptions of these services. In addition, discussions with focus groups of private clinicians were held in seven cities to assess their level of awareness and understanding of partner services and their perceptions of the importance and effectiveness of such services. Finally, a detailed review was conducted of state laws related to HIV partner services to identify legal concerns and provide a framework of the legal and regulatory environment in which partner services are delivered. A draft of recommendations was developed and in November 2006, a meeting was convened in Atlanta, Georgia, to obtain input. The meeting was attended by approximately 70 participants from 23 states and the District of Columbia (DC). Participants included representatives of other federal agencies; state and local HIV and STD health department directors, program managers, and staff members; academic research experts; ethicists; representatives from legal, medical, and other professional organizations; and representatives from CBOs, correctional facility health organizations, community advocacy groups, and training centers with expertise in partner services. After the meeting, CDC convened seven workgroups, which included CDC staff members and non-CDC participants recruited from the meeting, to revise the draft of the recommendations based on input from meeting participants. In January 2008, a revised draft was distributed for review to federal agencies, health departments, academic and research centers, professional organizations, CBOs, and community advocacy groups. In compliance with requirements of the Office of Management and Budget for influential scientific assessments, CDC also solicited reviews from nonfederal subject-matter experts. The recommendations were revised after reviewer comments were received. # How These Recommendations Differ from Previous Partner Services Guidelines These recommendations integrate previously separate guidelines for partner services for HIV infection, syphilis, gonorrhea, and chlamydial infection into a single set of recommendations; a complete summary of these new recommendations is provided (Appendix A). These recommendations have increased emphasis on the following: • integration of services at the client level; • linkage between surveillance and program activities to help ensure that partner services are offered to all persons who test positive for HIV and early syphilis; • direct public health program involvement in partner ser vices as quickly as possible after diagnosis; • rationale for selection of the preferred notification strat egy for each disease; • active linkage to medical and prevention services for per sons identified as infected with HIV; • collaboration with internal and external partners involved in all aspects of partner services, including ensuring that partner services are available for all HIV-infected persons throughout the prevention and care continuum; • program monitoring and evaluation and quality improve ment; and • a focus on which types of activities HIV and STD pro grams should be performing rather than precisely how they should be performing them The 1998 HIV Partner Counseling and Referral Services Guidance used the term partner counseling and referral services rather than contact tracing or partner notification to describe the type and range of public health services recommended for sex and drug-injection partners of HIV-infected persons (2). The 2001 Program Operations Guidelines for STD Prevention used the term partner services to describe similar activities (1). This report uses the term partner services to describe services offered to persons with HIV or other STDs. The term partner services is broad and encompasses services typically included in partner counseling and referral services and other services (e.g., screening for other STDs, screening for chronic infection with hepatitis B virus [HBV] and hepatitis C virus [HCV], and vaccination for hepatitis A virus [HAV] and HBV). In addition, the principles of notifying an exposed person do not differ substantially among diseases, and persons with STDs other than HIV often need the same array of services as persons with HIV infection. Using the same term for partner services for HIV and other STDs emphasizes these points. # Terminology Many terms used in this report are familiar to persons with experience in partner services for HIV and other STDs; however, certain terms might be used differently than they were in previous guidelines, and certain new terms are used. Following are terms used frequently in this report; a glossary and list of abbreviations also are provided (Appendices B and C). • Client, patient. These recommendations include both terms, depending on context. In certain instances, the term patient best describes a person receiving a service (e.g., a person being treated for an infection), whereas in other situations, the term client is a better descriptor of a person receiving services (e.g., a person receiving referral services). • Index patient. Person with newly diagnosed or reported STDs/HIV infection. • Partner. For persons with syphilis, gonorrhea, or chlamydial infection: refers to sex partners (i.e., persons with whom an index patient has had sex at least once); for persons with HIV infection: refers to sex and druginjection partners (i.e., persons with whom an index patient has had sex or shared drug-injection equipment at least once). • Drug-injection partner. A person with whom an index patient shares drug-injection equipment (e.g., needles, syringes, cottons, cookers, or rinse water). • Disease intervention specialists (DISs). Health department personnel who are specifically trained to provide partner services. Some health departments use different titles for persons providing partner services. In addition, in certain jurisdictions, other persons (e.g., HIV counselors or clinicians) either inside or outside of the health department provide certain or all elements of partner services. • Provider referral. Partner notification carried out by health department staff members. • Third-party referral. Partner notification carried out by professionals other than health department staff members (e.g., HIV counselors or clinicians who are not part of a health department). • Social contacts. Persons who are named by index patients as part of their social network but who are not sex or drug-injection partners. Social contacts were referred to as suspects in previous STD partner services guidelines. # Definition and Overview of Partner Services Partner services are a broad array of services that should be offered to persons with HIV infection, syphilis, gonorrhea, or chlamydial infection and their partners. A critical function of partner services is partner notification, a process through which infected persons are interviewed to elicit information about their partners, who can then be confidentially notified of their possible exposure or potential risk. Other functions of partner services include prevention counseling, testing for HIV and other types of STDs (not necessarily limited to syphilis, gonorrhea, and chlamydial infection), hepatitis screening and vaccination, treatment or linkage to medical care, linkage or referral to other prevention services, and linkage or referral to other services (e.g., reproductive health services, prenatal care, substance abuse treatment, social support, housing assistance, legal services, and mental health services). The rationale for use of partner services is that appropriate use of public health resources to identify infected persons, notify their partners of their possible exposure, and provide infected persons and their partners a range of medical, prevention, and psychosocial services can have positive results including 1) positive behavior changes and reduced infectiousness; 2) decreased STD/HIV transmission; and 3) reduced STD/HIV incidence and improved public health (Figure 1). The value of partner notification in the control of syphilis and gonorrhea is widely accepted (3). In recent times, syphilis prevalence peaked in approximately 1990, resulting in a concerted national attempt to apply public health resources, including partner services, toward its reduction and, later, elimination (4). Subsequently, syphilis prevalence decreased to historic lows (approximately 6,000 primary and secondary cases in 2000). Cost data from the early 1990s on syphilis partner services suggest costs per partner treated are commensurate with current costs of other syphilis-elimination strategies in the United States (5). However, recent increases in primary and secondary syphilis cases to approximately 10,000 cases in 2007 indicate that continued vigilance in syphilis control is needed. In New York, notification and referral services for gonor rhea have targeted specific geographic areas with notification services rather than attempting to interview all index patients and notify all partners in person. Evaluation of 10 years of data from the New York program, as well as of other program data, has shown a reduction in gonorrhea prevalence (6,7). Treatment of partners is valuable for control of chlamydial infection and cost-effective in averting sequelae. When used, partner services via provider referral seems to identify enough infected partners to decrease transmission and therefore pro mote infection-control measures, and more partners are treated through partner services than through other strategies (8)(9)(10). However, provider referral coverage for chlamydial infection is low and not a significant contributor to controlling this infec tion (8,11,12). For example, one survey indicated that only 12% of patients with chlamydial infection were interviewed by health department staff members about their partners (13). Partner services can play an essential role in preventing and controlling HIV in the United States. Of approximately 1-1.2 million persons living with HIV infection in the United States, approximately 25% are not aware of their infection; transmission from persons not aware of their infection accounts for 54%-70% of new infections (14,15). Partner notification, a critical component of partner services, effectively identifies persons with previously undiagnosed HIV infection. A review of the case-finding effectiveness of partner notification found that among partners for whom notification was initiated, the median percentage with newly diagnosed cases was 8%, approximately the same as for syphilis (8); in the reports included in this review, eight index patients were interviewed for partner notification to discover one newly diagnosed case of HIV, on average. A systematic literature review conducted for the Task Force on Community Preventive Services found that among the nine studies included, a range of one to eight partners was identified per index patient with HIV infection, a mean of 67% of partners were notified of their exposure to HIV, a mean of 63% of persons notified of exposure were tested, and a mean of 20% of those tested were newly diagnosed as infected with HIV (range: 14%-26%). On the basis of this review, the task force concluded that sufficient evidence exists to demonstrate that partner services, with partner notification by a public health professional, increases identification of a high-prevalence population for HIV testing and increases the identification of HIV-infected persons (16,17). Although limited, additional data also suggest that HIV partner services are cost-effective (18)(19)(20)(21)(22). Despite the potential benefits, HIV partner services are highly underused (23). The services are more frequently provided to persons who receive diagnoses in publicly funded HIV testing sites than outside of public health sites (23). On the basis of evidence of the effectiveness and costeffectiveness of partner services, CDC strongly recommends that all persons with newly diagnosed or reported HIV infection or early syphilis receive partner services with active health department involvement. All persons who receive a diagnosis of or who are reported with gonorrhea or chlamydial infection also are suitable candidates for partner services; however, high numbers of cases and resource limitations might preclude direct health department involvement in all instances. Health departments might need to limit their direct involvement in partner services for gonorrhea and chlamydial infection to selected high-priority cases and use other strategies for the remainder. # Principles of Partner Services The following principles serve as the foundation for providing partner services to persons with HIV infection or other STDs and their partners: • Client centered. All steps of the partner services process should be tailored to the behaviors, circumstances, and specific needs of each client. • Confidential. Confidentiality should be maintained and is essential to the success of partner services. Confidentiality also applies to data collected as part of the partner services process. When notifying partners of exposure, the identity of the index patient must never be revealed, and no information about partners should be conveyed back to the index patient. • Voluntary and noncoercive. Participating in partner services should be voluntary for both infected persons and their partners; they should not be coerced into participation. • Free. Partner services should be free of charge for infected persons and their partners. • Evidence based. Partner services should be as evidence based as possible. • Culturally, linguistically, and developmentally appropriate. Partner services should be provided in a nonjudgmental way and be appropriate for the cultural, linguistic, and developmental characteristics of each client. • Accessible and available to all. Partner services should be accessible and available to all infected persons regardless of where they are tested or receive a diagnosis and whether they are tested confidentially or anonymously. Because of the chronic nature of HIV infection, partner services for HIV should not be a one-time event. They should be offered as soon as HIV-infected persons learn their serostatus and should be available throughout their counseling and treatment. HIV-infected persons should have the ability to access partner services whenever needed. • Comprehensive and integrative. Partner services should be part of an array of services that are integrated to the greatest extent possible for persons with HIV infection or other STDs and their partners. # Goals of Partner Services The goals of partner services for infected persons, their partners, and the community are as follows: • Infected persons -Maximize access to partner services by providing all infected persons with support to ensure that the partners are confidentially informed of their exposure. -Maximize effective linkage to medical care, treatment, prevention interventions to reduce the risk for transmission to others, and other services. • Partners of infected persons -Maximize the proportion of partners who are notified of their exposure. -Maximize early linkage of partners to testing, medical care, prevention interventions, and other services. • Community -Reduce future rates of transmission by aiding in early diagnosis and treatment (or linkage to treatment, for those with HIV infection) and provision of preven tion services to infected persons. # Benefits of Partner Services Partner services programs offer substantial benefits to three principal groups: persons infected with HIV infection or other STDs, their partners, and the community (Figure 1). A primary benefit for index patients is that DISs can help them ensure that partners are notified of their possible exposure to the infection, while protecting the confidentiality of the patients. For index patients who expect to notify partners themselves, DISs can provide coaching and assistance with this process and provide support if the index patient is unable to complete the notification successfully. In addition, when interviewing index patients, DISs can assess whether they have been adequately treated or linked to appropriate medical and prevention services and, for those who have not, facilitate access to these services. DISs also can assess whether index patients need other services (e.g., reproductive health services or substance abuse treatment) and make appropriate referrals for such services. Finally, when persons are repeatedly reported as index patients for syphilis or gonorrhea or have been previously reported with HIV infection, DISs can provide additional prevention counseling or help them access more intensive riskreduction interventions. For persons having difficulty achieving and maintaining behavior changes, these services can help develop skills to reduce their risk for repeatedly acquiring new STDs or transmitting HIV to current or future partners. Partners of persons with HIV infection or other types of STDs are at high risk for infection, as indicated by the high prevalence of infection among notified partners (8,16). In the case of HIV, many partners are not aware of their risk and have never been tested for HIV (24). Partner services provide a confidential process for these persons to become aware of their risk and access appropriate diagnostic, treatment, and prevention services. Recently exposed partners of persons with early syphilis and gonorrhea who do not yet have evidence of infection can be treated preventively, and partners with evidence of infection can be treated for cure. All partners can be assessed to determine whether they need other services (e.g., reproductive health services or substance abuse treatment) and receive appropriate referrals. Partner services might also benefit the community by helping reduce transmission rates, reducing effects of disease, and facilitating earlier identification and treatment of previously undiagnosed STDs/HIV infection among its members. Demonstrating that a specific prevention intervention (e.g., comprehensive risk counseling and services) reduces transmission rates at the community level is difficult. Nevertheless, studies have demonstrated that 1) quality prevention counseling can reduce risk for acquiring a new STD, 2) behavioral interventions can reduce transmission risk behaviors, and 3) persons with HIV infection who are aware of their infection have substantially lower levels of transmission risk behaviors than those who are not aware (15,(25)(26)(27)(28)(29)(30)(31). Thus, by increasing access to prevention counseling and other prevention interventions and by providing counseling and testing to persons at very high risk for infection (i.e., known partners of infected persons), partner services should result in lower transmission rates. In addition, by reducing the viral load in HIV-infected persons to undetectable levels, antiretroviral therapy (ART) likely reduces (but does not eliminate) infectiousness and risk for sex-and injection-related transmission (32)(33)(34)(35)(36)(37). Therefore, identifying persons with previously undiagnosed HIV infection and linking them to medical care services, and possibly to ART, also might reduce transmission within the community. Finally, partner services can improve disease surveillance and identify sex and druginjection networks at high risk for infection that can then be targeted for screening and prevention services (38). # Challenges for Partner Services Challenges for partner services include whether the services will be accepted by patients, the potential for abuse resulting from partner notification, and potential negative effects on relationships after partner notification. DIS training includes methods to maximize acceptability of partner services among patients. A recent systematic review of the acceptability of HIV partner counseling and referral services found that among participants in the studies reviewed, 1) the majority of surveyed potential clients (i.e., HIV-positive or HIV-negative persons who had no direct experience with HIV partner counseling and referral services) indicated that they would be willing to participate in client referral (i.e., notify a partner themselves); 2) most potential clients would be willing for health department personnel to notify their partners; 3) the majority of HIV-positive clients receiving partner counseling and referral services used provider referral to notify one or more partners; 4) the majority of partners either wanted to be notified or were comfortable with a health-care provider notifying them; and 5) the majority of providers were in favor of partner notification (39). The high level of acceptability of HIV partner services among diverse groups suggests that, when provided appropriately, they are considered a service rather than an imposition by those for whom they are intended. A second challenge is the potential for emotional or physical abuse by or against the index patient as a result of partner notification. Available data suggest that the rate of violence attributable to partner notification is likely low; however, data are limited, and additional study is needed (40)(41)(42)(43). A third frequently cited challenge is the potential negative effect of partner notification on relationships (e.g., dissolution of a long-standing relationship) (39,40,44). In one study, the rate of partnership dissolution was 46.8% among partnerships involving syphilis or HIV cases, with no significant difference between the two infections; however, the rate was lower in partnerships for which partner notification was completed than in those for which notification was not completed (24.3% and 75.7%, respectively) (40). A similar study addressing the effect of HIV partner notification on partnership dissolution MMWR November 7, 2008 found that although the rate of partnership dissolution was high (65% at 6 months postinterview), the rate was not increased by partner notification (44). Study design and low enrollment make drawing firm conclusions from these studies difficult; however, the studies suggest that partner notification itself does not increase rates of partnership dissolution. # Legal and Ethical Concerns Well-implemented partner services balance the interests of infected persons, their partners, and the community. Describing a single plan for successfully balancing the interests of all involved parties is difficult because the legal context within which partner services programs operate varies among states and jurisdictions. Nonetheless, recognition of and adherence to certain principles is essential for all partner services programs. This report does not include a comprehensive discussion of all areas of law relevant to partner services. Program managers should consult with the legal counsel of their agency to gain a thorough understanding of the legal framework in which their specific programs operate, including their own legal authorities and those of other agencies (e.g., law enforcement) with whom they might interact. These CDC recommendations should not be taken as legal advice or as CDC interpretation of the laws of any jurisdiction. # Legal Authorities States hold the legal authority for the notification and referral of partners of persons with HIV infection and other types of STDs. One federal law specifically addresses HIV partner notification services for spouses: the Ryan White CARE Act Amendments of 1996 (Pub. L. No. 104-146 [May, 2, 1996]) require that states receiving funds under part B of title XXVI of the Public Health Service Act (42 U.S.C. Sect. 300ff-27a [1996]) take "administrative or legislative action to require that a good faith effort be made to notify a spouse of a known HIV-infected patient that such spouse might have been exposed to the human immunodeficiency virus and should seek testing." A spouse is defined as any person who is the marriage partner of an HIV-infected patient or has been the marriage partner of that patient at any time within the 10-year period before the diagnosis of HIV infection. # Voluntary and Informed Nature of Participation in Partner Services Participation in partner services is voluntary only if it is informed and not coerced. The effectiveness of partner services as a public health intervention relies on the voluntary cooperation and participation of index patients, partners, social contacts, and associates. These persons voluntarily choose to 1) provide information about themselves and others in response to questions and requests from a DIS; 2) notify others of their possible exposure to HIV, syphilis, gonorrhea, or chlamydia; 3) accept STD/HIV testing and treatment; and 4) engage in behaviors that promote health and reduce risk for transmission or acquisition of HIV infection and all other types of STDs. Ethically, for a public health official or health-care provider to coerce, deceive, or withhold information from persons to influence them to take any of these actions is inappropriate. In addition, persons who believe that they are being coerced might lie or withhold information. These considerations do not preclude use of persuasive reasoning to gain the cooperation of index patients and others and to motivate them to participate actively in partner services. However, for partner services to be truly voluntary, all persons should be clearly informed of the known benefits and risks for themselves and others that might result from their participation. # Confidentiality In the context of partner services, confidentiality refers to keeping information obtained from or about index patients, partners, social contacts, and associates in confidence; information is not divulged to others or obtained or maintained in a way that makes it accessible to others. The concept of confidentiality is related to privacy, which might be a legal right in certain instances. That is, laws might prohibit forcing persons to reveal certain types of information, and persons who decline to provide certain types of information are not prevented from receiving services. When a person agrees to disclose private information, especially in the context of a service aimed at helping others, such information should be held in strict confidence, both because of its private nature and as a sign of respect for the person who is volunteering to share the information. Research has demonstrated that the degree to which confidentiality is maintained by partner services programs is an important determinant of the acceptability of those services to clients and client willingness to participate in partner services (39,(45)(46)(47). Real or perceived breaches of confidentiality can endanger persons being served, who might face stereotyping; social isolation; loss of social or financial support; barriers to accessing housing, employment, and various social and medical services; and physical or emotional abuse (48,49). Such breaches also can undermine community trust in and access to essential public health programs and services. For these reasons, policies and procedures for protecting confidentiality are critical. State laws generally protect the confidentiality of all STD information, including information related to HIV and acquired immunodeficiency syndrome (AIDS). In certain states, specific laws or regulations prescribe the parameters of information to be kept confidential and establish penalties for confidentiality breaches. Although confidentiality is a central principle of partner services, it is subject to legal exceptions such as those stipulated in certain duty-to-warn laws, which in certain situations require medical or public health officials to notify known partners who are at risk for infection, even against the specific wishes of the index patient. Confidentiality also is subject to practical limits, including the possibility that partners might guess the identity of the index patient at any point during the process. Because partner services programs cannot absolutely guarantee patient or partner anonymity, health officials must make all reasonable attempts to ensure that the confidential nature of communication with a DIS is respected and protected to the fullest extent allowed by law. # Duty and Privilege to Warn The legal duty to warn has its foundation in a 1976 case, Tarasoff v. Regents of the University of California, in which the family of a murdered woman sued because the killer's therapist did not warn their daughter that his patient planned to kill her (49). The Tarasoff decision indicates that a patient's intention to seriously harm another person could result in a provider's duty to warn. The Tarasoff decision does not overshadow the importance of confidentiality and trust in a therapeutic relationship but emphasizes that the threatened harm must be serious, imminent, targeted at an identified (or identifiable) person, and articulated in the context of an existing therapeutic relationship. At the state level, the legal concept of the duty to warn is complex; consultation with legal counsel is necessary. Certain states have laws requiring practitioners (directly or with the assistance of public health authorities) to warn persons they know to be at risk for infection with a communicable disease, an STD, or HIV by their patients. Many other states have laws permitting but not requiring practitioners to warn persons that they are at risk (i.e., privilege to warn). DISs generally must avoid disclosing the name of an index patient. However, because cases involving duty to warn require the health-care providers to provide sufficient information for partners to protect themselves, situations involving a duty to warn might require a provider to reveal the name of an index patient to at-risk partners, thereby breaching the confidential relationship between the provider and the patient (50). Programs that too readily assume that the duty to warn is applicable in a specific case and alert partners against the will of or without the knowledge of an index patient might find future patients reluctant to be honest about sexual or drugsharing activities or unwilling to accept testing or medical care. In such situations, important opportunities for counseling, support for disclosure, and prevention education might be lost. Accordingly, health-care providers and public health program managers should proceed cautiously and seek legal counsel before assuming that a duty to warn has been triggered or that they have a privilege to warn. # Criminal Transmission and Exposure Despite extensive education and counseling to prevent transmission and acquisition of HIV infection and other types of STDs, certain persons persistently engage in behaviors that put themselves and others at risk for infection. Certain criminal laws of general application, such as assault, battery, or reckless endangerment laws, might be used to prosecute a person who intentionally exposes another person to infection. However, many states have enacted criminal laws focusing either specifically on HIV transmission or generally on transmission of sexually transmitted infections. These laws vary according to several factors, including 1) which types of conduct are considered criminal (e.g., with HIV, most states proscribe engaging in conduct that exposes someone else to HIV rather than limiting liability to situations in which transmission has occurred) (51); 2) the specificity with which the proscribed conduct is described (e.g., most statutes that consider exposing someone to HIV to be a criminal act do not define exposure, although certain statutes specifically proscribe exposure by transfer of body fluids or tissues, engaging in sexual activities, or needle sharing) (51); and 3) the knowledge required (e.g., for exposure to be considered criminal, almost all states require that infected persons who expose another person to HIV must have had knowledge of being infected with HIV) (51). Laws might also vary depending on whether disclosure of HIV status before engaging in the conduct 1) means that no crime has been committed, 2) is an affirmative defense that can be raised by a person charged with criminal transmission or exposure, or 3) means that the person is not legally liable. Depending on the unique circumstances of each case, options available to partner services program managers in cases involving persons who persistently engage in behaviors that put themselves and others at risk might include 1) initiating increasingly intensive prevention interventions (e.g., comprehensive risk counseling and services); 2) facilitating access to HIV primary care; 3) arranging linkage to substance abuse treatment, mental health services, or other relevant services; 4) initiating epidemiologic investigation of situations involving possible exposure of persons to infection; and 5) seeking legal advice when public health interventions are not sufficient or appropriate. Determining the most appropriate course of action requires consideration of the details of the specific situation; every case must be managed carefully and confidentially. # Recommendations for Legal and Ethical Concerns • Public health agencies responsible for partner services should conduct a thorough review of all laws relevant to their provision of these services. This review should serve as a basis for developing policies and procedures for partner services programs. Program managers should also ensure that program staff members understand the implications these laws have for conducting partner services. Laws relevant to provision of these services include the following: -the legal authority for the public health agencies for partner services; -provisions related to privacy and confidentiality (e.g., requirements of the federal Health Insurance Portability and Accountability Act [HIPAA]); -provisions related to duty or privilege to warn and criminal transmission and exposure; and -the ability of the public health agencies to coordinate with other agencies (e.g., law enforcement). • Program managers should ensure that their staff members understand the legal basis for their work, legal restrictions on their practice (e.g., duty or privilege to warn), the extent to which they are protected from civil litigation, and how to coordinate with law enforcement officials in ways that protect the civil and procedural rights of the persons involved. • To ensure that program staff members invoke their duty or privilege to warn appropriately, partner services programs should have written policies and procedures to guide staff members in handling complex cases. Guidelines and protocols should be based on the jurisdiction's statutory and case law and developed in consultation with legal counsel. Legal counsel should also be consulted regarding specific cases in which duty to warn or privilege to warn might apply. • Program managers should be aware of the applicable laws regarding criminal transmission and exposure in their jurisdictions and should coordinate with legal counsel regarding specific cases in which allegations of criminal transmission or exposure are made. # Elements of Partner Services Partner services include several essential elements (Figure 1). In general, these elements are relevant for partner services for HIV, early syphilis, gonorrhea, and chlamydial infection, although differences in how they are implemented vary by infection. Program managers should ensure that policies and procedures adequately address each of these elements. # Index Patients • identifying index patients (i.e., infected persons who are candidates for partner services) and prioritizing them for partner services; • introducing partner services to index patients and conducting interviews to elicit information about their partners; • counseling index patients about reducing their risk for acquiring or transmitting infection to others and referring them for additional prevention services, if needed; • treating index patients or linking them to medical care and treatment; and • referring index patients to other services. # Partners • notifying partners of their exposure; • counseling partners about reducing their risk for acquiring HIV infection and other types of STDs and referring them for additional prevention services, if needed; • offering partners STD/HIV testing; • treating partners or linking them to medical care and treatment; and • referring partners to other services. # Identifying Index Patients Identifying persons who are candidates for partner services (i.e., index patients) is a critical step in the partner services process. For early syphilis and, in certain instances, gonorrhea, standard identification of index patients occurs 1) when persons seek care with no prompting (i.e., volunteers) and 2) when persons receive screening or testing and their case reports are provided to STD programs for treatment, case management, and partner services. For early syphilis, public health records indicate that since the 1940s, index patients routinely have been interviewed and their partners followed. In modern times, a survey of partner notification for STDs/ HIV found that 89% of syphilis-infected persons in highmorbidity geographic areas were interviewed (13). The same survey found that a markedly lower proportion (17%) of persons with gonorrhea were interviewed, although certain jurisdictions still attempt to interview all patients with gonorrhea. Other jurisdictions that lack resources to interview all patients with gonorrhea have focused their interviews on patients in high-morbidity areas (i.e., core areas) (7). Interview strategies for chlamydial infection tend to be similar to those for gonorrhea, although interviews are generally considered lower priority than interviews for gonorrhea. Among highmorbidity jurisdictions in a survey of STD/HIV partner services, only 12% of persons with chlamydial infection were interviewed (13). The workload for health departments is related to the number of cases reported, which is an essential factor affecting approaches to partner services for early syphilis, gonorrhea, and chlamydial infection. During 2000-2007, fewer than 50,000 cases of early syphilis (i.e., primary, secondary, and early latent) were diagnosed each year. In contrast, estimates of annual prevalence of gonorrhea and chlamydial infection are one to two orders of magnitude higher (52,53), far too many patients for public health staff members, at the current staffing level, to interview directly. Available evidence suggests that the majority of HIV-infected persons are not interviewed for HIV partner services. A survey found that in 22 jurisdictions with HIV reporting, health departments interviewed 32% of 20,353 persons with newly reported HIV infection (23). Active strategies for identifying more candidates for partner services are needed. Because an extensive literature search did not identify any published studies or program evaluations that examined this topic, recommendations in this report for identifying HIV index patients were based on input from consultants with partner services expertise. For HIV, although the main emphasis of partner services programs should be on persons with newly diagnosed or reported infection, partner services also might be appropriate for persons with previously diagnosed infection on an as-needed basis (54). some or all HIV partner services might be provided exclusively by HIV program staff members. In these situations, managers of both programs should establish policies and procedures to ensure that persons with a diagnosis of HIV infection, syphilis, gonorrhea, or chlamydial infection by either program receive appropriate partner services. Systems also are needed to ensure that persons with a diagnosis of HIV infection or any of these three other STDs in other health department clinics (e.g., tuberculosis [TB] or reproductive health clinics) are linked to the partner services program. Certain patients receive a diagnosis of HIV infection and of another STD simultaneously. Policies and procedures are needed to ensure that these patients and their partners receive partner services for both infections from only one DIS to improve services for the patients and partners and maximize program resources. Identification of syphilis cases can be complicated because treated and noninfectious persons can have reactive syphilis tests indefinitely. Titration of the rapid plasma reagin (RPR) test can yield elevated RPR titers for persons who have already been treated and clinically cured of syphilis. Therefore, CDC encourages programs to use syphilis treatment registries and algorithms for prioritizing follow-up investigations of persons with reactive syphilis tests (i.e., reactors). A syphilis reactor grid is constructed from a combination of quantitative test results, age, and sex to identify which persons with reactive tests are most likely to be both untreated and infectious. Individual programs vary in precisely how they use a reactor grid but generally investigate all persons with RPR titers higher than a specified level, all persons younger than a certain age, and persons most at risk for negative outcomes (e.g., pregnant women). A recent evaluation of syphilis reactor grids suggested that most missed cases of early syphilis were among men aged 30-50 years and women aged 20-40 years with low RPR titers (55). # Diagnoses Received in Settings Other than Health Department Clinics Most types of STDs are frequently diagnosed in settings other than health departments (56), such as public hospitals and clinics, private hospitals and medical practices, community health centers, Veterans Administration health-care facilities, Indian Health Service and tribal health-care facilities, correctional facilities, CBOs, reproductive health service organizations, substance abuse treatment centers, and student health centers. In particular, chlamydial infection and gonorrhea are more frequently diagnosed in private care settings. Reporting delays, especially for cases diagnosed when patients are the most infectious, diminish the effectiveness of partner services in infection control. Approximately 90% of all HIV tests and 70% of positive HIV tests are performed in settings other than health department clinics (57). # MMWR November 7, 2008 Persons diagnosed in settings other than health department clinics might not be directly linked to partner services if the provider does not notify the partner services program; therefore, program managers should establish strategies for rapidly identifying these persons and offering them partner services. This can be accomplished by linking disease reporting systems and partner services programs, conducting active outreach to service providers (e.g., physicians and health-care facilities that frequently diagnose STDs/HIV infection, HIV counseling and testing providers, and case managers) and diagnostic laboratories, or using a combination of these strategies. Each strategy has potential advantages and disadvantages. For example, linking disease reporting activities and partner services programs might maximize the number of newly diagnosed persons identified for partner services, but reporting delays might reduce the timeliness with which partner services are initiated. In contrast, active outreach to health-care providers might improve the timeliness of partner services but result in more missed cases because reaching all providers is difficult. For most programs, a combination of these two strategies will likely be most effective. Program managers might also develop other strategies for identifying persons with newly diagnosed infection. Strategies should be monitored for how effectively they identify index patients and the timeliness with which they provide services. Linkage with Disease Reporting. For surveillance purposes, cases of HIV/AIDS and other STDs might be reported to health departments by service providers (e.g., clinicians or CBOs providing testing services), diagnostic laboratories, or both. Data collected through HIV/AIDS and STD surveil lance systems are used for many complementary public health purposes at the national, state, and local levels. Examples of such uses include disease monitoring, estimating incidence of infection, identifying changing trends in transmission, tar geting and evaluating prevention interventions, and allocat ing funds for care and prevention services. Certain states and territories also use case reports to initiate partner services for infected persons and offer referrals for prevention, medical care, and supportive services. In 2007, the Council of State and Territorial Epidemiologists (CSTE) conducted a national assessment of HIV/AIDS surveillance capacity and training by surveying HIV surveillance coordinators in 65 state, large city, and territorial health departments. Several questions as sessed current practices regarding use of HIV surveillance data to support partner services. Seventy-one percent of respon dents (30 of 42 respondents to the question) reported sharing data in some form with partner services programs; 43% (24 of 56 respondents to the question) reported sharing individuallevel data that included personal identifiers with partner ser vices (CSTE, unpublished data, 2007). Sharing information between HIV/AIDS and STD surveil lance programs and partner services programs is important for comprehensive disease intervention and offers many po tential mutual benefits, including the following: • Surveillance data can provide information about demographic and behavioral characteristics of persons newly diagnosed with HIV, leading to a more complete understanding of the population of persons in need of partner services in both the public and private sectors. • Using surveillance data to initiate partner services can help ensure that partner services are offered to the greatest possible number of newly identified or reported infected persons for whom services are appropriate, thereby supporting the public health goal of maximizing access to partner services. • Linking surveillance and partner services can help ensure that patients who test positive receive and understand their test results, that they receive appropriate treatment or are linked to medical care services, and that they receive appropriate prevention counseling. • Surveillance data can supplement client-level program information regarding demographic and risk characteristics and testing history and inform DISs before initial contact with clients. • Partner services programs can supplement surveillance data by obtaining more complete and accurate demographic and risk information and identifying duplicate reporting. • Sharing information might help streamline surveillance and partner services activities and increase efficiency (e.g., might limit the number of times the same medical record is reviewed or a medical provider is contacted about the same person). • Partner services programs can use surveillance data to identify health-care providers who diagnose and treat persons with HIV infection and other STDs; DISs can then contact these providers and ensure that they are well informed about the benefits of partner services. • Through collaborative relationships with health-care providers, partner services can encourage complete and timely reporting of HIV/AIDS and other STDs. Before using surveillance data to identify candidates for partner services, health departments should consider staffing and resources, relevant state and local laws and regulations, and level of community awareness and acceptance. The organizational structure of the health department also affects the way surveillance and partner services programs interact. For example, health departments in which surveillance and partner services programs are integrated often share staff members, have similar missions, have programmatic and administrative commonalities, and receive oversight from a shared overall responsible party (ORP, an official who has overall responsibility for implementing and enforcing HIV/ AIDS and STD surveillance security standards), all of which might facilitate information sharing for partner services purposes. Potential barriers to sharing surveillance data include a negative impact on provider reporting because of concerns about confidentiality of information, increased workload for surveillance staff members, and, for HIV, perceived negative effects on HIV-testing behaviors of providers or persons at risk for infection. For most STDs, data from a physician survey suggest that although physicians might be reluctant to collect partner services data themselves, they are willing to report cases to health departments to ensure that their patients receive partner services (58). Although the data from this survey do not include HIV, other surveys have found that the majority of health-care providers favor HIV partner notification (39). To facilitate information sharing between partner services and surveillance programs, health departments should review state and local laws and regulations that might apply to data sharing. Engaging key stakeholders such as medical providers, community advocates, and CPGs in the design and implementation of surveillance and partner services data linkage processes can result in support of and success in these measures. Clear, well-defined security and confidentiality policies and procedures that are followed by both surveillance and partner services program staff members increase the likelihood that surveillance data will be kept secure and patient information confidential, leading to patient and medical provider trust and cooperation with partner services programs. Historically, certain programs have limited the sharing of HIV/AIDS surveillance data with partner services programs. In certain situations, programs imposed these limits after collaboration with communities and medical providers on implementation of named-based HIV reporting, which resulted in use of reporting methods that separate surveillance and partner services. When considering changes in data-sharing policies, programs should use the same careful collaboration and deliberation with medical providers and affected communities to prevent erosion of the public trust and of the integrity of the systems already in place. Levels of Surveillance Information. Three levels of sur veillance data can support partner services: 1) individual, 2) provider, and 3) aggregate. These range from very sensitive data requiring high levels of security and confidentiality (in dividual level) to substantially less sensitive data (aggregate level). Individual-level data are the most valuable for immedi ate provision of partner services, although provider-and ag gregate-level data also can be useful. • # Security and Confidentiality. Partner services data for HIV infection and other types of STDs, with or without data ob tained from disease reporting systems, are among the most sensitive public health data routinely collected and should re ceive careful protection. HIV and STD partner services pro grams have an excellent record of maintaining confidentiality, and continued vigilance is critical to future success. Programs considering operational and policy changes, should carefully review the proposed changes to ensure that they will not de crease security or confidentiality. CDC and CSTE have published technical guidance describ ing minimum standards for HIV/AIDS data security and con fidentiality that should be met by surveillance programs; these standards reflect best practices for protecting HIV/AIDS sur veillance data (59). With minor adjustments to accommo date practical realities encountered in many health departments, the same standards should be upheld by any partner services program with which HIV/AIDS surveillance programs share individual-level data (Appendix D). To en sure that appropriate policies and procedures are developed and followed, HIV/AIDS surveillance programs designate an ORP, who is responsible for security of the program's infor mation collection and management systems, including pro cesses, data, information, software, and hardware. Although this guidance was developed specifically for HIV/AIDS sur veillance activities, it might be useful for data and informa tion collected and used by all programs conducting partner services. Outreach to Service Providers and Diagnostic Labora tories. Persons might receive a diagnosis of HIV or other STDs from various service providers outside of health department clinics. In addition to using disease reporting systems to iden tify potential candidates for partner services, programs can collaborate with service providers and diagnostic laboratories to help ensure that persons who receive a diagnosis of STDs/ HIV are linked rapidly to health department partner services programs. Although reaching all service providers is unlikely to be feasible, a small number of providers or laboratories might account for a large proportion of new diagnoses. In this case, health department partner services program managers can collaborate with surveillance coordinators to identify these providers and laboratories to establish procedures for partner services referrals. Certain partner services programs have iden tified health-care facilities that diagnose large numbers of cases and have placed DISs in those facilities to meet with persons with new diagnoses. This strategy might reduce the need for extensive field work to locate individual index patients. How ever, such strategies should be monitored closely to assess their effectiveness and cost-effectiveness; no systematic evaluations of these strategies have been published. CDC recommends that in all health-care settings, volun tary screening for HIV infection should be performed rou tinely for all patients aged 13-64 years unless a patient declines HIV testing or has been tested recently (60). These recom mendations might produce a substantial increase in new HIV diagnoses. Therefore, program managers responsible for HIV partner services should work with health-care providers who implement the screening recommendations and diagnose nu merous HIV-infected persons to help ensure that those per sons are linked to partner services. # Anonymous HIV Testing Anonymous testing accounts for a small but significant pro portion of all HIV tests and might reach a subset of persons who might not otherwise be tested (61,62). Persons who test positive for HIV anonymously should be strongly encouraged to transfer to a confidential system; however, if they decline, HIV partner services can still be offered and performed. Part ner services might be more difficult to provide for persons using anonymous testing than for those using confidential testing. A study in Colorado assessed provider-referral part ner notification for persons who tested HIV positive during October 1990-March 1992 at a single anonymous test site in Denver and 13 confidential test sites throughout the state (63). The average number of named, notified, and counseled part ners was 30%-50% greater among index patients tested at sites offering confidential testing than among those tested at sites offering anonymous testing. A North Carolina study found that the number of partners notified and counseled per index patient interviewed was 2.7 times greater for index pa tients tested confidentially compared with those tested anony mously (64). A literature review of this topic indicated that two to three times more partners are notified when persons are tested confidentially than when they are tested anony mously (8). However, one study, conducted by the Multistate Evaluation of Surveillance for HIV Study Group in five states with name-based HIV reporting, found no difference in the number of notified partners between persons who were tested anonymously and those tested confidentially (65). Therefore, program managers who are responsible for HIV partner ser vices should work with providers who offer anonymous HIV testing to develop strategies for offering and providing part ner services to persons who test positive anonymously and elect not to enter a confidential system. (54). These recommendations urge HIV clinical care providers to 1) ask patients at the initial visit whether all their partners have been informed of their exposure to HIV; 2) regularly screen patients for HIV transmission risk behaviors, STDs, and pregnancy; 3) inquire at routine follow-up visits whether patients have had any new sex or drug-injection partners who have not been informed of their exposure; and 4) refer patients to the appropriate health department to discuss partners who have not been informed of their exposure and arrange for their notification and referral for HIV counseling and testing. Program managers responsible for HIV partner services can work actively with HIV clinical care providers and case managers to engage them in identifying patients who need partner services, offering them these services, and linking them to health department DISs when indicated. Persons who previously received a diagnosis of HIV also might be named as partners in the course of conducting partner services with other index patients. These persons should be interviewed to assess behavioral risk, provided partner services, and referred for more intensive prevention interventions, when indicated. # Recommendations for # IV Infection • HIV partner services programs should collaborate with health-care providers who provide HIV screening or testing, other HIV counseling and testing providers, HIV care providers, and HIV case managers to ensure that their clients and patients are offered HIV partner services as soon as possible after diagnosis and on an ongoing basis, as needed. # H • HIV partner services programs should work with providers of anonymous HIV testing services to develop strategies for providing partner services to persons who test positive, even if the person decides not to enter a confidential system. These providers should be trained on how to offer partner services and elicit partner information from persons with newly diagnosed HIV infection. # Prioritizing Index Patients All persons with newly diagnosed or reported HIV infection or early syphilis should be offered partner services and prioritized for interview, although some of these patients have a higher priority than others. Because of the high incidence of gonorrhea and chlamydial infection in many jurisdictions, attempts to reach and interview all patients might be hampered by various factors, including insufficient funds and staffing. Therefore, for these infections, programs might need to use partner services strategies that do not require interviews by DISs, focusing their interviewing on specific subsets of patients. To maximize available resources, programs should establish criteria for determining which index patients are prioritized for interview. In general, these criteria should include behavioral and clinical factors that affect the likelihood of additional transmission and, thus, increase the epidemiologic consequences of delayed receipt of partner services. This information might not be known until the index patient is interviewed; however, it might be available from the diagnosing clinician or counselor or through record review. Criteria for prioritizing index patients vary somewhat according to the infection involved. Program effectiveness and efficiency can be improved by periodically reviewing and adjusting criteria for prioritizing index patients for partner services. The following categories of persons are considered highpriority index patients for partner services, regardless of the infection involved: • Pregnant women and male index patients with pregnant partners. Pregnant women are at risk for transmitting HIV and other types of STDs to their fetus both in utero and during delivery. Newborns also are at risk for becoming infected with HIV through breastfeeding. Prioritizing pregnant women for interview gives DISs an opportunity to verify that the women have received appropriate treatment or, for those with HIV infection, have been successfully linked to medical services so that they can be treated with ART to reduce the risk for mother to-child transmission. • Index patients suspected of or known to be engaging in behaviors that substantially increase risk for # Syphilis, Gonorrhea, and Chlamydial Infection The following categories of persons also are considered high-priority index patients for partner services for syphilis, gonorrhea, and chlamydial infection. • Persons with clinical signs or symptoms suggestive of infection. Symptomatic persons have a high risk for disease transmission (68,69). Presence of clinical symptoms suggests recent sexual exposure and risk behavior, so partner services programs might have an opportunity for a primary disease intervention. • Infected persons from core areas. Prioritizing gonorrheainfected persons from core areas might offer an opportunity to reduce transmission at the community level. # HIV Infection The following categories of persons also are considered highpriority index patients for partner services for HIV. • # Interviewing Index Patients With the exception of interview period and timing of interviews, the following information is applicable to partner services for HIV infection, early syphilis, gonorrhea, and chlamydial infection. The success of partner services depends on the cooperation of index patients. If index patients do not provide complete, accurate information about partners, partner services are not effective. Obtaining accurate information largely depends on treating index patients with respect and gaining their trust. Withholding relevant information is likely to generate mistrust. When offering partner services, public health personnel should delicately balance the need to provide these important services with the knowledge that index patients can choose whether to participate. Index patients should have the following types of information explained to them: • the purpose of partner services; • what partners services entail; • benefits and potential risks of partner services for index patients and their partners and steps taken to minimize risks; • how and to what extent privacy and confidentiality can be protected; • the right to decline participation in partner services without being denied other services; and • available options for notifying partners. The amount of information an index patient needs about each of these topics varies. Regardless, all patients should be offered ample opportunities to ask questions and voice concerns. # Types of Interviews Interviewing index patients to elicit partner information is a cornerstone of partner services. Two types of interviews are used: the original interview and the reinterview. A supplementary approach, clustering, also is used by certain programs to obtain information about the index patient's social network. # Original Interviews and Reinterviews The purpose of the original interview is to gather information from index patients about partners they have had within a defined period (i.e., the interview period). In addition to eliciting as many partner names as possible, the interviewer attempts to obtain enough information about the partners so that they can be located and notified of their possible exposure. Most programs conduct a subsequent interview, the reinterview. The reinterview has several purposes: 1) to gather additional location information on partners identified by index patients in the original interview, if sufficient information was not initially obtained; 2) to follow up on the status of partners that index patients initially elected to notify themselves; 3) to elicit additional partners index patients might not have recalled in the original interview; and 4) to verify that index patients have received adequate treatment or additional tests. Frequently, more than one reinterview is conducted. Few studies have been conducted regarding the yield of reinterviewing or the relative yield of the original interview compared with the reinterview. Second interviews of 1,000 persons with STDs in a clinic in Berlin, Germany, in 1976 resulted in elicitation of 9% more partner names (D Brewer, unpublished manuscript, 2003). A subsequent sample of 110 persons from the same clinic were interviewed before diagnosis with gonorrhea then reinterviewed twice after diagnosis. The second and third interviews together elicited 12% more partner names compared with the first interview, resulting in an 11% increase in the total number of partners located and a 13% increase in the number of infected partners identified. In a study of forgetfulness as a cause of incomplete reporting of partner names, patients recalled roughly equal numbers of partners in the first and second interview; however, the sets of partners recalled in the two interviews tended to differ (71). Finally, in a randomized trial of supplementary techniques used during contact interviews for chlamydial infection, gonorrhea, and early syphilis, use of a combination of five sets of recall cues increased the number of partner names elicited by approximately 23% and the number of partners notified by approximately 11% per index patient. This approach was approximately two to three times as effective in eliciting additional partners as a second interview (72). Reinterviews are recommended for all early syphilis investigations and are standard practice in most partner services programs. Persons who have just been informed that they are infected with HIV are often willing to provide partner information and might address the topic of partners without being prompted. Other patients might be too overwhelmed by the new diagnosis to focus on identifying partners effectively or to hear and understand messages regarding prevention or linkage to care during the original interview. In these instances, using the first interaction with an index patient to help with various challenges arising from the HIV diagnosis and addressing partner elicitation in a subsequent interview might increase the likelihood that the index patient will identify partners. This approach must be weighed against the possibility that the index patient might not be available for a second interview. # Clustering A technique known as clustering has been recommended for use when interviewing index patients (1). Clustering involves eliciting information from index patients about persons in their social networks, other than partners, who might benefit from counseling, testing, and other services. These persons, referred to as social contacts (and referred to as suspects in previous guidelines), might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination (e.g., pregnant females). Clustering also might include eliciting information about venues in which the index patients and their social contacts interact socially (e.g., bars or clubs). Clustering differs from cluster interviewing, which involves asking uninfected partners or social contacts of index patients about their own social networks. Cluster interviewing is addressed in more detail in the section on partners. Data on the effectiveness of clustering for case finding are limited. A 6-month pilot project was conducted in which a network approach was used for routine syphilis partner notification in an Atlanta, Georgia, zip code with a high rate of early syphilis (260 cases per 100,000 population) (73). Among sex partners of syphilis index patients, 23.1% were infected with syphilis, whereas 5.9% of nonsexual contacts were infected. Another study included an analysis of 1993-1996 partner notification data for 12,927 patients with syphilis throughout Louisiana (74). Of 19,188 partners located and examined, 19% were newly identified as having syphilis; of 3,121 social contacts of index patients, 11% were newly identified as infected. A review of the effectiveness of partner notification and cluster investigations for identifying HIV and other STD cases indicated that, based on a small number of studies from the previous 20 years, the yield of cluster investigation for cases early syphilis was substantially less than the yield from partner notification for early syphilis (mean number of newly diagnosed cases found from interviewing one index patient was 0.002-0.11 for cluster investigation compared with 0.05-0.46 for partner notification) (8). Furthermore, the same review found that, compared with a few reports from previous years of syphilis control, the yield of cluster investigation has declined considerably, possibly related to the marked decline in early syphilis prevalence. In summary, data from a small number of reported studies suggest that the case-finding yield of clustering for early syphilis is substantially lower than that of partner notification. However, the yield is highly variable, and clustering might be more productive in areas with relatively high early syphilis case rates. Clustering and cluster investigation might be particularly useful during an outbreak. Published data on the case-finding yield of clustering for HIV are not available. Although data regarding the effectiveness of clustering for case finding are limited, information obtained through clustering has potential epidemiologic value. By obtaining and analyzing information about social contacts and venues of index patients, programs can gain insight into how and where infection is being transmitted in the community and develop strategies for conducting screening or other prevention interventions (e.g., social marketing campaigns) at the community level. # Interview Environments Because of confidentiality concerns, interviews generally should be conducted in environments that are private and comfortable enough that clients do not feel afraid or coerced. Public health clinics provide a safer environment for partner services staff members and a more confidential setting for interviewing and counseling than field settings. However, interviews conducted in settings other than the clinic might allow index patients to feel more comfortable discussing highly personal information. Interviews have traditionally been conducted in person; however, this approach is time and labor intensive and not always possible. The next most common method (and the most common in certain settings) is interview by telephone. Other interview methods, such as use of self-administered questionnaires and audio computer-assisted self-interviews have been suggested as alternatives or supplements to in-person interviews; however, little research has been done on this topic (D Brewer, unpublished manuscript, 2003). Although selfadministered questionnaires are frequently used in medical care settings to obtain information from patients before they are seen by a clinician, no studies of this approach for partner services have been published. Likewise, little data are available on telephone interviews and partner services. Previous CDC recommendations for STD partner services suggested that a telephone interview might be considered if attempts to meet with an index patient in person are unsuccessful or the index patient is in a different geographic location than the interviewer. One study, in which STD and community clinic attendees responded to varying hypothetical partner services providers and interview and notification conditions, showed that interview settings that were not in clinics were less favorably viewed than clinic interviews (75); telephone notification and letters by partner services providers were also less favorably viewed, although not significantly so. Although the available evidence suggests that audio computer-assisted self-interviews might effectively elicit partner information from index patients, no studies examining this particular use were found (76)(77)(78)(79)(80)(81)(82)(83)(84)(85). # Interview Techniques Incomplete reporting of partner names might stem from various factors, such as concern about potential negative consequences (e.g., fear of partner violence), perceived social undesirability of acknowledging participation in stigmatized or illegal activities, and forgetting or memory errors (71). However, although partner elicitation can be challenging, its effectiveness can be improved through systematic use of simple techniques. In a study of forgetting as a cause of incomplete reporting of partner names, using simple and nonspecific prompting (e.g., "Who else have you had sex with in the last 12 months?") and reading back the list of partners already named improved recall substantially (71). On average, these methods accounted for 10% of all partners recalled during an interview. In a randomized trial of interviewing techniques for persons at high risk for HIV infection, administering a set of five types of cues to participants, after they had freely recalled their partners, increased the number of sex and drug-injection partners elicited by an average of 40% and 123%, respectively (86). Eliciting partners in reverse chronological order, as suggested in previous CDC recommendations, was no more effective than using free recall. In a subsequent study of supplementary interview techniques for eliciting partners from index patients with chlamydial infection, gonorrhea, and early syphilis, patients were asked to freely recall partners, were prompted nonspecifically, and had the list of elicited partners read back (72). They were then administered three sets of cues, which increased the number of new cases found by 12% and identified network branches not previously recognized. Using supplementary interview techniques might be an efficient strategy for increasing the number of partners elicited and located. This approach seems to be effective for persons at risk for HIV as well as those with other STDs, suggesting that comprehensive, systematic use of such techniques during the original interview might enhance the yield of new partners identified. # Interview Period The interview period is the time interval for which index patients are asked to recall their partners. Ideally, the interview period covers the time from the earliest date an index patient could have been infected up to the date of treatment (i.e., the time period during which the patient could have become infected or transmitted the infection to others). Anyone who had sex with or, for those with HIV infection, shared druginjection paraphernalia with the index patient during this interval is at high risk for infection. Because of differences in biological factors and natural history, the interview periods for HIV, early syphilis, gonorrhea, and chlamydial infection differ (Table 1). # Syphilis, Gonorrhea, and Chlamydial Infection The interview period for early syphilis varies according to the stage of disease (primary, secondary, or early latent) because stages develop within well-defined timelines. Thus, the interview is used not only to find early syphilis cases but also to estimate which partners are most likely to have infected the index patient (i.e., the source) and which partners the index patient is most likely to have infected (i.e., spread). Source and spread information aid in defining the epidemiology of the infection and can be used to identify networks of infection. To some extent, source and spread can be estimated for gonorrhea and chlamydial infection but almost exclusively on the basis of interview results and generally not on the basis of stage of disease. The interview period for syphilis is based on the disease stage at the time of diagnosis and incorporates all maximum time periods for incubation and stage of disease. The interview period for a person with a diagnosis of primary syphilis is 4 months and 1 week, based on a 90-day maximum incubation plus 5 weeks (35-day maximum duration of lesion). The interview period for a person with a diagnosis of secondary syphilis is 8 months (34 weeks), based on a maximum 90-day incubation period and 5-week duration of primary syphilis, 10-week primary-secondary latency, and 6-week maximum duration of secondary symptoms. The maximum interview period is 12 months for early latent cases unless a credible primary or secondary history can be established and for cases of unknown duration. Unlike syphilis, which has multiple increases and decreases in level of infectivity, infectivity for gonorrhea and chlamydial infection increases to a single peak and then decreases. The standard interview period is 60 days before the date of specimen collection and should be extended through the date of treatment if the patient was not treated at the time the specimen was collected. For persons who seek treatment at a clinic because of signs or symptoms of gonorrhea and chlamydial infection, incubation is almost entirely covered within this 60-day period (although a few programs use 90 days). For asymptomatic cases of either STD (e.g., cases discovered during screening), the number of cases identified from partner notification can decrease substantially. This is especially relevant for chlamydial infection, which is most likely to be asymptomatic and for which widespread screening is most likely. In such instances, attempts to ascertain source and spread would have to be established on behavioral reports during interviews. However, data are useful for describing networks and the epidemiology of infection. # HIV Infection Determining when an index patient was infected with HIV often is difficult. Therefore, HIV programs frequently establish an interview period based on the estimated likelihood of being able to locate and contact the partners (e.g., 1-2 years before HIV diagnosis). The recommended interview period in a particular jurisdiction might subsequently be modified based on analysis of local data or availability of resources. Additional considerations might influence the interview period for specific index patients. Previous Negative HIV Test. A confirmed history of a nega tive HIV antibody test might be useful for defining the ap propriate interview period for a specific index patient. Knowing the date of the patient's most recent negative test and consid ering the window period (i.e., the time interval following in fection during which an HIV test might be negative because antibodies have not yet developed to a detectable level), the interviewer can establish how far back in time the interview period should extend. An estimated 95% of persons infected with HIV develop detectable HIV antibody within 6 months of infection, suggesting 6 months might be an appropriate interval to use as a window period; however, these estimates were developed using previous, less sensitive versions of the 1 year before start of treatment * The time interval for which an index patient is asked to recall sex or drug-injection partners. † The interview period is based on patient diagnosis and incorporates all maximum time periods. The interview period is not shortened, regardless of patient symptoms, serological history, or incidental treatment. If the patient claims having had no partners during the interview period, then the most recent partner before the interview period should be identified and notified. HIV enzyme immunosorbent assay (EIA) (87,88). More recent EIA tests (e.g., second-generation immunoglobulin G [IgG] tests and third-generation IgG/immunoglobulin M [IgM] tests) are considerably more sensitive than the previ ous tests and might allow the estimated window period to be shortened to 3 months (89,90). Evidence of Recent Infection. For certain patients, recent infection might be suggested by a clear history of an acute retroviral syndrome, which might result in the interview pe riod being shortened for these specific patients (91). Recently, HIV RNA testing has been used to screen pooled, HIV anti body-negative specimens to identify persons with acute or very recent infections (i.e., HIV RNA-positive and HIV an tibody-negative) (70,90,(92)(93)(94)(95)(96)(97)(98). For these index patients, the likely period of the date of infection can be narrowed consid erably, and the interview period can be adjusted accordingly. Spouses. As noted previously, the Ryan White CARE Act Amendments of 1996 require that states receiving funds un der part B of title XXVI of the Public Health Service Act en sure that a good-faith effort is made to notify the current spouse of an HIV-infected person or persons who have been legal spouses of that person during the 10 years before the diagno sis that such spouse might have been exposed to HIV and should seek testing. The 10-year interview period might be modified if a confirmed history of a negative HIV test or other laboratory testing indicates that the index patient was infected more recently; however, states should consult with their legal counsel to determine whether their laws allow them to make this modification. # Timing of Interviews The time in which partner services should be offered to reduce the disease transmission rate and the likelihood of reinfection might vary somewhat by disease. However, in general, partner services should be offered as soon as possible. # Syphilis, Gonorrhea, and Chlamydial Infection The pattern of infectiousness for early syphilis requires rapid notification and treatment of sex partners to have an effect on subsequent disease progression or transmission; therefore, partners should be notified quickly. For gonorrhea and chlamydial infection, the vast majority of additional transmission (i.e., by infected and untreated partners of the index patient) occurs quickly, and a delay in the interview is inadvisable. The morbidity for these two infections, especially chlamydial infection, have led to investigation of various notification and treatment options that are not widely advocated for syphilis (e.g., contact slips for patients to deliver to partners or patient delivery of oral medications). # HIV Infection Persons who test positive for HIV should be contacted and offered partner services as soon as possible after being identified by the partner services program, ideally within a few days. Rapid identification, notification, and testing of partners can reduce risk for additional transmission. A rapid interview allows partners to be identified and notified of possible exposure as soon as possible so that they can 1) obtain HIV counseling and testing; 2) take steps to avoid becoming infected or, if already infected, to avoid infecting others; and 3) access medical care and other services as soon after infection as possible. Patient reactions to learning about their HIV MMWR November 7, 2008 infection vary, and personal circumstances differ among patients. Partner services providers should recognize and, within reason, accommodate index patients who need particular concerns resolved before feeling ready to participate fully in partner services. For index patients who decline or are not ready to participate in an initial partner services interview at the time of first contact, a follow-up appointment should be arranged to discuss partner services concerns more thoroughly, preferably no later than 2 weeks after the initial contact. No studies are available related to introducing partner services to persons with reactive rapid HIV tests and interviewing them to elicit partner information. Partner services providers might consider conducting an initial interview and eliciting partner information when the reactive rapid test result is obtained and before results of confirmatory testing are available if the index patient accepts partner services at that time. However, persons with considerable partner services experience have suggested that partners not be contacted and notified until a positive confirmatory test is obtained. If a confirmatory test is not performed at the time the rapid test is found to be reactive, attempts can be made to locate the patient and obtain confirmatory testing. If the patient cannot be located or declines confirmatory testing, and the rapid test was performed on a blood specimen, the DIS can then contact the partners and notify them about their possible exposure to HIV through someone who had a reactive rapid test result. This suggestion is based on the high predictive value of a reactive rapid test, in most circumstances, when performed on a blood specimen. Local policies might preclude use of this approach. # Interviewers Traditionally, index patients have been interviewed by health department DISs. Certain evidence indicates that health department specialists might elicit more partner names from index patients with gonorrhea or chlamydial infection than other, presumably untrained, interviewers (99). A cohort study of the efficacy of partner notification for HIV infection found that although patients counseled by health department specialists reported more locatable partners than those counseled by physicians, the number of partners per index patient interviewed who were then identified as having a new diagnosis of HIV infection was similar for both groups of health-care providers (100). No such comparative data exist for gonorrhea or chlamydial infection, although the frequency with which both STDs are diagnosed outside public settings (especially STD clinics) suggests that collaboration with physicians is appropriate. Health departments might be able to expand access to and coverage of partner services by developing agreements with providers who are not in health departments to elicit information about partners and provide that information to a health department DIS. The DIS can then notify the partners. Existing relationships and rapport between these providers and their patients might facilitate partner elicitation; providers must inform patients that the information will be shared with health department DISs. Documented experience with this strategy is scarce; however, such approaches have been used by health departments in several jurisdictions, with anecdotal reports of success. Other than DISs, types of providers who might elicit partner information from index patients on behalf of partner services programs include the following: • other health department personnel (e.g., physicians, nurses, counselors, or case managers); • health care or service providers who are not in health departments (e.g., primary care providers) who provide STD screening and HIV counseling and testing to their patients; • counselors in publicly funded HIV counseling and testing sites; • counselors in other HIV counseling and testing sites; and • health care or service providers who are not in health departments (e.g., physicians, physician assistants, nurse practitioners, nurses, CBO staff members, or HIV case managers) who provide services, including screening for other STDs, to persons with HIV infection. These providers, who often have ongoing relationships with HIV-infected persons, might be particularly useful in providing ongoing partner services to their clients (i.e., periodically inquiring about new partners who might be at risk and initiating partner services as needed). If other types of providers participate in this way, roles and responsibilities should be clearly defined. # Unique Circumstances of Index Patients Unique characteristics of index patients and their individual circumstances might affect the partner services process. In certain instances, the mental health status and decision-making capabilities of an index patient might affect the approach to providing partner services. Guardians or others might be charged with making legal and health-care decisions for such persons. Local laws, regulations, and policies might address these concerns. Programs should develop policies and procedures that describe how to work with index patients who might have limited comprehension or other mitigating circumstances; this might require consultation with persons who have expertise in these areas. Examples of concerns that should be considered when developing protocols include age and developmental level, literacy level, language barriers, cultural concerns, hearing or visual impairments, alcoholism or abuse of other substances, mental health concerns, or potential violence (either on the part of index patients or their partners). # Recommendations for Interviewing Index Patients # General • In general, partner names should be elicited (partner elicitation) during the original interview. If this is not possible, a reinterview should be scheduled. • Programs should establish clear policies and procedures for the timing of interviews relative to date of diagnosis or report. • Index patients should be provided information about the following: -the purpose of partner services; -what partner services entail; -benefits and potential risks of partner services for index patients and their partners, and steps taken to minimize any risks; -how and to what extent privacy and confidentiality can be protected; -the right to decline participation in partner services without being denied other services; and -options available for notifying partners. • Program managers should ensure that policies and protocols are in place to safeguard the confidentiality of information shared with health department staff members during the partner notification process. Specifically, staff members must be trained to maintain confidentiality in both their professional and private lives. Confidentiality is particularly salient in rural areas, where a DIS might have substantial contact with clients outside of the professional environment (e.g., because they are neighbors, parents of children's classmates, or members of the same church) (101). • To ensure confidentiality, interviews should not be conducted with other persons present, except for quality assurance or for interpreting. • In general, partner-elicitation interviews should be conducted by trained health department specialists. However, to expand partner services coverage, health departments should consider enlisting other types of providers to conduct interviews on their behalf. Successfully eliciting information about partners requires skilled counseling and interviewing; therefore, all providers conducting interviews on behalf of the health department should receive appropriate training. The yield of interviews conducted by other providers should be carefully monitored. • In general, interviews should be conducted in person. Telephone interviews might be conducted if no reasonable alternative exists, with strict safeguards in place to verify the identity of the person being spoken with and ensure that privacy and confidentiality are protected. • Programs should use interview techniques that maximize the amount of information gathered in the original interview about the index patient's partners. Policies, procedures, and protocols should establish criteria for instances in which reinterviews should be done, how soon they should be done, and when they are unnecessary. The yield of original interviews and reinterviews should be monitored closely and policies, procedures, and protocols adjusted accordingly. • In addition to information about partners, interviewers also can elicit information about the index patient's social network, including venues frequented, for use in planning additional prevention activities. • Policies, procedures, and protocols should address circumstances that might require specific consideration in interviews with index patients (e.g., age and developmental level, literacy, language barriers, hearing or visual impairment, alcoholism or abuse of other substances, mental health concerns, or potential violence). # Syphilis, Gonorrhea, and Chlamydial Infection • For early stages of syphilis, policies, procedures, and protocols should specify that all index patients receive an original interview as close to the time of diagnosis and treatment as possible. Every reasonable effort should be made to ensure the partner notification process begins on the date of the original interview. • For cases of gonorrhea and chlamydial infections that partner services staff members will follow up, policies, procedures, and protocols should specify that all index patients receive an original interview as close as possible to the time of diagnosis and treatment. Unless the index patient has evidence of recent infection, notification primarily serves case-finding goals and might be briefly delayed, if necessary. • For cases of gonorrhea and chlamydial infection that partner services staff members will not follow up, patient referral instructions should be provided as close as possible to the time of diagnosis and treatment. • For STDs other than HIV, partner services programs should follow established recommendations for interview periods (Table 1). # HIV Infection • Policies, procedures, and protocols should specify that all index patients receive an original interview as soon as possible after diagnosis, ideally within a few days. For index patients who are not willing or able to provide partner information during the original interview, a reinterview should be scheduled, preferably no later than 2 weeks after contact was first made (and sooner, if possible, for index patients with acute infections). • Programs should develop criteria for establishing the interview period for index patients with HIV infection (Table 1). Criteria for prioritizing partners should be developed in consultation with persons who have expertise in clinical and laboratory aspects of HIV (e.g., viral and serologic markers of HIV infection). • Program managers should ensure that policies and procedures regarding notification of spouses adhere to requirements of the Ryan White CARE Act Amendments of 1996 and any other applicable laws. • Policies, procedures, and protocols should address interviews for persons with reactive rapid HIV tests, including when partner names should be elicited, when partners should be notified, and policies about notifying partners when a confirmatory test is not available. # Risk-Reduction Interventions for Index Patients Many HIV-infected persons are knowledgeable about STD/ HIV transmission and prevention; however, misconceptions and inadequate information about transmission and methods for reducing transmission risk are common (102)(103)(104)(105). All index patients likely can benefit from receiving information and brief prevention messages about adopting and maintaining safer behaviors to protect their own health and that of their partners (25,106). In the case of HIV infection, this includes discussing the index patients' responsibility for disclosing their HIV serostatus to current and future partners. These messages can be integrated easily into the activities of DISs. In addition to provision of information and brief prevention messages, prevention counseling can be relevant for all infected persons, regardless of the STD diagnosis. Project RESPECT, a risk-reduction intervention trial conducted during the mid 1990s, was aimed at preventing HIV and other STDs in HIVnegative, heterosexual STD clinic patients (25). Approximately one third of participants had an STD at the time of enrollment. Participants were randomly assigned into three groups and received either two sessions of interactive risk-reduction counseling; four sessions of enhanced interactive, theory-based counseling; or two brief sessions of didactic information. Compared with baseline, participants in all three groups reported higher levels of condom use at 3, 6, 9, and 12 months follow-up. At 3 and 6 months, participants receiving either of the two counseling interventions reported significantly higher levels of condom use than those receiving only didactic information. At 9 and 12 months, participants in all three groups continued to report higher levels of condom use than at baseline, but the differences between those in the two counseling groups and those in the didactic information group were no longer significant. In addition, compared with participants in the didactic information group, 30% fewer participants in the two counseling groups had new STDs after 6 months, and 20% fewer participants in either counseling group had new STDs through the 12-month interval. The relative effectiveness of counseling was greater among participants who had an STD diagnosis at enrollment than among those with no STD. Interactive and individually tailored counseling is likely similar to the communication between many DISs and patients regarding partner services and future behavior. However, use of the intervention in STD clinics, with at least two sessions, has been limited (107). Another study of counseling to prevent STDs and HIV infection in STD clinic patients compared the effectiveness of two 20-minute individual counseling sessions with four 1-hour group sessions with a follow-up session 2 months later. After 12 months, both groups had similar and significant increases in condom use, decreases in number of partners, and decreases in numbers of new infections with gonorrhea (14%), chlamydia (10%), or syphilis (2%) (108). # Syphilis, Gonorrhea, and Chlamydial Infection Although prevention counseling is relevant for persons with early syphilis, gonorrhea, or chlamydial infection, prevention counseling other than individualized attempts during an interview is typically composed of brief prevention messages delivered once. With early syphilis patients, repeated contact with DISs during the course of an investigation is common enough that they can establish a record of behavioral change or reinforce previous counseling. Except for repeat cases, health department-mediated prevention counseling with gonorrhea or chlamydial infection is almost certain to be a one-time session. The gap between demonstrated efficacy and implementation merits additional examination. Certain aspects of counseling for patients with syphilis, gonorrhea, and chlamydial infections are devoted to promoting rescreening at 3 months, which CDC recommends, given frequently high rates of reinfection among STD clinic attendees (3,109). In one study of STD clinics in Los Angeles County, California, and Maryland, telephone reminders and pointof-care interviews (approximately 20 minutes) to reinforce the importance of rescreening to the patient were both associated with increased rates of return at 3 months (110). Subsequent efficacy and cost-effectiveness analyses suggested the telephone reminder alone would be most efficient and most cost-effective, although the point-of-care interviews should be used in situations in which telephone contact is unlikely (110,111). Another condition tested in the study, a $20 incentive with brief instructions, was associated with higher return rates for men but not women. Although programs might consider incentives to improve return rates, offering them only to men would have ethical implications. Data on interventions to promote follow-up testing for syphilis recurrence would broaden the scope of evidence available for making program decisions about this disease. # HIV Infection Many persons substantially reduce HIV transmission risk behaviors after learning they are infected (28,30,(112)(113)(114). A metaanalysis of high-risk sexual behavior in HIV-infected persons aware and not aware of their infection found that the prevalence of unprotected anal or vaginal intercourse with any partner was an average of 53% lower for HIV-infected persons aware of their infection compared with HIV-infected persons not aware of their infection and 68% lower after adjusting data to focus on unprotected anal or vaginal intercourse with partners who were not already HIV infected (29). However, a considerable percentage (range: 10%-60%) do not consistently practice safer behaviors and might transmit infection to others or put themselves at risk for acquiring other STDs (26). Thus, although certain HIV-infected index patients might already have reduced their level of risky behaviors by the time they are interviewed for partner services, others are continuing risky behaviors and require additional prevention counseling or other more intensive prevention intervention. Index patients who need additional counseling or other riskreduction interventions can be identified through brief behavioral risk screening that can be integrated easily into the interview process (54). Questions used for behavioral risk screening need to be broad enough to identify most index patients engaging in risky behaviors. This includes index patients currently or recently engaging in risky sex or druginjection practices, those who have a current or recently diagnosed STD, those who might be pregnant or at risk for unintended pregnancy, those with other characteristics associated with risky behaviors (e.g., alcohol or other noninjection drug use), and those who were previously identified and are now named as partners by other index patients, which suggests ongoing risky sex or drug-injection behavior. Index patients whose risk screening indicates continuing risky behavior should be informed of the risks involved in continuing the behavior. They should also be provided prevention counseling or referred for counseling or more intensive prevention services. Several risk-reduction interventions designed specifically for HIV-infected persons have been demonstrated to be effective. Most of these interventions involve multiple sessions provided over time, usually in a group format (26,27,31). Most do not focus only on reducing transmission risk; rather, they address multiple life concerns faced by HIV-infected persons, which might increase the likelihood that patients can make and sustain behavioral changes. These interventions are not feasible to provide through partner services but might be available through CBOs in the area or as part of ongoing prevention activities incorporated into the medical care of persons living with HIV infection (54). Certain partner services programs might have adequate resources to assess and provide prevention counseling to index patients whose screenings indicate continued risky behaviors. However, health department DISs often have limited numbers of interactions with index patients. Furthermore, the time available for DISs to provide prevention counseling to index patients might be limited, especially if health departments expand their partner services activities to ensure that all persons with newly diagnosed or reported HIV infection receive adequate partner services. Consequently, in certain programs, health department DISs might have difficulty providing prevention counseling to all index patients for whom it is indicated. In these situations, and for index patients requiring more intensive prevention interventions, referral or linkage to agencies that provide these services or to case managers who can arrange them is appropriate. # Recommendations for Risk-Reduction Interventions for Index Patients • Program managers should develop protocols that establish the minimum amount of information and prevention messages that should be provided to all index patients. For patients with HIV infection, the information should include the index patients' responsibility for disclosing their HIV serostatus to current and future partners. # Treatment for Index Patients Syphilis, Gonorrhea, and Chlamydial Infection The CDC 2006 STD treatment guidelines provide preferred and alternative treatments for syphilis, gonorrhea, and chlamydial infection (3). DISs should verify that index patients have been treated appropriately. Because each of these STDs is curable, linkage to additional medical care (in the absence of coinfection with HIV) generally is not needed, although recommendations for follow-up testing are appropriate. # HIV Infection Effective and timely medical evaluation, initiation of currently recommended combination ART, and provision of appropriate vaccinations and other preventive health interventions have led to substantial reductions in HIV-related morbidity and mortality (115,116). HIV-infected persons who begin receiving (or reestablishing) medical care not only can benefit from ART but also can receive screening for other STDs and bloodborne infections (e.g., HBV and HCV), appropriate vaccinations for vaccine-preventable infections, and other medical services. In addition, through medical care and HIV case management, patients can be evaluated and receive referrals for a wide range of other medical and psychosocial services, and the medical care setting offers an opportunity for patients to be more completely assessed for HIV transmission risk and provided or referred for appropriate HIV prevention services (54). Furthermore, ART might decrease infectiousness and reduce risk for transmission to others by reducing the patient's viral load (32,117,118). However, delays in accessing medical care and inadequate use of care are common among persons who receive an HIV diagnosis (14,119,120). Linking HIV-infected persons to medical care and ongoing HIV case management as soon as possible after diagnosis is essential. Brief HIV case management for persons with newly diagnosed HIV infection increased attendance at HIV care facilities. The Antiretroviral Treatment Access Study, a multisite, randomized control intervention for persons with newly diagnosed HIV infection, directly compared passive referral (i.e., giving patients a list of medical providers) with brief HIV case management and found that those who received HIV case management were significantly more likely to be linked to and attend clinic visits over a 12-month period (121,122). In certain situations, these brief HIV casemanagement services were provided by DISs. This underscores the importance of DISs actively helping index patients with newly diagnosed or newly reported HIV infection to access medical care either directly or by linking them to HIV case managers. DISs also might be able to facilitate reestablishment of reentry into HIV case management and medical care for HIV-infected persons who are not currently receiving medical care but have in the past. # Recommendations for Treatment for Index Patients Syphilis, Gonorrhea, and Chlamydial Infection • Program managers should ensure that patients are treated according to CDC treatment guidelines for timely and efficacious treatment with appropriate instructions and attention to recommendations regarding the importance of follow-up testing. # HIV Infection • Program managers should create strong referral linkages with HIV care providers and case managers to help ensure that the medical needs of index patients are addressed. • HIV-infected index patients who are not receiving medical care should be referred or directly linked to medical care or to case managers who can then link them to care services. # Referring Index Patients to Other Services Many index patients have underlying problems that impede their ability to access medical care or adopt and maintain safer behaviors and would benefit from referrals to various psychosocial services. Because of the numerous U.S. cases of gonorrhea and chlamydial infection, and because medical management of syphilis, gonorrhea, and chlamydial infection does not generally require an ongoing care relationship with partners, the process of referral to other services for index patients with these STDs is less intense than it is for index patients with HIV infection. Nevertheless, many jurisdictions offer referrals for care on request or if the need for other services is ascertained during the course of interviewing the index patient. For index patients whose infections are likely related to their living conditions (e.g., homelessness or partner violence), attention to need for supportive services might reduce the likelihood of reinfection and contribute to infection control. Program collaboration and service integration facilitate this process. Index patients might need a range of services, such as the following: • # Notifying Partners of Exposure Notification Strategies After index patients have identified partners, the partners should be notified of the exposure as soon as possible. Traditionally, four strategies have been used to accomplish this: provider referral, self-referral, contract referral, and dual referral. Provider referral notification involves a partner being notified of their possible exposure by a health department specialist who has been specifically trained to locate and notify partners. The specialists then link the partners to medical, prevention, and support services while protecting the confidentiality of the index patient. The term provider referral has sometimes led to confusion, because health-care providers other than health department specialists might conduct some or all steps in the partner services process, especially for index patients who receive a diagnosis in a setting other than the health department. Therefore, these recommendations use the term provider referral to specifically describe notification carried out by health department staff members and the term third-party referral to describe partner notification carried out by other professionals (e.g., HIV counselors and clinicians who are not in health departments). Self-referral notification (also called client or patient referral notification) gives the index patient full responsibility for informing partners of exposure and referring them to appropriate services. Contract referral notification involves index patients selecting specific partners they prefer to notify themselves and agreeing to a specific time frame in which they will do so. Patients agree that if they do not notify the selected partners within the established time frame, the DIS will notify the partners. Dual referral notification involves an index patient and a provider (a DIS or third party) jointly notifying a partner of exposure. The notification strategies primarily differ in the degree of responsibility assumed by the DISs. Variations in the extent of DIS involvement, in turn, contribute to differences among the strategies in terms of effectiveness, intensity of resource use, and acceptability to index patients and partners (Table 2). The limited available data suggest the following: • Provider referral is the most effective single method for notifying partners. • Self-referral is the least effective single method for notifying partners. • Maximum notification rates for HIV are achieved when the provider and index patient share the responsibility for notification. • No data are available on the relative timeliness of the various partner notification strategies. # Provider Referral Notification STDs Other than HIV. A 1977 study comparing provider referral with self-referral for gonorrhea found that similar pro portions of partners were evaluated and treated, although pro vider referral follow-up was required for a small number of partners who originally had been randomly assigned to the self-referral group (123). In a study of partner notification for syphilis, for which provider referral is most strongly empha sized of all the STDs, a comparison of three referral approaches (two groups with provider referral, one with contract referral) revealed no clear evidence of increased effectiveness or costeffectiveness for any strategy compared with another (5). Be cause the majority of spread of infection of primary and secondary syphilis is likely to occur near the same time as the interview, infection control requires almost immediate part ner notification and referral. Such swift notification is most reliably accomplished through provider referral (although notification of Internet partners might be an exception). The effectiveness of provider referral (or third-party refer ral) depends on the ability and willingness of index patients to provide sufficient identifying and locating information. Index patients often cannot provide sufficient information to conduct provider referral for all partners, and other strategies might be needed. For example, during syphilis outbreaks in several U.S. cities during 2002-2005 among men who have sex with men (MSM) (124,125), program staff members con sidered using Internet-based notification when index patients could provide only e-mail addresses or chat-room nicknames as identifiers. Gonorrhea and chlamydial cases are frequently too numer ous to permit provider referral. The basis for notification in such instances should be self-referral, although basic instruc tions can be supplemented with brief oral counseling, written instructions, and contact information for patients to give to partners (most commonly known as contact slips or referral cards) (126,127). Circumstances in which index patients also are provided with medications or prescriptions to deliver to partners are known as patient-delivered partner therapy, a form of expedited partner therapy. HIV Infection. Provider referral has been found to be an effective means of identifying new cases of HIV. In nine stud ies that qualified for inclusion in the Guide to Community Preventive Services review, a range of one to eight partners were identified per index case. A mean of 67% of named partners were found and notified of their exposure to HIV (range: 44%-89%), a mean of 63% of those notified were tested, and of those tested, a mean of 20% were newly identified as HIV infected (range: 14%-26%) (16). Only two U.S. studies comparing provider referral with other referral strategies for HIV partner notification have been pub lished; both were included in the Guide to Community Pre ventive Services review. In one study comparing the effectiveness of provider referral and self-referral (i.e., patient referral) notification in three health departments in North Carolina, index patients were randomly assigned to provider referral or patient referral groups (128). In the provider refer ral group, index patients were given the option of selecting between provider referral conducted by a health department counselor and contract referral. With contract referral, they were given 2 weeks to notify a partner themselves, after which time a counselor attempted to notify any partners who had not been notified by the index patient. In the patient referral group, index patients were asked notify all of their partners themselves and were not given the option of requesting pro vider referral for any partners. Patients were given 1 month for notification, after which time the counselors attempted to notify any partners who had not been notified by the index patient. In the provider referral group, counselors notified 70 (45%) of 157 partners. In the patient referral group, index patients notified only 10 (7%) of 153 partners. Thus, in this study, provider referral was approximately 6.5 times more ef fective than patient referral. Of the 143 partners who were not notified by index patients in the patient referral group, counselors were able to notify only 40 (28%) partners. A sec ond study analyzed results of HIV partner notification ser vices provided by the Colorado Department of Health in 1988 (129). Of 84 partners for whom provider referral was intended, 71 (85%) were notified by providers. Of 30 partners for whom patient referral was intended, 17 (57%) were notified by in dex patients. Thus, in this analysis, provider referral was ap proximately 1.5 times more effective than patient referral. # Self-Referral Notification Syphilis, Gonorrhea, and Chlamydial Infection. Although provider referral is favored and generally expected for notify ing partners of persons with syphilis, self-referral is the typical form of partner notification for persons with chlamydial in fection. Successful public health involvement with partner no tification for chlamydial infection is likely to be limited to improving self-referral effectiveness through interventions provided at the time of diagnosis or treatment (e.g., brief counseling) and possibly through increased monitoring of the proportion of those seeking care who have been referred by a partner (11). Gonorrhea is somewhat more likely than chlamy dial infection to be targeted for provider referral in public clinic settings; nonetheless, strategies for chlamydial infection often are applicable for gonorrhea (especially outside public clinic settings); basic instructions can be supplemented with brief verbal counseling. A randomized, controlled trial in Brooklyn, New York, showed male notification rates of part ners could be improved with a brief counseling session (ap proximately 20 minutes) aimed at identifying and reducing barriers (130). Index patients' intentions, skills, and belief in their ability to notify (i.e., self-efficacy) have been associated with more successful referrals, including among adolescents, and interventions to increase the effectiveness of self-referral typically have incorporated approaches aimed at improving self-efficacy (131). Written instructions for index patients to deliver to part ners are known as contact slips or referral cards. Referral cards are used to add legitimacy to the index patient's notification of the partner, provide information to the partner, and pro vide information and a short history of exposure to any clini cian from whom the partner seeks evaluation. This ensures that the clinician has sufficient, accurate information to guide appropriate evaluation and management of the partner. In ideal circumstances, the referral card with treatment notes from the evaluating clinician is returned to a public health pro gram, but this situation rarely occurs. A referral card can in clude the specific type of exposure, where to go for timely evaluation, what to expect in an evaluation, the recommended treatment, and what to do until treatment begins (e.g., ab stain from sexual activity). For confidentiality reasons, no ju risdictions permit names on a referral card, and many jurisdictions have policies prohibiting naming the type of in fection. One British study showed that partners of index pa tients with chlamydial infection were much more likely to seek evaluation if their referral card specifically referred to chlamydial infection (84% versus 33%, p<0.01) (132). Among program evaluations in the United States and other industri alized nations, use of referral cards typically has been associ ated with improved notification and treatment rates. In one trial, their use was associated with reduction in reinfection of index patients but not improved notification (11,126). HIV Infection. As noted previously, a randomized, con trolled trial in North Carolina and an analysis of program data in Colorado both found self-referral notification strate gies to be less effective than provider referral for notifying partners of exposure, especially when index patients were re quired to notify their own partners and given no other op tions (128,129). However, in the North Carolina study, patients notified 14% of all partners who were eventually notified, and in the Colorado report, patients notified 20% of all partners who were eventually notified. Research of HIV disclosure practices and attitudes toward partner notification might offer insight into index patient and partner characteristics associated with higher likelihood of disclosure or self-referral. Disclosure or self-referral is more likely for partners described by the patient as primary, regu lar, or main partners than for partners described as nonmain, casual, or one-time partners, regardless of patient age or risk behaviors (133)(134)(135)(136)(137). Intention to notify also is associated with a higher likelihood of disclosure. In turn, intention is related to factors such as sense of duty or responsibility to the partner and an HIV-infected person's perceived self-efficacy for disclosing serostatus (138)(139)(140)(141)(142)(143). Increasing number of partners is inversely related to likelihood of disclosure; as the number of partners increases, the likelihood that the index patient will notify any of them decreases (134,(144)(145)(146)(147). # Contract Referral Notification Syphilis, Gonorrhea, and Chlamydial Infection. Con tract referral has not been widely evaluated for syphilis, gon orrhea, or chlamydial infection. A trial including provider and contract referral notification for syphilis infection revealed no clear advantages to either method (5). DISs must balance the efficiency gained by having to notify fewer partners in the short term (i.e., partners who are notified by the index pa tient and also seek evaluation) with the efficiency lost by con ducting additional interviews with index patients who did not notify partners as intended and with the potential for addi tional transmission because of delayed notification. HIV Infection. No published study has assessed directly the notification and case-finding effectiveness of contract re ferral for HIV partner notification. However, some insight might be gained from the previously discussed North Caro lina and Colorado studies (128,129). In the North Carolina study, 128 (41%) of 310 partners were notified by a combi nation of providers and patients, whereas of the 292 partners who providers attempted to notify alone, 110 (38%) were notified. In the Colorado study, 104 (91%) of 114 partners were notified by a combination of providers and patient, whereas of the 91 partners who providers attempted to notify alone, 81 (89%) were notified. These findings suggest that including index patients in the notification process might be as effective as relying solely on providers to carry out all noti fications and that the strategy certainly is efficient. # Dual Referral Notification Dual referral notification involves an index patient and provider, together, notifying a partner of exposure. Dual referral provides the index patient direct support in the notification process and might decrease the possibility of negative consequences such as violence or severe emotional reactions. The DIS is available to offer immediate counseling, provide accurate information, answer questions, address concerns, and provide referrals to other services. At the same time, participation by index patients might help patients begin to think about their infection status, increase the likelihood that partners are located and notified, and increase the acceptability of the partner services process to partners. In theory, dual referral has substantial advantages over other approaches; however, the frequency with which this approach is used and its effectiveness (either absolute or relative to other notification methods) are not known. # Third-Party Referral Notification Third-party referral notification involves partners being notified by providers who are not with health departments (e.g., private physicians). The frequency with which this strategy is used, its feasibility and effectiveness, and its acceptability to index patients, providers, and partners are not known. In general, the most appropriate roles for third parties in partner services are likely interviewing index patients to elicit partner information and possibly participating in partner notification when dual referral strategies are used. Because no data are available on the effectiveness and safety of third parties conducting field notification, the level of training and skill needed for third-party referral is unclear. State and local laws might have specific requirements related to duty to warn for third-party providers. # Prioritizing Partners for Notification All identified partners should be notified of their possible exposure as soon as possible, unless partner violence resulting from the notification is a concern. However, prioritizing certain partners for the most immediate notification is appropriate. In general, criteria for prioritizing partners for more immediate notification include behavioral and clinical factors that increase the likelihood of the partner having been infected as a result of exposure or of transmitting infection to others if the partners are infected. Criteria vary somewhat according to the infection involved. Program effectiveness can be improved by periodically reviewing and adjusting prioritization criteria. # HIV Infection, Syphilis, Gonorrhea, and Chlamydial Infection Following are categories of partners who are considered to have the highest priority for notification of exposure, regardless of the infection involved: • Female partners who are known or likely to be pregnant • Partners suspected of or known to be engaging in behaviors that substantially increase the risk for transmission to multiple other persons (e.g., those who have multiple partners) • Partners with whom the index patient reports having had unprotected anal or vaginal sex # HIV Infection Following are examples of other categories of partners who are considered to have the highest priority for notification of exposure to HIV: • -Partners whose earliest known exposure has been within the past 3 months. Studies suggest that the incubation period for HIV infection (time from infection to acute retroviral syndrome) ranges from 5 to 75 days, that serum viral load is likely to be highest in the month after infection, and that viral load in seminal and cervicovaginal fluid is likely to be highest in the first 2 months after infection (148)(149)(150). Therefore, partners who are likely to have been infected within the previous 3 months might be more likely to spread HIV to others. # Confidentiality When notifying partners of exposure, the identity of the index patient must never be revealed. Partners might correctly guess the identity of the index patient and pressure health department staff members to confirm their suspicions, but well-trained DISs avoid such confirmations, either orally or through body language. In addition, information about partners should not be reported back to the index patient. Steps can be taken to reduce the likelihood that neighbors, family, friends, or others are able to discern the purpose of health department staff members in the field looking for index patients or named partners, such as not wearing identification badges, not using marked vehicles, and not explaining to others the reason a particular person is being sought. # Screening for Potential Partner Violence The potential for violence initiated either by a partner or by an index patient during the process of partner notification is an important concern. Published data on violence associated with partner notification are limited. A study conducted in New Orleans, Louisiana, examining the effect of HIV and syphilis partner notification on partnerships found that, at baseline, 42.3% of index patients reported having experienced emotional abuse from a partner in the 3 months before interview and 23.6% reported having experienced physical violence from a partner during the same interval (40). No difference between HIV and syphilis partnerships was found in terms of the proportion of participants reporting either emotional abuse or physical abuse at baseline; during the 6 months after partner notification, emotional abuse and physical abuse decreased significantly among both HIV and syphilis partnerships, with no difference between the two. However, this study did not determine whether any of the abuse or violence was directly related to partner notification. A study of Mexican-American and African-American women with nonviral STDs examined factors related to whether the women had notified their male partners or intended to do so (43). Of 775 women in the study, 63% reported having ever been physically or sexually abused, but history of abuse was not associated with notification status. The women reported having experienced abusive behavior in relationships with 19% of the male partners; however, this also was not associated with notification status, and only 4% of the women cited concern about violence as a reason for not notifying a partner. Additional insight into the topic of notification-associated violence might be gained through studies of partner violence associated with disclosure of positive HIV serostatus, although the findings are less likely to apply to other STDs. A small number of surveys of HIV-infected women have indicated that rates of disclosure-associated partner violence might range from 0.5% to 4% (41). Interviews with 336 HIV-positive and 298 HIV-negative pregnant women in Brooklyn, New York; Connecticut; Miami, Florida; and North Carolina found that the proportion of women reporting violence was not higher among 142 HIV-positive women who received the HIV diagnosis during the current pregnancy (5.8%) than among seronegative women (10.7%) or HIV-positive women who previously received the diagnosis (9.4%) (42). Of 260 HIVpositive women with main male partners, 206 (79.2%) said their partner knew their serostatus; of these, one (0.5%) reported being physically assaulted when her partner found out she was infected. Thus, this study indicates that disclosureassociated partner violence was rare. However, 21% of the women had not disclosed their serostatus to their partners; the estimated risk for violence might have been higher had all these women disclosed their status Although the rate of violence directly attributable to partner notification is likely low, the available data are limited, and additional study is needed. The prevalence of partner violence among the populations studied in the few published reports is of substantial concern, regardless of whether the violence was precipitated by partner notification or was coincidental. Therefore, screening for potential risk for partner violence before notifying partners is important. # Recommendations for Notifying Partners of Exposure # Partners • All identified partners should be notified of their possible exposure as soon as possible, typically within 2-3 working days of identification, unless a potential for partner violence exists. • Program managers should ensure that protocols include screening for potential violence with each partner named before notification. If the provider considers a violent situation possible, the provider should seek expert advice before proceeding with notification. DISs should follow up on referrals for partner violence services to verify that referred persons are safe and have accessed these services. • Programs should establish criteria for prioritizing the order in which partners are notified. Criteria should be based on behavioral and clinical factors that confer a higher likelihood of the partner having been infected as a result of exposure or, if already infected, of transmitting infection to others. In addition, the Ryan White CARE Act Amendments of 1996 require that states receiving funds under part B of title XXVI of the Public Health Service Act should ensure that a good-faith effort is made to identify spouses of HIV-infected patients. Criteria should be reviewed at regular intervals (at least annually). • Programs should accommodate various notification strategies that allow the DIS and index patient to collaborate on the best approach for notifying each partner of exposure and ensure that the partner receives appropriate counseling and testing. Regardless of which strategy is used, the DIS and index patient should plan for potential unanticipated outcomes. • For partners for whom the index patient has provided a name (or other identifying information, such as an alias) and locating information, programs should strongly encourage provider referral but be supportive of index patients who choose contract referral for selected partners. • When contract referral is chosen, the DIS should establish an agreement with the index patient specifying when partners should be notified (typically within 24-48 hours), how the provider will confirm that partners were notified, and which follow-up services will be required for situations in which the index patient does not notify the partner within the allotted time frame. • Programs should allow for self-referral as permitted by state and local laws and regulations. Index patients who choose self-referral for certain or all partners should be informed of its disadvantages and informed about methods for accomplishing the notification safely and successfully. Self-referral should be discouraged if screening indicates a potentially violent situation. • Protocols for self-referral should, when possible, incorporate interventions that enhance its effectiveness and include instructing the index patient about the following: -when to notify the partner (e.g., within 24-48 hours); -where to notify the partner (e.g., private and safe setting); -how to tell the partner; -how to anticipate potential problems and respond to the partner's reactions; -how and where the partner can access counseling and testing for HIV and other types of STDs; -for persons with HIV infection, how to address the psychological and social impact of disclosing infection status to others; and -how to contact the DIS with any questions or concerns that might arise. • To the extent possible, programs should develop methods of monitoring whether partners who are to be notified by the index patient (i.e., via contract or self-referral) are actually notified and receive appropriate counseling and testing. • Dual referral should be an option for index patients who prefer to be directly involved in the notification but express a need for assistance and support from the DIS. When dual referral is chosen, the DIS and index patient should plan in advance how the session will be conducted. • Program managers should ensure that policies and procedures, consistent with applicable laws, are in place to protect the identities of index patients when informing partners of their exposure and to ensure that information about partners is not reported back to index patients. • Local reporting laws relating to domestic violence, including child abuse and abuse of older adults, must be followed when clients report risk or history of abuse. • Program managers should ensure that DISs are the following: -knowledgeable about HIV and STD infections, transmission, and prevention; -well informed about relevant laws and regulations; -familiar with HIV and STD program standards, objectives, and performance guidelines; -culturally competent in providing partner services; -skilled at problem solving and dealing with situations that might be encountered in the field (e.g., personal safety, intimate partner violence, and violence to others); and -trained how to screen for and address partner violence concerns. # Social Contacts General. In general, notification of partners should have a higher priority than notification of individual social contacts identified through clustering. Routine follow-up of social con tacts should be carried out only after the program is success fully interviewing most new patients with cases and locating and notifying most partners and only after carefully consider ing the potential case-finding yield and resource implications. If this strategy is used, the number of cases identified should be carefully monitored, and the approach should be contin ued only if its effectiveness and cost-effectiveness equal or ex ceed those of other case-finding strategies. Notification of social contacts might be given higher priority during an outbreak. HIV Infection. For persons with HIV infection, informa tion about social contacts should be used as an aid to under standing transmission dynamics in the community and to help guide additional prevention interventions at the community level (e.g., screening and social marketing). In general, if indi vidual social contacts are to be recruited for HIV testing, a self-referral approach rather than provider referral should be used. A provider referral approach should be used only after careful consideration of potential individual and community concerns about privacy and confidentiality. Provider referral might be appropriate during an outbreak. # Risk-Reduction Interventions for Partners Providing Information, Brief Prevention Messages, or Interactive Prevention Counseling Misconceptions and inadequate information about STD/ HIV transmission and methods for reducing transmission risk are common; all partners likely can benefit from receiving information and brief prevention messages about adopting and maintaining safer behaviors to reduce their risk for acquiring or transmitting STDs/HIV (25,106). These messages can be integrated easily into DIS activities. Previous CDC guidelines for HIV partner counseling and referral services and STD partner services have recommended interactive, client-centered prevention counseling for partners (1,2). No published studies are available regarding the effectiveness of prevention counseling specifically in the context of partner services. Some reduction in risk behavior after partner notification has been reported; however, overall, data are too limited to allow any conclusions to be drawn (44,151). A metaanalysis of HIV counseling and testing research published during 1985-1997 concluded that HIV counseling and testing did not seem to reduce risk behaviors among HIVnegative persons (112). However, the studies included generally provided little or no detail about the type of counseling used. Subsequently, the previously mentioned Project RESPECT trial (25) demonstrated that heterosexual STD clinic patients who tested negative for HIV and received either two sessions of brief, interactive, client-centered prevention counseling intervention or four sessions of enhanced, interactive, theorybased prevention counseling reported higher levels of condom use at 3-and 6-month follow-up than those who received two sessions of didactic information only; all three groups continued to report higher levels of condom use at 9 and 12 months than at baseline, but the difference between the two counseling groups and the didactic information group was no longer significant. Compared with participants in the didactic information group, 30% fewer participants in the two counseling groups had new STDs during the first 6 months following enrollment, and 20% fewer had new STDs during the entire 12-month follow-up period. A later study examined the effect of adding a follow-up counseling session 6 months after the initial 2-session counseling intervention (152). Participants who received the follow-up counseling session and those who did not had similar rates of new STDs during the subsequent 6 months. At the 9-month follow-up visit (3 months after the follow-up counseling session), participants who received the follow-up counseling session reported significantly less sexual risk behavior than those who did not receive the follow-up counseling; however, at the 12-month follow-up, this difference was no longer significant. Another study examined the relative efficacy of a single prevention counseling session in conjunction with rapid HIV testing compared with two prevention counseling sessions in conjunction with standard HIV testing (153). The incidence of new STDs among participants in the two groups during the subsequent 12 months was not significantly different (19.1% among rapid testers vs. 17.1% among standard testers). Brief group-level counseling of STD clinic patients also has been found to be effective (154)(155)(156). The possibility that prevention counseling might be more effective for notified partners than for persons in a more general population, given that the exposure risk for partners is personal and certain rather than hypothetical, has not been studied. As previously mentioned, many persons testing positive for HIV reduce transmission risk behaviors after learning they are infected (30,112,114). # Other Prevention Interventions For certain partners, more intensive prevention interventions might be appropriate. Behavioral risk screening might be useful for identifying these persons. Several more intensive riskreduction interventions have been demonstrated to be effective (26,27,31,157). As mentioned previously, these interventions cannot reasonably be delivered through partner services activities but might be available through other service providers in the area (e.g., CBOs) or as part of ongoing prevention activities incorporated into the medical care of persons living with HIV infection (54). DISs can play an important role in referring partners to these services. Many partners who are notified of exposure to HIV do not receive counseling and testing. In one review, only 63% of notified partners were known to have been counseled and tested (16). One reason for this might be that partner services programs are unaware when partners are counseled and tested by another provider or receive counseling and testing at a later date. # Recommendations for Risk-Reduction Interventions for Partners • Program managers should develop protocols that describe the minimum amount of general information and prevention messages that should be provided to all partners at the time of notification. • # Cluster Interviewing Partners Previous CDC guidelines for STD partner services have recommended the use of cluster interviews with partners (1). Cluster interviews involve eliciting information from uninfected partners about their own partners and other persons in their social networks who might benefit from counseling and testing. These persons, referred to as associates, might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination (e.g., pregnant females). Cluster interviewing might also include eliciting information about venues in which partners and their associates interact socially (e.g., bars or clubs). As with clustering of index patients, cluster interviews of partners can be used for identifying additional cases or for epidemiologic purposes. Data on the effectiveness of cluster interviewing for case finding are limited. In one study, a network approach was used to notify partners of persons with syphilis in an Atlanta, Georgia, zip code with a high syphilis rate. Among sex partners of uninfected partners, social contacts, and associates, 5.7% were infected with syphilis, whereas 5.3% of nonsexual contacts were infected (73). Another study analyzed partner notification for syphilis in Louisiana and found that a total of 29 (6%) of 503 associates who were located and examined had newly diagnosed cases of syphilis (74). As previously mentioned, a review of the case-finding effectiveness of cluster investigation for HIV and other STDs found that the number of cases identified through cluster investigations for syphilis is substantially less than the number identified from syphilis partner notification (8). Finally, during an outbreak of syphilis in a suburban Atlanta, Georgia, community, interview of social contacts and associates facilitated identification of an extensive sexual network that might otherwise have gone undetected (158). Data from a small number of reported studies suggest that the case-finding yield of cluster interviews for syphilis is substantially lower than that of partner notification, that this approach might be more productive in areas with relatively high syphilis case rates, and that it might be particularly useful during an outbreak. Published data on the case-finding yield of cluster interviews for HIV are not available. As with clustering of index patients, information obtained through cluster interviews has potential value for providing insight into how and where infection is being propagated in the community and might help guide screening or other prevention interventions (e.g., social marketing campaigns) at the community level. # Recommendations for Cluster Interviewing Partners # General • When notifying partners of their possible exposure, DISs might also elicit information about the partners' social networks, including venues frequented, for use in planning additional prevention activities. • In general, notification of partners should be prioritized over follow-up of individual associates identified through cluster interviews. Routine follow-up of associates should be done only after the program is successfully interviewing most new patients with cases and locating and notifying most partners, and only after carefully considering the potential case-finding yield and resource implications. If this strategy is used, its case-finding yield should be carefully monitored, and the strategy should be continued only if its effectiveness and cost-effectiveness equal or exceed those of other case-finding strategies. Follow-up of associates might be given higher priority during an outbreak. # HIV Infection • For persons with HIV infection, information about associates should be used as an aid to understanding transmission dynamics in the community and to help guide additional prevention interventions at the community level (e.g., screening and social marketing). In general, if individual associates are to be recruited for HIV testing, a self-referral approach rather than provider referral should be used. A provider referral approach should be used only after careful consideration of potential individual and community concerns about privacy and confidentiality. A provider referral approach might be appropriate during an outbreak. # Testing Partners After partners are notified of possible exposure to STDs/ HIV, they must have access to appropriate diagnostic testing and treatment as soon as possible. Many partners who are notified of possible exposure to HIV do not receive counseling and testing. The number of partners who are examined and receive counseling and testing might be increased if testing is performed at the time of notification, whether this occurs at the clinic or another health-care facility or in the field. # Syphilis Serologic testing remains the standard for syphilis testing and requires a blood sample (159). Blood can be drawn easily in a clinical setting; certain DISs are trained in phlebotomy and can draw blood in the field. Rapid tests have been developed but are not yet approved by the Food and Drug Administration for use. Moreover, rapid tests do not indicate stage of disease like reagin-based tests (i.e., through measuring titers). Whether partners are interviewed or have blood drawn in the field, they should be referred for evaluation and possible treatment. # Gonorrhea and Chlamydial Infection Gonorrhea and chlamydial infection both can be detected via culture; however, chlamydia cultures are demanding and lack sensitivity, and transport of both types of organisms require careful attention to ambient conditions. However, nucleic acid hybridization tests, and, increasingly, nucleic acid amplification tests (NAATs) have been used more frequently in recent years. Non-NAATs are less sensitive than NAATs, and NAATs can be used with urine samples as well as urethral (men) and endocervical (women) samples (160,161). Testing of samples in the field is not feasible; therefore, partners tested at the point of notification can only be referred for evaluation or dispensed medication on a prophylactic basis (i.e., via fielddelivered therapy). For those who are notified via telephone, follow-up evaluation can be conducted by obtaining urine samples via mailed kits; kits can be mailed to the partners and returned in person or by mail. No data are available on the application of mailed kits for testing, but use of this option for programlevel rescreening was moderately successful (i.e., a 22% response rate and 3% positivity) in one study with women (162). Although 22% is not a strong response rate in many settings, public health agents who are rescreening per CDC guidelines have 22% fewer patients (3). A similar approach was used for chlamydial screening (not rescreening) of men in a managed care organization; 7.8% of men who received a kit were tested, although this rate was higher than the rate achieved by a letter alone (3.6%) (163). However, testing rates might rise if tests were conducted in conjunction with notification, because partners might be more concerned about being infected. # HIV Infection Testing in clinic settings can be conducted with conventional test procedures or with rapid tests using oral fluid or blood. If notification is carried out in the field, a rapid test can be performed, an oral fluid specimen can be obtained or blood drawn for conventional testing, or the partner can be escorted or referred to a public health clinic or other test provider. Ensuring that partners who are tested, especially those who test positive, receive their test results is critical. At publicly funded counseling and testing sites in 2004, only 84% of persons testing positive and 78% of those testing negative received their test results (61). Research has shown that rapid testing is acceptable and feasible in various settings and that more persons might get tested and learn their results if they are tested with rapid rather than conventional tests (164)(165)(166)(167)(168)(169)(170). Rapid testing has also been found to promote earlier initiation of care compared with conventional testing (167). Although the use of rapid testing in partner services has not been well studied, in one survey of health departments, 16 (37.2%) of 43 departments that responded reported using rapid tests in their partner services programs (171). Partners might be infected with HIV but test negative because of the window period between infection and development of detectable levels of HIV antibodies. With recent EIA tests (e.g., second-generation IgG-sensitive tests and third-generation IgG/IgM-sensitive tests), most infected persons develop detectable antibody within 3 months of infection (89,90). Therefore, partners who test negative but whose last date of exposure is unknown might ordinarily be advised to be retested 3 months later; those known to have been exposed recently might be advised to be retested 3 months after the date of last known exposure. In partner services, suggestions for retesting are complicated because reference to any date might compromise the index patient's identity. For this reason, routinely suggesting that partners be tested at the time of notification and retested 3 months later might be the best course of action. Persons with acute or recent HIV infection might test negative because of the window period. HIV RNA testing has been used to screen pooled, HIV antibody-negative specimens to identify persons with acute or very recent infection (i.e., HIV RNA positive and HIV antibody negative) (70,90,(92)(93)(94)(95)(96)(97)(98). Given the high prevalence of previously undiagnosed HIV infection among partners and the possibility that partner notification might lead to earlier detection of HIV than other strategies, HIV RNA testing might also be useful in this context. However, prospective use of testing for acute or recent infection in the context of partner services has not been reported. # Screening for Concomitant Infections Although rates of coinfection vary considerably in different areas and settings, partners who are notified about exposure to one STD often are at risk for other STDs, including HBV. Drug-injection partners are at risk for both HBV and HCV (172). Consequently, partners being notified of exposure to any STD, including HIV, might benefit from 1) screening and treatment for other STDs and 2) HBV vaccination (and HAV vaccination for MSM) (3). Those with a history of injection drug use should be screened for both HBV and HCV. Screening for HIV, syphilis, chronic HBV, and chlamydial infection is currently recommended for all pregnant women, as is screening for gonorrhea and HCV in pregnant women at risk (3). For sexually active MSM, current screening recommendations include serologic tests for HIV and syphilis, tests for urethral gonorrhea and chlamydial infection in men who have had insertive intercourse in the preceding year, tests for rectal gonorrhea and chlamydial infection in men who have had receptive anal intercourse in the preceding year, and a test for pharyngeal gonorrhea in men who have had receptive oral intercourse in the preceding year (3). HBV vaccine is recommended for all nonvaccinated, uninfected persons being evaluated for an STD (3,173,174). HAV vaccine is recommended for MSM and users of illicit drugs (both injection and noninjection) (3,175). Specific details about hepatitis vaccination, including prevaccination serologic testing, are available at http://www.cdc.gov/hepatitis. Partner services provide an opportunity to integrate these services at the client level. Although integration might be difficult for logistical reasons (e.g., testing being done in the field by a person not authorized to administer vaccines) or because of limited resources, partner services and other health department program managers might be able to collaborate to make these services available to partners. # Recommendations for Testing Partners # General • To the extent possible, testing for HIV and other types of STDs should be done at the time of notification. Partners who are not tested at the time of notification should be escorted or referred to the health department for testing or linked to other health-care providers who can provide these services. • DISs should follow up on partners not tested at the time of notification to verify that testing has occurred, test results were received and understood, and other referral services were accessed. If another health jurisdiction has been asked to contact a partner, follow up should be conducted by the initiating health department to determine whether services have been received. • Program managers should explore ways in which screening for HIV, screening and treatment for other types of STDs, screening for HBV and HCV, and vaccination for HAV and HBV might be integrated in partner services programs. # Syphilis • Blood should be drawn in the field when DISs are trained to do so and when specimen maintenance conditions can be met. Partners should be referred for evaluation regardless of whether a specimen has been collected. # Gonorrhea and Chlamydial Infection • If provider referral is used, programs should consider protocols for collecting specimens in the field. # HIV Infection • Partner services programs should consider using rapid HIV tests to maximize the number of partners who are tested and receive test results. • When notification is done in the field, rapid tests should be used or a blood or an oral fluid specimen should be collected for conventional testing. If neither of these is possible, the partner should be escorted or referred to the clinic for testing. • Partners who test negative for HIV antibody should be advised to be retested in 3 months. # Treatment for Partners Syphilis, Gonorrhea, and Chlamydial Infection The principal goal for syphilis, gonorrhea, and chlamydial infection is immediate treatment, whether curative for infected partners or preventive if a partner tests negative or has an unknown status. Timely treatment of partners serves as a primary means of minimizing subsequent transmission. Expedited partner therapy (EPT) is a process through which treatment for partners of persons with a diagnosis of gonorrhea or chlamydial infection is administered before the clinical evaluation occurs. Most uses of EPT involve patient-delivered partner therapy (PDPT), or delivery of medications or prescriptions via the index patient. EPT is recommended as a clinical option for heterosexual men and women, especially for partners who are not likely to seek evaluation (3,176). On an individual basis, clinicians and patients decide whether to use EPT; at the program level, no evidence suggests that partners of persons with either gonorrhea or chlamydial infection seek care in sufficient proportions to stem transmission. Randomized, controlled trials of single-dose oral therapy for both STDs have shown reduced rates of reinfection among index patients exposed to EPT compared with controls; approximately 20% for chlamydial infection and 50% for gonorrhea (126,177,178). A 2007 metaanalysis of trials revealed that these were statistically significant overall reductions (179). Use of EPT also was associated with increased rates of index patient notification of partners and of partner treatment. However, EPT was not associated with reduced reinfections among women with trichomoniasis; in addition, EPT with MSM should be used cautiously because of lack of data showing efficacy of EPT for MSM, and because the risk of potential comorbidity with HIV is higher among MSM with STDs than among heterosexual males or females (3,127). Ensuring that EPT is accompanied by written instructions is important, including instructions for the medication, for the length of time to avoid sexual activity, and advice to seek evaluation. Essentially, instructions are equivalent to a referral card. Single-dose therapy with EPT is the most likely to result in treatment being administered appropriately and completely, just as with therapy prescribed to a patient. EPT with multidose regimens has not been evaluated (e.g., doxycycline for chlamydial infection). Other general treatment recommendations relevant to EPT include cotreatment for chlamydial infection in persons with a diagnosis of gonorrhea, but not vice versa. Although the high caseload of gonorrhea and chlamydial infections have inhibited provider referral, a few programs have used EPT through DIS delivery of medications, or fielddelivered therapy (FDT). The DIS (or public health nurse) delivering FDT should be licensed to do so under a protocol for standing orders or another similar arrangement. In 1999, the San Francisco Department of Public Health used FDT for partners of patients with gonorrhea and chlamydial infection (180). By 2000, the proportion of partners completing treatment increased from 62% to 81%. The advantage of FDT over PDPT is that DISs can be trained to watch for immediate adverse reactions (e.g., allergic reactions) and can verify treatment and deliver prevention messages directly, an approach similar to directly observed therapy for TB infections. The disadvantage of FDT is that a public health staff person is required to trace and notify partners; therefore, resources remain a vital consideration. Although unevaluated, FDT is a possible strategy for treating syphilis if 1) a person licensed to administer injections and monitor and respond to adverse reactions accompanies the DIS and 2) the partner's stage of disease and coinfection can be adequately addressed during the contact interview. Although treatment on the basis of exposure is a well-known public health strategy, the absence of a clear physician-patient relationship places EPT (especially in the form of PDPT) in an uncertain legal status in many jurisdictions. To aid programs in establishing formal programs that are clinically useful and legally defensible, CDC has a website (available at http://www.cdc.gov/ std/ept) with CDC guidance, guidance models from states in which EPT is specifically permitted, and a state-by-state analysis of the legal landscape of EPT, based on a recent survey of laws, regulations, court decisions, and policies (181). # HIV Infection As mentioned previously, effective and timely medical evaluation, initiation of currently recommended combination ART, provision of appropriate vaccinations and other preventive health interventions, and referrals for a wide range of other medical and psychosocial services are critical for persons with a new diagnosis of HIV infection. Linking partners who test positive for HIV to medical care and HIV case management is essential as soon after diagnosis as possible. The importance of linking HIV-infected partners to medical care and verifying that they have had a medical evaluation or received HIV case management at least once cannot be overemphasized. Accumulated data from animal and human clinical and observational studies suggest that PEP for sexual, injectiondrug use, and other substantial nonoccupational HIV exposure might prevent HIV infection and that potential risks from PEP (e.g., increase of risky sexual behavior, adverse reactions to medications, and selection of resistant virus) might be minimal (182). PEP is intended to be initiated within 72 hours of exposure to HIV, and antiretroviral medications must be taken for 28 days. Partners who have been exposed and can be notified within this time frame might be candidates for PEP (3). Because PEP is only intended for persons who are HIV negative and because partners might not be aware of their HIV status, access to rapid testing is necessary for this option to be offered. Incorporating PEP into partner services programs poses substantial logistical and resource challenges; however, certain health departments have developed program recommendations for PEP that might be useful for jurisdictions considering implementing such a program (183). Although PEP might be useful in certain partner services contexts (e.g., with new partners of the index patient), health departments will ultimately need to evaluate whether integrating PEP into their partner services programs is feasible and consistent with program objectives. # Recommendations for Treatment for Partners # Syphilis, Gonorrhea, and Chlamydial Infection • Program managers should ensure that partners are treated according to CDC treatment guidelines as soon as possible after notification. • Programs should consider FDT for gonorrhea and chlamydial infection when partners are notified via provider referral. • Because single-dose oral therapy is used for gonorrhea and chlamydial infection, programs should consider PDPT for partners who will not be notified via provider referral. • Programs should be sure that all appropriate parties are consulted to ensure that any EPT strategy in the jurisdiction is medically and legally sound. Appropriate parties vary by jurisdiction but might include state health commissioners or legislative bodies. HIV Infection • # Referring Partners to Other Services Whether partners test positive or negative for a particular disease, underlying factors might impede their ability to access medical care effectively or adopt and maintain safer behaviors, and they might benefit from referral to various psychosocial services. Considerations regarding referrals for partners are essentially the same as those for referrals for index patients. # Recommendations for Referring Partners to Other Services • Because of the diverse needs of partners, program managers should identify referral resources for psychosocial and other support services. DISs routinely should be provided updated information about referral resources. • Many referral needs of partners testing positive for HIV will be addressed through linkage to early intervention, medical care, and HIV case management; however, DISs should screen for immediate needs and make appropriate referrals. • Partners testing negative for HIV should be screened and referred for other medical and psychosocial needs and prevention services. # Specific Populations The recommendations in this report generally apply to all lients with HIV infection or other STDs regardless of setting, opulation, or disease. However, certain populations such as ouths, migrant and immigrant populations, and persons in orrectional facilities have unique characteristics and ircumstances. (184). ouths are at higher risk for HIV infection and other types of TDs because they frequently have unprotected intercourse, re biologically more susceptible to infection (especially emales), are engaged in sexual partnerships of limited uration, and face multiple obstacles to using health care . The unique biologic and cognitive developmental oncerns associated with youths require that services for them e developmentally appropriate and as comprehensive and eamless as possible. # artner Elicitation Approaching youths who have received a recent diagnosis f HIV or any other type of STD can be challenging. Before roaching the subject of partner elicitation with a young index atient, assessing immediate needs is important, especially for atients in need of housing or food. Youths might have many isperceptions and information gaps about partner services hat need to be addressed, such as understanding that partner ervices are voluntary and that they have the right to decline articipation. They also should understand the concept of confidentiality and that it includes not reporting to their parents unless the youth requests parent or guardian involvement. In addition, specific counseling skills might be necessary, especially for youths with a recent diagnosis of HIV, to ensure that they understand the ramifications of the diagnosis and how to prevent future acquisition of HIV and other types of STDs and transmission to others (190). Youths who fear losing partners and friends might find it especially difficult disclosing information about sexual or injection-drug partners and other social contacts (191). In addition, youths might be reluctant to provide information about adult partners because of fear of legal repercussions related to sex between an adult and a youth. In addition, fear of partner violence might prevent partner identification; therefore, assessing the potential for partner violence is essential for each partner identified. Assessing other potential violence or maltreatment situations that might occur involving parents, guardians, or friends also is critical. Finally, DISs providing services to youths should be sure to discuss the topic of sexual abuse with their clients; if sexual abuse is suspected, they should notify the appropriate authorities (e.g., child protective services agency) in accordance with applicable laws and regulations. # Notifying, Counseling, and Testing Partners Although the process of notifying partners named by youths and named by adults is the same, legal concerns might exist in situations with youths, especially when an adult partner is named. Knowledge of state laws is essential; if sexual abuse or statutory rape is suspected, staff members must be prepared to report to the appropriate agency. Counseling skills of partner services providers are especially important when partners are very young or immature. Developing simple and clear messages regarding the STD and HIV notification process is needed to ensure that youths are able to understand the purpose of notification and the urgency of getting tested if testing is not provided in the field (190). Being able to assess the maturity of the partner is a fundamental skill for DISs so that they can ensure that an appropriate plan of action is developed. Young partners might also require specific types of assistance to obtain testing. For example, partner services staff members should be prepared to call previously identified testing sites, make an appointment for testing, and then follow up with the youths to verify that they received the test. Youths might be reluctant to access services because of financial and transportation limitations and because of fears that parents must give permission or be informed. Youths must understand that, with a few exceptions, all adolescents in the United States can legally consent to receiving a confidential diagnosis and treatment of STDs (3) In all 50 states and DC, medical care for STDs can be provided to adolescents without parental consent or knowledge. In addition, in the majority of states, adolescents can consent to HIV counseling and testing. Consent laws for vaccination of adolescents differ by state. Several states consider provision of vaccine similar to treatment of STDs and provide vaccination services without parental consent. Because confidentiality is crucial, health-care providers should follow policies that provide confidentiality and comply with state laws for STD services. Partner services staff members should remain knowledgeable and updated on related state and local laws and regulations. # Treatment for Partners Because youths often are a medically underserved population compared with persons in other age groups, they might be less likely to receive office-based medical care or to use primary care services (192,193). Reasons for this include concerns about confidentiality, lack of health insurance, lack of adolescent-specific services including health-care providers with adolescent health experience, and appointment times that conflict with school schedules (185,(194)(195)(196)(197)(198). HIV-infected youths might face additional challenges, and health care providers serving HIV-infected youths report that acceptance of HIV diagnosis and return for care and treatment can take many months. Programs might be able to increase the likelihood of successfully linking adolescents to care and treatment by developing relationships with medical facilities that are sensitive to youth concerns and that have a strong case-management component (199,200). # Confidentiality and Privacy Although confidentiality is a basic principle for all steps of the partner services process, careful attention must be paid to providing a private and safe place for the interview and notification process for young index patients and their partners. However, ensuring confidentiality in cases involving suspected child or sexual abuse is not always possible. Local laws, statutes, and regulations define the limits of confidentiality in these cases. # Recommendations for Youths • Programs should have specific protocols in place to guide partner services for youths. Protocols should address assessment of maturity and extent of social support, use of age-appropriate counseling and communication models, provision of services in youth-friendly environments, and assessment for physical and sexual abuse. These protocols should be developed in collaboration with legal counsel to ensure that they are consistent with all applicable laws and regulations. # Immigrants and Migrants Data on the prevalence of HIV infection or other STDs among immigrant and migrant populations in the United States are limited. However, certain immigrant and migrant populations in the United States might be particularly vulnerable to HIV and other STDs because of inadequate knowledge about the infections, lack of information about and access to prevention and related health-care services, and delays in accessing HIV and other STD testing, treatment, and care (201,202). Immigrant and migrant women also might experience concerns related to power and economic disparities between men and women that make women more vulnerable to sexual abuse or domestic violence and decrease their ability to protect themselves from sexual exposures to infection (203). All of these concerns might contribute to HIV and other STD acquisition and transmission among these populations. Partner services programs can be an effective way to identify and reach members of immigrant and migrant populations who might not otherwise access HIV and other STD testing services. # Partner Elicitation Concerns affecting partner elicitation among migrants and immigrants might include difficulty in locating such persons because of their transient movement within the United States or across international borders (e.g., U.S.-Mexico border) (204). Interviews might be difficult because of language and cultural barriers. Index patients might be reluctant to provide information if translators are family members or are from their own communities. A lack of understanding about the voluntary and confidential nature of partner services makes it essential that simple and clear messages are provided to encourage participation and gain the trust of index patients. Partner elicitation might be hindered by concerns that named partners could be deported (205). Concern about individual stigma related to STDs or HIV infection and activities related to transmission (e.g., male-to-male sex or injection drug use) also might be a barrier to full participation in partner services. Because of fears of partner violence, which might be substantial among immigrant and migrant women, DISs must be able to adequately assess the potential of partner violence before initiating partner notification (206). # Notifying, Counseling, and Testing Partners Locating and notifying partners among immigrants and migrants might be difficult for the same reasons that partner elicitation is challenging. In addition, the usual counseling models might not be culturally appropriate because of cultural norms regarding discussion of sex and sexual behaviors. These concerns can make risk assessments or HIV and STD prevention counseling especially difficult. # Treatment for Partners Treatment and care services might not be available or easily accessible to immigrant and migrant populations because of a lack of financial resources, transportation, and child care resources. Concerns about confidentiality, loss of employment, and fear of deportation or other legal consequences also might make immigrant and migrant populations reluctant to access care. If they do access care, medical care providers might lack linguistically and culturally appropriate services. # Recommendations for Immigrants and Migrants • Program managers should review epidemiologic and other data to identify potential immigrant and migrant populations at high risk for infection in their jurisdictions and be prepared to provide partner services that are linguistically and culturally appropriate. # Incarcerated Populations The majority of the 2.2 million adults and juveniles residing in jails, detention centers, and state and federal prisons eventually will be released and rejoin the larger community. Persons in prisons are generally housed for longer periods of time than persons in other correctional facilities, such as jails. Certain persons in city and county jails and juvenile facilities are released in less than 24 hours, with the majority (93%) of jail inmates staying less than 1 year (207). Multiple studies and surveillance projects have demonstrated high rates of sexual risk and STD prevalence among persons entering prisons, jails, and juvenile correctional facilities (208)(209)(210). Data from the Bureau of Justice Statistics indicate that, as of December 31, 2005, a total of 22,480 (1.8%) state and federal prison inmates were infected with HIV or had confirmed AIDS. The prevalence was higher in state prisons (20,888 inmates, 1.8%) than in federal prisons (1,592 inmates, 1.0%) and was higher among female than male inmates (2.3% and 1.7%, respectively) (211). A study of syphilis cases during 1997-2002 in Indianapolis, Indiana, and Nashville, Tennessee, found that 19% of cases in women and 27% of cases in men were identified through jail screening; in certain situations, the casefinding yield of jail screening approached that for STD clinics (212). Many persons who are arrested are at high risk for STD and HIV infection because of high-risk behaviors (e.g., multiple sex partners or injection and other drug use) and poor health-care-seeking behaviors while in the community. Therefore, providing routine screening for HIV and other types of STDs during the correctional facility intake process offers an opportunity to identify infections, prevent complications, and reduce further transmission by improving access to treatment, care, and prevention. Many correctional facilities provide screening for HIV and other types of STDs. Conducting partner services for persons in correctional facilities who test positive presents a unique opportunity to access possibly hard-to-reach partners at high risk for infection both in the facility and in the community. Conducting partner services might lead to a better understanding of risk behaviors and prevention needs of inmates, help programs better target resources and evaluate prevention program performance, and possibly lead to a better understanding of disease transmission dynamics in the broader community. The extent to which partner services are conducted in correctional facilities varies with program resources and individual facilities. When public health staff members conduct these services in correctional facilities, formal collaboration mechanisms between the health department and the correctional facility are essential to help coordinate activities and ensure that all parties understand what is needed to conduct services within the facilities. Following are factors to consider when developing partner services programs for incarcerated populations. # Partner Elicitation Inmates who receive a diagnosis of HIV infection or another STD while incarcerated might not want to identify sex or injection-drug partners that reside in the community or the facility. Partner services providers should be aware that partners might include other inmates, correctional facility staff members, or visitors. Reasons for not wanting to identify partners might include fears of partnership dissolution, loss of privileges within the facility, and concerns about revealing possible illegal activities. Before partner services providers ask inmates for information about partners, the providers should ensure that the inmates understand the confidential and voluntary nature of partner services and the limits of confidentiality related to disclosing information about sex partners who reside within the facility. In all states, sex with another inmate or with correctional facility staff members is prohibited and might be required to be reported (213). Therefore, partner services programs should have a full understanding of these laws and regulations as well as of individual facility policies before initiating any partner services activities. Inmates have a right to privacy and confidentiality of their medical information, and DISs have a duty to protect all confidential information. However, maintaining the confidentiality of inmate health information might be challenging in correctional facilities. Partner services programs should work with medical staff members within the facilities to ensure that procedures are in place to reduce possible breaches of confidentiality. Breaches of confidentiality for inmates with HIV infection or other STDs might result in increased discrimination, stigmatization, and violence. Because incarcerated populations often are moved about within correctional systems, locating or accessing an index patient might be difficult. Partner services providers should work with correctional facility staff members to determine how best to locate and access inmates. In addition, other challenges might arise if a particular inmate has already been released, because released inmates are often transient, use aliases, or do not have a permanent address. If the inmate has already been released, DISs should obtain contact information from the correctional system to assist with partner services activities. Having a private space to conduct partner elicitation in correctional facilities might be a challenge. Correctional healthcare clinics often are busy, and space is not always available. In addition, security concerns often require that custodial staff members are able to see staff members and inmates at all times to ensure safety. Thus, clinic layout and proximity of nonhealth-care staff members can create an impression of lack of privacy or confidentiality. Partner services staff members must work with correctional facility staff members to identify a private area, whether in the clinic or in the housing area, to elicit partner names without compromising safety. The # Notifying, Counseling, and Testing Partners For named partners who are located in the community (i.e., not in the correctional facility), the notification process is no different than for partners named by persons outside correctional facilities. However, legal concerns might exist related to named partners who are located within the correctional system (e.g., other inmates or correctional facility staff members). Knowledge of state laws and possible reporting requirements are essential, and partner services staff members must be prepared to adhere to these regulations and should consult with program managers or legal counsel when questions arise regarding specific situation. # Treatment for Partners Ensuring medical care for partners who are inmates is the responsibility of the correctional facility. Facilities that release inmates before adequate care or treatment can be provided should provide referrals before the release. However, when program resources are available, partner services staff members can provide follow-up for recently released persons to verify that they are adequately treated or are linked to care. Correctional facilities or the health department also should consider partnering with local service providers, including CBOs, that provide transitional services. These agencies might be able to provide follow-up and possibly HIV case-management services especially for those who are HIV infected. # Recommendations for Incarcerated Populations • Program managers should become familiar with the federal, state, or county jail and correctional facilities in their jurisdictions. They should meet with key personnel in correctional facilities to discuss the services offered and goals of partner services as a public health intervention, the need for public health staff members to have access to facilities and adequate private space to meet with clients, and ways that partner services activities can be integrated into the facility response plans that are required by PREA. Follow-up meetings to facilitate communications and coordination should be held periodically. • Program managers and key correctional facility personnel should establish a formal written agreement to clearly outline roles and responsibilities for both public health and correctional facility staff members. • Program managers should collaborate with correctional facility staff members to develop protocols for partner services staff members to follow while in the facility, especially during emergencies. Ensuring that partner services staff members know and adhere to facility rules and regulations also is essential. Not adhering to the rules and regulations of a correctional facility will jeopardize implementation and continuation of the partner services program. • Program managers should collaborate with correctional facility staff members to develop protocols regarding administration of partner services for named partners within a correctional facility. # MMWR November 7, 2008 # Strategies to Enhance Case Finding and Partner Notification Core Areas A core area is a specific, typically geographically defined area, such as a neighborhood or census tract, that has a relatively high concentration of STDs and likely accounts for a large proportion of disease transmission in a community. Infected persons in a core area might not have any social or sexual connections; their only relationship might be geographic. An example of a core area is a zip code in which >50% of the gonorrhea cases in the county are identified. Core areas are different from core groups, which are socially defined groups of persons who are likely to be a source of continued disease transmission (i.e., core transmitters). In certain circumstances, programs might maximize resource use and prevention effectiveness by concentrating on specific core areas. For example, in New York state, targeting 100% of provider-referral partner-notification measures for gonorrhea in core areas (as defined by endemic prevalence, or census tracts containing 50% of reported annual gonorrhea cases) was associated with a substantial decline in incidence, even compared with a control area in which a larger proportion (60%-70%) of gonorrhea-infected persons were actually interviewed (7). In Colorado, partner notification services for gonorrhea that focused on a military base (the putative core area) and the surrounding civilian community produced a 13% decrease in overall gonorrhea cases and a 20% decrease in the civilian community (214). Military incidence was largely unchanged. Similar large-scale measures in the United Kingdom (i.e., the Tyneside scheme) have been associated with reductions in gonorrhea morbidity (215). Similar data for chlamydial infection are lacking, and whether core areas play a substantial role in chlamydial infections is uncertain (216). In general, syphilis is so geographically concentrated that syphilis infection-control measures, by definition, involve a core-area approach. # Recommendation for Core Areas • Health departments should assess the geographic concentration of gonorrhea and consider focusing providerreferral partner notification in core areas. # Social Networks A social network is a group of persons connected by various types of social relationships, such as family, work, and recreational relationships; sexual partnerships; and drug-use relationships. A social network also can include the venues in which interactions among the members of a social network occur. The persons in a social network might share social, economic, cultural, or behavioral characteristics that influence their risk for various health conditions, including HIV and other STDs (217). Consequently, members of the social network of a person with HIV infection or other STDs might also be at increased risk for these infections, even though they might not have a sexual or drug-injection relationship specifically with the infected person. By exploring the social, sexual, and drug-use connections among persons and places and diagramming these links, HIV/STD prevention programs might uncover more cases than by relying on partner notification and testing alone. This approach also can provide helpful information about a disease in a core area by integrating epidemiologic, geographic, and sociodemographic information. Using social network methods to identify persons with HIV infection can help bring previously undiagnosed HIVinfected persons into the partner services process and might also be used to identify persons who previously tested positive and left care or never received care. A program that uses this approach can track networks at several levels, first assessing persons and places and then possibly going further to look at geographically defined sociodemographic data. Although this approach can seem intimidating and labor intensive, DISs often collect much of these data during patient interviews and from field records, and certain programs use network approaches on a de facto basis. Other data can be added as resources permit. An established and periodically updated network diagram might aid in the investigation of outbreaks as they occur (rather than as a retrospective tool to explain why they occurred). Programs might also conduct more formal network analyses, which involve calculating various statistics that describe characteristics of a network (e.g., components, degree, betweenness, information centrality, and k-core) (158). However, the capacity to perform these analyses is not available in many health departments and might not be performed quickly enough to affect outbreaks as they occur. Nevertheless, analyses of outbreaks and endemicity can reveal details not otherwise identified and can therefore inform program needs and future actions (218,219). Peer referral is one type of social-network approach that has been used to identify HIV cases; clients are enlisted as recruiters and coached to refer persons from their social networks (peer referral) for counseling and testing. Those referred also can be enlisted to recruit others, creating a peer-driven cluster approach. With the peer-referral approach, virtually all contact with program staff members is at the point of care, and extensive field work is not needed. The approach can be refined by assessing which persons are more effective at referring infected persons or those at high risk for infection and concentrating on the persons who are the most effective. In a demonstration project conducted in seven U.S. cities, nine CBOs enrolled HIV-positive persons and HIV-negative persons at high risk for infection to serve as peer recruiters. These persons agreed to refer persons in their networks who they thought to be at risk for HIV infection for counseling, testing, and referral services (220). The 6% prevalence of newly identified HIV infection found among social network associates tested in this project was five times the average prevalence reported by publicly funded HIV counseling and testing sites. An evaluation project conducted in King County, Washington, enlisted and trained MSM who had received a diagnosis of HIV or other STDs to become peer recruiters and yielded similar results (221). Of the 438 recruited peers who had not previously received a diagnosis of HIV, 22 received a new diagnosis of HIV, an 8% increase in the health department's total HIV case-finding yield. The approach was particularly useful for identifying non-white MSM with HIV infection, increasing the health department's total case-finding yield for this group by 19%. This peer-referral approach was a more cost-effective strategy for identifying HIV cases among MSM in this area than other outreach approaches. (Additional information on implementing a social networks strategy for HIV case is available at http://www.cdc.gov/hiv/resources/ guidelines/snt.) Use of a network approach should not replace partner notification; instead, the approach should be used to enhance existing partner services practices. Initiation of a network approach can be labor intensive, and a full-scale network approach to describing disease in a given program area requires analytic capacity that not all programs possess. Nevertheless, basic network data are often already collected by DISs and other program staff members, and a program could link these data to produce a more complete representation of STDs/ HIV than previously possible. Additional research on the use of social networks for disease prevention is needed. Studies analyzing the use of social networks to enhance partner services and assess disease transmission for a particular area or population have produced encouraging results, but these results might not be generalizable. Peer-driven cluster referral has been most effective for finding cases of both HIV and HCV. As with cluster interviewing and clustering, the effectiveness of the approach in detecting cases is affected by the prevalence of the disease. For example, in Seattle, where the prevalences of gonorrhea and chlamydial infection are relatively low, peerdriven referral among MSM detected minimal numbers of cases of gonorrhea and chlamydial infections (221). The approach needs to be tested among groups with higher prevalence of bacterial STDs. # Recommendations for Social Networks • Programs should assess the social networks that influence disease transmission in the area as a strategy for finding persons who are at risk for disease but have not been identified by an index patient or partner. • This strategy should be used to enhance case finding, considering relevant epidemiological and behavioral information. # The Internet The Internet is used to facilitate formation of sexual partnerships and is a potential contributing factor in situations involving high-risk behaviors and transmission of HIV and other STDs (222)(223)(224)(225). Although most of the published research evaluating links between sexual risk behaviors and Internet use has focused on MSM, findings from studies of heterosexual male and female groups indicate trends that are similar to those identified among MSM; seeking sex partners online is associated with high-risk behaviors and acquisition of HIV and other types of STDs (222,(226)(227)(228)(229)(230). Certain partner services programs have used the Internet for partner notification when the only contact information available for a partner is an e-mail address or Internet screen name. Two studies have documented outcomes for HIV Internet partner notification, and the rate of response (i.e., number of partners who responded to contact attempts) differed substantially between the two studies. Public health staff members who conducted a cluster investigation among MSM in Minnesota used the Internet to contact 50 persons who had been exposed to HIV or other STDs but for whom the only available contact information was an e-mail address or screen name; responses were received from 30 (60%) (231). In Los Angeles, California, an HIV-infected index patient had 111 sex partners for whom he could provide only an e-mail address; of these, 29 (26%) responded to e-mails sent by staff members at the Los Angeles County Department of Health Services (LACDHS) (232). None of these partners would have been notified without Internet partner notification. In a survey of 1,848 U.S. MSM recruited by a banner advertisement on an MSM-targeted website for meeting sexual partners, acceptance of Internet partner notification was high: >92% of respondents indicated that they would use Internet partner notification in some way (i.e., use the health department to notify sex partners via e-mail, notify sex partners themselves via e-mail, or do both) to inform their sex partners if infected with an STD in the future (233). Available data regarding use of the Internet to notify partners exposed to other STDs such as syphilis are sparse but encouraging. In 1999, the San Francisco Department of Public Health (SFDPH) conducted a case-control study of seven early syphilis cases in persons that were associated with an online chat room (234). The mean number of partners per index patients was 5.9, and the only locating information for the sex partners was online screen names. Using the Internet to notify the partners of exposure resulted in 42% of the named partners being notified and confirmed as having been tested. In a review of early syphilis cases among MSM interviewed for partner management during January-April 2003, SFDPH identified 67 men who reported meeting sex partners through the Internet; 14 of these men provided information about 44 sex partners for whom the only locating information was an Internet e-mail address (235). Health department staff members were able to locate 15 (34%) of the Internet partners and ensure that they were evaluated and treated appropriately. In addition, LACDHS reported a case of recently diagnosed syphilis in an index patient who reported having met 16 sex partners through the Internet during his infectious period (232). The patient contacted 13 of these partners via e-mail; seven replied and made arrangements for evaluation. Finally, the Austin/Travis County Health Department sent e-mail messages to sex partners of persons infected with syphilis or HIV when e-mail contact was all that was available to DISs (236). Fifty percent of partners responded, and 81% of those (40% of all partners e-mailed) were evaluated. Thus, although response rates and overall proportion of partners evaluated were substantially lower than for in-person provider referral from the same health department, e-mail provider referral resulted in numerous partner notifications and evaluations when in-person notification was not possible. Internet-based partner notification services are available online for several U.S. cities and states (http://www.inspot.org). Website users can learn the individual-and community-level rationales for partner notification, find locations for testing resources, and send a notification card via e-mail (an e-card) to each partner exposed to an STD (of any type) through sexual contact. E-cards come in several designs and may be sent anonymously or with sender information attached; senders can tailor personal messages. All cards provide information on how to get tested. Both the site and cards provide the basic information that should be shared through any other form of patient-led referral: 1) that the recipient has been exposed to an STD; 2) to seek medical evaluation and where to do so; and 3) the importance of seeking medical evaluation. Use of Internet-based partner services programs is not necessarily restricted to health departments; health departments in areas where these services are available on the Internet generally facilitate access to them (e.g., by providing an index patient access to an on-site computer). The nature of the program makes the effectiveness difficult to evaluate, and no effectiveness data are available. Partner notification programs recognize that the Internet is a potential route for partner notification in certain situations and the only route in others. Nevertheless, certain programs face specific challenges when conducting partner notification using the Internet. Certain challenges are structural or bureaucratic, such as lack of access to computers in clinics or computer firewalls on agency computers meant to bar employees from visiting websites with sexual content (237). Other challenges include program staff members who need training regarding appropriate use of Internet partner notification or health department staff members who have difficulty reaching index patients' partners who rarely enter chat rooms during typical business hours. Compared with in-person notification, e-mail contact presents certain unique challenges for DISs. Ensuring that an e-mailed notification or a chat request is received only by the person for whom it is intended can be difficult. In addition, as with letters and telephone messages, confidentiality constraints often lead to nonspecific initial contacts; this nonspecific contact might increase the likelihood of a recipient deleting the notification e-mail or ignoring a chat request, especially when the sender is unknown. One study aimed at assessing the acceptability of various forms of electronically mediated interventions found that only 45% of 4,601 interviewed persons indicated that they would open an e-mail providing information on HIV and other STDs, and even fewer (30%) indicated that they would chat about the topic (226). Although the study was not directly related to online partner notification, the reasons provided by those surveyed are likely relevant. A substantial proportion of study respondents indicated that they were generally unwilling to open e-mail from unknown senders (40%); a smaller proportion (10%) also considered health department attempts to reach them through e-mail or chat venues to be an invasion of privacy. Strategies to increase the likelihood of a response have not been formally evaluated. However, e-mails that contain the name, occupation, and, particularly, contact numbers of DISs provide a channel for communication and might increase the likelihood of a response. Similar techniques might be used with persons contacted in chat rooms through instant messaging. Patient-led Internet-based partner notification mitigates certain structural and confidentiality concerns related to provider referral, although the approach has some drawbacks. First, malicious notification is a concern (i.e., using the notification process inappropriately, such as to frighten a partner who has not actually been exposed). However, the likelihood might decrease if the website posts injunctions against such use and incorporates protection against automated programs that attempt to use the site for mass e-mailing. Massachusetts offers a verification step that allows the e-mail recipient to contact the customer service department of the website and confirm the validity of the public health account used for partner notification. Second, because Internet-based approaches are easy to use and require less time and resources than the provider referral approach, DISs might use them instead of provider referral; however, verifying that the partner has actually been notified is easier with provider referral. # Recommendations for the Internet • When an index patient indicates having Internet partners, the DIS should attempt to obtain identifying and locating information about the partners (e.g., e-mail addresses, chat room handles, and names of chat rooms or websites where the partner might be located). • Internet partner notification is recommended for partners who cannot be contacted by other means or can be more efficiently contacted and notified through the Internet. This type of notification includes ensuring policies and protocols are in place to 1) ensure that confidentiality or anonymity of the index patient and partners are maintained on the Internet and 2) eliminate structural and bureaucratic barriers to staff member use of the Internet for partner notification. • Partner services programs should collaborate with community partners to develop strategies for addressing structural challenges to health department-mediated Internet partner notification. # Program Collaboration and Service Integration HIV and other STDs often occur simultaneously, and many populations at risk for these diseases are at risk for other infections (e.g., TB and viral hepatitis). Program collaboration and service integration is a method of organizing related health concerns, activities, and services to maximize the public health impact and facilitate comprehensive delivery of services. Improving collaboration, coordination, and communication can increase program efficiency, reduce duplication of services, and result in fewer missed opportunities for providing comprehensive prevention services to individual clients. Through linkages with other programs, greater flexibility and responsiveness to changes in the epidemics of HIV infection and other STDs can occur. Finally, by using local information from surveillance and essential monitoring and evaluation data among multiple programs, prevention services can be more comprehensive. The extent to which a state or local program can effectively coordinate and integrate STD/HIV partner services activities could substantially influence the success of the services. Service integration might best be achieved through program integration; however, program collaboration, if effective, can achieve the same goal. At a minimum, addressing all elements of partner services, especially for persons with more than one STD, requires collaboration among health department units responsible for conducting HIV and other STD reporting and surveillance, as well as among HIV and STD prevention programs (if any of these programs operate separately from one another). Ideally, program collaboration and service integration includes TB and hepatitis. Regardless of the way a health department is organized, the HIV and STD programs should be functionally arranged to ensure that the following occur: • resources (human and financial) are used efficiently; • all persons who receive a diagnosis of HIV or syphilis are offered partner services; • coinfected index patients are not interviewed separately (i.e., by different DISs) for HIV and other STDs; • partners of coinfected index patients are not notified of exposure to HIV and other STDs separately (i.e., by different DISs); • partners receive appropriate and comprehensive clinical services, including testing for HIV and other STDs, treatment or linkage to medical care or HIV case management, and prevention counseling; and • information needed to conduct and evaluate partner services is readily accessible to partner services providers and designated evaluators, respectively. Barriers to program collaboration and service integration exist. Separate funding mechanisms for HIV prevention, HIV care, STD services, substance abuse treatment, mental health care, hepatitis prevention, and TB prevention and treatment can present challenges to service integration. Other challenges include ideological differences in approaches to service delivery; distrust among the various entities involved; concern about loss of program identity; political, legislative, or regulatory obstacles; staff member resistance; and lack of staff member training. Despite these challenges, the potential benefits of program collaboration and service integration are substantial enough that program managers should attempt to align partner services programs with other health department units and service entities. Service alignment can lead to increased efficiency in program administration, service delivery, and use of resources and to more knowledgeable staff members (i.e., through training), increased flexibility in providing interventions for both HIV infection and other STDs, and more efficient data collection and analysis. # Coordination and Collaboration Within Health Departments The organization of HIV and STD prevention programs determine the mechanisms used to ensure a coordinated approach to partner services. To facilitate this process within HIV and STD programs, including disease reporting, surveillance, and other health department units (e.g., TB, hepatitis, vaccination, and reproductive health), programs might need to develop shared policies, memoranda of agreement, shared information systems, shared staffing plans and cross-training of staff. For example, staff members who conduct surveillance and staff members who conduct partner services might each have or develop information important to the other person's function. Having information-sharing agreements that encourage timely, accurate, and secure exchange of information can ensure early identification of potential index patients and more complete surveillance data. For STD programs that provide all partner services, defining how the STD program and the HIV program coordinate services for index patients, partners, social contacts, and associates is important. The level of coordination needed with other health department programs depends partly on local epidemiologic factors and needs of populations at high risk for infection. # Coordination and Collaboration Among Jurisdictions Secure and confidential sharing of information on patients, partners, and other social contacts among jurisdictions facilitates disease prevention. Index patients often name partners who live in a location other than the state or jurisdiction where the diagnosis was made. In addition, a person who tests positive for HIV or other STDs might move to another state or jurisdiction before the test result can be delivered or an interview conducted. Both situations require communication of confidential information from one state or jurisdiction to another; success depends on the willingness of each program manager to take the steps necessary to ensure that security and confidentiality standards are upheld and to hold others accountable when breaches occur. Trust, mutual cooperation, and shared professional ethics are essential. # Coordination and Collaboration with Medical Providers Organizations and agencies that are not part of a health department but are involved in particular aspects of partner services must collaborate to maximize results. HIV partner services program managers should work actively with healthcare providers who provide testing for HIV and other STDs, HIV care providers and case managers, and other social service agencies who provide services to HIV-infected persons to identify patients who have not received HIV partner services or who need additional services. In addition, educating private medical providers about the public health benefits of partner services might lead to increased referrals for partner services. Following are important topics to consider when conducting outreach and education activities with medical providers: • the potential benefits of partner services for medical care providers and their patients; • the role of medical providers in partner services (e.g., timely and accurate reporting of HIV/AIDS and other STD cases to the health department, encouraging clients to use health department partner services, and use of EPT and reporting that use); • health department goals and principles in the provision of partner services; • the importance of evaluating and treating partners of clients; and • the benefits of obtaining assistance from the health department (rather than medical care providers attempting to notify partners themselves), which include the following: 1) trained professionals contact clients and discreetly inform partners of risk, 2) client confidentiality is maintained, 3) clients can be coached on ways to notify partners, 4) patients can be linked to counseling and other prevention and social services support not readily available from medical providers, and 5) partner services are voluntary and free of charge. When medical providers want to provide any aspects of partner services themselves (e.g., partner elicitation, partner notification via dual referral, or EPT), the health department should collaborate with them to provide training and support. However, evidence suggests such collaboration is rare (238). For example, certain providers might be willing and able to elicit partner information that can then be provided to the health department, but most do not have the time or training needed to perform partner notification services for clients. These medical providers should be encouraged to use partner services provided by local health departments. In addition, program managers should consider any applicable legal or regulatory limits on medical care providers being involved in partner services. # Coordination and Collaboration with Other Agencies and Organizations Many CBOs and other health and human services organizations (e.g., community health centers) provide HIV prevention services, including HIV counseling and testing, to populations that are hard to reach and at high risk for transmitting or acquiring HIV. Therefore, CBOs can act as a partner services entry point for clients who might not otherwise be offered these services, and staff members can promote partner services to the communities. CBOs also might be adept at gaining trust and establishing rapport with wary, untrusting, and fearful clients and their partners. CBO staff members might effectively elicit partner information from HIV-infected clients and provide counseling and testing to partners who come to the CBOs for services. (Additional information is available from CDC's Provisional Procedural Guidance for Community Based Organizations [239]). Before partner services program managers determine how best to use CBOs in the partner services process, they should consider local laws and regulations. In certain jurisdictions, health departments and medical providers are the only entities with legal authority to notify persons of their exposure to HIV and other types of STDs. Because many index patients and their partners have multiple referral needs that cannot be solely addressed by the health department or CBOs, partner services program managers should coordinate and collaborate with other service organizations. Such needs include violence prevention programs, drug treatment programs, mental health agencies, reproductive health programs, community health centers, parole and probation agencies, faith-based organizations, agencies funded by the Ryan White CARE Act, homeless shelters, legal services, and homeless support services. Collaboration can be used to promote partner services, identify referral resources, establish formalized referral mechanisms, and minimize duplication of effort in the jurisdiction. # Communication with Communities and Community Planning Groups Although data indicate that clients are generally accepting of partner services, misperceptions still exist, especially regarding concerns about breaches in confidentiality (39). Program managers should consider developing educational campaigns directed to members of affected communities, advocacy groups, and medical care providers to address concerns and misperceptions about the partner services process. In addition, partner services programs should keep their respective HIV community planning groups (CPGs) informed of partner services activities and ensure that CPGs have access to analyses of current data, including potential implications for HIV prevention in the jurisdiction. Given the comorbidity of HIV and other STDs, as well as relationships among these conditions and various social behavioral risk factors, communication also is warranted among health departments, CPGs, and CBOs about early syphilis, gonorrhea, and chlamydial infection, even if the community groups are primarily focused on HIV. # Recommendations for Program Collaboration and Service Integration • To the extent possible, partner services program managers should ensure that persons receive coordinated HIV and STD prevention and related social services, particularly when the persons are affected by more than one disease. • Partner services program managers should assess and eliminate barriers to programmatic collaboration and service integration within the jurisdiction so that, at a minimum, services are well integrated at the client (i.e., service delivery) level. • Partner services program managers should ensure that shared protocols and policies are developed to help coordinate partner services for persons identified through HIV or STD clinics or other health department clinics. • Partner services program managers should encourage private medical care providers to support partner services through active communication mechanisms (e.g., by visiting key medical providers, making presentations about partner services at local and state meetings of providers of HIV care, mailing educational brochures, or providing a summary of these recommendations). • Partner services program managers should establish systems of communication and information to ensure widespread distribution of these recommendations to health department partners, medical providers, and CBOs. • HIV program managers should ensure that communica tion and information about the partner services recommen dations are shared with HIV prevention CPGs. • Partner services programs should ensure that clearly defined, written protocols and procedures that address confidentiality and data security are in place to address incoming and outgoing requests for intrastate and interstate transmission of information. # Program Monitoring, Evaluation, and Quality Improvement Partner services programs should be monitored to assess program performance and identify areas that need improvement. Additional information is available from the CDC's Practical Use of Program Evaluation Among Sexually Transmitted Disease (STD) Programs and CDC's Framework for Program Evaluation in Public Health (240,241). Specific performance measures for CDC-funded HIV and STD programs are published in CDC funding opportunity announcements. Recommendations in this section are intended for assessment of programs and not of individual staff members. Program monitoring includes the following: • tracking program productivity, including number of partners identified, initiated for follow-up, located and notified, examined, tested, treated or linked to care services, and, for HIV, newly identified as infected; • assessing essential steps in the partner services process to identify areas in which program performance can be improved; • gathering information that can be used to guide resource allocation and improve accountability to funders and stakeholders; • identifying demographic, geographic, and behavioral characteristics of index patients and partners to improve services to clients and better target screening and prevention activities to ensure that they are focused on subpopulations at most risk; • tracking temporal trends in demographic, geographic, and behavioral characteristics of index patients and partners to identify initial indications of shifts in the epidemic and identify potential outbreaks at early stages, when they are easier to control; and • identifying social, sexual, and drug-using networks that might be facilitating transmission in the community so that appropriate screening and preventive measures can be developed and implemented. # Monitoring Program Processes and Outcomes Program monitoring should be designed to address specific questions about program performance, both processes and outcomes; all data collected should be clearly related to answering these questions. Program monitoring data should be accessible to and used by program staff members and all levels of management to improve program effectiveness and efficiency. Program managers should review the data at least quarterly, and more frequently (e.g., monthly) for 1) new programs; 2) programs that are introducing substantial changes in policies, procedures, or program design; and 3) programs that have identified potential problems with any of their processes or outcomes. # Essential Questions The following four questions and measures that can be used to assess them must be addressed by managers of partner services programs. These questions were developed by identifying the steps involved in conducting partner services programs and then identifying essential processes and outcomes that can provide measures of program performance (Figure 2). For curable STDs such as syphilis, chlamydial infection, and gonorrhea, the term index case (question number 1) refers to individual episodes of infection. If an individual patient has recurrent episodes of an infection during the defined time period, each episode is counted as a separate index case; an index case does not represent an individual person. For example, a person who has three reported episodes of gonorrhea over a 1-year time period represents three index cases during that year. In contrast, once a person is infected with HIV, the person remains infected. Therefore, once identified as having an index case of HIV infection, the person does not count as another index case in the future (i.e., each index case of HIV infection represents a unique person). Named partners (question number 2) are partners for whom the index patient provides sufficient identifying and other information that the partner can reasonably be considered locatable. Identifying information includes an actual name, an alias, a specific e-mail address or chat-room screen name, or enough other descriptive information that the person can reasonably be considered identifiable. # How completely is the program identifying newly reported cases and interviewing patients for partner services? Assess cases of HIV infection, syphilis, gonorrhea, and chlamydial infection separately, for a defined time period [e.g., past month, past quarter, or past year]): • Number of new cases reported to the health department, including cases identified through surveillance activities • Of new cases reported to the health department, the number and proportion of patients who were eligible for partner services (i.e., not deceased or out of jurisdiction at the time of report [i.e., index patients]) • Of new patients eligible for partner services (i.e., index patients), the number and proportion who were interviewed to elicit partner information Assess cases of syphilis, gonorrhea, and chlamydial infection separately, for a defined time period [e.g., past month, past quarter, or past year]): • Of partners examined or tested, the number and proportion found to be infected • Of all named partners, the number and proportion found to be infected • Of all named partners, the number and proportion treated preventively • Of all named partners, the number and proportion treated for cure (i.e., infected and brought to treatment) # Additional Assessments In addition to addressing the previous four questions, most programs benefit from more detailed monitoring. For example, by considering how successfully the program is performing each step throughout the partner services process, program managers can identify specific steps that need improvement to enhance overall program performance. Qualitative information can be collected to identify factors contributing to areas of concern and aid in improvement. Stratifying the analysis by demographic and behavioral risk characteristics might provide information that allows services to be tailored to the needs of particular subpopulations. The timeliness with which various steps of the process are completed also can be examined. Following is an example: • the number of partners preventively treated within 7, 14, and 30 calendar days from day of interview of index patient per index case of primary and secondary syphilis and • the number of partners with new syphilis cases brought to treatment within 7, 14, and 30 calendar days from day of interview of index patient per index case of primary and secondary syphilis. Following are examples of stepwise process monitoring ques tions that programs should address for index patients, based on the detailed steps in the partner services process (Figure 2 2) can be used to create a similar series of stepwise questions for locatable partners that are identified from index patient interviews, such as, "Among identified partners of HIV index patients, how many are already known via record review to be HIV infected? Of these, what proportion is contacted and provided HIV prevention counseling?" Another important consideration for program managers is how the success of provider referral compares with that of self-referral (or third-party referral) for notifying partners of their risk. Outcomes for partners designated to be notified through self-referral usually are challenging to measure, because verifying that the partners have been notified and tested, what their test results are, and whether they have been linked to medical services, HIV case management, or prevention services are difficult. Several strategies have been used in attempts to obtain this information, but none have been adequately tested for reliability. Examples of such strategies include the following: • requesting that, after notification has occurred, the index patient ask the partner to contact the DIS to verify that the notification has occurred; • providing coded referral cards to the index patient, who then gives a card to each partner to be turned in when the partner arrives for counseling and testing; and • requesting that the index patient accompany the partner to the counseling and testing site, rather than simply referring the partner, which allows the index patient to validate that the partner has been notified. Finally, similar monitoring can be conducted to assess outcomes of clustering and cluster interviewing (e.g., assessing the relative number of new cases of syphilis and gonorrhea identified or of newly identified HIV-positive partners, social contacts, and associates). # Monitoring Program Objectives In addition to monitoring program processes and outcomes, program managers should monitor achievement of program objectives. Annually, programs should establish clear, specific, realistic, time-phased, measurable objectives for each key step or process in the program, as well as expected program outcomes. Progress toward achieving these objectives should be tracked continuously. If progress on one or more processes is unsatisfactory, possible reasons should be considered and processes modified accordingly. Certain originally established objectives might later be determined to be unrealistic and also can be modified. # Monitoring Use of Staff Members and Other Resources Program managers also should monitor program staff members and resource use to identify and quantify activities being performed by staff members, the number of staff members and amount of time required to perform each activity, the types and level of other resources required to implement and maintain the program, and the overall cost of the program. Using a combination of qualitative and quantitative data, this information can be used to adjust use of staff members and resources and plan future program activities. # Program Evaluation In general, evaluations require more rigorous design, analysis, and interpretation than monitoring and frequently require more resources. In certain situations, programs might need to consult with experts in evaluation. Following are examples of questions that might be addressed through evaluation: • Compared with other strategies (e.g., outreach counseling and testing), how effective are partner services as a casefinding method? • What are the most effective strategies for linking infected partners to medical services, HIV case management, and other prevention services? • Who more effectively elicits information regarding spouses and other partners and notifies them of their exposure to HIV: health department specialists, clinicians, counseling and testing providers, or others? • What are the most effective strategies for recruiting persons at high risk for infection into counseling and testing and ensuring that they receive their results? • How cost-effective are partner services compared with other strategies for identifying and testing persons at high risk for infection? • Do certain staff members seem to provide partner services more successfully than others? If so, what are some possible explanations? • Are partner services more effective with certain subpopu lations (e.g., men, women, youths, or racial/ethnic minority groups) or behavioral risk groups (e.g., MSM, injection-drug users, or heterosexuals at high risk for infection) than with others? # Support of Staff Members Staff Development and Assessment Staff assessment and staff development, training, and support have an important association: staff members who are not adequately prepared for and supported while performing their jobs have difficulty performing satisfactorily. Staff development and support begins with a clear description of staff roles and responsibilities, as well as of the knowledge and skills required for the job. This information is used to recruit staff members and identify an appropriate training curriculum to follow initially and at periodic intervals. In addition, assessment of individual strengths and weaknesses of staff members allows supervisors to help them design specific training plans for building their skills. All staff members conducting partner services activities need in-depth training on partner services goals and principles, methods of partner services, and any specific concerns related to specific infections. Training can be obtained through the CDC-supported Prevention Training Centers. After the initial training, updates should occur periodically; close supervision, observation, and mentoring of staff members is critical, especially for those new to the job. In addition, staff members should have easy access to all materials, tools (e.g., cellular telephones), and resources needed to perform the job efficiently and effectively; this is not the responsibility of individual staff members. Staff assessments should include both qualitative and quantitative outcome measures that are constructive and not punitive. These types of assessments are more likely to result in improvement of staff skills and performance than using a single, quantitative outcome measure. For example, the number of partners tested per index patient interviewed can be used as a single measure of staff proficiency; however, an assessment of each essential step in the process (e.g., proportion of index patients located and interviewed, number of partners elicited per index patient interviewed, proportion of partners located and notified, and proportion of located partners counseled, examined, and tested), supplemented with qualitative information, would provide a better assessment of the staff. Qualitative assessments can begin with supervisors routinely meeting with individual DISs to review the timeliness and completeness of specific cases, with a focus on barriers encountered in managing the case and strategies for overcoming these barriers. These one-on-one meetings provide supervisors an opportunity to review the quantitative measures of important steps with the staff member, discuss the validity of the measures, consider potential factors contributing to the performance of the staff member, and discuss strategies for improving certain skills. These meetings also provide an opportunity to assess staff member awareness of and adherence to program guidelines, protocols, and performance standards. Routine, periodic supervisor observation of DISs in all aspects of activities, with immediate feedback, can be very useful. Direct observation can be an important tool in assessing whether staff members have the necessary skills and knowledge to conduct interviews, provide referrals, and satisfy other client needs (242). For example, successful staff-client interactions, in which staff members demonstrate sensitivity to and interest in the client, as well as adherence to current policies and procedures, are essential for effective partner services. Observation and feedback should be structured and constructive and not punitive. Supervisors should reinforce positive performance and provide specific, constructive comments regarding areas that need improvement. A reasonable initial time frame for supervisor observation of DISs is twice monthly for the first 6 months, monthly for the second 6 months, and quarterly for staff members with more than 1 year of experience, depending on individual performance. This schedule might need to be modified depending on program experience. Case conferences also can be very useful for staff support as well as for quality improvement. Regularly scheduled group DIS meetings allow supervisors to understand the skills and areas that need improvement among staff members and provide an opportunity for staff members to learn from one another. Case conferences are a valuable forum for staff members to discuss specific concerns, address difficult situations, and share resources. Case conferences also give supervisors an opportunity to emphasize that conducting partner services is a team effort and that competitive behavior interferes with collaboration and sharing of valuable information and resources. Frequency of case conferences should be balanced with workload, with attempts to conduct such conferences at least monthly. Finally, although staff member assessments often focus on DISs, ensuring that supervisors and program managers themselves are adequately trained, supported, and assessed is equally if not more important. # Staff Safety Certain field activities can include unsafe situations for DISs. Program managers should develop and maintain detailed guidelines for ensuring staff safety. Examples of safety procedures that are often used by partner services programs include the following: • training that includes a common-sense approach to field work, such as appropriate dress, including not wearing jewelry that appears expensive; locking purses and other valuables out of sight; locking car doors and keeping windows rolled up; remaining aware of surroundings; and relying on instincts; • ensuring that program staff members carry photo identification when in the field; • maintaining an employee file, including name, address, physical description, emergency locating information, a recent photo of the employee, and a description of the employee's vehicle and vehicle license number, that can be shared with authorities in case of emergency; • encouraging field workers to work in pairs if needed; • providing cellular telephones, pagers, or electronic navigation systems and requiring staff members to call in when changing plans or when an investigation becomes problematic; • requiring field staff members to submit a daily route sheet of intended stops to the supervisor so that the route can be traced if an emergency arises; • having immediate supervisors or other experienced staff members accompany new field staff members to point out community locations that could be risky (e.g., drug houses, parks, bars, prostitution stroll areas, or areas controlled by gangs) and to model desired behavior; and • routinely discussing safety concerns and emerging problem areas during staff meetings and daily debriefings. The primary way staff members can avoid unsafe situations is to have knowledge of the community; consequently, spending time establishing personal rapport with members of the community is important. This can be accomplished while performing health department outreach activities, organizing field screenings, and participating with CBOs in outreach activities. Other safety concerns involve occupational infections in the workplace, particularly for programs that use DISs to draw blood or collect other specimens in the field. These programs should review all relevant state and local health and safety codes and local public health protocols to determine required training and certification procedures before performing these activities. They also must have in place an Occupational Infections in the Workplace policy that is at least as restrictive as applicable Occupational Safety and Health Administration (OSHA) policies in their areas. Policies and procedures should specifically address management of occupational exposure to HBV, HCV, and HIV, including PEP (243). DISs who might be collecting specimens in the field are strongly encouraged to receive an orientation to state or local Occupational Infections in the Workplace policies and supporting procedural manuals. • Public health agencies responsible for partner services should conduct a thorough review of all laws relevant to their provision of these services. This review should serve as a basis for developing policies and procedures for partner services programs. Program managers should also ensure that program staff members understand the implications these laws have for conducting partner services. Laws relevant to provision of these services include the following: # Recommendations for Support for Staff Members -the legal authority for the public health agencies for partner services; -provisions related to privacy and confidentiality (e.g., requirements of the Health Insurance Portability and Accountability Act [HIPAA]); -provisions related to duty or privilege to warn and criminal transmission and exposure; -the ability of the public health agencies to coordinate with other agencies (e.g., law enforcement). • Program managers should ensure that their staff members understand the legal basis for their work, legal restrictions on their practice (e.g., duty or privilege to warn), the extent to which they are protected from civil litigation, and how to coordinate with law enforcement officials in ways that protect the civil and procedural rights of the persons involved. • To ensure that program staff members invoke their duty or privilege to warn appropriately, partner services programs should have written policies and procedures to guide staff members in handling complex cases. Guidelines and protocols should be based on the jurisdiction's statutory and case law and developed in consultation with legal counsel. Legal counsel should also be consulted regarding specific cases in which duty to warn or privilege to warn might apply. • Program managers should be aware of the applicable laws regarding criminal transmission and exposure in their jurisdictions and should coordinate with legal counsel regarding specific cases in which allegations of criminal transmission or exposure are made. # HIV Infection • HIV partner services programs should collaborate with health-care providers who provide HIV screening or testing, other HIV counseling and testing providers, HIV care providers, and HIV case managers to ensure that their clients and patients are offered HIV partner services as soon as possible after diagnosis and on an ongoing basis, as needed. • HIV partner services programs should work with providers of anonymous HIV testing services to develop strategies for providing partner services to persons who test positive, even if the person decides not to enter a confidential system. These providers should be trained on how to offer partner services and elicit partner information from persons with newly diagnosed HIV infection. # Prioritizing Index Patients General • Program managers should establish criteria for prioritizing index patients to determine which patients will be interviewed first. In general, these criteria should include behavioral and clinical factors that affect the likelihood of additional transmission. Pregnant women should always be considered a high priority, regardless of behavioral or other clinical factors. • Persons with evidence of ongoing risk behaviors for transmission (e.g., recurrent sexually transmitted diseases [STDs] or being repeatedly named as a partner of other infected persons) might be playing an important role in transmission in the overall community and should be prioritized for partner services. # Syphilis • Many program areas use a reactor grid to assist with determining investigative priorities for syphilis reactors. The reactor grid is based on age and syphilis serology laboratory results (titers). Programs that use a reactor grid are strongly encouraged to validate its performance annually and during suspected outbreaks. # Interviewing Index Patients # yphilis, Gonorrhea, and Chlamydial nfection • For early stages of syphilis, policies, procedures, and protocols should specify that all index patients receive an original interview as close to the time of diagnosis and treatment as possible. Every reasonable effort should be made to ensure the partner notification process begins on the date of the original interview. • For cases of gonorrhea and chlamydial infections that partner services staff members will follow up, policies, procedures, and protocols should specify that all index patients receive an original interview as close as possible to the time of diagnosis and treatment. Unless the index patient has evidence of recent infection, notification primarily serves case-finding goals and might be briefly delayed, if necessary. • For cases of gonorrhea and chlamydial infection that partner services staff members will not follow up, patient referral instructions should be provided as close as possible to the time of diagnosis and treatment. • For STDs other than HIV, partner services programs should follow established recommendations for interview periods (Table 1). # IV Infection • Policies, procedures, and protocols should specify that all index patients receive an original interview as soon as possible after diagnosis, ideally within a few days. For index patients who are not willing or able to provide partner information during the original interview, a reinterview should be scheduled, preferably no later than 2 weeks after contact was first made (and sooner, if possible, for index patients with acute infections). • Programs should develop criteria for establishing the interview period for index patients with HIV infection ( # Syphilis • Blood should be drawn in the field when DISs are trained to do so and when specimen maintenance conditions can be met. Partners should be referred for evaluation regardless of whether a specimen has been collected. # Gonorrhea and Chlamydial Infection • If provider referral is used, programs should consider protocols for collecting specimens in the field. # HIV Infection • Partner services programs should consider using rapid HIV tests to maximize the number of partners who are tested and receive test results. • When notification is done in the field, rapid tests should be used or a blood or an oral fluid specimen should be collected for conventional testing. If neither of these is possible, the partner should be escorted or referred to the clinic for testing. • Partners who test negative for HIV antibody should be advised to be retested in 3 months. # Treatment for Partners # Syphilis, Gonorrhea, and Chlamydial Infection • Program managers should ensure that partners are treated according to CDC treatment guidelines as soon as possible after notification. • Programs should consider field-delivered therapy for gonorrhea and chlamydial infection when partners are notified via provider referral. • For STDs for which single-dose oral therapy is feasible (i.e., gonorrhea and chlamydial infection), programs should consider patient-delivered partner therapy for partners who will not be notified via provider referral. • Programs should be sure that all appropriate parties are consulted to ensure that any EPT strategy in the jurisdiction is medically and legally sound. Appropriate parties vary by jurisdiction but might include state health commissioners or legislative bodies. HIV Infection # Immigrants and Migrants • Program managers should review epidemiologic and other data to identify potential immigrant and migrant populations at high risk for infection in their jurisdictions and be prepared to provide partner services that are linguistically and culturally appropriate. # Strategies to Enhance Case Finding and Partner Notification Core Areas • Health departments should assess the geographic concentration of gonorrhea and consider focusing provider-referral partner notification in core areas. # Social Networks • Programs should assess the social networks that influence disease transmission in the area as a strategy for finding persons who are at risk for disease but have not been identified by an index patient or partner. • This strategy should be used to enhance case finding, considering relevant epidemiological and behavioral information. # The Internet • When an index patient indicates having Internet partners, the DIS should attempt to obtain identifying and locating information about the partners (e.g., e-mail addresses, chat room handles, and names of chat rooms or websites where the partner might be located). • Internet partner notification is recommended for partners who cannot be contacted by other means or can be more efficiently contacted and notified through the Internet. This type of notification includes ensuring policies and protocols are in place to 1) ensure that confidentiality or anonymity of the index patient and partners are maintained on the Internet and 2) eliminate structural and bureaucratic barriers to staff member use of the Internet for partner notification. • Partner services programs should collaborate with community partners to develop strategies for addressing structural challenges to health department-mediated Internet partner notification. # Program Collaboration and Service Integration • To the extent possible, partner services program managers should ensure that persons receive coordinated HIV and STD prevention and related social services, particularly when the persons are affected by more than one disease. • Partner services program managers should assess and eliminate barriers to programmatic collaboration and service integration within the jurisdiction so that, at a minimum, services are well integrated at the client (i.e., service delivery) level. # Program Monitoring, Evaluation, and Quality Improvement • Partner services programs should be monitored closely to assess program performance and identify areas that need improvement. • Monitoring should be designed to answer specific questions about program performance; all data collected should be clearly related to answering these questions. • Data should be analyzed and reviewed regularly and used to improve program effectiveness and efficiency. • At a minimum, the following questions should be addressed through monitoring: -How completely is the program identifying newly reported cases and intervewing patients for partner services? -How effectively is the program identifying partners, notifying them of their risk, and examining or testing them for infection? -How effectively is the program identifying new cases of syphilis, gonorrhea, and chlamydial infection Comprehensive risk counseling and services (CRCS). An intensive, client-centered counseling process aimed at ensuring the adoption and maintenance of HIV risk-reduction behaviors designed for HIV-infected persons who continue demonstrating risk behaviors and for HIV-negative persons who are at high risk for acquiring HIV infection and other types of STDs. Confidentiality. The ethical principle associated with the health profession (or the legal right of a client receiving healthcare services) in which health professionals do not disclose information relating to a patient unless the patient gives consent permitting disclosure or disclosure is necessary to protect public health. # Contract referral. A partner notification strategy in which an index patient identifies a specific partner to notify the partner of possible exposure and agrees to do so within a specific time frame, with the understanding that if notification does not occur within the designated time frame, the disease intervention specialist (DIS) will notify the partner. Core area. A specific, typically geographically defined area, such as a neighborhood or census tract, in which a relatively high concentration of disease exists and which likely accounts for a large proportion of transmission in a community. Core groups. Socially defined groups of persons who, as a consequence of continuing risky sexual or drug-injecting behavior, are likely to be sources of continued disease transmission in a network or community (i.e., are core transmitters). Core transmitter. A person who, as a consequence of continuing risky sexual or drug-injecting behavior, is likely to be a source of continued disease transmission in a network or community. Disease intervention. The process of stopping the spread of a disease and the complications of disease. # Disease intervention specialist (DIS). A health department staff member who is specially trained to interview persons infected with HIV or another STD (i.e., index patients); elicit information about their partners and associates; notify the partners of their possible exposure; ensure that the partners are offered appropriate services, including examination, treatment, and referrals; and provide prevention counseling to index patients, partners, social contacts, and associates. # Drug-injection partner. A person with whom a patient shares drug-injection equipment (e.g., needles, syringes, cottons, cookers, or rinse water). These persons have been traditionally referred to as needle-sharing partners or syringe-sharing partners. Dual referral. A notification strategy in which an index patient, together with a health-care provider (typically a disease intervention specialist) notifies a partner of the partner's possible exposure. The strategy allows the provider to provide direct support to the index patient during the notification process and provide the partner with immediate access to counseling, testing, and other information resources (e.g., referrals). # Duty to warn. A legal concept that a health-care provider who learns that an HIV-infected client is likely to transmit the virus to another identifiable person must take steps to warn that person. State laws determine which circumstances constitute a duty to warn. Early syphilis. Primary, secondary, and early latent syphilis. # Expedited partner therapy (EPT). The process by which treatment for partners of persons diagnosed with gonorrhea or chlamydial infection is administered before clinical evaluation. Medications or prescriptions are delivered through either 1) the index patient (i.e., patient-delivered partner therapy) or 2) a disease intervention specialist (i.e., field-delivered therapy). # HIV prevention community planning group (CPG). A planning group consisting of local health officials, representatives from affected communities, and technical experts who share responsibility for developing a comprehensive HIV prevention plan for their community. The intent of the process is to increase meaningful community involvement in prevention planning, to improve the scientific basis of program decisions, and to target resources to those communities at highest risk for HIV transmission and acquisition. HIV prevention counseling. An interactive process between client and counselor aimed at reducing risky sex and druginjection behaviors related to HIV acquisition or transmission. Index case. The first case recognized or reported during an outbreak or epidemic. In epidemiology, the term case generally refers to an episode of infection or disease, not to a unique person. An index case is not necessarily the source of an outbreak or epidemic; it is simply the first case identified. In the context of HIV/STD partner services, an index case is a newly reported case that prompts the initiation of an investigation to identify other possibly related cases. For curable STDs, the term index case refers to discrete episodes of infection. A person who has recurrent episodes of a curable STD during a defined time period is counted as a separate index case for each episode. For example, a person who has three reported episodes of gonorrhea during 1 year would represent three index cases during that year. In contrast, once a person is infected with HIV, the person remains infected; therefore, once a person with HIV infection is identified, the person will not be counted as an index case again in the future. Index patient. The person in whom an index case occurs and who prompts the initiation of an investigation to identify other possibly related cases. Index patients also are sometimes referred to as "original patients" (i.e., the original patient identified in an investigation, not necessarily the original patient in a chain of transmission). Indicator. A measure used to determine an organization's performance of a particular element of care over time. The indicator might measure a particular function, process, or outcome Interview period. The period of time for which an index patient is asked to recall sex or drug-injection partners. Because of differences in biological factors and progression of various diseases, the recommended interview period varies by disease. Ongoing partner services. The concept that partner services should be available to persons with HIV infection at any time needed throughout the course of their life. Original interview. The first interview conducted with an infected patient. The primary purpose of the original interview is to gather information from index patients about partners they have had during the relevant interview period. Original patient. See index patient. Outcomes. Benefits or other results (positive or negative) for clients that might occur during or after their participation in a program. Outcomes can be client level or system level. # Overall responsible party (ORP). The person who accepts overall responsibility for implementing and enforcing HIV/ AIDS and STD data security standards and who might be liable for any breaches of confidentiality. Partner. For persons with syphilis, gonorrhea, or chlamydial infection: refers to sex partners (i.e., persons with whom an index patient has had sex at least once, not just regular or main partners); for persons with HIV infection: refers to sex and drug-injection partners (i.e., persons with whom an index patient has had sex or shared drug-injection equipment at least once, not just regular or main partners). Partner elicitation. The process of obtaining the names, descriptions, and locating information of persons who are partners (or social contacts) of an index patient. Partner elicitation is one step in the process of partner referral Partner notification. The process of locating and confidentially notifying partners that they have been exposed to an infection. Partner notification is one step in the process of partner referral. Partner referral. The process in which partner names are elicited (i.e., partner elicitation), partners are located and notified of their exposure (i.e., partner notification), and notified partners receive a combination of counseling and referrals for testing (or in some cases, testing in the field) and other social support services. Partner services. A broad array of services that should be offered to persons with HIV infection, syphilis, gonorrhea, or chlamydial infection and their partners. Identifying partners and notifying them of their exposure (i.e., partner notification) are two critical elements of these services. Other elements include prevention counseling, testing for HIV and other types of STDs, linkage to medical evaluation and treatment, and linkage or referral to other services, such as reproductive health, prenatal care, substance abuse treatment, social support, housing, legal services and mental health services. # Patient. A client who is diagnosed with HIV infection or another STD. Patient referral. See self-referral. Performance measure. A quantitative tool that provides an indication of an organization's performance in relation to a specified process or outcome. # Personal identifier. A datum or collection of data that allows the identity of a single person to be determined with a specified degree of certainty. Postexposure prophylaxis (PEP). Administration of antiretroviral drugs to HIV-negative persons who have been exposed to HIV in an effort to prevent establishment of infection. The treatment is initiated within 72 hours of exposure and generally continues over the course of a 28-day period. Prevention counseling. An interactive process between client and counselor aimed at reducing risky sex and drug-injection behaviors related to acquisition or transmission of HIV and other types of STDs. # Prison Rape Elimination Act of 2003 (PREA). A public law that provides for analysis of the incidence and effects of prison rape in federal, state, and local institutions and for information, resources, recommendations, and funding to protect persons in prison from rape. Privilege to warn. The legal concept that a health-care worker is legally permitted to warn the partners of an HIV-infected person of the risk of past or future exposure to HIV. # Program collaboration and service integration. A mechanism of organizing and blending interrelated health concerns, separate activities, and services to maximize public health impact through new and established linkages among programs to facilitate delivery of services. Provider referral. A notification strategy in which a health department specialist (e.g., disease intervention specialist) confidentially notifies a partner of possible exposure. # Quality. The degree to which a health or social service meets or exceeds established professional standards and user expectations. Quality improvement. An approach to the continuous study and improvement of the processes of providing services to meet the needs of the person and others. Reactor grid. The use of quantitative test results, age, and sex criteria to identify which persons with reactive syphilis tests are most likely to be untreated and infectious cases. Reinterview. An interview that follows the original interview with an index patient. The reinterview is used to gather additional locating information about partners identified by index patients during the original interview, monitor the status of partners index patients initially decided to notify themselves, elicit names of additional partners index patients might not have recalled in the original interview, and verify that index patients have received adequate treatment or additional tests. Ryan White CARE Act Amendments of 1996. The law reauthorizing the Ryan White HIV/AIDS Program, a program administered by the Health Resources and Services Administration that provides for grants to support the medical care needs of low-income, uninsured, and underinsured persons living with acquired immunodeficiency syndrome (AIDS) and HIV infection. # Self-referral. A notification strategy in which an index patient accepts full responsibility for informing a partner of possible exposure and referring the partner to appropriate services. A health-care provider helps the index patient determine when, where, and how to notify the partner as well as how to cope with potential reactions. This process is also known as client referral and patient referral. # Social contact. A person named by the index patient during an interview as part of the social network who is not a sex or drug-injection partner of the index patient. Social contacts (referred to as suspects in previous STD partner services guidelines) might include persons with symptoms suggestive of disease, partners of other persons known to be infected, or others who might benefit from examination. # Social network. A group of persons connected by various types of social relationships, such as family, work and recreational relationships, sexual partnerships, and drug-using relationships. The social network might also include venues in which interactions among members of a social network occur. Persons in a social network might share social, economic, cultural, or behavioral characteristics that influence their risk for various health conditions, including HIV infection and other STDs. Standards. Elements or procedures that must be followed by CDC grantees in virtually all instances in which CDC funds are used to support services. # Suspect. A social contact. This term has historically been used to describe a person named by an index patient as part of the social network who is not a sex or drug-injection partner of the index patient. These persons might have symptoms suggestive of disease, might be partners of other persons known to be infected, or might be other persons who might benefit from examination. System. A group of related processes. Third-party provider. A health or social services professional not affiliated with a health department (e.g., physicians, nurses, or counselors) who might participate in certain aspects of partner services, such as partner elicitation or partner notification via dual referral Third-party referral. A notification strategy by which a partner is notified of exposure to HIV or another STD by a professional other than a health department staff member (e.g., a private physician). Window period. The time interval after infection during which a serologic test might be negative because antibodies have not reached a detectable level. Guiding Principle 5. Security practices and written policies will be reviewed and assessed continuously and, as necessary, changed to improve the protection of confidential partner services case information and data. Partner services programs should adhere to the following program standards when developing area-specific guidelines, policies, and procedures for individual-level record keeping and data collection, management, and security: Standard 1. All policies and procedures must be written and reviewed at least annually and revised as needed. # Standard 2. A policy must name the persons who act as the overall responsible party (ORP) for the security of the data that might be stored in various data systems. # Standard 3. A policy must describe the methods for review of security practices for data. Included in the policy should be a requirement for an ongoing review of evolving technology to ensure that information and data remain secure. # Standard 4. The ORP must certify annually that these standards are met. # Standard 5. Access to and use of individual-level information must be defined in a data-release policy. Standard 6. Policies must be readily accessible to any staff members having access to confidential, individual-level data. # Standard 7. A policy must define the roles and access level for all persons with authorized access and describe which standard procedures or methods will be used when accessed. Standard 8. All authorized staff members must sign a confidentiality statement annually. Newly hired staff members must sign a confidentiality statement before access to individual-level information and data is authorized. # Standard 9. A policy must outline procedures for handling incoming mail and faxes to the programs and outgoing mail and faxes from the programs. The amount and sensitivity of information contained in any piece of correspondence must remain minimal. Standard 10. All persons who are authorized to access individual-level information must be knowledgeable about the organization's information security policies and procedures. Standard 11. All staff members authorized to access individual-level information must be responsible for questioning persons who attempt to access this information but who are not authorized to do so. # Standard 12. All staff members who are authorized to access individual-level information are responsible for protecting their own computer workstation, laptop computer, or other devices with confidential, individuallevel information or data. This responsibility includes protecting keys, passwords, and codes that would allow access to confidential information or data. Staff members must be careful not to infect program software with computer viruses and not to damage hardware through exposure to extreme heat or cold. Standard 17. Partner services analysis data sets must be stored securely with protective software (i.e., software that controls the storage, removal, and use of the data), and personal identifiers should be removed when possible. Standard 18. Partner services information and data transfers and methods for data collection must be approved by the ORP and incorporate the use of access controls. Individual-level information and data must be encrypted before electronic transfer. When possible, databases and files with individual-level data must be encrypted when not in use. # Standard 19. When individual-level partner services information and data are electronically transmitted, any transmission that does not incorporate the use of an encryption package meeting the encryption standards of the National Institute of Standards and Technology (available at http://csrc.nist.gov/groups/stm/cmvp/ standards.html) and approved by the ORP must not contain identifying information or use terms easily associated with HIV, AIDS, or any other type of STD. The terms HIV and AIDS, terms that specifically identify other STDs, or specific behavioral information must not appear anywhere in the context of the transmission, including the sender and recipient address and label. Standard 20. When partner services information with personal identifiers or data are taken from secured areas and included in line lists or supporting notes, in either electronic or paper format, the documents must contain the least amount of information needed for completing a given task and, if possible, coded to disguise any information that could easily be associated with HIV, AIDS, or any other type of STD. # Standard 21. Individual-level information or data with personal identifiers must not be taken to private staff members' residences unless specific, documented permission is granted or the transfer is permitted according to a written policy established by the program manager or ORP. # Standard 22. Prior approval must be obtained from the program manager or approved procedures must be followed when planned business travel precludes the return of information with personal identifiers to the secured area by the close of business on the same day. Standard 23. Access to any partner services program information or data containing names for research purposes (i.e., for other than routine program purposes) must be contingent on a demonstrated need for the names, institutional review board (IRB) approval, and the signing of a confidentiality statement regarding rules of access and final disposition of the information. Access to partner services program information or data without names for research purposes beyond routine program activities might still require IRB approval, depending on the numbers and types of variables requested in accordance with local data release policies. # Standard 24. Access to any secured areas where individuallevel partner services information are stored must be limited to authorized persons as documented within policies and procedures (e.g., cleaning or maintenance staff members). # Standard 25. Access to confidential partner services information and data by personnel outside the partner services program must be limited to those authorized based on an expressed and justifiable public health need, must not compromise or impede program activities, must not affect the public perception of confidentiality of the data system, and should be approved by the ORP. # Standard 26. Access to partner services information and data with identifiers by those who maintain other disease data stores should be limited to those for whom the ORP has weighed the benefits and risks of allowing access and can certify that the level of security established is equivalent to these standards. Standard 27. Access to partner services information or data for purposes unrelated to public health (e.g., litigation, discovery, or court order) can only be granted to the extent required by law. Standard 28. All staff members who are authorized to access partner services information and data must be responsible for reporting suspected security breaches. Nonprogram staff members also must be informed of this directive. Standard 29. Any breach of protocol or procedures, regardless of whether personal information was released, must be investigated immediately to assess causes and implement remedies. Standard 30. A breach of confidentiality (i.e., a security infraction that results in the release of private information with or without harm to one or more persons) must be reported immediately to the ORP. In consultation with appropriate legal counsel, partner services staff members should determine whether a breach warrants reporting to law enforcement agencies. Standard 31. Laptop computers and other portable devices (e.g., personal digital assistants [PDAs], other handheld devices, and tablet personal computers [tablet PCs]) that receive or store partner services program information or data with personal identifiers must have encryption software. Program information with identifiers must be encrypted and stored on an external storage device or on the laptop removable hard drive. The external storage device or hard drive containing the information must be separated from the laptop and held securely when not in use. The decryption key cannot be on the laptop. Other portable devices without removable or external storage components must use encryption software that meets federal standards. Standard 32. All removable or external storage devices containing partner services information or data that contains personal identifiers must 1) include only the minimum amount of information necessary to accomplish assigned tasks as determined by the program manager; 2) be encrypted or stored under lock and key when not in use; and 3) be sanitized immediately after a given task (excludes devices used for backups). Before any device containing sensitive data is taken out of a secured area, the information or data must be encrypted. Methods for sanitizing a storage device must ensure that the information cannot be retrievable using "undelete" or other data-retrieval software. Hard drives that contain identifying information must be sanitized or destroyed before computers are labeled as excess or surplus, reassigned to non-program staff members, or sent off site for repair. # Quality Improvement Program managers should implement quality improvement systems to help ensure that services are delivered as intended, programs are responsive and accountable to the funders and consumers of the services, and program performance and quality of care are continuously improved. Quality improvement activities typically focus on the following areas: • awareness of services among all potential consumers and easy accessibility to such services; consumers include clinicians and counseling and testing providers who are diagnosing STD/HIV infections; persons with newly diagnosed STD/HIV infections; and persons with a previous STD/HIV diagnosis who might not have received partner services at the time of diagnosis or might need subsequent partner services; • appropriateness of services for client needs, including availability of services and materials appropriate for the culture, language, sex, sexual orientation, age, and developmental level of the clients; • continuity, availability, and accessibility of referral services appropriate for the clients, especially medical evaluation and management for persons with a new HIV diagnosis; • development, implementation, and accessibility of written program guidelines, protocols for provision of services, and performance standards; • adherence to program guidelines, protocols, and performance standards by all program staff members; • performance and proficiency (e.g., initial and ongoing competence and skill and appropriate training and credentialing) of staff members; and • supervision and support of staff members, including routine, timely feedback and record-keeping procedures that support efficiency and ensure client confidentiality and data security. Various methods can be used to help improve program quality, including the following: • regular, direct supervisor observation of staff performance and demonstration of appropriate skills and behavior; • case-management sessions that facilitate discussion of specific cases, safety concerns, social network analysis, All program standards and security considerations should be based on the following five guiding principles: Guiding Principle 1. Partner services information and data should be maintained in a physically secure environment. Guiding Principle 2. Electronic partner services data should be held in a technically secure environment, with the number of data repositories and persons permitted access kept to a minimum. Operational security procedures should be implemented and documented to minimize the number of staff members who have access to personal identifiers and to minimize the number of locations where personal identifiers are stored. Guiding Principle 3. Individual program staff members and persons authorized to access case-specific information are responsible for protecting confidential partner services case information and data; these persons will face legal action for confidentiality violations. Guiding Principle 4. Security breaches of partner services information or data will be investigated thoroughly and sanctions imposed as appropriate. # ACCREDITATION # Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 3.5 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been reviewed and approved as an # Continuing Nursing Education (CNE). CDC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. CDC will award 3.5 contact hour(s) in CNE credit. # Certified Health Education Specialist (CHES). CDC is a designated provider of continuing education contact hours (CECH) in health education by the National Commission for Health Education Credentialing, Inc. This program is a designated event for CHESs to receive 3.0 category I contact hour(s) in health education. The CDC provider number is GA0082. depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices # Goals and Objectives This report describes recommendations for conducting partner services for persons with human immunodeficiency virus (HIV) infection, syphilis, gonorrhea, or chlamydial infection. Upon completion of this educational activity, the reader should be able to 1) describe the goals and functions of partner services; 2) describe ways to identify and prioritize index patient for partner services; 3) identify ways to notify partners of their exposure to HIV, syphilis, gonorrhea, or chlamydia; 4) describe options for treating partners; and 5) identify ways to address the needs of specific populations with regard to partner services. To receive continuing education credit, please answer all of the following questions. # Expedited partner therapy is… A. the process of moving partners through the clinic faster than regular patients. B. the process of notifying partners of their exposure within 24 hours of diagnosis. C. the practice of treating partners before treating the index patient. D. the practice of treating partners before clinical evaluation. E. the practice of decreasing notification times within a partner services program. # Advantages of field delivered therapy are… A. requires index patients to take responsibility for their infection. B. allows the disease intervention specialist to monitor any adverse reactions to medication. C. reduces the amount of time disease intervention specialists spend in the field. D. all of these. E. none of these. # Which of the following statements is true about partner services for incarcerated populations? A. Privacy is not recommended for safety reasons. B. Because inmates are confined, protecting their confidentiality is not required. C. Inmates might not want to identify partners while they are incarcerated. D. Identified partners should be informed that the index patient is incarcerated. E. Ensuring medical care for partners is the responsibility of the health department. Failure to complete these items can result in a delay or rejection of your application for continuing education credit.	None	None
86830eda54a2adb24058f96fefe5d8dc7e5777c7	cdc	None	CDC created U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, from guidance developed by the World Health Organization (WHO) and finalized the recommendations after consultation with a group of health professionals who met in Atlanta, Georgia, during February 2009. This guidance comprises recommendations for the use of specific contraceptive methods by women and men who have certain characteristics or medical conditions. The majority of the U.S. guidance does not differ from the WHO guidance and covers >60 characteristics or medical conditions. However, some WHO recommendations were modified for use in the United States, including recommendations about contraceptive use for women with venous thromboembolism, valvular heart disease, ovarian cancer, and uterine fibroids and for postpartum and breastfeeding women. Recommendations were added to the U.S. guidance for women with rheumatoid arthritis, history of bariatric surgery, peripartum cardiomyopathy, endometrial hyperplasia, inflammatory bowel disease, and solid organ transplantation. The recommendations in this document are intended to assist health-care providers when they counsel women, men, and couples about contraceptive method choice. Although these recommendations are meant to serve as a source of clinical guidance, health-care providers should always consider the individual clinical circumstances of each person seeking family planning services.# Introduction In 1996, the World Health Organization (WHO) published the first edition of the Medical Eligibility Criteria for Contraceptive Use (MEC), which gave evidence-based guidance on the safety of contraceptive method use for women and men worldwide who had specific characteristics and medical conditions. Since that time, WHO has regularly updated its guidance on the basis of new evidence, and the WHO MEC is now in its fourth edition (1). CDC, through close collaboration with WHO, has contributed substantially during the last 15 years to creation of WHO's global family planning guidance, which includes four documents: the medical eligibility criteria for contraceptive use, the selected practice recommendations for contraceptive use, a decision-making tool for clients and providers, and a global family planning handbook. This WHO guidance has been based on the best available scientific evidence, and CDC has served as the lead for establishing that evidence base and presenting the evidence to WHO for use during its expert working group meetings to create and update the guidance. WHO has always intended for its global guidance to be used by local or regional policy makers, managers of family planning programs, and the scientific community as a reference when they develop family planning guidance at the country or program level. The United Kingdom is one example of a country that has adapted the WHO MEC for its own use (2). CDC undertook a formal process to adapt the WHO MEC at this time because the fourth edition of the WHO guidance is unlikely to undergo major revisions in the near future. Although the WHO guidance is already available in the United States through inclusion in textbooks, use by professional organizations, and incorporation into training programs, the adaptation of the guidance ensures its appropriateness for use in the United States and allows for further dissemination and implementation among U.S. health-care providers. Most of the U.S. guidance does not differ from the WHO guidance and covers approximately 60 characteristics or medical conditions. However, several changes have been made, including adaptations of selected WHO recommendations, addition of recommendations for new medical conditions, and removal of recommendations for contraceptive methods not currently available in the United States (Appendix A). This document contains recommendations for health-care providers for the safe use of contraceptive methods by women and men with various characteristics and medical conditions. It is intended to assist health-care providers when they counsel women, men, and couples about contraceptive method choice. These recommendations are meant to be a source of clinical guidance; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. # U S. Medical Eligibility Criteria for Contraceptive Use, 2010 Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition May 28, 2010 # Methods The process for adapting the WHO MEC for the United States comprised four major steps: 1) determination of the scope of and process for the adaptation, including a small meeting; 2) preparation and peer review of systematic reviews of the evidence to be used for the adaptation; 3) organization of a larger meeting to examine the evidence and provide input on the recommendations; and 4) finalization of the recommendations by CDC. In June 2008, CDC held a 2-day meeting of eight key partners and U.S. family planning experts to determine the scope of and process for a U.S. adaptation of the WHO MEC. Participants were family planning providers, who also had expertise in conducting research on contraceptive safety and translating research evidence into guidance. WHO guidance is used widely around the world, including in the United States, and contains approximately 1,800 separate recommendations. In most cases, the evidence base would be the same for the U.S. and the WHO recommendation, and-because of the extensive collaboration between WHO and CDC in creating the international guidance-the process for determining the recommendations also would be the same. Therefore, CDC determined that the global guidance also should be the U.S. guidance, except when a compelling reason existed for adaptation, and that CDC would accept the majority of WHO guidance for use in the United States. During the June 2008 meeting, CDC identified specific WHO recommendations for which a compelling reason existed to consider modification for the United States because of the availability of new scientific evidence or the context in which family planning services are provided in the United States. CDC also identified areas in which WHO guidance was inconsistent with current U.S. practice by contacting numerous professional and service organizations and individual providers. In addition, CDC assessed the need for adding recommendations for medical conditions not currently included in the WHO MEC. Through this process, a list was developed of existing WHO recommendations to consider adapting and new medical conditions to consider adding to the guidance. A systematic review of the scientific evidence was conducted for each of the WHO recommendations considered for adaptation and for each of the medical conditions considered for addition to the guidance. The purpose of these systematic reviews was to identify direct evidence about the safety of contraceptive method use by women (or men) with selected conditions (e.g., risk for disease progression or other adverse health effects in women with rheumatoid arthritis who use combined oral contraceptives). Information about indirect evidence (e.g., evidence from healthy women or animal studies) or theoretical considerations was obtained when direct evidence was not available. CDC conducted systematic reviews following standard guidelines (3,4), included thorough searches of PubMed and other databases of the scientific literature, and used the U.S. Preventive Services Task Force system to grade the strength and quality of the evidence (5). Each systematic review was peer-reviewed by two or three experts before being used in the adaptation process. These systematic reviews have been submitted for publication in peer-reviewed journals. For most recommendations in this document, a limited number of studies address the use of a specific contraceptive method by women with a specific condition. Therefore, within the WHO guidance, as well as with this U.S. adaptation of the guidance, most of the decisions about medical eligibility criteria were often necessarily based on 1) extrapolations from studies that primarily included healthy women, 2) theoretical considerations about risks and benefits, and 3) expert opinion. Evidence was particularly limited for newer contraceptive methods. The total body of evidence for each recommendation included evidence based on direct studies or observations of the contraceptive method used by women (or men) with the condition and may have included 1) evidence derived from effects of the contraceptive method used by women (or men) without the condition and 2) indirect evidence or theoretical concerns based on studies of suitable animal models, human laboratory studies, or analogous clinical situations. In February 2009, CDC held a meeting of 31 experts who were invited to provide their individual perspective on the scientific evidence presented and the discussions on potential recommendations that followed. This group included obstetricians/gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with expertise in contraceptive safety and provision. For each topic discussed, the evidence from the systematic review was presented; for most of the topics, an expert in the BOX 1. Categories of medical eligibility criteria for contraceptive use 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. specific medical condition (e.g., rheumatoid arthritis) also gave a brief presentation on the condition and specific issues about contraceptive safety. CDC gathered input from the experts during the meeting and finalized the recommendations in this document. CDC plans to develop a research agenda to address topics identified during the meeting that need further investigation. # How to Use this Document These recommendations are intended to help health-care providers determine the safe use of contraceptive methods among women and men with various characteristics and medical conditions. Providers also can use the synthesis of information in these recommendations when consulting with women, men, and couples about their selection of contraceptive methods. The tables in this document include recommendations for the use of contraceptive methods by women and men with particular characteristics or medical conditions. Each condition was defined as representing either an individual's characteristics (e.g., age, history of pregnancy) or a known preexisting medical/pathologic condition (e.g., diabetes and hypertension). The recommendations refer to contraceptive methods being used for contraceptive purposes; the recommendations do not consider the use of contraceptive methods for treatment of medical conditions because the eligibility criteria in these cases may differ. The conditions affecting eligibility for the use of each contraceptive method were classified under one of four categories (Box 1). # Using the Categories in Practice Health-care providers can use these categories when assessing the safety of contraceptive method use for women and men with specific medical conditions or characteristics. Category 1 comprises conditions for which no restrictions exist for use of the contraceptive method. Classification of a method/ condition as Category 2 indicates the method generally can be used, but careful follow-up may be required. For a method/ condition classified as Category 3, use of that method usually is not recommended unless other more appropriate methods are not available or acceptable. The severity of the condition and the availability, practicality, and acceptability of alternative methods should be taken into account, and careful follow-up will be required. Hence, provision of a method to a woman with a condition classified as Category 3 requires careful clinical judgement and access to clinical services. Category 4 comprises conditions that represent an unacceptable health risk if the method is used. For example, a smoker aged <35 years generally can use combined oral contraceptives (COCs) (Category 2). However, for a woman aged ≥35 years who smokes <15 cigarettes per day, the use of COCs usually is not recommended unless other methods are not available or acceptable to her (Category 3). A woman aged ≥35 years who smokes ≥15 cigarettes per day should not use COCs because of unacceptable health risks, primarily the risk for myocardial infarction and stroke (Category 4). The programmatic implications of these categories may depend on the circumstances of particular professional or service organizations (e.g., in some settings, a Category 3 may mean that special consultation is warranted). The recommendations address medical eligibility criteria for the initiation and continued use of all methods evaluated. The issue of continuation criteria is clinically relevant whenever a woman develops the condition while she is using the method. When the categories differ for initiation and continuation, these differences are noted in the columns Initiation and Continuation. Where Initiation and Continuation are not denoted, the category is the same for initiation and continuation of use. On the basis of this classification system, the eligibility criteria for initiating and continuing use of a specific contraceptive method are presented in tables (Appendices A-M). In these tables, the first column indicates the condition. Several conditions were divided into subconditions to differentiate between varying types or severity of the condition. The second column classifies the condition for initiation and/or continuation into Category 1, 2, 3, or 4. For some conditions, the numeric classification does not adequately capture the recommendation; in this case, the third column clarifies the numeric category. These clarifications were determined during the discussions of the scientific evidence and the numeric classification and are considered a necessary element of the recommendation. The third column also summarizes the evidence for the recommendation, where evidence exists. The recommendations for which no evidence is cited are based on expert opinion from either the WHO or U.S. expert working group meetings and may be based on evidence from sources other than systematic reviews and presented at those meetings. For selected recommendations, additional comments appear in the third column and generally come from the WHO or the U.S. expert working group participants. # Recommendations for Use of Contraceptive Methods The classifications for whether women with certain medical conditions or characteristics can use specific contraceptive methods are provided for combined hormonal contraceptive methods, including low-dose (containing ≤35 μg ethinyl estradiol) combined oral contraceptive pills, combined hormonal patch, and combined vaginal ring (Appendix B); progestin-only contraceptive methods, including progestinonly pills, depot medroxyprogesterone acetate injections, and etonogestrel implants (Appendix C); emergency contraceptive pills (Appendix D); intrauterine contraception, including the copper intrauterine device (IUD) and the levonorgestrel IUD (Appendix E); use of copper IUDs for emergency contraception (Appendix F); barrier contraceptive methods, including male and female condoms, spermicides, diaphragm with spermicide, and cervical cap (Appendix G); fertility awarenessbased methods (Appendix H); lactational amenorrhea method (Appendix I); coitus interruptus (Appendix J); and female and male sterilization (Appendix K). Tables at the end of the document summarize the classifications for the hormonal and intrauterine methods (Appendix L) and the evidence about potential drug interactions between hormonal contraceptives and antiretroviral therapies (Appendix M). # Contraceptive Method Choice Many elements need to be considered by women, men, or couples at any given point in their lifetimes when choosing the most appropriate contraceptive method. These elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. The guidance in this document focuses primarily on the safety of a given contraceptive method for a person with a particular characteristic or medical condition. Therefore, the classification of Category 1 means that the method can be used in that circumstance with no restrictions with regard to safety but does not necessarily imply that the method is the best choice for that person; other factors, such as effectiveness, availability, and acceptability, may play a key role in determining the most appropriate choice. Voluntary informed choice of contraceptive methods is an essential guiding principle, and contraceptive counseling, where applicable, may be an important contributor to the successful use of contraceptive methods. In choosing a method of contraception, the risk for sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), also must be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STIs. Consistent and correct use of the male latex condom reduces the risk for STIs (6). When a male condom cannot be used properly for infection prevention, a female condom should be considered (7). Women who use contraceptive methods other than condoms should be counseled about the use of condoms and the risk for STIs (7). Additional information about prevention and treatment of STIs is available from CDC's Sexually Transmitted Diseases Treatment Guidelines () (7). # Contraceptive Method Effectiveness Contraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Table 1). Methods that depend on consistent and correct use have a wide range of effectiveness. # Unintended Pregnancy and Increased Health Risk For women with conditions that may make unintended pregnancy an unacceptable health risk, long-acting, highly effective contraceptive methods may be the best choice (Table 1). Women with these conditions should be advised that sole use of barrier methods for contraception and behavior-based methods of contraception may not be the most appropriate choice because of their relatively higher typical-use rates of failure (Table 1). Conditions included in the U.S. MEC for which unintended pregnancy presents an unacceptable health risk are identified throughout the document (Box 2). # Keeping Guidance Up to Date As with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. CDC will continue to work with WHO to identify and assess all new relevant evidence and to determine whether changes to the recommendations are warranted (4). In most cases, the U.S. MEC will follow any updates in the WHO guidance, which typically occur every 3-4 years (or sooner if warranted by new data). However, CDC will review any WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations and medical conditions that are not included in the WHO guidance. CDC will completely review the U.S. MEC every 3-4 years as well. Updates to the guidance will appear on the CDC U.S. MEC website: http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USMEC.htm. The classification additions, deletions, and modifications from the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use, 4th Edition, are summarized below (Tables 1-3). For conditions for which # BOX. Categories for Classifying Hormonal Contraceptives and Intrauterine Devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. classification changed for ≥1 methods or the condition description underwent a major modification, WHO conditions and recommendations appear in curly brackets. May 28, 2010 Other deleted items Guidance for combined injectables, levonorgestrel implants, and norethisterone enanthate has been removed because these methods are not currently available in the United States. Guidance for "blood pressure measurement unavailable" and "history of hypertension, where blood pressure CANNOT be evaluated (including hypertension in pregnancy)" has been removed. # Unintended pregnancy and increased health risk The following conditions have been added to the WHO list of conditions that expose a woman to increased risk as a result of unintended pregnancy: history of bariatric surgery within the past 2 years, peripartum cardiomyopathy, and receiving a solid organ transplant within 2 years. Combined hormonal contraceptives (CHCs) include lowdose (containing ≤35 μg ethinyl estradiol ) combined oral contraceptives (COCs), the combined hormonal patch, and the combined vaginal ring. The combined hormonal patch and vaginal ring are relatively new contraceptive methods. Limited information is available about the safety of these methods among women with specific medical conditions. Moreover, epidemiologic data on the long-term effects of the combined hormonal patch and the vaginal ring were not available for review. Evidence indicates that the combined hormonal patch and the combined vaginal ring provide comparable safety and pharmacokinetic profiles to COCs with similar hormone formulations . Pending further studies, the evidence available for recommendations about COCs applies to the recommendations for the combined hormonal patch and vaginal ring. Therefore, the patch and ring should have the same categories (Box) as COCs, except where noted. The assigned categories should, therefore, be considered a preliminary, best judgement, which will be reevaluated as new data become available. CHCs do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # Appendix B Classifications for Combined Hormonal Contraceptives # BOX. Categories for Classifying Combined Hormonal Contraceptives 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. (34)(35)(36)(37)(38)(39)(40)(41). In premenopausal adult women, COC use has little to no effect on bone health while appearing to preserve bone mass in perimenopausal women (26,. Postmenopausal women who have ever used COCs have similar BMD to postmenopausal women who have never used COCs (54,58,68,81,(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110). BMD in adolescent or premenopausal women may not accurately predict postmenopausal fracture risk (109,(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122). # Postabortion Clarification: COCs, P, or R may be started immediately postabortion. a. First trimester 1 Evidence: Women who started taking COCs immediately after first trimester medical or surgical abortion did not experience more side effects or adverse vaginal bleeding outcomes or clinically significant changes in coagulation parameters than did women who used a placebo, an IUD, a nonhormonal contraceptive method, or delayed COC initiation (134)(135)(136)(137)(138)(139)(140). Limited evidence on women using the ring immediately after first trimester medical or surgical abortion found no serious adverse events and no infection related to use of the combined vaginal contraceptive ring during 3 cycles of follow-up postabortion (141). b. Second trimester 1 c. Immediate postseptic abortion 1 Past ectopic pregnancy 1 Comment: The risk for future ectopic pregnancy is increased among women who have had an ectopic pregnancy in the past. CHCs protect against pregnancy in general, including ectopic gestation. (147,(153)(154)(155)(156)(157)(158)(159). Limited evidence is inconsistent about whether COC effectiveness varies by body weight or BMI (160)(161)(162)(163)(164)(165). Limited evidence suggests obese women are no more likely to gain weight after 3 cycles of the vaginal ring or COC than overweight or normal weight women. A similar weight gain during the 3 months was noted between the COC group and the vaginal ring group across all BMI categories (166). The effectiveness of the patch decreased among women who weighed >90 kg; however, no association was found between pregnancy risk and BMI (18). Evidence: Among women with hypertension, COC users were at higher risk than nonusers for stroke, acute myocardial infarction, and peripheral arterial disease (142,144,(151)(152)(153)155,(171)(172)(173)(174)(175)(176)(177)(178)(179)(180)(181)(182)(183)(184)(185)(186). Discontinuation of COCs in women with hypertension might improve blood pressure control (187). ii. Systolic ≥160 mm Hg or diastolic ≥100 mm Hg § 4 c. Vascular disease 4 History of high blood pressure during pregnancy (where current blood pressure is measurable and normal) 2 Evidence: Women with a history of high blood pressure in pregnancy, who also used COCs, had a higher risk for myocardial infarction and VTE than did COC users who did not have a history of high blood pressure during pregnancy. The absolute risks for acute myocardial infarction and VTE in this population remained small (153,172,(184)(185)(186)(188)(189)(190)(191)(192)(193). ii. Lower risk for recurrent DVT/PE (no risk factors) Deep 3 Clarification: Women on anticoagulant therapy are at risk for gynecologic complications of therapy, such as hemorrhagic ovarian cysts and severe menorrhagia. Hormonal contraceptive methods can be of benefit in preventing or treating these complications. When a contraceptive method is used as a therapy, rather than solely to prevent pregnancy, the risk/benefit ratio may differ and should be considered on a case-bycase basis. d. Family history (first-degree relatives) 2 Comment: Some conditions that increase the risk for DVT/PE are heritable. e. Major surgery i. With prolonged immobilization 4 ii. Without prolonged immobilization 2 f. Minor surgery without immobilization 1 Known thrombogenic mutations § (e.g., factor V Leiden; prothrombin mutation; protein S, protein C, and antithrombin deficiencies) Clarification: Routine screening is not appropriate because of the rarity of the conditions and the high cost of screening. Evidence: Among women with thrombogenic mutations, COC users had a 2-fold to 20-fold higher risk for thrombosis than did nonusers (159,. (218). # Superficial venous thrombosis Comment: COCs might increase fluid retention in healthy women; fluid retention may worsen heart failure in women with peripartum cardiomyopathy. COCs might induce cardiac arrhythmias in healthy women; women with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias. Evidence: Among women with migraine, women who also had aura had a higher risk for stroke than did those without aura (248-250). Women with a history of migraine who use COCs are about 2-4 times as likely to have an ischemic stroke as nonusers with a history of migraine (142,157,179,180,(249)(250)(251)(252)(253)(254). Evidence: A Cochrane Collaboration Review identified 1 randomized controlled trial evaluating the effectiveness of COC use compared with naproxen and danazol in treating menorrhagic women. Women with menorrhagia did not report worsening of the condition or any adverse events related to COC use (265). # Rheumatic Diseases # Unexplained vaginal bleeding (suspicious for serious condition) Before evaluation 2 Clarification: If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. # Comment: No conditions that cause vaginal bleeding will be worsened in the short term by use of CHCs. # Endometriosis 1 Evidence: A Cochrane Collaboration Review identified 1 randomized controlled trial evaluating the effectiveness of COC use compared with a gonadotropin-releasing hormone analogue in treating the symptoms of endometriosis. Women with endometriosis did not report worsening of the condition or any adverse events related to COC use (266). # Benign ovarian tumors (including cysts) 1 Severe dysmenorrhea 1 Evidence: Risk for side effects with COC use was not higher among women with dysmenorrhea than among women not using COCs. Some COC users had a reduction in pain and bleeding (267,268). Gestational trophoblastic disease a. Decreasing or undetectable β-hCG levels 1 Evidence: After molar pregnancy evacuation, the balance of evidence found COC use did not increase the risk for postmolar trophoblastic disease, and β-hCG levels regressed more rapidly in some COC users than in nonusers (269-275). Limited evidence suggests that use of COCs during chemotherapy does not significantly affect the regression or treatment of postmolar trophoblastic disease compared with women who used a nonhormonal contraceptive method or DMPA during chemotherapy (276). b. Persistently elevated β-hCG levels or malignant disease § 1 Cervical ectropion 1 Comment: Cervical ectropion is not a risk factor for cervical cancer, and restriction of CHC use is unnecessary. # Cervical intraepithelial neoplasia 2 Evidence: Among women with persistent HPV infection, long-term COC use (≥5 years) might increase the risk for carcinoma in situ and invasive carcinoma (21,277). Limited evidence on women with low-grade squamous intraepithelial lesions found use of the vaginal ring did not worsen the condition (21). # Cervical cancer (awaiting treatment) 2 Comment: Theoretical concern exists that CHC use might affect prognosis of the existing disease. While awaiting treatment, women may use CHCs. In general, treatment of this condition can render a woman sterile. # Breast Disease a. Undiagnosed mass 2 Clarification: The woman should be evaluated as early as possible. b. Benign breast disease 1 c. Family history of cancer 1 Evidence: Women with breast cancer susceptibility genes (such as BRCA1 and BRCA2) have a higher baseline risk for breast cancer than do women without these genes. The baseline risk for breast cancer is also higher among women with a family history of breast cancer than among those who do not have such a history. However, current evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs (278)(279)(280)(281)(282)(283)(284)(285)(286)(287)(288)(289)(290)(291)(292)(293)(294)(295). d. Breast cancer § Comment: Breast cancer is a hormonally sensitive tumor, and the prognosis for women with current or recent breast cancer might worsen with CHC use. i. Current 4 ii. Past and no evidence of current disease for 5 yrs 3 # Endometrial hyperplasia 1 Endometrial cancer § 1 Comment: COC use reduces the risk for endometrial cancer; whether P or R use reduces the risk for endometrial cancer is not known. While awaiting treatment, women may use COCs, P, or R. In general, treatment of this condition renders a woman sterile. May 28, 2010 1 Comment: COC use reduces the risk for ovarian cancer; whether P or R use reduces the risk for ovarian cancer is not known. While awaiting treatment, women may use COCs, P, or R. In general, treatment of this condition can render a woman sterile. Uterine fibroids 1 Comment: COCs do not appear to cause growth of uterine fibroids, and P and R also are not expected to cause growth. # Pelvic inflammatory disease (PID) a. Past PID (assuming no current risk factors for STIs) Comment: COCs might reduce the risk for PID among women with STIs but do not protect against HIV or lower genital tract STIs. Whether use of P or R reduces the risk for PID among women with STIs is unknown, but they do not protect against HIV or lower genital tract STIs. i. With subsequent pregnancy 1 ii. . # HIV/AIDS High risk for HIV 1 Evidence: The balance of the evidence suggests no association between oral contraceptive use and HIV acquisition, although findings from studies conducted among higher risk populations have been inconsistent . # HIV infection § 1 Evidence: Most studies suggest no increased risk for HIV disease progression with hormonal contraceptive use, as measured by changes in CD4 cell count, viral load, or survival. Studies observing that women with HIV who use hormonal contraception have increased risks of acquiring STIs are generally consistent with reports among uninfected women. One direct study found no association between hormonal contraceptive use and an increased risk for HIV transmission to uninfected partners; several indirect studies reported mixed results about whether hormonal contraception is associated with increased risk for HIV-1 DNA or RNA shedding from the genital tract (377,(416)(417)(418)(419)(420)(421)(422)(423)(424)(425)(426)(427)(428)(429)(430)(431)(432). AIDS # Gastrointestinal Conditions Inflammatory bowel disease (IBD) (ulcerative colitis, Crohn disease) 2/3 Clarification: For women with mild IBD and no other risk factor for VTE, the benefits of COC/P/R use generally outweigh the risks (Category 2). However, for women with IBD who are at increased risk for VTE (e.g., those with active or extensive disease, surgery, immobilization, corticosteroid use, vitamin deficiencies, or fluid depletion), the risks of COC/P/R use generally outweigh the benefits (Category 3). Evidence: Risk for disease relapse was not significantly higher among women with IBD using oral contraceptives (most studies did not specify formulation) than among nonusers (461)(462)(463)(464)(465). Absorption of COCs among women with mild ulcerative colitis and no or small ileal resections was similar to the absorption among healthy women (466,467). Findings might not apply to women with Crohn disease or more extensive bowel resections. No data exist that evaluate the increased risk for VTE among women with IBD using COCs/P/R. However, women with IBD are at higher risk than unaffected women for VTE (468). Gallbladder disease a. Symptomatic Comment: COCs, P, or R might cause a small increased risk for gallbladder disease. COCs, P, or R might worsen existing gallbladder disease. Evidence: Data suggest that in women with chronic hepatitis, COC use does not increase the rate or severity of cirrhotic fibrosis, nor does it increase the risk for hepatocellular carcinoma (469,470). For women who are carriers, COC use does not appear to trigger liver failure or severe dysfunction (471)(472)(473). Evidence is limited for COC use during active hepatitis (474). Anemias Thalassemia 1 Comment: Anecdotal evidence from countries where thalassemia is prevalent indicates that COC use does not worsen the condition. # Sickle cell disease § 2 Iron deficiency anemia 1 Comment: CHC use may decrease menstrual blood loss. # Solid Organ Transplantation # Anticonvulsant therapy Clarification: Although the interaction of certain anticonvulsants with COCs, P, or R is not harmful to women, it is likely to reduce the effectiveness of COCs, P, or R. Use of other contraceptives should be encouraged for women who are long-term users of any of these drugs. When a COC is chosen, a preparation containing a minimum of 30 µg EE should be used. d. Rifampicin or rifabutin therapy 3 Clarification: Although the interaction of rifampicin or rifabutin therapy with COCs, P, or R is not harmful to women, it is likely to reduce the effectiveness of COCs, P, or R. Use of other contraceptives should be encouraged for women who are long-term users of either of these drugs. When a COC is chosen, a preparation containing a minimum of 30 µg EE should be used. # Evidence: The balance of the evidence suggests that rifampicin reduces the effectiveness of COCs (545)(546)(547)(548)(549)(550)(551)(552)(553)(554)(555)(556)(557)(558)(559)(560). Data on rifabutin are limited, but effects on metabolism of COCs are less than with rifampicin, and small studies have not shown evidence of ovulation (547,554). - Abbreviations: STI = sexually transmitted infection; HIV = human immunodeficiency virus; COC = combined oral contraceptive; P = patch; R = ring; EE = ethinyl estradiol; BMD = bone mineral density; CHC = combined hormonal contraceptive; IUD = intrauterine device; VTE = venous thromboembolism; BMI = body mass index; DVT = deep venous thrombosis; PE = pulmonary embolism; SLE = systemic lupus erythematosus; MEC = Medical Eligibility Criteria; hCG = human chorionic gonadotropin; DMPA = depot medroxyprogesterone acetate; HPV = human papillomavirus; PID = pelvic inflammatory disease; AIDS = acquired immunodeficiency syndrome; ARV = antiretroviral; IBD = inflammatory bowel disease; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor. † COCs/P/R do not protect against STI/HIV. If risk for STI/HIV (including during pregnancy or postpartum) exists, the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STI/HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # Classifications for Progestin-Only Contraceptives Classifications for progestin-only contraceptives (POCs) include those for progestin-only pills, depot medroxyprogesterone acetate, and progestin-only implants (Box). POCs do BOX. Categories for Classifying Progestin-Only Contraceptives 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). (115,116). Comment: Progestin-only implants might induce cardiac arrhythmias in healthy women; women with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias. May 28, 2010 # Unexplained vaginal bleeding (suspicious for serious condition) Clarification: If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. Comment: POCs might cause irregular bleeding patterns, which might mask symptoms of underlying pathology. The effects of DMPA might persist for some time after discontinuation. Before evaluation 2 3 3 Endometriosis 1 1 1 Benign ovarian tumors (including cysts) # Gastrointestinal Conditions Inflammatory bowel disease (IBD) (ulcerative colitis, Crohn disease) 2 2 1 Evidence: Risk for disease relapse among women with IBD using oral contraceptives (most studies did not specify formulation) did not increase significantly from that for nonusers (212)(213)(214)(215)(216). Comment: Absorption of POPs among women with IBD might be reduced if the woman has substantial malabsorption caused by severe disease or small bowel surgery. Women with IBD have a higher prevalence than the general population of osteoporosis and osteopenia. Use of DMPA, which has been associated with small changes in BMD, might be of concern. Early Release May 28, 2010 hCG = human chorionic gonadotropin; HPV = human papillomavirus; PID = pelvic inflammatory disease; AIDS = acquired immunodeficiency syndrome; IBD = inflammatory bowel disease; ARV = antiretroviral; LNG = levonorgestrel; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; ETG = etonogestrel. † POCs do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. - Abbreviations: STI = sexually transmitted infection; HIV = human immunodeficiency virus; ECP, emergency contraceptive pill; IUD = intrauterine device; COC = combined oral contraceptive; POP = progestin-only pill; CHC = combined hormonal contraceptive; POC = progestin-only contraceptive † ECPs do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # Gallbladder disease # Classifications for Intrauterine Devices Classifications for intrauterine devices (IUDs) are for the levonorgestrel-releasing (20 μg/24 hours) IUD and the copperbearing IUD (Box). IUDs do not protect against sexually BOX. Categories for Classifying Intrauterine Devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. Evidence: Risk for complications from immediate versus delayed insertion of an IUD after abortion did not differ. Expulsion was greater when an IUD was inserted after a second trimester abortion than when inserted after a first trimester abortion. Safety or expulsion for postabortion insertion of an LNG-IUD did not differ from that of a Cu-IUD (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). transmitted infections (STIs) or human immunodeficiency virus (HIV). (38)(39)(40). c. DVT/PE and established on anticoagulant therapy for at least 3 mos Evidence: No direct evidence exists on the use of POCs among women with acute DVT/PE. Although findings on the risk for venous thrombosis with the use of POCs in otherwise healthy women are inconsistent, any small increased risk is substantially less than that with COCs (38)(39)(40). Evidence: Limited evidence indicates that insertion of the LNG-IUD does not pose major bleeding risks in women on chronic anticoagulant therapy. (41)(42)(43)(44) Comment: The LNG-IUD might be a useful treatment for menorrhagia in women on long-term chronic anticoagulation therapy. i. Higher risk for recurrent DVT (77)(78)(79)(80)(81). Benign ovarian tumors (including cysts) 1 1 Severe dysmenorrhea 1 2 Comment: Dysmenorrhea might intensify with Cu-IUD use. LNG-IUD use has been associated with reduction of dysmenorrhea. Gestational trophoblastic disease a. Decreasing or undetectable β-hCG levels 3 3 Evidence: Limited evidence suggests that women using an IUD after uterine evacuation for a molar pregnancy are not at greater risk for postmolar trophoblastic disease than are women using other methods of contraception (82-84). b. Persistently elevated β-hCG levels or malignant disease § 4 4 Evidence: Limited evidence suggests that women using an IUD after uterine evacuation for a molar pregnancy are not at greater risk for postmolar trophoblastic disease than are women using other methods of contraception (82-84) # Cervical ectropion 1 1 Cervical intraepithelial neoplasia 2 1 Comment: Theoretical concern exists that LNG-IUDs might enhance progression of cervical intraepithelial neoplasia. # Cervical cancer (awaiting treatment) Initiation Continuation Initiation Continuation Comment: Concern exists about the increased risk for infection and bleeding at insertion. The IUD most likely will need to be removed at the time of treatment, but until then, the woman is at risk for pregnancy. Evidence: Among women with endometrial hyperplasia, no adverse health events occurred with LNG-IUD use; most women experienced disease regression (85)(86)(87)(88)(89)(90)(91)(92)(93). # Endometrial cancer § Initiation Continuation Initiation Continuation Comment: Concern exists about the increased risk for infection, perforation, and bleeding at insertion. The IUD most likely will need to be removed at the time of treatment, but until then, the woman is at risk for pregnancy. Ovarian cancer § 1 1 Comment: Women with ovarian cancer who undergo fertility sparing treatment and need contraception may use an IUD. # Uterine fibroids 2 2 Evidence: Among women with uterine fibroids using an LNG-IUD, most experienced improvements in serum levels of hemoglobin, hematocrit, and ferritin (73,(94)(95)(96)(97)(98)(99)(100) and menstrual blood loss (73,75,(94)(95)(96)(97)(98)(99)(100)(101). Rates of LNG-IUD expulsion were higher in women with uterine fibroids (11%) than in women without fibroids (0%-3%); these findings were not statistically significant or significance testing was not conducted (75,101). Rates of expulsion from noncomparative studies ranged from 0%-20% (94,(96)(97)(98)(99)(100). Comment: Women with heavy or prolonged bleeding should be assigned the category for that condition. # Anatomical abnormalities a. Distorted uterine cavity (any congenital or acquired uterine abnormality distorting the uterine cavity in a manner that is incompatible with IUD insertion) # Appendix H Classifications for Fertility Awareness-Based Methods Fertility awareness-based (FAB) methods of family planning involve identifying the fertile days of the menstrual cycle, whether by observing fertility signs such as cervical secretions and basal body temperature or by monitoring cycle days (Box). FAB methods can be used in combination with abstinence or barrier methods during the fertile time. If barrier methods are used, refer to Appendix G. No medical conditions become worse because of use of FAB methods. In general, FAB methods can be used without concern for health effects to persons who choose them. However, a number of conditions make their use more complex. The existence of these conditions suggests that 1) use of these methods should be delayed until the condition is corrected or resolved or 2) persons using FAB methods will require special counseling, and a more highly trained provider is generally necessary to ensure correct use. Women with conditions that make pregnancy an unacceptable risk should be advised that FAB methods might not be appropriate for them because of the relatively higher typical-use failure rates of these methods. FAB methods do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # Box. Definitions for terms associated with fertility awarenessbased methods # Symptoms-based methods : FAB methods based on observation of fertility signs (e.g., cervical secretions, basal body temperature) such as the Cervical Mucus Method, the Symptothermal Method, and the TwoDay Method. # Calendar-based methods : FAB methods based on calendar calculations such as the Calendar Rhythm Method and the Standard Days Method. # Acccept (A) : There is no medical reason to deny the particular FAB method to a woman in this circumstance. # Caution (C) : The method is normally provided in a routine setting but with extra preparation and precautions. For FAB methods, this usually means that special counselling might be needed to ensure correct use of the method by a woman in this circumstance. # Delay (D) : Use of this method should be delayed until the condition is evaluated or corrected. Alternative temporary methods of contraception should be offered. # Reproductive Tract Infections and Disorders Irregular vaginal bleeding D D Comment: Presence of this condition makes FAB methods unreliable. Therefore, barrier methods should be recommended until the bleeding pattern is compatible with proper method use. The condition should be evaluated and treated as necessary. Vaginal discharge D A Comment: Because vaginal discharge makes recognition of cervical secretions difficult, the condition should be evaluated and treated if needed before providing methods based on cervical secretions. # Other Use of drugs that affect cycle regularity, hormones, and/or fertility signs C/D C/D Comment: Use of certain mood-altering drugs such as lithium, tricyclic antidepressants, and antianxiety therapies, and certain antibiotics and anti-inflammatory drugs, might alter cycle regularity or affect fertility signs. The condition should be carefully evaluated and a barrier method offered until the degree of effect has been determined or the drug is no longer being used. Diseases that elevate body temperature a. Chronic diseases C A Comment: Elevated temperature levels might make basal body temperature difficult to interpret but have no effect on cervical secretions. Thus, use of a method that relies on temperature should be delayed until the acute febrile disease abates. Temperature-based methods are not appropriate for women with chronically elevated temperatures. In addition, some chronic diseases interfere with cycle regularity, making calendar-based methods difficult to interpret. b. Acute diseases D A - Abbreviations: FAB = fertility awareness-based; A = accept; C = caution; D = delay; STI = sexually transmitted infection; HIV = human immunodeficiency infection. † Fertility awareness-based methods do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. The Bellagio Consensus provided the scientific basis for defining the conditions under which breastfeeding can be used safely and effectively for birth-spacing purposes, and programmatic guidelines were developed for use of lactational amenorrhea in family planning (1,2). These guidelines include the following three criteria, all of which must be met to ensure adequate protection from an unplanned pregnancy: 1) amenorrhea; 2) fully or nearly fully breastfeeding, and 3) <6 months postpartum. The main indications for breastfeeding are to provide an ideal food for the infant and protect against disease. No medical conditions exist for which use of the lactational amenorrhea method for contraception is restricted. However, breastfeeding might not be recommended for women or infants with certain conditions. Women with conditions that make pregnancy an unacceptable risk should be advised that the lactational amenorrhea method might not be appropriate for them because of its relatively higher typical-use failure rates. The lactational amenorrhea method does not protect against sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. # HIV Infection HIV can be transmitted from mother to infant through breastfeeding. Therefore, in the United States, where replace-ment feeding is affordable, feasible, acceptable, sustainable, and safe, breastfeeding for women with HIV is not recommended (3,4). # Other Medical Conditions The American Academy of Pediatrics also recommends against breastfeeding for women with active untreated tuberculosis disease, who are positive for human T-cell lymphotropic virus types I or II, or who have herpes simplex lesions on a breast (infant can feed from the other breast). In addition, infants with classic galactosemia should not breastfeed (4). # Medication Used during Breastfeeding To protect infant health, the American Academy of Pediatrics does not recommend breastfeeding for women receiving certain drugs, including diagnostic or therapeutic radioactive isotopes or exposure to radioactive materials, antimetabolites or chemotherapeutic agents, and current use of drugs of abuse (4). May 28, 2010 Coitus interruptus (CI), also known as withdrawal, is a traditional family planning method in which the man completely removes his penis from the vagina, and away from the external genitalia of the female partner, before he ejaculates. CI prevents sperm from entering the woman's vagina, thereby preventing contact between spermatozoa and the ovum. This method might be appropriate for couples who are highly motivated and able to use this method - effectively; with religious or philosophical reasons for not using other - methods of contraception; who need contraception immediately and have entered - into a sexual act without alternative methods available; who need a temporary method while awaiting the start of - another method; or who have intercourse infrequently. - Some benefits of CI are that the method, if used correctly, does not affect breastfeeding and is always available for primary use or use as a back-up method. In addition, CI involves no economic cost or use of chemicals. CI has no directly associated health risks. CI does not protect against sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. CI is unforgiving of incorrect use, and its effectiveness depends on the willingness and ability of the couple to use withdrawal with every act of intercourse. Women with conditions that make pregnancy an unacceptable risk should be advised that CI might not be appropriate for them because of its relatively higher typical-use failure rates. # Appendix J Coitus Interruptus (Withdrawal) Tubal sterilization for women and vasectomy for men are permanent, safe, and highly effective methods of contraception. In general, no medical conditions would absolutely restrict a person's eligibility for sterilization (with the exception of known allergy or hypersensitivity to any materials used to complete the sterilization method). However, certain conditions place a woman at high surgical risk; in these cases, careful consideration should be given to the risks and benefits of other acceptable alternatives, including long-acting, highly effective, reversible methods and vasectomy. Female and male sterilization do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. Because these methods are intended to be irreversible, persons who choose sterilization should be certain that they want to prevent pregnancy permanently. Most persons who choose sterilization remain satisfied with their decision. However, a small proportion of women regret this decision (1%-26% from different studies, with higher rates of regret reported by women who were younger at sterilization) (1,2). Regret among men about vasectomy has been reported to be approximately 5% (3), similar to the proportion of women who report regretting their husbands' vasectomy (6%) (4). Therefore, all persons should be appropriately counseled about the permanency of sterilization and the availability of highly effective, reversible methods of contraception.	CDC created U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, from guidance developed by the World Health Organization (WHO) and finalized the recommendations after consultation with a group of health professionals who met in Atlanta, Georgia, during February 2009. This guidance comprises recommendations for the use of specific contraceptive methods by women and men who have certain characteristics or medical conditions. The majority of the U.S. guidance does not differ from the WHO guidance and covers >60 characteristics or medical conditions. However, some WHO recommendations were modified for use in the United States, including recommendations about contraceptive use for women with venous thromboembolism, valvular heart disease, ovarian cancer, and uterine fibroids and for postpartum and breastfeeding women. Recommendations were added to the U.S. guidance for women with rheumatoid arthritis, history of bariatric surgery, peripartum cardiomyopathy, endometrial hyperplasia, inflammatory bowel disease, and solid organ transplantation. The recommendations in this document are intended to assist health-care providers when they counsel women, men, and couples about contraceptive method choice. Although these recommendations are meant to serve as a source of clinical guidance, health-care providers should always consider the individual clinical circumstances of each person seeking family planning services.# Introduction In 1996, the World Health Organization (WHO) published the first edition of the Medical Eligibility Criteria for Contraceptive Use (MEC), which gave evidence-based guidance on the safety of contraceptive method use for women and men worldwide who had specific characteristics and medical conditions. Since that time, WHO has regularly updated its guidance on the basis of new evidence, and the WHO MEC is now in its fourth edition (1). CDC, through close collaboration with WHO, has contributed substantially during the last 15 years to creation of WHO's global family planning guidance, which includes four documents: the medical eligibility criteria for contraceptive use, the selected practice recommendations for contraceptive use, a decision-making tool for clients and providers, and a global family planning handbook. This WHO guidance has been based on the best available scientific evidence, and CDC has served as the lead for establishing that evidence base and presenting the evidence to WHO for use during its expert working group meetings to create and update the guidance. WHO has always intended for its global guidance to be used by local or regional policy makers, managers of family planning programs, and the scientific community as a reference when they develop family planning guidance at the country or program level. The United Kingdom is one example of a country that has adapted the WHO MEC for its own use (2). CDC undertook a formal process to adapt the WHO MEC at this time because the fourth edition of the WHO guidance is unlikely to undergo major revisions in the near future. Although the WHO guidance is already available in the United States through inclusion in textbooks, use by professional organizations, and incorporation into training programs, the adaptation of the guidance ensures its appropriateness for use in the United States and allows for further dissemination and implementation among U.S. health-care providers. Most of the U.S. guidance does not differ from the WHO guidance and covers approximately 60 characteristics or medical conditions. However, several changes have been made, including adaptations of selected WHO recommendations, addition of recommendations for new medical conditions, and removal of recommendations for contraceptive methods not currently available in the United States (Appendix A). This document contains recommendations for health-care providers for the safe use of contraceptive methods by women and men with various characteristics and medical conditions. It is intended to assist health-care providers when they counsel women, men, and couples about contraceptive method choice. These recommendations are meant to be a source of clinical guidance; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. # U S. Medical Eligibility Criteria for Contraceptive Use, 2010 Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition May 28, 2010 # Methods The process for adapting the WHO MEC for the United States comprised four major steps: 1) determination of the scope of and process for the adaptation, including a small meeting; 2) preparation and peer review of systematic reviews of the evidence to be used for the adaptation; 3) organization of a larger meeting to examine the evidence and provide input on the recommendations; and 4) finalization of the recommendations by CDC. In June 2008, CDC held a 2-day meeting of eight key partners and U.S. family planning experts to determine the scope of and process for a U.S. adaptation of the WHO MEC. Participants were family planning providers, who also had expertise in conducting research on contraceptive safety and translating research evidence into guidance. WHO guidance is used widely around the world, including in the United States, and contains approximately 1,800 separate recommendations. In most cases, the evidence base would be the same for the U.S. and the WHO recommendation, and-because of the extensive collaboration between WHO and CDC in creating the international guidance-the process for determining the recommendations also would be the same. Therefore, CDC determined that the global guidance also should be the U.S. guidance, except when a compelling reason existed for adaptation, and that CDC would accept the majority of WHO guidance for use in the United States. During the June 2008 meeting, CDC identified specific WHO recommendations for which a compelling reason existed to consider modification for the United States because of the availability of new scientific evidence or the context in which family planning services are provided in the United States. CDC also identified areas in which WHO guidance was inconsistent with current U.S. practice by contacting numerous professional and service organizations and individual providers. In addition, CDC assessed the need for adding recommendations for medical conditions not currently included in the WHO MEC. Through this process, a list was developed of existing WHO recommendations to consider adapting and new medical conditions to consider adding to the guidance. A systematic review of the scientific evidence was conducted for each of the WHO recommendations considered for adaptation and for each of the medical conditions considered for addition to the guidance. The purpose of these systematic reviews was to identify direct evidence about the safety of contraceptive method use by women (or men) with selected conditions (e.g., risk for disease progression or other adverse health effects in women with rheumatoid arthritis who use combined oral contraceptives). Information about indirect evidence (e.g., evidence from healthy women or animal studies) or theoretical considerations was obtained when direct evidence was not available. CDC conducted systematic reviews following standard guidelines (3,4), included thorough searches of PubMed and other databases of the scientific literature, and used the U.S. Preventive Services Task Force system to grade the strength and quality of the evidence (5). Each systematic review was peer-reviewed by two or three experts before being used in the adaptation process. These systematic reviews have been submitted for publication in peer-reviewed journals. For most recommendations in this document, a limited number of studies address the use of a specific contraceptive method by women with a specific condition. Therefore, within the WHO guidance, as well as with this U.S. adaptation of the guidance, most of the decisions about medical eligibility criteria were often necessarily based on 1) extrapolations from studies that primarily included healthy women, 2) theoretical considerations about risks and benefits, and 3) expert opinion. Evidence was particularly limited for newer contraceptive methods. The total body of evidence for each recommendation included evidence based on direct studies or observations of the contraceptive method used by women (or men) with the condition and may have included 1) evidence derived from effects of the contraceptive method used by women (or men) without the condition and 2) indirect evidence or theoretical concerns based on studies of suitable animal models, human laboratory studies, or analogous clinical situations. In February 2009, CDC held a meeting of 31 experts who were invited to provide their individual perspective on the scientific evidence presented and the discussions on potential recommendations that followed. This group included obstetricians/gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with expertise in contraceptive safety and provision. For each topic discussed, the evidence from the systematic review was presented; for most of the topics, an expert in the BOX 1. Categories of medical eligibility criteria for contraceptive use 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. specific medical condition (e.g., rheumatoid arthritis) also gave a brief presentation on the condition and specific issues about contraceptive safety. CDC gathered input from the experts during the meeting and finalized the recommendations in this document. CDC plans to develop a research agenda to address topics identified during the meeting that need further investigation. # How to Use this Document These recommendations are intended to help health-care providers determine the safe use of contraceptive methods among women and men with various characteristics and medical conditions. Providers also can use the synthesis of information in these recommendations when consulting with women, men, and couples about their selection of contraceptive methods. The tables in this document include recommendations for the use of contraceptive methods by women and men with particular characteristics or medical conditions. Each condition was defined as representing either an individual's characteristics (e.g., age, history of pregnancy) or a known preexisting medical/pathologic condition (e.g., diabetes and hypertension). The recommendations refer to contraceptive methods being used for contraceptive purposes; the recommendations do not consider the use of contraceptive methods for treatment of medical conditions because the eligibility criteria in these cases may differ. The conditions affecting eligibility for the use of each contraceptive method were classified under one of four categories (Box 1). # Using the Categories in Practice Health-care providers can use these categories when assessing the safety of contraceptive method use for women and men with specific medical conditions or characteristics. Category 1 comprises conditions for which no restrictions exist for use of the contraceptive method. Classification of a method/ condition as Category 2 indicates the method generally can be used, but careful follow-up may be required. For a method/ condition classified as Category 3, use of that method usually is not recommended unless other more appropriate methods are not available or acceptable. The severity of the condition and the availability, practicality, and acceptability of alternative methods should be taken into account, and careful follow-up will be required. Hence, provision of a method to a woman with a condition classified as Category 3 requires careful clinical judgement and access to clinical services. Category 4 comprises conditions that represent an unacceptable health risk if the method is used. For example, a smoker aged <35 years generally can use combined oral contraceptives (COCs) (Category 2). However, for a woman aged ≥35 years who smokes <15 cigarettes per day, the use of COCs usually is not recommended unless other methods are not available or acceptable to her (Category 3). A woman aged ≥35 years who smokes ≥15 cigarettes per day should not use COCs because of unacceptable health risks, primarily the risk for myocardial infarction and stroke (Category 4). The programmatic implications of these categories may depend on the circumstances of particular professional or service organizations (e.g., in some settings, a Category 3 may mean that special consultation is warranted). The recommendations address medical eligibility criteria for the initiation and continued use of all methods evaluated. The issue of continuation criteria is clinically relevant whenever a woman develops the condition while she is using the method. When the categories differ for initiation and continuation, these differences are noted in the columns Initiation and Continuation. Where Initiation and Continuation are not denoted, the category is the same for initiation and continuation of use. On the basis of this classification system, the eligibility criteria for initiating and continuing use of a specific contraceptive method are presented in tables (Appendices A-M). In these tables, the first column indicates the condition. Several conditions were divided into subconditions to differentiate between varying types or severity of the condition. The second column classifies the condition for initiation and/or continuation into Category 1, 2, 3, or 4. For some conditions, the numeric classification does not adequately capture the recommendation; in this case, the third column clarifies the numeric category. These clarifications were determined during the discussions of the scientific evidence and the numeric classification and are considered a necessary element of the recommendation. The third column also summarizes the evidence for the recommendation, where evidence exists. The recommendations for which no evidence is cited are based on expert opinion from either the WHO or U.S. expert working group meetings and may be based on evidence from sources other than systematic reviews and presented at those meetings. For selected recommendations, additional comments appear in the third column and generally come from the WHO or the U.S. expert working group participants. # Recommendations for Use of Contraceptive Methods The classifications for whether women with certain medical conditions or characteristics can use specific contraceptive methods are provided for combined hormonal contraceptive methods, including low-dose (containing ≤35 μg ethinyl estradiol) combined oral contraceptive pills, combined hormonal patch, and combined vaginal ring (Appendix B); progestin-only contraceptive methods, including progestinonly pills, depot medroxyprogesterone acetate injections, and etonogestrel implants (Appendix C); emergency contraceptive pills (Appendix D); intrauterine contraception, including the copper intrauterine device (IUD) and the levonorgestrel IUD (Appendix E); use of copper IUDs for emergency contraception (Appendix F); barrier contraceptive methods, including male and female condoms, spermicides, diaphragm with spermicide, and cervical cap (Appendix G); fertility awarenessbased methods (Appendix H); lactational amenorrhea method (Appendix I); coitus interruptus (Appendix J); and female and male sterilization (Appendix K). Tables at the end of the document summarize the classifications for the hormonal and intrauterine methods (Appendix L) and the evidence about potential drug interactions between hormonal contraceptives and antiretroviral therapies (Appendix M). # Contraceptive Method Choice Many elements need to be considered by women, men, or couples at any given point in their lifetimes when choosing the most appropriate contraceptive method. These elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. The guidance in this document focuses primarily on the safety of a given contraceptive method for a person with a particular characteristic or medical condition. Therefore, the classification of Category 1 means that the method can be used in that circumstance with no restrictions with regard to safety but does not necessarily imply that the method is the best choice for that person; other factors, such as effectiveness, availability, and acceptability, may play a key role in determining the most appropriate choice. Voluntary informed choice of contraceptive methods is an essential guiding principle, and contraceptive counseling, where applicable, may be an important contributor to the successful use of contraceptive methods. In choosing a method of contraception, the risk for sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), also must be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STIs. Consistent and correct use of the male latex condom reduces the risk for STIs (6). When a male condom cannot be used properly for infection prevention, a female condom should be considered (7). Women who use contraceptive methods other than condoms should be counseled about the use of condoms and the risk for STIs (7). Additional information about prevention and treatment of STIs is available from CDC's Sexually Transmitted Diseases Treatment Guidelines (http://www.cdc.gov/std/treatment) (7). # Contraceptive Method Effectiveness Contraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Table 1). Methods that depend on consistent and correct use have a wide range of effectiveness. # Unintended Pregnancy and Increased Health Risk For women with conditions that may make unintended pregnancy an unacceptable health risk, long-acting, highly effective contraceptive methods may be the best choice (Table 1). Women with these conditions should be advised that sole use of barrier methods for contraception and behavior-based methods of contraception may not be the most appropriate choice because of their relatively higher typical-use rates of failure (Table 1). Conditions included in the U.S. MEC for which unintended pregnancy presents an unacceptable health risk are identified throughout the document (Box 2). # Keeping Guidance Up to Date As with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. CDC will continue to work with WHO to identify and assess all new relevant evidence and to determine whether changes to the recommendations are warranted (4). In most cases, the U.S. MEC will follow any updates in the WHO guidance, which typically occur every 3-4 years (or sooner if warranted by new data). However, CDC will review any WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations and medical conditions that are not included in the WHO guidance. CDC will completely review the U.S. MEC every 3-4 years as well. Updates to the guidance will appear on the CDC U.S. MEC website: http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USMEC.htm. The classification additions, deletions, and modifications from the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use, 4th Edition, are summarized below (Tables 1-3). For conditions for which # BOX. Categories for Classifying Hormonal Contraceptives and Intrauterine Devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. classification changed for ≥1 methods or the condition description underwent a major modification, WHO conditions and recommendations appear in curly brackets. May 28, 2010 Other deleted items Guidance for combined injectables, levonorgestrel implants, and norethisterone enanthate has been removed because these methods are not currently available in the United States. Guidance for "blood pressure measurement unavailable" and "history of hypertension, where blood pressure CANNOT be evaluated (including hypertension in pregnancy)" has been removed. # Unintended pregnancy and increased health risk The following conditions have been added to the WHO list of conditions that expose a woman to increased risk as a result of unintended pregnancy: history of bariatric surgery within the past 2 years, peripartum cardiomyopathy, and receiving a solid organ transplant within 2 years. Combined hormonal contraceptives (CHCs) include lowdose (containing ≤35 μg ethinyl estradiol [EE]) combined oral contraceptives (COCs), the combined hormonal patch, and the combined vaginal ring. The combined hormonal patch and vaginal ring are relatively new contraceptive methods. Limited information is available about the safety of these methods among women with specific medical conditions. Moreover, epidemiologic data on the long-term effects of the combined hormonal patch and the vaginal ring were not available for review. Evidence indicates that the combined hormonal patch and the combined vaginal ring provide comparable safety and pharmacokinetic profiles to COCs with similar hormone formulations . Pending further studies, the evidence available for recommendations about COCs applies to the recommendations for the combined hormonal patch and vaginal ring. Therefore, the patch and ring should have the same categories (Box) as COCs, except where noted. The assigned categories should, therefore, be considered a preliminary, best judgement, which will be reevaluated as new data become available. CHCs do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # Appendix B Classifications for Combined Hormonal Contraceptives # BOX. Categories for Classifying Combined Hormonal Contraceptives 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. (34)(35)(36)(37)(38)(39)(40)(41). In premenopausal adult women, COC use has little to no effect on bone health while appearing to preserve bone mass in perimenopausal women (26,. Postmenopausal women who have ever used COCs have similar BMD to postmenopausal women who have never used COCs (54,58,68,81,(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110). BMD in adolescent or premenopausal women may not accurately predict postmenopausal fracture risk (109,(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122). # Postabortion Clarification: COCs, P, or R may be started immediately postabortion. a. First trimester 1 Evidence: Women who started taking COCs immediately after first trimester medical or surgical abortion did not experience more side effects or adverse vaginal bleeding outcomes or clinically significant changes in coagulation parameters than did women who used a placebo, an IUD, a nonhormonal contraceptive method, or delayed COC initiation (134)(135)(136)(137)(138)(139)(140). Limited evidence on women using the ring immediately after first trimester medical or surgical abortion found no serious adverse events and no infection related to use of the combined vaginal contraceptive ring during 3 cycles of follow-up postabortion (141). b. Second trimester 1 c. Immediate postseptic abortion 1 Past ectopic pregnancy 1 Comment: The risk for future ectopic pregnancy is increased among women who have had an ectopic pregnancy in the past. CHCs protect against pregnancy in general, including ectopic gestation. (147,(153)(154)(155)(156)(157)(158)(159). Limited evidence is inconsistent about whether COC effectiveness varies by body weight or BMI (160)(161)(162)(163)(164)(165). Limited evidence suggests obese women are no more likely to gain weight after 3 cycles of the vaginal ring or COC than overweight or normal weight women. A similar weight gain during the 3 months was noted between the COC group and the vaginal ring group across all BMI categories (166). The effectiveness of the patch decreased among women who weighed >90 kg; however, no association was found between pregnancy risk and BMI (18). Evidence: Among women with hypertension, COC users were at higher risk than nonusers for stroke, acute myocardial infarction, and peripheral arterial disease (142,144,(151)(152)(153)155,(171)(172)(173)(174)(175)(176)(177)(178)(179)(180)(181)(182)(183)(184)(185)(186). Discontinuation of COCs in women with hypertension might improve blood pressure control (187). ii. Systolic ≥160 mm Hg or diastolic ≥100 mm Hg § 4 c. Vascular disease 4 History of high blood pressure during pregnancy (where current blood pressure is measurable and normal) 2 Evidence: Women with a history of high blood pressure in pregnancy, who also used COCs, had a higher risk for myocardial infarction and VTE than did COC users who did not have a history of high blood pressure during pregnancy. The absolute risks for acute myocardial infarction and VTE in this population remained small (153,172,(184)(185)(186)(188)(189)(190)(191)(192)(193). ii. Lower risk for recurrent DVT/PE (no risk factors) Deep 3 Clarification: Women on anticoagulant therapy are at risk for gynecologic complications of therapy, such as hemorrhagic ovarian cysts and severe menorrhagia. Hormonal contraceptive methods can be of benefit in preventing or treating these complications. When a contraceptive method is used as a therapy, rather than solely to prevent pregnancy, the risk/benefit ratio may differ and should be considered on a case-bycase basis. d. Family history (first-degree relatives) 2 Comment: Some conditions that increase the risk for DVT/PE are heritable. e. Major surgery i. With prolonged immobilization 4 ii. Without prolonged immobilization 2 f. Minor surgery without immobilization 1 Known thrombogenic mutations § (e.g., factor V Leiden; prothrombin mutation; protein S, protein C, and antithrombin deficiencies) 4 Clarification: Routine screening is not appropriate because of the rarity of the conditions and the high cost of screening. Evidence: Among women with thrombogenic mutations, COC users had a 2-fold to 20-fold higher risk for thrombosis than did nonusers (159,. (218). # Superficial venous thrombosis Comment: COCs might increase fluid retention in healthy women; fluid retention may worsen heart failure in women with peripartum cardiomyopathy. COCs might induce cardiac arrhythmias in healthy women; women with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias. Evidence: Among women with migraine, women who also had aura had a higher risk for stroke than did those without aura (248-250). Women with a history of migraine who use COCs are about 2-4 times as likely to have an ischemic stroke as nonusers with a history of migraine (142,157,179,180,(249)(250)(251)(252)(253)(254). Evidence: A Cochrane Collaboration Review identified 1 randomized controlled trial evaluating the effectiveness of COC use compared with naproxen and danazol in treating menorrhagic women. Women with menorrhagia did not report worsening of the condition or any adverse events related to COC use (265). # Rheumatic Diseases # Unexplained vaginal bleeding (suspicious for serious condition) Before evaluation 2 Clarification: If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. # Comment: No conditions that cause vaginal bleeding will be worsened in the short term by use of CHCs. # Endometriosis 1 Evidence: A Cochrane Collaboration Review identified 1 randomized controlled trial evaluating the effectiveness of COC use compared with a gonadotropin-releasing hormone analogue in treating the symptoms of endometriosis. Women with endometriosis did not report worsening of the condition or any adverse events related to COC use (266). # Benign ovarian tumors (including cysts) 1 Severe dysmenorrhea 1 Evidence: Risk for side effects with COC use was not higher among women with dysmenorrhea than among women not using COCs. Some COC users had a reduction in pain and bleeding (267,268). Gestational trophoblastic disease a. Decreasing or undetectable β-hCG levels 1 Evidence: After molar pregnancy evacuation, the balance of evidence found COC use did not increase the risk for postmolar trophoblastic disease, and β-hCG levels regressed more rapidly in some COC users than in nonusers (269-275). Limited evidence suggests that use of COCs during chemotherapy does not significantly affect the regression or treatment of postmolar trophoblastic disease compared with women who used a nonhormonal contraceptive method or DMPA during chemotherapy (276). b. Persistently elevated β-hCG levels or malignant disease § 1 Cervical ectropion 1 Comment: Cervical ectropion is not a risk factor for cervical cancer, and restriction of CHC use is unnecessary. # Cervical intraepithelial neoplasia 2 Evidence: Among women with persistent HPV infection, long-term COC use (≥5 years) might increase the risk for carcinoma in situ and invasive carcinoma (21,277). Limited evidence on women with low-grade squamous intraepithelial lesions found use of the vaginal ring did not worsen the condition (21). # Cervical cancer (awaiting treatment) 2 Comment: Theoretical concern exists that CHC use might affect prognosis of the existing disease. While awaiting treatment, women may use CHCs. In general, treatment of this condition can render a woman sterile. # Breast Disease a. Undiagnosed mass 2 Clarification: The woman should be evaluated as early as possible. b. Benign breast disease 1 c. Family history of cancer 1 Evidence: Women with breast cancer susceptibility genes (such as BRCA1 and BRCA2) have a higher baseline risk for breast cancer than do women without these genes. The baseline risk for breast cancer is also higher among women with a family history of breast cancer than among those who do not have such a history. However, current evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs (278)(279)(280)(281)(282)(283)(284)(285)(286)(287)(288)(289)(290)(291)(292)(293)(294)(295). d. Breast cancer § Comment: Breast cancer is a hormonally sensitive tumor, and the prognosis for women with current or recent breast cancer might worsen with CHC use. i. Current 4 ii. Past and no evidence of current disease for 5 yrs 3 # Endometrial hyperplasia 1 Endometrial cancer § 1 Comment: COC use reduces the risk for endometrial cancer; whether P or R use reduces the risk for endometrial cancer is not known. While awaiting treatment, women may use COCs, P, or R. In general, treatment of this condition renders a woman sterile. May 28, 2010 1 Comment: COC use reduces the risk for ovarian cancer; whether P or R use reduces the risk for ovarian cancer is not known. While awaiting treatment, women may use COCs, P, or R. In general, treatment of this condition can render a woman sterile. Uterine fibroids 1 Comment: COCs do not appear to cause growth of uterine fibroids, and P and R also are not expected to cause growth. # Pelvic inflammatory disease (PID) a. Past PID (assuming no current risk factors for STIs) Comment: COCs might reduce the risk for PID among women with STIs but do not protect against HIV or lower genital tract STIs. Whether use of P or R reduces the risk for PID among women with STIs is unknown, but they do not protect against HIV or lower genital tract STIs. i. With subsequent pregnancy 1 ii. . # HIV/AIDS High risk for HIV 1 Evidence: The balance of the evidence suggests no association between oral contraceptive use and HIV acquisition, although findings from studies conducted among higher risk populations have been inconsistent . # HIV infection § 1 Evidence: Most studies suggest no increased risk for HIV disease progression with hormonal contraceptive use, as measured by changes in CD4 cell count, viral load, or survival. Studies observing that women with HIV who use hormonal contraception have increased risks of acquiring STIs are generally consistent with reports among uninfected women. One direct study found no association between hormonal contraceptive use and an increased risk for HIV transmission to uninfected partners; several indirect studies reported mixed results about whether hormonal contraception is associated with increased risk for HIV-1 DNA or RNA shedding from the genital tract (377,(416)(417)(418)(419)(420)(421)(422)(423)(424)(425)(426)(427)(428)(429)(430)(431)(432). AIDS # Gastrointestinal Conditions Inflammatory bowel disease (IBD) (ulcerative colitis, Crohn disease) 2/3 Clarification: For women with mild IBD and no other risk factor for VTE, the benefits of COC/P/R use generally outweigh the risks (Category 2). However, for women with IBD who are at increased risk for VTE (e.g., those with active or extensive disease, surgery, immobilization, corticosteroid use, vitamin deficiencies, or fluid depletion), the risks of COC/P/R use generally outweigh the benefits (Category 3). Evidence: Risk for disease relapse was not significantly higher among women with IBD using oral contraceptives (most studies did not specify formulation) than among nonusers (461)(462)(463)(464)(465). Absorption of COCs among women with mild ulcerative colitis and no or small ileal resections was similar to the absorption among healthy women (466,467). Findings might not apply to women with Crohn disease or more extensive bowel resections. No data exist that evaluate the increased risk for VTE among women with IBD using COCs/P/R. However, women with IBD are at higher risk than unaffected women for VTE (468). Gallbladder disease a. Symptomatic Comment: COCs, P, or R might cause a small increased risk for gallbladder disease. COCs, P, or R might worsen existing gallbladder disease. Evidence: Data suggest that in women with chronic hepatitis, COC use does not increase the rate or severity of cirrhotic fibrosis, nor does it increase the risk for hepatocellular carcinoma (469,470). For women who are carriers, COC use does not appear to trigger liver failure or severe dysfunction (471)(472)(473). Evidence is limited for COC use during active hepatitis (474). Anemias Thalassemia 1 Comment: Anecdotal evidence from countries where thalassemia is prevalent indicates that COC use does not worsen the condition. # Sickle cell disease § 2 Iron deficiency anemia 1 Comment: CHC use may decrease menstrual blood loss. # Solid Organ Transplantation # Anticonvulsant therapy Clarification: Although the interaction of certain anticonvulsants with COCs, P, or R is not harmful to women, it is likely to reduce the effectiveness of COCs, P, or R. Use of other contraceptives should be encouraged for women who are long-term users of any of these drugs. When a COC is chosen, a preparation containing a minimum of 30 µg EE should be used. d. Rifampicin or rifabutin therapy 3 Clarification: Although the interaction of rifampicin or rifabutin therapy with COCs, P, or R is not harmful to women, it is likely to reduce the effectiveness of COCs, P, or R. Use of other contraceptives should be encouraged for women who are long-term users of either of these drugs. When a COC is chosen, a preparation containing a minimum of 30 µg EE should be used. # Evidence: The balance of the evidence suggests that rifampicin reduces the effectiveness of COCs (545)(546)(547)(548)(549)(550)(551)(552)(553)(554)(555)(556)(557)(558)(559)(560). Data on rifabutin are limited, but effects on metabolism of COCs are less than with rifampicin, and small studies have not shown evidence of ovulation (547,554). * Abbreviations: STI = sexually transmitted infection; HIV = human immunodeficiency virus; COC = combined oral contraceptive; P = patch; R = ring; EE = ethinyl estradiol; BMD = bone mineral density; CHC = combined hormonal contraceptive; IUD = intrauterine device; VTE = venous thromboembolism; BMI = body mass index; DVT = deep venous thrombosis; PE = pulmonary embolism; SLE = systemic lupus erythematosus; MEC = Medical Eligibility Criteria; hCG = human chorionic gonadotropin; DMPA = depot medroxyprogesterone acetate; HPV = human papillomavirus; PID = pelvic inflammatory disease; AIDS = acquired immunodeficiency syndrome; ARV = antiretroviral; IBD = inflammatory bowel disease; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor. † COCs/P/R do not protect against STI/HIV. If risk for STI/HIV (including during pregnancy or postpartum) exists, the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STI/HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # Classifications for Progestin-Only Contraceptives Classifications for progestin-only contraceptives (POCs) include those for progestin-only pills, depot medroxyprogesterone acetate, and progestin-only implants (Box). POCs do BOX. Categories for Classifying Progestin-Only Contraceptives 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). (115,116). Comment: Progestin-only implants might induce cardiac arrhythmias in healthy women; women with peripartum cardiomyopathy have a high incidence of cardiac arrhythmias. May 28, 2010 # Unexplained vaginal bleeding (suspicious for serious condition) Clarification: If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. Comment: POCs might cause irregular bleeding patterns, which might mask symptoms of underlying pathology. The effects of DMPA might persist for some time after discontinuation. Before evaluation 2 3 3 Endometriosis 1 1 1 Benign ovarian tumors (including cysts) # Gastrointestinal Conditions Inflammatory bowel disease (IBD) (ulcerative colitis, Crohn disease) 2 2 1 Evidence: Risk for disease relapse among women with IBD using oral contraceptives (most studies did not specify formulation) did not increase significantly from that for nonusers (212)(213)(214)(215)(216). Comment: Absorption of POPs among women with IBD might be reduced if the woman has substantial malabsorption caused by severe disease or small bowel surgery. Women with IBD have a higher prevalence than the general population of osteoporosis and osteopenia. Use of DMPA, which has been associated with small changes in BMD, might be of concern. Early Release May 28, 2010 hCG = human chorionic gonadotropin; HPV = human papillomavirus; PID = pelvic inflammatory disease; AIDS = acquired immunodeficiency syndrome; IBD = inflammatory bowel disease; ARV = antiretroviral; LNG = levonorgestrel; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; ETG = etonogestrel. † POCs do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. * Abbreviations: STI = sexually transmitted infection; HIV = human immunodeficiency virus; ECP, emergency contraceptive pill; IUD = intrauterine device; COC = combined oral contraceptive; POP = progestin-only pill; CHC = combined hormonal contraceptive; POC = progestin-only contraceptive † ECPs do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # Gallbladder disease # Classifications for Intrauterine Devices Classifications for intrauterine devices (IUDs) are for the levonorgestrel-releasing (20 μg/24 hours) IUD and the copperbearing IUD (Box). IUDs do not protect against sexually BOX. Categories for Classifying Intrauterine Devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. Evidence: Risk for complications from immediate versus delayed insertion of an IUD after abortion did not differ. Expulsion was greater when an IUD was inserted after a second trimester abortion than when inserted after a first trimester abortion. Safety or expulsion for postabortion insertion of an LNG-IUD did not differ from that of a Cu-IUD (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). transmitted infections (STIs) or human immunodeficiency virus (HIV). (38)(39)(40). c. DVT/PE and established on anticoagulant therapy for at least 3 mos Evidence: No direct evidence exists on the use of POCs among women with acute DVT/PE. Although findings on the risk for venous thrombosis with the use of POCs in otherwise healthy women are inconsistent, any small increased risk is substantially less than that with COCs (38)(39)(40). Evidence: Limited evidence indicates that insertion of the LNG-IUD does not pose major bleeding risks in women on chronic anticoagulant therapy. (41)(42)(43)(44) Comment: The LNG-IUD might be a useful treatment for menorrhagia in women on long-term chronic anticoagulation therapy. i. Higher risk for recurrent DVT (77)(78)(79)(80)(81). Benign ovarian tumors (including cysts) 1 1 Severe dysmenorrhea 1 2 Comment: Dysmenorrhea might intensify with Cu-IUD use. LNG-IUD use has been associated with reduction of dysmenorrhea. Gestational trophoblastic disease a. Decreasing or undetectable β-hCG levels 3 3 Evidence: Limited evidence suggests that women using an IUD after uterine evacuation for a molar pregnancy are not at greater risk for postmolar trophoblastic disease than are women using other methods of contraception (82-84). b. Persistently elevated β-hCG levels or malignant disease § 4 4 Evidence: Limited evidence suggests that women using an IUD after uterine evacuation for a molar pregnancy are not at greater risk for postmolar trophoblastic disease than are women using other methods of contraception (82-84) # Cervical ectropion 1 1 Cervical intraepithelial neoplasia 2 1 Comment: Theoretical concern exists that LNG-IUDs might enhance progression of cervical intraepithelial neoplasia. # Cervical cancer (awaiting treatment) Initiation Continuation Initiation Continuation Comment: Concern exists about the increased risk for infection and bleeding at insertion. The IUD most likely will need to be removed at the time of treatment, but until then, the woman is at risk for pregnancy. Evidence: Among women with endometrial hyperplasia, no adverse health events occurred with LNG-IUD use; most women experienced disease regression (85)(86)(87)(88)(89)(90)(91)(92)(93). # Endometrial cancer § Initiation Continuation Initiation Continuation Comment: Concern exists about the increased risk for infection, perforation, and bleeding at insertion. The IUD most likely will need to be removed at the time of treatment, but until then, the woman is at risk for pregnancy. Ovarian cancer § 1 1 Comment: Women with ovarian cancer who undergo fertility sparing treatment and need contraception may use an IUD. # Uterine fibroids 2 2 Evidence: Among women with uterine fibroids using an LNG-IUD, most experienced improvements in serum levels of hemoglobin, hematocrit, and ferritin (73,(94)(95)(96)(97)(98)(99)(100) and menstrual blood loss (73,75,(94)(95)(96)(97)(98)(99)(100)(101). Rates of LNG-IUD expulsion were higher in women with uterine fibroids (11%) than in women without fibroids (0%-3%); these findings were not statistically significant or significance testing was not conducted (75,101). Rates of expulsion from noncomparative studies ranged from 0%-20% (94,(96)(97)(98)(99)(100). Comment: Women with heavy or prolonged bleeding should be assigned the category for that condition. # Anatomical abnormalities a. Distorted uterine cavity (any congenital or acquired uterine abnormality distorting the uterine cavity in a manner that is incompatible with IUD insertion) # Appendix H Classifications for Fertility Awareness-Based Methods Fertility awareness-based (FAB) methods of family planning involve identifying the fertile days of the menstrual cycle, whether by observing fertility signs such as cervical secretions and basal body temperature or by monitoring cycle days (Box). FAB methods can be used in combination with abstinence or barrier methods during the fertile time. If barrier methods are used, refer to Appendix G. No medical conditions become worse because of use of FAB methods. In general, FAB methods can be used without concern for health effects to persons who choose them. However, a number of conditions make their use more complex. The existence of these conditions suggests that 1) use of these methods should be delayed until the condition is corrected or resolved or 2) persons using FAB methods will require special counseling, and a more highly trained provider is generally necessary to ensure correct use. Women with conditions that make pregnancy an unacceptable risk should be advised that FAB methods might not be appropriate for them because of the relatively higher typical-use failure rates of these methods. FAB methods do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # Box. Definitions for terms associated with fertility awarenessbased methods # Symptoms-based methods • : FAB methods based on observation of fertility signs (e.g., cervical secretions, basal body temperature) such as the Cervical Mucus Method, the Symptothermal Method, and the TwoDay Method. # Calendar-based methods • : FAB methods based on calendar calculations such as the Calendar Rhythm Method and the Standard Days Method. # Acccept (A) • : There is no medical reason to deny the particular FAB method to a woman in this circumstance. # Caution (C) • : The method is normally provided in a routine setting but with extra preparation and precautions. For FAB methods, this usually means that special counselling might be needed to ensure correct use of the method by a woman in this circumstance. # Delay (D) • : Use of this method should be delayed until the condition is evaluated or corrected. Alternative temporary methods of contraception should be offered. # Reproductive Tract Infections and Disorders Irregular vaginal bleeding D D Comment: Presence of this condition makes FAB methods unreliable. Therefore, barrier methods should be recommended until the bleeding pattern is compatible with proper method use. The condition should be evaluated and treated as necessary. Vaginal discharge D A Comment: Because vaginal discharge makes recognition of cervical secretions difficult, the condition should be evaluated and treated if needed before providing methods based on cervical secretions. # Other Use of drugs that affect cycle regularity, hormones, and/or fertility signs C/D C/D Comment: Use of certain mood-altering drugs such as lithium, tricyclic antidepressants, and antianxiety therapies, and certain antibiotics and anti-inflammatory drugs, might alter cycle regularity or affect fertility signs. The condition should be carefully evaluated and a barrier method offered until the degree of effect has been determined or the drug is no longer being used. Diseases that elevate body temperature a. Chronic diseases C A Comment: Elevated temperature levels might make basal body temperature difficult to interpret but have no effect on cervical secretions. Thus, use of a method that relies on temperature should be delayed until the acute febrile disease abates. Temperature-based methods are not appropriate for women with chronically elevated temperatures. In addition, some chronic diseases interfere with cycle regularity, making calendar-based methods difficult to interpret. b. Acute diseases D A * Abbreviations: FAB = fertility awareness-based; A = accept; C = caution; D = delay; STI = sexually transmitted infection; HIV = human immunodeficiency infection. † Fertility awareness-based methods do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. The Bellagio Consensus provided the scientific basis for defining the conditions under which breastfeeding can be used safely and effectively for birth-spacing purposes, and programmatic guidelines were developed for use of lactational amenorrhea in family planning (1,2). These guidelines include the following three criteria, all of which must be met to ensure adequate protection from an unplanned pregnancy: 1) amenorrhea; 2) fully or nearly fully breastfeeding, and 3) <6 months postpartum. The main indications for breastfeeding are to provide an ideal food for the infant and protect against disease. No medical conditions exist for which use of the lactational amenorrhea method for contraception is restricted. However, breastfeeding might not be recommended for women or infants with certain conditions. Women with conditions that make pregnancy an unacceptable risk should be advised that the lactational amenorrhea method might not be appropriate for them because of its relatively higher typical-use failure rates. The lactational amenorrhea method does not protect against sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. # HIV Infection HIV can be transmitted from mother to infant through breastfeeding. Therefore, in the United States, where replace-ment feeding is affordable, feasible, acceptable, sustainable, and safe, breastfeeding for women with HIV is not recommended (3,4). # Other Medical Conditions The American Academy of Pediatrics also recommends against breastfeeding for women with active untreated tuberculosis disease, who are positive for human T-cell lymphotropic virus types I or II, or who have herpes simplex lesions on a breast (infant can feed from the other breast). In addition, infants with classic galactosemia should not breastfeed (4). # Medication Used during Breastfeeding To protect infant health, the American Academy of Pediatrics does not recommend breastfeeding for women receiving certain drugs, including diagnostic or therapeutic radioactive isotopes or exposure to radioactive materials, antimetabolites or chemotherapeutic agents, and current use of drugs of abuse (4). May 28, 2010 Coitus interruptus (CI), also known as withdrawal, is a traditional family planning method in which the man completely removes his penis from the vagina, and away from the external genitalia of the female partner, before he ejaculates. CI prevents sperm from entering the woman's vagina, thereby preventing contact between spermatozoa and the ovum. This method might be appropriate for couples who are highly motivated and able to use this method • effectively; with religious or philosophical reasons for not using other • methods of contraception; who need contraception immediately and have entered • into a sexual act without alternative methods available; who need a temporary method while awaiting the start of • another method; or who have intercourse infrequently. • Some benefits of CI are that the method, if used correctly, does not affect breastfeeding and is always available for primary use or use as a back-up method. In addition, CI involves no economic cost or use of chemicals. CI has no directly associated health risks. CI does not protect against sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. CI is unforgiving of incorrect use, and its effectiveness depends on the willingness and ability of the couple to use withdrawal with every act of intercourse. Women with conditions that make pregnancy an unacceptable risk should be advised that CI might not be appropriate for them because of its relatively higher typical-use failure rates. # Appendix J Coitus Interruptus (Withdrawal) Tubal sterilization for women and vasectomy for men are permanent, safe, and highly effective methods of contraception. In general, no medical conditions would absolutely restrict a person's eligibility for sterilization (with the exception of known allergy or hypersensitivity to any materials used to complete the sterilization method). However, certain conditions place a woman at high surgical risk; in these cases, careful consideration should be given to the risks and benefits of other acceptable alternatives, including long-acting, highly effective, reversible methods and vasectomy. Female and male sterilization do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. Because these methods are intended to be irreversible, persons who choose sterilization should be certain that they want to prevent pregnancy permanently. Most persons who choose sterilization remain satisfied with their decision. However, a small proportion of women regret this decision (1%-26% from different studies, with higher rates of regret reported by women who were younger at sterilization) (1,2). Regret among men about vasectomy has been reported to be approximately 5% (3), similar to the proportion of women who report regretting their husbands' vasectomy (6%) (4). Therefore, all persons should be appropriately counseled about the permanency of sterilization and the availability of highly effective, reversible methods of contraception. # Acknowledgements # Appendix C Appendix D Classifications for Emergency Contraceptive Pills # BOX. Categories for Classifying Emergency Contraceptive Pills 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. # TABLE. Classifications for emergency contraceptive pills, including levonorgestrel contraceptive pills and combined oral contraceptive pills* † # Condition Category Clarifications/Evidence/Comments Personal Characteristics and Reproductive History Pregnancy Not applicable Clarification: Although this method is not indicated for a woman with a known or suspected pregnancy, no harm to the woman, the course of her pregnancy, or the fetus if ECPs are inadvertently used is known to exist. # Breastfeeding 1 # Past ectopic pregnancy 1 History of bariatric surgery § a. Restrictive procedures: decrease storage capacity of the stomach (vertical banded gastroplasty, laparoscopic adjustable gastric band, laparoscopic sleeve gastrectomy) 1 b. Malabsorptive procedures: decrease absorption of nutrients and calories by shortening the functional length of the small intestine (Roux-en-Y gastric bypass, biliopancreatic diversion) 1 Comment: Bariatric surgical procedures involving a malabsorptive component have the potential to decrease oral contraceptive effectiveness, perhaps further decreased by postoperative complications such as long-term diarrhea and/or vomiting. Because of these malabsorptive concerns, an emergency IUD might be more appropriate than ECPs. # Cardiovascular Disease History of severe cardiovascular complications § (ischemic heart disease, cerebrovascular attack, or other thromboembolic conditions) 2 Comment: The duration of ECP use is less than that of regular use of COCs or POPs and thus would be expected to have less clinical impact. Angina pectoris 2 Comment: The duration of ECP use is less than that of regular use of COCs or POPs and thus would be expected to have less clinical impact. # Rheumatic Diseases Rheumatoid arthritis a. On immunosuppressive therapy 1 b. Not on immunosuppressive therapy 1 # Neurologic Conditions Migraine 2 Comment: The duration of ECP use is less than that of regular use of COCs or POPs and thus would be expected to have less clinical impact. # Gastrointestinal Conditions Inflammatory bowel disease (ulcerative colitis, Crohn disease) 1 Severe liver disease § (including jaundice) 2 Comment: The duration of ECP use is less than that of regular use of COCs or POPs and thus would be expected to have less clinical impact. # Solid Organ Transplantation Solid organ transplantation § a. Complicated: graft failure (acute or chronic), rejection, cardiac allograft vasculopathy 1 b. Uncomplicated 1 Classifications for emergency contraceptive pills (ECPs) are for both levonorgestrel and combined oral contraceptive pills. ECPs do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # Appendix E Evidence: Using an algorithm to classify STI risk status among IUD users, 1 study reported that 11% of women at high risk for STIs experienced IUD-related complications compared with 5% of those not classified as high risk (107). # HIV/AIDS # High risk for HIV Initiation Continuation Initiation Continuation 2 2 2 2 Evidence: Among women at risk for HIV, Cu-IUD use did not increase risk for HIV acquisition (112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122). HIV infection § 2 2 2 2 Evidence: Among IUD users, limited evidence shows no higher risk for overall complications or for infectious complications in HIVinfected than in HIV-uninfected women. IUD use did not adversely affect progression of HIV when compared with hormonal contraceptive use among HIV-infected women. Furthermore, IUD use among HIV-infected women was not associated with increased risk for transmission to sex partners (112,(123)(124)(125)(126)(127)(128)(129)(130). ARV = antiretroviral; IBD = inflammatory bowel disease; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor. † IUDs do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # BOX. Categories for Classifying Cu-IUDs as Emergency Contraception 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. # Appendix F Classifications for Copper Intrauterine Devices for Emergency Contraception A copper IUD (Cu-IUD) can be used within 5 days of unprotected intercourse as an emergency contraceptive. However, when the time of ovulation can be estimated, the Cu-IUD can be inserted beyond 5 days after intercourse, if necessary, as long as the insertion does not occur >5 days after ovulation. The eligibility criteria for interval Cu-IUD insertion also apply for the insertion of Cu-IUDs as emergency contraception (Box). Cu-IUDs for emergency contraception do not protect against sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). # TABLE. Classifications for copper intrauterine devices for emergency contraception* † # Condition Category Clarifications/Evidence/Comments Pregnancy 4 Clarification: IUD use is not indicated during pregnancy and should not be used because of the risk for serious pelvic infection and septic spontaneous abortion. Rape a. High risk for STI 3 Comment: IUDs do not protect against STI/HIV or PID. Among women with chlamydial infection or gonorrhea, the potential increased risk for PID with IUD insertion should be avoided. The concern is less for other STIs. b. Low risk for STI 1 * Abbreviations: IUD = intrauterine device; Cu-IUD = copper IUD; STI = sexually transmitted infection; HIV = human immunodeficiency virus; PID = pelvic inflammatory disease † Cu-IUDs for emergency contraception do not protect against STI/HIV. If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. # BOX. Categories for Classifying Barrier Methods 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. # Appendix G Classifications for Barrier Methods Classifications for barrier contraceptive methods include those for condoms, which include male latex condoms, male polyurethane condoms, and female condoms; spermicides; and diaphragm with spermicide or cervical cap (Box). Consistent and correct use of the male latex condom reduces the risk for STI/HIV transmission. Women with conditions that make pregnancy an unacceptable risk should be advised that barrier methods for pregnancy prevention may not be appropriate for those who cannot use them consistently and correctly because of the relatively higher typical-use failure rates of these methods. ARV = antiretroviral; hCG = human chorionic gonadotropin; PID = pelvic inflammatory disease; AIDS = acquired immunodeficiency syndrome; COC = combined oral contraceptive; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor. † If risk exists for STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method. Consistent and correct use of the male latex condom reduces the risk for STIs and HIV transmission. Women with conditions that make pregnancy an unacceptable risk should be advised that barrier methods for pregnancy prevention may not be appropriate for those who cannot use them consistently and correctly because of the relatively higher typical-use failure rates of these methods. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. # Appendix I Lactational Amenorrhea Method # Appendix K Female and Male Sterilization # BOX. Categories for Classifying Hormonal Contraceptives and IUDs 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. Health-care providers can use the summary table as a quick reference guide to the classifications for hormonal contraceptive methods and intrauterine contraception and to compare classifications across these methods. See the full appendix for each method for clarifications to the numeric categories, as well as for summaries of the evidence and additional comments. Benign ovarian tumors (including cysts) # Appendix L Summary of Classifications for Hormonal Contraceptive Methods and Intrauterine Devices Gestational trophoblastic disease a. Decreasing or undetectable ß-hCG levels # Appendix M Summary of Evidence Regarding Potential Drug Interactions between Hormonal Contraception and Antiretroviral therapies Limited data from small, mostly unpublished studies suggest that some antiretroviral (ARV) therapies might alter the pharmacokinetics of combined oral contraceptives (COCs). Few studies have measured clinical outcomes. However, contraceptive steroid levels in the blood decrease substantially with ritonavir-boosted protease inhibitors. Such decreases have the potential to compromise contraceptive effectiveness. Some of the interactions between contraceptives and ARVs also have led to increased ARV toxicity. For smaller effects that occur with non-nucleoside reverse transcriptase inhibitors, clinical significance is unknown, especially because studies have not examined steady-state levels of contraceptive hormones. No clinically significant interactions have been reported between contraceptive hormones and nucleoside reverse transcriptase inhibitors. Tables 1 and 2 summarize the evidence available about drug interactions between ARV therapies and hormonal contraceptives. For up-to-date, detailed information about human immunodeficiency virus (HIV) drug interactions, the following resources might be helpful: Guidelines (http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GradingTable_Clarification_August2009_Final.pdf). Grade 3 events are classified as severe. Severe events are defined as symptoms that limit activity or might require some assistance; require medical intervention or therapy; and might require hospitalization. Grade 4 events are classified as life threatening. Life-threatening events include symptoms that result in extreme limitation of activity and require substantial assistance; require substantial medical intervention and therapy; and probably require hospitalization or hospice. # Abbreviations and Acronyms	None	None
6dba0062710bb6cefd70cda47a3898d326eb6a9b	cdc	None	# Introduction All regions of the United States (U.S.) experience disasters. Many of these disasters increase morbidity and mortality. 1 Some disasters are large scale, such as hurricanes, forest fires, and earthquakes. Others are more localized, such as tornadoes or mudslides. Disasters can lead to "severe physical injuries, emotional distress, loss of life, and property damage to the point of destroying communities. " 2 Unfortunately, the number of disasters in the U.S. has been increasing, a trend that is expected to continue. At-risk groups, also referred to as socially vulnerable populations, require special attention in a disaster. During disasters, populations with higher levels of social vulnerability are more likely to be adversely affected. In emergency preparedness, a major goal is to be able to reach every person in a community. To do this, you, as emergency managers, must be able to get information to community members quickly. To do that, you need to know which groups are at risk, where the people in these groups live and work, and the best ways they receive information. Research by the National Center for Environmental Health (NCEH) at the Centers for Disease Control and Prevention (CDC) indicates that emergency managers would benefit from more information on how to identify at-risk groups within their communities. 3 In response, NCEH, other centers at CDC, and volunteers from the emergency management community created this guidance document on processes and tools that could help in these efforts. By knowing vulnerabilities in your community, you, as emergency managers, can better anticipate needs and provide information to the right people at the right time before, during, and after disasters. This document describes a process that will help you identify at-risk groups in your community. You can use this information to reduce vulnerabilities and enhance outcomes for a broader population of those at risk. Social vulnerability is defined in terms of the characteristics of a person or group that affect "their capacity to anticipate, cope with, resist, and recover from the impact" of a discrete and identifiable disaster in nature or society. 4 A person's vulnerability to disaster is influenced by many factors. The following six categories are among the most commonly accepted: socioeconomic status, age, gender, race and ethnicity, English language proficiency, and medical issues and disability. 1,5 These six categories described below can help you to identify the at-risk groups within your community that could be disproportionately affected by disasters. Keep in mind that many people might fit more than one category. # Socioeconomic status Socioeconomic status (SES) is one of the key factors of social vulnerability. It includes employment, income, housing (e.g., homelessness), and education level. 6,7,8 People with lower socioeconomic status more likely lack resources needed to follow emergency preparedness instructions. They might be unable to stockpile food, for example. They might be unwilling or unable to stay home from work and lose a day's pay, or evacuate and leave their home during an emergency. By identifying at-risk groups ahead of time, you can plan more efficient evacuations and specifically target people who need transportation or special assistance (e.g., those without a vehicle). # Age The old and the young are particularly vulnerable during emergencies. Older adults are more likely to have medical problems that put them at an increased risk during a disaster. They might have chronic health problems or limited mobility. They might have limited sight, hearing, or cognitive ability. Any of these health issues can limit their capacity to follow instructions. Older adults might also have reduced income, putting them at increased risk because of their limited resources. Some older adults are also isolated by their living situations or limited mass media use, making communication with this group difficult. Young children are also more at risk. They have yet to develop the resources, knowledge, or understanding to effectively cope with disaster, and they are more susceptible to injury and disease. 1,9 Young children also are more vulnerable when they are separated from their parents or guardians, for example, at school or in daycare. # Gender Gender does not necessarily indicate vulnerability or disadvantage. However, gender intersects with social patterns and inequalities can arise from gender differences. 10 During a disaster, females might be more vulnerable because of differences in employment, lower income, and family responsibilities, as most single-parent households are single-mother families. 11,12 However, females are a strong influence in mobilizing response to a warning. Females are also more likely to be effective risk communicators through being active participants in the community. They also might know more "neighborhood information" that can assist emergency managers. 10 Although many families evacuate together, it is not uncommon for males to stay behind to guard the property or to continue working as the family provider. Males are also more likely to be risk takers and might not heed warnings. 10 # Race and ethnicity Race and ethnicity contribute to social vulnerabilities. 1,6,7,11 Race and ethnicity are tied to issues of SES. Social and economic marginalization contributes to the vulnerability of these groups. # English language proficiency In the U.S., people with limited English proficiency (LEP) have a limited ability to read, speak, or write in English. 1 LEP groups might have trouble understanding public health directives if language barriers are not addressed when developing emergency preparedness messages. 1 Messages should also be culturally sensitive, paying attention to dialects and social norms, to ensure that LEP populations receive and respond to emergency directives. 1 These considerations should be taken into account for both populations who speak English as a second language, as well as native English speakers who have difficulty reading, interpreting, and calculating from written materials. # Medical issues and disability Persons with a disability include those with a cognitive, physical, or sensory impairment that limits a major life activity. People with physical impairments might include those with limited sight, hearing, or mobility or those who are dependent on electric power to operate medical equipment. For many people with medical conditions and disabilities, their ability to hear, understand, or respond to a warning is impaired. This category also includes individuals with access and functional needs, irrespective of diagnosis or status, and persons with medical conditions (e.g., cancer). By identifying vulnerabilities within a community, you can design and implement community-based efforts during all four phases of disasters (preparedness, response, recovery, and mitigation). 13 Having a clear understanding of how and where at-risk groups might be most affected during a disaster will help you allocate resources efficiently before, during, and after an emergency. 2 You can use information on at-risk groups during each of the four phases of a disaster: preparedness, response, recovery, and mitigation. Planning for an Emergency 3 # Phases of the disaster cycle You can apply the individual and population approaches presented in this document to all four phases of a disaster. These include preparedness, response, recovery, and mitigation. Addressing these four phases in your emergency preparedness plan will help you identify the specific information you need to collect. # Preparedness: In this phase, you develop emergency preparedness plans to save lives and minimize damage that can occur during a disaster. 16 During the preparedness phase, you will need to know: 5 - Which groups are less likely to prepare for disasters? - Which groups will lack essential emergency response items? Response: During this phase, you take action to save lives and prevent additional damage during a disaster. 16 During the response phase, you will need to know: 17 - Which groups are least likely to hear, understand and respond to warnings? - Which groups will have difficulty following emergency directives? - Which groups will need emergency medical care or continuation of medical care, and which groups are least likely to have access to emergency services? Recovery: After a disaster occurs, you and others act to help restore the community back to normal. This can include repairing, replacing, or rebuilding property. 16 During the recovery phase, you will need to know: 17 - Which groups are most likely to have suffered the most from impact? - Which groups are most likely to have experienced the most economic or emotional stress or altered social factors? Mitigation: This phase involves developing policies to reduce risks to people and property during a disaster. 16 During the mitigation phase, you will need to know: 17 - Which groups are most at risk during an emergency? - What resources are needed by at-risk groups during an emergency? The Strategies for Identifying At-Risk Groups: # Individual Approach To identify at-risk groups, emergency managers can benefit from obtaining information on an individual level. Two methods of collecting individual information are registries and Community Outreach Information Networks (COINs). You can use these two methods, described below, to identify at-risk groups to improve communication methods and promote resiliency. # Use of Registries A registry is "a voluntary database of individuals who meet the eligibility requirements for receiving additional emergency response services based on specific needs. " 14 Using a registry, you will be able to identify people who require assistance before, during, or after an emergency. In addition, you will also know the specific form of help these individuals need. The most common types of registries include the following: Access and functional needs registries-These are broad scope registries that include any person who needs special assistance. This can include people with physical or mental disability, impaired mobility, or dependence on medication or medical equipment. Medical needs registries-These are limited to people with specific medical needs. Individuals placed on medical needs registries can provide documentation from a doctor on their specific medical requirements. Transportation registries-These registries will help identify people with impaired mobility or those who require assistance in evacuating a location during an emergency. # Developing a Registry When developing a registry, identify the best method to collect information from at-risk community members. Recruiting people to participate in a registry might be difficult. Some groups might be distrustful of providing personal information to unknown people or organizations. Partnering with various community organizations can help in identifying and recruiting people to register. People often do not self-identify as being at risk. They might not know they should register or how to do so. You can address this by improving messaging and communication to increase awareness and encourage people to self-register. Options for outreach range from brochures and flyers to television announcements, websites, and community meetings. Some methods for collecting information from at-risk groups to create a database include the following: - Web form that people can use to submit and update their information. - Central phone number that people can call to register. - Direct mail registration forms that people can fill out and return. - Social service workers or volunteers who collect information from clients when they apply for other public health services. You will also need to consider certain legal liabilities when establishing a registry to provide assistance during an emergency. People who enroll in the registry might expect guaranteed assistance during a disaster. Therefore, it is important to inform registrants of the following: - With whom the information will be shared. - How information will be used. - Security measures in place for protecting information. - The type of help that might be available. - Limitations on help (i.e., help is not guaranteed). Transient populations, such as homeless people, can be difficult to reach before and during an emergency. Even if some people are registered before an emergency, locating them during an emergency can be difficult. # Challenges and Limitations to Registry Implementation After you develop a registry, you might face challenges during implementation, such as: - Eligible participants might not enroll because of concerns regarding the privacy and protection of their medical and personal information. - Potential enrollees might not believe they have a need for assistance. - Registries do not identify every person who might need assistance during an emergency. - Registry participants might believe that participation takes the place of personal preparedness. 14 # Maintenance of registries Registries must be updated regularly to account for changes to information among listed persons. People move. Their health and physical needs change. Additional changes to your community will occur as people move in and out of your jurisdiction. All these changes should be factored into your plans for keeping your registry up-to-date. # Suggestions for Maintaining and Updating Registries Suggestions include the following: - Send annual reminders (e.g., with utility bills) to registrants to review their information. - Maintain a database that people can update yearround by phone, online, or by mail. - Require that participants re-register every year. - Conduct calls regularly to ensure that registrants still need to be included in the registry. Be sure to allocate the appropriate resources (e.g., funding and staff) needed to maintain your registry and ensure the information does not become outdated. # Summary A registry can be helpful in emergency preparedness and response for at-risk groups. It gives you a database identifying community members and their specific needs. During a disaster you will know where these people live and the type of assistance they require. Mapping information within registries can provide a clear and specific picture of where at-risk groups live within your community. Having a visual representation of the areas with the most need will help you allocate resources appropriately before, during, and after a disaster. - potential uses of personal information, - security provisions and precautions in place to ensure personal privacy, - potential uses of personal information, - security provisions and precautions in place to ensure personal privacy, - limitations of liability, - limitations in service that may occur under various disaster situations, and # Community Outreach Information Network (COIN) Development In response to the Pandemic and All-Hazards Preparedness Act i , CDC created a process for public health planners to define, locate, and reach at-risk groups in an emergency. 19 The process leads to the development of a Community Outreach Information Network (COIN). This is a grassroots network of people and trusted community leaders who can assist with emergency planning and the delivery of information to at-risk groups before, during, and after an emergency. A COIN composed of trusted community leaders will be helpful in identifying and reaching at-risk people. There are three phases when developing a COIN, these are: The next phase provides strategies to locate the groups you have identified as at risk within your community. # Identify organizations and key contacts It is important to first identify any organizations or agencies already working in this area and what they have already done. You might, for example, check state, local, tribal, and territorial public health departments for information on the at-risk groups they serve. Locating at-risk groups will involve communicating and working with key organizations and contacts in your community to build a strong network of partners. Identify organizations that fund or partner with smaller, direct service providers to be part of your network. You might also include businesses and others who work with, represent, or belong to at-risk groups. In addition, you can ask COIN members about informal groups they belong to that reach at-risk groups. These contacts will be able to link you to organizations that serve at-risk groups in the community. As you identify potential organizations, also identify potential contacts within these organizations and the best way to reach them. After identifying key contacts to include in your network, your next step is to meet with these potential partners to discuss the importance of identifying at-risk groups during an emergency and the role they and their organization can play during an emergency. Other organizations or groups you can consider reaching out to include the following: - Faith-based organizations -These groups usually have missions or ministries that provide services to members of their local community. - University students who have disabilities -These students often form organizations that provide support and advocacy. You can contact the student activities department of local colleges and universities to locate such groups. - People who belong to various cultural and ethnic groups -These people might form close bonds with other people in the same groups. People who speak the same language or share a common country of origin or religion might gather in informal ways. Churches, mosques, or other houses of worship are often places where community needs, political opinions, and employment options are discussed. In some ethnic populations, community storefronts are gathering and information centers. Isolation is an important factor to consider in locating some at-risk groups. People can be isolated from the community in many different ways. These include geographic isolation, temporary residency, undocumented immigrant status, and religious and cultural practices. Isolated individuals can be difficult to reach during an emergency, because they might not use traditional means of communication. Non-traditional partners, such as businesses and non-profit organizations, might serve as important contacts. # Trusted sources It is important to include trusted or non-traditional leaders, such as a local pastor or respected teacher, as members of your COIN network. - Trusted sources are more likely to reach at-risk groups during an emergency. They are viewed as more credible and have established trust within the community. - A COIN might also include members of the media, especially those who have closer connections to at-risk groups, such as local ethnic media outlets. These media outlets can be a very powerful voice and provide a close connection to the populations they serve. - Another trusted source might be the director of a "culturespecific" community center or a community health worker. These contacts might already have a good network in place to reach community members through an e-mail listserv, telephone calling tree, mailing list, or simple word-of-mouth. One barrier faced by emergency managers trying to communicate and work with at-risk groups is distrust of the government. Working with existing, trusted sources in your community can help overcome this mistrust. People are more likely to listen and react when the message comes from a trusted source they view as credible. Existing services Identify at-risk groups that might already receive services through your agency. You can reach out to other departments within your agency to conduct an inventory of their existing activities for locating at-risk groups. Questions you can ask the different department representatives include the following: - Who are the at-risk groups served by the department? - Where are their gathering places? - What is the department's process for locating these people? - How do at-risk populations receive information from the department? - Who are their trusted sources? # Gathering places Another step is to locate and identify places where at-risk groups gather. These can include soup kitchens for homeless people, day-worker sites for undocumented immigrants, the post office, and shopping locations. Consult with your network of contacts to identify additional locations where at-risk groups gather. # Mapping Mapping will give you a clear and specific picture of where at-risk groups live within your community. Having a visual guide to the areas with the most need will help you allocate resources appropriately before, during, and after a disaster. You can partner with organizations that have access to digital mapping resources to help you map the location of at-risk groups. Such organizations might include You might also map the locations of members within your network to visualize your reach within the community. # Communication It will be beneficial to engage with your COIN as you go through the process of creating, implementing, and disseminating emergency preparedness information. - Establish ongoing communication strategies to engage your COIN members. - Identify the best means of communication (face-to-face, phone, mail, e-mail, etc.) with members of your network. - Provide brief updates on the progress of your work and seek feedback on emergency planning activities. - Establish a protocol for maintaining confidentiality of your COIN members. Let them know how and when their contact information might be used. This will also help with maintaining trust within your network. # Keeping track Finally, as you establish partnerships with various organizations, key contacts and trusted sources, consider creating a database to keep track of members within your network. Record information about key contacts at organizations and government agencies. Include their names, telephone numbers, and e-mail and postal addresses. Once established, your COIN will require regular updating. Through ongoing monitoring of community members and organizations you will be aware of changes to existing members and can identify new members who should be approached and engaged. # Phase 3: Reach At-Risk Groups In this phase, the goal is to identify the best communication method to share emergency messages with at-risk groups before and during a disaster. In an emergency, messages must inform, educate, and mobilize people to follow public health directives. Messages can be delivered through television, radio, newspaper, bill inserts, flyers, word-ofmouth, social and community networks, and other channels. As you develop your emergency preparedness plan you will benefit from identifying the most effective way to reach at-risk groups in your community. # Survey agencies and organizations Conduct a survey of agencies and organizations that regularly work with at-risk groups or provide direct services to at-risk groups. This survey can include people within and outside your agency. Information you collect through the survey will allow you to learn of successful and failed strategies for communicating with at-risk groups. Incorporating these lessons will ensure that you develop an effective communication plan. # Conduct community assessments Conduct a survey or focus group with members of the different at-risk groups you want to reach. This will allow you to collect firsthand information from your target population. You can ask questions on topics such as: If you lack the resources to conduct these activities through your agency, consider seeking help from members of your COIN (e.g., public health department, nonprofit organizations). They might be able to conduct the assessment for you or help in recruiting participants for the surveys or focus groups, or moderate the discussion with at-risk groups. Be sure to also seek their suggestions on the most appropriate method (telephone interview, written survey, focus group) to collect information from at-risk groups. Review the data from the surveys conducted with people who work with at-risk groups and the information you gather from members of the at-risk groups. Also, review the data collected during phases 1 and 2. Identify common characteristics, themes, and emerging patterns for a clearer idea of the best methods to reach at-risk groups. # Community Assessments for Public Health Emergency Response (CASPER) CASPER is a public health tool used to gather information from households within a community. This effective epidemiologic method can be designed to provide planners and responders, such as emergency managers, with household-based information quickly and at low cost. During a CASPER, you can ask closedended questions such as: - What is your main source of information regarding disaster or emergency events? - What would be a reason that might prevent you from evacuating if asked to do so? - Does your household currently have a 7-day supply of medication for each person who takes prescription meds? Uses for emergency managers: Ask your public health colleagues about their use of CASPERs in all stages of the disaster lifecycle. Public health departments commonly use CASPER during a response to determine immediate needs, such as the number of households in the assessment area that do not have access to potable water. They also use it during the preparedness phase to help with preparedness planning. They might use it to learn, for example, the number of households in the assessment area that have an emergency preparedness kit. You can work with public health departments to determine when to conduct a CASPER and what questions to include to prioritize response efforts and distribution of resources. For more information, go to: / CASPER_Toolkit_Version_2_0_508_Compliant.pdf # Focus groups The purpose of a focus or stakeholder group is to reveal attitudes, perceptions, and behaviors of people participating in the discussion. This method can help you gain an in-depth understanding of at-risk groups in your community. During a focus group, you should ask specific and open-ended questions, such as the following: - What sources do you usually use to get news and information? - When there is a disaster, how do you get information? - How do you prefer to have information communicated to you? - In the past, what has kept you from receiving important information? Uses for emergency managers: Focus groups are a common tool for obtaining feedback for existing public health interventions or information on designing new ones. You can work with public health departments to plan and conduct focus or stakeholder groups to collect information on attitudes, perceptions, and behaviors before, during, and after emergencies. Having a better understanding of the at-risk groups will increase your ability to reach and assist them. # Communication strategies Data collected through surveys and focus groups will help you understand the cultural and language barriers facing at-risk individuals in your community. Your communication plan must accommodate the needs of at-risk groups to provide concise instructions before, during, and after a disaster. Keep these communication tips in mind: - Use short sentences and plain language to allow for easy translation of materials. Consider using a sixth grade reading level or lower. - Provide written materials in bilingual or multi-lingual format. - Include visual aids such as pictures and maps to reinforce key messages. - Repeat key information. - Include directions and phone numbers. - Use large fonts. - Identify preferred communication methods (face-to-face, phone, word-of-mouth), and develop messages accordingly. - Identify preferred media through which messages are delivered. Is it the local newspaper, ethnic radio station, or the church pastor? - Consider working with media and communications specialists. # Gather information from your network community organizations on their communication experiences. Identify trusted messengers Some individuals in at-risk groups are apprehensive of people not considered part of their community. They will respond differently to messages based on the messenger. For example, people are more likely to be responsive to messages delivered by their neighbors than to those delivered by someone from a different background or community. - When developing an emergency communication plan to reach at-risk groups, identify appropriate and trusted messengers to deliver information. - Some members of your COIN might be considered trusted sources in the community. - You can also identify trusted sources by asking community representatives or members of your network who they would recommend to disseminate messages before and during an emergency. - Additional people to consider as messengers include the following: -Religious leaders. -Barbers and hair stylists. -Community and neighborhood leaders who are perceived as credible. -Reporters, editors, announcers, and news directors in media outlets that serve your community. Remember to include the ethnic media outlets as sources to disseminate your messages. -Many populations view certain individuals, such as the matriarch of a family or elders, as the most respected and trusted sources of information. People who live in lower threat areas or who have not experienced a major disaster are less likely to respond to emergency preparedness information. Trusted messengers can engage people to help them understand their risk. # Summary As you go through the different phases and steps to develop your COIN, you will create a comprehensive emergency plan that accounts for the distinct needs of at-risk groups before, during, and after an emergency. Your plan will clearly identify who you consider at risk in your community and the best strategies to communicate emergency directives to these groups. The SVI uses U.S. Census (/ index.html) and American Community Survey (ACS) (http:// www.census.gov/acs/www/) data to identify at-risk groups by ranking all U.S. census tracts by level of social vulnerability. Census tracts are subdivisions of counties for which the Census collects statistical data. 15 The SVI ranks, at national-level or state-level, each tract on 14 social factors. Figure 1 shows these factors, grouped into four main themes. # Figure 1. Social Vulnerability Index themes and social factors The variable for disability (percent of persons older than 5 years with a disability) was dropped for 2010 because it was not included in the ACS that year, but will be included in the 2015 update. # Using the Social Vulnerability Index You can access the SVI at /. The site has a variety of tools and resources that can help emergency managers locate at-risk groups. These tools and resources are listed as topics and can be easily accessed from the main homepage. # Interactive Map The SVI tool gives you an option to customize unique maps for your specific needs. You can use key findings from the individual and population approach to enhance existing communication plans by including at-risk population groups and designating appropriate, trusted spokespersons. 16 # D E K A L B D E K A L B - Information from the individual and population level can be combined to gain a broader picture of the needs of at-risk groups in the community. - You can use the SVI to identify areas with the highest number of at-risk persons. At the population level, the Vulnerable and At-Risk Populations Resource Guide generates custom maps using the SVI to give the jurisdiction an overview of their at-risk groups. At the individual level, the tool provides population-and partner-specific tools, materials, and tips to identify and engage at-risk groups (e.g., lessons learned from other communities, MOUs, templates) in emergency preparedness activities. # Conclusion This guidance document provides emergency managers like you with information on how to identify socially vulnerable or at-risk groups within their communities. These groups are disproportionately affected by disasters. The information in this document can help you better prepare and respond to the needs of these groups before, during, and after a disaster. This document focuses on two approaches to accomplishing this task, the individual approach and population approach. The individual approach provides you with detailed instructions on how to identify and recruit key organizations and contacts in your community to assist with emergency plans and communication strategies. These contacts and organizations should have experience working with at-risk groups and should be viewed as trusted sources within the community. Creating and maintaining registries is another individual approach that might be beneficial to emergency managers, depending on availability of resources. This document highlights the use of CDC's Social Vulnerability Index as a population level approach to planning for at-risk groups before and during a disaster. This index provides a visual representation of vulnerabilities within specified communities. We encourage you to discuss the strategies presented here with other professionals involved in your local emergency management efforts. Effective emergency preparations require an integration of individual and population level approaches to overcome barriers to locating and reaching at-risk persons before and during an emergency. We hope the information provided here inspires emergency managers to think critically about the identification and engagement of at-risk groups and how to best serve them over the course of a disaster. # Prepared County Maps You can also use the SVI to view prepared county maps. The maps display the social vulnerability for any county at the census tract level. After identifying your county of interest, use the dropdown menu to select the census tract year, state, and county, then click "View County Map. " The prepared county map is displayed as a PDF document showing the overall social vulnerability of a county and a breakdown by each of the four domains (see Figure 2). The areas with more vulnerable populations are indicated by the darker color and those less vulnerable are lighter in color. # Data Tools and Download Emergency managers like you might find it helpful to use SVI data in emergency planning. Nationwide and state-specific data are available. The nationwide database provides data on all U.S. census tracts ranked against one another. This is most useful for nationwide or multi-state mapping and analysis. For individual state mapping, select the state-specific database in which census tracts within a state are ranked against one another. Decide on the type of data (e.g., vulnerabilities, census tract, ZIP Code-level, hospitals, and schools) and year, then download the database. The SVI data are in geodatabase format (mdb). You can download files for use in Microsoft Access or a Geographic Information System (GIS) software program such as ArcGIS or QGIS. # How recently information was collected and how accurate it is compared to the current status of your jurisdiction should be considered when using population-level information. The information from the SVI should be used along with local knowledge of the area and information on environmental risks to obtain the most accurate picture of vulnerability. # Summary Information on the location and relative concentration of different types of social vulnerabilities in small geographic areas, such as census tracts can help emergency managers locate and plan for the specific needs of their communities. This type of information is especially helpful during the preparedness phase of disaster. If for example, you find that a particular area within your jurisdiction has a relatively high concentration of persons 5 years and older who speak English "less than well. " You might use local knowledge to determine languages other than English spoken in the area. You could then plan to translate your disaster communications into those languages. CDC's SVI is easy to access and relatively easy to use. If you do need assistance, partners within your community (public health, planning and development organizations, universities) who use SVI might be willing to help you get started. They can help interpret the information that you produce through SVI, or enrich your maps with additional social and geographic information specific to your community. You may also contact CDC's SVI coordinator for assistance ([email protected]). Additional examples of SVI tool use include the following: 17 A.Estimate the amount of needed supplies like food, water, medicine, and bedding. E. Plan the best way to evacuate people, accounting for those who have functional and access needs. These might include people without vehicles, older adults, or people who do not understand English well. F. Identify communities that will need continued support to recover after an emergency or natural disaster. ii # Glossary iii Access and functional needs population: A population that might require physical, program, or effective communication access. They might have additional needs before, during, or after an incident in functional areas, including but not limited to independence, communication, transportation, and health maintenance (this is a subset of socially vulnerable population). 18 American Community Survey (ACS): An ongoing, mandatory statistical survey that annually samples a small percentage of the overall U.S. population. The SVI uses ACS and 2010 Census data (/). Assistive technology: Any item, piece of equipment, or product system, whether acquired commercially, modified, or customized, used to increase, maintain, or improve functional capabilities of persons with disabilities. Also known as an assistive device. 18 At-risk group: A group within the overall population having a higher degree of demographic or socioeconomic vulnerability, rendering them more likely to be adversely affected by disaster. Also known as socially vulnerable population. # Community Assessment for Public Health Emergency Response (CASPER): An epidemiologic tool designed to provide to decision-makers household-based information about an affected community's needs quickly and in a simple format. # Census: The enumeration of an entire population usually with details being recorded on residence, age, sex, and race and ethnicity. The United States conducts a census every 10 years. At the time of publication of this document, the most recent census was in 2010. Census tract: A small, relatively permanent geographic entity within a county (or county equivalent) determined by local participants before to each census. Census tracts vary in population but average about 4,000 persons. # Community Outreach Information Network (COIN): A grassroots network of people and trusted community leaders who can help with emergency planning and the delivery of information to at-risk populations before, during, and after an emergency. Emergency Manager: Professionals at all levels of government and the private sector who prepare for, mitigate, respond to, assist in recovery from, and provide products and services for all emergencies, disasters, and threats to the nation's security. # Geographic Information System (GIS): An information system designed to store, integrate, analyze, and display all types of spatial or non-spatial data. # Metropolitan Planning Organization (MPO): An organization comprised of a Policy Board and Advisory Committees that help in planning for various modes of transportation, including highways, public transit, bicycles and pedestrians, and freight. Federal transportation legislation requires that an MPO be designated for each urbanized area with a population of more than 50,000 people to carry out the metropolitan transportation planning process, as a condition for federal aid. Registry: A voluntary database containing personally identifying and medical information about persons who might require assistance in the event of a disaster. 18 # Social vulnerability: A characteristic or characteristics of a person or group relating to their capacity to anticipate, cope with, resist, and recover from the impact of a discrete and identifiable disaster in nature or society. # Socially vulnerable population: A group within the overall population having a higher degree of demographic or socioeconomic vulnerability, rendering them more likely to be adversely affected by disaster. Also known as at-risk group. iii Many of the terms in this glossary are adapted from the Draft International Association of Emergency Managers (IAEM)-National Emergency Management Association (NEMA) Joint Task Force 2014 Quick Reference Glossary of Terminology for Emergency Management Whole Community Planning Efforts, developed by an IAEM-NEMA joint task force. # Centers for Disease Control and Prevention Division of Environmental Hazards and Health Effects National Center for Environmental Health Health Studies Branch	# Introduction All regions of the United States (U.S.) experience disasters. Many of these disasters increase morbidity and mortality. 1 Some disasters are large scale, such as hurricanes, forest fires, and earthquakes. Others are more localized, such as tornadoes or mudslides. Disasters can lead to "severe physical injuries, emotional distress, loss of life, and property damage to the point of destroying communities. " 2 Unfortunately, the number of disasters in the U.S. has been increasing, a trend that is expected to continue. At-risk groups, also referred to as socially vulnerable populations, require special attention in a disaster. During disasters, populations with higher levels of social vulnerability are more likely to be adversely affected. In emergency preparedness, a major goal is to be able to reach every person in a community. To do this, you, as emergency managers, must be able to get information to community members quickly. To do that, you need to know which groups are at risk, where the people in these groups live and work, and the best ways they receive information. Research by the National Center for Environmental Health (NCEH) at the Centers for Disease Control and Prevention (CDC) indicates that emergency managers would benefit from more information on how to identify at-risk groups within their communities. 3 In response, NCEH, other centers at CDC, and volunteers from the emergency management community created this guidance document on processes and tools that could help in these efforts. By knowing vulnerabilities in your community, you, as emergency managers, can better anticipate needs and provide information to the right people at the right time before, during, and after disasters. This document describes a process that will help you identify at-risk groups in your community. You can use this information to reduce vulnerabilities and enhance outcomes for a broader population of those at risk. Social vulnerability is defined in terms of the characteristics of a person or group that affect "their capacity to anticipate, cope with, resist, and recover from the impact" of a discrete and identifiable disaster in nature or society. 4 A person's vulnerability to disaster is influenced by many factors. The following six categories are among the most commonly accepted: socioeconomic status, age, gender, race and ethnicity, English language proficiency, and medical issues and disability. 1,5 These six categories described below can help you to identify the at-risk groups within your community that could be disproportionately affected by disasters. Keep in mind that many people might fit more than one category. # Socioeconomic status Socioeconomic status (SES) is one of the key factors of social vulnerability. It includes employment, income, housing (e.g., homelessness), and education level. 6,7,8 People with lower socioeconomic status more likely lack resources needed to follow emergency preparedness instructions. They might be unable to stockpile food, for example. They might be unwilling or unable to stay home from work and lose a day's pay, or evacuate and leave their home during an emergency. By identifying at-risk groups ahead of time, you can plan more efficient evacuations and specifically target people who need transportation or special assistance (e.g., those without a vehicle). # Age The old and the young are particularly vulnerable during emergencies. Older adults are more likely to have medical problems that put them at an increased risk during a disaster. They might have chronic health problems or limited mobility. They might have limited sight, hearing, or cognitive ability. Any of these health issues can limit their capacity to follow instructions. Older adults might also have reduced income, putting them at increased risk because of their limited resources. Some older adults are also isolated by their living situations or limited mass media use, making communication with this group difficult. Young children are also more at risk. They have yet to develop the resources, knowledge, or understanding to effectively cope with disaster, and they are more susceptible to injury and disease. 1,9 Young children also are more vulnerable when they are separated from their parents or guardians, for example, at school or in daycare. # Gender Gender does not necessarily indicate vulnerability or disadvantage. However, gender intersects with social patterns and inequalities can arise from gender differences. 10 During a disaster, females might be more vulnerable because of differences in employment, lower income, and family responsibilities, as most single-parent households are single-mother families. 11,12 However, females are a strong influence in mobilizing response to a warning. Females are also more likely to be effective risk communicators through being active participants in the community. They also might know more "neighborhood information" that can assist emergency managers. 10 Although many families evacuate together, it is not uncommon for males to stay behind to guard the property or to continue working as the family provider. Males are also more likely to be risk takers and might not heed warnings. 10 # Race and ethnicity Race and ethnicity contribute to social vulnerabilities. 1,6,7,11 Race and ethnicity are tied to issues of SES. Social and economic marginalization contributes to the vulnerability of these groups. # English language proficiency In the U.S., people with limited English proficiency (LEP) have a limited ability to read, speak, or write in English. 1 LEP groups might have trouble understanding public health directives if language barriers are not addressed when developing emergency preparedness messages. 1 Messages should also be culturally sensitive, paying attention to dialects and social norms, to ensure that LEP populations receive and respond to emergency directives. 1 These considerations should be taken into account for both populations who speak English as a second language, as well as native English speakers who have difficulty reading, interpreting, and calculating from written materials. # Medical issues and disability Persons with a disability include those with a cognitive, physical, or sensory impairment that limits a major life activity. People with physical impairments might include those with limited sight, hearing, or mobility or those who are dependent on electric power to operate medical equipment. For many people with medical conditions and disabilities, their ability to hear, understand, or respond to a warning is impaired. This category also includes individuals with access and functional needs, irrespective of diagnosis or status, and persons with medical conditions (e.g., cancer). By identifying vulnerabilities within a community, you can design and implement community-based efforts during all four phases of disasters (preparedness, response, recovery, and mitigation). 13 Having a clear understanding of how and where at-risk groups might be most affected during a disaster will help you allocate resources efficiently before, during, and after an emergency. 2 You can use information on at-risk groups during each of the four phases of a disaster: preparedness, response, recovery, and mitigation. Planning for an Emergency 3 # Phases of the disaster cycle You can apply the individual and population approaches presented in this document to all four phases of a disaster. These include preparedness, response, recovery, and mitigation. Addressing these four phases in your emergency preparedness plan will help you identify the specific information you need to collect. # Preparedness: In this phase, you develop emergency preparedness plans to save lives and minimize damage that can occur during a disaster. 16 During the preparedness phase, you will need to know: 5 • Which groups are less likely to prepare for disasters? • Which groups will lack essential emergency response items? Response: During this phase, you take action to save lives and prevent additional damage during a disaster. 16 During the response phase, you will need to know: 17 • Which groups are least likely to hear, understand and respond to warnings? • Which groups will have difficulty following emergency directives? • Which groups will need emergency medical care or continuation of medical care, and which groups are least likely to have access to emergency services? Recovery: After a disaster occurs, you and others act to help restore the community back to normal. This can include repairing, replacing, or rebuilding property. 16 During the recovery phase, you will need to know: 17 • Which groups are most likely to have suffered the most from impact? • Which groups are most likely to have experienced the most economic or emotional stress or altered social factors? Mitigation: This phase involves developing policies to reduce risks to people and property during a disaster. 16 During the mitigation phase, you will need to know: 17 • Which groups are most at risk during an emergency? • What resources are needed by at-risk groups during an emergency? The Strategies for Identifying At-Risk Groups: # Individual Approach To identify at-risk groups, emergency managers can benefit from obtaining information on an individual level. Two methods of collecting individual information are registries and Community Outreach Information Networks (COINs). You can use these two methods, described below, to identify at-risk groups to improve communication methods and promote resiliency. # Use of Registries A registry is "a voluntary database of individuals who meet the eligibility requirements for receiving additional emergency response services based on specific needs. " 14 Using a registry, you will be able to identify people who require assistance before, during, or after an emergency. In addition, you will also know the specific form of help these individuals need. The most common types of registries include the following: Access and functional needs registries-These are broad scope registries that include any person who needs special assistance. This can include people with physical or mental disability, impaired mobility, or dependence on medication or medical equipment. Medical needs registries-These are limited to people with specific medical needs. Individuals placed on medical needs registries can provide documentation from a doctor on their specific medical requirements. Transportation registries-These registries will help identify people with impaired mobility or those who require assistance in evacuating a location during an emergency. # Developing a Registry When developing a registry, identify the best method to collect information from at-risk community members. Recruiting people to participate in a registry might be difficult. Some groups might be distrustful of providing personal information to unknown people or organizations. Partnering with various community organizations can help in identifying and recruiting people to register. People often do not self-identify as being at risk. They might not know they should register or how to do so. You can address this by improving messaging and communication to increase awareness and encourage people to self-register. Options for outreach range from brochures and flyers to television announcements, websites, and community meetings. Some methods for collecting information from at-risk groups to create a database include the following: • Web form that people can use to submit and update their information. • Central phone number that people can call to register. • Direct mail registration forms that people can fill out and return. • Social service workers or volunteers who collect information from clients when they apply for other public health services. You will also need to consider certain legal liabilities when establishing a registry to provide assistance during an emergency. People who enroll in the registry might expect guaranteed assistance during a disaster. Therefore, it is important to inform registrants of the following: • With whom the information will be shared. • How information will be used. • Security measures in place for protecting information. • The type of help that might be available. • Limitations on help (i.e., help is not guaranteed). Transient populations, such as homeless people, can be difficult to reach before and during an emergency. Even if some people are registered before an emergency, locating them during an emergency can be difficult. # Challenges and Limitations to Registry Implementation After you develop a registry, you might face challenges during implementation, such as: • Eligible participants might not enroll because of concerns regarding the privacy and protection of their medical and personal information. • Potential enrollees might not believe they have a need for assistance. • Registries do not identify every person who might need assistance during an emergency. • Registry participants might believe that participation takes the place of personal preparedness. 14 # Maintenance of registries Registries must be updated regularly to account for changes to information among listed persons. People move. Their health and physical needs change. Additional changes to your community will occur as people move in and out of your jurisdiction. All these changes should be factored into your plans for keeping your registry up-to-date. # Suggestions for Maintaining and Updating Registries Suggestions include the following: • Send annual reminders (e.g., with utility bills) to registrants to review their information. • Maintain a database that people can update yearround by phone, online, or by mail. • Require that participants re-register every year. • Conduct calls regularly to ensure that registrants still need to be included in the registry. Be sure to allocate the appropriate resources (e.g., funding and staff) needed to maintain your registry and ensure the information does not become outdated. # Summary A registry can be helpful in emergency preparedness and response for at-risk groups. It gives you a database identifying community members and their specific needs. During a disaster you will know where these people live and the type of assistance they require. Mapping information within registries can provide a clear and specific picture of where at-risk groups live within your community. Having a visual representation of the areas with the most need will help you allocate resources appropriately before, during, and after a disaster. • potential uses of personal information, • security provisions and precautions in place to ensure personal privacy, • potential uses of personal information, • security provisions and precautions in place to ensure personal privacy, • limitations of liability, • limitations in service that may occur under various disaster situations, and # Community Outreach Information Network (COIN) Development In response to the Pandemic and All-Hazards Preparedness Act i , CDC created a process for public health planners to define, locate, and reach at-risk groups in an emergency. 19 The process leads to the development of a Community Outreach Information Network (COIN). This is a grassroots network of people and trusted community leaders who can assist with emergency planning and the delivery of information to at-risk groups before, during, and after an emergency. A COIN composed of trusted community leaders will be helpful in identifying and reaching at-risk people. There are three phases when developing a COIN, these are: The next phase provides strategies to locate the groups you have identified as at risk within your community. # Identify organizations and key contacts It is important to first identify any organizations or agencies already working in this area and what they have already done. You might, for example, check state, local, tribal, and territorial public health departments for information on the at-risk groups they serve. Locating at-risk groups will involve communicating and working with key organizations and contacts in your community to build a strong network of partners. Identify organizations that fund or partner with smaller, direct service providers to be part of your network. You might also include businesses and others who work with, represent, or belong to at-risk groups. In addition, you can ask COIN members about informal groups they belong to that reach at-risk groups. These contacts will be able to link you to organizations that serve at-risk groups in the community. As you identify potential organizations, also identify potential contacts within these organizations and the best way to reach them. After identifying key contacts to include in your network, your next step is to meet with these potential partners to discuss the importance of identifying at-risk groups during an emergency and the role they and their organization can play during an emergency. Other organizations or groups you can consider reaching out to include the following: • Faith-based organizations -These groups usually have missions or ministries that provide services to members of their local community. • University students who have disabilities -These students often form organizations that provide support and advocacy. You can contact the student activities department of local colleges and universities to locate such groups. • People who belong to various cultural and ethnic groups -These people might form close bonds with other people in the same groups. People who speak the same language or share a common country of origin or religion might gather in informal ways. Churches, mosques, or other houses of worship are often places where community needs, political opinions, and employment options are discussed. In some ethnic populations, community storefronts are gathering and information centers. Isolation is an important factor to consider in locating some at-risk groups. People can be isolated from the community in many different ways. These include geographic isolation, temporary residency, undocumented immigrant status, and religious and cultural practices. Isolated individuals can be difficult to reach during an emergency, because they might not use traditional means of communication. Non-traditional partners, such as businesses and non-profit organizations, might serve as important contacts. # Trusted sources It is important to include trusted or non-traditional leaders, such as a local pastor or respected teacher, as members of your COIN network. • Trusted sources are more likely to reach at-risk groups during an emergency. They are viewed as more credible and have established trust within the community. • A COIN might also include members of the media, especially those who have closer connections to at-risk groups, such as local ethnic media outlets. These media outlets can be a very powerful voice and provide a close connection to the populations they serve. • Another trusted source might be the director of a "culturespecific" community center or a community health worker. These contacts might already have a good network in place to reach community members through an e-mail listserv, telephone calling tree, mailing list, or simple word-of-mouth. One barrier faced by emergency managers trying to communicate and work with at-risk groups is distrust of the government. Working with existing, trusted sources in your community can help overcome this mistrust. People are more likely to listen and react when the message comes from a trusted source they view as credible. Existing services Identify at-risk groups that might already receive services through your agency. You can reach out to other departments within your agency to conduct an inventory of their existing activities for locating at-risk groups. Questions you can ask the different department representatives include the following: • Who are the at-risk groups served by the department? • Where are their gathering places? • What is the department's process for locating these people? • How do at-risk populations receive information from the department? • Who are their trusted sources? # Gathering places Another step is to locate and identify places where at-risk groups gather. These can include soup kitchens for homeless people, day-worker sites for undocumented immigrants, the post office, and shopping locations. Consult with your network of contacts to identify additional locations where at-risk groups gather. # Mapping Mapping will give you a clear and specific picture of where at-risk groups live within your community. Having a visual guide to the areas with the most need will help you allocate resources appropriately before, during, and after a disaster. You can partner with organizations that have access to digital mapping resources to help you map the location of at-risk groups. Such organizations might include You might also map the locations of members within your network to visualize your reach within the community. • # Communication It will be beneficial to engage with your COIN as you go through the process of creating, implementing, and disseminating emergency preparedness information. • Establish ongoing communication strategies to engage your COIN members. • Identify the best means of communication (face-to-face, phone, mail, e-mail, etc.) with members of your network. • Provide brief updates on the progress of your work and seek feedback on emergency planning activities. • Establish a protocol for maintaining confidentiality of your COIN members. Let them know how and when their contact information might be used. This will also help with maintaining trust within your network. # Keeping track Finally, as you establish partnerships with various organizations, key contacts and trusted sources, consider creating a database to keep track of members within your network. Record information about key contacts at organizations and government agencies. Include their names, telephone numbers, and e-mail and postal addresses. Once established, your COIN will require regular updating. Through ongoing monitoring of community members and organizations you will be aware of changes to existing members and can identify new members who should be approached and engaged. # Phase 3: Reach At-Risk Groups In this phase, the goal is to identify the best communication method to share emergency messages with at-risk groups before and during a disaster. In an emergency, messages must inform, educate, and mobilize people to follow public health directives. Messages can be delivered through television, radio, newspaper, bill inserts, flyers, word-ofmouth, social and community networks, and other channels. As you develop your emergency preparedness plan you will benefit from identifying the most effective way to reach at-risk groups in your community. # Survey agencies and organizations Conduct a survey of agencies and organizations that regularly work with at-risk groups or provide direct services to at-risk groups. This survey can include people within and outside your agency. Information you collect through the survey will allow you to learn of successful and failed strategies for communicating with at-risk groups. Incorporating these lessons will ensure that you develop an effective communication plan. # Conduct community assessments Conduct a survey or focus group with members of the different at-risk groups you want to reach. This will allow you to collect firsthand information from your target population. You can ask questions on topics such as: If you lack the resources to conduct these activities through your agency, consider seeking help from members of your COIN (e.g., public health department, nonprofit organizations). They might be able to conduct the assessment for you or help in recruiting participants for the surveys or focus groups, or moderate the discussion with at-risk groups. Be sure to also seek their suggestions on the most appropriate method (telephone interview, written survey, focus group) to collect information from at-risk groups. • Review the data from the surveys conducted with people who work with at-risk groups and the information you gather from members of the at-risk groups. Also, review the data collected during phases 1 and 2. Identify common characteristics, themes, and emerging patterns for a clearer idea of the best methods to reach at-risk groups. # Community Assessments for Public Health Emergency Response (CASPER) CASPER is a public health tool used to gather information from households within a community. This effective epidemiologic method can be designed to provide planners and responders, such as emergency managers, with household-based information quickly and at low cost. During a CASPER, you can ask closedended questions such as: • What is your main source of information regarding disaster or emergency events? • What would be a reason that might prevent you from evacuating if asked to do so? • Does your household currently have a 7-day supply of medication for each person who takes prescription meds? Uses for emergency managers: Ask your public health colleagues about their use of CASPERs in all stages of the disaster lifecycle. Public health departments commonly use CASPER during a response to determine immediate needs, such as the number of households in the assessment area that do not have access to potable water. They also use it during the preparedness phase to help with preparedness planning. They might use it to learn, for example, the number of households in the assessment area that have an emergency preparedness kit. You can work with public health departments to determine when to conduct a CASPER and what questions to include to prioritize response efforts and distribution of resources. For more information, go to: http://emergency.cdc.gov/disasters/surveillance/pdf/ CASPER_Toolkit_Version_2_0_508_Compliant.pdf # Focus groups The purpose of a focus or stakeholder group is to reveal attitudes, perceptions, and behaviors of people participating in the discussion. This method can help you gain an in-depth understanding of at-risk groups in your community. During a focus group, you should ask specific and open-ended questions, such as the following: • What sources do you usually use to get news and information? • When there is a disaster, how do you get information? • How do you prefer to have information communicated to you? • In the past, what has kept you from receiving important information? Uses for emergency managers: Focus groups are a common tool for obtaining feedback for existing public health interventions or information on designing new ones. You can work with public health departments to plan and conduct focus or stakeholder groups to collect information on attitudes, perceptions, and behaviors before, during, and after emergencies. Having a better understanding of the at-risk groups will increase your ability to reach and assist them. # Communication strategies Data collected through surveys and focus groups will help you understand the cultural and language barriers facing at-risk individuals in your community. Your communication plan must accommodate the needs of at-risk groups to provide concise instructions before, during, and after a disaster. Keep these communication tips in mind: • Use short sentences and plain language to allow for easy translation of materials. Consider using a sixth grade reading level or lower. • Provide written materials in bilingual or multi-lingual format. • Include visual aids such as pictures and maps to reinforce key messages. • Repeat key information. • Include directions and phone numbers. • Use large fonts. • Identify preferred communication methods (face-to-face, phone, word-of-mouth), and develop messages accordingly. • Identify preferred media through which messages are delivered. Is it the local newspaper, ethnic radio station, or the church pastor? • Consider working with media and communications specialists. # Gather information from your network community organizations on their communication experiences. Identify trusted messengers Some individuals in at-risk groups are apprehensive of people not considered part of their community. They will respond differently to messages based on the messenger. For example, people are more likely to be responsive to messages delivered by their neighbors than to those delivered by someone from a different background or community. • When developing an emergency communication plan to reach at-risk groups, identify appropriate and trusted messengers to deliver information. • Some members of your COIN might be considered trusted sources in the community. • You can also identify trusted sources by asking community representatives or members of your network who they would recommend to disseminate messages before and during an emergency. • Additional people to consider as messengers include the following: -Religious leaders. -Barbers and hair stylists. -Community and neighborhood leaders who are perceived as credible. -Reporters, editors, announcers, and news directors in media outlets that serve your community. Remember to include the ethnic media outlets as sources to disseminate your messages. -Many populations view certain individuals, such as the matriarch of a family or elders, as the most respected and trusted sources of information. People who live in lower threat areas or who have not experienced a major disaster are less likely to respond to emergency preparedness information. Trusted messengers can engage people to help them understand their risk. # Summary As you go through the different phases and steps to develop your COIN, you will create a comprehensive emergency plan that accounts for the distinct needs of at-risk groups before, during, and after an emergency. Your plan will clearly identify who you consider at risk in your community and the best strategies to communicate emergency directives to these groups. The SVI uses U.S. Census (http://quickfacts.census.gov/qfd/ index.html) and American Community Survey (ACS) (http:// www.census.gov/acs/www/) data to identify at-risk groups by ranking all U.S. census tracts by level of social vulnerability. Census tracts are subdivisions of counties for which the Census collects statistical data. 15 The SVI ranks, at national-level or state-level, each tract on 14 social factors. Figure 1 shows these factors, grouped into four main themes. # Figure 1. Social Vulnerability Index themes and social factors The variable for disability (percent of persons older than 5 years with a disability) was dropped for 2010 because it was not included in the ACS that year, but will be included in the 2015 update. # Using the Social Vulnerability Index You can access the SVI at http://svi.cdc.gov/. The site has a variety of tools and resources that can help emergency managers locate at-risk groups. These tools and resources are listed as topics and can be easily accessed from the main homepage. # Interactive Map The SVI tool gives you an option to customize unique maps for your specific needs. You can use key findings from the individual and population approach to enhance existing communication plans by including at-risk population groups and designating appropriate, trusted spokespersons. 16 # D E K A L B D E K A L B • Information from the individual and population level can be combined to gain a broader picture of the needs of at-risk groups in the community. • You can use the SVI to identify areas with the highest number of at-risk persons. At the population level, the Vulnerable and At-Risk Populations Resource Guide generates custom maps using the SVI to give the jurisdiction an overview of their at-risk groups. At the individual level, the tool provides population-and partner-specific tools, materials, and tips to identify and engage at-risk groups (e.g., lessons learned from other communities, MOUs, templates) in emergency preparedness activities. # Conclusion This guidance document provides emergency managers like you with information on how to identify socially vulnerable or at-risk groups within their communities. These groups are disproportionately affected by disasters. The information in this document can help you better prepare and respond to the needs of these groups before, during, and after a disaster. This document focuses on two approaches to accomplishing this task, the individual approach and population approach. The individual approach provides you with detailed instructions on how to identify and recruit key organizations and contacts in your community to assist with emergency plans and communication strategies. These contacts and organizations should have experience working with at-risk groups and should be viewed as trusted sources within the community. Creating and maintaining registries is another individual approach that might be beneficial to emergency managers, depending on availability of resources. This document highlights the use of CDC's Social Vulnerability Index as a population level approach to planning for at-risk groups before and during a disaster. This index provides a visual representation of vulnerabilities within specified communities. We encourage you to discuss the strategies presented here with other professionals involved in your local emergency management efforts. Effective emergency preparations require an integration of individual and population level approaches to overcome barriers to locating and reaching at-risk persons before and during an emergency. We hope the information provided here inspires emergency managers to think critically about the identification and engagement of at-risk groups and how to best serve them over the course of a disaster. # Prepared County Maps You can also use the SVI to view prepared county maps. The maps display the social vulnerability for any county at the census tract level. After identifying your county of interest, use the dropdown menu to select the census tract year, state, and county, then click "View County Map. " The prepared county map is displayed as a PDF document showing the overall social vulnerability of a county and a breakdown by each of the four domains (see Figure 2). The areas with more vulnerable populations are indicated by the darker color and those less vulnerable are lighter in color. # Data Tools and Download Emergency managers like you might find it helpful to use SVI data in emergency planning. Nationwide and state-specific data are available. The nationwide database provides data on all U.S. census tracts ranked against one another. This is most useful for nationwide or multi-state mapping and analysis. For individual state mapping, select the state-specific database in which census tracts within a state are ranked against one another. Decide on the type of data (e.g., vulnerabilities, census tract, ZIP Code-level, hospitals, and schools) and year, then download the database. The SVI data are in geodatabase format (mdb). You can download files for use in Microsoft Access or a Geographic Information System (GIS) software program such as ArcGIS or QGIS. # How recently information was collected and how accurate it is compared to the current status of your jurisdiction should be considered when using population-level information. The information from the SVI should be used along with local knowledge of the area and information on environmental risks to obtain the most accurate picture of vulnerability. # Summary Information on the location and relative concentration of different types of social vulnerabilities in small geographic areas, such as census tracts can help emergency managers locate and plan for the specific needs of their communities. This type of information is especially helpful during the preparedness phase of disaster. If for example, you find that a particular area within your jurisdiction has a relatively high concentration of persons 5 years and older who speak English "less than well. " You might use local knowledge to determine languages other than English spoken in the area. You could then plan to translate your disaster communications into those languages. CDC's SVI is easy to access and relatively easy to use. If you do need assistance, partners within your community (public health, planning and development organizations, universities) who use SVI might be willing to help you get started. They can help interpret the information that you produce through SVI, or enrich your maps with additional social and geographic information specific to your community. You may also contact CDC's SVI coordinator for assistance ([email protected]). Additional examples of SVI tool use include the following: 17 A.Estimate the amount of needed supplies like food, water, medicine, and bedding. E. Plan the best way to evacuate people, accounting for those who have functional and access needs. These might include people without vehicles, older adults, or people who do not understand English well. F. Identify communities that will need continued support to recover after an emergency or natural disaster. ii # Glossary iii Access and functional needs population: A population that might require physical, program, or effective communication access. They might have additional needs before, during, or after an incident in functional areas, including but not limited to independence, communication, transportation, and health maintenance (this is a subset of socially vulnerable population). 18 American Community Survey (ACS): An ongoing, mandatory statistical survey that annually samples a small percentage of the overall U.S. population. The SVI uses ACS and 2010 Census data (http://www.census.gov/acs/www/). Assistive technology: Any item, piece of equipment, or product system, whether acquired commercially, modified, or customized, used to increase, maintain, or improve functional capabilities of persons with disabilities. Also known as an assistive device. 18 At-risk group: A group within the overall population having a higher degree of demographic or socioeconomic vulnerability, rendering them more likely to be adversely affected by disaster. Also known as socially vulnerable population. # Community Assessment for Public Health Emergency Response (CASPER): An epidemiologic tool designed to provide to decision-makers household-based information about an affected community's needs quickly and in a simple format. # Census: The enumeration of an entire population usually with details being recorded on residence, age, sex, and race and ethnicity. The United States conducts a census every 10 years. At the time of publication of this document, the most recent census was in 2010. Census tract: A small, relatively permanent geographic entity within a county (or county equivalent) determined by local participants before to each census. Census tracts vary in population but average about 4,000 persons. # Community Outreach Information Network (COIN): A grassroots network of people and trusted community leaders who can help with emergency planning and the delivery of information to at-risk populations before, during, and after an emergency. Emergency Manager: Professionals at all levels of government and the private sector who prepare for, mitigate, respond to, assist in recovery from, and provide products and services for all emergencies, disasters, and threats to the nation's security. # Geographic Information System (GIS): An information system designed to store, integrate, analyze, and display all types of spatial or non-spatial data. # Metropolitan Planning Organization (MPO): An organization comprised of a Policy Board and Advisory Committees that help in planning for various modes of transportation, including highways, public transit, bicycles and pedestrians, and freight. Federal transportation legislation requires that an MPO be designated for each urbanized area with a population of more than 50,000 people to carry out the metropolitan transportation planning process, as a condition for federal aid. Registry: A voluntary database containing personally identifying and medical information about persons who might require assistance in the event of a disaster. 18 # Social vulnerability: A characteristic or characteristics of a person or group relating to their capacity to anticipate, cope with, resist, and recover from the impact of a discrete and identifiable disaster in nature or society. # Socially vulnerable population: A group within the overall population having a higher degree of demographic or socioeconomic vulnerability, rendering them more likely to be adversely affected by disaster. Also known as at-risk group. iii Many of the terms in this glossary are adapted from the Draft International Association of Emergency Managers (IAEM)-National Emergency Management Association (NEMA) Joint Task Force 2014 Quick Reference Glossary of Terminology for Emergency Management Whole Community Planning Efforts, developed by an IAEM-NEMA joint task force. # Centers for Disease Control and Prevention Division of Environmental Hazards and Health Effects National Center for Environmental Health Health Studies Branch	None	None
42c13336d4ff280f9299b02c43413c82a803be9b	cdc	None	This report updates and consolidates all previous U.S. Public Health Service recommendations for the management of health-care personnel (HCP) who have occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Recommendations for HBV postexposure management include initiation of the hepatitis B vaccine series to any susceptible, unvaccinated person who sustains an occupational blood or body fluid exposure. Postexposure prophylaxis (PEP) with hepatitis B immune globulin (HBIG) and/or hepatitis B vaccine series should be considered for occupational exposures after evaluation of the hepatitis B surface antigen status of the source and the vaccination and vaccine-response status of the exposed person. Guidance is provided to clinicians and exposed HCP for selecting the appropriate HBV PEP. Immune globulin and antiviral agents (e.g., interferon with or without ribavirin) are not recommended for PEP of hepatitis C. For HCV postexposure management, the HCV status of the source and the exposed person should be determined, and for HCP exposed to an HCV positive source, follow-up HCV testing should be performed to determine if infection develops. Recommendations for HIV PEP include a basic 4-week regimen of two drugs (zidovudine and lamivudine ; 3TC and stavudine ; or didanosine and d4T) for most HIV exposures and an expanded regimen that includes the addition of a third drug for HIV exposures that pose an increased risk for transmission. When the source person's virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended. In addition, this report outlines several special circumstances (e.g., delayed exposure report, unknown source person, pregnancy in the exposed person, resistance of the source virus to antiretroviral agents, or toxicity of the PEP regimen) when consultation with local experts and/or the National Clinicians' Post-Exposure Prophylaxis Hotline ( 1-888-448-4911) is advised. Occupational exposures should be considered urgent medical concerns to ensure timely postexposure management and administration of HBIG, hepatitis B vaccine, and/or HIV PEP. 2 MMWR June 29, 2001 This interagency working group comprised representatives of CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration, and the National Institutes of Health. Information included in these recommendations may not represent FDA approval or approved labeling for the particular product or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval.# INTRODUCTION Avoiding occupational blood exposures is the primary way to prevent transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in health-care settings (1 ). However, hepatitis B immunization and postexposure management are integral components of a complete program to prevent infection following bloodborne pathogen exposure and are important elements of workplace safety (2 ). The U.S. Public Health Service (PHS) has published previous guidelines for the management of HIV exposures that included considerations for postexposure prophylaxis (PEP) (3)(4)(5). Since publication of the 1998 HIV exposure guidelines (5 ), several new antiretroviral agents have been approved by the Food and Drug Administration (FDA), and more information is available about the use and safety of HIV PEP (6)(7)(8)(9)(10)(11). In addition, questions exist regarding considerations about PEP regimens when the source person's virus is known or suspected to be resistant to one or more of the antiretroviral agents that might be used for PEP. Concern also has arisen about the use of PEP when it is not warranted. Data indicate that some health-care personnel (HCP) take a full course of HIV PEP after exposures that do not confer an HIV transmission risk (10,11 ). In September 1999, a meeting of a PHS interagency working group- and expert consultants was convened by CDC. The PHS working group decided to issue updated recommendations for the management of occupational exposure to HIV. In addition, the report was to include recommendations for the management of occupational HBV and HCV exposures so that a single document could comprehensively address the management of occupational exposures to bloodborne pathogens. This report updates and consolidates the previous PHS guidelines and recommendations for occupational HBV, HCV, and HIV exposure management for HCP. Specific practice recommendations for the management of occupational bloodborne pathogen exposures are outlined to assist health-care institutions with the implementation of these PHS guidelines (Appendices A and B). As relevant information becomes available, updates of these recommendations will be published. Recommendations for nonoccupational (e.g., sexual, pediatric, and perinatal) HBV, HCV, and HIV exposures are not addressed in these guidelines and can be found elsewhere (12)(13)(14)(15). # Definition of Health-Care Personnel and Exposure In this report, health-care personnel (HCP) are defined as persons (e.g., employees, students, contractors, attending clinicians, public-safety workers, or volunteers) whose activities involve contact with patients or with blood or other body fluids from patients in a health-care, laboratory, or public-safety setting. The potential exists for blood and body fluid exposure to other workers, and the same principles of exposure management could be applied to other settings. An exposure that might place HCP at risk for HBV, HCV, or HIV infection is defined as a percutaneous injury (e.g., a needlestick or cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other body fluids that are potentially infectious (16,17 ). In addition to blood and body fluids containing visible blood, semen and vaginal secretions also are considered potentially infectious. Although semen and vaginal secretions have been implicated in the sexual transmission of HBV, HCV, and HIV, they have not been implicated in occupational transmission from patients to HCP. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for transmission of HBV, HCV, and HIV infection from these fluids is unknown; the potential risk to HCP from occupational exposures has not been assessed by epidemiologic studies in health-care settings. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they contain blood. The risk for transmission of HBV, HCV, and HIV infection from these fluids and materials is extremely low. Any direct contact (i.e., contact without barrier protection) to concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For human bites, the clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were exposed to bloodborne pathogens. Transmission of HBV or HIV infection only rarely has been reported by this route (18)(19)(20) (CDC, unpublished data, 1998). # BACKGROUND This section provides the rationale for the postexposure management and prophylaxis recommendations presented in this report. Additional details concerning the risk for occupational bloodborne pathogen transmission to HCP and management of occupational bloodborne pathogen exposures are available elsewhere (5,12,13,(21)(22)(23)(24). # Occupational Transmission of HBV # Risk for Occupational Transmission of HBV HBV infection is a well recognized occupational risk for HCP (25 ). The risk of HBV infection is primarily related to the degree of contact with blood in the work place and also to the hepatitis B e antigen (HBeAg) status of the source person. In studies of HCP who sustained injuries from needles contaminated with blood containing HBV, the risk of developing clinical hepatitis if the blood was both hepatitis B surface antigen (HBsAg)and HBeAg-positive was 22%-31%; the risk of developing serologic evidence of HBV infection was 37%-62%. By comparison, the risk of developing clinical hepatitis from a needle contaminated with HBsAg-positive, HBeAg-negative blood was 1%-6%, and the risk of developing serologic evidence of HBV infection, 23%-37% (26 ). Although percutaneous injuries are among the most efficient modes of HBV transmission, these exposures probably account for only a minority of HBV infections among HCP. In several investigations of nosocomial hepatitis B outbreaks, most infected HCP could not recall an overt percutaneous injury (27,28 ), although in some studies, up to one third of infected HCP recalled caring for a patient who was HBsAg-positive (29,30 ). In addition, HBV has been demonstrated to survive in dried blood at room temperature on environmental surfaces for at least 1 week (31 ). Thus, HBV infections that occur in HCP with no history of nonoccupational exposure or occupational percutaneous injury might have resulted from direct or indirect blood or body fluid exposures that inoculated HBV into cutaneous scratches, abrasions, burns, other lesions, or on mucosal surfaces (32)(33)(34). The potential for HBV transmission through contact with environmental surfaces has been demonstrated in investigations of HBV outbreaks among patients and staff of hemodialysis units (35)(36)(37). Blood contains the highest HBV titers of all body fluids and is the most important vehicle of transmission in the health-care setting. HBsAg is also found in several other body fluids, including breast milk, bile, cerebrospinal fluid, feces, nasopharyngeal washings, saliva, semen, sweat, and synovial fluid (38 ). However, the concentration of HBsAg in body fluids can be 100-1000-fold higher than the concentration of infectious HBV particles. Therefore, most body fluids are not efficient vehicles of transmission because they contain low quantities of infectious HBV, despite the presence of HBsAg. In serologic studies conducted in the United States during the 1970s, HCP had a prevalence of HBV infection approximately 10 times higher than the general population (39)(40)(41)(42). Because of the high risk of HBV infection among HCP, routine preexposure vaccination of HCP against hepatitis B and the use of standard precautions to prevent exposure to blood and other potentially infectious body fluids have been recommended since the early 1980s (43 ). Regulations issued by the Occupational Safety and Health Administration (OSHA) (2 ) have increased compliance with these recommendations. Since the implementation of these recommendations, a sharp decline has occurred in the incidence of HBV infection among HCP. # PEP for HBV Efficacy of PEP for HBV. The effectiveness of hepatitis B immune globulin (HBIG) and/ or hepatitis B vaccine in various postexposure settings has been evaluated by prospective studies. For perinatal exposure to an HBsAg-, HBeAg-positive mother, a regimen combining HBIG and initiation of the hepatitis B vaccine series at birth is 85%-95% effective in preventing HBV infection (44,45 ). Regimens involving either multiple doses of HBIG alone or the hepatitis B vaccine series alone are 70%-75% effective in preventing HBV infection (46 ). In the occupational setting, multiple doses of HBIG initiated within 1 week following percutaneous exposure to HBsAg-positive blood provides an estimated 75% protection from HBV infection (47)(48)(49). Although the postexposure efficacy of the combination of HBIG and the hepatitis B vaccine series has not been evaluated in the occupational setting, the increased efficacy of this regimen observed in the perinatal setting, compared with HBIG alone, is presumed to apply to the occupational setting as well. In addition, because persons requiring PEP in the occupational setting are generally at continued risk for HBV exposure, they should receive the hepatitis B vaccine series. Safety of PEP for HBV. Hepatitis B vaccines have been found to be safe when administered to infants, children, or adults (12,50 ). Through the year 2000, approximately 100 million persons have received hepatitis B vaccine in the United States. The most common side effects from hepatitis B vaccination are pain at the injection site and mild to moderate fever (50)(51)(52)(53)(54)(55). Studies indicate that these side effects are reported no more frequently among persons vaccinated than among those receiving placebo (51,52 ). Approximately 45 reports have been received by the Vaccine Adverse Event Reporting System (VAERS) of alopecia (hair loss) in children and adults after administration of plasma-derived and recombinant hepatitis B vaccine; four persons sustained hair loss following vaccination on more than one occasion (56 ). Hair loss was temporary for approximately two thirds of persons who experienced hair loss. An epidemiologic study conducted in the Vaccine Safety Datalink found no statistical association between alopecia and receipt of hepatitis B vaccine in children (CDC, unpublished data, 1998). A low rate of anaphylaxis has been observed in vaccine recipients based on reports to VAERS; the estimated incidence is 1 in 600,000 vaccine doses distributed. Although none of the persons who developed anaphylaxis died, anaphylactic reactions can be life-threatening; therefore, further vaccination with hepatitis B vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of vaccine. Hepatitis B immunization programs conducted on a large scale in Taiwan, Alaska, and New Zealand have observed no association between vaccination and the occurrence of serious adverse events. Furthermore, in the United States, surveillance of adverse events following hepatitis B vaccination has demonstrated no association between hepatitis B vaccine and the occurrence of serious adverse events, including Guillain-Barré syndrome, transverse myelitis, multiple sclerosis, optic neuritis, and seizures (57-59 ) (CDC, unpublished data, 1991). However, several case reports and case series have claimed an association between hepatitis B vaccination and such syndromes and diseases as multiple sclerosis, optic neuritis, rheumatoid arthritis, and other autoimmune diseases (57,(60)(61)(62)(63)(64)(65)(66). Most of these reported adverse events have occurred in adults, and no report has compared the frequency of the purported vaccine-associated syndrome/disease with the frequency in an unvaccinated population. In addition, recent case-control studies have demonstrated no association between hepatitis B vaccination and development or short-term risk of relapse of multiple sclerosis (67,68 ), and reviews by international panels of experts have concluded that available data do not demonstrate a causal association between hepatitis B vaccination and demyelinating diseases, including multiple sclerosis (69 ). HBIG is prepared from human plasma known to contain a high titer of antibody to HBsAg (anti-HBs). The plasma from which HBIG is prepared is screened for HBsAg and antibodies to HIV and HCV. The process used to prepare HBIG inactivates and eliminates HIV from the final product. Since 1996, the final product has been free of HCV RNA as determined by the polymerase chain reaction (PCR), and, since 1999, all products available in the United States have been manufactured by methods that inactivate HCV and other viruses. No evidence exists that HBV, HCV, or HIV have ever been transmitted by HBIG commercially available in the United States (70,71 ). Serious adverse effects from HBIG when administered as recommended have been rare. Local pain and tenderness at the injection site, urticaria and angioedema might occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin (IG) preparations (72 ). Persons with a history of anaphylactic reaction to IG should not receive HBIG. PEP for HBV During Pregnancy. No apparent risk exists for adverse effects to developing fetuses when hepatitis B vaccine is administered to pregnant women (CDC, unpublished data, 1990). The vaccine contains noninfectious HBsAg particles and should pose no risk to the fetus. HBV infection during pregnancy might result in severe disease for the mother and chronic infection for the newborn. Therefore, neither pregnancy nor lactation should be considered a contraindication to vaccination of women. HBIG is not contraindicated for pregnant or lactating women. # MMWR June 29, 2001 Occupational Transmission of HCV # Risk for Occupational Transmission of HCV HCV is not transmitted efficiently through occupational exposures to blood. The average incidence of anti-HCV seroconversion after accidental percutaneous exposure from an HCV-positive source is 1.8% (range: 0%-7%) (73)(74)(75)(76), with one study indicating that transmission occurred only from hollow-bore needles compared with other sharps (75 ). Transmission rarely occurs from mucous membrane exposures to blood, and no transmission in HCP has been documented from intact or nonintact skin exposures to blood (77,78 ). Data are limited on survival of HCV in the environment. In contrast to HBV, the epidemiologic data for HCV suggest that environmental contamination with blood containing HCV is not a significant risk for transmission in the health-care setting (79,80 ), with the possible exception of the hemodialysis setting where HCV transmission related to environmental contamination and poor infection-control practices have been implicated (81)(82)(83)(84). The risk for transmission from exposure to fluids or tissues other than HCV-infected blood also has not been quantified but is expected to be low. # Postexposure Management for HCV In several studies, researchers have attempted to assess the effectiveness of IG following possible exposure to non-A, non-B hepatitis. These studies have been difficult to interpret because they lack uniformity in diagnostic criteria and study design, and, in all but one study, the first dose of IG was administered before potential exposure (48,85,86 ). In an experiment designed to model HCV transmission by needlestick exposure in the health-care setting, high anti-HCV titer IG administered to chimpanzees 1 hour after exposure to HCV-positive blood did not prevent transmission of infection (87 ). In 1994, the Advisory Committee on Immunization Practices (ACIP) reviewed available data regarding the prevention of HCV infection with IG and concluded that using IG as PEP for hepatitis C was not supported (88 ). This conclusion was based on the following facts: - No protective antibody response has been identified following HCV infection. - Previous studies of IG use to prevent posttransfusion non-A, non-B hepatitis might not be relevant in making recommendations regarding PEP for hepatitis C. - Experimental studies in chimpanzees with IG containing anti-HCV failed to prevent transmission of infection after exposure. No clinical trials have been conducted to assess postexposure use of antiviral agents (e.g., interferon with or without ribavirin) to prevent HCV infection, and antivirals are not FDA-approved for this indication. Available data suggest that an established infection might need to be present before interferon can be an effective treatment. Kinetic studies suggest that the effect of interferon on chronic HCV infection occurs in two phases. During the first phase, interferon blocks the production or release of virus from infected cells. In the second phase, virus is eradicated from the infected cells (89 ); in this later phase, higher pretreatment alanine aminotransferase (ALT) levels correlate with an increasing decline in infected cells, and the rapidity of the decline correlates with viral clearance. In contrast, the effect of antiretrovirals when used for PEP after exposure to HIV is based on inhibition of HIV DNA synthesis early in the retroviral replicative cycle. In the absence of PEP for HCV, recommendations for postexposure management are intended to achieve early identification of chronic disease and, if present, referral for evaluation of treatment options. However, a theoretical argument is that intervention with antivirals when HCV RNA first becomes detectable might prevent the development of chronic infection. Data from studies conducted outside the United States suggest that a short course of interferon started early in the course of acute hepatitis C is associated with a higher rate of resolved infection than that achieved when therapy is begun after chronic hepatitis C has been well established (90)(91)(92). These studies used various treatment regimens and included persons with acute disease whose peak ALT levels were 500-1,000 IU/L at the time therapy was initiated (2.6-4 months after exposure). No studies have evaluated the treatment of acute infection in persons with no evidence of liver disease (i.e., HCV RNA-positive <6 months duration with normal ALT levels); among patients with chronic HCV infection, the efficacy of antivirals has been demonstrated only among patients who also had evidence of chronic liver disease (i.e., abnormal ALT levels). In addition, treatment started early in the course of chronic HCV infection (i.e., 6 months after onset of infection) might be as effective as treatment started during acute infection (13 ). Because 15%-25% of patients with acute HCV infection spontaneously resolve their infection (93 ), treatment of these patients during the acute phase could expose them unnecessarily to the discomfort and side effects of antiviral therapy. Data upon which to base a recommendation for therapy of acute infection are insufficient because a) no data exist regarding the effect of treating patients with acute infection who have no evidence of disease, b) treatment started early in the course of chronic infection might be just as effective and would eliminate the need to treat persons who will spontaneously resolve their infection, and c) the appropriate regimen is unknown. # Occupational Transmission of HIV # Risk for Occupational Transmission of HIV In prospective studies of HCP, the average risk of HIV transmission after a percutaneous exposure to HIV-infected blood has been estimated to be approximately 0.3% (95% confidence interval = 0.2%-0.5%) (94 ) and after a mucous membrane exposure, approximately 0.09% (95% CI = 0.006%-0.5%) (95 ). Although episodes of HIV transmission after nonintact skin exposure have been documented (96 ), the average risk for transmission by this route has not been precisely quantified but is estimated to be less than the risk for mucous membrane exposures (97 ). The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures (98 ). As of June 2000, CDC had received voluntary reports of 56 U.S. HCP with documented HIV seroconversion temporally associated with an occupational HIV exposure. An additional 138 episodes in HCP are considered possible occupational HIV transmissions. These workers had a history of occupational exposure to blood, other infectious body fluids, or laboratory solutions containing HIV, and no other risk for HIV infection was identified, but HIV seroconversion after a specific exposure was not documented (99 ). Epidemiologic and laboratory studies suggest that several factors might affect the risk of HIV transmission after an occupational exposure. In a retrospective case-control study of HCP who had percutaneous exposure to HIV, the risk for HIV infection was found to be increased with exposure to a larger quantity of blood from the source person as indicated by a) a device visibly contaminated with the patient's blood, b) a procedure that involved a needle being placed directly in a vein or artery, or c) a deep injury (100 ). The risk also was increased for exposure to blood from source persons with terminal illness, possibly reflecting either the higher titer of HIV in blood late in the course of AIDS or other factors (e.g., the presence of syncytia-inducing strains of HIV). A laboratory study that demonstrated that more blood is transferred by deeper injuries and hollow-bore needles lends further support for the observed variation in risk related to blood quantity (101 ). The use of source person viral load as a surrogate measure of viral titer for assessing transmission risk has not yet been established. Plasma viral load (e.g., HIV RNA) reflects only the level of cell-free virus in the peripheral blood; latently infected cells might transmit infection in the absence of viremia. Although a lower viral load (e.g., <1,500 RNA copies/mL) or one that is below the limits of detection probably indicates a lower titer exposure, it does not rule out the possibility of transmission. Some evidence exists regarding host defenses possibly influencing the risk for HIV infection. A study of HIV-exposed but uninfected HCP demonstrated an HIV-specific cytotoxic T-lymphocyte (CTL) response when peripheral blood mononuclear cells were stimulated in vitro with HIV-specific antigens (102 ). Similar CTL responses have been observed in other groups who experienced repeated HIV exposure without resulting infection (103)(104)(105)(106)(107)(108). Among several possible explanations for this observation is that the host immune response sometimes might prevent establishment of HIV infection after a percutaneous exposure; another is that the CTL response simply might be a marker for exposure. In a study of 20 HCP with occupational exposure to HIV, a comparison was made of HCP treated with zidovudine (ZDV) PEP and those not treated. The findings from this study suggest that ZDV blunted the HIV-specific CTL response and that PEP might inhibit early HIV replication (109 ). # Rationale for HIV PEP Considerations that influence the rationale and recommendations for PEP include - the pathogenesis of HIV infection, particularly the time course of early infection; - the biological plausibility that infection can be prevented or ameliorated by using antiretroviral drugs; - direct or indirect evidence of the efficacy of specific agents used for prophylaxis; and - the risk and benefit of PEP to exposed HCP. The following discussion considers each of these concerns. # Role of Pathogenesis in Considering Antiretroviral Prophylaxis. Information about primary HIV infection indicates that systemic infection does not occur immediately, leaving a brief window of opportunity during which postexposure antiretroviral intervention might modify or prevent viral replication. In a primate model of simian immunodeficiency virus (SIV) infection, infection of dendritic-like cells occurred at the site of inoculation during the first 24 hours following mucosal exposure to cell-free virus. Over the subsequent 24-48 hours, migration of these cells to regional lymph nodes occurred, and virus was detectable in the peripheral blood within 5 days (110 ). Theoretically, initiation of antiretroviral PEP soon after exposure might prevent or inhibit systemic infection by limiting the proliferation of virus in the initial target cells or lymph nodes. Efficacy of Antiretrovirals for PEP in Animal Studies. Data from animal studies have been difficult to interpret, in part, because of problems identifying an animal model that is comparable to humans. In early studies, differences in controlled variables (e.g., choice of viral strain , inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen) made extrapolation of the results to humans difficult. Recently, refinements in methodology have facilitated more relevant studies; in particular, the viral inocula used in animal studies have been reduced to levels more analogous to human exposures but sufficient to cause infection in control animals (111)(112)(113). These studies provide encouraging evidence of postexposure chemoprophylactic efficacy. Studies among primates and in murine and feline animal models have demonstrated that larger viral inocula decrease prophylactic efficacy (114)(115)(116)(117). In addition, delaying initiation, shortening the duration, or decreasing the antiretroviral dose of PEP, individually or in combination, decreased prophylactic efficacy (113,(118)(119)(120)(121)(122)(123)(124). For example, when (R)-9-(2-phosphonylmethoxypropyl) adenine (tenofovir) was administered 48 hours before, 4 hours after, or 24 hours after intravenous SIV inoculation to long-tailed macaques, a 4-week regimen prevented infection in all treated animals (122 ). A subsequent study confirmed the efficacy of tenofovir PEP when administered 24 hours after intravenous inoculation of a dose of SIV that uniformly results in infection in untreated macaques. In the same study, protection was incomplete if the tenofovir administration was delayed to 48 or 72 hours postexposure or if the total duration of treatment was curtailed to 3 or 10 days (123 ). Efficacy of Antiretrovirals for PEP in Human Studies. Little information exists from which the efficacy of PEP in humans can be assessed. Seroconversion is infrequent following an occupational exposure to HIV-infected blood; therefore, several thousands of exposed HCP would need to enroll in a prospective trial to achieve the statistical power necessary to directly demonstrate PEP efficacy (125 ). In the retrospective case-control study of HCP, after controlling for other risk factors for HIV transmission, use of ZDV as PEP was associated with a reduction in the risk of HIV infection by approximately 81% (95% CI = 43%-94%) (100 ). Although the results of this study suggest PEP efficacy, its limitations include the small number of cases studied and the use of cases and controls from different cohorts. In a multicenter trial in which ZDV was administered to HIV-infected pregnant women and their infants, the administration of ZDV during pregnancy, labor, and delivery and to the infant reduced transmission by 67% (126 ). Only part of the protective effect of ZDV was explained by reduction of the HIV viral load in the maternal blood, suggesting that ZDV prophylaxis, in part, involves a mechanism other than the reduction of maternal viral burden (127,128 ). Since 1998, studies have highlighted the importance of PEP for prevention of perinatal HIV transmission. In Africa, the use of ZDV in combination with lamivudine (3TC) decreased perinatal HIV transmission by 50% when administered during pregnancy, labor, and for 1 week postpartum, and by 37% when started at the onset of labor and continued for 1 week postpartum (129 ). Studies in the United States and Uganda also have demonstrated that rates of perinatal HIV transmission have been reduced with the use of abbreviated PEP regimens started intrapartum or during the first 48-72 hours of life (130)(131)(132). The limitations of all of these studies with animals and humans must be considered when reviewing evidence of PEP efficacy. The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for motherto-infant HIV transmission is not similar to occupational exposures; therefore, these findings might not be directly applicable to PEP in HCP. Reports of Failure of PEP. Failure of PEP to prevent HIV infection in HCP has been reported in at least 21 instances (78,(133)(134)(135)(136)(137)(138)(139). In 16 of the cases, ZDV was used alone as a single agent; in two cases, ZDV and didanosine (ddI) were used in combination (133,138 ); and in three cases, >3 drugs were used for PEP (137)(138)(139). Thirteen of the source persons were known to have been treated with antiretroviral therapy before the exposure. Antiretroviral resistance testing of the virus from the source person was performed in seven instances, and in four, the HIV infection transmitted was found to have decreased sensitivity to ZDV and/or other drugs used for PEP. In addition to possible exposure to an antiretroviral-resistant strain of HIV, other factors that might have contributed to these apparent failures might include a high titer and/or large inoculum exposure, delayed initiation and/or short duration of PEP, and possible factors related to the host (e.g., cellular immune system responsiveness) and/or to the source person's virus (e.g., presence of syncytia-forming strains) (133 ). Details regarding the cases of PEP failure involving combinations of antiretroviral agents are included in this report (Table 1). # Antiretroviral Agents for PEP Antiretroviral agents from three classes of drugs are available for the treatment of HIV infection. These agents include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Only antiretroviral agents that have been approved by FDA for treatment of HIV infection are discussed in these guidelines. Determining which agents and how many to use or when to alter a PEP regimen is largely empiric. Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, include recommendations for the use of three drugs (140 ); however, the applicability of these recommendations to PEP remains unknown. In HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance (141,142 ). A combination of drugs with activity at different stages in the viral replication cycle (e.g., nucleoside analogues with a PI) theoretically could offer an additional preventive effect in PEP, particularly for occupational exposures that pose an increased risk of transmission. Although the use of a threedrug regimen might be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third drug is justified for lower-risk exposures is uncertain. Therefore, the recommendations at the end of this document provide guidance for two-and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure. NRTI combinations that can be considered for PEP include ZDV and 3TC, 3TC and stavudine (d4T), and ddI and d4T. In previous PHS guidelines, a combination of ZDV and 3TC was considered the first choice for PEP regimens (3 ). Because ZDV and 3TC are available in a combination formulation (Combivir™, manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of this combination might be more convenient for HCP. However, recent data suggest that mutations associated with ZDV and 3TC resistance might be common in some areas (143 ). Thus, individual clinicians might prefer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease. The addition of a third drug for PEP following high-risk exposures is based on demonstrated effectiveness in reducing viral burden in HIV-infected persons. Previously, indinavir (IDV) or nelfinavir (NFV) were recommended as first-choice agents for inclusion in an expanded PEP regimen (5 ). Since the publication of the 1998 PEP guidelines, efavirenz (EFV), an NNRTI; abacavir (ABC), a potent NRTI; and Kaletra™, a PI, have been approved by FDA. Although side effects might be common with the NNRTIs, EFV might be considered for expanded PEP regimens, especially when resistance to PIs in the source person's virus is known or suspected. ABC has been associated with dangerous hypersensitivity reactions but, with careful monitoring, may be considered as a third drug for PEP. Kaletra, a combination of lopinavir and ritonavir, is a potent HIV inhibitor that, with expert consultation, may be considered in an expanded PEP regimen. Toxicity and Drug Interactions of Antiretroviral Agents. When administering PEP, an important goal is completion of a 4-week PEP regimen when PEP is indicated. Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration. All of the antiretroviral agents have been associated with side effects (Table 2). However, studies of adverse events have been conducted primarily with persons who have advanced disease (and longer treatment courses) and who therefore might not reflect the experience in persons who are uninfected (144 ). Several primary side effects are associated with antiretroviral agents (Table 2). Side effects associated with many of the NRTIs are chiefly gastrointestinal (e.g., nausea or diarrhea); however, ddI has been associated with cases of fatal and nonfatal pancreatitis among HIV-infected patients treated for >4 weeks. The use of PIs has been associated with new onset diabetes mellitus, hyperglycemia, diabetic ketoacidosis, exacerbation of preexisting diabetes mellitus, and dyslipidemia (145)(146)(147). Nephrolithiasis has been associated with IDV use; however, the incidence of this potential complication might be limited by drinking at least 48 ounces (1.5 L) of fluid per 24-hour period (e.g., six 8-ounce glasses of water throughout the day) (148 ). NFV has been associated with the development of diarrhea; however, this side effect might respond to treatment with antimotility agents that can be prescribed for use, if necessary, at the time the drug is recommended for PEP. The NNRTIs have been associated with severe skin reactions, including lifethreatening cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepatotoxicity, including fatal hepatic necrosis, has occurred in patients treated with nevirapine (NVP); some episodes began during the first few weeks of therapy (FDA, unpublished data, 2000). EFV has been associated with central nervous system side effects, including dizziness, somnolence, insomnia, and abnormal dreaming. All of the approved antiretroviral agents might have potentially serious drug interactions when used with certain other drugs (Appendix C). Careful evaluation of concomitant medications used by an exposed person is required before PEP is prescribed, and close monitoring for toxicity is also needed. Further information about potential drug interactions can be found in the manufacturer's package insert. Toxicity Associated with PEP. Information from the National Surveillance System for Health Care Workers (NaSH) and the HIV Postexposure Registry indicates that nearly 50% of HCP experience adverse symptoms (e.g., nausea, malaise, headache, anorexia, and headache) while taking PEP and that approximately 33% stop taking PEP because of adverse signs and symptoms (6,7,10,11 ). Some studies have demonstrated that side effects and discontinuation of PEP are more common among HCP taking three-drug (149 ). Participants in the San Francisco Project were followed at 1, 2, 4, 26, and 52 weeks postexposure and received medication adherence counseling; most participants took only two drugs for PEP. Serious side effects, including nephrolithiasis, hepatitis, and pancytopenia have been reported with the use of combination drugs for PEP (6,7,150,151 ). One case of NVPassociated fulminant liver failure requiring liver transplantation and one case of hypersensitivity syndrome have been reported in HCP taking NVP for HIV PEP (152 ). Including these two cases, from March 1997 through September 2000, FDA received reports of 22 cases of serious adverse events related to NVP taken for PEP (153 ). These events included 12 cases of hepatotoxicity, 14 cases of skin reaction (including one documented and two possible cases of Stevens-Johnson syndrome), and one case of rhabdomyolysis; four cases involved both hepatotoxicty and skin reaction, and one case involved both rhabdomyolysis and skin reaction. Resistance to Antiretroviral Agents. Known or suspected resistance of the source virus to antiretroviral agents, particularly to agents that might be included in a PEP regimen, is a concern for persons making decisions about PEP. Resistance to HIV infection occurs with all of the available antiretroviral agents, and cross-resistance within drug classes is frequent (154 ). Recent studies have demonstrated an emergence of drugresistant HIV among source persons for occupational exposures (143,155 ). A study conducted at seven U.S. sites during 1998-1999 found that 16 (39%) of 41 source persons whose virus was sequenced had primary genetic mutations associated with resistance to RTIs, and 4 (10%) had primary mutations associated with resistance to PIs (143 ). In addition, occupational transmission of resistant HIV strains, despite PEP with combination drug regimens, has been reported (137,139 ). In one case, a hospital worker became infected after an HIV exposure despite a PEP regimen that included ddI, d4T, and NVP (139 ). The transmitted HIV contained two primary genetic mutations associated with resistance to NNRTIs (the source person was taking EFV at the time of the exposure). Despite recent studies and case reports, the relevance of exposure to a resistant virus is still not well understood. Empiric decisions about the presence of antiretroviral drug resistance are often difficult to make because patients generally take more than one antiretroviral agent. Resistance should be suspected in source persons when they are experiencing clinical progression of disease or a persistently increasing viral load, and/or decline in CD4 T-cell count, despite therapy or a lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because the results will not be available in time to influence the choice of the initial PEP regimen. Furthermore, in this situation, whether modification of the PEP regimen is necessary or will influence the outcome of an occupational exposure is unknown. No data exist to suggest that modification of a PEP regimen after receiving results from resistance testing (usually a minimum of 1-2 weeks) improves efficacy of PEP. Antiretroviral Drugs During Pregnancy. Data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (156 ). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDAlicensed NRTIs. The relevance of animal data to humans is unknown; however, because teratogenic effects were observed in primates at drug exposures similar to those representing human therapeutic exposure, the use of EFV should be avoided in pregnant women (140 ). IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for a newborn. Because the half-life of IDV in adults is short, these concerns might be relevant only if the drug is administered shortly before delivery. In a recent study in France of perinatal HIV transmission, two cases of progressive neurologic disease and death were reported in uninfected infants exposed to ZDV and 3TC (157 ). Laboratory studies of these children suggested mitochondrial dysfunction. In a careful review of deaths in children followed in U.S. perinatal HIV cohorts, no deaths attributable to mitochondrial disease have been found (158 ). Recent reports of fatal and nonfatal lactic acidosis in pregnant women treated throughout gestation with a combination of d4T and ddI have prompted warnings about use of these drugs during pregnancy (159 ). Although the case-patients were HIV-infected women taking the drugs for >4 weeks, pregnant women and their providers should be advised to consider d4T and ddI only when the benefits of their use outweigh the risks. PEP Use in Hospitals in the United States. Analysis of data from NaSH provides information on the use of PEP following occupational exposures in 47 hospitals in the United States. A total of 11,784 exposures to blood and body fluids was reported from June 1996 through November 2000 (CDC, unpublished data, 2001). For all exposures with known sources, 6% were to HIV-positive sources, 74% to HIV-negative sources, and 20% to sources with an unknown HIV status. Sixty-three percent of HCP exposed to a known HIV-positive source started PEP, and 54% of HCP took it for at least 20 days, whereas 14% of HCP exposed to a source person subsequently found to be HIV-negative initiated PEP, and 3% of those took it for at least 20 days. Information recorded about HIV exposures in NaSH indicates that 46% of exposures involving an HIV-positive source warranted only a two-drug PEP regimen (i.e., the exposure was to mucous membranes or skin or was a superficial percutaneous injury and the source person did not have endstage AIDS or acute HIV illness); however, 53% of these exposed HCP took >3 drugs (CDC, unpublished data, 2000). Similarly, the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline) reported that PEPline staff recommended stopping or not starting PEP for approximately one half of the HCP who consulted them about exposures (D. Bangsberg, San Francisco General Hospital, unpublished data, September 1999). The observation that some HCP exposed to HIV-negative source persons take PEP from several days to weeks following their exposures suggests that strategies be employed such as the use of a rapid HIV antibody assay, which could minimize exposure to unnecessary PEP (11 ). A recent study demonstrated that use of a rapid HIV test for evaluation of source persons after occupational exposures not only resulted in decreased use of PEP, but also was cost-effective compared with use of the standard enzyme immunoassay (EIA) test for source persons subsequently found to be HIV-negative (160 ). # RECOMMENDATIONS FOR THE MANAGEMENT OF HCP POTENTIALLY EXPOSED TO HBV, HCV, or HIV Exposure prevention remains the primary strategy for reducing occupational bloodborne pathogen infections; however, occupational exposures will continue to occur. Health-care organizations should make available to their personnel a system that includes written protocols for prompt reporting, evaluation, counseling, treatment, and follow-up of occupational exposures that might place HCP at risk for acquiring a bloodborne infection. HCP should be educated concerning the risk for and prevention of bloodborne infections, including the need to be vaccinated against hepatitis B (17,21,(161)(162)(163). Employers are required to establish exposure-control plans that include postexposure follow-up for their employees and to comply with incident reporting requirements mandated by the 1992 OSHA bloodborne pathogen standard (2 ). Access to clinicians who can provide postexposure care should be available during all working hours, including nights and weekends. HBIG, hepatitis B vaccine, and antiretroviral agents for HIV PEP should be available for timely administration (i.e., either by providing access on-site or by creating linkages with other facilities or providers to make them available off-site). Persons responsible for providing postexposure management should be familiar with evaluation and treatment protocols and the facility's plans for accessing HBIG, hepatitis B vaccine, and antiretroviral drugs for HIV PEP. HCP should be educated to report occupational exposures immediately after they occur, particularly because HBIG, hepatitis B vaccine, and HIV PEP are most likely to be effective if administered as soon after the exposure as possible. HCP who are at risk for occupational exposure to bloodborne pathogens should be familiarized with the principles of postexposure management as part of job orientation and ongoing job training. # Hepatitis B Vaccination Any person who performs tasks involving contact with blood, blood-contaminated body fluids, other body fluids, or sharps should be vaccinated against hepatitis B (2,21 ). Prevaccination serologic screening for previous infection is not indicated for persons being vaccinated because of occupational risk, unless the hospital or health-care organization considers screening cost-effective. Hepatitis B vaccine should always be administered by the intramuscular route in the deltoid muscle with a needle 1-1.5 inches long. Hepatitis B vaccine can be administered at the same time as other vaccines with no interference with antibody response to the other vaccines (164 ). If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least 2 months. If only the third dose is delayed, it should be administered when convenient. HCP who have contact with patients or blood and are at ongoing risk for percutaneous injuries should be tested 1-2 months after completion of the 3-dose vaccination series for anti-HBs (21 ). Persons who do not respond to the primary vaccine series (i.e., anti-HBs <10 mIU/mL) should complete a second 3-dose vaccine series or be evaluated to determine if they are HBsAg-positive. Revaccinated persons should be retested at the completion of the second vaccine series. Persons who do not respond to an initial 3-dose vaccine series have a 30%-50% chance of responding to a second 3-dose series (165 ). Persons who prove to be HBsAg-positive should be counseled regarding how to prevent HBV transmission to others and regarding the need for medical evaluation (12,163,166 ). Nonresponders to vaccination who are HBsAg-negative should be considered susceptible to HBV infection and should be counseled regarding precautions to prevent HBV infection and the need to obtain HBIG prophylaxis for any known or probable parenteral exposure to HBsAg-positive blood. Booster doses of hepatitis B vaccine are not necessary, and periodic serologic testing to monitor antibody concentrations after completion of the vaccine series is not recommended. Any blood or body fluid exposure sustained by an unvaccinated, susceptible person should lead to the initiation of the hepatitis B vaccine series. # Treatment of an Exposure Site Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. No evidence exists that using antiseptics for wound care or expressing fluid by squeezing the wound further reduces the risk of bloodborne pathogen transmission; however, the use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended. # Exposure Report If an occupational exposure occurs, the circumstances and postexposure management should be recorded in the exposed person's confidential medical record (usually on a form the facility designates for this purpose) (Box 1). In addition, employers should follow all federal (including OSHA) and state requirements for recording and reporting occupational injuries and exposures. # BOX 1. Recommendations for the contents of the occupational exposure report - date and time of exposure; - details of the procedure being performed, including where and how the exposure occurred; if related to a sharp device, the type and brand of device and how and when in the course of handling the device the exposure occurred; - details of the exposure, including the type and amount of fluid or material and the severity of the exposure (e.g., for a percutaneous exposure, depth of injury and whether fluid was injected; for a skin or mucous membrane exposure, the estimated volume of material and the condition of the skin ); - details about the exposure source (e.g., whether the source material contained HBV, HCV, or HIV; if the source is HIV-infected, the stage of disease, history of antiretroviral therapy, viral load, and antiretroviral resistance information, if known); - details about the exposed person (e.g., hepatitis B vaccination and vaccine-response status); and - details about counseling, postexposure management, and follow-up. # Evaluation of the Exposure and the Exposure Source Evaluation of the Exposure The exposure should be evaluated for the potential to transmit HBV, HCV, and HIV based on the type of body substance involved and the route and severity of the exposure (Box 2). Blood, fluid containing visible blood, or other potentially infectious fluid (including semen; vaginal secretions; and cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids) or tissue can be infectious for bloodborne viruses. Exposures to these fluids or tissue through a percutaneous injury (i.e., needlestick or other penetrating sharps-related event) or through contact with a mucous membrane are situations that pose a risk for bloodborne virus transmission and require further evaluation. For HCV and HIV, exposure to a blood-filled hollow needle or visibly bloody device suggests a higher risk exposure than exposure to a needle that was most likely used for giving an injection. In addition, any direct contact (i.e, personal protective equipment either was not present or was ineffective in protecting skin or mucous membranes) with concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For skin exposure, follow-up is indicated only if it involves exposure to a body fluid previously listed and evidence exists of compromised skin integrity (e.g., dermatitis, abrasion, or open wound). In the clinical evaluation for human bites, possible exposure of both the person bitten and the person who inflicted the bite must be considered. If a bite results in blood exposure to either person involved, postexposure follow-up should be provided. # BOX 2. Factors to consider in assessing the need for follow-up of occupational exposures # Evaluation of the Exposure Source The person whose blood or body fluid is the source of an occupational exposure should be evaluated for HBV, HCV, and HIV infection (Box 3). Information available in the medical record at the time of exposure (e.g., laboratory test results, admitting diagnosis, or previous medical history) or from the source person, might confirm or exclude bloodborne virus infection. If the HBV, HCV, and/or HIV infection status of the source is unknown, the source person should be informed of the incident and tested for serologic evidence of bloodborne virus infection. Procedures should be followed for testing source persons, including obtaining informed consent, in accordance with applicable state and local laws. Any persons determined to be infected with HBV, HCV, or HIV should be referred for appropriate counseling and treatment. Confidentiality of the source person should be maintained at all times. Testing to determine the HBV, HCV, and HIV infection status of an exposure source should be performed as soon as possible. Hospitals, clinics and other sites that manage exposed HCP should consult their laboratories regarding the most appropriate test to use to expedite obtaining these results. An FDA-approved rapid HIV-antibody test kit should be considered for use in this situation, particularly if testing by EIA cannot be completed within 24-48 hours. Repeatedly reactive results by EIA or rapid HIV-antibody tests are considered to be highly suggestive of infection, whereas a negative result is an excellent indicator of the absence of HIV antibody. Confirmation of a reactive result by Western blot or immunofluorescent antibody is not necessary to make initial decisions about postexposure management but should be done to complete the testing process and before informing the source person. Repeatedly reactive results by EIA for anti-HCV should be confirmed by a supplemental test (i.e., recombinant immunoblot assay or HCV PCR). Direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA or HCV RNA) for routine HIV or HCV screening of source persons are not recommended. If the exposure source is unknown or cannot be tested, information about where and under what circumstances the exposure occurred should be assessed epidemiologically for the likelihood of transmission of HBV, HCV, or HIV. Certain situations as well as the type of exposure might suggest an increased or decreased risk; an important consideration is the prevalence of HBV, HCV, or HIV in the population group (i.e., institution or community) from which the contaminated source material is derived. For example, an exposure that occurs in a geographic area where injection-drug use is prevalent or involves a needle discarded in a drug-treatment facility would be considered epidemiologically to have a higher risk for transmission than an exposure that occurs in a nursing home for the elderly. Testing of needles or other sharp instruments implicated in an exposure, regardless of whether the source is known or unknown, is not recommended. The reliability and interpretation of findings in such circumstances are unknown, and testing might be hazardous to persons handling the sharp instrument. Examples of information to consider when evaluating an exposure source for possible HBV, HCV, or HIV infection include laboratory information (e.g., previous HBV, HCV, or HIV test results or results of immunologic testing ) or liver enzymes (e.g., ALT), clinical symptoms (e.g., acute syndrome suggestive of primary HIV infection or undiagnosed immunodeficiency disease), and history of recent (i.e., within 3 months) possible HBV, HCV, or HIV exposures (e.g., injection-drug use or sexual contact with a known positive partner). Health-care providers should be aware of local and state laws governing the collection and release of HIV serostatus information on a source person, following an occupational exposure. If the source person is known to have HIV infection, available information about this person's stage of infection (i.e., asymptomatic, symptomatic, or AIDS), CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic or phenotypic viral resistance testing should be gathered for consideration in choosing an appropriate PEP regimen. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of exposed HCP should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. If the source person is HIV seronegative and has no clinical evidence of AIDS or symptoms of HIV infection, no further testing of the person for HIV infection is indicated. The likelihood of the source person being in the "window period" of HIV infection in the absence of symptoms of acute retroviral syndrome is extremely small. # BOX 3. Evaluation of occupational exposure sources # Known sources - Test known sources for HBsAg, anti-HCV, and HIV antibody -Direct virus assays for routine screening of source patients are not recommended -Consider using a rapid HIV-antibody test -If the source person is not infected with a bloodborne pathogen, baseline testing or further follow-up of the exposed person is not necessary - For sources whose infection status remains unknown (e.g., the source person refuses testing), consider medical diagnoses, clinical symptoms, and history of risk behaviors - Do not test discarded needles for bloodborne pathogens # Unknown sources - For unknown sources, evaluate the likelihood of exposure to a source at high risk for infection -Consider likelihood of bloodborne pathogen infection among patients in the exposure setting # Management of Exposures to HBV For percutaneous or mucosal exposures to blood, several factors must be considered when making a decision to provide prophylaxis, including the HBsAg status of the source and the hepatitis B vaccination and vaccine-response status of the exposed person. Such exposures usually involve persons for whom hepatitis B vaccination is recommended. # MMWR 21 Any blood or body fluid exposure to an unvaccinated person should lead to initiation of the hepatitis B vaccine series. The hepatitis B vaccination status and the vaccine-response status (if known) of the exposed person should be reviewed. A summary of prophylaxis recommendations for percutaneous or mucosal exposure to blood according to the HBsAg status of the exposure source and the vaccination and vaccine-response status of the exposed person is included in this report (Table 3). When HBIG is indicated, it should be administered as soon as possible after exposure (preferably within 24 hours). The effectiveness of HBIG when administered >7 days after exposure is unknown. When hepatitis B vaccine is indicated, it should also be administered as soon as possible (preferably within 24 hours) and can be administered simultaneously with HBIG at a separate site (vaccine should always be administered in the deltoid muscle). For exposed persons who are in the process of being vaccinated but have not completed the vaccination series, vaccination should be completed as scheduled, and HBIG should be added as indicated (Table 3). Persons exposed to HBsAg-positive blood or body fluids who are known not to have responded to a primary vaccine series should receive a single dose of HBIG and reinitiate the hepatitis B vaccine series with the first dose of the hepatitis B vaccine as soon as possible after exposure. Alternatively, they should receive two doses of HBIG, one dose as soon as possible after exposure, and the second dose 1 month later. The option of administering one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who did not complete a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred. # Management of Exposures to HCV Individual institutions should establish policies and procedures for testing HCP for HCV after percutaneous or mucosal exposures to blood and ensure that all personnel are familiar with these policies and procedures. The following are recommendations for follow-up of occupational HCV exposures: - For the source, perform testing for anti-HCV. - For the person exposed to an HCV-positive source -perform baseline testing for anti-HCV and ALT activity; and -perform follow-up testing (e.g., at 4-6 months) for anti-HCV and ALT activity (if earlier diagnosis of HCV infection is desired, testing for HCV RNA may be performed at 4-6 weeks). - Confirm all anti-HCV results reported positive by enzyme immunoassay using supplemental anti-HCV testing (e.g., recombinant immunoblot assay ) Health-care professionals who provide care to persons exposed to HCV in the occupational setting should be knowledgeable regarding the risk for HCV infection and appropriate counseling, testing, and medical follow-up. IG and antiviral agents are not recommended for PEP after exposure to HCV-positive blood. In addition, no guidelines exist for administration of therapy during the acute - Persons who have previously been infected with HBV are immune to reinfection and do not require postexposure prophylaxis. † Hepatitis B surface antigen. § Hepatitis B immune globulin; dose is 0.06 mL/kg intramuscularly. ¶ Hepatitis B vaccine. A responder is a person with adequate levels of serum antibody to HBsAg (i.e., anti-HBs >10 mIU/mL). † † A nonresponder is a person with inadequate response to vaccination (i.e., serum anti-HBs < 10 mIU/mL). § § The option of giving one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who have not completed a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred. ¶ ¶ Antibody to HBsAg. phase of HCV infection. However, limited data indicate that antiviral therapy might be beneficial when started early in the course of HCV infection. When HCV infection is identified early, the person should be referred for medical management to a specialist knowledgeable in this area. # Counseling for HCP Exposed to Viral Hepatitis HCP exposed to HBV-or HCV-infected blood do not need to take any special precautions to prevent secondary transmission during the follow-up period (12,13 ); however, they should refrain from donating blood, plasma, organs, tissue, or semen. The exposed person does not need to modify sexual practices or refrain from becoming pregnant. If an exposed woman is breast feeding, she does not need to discontinue. No modifications to an exposed person's patient-care responsibilities are necessary to prevent transmission to patients based solely on exposure to HBV-or HCV-positive blood. If an exposed person becomes acutely infected with HBV, the person should be evaluated according to published recommendations for infected HCP (165 ). No recommendations exist regarding restricting the professional activities of HCP with HCV infection (13 ). As recommended for all HCP, those who are chronically infected with HBV or HCV should follow all recommended infection-control practices, including standard precautions and appropriate use of hand washing, protective barriers, and care in the use and disposal of needles and other sharp instruments (162 ). # Management of Exposures to HIV Clinical Evaluation and Baseline Testing of Exposed HCP HCP exposed to HIV should be evaluated within hours (rather than days) after their exposure and should be tested for HIV at baseline (i.e., to establish infection status at the time of exposure). If the source person is seronegative for HIV, baseline testing or further follow-up of the exposed person normally is not necessary. Serologic testing should be made available to all HCP who are concerned that they might have been occupationally infected with HIV. For purposes of considering HIV PEP, the evaluation also should include information about medications the exposed person might be taking and any current or underlying medical conditions or circumstances (i.e., pregnancy, breast feeding, or renal or hepatic disease) that might influence drug selection. # PEP for HIV The following recommendations (Tables 4 and 5) apply to situations when a person has been exposed to a source person with HIV infection or when information suggests the likelihood that the source person is HIV-infected. These recommendations are based on the risk for HIV infection after different types of exposure and on limited data regarding efficacy and toxicity of PEP. Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity must be carefully considered when prescribing PEP. To assist with the initial management of an HIV exposure, health-care facilities should have drugs for an initial PEP regimen selected and available for use. When possible, these recommendations should be implemented in consultation with persons who have expertise in antiretroviral therapy and HIV transmission (Box 4). consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. † Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). § Unknown source (e.g., a needle from a sharps disposal container). ¶ Less severe (e.g., solid needle and superficial injury). The designation "consider PEP" indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician. † † If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. § § More severe (e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient's artery or vein). consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. § Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). ¶ Unknown source (e.g., splash from inappropriately disposed blood). Small volume (i.e., a few drops). † † The designation, "consider PEP," indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician. § § If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. ¶ ¶ Large volume (i.e., major blood splash). # MMWR June 29, 2001 Timing and Duration of PEP. PEP should be initiated as soon as possible. The interval within which PEP should be initiated for optimal efficacy is not known. Animal studies have demonstrated the importance of starting PEP soon after an exposure (111,112,118 ). If questions exist about which antiretroviral drugs to use or whether to use a basic or expanded regimen, starting the basic regimen immediately rather than delaying PEP administration is probably better. Although animal studies suggest that PEP probably is substantially less effective when started more than 24-36 hours postexposure (112,119,122 ), the interval after which no benefit is gained from PEP for humans is undefined. Therefore, if appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours. Initiating therapy after a longer interval (e.g., 1 week) might be considered for exposures that represent an increased risk for transmission. The optimal duration of PEP is unknown. Because 4 weeks of ZDV appeared protective in occupational and animal studies (100,123 ), PEP probably should be administered for 4 weeks, if tolerated. Use of PEP When HIV Infection Status of Source Person is Unknown. If the source person's HIV infection status is unknown at the time of exposure, use of PEP should be decided on a case-by-case basis, after considering the type of exposure and the clinical and/or epidemiologic likelihood of HIV infection in the source (Tables 4 and 5). If these considerations suggest a possibility for HIV transmission and HIV testing of the source person is pending, initiating a two-drug PEP regimen until laboratory results have been obtained and later modifying or discontinuing the regimen accordingly is reasonable. The following are recommendations regarding HIV postexposure prophylaxis: - If indicated, start PEP as soon as possible after an exposure. - Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. - Administer PEP for 4 weeks, if tolerated. - If a source person is determined to be HIV-negative, PEP should be discontinued. PEP for Pregnant HCP. If the exposed person is pregnant, the evaluation of risk of infection and need for PEP should be approached as with any other person who has had an HIV exposure. However, the decision to use any antiretroviral drug during pregnancy should involve discussion between the woman and her health-care provider(s) regarding the potential benefits and risks to her and her fetus. Certain drugs should be avoided in pregnant women. Because teratogenic effects were observed in primate studies, EFV is not recommended during pregnancy. Reports of fatal lactic acidosis in pregnant women treated with a combination of d4T and ddI have prompted warnings about these drugs during pregnancy. Because of the risk of hyperbilirubinemia in newborns, IDV should not be administered to pregnant women shortly before delivery. # Recommendations for the Selection of Drugs for HIV PEP Health-care providers must strive to balance the risk for infection against the potential toxicity of the agent(s) used when selecting a drug regimen for HIV PEP. Because PEP is potentially toxic, its use is not justified for exposures that pose a negligible risk for transmission (Tables 4 and 5). Also, insufficient evidence exists to support recommending a three-drug regimen for all HIV exposures. Therefore, two regimens for PEP are provided (Appendix C): a "basic" two-drug regimen that should be appropriate for most HIV exposures and an "expanded" three-drug regimen that should be used for exposures that pose an increased risk for transmission (Tables 4 and 5). When possible, the regimens should be implemented in consultation with persons who have expertise in antiretroviral treatment and HIV transmission. Most HIV exposures will warrant a two-drug regimen using two nucleoside analogues (e.g., ZDV and 3TC; or 3TC and d4T; or d4T and ddI). The addition of a third drug should be considered for exposures that pose an increased risk for transmission. Selection of the PEP regimen should consider the comparative risk represented by the exposure and information about the exposure source, including history of and response to antiretroviral therapy based on clinical response, CD4+ T-cell counts, viral load measurements, and current disease stage. When the source person's virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended; expert consultation is advised. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. # Follow-up of HCP Exposed to HIV Postexposure Testing. HCP with occupational exposure to HIV should receive followup counseling, postexposure testing, and medical evaluation, regardless of whether they receive PEP. HIV-antibody testing should be performed for at least 6 months postexposure (e.g., at 6 weeks, 12 weeks, and 6 months). Extended HIV follow-up (e.g., for 12 months) is recommended for HCP who become infected with HCV following exposure to a source coinfected with HIV and HCV. Whether extended follow-up is indicated in other circumstances (e.g., exposure to a source coinfected with HIV and HCV in the absence of HCV seroconversion or for exposed persons with a medical history suggesting an impaired ability to develop an antibody response to acute infection) is unclear. Although rare instances of delayed HIV seroconversion have been reported (167,168 ), the infrequency of this occurrence does not warrant adding to the anxiety level of the exposed persons by routinely extending the duration of postexposure follow-up. However, this recommendation should not preclude a decision to extend follow-up in an individual situation based on the clinical judgement of the exposed person's health-care provider. HIV testing should be performed on any exposed person who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure. When HIV infection is identified, the person should be referred to a specialist knowledgeable in the area of HIV treatment and counseling for medical management. HIV-antibody testing with EIA should be used to monitor for seroconversion. The routine use of direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA) to detect infection in exposed HCP generally is not recommended (169 ). The high rate of falsepositive results of these tests in this setting could lead to unnecessary anxiety and/or treatment (170,171 ). Despite the ability of direct virus assays to detect HIV infection a few days earlier than EIA, the infrequency of occupational seroconversion and increased costs of these tests do not warrant their routine use in this setting. - HIV-antibody testing should be performed for at least 6 months postexposure. - Direct virus assays for routine follow-up of HCP are not recommended. - HIV testing should be performed on any exposed person who has an illness compatible with an acute retroviral syndrome. Monitoring and Management of PEP Toxicity. If PEP is used, HCP should be monitored for drug toxicity by testing at baseline and again 2 weeks after starting PEP. The scope of testing should be based on medical conditions in the exposed person and the toxicity of drugs included in the PEP regimen. Minimally, lab monitoring for toxicity should include a complete blood count and renal and hepatic function tests. Monitoring for evidence of hyperglycemia should be included for HCP whose regimens include any PI; if the exposed person is receiving IDV, monitoring for crystalluria, hematuria, hemolytic anemia, and hepatitis also should be included. If toxicity is noted, modification of the regimen should be considered after expert consultation; further diagnostic studies may be indicated. Exposed HCP who choose to take PEP should be advised of the importance of completing the prescribed regimen. Information should be provided to HCP about potential drug interactions and the drugs that should not be taken with PEP, the side effects of the drugs that have been prescribed, measures to minimize these effects, and the methods of clinical monitoring for toxicity during the follow-up period. HCP should be advised that the evaluation of certain symptoms should not be delayed (e.g., rash, fever, back or abdominal pain, pain on urination or blood in the urine, or symptoms of hyperglycemia ). HCP who fail to complete the recommended regimen often do so because of the side effects they experience (e.g., nausea and diarrhea). These symptoms often can be managed with antimotility and antiemetic agents or other medications that target the specific symptoms without changing the regimen. In other situations, modifying the dose interval (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), might facilitate adherence to the regimen. Serious adverse events should be reported to FDA's MedWatch Program. Counseling and Education. Although HIV infection following an occupational exposure occurs infrequently, the emotional effect of an exposure often is substantial (172)(173)(174). In addition, HCP are given seemingly conflicting information. Although HCP are told that a low risk exists for HIV transmission, a 4-week regimen of PEP might be recommended, and they are asked to commit to behavioral measures (e.g., sexual abstinence or condom use) to prevent secondary transmission, all of which influence their lives for several weeks to months (172 ). Therefore, access to persons who are knowledgeable about occupational HIV transmission and who can deal with the many concerns an HIV exposure might generate for the exposed person is an important element of postexposure management. HIV-exposed HCP should be advised to use the following measures to prevent secondary transmission during the follow-up period, especially the first 6-12 weeks after the exposure when most HIV-infected persons are expected to seroconvert: exercise sexual abstinence or use condoms to prevent sexual transmission and to avoid pregnancy; and refrain from donating blood, plasma, organs, tissue, or semen. If an exposed woman is breast feeding, she should be counseled about the risk of HIV transmission through breast milk, and discontinuation of breast feeding should be considered, especially for high-risk exposures. Additionally, NRTIs are known to pass into breast milk, as is NVP; whether this also is true for the other approved antiretroviral drugs is unknown. # MMWR 29 The patient-care responsibilities of an exposed person do not need to be modified, based solely on an HIV exposure, to prevent transmission to patients. If HIV seroconversion is detected, the person should be evaluated according to published recommendations for infected HCP (175 ). Exposed HCP should be advised to seek medical evaluation for any acute illness that occurs during the follow-up period. Such an illness, particularly if characterized by fever, rash, myalgia, fatigue, malaise, or lymphadenopathy, might be indicative of acute HIV infection but also might be indicative of a drug reaction or another medical condition. For exposures for which PEP is considered appropriate, HCP should be informed that a) knowledge about the efficacy of drugs used for PEP is limited; b) experts recommend combination drug regimens because of increased potency and concerns about drugresistant virus; c) data regarding toxicity of antiretroviral drugs in persons without HIV infection or in pregnant women are limited; d) although the short-term toxicity of antiretroviral drugs is usually limited, serious adverse events have occurred in persons taking PEP; and e) any or all drugs for PEP may be declined or stopped by the exposed person. HCP who experience HIV occupational exposures for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the negligible risk of transmission posed by the type of exposure. # Guidelines for counseling and educating HCP with HIV exposure include - Exposed HCP should be advised to use precautions to prevent secondary transmission during the follow-up period. - For exposures for which PEP is prescribed, HCP should be informed about possible drug toxicities and the need for monitoring, and possible drug interactions. # Occupational Exposure Management Resources Several resources are available that provide guidance to HCP regarding the management of occupational exposures. These resources include PEPline; the Needlestick! website; the Hepatitis Hotline; CDC (receives reports of occupationally acquired HIV infections and failures of PEP); the HIV Antiretroviral Pregnancy Registry; FDA (receives reports of unusual or severe toxicity to antiretroviral agents); and the HIV/AIDS Treatment Information Service (Box 5). # MMWR June 29, 2001 -Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person. -Nervous system side effects (e.g., dizziness, somnolence, insomnia, and/or abnormal dreaming) are common. Severe psychiatric symptoms are possible (dosing before bedtime might minimize these side effects). -Should not be used during pregnancy because of concerns about teratogenicity. -Concomitant use of astemizole, cisapride, midazolam, triazolam, ergot derivatives, or St. John's Wort is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or lifethreatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). -Potential for oncogenic toxicity is unknown. - Abacavir (ZIAGEN™; ABC); available as TRIZIVIR™, a combination of ZDV, 3TC, and ABC -300 mg twice daily. # Advantages -potent HIV inhibitor, and -well tolerated in patients with HIV infection. # Disadvantages -Severe hypersensitivity reactions can occur, usually within the first 6 weeks of treatment. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. - Amprenavir (AGENERASE™; AMP) # ANTIRETROVIRAL AGENTS FOR USE AS PEP ONLY WITH EXPERT CONSULTATION # Disadvantages -Dosage consists of eight large pills taken twice daily. -Many drug interactions. - Delavirdine (RESCRIPTOR™; DLV) # Disadvantages -Drug is associated with rash (early onset) that can be severe and progress to Stevens-Johnson syndrome. -Many drug interactions. - Lopinavir/Ritonavir (KALETRA™) -400/100 mg twice daily. # Advantages -potent HIV inhibitor, and -well tolerated in patients with HIV infection. # Disadvantages -Concomitant use of flecainide, propafenone, astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). -May accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # ANTIRETROVIRAL AGENTS GENERALLY NOT RECOMMENDED FOR USE AS PEP - Nevirapine (VIRAMUNE™; NVP) -200 mg daily for 2 weeks, then 200 mg twice daily. # MMWR June 29, 2001 - Delayed (i.e., later than 24-36 hours) exposure report -the interval after which there is no benefit from postexposure prophylaxis (PEP) is undefined - Unknown source (e.g., needle in sharps disposal container or laundry) -decide use of PEP on a case-by-case basis -consider the severity of the exposure and the epidemiologic likelihood of HIV exposure -do not test needles or other sharp instruments for HIV - Known or suspected pregnancy in the exposed person -does not preclude the use of optimal PEP regimens -do not deny PEP solely on the basis of pregnancy - Resistance of the source virus to antiretroviral agents -influence of drug resistance on transmission risk is unknown -selection of drugs to which the source person's virus is unlikely to be resistant is recommended, if the source person's virus is known or suspected to be resistant to >1 of the drugs considered for the PEP regimen -resistance testing of the source person's virus at the time of the exposure is not recommended - Toxicity of the initial PEP regimen -adverse symptoms, such as nausea and diarrhea are common with PEP -symptoms often can be managed without changing the PEP regimen by prescribing antimotility and/or antiemetic agents -modification of dose intervals (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), in other situations, might help alleviate symptoms Local experts and/or the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline HCF should provide medication adherence counseling to assist HCP in completing HIV PEP as necessary. Monitor for adverse effects HCP taking antiretroviral PEP should be monitored of PEP. periodically for adverse effects of PEP through baseline and testing (every 2 weeks) and clinical evaluation. Monitor for seroconversion. HCF should develop a system to encourage exposed HCP to return for follow-up testing. Exposed HCP should be tested for HCV and HIV. Monitor exposure HCF should develop a system to monitor reporting management programs. and management of occupational exposures to ensure timely and appropriate response. # Evaluate - exposure reports for completeness and accuracy, - access to care (i.e., the time of exposure to the time of evaluation), and - laboratory result reporting time. # Review - exposures to ensure that HCP exposed to sources not infected with bloodborne pathogens do not receive PEP or that PEP is stopped. # Monitor - completion rates of HBV vaccination and HIV PEP and - completion of exposure follow-up. # Practice recommendation Implementation checklist Vol. 50 / No. RR-11 MMWR 45 APPENDIX B. # Management of Occupational Blood Exposures Provide immediate care to the exposure site. - Wash wounds and skin with soap and water. - Flush mucous membranes with water. # Determine risk associated with exposure by - type of fluid (e.g., blood, visibly bloody fluid, other potentially infectious fluid or tissue, and concentrated virus) and - type of exposure (i.e., percutaneous injury, mucous membrane or nonintact skin exposure, and bites resulting in blood exposure). Evaluate exposure source. - Assess the risk of infection using available information. - Test known sources for HBsAg, anti-HCV, and HIV antibody (consider using rapid testing). - For unknown sources, assess risk of exposure to HBV, HCV, or HIV infection. - Do not test discarded needles or syringes for virus contamination. Evaluate the exposed person. - Assess immune status for HBV infection (i.e., by history of hepatitis B vaccination and vaccine response). Give PEP for exposures posing risk of infection transmission. - HBV: See Table 3. - HCV: PEP not recommended. - HIV: See Tables 4 and 5. -Initiate PEP as soon as possible, preferably within hours of exposure. -Offer pregnancy testing to all women of childbearing age not known to be pregnant. -Seek expert consultation if viral resistance is suspected. -Administer PEP for 4 weeks if tolerated. # MMWR June 29, 2001 Perform follow-up testing and provide counseling. - Advise exposed persons to seek medical evaluation for any acute illness occurring during follow-up. # HBV exposures - Perform follow-up anti-HBs testing in persons who receive hepatitis B vaccine. -Test for anti-HBs 1-2 months after last dose of vaccine. -Anti-HBs response to vaccine cannot be ascertained if HBIG was received in the previous 3-4 months. # HCV exposures - Perform baseline and follow-up testing for anti-HCV and alanine aminotransferase (ALT) 4-6 months after exposures. - Perform HCV RNA at 4-6 weeks if earlier diagnosis of HCV infection desired. - Confirm repeatedly reactive anti-HCV enzyme immunoassays (EIAs) with supplemental tests. # HIV exposures - Perform HIV-antibody testing for at least 6 months postexposure (e.g., at baseline, 6 weeks, 3 months, and 6 months). - Perform HIV antibody testing if illness compatible with an acute retroviral syndrome occurs. - Advise exposed persons to use precautions to prevent secondary transmission during the follow-up period. # Advantages -ZDV is associated with decreased risk of HIV transmission in the CDC casecontrol study of occupational HIV infection. -ZDV has been used more than the other drugs for PEP in HCP. -Serious toxicity is rare when used for PEP. -Side effects are predictable and manageable with antimotility and antiemetic agents. -Probably a safe regimen for pregnant HCP. -Can be given as a single tablet (COMBIVIR™) twice daily. # Disadvantages -Side effects are common and might result in low adherence. -Source patient virus might have resistance to this regimen. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # ALTERNATE BASIC REGIMENS - Lamivudine (3TC) + Stavudine (ZERIT™; d4T) -3TC: 150 mg twice daily, and -d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily. # Advantages -well tolerated in patients with HIV infection, resulting in good adherence, -serious toxicity appears to be rare, and -twice daily dosing might improve adherence. # MMWR June 29, 2001 Disadvantages -Source patient virus might be resistant to this regimen. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. - Didanosine (VIDEX™, chewable/dispersable buffered tablet; VIDEX™ EC, delayed-release capsule; ddI) + Stavudine (d4T) -ddI: 400 mg (if body weight is <60 kg, 125 mg twice daily) daily, on an empty stomach. -d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily. Advantages -Likely to be effective against HIV strains from source patients who are taking ZDV and 3TC. # Disadvantages -ddl is difficult to administer and unpalatable. -Chewable/dispersable buffered tablet formulation of ddI interferes with absorption of some drugs (e.g., quinolone antibiotics, and indinavir). -Serious toxicity (e.g., neuropathy, pancreatitis, or hepatitis) can occur. Fatal and nonfatal pancreatitis has occurred in HIV-positive, treatment-naive patients. Patients taking ddI and d4T should be carefully assessed and closely monitored for pancreatitis, lactic acidosis, and hepatitis. -Side effects are common; anticipate diarrhea and low adherence. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # EXPANDED REGIMEN Basic regimen plus one of the following: - Indinavir (CRIXIVAN™; IDV) -800 mg every 8 hours, on an empty stomach. # Advantages -Potent HIV inhibitor. # Disadvantages -Serious toxicity (e.g., nephrolithiasis) can occur; must take 8 glasses of fluid per day. -Hyperbilirubinemia common; must avoid this drug during late pregnancy. -Requires acid for absorption and cannot be taken simultaneously with ddI in chewable/dispersable buffered tablet formulation (doses must be separated by at least 1 hour). -Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. - Nelfinavir (VIRACEPT™; NFV) -750 mg three times daily, with meals or snack, or -1250 mg twice daily, with meals or snack. # Advantages -potent HIV inhibitor, and -twice dosing per day might improve adherence. # Disadvantages -Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. -Might accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. - Efavirenz (SUSTIVA™; EFV) -600 mg daily, at bedtime. # Advantages -Does not require phosphorylation before activation and might be active earlier than other antiretroviral agents (note: this might be only a theoretical advantage of no clinical benefit.) -One dose daily might improve adherence. # Disadvantages -Drug is associated with rash (early onset) that can be severe and might rarely progress to Stevens-Johnson syndrome. # Disadvantages -Associated with severe hepatotoxicity (including at least one case of liver failure requiring liver transplantation in an exposed person taking PEP), -Associated with rash (early onset) that can be severe and progress to Stevens-Johnson syndrome, -Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person, and -Concomitant use of St. John's Wort is not recommended because this might result in suboptimal antiretroviral drug concentrations. # ACCREDITATION # Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.75 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards .15 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 # MMWR June 29, 2001 # GOALS and OBJECTIVES: The MMWR provides recommendations regarding the guidance of clinical practice and policy development related to the management of occupational exposures to blood and bloodborne pathogens, including the appropriate use of postexposure prophylaxis (PEP). Upon completion of this educational activity, the reader should be able to a) describe the management process following an occupational exposure to blood; b) describe the evaluation of the exposure and assessment of the risk for bloodborne pathogen transmission; c) describe appropriate laboratory evaluation of the exposed worker and source person; d) describe appropriate selection and use of PEP; and e) describe the follow-up evaluation and counseling of exposed health-care personnel (HCP). To receive continuing education credit, please answer all of the following questions. # Factors to consider in assessing the need for follow-up after an occupational exposure include A. The type of exposure. B. The type of fluid. C. The bloodborne pathogen infection status of the source. D. The susceptibility of the exposed. E. All of the above. F. None of the above. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp/. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # IU.S. Government Printing Office: 2001-633-173/48237 Region IV	This report updates and consolidates all previous U.S. Public Health Service recommendations for the management of health-care personnel (HCP) who have occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Recommendations for HBV postexposure management include initiation of the hepatitis B vaccine series to any susceptible, unvaccinated person who sustains an occupational blood or body fluid exposure. Postexposure prophylaxis (PEP) with hepatitis B immune globulin (HBIG) and/or hepatitis B vaccine series should be considered for occupational exposures after evaluation of the hepatitis B surface antigen status of the source and the vaccination and vaccine-response status of the exposed person. Guidance is provided to clinicians and exposed HCP for selecting the appropriate HBV PEP. Immune globulin and antiviral agents (e.g., interferon with or without ribavirin) are not recommended for PEP of hepatitis C. For HCV postexposure management, the HCV status of the source and the exposed person should be determined, and for HCP exposed to an HCV positive source, follow-up HCV testing should be performed to determine if infection develops. Recommendations for HIV PEP include a basic 4-week regimen of two drugs (zidovudine [ZDV] and lamivudine [3TC]; 3TC and stavudine [d4T]; or didanosine [ddI] and d4T) for most HIV exposures and an expanded regimen that includes the addition of a third drug for HIV exposures that pose an increased risk for transmission. When the source person's virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended. In addition, this report outlines several special circumstances (e.g., delayed exposure report, unknown source person, pregnancy in the exposed person, resistance of the source virus to antiretroviral agents, or toxicity of the PEP regimen) when consultation with local experts and/or the National Clinicians' Post-Exposure Prophylaxis Hotline ([PEPline] 1-888-448-4911) is advised. Occupational exposures should be considered urgent medical concerns to ensure timely postexposure management and administration of HBIG, hepatitis B vaccine, and/or HIV PEP. 2 MMWR June 29, 2001 This interagency working group comprised representatives of CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration, and the National Institutes of Health. Information included in these recommendations may not represent FDA approval or approved labeling for the particular product or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval.# INTRODUCTION Avoiding occupational blood exposures is the primary way to prevent transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in health-care settings (1 ). However, hepatitis B immunization and postexposure management are integral components of a complete program to prevent infection following bloodborne pathogen exposure and are important elements of workplace safety (2 ). The U.S. Public Health Service (PHS) has published previous guidelines for the management of HIV exposures that included considerations for postexposure prophylaxis (PEP) (3)(4)(5). Since publication of the 1998 HIV exposure guidelines (5 ), several new antiretroviral agents have been approved by the Food and Drug Administration (FDA), and more information is available about the use and safety of HIV PEP (6)(7)(8)(9)(10)(11). In addition, questions exist regarding considerations about PEP regimens when the source person's virus is known or suspected to be resistant to one or more of the antiretroviral agents that might be used for PEP. Concern also has arisen about the use of PEP when it is not warranted. Data indicate that some health-care personnel (HCP) take a full course of HIV PEP after exposures that do not confer an HIV transmission risk (10,11 ). In September 1999, a meeting of a PHS interagency working group and expert consultants was convened by CDC. The PHS working group decided to issue updated recommendations for the management of occupational exposure to HIV. In addition, the report was to include recommendations for the management of occupational HBV and HCV exposures so that a single document could comprehensively address the management of occupational exposures to bloodborne pathogens. This report updates and consolidates the previous PHS guidelines and recommendations for occupational HBV, HCV, and HIV exposure management for HCP. Specific practice recommendations for the management of occupational bloodborne pathogen exposures are outlined to assist health-care institutions with the implementation of these PHS guidelines (Appendices A and B). As relevant information becomes available, updates of these recommendations will be published. Recommendations for nonoccupational (e.g., sexual, pediatric, and perinatal) HBV, HCV, and HIV exposures are not addressed in these guidelines and can be found elsewhere (12)(13)(14)(15). # Definition of Health-Care Personnel and Exposure In this report, health-care personnel (HCP) are defined as persons (e.g., employees, students, contractors, attending clinicians, public-safety workers, or volunteers) whose activities involve contact with patients or with blood or other body fluids from patients in a health-care, laboratory, or public-safety setting. The potential exists for blood and body fluid exposure to other workers, and the same principles of exposure management could be applied to other settings. An exposure that might place HCP at risk for HBV, HCV, or HIV infection is defined as a percutaneous injury (e.g., a needlestick or cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other body fluids that are potentially infectious (16,17 ). In addition to blood and body fluids containing visible blood, semen and vaginal secretions also are considered potentially infectious. Although semen and vaginal secretions have been implicated in the sexual transmission of HBV, HCV, and HIV, they have not been implicated in occupational transmission from patients to HCP. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for transmission of HBV, HCV, and HIV infection from these fluids is unknown; the potential risk to HCP from occupational exposures has not been assessed by epidemiologic studies in health-care settings. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they contain blood. The risk for transmission of HBV, HCV, and HIV infection from these fluids and materials is extremely low. Any direct contact (i.e., contact without barrier protection) to concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For human bites, the clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were exposed to bloodborne pathogens. Transmission of HBV or HIV infection only rarely has been reported by this route (18)(19)(20) (CDC, unpublished data, 1998). # BACKGROUND This section provides the rationale for the postexposure management and prophylaxis recommendations presented in this report. Additional details concerning the risk for occupational bloodborne pathogen transmission to HCP and management of occupational bloodborne pathogen exposures are available elsewhere (5,12,13,(21)(22)(23)(24). # Occupational Transmission of HBV # Risk for Occupational Transmission of HBV HBV infection is a well recognized occupational risk for HCP (25 ). The risk of HBV infection is primarily related to the degree of contact with blood in the work place and also to the hepatitis B e antigen (HBeAg) status of the source person. In studies of HCP who sustained injuries from needles contaminated with blood containing HBV, the risk of developing clinical hepatitis if the blood was both hepatitis B surface antigen (HBsAg)and HBeAg-positive was 22%-31%; the risk of developing serologic evidence of HBV infection was 37%-62%. By comparison, the risk of developing clinical hepatitis from a needle contaminated with HBsAg-positive, HBeAg-negative blood was 1%-6%, and the risk of developing serologic evidence of HBV infection, 23%-37% (26 ). Although percutaneous injuries are among the most efficient modes of HBV transmission, these exposures probably account for only a minority of HBV infections among HCP. In several investigations of nosocomial hepatitis B outbreaks, most infected HCP could not recall an overt percutaneous injury (27,28 ), although in some studies, up to one third of infected HCP recalled caring for a patient who was HBsAg-positive (29,30 ). In addition, HBV has been demonstrated to survive in dried blood at room temperature on environmental surfaces for at least 1 week (31 ). Thus, HBV infections that occur in HCP with no history of nonoccupational exposure or occupational percutaneous injury might have resulted from direct or indirect blood or body fluid exposures that inoculated HBV into cutaneous scratches, abrasions, burns, other lesions, or on mucosal surfaces (32)(33)(34). The potential for HBV transmission through contact with environmental surfaces has been demonstrated in investigations of HBV outbreaks among patients and staff of hemodialysis units (35)(36)(37). Blood contains the highest HBV titers of all body fluids and is the most important vehicle of transmission in the health-care setting. HBsAg is also found in several other body fluids, including breast milk, bile, cerebrospinal fluid, feces, nasopharyngeal washings, saliva, semen, sweat, and synovial fluid (38 ). However, the concentration of HBsAg in body fluids can be 100-1000-fold higher than the concentration of infectious HBV particles. Therefore, most body fluids are not efficient vehicles of transmission because they contain low quantities of infectious HBV, despite the presence of HBsAg. In serologic studies conducted in the United States during the 1970s, HCP had a prevalence of HBV infection approximately 10 times higher than the general population (39)(40)(41)(42). Because of the high risk of HBV infection among HCP, routine preexposure vaccination of HCP against hepatitis B and the use of standard precautions to prevent exposure to blood and other potentially infectious body fluids have been recommended since the early 1980s (43 ). Regulations issued by the Occupational Safety and Health Administration (OSHA) (2 ) have increased compliance with these recommendations. Since the implementation of these recommendations, a sharp decline has occurred in the incidence of HBV infection among HCP. # PEP for HBV Efficacy of PEP for HBV. The effectiveness of hepatitis B immune globulin (HBIG) and/ or hepatitis B vaccine in various postexposure settings has been evaluated by prospective studies. For perinatal exposure to an HBsAg-, HBeAg-positive mother, a regimen combining HBIG and initiation of the hepatitis B vaccine series at birth is 85%-95% effective in preventing HBV infection (44,45 ). Regimens involving either multiple doses of HBIG alone or the hepatitis B vaccine series alone are 70%-75% effective in preventing HBV infection (46 ). In the occupational setting, multiple doses of HBIG initiated within 1 week following percutaneous exposure to HBsAg-positive blood provides an estimated 75% protection from HBV infection (47)(48)(49). Although the postexposure efficacy of the combination of HBIG and the hepatitis B vaccine series has not been evaluated in the occupational setting, the increased efficacy of this regimen observed in the perinatal setting, compared with HBIG alone, is presumed to apply to the occupational setting as well. In addition, because persons requiring PEP in the occupational setting are generally at continued risk for HBV exposure, they should receive the hepatitis B vaccine series. Safety of PEP for HBV. Hepatitis B vaccines have been found to be safe when administered to infants, children, or adults (12,50 ). Through the year 2000, approximately 100 million persons have received hepatitis B vaccine in the United States. The most common side effects from hepatitis B vaccination are pain at the injection site and mild to moderate fever (50)(51)(52)(53)(54)(55). Studies indicate that these side effects are reported no more frequently among persons vaccinated than among those receiving placebo (51,52 ). Approximately 45 reports have been received by the Vaccine Adverse Event Reporting System (VAERS) of alopecia (hair loss) in children and adults after administration of plasma-derived and recombinant hepatitis B vaccine; four persons sustained hair loss following vaccination on more than one occasion (56 ). Hair loss was temporary for approximately two thirds of persons who experienced hair loss. An epidemiologic study conducted in the Vaccine Safety Datalink found no statistical association between alopecia and receipt of hepatitis B vaccine in children (CDC, unpublished data, 1998). A low rate of anaphylaxis has been observed in vaccine recipients based on reports to VAERS; the estimated incidence is 1 in 600,000 vaccine doses distributed. Although none of the persons who developed anaphylaxis died, anaphylactic reactions can be life-threatening; therefore, further vaccination with hepatitis B vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of vaccine. Hepatitis B immunization programs conducted on a large scale in Taiwan, Alaska, and New Zealand have observed no association between vaccination and the occurrence of serious adverse events. Furthermore, in the United States, surveillance of adverse events following hepatitis B vaccination has demonstrated no association between hepatitis B vaccine and the occurrence of serious adverse events, including Guillain-Barré syndrome, transverse myelitis, multiple sclerosis, optic neuritis, and seizures (57-59 ) (CDC, unpublished data, 1991). However, several case reports and case series have claimed an association between hepatitis B vaccination and such syndromes and diseases as multiple sclerosis, optic neuritis, rheumatoid arthritis, and other autoimmune diseases (57,(60)(61)(62)(63)(64)(65)(66). Most of these reported adverse events have occurred in adults, and no report has compared the frequency of the purported vaccine-associated syndrome/disease with the frequency in an unvaccinated population. In addition, recent case-control studies have demonstrated no association between hepatitis B vaccination and development or short-term risk of relapse of multiple sclerosis (67,68 ), and reviews by international panels of experts have concluded that available data do not demonstrate a causal association between hepatitis B vaccination and demyelinating diseases, including multiple sclerosis (69 ). HBIG is prepared from human plasma known to contain a high titer of antibody to HBsAg (anti-HBs). The plasma from which HBIG is prepared is screened for HBsAg and antibodies to HIV and HCV. The process used to prepare HBIG inactivates and eliminates HIV from the final product. Since 1996, the final product has been free of HCV RNA as determined by the polymerase chain reaction (PCR), and, since 1999, all products available in the United States have been manufactured by methods that inactivate HCV and other viruses. No evidence exists that HBV, HCV, or HIV have ever been transmitted by HBIG commercially available in the United States (70,71 ). Serious adverse effects from HBIG when administered as recommended have been rare. Local pain and tenderness at the injection site, urticaria and angioedema might occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin (IG) preparations (72 ). Persons with a history of anaphylactic reaction to IG should not receive HBIG. PEP for HBV During Pregnancy. No apparent risk exists for adverse effects to developing fetuses when hepatitis B vaccine is administered to pregnant women (CDC, unpublished data, 1990). The vaccine contains noninfectious HBsAg particles and should pose no risk to the fetus. HBV infection during pregnancy might result in severe disease for the mother and chronic infection for the newborn. Therefore, neither pregnancy nor lactation should be considered a contraindication to vaccination of women. HBIG is not contraindicated for pregnant or lactating women. # MMWR June 29, 2001 Occupational Transmission of HCV # Risk for Occupational Transmission of HCV HCV is not transmitted efficiently through occupational exposures to blood. The average incidence of anti-HCV seroconversion after accidental percutaneous exposure from an HCV-positive source is 1.8% (range: 0%-7%) (73)(74)(75)(76), with one study indicating that transmission occurred only from hollow-bore needles compared with other sharps (75 ). Transmission rarely occurs from mucous membrane exposures to blood, and no transmission in HCP has been documented from intact or nonintact skin exposures to blood (77,78 ). Data are limited on survival of HCV in the environment. In contrast to HBV, the epidemiologic data for HCV suggest that environmental contamination with blood containing HCV is not a significant risk for transmission in the health-care setting (79,80 ), with the possible exception of the hemodialysis setting where HCV transmission related to environmental contamination and poor infection-control practices have been implicated (81)(82)(83)(84). The risk for transmission from exposure to fluids or tissues other than HCV-infected blood also has not been quantified but is expected to be low. # Postexposure Management for HCV In several studies, researchers have attempted to assess the effectiveness of IG following possible exposure to non-A, non-B hepatitis. These studies have been difficult to interpret because they lack uniformity in diagnostic criteria and study design, and, in all but one study, the first dose of IG was administered before potential exposure (48,85,86 ). In an experiment designed to model HCV transmission by needlestick exposure in the health-care setting, high anti-HCV titer IG administered to chimpanzees 1 hour after exposure to HCV-positive blood did not prevent transmission of infection (87 ). In 1994, the Advisory Committee on Immunization Practices (ACIP) reviewed available data regarding the prevention of HCV infection with IG and concluded that using IG as PEP for hepatitis C was not supported (88 ). This conclusion was based on the following facts: • No protective antibody response has been identified following HCV infection. • Previous studies of IG use to prevent posttransfusion non-A, non-B hepatitis might not be relevant in making recommendations regarding PEP for hepatitis C. • Experimental studies in chimpanzees with IG containing anti-HCV failed to prevent transmission of infection after exposure. No clinical trials have been conducted to assess postexposure use of antiviral agents (e.g., interferon with or without ribavirin) to prevent HCV infection, and antivirals are not FDA-approved for this indication. Available data suggest that an established infection might need to be present before interferon can be an effective treatment. Kinetic studies suggest that the effect of interferon on chronic HCV infection occurs in two phases. During the first phase, interferon blocks the production or release of virus from infected cells. In the second phase, virus is eradicated from the infected cells (89 ); in this later phase, higher pretreatment alanine aminotransferase (ALT) levels correlate with an increasing decline in infected cells, and the rapidity of the decline correlates with viral clearance. In contrast, the effect of antiretrovirals when used for PEP after exposure to HIV is based on inhibition of HIV DNA synthesis early in the retroviral replicative cycle. In the absence of PEP for HCV, recommendations for postexposure management are intended to achieve early identification of chronic disease and, if present, referral for evaluation of treatment options. However, a theoretical argument is that intervention with antivirals when HCV RNA first becomes detectable might prevent the development of chronic infection. Data from studies conducted outside the United States suggest that a short course of interferon started early in the course of acute hepatitis C is associated with a higher rate of resolved infection than that achieved when therapy is begun after chronic hepatitis C has been well established (90)(91)(92). These studies used various treatment regimens and included persons with acute disease whose peak ALT levels were 500-1,000 IU/L at the time therapy was initiated (2.6-4 months after exposure). No studies have evaluated the treatment of acute infection in persons with no evidence of liver disease (i.e., HCV RNA-positive <6 months duration with normal ALT levels); among patients with chronic HCV infection, the efficacy of antivirals has been demonstrated only among patients who also had evidence of chronic liver disease (i.e., abnormal ALT levels). In addition, treatment started early in the course of chronic HCV infection (i.e., 6 months after onset of infection) might be as effective as treatment started during acute infection (13 ). Because 15%-25% of patients with acute HCV infection spontaneously resolve their infection (93 ), treatment of these patients during the acute phase could expose them unnecessarily to the discomfort and side effects of antiviral therapy. Data upon which to base a recommendation for therapy of acute infection are insufficient because a) no data exist regarding the effect of treating patients with acute infection who have no evidence of disease, b) treatment started early in the course of chronic infection might be just as effective and would eliminate the need to treat persons who will spontaneously resolve their infection, and c) the appropriate regimen is unknown. # Occupational Transmission of HIV # Risk for Occupational Transmission of HIV In prospective studies of HCP, the average risk of HIV transmission after a percutaneous exposure to HIV-infected blood has been estimated to be approximately 0.3% (95% confidence interval [CI] = 0.2%-0.5%) (94 ) and after a mucous membrane exposure, approximately 0.09% (95% CI = 0.006%-0.5%) (95 ). Although episodes of HIV transmission after nonintact skin exposure have been documented (96 ), the average risk for transmission by this route has not been precisely quantified but is estimated to be less than the risk for mucous membrane exposures (97 ). The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures (98 ). As of June 2000, CDC had received voluntary reports of 56 U.S. HCP with documented HIV seroconversion temporally associated with an occupational HIV exposure. An additional 138 episodes in HCP are considered possible occupational HIV transmissions. These workers had a history of occupational exposure to blood, other infectious body fluids, or laboratory solutions containing HIV, and no other risk for HIV infection was identified, but HIV seroconversion after a specific exposure was not documented (99 ). Epidemiologic and laboratory studies suggest that several factors might affect the risk of HIV transmission after an occupational exposure. In a retrospective case-control study of HCP who had percutaneous exposure to HIV, the risk for HIV infection was found to be increased with exposure to a larger quantity of blood from the source person as indicated by a) a device visibly contaminated with the patient's blood, b) a procedure that involved a needle being placed directly in a vein or artery, or c) a deep injury (100 ). The risk also was increased for exposure to blood from source persons with terminal illness, possibly reflecting either the higher titer of HIV in blood late in the course of AIDS or other factors (e.g., the presence of syncytia-inducing strains of HIV). A laboratory study that demonstrated that more blood is transferred by deeper injuries and hollow-bore needles lends further support for the observed variation in risk related to blood quantity (101 ). The use of source person viral load as a surrogate measure of viral titer for assessing transmission risk has not yet been established. Plasma viral load (e.g., HIV RNA) reflects only the level of cell-free virus in the peripheral blood; latently infected cells might transmit infection in the absence of viremia. Although a lower viral load (e.g., <1,500 RNA copies/mL) or one that is below the limits of detection probably indicates a lower titer exposure, it does not rule out the possibility of transmission. Some evidence exists regarding host defenses possibly influencing the risk for HIV infection. A study of HIV-exposed but uninfected HCP demonstrated an HIV-specific cytotoxic T-lymphocyte (CTL) response when peripheral blood mononuclear cells were stimulated in vitro with HIV-specific antigens (102 ). Similar CTL responses have been observed in other groups who experienced repeated HIV exposure without resulting infection (103)(104)(105)(106)(107)(108). Among several possible explanations for this observation is that the host immune response sometimes might prevent establishment of HIV infection after a percutaneous exposure; another is that the CTL response simply might be a marker for exposure. In a study of 20 HCP with occupational exposure to HIV, a comparison was made of HCP treated with zidovudine (ZDV) PEP and those not treated. The findings from this study suggest that ZDV blunted the HIV-specific CTL response and that PEP might inhibit early HIV replication (109 ). # Rationale for HIV PEP Considerations that influence the rationale and recommendations for PEP include • the pathogenesis of HIV infection, particularly the time course of early infection; • the biological plausibility that infection can be prevented or ameliorated by using antiretroviral drugs; • direct or indirect evidence of the efficacy of specific agents used for prophylaxis; and • the risk and benefit of PEP to exposed HCP. The following discussion considers each of these concerns. # Role of Pathogenesis in Considering Antiretroviral Prophylaxis. Information about primary HIV infection indicates that systemic infection does not occur immediately, leaving a brief window of opportunity during which postexposure antiretroviral intervention might modify or prevent viral replication. In a primate model of simian immunodeficiency virus (SIV) infection, infection of dendritic-like cells occurred at the site of inoculation during the first 24 hours following mucosal exposure to cell-free virus. Over the subsequent 24-48 hours, migration of these cells to regional lymph nodes occurred, and virus was detectable in the peripheral blood within 5 days (110 ). Theoretically, initiation of antiretroviral PEP soon after exposure might prevent or inhibit systemic infection by limiting the proliferation of virus in the initial target cells or lymph nodes. Efficacy of Antiretrovirals for PEP in Animal Studies. Data from animal studies have been difficult to interpret, in part, because of problems identifying an animal model that is comparable to humans. In early studies, differences in controlled variables (e.g., choice of viral strain [based on the animal model used], inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen) made extrapolation of the results to humans difficult. Recently, refinements in methodology have facilitated more relevant studies; in particular, the viral inocula used in animal studies have been reduced to levels more analogous to human exposures but sufficient to cause infection in control animals (111)(112)(113). These studies provide encouraging evidence of postexposure chemoprophylactic efficacy. Studies among primates and in murine and feline animal models have demonstrated that larger viral inocula decrease prophylactic efficacy (114)(115)(116)(117). In addition, delaying initiation, shortening the duration, or decreasing the antiretroviral dose of PEP, individually or in combination, decreased prophylactic efficacy (113,(118)(119)(120)(121)(122)(123)(124). For example, when (R)-9-(2-phosphonylmethoxypropyl) adenine (tenofovir) was administered 48 hours before, 4 hours after, or 24 hours after intravenous SIV inoculation to long-tailed macaques, a 4-week regimen prevented infection in all treated animals (122 ). A subsequent study confirmed the efficacy of tenofovir PEP when administered 24 hours after intravenous inoculation of a dose of SIV that uniformly results in infection in untreated macaques. In the same study, protection was incomplete if the tenofovir administration was delayed to 48 or 72 hours postexposure or if the total duration of treatment was curtailed to 3 or 10 days (123 ). Efficacy of Antiretrovirals for PEP in Human Studies. Little information exists from which the efficacy of PEP in humans can be assessed. Seroconversion is infrequent following an occupational exposure to HIV-infected blood; therefore, several thousands of exposed HCP would need to enroll in a prospective trial to achieve the statistical power necessary to directly demonstrate PEP efficacy (125 ). In the retrospective case-control study of HCP, after controlling for other risk factors for HIV transmission, use of ZDV as PEP was associated with a reduction in the risk of HIV infection by approximately 81% (95% CI = 43%-94%) (100 ). Although the results of this study suggest PEP efficacy, its limitations include the small number of cases studied and the use of cases and controls from different cohorts. In a multicenter trial in which ZDV was administered to HIV-infected pregnant women and their infants, the administration of ZDV during pregnancy, labor, and delivery and to the infant reduced transmission by 67% (126 ). Only part of the protective effect of ZDV was explained by reduction of the HIV viral load in the maternal blood, suggesting that ZDV prophylaxis, in part, involves a mechanism other than the reduction of maternal viral burden (127,128 ). Since 1998, studies have highlighted the importance of PEP for prevention of perinatal HIV transmission. In Africa, the use of ZDV in combination with lamivudine (3TC) decreased perinatal HIV transmission by 50% when administered during pregnancy, labor, and for 1 week postpartum, and by 37% when started at the onset of labor and continued for 1 week postpartum (129 ). Studies in the United States and Uganda also have demonstrated that rates of perinatal HIV transmission have been reduced with the use of abbreviated PEP regimens started intrapartum or during the first 48-72 hours of life (130)(131)(132). The limitations of all of these studies with animals and humans must be considered when reviewing evidence of PEP efficacy. The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for motherto-infant HIV transmission is not similar to occupational exposures; therefore, these findings might not be directly applicable to PEP in HCP. Reports of Failure of PEP. Failure of PEP to prevent HIV infection in HCP has been reported in at least 21 instances (78,(133)(134)(135)(136)(137)(138)(139). In 16 of the cases, ZDV was used alone as a single agent; in two cases, ZDV and didanosine (ddI) were used in combination (133,138 ); and in three cases, >3 drugs were used for PEP (137)(138)(139). Thirteen of the source persons were known to have been treated with antiretroviral therapy before the exposure. Antiretroviral resistance testing of the virus from the source person was performed in seven instances, and in four, the HIV infection transmitted was found to have decreased sensitivity to ZDV and/or other drugs used for PEP. In addition to possible exposure to an antiretroviral-resistant strain of HIV, other factors that might have contributed to these apparent failures might include a high titer and/or large inoculum exposure, delayed initiation and/or short duration of PEP, and possible factors related to the host (e.g., cellular immune system responsiveness) and/or to the source person's virus (e.g., presence of syncytia-forming strains) (133 ). Details regarding the cases of PEP failure involving combinations of antiretroviral agents are included in this report (Table 1). # Antiretroviral Agents for PEP Antiretroviral agents from three classes of drugs are available for the treatment of HIV infection. These agents include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Only antiretroviral agents that have been approved by FDA for treatment of HIV infection are discussed in these guidelines. Determining which agents and how many to use or when to alter a PEP regimen is largely empiric. Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, include recommendations for the use of three drugs (140 ); however, the applicability of these recommendations to PEP remains unknown. In HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance (141,142 ). A combination of drugs with activity at different stages in the viral replication cycle (e.g., nucleoside analogues with a PI) theoretically could offer an additional preventive effect in PEP, particularly for occupational exposures that pose an increased risk of transmission. Although the use of a threedrug regimen might be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third drug is justified for lower-risk exposures is uncertain. Therefore, the recommendations at the end of this document provide guidance for two-and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure. NRTI combinations that can be considered for PEP include ZDV and 3TC, 3TC and stavudine (d4T), and ddI and d4T. In previous PHS guidelines, a combination of ZDV and 3TC was considered the first choice for PEP regimens (3 ). Because ZDV and 3TC are available in a combination formulation (Combivir™, manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of this combination might be more convenient for HCP. However, recent data suggest that mutations associated with ZDV and 3TC resistance might be common in some areas (143 ). Thus, individual clinicians might prefer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease. The addition of a third drug for PEP following high-risk exposures is based on demonstrated effectiveness in reducing viral burden in HIV-infected persons. Previously, indinavir (IDV) or nelfinavir (NFV) were recommended as first-choice agents for inclusion in an expanded PEP regimen (5 ). Since the publication of the 1998 PEP guidelines, efavirenz (EFV), an NNRTI; abacavir (ABC), a potent NRTI; and Kaletra™, a PI, have been approved by FDA. Although side effects might be common with the NNRTIs, EFV might be considered for expanded PEP regimens, especially when resistance to PIs in the source person's virus is known or suspected. ABC has been associated with dangerous hypersensitivity reactions but, with careful monitoring, may be considered as a third drug for PEP. Kaletra, a combination of lopinavir and ritonavir, is a potent HIV inhibitor that, with expert consultation, may be considered in an expanded PEP regimen. Toxicity and Drug Interactions of Antiretroviral Agents. When administering PEP, an important goal is completion of a 4-week PEP regimen when PEP is indicated. Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration. All of the antiretroviral agents have been associated with side effects (Table 2). However, studies of adverse events have been conducted primarily with persons who have advanced disease (and longer treatment courses) and who therefore might not reflect the experience in persons who are uninfected (144 ). Several primary side effects are associated with antiretroviral agents (Table 2). Side effects associated with many of the NRTIs are chiefly gastrointestinal (e.g., nausea or diarrhea); however, ddI has been associated with cases of fatal and nonfatal pancreatitis among HIV-infected patients treated for >4 weeks. The use of PIs has been associated with new onset diabetes mellitus, hyperglycemia, diabetic ketoacidosis, exacerbation of preexisting diabetes mellitus, and dyslipidemia (145)(146)(147). Nephrolithiasis has been associated with IDV use; however, the incidence of this potential complication might be limited by drinking at least 48 ounces (1.5 L) of fluid per 24-hour period (e.g., six 8-ounce glasses of water throughout the day) (148 ). NFV has been associated with the development of diarrhea; however, this side effect might respond to treatment with antimotility agents that can be prescribed for use, if necessary, at the time the drug is recommended for PEP. The NNRTIs have been associated with severe skin reactions, including lifethreatening cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepatotoxicity, including fatal hepatic necrosis, has occurred in patients treated with nevirapine (NVP); some episodes began during the first few weeks of therapy (FDA, unpublished data, 2000). EFV has been associated with central nervous system side effects, including dizziness, somnolence, insomnia, and abnormal dreaming. All of the approved antiretroviral agents might have potentially serious drug interactions when used with certain other drugs (Appendix C). Careful evaluation of concomitant medications used by an exposed person is required before PEP is prescribed, and close monitoring for toxicity is also needed. Further information about potential drug interactions can be found in the manufacturer's package insert. Toxicity Associated with PEP. Information from the National Surveillance System for Health Care Workers (NaSH) and the HIV Postexposure Registry indicates that nearly 50% of HCP experience adverse symptoms (e.g., nausea, malaise, headache, anorexia, and headache) while taking PEP and that approximately 33% stop taking PEP because of adverse signs and symptoms (6,7,10,11 ). Some studies have demonstrated that side effects and discontinuation of PEP are more common among HCP taking three-drug (149 ). Participants in the San Francisco Project were followed at 1, 2, 4, 26, and 52 weeks postexposure and received medication adherence counseling; most participants took only two drugs for PEP. Serious side effects, including nephrolithiasis, hepatitis, and pancytopenia have been reported with the use of combination drugs for PEP (6,7,150,151 ). One case of NVPassociated fulminant liver failure requiring liver transplantation and one case of hypersensitivity syndrome have been reported in HCP taking NVP for HIV PEP (152 ). Including these two cases, from March 1997 through September 2000, FDA received reports of 22 cases of serious adverse events related to NVP taken for PEP (153 ). These events included 12 cases of hepatotoxicity, 14 cases of skin reaction (including one documented and two possible cases of Stevens-Johnson syndrome), and one case of rhabdomyolysis; four cases involved both hepatotoxicty and skin reaction, and one case involved both rhabdomyolysis and skin reaction. Resistance to Antiretroviral Agents. Known or suspected resistance of the source virus to antiretroviral agents, particularly to agents that might be included in a PEP regimen, is a concern for persons making decisions about PEP. Resistance to HIV infection occurs with all of the available antiretroviral agents, and cross-resistance within drug classes is frequent (154 ). Recent studies have demonstrated an emergence of drugresistant HIV among source persons for occupational exposures (143,155 ). A study conducted at seven U.S. sites during 1998-1999 found that 16 (39%) of 41 source persons whose virus was sequenced had primary genetic mutations associated with resistance to RTIs, and 4 (10%) had primary mutations associated with resistance to PIs (143 ). In addition, occupational transmission of resistant HIV strains, despite PEP with combination drug regimens, has been reported (137,139 ). In one case, a hospital worker became infected after an HIV exposure despite a PEP regimen that included ddI, d4T, and NVP (139 ). The transmitted HIV contained two primary genetic mutations associated with resistance to NNRTIs (the source person was taking EFV at the time of the exposure). Despite recent studies and case reports, the relevance of exposure to a resistant virus is still not well understood. Empiric decisions about the presence of antiretroviral drug resistance are often difficult to make because patients generally take more than one antiretroviral agent. Resistance should be suspected in source persons when they are experiencing clinical progression of disease or a persistently increasing viral load, and/or decline in CD4 T-cell count, despite therapy or a lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because the results will not be available in time to influence the choice of the initial PEP regimen. Furthermore, in this situation, whether modification of the PEP regimen is necessary or will influence the outcome of an occupational exposure is unknown. No data exist to suggest that modification of a PEP regimen after receiving results from resistance testing (usually a minimum of 1-2 weeks) improves efficacy of PEP. Antiretroviral Drugs During Pregnancy. Data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (156 ). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDAlicensed NRTIs. The relevance of animal data to humans is unknown; however, because teratogenic effects were observed in primates at drug exposures similar to those representing human therapeutic exposure, the use of EFV should be avoided in pregnant women (140 ). IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for a newborn. Because the half-life of IDV in adults is short, these concerns might be relevant only if the drug is administered shortly before delivery. In a recent study in France of perinatal HIV transmission, two cases of progressive neurologic disease and death were reported in uninfected infants exposed to ZDV and 3TC (157 ). Laboratory studies of these children suggested mitochondrial dysfunction. In a careful review of deaths in children followed in U.S. perinatal HIV cohorts, no deaths attributable to mitochondrial disease have been found (158 ). Recent reports of fatal and nonfatal lactic acidosis in pregnant women treated throughout gestation with a combination of d4T and ddI have prompted warnings about use of these drugs during pregnancy (159 ). Although the case-patients were HIV-infected women taking the drugs for >4 weeks, pregnant women and their providers should be advised to consider d4T and ddI only when the benefits of their use outweigh the risks. PEP Use in Hospitals in the United States. Analysis of data from NaSH provides information on the use of PEP following occupational exposures in 47 hospitals in the United States. A total of 11,784 exposures to blood and body fluids was reported from June 1996 through November 2000 (CDC, unpublished data, 2001). For all exposures with known sources, 6% were to HIV-positive sources, 74% to HIV-negative sources, and 20% to sources with an unknown HIV status. Sixty-three percent of HCP exposed to a known HIV-positive source started PEP, and 54% of HCP took it for at least 20 days, whereas 14% of HCP exposed to a source person subsequently found to be HIV-negative initiated PEP, and 3% of those took it for at least 20 days. Information recorded about HIV exposures in NaSH indicates that 46% of exposures involving an HIV-positive source warranted only a two-drug PEP regimen (i.e., the exposure was to mucous membranes or skin or was a superficial percutaneous injury and the source person did not have endstage AIDS or acute HIV illness); however, 53% of these exposed HCP took >3 drugs (CDC, unpublished data, 2000). Similarly, the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline) reported that PEPline staff recommended stopping or not starting PEP for approximately one half of the HCP who consulted them about exposures (D. Bangsberg, San Francisco General Hospital, unpublished data, September 1999). The observation that some HCP exposed to HIV-negative source persons take PEP from several days to weeks following their exposures suggests that strategies be employed such as the use of a rapid HIV antibody assay, which could minimize exposure to unnecessary PEP (11 ). A recent study demonstrated that use of a rapid HIV test for evaluation of source persons after occupational exposures not only resulted in decreased use of PEP, but also was cost-effective compared with use of the standard enzyme immunoassay (EIA) test for source persons subsequently found to be HIV-negative (160 ). # RECOMMENDATIONS FOR THE MANAGEMENT OF HCP POTENTIALLY EXPOSED TO HBV, HCV, or HIV Exposure prevention remains the primary strategy for reducing occupational bloodborne pathogen infections; however, occupational exposures will continue to occur. Health-care organizations should make available to their personnel a system that includes written protocols for prompt reporting, evaluation, counseling, treatment, and follow-up of occupational exposures that might place HCP at risk for acquiring a bloodborne infection. HCP should be educated concerning the risk for and prevention of bloodborne infections, including the need to be vaccinated against hepatitis B (17,21,(161)(162)(163). Employers are required to establish exposure-control plans that include postexposure follow-up for their employees and to comply with incident reporting requirements mandated by the 1992 OSHA bloodborne pathogen standard (2 ). Access to clinicians who can provide postexposure care should be available during all working hours, including nights and weekends. HBIG, hepatitis B vaccine, and antiretroviral agents for HIV PEP should be available for timely administration (i.e., either by providing access on-site or by creating linkages with other facilities or providers to make them available off-site). Persons responsible for providing postexposure management should be familiar with evaluation and treatment protocols and the facility's plans for accessing HBIG, hepatitis B vaccine, and antiretroviral drugs for HIV PEP. HCP should be educated to report occupational exposures immediately after they occur, particularly because HBIG, hepatitis B vaccine, and HIV PEP are most likely to be effective if administered as soon after the exposure as possible. HCP who are at risk for occupational exposure to bloodborne pathogens should be familiarized with the principles of postexposure management as part of job orientation and ongoing job training. # Hepatitis B Vaccination Any person who performs tasks involving contact with blood, blood-contaminated body fluids, other body fluids, or sharps should be vaccinated against hepatitis B (2,21 ). Prevaccination serologic screening for previous infection is not indicated for persons being vaccinated because of occupational risk, unless the hospital or health-care organization considers screening cost-effective. Hepatitis B vaccine should always be administered by the intramuscular route in the deltoid muscle with a needle 1-1.5 inches long. Hepatitis B vaccine can be administered at the same time as other vaccines with no interference with antibody response to the other vaccines (164 ). If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least 2 months. If only the third dose is delayed, it should be administered when convenient. HCP who have contact with patients or blood and are at ongoing risk for percutaneous injuries should be tested 1-2 months after completion of the 3-dose vaccination series for anti-HBs (21 ). Persons who do not respond to the primary vaccine series (i.e., anti-HBs <10 mIU/mL) should complete a second 3-dose vaccine series or be evaluated to determine if they are HBsAg-positive. Revaccinated persons should be retested at the completion of the second vaccine series. Persons who do not respond to an initial 3-dose vaccine series have a 30%-50% chance of responding to a second 3-dose series (165 ). Persons who prove to be HBsAg-positive should be counseled regarding how to prevent HBV transmission to others and regarding the need for medical evaluation (12,163,166 ). Nonresponders to vaccination who are HBsAg-negative should be considered susceptible to HBV infection and should be counseled regarding precautions to prevent HBV infection and the need to obtain HBIG prophylaxis for any known or probable parenteral exposure to HBsAg-positive blood. Booster doses of hepatitis B vaccine are not necessary, and periodic serologic testing to monitor antibody concentrations after completion of the vaccine series is not recommended. Any blood or body fluid exposure sustained by an unvaccinated, susceptible person should lead to the initiation of the hepatitis B vaccine series. # Treatment of an Exposure Site Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. No evidence exists that using antiseptics for wound care or expressing fluid by squeezing the wound further reduces the risk of bloodborne pathogen transmission; however, the use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended. # Exposure Report If an occupational exposure occurs, the circumstances and postexposure management should be recorded in the exposed person's confidential medical record (usually on a form the facility designates for this purpose) (Box 1). In addition, employers should follow all federal (including OSHA) and state requirements for recording and reporting occupational injuries and exposures. # BOX 1. Recommendations for the contents of the occupational exposure report • date and time of exposure; • details of the procedure being performed, including where and how the exposure occurred; if related to a sharp device, the type and brand of device and how and when in the course of handling the device the exposure occurred; • details of the exposure, including the type and amount of fluid or material and the severity of the exposure (e.g., for a percutaneous exposure, depth of injury and whether fluid was injected; for a skin or mucous membrane exposure, the estimated volume of material and the condition of the skin [e.g., chapped, abraded, intact]); • details about the exposure source (e.g., whether the source material contained HBV, HCV, or HIV; if the source is HIV-infected, the stage of disease, history of antiretroviral therapy, viral load, and antiretroviral resistance information, if known); • details about the exposed person (e.g., hepatitis B vaccination and vaccine-response status); and • details about counseling, postexposure management, and follow-up. # Evaluation of the Exposure and the Exposure Source Evaluation of the Exposure The exposure should be evaluated for the potential to transmit HBV, HCV, and HIV based on the type of body substance involved and the route and severity of the exposure (Box 2). Blood, fluid containing visible blood, or other potentially infectious fluid (including semen; vaginal secretions; and cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids) or tissue can be infectious for bloodborne viruses. Exposures to these fluids or tissue through a percutaneous injury (i.e., needlestick or other penetrating sharps-related event) or through contact with a mucous membrane are situations that pose a risk for bloodborne virus transmission and require further evaluation. For HCV and HIV, exposure to a blood-filled hollow needle or visibly bloody device suggests a higher risk exposure than exposure to a needle that was most likely used for giving an injection. In addition, any direct contact (i.e, personal protective equipment either was not present or was ineffective in protecting skin or mucous membranes) with concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For skin exposure, follow-up is indicated only if it involves exposure to a body fluid previously listed and evidence exists of compromised skin integrity (e.g., dermatitis, abrasion, or open wound). In the clinical evaluation for human bites, possible exposure of both the person bitten and the person who inflicted the bite must be considered. If a bite results in blood exposure to either person involved, postexposure follow-up should be provided. # BOX 2. Factors to consider in assessing the need for follow-up of occupational exposures # Evaluation of the Exposure Source The person whose blood or body fluid is the source of an occupational exposure should be evaluated for HBV, HCV, and HIV infection (Box 3). Information available in the medical record at the time of exposure (e.g., laboratory test results, admitting diagnosis, or previous medical history) or from the source person, might confirm or exclude bloodborne virus infection. If the HBV, HCV, and/or HIV infection status of the source is unknown, the source person should be informed of the incident and tested for serologic evidence of bloodborne virus infection. Procedures should be followed for testing source persons, including obtaining informed consent, in accordance with applicable state and local laws. Any persons determined to be infected with HBV, HCV, or HIV should be referred for appropriate counseling and treatment. Confidentiality of the source person should be maintained at all times. Testing to determine the HBV, HCV, and HIV infection status of an exposure source should be performed as soon as possible. Hospitals, clinics and other sites that manage exposed HCP should consult their laboratories regarding the most appropriate test to use to expedite obtaining these results. An FDA-approved rapid HIV-antibody test kit should be considered for use in this situation, particularly if testing by EIA cannot be completed within 24-48 hours. Repeatedly reactive results by EIA or rapid HIV-antibody tests are considered to be highly suggestive of infection, whereas a negative result is an excellent indicator of the absence of HIV antibody. Confirmation of a reactive result by Western blot or immunofluorescent antibody is not necessary to make initial decisions about postexposure management but should be done to complete the testing process and before informing the source person. Repeatedly reactive results by EIA for anti-HCV should be confirmed by a supplemental test (i.e., recombinant immunoblot assay [RIBA™] or HCV PCR). Direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA or HCV RNA) for routine HIV or HCV screening of source persons are not recommended. If the exposure source is unknown or cannot be tested, information about where and under what circumstances the exposure occurred should be assessed epidemiologically for the likelihood of transmission of HBV, HCV, or HIV. Certain situations as well as the type of exposure might suggest an increased or decreased risk; an important consideration is the prevalence of HBV, HCV, or HIV in the population group (i.e., institution or community) from which the contaminated source material is derived. For example, an exposure that occurs in a geographic area where injection-drug use is prevalent or involves a needle discarded in a drug-treatment facility would be considered epidemiologically to have a higher risk for transmission than an exposure that occurs in a nursing home for the elderly. Testing of needles or other sharp instruments implicated in an exposure, regardless of whether the source is known or unknown, is not recommended. The reliability and interpretation of findings in such circumstances are unknown, and testing might be hazardous to persons handling the sharp instrument. Examples of information to consider when evaluating an exposure source for possible HBV, HCV, or HIV infection include laboratory information (e.g., previous HBV, HCV, or HIV test results or results of immunologic testing [e.g., CD4+ T-cell count]) or liver enzymes (e.g., ALT), clinical symptoms (e.g., acute syndrome suggestive of primary HIV infection or undiagnosed immunodeficiency disease), and history of recent (i.e., within 3 months) possible HBV, HCV, or HIV exposures (e.g., injection-drug use or sexual contact with a known positive partner). Health-care providers should be aware of local and state laws governing the collection and release of HIV serostatus information on a source person, following an occupational exposure. If the source person is known to have HIV infection, available information about this person's stage of infection (i.e., asymptomatic, symptomatic, or AIDS), CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic or phenotypic viral resistance testing should be gathered for consideration in choosing an appropriate PEP regimen. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of exposed HCP should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. If the source person is HIV seronegative and has no clinical evidence of AIDS or symptoms of HIV infection, no further testing of the person for HIV infection is indicated. The likelihood of the source person being in the "window period" of HIV infection in the absence of symptoms of acute retroviral syndrome is extremely small. # BOX 3. Evaluation of occupational exposure sources # Known sources • Test known sources for HBsAg, anti-HCV, and HIV antibody -Direct virus assays for routine screening of source patients are not recommended -Consider using a rapid HIV-antibody test -If the source person is not infected with a bloodborne pathogen, baseline testing or further follow-up of the exposed person is not necessary • For sources whose infection status remains unknown (e.g., the source person refuses testing), consider medical diagnoses, clinical symptoms, and history of risk behaviors • Do not test discarded needles for bloodborne pathogens # Unknown sources • For unknown sources, evaluate the likelihood of exposure to a source at high risk for infection -Consider likelihood of bloodborne pathogen infection among patients in the exposure setting # Management of Exposures to HBV For percutaneous or mucosal exposures to blood, several factors must be considered when making a decision to provide prophylaxis, including the HBsAg status of the source and the hepatitis B vaccination and vaccine-response status of the exposed person. Such exposures usually involve persons for whom hepatitis B vaccination is recommended. # MMWR 21 Any blood or body fluid exposure to an unvaccinated person should lead to initiation of the hepatitis B vaccine series. The hepatitis B vaccination status and the vaccine-response status (if known) of the exposed person should be reviewed. A summary of prophylaxis recommendations for percutaneous or mucosal exposure to blood according to the HBsAg status of the exposure source and the vaccination and vaccine-response status of the exposed person is included in this report (Table 3). When HBIG is indicated, it should be administered as soon as possible after exposure (preferably within 24 hours). The effectiveness of HBIG when administered >7 days after exposure is unknown. When hepatitis B vaccine is indicated, it should also be administered as soon as possible (preferably within 24 hours) and can be administered simultaneously with HBIG at a separate site (vaccine should always be administered in the deltoid muscle). For exposed persons who are in the process of being vaccinated but have not completed the vaccination series, vaccination should be completed as scheduled, and HBIG should be added as indicated (Table 3). Persons exposed to HBsAg-positive blood or body fluids who are known not to have responded to a primary vaccine series should receive a single dose of HBIG and reinitiate the hepatitis B vaccine series with the first dose of the hepatitis B vaccine as soon as possible after exposure. Alternatively, they should receive two doses of HBIG, one dose as soon as possible after exposure, and the second dose 1 month later. The option of administering one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who did not complete a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred. # Management of Exposures to HCV Individual institutions should establish policies and procedures for testing HCP for HCV after percutaneous or mucosal exposures to blood and ensure that all personnel are familiar with these policies and procedures. The following are recommendations for follow-up of occupational HCV exposures: • For the source, perform testing for anti-HCV. • For the person exposed to an HCV-positive source -perform baseline testing for anti-HCV and ALT activity; and -perform follow-up testing (e.g., at 4-6 months) for anti-HCV and ALT activity (if earlier diagnosis of HCV infection is desired, testing for HCV RNA may be performed at 4-6 weeks). • Confirm all anti-HCV results reported positive by enzyme immunoassay using supplemental anti-HCV testing (e.g., recombinant immunoblot assay [RIBA™]) . Health-care professionals who provide care to persons exposed to HCV in the occupational setting should be knowledgeable regarding the risk for HCV infection and appropriate counseling, testing, and medical follow-up. IG and antiviral agents are not recommended for PEP after exposure to HCV-positive blood. In addition, no guidelines exist for administration of therapy during the acute * Persons who have previously been infected with HBV are immune to reinfection and do not require postexposure prophylaxis. † Hepatitis B surface antigen. § Hepatitis B immune globulin; dose is 0.06 mL/kg intramuscularly. ¶ Hepatitis B vaccine. A responder is a person with adequate levels of serum antibody to HBsAg (i.e., anti-HBs >10 mIU/mL). † † A nonresponder is a person with inadequate response to vaccination (i.e., serum anti-HBs < 10 mIU/mL). § § The option of giving one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who have not completed a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred. ¶ ¶ Antibody to HBsAg. phase of HCV infection. However, limited data indicate that antiviral therapy might be beneficial when started early in the course of HCV infection. When HCV infection is identified early, the person should be referred for medical management to a specialist knowledgeable in this area. # Counseling for HCP Exposed to Viral Hepatitis HCP exposed to HBV-or HCV-infected blood do not need to take any special precautions to prevent secondary transmission during the follow-up period (12,13 ); however, they should refrain from donating blood, plasma, organs, tissue, or semen. The exposed person does not need to modify sexual practices or refrain from becoming pregnant. If an exposed woman is breast feeding, she does not need to discontinue. No modifications to an exposed person's patient-care responsibilities are necessary to prevent transmission to patients based solely on exposure to HBV-or HCV-positive blood. If an exposed person becomes acutely infected with HBV, the person should be evaluated according to published recommendations for infected HCP (165 ). No recommendations exist regarding restricting the professional activities of HCP with HCV infection (13 ). As recommended for all HCP, those who are chronically infected with HBV or HCV should follow all recommended infection-control practices, including standard precautions and appropriate use of hand washing, protective barriers, and care in the use and disposal of needles and other sharp instruments (162 ). # Management of Exposures to HIV Clinical Evaluation and Baseline Testing of Exposed HCP HCP exposed to HIV should be evaluated within hours (rather than days) after their exposure and should be tested for HIV at baseline (i.e., to establish infection status at the time of exposure). If the source person is seronegative for HIV, baseline testing or further follow-up of the exposed person normally is not necessary. Serologic testing should be made available to all HCP who are concerned that they might have been occupationally infected with HIV. For purposes of considering HIV PEP, the evaluation also should include information about medications the exposed person might be taking and any current or underlying medical conditions or circumstances (i.e., pregnancy, breast feeding, or renal or hepatic disease) that might influence drug selection. # PEP for HIV The following recommendations (Tables 4 and 5) apply to situations when a person has been exposed to a source person with HIV infection or when information suggests the likelihood that the source person is HIV-infected. These recommendations are based on the risk for HIV infection after different types of exposure and on limited data regarding efficacy and toxicity of PEP. Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity must be carefully considered when prescribing PEP. To assist with the initial management of an HIV exposure, health-care facilities should have drugs for an initial PEP regimen selected and available for use. When possible, these recommendations should be implemented in consultation with persons who have expertise in antiretroviral therapy and HIV transmission (Box 4). consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. † Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). § Unknown source (e.g., a needle from a sharps disposal container). ¶ Less severe (e.g., solid needle and superficial injury). The designation "consider PEP" indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician. † † If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. § § More severe (e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient's artery or vein). consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. § Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). ¶ Unknown source (e.g., splash from inappropriately disposed blood). ** Small volume (i.e., a few drops). † † The designation, "consider PEP," indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician. § § If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. ¶ ¶ Large volume (i.e., major blood splash). # MMWR June 29, 2001 Timing and Duration of PEP. PEP should be initiated as soon as possible. The interval within which PEP should be initiated for optimal efficacy is not known. Animal studies have demonstrated the importance of starting PEP soon after an exposure (111,112,118 ). If questions exist about which antiretroviral drugs to use or whether to use a basic or expanded regimen, starting the basic regimen immediately rather than delaying PEP administration is probably better. Although animal studies suggest that PEP probably is substantially less effective when started more than 24-36 hours postexposure (112,119,122 ), the interval after which no benefit is gained from PEP for humans is undefined. Therefore, if appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours. Initiating therapy after a longer interval (e.g., 1 week) might be considered for exposures that represent an increased risk for transmission. The optimal duration of PEP is unknown. Because 4 weeks of ZDV appeared protective in occupational and animal studies (100,123 ), PEP probably should be administered for 4 weeks, if tolerated. Use of PEP When HIV Infection Status of Source Person is Unknown. If the source person's HIV infection status is unknown at the time of exposure, use of PEP should be decided on a case-by-case basis, after considering the type of exposure and the clinical and/or epidemiologic likelihood of HIV infection in the source (Tables 4 and 5). If these considerations suggest a possibility for HIV transmission and HIV testing of the source person is pending, initiating a two-drug PEP regimen until laboratory results have been obtained and later modifying or discontinuing the regimen accordingly is reasonable. The following are recommendations regarding HIV postexposure prophylaxis: • If indicated, start PEP as soon as possible after an exposure. • Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. • Administer PEP for 4 weeks, if tolerated. • If a source person is determined to be HIV-negative, PEP should be discontinued. PEP for Pregnant HCP. If the exposed person is pregnant, the evaluation of risk of infection and need for PEP should be approached as with any other person who has had an HIV exposure. However, the decision to use any antiretroviral drug during pregnancy should involve discussion between the woman and her health-care provider(s) regarding the potential benefits and risks to her and her fetus. Certain drugs should be avoided in pregnant women. Because teratogenic effects were observed in primate studies, EFV is not recommended during pregnancy. Reports of fatal lactic acidosis in pregnant women treated with a combination of d4T and ddI have prompted warnings about these drugs during pregnancy. Because of the risk of hyperbilirubinemia in newborns, IDV should not be administered to pregnant women shortly before delivery. # Recommendations for the Selection of Drugs for HIV PEP Health-care providers must strive to balance the risk for infection against the potential toxicity of the agent(s) used when selecting a drug regimen for HIV PEP. Because PEP is potentially toxic, its use is not justified for exposures that pose a negligible risk for transmission (Tables 4 and 5). Also, insufficient evidence exists to support recommending a three-drug regimen for all HIV exposures. Therefore, two regimens for PEP are provided (Appendix C): a "basic" two-drug regimen that should be appropriate for most HIV exposures and an "expanded" three-drug regimen that should be used for exposures that pose an increased risk for transmission (Tables 4 and 5). When possible, the regimens should be implemented in consultation with persons who have expertise in antiretroviral treatment and HIV transmission. Most HIV exposures will warrant a two-drug regimen using two nucleoside analogues (e.g., ZDV and 3TC; or 3TC and d4T; or d4T and ddI). The addition of a third drug should be considered for exposures that pose an increased risk for transmission. Selection of the PEP regimen should consider the comparative risk represented by the exposure and information about the exposure source, including history of and response to antiretroviral therapy based on clinical response, CD4+ T-cell counts, viral load measurements, and current disease stage. When the source person's virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended; expert consultation is advised. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. # Follow-up of HCP Exposed to HIV Postexposure Testing. HCP with occupational exposure to HIV should receive followup counseling, postexposure testing, and medical evaluation, regardless of whether they receive PEP. HIV-antibody testing should be performed for at least 6 months postexposure (e.g., at 6 weeks, 12 weeks, and 6 months). Extended HIV follow-up (e.g., for 12 months) is recommended for HCP who become infected with HCV following exposure to a source coinfected with HIV and HCV. Whether extended follow-up is indicated in other circumstances (e.g., exposure to a source coinfected with HIV and HCV in the absence of HCV seroconversion or for exposed persons with a medical history suggesting an impaired ability to develop an antibody response to acute infection) is unclear. Although rare instances of delayed HIV seroconversion have been reported (167,168 ), the infrequency of this occurrence does not warrant adding to the anxiety level of the exposed persons by routinely extending the duration of postexposure follow-up. However, this recommendation should not preclude a decision to extend follow-up in an individual situation based on the clinical judgement of the exposed person's health-care provider. HIV testing should be performed on any exposed person who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure. When HIV infection is identified, the person should be referred to a specialist knowledgeable in the area of HIV treatment and counseling for medical management. HIV-antibody testing with EIA should be used to monitor for seroconversion. The routine use of direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA) to detect infection in exposed HCP generally is not recommended (169 ). The high rate of falsepositive results of these tests in this setting could lead to unnecessary anxiety and/or treatment (170,171 ). Despite the ability of direct virus assays to detect HIV infection a few days earlier than EIA, the infrequency of occupational seroconversion and increased costs of these tests do not warrant their routine use in this setting. • HIV-antibody testing should be performed for at least 6 months postexposure. • Direct virus assays for routine follow-up of HCP are not recommended. • HIV testing should be performed on any exposed person who has an illness compatible with an acute retroviral syndrome. Monitoring and Management of PEP Toxicity. If PEP is used, HCP should be monitored for drug toxicity by testing at baseline and again 2 weeks after starting PEP. The scope of testing should be based on medical conditions in the exposed person and the toxicity of drugs included in the PEP regimen. Minimally, lab monitoring for toxicity should include a complete blood count and renal and hepatic function tests. Monitoring for evidence of hyperglycemia should be included for HCP whose regimens include any PI; if the exposed person is receiving IDV, monitoring for crystalluria, hematuria, hemolytic anemia, and hepatitis also should be included. If toxicity is noted, modification of the regimen should be considered after expert consultation; further diagnostic studies may be indicated. Exposed HCP who choose to take PEP should be advised of the importance of completing the prescribed regimen. Information should be provided to HCP about potential drug interactions and the drugs that should not be taken with PEP, the side effects of the drugs that have been prescribed, measures to minimize these effects, and the methods of clinical monitoring for toxicity during the follow-up period. HCP should be advised that the evaluation of certain symptoms should not be delayed (e.g., rash, fever, back or abdominal pain, pain on urination or blood in the urine, or symptoms of hyperglycemia [increased thirst and/or frequent urination]). HCP who fail to complete the recommended regimen often do so because of the side effects they experience (e.g., nausea and diarrhea). These symptoms often can be managed with antimotility and antiemetic agents or other medications that target the specific symptoms without changing the regimen. In other situations, modifying the dose interval (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), might facilitate adherence to the regimen. Serious adverse events should be reported to FDA's MedWatch Program. Counseling and Education. Although HIV infection following an occupational exposure occurs infrequently, the emotional effect of an exposure often is substantial (172)(173)(174). In addition, HCP are given seemingly conflicting information. Although HCP are told that a low risk exists for HIV transmission, a 4-week regimen of PEP might be recommended, and they are asked to commit to behavioral measures (e.g., sexual abstinence or condom use) to prevent secondary transmission, all of which influence their lives for several weeks to months (172 ). Therefore, access to persons who are knowledgeable about occupational HIV transmission and who can deal with the many concerns an HIV exposure might generate for the exposed person is an important element of postexposure management. HIV-exposed HCP should be advised to use the following measures to prevent secondary transmission during the follow-up period, especially the first 6-12 weeks after the exposure when most HIV-infected persons are expected to seroconvert: exercise sexual abstinence or use condoms to prevent sexual transmission and to avoid pregnancy; and refrain from donating blood, plasma, organs, tissue, or semen. If an exposed woman is breast feeding, she should be counseled about the risk of HIV transmission through breast milk, and discontinuation of breast feeding should be considered, especially for high-risk exposures. Additionally, NRTIs are known to pass into breast milk, as is NVP; whether this also is true for the other approved antiretroviral drugs is unknown. # MMWR 29 The patient-care responsibilities of an exposed person do not need to be modified, based solely on an HIV exposure, to prevent transmission to patients. If HIV seroconversion is detected, the person should be evaluated according to published recommendations for infected HCP (175 ). Exposed HCP should be advised to seek medical evaluation for any acute illness that occurs during the follow-up period. Such an illness, particularly if characterized by fever, rash, myalgia, fatigue, malaise, or lymphadenopathy, might be indicative of acute HIV infection but also might be indicative of a drug reaction or another medical condition. For exposures for which PEP is considered appropriate, HCP should be informed that a) knowledge about the efficacy of drugs used for PEP is limited; b) experts recommend combination drug regimens because of increased potency and concerns about drugresistant virus; c) data regarding toxicity of antiretroviral drugs in persons without HIV infection or in pregnant women are limited; d) although the short-term toxicity of antiretroviral drugs is usually limited, serious adverse events have occurred in persons taking PEP; and e) any or all drugs for PEP may be declined or stopped by the exposed person. HCP who experience HIV occupational exposures for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the negligible risk of transmission posed by the type of exposure. # Guidelines for counseling and educating HCP with HIV exposure include • Exposed HCP should be advised to use precautions to prevent secondary transmission during the follow-up period. • For exposures for which PEP is prescribed, HCP should be informed about possible drug toxicities and the need for monitoring, and possible drug interactions. # Occupational Exposure Management Resources Several resources are available that provide guidance to HCP regarding the management of occupational exposures. These resources include PEPline; the Needlestick! website; the Hepatitis Hotline; CDC (receives reports of occupationally acquired HIV infections and failures of PEP); the HIV Antiretroviral Pregnancy Registry; FDA (receives reports of unusual or severe toxicity to antiretroviral agents); and the HIV/AIDS Treatment Information Service (Box 5). # MMWR June 29, 2001 -Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person. -Nervous system side effects (e.g., dizziness, somnolence, insomnia, and/or abnormal dreaming) are common. Severe psychiatric symptoms are possible (dosing before bedtime might minimize these side effects). -Should not be used during pregnancy because of concerns about teratogenicity. -Concomitant use of astemizole, cisapride, midazolam, triazolam, ergot derivatives, or St. John's Wort is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or lifethreatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). -Potential for oncogenic toxicity is unknown. • Abacavir (ZIAGEN™; ABC); available as TRIZIVIR™, a combination of ZDV, 3TC, and ABC -300 mg twice daily. # Advantages -potent HIV inhibitor, and -well tolerated in patients with HIV infection. # Disadvantages -Severe hypersensitivity reactions can occur, usually within the first 6 weeks of treatment. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. • Amprenavir (AGENERASE™; AMP) # ANTIRETROVIRAL AGENTS FOR USE AS PEP ONLY WITH EXPERT CONSULTATION # Disadvantages -Dosage consists of eight large pills taken twice daily. -Many drug interactions. • Delavirdine (RESCRIPTOR™; DLV) # Disadvantages -Drug is associated with rash (early onset) that can be severe and progress to Stevens-Johnson syndrome. -Many drug interactions. • Lopinavir/Ritonavir (KALETRA™) -400/100 mg twice daily. # Advantages -potent HIV inhibitor, and -well tolerated in patients with HIV infection. # Disadvantages -Concomitant use of flecainide, propafenone, astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). -May accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # ANTIRETROVIRAL AGENTS GENERALLY NOT RECOMMENDED FOR USE AS PEP • Nevirapine (VIRAMUNE™; NVP) -200 mg daily for 2 weeks, then 200 mg twice daily. # MMWR June 29, 2001 • Delayed (i.e., later than 24-36 hours) exposure report -the interval after which there is no benefit from postexposure prophylaxis (PEP) is undefined • Unknown source (e.g., needle in sharps disposal container or laundry) -decide use of PEP on a case-by-case basis -consider the severity of the exposure and the epidemiologic likelihood of HIV exposure -do not test needles or other sharp instruments for HIV • Known or suspected pregnancy in the exposed person -does not preclude the use of optimal PEP regimens -do not deny PEP solely on the basis of pregnancy • Resistance of the source virus to antiretroviral agents -influence of drug resistance on transmission risk is unknown -selection of drugs to which the source person's virus is unlikely to be resistant is recommended, if the source person's virus is known or suspected to be resistant to >1 of the drugs considered for the PEP regimen -resistance testing of the source person's virus at the time of the exposure is not recommended • Toxicity of the initial PEP regimen -adverse symptoms, such as nausea and diarrhea are common with PEP -symptoms often can be managed without changing the PEP regimen by prescribing antimotility and/or antiemetic agents -modification of dose intervals (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), in other situations, might help alleviate symptoms *Local experts and/or the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline [1-888-448-4911] HCF should provide medication adherence counseling to assist HCP in completing HIV PEP as necessary. Monitor for adverse effects HCP taking antiretroviral PEP should be monitored of PEP. periodically for adverse effects of PEP through baseline and testing (every 2 weeks) and clinical evaluation. Monitor for seroconversion. HCF should develop a system to encourage exposed HCP to return for follow-up testing. Exposed HCP should be tested for HCV and HIV. Monitor exposure HCF should develop a system to monitor reporting management programs. and management of occupational exposures to ensure timely and appropriate response. # Evaluate • exposure reports for completeness and accuracy, • access to care (i.e., the time of exposure to the time of evaluation), and • laboratory result reporting time. # Review • exposures to ensure that HCP exposed to sources not infected with bloodborne pathogens do not receive PEP or that PEP is stopped. # Monitor • completion rates of HBV vaccination and HIV PEP and • completion of exposure follow-up. # Practice recommendation Implementation checklist Vol. 50 / No. RR-11 MMWR 45 APPENDIX B. # Management of Occupational Blood Exposures Provide immediate care to the exposure site. • Wash wounds and skin with soap and water. • Flush mucous membranes with water. # Determine risk associated with exposure by • type of fluid (e.g., blood, visibly bloody fluid, other potentially infectious fluid or tissue, and concentrated virus) and • type of exposure (i.e., percutaneous injury, mucous membrane or nonintact skin exposure, and bites resulting in blood exposure). Evaluate exposure source. • Assess the risk of infection using available information. • Test known sources for HBsAg, anti-HCV, and HIV antibody (consider using rapid testing). • For unknown sources, assess risk of exposure to HBV, HCV, or HIV infection. • Do not test discarded needles or syringes for virus contamination. Evaluate the exposed person. • Assess immune status for HBV infection (i.e., by history of hepatitis B vaccination and vaccine response). Give PEP for exposures posing risk of infection transmission. • HBV: See Table 3. • HCV: PEP not recommended. • HIV: See Tables 4 and 5. -Initiate PEP as soon as possible, preferably within hours of exposure. -Offer pregnancy testing to all women of childbearing age not known to be pregnant. -Seek expert consultation if viral resistance is suspected. -Administer PEP for 4 weeks if tolerated. # MMWR June 29, 2001 Perform follow-up testing and provide counseling. • Advise exposed persons to seek medical evaluation for any acute illness occurring during follow-up. # HBV exposures • Perform follow-up anti-HBs testing in persons who receive hepatitis B vaccine. -Test for anti-HBs 1-2 months after last dose of vaccine. -Anti-HBs response to vaccine cannot be ascertained if HBIG was received in the previous 3-4 months. # HCV exposures • Perform baseline and follow-up testing for anti-HCV and alanine aminotransferase (ALT) 4-6 months after exposures. • Perform HCV RNA at 4-6 weeks if earlier diagnosis of HCV infection desired. • Confirm repeatedly reactive anti-HCV enzyme immunoassays (EIAs) with supplemental tests. # HIV exposures • Perform HIV-antibody testing for at least 6 months postexposure (e.g., at baseline, 6 weeks, 3 months, and 6 months). • Perform HIV antibody testing if illness compatible with an acute retroviral syndrome occurs. • Advise exposed persons to use precautions to prevent secondary transmission during the follow-up period. • # Advantages -ZDV is associated with decreased risk of HIV transmission in the CDC casecontrol study of occupational HIV infection. -ZDV has been used more than the other drugs for PEP in HCP. -Serious toxicity is rare when used for PEP. -Side effects are predictable and manageable with antimotility and antiemetic agents. -Probably a safe regimen for pregnant HCP. -Can be given as a single tablet (COMBIVIR™) twice daily. # Disadvantages -Side effects are common and might result in low adherence. -Source patient virus might have resistance to this regimen. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # ALTERNATE BASIC REGIMENS • Lamivudine (3TC) + Stavudine (ZERIT™; d4T) -3TC: 150 mg twice daily, and -d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily. # Advantages -well tolerated in patients with HIV infection, resulting in good adherence, -serious toxicity appears to be rare, and -twice daily dosing might improve adherence. # MMWR June 29, 2001 Disadvantages -Source patient virus might be resistant to this regimen. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. • Didanosine (VIDEX™, chewable/dispersable buffered tablet; VIDEX™ EC, delayed-release capsule; ddI) + Stavudine (d4T) -ddI: 400 mg (if body weight is <60 kg, 125 mg twice daily) daily, on an empty stomach. -d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily. Advantages -Likely to be effective against HIV strains from source patients who are taking ZDV and 3TC. # Disadvantages -ddl is difficult to administer and unpalatable. -Chewable/dispersable buffered tablet formulation of ddI interferes with absorption of some drugs (e.g., quinolone antibiotics, and indinavir). -Serious toxicity (e.g., neuropathy, pancreatitis, or hepatitis) can occur. Fatal and nonfatal pancreatitis has occurred in HIV-positive, treatment-naive patients. Patients taking ddI and d4T should be carefully assessed and closely monitored for pancreatitis, lactic acidosis, and hepatitis. -Side effects are common; anticipate diarrhea and low adherence. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. # EXPANDED REGIMEN Basic regimen plus one of the following: • Indinavir (CRIXIVAN™; IDV) -800 mg every 8 hours, on an empty stomach. # Advantages -Potent HIV inhibitor. # Disadvantages -Serious toxicity (e.g., nephrolithiasis) can occur; must take 8 glasses of fluid per day. -Hyperbilirubinemia common; must avoid this drug during late pregnancy. -Requires acid for absorption and cannot be taken simultaneously with ddI in chewable/dispersable buffered tablet formulation (doses must be separated by at least 1 hour). -Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. • Nelfinavir (VIRACEPT™; NFV) -750 mg three times daily, with meals or snack, or -1250 mg twice daily, with meals or snack. # Advantages -potent HIV inhibitor, and -twice dosing per day might improve adherence. # Disadvantages -Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John's Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. -Might accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). -Potential for delayed toxicity (oncogenic/teratogenic) is unknown. • Efavirenz (SUSTIVA™; EFV) -600 mg daily, at bedtime. # Advantages -Does not require phosphorylation before activation and might be active earlier than other antiretroviral agents (note: this might be only a theoretical advantage of no clinical benefit.) -One dose daily might improve adherence. # Disadvantages -Drug is associated with rash (early onset) that can be severe and might rarely progress to Stevens-Johnson syndrome. # Disadvantages -Associated with severe hepatotoxicity (including at least one case of liver failure requiring liver transplantation in an exposed person taking PEP), -Associated with rash (early onset) that can be severe and progress to Stevens-Johnson syndrome, -Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person, and -Concomitant use of St. John's Wort is not recommended because this might result in suboptimal antiretroviral drug concentrations. # ACCREDITATION # Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.75 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards .15 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 # MMWR June 29, 2001 # GOALS and OBJECTIVES: The MMWR provides recommendations regarding the guidance of clinical practice and policy development related to the management of occupational exposures to blood and bloodborne pathogens, including the appropriate use of postexposure prophylaxis (PEP). Upon completion of this educational activity, the reader should be able to a) describe the management process following an occupational exposure to blood; b) describe the evaluation of the exposure and assessment of the risk for bloodborne pathogen transmission; c) describe appropriate laboratory evaluation of the exposed worker and source person; d) describe appropriate selection and use of PEP; and e) describe the follow-up evaluation and counseling of exposed health-care personnel (HCP). To receive continuing education credit, please answer all of the following questions. # Factors to consider in assessing the need for follow-up after an occupational exposure include A. The type of exposure. B. The type of fluid. C. The bloodborne pathogen infection status of the source. D. The susceptibility of the exposed. E. All of the above. F. None of the above. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/mmwr/ or from CDC's file transfer protocol server at ftp://ftp.cdc.gov/pub/Publications/mmwr/. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # IU.S. Government Printing Office: 2001-633-173/48237 Region IV	None	None
acd3525986da06238db446a165df3510296d17d8	cdc	None	The purpose of this Compendium is to provide rabies information to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies control program. This document is reviewed annually and revised as necessary. Immunization procedure recommendations are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control.# B. Vaccine Selection In comprehensive rabies control programs, only vaccines with a 3-year duration of immunity should be used. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population. (See Part II.) # C. Route of Inoculation All vaccines must be administered in accordance with the specifications of the product label or package insert. If administered intramuscularly, it must be at one site in the thigh. # D. Wildlife Vaccination Vaccination of wildlife is not recommended since no rabies vaccine is licensed for wild animals. Because of their susceptibility to rabies, neither wild nor exotic carnivores, nor bats should be kept as pets. Hybrids (offspring of wild animals bred with domestic dogs or cats) are considered wild animals. # E. Accidental Human Exposure to Vaccine Accidental inoculation may occur during administration of animal rabies vaccine. Such exposure to inactivated vaccines constitutes no rabies hazard. # F. Identification of Vaccinated Animals All agencies and veterinarians should adopt the standard tag system. This practice will aid the administration of local, state, national, and international control procedures. Animal license tags should be distinguishable in shape and color from rabies tags. Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. a. Licensure. Registration or licensure of all dogs and cats may be used to control rabies. A fee is frequently charged for such licensure and revenues collected are used to maintain rabies or animal control programs. Vaccination is an essential prerequisite to licensure. # Rabies Tags b. Canvassing of Area. House-to-house canvassing by animal control personnel facilitates enforcement of vaccination and licensure requirements. c. Citations. Citations are legal summonses issued to owners for violations, including the failure to vaccinate or license their animals. The authority for officers to issue citations should be an integral part of each animal control program. d. Animal Control. All communities should incorporate stray animal control, leash laws, and training of personnel in their programs. 5. Postexposure Management. Any animal bitten or scratched by a wild, carnivorous mammal (or a bat) not available for testing should be regarded as having been exposed to rabies. a. Dogs and Cats. Unvaccinated dogs and cats bitten by a rabid animal should be euthanized immediately. If the owner is unwilling to have this done, the animal should be placed in strict isolation for 6 months and vaccinated 1 month before being released. Dogs and cats that are currently vaccinated should be revaccinated immediately and confined and observed for 90 days. b. Livestock. All species of livestock are susceptible to rabies; cattle and horses are among the most frequently infected of all domestic animals. Livestock bitten by a rabid animal and currently vaccinated with a vaccine approved by USDA for that species should be revaccinated immediately and observed for 90 days. Unvaccinated livestock should be slaughtered immediately. If the owner is unwilling to have this done, the animal should be kept under very close observation for 6 months. The following are recommendations for owners of unvaccinated livestock exposed to rabid animals: 1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk of infection, provided liberal portions of the exposed area are discarded. Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months. 2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption. However, since pasteurization temperatures will inactivate rabies virus, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure. 3) It is rare to have more than one rabid animal in a herd, or herbivore to herbivore transmission, and therefore it may not be necessary to restrict the rest of the herd if a single animal has been exposed to or infected by rabies. c. Other Animals. Other animals bitten by a rabid animal should be euthanized immediately. Such animals currently vaccinated with a vaccine approved by USDA for that species may be revaccinated immediately and placed in strict isolation for at least 90 days. 6. Management of Animals that Bite Humans. A healthy dog or cat that bites a person should be confined and observed for 10 days; it is recommended that rabies vaccine not be administered during the observation period. Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be humanely killed, its head removed, and the head shipped under refrigeration for examination by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog or cat that bites a person may be humanely killed immediately and the head submitted as described above for rabies examination. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Prior vaccination of an animal may not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species. Management of animals other than dogs and cats depends on the species, the circumstances of the bite, and the epidemiology of rabies in the area. # C. Control Methods in Wild Animals The public should be warned not to handle wild animals. Wild carnivorous mammals and bats (as well as the offspring of wild animals crossbred with domestic dogs and cats) that bite people should be humanely killed and the head submitted for rabies examination. A person bitten by any wild animal should immediately report the incident to a physician who can evaluate the need for antirabies treatment. (See current rabies prophylaxis recommendations of the ACIP.) 1. Terrestrial Mammals. Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis. However, limited control in high-contact areas (picnic grounds, camps, suburban areas) may be indicated for the removal of selected high-risk species of wild animals. The state wildlife agency and state health department should be consulted for coordination of any proposed population reduction programs. 2. Bats a. Indigenous rabid bats have been reported from every state except Alaska and Hawaii and have caused rabies in at least 18 humans in the United States. It is neither feasible nor desirable, however, to control rabies in bats by programs to reduce bat populations. b. Bats should be excluded from houses and surrounding structures to prevent direct association with humans. Such structures should then be made batproof by sealing entrances used by bats.	The purpose of this Compendium is to provide rabies information to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies control program. This document is reviewed annually and revised as necessary. Immunization procedure recommendations are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control.# B. Vaccine Selection In comprehensive rabies control programs, only vaccines with a 3-year duration of immunity should be used. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population. (See Part II.) # C. Route of Inoculation All vaccines must be administered in accordance with the specifications of the product label or package insert. If administered intramuscularly, it must be at one site in the thigh. # D. Wildlife Vaccination Vaccination of wildlife is not recommended since no rabies vaccine is licensed for wild animals. Because of their susceptibility to rabies, neither wild nor exotic carnivores, nor bats should be kept as pets. Hybrids (offspring of wild animals bred with domestic dogs or cats) are considered wild animals. # E. Accidental Human Exposure to Vaccine Accidental inoculation may occur during administration of animal rabies vaccine. Such exposure to inactivated vaccines constitutes no rabies hazard. # F. Identification of Vaccinated Animals All agencies and veterinarians should adopt the standard tag system. This practice will aid the administration of local, state, national, and international control procedures. Animal license tags should be distinguishable in shape and color from rabies tags. Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. a. Licensure. Registration or licensure of all dogs and cats may be used to control rabies. A fee is frequently charged for such licensure and revenues collected are used to maintain rabies or animal control programs. Vaccination is an essential prerequisite to licensure. # Rabies Tags b. Canvassing of Area. House-to-house canvassing by animal control personnel facilitates enforcement of vaccination and licensure requirements. c. Citations. Citations are legal summonses issued to owners for violations, including the failure to vaccinate or license their animals. The authority for officers to issue citations should be an integral part of each animal control program. d. Animal Control. All communities should incorporate stray animal control, leash laws, and training of personnel in their programs. 5. Postexposure Management. Any animal bitten or scratched by a wild, carnivorous mammal (or a bat) not available for testing should be regarded as having been exposed to rabies. a. Dogs and Cats. Unvaccinated dogs and cats bitten by a rabid animal should be euthanized immediately. If the owner is unwilling to have this done, the animal should be placed in strict isolation for 6 months and vaccinated 1 month before being released. Dogs and cats that are currently vaccinated should be revaccinated immediately and confined and observed for 90 days. b. Livestock. All species of livestock are susceptible to rabies; cattle and horses are among the most frequently infected of all domestic animals. Livestock bitten by a rabid animal and currently vaccinated with a vaccine approved by USDA for that species should be revaccinated immediately and observed for 90 days. Unvaccinated livestock should be slaughtered immediately. If the owner is unwilling to have this done, the animal should be kept under very close observation for 6 months. The following are recommendations for owners of unvaccinated livestock exposed to rabid animals: 1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk of infection, provided liberal portions of the exposed area are discarded. Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months. 2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption. However, since pasteurization temperatures will inactivate rabies virus, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure. 3) It is rare to have more than one rabid animal in a herd, or herbivore to herbivore transmission, and therefore it may not be necessary to restrict the rest of the herd if a single animal has been exposed to or infected by rabies. c. Other Animals. Other animals bitten by a rabid animal should be euthanized immediately. Such animals currently vaccinated with a vaccine approved by USDA for that species may be revaccinated immediately and placed in strict isolation for at least 90 days. 6. Management of Animals that Bite Humans. A healthy dog or cat that bites a person should be confined and observed for 10 days; it is recommended that rabies vaccine not be administered during the observation period. Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be humanely killed, its head removed, and the head shipped under refrigeration for examination by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog or cat that bites a person may be humanely killed immediately and the head submitted as described above for rabies examination. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Prior vaccination of an animal may not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species. Management of animals other than dogs and cats depends on the species, the circumstances of the bite, and the epidemiology of rabies in the area. # C. Control Methods in Wild Animals The public should be warned not to handle wild animals. Wild carnivorous mammals and bats (as well as the offspring of wild animals crossbred with domestic dogs and cats) that bite people should be humanely killed and the head submitted for rabies examination. A person bitten by any wild animal should immediately report the incident to a physician who can evaluate the need for antirabies treatment. (See current rabies prophylaxis recommendations of the ACIP.) 1. Terrestrial Mammals. Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis. However, limited control in high-contact areas (picnic grounds, camps, suburban areas) may be indicated for the removal of selected high-risk species of wild animals. The state wildlife agency and state health department should be consulted for coordination of any proposed population reduction programs. 2. Bats a. Indigenous rabid bats have been reported from every state except Alaska and Hawaii and have caused rabies in at least 18 humans in the United States. It is neither feasible nor desirable, however, to control rabies in bats by programs to reduce bat populations. b. Bats should be excluded from houses and surrounding structures to prevent direct association with humans. Such structures should then be made batproof by sealing entrances used by bats.	None	None
eddf5fa664d1a96ef76355f72210d67e4db19982	cdc	None	NOTE: Self-evident statements were not rated(see statements below) Statement 1: "MSM may choose to be circumcised despite i.e. the lack of definitive evidence of circumcision decreasing the risk for the insertive anal sex partner of acquiring HIV infection, but male circumcision involves potential risks (see Adverse Events section of Box 1) and costs." Statement 2: "However, current risks for either HIV or other non-HIV STIs may not remain constant in the future and the future risk for any individual neonate child, or adolescent cannot be definitively defined at the time that a circumcision decision is made." Statement 3: "Those who enjoy the sensation of the foreskin during sexual relations will no longer experience that sensation." (after circumcision)# Health benefits and risks of elective neonatal, adolescent, or adult medically performed male circumcision should be considered in consultation with medical providers while taking into account factors associated with decision-making around male circumcision, including religion, societal norms and social customs, hygiene, aesthetic preference, and ethical considerations. See below acquiring HIV and some STIs during penile-vaginal sex. In clinical trials, medically performed male circumcision reduced the incidence of genital ulcer disease (GUD) by 48% and the prevalence by 47%, reduced the prevalence of HR-HPV by 23 -47%, and reduced the incidence of syphilis by 42% among circumcised men. . Siegfried N, Muller M, Deeks J, Volmink J. Male circumcision for Meta-analysis of 3 RCTs HIV incidence (acquisition) Decrease Uganda, South Africa, Kenya AIa The overall relative risk reduction of acquiring HIV was 50% at 12 months and 54% at 21 or 24 months following circumcision prevention of heterosexual acquisition of HIV in men (review). Heterosexual adult males Cochrane database of systematic reviews. 2009;15(2):CD003362. . Byakika-Tusiime J. Circumcision and HIV Infection: Assessment of Meta-analysis of 13 studies HIV incidence (acquisition) Decrease Observational studies: United States, BIIa 61% reduced risk of HIV infection among circumcised men (aRR 0.39, 95% CI 0.27-0.56) Causality. AIDS Behav. 2008;12(6):835-841. Analysis limited to 10 India, Kenya, Malawi, Cote d'Ivoire, observations studies (6 cohort Sengal, Tanzania studies, 1 nested case-control Heterosexual adult males study, 3 case control studies) . Lei JH, Liu LR, Wei Q, et al. Circumcision status and risk of HIV Meta-analysis of 9 studies related HIV incidence (acquisition) Decrease Prospective Cohort Studies: Kenya, BIIa Male circumcision was associated with 70% reduction in the risk for HIV acquisition (pooled adjusted risk ratio 0.40, 95% CI 0.31-0.53) acquisition during heterosexual intercourse for both males and to female-to-male transmission (3 Uganda, India Heterosexual adult females: a meta-analysis. PLOS ONE. 2015;10(5) is biologically plausible Male circumcision has not been shown to reduce the risk of HIV transmission to female partners. However, in clinical trials, medically performed male circumcision reduced the incidence of syphilis by 59%, and reduced the prevalence of GUD by 22%, HR-HPV by 22%, T. vaginalis by 45%, and bacterial vaginosis by 40% among female partners. Weiss HA, Hankins CA, Dickson K. Male circumcision and risk of HIV infection in women: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:669-677. Systematic review and random effects meta-analysis (1 RCT and 6 longitudinal analyses) # HIV acquisition No difference RCT: Uganda Longitudinal studies: 14 sites and southern Africa; Uganda; Zimbabwe, Tanzania in east AIb A systematic review and meta-analysis of the evidence for a direct effect of male circumcision on the risk of women becoming infected with HIV identified 19 epidemiological analyses from 11 study populations. The meta-analysis of data from the 1 RCT and 6 longitudinal analyses showed little evidence that male circumcision directly affects the risk of HIV acquisition in women (RR 0. lower BV prevalence compared to female partners of uncircumcised men (aPRR Male circumcision has also been shown to reduce the risk of urinary tract infections in males aged 0-1 years by 90%, males aged 1-16 years by 85%., and males aged >16 years by 71%. Morris BJ, Wiswell TE. Circumcision and lifetime risk of urinary tract infection: a systematic review and meta-analysis. J Urol. 2013;189( 6 # BIIb Early resumption of sexual relations following male circumcision was significantly associated with higher risk for HIV acquisition among female participants, with a rate ratio versus control of 3.50 (95% CI = 1.14-10.76). Among couples in the immediate male circumcision arm who delayed resumption of sex until after wound healing, there was no significant difference in HIV incidence relative to uncircumcised controls (rate ratio 1. In a vaccine preparedness cohort of MSM followed from 1995 to 1997, circumcision was significantly associated with a decreased risk for HIV seroconversion (aOR = 0.5; 95% CI 0.3-0.9), controlling for number of male sex partners and unprotected sex with an HIV-positive partner . In a crosssectional survey of gay men in Seattle in the early 1990s, circumcision was associated with decreased odds of prevalent HIV infection (aOR = 0.5; 95% CI 0.25-1.0) . While falling short of the quality of data from a randomized intervention trial, these limited data suggest that circumcised MSM in the US may have decreased risk of HIV infection. However, it is possible that the noted associations in these two observational studies were related to uncontrolled bias. A small cross-sectional study of Australian MSM found no association between circumcision status and risk of HIV infection, when stratifying by insertive and receptive roles . Row no. CIIIb . When providing information to parents about male circumcision for an adolescent minor, the adolescent should be included in the decision-making process about undergoing elective male circumcision. When counseling an adolescent inquiring about male circumcision, parents should be engaged in the discussion, unless the adolescent is legally emancipated. Minors may be deemed emancipated, giving them sole authority to make health care decisions on their own behalf under certain circumstances, which vary by state law; for example, if the minor 1) lives independently and is self-supporting, 2) is married, 3) is pregnant or a parent, 4) is in the military, or 5) is declared emancipated by a court as defined in the mature minor section. # BIIb When estimated by age group, the incidence of probable AEs was 0.40%, 9.06%, and 5.31% for males aged < respectively. The incidence of AEs was 10-20-fold higher for males in older age groups compared with infants. # BIIa In a meta-analysis of 18 studies and 22,919 children mainly from the United States, the pooled prevalence of UTI in infants presenting with fever in outpatient clinics and emergency departments was 7.0% (95% CI = 5.5-8.4), but was as high as 20.1% (95% CI = 16.8-23.4) among febrile uncircumcised males aged < 3 months compared with 2.4% (95% CI = 1.4-3.5) among febrile circumcised males aged < 3 months and with 7.8% (95% CI = 6.6-8.9) among both febrile and afebrile older children aged < 19 years 95 o Complications of medically performed male circumcision in the United States are typically uncommon and easily managed. Severe complications are rare in all age groups and occur in 0.23% of all circumcised males overall. # BIIb Approximately 0.4% of male newborns in the first year of life experienced an adverse event associated with circumcision. Severe complications are rare in all age groups and rates of potentially serious male circumcision adverse events range from 0.8 per million male circumcisions for stricture of male genital organs to 703.2 per million male circumcision for repair of incomplete circumcision. # CIIIb In a review article, data from a myriad of sources were compiled, including personal correspondence, to estimate the following rates of AEs per circumcisions performed in the United States: excessive bleeding requiring ligature, 1 per 4,000; bleeding requiring transfusion, 1 per 20,000; severe infection requiring parenteral antibiotics, 1 per 4,000; subsequent surgery (e.g., for skin bridges), 1 per 1,000; repair of traumatic injury, 1 per 15,000; and loss of entire penis, less than 1 per 1,000,000. There were 3 deaths due to male circumcision during 1954-1989. BIIb "Nine AEs were significantly less likely to occur in circumcised infants compared with uncircumcised infants at P < .05. Circumcised newborn males had a higher risk for wounds, correctional procedures, inflammation, and bleeding compared with uncircumcised newborn males but had a lower risk for surgical procedures, penile disorders and gangrene, pneumothorax, and infections. Among the extremely rare but serious AEs occurring only among circumcised newborns (but once or none among uncircumcised newborns), we found 0 cases of complete amputation of penis, 1 case of stricture of male genital organs, 3 cases of partial amputation of penis, 4 cases of replantation of penis, and 16 cases of suture of artery." o On average, adult men who undergo circumcision generally report minimal or no change in sexual satisfaction or function. Grade-consensus Comments o Some men enjoy the sensation of the foreskin during sexual relations, and such a sensation will not be experienced after circumcision; however, the bulk of scientific evidence states that men on average, do not experience a loss of sexual pleasure or function because of circumcision. # AIb In another systematic review and meta-analysis including 10 studies and 9,317 circumcised men and 9,423 uncircumcised men, there were no significant associations between male circumcision and sexual desire, dyspareunia, premature ejaculation, ejaculation latency time, erectile dysfunction, or orgasm difficulties. AIb IRR 0.55, 95% CI 0.32-0.949 (AT analysis) Note: When men who crossed over from control arm to intervention arm were included in the case arm analysis, the circumcision effect changed from "no difference" (in the intention-to-treat analysis, to "decrease" (as treated analysis) See below. Grade-consensus Comments During adulthood, the prevalence of invasive penile cancer is lower in males circumcised prior to 10 years of age (6%) compared with males not circumcised prior to 10 years of age (12%)	NOTE: Self-evident statements were not rated(see statements below) Statement 1: "MSM may choose to be circumcised despite i.e. the lack of definitive evidence of circumcision decreasing the risk for the insertive anal sex partner of acquiring HIV infection, but male circumcision involves potential risks (see Adverse Events section of Box 1) and costs." Statement 2: "However, current risks for either HIV or other non-HIV STIs may not remain constant in the future and the future risk for any individual neonate child, or adolescent cannot be definitively defined at the time that a circumcision decision is made." Statement 3: "Those who enjoy the sensation of the foreskin during sexual relations will no longer experience that sensation." (after circumcision)# Health benefits and risks of elective neonatal, adolescent, or adult medically performed male circumcision should be considered in consultation with medical providers while taking into account factors associated with decision-making around male circumcision, including religion, societal norms and social customs, hygiene, aesthetic preference, and ethical considerations. See below acquiring HIV and some STIs during penile-vaginal sex. In clinical trials, medically performed male circumcision reduced the incidence of genital ulcer disease (GUD) by 48% and the prevalence by 47%, reduced the prevalence of HR-HPV by 23 -47%, and reduced the incidence of syphilis by 42% among circumcised men. . Siegfried N, Muller M, Deeks J, Volmink J. Male circumcision for Meta-analysis of 3 RCTs HIV incidence (acquisition) Decrease Uganda, South Africa, Kenya AIa The overall relative risk reduction of acquiring HIV was 50% at 12 months and 54% at 21 or 24 months following circumcision prevention of heterosexual acquisition of HIV in men (review). Heterosexual adult males Cochrane database of systematic reviews. 2009;15(2):CD003362. . Byakika-Tusiime J. Circumcision and HIV Infection: Assessment of Meta-analysis of 13 studies HIV incidence (acquisition) Decrease Observational studies: United States, BIIa 61% reduced risk of HIV infection among circumcised men (aRR 0.39, 95% CI 0.27-0.56) Causality. AIDS Behav. 2008;12(6):835-841. Analysis limited to 10 India, Kenya, Malawi, Cote d'Ivoire, observations studies (6 cohort Sengal, Tanzania studies, 1 nested case-control Heterosexual adult males study, 3 case control studies) . Lei JH, Liu LR, Wei Q, et al. Circumcision status and risk of HIV Meta-analysis of 9 studies related HIV incidence (acquisition) Decrease Prospective Cohort Studies: Kenya, BIIa Male circumcision was associated with 70% reduction in the risk for HIV acquisition (pooled adjusted risk ratio [aRR] 0.40, 95% CI 0.31-0.53) acquisition during heterosexual intercourse for both males and to female-to-male transmission (3 Uganda, India Heterosexual adult females: a meta-analysis. PLOS ONE. 2015;10(5) is biologically plausible Male circumcision has not been shown to reduce the risk of HIV transmission to female partners. However, in clinical trials, medically performed male circumcision reduced the incidence of syphilis by 59%, and reduced the prevalence of GUD by 22%, HR-HPV by 22%, T. vaginalis by 45%, and bacterial vaginosis by 40% among female partners. Weiss HA, Hankins CA, Dickson K. Male circumcision and risk of HIV infection in women: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:669-677. Systematic review and random effects meta-analysis (1 RCT and 6 longitudinal analyses) # HIV acquisition No difference RCT: Uganda Longitudinal studies: 14 sites and southern Africa; Uganda; Zimbabwe, Tanzania in east AIb A systematic review and meta-analysis of the evidence for a direct effect of male circumcision on the risk of women becoming infected with HIV identified 19 epidemiological analyses from 11 study populations. The meta-analysis of data from the 1 RCT and 6 longitudinal analyses showed little evidence that male circumcision directly affects the risk of HIV acquisition in women (RR 0. lower BV prevalence compared to female partners of uncircumcised men (aPRR Male circumcision has also been shown to reduce the risk of urinary tract infections in males aged 0-1 years by 90%, males aged 1-16 years by 85%., and males aged >16 years by 71%. Morris BJ, Wiswell TE. Circumcision and lifetime risk of urinary tract infection: a systematic review and meta-analysis. J Urol. 2013;189( 6 # BIIb Early resumption of sexual relations following male circumcision was significantly associated with higher risk for HIV acquisition among female participants, with a rate ratio versus control of 3.50 (95% CI = 1.14-10.76). Among couples in the immediate male circumcision arm who delayed resumption of sex until after wound healing, there was no significant difference in HIV incidence relative to uncircumcised controls (rate ratio 1. In a vaccine preparedness cohort of MSM followed from 1995 to 1997, circumcision was significantly associated with a decreased risk for HIV seroconversion (aOR = 0.5; 95% CI 0.3-0.9), controlling for number of male sex partners and unprotected sex with an HIV-positive partner [19]. In a crosssectional survey of gay men in Seattle in the early 1990s, circumcision was associated with decreased odds of prevalent HIV infection (aOR = 0.5; 95% CI 0.25-1.0) [20]. While falling short of the quality of data from a randomized intervention trial, these limited data suggest that circumcised MSM in the US may have decreased risk of HIV infection. However, it is possible that the noted associations in these two observational studies were related to uncontrolled bias. A small cross-sectional study of Australian MSM found no association between circumcision status and risk of HIV infection, when stratifying by insertive and receptive roles [21]. Row no. CIIIb . When providing information to parents about male circumcision for an adolescent minor, the adolescent should be included in the decision-making process about undergoing elective male circumcision. When counseling an adolescent inquiring about male circumcision, parents should be engaged in the discussion, unless the adolescent is legally emancipated. Minors may be deemed emancipated, giving them sole authority to make health care decisions on their own behalf under certain circumstances, which vary by state law; for example, if the minor 1) lives independently and is self-supporting, 2) is married, 3) is pregnant or a parent, 4) is in the military, or 5) is declared emancipated by a court as defined in the mature minor section. # BIIb When estimated by age group, the incidence of probable AEs was 0.40%, 9.06%, and 5.31% for males aged < respectively. The incidence of AEs was 10-20-fold higher for males in older age groups compared with infants. # BIIa In a meta-analysis of 18 studies and 22,919 children mainly from the United States, the pooled prevalence of UTI in infants presenting with fever in outpatient clinics and emergency departments was 7.0% (95% CI = 5.5-8.4), but was as high as 20.1% (95% CI = 16.8-23.4) among febrile uncircumcised males aged < 3 months compared with 2.4% (95% CI = 1.4-3.5) among febrile circumcised males aged < 3 months and with 7.8% (95% CI = 6.6-8.9) among both febrile and afebrile older children aged < 19 years 95 o Complications of medically performed male circumcision in the United States are typically uncommon and easily managed. Severe complications are rare in all age groups and occur in 0.23% of all circumcised males overall. # BIIb Approximately 0.4% of male newborns in the first year of life experienced an adverse event associated with circumcision. Severe complications are rare in all age groups and rates of potentially serious male circumcision adverse events range from 0.8 per million male circumcisions for stricture of male genital organs to 703.2 per million male circumcision for repair of incomplete circumcision. # CIIIb In a review article, data from a myriad of sources were compiled, including personal correspondence, to estimate the following rates of AEs per circumcisions performed in the United States: excessive bleeding requiring ligature, 1 per 4,000; bleeding requiring transfusion, 1 per 20,000; severe infection requiring parenteral antibiotics, 1 per 4,000; subsequent surgery (e.g., for skin bridges), 1 per 1,000; repair of traumatic injury, 1 per 15,000; and loss of entire penis, less than 1 per 1,000,000. There were 3 deaths due to male circumcision during 1954-1989. BIIb "Nine AEs were significantly less likely to occur in circumcised infants compared with uncircumcised infants at P < .05. Circumcised newborn males had a higher risk for wounds, correctional procedures, inflammation, and bleeding compared with uncircumcised newborn males but had a lower risk for surgical procedures, penile disorders and gangrene, pneumothorax, and infections. Among the extremely rare but serious AEs occurring only among circumcised newborns (but once or none among uncircumcised newborns), we found 0 cases of complete amputation of penis, 1 case of stricture of male genital organs, 3 cases of partial amputation of penis, 4 cases of replantation of penis, and 16 cases of suture of artery." o On average, adult men who undergo circumcision generally report minimal or no change in sexual satisfaction or function. Grade-consensus Comments o Some men enjoy the sensation of the foreskin during sexual relations, and such a sensation will not be experienced after circumcision; however, the bulk of scientific evidence states that men on average, do not experience a loss of sexual pleasure or function because of circumcision. # AIb In another systematic review and meta-analysis including 10 studies and 9,317 circumcised men and 9,423 uncircumcised men, there were no significant associations between male circumcision and sexual desire, dyspareunia, premature ejaculation, ejaculation latency time, erectile dysfunction, or orgasm difficulties. # AIb IRR 0.55, 95% CI 0.32-0.949 (AT analysis) Note: When men who crossed over from control arm to intervention arm were included in the case arm analysis, the circumcision effect changed from "no difference" (in the intention-to-treat analysis, to "decrease" (as treated analysis) See below. Grade-consensus Comments During adulthood, the prevalence of invasive penile cancer is lower in males circumcised prior to 10 years of age (6%) compared with males not circumcised prior to 10 years of age (12%)	None	None
cc5ad33d3b2873dd0bc37fc84235387bdc89dadb	cdc	None	The views expressed and conclusions reached in this document, together with the recommendations for a standard, are those of NIOSH, after review of the evidence and consideration of the comments of reviewers. These views and conclusions are not necessarily those of the consultants, other federal agencies, and professional societies that reviewed the document, or of the contractor. recommends that employee exposure to ethylene dibromide in the workplace be controlled by adherence to the following sections. # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR ETHYLENE DIBROMIDE The standard is designed to protect the health and provide for the safety of employees for up to a 10-hour workday, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should prevent adverse effects of ethylene dibromide on the health of employees and provide for their safety. Techniques recommended in the standard are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. Although NIOSH considers the workplace environmental limit to be a safe level based on current information, the employer should regard it as the upper boundary of exposure and make every effort to maintain the exposure as low as is technically feasible. The criteria and standard will be subject to review and revision as necessary. The possible health effects of employees chronically exposed to ethylene dibromide may include the induction of cancers, malformations and heritable changes in offspring, and sterility. Ethylene dibromide may also cause adverse effects to the liver, kidneys, heart, and other internal organs and systems. Direct contact of the skin with ethylene dibromide may induce chemical burns as well as systemic effects, and ingestion of ethylene dibromide may damage internal organ systems, or even be fatal. The alkylation of cellular constituents, including the genetic material, deoxyribonucleic acid (DNA), is the most plausible molecular basis for the induction of adverse effects after exposure to ethylene dibromide. These criteria and the recommended standard apply to occupational exposure of workers to the brominated hydrocarbon BrCH2CH2Br, hereinafter referred to as "ethylene dibromide." Synonyms for ethylene dibromide include ethylene bromide, dibromoethane, sym-dibromoethane, 1,2dibromoethane, glycol dibromide, and EDB. The major uses of ethylene dibromide are as an additive to leaded gasoline and as a component of fumigants. "Occupational exposure to ethylene dibromide" is defined as work in any establishment where ethylene dibromide is manufactured, blended, stored, used, handled, or otherwise present. The "action level" is defined as one-half of the recommended workplace exposure concentration designated as a ceiling limit for ethylene dibromide. Exposure to airborne ethylene dibromide at concentrations less than the action level, as determined in accordance with Section 8, will not require adherence to Sections 2, 3, 4(a), or 8(c,d). If exposure to other chemicals also occurs, the employer shall comply with any applicable standard for the other chemicals. # Section 1 -Environmental (Workplace Air) (a) Concentration The employer shall control workplace concentrations of ethylene dibromide so that no employee is exposed in his workplace to concentrations greater than 1.0 mg/cu m (0.13 ppm) as a ceiling limit, as determined by a sampling period of 15 minutes. (b) # Sampling and Analysis Procedures for the collection and analysis of workroom air samples for compliance with the standard shall be as provided in Appendices I and II, or by any methods shown to be at least equivalent in precision, sensitivity, and accuracy to the methods specified. # Section 2 -Medical Medical surveillance shall be made available to employees as outlined below: (a) Comprehensive preplacement and annual medical examinations unless a more frequent schedule is indicated by professional medical judgment based on such factors as emergencies, variations in work periods, and the preexisting health status of the individual worker. (b) These examinations shall include at least: (1) Comprehensive or interim medical and work histories, with special emphasis directed to disorders of the heart, liver, kidneys, and nervous system. (2) A comprehensive physical examination, with particular emphasis given to cardiovascular, pulmonary, neurologic, hepatic, and renal systems, and to the skin. (3) An evaluation of the employee's physical ability to safely wear a negative or positive pressure respirator. (c) Employees shall be counseled by the physician to ensure that each employee is aware that ethylene dibromide has been shown to induce in experimental animals adverse effects in reproductive processes, including abnormalities in offspring, mutations, and stomach cancer following direct administration. The relevancy of these findings in animals to male or female employees has not yet been established. They do indicate, however, that both employers and employees should do everything possible to minimize exposures to ethylene dibromide. If a physician becomes aware of any adverse effects on the reproductive system, or cancers in individuals who have been exposed to ethylene dibromide, or any abnormal babies born to parents either or both of whom have been exposed to ethylene dibromide, such information should be forwarded to the Director, National Institute for Occupational Safety and Health, as promptly as possible. (d) Medical attention shall be provided promptly to all employees suspected of being exposed to ethylene dibromide vapor at or above the action level or to liquid ethylene dibromide. A 48-hour medical observation period for delayed systemic or dermal effects is recommended. (e) Examinations of current employees shall be performed as soon as practicable after the promulgation of a standard based on these recommendations. (f) The employer shall maintain medical records for all persons exposed to ethylene dibromide at or above the action level. All medical records, including information on required medical examinations and supporting documents, shall be kept for at least 30 years after the termination of the individual's employment. (g) The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employee or former employee, and of the employer shall have access to these medical records. # Section 3 -Labeling and Posting All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers. Illiterate workers and workers reading languages other than those used on labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on labels and signs. (a) Labeling The following warning label shall be affixed in a readily visible location on ethylene dibromide processing or other equipment and on ethylene dibromide storage tanks or containers: (C) During emergencies when air concentrations of ethylene dibromide may exceed the recommended occupational exposure limit. ETHYLENE # C2) When a respirator is permitted by paragraph (a)(1) of this section, it shall be selected and used pursuant to the following requirements: (A) The employer shall ensure that no employee is exposed to ethylene dibromide because of improper respirator selection, fit, use, or maintenance. (B) The employer shall establish and enforce a respirator program meeting the requirements of 29 CFR 1910.134 as amended. (C) The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided when necessary. (D) Respiratory protective devices described in (1) Supplied-air respirator with full facepiece, helmet, or hood (2) Self-contained breathing appara tus with full facepiece Type C supplied-air respirator with full facepiece operated in pressuredemand or other positive pressure mode or with full facepiece, hood, or hel met operated in continuous-flow mode (1) Self-contained breathing appara tus with full facepiece operated in pressure-demand or other positive pressure mode (2) Combination respirator that in cludes Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and auxiliary self-contained breathing apparatus op erated in pressure-demand or positive pressure mode (3) Supplied-air suits may be neces sary (b) Eye Protection Eye protective devices shall be provided by the employer and used by each employee where contact of ethylene dibromide with the eyes is likely. Chemical safety goggles or plastic face shields (8-inch minimum) with goggles made completely of ethylene dibromide-resistant materials shall be used. Selection, use, and maintenance of eye protective devices shall be in accordance with 29 CFR 1910.133. (c) Protective Clothing Protective clothing shall be resistant to the penetration and to the chemical action of ethylene dibromide. Additional protection, including gloves, bib-type aprons, boots, and overshoes, shall be provided for, and worn by, each employee while in any operation that may cause direct contact with liquid ethylene dibromide. Supplied-air hoods or suits resistant to penetration by ethylene dibromide shall be worn when entering confined spaces, such as pits or storage tanks. In situations where heat stress is likely to occur, supplied-air suits, preferably cooled, are recommended. The employer shall ensure that all personal protective clothing is inspected regularly for defects and is maintained in a clean and satisfactory condition by the employee. Records of such training should be kept for inspection by authorized personnel as required. This program shall be held for all employees with occupational exposure to ethylene dibromide at intervals not greater than quarterly, or whenever there is a process change. For all work areas where emergencies may occur, the employer shall take all necessary steps to ensure that employees are instructed in and follow the procedures specified below and any others appropriate to the specific operation or process. Procedures shall include at least prearranged plans for : ( (2) Evacuation alarm systems shall be provided by the employer. (3) Personal protective equipment and clothing as specified in Section 4 shall be used by trained personnel essential to emergency operations. (4) Nonessential employees shall be evacuated from hazardous areas during emergencies. Perimeters of these areas shall be delineated, posted, and secured. The employees in adjacent areas shall be trained in evacuation procedures if these work areas become involved. # C5) Only personnel trained in the emergency procedures and protected against the attendant hazards shall shut off sources of ethylene dibromide, clean up spills, control and repair leaks, and fight fires in ethylene dibromide areas. (6) Firefighting procedures shall be established for areas where flammable materials are used with ethylene dibromide. Chemical foam, carbon dioxide, or dry chemicals shall be used for fighting fires in areas where ethylene dibromide is present. Proper protective respirators and clothing shall be worn by all personnel in the hazard area until concentrations of airborne ethylene dibromide have been demonstrated by monitoring to be below the recommended occupational exposure limit. Showers, eyewash fountains, and washroom facilities shall be provided and so located as to be readily accessible to workers in all areas where skin or eye contact with liquid ethylene dibromide is likely. If liquid ethylene dibromide is splashed on the clothing or skin, contaminated clothing shall be promptly removed and the skin washed thoroughly with soap and water for at least 15 minutes. If liquid ethylene dibromide gets into the eyes, they shall be irrigated immediately with copious quantities of running water for at least 15 minutes. (1) Suitable engineering controls designed to limit exposure to ethylene dibromide to that prescribed in Section 1(a) shall be used. The use of completely enclosed processes is the recommended method of control for ethylene dibromide. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. When a local exhaust ventilation system is used, it shall be designed to prevent the accumulation or recirculation of ventilation control or process air in the workroom, to maintain ethylene dibromide concentrations below the limit of the recommended standard, and to remove ethylene dibromide from the breathing zones of employees. Exhaust systems discharging into outside air must conform with applicable local, state, and federal air pollution regulations. Ventilation systems shall be subjected to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic airflow measurements at least every 3 months. Measurements of system efficiency shall also be made immediately by personnel properly attired in specified protective equipment when any change in production, process, or control might result in increased concentrations of airborne ethylene dibromide. Tempered makeup air shall be provided to work areas in which exhaust ventilation is operating. (2) Forced-draft ventilation systems shall be equipped with remote manual controls and shall be designed to turn off automatically in the event of a fire in the work area. # C2) Prompt medical attention shall be provided if there is known or suspected exposure to ethylene dibromide, whether or not symptoms are present. # C3) The employer shall ensure that safety showers, eyewash fountains, and other emergency equipment is in proper working order through regularly scheduled inspections performed by qualified maintenance personnel. (4) Ethylene dibromide operating systems shall be inspected daily for signs of leaks by personnel attired in specified protective equipment. All equipment including valves, fittings, and connections shall be checked for tightness and good working order. All newly made connections shall be checked for leaks immediately after ethylene dibromide is introduced by trained personnel attired in prescribed personal protective equipment. If there is a leak, the leak shall be corrected immediately. Work shall resume normally only after necessary repair or replacement has been completed, the area has been ventilated, and the concentration of ethylene dibromide has been determined by monitoring to be below the recommended occupational exposure limit. (6) Transportation and use of ethylene dibromide shall comply with all applicable local, state, and federal regulations. Where ethylene dibromide is used as a fumigant, strict adherence to the pesticide container label requirements for application and personal protection shall be followed. Additional standards for pesticide use by agricultural workers can be found in 40 CFR 170. (7) When ethylene dibromide containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control while moving. (8) Process valves and pumps shall be readily accessible and should not be located in pits and congested areas. Containers and systems shall be handled and opened with care. Approved protective equipment as specified in Section 4 shall be worn while opening, connecting, and disconnecting ethylene dibromide containers and systems. Adequate ventilation shall be available to prevent exposure to ethylene dibromide when opening containers and systems. (10) Personnel shall work in teams when ethylene dibromide is first admitted to a system, while repairing leaks, or when entering a confined or enclosed space. (11) Any odor of ethylene dibromide shall be reported to a responsible authority and an alarm sounded immediately. # (d) Work Areas (1) Ethylene Dibromide Hazard Areas A hazard area shall be considered as any space workers may enter that has physical characteristics and sources of ethylene dibromide that could result in air concentrations exceeding the recommended limit. Exits shall be plainly marked and shall open outward. Emergency exit doors shall be conveniently located and shall open into areas which will remain free of contamination in an emergency. At least two separate means of exit shall be provided from each room or building in which ethylene dibromide is stored, handled, or used in quantities that could create a hazard. # Confined or Enclosed Spaces Entry into confined spaces, such as tanks, pits, process vessels, tank cars, sewers, or tunnels, where there may be limited egress shall be controlled by a permit system. Permits shall be signed by an authorized employer representative certifying that preventive and protective measures have been followed. Confined spaces which have contained ethylene dibromide shall be thoroughly ventilated to ensure an adequate supply of oxygen, tested for ethylene dibromide and other contaminants, and inspected for compliance with these requirements prior to each entry. Adequate ventilation shall be maintained while workers are in the space. Leakage of ethylene dibromide into the confined space while work is in progress shall be prevented by disconnecting and blanking the ethylene dibromide supply lines. An individual entering confined spaces shall be furnished with appropriate personal protective equipment and protected by a lifeline harness tended by another worker outside the space, who shall also be equipped for entry with approved personal protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephone, radio, or other suitable means) shall be maintained by the standby person with the employee inside the confined or enclosed space. A third employee, equipped to proceed to the aid of the other two if necessary, shall have general surveillance of their activities. (e) Storage (1) Storage facilities shall be designed to contain spills completely within a surrounding dike and to prevent contamination of workroom air. Storage of ethylene dibromlde in the same area as reactive metals, such as aluminum or magnesium, or as liquid ammonia shall be prohibited. (3) Ethylene dibromide shall be stored in tightly closed containers in a well-ventilated area away from excessive heat and sunlight. # C4) Storage containers shall be periodically inspected for leakage. (5) Ventilation switches and emergency respiratory equipment shall be located outside storage areas in readily accessible locations which will be free of ethylene dibromide in an emergency. (f) Spills, Leaks, and Waste Disposal (1) If ethylene dibromide leaks or is spilled, the following steps shall be taken: (A) Evacuate all nonessential personnel from the area. # (B) Adequately ventilate the area of the spill or leak to prevent accumulation of the vapor. (C) If in liquid form, collect spilled material for reclamation or absorb in vermiculite, dry sand, earth, or similar nonreactive material. (D) If in solid form, collect spilled material in the most convenient and safe manner for reclamation or for disposal. (2) Personnel entering the spill or leak area shall be furnished with appropriate personal protective equipment. All other personnel shall be excluded from the area. All wastes and residues containing ethylene dibromide shall be collected in ethylene dibromide-resistant containers and incinerated or buried in such a manner that no ethylene dibromide or toxic decomposition products are released to the environment. Clothing contaminated with liquid ethylene dibromide shall be immediately removed and placed in a closed container in a well-ventilated area for later disposal or decontamination. Employers shall require personnel who work with ethylene dibromide to shower before leaving the workplace at the end of a workday. (c) Employers shall ensure that employees who handle ethylene dibromide wash their hands thoroughly with soap and water before eating, smoking, or using toilet facilities. # (d) The storage, dispensing, preparation, and consumption of food, beverages, or tobacco shall be prohibited in ethylene dibromide work areas. (e) The employer shall ensure that personnel who launder and clean clothing or equipment contaminated with ethylene dibromide are provided adequate personal protective equipment to prevent exposure and shall ensure that these employees are aware of the potential hazards of exposure to ethylene dibromide. where ethylene dibromide is handled, processed, or stored. Records of these surveys, including the basis for concluding that environmental concentrations are below the recommended limit or below the action level, shall be maintained. Surveys shall be repeated every month or whenever a process change is made. (b) Where exposure concentrations have not been determined, they shall be determined as soon as practicable after the promulgation of a standard based on these recommendations. # (c) Requirements set forth below apply to work areas in which the concentration of ethylene dibromide has been determined to be at or above the action level. (1) An adequate number of samples shall be collected monthly in accordance with Appendix I for the evaluation of the work environment with respect to the occupational exposure of the employees. (2) Environmental samples shall be taken when a new process is installed or process changes are made which may cause an increase in environmental concentrations. Significantly increased production, relocation of existing operations, interruption of normal maintenance schedules, or other functions which may increase ethylene dibromide concentrations shall require resampling and analysis. (3) In all monitoring, samples shall be collected in accordance with the provisions prescribed in Section 1(b). The minimum number of representative exposure determinations for an operation or process shall be based on variations in exposures and production schedules and in accordance with the provisions prescribed in Section 1(b). (5) If initial, periodic, or special evaluations indicate that the recommended limit is exceeded, corrective engineering or other control measures shall be immediately instituted to ensure the safety of employees until a concentration below the recommended occupational exposure limit is achieved. In such cases, sampling of each operation and work location shall be conducted at least weekly until two consecutive employee exposure measurements, taken at least 1 week apart, reveal that the employee is not exposed to ethylene dibromide above the recommended occupational exposure limit. Employers shall notify in writing, within 5 days, every employee who is found to be exposed to ethylene dibromide above the recommended environmental limit. Adherence to the recommended standard for occupational exposure to ethylene dibromide is intended to minimize the potentials for the induction of sterility, carcinogenesis, mutagenesis, or teratogenesis in employees and their offspring from exposure to ethylene dibromide in the workplace. Adherence to the recommended standard is also intended to minimize the hazards from skin penetration and irritation associated with exposure to liquid ethylene dibromide and the delayed and insidious long-term systemic effects resulting from exposure to bath liquid and vaporous ethylene dibromide. III. # BIOLOGIC EFFECTS OF EXPOSURE Ethylene dlbromide, also known as 1,2-dibromoethane and ethylene bromide, is a clear, colorless, heavy liquid at room temperature with a distinctive odor described as "characteristic, mildly sweet" . The minimum concentrations of ethylene dibromide in air reported to be detectable by odor range from 10 ppm (77 mg/cu m) to 25 ppm (192.5 mg/cu m) . Selected chemical and physical properties of ethylene dibromide are listed in Table XII Ethylene dibromide is a reactive molecule which may form covalent bonds under biologic conditions . Because of the two replaceable bromine atoms, ethylene dibromide is considered to be a bifunctional alkylating agent that is capable of introducing cross-links into biologic materials . It tends to react with nucleophilic organic compounds more readily with those that are relatively easily polarized, such as those containing sulfhydryl or amino groups, than with those that are less readily polarized, such as acids and ketones. The half-life of ethylene dibromide in water at 20 C and at a pH of 7 is about 14 years . Although the biologic half-life of ethylene dibromide in humans is unknown, the presence of large numbers of nucleophiles in biologic tissue suggests that the half-life would be considerably shorter than that in water. The approximate biologic halflife of ethylene dibromide after intravenous (iv) injection in rats was less than 2 hours, and in chicks, it was less than 12 hours . An approximate biologic half-life of 14C-labeled ethylene dibromide in mice and in guinea pigs can be estimated from the data presented by Edwards et al and Plotnick and Conner as less than 48 hours. This indicates that either spontaneous reactions with nucleophiles, enzymatically catalyzed degradative reactions, or efficient excretory mechanisms predominate in biologic systems. Alkyl bromides, such as ethylene dibromide, readily react with thiols, amines, alcohols, and other nucleophilic biochemical constituents . The initial monoalkylation product between ethylene dibromide and substrate heteroatoms, such as nitrogen, oxygen, or sulfur, is a "half mustard" (a thiane) reagent which may spontaneously cyclize under biologic conditions to form a strained three-membered ring. This highly reactive intermediate product may then undergo a second alkylation reaction with cellular constituents. When both alkylation reactions occur with cellular DNA, the covalent cross-links between the DNA strands may prevent the normal separation of the strands during DNA synthesis and subsequent cell division . Thus, such bifunctional alkylating agents as ethylene dibromide tend to possess a considerably greater biologic activity than monofunctional agents of the same primary reactivities . The covalent reaction of ethylene dibromide with biologic materials may alter the chemical behavior and physical characteristics of the cellular constituents so as to prevent the altered molecules from functioning normally in physiologic processes. The formation of stable reaction products may account, in part, for the subsequent deleterious effects observed in biologic systems exposed to ethylene dibromide. The alkylation by foreign chemicals of the biologic materials controlling cellular metabolism is the most plausible basis for the induction of genetic and neoplastic alterations after the exposure of biologic populations to alkylating agents. When the risk of induction of adverse biologic changes, such as mutation and neoplasia, increase as a cumulative function of the total dosage, then the observation of measurable effects may not be possible until after long periods of exposure to low concentrations of the inducing agent . # Extent of Exposure Ethylene dibromide-manufacturing processes are based on the bromination of ethylene . Natural bromide-containing brines are treated with chlorine to release elemental bromine through anionic replacement. The reaction between gaseous ethylene and liquid bromine (which may contain traces of chlorine) yields a mixture of ethylene dibromide and reaction side-products, including very small amounts of vinyl bromide, ethyl bromide, and ethyl chlorobromide . If the reaction temperatures and pressures are carefully controlled, the purity of the ethylene dibromide can approach 99.95% . Ethylene dibromide can also be produced by the hydrobromination of acetylene , although this process is of little commercial value today. In 1921, the antiknock properties of tetraalkyl lead compounds in the internal combustion engine were discovered . To prevent the deposition of lead on the cylinder walls, a substance capable of reacting with the lead to aid its removal from the engine was needed. Ethylene dibromide was found to be such a substance and has been used since then in leaded gasoline as a lead scavenger. The US production of ethylene dibromide increased from an estimated 64 million pounds in 1940 to over 331 million pounds in 1973 . This fivefold increase can be related to the increased consumption of gasoline containing ethylene dibromide as an additive, which has always been its largest use . About 85% of the ethylene dibromide produced during the The production of ethylene dibromide is the largest single use of bromine, and, as such, the locations of manufacturing plants have usually been near the major sources of bromine . Until 1961, the major source of bromine for ethylene dibromide manufacture was seawater; since 1961, the major source of bromine has been underground brine deposits, and the manufacturing of ethylene dibromide has been redistributed to be near these natural bromide brine wells in Michigan and Arkansas . A number of other occupations in which a potential for ethylene dibromide exposure exists are listed in Table XII last NIOSH estimates that approximately 9,000 employees (manufacturing, formulating, fumigating) are potentially exposed to ethylene dibromide in the workplace. If one includes gasoline station attendants, this figure becomes much larger (about 660,000). # Historical Reports One of the first instances of ethylene dibromide intoxication was described by Marmetschke in 1910. This case history described the accidental use of ethylene dibromide instead of ethyl bromide as an anesthetic or narcotic agent. Although this report is historical rather than clinical, it is one of the few relating to human exposure which give the amount of ethylene dibromide administered to each patient and the clinical symptoms resulting from the exposures. Thus, this report will be discussed in detail in Effects on Humans. Another early case of occupational exposure to ethylene dibromide, which will also be discussed in Effects on Humans, was described in 1928 by Kochmann . # Effects on Humans In 1910, Marmetschke wrote about a case of ethylene dibromide poisoning that occurred as the result of the mistaken administration of ethylene dibromide to a patient instead of ethyl bromide. A woman was administered the contents of a 70-g bottle of ethylene dibromide in aliquots of about 10 ml (22.0 g) through a gauze mask without producing the expected anesthesia. She coughed constantly during the administration and was dizzy at the completion of the application. She began to vomit and continued vomiting throughout the night. The patient complained of a burning sensation in her chest and of inability to sleep. During the night, she had diarrhea, and the next day she became dizzy again after exertion. She became very restless and nervous and complained of having trouble in breathing. She continued to complain of thirst, abdominal pain, and a burning sensation in her chest. The next day, she had uterine hemorrhaging, and died approximately 44 hours after she received the ethylene dibromide. The results of the autopsy showed that the skin was a very pale blue and that the vessels of the skin were filled with blood Pflesser subjected eight human volunteers and himself to the gauge fluid and to each of the components separately to determine their effects on the skin. One milliliter of the gauge fluid was placed on the hands of the volunteers and rubbed between the hands for about 1 minute. Two hours later, the hands were washed with soap and water. None of the subjects developed any symptoms of adverse effects on the day of the test or later. Pflesser observed that, after rubbing the fluid between the hands for 1 minute, the liquid could no longer be seen on the skin, and he concluded that it had been absorbed or had evaporated. In an additional experiment , the same volunteers rubbed 1 ml of the gauge fluid into the skin of the right forearm for 1 minute. Again, washing with soap and water was done after 2 hours. No symptoms of irritation were seen immediately after the exposure or later. In a third experiment , the same volunteers were subjected to 1 ml of the gauge fluid on a cotton swab that was placed on the left forearm and covered; exposure time was 2 hours. After a few minutes, all eight subjects noted a sensation of heat at the application site, sometimes complaining of a pronounced burning of the skin. At the end of the 2-hour exposure, a strong reddening of the skin had appeared at the application site in all cases, and, in one case, pinhead-sized blisters had developed. During the next 12 hours, a severe burning pain developed in addition to small blisters which merged into large ones. The blisters initially contained a clear, amber-yellow, thick liquid, but the liquid had a pronounced tendency to coagulate because of its high protein content. The area immediately surrounding the application site was edematous and swollen, and, in some cases, the swelling extended from the fingertips to the upper arm. In one case, the axillary lymph nodes were moderately swollen and painful. Even with topical cod liver oil treatment, the skin did not grow back until 13-17 days after exposure, and surface scars persisted for at least 4 months. Pflesser stated that all subjects felt severely ill during the first days following exposure. In two subjects, dermatitis, consisting of severe swelling and reddening of the skin accompanied by intensive itching, persisted in the area of the application for several weeks. To determine which component of the gauge fluid was responsible for the adverse effects on the skin, Pflesser subjected the same eight subjects and himself to each of the individual components. The results of the tests with the paraffin oil, Sudan Red B, and tetrachlorethane were negative. During the 1-hour exposure to 0.5 ml of tetrachlorethane, several individuals noted a slight sensation of heat at the application site, but no symptoms similar to those for the gauge fluid were subsequently noted. All volunteers rubbed 0.5 ml (1.1 g) of ethylene dibromide into the skin of the forearm for 1 minute and washed with soap and water 30 minutes later. All subjects developed swelling and reddening of the exposed area, as well as itching, during the 24 hours immediately after exposure. The symptoms subsided without supportive treatment within 2-3 days. In an additional experiment , the subjects received 0.5 ml (1.1 g) of ethylene dibromide applied to the skin on a swab, the swab and the application site being covered for 10 minutes. The swab was then removed and the area was washed with soap and water. A sensation of heat or slight burning was noticed during the exposure; and, during the next 24 hours a painful reddening and swelling of the skin developed. However, no blistering was noticed in any of the subjects. The injuries disappeared in 3-5 days without leaving visible traces. In a subsequent experiment , this procedure was repeated except that the application site was covered for 30 minutes. After this exposure period, the swab was removed and the area was washed with soap and water. During the 30-minute exposure, the subjects reported the customary heat or burning sensation at the application site. After exposure, a very painful inflammation of the skin occurred, including reddening, swelling, and blistering, within 15-20 hours. The damaged skin grew back after 7-13 days of supportive treatment. The author experienced such a strong burning pain in his skin immediately after application that increased so rapidly that the swab containing the ethylene dibromide had to be removed after 3 minutes. The pain and reddening of the skin subsided, but then increased again after a few hours until a blister the size of a crab apple had formed at the application site after 18 hours. Very strong pain was associated with the blister. When the blister was opened, Pflesser collected 21 ml of a clear exudate, which coagulated soon afterward, and over 245 ml of fluid within the first 3 days after application. In addition, the author stated that when the blister appeared on the right arm, all places that had previously been exposed to ethylene dibromide or to the gauge fluid on both the left and right arms began swelling, reddening, and itching. A moderately strong, painful glandular swelling occurred in the left armpit (opposite the arm of the application site). Pflesser also reported that only a slight edema had occurred surrounding the application site after the 1st day, but that, on the 2nd day, an extensive edema of the entire right forearm and right hand suddenly developed. During these first few days after exposure, there was a pronounced feeling of illness and a slight temperature increase in addition to the physical manifestations at the exposure site. Healing of the damaged skin was complete after 17 days of zinc-sulfur ointment supportive treatment, leaving only a surface scar. From this series of experiments, Pflesser concluded that ethylene dibromide was the component of the gauge fluid that was responsible for the swelling, reddening, and blistering of the skin of the seaman on the destroyer. He also concluded that the effects and their intensities depended on the duration of exposure to the skin, and that covering the application site to prevent evaporation greatly increased the extent of damage from exposure. Pflesser concluded that ethylene dibromide was absorbed through the skin, causing tissue death, general inflammation, and plasma exudation. He further postulated that ethylene dibromide possessed a sensitization potential, citing the symptoms that appeared at previous application sites after his own exposure for 3 minutes to 0.5 ml of ethylene dibromide as proof of the assumption. In 1960, Olmstead Macroscopic and microscopic examinations of the internal organs showed a pronounced granular degeneration of the parenchymal tissue of the kidneys and smaller amounts of damage in the pancreas, spleen, heart, liver, and adrenals. In addition, the authors observed that ethylene dibromide exposure produced swelling and a generalized interstitial edematous degeneration of the endothelial lining of the abdominal vascular system that was not described further. Thomas and Yant noted that commercial and purified ethylene dibromide applied to the shaved abdomens of three groups of two rats each over a 2-cm square area killed all of the animals within 6-18 hours at doses of 0.25, 0.50, or 1.00 ml (0.55, 1.1, or 2.2 g)/animal. No attempt was made to determine the minimum lethal dose. The application site showed marked hyperemia of the small cutaneous blood vessels, and the abdominal muscles became contracted and remained tense. By 20 minutes, the reflexes became weak and the animals were scarcely able to stand. A slight, temporary increase in activity was noted during the next 10 minutes, but the general appearance remained that of great weakness. Macroscopic and microscopic examinations of tissues were similar to those in guinea pigs after vapor inhalation. The only difference observed between the two routes of exposure concerned the spleen: gross examination of the guinea pigs exposed to the vapor of airborne ethylene dibromide revealed that spleens were pale and edematous, whereas spleens of the dermally exposed rats were highly congested and edematous. No microscopic characterization of these differences was given. In 1928, Lucas published the results of an experiment in which two adult rabbits inhaled ethylene dibromide vapor in quantities sufficient to produce light or deep anesthesia (concentrations not reported). Very light anesthesia was maintained in one rabbit by inhalation of ethylene dibromide for about 10 minutes. The rabbit vocalized during exposure, presumably responding to the irritating effects of ethylene dibromide. Respiration became extremely rapid during exposure and there was considerable phonation. The mucous membranes of the mouth were a peculiar "old rose" color after recovery from the anesthesia. This may have been due to a combination of vascular congestion and cyanosis. Death occurred within 18 hours, and, at autopsy, the liver was enlarged and mottled. Microscopic examination of the liver showed slight-to-moderate diffuse fatty changes, which tended to be more marked in the portal regions. Another rabbit deeply anesthetized by inhalation of ethylene dibromide for about 12 minutes exhibited signs of marked irritation from the gas, considerable phonation, rapid breathing progressing as the anesthesia continued, and snuffling in its breathing after recovery from the anesthesia . Death occurred within 15 hours. Autopsy showed the lungs to be enlarged and filled with a frothy exudate. About 10 ml of fluid was found in the pleural cavity. The liver was swollen and markedly congested. Lucas postulated that these results may have been caused by the decomposition of ethylene dibromide to hydrogen bromide and that local high concentrations of this material would be sufficient to bring about the observed changes. The next day, the animals began to tremble while in the cage, tears began forming, and the nasal mucosa was strongly reddened. After 11 exposures, the survivors were very weak and maintained a reclining posture, and strong trembling was observed, especially in the extremities. These conditions persisted until death occurred. There was a general weight loss during the exposures. Autopsy showed that the body cavities contained a clear, yellowish liquid. The lungs contained dark red discolorations and were judged by the author to be partially nonfunctional. The spleen was slightly enlarged and the kidneys were swollen and yellow colored. Kochmann diagnosed the condition of the cats after exposure to ethylene dibromide as follows: rhinitis, conjunctivitis, ascites, pleural effusion, pneumonia in the left superior lobe of the lung, and incipient fatty degeneration of the liver and possibly degeneration of the tubules of the kidneys. Similar adverse signs of intoxication, including rhinitis, conjunctivitis, anorexia, and loss of weight, appeared in rabbits. Autopsies of the rabbits showed that the small intestine contained an excessive amount of liquid, that the colon contained blood, and that the liver and kidneys were hyperemic. In an additional experiment, the animals inhaled ethylene dibromide at a concentration of 0.01% (770 mg/cu m) once for 30 minutes, and the author noted that there was a reduction in appetite, a corresponding loss of weight, a distinctly reduced hemoglobin content in the blood, and a slow recovery to the pretreatment conditions of the test animals. disappeared immediately after the guinea pigs were removed from the exposure chamber. Paralysis of the rear extremities occurred 24 hours after the sixth exposure, but it had partially disappeared after 5 additional days and was completely gone after another 8 days. The authors concluded that the adverse effects, such as paralysis of the extremities and spasms of the diaphragm, appeared at a lower concentration and in a much shorter time than did the adverse effects in a concurrent experiment with methyl bromide. They also concluded that the signs of toxicity remained longer than those observed from methyl bromide. In 1929, Kistler and Luckhardt reported the effects on respiration, muscle reflexes, and blood pressure in dogs exposed to ethylene dibromide by inhalation, ingestion, and injection. Dogs, anesthetized with sodium barbital, were sequentially injected iv with 0.2-1.0 ml (0.44-2.2 g) of ethylene dibromide for a total of 5.5 ml (12 g). Marked decreases in respiratory rate, blood pressure, and muscle reflexes resulted. Ethylene dibromide at 0.3 ml (0.66 g) injected iv caused cessation of respiration which was "momentary" or lasted as long as 40 seconds in the dogs tested. The cessation was followed by panting and a gradual return to almost normal breathing rate. The same dose produced a 75% decrease in blood pressure, the fall being immediate and sharp. The blood pressure gradually returned toward normal in a period of 2-12 minutes; but, in some cases, it remained 30% below normal. Ethylene dibromide at doses of 0.1-0.3 ml (0.22-0.66 g) injected iv caused a profound and rapid depression of the knee jerk reflex, which never returned to normal after the exposure. The effects on dogs exposed to 1.0-10.0 ml (2.2-22.0 g) of ethylene dibromide vaporized from an ether bottle were essentially the same as those caused by the iv injections, differing only slightly in the extent of the decreases . The recovery times were described as being prolonged because of the longer exposure times, but complete experimental details were not given. The investigators The autopsy showed bronchopneumonic foci and severe hyperemia in both lungs. A spherical thrombus was found in the heart, and the liver showed pronounced fatty degeneration. The effects noted above in the hearts of the dogs exposed to ethylene dibromide were also found in isolated, perfused hearts from male frogs (Rana temporaria) subjected to 400, 800, or 1,600 ppm of ethylene dibromide in Ringer's solution . Immediate diastolic arrest occurred at 800 and 1,600 ppm with no recovery of function. At 400 ppm, there was diastolic arrest after 1 minute, but washing produced a gradual recovery to normal function. No cardiac arrest or change in the heart rate was found at a concentration of 200 ppm of ethylene dibromide. In 1946, Aman et al studied the effects of repeated oral administration of ethylene dibromide on rats and guinea pigs. Nineteen animals were administered ethylene dibromide at average daily doses of 0, Total accumulated dosages of ethylene dibromide ranged from 0 to 1,420 mg. One rat, given 20 mg of ethylene dibromide daily, died after 3 months. All other rats and guinea pigs appeared to have gained weight normally during the experimental periods, and no untoward signs of toxicity were noted. Autopsy and microscopic examinations were not mentioned. The authors concluded that daily administration of ethylene dibromide for periods up to 4 months did not adversely affect the growth and outward physical appearance of rats and guinea pigs. The lack of experimental detail and data, the ambiguity of the data given, the inadequate number of control and experimental animals, and the absence of autopsies make this study difficult to evaluate and its importance questionable. In 1952, Rowe et al investigated the effects of ethylene dibromide administered to rats, guinea pigs, rabbits, mice, chickens, and monkeys by single oral intubations, eye contact, dermal contact, dermal absorption, single exposure inhalation, or repeated exposure inhalations. The ethylene dibromide used in these studies was the 99% pure, commercial quality product, except that the inhalation studies were conducted with a repurified commercial product of essentially 100% purity. Ethylene dibromide was administered in undiluted form for eye and dermal contact, dermal absorption, and inhalation studies; in olive oil and acacia emulsion or olive oil solution for oral intubation studies; in propylene glycol solution for eye contact studies; or in butyl carbitol acetate solution for dermal contact studies. Fifty-five female rabbits, 28 chicks, 40 male and female guinea pigs, 40 female rats, 60 male rats, and 20 female mice were administered ethylene dibromide at sufficient doses to enable calculation of single oral-dose LD50's of 55 mg/kg, 79 mg/kg, 110 mg/kg, 117 mg/kg, 146 mg/kg, and 420 mg/kg, respectively . The LD50's for male and female rats were significantly different (P<0.05). Of the five species tested, rabbits were the most sensitive to ethylene dibromide and mice were the least sensitive. Rowe et al found that undiluted ethylene dibromide promptly caused obvious pain and conlunctival irritation when introduced into the eyes of rabbits. The undiluted material was in contact with the eyes for 30 seconds before one eye was thoroughly flushed for 3 minutes with running water; the other eye was not washed. Both eyes of each rabbit were then observed for injury. The conjunctival irritation cleared within 48 hours, and a very slight amount of superficial necrosis of the cornea healed promptly and completely. When a 10% solution of ethylene dibromide in propylene glycol was tested in rabbits bv the same procedure used with the undiluted material, it produced a more severe response than did the undiluted material. Moderate conjunctival irritation developed within 2 hours and persisted for 48 hours before remission began to occur. Moderate-to-severe corneal injury also persisted for about 48 hours before tissue repair became evident. Healing was complete 12 days after exposure without corneal scarring being evident. No injury to the iris or the lens of the eye was noted. A 1% solution in propylene glycol elicited a response in the rabbit eye very similar to that of the undiluted material. The authors noted that prompt washing of the treated eyes had a beneficial effect in all cases, slightly reducing the intensity of the response and shortening the healing time. Application of undiluted ethylene dibromide or 10% solutions in butyl carbitol acetate to the shaved skins of rabbits killed the animals within 24 hours . It was apparent that a few hours of confined contact of the material with the skin caused marked erythema and edema. When evaporation was not inhibited by a covering, only slight erythema was noted. A 1.0% solution of ethylene dibromide in butyl carbitol acetate applied to rabbit ears 10 times in 14 days caused only slight erythema and exfoliation. When the solution was applied repeatedly for 10 times in 14 days onto the shaved abdomen of the rabbit and then bandaged, marked erythema and edema, which progressed to necrosis and exfoliation, were observed. Healing was complete without scarring within 7 days after termination of both exposures. Rowe et al found that absorption of undiluted ethylene dibromide at doses of 210, 300, 650, or 1,100 mg/kg through the intact skin killed 1 of 15 rabbits at 210 mg/kg and all 5 rabbits at 1,100 mg/kg when the exposures lasted for 24 hours. In all of the exposed animals, the material produced a moderate-to-severe erythema, edema, and necrosis of the skin and caused scar formation in the survivors. Marked central nervous system (CNS) depression was seen in rabbits at all of the doses. At the 650 and 1,100 mg/kg doses, the animals felt cold to the touch. Deaths occurred within 4 days or not at all. The authors did not calculate an LD50 for dermal absorption in the rabbits; however, an LD50 of approximately 400 mg/kg for ethylene dibromide can be estimated from the dose-response data. These investigators also studied the effects of single exposures of ethylene dibromide vapor to groups of 4-30 rats of both sexes at concentrations of 100, 200, 400, 800, 1,600, 3,000, 5,000, or 10,000 ppm (770, 1,540, 3,080, 6,160, 12,300, 23,100, 38,500, or 77,000 mg/cu m, respectively) and to guinea pigs of both sexes at 200 or 400 ppm (1,540 or 3,080 mg/cu m ) . At each concentration, the rats were exposed to the vapor for durations ranging from 0.02 to 16.0 hours to allow for the determination of concentration versus period of exposure values that represent death in essentially all of the rats, death in 50% of the rats, and death in essentially none of the rats. The findings of this study are presented in Table III-l. These data suggest that at concentrations above about 5,500 mg/cu m (715 ppm), the Haber product becomes actually almost a constant but that, at lower concentrations of ethylene dibromide, the Haber product increases rapidly as the concentration is lowered further. This suggests, in turn, that exposure of the rat to a concentration of about 5,500 mg/cu m (715 ppm, 29.2 /jmoles/liter) of ethylene dibromide saturates some detoxification mechanism. Whether this is metabolic or excretory in nature cannot be judged from these data. Adapted from Rowe et al Ethylene dibromlde produced only slight anesthetic effects at the concentrations used . Depression of the CNS was observed in rats exposed at the higher concentrations (unspecified). Deaths usually occurred within 24 hours at the higher concentrations and were caused by respiratory or cardiac failure. Deaths occurring from exposures at lower concentrations (unspecified) were generally delayed, sometimes for as long as 12 days after exposure. The majority of these deaths were caused by pneumonia. These animals usually lost weight, appeared rough and unkempt, became quite irritable, discharged what appeared to be a blood-tinged fluid from the nose, and finally died. Animals surviving the exposure at the lower concentrations exhibited a similar progression of toxic signs for several days before recovery was apparent. Rats exposed at concentrations producing mortality and killed for autopsy 16-24 hours after exposure showed an increase in the weight of the lungs, liver, and kidneys. The lungs were congested, edematous, hemorrhagic, and inflamed; the liver had cloudy swelling, centrilobular fatty degeneration, and necrosis; and the kidneys exhibited slight interstitial congestion and edema, with slight cloudy swelling of the tubular epithelium in some cases. Guinea pigs appeared to be slightly less susceptible than rats to the effects of ethylene dibromide vapor when exposed to the same concentrations. All guinea pigs exposed at 400 ppm (3,080 mg/cu m) for 7 hours died, whereas all those exposed at 400 ppm (3,080 mg/cu m) for 7 hours and at 200 ppm (1,540 mg/cu m) for 7 hours lived. The authors made no attempt to determine concentrations and corresponding exposure durations that would produce an LD99.99, LD50, or LD0.01 in guinea pigs, but they did postulate that 30 ppm (231 mg/cu m) for 5 hours was the most severe repeated exposure without detectable adverse effects. Rowe et al subjected rabbits, monkeys, guinea pigs, and rats to Two groups of controls, well-matched with the experimental animals with respect to number, age, sex, and body weight, were used in the experiment. One group was exposed to the same experimental regimen as the group exposed to ethylene dibromide, but in a chamber ventilated with clean air. The second control group was simply maintained in the animal quarters. During the test period, 10 of 20 ethylene dibromide-exposed male rats died, primarily from pneumonia and upper respiratory tract infections, and 3 of 20 ethylene dibromide-exposed female rats died from unspecified causes . Twenty-three additional female rats subjected to 13 7-hour exposures at 25 ppm (192.5 mg/cu m) in 17 days showed no ill effects and were found to have total liver lipid contents similar to those of control rats. Groups of 8 male and 8 female guinea pigs tolerated 145 7-hour exposures at 25 ppm (192.5 mg/cu m) in 205 days without evidence of adverse effects as judged by the same criteria used to evaluate the rat data, except that liver lipid determinations were not conducted. Mortality during the experiment, caused by pulmonary infections, was 50% in male and 25% in female guinea pigs exposed to ethylene dibromide. Eighteen of the 20 animals in both the male and female control groups exposed to clean air survived the experimental regimen, but only 7 and 8 of the 20 females and males, respectively, in the unexposed control groups survived. An additional group of 8 female guinea pigs received 13 7-hour exposures at 25 ppm (192.5 mg/cu m) in 17 days without exhibiting adverse effects. Rabbits, 3 male and 1 female, and monkeys, 1 male and 1 female, were subjected to 152 7-hour exposures in 214 days and 156 7-hour exposures in 220 days, respectively, at 25 ppm (192.5 mg/cu m ) . There were no signs of adverse effects in the rabbits and monkeys when judged by the above criteria for the guinea pig data. Since an unusually high mortality rate was observed in the nonexposed control rats but not in the air-exposed control animals, no decisive conclusions can be drawn from the published data with respect to the hazard resulting from exposure to ethylene dibromide at 25 ppm (192.5 mg/cu m ) . Rowe and his colleagues found that rats, guinea pigs, monkeys, and rabbits did not tolerate ethylene dibromide well at a concentration of 50 ppm (385 mg/cu m) administered 7 hours/day, 5 days/week, for 70-90 days. The group of 20 male and 20 female rats receiving 63 exposures in 91 days exhibited increased liver and kidney weights in both sexes, increased lung weights in males, decreased spleen weights in females, and decreased testis weights in males at autopsy. The group of 8 male and 8 female guinea pigs receiving 57 exposures in 80 days showed decreased rates of growth and final body weights, increased organ weights, slight central fatty degeneration of the livers, and slight interstitial congestion and edema with degeneration of the tubular epithelium in the kidneys. The 1 male and 3 female rabbits receiving 59 exposures in 84 days showed only small increases in liver and kidney weights; no other adverse effects were noted. The male and female monkeys receiving 49 exposures in 70 days appeared ill, nervous, and unkempt throughout the experimental period. Liver weights were increased and very slight central fatty degeneration of the liver was noted; no other adverse effects were noted from microscopic examination of the body organs. At concentrations of 100 ppm (770 mg/cu m) of ethylene dibromide vapor, 10 female rats steadily lost weight and 3 died after 1, 5, and 7 exposures, respectively, for 7 hours/day . The remaining rats appeared thin and unkempt at the time of autopsy after seven exposures in 9 days. The stomachs were full of food which appeared blood tinged, and lung, liver, and kidney weights were increased markedly. Microscopic examination showed some thickening of the alveolar walls with slight leukocytic infiltration of the lungs, widespread cloudy swelling of the liver, and slight congestion and hemosiderin deposition in the spleen. Rabbits subjected to the same concentration suffered severe intoxication to the extent that two of four died after the second 7-hour exposure and the third died while receiving the third exposure. The fourth animal was killed after receiving the fourth exposure in 4 days. Microscopic examination of tissues from the last two rabbits showed widespread central fatty degeneration of the liver with some necrosis. The authors concluded from the above series of experiments that ethylene dibromide was a fairly toxic, markedly irritating material. They postulated that ingestion of 1.5-2.0 ml (3.3-4.4 g) of undiluted ethylene dibromide could jeopardize the life of the average human and that this amount of material could easily be swallowed by accident. Rowe et al pointed out that, although ethylene dibromide was not likely to cause permanent injury to the eye, it probably would cause appreciable pain and suffering; thus, eye protection was strongly recommended for those handling ethylene dibromide. Although the hazard of contact with uncovered skin was not thought to be particularly serious unless repeated or prolonged, marked irritation and rapid absorption of ethylene dibromide occurred when it was confined to the skin. Ethylene dibromide vapor at 50 ppm (385 mg/cu m) repeated daily was not well tolerated by the species tested, whereas adverse effects were not believed to have resulted from exposure at 25 ppm Ethylene dibromide administration was discontinued in two of the four bulls to ascertain the reversibility of the exposure, and was later readministered to one of these two to determine the time needed for ethylene dibromide's action to be effective . In the first animal, almost normal spermatozoa (the acrosomes were not entirely restored) were obtained after exposure had been discontinued for 1 month; semen of normal density, spermatozoic motility, and sperm cell forms was obtained 3.5 months after discontinuation. In the second bull, normal semen was obtained 10 days after administration was stopped. After 2 further weeks of renewed exposure, semen from the second bull began exhibiting the same abnormalities as described above for bulls receiving ethylene dibromide on the continuous schedule. A previously unexposed 16-month-old bull of the same breed was fed ethylene dibromide at 2 mg/kg/day for 3 weeks. After 2 weeks, his semen exhibited the abnormalities described above, which persisted for a month after exposure ended. The semen quality improved, but normal semen was not obtained until 2-3 months after administration stopped. From these experiments, the authors concluded that quantities of ethylene dibromide, equivalent to two or three times that expected in insufficiently aired grains, caused definite reproductive impairment when fed daily or every other day to bulls. Semen density and spermatozoic motility decreased sharply and the spermatozoa were of abnormal shape after only 2 weeks of exposure. Recovery occurred in 10 days-3 months in the animals tested. Resumption of exposure caused the abnormalities to return. Studies to determine whether the reproductive impairment was prolonged after repeated removal and reinstatement of ethylene dibromide diets were not conducted. However, in the one bull that was reexposed after a period of discontinuation, the time necessary for recovery of normal spermatozoic production increased from 10 days after the first discontinuation to 2-3 months after the second. In Eleven bulls (D Amir, written communication, August 1976) given ethylene dibromide in olive oil were 15-24 months of age and weighed 400-500 kg. The two remaining bulls given ethylene dibromide in olive oil were 4.5 and 5 years of age and weighed 950 and 1,050 kg, respectively. Six young bulls, 15-24 months of age, were used as controls; three were given olive oil and three remained as negative controls. Six of the 11 young bulls given ethylene dibromide and the 6 control bulls were castrated or killed (number killed or castrated not specified) 1 day after receiving the last oral dose. Semen was collected from the seven remaining bulls two or three times a week for 2 months after the first dose and once or twice a week for the next 2 months. Spermatozoic concentration, motility, and malformation were determined microscopically from at least 400 randomly chosen spermatozoa from each semen sample. In the control bulls, 2-4% of the spermatozoa taken from various places along the genital tract had misshapen heads, and distribution of the malformed spermatozoa was uniform throughout the tract. In the animals that were killed or castrated, the number of spermatozoa exhibiting abnormal, mainly pear-shaped heads was markedly increased in the ethylene dibromide bulls over that of the controls and varied in distribution in the genital tracts of the different bulls. Amir attributed the distributional pattern of abnormal spermatozoa in the genital tract to the variation in the time of release of the spermatozoa through the ductus deferens caused by individual variations in the doseresponse threshold of the bulls. In the semen samples collected from the five young bulls, maximum numbers of spermatozoa with misshapen heads appeared in the ejaculates 2-10 days after the cessation of ethylene dibromide administration . Again, these differences were thought to be caused by differences in the sperm transit time through the epididymis as well as to the variation in release time of the affected spermatozoa from the testes. The effect of ethylene dibromide was more acute in the adult than in the young bulls. The concentrations of spermatozoa in the younger bulls were only slightly affected by the doses, but were greatly reduced in the older bulls. Normal spermatozoic concentrations were regained after 1 and 4 months in the two older bulls. During the period of low spermatozoic concentration, the ejaculates of the older bulls contained much spermatozoic debris and many spermatids and spermatocytes; the debris presumably came from further disintegration of the abnormal spermatozoa. The number of abnormal spermatozoa in the young bulls decreased to about normal within 3 weeks after the last dose, but remained elevated in the two adult bulls for about 15 weeks. The author concluded that ethylene dibromide affected spermiogenesis in the young bulls since the abnormalities in the spermatozoa observed in the ejaculates persisted for a period that coincided with the duration of spermiogenesis in the bull, which is about 3 weeks. Amir also concluded that either ethylene dibromide affected earlier stages of the spermatogenic process in adult bulls or its elimination from the circulation of young bulls was more rapid. In 3 weeks. They also observed that hens that had ceased egg production could not be induced to lay again by feeding them a bromide-free diet, even after feeding continued for several months. To determine the effects of small amounts of ethylene dibromide in grain on egg laying, the authors subjected 4 groups of 16 6-month-old hens each at concentrations of ethylene dibromide in grain ranging from 0 to 30 ppm (total ration concentrations of 0-15 ppm). In addition to the ethylene dibromide, small amounts of "residual bromide," defined as the bromine-containing material remaining in sorghum grain that had been fumigated with ethylene dibromide and then aerated to remove free ethylene Sixty 1-day-old female chicks were divided equally into two groups, the first was fed twice daily a commercial mash containing 40 ppm of ethylene dibromide and the second served as controls in a paired-feeding design. Weights and feed consumption were recorded weekly up to 10 weeks of age. Feed intake, weight gain, onset of egg production at 4.5-5 months, and incidence of double-yolked eggs were the same for the experimental and control groups. The weight of eggs from the group receiving ethylene dibromide was significantly lower (P<0.01) than from the controls and the number of eggs laid by the hens receiving ethylene dibromide approached statistical significance, lowering below that of the control hens. In a second experiment , two groups of 12 1-year-old hens in full egg production were fed for 4 weeks a commercial mash with or without 100 ppm of ethylene dibromide. At the end of 4 weeks, egg weight in the hens fed ethylene dibromide had significantly decreased from an average of 63 to 43 g. Both groups were then artificially inseminated twice at 7-day intervals with 0.1 ml of semen/hen. Eggs collected between the 2nd day after the first insemination and the 7th day after the second insemination were examined for embryos. A striking reduction in the fertilization rate, with no live embryos at all, was noted in the ethylene dibromide-fed group; only 2 of 16 eggs were fertilized as compared with 48 of 56 eggs from the control group, and both fertilized eggs from the ethylene dibromide group contained dead embryos. Similarly, a third experiment was conducted to determine the effects of ethylene dibromide on male chicken growth rate and sexual development. Three groups of 20 3-day-old cockerels were fed mash containing 0, 80, or 180 ppm of ethylene dibromide in which the amount of feed intake by the 180-ppm group determined the amounts of food given to the control and 80-ppm groups. Three additional groups of 25 cockerels were each fed mash containing 0, 150, or 300 ppm of ethylene dibromide without restrictions on the intake. At 6 weeks, the cockerels fed 150 ppm of ethylene dibromide showed a reduced weight gain when compared with the controls. Only cockerels fed the 300-ppm ethylene dibromide diet without restrictions on food intake showed significant growth retardation and an apparent feed intake depression at 12 weeks of age; however, the weight gain to feed intake ratio was not significantly different. The cockerels receiving the regulated diets were killed at 3 months of age, and the bromide content of the testes, spermatozoic count and activity, and testes weight were determined. Significant amounts of bromide were found in the testes of the ethylene dibromide-fed groups, but differences were not observed in spermiogenic activity, spermatozoic count, or testes weight between the control and ethylene dibromide-fed groups. The remaining unrestricted-intake cockerel groups were examined at the age of 9 months by collecting semen samples three times at weekly intervals and were killed at 12 months of age for testicular examination and measurement of body, testes, and comb weights. Semen collected and examined from ethylene dibromide-fed cockerels did not differ significantly from that of the controls. Comb weights at death declined sharply with increasing concentrations of ethylene dibromide in the diet; however, body and testes weights were not affected by the ethylene dibromide. Another experiment was conducted to determine if ethylene dibromide administration to adult cockerels would affect fertility rates and hatchability of eggs. Eleven mature cockerels each were fed for 105 days a control mash or mash containing 300 ppm of ethylene dibromide. Semen was collected about 2, 4, 8, and 10 weeks after the beginning of the experiment. No significant differences were seen between the semen of the controls and that of the cockerels fed ethylene dibromide with respect to ejaculated volume and spermatozoic motility and concentration. Subsequent fertilization tests in hens conducted with the pooled semen collected from the ethylene dibromide-fed and control groups gave no significant differences in fertilization rate or hatchability of eggs at 60 or 105 days. The authors concluded that prolonged feeding of mash containing ethylene dibromide significantly depressed growth of male chickens when fed without restrictions, but that the depression seemed to result from reduced food intake and not from the direct action of ethylene dibromide. They also concluded that ethylene dibromide had no effect on the onset of egg production in hens fed from birth, on sexual development in males and females, and on sperm characteristics or fertility in mature males. However, statistically significant reductions in egg size and egg fertility were noted in hens fed ethylene dibromide. previously given ethylene dibromide as described above. The weights of whole eggs and yolks were compared for each hen prior to, during, and for 10 days after the injections. Injection of the purified hormone did not change the total egg weight or the weight of the yolks, which both remained lower than comparable control values. The authors concluded from the above four experiments that ethylene dibromide did not affect pituitary FSH concentrations in treated hens. The injection of FSH preparations did not reverse the adverse effects of ethylene dibromide; therefore, the effects of ethylene dibromide on egg laying did not seem to be connected with impaired formation or release of FSH. In an attempt to clarify the causes of smaller eggs in laying hens fed ethylene dibromide-fumigated mash In 1970, Edwards et al investigated the antifertility effects of ethylene dibromide in an unspecified number of adult male Wistar rats. Doses of 10 mg/kg were injected ip into 250-g rats for 5 consecutive days. The average live litter size from six female rats serially mated on a weekly schedule with the males receiving ethylene dibromide decreased substantially during the 3rd week and drastically (to zero) during the 4th week after administration. From the authors' data, the average litter size appears normal during the 5th week and for every week thereafter. The authors concluded that the antifertility effects resulted from ethylene dibromide selectively damaging the spermatid cells, since the short course of exposure produced only transient sterility in rats and corresponded in time to changes that would result from spermatid damage. In an additional study , the major metabolite of ethylene dibromide in urine, S-(2hydroxyethyl)-cysteine, was reported to have produced no effect on male mouse fertility at a dose of 1,000 mg/kg when administered daily for 5 days by oral intubation, although experimental details and data were not presented. The data indicate that oral exposure to ethylene dibromide induces temporary sterility in male rats. However, further evaluation of the data is not possible because of the lack of experimental details, such as number of test animals or any data about control animals, that were not given by the authors in the publication. Differences have been reported in the abilities of rats and chickens to detoxify ethylene dibromide. Nachtomi et al and Nachtomi and Alumot observed that rats possessed a much greater ability to conjugate glutathione with ethylene dibromide than chicks . In addition, the rat liver formed significant amounts of lipids containing conjugated double bonds as a result of the peroxidation of lipids induced by ethylene dibromide in the liver microsomal supernatant fraction, whereas chicken liver was relatively inactive . Also, the concentration of triglycerides increased significantly in the rat liver, probably as a direct result of the formation of conjugated double bonds discussed above. In 1970, Edwards and coworkers reported the tissue distribution of radioisotope at various time periods after an ip injection of 40 mg/kg of carbon-labeled (14 C) ethylene dibromide in mice. The data are presented in Table XII-3. One hour after injection, most of the 14Cradioactivity was found in the small intestine, with smaller amounts being found, in descending order, in the kidneys, liver, blood plasma, whole blood, large intestine, fat, and spleen. After 3 hours, the majority of the radioisotope was present in the large intestine, kidneys, and blood plasma, with smaller amounts being present in the whole blood, liver, small intestine, and spleen. After 24 hours, all tissues were below 1.0% retention of 14C-radioisotope except for the whole blood, blood plasma, stomach, and kidneys. After 1 hour, essentially all of the administered radioisotope was present in the various mouse tissues, whereas only 89% was present after 3 hours and 16% after 24 hours. It is of interest to note that 3.1, 4.4, and 0.66% of the administered radioisotope was detected in the tail of the epididymis 1, 3, and 24 hours after injection, respectively. Smaller amounts of 14C-radioisotope, up to 1.5% at 3 hours, were also present in the testes. The data presented by the authors suggest that ethylene dibromide is rapidly distributed to a wide variety of tissues. Major concentrations of radioisotope accumulated in the liver, kidneys, and digestive tract. There also seems to be a rapid depletion of radioisotope from the tissues, but the residual radioactive material is still widely distributed throughout the body tissues. In 1976, Plotnick and Conner conducted a similar study of the tissue distribution of carbon-labeled (14 C) ethylene dibromide in guinea pigs. The ethylene dibromide was administered in a single ip injection of 30 mg/kg and tissue samples were collected 4-72 hours after the injection. The data are presented in Tables XII-4 and XII-5. At all intervals studied, the highest concentration of radioactivity derived from ethylene dibromide as lig/g of tissue was found in the kidneys, liver, and adrenal glands. At all time periods studied, the organs containing the highest percentage of the administered dose were the liver and kidneys. Approximately 66% of the injected dose was excreted in the urine over the 72-hour study, 15% of which was in the first 4 hours, and approximately 3% was excreted in the feces. Plotnick and Conner mentioned that unpublished preliminary studies by their laboratory "strongly suggest that excretion of unchanged ethylene dibromide in the expired air also represents a significant (10-12% of the dose) route of excretion." From the data of Edwards et al and Plotnick and Conner , it seems that a relationship may exist between the tissue distribution and the destructive tissue changes, particularly with respect to the liver and kidney damage, in other animal and human studies reported previously in this chapter. # Carcinogenic, Mutagenic, and Teratogenic Studies (a) Carcinogenesis In 1973, Olson et al reported the results of a preliminary investigation to determine the potential carcinogenic effects of ethylene dibromide in rats and mice of both sexes by oral administration. Further statements by Powers et al and Ward and Habermann Initially the only deleterious effect of ethylene dibromide on the rats was a depression in weight gain . As early as 10 weeks after the initiation of the experiment (dose not stated), one squamous cell carcinoma of the stomach was noted in one male and in one female rat. Squamous cell carcinomas of the stomach became more prevalent as the experiment progressed, developing in 83 of 100 male rats and in 70 of 100 female rats intubated with ethylene dibromide. The tumors originated in the forestomach, invaded locally, and eventually metastasized throughout the abdominal cavity. Only one mammary tumor in a female rat was noted in the concurrent corn oil controls; however, in the untreated control group, 6 of 20 male rats and 14 of 20 female rats developed tumors, none of which were squamous cell carcinomas of the stomach. Tumor incidence was 68% in the male rats receiving ethylene dibromide at 80 mg/kg/day versus 98% in those receiving 40 mg/kg/day, and it was 58% in the female rats at 80 mg/kg/day versus 82% at 40 mg/kg/day. Olson et al postulated that this decreased incidence of tumorigenesis may have resulted from the earlier death of the animals receiving the higher dose or because the animals did not receive ethylene dibromide for a 14-week period between weeks 16 and 30. The induction sequence and results of microscopic examinations were discussed in detail only for the male rats receiving the 40 mg/kg dose, since the authors considered the induction and progression of the tumors to be similar in all experimental groups . All 50 male rats had stomach lesions, although one did not contain a neoplasm. The forestomachs had diffuse squamous cell hyperplasia with many papillomatous projections. Focal areas of invasion were reported from the origin of the carcinomas. Invasion occurred through the stomach wall to the peritoneal cavity, where nodules were reported in 70% of the rats. The metastatic tumors were less differentiated or formed keratin pearls, often accompanied by abcesses or peritonitis. The authors stated that other types of tumors and lesions were also present in a few rats, including mesotheliomas, intestinal tumors, nodular hyperplasias of the liver, and poorly differentiated stomach tumors. Each group of mice received ethylene dibromide in doses of 60 or 120 mg/kg/day for 13 weeks . After 13 weeks, the doses were increased to 100 and 200 mg/kg/day but were reduced to the original doses after 2 weeks because of toxicity. At 42 weeks, the daily dose of ethylene dibromide for all mice was changed to 60 mg/kg/day. At 42 weeks, one male and one female mouse developed squamous cell carcinomas of the stomach at the higher dose regimen, and three males and two females at the lower regimen. High early mortality was encountered in mice receiving the higher dose (40%). No It seems that ethylene dibromide caused an increased incidence of gastric carcinoma in rats treated by intubation with either 40 mg/kg/day or an ordered combination of 80, 0, and 40 mg/kg/day. Carcinomas were found to originate at the site of administration (the stomach) in both species, to invade locally, and eventually to metastasize throughout the abdomen . Also, 72 of 145 mice that developed squamous cell carcinomas were diagnosed after week 59, whereas the vehicle controls were killed at week 59. # (b) Mutagenesis In 1972, Buselmaier et al reported the results of an investigation to determine the potential for ethylene dibromide to induce mutations in the host-mediated assay with Salmonella typhimurium G46 and Serratia marcescens a21 Leu-in NMRI mice and in the in vitro plate test with Salmonella typhimurium G46. Immediately after ip inlection of each bacterial strain, 500 mg/kg of ethylene dibromide emulsified in edible oil was injected subcutaneously into one hind leg of six 10-to 12-week-old mice. Three hours after the injections, they were killed and the fluid from the peritoneal cavity was collected for plating to determine the number of mutant colonies induced. In the comparative in vitro plate test with Salmonella typhimurium, a concentration equivalent to the 500 mg/kg dose was applied to a filter paper disc in the center of the plate, and after a 12-hour incubation, the number of mutant colonies were counted. The investigators found that ethylene dibromide was definitely mutagenic in the host-mediated assay with Salmonella typhimurium G46 and in vitro with the same organism. The mutation frequencies for Salmonella typhimurium G46 in the host-mediated assay were 0.77 x 10"8 in the control test and 6.23 x 10-8 in the experimental test. The ethylene dibromideexposed mutation frequency was significantly different (P<0.01) from the control. The in vitro plate test results were also positive. Ethylene dibromide did not induce a significant number of mutants in the hostmediated assay with Serratia marcescens a21 (6.93 x 10"7 for control, 2.43 x 10" 7 for ethylene dibromide-exposed). The authors concluded that ethylene dibromide did not require activation through in vivo metabolism to exert its mutagenic effects on Salmonella typhimurium, nor did metabolism of ethylene dibromide sufficiently deactivate its mutagenic potential, since both the host-mediated assay and the in vitro plate tests were positive. In 1972, Epstein et al published the results of a screening study on the detection of chemical mutagens by a dominant lethal assay in ICR/Ha Swiss mice. Ethylene dibromide was tested along with 173 other industrially important chemicals or chemical mixtures. Ten male mice, 8to 10-weeks-old, were given 0, 50, or 100 mg/kg of ethylene dibromide for 5 consecutive days by oral administration and were then mated weekly with three different virgin 8-to 10-week-old female mice for 8 consecutive weeks. One male mouse died at the 50 mg/kg dose and two males died at the 100 mg/kg dose during the experiment. Two different groups of seven or nine male mice received single ip injections of 18 or 90 mg/kg of ethylene dibromide, respectively, and were then mated as above. The mated females were killed about the 13th day after presumptive mating and were scored for the number of total implants, live implants, early fetal deaths, and pregnancies. The experimental animal scores were contrasted to concurrent control scores. The authors included ethylene dibromide in a class of agents which did not meet "any screening criteria for mutagenic effects," although specific data for ethylene dibromide were not presented. No effect of ethylene dibromide on fertility was reported in this paper, which differs from the finding of Edwards et al . In 1973, Clive tested the mutagenic potential of ethylene dibromide on the back mutation frequency of the thymidine kinase locus in a mammalian somatic cell tissue culture derived from mouse lymphoma cells. The L5178Y mouse lymphoma cells were exposed to ethylene dibromide at concentrations of 0.0-3.0 mM in culture media for 2 hours. The exposed cells displayed an induced mutational frequency that was dose related and typical of other alkylating agents, such as methyl methanesulfonate and ethyl methanesulfonate. Thirteen new mutations for each 10,000 surviving cells were found under these experimental conditions . The frequency of induced mutations generally increased monotonically after exposure of the cells to increasing concentrations of ethylene dibromide. The induced mutation frequency indicated that ethylene dibromide was mutagenic over the entire range of experimental concentrations when plotted against the growth inhibition, although less potent than ethyl methanesulfonate (an induced mutational frequency of about 2/10,000 cells versus one of 7/10,000 cells at 60% growth inhibition, respectively). The induced mutational frequency in L5178Y mouse lymphoma cells corresponded with that of a mutational frequency of over 600 R of X-irradiation at the highest concentration. Clive concluded that ethylene dibromide was mutagenic to the L5178Y mouse lymphoma cells although not as potent as ethyl methanesulfonate. In 1974, Meneghini reported the results of an investigation to determine the potential for ethylene dibromide to induce DNA repair synthesis in cultured opossum lymphocytes. Two-year-old opossums, Didelphis virginiana, were used to obtain lymphocytes for culture. Blood was removed from their tails and lymphocyte suspensions were prepared and maintained at 37 C. Samples containing about 5 x 10^ cells/ml were incubated with various concentrations of ethylene dibromide for 1 hour at 37 C. At the end of this period, the cells were incubated in culture media with 3H-thymidine for 4 hours to allow for DNA radiolabeling to occur. Control cells were processed as above, but without exposure with ethylene dibromide. At concentrations between 0.001 and 1 mM, ethylene dibromide was very effective in inducing DNA repair in opossum lymphocytes . Repair induction decreased at a concentration of 10 mM of ethylene dibromide, which was presumed to be the result of repair-inhibition phenomena such as those observed for ultraviolet-induced repair. The author indicated that ethylene dibromide was very effective in inducing DNA repair in a manner similar to other alkylating agents, such as methyl methanesulfonate and ethyl methanesulfonate, which were also studied. He stated that only compounds that interact with DNA through covalent bonds induce repair synthesis. Therefore, these data suggest that ethylene dibromide, or its metabolites, may interact via covalent bonding with DNA. In 1974, Vogel and Chandler measured the possible genetic effects induced by ethylene dibromide in sex-linked lethal tests with fruit flies, Drosophila melanogaster. The adult Berlin K male flies were allowed to feed on a 0.3-mM ethylene dibromide solution for 3 days before being allowed to mate with two females for 3 days. A sequence of two 3-day brood periods was initiated (broods 1 and 2), followed by one 4-day brood period (brood 3). At the end of each 3-day breeding period, the treated males were transferred to a new vial and were allowed to mate with two new females. The frequencies of recessive lethal mutations in meiotic and postmeiotic germ cells were determined in the offspring of treated and control males. Ethylene dibromide induced significant numbers of recessive lethal mutations in the offspring of all three broods. These were 0.50, 1.49, and 1.30% in broods 1, 2, and 3, respectively, and an average lethal frequency for all broods of 1.10%. The authors concluded that the brood pattern resulting from ethylene dibromide exposure was consistent with the action of chemicals that affect spermatids and spermatocytes because of the higher incidence of recessive lethal mutations in broods 2 and 3. The authors considered ethylene dibromide to be a bifunctional alkylating agent capable of introducing cross-links into large biologic molecules, and to be definitely mutagenic in Drosophila melanogaster. In 1971, Ames published the results of an experiment to determine the mutagenic potential of ethylene dibromide to the his-G46 and TA 1530 strains of Salmonella typhimurium. Ethylene dibromide inhibited the growth of the E coli pol Al-strain preferentially to isogenic pol A+ strain as indicated by zone of inhibition diameters of 20 versus 15 mm, respectively, at concentrations of 10 /¿I (22.0 mg)/plate . for the induction of back mutations at the his-G46 locus in Salmonella typhimurium. In 1975, Alper and Ames published the results of a study to determine whether ethylene dibromide or 39 other agents could cause mutants by chromosomal deletions of various lengths in Salmonella typhimurium LT2 and Salmonella typhimurium galE503. Bacteria were poured onto agar plates as suspensions in top agar and were incubated for 8 hours. A few drops of the test compound, 1-5 ¡il (2.2-11.0 mg), were placed near the edge of the plate immediately after the top agar had solidified. The number of colonies clustered within a 3.5-cm radius of the spot where the compound was applied was used as an index of the extent of mutagenesis. The zone of inhibition for ethylene dibromide was reported as less than 1.5 cm from the application spot, but specific data were not presented. Although no experimental data were given, ethylene dibromide was included in a list of compounds which failed to increase the frequency of deletion mutants by as much as fourfold over that of the control. In 1974, Sparrow et al # Ethylene dibromide has been reported to induce mutations in Neurospora crassa , but complete experimental details were not given in these abstracts. (c) # Teratogenesis In 1976, Short et al examined the effects of ethylene dibromide vapor on rats and mice during organogenesis. The production of congenital defects was used as a measure of inherent toxicity. Female Charles River CD rats or female CD-I mice were caged overnight with proven male breeders; successfully bred females were identified the next morning by the presence of sperm in vaginal smears from rats or of copulation plugs in mice. Pregnant animals were divided into a control group of 18 rats and 17 mice which would receive a normal diet without inhalation exposure to ethylene dibromide, a group of 18 rats and 13 mice to receive 31.6 ppm (243.32 mg/cu m) of ethylene dibromide and a normal diet, and a group of 17 rats and 9 mice to receive a restricted diet without exposure to ethylene dibromide. All groups of animals were housed in the inhalation chambers for 10 consecutive days beginning on day 6 of gestation. During this time, the groups to be given ethylene dibromide were exposed to the vapor at an average concentration of 31.6 ±1.9 ppm (243.32 ± 14.63 mg/cu m) for 23 hours a day. Rats and mice were killed on gestational day 20 or 18, respectively. Fetuses were surgically removed from the dams, weighed, examined for external anomalies, and fixed for either soft-tissue or skeletal examinations. Ethylene dibromide exposure did not produce mortality in either pregnant rats or mice during the 10-day inhalation period; however, two of nine pregnant mice from the restricted diet group died. Both rats and mice exposed to ethylene dibromide consumed less feed and gained significantly (P<0.05) less weight than the controls during the exposure period, although feed consumption and weight gain returned to normal after cessation of the exposure on the 15th day of pregnancy. Ethylene dibromide-exposed rats consumed about twice as much food daily as did the feed-restricted rats (10.5 ± 0.6 versus 5.0 ± 0.1 g/day, respectively), but only about one-half of that consumed by the controls (10.5 ± 0.6 versus 21.1 ± 0.4 g/day, respectively). Rats exposed to ethylene dibromide at a concentration of 31.6 ppm The authors concluded that the above-mentioned effects of ethylene dibromide exposure in mice were most likely attributable to malnourishment rather than to ethylene dibromide exposure. It is apparent from the authors' data that some of the anomalies may be compounded by the presence of ethylene dibromide. In addition, if the malnourished controls and ethylene dibromide-exposed animals had been compared with the nonexposed controls at the same statistical probability levels, only the ethylene dibromide-exposed animals would have been significantly different from the controls. Skeletal anomalies, in particular the variations in ossification of the incus and supraoccipital bones, were much more prevalent in the ethylene dibromide-exposed mice than in the feedrestricted mice (80-90% of the litters versus 33-50%, respectively). The authors also attributed many of the observed anomalies in the rat dams and fetuses exposed to ethylene dibromide to malnutrition rather than to direct effects of ethylene dibromide exposure. However, they concluded that the increase in the fourth ventricular "hydrocephaly," the reduction in the occurrence of the fourteenth rib, and the increase in the frequency of wavy ribs could be correlated to ethylene dibromide exposure in the rat. The significance of the effects of malnutrition in rats is not clear, and even though ethylene dibromide-exposed rats consumed less food than did controls, they consumed more food than did the rats in the feed-restricted group. It is apparent, however, that an increase in the incidence of anomalies in fetal rats was induced by exposure to the one concentration of ethylene dibromide, but no dose-response relationship for this action is available. # Correlation of Exposure and Effect Neither studies that correlate workplace concentrations of ethylene dibromide with observed toxic effects nor any epidemiologic studies have been found. Few reports of human exposure to ethylene dibromide exist. Adverse effects resulting from exposure of experimental animals to ethylene dibromide are similar to those described for human exposures and include ocular, dermal, and respiratory irritation and systemic effects on the liver, kidneys, spleen, circulatory system, and nervous system. The effects of ethylene dibromide exposure on the eyes have been noted in several animal species. Merzbach discovered that a dog exposed for 1 hour to 1 ml (2.2 g) of ethylene dibromide vaporized into a 100-liter chamber showed signs of ocular irritation during the exposure. Five hours after the exposure ended, a milky-blue corneal opacity developed which became more pronounced and developed into purulent conjunctivitis in both eyes and an ulcer in one eye. Kochmann showed that 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day produced conjunctivitis in cats exposed to the vapor repeatedly until death occurred at approximately 10 days. Rowe et al reported that instillation of undiluted ezhylene dibromide into the eyes of rabbits caused conjunctival izritation that cleared within 48 hours and left only very slight superficial corneal necrosis which healed completely. Rowe et al also found that a 10% solution of ethylene dibromide in propylene glycol produced a more severe reaction in the eye than did the undiluted material. Moderate conjunctival and corneal irritation developed and persisted for 48 hours; healing was complete within 12 days without corneal scarring. A 1% solution produced an effect similar to that caused by the undiluted material. These reports indicate that ethylene dibromide can cause adverse ocular effects after exposure to 1 and 10% solutions, as well as to the undiluted material. The skin of experimental animals is susceptible to penetration and local surface effects resulting from exposure to ethylene dibromide. Thomas and Yant noted that liquid ethylene dibromide at doses of 0.25, 0.50, and 1.0 ml (0.55, 1.1 and 2.2 g)/animal produced marked hyperemia of the small cutaneous blood vessels of the shaved abdomens of rats. All animals died within 6-18 hours after application. Rowe et al found that undiluted ethylene dibromide or a 10% solution in butyl carbitol acetate killed within 24 hours all rabbits to which it was applied dermally; subsequent experiments showed that the dermal LD50 was about 400 mg/kg. Marked erythema and edema were noted when the material was prevented from evaporating from the skin, whereas only slight erythema was noted when evaporation was not inhibited. Undiluted doses of about 210 mg/kg produced a moderate-to-severe erythema, edema, and necrosis of the skin. Similar results were described by Pflesser in human volunteers exposed to 0.5 ml (1.1 g) of liquid ethylene dibromide for 1-30 minutes by placing small quantities on their arms or hands. Confinement produced more extensive erythema and edema surrounding the application site, and, in one case, blistering occurred as a result of continued contact between ethylene dibromide and the skin. These investigations indicate that localized surface effects on the skin, such as erythema, edema, blistering, or necrosis, may occur after contact with either undiluted or 10% solutions of ethylene dibromide. Percutaneous absorption of 10% solutions has also caused death in experimental animals. Respiratory irritation after single exposures to ethylene dibromide vapor has been reported in guinea pigs at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, and 2,000 ppm (15,400 mg/cu m) for 150 minutes , and in cats exposed at 100 ppm (770 mg/cu m) for 30 minutes . In cats, three 30-minute exposures at 100 ppm (770 mg/cu tn) produced signs of nasal irritation that consisted of a strong reddening of the nasal mucosa . Lucas demonstrated that a 12-minute exposure of a rabbit to ethylene dibromide vapor caused the lungs to become enlarged and filled with a frothy exudate. Merzbach found that 5 ml (11.0 g) of ethylene dibromide allowed to vaporize in a 100-liter chamber produced severe bleeding in the right lung of a dog exposed for 1 hour. Another dog exposed to the vapor of 1 ml (2.2 g) for 1 hour developed severe hyperemia and bronchopneumonic foci in both lungs. Rowe et al showed that death occurring in rats exposed to ethylene dibromide at concentrations of 100-10,000 ppm (770-77,000 mg/cu m) for 0.02-16.0 hours was caused by respiratory or cardiac failure at the higher exposures and by pneumonia at the lower ones. The lungs of animals exposed at these concentrations were congested, edematous, hemorrhagic, and inflamed. Respiratory irritation has also been noted after the repeated inhalation exposure of cats at 100 ppm (770 mg/cu m) to ethylene dibromide for 30 minutes daily for an average of 10 days. This concentration produced dark red discolorations in the lungs, and the lungs were partially nonfunctional . Rowe et al reported on lethal dose rates in rats exposed to ethylene dibromide for 0.02-16.0 hours at concentrations of 100-10,000 ppm (770-77,000 mg/cu m). Death was caused by respiratory or cardiac failure at the higher concentrations and by pneumonia at the lower ones. Half of the male rats exposed at 25 ppm (192.5 mg/cu m) for 7 hours/day for 151 exposures in 213 days died during the experiment, primarily from pneumonia and upper respiratory tract infection. Pulmonary infections were also responsible for a 50% mortality in male guinea pigs and a 25% mortality in females exposed at 25 ppm (192.5 mg/cu m) for 7 hours/day for 145 exposures in 205 days . Systemic parenchymal cell damage, particularly in the liver, kidneys, and spleen, develops after single and repeated exposure of experimental animals to ethylene dibromide vapor. Thomas and Yant observed that guinea pigs receiving single exposures of ethylene dibromide vapor at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes had a slight granular degeneration of the parenchymal tissue of the liver. Rabbits exposed to an unknown concentration of ethylene dibromide vapor for 10 or 12 minutes had enlarged livers, with slight-to-moderate diffuse fatty changes evident in the rabbit exposed for 10 minutes . Merzbach published a study detailing similar results in a dog exposed to 1 ml (2.2 g) of vaporized ethylene dibromide in a 100-liter chamber for 1 hour; autopsy showed that a pronounced fatty degeneration of the liver had occurred. Rowe et al observed that rats exposed at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours developed cloudy swelling, centrilobular fatty degeneration, and necrosis of the liver. Repeated exposure at approximately 100 ppm (770 mg/cu m) for 30 minutes/day for up to 10 days caused incipient fatty degeneration in the liver of cats . According to Rowe et al , rats exposed to 100 ppm (770 mg/cu m) of ethylene dibromide for 7 hours/day for seven exposures in 9 days had a cloudy swelling of the liver, whereas rabbits exposed to the same concentration for three or four exposures had widespread central fatty degeneration and some necrosis of the other cells of the liver. Rowe et al reported that slight central fatty degeneration of the liver developed in guinea pigs repeatedly exposed to 50 ppm (385 mg/cu m) of ethylene dibromide for 7 hours/day for 57 exposures in 80 days and in monkeys repeatedly exposed to the same concentration for 49 times in 70 days. Renal damage, in the form of pronounced granular degenerative changes in the parenchymal tissues, occurred in guinea pigs exposed to ethylene dibromide at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes . Rowe et al demonstrated that the kidneys of rats exposed at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide vapor for 0.02-16.0 hours showed slight interstitial congestion and edema, with slight cloudy swelling of the tubular epithelium in some cases. Repeated exposures at approximately 100 ppm (770 mg/cu m) for 30 minutes/day for an average of 10 days in cats produced a swelling and discoloration of the kidneys and possibly a slight degeneration of the tubules . Rowe et al reported that repeated exposure of guinea pigs at 50 ppm (385 mg/cu m) of ethylene dibromide for 7 hours/day for 57 times in 80 days produced a slight interstitial congestion and edematous condition in the kidneys which was accompanied by degeneration of the tubular epithelium. From these data, it can be concluded that renal damage can occur in experimental animals after exposure to single or repeated exposures of ethylene dibromide. Adverse splenic effects have been seen in experimental animals after exposure to ethylene dibromide. Single exposures of ethylene dibromide at 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes produced a slight granular degeneration of the parenchymal tissue in the spleen of guinea pigs . Rats exposed to 0.25, 0.50, or 1.0 ml (0.55, 1.1, or 2.2 g) of ethylene dibromide applied on the abdomen died within 6-18 hours; autopsy showed that the spleens of these animals were highly congested and edematous . Kochmann noted a slight enlargement of the spleens of cats exposed at 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day for an average of 10 days. Rowe et al observed that rats receiving seven exposures to ethylene dibromide at 100 ppm (770 mg/cu m), 7 hours/day, for 9 days developed a slight congestion of the spleen and some hemosiderin deposition. The results from these experiments indicate that adverse effects to the spleen can occur after exposure to ethylene dibromide by inhalation or by percutaneous absorption. Cardiovascular system effects have been noted in experimental animals subjected to single or multiple exposures of ethylene dibromide. Concentrations of 8,000, 4,000, and 2,000 ppm (61,600, 30,800, and 15,400 mg/cu m) of ethylene dibromide for 30, 60, and 150 minutes, respectively, produced a slight granular degeneration of the muscular tissue of the heart and a generalized interstitial edematous degeneration of the endothelial lining in the abdominal vascular system in guinea pigs . Merzbach exposed a dog to the vapor of 5 ml (11.0 g) of ethylene dibromide in a 100- postulated that death resulting from exposure of cats and rabbits at 50-100 ppm (385-770 mg/cu m) of ethylene dibromide for up to 22 days was caused by injury to the circulatory system, especially to the heart and blood vessels. Rowe et al also concluded that deaths occurring at the higher concentrations after exposure of rats at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours were caused by cardiac or respiratory failure. Few studies have specifically addressed the potential of ethylene dibromide to adversely affect the CNS. Rowe et al reported that CNS depression was observed at the higher concentrations in rats exposed to 100-10,000 ppm (770-77,000 mg/cu m) for 0.02-16.0 hours, but did not further elucidate the nature of the effects. Rowe et al Experiments with bulls receiving 4 mg/kg on alternate days for 7 or 10 doses showed that the abnormal spermatozoa were present in both the epididymis and testes after 7 doses. After 10 doses, abnormal spermatozoa constituted 67% of the population in the ductus deferens and 77% of the ejaculate, with almost all the abnormal spermatozoa exhibiting tail and acrosomal defects . These spermatozoic abnormalities may lead to a decrease in the fertility of the bulls and might induce sterility if they continued long enough, although reports have not been found that experimentally test this hypothesis. In rats, ip injections of ethylene dibromide at a dose of 10 mg/kg for 5 days produced a decrease in the average live litter size in female rats mated with experimental males . This decrease in fertility occurred during the 3rd and 4th weeks following administration, which corresponds to the maturation cycle of spermatids in the genital tract of rats. This finding, which corresponds with the findings of the reports of spermiogenic impairment in bulls, supports the postulated sterilizing effect discussed above. It is important to point out that reports have not been found delineating a no-effect level for the reproductive system abnormalities caused by the repeated administration of ethylene dibromide to bulls. In chickens, the function of the female reproductive system is impaired by ethylene dibromide exposure , but the male system appears to be unaffected . Cockerels fed 300 ppm of ethylene dibromide for 12 months showed significant growth retardation at 12 weeks of age; however, semen collected between 9 and 12 months did not differ from control semen, and body and testicular weights were comparable with those of controls . Semen collected between 2 and 10 weeks from cockerels fed 300 ppm for 105 days showed no significant differences when compared with control semen with respect to ejaculated volume and spermatozoic motility and concentrations. Subsequent fertility tests at 60 or 105 days in hens gave no significant differences in fertilization rates or hatchability of eggs. These results indicate that the reproductive system in male chickens was not detectably affected by ethylene dibromide under these experimental conditions. This is in contrast to the effects reported in two mammalian species, cattle and rats, in which definite impairments of the male reproductive system have been noted. A striking reduction (12 versus 86% in the control) in the fertilization rate was seen in hens fed 100 ppm of ethylene dibromide for 4 weeks; all embryos in the eggs from the experimental group were dead . These results indicate that the female reproductive system in chickens is affected by ethylene dibromide. Although no reports have been found that explore the potential of ethylene dibromide to affect fertility in females of mammalian species, the avian data suggest the potential of ethylene dibromide to impair female fertility. However, until experiments are conducted with mammalian species to assess this potential, extrapolation of the effects seen in chickens to mammals and humans must be uncertain. There has been only one study concerning the potential of ethylene dibromide to induce cancer in rats and mice . In this study, rats and mice were given the maximum tolerated dose (80 mg/kg for rats, 120 mg/kg for mice) and one-half the maximum tolerated dose by daily intubation for 54 or 62 weeks, except when toxicity forced the total discontinuation of administration or reduction of the maximum tolerated dose to that of one-half the maximum tolerated dose during the experiment. The tumors (squamous cell carcinomas), which were first noted during the 10th week of ethylene dibromide administration in rats, originated in the forestomach, invaded locally, and metastasized throughout the abdominal cavity. The fraction of animals with tumors was greater in the male rats than in the females (an average of 83% of the males developed tumors versus 70% of the females), and was greater at the lower dose than at the higher dose in rats at the termination of the experiment at 54 weeks (98 versus 68% in males and 82 versus 58% in females, respectively). The concurrent control populations did not develop squamous cell carcinomas of the stomach. The fraction of mice that developed squamous cell carcinomas was 74% in males and 72% in females by the termination of the experiment at weeks . The irregularities in the dose regimens of both species, the use of the suggested maximum tolerated dose, and the route of administration do not negate the importance of the fact that ethylene dibromide has induced carcinomas in two mammalian species. The data from this single study indicate that ethylene dibromide is a carcinogen after daily introduction of about one-half the maximum tolerated dose into the stomach of rats and mice for up to 62 weeks. The mutagenic potential of ethylene dibromide has been established in a wide spectrum of procaryotic and eucaryotic mutational test systems. It has induced mutations in vertebrate cell cultures , insects , bacteria , plants , and fungi . It has induced mutations or mutagenic events in a number of experimental test systems, including the recessive lethal test in Drosophila melanogaster , the host mediated assay in mice with Salmonella typhimurium , and a backward mutation system with mouse lymphoma cells . In addition, positive mutagenic induction has been reported in tests with back mutational systems in certain strains of Salmonella typhimurium . Ethylene dibromide has also been reported to have given negative results in the dominant lethal test in mice and in the back mutational test system with Serratia marcescens in the host mediated assay . The dominant lethal test conducted in male mice given 50 or 100 mg/kg of ethylene dibromide for 5 consecutive days by oral intubation or given 18 or 90 mg/kg by ip injection did not induce a significant increase in the number of dead implants when compared with controls , although specific data were not presented for evaluation. Buselmaier et al reported that ethylene dibromide was mutagenic in the host mediated assay with Salmonella typhimurium G46 at a dose of 500 mg/kg injected subcutaneously in mice and in vitro with the same organism at an equivalent dose. The mutational frequency for the experimental group was significantly (P<0.01) different from the control mutational frequency. The positive results in the in vivo and in vitro tests indicate that metabolic activation is not necessary for ethylene dibromide to exert its mutagenic effects and that metabolic deactivation does not reduce the mutagenic effect. Buselmaier et al reported that a similar in vivo test with Serratia marcescens, also a back mutational test system, was negative; this finding may only indicate that species differences exist in reactions with ethylene dibromide. In a recessive lethal test with Drosophila melanogaster, Vogel and Chandler reported that 0.3 mM of ethylene dibromide fed to adult males for 3 days induced significant numbers of recessive lethal mutations in the offspring of three successive broods. The brood patterns resulting from ethylene dibromide exposure indicated that ethylene dibromide affected spermatozoic maturation more than spermatozoic formation. The authors considered ethylene dibromide typical of a bifunctional alkylating agent and capable of introducing cross-links into biologic molecules. A mammalian somatic cell tissue culture of L5178Y mouse lymphoma cells was exposed to 0.0-3.0 mM of ethylene dibromide in culture media . The induced mutagenic frequency was dose related, typical of other alkylating agents tested, and approximately equivalent to a dose of 600 R of X-irradiation at the highest concentration. Meneghini noted that ethylene dibromide very effectively induced DNA repair synthesis in opossum lymphocyte cell cultures at concentrations between 0.001 and 1 iriM but decreased at 10 mM. Only compounds that interact with DNA through covalent bonds induce repair synthesis; therefore, ethylene dibromide is typical of other alkylating agents in forming covalent bonds with DNA. Bacterial and other plant systems have also been used to show the mutagenic potential of ethylene dibromide. Ames hours. The ability of ethylene dibromide to induce mutations in a wide variety of test systems is suggestive of its potential to induce mutations in human populations, but there is no evidence available to enable an adequate assessment of the quantitative aspects of the relative risks for human populations. Since ethylene dibromide is a bifunctional alkylating agent, the most plausible basis for the induction of mutations in these systems is the covalent bonding of ethylene dibromide to the genetic material, DNA. The linear relation between the number of induced mutations and the concentration of ethylene dibromide in Tradescantia is consistent with the idea of covalent bonding between ethylene dibromide and DNA. Only one study pertaining to the potential of ethylene dibromide to induce fetal anomalies has been found . Fetuses from pregnant mice and rats exposed to approximately 31.6 ppm (243.32 mg/cu m) of ethylene dibromide for 23 hours/day during days 6-15 of gestation were significantly different from fetuses of pregnant control mice and rats. These differences include costal anomalies and hydrocephaly in rat fetuses, and additional anomalies in other ossification processes in mice fetuses. Fetuses from control mice fed a feed-restricted diet during the experiment to simulate malnourishment exhibited some of the effects found in ethylene dibromide-exposed mice fetuses; however, the frequency of the type and number of anomalies formed in the malnourished group was reduced, but the degree of significance was not as great as that found in the ethylene dibromide-exposed mice fetuses. Although it can be argued that the effects produced by ethylene dibromide exposure are similar in part to those produced by malnourishment, the anomalies in both rat and mouse fetuses from ethylene dibromide-exposed dams were significantly different from those produced by malnourishment alone when both were compared with those found in fetuses from control dams. From these data, it is evident that ethylene dibromide caused fetal abnormalities in mice and rats that were not caused by malnourishment alone. In summary, it is concluded from the data from human and experimental studies that the adverse systemic effects resulting from exposure to ethylene dibromide may include ocular, dermal, and respiratory irritation, The concentration of airborne ethylene dibromide on the premises of an oil refinery ranged from 0. In this report, both the most likely and worst-case emission concentrations were calculated, using the average value of 0.9-1.3 g of ethylene dibromide/gal of automotive fuel (one equivalent of organic bromine is added to gasoline for each two equivalents of lead added). The estimated emission rate for ethylene dibromide by measurement was reported to be 0.000063 g/g lead/gal. The reported losses for entrainment and spillage each were 0.000047 g/g lead/gal. Thus, the total loss because of refueling was reported to be 0.000157 g/g lead/gal. Evaporative losses were calculated to be 0.00014 g/g lead/gal from the automobile fuel tanks. in The most likely estimate of loss from the carburetor was 0.0016 g/g lead/gal, whereas the worst case was 0.0043 g/g lead/gal. Exhaust emissions were also calculated, the most likely being 0.0065 g/g lead/gal and the worst case being 0.3 g/g lead/gal. Summarizing the three types of emissions, the total emissions calculated for refueling, evaporation, and exhaust was most likely 0.008397 g/g lead/gal and the worst case, 0.304597 g/g lead/gal. The total emissions can also be estimated directly in terms Liquid absorption media, such as a 1:1 mixture of monoethanolamine and dioxane, have been used as trapping solutions for ethylene dibromide . This medium decomposes ethylene dibromide and many other brominated organic contaminants to inorganic bromide and, as such, is not specific for ethylene dibromide. Porous polymer beads have been used as a collection medium for chlorinated and brominated hydrocarbons . This procedure has not been tested specifically for ethylene dibromide but has been used successfully for closely related halogenated hydrocarbons; thus, it seems feasible that ethylene dibromide could also be collected by this method. The same column is used for sample collection and gas-liquid chromatographic analysis, but only one analysis can be made on each sample. Silica gel has been used as a collection medium for ethylene dibromide . One advantage of using a solid adsorbent is that sample loss cannot occur from spillage during sampling or in transit for analysis. However, silica gel is a polar adsorbent and shows pronounced selectivity in adsorbing polar molecules, particularly water . Studies with silica gel tubes indicated that water vapor could displace organic molecules during a normal sampling operation . Although similar studies have not been conducted for ethylene dibromide, it is reasonable to assume that similar displacement of significant quantities of ethylene dibromide by water vapor could occur. Activated charcoal has been used as an adsorbent in conjunction with gas-liquid chromatography . Charcoal is an excellent collecting medium because of its nonpolarity and its affinity for organic vapors and gases. As such, water vapor does not readily displace organic molecules as is the case with silica gel. However, adsorption and desorption efficiencies may vary with different batches of charcoal; therefore, it is necessary to determine the desorption efficiency for each new batch of charcoal. Charcoal tubes containing as much as 600 mg of activated charcoal are commercially available , In the past several years, direct-reading instruments and devices have been developed which make continuous or "on-the-spot" monitoring of halogenated hydrocarbons, including ethylene dibromide, feasible. These devices, when properly calibrated and used within their performance characteristics and limitations, can be helpful in monitoring airborne halogenated hydrocarbons . Colorimetric indicator tubes are available from at least three sources which provide semiquantitative measurement in the range of 1-200 ppm, although no detector tubes have been certified as yet by NIOSH for response to ethylene dibromide. The use of infrared light absorption at a wavelength of 8.4 jum is claimed to detect airborne ethylene dibromide at a concentration of 0.1 ppm. These direct-reading instruments are portable and also may be used as part of a multipoint sampling system for continuous, unattended monitors. Other sampling devices used for the collection of organic solvents and halogenated hydrocarbons may be adaptable to ethylene dibromide collection. These include sampling bottles , bubblers , and plastic bags . Chemical analysis has been used to estimate ethylene dibromide concentrations in the collection media. Aeration has been used by Peterson et al to desorb ethylene dibromide from the silica gel; pyrolysis of the free ethylene dibromide produced bromine and hydrobromic acid. These products were collected in a second absorption solution of 1% sodium carbonate and 1% sodium formate in deionized water and quantitated by titrimetric analysis of the inorganic bromide present. Aman et al 132 estimated the airborne ethylene dibromide concentration by absorbing the free ethylene dibromide with 1% sodium hydroxide and by quantitating the hypobromite formed iodometrically. Dumas determined airborne ethylene dibromide concentrations by coulometric titration of sodium bromide after absorption of ethylene dibromide in methanolic sodium hydroxide and digestion by boiling under reflux for 15 minutes on a steam bath. These methods, like most chemical methods, require somewhat bulky apparatus and are not specific for ethylene dibromide since any aliphatic brominated compound will interfere and be included in the quantitative estimate. Physicochemical methods have been developed or adapted to identify and quantitate concentrations of airborne ethylene dibromide. Christie et al modified a refrigerant leak-detector lamp to detect organic halogen compounds, including ethylene dibromide, in the atmosphere at a minimum concentration of 5 ppm. The procedure is dependent on visual estimation of the intensity of a flame color in response to the vapor concentration and is not specific for ethylene dibromide. Flame chemiluminescence has been reported by Crider to detect ethylene dibromide concentrations in air of 0.03 ppm. This method has not been tested on mixtures of halogenated hydrocarbons, and it is too early in its development to enable prediction of the practicality of the method for area or personal monitoring in an occupational environment. Other physicochemical methods have been developed for halogen compounds, but they have not been tested for identification and quantitation of ethylene dibromide. One of these methods, based on nitrogen enhancement of an AC spark, has been used for continuous measurement of halogenated compounds in field situations . The instrument is lightweight, portable, fast-responding, and reportedly capable of detecting halogenated hydrocarbons in the ppm range. However, until testing with ethylene dibromide has been conducted, the feasibility and reliability of this instrument is not known. In recent years, gas-liquid chromatography has become the most prevalent method for the detection and analysis of organic materials . Direct analysis of airborne ethylene dibromide has been reported to result in measurement of amounts as small as 0. (1) the delayed and insidious onset of symptoms, (2) an odor threshold which is not adequate to provide warning of dangerous concentrations, (3) its irritating and penetrating effects on the skin, and (4) its potential for causing cancer, mutations, sterility, and fetal anomalies. The principal method for manufacturing ethylene dibromide is the bromination of ethylene . Small quantities of vinyl bromide, ethyl bromide, and ethyl chlorobromide may be formed as impurities in the production of ethylene dibromide , and caution must be taken to avoid exposure to these substances as well. Ethylene dibromide is nonflammable and nonexplosive at ordinary temperatures, but since it can be decomposed to toxic and corrosive compounds, such as hydrobromic acid, by contact with open flames or red-hot surfaces , it should be appropriately stored and handled to prevent such contacts. Special precautions are necessary for maintenance and emergency repair work, such as welding, cutting, or any spark-and flame-generating operations. Furthermore, it is recommended that smoking be prohibited in workplace areas where ethylene dibromide is manufactured, handled, blended, or stored. Since decomposition may occur and highly toxic aldehyde vapors and acid gases may be emitted , ethylene dibromide must be protected from direct light and excessive temperature. Ethylene dibromide reacts rapidly with certain metals, such as aluminum and magnesium, to form combustible and explosive organometallic compounds and with liquid ammonia , Therefore, it is recommended that reasonable precautions be taken to keep ethylene dibromide separated from these materials. Engineering controls should be used to keep the concentration of airborne ethylene dibromide below the recommended occupational exposure All containers used to transport, hold, or process ethylene dibromide should be made of ethylene dibromide-resistant materials, such as lined steel or stainless steel, and should be periodically inspected for signs of wear, corrosion, or leaks by manual and instrumental means. All valves, pipes, and seals used in pumping ethylene dibromide from processing areas to storage areas or transportation loading sites should be made of ethylene dibromide-resistant materials and should be periodically inspected for possible leaks, weak points, or signs of wear. Ethylene dibromide is a severe eye and skin irritant in humans (G Ter Haar, written communication, January 1977) and can be absorbed through the intact skin of animals in quantities sufficient to present an imminent hazard . In view of this, the use of personal protective equipment, including nylon-impregnated neoprene gloves , ethylene dibromideresistant and fire-retardant clothing, rubber boots or overshoes, bib-type aprons, and chemical safety goggles is recommended when contact by liquid ethylene dibromide with the skin and eyes is possible. In addition, it is recommended that proper respiratory protection be worn when entering an area where the concentration of the vapor of ethylene dibromide may be greater than the recommended occupational exposure limit. Clothing should be immediately removed if it becomes contaminated, and the skin of the exposed area should be thoroughly washed with water. Personnel working with ethylene dibromide must be instructed in emergency procedures and participate in periodic, simulated emergency drills. All personnel not involved in the specified emergency operations must be immediately evacuated from the area. Special training sessions must be held and written emergency procedures must be updated periodically. These should include the location, use, and maintenance of first-aid, firefighting, and decontamination equipment. To prevent the adverse effects caused by ethylene dibromide, it is recommended that exposure to ethylene dibromide vapor or liquid be kept at a minimum. Routine visual and functional inspections must be made by trained personnel to ensure that processes in which ethylene dibromide is used are completely closed. If leaks or spills occur in the processing, handling, or storage of ethylene dibromide, these must be promptly corrected, regardless of the ethylene dibromide concentration in the environment. It is recommended that nonessential personnel be evacuated from the immediate area where a leak or spill has occurred until decontamination of the area is complete. If employees must withdraw samples from a process involving the use of ethylene dibromide, an impervious suit, including gloves, boots, and air-supplied hood, should be worn. An effective exhaust system for trapping any ethylene dibromide vapor may be used in place of the air-supplied hood. Any waste or residues containing ethylene dibromide should be incinerated, buried, or otherwise disposed of so that no ethylene dibromide is released into the environment. Applicable local, state, and federal regulations should be followed. Air exhausted from ethylene dibromide workplace areas must be decontaminated by incineration, chemical treatment, or other effective means so that the release of ethylene dibromide into the environment will be minimized. Safety showers and eyewash fountains should be located in or near areas where ethylene dibromide exposures are likely to occur and should be properly maintained. It is recommended that employees immediately remove contaminated clothing, flush all affected skin surfaces with water for at least 15 minutes, and then obtain medical attention. Since ethylene dibromide is toxic when ingested and has caused death in a woman after ingestion , it is recommended that handwashing facilities, soap, and water be made available to the employees. As a good hygiene practice, it is recommended that employees wash their hands before consuming beverages or food, using tobacco, or using toilet facilities. The employer should provide lunchroom facilities physically separated from the ethylene dibromide work areas. It is recommended that any contaminated article of personal protective equipment be discarded or, if feasible, decontaminated with soap and water. It is also recommended that employer-supplied clothing be worn while working with ethylene dibromide and that the employer arrange to have this clothing laundered daily and properly maintained. The employer should inform the launderers of the possible hazard of coming into contact with contaminated clothing and advise him on safe methods of handling such material. The employer should provide separate locker and change facilities for work and street clothes. As a good hygiene practice, it is recommended that shower facilities be provided for the employees and that they be required to shower before leaving the workplace at the end of the work shift. Since ethylene dibromide is a component of some insecticidal fumigants and conventional work practice guidelines are inappropriate to protect agricultural workers from the hazards of exposure, it is recommended that the label precautions on such pesticides be followed and stringently adhered to. These label requirements usually specify allowable time limits before a fumigated space or area may be reentered and safe practices for the application of the particular fumigant mixture. Specific requirements of worker protection standards for agricultural pesticides can be found in 40 CFR 170. In summary, precautions should be exercised with ethylene dibromide to prevent serious consequences which may result from ingestion, inhalation, and skin or eye contact. Processes in which ethylene dibromide is used in large quantities should be carried out in closed systems. Well-designed hoods, ventilation systems, and exhaust systems should be used to maintain concentrations below those specified by this standard. Personal protective equipment and clothing should be worn by employees engaged in the manufacture, handling, or blending of ethylene dibromide. It is important that employees be informed of the hazards associated with ethylene dibromide before job placement and whenever changes are made in any process that may alter their exposure. # VI. DEVELOPMENT OF STANDARD Basis for Previous Standards In 1953, the American Conference of Governmental Industrial Hygienists (ACGIH) adopted a threshold limit value (TLV) of 25 ppm as an 8hour TWA concentration for 1,2-dibromoethane (ethylene dibromide) . No specific basis for this TLV has been found. In 1954, the ACGIH changed the name to ethylene dibromide in the official TLV list, and, in 1956, they added the value of 190 mg/cu m to the official entry . In al reported that ethylene dibromide was readily absorbed through the intact skin of rabbits and from the gastrointestinal tract of rats, mice, guinea pigs, chickens, and rabbits. Ethylene dibromide vapor caused CNS depression, pulmonary irritation, and liver and kidney damage in rats and guinea pigs after single exposures. Rats, guinea pigs, monkeys, and rabbits tolerated repeated exposures of ethylene dibromide vapor at 25 ppm for 7 hours/day, 5 days/week, for about 6 months without adverse effects, but these species did not tolerate well a similar exposure at 50 ppm. In 1965, the ACGIH recommended that special emphasis be given to the potential for skin absorption of 1,2-dibromoethane by adding the designation "skin" after the name in the TLV list. Such a notation refers to the potential contribution to overall exposure by the dermal route, including mucous membranes and eyes, either by airborne, or more particularly, by direct contact with ethylene dibromide. This designation was intended to indicate that measures for the prevention of absorption from skin and mucous membranes were necessary if the TLV was to be successful in limiting occupational exposure to a safe level. In 1965, the ACGIH also recommended that the TLV of 25 ppm as a TWA concentration for ethylene dibromide be tentatively changed to a ceiling limit of 25 ppm. The basis for this limit was primarily the report by Rowe et al , discussed previously, and the paper by Lucas . Lucas observed that single 10-to 12-minute exposures of rabbits to a concentration of ethylene dibromide vapor sufficient to produce anesthesia resulted in rapid breathing, phonation, and death within 15-18 hours. The shift of the TLV from a TWA value to a ceiling limit was made final in 1967. In 1971, the ACGIH recommended changing the ceiling limit of 25 ppm to an 8-hour TWA concentration of 20 ppm (145 mg/cu m ) . The 1971 Documentation of the Threshold Limit Values for Substances in Workroom Air cited several studies with no particular emphasis on how the limit was set. These reports included Rowe et al , Lucas , Kochmann , Olmstead , Rowe et al , and McCollister et al , which are discussed in Chapter III. Presumably, the study by Rowe et al was the principal basis on which the new limit was set. The proposed value of 20 ppm as a TWA concentration was adopted in 1973 . The basis for this change as stated in the 1974 supplement of the 1971 Documentation , did not differ from that stated in 1971. In 1976, the ACGIH added to the TWA value a tentative short term exposure limit (STEL) of 30 ppm (220 mg/cu m) , which is defined as a maximal concentration to which workers can be exposed for a period up to 15 minutes continuously. No more than 4 such excursions are permitted each day, with at least 60 minutes between successive exposure periods. Also, the daily TLV-TWA is not to be exceeded. Florida, Mississippi, Pennsylvania, and South Carolina have adopted a TWA concentration of 25 ppm (190 mg/cu m) as their environmental limit for ethylene dibromide . In Finland, the German Democratic Republic, and Yugoslavia, the maximum allowable concentration (MAC) for the workplace environment is 190 mg/cu m (25 ppm) . In the Rumanian Socialist Republic, 200 mg/cu m (approximately 26 ppm) of ethylene dibromide is the maximum concentration allowed in the occupational environment, whereas in Poland, the MAC allowed for ethylene dibromide is 100 mg/cu m (13 ppm) . Although the USSR does not currently recommend a standard for ethylene dibromide, the US recommendation of 145 mg/cu m (20 ppm) is stated to be inadmissibly high. The 1976 edition of the Handbook for Chemists, Engineers and Physicians states that, in all likelihood, the permissible concentration should be on the same order as the Russian MAC for dichloroethane (12.5 ppm) or lower . No bases for these standards have been found. The current federal standard (29 CFR 1910(29 CFR .1000) for occupational exposure to ethylene dibromide is 20 ppm as an 8-hour TWA limit, with an acceptable ceiling concentration of 30 ppm. A maximum peak above the acceptable ceiling concentration for an 8-hour work shift of 50 ppm not to exceed 5 minutes (Federal Register 40:103, May 28,1975) is also permitted. This standard was adopted from the American National Standards Institute (ANSI) recommendation Z37.31-1970 , which was based on the reports of Rowe et al and Olmstead , and the summary presentation by Irish , which includes synopses of several other reports discussed in Chapter III. , and conjunctival irritation was noted in rabbits after instillation of undiluted, 10%, or 1% solutions of ethylene dibromide . The irritation subsided within 2-12 days in the rabbits without causing corneal scarring. Marked hyperemia of the cutaneous blood vessels surrounding the application site was found after 0.25, 0.50, or 1.0 ml (0.55, 1.1, or 2.2 g) of ethylene dibromide was applied to the abdomen of rats . Rabbits responded similarly when undiluted or 10% solutions of ethylene dibromide were applied to the abdomen . Application of 210 mg/kg of the undiluted chemical caused marked erythema, edema, and necrosis of the skin. Respiratory tract irritation caused by ethylene dibromide vapor has been seen in guinea pigs after single exposures at 2,000 ppm (15,400 mg/cu m) for 150 minutes , and for cats after exposures as low as 100 Other systemic damage also occurred in animals after single and repeated exposures to ethylene dibromide vapor. Guinea pigs exposed at concentrations of ethylene dibromide of 2,000 ppm (15,400 mg/cu m) for 150 minutes developed a pronounced granular degeneration of the parenchymal tissue of the kidneys and a slight degeneration of the parenchymal tissue of the liver, spleen, and heart . Rats exposed at concentrations between 100 and 10,000 ppm (770 and 77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours developed cloudy swelling, centrilobular fatty degeneration, and necrosis of the liver, cloudy swelling and a slight interstitial congestion and edema of the kidneys, and CNS depression at the higher concentrations . Repeated inhalation exposures of rats for 7 days and rabbits for 3-4 days at 100 ppm (770 mg/cu m) of ethylene dibromide for 7 hours/day produced slight congestion of the spleens of rats, cloudy swelling and a slight leukocytic infiltration in the livers of rats, and widespread central fatty degeneration and some necrosis in the livers of rabbits . Exposure of guinea pigs and monkeys at 50 ppm (285 mg/cu m) of ethylene dibromide for 7 hours/day, 5 days/week, for 70-80 days caused only slight central fatty degeneration of the liver . Cats exposed at 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day for about 10 days had enlarged spleens. Death resulted from circulatory system damage to the heart and vessels . CNS effects, such as agitation, restlessness, body tremors, or unconsciousness, are caused by exposure to ethylene dibromide ], but they have not been sufficiently described to permit an adequate evaluation or quantitation of their relevance or validity. The information provided by the few reports on humans and such experimental animal data as those given in the following references indicates that many effects produced by ethylene dibromide on humans and animals are similar and differ only in magnitude. Respiratory tract irritation, damage to the liver, kidneys, spleen, and lungs, irritation of the skin and eyes, and gastrointestinal disturbances are the predominant effects of ethylene dibromide exposure. Since systemic effects may occur from ingestion, inhalation, or dermal contact with ethylene dibromide, NIOSH recommends that work practices be used to minimize employee exposure to ethylene dibromide liquid or vapor through inhalation, body or eye contact, or ingestion. Mammalian studies indicate that reproductive abnormalities, including antifertility and spermatozoic anomalies , occur from exposure to ethylene dibromide. One report indicated that five ip injections of 10 mg/kg given to male rats produced a decrease in fertility only during the 3rd and 4th weeks after injection. Since spermatids require about 3-4 weeks to mature into spermatozoa in the rat, the evidence indicates that ethylene dibromide affects the development of the spermatids that were present at the time of injection. This is further supported by the return of normal fertility 5 weeks after the injection. Three studies with bulls In another experiment , production of abnormal spermatozoa occurred with a dose as small as 4 mg/kg given on alternate days for seven doses. These spermatozoic abnormalities would greatly reduce the fertility, even if they did not cause total sterility. Although these effects were from the ingestion of ethylene dibromide and not from inhalation or dermal contact, they indicate that a hazard, including decreased fertility and even temporary sterility, may result from inhalation or percutaneous absorption of ethylene dibromide. One study, reported by several authors , was conducted to determine the carcinogenic properties of ethylene dibromide. Rats and mice given daily oral doses by gavage of ethylene dibromide at 40 and 60 mg/kg, respectively, for 52-64 weeks developed squamous cell carcinomas in the stomach. These carcinomas invaded locally and metastasized throughout the abdominal cavity. Male and female rats developed stomach carcinomas as early as 10 weeks after the start of administration of ethylene dibromide. The carcinomas became more prevalent as the daily doses of ethylene dibromide were continued, and the final percentage of male rats with tumors after administration of 40 mg/kg/day was 98% after termination of the experiment at 54 weeks. Male rats were more susceptible to tumorigenesis than female rats; 80% of all the males in the study developed tumors versus 38% of all the females. The concurrent control populations did not develop squamous cell carcinomas. More than 70% of all the mice were reported to The mutagenic potential of ethylene dibromide is well established in both animal and plant systems. It induces mutations in vertebrate cell cultures , insects , bacteria , plants , and fungi . One study with Drosophila melanogaster showed that ethylene dibromide induced a significant number of recessive lethal mutations in three successive broods of offspring. The adult males fed 0.3 mM of ethylene dibromide for 3 days produced subsequent brood patterns indicative of impaired spermatozoic maturation rather than of impaired formation. Studies with mouse lymphoma cells indicated that a dose-related effect, typical of those of other alkylating agents tested, existed over the range of 0.0-3.0 mM ethylene dibromide. The effect of the highest concentration was approximately equal to that of a dose of 600 R of Xirradiation. A study in a host-mediated assay system with Salmonella typhimurium G46 in mice suggested that ethylene dibromide was mutagenic at a dose of 500 mg/kg. A second part of this study showed that an equivalent dose produced a positive mutagenic effect on Salmonella typhimurium G46 in vitro, indicating that ethylene dibromide did not require metabolic activation and was not deactivated by metabolism. Similar positive mutagenic results occurred in Salmonella typhimurium TA Several studies suggest that the mechanism of mutagenic activity of ethylene dibromide is based on its ability to alkylate, or covalently bond to, DNA in the exposed cells. Ethylene dibromide is a bifunctional alkylating agent capable of introducing cross-links into biologic materials by displacement of the two reactive bromine atoms by reacting with amine, sulfhydryl, carboxy or other electron-donating groups. Ethylene dibromide, or its metabolites, has interacted with DNA through covalent bonds to induce DNA repair synthesis in opossum lymphocyte cells . Another indication of ethylene dibromide's ability to alkylate DNA is that ethylene dibromide is mutagenic in Salmonella typhimurium TA 1530 and TA 1535, both transitional mutational systems . These data suggest strongly that the most plausible chemical basis for the mutagenic activity of ethylene dibromide in procaryotic and eucaryotic organisms is its alkylation of cellular constituents such as DNA. This broad biologic reactivity suggests that ethylene dibromide may be capable of increasing spontaneous mutation rates in humans. However, the quantitative aspects of this potential have not been determined. Since the process of induction of mutations is a stochastic, virtually irreversible process, any increased frequency of mutation in exposed populations would accumulate as a function of the total absorbed dose of ethylene dibromide. Therefore, an adequate assessment of the importance of the plant and submammalian animal data in extrapolating to the concentrations of airborne ethylene dibromide present in the workplace environment is difficult, but the widespread mutagenic activity of ethylene dibromide does give cause for concern about damage to the genetic mechanisms in employees working with it. The teratogenic effects found in a rat and mouse study involved brain and costal anomalies in the offspring of dams exposed to ethylene dibromide. Pregnant rats and mice were exposed at a concentration of about 32 ppm of ethylene dibromide for 23 hours/day on days 6-16 of gestation. Some of the effects were attributed to malnourishment, but the abnormalities in the ethylene dibromide-exposed rats and mice were significantly different, both qualitatively and quantitatively, from those in the nonexposed controls; some of these abnormalities did not appear in mice fed a restricted amount of the normal diet whereas others appeared in both the restricted and the control mice with about the same incidences. These data suggest that ethylene dibromide causes fetal anomalies in mice and rats that are not caused by malnourishment alone. Since inhalation is one of the major routes of exposure for the employee, these data suggest also that the babies of female employees may be subject to increased risks of developmental defects if their mothers are exposed to ethylene dibromide in the workplace during the critical phases of pregnancy. The total risk to the health of employees exposed to ethylene dibromide is the result of the compounded risks from carcinogenicity, mutagenicity, teratogenicity, sterility, and damage to the kidneys, liver, spleen, respiratory tract, central nervous system, circulatory system, skin, and eyes. Although no comprehensive epidemiologic studies have been conducted to assess adequately these risks in the industrial environment, evidence of their existence in experimental animal systems or in isolated human exposures to ethylene dibromide has been discussed above and in Chapter III. Experimentation conducted with animal models, as outlined above, generally supports the findings observed in the limited number of human exposures. Concern for employee health requires that the probability of the occurrence of long-term effects of ethylene dibromide be minimized. The preliminary report available to NIOSH from a review of the mortality experience of 161 employees of one manufacturer induced stomach cancer in the rat. In addition, the extensive experimental evidence on the induction of adverse effects in lower species 9,33,62,66,69] and the formation of stable covalent bonds between ethylene dibromide and cellular constituents indicate that the occupational exposure limit should be lowered to decrease the potential hazard to employees. Because of the intrinsic, stochastic, and virtually irreversible character of the chemical reactions that initiate the carcinogenic and mutagenic processes, the risk of adverse effects is a function of the rate of absorption and the total absorbed dose. Consequently, this risk can be reduced to any value necessary to protect the employees by decreasing both the absorption rate (to prevent saturation of the enzymatic detoxification mechanisms) and the total lifetime dose (to reduce the probability of deleterious stochastic processes, such as carcinogenesis and mutagenesis, from occurring). The unusual complexity of the dynamics of the cellular response mechanisms to ethylene dibromide intoxication is emphasized by the doserate effect relationship observed for induction of gastric neoplasms. Daily intragastric doses of 40 and 60 mg/kg induced tumors in rats and mice within 10 weeks , whereas daily 7-hour inhalation exposures of about 49 mg/kg did not result in the observation of tumors even after 30 weeks . The data suggest that one of the major factors in the development of gastic carcinomas is direct contact between the mucosal cells and ethylene dibromide, and that a major difference in tumor induction may exist between the two routes of exposure. However, the animals used in the inhalation study were not maintained until the end of their normal lifespan; therefore, a direct comparison between the final incidences of tumors initiated by the two routes of exposure cannot be made. A plausible pharmacokinetic explanation for the observed differences exists. Since the rat's capacity to metabolize ethylene dibromide exceeds the rate of absorption (at 25 ppm) by a factor of at least 100, the concentration of ethylene dibromide in tissues should be considerably less than that in the air, which is about 1.02 /umoles/liter at 25 ppm . The concentration of ethylene dibromide in corn oil used in the intubation study ranged between 0.066 and 0.132 moles/liter. Consequently, the mucosal cells of the stomach may have been exposed for short periods to concentrations of ethylene dibromide up to 100,000 times that to which lung tissue would be exposed during inhalation exposures at 25 ppm (192.5 mg/cu m ) . The saturation of enzymatically catalyzed detoxification and repair mechanisms may occur in the stomach tissues, resulting in an amplification of the tissue damage, which otherwise may be minimal. These pharmacokinetic considerations are consistent with the experimental results of Rowe et al , where the product of the concentration and duration of exposure to produce 50% mortality among the exposed rats was found to be approximately constant for higher concentrations of ethylene dibromide but not for lower ones. The evidence indicates that tissue detoxication and repair mechanisms exist, but that they cannot negate completely the intrinsic capacity of ethylene dibromide to alkylate cellular constituents. Because of this, exposure to ethylene dibromide has potentials for the A major factor in the development of gastric carcinoma in the rats and mice is considered to be the direct contact between mucosal cells and concentrated ethylene dibromide in a quantity which exceeded the ability of the tissues to handle the chemical. Mutagenic effects from ethylene dibromide have been demonstrated in microbes, plants, insects, and mammalian cells in vitro, presumably due to its ability to alkylate, or covalently bond, to DNA in a cross-linking mechanism by virtue of its bifunctional structure. Although this potential has not been demonstrated in humans, the broad biologic activity of ethylene dibromide warrants concern about possible damage to genetic mechanisms in employees exposed to it. Teratogenic effects which seem to be due to maternal exposure to ethylene dibromide have been confined to brain and costal anomalies in fetal mice and rats, but malnourishment as a contributing factor cannot be discredited unequivocally. Although it is not possible at this time to state categorically an exposure concentration at which ethylene dibromide may be regarded to be completely without risk, NIOSH considers that the recommended occupational exposure limit should be substantially lower than the current federal standard of 20 ppm as an 8-hour TWA limit, 30 ppm ceiling. The recommended occupational exposure limit for ethylene dibromide, at the least, should be reduced sufficiently to keep the total lifetime dose well below the cumulative doses shown to be hazardous in animal experiments. In considering the alkylating capability of ethylene dibromide and the potential adverse effects on the organism which may result, especially at the subcellular level, NIOSH recommends that the occupational exposure limit for ethylene dibromide be reduced to a ceiling concentration of 1.0 mg/cu m (0.13 ppm) for any 15-minute sampling period. This represents a reduction to one-two-hundred and thirtieth of the current federal ceiling limit for ethylene dibromide and is a level at which an employee would inhale a maximum of about 686 mg/kg of ethylene dibromide during a 40-year working lifetime, which is substantially below that total dose known to induce adverse effects in experimental animals. It is believed that so long as care is taken to prevent entrance of any appreciable amount of ethylene dibromide into the digestive tract, adherence to this exposure limit will protect against acute adverse effects and will reduce the potential long-term effects to a negligible level. NIOSH concludes that reduction to a ceiling concentration of 1.0 mg/cu m (0.13 ppm) will protect employees from acute illness resulting from exposure to ethylene dibromide and will reduce markedly, and perhaps remove entirely, any hazard of adverse effects on health from long-term exposure to this chemical. Studies should be conducted to determine the feasibility of using body fluids, such as blood or urine, as the basis of a method for biologic monitoring of workers that are occupationally exposed to ethylene dibromide. (h) # Long-term Animal Exposure Studies Long-term exposure of several animal species at a variety of concentrations of ethylene dibromide vapor approaching the recommended environmental limit is needed. These studies should simulate occupational exposure conditions of 8-10 hours/day, 4-5 days/week, for at least 18-24 months and the animals maintained until the end of their natural life. These studies should be properly designed and performed to allow for assessment of general body parameters, biochemical/physiologic parameters, and gross or microscopic examinations of involved organs including at least the liver, lungs, spleen, kidneys, CNS, and circulatory system. In addition, repeated long-term experiments should be performed to determine the effects of ethylene dibromide absorption through the skin. Similar schedules and experimental designs as those for inhalation studies should be followed. The National Cancer Institute has informed NIOSH that a long-term experiment to study the possible carcinogenic effects from the inhalation of ethylene dibromide is presently being conducted. Several studies have indicated that ethylene dibromide, or its metabolites, is widely circulated throughout the body and remains widely distributed in the body tissues for a considerable time. These studies also indicated that ethylene dibromide, or its metabolites, is excreted in the urine and eliminated in the feces. The sampling train consists of a charcoal tube and a vacuum pump. (1) Charcoal tubes: Glass tubes, with both ends flamesealed, 7-cm long, with a 6-mm OD and a 4-mm ID, containing two sections of 20/40 mesh activated charcoal separated by a 2-mm portion of polyurethane foam. The activated charcoal is prepared from coconut shells and is fired at 600 C prior to packing. The primary section contains 100 mg of charcoal, the backup section, 50 mg. A 3-mm portion of polyurethane foam is placed between the outlet end of the tube and the backup section. A plug of silylated glass wool is placed in front of the primary section. # METHOD FOR SAMPLING ETHYLENE DIBROMIDE IN AIR The pressure drop across the tube when in use must be less than 1 inch of mercury at a flowrate of 1 liter/minute. Tubes with the above specifications are commercially available. (2) Pump: A battery-operated pump, complete with clip for attachment to the employee's belt, capable of operation at 200 ml/minute or less with a controlled accuracy of + 5%. # (b) Calibration The accurate calibration of a sampling pump is essential for the correct interpretation of the volume sampled. The frequency of calibration is dependent on the use, care, and handling to which the pump is subjected. Pumps should also be recalibrated if they have been misused or if they have just been repaired or received from a manufacturer. If the pump receives hard usage, more frequent calibration may be necessary. Maintenance and calibration should be performed on a regular schedule and records of these should be kept. Ordinarily, pumps should be calibrated in the laboratory both before they are used in the field and after they have been used to collect a large number of field samples. The accuracy of calibration is dependent on the type of instrument used as a reference. The choice of calibration instrument will depend largely on where the calibration is to be performed. (2) Break the tips of a charcoal tube to produce openings of at least 2 mm in diameter. Repeat the procedure in (7) above at least three times, average the results, and calculate the flowrate by dividing the volume between the preselected marks by the time required for the soapbubble to traverse the distance. If, for the pump being calibrated, the volume of air sampled is calculated as the product of the number of strokes times a stroke factor (given in units of volume/stroke), the stroke factor is the quotient of the volume between the two preselected marks divided by the number of strokes. Therefore, if the analysis cannot be performed within 16-24 hours after sampling has been completed, the samples must be stored at -25 C or below. Refrigerated samples may be stored for two weeks. (25 liters), the probable range of this method is 40-800 nanograms/sample solution at a detector sensitivity that gives nearly full deflection on the strip chart recorder for a 1-mg sample. The method may be capable of measuring much smaller amounts if the desorption efficiency is adequate and if a photon-ionization detector is used on the chromatograph. Desorption efficiency must be determined over the range used. The upper limit of the range of the method is dependent on the adsorptive capacity of the charcoal tube. This capacity varies with the concentrations of ethylene dibromide and other substances in the air. The first section of the charcoal tube held at least 21.4 mg of ethylene dibromide when a test atmosphere containing 446 mg/cu m of ethylene dibromide in dry air was sampled at 200 ml/minute for 240 minutes; at that time, the concentration of ethylene dibromide in the effluent was less than 2% of that in the influent. If a particular atmosphere is suspected of containing a large amount of contaminant, a smaller sampling volume should be taken. # Interferences Compounds which have about the same retention time as ethylene dibromide and which are detected by the electron capture detector will interfere with the analysis. This type of interference can be overcome by changing the operating conditions of the instrument, usually by modifying the column, the column temperature, or both. Ethylene dibromide will not be efficiently trapped when the amount of water vapor in the air is so great that condensation occurs in the trapping media. Lesser amounts of water vapor in the air may severely decrease the breakthrough volume. When interfering compounds are known or suspected to be present in the air, such information including their suspected identities could be transmitted with the sample. # Precision and Accuracy The relative standard deviation for the combined analytical and sampling method in the prescribed range of 203-2,370 nanograms/charcoal tube was 0.070. # Advantages and Disadvantages of the Method This method uses a sampling device that is small, portable, and involves no liquids. Interferences are minimal and can usually be eliminated by altering chromatographic conditions. Analysis of the charcoal tubes can be accomplished rapidly. Simultaneous analysis of two or more compounds suspected of being present in the same sample can usually be accomplished by simply changing chromatographic conditions. One disadvantage of the method is that the amount of sample which can be collected by this method is limited by the weight of ethylene dibromide which the tube will hold before breakthrough. When the sample value obtained for the backup section of charcoal exceeds 25% of that found in the front section, the possibility of appreciable sample loss exists. Recoveries of ethylene dibromide from charcoal are decreased upon storage of the charcoal tube samples at room temperature, particularly with lesser amounts of analyte. The use of an internal standard is required in order to attain good precision. Other organic compounds in high concentrations may displace ethylene dibromide from the charcoal. High humidity may decrease the absorptive efficiency and capacity of the charcoal. The precision of the method is limited by the reproducibility of the pressure drop across the charcoal tube. This drop will affect the flowrate and the volume of air sampled, since the pump is usually calibrated for one tube only. (e) # Measurement of area: The areas of the sample peaks are measured by electronic integration or some other suitable method of area measurement. Preliminary sample results are read from a standard curve prepared as outlined below. (f) The approximate retention times of ethylene dibromide and two potential internal standards under the GC conditions described in this method are: In the case of the internal standard method, prepare standard curves by plotting concentration in mg/ml versus the ratio of the peak areas of ethylene dibromide to n-pentadecane. Compound # Calculations Read the weight in milligrams of ethylene dibromide corresponding to the total peak area from the standard curve. No volume corrections are needed because the standard curve is based on mg ethylene dibromide/ml of benzene-methanol and the volume of sample injected is identical to the volume of the standards injected. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50- The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees. Respirators shall be specified as to type and NIOSH or US Bureau of Mines approval class, ie, "Supplied air," "Organic vapor canister," etc. Protective equipment must be specified as to type and materials of construction. Adapted from reference 9 # PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R (f) 99:1 Benzene-methanol (v/v). # Analysis of Samples All glassware used for the laboratory analysis should be washed in detergent and rinsed with tap and distilled water.	# The views expressed and conclusions reached in this document, together with the recommendations for a standard, are those of NIOSH, after review of the evidence and consideration of the comments of reviewers. These views and conclusions are not necessarily those of the consultants, other federal agencies, and professional societies that reviewed the document, or of the contractor. recommends that employee exposure to ethylene dibromide in the workplace be controlled by adherence to the following sections. # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR ETHYLENE DIBROMIDE The standard is designed to protect the health and provide for the safety of employees for up to a 10-hour workday, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should prevent adverse effects of ethylene dibromide on the health of employees and provide for their safety. Techniques recommended in the standard are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. Although NIOSH considers the workplace environmental limit to be a safe level based on current information, the employer should regard it as the upper boundary of exposure and make every effort to maintain the exposure as low as is technically feasible. The criteria and standard will be subject to review and revision as necessary. The possible health effects of employees chronically exposed to ethylene dibromide may include the induction of cancers, malformations and heritable changes in offspring, and sterility. Ethylene dibromide may also cause adverse effects to the liver, kidneys, heart, and other internal organs and systems. Direct contact of the skin with ethylene dibromide may induce chemical burns as well as systemic effects, and ingestion of ethylene dibromide may damage internal organ systems, or even be fatal. The alkylation of cellular constituents, including the genetic material, deoxyribonucleic acid (DNA), is the most plausible molecular basis for the induction of adverse effects after exposure to ethylene dibromide. These criteria and the recommended standard apply to occupational exposure of workers to the brominated hydrocarbon BrCH2CH2Br, hereinafter referred to as "ethylene dibromide." Synonyms for ethylene dibromide include ethylene bromide, dibromoethane, sym-dibromoethane, 1,2dibromoethane, glycol dibromide, and EDB. The major uses of ethylene dibromide are as an additive to leaded gasoline and as a component of fumigants. "Occupational exposure to ethylene dibromide" is defined as work in any establishment where ethylene dibromide is manufactured, blended, stored, used, handled, or otherwise present. The "action level" is defined as one-half of the recommended workplace exposure concentration designated as a ceiling limit for ethylene dibromide. Exposure to airborne ethylene dibromide at concentrations less than the action level, as determined in accordance with Section 8, will not require adherence to Sections 2, 3, 4(a), or 8(c,d). If exposure to other chemicals also occurs, the employer shall comply with any applicable standard for the other chemicals. # Section 1 -Environmental (Workplace Air) (a) Concentration The employer shall control workplace concentrations of ethylene dibromide so that no employee is exposed in his workplace to concentrations greater than 1.0 mg/cu m (0.13 ppm) as a ceiling limit, as determined by a sampling period of 15 minutes. (b) # Sampling and Analysis Procedures for the collection and analysis of workroom air samples for compliance with the standard shall be as provided in Appendices I and II, or by any methods shown to be at least equivalent in precision, sensitivity, and accuracy to the methods specified. # Section 2 -Medical Medical surveillance shall be made available to employees as outlined below: (a) Comprehensive preplacement and annual medical examinations unless a more frequent schedule is indicated by professional medical judgment based on such factors as emergencies, variations in work periods, and the preexisting health status of the individual worker. (b) These examinations shall include at least: (1) Comprehensive or interim medical and work histories, with special emphasis directed to disorders of the heart, liver, kidneys, and nervous system. (2) A comprehensive physical examination, with particular emphasis given to cardiovascular, pulmonary, neurologic, hepatic, and renal systems, and to the skin. (3) An evaluation of the employee's physical ability to safely wear a negative or positive pressure respirator. (c) Employees shall be counseled by the physician to ensure that each employee is aware that ethylene dibromide has been shown to induce in experimental animals adverse effects in reproductive processes, including abnormalities in offspring, mutations, and stomach cancer following direct administration. The relevancy of these findings in animals to male or female employees has not yet been established. They do indicate, however, that both employers and employees should do everything possible to minimize exposures to ethylene dibromide. If a physician becomes aware of any adverse effects on the reproductive system, or cancers in individuals who have been exposed to ethylene dibromide, or any abnormal babies born to parents either or both of whom have been exposed to ethylene dibromide, such information should be forwarded to the Director, National Institute for Occupational Safety and Health, as promptly as possible. (d) Medical attention shall be provided promptly to all employees suspected of being exposed to ethylene dibromide vapor at or above the action level or to liquid ethylene dibromide. A 48-hour medical observation period for delayed systemic or dermal effects is recommended. (e) Examinations of current employees shall be performed as soon as practicable after the promulgation of a standard based on these recommendations. (f) The employer shall maintain medical records for all persons exposed to ethylene dibromide at or above the action level. All medical records, including information on required medical examinations and supporting documents, shall be kept for at least 30 years after the termination of the individual's employment. (g) The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employee or former employee, and of the employer shall have access to these medical records. # Section 3 -Labeling and Posting All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers. Illiterate workers and workers reading languages other than those used on labels and posted signs shall receive information regarding hazardous areas and shall be informed of the instructions printed on labels and signs. (a) Labeling The following warning label shall be affixed in a readily visible location on ethylene dibromide processing or other equipment and on ethylene dibromide storage tanks or containers: (C) During emergencies when air concentrations of ethylene dibromide may exceed the recommended occupational exposure limit. ETHYLENE # C2) When a respirator is permitted by paragraph (a)(1) of this section, it shall be selected and used pursuant to the following requirements: (A) The employer shall ensure that no employee is exposed to ethylene dibromide because of improper respirator selection, fit, use, or maintenance. (B) The employer shall establish and enforce a respirator program meeting the requirements of 29 CFR 1910.134 as amended. (C) The employer shall provide respirators in accordance with Table 1-1 and shall ensure that the employee uses the respirator provided when necessary. (D) Respiratory protective devices described in (1) Supplied-air respirator with full facepiece, helmet, or hood (2) Self-contained breathing appara tus with full facepiece Type C supplied-air respirator with full facepiece operated in pressuredemand or other positive pressure mode or with full facepiece, hood, or hel met operated in continuous-flow mode (1) Self-contained breathing appara tus with full facepiece operated in pressure-demand or other positive pressure mode (2) Combination respirator that in cludes Type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and auxiliary self-contained breathing apparatus op erated in pressure-demand or positive pressure mode (3) Supplied-air suits may be neces sary (b) Eye Protection Eye protective devices shall be provided by the employer and used by each employee where contact of ethylene dibromide with the eyes is likely. Chemical safety goggles or plastic face shields (8-inch minimum) with goggles made completely of ethylene dibromide-resistant materials shall be used. Selection, use, and maintenance of eye protective devices shall be in accordance with 29 CFR 1910.133. (c) Protective Clothing Protective clothing shall be resistant to the penetration and to the chemical action of ethylene dibromide. Additional protection, including gloves, bib-type aprons, boots, and overshoes, shall be provided for, and worn by, each employee while in any operation that may cause direct contact with liquid ethylene dibromide. Supplied-air hoods or suits resistant to penetration by ethylene dibromide shall be worn when entering confined spaces, such as pits or storage tanks. In situations where heat stress is likely to occur, supplied-air suits, preferably cooled, are recommended. The employer shall ensure that all personal protective clothing is inspected regularly for defects and is maintained in a clean and satisfactory condition by the employee. Records of such training should be kept for inspection by authorized personnel as required. This program shall be held for all employees with occupational exposure to ethylene dibromide at intervals not greater than quarterly, or whenever there is a process change. For all work areas where emergencies may occur, the employer shall take all necessary steps to ensure that employees are instructed in and follow the procedures specified below and any others appropriate to the specific operation or process. (1) Procedures shall include at least prearranged plans for : ( (2) Evacuation alarm systems shall be provided by the employer. (3) Personal protective equipment and clothing as specified in Section 4 shall be used by trained personnel essential to emergency operations. (4) Nonessential employees shall be evacuated from hazardous areas during emergencies. Perimeters of these areas shall be delineated, posted, and secured. The employees in adjacent areas shall be trained in evacuation procedures if these work areas become involved. # C5) Only personnel trained in the emergency procedures and protected against the attendant hazards shall shut off sources of ethylene dibromide, clean up spills, control and repair leaks, and fight fires in ethylene dibromide areas. (6) Firefighting procedures shall be established for areas where flammable materials are used with ethylene dibromide. Chemical foam, carbon dioxide, or dry chemicals shall be used for fighting fires in areas where ethylene dibromide is present. Proper protective respirators and clothing shall be worn by all personnel in the hazard area until concentrations of airborne ethylene dibromide have been demonstrated by monitoring to be below the recommended occupational exposure limit. Showers, eyewash fountains, and washroom facilities shall be provided and so located as to be readily accessible to workers in all areas where skin or eye contact with liquid ethylene dibromide is likely. If liquid ethylene dibromide is splashed on the clothing or skin, contaminated clothing shall be promptly removed and the skin washed thoroughly with soap and water for at least 15 minutes. If liquid ethylene dibromide gets into the eyes, they shall be irrigated immediately with copious quantities of running water for at least 15 minutes. (1) Suitable engineering controls designed to limit exposure to ethylene dibromide to that prescribed in Section 1(a) shall be used. The use of completely enclosed processes is the recommended method of control for ethylene dibromide. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. When a local exhaust ventilation system is used, it shall be designed to prevent the accumulation or recirculation of ventilation control or process air in the workroom, to maintain ethylene dibromide concentrations below the limit of the recommended standard, and to remove ethylene dibromide from the breathing zones of employees. Exhaust systems discharging into outside air must conform with applicable local, state, and federal air pollution regulations. Ventilation systems shall be subjected to regular preventive maintenance and cleaning to ensure effectiveness, which shall be verified by periodic airflow measurements at least every 3 months. Measurements of system efficiency shall also be made immediately by personnel properly attired in specified protective equipment when any change in production, process, or control might result in increased concentrations of airborne ethylene dibromide. Tempered makeup air shall be provided to work areas in which exhaust ventilation is operating. (2) Forced-draft ventilation systems shall be equipped with remote manual controls and shall be designed to turn off automatically in the event of a fire in the work area. # C2) Prompt medical attention shall be provided if there is known or suspected exposure to ethylene dibromide, whether or not symptoms are present. # C3) The employer shall ensure that safety showers, eyewash fountains, and other emergency equipment is in proper working order through regularly scheduled inspections performed by qualified maintenance personnel. (4) Ethylene dibromide operating systems shall be inspected daily for signs of leaks by personnel attired in specified protective equipment. All equipment including valves, fittings, and connections shall be checked for tightness and good working order. All newly made connections shall be checked for leaks immediately after ethylene dibromide is introduced by trained personnel attired in prescribed personal protective equipment. ( )5 If there is a leak, the leak shall be corrected immediately. Work shall resume normally only after necessary repair or replacement has been completed, the area has been ventilated, and the concentration of ethylene dibromide has been determined by monitoring to be below the recommended occupational exposure limit. (6) Transportation and use of ethylene dibromide shall comply with all applicable local, state, and federal regulations. Where ethylene dibromide is used as a fumigant, strict adherence to the pesticide container label requirements for application and personal protection shall be followed. Additional standards for pesticide use by agricultural workers can be found in 40 CFR 170. (7) When ethylene dibromide containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control while moving. (8) Process valves and pumps shall be readily accessible and should not be located in pits and congested areas. Containers and systems shall be handled and opened with care. Approved protective equipment as specified in Section 4 shall be worn while opening, connecting, and disconnecting ethylene dibromide containers and systems. Adequate ventilation shall be available to prevent exposure to ethylene dibromide when opening containers and systems. (10) Personnel shall work in teams when ethylene dibromide is first admitted to a system, while repairing leaks, or when entering a confined or enclosed space. (11) Any odor of ethylene dibromide shall be reported to a responsible authority and an alarm sounded immediately. # (d) Work Areas (1) Ethylene Dibromide Hazard Areas A hazard area shall be considered as any space workers may enter that has physical characteristics and sources of ethylene dibromide that could result in air concentrations exceeding the recommended limit. Exits shall be plainly marked and shall open outward. Emergency exit doors shall be conveniently located and shall open into areas which will remain free of contamination in an emergency. At least two separate means of exit shall be provided from each room or building in which ethylene dibromide is stored, handled, or used in quantities that could create a hazard. (2) # Confined or Enclosed Spaces Entry into confined spaces, such as tanks, pits, process vessels, tank cars, sewers, or tunnels, where there may be limited egress shall be controlled by a permit system. Permits shall be signed by an authorized employer representative certifying that preventive and protective measures have been followed. Confined spaces which have contained ethylene dibromide shall be thoroughly ventilated to ensure an adequate supply of oxygen, tested for ethylene dibromide and other contaminants, and inspected for compliance with these requirements prior to each entry. Adequate ventilation shall be maintained while workers are in the space. Leakage of ethylene dibromide into the confined space while work is in progress shall be prevented by disconnecting and blanking the ethylene dibromide supply lines. An individual entering confined spaces shall be furnished with appropriate personal protective equipment and protected by a lifeline harness tended by another worker outside the space, who shall also be equipped for entry with approved personal protective equipment and who has contact with a third party. Communication (visual, voice, signal line, telephone, radio, or other suitable means) shall be maintained by the standby person with the employee inside the confined or enclosed space. A third employee, equipped to proceed to the aid of the other two if necessary, shall have general surveillance of their activities. (e) Storage (1) Storage facilities shall be designed to contain spills completely within a surrounding dike and to prevent contamination of workroom air. ( Storage of ethylene dibromlde in the same area as reactive metals, such as aluminum or magnesium, or as liquid ammonia shall be prohibited. (3) Ethylene dibromide shall be stored in tightly closed containers in a well-ventilated area away from excessive heat and sunlight. # C4) Storage containers shall be periodically inspected for leakage. (5) Ventilation switches and emergency respiratory equipment shall be located outside storage areas in readily accessible locations which will be free of ethylene dibromide in an emergency. (f) Spills, Leaks, and Waste Disposal (1) If ethylene dibromide leaks or is spilled, the following steps shall be taken: (A) Evacuate all nonessential personnel from the area. # (B) Adequately ventilate the area of the spill or leak to prevent accumulation of the vapor. (C) If in liquid form, collect spilled material for reclamation or absorb in vermiculite, dry sand, earth, or similar nonreactive material. (D) If in solid form, collect spilled material in the most convenient and safe manner for reclamation or for disposal. (2) Personnel entering the spill or leak area shall be furnished with appropriate personal protective equipment. All other personnel shall be excluded from the area. (3) All wastes and residues containing ethylene dibromide shall be collected in ethylene dibromide-resistant containers and incinerated or buried in such a manner that no ethylene dibromide or toxic decomposition products are released to the environment. Clothing contaminated with liquid ethylene dibromide shall be immediately removed and placed in a closed container in a well-ventilated area for later disposal or decontamination. Employers shall require personnel who work with ethylene dibromide to shower before leaving the workplace at the end of a workday. (c) Employers shall ensure that employees who handle ethylene dibromide wash their hands thoroughly with soap and water before eating, smoking, or using toilet facilities. # (d) The storage, dispensing, preparation, and consumption of food, beverages, or tobacco shall be prohibited in ethylene dibromide work areas. (e) The employer shall ensure that personnel who launder and clean clothing or equipment contaminated with ethylene dibromide are provided adequate personal protective equipment to prevent exposure and shall ensure that these employees are aware of the potential hazards of exposure to ethylene dibromide. where ethylene dibromide is handled, processed, or stored. Records of these surveys, including the basis for concluding that environmental concentrations are below the recommended limit or below the action level, shall be maintained. Surveys shall be repeated every month or whenever a process change is made. (b) Where exposure concentrations have not been determined, they shall be determined as soon as practicable after the promulgation of a standard based on these recommendations. # (c) Requirements set forth below apply to work areas in which the concentration of ethylene dibromide has been determined to be at or above the action level. (1) An adequate number of samples shall be collected monthly in accordance with Appendix I for the evaluation of the work environment with respect to the occupational exposure of the employees. (2) Environmental samples shall be taken when a new process is installed or process changes are made which may cause an increase in environmental concentrations. Significantly increased production, relocation of existing operations, interruption of normal maintenance schedules, or other functions which may increase ethylene dibromide concentrations shall require resampling and analysis. (3) In all monitoring, samples shall be collected in accordance with the provisions prescribed in Section 1(b). The minimum number of representative exposure determinations for an operation or process shall be based on variations in exposures and production schedules and in accordance with the provisions prescribed in Section 1(b). (5) If initial, periodic, or special evaluations indicate that the recommended limit is exceeded, corrective engineering or other control measures shall be immediately instituted to ensure the safety of employees until a concentration below the recommended occupational exposure limit is achieved. In such cases, sampling of each operation and work location shall be conducted at least weekly until two consecutive employee exposure measurements, taken at least 1 week apart, reveal that the employee is not exposed to ethylene dibromide above the recommended occupational exposure limit. Employers shall notify in writing, within 5 days, every employee who is found to be exposed to ethylene dibromide above the recommended environmental limit. Adherence to the recommended standard for occupational exposure to ethylene dibromide is intended to minimize the potentials for the induction of sterility, carcinogenesis, mutagenesis, or teratogenesis in employees and their offspring from exposure to ethylene dibromide in the workplace. Adherence to the recommended standard is also intended to minimize the hazards from skin penetration and irritation associated with exposure to liquid ethylene dibromide and the delayed and insidious long-term systemic effects resulting from exposure to bath liquid and vaporous ethylene dibromide. III. # BIOLOGIC EFFECTS OF EXPOSURE Ethylene dlbromide, also known as 1,2-dibromoethane and ethylene bromide, is a clear, colorless, heavy liquid at room temperature with a distinctive odor described as "characteristic, mildly sweet" [1]. The minimum concentrations of ethylene dibromide in air reported to be detectable by odor range from 10 ppm (77 mg/cu m) [2] to 25 ppm (192.5 mg/cu m) [3]. Selected chemical and physical properties of ethylene dibromide are listed in Table XII -1 [1,3,4]. Ethylene dibromide is a reactive molecule which may form covalent bonds under biologic conditions [5,6]. Because of the two replaceable bromine atoms, ethylene dibromide is considered to be a bifunctional alkylating agent that is capable of introducing cross-links into biologic materials [6]. It tends to react with nucleophilic organic compounds [7] more readily with those that are relatively easily polarized, such as those containing sulfhydryl or amino groups, than with those that are less readily polarized, such as acids and ketones. The half-life of ethylene dibromide in water at 20 C and at a pH of 7 is about 14 years [7]. Although the biologic half-life of ethylene dibromide in humans is unknown, the presence of large numbers of nucleophiles in biologic tissue suggests that the half-life would be considerably shorter than that in water. The approximate biologic halflife of ethylene dibromide after intravenous (iv) injection in rats was less than 2 hours, and in chicks, it was less than 12 hours [8]. An approximate biologic half-life of 14C-labeled ethylene dibromide in mice and in guinea pigs can be estimated from the data presented by Edwards et al [9] and Plotnick and Conner [10] as less than 48 hours. This indicates that either spontaneous reactions with nucleophiles, enzymatically catalyzed degradative reactions, or efficient excretory mechanisms predominate in biologic systems. Alkyl bromides, such as ethylene dibromide, readily react with thiols, amines, alcohols, and other nucleophilic biochemical constituents [11][12][13] . The initial monoalkylation product between ethylene dibromide and substrate heteroatoms, such as nitrogen, oxygen, or sulfur, is a "half mustard" (a thiane) reagent which may spontaneously cyclize under biologic conditions to form a strained three-membered ring. This highly reactive intermediate product may then undergo a second alkylation reaction with cellular constituents. When both alkylation reactions occur with cellular DNA, the covalent cross-links between the DNA strands may prevent the normal separation of the strands during DNA synthesis and subsequent cell division [11,13]. Thus, such bifunctional alkylating agents as ethylene dibromide tend to possess a considerably greater biologic activity than monofunctional agents of the same primary reactivities [11]. The covalent reaction of ethylene dibromide with biologic materials may alter the chemical behavior and physical characteristics of the cellular constituents so as to prevent the altered molecules from functioning normally in physiologic processes. The formation of stable reaction products may account, in part, for the subsequent deleterious effects observed in biologic systems exposed to ethylene dibromide. The alkylation by foreign chemicals of the biologic materials controlling cellular metabolism is the most plausible basis for the induction of genetic and neoplastic alterations after the exposure of biologic populations to alkylating agents. When the risk of induction of adverse biologic changes, such as mutation and neoplasia, increase as a cumulative function of the total dosage, then the observation of measurable effects may not be possible until after long periods of exposure to low concentrations of the inducing agent [7,14]. # Extent of Exposure Ethylene dibromide-manufacturing processes are based on the bromination of ethylene [1]. Natural bromide-containing brines are treated with chlorine to release elemental bromine through anionic replacement. The reaction between gaseous ethylene and liquid bromine (which may contain traces of chlorine) yields a mixture of ethylene dibromide and reaction side-products, including very small amounts of vinyl bromide, ethyl bromide, and ethyl chlorobromide [15]. If the reaction temperatures and pressures are carefully controlled, the purity of the ethylene dibromide can approach 99.95% [15]. Ethylene dibromide can also be produced by the hydrobromination of acetylene [2], although this process is of little commercial value today. In 1921, the antiknock properties of tetraalkyl lead compounds in the internal combustion engine were discovered [16]. To prevent the deposition of lead on the cylinder walls, a substance capable of reacting with the lead to aid its removal from the engine was needed. Ethylene dibromide was found to be such a substance and has been used since then in leaded gasoline as a lead scavenger. The US production of ethylene dibromide increased from an estimated 64 million pounds in 1940 to over 331 million pounds in 1973 [17]. This fivefold increase can be related to the increased consumption of gasoline containing ethylene dibromide as an additive, which has always been its largest use [1]. About 85% of the ethylene dibromide produced during the The production of ethylene dibromide is the largest single use of bromine, and, as such, the locations of manufacturing plants have usually been near the major sources of bromine [1]. Until 1961, the major source of bromine for ethylene dibromide manufacture was seawater; since 1961, the major source of bromine has been underground brine deposits, and the manufacturing of ethylene dibromide has been redistributed to be near these natural bromide brine wells in Michigan and Arkansas [1]. A number of other occupations in which a potential for ethylene dibromide exposure exists are listed in Table XII last -2 [21]. NIOSH estimates that approximately 9,000 employees (manufacturing, formulating, fumigating) are potentially exposed to ethylene dibromide in the workplace. If one includes gasoline station attendants, this figure becomes much larger (about 660,000). # Historical Reports One of the first instances of ethylene dibromide intoxication was described by Marmetschke [22] in 1910. This case history described the accidental use of ethylene dibromide instead of ethyl bromide as an anesthetic or narcotic agent. Although this report is historical rather than clinical, it is one of the few relating to human exposure which give the amount of ethylene dibromide administered to each patient and the clinical symptoms resulting from the exposures. Thus, this report will be discussed in detail in Effects on Humans. Another early case of occupational exposure to ethylene dibromide, which will also be discussed in Effects on Humans, was described in 1928 by Kochmann [23]. # Effects on Humans In 1910, Marmetschke [22] wrote about a case of ethylene dibromide poisoning that occurred as the result of the mistaken administration of ethylene dibromide to a patient instead of ethyl bromide. A woman was administered the contents of a 70-g bottle of ethylene dibromide in aliquots of about 10 ml (22.0 g) through a gauze mask without producing the expected anesthesia. She coughed constantly during the administration and was dizzy at the completion of the application. She began to vomit and continued vomiting throughout the night. The patient complained of a burning sensation in her chest and of inability to sleep. During the night, she had diarrhea, and the next day she became dizzy again after exertion. She became very restless and nervous and complained of having trouble in breathing. She continued to complain of thirst, abdominal pain, and a burning sensation in her chest. The next day, she had uterine hemorrhaging, and died approximately 44 hours after she received the ethylene dibromide. The results of the autopsy showed that the skin was a very pale blue and that the vessels of the skin were filled with blood Pflesser [24] subjected eight human volunteers and himself to the gauge fluid and to each of the components separately to determine their effects on the skin. One milliliter of the gauge fluid was placed on the hands of the volunteers and rubbed between the hands for about 1 minute. Two hours later, the hands were washed with soap and water. None of the subjects developed any symptoms of adverse effects on the day of the test or later. Pflesser observed that, after rubbing the fluid between the hands for 1 minute, the liquid could no longer be seen on the skin, and he concluded that it had been absorbed or had evaporated. In an additional experiment [24], the same volunteers rubbed 1 ml of the gauge fluid into the skin of the right forearm for 1 minute. Again, washing with soap and water was done after 2 hours. No symptoms of irritation were seen immediately after the exposure or later. In a third experiment [24], the same volunteers were subjected to 1 ml of the gauge fluid on a cotton swab that was placed on the left forearm and covered; exposure time was 2 hours. After a few minutes, all eight subjects noted a sensation of heat at the application site, sometimes complaining of a pronounced burning of the skin. At the end of the 2-hour exposure, a strong reddening of the skin had appeared at the application site in all cases, and, in one case, pinhead-sized blisters had developed. During the next 12 hours, a severe burning pain developed in addition to small blisters which merged into large ones. The blisters initially contained a clear, amber-yellow, thick liquid, but the liquid had a pronounced tendency to coagulate because of its high protein content. The area immediately surrounding the application site was edematous and swollen, and, in some cases, the swelling extended from the fingertips to the upper arm. In one case, the axillary lymph nodes were moderately swollen and painful. Even with topical cod liver oil treatment, the skin did not grow back until 13-17 days after exposure, and surface scars persisted for at least 4 months. Pflesser [24] stated that all subjects felt severely ill during the first days following exposure. In two subjects, dermatitis, consisting of severe swelling and reddening of the skin accompanied by intensive itching, persisted in the area of the application for several weeks. To determine which component of the gauge fluid was responsible for the adverse effects on the skin, Pflesser [24] subjected the same eight subjects and himself to each of the individual components. The results of the tests with the paraffin oil, Sudan Red B, and tetrachlorethane were negative. During the 1-hour exposure to 0.5 ml of tetrachlorethane, several individuals noted a slight sensation of heat at the application site, but no symptoms similar to those for the gauge fluid were subsequently noted. All volunteers rubbed 0.5 ml (1.1 g) of ethylene dibromide into the skin of the forearm for 1 minute and washed with soap and water 30 minutes later. All subjects developed swelling and reddening of the exposed area, as well as itching, during the 24 hours immediately after exposure. The symptoms subsided without supportive treatment within 2-3 days. In an additional experiment [24], the subjects received 0.5 ml (1.1 g) of ethylene dibromide applied to the skin on a swab, the swab and the application site being covered for 10 minutes. The swab was then removed and the area was washed with soap and water. A sensation of heat or slight burning was noticed during the exposure; and, during the next 24 hours a painful reddening and swelling of the skin developed. However, no blistering was noticed in any of the subjects. The injuries disappeared in 3-5 days without leaving visible traces. In a subsequent experiment [24], this procedure was repeated except that the application site was covered for 30 minutes. After this exposure period, the swab was removed and the area was washed with soap and water. During the 30-minute exposure, the subjects reported the customary heat or burning sensation at the application site. After exposure, a very painful inflammation of the skin occurred, including reddening, swelling, and blistering, within 15-20 hours. The damaged skin grew back after 7-13 days of supportive treatment. The author experienced such a strong burning pain in his skin immediately after application that increased so rapidly that the swab containing the ethylene dibromide had to be removed after 3 minutes. The pain and reddening of the skin subsided, but then increased again after a few hours until a blister the size of a crab apple had formed at the application site after 18 hours. Very strong pain was associated with the blister. When the blister was opened, Pflesser collected 21 ml of a clear exudate, which coagulated soon afterward, and over 245 ml of fluid within the first 3 days after application. In addition, the author stated that when the blister appeared on the right arm, all places that had previously been exposed to ethylene dibromide or to the gauge fluid on both the left and right arms began swelling, reddening, and itching. A moderately strong, painful glandular swelling occurred in the left armpit (opposite the arm of the application site). Pflesser also reported that only a slight edema had occurred surrounding the application site after the 1st day, but that, on the 2nd day, an extensive edema of the entire right forearm and right hand suddenly developed. During these first few days after exposure, there was a pronounced feeling of illness and a slight temperature increase in addition to the physical manifestations at the exposure site. Healing of the damaged skin was complete after 17 days of zinc-sulfur ointment supportive treatment, leaving only a surface scar. From this series of experiments, Pflesser [24] concluded that ethylene dibromide was the component of the gauge fluid that was responsible for the swelling, reddening, and blistering of the skin of the seaman on the destroyer. He also concluded that the effects and their intensities depended on the duration of exposure to the skin, and that covering the application site to prevent evaporation greatly increased the extent of damage from exposure. Pflesser concluded that ethylene dibromide was absorbed through the skin, causing tissue death, general inflammation, and plasma exudation. He further postulated that ethylene dibromide possessed a sensitization potential, citing the symptoms that appeared at previous application sites after his own exposure for 3 minutes to 0.5 ml of ethylene dibromide as proof of the assumption. In 1960, Olmstead [25] Macroscopic and microscopic examinations of the internal organs showed a pronounced granular degeneration of the parenchymal tissue of the kidneys and smaller amounts of damage in the pancreas, spleen, heart, liver, and adrenals. In addition, the authors observed that ethylene dibromide exposure produced swelling and a generalized interstitial edematous degeneration of the endothelial lining of the abdominal vascular system that was not described further. Thomas and Yant [27] noted that commercial and purified ethylene dibromide applied to the shaved abdomens of three groups of two rats each over a 2-cm square area killed all of the animals within 6-18 hours at doses of 0.25, 0.50, or 1.00 ml (0.55, 1.1, or 2.2 g)/animal. No attempt was made to determine the minimum lethal dose. The application site showed marked hyperemia of the small cutaneous blood vessels, and the abdominal muscles became contracted and remained tense. By 20 minutes, the reflexes became weak and the animals were scarcely able to stand. A slight, temporary increase in activity was noted during the next 10 minutes, but the general appearance remained that of great weakness. Macroscopic and microscopic examinations of tissues were similar to those in guinea pigs after vapor inhalation. The only difference observed between the two routes of exposure concerned the spleen: gross examination of the guinea pigs exposed to the vapor of airborne ethylene dibromide revealed that spleens were pale and edematous, whereas spleens of the dermally exposed rats were highly congested and edematous. No microscopic characterization of these differences was given. In 1928, Lucas [28] published the results of an experiment in which two adult rabbits inhaled ethylene dibromide vapor in quantities sufficient to produce light or deep anesthesia (concentrations not reported). Very light anesthesia was maintained in one rabbit by inhalation of ethylene dibromide for about 10 minutes. The rabbit vocalized during exposure, presumably responding to the irritating effects of ethylene dibromide. Respiration became extremely rapid during exposure and there was considerable phonation. The mucous membranes of the mouth were a peculiar "old rose" color after recovery from the anesthesia. This may have been due to a combination of vascular congestion and cyanosis. Death occurred within 18 hours, and, at autopsy, the liver was enlarged and mottled. Microscopic examination of the liver showed slight-to-moderate diffuse fatty changes, which tended to be more marked in the portal regions. Another rabbit deeply anesthetized by inhalation of ethylene dibromide for about 12 minutes exhibited signs of marked irritation from the gas, considerable phonation, rapid breathing progressing as the anesthesia continued, and snuffling in its breathing after recovery from the anesthesia [28]. Death occurred within 15 hours. Autopsy showed the lungs to be enlarged and filled with a frothy exudate. About 10 ml of fluid was found in the pleural cavity. The liver was swollen and markedly congested. Lucas postulated that these results may have been caused by the decomposition of ethylene dibromide to hydrogen bromide and that local high concentrations of this material would be sufficient to bring about the observed changes. The next day, the animals began to tremble while in the cage, tears began forming, and the nasal mucosa was strongly reddened. After 11 exposures, the survivors were very weak and maintained a reclining posture, and strong trembling was observed, especially in the extremities. These conditions persisted until death occurred. There was a general weight loss during the exposures. Autopsy showed that the body cavities contained a clear, yellowish liquid. The lungs contained dark red discolorations and were judged by the author to be partially nonfunctional. The spleen was slightly enlarged and the kidneys were swollen and yellow colored. Kochmann diagnosed the condition of the cats after exposure to ethylene dibromide as follows: rhinitis, conjunctivitis, ascites, pleural effusion, pneumonia in the left superior lobe of the lung, and incipient fatty degeneration of the liver and possibly degeneration of the tubules of the kidneys. Similar adverse signs of intoxication, including rhinitis, conjunctivitis, anorexia, and loss of weight, appeared in rabbits. Autopsies of the rabbits showed that the small intestine contained an excessive amount of liquid, that the colon contained blood, and that the liver and kidneys were hyperemic. In an additional experiment, the animals inhaled ethylene dibromide at a concentration of 0.01% (770 mg/cu m) once for 30 minutes, and the author [23] noted that there was a reduction in appetite, a corresponding loss of weight, a distinctly reduced hemoglobin content in the blood, and a slow recovery to the pretreatment conditions of the test animals. disappeared immediately after the guinea pigs were removed from the exposure chamber. Paralysis of the rear extremities occurred 24 hours after the sixth exposure, but it had partially disappeared after 5 additional days and was completely gone after another 8 days. The authors concluded that the adverse effects, such as paralysis of the extremities and spasms of the diaphragm, appeared at a lower concentration and in a much shorter time than did the adverse effects in a concurrent experiment with methyl bromide. They also concluded that the signs of toxicity remained longer than those observed from methyl bromide. In 1929, Kistler and Luckhardt [30] reported the effects on respiration, muscle reflexes, and blood pressure in dogs exposed to ethylene dibromide by inhalation, ingestion, and injection. Dogs, anesthetized with sodium barbital, were sequentially injected iv with 0.2-1.0 ml (0.44-2.2 g) of ethylene dibromide for a total of 5.5 ml (12 g). Marked decreases in respiratory rate, blood pressure, and muscle reflexes resulted. Ethylene dibromide at 0.3 ml (0.66 g) injected iv caused cessation of respiration which was "momentary" or lasted as long as 40 seconds in the dogs tested. The cessation was followed by panting and a gradual return to almost normal breathing rate. The same dose produced a 75% decrease in blood pressure, the fall being immediate and sharp. The blood pressure gradually returned toward normal in a period of 2-12 minutes; but, in some cases, it remained 30% below normal. Ethylene dibromide at doses of 0.1-0.3 ml (0.22-0.66 g) injected iv caused a profound and rapid depression of the knee jerk reflex, which never returned to normal after the exposure. The effects on dogs exposed to 1.0-10.0 ml (2.2-22.0 g) of ethylene dibromide vaporized from an ether bottle were essentially the same as those caused by the iv injections, differing only slightly in the extent of the decreases [30]. The recovery times were described as being prolonged because of the longer exposure times, but complete experimental details were not given. The investigators [30] The autopsy showed bronchopneumonic foci and severe hyperemia in both lungs. A spherical thrombus was found in the heart, and the liver showed pronounced fatty degeneration. The effects noted above in the hearts of the dogs exposed to ethylene dibromide were also found in isolated, perfused hearts from male frogs (Rana temporaria) subjected to 400, 800, or 1,600 ppm of ethylene dibromide in Ringer's solution [31]. Immediate diastolic arrest occurred at 800 and 1,600 ppm with no recovery of function. At 400 ppm, there was diastolic arrest after 1 minute, but washing produced a gradual recovery to normal function. No cardiac arrest or change in the heart rate was found at a concentration of 200 ppm of ethylene dibromide. In 1946, Aman et al [32] studied the effects of repeated oral administration of ethylene dibromide on rats and guinea pigs. Nineteen animals were administered ethylene dibromide at average daily doses of 0, Total accumulated dosages of ethylene dibromide ranged from 0 to 1,420 mg. One rat, given 20 mg of ethylene dibromide daily, died after 3 months. All other rats and guinea pigs appeared to have gained weight normally during the experimental periods, and no untoward signs of toxicity were noted. Autopsy and microscopic examinations were not mentioned. The authors concluded that daily administration of ethylene dibromide for periods up to 4 months did not adversely affect the growth and outward physical appearance of rats and guinea pigs. The lack of experimental detail and data, the ambiguity of the data given, the inadequate number of control and experimental animals, and the absence of autopsies make this study difficult to evaluate and its importance questionable. In 1952, Rowe et al [33] investigated the effects of ethylene dibromide administered to rats, guinea pigs, rabbits, mice, chickens, and monkeys by single oral intubations, eye contact, dermal contact, dermal absorption, single exposure inhalation, or repeated exposure inhalations. The ethylene dibromide used in these studies was the 99% pure, commercial quality product, except that the inhalation studies were conducted with a repurified commercial product of essentially 100% purity. Ethylene dibromide was administered in undiluted form for eye and dermal contact, dermal absorption, and inhalation studies; in olive oil and acacia emulsion or olive oil solution for oral intubation studies; in propylene glycol solution for eye contact studies; or in butyl carbitol acetate solution for dermal contact studies. Fifty-five female rabbits, 28 chicks, 40 male and female guinea pigs, 40 female rats, 60 male rats, and 20 female mice were administered ethylene dibromide at sufficient doses to enable calculation of single oral-dose LD50's of 55 mg/kg, 79 mg/kg, 110 mg/kg, 117 mg/kg, 146 mg/kg, and 420 mg/kg, respectively [33]. The LD50's for male and female rats were significantly different (P<0.05). Of the five species tested, rabbits were the most sensitive to ethylene dibromide and mice were the least sensitive. Rowe et al [33] found that undiluted ethylene dibromide promptly caused obvious pain and conlunctival irritation when introduced into the eyes of rabbits. The undiluted material was in contact with the eyes for 30 seconds before one eye was thoroughly flushed for 3 minutes with running water; the other eye was not washed. Both eyes of each rabbit were then observed for injury. The conjunctival irritation cleared within 48 hours, and a very slight amount of superficial necrosis of the cornea healed promptly and completely. When a 10% solution of ethylene dibromide in propylene glycol was tested in rabbits bv the same procedure used with the undiluted material, it produced a more severe response than did the undiluted material. Moderate conjunctival irritation developed within 2 hours and persisted for 48 hours before remission began to occur. Moderate-to-severe corneal injury also persisted for about 48 hours before tissue repair became evident. Healing was complete 12 days after exposure without corneal scarring being evident. No injury to the iris or the lens of the eye was noted. A 1% solution in propylene glycol elicited a response in the rabbit eye very similar to that of the undiluted material. The authors noted that prompt washing of the treated eyes had a beneficial effect in all cases, slightly reducing the intensity of the response and shortening the healing time. Application of undiluted ethylene dibromide or 10% solutions in butyl carbitol acetate to the shaved skins of rabbits killed the animals within 24 hours [33]. It was apparent that a few hours of confined contact of the material with the skin caused marked erythema and edema. When evaporation was not inhibited by a covering, only slight erythema was noted. A 1.0% solution of ethylene dibromide in butyl carbitol acetate applied to rabbit ears 10 times in 14 days caused only slight erythema and exfoliation. When the solution was applied repeatedly for 10 times in 14 days onto the shaved abdomen of the rabbit and then bandaged, marked erythema and edema, which progressed to necrosis and exfoliation, were observed. Healing was complete without scarring within 7 days after termination of both exposures. Rowe et al [33] found that absorption of undiluted ethylene dibromide at doses of 210, 300, 650, or 1,100 mg/kg through the intact skin killed 1 of 15 rabbits at 210 mg/kg and all 5 rabbits at 1,100 mg/kg when the exposures lasted for 24 hours. In all of the exposed animals, the material produced a moderate-to-severe erythema, edema, and necrosis of the skin and caused scar formation in the survivors. Marked central nervous system (CNS) depression was seen in rabbits at all of the doses. At the 650 and 1,100 mg/kg doses, the animals felt cold to the touch. Deaths occurred within 4 days or not at all. The authors did not calculate an LD50 for dermal absorption in the rabbits; however, an LD50 of approximately 400 mg/kg for ethylene dibromide can be estimated from the dose-response data. These investigators [33] also studied the effects of single exposures of ethylene dibromide vapor to groups of 4-30 rats of both sexes at concentrations of 100, 200, 400, 800, 1,600, 3,000, 5,000, or 10,000 ppm (770, 1,540, 3,080, 6,160, 12,300, 23,100, 38,500, or 77,000 mg/cu m, respectively) and to guinea pigs of both sexes at 200 or 400 ppm (1,540 or 3,080 mg/cu m ) . At each concentration, the rats were exposed to the vapor for durations ranging from 0.02 to 16.0 hours to allow for the determination of concentration versus period of exposure values that represent death in essentially all of the rats, death in 50% of the rats, and death in essentially none of the rats. The findings of this study are presented in Table III-l. These data suggest that at concentrations above about 5,500 mg/cu m (715 ppm), the Haber product [the product of the exposure concentration (LC50) and the duration of exposure] becomes actually almost a constant but that, at lower concentrations of ethylene dibromide, the Haber product increases rapidly as the concentration is lowered further. This suggests, in turn, that exposure of the rat to a concentration of about 5,500 mg/cu m (715 ppm, 29.2 /jmoles/liter) of ethylene dibromide saturates some detoxification mechanism. Whether this is metabolic or excretory in nature cannot be judged from these data. Adapted from Rowe et al [33] Ethylene dibromlde produced only slight anesthetic effects at the concentrations used [33]. Depression of the CNS was observed in rats exposed at the higher concentrations (unspecified). Deaths usually occurred within 24 hours at the higher concentrations and were caused by respiratory or cardiac failure. Deaths occurring from exposures at lower concentrations (unspecified) were generally delayed, sometimes for as long as 12 days after exposure. The majority of these deaths were caused by pneumonia. These animals usually lost weight, appeared rough and unkempt, became quite irritable, discharged what appeared to be a blood-tinged fluid from the nose, and finally died. Animals surviving the exposure at the lower concentrations exhibited a similar progression of toxic signs for several days before recovery was apparent. Rats exposed at concentrations producing mortality and killed for autopsy 16-24 hours after exposure showed an increase in the weight of the lungs, liver, and kidneys. The lungs were congested, edematous, hemorrhagic, and inflamed; the liver had cloudy swelling, centrilobular fatty degeneration, and necrosis; and the kidneys exhibited slight interstitial congestion and edema, with slight cloudy swelling of the tubular epithelium in some cases. Guinea pigs appeared to be slightly less susceptible than rats to the effects of ethylene dibromide vapor when exposed to the same concentrations. All guinea pigs exposed at 400 ppm (3,080 mg/cu m) for 7 hours died, whereas all those exposed at 400 ppm (3,080 mg/cu m) for 7 hours and at 200 ppm (1,540 mg/cu m) for 7 hours lived. The authors made no attempt to determine concentrations and corresponding exposure durations that would produce an LD99.99, LD50, or LD0.01 in guinea pigs, but they did postulate that 30 ppm (231 mg/cu m) for 5 hours was the most severe repeated exposure without detectable adverse effects. Rowe et al [33] subjected rabbits, monkeys, guinea pigs, and rats to Two groups of controls, well-matched with the experimental animals with respect to number, age, sex, and body weight, were used in the experiment. One group was exposed to the same experimental regimen as the group exposed to ethylene dibromide, but in a chamber ventilated with clean air. The second control group was simply maintained in the animal quarters. During the test period, 10 of 20 ethylene dibromide-exposed male rats died, primarily from pneumonia and upper respiratory tract infections, and 3 of 20 ethylene dibromide-exposed female rats died from unspecified causes [33]. Twenty-three additional female rats subjected to 13 7-hour exposures at 25 ppm (192.5 mg/cu m) in 17 days showed no ill effects and were found to have total liver lipid contents similar to those of control rats. Groups of 8 male and 8 female guinea pigs tolerated 145 7-hour exposures at 25 ppm (192.5 mg/cu m) in 205 days without evidence of adverse effects as judged by the same criteria used to evaluate the rat data, except that liver lipid determinations were not conducted. Mortality during the experiment, caused by pulmonary infections, was 50% in male and 25% in female guinea pigs exposed to ethylene dibromide. Eighteen of the 20 animals in both the male and female control groups exposed to clean air survived the experimental regimen, but only 7 and 8 of the 20 females and males, respectively, in the unexposed control groups survived. An additional group of 8 female guinea pigs received 13 7-hour exposures at 25 ppm (192.5 mg/cu m) in 17 days without exhibiting adverse effects. Rabbits, 3 male and 1 female, and monkeys, 1 male and 1 female, were subjected to 152 7-hour exposures in 214 days and 156 7-hour exposures in 220 days, respectively, at 25 ppm (192.5 mg/cu m ) . There were no signs of adverse effects in the rabbits and monkeys when judged by the above criteria for the guinea pig data. Since an unusually high mortality rate was observed in the nonexposed control rats but not in the air-exposed control animals, no decisive conclusions can be drawn from the published data with respect to the hazard resulting from exposure to ethylene dibromide at 25 ppm (192.5 mg/cu m ) . Rowe and his colleagues [33] found that rats, guinea pigs, monkeys, and rabbits did not tolerate ethylene dibromide well at a concentration of 50 ppm (385 mg/cu m) administered 7 hours/day, 5 days/week, for 70-90 days. The group of 20 male and 20 female rats receiving 63 exposures in 91 days exhibited increased liver and kidney weights in both sexes, increased lung weights in males, decreased spleen weights in females, and decreased testis weights in males at autopsy. The group of 8 male and 8 female guinea pigs receiving 57 exposures in 80 days showed decreased rates of growth and final body weights, increased organ weights, slight central fatty degeneration of the livers, and slight interstitial congestion and edema with degeneration of the tubular epithelium in the kidneys. The 1 male and 3 female rabbits receiving 59 exposures in 84 days showed only small increases in liver and kidney weights; no other adverse effects were noted. The male and female monkeys receiving 49 exposures in 70 days appeared ill, nervous, and unkempt throughout the experimental period. Liver weights were increased and very slight central fatty degeneration of the liver was noted; no other adverse effects were noted from microscopic examination of the body organs. At concentrations of 100 ppm (770 mg/cu m) of ethylene dibromide vapor, 10 female rats steadily lost weight and 3 died after 1, 5, and 7 exposures, respectively, for 7 hours/day [33]. The remaining rats appeared thin and unkempt at the time of autopsy after seven exposures in 9 days. The stomachs were full of food which appeared blood tinged, and lung, liver, and kidney weights were increased markedly. Microscopic examination showed some thickening of the alveolar walls with slight leukocytic infiltration of the lungs, widespread cloudy swelling of the liver, and slight congestion and hemosiderin deposition in the spleen. Rabbits subjected to the same concentration suffered severe intoxication to the extent that two of four died after the second 7-hour exposure and the third died while receiving the third exposure. The fourth animal was killed after receiving the fourth exposure in 4 days. Microscopic examination of tissues from the last two rabbits showed widespread central fatty degeneration of the liver with some necrosis. The authors [33] concluded from the above series of experiments that ethylene dibromide was a fairly toxic, markedly irritating material. They postulated that ingestion of 1.5-2.0 ml (3.3-4.4 g) of undiluted ethylene dibromide could jeopardize the life of the average human and that this amount of material could easily be swallowed by accident. Rowe et al pointed out that, although ethylene dibromide was not likely to cause permanent injury to the eye, it probably would cause appreciable pain and suffering; thus, eye protection was strongly recommended for those handling ethylene dibromide. Although the hazard of contact with uncovered skin was not thought to be particularly serious unless repeated or prolonged, marked irritation and rapid absorption of ethylene dibromide occurred when it was confined to the skin. Ethylene dibromide vapor at 50 ppm (385 mg/cu m) repeated daily was not well tolerated by the species tested, whereas adverse effects were not believed to have resulted from exposure at 25 ppm Ethylene dibromide administration was discontinued in two of the four bulls to ascertain the reversibility of the exposure, and was later readministered to one of these two to determine the time needed for ethylene dibromide's action to be effective [41]. ( In the first animal, almost normal spermatozoa (the acrosomes were not entirely restored) were obtained after exposure had been discontinued for 1 month; semen of normal density, spermatozoic motility, and sperm cell forms was obtained 3.5 months after discontinuation. In the second bull, normal semen was obtained 10 days after administration was stopped. After 2 further weeks of renewed exposure, semen from the second bull began exhibiting the same abnormalities as described above for bulls receiving ethylene dibromide on the continuous schedule. A previously unexposed 16-month-old bull of the same breed was fed ethylene dibromide at 2 mg/kg/day for 3 weeks. After 2 weeks, his semen exhibited the abnormalities described above, which persisted for a month after exposure ended. The semen quality improved, but normal semen was not obtained until 2-3 months after administration stopped. From these experiments, the authors [41] concluded that quantities of ethylene dibromide, equivalent to two or three times that expected in insufficiently aired grains, caused definite reproductive impairment when fed daily or every other day to bulls. Semen density and spermatozoic motility decreased sharply and the spermatozoa were of abnormal shape after only 2 weeks of exposure. Recovery occurred in 10 days-3 months in the animals tested. Resumption of exposure caused the abnormalities to return. Studies to determine whether the reproductive impairment was prolonged after repeated removal and reinstatement of ethylene dibromide diets were not conducted. However, in the one bull that was reexposed after a period of discontinuation, the time necessary for recovery of normal spermatozoic production increased from 10 days after the first discontinuation to 2-3 months after the second. In Eleven bulls (D Amir, written communication, August 1976) given ethylene dibromide in olive oil were 15-24 months of age and weighed 400-500 kg. The two remaining bulls given ethylene dibromide in olive oil were 4.5 and 5 years of age and weighed 950 and 1,050 kg, respectively. Six young bulls, 15-24 months of age, were used as controls; three were given olive oil and three remained as negative controls. Six of the 11 young bulls given ethylene dibromide and the 6 control bulls were castrated or killed (number killed or castrated not specified) 1 day after receiving the last oral dose. Semen was collected from the seven remaining bulls two or three times a week for 2 months after the first dose and once or twice a week for the next 2 months. Spermatozoic concentration, motility, and malformation were determined microscopically from at least 400 randomly chosen spermatozoa from each semen sample. In the control bulls, 2-4% of the spermatozoa taken from various places along the genital tract had misshapen heads, and distribution of the malformed spermatozoa was uniform throughout the tract. In the animals that were killed or castrated, the number of spermatozoa exhibiting abnormal, mainly pear-shaped heads was markedly increased in the ethylene dibromide bulls over that of the controls and varied in distribution in the genital tracts of the different bulls. Amir [43] attributed the distributional pattern of abnormal spermatozoa in the genital tract to the variation in the time of release of the spermatozoa through the ductus deferens caused by individual variations in the doseresponse threshold of the bulls. In the semen samples collected from the five young bulls, maximum numbers of spermatozoa with misshapen heads appeared in the ejaculates 2-10 days after the cessation of ethylene dibromide administration [43, and written communication, August 1976]. Again, these differences were thought to be caused by differences in the sperm transit time through the epididymis as well as to the variation in release time of the affected spermatozoa from the testes. The effect of ethylene dibromide was more acute in the adult than in the young bulls. The concentrations of spermatozoa in the younger bulls were only slightly affected by the doses, but were greatly reduced in the older bulls. Normal spermatozoic concentrations were regained after 1 and 4 months in the two older bulls. During the period of low spermatozoic concentration, the ejaculates of the older bulls contained much spermatozoic debris and many spermatids and spermatocytes; the debris presumably came from further disintegration of the abnormal spermatozoa. The number of abnormal spermatozoa in the young bulls decreased to about normal within 3 weeks after the last dose, but remained elevated in the two adult bulls for about 15 weeks. The author concluded that ethylene dibromide affected spermiogenesis in the young bulls since the abnormalities in the spermatozoa observed in the ejaculates persisted for a period that coincided with the duration of spermiogenesis in the bull, which is about 3 weeks. Amir also concluded that either ethylene dibromide affected earlier stages of the spermatogenic process in adult bulls or its elimination from the circulation of young bulls was more rapid. In 3 weeks. They also observed that hens that had ceased egg production could not be induced to lay again by feeding them a bromide-free diet, even after feeding continued for several months. To determine the effects of small amounts of ethylene dibromide in grain on egg laying, the authors [44] subjected 4 groups of 16 6-month-old hens each at concentrations of ethylene dibromide in grain ranging from 0 to 30 ppm (total ration concentrations of 0-15 ppm). In addition to the ethylene dibromide, small amounts of "residual bromide," defined as the bromine-containing material remaining in sorghum grain that had been fumigated with ethylene dibromide and then aerated to remove free ethylene Sixty 1-day-old female chicks were divided equally into two groups, the first was fed twice daily a commercial mash containing 40 ppm of ethylene dibromide and the second served as controls in a paired-feeding design. Weights and feed consumption were recorded weekly up to 10 weeks of age. Feed intake, weight gain, onset of egg production at 4.5-5 months, and incidence of double-yolked eggs were the same for the experimental and control groups. The weight of eggs from the group receiving ethylene dibromide was significantly lower (P<0.01) than from the controls and the number of eggs laid by the hens receiving ethylene dibromide approached statistical significance, lowering below that of the control hens. In a second experiment [45], two groups of 12 1-year-old hens in full egg production were fed for 4 weeks a commercial mash with or without 100 ppm of ethylene dibromide. At the end of 4 weeks, egg weight in the hens fed ethylene dibromide had significantly decreased from an average of 63 to 43 g. Both groups were then artificially inseminated twice at 7-day intervals with 0.1 ml of semen/hen. Eggs collected between the 2nd day after the first insemination and the 7th day after the second insemination were examined for embryos. A striking reduction in the fertilization rate, with no live embryos at all, was noted in the ethylene dibromide-fed group; only 2 of 16 eggs were fertilized as compared with 48 of 56 eggs from the control group, and both fertilized eggs from the ethylene dibromide group contained dead embryos. Similarly, a third experiment [45] was conducted to determine the effects of ethylene dibromide on male chicken growth rate and sexual development. Three groups of 20 3-day-old cockerels were fed mash containing 0, 80, or 180 ppm of ethylene dibromide in which the amount of feed intake by the 180-ppm group determined the amounts of food given to the control and 80-ppm groups. Three additional groups of 25 cockerels were each fed mash containing 0, 150, or 300 ppm of ethylene dibromide without restrictions on the intake. At 6 weeks, the cockerels fed 150 ppm of ethylene dibromide showed a reduced weight gain when compared with the controls. Only cockerels fed the 300-ppm ethylene dibromide diet without restrictions on food intake showed significant growth retardation and an apparent feed intake depression at 12 weeks of age; however, the weight gain to feed intake ratio was not significantly different. The cockerels receiving the regulated diets were killed at 3 months of age, and the bromide content of the testes, spermatozoic count and activity, and testes weight were determined. Significant amounts of bromide were found in the testes of the ethylene dibromide-fed groups, but differences were not observed in spermiogenic activity, spermatozoic count, or testes weight between the control and ethylene dibromide-fed groups. The remaining unrestricted-intake cockerel groups were examined at the age of 9 months by collecting semen samples three times at weekly intervals and were killed at 12 months of age for testicular examination and measurement of body, testes, and comb weights. Semen collected and examined from ethylene dibromide-fed cockerels did not differ significantly from that of the controls. Comb weights at death declined sharply with increasing concentrations of ethylene dibromide in the diet; however, body and testes weights were not affected by the ethylene dibromide. Another experiment [45] was conducted to determine if ethylene dibromide administration to adult cockerels would affect fertility rates and hatchability of eggs. Eleven mature cockerels each were fed for 105 days a control mash or mash containing 300 ppm of ethylene dibromide. Semen was collected about 2, 4, 8, and 10 weeks after the beginning of the experiment. No significant differences were seen between the semen of the controls and that of the cockerels fed ethylene dibromide with respect to ejaculated volume and spermatozoic motility and concentration. Subsequent fertilization tests in hens conducted with the pooled semen collected from the ethylene dibromide-fed and control groups gave no significant differences in fertilization rate or hatchability of eggs at 60 or 105 days. The authors [45] concluded that prolonged feeding of mash containing ethylene dibromide significantly depressed growth of male chickens when fed without restrictions, but that the depression seemed to result from reduced food intake and not from the direct action of ethylene dibromide. They also concluded that ethylene dibromide had no effect on the onset of egg production in hens fed from birth, on sexual development in males and females, and on sperm characteristics or fertility in mature males. However, statistically significant reductions in egg size and egg fertility were noted in hens fed ethylene dibromide. previously given ethylene dibromide as described above. The weights of whole eggs and yolks were compared for each hen prior to, during, and for 10 days after the injections. Injection of the purified hormone did not change the total egg weight or the weight of the yolks, which both remained lower than comparable control values. The authors concluded from the above four experiments that ethylene dibromide did not affect pituitary FSH concentrations in treated hens. The injection of FSH preparations did not reverse the adverse effects of ethylene dibromide; therefore, the effects of ethylene dibromide on egg laying did not seem to be connected with impaired formation or release of FSH. In an attempt to clarify the causes of smaller eggs in laying hens fed ethylene dibromide-fumigated mash In 1970, Edwards et al [9] investigated the antifertility effects of ethylene dibromide in an unspecified number of adult male Wistar rats. Doses of 10 mg/kg were injected ip into 250-g rats for 5 consecutive days. The average live litter size from six female rats serially mated on a weekly schedule with the males receiving ethylene dibromide decreased substantially during the 3rd week and drastically (to zero) during the 4th week after administration. From the authors' data, the average litter size appears normal during the 5th week and for every week thereafter. The authors concluded that the antifertility effects resulted from ethylene dibromide selectively damaging the spermatid cells, since the short course of exposure produced only transient sterility in rats and corresponded in time to changes that would result from spermatid damage. In an additional study [9], the major metabolite of ethylene dibromide in urine, S-(2hydroxyethyl)-cysteine, was reported to have produced no effect on male mouse fertility at a dose of 1,000 mg/kg when administered daily for 5 days by oral intubation, although experimental details and data were not presented. The data indicate that oral exposure to ethylene dibromide induces temporary sterility in male rats. However, further evaluation of the data is not possible because of the lack of experimental details, such as number of test animals or any data about control animals, that were not given by the authors in the publication. Differences have been reported in the abilities of rats and chickens to detoxify ethylene dibromide. Nachtomi et al [55] and Nachtomi and Alumot [8] observed that rats possessed a much greater ability to conjugate glutathione with ethylene dibromide than chicks [55]. In addition, the rat liver formed significant amounts of lipids containing conjugated double bonds as a result of the peroxidation of lipids induced by ethylene dibromide in the liver microsomal supernatant fraction, whereas chicken liver was relatively inactive [8]. Also, the concentration of triglycerides increased significantly in the rat liver, probably as a direct result of the formation of conjugated double bonds discussed above. In 1970, Edwards and coworkers [9] reported the tissue distribution of radioisotope at various time periods after an ip injection of 40 mg/kg of carbon-labeled (14 C) ethylene dibromide in mice. The data are presented in Table XII-3. One hour after injection, most of the 14Cradioactivity was found in the small intestine, with smaller amounts being found, in descending order, in the kidneys, liver, blood plasma, whole blood, large intestine, fat, and spleen. After 3 hours, the majority of the radioisotope was present in the large intestine, kidneys, and blood plasma, with smaller amounts being present in the whole blood, liver, small intestine, and spleen. After 24 hours, all tissues were below 1.0% retention of 14C-radioisotope except for the whole blood, blood plasma, stomach, and kidneys. After 1 hour, essentially all of the administered radioisotope was present in the various mouse tissues, whereas only 89% was present after 3 hours and 16% after 24 hours. It is of interest to note that 3.1, 4.4, and 0.66% of the administered radioisotope was detected in the tail of the epididymis 1, 3, and 24 hours after injection, respectively. Smaller amounts of 14C-radioisotope, up to 1.5% at 3 hours, were also present in the testes. The data presented by the authors suggest that ethylene dibromide is rapidly distributed to a wide variety of tissues. Major concentrations of radioisotope accumulated in the liver, kidneys, and digestive tract. There also seems to be a rapid depletion of radioisotope from the tissues, but the residual radioactive material is still widely distributed throughout the body tissues. In 1976, Plotnick and Conner [10] conducted a similar study of the tissue distribution of carbon-labeled (14 C) ethylene dibromide in guinea pigs. The ethylene dibromide was administered in a single ip injection of 30 mg/kg and tissue samples were collected 4-72 hours after the injection. The data are presented in Tables XII-4 and XII-5. At all intervals studied, the highest concentration of radioactivity derived from ethylene dibromide as lig/g of tissue was found in the kidneys, liver, and adrenal glands. At all time periods studied, the organs containing the highest percentage of the administered dose were the liver and kidneys. Approximately 66% of the injected dose was excreted in the urine over the 72-hour study, 15% of which was in the first 4 hours, and approximately 3% was excreted in the feces. Plotnick and Conner mentioned that unpublished preliminary studies by their laboratory "strongly suggest that excretion of unchanged ethylene dibromide in the expired air also represents a significant (10-12% of the dose) route of excretion." From the data of Edwards et al [9] and Plotnick and Conner [10], it seems that a relationship may exist between the tissue distribution and the destructive tissue changes, particularly with respect to the liver and kidney damage, in other animal [27,33] and human [22,25] studies reported previously in this chapter. # Carcinogenic, Mutagenic, and Teratogenic Studies (a) Carcinogenesis In 1973, Olson et al [56] reported the results of a preliminary investigation to determine the potential carcinogenic effects of ethylene dibromide in rats and mice of both sexes by oral administration. Further statements by Powers et al [57] and Ward and Habermann [58,59] Initially the only deleterious effect of ethylene dibromide on the rats was a depression in weight gain [56]. As early as 10 weeks after the initiation of the experiment (dose not stated), one squamous cell carcinoma of the stomach was noted in one male and in one female rat. Squamous cell carcinomas of the stomach became more prevalent as the experiment progressed, developing in 83 of 100 male rats and in 70 of 100 female rats intubated with ethylene dibromide. The tumors originated in the forestomach, invaded locally, and eventually metastasized throughout the abdominal cavity. Only one mammary tumor in a female rat was noted in the concurrent corn oil controls; however, in the untreated control group, 6 of 20 male rats and 14 of 20 female rats developed tumors, none of which were squamous cell carcinomas of the stomach. Tumor incidence was 68% in the male rats receiving ethylene dibromide at 80 mg/kg/day versus 98% in those receiving 40 mg/kg/day, and it was 58% in the female rats at 80 mg/kg/day versus 82% at 40 mg/kg/day. Olson et al [56] postulated that this decreased incidence of tumorigenesis may have resulted from the earlier death of the animals receiving the higher dose or because the animals did not receive ethylene dibromide for a 14-week period between weeks 16 and 30. The induction sequence and results of microscopic examinations were discussed in detail only for the male rats receiving the 40 mg/kg dose, since the authors considered the induction and progression of the tumors to be similar in all experimental groups [59]. All 50 male rats had stomach lesions, although one did not contain a neoplasm. The forestomachs had diffuse squamous cell hyperplasia with many papillomatous projections. Focal areas of invasion were reported from the origin of the carcinomas. Invasion occurred through the stomach wall to the peritoneal cavity, where nodules were reported in 70% of the rats. The metastatic tumors were less differentiated or formed keratin pearls, often accompanied by abcesses or peritonitis. The authors [59] stated that other types of tumors and lesions were also present in a few rats, including mesotheliomas, intestinal tumors, nodular hyperplasias of the liver, and poorly differentiated stomach tumors. Each group of mice received ethylene dibromide in doses of 60 or 120 mg/kg/day for 13 weeks [56]. After 13 weeks, the doses were increased to 100 and 200 mg/kg/day but were reduced to the original doses after 2 weeks because of toxicity. At 42 weeks, the daily dose of ethylene dibromide for all mice was changed to 60 mg/kg/day. At 42 weeks, one male and one female mouse developed squamous cell carcinomas of the stomach at the higher dose regimen, and three males and two females at the lower regimen. High early mortality was encountered in mice receiving the higher dose (40%). No It seems that ethylene dibromide caused an increased incidence of gastric carcinoma in rats treated by intubation with either 40 mg/kg/day or an ordered combination of 80, 0, and 40 mg/kg/day. Carcinomas were found to originate at the site of administration (the stomach) in both species, to invade locally, and eventually to metastasize throughout the abdomen [56,58,59]. Also, 72 of 145 mice that developed squamous cell carcinomas were diagnosed after week 59, whereas the vehicle controls were killed at week 59. # (b) Mutagenesis In 1972, Buselmaier et al [60] reported the results of an investigation to determine the potential for ethylene dibromide to induce mutations in the host-mediated assay with Salmonella typhimurium G46 and Serratia marcescens a21 Leu-in NMRI mice and in the in vitro plate test with Salmonella typhimurium G46. Immediately after ip inlection of each bacterial strain, 500 mg/kg of ethylene dibromide emulsified in edible oil was injected subcutaneously into one hind leg of six 10-to 12-week-old mice. Three hours after the injections, they were killed and the fluid from the peritoneal cavity was collected for plating to determine the number of mutant colonies induced. In the comparative in vitro plate test with Salmonella typhimurium, a concentration equivalent to the 500 mg/kg dose was applied to a filter paper disc in the center of the plate, and after a 12-hour incubation, the number of mutant colonies were counted. The investigators [60] found that ethylene dibromide was definitely mutagenic in the host-mediated assay with Salmonella typhimurium G46 and in vitro with the same organism. The mutation frequencies for Salmonella typhimurium G46 in the host-mediated assay were 0.77 x 10"8 in the control test and 6.23 x 10-8 in the experimental test. The ethylene dibromideexposed mutation frequency was significantly different (P<0.01) from the control. The in vitro plate test results were also positive. Ethylene dibromide did not induce a significant number of mutants in the hostmediated assay with Serratia marcescens a21 (6.93 x 10"7 for control, 2.43 x 10" 7 for ethylene dibromide-exposed). The authors [60] concluded that ethylene dibromide did not require activation through in vivo metabolism to exert its mutagenic effects on Salmonella typhimurium, nor did metabolism of ethylene dibromide sufficiently deactivate its mutagenic potential, since both the host-mediated assay and the in vitro plate tests were positive. In 1972, Epstein et al [61] published the results of a screening study on the detection of chemical mutagens by a dominant lethal assay in ICR/Ha Swiss mice. Ethylene dibromide was tested along with 173 other industrially important chemicals or chemical mixtures. Ten male mice, 8to 10-weeks-old, were given 0, 50, or 100 mg/kg of ethylene dibromide for 5 consecutive days by oral administration and were then mated weekly with three different virgin 8-to 10-week-old female mice for 8 consecutive weeks. One male mouse died at the 50 mg/kg dose and two males died at the 100 mg/kg dose during the experiment. Two different groups of seven or nine male mice received single ip injections of 18 or 90 mg/kg of ethylene dibromide, respectively, and were then mated as above. The mated females were killed about the 13th day after presumptive mating and were scored for the number of total implants, live implants, early fetal deaths, and pregnancies. The experimental animal scores were contrasted to concurrent control scores. The authors included ethylene dibromide in a class of agents which did not meet "any screening criteria for mutagenic effects," although specific data for ethylene dibromide were not presented. No effect of ethylene dibromide on fertility was reported in this paper, which differs from the finding of Edwards et al [9]. In 1973, Clive [62] tested the mutagenic potential of ethylene dibromide on the back mutation frequency of the thymidine kinase locus in a mammalian somatic cell tissue culture derived from mouse lymphoma cells. The L5178Y mouse lymphoma cells were exposed to ethylene dibromide at concentrations of 0.0-3.0 mM in culture media for 2 hours. The exposed cells displayed an induced mutational frequency that was dose related and typical of other alkylating agents, such as methyl methanesulfonate and ethyl methanesulfonate. Thirteen new mutations for each 10,000 surviving cells were found under these experimental conditions [62]. The frequency of induced mutations generally increased monotonically after exposure of the cells to increasing concentrations of ethylene dibromide. The induced mutation frequency indicated that ethylene dibromide was mutagenic over the entire range of experimental concentrations when plotted against the growth inhibition, although less potent than ethyl methanesulfonate (an induced mutational frequency of about 2/10,000 cells versus one of 7/10,000 cells at 60% growth inhibition, respectively). The induced mutational frequency in L5178Y mouse lymphoma cells corresponded with that of a mutational frequency of over 600 R of X-irradiation at the highest concentration. Clive concluded that ethylene dibromide was mutagenic to the L5178Y mouse lymphoma cells although not as potent as ethyl methanesulfonate. In 1974, Meneghini [5] reported the results of an investigation to determine the potential for ethylene dibromide to induce DNA repair synthesis in cultured opossum lymphocytes. Two-year-old opossums, Didelphis virginiana, were used to obtain lymphocytes for culture. Blood was removed from their tails and lymphocyte suspensions were prepared and maintained at 37 C. Samples containing about 5 x 10^ cells/ml were incubated with various concentrations of ethylene dibromide for 1 hour at 37 C. At the end of this period, the cells were incubated in culture media with 3H-thymidine for 4 hours to allow for DNA radiolabeling to occur. Control cells were processed as above, but without exposure with ethylene dibromide. At concentrations between 0.001 and 1 mM, ethylene dibromide was very effective in inducing DNA repair in opossum lymphocytes [5]. Repair induction decreased at a concentration of 10 mM of ethylene dibromide, which was presumed to be the result of repair-inhibition phenomena such as those observed for ultraviolet-induced repair. The author indicated that ethylene dibromide was very effective in inducing DNA repair in a manner similar to other alkylating agents, such as methyl methanesulfonate and ethyl methanesulfonate, which were also studied. He stated that only compounds that interact with DNA through covalent bonds induce repair synthesis. Therefore, these data suggest that ethylene dibromide, or its metabolites, may interact via covalent bonding with DNA. In 1974, Vogel and Chandler [6] measured the possible genetic effects induced by ethylene dibromide in sex-linked lethal tests with fruit flies, Drosophila melanogaster. The adult Berlin K male flies were allowed to feed on a 0.3-mM ethylene dibromide solution for 3 days before being allowed to mate with two females for 3 days. A sequence of two 3-day brood periods was initiated (broods 1 and 2), followed by one 4-day brood period (brood 3). At the end of each 3-day breeding period, the treated males were transferred to a new vial and were allowed to mate with two new females. The frequencies of recessive lethal mutations in meiotic and postmeiotic germ cells were determined in the offspring of treated and control males. Ethylene dibromide induced significant numbers of recessive lethal mutations in the offspring of all three broods. These were 0.50, 1.49, and 1.30% in broods 1, 2, and 3, respectively, and an average lethal frequency for all broods of 1.10%. The authors concluded that the brood pattern resulting from ethylene dibromide exposure was consistent with the action of chemicals that affect spermatids and spermatocytes because of the higher incidence of recessive lethal mutations in broods 2 and 3. The authors considered ethylene dibromide to be a bifunctional alkylating agent capable of introducing cross-links into large biologic molecules, and to be definitely mutagenic in Drosophila melanogaster. In 1971, Ames [63] published the results of an experiment to determine the mutagenic potential of ethylene dibromide to the his-G46 and TA 1530 strains of Salmonella typhimurium. Ethylene dibromide inhibited the growth of the E coli pol Al-strain preferentially to isogenic pol A+ strain as indicated by zone of inhibition diameters of 20 versus 15 mm, respectively, at concentrations of 10 /¿I (22.0 mg)/plate [64]. [60] for the induction of back mutations at the his-G46 locus in Salmonella typhimurium. In 1975, Alper and Ames [65] published the results of a study to determine whether ethylene dibromide or 39 other agents could cause mutants by chromosomal deletions of various lengths in Salmonella typhimurium LT2 and Salmonella typhimurium galE503. Bacteria were poured onto agar plates as suspensions in top agar and were incubated for 8 hours. A few drops of the test compound, 1-5 ¡il (2.2-11.0 mg), were placed near the edge of the plate immediately after the top agar had solidified. The number of colonies clustered within a 3.5-cm radius of the spot where the compound was applied was used as an index of the extent of mutagenesis. The zone of inhibition for ethylene dibromide was reported as less than 1.5 cm from the application spot, but specific data were not presented. Although no experimental data were given, ethylene dibromide was included in a list of compounds which failed to increase the frequency of deletion mutants by as much as fourfold over that of the control. In 1974, Sparrow et al [66] # Ethylene dibromide has been reported to induce mutations in Neurospora crassa [67,68], but complete experimental details were not given in these abstracts. (c) # Teratogenesis In 1976, Short et al [69] examined the effects of ethylene dibromide vapor on rats and mice during organogenesis. The production of congenital defects was used as a measure of inherent toxicity. Female Charles River CD rats or female CD-I mice were caged overnight with proven male breeders; successfully bred females were identified the next morning by the presence of sperm in vaginal smears from rats or of copulation plugs in mice. Pregnant animals were divided into a control group of 18 rats and 17 mice which would receive a normal diet without inhalation exposure to ethylene dibromide, a group of 18 rats and 13 mice to receive 31.6 ppm (243.32 mg/cu m) of ethylene dibromide and a normal diet, and a group of 17 rats and 9 mice to receive a restricted diet without exposure to ethylene dibromide. All groups of animals were housed in the inhalation chambers for 10 consecutive days beginning on day 6 of gestation. During this time, the groups to be given ethylene dibromide were exposed to the vapor at an average concentration of 31.6 ±1.9 ppm (243.32 ± 14.63 mg/cu m) for 23 hours a day. Rats and mice were killed on gestational day 20 or 18, respectively. Fetuses were surgically removed from the dams, weighed, examined for external anomalies, and fixed for either soft-tissue or skeletal examinations. Ethylene dibromide exposure did not produce mortality in either pregnant rats or mice during the 10-day inhalation period; however, two of nine pregnant mice from the restricted diet group died. Both rats and mice exposed to ethylene dibromide consumed less feed and gained significantly (P<0.05) less weight than the controls during the exposure period, although feed consumption and weight gain returned to normal after cessation of the exposure on the 15th day of pregnancy. Ethylene dibromide-exposed rats consumed about twice as much food daily as did the feed-restricted rats (10.5 ± 0.6 versus 5.0 ± 0.1 g/day, respectively), but only about one-half of that consumed by the controls (10.5 ± 0.6 versus 21.1 ± 0.4 g/day, respectively). Rats exposed to ethylene dibromide at a concentration of 31.6 ppm The authors [69] concluded that the above-mentioned effects of ethylene dibromide exposure in mice were most likely attributable to malnourishment rather than to ethylene dibromide exposure. It is apparent from the authors' data that some of the anomalies may be compounded by the presence of ethylene dibromide. In addition, if the malnourished controls and ethylene dibromide-exposed animals had been compared with the nonexposed controls at the same statistical probability levels, only the ethylene dibromide-exposed animals would have been significantly different from the controls. ( Skeletal anomalies, in particular the variations in ossification of the incus and supraoccipital bones, were much more prevalent in the ethylene dibromide-exposed mice than in the feedrestricted mice (80-90% of the litters versus 33-50%, respectively). The authors also attributed many of the observed anomalies in the rat dams and fetuses exposed to ethylene dibromide to malnutrition rather than to direct effects of ethylene dibromide exposure. However, they concluded that the increase in the fourth ventricular "hydrocephaly," the reduction in the occurrence of the fourteenth rib, and the increase in the frequency of wavy ribs could be correlated to ethylene dibromide exposure in the rat. The significance of the effects of malnutrition in rats is not clear, and even though ethylene dibromide-exposed rats consumed less food than did controls, they consumed more food than did the rats in the feed-restricted group. It is apparent, however, that an increase in the incidence of anomalies in fetal rats was induced by exposure to the one concentration of ethylene dibromide, but no dose-response relationship for this action is available. # Correlation of Exposure and Effect Neither studies that correlate workplace concentrations of ethylene dibromide with observed toxic effects nor any epidemiologic studies have been found. Few reports of human exposure to ethylene dibromide exist. Adverse effects resulting from exposure of experimental animals to ethylene dibromide are similar to those described for human exposures and include ocular, dermal, and respiratory irritation and systemic effects on the liver, kidneys, spleen, circulatory system, and nervous system. The effects of ethylene dibromide exposure on the eyes have been noted in several animal species. Merzbach [31] discovered that a dog exposed for 1 hour to 1 ml (2.2 g) of ethylene dibromide vaporized into a 100-liter chamber showed signs of ocular irritation during the exposure. Five hours after the exposure ended, a milky-blue corneal opacity developed which became more pronounced and developed into purulent conjunctivitis in both eyes and an ulcer in one eye. Kochmann [23] showed that 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day produced conjunctivitis in cats exposed to the vapor repeatedly until death occurred at approximately 10 days. Rowe et al [33] reported that instillation of undiluted ezhylene dibromide into the eyes of rabbits caused conjunctival izritation that cleared within 48 hours and left only very slight superficial corneal necrosis which healed completely. Rowe et al [33] also found that a 10% solution of ethylene dibromide in propylene glycol produced a more severe reaction in the eye than did the undiluted material. Moderate conjunctival and corneal irritation developed and persisted for 48 hours; healing was complete within 12 days without corneal scarring. A 1% solution produced an effect similar to that caused by the undiluted material. These reports indicate that ethylene dibromide can cause adverse ocular effects after exposure to 1 and 10% solutions, as well as to the undiluted material. The skin of experimental animals is susceptible to penetration and local surface effects resulting from exposure to ethylene dibromide. Thomas and Yant [27] noted that liquid ethylene dibromide at doses of 0.25, 0.50, and 1.0 ml (0.55, 1.1 and 2.2 g)/animal produced marked hyperemia of the small cutaneous blood vessels of the shaved abdomens of rats. All animals died within 6-18 hours after application. Rowe et al [33] found that undiluted ethylene dibromide or a 10% solution in butyl carbitol acetate killed within 24 hours all rabbits to which it was applied dermally; subsequent experiments showed that the dermal LD50 was about 400 mg/kg. Marked erythema and edema were noted when the material was prevented from evaporating from the skin, whereas only slight erythema was noted when evaporation was not inhibited. Undiluted doses of about 210 mg/kg produced a moderate-to-severe erythema, edema, and necrosis of the skin. Similar results were described by Pflesser [24] in human volunteers exposed to 0.5 ml (1.1 g) of liquid ethylene dibromide for 1-30 minutes by placing small quantities on their arms or hands. Confinement produced more extensive erythema and edema surrounding the application site, and, in one case, blistering occurred as a result of continued contact between ethylene dibromide and the skin. These investigations indicate that localized surface effects on the skin, such as erythema, edema, blistering, or necrosis, may occur after contact with either undiluted or 10% solutions of ethylene dibromide. Percutaneous absorption of 10% solutions has also caused death in experimental animals. Respiratory irritation after single exposures to ethylene dibromide vapor has been reported in guinea pigs at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, and 2,000 ppm (15,400 mg/cu m) for 150 minutes [27], and in cats exposed at 100 ppm (770 mg/cu m) for 30 minutes [23]. In cats, three 30-minute exposures at 100 ppm (770 mg/cu tn) produced signs of nasal irritation that consisted of a strong reddening of the nasal mucosa [23]. Lucas [28] demonstrated that a 12-minute exposure of a rabbit to ethylene dibromide vapor caused the lungs to become enlarged and filled with a frothy exudate. Merzbach [31] found that 5 ml (11.0 g) of ethylene dibromide allowed to vaporize in a 100-liter chamber produced severe bleeding in the right lung of a dog exposed for 1 hour. Another dog exposed to the vapor of 1 ml (2.2 g) for 1 hour developed severe hyperemia and bronchopneumonic foci in both lungs. Rowe et al [33] showed that death occurring in rats exposed to ethylene dibromide at concentrations of 100-10,000 ppm (770-77,000 mg/cu m) for 0.02-16.0 hours was caused by respiratory or cardiac failure at the higher exposures and by pneumonia at the lower ones. The lungs of animals exposed at these concentrations were congested, edematous, hemorrhagic, and inflamed. Respiratory irritation has also been noted after the repeated inhalation exposure of cats at 100 ppm (770 mg/cu m) to ethylene dibromide for 30 minutes daily for an average of 10 days. This concentration produced dark red discolorations in the lungs, and the lungs were partially nonfunctional [23]. Rowe et al [33] reported on lethal dose rates in rats exposed to ethylene dibromide for 0.02-16.0 hours at concentrations of 100-10,000 ppm (770-77,000 mg/cu m). Death was caused by respiratory or cardiac failure at the higher concentrations and by pneumonia at the lower ones. Half of the male rats exposed at 25 ppm (192.5 mg/cu m) for 7 hours/day for 151 exposures in 213 days died during the experiment, primarily from pneumonia and upper respiratory tract infection. Pulmonary infections were also responsible for a 50% mortality in male guinea pigs and a 25% mortality in females exposed at 25 ppm (192.5 mg/cu m) for 7 hours/day for 145 exposures in 205 days [33]. Systemic parenchymal cell damage, particularly in the liver, kidneys, and spleen, develops after single and repeated exposure of experimental animals to ethylene dibromide vapor. Thomas and Yant [27] observed that guinea pigs receiving single exposures of ethylene dibromide vapor at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes had a slight granular degeneration of the parenchymal tissue of the liver. Rabbits exposed to an unknown concentration of ethylene dibromide vapor for 10 or 12 minutes had enlarged livers, with slight-to-moderate diffuse fatty changes evident in the rabbit exposed for 10 minutes [28]. Merzbach [31] published a study detailing similar results in a dog exposed to 1 ml (2.2 g) of vaporized ethylene dibromide in a 100-liter chamber for 1 hour; autopsy showed that a pronounced fatty degeneration of the liver had occurred. Rowe et al [33] observed that rats exposed at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours developed cloudy swelling, centrilobular fatty degeneration, and necrosis of the liver. Repeated exposure at approximately 100 ppm (770 mg/cu m) for 30 minutes/day for up to 10 days caused incipient fatty degeneration in the liver of cats [23]. According to Rowe et al [33], rats exposed to 100 ppm (770 mg/cu m) of ethylene dibromide for 7 hours/day for seven exposures in 9 days had a cloudy swelling of the liver, whereas rabbits exposed to the same concentration for three or four exposures had widespread central fatty degeneration and some necrosis of the other cells of the liver. Rowe et al [33] reported that slight central fatty degeneration of the liver developed in guinea pigs repeatedly exposed to 50 ppm (385 mg/cu m) of ethylene dibromide for 7 hours/day for 57 exposures in 80 days and in monkeys repeatedly exposed to the same concentration for 49 times in 70 days. Renal damage, in the form of pronounced granular degenerative changes in the parenchymal tissues, occurred in guinea pigs exposed to ethylene dibromide at concentrations of 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes [27]. Rowe et al [33] demonstrated that the kidneys of rats exposed at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide vapor for 0.02-16.0 hours showed slight interstitial congestion and edema, with slight cloudy swelling of the tubular epithelium in some cases. Repeated exposures at approximately 100 ppm (770 mg/cu m) for 30 minutes/day for an average of 10 days in cats produced a swelling and discoloration of the kidneys and possibly a slight degeneration of the tubules [23]. Rowe et al [33] reported that repeated exposure of guinea pigs at 50 ppm (385 mg/cu m) of ethylene dibromide for 7 hours/day for 57 times in 80 days produced a slight interstitial congestion and edematous condition in the kidneys which was accompanied by degeneration of the tubular epithelium. From these data, it can be concluded that renal damage can occur in experimental animals after exposure to single or repeated exposures of ethylene dibromide. Adverse splenic effects have been seen in experimental animals after exposure to ethylene dibromide. Single exposures of ethylene dibromide at 8,000 ppm (61,600 mg/cu m) for 30 minutes, 4,000 ppm (30,800 mg/cu m) for 60 minutes, or 2,000 ppm (15,400 mg/cu m) for 150 minutes produced a slight granular degeneration of the parenchymal tissue in the spleen of guinea pigs [27]. Rats exposed to 0.25, 0.50, or 1.0 ml (0.55, 1.1, or 2.2 g) of ethylene dibromide applied on the abdomen died within 6-18 hours; autopsy showed that the spleens of these animals were highly congested and edematous [27]. Kochmann [23] noted a slight enlargement of the spleens of cats exposed at 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day for an average of 10 days. Rowe et al [33] observed that rats receiving seven exposures to ethylene dibromide at 100 ppm (770 mg/cu m), 7 hours/day, for 9 days developed a slight congestion of the spleen and some hemosiderin deposition. The results from these experiments indicate that adverse effects to the spleen can occur after exposure to ethylene dibromide by inhalation or by percutaneous absorption. Cardiovascular system effects have been noted in experimental animals subjected to single or multiple exposures of ethylene dibromide. Concentrations of 8,000, 4,000, and 2,000 ppm (61,600, 30,800, and 15,400 mg/cu m) of ethylene dibromide for 30, 60, and 150 minutes, respectively, produced a slight granular degeneration of the muscular tissue of the heart and a generalized interstitial edematous degeneration of the endothelial lining in the abdominal vascular system in guinea pigs [27]. Merzbach [31] exposed a dog to the vapor of 5 ml (11.0 g) of ethylene dibromide in a 100- postulated that death resulting from exposure of cats and rabbits at 50-100 ppm (385-770 mg/cu m) of ethylene dibromide for up to 22 days was caused by injury to the circulatory system, especially to the heart and blood vessels. Rowe et al [33] also concluded that deaths occurring at the higher concentrations after exposure of rats at 100-10,000 ppm (770-77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours were caused by cardiac or respiratory failure. Few studies have specifically addressed the potential of ethylene dibromide to adversely affect the CNS. Rowe et al [33] reported that CNS depression was observed at the higher concentrations in rats exposed to 100-10,000 ppm (770-77,000 mg/cu m) for 0.02-16.0 hours, but did not further elucidate the nature of the effects. Rowe et al [33] Experiments with bulls receiving 4 mg/kg on alternate days for 7 or 10 doses showed that the abnormal spermatozoa were present in both the epididymis and testes after 7 doses. After 10 doses, abnormal spermatozoa constituted 67% of the population in the ductus deferens and 77% of the ejaculate, with almost all the abnormal spermatozoa exhibiting tail and acrosomal defects [42] . These spermatozoic abnormalities may lead to a decrease in the fertility of the bulls and might induce sterility if they continued long enough, although reports have not been found that experimentally test this hypothesis. In rats, ip injections of ethylene dibromide at a dose of 10 mg/kg for 5 days produced a decrease in the average live litter size in female rats mated with experimental males [9]. This decrease in fertility occurred during the 3rd and 4th weeks following administration, which corresponds to the maturation cycle of spermatids in the genital tract of rats. This finding, which corresponds with the findings of the reports of spermiogenic impairment in bulls, supports the postulated sterilizing effect discussed above. It is important to point out that reports have not been found delineating a no-effect level for the reproductive system abnormalities caused by the repeated administration of ethylene dibromide to bulls. In chickens, the function of the female reproductive system is impaired by ethylene dibromide exposure [44][45][46], but the male system appears to be unaffected [45]. Cockerels fed 300 ppm of ethylene dibromide for 12 months showed significant growth retardation at 12 weeks of age; however, semen collected between 9 and 12 months did not differ from control semen, and body and testicular weights were comparable with those of controls [45]. Semen collected between 2 and 10 weeks from cockerels fed 300 ppm for 105 days showed no significant differences when compared with control semen with respect to ejaculated volume and spermatozoic motility and concentrations. Subsequent fertility tests at 60 or 105 days in hens gave no significant differences in fertilization rates or hatchability of eggs. These results indicate that the reproductive system in male chickens was not detectably affected by ethylene dibromide under these experimental conditions. This is in contrast to the effects reported in two mammalian species, cattle and rats, in which definite impairments of the male reproductive system have been noted. A striking reduction (12 versus 86% in the control) in the fertilization rate was seen in hens fed 100 ppm of ethylene dibromide for 4 weeks; all embryos in the eggs from the experimental group were dead [45] . These results indicate that the female reproductive system in chickens is affected by ethylene dibromide. Although no reports have been found that explore the potential of ethylene dibromide to affect fertility in females of mammalian species, the avian data suggest the potential of ethylene dibromide to impair female fertility. However, until experiments are conducted with mammalian species to assess this potential, extrapolation of the effects seen in chickens to mammals and humans must be uncertain. There has been only one study concerning the potential of ethylene dibromide to induce cancer in rats and mice [56][57][58][59]. In this study, rats and mice were given the maximum tolerated dose (80 mg/kg for rats, 120 mg/kg for mice) and one-half the maximum tolerated dose by daily intubation for 54 or 62 weeks, except when toxicity forced the total discontinuation of administration or reduction of the maximum tolerated dose to that of one-half the maximum tolerated dose during the experiment. The tumors (squamous cell carcinomas), which were first noted during the 10th week of ethylene dibromide administration in rats, originated in the forestomach, invaded locally, and metastasized throughout the abdominal cavity. The fraction of animals with tumors was greater in the male rats than in the females (an average of 83% of the males developed tumors versus 70% of the females), and was greater at the lower dose than at the higher dose in rats at the termination of the experiment at 54 weeks (98 versus 68% in males and 82 versus 58% in females, respectively). The concurrent control populations did not develop squamous cell carcinomas of the stomach. The fraction of mice that developed squamous cell carcinomas was 74% in males and 72% in females by the termination of the experiment at weeks [57]. The irregularities in the dose regimens of both species, the use of the suggested maximum tolerated dose, and the route of administration do not negate the importance of the fact that ethylene dibromide has induced carcinomas in two mammalian species. The data from this single study indicate that ethylene dibromide is a carcinogen after daily introduction of about one-half the maximum tolerated dose into the stomach of rats and mice for up to 62 weeks. The mutagenic potential of ethylene dibromide has been established in a wide spectrum of procaryotic and eucaryotic mutational test systems. It has induced mutations in vertebrate cell cultures [62], insects [6], bacteria [60,63,64], plants [66], and fungi [67,68]. It has induced mutations or mutagenic events in a number of experimental test systems, including the recessive lethal test in Drosophila melanogaster [6], the host mediated assay in mice with Salmonella typhimurium [60], and a backward mutation system with mouse lymphoma cells [62]. In addition, positive mutagenic induction has been reported in tests with back mutational systems in certain strains of Salmonella typhimurium [60,63,64]. Ethylene dibromide has also been reported to have given negative results in the dominant lethal test in mice [61] and in the back mutational test system with Serratia marcescens in the host mediated assay [60]. The dominant lethal test conducted in male mice given 50 or 100 mg/kg of ethylene dibromide for 5 consecutive days by oral intubation or given 18 or 90 mg/kg by ip injection did not induce a significant increase in the number of dead implants when compared with controls [61], although specific data were not presented for evaluation. Buselmaier et al [60] reported that ethylene dibromide was mutagenic in the host mediated assay with Salmonella typhimurium G46 at a dose of 500 mg/kg injected subcutaneously in mice and in vitro with the same organism at an equivalent dose. The mutational frequency for the experimental group was significantly (P<0.01) different from the control mutational frequency. The positive results in the in vivo and in vitro tests indicate that metabolic activation is not necessary for ethylene dibromide to exert its mutagenic effects and that metabolic deactivation does not reduce the mutagenic effect. Buselmaier et al [60] reported that a similar in vivo test with Serratia marcescens, also a back mutational test system, was negative; this finding may only indicate that species differences exist in reactions with ethylene dibromide. In a recessive lethal test with Drosophila melanogaster, Vogel and Chandler [6] reported that 0.3 mM of ethylene dibromide fed to adult males for 3 days induced significant numbers of recessive lethal mutations in the offspring of three successive broods. The brood patterns resulting from ethylene dibromide exposure indicated that ethylene dibromide affected spermatozoic maturation more than spermatozoic formation. The authors considered ethylene dibromide typical of a bifunctional alkylating agent and capable of introducing cross-links into biologic molecules. A mammalian somatic cell tissue culture of L5178Y mouse lymphoma cells was exposed to 0.0-3.0 mM of ethylene dibromide in culture media [62]. The induced mutagenic frequency was dose related, typical of other alkylating agents tested, and approximately equivalent to a dose of 600 R of X-irradiation at the highest concentration. Meneghini [5] noted that ethylene dibromide very effectively induced DNA repair synthesis in opossum lymphocyte cell cultures at concentrations between 0.001 and 1 iriM but decreased at 10 mM. Only compounds that interact with DNA through covalent bonds induce repair synthesis; therefore, ethylene dibromide is typical of other alkylating agents in forming covalent bonds with DNA. Bacterial and other plant systems have also been used to show the mutagenic potential of ethylene dibromide. Ames [63] hours. The ability of ethylene dibromide to induce mutations in a wide variety of test systems is suggestive of its potential to induce mutations in human populations, but there is no evidence available to enable an adequate assessment of the quantitative aspects of the relative risks for human populations. Since ethylene dibromide is a bifunctional alkylating agent, the most plausible basis for the induction of mutations in these systems is the covalent bonding of ethylene dibromide to the genetic material, DNA. The linear relation between the number of induced mutations and the concentration of ethylene dibromide in Tradescantia [66] is consistent with the idea of covalent bonding between ethylene dibromide and DNA. Only one study pertaining to the potential of ethylene dibromide to induce fetal anomalies has been found [69]. Fetuses from pregnant mice and rats exposed to approximately 31.6 ppm (243.32 mg/cu m) of ethylene dibromide for 23 hours/day during days 6-15 of gestation were significantly different from fetuses of pregnant control mice and rats. These differences include costal anomalies and hydrocephaly in rat fetuses, and additional anomalies in other ossification processes in mice fetuses. Fetuses from control mice fed a feed-restricted diet during the experiment to simulate malnourishment exhibited some of the effects found in ethylene dibromide-exposed mice fetuses; however, the frequency of the type and number of anomalies formed in the malnourished group was reduced, but the degree of significance was not as great as that found in the ethylene dibromide-exposed mice fetuses. Although it can be argued that the effects produced by ethylene dibromide exposure are similar in part to those produced by malnourishment, the anomalies in both rat and mouse fetuses from ethylene dibromide-exposed dams were significantly different from those produced by malnourishment alone when both were compared with those found in fetuses from control dams. From these data, it is evident that ethylene dibromide caused fetal abnormalities in mice and rats that were not caused by malnourishment alone. In summary, it is concluded from the data from human and experimental studies that the adverse systemic effects resulting from exposure to ethylene dibromide may include ocular, dermal, and respiratory irritation, The concentration of airborne ethylene dibromide on the premises of an oil refinery ranged from 0. In this report, both the most likely and worst-case emission concentrations were calculated, using the average value of 0.9-1.3 g of ethylene dibromide/gal of automotive fuel (one equivalent of organic bromine is added to gasoline for each two equivalents of lead added). The estimated emission rate for ethylene dibromide by measurement was reported to be 0.000063 g/g lead/gal. The reported losses for entrainment and spillage each were 0.000047 g/g lead/gal. Thus, the total loss because of refueling was reported to be 0.000157 g/g lead/gal. Evaporative losses were calculated to be 0.00014 g/g lead/gal from the automobile fuel tanks. in The most likely estimate of loss from the carburetor was 0.0016 g/g lead/gal, whereas the worst case was 0.0043 g/g lead/gal. Exhaust emissions were also calculated, the most likely being 0.0065 g/g lead/gal and the worst case being 0.3 g/g lead/gal. Summarizing the three types of emissions, the total emissions calculated for refueling, evaporation, and exhaust was most likely 0.008397 g/g lead/gal and the worst case, 0.304597 g/g lead/gal. The total emissions can also be estimated directly in terms Liquid absorption media, such as a 1:1 mixture of monoethanolamine and dioxane, have been used as trapping solutions for ethylene dibromide [72,73]. This medium decomposes ethylene dibromide and many other brominated organic contaminants to inorganic bromide and, as such, is not specific for ethylene dibromide. Porous polymer beads have been used as a collection medium for chlorinated and brominated hydrocarbons [74]. This procedure has not been tested specifically for ethylene dibromide but has been used successfully for closely related halogenated hydrocarbons; thus, it seems feasible that ethylene dibromide could also be collected by this method. The same column is used for sample collection and gas-liquid chromatographic analysis, but only one analysis can be made on each sample. Silica gel has been used as a collection medium for ethylene dibromide [75]. One advantage of using a solid adsorbent is that sample loss cannot occur from spillage during sampling or in transit for analysis. However, silica gel is a polar adsorbent and shows pronounced selectivity in adsorbing polar molecules, particularly water [76]. Studies with silica gel tubes indicated that water vapor could displace organic molecules during a normal sampling operation [77]. Although similar studies have not been conducted for ethylene dibromide, it is reasonable to assume that similar displacement of significant quantities of ethylene dibromide by water vapor could occur. Activated charcoal has been used as an adsorbent in conjunction with gas-liquid chromatography [78,79]. Charcoal is an excellent collecting medium because of its nonpolarity and its affinity for organic vapors and gases. As such, water vapor does not readily displace organic molecules as is the case with silica gel. However, adsorption and desorption efficiencies may vary with different batches of charcoal; therefore, it is necessary to determine the desorption efficiency for each new batch of charcoal. Charcoal tubes containing as much as 600 mg of activated charcoal are commercially available [1], In the past several years, direct-reading instruments and devices have been developed which make continuous or "on-the-spot" monitoring of halogenated hydrocarbons, including ethylene dibromide, feasible. These devices, when properly calibrated and used within their performance characteristics and limitations, can be helpful in monitoring airborne halogenated hydrocarbons [80]. Colorimetric indicator tubes are available from at least three sources [81][82][83] which provide semiquantitative measurement in the range of 1-200 ppm, although no detector tubes have been certified as yet by NIOSH for response to ethylene dibromide. The use of infrared light absorption at a wavelength of 8.4 jum [84] is claimed to detect airborne ethylene dibromide at a concentration of 0.1 ppm. These direct-reading instruments are portable and also may be used as part of a multipoint sampling system for continuous, unattended monitors. Other sampling devices used for the collection of organic solvents and halogenated hydrocarbons may be adaptable to ethylene dibromide collection. These include sampling bottles [85], bubblers [86], and plastic bags [87,88]. Chemical analysis has been used to estimate ethylene dibromide concentrations in the collection media. Aeration has been used by Peterson et al [75] to desorb ethylene dibromide from the silica gel; pyrolysis of the free ethylene dibromide produced bromine and hydrobromic acid. These products were collected in a second absorption solution of 1% sodium carbonate and 1% sodium formate in deionized water and quantitated by titrimetric analysis of the inorganic bromide present. Aman et al [32] 132 estimated the airborne ethylene dibromide concentration by absorbing the free ethylene dibromide with 1% sodium hydroxide and by quantitating the hypobromite formed iodometrically. Dumas [92] determined airborne ethylene dibromide concentrations by coulometric titration of sodium bromide after absorption of ethylene dibromide in methanolic sodium hydroxide and digestion by boiling under reflux for 15 minutes on a steam bath. These methods, like most chemical methods, require somewhat bulky apparatus and are not specific for ethylene dibromide since any aliphatic brominated compound will interfere and be included in the quantitative estimate. Physicochemical methods have been developed or adapted to identify and quantitate concentrations of airborne ethylene dibromide. Christie et al [93] modified a refrigerant leak-detector lamp to detect organic halogen compounds, including ethylene dibromide, in the atmosphere at a minimum concentration of 5 ppm. The procedure is dependent on visual estimation of the intensity of a flame color in response to the vapor concentration and is not specific for ethylene dibromide. Flame chemiluminescence has been reported by Crider [94] to detect ethylene dibromide concentrations in air of 0.03 ppm. This method has not been tested on mixtures of halogenated hydrocarbons, and it is too early in its development to enable prediction of the practicality of the method for area or personal monitoring in an occupational environment. Other physicochemical methods have been developed for halogen compounds, but they have not been tested for identification and quantitation of ethylene dibromide. One of these methods, based on nitrogen enhancement of an AC spark, has been used for continuous measurement of halogenated compounds in field situations [95]. The instrument is lightweight, portable, fast-responding, and reportedly capable of detecting halogenated hydrocarbons in the ppm range. However, until testing with ethylene dibromide has been conducted, the feasibility and reliability of this instrument is not known. In recent years, gas-liquid chromatography has become the most prevalent method for the detection and analysis of organic materials [1,[96][97][98][99][100][101]. Direct analysis of airborne ethylene dibromide has been reported to result in measurement of amounts as small as 0. (1) the delayed and insidious onset of symptoms, (2) an odor threshold which is not adequate to provide warning of dangerous concentrations, (3) its irritating and penetrating effects on the skin, and (4) its potential for causing cancer, mutations, sterility, and fetal anomalies. The principal method for manufacturing ethylene dibromide is the bromination of ethylene [1]. Small quantities of vinyl bromide, ethyl bromide, and ethyl chlorobromide may be formed as impurities in the production of ethylene dibromide [15], and caution must be taken to avoid exposure to these substances as well. Ethylene dibromide is nonflammable and nonexplosive at ordinary temperatures, but since it can be decomposed to toxic and corrosive compounds, such as hydrobromic acid, by contact with open flames or red-hot surfaces [1], it should be appropriately stored and handled to prevent such contacts. Special precautions are necessary for maintenance and emergency repair work, such as welding, cutting, or any spark-and flame-generating operations. Furthermore, it is recommended that smoking be prohibited in workplace areas where ethylene dibromide is manufactured, handled, blended, or stored. Since decomposition may occur [16] and highly toxic aldehyde vapors and acid gases may be emitted [104], ethylene dibromide must be protected from direct light and excessive temperature. Ethylene dibromide reacts rapidly with certain metals, such as aluminum and magnesium, to form combustible and explosive organometallic compounds [104] and with liquid ammonia [16], Therefore, it is recommended that reasonable precautions be taken to keep ethylene dibromide separated from these materials. Engineering controls should be used to keep the concentration of airborne ethylene dibromide below the recommended occupational exposure All containers used to transport, hold, or process ethylene dibromide should be made of ethylene dibromide-resistant materials, such as lined steel or stainless steel, and should be periodically inspected for signs of wear, corrosion, or leaks by manual and instrumental means. All valves, pipes, and seals used in pumping ethylene dibromide from processing areas to storage areas or transportation loading sites should be made of ethylene dibromide-resistant materials and should be periodically inspected for possible leaks, weak points, or signs of wear. Ethylene dibromide is a severe eye and skin irritant in humans (G Ter Haar, written communication, January 1977) and can be absorbed through the intact skin of animals in quantities sufficient to present an imminent hazard [33]. In view of this, the use of personal protective equipment, including nylon-impregnated neoprene gloves [105], ethylene dibromideresistant and fire-retardant clothing, rubber boots or overshoes, bib-type aprons, and chemical safety goggles is recommended when contact by liquid ethylene dibromide with the skin and eyes is possible. In addition, it is recommended that proper respiratory protection be worn when entering an area where the concentration of the vapor of ethylene dibromide may be greater than the recommended occupational exposure limit. Clothing should be immediately removed if it becomes contaminated, and the skin of the exposed area should be thoroughly washed with water. Personnel working with ethylene dibromide must be instructed in emergency procedures and participate in periodic, simulated emergency drills. All personnel not involved in the specified emergency operations must be immediately evacuated from the area. Special training sessions must be held and written emergency procedures must be updated periodically. These should include the location, use, and maintenance of first-aid, firefighting, and decontamination equipment. To prevent the adverse effects caused by ethylene dibromide, it is recommended that exposure to ethylene dibromide vapor or liquid be kept at a minimum. Routine visual and functional inspections must be made by trained personnel to ensure that processes in which ethylene dibromide is used are completely closed. If leaks or spills occur in the processing, handling, or storage of ethylene dibromide, these must be promptly corrected, regardless of the ethylene dibromide concentration in the environment. It is recommended that nonessential personnel be evacuated from the immediate area where a leak or spill has occurred until decontamination of the area is complete. If employees must withdraw samples from a process involving the use of ethylene dibromide, an impervious suit, including gloves, boots, and air-supplied hood, should be worn. An effective exhaust system for trapping any ethylene dibromide vapor may be used in place of the air-supplied hood. Any waste or residues containing ethylene dibromide should be incinerated, buried, or otherwise disposed of so that no ethylene dibromide is released into the environment. Applicable local, state, and federal regulations should be followed. Air exhausted from ethylene dibromide workplace areas must be decontaminated by incineration, chemical treatment, or other effective means so that the release of ethylene dibromide into the environment will be minimized. Safety showers and eyewash fountains should be located in or near areas where ethylene dibromide exposures are likely to occur and should be properly maintained. It is recommended that employees immediately remove contaminated clothing, flush all affected skin surfaces with water for at least 15 minutes, and then obtain medical attention. Since ethylene dibromide is toxic when ingested and has caused death in a woman after ingestion [25], it is recommended that handwashing facilities, soap, and water be made available to the employees. As a good hygiene practice, it is recommended that employees wash their hands before consuming beverages or food, using tobacco, or using toilet facilities. The employer should provide lunchroom facilities physically separated from the ethylene dibromide work areas. It is recommended that any contaminated article of personal protective equipment be discarded or, if feasible, decontaminated with soap and water. It is also recommended that employer-supplied clothing be worn while working with ethylene dibromide and that the employer arrange to have this clothing laundered daily and properly maintained. The employer should inform the launderers of the possible hazard of coming into contact with contaminated clothing and advise him on safe methods of handling such material. The employer should provide separate locker and change facilities for work and street clothes. As a good hygiene practice, it is recommended that shower facilities be provided for the employees and that they be required to shower before leaving the workplace at the end of the work shift. Since ethylene dibromide is a component of some insecticidal fumigants and conventional work practice guidelines are inappropriate to protect agricultural workers from the hazards of exposure, it is recommended that the label precautions on such pesticides be followed and stringently adhered to. These label requirements usually specify allowable time limits before a fumigated space or area may be reentered and safe practices for the application of the particular fumigant mixture. Specific requirements of worker protection standards for agricultural pesticides can be found in 40 CFR 170. In summary, precautions should be exercised with ethylene dibromide to prevent serious consequences which may result from ingestion, inhalation, and skin or eye contact. Processes in which ethylene dibromide is used in large quantities should be carried out in closed systems. Well-designed hoods, ventilation systems, and exhaust systems should be used to maintain concentrations below those specified by this standard. Personal protective equipment and clothing should be worn by employees engaged in the manufacture, handling, or blending of ethylene dibromide. It is important that employees be informed of the hazards associated with ethylene dibromide before job placement and whenever changes are made in any process that may alter their exposure. # VI. DEVELOPMENT OF STANDARD Basis for Previous Standards In 1953, the American Conference of Governmental Industrial Hygienists (ACGIH) adopted a threshold limit value (TLV) of 25 ppm as an 8hour TWA concentration for 1,2-dibromoethane (ethylene dibromide) [106]. No specific basis for this TLV has been found. In 1954, the ACGIH [107] changed the name to ethylene dibromide in the official TLV list, and, in 1956, they added the value of 190 mg/cu m to the official entry [108]. In al [33] reported that ethylene dibromide was readily absorbed through the intact skin of rabbits and from the gastrointestinal tract of rats, mice, guinea pigs, chickens, and rabbits. Ethylene dibromide vapor caused CNS depression, pulmonary irritation, and liver and kidney damage in rats and guinea pigs after single exposures. Rats, guinea pigs, monkeys, and rabbits tolerated repeated exposures of ethylene dibromide vapor at 25 ppm for 7 hours/day, 5 days/week, for about 6 months without adverse effects, but these species did not tolerate well a similar exposure at 50 ppm. In 1965, the ACGIH [110] recommended that special emphasis be given to the potential for skin absorption of 1,2-dibromoethane by adding the designation "skin" after the name in the TLV list. Such a notation refers to the potential contribution to overall exposure by the dermal route, including mucous membranes and eyes, either by airborne, or more particularly, by direct contact with ethylene dibromide. This designation was intended to indicate that measures for the prevention of absorption from skin and mucous membranes were necessary if the TLV was to be successful in limiting occupational exposure to a safe level. In 1965, the ACGIH [110] also recommended that the TLV of 25 ppm as a TWA concentration for ethylene dibromide be tentatively changed to a ceiling limit of 25 ppm. The basis [111] for this limit was primarily the report by Rowe et al [33], discussed previously, and the paper by Lucas [28]. Lucas [28] observed that single 10-to 12-minute exposures of rabbits to a concentration of ethylene dibromide vapor sufficient to produce anesthesia resulted in rapid breathing, phonation, and death within 15-18 hours. The shift of the TLV from a TWA value to a ceiling limit was made final in 1967. In 1971, the ACGIH [112] recommended changing the ceiling limit of 25 ppm to an 8-hour TWA concentration of 20 ppm (145 mg/cu m ) . The 1971 Documentation of the Threshold Limit Values for Substances in Workroom Air [113] cited several studies with no particular emphasis on how the limit was set. These reports included Rowe et al [33], Lucas [28], Kochmann [23], Olmstead [25], Rowe et al [38], and McCollister et al [37], which are discussed in Chapter III. Presumably, the study by Rowe et al [33] was the principal basis on which the new limit was set. The proposed value of 20 ppm as a TWA concentration was adopted in 1973 [114]. The basis for this change as stated in the 1974 supplement of the 1971 Documentation [113], did not differ from that stated in 1971. In 1976, the ACGIH [115] added to the TWA value a tentative short term exposure limit (STEL) of 30 ppm (220 mg/cu m) , which is defined as a maximal concentration to which workers can be exposed for a period up to 15 minutes continuously. No more than 4 such excursions are permitted each day, with at least 60 minutes between successive exposure periods. Also, the daily TLV-TWA is not to be exceeded. Florida, Mississippi, Pennsylvania, and South Carolina have adopted a TWA concentration of 25 ppm (190 mg/cu m) as their environmental limit for ethylene dibromide [116]. In Finland, the German Democratic Republic, and Yugoslavia, the maximum allowable concentration (MAC) for the workplace environment is 190 mg/cu m (25 ppm) [116]. In the Rumanian Socialist Republic, 200 mg/cu m (approximately 26 ppm) of ethylene dibromide is the maximum concentration allowed in the occupational environment, whereas in Poland, the MAC allowed for ethylene dibromide is 100 mg/cu m (13 ppm) [116]. Although the USSR does not currently recommend a standard for ethylene dibromide, the US recommendation of 145 mg/cu m (20 ppm) is stated to be inadmissibly high. The 1976 edition of the Handbook for Chemists, Engineers and Physicians [117] states that, in all likelihood, the permissible concentration should be on the same order as the Russian MAC for dichloroethane (12.5 ppm) or lower [117]. No bases for these standards have been found. The current federal standard (29 CFR 1910(29 CFR .1000) for occupational exposure to ethylene dibromide is 20 ppm as an 8-hour TWA limit, with an acceptable ceiling concentration of 30 ppm. A maximum peak above the acceptable ceiling concentration for an 8-hour work shift of 50 ppm not to exceed 5 minutes (Federal Register 40:103, May 28,1975) is also permitted. This standard was adopted from the American National Standards Institute (ANSI) recommendation Z37.31-1970 [3], which was based on the reports of Rowe et al [33] and Olmstead [25], and the summary presentation by Irish [4], which includes synopses of several other reports [23,24,27,33] discussed in Chapter III. [23], and conjunctival irritation was noted in rabbits after instillation of undiluted, 10%, or 1% solutions of ethylene dibromide [33]. The irritation subsided within 2-12 days in the rabbits without causing corneal scarring. Marked hyperemia of the cutaneous blood vessels surrounding the application site was found after 0.25, 0.50, or 1.0 ml (0.55, 1.1, or 2.2 g) of ethylene dibromide was applied to the abdomen of rats [27]. Rabbits responded similarly when undiluted or 10% solutions of ethylene dibromide were applied to the abdomen [33]. Application of 210 mg/kg of the undiluted chemical caused marked erythema, edema, and necrosis of the skin. Respiratory tract irritation caused by ethylene dibromide vapor has been seen in guinea pigs after single exposures at 2,000 ppm (15,400 mg/cu m) for 150 minutes [27], and for cats after exposures as low as 100 Other systemic damage also occurred in animals after single and repeated exposures to ethylene dibromide vapor. Guinea pigs exposed at concentrations of ethylene dibromide of 2,000 ppm (15,400 mg/cu m) for 150 minutes developed a pronounced granular degeneration of the parenchymal tissue of the kidneys and a slight degeneration of the parenchymal tissue of the liver, spleen, and heart [27]. Rats exposed at concentrations between 100 and 10,000 ppm (770 and 77,000 mg/cu m) of ethylene dibromide for 0.02-16.0 hours developed cloudy swelling, centrilobular fatty degeneration, and necrosis of the liver, cloudy swelling and a slight interstitial congestion and edema of the kidneys, and CNS depression at the higher concentrations [33]. Repeated inhalation exposures of rats for 7 days and rabbits for 3-4 days at 100 ppm (770 mg/cu m) of ethylene dibromide for 7 hours/day produced slight congestion of the spleens of rats, cloudy swelling and a slight leukocytic infiltration in the livers of rats, and widespread central fatty degeneration and some necrosis in the livers of rabbits [33]. Exposure of guinea pigs and monkeys at 50 ppm (285 mg/cu m) of ethylene dibromide for 7 hours/day, 5 days/week, for 70-80 days caused only slight central fatty degeneration of the liver [33]. Cats exposed at 100 ppm (770 mg/cu m) of ethylene dibromide for 30 minutes/day for about 10 days had enlarged spleens. Death resulted from circulatory system damage to the heart and vessels [23]. CNS effects, such as agitation, restlessness, body tremors, or unconsciousness, are caused by exposure to ethylene dibromide [23, [29][30][31]], but they have not been sufficiently described to permit an adequate evaluation or quantitation of their relevance or validity. The information provided by the few reports on humans [22][23][24][25] and such experimental animal data as those given in the following references [23,27,31,33] indicates that many effects produced by ethylene dibromide on humans and animals are similar and differ only in magnitude. Respiratory tract irritation, damage to the liver, kidneys, spleen, and lungs, irritation of the skin and eyes, and gastrointestinal disturbances are the predominant effects of ethylene dibromide exposure. Since systemic effects may occur from ingestion, inhalation, or dermal contact with ethylene dibromide, NIOSH recommends that work practices be used to minimize employee exposure to ethylene dibromide liquid or vapor through inhalation, body or eye contact, or ingestion. Mammalian studies indicate that reproductive abnormalities, including antifertility [9] and spermatozoic anomalies [41][42][43], occur from exposure to ethylene dibromide. One report [9] indicated that five ip injections of 10 mg/kg given to male rats produced a decrease in fertility only during the 3rd and 4th weeks after injection. Since spermatids require about 3-4 weeks to mature into spermatozoa in the rat, the evidence indicates that ethylene dibromide affects the development of the spermatids that were present at the time of injection. This is further supported by the return of normal fertility 5 weeks after the injection. Three studies with bulls In another experiment [42], production of abnormal spermatozoa occurred with a dose as small as 4 mg/kg given on alternate days for seven doses. These spermatozoic abnormalities would greatly reduce the fertility, even if they did not cause total sterility. Although these effects were from the ingestion of ethylene dibromide and not from inhalation or dermal contact, they indicate that a hazard, including decreased fertility and even temporary sterility, may result from inhalation or percutaneous absorption of ethylene dibromide. One study, reported by several authors [56][57][58][59], was conducted to determine the carcinogenic properties of ethylene dibromide. Rats and mice given daily oral doses by gavage of ethylene dibromide at 40 and 60 mg/kg, respectively, for 52-64 weeks developed squamous cell carcinomas in the stomach. These carcinomas invaded locally and metastasized throughout the abdominal cavity. Male and female rats developed stomach carcinomas as early as 10 weeks after the start of administration of ethylene dibromide. The carcinomas became more prevalent as the daily doses of ethylene dibromide were continued, and the final percentage of male rats with tumors after administration of 40 mg/kg/day was 98% after termination of the experiment at 54 weeks. Male rats were more susceptible to tumorigenesis than female rats; 80% of all the males in the study developed tumors versus 38% of all the females. The concurrent control populations did not develop squamous cell carcinomas. More than 70% of all the mice were reported to The mutagenic potential of ethylene dibromide is well established in both animal and plant systems. It induces mutations in vertebrate cell cultures [62], insects [6], bacteria [60,63,64], plants [66], and fungi [67,68] . One study with Drosophila melanogaster [6] showed that ethylene dibromide induced a significant number of recessive lethal mutations in three successive broods of offspring. The adult males fed 0.3 mM of ethylene dibromide for 3 days produced subsequent brood patterns indicative of impaired spermatozoic maturation rather than of impaired formation. Studies with mouse lymphoma cells [62] indicated that a dose-related effect, typical of those of other alkylating agents tested, existed over the range of 0.0-3.0 mM ethylene dibromide. The effect of the highest concentration was approximately equal to that of a dose of 600 R of Xirradiation. A study in a host-mediated assay system [60] with Salmonella typhimurium G46 in mice suggested that ethylene dibromide was mutagenic at a dose of 500 mg/kg. A second part of this study [60] showed that an equivalent dose produced a positive mutagenic effect on Salmonella typhimurium G46 in vitro, indicating that ethylene dibromide did not require metabolic activation and was not deactivated by metabolism. Similar positive mutagenic results occurred in Salmonella typhimurium TA Several studies [5,6,64] suggest that the mechanism of mutagenic activity of ethylene dibromide is based on its ability to alkylate, or covalently bond to, DNA in the exposed cells. Ethylene dibromide is a bifunctional alkylating agent capable of introducing cross-links into biologic materials [6] by displacement of the two reactive bromine atoms by reacting with amine, sulfhydryl, carboxy or other electron-donating groups. Ethylene dibromide, or its metabolites, has interacted with DNA through covalent bonds to induce DNA repair synthesis in opossum lymphocyte cells [5]. Another indication of ethylene dibromide's ability to alkylate DNA is that ethylene dibromide is mutagenic in Salmonella typhimurium TA 1530 and TA 1535, both transitional mutational systems [64]. These data [5,6,64] suggest strongly that the most plausible chemical basis for the mutagenic activity of ethylene dibromide in procaryotic and eucaryotic organisms is its alkylation of cellular constituents such as DNA. This broad biologic reactivity suggests that ethylene dibromide may be capable of increasing spontaneous mutation rates in humans. However, the quantitative aspects of this potential have not been determined. Since the process of induction of mutations is a stochastic, virtually irreversible process, any increased frequency of mutation in exposed populations would accumulate as a function of the total absorbed dose of ethylene dibromide. Therefore, an adequate assessment of the importance of the plant and submammalian animal data in extrapolating to the concentrations of airborne ethylene dibromide present in the workplace environment is difficult, but the widespread mutagenic activity of ethylene dibromide does give cause for concern about damage to the genetic mechanisms in employees working with it. The teratogenic effects found in a rat and mouse study [69] involved brain and costal anomalies in the offspring of dams exposed to ethylene dibromide. Pregnant rats and mice were exposed at a concentration of about 32 ppm of ethylene dibromide for 23 hours/day on days 6-16 of gestation. Some of the effects were attributed to malnourishment, but the abnormalities in the ethylene dibromide-exposed rats and mice were significantly different, both qualitatively and quantitatively, from those in the nonexposed controls; some of these abnormalities did not appear in mice fed a restricted amount of the normal diet whereas others appeared in both the restricted and the control mice with about the same incidences. These data suggest that ethylene dibromide causes fetal anomalies in mice and rats that are not caused by malnourishment alone. Since inhalation is one of the major routes of exposure for the employee, these data suggest also that the babies of female employees may be subject to increased risks of developmental defects if their mothers are exposed to ethylene dibromide in the workplace during the critical phases of pregnancy. The total risk to the health of employees exposed to ethylene dibromide is the result of the compounded risks from carcinogenicity, mutagenicity, teratogenicity, sterility, and damage to the kidneys, liver, spleen, respiratory tract, central nervous system, circulatory system, skin, and eyes. Although no comprehensive epidemiologic studies have been conducted to assess adequately these risks in the industrial environment, evidence of their existence in experimental animal systems or in isolated human exposures to ethylene dibromide has been discussed above and in Chapter III. Experimentation conducted with animal models, as outlined above, generally supports the findings observed in the limited number of human exposures. Concern for employee health requires that the probability of the occurrence of long-term effects of ethylene dibromide be minimized. The preliminary report available to NIOSH from a review of the mortality experience of 161 employees of one manufacturer [26,71] induced stomach cancer in the rat. In addition, the extensive experimental evidence on the induction of adverse effects in lower species [5][6][7]9,33,[41][42][43][56][57][58][59][60]62,66,69] and the formation of stable covalent bonds between ethylene dibromide and cellular constituents [7,11] indicate that the occupational exposure limit should be lowered to decrease the potential hazard to employees. Because of the intrinsic, stochastic, and virtually irreversible character of the chemical reactions that initiate the carcinogenic and mutagenic processes, the risk of adverse effects is a function of the rate of absorption and the total absorbed dose. Consequently, this risk can be reduced to any value necessary to protect the employees by decreasing both the absorption rate (to prevent saturation of the enzymatic detoxification mechanisms) and the total lifetime dose (to reduce the probability of deleterious stochastic processes, such as carcinogenesis and mutagenesis, from occurring). The unusual complexity of the dynamics of the cellular response mechanisms to ethylene dibromide intoxication is emphasized by the doserate effect relationship observed for induction of gastric neoplasms. Daily intragastric doses of 40 and 60 mg/kg induced tumors in rats and mice within 10 weeks [56], whereas daily 7-hour inhalation exposures of about 49 mg/kg did not result in the observation of tumors even after 30 weeks [33]. The data suggest that one of the major factors in the development of gastic carcinomas is direct contact between the mucosal cells and ethylene dibromide, and that a major difference in tumor induction may exist between the two routes of exposure. However, the animals used in the inhalation study were not maintained until the end of their normal lifespan; therefore, a direct comparison between the final incidences of tumors initiated by the two routes of exposure cannot be made. A plausible pharmacokinetic explanation for the observed differences exists. Since the rat's capacity to metabolize ethylene dibromide [50] exceeds the rate of absorption (at 25 ppm) by a factor of at least 100, the concentration of ethylene dibromide in tissues should be considerably less than that in the air, which is about 1.02 /umoles/liter at 25 ppm [33]. The concentration of ethylene dibromide in corn oil used in the intubation study ranged between 0.066 and 0.132 moles/liter. Consequently, the mucosal cells of the stomach may have been exposed for short periods to concentrations of ethylene dibromide up to 100,000 times that to which lung tissue would be exposed during inhalation exposures at 25 ppm (192.5 mg/cu m ) . The saturation of enzymatically catalyzed detoxification and repair mechanisms may occur in the stomach tissues, resulting in an amplification of the tissue damage, which otherwise may be minimal. These pharmacokinetic considerations are consistent with the experimental results of Rowe et al [33], where the product of the concentration and duration of exposure to produce 50% mortality among the exposed rats was found to be approximately constant for higher concentrations of ethylene dibromide but not for lower ones. The evidence indicates that tissue detoxication and repair mechanisms exist, but that they cannot negate completely the intrinsic capacity of ethylene dibromide to alkylate cellular constituents. Because of this, exposure to ethylene dibromide has potentials for the A major factor in the development of gastric carcinoma in the rats and mice is considered to be the direct contact between mucosal cells and concentrated ethylene dibromide in a quantity which exceeded the ability of the tissues to handle the chemical. Mutagenic effects from ethylene dibromide have been demonstrated in microbes, plants, insects, and mammalian cells in vitro, presumably due to its ability to alkylate, or covalently bond, to DNA in a cross-linking mechanism by virtue of its bifunctional structure. Although this potential has not been demonstrated in humans, the broad biologic activity of ethylene dibromide warrants concern about possible damage to genetic mechanisms in employees exposed to it. Teratogenic effects which seem to be due to maternal exposure to ethylene dibromide have been confined to brain and costal anomalies in fetal mice and rats, but malnourishment as a contributing factor cannot be discredited unequivocally. Although it is not possible at this time to state categorically an exposure concentration at which ethylene dibromide may be regarded to be completely without risk, NIOSH considers that the recommended occupational exposure limit should be substantially lower than the current federal standard of 20 ppm as an 8-hour TWA limit, 30 ppm ceiling. The recommended occupational exposure limit for ethylene dibromide, at the least, should be reduced sufficiently to keep the total lifetime dose well below the cumulative doses shown to be hazardous in animal experiments. In considering the alkylating capability of ethylene dibromide and the potential adverse effects on the organism which may result, especially at the subcellular level, NIOSH recommends that the occupational exposure limit for ethylene dibromide be reduced to a ceiling concentration of 1.0 mg/cu m (0.13 ppm) for any 15-minute sampling period. This represents a reduction to one-two-hundred and thirtieth of the current federal ceiling limit for ethylene dibromide and is a level at which an employee would inhale a maximum of about 686 mg/kg of ethylene dibromide during a 40-year working lifetime, which is substantially below that total dose known to induce adverse effects in experimental animals. It is believed that so long as care is taken to prevent entrance of any appreciable amount of ethylene dibromide into the digestive tract, adherence to this exposure limit will protect against acute adverse effects and will reduce the potential long-term effects to a negligible level. NIOSH concludes that reduction to a ceiling concentration of 1.0 mg/cu m (0.13 ppm) will protect employees from acute illness resulting from exposure to ethylene dibromide and will reduce markedly, and perhaps remove entirely, any hazard of adverse effects on health from long-term exposure to this chemical. Studies should be conducted to determine the feasibility of using body fluids, such as blood or urine, as the basis of a method for biologic monitoring of workers that are occupationally exposed to ethylene dibromide. (h) # Long-term Animal Exposure Studies Long-term exposure of several animal species at a variety of concentrations of ethylene dibromide vapor approaching the recommended environmental limit is needed. These studies should simulate occupational exposure conditions of 8-10 hours/day, 4-5 days/week, for at least 18-24 months and the animals maintained until the end of their natural life. These studies should be properly designed and performed to allow for assessment of general body parameters, biochemical/physiologic parameters, and gross or microscopic examinations of involved organs including at least the liver, lungs, spleen, kidneys, CNS, and circulatory system. In addition, repeated long-term experiments should be performed to determine the effects of ethylene dibromide absorption through the skin. Similar schedules and experimental designs as those for inhalation studies should be followed. The National Cancer Institute has informed NIOSH that a long-term experiment to study the possible carcinogenic effects from the inhalation of ethylene dibromide is presently being conducted. Several studies [9,10] have indicated that ethylene dibromide, or its metabolites, is widely circulated throughout the body and remains widely distributed in the body tissues for a considerable time. These studies also indicated that ethylene dibromide, or its metabolites, is excreted in the urine and eliminated in the feces. The sampling train consists of a charcoal tube and a vacuum pump. (1) Charcoal tubes: Glass tubes, with both ends flamesealed, 7-cm long, with a 6-mm OD and a 4-mm ID, containing two sections of 20/40 mesh activated charcoal separated by a 2-mm portion of polyurethane foam. The activated charcoal is prepared from coconut shells and is fired at 600 C prior to packing. The primary section contains 100 mg of charcoal, the backup section, 50 mg. A 3-mm portion of polyurethane foam is placed between the outlet end of the tube and the backup section. A plug of silylated glass wool is placed in front of the primary section. # METHOD FOR SAMPLING ETHYLENE DIBROMIDE IN AIR The pressure drop across the tube when in use must be less than 1 inch of mercury at a flowrate of 1 liter/minute. Tubes with the above specifications are commercially available. (2) Pump: A battery-operated pump, complete with clip for attachment to the employee's belt, capable of operation at 200 ml/minute or less with a controlled accuracy of + 5%. # (b) Calibration The accurate calibration of a sampling pump is essential for the correct interpretation of the volume sampled. The frequency of calibration is dependent on the use, care, and handling to which the pump is subjected. Pumps should also be recalibrated if they have been misused or if they have just been repaired or received from a manufacturer. If the pump receives hard usage, more frequent calibration may be necessary. Maintenance and calibration should be performed on a regular schedule and records of these should be kept. Ordinarily, pumps should be calibrated in the laboratory both before they are used in the field and after they have been used to collect a large number of field samples. The accuracy of calibration is dependent on the type of instrument used as a reference. The choice of calibration instrument will depend largely on where the calibration is to be performed. (2) Break the tips of a charcoal tube to produce openings of at least 2 mm in diameter. Repeat the procedure in (7) above at least three times, average the results, and calculate the flowrate by dividing the volume between the preselected marks by the time required for the soapbubble to traverse the distance. If, for the pump being calibrated, the volume of air sampled is calculated as the product of the number of strokes times a stroke factor (given in units of volume/stroke), the stroke factor is the quotient of the volume between the two preselected marks divided by the number of strokes. Therefore, if the analysis cannot be performed within 16-24 hours after sampling has been completed, the samples must be stored at -25 C or below. Refrigerated samples may be stored for two weeks. (25 liters), the probable range of this method is 40-800 nanograms/sample solution at a detector sensitivity that gives nearly full deflection on the strip chart recorder for a 1-mg sample. The method may be capable of measuring much smaller amounts if the desorption efficiency is adequate and if a photon-ionization detector is used on the chromatograph. Desorption efficiency must be determined over the range used. The upper limit of the range of the method is dependent on the adsorptive capacity of the charcoal tube. This capacity varies with the concentrations of ethylene dibromide and other substances in the air. The first section of the charcoal tube held at least 21.4 mg of ethylene dibromide when a test atmosphere containing 446 mg/cu m of ethylene dibromide in dry air was sampled at 200 ml/minute for 240 minutes; at that time, the concentration of ethylene dibromide in the effluent was less than 2% of that in the influent. If a particular atmosphere is suspected of containing a large amount of contaminant, a smaller sampling volume should be taken. # Interferences Compounds which have about the same retention time as ethylene dibromide and which are detected by the electron capture detector will interfere with the analysis. This type of interference can be overcome by changing the operating conditions of the instrument, usually by modifying the column, the column temperature, or both. Ethylene dibromide will not be efficiently trapped when the amount of water vapor in the air is so great that condensation occurs in the trapping media. Lesser amounts of water vapor in the air may severely decrease the breakthrough volume. When interfering compounds are known or suspected to be present in the air, such information including their suspected identities could be transmitted with the sample. # Precision and Accuracy The relative standard deviation for the combined analytical and sampling method in the prescribed range of 203-2,370 nanograms/charcoal tube was 0.070. # Advantages and Disadvantages of the Method This method uses a sampling device that is small, portable, and involves no liquids. Interferences are minimal and can usually be eliminated by altering chromatographic conditions. Analysis of the charcoal tubes can be accomplished rapidly. Simultaneous analysis of two or more compounds suspected of being present in the same sample can usually be accomplished by simply changing chromatographic conditions. One disadvantage of the method is that the amount of sample which can be collected by this method is limited by the weight of ethylene dibromide which the tube will hold before breakthrough. When the sample value obtained for the backup section of charcoal exceeds 25% of that found in the front section, the possibility of appreciable sample loss exists. Recoveries of ethylene dibromide from charcoal are decreased upon storage of the charcoal tube samples at room temperature, particularly with lesser amounts of analyte. The use of an internal standard is required in order to attain good precision. Other organic compounds in high concentrations may displace ethylene dibromide from the charcoal. High humidity may decrease the absorptive efficiency and capacity of the charcoal. The precision of the method is limited by the reproducibility of the pressure drop across the charcoal tube. This drop will affect the flowrate and the volume of air sampled, since the pump is usually calibrated for one tube only. (e) # Measurement of area: The areas of the sample peaks are measured by electronic integration or some other suitable method of area measurement. Preliminary sample results are read from a standard curve prepared as outlined below. (f) The approximate retention times of ethylene dibromide and two potential internal standards under the GC conditions described in this method are: In the case of the internal standard method, prepare standard curves by plotting concentration in mg/ml versus the ratio of the peak areas of ethylene dibromide to n-pentadecane. Compound # Calculations Read the weight in milligrams of ethylene dibromide corresponding to the total peak area from the standard curve. No volume corrections are needed because the standard curve is based on mg ethylene dibromide/ml of benzene-methanol and the volume of sample injected is identical to the volume of the standards injected. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50- The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees. Respirators shall be specified as to type and NIOSH or US Bureau of Mines approval class, ie, "Supplied air," "Organic vapor canister," etc. Protective equipment must be specified as to type and materials of construction. Adapted from reference 9 # PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R # (f) 99:1 Benzene-methanol (v/v). # Analysis of Samples All glassware used for the laboratory analysis should be washed in detergent and rinsed with tap and distilled water.	None	None
97632dc52720c357a5c2950d4521a078d1f69c25	cdc	None	The standard is designed to protect the health and safety of employees for up to a 10-hour work shift, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should therefore prevent adverse effects of carbaryl on the health and safety of employees. The recommended standard Is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The criteria and standard will be subject to review and revision as necessary. The criteria and the recommended standard apply to any manufacturing, formulating, or applying operation in which carbaryl is produced, packaged, processed, mixed, blended, handled, or used, or where employees are otherwise potentially exposed. "Carbaryl" is the generic name for the 1naphthyl ester of N-methylcarbamic acid or 1-naphthyl N-methylcarbamate. "Action level" is defined as one-half the recommended time-weighted average (TWA) environmental exposure limit for carbaryl. "Occupational exposure to carbaryl" is defined as exposure to airborne carbaryl at concentrations greater than the action level. Exposure to carbaryl at concentrations less than or equal to the action level shall not require adherence to the recommended standard, except for Sections 3, 4(a,b), and 7(b). If employees are potentially exposed to other chemicals, such as pesticide vehicles, diluents, or emulsifiers or other pesticides, provisions of any (7) At the time of the preplacement examination, it Is recommended that a preexposure baseline erythrocyte cholinesterase activity be determined. (8) A judgment of the worker's physical ability to use negative or positive pressure respirators. (b) Emergency first-aid services shall be established, under the direction of the responsible physician, to provide care to any worker acutely intoxicated by carbaryl (See Appendix III). (c) Appropriate medical services and surveillance shall be provided to any worker with adverse health effects from exposure to carbaryl. (d) Pertinent medical records shall be maintained for all workers occupationally exposed to carbaryl for at least 5 years after termination of employment. These records shall be available to the designated medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employee or former employee, and of the employer. Section 3 -Labeling and Posting (a) Labeling Containers of carbaryl shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances: 4 CARBARYL CAUTION! HARMFUL IF INHALED, SWALLOWED, OR LEFT ON THE SKIN NO SMOKING Avoid breathing dust or spray mist. Avoid contact with eyes, skin, and clothing. Wash hands and face thoroughly before eating. Wear long-sleeved work clothes. Shower or bathe and change into clean clothing after work. First Aid: On skin contact with carbary1, wash with soap and water. On eye contact, flush eyes with copious amounts of water. If inhaled or swallowed, consult a physician. Note to Physician: Carbaryl is a moderate, reversible Cholinesterase inhibitor. Atropine sulfate is the antidote. Do not use pralidoxime chloride (2-PAM). (b) Posting The following sign shall be posted in a readily visible location at or near entrances to manufacturing and formulating areas containing carbaryl, and at other areas in which there is a risk of exposure: CARBARYL CAUTION! HARMFUL IF INHALED, SWALLOWED, OR LEFT ON THE SKIN NO SMOKING Avoid breathing dust or spray mist. Avoid contact with eyes, skin, and clothing. Wash hands and face thoroughly before eating. Wear long-sleeved work clothes. Shower or bathe and change into clean clothing after work. First Aid: On skin contact with carbaryl, wash with soap and water. On eye contact, flush eyes with copious amounts of water. If inhaled or swallowed, consult a physician.# applicable standards for such chemicals shall also be followed. (2) Any employee applying carbaryl by aircraft shall be provided with, and required to carry in the aircraft, a respirator as specified in Table 1-1. (3) Employees working as flaggers shall wear appropriate respirators as specified in Table 1-1 when exposure to an airborne carbaryl concentration above that specified in Section 1 is likely to occur. # Respirators may also be worn during the time necessary to # III. BIOLOGIC EFFECTS OF EXPOSURE The carbamate insecticides, one of which is carbaryl, and the organophosphate insecticides as well, exert their insecticidal action by Inhibiting cholinesterase enzymes. This inhibition is the primary mechanism by which these insecticides cause toxicity in mammals. The When this absorption value of carbaryl (5.6 mg/8 hours) was compared to the total potential dermal and respiratory exposure value (600 mg/8 hours) for the formulating-plant workers, it was suggested that absorption from dermal contact with carbaryl dust was probably not very complete. The authors concluded that dermal absorption of carbaryl from dry formulations in formulating plants may be only a small fraction of the total potential calculated exposure. probably makes the degree of inhibition by carbaryl at any given time elusive. The enzyme activity when analyzed in the sample tends to be higher than was the actual case when the blood sample was obtained, and thus the degree of inhibition may be interpreted as less than actually occurred. Degenerative changes in the testes, including edema of interstitial tissue and destruction of germinal epithelium, were noted in carbaryl-treated male rats. In females, the estrus cycle was prolonged at the 14 and 70 mg/kg doses. In a three-generation reproduction study on gerbils given carbaryl in the diet (2,000, 4,000, 6,000, and 10,000 ppm), Collins et al reported that no litters were produced at 10,000 ppm in the F3b generation, and that there was a decrease in fertility, pup viability, litter size, and survival of pups (to day 4 and to weaning) which appeared sporadically at all dose levels. In a similar three-generation reproduction study, Collins et al reported that doses of 5,000 and 10,000 ppm carbaryl in the diet reduced survival of offspring, viability of the pups, and litter size in rats from the first generation on. At 2,000 ppm, only body weight gain of the parents and weanling weight were affected. In contrast, Weil et al did not see any effect when carbaryl was administered by dietary inclusion to rats in a dose range of 7-100 mg/kg. An increased duration of the gestation period was the only effect seen at 200 mg/kg in the diet. Administration of carbary1 by gastric intubation to rats in a dose range of The carcinogenic potential of carbaryl has been investigated in mice. Male mice received 10 mg carbaryl subcutaneously once weekly during their 3rd to 8th months of life. by measurement of urinary 1-naphthol levels. To provide a safety factor for protection against systemic effects, a Threshold Limit Value of 5.0 mg/cu m was recommended. While available data to derive a safe limit are insufficient, there is no significant evidence indicating that the limit should be changed. In the absence of these needed data, it is proposed that the present workplace environmental limit of 5.0 mg carbaryl/cu m as a TWA concentration be continued. Available data do not indicate that exposure of workers at this concentration will result in intoxication, and some data suggest that this limit offers a good margin of safety. However, pertinent investigations, including epidemiologic studies of workers exposed to carbary1, are needed to validate this recommended limit or, if appropriate, to provide a basis for a better limit. Sampling and analysis methods were reviewed in Chapter IV. Airborne particulate carbaryl should be collected on a glass-fiber membrane filter mounted with a backup pad in a two-piece closed-face cassette. This sampling method, chosen because it is the best now available, has been shown to provide the required degree of collection efficiency for airborne particulate carbaryl. A colorimetric method was selected for analysis of carbaryl because it is reliable, sensitive, and simple to carry out. The selected method is not entirely specific for carbaryl analysis and several compounds including 1-naphthol can interfere with the precision of the method if they are present in the air sample to be analyzed. # VI. WORK PRACTICES Occupational exposures to carbaryl may occur among people engaged in the manufacture, formulation, or application of the insecticide. Potentially exposed applicators include agricultural workers, spray pilots, and exterminators. Even though absorption of pesticides by the oral and respiratory routes may be more rapid and more complete than by the percutaneous route, the amount of absorption by ingestion and inhalation is probably too small a fraction of the total potential exposure to be considered the main factor in most cases of intoxication of workers in the field. Studies also showed that considerably more insecticide was deposited on exposed skin surfaces than that reaching the respiratory tract. # FIGURE XIII-1 CALIBRATION SETUP FOR PERSONAL SAMPLING PUMP WITH FILTER CASSETTE D E P A R T M E N T OF HEALTH, EDUCATION. A N D W E L F A R E P U B L IC H E A L T H SER VIC E C E N T E R F O R D IS E A S E C O N T R O L N A T I O N A L IN S T IT U T E FO R O C C U P A T IO N A L S A FE TY A N D H E A L T H R O B E R T A. T A F T L A B O R The head and neck should be protected from contact with carbaryl. Therefore, some type of protective headgear, such as waterproof rainhats and washable safety hardhats and caps, should be worn. Waterproof or water-repellant parkas also may be used to protect the head and neck at the same time. Materials impervious to all carbaryl formulations should be identified for use in protective clothing. # Wills JH: The measurement and significance of changes in the Cholinesterase activities of erythrocytes and plasma in man and animals. MATERIAL SAFETY DATA SHEET # IO N R A T E (B U T Y L A C E T A T E M I A P P E A R A N C E	The standard is designed to protect the health and safety of employees for up to a 10-hour work shift, 40-hour workweek, over a working lifetime. Compliance with all sections of the standard should therefore prevent adverse effects of carbaryl on the health and safety of employees. The recommended standard Is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The criteria and standard will be subject to review and revision as necessary. The criteria and the recommended standard apply to any manufacturing, formulating, or applying operation in which carbaryl is produced, packaged, processed, mixed, blended, handled, or used, or where employees are otherwise potentially exposed. "Carbaryl" is the generic name for the 1naphthyl ester of N-methylcarbamic acid or 1-naphthyl N-methylcarbamate. "Action level" is defined as one-half the recommended time-weighted average (TWA) environmental exposure limit for carbaryl. "Occupational exposure to carbaryl" is defined as exposure to airborne carbaryl at concentrations greater than the action level. Exposure to carbaryl at concentrations less than or equal to the action level shall not require adherence to the recommended standard, except for Sections 3, 4(a,b), and 7(b). If employees are potentially exposed to other chemicals, such as pesticide vehicles, diluents, or emulsifiers or other pesticides, provisions of any (7) At the time of the preplacement examination, it Is recommended that a preexposure baseline erythrocyte cholinesterase activity be determined. (8) A judgment of the worker's physical ability to use negative or positive pressure respirators. (b) Emergency first-aid services shall be established, under the direction of the responsible physician, to provide care to any worker acutely intoxicated by carbaryl (See Appendix III). (c) Appropriate medical services and surveillance shall be provided to any worker with adverse health effects from exposure to carbaryl. (d) Pertinent medical records shall be maintained for all workers occupationally exposed to carbaryl for at least 5 years after termination of employment. These records shall be available to the designated medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employee or former employee, and of the employer. Section 3 -Labeling and Posting (a) Labeling Containers of carbaryl shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances: 4 CARBARYL CAUTION! HARMFUL IF INHALED, SWALLOWED, OR LEFT ON THE SKIN NO SMOKING Avoid breathing dust or spray mist. Avoid contact with eyes, skin, and clothing. Wash hands and face thoroughly before eating. Wear long-sleeved work clothes. Shower or bathe and change into clean clothing after work. First Aid: On skin contact with carbary1, wash with soap and water. On eye contact, flush eyes with copious amounts of water. If inhaled or swallowed, consult a physician. Note to Physician: Carbaryl is a moderate, reversible Cholinesterase inhibitor. Atropine sulfate is the antidote. Do not use pralidoxime chloride (2-PAM). (b) Posting The following sign shall be posted in a readily visible location at or near entrances to manufacturing and formulating areas containing carbaryl, and at other areas in which there is a risk of exposure: CARBARYL CAUTION! HARMFUL IF INHALED, SWALLOWED, OR LEFT ON THE SKIN NO SMOKING Avoid breathing dust or spray mist. Avoid contact with eyes, skin, and clothing. Wash hands and face thoroughly before eating. Wear long-sleeved work clothes. Shower or bathe and change into clean clothing after work. First Aid: On skin contact with carbaryl, wash with soap and water. On eye contact, flush eyes with copious amounts of water. If inhaled or swallowed, consult a physician.# applicable standards for such chemicals shall also be followed. (2) Any employee applying carbaryl by aircraft shall be provided with, and required to carry in the aircraft, a respirator as specified in Table 1-1. (3) Employees working as flaggers shall wear appropriate respirators as specified in Table 1-1 when exposure to an airborne carbaryl concentration above that specified in Section 1 is likely to occur. # Respirators may also be worn during the time necessary to # III. BIOLOGIC EFFECTS OF EXPOSURE The carbamate insecticides, one of which is carbaryl, and the organophosphate insecticides as well, exert their insecticidal action by Inhibiting cholinesterase enzymes. [1] This inhibition is the primary mechanism by which these insecticides cause toxicity in mammals. The When this absorption value of carbaryl (5.6 mg/8 hours) was compared to the total potential dermal and respiratory exposure value (600 mg/8 hours) for the formulating-plant workers, it was suggested that absorption from dermal contact with carbaryl dust was probably not very complete. The authors concluded that dermal absorption of carbaryl from dry formulations in formulating plants may be only a small fraction of the total potential calculated exposure. probably makes the degree of inhibition by carbaryl at any given time elusive. The enzyme activity when analyzed in the sample tends to be higher than was the actual case when the blood sample was obtained, and thus the degree of inhibition may be interpreted as less than actually occurred. Degenerative changes in the testes, including edema of interstitial tissue and destruction of germinal epithelium, were noted in carbaryl-treated male rats. In females, the estrus cycle was prolonged at the 14 and 70 mg/kg doses. In a three-generation reproduction study on gerbils given carbaryl in the diet (2,000, 4,000, 6,000, and 10,000 ppm), Collins et al [78] reported that no litters were produced at 10,000 ppm in the F3b generation, and that there was a decrease in fertility, pup viability, litter size, and survival of pups (to day 4 and to weaning) which appeared sporadically at all dose levels. In a similar three-generation reproduction study, Collins et al [78] reported that doses of 5,000 and 10,000 ppm carbaryl in the diet reduced survival of offspring, viability of the pups, and litter size in rats from the first generation on. At 2,000 ppm, only body weight gain of the parents and weanling weight were affected. In contrast, Weil et al [72] did not see any effect when carbaryl was administered by dietary inclusion to rats in a dose range of 7-100 mg/kg. An increased duration of the gestation period was the only effect seen at 200 mg/kg in the diet. Administration of carbary1 by gastric intubation to rats in a dose range of The carcinogenic potential of carbaryl has been investigated in mice. [27] Male mice received 10 mg carbaryl subcutaneously once weekly during their 3rd to 8th months of life. by measurement of urinary 1-naphthol levels. To provide a safety factor for protection against systemic effects, a Threshold Limit Value of 5.0 mg/cu m was recommended. While available data to derive a safe limit are insufficient, there is no significant evidence indicating that the limit should be changed. In the absence of these needed data, it is proposed that the present workplace environmental limit of 5.0 mg carbaryl/cu m as a TWA concentration be continued. Available data do not indicate that exposure of workers at this concentration will result in intoxication, and some data suggest that this limit offers a good margin of safety. However, pertinent investigations, including epidemiologic studies of workers exposed to carbary1, are needed to validate this recommended limit or, if appropriate, to provide a basis for a better limit. Sampling and analysis methods were reviewed in Chapter IV. Airborne particulate carbaryl should be collected on a glass-fiber membrane filter mounted with a backup pad in a two-piece closed-face cassette. This sampling method, chosen because it is the best now available, has been shown to provide the required degree of collection efficiency for airborne particulate carbaryl. A colorimetric method was selected for analysis of carbaryl because it is reliable, sensitive, and simple to carry out. The selected method is not entirely specific for carbaryl analysis and several compounds including 1-naphthol can interfere with the precision of the method if they are present in the air sample to be analyzed. # VI. WORK PRACTICES Occupational exposures to carbaryl may occur among people engaged in the manufacture, formulation, or application of the insecticide. Potentially exposed applicators include agricultural workers, spray pilots, and exterminators. [22] Even though absorption of pesticides by the oral and respiratory routes may be more rapid and more complete than by the percutaneous route, the amount of absorption by ingestion and inhalation is probably too small a fraction of the total potential exposure to be considered the main factor in most cases of intoxication of workers in the field. [152] Studies also showed that considerably more insecticide was deposited on exposed skin surfaces than that reaching the respiratory tract. [ # FIGURE XIII-1 CALIBRATION SETUP FOR PERSONAL SAMPLING PUMP WITH FILTER CASSETTE D E P A R T M E N T OF HEALTH, EDUCATION. A N D W E L F A R E P U B L IC H E A L T H SER VIC E C E N T E R F O R D IS E A S E C O N T R O L N A T I O N A L IN S T IT U T E FO R O C C U P A T IO N A L S A FE TY A N D H E A L T H R O B E R T A. T A F T L A B O R # The head and neck should be protected from contact with carbaryl. [156] Therefore, some type of protective headgear, such as waterproof rainhats and washable safety hardhats and caps, should be worn. Waterproof or water-repellant parkas also may be used to protect the head and neck at the same time. Materials impervious to all carbaryl formulations should be identified for use in protective clothing. # Wills JH: The measurement and significance of changes in the Cholinesterase activities of erythrocytes and plasma in man and animals. MATERIAL SAFETY DATA SHEET # IO N R A T E (B U T Y L A C E T A T E M I A P P E A R A N C E	None	None
4a9e7563c795cf1355352a96ae33bd02e1fd89ba	cdc	None	Foodborne illness is a serious public health problem. The Centers for Disease Control and Prevention (CDC) estimates that each year 76 million people get sick, more than 300,000 are hospitalized, and 5,000 Americans die as a result of foodborne illnesses, primarily the very young, elderly, and the immunocompromised. Recent changes in human demographics and food preferences, changes in food production and distribution systems, microbial adaptation, and lack of support for public health resources and infrastructure have led to the emergence of novel as well as traditional foodborne diseases. With increasing travel and trade opportunities, it is not surprising that the risk of contracting and spreading a foodborne illness now exists locally, regionally, and even globally. Physicians have a critical role in the prevention and control of food-related disease outbreaks. This primer is intended to help physicians in this role by providing them with practical and concise information on the diagnosis, treatment, and reporting of foodborne illnesses. It was developed collaboratively by the American Medical Association, the Centers for Disease Control and Prevention, the Food and Drug Administration's Center for Food Safety and Applied Nutrition, and the US Department of Agriculture's Food Safety and Inspection Service as part of President Clinton's National Food Safety Initiative. We encourage you to review this information and participate in the attached continuing medical education (CME) program. Even if you choose not to participate in the CME component, please take time to complete and return the "Program Evaluation Form." Your feedback is valuable for updating this primer and for planning future physician education programs.# This primer is directed to primary care physicians, who are more likely to see the index case of a potential food-related disease outbreak. It is a teaching tool to update primary care physicians about foodborne illness and remind them of their important role in recognizing suspicious symptoms, disease clusters, and etiologic agents, and reporting cases of foodborne illness to public health authorities. Specifically, this guide urges physicians to: - Recognize the potential for a foodborne etiology in a patient's illness; - Realize that many but not all cases of foodborne illness have gastrointestinal tract symptoms; - Obtain stool cultures in appropriate settings, and recognize that testing for some specific pathogens, e.g. E. coli O157:H7, Vibrio spp., must be requested; - Report suspect cases to appropriate public health officials; - Talk with patients about ways to prevent food-related diseases; and - Appreciate that any patient with foodborne illness may represent the sentinel case of a more widespread outbreak. Foodborne illness is considered to be any illness that is related to food ingestion; gastrointestinal tract symptoms are the most common clinical manifestations of foodborne illnesses. This document provides detailed summary tables and charts, references, and resources for healthcare professionals. Patient scenarios and clinical vignettes are included for self-evaluation and to reinforce information presented in this primer. Also included is a CME component worth 3 credit hours. This primer is not a clinical guideline or definitive resource for the diagnosis and treatment of foodborne illness. Safe food handling practices and technologies (e.g. irradiation, food processing and storage) also are not addressed. More detailed information on these topics is available in the references and resources listed in this document, as well as from medical specialists and medical specialty societies, state and local public health authorities, and federal government agencies. For additional copies, please contact: L J Tan, PhD American Medical Association 515 North State Street Chicago, Illinois 60610 312 464-4147 312 464-5841 (fax) [email protected] (E-mail) # CLINICAL CONSIDERATIONS Food-related disease threats are numerous and varied, involving biological and nonbiological agents. Foodborne illnesses can be caused by microorganisms and their toxins, marine organisms and their toxins, fungi and their related toxins, and chemical contaminants. During the last 20 years, some foods that have been linked to outbreaks include: milk (Campylobacter ); shellfish (Norwalk-like viruses); unpasteurized apple cider (Escherichia coli O157:H7), eggs (Salmonella ); fish (ciguatera poisoning); raspberries (Cyclospora ); strawberries (hepatitis A virus); and ready-to-eat meats (Listeria ). While physicians have a critical role in surveillance for and prevention of potential disease outbreaks, only a fraction of the people who experience gastrointestinal tract symptoms from foodborne illness seek medical care. In those who do seek care and submit specimens, bacteria are more likely than other pathogens to be identified as causative agents. Bacterial agents most often identified in patients with foodborne illness in the United States are Campylobacter, Salmonella, and Shigella species, with substantial variation occurring by geographic area and season. Testing for viral etiologies of diarrheal disease is rarely done, but viruses are considered the most common cause of foodborne illness. This section and the Foodborne Illnesses Tables summarize diagnostic features and laboratory testing for bacterial, viral, parasitic, and noninfectious causes of foodborne illness. For more specific guidance, consult an appropriate medical specialist or medical specialty society, as well as various resources listed in other sections of this document. Also refer to this section and the Foodborne Illnesses Tables when working through the Patient Scenarios and Clinical Vignettes of this primer. # RECOGNIZING FOODBORNE ILLNESSES Patients with foodborne illnesses typically present with gastrointestinal tract symptoms (e.g. vomiting, diarrhea, and abdominal pain); however, nonspecific symptoms and neurologic symptoms may also occur. Every outbreak begins with an index case who may not be severely ill. A physician who encounters this person may be the only one with the opportunity to make an early and expeditious diagnosis. Thus, the physician must have a high index of suspicion and ask appropriate questions to recognize that an illness may have a foodborne etiology. Important clues to determining the etiology of a foodborne disease are the: - Incubation period; - Duration of the resultant illness; - Predominant clinical symptoms; and - Population involved in the outbreak. Additional clues may be derived by asking whether the patient has consumed raw or poorly cooked foods (e.g. raw or undercooked eggs, meats, shellfish, fish), unpasteurized milk or juices, home canned goods, fresh produce, or soft cheeses made from unpasteurized milk. Inquire whether any of the patient's family members or close friends has similar symptoms. Inquiries about living on or visiting a farm, pet contact, day care attendance, occupation, foreign travel, travel to coastal areas, camping excursions to mountains or other areas where untreated water is consumed, and attendance at group picnics or similar outings also may provide clues for determining the etiology of the illness. If a foodborne illness is suspected, submit appropriate specimens for laboratory testing and contact the state or local health department for advice about epidemiologic investigation. For the physician, implication of a specific source in disease transmission is difficult from a single patient encounter. Attempts to identify the source of the outbreak are best left to public health authorities. Because infectious diarrhea can be contagious and is easily spread, rapid and definitive identification of an etiologic agent may help control a disease outbreak. An individual physician who obtains testing can contribute the necessary piece of data that ultimately leads to identification of the source of an outbreak. # DIAGNOSING FOODBORNE ILLNESSES Differential Diagnosis As shown in Table 1 and the Foodborne Illnesses Tables a variety of infectious and noninfectious agents must be considered in patients suspected of having a foodborne illness. Establishing a diagnosis can be difficult, however, particularly in patients with persistent or chronic diarrhea, those with severe abdominal pain, and when there is an underlying disease process. The extent of diagnostic evaluation depends on the clinical picture, the differential diagnosis considered, and clinical judgment. If any of the following signs and symptoms occur, alone or in combination, laboratory testing may provide important diagnostic clues (particular attention should be given to very young and elderly patients and to immunocompromised patients, all of whom are more vulnerable): - Bloody diarrhea - Weight loss - Diarrhea leading to dehydration - Fever - Prolonged diarrhea (3 or more unformed stools per day, persisting several days) - Neurologic involvement such as paresthesias, motor weakness, cranial nerve palsies - Sudden onset of nausea, vomiting, diarrhea - Severe abdominal pain In addition to foodborne causes, a differential diagnosis of gastrointestinal tract disease should include underlying medical conditions such as irritable bowel syndrome; inflammatory bowel diseases such as Crohn's disease or ulcerative colitis; malignancy; medication use (including antibiotic-related Clostridium difficile toxin colitis); gastrointestinal tract surgery or radiation; malabsorption syndromes; immune deficiencies; Brainerd diarrhea; and numerous other structural, functional, and metabolic etiologies. Consideration also should be given to exogenous factors such as the association of the illness with travel, occupation, emotional stress, sexual practices, exposure to other ill persons, recent hospitalization, child care center attendance, and nursing home residence. The differential diagnosis of patients presenting with neurological symptoms due to a foodborne illness is also complex. Possible food-related causes to consider include recent ingestion of contaminated seafood, mushroom poisoning, and chemical poisoning. Because the ingestion of certain toxins (e.g. botulinum toxin, tetrodotoxin) and chemicals (e.g. organophosphates) can be life-threatening, a differential diagnosis must be made quickly with concern for aggressive therapy and life support measures (e.g. respiratory support, administration of antitoxin or atropine), and possible hospital admission. # Clinical Microbiology Testing When submitting specimens for microbiologic testing, it is important to realize that clinical microbiology laboratories differ in protocols used for the detection of pathogens. To optimize recovery of an etiologic agent, physicians should understand routine specimen collection and testing procedures as well as circumstances and procedures for making special test requests. Some complex tests (e.g. toxin testing, serotyping, molecular techniques) may only be available from large commercial and public health laboratories. Contact your microbiology laboratory for more information. Stool cultures are indicated if the patient is immunocompromised, febrile, has bloody diarrhea, has severe abdominal pain, or if the illness is clinically severe or persistent. Stool cultures are also indicated if many fecal leukocytes are present, which indicates diffuse colonic inflammation and is suggestive of invasive bacterial pathogens such as Shigella, Salmonella, and Campylobacter species, and invasive E. coli. In most laboratories, routine stool cultures are limited to screening for Salmonella and Shigella species, and Campylobacter jejuni/coli. Cultures for Vibrio and Yersinia species, E. coli O157:H7, and Campylobacter species other than jejuni/coli require additional media or incubation conditions and therefore require advance notification or communication with laboratory and infectious disease personnel. Stool examination for parasites generally is indicated for patients with suggestive travel histories, who are immunocompromised, who suffer chronic or persistent diarrhea, or when the diarrheal illness is unresponsive to appropriate antimicrobial therapy. Stool examination for parasites is also indicated for gastrointestinal tract illnesses that appear to have a long incubation period. Requests for ova and parasite examination of a stool specimen will often enable identification of Giardia lamblia and Entamoeba histolytica, but a special request may be needed for detection of Cryptosporidium parvum and Cyclospora cayetanensis. Each laboratory may vary in its routine procedures for detecting parasites so it is important to contact your laboratory. Blood cultures should be obtained when bacteremia or systemic infection are suspected. Direct antigen detection tests and molecular biology techniques are available for rapid identification of certain bacterial, viral, and parasitic agents in clinical specimens. In some circumstances, microbiologic and chemical laboratory testing of vomitus or implicated food items also is warranted. For more information on laboratory procedures for - Noninflammatory diarrhea is characterized by mucosal hypersecretion or decreased absorption without mucosal destruction and generally involves the small intestine. Some affected patients may be dehydrated because of severe watery diarrhea and may appear seriously ill. This is more common in the young and the elderly. Most patients experience minimal dehydration and appear mildly ill with scant physical findings. Illness typically occurs with abrupt onset and brief duration. Fever and systemic symptoms usually are absent (except for symptoms related directly to intestinal fluid loss). † Inflammatory diarrhea is characterized by mucosal invasion with resulting inflammation and is caused by invasive or cytotoxigenic microbial pathogens. The diarrheal illness usually involves the large intestine and may be associated with fever, abdominal pain and tenderness, headache, nausea, vomiting, malaise, and myalgia. Stools may be bloody and may contain many fecal leukocytes. # TREATING FOODBORNE ILLNESSES Selection of appropriate treatment depends on identification of the responsible pathogen (if possible) and determining if specific therapy is available. Many episodes of acute gastroenteritis are self limiting and require fluid replacement and supportive care. Oral rehydration is indicated for patients who are mildly to moderately dehydrated; intravenous therapy may be required for more severe dehydration. Because many antidiarrheal agents have potentially serious adverse effects in infants and young children, their routine use is not recommended in this age group. Choice of antimicrobial therapy should be based on: - Clinical signs and symptoms; - Organism detected in clinical specimens; - Antimicrobial susceptibility tests; and - Appropriateness of treating with an antibiotic (some enteric bacterial infections are best not treated). Knowledge of the infectious agent and its antimicrobial susceptibility pattern allows the physician to initiate, change, or discontinue antimicrobial therapy. Such information also can support public health surveillance of infectious disease and antimicrobial resistance trends in the community. Antimicrobial resistance has increased for some enteric pathogens, which requires judicious use of this therapy. # SURVEILLANCE AND REPORTING OF FOODBORNE ILLNESSES Reporting of foodborne illnesses in the United States began more than 50 years ago when state health officers, concerned about the high morbidity and mortality caused by typhoid fever and infantile diarrhea, recommended that cases of "enteric fever" be investigated and reported. The intent of investigating and reporting these cases was to obtain information about the role of food, milk, and water in outbreaks of gastrointestinal tract illness as the basis for public health actions. These early reporting efforts led to the enactment of important public health measures (e.g. the Pasteurized Milk Ordinance) that profoundly decreased the incidence of foodborne illnesses. Often health care professionals may suspect foodborne illness either because of the organism involved or because of other available information, such as several ill patients who have eaten the same food. Health care professionals can serve as the eyes and ears for the health department by providing such information to the local or state public health authorities. Foodborne disease reporting is not only important for disease prevention and control, but more accurate assessments of the burden of foodborne illness in the community occur when physicians report foodborne illnesses to the local or state health department. In addition, reporting of cases of foodborne illness by practicing physicians to the local health department may help the health officer identify a foodborne disease outbreak in the community. This may lead to early identification and removal of contaminated products from the commercial market. If a restaurant or other food service establishment is identified as the source of the outbreak, health officers will work to correct inadequate food preparation practices, if necessary. If the home is the likely source of the contamination, health officers can institute public education about proper food handling practices. Occasionally, reporting may lead to the identification of a previously unrecognized agent of foodborne illness. Reporting also may lead to identification and appropriate management of human carriers of known foodborne pathogens, especially those with high-risk occupations for disease transmission such as foodworkers. Table 2 lists current reporting requirements for foodborne diseases and conditions in the United States. National reporting requirements are determined collaboratively by the Council of State and Territorial Epidemiologists and the Centers for Disease Control and Prevention (CDC). Typically, the appropriate procedure for physicians to follow in reporting foodborne illnesses is to contact the local or state health department whenever they identify a specific notifiable disease. However, it is often unclear if a patient has a foodborne illness prior to diagnostic tests, so physicians should also report potential foodborne illnesses, such as when two or more patients present with a similar illness that may have resulted from the ingestion of a common food. Local health departments then report the illnesses to the state health department and determine if further investigation is warranted. Each state health department reports foodborne illnesses to the CDC. The CDC compiles this data nationally and disseminates information to the public through annual summary reports. The CDC assists state and local public health authorities with epidemiologic investigations and the design of interventions to prevent and control food-related outbreaks. The CDC also coordinates a national network of public health laboratories, called PulseNet, which perform "molecular fingerprinting" of bacteria (by pulsed-field gel electrophoresis) to support epidemiolgic investigations. Thus, in addition to reporting cases of potential foodborne illnesses, it is important for physicians to report noticeable increases in unusual illnesses, symptom complexes, or disease patterns (even without definitive diagnosis) to public health authorities. Prompt reporting of unusual patterns of diarrheal/gastrointestinal tract illness, for example, can allow public health officials to initiate an epidemiologic investigation earlier than would be possible if the report awaited definitive etiologic diagnosis. Finally, new information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated whenever new data about preventing foodborne illnesses become available. Physicians and other health care professionals need to be aware of and follow the most current information on food safety. # Foodborne Diseases and Conditions Designated as Notifiable at the National Level -United States 2000 In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Infants infected from mother at risk for sepsis or meningitis. 5-10 days. # 3->7 days Variable Undercooked beef, unpasteurized milk and juice, raw fruits and vegetables (e.g. sprouts), salami, salad dressing, and contaminated water. Water or food contaminated with human feces. Fresh soft cheeses, unpasteurized milk, inadequately pasteurized milk, ready-to-eat deli meats, hot dogs. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: / mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. # Foodborne Diseases and Conditions Designated as Notifiable at the National Level -United States 2000 In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Supportive care, usually mild, self-limiting. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: / mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: / mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # BOTULISM POISONING: A PATIENT SCENARIO On Sunday morning at 6am, you receive a call from the wife of a 35-year-old man who awoke complaining of dry mouth and blurred vision. His symptoms rapidly progressed over the next 2 hours to include diplopia, dysphagia, and weakness in his arms. You ask to talk with him directly, but he is having difficulty speaking. He was previously healthy. You meet them in the local emergency department. On physical examination, he is afebrile with a heart rate of 80 beats per minute, a blood pressure of 120/80 mm Hg, and a respiratory rate of 12 breaths per minute. His pulse oximetry is 98% oxygen saturation. He has a hoarse voice, bilateral ptosis, a weak gag reflex, and bilateral proximal upper extremity weakness. He has no lower extremity weakness. Sensation is intact in all extremities. His mental status is normal. # What is the possible differential diagnosis for his chief complaint? - The patient denies having a flu-like illness within the last month. Neither he nor his family members have had similar symptoms. There is no family history of stroke or other neurological disorders, and he does not have hypertension or hypercholesterolemia. He has not discovered any ticks on himself or in his environment, and he has not been # MMWR January 26,2001 camping, hiking, or in any tick-infested area within the last week. He has had no occupational or recreational exposures to heavy metals or organophosphates. He denies eating any home-canned foods. He cannot remember everything he ate during the last 72 hours, but recalls eating lunch at a coffee shop near his office. He and his wife hosted a barbeque one evening at which they served grilled chicken, vegetables, and homemade ice cream. The night before onset of his symptoms, they ate at their favorite Italian restaurant where they shared a calamari appetizer, had salad prepared by the waiter at the table, and shared an entree of Fettuccine Fra Diablo. They finished the meal with a cappuccino and tiramisu. # How does this information assist with the diagnosis? Guillain-Barré Syndrome (GBS) is usually preceded by a diarrheal or flu-like illness within 5 days to 3 weeks before onset of symptoms. It characteristically presents with an ascending pattern of muscle weakness; however, the Miller-Fisher variant of GBS may present with a descending pattern of muscle weakness. Myasthenia gravis is characterized by muscle fatigue after exercise, and the symptoms fluctuate over time. Tick-borne paralysis should be ruled out by a thorough examination for a tick; it also usually presents with an ascending pattern of muscle paralysis. Heavy metal poisoning may cause gastrointestinal tract symptoms, alopecia, mental disturbances (irritability, concentration difficulties, and somnolence) and peripheral neuropathy. Organophosphate toxicity causes a cholinergic syndrome. Botulism is a probable diagnosis despite the absence of a history of consumption of home-canned foods; bilateral cranial nerve palsies and a descending pattern of weakness are classic symptoms of botulism. The incubation period for this illness is typically 18 to 36 hours; therefore, it is important to obtain as complete a dietary history as possible for this time period. It is important that the local or state health department be contacted immediately when botulism is suspected. In cases of botulism intoxication, an EMG of the affected muscles done with rapid repetitive stimulation at 20-50 Hertz will usually demonstrate a potentiated response in muscle action potentials; whereas in GBS and myasthenia gravis rapid repetitive stimulation yields flat and decremental responses, respectively. Administration of Tensilon (edrophonium) will help confirm the diagnosis of myasthenia gravis by showing improved muscle strength after injection of this compound. CSF protein levels are normal in botulism but are almost always elevated in GBS except early in the course of the illness. A CT scan of the head with and without contrast may help rule out a significant cerebrovascular accident or encephalitis. An MRI may be helpful to distinguish soft tissue abnormalities or midbrain lesions. If the history suggests heavy metal or organophosphate toxicity, special tests including evaluation of hair or blood can be done. # What diagnostic tests are needed? You order the EMG, Tensilon test, CSF studies, and the CT scan of the head. The EMG shows a potentiated muscle action potential with rapid repetitive stimulation at 20 Hertz, consistent with botulism intoxication. The Tensilon test is negative (no improvement with Tensilon) and the CSF protein, glucose, and cell counts are normal. CT scan of the head shows no meningeal enhancement or evidence of intracranial hemorrhage. # What diagnostic test(s) will confirm the diagnosis of botulism? To confirm the diagnosis of botulism, serum, stool, and any leftover suspect food should be tested for the presence of botulinum toxin. The test is a mouse bioassay. Mice are given injections of dilutions of sera, stool, and food extract followed by injections of monovalent antitoxins A, B, and E and polyvalent antitoxin ABCEF, and observed for signs of botulism and death. Stool and food also can be cultured for the bacterium Clostridium botulinum, which produces the toxins. To order tests for botulinum toxin and C. botulinum culture, the state health department should be contacted. It can provide information about what specimens should be collected and how they should be stored, and will forward the specimens to the state public health laboratory or to the Centers for Disease Control and Prevention (CDC) if the state does not have the capacity to test for botulism. # What treatment is needed? The most important treatment for botulism is supportive care. The patient's cardiorespiratory status should be monitored continuously in an intensive care unit. His respiratory function as measured by forced vital capacity should be monitored frequently, and he should be placed on assisted ventilation at the first sign of respiratory decompensation. Induced vomiting or gastric lavage are sometimes recommended to eliminate unabsorbed toxin from the stomach. These therapies are only done with a protected airway when the risk of aspiration is low. Cathartic agents or enemas are sometimes recommended to remove unabsorbed toxin from the gastrointestinal tract. The only pharmacological treatment for botulism is antitoxin. The currently available licensed antitoxins are equine antibodies to toxin; one product has antibodies to toxin types A and B, the most common causes of botulism, and the other product has antibodies to toxin types A, B, and E. Use of the product containing antibodies to type E toxin is reserved for patients at high risk of type E botulism intoxication including those patients who were exposed to botulinum toxin in Alaska, or those who have a history of consumption of preserved fish, fish eggs, seal, walrus, whale, or beaver tail. Antitoxin is most effective in preventing progression of the illness and shortening the duration of ventilatory failure if administered early (24-48 hours) after the onset of neurologic symptoms. If a diagnosis of botulism intoxication is strongly suspected, antitoxin should be administered promptly and should not be delayed until the diagnosis is confirmed. Hypersensitivity reactions have been reported in up to 9% of patients who receive antitoxin; therefore, skin testing is recommended prior to administration of antitoxin. Antimicrobials have not been of benefit in the treatment of foodborne botulism intoxication. Botulinum antitoxin is obtained from quarantine stations with permission for release from the CDC and some state health departments; this should be arranged through the state health department. Epidemiologists within the Foodborne and Diarrheal Diseases . # Should this case be reported to the local health department? All suspected cases of botulism intoxication should be reported immediately to the local health department. It will then notify the state health department, which will notify the CDC. In collaboration with state health departments, the CDC will assist with laboratory tests, arrange for treatment with botulinum antitoxin, and notify the Food and Drug Administration (FDA). The FDA is responsible for investigating commercial products possibly contaminated with botulinum toxin and assessing the need for a recall. In the present scenario, the patient denied consuming home-canned foods, suggesting the source of botulinum toxin was a commercial product. A contaminated, widely distributed commercial product could be a potential hazard to many people. State and local health officials with the assistance of the FDA will begin a more thorough investigation, searching for other cases and identifying suspect food exposures. # What was the most likely source of botulism intoxication in this patient? What commercial foods are potential sources of botulism intoxication? Home-canned foods are responsible for over 90% of all cases of foodborne botulism. However, commercial products have also occasionally been implicated. A product with an anaerobic environment allows for the growth of C. botulinum spores and toxin production. The toxins are resistant to digestion by gastric enzymes. In the present scenario, the salad dressing was contaminated. The patient's wife had the house Dijon on her salad, but the patient had garlic-infused olive oil. The oil created an anaerobic environment, which allowed C. botulinum spores that were on the garlic to germinate and produce toxin. The oil was not acidified or refrigerated; these procedures could have prevented C. botulinum spore growth and toxin production. # How can botulism be prevented? C. botulinum spores are highly heat-resistant; commercial and home-canning procedures should be done at the appropriate temperature and pressure to kill these spores. A pressure cooker must be used to can vegetables at home safely because it can reach temperatures above boiling (>212°F or >100°C). Information on safe home-canning procedures is available from local county extension home economists. Botulinum toxin is readily inactivated by heat; nevertheless, the FDA recommends that any food suspected to contain botulinum toxin be destroyed. Proper acidification and refrigeration of commercial products such as herb-infused oils will inhibit spore growth and toxin production. Growth of C. botulinum in food may cause container lids to bulge and cause foods to have a bad odor. Commercial or home-canned food products with bulging lids or a bad odor should not be eaten. However, botulism has also been associated with foods that smell and taste normally; therefore, the smell and taste of food should not be used to determine if it is contaminated. The patient's serum and stool contained type A botulinum toxin. An investigation by the state and local health department found four other cases of intoxication associated with the garlic-infused oil at the restaurant. Two of the patients had been hospitalized with a diagnosis of stroke, one had been hospitalized with a diagnosis of myasthenia gravis, and one had been hospitalized with an unknown diagnosis. The patient in this scenario required assisted ventilation, but his respiratory muscle function improved after he received antitoxin. He fully recovered within 3 weeks of the onset of his symptoms. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # ESCHERICHIA COLI O157:H7 INFECTION: A PATIENT SCENARIO Pierre is a 3-year-old who was brought to the outpatient clinic by his mother. He had a 2-day history of severe abdominal cramps and diarrhea (5 to 7 watery stools daily). He has had no fever or vomiting. His mother was especially alarmed this morning when she noticed blood in his diarrheal stools. He refuses to eat, but has been drinking a few ounces of liquids every 2 to 3 hours. She has been unable to assess his urine output because of his diarrhea. Pierre previously has been healthy, and has had no significant weight loss or other symptoms. On physical examination, he is afebrile with normal blood pressure, respirations and capillary refill. His oral mucosa and skin are dry, but his skin turgor is normal. His abdomen has hyperactive bowel sounds, mild distension, and diffuse tenderness, but is soft with no rebound or guarding. He has loose stool in the rectal vault, which is grossly bloody. # What is the possible differential diagnosis for his chief complaint? - Inflammatory bowel disease - Polyps - Meckel's diverticulum - Intussusception - Coagulopathy - Infectious enteritis # What additional information would assist with the diagnosis? - Has he had similar symptoms before? - Is there a family history of inflammatory bowel disease? - Is there a family history of bleeding disorders? - Do other household members or close acquaintances have diarrhea or bloody diarrhea? - Does he attend child care? If "yes," have there been reports of diarrhea or bloody diarrhea in other children attending the child care facility? There is no family history of inflammatory bowel disease or bleeding disorders. Pierre's mother reports that he usually has 1 to 2 episodes of self-limited diarrhea each year, but has never had bloody diarrhea. No other household members have had diarrhea or bloody diarrhea; however, his grandmother and 15-year-old sister have had mild abdominal cramps. He does not attend child care; his mother has not heard that any of his playmates have been ill. # MMWR January 26, 2001 How does this information assist with the diagnosis? Inflammatory bowel disease is an unlikely diagnosis because of his young age, the acute onset of diarrhea, and the absence of a history of recurrent diarrhea and other symptoms such as weight loss, fever, and arthritis. Even if inflammatory bowel disease is suspected, it would be appropriate to rule out an infectious etiology before proceeding with further work-up. Polyps and Meckel's diverticulum usually cause painless hematochezia. They can be complicated by intussusception, which is characterized by a tense abdomen and absent bowel sounds. If intussusception is suspected, evaluation with abdominal radiography and therapeutic enema may be performed. There is no family history of coagulopathic disorders and Pierre has not had a history of abnormal hemostasis. The symptoms of abdominal pain in other household members suggest an infectious etiology. # The most likely diagnosis is infectious enteritis. What additional historical information could assist with the identification of the etiologic agent? - What foods has he consumed within the last week? Specifically, has he consumed undercooked ground beef, unpasteurized juices, or alfalfa sprouts? - Has he traveled to a foreign country within the last month? - Does he have any pets, specifically reptiles such as an iguana or turtle? - What is the family's source of drinking water? - Have there been any outbreaks of diarrhea in the community, at church, or at his sibling's school? - Has he recently visited a petting zoo? The most worrisome diagnosis in a child with bloody diarrhea is infection with Shiga toxin-producing E. coli, the most common being E. coli O157:H7. E. coli O157:H7 is associated with serious complications including the hemolytic uremic syndrome (HUS). Campylobacter, Salmonella, and Shigella infections also may cause bloody stools. The incubation periods for these four bacterial infections are 1 to 8 days, 2 to 5 days, 1 to 3 days, and 1 to 2 days, respectively. Therefore, any contaminated food that he consumed within the prior week could have contributed to his illness. Pierre's favorite and most frequently consumed foods are hot dogs and spaghetti. He usually has cereal for breakfast, although he occasionally eats an egg, which he prefers sunny-side-up. He has hot dogs or spaghetti with cheese or fruit for lunch, and has dinner with other family members. During the last week, his mother recalls that dinner has included baked chicken, meatloaf, hamburgers, and pizza from the local pizzeria. She reports the meatloaf was well cooked to 165°C; she checked the internal temperature with a meat thermometer before serving. The burger appeared to be well cooked; it was brown in the middle. The family doesn't eat alfalfa sprouts. The family vacationed at a United States resort but has not traveled to a foreign country for 2 years. They have a menagerie of pets including a dog, a cat, two hamsters, a parrot, a Sicilian worm, and a new iguana. Pierre has not visited a petting zoo nor had contact with other animals. They live on a vegetable farm; they have no cows, pigs, or sheep. Their main source of water is from a well, but they use bottled water for drinking. They know of no other outbreaks of diarrhea or bloody diarrhea in the community, church, or school. The local health department has not had other reports of bloody diarrhea or E. coli O157:H7 infection from the community. Just as you are about to leave the room, the mother recalls that the nanny, who is a vegetarian and loves to introduce Pierre to various "veggie delights," related a story last week about how she prepared for Pierre a veggie sandwich with cucumber, cream cheese, and alfalfa sprouts. The nanny said he ate only one bite of the sandwich and refused the rest, begging for spaghetti instead. # Are diagnostic tests needed? Identification of the cause of Pierre's diarrhea is important because it will influence antimicrobial therapy, follow-up, and prognosis, and may obviate the need for invasive diagnostic procedures such as laparotomy or colonoscopy. The child's dietary, environmental, and travel history suggest he is at high risk for three of the infectious agents discussed above (i.e., Salmonella, Campylobacter, and E. coli O157:H7). For example, E. coli O157:H7 infection has been associated with undercooked ground beef. Although the hamburger he consumed appeared to be well-cooked (brown in the middle), recent studies have shown that a significant proportion of ground beef patties are brown in the middle before they have reached an internal temperature high enough to kill E. coli O157:H7 (160°F). Recently, E. coli O157:H7 outbreaks have also been associated with fresh produce such as unpasteurized apple juice, cabbage, and alfalfa sprouts. The infectious dose of E. coli O157:H7 is low; ground beef patties with less than 700 organisms per uncooked patty have been associated with illness. Pierre also could have Campylobacter infection. Transmission of Campylobacter infection has been associated with the preparation or consumption of raw or undercooked chicken, and consumption of contaminated water and unpasteurized milk. Campylobacter can cross-contaminate fruits and vegetables when they contact surfaces that may have touched raw chicken such as knives and cutting boards. Campylobacter also has a low infectious dose. Finally, Pierre is at risk for Salmonella infection. Children living in households with reptiles, such as iguanas, are at increased risk. Since 1985, Salmonella serotype Enteritidis has emerged as a pathogen in raw shell eggs. Chickens may become bacteremic with Salmonella Enteritidis, which seeds the eggs transovarially. Therefore, an egg that is clean and has a normal appearance may be contaminated. Many outbreaks of Salmonella infection have been associated with foods that contain raw or undercooked eggs. Salmonella infections also have been associated with undercooked meat and poultry and fresh fruits and vegetables. Shigella is a less likely cause of his illness; it usually causes outbreaks in child care settings where person-to-person transmission is common. However, food products such as raw produce can be contaminated with Shigella and lead to illness. # What diagnostic tests are needed? Routine stool cultures will detect common enteric bacterial enteropathogens such as Campylobacter and Salmonella. However, many clinical laboratories do not screen stools routinely for E. coli O157:H7; it is incumbent upon the clinician to request such testing when E. coli O157:H7 infection is suspected, especially for patients with bloody diarrhea. Bloody diarrhea is very common in patients with E. coli O157:H7 infection, although the absence of bloody diarrhea does not rule out the diagnosis. Culturing for E. coli O157:H7 is relatively simple and inexpensive; this bacteria does not ferment sorbitol and, therefore, appears as a colorless colony on sorbitol-MacConkey (SMAC) agar. Colorless colonies on SMAC agar are selected and assayed for O157 antigen using a commercial kit. All strains of E. coli that agglutinate with the O157 antibody are presumed to be E. coli O157:H7 and should be reported to the local public health authorities. Confirmation of the H flagellar antigen is usually done by a reference laboratory. Recently, rapid diagnostic kits that test for the presence of Shiga toxin have become available for use in clinical laboratories. Specimens that test positive should be forwarded to the public health laboratory for further evaluation. The lab calls you with the results of the stool culture. Pierre's stool grew E. coli O157:H7. # What treatment is needed? The treatment of E. coli O157:H7 infection is largely supportive. Dehydration should be treated with liberal oral or intravenous rehydration to reduce the stress of volume depletion on the kidneys. This is often best accomplished in the hospital with intravenous fluids and close monitoring. The use of antimicrobial therapy is controversial. Data suggest that antimicrobial agents may be harmful. Antimicrobial agents may kill or disrupt intracolonic E. coli O157:H7 organisms, allowing them to release toxin that is absorbed systemically, and may increase the risk of hemolytic uremic syndrome (HUS). Antimicrobials also have not been shown to decrease illness severity. Antidiarrheal medications, especially those that slow intestinal motility, should be avoided. They may delay clearance of the organism, increase the time for toxin absorption, and increase the risk and severity of HUS. # What are the complications of E. coli O157:H7 infection? What follow-up is needed? Within one week after the onset of diarrhea, 10% of children <10 years of age with E. coli O157:H7 infection develop HUS, which is characterized by hemolytic anemia, thrombocytopenia, oliguria-anuria, and rarely seizures. Children with visible blood in their stools are at increased risk of developing HUS. If HUS has not developed within 2 to 3 days after the diarrhea has resolved, this complication is unlikely to occur. Pierre's parents should be instructed to watch for signs and symptoms of HUS, and he should be evaluated by a clinician if he develops these. Regardless of other symptoms, if his diarrhea continues longer than 4 to 5 days, a complete blood count, platelet count, and blood smear analysis should be considered. Adults with E. coli O157:H7 infection may develop HUS or thrombotic thrombocytopenic purpura (TTP), a microangiopathic disorder that resembles HUS but is accompanied by neurologic abnormalities. The mortality rate with E. coli O157:H7-associated HUS is approximately 3% to 5% in children, but may be higher in elderly patients who develop TTP. # Should this case be reported to the local health department? All cases of E. coli O157:H7 infection, post-diarrheal HUS, and post-diarrheal TTP should be reported to the local public health department. The ease with which person-to-person transmission occurs, especially from children who are not toilet-trained, makes diagnosis and reporting very important. The health department can use this information to identify clusters of infection, discover common sources of exposure, and take measures to remove the source of the infection (i.e., remove the contaminated food) and prevent transmission of the organism to others. In addition to reporting cases of E. coli O157:H7 infection, it also is helpful to send E. coli O157:H7 isolates to the local health department. Isolates can be subtyped by pulsed-field gel electrophoresis (PFGE) to determine if other reported cases of E. coli O157:H7 infection are related. Many state public health laboratories now have the capacity to do molecular subtyping. In 1995, the Centers for Disease Control and Prevention (CDC) initiated PulseNet, a national computer network of public health laboratories that employs standard methods to subtype E. coli O157:H7 strains. As of May 2000, there were 34 public health laboratories from various states participating in PulseNet, as well as laboratories from the US Department of Agriculture Food Safety and Inspection Service (USDA-FSIS), and the Food and Drug Administration (FDA). Laboratories within the network can transmit PFGE patterns electronically to a databank at the CDC where they are automatically compared to patterns of other isolates. If the patterns submitted by laboratories in different locations during a defined time period are found to match, the CDC computer will alert PulseNet participants of a possible multistate outbreak. The information can be used by the CDC, the USDA-FSIS, the FDA, and the state health departments to rapidly initiate outbreak investigations and preventive actions. # How can E. coli O157:H7 infection be prevented? Consumers should avoid eating undercooked ground beef. The most reliable way to determine whether ground beef is cooked to a temperature high enough to destroy E. coli O157:H7 is to use a meat thermometer and cook to an internal temperature of 160°F. Use of meat thermometers when cooking ground beef is especially important for children, older persons, and the immunocompromised who are at highest risk of contracting foodborne diseases, of developing severe foodborne illness, and of dying from foodborne diseases. If a meat thermometer is not available, consumers should not eat ground beef that is pink in the middle. If served an undercooked (pink) hamburger at a restaurant, consumers should send it back and have it cooked longer. Consumers should avoid unpasteurized juices and milk, and should wash all fresh produce thoroughly before consumption. Children under 5 years of age, immunocompromised persons, and the elderly should avoid eating alfalfa sprouts. Infected persons, especially children, should be encouraged to wash their hands carefully and frequently with soap and water to reduce the risk of spreading the infection. Preventive measures to reduce the number of cattle that carry E. coli O157:H7 and to reduce contamination of meat during slaughter and grinding are also underway. Pierre continued to have bloody diarrhea. On the fifth day of illness, a complete blood count showed a hemoglobin of 9g/dL and a platelet count of 79 x 10 9 /L. A peripheral blood smear revealed evidence of hemolysis. Despite hydration and appropriate supportive care, he developed renal insufficiency, which required dialysis. His renal function improved after 4 weeks of dialysis, and he eventually recovered with no other complications. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # ENTEROTOXIGENIC ESCHERICHIA COLI INFECTION: A PATIENT SCENARIO Stephanie is a 35-year-old who presents to your office with a 4-day history of abdominal cramps, headache, and 8-10 episodes/day of watery diarrhea. She has had a few episodes of vomiting but denies fever or bloody diarrhea. She has no complaints of dysuria or back pain. She was previously healthy. Physical examination reveals she is afebrile with a blood pressure of 120/80 mm Hg and normal capillary refill. She has a soft and diffusely tender abdomen with hyperactive bowel sounds but no rebound or guarding. She has no costovertebral angle (CVA) tenderness and stool examination is negative for occult blood. Stephanie reports she rarely has diarrhea, usually less than one episode a year. She denies a family history of malabsorptive or endocrine disorders, and has had none of the other symptoms listed above. She is an art therapist for a local children's mental health clinic, and is not aware that any of her patients have had gastrointestinal tract symptoms or diarrhea. Other household members are well; however, several of her extended family members and friends who attended her younger sibling's high school graduation picnic last weekend also have diarrhea. In fact, her aunt (the hostess of the party) called the local health department because she was concerned that the illnesses might be associated with food that was served at the event from a local restaurant (Restaurant A). Stephanie is uncertain what her aunt learned from the health department. # How does this information assist with the diagnosis? This information suggests that Stephanie's case of diarrhea may be part of a larger outbreak. The most appropriate next step in her management is to contact the local health department and ask if it is aware of an outbreak of foodborne disease, or if it has had reports of diarrheal illness from other patrons or partygoers who consumed food from Restaurant A. The health department also may provide information about the etiologic agent or suspected etiologic agent, and provide recommendations for treatment. You call the health department and learn that there is an outbreak of foodborne illness associated with consumption of food from Restaurant A. Similar to Stephanie, most patients have had abdominal cramps and watery diarrhea, few have had fever, and no one has reported bloody diarrhea. The median incubation period is 42 hours and the diarrhea lasts 3 to 7 days. At this time, neither the vehicle of transmission nor the etiologic agent has been identified. The health department officials request that you obtain a stool culture and report the results back to them. # What are the possible etiologic agents of this outbreak of foodborne illness? Based on its investigation, the health department suspects the vehicle for this outbreak was a food item consumed at Restaurant A, 42 hours before the illness. If this is so, the most likely etiologic agent is a bacterial pathogen as suggested by the moderate incubation period, the lack of vomiting, and the significant duration of illness. Foodborne illness caused by the most common enteric viral pathogens typically has a shorter incubation period, more vomiting, less diarrhea, and a shorter duration of symptoms. By contrast, parasitic infections usually have a longer incubation period (1 to 2 weeks) and a longer duration of illness (>2 to 3 weeks). The bacterial enteric pathogens that should be considered as possible sources of the outbreak are Campylobacter and Salmonella, the two most common causes of bacterial foodborne diseases in the United States. Typically these infections are characterized by fever in addition to abdominal cramps and diarrhea, and bloody stools are possible but not common. E. coli O157:H7 infection should also be considered, although bloody stools frequently are reported with this infection. Vibrios and enterotoxigenic E. coli rarely are diagnosed causes of foodborne illness in the United States but should remain in the differential diagnosis given the profuse watery diarrhea that characterizes this outbreak. A stool culture for bacterial enteropathogens including Salmonella, Shigella, Campylobacter, Yersinia, and E. coli O157:H7 is negative. You report this information to the health department and learn that the routine stool cultures from other patients in the outbreak are also negative. The state public health laboratory examined stools for common viral enteric pathogens; those preliminary studies are negative. # What other pathogen(s) should be considered? How are they identified? The most likely etiologic agent of this outbreak is enterotoxigenic E. coli (ETEC). ETEC is a common cause of traveler's diarrhea and is an increasingly recognized cause of foodborne illness in the United States. This bacterium elaborates one or more enterotoxins that cause intestinal secretion and diarrhea. The incubation period, symptoms, and duration of diarrhea described for persons involved in this outbreak are characteristic of # What should the patient know about ETEC infections? What is the next step in management? ETEC is the most common cause of "traveler's diarrhea" and is becoming a more frequently recognized cause of foodborne illness in the United States. The illness is self-limited; the diarrhea usually lasts fewer than 5 days. Because the duration of illness is short, ETEC infections generally do not require antibiotic therapy. Treatment is mainly supportive including oral or intravenous fluids for rehydration. Occasionally antibiotics, such as ciprofloxacin for adults and trimethoprim/ sulfamethoxazole for children, are given if the patient has an underlying illness or if the diarrhea is severe. ETEC infection may cause dehydration but there are generally no serious complications or long-term sequelae from this infection. Patients should be reminded to wash their hands with warm running water and soap after using the bathroom and before and after eating to avoid transmitting the infection to others. They should tell friends who might have attended other parties at which food from Restaurant A was served to call the local health department to report cases of illness. # How can ETEC infections be prevented? Human and animal wastes are the ultimate source of ETEC contamination. Travelers in developing countries should avoid foods that could be contaminated with bacteria. They should eat thoroughly cooked foods prepared in facilities that practice proper food handling techniques. They should avoid unpasteurized juices and milk, and drink bottled beverages, or water that has been boiled or adequately chlorinated. They should avoid raw foods (e.g. salads, peeled fruit or vegetables, raw seafood, undercooked meat or poultry) and foods from street vendors. In the United States, proper food preparation and handling practices will reduce the risk of ETEC infections. This should include careful handwashing with warm water and soap after using the bathroom and before and after preparing or consuming food. Stephanie's watery diarrhea resolved after 5 days. She was mildly dehydrated and missed 3 days of work, but recovered completely with no long-term complications. # What additional information would assist with the diagnosis? - What season of the year is it? - Do other household members have similar symptoms? - What is her occupation? - Has she been around ill children or adolescents? - Has she been camping, hiking, or exposed to ticks? - When did she travel to Kenya; where did she visit? - Did she take malaria prophylaxis, and what medication? - Has she been sexually active with more than one partner during the last 6 months? - Is she on any medications currently? - Has she had any animal exposures? It is early autumn and no other household members are ill. She is a legal secretary; none of the clients with whom she has worked have been ill, and she has not been around ill children or adolescents. Her 2-year-old son attends day care; he has been well and there have been no reports of ill children from the center director. She traveled to Nairobi, Kenya, at 15 weeks' gestation, and was well throughout the trip. She took mefloquine for malaria prophylaxis once weekly, and did not forget any doses. She has not been camping or hiking, and is unaware of tick exposure. She recalls only one day of mild illness during her pregnancy, which occurred about 5 weeks earlier and was characterized by 2 or 3 episodes of vomiting and a few loose stools. She attributed the symptoms to a change in diet; she increased milk and fruit consumption in an attempt to be "healthy for the baby." She and her husband have been happily married for 5 years; she denies having any other sexual partners. She is currently taking no medications, and she has had no animal exposures except for her pet dog. # How does this information assist with the diagnosis? Influenza is an unlikely diagnosis; it is early autumn and Sandy has not been exposed to other ill persons at home or work. Her sexual history indicates her risk for HIV, herpes, and gonorrhea infection is low. Her recreational history suggests tickborne disease is improbable. Malaria is a possible diagnosis but she has had no fever in the 12 weeks since she returned from Nairobi, a city over 5,000 feet above sea level where the risk of contracting malaria is low. Mycoplasma, adenovirus, coxsackie virus, group A Streptococcus, CMV, EBV, parvovirus, and other viral agents could account for her symptoms. She could also be bacteremic, but has no symptoms to indicate she is septic. # What diagnostic tests are needed? Consider rapid antigen screen for group A Streptococcus Consider rapid test for infectious mononucleosis Consider urinalysis and thick and thin blood smear The rapid tests for group A Streptococcus and infectious mononucleosis are negative. Urinalysis is negative for bacteria and thick and thin blood smear shows no evidence of malaria parasites. One hour after an appropriate dose of acetaminophen, her temperature is 101°F, and she continues to have flu-like symptoms. Her blood pressure, capillary refill, and the rest of her physical examination are normal. She returns home with instructions to call you if she develops new symptoms, her symptoms worsen, or her symptoms do not abate in the next 24 hours. Four weeks later, you receive another call from Sandy. She reports her water just broke. She has otherwise been well; the flu-like symptoms she had at her last visit resolved within 48 hours. You meet her in the labor and delivery suite, and confirm by physical examination that her membranes are prematurely ruptured. Despite tocolytic therapy, her labor progresses and she delivers an infant girl at 32 weeks' gestation. After delivery, Sandy has a normal post-partum course. The infant is admitted to the neonatal intensive care unit and requires supplemental oxygen for the first few hours of life, but soon after is weaned off oxygen and tolerates her first feeding without difficulty. At 22 hours of age, the infant's nurse notes she is tachypneic with intercostal retractions. The infant's blood pressure is in the low range of normal. The nurse is repeating the blood pressure measurement when the infant becomes bradycardic with delayed capillary refill. Despite full resuscitation efforts including intubation and inotropic support, the infant dies. The next morning you receive a report from the microbiology laboratory that blood cultures drawn just before the infant's death are growing gram-positive short rods/cocci. # What were the most likely causes of the infant's sepsis? - Group B Streptococcus - Staphylococcus aureus - Coagulase-negative Staphylococcus - Enterococcus - a-hemolytic Streptococcus - Listeria monocytogenes Group B Streptococcus and Escherichia coli (a gram-negative rod) are responsible for up to 75% of cases of early-onset neonatal sepsis. Listeria monocytogenes, a less common cause of early-onset neonatal sepsis, also causes an illness that clinically parallels that of group B Streptococcus; infants are infected in utero and develop illness at birth or shortly thereafter. The following morning, the microbiology laboratory calls to report it has identified the gram-positive short rods/cocci in the blood as Listeria monocytogenes. # What, if anything, could have been done to prevent this infant's death? Listeriosis is an uncommon disease; approximately 1,200 cases of Listeria monocytogenes infection are reported each year in the United States. Up to one third of these infections occur in pregnant women, and can be complicated by maternal bacteremia, fetal loss, or infant bacteremia and meningitis. The symptoms associated with listeriosis during pregnancy are often nonspecific and may imitate those of influenza. These flu-like symptoms coincide with the bacteremic phase of infection. In pregnant women with a febrile illness, appropriate clinical management may include obtaining blood cultures to rule out listeriosis. MMWR 53 Send stool samples to health department (Vibrio cholerae, other Vibrios, E. coli O157:H7, special toxin tests, Clostridium perfringens, Clostridium botulinum ). 6. Not detected by routine stool cultures (E. coli O157:H7, Vibrio cholerae, other Vibrios ). 7. Should test for viral agents. 8. For cysts, ova, and parasite detection, at least 3 stool samples must be collected. Sometimes the organism may still be missed; thus sampling via endoscopy may be necessary. 9. Test for appropriate metal. 10. Special test needed to identify a fish toxin. 11. Consult a mycologist to identify the mushroom. 12. Blood culture is the best source for diagnosis. 13. Blood test helpful to identify the agent. # PROGRAM EVALUATION FORM Please circle your answers and add comments as desired. Please fax this form back to: L J Tan, PhD at 312 464-5841, or see back side for mailing instructions. 1. The primer increased my ability to recognize foodborne illnesses and increased the likelihood that I will consider such illnesses in my patients. Provide any additional comments about this primer, your experiences with foodborne illnesses, and suggestions for future physician education efforts: Please fax the completed survey to: L J Tan, PhD at 312 464-5841 or fold on the dotted lines with the mailing side out, tape, and mail this form back with first class postage. Thank you. # Diagnosis and Management of Foodborne # MMWR January 26, 2001 This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # LISTERIA MONOCYTOGENES INFECTION: A PATIENT SCENARIO Sandy, the pregnant mother of a 2-year-old boy presents to your office at 28 weeks' gestation complaining of fever, chills, headache, myalgias, and sore throat. She has previously been healthy and has had an uncomplicated pregnancy. She is somewhat concerned about the illness because she just returned from Kenya a few weeks earlier. Physical examination reveals a temperature of 102°F, pulse of 100 beats per minute, respirations of 20 breaths per minute, and a blood pressure of 100/60 mm Hg. Her posterior pharynx is nonerythematous with no tonsillar enlargement or exudates. She has no remarkable cervical lymphadenopathy. Breath sounds are clear and equal bilaterally, and her abdomen is remarkable only for her gravid uterus. She has normal capillary refill and no petechiae or rashes. What should be included in the differential diagnosis? Fetal infection most likely results from transplacental transmission of maternal bacteremia. Neonatal infection can be prevented if maternal Listeria monocytogenes is treated with the appropriate antibiotics during pregnancy. Listeria has been epidemiologically linked to such foods as fresh soft cheeses, ready-to-eat deli meats, hot dogs, and unpasteurized and inadequately pasteurized milk. Its ability to grow at temperatures as low as 3°C permits multiplication in refrigerated foods. Any one of these could have been the vector for this case. All pregnant women should receive dietary counseling to avoid foods that increase the risk of Listeria monocytogenes infection. They should be advised to avoid unpasteurized milk and cheeses made from unpasteurized milk (particularly fresh soft cheeses) during pregnancy. All pregnant women should cook (until steaming hot) leftover foods or ready-to-eat foods such as hot dogs, before eating, and wash their hands carefully to avoid cross-contamination if preparing these foods for others. Other groups at high risk for listeriosis are elderly and immunocompromised patients. They frequently present with sepsis or meningitis. People in these high-risk groups should also receive dietary counseling to avoid high-risk foods. # PATIENT VIGNETTES -WHAT'S YOUR CALL? The following clinical vignettes are provided for your self-evaluation. All are possible situations that may present at your practice. The Clinical Considerations booklet and the Foodborne Illnesses Tables that are also part of this primer will provide the information necessary for you to adequately address these clinical situations. Note that these vignettes include both infectious and noninfectious forms of foodborne illness. For the following clinical vignettes, choose the best answer from the choices listed at the end of the vignettes: A -likely diagnosis; choose the best possible answer listed on "answer selections" page under A selections. B -most appropriate choice to confirm the diagnosis (there may be more than one correct answer -list all of them). Choose from the possible answers listed on "answer selections" page under the B section. Finally, decide whether the situation warrants reporting to the local or state health department. # Clinical Vignettes # I. You receive a long-distance call from a patient who is an outdoorsman. He is with a group that collected and ate some wild mushrooms less than 2 hours ago. Several members of the group have since developed vomiting, diarrhea, and some mental confusion. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No # II. A newborn child has symptoms of sepsis. Cerebrospinal fluid studies are consistent with meningitis. The mother had a flu-like syndrome prior to delivery. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No III. This patient has just returned today from Latin America following a 2-day business trip where he reports eating several meals of fish that he bought from street venders around his hotel. He feels very ill with profuse, watery diarrhea and vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No IV. An 18-month child is brought to your office with fever, bloody diarrhea, and some vomiting. She has been drinking unpasteurized milk in the last 48 hours. No other family members are ill. A VIII. The parents of a 6-month old infant are concerned because she is listless and weak. The infant is feeding poorly, has poor head control, and is constipated. There is no fever or vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No IX. A businessman who travels frequently is ill with fatigue, jaundice, abdominal pain and diarrhea. About 1 month ago, he returned from an international trip during which he consumed raw oysters. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department Yes No X. Several members of a single family are ill with abdominal cramps and watery diarrhea. They just returned from visiting friends on the East Coast of the United States where they consumed raw oysters 48 hours ago. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No XI. A minister at a local church calls to report that many members began developing watery diarrhea on the morning after the annual ham dinner fundraiser. Some people also reported nausea and abdominal cramps, but no one has fever or bloody stools. A XII. You receive a long-distance call from a patient on a fishing vacation off the coast of Belize. Her family has been eating a variety of local fish and shellfish that they caught. She reports that several family members developed abdominal pain, severe diarrhea, and weakness the morning after they consumed the seafood for dinner. One family member began having difficulty speaking later on that same night. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No XIII. A family in a rural community is worried that their father may be having a stroke. He is complaining of double vision and is having trouble swallowing. They have a large garden and eat home-canned vegetables. A Clinical diagnosis; laboratory tests may not always be indicated. Generally detected on routine stool cultures. Generally, a reference laboratory is needed to identify the toxin from food, stool, or vomitus. 4. Important to identify causative organism for public health reasons. # Diagnosis and Management of Foodborne # AVOID FOODBORNE ILLNESS: FIGHT BAC! ™ The US food supply is among the safest in the world, but organisms that you can't see, smell, or taste -bacteria, viruses and tiny parasites -are everywhere in the environment. These microorganisms -called pathogens -can invade food and cause illness, sometimes severe and even life-threatening illness, especially in young children, older adults, and persons with weakened immune systems. In pregnant women, foodborne illness can endanger their unborn babies. The most common symptoms of foodborne illness are diarrhea, abdominal cramps, vomiting, head-or muscle-aches, and fever. Symptoms usually appear 12 to 72 hours after eating contaminated food but may occur between 30 minutes and 4 weeks later. Most people recover within 4 to 7 days without needing antibiotic treatment. If symptoms are severe or the ill person is very young, very old, pregnant, or already ill, call your doctor immediately. # Who Is At Risk If you are among those at high risk, you need to be aware of and follow the most current information on food safety. Young children, pregnant women, older adults, and persons with weakened immune systems are at a higher risk for foodborne illness. Immune systems may be weakened by medical treatments, such as steroids or chemotherapy, or by conditions, such as AIDS, cancer, or diabetes. You are also at increased risk if you suffer from liver disease or alcoholism or if you have decreased stomach acidity (due to gastric surgery or the regular use of antacids). # If You Are At Risk If you face a higher risk of foodborne illness, you are advised not to eat: - Unpasteurized fruit or vegetable juices (These juices will carry a warning label) It is also important to reheat some foods that are bought pre-cooked, because they can become contaminated with pathogens after they have been processed and packaged. These foods include: hot dogs, luncheon meats (cold cuts), fermented and dry sausage, and other deli-style meat and poultry products. New information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated as scientists learn more about preventing foodborne illness. Bacteria, viruses, and parasites can be spread throughout the kitchen and get onto cutting boards, utensils, and countertops. Here's how to Fight BAC! ™ : - Wash your hands with hot, soapy water before and after handling food and after using the bathroom, changing diapers, and handling pets. - Wash your cutting boards, dishes, utensils, and countertops with hot, soapy water after preparing each food item and before you go on to the next food. - Important: Rinse raw produce in water. Don't use soap or detergents. If necessary, use a small vegetable brush to remove surface dirt. # Separate: Don't cross-contaminate. Cross-contamination is the word for how bacteria, viruses, and parasites can be spread from one food product to another. This is especially true when handling raw meat, poultry, seafood, and eggs, so keep these foods and their juices away from ready-to-eat foods. Here's how to Fight BAC! ™ : - Separate raw meat, poultry, and seafood from other foods in your grocery shopping cart and in your refrigerator. - If possible, use a different cutting board for raw meat, poultry and seafood products. - Always wash hands, cutting boards, dishes, and utensils with hot, soapy water after they come in contact with raw meat, poultry, seafood, and eggs. - Use separate plates for cooked food and raw foods. # Cook: Cook to proper temperatures. Food safety experts agree that foods are properly cooked when they are heated for a long enough time and at a high enough temperature to kill the harmful pathogens that cause foodborne illness. The best way to Fight BAC! ™ is to: - Use a clean thermometer that measures the internal temperature of cooked food to make sure meat, poultry, and casseroles are cooked to the temperatures in the chart at right. - Cook eggs until the yolk and white are firm. If you use recipes in which eggs remain raw or only partially cooked, use pasteurized eggs. - Fish should be opaque and flake easily with a fork. - When cooking in a microwave oven, make sure there are no cold spots where pathogens can survive. For best results, cover food, stir, and rotate for even cooking. If there is no turntable, rotate the dish by hand once or twice during cooking. - Bring sauces, soups, and gravy to a boil when reheating. Heat other leftovers thoroughly to at least 165°F. Refrigerate foods quickly because cold temperatures keep harmful pathogens from growing and multiplying. So, set your refrigerator no higher than 40°F and the freezer at 0°F. Check these temperatures occasionally with an appliance thermometer. Then, Fight BAC! ™ by following these steps: - Refrigerate or freeze perishables, prepared foods, and leftovers within two hours or sooner. - Never defrost food at room temperature. Thaw food in the refrigerator, under cold running water, or in the microwave. # GOALS and OBJECTIVES This MMWR provides guidelines for the diagnosis, treatment, and reporting of foodborne illnesses. The goals of this MMWR are to provide physicians and health-care providers with the most current, scientific guidelines for the diagnosis, treatment, and reporting of foodborne illnesses; and with patient education materials that can be used to educate patients, including those who are at high risk for foodborne illness. Upon completion of this educational activity, the reader should be able to a) identify six etiologic agents to consider for manifestations of foodborne illness; b) identify four criteria for prescribing antibacterial therapy for foodborne illness; c) identity how to access the most current reporting requirements for foodborne illness; and d) identify three groups of people who are most at risk for foodborne illness. To receive continuing education credit, please answer all of the following questions: Vol.	Foodborne illness is a serious public health problem. The Centers for Disease Control and Prevention (CDC) estimates that each year 76 million people get sick, more than 300,000 are hospitalized, and 5,000 Americans die as a result of foodborne illnesses, primarily the very young, elderly, and the immunocompromised. Recent changes in human demographics and food preferences, changes in food production and distribution systems, microbial adaptation, and lack of support for public health resources and infrastructure have led to the emergence of novel as well as traditional foodborne diseases. With increasing travel and trade opportunities, it is not surprising that the risk of contracting and spreading a foodborne illness now exists locally, regionally, and even globally. Physicians have a critical role in the prevention and control of food-related disease outbreaks. This primer is intended to help physicians in this role by providing them with practical and concise information on the diagnosis, treatment, and reporting of foodborne illnesses. It was developed collaboratively by the American Medical Association, the Centers for Disease Control and Prevention, the Food and Drug Administration's Center for Food Safety and Applied Nutrition, and the US Department of Agriculture's Food Safety and Inspection Service as part of President Clinton's National Food Safety Initiative. We encourage you to review this information and participate in the attached continuing medical education (CME) program. Even if you choose not to participate in the CME component, please take time to complete and return the "Program Evaluation Form." Your feedback is valuable for updating this primer and for planning future physician education programs.# This primer is directed to primary care physicians, who are more likely to see the index case of a potential food-related disease outbreak. It is a teaching tool to update primary care physicians about foodborne illness and remind them of their important role in recognizing suspicious symptoms, disease clusters, and etiologic agents, and reporting cases of foodborne illness to public health authorities. Specifically, this guide urges physicians to: • Recognize the potential for a foodborne etiology in a patient's illness; • Realize that many but not all cases of foodborne illness have gastrointestinal tract symptoms; • Obtain stool cultures in appropriate settings, and recognize that testing for some specific pathogens, e.g. E. coli O157:H7, Vibrio spp., must be requested; • Report suspect cases to appropriate public health officials; • Talk with patients about ways to prevent food-related diseases; and • Appreciate that any patient with foodborne illness may represent the sentinel case of a more widespread outbreak. Foodborne illness is considered to be any illness that is related to food ingestion; gastrointestinal tract symptoms are the most common clinical manifestations of foodborne illnesses. This document provides detailed summary tables and charts, references, and resources for healthcare professionals. Patient scenarios and clinical vignettes are included for self-evaluation and to reinforce information presented in this primer. Also included is a CME component worth 3 credit hours. This primer is not a clinical guideline or definitive resource for the diagnosis and treatment of foodborne illness. Safe food handling practices and technologies (e.g. irradiation, food processing and storage) also are not addressed. More detailed information on these topics is available in the references and resources listed in this document, as well as from medical specialists and medical specialty societies, state and local public health authorities, and federal government agencies. For additional copies, please contact: L J Tan, PhD American Medical Association 515 North State Street Chicago, Illinois 60610 312 464-4147 312 464-5841 (fax) [email protected] (E-mail) # CLINICAL CONSIDERATIONS Food-related disease threats are numerous and varied, involving biological and nonbiological agents. Foodborne illnesses can be caused by microorganisms and their toxins, marine organisms and their toxins, fungi and their related toxins, and chemical contaminants. During the last 20 years, some foods that have been linked to outbreaks include: milk (Campylobacter ); shellfish (Norwalk-like viruses); unpasteurized apple cider (Escherichia coli O157:H7), eggs (Salmonella ); fish (ciguatera poisoning); raspberries (Cyclospora ); strawberries (hepatitis A virus); and ready-to-eat meats (Listeria ). While physicians have a critical role in surveillance for and prevention of potential disease outbreaks, only a fraction of the people who experience gastrointestinal tract symptoms from foodborne illness seek medical care. In those who do seek care and submit specimens, bacteria are more likely than other pathogens to be identified as causative agents. Bacterial agents most often identified in patients with foodborne illness in the United States are Campylobacter, Salmonella, and Shigella species, with substantial variation occurring by geographic area and season. Testing for viral etiologies of diarrheal disease is rarely done, but viruses are considered the most common cause of foodborne illness. This section and the Foodborne Illnesses Tables summarize diagnostic features and laboratory testing for bacterial, viral, parasitic, and noninfectious causes of foodborne illness. For more specific guidance, consult an appropriate medical specialist or medical specialty society, as well as various resources listed in other sections of this document. Also refer to this section and the Foodborne Illnesses Tables when working through the Patient Scenarios and Clinical Vignettes of this primer. # RECOGNIZING FOODBORNE ILLNESSES Patients with foodborne illnesses typically present with gastrointestinal tract symptoms (e.g. vomiting, diarrhea, and abdominal pain); however, nonspecific symptoms and neurologic symptoms may also occur. Every outbreak begins with an index case who may not be severely ill. A physician who encounters this person may be the only one with the opportunity to make an early and expeditious diagnosis. Thus, the physician must have a high index of suspicion and ask appropriate questions to recognize that an illness may have a foodborne etiology. Important clues to determining the etiology of a foodborne disease are the: • Incubation period; • Duration of the resultant illness; • Predominant clinical symptoms; and • Population involved in the outbreak. Additional clues may be derived by asking whether the patient has consumed raw or poorly cooked foods (e.g. raw or undercooked eggs, meats, shellfish, fish), unpasteurized milk or juices, home canned goods, fresh produce, or soft cheeses made from unpasteurized milk. Inquire whether any of the patient's family members or close friends has similar symptoms. Inquiries about living on or visiting a farm, pet contact, day care attendance, occupation, foreign travel, travel to coastal areas, camping excursions to mountains or other areas where untreated water is consumed, and attendance at group picnics or similar outings also may provide clues for determining the etiology of the illness. If a foodborne illness is suspected, submit appropriate specimens for laboratory testing and contact the state or local health department for advice about epidemiologic investigation. For the physician, implication of a specific source in disease transmission is difficult from a single patient encounter. Attempts to identify the source of the outbreak are best left to public health authorities. Because infectious diarrhea can be contagious and is easily spread, rapid and definitive identification of an etiologic agent may help control a disease outbreak. An individual physician who obtains testing can contribute the necessary piece of data that ultimately leads to identification of the source of an outbreak. # DIAGNOSING FOODBORNE ILLNESSES Differential Diagnosis As shown in Table 1 and the Foodborne Illnesses Tables a variety of infectious and noninfectious agents must be considered in patients suspected of having a foodborne illness. Establishing a diagnosis can be difficult, however, particularly in patients with persistent or chronic diarrhea, those with severe abdominal pain, and when there is an underlying disease process. The extent of diagnostic evaluation depends on the clinical picture, the differential diagnosis considered, and clinical judgment. If any of the following signs and symptoms occur, alone or in combination, laboratory testing may provide important diagnostic clues (particular attention should be given to very young and elderly patients and to immunocompromised patients, all of whom are more vulnerable): • Bloody diarrhea • Weight loss • Diarrhea leading to dehydration • Fever • Prolonged diarrhea (3 or more unformed stools per day, persisting several days) • Neurologic involvement such as paresthesias, motor weakness, cranial nerve palsies • Sudden onset of nausea, vomiting, diarrhea • Severe abdominal pain In addition to foodborne causes, a differential diagnosis of gastrointestinal tract disease should include underlying medical conditions such as irritable bowel syndrome; inflammatory bowel diseases such as Crohn's disease or ulcerative colitis; malignancy; medication use (including antibiotic-related Clostridium difficile toxin colitis); gastrointestinal tract surgery or radiation; malabsorption syndromes; immune deficiencies; Brainerd diarrhea; and numerous other structural, functional, and metabolic etiologies. Consideration also should be given to exogenous factors such as the association of the illness with travel, occupation, emotional stress, sexual practices, exposure to other ill persons, recent hospitalization, child care center attendance, and nursing home residence. The differential diagnosis of patients presenting with neurological symptoms due to a foodborne illness is also complex. Possible food-related causes to consider include recent ingestion of contaminated seafood, mushroom poisoning, and chemical poisoning. Because the ingestion of certain toxins (e.g. botulinum toxin, tetrodotoxin) and chemicals (e.g. organophosphates) can be life-threatening, a differential diagnosis must be made quickly with concern for aggressive therapy and life support measures (e.g. respiratory support, administration of antitoxin or atropine), and possible hospital admission. # Clinical Microbiology Testing When submitting specimens for microbiologic testing, it is important to realize that clinical microbiology laboratories differ in protocols used for the detection of pathogens. To optimize recovery of an etiologic agent, physicians should understand routine specimen collection and testing procedures as well as circumstances and procedures for making special test requests. Some complex tests (e.g. toxin testing, serotyping, molecular techniques) may only be available from large commercial and public health laboratories. Contact your microbiology laboratory for more information. Stool cultures are indicated if the patient is immunocompromised, febrile, has bloody diarrhea, has severe abdominal pain, or if the illness is clinically severe or persistent. Stool cultures are also indicated if many fecal leukocytes are present, which indicates diffuse colonic inflammation and is suggestive of invasive bacterial pathogens such as Shigella, Salmonella, and Campylobacter species, and invasive E. coli. In most laboratories, routine stool cultures are limited to screening for Salmonella and Shigella species, and Campylobacter jejuni/coli. Cultures for Vibrio and Yersinia species, E. coli O157:H7, and Campylobacter species other than jejuni/coli require additional media or incubation conditions and therefore require advance notification or communication with laboratory and infectious disease personnel. Stool examination for parasites generally is indicated for patients with suggestive travel histories, who are immunocompromised, who suffer chronic or persistent diarrhea, or when the diarrheal illness is unresponsive to appropriate antimicrobial therapy. Stool examination for parasites is also indicated for gastrointestinal tract illnesses that appear to have a long incubation period. Requests for ova and parasite examination of a stool specimen will often enable identification of Giardia lamblia and Entamoeba histolytica, but a special request may be needed for detection of Cryptosporidium parvum and Cyclospora cayetanensis. Each laboratory may vary in its routine procedures for detecting parasites so it is important to contact your laboratory. Blood cultures should be obtained when bacteremia or systemic infection are suspected. Direct antigen detection tests and molecular biology techniques are available for rapid identification of certain bacterial, viral, and parasitic agents in clinical specimens. In some circumstances, microbiologic and chemical laboratory testing of vomitus or implicated food items also is warranted. For more information on laboratory procedures for * Noninflammatory diarrhea is characterized by mucosal hypersecretion or decreased absorption without mucosal destruction and generally involves the small intestine. Some affected patients may be dehydrated because of severe watery diarrhea and may appear seriously ill. This is more common in the young and the elderly. Most patients experience minimal dehydration and appear mildly ill with scant physical findings. Illness typically occurs with abrupt onset and brief duration. Fever and systemic symptoms usually are absent (except for symptoms related directly to intestinal fluid loss). † Inflammatory diarrhea is characterized by mucosal invasion with resulting inflammation and is caused by invasive or cytotoxigenic microbial pathogens. The diarrheal illness usually involves the large intestine and may be associated with fever, abdominal pain and tenderness, headache, nausea, vomiting, malaise, and myalgia. Stools may be bloody and may contain many fecal leukocytes. # TREATING FOODBORNE ILLNESSES Selection of appropriate treatment depends on identification of the responsible pathogen (if possible) and determining if specific therapy is available. Many episodes of acute gastroenteritis are self limiting and require fluid replacement and supportive care. Oral rehydration is indicated for patients who are mildly to moderately dehydrated; intravenous therapy may be required for more severe dehydration. Because many antidiarrheal agents have potentially serious adverse effects in infants and young children, their routine use is not recommended in this age group. Choice of antimicrobial therapy should be based on: • Clinical signs and symptoms; • Organism detected in clinical specimens; • Antimicrobial susceptibility tests; and • Appropriateness of treating with an antibiotic (some enteric bacterial infections are best not treated). Knowledge of the infectious agent and its antimicrobial susceptibility pattern allows the physician to initiate, change, or discontinue antimicrobial therapy. Such information also can support public health surveillance of infectious disease and antimicrobial resistance trends in the community. Antimicrobial resistance has increased for some enteric pathogens, which requires judicious use of this therapy. # SURVEILLANCE AND REPORTING OF FOODBORNE ILLNESSES Reporting of foodborne illnesses in the United States began more than 50 years ago when state health officers, concerned about the high morbidity and mortality caused by typhoid fever and infantile diarrhea, recommended that cases of "enteric fever" be investigated and reported. The intent of investigating and reporting these cases was to obtain information about the role of food, milk, and water in outbreaks of gastrointestinal tract illness as the basis for public health actions. These early reporting efforts led to the enactment of important public health measures (e.g. the Pasteurized Milk Ordinance) that profoundly decreased the incidence of foodborne illnesses. Often health care professionals may suspect foodborne illness either because of the organism involved or because of other available information, such as several ill patients who have eaten the same food. Health care professionals can serve as the eyes and ears for the health department by providing such information to the local or state public health authorities. Foodborne disease reporting is not only important for disease prevention and control, but more accurate assessments of the burden of foodborne illness in the community occur when physicians report foodborne illnesses to the local or state health department. In addition, reporting of cases of foodborne illness by practicing physicians to the local health department may help the health officer identify a foodborne disease outbreak in the community. This may lead to early identification and removal of contaminated products from the commercial market. If a restaurant or other food service establishment is identified as the source of the outbreak, health officers will work to correct inadequate food preparation practices, if necessary. If the home is the likely source of the contamination, health officers can institute public education about proper food handling practices. Occasionally, reporting may lead to the identification of a previously unrecognized agent of foodborne illness. Reporting also may lead to identification and appropriate management of human carriers of known foodborne pathogens, especially those with high-risk occupations for disease transmission such as foodworkers. Table 2 lists current reporting requirements for foodborne diseases and conditions in the United States. National reporting requirements are determined collaboratively by the Council of State and Territorial Epidemiologists and the Centers for Disease Control and Prevention (CDC). Typically, the appropriate procedure for physicians to follow in reporting foodborne illnesses is to contact the local or state health department whenever they identify a specific notifiable disease. However, it is often unclear if a patient has a foodborne illness prior to diagnostic tests, so physicians should also report potential foodborne illnesses, such as when two or more patients present with a similar illness that may have resulted from the ingestion of a common food. Local health departments then report the illnesses to the state health department and determine if further investigation is warranted. Each state health department reports foodborne illnesses to the CDC. The CDC compiles this data nationally and disseminates information to the public through annual summary reports. The CDC assists state and local public health authorities with epidemiologic investigations and the design of interventions to prevent and control food-related outbreaks. The CDC also coordinates a national network of public health laboratories, called PulseNet, which perform "molecular fingerprinting" of bacteria (by pulsed-field gel electrophoresis) to support epidemiolgic investigations. Thus, in addition to reporting cases of potential foodborne illnesses, it is important for physicians to report noticeable increases in unusual illnesses, symptom complexes, or disease patterns (even without definitive diagnosis) to public health authorities. Prompt reporting of unusual patterns of diarrheal/gastrointestinal tract illness, for example, can allow public health officials to initiate an epidemiologic investigation earlier than would be possible if the report awaited definitive etiologic diagnosis. Finally, new information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated whenever new data about preventing foodborne illnesses become available. Physicians and other health care professionals need to be aware of and follow the most current information on food safety. # Foodborne Diseases and Conditions Designated as Notifiable at the National Level -United States 2000 In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Infants infected from mother at risk for sepsis or meningitis. 5-10 days. # 3->7 days Variable Undercooked beef, unpasteurized milk and juice, raw fruits and vegetables (e.g. sprouts), salami, salad dressing, and contaminated water. Water or food contaminated with human feces. Fresh soft cheeses, unpasteurized milk, inadequately pasteurized milk, ready-to-eat deli meats, hot dogs. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: http://www2.cdc.gov/ mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. # Foodborne Diseases and Conditions Designated as Notifiable at the National Level -United States 2000 In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Supportive care, usually mild, self-limiting. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: http://www2.cdc.gov/ mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. In the United States, requirements for reporting diseases and conditions are mandated by state and territorial laws and/or regulations. However, physicians are highly encouraged to report foodborne illness that they may encounter in the event that an outbreak situation may be present. Reporting will facilitate the tracking of the outbreak and in fact, the case identified may even be the sentinel case! Differences exist between states and territories as to which diseases and conditions are reportable. Please call the state health department for more information on specific foodborne illnesses. These telephone numbers are available at: http://www2.cdc.gov/ mmwr/international/relres.html. See the reverse side for information hotlines and list of notifiable diseases. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # BOTULISM POISONING: A PATIENT SCENARIO On Sunday morning at 6am, you receive a call from the wife of a 35-year-old man who awoke complaining of dry mouth and blurred vision. His symptoms rapidly progressed over the next 2 hours to include diplopia, dysphagia, and weakness in his arms. You ask to talk with him directly, but he is having difficulty speaking. He was previously healthy. You meet them in the local emergency department. On physical examination, he is afebrile with a heart rate of 80 beats per minute, a blood pressure of 120/80 mm Hg, and a respiratory rate of 12 breaths per minute. His pulse oximetry is 98% oxygen saturation. He has a hoarse voice, bilateral ptosis, a weak gag reflex, and bilateral proximal upper extremity weakness. He has no lower extremity weakness. Sensation is intact in all extremities. His mental status is normal. # What is the possible differential diagnosis for his chief complaint? • The patient denies having a flu-like illness within the last month. Neither he nor his family members have had similar symptoms. There is no family history of stroke or other neurological disorders, and he does not have hypertension or hypercholesterolemia. He has not discovered any ticks on himself or in his environment, and he has not been # MMWR January 26,2001 camping, hiking, or in any tick-infested area within the last week. He has had no occupational or recreational exposures to heavy metals or organophosphates. He denies eating any home-canned foods. He cannot remember everything he ate during the last 72 hours, but recalls eating lunch at a coffee shop near his office. He and his wife hosted a barbeque one evening at which they served grilled chicken, vegetables, and homemade ice cream. The night before onset of his symptoms, they ate at their favorite Italian restaurant where they shared a calamari appetizer, had salad prepared by the waiter at the table, and shared an entree of Fettuccine Fra Diablo. They finished the meal with a cappuccino and tiramisu. # How does this information assist with the diagnosis? Guillain-Barré Syndrome (GBS) is usually preceded by a diarrheal or flu-like illness within 5 days to 3 weeks before onset of symptoms. It characteristically presents with an ascending pattern of muscle weakness; however, the Miller-Fisher variant of GBS may present with a descending pattern of muscle weakness. Myasthenia gravis is characterized by muscle fatigue after exercise, and the symptoms fluctuate over time. Tick-borne paralysis should be ruled out by a thorough examination for a tick; it also usually presents with an ascending pattern of muscle paralysis. Heavy metal poisoning may cause gastrointestinal tract symptoms, alopecia, mental disturbances (irritability, concentration difficulties, and somnolence) and peripheral neuropathy. Organophosphate toxicity causes a cholinergic syndrome. Botulism is a probable diagnosis despite the absence of a history of consumption of home-canned foods; bilateral cranial nerve palsies and a descending pattern of weakness are classic symptoms of botulism. The incubation period for this illness is typically 18 to 36 hours; therefore, it is important to obtain as complete a dietary history as possible for this time period. It is important that the local or state health department be contacted immediately when botulism is suspected. In cases of botulism intoxication, an EMG of the affected muscles done with rapid repetitive stimulation at 20-50 Hertz will usually demonstrate a potentiated response in muscle action potentials; whereas in GBS and myasthenia gravis rapid repetitive stimulation yields flat and decremental responses, respectively. Administration of Tensilon (edrophonium) will help confirm the diagnosis of myasthenia gravis by showing improved muscle strength after injection of this compound. CSF protein levels are normal in botulism but are almost always elevated in GBS except early in the course of the illness. A CT scan of the head with and without contrast may help rule out a significant cerebrovascular accident or encephalitis. An MRI may be helpful to distinguish soft tissue abnormalities or midbrain lesions. If the history suggests heavy metal or organophosphate toxicity, special tests including evaluation of hair or blood can be done. # What diagnostic tests are needed? You order the EMG, Tensilon test, CSF studies, and the CT scan of the head. The EMG shows a potentiated muscle action potential with rapid repetitive stimulation at 20 Hertz, consistent with botulism intoxication. The Tensilon test is negative (no improvement with Tensilon) and the CSF protein, glucose, and cell counts are normal. CT scan of the head shows no meningeal enhancement or evidence of intracranial hemorrhage. # What diagnostic test(s) will confirm the diagnosis of botulism? To confirm the diagnosis of botulism, serum, stool, and any leftover suspect food should be tested for the presence of botulinum toxin. The test is a mouse bioassay. Mice are given injections of dilutions of sera, stool, and food extract followed by injections of monovalent antitoxins A, B, and E and polyvalent antitoxin ABCEF, and observed for signs of botulism and death. Stool and food also can be cultured for the bacterium Clostridium botulinum, which produces the toxins. To order tests for botulinum toxin and C. botulinum culture, the state health department should be contacted. It can provide information about what specimens should be collected and how they should be stored, and will forward the specimens to the state public health laboratory or to the Centers for Disease Control and Prevention (CDC) if the state does not have the capacity to test for botulism. # What treatment is needed? The most important treatment for botulism is supportive care. The patient's cardiorespiratory status should be monitored continuously in an intensive care unit. His respiratory function as measured by forced vital capacity should be monitored frequently, and he should be placed on assisted ventilation at the first sign of respiratory decompensation. Induced vomiting or gastric lavage are sometimes recommended to eliminate unabsorbed toxin from the stomach. These therapies are only done with a protected airway when the risk of aspiration is low. Cathartic agents or enemas are sometimes recommended to remove unabsorbed toxin from the gastrointestinal tract. The only pharmacological treatment for botulism is antitoxin. The currently available licensed antitoxins are equine antibodies to toxin; one product has antibodies to toxin types A and B, the most common causes of botulism, and the other product has antibodies to toxin types A, B, and E. Use of the product containing antibodies to type E toxin is reserved for patients at high risk of type E botulism intoxication including those patients who were exposed to botulinum toxin in Alaska, or those who have a history of consumption of preserved fish, fish eggs, seal, walrus, whale, or beaver tail. Antitoxin is most effective in preventing progression of the illness and shortening the duration of ventilatory failure if administered early (24-48 hours) after the onset of neurologic symptoms. If a diagnosis of botulism intoxication is strongly suspected, antitoxin should be administered promptly and should not be delayed until the diagnosis is confirmed. Hypersensitivity reactions have been reported in up to 9% of patients who receive antitoxin; therefore, skin testing is recommended prior to administration of antitoxin. Antimicrobials have not been of benefit in the treatment of foodborne botulism intoxication. Botulinum antitoxin is obtained from quarantine stations with permission for release from the CDC and some state health departments; this should be arranged through the state health department. Epidemiologists within the Foodborne and Diarrheal Diseases . # Should this case be reported to the local health department? All suspected cases of botulism intoxication should be reported immediately to the local health department. It will then notify the state health department, which will notify the CDC. In collaboration with state health departments, the CDC will assist with laboratory tests, arrange for treatment with botulinum antitoxin, and notify the Food and Drug Administration (FDA). The FDA is responsible for investigating commercial products possibly contaminated with botulinum toxin and assessing the need for a recall. In the present scenario, the patient denied consuming home-canned foods, suggesting the source of botulinum toxin was a commercial product. A contaminated, widely distributed commercial product could be a potential hazard to many people. State and local health officials with the assistance of the FDA will begin a more thorough investigation, searching for other cases and identifying suspect food exposures. # What was the most likely source of botulism intoxication in this patient? What commercial foods are potential sources of botulism intoxication? Home-canned foods are responsible for over 90% of all cases of foodborne botulism. However, commercial products have also occasionally been implicated. A product with an anaerobic environment allows for the growth of C. botulinum spores and toxin production. The toxins are resistant to digestion by gastric enzymes. In the present scenario, the salad dressing was contaminated. The patient's wife had the house Dijon on her salad, but the patient had garlic-infused olive oil. The oil created an anaerobic environment, which allowed C. botulinum spores that were on the garlic to germinate and produce toxin. The oil was not acidified or refrigerated; these procedures could have prevented C. botulinum spore growth and toxin production. # How can botulism be prevented? C. botulinum spores are highly heat-resistant; commercial and home-canning procedures should be done at the appropriate temperature and pressure to kill these spores. A pressure cooker must be used to can vegetables at home safely because it can reach temperatures above boiling (>212°F or >100°C). Information on safe home-canning procedures is available from local county extension home economists. Botulinum toxin is readily inactivated by heat; nevertheless, the FDA recommends that any food suspected to contain botulinum toxin be destroyed. Proper acidification and refrigeration of commercial products such as herb-infused oils will inhibit spore growth and toxin production. Growth of C. botulinum in food may cause container lids to bulge and cause foods to have a bad odor. Commercial or home-canned food products with bulging lids or a bad odor should not be eaten. However, botulism has also been associated with foods that smell and taste normally; therefore, the smell and taste of food should not be used to determine if it is contaminated. The patient's serum and stool contained type A botulinum toxin. An investigation by the state and local health department found four other cases of intoxication associated with the garlic-infused oil at the restaurant. Two of the patients had been hospitalized with a diagnosis of stroke, one had been hospitalized with a diagnosis of myasthenia gravis, and one had been hospitalized with an unknown diagnosis. The patient in this scenario required assisted ventilation, but his respiratory muscle function improved after he received antitoxin. He fully recovered within 3 weeks of the onset of his symptoms. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # ESCHERICHIA COLI O157:H7 INFECTION: A PATIENT SCENARIO Pierre is a 3-year-old who was brought to the outpatient clinic by his mother. He had a 2-day history of severe abdominal cramps and diarrhea (5 to 7 watery stools daily). He has had no fever or vomiting. His mother was especially alarmed this morning when she noticed blood in his diarrheal stools. He refuses to eat, but has been drinking a few ounces of liquids every 2 to 3 hours. She has been unable to assess his urine output because of his diarrhea. Pierre previously has been healthy, and has had no significant weight loss or other symptoms. On physical examination, he is afebrile with normal blood pressure, respirations and capillary refill. His oral mucosa and skin are dry, but his skin turgor is normal. His abdomen has hyperactive bowel sounds, mild distension, and diffuse tenderness, but is soft with no rebound or guarding. He has loose stool in the rectal vault, which is grossly bloody. # What is the possible differential diagnosis for his chief complaint? • Inflammatory bowel disease • Polyps • Meckel's diverticulum • Intussusception • Coagulopathy • Infectious enteritis # What additional information would assist with the diagnosis? • Has he had similar symptoms before? • Is there a family history of inflammatory bowel disease? • Is there a family history of bleeding disorders? • Do other household members or close acquaintances have diarrhea or bloody diarrhea? • Does he attend child care? If "yes," have there been reports of diarrhea or bloody diarrhea in other children attending the child care facility? There is no family history of inflammatory bowel disease or bleeding disorders. Pierre's mother reports that he usually has 1 to 2 episodes of self-limited diarrhea each year, but has never had bloody diarrhea. No other household members have had diarrhea or bloody diarrhea; however, his grandmother and 15-year-old sister have had mild abdominal cramps. He does not attend child care; his mother has not heard that any of his playmates have been ill. # MMWR January 26, 2001 How does this information assist with the diagnosis? Inflammatory bowel disease is an unlikely diagnosis because of his young age, the acute onset of diarrhea, and the absence of a history of recurrent diarrhea and other symptoms such as weight loss, fever, and arthritis. Even if inflammatory bowel disease is suspected, it would be appropriate to rule out an infectious etiology before proceeding with further work-up. Polyps and Meckel's diverticulum usually cause painless hematochezia. They can be complicated by intussusception, which is characterized by a tense abdomen and absent bowel sounds. If intussusception is suspected, evaluation with abdominal radiography and therapeutic enema may be performed. There is no family history of coagulopathic disorders and Pierre has not had a history of abnormal hemostasis. The symptoms of abdominal pain in other household members suggest an infectious etiology. # The most likely diagnosis is infectious enteritis. What additional historical information could assist with the identification of the etiologic agent? • What foods has he consumed within the last week? Specifically, has he consumed undercooked ground beef, unpasteurized juices, or alfalfa sprouts? • Has he traveled to a foreign country within the last month? • Does he have any pets, specifically reptiles such as an iguana or turtle? • What is the family's source of drinking water? • Have there been any outbreaks of diarrhea in the community, at church, or at his sibling's school? • Has he recently visited a petting zoo? The most worrisome diagnosis in a child with bloody diarrhea is infection with Shiga toxin-producing E. coli, the most common being E. coli O157:H7. E. coli O157:H7 is associated with serious complications including the hemolytic uremic syndrome (HUS). Campylobacter, Salmonella, and Shigella infections also may cause bloody stools. The incubation periods for these four bacterial infections are 1 to 8 days, 2 to 5 days, 1 to 3 days, and 1 to 2 days, respectively. Therefore, any contaminated food that he consumed within the prior week could have contributed to his illness. Pierre's favorite and most frequently consumed foods are hot dogs and spaghetti. He usually has cereal for breakfast, although he occasionally eats an egg, which he prefers sunny-side-up. He has hot dogs or spaghetti with cheese or fruit for lunch, and has dinner with other family members. During the last week, his mother recalls that dinner has included baked chicken, meatloaf, hamburgers, and pizza from the local pizzeria. She reports the meatloaf was well cooked to 165°C; she checked the internal temperature with a meat thermometer before serving. The burger appeared to be well cooked; it was brown in the middle. The family doesn't eat alfalfa sprouts. The family vacationed at a United States resort but has not traveled to a foreign country for 2 years. They have a menagerie of pets including a dog, a cat, two hamsters, a parrot, a Sicilian worm, and a new iguana. Pierre has not visited a petting zoo nor had contact with other animals. They live on a vegetable farm; they have no cows, pigs, or sheep. Their main source of water is from a well, but they use bottled water for drinking. They know of no other outbreaks of diarrhea or bloody diarrhea in the community, church, or school. The local health department has not had other reports of bloody diarrhea or E. coli O157:H7 infection from the community. Just as you are about to leave the room, the mother recalls that the nanny, who is a vegetarian and loves to introduce Pierre to various "veggie delights," related a story last week about how she prepared for Pierre a veggie sandwich with cucumber, cream cheese, and alfalfa sprouts. The nanny said he ate only one bite of the sandwich and refused the rest, begging for spaghetti instead. # Are diagnostic tests needed? Identification of the cause of Pierre's diarrhea is important because it will influence antimicrobial therapy, follow-up, and prognosis, and may obviate the need for invasive diagnostic procedures such as laparotomy or colonoscopy. The child's dietary, environmental, and travel history suggest he is at high risk for three of the infectious agents discussed above (i.e., Salmonella, Campylobacter, and E. coli O157:H7). For example, E. coli O157:H7 infection has been associated with undercooked ground beef. Although the hamburger he consumed appeared to be well-cooked (brown in the middle), recent studies have shown that a significant proportion of ground beef patties are brown in the middle before they have reached an internal temperature high enough to kill E. coli O157:H7 (160°F). Recently, E. coli O157:H7 outbreaks have also been associated with fresh produce such as unpasteurized apple juice, cabbage, and alfalfa sprouts. The infectious dose of E. coli O157:H7 is low; ground beef patties with less than 700 organisms per uncooked patty have been associated with illness. Pierre also could have Campylobacter infection. Transmission of Campylobacter infection has been associated with the preparation or consumption of raw or undercooked chicken, and consumption of contaminated water and unpasteurized milk. Campylobacter can cross-contaminate fruits and vegetables when they contact surfaces that may have touched raw chicken such as knives and cutting boards. Campylobacter also has a low infectious dose. Finally, Pierre is at risk for Salmonella infection. Children living in households with reptiles, such as iguanas, are at increased risk. Since 1985, Salmonella serotype Enteritidis has emerged as a pathogen in raw shell eggs. Chickens may become bacteremic with Salmonella Enteritidis, which seeds the eggs transovarially. Therefore, an egg that is clean and has a normal appearance may be contaminated. Many outbreaks of Salmonella infection have been associated with foods that contain raw or undercooked eggs. Salmonella infections also have been associated with undercooked meat and poultry and fresh fruits and vegetables. Shigella is a less likely cause of his illness; it usually causes outbreaks in child care settings where person-to-person transmission is common. However, food products such as raw produce can be contaminated with Shigella and lead to illness. # What diagnostic tests are needed? Routine stool cultures will detect common enteric bacterial enteropathogens such as Campylobacter and Salmonella. However, many clinical laboratories do not screen stools routinely for E. coli O157:H7; it is incumbent upon the clinician to request such testing when E. coli O157:H7 infection is suspected, especially for patients with bloody diarrhea. Bloody diarrhea is very common in patients with E. coli O157:H7 infection, although the absence of bloody diarrhea does not rule out the diagnosis. Culturing for E. coli O157:H7 is relatively simple and inexpensive; this bacteria does not ferment sorbitol and, therefore, appears as a colorless colony on sorbitol-MacConkey (SMAC) agar. Colorless colonies on SMAC agar are selected and assayed for O157 antigen using a commercial kit. All strains of E. coli that agglutinate with the O157 antibody are presumed to be E. coli O157:H7 and should be reported to the local public health authorities. Confirmation of the H flagellar antigen is usually done by a reference laboratory. Recently, rapid diagnostic kits that test for the presence of Shiga toxin have become available for use in clinical laboratories. Specimens that test positive should be forwarded to the public health laboratory for further evaluation. The lab calls you with the results of the stool culture. Pierre's stool grew E. coli O157:H7. # What treatment is needed? The treatment of E. coli O157:H7 infection is largely supportive. Dehydration should be treated with liberal oral or intravenous rehydration to reduce the stress of volume depletion on the kidneys. This is often best accomplished in the hospital with intravenous fluids and close monitoring. The use of antimicrobial therapy is controversial. Data suggest that antimicrobial agents may be harmful. Antimicrobial agents may kill or disrupt intracolonic E. coli O157:H7 organisms, allowing them to release toxin that is absorbed systemically, and may increase the risk of hemolytic uremic syndrome (HUS). Antimicrobials also have not been shown to decrease illness severity. Antidiarrheal medications, especially those that slow intestinal motility, should be avoided. They may delay clearance of the organism, increase the time for toxin absorption, and increase the risk and severity of HUS. # What are the complications of E. coli O157:H7 infection? What follow-up is needed? Within one week after the onset of diarrhea, 10% of children <10 years of age with E. coli O157:H7 infection develop HUS, which is characterized by hemolytic anemia, thrombocytopenia, oliguria-anuria, and rarely seizures. Children with visible blood in their stools are at increased risk of developing HUS. If HUS has not developed within 2 to 3 days after the diarrhea has resolved, this complication is unlikely to occur. Pierre's parents should be instructed to watch for signs and symptoms of HUS, and he should be evaluated by a clinician if he develops these. Regardless of other symptoms, if his diarrhea continues longer than 4 to 5 days, a complete blood count, platelet count, and blood smear analysis should be considered. Adults with E. coli O157:H7 infection may develop HUS or thrombotic thrombocytopenic purpura (TTP), a microangiopathic disorder that resembles HUS but is accompanied by neurologic abnormalities. The mortality rate with E. coli O157:H7-associated HUS is approximately 3% to 5% in children, but may be higher in elderly patients who develop TTP. # Should this case be reported to the local health department? All cases of E. coli O157:H7 infection, post-diarrheal HUS, and post-diarrheal TTP should be reported to the local public health department. The ease with which person-to-person transmission occurs, especially from children who are not toilet-trained, makes diagnosis and reporting very important. The health department can use this information to identify clusters of infection, discover common sources of exposure, and take measures to remove the source of the infection (i.e., remove the contaminated food) and prevent transmission of the organism to others. In addition to reporting cases of E. coli O157:H7 infection, it also is helpful to send E. coli O157:H7 isolates to the local health department. Isolates can be subtyped by pulsed-field gel electrophoresis (PFGE) to determine if other reported cases of E. coli O157:H7 infection are related. Many state public health laboratories now have the capacity to do molecular subtyping. In 1995, the Centers for Disease Control and Prevention (CDC) initiated PulseNet, a national computer network of public health laboratories that employs standard methods to subtype E. coli O157:H7 strains. As of May 2000, there were 34 public health laboratories from various states participating in PulseNet, as well as laboratories from the US Department of Agriculture Food Safety and Inspection Service (USDA-FSIS), and the Food and Drug Administration (FDA). Laboratories within the network can transmit PFGE patterns electronically to a databank at the CDC where they are automatically compared to patterns of other isolates. If the patterns submitted by laboratories in different locations during a defined time period are found to match, the CDC computer will alert PulseNet participants of a possible multistate outbreak. The information can be used by the CDC, the USDA-FSIS, the FDA, and the state health departments to rapidly initiate outbreak investigations and preventive actions. # How can E. coli O157:H7 infection be prevented? Consumers should avoid eating undercooked ground beef. The most reliable way to determine whether ground beef is cooked to a temperature high enough to destroy E. coli O157:H7 is to use a meat thermometer and cook to an internal temperature of 160°F. Use of meat thermometers when cooking ground beef is especially important for children, older persons, and the immunocompromised who are at highest risk of contracting foodborne diseases, of developing severe foodborne illness, and of dying from foodborne diseases. If a meat thermometer is not available, consumers should not eat ground beef that is pink in the middle. If served an undercooked (pink) hamburger at a restaurant, consumers should send it back and have it cooked longer. Consumers should avoid unpasteurized juices and milk, and should wash all fresh produce thoroughly before consumption. Children under 5 years of age, immunocompromised persons, and the elderly should avoid eating alfalfa sprouts. Infected persons, especially children, should be encouraged to wash their hands carefully and frequently with soap and water to reduce the risk of spreading the infection. Preventive measures to reduce the number of cattle that carry E. coli O157:H7 and to reduce contamination of meat during slaughter and grinding are also underway. Pierre continued to have bloody diarrhea. On the fifth day of illness, a complete blood count showed a hemoglobin of 9g/dL and a platelet count of 79 x 10 9 /L. A peripheral blood smear revealed evidence of hemolysis. Despite hydration and appropriate supportive care, he developed renal insufficiency, which required dialysis. His renal function improved after 4 weeks of dialysis, and he eventually recovered with no other complications. This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # ENTEROTOXIGENIC ESCHERICHIA COLI INFECTION: A PATIENT SCENARIO Stephanie is a 35-year-old who presents to your office with a 4-day history of abdominal cramps, headache, and 8-10 episodes/day of watery diarrhea. She has had a few episodes of vomiting but denies fever or bloody diarrhea. She has no complaints of dysuria or back pain. She was previously healthy. Physical examination reveals she is afebrile with a blood pressure of 120/80 mm Hg and normal capillary refill. She has a soft and diffusely tender abdomen with hyperactive bowel sounds but no rebound or guarding. She has no costovertebral angle (CVA) tenderness and stool examination is negative for occult blood. Stephanie reports she rarely has diarrhea, usually less than one episode a year. She denies a family history of malabsorptive or endocrine disorders, and has had none of the other symptoms listed above. She is an art therapist for a local children's mental health clinic, and is not aware that any of her patients have had gastrointestinal tract symptoms or diarrhea. Other household members are well; however, several of her extended family members and friends who attended her younger sibling's high school graduation picnic last weekend also have diarrhea. In fact, her aunt (the hostess of the party) called the local health department because she was concerned that the illnesses might be associated with food that was served at the event from a local restaurant (Restaurant A). Stephanie is uncertain what her aunt learned from the health department. # How does this information assist with the diagnosis? This information suggests that Stephanie's case of diarrhea may be part of a larger outbreak. The most appropriate next step in her management is to contact the local health department and ask if it is aware of an outbreak of foodborne disease, or if it has had reports of diarrheal illness from other patrons or partygoers who consumed food from Restaurant A. The health department also may provide information about the etiologic agent or suspected etiologic agent, and provide recommendations for treatment. You call the health department and learn that there is an outbreak of foodborne illness associated with consumption of food from Restaurant A. Similar to Stephanie, most patients have had abdominal cramps and watery diarrhea, few have had fever, and no one has reported bloody diarrhea. The median incubation period is 42 hours and the diarrhea lasts 3 to 7 days. At this time, neither the vehicle of transmission nor the etiologic agent has been identified. The health department officials request that you obtain a stool culture and report the results back to them. # What are the possible etiologic agents of this outbreak of foodborne illness? Based on its investigation, the health department suspects the vehicle for this outbreak was a food item consumed at Restaurant A, 42 hours before the illness. If this is so, the most likely etiologic agent is a bacterial pathogen as suggested by the moderate incubation period, the lack of vomiting, and the significant duration of illness. Foodborne illness caused by the most common enteric viral pathogens typically has a shorter incubation period, more vomiting, less diarrhea, and a shorter duration of symptoms. By contrast, parasitic infections usually have a longer incubation period (1 to 2 weeks) and a longer duration of illness (>2 to 3 weeks). The bacterial enteric pathogens that should be considered as possible sources of the outbreak are Campylobacter and Salmonella, the two most common causes of bacterial foodborne diseases in the United States. Typically these infections are characterized by fever in addition to abdominal cramps and diarrhea, and bloody stools are possible but not common. E. coli O157:H7 infection should also be considered, although bloody stools frequently are reported with this infection. Vibrios and enterotoxigenic E. coli rarely are diagnosed causes of foodborne illness in the United States but should remain in the differential diagnosis given the profuse watery diarrhea that characterizes this outbreak. A stool culture for bacterial enteropathogens including Salmonella, Shigella, Campylobacter, Yersinia, and E. coli O157:H7 is negative. You report this information to the health department and learn that the routine stool cultures from other patients in the outbreak are also negative. The state public health laboratory examined stools for common viral enteric pathogens; those preliminary studies are negative. # What other pathogen(s) should be considered? How are they identified? The most likely etiologic agent of this outbreak is enterotoxigenic E. coli (ETEC). ETEC is a common cause of traveler's diarrhea and is an increasingly recognized cause of foodborne illness in the United States. This bacterium elaborates one or more enterotoxins that cause intestinal secretion and diarrhea. The incubation period, symptoms, and duration of diarrhea described for persons involved in this outbreak are characteristic of # What should the patient know about ETEC infections? What is the next step in management? ETEC is the most common cause of "traveler's diarrhea" and is becoming a more frequently recognized cause of foodborne illness in the United States. The illness is self-limited; the diarrhea usually lasts fewer than 5 days. Because the duration of illness is short, ETEC infections generally do not require antibiotic therapy. Treatment is mainly supportive including oral or intravenous fluids for rehydration. Occasionally antibiotics, such as ciprofloxacin for adults and trimethoprim/ sulfamethoxazole for children, are given if the patient has an underlying illness or if the diarrhea is severe. ETEC infection may cause dehydration but there are generally no serious complications or long-term sequelae from this infection. Patients should be reminded to wash their hands with warm running water and soap after using the bathroom and before and after eating to avoid transmitting the infection to others. They should tell friends who might have attended other parties at which food from Restaurant A was served to call the local health department to report cases of illness. # How can ETEC infections be prevented? Human and animal wastes are the ultimate source of ETEC contamination. Travelers in developing countries should avoid foods that could be contaminated with bacteria. They should eat thoroughly cooked foods prepared in facilities that practice proper food handling techniques. They should avoid unpasteurized juices and milk, and drink bottled beverages, or water that has been boiled or adequately chlorinated. They should avoid raw foods (e.g. salads, peeled fruit or vegetables, raw seafood, undercooked meat or poultry) and foods from street vendors. In the United States, proper food preparation and handling practices will reduce the risk of ETEC infections. This should include careful handwashing with warm water and soap after using the bathroom and before and after preparing or consuming food. Stephanie's watery diarrhea resolved after 5 days. She was mildly dehydrated and missed 3 days of work, but recovered completely with no long-term complications. # What additional information would assist with the diagnosis? • What season of the year is it? • Do other household members have similar symptoms? • What is her occupation? • Has she been around ill children or adolescents? • Has she been camping, hiking, or exposed to ticks? • When did she travel to Kenya; where did she visit? • Did she take malaria prophylaxis, and what medication? • Has she been sexually active with more than one partner during the last 6 months? • Is she on any medications currently? • Has she had any animal exposures? It is early autumn and no other household members are ill. She is a legal secretary; none of the clients with whom she has worked have been ill, and she has not been around ill children or adolescents. Her 2-year-old son attends day care; he has been well and there have been no reports of ill children from the center director. She traveled to Nairobi, Kenya, at 15 weeks' gestation, and was well throughout the trip. She took mefloquine for malaria prophylaxis once weekly, and did not forget any doses. She has not been camping or hiking, and is unaware of tick exposure. She recalls only one day of mild illness during her pregnancy, which occurred about 5 weeks earlier and was characterized by 2 or 3 episodes of vomiting and a few loose stools. She attributed the symptoms to a change in diet; she increased milk and fruit consumption in an attempt to be "healthy for the baby." She and her husband have been happily married for 5 years; she denies having any other sexual partners. She is currently taking no medications, and she has had no animal exposures except for her pet dog. # How does this information assist with the diagnosis? Influenza is an unlikely diagnosis; it is early autumn and Sandy has not been exposed to other ill persons at home or work. Her sexual history indicates her risk for HIV, herpes, and gonorrhea infection is low. Her recreational history suggests tickborne disease is improbable. Malaria is a possible diagnosis but she has had no fever in the 12 weeks since she returned from Nairobi, a city over 5,000 feet above sea level where the risk of contracting malaria is low. Mycoplasma, adenovirus, coxsackie virus, group A Streptococcus, CMV, EBV, parvovirus, and other viral agents could account for her symptoms. She could also be bacteremic, but has no symptoms to indicate she is septic. # What diagnostic tests are needed? Consider rapid antigen screen for group A Streptococcus Consider rapid test for infectious mononucleosis Consider urinalysis and thick and thin blood smear The rapid tests for group A Streptococcus and infectious mononucleosis are negative. Urinalysis is negative for bacteria and thick and thin blood smear shows no evidence of malaria parasites. One hour after an appropriate dose of acetaminophen, her temperature is 101°F, and she continues to have flu-like symptoms. Her blood pressure, capillary refill, and the rest of her physical examination are normal. She returns home with instructions to call you if she develops new symptoms, her symptoms worsen, or her symptoms do not abate in the next 24 hours. Four weeks later, you receive another call from Sandy. She reports her water just broke. She has otherwise been well; the flu-like symptoms she had at her last visit resolved within 48 hours. You meet her in the labor and delivery suite, and confirm by physical examination that her membranes are prematurely ruptured. Despite tocolytic therapy, her labor progresses and she delivers an infant girl at 32 weeks' gestation. After delivery, Sandy has a normal post-partum course. The infant is admitted to the neonatal intensive care unit and requires supplemental oxygen for the first few hours of life, but soon after is weaned off oxygen and tolerates her first feeding without difficulty. At 22 hours of age, the infant's nurse notes she is tachypneic with intercostal retractions. The infant's blood pressure is in the low range of normal. The nurse is repeating the blood pressure measurement when the infant becomes bradycardic with delayed capillary refill. Despite full resuscitation efforts including intubation and inotropic support, the infant dies. The next morning you receive a report from the microbiology laboratory that blood cultures drawn just before the infant's death are growing gram-positive short rods/cocci. # What were the most likely causes of the infant's sepsis? • Group B Streptococcus • Staphylococcus aureus • Coagulase-negative Staphylococcus • Enterococcus • a-hemolytic Streptococcus • Listeria monocytogenes Group B Streptococcus and Escherichia coli (a gram-negative rod) are responsible for up to 75% of cases of early-onset neonatal sepsis. Listeria monocytogenes, a less common cause of early-onset neonatal sepsis, also causes an illness that clinically parallels that of group B Streptococcus; infants are infected in utero and develop illness at birth or shortly thereafter. The following morning, the microbiology laboratory calls to report it has identified the gram-positive short rods/cocci in the blood as Listeria monocytogenes. # What, if anything, could have been done to prevent this infant's death? Listeriosis is an uncommon disease; approximately 1,200 cases of Listeria monocytogenes infection are reported each year in the United States. Up to one third of these infections occur in pregnant women, and can be complicated by maternal bacteremia, fetal loss, or infant bacteremia and meningitis. The symptoms associated with listeriosis during pregnancy are often nonspecific and may imitate those of influenza. These flu-like symptoms coincide with the bacteremic phase of infection. In pregnant women with a febrile illness, appropriate clinical management may include obtaining blood cultures to rule out listeriosis. MMWR 53 # 5. Send stool samples to health department (Vibrio cholerae, other Vibrios, E. coli O157:H7, special toxin tests, Clostridium perfringens, Clostridium botulinum ). 6. Not detected by routine stool cultures (E. coli O157:H7, Vibrio cholerae, other Vibrios ). 7. Should test for viral agents. 8. For cysts, ova, and parasite detection, at least 3 stool samples must be collected. Sometimes the organism may still be missed; thus sampling via endoscopy may be necessary. 9. Test for appropriate metal. 10. Special test needed to identify a fish toxin. 11. Consult a mycologist to identify the mushroom. 12. Blood culture is the best source for diagnosis. 13. Blood test helpful to identify the agent. # PROGRAM EVALUATION FORM Please circle your answers and add comments as desired. Please fax this form back to: L J Tan, PhD at 312 464-5841, or see back side for mailing instructions. 1. The primer increased my ability to recognize foodborne illnesses and increased the likelihood that I will consider such illnesses in my patients. Provide any additional comments about this primer, your experiences with foodborne illnesses, and suggestions for future physician education efforts: Please fax the completed survey to: L J Tan, PhD at 312 464-5841 or fold on the dotted lines with the mailing side out, tape, and mail this form back with first class postage. Thank you. # Diagnosis and Management of Foodborne # MMWR January 26, 2001 # This learning scenario can be used to reinforce medical management information pertaining to foodborne illnesses, such as that provided from the other booklets of this primer. This case study provides questions that need to be considered when dealing with a potential case of foodborne illness. Answers are provided immediately following the questions to enhance the learning process. Similar learning scenarios are also available for other foodborne pathogens. # LISTERIA MONOCYTOGENES INFECTION: A PATIENT SCENARIO Sandy, the pregnant mother of a 2-year-old boy presents to your office at 28 weeks' gestation complaining of fever, chills, headache, myalgias, and sore throat. She has previously been healthy and has had an uncomplicated pregnancy. She is somewhat concerned about the illness because she just returned from Kenya a few weeks earlier. Physical examination reveals a temperature of 102°F, pulse of 100 beats per minute, respirations of 20 breaths per minute, and a blood pressure of 100/60 mm Hg. Her posterior pharynx is nonerythematous with no tonsillar enlargement or exudates. She has no remarkable cervical lymphadenopathy. Breath sounds are clear and equal bilaterally, and her abdomen is remarkable only for her gravid uterus. She has normal capillary refill and no petechiae or rashes. What should be included in the differential diagnosis? Fetal infection most likely results from transplacental transmission of maternal bacteremia. Neonatal infection can be prevented if maternal Listeria monocytogenes is treated with the appropriate antibiotics during pregnancy. Listeria has been epidemiologically linked to such foods as fresh soft cheeses, ready-to-eat deli meats, hot dogs, and unpasteurized and inadequately pasteurized milk. Its ability to grow at temperatures as low as 3°C permits multiplication in refrigerated foods. Any one of these could have been the vector for this case. All pregnant women should receive dietary counseling to avoid foods that increase the risk of Listeria monocytogenes infection. They should be advised to avoid unpasteurized milk and cheeses made from unpasteurized milk (particularly fresh soft cheeses) during pregnancy. All pregnant women should cook (until steaming hot) leftover foods or ready-to-eat foods such as hot dogs, before eating, and wash their hands carefully to avoid cross-contamination if preparing these foods for others. Other groups at high risk for listeriosis are elderly and immunocompromised patients. They frequently present with sepsis or meningitis. People in these high-risk groups should also receive dietary counseling to avoid high-risk foods. # PATIENT VIGNETTES -WHAT'S YOUR CALL? The following clinical vignettes are provided for your self-evaluation. All are possible situations that may present at your practice. The Clinical Considerations booklet and the Foodborne Illnesses Tables that are also part of this primer will provide the information necessary for you to adequately address these clinical situations. Note that these vignettes include both infectious and noninfectious forms of foodborne illness. For the following clinical vignettes, choose the best answer from the choices listed at the end of the vignettes: A -likely diagnosis; choose the best possible answer listed on "answer selections" page under A selections. B -most appropriate choice to confirm the diagnosis (there may be more than one correct answer -list all of them). Choose from the possible answers listed on "answer selections" page under the B section. Finally, decide whether the situation warrants reporting to the local or state health department. # Clinical Vignettes # I. You receive a long-distance call from a patient who is an outdoorsman. He is with a group that collected and ate some wild mushrooms less than 2 hours ago. Several members of the group have since developed vomiting, diarrhea, and some mental confusion. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No # II. A newborn child has symptoms of sepsis. Cerebrospinal fluid studies are consistent with meningitis. The mother had a flu-like syndrome prior to delivery. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No III. This patient has just returned today from Latin America following a 2-day business trip where he reports eating several meals of fish that he bought from street venders around his hotel. He feels very ill with profuse, watery diarrhea and vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No IV. An 18-month child is brought to your office with fever, bloody diarrhea, and some vomiting. She has been drinking unpasteurized milk in the last 48 hours. No other family members are ill. A VIII. The parents of a 6-month old infant are concerned because she is listless and weak. The infant is feeding poorly, has poor head control, and is constipated. There is no fever or vomiting. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No IX. A businessman who travels frequently is ill with fatigue, jaundice, abdominal pain and diarrhea. About 1 month ago, he returned from an international trip during which he consumed raw oysters. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department Yes No X. Several members of a single family are ill with abdominal cramps and watery diarrhea. They just returned from visiting friends on the East Coast of the United States where they consumed raw oysters 48 hours ago. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No XI. A minister at a local church calls to report that many members began developing watery diarrhea on the morning after the annual ham dinner fundraiser. Some people also reported nausea and abdominal cramps, but no one has fever or bloody stools. A XII. You receive a long-distance call from a patient on a fishing vacation off the coast of Belize. Her family has been eating a variety of local fish and shellfish that they caught. She reports that several family members developed abdominal pain, severe diarrhea, and weakness the morning after they consumed the seafood for dinner. One family member began having difficulty speaking later on that same night. A -likely diagnosis: B -most appropriate test to confirm etiology/follow-up action: Report to the health department? Yes No XIII. A family in a rural community is worried that their father may be having a stroke. He is complaining of double vision and is having trouble swallowing. They have a large garden and eat home-canned vegetables. A Clinical diagnosis; laboratory tests may not always be indicated. # 2. Generally detected on routine stool cultures. # 3. Generally, a reference laboratory is needed to identify the toxin from food, stool, or vomitus. 4. Important to identify causative organism for public health reasons. # Diagnosis and Management of Foodborne # AVOID FOODBORNE ILLNESS: FIGHT BAC! ™ The US food supply is among the safest in the world, but organisms that you can't see, smell, or taste -bacteria, viruses and tiny parasites -are everywhere in the environment. These microorganisms -called pathogens -can invade food and cause illness, sometimes severe and even life-threatening illness, especially in young children, older adults, and persons with weakened immune systems. In pregnant women, foodborne illness can endanger their unborn babies. The most common symptoms of foodborne illness are diarrhea, abdominal cramps, vomiting, head-or muscle-aches, and fever. Symptoms usually appear 12 to 72 hours after eating contaminated food but may occur between 30 minutes and 4 weeks later. Most people recover within 4 to 7 days without needing antibiotic treatment. If symptoms are severe or the ill person is very young, very old, pregnant, or already ill, call your doctor immediately. # Who Is At Risk If you are among those at high risk, you need to be aware of and follow the most current information on food safety. Young children, pregnant women, older adults, and persons with weakened immune systems are at a higher risk for foodborne illness. Immune systems may be weakened by medical treatments, such as steroids or chemotherapy, or by conditions, such as AIDS, cancer, or diabetes. You are also at increased risk if you suffer from liver disease or alcoholism or if you have decreased stomach acidity (due to gastric surgery or the regular use of antacids). # If You Are At Risk If you face a higher risk of foodborne illness, you are advised not to eat: • Unpasteurized fruit or vegetable juices (These juices will carry a warning label) It is also important to reheat some foods that are bought pre-cooked, because they can become contaminated with pathogens after they have been processed and packaged. These foods include: hot dogs, luncheon meats (cold cuts), fermented and dry sausage, and other deli-style meat and poultry products. New information on food safety is constantly emerging. Recommendations and precautions for people at high risk are updated as scientists learn more about preventing foodborne illness. Bacteria, viruses, and parasites can be spread throughout the kitchen and get onto cutting boards, utensils, and countertops. Here's how to Fight BAC! ™ : • Wash your hands with hot, soapy water before and after handling food and after using the bathroom, changing diapers, and handling pets. • Wash your cutting boards, dishes, utensils, and countertops with hot, soapy water after preparing each food item and before you go on to the next food. • Important: Rinse raw produce in water. Don't use soap or detergents. If necessary, use a small vegetable brush to remove surface dirt. # Separate: Don't cross-contaminate. Cross-contamination is the word for how bacteria, viruses, and parasites can be spread from one food product to another. This is especially true when handling raw meat, poultry, seafood, and eggs, so keep these foods and their juices away from ready-to-eat foods. Here's how to Fight BAC! ™ : • Separate raw meat, poultry, and seafood from other foods in your grocery shopping cart and in your refrigerator. • If possible, use a different cutting board for raw meat, poultry and seafood products. • Always wash hands, cutting boards, dishes, and utensils with hot, soapy water after they come in contact with raw meat, poultry, seafood, and eggs. • Use separate plates for cooked food and raw foods. # Cook: Cook to proper temperatures. Food safety experts agree that foods are properly cooked when they are heated for a long enough time and at a high enough temperature to kill the harmful pathogens that cause foodborne illness. The best way to Fight BAC! ™ is to: • Use a clean thermometer that measures the internal temperature of cooked food to make sure meat, poultry, and casseroles are cooked to the temperatures in the chart at right. • Cook eggs until the yolk and white are firm. If you use recipes in which eggs remain raw or only partially cooked, use pasteurized eggs. • Fish should be opaque and flake easily with a fork. • When cooking in a microwave oven, make sure there are no cold spots where pathogens can survive. For best results, cover food, stir, and rotate for even cooking. If there is no turntable, rotate the dish by hand once or twice during cooking. • Bring sauces, soups, and gravy to a boil when reheating. Heat other leftovers thoroughly to at least 165°F. Refrigerate foods quickly because cold temperatures keep harmful pathogens from growing and multiplying. So, set your refrigerator no higher than 40°F and the freezer at 0°F. Check these temperatures occasionally with an appliance thermometer. Then, Fight BAC! ™ by following these steps: • Refrigerate or freeze perishables, prepared foods, and leftovers within two hours or sooner. • Never defrost food at room temperature. Thaw food in the refrigerator, under cold running water, or in the microwave. # GOALS and OBJECTIVES This MMWR provides guidelines for the diagnosis, treatment, and reporting of foodborne illnesses. The goals of this MMWR are to provide physicians and health-care providers with the most current, scientific guidelines for the diagnosis, treatment, and reporting of foodborne illnesses; and with patient education materials that can be used to educate patients, including those who are at high risk for foodborne illness. Upon completion of this educational activity, the reader should be able to a) identify six etiologic agents to consider for manifestations of foodborne illness; b) identify four criteria for prescribing antibacterial therapy for foodborne illness; c) identity how to access the most current reporting requirements for foodborne illness; and d) identify three groups of people who are most at risk for foodborne illness. To receive continuing education credit, please answer all of the following questions: Vol.	None	None
b70105f6e5ad9cbdc7b594594e0401d28120ec4a	cdc	None	depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Part I: Rabies Prevention and Control A. Principles of Rabies Prevention and Control. 1. Rabies Exposure. Rabies is transmitted only when the virus is introduced into bite wounds, open cuts in skin, or onto mucous membranes from saliva or other potentially infectious material such as neural tissue (2). Questions regarding possible exposures should be directed promptly to state or local public health authorities. 2. Public Health Education. Essential components of rabies prevention and control include ongoing public health education, responsible pet ownership, routine veterinary care, and professional continuing education. The majority of animal and human exposures to rabies can be prevented by raising awareness concerning rabies transmission routes; avoiding contact with wildlife; and following appropriate veterinary care. Prompt recognition and reporting of possible exposures to medical professionals and local public health authorities are critical. # Human Rabies Prevention. Rabies in humans can be prevented either by eliminating exposures to rabid animals or by providing exposed persons with prompt local treatment of wounds combined with the administration of human rabies immune globulin and vaccine. The rationale for recommending preexposure and postexposure rabies prophylaxis and details of their administration can be found in the current recommendations of the Advisory Committee on Immunization Practices (ACIP) (2). These recommendations, along with information concerning the current local and regional epidemiology of animal rabies and the availability of human rabies biologics, are available from state health departments. 4. Domestic Animals. Local governments should initiate and maintain effective programs to ensure vaccination of all dogs, cats, and ferrets and to remove strays and unwanted animals. Such procedures in the United States have reduced laboratory-confirmed cases of rabies in dogs from 6,949 in 1947 to 76 in 2005 (3). Because more rabies cases are reported annually involving cats (269 in 2005) than dogs, vaccination of cats should be required (3). Animal shelters and animal-control authorities should establish policies to ensure that adopted animals are vaccinated against rabies. The recommended vaccination procedures and the licensed animal vaccines are specified in Parts II and III of this compendium, respectively. Rabies vaccinations also may be administered under the supervision of a veterinarian to animals held in animalcontrol shelters before release. Any veterinarian signing a rabies certificate must ensure that the person administering vaccine is identified on the certificate and is appropriately trained in vaccine storage, handling, administration, and in the management of adverse events. This practice ensures that a qualified and responsible person can be held accountable for properly vaccinating the animal. Within 28 days after initial vaccination, a peak rabies virus antibody titer is reached, and the animal can be considered immunized. An animal is considered currently vaccinated and immunized if the initial vaccination was administered at least 28 days previously or booster vaccinations have been administered in accordance with this compendium. # Rabies in Regardless of the age of the animal at initial vaccination, a booster vaccination should be administered 1 year later (see Parts II and III for vaccines and procedures). No laboratory or epidemiologic data exist to support the annual or biennial administration of 3-or 4-year vaccines following the initial series. Because a rapid anamnestic response is expected, an animal is considered currently vaccinated immediately after a booster vaccination. a. Dogs, Cats, and Ferrets. All dogs, cats, and ferrets should be vaccinated and revaccinated against rabies in accordance with Part III of this compendium. If a previously vaccinated animal is overdue for a booster, it should be revaccinated. Immediately following the booster, the animal is considered currently vaccinated and should be placed on a vaccination schedule according to the labeled duration of the vaccine used. b. Livestock. Consideration should be given to vaccinating livestock that are particularly valuable. Animals that have frequent contact with humans (e.g., in petting zoos, fairs, and other public exhibitions) and horses traveling interstate should be currently vaccinated against rabies (12,13). c. Confined Animals. 1.) Wild. No parenteral rabies vaccines are licensed for use in wild animals or hybrids (i.e., the offspring of wild animals crossbred to domestic animals). The AVMA has recommended that wild animals or hybrids should not be kept as pets (14-17). # 2.) Maintained in Exhibits and in Zoological Parks. Handling and consumption of tissues from exposed animals might carry a risk for rabies transmission. The risk depends in part on the site(s) of exposure, amount of virus present, severity of wounds, and whether sufficient contaminated tissue is later excised. If an exposed animal is to be slaughtered for consumption, it should be done immediately after exposure. Barrier precautions should be used by persons handling the animal, and all tissues should be cooked thoroughly. Historically, federal guidelines for meat inspectors have required that any animal known to have been exposed to rabies within 8 months be rejected for slaughter. USDA Food and Inspection Service (FSIS) meat inspectors should be notified if such exposures occur in food animals before slaughter. In infected animals, rabies virus might be widely distributed in tissues (21). Tissues and products from a rabid animal should not be used for human or animal consumption (22). However, pasteurization temperatures will inactivate rabies virus; therefore, drinking pasteurized milk or eating thoroughly cooked animal products does not constitute a rabies exposure. Multiple rabid animals in a herd or herbivoreto-herbivore transmission is uncommon; therefore, restricting the rest of the herd if a single animal has been exposed to or infected by rabies is usually not necessary. c. Other Animals. Other mammals exposed to a rabid animal should be euthanized immediately. Animals maintained in USDA-licensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis. 6. Management of Animals that Bite Humans. a. Dogs, Cats, and Ferrets. Rabies virus might be excreted in the saliva of infected dogs, cats, and ferrets during illness and/or for only a few days before illness or death (23)(24)(25). A healthy dog, cat, or ferret that bites a person should be confined and observed daily for 10 days (26); administration of rabies vaccine to the animal is not recommended during the observation period to avoid confusing signs of rabies with possible side effects of vaccination. Animals in confinement should be evaluated by a veterinarian at the first sign of illness. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be euthanized and the head shipped for testing as described in Part I.A.8. Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted for rabies examination. b. Other Biting Animals. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Management of animals other than dogs, cats, and ferrets depends on the species, the circumstances of the bite, the epidemiology of rabies in the area, the biting animal's history, current health status, and the animal's potential for exposure to rabies. Previous vaccination of these animals might not preclude the necessity for euthanasia and testing. 7. Outbreak Prevention and Control. The emergence of new rabies virus variants and the introduction of nonindigenous viruses pose a substantial risk to humans, domestic animals, and wildlife (27)(28)(29)(30)(31)(32)(33)(34). In such situations, the public health response should be rapid and comprehensive and should include the following measures: a. Characterize the virus at a national or regional reference laboratory. b. Identify and control the source of the introduction. c. Enhance laboratory-based surveillance in wild and domestic animals. d. Increase animal rabies vaccination rates. e. Restrict the movement of animals at risk. f. Evaluate the need for vector population reduction. g. Coordinate a multi-agency response. h. Provide public and professional outreach and education. USDA and marketed in the United States at the time of publication. New vaccine approvals or changes in label specifications made subsequent to publication should be added to this list. Any of the listed vaccines can be used for revaccination, even if the product is not the same as previously administered. Vaccines used in state and local rabiescontrol programs should have at least a 3-year duration of immunity. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population (46). No laboratory or epidemiologic data exist to support the annual or biennial administration of 3-or 4-year vaccines following the initial series. C. Adverse Events. Currently, no epidemiologic association exists between any licensed vaccine and adverse events, including vaccine failure (47,48)	depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Part I: Rabies Prevention and Control A. Principles of Rabies Prevention and Control. 1. Rabies Exposure. Rabies is transmitted only when the virus is introduced into bite wounds, open cuts in skin, or onto mucous membranes from saliva or other potentially infectious material such as neural tissue (2). Questions regarding possible exposures should be directed promptly to state or local public health authorities. 2. Public Health Education. Essential components of rabies prevention and control include ongoing public health education, responsible pet ownership, routine veterinary care, and professional continuing education. The majority of animal and human exposures to rabies can be prevented by raising awareness concerning rabies transmission routes; avoiding contact with wildlife; and following appropriate veterinary care. Prompt recognition and reporting of possible exposures to medical professionals and local public health authorities are critical. # Human Rabies Prevention. Rabies in humans can be prevented either by eliminating exposures to rabid animals or by providing exposed persons with prompt local treatment of wounds combined with the administration of human rabies immune globulin and vaccine. The rationale for recommending preexposure and postexposure rabies prophylaxis and details of their administration can be found in the current recommendations of the Advisory Committee on Immunization Practices (ACIP) (2). These recommendations, along with information concerning the current local and regional epidemiology of animal rabies and the availability of human rabies biologics, are available from state health departments. 4. Domestic Animals. Local governments should initiate and maintain effective programs to ensure vaccination of all dogs, cats, and ferrets and to remove strays and unwanted animals. Such procedures in the United States have reduced laboratory-confirmed cases of rabies in dogs from 6,949 in 1947 to 76 in 2005 (3). Because more rabies cases are reported annually involving cats (269 in 2005) than dogs, vaccination of cats should be required (3). Animal shelters and animal-control authorities should establish policies to ensure that adopted animals are vaccinated against rabies. The recommended vaccination procedures and the licensed animal vaccines are specified in Parts II and III of this compendium, respectively. Rabies vaccinations also may be administered under the supervision of a veterinarian to animals held in animalcontrol shelters before release. Any veterinarian signing a rabies certificate must ensure that the person administering vaccine is identified on the certificate and is appropriately trained in vaccine storage, handling, administration, and in the management of adverse events. This practice ensures that a qualified and responsible person can be held accountable for properly vaccinating the animal. Within 28 days after initial vaccination, a peak rabies virus antibody titer is reached, and the animal can be considered immunized. An animal is considered currently vaccinated and immunized if the initial vaccination was administered at least 28 days previously or booster vaccinations have been administered in accordance with this compendium. # Rabies in Regardless of the age of the animal at initial vaccination, a booster vaccination should be administered 1 year later (see Parts II and III for vaccines and procedures). No laboratory or epidemiologic data exist to support the annual or biennial administration of 3-or 4-year vaccines following the initial series. Because a rapid anamnestic response is expected, an animal is considered currently vaccinated immediately after a booster vaccination. a. Dogs, Cats, and Ferrets. All dogs, cats, and ferrets should be vaccinated and revaccinated against rabies in accordance with Part III of this compendium. If a previously vaccinated animal is overdue for a booster, it should be revaccinated. Immediately following the booster, the animal is considered currently vaccinated and should be placed on a vaccination schedule according to the labeled duration of the vaccine used. b. Livestock. Consideration should be given to vaccinating livestock that are particularly valuable. Animals that have frequent contact with humans (e.g., in petting zoos, fairs, and other public exhibitions) and horses traveling interstate should be currently vaccinated against rabies (12,13). c. Confined Animals. 1.) Wild. No parenteral rabies vaccines are licensed for use in wild animals or hybrids (i.e., the offspring of wild animals crossbred to domestic animals). The AVMA has recommended that wild animals or hybrids should not be kept as pets (14-17). # 2.) Maintained in Exhibits and in Zoological Parks. Handling and consumption of tissues from exposed animals might carry a risk for rabies transmission. The risk depends in part on the site(s) of exposure, amount of virus present, severity of wounds, and whether sufficient contaminated tissue is later excised. If an exposed animal is to be slaughtered for consumption, it should be done immediately after exposure. Barrier precautions should be used by persons handling the animal, and all tissues should be cooked thoroughly. Historically, federal guidelines for meat inspectors have required that any animal known to have been exposed to rabies within 8 months be rejected for slaughter. USDA Food and Inspection Service (FSIS) meat inspectors should be notified if such exposures occur in food animals before slaughter. In infected animals, rabies virus might be widely distributed in tissues (21). Tissues and products from a rabid animal should not be used for human or animal consumption (22). However, pasteurization temperatures will inactivate rabies virus; therefore, drinking pasteurized milk or eating thoroughly cooked animal products does not constitute a rabies exposure. Multiple rabid animals in a herd or herbivoreto-herbivore transmission is uncommon; therefore, restricting the rest of the herd if a single animal has been exposed to or infected by rabies is usually not necessary. c. Other Animals. Other mammals exposed to a rabid animal should be euthanized immediately. Animals maintained in USDA-licensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis. 6. Management of Animals that Bite Humans. a. Dogs, Cats, and Ferrets. Rabies virus might be excreted in the saliva of infected dogs, cats, and ferrets during illness and/or for only a few days before illness or death (23)(24)(25). A healthy dog, cat, or ferret that bites a person should be confined and observed daily for 10 days (26); administration of rabies vaccine to the animal is not recommended during the observation period to avoid confusing signs of rabies with possible side effects of vaccination. Animals in confinement should be evaluated by a veterinarian at the first sign of illness. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be euthanized and the head shipped for testing as described in Part I.A.8. Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted for rabies examination. b. Other Biting Animals. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Management of animals other than dogs, cats, and ferrets depends on the species, the circumstances of the bite, the epidemiology of rabies in the area, the biting animal's history, current health status, and the animal's potential for exposure to rabies. Previous vaccination of these animals might not preclude the necessity for euthanasia and testing. 7. Outbreak Prevention and Control. The emergence of new rabies virus variants and the introduction of nonindigenous viruses pose a substantial risk to humans, domestic animals, and wildlife (27)(28)(29)(30)(31)(32)(33)(34). In such situations, the public health response should be rapid and comprehensive and should include the following measures: a. Characterize the virus at a national or regional reference laboratory. b. Identify and control the source of the introduction. c. Enhance laboratory-based surveillance in wild and domestic animals. d. Increase animal rabies vaccination rates. e. Restrict the movement of animals at risk. f. Evaluate the need for vector population reduction. g. Coordinate a multi-agency response. h. Provide public and professional outreach and education. USDA and marketed in the United States at the time of publication. New vaccine approvals or changes in label specifications made subsequent to publication should be added to this list. Any of the listed vaccines can be used for revaccination, even if the product is not the same as previously administered. Vaccines used in state and local rabiescontrol programs should have at least a 3-year duration of immunity. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population (46). No laboratory or epidemiologic data exist to support the annual or biennial administration of 3-or 4-year vaccines following the initial series. C. Adverse Events. Currently, no epidemiologic association exists between any licensed vaccine and adverse events, including vaccine failure (47,48)	None	None
b2e610975990ba0275db81e3f7f7cb571bce57c9	cdc	None	jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and bettertolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice. Keywords. Mycobacterium tuberculosis; HIV infections; antitubercular agents; case management; public health.# and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. Nine PICO (population, intervention, comparators, outcomes) questions and associated recommendations, developed based on the evidence that was appraised using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology , are summarized below. A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pharmacokinetics, pediatrics, primary care, public health, and systematic review methodology were assembled and used GRADE methods to assess the certainty in the evidence (also known as the quality of evidence) and strength of the recommendations (see Supplementary Appendix A: Methods and Table 1). This executive summary is a condensed version of the panel's recommendations. Additional detailed discussion of the management of pulmonary and extrapulmonary tuberculosis is available in the fulltext version of this guideline. # OBJECTIVES OF ANTITUBERCULOSIS THERAPY Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons, thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. The objectives of tuberculosis therapy are (1) to rapidly reduce the number of actively growing bacilli in the patient, thereby decreasing severity of the disease, preventing death and halting transmission of M. tuberculosis; (2) to eradicate populations of persisting bacilli in order to achieve durable cure ( prevent relapse) after completion of therapy; and (3) to prevent acquisition of drug resistance during therapy. The decision to initiate combination chemotherapy for tuberculosis is based on clinical, radiographic, laboratory, patient, and public health factors (Figure 1). In addition, clinical judgment and the index of suspicion for tuberculosis are critical in making a decision to initiate treatment. For example, in patients (children and adults) who, based on these considerations, have a high likelihood of having tuberculosis or are seriously ill with a disorder suspicious for tuberculosis, empiric treatment with a 4-drug regimen (Tables 2 and 3) should be initiated promptly even before the results of acid-fast bacilli (AFB) smear microscopy, molecular tests, and mycobacterial culture are known. Sixty-five years of investigation, including many clinical trials, have consistently supported the necessity of treating with multiple drugs to achieve these treatment objectives, minimize drug toxicity, and maximize the likelihood of treatment completion . The success of drug treatment, however, depends upon many factors, and numerous studies have found an increased risk of relapse among patients with signs of more extensive disease (ie, cavitation or more extensive disease on chest radiograph) , and/or slower response to treatment (ie, delayed culture conversion at 2-3 months) . # ORGANIZATION AND SUPERVISION OF TREATMENT Because of the public health implications of prompt diagnosis and effective treatment of tuberculosis, most low-incidence countries designate a government public health agency as legal authority for controlling tuberculosis . The optimal organization of tuberculosis treatment often requires the coordination of public and private sectors . In most settings, a patient is assigned a public health case manager who assesses needs and barriers that may interfere with treatment adherence . With active input from the patient and healthcare providers, the case manager, together with the patient, develops an individualized "case management plan" with interventions to address the identified needs and barriers (see PICO Question 1 and Supplementary Appendix B, Evidence Profiles 1-3). The least restrictive public health interventions that are effective are used to achieve adherence, thereby balancing the rights of the patient and public safety. Given that tuberculosis treatment requires multiple drugs be given for several months, it is crucial that the patient be involved in a meaningful way in making decisions concerning treatment supervision and overall care. International standards have been developed that also emphasize the importance of using patientcentered approaches to the management of tuberculosis . Key considerations when developing a case management plan include (1) improving "treatment literacy" by educating the Patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not. The majority of individuals in this situation would want the suggested course of action, but many would not. # Clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences. # Policy The recommendation can be adopted as policy in most situations. Policymaking will require substantial debate and involvement of various stakeholders. Source: Grading of Recommendations Assessment, Development and Evaluation Working Group . patient about tuberculosis and its treatment, including possible adverse effects ; (2) discussing expected outcomes of treatment, specifically the ability to cure the patient of the disease; (3) reviewing methods of adherence support and plans for assessing response to therapy; and (4) discussing infectiousness and infection control measures using terminology that is appropriate to the culture, language, age, and reading level of the patient . For non-English-speaking patients, the use of medical interpreter services is preferred over using family or friends as interpreters . Relevant information should be reinforced at each visit. Other components of the case management plan include, but are not limited to, setting up patient reminders and systems to follow-up missed appointments , use of incentives and enablers , field and home visits , and integration and coordination of tuberculosis care with the patient's primary and specialty care (including mental health services, if appropriate and requested by the patient) (Table 4). PICO Question 1: Does adding case management interventions to curative therapy improve outcomes compared to curative therapy alone among patients with tuberculosis? (Case management is defined as patient education/counseling, field/home visits, integration/coordination of care with specialists and medical home, patient reminders, and incentives/enablers). Recommendation 1: We suggest using case management interventions during treatment of patients with tuberculosis (conditional recommendation; very low certainty in the evidence). Given the critical importance of chemotherapy, both to the patient and to the public, approaches to ensuring adherence to the treatment regimen are a major focus of the overall management plan. To maximize completion of therapy, management strategies should utilize a broad range of approaches (see "Patient-Centered Care and Case Management" in the full-text version of the guideline). Among these, directly observed therapy (DOT), the practice of observing the patient swallow their antituberculosis medications, has been widely used as the standard of practice in many tuberculosis programs, and deserves special emphasis (see PICO Question 2 and Supplementary Appendix B, Evidence Profile 4). The systematic review conducted to obtain evidence in support of this practice guideline did not find any significant differences between selfadministered therapy (SAT) and DOT when assessing several outcomes of interest, including mortality, treatment completion, and relapse. However, DOT was significantly associated with improved treatment success (the sum of patients cured and patients completing treatment) and with increased sputum smear conversion during treatment, as compared to SAT. Because DOT is a multifaceted public health intervention that is not amenable to the conventional clinical trial approaches to assessing benefits, and because participation in DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities, for allowing providers to establish rapport with the patient and for addressing treatment complications expeditiously, DOT remains the standard of practice in the majority of tuberculosis programs in the United States and Europe (Table 5). To be consistent with the principles of patient-centered care noted previously, decisions regarding the use of DOT must be made in concert with the patient . For example, DOT can be provided in the office, clinic, or in the "field" ( patient's home, place of employment, school, or any other site that is mutually agreeable) by appropriately trained personnel . PICO Question 2: Does self-administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of tuberculosis? Recommendation 2: We suggest using DOT rather than SAT for routine treatment of patients with all forms of tuberculosis (conditional recommendation; low certainty in the evidence). # RECOMMENDED TREATMENT REGIMENS The preferred regimen for treating adults with tuberculosis caused by organisms that are not known or suspected to be drug resistant is a regimen consisting of an intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF (see Tables 2,3,10,11, and Supplementary Appendix C) . The intensive phase of treatment consists of 4 drugs (INH, RIF, PZA, EMB) because of the current proportion of new tuberculosis cases worldwide caused by organisms that are resistant to INH ; however, if therapy is being initiated after drug susceptibility test results are known and the patient's isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (eg, pregnant women; breastfeeding infants; persons infected with human immunodeficiency virus ; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or those who are of advanced age) . With respect to administration schedule, the preferred frequency is once daily for both the intensive and continuation phases (see PICO Questions 3 and 4 and Supplementary Appendix B, Evidence . Although administration of antituberculosis drugs using DOT 5 days a week has been reported in a large number of studies, it has not been compared with 7-day administration in a clinical trial. Nonetheless, on the basis of substantial clinical experience, experts believe that 5-days-a-week drug administration by DOT is an acceptable alternative to 7-days-a-week administration, and either approach Do not use twice-weekly regimens in HIV-infected patients or patients with smear-positive and/or cavitary disease. If doses are missed, then therapy is equivalent to once weekly, which is inferior. Abbreviations: DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin. a Other combinations may be appropriate in certain circumstances; additional details are provided in the section "Recommended Treatment Regimens." b When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. DOT should be used when drugs are administered <7 days per week. c Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase. d Pyridoxine (vitamin B6), 25-50 mg/day, is given with INH to all persons at risk of neuropathy (eg, pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day. e See . Alternatively, some US tuberculosis control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses. There are inadequate data to support intermittent administration. Children 15-20 mg/kg total (divided 1-2 times daily) # Streptomycin Aqueous solution (1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. Children 15-20 mg/kg ... 2 5 -30 mg/kg i . . . # Amikacin/ kanamycin Aqueous solution (500 mg and 1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function, including older patients, may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. Children 15-20 mg/kg ... 2 5 -30 mg/kg i . . . # Capreomycin Aqueous solution (1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function, including older patients, may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. There are inadequate data to support intermittent administration. Children 200-300 mg/kg total (usually divided 100 mg/kg given 2 to 3 times daily) may be considered as meeting the definition of "daily" dosing. There are alternative regimens that are variations of the preferred regimen, which may be acceptable in certain clinical and/or public health situations (see "Other Regimens" and "Treatment in Special Situations" in the full-text version of the guideline). PICO Question 3: Does intermittent dosing in the intensive phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug-susceptible pulmonary tuberculosis? Recommendation 3a: We recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 3b: Use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; low certainty in the evidence). Recommendation 3c: In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; very low certainty in the evidence). Note: If doses are missed in a regimen using twice-weekly dosing, then therapy is equivalent to once weekly, which is inferior (see PICO Question 4). # Children The optimal dose is not known. Some experts use 10 mg/kg daily dosing, though lack of formulations makes such titration challenging. Aiming for serum concentrations of 3-5 µL/mL 2 h postdose is proposed by experts as a reasonable target. Abbreviations: FDA, US Food and Drug Administration; HIV, human immunodeficiency virus; IM, intramuscular; INH, isoniazid; IV, intravenous. a Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight ), dosing based on IBW may be preferred for initial doses. Some clinicians prefer a modified IBW (IBW + ) as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been established, therapeutic drug monitoring may be considered for such patients. b For purposes of this document, adult dosing begins at age 15 years or at a weight of >40 kg in younger children. The optimal doses for thrice-weekly therapy in children and adolescents have not been established. Some experts use in adolescents the same doses as recommended for adults, and for younger children the same doses as recommended for twice-weekly therapy. c Higher doses of rifampin, currently as high as 35 mg/kg, are being studied in clinical trials. d Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. e TBTC Study 22 used rifapentine (RPT) dosage of 10 mg/kg in the continuation phase of treatment for active disease . However, RIFAQUIN and PREVENT TB safely used higher dosages of RPT, administered once weekly . Daily doses of 1200 mg RPT are being studied in clinical trials for active tuberculosis disease. f As an approach to avoiding ethambutol (EMB) ocular toxicity, some clinicians use a 3-drug regimen (INH, rifampin, and pyrazinamide) in the initial 2 months of treatment for children who are HIV-uninfected, have no prior tuberculosis treatment history, are living in an area of low prevalence of drug-resistant tuberculosis, and have no exposure to an individual from an area of high prevalence of drug-resistant tuberculosis. However, because the prevalence of and risk for drug-resistant tuberculosis can be difficult to ascertain, the American Academy of Pediatrics and most experts include EMB as part of the intensive-phase regimen for children with tuberculosis. g Clinicians experienced with using cycloserine suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations often are useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily. h Ethionamide can be given at bedtime or with a main meal in an attempt to reduce nausea. Clinicians experienced with using ethionamide suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations may be useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily. i Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations. j RIFAQUIN trial studied a 6-month regimen. Daily isoniazid was replaced by daily moxifloxacin 400 mg for the first 2 months, followed by once-weekly doses of moxifloxacin 400 mg and RPT 1200 mg for the remaining 4 months. Two hundred twelve patients were studied (each dose of RPT was preceded by a meal of 2 hard-boiled eggs and bread). This regimen was shown to be noninferior to a standard daily administered 6-month regimen . # Enablers Incentives Interventions to assist the patient in completing therapy Interventions to motivate the patient, tailored to individual patient wishes and needs and, thus, meaningful to the patient Transportation vouchers Food stamps or snacks and meals Convenient clinic hours and locations Restaurant and grocery store coupons Clinic personnel who speak the languages of the populations served Assistance in finding or provision of housing Reminder systems and follow-up of missed appointments Clothing or other personal products Social service assistance (referrals for substance abuse treatment and counseling, housing, and other services) Books Outreach workers (bilingual/bicultural as needed; can provide many services related to maintaining patient adherence, including provision of directly observed therapy, follow-up on missed appointments, monthly monitoring, transportation, sputum collection, social service assistance, and educational reinforcement) Stipends Integration of care for tuberculosis with care for other conditions Patient contract Recommended baseline and follow-up evaluations for patients suspected of having tuberculosis and treated with first-line medications are summarized in Figure 2. During treatment, a sputum specimen for AFB smear and culture are obtained at monthly intervals until 2 consecutive specimens are negative on culture. Duration of the continuation phase regimen hinges on the microbiological status at the end of the intensive phase of treatment; thus, obtaining sputum specimens at the time of completion of 2 months of treatment is critical if sputum culture conversion to negative has not already been documented. The culture result of a sputum specimen obtained at the completion of the intensive phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis, albeit with low sensitivity . Cavitation on the initial chest radiograph has also been shown to be a risk factor for relapse . In patients treated for 6 months, having both cavitation and a positive culture at completion of 2 months of therapy has been associated with rates of relapse of approximately 20% compared with 2% among patients with neither factor . In view of this evidence, for patients who have cavitation on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy, expert opinion is to extend the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy). Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being >10% below ideal body weight; being an active smoker; having diabetes, HIV infection, or any other immunosuppressing condition; or having extensive disease on chest radiograph . Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart treatment from the beginning (Table 6). Continuous treatment is more important in the intensive phase of therapy when the bacillary population is highest and the chance of developing drug resistance greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriologic status of the patient prior to and after the Baseline and follow-up evaluations for patients treated with first-line tuberculosis medications. Shading around boxes indicates activities that are optional or contingent on other information. 1 Obtain sputa for smear and culture at baseline, then monthly until 2 consecutive specimens are negative. Collecting sputa more often early in treatment for assessment of treatment response and at end of treatment is optional. At least one baseline specimen should be tested using a rapid molecular test. 2 Drug susceptibility for isoniazid, rifampin, ethambutol (EMB), and pyrazinamide should be obtained. Repeat drug susceptibility testing if patient remains culture positive after completing 3 months of treatment. Molecular resistance testing should be performed for patients with risk for drug resistance. 3 Obtain chest radiograph at baseline for all patients, and also at month 2 if baseline cultures are negative. End-of-treatment chest radiograph is optional. Other imaging for monitoring of extrapulmonary disease. 4 Monitor weight monthly to assess response to treatment; adjust medication dose if needed. 5 Assess adherence and monitor improvement in tuberculosis symptoms (eg, cough, fever, fatigue, night sweats) as well as development of medication adverse effects (eg, jaundice, dark urine, nausea, vomiting, abdominal pain, fever, rash, anorexia, malaise, neuropathy, arthralgias). 6 Patients on EMB: baseline visual acuity (Snellen test) and color discrimination tests, followed by monthly inquiry about visual disturbance and monthly color discrimination tests. 7 Liver function tests only at baseline unless there were abnormalities at baseline, symptoms consistent with hepatotoxicity develop, or for patients who chronically consume alcohol, take other potentially hepatotoxic medications, or have viral hepatitis or history of liver disease, human immunodeficiency virus (HIV) infection, or prior drug-induced liver injury. 8 Baseline for all patients. Further monitoring if there are baseline abnormalities or as clinically indicated. 9 HIV testing in all patients. CD4 lymphocyte count and HIV RNA load if positive. 10 Patients with hepatitis B or C risk factor (eg, injection drug use, birth in Asia or Africa, or HIV infection) should have screening tests for these viruses. 11 Fasting glucose or hemoglobin A1c for patients with risk factors for diabetes according to the American Diabetes Association including: age >45 years, body mass index >25 kg/m 2 , first-degree relative with diabetes, and race/ethnicity of African American, Asian, Hispanic, American Indian/Alaska Native, or Hawaiian Native/Pacific Islander. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. interruption are also important considerations (see "Interruptions in Therapy" in the full-text version of the guideline). PICO Question 4: Does intermittent dosing in the continuation phase have similar outcomes compared to daily dosing in the continuation phase in patients with drug-susceptible pulmonary tuberculosis patients? Recommendation 4a: We recommend the use of daily or thriceweekly dosing in the continuation phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 4b: If intermittent therapy is to be administered in the continuation phase, then we suggest use of thrice-weekly instead of twice-weekly therapy (conditional recommendation; low certainty in the evidence). This recommendation allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior. Recommendation 4c: We recommend against use of once-weekly therapy with INH 900 mg and rifapentine 600 mg in the continuation phase (strong recommendation; high certainty in the evidence). In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus rifapentine 600 mg may be considered for use only in HIVuninfected persons without cavitation on chest radiography. # PRACTICAL ASPECTS OF TREATMENT Guidance on the practical aspects of tuberculosis treatment, drug-drug interactions, therapeutic drug monitoring (TDM), and management of adverse effects are available in the full-text version of this guideline. In brief, mild adverse effects usually can be managed with treatment directed at controlling the symptoms; severe effects usually require the offending drug(s) to be discontinued, and may require expert consultation on management. If a drug is permanently discontinued, then a replacement drug, typically from a different drug class, is included in the regimen. Patients with severe tuberculosis often require the initiation of an alternate regimen during the time the offending drug(s) are held. In general, for complicated diagnostic or management situations, consultation with local and state health departments is advised. In the United States, the Centers for Disease Control and Prevention's Division of Tuberculosis Elimination funds tuberculosis regional training and medical consultation centers (/), which provide medical consultation to programs and health providers on management of tuberculosis. In Europe, the World Health Organization (WHO)/ERS Tuberculosis Consilium (. org) provides similar consultation services regarding the diagnosis and treatment of tuberculosis. Gastrointestinal reactions are common, especially early in therapy . The optimum approach to management of epigastric distress or nausea with tuberculosis drugs is not clear. To minimize symptoms, patients receiving SAT may take the medications at bedtime. Gastrointestinal intolerance not associated with hepatotoxicity can be treated with antacids, which have less impact on absorption or peak concentration of first-line drugs than administration with food . Any combination of otherwise unexplained nausea, vomiting, and abdominal pain is evaluated with a physical examination and liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase to assess for possible hepatotoxicity . Drug-induced hepatitis is the most frequent serious adverse reaction to the first-line drugs. INH, RIF, and PZA can cause drug-induced liver injury (DILI), which is suspected when the ALT level is ≥3 times the upper limit of normal in the presence of hepatitis symptoms, or ≥5 the upper limit of normal in the absence of symptoms. In either situation, hepatotoxic drugs are stopped immediately and the patient is evaluated carefully. Other causes of abnormal liver function tests must be excluded before diagnosing druginduced hepatotoxicity (Table 7). An official American Thoracic Society statement on the hepatotoxicity of antituberculosis therapy (/ hepatotoxicity-of-antituberculosis-therapy.pdf ) provides additional details on the management of tuberculosis in the setting of drug-induced liver injury, as well as suggestions on drug rechallenge ; however, the optimal approach to reintroducing tuberculosis treatment after hepatotoxicity is still not known . TREATMENT # HIV Infection Treatment of tuberculosis in patients with HIV infection has several important differences compared with treatment of patients who do not have HIV infection. The need for antiretroviral therapy (ART), the potential for drug-drug interactions, especially between the rifamycins and antiretroviral agents (Table 8), paradoxical reactions that may be interpreted as clinical worsening, and the potential for developing resistance to rifamycins when using intermittent tuberculosis therapy are some of these differences. Detailed information on these topics is provided in the full-text version of this practice guideline. In regard to duration of treatment for drug-susceptible pulmonary tuberculosis in the presence of HIV infection, our updated systematic review of randomized trials and cohort studies comparing various durations of tuberculosis therapy (6 months vs 8 months or longer), most of which were conducted prior to the era of highly active ART, showed that the risk of recurrence is lower when the continuation phase of treatment is extended. However, it is important to note that the majority of these studies were reports on nonrandomized cohorts, most were completed prior to the era of routine antiretroviral use, many tested intermittent regimens and few distinguished between reinfection and relapse (see "HIV Infection" in the full-text version of the guideline). As discussed below, based on data that show significant reductions in mortality and AIDS-defining illnesses, patients with HIV infection and tuberculosis should receive ART in conjunction with daily antituberculosis medications. For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis. In the uncommon situation in which an HIV-infected patient does not receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drug-susceptible pulmonary tuberculosis (see PICO Question 5 and Supplementary Appendix B, Evidence Profile 12). As is noted for drug-susceptible pulmonary tuberculosis in patients without HIV coinfection, the continuation phase is extended in specific situations that are known to increase risk for relapse, as well as for selected extrapulmonary sites of disease, namely tuberculous meningitis, and bone, joint, and spinal tuberculosis (see "Identification and Management of Patients at Increased Risk of Relapse" and "Extrapulmonary Tuberculosis" in the full-text version of the guideline). PICO Question 5: Does extending treatment beyond 6 months improve outcomes compared to the standard 6-month treatment regimen among pulmonary tuberculosis patients coinfected with HIV? Recommendation 5a: For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Recommendation 5b: In uncommon situations in which HIV-infected patients do NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drugsusceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Use of intermittent tuberculosis treatment regimens in HIVinfected patients has been associated with high rates of relapse and the emergence of drug resistance . In a trial of rifabutin (RFB)-based antituberculosis therapy in combination with antiretroviral drugs, patients treated with twice-weekly RFB had a relapse rate of 5.3%, but 8 of 9 patients with relapse had acquired rifamycin resistance . Relapse and resistance were associated with low CD4 lymphocyte counts, as all recurrences occurred in patients with baseline CD4 lymphocyte counts <100 cells/µL. In the pharmacokinetic substudy of the trial, lower plasma concentrations of RFB and INH were identified as key risk factors for acquiring rifamycin resistance . More recently, the use of a thrice-weekly RIF-based regimen during the intensive and continuation phases of treatment was associated with a higher rate of relapse and emergence of # Atovaquone Consider alternate form of Pneumocystis jirovecii treatment or prophylaxis. # Chloramphenicol Consider an alternative antibiotic. # Mefloquine Consider alternate form of malaria prophylaxis. # Hormone therapy Ethinylestradiol, norethindrone Women of reproductive potential on oral contraceptives should be advised to add a barrier method of contraception when on a rifamycin. # Tamoxifen May require alternate therapy or use of a non-rifamycin-containing regimen. rifamycin resistance in HIV-infected individuals not receiving antiretrovirals compared with HIV-infected patients also receiving antiretrovirals or HIV-uninfected patients . Based in part on systematic reviews conducted to obtain evidence in support of this guideline, our expert opinion is that treatment of HIV-related tuberculosis be given daily in both the intensive and continuation phases to avoid recurrent disease and the emergence of rifamycin resistance (see "Recommended Treatment Regimens" in the full-text version of the guideline). Mortality among patients with HIV and tuberculosis is high, principally due to complications of immunosuppression and occurrence of other HIV-related opportunistic diseases. Cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis has been shown to reduce morbidity and mortality in HIV-infected patients with newly diagnosed tuberculosis . Whereas cotrimoxazole is recommended by WHO for all HIV-infected people with active tuberculosis disease regardless of the CD4 cell count , in high-income countries, co-trimoxazole is primarily used in HIV-infected patients with CD4 counts <200 cells/µL . The use of ART during tuberculosis treatment in persons with HIV infection also reduces mortality rates significantly and decreases the risk of developing AIDS-related conditions. We performed a systematic review and meta-analysis to address the concurrent initiation of ART with tuberculosis treatment. On the basis of high certainty in the evidence that the benefits outweigh the harms, we recommend that patients with tuberculosis and HIV infection receive ART during antituberculosis treatment. ART should ideally be started within 2 weeks for those patients with a CD4 count <50 cells/µL and by 8-12 weeks for those with a CD4 count ≥50 cells/µL (see PICO Question 6 and Supplementary Appendix B, Evidence Profile 13). An exception is HIV-infected patients with tuberculous meningitis, in whom ART is not initiated in the first 8 weeks of antituberculosis therapy (see full-text version of the guideline). The concurrent administration of antiretrovirals and rifamycins is a major therapeutic challenge, and additional details on the coadministration of these medications, including the use of RFB, are available in the full-text version of this guideline. PICO Question 6: Does initiation of ART during tuberculosis treatment compared to at the end of tuberculosis treatment improve outcomes among tuberculosis patients coinfected with HIV? Recommendation 6: We recommend initiating ART during tuberculosis treatment. ART should ideally be initiated within the first 2 weeks of tuberculosis treatment for patients with CD4 counts <50 cells/µL and by 8-12 weeks of tuberculosis treatment initiation for patients with CD4 counts ≥50 cells/µL (strong recommendation; high certainty in the evidence). Note: an exception is patients with HIV infection and tuberculous meningitis (see Immune Reconstitution Inflammatory Syndrome). Patients with HIV infection and tuberculosis are at increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the immune reconstitution inflammatory syndrome (IRIS). Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4 + cell counts <50 cells/µL . Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses . Such findings are attributed to IRIS only after excluding other possible causes, especially tuberculosis treatment failure from drug-resistant tuberculosis or another opportunistic disease, such as non-Hodgkin lymphoma or infection. Management of IRIS is symptomatic. Based on expert opinion, for most patients with mild IRIS, tuberculosis and antiretroviral therapies can be continued with the addition of anti-inflammatory agents such as ibuprofen. For patients with worsening pleural effusions or abscesses, drainage may be necessary. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures . For patients who develop IRIS, prednisone may be given at a dose of 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks, with tapering over a period of 6-12 weeks or longer. # Tuberculous Pericarditis Based on small studies that have shown mortality and morbidity benefits , corticosteroids have previously been universally recommended in combination with a standard 6-month regimen (Table 2) for treating tuberculosis pericarditis; however, a recent placebo-controlled randomized clinical trial with 1400 participants did not find a difference in the combined primary endpoint of the trial, which included mortality, cardiac tamponade, or constrictive pericarditis, between patients treated with adjunctive corticosteroids vs placebo . A subgroup analysis, however, did suggest a benefit in preventing constrictive pericarditis. Similarly, a systematic review conducted to obtain evidence in support of this guideline did not find a statistically significant benefit in terms of mortality or constrictive pericarditis from the use of corticosteroids . Therefore, we suggest that adjunctive corticosteroids should not be used routinely in the treatment of patients with pericardial tuberculosis (see PICO Question 7 and Supplementary Appendix B, Evidence Profile 14). However, selective use of corticosteroids in patients who are at the highest risk for inflammatory complications might be appropriate. Such patients might include those with large pericardial effusions, those with high levels of inflammatory cells or markers in pericardial fluid, or those with early signs of constriction . PICO Question 7: Does the use of adjuvant corticosteroids in tuberculous pericarditis provide mortality and morbidity benefits? Recommendation 7: We suggest initial adjunctive corticosteroid therapy not be routinely used in patients with tuberculous pericarditis (conditional recommendation; very low certainty in the evidence). # Tuberculous Meningitis Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy. In children with tuberculous meningitis, the American Academy of Pediatrics (AAP) lists an initial 4-drug regimen composed of INH, RIF, PZA, and ethionamide, if possible, or an aminoglycoside, followed by 7-10 months of INH and RIF as the preferred regimen . There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis . Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our guideline committee prefers using EMB as the fourth drug in the regimen for tuberculous meningitis. The role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis has been reported by numerous studies , and our updated systematic review found a mortality benefit from the use of adjuvant corticosteroids. Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (see PICO Question 8 and Supplementary Appendix B, Evidence Profile 15). PICO Question 8: Does the use of adjuvant corticosteroids in tuberculous meningitis provide mortality and morbidity benefits? Recommendation 8: We recommend initial adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (strong recommendation; moderate certainty in the evidence). # Culture-Negative Pulmonary Tuberculosis in Adults Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active tuberculosis. Some causes of failure to isolate organisms include low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing . Alternative diagnoses must be considered and appropriate diagnostic studies undertaken in patients who appear to have culturenegative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis have 2 sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria or for rapid molecular testing for M. tuberculosis as part of the diagnostic evaluation. Other diagnostic procedures, such as bronchoscopy with bronchoalveolar lavage and biopsy, are considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture or a rapid molecular test is positive, treatment for active disease is continued for a full, standard 6-month course (Table 2), if appropriate based on drug susceptibility test results. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have thorough clinical and radiographic follow-up after 2-3 months of therapy . If there is clinical or radiographic improvement and no other etiology is identified, treatment should be continued. The optimum treatment regimens and duration for smearnegative, culture-negative tuberculosis have not been convincingly established. We performed a systematic review that evaluated treatment regimens of varying durations in adult patients with culture-negative, paucibacillary tuberculosis, and we suggest that a 4-month treatment regimen is adequate for smearnegative, culture-negative pulmonary tuberculosis (see PICO Question 9 and Supplementary Appendix B, Evidence Profile 16). Operationally, treatment is initiated with an intensive phase of INH, RIF, PZA, and EMB daily and continued even when the initial bacteriologic studies are negative. If all cultures on adequate samples are negative (defining culture-negative tuberculosis) and there is clinical or radiographic response after 2 months of intensive phase therapy, the continuation phase with INH and RIF can be shortened to 2 months. Alternatively, if there is concern about the adequacy of workup or the accuracy of the microbiologic evaluations, a standard 6-month regimen remains preferred (see Table 2 and "Culture-Negative Pulmonary Tuberculosis" in the full-text version of the guideline) . PICO Question 9: Does a shorter duration of treatment have similar outcomes compared to the standard 6-month treatment duration among HIV-uninfected patients with paucibacillary tuberculosis (ie, smear negative, culture negative)? Recommendation 9: We suggest that a 4-month treatment regimen is adequate for treatment of HIV-uninfected adult patients with AFB smear-and culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). # CONCLUSIONS Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of M. tuberculosis to other persons, thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. A 4-drug regimen of INH, RIF, PZA, and EMB remains the preferred initial treatment for drugsusceptible pulmonary tuberculosis. Treatment is initiated promptly even before AFB smear microscopy, molecular tests, and mycobacterial culture results are known in patients with high likelihood of having tuberculosis or those seriously ill with a disorder suspicious for tuberculosis. Initiation of treatment should not be delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. There are variations of the preferred regimen that are appropriate in certain public health situations or in special clinical situations. Additional detailed and extensively referenced information on treatment of tuberculosis in special situations ( patients with renal disease or hepatic disease, those of advanced age, etc), the use of case management strategies (including DOT), regimen and dosing selection in adults and children (daily vs intermittent), the role of TDM, treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of ART), treatment of tuberculosis in children, treatment of tuberculosis during pregnancy, and treatment of extrapulmonary tuberculosis, as well as key research priorities, are provided in the full-text version of this practice guideline. # BACKGROUND The ATS, the CDC, and the IDSA have jointly developed this guideline for the treatment of drug-susceptible tuberculosis. This document provides guidance on the clinical and public health management of tuberculosis in low-incidence countries. The current document differs from its predecessor, published in 2003 , in 3 important areas. First, the process by which the recommendations were developed was substantially modified. For the first time, the Guideline Writing Committee based its recommendations on the certainty in the evidence (also known as the quality of evidence) assessed according to the GRADE methodology (see Supplementary Appendix A: Methods), which incorporates patient values and costs as well as judgments about trade-offs between benefits and harms . A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pharmacokinetics, pediatrics, primary care, public health, and systematic review methodology were assembled to assess the evidence supporting each recommendation. The GRADE method was used to assess the certainty in the evidence and to rate the strength of the recommendations. Second, the ERS has become an endorser of the statement, along with the US NTCA. Representatives from the AAP, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the WHO also participated in the development of this guideline. Together, these committee members served to provide broader input, thereby expanding the applicability of the guidance beyond North America to include Europe and other low-incidence settings. Last, practice guidelines for the treatment of drug-resistant tuberculosis (including INH monoresistance) are no longer included in this statement and are now covered in a separate practice guideline under development by the ATS, CDC, ERS, and IDSA. Whereas significant changes have been made, the current document also retains many of the basic principles of tuberculosis care described in the 2003 version. As before, a fundamental aspect of tuberculosis care, regardless of the treatment selected, is ensuring patient adherence to the drug regimen and successful completion of therapy. The responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse . Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. The recommendations in this statement are not applicable under all epidemiological circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. It should be emphasized that these guidelines are intended for areas in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic facilities are available on a routine basis-typically low-incidence (<100 tuberculosis cases per million population), well-resourced countries, where in some settings tuberculosis epidemiology is at or nearing preelimination levels (<10 cases per million) . The WHO has developed tuberculosis practice guidelines (currently under revision) specifically for high-incidence, resource-limited areas of the world . # OBJECTIVES OF ANTITUBERCULOSIS THERAPY Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons; successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. The objectives of tuberculosis therapy are: 1. To reduce the bacillary population rapidly thereby decreasing severity of the disease, preventing death and halting transmission of M. tuberculosis; 2. To eradicate persisting bacilli in order to achieve durable cure ( prevent relapse) after completion of therapy; and 3. To prevent acquisition of drug resistance during therapy. Sixty-five years of investigation, including many clinical trials, have consistently supported the requirement for treatment with multiple drugs to achieve these objectives, minimize drug toxicity, and maximize the likelihood of treatment completion . The most effective agents to curtail rapid multiplication of tuberculous bacilli are INH and the fluoroquinolones. Persisting bacilli appear to curtail their metabolic activity; drugs known to be effective against such persisters include the rifamycins and PZA, the latter with activity believed limited to special microenvironments of relatively increased acidity . Objective 1: Rapid killing of multiplying bacilli ("bactericidal effect"): Rapid reduction in the number of replicating bacilli reduces mortality risk , and appears to diminish infectiousness, but even optimal therapy on average requires 4-5 weeks to render sputum cultures negative . Studies of early bactericidal activity (EBA) measure the rate of decline in bacillary numbers in sputum during the initial 1-2 weeks of treatment; EBA studies have been used in the initial evaluation of virtually every new tuberculosis drug since 1980 . However, the relationship of a drug or regimen's EBA to its ability to achieve durable cure is still uncertain . For example, INH has a remarkable EBA but acts only slowly on persisting bacilli; RIF at the dose currently used (10 mg/kg) has moderate EBA but potent activity against persisters; and PZA has almost no measurable EBA, but acts potently to assist in achieving durable cure . Objective 2: Achievement of relapse-free cure ("sterilizing effect"): Demonstration of relapse-free cure requires lengthy clinical trials. Among the few drugs effective in preventing relapse, the most prominent have been the rifamycins. Rapid and reliable measurement of the sterilizing effect of antituberculous agents remains elusive. In vitro models are not entirely predictive . The most commonly used animal model is the murine model, which has reliably reproduced the results of standard short-course chemotherapy ; however, the murine model has been criticized because mice do not develop cavities and caseous necrosis, pathologic hallmarks of human tuberculosis . Other animal models have been proposed, but none fully replicates the human response to M. tuberculosis . Recent evidence suggests that extracellular bacilli in necrotic material within cavities may be the major challenge to prevention of relapse after therapy. Studies using sensitive analytic tools such as positron emission tomography-computed tomography scanning and matrix-assisted laser desorption/ ionization mass spectrometry imaging in experimental animals and in patients undergoing pulmonary resection have provided evidence of the marked differences in the ability of key drugs (RIF, PZA, levofloxacin, moxifloxacin) to penetrate into pulmonary tissue, into the cellular granuloma, and into caseous material within cavities . However, the pathologic sites from which relapses arise remain unclear. Objective 3: Protection against acquisition of drug resistance (through use of multidrug therapy): The basic biology underlying the acquisition of drug resistance is well understood, though the details involving some individual agents are still uncertain. As a rule, genetic mutations conferring substantial resistance to individual antituberculous agents occur at constant low rates. For example, rifamycins act primarily by inhibiting the action of bacterial RNA polymerase in the translation of DNA to RNA, by binding to and obstructing access to a subunit of the bacterial RNA polymerase. Mutations in a relatively limited (81 base pairs ) genomic segment encoding for this subunit lead to obstruction of rifamycin binding to the polymerase β subunit (rpoB); more than half a dozen amino acid substitutions conferring RIF resistance have been well described. In the case of PZA, resistance is most often conferred by mutations in the pncA gene, which encodes for an amidase that is required to convert PZA, a prodrug, into its active form, pyrazinoic acid. The pncA mutations occur throughout the 350-bp gene, with no notable preference for specific mutations yet described. INH is also a prodrug requiring activation by a bacterial catalase-peroxidase enzyme (encoded by katG), coupling with NADH, and binding to an acyl carrier protein reductase (encoded by inhA); the process inhibits the synthesis of mycolic acid needed for the mycobacterial cell wall. Resistance to INH arises through multiple mechanisms, including loss of the katG-encoded catalase peroxidase activity, and overexpression or alterations in the inhAencoded reductase . The frequency of mutation engendering resistance to specific agents was estimated some 40 years ago; the highest proportion of resistant mutants expected in an unselected bacterial population were 3.5 × 10 −6 for INH and 3.1 × 10 −8 for RIF . Because these mutations generally occur independently, the likelihood of simultaneous resistance mutations to both INH and RIF is in the range of 11 × 10 −14 . Thus, in patients with very high bacillary burdens, the occurrence of mutations conferring resistance to a single drug is likely, to 2 drugs is possible, but to 3 drugs is highly unlikely . Acquisition of drug resistance might occur more readily if there is irregular or sporadic drug taking, inadequate drug absorption, inadequate drug dosing, or ill-informed use of single drug treatment (either by error, or because tuberculosis has not been recognized or considered). If resistance to a specific drug occurs, then the resistant clone will possess an advantage relative to susceptible strains when confronted with that drug, and will have no advantage (or possibly a modest disadvantage, if the mutation confers some biologic "cost") if the drug is not used. In the situation of the standard 3-drug regimen (INH, RIF, PZA), 3 circumstances must likely be present for resistance to RIF to emerge: (1) some mutant bacilli resistant to RIF must be present or appear; (2) the bacilli must be exposed to RIF to favor multiplication of the resistant bacteria; and (3) INH and PZA must not be present in sufficient concentration to offset the survival advantage enjoyed by the RIF-resistant clones; this could occur because they are not employed at all (ie, single drug therapy), or because some combination of circumstances affects the other drugs (eg, a nonacidic compartment is involved thereby disadvantaging PZA, and INH happens to be rapidly metabolized , so that INH is not present in adequate concentration) . # Multiple Factors Influence the Outcome of Tuberculosis Treatment Multiple interrelated factors have been associated with the outcome of tuberculosis therapy. These include: - Patient factors, such as age, comorbid conditions, immunologic competence, nutritional status, alcohol abuse; - Radiographic features, such as extent of disease, presence and size of cavities; - Microbiologic factors, such as baseline colony count, culture positivity at 2 or 3 months; - Genetic factors, including individual genetic features of drug absorption and metabolism, individual vulnerability to toxicities, immunologic characteristics; - Programmatic factors, including adherence support interventions (enhancers, enablers, monitoring, supervision/DOT), dosing frequency; - Pharmacokinetic factors, such as absorption, metabolism, protein binding, drug clearance, total drug quantities administered; - Bacillary factors, such as drug tolerance, strain susceptibilities to drugs in the regimen; and - Regimen factors, such as number of active drugs, bactericidal and sterilizing potency, synergy or antagonism, and duration of therapy in relation to drugs employed. The success of therapy depends upon many diverse elements, only some of which are presently predictable, identifiable, or modifiable. Numerous studies have found an increased risk of relapse among patients with signs of more extensive disease (ie, cavitation or more extensive disease on chest radiograph) , and/or slower response to treatment (ie, culture status at 2 or 3 months) . Better understanding of the causal pathways through which these elements exert their effect, and greater ability to identify and quantify each of these, should lead to increased therapeutic success, and will inform efforts to develop shorter, less toxic, and better-tolerated treatment regimens in the future . # ORGANIZATION AND SUPERVISION OF TREATMENT PICO Question 1: Does adding case management interventions to curative therapy improve outcomes compared to curative therapy alone among patients with tuberculosis? (Case management is defined as patient education/counseling, field/ home visits, integration/coordination of care with specialists and medical home, patient reminders, incentives/enablers). Recommendation 1: We suggest using case management interventions during treatment of patients with tuberculosis (conditional recommendation; low certainty in the evidence). PICO Question 2: Does self-administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of tuberculosis? Recommendation 2: We suggest using DOT rather than SAT for routine treatment of patients with all forms of tuberculosis (conditional recommendation; low certainty in the evidence). # Role of Health Department Due to the public health implications of prompt diagnosis and effective treatment of tuberculosis, most low-incidence countries designate a government public health agency as having legal authority for controlling tuberculosis . To effectively carry out this charge, the public health agency conducts ongoing epidemiologic surveillance of tuberculosis, ensures access to quality-assured microbiological laboratory services, maintains an uninterrupted supply of antituberculosis medications, and monitors and reports treatment outcomes . The public health agency may also have the authority to apply legal measures in situations of nonadherence as a last resort where other interventions have been pursued without effect. In some jurisdictions diagnostic and treatment services are provided directly by the public health agency, whereas in others, these services are provided by the private sector or by a combination of public and private providers. # Patient-Centered Care and Case Management Patient-centered care respects an individual's right to participate actively as an informed partner in decisions and activities related to tuberculosis diagnosis and treatment . The Institute of Medicine defines patient-centered care as "providing care that is respectful of and responsive to individual patient preferences, needs, and values, and ensuring that patient values guide all clinical decisions" . Given that tuberculosis treatment requires multiple drugs be given for several months, it is crucial that the patient be involved in a meaningful way in making decisions concerning treatment supervision and overall care. International standards have been developed that also support using patient-centered approaches to the management of tuberculosis . The optimal organization of tuberculosis treatment often requires the coordination not only of primary and specialty clinical care services, but also community-based organizations and agencies in the public and private sectors . The inherent complexities of the healthcare delivery system combined with the diversity of characteristics of patients are best addressed by providing individualized patient-centered case management . In most settings, a patient is assigned a case manager who assesses needs and barriers that may interfere with treatment adherence . With active input from the patient and healthcare providers, the case manager, together with the patient, develops an individualized case management plan with interventions to address the identified needs and barriers . The plan is reviewed periodically and revised as needed with the patient and medical team to evaluate the clinical response to therapy, monitor potential drug toxicities, and address any challenges identified with adherence. The spectrum of interventions for achieving adherence may range from routine monthly monitoring to legal confinement , with confinement being used only as a last resort. The least restrictive public health interventions that are effective are used to achieve adherence. Key considerations when developing a case management plan include (1) improving "treatment literacy" by educating the patient about tuberculosis and its treatment, including possible adverse effects ; (2) discussing expected outcomes of treatment, specifically the ability to cure the patient of the disease; (3) reviewing methods of supervision and assessing response to therapy; and (4) discussing infectiousness and infection control measures using terminology that is appropriate to the culture, language, age, and reading level of the patient . For non-English-speaking patients, the use of medical interpreter services is preferred over using family or friends as interpreters . Relevant information should be reinforced at each visit. Other components of the patient-centered case management plan include, but are not limited to, setting up patient reminders and systems to follow-up missed appointments , use of incentives and enablers , field and home visits , integration and coordination of tuberculosis care with the patient's primary and specialty care, and legal interventions when indicated (Table 4). Overall, the quality of evidence is variable in the few studies examining the impact of case management interventions on outcomes such as treatment success; however, these studies suggest that for the most part, patient-centered case management interventions are helpful with little evidence of harm to patients (see Supplementary Appendix B, Evidence Profiles 1-3). For these reasons, we suggest using case management interventions during treatment of patients with tuberculosis (Recommendation 1: conditional recommendation; very low certainty in the evidence). # Approaches to Ensuring Adherence and Treatment Success Given the critical importance of chemotherapy, both to the patient and to the public, approaches to ensuring adherence to the treatment regimen are a major focus of the overall management plan. To maximize completion of therapy, management strategies should utilize a broad range of approaches. Among these, DOT, the practice of observing the patient swallow her or his antituberculosis medications, has been widely used and deserves special emphasis. To be consistent with the principles of patient-centered care, decisions regarding the use of DOT must be made in concert with the patient . For example, DOT can be provided in the office, clinic, or in the "field" ( patient's home, place of employment, school, or any other site that is mutually agreeable) by appropriately trained personnel . DOT enables early identification of adverse drug reactions, clinical worsening of tuberculosis, and nonadherence . Moreover, frequent contact with the patient allows providers to facilitate linkage to other medical care and services. However, the implementation of DOT may not be readily feasible when resources are limited . In such circumstances, patients who are more likely to present a transmission risk to others or are more likely to have difficulty with adherence are prioritized for DOT . In addition, experts advise that DOT must be used with regimens that use intermittent drug administration because of the potential serious consequences of missed doses. Careful attention is needed to ensure that ingestion of the medication is, in fact, observed, as the use of DOT does not guarantee ingestion of all doses of every medication . Patients may miss appointments, may not actually swallow the tablets or capsules, or may deliberately regurgitate the medications. Consequently, the use of DOT does not mitigate the continued need for monitoring for signs of treatment failure. DOT is also advised for all patients residing in institutional settings such as hospitals, nursing homes, opiate replacement clinics, or correctional facilities. In special populations such as individuals with treatment failure, recurrence, or at risk for disseminated tuberculosis (eg, HIV coinfected), experts recommend against the use of SAT given the risks involved in developing drug resistance (Table 5). In recent years, DOT has expanded to other modalities such as web-based video and mobile phones, which have been well received by both patients and health department staff . Special attention to maintaining patient privacy is needed when web-based and wireless modalities are used for monitoring. Systematic reviews of studies conducted in countries with high, medium, and low burdens of tuberculosis have not shown improvement in cure or treatment completion in patients receiving their antituberculosis treatment by DOT compared with SAT . The systematic review conducted to obtain evidence in support of this practice guideline also did not find any significant differences between SAT and DOT when assessing several outcomes of interest, including mortality, treatment completion, and relapse (see Supplementary Appendix B, Evidence Profile 4). However, DOT was significantly associated with improved treatment success (the sum of patients cured and patients completing treatment) and with increased sputum smear conversion during treatment, as compared to SAT. Because DOT is a multifaceted public health intervention that is not amenable to the conventional clinical trials approaches to assessing benefits, and because participation in DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities, for allowing providers to establish rapport with the patient and for addressing treatment complications expeditiously, DOT remains the standard of practice in the majority of tuberculosis programs in the United States and Europe . Population-based studies (representing a low quality of evidence) have suggested that tuberculosis treatment by DOT in comparison to SAT is associated with a reduction in the acquisition and transmission of drugresistant M. tuberculosis (Texas), increased treatment success in HIV-infected patients receiving RFB-containing regimens, shorter duration for completion of treatment (New York City), higher treatment completion rates in incarcerated patients transitioning to the community (Chicago), and a reduction in mortality and loss to follow-up (Brazil) . Consequently, we suggest using DOT rather than SAT for routine treatment of patients for all forms of tuberculosis (Recommendation 2: conditional recommendation; low certainty in the evidence). # Transfers Between Jurisdictions Patients being treated for tuberculosis who move from one jurisdiction to another before completion of therapy are more likely to be lost to follow-up than patients who do not move . In the United States, health departments track patients via interjurisdictional referrals, and can use other patient tracking mechanisms (eg, TBNet at / services/network/tbnet.html) for patients who travel internationally) . # Legal Interventions to Protect Public Health In extreme circumstances, nonadherent patients may be subject to legal intervention in the form of court-ordered medical examination, DOT, completion of therapy, or civil or criminal detention for completion of tuberculosis treatment when less restrictive measures have been tried and shown to fail . These situations involve special circumstances such as drug resistance, evidence of treatment failure or relapse, and continued concern for transmission in the community, thereby justifying the temporary restriction of individual rights to protect the public's health and safety. Public health laws exist in most jurisdictions that allow these legal interventions, at least for patients who remain infectious, but they should be pursued as a plan of last resort. In the United States, health departments have the sole authority to initiate legal action, and generally the interventions produce good outcomes with treatment completion rates >95% . Outside the United States, legal authority to enforce tuberculosis adherence may originate in other government agencies outside the health department . RECOMMENDED TREATMENT REGIMENS PICO Question 3: Does intermittent dosing in the intensive phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug-susceptible pulmonary tuberculosis? Recommendation 3a: We recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 3b: Use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; low certainty in the evidence). Recommendation 3c: In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; very low certainty in the evidence). Note: If doses are missed in a regimen using twice-weekly dosing then therapy is equivalent to once weekly, which is inferior (see PICO Question 4). PICO Question 4: Does intermittent dosing in the continuation phase have similar outcomes compared to daily dosing in the continuation phase in patients with drug-susceptible pulmonary tuberculosis patients? Recommendation 4a: We recommend the use of daily or thriceweekly dosing in the continuation phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 4b: If intermittent therapy is to be administered in the continuation phase, then we suggest use of thrice-weekly instead of twice-weekly therapy (conditional recommendation; low certainty in the evidence). This recommendation allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior. Recommendation 4c: We recommend against use of once-weekly therapy with INH 900 mg and rifapentine (RPT) 600 mg in the continuation phase (strong recommendation; high certainty in the evidence). In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus RPT 600 mg may be considered for use only in HIV-uninfected persons without cavitation on chest radiography. # Deciding to Initiate Treatment Empiric treatment with a 4-drug regimen is initiated promptly in patients (children and adults) with high likelihood of having tuberculosis or those seriously ill with a disorder suspicious for tuberculosis, even before AFB smear microscopy, molecular tests, and mycobacterial culture results are known. Initiation of treatment is not delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. The decision to initiate combination chemotherapy for tuberculosis is based on multiple factors including clinical, radiographic, laboratory, patient, and public health factors (Figure 1). Clinical judgment and index of suspicion also play a critical role in deciding to initiate treatment. In addition to smear microscopy and mycobacterial culture, CDC recommends the use of a rapid molecular test on at least one specimen from each patient with signs and symptoms of pulmonary tuberculosis for whom a diagnosis of tuberculosis is being considered but has not been established, and for whom the test result would alter case management or tuberculosis control activities . Use of molecular tests directly on clinical samples has been shown to shorten time to diagnosis, and some tests have the additional ability to provide information on drug susceptibility . In the presence of a clinical syndrome compatible with tuberculosis, a positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive rapid molecular test, or is strongly inferred from clinical or radiographic improvement consistent with a response to tuberculosis treatment, the regimen is continued to complete a standard course of therapy. In patients with a positive AFB smear, but a negative rapid molecular test (including an assessment for polymerase chain reaction inhibitors, reported to be present in 2%-5% of respiratory specimens tested by nucleic acid amplification tests ), it is unlikely that the positive smear is due to M. tuberculosis, particularly when molecular testing of a second smear-positive specimen is also negative . If empiric treatment is started, cultures throughout are negative, and there is no response to treatment, yet the interferon-γ release assay (IGRA) or purified protein derivative (PPD)-tuberculin skin test (TST) is positive, consideration is given to treatment of latent tuberculosis infection using the following options: (1) stop treatment if RIF and PZA were included in the initial empiric 4-drug therapy, administered for at least 2 months ; (2) continue treatment with RIF, with or without INH, for a total of 4 months; (3) give 12 weekly doses of INH/RPT by DOT ; or (4) continue treatment with INH for a total of 9 months . In patients in whom there is a low suspicion for active tuberculosis (not initially treated), if cultures remain negative, the IGRA or PPD-TST is positive (≥5 mm), and the abnormal chest radiograph is unchanged after 2 months (ATS/CDC class 4), treatment for latent tuberculosis infection is indicated . If not previously treated, these patients are at increased risk for development of active tuberculosis with case rates 2.5-19 times higher than those of persons infected by M. tuberculosis with normal chest radiographs . These patients are high-priority candidates for treatment of latent tuberculosis infection. If clinical suspicion for active tuberculosis is low, the options are to begin treatment with combination chemotherapy or to defer treatment until additional data have been obtained to clarify the situation (usually within 2 months). An advantage of the early use of combination chemotherapy is that once active disease is excluded by negative cultures and lack of clinical or radiographic response to treatment, the patient will have completed 2 months of combination treatment that can be applied to the total duration of treatment for latent tuberculosis infection. Even when the suspicion for active tuberculosis is low, treatment for latent tuberculosis infection with a single drug is not initiated until active tuberculosis has been excluded, usually by negative cultures. In general, for complicated diagnostic or management situations, consultation with local and state health departments is advised. In the United States, the CDC's Division of Tuberculosis Elimination funds tuberculosis regional training and medical consultation centers (/), which provide medical consultation to programs and health providers on management of tuberculosis. In Europe, the WHO and ERS Tuberculosis Consilium (. tbconsilium.org) provides similar consultation services regarding the diagnosis and treatment of tuberculosis. # Regimens The preferred regimen and other choices are listed in Table 2. Patient factors should be considered when selecting administration schedule (intermittency), and in some instances regimen composition. Feasibility of DOT is sometimes an additional consideration when selecting frequency of administration. Regimens for adults and children are identical except in uncommon circumstances where it may be acceptable to omit EMB from the initial treatment regimen for young children (see "Children"). For all regimens, patients are treated until they have received the specified total number of doses for the treatment regimen (ie, not solely based on duration of treatment). # Preferred Regimen The preferred regimen for treating adults with tuberculosis caused by organisms that are not known or suspected to be drug resistant is a regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF . To reduce the risk of relapse, the continuation phase of treatment is extended for an additional 3 months for patients who had cavitation on the initial (or follow-up) chest radiograph and, in addition, are culture positive at the time of completion of the intensive phase of treatment. The intensive phase of treatment consists of 4 drugs (INH, RIF, PZA, EMB) because of the current proportion of new tuberculosis cases worldwide caused by organisms that are resistant to INH ; however, if therapy is being initiated after drug susceptibility test results are known and the patient's isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. With respect to administration schedule, the preferred frequency is once daily for both the intensive and continuation phases. Based on systematic reviews conducted to obtain evidence in support of this guideline (see Supplementary Appendix B, Evidence Profiles 5-10), we recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drug-susceptible pulmonary tuberculosis (Recommendation 3a: strong recommendation; moderate certainty in the evidence). For the continuation phase, based on systematic reviews conducted to obtain evidence in support of this guideline (see Supplementary Appendix B, Evidence Profiles 5-10), we recommend use of daily or thrice-weekly dosing for the continuation phase of therapy (Recommendation 4a: strong recommendation; moderate certainty in the evidence). Although administration of antituberculosis drugs using DOT 5 days a week has been reported in a large number of studies, it has not been compared with 7-day administration in a clinical trial. Nonetheless, on the basis of substantial clinical experience, experts believe that 5-days-a-week drug administration by DOT is an acceptable alternative to 7-days-a-week administration, and either approach may be considered as meeting the definition of "daily" dosing. Patient-centered care, case management, and DOT are discussed in the "Organization and Supervision of Treatment" section of this guideline. # Other Regimens There are alternative regimens that are variations of the preferred regimen. As described below, alternative regimens may be acceptable in certain clinical and/or public health situations (see "Treatment in Special Situations"). An administration frequency of less than daily in the intensive phase of treatment is generally not preferred. # Thrice-Weekly Dosing Throughout In HIV-uninfected patients with noncavitary disease caused by drug-susceptible organisms, thrice-weekly (ie, 3 times per week) dosing throughout both intensive and continuation phases of treatment by DOT may be considered when daily treatment is not feasible or poorly tolerated. Thrice-weekly dosing has been associated with higher rates of treatment failure, relapse, and acquired drug resistance in high-quality systematic reviews . The risks for these poor outcomes of treatment were higher in HIV-infected patients (especially if not treated with antiretrovirals), and patients with cavitary disease or baseline drug resistance. Based on evidence supporting the recommendations obtained through systematic reviews (see Supplementary Appendix B, Evidence Profiles 5,6,8-10), use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (Recommendation 3b: conditional recommendation; low certainty in the evidence). # Twice-Weekly Dosing Throughout or Twice-Weekly Dosing After 2-3 Weeks of Daily Dosing Twice-weekly dosing (ie, 2 times per week) either throughout treatment or after an initial period of 2-3 weeks of daily therapy is not generally recommended because of a lack of high-quality evidence to support its use, and because in twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior (see "Once-Weekly Continuation Phase," below). However, some tuberculosis programs have reported longstanding programmatic treatment success with an initial daily regimen followed by twice-weekly therapy , and this regimen remains in use by some public health programs in the United States. In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV infected and are also at low risk of relapse ( pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (Recommendation 3c: conditional recommendation; very low certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 7). # Twice-Weekly Continuation Phase Twice weekly treatment in the continuation phase has been studied in clinical trials , and is used by US tuberculosis control programs. Based on our systematic review, if intermittent therapy during the continuation phase is considered, then we suggest use of thrice-weekly instead of twice-weekly therapy. (Recommendation 4b: conditional recommendation; low certainty in the evidence) (see Supplementary Appendix B, Evidence Profiles 5-8). As noted above for twice-weekly regimens, an advantage of a thrice-weekly regimen is that it allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior (see "Once-Weekly Continuation Phase," below). # Once-Weekly Continuation Phase In clinical trials, once-weekly treatment with INH plus RPT 600 mg was less active than standard RIF-based treatment . In the Tuberculosis Trials Consortium (TBTC) Study 22, characteristics independently associated with increased risk of failure or relapse were sputum culture positivity at the end of intensive phase, cavitation on chest radiograph, being underweight, bilateral pulmonary involvement, and being a non-Hispanic white person . Furthermore, relapse with rifamycin-monoresistant tuberculosis occurred among HIV-infected tuberculosis patients treated with the once-weekly INH/RPT continuation phase regimen . In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus RPT 600 mg may be considered for use only in HIV-uninfected persons without cavitation on chest radiography. Otherwise, we recommend against use of once-weekly therapy with INH 900 mg plus RPT 600 mg (Recommendation 4c: strong recommendation; high certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 11). # Alternative Regimen Composition In some cases, either because of intolerance to first-line drugs or the presence of monoresistance, an alternative regimen may be required. If PZA cannot be included in the initial regimen, or the isolate is determined to be resistant to PZA (an unusual circumstance, except for M. bovis and M. bovis var BCG), experts recommend a regimen consisting of INH, RIF, and EMB for the initial 2 months followed by INH and RIF for 7 months given either daily or thrice weekly. # Fluoroquinolones (Moxifloxacin and Levofloxacin) In scenarios in which EMB or INH cannot be used, the role of moxifloxacin or levofloxacin has not been established through clinical trials. Experts on occasion use moxifloxacin or levofloxacin in place of EMB during intensive phase in adults in whom EMB cannot be used, or in place of INH throughout treatment in adults in whom INH cannot be used (see Supplementary Appendix C: Drugs in Current Use for details on adverse effects of fluoroquinolones, including QT prolongation). There is no evidence that moxifloxacin or levofloxacin can be used in place of a rifamycin or PZA while maintaining a 6-month treatment duration. If a rifamycin cannot be included in the initial regimen due to resistance or intolerance, then a regimen based on the principles described for treating drug-resistant tuberculosis is used. In situations in which several of the first-line agents cannot be used because of intolerance, regimens based on the principles described for treating drug-resistant tuberculosis are used. Importantly, all alternative regimens using fluoroquinolones in place of EMB or INH are 6 months or longer in duration. There is definitive clinical trial evidence that 4-month daily regimens that substitute moxifloxacin or gatifloxacin for EMB, or moxifloxacin for INH, are significantly less effective than the preferred, standard daily 6-month treatment for drug-susceptible pulmonary tuberculosis . Therefore we recommend against the routine use of 4-month fluoroquinolone-containing regimens for treatment of drug-susceptible pulmonary tuberculosis. A single randomized trial showed that a regimen of daily moxifloxacin/RIF/PZA/EMB for 2 months followed by once-weekly 1200 mg RPT + 400 mg moxifloxacin for 4 continuation phase months had relapse rates similar to the standard 6-month regimen given daily . Use of this regimen (including a daily moxifloxacin-containing intensive phase) may be considered. It is important to note that each dose of RPT was preceded by a meal of 2 boiled eggs and slices of bread, provided to increase the absorption of RPT. If this regimen is used, it is ideally implemented within the context of program-based operational research with suitable monitoring . Of note, there is no evidence that a once-weekly continuation phase comprised of 1200 mg RPT + 400 mg moxifloxacin after 2 months of intensive phase INH/RIF/PZA/EMB (ie, without moxifloxacin in place of EMB in the intensive phase), would achieve similar outcomes. # Baseline and Follow-up Evaluations Recommended baseline and follow-up evaluations for patients suspected of having tuberculosis and treated with first-line medications are summarized in Figure 2. At baseline, patients in whom pulmonary tuberculosis is suspected have 3 appropriate sputum specimens collected for microscopic examination and mycobacterial culture, and at least one specimen is tested with a rapid molecular test. When the lung is the site of disease, 3 sputum specimens are obtained 8-24 hours apart . In patients who are not producing sputum spontaneously, induction of sputum using aerosolized hypertonic saline or bronchoscopy ( performed under appropriate infection-control procedures) may be necessary to obtain specimens. Susceptibility testing for INH, RIF, EMB, and PZA is performed on an initial positive culture, regardless of the source. A rapid molecular test for drug resistance is performed in patients at risk for drugresistant tuberculosis, and when resources permit, may be performed in all patients . Second-line drug susceptibility testing should be done only in reference laboratories and is limited to specimens from patients who have had prior therapy, have been in contact with a patient with known multidrug or extensively drug-resistant tuberculosis, have suspected or demonstrated resistance to RIF and/or other first-line drugs, are unable to tolerate RIF, or who have positive cultures after >3 months of treatment . During treatment of patients with pulmonary tuberculosis, at a minimum, a sputum specimen for AFB smear and culture are obtained at monthly intervals until 2 consecutive specimens are negative on culture. Duration of the continuation phase regimen hinges on the microbiological status at the end of the intensive phase of treatment, thus, obtaining sputum specimens at the time of completion of 2 months of treatment is critical if sputum culture conversion to negative has not already been documented. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (for example, every 2 weeks until 2 consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations with high risk of transmission. On occasion, AFB-positive sputa are culture-negative; this occurs most frequently among patients with far-advanced cavitary tuberculosis after the first few months of treatment. It is thought that AFB smear positive (but culture-negative) sputa contain organisms that are dead and that their presence is not a sign of treatment failure, even when noted later in treatment. Dead organisms also can cause a positive result on molecular tests; routine performance of molecular tests on follow-up sputum samples, after an initial positive test, is not useful. Drug susceptibility tests are repeated on M. tuberculosis isolated in culture from sputum obtained after a patient has been on treatment for ≥3 months. As described in the "Treatment Failure" section, patients who have M. tuberculosis isolated in culture from sputum obtained after 4 months of treatment are considered as having failed treatment and managed accordingly. For patients with positive cultures at diagnosis, a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential. Tuberculosis programs often conduct a chest radiograph at completion of therapy as it provides a baseline against which subsequent examinations can be compared, but, as with the 2-month examination, it is not essential. When the initial sputum cultures are negative, a presumptive diagnosis can be made if radiographic improvement is noted, generally by the time 2-3 months of treatment have been completed . Thus, based on expert opinion, in patients with negative initial cultures, a chest radiograph is recommended after 2-3 months of treatment and at the completion of treatment to document response to therapy. Generally, systematic follow-up after completion of therapy is not necessary. In addition to the microbiological and imaging examinations discussed here, other appropriate assessments and laboratory tests are summarized in Figure 2. For patients with extrapulmonary tuberculosis, the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained. Monitoring assessments for patients treated with second-line drugs are listed by drug in Supplementary Appendix C: Drugs in Current Use. # Identification and Management of Patients at Increased Risk of Relapse The culture result of a sputum specimen obtained at the completion of the intensive phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis, albeit with low sensitivity . Cavitation on the initial chest radiograph has also been shown to be a risk factor for relapse . In patients treated for 6 months, having both cavitation and a positive culture at completion of 2 months of therapy has been associated with rates of relapse of approximately 20% compared with 2% among patients with neither factor . The most effective means of decreasing the likelihood of relapse for patients at risk has not yet been determined by clinical trials; however, indirect evidence from a controlled clinical trial and an observational study among patients with pulmonary tuberculosis in Hong Kong showed that prolonging treatment decreased the rate of relapse . It has also been reported that for patients at high risk of relapse, prolongation of the once-weekly INH/RPT continuation phase from 4 to 7 months resulted in a decreased rate of relapse . In view of this evidence, for patients who have cavitation on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy, expert opinion is to extend the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy). Because patients who had either cavitation on the initial chest radiograph or a positive culture at 2 months had an increased rate of relapse , patients with one or the other of these risk factors are followed more closely and consideration given to extending treatment duration if there are suggestions of a poor response. Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being >10% below ideal body weight; being a smoker; having diabetes, HIV infection, or other immunosuppressing condition; or having extensive disease on chest radiograph . # Interruptions in Therapy Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart treatment from the beginning. Continuous treatment is more important in the intensive phase of therapy when the bacillary population is highest and the chance of developing drug resistance greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriologic status of the patient prior to and after the interruption are also important considerations. There is no evidence upon which to base detailed recommendations for managing interruptions in treatment, and no recommendations will cover all of the situations that may arise. The approach summarized in Table 6 (modified from the New York City Bureau of Tuberculosis Control ) is presented as an example. When interruptions are due to an interim loss of follow-up, at the time the patient is returned to treatment, additional sputum are obtained for repeat culture and drug susceptibility testing. If the cultures are still positive, the treatment regimen is restarted. If sputum cultures are negative, the patient could be treated as having culture-negative tuberculosis and given an additional 4 months of INH and RIF chemotherapy, as long as the original specimen was drug susceptible and the original intensive phase regimen included INH, RIF, and PZA. Regardless of the timing and duration of the interruption, DOT is used subsequently. If the patient was already being managed with DOT, additional measures will be necessary to ensure completion of therapy. Consultation with an expert is advised to assist in managing treatment interruptions. # Definition of Completion of Therapy The determination of whether or not treatment has been completed is based on the total number of doses taken-not solely on the duration of therapy (Table 2). Tuberculosis control program practice in the United States and in several European countries is to administer all of the specified number of doses for the intensive phase within months and those for the 4-month continuation phase within 6 months, so that the 6-month regimen is completed within 9 months. If these targets are not met, the patient must be considered to have interrupted therapy and be managed as described above (Table 6). # PRACTICAL ASPECTS OF TREATMENT # Drug Administration In general, tuberculosis drugs are administered together, at one dosing so as to achieve maximal peak serum concentrations and to facilitate DOT. Bioavailability of all of the drugs (except for RPT) is greatest when taken on an empty stomach. The exception is RPT, for which bioavailability increases by up to 86% with high-fat meals . If medications need to be combined with food or liquid for dosing, keep in mind that INH absorption decreases when combined with glucose or lactose; crushed INH tablets in foods containing low glucose, such as sugar-free pudding, are stable. However, crushed tablets mixed with food should not be stored for later use . The commercially prepared INH elixir uses sorbitol as the vehicle; sorbitol may also cause diarrhea, thereby limiting its use. Parenteral drug administration is indicated for severely ill patients who cannot take oral therapy, and may be useful for the uncommon patient with suspected or documented malabsorption. Of the first-line drugs, parenteral preparations of INH and RIF, as well as most fluoroquinolones, are available. # Fixed-Dose Combination Preparations Clinical trials and a recent systematic review have concluded that overall, there is no significant difference between fixeddose combinations (FDCs) and single-drug combinations for key outcomes, including sputum smear or culture conversion, failure, relapse, death, serious adverse events, or adverse events that lead to discontinuation of therapy . The patient-specific advantages to using FDC drugs include ease of administration and the potential for reducing medication errors. The key program and clinician-specific advantage of FDC formulations is the simplification of drug supply management ( procurement, storage, and distribution) and simpler prescription writing. If FDCs are used, clinicians should be aware that FDC and non-FDC products have similar commercial names with different drug compositions, including Rifadin (RIF only), Rifamate (INH and RIF), and Rifater (INH, RIF, and PZA) (see Supplementary Appendix C). # Management of Common Adverse Effects Mild adverse effects usually can be managed with treatment directed at controlling the symptoms; severe effects usually require the offending drug(s) to be discontinued. If a drug is permanently discontinued, then a replacement drug, typically from a different drug class, is included in the regimen. Patients with severe tuberculosis often require the initiation of an alternate regimen during the time the offending drug(s) are held. Management of serious adverse effects often requires expert consultation. The suggested practices listed below for handling common adverse effects during treatment (ordered from most to least common) are based on expert opinion. Gastrointestinal Upset; Nausea, Vomiting, Poor Appetite, Abdominal Pain Gastrointestinal reactions are common, especially early in therapy . The optimum approach to management of epigastric distress or nausea with tuberculosis drugs is not clear. To minimize symptoms, patients receiving SAT may take the medications at bedtime. Gastrointestinal intolerance not associated with hepatotoxicity can be treated with antacids, which have less impact on absorption or peak concentration of first-line drugs than administration with food . Some experts report success with proton pump inhibitors for reducing gastrointestinal upset. Any combination of otherwise unexplained nausea, vomiting, and abdominal pain is evaluated with a physical examination and liver function tests, including ALT, AST, bilirubin, and alkaline phosphatase to assess for possible hepatotoxicity . Alternatively, a light snack (low-fat food) such as a cracker might suffice for some patients. Either option is preferable to splitting a dose or changing to a second-line drug. It is important to note that divalent cations (calcium, iron, zinc) as occur in some antacids and nutritional supplements are not coadministered with fluoroquinolones because they decrease absorption of the drug, possibly leading to treatment failure . # Rash All antituberculosis drugs can cause a rash, the severity of which determines management . If the rash is mainly itchy without mucous membrane involvement or systemic signs such as fever, treatment is symptomatic with antihistamines, and all antituberculosis medications can be continued. A petechial rash is more concerning and suggests thrombocytopenia from a rifamycin (ie, RIF, RFB, RPT) hypersensitivity . If the platelet count is low, the rifamycin is permanently stopped and the platelet count closely monitored until definite improvement is noted. Drugs are also stopped if the patient has a generalized erythematous rash. Fever and/or mucous membrane involvement suggests Stevens-Johnson syndrome, toxic epidermal necrosis, or drug reaction with eosinophilia and systemic symptoms syndrome or drug hypersensitivity syndrome. Hypersensitive reactions to multiple antituberculosis drugs have been noted, particularly in persons with HIV infection . Some experts manage severe systemic reactions in the inpatient setting, using an interval of several days between drug rechallenges, closely monitoring markers of hypersensitivity (such as rash, fever, transaminitis, eosinophilia, pruritus, etc). If any of these markers develop, then the drug is stopped and identified as the offender, eliminating it from the regimen. Systemic corticosteroids may be used to treat severe systemic reactions. Using steroids to treat systemic reactions, even in the setting of severe tuberculosis, has not worsened outcomes . When the rash has substantially improved, medications can be restarted individually at intervals of 2-3 days. RIF is restarted first (the most potent drug), followed by INH, then EMB or PZA. If the rash recurs, the last drug added is stopped. If the first 3 drugs have been restarted without a rash, the fourth drug is not restarted unless the rash was mild and that drug essential. Research evaluating drug provocation tests or drug desensitization strategies is needed . # Drug Fever Drug fever is essentially a diagnosis of exclusion. Other causes of fever such as tuberculosis (fever may persist 2 months or longer into treatment) ; paradoxical reaction, especially in HIV-infected patients (See "HIV Infection") ; and superinfection must be excluded. Patients with drug fever generally feel well despite body temperatures ≥39°C. Drug fever does not follow a specific pattern and eosinophilia need not be present. Stopping drugs usually resolves the fever within 24 hours. Once afebrile, the patient should restart drugs individually every 2-3 days, similar to the approach to drug rechallenge for rash. # Hepatotoxicity Drug-induced hepatitis is the most frequent serious adverse reaction to the first-line drugs (see "Hepatic Disease" and Supplementary Appendix C). INH, RIF, and PZA can cause druginduced liver injury, which is suspected when the ALT level is ≥3 times the upper limit of normal in the presence of hepatitis symptoms, or ≥5 times the upper limit of normal in the absence of symptoms . If the ALT level is 10 times normal (ie, >500 IU) is severe. An asymptomatic increase in ALT concentration occurs in nearly 20% of patients treated with the standard 4-drug regimen . In the absence of symptoms, therapy should not be altered because of modest asymptomatic elevations of ALT, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic ALT elevations resolve spontaneously. However, if ALT levels are ≥5 times the upper limit of normal (with or without symptoms) or ≥3 times normal in the presence of symptoms, hepatotoxic drugs are stopped immediately and the patient is evaluated carefully. Similarly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation; disproportionate increases in bilirubin and alkaline phosphatase (as compared to increases in serum ALT) may be seen with RIF hepatotoxicity . Other causes of abnormal liver tests must be excluded before diagnosing drug-induced hepatitis (Table 7). If ALT levels are consistent with hepatotoxicity, all hepatotoxic drugs must be stopped and serum ALT and prothrombin time or international normalized ratio (INR) levels followed until levels return to baseline. Consult a liver specialist if the patient's clinical or laboratory status continues to worsen. Once the ALT concentration returns to <2 times the upper limit of normal, antituberculosis medications are restarted individually (see for additional details). In patients with elevated baseline ALT from preexisting liver disease, drugs are restarted when the ALT returns to near-baseline levels. The optimal approach to reintroducing tuberculosis treatment after hepatotoxicity is not known ; however, most tuberculosis programs use sequential reintroduction of drugs. Because RIF is much less likely to cause hepatotoxicity than INH or PZA, it is restarted first. If there is no increase in ALT after approximately 1 week, INH may be restarted. PZA can be started 1 week after INH if ALT does not increase. If symptoms recur or ALT increases, the last drug added should be stopped. If RIF and INH are tolerated and hepatitis was severe, PZA can be assumed to be responsible and is discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, the total duration of therapy might be extended to 9 months. # Optic Neuritis EMB-related visual impairment during treatment of active tuberculosis has been estimated to occur in 22.5 per 1000 persons (2.25%) receiving EMB at standard doses (see Supplementary Appendix C). The onset of optic neuritis is usually >1 month after treatment initiation but can occur within days . The opinion of experts is that baseline visual acuity (Snellen test) and color discrimination tests followed by monthly color discrimination tests are performed during EMB use. To avoid permanent deficits, EMB is promptly discontinued if visual abnormalities are found. If vision does not improve with cessation of EMB, experts recommend stopping INH as well, as it is also a rare cause of optic neuritis . # Drug-Drug Interactions # Interactions Affecting Antituberculosis Drugs Drug-drug interactions can change the concentrations of the drugs involved. Relatively few interactions substantially change antituberculosis drug concentrations; much more often, the antituberculosis drugs cause clinically relevant changes in the concentrations of other drugs. The exceptions to this general rule are RFB and the fluoroquinolones. - Inhibitors of CYP3A increase the serum concentrations of RFB and one of its metabolites (25-O-desacetyl-rifabutin), sometimes producing toxicities. For example, administering ritonavir, a very potent CYP3A inhibitor, with the standard daily dose of RFB (300 mg) increases the serum concentrations of RFB (4-fold) and 25-O-desacetyl-rifabutin (35-fold) and is associated with increased rates of leukopenia, arthralgias, skin discoloration, and anterior uveitis . Conversely, administering RFB with a CYP3A inducer such as efavirenz or phenytoin may decrease RFB concentrations , and this may lead to clinical failures and the selection of rifamycin-resistant M. tuberculosis. Recommendations for RFB dose adjustments are available at AIDSinfo, and at the CDC website (/ default.htm). Because interactions are complex and given the rapid emergence of new data on antiretroviral therapy (ART), the management of HIV-related tuberculosis cases should involve a physician with experience in this field. - Absorption of the fluoroquinolones is markedly decreased by ingestion of medications containing divalent cations (calcium, iron, zinc) including antacids ; supplements or vitamins containing calcium, iron, or zinc ; sucralfate ; and the chewable tablet formulation of didanosine . These drug interactions can be avoided by ingesting medications containing divalent cations at least 2 hours apart from fluoroquinolones . In addition, moxifloxacin serum concentrations are decreased by 25%-30% in the presence of RIF due to the induction of phase II metabolic enzymes (sulfation and glucuronidation) . RPT and RFB also may decrease moxifloxacin serum concentrations, though the clinical significance of these drug-drug interactions in individual patients is uncertain. # Antituberculosis Drugs Affecting Other Drugs # Drug Interactions Due to Rifamycins Most of the clinically relevant drug-drug interactions involving the antituberculosis drugs are due to the effect of the rifamycins (RIF, RFB, and RPT) on the metabolism of other drugs . All of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 (CYP) system . By inducing the activity of metabolic enzymes, rifamycins decrease the serum concentrations of many drugs, sometimes to subtherapeutic levels . RIF is the most potent enzyme inducer and RFB the least, while RPT's potency depends on its frequency of administration . Daily RPT is at least as potent as daily RIF, while onceweekly RPT (as used in combination with INH for latent tuberculosis infection ) has limited effects on other drugs. The well-described, clinically relevant, drug-drug interactions involving the rifamycins are presented in Table 8 ; however, many possible interactions involving the rifamycins have not been fully investigated and additional clinically relevant interactions undoubtedly will be described. Therefore, it is important to check all concomitant medications for possible, as well as confirmed, drug-drug interactions with rifamycins. Rifamycin inductive effects typically take approximately 1-2 weeks to reach steady state after the rifamycin is started, and inductive effects typically resolve over approximately 2 weeks after the rifamycin is discontinued . If the dose of a medication is increased to compensate for the effect of a rifamycin, it is critical to reduce the dose within 2 weeks after the rifamycin is discontinued and its inductive effect resolves. RFB can be used in place of RIF if there is an unacceptable drug-drug interaction between RIF and another drug such as cyclosporine and most of the HIV-1 protease inhibitors . All the rifamycins may cause unacceptable decreases in the serum concentrations of certain drugs such as itraconazole . # Drug Interactions Due to INH INH is a relatively potent inhibitor of several CYP isozymes and increases concentrations of some drugs to the point of toxicity such as the anticonvulsants phenytoin and carbamazepine . INH also increases concentrations of benzodiazepines metabolized by oxidation, such as diazepam and triazolam, but not those metabolized by conjugation, such as oxazepam . Of note, the inductive effect of RIF on CYP isozymes outweighs the inhibitory effect of INH, so that the overall effect of combined therapy with RIF and INH is a decrease in the concentrations of drugs such as phenytoin and diazepam . INH may increase toxicity of other drugs-acetaminophen , valproate , serotonergic antidepressants , warfarin , and theophylline -but these potential interactions have not been well studied. A possible interaction between INH and disulfiram was initially described ; however, a retrospective study found that disulfiram was safe when added to intermittent, directly observed INH-containing tuberculosis treatment . # Drug Interactions Due to the Fluoroquinolones Ciprofloxacin inhibits the metabolism of theophylline and can cause clinical theophylline toxicity ; however, levofloxacin , gatifloxacin , and moxifloxacin do not affect theophylline metabolism. # Useful Websites Regarding Drug Interactions Useful websites regarding drug interactions (tuberculosis/HIV and other) are available through the following hyperlinks: AIDSinfo, Centers for Disease Control and Prevention, University of California San Francisco, University of Liverpool, Indiana University, and University of Maryland. # Therapeutic Drug Monitoring TDM generally consists of measurements of drug concentrations in serum specimens typically collected at 2 and 6 hours after a dose of the drug, or drugs, in question. Other sampling times may be used for selected situations. Blood samples are centrifuged; the serum is harvested and frozen, and then shipped frozen to a reference laboratory. Quality-assured laboratories in the United States and in Europe offer assays for some or all of the antituberculosis drugs . There are no prospective randomized trials that clearly define the role of TDM for antituberculosis drugs. As such, opinions vary regarding the utility of TDM. Experts generally use TDM as a specialized tool, providing insight into the adequacy of drug dosing . For example, serum concentrations of tuberculosis drugs among children and HIV-infected patients with tuberculosis are frequently lower than those in healthy volunteers, at the same (mg/kg body weight) dose . In some reports, lower concentrations did not have an impact on treatment response or cure . Other reports have found an association between low drug exposure and failure, relapse, and acquired rifamycin resistance . TDM cannot predict who will be cured, fail, or relapse; however, it does allow for timely, informed decisions regarding the need for dose adjustment when necessary. Experts suggest that TDM may be particularly helpful in situations in which drug malabsorption, drug underdosing, or clinically important drug-drug interactions are suspected (Table 9). Examples of situations in which TDM may be useful include (1) patients with delayed sputum conversion or treatment failure not explained by nonadherence or drug resistance; (2) patients with medical conditions (eg, reduced renal function) that are suspected of leading to subtherapeutic or toxic drug concentrations; and (3) patients undergoing treatment for drug-resistant tuberculosis. # TREATMENT IN SPECIAL SITUATIONS # HIV Infection PICO Question 5: Does extending treatment beyond 6 months improve outcomes compared to the standard 6-month treatment regimen among pulmonary tuberculosis patients coinfected with HIV? Recommendation 5a: For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Recommendation 5b: In uncommon situations in which HIV-infected patients do NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drugsusceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). PICO Question 6: Does initiation of ART during tuberculosis treatment compared to at the end of tuberculosis treatment improve outcomes among tuberculosis patients coinfected with HIV? Recommendation 6: We recommend initiating ART during tuberculosis treatment. Antiretroviral therapy should ideally be initiated within the first 2 weeks of tuberculosis treatment for patients with CD4 counts <50 cells/µL and by 8-12 weeks of tuberculosis treatment initiation for patients with CD4 counts ≥50 cells/µL (strong recommendation; high certainty in the evidence). Note: an exception is patients with HIV infection and tuberculous meningitis (see Immune Reconstitution Inflammatory Syndrome). Both the CDC and WHO recommend routine HIV testing and counseling to all patients with presumptive and diagnosed tuberculosis . Treatment of tuberculosis in patients with HIV infection has several important differences compared with treatment of patients who do not have HIV infection. These differences include the need for ART, the potential for drug-drug interactions, especially between the rifamycins and antiretroviral agents, paradoxical reactions that may be interpreted as clinical worsening, and the potential for developing resistance to rifamycins when using intermittent tuberculosis therapy. Because of the strong epidemiological association between HIV and tuberculosis infections and the clinical considerations discussed below, all individuals diagnosed with tuberculosis are tested for HIV infection. # Clinical Trials of Treatment for Tuberculosis in HIV-Infected Patients There have been a number of prospective studies, including 4 randomized controlled trials, of 6-month regimens for the treatment of pulmonary tuberculosis in patients with HIV infection for which recurrence data were reported . All reported a good early clinical response to tuberculosis therapy. The time required for sputum culture conversion from positive to negative and tuberculosis treatment failure rates were similar to these indices of treatment efficacy in patients without HIV infection. Recurrence of tuberculosis after treatment completion may be due to relapse or reinfection. Relapse of tuberculosis in HIV-infected individuals is associated with nonadherence to treatment, use of intermittent regimens, and with low plasma drug concentrations, all of which also contribute to the emergence of rifamycin resistance 250]. Reinfection with a new strain of M. tuberculosis is well documented in patients with HIV infection and occurs in settings where transmission is more common, such as in countries with high rates of tuberculosis or congregate living facilities (eg, prisons or hospitals) where infection control is inadequate. A study in Democratic Republic of the Congo (formerly Zaire) found that extending treatment from 6 to 12 months reduced the recurrence rate from 9% to 3% . A randomized trial in Haiti found that 6-month treatment with a standard regimen followed by 12 months of INH preventive therapy reduced recurrences from 7.8 per 100 person-years to 1.4 per 100 personyears . Therefore, in areas where reinfection is likely, the opinion of experts is that secondary preventive therapy with INH may be justified. In regard to duration of treatment for drug-susceptible pulmonary tuberculosis in the presence of HIV infection, the standard regimen currently used worldwide is the 6-month regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF . There is, however, a paucity of data on the optimal duration of tuberculosis treatment for HIV-infected patients receiving highly active antiretroviral therapy (HAART), though it is widely believed that the standard 6-month regimen is effective and achieves tuberculosis cure rates comparable to those reported for HIV-uninfected patients. In the TB-HAART (Early Versus Delayed Initiation of HAART for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis) trial, patients with CD4 counts ≥220 cells/µL were randomized on timing of ART initiation . All patients were treated with the standard 6-month regimen for tuberculosis and were followed for 12 months. Among patients who completed treatment, recurrence of tuberculosis occurred in 2.0%, providing indirect but supportive evidence that a 6-month regimen is effective in HIV-infected patients receiving ART. In our updated systematic review of randomized trials and cohort studies comparing various durations of tuberculosis therapy (6 months vs 8 months or longer), most of which were conducted prior to the era of HAART, we found that the risk of recurrence is lower when the continuation phase of treatment is extended. However, it is important to note that the majority of these studies were reports on nonrandomized cohorts, most were completed prior to the era of routine antiretroviral use, many tested intermittent regimens, and few distinguished between reinfection and relapse (see Supplementary Appendix B). As discussed below, based on data that show significant reductions in mortality and AIDS-defining illnesses, patients with HIV infection and tuberculosis should receive ART in conjunction with daily antituberculosis medications. For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (Recommendation 5a: conditional recommendation; very low certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 12). In the uncommon situation in which an HIV-infected patient does NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drug-susceptible pulmonary tuberculosis (Recommendation 5b: conditional recommendation; very low certainty in the evidence). As is noted for drugsusceptible pulmonary tuberculosis in patients without HIV coinfection, the continuation phase is extended in specific situations that are known to increase risk for relapse (see "Identification and Management of Patients at Increased Risk of Relapse"), as well as for selected extrapulmonary sites of disease, namely tuberculous meningitis, and bone, joint, and spinal tuberculosis (see "Extrapulmonary Tuberculosis"). c Numbers in parentheses are the calculated mg/kg doses for patients at the highest and lowest body weights in the weight band. Use of intermittent tuberculosis treatment regimens in HIVinfected patients has been associated with high rates of relapse and the emergence of drug resistance. In TBTC Study 22, patients with HIV infection who received once-weekly RPT and INH or twice-weekly RIF and INH in the continuation phase had an unacceptably high rate of relapse: 5 of 30 (16.7%) in the former and 3/31 (9.8%) in the latter group . In addition, for those receiving weekly therapy, 4 patients relapsing had acquired rifamycin resistance, which was associated with low serum concentrations of INH and was presumably the result of unopposed rifamycin exposure . In a trial of RFB-based antituberculosis therapy in combination with antiretroviral drugs, patients treated with twice-weekly RFB had a relapse rate of 5.3%, but 8 of 9 relapses had acquired rifamycin resistance . Relapse and resistance were associated with low CD4 lymphocyte counts, as all recurrences occurred in patients with baseline CD4 lymphocyte counts <100 cells/µL. In the pharmacokinetic substudy of the trial, lower plasma concentrations of RFB and INH were identified as key risk factors for acquiring rifamycin resistance . More recently, the use of a thrice-weekly RIF-based regimen during the intensive and continuation phases of treatment was associated with a higher rate of relapse and emergence of rifamycin resistance in HIVinfected individuals not receiving antiretrovirals compared with HIV-infected patients also receiving antiretrovirals or HIV-uninfected patients . Based in part on systematic reviews conducted to obtain evidence in support of this guideline, our expert opinion is that treatment of HIV-related tuberculosis be given daily in both the intensive and continuation phases to avoid recurrent disease and the emergence of rifamycin resistance (see "Recommended Treatment Regimens"). Mortality among patients with HIV and tuberculosis is high, principally due to complications of immunosuppression and occurrence of other HIV-related opportunistic diseases. In this regard, the value of co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis in reducing morbidity and mortality in HIV-infected patients with newly diagnosed tuberculosis is well established . Whereas the WHO recommends routine co-trimoxazole prophylaxis for all HIV-infected people with active tuberculosis disease regardless of the CD4 cell count , in high-income countries, co-trimoxazole prophylaxis is primarily used in tuberculosis patients coinfected with HIV with CD4 counts 50 cells/µL . All of these studies also showed that immediate ART was associated with significantly greater rates of IRIS, most of which was not severe. More recently, the TB-HAART trial found that among patients with HIV and CD4 counts >220 cells/µL, immediate initiation of ART did not reduce mortality compared with waiting until completion of 6 months of antituberculosis treatment to start ART . Unlike the SAPiT and STRIDE trials, however, TB-HAART did not assess progression of HIV disease as a study endpoint. Although the study did not find a survival benefit in patients with HIV-related tuberculosis and higher CD4 lymphocyte counts, it did confirm the safety of co-treatment of tuberculosis and HIV infection and documented good outcomes of tuberculosis treatment in those patients receiving dual therapy. We performed a systematic review and meta-analysis to obtain evidence in support of this guideline, which included the 4 trials above and 4 additional studies (see Supplementary Appendix B, Evidence Profile 13) . We found that the overall reduction in mortality with ART initiated during treatment of tuberculosis was 24% (risk ratio, 0.76; 95% confidence interval , .57-1.01). The overall risk of HIV disease progression was reduced by 34% with early or immediate ART (4 studies: risk ratio, 0.66; 95% CI, .47-.91). Initiation of ART during antituberculosis therapy was associated with an increased risk of IRIS (8 studies: risk ratio, 1.88; 95% CI, 1.31-2.69). Our metaanalysis identified no increase in the risk of other adverse events or poor outcome of tuberculosis therapy. Consequently, on the basis of high certainty in the evidence that the benefits outweigh the harms, we recommend that patients with tuberculosis and HIV infection receive ART during antituberculosis treatment. Antiretroviral therapy should ideally be started within 2 weeks for those patients with a CD4 count <50 cells/µL and by 8-12 weeks for those with a CD4 count ≥50 cells/µL (Recommendation 6: strong recommendation; high certainty in the evidence). An important exception is HIV-infected patients with tuberculous meningitis, in whom ART should not be initiated in the first 8 weeks of antituberculosis therapy (see "Immune Reconstitution Inflammatory Syndrome"). # Concurrent Administration of Antiretrovirals and Rifamycins Interaction of RIF with antiretroviral agents is a major treatment concern (see "Drug-Drug Interactions"). RIF is a potent inducer of drug metabolizing enzymes in the CYP family and drug transporters such as P-glycoprotein . Coadministration of RIF with drugs metabolized or transported by these compounds may lead to reductions in exposure and loss of efficacy . HIV protease inhibitors are metabolized by CYP3A4, and their concomitant administration with RIF leads to >80% reductions in serum concentrations of the protease inhibitors and loss of therapeutic benefit. RIF also increases the metabolism of nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and CCR-5 inhibitors. Detailed recommendations for coadministration of rifamycins and antiretroviral drugs have been published by the CDC, and we support these guidelines . The NNRTI efavirenz is the most widely used antiretroviral drug and is the preferred initial treatment for HIV (in combination with other antiretroviral drugs) in many countries. Coadministration of RIF-containing antituberculosis regimens with efavirenz results in satisfactory antiviral efficacy, despite reductions in trough efavirenz concentrations . INH is an inhibitor of an alternative, minor CYP pathway involved in efavirenz metabolism. Thus, when INH and RIF are given to individuals with genetic polymorphisms associated with slow efavirenz clearance, efavirenz serum concentrations may reach supratherapeutic levels. The US Food and Drug Administration (FDA) recommends that the dosage of efavirenz be increased from 600 mg/day to 800 mg/day for patients weighing >60 kg on the basis of pharmacokinetic modeling of data from healthy volunteers; however, data from clinical studies, including the STRIDE study, do not support this advice , and many other experts believe that efavirenz should be administered at the standard dose of 600 mg/day in patients receiving standard dose RIF-containing regimens. A treatment-shortening trial evaluating high-dose daily RPT used in combination with efavirenz-based ART for HIV-infected patients is under way (ClinicalTrials.gov identifier: NCT02410772). The NNRTI nevirapine has also been studied as an alternative treatment for HIV-infected patients with tuberculosis . However, RIF also reduces concentrations of nevirapine, a drug that induces its own metabolism . Due to this autoinduction, nevirapine is initially given at a dosage of 200 mg/day for 2 weeks and then increased to 200 mg/twice daily or 400 mg/ once daily. When nevirapine is started during antituberculosis treatment, use of the 200 mg daily lead-in dose can lead to subtherapeutic concentrations, loss of antiviral efficacy, and emergence of drug resistance . Therefore, expert opinion is that if nevirapine is used during treatment with RIF, the initiation dose should be at the full 400-mg daily dosage (200 mg twice daily or 400 mg daily). The INSTIs are now considered first-line agents for HIV infection in the United States and in Europe. Raltegravir and dolutegravir are metabolized mainly by uridine 5′-diphosphoglucuronosyltransferase 1A1 , and concomitant use of RIF reduces trough concentrations significantly. The "Raltegravir for the treatment of patients co-infected with HIV and tuberculosis" (Reflate TB) trial showed that coadministration of RIFbased antituberculosis treatment and raltegravir at 400 mg/twice daily was associated with similar antiviral effectiveness compared to coadministration of RIF-based antituberculosis treatment and raltegravir 800 mg twice daily; both were somewhat more effective than efavirenz 600 mg daily . However, pharmacokinetic data favor increasing the dose to 800 mg twice daily, and expert opinion in the United States favors this strategy . Pharmacokinetic studies demonstrate that coadministration of RIF and dolutegravir at a dosage of 50 mg given twice daily results in adequate trough concentrations of dolutegravir . A clinical study of patients with active tuberculosis given RIF and dolutegravir is under way (ClinicalTrials.gov identifier: NCT02178592). RFB is less potent an inducer of CYP isoenzymes and may be used in patients receiving ART; however, RFB itself is metabolized by CYP3A enzymes, and the antiretroviral agent ritonavir (used to boost protease inhibitor levels) inhibits CYP3A enzymes, which increases concentrations of RFB. High concentrations of RFB are associated with an increased risk of uveitis and other toxicities, so dose adjustment of the standard RFB dosage of 300 mg daily is necessary . Expert opinion is to use RFB at a dose of 150 mg/day or 300 mg every other day as part of a combination antituberculosis regimen for patients receiving ritonavir-boosted protease inhibitors . In patients receiving dose-adjusted RFB because of concomitant protease inhibitor use, frequent assessment of adherence to both medicines is prudent, as discontinuation of the protease inhibitor while continuing dose-adjusted RFB (ie, in the context of DOT tuberculosis therapy but self-administered antiretrovirals) would be expected to result in subtherapeutic concentrations of the rifamycin, possibly with consequent poor treatment outcome and acquired rifamycin resistance. Efavirenz is also a CYP3A inducer, and when RFB is coadministered with this agent the RFB dosage needs to be increased to 600 mg/day; however, indications to use RFB instead of RIF in patients receiving efavirenz are rare. When RFB is not available and treatment with a protease inhibitor is required because of resistance to NNRTIs and/or INSTIs, use of RIF with a lopinavir/ritonavir regimen may be attempted. For adults, this generally entails increasing the dosage of lopinavir/ritonavir from 400 mg/100 mg twice daily to 800 mg/200 mg twice daily over 2 weeks. This so-called "double dosing" of boosted lopinavir may result in hepatotoxicity and careful clinical monitoring is necessary . Alternatively, "super boosting" of lopinavir, though poorly tolerated in adults, is sometimes effective, especially in children. In this instance, the dosage of lopinavir is maintained at 400 mg twice daily, but ritonavir dosage is increased from 100 mg twice daily to 400 mg twice daily. Super boosting of ritonavir is poorly tolerated in adults, however, and the double-dosing strategy is preferred. These complicated interactions underscore the importance of expert consultation in treating individuals with concurrent HIV and tuberculosis infections. For situations involving complex drug-drug interactions, some clinicians prefer to measure the concentrations of the interacting drugs, and to dose these drugs based upon individualized data . # Immune Reconstitution Inflammatory Syndrome Transient worsening of tuberculosis symptoms and lesions in response to antituberculous therapy has previously been reported in HIV-uninfected patients . Patients with HIV infection and tuberculosis are at an increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. These reactions develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the IRIS. Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4 + lymphocyte counts <50 cells/ µL. In the STRIDE study, IRIS occurrence was infrequent at 7.6%. When tuberculosis IRIS occurred, the majority (69%) of cases were mild to moderate in severity; however, 31% were hospitalized with tuberculosis IRIS and more than half received corticosteroids . Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system (CNS) lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses . Such findings are attributed to IRIS only after excluding other possible causes, especially tuberculosis treatment failure from drug-resistant tuberculosis or another opportunistic disease, such as non-Hodgkin lymphoma or infection. Antiretroviral treatment of patients with incubating, subclinical tuberculosis may also result in what is called "unmasking IRIS," where tuberculosis symptoms and clinical manifestations become more pronounced, though whether this represents normal progression of untreated tuberculosis is not known . The relative risk of developing IRIS for patients who receive ART during therapy for tuberculosis is 1.88 (95% CI, 1.31-2.69), and those who start ART within 2 weeks after starting tuberculosis therapy have higher rates than those who start between 8-12 weeks . In general, development of IRIS does not worsen treatment outcomes for either tuberculosis or HIV infection, and most episodes can be managed symptomatically. An exception to this is the development of IRIS in patients with CNS tuberculosis, where IRIS may cause severe or fatal neurological complications. In a study of patients with tuberculosis meningitis and HIV infection, early initiation of ART (within 2 weeks) was associated with increased rates of adverse events and higher mortality . Thus, ART is not initiated in the first 8 weeks of antituberculosis therapy for patients with HIV infection and tuberculous meningitis (or other CNS tuberculosis), even for patients with CD4 cell counts <50 cells/µL. Management of IRIS is symptomatic. Based on expert opinion, for most patients with mild IRIS, tuberculosis and antiretroviral therapies can be continued with the addition of antiinflammatory agents such as ibuprofen. For patients with worsening pleural effusions or abscesses, drainage may be necessary. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures . For patients who develop IRIS, prednisone may be given at a dose of 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks, with tapering over a period of 6-12 weeks or longer. Controlled trials investigating whether treatment with nonsteroidal anti-inflammatory agents or corticosteroids can prevent the development of IRIS are under way or in development. # Children Children commonly develop tuberculosis as a complication of the initial infection with M. tuberculosis ( primary tuberculosis). The radiographic presentation of primary tuberculosis in children is characterized by intrathoracic lymphadenopathy with or without lung opacities, occasionally presenting with lymph node enlargement to a degree that there is compression of airways with or without hyperinflation or collapse of lobe or lung; breakthrough of node(s) in the airways can manifest with lobar or segmental infiltration, and a miliary pattern . The diagnosis of tuberculosis in children is challenging, especially in young children (<5 years) due to the paucibacillary nature of the disease. Depending on the setting and resources, diagnosis is microbiologically confirmed in only 15%-50% of pediatric cases, and clinical case definitions for tuberculosis in children have recently been updated . Children, rarely, and adolescents, more frequently, can also develop adult-type tuberculosis (upper lobe opacities and cavitation associated with sputum production). The lesions of primary tuberculosis have fewer M. tuberculosis organisms than those of adult-type pulmonary tuberculosis; thus, treatment failure, relapse, and development of secondary resistance are less common events among children when standard treatment regimens are initiated in a timely manner. However, it is often more difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis than from an adult. Therefore, choosing appropriate treatment drugs often requires the results of specimen culture and drug susceptibility tests from the person presumed to be the source of the child's infection. Based on expert opinion, when drug resistance is suspected or no source-case isolate is available, attempts to isolate organisms are critical; approaches including obtaining 3 early morning gastric aspirations (optimally during hospitalization), sputum induction , bronchoalveolar lavage , or tissue biopsy must be considered. Any information gained from molecular and phenotypic tests conducted on these samples is used to select an individualized regimen for the patient. Because tuberculosis in infants and children <4 years of age is more likely to disseminate and result in subsequent morbidity and mortality, empiric treatment is started as soon as the diagnosis is suspected, and particular care is given to drug dosage selection as an important component of achieving adequate concentrations of bactericidal drugs in body fluids, including the cerebrospinal fluid . Several controlled and many observational trials of 6-month therapy in children with known or presumed drug-susceptible pulmonary tuberculosis have been published . Based on systematic reviews of the literature, both the AAP and the WHO , list a 4-drug regimen (INH, RIF, PZA, and EMB) for 2 months followed by a 2-drug (INH and RIF) regimen for 4 months as the preferred regimen for children with suspected or confirmed pulmonary tuberculosis. The AAP Red Book also states that children who are receiving EMB should be monitored monthly for visual acuity and redgreen color discrimination if they are old enough to cooperate. The AAP further notes that the use of EMB in young children whose visual acuity cannot be monitored requires consideration of risks and benefits, but it can be used routinely to treat tuberculosis disease in infants and children unless otherwise contraindicated . As an approach to avoiding EMB ocular toxicity, some clinicians use a 3-drug regimen (INH, RIF, and PZA) in the initial 2 months of treatment for children who are HIV uninfected, have no prior tuberculosis treatment history, are living in an area of low prevalence of drug-resistant tuberculosis, and have no exposure to an individual from an area of high prevalence of drug-resistant tuberculosis. However, because the prevalence of and risk for drug-resistant tuberculosis can be difficult to ascertain, the AAP and most experts include EMB as part of the intensive phase regimen for children with tuberculosis. Pyridoxine, 25-50 mg/day, is given to infants, children, and adolescents undergoing INH treatment if they have nutritional deficiencies, symptomatic HIV infection, or are breastfeeding. Pyridoxine is also given to breastfeeding infants of mothers who are receiving INH . The lack of approved pediatric dosage forms for most antituberculosis medications has resulted in the creation and use of improvised formulations. This has entailed crushing tablets or opening capsules to access the drug, followed by weighing or proportioning of the contents that are in turn admixed with food or prepared into a suspension. With the recent development of child-friendly antituberculosis formulations meeting the dosage guidelines set by the WHO, procedures for making such improvised formulations should no longer be needed . In the United States, DOT has become the default programmatic approach to treating children with tuberculosis . Based on expert opinion, parents should not supervise DOT for their children. Even when drugs are administered under DOT, tolerance of the medications must be monitored closely. When feasible, daily dosing is preferred by experts ; however, twice-or thrice-weekly dosing has also been endorsed during the continuation phase of treatment for HIV-uninfected children in settings where DOT is well established (see Supplementary Appendix C and Table 3 for dosing of antituberculosis drugs in children). Monitoring response to treatment in children can be challenging because of the difficulties in demonstrating M. tuberculosis in children. Clinical and radiographic worsening may not be accompanied by positive AFB smears or mycobacterial cultures. According to experts, continued child growth and development while on treatment for tuberculosis usually predicts a positive outcome of treatment. A decision to modify the drug regimen should be undertaken with caution. Changes to the regimen are usually based on clinical and radiographic grounds. However, experts note that hilar adenopathy and resultant atelectasis in children on occasion can require 1-2 years to resolve; thus, an improving but persistent abnormality on a chest radiograph in an asymptomatic child is not believed to justify an extension of therapy. If there is concern that poor treatment response may be due to possible drug-resistant tuberculosis, expert opinion is that the child should be fully reinvestigated, verifying contact history and source case drug susceptibility test results, as well as obtaining additional specimens for cultures and drug susceptibility testing. According to expert opinion, most forms of extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease ; however, for children with confirmed or suspected tuberculous meningitis or osteoarticular tuberculosis caused by a drug-susceptible organism, expert opinion is that the duration of the continuation phase should be extended (See "Tuberculous Meningitis"). For tuberculous meningitis, the AAP lists an initial 4-drug regimen of INH, RIF, PZA, and an aminoglycoside or ethionamide for 2 months, followed by 7-10 months of INH and RIF. For patients who may have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin is used instead of streptomycin . Fluoroquinolones have been studied in adults with tuberculous meningitis , and these studies provide some evidence in support of their use; however, there have been no published trials of their use for tuberculous meningitis in children. Extrapulmonary Tuberculosis PICO Question 7: Does the use of adjuvant corticosteroids in tuberculous pericarditis provide mortality and morbidity benefits? Recommendation 7: We suggest initial adjunctive corticosteroid therapy not be routinely used in patients with tuberculous pericarditis (conditional recommendation; very low certainty in the evidence). PICO Question 8: Does the use of adjuvant corticosteroids in tuberculous meningitis provide mortality and morbidity benefits? Recommendation 8: We recommend initial adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (strong recommendation; moderate certainty in the evidence). Tuberculosis can involve virtually any organ or tissue in the body. The principles underlying the treatment of pulmonary tuberculosis also apply to extrapulmonary disease. Chemotherapy for extrapulmonary tuberculosis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for extrapulmonary tuberculosis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued during a continuation phase. Increasing evidence, including randomized controlled trials, suggests that 6-9 month INH and RIF-containing regimens are effective for the majority of extrapulmonary sites of disease. The exception is tuberculous meningitis where the optimal duration of therapy has not been established through randomized controlled trials, but most experts and society guidelines prescribe 12 months of treatment . The opinion of experts is that the preferred frequency of dosing for extrapulmonary tuberculosis is once daily for both the intensive and continuation phases. No randomized controlled trials have studied intermittent drug administration for extrapulmonary tuberculosis. If intermittent regimens are used, experts believe that highly intermittent, once-weekly regimens should be avoided because of insufficient experience with this regimen in extrapulmonary tuberculosis. In regard to treatment monitoring, bacteriologic evaluation is often limited by the difficulty in obtaining follow-up specimens. Sputum specimens are obtained when there is concurrent pulmonary involvement, otherwise, response to treatment in extrapulmonary diseases is often judged on the basis of clinical and radiographic findings. # Lymph Node Tuberculosis We believe a 6-month regimen is adequate for initial treatment of all patients with drug-susceptible tuberculous lymphadenitis . Affected lymph nodes may enlarge and new nodes can appear during or after therapy without any evidence of bacteriological relapse . Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration has been reported by some experts to be beneficial, although this approach has not been examined systematically. Incision and drainage techniques applied to cervical lymphadenitis, however, have been reported to be associated with prolonged wound discharge and scarring . Of note, the majority of lymphatic cases of mycobacterial disease in US children are caused by nontuberculous mycobacteria . Bone, Joint, and Spinal Tuberculosis Six-to 9-month regimens containing RIF for treatment of bone, joint, and spinal tuberculosis are at least as effective as 18-month regimens that do not contain RIF . Because of the difficulties in assessing response, however, some experts tend to favor the 9-month duration, and in the setting of extensive orthopedic hardware, some experts extend the duration of treatment further to 12 months. Several trials found no additional benefit of surgical debridement in combination with chemotherapy compared with chemotherapy alone for spinal tuberculosis . As such, uncomplicated cases of spinal tuberculosis are managed with medical rather than surgical treatment. However, based on expert opinion, surgery can be considered in situations in which (1) there is poor response to chemotherapy with evidence of ongoing infection or ongoing deterioration; (2) relief of cord compression is needed in patients with persistence or recurrence of neurologic deficits; or (3) there is instability of the spine . Spinal tuberculosis with evidence of meningitis is managed as tuberculous meningitis, including consideration of adjunctive corticosteroids (see Tuberculous Meningitis). # Pericardial Tuberculosis A 6-month regimen is adequate for patients with pericardial tuberculosis. Based on small studies that have shown mortality and morbidity benefits , corticosteroids have previously been universally recommended as adjunctive therapy for tuberculous pericarditis, however, a recent placebo-controlled randomized clinical trial with 1400 participants did not find a difference in the combined primary endpoint of the trial, which included mortality, cardiac tamponade, or constrictive pericarditis, between patients treated with adjunctive corticosteroids vs placebo . A subgroup analysis, however, did suggest a benefit in preventing constrictive pericarditis. Similarly, a systematic review conducted to obtain evidence in support of this guideline did not find a statistically significant benefit in terms of mortality or constrictive pericarditis from the use of corticosteroids (see Supplementary Appendix B, Evidence Profile 14) . Therefore, we suggest that adjunctive corticosteroids should not be used routinely in the treatment of patients with pericardial tuberculosis (Recommendation 7: conditional recommendation; very low certainty in the evidence). However, selective use of glucocorticoids in patients who are at the highest risk for inflammatory complications might be appropriate. Such patients might include those with large pericardial effusions, those with high levels of inflammatory cells or markers in pericardial fluid, or those with early signs of constriction . # Pleural Tuberculosis A standard 6-month regimen (Table 2) is also adequate for treating pleural tuberculosis. Some clinicians consider using adjunctive corticosteroid therapy for tuberculous pleural effusions, and a number of studies have examined the risks and benefits of this approach . Four have been prospective, double blind, and randomized , one of which was conducted in patients with HIV infection . In all 4 studies, prednisone (or prednisolone) administration did not confer a beneficial effect on residual pleural thickening or prevention of other longterm pleural sequelae. In one study, an increased risk for Kaposi sarcoma was noted with the use of prednisolone in HIV-associated tuberculous pleurisy . Based on these randomized clinical trials and a systematic review, there is no evidence to support the routine use of adjunctive corticosteroids in patients with tuberculous pleurisy. Tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy . The optimum duration of treatment for this unusual form of tuberculosis has not been established. # Tuberculous Meningitis Tuberculous meningitis remains a potentially devastating disease associated with a high morbidity and mortality in children and adults, despite prompt initiation of adequate chemotherapy . HIV-infected individuals appear to be at increased risk for developing tuberculous meningitis, but the clinical features of the disease are similar to those in tuberculous meningitis patients without HIV infection . High short-term morbidity and mortality is reported regardless of HIV serostatus ; however, 9-month survival was further decreased in HIV-infected patients compared with HIV-uninfected patients in one cohort study . Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy. In children with tuberculous meningitis, the AAP lists an initial 4-drug regimen of INH, RIF, PZA, and ethionamide or an aminoglycoside for 2 months (in place of EMB), followed by 7-10 months of INH and RIF . There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis . Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our writing committee prefers using EMB as the fourth drug. Fluoroquinolones, as well as higher doses of intravenous RIF, are being evaluated in adults with tuberculous meningitis ; a large randomized controlled trial (ISRCTN61649292) is under way to evaluate the impact on reducing mortality of levofloxacin combined with higher-dose rifampicin during the intensive phase of treatment . Selected complications of tuberculous meningitis warranting neurosurgical referral include hydrocephalus, tuberculous cerebral abscess, and clinical situations in which there is paraparesis . A number of studies have examined the role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis . Our updated systematic review found a mortality benefit from the use of adjuvant corticosteroids (See Supplementary Appendix B, Evidence Profile 15). Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (Recommendation 8: strong recommendation; moderate certainty in the evidence). # Disseminated Tuberculosis Based on expert opinion, a standard daily 6-month regimen (Table 2) is adequate for tuberculosis at multiple sites and for miliary tuberculosis; however, supporting data from controlled clinical trials are limited. Some experts believe concurrent corticosteroid therapy is indicated for treating severe respiratory failure or adrenal insufficiency caused by disseminated tuberculosis , though the role of adjunct corticosteroid treatment in patients with miliary tuberculosis remains unclear . Patients with disseminated tuberculosis may have concomitant neurologic complications, with indolent symptoms of CNS involvement, which should be appropriately worked up . Treatment recommendations for tuberculous meningitis are followed when there is CNS involvement. # Genitourinary Tuberculosis Renal tuberculosis is treated primarily with medical rather than surgical therapy, and expert opinion is that a standard daily 6-month regimen (Table 2) is adequate . If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal drainage by stenting or nephrostomy is advised by experts . Nephrectomy is considered when there is a nonfunctioning or poorly functioning kidney, particularly if hypertension or continuous flank pain is present. Dose adjustment is required in patients with coexistent renal failure. Tuberculosis of the female or male genital tract responds well to standard chemotherapy, although surgery may be indicated for residual, large, tubo-ovarian abscesses. A positive urine culture for M. tuberculosis is a component of the diagnostic assessment of genitourinary tuberculosis . A positive urine culture for M. tuberculosis is also sometimes seen in tuberculosis patients with advanced HIV infection, and may reflect disseminated disease and/or occult genitourinary tract involvement. Rarely, a positive culture may occur in the absence of any abnormalities on urinalysis and does not necessarily represent invasive genitourinary tract involvement . # Abdominal Tuberculosis Expert opinion is that a 6-month regimen is adequate for patients with peritoneal or intestinal tuberculosis . The nonspecific presentation of abdominal tuberculosis means that a high index of suspicion is an important factor in early diagnosis and initiation of treatment . Data on adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis are limited ; thus, experts believe it should not be prescribed routinely. # Other Sites of Involvement As noted above, tuberculosis can involve any organ or tissue. When treating tuberculosis in sites other than those mentioned, the basic principles of therapy apply, but experts should be consulted. Culture-Negative Pulmonary Tuberculosis in Adults PICO Question 9: Does a shorter duration of treatment have similar outcomes compared to the standard 6-month treatment duration among HIV-uninfected patients with paucibacillary tuberculosis (ie, smear negative, culture negative)? Recommendation 9: We suggest that a 4-month treatment regimen is adequate for treatment of HIV-uninfected adult patients with AFB smear-and culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active pulmonary tuberculosis. Some causes of failure to isolate organisms include the recent use of antibiotics with bactericidal activity against M. tuberculosis (eg, fluoroquinolones), low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing . Alternative diagnoses must be considered and appropriate diagnostic studies undertaken in patients who appear to have culture-negative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis have 2 sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria or for rapid molecular testing for M. tuberculosis as part of the diagnostic evaluation. Other diagnostic procedures, such as bronchoscopy with bronchoalveolar lavage and biopsy, are considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture or a rapid molecular test is positive, treatment for active disease is continued for a full, standard 6month course (Table 2), if appropriate based on drug susceptibility test results. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have thorough clinical and radiographic follow-up after 2 months of therapy. If there is clinical or radiographic improvement and no other etiology is identified, treatment should be continued. The optimum treatment regimens and duration for culturenegative tuberculosis have not been convincingly established. We performed a systematic review that evaluated 4-and 6-month treatment regimens using available clinical trials data in adult (>15 years of age) patients. No clinical trials data on shortened treatments in children were available. A study from Hong Kong demonstrated that for adults with smear-negative, culture-positive, and culture-negative pulmonary tuberculosis, a 4-month regimen of INH, RIF, streptomycin, and PZA given either daily or thrice weekly was highly successful . In Arkansas, a 4-month INH and RIF regimen for culture-negative tuberculosis was successful with only 1.2% relapses during an average follow-up of 44 months . In Singapore, a study of a small number of patients with smearnegative and either culture-positive or culture-negative tuberculosis treated with INH, RIF, and PZA daily for 2 months followed by INH and RIF either daily or thrice weekly for 2 months showed a high degree of success in both groups . Overall, these 3 studies report a proportion relapsing of only 1.9% among a total of 940 patients treated for 4 months, all of whom had at least 3 negative smears/cultures prior to starting therapy. Our systematic review of available clinical trials data in adult (>15 years of age) patients did not identify a significant difference in the risk of relapse in culture-negative tuberculosis treated for either 4 or 6 months (see Supplementary Appendix B, Evidence Profile 16). Consequently, we suggest that a 4month treatment regimen is adequate for HIV-uninfected adults with culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Operationally, treatment is initiated with an intensive phase of INH, RIF, PZA, and EMB daily and continued in all patients suspected of having pulmonary tuberculosis even when the initial bacteriologic studies are negative. If all cultures on samples deemed to be adequate are negative and there is clinical or radiographic response after 2 months of intensive phase therapy, the continuation phase with INH and RIF can be shortened to 2 months. Clinical and radiographic response, assessed at the end of treatment, is used to determine whether an extension in treatment to a full standard 6-month regimen is needed. Alternatively, if there is concern about the adequacy of workup or the accuracy of the microbiologic evaluations, a standard 6-month regimen remains preferred (Table 2) . On occasion, patients who are being evaluated for pulmonary tuberculosis will be found to have positive AFB smears but negative cultures. Potential causes include the possibilities that the acid-fast organisms are fastidious mycobacteria other than M. tuberculosis complex, that they are nonviable M. tuberculosis, or that the results are due to laboratory error (false-positive smear, or false-negative culture). The approach in such cases is individualized on the basis of clinical and radiographic findings, as well as the results of rapid molecular diagnostic studies; discussion with the microbiologist performing the cultures is prudent. If clinical suspicion of tuberculosis is high, particularly if there is clinical and radiologic improvement since the start of therapy, then therapy is continued for a minimum of 6 months as for culture-positive pulmonary tuberculosis. # Pregnancy and Breastfeeding Treatment for tuberculosis is initiated whenever the probability of maternal disease is moderate to high because of the risk of untreated tuberculosis to a pregnant woman and her fetus . Although antituberculosis drugs cross the placenta, they do not appear to have teratogenic effects in humans . However, the inclusion of PZA in the treatment regimen for pregnant women is controversial in the United States. The FDA previously classified all 4 first-line drugs, INH, RIF, PZA, and EMB, as having equal potential for teratogenicity (all assigned to category C according to the previous FDA letter-based classification system, which is currently being revised ). We suggest that clinicians evaluate the risks and benefits of prescribing PZA on a case-by-case basis, allowing the patient to make an informed and educated decision, recognizing that for all first-line drugs, risk cannot be ruled out as there are no adequate and wellcontrolled studies in humans, but potential benefits warrant use of the drug in pregnant women despite potential risks. It is also important to recognize that PZA has been used extensively in high-burden countries for many years, and is recommended by the WHO for tuberculosis in pregnancy, as part of the standard treatment regimen . Expert opinion is that in pregnant women with tuberculosis and HIV, extrapulmonary or severe tuberculosis, it is more beneficial to include PZA in the treatment regimen than to not include PZA. If a decision is made to exclude PZA from the regimen, a minimum of 9 months of INH, RIF, and EMB is used for most pregnant women with drug-susceptible tuberculosis. Expert consultation should be sought when first-line drugs cannot be used due to adverse effects or antibiotic resistance, when there is extensive disease and/or a risk of noncompliance. Although the fetal effects of many second-line drugs are not well established, small case series of pregnant women treated with second-line drugs (from studies in drug-resistant tuberculosis) suggest that good outcomes are achievable and that termination of the pregnancy is not necessary . Overall, the absence of high-quality studies combined with estimates of >200 000 cases of tuberculosis in pregnant women each year highlight the need for additional research in this area . Breastfeeding is encouraged for women who are deemed noninfectious and are being treated with first-line agents. The small concentrations of antituberculosis drugs measured in breast milk have not been reported to produce toxic effects in the nursing infant . Conversely, drugs in breast milk should not be considered to serve as effective treatment for active tuberculosis or latent tuberculosis infection in a nursing infant. Whenever INH is given to a pregnant or nursing woman, supplementary pyridoxine, 25-50 mg/day, is prescribed . According to the AAP, supplementary pyridoxine (1-2 mg/kg/day) is also prescribed to exclusively breastfed infants, even those not receiving INH . # Renal Disease Patients with renal insufficiency or end-stage renal disease (ESRD) are immunocompromised . Tuberculosis patients with chronic renal failure have worse clinical outcomes than those without renal failure, and, thus, experts recommend close monitoring during tuberculosis treatment . The pharmacokinetics of antituberculosis drugs are altered as some are cleared by the kidneys and/or removed via hemodialysis . Therefore, dose adjustment in patients with renal insufficiency or ESRD may be required (Table 3 and Table 12). Decreasing the dose lowers peak serum drug concentrations and can compromise treatment efficacy. Based on expert opinion, the interval between drug doses in patients with a creatinine clearance of 30 mL/min creatinine clearance. In such patients, standard doses are used by experts, but measurement of serum concentrations 2 and 6 hours after timed administration can be used to assist with optimizing drug dosages. RIF and INH are metabolized by the liver, and conventional dosing can be used in the setting of renal insufficiency. Although PZA is metabolized by the liver, its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) may accumulate in patients with renal insufficiency. EMB is approximately 80% cleared by the kidneys and may accumulate in patients with renal insufficiency. Experts suggest a longer interval between doses (ie, thrice weekly) for PZA and EMB . With hemodialysis, PZA and, presumably, its metabolites are cleared to a significant degree, INH and EMB are cleared to some degree, and RIF is not cleared by hemodialysis . The fluoroquinolones are also cleared variably by the kidneys. Levofloxacin undergoes greater renal clearance than moxifloxacin . Postdialysis administration of all antituberculosis medications is preferred to facilitate DOT and to avoid premature clearance of drugs such as PZA. Monitoring serum drug concentrations, along with careful clinical and pharmacological assessment, in patients with ESRD, may be necessary. ESRD patients are often taking other medications that interact with antituberculosis drugs or have comorbid clinical conditions that could affect drug absorption, such as diabetes mellitus with gastroparesis. For patients receiving peritoneal dialysis, there is currently a paucity of pharmacokinetic and dosing data, and the dosages in Table 12 may not apply to patients receiving peritoneal dialysis. Such patients may require close monitoring for toxicity, and measurements of the serum concentrations of antituberculosis drugs before and after peritoneal dialysis should be considered. # Hepatic Disease Tuberculosis treatment in patients with preexisting advanced liver disease poses significant challenges. The likelihood of drug-induced hepatitis is increased with prior advanced liver disease , liver transplant , or hepatitis C infection . Abnormal baseline aminotransferases alone are an independent risk factor for DILI . Experts recommend that patients with a history of injection drug use, birth in Asia or Africa (or other hepatitis virus endemic regions), or HIV infection have hepatitis B and C virus screening at baseline (Table 7). For patients with marginal hepatic reserve, superimposed DILI may be severe, even life-threatening . Fluctuations of serum aminotransferases and total bilirubin from preexisting liver disease can confound monitoring for DILI. Hepatic tuberculosis may also cause elevated aminotransferases, which improve with effective tuberculosis treatment. Regimens with fewer potentially hepatotoxic agents are selected in patients with advanced liver disease or whose serum ALT is >3 times the upper limit of normal at baseline (and not thought to be caused by tuberculosis). The crucial efficacy of INH and particularly RIF warrant their use and retention, if at all possible, even in the face of preexisting liver disease. Expert consultation is advisable. Adjustments during treatment may be necessary. Drug susceptibility testing to fluoroquinolones and injectables is indicated if use of these drugs is being considered. Alternative regimens for use in patients with hepatic disease include: - Treatment without PZA: PZA has often been implicated in DILI. A potential regimen could be INH, RIF, and EMB for 2 months, followed by 7 months of INH and RIF . - Treatment without INH and PZA: For advanced liver disease patients, RIF and EMB with a fluoroquinolone, injectable, or cycloserine for 12-18 months, depending on the extent of the disease and response could be considered . - Treatment without INH: Based on outcomes of studies on INH-resistant tuberculosis, a regimen of RIF, PZA, and EMB with or without a fluoroquinolone could be considered for a total duration of at least 6 months . Although this regimen has 2 potentially hepatotoxic medications, it has the advantage of retaining a treatment duration of 6 months. - Regimens with little or no potential hepatotoxicity: For patients with severe, unstable liver disease, EMB combined with a fluoroquinolone, cycloserine, and second-line injectable for 18-24 months (similar to an multidrug-resistant tuberculosis regimen) can be considered . Some experts avoid aminoglycosides in patients with severe, unstable liver disease due to concerns about renal insufficiency or bleeding from the site of injected medication due to thrombocytopenia and/ or coagulopathy. - Standard doses are given unless there is intolerance. - The medications should be given after hemodialysis on the day of hemodialysis. - Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation, and to assist in avoiding toxicity. - Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving hemodialysis and verify adequacy of dosing using serum concentration monitoring. - In patients with 30-50 mL/min creatinine clearance, standard doses are used by experts, but measurement of serum concentrations 2 and 6 hours after timed administration can be used to assist with optimizing drug dosages. a Including adult patients receiving hemodialysis. b The appropriateness of 250-mg daily doses has not been established. There should be careful monitoring for evidence of neurotoxicity. Data to guide the monitoring of patients with preexisting severe liver disease are scarce. Clinical monitoring and patient education for manifestations of liver injury is warranted for all patients . Experts in the field recommend measuring serum aminotransferases and total bilirubin concentrations every 1-4 weeks for at least the first 2-3 months of treatment. The INR may also be periodically followed for patients with severe hepatic impairment . An increase in serum ALT is more specific for hepatocellular injury than an increase in AST, which can also signify abnormalities in muscle, heart, or kidney . In patients with more advanced preexisting disease, such as those with cirrhosis or encephalopathy, the ALT thresholds for treatment interruption have not been defined. Some experts recommend, in addition to weekly or twice-weekly ALT monitoring, interrupting treatment for only a 3-fold elevation of ALT, even if asymptomatic . Reintroduction of antituberculous treatment may entail rechallenge and/or substitution of agents, while trying to retain the most effective medications . Whenever feasible, management of tuberculosis in the setting of severe hepatic disease is undertaken in consultation with experts. # Advanced Age The risk of drug-induced hepatitis and other serious adverse effects increases with advancing age because of less efficient drug elimination due to reduced renal and hepatic clearance . Because PZA is the most common culprit , the benefits of including PZA in the initial regimen for elderly patients with modest disease and low risk of drug resistance may be outweighed by the risk of serious adverse events. Consequently, some experts avoid the use of PZA during the intensive phase among patients >75 years of age. In such cases, the initial regimen consists of INH, RIF, and EMB. If PZA is not used during the intensive phase, then the total duration of tuberculosis treatment should be extended to at least 9 months. When the elderly patient has active tuberculosis with high bacillary burden (ie, bilateral cavitation) and, thus, treatment failure or the development of drug resistance is a concern, benefits and risks of adding PZA or a fluoroquinolone (eg, levofloxacin, moxifloxacin) vs no fourth drug should be carefully considered. The risk of drug interaction is increased in the elderly and consideration may need to be given to dose adjustments or use of alternative regimens. Careful clinical monitoring to detect intolerance and adverse reactions is warranted. # Other Comorbid Conditions As noted previously, the CDC and WHO recommend routine HIV testing and counseling to all patients with presumptive and diagnosed tuberculosis . Experts also recommend that patients with a history of injection drug use, HIV infection, or birth in Asia or Africa (or other hepatitis virus endemic regions) undergo hepatitis B and C virus screening at baseline. Based on limited data, some experts also suggest screening for helminthic infections, including malaria, strongyloides, and schistosomiasis in patients originating from regions hyperendemic for these diseases. In general, tuberculosis treatment for patients with diseases or conditions that alter immune responsiveness, including HIV infection, parasitic and helminthic infections, hematologic or reticuloendothelial malignancies, immunosuppressive therapy (eg, TNF-α inhibitors) , chronic renal failure , diabetes mellitus, and malnutrition is based on the standard, daily 6-month regimen (Table 2). Nonetheless, decisions regarding treatment of comorbidities and the duration of tuberculosis treatment can be individualized, taking into account disease severity, organs involved, and response to treatment. For example, based on increased rates of tuberculosis recurrence, some experts suggest extending the total duration of tuberculosis treatment to 9 months in poorly controlled diabetes mellitus . Similarly, for patients with silicotuberculosis, data demonstrate that cure rate is improved if the continuation phase is extended by at least 2 months . Based on data suggesting increased mortality with shorter durations of treatment, some experts also suggest extending the total duration of tuberculosis treatment to at least 9 months for all solid organ transplant recipients . The management of immunosuppressive therapy in patients who develop active tuberculosis varies based on the comorbid condition. If possible, steps are taken to correct immunodeficiency. In patients with rheumatologic disease, expert opinion is that TNF-α inhibitor therapy is held if clinically feasible, when active tuberculosis is suspected or confirmed. There is no consensus on when TNF-α inhibitor therapy can be resumed. However, small case series suggest that it is safe to resume TNF-α inhibitor therapy in patients who complete at least 2 months of antituberculosis treatment and have a good clinical response . The decision to restart TNF-α inhibitor treatment should be individualized, taking into account the clinical need for immunosuppressive therapy, the extent of tuberculosis disease, and clinical response to antituberculosis treatment. Of note, severe IRIS-like reactions in the setting of holding TNF-α inhibitor treatment have been reported . In solid organ transplant recipients, significant pharmacological interactions can occur between rifamycin-based antituberculosis regimens ( particularly RIF) and calcineurin inhibitors or rapamycin; on this basis, strict monitoring of serum drug concentrations is needed to prevent rejection . # RECURRENT TUBERCULOSIS, TREATMENT FAILURE, AND DRUG RESISTANCE # Recurrent Tuberculosis Recurrence refers to the circumstance in which a patient whose sputa had become and remained culture negative while receiving antituberculosis drugs becomes culture positive or experiences clinical or radiographic deterioration consistent with active tuberculosis after completion of therapy. In such patients, vigorous efforts are made to establish a diagnosis and to obtain microbiologic confirmation of the relapse to enable testing for drug resistance. True relapses, defined as recurrent tuberculosis caused by the same strain as was identified at baseline, are thought to be due to failure of chemotherapy to sterilize the host tissues, thereby enabling endogenous recrudescence of the original infection. In high-incidence settings or where infection control is poor, however, exogenous reinfection with a new strain of M. tuberculosis may be responsible for the apparent recurrence (in this context, not referred to as relapse) . Patients at risk for relapses are those with extensive disease at baseline and whose sputum cultures remain positive after completion of the intensive phase of treatment . However, the sensitivity of culture-positive status at 2 months for predicting relapse is low . Most relapses occur within the first 6-12 months after completion of therapy . In the majority of patients with tuberculosis caused by drug-susceptible organisms who were treated by DOT with rifamycin-containing regimens, relapses occur with susceptible organisms . However, the risk of acquired drug resistance is substantial in patients who have a relapse after receiving SAT, a highly intermittent regimen in the setting of HIV infection, a non-rifamycin-containing regimen (including receiving only INH and EMB in the continuation phase of treatment), or a second-course of a first-line regimen reinforced by streptomycin . In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen using DOT, a high likelihood exists that the organisms were resistant from the outset . To help guide regimen selection, rapid molecular tests have been used at the time of suspected recurrence as an approach to rapidly identifying the presence of resistance-conferring mutations; however, the detection of M. tuberculosis DNA and RIF resistance have been reported as being false positive . Experts suggest caution in interpreting results from molecular tests used at the time of suspected recurrence. The selection of empiric treatment regimens for patients with relapses is based on the prior treatment scheme. For patients with relapse who were treated for drug-susceptible tuberculosis using DOT, experts recommend retreatment using the standard intensive phase regimen until the results of susceptibility tests are known. For patients who did not receive DOT or had irregular treatment, it is prudent to infer a higher risk of acquired drug resistance. Whenever feasible, rapid molecular and phenotypic diagnostics for detection of drug resistance should be used to inform regimen selection. When immediate treatment initiation is necessary, consider the use of an expanded empiric regimen in consultation with experts in the treatment of drug-resistant disease. If started, an expanded empiric regimen is administered until the results of susceptibility tests are known and commonly consists of the standard intensive phase regimen of daily INH, RIF, PZA, and EMB, plus a later-generation fluoroquinolone, an injectable, and depending on the severity of disease or the anticipated extensiveness of resistance, an additional second-line drug . All drugs are administered using DOT. An expanded regimen is indicated especially in patients with impaired immunity, limited respiratory reserve, CNS involvement, other lifethreatening circumstances, or any other situation in which treatment with an inadequate regimen could have severe consequences to the individual or the community. When epidemiological circumstances render exogenous reinfection the most likely cause of apparent relapse, the regimen choice is influenced by the drug susceptibility pattern of the presumed source case and/or drug-resistance testing. If the presumed source case is known to have drug-resistant organisms, an expanded empiric regimen based on the resistance profile of the putative source case may be suitable. # Poor Treatment Response and Treatment Failure In the United States, treatment failure is defined as continuously or recurrently positive cultures after 4 months (5 months in Europe and WHO guidelines ) of treatment in a patient receiving appropriate chemotherapy. Among patients with drugsusceptible pulmonary tuberculosis, even with extensive lung cavitation, 90%-95% will be culture negative after 3 months of treatment with a regimen that contains INH and RIF. During this time, the vast majority of patients show clinical improvement, including reduced fever, reduced cough, and weight gain. Thus, patients with persistently positive cultures after 3 months of chemotherapy, with or without ongoing symptoms, are evaluated carefully to identify the cause of delayed response. Multiple reasons for poor treatment response and treatment failure exist. For patients not receiving DOT, one explanation may be nonadherence to the treatment regimen. Among patients receiving DOT, cryptic nonadherence (spitting out or deliberately regurgitating tablets or capsules) or failure of the healthcare system to reliably deliver the drugs may be a cause. Other potential reasons include unrecognized drug resistance (drug susceptibility testing not done, misreported, or misinterpreted; reinfection with a drug-resistant strain), malabsorption (diarrhea, or prior resection surgery of the stomach or small intestine, or taking tuberculosis medications with antacids or other drugs/substances that might bind or interfere with drug absorption), or diabetes mellitus with or without gastroparesis . Some experts use TDM to evaluate poor drug exposure as a contributing factor to treatment failure . Laboratory error (eg, cross-contamination or mislabeling of specimens) is also a possible reason for a positive culture in a patient who is doing well clinically . Clinicians should be alert, as well, to the possibility of transient clinical or radiographic worsening ( paradoxical reactions), despite appropriate therapy that would eventually result in cure. Examples of this include ongoing inflammation at sites of lymphadenitis, worsened abnormalities on chest radiographs after several months of treatment, or the new appearance of pleural effusions during therapy for pulmonary tuberculosis. Such paradoxical worsening during treatment can occur in HIV-uninfected patients, as well as in HIV-infected patients (see "Immune Reconstitution Inflammatory Syndrome"). The diagnosis of a paradoxical reaction is made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure and drug resistance. For patients who meet criteria for treatment failure, the possible reasons listed above should be addressed promptly. Recent mycobacterial isolates should be sent to a reference laboratory for susceptibility testing to both first-and second-line drugs. If clinicians are not familiar with the management of drugresistant tuberculosis, immediate referral to, or consultation with a specialty center is indicated. If treatment failure is presumably due to drug resistance and the patient is seriously ill or has a positive sputum AFB smear, an empiric regimen is started immediately and continued until susceptibility tests are available to guide therapy; however, if the patient's clinical presentation is not severe, one may either initiate an empiric retreatment regimen or wait for drug susceptibility results from a recent isolate. Of note, patients who are not on the correct regimen remain infectious . A single new drug is never to be added to a failing regimen as it can lead to amplification of drug resistance, including acquired resistance to the newly added drug . To lessen the likelihood of increasing resistance, it is generally prudent to add 2-3 new drugs to which susceptibility could logically be inferred (eg, using regional drug-resistance surveillance data and the patient's history of medication use). When drug susceptibility results are available, the regimen is adjusted accordingly. # Tuberculosis Caused by Drug-Resistant Organisms Mycobacterium tuberculosis bacilli are continually undergoing spontaneous mutations that create resistance to individual antituberculosis drugs; however, the frequency of these mutations is sufficiently low that with appropriate combination chemotherapy that is reliably ingested, clinically significant resistance is very unlikely to develop . Acquired drug resistance can occur, however, when there is a large bacillary population (such as in pulmonary cavities), an inadequate drug regimen, a combined failure of both the patient and the provider to ensure that an adequate regimen is ingested, or malabsorption of one or more antituberculosis drugs . During extended or repeated treatment, amplification of resistance to multiple agents may occur. Patients with acquired drug resistance may transmit their strains to others who, if they develop tuberculosis, will have primary drug resistance. Notable clinical and demographic risk factors for drug-resistant tuberculosis include having a previous episode of tuberculosis treatment (in particular if the regimen was inadequate or adherence to the regimen was low), originating from or living for an extended period in a country with a high prevalence of drug-resistant tuberculosis, and having a history of exposure to an index case with drug-resistant tuberculosis. Comprehensive guidance on the management of drugresistant tuberculosis is beyond the scope of this document, though international guidelines exist . An ATS/CDC/ ERS/IDSA practice guideline for the management of drugresistant tuberculosis is also currently under development using GRADE methodology. # RESEARCH AGENDA FOR TUBERCULOSIS TREATMENT Much progress has been made over the last 10 years in the treatment of tuberculosis . The corpus of knowledge on new drug combinations, drug interaction with antiretrovirals, methods of dosing, and timing of dosing is increasing. Based on the writing of this guideline, however, several priority areas in need of additional research were identified. # New Antituberculosis Drugs and Regimens Treatment of tuberculosis remains centered around the same 6-month, 4-drug regimen introduced >40 years ago. The identification of more potent drugs and drug regimens that permit shortening the duration of treatment remains a key priority. A number of new drugs and regimens for tuberculosis are currently being investigated in clinical trials. This includes repurposed drugs (eg, daily high-dose RPT and higher dosages of RIF, linezolid and carbapenems) and new drugs (eg, bedaquiline, delamanid, and pretomanid ). Highdose, daily RPT is being tested in a treatment-shortening phase 3 clinical trial, with dosage selected based on dose-ranging, drug-exposure optimization studies (ClinicalTrials.gov identifier: NCT02410772) . Pretomanid is being tested as part of a combination regimen including moxifloxacin and PZA for the treatment of both drug-susceptible and drug-resistant tuberculosis (ClinicalTrials.gov identifier: NCT02193776). Bedaquiline, approved by the US FDA for treatment of multidrug-resistant tuberculosis in 2012, is also being investigated in drug-susceptible disease as part of a combination regimen including pretomanid and PZA and/or clofazimine in a phase 2 study (ClinicalTrials.gov identifier: NCT01691534). Broadly, the tuberculosis therapeutics development field would greatly benefit from dose-ranging and drug-drug interaction studies for new and existing drugs so as to identify the drug exposures and optimal combinations necessary to achieve maximal efficacy, while improving safety and tolerability. # Biomarkers of Treatment Effect and Individualization of Therapy The success of therapy depends upon many diverse factors and only some are presently predictable, identifiable, or modifiable. Inclusion of biomarker substudies that assess both microbial and host biomarkers within phase 3 clinical trials will yield important knowledge on the factors that impact therapeutic success. Additionally, data on pharmacokinetic/pharmacodynamic properties that influence drug safety and efficacy, data on drug penetration and distribution, and the pursuit of sensitive and specific biomarkers that can reliably predict relapse will be critically important to advancing the tuberculosis therapeutics field . New biomarkers of treatment effect that can be implemented in the field and accurately monitor response to treatment on an individual basis may also allow for the individualization of the duration of treatment . However, a considerable increase in investment in fundamental research is needed to develop and validate biomarkers of durable cure . # Treatment of Tuberculosis in Special Situations Based on the writing of this guideline, the need for additional research was notable for treatment of tuberculosis in special situations. In particular, there is a paucity of high-quality studies on tuberculosis in pregnant women, breastfeeding women, and children. A recent US National Institutes of Health convened workshop examining the inclusion of pregnant and postpartum women in tuberculosis drug trials has provided consensus statements to help accelerate research in this area . The lack of pediatric dosage forms of most antituberculosis medications has up to now necessitated using crushed tablets or opening capsules and creating suspensions to facilitate dosing in young children, and additionally has hampered inclusion of children in drug trials. As a result of key partnerships and concerted investments in pediatric therapeutics research, an affordable, highquality, child-friendly fixed-dose combination meeting WHO quality assurance metrics is now being produced; however, these products are not yet registered in the United States or Europe . Broadly, to address the paucity of data on the optimal treatment of children with tuberculosis, the drug development field should design trials to be more inclusive of children as study participants across key stages of therapeutics research, from pharmacokinetic studies through to phase 3 clinical trials. Examples of ongoing tuberculosis treatment trials that enroll children and adolescents are the SHINE study (Shorter Treatment for Minimal TB in Children Study; ISRCTN63579542), and TBTC Study 31/ACTG A5349 (Rifapentine-Containing Tuberculosis Treatment Shortening Regimens; NCT02410772) . # Implementation Research Even as new drugs and new regimens are being developed, there remains a critical need to improve the delivery of tuberculosis treatment. DOT has been the dominant mode of treatment delivery, but evidence supporting its use has been weak. Strategies that are more convenient for patients and less resource-intensive for public health programs should be further explored . For example, in low-incidence countries, early studies have shown that video DOT using smartphones is feasible, has high patient uptake, and is associated with similar adherence rates as in-person DOT . Research to improve tuberculosis treatment delivery strategies should be informed by behavioral studies and/or implementation science frameworks, which have been shown to increase the likelihood of identifying successful multifaceted individual behavior change and health system interventions. Finally, research on the optimal introduction of new drugs is needed (even after approval from regulatory bodies) provide data that will facilitate key implementation decisions around programmatic feasibility, cost-effectiveness, and optimal approaches to surveillance of drug resistance and prevention of emergence of new drug resistance . # Supplementary Data Supplementary materials are available at . Consisting of data provided by the author to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the author, so questions or comments should be addressed to the author. Financial support. Support for this guideline was provided by the American Thoracic Society, the IDSA, and the CDC. # Notes Potential conflicts of interest. The authors have reported to the American Thoracic Society the following: P. M. B. reported that his spouse previously owned stocks or options of Merck. R. E. C. reported service as a consultant and ownership of stocks or options for Merck. C. L. D. received research support from Insmed and served on data and safety monitoring boards of Otsuka America Pharmaceutical and Sanofi Pasteur. C. A. P. received research support from Jacobus Pharmaceuticals. J. S. reported service on a data safety and monitoring board of Otsuka Pharmaceuticals. A. V. reported serving as the chief of a CDC clinical research branch doing clinical trials in tuberculosis, which supports and works with the TB Trials Consortium (TBTC) that collaborates with pharmaceutical companies, which may provide support such as drug supplies or laboratory funding for pharmacokinetic substudies. Specifically, Sanofi Aventis has provided approximately $2.8 million in unrestricted grants to the CDC Foundation to facilitate or support TBTC work related to rifapentine, including contract research staff, pharmacokinetic substudies, travel to TBTC scientific meetings for invited speakers, and expenses related to fulfillment of company requests for data and data formats as part of use of TBTC data in support of regulatory filings. TBTC has studies under way involving rifapentine and levofloxacin that may have relevance for future regimens for drug-susceptible tuberculosis and for multidrug-resistant tuberculosis. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.	jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and bettertolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice. Keywords. Mycobacterium tuberculosis; HIV infections; antitubercular agents; case management; public health.# and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. Nine PICO (population, intervention, comparators, outcomes) questions and associated recommendations, developed based on the evidence that was appraised using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology [1,2], are summarized below. A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pharmacokinetics, pediatrics, primary care, public health, and systematic review methodology were assembled and used GRADE methods to assess the certainty in the evidence (also known as the quality of evidence) and strength of the recommendations (see Supplementary Appendix A: Methods and Table 1). This executive summary is a condensed version of the panel's recommendations. Additional detailed discussion of the management of pulmonary and extrapulmonary tuberculosis is available in the fulltext version of this guideline. # OBJECTIVES OF ANTITUBERCULOSIS THERAPY Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons, thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. The objectives of tuberculosis therapy are (1) to rapidly reduce the number of actively growing bacilli in the patient, thereby decreasing severity of the disease, preventing death and halting transmission of M. tuberculosis; (2) to eradicate populations of persisting bacilli in order to achieve durable cure ( prevent relapse) after completion of therapy; and (3) to prevent acquisition of drug resistance during therapy. The decision to initiate combination chemotherapy for tuberculosis is based on clinical, radiographic, laboratory, patient, and public health factors (Figure 1). In addition, clinical judgment and the index of suspicion for tuberculosis are critical in making a decision to initiate treatment. For example, in patients (children and adults) who, based on these considerations, have a high likelihood of having tuberculosis or are seriously ill with a disorder suspicious for tuberculosis, empiric treatment with a 4-drug regimen (Tables 2 and 3) should be initiated promptly even before the results of acid-fast bacilli (AFB) smear microscopy, molecular tests, and mycobacterial culture are known. Sixty-five years of investigation, including many clinical trials, have consistently supported the necessity of treating with multiple drugs to achieve these treatment objectives, minimize drug toxicity, and maximize the likelihood of treatment completion [3,4]. The success of drug treatment, however, depends upon many factors, and numerous studies have found an increased risk of relapse among patients with signs of more extensive disease (ie, cavitation or more extensive disease on chest radiograph) [5][6][7][8][9], and/or slower response to treatment (ie, delayed culture conversion at 2-3 months) [4,6,10,11]. # ORGANIZATION AND SUPERVISION OF TREATMENT Because of the public health implications of prompt diagnosis and effective treatment of tuberculosis, most low-incidence countries designate a government public health agency as legal authority for controlling tuberculosis [12,13]. The optimal organization of tuberculosis treatment often requires the coordination of public and private sectors [14][15][16]. In most settings, a patient is assigned a public health case manager who assesses needs and barriers that may interfere with treatment adherence [17]. With active input from the patient and healthcare providers, the case manager, together with the patient, develops an individualized "case management plan" with interventions to address the identified needs and barriers [18][19][20] (see PICO Question 1 and Supplementary Appendix B, Evidence Profiles 1-3). The least restrictive public health interventions that are effective are used to achieve adherence, thereby balancing the rights of the patient and public safety. Given that tuberculosis treatment requires multiple drugs be given for several months, it is crucial that the patient be involved in a meaningful way in making decisions concerning treatment supervision and overall care. International standards have been developed that also emphasize the importance of using patientcentered approaches to the management of tuberculosis [14][15][16]. Key considerations when developing a case management plan include (1) improving "treatment literacy" by educating the Patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not. The majority of individuals in this situation would want the suggested course of action, but many would not. # Clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences. # Policy The recommendation can be adopted as policy in most situations. Policymaking will require substantial debate and involvement of various stakeholders. Source: Grading of Recommendations Assessment, Development and Evaluation Working Group [1,2]. patient about tuberculosis and its treatment, including possible adverse effects [21,22]; (2) discussing expected outcomes of treatment, specifically the ability to cure the patient of the disease; (3) reviewing methods of adherence support and plans for assessing response to therapy; and (4) discussing infectiousness and infection control measures using terminology that is appropriate to the culture, language, age, and reading level of the patient [23]. For non-English-speaking patients, the use of medical interpreter services is preferred over using family or friends as interpreters [24]. Relevant information should be reinforced at each visit. Other components of the case management plan include, but are not limited to, setting up patient reminders and systems to follow-up missed appointments [23,[25][26][27][28][29], use of incentives and enablers [30,31], field and home visits [32], and integration and coordination of tuberculosis care with the patient's primary and specialty care (including mental health services, if appropriate and requested by the patient) (Table 4). PICO Question 1: Does adding case management interventions to curative therapy improve outcomes compared to curative therapy alone among patients with tuberculosis? (Case management is defined as patient education/counseling, field/home visits, integration/coordination of care with specialists and medical home, patient reminders, and incentives/enablers). Recommendation 1: We suggest using case management interventions during treatment of patients with tuberculosis (conditional recommendation; very low certainty in the evidence). Given the critical importance of chemotherapy, both to the patient and to the public, approaches to ensuring adherence to the treatment regimen are a major focus of the overall management plan. To maximize completion of therapy, management strategies should utilize a broad range of approaches (see "Patient-Centered Care and Case Management" in the full-text version of the guideline). Among these, directly observed therapy (DOT), the practice of observing the patient swallow their antituberculosis medications, has been widely used as the standard of practice in many tuberculosis programs, and deserves special emphasis (see PICO Question 2 and Supplementary Appendix B, Evidence Profile 4). The systematic review conducted to obtain evidence in support of this practice guideline did not find any significant differences between selfadministered therapy (SAT) and DOT when assessing several outcomes of interest, including mortality, treatment completion, and relapse. However, DOT was significantly associated with improved treatment success (the sum of patients cured and patients completing treatment) and with increased sputum smear conversion during treatment, as compared to SAT. Because DOT is a multifaceted public health intervention that is not amenable to the conventional clinical trial approaches to assessing benefits, and because participation in DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities, for allowing providers to establish rapport with the patient and for addressing treatment complications expeditiously, DOT remains the standard of practice in the majority of tuberculosis programs in the United States [33][34][35] and Europe [15] (Table 5). To be consistent with the principles of patient-centered care noted previously, decisions regarding the use of DOT must be made in concert with the patient [14][15][16]. For example, DOT can be provided in the office, clinic, or in the "field" ( patient's home, place of employment, school, or any other site that is mutually agreeable) by appropriately trained personnel [32]. PICO Question 2: Does self-administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of tuberculosis? Recommendation 2: We suggest using DOT rather than SAT for routine treatment of patients with all forms of tuberculosis (conditional recommendation; low certainty in the evidence). # RECOMMENDED TREATMENT REGIMENS The preferred regimen for treating adults with tuberculosis caused by organisms that are not known or suspected to be drug resistant is a regimen consisting of an intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF (see Tables 2,3,10,11, and Supplementary Appendix C) [3,36,37]. The intensive phase of treatment consists of 4 drugs (INH, RIF, PZA, EMB) because of the current proportion of new tuberculosis cases worldwide caused by organisms that are resistant to INH [38][39][40][41]; however, if therapy is being initiated after drug susceptibility test results are known and the patient's isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (eg, pregnant women; breastfeeding infants; persons infected with human immunodeficiency virus [HIV]; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or those who are of advanced age) [42,43]. With respect to administration schedule, the preferred frequency is once daily for both the intensive and continuation phases (see PICO Questions 3 and 4 and Supplementary Appendix B, Evidence . Although administration of antituberculosis drugs using DOT 5 days a week has been reported in a large number of studies, it has not been compared with 7-day administration in a clinical trial. Nonetheless, on the basis of substantial clinical experience, experts believe that 5-days-a-week drug administration by DOT is an acceptable alternative to 7-days-a-week administration, and either approach 62 Do not use twice-weekly regimens in HIV-infected patients or patients with smear-positive and/or cavitary disease. If doses are missed, then therapy is equivalent to once weekly, which is inferior. Abbreviations: DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin. a Other combinations may be appropriate in certain circumstances; additional details are provided in the section "Recommended Treatment Regimens." b When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. DOT should be used when drugs are administered <7 days per week. c Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase. d Pyridoxine (vitamin B6), 25-50 mg/day, is given with INH to all persons at risk of neuropathy (eg, pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day. e See [426]. Alternatively, some US tuberculosis control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses. There are inadequate data to support intermittent administration. Children 15-20 mg/kg total (divided 1-2 times daily) # Streptomycin Aqueous solution (1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. Children 15-20 mg/kg [427] ... 2 5 -30 mg/kg i . . . # Amikacin/ kanamycin Aqueous solution (500 mg and 1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function, including older patients, may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. Children 15-20 mg/kg [427] ... 2 5 -30 mg/kg i . . . # Capreomycin Aqueous solution (1 g vials) for IM or IV administration. Adults 15 mg/kg daily. Some clinicians prefer 25 mg/kg 3 times weekly. Patients with decreased renal function, including older patients, may require the 15 mg/kg dose to be given only 3 times weekly to allow for drug clearance. There are inadequate data to support intermittent administration. Children 200-300 mg/kg total (usually divided 100 mg/kg given 2 to 3 times daily) may be considered as meeting the definition of "daily" dosing. There are alternative regimens that are variations of the preferred regimen, which may be acceptable in certain clinical and/or public health situations (see "Other Regimens" and "Treatment in Special Situations" in the full-text version of the guideline). PICO Question 3: Does intermittent dosing in the intensive phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug-susceptible pulmonary tuberculosis? Recommendation 3a: We recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 3b: Use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; low certainty in the evidence). Recommendation 3c: In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; very low certainty in the evidence). Note: If doses are missed in a regimen using twice-weekly dosing, then therapy is equivalent to once weekly, which is inferior (see PICO Question 4). # Children The optimal dose is not known. Some experts use 10 mg/kg daily dosing, though lack of formulations makes such titration challenging. Aiming for serum concentrations of 3-5 µL/mL 2 h postdose is proposed by experts as a reasonable target. Abbreviations: FDA, US Food and Drug Administration; HIV, human immunodeficiency virus; IM, intramuscular; INH, isoniazid; IV, intravenous. a Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight [IBW]), dosing based on IBW may be preferred for initial doses. Some clinicians prefer a modified IBW (IBW + [0.40 × (actual weight -IBW)]) as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been established, therapeutic drug monitoring may be considered for such patients. b For purposes of this document, adult dosing begins at age 15 years or at a weight of >40 kg in younger children. The optimal doses for thrice-weekly therapy in children and adolescents have not been established. Some experts use in adolescents the same doses as recommended for adults, and for younger children the same doses as recommended for twice-weekly therapy. c Higher doses of rifampin, currently as high as 35 mg/kg, are being studied in clinical trials. d Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. e TBTC Study 22 used rifapentine (RPT) dosage of 10 mg/kg in the continuation phase of treatment for active disease [9]. However, RIFAQUIN and PREVENT TB safely used higher dosages of RPT, administered once weekly [164,210]. Daily doses of 1200 mg RPT are being studied in clinical trials for active tuberculosis disease. f As an approach to avoiding ethambutol (EMB) ocular toxicity, some clinicians use a 3-drug regimen (INH, rifampin, and pyrazinamide) in the initial 2 months of treatment for children who are HIV-uninfected, have no prior tuberculosis treatment history, are living in an area of low prevalence of drug-resistant tuberculosis, and have no exposure to an individual from an area of high prevalence of drug-resistant tuberculosis. However, because the prevalence of and risk for drug-resistant tuberculosis can be difficult to ascertain, the American Academy of Pediatrics and most experts include EMB as part of the intensive-phase regimen for children with tuberculosis. g Clinicians experienced with using cycloserine suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations often are useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily. h Ethionamide can be given at bedtime or with a main meal in an attempt to reduce nausea. Clinicians experienced with using ethionamide suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations may be useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily. i Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations. j RIFAQUIN trial studied a 6-month regimen. Daily isoniazid was replaced by daily moxifloxacin 400 mg for the first 2 months, followed by once-weekly doses of moxifloxacin 400 mg and RPT 1200 mg for the remaining 4 months. Two hundred twelve patients were studied (each dose of RPT was preceded by a meal of 2 hard-boiled eggs and bread). This regimen was shown to be noninferior to a standard daily administered 6-month regimen [164]. # Enablers Incentives Interventions to assist the patient in completing therapy [130] Interventions to motivate the patient, tailored to individual patient wishes and needs and, thus, meaningful to the patient [130] Transportation vouchers [30] Food stamps or snacks and meals [30] Convenient clinic hours and locations [30] Restaurant and grocery store coupons [30] Clinic personnel who speak the languages of the populations served [428] Assistance in finding or provision of housing [429] Reminder systems and follow-up of missed appointments [28] Clothing or other personal products [30] Social service assistance (referrals for substance abuse treatment and counseling, housing, and other services) [429] Books [428] Outreach workers (bilingual/bicultural as needed; can provide many services related to maintaining patient adherence, including provision of directly observed therapy, follow-up on missed appointments, monthly monitoring, transportation, sputum collection, social service assistance, and educational reinforcement) [428] Stipends [30] Integration of care for tuberculosis with care for other conditions [428] Patient contract [30] Recommended baseline and follow-up evaluations for patients suspected of having tuberculosis and treated with first-line medications are summarized in Figure 2. During treatment, a sputum specimen for AFB smear and culture are obtained at monthly intervals until 2 consecutive specimens are negative on culture. Duration of the continuation phase regimen hinges on the microbiological status at the end of the intensive phase of treatment; thus, obtaining sputum specimens at the time of completion of 2 months of treatment is critical if sputum culture conversion to negative has not already been documented. The culture result of a sputum specimen obtained at the completion of the intensive phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis, albeit with low sensitivity [9,[44][45][46]. Cavitation on the initial chest radiograph has also been shown to be a risk factor for relapse [9,47]. In patients treated for 6 months, having both cavitation and a positive culture at completion of 2 months of therapy has been associated with rates of relapse of approximately 20% compared with 2% among patients with neither factor [9,45]. In view of this evidence, for patients who have cavitation on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy, expert opinion is to extend the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy). Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being >10% below ideal body weight; being an active smoker; having diabetes, HIV infection, or any other immunosuppressing condition; or having extensive disease on chest radiograph [46,[48][49][50][51][52]. Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart treatment from the beginning (Table 6). Continuous treatment is more important in the intensive phase of therapy when the bacillary population is highest and the chance of developing drug resistance greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriologic status of the patient prior to and after the Baseline and follow-up evaluations for patients treated with first-line tuberculosis medications. Shading around boxes indicates activities that are optional or contingent on other information. 1 Obtain sputa for smear and culture at baseline, then monthly until 2 consecutive specimens are negative. Collecting sputa more often early in treatment for assessment of treatment response and at end of treatment is optional. At least one baseline specimen should be tested using a rapid molecular test. 2 Drug susceptibility for isoniazid, rifampin, ethambutol (EMB), and pyrazinamide should be obtained. Repeat drug susceptibility testing if patient remains culture positive after completing 3 months of treatment. Molecular resistance testing should be performed for patients with risk for drug resistance. 3 Obtain chest radiograph at baseline for all patients, and also at month 2 if baseline cultures are negative. End-of-treatment chest radiograph is optional. Other imaging for monitoring of extrapulmonary disease. 4 Monitor weight monthly to assess response to treatment; adjust medication dose if needed. 5 Assess adherence and monitor improvement in tuberculosis symptoms (eg, cough, fever, fatigue, night sweats) as well as development of medication adverse effects (eg, jaundice, dark urine, nausea, vomiting, abdominal pain, fever, rash, anorexia, malaise, neuropathy, arthralgias). 6 Patients on EMB: baseline visual acuity (Snellen test) and color discrimination tests, followed by monthly inquiry about visual disturbance and monthly color discrimination tests. 7 Liver function tests only at baseline unless there were abnormalities at baseline, symptoms consistent with hepatotoxicity develop, or for patients who chronically consume alcohol, take other potentially hepatotoxic medications, or have viral hepatitis or history of liver disease, human immunodeficiency virus (HIV) infection, or prior drug-induced liver injury. 8 Baseline for all patients. Further monitoring if there are baseline abnormalities or as clinically indicated. 9 HIV testing in all patients. CD4 lymphocyte count and HIV RNA load if positive. 10 Patients with hepatitis B or C risk factor (eg, injection drug use, birth in Asia or Africa, or HIV infection) should have screening tests for these viruses. 11 Fasting glucose or hemoglobin A1c for patients with risk factors for diabetes according to the American Diabetes Association including: age >45 years, body mass index >25 kg/m 2 , first-degree relative with diabetes, and race/ethnicity of African American, Asian, Hispanic, American Indian/Alaska Native, or Hawaiian Native/Pacific Islander. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. interruption are also important considerations (see "Interruptions in Therapy" in the full-text version of the guideline). PICO Question 4: Does intermittent dosing in the continuation phase have similar outcomes compared to daily dosing in the continuation phase in patients with drug-susceptible pulmonary tuberculosis patients? Recommendation 4a: We recommend the use of daily or thriceweekly dosing in the continuation phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 4b: If intermittent therapy is to be administered in the continuation phase, then we suggest use of thrice-weekly instead of twice-weekly therapy (conditional recommendation; low certainty in the evidence). This recommendation allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior. Recommendation 4c: We recommend against use of once-weekly therapy with INH 900 mg and rifapentine 600 mg in the continuation phase (strong recommendation; high certainty in the evidence). In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus rifapentine 600 mg may be considered for use only in HIVuninfected persons without cavitation on chest radiography. # PRACTICAL ASPECTS OF TREATMENT Guidance on the practical aspects of tuberculosis treatment, drug-drug interactions, therapeutic drug monitoring (TDM), and management of adverse effects are available in the full-text version of this guideline. In brief, mild adverse effects usually can be managed with treatment directed at controlling the symptoms; severe effects usually require the offending drug(s) to be discontinued, and may require expert consultation on management. If a drug is permanently discontinued, then a replacement drug, typically from a different drug class, is included in the regimen. Patients with severe tuberculosis often require the initiation of an alternate regimen during the time the offending drug(s) are held. In general, for complicated diagnostic or management situations, consultation with local and state health departments is advised. In the United States, the Centers for Disease Control and Prevention's Division of Tuberculosis Elimination funds tuberculosis regional training and medical consultation centers (http://www.cdc.gov/tb/education/rtmc/), which provide medical consultation to programs and health providers on management of tuberculosis. In Europe, the World Health Organization (WHO)/ERS Tuberculosis Consilium (https://www.tbconsilium. org) provides similar consultation services regarding the diagnosis and treatment of tuberculosis. Gastrointestinal reactions are common, especially early in therapy [53]. The optimum approach to management of epigastric distress or nausea with tuberculosis drugs is not clear. To minimize symptoms, patients receiving SAT may take the medications at bedtime. Gastrointestinal intolerance not associated with hepatotoxicity can be treated with antacids, which have less impact on absorption or peak concentration of first-line drugs than administration with food [54]. Any combination of otherwise unexplained nausea, vomiting, and abdominal pain is evaluated with a physical examination and liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase to assess for possible hepatotoxicity [55]. Drug-induced hepatitis is the most frequent serious adverse reaction to the first-line drugs. INH, RIF, and PZA can cause drug-induced liver injury (DILI), which is suspected when the ALT level is ≥3 times the upper limit of normal in the presence of hepatitis symptoms, or ≥5 the upper limit of normal in the absence of symptoms. In either situation, hepatotoxic drugs are stopped immediately and the patient is evaluated carefully. Other causes of abnormal liver function tests must be excluded before diagnosing druginduced hepatotoxicity (Table 7). An official American Thoracic Society statement on the hepatotoxicity of antituberculosis therapy (http://www.thoracic.org/statements/resources/mtpi/ hepatotoxicity-of-antituberculosis-therapy.pdf ) provides additional details on the management of tuberculosis in the setting of drug-induced liver injury, as well as suggestions on drug rechallenge [56]; however, the optimal approach to reintroducing tuberculosis treatment after hepatotoxicity is still not known [57,58]. TREATMENT # HIV Infection Treatment of tuberculosis in patients with HIV infection has several important differences compared with treatment of patients who do not have HIV infection. The need for antiretroviral therapy (ART), the potential for drug-drug interactions, especially between the rifamycins and antiretroviral agents (Table 8), paradoxical reactions that may be interpreted as clinical worsening, and the potential for developing resistance to rifamycins when using intermittent tuberculosis therapy are some of these differences. Detailed information on these topics is provided in the full-text version of this practice guideline. In regard to duration of treatment for drug-susceptible pulmonary tuberculosis in the presence of HIV infection, our updated systematic review of randomized trials and cohort studies comparing various durations of tuberculosis therapy (6 months vs 8 months or longer), most of which were conducted prior to the era of highly active ART, showed that the risk of recurrence is lower when the continuation phase of treatment is extended. However, it is important to note that the majority of these studies were reports on nonrandomized cohorts, most were completed prior to the era of routine antiretroviral use, many tested intermittent regimens and few distinguished between reinfection and relapse (see "HIV Infection" in the full-text version of the guideline). As discussed below, based on data that show significant reductions in mortality and AIDS-defining illnesses, patients with HIV infection and tuberculosis should receive ART in conjunction with daily antituberculosis medications. For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis. In the uncommon situation in which an HIV-infected patient does not receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drug-susceptible pulmonary tuberculosis (see PICO Question 5 and Supplementary Appendix B, Evidence Profile 12). As is noted for drug-susceptible pulmonary tuberculosis in patients without HIV coinfection, the continuation phase is extended in specific situations that are known to increase risk for relapse, as well as for selected extrapulmonary sites of disease, namely tuberculous meningitis, and bone, joint, and spinal tuberculosis (see "Identification and Management of Patients at Increased Risk of Relapse" and "Extrapulmonary Tuberculosis" in the full-text version of the guideline). PICO Question 5: Does extending treatment beyond 6 months improve outcomes compared to the standard 6-month treatment regimen among pulmonary tuberculosis patients coinfected with HIV? Recommendation 5a: For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Recommendation 5b: In uncommon situations in which HIV-infected patients do NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drugsusceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Use of intermittent tuberculosis treatment regimens in HIVinfected patients has been associated with high rates of relapse and the emergence of drug resistance [9,59]. In a trial of rifabutin (RFB)-based antituberculosis therapy in combination with antiretroviral drugs, patients treated with twice-weekly RFB had a relapse rate of 5.3%, but 8 of 9 patients with relapse had acquired rifamycin resistance [60]. Relapse and resistance were associated with low CD4 lymphocyte counts, as all recurrences occurred in patients with baseline CD4 lymphocyte counts <100 cells/µL. In the pharmacokinetic substudy of the trial, lower plasma concentrations of RFB and INH were identified as key risk factors for acquiring rifamycin resistance [61]. More recently, the use of a thrice-weekly RIF-based regimen during the intensive and continuation phases of treatment was associated with a higher rate of relapse and emergence of # Atovaquone Consider alternate form of Pneumocystis jirovecii treatment or prophylaxis. # Chloramphenicol Consider an alternative antibiotic. # Mefloquine Consider alternate form of malaria prophylaxis. # Hormone therapy Ethinylestradiol, norethindrone Women of reproductive potential on oral contraceptives should be advised to add a barrier method of contraception when on a rifamycin. # Tamoxifen May require alternate therapy or use of a non-rifamycin-containing regimen. rifamycin resistance in HIV-infected individuals not receiving antiretrovirals compared with HIV-infected patients also receiving antiretrovirals or HIV-uninfected patients [62]. Based in part on systematic reviews conducted to obtain evidence in support of this guideline, our expert opinion is that treatment of HIV-related tuberculosis be given daily in both the intensive and continuation phases to avoid recurrent disease and the emergence of rifamycin resistance (see "Recommended Treatment Regimens" in the full-text version of the guideline). Mortality among patients with HIV and tuberculosis is high, principally due to complications of immunosuppression and occurrence of other HIV-related opportunistic diseases. Cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis has been shown to reduce morbidity and mortality in HIV-infected patients with newly diagnosed tuberculosis [63][64][65]. Whereas cotrimoxazole is recommended by WHO for all HIV-infected people with active tuberculosis disease regardless of the CD4 cell count [66], in high-income countries, co-trimoxazole is primarily used in HIV-infected patients with CD4 counts <200 cells/µL [67]. The use of ART during tuberculosis treatment in persons with HIV infection also reduces mortality rates significantly and decreases the risk of developing AIDS-related conditions. We performed a systematic review and meta-analysis to address the concurrent initiation of ART with tuberculosis treatment. On the basis of high certainty in the evidence that the benefits outweigh the harms, we recommend that patients with tuberculosis and HIV infection receive ART during antituberculosis treatment. ART should ideally be started within 2 weeks for those patients with a CD4 count <50 cells/µL and by 8-12 weeks for those with a CD4 count ≥50 cells/µL (see PICO Question 6 and Supplementary Appendix B, Evidence Profile 13). An exception is HIV-infected patients with tuberculous meningitis, in whom ART is not initiated in the first 8 weeks of antituberculosis therapy (see full-text version of the guideline). The concurrent administration of antiretrovirals and rifamycins is a major therapeutic challenge, and additional details on the coadministration of these medications, including the use of RFB, are available in the full-text version of this guideline. PICO Question 6: Does initiation of ART during tuberculosis treatment compared to at the end of tuberculosis treatment improve outcomes among tuberculosis patients coinfected with HIV? Recommendation 6: We recommend initiating ART during tuberculosis treatment. ART should ideally be initiated within the first 2 weeks of tuberculosis treatment for patients with CD4 counts <50 cells/µL and by 8-12 weeks of tuberculosis treatment initiation for patients with CD4 counts ≥50 cells/µL (strong recommendation; high certainty in the evidence). Note: an exception is patients with HIV infection and tuberculous meningitis (see Immune Reconstitution Inflammatory Syndrome). Patients with HIV infection and tuberculosis are at increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the immune reconstitution inflammatory syndrome (IRIS). Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4 + cell counts <50 cells/µL [68]. Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses [69]. Such findings are attributed to IRIS only after excluding other possible causes, especially tuberculosis treatment failure from drug-resistant tuberculosis or another opportunistic disease, such as non-Hodgkin lymphoma or infection. Management of IRIS is symptomatic. Based on expert opinion, for most patients with mild IRIS, tuberculosis and antiretroviral therapies can be continued with the addition of anti-inflammatory agents such as ibuprofen. For patients with worsening pleural effusions or abscesses, drainage may be necessary. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures [70]. For patients who develop IRIS, prednisone may be given at a dose of 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks, with tapering over a period of 6-12 weeks or longer. # Tuberculous Pericarditis Based on small studies that have shown mortality and morbidity benefits [71][72][73], corticosteroids have previously been universally recommended in combination with a standard 6-month regimen (Table 2) for treating tuberculosis pericarditis; however, a recent placebo-controlled randomized clinical trial with 1400 participants did not find a difference in the combined primary endpoint of the trial, which included mortality, cardiac tamponade, or constrictive pericarditis, between patients treated with adjunctive corticosteroids vs placebo [74]. A subgroup analysis, however, did suggest a benefit in preventing constrictive pericarditis. Similarly, a systematic review conducted to obtain evidence in support of this guideline did not find a statistically significant benefit in terms of mortality or constrictive pericarditis from the use of corticosteroids [71][72][73][74][75]. Therefore, we suggest that adjunctive corticosteroids should not be used routinely in the treatment of patients with pericardial tuberculosis (see PICO Question 7 and Supplementary Appendix B, Evidence Profile 14). However, selective use of corticosteroids in patients who are at the highest risk for inflammatory complications might be appropriate. Such patients might include those with large pericardial effusions, those with high levels of inflammatory cells or markers in pericardial fluid, or those with early signs of constriction [76]. PICO Question 7: Does the use of adjuvant corticosteroids in tuberculous pericarditis provide mortality and morbidity benefits? Recommendation 7: We suggest initial adjunctive corticosteroid therapy not be routinely used in patients with tuberculous pericarditis (conditional recommendation; very low certainty in the evidence). # Tuberculous Meningitis Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy. In children with tuberculous meningitis, the American Academy of Pediatrics (AAP) lists an initial 4-drug regimen composed of INH, RIF, PZA, and ethionamide, if possible, or an aminoglycoside, followed by 7-10 months of INH and RIF as the preferred regimen [77]. There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis [78]. Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our guideline committee prefers using EMB as the fourth drug in the regimen for tuberculous meningitis. The role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis has been reported by numerous studies [79][80][81][82][83][84][85][86][87][88][89][90][91], and our updated systematic review found a mortality benefit from the use of adjuvant corticosteroids. Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (see PICO Question 8 and Supplementary Appendix B, Evidence Profile 15). PICO Question 8: Does the use of adjuvant corticosteroids in tuberculous meningitis provide mortality and morbidity benefits? Recommendation 8: We recommend initial adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (strong recommendation; moderate certainty in the evidence). # Culture-Negative Pulmonary Tuberculosis in Adults Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active tuberculosis. Some causes of failure to isolate organisms include low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing [92]. Alternative diagnoses must be considered and appropriate diagnostic studies undertaken in patients who appear to have culturenegative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis have 2 sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria or for rapid molecular testing for M. tuberculosis as part of the diagnostic evaluation. Other diagnostic procedures, such as bronchoscopy with bronchoalveolar lavage and biopsy, are considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture or a rapid molecular test is positive, treatment for active disease is continued for a full, standard 6-month course (Table 2), if appropriate based on drug susceptibility test results. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have thorough clinical and radiographic follow-up after 2-3 months of therapy [93]. If there is clinical or radiographic improvement and no other etiology is identified, treatment should be continued. The optimum treatment regimens and duration for smearnegative, culture-negative tuberculosis have not been convincingly established. We performed a systematic review that evaluated treatment regimens of varying durations in adult patients with culture-negative, paucibacillary tuberculosis, and we suggest that a 4-month treatment regimen is adequate for smearnegative, culture-negative pulmonary tuberculosis (see PICO Question 9 and Supplementary Appendix B, Evidence Profile 16). Operationally, treatment is initiated with an intensive phase of INH, RIF, PZA, and EMB daily and continued even when the initial bacteriologic studies are negative. If all cultures on adequate samples are negative (defining culture-negative tuberculosis) and there is clinical or radiographic response after 2 months of intensive phase therapy, the continuation phase with INH and RIF can be shortened to 2 months. Alternatively, if there is concern about the adequacy of workup or the accuracy of the microbiologic evaluations, a standard 6-month regimen remains preferred (see Table 2 and "Culture-Negative Pulmonary Tuberculosis" in the full-text version of the guideline) [14,15]. PICO Question 9: Does a shorter duration of treatment have similar outcomes compared to the standard 6-month treatment duration among HIV-uninfected patients with paucibacillary tuberculosis (ie, smear negative, culture negative)? Recommendation 9: We suggest that a 4-month treatment regimen is adequate for treatment of HIV-uninfected adult patients with AFB smear-and culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). # CONCLUSIONS Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of M. tuberculosis to other persons, thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. A 4-drug regimen of INH, RIF, PZA, and EMB remains the preferred initial treatment for drugsusceptible pulmonary tuberculosis. Treatment is initiated promptly even before AFB smear microscopy, molecular tests, and mycobacterial culture results are known in patients with high likelihood of having tuberculosis or those seriously ill with a disorder suspicious for tuberculosis. Initiation of treatment should not be delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. There are variations of the preferred regimen that are appropriate in certain public health situations or in special clinical situations. Additional detailed and extensively referenced information on treatment of tuberculosis in special situations ( patients with renal disease or hepatic disease, those of advanced age, etc), the use of case management strategies (including DOT), regimen and dosing selection in adults and children (daily vs intermittent), the role of TDM, treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of ART), treatment of tuberculosis in children, treatment of tuberculosis during pregnancy, and treatment of extrapulmonary tuberculosis, as well as key research priorities, are provided in the full-text version of this practice guideline. # BACKGROUND The ATS, the CDC, and the IDSA have jointly developed this guideline for the treatment of drug-susceptible tuberculosis. This document provides guidance on the clinical and public health management of tuberculosis in low-incidence countries. The current document differs from its predecessor, published in 2003 [94], in 3 important areas. First, the process by which the recommendations were developed was substantially modified. For the first time, the Guideline Writing Committee based its recommendations on the certainty in the evidence (also known as the quality of evidence) assessed according to the GRADE methodology (see Supplementary Appendix A: Methods), which incorporates patient values and costs as well as judgments about trade-offs between benefits and harms [1, 2]. A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pharmacokinetics, pediatrics, primary care, public health, and systematic review methodology were assembled to assess the evidence supporting each recommendation. The GRADE method was used to assess the certainty in the evidence and to rate the strength of the recommendations. Second, the ERS has become an endorser of the statement, along with the US NTCA. Representatives from the AAP, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the WHO also participated in the development of this guideline. Together, these committee members served to provide broader input, thereby expanding the applicability of the guidance beyond North America to include Europe and other low-incidence settings. Last, practice guidelines for the treatment of drug-resistant tuberculosis (including INH monoresistance) are no longer included in this statement and are now covered in a separate practice guideline under development by the ATS, CDC, ERS, and IDSA. Whereas significant changes have been made, the current document also retains many of the basic principles of tuberculosis care described in the 2003 version. As before, a fundamental aspect of tuberculosis care, regardless of the treatment selected, is ensuring patient adherence to the drug regimen and successful completion of therapy. The responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse [95]. Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. The recommendations in this statement are not applicable under all epidemiological circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. It should be emphasized that these guidelines are intended for areas in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic facilities are available on a routine basis-typically low-incidence (<100 tuberculosis cases per million population), well-resourced countries, where in some settings tuberculosis epidemiology is at or nearing preelimination levels (<10 cases per million) [96,97]. The WHO has developed tuberculosis practice guidelines (currently under revision) specifically for high-incidence, resource-limited areas of the world [98]. # OBJECTIVES OF ANTITUBERCULOSIS THERAPY Treatment of tuberculosis is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons; successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. The objectives of tuberculosis therapy are: 1. To reduce the bacillary population rapidly thereby decreasing severity of the disease, preventing death and halting transmission of M. tuberculosis; 2. To eradicate persisting bacilli in order to achieve durable cure ( prevent relapse) after completion of therapy; and 3. To prevent acquisition of drug resistance during therapy. Sixty-five years of investigation, including many clinical trials, have consistently supported the requirement for treatment with multiple drugs to achieve these objectives, minimize drug toxicity, and maximize the likelihood of treatment completion [3,4]. The most effective agents to curtail rapid multiplication of tuberculous bacilli are INH and the fluoroquinolones. Persisting bacilli appear to curtail their metabolic activity; drugs known to be effective against such persisters include the rifamycins and PZA, the latter with activity believed limited to special microenvironments of relatively increased acidity [99]. Objective 1: Rapid killing of multiplying bacilli ("bactericidal effect"): Rapid reduction in the number of replicating bacilli reduces mortality risk [100,101], and appears to diminish infectiousness, but even optimal therapy on average requires 4-5 weeks to render sputum cultures negative [102][103][104][105]. Studies of early bactericidal activity (EBA) measure the rate of decline in bacillary numbers in sputum during the initial 1-2 weeks of treatment; EBA studies have been used in the initial evaluation of virtually every new tuberculosis drug since 1980 [106,107]. However, the relationship of a drug or regimen's EBA to its ability to achieve durable cure is still uncertain [108]. For example, INH has a remarkable EBA but acts only slowly on persisting bacilli; RIF at the dose currently used (10 mg/kg) has moderate EBA but potent activity against persisters; and PZA has almost no measurable EBA, but acts potently to assist in achieving durable cure [99,109]. Objective 2: Achievement of relapse-free cure ("sterilizing effect"): Demonstration of relapse-free cure requires lengthy clinical trials. Among the few drugs effective in preventing relapse, the most prominent have been the rifamycins. Rapid and reliable measurement of the sterilizing effect of antituberculous agents remains elusive. In vitro models are not entirely predictive [110,111]. The most commonly used animal model is the murine model, which has reliably reproduced the results of standard short-course chemotherapy [112]; however, the murine model has been criticized because mice do not develop cavities and caseous necrosis, pathologic hallmarks of human tuberculosis [113]. Other animal models have been proposed, but none fully replicates the human response to M. tuberculosis [114]. Recent evidence suggests that extracellular bacilli in necrotic material within cavities may be the major challenge to prevention of relapse after therapy. Studies using sensitive analytic tools such as positron emission tomography-computed tomography scanning and matrix-assisted laser desorption/ ionization mass spectrometry imaging in experimental animals and in patients undergoing pulmonary resection have provided evidence of the marked differences in the ability of key drugs (RIF, PZA, levofloxacin, moxifloxacin) to penetrate into pulmonary tissue, into the cellular granuloma, and into caseous material within cavities [115][116][117][118][119]. However, the pathologic sites from which relapses arise remain unclear. Objective 3: Protection against acquisition of drug resistance (through use of multidrug therapy): The basic biology underlying the acquisition of drug resistance is well understood, though the details involving some individual agents are still uncertain. As a rule, genetic mutations conferring substantial resistance to individual antituberculous agents occur at constant low rates. For example, rifamycins act primarily by inhibiting the action of bacterial RNA polymerase in the translation of DNA to RNA, by binding to and obstructing access to a subunit of the bacterial RNA polymerase. Mutations in a relatively limited (81 base pairs [bp]) genomic segment encoding for this subunit lead to obstruction of rifamycin binding to the polymerase β subunit (rpoB); more than half a dozen amino acid substitutions conferring RIF resistance have been well described. In the case of PZA, resistance is most often conferred by mutations in the pncA gene, which encodes for an amidase that is required to convert PZA, a prodrug, into its active form, pyrazinoic acid. The pncA mutations occur throughout the 350-bp gene, with no notable preference for specific mutations yet described. INH is also a prodrug requiring activation by a bacterial catalase-peroxidase enzyme (encoded by katG), coupling with NADH, and binding to an acyl carrier protein reductase (encoded by inhA); the process inhibits the synthesis of mycolic acid needed for the mycobacterial cell wall. Resistance to INH arises through multiple mechanisms, including loss of the katG-encoded catalase peroxidase activity, and overexpression or alterations in the inhAencoded reductase [120]. The frequency of mutation engendering resistance to specific agents was estimated some 40 years ago; the highest proportion of resistant mutants expected in an unselected bacterial population were 3.5 × 10 −6 for INH and 3.1 × 10 −8 for RIF [4,121]. Because these mutations generally occur independently, the likelihood of simultaneous resistance mutations to both INH and RIF is in the range of 11 × 10 −14 . Thus, in patients with very high bacillary burdens, the occurrence of mutations conferring resistance to a single drug is likely, to 2 drugs is possible, but to 3 drugs is highly unlikely [10]. Acquisition of drug resistance might occur more readily if there is irregular or sporadic drug taking, inadequate drug absorption, inadequate drug dosing, or ill-informed use of single drug treatment (either by error, or because tuberculosis has not been recognized or considered). If resistance to a specific drug occurs, then the resistant clone will possess an advantage relative to susceptible strains when confronted with that drug, and will have no advantage (or possibly a modest disadvantage, if the mutation confers some biologic "cost") if the drug is not used. In the situation of the standard 3-drug regimen (INH, RIF, PZA), 3 circumstances must likely be present for resistance to RIF to emerge: (1) some mutant bacilli resistant to RIF must be present or appear; (2) the bacilli must be exposed to RIF to favor multiplication of the resistant bacteria; and (3) INH and PZA must not be present in sufficient concentration to offset the survival advantage enjoyed by the RIF-resistant clones; this could occur because they are not employed at all (ie, single drug therapy), or because some combination of circumstances affects the other drugs (eg, a nonacidic compartment is involved thereby disadvantaging PZA, and INH happens to be rapidly metabolized [so-called rapid acetylation due to genetic polymorphisms affecting N-acetyl transferase], so that INH is not present in adequate concentration) [59]. # Multiple Factors Influence the Outcome of Tuberculosis Treatment Multiple interrelated factors have been associated with the outcome of tuberculosis therapy. These include: • Patient factors, such as age, comorbid conditions, immunologic competence, nutritional status, alcohol abuse; • Radiographic features, such as extent of disease, presence and size of cavities; • Microbiologic factors, such as baseline colony count, culture positivity at 2 or 3 months; • Genetic factors, including individual genetic features of drug absorption and metabolism, individual vulnerability to toxicities, immunologic characteristics; • Programmatic factors, including adherence support interventions (enhancers, enablers, monitoring, supervision/DOT), dosing frequency; • Pharmacokinetic factors, such as absorption, metabolism, protein binding, drug clearance, total drug quantities administered; • Bacillary factors, such as drug tolerance, strain susceptibilities to drugs in the regimen; and • Regimen factors, such as number of active drugs, bactericidal and sterilizing potency, synergy or antagonism, and duration of therapy in relation to drugs employed. The success of therapy depends upon many diverse elements, only some of which are presently predictable, identifiable, or modifiable. Numerous studies have found an increased risk of relapse among patients with signs of more extensive disease (ie, cavitation or more extensive disease on chest radiograph) [5][6][7][8][9], and/or slower response to treatment (ie, culture status at 2 or 3 months) [4,6,10,11]. Better understanding of the causal pathways through which these elements exert their effect, and greater ability to identify and quantify each of these, should lead to increased therapeutic success, and will inform efforts to develop shorter, less toxic, and better-tolerated treatment regimens in the future [122]. # ORGANIZATION AND SUPERVISION OF TREATMENT PICO Question 1: Does adding case management interventions to curative therapy improve outcomes compared to curative therapy alone among patients with tuberculosis? (Case management is defined as patient education/counseling, field/ home visits, integration/coordination of care with specialists and medical home, patient reminders, incentives/enablers). Recommendation 1: We suggest using case management interventions during treatment of patients with tuberculosis (conditional recommendation; low certainty in the evidence). PICO Question 2: Does self-administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of tuberculosis? Recommendation 2: We suggest using DOT rather than SAT for routine treatment of patients with all forms of tuberculosis (conditional recommendation; low certainty in the evidence). # Role of Health Department Due to the public health implications of prompt diagnosis and effective treatment of tuberculosis, most low-incidence countries designate a government public health agency as having legal authority for controlling tuberculosis [12,13]. To effectively carry out this charge, the public health agency conducts ongoing epidemiologic surveillance of tuberculosis, ensures access to quality-assured microbiological laboratory services, maintains an uninterrupted supply of antituberculosis medications, and monitors and reports treatment outcomes [13]. The public health agency may also have the authority to apply legal measures in situations of nonadherence as a last resort where other interventions have been pursued without effect. In some jurisdictions diagnostic and treatment services are provided directly by the public health agency, whereas in others, these services are provided by the private sector or by a combination of public and private providers. # Patient-Centered Care and Case Management Patient-centered care respects an individual's right to participate actively as an informed partner in decisions and activities related to tuberculosis diagnosis and treatment [123,124]. The Institute of Medicine defines patient-centered care as "providing care that is respectful of and responsive to individual patient preferences, needs, and values, and ensuring that patient values guide all clinical decisions" [125]. Given that tuberculosis treatment requires multiple drugs be given for several months, it is crucial that the patient be involved in a meaningful way in making decisions concerning treatment supervision and overall care. International standards have been developed that also support using patient-centered approaches to the management of tuberculosis [14][15][16]. The optimal organization of tuberculosis treatment often requires the coordination not only of primary and specialty clinical care services, but also community-based organizations and agencies in the public and private sectors [14][15][16]. The inherent complexities of the healthcare delivery system combined with the diversity of characteristics of patients are best addressed by providing individualized patient-centered case management [13]. In most settings, a patient is assigned a case manager who assesses needs and barriers that may interfere with treatment adherence [17]. With active input from the patient and healthcare providers, the case manager, together with the patient, develops an individualized case management plan with interventions to address the identified needs and barriers [18][19][20]. The plan is reviewed periodically and revised as needed with the patient and medical team to evaluate the clinical response to therapy, monitor potential drug toxicities, and address any challenges identified with adherence. The spectrum of interventions for achieving adherence may range from routine monthly monitoring to legal confinement [126,127], with confinement being used only as a last resort. The least restrictive public health interventions that are effective are used to achieve adherence. Key considerations when developing a case management plan include (1) improving "treatment literacy" by educating the patient about tuberculosis and its treatment, including possible adverse effects [21,22]; (2) discussing expected outcomes of treatment, specifically the ability to cure the patient of the disease; (3) reviewing methods of supervision and assessing response to therapy; and (4) discussing infectiousness and infection control measures using terminology that is appropriate to the culture, language, age, and reading level of the patient [23]. For non-English-speaking patients, the use of medical interpreter services is preferred over using family or friends as interpreters [24]. Relevant information should be reinforced at each visit. Other components of the patient-centered case management plan include, but are not limited to, setting up patient reminders and systems to follow-up missed appointments [23,28,29], use of incentives and enablers [25-27, 30, 31], field and home visits [32], integration and coordination of tuberculosis care with the patient's primary and specialty care, and legal interventions when indicated (Table 4). Overall, the quality of evidence is variable in the few studies examining the impact of case management interventions on outcomes such as treatment success; however, these studies suggest that for the most part, patient-centered case management interventions are helpful with little evidence of harm to patients [128] (see Supplementary Appendix B, Evidence Profiles 1-3). For these reasons, we suggest using case management interventions during treatment of patients with tuberculosis (Recommendation 1: conditional recommendation; very low certainty in the evidence). # Approaches to Ensuring Adherence and Treatment Success Given the critical importance of chemotherapy, both to the patient and to the public, approaches to ensuring adherence to the treatment regimen are a major focus of the overall management plan. To maximize completion of therapy, management strategies should utilize a broad range of approaches. Among these, DOT, the practice of observing the patient swallow her or his antituberculosis medications, has been widely used and deserves special emphasis. To be consistent with the principles of patient-centered care, decisions regarding the use of DOT must be made in concert with the patient [14][15][16]. For example, DOT can be provided in the office, clinic, or in the "field" ( patient's home, place of employment, school, or any other site that is mutually agreeable) by appropriately trained personnel [32]. DOT enables early identification of adverse drug reactions, clinical worsening of tuberculosis, and nonadherence [33]. Moreover, frequent contact with the patient allows providers to facilitate linkage to other medical care and services. However, the implementation of DOT may not be readily feasible when resources are limited [129]. In such circumstances, patients who are more likely to present a transmission risk to others or are more likely to have difficulty with adherence are prioritized for DOT [17]. In addition, experts advise that DOT must be used with regimens that use intermittent drug administration because of the potential serious consequences of missed doses. Careful attention is needed to ensure that ingestion of the medication is, in fact, observed, as the use of DOT does not guarantee ingestion of all doses of every medication [130]. Patients may miss appointments, may not actually swallow the tablets or capsules, or may deliberately regurgitate the medications. Consequently, the use of DOT does not mitigate the continued need for monitoring for signs of treatment failure. DOT is also advised for all patients residing in institutional settings such as hospitals, nursing homes, opiate replacement clinics, or correctional facilities. In special populations such as individuals with treatment failure, recurrence, or at risk for disseminated tuberculosis (eg, HIV coinfected), experts recommend against the use of SAT given the risks involved in developing drug resistance (Table 5). In recent years, DOT has expanded to other modalities such as web-based video and mobile phones, which have been well received by both patients and health department staff [131][132][133]. Special attention to maintaining patient privacy is needed when web-based and wireless modalities are used for monitoring. Systematic reviews of studies conducted in countries with high, medium, and low burdens of tuberculosis have not shown improvement in cure or treatment completion in patients receiving their antituberculosis treatment by DOT compared with SAT [134][135][136]. The systematic review conducted to obtain evidence in support of this practice guideline also did not find any significant differences between SAT and DOT when assessing several outcomes of interest, including mortality, treatment completion, and relapse (see Supplementary Appendix B, Evidence Profile 4). However, DOT was significantly associated with improved treatment success (the sum of patients cured and patients completing treatment) and with increased sputum smear conversion during treatment, as compared to SAT. Because DOT is a multifaceted public health intervention that is not amenable to the conventional clinical trials approaches to assessing benefits, and because participation in DOT can be advantageous for early recognition of adverse drug reactions and treatment irregularities, for allowing providers to establish rapport with the patient and for addressing treatment complications expeditiously, DOT remains the standard of practice in the majority of tuberculosis programs in the United States [33][34][35] and Europe [15]. Population-based studies (representing a low quality of evidence) have suggested that tuberculosis treatment by DOT in comparison to SAT is associated with a reduction in the acquisition and transmission of drugresistant M. tuberculosis (Texas), increased treatment success in HIV-infected patients receiving RFB-containing regimens, shorter duration for completion of treatment (New York City), higher treatment completion rates in incarcerated patients transitioning to the community (Chicago), and a reduction in mortality and loss to follow-up (Brazil) [34,[137][138][139][140]. Consequently, we suggest using DOT rather than SAT for routine treatment of patients for all forms of tuberculosis (Recommendation 2: conditional recommendation; low certainty in the evidence). # Transfers Between Jurisdictions Patients being treated for tuberculosis who move from one jurisdiction to another before completion of therapy are more likely to be lost to follow-up than patients who do not move [141]. In the United States, health departments track patients via interjurisdictional referrals, and can use other patient tracking mechanisms (eg, TBNet at http://www.migrantclinician.org/ services/network/tbnet.html) for patients who travel internationally) [142][143][144]. # Legal Interventions to Protect Public Health In extreme circumstances, nonadherent patients may be subject to legal intervention in the form of court-ordered medical examination, DOT, completion of therapy, or civil or criminal detention for completion of tuberculosis treatment when less restrictive measures have been tried and shown to fail [126,127,145]. These situations involve special circumstances such as drug resistance, evidence of treatment failure or relapse, and continued concern for transmission in the community, thereby justifying the temporary restriction of individual rights to protect the public's health and safety. Public health laws exist in most jurisdictions that allow these legal interventions, at least for patients who remain infectious, but they should be pursued as a plan of last resort. In the United States, health departments have the sole authority to initiate legal action, and generally the interventions produce good outcomes with treatment completion rates >95% [126,127]. Outside the United States, legal authority to enforce tuberculosis adherence may originate in other government agencies outside the health department [146]. RECOMMENDED TREATMENT REGIMENS PICO Question 3: Does intermittent dosing in the intensive phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug-susceptible pulmonary tuberculosis? Recommendation 3a: We recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 3b: Use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; low certainty in the evidence). Recommendation 3c: In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (conditional recommendation; very low certainty in the evidence). Note: If doses are missed in a regimen using twice-weekly dosing then therapy is equivalent to once weekly, which is inferior (see PICO Question 4). PICO Question 4: Does intermittent dosing in the continuation phase have similar outcomes compared to daily dosing in the continuation phase in patients with drug-susceptible pulmonary tuberculosis patients? Recommendation 4a: We recommend the use of daily or thriceweekly dosing in the continuation phase of therapy for drugsusceptible pulmonary tuberculosis (strong recommendation; moderate certainty in the evidence). Recommendation 4b: If intermittent therapy is to be administered in the continuation phase, then we suggest use of thrice-weekly instead of twice-weekly therapy (conditional recommendation; low certainty in the evidence). This recommendation allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior. Recommendation 4c: We recommend against use of once-weekly therapy with INH 900 mg and rifapentine (RPT) 600 mg in the continuation phase (strong recommendation; high certainty in the evidence). In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus RPT 600 mg may be considered for use only in HIV-uninfected persons without cavitation on chest radiography. # Deciding to Initiate Treatment Empiric treatment with a 4-drug regimen is initiated promptly in patients (children and adults) with high likelihood of having tuberculosis or those seriously ill with a disorder suspicious for tuberculosis, even before AFB smear microscopy, molecular tests, and mycobacterial culture results are known. Initiation of treatment is not delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. The decision to initiate combination chemotherapy for tuberculosis is based on multiple factors including clinical, radiographic, laboratory, patient, and public health factors (Figure 1). Clinical judgment and index of suspicion also play a critical role in deciding to initiate treatment. In addition to smear microscopy and mycobacterial culture, CDC recommends the use of a rapid molecular test on at least one specimen from each patient with signs and symptoms of pulmonary tuberculosis for whom a diagnosis of tuberculosis is being considered but has not been established, and for whom the test result would alter case management or tuberculosis control activities [147]. Use of molecular tests directly on clinical samples has been shown to shorten time to diagnosis, and some tests have the additional ability to provide information on drug susceptibility [147,148]. In the presence of a clinical syndrome compatible with tuberculosis, a positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive rapid molecular test, or is strongly inferred from clinical or radiographic improvement consistent with a response to tuberculosis treatment, the regimen is continued to complete a standard course of therapy. In patients with a positive AFB smear, but a negative rapid molecular test (including an assessment for polymerase chain reaction inhibitors, reported to be present in 2%-5% of respiratory specimens tested by nucleic acid amplification tests [149,150]), it is unlikely that the positive smear is due to M. tuberculosis, particularly when molecular testing of a second smear-positive specimen is also negative [147]. If empiric treatment is started, cultures throughout are negative, and there is no response to treatment, yet the interferon-γ release assay (IGRA) or purified protein derivative (PPD)-tuberculin skin test (TST) is positive, consideration is given to treatment of latent tuberculosis infection using the following options: (1) stop treatment if RIF and PZA were included in the initial empiric 4-drug therapy, administered for at least 2 months [151]; (2) continue treatment with RIF, with or without INH, for a total of 4 months; (3) give 12 weekly doses of INH/RPT by DOT [152]; or (4) continue treatment with INH for a total of 9 months [83,153,154]. In patients in whom there is a low suspicion for active tuberculosis (not initially treated), if cultures remain negative, the IGRA or PPD-TST is positive (≥5 mm), and the abnormal chest radiograph is unchanged after 2 months (ATS/CDC class 4), treatment for latent tuberculosis infection is indicated [155]. If not previously treated, these patients are at increased risk for development of active tuberculosis with case rates 2.5-19 times higher than those of persons infected by M. tuberculosis with normal chest radiographs [156][157][158][159]. These patients are high-priority candidates for treatment of latent tuberculosis infection. If clinical suspicion for active tuberculosis is low, the options are to begin treatment with combination chemotherapy or to defer treatment until additional data have been obtained to clarify the situation (usually within 2 months). An advantage of the early use of combination chemotherapy is that once active disease is excluded by negative cultures and lack of clinical or radiographic response to treatment, the patient will have completed 2 months of combination treatment that can be applied to the total duration of treatment for latent tuberculosis infection. Even when the suspicion for active tuberculosis is low, treatment for latent tuberculosis infection with a single drug is not initiated until active tuberculosis has been excluded, usually by negative cultures. In general, for complicated diagnostic or management situations, consultation with local and state health departments is advised. In the United States, the CDC's Division of Tuberculosis Elimination funds tuberculosis regional training and medical consultation centers (http://www.cdc.gov/tb/education/rtmc/), which provide medical consultation to programs and health providers on management of tuberculosis. In Europe, the WHO and ERS Tuberculosis Consilium (https://www. tbconsilium.org) provides similar consultation services regarding the diagnosis and treatment of tuberculosis. # Regimens The preferred regimen and other choices are listed in Table 2. Patient factors should be considered when selecting administration schedule (intermittency), and in some instances regimen composition. Feasibility of DOT is sometimes an additional consideration when selecting frequency of administration. Regimens for adults and children are identical except in uncommon circumstances where it may be acceptable to omit EMB from the initial treatment regimen for young children (see "Children"). For all regimens, patients are treated until they have received the specified total number of doses for the treatment regimen (ie, not solely based on duration of treatment). # Preferred Regimen The preferred regimen for treating adults with tuberculosis caused by organisms that are not known or suspected to be drug resistant is a regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF [3,36,37]. To reduce the risk of relapse, the continuation phase of treatment is extended for an additional 3 months for patients who had cavitation on the initial (or follow-up) chest radiograph and, in addition, are culture positive at the time of completion of the intensive phase of treatment. The intensive phase of treatment consists of 4 drugs (INH, RIF, PZA, EMB) because of the current proportion of new tuberculosis cases worldwide caused by organisms that are resistant to INH [38][39][40][41]; however, if therapy is being initiated after drug susceptibility test results are known and the patient's isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. With respect to administration schedule, the preferred frequency is once daily for both the intensive and continuation phases. Based on systematic reviews conducted to obtain evidence in support of this guideline (see Supplementary Appendix B, Evidence Profiles 5-10), we recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drug-susceptible pulmonary tuberculosis (Recommendation 3a: strong recommendation; moderate certainty in the evidence). For the continuation phase, based on systematic reviews conducted to obtain evidence in support of this guideline (see Supplementary Appendix B, Evidence Profiles 5-10), we recommend use of daily or thrice-weekly dosing for the continuation phase of therapy (Recommendation 4a: strong recommendation; moderate certainty in the evidence). Although administration of antituberculosis drugs using DOT 5 days a week has been reported in a large number of studies, it has not been compared with 7-day administration in a clinical trial. Nonetheless, on the basis of substantial clinical experience, experts believe that 5-days-a-week drug administration by DOT is an acceptable alternative to 7-days-a-week administration, and either approach may be considered as meeting the definition of "daily" dosing. Patient-centered care, case management, and DOT are discussed in the "Organization and Supervision of Treatment" section of this guideline. # Other Regimens There are alternative regimens that are variations of the preferred regimen. As described below, alternative regimens may be acceptable in certain clinical and/or public health situations (see "Treatment in Special Situations"). An administration frequency of less than daily in the intensive phase of treatment is generally not preferred. # Thrice-Weekly Dosing Throughout In HIV-uninfected patients with noncavitary disease caused by drug-susceptible organisms, thrice-weekly (ie, 3 times per week) dosing throughout both intensive and continuation phases of treatment by DOT may be considered when daily treatment is not feasible or poorly tolerated. Thrice-weekly dosing has been associated with higher rates of treatment failure, relapse, and acquired drug resistance in high-quality systematic reviews [36,160]. The risks for these poor outcomes of treatment were higher in HIV-infected patients (especially if not treated with antiretrovirals), and patients with cavitary disease or baseline drug resistance. Based on evidence supporting the recommendations obtained through systematic reviews (see Supplementary Appendix B, Evidence Profiles 5,6,8-10), use of thrice-weekly therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV-infected and are also at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (Recommendation 3b: conditional recommendation; low certainty in the evidence). # Twice-Weekly Dosing Throughout or Twice-Weekly Dosing After 2-3 Weeks of Daily Dosing Twice-weekly dosing (ie, 2 times per week) either throughout treatment or after an initial period of 2-3 weeks of daily therapy is not generally recommended because of a lack of high-quality evidence to support its use, and because in twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior (see "Once-Weekly Continuation Phase," below). However, some tuberculosis programs have reported longstanding programmatic treatment success with an initial daily regimen followed by twice-weekly therapy [161], and this regimen remains in use by some public health programs in the United States. In situations where daily or thrice-weekly DOT therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV infected and are also at low risk of relapse ( pulmonary tuberculosis caused by drug-susceptible organisms, that at the start of treatment is noncavitary and/or smear negative) (Recommendation 3c: conditional recommendation; very low certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 7). # Twice-Weekly Continuation Phase Twice weekly treatment in the continuation phase has been studied in clinical trials [36], and is used by US tuberculosis control programs. Based on our systematic review, if intermittent therapy during the continuation phase is considered, then we suggest use of thrice-weekly instead of twice-weekly therapy. (Recommendation 4b: conditional recommendation; low certainty in the evidence) (see Supplementary Appendix B, Evidence Profiles 5-8). As noted above for twice-weekly regimens, an advantage of a thrice-weekly regimen is that it allows for the possibility of some doses being missed; with twice-weekly therapy, if doses are missed then therapy is equivalent to once weekly, which is inferior (see "Once-Weekly Continuation Phase," below). # Once-Weekly Continuation Phase In clinical trials, once-weekly treatment with INH plus RPT 600 mg was less active than standard RIF-based treatment [9,162]. In the Tuberculosis Trials Consortium (TBTC) Study 22, characteristics independently associated with increased risk of failure or relapse were sputum culture positivity at the end of intensive phase, cavitation on chest radiograph, being underweight, bilateral pulmonary involvement, and being a non-Hispanic white person [9]. Furthermore, relapse with rifamycin-monoresistant tuberculosis occurred among HIV-infected tuberculosis patients treated with the once-weekly INH/RPT continuation phase regimen [59]. In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus RPT 600 mg may be considered for use only in HIV-uninfected persons without cavitation on chest radiography. Otherwise, we recommend against use of once-weekly therapy with INH 900 mg plus RPT 600 mg (Recommendation 4c: strong recommendation; high certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 11). # Alternative Regimen Composition In some cases, either because of intolerance to first-line drugs or the presence of monoresistance, an alternative regimen may be required. If PZA cannot be included in the initial regimen, or the isolate is determined to be resistant to PZA (an unusual circumstance, except for M. bovis and M. bovis var BCG), experts recommend a regimen consisting of INH, RIF, and EMB for the initial 2 months followed by INH and RIF for 7 months given either daily or thrice weekly. # Fluoroquinolones (Moxifloxacin and Levofloxacin) In scenarios in which EMB or INH cannot be used, the role of moxifloxacin or levofloxacin has not been established through clinical trials. Experts on occasion use moxifloxacin or levofloxacin in place of EMB during intensive phase in adults in whom EMB cannot be used, or in place of INH throughout treatment in adults in whom INH cannot be used (see Supplementary Appendix C: Drugs in Current Use for details on adverse effects of fluoroquinolones, including QT prolongation). There is no evidence that moxifloxacin or levofloxacin can be used in place of a rifamycin or PZA while maintaining a 6-month treatment duration. If a rifamycin cannot be included in the initial regimen due to resistance or intolerance, then a regimen based on the principles described for treating drug-resistant tuberculosis is used. In situations in which several of the first-line agents cannot be used because of intolerance, regimens based on the principles described for treating drug-resistant tuberculosis are used. Importantly, all alternative regimens using fluoroquinolones in place of EMB or INH are 6 months or longer in duration. There is definitive clinical trial evidence that 4-month daily regimens that substitute moxifloxacin or gatifloxacin for EMB, or moxifloxacin for INH, are significantly less effective than the preferred, standard daily 6-month treatment for drug-susceptible pulmonary tuberculosis [5,163,164]. Therefore we recommend against the routine use of 4-month fluoroquinolone-containing regimens for treatment of drug-susceptible pulmonary tuberculosis. A single randomized trial showed that a regimen of daily moxifloxacin/RIF/PZA/EMB for 2 months followed by once-weekly 1200 mg RPT + 400 mg moxifloxacin for 4 continuation phase months had relapse rates similar to the standard 6-month regimen given daily [164]. Use of this regimen (including a daily moxifloxacin-containing intensive phase) may be considered. It is important to note that each dose of RPT was preceded by a meal of 2 boiled eggs and slices of bread, provided to increase the absorption of RPT. If this regimen is used, it is ideally implemented within the context of program-based operational research with suitable monitoring [165]. Of note, there is no evidence that a once-weekly continuation phase comprised of 1200 mg RPT + 400 mg moxifloxacin after 2 months of intensive phase INH/RIF/PZA/EMB (ie, without moxifloxacin in place of EMB in the intensive phase), would achieve similar outcomes. # Baseline and Follow-up Evaluations Recommended baseline and follow-up evaluations for patients suspected of having tuberculosis and treated with first-line medications are summarized in Figure 2. At baseline, patients in whom pulmonary tuberculosis is suspected have 3 appropriate sputum specimens collected for microscopic examination and mycobacterial culture, and at least one specimen is tested with a rapid molecular test. When the lung is the site of disease, 3 sputum specimens are obtained 8-24 hours apart [166,167]. In patients who are not producing sputum spontaneously, induction of sputum using aerosolized hypertonic saline or bronchoscopy ( performed under appropriate infection-control procedures) may be necessary to obtain specimens. Susceptibility testing for INH, RIF, EMB, and PZA is performed on an initial positive culture, regardless of the source. A rapid molecular test for drug resistance is performed in patients at risk for drugresistant tuberculosis, and when resources permit, may be performed in all patients [15,168]. Second-line drug susceptibility testing should be done only in reference laboratories and is limited to specimens from patients who have had prior therapy, have been in contact with a patient with known multidrug or extensively drug-resistant tuberculosis, have suspected or demonstrated resistance to RIF and/or other first-line drugs, are unable to tolerate RIF, or who have positive cultures after >3 months of treatment [15,168]. During treatment of patients with pulmonary tuberculosis, at a minimum, a sputum specimen for AFB smear and culture are obtained at monthly intervals until 2 consecutive specimens are negative on culture. Duration of the continuation phase regimen hinges on the microbiological status at the end of the intensive phase of treatment, thus, obtaining sputum specimens at the time of completion of 2 months of treatment is critical if sputum culture conversion to negative has not already been documented. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (for example, every 2 weeks until 2 consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations with high risk of transmission. On occasion, AFB-positive sputa are culture-negative; this occurs most frequently among patients with far-advanced cavitary tuberculosis after the first few months of treatment. It is thought that AFB smear positive (but culture-negative) sputa contain organisms that are dead and that their presence is not a sign of treatment failure, even when noted later in treatment. Dead organisms also can cause a positive result on molecular tests; routine performance of molecular tests on follow-up sputum samples, after an initial positive test, is not useful. Drug susceptibility tests are repeated on M. tuberculosis isolated in culture from sputum obtained after a patient has been on treatment for ≥3 months. As described in the "Treatment Failure" section, patients who have M. tuberculosis isolated in culture from sputum obtained after 4 months of treatment are considered as having failed treatment and managed accordingly. For patients with positive cultures at diagnosis, a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential. Tuberculosis programs often conduct a chest radiograph at completion of therapy as it provides a baseline against which subsequent examinations can be compared, but, as with the 2-month examination, it is not essential. When the initial sputum cultures are negative, a presumptive diagnosis can be made if radiographic improvement is noted, generally by the time 2-3 months of treatment have been completed [93]. Thus, based on expert opinion, in patients with negative initial cultures, a chest radiograph is recommended after 2-3 months of treatment and at the completion of treatment to document response to therapy. Generally, systematic follow-up after completion of therapy is not necessary. In addition to the microbiological and imaging examinations discussed here, other appropriate assessments and laboratory tests are summarized in Figure 2. For patients with extrapulmonary tuberculosis, the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained. Monitoring assessments for patients treated with second-line drugs are listed by drug in Supplementary Appendix C: Drugs in Current Use. # Identification and Management of Patients at Increased Risk of Relapse The culture result of a sputum specimen obtained at the completion of the intensive phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis, albeit with low sensitivity [9,[44][45][46]. Cavitation on the initial chest radiograph has also been shown to be a risk factor for relapse [9,47]. In patients treated for 6 months, having both cavitation and a positive culture at completion of 2 months of therapy has been associated with rates of relapse of approximately 20% compared with 2% among patients with neither factor [9,45]. The most effective means of decreasing the likelihood of relapse for patients at risk has not yet been determined by clinical trials; however, indirect evidence from a controlled clinical trial and an observational study among patients with pulmonary tuberculosis in Hong Kong showed that prolonging treatment decreased the rate of relapse [47,169]. It has also been reported that for patients at high risk of relapse, prolongation of the once-weekly INH/RPT continuation phase from 4 to 7 months resulted in a decreased rate of relapse [170]. In view of this evidence, for patients who have cavitation on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy, expert opinion is to extend the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy). Because patients who had either cavitation on the initial chest radiograph or a positive culture at 2 months had an increased rate of relapse [9,45], patients with one or the other of these risk factors are followed more closely and consideration given to extending treatment duration if there are suggestions of a poor response. Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being >10% below ideal body weight; being a smoker; having diabetes, HIV infection, or other immunosuppressing condition; or having extensive disease on chest radiograph [46,[48][49][50][51][52]. # Interruptions in Therapy Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart treatment from the beginning. Continuous treatment is more important in the intensive phase of therapy when the bacillary population is highest and the chance of developing drug resistance greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriologic status of the patient prior to and after the interruption are also important considerations. There is no evidence upon which to base detailed recommendations for managing interruptions in treatment, and no recommendations will cover all of the situations that may arise. The approach summarized in Table 6 (modified from the New York City Bureau of Tuberculosis Control [171]) is presented as an example. When interruptions are due to an interim loss of follow-up, at the time the patient is returned to treatment, additional sputum are obtained for repeat culture and drug susceptibility testing. If the cultures are still positive, the treatment regimen is restarted. If sputum cultures are negative, the patient could be treated as having culture-negative tuberculosis and given an additional 4 months of INH and RIF chemotherapy, as long as the original specimen was drug susceptible and the original intensive phase regimen included INH, RIF, and PZA. Regardless of the timing and duration of the interruption, DOT is used subsequently. If the patient was already being managed with DOT, additional measures will be necessary to ensure completion of therapy. Consultation with an expert is advised to assist in managing treatment interruptions. # Definition of Completion of Therapy The determination of whether or not treatment has been completed is based on the total number of doses taken-not solely on the duration of therapy (Table 2). Tuberculosis control program practice in the United States and in several European countries is to administer all of the specified number of doses for the intensive phase within months and those for the 4-month continuation phase within 6 months, so that the 6-month regimen is completed within 9 months. If these targets are not met, the patient must be considered to have interrupted therapy and be managed as described above (Table 6). # PRACTICAL ASPECTS OF TREATMENT # Drug Administration In general, tuberculosis drugs are administered together, at one dosing so as to achieve maximal peak serum concentrations and to facilitate DOT. Bioavailability of all of the drugs (except for RPT) is greatest when taken on an empty stomach. The exception is RPT, for which bioavailability increases by up to 86% with high-fat meals [172]. If medications need to be combined with food or liquid for dosing, keep in mind that INH absorption decreases when combined with glucose or lactose; crushed INH tablets in foods containing low glucose, such as sugar-free pudding, are stable. However, crushed tablets mixed with food should not be stored for later use [173]. The commercially prepared INH elixir uses sorbitol as the vehicle; sorbitol may also cause diarrhea, thereby limiting its use. Parenteral drug administration is indicated for severely ill patients who cannot take oral therapy, and may be useful for the uncommon patient with suspected or documented malabsorption. Of the first-line drugs, parenteral preparations of INH and RIF, as well as most fluoroquinolones, are available. # Fixed-Dose Combination Preparations Clinical trials and a recent systematic review have concluded that overall, there is no significant difference between fixeddose combinations (FDCs) and single-drug combinations for key outcomes, including sputum smear or culture conversion, failure, relapse, death, serious adverse events, or adverse events that lead to discontinuation of therapy [174][175][176][177][178]. The patient-specific advantages to using FDC drugs include ease of administration and the potential for reducing medication errors. The key program and clinician-specific advantage of FDC formulations is the simplification of drug supply management ( procurement, storage, and distribution) and simpler prescription writing. If FDCs are used, clinicians should be aware that FDC and non-FDC products have similar commercial names with different drug compositions, including Rifadin (RIF only), Rifamate (INH and RIF), and Rifater (INH, RIF, and PZA) (see Supplementary Appendix C). # Management of Common Adverse Effects Mild adverse effects usually can be managed with treatment directed at controlling the symptoms; severe effects usually require the offending drug(s) to be discontinued. If a drug is permanently discontinued, then a replacement drug, typically from a different drug class, is included in the regimen. Patients with severe tuberculosis often require the initiation of an alternate regimen during the time the offending drug(s) are held. Management of serious adverse effects often requires expert consultation. The suggested practices listed below for handling common adverse effects during treatment (ordered from most to least common) are based on expert opinion. Gastrointestinal Upset; Nausea, Vomiting, Poor Appetite, Abdominal Pain Gastrointestinal reactions are common, especially early in therapy [53]. The optimum approach to management of epigastric distress or nausea with tuberculosis drugs is not clear. To minimize symptoms, patients receiving SAT may take the medications at bedtime. Gastrointestinal intolerance not associated with hepatotoxicity can be treated with antacids, which have less impact on absorption or peak concentration of first-line drugs than administration with food [54]. Some experts report success with proton pump inhibitors for reducing gastrointestinal upset. Any combination of otherwise unexplained nausea, vomiting, and abdominal pain is evaluated with a physical examination and liver function tests, including ALT, AST, bilirubin, and alkaline phosphatase to assess for possible hepatotoxicity [55]. Alternatively, a light snack (low-fat food) such as a cracker might suffice for some patients. Either option is preferable to splitting a dose or changing to a second-line drug. It is important to note that divalent cations (calcium, iron, zinc) as occur in some antacids and nutritional supplements are not coadministered with fluoroquinolones because they decrease absorption of the drug, possibly leading to treatment failure [179]. # Rash All antituberculosis drugs can cause a rash, the severity of which determines management [180]. If the rash is mainly itchy without mucous membrane involvement or systemic signs such as fever, treatment is symptomatic with antihistamines, and all antituberculosis medications can be continued. A petechial rash is more concerning and suggests thrombocytopenia from a rifamycin (ie, RIF, RFB, RPT) hypersensitivity [181]. If the platelet count is low, the rifamycin is permanently stopped and the platelet count closely monitored until definite improvement is noted. Drugs are also stopped if the patient has a generalized erythematous rash. Fever and/or mucous membrane involvement suggests Stevens-Johnson syndrome, toxic epidermal necrosis, or drug reaction with eosinophilia and systemic symptoms syndrome or drug hypersensitivity syndrome. Hypersensitive reactions to multiple antituberculosis drugs have been noted, particularly in persons with HIV infection [180]. Some experts manage severe systemic reactions in the inpatient setting, using an interval of several days between drug rechallenges, closely monitoring markers of hypersensitivity (such as rash, fever, transaminitis, eosinophilia, pruritus, etc). If any of these markers develop, then the drug is stopped and identified as the offender, eliminating it from the regimen. Systemic corticosteroids may be used to treat severe systemic reactions. Using steroids to treat systemic reactions, even in the setting of severe tuberculosis, has not worsened outcomes [182]. When the rash has substantially improved, medications can be restarted individually at intervals of 2-3 days. RIF is restarted first (the most potent drug), followed by INH, then EMB or PZA. If the rash recurs, the last drug added is stopped. If the first 3 drugs have been restarted without a rash, the fourth drug is not restarted unless the rash was mild and that drug essential. Research evaluating drug provocation tests or drug desensitization strategies is needed [180]. # Drug Fever Drug fever is essentially a diagnosis of exclusion. Other causes of fever such as tuberculosis (fever may persist 2 months or longer into treatment) [183,184]; paradoxical reaction, especially in HIV-infected patients (See "HIV Infection") [185][186][187]; and superinfection must be excluded. Patients with drug fever generally feel well despite body temperatures ≥39°C. Drug fever does not follow a specific pattern and eosinophilia need not be present. Stopping drugs usually resolves the fever within 24 hours. Once afebrile, the patient should restart drugs individually every 2-3 days, similar to the approach to drug rechallenge for rash. # Hepatotoxicity Drug-induced hepatitis is the most frequent serious adverse reaction to the first-line drugs (see "Hepatic Disease" and Supplementary Appendix C). INH, RIF, and PZA can cause druginduced liver injury, which is suspected when the ALT level is ≥3 times the upper limit of normal in the presence of hepatitis symptoms, or ≥5 times the upper limit of normal in the absence of symptoms [56]. If the ALT level is <5 times the upper limit of normal, toxicity can be considered mild, an ALT level 5-10 times normal defines moderate toxicity, and an ALT level >10 times normal (ie, >500 IU) is severe. An asymptomatic increase in ALT concentration occurs in nearly 20% of patients treated with the standard 4-drug regimen [188,189]. In the absence of symptoms, therapy should not be altered because of modest asymptomatic elevations of ALT, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic ALT elevations resolve spontaneously. However, if ALT levels are ≥5 times the upper limit of normal (with or without symptoms) or ≥3 times normal in the presence of symptoms, hepatotoxic drugs are stopped immediately and the patient is evaluated carefully. Similarly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation; disproportionate increases in bilirubin and alkaline phosphatase (as compared to increases in serum ALT) may be seen with RIF hepatotoxicity [56]. Other causes of abnormal liver tests must be excluded before diagnosing drug-induced hepatitis (Table 7). If ALT levels are consistent with hepatotoxicity, all hepatotoxic drugs must be stopped and serum ALT and prothrombin time or international normalized ratio (INR) levels followed until levels return to baseline. Consult a liver specialist if the patient's clinical or laboratory status continues to worsen. Once the ALT concentration returns to <2 times the upper limit of normal, antituberculosis medications are restarted individually (see [56] for additional details). In patients with elevated baseline ALT from preexisting liver disease, drugs are restarted when the ALT returns to near-baseline levels. The optimal approach to reintroducing tuberculosis treatment after hepatotoxicity is not known [57,58]; however, most tuberculosis programs use sequential reintroduction of drugs. Because RIF is much less likely to cause hepatotoxicity than INH or PZA, it is restarted first. If there is no increase in ALT after approximately 1 week, INH may be restarted. PZA can be started 1 week after INH if ALT does not increase. If symptoms recur or ALT increases, the last drug added should be stopped. If RIF and INH are tolerated and hepatitis was severe, PZA can be assumed to be responsible and is discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, the total duration of therapy might be extended to 9 months. # Optic Neuritis EMB-related visual impairment during treatment of active tuberculosis has been estimated to occur in 22.5 per 1000 persons (2.25%) receiving EMB at standard doses [190] (see Supplementary Appendix C). The onset of optic neuritis is usually >1 month after treatment initiation but can occur within days [191,192]. The opinion of experts is that baseline visual acuity (Snellen test) and color discrimination tests followed by monthly color discrimination tests are performed during EMB use. To avoid permanent deficits, EMB is promptly discontinued if visual abnormalities are found. If vision does not improve with cessation of EMB, experts recommend stopping INH as well, as it is also a rare cause of optic neuritis [193]. # Drug-Drug Interactions # Interactions Affecting Antituberculosis Drugs Drug-drug interactions can change the concentrations of the drugs involved. Relatively few interactions substantially change antituberculosis drug concentrations; much more often, the antituberculosis drugs cause clinically relevant changes in the concentrations of other drugs. The exceptions to this general rule are RFB and the fluoroquinolones. • Inhibitors of CYP3A increase the serum concentrations of RFB and one of its metabolites (25-O-desacetyl-rifabutin), sometimes producing toxicities. For example, administering ritonavir, a very potent CYP3A inhibitor, with the standard daily dose of RFB (300 mg) increases the serum concentrations of RFB (4-fold) and 25-O-desacetyl-rifabutin (35-fold) [194] and is associated with increased rates of leukopenia, arthralgias, skin discoloration, and anterior uveitis [195,196]. Conversely, administering RFB with a CYP3A inducer such as efavirenz or phenytoin may decrease RFB concentrations [197], and this may lead to clinical failures and the selection of rifamycin-resistant M. tuberculosis. Recommendations for RFB dose adjustments are available at AIDSinfo, and at the CDC website (http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/ default.htm). Because interactions are complex and given the rapid emergence of new data on antiretroviral therapy (ART), the management of HIV-related tuberculosis cases should involve a physician with experience in this field. • Absorption of the fluoroquinolones is markedly decreased by ingestion of medications containing divalent cations (calcium, iron, zinc) including antacids [198,199]; supplements or vitamins containing calcium, iron, or zinc [200]; sucralfate [201]; and the chewable tablet formulation of didanosine [202]. These drug interactions can be avoided by ingesting medications containing divalent cations at least 2 hours apart from fluoroquinolones [203]. In addition, moxifloxacin serum concentrations are decreased by 25%-30% in the presence of RIF due to the induction of phase II metabolic enzymes (sulfation and glucuronidation) [204]. RPT and RFB also may decrease moxifloxacin serum concentrations, though the clinical significance of these drug-drug interactions in individual patients is uncertain. # Antituberculosis Drugs Affecting Other Drugs # Drug Interactions Due to Rifamycins Most of the clinically relevant drug-drug interactions involving the antituberculosis drugs are due to the effect of the rifamycins (RIF, RFB, and RPT) on the metabolism of other drugs [205]. All of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 (CYP) system [206]. By inducing the activity of metabolic enzymes, rifamycins decrease the serum concentrations of many drugs, sometimes to subtherapeutic levels [207]. RIF is the most potent enzyme inducer and RFB the least, while RPT's potency depends on its frequency of administration [208,209]. Daily RPT is at least as potent as daily RIF, while onceweekly RPT (as used in combination with INH for latent tuberculosis infection [210]) has limited effects on other drugs. The well-described, clinically relevant, drug-drug interactions involving the rifamycins are presented in Table 8 [206,211]; however, many possible interactions involving the rifamycins have not been fully investigated and additional clinically relevant interactions undoubtedly will be described. Therefore, it is important to check all concomitant medications for possible, as well as confirmed, drug-drug interactions with rifamycins. Rifamycin inductive effects typically take approximately 1-2 weeks to reach steady state after the rifamycin is started, and inductive effects typically resolve over approximately 2 weeks after the rifamycin is discontinued [209]. If the dose of a medication is increased to compensate for the effect of a rifamycin, it is critical to reduce the dose within 2 weeks after the rifamycin is discontinued and its inductive effect resolves. RFB can be used in place of RIF if there is an unacceptable drug-drug interaction between RIF and another drug such as cyclosporine [212,213] and most of the HIV-1 protease inhibitors [208,214,215]. All the rifamycins may cause unacceptable decreases in the serum concentrations of certain drugs such as itraconazole [216][217][218]. # Drug Interactions Due to INH INH is a relatively potent inhibitor of several CYP isozymes [219,220] and increases concentrations of some drugs to the point of toxicity such as the anticonvulsants phenytoin [221,222] and carbamazepine [223,224]. INH also increases concentrations of benzodiazepines metabolized by oxidation, such as diazepam [225] and triazolam, but not those metabolized by conjugation, such as oxazepam [226]. Of note, the inductive effect of RIF on CYP isozymes outweighs the inhibitory effect of INH, so that the overall effect of combined therapy with RIF and INH is a decrease in the concentrations of drugs such as phenytoin [227] and diazepam [225]. INH may increase toxicity of other drugs-acetaminophen [228], valproate [229], serotonergic antidepressants [230], warfarin [231], and theophylline [232]-but these potential interactions have not been well studied. A possible interaction between INH and disulfiram was initially described [233]; however, a retrospective study found that disulfiram was safe when added to intermittent, directly observed INH-containing tuberculosis treatment [234]. # Drug Interactions Due to the Fluoroquinolones Ciprofloxacin [235] inhibits the metabolism of theophylline and can cause clinical theophylline toxicity [236]; however, levofloxacin [237], gatifloxacin [238], and moxifloxacin [239] do not affect theophylline metabolism. # Useful Websites Regarding Drug Interactions Useful websites regarding drug interactions (tuberculosis/HIV and other) are available through the following hyperlinks: AIDSinfo, Centers for Disease Control and Prevention, University of California San Francisco, University of Liverpool, Indiana University, and University of Maryland. # Therapeutic Drug Monitoring TDM generally consists of measurements of drug concentrations in serum specimens typically collected at 2 and 6 hours after a dose of the drug, or drugs, in question. Other sampling times may be used for selected situations. Blood samples are centrifuged; the serum is harvested and frozen, and then shipped frozen to a reference laboratory. Quality-assured laboratories in the United States and in Europe offer assays for some or all of the antituberculosis drugs [240,241]. There are no prospective randomized trials that clearly define the role of TDM for antituberculosis drugs. As such, opinions vary regarding the utility of TDM. Experts generally use TDM as a specialized tool, providing insight into the adequacy of drug dosing [242]. For example, serum concentrations of tuberculosis drugs among children and HIV-infected patients with tuberculosis are frequently lower than those in healthy volunteers, at the same (mg/kg body weight) dose [243][244][245][246]. In some reports, lower concentrations did not have an impact on treatment response or cure [247][248][249]. Other reports have found an association between low drug exposure and failure, relapse, and acquired rifamycin resistance [250][251][252]. TDM cannot predict who will be cured, fail, or relapse; however, it does allow for timely, informed decisions regarding the need for dose adjustment when necessary. Experts suggest that TDM may be particularly helpful in situations in which drug malabsorption, drug underdosing, or clinically important drug-drug interactions are suspected (Table 9). Examples of situations in which TDM may be useful include (1) patients with delayed sputum conversion or treatment failure not explained by nonadherence or drug resistance; (2) patients with medical conditions (eg, reduced renal function) that are suspected of leading to subtherapeutic or toxic drug concentrations; and (3) patients undergoing treatment for drug-resistant tuberculosis. # TREATMENT IN SPECIAL SITUATIONS # HIV Infection PICO Question 5: Does extending treatment beyond 6 months improve outcomes compared to the standard 6-month treatment regimen among pulmonary tuberculosis patients coinfected with HIV? Recommendation 5a: For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Recommendation 5b: In uncommon situations in which HIV-infected patients do NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drugsusceptible pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). PICO Question 6: Does initiation of ART during tuberculosis treatment compared to at the end of tuberculosis treatment improve outcomes among tuberculosis patients coinfected with HIV? Recommendation 6: We recommend initiating ART during tuberculosis treatment. Antiretroviral therapy should ideally be initiated within the first 2 weeks of tuberculosis treatment for patients with CD4 counts <50 cells/µL and by 8-12 weeks of tuberculosis treatment initiation for patients with CD4 counts ≥50 cells/µL (strong recommendation; high certainty in the evidence). Note: an exception is patients with HIV infection and tuberculous meningitis (see Immune Reconstitution Inflammatory Syndrome). Both the CDC and WHO recommend routine HIV testing and counseling to all patients with presumptive and diagnosed tuberculosis [253,254]. Treatment of tuberculosis in patients with HIV infection has several important differences compared with treatment of patients who do not have HIV infection. These differences include the need for ART, the potential for drug-drug interactions, especially between the rifamycins and antiretroviral agents, paradoxical reactions that may be interpreted as clinical worsening, and the potential for developing resistance to rifamycins when using intermittent tuberculosis therapy. Because of the strong epidemiological association between HIV and tuberculosis infections and the clinical considerations discussed below, all individuals diagnosed with tuberculosis are tested for HIV infection. # Clinical Trials of Treatment for Tuberculosis in HIV-Infected Patients There have been a number of prospective studies, including 4 randomized controlled trials, of 6-month regimens for the treatment of pulmonary tuberculosis in patients with HIV infection for which recurrence data were reported [59,247,248,[255][256][257]. All reported a good early clinical response to tuberculosis therapy. The time required for sputum culture conversion from positive to negative and tuberculosis treatment failure rates were similar to these indices of treatment efficacy in patients without HIV infection. Recurrence of tuberculosis after treatment completion may be due to relapse or reinfection. Relapse of tuberculosis in HIV-infected individuals is associated with nonadherence to treatment, use of intermittent regimens, and with low plasma drug concentrations, all of which also contribute to the emergence of rifamycin resistance [9,[59][60][61][62]250]. Reinfection with a new strain of M. tuberculosis is well documented in patients with HIV infection and occurs in settings where transmission is more common, such as in countries with high rates of tuberculosis or congregate living facilities (eg, prisons or hospitals) where infection control is inadequate. A study in Democratic Republic of the Congo (formerly Zaire) found that extending treatment from 6 to 12 months reduced the recurrence rate from 9% to 3% [255]. A randomized trial in Haiti found that 6-month treatment with a standard regimen followed by 12 months of INH preventive therapy reduced recurrences from 7.8 per 100 person-years to 1.4 per 100 personyears [258]. Therefore, in areas where reinfection is likely, the opinion of experts is that secondary preventive therapy with INH may be justified. In regard to duration of treatment for drug-susceptible pulmonary tuberculosis in the presence of HIV infection, the standard regimen currently used worldwide is the 6-month regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF [10,67,98]. There is, however, a paucity of data on the optimal duration of tuberculosis treatment for HIV-infected patients receiving highly active antiretroviral therapy (HAART), though it is widely believed that the standard 6-month regimen is effective and achieves tuberculosis cure rates comparable to those reported for HIV-uninfected patients. In the TB-HAART (Early Versus Delayed Initiation of HAART for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis) trial, patients with CD4 counts ≥220 cells/µL were randomized on timing of ART initiation [259]. All patients were treated with the standard 6-month regimen for tuberculosis and were followed for 12 months. Among patients who completed treatment, recurrence of tuberculosis occurred in 2.0%, providing indirect but supportive evidence that a 6-month regimen is effective in HIV-infected patients receiving ART. In our updated systematic review of randomized trials and cohort studies comparing various durations of tuberculosis therapy (6 months vs 8 months or longer), most of which were conducted prior to the era of HAART, we found that the risk of recurrence is lower when the continuation phase of treatment is extended. However, it is important to note that the majority of these studies were reports on nonrandomized cohorts, most were completed prior to the era of routine antiretroviral use, many tested intermittent regimens, and few distinguished between reinfection and relapse (see Supplementary Appendix B). As discussed below, based on data that show significant reductions in mortality and AIDS-defining illnesses, patients with HIV infection and tuberculosis should receive ART in conjunction with daily antituberculosis medications. For HIV-infected patients receiving ART, we suggest using the standard 6-month daily regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF for the treatment of drug-susceptible pulmonary tuberculosis (Recommendation 5a: conditional recommendation; very low certainty in the evidence) (see Supplementary Appendix B, Evidence Profile 12). In the uncommon situation in which an HIV-infected patient does NOT receive ART during tuberculosis treatment, we suggest extending the continuation phase with INH and RIF for an additional 3 months (ie, a continuation phase of 7 months in duration, corresponding to a total of 9 months of therapy) for treatment of drug-susceptible pulmonary tuberculosis (Recommendation 5b: conditional recommendation; very low certainty in the evidence). As is noted for drugsusceptible pulmonary tuberculosis in patients without HIV coinfection, the continuation phase is extended in specific situations that are known to increase risk for relapse (see "Identification and Management of Patients at Increased Risk of Relapse"), as well as for selected extrapulmonary sites of disease, namely tuberculous meningitis, and bone, joint, and spinal tuberculosis (see "Extrapulmonary Tuberculosis"). c Numbers in parentheses are the calculated mg/kg doses for patients at the highest and lowest body weights in the weight band. Use of intermittent tuberculosis treatment regimens in HIVinfected patients has been associated with high rates of relapse and the emergence of drug resistance. In TBTC Study 22, patients with HIV infection who received once-weekly RPT and INH or twice-weekly RIF and INH in the continuation phase had an unacceptably high rate of relapse: 5 of 30 (16.7%) in the former and 3/31 (9.8%) in the latter group [9]. In addition, for those receiving weekly therapy, 4 patients relapsing had acquired rifamycin resistance, which was associated with low serum concentrations of INH and was presumably the result of unopposed rifamycin exposure [59]. In a trial of RFB-based antituberculosis therapy in combination with antiretroviral drugs, patients treated with twice-weekly RFB had a relapse rate of 5.3%, but 8 of 9 relapses had acquired rifamycin resistance [60]. Relapse and resistance were associated with low CD4 lymphocyte counts, as all recurrences occurred in patients with baseline CD4 lymphocyte counts <100 cells/µL. In the pharmacokinetic substudy of the trial, lower plasma concentrations of RFB and INH were identified as key risk factors for acquiring rifamycin resistance [250]. More recently, the use of a thrice-weekly RIF-based regimen during the intensive and continuation phases of treatment was associated with a higher rate of relapse and emergence of rifamycin resistance in HIVinfected individuals not receiving antiretrovirals compared with HIV-infected patients also receiving antiretrovirals or HIV-uninfected patients [62]. Based in part on systematic reviews conducted to obtain evidence in support of this guideline, our expert opinion is that treatment of HIV-related tuberculosis be given daily in both the intensive and continuation phases to avoid recurrent disease and the emergence of rifamycin resistance (see "Recommended Treatment Regimens"). Mortality among patients with HIV and tuberculosis is high, principally due to complications of immunosuppression and occurrence of other HIV-related opportunistic diseases. In this regard, the value of co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis in reducing morbidity and mortality in HIV-infected patients with newly diagnosed tuberculosis is well established [63][64][65]. Whereas the WHO recommends routine co-trimoxazole prophylaxis for all HIV-infected people with active tuberculosis disease regardless of the CD4 cell count [66], in high-income countries, co-trimoxazole prophylaxis is primarily used in tuberculosis patients coinfected with HIV with CD4 counts <200 cells/µL [67]. The use of ART during tuberculosis treatment in persons with HIV infection also reduces mortality rates significantly for those with advanced HIV disease and decreases the risk of developing AIDS-related conditions. The Starting Antiretroviral therapy at Three Points in Tuberculosis (SAPiT) trial randomized patients with tuberculosis and HIV with CD4 lymphocyte counts <500 cells/µL to initiate ART after 2 weeks (immediate), 8 weeks (early), or 6 months (deferred) of tuberculosis treatment [260]. Patients receiving immediate or early ART had a 56% reduction in the relative risk of death compared with patients receiving deferred ART (5.6 per 100 person-years vs 12.1 per 100 person-years). The benefit of ART given immediately or early was seen in patients with CD4 lymphocyte counts <200 cells/µL and 200-500 cells/µL. Subsequently, the Cambodian Early Versus Late Introduction of Antiretrovirals trial showed that initiation of ART within 2 weeks of starting antituberculosis treatment reduced mortality rate by 34% compared to starting after 8 weeks, in a population of HIV-infected individuals with very low CD4 cell counts (median, 25 cells/µL) [261]. The Immediate vs Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis (STRIDE) trial and the second phase of the SAPiT study, both of which compared immediate (2 weeks) with early (8-12 weeks) ART for HIV-infected patients beginning antituberculosis treatment, showed that immediate therapy was associated with significantly lower rates of progression of HIV disease to new AIDS-defining conditions or death compared to early therapy for patients with CD4 counts <50 cells/ µL, but starting ART within 2 weeks was not superior to starting at 8 weeks for individuals with CD4 counts >50 cells/µL [262,263]. All of these studies also showed that immediate ART was associated with significantly greater rates of IRIS, most of which was not severe. More recently, the TB-HAART trial found that among patients with HIV and CD4 counts >220 cells/µL, immediate initiation of ART did not reduce mortality compared with waiting until completion of 6 months of antituberculosis treatment to start ART [259]. Unlike the SAPiT and STRIDE trials, however, TB-HAART did not assess progression of HIV disease as a study endpoint. Although the study did not find a survival benefit in patients with HIV-related tuberculosis and higher CD4 lymphocyte counts, it did confirm the safety of co-treatment of tuberculosis and HIV infection and documented good outcomes of tuberculosis treatment in those patients receiving dual therapy. We performed a systematic review and meta-analysis to obtain evidence in support of this guideline, which included the 4 trials above and 4 additional studies (see Supplementary Appendix B, Evidence Profile 13) [259][260][261][262][263][264][265][266]. We found that the overall reduction in mortality with ART initiated during treatment of tuberculosis was 24% (risk ratio, 0.76; 95% confidence interval [CI], .57-1.01). The overall risk of HIV disease progression was reduced by 34% with early or immediate ART (4 studies: risk ratio, 0.66; 95% CI, .47-.91). Initiation of ART during antituberculosis therapy was associated with an increased risk of IRIS (8 studies: risk ratio, 1.88; 95% CI, 1.31-2.69). Our metaanalysis identified no increase in the risk of other adverse events or poor outcome of tuberculosis therapy. Consequently, on the basis of high certainty in the evidence that the benefits outweigh the harms, we recommend that patients with tuberculosis and HIV infection receive ART during antituberculosis treatment. Antiretroviral therapy should ideally be started within 2 weeks for those patients with a CD4 count <50 cells/µL and by 8-12 weeks for those with a CD4 count ≥50 cells/µL (Recommendation 6: strong recommendation; high certainty in the evidence). An important exception is HIV-infected patients with tuberculous meningitis, in whom ART should not be initiated in the first 8 weeks of antituberculosis therapy (see "Immune Reconstitution Inflammatory Syndrome"). # Concurrent Administration of Antiretrovirals and Rifamycins Interaction of RIF with antiretroviral agents is a major treatment concern (see "Drug-Drug Interactions"). RIF is a potent inducer of drug metabolizing enzymes in the CYP family and drug transporters such as P-glycoprotein [206]. Coadministration of RIF with drugs metabolized or transported by these compounds may lead to reductions in exposure and loss of efficacy [207]. HIV protease inhibitors are metabolized by CYP3A4, and their concomitant administration with RIF leads to >80% reductions in serum concentrations of the protease inhibitors and loss of therapeutic benefit. RIF also increases the metabolism of nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and CCR-5 inhibitors. Detailed recommendations for coadministration of rifamycins and antiretroviral drugs have been published by the CDC, and we support these guidelines [215]. The NNRTI efavirenz is the most widely used antiretroviral drug and is the preferred initial treatment for HIV (in combination with other antiretroviral drugs) in many countries. Coadministration of RIF-containing antituberculosis regimens with efavirenz results in satisfactory antiviral efficacy, despite reductions in trough efavirenz concentrations [267,268]. INH is an inhibitor of an alternative, minor CYP pathway involved in efavirenz metabolism. Thus, when INH and RIF are given to individuals with genetic polymorphisms associated with slow efavirenz clearance, efavirenz serum concentrations may reach supratherapeutic levels. The US Food and Drug Administration (FDA) recommends that the dosage of efavirenz be increased from 600 mg/day to 800 mg/day for patients weighing >60 kg on the basis of pharmacokinetic modeling of data from healthy volunteers; however, data from clinical studies, including the STRIDE study, do not support this advice [267,268], and many other experts believe that efavirenz should be administered at the standard dose of 600 mg/day in patients receiving standard dose RIF-containing regimens. A treatment-shortening trial evaluating high-dose daily RPT used in combination with efavirenz-based ART for HIV-infected patients is under way (ClinicalTrials.gov identifier: NCT02410772). The NNRTI nevirapine has also been studied as an alternative treatment for HIV-infected patients with tuberculosis [269]. However, RIF also reduces concentrations of nevirapine, a drug that induces its own metabolism [270]. Due to this autoinduction, nevirapine is initially given at a dosage of 200 mg/day for 2 weeks and then increased to 200 mg/twice daily or 400 mg/ once daily. When nevirapine is started during antituberculosis treatment, use of the 200 mg daily lead-in dose can lead to subtherapeutic concentrations, loss of antiviral efficacy, and emergence of drug resistance [271][272][273]. Therefore, expert opinion is that if nevirapine is used during treatment with RIF, the initiation dose should be at the full 400-mg daily dosage (200 mg twice daily or 400 mg daily). The INSTIs are now considered first-line agents for HIV infection in the United States and in Europe. Raltegravir and dolutegravir are metabolized mainly by uridine 5′-diphosphoglucuronosyltransferase 1A1 [274,275], and concomitant use of RIF reduces trough concentrations significantly. The "Raltegravir for the treatment of patients co-infected with HIV and tuberculosis" (Reflate TB) trial showed that coadministration of RIFbased antituberculosis treatment and raltegravir at 400 mg/twice daily was associated with similar antiviral effectiveness compared to coadministration of RIF-based antituberculosis treatment and raltegravir 800 mg twice daily; both were somewhat more effective than efavirenz 600 mg daily [274]. However, pharmacokinetic data favor increasing the dose to 800 mg twice daily, and expert opinion in the United States favors this strategy [276]. Pharmacokinetic studies demonstrate that coadministration of RIF and dolutegravir at a dosage of 50 mg given twice daily results in adequate trough concentrations of dolutegravir [275]. A clinical study of patients with active tuberculosis given RIF and dolutegravir is under way (ClinicalTrials.gov identifier: NCT02178592). RFB is less potent an inducer of CYP isoenzymes and may be used in patients receiving ART; however, RFB itself is metabolized by CYP3A enzymes, and the antiretroviral agent ritonavir (used to boost protease inhibitor levels) inhibits CYP3A enzymes, which increases concentrations of RFB. High concentrations of RFB are associated with an increased risk of uveitis and other toxicities, so dose adjustment of the standard RFB dosage of 300 mg daily is necessary [215]. Expert opinion is to use RFB at a dose of 150 mg/day or 300 mg every other day as part of a combination antituberculosis regimen for patients receiving ritonavir-boosted protease inhibitors [214]. In patients receiving dose-adjusted RFB because of concomitant protease inhibitor use, frequent assessment of adherence to both medicines is prudent, as discontinuation of the protease inhibitor while continuing dose-adjusted RFB (ie, in the context of DOT tuberculosis therapy but self-administered antiretrovirals) would be expected to result in subtherapeutic concentrations of the rifamycin, possibly with consequent poor treatment outcome and acquired rifamycin resistance. Efavirenz is also a CYP3A inducer, and when RFB is coadministered with this agent the RFB dosage needs to be increased to 600 mg/day; however, indications to use RFB instead of RIF in patients receiving efavirenz are rare. When RFB is not available and treatment with a protease inhibitor is required because of resistance to NNRTIs and/or INSTIs, use of RIF with a lopinavir/ritonavir regimen may be attempted. For adults, this generally entails increasing the dosage of lopinavir/ritonavir from 400 mg/100 mg twice daily to 800 mg/200 mg twice daily over 2 weeks. This so-called "double dosing" of boosted lopinavir may result in hepatotoxicity and careful clinical monitoring is necessary [215]. Alternatively, "super boosting" of lopinavir, though poorly tolerated in adults, is sometimes effective, especially in children. In this instance, the dosage of lopinavir is maintained at 400 mg twice daily, but ritonavir dosage is increased from 100 mg twice daily to 400 mg twice daily. Super boosting of ritonavir is poorly tolerated in adults, however, and the double-dosing strategy is preferred. These complicated interactions underscore the importance of expert consultation in treating individuals with concurrent HIV and tuberculosis infections. For situations involving complex drug-drug interactions, some clinicians prefer to measure the concentrations of the interacting drugs, and to dose these drugs based upon individualized data [242]. # Immune Reconstitution Inflammatory Syndrome Transient worsening of tuberculosis symptoms and lesions in response to antituberculous therapy has previously been reported in HIV-uninfected patients [277]. Patients with HIV infection and tuberculosis are at an increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. These reactions develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the IRIS. Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4 + lymphocyte counts <50 cells/ µL. In the STRIDE study, IRIS occurrence was infrequent at 7.6%. When tuberculosis IRIS occurred, the majority (69%) of cases were mild to moderate in severity; however, 31% were hospitalized with tuberculosis IRIS and more than half received corticosteroids [68]. Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system (CNS) lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses [69]. Such findings are attributed to IRIS only after excluding other possible causes, especially tuberculosis treatment failure from drug-resistant tuberculosis or another opportunistic disease, such as non-Hodgkin lymphoma or infection. Antiretroviral treatment of patients with incubating, subclinical tuberculosis may also result in what is called "unmasking IRIS," where tuberculosis symptoms and clinical manifestations become more pronounced, though whether this represents normal progression of untreated tuberculosis is not known [187]. The relative risk of developing IRIS for patients who receive ART during therapy for tuberculosis is 1.88 (95% CI, 1.31-2.69), and those who start ART within 2 weeks after starting tuberculosis therapy have higher rates than those who start between 8-12 weeks [261][262][263]. In general, development of IRIS does not worsen treatment outcomes for either tuberculosis or HIV infection, and most episodes can be managed symptomatically. An exception to this is the development of IRIS in patients with CNS tuberculosis, where IRIS may cause severe or fatal neurological complications. In a study of patients with tuberculosis meningitis and HIV infection, early initiation of ART (within 2 weeks) was associated with increased rates of adverse events and higher mortality [278]. Thus, ART is not initiated in the first 8 weeks of antituberculosis therapy for patients with HIV infection and tuberculous meningitis (or other CNS tuberculosis), even for patients with CD4 cell counts <50 cells/µL. Management of IRIS is symptomatic. Based on expert opinion, for most patients with mild IRIS, tuberculosis and antiretroviral therapies can be continued with the addition of antiinflammatory agents such as ibuprofen. For patients with worsening pleural effusions or abscesses, drainage may be necessary. For more severe cases of IRIS, treatment with corticosteroids is effective. In a placebo-controlled trial of prednisone for patients with moderate IRIS, prednisone 1.25 mg/kg/day significantly reduced the need for hospitalization or surgical procedures [70]. For patients who develop IRIS, prednisone may be given at a dose of 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks, with tapering over a period of 6-12 weeks or longer. Controlled trials investigating whether treatment with nonsteroidal anti-inflammatory agents or corticosteroids can prevent the development of IRIS are under way or in development. # Children Children commonly develop tuberculosis as a complication of the initial infection with M. tuberculosis ( primary tuberculosis). The radiographic presentation of primary tuberculosis in children is characterized by intrathoracic lymphadenopathy with or without lung opacities, occasionally presenting with lymph node enlargement to a degree that there is compression of airways with or without hyperinflation or collapse of lobe or lung; breakthrough of node(s) in the airways can manifest with lobar or segmental infiltration, and a miliary pattern [279,280]. The diagnosis of tuberculosis in children is challenging, especially in young children (<5 years) due to the paucibacillary nature of the disease. Depending on the setting and resources, diagnosis is microbiologically confirmed in only 15%-50% of pediatric cases, and clinical case definitions for tuberculosis in children have recently been updated [281]. Children, rarely, and adolescents, more frequently, can also develop adult-type tuberculosis (upper lobe opacities and cavitation associated with sputum production). The lesions of primary tuberculosis have fewer M. tuberculosis organisms than those of adult-type pulmonary tuberculosis; thus, treatment failure, relapse, and development of secondary resistance are less common events among children when standard treatment regimens are initiated in a timely manner. However, it is often more difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis than from an adult. Therefore, choosing appropriate treatment drugs often requires the results of specimen culture and drug susceptibility tests from the person presumed to be the source of the child's infection. Based on expert opinion, when drug resistance is suspected or no source-case isolate is available, attempts to isolate organisms are critical; approaches including obtaining 3 early morning gastric aspirations (optimally during hospitalization), sputum induction [282], bronchoalveolar lavage [283], or tissue biopsy must be considered. Any information gained from molecular and phenotypic tests conducted on these samples is used to select an individualized regimen for the patient. Because tuberculosis in infants and children <4 years of age is more likely to disseminate and result in subsequent morbidity and mortality, empiric treatment is started as soon as the diagnosis is suspected, and particular care is given to drug dosage selection as an important component of achieving adequate concentrations of bactericidal drugs in body fluids, including the cerebrospinal fluid [284]. Several controlled and many observational trials of 6-month therapy in children with known or presumed drug-susceptible pulmonary tuberculosis have been published [285]. Based on systematic reviews of the literature, both the AAP [77] and the WHO [286,287], list a 4-drug regimen (INH, RIF, PZA, and EMB) for 2 months followed by a 2-drug (INH and RIF) regimen for 4 months as the preferred regimen for children with suspected or confirmed pulmonary tuberculosis. The AAP Red Book also states that children who are receiving EMB should be monitored monthly for visual acuity and redgreen color discrimination if they are old enough to cooperate. The AAP further notes that the use of EMB in young children whose visual acuity cannot be monitored requires consideration of risks and benefits, but it can be used routinely to treat tuberculosis disease in infants and children unless otherwise contraindicated [77]. As an approach to avoiding EMB ocular toxicity, some clinicians use a 3-drug regimen (INH, RIF, and PZA) in the initial 2 months of treatment for children who are HIV uninfected, have no prior tuberculosis treatment history, are living in an area of low prevalence of drug-resistant tuberculosis, and have no exposure to an individual from an area of high prevalence of drug-resistant tuberculosis. However, because the prevalence of and risk for drug-resistant tuberculosis can be difficult to ascertain, the AAP and most experts include EMB as part of the intensive phase regimen for children with tuberculosis. Pyridoxine, 25-50 mg/day, is given to infants, children, and adolescents undergoing INH treatment if they have nutritional deficiencies, symptomatic HIV infection, or are breastfeeding. Pyridoxine is also given to breastfeeding infants of mothers who are receiving INH [42,77,288,289]. The lack of approved pediatric dosage forms for most antituberculosis medications has resulted in the creation and use of improvised formulations. This has entailed crushing tablets or opening capsules to access the drug, followed by weighing or proportioning of the contents that are in turn admixed with food or prepared into a suspension. With the recent development of child-friendly antituberculosis formulations meeting the dosage guidelines set by the WHO, procedures for making such improvised formulations should no longer be needed [290]. In the United States, DOT has become the default programmatic approach to treating children with tuberculosis [17]. Based on expert opinion, parents should not supervise DOT for their children. Even when drugs are administered under DOT, tolerance of the medications must be monitored closely. When feasible, daily dosing is preferred by experts [77,279,287]; however, twice-or thrice-weekly dosing has also been endorsed during the continuation phase of treatment for HIV-uninfected children in settings where DOT is well established [77] (see Supplementary Appendix C and Table 3 for dosing of antituberculosis drugs in children). Monitoring response to treatment in children can be challenging because of the difficulties in demonstrating M. tuberculosis in children. Clinical and radiographic worsening may not be accompanied by positive AFB smears or mycobacterial cultures. According to experts, continued child growth and development while on treatment for tuberculosis usually predicts a positive outcome of treatment. A decision to modify the drug regimen should be undertaken with caution. Changes to the regimen are usually based on clinical and radiographic grounds. However, experts note that hilar adenopathy and resultant atelectasis in children on occasion can require 1-2 years to resolve; thus, an improving but persistent abnormality on a chest radiograph in an asymptomatic child is not believed to justify an extension of therapy. If there is concern that poor treatment response may be due to possible drug-resistant tuberculosis, expert opinion is that the child should be fully reinvestigated, verifying contact history and source case drug susceptibility test results, as well as obtaining additional specimens for cultures and drug susceptibility testing. According to expert opinion, most forms of extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease [77,286]; however, for children with confirmed or suspected tuberculous meningitis or osteoarticular tuberculosis caused by a drug-susceptible organism, expert opinion is that the duration of the continuation phase should be extended (See "Tuberculous Meningitis"). For tuberculous meningitis, the AAP lists an initial 4-drug regimen of INH, RIF, PZA, and an aminoglycoside or ethionamide for 2 months, followed by 7-10 months of INH and RIF. For patients who may have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin is used instead of streptomycin [77]. Fluoroquinolones have been studied in adults with tuberculous meningitis [291], and these studies provide some evidence in support of their use; however, there have been no published trials of their use for tuberculous meningitis in children. Extrapulmonary Tuberculosis PICO Question 7: Does the use of adjuvant corticosteroids in tuberculous pericarditis provide mortality and morbidity benefits? Recommendation 7: We suggest initial adjunctive corticosteroid therapy not be routinely used in patients with tuberculous pericarditis (conditional recommendation; very low certainty in the evidence). PICO Question 8: Does the use of adjuvant corticosteroids in tuberculous meningitis provide mortality and morbidity benefits? Recommendation 8: We recommend initial adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (strong recommendation; moderate certainty in the evidence). Tuberculosis can involve virtually any organ or tissue in the body. The principles underlying the treatment of pulmonary tuberculosis also apply to extrapulmonary disease. Chemotherapy for extrapulmonary tuberculosis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for extrapulmonary tuberculosis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued during a continuation phase. Increasing evidence, including randomized controlled trials, suggests that 6-9 month INH and RIF-containing regimens are effective for the majority of extrapulmonary sites of disease. The exception is tuberculous meningitis where the optimal duration of therapy has not been established through randomized controlled trials, but most experts and society guidelines prescribe 12 months of treatment [78,292]. The opinion of experts is that the preferred frequency of dosing for extrapulmonary tuberculosis is once daily for both the intensive and continuation phases. No randomized controlled trials have studied intermittent drug administration for extrapulmonary tuberculosis. If intermittent regimens are used, experts believe that highly intermittent, once-weekly regimens should be avoided because of insufficient experience with this regimen in extrapulmonary tuberculosis. In regard to treatment monitoring, bacteriologic evaluation is often limited by the difficulty in obtaining follow-up specimens. Sputum specimens are obtained when there is concurrent pulmonary involvement, otherwise, response to treatment in extrapulmonary diseases is often judged on the basis of clinical and radiographic findings. # Lymph Node Tuberculosis We believe a 6-month regimen is adequate for initial treatment of all patients with drug-susceptible tuberculous lymphadenitis [293][294][295][296][297][298]. Affected lymph nodes may enlarge and new nodes can appear during or after therapy without any evidence of bacteriological relapse [293,295,296,299]. Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration has been reported by some experts to be beneficial, although this approach has not been examined systematically. Incision and drainage techniques applied to cervical lymphadenitis, however, have been reported to be associated with prolonged wound discharge and scarring [300]. Of note, the majority of lymphatic cases of mycobacterial disease in US children are caused by nontuberculous mycobacteria [301]. Bone, Joint, and Spinal Tuberculosis Six-to 9-month regimens containing RIF for treatment of bone, joint, and spinal tuberculosis are at least as effective as 18-month regimens that do not contain RIF [302][303][304]. Because of the difficulties in assessing response, however, some experts tend to favor the 9-month duration, and in the setting of extensive orthopedic hardware, some experts extend the duration of treatment further to 12 months. Several trials found no additional benefit of surgical debridement in combination with chemotherapy compared with chemotherapy alone for spinal tuberculosis [80,[303][304][305][306]. As such, uncomplicated cases of spinal tuberculosis are managed with medical rather than surgical treatment. However, based on expert opinion, surgery can be considered in situations in which (1) there is poor response to chemotherapy with evidence of ongoing infection or ongoing deterioration; (2) relief of cord compression is needed in patients with persistence or recurrence of neurologic deficits; or (3) there is instability of the spine [307]. Spinal tuberculosis with evidence of meningitis is managed as tuberculous meningitis, including consideration of adjunctive corticosteroids (see Tuberculous Meningitis). # Pericardial Tuberculosis A 6-month regimen is adequate for patients with pericardial tuberculosis. Based on small studies that have shown mortality and morbidity benefits [71][72][73], corticosteroids have previously been universally recommended as adjunctive therapy for tuberculous pericarditis, however, a recent placebo-controlled randomized clinical trial with 1400 participants did not find a difference in the combined primary endpoint of the trial, which included mortality, cardiac tamponade, or constrictive pericarditis, between patients treated with adjunctive corticosteroids vs placebo [74]. A subgroup analysis, however, did suggest a benefit in preventing constrictive pericarditis. Similarly, a systematic review conducted to obtain evidence in support of this guideline did not find a statistically significant benefit in terms of mortality or constrictive pericarditis from the use of corticosteroids (see Supplementary Appendix B, Evidence Profile 14) [71][72][73][74][75]. Therefore, we suggest that adjunctive corticosteroids should not be used routinely in the treatment of patients with pericardial tuberculosis (Recommendation 7: conditional recommendation; very low certainty in the evidence). However, selective use of glucocorticoids in patients who are at the highest risk for inflammatory complications might be appropriate. Such patients might include those with large pericardial effusions, those with high levels of inflammatory cells or markers in pericardial fluid, or those with early signs of constriction [76]. # Pleural Tuberculosis A standard 6-month regimen (Table 2) is also adequate for treating pleural tuberculosis. Some clinicians consider using adjunctive corticosteroid therapy for tuberculous pleural effusions, and a number of studies have examined the risks and benefits of this approach [308]. Four have been prospective, double blind, and randomized [309][310][311], one of which was conducted in patients with HIV infection [312]. In all 4 studies, prednisone (or prednisolone) administration did not confer a beneficial effect on residual pleural thickening or prevention of other longterm pleural sequelae. In one study, an increased risk for Kaposi sarcoma was noted with the use of prednisolone in HIV-associated tuberculous pleurisy [312]. Based on these randomized clinical trials and a systematic review, there is no evidence to support the routine use of adjunctive corticosteroids in patients with tuberculous pleurisy. Tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy [313]. The optimum duration of treatment for this unusual form of tuberculosis has not been established. # Tuberculous Meningitis Tuberculous meningitis remains a potentially devastating disease associated with a high morbidity and mortality in children and adults, despite prompt initiation of adequate chemotherapy [314]. HIV-infected individuals appear to be at increased risk for developing tuberculous meningitis, but the clinical features of the disease are similar to those in tuberculous meningitis patients without HIV infection [315][316][317]. High short-term morbidity and mortality is reported regardless of HIV serostatus [315][316][317]; however, 9-month survival was further decreased in HIV-infected patients compared with HIV-uninfected patients in one cohort study [318]. Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7-10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy. In children with tuberculous meningitis, the AAP lists an initial 4-drug regimen of INH, RIF, PZA, and ethionamide or an aminoglycoside for 2 months (in place of EMB), followed by 7-10 months of INH and RIF [77]. There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis [78]. Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our writing committee prefers using EMB as the fourth drug. Fluoroquinolones, as well as higher doses of intravenous RIF, are being evaluated in adults with tuberculous meningitis [291,319]; a large randomized controlled trial (ISRCTN61649292) is under way to evaluate the impact on reducing mortality of levofloxacin combined with higher-dose rifampicin during the intensive phase of treatment [320]. Selected complications of tuberculous meningitis warranting neurosurgical referral include hydrocephalus, tuberculous cerebral abscess, and clinical situations in which there is paraparesis [78]. A number of studies have examined the role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis [79][80][81][82][83][84][85][86][87][88][89][90][91]. Our updated systematic review found a mortality benefit from the use of adjuvant corticosteroids (See Supplementary Appendix B, Evidence Profile 15). Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis (Recommendation 8: strong recommendation; moderate certainty in the evidence). # Disseminated Tuberculosis Based on expert opinion, a standard daily 6-month regimen (Table 2) is adequate for tuberculosis at multiple sites and for miliary tuberculosis; however, supporting data from controlled clinical trials are limited. Some experts believe concurrent corticosteroid therapy is indicated for treating severe respiratory failure or adrenal insufficiency caused by disseminated tuberculosis [321][322][323], though the role of adjunct corticosteroid treatment in patients with miliary tuberculosis remains unclear [324]. Patients with disseminated tuberculosis may have concomitant neurologic complications, with indolent symptoms of CNS involvement, which should be appropriately worked up [325]. Treatment recommendations for tuberculous meningitis are followed when there is CNS involvement. # Genitourinary Tuberculosis Renal tuberculosis is treated primarily with medical rather than surgical therapy, and expert opinion is that a standard daily 6-month regimen (Table 2) is adequate [326][327][328][329]. If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal drainage by stenting or nephrostomy is advised by experts [330]. Nephrectomy is considered when there is a nonfunctioning or poorly functioning kidney, particularly if hypertension or continuous flank pain is present. Dose adjustment is required in patients with coexistent renal failure. Tuberculosis of the female or male genital tract responds well to standard chemotherapy, although surgery may be indicated for residual, large, tubo-ovarian abscesses. A positive urine culture for M. tuberculosis is a component of the diagnostic assessment of genitourinary tuberculosis [331]. A positive urine culture for M. tuberculosis is also sometimes seen in tuberculosis patients with advanced HIV infection, and may reflect disseminated disease and/or occult genitourinary tract involvement. Rarely, a positive culture may occur in the absence of any abnormalities on urinalysis and does not necessarily represent invasive genitourinary tract involvement [332]. # Abdominal Tuberculosis Expert opinion is that a 6-month regimen is adequate for patients with peritoneal or intestinal tuberculosis [333][334][335]. The nonspecific presentation of abdominal tuberculosis means that a high index of suspicion is an important factor in early diagnosis and initiation of treatment [336,337]. Data on adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis are limited [338]; thus, experts believe it should not be prescribed routinely. # Other Sites of Involvement As noted above, tuberculosis can involve any organ or tissue. When treating tuberculosis in sites other than those mentioned, the basic principles of therapy apply, but experts should be consulted. Culture-Negative Pulmonary Tuberculosis in Adults PICO Question 9: Does a shorter duration of treatment have similar outcomes compared to the standard 6-month treatment duration among HIV-uninfected patients with paucibacillary tuberculosis (ie, smear negative, culture negative)? Recommendation 9: We suggest that a 4-month treatment regimen is adequate for treatment of HIV-uninfected adult patients with AFB smear-and culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active pulmonary tuberculosis. Some causes of failure to isolate organisms include the recent use of antibiotics with bactericidal activity against M. tuberculosis (eg, fluoroquinolones), low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing [92]. Alternative diagnoses must be considered and appropriate diagnostic studies undertaken in patients who appear to have culture-negative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis have 2 sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria or for rapid molecular testing for M. tuberculosis as part of the diagnostic evaluation. Other diagnostic procedures, such as bronchoscopy with bronchoalveolar lavage and biopsy, are considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture or a rapid molecular test is positive, treatment for active disease is continued for a full, standard 6month course (Table 2), if appropriate based on drug susceptibility test results. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have thorough clinical and radiographic follow-up after 2 months of therapy. If there is clinical or radiographic improvement and no other etiology is identified, treatment should be continued. The optimum treatment regimens and duration for culturenegative tuberculosis have not been convincingly established. We performed a systematic review that evaluated 4-and 6-month treatment regimens using available clinical trials data in adult (>15 years of age) patients. No clinical trials data on shortened treatments in children were available. A study from Hong Kong demonstrated that for adults with smear-negative, culture-positive, and culture-negative pulmonary tuberculosis, a 4-month regimen of INH, RIF, streptomycin, and PZA given either daily or thrice weekly was highly successful [339]. In Arkansas, a 4-month INH and RIF regimen for culture-negative tuberculosis was successful with only 1.2% relapses during an average follow-up of 44 months [340]. In Singapore, a study of a small number of patients with smearnegative and either culture-positive or culture-negative tuberculosis treated with INH, RIF, and PZA daily for 2 months followed by INH and RIF either daily or thrice weekly for 2 months showed a high degree of success in both groups [341]. Overall, these 3 studies report a proportion relapsing of only 1.9% among a total of 940 patients treated for 4 months, all of whom had at least 3 negative smears/cultures prior to starting therapy. Our systematic review of available clinical trials data in adult (>15 years of age) patients did not identify a significant difference in the risk of relapse in culture-negative tuberculosis treated for either 4 or 6 months (see Supplementary Appendix B, Evidence Profile 16). Consequently, we suggest that a 4month treatment regimen is adequate for HIV-uninfected adults with culture-negative pulmonary tuberculosis (conditional recommendation; very low certainty in the evidence). Operationally, treatment is initiated with an intensive phase of INH, RIF, PZA, and EMB daily and continued in all patients suspected of having pulmonary tuberculosis even when the initial bacteriologic studies are negative. If all cultures on samples deemed to be adequate are negative and there is clinical or radiographic response after 2 months of intensive phase therapy, the continuation phase with INH and RIF can be shortened to 2 months. Clinical and radiographic response, assessed at the end of treatment, is used to determine whether an extension in treatment to a full standard 6-month regimen is needed. Alternatively, if there is concern about the adequacy of workup or the accuracy of the microbiologic evaluations, a standard 6-month regimen remains preferred (Table 2) [14,15]. On occasion, patients who are being evaluated for pulmonary tuberculosis will be found to have positive AFB smears but negative cultures. Potential causes include the possibilities that the acid-fast organisms are fastidious mycobacteria other than M. tuberculosis complex, that they are nonviable M. tuberculosis, or that the results are due to laboratory error (false-positive smear, or false-negative culture). The approach in such cases is individualized on the basis of clinical and radiographic findings, as well as the results of rapid molecular diagnostic studies; discussion with the microbiologist performing the cultures is prudent. If clinical suspicion of tuberculosis is high, particularly if there is clinical and radiologic improvement since the start of therapy, then therapy is continued for a minimum of 6 months as for culture-positive pulmonary tuberculosis. # Pregnancy and Breastfeeding Treatment for tuberculosis is initiated whenever the probability of maternal disease is moderate to high because of the risk of untreated tuberculosis to a pregnant woman and her fetus [342][343][344][345]. Although antituberculosis drugs cross the placenta, they do not appear to have teratogenic effects in humans [346][347][348][349]. However, the inclusion of PZA in the treatment regimen for pregnant women is controversial in the United States. The FDA previously classified all 4 first-line drugs, INH, RIF, PZA, and EMB, as having equal potential for teratogenicity (all assigned to category C according to the previous FDA letter-based classification system, which is currently being revised [350]). We suggest that clinicians evaluate the risks and benefits of prescribing PZA on a case-by-case basis, allowing the patient to make an informed and educated decision, recognizing that for all first-line drugs, risk cannot be ruled out as there are no adequate and wellcontrolled studies in humans, but potential benefits warrant use of the drug in pregnant women despite potential risks. It is also important to recognize that PZA has been used extensively in high-burden countries for many years, and is recommended by the WHO for tuberculosis in pregnancy, as part of the standard treatment regimen [98]. Expert opinion is that in pregnant women with tuberculosis and HIV, extrapulmonary or severe tuberculosis, it is more beneficial to include PZA in the treatment regimen than to not include PZA. If a decision is made to exclude PZA from the regimen, a minimum of 9 months of INH, RIF, and EMB is used for most pregnant women with drug-susceptible tuberculosis. Expert consultation should be sought when first-line drugs cannot be used due to adverse effects or antibiotic resistance, when there is extensive disease and/or a risk of noncompliance. Although the fetal effects of many second-line drugs are not well established, small case series of pregnant women treated with second-line drugs (from studies in drug-resistant tuberculosis) suggest that good outcomes are achievable and that termination of the pregnancy is not necessary [351][352][353][354]. Overall, the absence of high-quality studies combined with estimates of >200 000 cases of tuberculosis in pregnant women each year highlight the need for additional research in this area [355,356]. Breastfeeding is encouraged for women who are deemed noninfectious and are being treated with first-line agents. The small concentrations of antituberculosis drugs measured in breast milk have not been reported to produce toxic effects in the nursing infant [77]. Conversely, drugs in breast milk should not be considered to serve as effective treatment for active tuberculosis or latent tuberculosis infection in a nursing infant. Whenever INH is given to a pregnant or nursing woman, supplementary pyridoxine, 25-50 mg/day, is prescribed [42,43,357,358]. According to the AAP, supplementary pyridoxine (1-2 mg/kg/day) is also prescribed to exclusively breastfed infants, even those not receiving INH [77,289]. # Renal Disease Patients with renal insufficiency or end-stage renal disease (ESRD) are immunocompromised [359]. Tuberculosis patients with chronic renal failure have worse clinical outcomes than those without renal failure, and, thus, experts recommend close monitoring during tuberculosis treatment [360]. The pharmacokinetics of antituberculosis drugs are altered as some are cleared by the kidneys and/or removed via hemodialysis [361,362]. Therefore, dose adjustment in patients with renal insufficiency or ESRD may be required (Table 3 and Table 12). Decreasing the dose lowers peak serum drug concentrations and can compromise treatment efficacy. Based on expert opinion, the interval between drug doses in patients with a creatinine clearance of <30 mL/minute and those receiving hemodialysis should be increased instead. In patients with borderline renal function, a 24-hour urine collection may be needed to more accurately define the degree of renal insufficiency prior to making regimen changes [242,363]. Insufficient data exist to guide dosing recommendations for patients with a reduced but >30 mL/min creatinine clearance. In such patients, standard doses are used by experts, but measurement of serum concentrations 2 and 6 hours after timed administration can be used to assist with optimizing drug dosages. RIF and INH are metabolized by the liver, and conventional dosing can be used in the setting of renal insufficiency. Although PZA is metabolized by the liver, its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) may accumulate in patients with renal insufficiency. EMB is approximately 80% cleared by the kidneys and may accumulate in patients with renal insufficiency. Experts suggest a longer interval between doses (ie, thrice weekly) for PZA and EMB [242,363]. With hemodialysis, PZA and, presumably, its metabolites are cleared to a significant degree, INH and EMB are cleared to some degree, and RIF is not cleared by hemodialysis [361]. The fluoroquinolones are also cleared variably by the kidneys. Levofloxacin undergoes greater renal clearance than moxifloxacin [179]. Postdialysis administration of all antituberculosis medications is preferred to facilitate DOT and to avoid premature clearance of drugs such as PZA. Monitoring serum drug concentrations, along with careful clinical and pharmacological assessment, in patients with ESRD, may be necessary. ESRD patients are often taking other medications that interact with antituberculosis drugs or have comorbid clinical conditions that could affect drug absorption, such as diabetes mellitus with gastroparesis. For patients receiving peritoneal dialysis, there is currently a paucity of pharmacokinetic and dosing data, and the dosages in Table 12 may not apply to patients receiving peritoneal dialysis. Such patients may require close monitoring for toxicity, and measurements of the serum concentrations of antituberculosis drugs before and after peritoneal dialysis should be considered. # Hepatic Disease Tuberculosis treatment in patients with preexisting advanced liver disease poses significant challenges. The likelihood of drug-induced hepatitis is increased with prior advanced liver disease [364], liver transplant [365], or hepatitis C infection [366,367]. Abnormal baseline aminotransferases alone are an independent risk factor for DILI [364,368]. Experts recommend that patients with a history of injection drug use, birth in Asia or Africa (or other hepatitis virus endemic regions), or HIV infection have hepatitis B and C virus screening at baseline (Table 7). For patients with marginal hepatic reserve, superimposed DILI [56] may be severe, even life-threatening [369]. Fluctuations of serum aminotransferases and total bilirubin from preexisting liver disease can confound monitoring for DILI. Hepatic tuberculosis may also cause elevated aminotransferases, which improve with effective tuberculosis treatment. Regimens with fewer potentially hepatotoxic agents are selected in patients with advanced liver disease or whose serum ALT is >3 times the upper limit of normal at baseline (and not thought to be caused by tuberculosis). The crucial efficacy of INH and particularly RIF warrant their use and retention, if at all possible, even in the face of preexisting liver disease. Expert consultation is advisable. Adjustments during treatment may be necessary. Drug susceptibility testing to fluoroquinolones and injectables is indicated if use of these drugs is being considered. Alternative regimens for use in patients with hepatic disease include: • Treatment without PZA: PZA has often been implicated in DILI. A potential regimen could be INH, RIF, and EMB for 2 months, followed by 7 months of INH and RIF [370,371]. • Treatment without INH and PZA: For advanced liver disease patients, RIF and EMB with a fluoroquinolone, injectable, or cycloserine for 12-18 months, depending on the extent of the disease and response could be considered [372]. • Treatment without INH: Based on outcomes of studies on INH-resistant tuberculosis, a regimen of RIF, PZA, and EMB with or without a fluoroquinolone could be considered for a total duration of at least 6 months [373]. Although this regimen has 2 potentially hepatotoxic medications, it has the advantage of retaining a treatment duration of 6 months. • Regimens with little or no potential hepatotoxicity: For patients with severe, unstable liver disease, EMB combined with a fluoroquinolone, cycloserine, and second-line injectable for 18-24 months (similar to an multidrug-resistant tuberculosis regimen) can be considered [374]. Some experts avoid aminoglycosides in patients with severe, unstable liver disease due to concerns about renal insufficiency or bleeding from the site of injected medication due to thrombocytopenia and/ or coagulopathy. • Standard doses are given unless there is intolerance. • The medications should be given after hemodialysis on the day of hemodialysis. • Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation, and to assist in avoiding toxicity. • Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving hemodialysis and verify adequacy of dosing using serum concentration monitoring. • In patients with 30-50 mL/min creatinine clearance, standard doses are used by experts, but measurement of serum concentrations 2 and 6 hours after timed administration can be used to assist with optimizing drug dosages. a Including adult patients receiving hemodialysis. b The appropriateness of 250-mg daily doses has not been established. There should be careful monitoring for evidence of neurotoxicity. Data to guide the monitoring of patients with preexisting severe liver disease are scarce. Clinical monitoring and patient education for manifestations of liver injury is warranted for all patients [56]. Experts in the field recommend measuring serum aminotransferases and total bilirubin concentrations every 1-4 weeks for at least the first 2-3 months of treatment. The INR may also be periodically followed for patients with severe hepatic impairment [56,375,376]. An increase in serum ALT is more specific for hepatocellular injury than an increase in AST, which can also signify abnormalities in muscle, heart, or kidney [56,377]. In patients with more advanced preexisting disease, such as those with cirrhosis or encephalopathy, the ALT thresholds for treatment interruption have not been defined. Some experts recommend, in addition to weekly or twice-weekly ALT monitoring, interrupting treatment for only a 3-fold elevation of ALT, even if asymptomatic [375,376]. Reintroduction of antituberculous treatment may entail rechallenge and/or substitution of agents, while trying to retain the most effective medications [56]. Whenever feasible, management of tuberculosis in the setting of severe hepatic disease is undertaken in consultation with experts. # Advanced Age The risk of drug-induced hepatitis and other serious adverse effects increases with advancing age because of less efficient drug elimination due to reduced renal and hepatic clearance [56]. Because PZA is the most common culprit [378,379], the benefits of including PZA in the initial regimen for elderly patients with modest disease and low risk of drug resistance may be outweighed by the risk of serious adverse events. Consequently, some experts avoid the use of PZA during the intensive phase among patients >75 years of age. In such cases, the initial regimen consists of INH, RIF, and EMB. If PZA is not used during the intensive phase, then the total duration of tuberculosis treatment should be extended to at least 9 months. When the elderly patient has active tuberculosis with high bacillary burden (ie, bilateral cavitation) and, thus, treatment failure or the development of drug resistance is a concern, benefits and risks of adding PZA or a fluoroquinolone (eg, levofloxacin, moxifloxacin) vs no fourth drug should be carefully considered. The risk of drug interaction is increased in the elderly and consideration may need to be given to dose adjustments or use of alternative regimens. Careful clinical monitoring to detect intolerance and adverse reactions is warranted. # Other Comorbid Conditions As noted previously, the CDC and WHO recommend routine HIV testing and counseling to all patients with presumptive and diagnosed tuberculosis [253,254]. Experts also recommend that patients with a history of injection drug use, HIV infection, or birth in Asia or Africa (or other hepatitis virus endemic regions) undergo hepatitis B and C virus screening at baseline. Based on limited data, some experts also suggest screening for helminthic infections, including malaria, strongyloides, and schistosomiasis in patients originating from regions hyperendemic for these diseases. In general, tuberculosis treatment for patients with diseases or conditions that alter immune responsiveness, including HIV infection, parasitic and helminthic infections, hematologic or reticuloendothelial malignancies, immunosuppressive therapy (eg, TNF-α inhibitors) [380], chronic renal failure [381], diabetes mellitus, and malnutrition is based on the standard, daily 6-month regimen (Table 2). Nonetheless, decisions regarding treatment of comorbidities and the duration of tuberculosis treatment can be individualized, taking into account disease severity, organs involved, and response to treatment. For example, based on increased rates of tuberculosis recurrence, some experts suggest extending the total duration of tuberculosis treatment to 9 months in poorly controlled diabetes mellitus [49,50,382,383]. Similarly, for patients with silicotuberculosis, data demonstrate that cure rate is improved if the continuation phase is extended by at least 2 months [169,384]. Based on data suggesting increased mortality with shorter durations of treatment, some experts also suggest extending the total duration of tuberculosis treatment to at least 9 months for all solid organ transplant recipients [385]. The management of immunosuppressive therapy in patients who develop active tuberculosis varies based on the comorbid condition. If possible, steps are taken to correct immunodeficiency. In patients with rheumatologic disease, expert opinion is that TNF-α inhibitor therapy is held if clinically feasible, when active tuberculosis is suspected or confirmed. There is no consensus on when TNF-α inhibitor therapy can be resumed. However, small case series suggest that it is safe to resume TNF-α inhibitor therapy in patients who complete at least 2 months of antituberculosis treatment and have a good clinical response [380,386,387]. The decision to restart TNF-α inhibitor treatment should be individualized, taking into account the clinical need for immunosuppressive therapy, the extent of tuberculosis disease, and clinical response to antituberculosis treatment. Of note, severe IRIS-like reactions in the setting of holding TNF-α inhibitor treatment have been reported [388]. In solid organ transplant recipients, significant pharmacological interactions can occur between rifamycin-based antituberculosis regimens ( particularly RIF) and calcineurin inhibitors or rapamycin; on this basis, strict monitoring of serum drug concentrations is needed to prevent rejection [389]. # RECURRENT TUBERCULOSIS, TREATMENT FAILURE, AND DRUG RESISTANCE # Recurrent Tuberculosis Recurrence refers to the circumstance in which a patient whose sputa had become and remained culture negative while receiving antituberculosis drugs becomes culture positive or experiences clinical or radiographic deterioration consistent with active tuberculosis after completion of therapy. In such patients, vigorous efforts are made to establish a diagnosis and to obtain microbiologic confirmation of the relapse to enable testing for drug resistance. True relapses, defined as recurrent tuberculosis caused by the same strain as was identified at baseline, are thought to be due to failure of chemotherapy to sterilize the host tissues, thereby enabling endogenous recrudescence of the original infection. In high-incidence settings or where infection control is poor, however, exogenous reinfection with a new strain of M. tuberculosis may be responsible for the apparent recurrence (in this context, not referred to as relapse) [390,391]. Patients at risk for relapses are those with extensive disease at baseline and whose sputum cultures remain positive after completion of the intensive phase of treatment [9,392]. However, the sensitivity of culture-positive status at 2 months for predicting relapse is low [46]. Most relapses occur within the first 6-12 months after completion of therapy [393]. In the majority of patients with tuberculosis caused by drug-susceptible organisms who were treated by DOT with rifamycin-containing regimens, relapses occur with susceptible organisms [394,395]. However, the risk of acquired drug resistance is substantial in patients who have a relapse after receiving SAT, a highly intermittent regimen in the setting of HIV infection, a non-rifamycin-containing regimen (including receiving only INH and EMB in the continuation phase of treatment), or a second-course of a first-line regimen reinforced by streptomycin [59,60,[396][397][398][399][400]. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen using DOT, a high likelihood exists that the organisms were resistant from the outset [399,401,402]. To help guide regimen selection, rapid molecular tests have been used at the time of suspected recurrence as an approach to rapidly identifying the presence of resistance-conferring mutations; however, the detection of M. tuberculosis DNA and RIF resistance have been reported as being false positive [403]. Experts suggest caution in interpreting results from molecular tests used at the time of suspected recurrence. The selection of empiric treatment regimens for patients with relapses is based on the prior treatment scheme. For patients with relapse who were treated for drug-susceptible tuberculosis using DOT, experts recommend retreatment using the standard intensive phase regimen until the results of susceptibility tests are known. For patients who did not receive DOT or had irregular treatment, it is prudent to infer a higher risk of acquired drug resistance. Whenever feasible, rapid molecular and phenotypic diagnostics for detection of drug resistance should be used to inform regimen selection. When immediate treatment initiation is necessary, consider the use of an expanded empiric regimen in consultation with experts in the treatment of drug-resistant disease. If started, an expanded empiric regimen is administered until the results of susceptibility tests are known and commonly consists of the standard intensive phase regimen of daily INH, RIF, PZA, and EMB, plus a later-generation fluoroquinolone, an injectable, and depending on the severity of disease or the anticipated extensiveness of resistance, an additional second-line drug [404]. All drugs are administered using DOT. An expanded regimen is indicated especially in patients with impaired immunity, limited respiratory reserve, CNS involvement, other lifethreatening circumstances, or any other situation in which treatment with an inadequate regimen could have severe consequences to the individual or the community. When epidemiological circumstances render exogenous reinfection the most likely cause of apparent relapse, the regimen choice is influenced by the drug susceptibility pattern of the presumed source case and/or drug-resistance testing. If the presumed source case is known to have drug-resistant organisms, an expanded empiric regimen based on the resistance profile of the putative source case may be suitable. # Poor Treatment Response and Treatment Failure In the United States, treatment failure is defined as continuously or recurrently positive cultures after 4 months (5 months in Europe and WHO guidelines [98]) of treatment in a patient receiving appropriate chemotherapy. Among patients with drugsusceptible pulmonary tuberculosis, even with extensive lung cavitation, 90%-95% will be culture negative after 3 months of treatment with a regimen that contains INH and RIF. During this time, the vast majority of patients show clinical improvement, including reduced fever, reduced cough, and weight gain. Thus, patients with persistently positive cultures after 3 months of chemotherapy, with or without ongoing symptoms, are evaluated carefully to identify the cause of delayed response. Multiple reasons for poor treatment response and treatment failure exist. For patients not receiving DOT, one explanation may be nonadherence to the treatment regimen. Among patients receiving DOT, cryptic nonadherence (spitting out or deliberately regurgitating tablets or capsules) or failure of the healthcare system to reliably deliver the drugs may be a cause. Other potential reasons include unrecognized drug resistance (drug susceptibility testing not done, misreported, or misinterpreted; reinfection with a drug-resistant strain), malabsorption (diarrhea, or prior resection surgery of the stomach or small intestine, or taking tuberculosis medications with antacids or other drugs/substances that might bind or interfere with drug absorption), or diabetes mellitus with or without gastroparesis [198,199,201,[405][406][407][408][409][410]. Some experts use TDM to evaluate poor drug exposure as a contributing factor to treatment failure [242]. Laboratory error (eg, cross-contamination or mislabeling of specimens) is also a possible reason for a positive culture in a patient who is doing well clinically [411]. Clinicians should be alert, as well, to the possibility of transient clinical or radiographic worsening ( paradoxical reactions), despite appropriate therapy that would eventually result in cure. Examples of this include ongoing inflammation at sites of lymphadenitis, worsened abnormalities on chest radiographs after several months of treatment, or the new appearance of pleural effusions during therapy for pulmonary tuberculosis. Such paradoxical worsening during treatment can occur in HIV-uninfected patients, as well as in HIV-infected patients (see "Immune Reconstitution Inflammatory Syndrome"). The diagnosis of a paradoxical reaction is made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure and drug resistance. For patients who meet criteria for treatment failure, the possible reasons listed above should be addressed promptly. Recent mycobacterial isolates should be sent to a reference laboratory for susceptibility testing to both first-and second-line drugs. If clinicians are not familiar with the management of drugresistant tuberculosis, immediate referral to, or consultation with a specialty center is indicated. If treatment failure is presumably due to drug resistance and the patient is seriously ill or has a positive sputum AFB smear, an empiric regimen is started immediately and continued until susceptibility tests are available to guide therapy; however, if the patient's clinical presentation is not severe, one may either initiate an empiric retreatment regimen or wait for drug susceptibility results from a recent isolate. Of note, patients who are not on the correct regimen remain infectious [102,412]. A single new drug is never to be added to a failing regimen as it can lead to amplification of drug resistance, including acquired resistance to the newly added drug [413]. To lessen the likelihood of increasing resistance, it is generally prudent to add 2-3 new drugs to which susceptibility could logically be inferred (eg, using regional drug-resistance surveillance data and the patient's history of medication use). When drug susceptibility results are available, the regimen is adjusted accordingly. # Tuberculosis Caused by Drug-Resistant Organisms Mycobacterium tuberculosis bacilli are continually undergoing spontaneous mutations that create resistance to individual antituberculosis drugs; however, the frequency of these mutations is sufficiently low that with appropriate combination chemotherapy that is reliably ingested, clinically significant resistance is very unlikely to develop [121,414]. Acquired drug resistance can occur, however, when there is a large bacillary population (such as in pulmonary cavities), an inadequate drug regimen, a combined failure of both the patient and the provider to ensure that an adequate regimen is ingested, or malabsorption of one or more antituberculosis drugs [415,416]. During extended or repeated treatment, amplification of resistance to multiple agents may occur. Patients with acquired drug resistance may transmit their strains to others who, if they develop tuberculosis, will have primary drug resistance. Notable clinical and demographic risk factors for drug-resistant tuberculosis include having a previous episode of tuberculosis treatment (in particular if the regimen was inadequate or adherence to the regimen was low), originating from or living for an extended period in a country with a high prevalence of drug-resistant tuberculosis, and having a history of exposure to an index case with drug-resistant tuberculosis. Comprehensive guidance on the management of drugresistant tuberculosis is beyond the scope of this document, though international guidelines exist [404]. An ATS/CDC/ ERS/IDSA practice guideline for the management of drugresistant tuberculosis is also currently under development using GRADE methodology. # RESEARCH AGENDA FOR TUBERCULOSIS TREATMENT Much progress has been made over the last 10 years in the treatment of tuberculosis [109,417]. The corpus of knowledge on new drug combinations, drug interaction with antiretrovirals, methods of dosing, and timing of dosing is increasing. Based on the writing of this guideline, however, several priority areas in need of additional research were identified. # New Antituberculosis Drugs and Regimens Treatment of tuberculosis remains centered around the same 6-month, 4-drug regimen introduced >40 years ago. The identification of more potent drugs and drug regimens that permit shortening the duration of treatment remains a key priority. A number of new drugs and regimens for tuberculosis are currently being investigated in clinical trials. This includes repurposed drugs (eg, daily high-dose RPT and higher dosages of RIF, linezolid and carbapenems) and new drugs (eg, bedaquiline, delamanid, and pretomanid [formerly PA-824]). Highdose, daily RPT is being tested in a treatment-shortening phase 3 clinical trial, with dosage selected based on dose-ranging, drug-exposure optimization studies (ClinicalTrials.gov identifier: NCT02410772) [418]. Pretomanid is being tested as part of a combination regimen including moxifloxacin and PZA for the treatment of both drug-susceptible and drug-resistant tuberculosis (ClinicalTrials.gov identifier: NCT02193776). Bedaquiline, approved by the US FDA for treatment of multidrug-resistant tuberculosis in 2012, is also being investigated in drug-susceptible disease as part of a combination regimen including pretomanid and PZA and/or clofazimine in a phase 2 study (ClinicalTrials.gov identifier: NCT01691534). Broadly, the tuberculosis therapeutics development field would greatly benefit from dose-ranging and drug-drug interaction studies for new and existing drugs so as to identify the drug exposures and optimal combinations necessary to achieve maximal efficacy, while improving safety and tolerability. # Biomarkers of Treatment Effect and Individualization of Therapy The success of therapy depends upon many diverse factors and only some are presently predictable, identifiable, or modifiable. Inclusion of biomarker substudies that assess both microbial and host biomarkers within phase 3 clinical trials will yield important knowledge on the factors that impact therapeutic success. Additionally, data on pharmacokinetic/pharmacodynamic properties that influence drug safety and efficacy, data on drug penetration and distribution, and the pursuit of sensitive and specific biomarkers that can reliably predict relapse will be critically important to advancing the tuberculosis therapeutics field [116,418,419]. New biomarkers of treatment effect that can be implemented in the field and accurately monitor response to treatment on an individual basis may also allow for the individualization of the duration of treatment [420]. However, a considerable increase in investment in fundamental research is needed to develop and validate biomarkers of durable cure [421]. # Treatment of Tuberculosis in Special Situations Based on the writing of this guideline, the need for additional research was notable for treatment of tuberculosis in special situations. In particular, there is a paucity of high-quality studies on tuberculosis in pregnant women, breastfeeding women, and children. A recent US National Institutes of Health convened workshop examining the inclusion of pregnant and postpartum women in tuberculosis drug trials has provided consensus statements to help accelerate research in this area [422]. The lack of pediatric dosage forms of most antituberculosis medications has up to now necessitated using crushed tablets or opening capsules and creating suspensions to facilitate dosing in young children, and additionally has hampered inclusion of children in drug trials. As a result of key partnerships and concerted investments in pediatric therapeutics research, an affordable, highquality, child-friendly fixed-dose combination meeting WHO quality assurance metrics is now being produced; however, these products are not yet registered in the United States or Europe [290]. Broadly, to address the paucity of data on the optimal treatment of children with tuberculosis, the drug development field should design trials to be more inclusive of children as study participants across key stages of therapeutics research, from pharmacokinetic studies through to phase 3 clinical trials. Examples of ongoing tuberculosis treatment trials that enroll children and adolescents are the SHINE study (Shorter Treatment for Minimal TB in Children Study; ISRCTN63579542), and TBTC Study 31/ACTG A5349 (Rifapentine-Containing Tuberculosis Treatment Shortening Regimens; NCT02410772) [423]. # Implementation Research Even as new drugs and new regimens are being developed, there remains a critical need to improve the delivery of tuberculosis treatment. DOT has been the dominant mode of treatment delivery, but evidence supporting its use has been weak. Strategies that are more convenient for patients and less resource-intensive for public health programs should be further explored [424]. For example, in low-incidence countries, early studies have shown that video DOT using smartphones is feasible, has high patient uptake, and is associated with similar adherence rates as in-person DOT [131]. Research to improve tuberculosis treatment delivery strategies should be informed by behavioral studies and/or implementation science frameworks, which have been shown to increase the likelihood of identifying successful multifaceted individual behavior change and health system interventions. Finally, research on the optimal introduction of new drugs is needed (even after approval from regulatory bodies) provide data that will facilitate key implementation decisions around programmatic feasibility, cost-effectiveness, and optimal approaches to surveillance of drug resistance and prevention of emergence of new drug resistance [425]. # Supplementary Data Supplementary materials are available at http://cid.oxfordjournals.org. Consisting of data provided by the author to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the author, so questions or comments should be addressed to the author. Financial support. Support for this guideline was provided by the American Thoracic Society, the IDSA, and the CDC. # Notes Potential conflicts of interest. The authors have reported to the American Thoracic Society the following: P. M. B. reported that his spouse previously owned stocks or options of Merck. R. E. C. reported service as a consultant and ownership of stocks or options for Merck. C. L. D. received research support from Insmed and served on data and safety monitoring boards of Otsuka America Pharmaceutical and Sanofi Pasteur. C. A. P. received research support from Jacobus Pharmaceuticals. J. S. reported service on a data safety and monitoring board of Otsuka Pharmaceuticals. A. V. reported serving as the chief of a CDC clinical research branch doing clinical trials in tuberculosis, which supports and works with the TB Trials Consortium (TBTC) that collaborates with pharmaceutical companies, which may provide support such as drug supplies or laboratory funding for pharmacokinetic substudies. Specifically, Sanofi Aventis has provided approximately $2.8 million in unrestricted grants to the CDC Foundation to facilitate or support TBTC work related to rifapentine, including contract research staff, pharmacokinetic substudies, travel to TBTC scientific meetings for invited speakers, and expenses related to fulfillment of company requests for data and data formats as part of use of TBTC data in support of regulatory filings. TBTC has studies under way involving rifapentine and levofloxacin that may have relevance for future regimens for drug-susceptible tuberculosis and for multidrug-resistant tuberculosis. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.	None	None
9aba444af572deb5a587f2c44ba59085b71d3a2e	cdc	None	These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 18-30, 2009. The information in this report updates the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (MMWR 2006;55). Included in these updated guidelines is new information regarding 1) the expanded diagnostic evaluation for cervicitis and trichomoniasis; 2) new treatment recommendations for bacterial vaginosis and genital warts; 3) the clinical efficacy of azithromycin for chlamydial infections in pregnancy; 4) the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications; 5) lymphogranuloma venereum proctocolitis among men who have sex with men; 6) the criteria for spinal fluid examination to evaluate for neurosyphilis; 7) the emergence of azithromycin-resistant Treponema pallidum; 8) the increasing prevalence of antimicrobial-resistant Neisseria gonorrhoeae; 9) the sexual transmission of hepatitis C; 10) diagnostic evaluation after sexual assault; and 11) STD prevention approaches.# Introduction The term sexually transmitted diseases (STDs) is used to refer to a variety of clinical syndromes caused by pathogens that can be acquired and transmitted through sexual activity. Physicians and other health-care providers play a critical role in preventing and treating STDs. These guidelines for the treatment of STDs are intended to assist with that effort. Although these guidelines emphasize treatment, prevention strategies and diagnostic recommendations also are discussed. These recommendations should be regarded as a source of clinical guidance and not prescriptive standards; health-care providers should always consider the clinical circumstances of each person in the context of local disease prevalence. They are applicable to various patient-care settings, including familyplanning clinics, private physicians' offices, managed care organizations, and other primary-care facilities. These guidelines focus on the treatment and counseling of individual patients and do not address other community services and interventions that are essential to STD/human immunodeficiency virus (HIV) prevention efforts. # Methods These guidelines were developed using a multistage process. Beginning in 2008, CDC staff members and public and private sector experts knowledgeable in the field of STDs systematically reviewed literature using an evidence-based approach (e.g., published abstracts and peer-reviewed journal articles), focusing on the common STDs and information that had become available since publication of the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (1). CDC staff members and STD experts developed background papers and tables of evidence that summarized the type of study (e.g., randomized controlled trial or case series), study population and setting, treatments or other interventions, outcome measures assessed, reported findings, and weaknesses and biases in study design and analysis. CDC staff then developed a draft document on the basis of this evidence-based review. In April 2009, this information was presented at a meeting of invited consultants (including public-and private-sector professionals knowledgeable in the treatment of patients with STDs), where all evidence from the literature reviews pertaining to STD management was discussed. Specifically, participants identified key questions regarding STD treatment that emerged from the literature reviews and discussed the information available to answer those questions. Discussion focused on four principal outcomes of STD therapy for each individual disease: 1) treatment of infection based on microbiologic eradication; 2) alleviation of signs and symptoms; 3) prevention of sequelae; and 4) prevention of transmission. Cost-effectiveness and other advantages (e.g., single-dose formulations and directly observed therapy ) of specific regimens also were discussed. The consultants then assessed whether the questions identified were relevant, ranked them in order of priority, and answered the questions using the available evidence. In addition, the consultants evaluated the quality of evidence supporting the answers on the basis of the number, type, and quality of the studies. The sections on hepatitis B virus (HBV) and hepatitis A virus (HAV) infections are based on previously published recommendations of the Advisory Committee on Immunization Practices (ACIP) (2)(3)(4). The recommendations for STD screening during pregnancy and cervical cancer screening were developed after CDC staff reviewed the published recommendations from other professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), United States Preventive Services Task Force (USPSTF), and ACIP. Throughout this report, the evidence used as the basis for specific recommendations is discussed briefly. More comprehensive, annotated discussions of such evidence will appear in background papers that will be published in a supplement issue of the journal Clinical Infectious Diseases. When more than one therapeutic regimen is recommended, the sequence is alphabetized unless the choices for therapy are prioritized based on efficacy, convenience, or cost. For those infections with more than one recommended regimen, almost all regimens have similar efficacy and similar rates of intolerance or toxicity unless otherwise specified. Recommended regimens should be used primarily; alternative regimens can be considered in instances of significant drug allergy or other contraindications to the recommended regimens. # Clinical Prevention Guidance The prevention and control of STDs are based on the following five major strategies: - education and counseling of persons at risk on ways to avoid STDs through changes in sexual behaviors and use of recommended prevention services; - identification of asymptomatically infected persons and of symptomatic persons unlikely to seek diagnostic and treatment services; - effective diagnosis, treatment, and counseling of infected persons; - evaluation, treatment, and counseling of sex partners of persons who are infected with an STD; and - pre-exposure vaccination of persons at risk for vaccinepreventable STDs. Primary prevention of STDs begins with changing the sexual behaviors that place persons at risk for infection. Health-care providers have a unique opportunity to provide education and counseling to their patients (5,6). As part of the clinical interview, health-care providers should routinely and regularly obtain sexual histories from their patients and address management of risk reduction as indicated in this report. Guidance in obtaining a sexual history is available in Contraceptive Technology, 19th edition (7) and in the curriculum provided by CDC's STD/ HIV Prevention Training Centers (). Effective interviewing and counseling skills, characterized by respect, compassion, and a nonjudgmental attitude toward all patients, are essential to obtaining a thorough sexual history and to delivering prevention messages effectively. Key techniques that can be effective in facilitating rapport with patients include the use of 1) open-ended questions (e.g., "Tell me about any new sex partners you've had since your last visit," and "What's your experience with using condoms been like?"); 2) understandable language ("Have you ever had a sore or scab on your penis?"); and 3) normalizing language ("Some of my patients have difficulty using a condom with every sex act. How is it for you?"). The "Five P's" approach to obtaining a sexual history is an example of an effective strategy for eliciting information concerning five key areas of interest (Box 1). Efforts should be made to ensure that all patients are treated regardless of individual circumstances (e.g., ability to pay, citizenship or immigration status, language spoken, or specific sex practices). Patients seeking treatment or screening for a particular STD should be evaluated for all common STDs. All patients should be informed about all the STDs for which they are being tested and notified about tests for common STDs (e.g., genital herpes) that are available but not being performed. # STD/HIV Prevention Counseling USPSTF recommends high-intensity behavioral counseling for all sexually active adolescents and for adults at increased risk for STDs and HIV (5,6). All providers should routinely obtain a sexual history from their patients and encourage riskreduction using various strategies; effective delivery of prevention messages requires that providers communicate general riskreduction messages relevant to the client and that providers educate the client about specific actions that can reduce the risk for STD/HIV transmission (e.g., abstinence, condom use, limiting the number of sex partners, modifying sexual practices, and vaccination), each of which is discussed separately in this report (see Prevention Methods). Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the patient's culture, language, sex, sexual orientation, age, and developmental level. Interactive counseling approaches directed at a patient's personal risk, the situations in which risk occurs, and the use of personalized goal-setting strategies are effective in STD/ HIV prevention (5,6). One such approach, known as clientcentered STD/HIV prevention counseling, involves tailoring a discussion of risk reduction to the patient's individual situation. Client-centered counseling can increase the likelihood that the patient undertakes or enhances current risk-reduction practices, especially among persons seeking STD care. One such approach, known as Project RESPECT, demonstrated that a brief counseling intervention led to a reduced frequency of STD/HIV riskrelated behaviors and resulted in lowered acquisition rates for curable STDs, including trichomoniasis, chlamydia, gonorrhea, and syphilis (8,9). Practice models based on Project RESPECT have been successfully implemented in clinic-based settings. Other approaches use motivational interviewing to move clients toward achievable risk reduction goals. CDC provides additional information on these and other effective behavioral interventions at . Interactive counseling can be used effectively by all healthcare providers, counselors, and other clinical staff trained in counseling approaches. Extensive training is not a prerequisite for effective risk reduction counseling; however, the quality of counseling is improved when providers receive training in prevention counseling methods and skill-building approaches, providers are periodically observed when providing counseling and given immediate feedback by persons with expertise in the counseling approach, counselors are periodically evaluated and patients asked to evaluate their level of satisfaction, and providers have access to expert assistance or referral for challenging situations. Training in client-centered counseling is available through the CDC STD/HIV Prevention Training Centers (). In addition to individual prevention counseling, videos and large group presentations can provide explicit information concerning STDs and instruction to reduce disease transmission (e.g., how to use condoms correctly). Group-based strategies have been effective in reducing the occurrence of additional STDs among persons at high risk, including those attending STD clinics (10). Because the incidence of some STDs, notably syphilis, is higher in HIV-infected persons, the use of client-centered STD counseling for HIV-infected persons has been strongly encouraged by public health agencies and other health organizations. Consensus guidelines issued by CDC, the Health Resources and Services Administration, the HIV Medicine Association of the Infectious Diseases Society of America, and the National Institutes of Health emphasize that STD/HIV risk assessment, # Partners - "Do you have sex with men, women, or both?" - "In the past 2 months, how many partners have you had sex with?" - "In the past 12 months, how many partners have you had sex with?" - "Is it possible that any of your sex partners in the past 12 months had sex with someone else while they were still in a sexual relationship with you?" 2. Prevention of pregnancy - "What are you doing to prevent pregnancy?" 3. Protection from STDs - "What do you do to protect yourself from STDs and HIV?" 4. Practices - "To understand your risks for STDs, I need to understand the kind of sex you have had recently." - "Have you had vaginal sex, meaning 'penis in vagina sex'?" If yes, "Do you use condoms: never, sometimes, or always?" - "Have you had anal sex, meaning 'penis in rectum/ anus sex'?" If yes, "Do you use condoms: never, sometimes, or always?" - "Have you had oral sex, meaning 'mouth on penis/ vagina'?" For condom answers: - If "never:" "Why don't you use condoms?" - If "sometimes:" "In what situations (or with whom) do you not use condoms?" 5. Past history of STDs - "Have you ever had an STD?" - "Have any of your partners had an STD?" Additional questions to identify HIV and viral hepatitis risk include: - "Have you or any of your partners ever injected drugs?" - "Have any of your partners exchanged money or drugs for sex?" - "Is there anything else about your sexual practices that I need to know about?" STD screening, and client-centered risk reduction counseling should be provided routinely to HIV-infected persons (11). Several specific methods have been designed for the HIV care setting (12)(13)(14), and additional information regarding these approaches is available at . # Prevention Methods # Abstinence and Reduction of number of Sex Partners A reliable way to avoid transmission of STDs is to abstain from oral, vaginal, and anal sex or to be in a long-term, mutually monogamous relationship with an uninfected partner. For persons who are being treated for an STD (or whose partners are undergoing treatment), counseling that encourages abstinence from sexual intercourse until completion of the entire course of medication is crucial. A more comprehensive discussion of abstinence and other sexual practices than can help persons reduce their risk for STDs is available in Contraceptive Technology, 19th Edition (7). For persons embarking on a mutually monogamous relationship, screening for common STDs before initiating sex might reduce the risk for future disease transmission. # Pre-exposure Vaccination Pre-exposure vaccination is one of the most effective methods for preventing transmission of some STDs. Two human papillomavirus (HPV) vaccines are available for females aged 9-26 years to prevent cervical precancer and cancer (15,16): the quadrivalent HPV vaccine (Gardasil) and the bivalent HPV vaccine (Cervarix). Gardasil also prevents genital warts. Routine vaccination of females aged 11 or 12 years is recommended with either vaccine, as is catch-up vaccination for females aged 13-26 years. Gardasil can be administered to males aged 9-26 years to prevent genital warts (17). Details regarding HPV vaccination are available at www.cdc.gov/std/hpv. Hepatitis B vaccination is recommended for all unvaccinated, uninfected persons being evaluated for an STD (3,4). In addition, hepatitis A and B vaccines are recommended for men who have sex with men (MSM) and injection-drug users (IDUs) (2)(3)(4); each of these vaccines should also be administered to HIV-infected persons who have not yet been infected with one or both types of hepatitis virus. Details regarding hepatitis A and B vaccination are available at . gov/hepatitis. # Male Condoms When used consistently and correctly, male latex condoms are highly effective in preventing the sexual transmission of HIV infection. In heterosexual serodiscordant relationships (i.e., those involving one infected and one uninfected partner) in which condoms were consistently used, HIV-negative partners were 80% less likely to become HIV-infected compared with persons in similar relationships in which condoms were not used (18). Moreover, studies show condoms can reduce the risk for other STDs, including chlamydia, gonorrhea, and trichomoniasis; by limiting lower genital tract infections, condoms also might reduce the risk for women developing pelvic inflammatory disease (PID) (19,20). In addition, consistent and correct use of latex condoms also reduces the risk for genital herpes, syphilis, and chancroid when the infected area or site of potential exposure is covered, although data for this effect are more limited (21)(22)(23)(24). Additional information is available at www.cdc.gov/condomeffectiveness/latex.htm. Cohort studies have demonstrated that condoms protect against the acquisition of genital HPV infection. A prospective study among newly sexually active women who were attending college demonstrated that consistent and correct condom use was associated with a 70% reduction in risk for HPV transmission (25). Use of condoms also appears to reduce the risk for HPV-associated diseases (e.g., genital warts and cervical cancer) and mitigate the adverse consequences of infection with HPV. Condom use has been associated with higher rates of regression of cervical intraepithelial neoplasia (CIN) and clearance of HPV infection in women (26) and with regression of HPV-associated penile lesions in men (27). Condoms are regulated as medical devices and are subject to random sampling and testing by the U.S. Food and Drug Administration (FDA). Each latex condom manufactured in the United States is tested electronically for holes before packaging. Rates of condom breakage during sexual intercourse and withdrawal are approximately two broken condoms per 100 condoms used in the United States. The failure of condoms to protect against STD transmission or unintended pregnancy usually results from inconsistent or incorrect use rather than condom breakage (28). Male condoms made of materials other than latex are available in the United States. Two general categories of nonlatex condoms exist. The first type is made of polyurethane or other synthetic material and provides protection against STDs/HIV and pregnancy equal to that of latex condoms (29). These can be substituted for latex condoms by persons with latex allergy. Although they have had higher breakage and slippage rates when compared with latex condoms and are usually more costly, the pregnancy rates among women whose partners use these condoms are similar to those asociated with use of latex condoms (30). The second type is natural membrane condoms (frequently called "natural" condoms or, incorrectly, "lambskin" condoms). These condoms are usually made from lamb cecum and can have pores up to 1,500 nm in diameter. Although these pores do not allow the passage of sperm, they are more than 10 times the diameter of HIV and more than 25 times that of HBV (29). Moreover, laboratory studies demonstrate that viral STD transmission can occur with natural membrane condoms (29). Use of natural membrane condoms for prevention of STDs is not recommended. Providers should advise their patients that condoms must be used consistently and correctly to be effective in preventing STDs; providing instructions about the correct use of condoms can be useful. Communicating the following recommendations can help ensure that patients use male condoms correctly: - Use a new condom with each sex act (i.e., oral, vaginal, and anal). - Carefully handle the condom to avoid damaging it with fingernails, teeth, or other sharp objects. - Put the condom on after the penis is erect and before any genital, oral, or anal contact with the partner. - Use only water-based lubricants (e.g., K-Y Jelly, Astroglide, AquaLube, and glycerin) with latex condoms. Oil-based lubricants (e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, and cooking oil) can weaken latex and should not be used. - Ensure adequate lubrication during vaginal and anal sex, which might require the use of exogenous water-based lubricants. - To prevent the condom from slipping off, hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect. # Female Condoms Laboratory studies indicate that the female condom (Reality) is an effective mechanical barrier to viruses, including HIV, and to semen. The first female condom approved for use in the United States consisted of a lubricated polyurethane sheath with a ring on each end that is inserted into the vagina. A newer version made from nitrile is now available in the United States. A limited number of clinical studies have evaluated the efficacy of female condoms in providing protection from STDs, including HIV (31,32). Although female condoms are costly compared with male condoms, sex partners should consider using a female condom when a male condom cannot be used properly. The female condom also has been used for STDs/HIV protection during receptive anal intercourse (33); although it might provide some protection in this setting, its efficacy remains unknown. # Cervical Diaphragms In observational studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis (34). A recent trial examined the effect of use of a diaphragm plus polycarbophil (Replens) lubricant on HIV acquisition in women in Africa relative to male condom use alone. The study revealed that neither the diaphragm nor the lubricant gel provided additional protective effect when compared with the use of condoms alone (35). Likewise, no difference by study arm in the rate of acquisition of chlamydia or gonorrhea occurred; however, data from participants who reported following the protocol for the use of these products suggested that consistent use of the diaphragm plus gel might reduce acquisition of gonorrhea (36). Diaphragms should not be relied on as the sole source of protection against HIV infection. Diaphragm and nonoxynol-9 (N-9) spermicide use have been associated with an increased risk for bacterial urinary-tract infections in women (37). # Topical Microbicides and Spermicides Studies examining nonspecific topical microbicides for the prevention of HIV and STD have demonstrated that these products are ineffective (38,39). Studies of spermicides containing N-9 have demonstrated that they should not be recommended for STDs/HIV prevention (40), and more recent randomized controlled trials have failed to show a protective effect against HIV acquisition for BufferGel (a vaginal buffering agent), Carraguard (a carrageenan derivative) (41), cellulose sulfate (an HIV entry inhibitor), (42) and SAVVY (1.0% C31G, a surfactant) (43,44). Initial results from a study in which participants used 0.5% PRO2000 vaginal gel (a synthetic polyanion polymer that blocks cellular entry of HIV) on a daily basis appeared promising, reducing the rate of HIV acquisition by 30% relative to no gel (45). However, a recent randomized trial of approximately 9,000 women failed to show any protective effect (46). Topical antiretroviral agents for the prevention of HIV appear more promising. Use of tenofovir gel during sexual intercourse significantly reduced the rate of HIV acquisition (i.e., by 39%) in a study of South African women (47). Additional studies are being undertaken to elucidate the optimal dosing regimens for this drug. Other products remain under study, including VivaGel, a topical vaginal microbicide. A list of products under development is maintained by the Alliance for Microbicide Development at www.microbicide.org. # Condoms and n-9 Vaginal Spermicides Condoms lubricated with spermicides are no more effective than other lubricated condoms in protecting against the transmission of HIV and other STDs (www.cdc.gov/condomeffectiveness/latex.htm). Furthermore, frequent use of spermicides containing N-9 has been associated with disruption of the genital epithelium, which might be associated with an increased risk for HIV transmission (40). Therefore, use of condoms lubricated with N-9 is not recommended for STD/ HIV prevention; in addition, spermicide-coated condoms cost more, have a shorter shelf-life than other lubricated condoms, and have been associated with urinary-tract infection in young women (37). # Rectal Use of n-9 Spermicides N-9 can damage the cells lining the rectum, which might provide a portal of entry for HIV and other sexually transmissible agents. Therefore, it should not used as a microbicide or lubricant during anal intercourse by MSM or by women. # nonbarrier Contraception, Surgical Sterilization, and Hysterectomy Contraceptive methods that are not mechanical barriers offer no protection against HIV or other STDs. Sexually active women who use hormonal contraception (i.e., oral contraceptives, Norplant, and Depo-Provera), have intrauterine devices (IUDs), have been surgically sterilized, or have had hysterectomies should be counseled regarding the use of condoms and the risk for STDs, including HIV infection, because these women might incorrectly perceive that they are not at risk for these diseases. Women who take oral contraceptives and are prescribed certain antibiotics should be counseled about potential interactions (7). # Male Circumcision Although male circumcision should not be substituted for other HIV risk-reduction strategies, it has been shown to reduce the risk for HIV and some STDs in heterosexual men. Three randomized, controlled trials performed in regions of sub-Saharan Africa where generalized HIV epidemics involving predominantly heterosexual transmission were occurring demonstrated that male circumcision reduced the risk for HIV acquisition among men by 50%-60% (48)(49)(50). In these trials, circumcision was also protective against other STDs, including high-risk genital HPV infection and genital herpes (51)(52)(53)(54). Despite these data, male circumcision has not been demonstrated to reduce the risk for HIV or other STDs among MSM (55). The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have recommended that male circumcision be scaled up as an effective intervention for the prevention of heterosexually acquired HIV infection (56). These organizations also recommend that countries with hyperendemic and generalized HIV epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support. Similar recommendations have not been made in the United States, although evidence regarding the role of male circumcision in the prevention of HIV/ AIDS is under review (57). # Emergency Contraception (EC) Women who might have been exposed to STDs during a recent act of unprotected intercourse also are at risk for pregnancy. Providers managing such women should offer counseling about the option of EC if pregnancy is not desired. In the United States, EC products are available over-the-counter to women aged ≥17 years and by prescription to younger women. If these EC pill products are not readily accessible, many commonly available brands of oral contraceptive pills can effectively provide EC, but women must be instructed to take an appropriate and specified number of tablets at one time. All oral EC regimens are efficacious when initiated as soon as possible after unprotected sex, but have some efficacy as long as 5 days later. EC is ineffective (but is also not harmful) if the woman is already pregnant (58). More information about EC is available in the 19th edition of Contraceptive Technology (7) or . Insertion of an IUD up to 7 days after unprotected sex can reduce pregnancy risk by more than 99% (7). However, this method is not advisable for a woman who may have untreated cervical gonorrhea or chlamydia, who is already pregnant, or who has other contraindications to IUD use. # Postexposure Prophylaxis (PEP) for HIV and STD Guidelines for the use of PEP aimed at preventing HIV infection as a result of sexual exposure are available and are discussed in this report (see Sexual Assault and STDs). Genital hygiene methods (e.g., vaginal washing and douching) after sexual exposure are ineffective in protecting against HIV and STD and might increase the risk for bacterial vaginosis, some STDs, and HIV (59). # Pre-exposure Prophylaxis (PrEP) for HIV and STD Antiretroviral therapy (ART) has the potential to impact transmission and acquisition of HIV. In HIV-infected persons, ART reduces viral load and presumably reduces infectiousness (60). In HIV-uninfected persons, ART might reduce susceptibility to infection, a concept supported both by animal studies and by a study of safety and acceptability involving West African women (61,62). A randomized, placebo-controlled trial involving South African women recently demonstrated that use of tenofovir gel associated with sexual intercourse significantly reduced the rate of HIV and herpes simplex virus type 2 (HSV-2) acquisition by 39% and 51%, respectively (47,63). Several large randomized controlled trials of PrEP are either underway or planned. These involve the oral use of non-nucleoside reverse transcriptase inhibitors (tenofovir or tenofovir-emtricitabine) or vaginal use of 1% tenofovir gel. # Retesting to Detect Repeat Infections Retesting several months after a diagnosis of chlamydia or gonorrhea can detect repeat infection and potentially can be used to enhance population-based prevention (64). Further details on retesting can be found in the specific sections on chlamydia and gonorrhea within this report. # Partner Management Partner management refers to a continuum of activities designed to increase the number of infected persons brought to treatment and disrupt transmission networks. Part of this continuum is partner notification -the process by which providers or public health authorities learn about the sex-and needle-sharing partners of infected patients and help to arrange for partner evaluation and treatment. Clinical-care providers can obtain this information and help to arrange for evaluation and treatment of sex partners directly or by cooperating with state and local health departments. The types and comprehensiveness of existing partner services and the specific STDs for which they are offered vary by provider, public health agency, and geographic area. Ideally, persons referred to such services should also receive health counseling and should be referred for other health services as appropriate. Data are limited regarding whether partner notification effectively decreases exposure to STDs and whether it reduces the incidence and prevalence of these infections in a community. Nevertheless, evaluations of partner notification interventions have documented the important contribution this approach can make to case-finding in clinical and community contexts (65). When partners are treated, index patients have reduced risk for reinfection. Therefore, providers should encourage persons with STDs to notify their sex partners and urge them to seek medical evaluation and treatment. Further, providers can ask patients to bring partners with them when returning for treatment. Time spent with index patients to counsel them on the importance of notifying partners is associated with improved notification outcomes (66). When patients diagnosed with chlamydia or gonorrhea indicate that their partners are unlikely to seek evaluation and treatment, providers can offer patient-delivered partner therapy (PDPT), a form of expedited partner therapy (EPT) in which partners of infected persons are treated without previous medical evaluation or prevention counseling. Because EPT might be prohibited in some states and is the topic of ongoing legislation in others (67), providers should visit www.cdc.gov/std/ept to obtain updated information for their individual jurisdiction. Any medication or prescription provided for PDPT should be accompanied by treatment instructions, appropriate warnings about taking medications (if the partner is pregnant or has an allergy to the medication), general health counseling, and a statement advising that partners seek personal medical evaluation, particularly women with symptoms of STDs or PID. The evidence supporting PDPT is based on three clinical trials that included heterosexual men and women with chlamydia or gonorrhea. The trials and meta-analyses revealed that the magnitude of reduction in reinfection of index case-patients compared with patient referral differed according to the STD and the sex of the index case-patient (68)(69)(70)(71). However, across trials, reductions in chlamydia prevalence at follow-up were approximately 20%; reductions in gonorrhea at follow-up were approximately 50%. Rates of notification increased in some trials and were equivalent to patient referral without PDPT in others. Existing data suggest that PDPT also might have a role in partner management for trichomoniasis; however, no single partner management intervention has been shown to be more effective than any other in reducing reinfection rates (72,73). No data support the use of PDPT in the routine management of patients with syphilis. No studies have been published involving PDPT for gonorrhea or chlamydia among MSM. Public health program involvement with partner notification services varies by locale and by STD. Some programs have considered partner notification in a broader context, developing interventions to address sexual and social networks in which persons are exposed to STDs. Prospective evaluations incorporating the assessment of venues, community structure, and social and sexual contacts in conjunction with partner notification efforts have improved case-finding and illustrated transmission networks (74,75). While such efforts are beyond the scope of individual clinicians, support of and collaboration with STD programs by clinicians are critical to the success of social network-based interventions. Certain evidence supports the use of the internet to facilitate partner notification (76), especially among MSM and in cases where no other identifying information is available, and many health departments now conduct formal internet partner notification (IPN) (/ wysiwyg/documents/NGuidelinesforInternet.htm). Clinical providers are unlikely to participate directly in IPN. However, when discussing partner notification approaches with patients, they should be aware of the value of the internet in this type of communication and should know where to refer patients who are interested in using the internet to notify partners about their diagnosis. # Reporting and Confidentiality The accurate and timely reporting of STDs is integral to efforts to assess morbidity trends, allocate limited resources, and assist local health authorities in partner notification and treatment. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with state and local statutory requirements. Syphilis, gonorrhea, chlamydia, chancroid, HIV infection, and AIDS are reportable diseases in every state. Because the requirements for reporting other STDs differ by state, clinicians should be familiar with the reporting requirements applicable within their jurisdictions. Reporting can be provider-or laboratory-based. Clinicians who are unsure of state and local reporting requirements should seek advice from state or local health departments or STD programs. STDs and HIV reports are kept strictly confidential. In most jurisdictions, such reports are protected by statute from subpoena. Before conducting a follow-up of a positive STD-test result, public health professionals should consult the patient's health-care provider to verify the diagnosis and to determine the treatments being received. # Special Populations Pregnant Women Intrauterine or perinatally transmitted STDs can have severely debilitating effects on pregnant women, their partners, and their fetuses. All pregnant women and their sex partners should be asked about STDs, counseled about the possibility of perinatal infections, and provided access to treatment, if needed. # Recommended Screening Tests - All pregnant women in the United States should be screened for HIV infection as early in pregnancy as possible (77). Screening should be conducted after the woman is notified that she will be screened for HIV as part of the routine panel of prenatal tests, unless she declines (i.e., opt-out screening). For women who decline HIV testing, providers should address their objections, and when appropriate, continue to encourage testing strongly. Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy. Testing pregnant women and treating those who are infected are vital not only to maintain the health of the patient, but to reduce perinatal transmission of HIV through available antiretroviral and obstetrical interventions. Retesting in the third trimester (preferably before 36 weeks' gestation) is recommended for women at high risk for acquiring HIV infection (e.g., women who use illicit drugs, have STDs during pregnancy, have multiple sex partners during pregnancy, live in areas with high HIV prevalence, or have HIV-infected partners). Rapid HIV screening should be performed on any woman in labor who has an undocumented HIV status unless she declines. If a rapid HIV test result is positive in these women, antiretroviral prophylaxis should be administered without waiting for the results of the confirmatory test (78). - A serologic test for syphilis should be performed on all pregnant women at the first prenatal visit (79). In populations in which the amount of prenatal care delivered is not optimal, rapid plasma reagin (RPR) card test screening (and treatment, if that test is reactive) should be performed at the time that a pregnancy is confirmed. Women who are at high risk for syphilis, live in areas of high syphilis morbidity, or are previously untested should be screened again early in the third trimester (at approximately 28 weeks' gestation) and at delivery. Some states require all women to be screened at delivery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a stillborn infant should be tested for syphilis. - All pregnant women should be routinely tested for hepatitis B surface antigen (HBsAg) during an early prenatal visit (i.e., a visit during the first trimester), even if they have been previously vaccinated or tested (80). Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infection (e.g., having had more than one sex partner in the previous 6 months, evaluation or treatment for an STD, recent or current injection-drug use, and an HBsAg-positive sex partner) and those with clinical hepatitis should be retested at the time of admission to the hospital for delivery. Pregnant women at risk for HBV infection also should be vaccinated. (83,84). -ther Tests - Evidence does not support routine testing for bacterial vaginosis (BV) in pregnancy. For asymptomatic pregnant women at high risk for preterm delivery, evidence is insufficient to assess the balance of benefits and harms of screening for BV (85). Symptomatic women should be evaluated and treated (see Bacterial Vaginosis). (85). Recommendations to screen pregnant women for STDs are based on disease severity and sequelae, prevalence in the population, costs, medicolegal considerations (e.g., state laws), and other factors. The screening recommendations in this report are generally broader (i.e., if followed, more women will be screened for more STDs than would by following other screening recommendations) and are also consistent with other CDC guidelines. # Adolescents In the United States, prevalence rates of many sexually acquired infections are highest among adolescents (92,93). For example, the reported rates of chlamydia and gonorrhea are highest among females aged 15-19 years, and many persons acquire HPV infection during their adolescent years. Persons who initiate sex early in adolescence are at higher risk for STDs, along with persons residing in detention facilities, attending STD clinics, young men having sex with men (YMSM), and youth who use injection drugs. Factors contributing to this increased risk during adolescence include having multiple sexual partners concurrently, having sequential sexual partnerships of limited duration, failing to use barrier protection consistently and correctly, having increased biologic susceptibility to infection, and experiencing multiple obstacles to accessing health care (92). All 50 states and the District of Columbia explicitly allow minors to consent for their own health services for STDs. No state requires parental consent for STD care or requires that providers notify parents that an adolescent minor has received STD services, except in limited or unusual circumstances. Protecting confidentiality for such care, particularly for adolescents enrolled in private health insurance plans, presents multiple problems. After a claim has been reported, many states mandate that health plans provide a written statement to a beneficiary indicating the benefits and charges covered or not covered by the health plan (i.e., explanation of benefit ). In addition, federal laws obligate notices to beneficiaries when claims are denied, including alerting consumers who need to pay for care until the allowable deductable is reached. For STD detection-and treatment-related care, an EOB or medical bill that is received by a parent might disclose services provided and list any laboratory tests performed. This type of mandated notification breeches confidentiality, and at a minimum, could prompt parents and guardians to question the costs and reasons for service provision. Despite the high rates of infections documented in the adolescent population, providers frequently fail to inquire about sexual behaviors, assess STD risks, provide risk reduction counseling, and ultimately, fail to screen for asymptomatic infections during clinical encounters. Sexual health discussions should be appropriate for the patient's developmental level and should be aimed at identifying risk behaviors (e.g., unprotected oral, anal, or vaginal sex and drug-use behaviors). Careful, nonjudgmental, and thorough counseling is particularly vital for adolescents who might not feel comfortable acknowledging their engagement in behaviors that place them at high risk for STDs. # Screening Recommendations Routine laboratory screening for common STDs is indicated for sexually active adolescents. The following screening recommendations summarize published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents: - Routine screening for C. trachomatis of all sexually active females aged ≤25 years is recommended annually (81). Evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men based on feasibility, efficacy, and cost-effectiveness. However, screening of sexually active young men should be considered in clinical settings associated with high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics) (81,94). - Routine screening for N. gonorrhoeae in all sexually active women at risk for infection is recommended annually (82). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors that place women at increased risk include a previous gonorrhea infection, the presence of other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. - HIV screening should be discussed with all adolescents and encouraged for those who are sexually active and those who use injection drugs (77,95). - The routine screening of adolescents who are asymptomatic for certain STDs (e.g., syphilis, trichomoniasis, BV, HSV, HPV, HAV, and HBV) is not recommended. However, YMSM and pregnant adolescent females might require more thorough evaluation. - Guidelines from USPSTF and ACOG recommend that cervical cancer screening begin at age 21 years (96,97), a recommendation based on the low incidence of cervical cancer and limited utility of screening for younger adolescents (98). However, the American Cancer Society (ACS) recommends that women start cervical screening with Pap tests 3 years after initiating sexual activity, but by no later than age 21 years (99). # Primary Prevention Recommendations Primary prevention and anticipatory guidance to recognize symptoms and behaviors associated with STDs are strategies that can be incorporated into any or all types of health-care visits. The following recommendations for primary prevention of STDs (i.e., vaccination and counseling) are based on published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents: - The HPV vaccine, either Cervarix or Gardasil, is recommended for 11 and 12 year-old females. The vaccine series can be started at 9 years of age. Catch-up vaccination is recommended for females aged 13-26 years who have not yet received or completed the vaccine series (16). The quadrivalent (Gardasil) HPV vaccine can also be used in males and females aged 9-26 years to prevent genital warts (17). (6). # Children Management of children who have STDs requires close cooperation between clinicians, laboratorians, and childprotection authorities. Official investigations, when indicated, should be initiated promptly. Certain diseases (e.g., gonorrhea, syphilis, and chlamydia), if acquired after the neonatal period, are virtually 100% indicative of sexual contact. For other diseases (e.g., HPV infections and vaginitis), the association with sexual contact is not as clear (see Sexual Assault and STDs). # Persons in Correctional Facilities Multiple studies have demonstrated that persons entering correctional facilities have high rates of STDs (including HIV) and viral hepatitis, especially those aged ≤35 years (93). Incarcerated persons are more likely to have low socioeconomic status, live in urban areas, and be ethnic and racial minorities. Risk behaviors for contracting STDs (e.g., having unprotected sex; having multiple sexual partners; using drugs and alcohol; and engaging in commercial, survival , or coerced sex) are common among incarcerated populations. Before incarceration, many have had limited access to medical care, especially to community-based clinical prevention services. Although no comprehensive national guidelines regarding STD care and management have been developed for correctional populations, the utility of expanded STD services in correctional settings has been reported (100). Capacity to provide STD care also varies by type of correctional facility. For example, local juvenile detention facilities and jails are shortterm facilities (often housing entrants for ≤1 year) where up to half of all entrants are released back to the community within 48 hours of arrest, thereby complicating efforts to provide comprehensive STD services. These services are likely more conducive to prisons and state juvenile confinement facilities, which are long-term, secure facilities where entrants are held for a longer period of time. Most institutions, especially those for adults, do not routinely screen for STDs. Diagnostic testing of inmates with symptoms indicative of an STD is the more common practice in juvenile detention and jail facilities. However, screening for asymptomatic infections facilitates the identification and MMWR December 17, 2010 treatment of persons with otherwise undetected infections, which not only eliminates complications for the individual, but reduces the prevalence of infection among detainees who are released back into the local community. Females in juvenile detention facilities and young women ≤35 years of age have been reported to have high rates of chlamydia (101) and gonorrhea (93). Syphilis seroprevalence rates, which can indicate previous infection, are considerably higher among adult men and women than in adolescents, consistent with the overall national syphilis trends (102). # Chlamydia and Gonorrhea Screening Universal screening of adolescent females for chlamydia and gonorrhea should be conducted at intake in juvenile detention or jail facilities. Universal screening of adult females should be conducted at intake among adult females up to 35 years of age (or on the basis of local institutional prevalence data). # Syphilis Screening Universal screening should be conducted on the basis of the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis. # MSM Subgroups of MSM are at high risk for HIV infection and other viral and bacterial STDs. The frequency of unsafe sexual practices and the reported rates of bacterial STDs and incident HIV infection declined substantially in MSM from the 1980s through the mid-1990s. However, since that time, increased rates of early syphilis (primary, secondary, or early latent), gonorrhea, and chlamydial infection and higher rates of unsafe sexual behaviors have been documented among MSM in the United States and virtually all industrialized countries (103,104). The effect of these behavioral changes on HIV transmission has not been ascertained, but preliminary data suggest that the incidence of HIV infection is increasing among MSM in some urban centers, particularly among MSM from racial and ethnic minority groups (105) and among those who use nonprescription drugs during sex, particularly methamphetamine and volatile nitrites (also known as "poppers"). These adverse trends likely reflect the 1) changing attitudes concerning HIV infection that have accompanied advances in HIV therapy, resulting in improved quality of life and survival for HIV-infected persons; 2) changing patterns of substance abuse; 3) demographic shifts in MSM populations; and 4) changes in sex partner networks resulting from new venues for partner acquisition (e.g., the internet). Increases in bacterial STDs are not necessarily accompanied by increases in HIV incidence; for example, oral sex may permit efficient spread of bacterial STDs but not HIV, as does serosorting (preferential selection of sex partners of the same serostatus) among HIV-infected MSM (106,107). Clinicians should assess the STD-related risks for all male patients, including a routine inquiry about the sex of sex partners. MSM, including those with HIV infection, should routinely undergo nonjudgmental STD/HIV risk assessment and client-centered prevention counseling to reduce the likelihood of acquiring or transmitting HIV or other STDs. Clinicians should be familiar with the local community resources available to assist MSM at high risk in facilitating behavioral change and to enable the conduct of partner notification activities. Clinicians also should routinely ask sexually active MSM about symptoms consistent with common STDs, including urethral discharge, dysuria, genital and perianal ulcers, regional lymphadenopathy, skin rash, and anorectal symptoms consistent with proctitis, including discharge and pain on defecation or during anal intercourse. Clinicians should perform appropriate diagnostic testing on all symptomatic patients. Routine laboratory screening for common STDs is indicated for all sexually active MSM. The following screening tests should be performed at least annually for sexually active MSM: - HIV serology, if HIV negative or not tested within the previous year; - syphilis serology, with a confirmatory testing to establish whether persons with reactive serologies have incident untreated syphilis, have partially treated syphilis, or are manifesting a slow serologic response to appropriate prior therapy; - a test for urethral infection with N. gonorrhoeae and C. trachomatis in men who have had insertive intercourse † during the preceding year; testing of the urine using nucleic acid amplification testing (NAAT) is the preferred approach; - a test for rectal infection § with N. gonorrhoeae and C. trachomatis in men who have had receptive anal intercourse † during the preceding year (NAAT of a rectal swab is the preferred approach); and - a test for pharyngeal infection § with N. gonorrhoeae in men who have had receptive oral intercourse † during the preceding year (NAAT is the preferred approach). Testing for C. trachomatis pharyngeal infection is not recommended. Evaluation for HSV-2 infection with type-specific serologic tests also can be considered if infection status is unknown; knowledge of HSV-2 serostatus might be helpful in identifying persons with previously undiagnosed genital tract infection. † Regardless of history of condom use during exposure. § Commercially available NAATS are not FDA cleared for these indications, but they can be used by laboratories that have met all regulatory requirements for an off-label procedure. Because of the increased incidence of anal cancer in HIVinfected MSM, screening for anal cytologic abnormalities can be considered; however, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic support needed for such a screening activity. More frequent STD screening (i.e., at 3-6-month intervals) is indicated for MSM who have multiple or anonymous partners. In addition, MSM who have sex in conjunction with illicit drug use (particularly methamphetamine use) or whose sex partners participate in these activities should be screened more frequently. All MSM should be tested for HBsAg to detect HBV infection. Prompt identification of chronic infection with HBV is essential to ensure necessary care and services to prevent transmission to others (108). HBsAg testing should be made available in STD treatment settings. In addition, screening among past or current drug users should include HCV and HBV testing. Vaccination against hepatitis A and B is recommended for all MSM in whom previous infection or vaccination cannot be documented (2,3). Preimmunization serologic testing might be considered to reduce the cost of vaccinating MSM who are already immune to these infections, but this testing should not delay vaccination. Vaccinating persons who are immune to HAV or HBV infection because of previous infection or vaccination does not increase the risk for vaccine-related adverse events (see Hepatitis B, Prevaccination Antibody Screening). Sexual transmission of hepatitis C virus infection can occur, especially among HIV-infected MSM. Serologic screening for hepatitis C infection is recommended at initial evaluation of newly diagnosed HIV-infected persons. HIV-infected MSM can also acquire HCV after initial screening; therefore, men with new and unexplained increases in alanine aminotransferase (ALT) should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. # Women Who Have Sex with Women Women who have sex with women (WSW) are a diverse group with variations in sexual identity, sexual behaviors, sexual practices, and risk behaviors. Recent studies indicate that some WSW, particularly adolescents, young women, and women with both male and female partners, might be at increased risk for STDs and HIV as a result of certain reported risk behaviors (109)(110)(111)(112). WSW are at risk for acquiring bacterial, viral, and protozoal infections from current and prior partners, both male and female. WSW should not be presumed to be at low or no risk for STDs based on sexual orientation. Effective screening requires that providers and their female clients engage in a comprehensive and open discussion not only about sexual identify, but sexual and behavioral risks. Few data are available on the risk for STDs transmitted by sex between women, but risk probably varies by the specific STD and sexual practice (e.g., oral-genital sex; vaginal or anal sex using hands, fingers, or penetrative sex items; and oral-anal sex ). Practices involving digital-vaginal or digitalanal contact, particularly with shared penetrative sex items, present a possible means for transmission of infected cervicovaginal secretions. This possibility is most directly supported by reports of metronidazole-resistant trichomoniasis (115) and genotype-concordant HIV transmitted sexually between women who reported these behaviors (116) and by the high prevalence of BV among monogamous WSW (117). Transmission of HPV can occur with skin-to-skin or skin-to-mucosa contact, which can occur during sex between women. HPV DNA has been detected through polymerase chain reaction (PCR)-based methods from the cervix, vagina, and vulva in 13%-30% of WSW, and high-and low-grade squamous intraepithelial lesions (SIL) have been detected on Pap tests in WSW who reported no previous sex with men (118). However, most self-identified WSW (53%-99%) report having had sex with men and indicate that they might continue this practice in the future (119). Therefore, routine cervical cancer screening should be offered to all women, regardless of sexual preference or sexual practices, and women should be offered HPV vaccine in accordance with current guidelines. Limited data demonstrate that HSV-2 genital transmission between female sex partners is probably inefficient but can occur. The relatively frequent practice of orogenital sex among WSW might place them at higher risk for genital infection with herpes simplex virus type 1 (HSV-1), a hypothesis supported by the recognized association between HSV-1 seropositivity and number of female partners among WSW (120). Although the rate of transmission of C. trachomatis between women remains largely unknown, infection also can be acquired from past or current male partners. Recent data suggest that C. trachomatis infection among WSW might be more common than previously thought (121); transmission of syphilis between female sex partners (likely through oral sex) also has been reported. Therefore, report of same-sex behavior in women should not deter providers from screening these women for STDs, including chlamydia and syphilis, as recommended. BV is common among women in general and even more so among women with female partners. Sexual behaviors that facilitate the transfer of vaginal fluid and/or bacteria between partners might be involved in the pathogenesis of BV. A recent study demonstrated that female sex partners frequently share identical genital Lactobacillus strains (122). Although BV is common in WSW, routine screening for BV is not recommended, nor is the treatment of partners of women with BV. Encouraging awareness of signs and symptoms of BV in women and encouraging healthy sexual practices (e.g., cleaning shared sex toys between uses) might be helpful. # HIV Infection: Detection, Counseling, and Referral HIV infection represents a spectrum of disease that can begin with a brief acute retroviral syndrome that typically transitions to a multiyear chronic and clinically latent illness. Without treatment, this illness eventually progresses to a symptomatic, life-threatening immunodeficiency disease known as AIDS. In untreated patients, the time between HIV infection and the development of AIDS varies, ranging from a few months to many years with an estimated median time of approximately 11 years (123). HIV replication is present during all stages of the infection and progressively depletes CD4 lymphocytes, which are critical for maintenance of effective immune function. When the CD4 cell count falls below 200 cells/µL, patients are at high risk for life-threatening AIDS-defining opportunistic infections (e.g., Pneumocystis pneumonia, Toxoplasma gondii encephalitis, disseminated Mycobacterium avium complex disease, tuberculosis, and bacterial pneumonia). In the absence of treatment, virtually all HIV-infected persons will die of AIDS. Early diagnosis of HIV infection is essential to ensuring that patients are referred promptly for evaluation, provided treatment (if indicated), and linked into counseling and related support services to help them reduce their risk for transmitting HIV to others. Diagnosing persons during acute infection is particularly important. It is during this phase that HIV-infected persons are most infectious (124)(125)(126), but test negative for HIV antibodies and therefore unknowingly continue to engage in those high-risk behaviors associated with HIV transmission. Providers are in a particularly good position to diagnose persons during acute HIV infection because such persons might present for assessment and treatment of a concomitantly acquired STD during this phase of the disease. Knowing that a patient is infected with HIV has important clinical implications because HIV infection alters the immune system and thereby affects the diagnosis, evaluation, treatment, and follow-up of other STDs. Even in the era of highly effective antiretroviral therapy (HAART), HIV infection is often diagnosed in persons with advanced infection (i.e., persons with low CD4 cell counts). Nationally, the proportion of patients diagnosed with AIDS at or within 12 months of their HIV diagnosis in 2007 was 32% (127). Since 2006, CDC has endorsed efforts to increase HIV testing by streamlining the consent process and expanding opt-out testing to all health-care settings, especially STD clinics (77). However, rates of testing remain unacceptably low: in 2006, only 40% of surveyed adults had ever been tested, and <25% of high-risk adults had been tested during the preceding 12 months (128). Proper management of HIV infection requires medical therapy, which for many patients should be coupled with behavioral and psychosocial services. Comprehensive HIV treatment services are usually not available in facilities focusing primarily on STD treatment (e.g., STD clinics); therefore, patients diagnosed in these settings ideally should be referred to a healthcare provider or facility experienced in caring for HIV-infected patients. Nonetheless, providers working in STD-treatment facilities should be knowledgeable about the treatment options available in their communities, educate persons who test positive for HIV about the illness, and know where to refer their patients for support services and HIV care. A detailed discussion of the complex issues required for the management of HIV infection is beyond the scope of this report; however this information is available in other published resources (129)(130)(131). In subsequent sections of this report, additional types of HIV-related information about the diagnosis of HIV infection, counseling of HIV-infected patients, referral of patients for support services (including medical care), and management of sex and injection-drug partners in STD-treatment facilities is provided. In addition, this report discusses HIV infection during pregnancy and among infants and children. # Detection of HIV Infection: Screening and Establishing a Diagnosis All persons who seek evaluation and treatment for STDs should be screened for HIV infection. Screening should be routine, regardless of whether the patient is known or suspected to have specific behavioral risks for HIV infection. # Consent and Pretest Information CDC recommends HIV screening for patients aged 13-64 years in all health-care settings (77). Patients should be notified that testing will be performed, but given the option to decline or defer testing (i.e., provided with opt-out testing) (128). Assent is inferred unless the patient verbally declines testing. Separate written consent for HIV testing should not be required; in most facilities, general consent for medical care is considered sufficient to encompass consent for HIV testing. Providing prevention counseling along with HIV diagnostic testing or as part of HIV screening programs is not a requirement within health-care settings. In addition, routine opt-out testing (instead of traditional written informed consent with pre-and post-test counseling) might be precluded in some jurisdictions by local laws and regulations, although many state and local authorities have updated laws and regulations to facilitate adoption of routine opt-out testing. Information about regulations in specific jurisdictions is available through the National Clinicians Consultation Center at www.nccc. ucsf.edu. # Prevention Counseling Prevention counseling should be offered and encouraged in all health-care facilities that serve patients at high risk (e.g., STD clinics), because these facilities routinely elicit information about the behaviors that place persons at high risk for HIV. Prevention counseling need not be explicitly linked to HIV testing. However, some patients might be more likely to think about HIV and consider their risk-related behavior when undergoing an HIV test. HIV testing presents an excellent opportunity to provide or arrange for prevention counseling to assist with behavior changes that can reduce risk for acquiring HIV infection. # Establishing the Diagnosis of HIV Infection HIV infection can be diagnosed by serologic tests that detect antibodies against HIV-1 and HIV-2 and by virologic tests that can detect HIV antigens or ribonucleic acid (RNA). Antibody testing begins with a sensitive screening test (e.g., the conventional or rapid enzyme immunoassay ). Currently available serologic tests are both highly sensitive and specific and can detect all known subtypes of HIV-1. Most can also detect HIV-2 and uncommon variants of HIV-1 (e.g., Group O and Group N). The advent of HIV rapid serologic testing has enabled clinicians to make an accurate presumptive diagnosis of HIV infection within half an hour, which could potentially facilitate the identification of the approximately 250,000 persons estimated to be living with undiagnosed HIV in the United States (127). Reactive screening tests must be confirmed by a supplemental antibody test (i.e., Western blot and indirect immunofluorescence assay ) or virologic test (i.e., the HIV-1 RNA assay) (132). A confirmed positive antibody test result indicates that a person is infected with HIV and capable of transmitting the virus to others. HIV antibody is detectable in at least 95% of patients within 3 months after infection. Although a negative antibody test result usually indicates that a person is not infected, antibody tests cannot exclude recent infection. Virologic tests for HIV-1 RNA can also be used to identify acute infection in persons who are negative for HIV antibodies. The majority of HIV infections in the United States are caused by HIV-1. However, HIV-2 infection should be suspected in persons who have epidemiologic risk factors or an unusual clinical presentation. Epidemiologic factors associated with HIV-2 infection include having lived in or having a sex partner from an HIV-2 endemic area (e.g., West Africa and some European countries such as Portugal, where HIV-2 prevalence is increasing), having a sex partner known to be infected with HIV-2, or having received a blood transfusion or nonsterile injection in an HIV-2-endemic area. Specific testing for HIV-2 is also indicated when clinical evidence of HIV infection exists but tests for HIV-1 antibodies or HIV-1 viral load are negative, or when HIV-1 WB results exhibit the unusual indeterminate pattern of gag (p55, p24, p17) plus pol (p66, p51, p31) bands in the absence of env (gp160, gp120, gp41) bands. Health-care providers should be knowledgeable about acute HIV infection and the symptoms and signs of acute retroviral syndrome, which develops in 50%-80% of acutely infected patients. Acute retroviral syndrome is characterized by nonspecific symptoms, including fever, malaise, lymphadenopathy, and skin rash. It frequently occurs in the first few weeks after HIV infection, before antibody test results become positive. Suspicion of acute retroviral syndrome should result in prompt nucleic acid testing (HIV plasma RNA) in addition to an HIV antibody test to detect the presence of HIV. A positive HIV nucleic acid test should be confirmed by subsequent antibody testing to document seroconversion. Acutely infected patients are highly contagious during this stage of infection because the concentration of virus in plasma and genital secretions is extremely elevated (125,133). Antiretroviral therapy might benefit the health of persons with recently acquired HIV infection and reduce their infectiousness to others, but evidence to support this recommendation is still inconclusive and awaits the outcomes of several clinical trials currently underway (129). Notwithstanding, patients with acute HIV infection should be referred immediately to an HIV clinical-care provider. Diagnosis of HIV infection should prompt efforts to reduce behaviors that could transmit HIV to others (134). The following are specific recommendations that apply to testing for HIV infection: - HIV screening is recommended for all persons who seek evaluation and treatment for STDs. - HIV testing must be voluntary and free from coercion. Patients must not be tested without their knowledge. - HIV screening after notifying the patient that an HIV test will be performed (unless the patient declines) is recommended in all health-care settings. - tuberculin skin test (sometimes referred to as a purified protein derivative); - urinalysis; and - chest radiograph. Type-specific testing for HSV-2 infection can be considered if herpes infection status is unknown. A first dose of hepatitis A and hepatitis B vaccine should be administered at this first visit for previously unvaccinated persons for whom vaccine is recommended (see Hepatitis A and Hepatitis B). In subsequent visits, when the results of laboratory tests are available, antiretroviral therapy can be offered based on existing guidance (129). Recommendations for the prophylaxis of opportunistic infections and vaccinations in HIV-infected adults and adolescents are available (130,131). Providers should be alert to the possibility of new or recurrent STDs and should treat such conditions aggressively. Diagnosis of an STD in an HIV-infected person indicates on-going or recurrent high-risk behavior and should prompt referral for counseling. Because many STDs are asymptomatic, routine screening for curable STDs (e.g., syphilis, gonorrhea, and chlamydia) should be performed at least annually for all sexually active, HIV-positive persons. Women should be screened annually for cervical cancer precursor lesions by cervical Pap tests. More frequent STD screening might be appropriate depending on individual risk behaviors, the local epidemiology of STDs, and whether incident STDs are detected by screening or by the presence of symptoms. Recently identified HIV infection might not have been recently acquired; persons newly diagnosed with HIV might be at any stage of infection. Therefore, health-care providers should be alert for symptoms or signs that suggest advanced HIV infection (e.g., fever, weight loss, diarrhea, cough, shortness of breath, and oral candidiasis). The presence of any of these symptoms should prompt urgent referral to an infectious diseases provider. Similarly, providers should be alert for signs of psychological distress and be prepared to refer patients accordingly (see Counseling for Patients with HIV Infection and Referral to Support Services). # Counseling for Patients with HIV Infection and Referral to Support Services Those persons who test positive for HIV should receive prevention counseling before leaving the testing site. Such persons should receive or be referred for a medical evaluation and, if indicated, be provided with behavioral and psychological services as determined by a thorough psychosocial evaluation, which can also be used to identify high-risk behaviors. Providers who refer their HIV-positive patients to other professionals should establish means to ensure that these patients are linked successfully to such services, especially to on-going medical care. Providers should expect persons to be distressed when first informed of a positive HIV test result. Such persons face multiple major adaptive challenges, including coping with the reactions of others to a stigmatizing illness, developing and adopting strategies for maintaining physical and emotional health, initiating changes in behavior to prevent HIV transmission to others, and reducing the risk for acquiring additional STDs. Many persons will require assistance with making reproductive choices, gaining access to health services, and coping with changes in personal relationships. Therefore, behavioral and psychosocial services are an integral part of health care for HIV-infected persons. Patients testing positive for HIV have unique needs. Some patients require referral for specific behavioral interventions (e.g., a substance abuse program), mental health disorders (e.g., depression), or emotional distress. Others might require assistance with securing and maintaining employment and housing. Women should be counseled or appropriately referred regarding reproductive choices and contraceptive options, and patients with multiple psychosocial problems might be candidates for comprehensive risk-reduction counseling and services. The following are specific recommendations for HIV counseling and referral: Involvement of nongovernment organizations and communitybased organizations might complement such efforts in the clinical setting. # Management of Sex Partners and Injection-Drug Partners Clinicians evaluating HIV-infected persons should determine whether any partners should be notified concerning possible exposure to HIV (77,137). In the context of HIV management, the term "partner" includes not only sex partners, but persons who share syringes or other injection equipment. Partner notification is an important component of disease management, because early diagnosis and treatment of HIV infection might reduce morbidity and provide the opportunity to encourage risk-reduction behaviors. Partner notification for HIV infection should be confidential. Specific guidance regarding spousal notification varies by jurisdiction. Detailed recommendations concerning identification, notification, diagnosis, and treatment of exposed partners are available in Recommendations for Partner Services Programs for HIV Infection, Syphilis, Gonorrhea, and Chlamydial Infections (137). Two complementary notification processes, patient referral and provider referral, can be used to identify partners. With patient referral, patients directly inform their partners of their exposure to HIV infection, whereas with provider referral, trained health department personnel locate partners on the basis of information provided by the patient. During the provider referral notification process, the confidentiality of patients is protected; their names are not revealed to partners who are notified. Many state and local health departments provide these services. The following are specific recommendations for implementing partner-notification procedures: - HIV-infected patients should be encouraged to notify their partners and to refer them for counseling and testing. If requested by the patient, health-care providers should assist in this process, either directly or by referral to health department partner-notification programs. - If patients are unwilling to notify their partners or if they cannot ensure that their partners will seek counseling, physicians or health department personnel should use confidential partner notification procedures. - Partners who have been reached and were exposed to genital secretions and/or blood of an HIV-infected partner though sex or injection-drug use within the preceding 72 hours should be offered postexposure prophylaxis with combination antiretrovirals (78). # Special Considerations Pregnancy All pregnant women in the United States should be tested for HIV infection as early during pregnancy as possible. A second test during the third trimester, preferably at <36 weeks' gestation, should be considered for all pregnant women and is recommended for women known to be at high risk for acquiring HIV, those who receive health care in jurisdictions with elevated incidence of HIV or AIDS among women, and women living in facilities in which prenatal screening identifies at least one HIV-infected pregnant women per 1,000 women screened (77). An RNA test should be used in conjunction with an HIV antibody test for women who have signs or symptoms consistent with acute HIV infection. The patient should first be informed that she will be tested for HIV as part of the panel of prenatal tests, unless she declines, or opts-out, of screening (77,86). For women who decline, providers should continue to strongly encourage testing and address concerns that pose obstacles to testing. Women who decline testing because they have had a previous negative HIV test should be informed about the importance of retesting during each pregnancy. Testing pregnant women is particularly important not only to maintain the health of the patient, but because interventions (i.e., antiretroviral and obstetrical) can reduce the risk for perinatal transmission of HIV. After a pregnant woman has been identified as being HIVinfected, she should be educated about the risk for perinatal infection. Evidence indicates that, in the absence of antiretroviral and other interventions, 15%-25% of infants born to HIV-infected mothers will become infected with HIV; such evidence also indicates that an additional 12%-14% of infants born to infected mothers who breastfeed into the second year of life will become infected (138,139). The risk for perinatal HIV transmission can be reduced to <2% through the use of antiretroviral regimens and obstetrical interventions (i.e., zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy) and by avoiding breastfeeding (138,140). Pregnant women who are HIVinfected should be counseled concerning their options (either on-site or by referral), given appropriate antenatal treatment, and advised not to breastfeed their infants. # HIV Infection Among Infants and Children Diagnosis of HIV infection in a pregnant woman indicates the need to consider whether the woman's other children might be infected. Infants and young children with HIV infection differ from adults and adolescents with respect to the diagnosis, clinical presentation, and management of HIV disease. For example, because maternal HIV antibody passes through the placenta, antibody tests for HIV are expected to be positive in the sera of both infected and uninfected infants born to seropositive mothers. A definitive determination of HIV infection for an infant aged <18 months is usually based on HIV nucleic acid testing (141). Management of infants, children, and adolescents who are known or suspected to be infected with HIV requires referral to physicians familiar with the manifestations and treatment of pediatric HIV infection (142,143). # Diseases Characterized by Genital, Anal, or Perianal Ulcers In the United States, most young, sexually active patients who have genital, anal, or perianal ulcers have either genital herpes or syphilis. The frequency of each condition differs by geographic area and population; however, genital herpes is the most prevalent of these diseases. More than one etiologic agent (e.g., herpes and syphilis) can be present in a genital, anal, or perianal ulcer. Less common infectious causes of genital, anal, or perianal ulcers include chancroid and donovanosis. HSV, syphilis, and chancroid have been associated with an increased risk for HIV transmission, and genital, anal, or perianal lesions might be associated with conditions that are not sexually transmitted (e.g., yeast, trauma, carcinoma, aphthae, fixed drug eruption, and psoriasis). A diagnosis based only on the patient's medical history and physical examination frequently is inaccurate. Therefore, all patients who have genital, anal, or perianal ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should also be performed. Specific tests for evaluation of genital, anal, or perianal ulcers include 1) syphilis serology and darkfield examination; 2) culture for HSV or PCR testing for HSV; and 3) serologic testing for type-specific HSV antibody. No FDA-cleared PCR test to diagnose either herpes or syphilis is available in the United States; however, such testing can be performed by clinical laboratories that have developed their own tests and have conducted a Clinical Laboratory Improvement Amendment (CLIA) verification study. Typespecific serology for HSV-2 might be helpful in identifying persons with genital herpes (see Genital Herpes, Type-Specific Serologic Tests). In addition, biopsy of genital, anal, or perianal ulcers can help identify the cause of ulcers that are unusual or that do not respond to initial therapy. HIV testing should be performed on all persons with genital, anal, or perianal ulcers who are not known to have HIV infection (see Diagnostic Considerations, sections on Syphilis, Chancroid, and Genital Herpes Simplex Virus). Health-care providers frequently must treat patients before test results are available, because early treatment decreases the possibility of ongoing transmission and because successful treatment of genital herpes depends on prompt initiation of therapy. The clinician should empirically treat for the diagnosis considered most likely on the basis of clinical presentation and epidemiologic circumstances (including travel history); even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis. # Chancroid The prevalence of chancroid has declined in the United States (93). When infection does occur, it is usually associated with sporadic outbreaks. Worldwide, chancroid appears to have declined as well, although infection might still occur in some regions of Africa and the Caribbean. Chancroid, as well as genital herpes and syphilis, is a risk factor in the transmission of HIV infection (144). A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is <80% (145). No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and have conducted a CLIA verification study. The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid (146). A probable diagnosis of chancroid, for both clinical and surveillance purposes, can be made if all of the following criteria are met: 1) the patient has one or more painful genital ulcers; 2) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; 3) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and 4) a test for HSV performed on the ulcer exudate is negative. # Treatment Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents transmission to others. In advanced cases, scarring can result, despite successful therapy. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Ceftriaxone 250 mg intramuscularly (IM) in a single dose OR Ciprofloxacin- 500 mg orally twice a day for 3 days- OR Erythromycin base 500 mg orally three times a day for 7 days - Ciprofloxacin is contraindicated for pregnant and lactating women. Azithromycin and ceftriaxone offer the advantage of singledose therapy. Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported. However, because cultures are not routinely performed, data are limited regarding the current prevalence of antimicrobial resistance. # other Management Considerations Men who are uncircumcised and patients with HIV infection do not respond as well to treatment as persons who are circumcised or HIV-negative. Patients should be tested for HIV infection at the time chancroid is diagnosed. If the initial test results were negative, a serologic test for syphilis and HIV infection should be performed 3 months after the diagnosis of chancroid. # Follow-Up Patients should be re-examined 3-7 days after initiation of therapy. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether 1) the diagnosis is correct, 2) the patient is coinfected with another STD, 3) the patient is infected with HIV, 4) the treatment was not used as instructed, or 5) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial. The time required for complete healing depends on the size of the ulcer; large ulcers might require >2 weeks. In addition, healing is slower for some uncircumcised men who have ulcers under the foreskin. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and might require needle aspiration or incision and drainage, despite otherwise successful therapy. Although needle aspiration of buboes is a simpler procedure, incision and drainage might be preferred because of reduced need for subsequent drainage procedures. # Management of Sex Partners Regardless of whether symptoms of the disease are present, sex partners of patients who have chancroid should be examined and treated if they had sexual contact with the patient during the 10 days preceding the patient's onset of symptoms. # Special Considerations # Pregnancy Ciprofloxacin is contraindicated during pregnancy and lactation. No adverse effects of chancroid on pregnancy outcome have been reported. # HIV Infection HIV-infected patients who have chancroid should be monitored closely because, as a group, they are more likely to experience treatment failure and to have ulcers that heal more slowly. HIV-infected patients might require repeated or longer courses of therapy than those recommended for HIV-negative patients, and treatment failures can occur with any regimen. Because data are limited concerning the therapeutic efficacy of the recommended ceftriaxone and azithromycin regimens in HIV-infected patients, these regimens should be used for such patients only if follow-up can be ensured. # Genital HSV Infections Genital herpes is a chronic, life-long viral infection. Two types of HSV have been identified as causing genital herpes: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and at least 50 million persons in the United States are infected with this type of genital herpes (147). However, an increasing proportion of anogenital herpetic infections in some populations has been attributed to HSV-1 infection. Most persons infected with HSV-2 have not been diagnosed with genital herpes. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. As a result, the majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Management of genital HSV should address the chronic nature of the disease and go beyond the treatment of acute episodes of genital ulcers. # Diagnosis of HSV Infection The clinical diagnosis of genital herpes is both nonsensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected persons. HSV-1 is causing an increasing proportion of first episodes of anogenital herpes in some populations (e.g., young women and MSM) and might now account for most of these infections (148,149). Recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for genital HSV-2 infection (150,151). A patient's prognosis and the type of counseling needed depends on the type of genital herpes (HSV-1 or HSV-2) causing the infection; therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing (152). Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for persons diagnosed with or at risk for STDs. # Virologic Tests Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions. The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and are increasingly used in many settings (153,154). PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS). Viral culture isolates should be typed to determine which type of HSV is causing the infection. Failure to detect HSV by culture or PCR does not indicate an absence of HSV infection, because viral shedding is intermittent. The use of cytologic detection of cellular changes of HSV infection is an insensitive and nonspecific method of diagnosis, both for genital lesions (i.e., Tzanck preparation) and for cervical Pap smears and therefore should not be relied upon. # Type-Specific Serologic Tests Both type-specific and nontype-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody (despite claims to the contrary) remain on the market (155); providers should specifically request serologic type-specific glycoprotein G (gG)-based assays when serology is performed for their patients (156)(157)(158). Both laboratory-based assays and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available. The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%-98%, and false-negative results might be more frequent at early stages of infection. The specificities of these assays are ≥96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Repeat or confirmatory testing might be indicated in some settings, especially if recent acquisition of genital herpes is suspected. IgM testing for HSV is not useful, because the IgM tests are not type-specific and might be positive during recurrent episodes of herpes (159). Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. In this instance, education and counseling appropriate for persons with genital herpes should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. Most persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital HSV-1 also can be asymptomatic (147)(148)(149). Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection, and regardless of site of infection, these persons remain at risk for acquiring HSV-2. Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV cultures; 2) a clinical diagnosis of genital herpes without laboratory confirmation; or 3) a partner with genital herpes. HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition. Screening for HSV-1 and HSV-2 in the general population is not indicated. # Management of Genital Herpes Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management. Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat first clinical and recurrent episodes, or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (160)(161)(162)(163)(164)(165)(166)(167)(168). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged. # First Clinical Episode of Genital Herpes Newly acquired genital herpes can cause a prolonged clinical illness with severe genital ulcerations and neurologic involvement. Even persons with first-episode herpes who have mild clinical manifestations initially can develop severe or pro-longed symptoms. Therefore, all patients with first episodes of genital herpes should receive antiviral therapy. # Recommended Regimens* Acyclovir 400 mg orally three times a day for 7-10 days OR Acyclovir 200 mg orally five times a day for 7-10 days OR Famciclovir 250 mg orally three times a day for 7-10 days OR Valacyclovir 1 g orally twice a day for 7-10 days Treatment can be extended if healing is incomplete after 10 days of therapy. # Established HSV-2 Infection Almost all persons with symptomatic first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions. Some persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Many persons might prefer suppressive therapy, which has the additional advantage of decreasing the risk for genital HSV-2 transmission to susceptible partners (169,170). # Suppressive Therapy for Recurrent Genital Herpes Suppressive therapy reduces the frequency of genital herpes recurrences by 70%-80% in patients who have frequent recurrences (166)(167)(168)(169); many persons receiving such therapy report having experienced no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year (171,172). Quality of life is improved in many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment. The frequency of recurrent genital herpes outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease might change. Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy with the patient. Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (170). Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes. Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes, but famciclovir appears somewhat less effective for suppression of viral shedding (163)(164)(165)(166)(167)173). Ease of administration and cost also are important considerations for prolonged treatment. # Recommended Regimens # Episodic Therapy for Recurrent Genital Herpes Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin. # Recommended Regimens # Severe Disease Intravenous (IV) acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis). The recommended regimen is acyclovir 5-10 mg/ kg IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. Acyclovir dose adjustment is recommended for impaired renal function. # Counseling Counseling of infected persons and their sex partners is critical to the management of genital herpes. The goals of counseling include 1) helping patients cope with the infection and 2) preventing sexual and perinatal transmission (174,175). Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites () and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling. Although the psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears minimal and transient (176), some HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled. The following recommendations apply to counseling of persons with genital HSV infection: # Management of Sex Partners The sex partners of patients who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection. # Special Considerations Allergy, Intolerance, and Adverse Reactions Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (179). # HIV Infection Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical. HSV shedding is increased in HIV-infected persons. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (180). Clinical manifestations of genital herpes might worsen during immune reconstitution after initiation of antiretroviral therapy. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive persons (181)(182)(183). The extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. HSV type-specific serologies can be offered to HIV-positive persons during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection. Acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of genital herpes. For severe HSV disease, initiating therapy with acyclovir 5-10 mg/kg IV every 8 hours might be necessary. # Recommended Regimens for Daily Suppressive Therapy in Persons with HIV If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing (184). Such persons should be managed in consultation with an HIV specialist, and alternate therapy should be administered. All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet, 40 mg/kg IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. Intravenous cidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days. Clinical management of antiviral resistance remains challenging among HIV-infected patients, and other preventative approaches might be necessary. However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy with outbreaks (185). # Genital Herpes in Pregnancy Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes (186). The risk for transmission to the neonate from an infected mother is high (30%-50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy (187). However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Because the risk for herpes is high in infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with an infectious disease specialist. Women without known genital herpes should be counseled to abstain from intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes. Some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy and that such testing should be offered to uninfected women whose sex partner has HSV infection. However, the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied. All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Although cesarean section does not completely eliminate the risk for HSV transmission to the infant, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to prevent neonatal HSV infection. The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been definitively established. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester (188) -findings that provide assurance to women who have had prenatal exposure to acyclovir. However, data regarding prenatal exposure to valacyclovir and famciclovir are too limited to provide useful information on pregnancy outcomes. Acyclovir can be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (189)(190)(191); the effect of antiviral therapy late in pregnancy on the incidence of neonatal herpes is not known. No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes. # neonatal Herpes Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious disease specialist. Surveillance cultures of mucosal surfaces to detect HSV infection might be considered before the development of clinical signs of neonatal herpes. In addition, administration of acyclovir might be considered for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants. All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes. # Granuloma Inguinale (Donovanosis) Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The disease occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa (192,193). Clinically, the disease is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudoboboes) might also occur. The lesions are highly vascular (i.e., beefy red appearance) and bleed easily on contact. The clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intraabdominal organs, bones, or the mouth. The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens. The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared molecular tests for the detection of K. granulomatis DNA exist, but such an assay might be useful when undertaken by laboratories that have conducted a CLIA verification study. # Treatment Several antimicrobial regimens have been effective, but only a limited number of controlled trials have been published (192). Treatment has been shown to halt progression of lesions, and healing typically proceeds inward from the ulcer margins; prolonged therapy is usually required to permit granulation and reepithelialization of the ulcers. Relapse can occur 6-18 months after apparently effective therapy. # Recommended Regimen Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed # Alternative Regimens Azithromycin 1 g orally once per week for at least 3 weeks and until all lesions have completely healed OR Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed OR Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed OR Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed The addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to these regimens can be considered if improvement is not evident within the first few days of therapy. # Follow-Up Patients should be followed clinically until signs and symptoms have resolved. # Management of Sex Partners Persons who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient's symptoms should be examined and offered therapy. However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established. # Special Considerations Pregnancy Pregnancy is a relative contraindication to the use of sulfonamides. Pregnant and lactating women should be treated with the erythromycin regimen, and consideration should be given to the addition of a parenteral aminoglycoside (e.g., gentamicin). Azithromycin might prove useful for treating granuloma inguinale during pregnancy, but published data are lacking. Doxycycline and ciprofloxacin are contraindicated in pregnant women. # HIV Infection Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who are HIV negative; however, the addition of a parenteral aminoglycoside (e.g., gentamicin) can also be considered. # Lymphogranuloma Venereum Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3 (194). The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis, including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus (195,196). LGV is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic, colorectal fistulas and strictures. Genital and colorectal LGV lesions can also develop secondary bacterial infection or can be coinfected with other sexually and nonsexually transmitted pathogens. Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers. C. trachomatis testing also should be conducted, if available. Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. NAATs for C. trachomatis are not FDA-cleared for testing rectal specimens, although some laboratories have performed the CLIA validation studies that are needed to provide results for clinical management. Additional molecular procedures (e.g., PCR-based genotyping) can be used to differentiate LGV from non-LGV C. trachomatis, but these are not widely available. Chlamydia serology (complement fixation titers >1:64) can support the diagnosis of LGV in the appropriate clinical context. Comparative data between types of serologic tests are lacking, and the diagnostic utility of serologic methods other than complement fixation and some microimmunofluorescence procedures has not been established. Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available. In the absence of specific LGV diagnostic testing, patients with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be treated for LGV as described in this report. # Treatment Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the infection can result in scarring. Buboes might require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/ femoral ulcerations. Doxycycline is the preferred treatment. # Recommended Regimen Doxycycline 100 mg orally twice a day for 21 days # Alternative Regimen Erythromycin base 500 mg orally four times a day for 21 days Although clinical data are lacking, azithromycin 1 g orally once weekly for 3 weeks is probably effective based on its chlamydial antimicrobial activity. Fluoroquinolone-based treatments might also be effective, but extended treatment intervals are likely required. # Follow-Up Patients should be followed clinically until signs and symptoms have resolved. # Management of Sex Partners Persons who have had sexual contact with a patient who has LGV within the 60 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a chlamydia regimen (azithromycin 1 gm orally single dose or doxycycline 100 mg orally twice a day for 7 days). # Special Considerations Pregnancy Pregnant and lactating women should be treated with erythromycin. Azithromycin might prove useful for treatment of LGV in pregnancy, but no published data are available regarding its safety and efficacy. Doxycycline is contraindicated in pregnant women. # HIV Infection Persons with both LGV and HIV infection should receive the same regimens as those who are HIV negative. Prolonged therapy might be required, and delay in resolution of symptoms might occur. # Syphilis Syphilis is a systemic disease caused by Treponema pallidum. On the basis of clinical findings, the disease has been divided into a series of overlapping stages, which are used to help guide treatment and follow-up. Persons who have syphilis might seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include, but are not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), neurologic infection (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities, which might occur through the natural history of untreated infection), or tertiary infection (i.e., cardiac or gummatous lesions). Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are either late latent syphilis or latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis might require a longer duration of therapy because organisms might be dividing more slowly; however, the validity of this concept has not been assessed. # Diagnostic Considerations Darkfield examinations and tests to detect T. pallidum in lesion exudate or tissue are the definitive methods for diagnosing early syphilis (197). Although no T. pallidum detection tests are commercially available, some laboratories provide locally developed PCR tests for the detection of T. pallidum. A presumptive diagnosis of syphilis is possible with the use of two types of serologic tests: 1) nontreponemal tests (e.g., Venereal Disease Research Laboratory and RPR) and 2) treponemal tests (e.g., fluorescent treponemal antibody absorbed tests, the T. pallidum passive particle agglutination assay, various EIAs, and chemiluminescence immunoassays). The use of only one type of serologic test is insufficient for diagnosis, because each type of test has limitations, including the possibility of false-positive test results in persons without syphilis. False-positive nontreponemal test results can be associated with various medical conditions unrelated to syphilis, including autoimmune conditions, older age, and injection-drug use (198,199); therefore, persons with a reactive nontreponemal test should receive a treponemal test to confirm the diagnosis of syphilis. Nontreponemal test antibody titers may correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained using the same serologic test. Sequential serologic tests in individual patients should be performed using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers frequently are slightly higher than VDRL titers. Nontreponemal test titers usually decline after treatment and might become nonreactive with time; however, in some persons, nontreponemal antibodies can persist for a long period of time -a response referred to as the "serofast reaction." Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%-25% of patients treated during the primary stage revert to being serologically nonreactive after 2-3 years (200). Treponemal test antibody titers should not be used to assess treatment response. Some clinical laboratories and blood banks have begun to screen samples using treponemal tests, typically by EIA or chemiluminescence immunoassays (201,202). This strategy will identify both persons with previous treatment for syphilis and persons with untreated or incompletely treated syphilis. The positive predictive value for syphilis associated with a treponemal screening test result might be lower among populations with a low prevalence of syphilis. Persons with a positive treponemal screening test should have a standard nontreponemal test with titer performed reflexively by the laboratory to guide patient management decisions. If the nontreponemal test is negative, then the laboratory should perform a different treponemal test (preferably one based on different antigens than the original test) to confirm the results of the initial test. If a second treponemal test is positive, persons with a history of previous treatment will require no further management unless sexual history suggests likelihood of re-exposure. Those without a history of treatment for syphilis should be offered treatment. Unless history or results of a physical examination suggest a recent infection, previously untreated persons should be treated for late latent syphilis. If the second treponemal test is negative, further evaluation or treatment is not indicated. For most HIV-infected persons, serologic tests are accurate and reliable for the diagnosis of syphilis and for following a patient's response to treatment. However, atypical syphilis serologic test results (i.e., unusually high, unusually low, or fluctuating titers) can occur in HIV-infected persons. When serologic tests do not correspond with clinical findings suggestive of early syphilis, use of other tests (e.g., biopsy and darkfield microscopy) should be considered. Clinical signs of neurosyphilis (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities) warrant further investigation and treatment for neurosyphilis. Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances. Cerebrospinal fluid (CSF) laboratory abnormalities are common in persons with early syphilis. The VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard serologic test for CSF. When reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis; however in early syphilis, it can be of unknown prognostic significance (203). Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, and a reactive CSF-VDRL with or without clinical manifestations. Among persons with HIV infection, the CSF leukocyte count usually is elevated (>5 white blood cell count /mm 3 ); using a higher cutoff (>20 WBC/ mm 3 ) might improve the specificity of neurosyphilis diagnosis (204). The CSF-VDRL might be nonreactive even when neurosyphilis is present; therefore, additional evaluation using FTA-ABS testing on CSF can be considered. The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive; neurosyphilis is highly unlikely with a negative CSF FTA-ABS test (205). # Treatment Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by some forms of penicillin. Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis. Reports have indicated that practitioners have inadvertently prescribed combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) widely used in the United States. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the inappropriate combination therapy agent for treating syphilis (206). The effectiveness of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based not only on clinical trials and observational studies, but approximately 50 years of clinical experience. Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, fever, and other symptoms that usually occur within the first 24 hours after the initiation of any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis, presumably because bacterial burdens are higher during these stages. Antipyretics can be used to manage symptoms, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this should not prevent or delay therapy (see Syphilis During Pregnancy). # Management of Sex Partners Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present. Although such manifestations are uncommon after the first year of infection, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically and treated with a recommended regimen, according to the following recommendations: - Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively. - Persons who were exposed >90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain. - For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) can be assumed to have early syphilis. For the purpose of determining a treatment regimen, however, serologic titers should not be used to differentiate early from late latent syphilis (see Latent Syphilis, Treatment). - Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings. Sexual partners of infected patients should be considered at risk and provided treatment if they have had sexual contact with the patient within 3 months plus the duration of symptoms for patients diagnosed with primary syphilis, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for patients with early latent syphilis. # Primary and Secondary Syphilis Treatment Parenteral penicillin G has been used effectively for more than 50 years to achieve clinical resolution (i.e., the healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no comparative trials have been adequately conducted to guide the selection of an optimal penicillin regimen (i.e., the dose, duration, and preparation). Substantially fewer data are available for nonpenicillin regimens. Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis (primary, secondary, and early latent) do not enhance efficacy, regardless of HIV status. # Recommended Regimen for Adults # Recommended Regimen for Infants and Children Infants and children aged ≥1 month diagnosed with syphilis should have a CSF examination to detect asymptomatic neurosyphilis, and birth and maternal medical records should be reviewed to assess whether such children have congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (e.g., through consultation with child-protection services) (see Sexual Assault or Abuse of Children) and treated by using the following pediatric regimen. # Recommended Regimen for Infants and Children Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose # other Management Considerations All persons who have syphilis should be tested for HIV infection. In geographic areas in which the prevalence of HIV is high, persons who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative. Patients who have syphilis and symptoms or signs suggesting neurologic disease (e.g., meningitis and hearing loss) or ophthalmic disease (e.g., uveitis, iritis, neuroretinitis, and optic neuritis) should have an evaluation that includes CSF analysis, ocular slit-lamp ophthalmologic examination, and otologic examination. Treatment should be guided by the results of this evaluation. Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis (203). Therefore, in the absence of clinical neurologic findings, no evidence exists to support variation from the recommended treatment regimen for early syphilis. Symptomatic neurosyphilis develops in only a limited number of persons after treatment with the penicillin regimens recommended for primary and secondary syphilis. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present or treatment failure is documented, routine CSF analysis is not recommended for persons who have primary or secondary syphilis. # Follow-Up Treatment failure can occur with any regimen. However, assessing response to treatment frequently is difficult, and definitive criteria for cure or failure have not been established. In addition, nontreponemal test titers might decline more slowly for persons who previously have had syphilis (207). Clinical and serologic evaluation should be performed 6 months and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain. Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed. Although failure of nontreponemal test titers to decline fourfold within 6-12 months after therapy for primary or secondary syphilis might be indicative of treatment failure, clinical trial data have demonstrated that >15% of patients with early syphilis treated with the recommended therapy will not achieve the two dilution decline in nontreponemal titer used to define response at 1 year after treatment (208). Persons whose titers do not decline should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should receive additional clinical and serologic follow-up. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations. For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis). In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline 100 mg orally twice daily for 14 days (209,210) and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years. Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone (1 g daily either IM or IV for 10-14 days) is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined (211). Azithromycin as a single 2-g oral dose is effective for treating early syphilis (212)(213)(214). However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in several geographical areas in the United States (215)(216)(217). As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used in MSM or pregnant women. Close followup of persons receiving any alternative therapies is essential. Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Patients Who Have a History of Penicillin Allergy). # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Latent Syphilis Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis. Patients' conditions can be diagnosed as early latent syphilis if, during the year preceding the evaluation, they had 1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis. In addition, for persons whose only possible exposure occurred during the previous 12 months, reactive nontreponemal and treponemal tests are indicative of early latent syphilis. In the absence of these conditions, an asymptomatic person should be considered to have late latent syphilis or syphilis of unknown duration. Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, perianal area, perineum and vagina in women, and underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection. # Treatment Because latent syphilis is not transmitted sexually, the objective of treating patients with this stage of disease is to prevent complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens. The following regimens are recommended for penicillin nonallergic patients who have normal CSF examinations (if performed). # Recommended Regimens for Adults- Early Latent Syphilis Benzathine penicillin G 2.4 million units IM in a single dose # Late Latent Syphilis or Latent Syphilis of Unknown Duration Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals - Recommendations for treating syphilis in HIV-infected persons and pregnant women are discussed later in this report (see Syphilis among HIV-Infected Persons and Syphilis in Pregnancy). Available data demonstrate no enhanced efficacy of additional doses of penicillin G, amoxicillin, or other antibiotics in early syphilis, regardless of HIV status. Infants and children aged ≥1 month who have been diagnosed with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results. # Recommended Regimens for Children Early Latent Syphilis Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose # Late Latent Syphilis or Latent Syphilis of Unknown Duration Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units) # other Management Considerations Patients diagnosed with latent syphilis who demonstrate any of the following criteria should have a prompt CSF examination: - Neurologic (e.g., auditory disease, cranial nerve dysfunction, acute or chronic meningitis, stroke, acute or chronic altered mental status, and loss of vibration sense) or ophthalmic signs or symptoms (e.g., iritis and uveitis); - evidence of active tertiary syphilis (e.g., aortitis and gumma); or - serologic treatment failure. If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, the appropriate course of action is unclear. Pharmacologic considerations suggest that an interval of 10-14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections. Missed doses are not acceptable for pregnant patients receiving therapy for late latent syphilis. Pregnant women who miss any dose of therapy must repeat the full course of therapy. # Follow-Up Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. A CSF examination should be performed if 1) titers increase fourfold, 2) an initially high titer (≥1:32) fails to decline at least fourfold (i.e., two dilutions) within 12-24 months of therapy, or 3) signs or symptoms attributable to syphilis develop. In such circumstances, even if the CSF examination is negative, retreatment for latent syphilis should be initiated. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers might fail to decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment). The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), both for 28 days. These therapies should be used only in conjunction with close serologic and clinical follow-up. Based on biologic plausibility and pharmacologic properties, ceftriaxone might be effective for treating late latent syphilis or syphilis of unknown duration. However, the optimal dose and duration of ceftriaxone therapy have not been defined, and treatment decisions should be discussed in consultation with a specialist. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. The efficacy of these alternative regimens in HIVinfected persons has not been well studied. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Tertiary Syphilis Tertiary syphilis refers to gumma and cardiovascular syphilis but not to all neurosyphilis. Patients who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen. # MMWR December 17, 2010 # Recommended Regimen Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals other Management Considerations Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. These patients should be managed in consultation with an infectious disease specialist. # Follow-Up Limited information is available concerning clinical response and follow-up of patients who have tertiary syphilis. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Patients allergic to penicillin should be treated in consultation with an infectious disease specialist. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. neurosyphilis Treatment CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed. Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response. # Recommended Regimen Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days If compliance with therapy can be ensured, the following alternative regimen might be considered. # Alternative Regimen Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10-14 days The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy. # other Management Considerations Other considerations in the management of patients who have neurosyphilis are as follows: - All persons who have syphilis should be tested for HIV. - Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial. # Follow-Up If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important (219,220). The leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered. Limited data suggest that in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters (220). # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10-14 days can be used as an alternative treatment for patients with neurosyphilis (221,222). However, the possibility of cross-reactivity between ceftriaxone and penicillin exists. Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, desensitization in consultation with a specialist. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Syphilis Among HIV-Infected Persons Diagnostic Considerations Although they are uncommon, unusual serologic responses have been observed among HIV-infected persons who have syphilis. Most reports have involved serologic titers that were higher than expected, but false-negative serologic test results and delayed appearance of seroreactivity also have been reported (223). Regardless, both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for most patients who are coinfected with T. pallidum and HIV. When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons. # Treatment Compared with HIV-negative patients, HIV-positive patients who have early syphilis might be at increased risk for neurologic complications (224) and might have higher rates of serologic treatment failure with currently recommended regimens. The magnitude of these risks is not defined precisely, but is likely small. No treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-negative patients (208). Careful follow-up after therapy is essential. # Primary and Secondary Syphilis Among HIV-Infected Persons # Treatment Treatment of primary and secondary syphilis among HIVinfected persons is benzathine penicillin G, 2.4 million units IM in a single dose. Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis do not result in enhanced efficacy, regardless of HIV status (208). # Other Management Considerations Most HIV-infected persons respond appropriately to standard benzathine penicillin for primary and secondary syphilis. CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in HIV-infected persons, even in those without neurologic symptoms, although the clinical and prognostic significance of such CSF abnormalities with primary and secondary syphilis is unknown. Several studies have demonstrated that among persons infected with both HIV and syphilis, clinical and CSF abnormalities consistent with neurosyphilis are associated with a CD4 count of ≤350 cells/mL and/or an RPR titer of ≥1:32 (204,225,226); however, unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes. The use of antiretroviral therapy as per current guidelines might improve clinical outcomes in HIV-infected persons with syphilis (220,227,228). # Follow-Up HIV-infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. HIV-infected persons who meet the criteria for treatment failure (i.e., signs or symptoms that persist or recur or persons who have a sustained fourfold increase in nontreponemal test titer) should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment). CSF examination and retreatment also should be strongly considered for persons whose nontreponemal test titers do not decrease fourfold within 6-12 months of therapy. If CSF examination is normal, treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. HIV-infected, penicillin-allergic patients who have primary or secondary syphilis should be managed according to the recommendations for penicillin-allergic, HIVnegative patients. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). The use of alternatives to penicillin has not been well studied in HIV-infected patients. These therapies should be used only in conjunction with close serologic and clinical follow-up. # Latent Syphilis Among HIV-Infected Persons # Treatment HIV-infected persons with latent syphilis should be treated according to the stage-specific recommendations for HIVnegative persons. - Treatment of early latent syphilis among HIV-infected persons is benzathine penicillin G, 2.4 million units IM in a single dose. - Treatment of late latent syphilis or syphilis of unknown duration among HIV-infected persons is benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks. # Other Management Considerations All HIV-infected persons with syphilis and neurologic symptoms should undergo immediate CSF examination. Some studies have demonstrated that clinical and CSF abnormalities consistent with neurosyphilis are most likely in HIV-infected persons who have been diagnosed with syphilis and have a CD4 count of ≤350 cells/ml and/or an RPR titer of ≥1:32 (204,225,226); however unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes. # Follow-Up Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. If during 12-24 months the nontreponemal titer does not decline fourfold, CSF examination should be strongly considered and treatment administered accordingly. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. The efficacy of alternative nonpenicillin regimens in HIV-infected persons has not been well studied. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). These therapies should be used only in conjunction with close serologic and clinical follow-up. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective (229,230). However, the optimal dose and duration of ceftriaxone therapy have not been defined. # neurosyphilis Among HIV-Infected Persons # Treatment HIV-infected patients with neurosyphilis should be treated according to the recommendations for HIV-negative patients with neurosyphilis (see Neurosyphilis). # Follow Up If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to gauge response after therapy. Limited data suggest that changes in CSF parameters might occur more slowly in HIV-infected patients, especially those with more advanced immunosuppression (219,227). If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, retreatment should be considered. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. HIV-infected, penicillin-allergic patients who have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis. Several small observational studies conducted in HIV-infected patients with neurosyphilis suggest that ceftriaxone 1-2 g IV daily for 10-14 days might be effective as an alternate agent (218,229,230). # Syphilis During Pregnancy All women should be screened serologically for syphilis early in pregnancy. Most states mandate screening at the first prenatal visit for all women (231); antepartum screening by nontreponemal antibody testing is typical, but in some settings, treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers. In populations in which use of prenatal care is not optimal, RPR test screening and treatment (if the RPR test is reactive) should be performed at the time that pregnancy is confirmed (232). For communities and populations in which the prevalence of syphilis is high and for patients at high risk, serologic testing should be performed twice during the third trimester (ideally at 28-32 weeks' gestation) and at delivery. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy. # Diagnostic Considerations Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined. Serofast low antibody titers might not require treatment; however, persistent higher titer antibody tests might indicate reinfection, and treatment might be required. # Treatment Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection (233). Evidence is insufficient to determine optimal, recommended penicillin regimens (234). # Recommended Regimen Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection. # other Management Considerations Some evidence suggests that additional therapy can be beneficial for pregnant women in some settings (e.g., a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis) (235). When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure (231); such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction (236). These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection. # Follow-Up Coordinated prenatal care and treatment are vital. Serologic titers should be repeated at 28-32 weeks' gestation and at delivery as recommended for the disease stage. Providers should ensure that the clinical and antibody responses are appropriate for the patient's stage of disease, although most women will deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer at delivery is fourfold higher than the pretreatment titer. Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Oral step-wise penicillin dose challenge or skin testing might be helpful in identifying women at risk for acute allergic reactions (see Management of Patients Who Have a History of Penicillin Allergy). Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin and azithromycin should not be used, because neither reliably cures maternal infection or treats an infected fetus (234). Data are insufficient to recommend ceftriaxone for treatment of maternal infection and prevention of congenital syphilis. # MMWR December 17, 2010 # HIV Infection Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIVinfected women should be evaluated for syphilis and receive treatment as recommended. Data are insufficient to recommend a specific regimen for HIV-infected pregnant women (see Syphilis Among HIV-Infected Patients). # Congenital Syphilis Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. In communities and populations in which the risk for congenital syphilis is high, serologic testing and a sexual history also should be obtained at 28 weeks' gestation and at delivery. Moreover, as part of the management of pregnant women who have syphilis, information concerning the treatment of sex partners should be obtained to assess the risk for reinfection. Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother's serum is preferred rather than testing of the infant's serum because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or the mother was infected late in pregnancy (see Diagnostic Considerations and Use of Serologic Tests). Screening can be performed using either a nontreponemal or treponemal test. If either screening test is positive, testing must be performed immediately using the other complimentary test (i.e., nontreponemal test followed by treponemal test or vice-versa). No infant or mother should leave the hospital unless maternal serologic status has been documented at least once during pregnancy; in communities and populations in which the risk for congenital syphilis is high, documentation should also occur at delivery. # Evaluation and Treatment of Infants During the First Month of Life The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus, which can complicate the interpretation of reactive serologic tests for syphilis in infants. Therefore, treatment decisions frequently must be made on the basis of 1) identification of syphilis in the mother; 2) adequacy of maternal treatment; 3) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and 4) comparison of maternal (at delivery) and infant nontreponemal serologic titers using the same test conducted preferably by the same laboratory. All infants born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on infant serum, because umbilical cord blood can become contaminated with maternal blood and yield a falsepositive result. Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or chemiluminescence assay) on a newborn's serum is not necessary. No commercially available immunoglobulin (IgM) test can be recommended. All infants born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (e.g., nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and pseudoparalysis of an extremity). Pathologic examination of the placenta or umbilical cord using specific fluorescent antitreponemal antibody staining is suggested. Darkfield microscopic examination of suspicious lesions or body fluids (e.g., nasal discharge) also should be performed. The following scenarios describe the evaluation and treatment of infants for congenital syphilis. # Scenario 1 Infants with proven or highly probable disease and 1. an abnormal physical examination that is consistent with congenital syphilis; 2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; ¶ or 3. a positive darkfield test of body fluid(s). # Recommended Evaluation - CSF analysis for VDRL, cell count, and protein # Recommended Regimens Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant. # Scenario 2 Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother was not treated, inadequately treated, or has no documentation of having received treatment; 2. mother was treated with erythromycin or another nonpenicillin regimen; † † or 3. mother received treatment <4 weeks before delivery. # Recommended Evaluation - CSF analysis for VDRL, cell count, and protein - CBC, differential, and platelet count - Long-bone radiographs A complete evaluation is not necessary if 10 days of parenteral therapy is administered, although such evaluations might be useful. For instance, a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) can be performed to further support a diagnosis of congenital syphilis. If a single dose of benzathine penicillin G is used, then the infant must be fully evaluated (i.e., by CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and follow-up must be certain. If any part of the infant's evaluation is abnormal or not performed or if the CSF analysis is rendered uninterpretable because of contamination with blood, then a 10-day course of penicillin is required. § § # Recommended Regimens Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days OR Benzathine penicillin G 50,000 units/kg/dose IM in a single dose If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered. # Scenario 3 Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and 2. mother has no evidence of reinfection or relapse. # Recommended Evaluation No evaluation is required. # Recommended Regimen Benzathine penicillin G 50,000 units/kg/dose IM in a single dose- - Another approach involves not treating the infant, but rather providing close serologic follow-up in those whose mother's nontreponemal titers decreased fourfold after appropriate therapy for early syphilis or remained stable or low for late syphilis. # Scenario 4 Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother's treatment was adequate before pregnancy and 2. mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4). # Recommended Evaluation No evaluation is required. # Recommended Regimen No treatment is required; however, benzathine penicillin G 50,000 units/kg as a single IM injection might be considered, particularly if follow-up is uncertain. † † A woman treated with a regimen other than those recommended in these guidelines for treatment should be considered untreated. § § If the infant's nontreponemal test is nonreactive and the provider determines that the mother's risk for untreated syphilis is low, treatment of the infant (single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis) without an evaluation can be considered. # Evaluation and Treatment of older Infants and Children Older infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children). Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection. # Recommended Evaluation - CSF analysis for VDRL, cell count, and protein - CBC, differential, and platelet count - Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, and auditory brain stem response) # Recommended Regimen Aqueous crystalline penicillin G 200,000-300,000 units/kg/day IV, administered as 50,000 units/kg every 4-6 hours for 10 days If the child has no clinical manifestations of disease, the CSF examination is normal, and the CSF VDRL test result is negative, treatment with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM can be considered. Any child who is suspected of having congenital syphilis or who has neurologic involvement should be treated with aqueous penicillin G. A single dose of benzathine penicillin G, 50,000 units/kg IM after the 10-day course of IV aqueous penicillin can be considered. This treatment also would be adequate for children who might have other treponemal infections. # Follow-Up All seroreactive infants (or infants whose mothers were seroreactive at delivery) should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2-3 months until the test becomes nonreactive or the titer has decreased fourfold. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months if the infant is not infected (i.e., if the reactive test result was caused by passive transfer of maternal IgG antibody) or was infected but adequately treated. The serologic response after therapy might be slower for infants treated after the neonatal period. If these titers are stable or increase after age 6-12 months, the child should be evaluated (e.g., given a CSF examination) and treated with a 10-day course of parenteral penicillin G. Treponemal tests should not be used to evaluate treatment response, because the results for an infected child can remain positive despite effective therapy. Passively transferred maternal treponemal antibodies can be present in an infant until age 15 months; therefore, a reactive treponemal test after age 18 months is diagnostic of congenital syphilis. If the nontreponemal test is nonreactive at this time, no further evaluation or treatment is necessary. If the nontreponemal test is reactive at age 18 months, the infant should be fully (re)evaluated and treated for congenital syphilis. Infants whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. A reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis. Follow-up of children treated for congenital syphilis after the newborn period should be conducted as recommended for neonates. # Special Considerations # Penicillin Allergy Infants and children who require treatment for syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized, if necessary, and then treated with penicillin (see Management of Patients With a History of Penicillin Allergy). Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone); if a nonpenicillin agent is used, close serologic and CSF follow-up are indicated. # Penicillin Shortage During periods when the availability of penicillin is compromised, the following is recommended (see . gov/std/treatment/misc/penicillinG.htm). 1. For infants with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days). If aqueous or procaine penicillin G is not available, ceftriaxone (in doses appropriate for age and weight) can be considered with careful clinical and serologic follow-up. Ceftriaxone must be used with caution in infants with jaundice. For infants aged ≥30 days, use 75 mg/kg IV/IM a day in a single daily dose for 10-14 days; however, dose adjustment might be necessary based on current weight. For older infants, the dose should be 100 mg/kg a day in a single daily dose. Evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis. Therefore, ceftriaxone should be used in consultation with a specialist in the treatment of infants with congenital syphilis. Management may include a repeat CSF examination at age 6 months if the initial examination was abnormal. # HIV Infection Evidence is insufficient to determine whether infants who have congenital syphilis and whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants. # Management of Persons Who Have a History of Penicillin Allergy No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%-10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin (238,239), such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Readministration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity. Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin continue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE (238,239). These persons can then be treated safely with penicillin. Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions (238,239). Although these reagents are easily generated and have been available for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen ) and penicillin G have been available commercially. These two tests identify an estimated 90%-97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%-10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant-positive patients, caution should be exercised when the full battery of skin-test reagents is not available (Box 2). Manufacturers are working to ensure better availability of the Pre-Pen skin test reagent as well as an accompanying minor determinant mixture. # Recommendations If the full battery of skin-test reagents is available, including both major and minor determinants (see Penicillin Allergy Skin Testing), patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test-positive patients should be desensitized before initiating treatment. If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. One approach suggests that persons with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another approach in those with negative skin-test results involves testdosing gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided. If the major determinant (Pre-Pen) is not available for skin testing, all patients with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In patients with reactions not likely to be IgE-mediated, outpatient-monitored test doses can be considered. # Penicillin Allergy Skin Testing Patients at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous or 2) are being treated with beta-adrenergic blocking agents, should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or fexafenadine during the preceding 24 hours, diphenhydramine HCl during the preceding 4 days, or hydroxyzine or phenathiazines during the preceding 3 weeks). # Procedures Dilute the antigens either 100-fold for preliminary testing (if the patient has had a life-threatening reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year). # Epicutaneous (Prick) Tests Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is ≥4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs. # Intradermal Test If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26-or 27-gauge needle on a syringe. The margins of the wheals induced by the injections should be marked with a ball point pen. An intradermal test is positive if the average wheal diameter 15 minutes after injection is >2 mm larger than the initial wheal size and also is >2 mm larger than the negative controls. Otherwise, the tests are negative. # Desensitization Patients who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1). This is a straightforward, relatively safe procedure that can be performed orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur. Desensitization usually can be completed in approximately 4-12 hours, after which time the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy. # Diseases Characterized by Urethritis and Cervicitis Urethritis Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are common. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis (240)(241)(242)(243). If clinic-based diagnostic tools (e.g., Gram-stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to health departments and a specific diagnosis might improve partner notification and treatment. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and hybridization tests require urethral swab specimens, whereas NAATs can be performed on urine specimens. Because of their Penicillin G should be freshly prepared or should come from a freshfrozen source. higher sensitivity, NAATs are preferred for the detection of C. trachomatis (197). # Etiology Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU), which is diagnosed when examination findings or microscopy indicate inflammation without GNID, is caused by C. trachomatis in 15%-40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men (244). Complications of NGU among males infected with C. trachomatis include epididymitis and Reiter's syndrome. Documentation of chlamydial infection is essential because of the need for partner referral for evaluation and treatment. In most cases of nonchlamydial NGU, no pathogen can be detected. M. genitalium, which appears to be sexually transmitted, is associated with both symptoms of urethritis and urethral inflammation and accounts for 15%-25% of NGU cases in the United States (240)(241)(242)(243). T. vaginalis, HSV, and adenovirus also can cause NGU, but data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent (244)(245)(246)(247). Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, genital lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (244). # Confirmed Urethritis Clinicians should attempt to obtain objective evidence of urethral inflammation. However, if clinic-based diagnostic tools (e.g., Gram-stain microscopy) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Urethritis can be documented on the basis of any of the following signs or laboratory tests: - Mucopurulent or purulent discharge on examination. - Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis and is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing GNID. - Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high-power field. If none of these criteria are present, testing for N. gonorrhoeae and C. trachomatis using NAATs might identify additional infections (248). If the results demonstrate infection with either of these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment. If none of these criteria are present, empiric treatment of symptomatic males is recommended only for men at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated with drug regimens effective against gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated, if indicated. # nongonococcal Urethritis Diagnosis All patients who have confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Testing for chlamydia is strongly recommended because of the increased utility and availability of highly sensitive and specific testing methods (e.g., NAATs) and because a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in the exposed partner. # Treatment Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium respond better to azithromycin (249,250). Single-dose regimens have the advantage of improved compliance and directly observed treatment. To maximize compliance with recommended therapies, medications should be dispensed on-site in the clinic, and the first dose should be directly observed. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days To minimize transmission, men treated for NGU should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen, provided their symptoms have resolved. To minimize the risk for reinfection, men should be instructed to abstain from sexual intercourse until all of their sex partners are treated. Persons who have been diagnosed with a new STD should receive testing for other infections, including syphilis and HIV. # Follow-Up Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment. Providers should be alert to the possibility of chronic prostatitis/ chronic pelvic pain syndrome in male patients experiencing persistent pain (perineal, penile, or pelvic), discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months. Unless a patient's symptoms persist or therapeutic noncompliance or reinfection is suspected by the provider, a test-ofcure (i.e., repeat testing 3-4 weeks after completing therapy) is not recommended for persons with documented chlamydia or gonococcal infections who have received treatment with recommended or alterative regimens. However, because men with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment (251,252), repeat testing of all men diagnosed with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether patients believe that their sex partners were treated (251). # Partner Referral A specific diagnosis might facilitate partner referral. Therefore, testing for gonorrhea and chlamydia is encouraged. Because a substantial proportion of female partners of males with nonchlamydial NGU are infected with chlamydia, partner management is recommended for males with NGU regardless of whether a specific etiology is identified. All sex partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment with a drug regimen effective against chlamydia. Expedited partner treatment and patient referral are alternative approaches to treating partners (71). # Recurrent and Persistent Urethritis Objective signs of urethritis should be present before the initiation of antimicrobial therapy. In persons who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or recurrent urethritis can be retreated with the initial regimen if they did not comply with the treatment regimen or if they were reexposed to an untreated sex partner. Persistent urethritis after doxycycline treatment might be caused by doxycyclineresistant U. urealyticum or M. genitalium. T. vaginalis is also known to cause urethritis in men; a urethral swab, first void urine, or semen for culture or a NAAT (PCR or TMA) on a urethral swab or urine can be performed. If compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended while awaiting the results of the diagnostic tests. Studies involving a limited number of patients who experienced NGU treatment failures have demonstrated that Moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium (253,254). Men with a low probability of T. vaginalis (e.g., MSM) are unlikely to benefit from the addition of metronidazole or tinidazole. # Recommended Regimens Urologic examinations usually do not reveal a specific etiology for urethritis. A four-glass Meares-Stamey lower-urinarytract localization procedure (or four-glass test) might be helpful in localizing pathogens to the prostate (255). A substantial proportion of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. Estimates vary considerably depending on the source and sensitivity of the assay, but one study demonstrated that in 50% of men with this syndrome, ≥5 WBCs per high-power field were detected in expressed prostatic secretions (256). Referral to a urologist should be considered for men who experience pain for more than 3 months within a 6-month period. If men require treatment with a new antibiotic regimen for persistent urethritis and a sexually transmitted agent is the suspected cause, all partners in the past 60 days before the initial diagnosis and any interim partners should be referred for evaluation and appropriate treatment. # Special Considerations HIV Infection Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might facilitate HIV transmission. Patients who have NGU and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Cervicitis Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis or cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (257,258). Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in most clinical settings. Finally, although the presence of GNID on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is not a sensitive indicator, because it is observed in only 50% of women with this infection. # Etiology When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in most cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (e.g., women aged >30 years). Limited data indicate that infection with M. genitalium and BV and frequent douching might cause cervicitis (259)(260)(261)(262)(263). For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because most persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other factors (e.g., persistent abnormality of vaginal flora, douching , or idiopathic inflammation in the zone of ectopy) might be involved. # Diagnosis Because cervicitis might be a sign of upper-genital-tract infection (endometritis), women who seek medical treatment for a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with the most sensitive and specific test available. Women with cervicitis also should be evaluated for the presence of BV and trichomoniasis, and if these organisms are detected, they should be treated. Because the sensitivity of microscopy to detect T. vaginalis is relatively low (approximately 50%), symptomatic women with cervicitis and negative microscopy for trichomonads should receive further testing (i.e., culture or other FDA-cleared method). Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (i.e., culture or serologic testing) for HSV-2 in this setting is unknown. Standardized diagnostic tests for M. genitalium are not commercially available. As discussed, NAAT should be used for diagnosing C. trachomatis and N. gonorrhoeae in women with cervicitis; this testing can be performed on either vaginal, cervical, or urine samples (197). A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (264,265). # Treatment Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided for those women at increased risk for this common STD (e.g., those aged ≤25 years, those with new or multiple sex partners, and those who engage in unprotected sex), especially if follow-up cannot be ensured and if a relatively insensitive diagnostic test is used in place of NAAT. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is >5% (those in younger age groups and those living in certain facilities). Trichomoniasis and BV should also be treated if detected. For women in whom any component of (or all) presumptive therapy is deferred, the results of sensitive tests for C. trachomatis and N. gonorrhoeae (e.g., NAATs) should determine the need for treatment subsequent to the initial evaluation. # Recommended Regimens for Presumptive Treatment* Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days - Consider concurrent treatment for gonococcal infection if prevalence of gonorrhea is high in the patient population under assessment. # Recurrent and Persistent Cervicitis Women with persistent cervicitis should be reevaluated for possible reexposure to an STD. If relapse and/or reinfection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined; in addition, the utility of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis remains unknown. Women who receive such therapy should return after treatment so that a determination can be made regarding whether cervicitis has resolved. Research is needed on the etiology of persistent cervicitis including the potential role of M. genitalium (266). In women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered. # Follow-Up Follow-up should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for re-evaluation because women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment. Therefore, repeat testing of all women with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267). # Management of Sex Partners Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the index patient; these partners should then be treated for the STDs for which the index patient received treatment. To avoid reinfection, patients and their sex partners should abstain from sexual intercourse until therapy is completed (i.e., 7 days after a single-dose regimen or after completion of a 7-day regimen). Expedited partner treatment and patient referral (see Partner Management) are alternative approaches to treating male partners of women that have chlamydia or gonococcal infections (68,69,71). # Special Considerations HIV Infection Patients who have cervicitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (268)(269)(270). # Chlamydial Infections Chlamydial Infections in Adolescents and Adults Chlamydial genital infection is the most frequently reported infectious disease in the United States, and prevalence is highest in persons aged ≤25 years (93). Several important sequelae can result from C. trachomatis infection in women, the most serious of which include PID, ectopic pregnancy, and infertility. Some women who have uncomplicated cervical infection already have subclinical upper-reproductive-tract infection upon diagnosis. Asymptomatic infection is common among both men and women. To detect chlamydial infections, health-care providers frequently rely on screening tests. Annual screening of all sexually active women aged ≤25 years is recommended, as is screening of older women with risk factors (e.g., those who have a new sex partner or multiple sex partners). In June 2007, USPSTF reviewed and updated their chlamydia screening guidance and found that the epidemiology of chlamydial infection in the United States had not changed since the last review (81,271). In issuing recommendations, USPSTF made the decision to alter the age groups used to demonstrate disease incidence (i.e., from persons aged ≤25 years to those aged ≤24 years). CDC has not changed its age cutoff, and thus continues to recommend annual chlamydia screening of sexually active women aged ≤25 years. Screening programs have been demonstrated to reduce both the prevalence of C. trachomatis infection and rates of PID in women (272,273). Although evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men because of several factors (including feasibility, efficacy, and cost-effectiveness) ( 94), the screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics). Among women, the primary focus of chlamydia screening efforts should be to detect chlamydia and prevent complications, whereas targeted chlamydia screening in men should only be considered when resources permit and do not hinder chlamydia screening efforts in women (274 275). An appropriate sexual risk assessment should be conducted for all persons and might indicate more frequent screening for some women or certain men (see MSM). # Diagnostic Considerations C. trachomatis urogenital infection in women can be diagnosed by testing urine or by collecting swab specimens from the endocervix or vagina. Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatis infections in persons that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. NAATs, cell culture, direct immunofluorescence, EIA, and nucleic acid hybridization tests are available for the detection of C. trachomatis on endocervical specimens and urethral swab specimens from men (197). NAATs are the most sensitive tests for these specimens and are FDA-cleared for use with urine. Some NAATs are cleared for use with vaginal swab specimens, which can be collected by a provider or self-collected by a patient. Self-collected vaginal swab specimens perform at least as well as with other approved specimens using NAATs (276,277), and women find this screening strategy highly acceptable. Rectal and oropharyngeal C. trachomatis infection in persons engaging in receptive anal or oral intercourse can be diagnosed by testing at the anatomic site of exposure. Most tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal or oropharyngeal swab specimens, and chlamydia culture is not widely available for this purpose. However, NAATs have demonstrated improved sensitivity and specificity compared with culture for the detection of C. trachomatis at rectal sites (278)(279)(280) and at oropharyngeal sites among men (278)(279)(280)(281). Some laboratories have met CLIA requirements and have validated NAAT testing on rectal swab specimens for C. trachomatis. Recent evidence suggests that the liquid-based cytology specimens collected for Pap smears might be acceptable specimens for NAAT testing, although test sensitivity using these specimens might be lower than those resulting from the use of cervical swab specimens (282); regardless, certain NAATs have been FDA-cleared for use on liquid-based cytology specimens. Persons who undergo testing and are diagnosed with chlamydia should be tested for other STDs. # Treatment Treating infected patients prevents sexual transmission of the disease, and treating all sex partners of those testing positive for chlamydia can prevent reinfection of the index patient and infection of other partners. Treating pregnant women usually prevents transmission of C. trachomatis to infants during birth. Chlamydia treatment should be provided promptly for all persons testing positive for infection; delays in receiving chlamydia treatment have been associated with complications (e.g., PID) in a limited proportion of chlamydia-infected subjects (283). Coinfection with C. trachomatis frequently occurs among patients who have gonococcal infection; therefore, presumptive treatment of such patients for chlamydia is appropriate (see Gonococcal Infection, Dual Therapy for Gonococcal and Chlamydial Infections). The following recommended treatment regimens and alternative regimens cure infection and usually relieve symptoms. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of genital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively (284). These studies were conducted primarily in populations in which follow-up was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT) was used for determining microbiological outcome. Azithromycin should always be available to treat patients for whom compliance with multiday dosing is uncertain. The clinical significance and transmissibility of C. trachomatis detected at oropharyngeal sites is unclear (285), and the efficacy of different antibiotic regimens in resolving oropharyngeal chlamydia remains unknown. In patients who have erratic health-care-seeking behavior, poor treatment compliance, or unpredictable follow-up, azithromycin might be more cost-effective in treating chlamydia because it enables the provision of a single-dose of directly observed therapy (284). Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that can lead to noncompliance. Levofloxacin and ofloxacin are effective treatment alternatives but are more expensive and offer no advantage in the dosage regimen. Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately. To maximize compliance with recommended therapies, medications for chlamydial infections should be dispensed on site, and the first dose should be directly observed. To minimize disease transmission to sex partners, persons treated for chlamydia should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen. To minimize the risk for reinfection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated. # Follow-Up Except in pregnant women, test-of-cure (i.e., repeat testing 3-4 weeks after completing therapy) is not advised for persons treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected. Moreover, the validity of chlamydial diagnostic testing at <3 weeks after completion of therapy (to identify patients who did not respond to therapy) has not been established. False-negative results might occur in the presence of persistent infections involving limited numbers of chlamydial organisms. In addition, NAAT conducted at <3 weeks after completion of therapy in persons who were treated successfully could yield false-positive results because of the continued presence of nonviable organisms (197). A high prevalence of C. trachomatis infection has been observed in women and men who were treated for chlamydial infection during the preceding several months (251,267,(286)(287)(288). Most post-treatment infections result from reinfection caused by failure of sex partners to receive treatment or the initiation of sexual activity with a new infected partner. Repeat infections confer an elevated risk for PID and other complications. Unlike the test-of-cure, which is not recommended, repeat C. trachomatis testing of recently infected women or men should be a priority for providers. Chlamydia-infected women and men should be retested approximately 3 months after treatment, regardless of whether they believe that their sex partners were treated (251,267). If retesting at 3 months is not possible, clinicians should retest whenever persons next present for medical care in the 12 months following initial treatment. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation, testing, and treatment if they had sexual contact with the patient during the 60 days preceding onset of the patient's symptoms or chlamydia diagnosis. Although the exposure intervals defined for the identification of at-risk sex partners are based on limited evaluation, the most recent sex partner should be evaluated and treated, even if the time of the last sexual contact was >60 days before symptom onset or diagnosis. Among heterosexual patients, if concerns exist that sex partners who are referred to evaluation and treatment will not seek these services (or if other management strategies are impractical or unsuccessful), patient delivery of antibiotic therapy to their partners can be considered (see Partner Management). Compared with standard partner referral, this approach, which involves delivering a prescription or the medication itself, has been associated with a trend toward a decrease in rates of persistent or recurrent chlamydia (68,69,71). Patients must also inform their partners of their infection and provide them with written materials about the importance of seeking evaluation for any symptoms suggestive of complications (e.g., testicular pain in men and pelvic or abdominal pain in women). Patient-delivered partner therapy is not routinely recommended for MSM because of a high risk for coexisting infections, especially undiagnosed HIV infection, in their partners. Patients should be instructed to abstain from sexual intercourse until they and their sex partners have completed treatment. Abstinence should be continued until 7 days after a single-dose regimen or after completion of a multiple-dose regimen. Timely treatment of sex partners is essential for decreasing the risk for reinfecting the index patient. # Special Considerations Pregnancy Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women. However, clinical experience and published studies suggest that azithromycin is safe and effective (289)(290)(291). Repeat testing to document chlamydial eradication (preferably by NAAT) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women to ensure therapeutic cure, considering the severe sequelae that might occur in mothers and neonates if the infection persists. Women aged <25 years and those at increased risk for chlamydia (i.e., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant (81). Pregnant women diagnosed with a chlamydial infection during the first trimester should not only receive a test to document chlamydial eradication, but be retested 3 months after treatment. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Amoxicillin 500 mg orally three times a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin base 250 mg orally four times a day for 14 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 400 mg orally four times a day for 14 days The frequent gastrointestinal side effects associated with erythromycin can result in noncompliance with the alternative regimens. Although erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity, the lower dose 14-day erythromycin regimens can be considered if gastrointestinal tolerance is a concern. # HIV Infection Patients who have chlamydial infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Chlamydial Infections Among Infants Prenatal screening and treatment of pregnant women can prevent chlamydial infection among neonates. Pregnant women aged <25 years are at high risk for infection. C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. Although neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant, ocular prophylaxis with these agents does prevent gonococcal ophthalmia and therefore should be administered (see Ophthalmia Neonatorum Prophylaxis). Initial C. trachomatis perinatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, although infection might be asymptomatic in these locations. Instead, C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5-12 days after birth. C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1-3 months. Although C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, perinatal chlamydial infections (including ophthalmia and pneumonia) have occurred less frequently because of the institution of widespread prenatal screening and treatment of pregnant women. # ophthalmia neonatorum Caused by C. trachomatis A chlamydial etiology should be considered for all infants aged ≤30 days who have conjunctivitis, especially if the mother has a history of untreated chlamydia infection. # Diagnostic Considerations Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescence antibody tests, EIA, and NAAT). Most nonculture tests are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations. Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a dacron-tipped swab or the swab specified by the manufacturer's test kit, and they must contain conjunctival cells, not exudate alone. Specific diagnosis of C. trachomatis infection confirms the need for treatment not only for the neonate, but also for the mother and her sex partner(s). Ocular specimens from infants being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae. # MMWR December 17, 2010 # Recommended Regimen Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days- , † - An association between oral erythromycin and infantile hypertrophic pyloric stenosis (IHIS) has been reported in infants aged <6 weeks who were treated with this drug. Infants treated with erythromycin should be followed for signs and symptoms of IHPS. † Data on use of other macrolides (e.g., azithromycin and clarithromycin) for the treatment of neonatal chlamydia infection are limited. The results of one study involving a limited number of patients suggest that a short course of azithromycin, 20 mg/kg/day orally, 1 dose daily for 3 days, might be effective (292). Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered. # Follow-Up Because the efficacy of erythromycin treatment is only approximately 80%, a second course of therapy might be required. Therefore, follow-up of infants is recommended to determine whether initial treatment was effective. The possibility of concomitant chlamydial pneumonia should be considered. # Management of Mothers and Their Sex Partners The mothers of infants who have chlamydial infection and the sex partners of these women should be evaluated and treated (see Chlamydial Infection in Adolescents and Adults). # Infant Pneumonia Caused by C. trachomatis Characteristic signs of chlamydial pneumonia in infants include 1) a repetitive staccato cough with tachypnea and 2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. In addition, peripheral eosinophilia (≥400 cells/ mm 3 ) occurs frequently. Wheezing is rare, and infants are typically afebrile. Because clinical presentations differ, initial treatment and diagnostic tests should include C. trachomatis for all infants aged 1-3 months who are suspected of having pneumonia (especially those whose mothers have untreated chlamydial infection). # Diagnostic Considerations Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, DFA, and NAAT) can be used, although nonculture tests of nasopharyngeal specimens have a lower sensitivity and specificity than nonculture tests of ocular specimens. DFA is the only FDA-cleared test for the detection of C. trachomatis from nasopharyngeal specimens. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis. Because test results for chlamydia often are not available in a timely manner, the decision to provide treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings. The results of tests for chlamydial infection assist in the management of an infant's illness and can help determine the need for treating the mother and her sex partner(s). # Recommended Regimen Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days # Follow-Up The effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%; a second course of therapy might be required. Follow-up of infants is recommended to determine whether the pneumonia has resolved, although some infants with chlamydial pneumonia continue to have abnormal pulmonary function tests later in childhood. # Management of Mothers and Their Sex Partners Mothers of infants who have chlamydia pneumonia and the sex partners of these women should be evaluated and treated according to the recommended treatment of adults for chlamydial infections (see Chlamydial Infection in Adolescents and Adults). # Infants Born to Mothers Who Have Chlamydial Infection Infants born to mothers who have untreated chlamydia are at high risk for infection; however, prophylatic antibiotic treatment is not indicated, and the efficacy of such treatment is unknown. Infants should be monitored to ensure appropriate treatment if symptoms develop. # Chlamydial Infections Among Children Sexual abuse must be considered a cause of chlamydial infection in preadolescent children, although perinatally transmitted C. trachomatis infection of the nasopharynx, urogenital tract, and rectum might persist for >1 year (see Sexual Assault or Abuse of Children). # Diagnostic Considerations Nonculture, nonamplified probe tests for chlamydia (EIA and DFA) should not be used because of the possibility of false-positive test results. With respiratory-tract specimens, false-positive results can occur because of cross-reaction of test reagents with C. pneumoniae; with genital and anal specimens, false-positive results might occur as a result of cross-reaction with fecal flora. # Recommended Regimen for Children Who Weigh <45 kg Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days # Recommended Regimen for Children Who Weigh ≥45 kg but Who Are Aged <8 Years Azithromycin 1 g orally in a single dose # Recommended Regimens for Children Aged ≥8 years # Follow-Up Follow-up cultures are necessary to ensure that treatment has been effective. # Gonococcal Infections Gonococcal Infections in Adolescents and Adults In the United States, an estimated 700,000 new N. gonorrhoeae infections occur each year (93,293). Gonorrhea is the second most commonly reported bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce symptoms that cause them to seek curative treatment soon enough to prevent serious sequelae, but treatment might not be soon enough to prevent transmission to others. Among women, gonococcal infections might not produce recognizable symptoms until complications (e.g., PID) have occurred. PID can result in tubal scarring that can lead to infertility or ectopic pregnancy. The prevalence of gonorrhea varies widely among communities and populations; health-care providers should consider local gonorrhea epidemiology when making screening decisions. Although widespread screening is not recommended because gonococcal infections among women are frequently asymptomatic, targeted screening of young women (i.e., those aged <25 years) at increased risk for infection is a primary component of gonorrhea control in the United States. For sexually active women, including those who are pregnant, USPSTF (82) recommends that clinicians provide gonorrhea screening only to those at increased risk for infection (e.g., women with previous gonorrhea infection, other STDs, new or multiple sex partners, and inconsistent condom use; those who engage in commercial sex work and drug use; women in certain demographic groups; and those living in communities with a high prevalence of disease). USPSTF does not recommend screening for gonorrhea in men and women who are at low risk for infection (82). # Diagnostic Considerations Because of its high specificity (>99%) and sensitivity (>95%), a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men. In addition, Gram stain of endocervical specimens, pharyngeal, or rectal specimens also are not sufficient to detect infection, and therefore are not recommended. Specific testing for N. gonorrhoeae is recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification. Specific diagnosis of infection with N. gonorrhoeae can be performed by testing endocervical, vaginal, urethral (men only), or urine specimens. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of genitourinary infection with N. gonorrhoeae (197). Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens. NAATs allow testing of the widest variety of specimen types including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women), and they are FDA-cleared for use. However, product inserts for each NAAT vendor must be carefully examined, because specimen types that are FDA-cleared for use vary by test. NAAT tests are not FDA-cleared for use in the rectum, pharynx, and conjunctiva; however, some public and private laboratories have established performance specifications for using NAAT with rectal and pharyngeal swab specimens, thereby allowing results to be used for clinical management. Laboratories that establish performance specifications for the use of NAATs with nongenital specimens must ensure that specificity is not compromised by cross-reaction with nongonococcal Neisseria species. The sensitivity of NAATs for the detection of N. gonorrhoeae in genital and nongenital anatomic sites is superior to culture but varies by NAAT type (197,(278)(279)(280)(281). Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing. All persons found to have who have gonorrhea also should be tested for other STDs, including chlamydia, syphilis, and HIV. # Dual Therapy for Gonococcal and Chlamydial Infections Patients infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the recommendation that patients treated for gonococcal infection also be treated routinely with a regimen that is effective against uncomplicated genital C. trachomatis infection (294). Because most gonococci in the United States are susceptible to doxycycline and azithromycin, routine cotreatment might also hinder the development of antimicrobial-resistant N. gonorrhoeae. Limited data suggest that dual treatment with azithromycin might enhance treatment efficacy for pharyngeal infection when using oral cephalosporins (295,296). # Antimicrobial-Resistant N. gonorrhoeae Gonorrhea treatment is complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobial therapies (297). Quinolone-resistant N. gonorrhoeae strains are now widely disseminated throughout the United States and the world (298). As of April 2007, quinolones are no longer recommended in the United States for the treatment of gonorrhea and associated conditions, such as PID (299). Consequently, only one class of antimicrobials, the cephalosporins, is recommended and available for the treatment of gonorrhea in the United States. The CDC website (/ gisp) and state health departments can provide the most current information. The proportion of isolates in CDC's Gonococcal Isolate Surveillance Project (GISP) demonstrating decreased susceptibility to ceftriaxone or cefixime has remained very low over time; during 1987-2008, only four isolates were found to have decreased susceptibility to ceftriaxone, and 48 isolates had decreased susceptibility to cefixime. In 2008, no isolates demonstrated decreased susceptibility to ceftriaxone; cefixime was not part of test panel during that year (93). Although only two cases of suspected treatment failure with ceftriaxone have been reported (300), approximately 50 patients are thought to have failed oral cephalosporin treatment (301)(302)(303)(304). Most of the treatment failures resulting from use of oral cephalosporins have been reported from Asian countries, although one possible case was reported in Hawaii in 2001 (305). To ensure appropriate antibiotic therapy, clinicians should ask patients testing positive for gonorrhea about recent travel to and sexual activity in these countries. Decreased susceptibility of N. gonorrhoeae to cephalosporins and other antimicrobials is expected to continue to spread; therefore, state and local surveillance for antimicrobial resistance is crucial for guiding local therapy recommendations (297). GISP, which samples approximately 3% of all U.S. men who have gonococcal infections, is a mainstay of surveillance. However, surveillance by clinicians also is critical. Clinicians who diagnose N. gonorrhoeae infection in a patient with suspected cephalosporin treatment failure should perform culture and susceptibility testing of relevant clinical specimens, consult a specialist for guidance in clinical management, and report the case to CDC through state and local public health authorities. Health departments should prioritize partner notification and contact tracing of patients with N. gonorrhoeae infection thought to be associated with cephalosporin treatment failure or associated with patients whose isolates demonstrate decreased susceptibility to cephalosporin. To maximize compliance with recommended therapies, medications for gonococcal infections should be dispensed on site. Ceftriaxone in a single injection of 250 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 99.2% of uncomplicated urogenital and anorectal and 98.9% of pharyngeal infections in published clinical trials (306,307). A 250-mg dose of ceftriaxone is now recommended over a 125-mg dose given the 1) increasingly wide geographic distribution of isolates demonstrating decreased susceptibility to cephalosporins in vitro, 2) reports of ceftriaxone treatment failures, 3) improved efficacy of ceftriaxone 250 mg in pharyngeal infection (which is often unrecognized), and 4) the utility of having a simple and consistent recommendation for treatment regardless of the anatomic site involved. # Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum # Recommended Regimens A 400-mg oral dose of cefixime does not provide as high, nor as sustained, a bactericidal level as that provided by the 250-mg dose of ceftriaxone. In published clinical trials, the 400-mg dose cured 97.5% of uncomplicated urogenital and anorectal (95% CI = 95.4%-99.8%) and 92.3% of pharyngeal gonococcal infections (95% CI = 74.9%-99.1%) (306,307). Although cefixime can be administered orally, this advantage is offset by the limited efficacy of cefixime (as well as other oral cephalosporins) for treating gonococcal infections of the pharynx. Providers should inquire about oral sexual exposure and if reported, treat these patients with ceftriaxone because of this drug's well documented efficacy in treating pharyngeal infection. Single-dose injectible cephalosporin regimens (other than ceftriaxone 250 mg IM) that are safe and highly effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg, administered IM), cefoxitin (2 g, administered IM with probenecid 1 g orally), and cefotaxime (500 mg, administered IM). None of the injectible cephalosporins offer any advantage over ceftriaxone for urogenital infection, and efficacy for pharyngeal infection is less certain (306,307). # Alternative Regimens Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimens, and they should not be used if pharyngeal infection is suspected. Some evidence suggests that cefpodoxime 400mg orally can be considered an alternative in the treatment of uncomplicated urogenital gonorrhea; this regimen meets the minimum efficacy criteria for alternative regimens for urogenital infection (demonstrated efficacy of ≥95% in clinical trials with lower 95% CI of >90%) (307). In one clinical trial, cefpodoxime 400 mg orally was found to have a urogenital and rectal cure rate of 96.6% (95% CI = 93.9%), but the efficacy of cefpodoxime 400 mg orally at the pharyngeal site was poor (70.3%, 95% CI = 53.0%) (Hall, unpublished data, 2010). Gonococcal strains with decreased susceptibility to oral cephalosporins have been reported in the United States (308). With a cure rate of 96.5% (95% CI = 93.6%-98.3%) for urogenital and rectal infection, cefpodoxime proxetil 200 mg orally meets the criteria for an alternative regimen; however, its use is not advised because of concerns about the pharmacodynamics of cefpodoxime using this dose. Efficacy in treating pharyngeal infection with cefpodoxime 200 mg is unsatisfactory (78.9%; 95% CI = 54.5%-94%), as with cefpodoxime at the 400-mg dose. Treatment with cefuroxime axetil 1 g orally meets the criteria for minimum efficacy as an alternative regimen for urogenital and rectal infection (95.9%; 95% CI = 94.3%-97.2%), but the pharmacodynamics of cefuroxime axetil 1 g orally are less favorable than those of cefpodoxime 400 mg, cefixime 400 mg, or ceftriaxone 125 mg (309). The efficacy of cefuroxime axetil 1 g orally in treating pharyngeal infection is poor (56.9%; 95% CI = 42.2%-70.7%). Spectinomycin, which is useful in persons who cannot tolerate cephalosporins, is expensive, must be injected, and is not available in the United States (updates available at: www. cdc.gov/std/treatment) (310). However, it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections. Spectinomycin has poor efficacy against pharyngeal infection (51.8%; 95% CI = 38.7%-64.9%) (306). Azithromycin 2 g orally is effective against uncomplicated gonococcal infection (99.2%; 95% CI = 97.3%-99.9%), but concerns over the ease with which N. gonorrhoeae can develop resistance to macrolides should restrict its use to limited circumstances. Although azithromycin 1 g meets alternative regimen criteria (97.6%; 95% CI = 95.7%-98.9%), it is not recommended because several studies have documented treatment failures, and concerns about possible rapid emergence of antimicrobial resistance with the 1-g dose of azithromycin are even greater than with the 2-g dose (311)(312)(313). N. gonorrhoeae in the United States is not adequately susceptible to penicillins, tetracyclines, and older macrolides (e.g., erythromycin) for these antimicrobials to be recommended. # Uncomplicated Gonococcal Infections of the Pharynx Most gonococcal infections of the pharynx are asymptomatic and can be relatively common in some populations (103,278,279,314). Gonococcal infections of the pharynx are more difficult to eradicate than infections at urogenital and anorectal sites (315). Few antimicrobial regimens, including those involving oral cephalosporins, can reliably cure >90% of gonococcal pharyngeal infections (306,307). Providers should ask their patients about oral sexual exposure; if reported, patients should be treated with a regimen with acceptable efficacy against pharyngeal infection. Chlamydial coinfection of the pharynx is unusual; however, because coinfection at genital sites sometimes occurs, treatment for both gonorrhea and chlamydia is recommended. # Recommended Regimens # Follow-Up Patients diagnosed with uncomplicated gonorrhea who are treated with any of the recommended or alternative regimens do not need a test-of-cure (i.e., repeat testing 3-4 weeks after completing therapy). Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Persistent urethritis, cervicitis, or proctitis also might be caused by C. trachomatis or other organisms. N. gonorrhoeae infection is prevalent among patients who have been diagnosed with and treated for gonorrhea in the preceding several months (64,251,252,267). Most infections result from reinfection rather than treatment failure, indicating a need for improved patient education and referral of sex partners. Clinicians should advise patients with gonorrhea to be retested 3 months after treatment. If patients do not seek medical care for retesting in 3 months, providers are encouraged to test these patients whenever they next seek medical care within the following 12 months, regardless of whether the patients believe that their sex partners were treated. Retesting is distinct from test-of-cure to detect therapeutic failure, which is not recommended. # Management of Sex Partners Effective clinical management of patients with treatable STDs requires treatment of the patients' recent sex partners to prevent reinfection and curtail further transmission. Patients should be instructed to refer their sex partners for evaluation and treatment. Sex partners of patients with N. gonorrhoeae infection whose last sexual contact with the patient was within 60 days before onset of symptoms or diagnosis of infection in the patient should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. For heterosexual patients with gonorrhea whose partners' treatment cannot be ensured or is unlikely, delivery of antibiotic therapy for gonorrhea (as well as for chlamydia) by the patients to their partners can be considered (see Partner Management). Use of this approach (68,71) should always be accompanied by efforts to educate partners about symptoms and to encourage partners to seek clinical evaluation. For male patients informing female partners, educational materials should include information about the importance of seeking medical evaluation for PID (especially if symptomatic). Possible undertreatment of PID in female partners and possible missed opportunities to diagnose other STDs are of concern and have not been evaluated in comparison with patient-delivered therapy and partner referral. This approach should not be considered a routine partner management strategy in MSM because of the high risk for coexisting undiagnosed STDs or HIV infection. # Special Considerations Allergy, Intolerance, and Adverse Reactions Reactions to first generation cephalosporins occur in approximately 5%-10% of persons with a history of penicillin allergy and occur less frequently with third-generation cephalosporins (239). In those persons with a history of penicillin allergy, the use of cephalosporins should be contraindicated only in those with a history of a severe reaction to penicillin (e.g., anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) (316). Because data are limited regarding alternative regimens for treating gonorrhea among persons who have severe cephalosporin allergy, providers treating such patients should consult infectious disease specialists. Azithromycin 2 g orally is effective against uncomplicated gonococcal infection, but because of concerns over emerging antimicrobial resistance to macrolides, its use should be limited. Cephalosporin treatment following desensitization is impractical in most clinical settings. # Pregnancy As with other patients, pregnant women infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin. Because spectinomycin is not available in the United States, azithromycin 2 g orally can be considered for women who cannot tolerate a cephalosporin. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. trachomatis infection during pregnancy (see Chlamydial Infections). # HIV Infection Patients who have gonococcal infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Suspected Cephalosporin Treatment Failure or Resistance Suspected treatment failure has been reported among persons receiving oral and injectable cephalosporins (300)(301)(302)(303)(304). Therefore, clinicians of patients with suspected treatment failure or persons infected with a strain found to demonstrate in vitro resistance should consult an infectious disease specialist, conduct culture and susceptibility testing of relevant clinical specimens, retreat with at least 250 mg of ceftriaxone IM or IV, ensure partner treatment, and report the situation to CDC through state and local public health authorities. # Gonococcal Conjunctivitis In the only published study of the treatment of gonococcal conjunctivitis among U.S. adults, all 12 study participants responded to a single 1-g IM injection of ceftriaxone (317). # Recommended Regimen Ceftriaxone 1 g IM in a single dose Consider lavage of the infected eye with saline solution once. Persons treated for gonococcal conjunctivitis should be treated presumptively for concurrent C. trachomatis infection. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infections, Management of Sex Partners). # Disseminated Gonococcal Infection (DGI) DGI frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation. No recent studies have been published on the treatment of DGI. # Treatment Hospitalization is recommended for initial therapy, especially for patients who might not comply with treatment, for those in whom diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Examination for clinical evidence of endocarditis and meningitis should be performed. Persons treated for DGI should be treated presumptively for concurrent C. trachomatis infection. All of the preceding regimens should be continued for 24-48 hours after improvement begins, at which time therapy can be switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. No treatment failures have been reported with the recommended regimens. # Recommended Regimen # Management of Sex Partners Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated gonococcal infections, patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners). # Gonococcal Meningitis and Endocarditis # Recommended Regimen Ceftriaxone 1-2 g IV every 12 hours Therapy for meningitis should be continued for 10-14 days; therapy for endocarditis should be continued for at least 4 weeks. Treatment of complicated DGI should be undertaken in consultation with an infectious disease specialist. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners). # Gonococcal Infections Among Infants Gonococcal infection among infants usually is caused by exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2-5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and reinfection at sites of fetal monitoring. # ophthalmia neonatorum Caused by N. gonorrhoeae Although N. gonorrhoeae causes ophthalmia neonatorum relatively infrequently in the United States, identifying and treating this infection is especially important because ophthalmia neonatorum can result in perforation of the globe of the eye and blindness. Infants at increased risk for gonococcal ophthalmia are those who do not receive ophthalmia prophylaxis and those whose mothers have had no prenatal care or whose mothers have a history of STDs or substance abuse. Gonococcal ophthalmia is strongly suspected when intracellular gram-negative diplococci are identified in conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures for N. gonorrhoeae are obtained. Appropriate chlamydial testing should be done simultaneously. Presumptive treatment for N. gonorrhoeae might be indicated for newborns who are at increased risk for gonococcal ophthalmia and who have increased WBCs (but not gonococci) in a Gram-stained smear of conjunctival exudate. In all cases of neonatal conjunctivitis, conjunctival exudates should be cultured for N. gonorrhoeae and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is vital because of the public health and social consequences of a diagnosis of gonorrhea. Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species, organisms that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory. # Recommended Regimen Ceftriaxone 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered. # other Management Considerations Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. trachomatis). Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely. # Follow-Up Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (e.g., sepsis, arthritis, and meningitis). One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis. # Management of Mothers and Their Sex Partners The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treating gonococcal infections in adults (see Gonococcal Infections in Adolescents and Adults). # DGI and Gonococcal Scalp Abscesses in newborns Sepsis, arthritis, and meningitis (or any combination of these conditions) are rare complications of neonatal gonococcal infection. Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate on chocolate agar. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum that are cultured on gonococcal selective medium are useful for identifying the primary site(s) of infection, especially if inflammation is present. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Diagnoses based on Gram-stained smears or presumptive identification of cultures should be confirmed with definitive tests on culture isolates. # Recommended Regimens Ceftriaxone 25-50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10-14 days, if meningitis is documented OR Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10-14 days, if meningitis is documented # Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection Infants born to mothers who have untreated gonorrhea are at high risk for infection. # Recommended Regimen in the Absence of Signs of Gonococcal Infection Ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg, in a single dose other Management Considerations Both mother and infant should be tested for chlamydial infection. # Follow-Up Follow-up examination is not required. # Management of Mothers and Their Sex Partners The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treatment of gonococcal infections in adults (see Gonococcal Infections). # Gonococcal Infections Among Children Sexual abuse is the most frequent cause of gonococcal infection in preadolescent children (see Sexual Assault or Abuse of Children). For preadolescent girls, vaginitis is the most common manifestation of this infection; gonococcalassociated PID after vaginal infection is likely less common in preadolescents than adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are common and frequently asymptomatic. # Diagnostic Considerations Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, culture remains the preferred method for diagnosis. Gram stains are inadequate for evaluating prepubertal children for gonorrhea and should not be used to diagnose or exlude gonorrhea. NAATs for the detection of N. gonorrhoeae can be used under certain circumstances (see Sexual Assault or Abuse of Children) # Recommended Regimen for Children Who Weigh >45 kg Treat with one of the regimens recommended for adults (see Gonococcal Infections) # Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Uncomplicated Gonococcal Vulvovaginitis, Cervicitis, Urethritis, Pharyngitis, or Proctitis Ceftriaxone 125 mg IM in a single dose # Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Bacteremia or Arthritis Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose daily for 7 days # Recommended Regimen for Children Who Weigh >45 kg and Who Have Bacteremia or Arthritis Ceftriaxone 50 mg/kg IM or IV in a single dose daily for 7 days # Follow-Up Follow-up cultures are unnecessary if ceftriaxone is used. # other Management Considerations Only parenteral cephalosporins (i.e., ceftriaxone) are recommended for use in children; cefotaxime is approved for gonococcal ophthalmia only. No data are available regarding the use of oral cefixime to treat gonococcal infections in children. All children found to have gonococcal infections should be evaluated for coinfection with syphilis and C. trachomatis. (For a discussion of concerns regarding sexual assault, see Sexual Assault or Abuse of Children.) # ophthalmia neonatorum Prophylaxis To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into the eyes of all newborn infants; this procedure is required by law in most states. All of the recommended prophylactic regimens in this section prevent gonococcal ophthalmia. However, the efficacy of these preparations in preventing chlamydial ophthalmia is less clear, and they do not eliminate nasopharyngeal colonization by C. trachomatis. The diagnosis and treatment of gonococcal and chlamydial infections in pregnant women is the best method for preventing neonatal gonococcal and chlamydial disease. Not all women, however, receive prenatal care, and therefore go untreated. Ocular prophylaxis is warranted for neonates, because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive. # Recommended Regimen Erythromycin (0.5%) ophthalmic ointment in each eye in a single application This preparation should be instilled into both eyes of every neonate as soon as possible after delivery. Ideally, ointment should be applied using single-use tubes or ampules rather than multiple-use tubes. If prophylaxis is delayed (i.e., not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis. All infants should be administered ocular prophylaxis, regardless of whether they are delivered vaginally or by cesarean section. Erythromycin is the only antibiotic ointment recommended for use in neonates. Silver nitrate and tetracycline ophthalmic ointment are no longer manufactured in the United States, bacitracin is not effective, and povidone iodine has not been studied adequately. If erythromycin ointment is not available, infants at risk for exposure to N. gonorrhoeae (especially those born to a mother with untreated gonococcal infection or who has received no prenatal care) can be administered ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg in a single dose. # Diseases Characterized by Vaginal Discharge Most women will have a vaginal infection, characterized by discharge, itching, or odor, during their lifetime. With the availability of complementary and alternative therapies and over-the-counter medications for candidiasis, many symptomatic women seek these products before or in addition to an evaluation by a medical provider. Obtaining a medical history alone has been shown to be insufficient for accurate diagnosis of vaginitis and can lead to the inappropriate administration of medication. Therefore, a careful history, examination, and laboratory testing to determine the etiology of vaginal complaints are warranted. Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (such as douching), and other medications should be elicited. The three diseases most frequently associated with vaginal discharge are BV (caused by the replacement of the vaginal flora by an overgrowth of anaerobic bacteria including Prevotella sp., Mobiluncus sp., G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes) trichomoniasis (caused by T. vaginalis), and candidiasis (usually caused by Candida albicans). Cervicitis also can sometimes cause a vaginal discharge. Although vulvovaginal candidiasis (VVC) usually is not transmitted sexually, it is included in this section because it is frequently diagnosed in women who have vaginal complaints or who are being evaluated for STDs. Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge. Clinical laboratory testing can identify the cause of vaginitis in most women and is discussed in detail in the sections of this report dedicated to each condition. In the clinician's office, the cause of vaginal symptoms might be determined by pH, a potassium hydroxide (KOH) test, and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (i.e., >4.5) is common with BV or trichomoniasis. Because pH testing is not highly specific, discharge should be further examined microscopically by first diluting one sample in one to two drops of 0.9% normal saline solution on one slide and a second sample in 10% KOH solution (samples that emit an amine odor immediately upon application of KOH suggest BV or trichomoniasis infection). Cover slips are then placed on the slides, and they are examined under a microscope at low and high power. The saline-solution specimen might yield motile T. vaginalis, or clue cells (i.e., epithelial cells with borders obscured by small bacteria), which are characteristic of BV, whereas the presence of WBCs without evidence of trichomonads or yeast in this solution is suggestive of cervicitis (see Cervicitis). The KOH specimen typically is used to identify the yeast or pseudohyphae of Candida species. However, the absence of trichomonads or pseudohyphae in KOH samples does not rule out these infections, because the sensitivity of microscropy is approximately 50% compared with NAAT (trichomoniasis) or culture (yeast). In settings where pH paper, KOH, and microscopy are not available, alternative commercially available point-of-care tests or clinical laboratory testing can be used to diagnose vaginitis. The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens after laboratory testing, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. # Bacterial Vaginosis BV is a polymicrobial clinical syndrome resulting from replacement of the normal hydrogen peroxide producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes. Some women experience transient vaginal microbial changes, whereas others experience them for a longer intervals of time. Among women presenting for care, BV is the most prevalent cause of vaginal discharge or malodor; however, in a nationally representative survey, most women with BV were asymptomatic (318). BV is associated with having multiple male or female partners, a new sex partner, douching, lack of condom use, and lack of vaginal lactobacilli; women who have never been sexually active can also be affected. The cause of the microbial alteration that characterizes BV is not fully understood, nor is whether BV results from acquisition of a sexually transmitted pathogen. Nonetheless, women with BV are at increased risk for the acquisition of some STDs (e.g., HIV, N. gonorrhoeae, C. trachomatis, and HSV-2), complications after gynecologic surgery, complications of pregnancy, and recurrence of BV. Treatment of male sex partners has not been beneficial in preventing the recurrence of BV. # Diagnostic Considerations BV can be diagnosed by the use of clinical criteria (i.e., Amsel's Diagnostic Criteria) (319) or Gram stain. A Gram stain (considered the gold standard laboratory method for diagnosing BV) is used to determine the relative concentration of lactobacilli (i.e., long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (i.e., G. vaginalis, Prevotella, Porphyromonas, and peptostreptococci), and curved Gramnegative rods (i.e., Mobiluncus) characteristic of BV. If a Gram stain is not available, clinical criteria can be used and require three of the following symptoms or signs: - homogeneous, thin, white discharge that smoothly coats the vaginal walls; - presence of clue cells on microscopic examination; - pH of vaginal fluid >4.5; or - a fishy odor of vaginal discharge before or after addition of 10% KOH (i.e., the whiff test). Detection of three of these criteria has been correlated with results by Gram stain (320). Other tests, including a DNA probebased test for high concentrations of G. vaginalis (Affirm VP III, Becton Dickinson, Sparks, Maryland), a prolineaminopeptidase test card (Pip Activity TestCard, Quidel, San Diego, California), and the OSOM BVBlue test have acceptable performance characteristics compared with Gram stain. Although a card test is available for the detection of elevated pH and trimethylamine, it has low sensitivity and specificity and therefore is not recommended. PCR also has been used in research settings for the detection of a variety of organisms associated with BV, but evaluation of its clinical utility is uncertain. Detection of one organism or group of organisms might be predictive of BV by Gram stain (321). However, additional evaluations are needed to confirm these associations. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. Cervical Pap tests have no clinical utility for the diagnosis of BV because of their low sensitivity. # Treatment Treatment is recommended for women with symptoms. The established benefits of therapy in nonpregnant women are to relieve vaginal symptoms and signs of infection. Other potential benefits to treatment include reduction in the risk for acquiring C. trachomatis or N. gonorrhoeae (322), HIV, and other viral STDs. # Recommended Regimens Metronidazole 500 mg orally twice a day for 7 days- OR Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days † - Consuming alcohol should be avoided during treatment and for 24 hours thereafter. † Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use (refer to clindamycin product labeling for additional information). Providers should consider patient preference, possible side-effects, drug interactions, and other coinfections when selecting a regimen. Women should be advised to refrain from intercourse or to use condoms consistently and correctly during the treatment regimen. Douching might increase the risk for relapse, and no data support the use of douching for treatment or relief of symptoms. # Alternative Regimens Tinidazole 2 g orally once daily for 2 days OR Tinidazole 1 g orally once daily for 5 days OR Clindamycin 300 mg orally twice daily for 7 days OR Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days Alternative regimens include several tinidazole regimens (323) or clindamycin (oral or intravaginal) (324). Additional regimens include metronidazole (750-mg extended release tablets once daily for 7 days), or a single dose of clindamycin intravaginal cream, although data on the performance of these alternative regimens are limited. Several studies have evaluated the clinical and microbiologic efficacy of using intravaginal lactobacillus formulations to treat BV and restore normal flora (325)(326)(327). Further research efforts to determine the role of these regimens in BV treatment and prevention are ongoing. # Follow-Up Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is common, women should be advised to return for evaluation if symptoms recur. Detection of certain BV-associated organisms have been associated with antimicrobial resistance and might determine risk for subsequent treatment failure (328)(329)(330)(331)(332)(333). Limited data are available regarding optimal management strategies for women with early treatment failure. Using a different treatment regimen might be an option in patients who have a recurrence; however, retreatment with the same topical regimen is another acceptable approach for treating recurrent BV during the early stages of infection (334). For women with multiple recurrences after completion of a recommended regimen, metronidazole gel twice weekly for 4-6 months has been shown to reduce recurrences, although this benefit might not persist when suppressive therapy is discontinued (335). Limited data suggest that oral nitroimidazole followed by intravaginal boric acid and suppressive metronidazole gel for those women in remission might be an option in women with recurrent BV (336). Monthly oral metronidazole administered with fluconazole has also been evaluated as suppressive therapy (337). # Management of Sex Partners The results of clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s). Therefore, routine treatment of sex partners is not recommended. # Special Considerations # Allergy or Intolerance to the Recommended Therapy Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole or tinidazole. Intravaginal metronidazole gel can be considered for women who do not tolerate systemic metronidazole. Intravaginal metronidazole should not be administered to women allergic to metronidazole. # Pregnancy Treatment is recommended for all pregnant women with symptoms. Although BV is associated with adverse pregnancy outcomes, including premature rupture of membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis, the only established benefit of therapy for BV in pregnant women is the reduction of symptoms and signs of vaginal infection. Additional potential benefits include reducing the risk for infectious complications associated with BV during pregnancy and reducing the risk for other infections (other STDs or HIV). Several trials have been undertaken to determine the efficacy of BV treatment among pregnant women. Two trials demonstrated that metronidazole was efficacious during pregnancy using the 250-mg regimen (338,339); however, metronidazole administered at 500 mg twice daily can be used. One trial involving a limited number of participants revealed that treatment with oral metronidazole 500 mg twice daily was equally effective as metronidazole gel, with cure rates of 70% using Amsel criteria to define cure (340), and a recent trial demonstrated a cure rate of 85% using Gram stain criteria after 4 weeks with oral clindamycin (341). Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns (342,343). Regardless of the antimicrobial agent used to treat pregnant women, oral therapy is preferred because of the possibility of subclinical upper-genital-tract infection. # Recommended Regimens for Pregnant Women Metronidazole 500 mg orally twice a day for 7 days OR Metronidazole 250 mg orally three times a day for 7 days OR Clindamycin 300 mg orally twice a day for 7 days Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i.e., those with a previous preterm birth) has been evaluated by several studies, which have yielded mixed results. Seven trials have evaluated treatment of pregnant women with asymptomatic BV at high risk for preterm delivery; one showed harm (344), two showed no benefit (345,346), and four demonstrated benefit (338,339,347,348). Therefore, evidence is insufficient to assess the impact of screening for BV in pregnant women at high risk for preterm delivery (85). Similarly, data are inconsistent regarding whether the treatment of asymptomatic pregnant women with BV who are at low risk for preterm delivery reduces adverse outcomes of pregnancy. Although USPSTF recommends against screening these women (85), one trial demonstrated a 40% reduction in spontaneous preterm birth among women using oral clindamycin during weeks 13-22 of gestation (348). Several additional trials have shown that intravaginal clindamycin given at an average gestation of later than 20 weeks did not reduce preterm birth, and in three of these trials, intravaginal clindamycin cream administered at 16-32 weeks' gestation was associated with an increase in adverse events (e.g., low birth weight and neonatal infections) in newborns (346,(349)(350)(351). Providers should be aware that intravaginal clindamycin cream might be associated with adverse outcomes if used in the latter half of pregnancy. # HIV Infection BV appears to recur with higher frequency in HIV-positive women (352). Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Trichomoniasis Trichomoniasis is caused by the protozoan T. vaginalis. Some men who are infected with T. vaginalis might not have symptoms; others have NGU. Some women have symptoms characterized by a diffuse, malodorous, yellow-green vaginal discharge with vulvar irritation. However, many women have minimal or no symptoms. Because of the high prevalence of trichomoniasis in clinical and nonclinical settings (64,92,353,354), testing for T. vaginalis should be performed in women seeking care for vaginal discharge. Screening for T. vaginalis in women can be considered in those at high risk for infection (i.e., women who have new or multiple partners, have a history of STDs, exchange sex for payment, and use injection drugs). Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only approximately 60%-70% and requires immediate evaluation of wet preparation slide for optimal results. FDA-cleared tests for trichomoniasis in women include OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic capillary flow dipstick technology, and the Affirm VP III (Becton Dickenson, San Jose, California), a nucleic acid probe test that evaluates for T. vaginalis, G. vaginalis, and C. albicans. Each of these tests, which are performed on vaginal secretions, have a sensitivity of >83% and a specificity of >97%. Both tests are considered point-of-care diagnostics. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, whereas results of the Affirm VP III are available within 45 minutes. Although these tests tend to be more sensitive than those requiring vaginal wet preparation, false positives might occur, especially in populations with a low prevalence of disease. Culture is another sensitive and highly specific commercially available method of diagnosis. Among women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions should be cultured for T. vaginalis. While the sensitivity of a Pap test for T. vaginalis diagnosis is poor, use of a liquid-based testing has demonstrated enhanced sensitivity; however, false-positive tests can occur, and confirmatory testing might be needed in some circumstances (355). An FDA-cleared PCR assay for detection of gonorrhea and chlamydial infection (Amplicor, manufactured by Roche Diagnostic Corp.) has been modified for T. vaginalis detection in vaginal or endocervical swabs and in urine from women and men; sensitivity ranges from 88%-97% and specificity from 98%-99% (356). APTIMA T. vaginalis Analyte Specific Reagents (ASR; manufactured by Gen-Probe, Inc.) also can detect T. vaginalis RNA by transcription-mediated amplification using the same instrumentation platforms available for the FDA-cleared APTIMA Combo2 assay for diagnosis of gonorrhea and chlamydial infection; published validation studies of T. vaginalis ASR found sensitivity ranging from 74%-98% and specificity of 87%-98% (357)(358)(359). Laboratories that use the Gen-Probe APTIMA Combo2 test for detection of N. gonorrhoeae and C. trachomatis can consider adding the T. vaginalis ASR to their testing armentarium, as long as the necessary CLIA verification studies have been conducted. In men, wet preparation is not a sensitive test, and no approved point-of-care tests are available. Culture testing of urethral swab, urine, or semen is one diagnostic option; however, NAATs (i.e., PCR or transcription-mediated amplification ) have superior sensitivity for T. vaginalis diagnosis in men (356,359). T. vaginalis has not been found to infect oral sites, and rectal prevalence appears low in MSM (360). Therefore, oral and rectal testing for T. vaginalis is not recommended. # Recommended Regimens Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose # Alternative Regimen Metronidazole 500 mg orally twice a day for 7 days- - Patients should be advised to avoid consuming alcohol during treatment with metronidazole or tinidazole. Abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole. The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these drugs, metronidazole and tinidazole are available in the United States and are cleared by the FDA for the treatment of trichomoniasis. In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90%-95%, and the recommended tinidazole regimen has resulted in cure rates of approximately 86%-100%. The appropriate treatment of sex partners might increase these reported rates. Randomized controlled trials comparing single 2-g doses of metronidazole and tinidazole suggest that tinidazole is equivalent or superior to metronidazole in achieving parasitologic cure and resolution of symptoms (361). Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission. Metronidazole gel is considerably less efficacious for the treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Topically applied antimicrobials (e.g., metronidazole gel) are unlikely to achieve therapeutic levels in the urethra or perivaginal glands; therefore, use of this gel is not recommended. Several other topically applied antimicrobials occasionally have been used for treatment of trichomoniasis; however, these preparations likely are no more effective than metronidazole gel. # Follow-Up Because of the high rate of reinfection among patients in whom trichomoniasis was diagnosed (17% were reinfected within 3 months in one study), rescreening for T. vaginalis at 3 months following initial infection can be considered for sexually active women with trichomoniasis; the benefit of this approach, however, has not been fully evaluated (64). No data support rescreening in men diagnosed with T. vaginalis. While most recurrent T. vaginalis infections are thought to result from having sex with an untreated partner (i.e., reinfection), some recurrent cases can be attributed to diminished susceptibility to metronidazole. Low-level metronidazole resistance has been identified in 2%-5% of cases of vaginal trichomoniasis (362,363), but high-level resistance only rarely occurs. Fortunately, infections caused by most of these organisms respond to tinidazole or higher doses of metronidazole. Tinidazole has a longer serum half-life and reaches higher levels in genitourinary tissues than metronidazole. In addition, many T. vaginalis isolates have lower minimal lethal concentrations (MLCs) to tinidazole than metronidazole. If treatment failure occurs with metronidazole 2-g single dose and reinfection is excluded, the patient can be treated with metronidazole 500 mg orally twice daily for 7 days. For patients failing this regimen, treatment with tinidazole or metronidazole at 2 g orally for 5 days should be considered. If these therapies are not effective, further management should be discussed with a specialist. The consultation should ideally include determination of the susceptibility of T. vaginalis to metronidazole and tinidazole. Consultation and T. vaginalis susceptibility testing is available from CDC (telephone: 404-718-4141; website: ). # Management of Sex Partners Sex partners of patients with T. vaginalis should be treated. Patients should be instructed to abstain from sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner are asymptomatic). Existing data suggest that patient-delivered partner therapy might have a role in partner management for trichomoniasis; however, no one partner management intervention has shown superiority over another in reducing reinfection rates (72,73). Although no data are available to guide treatment of the male partners of women with nitroimidazole treatment failure, on the basis of expert opinion, male partners should be evaluated and treated with either tinidazole in a single dose of 2 g orally or metronidazole twice a day at 500 mg orally for 7 days. # Special Considerations Allergy, Intolerance, and Adverse Reactions Metronidazole and tinidazole are both nitroimidazoles. Patients with an immediate-type allergy to a nitroimidazole can be managed by metronidazole desensitization in consultation with a specialist (364)(365)(366). Topical therapy with drugs other than nitroimidazoles can be attempted, but cure rates are low (<50%). # Pregnancy Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, particularly premature rupture of membranes, preterm delivery, and low birth weight. However, metronidazole treatment has not been shown to reduce perinatal morbidity. Although some trials suggest the possibility of increased prematurity or low birth weight after metronidazole treatment, limitations of the studies prevent definitive conclusions regarding risks for treatment (367,368). Treatment of T. vaginalis might relieve symptoms of vaginal discharge in pregnant women and might prevent respiratory or genital infection of the newborn and further sexual transmission. Clinicians should counsel patients regarding the potential risks and benefits of treatment and communicate the option of therapy deferral in asymptomatic pregnant women until after 37 weeks' gestation. All symptomatic pregnant women should not only be considered for treatment regardless of pregnancy stage, but be provided careful counseling regarding condom use and the continued risk of sexual transmission. Women can be treated with 2 g metronidazole in a single dose at any stage of pregnancy. Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants (342,343,369). The safety of tinidazole in pregnant women, however, has not been well evaluated. In lactating women who are administered metronidazole, withholding breastfeeding during treatment and for 12-24 hours after the last dose will reduce the exposure of the infant to metronidazole. For women treated with tinidazole, interruption of breastfeeding is recommended during treatment and for 3 days after the last dose. # HIV Infection There is increasing evidence for epidemiologic and biologic interaction between HIV and T. vaginalis (370)(371)(372)(373)(374)(375). T. vaginalis infection in HIV-infected women might enhance HIV transmission by increasing genital shedding of the virus (376,377), and treatment for T. vaginalis has been shown to reduce HIV shedding (376,377). For sexually active women who are HIV-positive, screening for trichomoniasis at entry into care with subsequent screening performed at least annually is recommended based on the reported prevalence of T. vaginalis, the effect of treatment at reducing vaginal HIV shedding, and the potential complications of upper-genital-tract infections among women who are left untreated (130,(370)(371)(372)(373)(374)(375). Rescreening 3 months after completion of therapy should be considered among HIV-positive women with trichomoniasis, a recommendation based on the high proportion of recurrent or persistent infection and the association between HIV and T. vaginalis infection (64,374,378). A recent randomized clinical trial involving women coinfected with trichomoniasis and HIV demonstrated that a single dose of metronidazole 2 gm orally was not as effective as 500 mg twice daily for 7 days (379). Therefore, a multi-dose treatment regimen for T. vaginalis can be considered in HIV-infected women. # Vulvovaginal Candidiasis VVC usually is caused by C. albicans, but occasionally is caused by other Candida sp. or yeasts. Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge. None of these symptoms is specific for VVC. An estimated 75% of women will have at least one episode of VVC, and 40%-45% will have two or more episodes within their lifetime. On the basis of clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (Box 3). Approximately 10%-20% of women will have complicated VVC that necessitates diagnostic and therapeutic considerations. # Uncomplicated VVC Diagnostic Considerations A diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritus, pain, swelling, and redness. Signs include vulvar edema, fissures, excoriations, or thick, curdy vaginal discharge. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either 1) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts, hyphae, or pseudohyphae or 2) a culture or other test yields a yeast species. Candida vaginitis is associated with a normal vaginal pH (<4.5), and therefore, pH testing is not a useful diagnostic tool. Use of 10% KOH in wet preparations improves the visualization of yeast and mycelia by disrupting cellular material that might obscure the yeast or pseudohyphae. Examination of a wet mount with KOH preparation should be performed for all women with symptoms or signs of VVC, and women with a positive result should receive treatment. For women with negative wet mounts who are symptomatic, vaginal cultures for Candida should be considered. If the wet mount is negative and Candida cultures cannot be done, empiric treatment can be considered for symptomatic women with any sign of VVC on examination. Identifying Candida by culture in the absence of symptoms or signs is not an indication for treatment, because approximately 10%-20% of women harbor Candida sp. and other yeasts in the vagina. VVC can occur concomitantly with STDs. Most healthy women with uncomplicated VVC have no identifiable precipitating factors. # Treatment Short-course topical formulations (i.e., single dose and regimens of 1-3 days) effectively treat uncomplicated VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures in 80%-90% of patients who complete therapy. The creams and suppositories in this regimen are oil-based and might weaken latex condoms and diaphragms. Patients and providers should refer to condom product labeling for further information. # Recommended Regimens Intravaginal preparations of butaconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC). Women whose condition has previously been diagnosed with VVC are not necessarily more capable of diagnosing themselves; therefore, any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should be evaluated with office-based testing. Unnecessary or inappropriate use of OTC preparations is common and can lead to a delay in the treatment of other vulvovaginitis etiologies, which can result in adverse clinical outcomes. # Follow-Up Patients should be instructed to return for follow-up visits only if symptoms persist or recur within 2 months of onset of the initial symptoms. # Management of Sex Partners VVC is not usually acquired through sexual intercourse; no data support the treatment of sex partners. A minority of male sex partners might have balanitis, which is characterized by erythematous areas on the glans of the penis in conjunction with pruritus or irritation. These men benefit from treatment with topical antifungal agents to relieve symptoms. # Special Considerations # Allergy, Intolerance, and Adverse Reactions Topical agents usually cause no systemic side effects, although local burning or irritation might occur. Oral agents occasionally cause nausea, abdominal pain, and headache. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Clinically important interactions can occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, rifampin, and warfarin. # Complicated VVC Recurrent Vulvovaginal Candidiasis (RVVC) RVVC, usually defined as four or more episodes of symptomatic VVC in 1 year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and most women with RVVC have no apparent predisposing or underlying conditions. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis and to identify unusual species (including nonalbicans species), particularly Candida glabrata. Although C. glabrata and other nonalbicans Candidia species are observed in 10%-20% of patients with RVVC, C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy. Conventional antimycotic therapies are not as effective against these species as they are against C. albicans. # Treatment Each individual episode of RVVC caused by C. albicans responds well to short-duration oral or topical azole therapy. However, to maintain clinical and mycologic control, some specialists recommend a longer duration of initial therapy (e.g., 7-14 days of topical therapy or a 100-mg, 150-mg, or 200-mg oral dose of fluconazole every third day for a total of 3 doses ) to attempt mycologic remission before initiating a maintenance antifungal regimen. # Maintenance Regimens Oral fluconazole (i.e., 100-mg, 150-mg, or 200-mg dose) weekly for 6 months is the first line of treatment. If this regimen is not feasible, topical treatments used intermittently as a maintenance regimen can be considered. Suppressive maintenance antifungal therapies are effective in reducing RVVC. However, 30%-50% of women will have recurrent disease after maintenance therapy is discontinued. Routine treatment of sex partners is controversial. C. albicans azole resistance is rare in vaginal isolates, and susceptibility testing is usually not warranted for individual treatment guidance. # Severe VVC Severe vulvovaginitis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) is associated with lower clinical response rates in patients treated with short courses of topical or oral therapy. Either 7-14 days of topical azole or 150 mg of fluconazole in two sequential doses (second dose 72 hours after initial dose) is recommended. # nonalbicans VVC The optimal treatment of nonalbicans VVC remains unknown. Options include longer duration of therapy (7-14 # Uncomplicated VVC - (380). If symptoms recur, referral to a specialist is advised. # Special Considerations Compromised Host Women with underlying debilitating medical conditions (e.g., those with uncontrolled diabetes or those receiving corticosteroid treatment) do not respond as well to short-term therapies. Efforts to correct modifiable conditions should be made, and more prolonged (i.e., 7-14 days) conventional antimycotic treatment is necessary. # Pregnancy VVC frequently occurs during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women. # HIV Infection The incidence of VVC in HIV-infected women is unknown. Vaginal Candida colonization rates among HIV-infected women are higher than among those for seronegative women with similar demographic characteristics and high-risk behaviors, and the colonization rates correlate with increasing severity of immunosuppression. Symptomatic VVC is more frequent in seropositive women and similarly correlates with severity of immunodeficiency. In addition, among HIV-infected women, systemic azole exposure is associated with the isolation of nonalbicans Candida species from the vagina. On the basis of available data, therapy for VVC in HIVinfected women should not differ from that for seronegative women. Although long-term prophylactic therapy with fluconazole at a dose of 200 mg weekly has been effective in reducing C. albicans colonization and symptomatic VVC (381), this regimen is not recommended for routine primary prophylaxis in HIV-infected women in the absence of recurrent VVC (129). Given the frequency at which RVVC occurs in the immmunocompetent healthy population, the occurrence of RVVC should not be considered an indication for HIV testing among women previously testing HIV negative. Although VVC is associated with increased HIV seroconversion in HIVnegative women and increased HIV cervicovaginal levels in HIV-positive women, the effect of treatment for VVC on HIV acquisition and transmission remains unknown. # Pelvic Inflammatory Disease PID comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis (382). Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in many cases; however, microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) also have been associated with PID (383). In addition, cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium might be associated with some cases of PID (263,(384)(385)(386). All women who have acute PID should be tested for N. gonorrhoeae and C. trachomatis and should be screened for HIV infection. # Diagnostic Considerations Acute PID is difficult to diagnose because of the wide variation in the symptoms and signs. Many women with PID have subtle or mild symptoms. Delay in diagnosis and treatment probably contributes to inflammatory sequelae in the upper reproductive tract. Laparoscopy can be used to obtain a more accurate diagnosis of salpingitis and a more complete bacteriologic diagnosis. However, this diagnostic tool frequently is not readily available, and its use is not easy to justify when symptoms are mild or vague. Moreover, laparoscopy will not detect endometritis and might not detect subtle inflammation of the fallopian tubes. Consequently, a diagnosis of PID usually is based on clinical findings. The clinical diagnosis of acute PID is imprecise (387,388). Data indicate that a clinical diagnosis of symptomatic PID has a positive predictive value (PPV) for salpingitis of 65%-90% compared with laparoscopy. The PPV of a clinical diagnosis of acute PID depends on the epidemiologic characteristics of the population, with higher PPVs among sexually active young women (particularly adolescents), patients attending STD clinics, and those who live in other settings where the rates of gonorrhea or chlamydia are high. Regardlesss of PPV, however, in all settings, no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID. Combinations of diagnostic findings that improve either sensitivity (i.e., detect more women who have PID) or specificity (i.e., exclude more women who do not have PID) do so only at the expense of the other. For example, requiring two or more findings excludes more women who do not have PID but also reduces the number of women with PID who are identified. Many episodes of PID go unrecognized. Although some cases are asymptomatic, others are not diagnosed because the patient or the health-care provider fails to recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge). Because of the difficulty of diagnosis and the potential for damage to the reproductive health of women (even by apparently mild or subclinical PID), health-care providers should maintain a low threshold for the diagnosis of PID (382). The optimal treatment regimen and long-term outcome of early treatment of women with asymptomatic or subclinical PID are unknown. The following recommendations for diagnosing PID are intended to help health-care providers recognize when PID should be suspected and when they need to obtain additional information to increase diagnostic certainty. Diagnosis and management of other common causes of lower abdominal pain (e.g., ectopic pregnancy, acute appendicitis, and functional pain) are unlikely to be impaired by initiating empiric antimicrobial therapy for PID. Empiric treatment for PID should be initiated in sexually active young women and other women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than PID can be identified, and if one or more of the following minimum criteria are present on pelvic examination: - cervical motion tenderness or - uterine tenderness or - adnexal tenderness. The requirement that all three minimum criteria be present before the initiation of empiric treatment could result in insufficient sensitivity for the diagnosis of PID. The presence of signs of lower-genital-tract inflammation (predominance of leukocytes in vaginal secretions, cervical exudates, or cervical friability), in addition to one of the three minimum criteria, increases the specificity of the diagnosis. Upon deciding whether to initiate empiric treatment, clinicians should also consider the risk profile of the patient for STDs. More elaborate diagnostic evaluation frequently is needed because incorrect diagnosis and management of PID might cause unnecessary morbidity. One or more of the following additional criteria can be used to enhance the specificity of the minimum criteria and support a diagnosis of PID: - oral temperature >101° F (>38.3° C); - abnormal cervical or vaginal mucopurulent discharge; - presence of abundant numbers of WBC on saline microscopy of vaginal fluid; - elevated erythrocyte sedimentation rate; - elevated C-reactive protein; and - laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis. Most women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid (i.e., wet prep). If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of pain should be considered. A wet prep of vaginal fluid offers the ability to detect the presence of concomitant infections (e.g., BV and trichomoniasis). The most specific criteria for diagnosing PID include: - endometrial biopsy with histopathologic evidence of endometritis; - transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, or Doppler studies suggesting pelvic infection (e.g., tubal hyperemia); or - laparoscopic abnormalities consistent with PID. A diagnostic evaluation that includes some of these more extensive procedures might be warranted in some cases. Endometrial biopsy is warranted in women undergoing laparoscopy who do not have visual evidence of salpingitis, because endometritis is the only sign of PID for some women. # Treatment PID treatment regimens must provide empiric, broad spectrum coverage of likely pathogens. Several antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with short-term follow-up. However, only a limited number of investigations have assessed and compared these regimens with regard to elimination of infection in the endometrium and fallopian tubes or determined the incidence of long-term complications (e.g., tubal infertility and ectopic pregnancy) after antimicrobial regimens (389)(390)(391). All regimens used to treat PID should also be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper-reproductive-tract infection. The need to eradicate anaerobes from women who have PID has not been determined definitively. Anaerobic bacteria have been isolated from the upper-reproductive tract of women who have PID, and data from in vitro studies have revealed that some anaerobes (e.g., Bacteroides fragilis) can cause tubal and epithelial destruction. BV also is present in many women who have PID (383,391). Until treatment regimens that do not adequately cover these microbes have been demonstrated to prevent long-term sequelae (e.g., infertility and ectopic pregnancy) as successfully as the regimens that are effective against these microbes, the use of regimens with anaerobic activity should be considered. Treatment should be initiated as soon as the presumptive diagnosis has been made because prevention of long-term sequelae is dependent on early administration of appropriate antibiotics. When selecting a treatment regimen, health-care providers should consider availability, cost, patient acceptance, and antimicrobial susceptibility (392). In women with PID of mild or moderate clinical severity, outpatient therapy yields short-and long-term clinical outcomes similar to inpatient therapy. The decision of whether hospitalization is necessary should be based on the judgment of the provider and whether the patient meets any of the following suggested criteria: - surgical emergencies (e.g., appendicitis) cannot be excluded; - the patient is pregnant; - the patient does not respond clinically to oral antimicrobial therapy; - the patient is unable to follow or tolerate an outpatient oral regimen; - the patient has severe illness, nausea and vomiting, or high fever; or - the patient has a tubo-ovarian abscess. No evidence is available to suggest that adolescents benefit from hospitalization for treatment of PID. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women. Younger women with mild-to-moderate acute PID have similar outcomes with either outpatient or inpatient therapy, and clinical response to outpatient treatment is similar among younger and older women. # Parenteral Treatment For women with PID of mild or moderate severity, parenteral and oral therapies appear to have similar clinical efficacy. Many randomized trials have demonstrated the efficacy of both parenteral and oral regimens (390,391,393). Clinical experience should guide decisions regarding transition to oral therapy, which usually can be initiated within 24-48 hours of clinical improvement. In women with tubo-ovarian abscesses, at least 24 hours of direct inpatient observation is recommended. Because of the pain associated with intravenous infusion, doxycycline should be administered orally when possible. Oral and IV administration of doxycycline provide similar bioavailability. Parenteral therapy can be discontinued 24 hours after clinical improvement, but oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, clindamycin or metronidazole with doxycycline can be used for continued therapy rather than doxycycline alone because this regimen provides more effective anaerobic coverage. Limited data are available to support the use of other second-or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone), which also might be effective therapy for PID and could potentially replace cefotetan or cefoxitin. However, these cephalosporins are less active than cefotetan or cefoxitin against anaerobic bacteria. # Recommended Parenteral Regimen B Clindamycin 900 mg IV every 8 hours PLUS Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing (3-5 mg/kg) can be substituted. Although use of a single daily dose of gentamicin has not been evaluated for the treatment of PID, it is efficacious in analogous situations. Parenteral therapy can be discontinued 24 hours after clinical improvement; ongoing oral therapy should consist of doxycycline 100 mg orally twice a day, or clindamycin 450 mg orally four times a day to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, clindamycin should be continued rather than doxycycline, because clindamycin provides more effective anaerobic coverage. # Alternative Parenteral Regimens Limited data are available to support the use of other parenteral regimens. The following regimen has been investigated in at least one clinical trial and has broad-spectrum coverage (394). # Alternative Parenteral Regimens Ampicillin/Sulbactam 3 g IV every 6 hours PLUS Doxycycline 100 mg orally or IV every 12 hours Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. One trial demonstrated high short-term clinical cure rates with azithromycin, either as monotherapy for 1 week (500 mg IV for 1 or 2 doses followed by 250 mg orally for 5-6 days) or combined with a 12-day course of metronidazole (395). # oral Treatment Outpatient, oral therapy can be considered for women with mild-to-moderately severe acute PID, because the clinical outcomes among women treated with oral therapy are similar to those treated with parenteral therapy (390). The following regimens provide coverage against the frequent etiologic agents of PID. Patients who do not respond to oral therapy within 72 hours should be reevaluated to confirm the diagnosis and should be administered parenteral therapy on either an outpatient or inpatient basis. The optimal choice of a cephalosporin is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae. A single dose of cefoxitin is effective in obtaining short-term clinical response in women who have PID. However, the theoretical limitations in coverage of anaerobes by recommended cephalosporin antimicrobials might require the addition of metronidazole to the treatment regimen (393). Adding metronidazole also will effectively treat BV, which is frequently associated with PID. No data have been published regarding the use of oral cephalosporins for the treatment of PID. # Recommended Regimen # Alternative oral Regimens Although information regarding other outpatient regimens is limited, other regimens have undergone at least one clinical trial and have demonstrated broad spectrum coverage. In a single clinical trial, amoxicillin/clavulanic acid and doxycycline were effective together in obtaining short-term clinical response (394); however, gastrointestinal symptoms might limit compliance with this regimen. Azithromycin has demonstrated short-term effectiveness in one randomized trial (395), and in another study, it was effective when used combination with ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks (396). When considering alternative regimens, the addition of metronidazole should be considered because anaerobic organisms are suspected in the etiology of PID and metronidazole will also treat BV. As a result of the emergence of quinolone-resistant Neisseria gonorrhoeae, regimens that include a quinolone agent are no longer recommended for the treatment of PID. If parenteral cephalosporin therapy is not feasible, use of fluoroquinolones (levofloxacin 500 mg orally once daily or ofloxacin 400 mg twice daily for 14 days) with or without metronidazole (500 mg orally twice daily for 14 days) can be considered if the community prevalence and individual risk for gonorrhea are low. Diagnostic tests for gonorrhea must be performed before instituting therapy and the patient managed as follows if the test is positive. - If the culture for gonorrhea is positive, treatment should be based on results of antimicrobial susceptibility. - If the isolate is determined to be quinolone-resistant N. gonorrhoeae (QRNG) or if antimicrobial susceptibility cannot be assessed (e.g., if only NAAT testing is available), parenteral cephalosporin is recommended. However, if cephalosporin therapy is not feasible, the addition of azithromycin 2 g orally as a single dose to a quinolone-based PID regimen is recommended. # Follow-Up Patients should demonstrate substantial clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; and reduction in uterine, adnexal, and cervical motion tenderness) within 3 days after initiation of therapy. Patients who do not improve within this period usually require hospitalization, additional diagnostic tests, and surgical intervention. If no clinical improvement has occurred within 72 hours after outpatient oral or parenteral therapy, further assessment should be performed. Subsequent hospitalization and an assessment of the antimicrobial regimen and diagnostics (including the consideration of diagnostic laparoscopy for alternative diagnoses) are recommended in women without clinical improvement. Women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months of treatment. Repeat testing of all women who have been diagnosed with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267). All women diagnosed with acute PID should be offered HIV testing. # Management of Sex Partners Male sex partners of women with PID should be examined and treated if they had sexual contact with the patient during the 60 days preceding the patient's onset of symptoms. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. Evaluation and treatment are imperative because of the risk for reinfection of the patient and the strong likelihood of urethral gonococcal or chlamydial infection in the sex partner. Male partners of women who have PID caused by C. trachomatis and/or N. gonorrhoeae frequently are asymptomatic. Sex partners should be treated empirically with regimens effective against both of these infections, regardless of the etiology of PID or pathogens isolated from the infected woman. Even in clinical settings in which only women are treated, arrangements should be made to provide care or appropriate referral for male sex partners of women who have PID (see Partner Management). Expedited partner treatment and enhanced patient referral (see Partner Management) are alternative approaches to treating male partners of women who have chlamydia or gonococcal infections (68,69). # Prevention Screening and treating sexually active women for chlamydia reduces their risk for PID (272). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear (383,391). # Special Considerations Pregnancy Because of the high risk for maternal morbidity and preterm delivery, pregnant women who have suspected PID should be hospitalized and treated with parenteral antibiotics. # HIV Infection Differences in the clinical manifestations of PID between HIV-infected women and HIV-negative women have not been well delineated. In previous observational studies, HIV-infected women with PID were more likely to require surgical intervention; more comprehensive observational and controlled studies now have demonstrated that HIV-infected women with PID have similar symptoms when compared with uninfected controls (397)(398)(399), except they were more likely to have a tubo-ovarian abscess; both groups of women responded equally well to standard parenteral and oral antibiotic regimens. The microbiologic findings for HIV-positive and HIV-negative women were similar, except HIV-infected women had higher rates of concomitant M. hominis, candida, streptococcal, and HPV infections and HPV-related cytologic abnormalities. Regardlesss of these data, whether the management of immunodeficient HIV-infected women with PID requires more aggressive interventions (e.g., hospitalization or parenteral antimicrobial regimens) has not been determined. # Intrauterine Contraceptive Devices IUDs are popular contraceptive choices for women. Both levonorgestrel and copper-containing devices are marketed in the United States. The risk for PID associated with IUD use is primarily confined to the first 3 weeks after insertion and is uncommon thereafter (400,401). Given the popularity of IUDs, practitioners might encounter PID in IUD users. Evidence is insufficient to recommend that the removal of IUDs in women diagnosed with acute PID. However, caution should be exercised if the IUD remains in place, and close clinical follow-up is mandatory. The rate of treatment failure and recurrent PID in women continuing to use an IUD is unknown, and no data have been collected regarding treatment outcomes by type of IUD (e.g., copper or levonorgestrel). # Epididymitis Acute epididymitis is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis that lasts <6 weeks (402). Chronic epididymitis is characterized by a ≥6 week history of symptoms of discomfort and/or pain in the scrotum, testicle, or epididymis. In most cases of acute epididymitis, the testis is also involved in the process -a condition referred to as epididymo-orchitis. Chronic epididymitis has been subcategorized into inflammatory chronic epididymitis, obstructive chronic epididymitis, and chronic epididymalgia (403). Among sexually active men aged <35 years, acute epididymitis is most frequently caused by C. trachomatis or N. gonorrhoeae. Acute epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli and Pseudomonas spp.) also occurs among men who are the insertive partner during anal intercourse. Sexually transmitted acute epididymitis usually is accompanied by urethritis, which frequently is asymptomatic. In men aged >35 years, sexually transmitted epididymitis is uncommon, whereas bacteriuria secondary to obstructive urinary disease (e.g., benign prostatic hyperplasia) is more common. In this older population, nonsexually transmitted epididymitis is associated with urinary tract instrumentation or surgery, systemic disease, and immunosuppression. Chronic infectious epididymitis is most frequently seen in conditions associated with granulomatous reaction; Mycobacterium tuberculosis (TB) is the most common granulomatous disease affecting the epididymis. Up to 25% of patients can have bilateral disease, with ultrasound demonstrating an enlarged hyperemic epididymis with multiple cysts and calcifications. Tuberculous epididymitis should be suspected in all patients with a known history of or recent exposure to TB or in patients whose clinical status worsens despite appropriate antibiotic treatment. # Diagnostic Considerations Men who have acute epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present. Although the inflammation and swelling usually begin in the tail of the epididymis, they can spread to involve the rest of the epididymis and testicle. The spermatic cord is usually tender and swollen. Testicular torsion, a surgical emergency, should be considered in all cases, but it occurs more frequently among adolescents and in men without evidence of inflammation or infection. Emergency testing for torsion might be indicated when the onset of pain is sudden, pain is severe, or the test results available during the initial examination do not support a diagnosis of urethritis or urinary-tract infection. If the diagnosis is questionable, a urologist should be consulted immediately because testicular viability might be compromised. Radionuclide scanning of the scrotum is the most accurate radiologic method of diagnosis, but it is not routinely available. Although ultrasound is primarily used for ruling out torsion of the spermatic cord in cases of acute scrotum swelling, it will often demonstrate epididymal hyperemia and swelling in men with epididymitis. However, differentiation between testicular torsion and epididymitis must be made on the basis of clinical evaluation, because partial spermatic cord torsion can mimic epididymitis on scrotal ultrasound. Ultrasound provides minimal utility for men with a clinical presentation consistent with epididymitis; a negative ultrasound does not alter physician management of clinical epididymitis. Ultrasound, therefore, should be reserved for patients with scrotal pain who cannot be diagnosed accurately by physical examination, history, and objective laboratory findings. The evaluation of men for epididymitis should include one of the following: - Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. Gram stain is the preferred rapid diagnostic test for evaluating urethritis because it is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing intracellular Gram-negative diplococci on urethral Gram stain. - Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high power field. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and nucleic acid hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine or urethral specimens. Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis. Depending on the risk, patients whose conditions are associated with acquiring an STD should receive testing for other STDs. # Treatment Empiric therapy is indicated before laboratory test results are available. The goals of treatment of acute epididymitis caused by C. trachomatis or N. gonorrhoeae are 1) microbiologic cure of infection, 2) improvement of signs and symptoms, 3) prevention of transmission to others, and 4) a decrease in potential complications (e.g., infertility or chronic pain). As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided. Because empiric therapy is often initiated before laboratory tests are available, all patients should receive ceftriaxone plus doxycycline for the initial therapy of epididymitis. Additional therapy can include a fluoroquinolone if acute epididymitis is not found to be caused by gonorrhea by NAAT or if the infection is most likely caused by enteric organisms. For men who are at risk for both sexually transmitted and enteric organisms (e.g., MSM who report insertive anal intercourse), ceftriaxone with a fluoroquinolone are recommended. # Recommended Regimens Ceftriaxone 250 mg IM in a single dose PLUS Doxycycline 100 mg orally twice a day for 10 days # For acute epididymitis most likely caused by enteric organisms Levofloxacin 500 mg orally once daily for 10 days OR Ofloxacin 300 mg orally twice a day for 10 days Although most patients can be treated on an out-patient basis, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess) or when patients are unable or unlikely to comply with an antimicrobial regimen. Because high fever is uncommon and indicates a complicated infection, these patients should be admitted for further evaluation. # Follow-Up Patients should be instructed to return to their health-care providers if their symptoms fail to improve within 48 hours of the initiation of treatment. Signs and symptoms of epididymitis that do not subside within 3 days requires re-evaluation of the diagnosis and therapy. Swelling and tenderness that persist after completion of antimicrobial therapy should be evaluated comprehensively. Differential diagnoses include tumor, abscess, infarction, testicular cancer, TB, and fungal epididymitis. # Management of Sex Partners Patients who have acute epididymitis that is confirmed or suspected to be caused by N. gonorrhoeae or C. trachomatis should be instructed to refer sex partners for evaluation and treatment if their contact with the index patient was within the 60 days preceding onset of their own symptoms. Patients should be instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (i.e., until therapy is completed and patient and partners no longer have symptoms). # Special Considerations HIV Infection Patients who have uncomplicated acute epididymitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Other etiologic agents have been implicated in acute epididymitis in HIV infection including CMV, salmonella, toxoplasmosis, Ureaplasma urealyticum, Corynebacterium sp., Mycoplasma sp., and Mima polymorpha. Fungi and mycobacteria are also more likely to cause acute epididymitis in immunosuppressed men than in immunocompetent men. # Human Papillomavirus (HPV) Infection More than 100 types of HPV exist, more than 40 of which can infect the genital area. Most HPV infections are asymptomatic, unrecognized, or subclinical. Oncogenic, or high-risk HPV types (e.g., HPV types 16 and 18), are the cause of cervical cancers. These HPV types are also associated with other anogenital cancers in men and women, including penile, vulvar, vaginal, and anal cancer, as well a subset of oropharyngeal cancers (404). Nononcogenic, or low-risk HPV types (e.g., HPV types 6 and 11), are the cause of genital warts and recurrent respiratory papillomatosis. Asymptomatic genital HPV infection is common and usually self-limited; it is estimated that more than 50% of sexually active persons become infected at least once in their lifetime (405). Persistent oncogenic HPV infection is the strongest risk factor for development of precancers and cancers. # HPV Tests HPV tests are available for women aged >30 years undergoing cervical cancer screening. These tests should not be used for men, for women <20 years of age, or as a general test for STDs. These HPV tests detect viral nucleic acid (i.e., DNA or RNA) or capsid protein. # Treatment Treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e, precancerous) lesions caused by infection. Subclinical genital HPV infection typically clears spontaneously, and therefore specific antiviral therapy is not recommended to eradicate HPV infection. In the absence of lesions, treatment is not recommended for subclinical genital HPV infection whether it is diagnosed by colposcopy, acetic acid application, or by laboratory tests for HPV DNA. Treatment also is not recommended for cervical intraepithelial neoplasia 1 (CIN1). # Prevention Two HPV vaccines are licensed in the United States: a bivalent vaccine (Cervarix) containing HPV types 16 and 18 and a quadrivalent vaccine (Gardasil) vaccine containing HPV types 6, 11, 16, and 18. Both vaccines offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18), and the quadrivalent HPV vaccine also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). Either vaccine can be administered to girls aged 11-12 years and can be administered to those as young as 9 years of age (15,16); girls and women ages 13-26 years who have not started or completed the vaccine series also should receive the vaccine. HPV vaccine is indicated for girls in this age group, because benefit is greatest if it is administered before the onset of sexual activity. The quadrivalent (Gardasil) HPV vaccine can also be used in males aged 9-26 years to prevent genital warts (17). Administering the vaccine to boys before the onset of sexual activity is optimal. Both HPV vaccines are administered as a 3-dose series of IM injections over a 6-month period, with the second and third doses given 1-2 and then 6 months after the first dose. Ideally, the same vaccine product should be used for the entire 3-dose series. HPV vaccine is available for eligible children and adolescents aged <19 years through the Vaccines for Children (VFC) program (available by calling CDC INFO [800- ). Women who have received HPV vaccine should continue routine cervical cancer screening because 30% of cervical cancers are caused by HPV types other than 16 or 18. In the United States, the vaccines are not licensed or recommended for use in women >26 years of age. No published data are available on the effectiveness, programmatic requirements, or cost-effectiveness of administering the HPV vaccine in STD clinic settings. # Genital Warts Of genital warts, 90% are caused by HPV 6 or 11. HPV types 6 or 11 are commonly found before, or at the time of, detection of genital warts (406). HPV types 16, 18, 31, 33, and 35 are found occasionally in visible genital warts (usually as coinfections with HPV 6 or 11) and can be associated with foci of high-grade intraepithelial neoplasia, particularly in persons who are infected with HIV infection. In addition to warts on genital areas, HPV types 6 and 11 have been associated with conjunctival, nasal, oral, and laryngeal warts. Genital warts are usually asymptomatic, but depending on the size and anatomic location, they can be painful or pruritic. Genital warts are usually flat, papular, or pedunculated growths on the genital mucosa. Genital warts occur commonly at certain anatomic sites, including around the introitus in women, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis. Genital warts can also occur at multiple sites in the anogenital epithelium or within the anogenital tract (e.g., cervix, vagina, urethra, perineum, perianal skin, and scrotum). Intra-anal warts are observed predominantly in persons who have had receptive anal intercourse, but they can also occur in men and women who do not have a history of anal sexual contact. Diagnosis of genital warts is usually clinical, made by visual inspection. Genital warts can be confirmed by biopsy, which might be indicated if 1) the diagnosis is uncertain; 2) the lesions do not respond to standard therapy; 3) the disease worsens during therapy; 4) the lesion is atypical; 5) the patient has comprised immunity; or 6) the warts are pigmented, indurated, fixed, bleeding, or ulcerated. Genital warts are usually asymptomatic, but depending on the size and anatomic location, they might be painful or pruritic. The use of HPV DNA testing for genital wart diagnosis is not recommended, because test results would not alter clinical management of the condition. The application of 3%-5% acetic acid, which causes skin color to turn white, has been used by some providers to detect HPV-infected genital mucosa. However, acetic acid application is not a specific test for HPV infection. Therefore, the routine use of this procedure for screening to detect mucosal changes attributed to HPV infection is not recommended. # Treatment The primary reason for treating genital warts is the amelioration of symptoms (including relieving cosmetic concerns) and ultimately, removal of the warts. In most patients, treatment can induce wart-free periods. If left untreated, visible genital warts can resolve on their own, remain unchanged, or increase in size or number. Available therapies for genital warts likely reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA resulting from treatment reduces future transmission remains unclear. No evidence indicates that the presence of genital warts or their treatment is associated with the development of cervical cancer. # Regimens Treatment of genital warts should be guided by the preference of the patient, available resources, and the experience of the health-care provider. No definitive evidence suggests that any of the available treatments are superior to any other, and no single treatment is ideal for all patients or all warts. The use of locally developed and monitored treatment algorithms has been associated with improved clinical outcomes and should be encouraged. Because of uncertainty regarding the effect of treatment on future transmission of HPV and the possibility of spontaneous resolution, an acceptable alternative for some persons is to forego treatment and wait for spontaneous resolution. Factors that influence selection of treatment include wart size, wart number, anatomic site of the wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience. Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy, which can consist of either a single treatment or complete course of treatment. In general, warts located on moist surfaces or in intertriginous areas respond best to topical treatment. The treatment modality should be changed if a patient has not improved substantially after a complete course of treatment or if side effects are severe. Most genital warts respond within 3 months of therapy. The response to treatment and any side effects should be evaluated throughout the course of therapy. Complications occur rarely when treatment is administered properly. Patients should be warned that persistent hypopigmentation or hyperpigmentation occurs commonly with ablative modalities and has also been described with immune modulating therapies (imiquimod). Depressed or hypertrophic scars are uncommon but can occur, especially if the patient has had insufficient time to heal between treatments. Rarely, treatment can result in disabling chronic pain syndromes (e.g., vulvodynia and hyperesthesia of the treatment site) or, in the case of anal warts, painful defecation or fistulas. A limited number of case reports of severe systemic effects resulting from treatment with podophyllin resin and interferon have been documented. Treatment regimens are classified into patient-applied and provider-applied modalities. Patient-applied modalities are preferred by some patients because they can be administered in the privacy of the patient's home. To ensure that patientapplied modalities are effective, patients must comply with the treatment regimen and must be capable of identifying and reaching all genital warts. Follow-up visits are not required for persons using patient-applied therapy. However, follow-up visits after several weeks of therapy enable providers to answer any questions patients might have about the use of the medication and any side effects they have experienced; follow-up visits also facilitate the assessment of a patient's response to treatment. Podofilox is an antimitotic drug that destroys warts, is relatively inexpensive, easy to use, safe, and self-applied. Podofilox solution should be applied with a cotton swab, or podofilox gel with a finger, to visible genital warts twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated, as necessary, for up to four cycles. The total wart area treated should not exceed 10 cm 2 , and the total volume of podofilox should be limited to 0.5 mL per day. If possible, the healthcare provider should apply the initial treatment to demonstrate the proper application technique and identify which warts should be treated. Mild to moderate pain or local irritation might develop after treatment. The safety of podofilox during pregnancy has not been established. # Recommended Regimens for External Genital Warts Imiquimod is a topically active immune enhancer that stimulates production of interferon and other cytokines. Imiquimod cream should be applied once daily at bedtime, three times a week for up to 16 weeks (407). The treatment area should be washed with soap and water 6-10 hours after the application. Local inflammatory reactions, including redness, irritation, induration, ulceration/erosions, and vesicles, are common with the use of imiquimod, and hypopigmentation has also been described (408). Imiquimod might weaken condoms and vaginal diaphragms. The safety of imiquimod during pregnancy has not been established. Sinecatechin ointment, a green-tea extract with an active product (catechins), should be applied three times daily (0.5cm strand of ointment to each wart) using a finger to ensure coverage with a thin layer of ointment until complete clearance of warts. This product should not be continued for longer than 16 weeks (409)(410)(411). The medication should not be washed off after use. Sexual (i.e., genital, anal, or oral) contact should be avoided while the ointment is on the skin. The most common side effects of sinecatechins 15% are erythema, pruritis/ burning, pain, ulceration, edema, induration, and vesicular rash. This medication may weaken condoms and diaphragms. No clinical data are available regarding the efficacy or safety of sinecatechins compared with other available anogenital wart treatment modalities. The medication is not recommended for HIV-infected persons, immunocompromised persons, or persons with clinical genital herpes because the safety and efficacy of therapy in these settings has not been established. The safety of sinecatechins during pregnancy also is unknown. Cryotherapy destroys warts by thermal-induced cytolysis. Health-care providers must be trained on the proper use of this therapy because over-and undertreatment can result in complications or low efficacy. Pain after application of the liquid nitrogen, followed by necrosis and sometimes blistering, is common. Local anesthesia (topical or injected) might facilitate therapy if warts are present in many areas or if the area of warts is large. Pedophyllin resin 10%-25% should be applied to each wart and allowed to air-dry before the treated area comes into contact with clothing; overapplication or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The treatment can be repeated weekly, if necessary. To avoid the possibility of complications associated with systemic absorption and toxicity, two guidelines should be followed: 1) application should be limited to <0.5 mL of podophyllin or an area of <10 cm 2 of warts per session and 2) the area to which treatment is administered should not contain any open lesions or wounds. The preparation should be thoroughly washed off 1-4 hours after application to reduce local irritation. The safety of podophyllin during pregnancy has not been established. Podophyllin resin preparations differ in the concentration of active components and contaminants. The shelf life and stability of podophyllin preparations are unknown. Both TCA and BCA are caustic agents that destroy warts by chemical coagulation of proteins. Although these preparations are widely used, they have not been investigated thoroughly. TCA solutions have a low viscosity comparable with that of water and can spread rapidly if applied excessively; therefore, they can damage adjacent tissues. A small amount should be applied only to the warts and allowed to dry before the patient sits or stands, at which time a white frosting develops. If pain is intense, the acid can be neutralized with soap or sodium bicarbonate. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate (i.e., baking soda), or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. Surgical therapy has the advantage of usually eliminating warts at a single visit. However, such therapy requires substantial clinical training, additional equipment, and a longer office visit. After local anesthesia is applied, the visible genital warts can be physically destroyed by electrocautery, in which case no additional hemostasis is required. Care must be taken to control the depth of electrocautery to prevent scarring. Alternatively, the warts can be removed either by tangential excision with a pair of fine scissors or a scalpel, by laser, or by curettage. Because most warts are exophytic, this procedure can be accomplished with a resulting wound that only extends into the upper dermis. Hemostasis can be achieved with an electrocautery unit or a chemical styptic (e.g., an aluminum chloride solution). Suturing is neither required nor indicated in most cases if surgical removal is performed properly. Surgical therapy is most beneficial for patients who have a large number or area of genital warts. Both carbon dioxide laser and surgery might be useful in the management of extensive warts or intraurethral warts, particularly for those persons who have not responded to other treatments. Because all available treatments have shortcomings, some clinics employ combination therapy (simultaneous use of two or more modalities on the same wart at the same time). Data are limited regarding the efficacy or risk of complications associated with use of such combinations. # Alternative Regimens Alternative regimens include treatment options that might be associated with more side effects and/or less data on efficacy. Alternative regimens include intralesional interferon, photodynamic therapy, and topical cidofovir. # Recommended Regimen for Cervical Warts For women who have exophytic cervical warts, a biopsy evaluation to exclude high-grade SIL must be performed before treatment is initiated. Management of exophytic cervical warts should include consultation with a specialist. # Recommended Regimens for Vaginal Warts Cryotherapy with liquid nitrogen. The use of a cryoprobe in the vagina is not recommended because of the risk for vaginal perforation and fistula formation. OR TCA or BCA 80%-90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. # Recommended Regimens for Urethral Meatus Warts Cryotherapy with liquid nitrogen OR Podophyllin 10%-25% in compound tincture of benzoin. The treatment area and adjacent normal skin must be dry before contact with podophyllin. This treatment can be repeated weekly, if necessary. The safety of podophyllin during pregnancy has not been established. Data are limited on the use of podofilox and imiquimod for treatment of distal meatal warts. # Recommended Regimens for Anal Warts Cryotherapy with liquid nitrogen OR TCA or BCA 80%-90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. # OR # Surgical removal Intra-anal warts should be managed in consultation with a specialist. Many persons with warts on the anal mucosa also have warts on the rectal mucosa, so persons with anal and/ or intra-anal warts might benefit from an inspection of the rectal mucosa by digital examination, standard anoscopy, or high-resolution anoscopy. # Counseling The following key counseling messages should be conveyed to all patients diagnosed with HPV infection: - Genital HPV infection is very common. Many types of HPV are passed on through genital contact, most often during vaginal and anal sexual contact. HPV can also be spread by oral sexual contact. - Most sexually active adults will get HPV at some point in their lives, though most will never know it because HPV infection usually has no signs or symptoms. - In most cases, HPV infection clears spontaneously, without causing any health problems. Nevertheless, some infections do progress to genital warts, precancers, and cancers. - The types of HPV that cause genital warts are different from the types that can cause anogenital cancers. - Within an ongoing sexual relationship, both partners are usually infected at the time one person is diagnosed with HPV infection, even though signs of infection might not be apparent. - A diagnosis of HPV in one sex partner is not indicative of sexual infidelity in the other partner. - Treatments are available for the conditions caused by HPV (e.g., genital warts), but not for the virus itself. - HPV does not affect a woman's fertility or ability to carry a pregnancy to term. - Correct and consistent male condom use might lower the chances of giving or getting genital HPV, but such use is not fully protective, because HPV can infect areas that are not covered by a condom. # Sexually active persons can lower their chances of getting HPV by limiting their number of partners. However, HPV is common and often goes unrecognized; persons with only one lifetime sex partner can have the infection. For this reason, the only definitive method to avoid giving and getting HPV infection and genital warts is to abstain from sexual activity. - Tests for HPV are now available to help providers screen for cervical cancer in certain women. These tests are not useful for screening adolescent females for cervical cancer, nor are they useful for screening for other HPV-related cancers or genital warts in men or women. HPV tests should not be used to screen: -men; -partners of women with HPV; -adolescent females; or -for health conditions other than cervical cancer. - Two HPV vaccines are available, both of which offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18); the quadrivalent vaccine (Gardasil) also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). These vaccines are most effective when all doses are administered before sexual contact. Either vaccine is recommended for 11and 12-year-old girls and for females aged 13-26 years who did not receive or complete the vaccine series when they were younger. The quadrivalent HPV vaccine can be used in males aged 9-26 years to prevent genital warts. The following are specific counseling messages for those persons diagnosed with genital warts and their partners: - Genital warts are not life threatening. If left untreated, genital warts might go away, stay the same, or grow in size or number. Except in very rare and unusual cases, genital warts will not turn into cancer. - It is difficult to determine how or when a person became infected with HPV; genital warts can be transmitted to others even when no visible signs of warts are present, even after warts are treated. - It is not known how long a person remains contagious after warts are treated. It is also unclear whether informing subsequent sex partners about a past diagnosis of genital warts is beneficial to the health of those partners. - Genital warts commonly recur after treatment, especially in the first 3 months. - Women should get regular Pap tests as recommended, regardless of vaccination or genital wart history. Women with genital warts do not need to get Pap tests more often than recommended. - HPV testing is unnecessary in sexual partners of persons with genital warts. - If one sex partner has genital warts, both sex partners benefit from getting screened for other STDs. - Persons with genital warts should inform current sex partner(s) because the warts can be transmitted to other partners. In addition, they should refrain from sexual activity until the warts are gone or removed. - Correct and consistent male condom use can lower the chances of giving or getting genital warts, but such use is not fully protective because HPV can infect areas that are not covered by a condom. - The Gardasil vaccine, which has been approved for use in males and females aged 9-26 years, protects against the HPV types that cause 90% of genital warts (i.e., types 6 and 11). # Special Considerations Pregnancy Imiquimod, sinecatechins, podophyllin, and podofilox should not be used during pregnancy. Genital warts can proliferate and become friable during pregnancy. Although removal of warts during pregnancy can be considered, resolution might be incomplete or poor until pregnancy is complete. Rarely, HPV types 6 and 11 can cause respiratory papillomatosis in infants and children, although the route of transmission (i.e., transplacental, perinatal, or postnatal) is not completely understood. Whether cesarean section prevents respiratory papillomatosis in infants and children also is unclear (412); therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn. Cesarean delivery is indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding. Pregnant women with genital warts should be counseled concerning the low risk for warts on the larynx (recurrent respiratory papillomatosis) in their infants or children. # HIV Infection Persons who are HIV-infected are more likely to develop genital warts then persons who are not HIV-infected (413); moreover, lesions are more recalcitrant to treatment due to depressed cell-mediated immunity. No data suggest that treatment modalities for external genital warts should be different for HIV-infected persons. However, persons who are immunosuppressed because of HIV or other reasons might have larger or more numerous warts, might not respond as well as immunocompetent persons to therapy for genital warts, and might have more frequent recurrences after treatment (414)(415)(416). Squamous cell carcinomas arising in or resembling genital warts might occur more frequently among immunosuppressed persons, therefore requiring biopsy for confirmation of diagnosis for suspicious cases. Because of the increased incidence of anal cancer in HIVinfected MSM, screening for anal intraepithelial neoplasia by cytology can be considered (417). However, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic considerations that would support this screening approach. # Squamous Cell Carcinoma in Situ Persons in whom squamous cell carcinoma in situ of the genitalia is diagnosed should be referred to a specialist for treatment. Ablative modalities usually are effective, but careful follow-up is essential for patient management. # Cervical Cancer Screening for Women Who Attend STD Clinics or Have a History of STDs Women attending STD clinics for the treatment of genital infection with high-risk types of Human Papillomavirus (HR-HPV) might be at increased risk for cervical cancer; persistence of HR-HPV can cause cervical cancer and its precancerous lesions. One study demonstrated an HR-HPV prevalence of 27% among women receiving treatment in an STD clinic setting; prevalence was highest among persons aged 14-19 and decreased with increasing age (418). In an evaluation of women attending STD clinics, over half of women were at increased risk for cervical cancer as a result of HPV infection, cervical disease, or history of cervical disease compared with women without these characteristics (419). Cervical cytology (i.e., a Pap test) is an effective, low-cost screening test for preventing invasive cervical cancer. In a 2004 survey, 49% of all STD clinics in the United States reported providing cervical screening services, and 20% reported use of HPV DNA testing (419). Current guidelines from USPSTF and ACOG recommend that cervical screening begin at age 21 years (96,97). This recommendation is based on the low incidence of cervical cancer and limited utility of screening in younger women (98). ACS recommends that women start cervical screening with Pap tests after 3 years of initiating sexual activity but by no later than age 21 years (98). Recommended screening intervals (. cdc.gov/cancer/cervical/pdf/guidelines.pdf ) should continue through 65 years according to USPSTF (. gov/clinic/uspstf/uspscerv.htm) or 70 years according to ACS ( detection_guidelines_36.asp). # Screening Recommendations STD clinics that provide routine cervical screening services should follow the available guidelines. However, to ensure the provision of adequate care, follow-up and referral sources must be in place. Cervical screening should be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests) and can include HR-HPV DNA tests in specific circumstances (420). For cythopathologic and HPV/DNA testing, STD clinics should use CLIA certified laboratories (421) and those that report cytopathology findings according to the following Bethesda 2001 terminology (422): atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and high-grade intraepithelial lesions (HSIL). The ASC category is subdivided into atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells-cannot exclude HSIL (ASC-H). During appointments in which a pelvic examination for STD screening is performed, the health-care provider should inquire about the result of the patient's most recent Pap test and discuss the following information with the patient: # HPV Tests HPV tests are available for clinical use and are recommended for the triage of women aged ≥21 years who have abnormal Pap test results (ASC-US). Additionally, these tests can be used in conjunction with a Pap test (adjunct testing) for cervical cancer screening of women aged ≥30 years. These tests should not be used for women aged <20 years for screening or management of abnormal Pap tests or for STD screening. Current FDA-approved HPV tests detect viral nucleic acid (DNA). Several FDA-approved tests for high-risk HPV testing are available for use in the United States. The Hybrid Capture 2 High-Risk HPV DNA test (Qiagen, Gaithersburg, Maryland) and the Cervista HPV High-Risk test (Hologics, Beford, Massachusetts) detect any of 13-14 high-risk HPV types, whereas the Cervista HPV 16/18 test detects type-specific infection with HPV types 16 and 18. The Digene HC2 HPV DNA test (Qiagen, Gaithersburg, Maryland) detects any of 13 high-risk or five low-risk HPV types, although use of this test is not indicated in the STD clinic setting (i.e., only high-risk HPV DNA testing is necessary) (423). High-risk HPV DNA tests are recommended for the triage of women aged ≥21 years who have ASC-US cytology results. In addition, these tests are recommended for routine adjunctive testing (along with cervical cytology) used to screen women aged ≥30 years (424). HPV DNA testing (including HR HPV and HPV 16/18 tests) is not recommended for the following situations (425)(426)(427): - deciding whether to vaccinate for HPV; - conducting STD screening for HPV; - triaging LSIL; - testing adolescents aged <21 years; and - screening for primary cervical cancer as a stand-alone test (i.e., without a Pap test). Women might benefit from receiving printed information about the value of and indication for cervical cancer screening (i.e., Pap testing), and they should be provided a clinic visit report that states whether a Pap test was obtained during the clinic visit. When available, a copy of the Pap test result should be provided. Women with abnormal screening or diagnostic tests should be referred to clinic settings that employ providers who are experienced in managing these cases (see Follow-Up). Cervical screening programs should screen women who have received HPV vaccination in the same manner as unvaccinated women. # Follow-Up Among women aged ≥30 years with normal Pap tests and negative tests for HR-HPV, the screening interval can be increased to 3 years. At that time, routine testing with either a Pap test or a Pap and HR-HPV testing can resume (428). If the results of the Pap test are abnormal, follow-up care should be provided according to the ASCCP 2006 Consensus Guidelines for Management of Abnormal Cervical Cytology (429) (information regarding management and follow-up care is available at ). If resources in STD clinics do not allow for follow-up of women with abnormal results, protocols for referral for follow-up and case management should be in place. - or ASC-US usually need a referral to other local health-care providers or clinics for colposcopy and biopsy. Clinics and health-care providers who offer cervical screening services but cannot provide appropriate colposcopic follow-up of abnormal Pap tests should arrange referral to health-care facilities that will promptly evaluate and treat patients and report evaluation results to the referring clinic or health-care provider. Clinics and health-care providers should develop protocols that identify women who miss follow-up appointments so that these women can be located and scheduled for needed studies and management, and they should reevaluate these protocols routinely. Pap-test results, type and location of follow-up appointments, and results of follow-up appointment should be clearly documented in the clinic record. The establishment of colposcopy and biopsy services in local health departments, especially in circumstances in which referrals are difficult and follow-up is unlikely, should be considered if resources are available. # other Management Considerations The following additional considerations are associated with performing Pap tests: - The Pap test should not be considered a screening test for STDs. - All women receiving care in an STD-clinic setting should be considered for cervical cancer screening, regardless of sexual orientation (i.e., heterosexual women and those who identify themselves as lesbian or bisexual). # If a woman is menstruating, a conventional cytology Pap test should be postponed, and the woman should be advised to have a Pap test at the earliest opportunity. - If specific infections other than HPV are identified, the patient might need to have a repeat Pap test after appropriate treatment for those infections. However, in most instances (even in the presence of some severe infections), Pap tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the Pap test after treatment is received. - When it is necessary to repeat the Pap test because the report was interpreted as unsatisfactory, the repeat test must be determined by the laboratory to be satisfactory and negative before screening can be resumed at regularly scheduled intervals. - The presence of a mucopurulent discharge should not delay the Pap test. The test can be performed after careful removal of the discharge with a saline-soaked cotton swab. - In the absence of other indications, women who have external genital warts do not need Pap tests more frequently than women who do not have warts. # Special Considerations Pregnancy Pregnant women should be screened at the same frequency as nonpregnant women; however, recommendations for management differ in this population (83,84,424). A swab and an Ayre's spatula can be used for obtaining Pap tests in pregnant women, but cytobrushes are not recommended. # HIV Infection Several studies have documented an increased prevalence of SIL in HIV-infected women (416,436). The following recommendations for Pap test screening among HIV-infected women are consistent with most of the guidelines published by the U.S. Department of Health and Human Services (HHS) (129) and are based partially on the opinions of professionals knowledgeable about the care and management of cervical cancer and HIV infection in women. HIV-positive women should be provided cervical cytology screening twice (every 6 months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter. HIV-positive women with ASC-H, LSIL, or HSIL on cytologic screening should undergo colposcopic evaluation. Recommendations for management of HIV-positive women with ASC-US vary. HHS recommends a more conservative management approach (i.e., immediate colposcopy), whereas ASCCP recommends that these women be managed like HIV-negative women with ASC-US (i.e., tested for HR HPV DNA) (424,429). # Adolescents Prevalence of HR HPV is high among adolescents aged <21 years (425). Infections in adolescent patients tend to clear rapidly, and lesions caused by these infections also have high rates of regression to normal. Therefore, ASCCP and ACOG recommend that adolescents with ASC-US or low-grade SIL be managed with repeat cytologic testing at 12 months and 24 months. Only those with HSIL at either follow-up visit or persistence of ASC-US or LSIL at 24 months should be referred for colposcopic evaluation. # Counseling Messages for Women Receiving Cervical Cancer Screening and HPV Testing When a woman receives abnormal cervical cytology test results, she might experience considerable anxiety, distress, fear, and confusion, which can serve as barriers to follow-up care. Furthermore, a positive HPV DNA test result might exacerbate these feelings and might also elicit partner concerns, worry about disclosure, and feelings of guilt, anger, and stigmatization. Health-care providers are the most trusted source of information about HPV and abnormal cervical cytology test results. Therefore, they have an important role to play in educating women about high-risk HPV and moderating the psychosocial impact of the diagnosis. STD clinic providers should offer patients counseling and information both verbally and in print when delivering HPV and Pap test results. Print materials are available at several websites (/; . ashastd.org/hpv/hpv_publications.cfm). The manner in which this information is communicated to patients can influence the psychological effect of this diagnosis, as well as a woman's likelihood of following up with necessary testing or treatment. Providers should frame high-risk HPV in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Also, the provider should emphasize that HPV is often shared between partners and can lie dormant for many years; having HPV does not imply infidelity, nor should it necessarily raise concerns about a partner's health. In counseling women with high-risk HPV infections about partner management, messages should be tailored to the individual woman's circumstances. While no evidence supports either partner notification (PN) or clinical-evaluation referral for partners of patients with high-risk HPV, some women might benefit from having an informed discussion about their diagnosis with their partners. This type of communication can foster partner support and ensure the sharing of information that can inform decision-making (e.g., decisions regarding condom use). The following specific key messages should be communicated to patients receiving cervical screening: - The purpose of regular, lifelong cervical cancer screening is to identify cervical cancer precursors, which can be treated before progression to cervical cancer. - A positive high-risk HPV DNA test or an abnormal cervical cytology test is not indicative of cervical cancer. Appropriate follow-up is necessary to ensure that cervical abnormalities do not progress. Follow-up evaluation is essential to monitor cervical cytology. - A Pap test that reveals ASC-US indicates some abnormal areas on the cervix that may require close follow-up or treatment so that they do not progress. Additional testing might be required to confirm these results. It is essential that patients return for all follow-up appointments and recommended tests. Discussion concerning disclosure of a positive high-risk HPV test to sex partners might be appropriate and can include the following information: - HPV is very common. It can infect the genital areas of both men and women. It usually has no signs or symptoms. - Most sexually active persons get HPV at some time in their lives, though most will never know it. Even persons with only one lifetime sex partner can get HPV if their partner was infected. - While the immune system clears HPV infection most of the time, in some persons, HPV infection does not resolve. - No clinically validated test exists for men to determine if they have HPV infection. The most common manifestation of HPV infection in men is genital warts. High-risk HPV types seldom cause genital warts. - Partners who are in a long-term relationship tend to share HPV. Sexual partners of HPV-infected patients also likely have HPV, even though they might have no signs or symptoms of infection. - Detection of high-risk HPV infection in a woman does not mean that the woman or her partner is engaging in sexual activity outside of a relationship. HPV infection can be present for many years before it is detected, and no method can accurately confirm when HPV infection was acquired. Prevention measures for current and subsequent sex partners and risk reduction should be discussed. Providers should counsel women about condom use depending on their current circumstances. Consistent condom use by male partners of sexually active women can reduce the risk for cervical and vulvovaginal HPV infection (25), and condom use by couples in long-term partnerships might decrease the time required to clear HPV in the infected woman. Skin not covered by a condom remains vulnerable to HPV infection. HPV vaccines are available and recommended for girls and young women aged 9-26 years, even those who have been diagnosed with HPV infection. Male partners can be vaccinated with the quadrivalent vaccine (Gardasil) to prevent genital warts. # Vaccine-Preventable STDs Several STDs can be effectively prevented through preexposure vaccination with widely available vaccines, including HAV, HBV, and HPV. Vaccines for other STDs (e.g., HIV and HSV) are under development or are undergoing clinical trials. This guidance focuses largely on integrating the use of available vaccines into STD prevention and treatment activities. Every person being evaluated or treated for an STD should receive hepatitis B vaccination unless already vaccinated. In addition, some persons (e.g., MSM and IDUs) should receive hepatitis A vaccination. # Hepatitis A Hepatitis A, caused by infection with HAV, has an incubation period of approximately 28 days (range: 15-50 days). HAV replicates in the liver and is shed in high concentrations in feces from 2 weeks before to 1 week after the onset of clini-cal illness. HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease (CLD). However, 10%-15% of patients experience a relapse of symptoms during the 6 months after acute illness. Acute liver failure from hepatitis A is rare (overall case-fatality rate: 0.5%). The risk for symptomatic infection is directly related to age, with >80% of adults having symptoms compatible with acute viral hepatitis and most children having either asymptomatic or unrecognized infection. Antibody produced in response to HAV infection persists for life and confers protection against reinfection. HAV infection is primarily transmitted by the fecal-oral route, by either person-to-person contact or through consumption of contaminated food or water. Although viremia occurs early in infection and can persist for several weeks after onset of symptoms, bloodborne transmission of HAV is uncommon. HAV occasionally is detected in saliva in experimentally infected animals, but transmission by saliva has not been demonstrated. In the United States, almost half of all persons with hepatitis A report having no risk factor for the disease. Among adults with identified risk factors, most cases occur among international travelers, household or sexual contacts, nonhousehold contacts (e.g., those encountered through play and daycare), and IDUs (437). Because transmission of HAV during sexual activity probably results from fecal-oral contact, measures typically used to prevent the transmission of other STDs (e.g., use of condoms) do not prevent HAV transmission. In addition, efforts to promote good personal hygiene have not been successful in interrupting outbreaks of hepatitis A. Vaccination is the most effective means of preventing HAV transmission among persons at risk for infection (e.g., MSM, illegal drug users, and persons with CLD), many of whom might seek services in STD clinics. # Diagnosis The diagnosis of hepatitis A cannot be made on clinical grounds alone; serologic testing also is required. The presence of IgM antibody to HAV is diagnostic of acute HAV infection. A positive test for total anti-HAV indicates immunity to HAV infection but does not differentiate current from previous HAV infection. Although usually not sensitive enough to detect the low level of protective antibody after vaccination, anti-HAV tests also might be positive after hepatitis A vaccination. # Treatment Patients with acute hepatitis A usually require only supportive care, with no restrictions in diet or activity. Hospitalization might be necessary for patients who become dehydrated because of nausea and vomiting and is critical for patients with signs or symptoms of acute liver failure. Medications that might cause liver damage or are metabolized by the liver should be used with caution among persons with hepatitis A. # Prevention Two products are available for the prevention of HAV infection: hepatitis A vaccine (Table 2) and immune globulin (IG) for IM administration. Hepatitis A vaccines are prepared from formalin-inactivated, cell-culture-derived HAV and have been available in the United States since 1995, initially for persons aged ≥2 years. In 2005, the vaccines were approved by FDA for persons aged ≥12 months, and the vaccine is available for eligible children and adolescents aged <19 years through the VFC program (telephone: 800-232-4636). Administered IM in a 2-dose series at 0 and 6-12 months, these vaccines induce protective antibody levels in virtually all adults. By 1 month after the first dose, 94%-100% of adults have protective antibody levels; 100% of adults develop protective antibody after a second dose. In randomized controlled trials, the equivalent of 1 dose of hepatitis A vaccine administered before exposure has been 94%-100% effective in preventing clinical hepatitis A (2). Kinetic models of antibody decline indicate that protective levels of antibody persist for at least 20 years. IG is a sterile solution of concentrated immunoglobulins prepared from pooled human plasma processed by cold ethanol fractionation. In the United States, IG is produced only from plasma that has tested negative for hepatitis B surface antigen, antibodies to HIV and HCV, and HCV RNA. In addition, the process used to manufacture IG inactivates viruses (e.g., HBV, HCV, and HIV). When administered IM before or within 2 weeks after exposure to HAV, IG is >85% effective in preventing HAV infections. A combined hepatitis A and hepatitis B vaccine has been developed and licensed for use as a 3-dose series in adults aged ≥18 years (Table 3). When administered IM on a 0-, 1-, and 6-month schedule, the vaccine has equivalent immunogenicity to that of the monovalent vaccines. # Pre-exposure Vaccination Persons in the following groups who are likely to be treated in STD clinic settings should be offered hepatitis A vaccine: 1) all MSM; 2) illegal drug users (of both injection and noninjection drugs); and 3) persons with CLD, including persons with chronic HBV and HCV infection who have evidence of CLD. # Prevaccination Serologic Testing for Susceptibility Approximately one third of the U.S. population has serologic evidence of previous HAV infection, which increases with age and reaches 75% among persons aged >70 years. Screening for HAV infection might be cost-effective in populations where the prevalence of infection is likely to be high (e.g., persons aged >40 years and persons born in areas of high HAV endemicity). The potential cost-savings of testing should be weighed against the cost and the likelihood that testing will interfere with initiating vaccination. Vaccination of a person who is already immune is not harmful. # Postvaccination Serologic Testing Postvaccination serologic testing is not indicated because most persons respond to the vaccine. In addition, the commercially available serologic test is not sensitive enough to detect the low, but protective, levels of antibody produced by vaccination. # Postexposure Prophylaxis Persons who recently have been exposed to HAV and who previously have not received hepatitis A vaccine should be administered a single dose of single-antigen vaccine or IG (0.02 mL/kg) as soon as possible. Information about the relative efficacy of vaccine compared with IG postexposure is limited, and no data are available for persons aged >40 years or those with underlying medical conditions. Therefore, decisions to use vaccine or IG should take into account patient characteristics associated with more severe manifestations of hepatitis A, including older age and CLD. For healthy persons aged 12 months to 40 years, singleantigen hepatitis A vaccine at the age-appropriate dose is preferred over IG because of vaccine advantages, including long-term protection and ease of administration. For persons aged >40 years, IG is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group; vaccine can be used if IG cannot be obtained. The magnitude of the risk for HAV transmission from the exposure should be considered in decisions to use IG or vaccine. IG should be used for children aged <12 months, immunocompromised persons, persons who have had diagnosed CLD, and persons for whom vaccine is contraindicated. If IG is administered to persons for whom hepatitis A vaccine also is recommended, a dose of vaccine should be provided simultaneously with IG. The second vaccine dose should be administered according to the licensed schedule to complete the series. The efficacy of IG or vaccine when administered >2 weeks after exposure has not been established (438). # Special Considerations Limited data indicate that vaccination of persons with CLD and of persons with advanced HIV infection results in lower seroprotection rates and antibody concentrations (4). In HIV-infected persons, antibody response might be directly related to CD4+ levels. # Hepatitis B Hepatitis B is caused by infection with the hepatitis B virus (HBV). The incubation period from the time of exposure to onset of symptoms is 6 weeks to 6 months. The highest concentrations of HBV are found in blood, with lower concentrations found in other body fluids including wound exudates, semen, vaginal secretions, and saliva (439,440). HBV is more infectious and relatively more stable in the environment than other bloodborne pathogens like HCV and HIV. HBV infection can be self-limited or chronic. In adults, only approximately half of newly acquired HBV infections are symptomatic, and approximately 1% of reported cases result in acute liver failure and death. Risk for chronic infection is inversely related to age at acquisition; approximately 90% of infected infants and 30% of infected children aged <5 years become chronically infected, compared with 2%-6% of persons who become infected as adults. Among persons with chronic HBV infection, the risk for premature death from cirrhosis or hepatocellular carcinoma (HCC) is 15%-25%. HBV is efficiently transmitted by percutaneous or mucous membrane exposure to blood or body fluids that contain blood. The primary risk factors associated with infection among adolescents and adults are unprotected sex with an infected partner, unprotected sex with more than one partner, MSM, history of other STDs, and illegal injection-drug use. In addition, several studies have demonstrated the horizontal transmission of HBV, including through premastication, as a less common source of transmission (441,442). CDC's national strategy to eliminate transmission of HBV infection includes 1) prevention of perinatal infection through routine screening of all pregnant women for HBsAg and immunoprophylaxis of infants born to HBsAg-positive mothers or mothers whose HBsAg status is unknown, 2) routine infant vaccination, 3) vaccination of previously unvaccinated children and adolescents through age 18 years, and 4) vaccination of previously unvaccinated adults at increased risk for infection (3,4). High vaccination coverage rates, with subsequent declines in acute hepatitis B incidence, have been achieved among infants and adolescents (4,437,443). In contrast, vaccination coverage among most high-risk adult groups (e.g., persons with more than one sex partner in the previous 6 months, MSM, and IDUs) has remained low, and most new infections occur in these high-risk groups (3,108,(444)(445)(446). STD clinics and other settings that provide services to high-risk adults are ideal sites in which to provide hepatitis B vaccination to adults at risk for HBV infection. All unvaccinated adults seeking services in these settings should be assumed to be at risk for hepatitis B and should be offered hepatitis B vaccination. # Diagnosis Diagnosis of acute or chronic HBV infection requires serologic testing (Table 4). Because HBsAg is present in both acute and chronic infection, the presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is diagnostic of acute or recently acquired HBV infection. Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection. The presence of anti-HBc alone might indicate a false-positive result or acute, resolved, or chronic infection. # Treatment No specific therapy is available for persons with acute hepatitis B; treatment is supportive. Persons with chronic HBV infection should be referred for evaluation to a physician experienced in the management of CLD. Therapeutic agents cleared by FDA for treatment of chronic hepatitis B can achieve sustained suppression of HBV replication and remission of liver disease in some persons. In addition, patients with chronic hepatitis B might benefit from screening to detect HCC at an early stage. adults, Twinrix (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania), also is available. The recommended HBV dose varies by product and age of recipient (Table 3). When selecting a hepatitis B vaccination schedule, the health-care provider should consider the need to achieve completion of the vaccine series. Approved adolescent and adult schedules for both monovalent hepatitis B vaccine (i.e., Engerix-B and Recombivax HB) include the following: 0, 1, and 6 months; 0, 1, and 4 months; and 0, 2, and 4 months. A 4-dose schedule of Engerix-B at 0, 1, 2, and 12 months is licensed for all age groups. A 2-dose schedule of Recombivax HB adult formulation (10 µg) is licensed for adolescents aged 11-15 years. When scheduled to receive the second dose, adolescents aged >15 years should be switched to a 3-dose series, with doses two and three consisting of the pediatric formulation (5 µg) administered on an appropriate schedule. Twinrix can be administered to persons aged ≥18 years at risk for both HAV and HBV infections at 0, 1, and 6 months. Hepatitis B vaccine should be administered IM in the deltoid muscle and can be administered simultaneously with other vaccines. For adolescents and adults, the needle length should be 1-2 inches, depending on the recipient's weight (1 inch for females weighing 120 kg and >100 kg, respectively). A 22-to 25-gauge needle is recommended. If the vaccine series is interrupted after the first or second dose of vaccine, the missed dose should be administered as soon as possible. The series does not need to be restarted after a missed dose. In adolescents and healthy adults aged 90% after the third. Vaccineinduced immune memory has been demonstrated to persist for at least 15-20 years. Periodic testing to determine antibody levels after routine vaccination in immunocompetent persons is not necessary, and booster doses of vaccine are not currently recommended. Hepatitis B vaccination is generally well-tolerated by most recipients. Pain at the injection site and low-grade fever are reported by a minority of recipients. For children and adolescents, a causal association exists between receipt of hepatitis B vaccination and anaphylaxis: for each 1.1 million doses of vaccine administered, approximately one vaccinee will experience this type of reaction. No deaths have been reported in these patients (3,4,447). Vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of hepatitis B vaccine and in persons with a known anaphylactic reaction to any vaccine component. No evidence for a causal association has been demonstrated for other adverse events after administration of hepatitis B vaccine. # Pre-exposure Vaccination Hepatitis B vaccination is recommended for all unvaccinated adolescents, all unvaccinated adults at risk for HBV infection, and all adults seeking protection from HBV infection. For adults, acknowledgement of a specific risk factor is not a requirement for vaccination. Hepatitis B vaccine should be routinely offered to all unvaccinated persons attending STD clinics and to all unvaccinated persons seeking treatment for STDs in other settings. Other settings where all unvaccinated adults should be assumed to be at risk for hepatitis B and should receive hepatitis B vaccination include correctional facilities, facilities providing drug abuse treatment and prevention services, health-care settings serving MSM, and HIV testing and treatment facilities. All persons who receive clinical services in these settings should be offered hepatitis B vaccine unless they have a reliable vaccination history (i.e., a written, dated record of each dose of a complete series). In all settings, vaccination should be initiated even when completion of the vaccine series cannot be ensured. # Prevaccination Antibody Screening Prevaccination serologic testing for susceptibility might be considered to reduce the cost of vaccinating adult populations that have an expected high prevalence (20%-30%) of HBV infection (e.g., IDUs and MSM, especially those in older age groups). In addition, prevaccination testing for susceptibility is recommended for unvaccinated household, sexual, and needlesharing contacts of HBsAg-positive persons (108). Anti-HBc is the test of choice for prevaccination testing; persons who are anti-HBc-positive should be tested for HBsAg. If persons are determined to be HBsAg negative, no further action is required. If persons are determined to be HBsAg positive, the person should be referred for medical follow-up to include counseling and evaluation for antiviral treatment (see Management of HBsAg-Positive Persons). In addition, all household members, sex partners, and needle-sharing partners of HBsAg-positive persons should be vaccinated. Serologic testing should not be a barrier to vaccination of susceptible persons, especially in populations that are difficult to access. In most cases, the first vaccine dose should be administered immediately after collection of the blood sample for serologic testing. Vaccination of persons who are immune to HBV infection because of current or previous infection or vaccination does not increase the risk for adverse events. # Postvaccination Testing for Serologic Response Serologic testing for immunity is not necessary after routine vaccination of adolescents or adults. However, such testing is recommended for persons whose subsequent clinical management depends on knowledge of their immune status (e.g., health-care workers or public safety workers at high risk for continued percutaneous or mucosal exposure to blood or body fluids). In addition, postvaccination testing is recommended for 1) HIV-infected persons and other immunocompromised persons to determine the need for revaccination and the type of follow-up testing and 2) sex and needle-sharing partners of HBsAg-positive persons to determine the need for revaccination and for other methods to protect themselves from HBV infection. If indicated, testing should be performed 1-2 months after administration of the last dose of the vaccine series by using a method that allows determination of a protective level of anti-HBs (i.e., ≥10 mIU/mL). Persons determined to have anti-HBs levels of <10 mIU/mL after the primary vaccine series should be revaccinated with a 3-dose series and provided with anti-HBs testing 1-2 months after the third dose. Persons who do not respond to revaccination should be tested for HBsAg. If HBsAg positive, the person should receive appropriate management (see Management of HBsAg-Positive Persons); if HBsAg negative, the person should be considered susceptible to HBV infection and counseled concerning precautions to prevent HBV infection and the need for HBIG PEP for any known exposure (see Postexposure Prophylaxis). # Postexposure Prophylaxis Both passive-active PEP (the administration of HBIG and hepatitis B vaccine at separate sites) and active PEP (the administration of hepatitis B vaccination alone) have been demonstrated to be highly effective in preventing transmission after exposure to HBV (4). HBIG alone also has been demonstrated to be effective in preventing HBV transmission, but with the availability of hepatitis B vaccine, HBIG typically is used as an adjunct to vaccination. # Exposure to HBsAg-Positive Source Unvaccinated persons or persons known not to have responded to a complete hepatitis B vaccine series should receive both HBIG and hepatitis vaccine as soon as possible (preferably ≤24 hours) after a discrete, identifiable exposure to blood or body fluids that contain blood from an HBsAgpositive source (Table 5). Hepatitis B vaccine should be administered simultaneously with HBIG at a separate injection site, and the vaccine series should be completed by using the age-appropriate vaccine dose and schedule (Table 3). Exposed persons who are in the process of being vaccinated but who have not completed the vaccine series should receive the appropriate dose of HBIG (i.e., 0.06 mL/kg) and should complete the vaccine series. Exposed persons who are known to have responded to vaccination are considered protected; therefore, they need no additional doses of vaccine. Persons who have written documentation of a complete hepatitis B vaccine series who did not receive postvaccination testing should receive a single vaccine booster dose. Alternatively, these persons can be managed according to guidelines for management of persons with occupational exposure to blood or body fluids that contain blood (446). # Exposure to Source with Unknown HBsAg Status Unvaccinated persons who have a discrete, identifiable exposure to blood or body fluids containing blood from a source with unknown HBsAg status should receive the hepatitis B vaccine series, with the first dose initiated as soon as possible after exposure (preferably within 24 hours) and the series completed by using the age-appropriate dose and schedule. Exposed persons who are not fully vaccinated should complete the vaccine series. Exposed persons with written documentation of a complete hepatitis B vaccine series require no further treatment. # Special Considerations Pregnancy All pregnant women receiving STD services should be tested for HBsAg, regardless of whether they have been previously tested or vaccinated. All HBsAg-positive pregnant women should be reported to state and local perinatal hepatitis B prevention programs. HBsAg-negative pregnant women seeking STD treatment who have not been previously vaccinated should receive hepatitis B vaccination. Additional information regarding management of HBsAg-positive pregnant women and their infants is available at . cdc.gov/mmwr/PDF/rr/rr5416.pdf. # HIV Infection HIV infection can impair the response to hepatitis B vaccination. HIV-infected persons should be tested for anti-HBs 1-2 months after the third vaccine dose (see Postvaccination Testing for Serologic Response). Modified dosing regimens, including a doubling of the standard antigen dose and administration of additional doses, might increase the response rate (130). # Management of HBsAg-Positive Persons This section provides recommendations for management of all HBsAg-positive persons. Additional recommendations for management of HBsAg-positive persons who are coinfected with HIV are available (130). - All persons with HBsAg-positive laboratory results should be reported to the state or local health department. † Immunoprophylaxis should be administered as soon as possible, preferably ≤24 hours. Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposures and 14 days for sexual exposures. The complete, 3-dose hepatitis B vaccine series should be administered. -refrain from donating blood, plasma, body organs, other tissue, or semen; and -refrain from sharing household articles (e.g., toothbrushes, razors, or personal injection equipment) that could become contaminated with blood. In addition, HBsAg-positive persons should refrain from premasticating food provided to susceptible persons. - To protect the liver from further harm, HBsAg-positive persons should be advised to: -avoid or limit alcohol consumption because of the effects of alcohol on the liver; -refrain from starting any new medicines, including OTC and herbal medicines, without checking with their health-care provider; and -obtain vaccination against hepatitis A if liver disease is determined to be present. When seeking medical or dental care, HBsAg-positive persons should be advised to inform their health-care providers of their HBsAg status so that they can be appropriately evaluated and managed. The following counseling messages should be considered for HBsAg-positive persons: - HBV is not usually spread by hugging, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact. - Persons should not be excluded from work, school, play, child care, or other settings because they are infected with HBV. - Involvement with a support group might help patients cope with chronic HBV infection. # Hepatitis C Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States; an estimated 3.2 million persons are chronically infected (449). Although HCV is not efficiently transmitted sexually, persons at risk for infection through injection-drug use might seek care in STD treatment facilities, HIV counseling and testing facilities, correctional facilities, drug treatment facilities, and other public health settings where STD and HIV prevention and control services are available. Persons newly infected with HCV typically are either asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1-3 weeks after exposure. The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8-9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure. Chronic HCV infection develops in 70%-85% of HCV-infected persons; 60%-70% of chronically infected persons develop evidence of active liver disease. Most infected persons remain unaware of their infection because they are not clinically ill. However, infected persons serve as a source of transmission to others and are at risk for CLD and other HCV-related chronic diseases for decades after infection. HCV is transmitted through parenteral exposures to contaminated blood, usually through use of injection drugs (sharing of needles or works) and to a lesser extent through exposures in health-care settings as a consequence of inadequate infection-control practices. Transmission rarely follows receipt of blood, tissues, and organs from HCV-infected donors who were not identified during routine screening activities, which have been mandated in the United States since 1992. Occupational and perinatal exposures, although less efficient, also can result in transmission of HCV. Sexual transmission of HCV had been considered to occur rarely. However, recent data indicate that sexual transmission of HCV can occur, especially among HIV-infected persons. CDC surveillance data demonstrate that 10% of persons with acute HCV infection report contact with a known HCV-infected sex partner as their only risk for infection (437). Specific studies of HCV transmission between heterosexual or homosexual couples have yielded mixed results, but generally have found low but increased rates of HCV infection in partners of persons with HCV infection compared with those whose partners are not HCV-infected (450)(451)(452)(453)(454)(455). Several studies have revealed that risk increases commensurate with increasing numbers of sex partners among heterosexual persons (450,451,(456)(457)(458) and MSM (459)(460)(461)(462), especially if those partners are coinfected with HIV (459)(460)(461)(462)(463)(464)(465). Apparent sexual transmission of HCV has recently been reported among HIV-infected MSM in multiple European cities (464,465) and New York City (466). Common practices associated with these clusters of infection include serosorting (i.e., HIV-infected men having sex with one another), group sex, and the use of cocaine and other nonintravenous drugs during sex. All persons with HIV infection should undergo serologic testing for HCV at initial evaluation (130,131). HIV-infected MSM can also acquire HCV after initial screening. Liver function tests should be serially monitored for abnormalities that could be caused by acute viral hepatitis or medication toxicity. HIV-infected persons with new and unexplained increases in ALT should be tested for acute HCV infection. To ensure the detection of acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Acute hepatitis C is a reportable condition in 49 states, and matching viral hepatitis and HIV surveillance registries can facilitate early detection of social networks of HCV transmission among HIV-infected MSM. Suspected clusters of acute infection should be reported to the appropriate public health authorities. Unprotected sexual contact between HIV-infected partners can facilitate spread of HCV, as the virus can be recovered from the semen of men coinfected with HIV (467). Specific prevention practices (e.g., barrier precautions that limit contact with body fluids during sexual contact with other MSM) should be discussed with patients. # Diagnosis and Treatment Anti-HCV testing is recommended for routine screening of asymptomatic persons based on their risk for infection or based on a recognized exposure (see Hepatitis C, Prevention). For such persons, testing for HCV infection should include the use of an FDA-cleared test for antibody to HCV (i.e., immunoassay, EIA, or enhanced chemiluminescence imunoassay and, if recommended, a supplemental antibody test) (468). Persons counseled and tested for HCV infection and determined to be anti-HCV positive should be evaluated (by referral or consultation, if appropriate) for the presence of active infection, presence or development of CLD, and possible treatment. Nucleic acid testing, including reverse transcriptase polymerase chain reaction (RT-PCR) to detect HCV RNA, is necessary to confirm the diagnosis of current HCV infection, and an elevated ALT level is biochemical evidence of CLD. Combination therapy with pegylated interferon and ribavirin is the treatment of choice for patients with chronic hepatitis C. Providers should consult with specialists knowledgeable about management of hepatitis C infection because these experts remain cognizant of the latest advances in the field of antiviral therapy for acute and chronic hepatitis C. # Prevention No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure. Reducing the burden of HCV infection and disease in the United States requires implementation of both primary and secondary prevention activities. Primary prevention reduces or eliminates HCV transmission, whereas secondary prevention activities are aimed at reducing CLD and other chronic diseases in HCV-infected persons by first identifying them and then providing medical management and antiviral therapy, if appropriate. Most scientific evidence demonstrates that although HCV can be transmitted sexually, such transmission happens rarely. Because incident HCV has not been demonstrated to occur in heterosexual partner-pairs followed over time (452)(453)(454), condom use might not be necessary in such circumstances. However, heterosexual and homosexual persons, especially those with concurrent HIV infection or with more than one partner, should protect themselves and their partners against transmission of HCV, HBV, HIV, and other pathogens by use of male latex condoms. Condom use is especially important for HIV-infected men, who might spread HCV to other men though unprotected sexual activity (464)(465)(466). Providers in STD clinics and other primary-care settings should identify those persons who should be offered HCV counseling and testing. In STD clinics and other settings that serve large numbers of persons at high risk for bloodborne infections (e.g., correctional settings), the major risk factor necessitating screening for HCV infection is past or current injection of illegal drugs. Because both HCV and HIV are transmitted through injection-drug use, about one fourth of all HIV patients are also coinfected with HCV. For this reason, all persons with HIV infection should be offered HCV counseling and testing. Other risk factors for which routine HCV testing is recommended include: - having had a blood transfusion or solid organ transplant before July 1992; - having received clotting factor concentrates produced before 1987; - having been on long-term dialysis; and - having signs and symptoms of liver disease (e.g., abnormal ALT). Persons who test negative for anti-HCV who had an exposure previously should be reassured that they are not infected. Those who test positive for anti-HCV (see Diagnosis and Treatment) should be provided information regarding how to protect their liver from further harm; for instance, HCVpositive persons should be advised to avoid drinking alcohol and taking any new medicines (including OTC and herbals) without checking with their clinician. To reduce the risk for transmission to others, HCV-positive persons should be advised to 1) not donate blood, body organs, other tissue, or semen; 2) not share any personal items that might have blood on them (e.g., toothbrushes and razors); and 3) cover cuts and sores on the skin to keep the virus from spreading by blood or secretions. HCV-positive persons with one long-term, steady sex partner do not need to change their sexual practices. They should discuss the low but present risk for transmission with their partner and discuss the need for counseling and testing. HCV-positive women do not need to avoid pregnancy or breastfeeding. HCV-positive persons should be evaluated (by referral or consultation, if appropriate) to detect active HCV infection and the presence of CLD. Evaluation should involve testing for liver function, additional assessment of the severity of liver disease, possible treatment, and the determination for the need of hepatitis A and B vaccination. Regardless of test results, persons who use or inject illegal drugs should be counseled to stop using and injecting drugs and to enter and complete substance abuse treatment (including relapse prevention). Persons who continue to inject drugs despite counseling should be encouraged to take the following steps to reduce personal and public health risks: - never reuse or share syringes, water, or drug preparation equipment; # Postexposure Follow-Up No PEP has been demonstrated to be effective against HCV. Testing to determine whether HCV infection has developed is recommended for health-care workers after percutaneous or permucosal exposures to HCV-positive blood. Children born to HCV-positive women also should be tested for HCV. Prompt identification of acute infection is important, because outcomes are improved when treatment is initiated earlier in the course of illness. # Special Considerations Pregnancy Routine testing for HCV infection is not recommended for all pregnant women. Pregnant women with a known risk factor for HCV infection should be offered counseling and testing. Patients should be advised that approximately six of every 100 infants born to HCV-infected woman become infected; this infection occurs predominantly during or near delivery, and no treatment or delivery method-such as caesarian section-has been demonstrated to decrease this risk. The risk is increased, however, by the presence of maternal HCV viremia at delivery and also is greater (2-3 times) if the woman is coinfected with HIV. HCV has not been shown to be transmitted through breast milk, although HCV-positive mothers should consider abstaining from breastfeeding if their nipples are cracked or bleeding. Infants born to HCV-positive mothers should be tested for HCV infection and, if positive, evaluated for the presence of CLD. # HIV Infection Because of the high prevalence of HIV/HCV coinfection and because of critical clinical management issues for coinfected persons, all persons with HIV infection should undergo serologic testing for HCV. Providers should be aware of the likelihood that HIV-infected MSM will acquire HCV after initial screening. Liver function tests should be serially monitored, and those persons with new and unexplained increases in ALT should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Because a small percentage of coinfected persons fail to acquire HCV antibodies, HCV RNA should be tested in HIV-positive persons with unexplained liver disease who are anti-HCV negative. The course of liver disease is more rapid in HIV/HCV coinfected persons, and the risk for cirrhosis is nearly twice that of persons with HCV infection alone. Coinfected persons receiving HIV antiviral regimens are now being treated for HCV after their CD4+ cell counts increase, optimizing their immune response. # Proctitis, Proctocolitis, and Enteritis Sexually transmitted gastrointestinal syndromes include proctitis, proctocolitis, and enteritis. Evaluation for these syndromes should include appropriate diagnostic procedures (e.g., anoscopy or sigmoidoscopy, stool examination, and culture). Proctitis is inflammation of the rectum (i.e., the distal 10-12 cm) that can be associated with anorectal pain, tenesmus, or rectal discharge. N. gonorrhoeae, C. trachomatis (including LGV serovars), T. pallidum, and HSV are the most common sexually transmitted pathogens involved. In patients coinfected with HIV, herpes proctitis can be especially severe. Proctitis occurs predominantly among persons who participate in receptive anal intercourse. Proctocolitis is associated with symptoms of proctitis, diarrhea or abdominal cramps, and inflammation of the colonic mucosa extending to 12 cm above the anus. Fecal leukocytes might be detected on stool examination, depending on the pathogen. Pathogenic organisms include Campylobacter sp., Shigella sp., Entamoeba histolytica, and LGV serovars of C. trachomatis. CMV or other opportunistic agents can be involved in immunosuppressed HIV-infected patients. Proctocolitis can be acquired by the oral route or by oral-anal contact, depending on the pathogen. Enteritis usually results in diarrhea and abdominal cramping without signs of proctitis or proctocolitis; it occurs among persons whose sexual practices include oral-anal contact. In otherwise healthy persons, Giardia lamblia is most frequently implicated. When outbreaks of gastrointestinal illness occur among social or sexual networks of MSM, clinicians should consider sexual transmission as a mode of spread and provide counseling accordingly. Among HIV-infected patients, gastrointestinal illness can be caused by other infections that usually are not sexually transmitted, including CMV, Mycobacterium avium-intracellulare, Salmonella sp., Campylobacter sp., Shigella sp., Cryptosporidium, Microsporidium, and Isospora. Multiple stool examinations might be necessary to detect Giardia, and special stool preparations are required to diagnose cryptosporidiosis and microsporidiosis. In addition, enteritis can be directly caused by HIV infection. When laboratory diagnostic capabilities are available, treatment decisions should be based on the specific diagnosis. Diagnostic and treatment recommendations for all enteric infections are beyond the scope of these guidelines. # Treatment for Proctitis Acute proctitis of recent onset among persons who have recently practiced receptive anal intercourse is usually sexually acquired (469,470). Such patients should be examined by anoscopy and should be evaluated for infection with HSV, N. gonorrhoeae, C. trachomatis, and T. pallidum. If an anorectal exudate is detected on examination or if polymorphonuclear leukocytes are detected on a Gram-stained smear of anorectal secretions, the following therapy should be prescribed while awaiting additional laboratory tests. # Recommended Regimen Ceftriaxone 250 mg IM PLUS Doxycycline 100 mg orally twice a day for 7 days Patients with suspected or documented herpes proctitis should be managed in the same manner as those with genital herpes (see Genital HSV Infections). If painful perianal ulcers are present or mucosal ulcers are detected on anoscopy, presumptive therapy should include a regimen for genital herpes and LGV. Appropriate diagnostic testing for LGV should be conducted in accordance with state or federal guidelines, and doxycycline therapy should be administered 100 mg orally twice daily for 3 weeks. For MSM, treatment for LGV proctitis/proctocolitis with 3 weeks of doxycycline in those with anorectal chlamydia and either 1) proctitis (as detected by proctoscopic examination and the presence of >10 white-blood cells upon high-power field examination of an anorectal smear specimen) or 2) HIV infection can be considered. # Follow-Up Follow-up should be based on specific etiology and severity of clinical symptoms. Reinfection might be difficult to distinguish from treatment failure. # Management of Sex Partners Partners of persons with sexually transmitted enteric infections should be evaluated for any diseases diagnosed in the index patient. # Ectoparasitic Infections Pediculosis Pubis Persons who have pediculosis pubis (i.e., pubic lice) usually seek medical attention because of pruritus or because they notice lice or nits on their pubic hair. Pediculosis pubis is usually transmitted by sexual contact. Reported resistance to pediculicides has been increasing and is widespread (471)(472)(473). Malathion can be used when treatment failure is believed to have resulted from drug resistance. The odor and long duration of application for malathion make it a less attractive alternative than the recommended pediculcides. Ivermectin has been successfully used to treat lice, but it has only been evaluated in studies involving a limited number of participants. # Recommended Regimens # other Management Considerations The recommended regimens should not be applied to the eyes. Pediculosis of the eyelashes should be treated by applying occlusive ophthalmic ointment to the eyelid margins twice a day for 10 days. Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the heat cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is not necessary. Patients with pediculosis pubis should be evaluated for other STDs. # Follow-Up Patients should be evaluated after 1 week if symptoms persist. Retreatment might be necessary if lice are found or if eggs are observed at the hair-skin junction. Patients who do not respond to one of the recommended regimens should be retreated with an alternative regimen. # Management of Sex Partners Sex partners that have had sexual contact with the patient within the previous month should be treated. Patients should abstain from sexual contact with their sex partner(s) until patients and partners have been treated and reevaluated to rule out persistent disease. # Special Considerations # Pregnancy Pregnant and lactating women should be treated with either permethrin or pyrethrins with piperonyl butoxide; lindane and ivermectin are contraindicated in pregnancy and lactating women. # HIV Infection Patients who have pediculosis pubis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Scabies The predominant symptom of scabies is pruritus, but sensitization to Sarcoptes scabiei occurs before pruritus begins. The first time a person is infested with S. scabiei, sensitization can take several weeks to develop. However, pruritus might occur within 24 hours after a subsequent reinfestation. Scabies in adults frequently is sexually acquired, although scabies in children usually is not. # Recommended Regimens Permethrin cream (5%) applied to all areas of the body from the neck down and washed off after 8-14 hours OR Ivermectin 200 µg/kg orally, repeated in 2 weeks # Alternative Regimen Lindane (1%) 1 oz. of lotion (or 30 g of cream) applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours Lindane is not recommended as first-line therapy because of toxicity (471). It should only be used as an alternative if the patient cannot tolerate other therapies or if other therapies have failed. Lindane should not be used immediately after a bath or shower, and it should not be used by persons who have extensive dermatitis, women who are pregnant or lactating, or children aged <2 years. Lindane resistance has been reported in some areas of the world, including parts of the United States (474). Seizures have occurred when lindane was applied after a bath or used by patients who had extensive dermatitis. Aplastic anemia after lindane use also has been reported (471,474). Permethrin is effective and safe and less expensive than ivermectin (471,474). One study demonstrated increased mortality among elderly, debilitated persons who received ivermectin, but this observation has not been confirmed in subsequent studies (475). # other Management Considerations Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the hot cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is unnecessary. # Crusted Scabies Crusted scabies (i.e., Norwegian scabies) is an aggressive infestation that usually occurs in immunodeficient, debilitated, or malnourished persons (476). Patients who are receiving systemic or potent topical glucocorticoids, organ transplant recipients, mentally retarded or physically incapacitated persons, HIV-infected or human T-lymphotrophic virus-1-infected persons, and persons with various hematologic malignancies are at risk for developing crusted scabies. Crusted scabies is associated with greater transmissibility than scabies. No controlled therapeutic studies for crusted scabies have been conducted, and the appropriate treatment remains unclear. Substantial risk for treatment failure might exist with a single topical scabicide or with oral ivermectin treatment. Combined treatment with a topical scabicide and repeated treatment with oral ivermectin 200 µg/kg on days 1, 2, 8, 9, and 15 are suggested. Additional treatment on days 22 and 29 might be required for severe cases. Ivermectin should be combined with the application of either 5% topical benzyl benzoate or 5% topical permethrin (full body application to be repeated daily for 7 days then 2 times weekly until release from care or cure). Lindane should be avoided because of the risks for neurotoxicity associated with both heavy applications and denuded skin. Fingernails should be closely trimmed to reduce injury from excessive scratching. # Follow-Up Patients should be informed that the rash and pruritus of scabies might persist for up to 2 weeks after treatment. Symptoms or signs that persist for >2 weeks can be attributed to several factors. Treatment failure can be caused by resistance to medication, although faulty application of topical scabicides also can contribute to persistence -patients with crusted scabies might have poor penetration into thick scaly skin and harbor mites in these difficult-to-penetrate layers. Particular attention must be given to the fingernails of these patients. Reinfection from family members or fomites can occur in the absence of appropriate contact treatment and washing of bedding and clothing. Even when treatment is successful and reinfection is avoided, symptoms can persist or worsen as a result of allergic dermatitis. Finally, the presence of household mites can cause symptoms to persist as a result of cross reactivity between antigens. Retreatment can be considered after 1-2 weeks for patients who are still symptomatic or if live mites are present. Treatment with an alternative regimen is recommended for persons who do not respond to the recommended treatment. # Management of Sex Partners and Household Contacts Sexual contacts and those that have had close personal or household contact with the patient within the preceding month should be examined and treated. # Management of outbreaks in Communities, nursing Homes, and other Institutional Settings Scabies outbreaks frequently occur in nursing homes, hospitals, residential facilities, and other communities. Control of an epidemic can only be achieved by treatment of the entire population at risk. Ivermectin can be considered in this setting, especially if treatment with topical scabicides fails. Epidemics should be managed in consultation with an infectious disease specialist. # Special Considerations Infants, Young Children, and Pregnant or Lactating Women Infants, young children, and pregnant or lactating women should not be treated with lindane; however, they can be treated with permethrin. Ivermectin is not recommended for pregnant or lactating patients, and the safety of ivermectin in children who weigh <15 kg has not been determined. # HIV Infection Patients who have uncomplicated scabies and also are infected with HIV should receive the same treatment regimens as those who are HIV negative. HIV-infected patients and others who are immunosuppressed are at increased risk for crusted scabies, for which ivermectin has been reported to be effective in noncontrolled studies involving only a limited number of participants. HIV-infected patients with crusted scabies should be managed in consultation with an infectious disease specialist. # Sexual Assault and STDs # Adults and Adolescents The recommendations in this report are limited to the identification, prophylaxis, and treatment of STDs and conditions commonly identified in the management of such infections. The documentation of findings, collection of nonmicrobiologic specimens for forensic purposes, and management of potential pregnancy or physical and psychological trauma are beyond the scope of this report. Examinations of survivors of sexual assault should be conducted by an experienced clinician in a way that minimizes further trauma to the survivor. The decision to obtain genital or other specimens for STD diagnosis should be made on an individual basis. Care systems for survivors should be designed to ensure continuity (including timely review of test results), support adherence, and monitor for adverse reactions to any therapeutic or prophylactic regimens prescribed at initial examination. Laws in all 50 states strictly limit the evidentiary use of a survivor's previous sexual history, including evidence of previously acquired STDs, as part of an effort to undermine the credibility of the survivor's testimony. Evidentiary privilege against revealing any aspect of the examination or treatment also is enforced in most states. Although it rarely occurs, STD diagnoses might later be accessed, and the survivor and clinician might opt to defer testing for this reason. While collection of specimens at initial examination for laboratory STD diagnosis gives the survivor and clinician the option to defer empiric prophylactic antimicrobial treatment, compliance with follow up visits is traditionally poor (477,478). Among sexually active adults, the identification of an STD might represent an infection acquired prior to the assault, and therefore might be more important for the psychological and medical management of the patient than for legal purposes. Trichomoniasis, BV, gonorrhea, and chlamydial infection are the most frequently diagnosed infections among women who have been sexually assaulted. Such conditions are relatively prevalent, and the presence after an assault does not necessarily imply acquisition during the assault. However, a postassault examination presents an important opportunity to identify or prevent STDs. Chlamydial and gonococcal infections in women are of particular concern because of the possibility of ascending infection. In addition, HBV infection can be prevented by postexposure administration of hepatitis B vaccine. Reproductive-aged female survivors should be evaluated for pregnancy, if appropriate. # Evaluating Adults and Adolescents for Sexually Transmitted Diseases Initial Examination An initial examination might include the following procedures: - NAATs for C. trachomatis and N. gonorrhoeae. These tests are preferred for the diagnostic evaluation of sexual assault victims, regardless of the sites of penetration or attempted penetration (197). - Wet mount and culture or point-of-care testing of a vaginal-swab specimen for T. vaginalis infection. The wet mount also should be examined for evidence of BV and candidiasis, especially if vaginal discharge, malodor, or itching is evident. - A serum sample for immediate evaluation for HIV infection, hepatitis B, and syphilis. Decisions to perform these tests should be made on an individual basis. # Follow-Up Examinations After the initial postassault examination, follow-up examinations provide an opportunity to 1) detect new infections acquired during or after the assault; 2) complete hepatitis B vaccination, if indicated; 3) complete counseling and treatment for other STDs; and 4) monitor side effects and adherence to postexposure prophylactic medication, if prescribed. Examination for STDs can be repeated within 1-2 weeks of the assault. Because infectious agents acquired through assault might not have produced sufficient concentrations of organisms to result in positive test results at the initial examination, testing can be repeated during the follow-up visit, unless prophylactic treatment was provided. If treatment was provided, testing should be conducted only if the survivor reports having symptoms. If treatment was not provided, follow-up examination should be conducted within 1 week to ensure that results of positive tests can be discussed promptly with the survivor and that treatment is provided. Serologic tests for syphilis and HIV infection can be repeated 6 weeks, 3 months, and 6 months after the assault if initial test results were negative and infection in the assailant could not be ruled out (see Sexual Assault and STDs, Risk for Acquiring HIV Infection). # Prophylaxis Compliance with follow-up visits is poor among survivors of sexual assault (477,478). As a result, routine preventive therapy after a sexual assault should be encouraged. The following prophylactic regimen is suggested as preventive therapy: - Postexposure hepatitis B vaccination, without HBIG. This vaccine should be administered to sexual assault survivors at the time of the initial examination if they have not been previously vaccinated. Follow-up doses of vaccine should be administered 1-2 and 4-6 months after the first dose. For those requiring alternative treatments, refer to the specific sections in this report relevant to the specific agent. The efficacy of these regimens in preventing infections after sexual assault has not been evaluated. Clinicians should counsel patients regarding the possible benefits and toxicities associated with these treatment regimens; gastrointestinal side effects can occur with this combination. # other Management Considerations At the initial examination and, if indicated, at follow-up examinations, patients should be counseled regarding 1) symptoms of STDs and the need for immediate examination if symptoms occur and 2) abstinence from sexual intercourse until STD prophylactic treatment is completed. # Risk for Acquiring HIV Infection HIV seroconversion has occurred in persons whose only known risk factor was sexual assault or sexual abuse, but the frequency of this occurrence is probably low. In consensual sex, the risk for HIV transmission from vaginal intercourse is 0.1%-0.2% and for receptive rectal intercourse, 0.5%-3% (479). The risk for HIV transmission from oral sex is substantially lower. Specific circumstances of an assault (e.g., bleeding, which often accompanies trauma) might increase risk for HIV transmission in cases involving vaginal, anal, or oral penetration. Site of exposure to ejaculate, viral load in ejaculate, and the presence of an STD or genital lesions in the assailant or survivor also might increase the risk for HIV. Children might be at higher risk for transmission, because the sexual abuse of children is frequently associated with multiple episodes of assault and might result in mucosal trauma (see Sexual Assault or Abuse of Children). Postexposure therapy with zidovudine was associated with a reduced risk for acquiring HIV in a study of health-care workers who had percutaneous exposures to HIV-infected blood (480). On the basis of these results and the results of animal studies, PEP has been recommended for health-care workers who have occupational exposures to HIV (446). These findings have been extrapolated to other types of HIV exposure, including sexual assault (78). If HIV exposure has occurred, initiation of PEP as soon as possible after the exposure likely increases benefit. Although a definitive statement of benefit cannot be made regarding PEP after sexual assault, the possibility of HIV exposure from the assault should be assessed at the time of the postassault examination. The possible benefit of PEP in preventing HIV infection also should be discussed with the assault survivor if the assault poses a risk for HIV exposure. Several factors impact the medical recommendation for PEP and affect the assault survivor's acceptance of that recommendation, including 1) the likelihood of the assailant having HIV, 2) any exposure characteristics that might increase the risk for HIV transmission, 3) the time elapsed after the event, and 4) the potential benefits and risks associated with the PEP (78). Determination of the assailant's HIV status at the time of the assault examination usually in not possible. Therefore, the health-care provider should assess any available information concerning 1) characteristics and HIV risk behaviors of the assailant(s) (e.g., a man who has sex with other men and persons who use injection drugs or crack cocaine), 2) local epidemiology of HIV/AIDS, and 3) exposure characteristics of the assault. When an assailant's HIV status is unknown, factors that should be considered in determining whether an increased risk for HIV transmission exists include 1) whether vaginal or anal penetration occurred; 2) whether ejaculation occurred on mucous membranes; 3) whether multiple assailants were involved; 4) whether mucosal lesions are present in the assailant or survivor; and 5) any other characteristics of the assault, survivor, or assailant that might increase risk for HIV transmission. If PEP is offered, the following information should be discussed with the patient: 1) the unproven benefit and known toxicities of antiretrovirals; 2) the importance of close follow-up; 3) the benefit of adherence to recommended dosing; and 4) the necessity of early initiation of PEP to optimize potential benefits (i.e., as soon as possible after and up to 72 hours after the assault). Providers should emphasize that PEP appears to be well-tolerated in both adults and children and that severe adverse effects are rare (481)(482)(483). Clinical management of the survivor should be implemented according to the following guidelines (78). Specialist consultation on PEP regimens is recommended if HIV exposure during the assault was possible and if PEP is being considered. The sooner PEP is initiated after the exposure, the higher the likelihood that it will prevent HIV transmission if HIV exposure occurred; however, distress after an assault also might prevent the survivor from accurately weighing exposure risks and benefits of PEP and from making an informed decision to start such therapy. If use of PEP is judged to be warranted, the survivor should be offered a 3-5-day supply of PEP, and a follow-up visit should be scheduled several days later to allow for additional counseling. # Recommendations for Postexposure Assessment of Adolescent and Adult Survivors Within 72 Hours of Sexual Assault § § - Assess risk for HIV infection in the assailant. - Evaluate characteristics of the assault event that might increase risk for HIV transmission. - Consult with a specialist in HIV treatment, if PEP is being considered. - If the survivor appears to be at risk for HIV transmission from the assault, discuss antiretroviral prophylaxis, including toxicity and lack of proven benefit. - If the survivor chooses to start antiretroviral PEP (78), provide enough medication to last until the next return visit; reevaluate the survivor 3-7 days after initial assessment and assess tolerance of medications. - If PEP is started, perform CBC and serum chemistry at baseline (initiation of PEP should not be delayed, pending results). - Perform HIV antibody test at original assessment; repeat at 6 weeks, 3 months, and 6 months. # Sexual Assault or Abuse of Children Recommendations in this report are limited to the identification and treatment of STDs. Management of the psychosocial aspects of the sexual assault or abuse of children is beyond the scope of these recommendations. The identification of sexually transmissible agents in children beyond the neonatal period suggests sexual abuse. The significance of the identification of a sexually transmitted agent in such children as evidence of possible child sexual abuse varies by pathogen. Postnatally acquired gonorrhea; syphilis; and nontransfusion, nonperinatally acquired HIV are usually diagnostic of sexual abuse. Sexual abuse should be suspected when genital herpes is diagnosed. The investigation of sexual abuse among children who have an infection that could have been transmitted sexually should be conducted in compliance with recommendations by clinicians who have experience and training in all elements of the evaluation of child abuse, neglect, and assault. The social significance of an infection that might have been acquired sexually and the recommended action regarding reporting of suspected child sexual abuse varies by the specific organism, as do the recommendations regarding reporting of suspected child sexual abuse (Table 6). In all cases in which an STD has been diagnosed in a child, efforts should be made to detect evidence of sexual abuse, including conducting diagnostic testing for other commonly occurring STDs (484)(485)(486). The general rule that sexually transmissible infections beyond the neonatal period are evidence of sexual abuse has exceptions. For example, rectal or genital infection with C. trachomatis among young children might be the result of perinatally acquired infection and has, in some cases, persisted for as long as 2-3 years. Genital warts have been diagnosed in children who have been sexually abused, but also in children who have no other evidence of sexual abuse (487,488). BV has been diagnosed in children who have been abused, but its presence alone does not prove sexual abuse. In addition, most HBV infections in children result from household exposure to persons who have chronic HBV infection. The possibility of sexual abuse should be strongly considered if no conclusive explanation for nonsexual transmission of an STD can be identified. - A suspected assailant is known to have an STD or to be at high risk for STDs (e.g., has multiple sex partners or a history of STDs). - A sibling or another child or adult in the household or child's immediate environment has an STD. - The patient or parent requests testing. - Evidence of genital, oral, or anal penetration or ejaculation is present. If a child has symptoms, signs, or evidence of an infection that might be sexually transmitted, the child should be tested for other common STDs before the initiation of any treatment that could interfere with the diagnosis of those other STDs. Because of the legal and psychosocial consequences of a false-positive diagnosis, only tests with high specificities should be used. The potential benefit to the child of a reliable diagnosis of an STD justifies deferring presumptive treatment until specimens for highly specific tests are obtained by providers with experience in the evaluation of sexually abused and assaulted children. The scheduling of an examination should depend on the history of assault or abuse. If the initial exposure was recent, the infectious agents acquired through the exposure might not have produced sufficient concentrations of organisms to result in positive test results. A follow-up visit approximately 2 weeks after the most recent sexual exposure can include a repeat physical examination and collection of additional specimens. To allow sufficient time for antibodies to develop, another follow-up visit approximately 12 weeks after the most recent sexual exposure might be necessary to collect sera. A single examination might be sufficient if the child was abused for an extended period and if a substantial amount of time elapsed between the last suspected episode of abuse and the medical evaluation. The following recommendations for scheduling examinations serve as a general guide. The exact timing and nature of follow-up examinations should be determined on an individual basis and should be performed to minimize the possibility for psychological trauma and social stigma. Compliance with follow-up appointments might be improved when law enforcement personnel or child protective services are involved. # Initial and 2-Week Follow-Up Examinations During the initial examination and 2-week followup examination (if indicated), the following should be performed. - Visual inspection of the genital, perianal, and oral areas for genital discharge, odor, bleeding, irritation, warts, and ulcerative lesions. The clinical manifestations of some STDs are different in children than in adults. For example, typical vesicular lesions might not be present in the presence of HSV infection. Because this infection can be indicative of sexual abuse, specimens should be obtained from all vesicular or ulcerative genital or perianal lesions compatible with genital herpes and then sent for viral culture. - Specimen collection for N. gonorrhoeae culture from the pharynx and anus in boys and girls, the vagina in girls, and the urethra in boys. Cervical specimens are not recommended for prepubertal girls. For boys with a urethral discharge, a meatal specimen discharge is an adequate substitute for an intraurethral swab specimen. (197,486). Consultation with an expert is necessary before using NAATs in this context to minimize the possibility of cross-reaction with nongonococcal Neisseria species and other commensals (e.g., N. meningitidis, N. sicca, N. lactamica, N. cinerea, and Moraxella catarrhalis). NAATs can be used as an alternative to culture with vaginal specimens or urine from girls, whereas culture remains the preferred method for urethral specimens or urine from boys and for extragenital specimens (pharynx and rectum) from all children. All positive specimens should be retained for additional testing. HIV infection has been reported in children whose only known risk factor was sexual abuse. Serologic testing for HIV infection should be considered for abused children. The decision to test for HIV infection should be made on a case-bycase basis, depending on the likelihood of infection among assailant(s). Although data are insufficient concerning the efficacy and safety of PEP among both children and adults, treatment is well tolerated by infants and children (with and without HIV infection), and children have a minimal risk for serious adverse reactions because of the short period recommended for prohylaxis. (78,138). In considering whether to offer antiretroviral PEP, health-care providers should consider whether the child can be treated soon after the sexual exposure (i.e., within 72 hours), the likelihood that the assailant is infected with HIV, and the likelihood of high compliance with the prophylactic regimen. The potential benefit of treating a sexually abused child should be weighed against the risk for adverse reactions. If antiretroviral PEP is being considered, a provider specializing in evaluating or treating HIV-infected children should be consulted. # Recommendations for HIV-Related Postexposure Assessment of Children within 72 Hours of Sexual Assault - Review HIV/AIDS local epidemiology and assess risk for HIV infection in the assailant. - Evaluate circumstances of assault that might affect risk for HIV transmission. - Consult with a specialist in treating HIV-infected children if PEP is considered. - If the child appears to be at risk for HIV transmission from the assault, discuss PEP with the caregiver(s), including its toxicity and unknown efficacy. - If caregivers choose for the child to receive antiretroviral PEP (78,142,489), provide enough medication to last until the return visit at 3-7 days after the initial assessment, at which time the child should be reevaluated and tolerance of medication assessed; dosages should not exceed those for adults. - Perform HIV antibody test at original assessment, 6 weeks, 3 months, and 6 months. # Follow-Up Examination After Assault In circumstances in which transmission of syphilis, HIV, or hepatitis B is a concern but baseline tests are negative, an examination approximately 6 weeks, 3 months, and 6 months after the last suspected sexual exposure is recommended to allow time for antibodies to infectious agents to develop. In addition, results of HBsAg testing must be interpreted carefully, because HBV can be transmitted nonsexually. Decisions regarding which tests should be performed must be made on an individual basis. # Presumptive Treatment The risk of a child acquiring an STD as a result of sexual abuse or assault has not been well studied. Presumptive treatment for children who have been sexually assaulted or abused is not recommended because 1) the incidence of most STDs in children is low after abuse/assault, 2) prepubertal girls appear to be at lower risk for ascending infection than adolescent or adult women, and 3) regular follow-up of children usually can be ensured. However, some children or their parent(s) or guardian(s) might be concerned about the possibility of infection with an STD, even if the risk is perceived to be low by the health-care provider. Such concerns might be an appropriate indication for presumptive treatment in some settings and might be considered after all specimens for diagnostic tests relevant to the investigation have been collected. # Diagnostic Considerations # Prevention Two products have been approved for hepatitis B prevention: hepatitis B immune globulin (HBIG) and hepatitis B vaccine (3,4). HBIG provides temporary (i.e., 3-6 months) protection from HBV infection and is typically used as PEP either as an adjunct to hepatitis B vaccination in previously unvaccinated persons or alone in persons who have not responded to vaccination. HBIG is prepared from plasma known to contain high concentrations of anti-HBs. The recommended dose of HBIG is 0.06 mL/kg. Hepatitis B vaccine contains HBsAg produced in yeast by recombinant DNA technology and provides protection from HBV infection when used for both pre-exposure vaccination and PEP. The two available monovalent hepatitis B vaccines for use in adolescents and adults are Recombivax HB (Merck and Co., Inc., Whitehouse Station, New Jersey) and Engerix-B (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania). A combination vaccine (hepatitis A and hepatitis B) for use in - Combined hepatitis A and hepatitis B vaccine. This vaccine is recommended for persons aged ≥18 years who are at increased risk for both hepatitis B and hepatitis A virus infections. † Recombinant hepatitis B surface antigen protein dose, in micrograms. § Pediatric formulation administered on a 3-dose schedule; higher doses might be more immunogenic, but no specific recommendations have been made. ¶ Adult formulation administered on a 2-dose schedule. Dialysis formulation administered on a 3-dose schedule at 0, 1, and 6 months. † † Two 1.0-mL doses of the adult formulation administered at one site on a 4-dose schedule at 0, 1, 2, and 6 months. # Reporting All U.S. states and territories have laws that require the reporting of child abuse. Although the exact requirements differ by state, if a health-care provider has reasonable cause to suspect child abuse, a report must be made. Health-care providers should contact their state or local child-protection service agency regarding child-abuse reporting requirements in their states. # Evaluating Children for Sexually Transmitted Diseases Examinations of children for sexual assault or abuse should be conducted in a manner designed to minimize pain and trauma to the child. Collection of vaginal specimens in prepubertal children can be very uncomfortable and should be performed by an experienced clinician to avoid psychological and physical trauma to the child. The decision to obtain genital or other specimens from a child to conduct an STD evaluation must be made on an individual basis. The following situations place children at high-risk for STDs and constitute a strong indication for testing. - The child has or has had symptoms or signs of an STD or of an infection that can be sexually transmitted, even in the absence of suspicion of sexual abuse. Among the signs that are associated with a confirmed STD diagnosis are vaginal discharge or pain, genital itching or odor, urinary symptoms, and genital ulcers or lesions.	These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 18-30, 2009. The information in this report updates the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (MMWR 2006;55[No. RR-11]). Included in these updated guidelines is new information regarding 1) the expanded diagnostic evaluation for cervicitis and trichomoniasis; 2) new treatment recommendations for bacterial vaginosis and genital warts; 3) the clinical efficacy of azithromycin for chlamydial infections in pregnancy; 4) the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications; 5) lymphogranuloma venereum proctocolitis among men who have sex with men; 6) the criteria for spinal fluid examination to evaluate for neurosyphilis; 7) the emergence of azithromycin-resistant Treponema pallidum; 8) the increasing prevalence of antimicrobial-resistant Neisseria gonorrhoeae; 9) the sexual transmission of hepatitis C; 10) diagnostic evaluation after sexual assault; and 11) STD prevention approaches.# Introduction The term sexually transmitted diseases (STDs) is used to refer to a variety of clinical syndromes caused by pathogens that can be acquired and transmitted through sexual activity. Physicians and other health-care providers play a critical role in preventing and treating STDs. These guidelines for the treatment of STDs are intended to assist with that effort. Although these guidelines emphasize treatment, prevention strategies and diagnostic recommendations also are discussed. These recommendations should be regarded as a source of clinical guidance and not prescriptive standards; health-care providers should always consider the clinical circumstances of each person in the context of local disease prevalence. They are applicable to various patient-care settings, including familyplanning clinics, private physicians' offices, managed care organizations, and other primary-care facilities. These guidelines focus on the treatment and counseling of individual patients and do not address other community services and interventions that are essential to STD/human immunodeficiency virus (HIV) prevention efforts. # Methods These guidelines were developed using a multistage process. Beginning in 2008, CDC staff members and public and private sector experts knowledgeable in the field of STDs systematically reviewed literature using an evidence-based approach (e.g., published abstracts and peer-reviewed journal articles), focusing on the common STDs and information that had become available since publication of the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (1). CDC staff members and STD experts developed background papers and tables of evidence that summarized the type of study (e.g., randomized controlled trial or case series), study population and setting, treatments or other interventions, outcome measures assessed, reported findings, and weaknesses and biases in study design and analysis. CDC staff then developed a draft document on the basis of this evidence-based review. In April 2009, this information was presented at a meeting of invited consultants (including public-and private-sector professionals knowledgeable in the treatment of patients with STDs), where all evidence from the literature reviews pertaining to STD management was discussed. Specifically, participants identified key questions regarding STD treatment that emerged from the literature reviews and discussed the information available to answer those questions. Discussion focused on four principal outcomes of STD therapy for each individual disease: 1) treatment of infection based on microbiologic eradication; 2) alleviation of signs and symptoms; 3) prevention of sequelae; and 4) prevention of transmission. Cost-effectiveness and other advantages (e.g., single-dose formulations and directly observed therapy [DOT]) of specific regimens also were discussed. The consultants then assessed whether the questions identified were relevant, ranked them in order of priority, and answered the questions using the available evidence. In addition, the consultants evaluated the quality of evidence supporting the answers on the basis of the number, type, and quality of the studies. The sections on hepatitis B virus (HBV) and hepatitis A virus (HAV) infections are based on previously published recommendations of the Advisory Committee on Immunization Practices (ACIP) (2)(3)(4). The recommendations for STD screening during pregnancy and cervical cancer screening were developed after CDC staff reviewed the published recommendations from other professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), United States Preventive Services Task Force (USPSTF), and ACIP. Throughout this report, the evidence used as the basis for specific recommendations is discussed briefly. More comprehensive, annotated discussions of such evidence will appear in background papers that will be published in a supplement issue of the journal Clinical Infectious Diseases. When more than one therapeutic regimen is recommended, the sequence is alphabetized unless the choices for therapy are prioritized based on efficacy, convenience, or cost. For those infections with more than one recommended regimen, almost all regimens have similar efficacy and similar rates of intolerance or toxicity unless otherwise specified. Recommended regimens should be used primarily; alternative regimens can be considered in instances of significant drug allergy or other contraindications to the recommended regimens. # Clinical Prevention Guidance The prevention and control of STDs are based on the following five major strategies: • education and counseling of persons at risk on ways to avoid STDs through changes in sexual behaviors and use of recommended prevention services; • identification of asymptomatically infected persons and of symptomatic persons unlikely to seek diagnostic and treatment services; • effective diagnosis, treatment, and counseling of infected persons; • evaluation, treatment, and counseling of sex partners of persons who are infected with an STD; and • pre-exposure vaccination of persons at risk for vaccinepreventable STDs. Primary prevention of STDs begins with changing the sexual behaviors that place persons at risk for infection. Health-care providers have a unique opportunity to provide education and counseling to their patients (5,6). As part of the clinical interview, health-care providers should routinely and regularly obtain sexual histories from their patients and address management of risk reduction as indicated in this report. Guidance in obtaining a sexual history is available in Contraceptive Technology, 19th edition (7) and in the curriculum provided by CDC's STD/ HIV Prevention Training Centers (http://www.stdhivpreventiontraining.org). Effective interviewing and counseling skills, characterized by respect, compassion, and a nonjudgmental attitude toward all patients, are essential to obtaining a thorough sexual history and to delivering prevention messages effectively. Key techniques that can be effective in facilitating rapport with patients include the use of 1) open-ended questions (e.g., "Tell me about any new sex partners you've had since your last visit," and "What's your experience with using condoms been like?"); 2) understandable language ("Have you ever had a sore or scab on your penis?"); and 3) normalizing language ("Some of my patients have difficulty using a condom with every sex act. How is it for you?"). The "Five P's" approach to obtaining a sexual history is an example of an effective strategy for eliciting information concerning five key areas of interest (Box 1). Efforts should be made to ensure that all patients are treated regardless of individual circumstances (e.g., ability to pay, citizenship or immigration status, language spoken, or specific sex practices). Patients seeking treatment or screening for a particular STD should be evaluated for all common STDs. All patients should be informed about all the STDs for which they are being tested and notified about tests for common STDs (e.g., genital herpes) that are available but not being performed. # STD/HIV Prevention Counseling USPSTF recommends high-intensity behavioral counseling for all sexually active adolescents and for adults at increased risk for STDs and HIV (5,6). All providers should routinely obtain a sexual history from their patients and encourage riskreduction using various strategies; effective delivery of prevention messages requires that providers communicate general riskreduction messages relevant to the client and that providers educate the client about specific actions that can reduce the risk for STD/HIV transmission (e.g., abstinence, condom use, limiting the number of sex partners, modifying sexual practices, and vaccination), each of which is discussed separately in this report (see Prevention Methods). Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the patient's culture, language, sex, sexual orientation, age, and developmental level. Interactive counseling approaches directed at a patient's personal risk, the situations in which risk occurs, and the use of personalized goal-setting strategies are effective in STD/ HIV prevention (5,6). One such approach, known as clientcentered STD/HIV prevention counseling, involves tailoring a discussion of risk reduction to the patient's individual situation. Client-centered counseling can increase the likelihood that the patient undertakes or enhances current risk-reduction practices, especially among persons seeking STD care. One such approach, known as Project RESPECT, demonstrated that a brief counseling intervention led to a reduced frequency of STD/HIV riskrelated behaviors and resulted in lowered acquisition rates for curable STDs, including trichomoniasis, chlamydia, gonorrhea, and syphilis (8,9). Practice models based on Project RESPECT have been successfully implemented in clinic-based settings. Other approaches use motivational interviewing to move clients toward achievable risk reduction goals. CDC provides additional information on these and other effective behavioral interventions at http://effectiveinterventions.org. Interactive counseling can be used effectively by all healthcare providers, counselors, and other clinical staff trained in counseling approaches. Extensive training is not a prerequisite for effective risk reduction counseling; however, the quality of counseling is improved when providers receive training in prevention counseling methods and skill-building approaches, providers are periodically observed when providing counseling and given immediate feedback by persons with expertise in the counseling approach, counselors are periodically evaluated and patients asked to evaluate their level of satisfaction, and providers have access to expert assistance or referral for challenging situations. Training in client-centered counseling is available through the CDC STD/HIV Prevention Training Centers (http://www.stdhivpreventiontraining.org). In addition to individual prevention counseling, videos and large group presentations can provide explicit information concerning STDs and instruction to reduce disease transmission (e.g., how to use condoms correctly). Group-based strategies have been effective in reducing the occurrence of additional STDs among persons at high risk, including those attending STD clinics (10). Because the incidence of some STDs, notably syphilis, is higher in HIV-infected persons, the use of client-centered STD counseling for HIV-infected persons has been strongly encouraged by public health agencies and other health organizations. Consensus guidelines issued by CDC, the Health Resources and Services Administration, the HIV Medicine Association of the Infectious Diseases Society of America, and the National Institutes of Health emphasize that STD/HIV risk assessment, # Partners • "Do you have sex with men, women, or both?" • "In the past 2 months, how many partners have you had sex with?" • "In the past 12 months, how many partners have you had sex with?" • "Is it possible that any of your sex partners in the past 12 months had sex with someone else while they were still in a sexual relationship with you?" 2. Prevention of pregnancy • "What are you doing to prevent pregnancy?" 3. Protection from STDs • "What do you do to protect yourself from STDs and HIV?" 4. Practices • "To understand your risks for STDs, I need to understand the kind of sex you have had recently." • "Have you had vaginal sex, meaning 'penis in vagina sex'?" If yes, "Do you use condoms: never, sometimes, or always?" • "Have you had anal sex, meaning 'penis in rectum/ anus sex'?" If yes, "Do you use condoms: never, sometimes, or always?" • "Have you had oral sex, meaning 'mouth on penis/ vagina'?" For condom answers: • If "never:" "Why don't you use condoms?" • If "sometimes:" "In what situations (or with whom) do you not use condoms?" 5. Past history of STDs • "Have you ever had an STD?" • "Have any of your partners had an STD?" Additional questions to identify HIV and viral hepatitis risk include: • "Have you or any of your partners ever injected drugs?" • "Have any of your partners exchanged money or drugs for sex?" • "Is there anything else about your sexual practices that I need to know about?" STD screening, and client-centered risk reduction counseling should be provided routinely to HIV-infected persons (11). Several specific methods have been designed for the HIV care setting (12)(13)(14), and additional information regarding these approaches is available at http://effectiveinterventions.org. # Prevention Methods # Abstinence and Reduction of number of Sex Partners A reliable way to avoid transmission of STDs is to abstain from oral, vaginal, and anal sex or to be in a long-term, mutually monogamous relationship with an uninfected partner. For persons who are being treated for an STD (or whose partners are undergoing treatment), counseling that encourages abstinence from sexual intercourse until completion of the entire course of medication is crucial. A more comprehensive discussion of abstinence and other sexual practices than can help persons reduce their risk for STDs is available in Contraceptive Technology, 19th Edition (7). For persons embarking on a mutually monogamous relationship, screening for common STDs before initiating sex might reduce the risk for future disease transmission. # Pre-exposure Vaccination Pre-exposure vaccination is one of the most effective methods for preventing transmission of some STDs. Two human papillomavirus (HPV) vaccines are available for females aged 9-26 years to prevent cervical precancer and cancer (15,16): the quadrivalent HPV vaccine (Gardasil) and the bivalent HPV vaccine (Cervarix). Gardasil also prevents genital warts. Routine vaccination of females aged 11 or 12 years is recommended with either vaccine, as is catch-up vaccination for females aged 13-26 years. Gardasil can be administered to males aged 9-26 years to prevent genital warts (17). Details regarding HPV vaccination are available at www.cdc.gov/std/hpv. Hepatitis B vaccination is recommended for all unvaccinated, uninfected persons being evaluated for an STD (3,4). In addition, hepatitis A and B vaccines are recommended for men who have sex with men (MSM) and injection-drug users (IDUs) (2)(3)(4); each of these vaccines should also be administered to HIV-infected persons who have not yet been infected with one or both types of hepatitis virus. Details regarding hepatitis A and B vaccination are available at http://www.cdc. gov/hepatitis. # Male Condoms When used consistently and correctly, male latex condoms are highly effective in preventing the sexual transmission of HIV infection. In heterosexual serodiscordant relationships (i.e., those involving one infected and one uninfected partner) in which condoms were consistently used, HIV-negative partners were 80% less likely to become HIV-infected compared with persons in similar relationships in which condoms were not used (18). Moreover, studies show condoms can reduce the risk for other STDs, including chlamydia, gonorrhea, and trichomoniasis; by limiting lower genital tract infections, condoms also might reduce the risk for women developing pelvic inflammatory disease (PID) (19,20). In addition, consistent and correct use of latex condoms also reduces the risk for genital herpes, syphilis, and chancroid when the infected area or site of potential exposure is covered, although data for this effect are more limited (21)(22)(23)(24). Additional information is available at www.cdc.gov/condomeffectiveness/latex.htm. Cohort studies have demonstrated that condoms protect against the acquisition of genital HPV infection. A prospective study among newly sexually active women who were attending college demonstrated that consistent and correct condom use was associated with a 70% reduction in risk for HPV transmission (25). Use of condoms also appears to reduce the risk for HPV-associated diseases (e.g., genital warts and cervical cancer) and mitigate the adverse consequences of infection with HPV. Condom use has been associated with higher rates of regression of cervical intraepithelial neoplasia (CIN) and clearance of HPV infection in women (26) and with regression of HPV-associated penile lesions in men (27). Condoms are regulated as medical devices and are subject to random sampling and testing by the U.S. Food and Drug Administration (FDA). Each latex condom manufactured in the United States is tested electronically for holes before packaging. Rates of condom breakage during sexual intercourse and withdrawal are approximately two broken condoms per 100 condoms used in the United States. The failure of condoms to protect against STD transmission or unintended pregnancy usually results from inconsistent or incorrect use rather than condom breakage (28). Male condoms made of materials other than latex are available in the United States. Two general categories of nonlatex condoms exist. The first type is made of polyurethane or other synthetic material and provides protection against STDs/HIV and pregnancy equal to that of latex condoms (29). These can be substituted for latex condoms by persons with latex allergy. Although they have had higher breakage and slippage rates when compared with latex condoms and are usually more costly, the pregnancy rates among women whose partners use these condoms are similar to those asociated with use of latex condoms (30). The second type is natural membrane condoms (frequently called "natural" condoms or, incorrectly, "lambskin" condoms). These condoms are usually made from lamb cecum and can have pores up to 1,500 nm in diameter. Although these pores do not allow the passage of sperm, they are more than 10 times the diameter of HIV and more than 25 times that of HBV (29). Moreover, laboratory studies demonstrate that viral STD transmission can occur with natural membrane condoms (29). Use of natural membrane condoms for prevention of STDs is not recommended. Providers should advise their patients that condoms must be used consistently and correctly to be effective in preventing STDs; providing instructions about the correct use of condoms can be useful. Communicating the following recommendations can help ensure that patients use male condoms correctly: • Use a new condom with each sex act (i.e., oral, vaginal, and anal). • Carefully handle the condom to avoid damaging it with fingernails, teeth, or other sharp objects. • Put the condom on after the penis is erect and before any genital, oral, or anal contact with the partner. • Use only water-based lubricants (e.g., K-Y Jelly, Astroglide, AquaLube, and glycerin) with latex condoms. Oil-based lubricants (e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, and cooking oil) can weaken latex and should not be used. • Ensure adequate lubrication during vaginal and anal sex, which might require the use of exogenous water-based lubricants. • To prevent the condom from slipping off, hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect. # Female Condoms Laboratory studies indicate that the female condom (Reality) is an effective mechanical barrier to viruses, including HIV, and to semen. The first female condom approved for use in the United States consisted of a lubricated polyurethane sheath with a ring on each end that is inserted into the vagina. A newer version made from nitrile is now available in the United States. A limited number of clinical studies have evaluated the efficacy of female condoms in providing protection from STDs, including HIV (31,32). Although female condoms are costly compared with male condoms, sex partners should consider using a female condom when a male condom cannot be used properly. The female condom also has been used for STDs/HIV protection during receptive anal intercourse (33); although it might provide some protection in this setting, its efficacy remains unknown. # Cervical Diaphragms In observational studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis (34). A recent trial examined the effect of use of a diaphragm plus polycarbophil (Replens) lubricant on HIV acquisition in women in Africa relative to male condom use alone. The study revealed that neither the diaphragm nor the lubricant gel provided additional protective effect when compared with the use of condoms alone (35). Likewise, no difference by study arm in the rate of acquisition of chlamydia or gonorrhea occurred; however, data from participants who reported following the protocol for the use of these products suggested that consistent use of the diaphragm plus gel might reduce acquisition of gonorrhea (36). Diaphragms should not be relied on as the sole source of protection against HIV infection. Diaphragm and nonoxynol-9 (N-9) spermicide use have been associated with an increased risk for bacterial urinary-tract infections in women (37). # Topical Microbicides and Spermicides Studies examining nonspecific topical microbicides for the prevention of HIV and STD have demonstrated that these products are ineffective (38,39). Studies of spermicides containing N-9 have demonstrated that they should not be recommended for STDs/HIV prevention (40), and more recent randomized controlled trials have failed to show a protective effect against HIV acquisition for BufferGel (a vaginal buffering agent), Carraguard (a carrageenan derivative) (41), cellulose sulfate (an HIV entry inhibitor), (42) and SAVVY (1.0% C31G, a surfactant) (43,44). Initial results from a study in which participants used 0.5% PRO2000 vaginal gel (a synthetic polyanion polymer that blocks cellular entry of HIV) on a daily basis appeared promising, reducing the rate of HIV acquisition by 30% relative to no gel (45). However, a recent randomized trial of approximately 9,000 women failed to show any protective effect (46). Topical antiretroviral agents for the prevention of HIV appear more promising. Use of tenofovir gel during sexual intercourse significantly reduced the rate of HIV acquisition (i.e., by 39%) in a study of South African women (47). Additional studies are being undertaken to elucidate the optimal dosing regimens for this drug. Other products remain under study, including VivaGel, a topical vaginal microbicide. A list of products under development is maintained by the Alliance for Microbicide Development at www.microbicide.org. # Condoms and n-9 Vaginal Spermicides Condoms lubricated with spermicides are no more effective than other lubricated condoms in protecting against the transmission of HIV and other STDs (www.cdc.gov/condomeffectiveness/latex.htm). Furthermore, frequent use of spermicides containing N-9 has been associated with disruption of the genital epithelium, which might be associated with an increased risk for HIV transmission (40). Therefore, use of condoms lubricated with N-9 is not recommended for STD/ HIV prevention; in addition, spermicide-coated condoms cost more, have a shorter shelf-life than other lubricated condoms, and have been associated with urinary-tract infection in young women (37). # Rectal Use of n-9 Spermicides N-9 can damage the cells lining the rectum, which might provide a portal of entry for HIV and other sexually transmissible agents. Therefore, it should not used as a microbicide or lubricant during anal intercourse by MSM or by women. # nonbarrier Contraception, Surgical Sterilization, and Hysterectomy Contraceptive methods that are not mechanical barriers offer no protection against HIV or other STDs. Sexually active women who use hormonal contraception (i.e., oral contraceptives, Norplant, and Depo-Provera), have intrauterine devices (IUDs), have been surgically sterilized, or have had hysterectomies should be counseled regarding the use of condoms and the risk for STDs, including HIV infection, because these women might incorrectly perceive that they are not at risk for these diseases. Women who take oral contraceptives and are prescribed certain antibiotics should be counseled about potential interactions (7). # Male Circumcision Although male circumcision should not be substituted for other HIV risk-reduction strategies, it has been shown to reduce the risk for HIV and some STDs in heterosexual men. Three randomized, controlled trials performed in regions of sub-Saharan Africa where generalized HIV epidemics involving predominantly heterosexual transmission were occurring demonstrated that male circumcision reduced the risk for HIV acquisition among men by 50%-60% (48)(49)(50). In these trials, circumcision was also protective against other STDs, including high-risk genital HPV infection and genital herpes (51)(52)(53)(54). Despite these data, male circumcision has not been demonstrated to reduce the risk for HIV or other STDs among MSM (55). The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have recommended that male circumcision be scaled up as an effective intervention for the prevention of heterosexually acquired HIV infection (56). These organizations also recommend that countries with hyperendemic and generalized HIV epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support. Similar recommendations have not been made in the United States, although evidence regarding the role of male circumcision in the prevention of HIV/ AIDS is under review (57). # Emergency Contraception (EC) Women who might have been exposed to STDs during a recent act of unprotected intercourse also are at risk for pregnancy. Providers managing such women should offer counseling about the option of EC if pregnancy is not desired. In the United States, EC products are available over-the-counter to women aged ≥17 years and by prescription to younger women. If these EC pill products are not readily accessible, many commonly available brands of oral contraceptive pills can effectively provide EC, but women must be instructed to take an appropriate and specified number of tablets at one time. All oral EC regimens are efficacious when initiated as soon as possible after unprotected sex, but have some efficacy as long as 5 days later. EC is ineffective (but is also not harmful) if the woman is already pregnant (58). More information about EC is available in the 19th edition of Contraceptive Technology (7) or http://ec.princeton.edu/emergency-contraception.html. Insertion of an IUD up to 7 days after unprotected sex can reduce pregnancy risk by more than 99% (7). However, this method is not advisable for a woman who may have untreated cervical gonorrhea or chlamydia, who is already pregnant, or who has other contraindications to IUD use. # Postexposure Prophylaxis (PEP) for HIV and STD Guidelines for the use of PEP aimed at preventing HIV infection as a result of sexual exposure are available and are discussed in this report (see Sexual Assault and STDs). Genital hygiene methods (e.g., vaginal washing and douching) after sexual exposure are ineffective in protecting against HIV and STD and might increase the risk for bacterial vaginosis, some STDs, and HIV (59). # Pre-exposure Prophylaxis (PrEP) for HIV and STD Antiretroviral therapy (ART) has the potential to impact transmission and acquisition of HIV. In HIV-infected persons, ART reduces viral load and presumably reduces infectiousness (60). In HIV-uninfected persons, ART might reduce susceptibility to infection, a concept supported both by animal studies and by a study of safety and acceptability involving West African women (61,62). A randomized, placebo-controlled trial involving South African women recently demonstrated that use of tenofovir gel associated with sexual intercourse significantly reduced the rate of HIV and herpes simplex virus type 2 (HSV-2) acquisition by 39% and 51%, respectively (47,63). Several large randomized controlled trials of PrEP are either underway or planned. These involve the oral use of non-nucleoside reverse transcriptase inhibitors (tenofovir or tenofovir-emtricitabine) or vaginal use of 1% tenofovir gel. # Retesting to Detect Repeat Infections Retesting several months after a diagnosis of chlamydia or gonorrhea can detect repeat infection and potentially can be used to enhance population-based prevention (64). Further details on retesting can be found in the specific sections on chlamydia and gonorrhea within this report. # Partner Management Partner management refers to a continuum of activities designed to increase the number of infected persons brought to treatment and disrupt transmission networks. Part of this continuum is partner notification -the process by which providers or public health authorities learn about the sex-and needle-sharing partners of infected patients and help to arrange for partner evaluation and treatment. Clinical-care providers can obtain this information and help to arrange for evaluation and treatment of sex partners directly or by cooperating with state and local health departments. The types and comprehensiveness of existing partner services and the specific STDs for which they are offered vary by provider, public health agency, and geographic area. Ideally, persons referred to such services should also receive health counseling and should be referred for other health services as appropriate. Data are limited regarding whether partner notification effectively decreases exposure to STDs and whether it reduces the incidence and prevalence of these infections in a community. Nevertheless, evaluations of partner notification interventions have documented the important contribution this approach can make to case-finding in clinical and community contexts (65). When partners are treated, index patients have reduced risk for reinfection. Therefore, providers should encourage persons with STDs to notify their sex partners and urge them to seek medical evaluation and treatment. Further, providers can ask patients to bring partners with them when returning for treatment. Time spent with index patients to counsel them on the importance of notifying partners is associated with improved notification outcomes (66). When patients diagnosed with chlamydia or gonorrhea indicate that their partners are unlikely to seek evaluation and treatment, providers can offer patient-delivered partner therapy (PDPT), a form of expedited partner therapy (EPT) in which partners of infected persons are treated without previous medical evaluation or prevention counseling. Because EPT might be prohibited in some states and is the topic of ongoing legislation in others (67), providers should visit www.cdc.gov/std/ept to obtain updated information for their individual jurisdiction. Any medication or prescription provided for PDPT should be accompanied by treatment instructions, appropriate warnings about taking medications (if the partner is pregnant or has an allergy to the medication), general health counseling, and a statement advising that partners seek personal medical evaluation, particularly women with symptoms of STDs or PID. The evidence supporting PDPT is based on three clinical trials that included heterosexual men and women with chlamydia or gonorrhea. The trials and meta-analyses revealed that the magnitude of reduction in reinfection of index case-patients compared with patient referral differed according to the STD and the sex of the index case-patient (68)(69)(70)(71). However, across trials, reductions in chlamydia prevalence at follow-up were approximately 20%; reductions in gonorrhea at follow-up were approximately 50%. Rates of notification increased in some trials and were equivalent to patient referral without PDPT in others. Existing data suggest that PDPT also might have a role in partner management for trichomoniasis; however, no single partner management intervention has been shown to be more effective than any other in reducing reinfection rates (72,73). No data support the use of PDPT in the routine management of patients with syphilis. No studies have been published involving PDPT for gonorrhea or chlamydia among MSM. Public health program involvement with partner notification services varies by locale and by STD. Some programs have considered partner notification in a broader context, developing interventions to address sexual and social networks in which persons are exposed to STDs. Prospective evaluations incorporating the assessment of venues, community structure, and social and sexual contacts in conjunction with partner notification efforts have improved case-finding and illustrated transmission networks (74,75). While such efforts are beyond the scope of individual clinicians, support of and collaboration with STD programs by clinicians are critical to the success of social network-based interventions. Certain evidence supports the use of the internet to facilitate partner notification (76), especially among MSM and in cases where no other identifying information is available, and many health departments now conduct formal internet partner notification (IPN) (http://www.ncsddc.org/upload/ wysiwyg/documents/NGuidelinesforInternet.htm). Clinical providers are unlikely to participate directly in IPN. However, when discussing partner notification approaches with patients, they should be aware of the value of the internet in this type of communication and should know where to refer patients who are interested in using the internet to notify partners about their diagnosis. # Reporting and Confidentiality The accurate and timely reporting of STDs is integral to efforts to assess morbidity trends, allocate limited resources, and assist local health authorities in partner notification and treatment. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with state and local statutory requirements. Syphilis, gonorrhea, chlamydia, chancroid, HIV infection, and AIDS are reportable diseases in every state. Because the requirements for reporting other STDs differ by state, clinicians should be familiar with the reporting requirements applicable within their jurisdictions. Reporting can be provider-or laboratory-based. Clinicians who are unsure of state and local reporting requirements should seek advice from state or local health departments or STD programs. STDs and HIV reports are kept strictly confidential. In most jurisdictions, such reports are protected by statute from subpoena. Before conducting a follow-up of a positive STD-test result, public health professionals should consult the patient's health-care provider to verify the diagnosis and to determine the treatments being received. # Special Populations Pregnant Women Intrauterine or perinatally transmitted STDs can have severely debilitating effects on pregnant women, their partners, and their fetuses. All pregnant women and their sex partners should be asked about STDs, counseled about the possibility of perinatal infections, and provided access to treatment, if needed. # Recommended Screening Tests • All pregnant women in the United States should be screened for HIV infection as early in pregnancy as possible (77). Screening should be conducted after the woman is notified that she will be screened for HIV as part of the routine panel of prenatal tests, unless she declines (i.e., opt-out screening). For women who decline HIV testing, providers should address their objections, and when appropriate, continue to encourage testing strongly. Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy. Testing pregnant women and treating those who are infected are vital not only to maintain the health of the patient, but to reduce perinatal transmission of HIV through available antiretroviral and obstetrical interventions. Retesting in the third trimester (preferably before 36 weeks' gestation) is recommended for women at high risk for acquiring HIV infection (e.g., women who use illicit drugs, have STDs during pregnancy, have multiple sex partners during pregnancy, live in areas with high HIV prevalence, or have HIV-infected partners). Rapid HIV screening should be performed on any woman in labor who has an undocumented HIV status unless she declines. If a rapid HIV test result is positive in these women, antiretroviral prophylaxis should be administered without waiting for the results of the confirmatory test (78). • A serologic test for syphilis should be performed on all pregnant women at the first prenatal visit (79). In populations in which the amount of prenatal care delivered is not optimal, rapid plasma reagin (RPR) card test screening (and treatment, if that test is reactive) should be performed at the time that a pregnancy is confirmed. Women who are at high risk for syphilis, live in areas of high syphilis morbidity, or are previously untested should be screened again early in the third trimester (at approximately 28 weeks' gestation) and at delivery. Some states require all women to be screened at delivery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a stillborn infant should be tested for syphilis. • All pregnant women should be routinely tested for hepatitis B surface antigen (HBsAg) during an early prenatal visit (i.e., a visit during the first trimester), even if they have been previously vaccinated or tested (80). Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infection (e.g., having had more than one sex partner in the previous 6 months, evaluation or treatment for an STD, recent or current injection-drug use, and an HBsAg-positive sex partner) and those with clinical hepatitis should be retested at the time of admission to the hospital for delivery. Pregnant women at risk for HBV infection also should be vaccinated. (83,84). other Tests • Evidence does not support routine testing for bacterial vaginosis (BV) in pregnancy. For asymptomatic pregnant women at high risk for preterm delivery, evidence is insufficient to assess the balance of benefits and harms of screening for BV (85). Symptomatic women should be evaluated and treated (see Bacterial Vaginosis). (85). Recommendations to screen pregnant women for STDs are based on disease severity and sequelae, prevalence in the population, costs, medicolegal considerations (e.g., state laws), and other factors. The screening recommendations in this report are generally broader (i.e., if followed, more women will be screened for more STDs than would by following other screening recommendations) and are also consistent with other CDC guidelines. # Adolescents In the United States, prevalence rates of many sexually acquired infections are highest among adolescents (92,93). For example, the reported rates of chlamydia and gonorrhea are highest among females aged 15-19 years, and many persons acquire HPV infection during their adolescent years. Persons who initiate sex early in adolescence are at higher risk for STDs, along with persons residing in detention facilities, attending STD clinics, young men having sex with men (YMSM), and youth who use injection drugs. Factors contributing to this increased risk during adolescence include having multiple sexual partners concurrently, having sequential sexual partnerships of limited duration, failing to use barrier protection consistently and correctly, having increased biologic susceptibility to infection, and experiencing multiple obstacles to accessing health care (92). All 50 states and the District of Columbia explicitly allow minors to consent for their own health services for STDs. No state requires parental consent for STD care or requires that providers notify parents that an adolescent minor has received STD services, except in limited or unusual circumstances. Protecting confidentiality for such care, particularly for adolescents enrolled in private health insurance plans, presents multiple problems. After a claim has been reported, many states mandate that health plans provide a written statement to a beneficiary indicating the benefits and charges covered or not covered by the health plan (i.e., explanation of benefit [EOB]). In addition, federal laws obligate notices to beneficiaries when claims are denied, including alerting consumers who need to pay for care until the allowable deductable is reached. For STD detection-and treatment-related care, an EOB or medical bill that is received by a parent might disclose services provided and list any laboratory tests performed. This type of mandated notification breeches confidentiality, and at a minimum, could prompt parents and guardians to question the costs and reasons for service provision. Despite the high rates of infections documented in the adolescent population, providers frequently fail to inquire about sexual behaviors, assess STD risks, provide risk reduction counseling, and ultimately, fail to screen for asymptomatic infections during clinical encounters. Sexual health discussions should be appropriate for the patient's developmental level and should be aimed at identifying risk behaviors (e.g., unprotected oral, anal, or vaginal sex and drug-use behaviors). Careful, nonjudgmental, and thorough counseling is particularly vital for adolescents who might not feel comfortable acknowledging their engagement in behaviors that place them at high risk for STDs. # Screening Recommendations Routine laboratory screening for common STDs is indicated for sexually active adolescents. The following screening recommendations summarize published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents: • Routine screening for C. trachomatis of all sexually active females aged ≤25 years is recommended annually (81). Evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men based on feasibility, efficacy, and cost-effectiveness. However, screening of sexually active young men should be considered in clinical settings associated with high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics) (81,94). • Routine screening for N. gonorrhoeae in all sexually active women at risk for infection is recommended annually (82). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors that place women at increased risk include a previous gonorrhea infection, the presence of other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. • HIV screening should be discussed with all adolescents and encouraged for those who are sexually active and those who use injection drugs (77,95). • The routine screening of adolescents who are asymptomatic for certain STDs (e.g., syphilis, trichomoniasis, BV, HSV, HPV, HAV, and HBV) is not recommended. However, YMSM and pregnant adolescent females might require more thorough evaluation. • Guidelines from USPSTF and ACOG recommend that cervical cancer screening begin at age 21 years (96,97), a recommendation based on the low incidence of cervical cancer and limited utility of screening for younger adolescents (98). However, the American Cancer Society (ACS) recommends that women start cervical screening with Pap tests 3 years after initiating sexual activity, but by no later than age 21 years (99). # Primary Prevention Recommendations Primary prevention and anticipatory guidance to recognize symptoms and behaviors associated with STDs are strategies that can be incorporated into any or all types of health-care visits. The following recommendations for primary prevention of STDs (i.e., vaccination and counseling) are based on published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents: • The HPV vaccine, either Cervarix or Gardasil, is recommended for 11 and 12 year-old females. The vaccine series can be started at 9 years of age. Catch-up vaccination is recommended for females aged 13-26 years who have not yet received or completed the vaccine series (16). The quadrivalent (Gardasil) HPV vaccine can also be used in males and females aged 9-26 years to prevent genital warts (17). (6). • # Children Management of children who have STDs requires close cooperation between clinicians, laboratorians, and childprotection authorities. Official investigations, when indicated, should be initiated promptly. Certain diseases (e.g., gonorrhea, syphilis, and chlamydia), if acquired after the neonatal period, are virtually 100% indicative of sexual contact. For other diseases (e.g., HPV infections and vaginitis), the association with sexual contact is not as clear (see Sexual Assault and STDs). # Persons in Correctional Facilities Multiple studies have demonstrated that persons entering correctional facilities have high rates of STDs (including HIV) and viral hepatitis, especially those aged ≤35 years (93). Incarcerated persons are more likely to have low socioeconomic status, live in urban areas, and be ethnic and racial minorities. Risk behaviors for contracting STDs (e.g., having unprotected sex; having multiple sexual partners; using drugs and alcohol; and engaging in commercial, survival [prostitution to earn money for food, shelter, or drugs], or coerced sex) are common among incarcerated populations. Before incarceration, many have had limited access to medical care, especially to community-based clinical prevention services. Although no comprehensive national guidelines regarding STD care and management have been developed for correctional populations, the utility of expanded STD services in correctional settings has been reported (100). Capacity to provide STD care also varies by type of correctional facility. For example, local juvenile detention facilities and jails are shortterm facilities (often housing entrants for ≤1 year) where up to half of all entrants are released back to the community within 48 hours of arrest, thereby complicating efforts to provide comprehensive STD services. These services are likely more conducive to prisons and state juvenile confinement facilities, which are long-term, secure facilities where entrants are held for a longer period of time. Most institutions, especially those for adults, do not routinely screen for STDs. Diagnostic testing of inmates with symptoms indicative of an STD is the more common practice in juvenile detention and jail facilities. However, screening for asymptomatic infections facilitates the identification and MMWR December 17, 2010 treatment of persons with otherwise undetected infections, which not only eliminates complications for the individual, but reduces the prevalence of infection among detainees who are released back into the local community. Females in juvenile detention facilities and young women ≤35 years of age have been reported to have high rates of chlamydia (101) and gonorrhea (93). Syphilis seroprevalence rates, which can indicate previous infection, are considerably higher among adult men and women than in adolescents, consistent with the overall national syphilis trends (102). # Chlamydia and Gonorrhea Screening Universal screening of adolescent females for chlamydia and gonorrhea should be conducted at intake in juvenile detention or jail facilities. Universal screening of adult females should be conducted at intake among adult females up to 35 years of age (or on the basis of local institutional prevalence data). # Syphilis Screening Universal screening should be conducted on the basis of the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis. # MSM Subgroups of MSM are at high risk for HIV infection and other viral and bacterial STDs. The frequency of unsafe sexual practices and the reported rates of bacterial STDs and incident HIV infection declined substantially in MSM from the 1980s through the mid-1990s. However, since that time, increased rates of early syphilis (primary, secondary, or early latent), gonorrhea, and chlamydial infection and higher rates of unsafe sexual behaviors have been documented among MSM in the United States and virtually all industrialized countries (103,104). The effect of these behavioral changes on HIV transmission has not been ascertained, but preliminary data suggest that the incidence of HIV infection is increasing among MSM in some urban centers, particularly among MSM from racial and ethnic minority groups (105) and among those who use nonprescription drugs during sex, particularly methamphetamine and volatile nitrites (also known as "poppers"). These adverse trends likely reflect the 1) changing attitudes concerning HIV infection that have accompanied advances in HIV therapy, resulting in improved quality of life and survival for HIV-infected persons; 2) changing patterns of substance abuse; 3) demographic shifts in MSM populations; and 4) changes in sex partner networks resulting from new venues for partner acquisition (e.g., the internet). Increases in bacterial STDs are not necessarily accompanied by increases in HIV incidence; for example, oral sex may permit efficient spread of bacterial STDs but not HIV, as does serosorting (preferential selection of sex partners of the same serostatus) among HIV-infected MSM (106,107). Clinicians should assess the STD-related risks for all male patients, including a routine inquiry about the sex of sex partners. MSM, including those with HIV infection, should routinely undergo nonjudgmental STD/HIV risk assessment and client-centered prevention counseling to reduce the likelihood of acquiring or transmitting HIV or other STDs. Clinicians should be familiar with the local community resources available to assist MSM at high risk in facilitating behavioral change and to enable the conduct of partner notification activities. Clinicians also should routinely ask sexually active MSM about symptoms consistent with common STDs, including urethral discharge, dysuria, genital and perianal ulcers, regional lymphadenopathy, skin rash, and anorectal symptoms consistent with proctitis, including discharge and pain on defecation or during anal intercourse. Clinicians should perform appropriate diagnostic testing on all symptomatic patients. Routine laboratory screening for common STDs is indicated for all sexually active MSM. The following screening tests should be performed at least annually for sexually active MSM: • HIV serology, if HIV negative or not tested within the previous year; • syphilis serology, with a confirmatory testing to establish whether persons with reactive serologies have incident untreated syphilis, have partially treated syphilis, or are manifesting a slow serologic response to appropriate prior therapy; • a test for urethral infection with N. gonorrhoeae and C. trachomatis in men who have had insertive intercourse † during the preceding year; testing of the urine using nucleic acid amplification testing (NAAT) is the preferred approach; • a test for rectal infection § with N. gonorrhoeae and C. trachomatis in men who have had receptive anal intercourse † during the preceding year (NAAT of a rectal swab is the preferred approach); and • a test for pharyngeal infection § with N. gonorrhoeae in men who have had receptive oral intercourse † during the preceding year (NAAT is the preferred approach). Testing for C. trachomatis pharyngeal infection is not recommended. Evaluation for HSV-2 infection with type-specific serologic tests also can be considered if infection status is unknown; knowledge of HSV-2 serostatus might be helpful in identifying persons with previously undiagnosed genital tract infection. † Regardless of history of condom use during exposure. § Commercially available NAATS are not FDA cleared for these indications, but they can be used by laboratories that have met all regulatory requirements for an off-label procedure. Because of the increased incidence of anal cancer in HIVinfected MSM, screening for anal cytologic abnormalities can be considered; however, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic support needed for such a screening activity. More frequent STD screening (i.e., at 3-6-month intervals) is indicated for MSM who have multiple or anonymous partners. In addition, MSM who have sex in conjunction with illicit drug use (particularly methamphetamine use) or whose sex partners participate in these activities should be screened more frequently. All MSM should be tested for HBsAg to detect HBV infection. Prompt identification of chronic infection with HBV is essential to ensure necessary care and services to prevent transmission to others (108). HBsAg testing should be made available in STD treatment settings. In addition, screening among past or current drug users should include HCV and HBV testing. Vaccination against hepatitis A and B is recommended for all MSM in whom previous infection or vaccination cannot be documented (2,3). Preimmunization serologic testing might be considered to reduce the cost of vaccinating MSM who are already immune to these infections, but this testing should not delay vaccination. Vaccinating persons who are immune to HAV or HBV infection because of previous infection or vaccination does not increase the risk for vaccine-related adverse events (see Hepatitis B, Prevaccination Antibody Screening). Sexual transmission of hepatitis C virus infection can occur, especially among HIV-infected MSM. Serologic screening for hepatitis C infection is recommended at initial evaluation of newly diagnosed HIV-infected persons. HIV-infected MSM can also acquire HCV after initial screening; therefore, men with new and unexplained increases in alanine aminotransferase (ALT) should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. # Women Who Have Sex with Women Women who have sex with women (WSW) are a diverse group with variations in sexual identity, sexual behaviors, sexual practices, and risk behaviors. Recent studies indicate that some WSW, particularly adolescents, young women, and women with both male and female partners, might be at increased risk for STDs and HIV as a result of certain reported risk behaviors (109)(110)(111)(112). WSW are at risk for acquiring bacterial, viral, and protozoal infections from current and prior partners, both male and female. WSW should not be presumed to be at low or no risk for STDs based on sexual orientation. Effective screening requires that providers and their female clients engage in a comprehensive and open discussion not only about sexual identify, but sexual and behavioral risks. Few data are available on the risk for STDs transmitted by sex between women, but risk probably varies by the specific STD and sexual practice (e.g., oral-genital sex; vaginal or anal sex using hands, fingers, or penetrative sex items; and oral-anal sex [113,114]). Practices involving digital-vaginal or digitalanal contact, particularly with shared penetrative sex items, present a possible means for transmission of infected cervicovaginal secretions. This possibility is most directly supported by reports of metronidazole-resistant trichomoniasis (115) and genotype-concordant HIV transmitted sexually between women who reported these behaviors (116) and by the high prevalence of BV among monogamous WSW (117). Transmission of HPV can occur with skin-to-skin or skin-to-mucosa contact, which can occur during sex between women. HPV DNA has been detected through polymerase chain reaction (PCR)-based methods from the cervix, vagina, and vulva in 13%-30% of WSW, and high-and low-grade squamous intraepithelial lesions (SIL) have been detected on Pap tests in WSW who reported no previous sex with men (118). However, most self-identified WSW (53%-99%) report having had sex with men and indicate that they might continue this practice in the future (119). Therefore, routine cervical cancer screening should be offered to all women, regardless of sexual preference or sexual practices, and women should be offered HPV vaccine in accordance with current guidelines. Limited data demonstrate that HSV-2 genital transmission between female sex partners is probably inefficient but can occur. The relatively frequent practice of orogenital sex among WSW might place them at higher risk for genital infection with herpes simplex virus type 1 (HSV-1), a hypothesis supported by the recognized association between HSV-1 seropositivity and number of female partners among WSW (120). Although the rate of transmission of C. trachomatis between women remains largely unknown, infection also can be acquired from past or current male partners. Recent data suggest that C. trachomatis infection among WSW might be more common than previously thought (121); transmission of syphilis between female sex partners (likely through oral sex) also has been reported. Therefore, report of same-sex behavior in women should not deter providers from screening these women for STDs, including chlamydia and syphilis, as recommended. BV is common among women in general and even more so among women with female partners. Sexual behaviors that facilitate the transfer of vaginal fluid and/or bacteria between partners might be involved in the pathogenesis of BV. A recent study demonstrated that female sex partners frequently share identical genital Lactobacillus strains (122). Although BV is common in WSW, routine screening for BV is not recommended, nor is the treatment of partners of women with BV. Encouraging awareness of signs and symptoms of BV in women and encouraging healthy sexual practices (e.g., cleaning shared sex toys between uses) might be helpful. # HIV Infection: Detection, Counseling, and Referral HIV infection represents a spectrum of disease that can begin with a brief acute retroviral syndrome that typically transitions to a multiyear chronic and clinically latent illness. Without treatment, this illness eventually progresses to a symptomatic, life-threatening immunodeficiency disease known as AIDS. In untreated patients, the time between HIV infection and the development of AIDS varies, ranging from a few months to many years with an estimated median time of approximately 11 years (123). HIV replication is present during all stages of the infection and progressively depletes CD4 lymphocytes, which are critical for maintenance of effective immune function. When the CD4 cell count falls below 200 cells/µL, patients are at high risk for life-threatening AIDS-defining opportunistic infections (e.g., Pneumocystis pneumonia, Toxoplasma gondii encephalitis, disseminated Mycobacterium avium complex disease, tuberculosis, and bacterial pneumonia). In the absence of treatment, virtually all HIV-infected persons will die of AIDS. Early diagnosis of HIV infection is essential to ensuring that patients are referred promptly for evaluation, provided treatment (if indicated), and linked into counseling and related support services to help them reduce their risk for transmitting HIV to others. Diagnosing persons during acute infection is particularly important. It is during this phase that HIV-infected persons are most infectious (124)(125)(126), but test negative for HIV antibodies and therefore unknowingly continue to engage in those high-risk behaviors associated with HIV transmission. Providers are in a particularly good position to diagnose persons during acute HIV infection because such persons might present for assessment and treatment of a concomitantly acquired STD during this phase of the disease. Knowing that a patient is infected with HIV has important clinical implications because HIV infection alters the immune system and thereby affects the diagnosis, evaluation, treatment, and follow-up of other STDs. Even in the era of highly effective antiretroviral therapy (HAART), HIV infection is often diagnosed in persons with advanced infection (i.e., persons with low CD4 cell counts). Nationally, the proportion of patients diagnosed with AIDS at or within 12 months of their HIV diagnosis in 2007 was 32% (127). Since 2006, CDC has endorsed efforts to increase HIV testing by streamlining the consent process and expanding opt-out testing to all health-care settings, especially STD clinics (77). However, rates of testing remain unacceptably low: in 2006, only 40% of surveyed adults had ever been tested, and <25% of high-risk adults had been tested during the preceding 12 months (128). Proper management of HIV infection requires medical therapy, which for many patients should be coupled with behavioral and psychosocial services. Comprehensive HIV treatment services are usually not available in facilities focusing primarily on STD treatment (e.g., STD clinics); therefore, patients diagnosed in these settings ideally should be referred to a healthcare provider or facility experienced in caring for HIV-infected patients. Nonetheless, providers working in STD-treatment facilities should be knowledgeable about the treatment options available in their communities, educate persons who test positive for HIV about the illness, and know where to refer their patients for support services and HIV care. A detailed discussion of the complex issues required for the management of HIV infection is beyond the scope of this report; however this information is available in other published resources (129)(130)(131). In subsequent sections of this report, additional types of HIV-related information about the diagnosis of HIV infection, counseling of HIV-infected patients, referral of patients for support services (including medical care), and management of sex and injection-drug partners in STD-treatment facilities is provided. In addition, this report discusses HIV infection during pregnancy and among infants and children. # Detection of HIV Infection: Screening and Establishing a Diagnosis All persons who seek evaluation and treatment for STDs should be screened for HIV infection. Screening should be routine, regardless of whether the patient is known or suspected to have specific behavioral risks for HIV infection. # Consent and Pretest Information CDC recommends HIV screening for patients aged 13-64 years in all health-care settings (77). Patients should be notified that testing will be performed, but given the option to decline or defer testing (i.e., provided with opt-out testing) (128). Assent is inferred unless the patient verbally declines testing. Separate written consent for HIV testing should not be required; in most facilities, general consent for medical care is considered sufficient to encompass consent for HIV testing. Providing prevention counseling along with HIV diagnostic testing or as part of HIV screening programs is not a requirement within health-care settings. In addition, routine opt-out testing (instead of traditional written informed consent with pre-and post-test counseling) might be precluded in some jurisdictions by local laws and regulations, although many state and local authorities have updated laws and regulations to facilitate adoption of routine opt-out testing. Information about regulations in specific jurisdictions is available through the National Clinicians Consultation Center at www.nccc. ucsf.edu. # Prevention Counseling Prevention counseling should be offered and encouraged in all health-care facilities that serve patients at high risk (e.g., STD clinics), because these facilities routinely elicit information about the behaviors that place persons at high risk for HIV. Prevention counseling need not be explicitly linked to HIV testing. However, some patients might be more likely to think about HIV and consider their risk-related behavior when undergoing an HIV test. HIV testing presents an excellent opportunity to provide or arrange for prevention counseling to assist with behavior changes that can reduce risk for acquiring HIV infection. # Establishing the Diagnosis of HIV Infection HIV infection can be diagnosed by serologic tests that detect antibodies against HIV-1 and HIV-2 and by virologic tests that can detect HIV antigens or ribonucleic acid (RNA). Antibody testing begins with a sensitive screening test (e.g., the conventional or rapid enzyme immunoassay [EIA]). Currently available serologic tests are both highly sensitive and specific and can detect all known subtypes of HIV-1. Most can also detect HIV-2 and uncommon variants of HIV-1 (e.g., Group O and Group N). The advent of HIV rapid serologic testing has enabled clinicians to make an accurate presumptive diagnosis of HIV infection within half an hour, which could potentially facilitate the identification of the approximately 250,000 persons estimated to be living with undiagnosed HIV in the United States (127). Reactive screening tests must be confirmed by a supplemental antibody test (i.e., Western blot [WB] and indirect immunofluorescence assay [IFA]) or virologic test (i.e., the HIV-1 RNA assay) (132). A confirmed positive antibody test result indicates that a person is infected with HIV and capable of transmitting the virus to others. HIV antibody is detectable in at least 95% of patients within 3 months after infection. Although a negative antibody test result usually indicates that a person is not infected, antibody tests cannot exclude recent infection. Virologic tests for HIV-1 RNA can also be used to identify acute infection in persons who are negative for HIV antibodies. The majority of HIV infections in the United States are caused by HIV-1. However, HIV-2 infection should be suspected in persons who have epidemiologic risk factors or an unusual clinical presentation. Epidemiologic factors associated with HIV-2 infection include having lived in or having a sex partner from an HIV-2 endemic area (e.g., West Africa and some European countries such as Portugal, where HIV-2 prevalence is increasing), having a sex partner known to be infected with HIV-2, or having received a blood transfusion or nonsterile injection in an HIV-2-endemic area. Specific testing for HIV-2 is also indicated when clinical evidence of HIV infection exists but tests for HIV-1 antibodies or HIV-1 viral load are negative, or when HIV-1 WB results exhibit the unusual indeterminate pattern of gag (p55, p24, p17) plus pol (p66, p51, p31) bands in the absence of env (gp160, gp120, gp41) bands. Health-care providers should be knowledgeable about acute HIV infection and the symptoms and signs of acute retroviral syndrome, which develops in 50%-80% of acutely infected patients. Acute retroviral syndrome is characterized by nonspecific symptoms, including fever, malaise, lymphadenopathy, and skin rash. It frequently occurs in the first few weeks after HIV infection, before antibody test results become positive. Suspicion of acute retroviral syndrome should result in prompt nucleic acid testing (HIV plasma RNA) in addition to an HIV antibody test to detect the presence of HIV. A positive HIV nucleic acid test should be confirmed by subsequent antibody testing to document seroconversion. Acutely infected patients are highly contagious during this stage of infection because the concentration of virus in plasma and genital secretions is extremely elevated (125,133). Antiretroviral therapy might benefit the health of persons with recently acquired HIV infection and reduce their infectiousness to others, but evidence to support this recommendation is still inconclusive and awaits the outcomes of several clinical trials currently underway (129). Notwithstanding, patients with acute HIV infection should be referred immediately to an HIV clinical-care provider. Diagnosis of HIV infection should prompt efforts to reduce behaviors that could transmit HIV to others (134). The following are specific recommendations that apply to testing for HIV infection: • HIV screening is recommended for all persons who seek evaluation and treatment for STDs. • HIV testing must be voluntary and free from coercion. Patients must not be tested without their knowledge. • HIV screening after notifying the patient that an HIV test will be performed (unless the patient declines) is recommended in all health-care settings. • tuberculin skin test (sometimes referred to as a purified protein derivative); • urinalysis; and • chest radiograph. Type-specific testing for HSV-2 infection can be considered if herpes infection status is unknown. A first dose of hepatitis A and hepatitis B vaccine should be administered at this first visit for previously unvaccinated persons for whom vaccine is recommended (see Hepatitis A and Hepatitis B). In subsequent visits, when the results of laboratory tests are available, antiretroviral therapy can be offered based on existing guidance (129). Recommendations for the prophylaxis of opportunistic infections and vaccinations in HIV-infected adults and adolescents are available (130,131). Providers should be alert to the possibility of new or recurrent STDs and should treat such conditions aggressively. Diagnosis of an STD in an HIV-infected person indicates on-going or recurrent high-risk behavior and should prompt referral for counseling. Because many STDs are asymptomatic, routine screening for curable STDs (e.g., syphilis, gonorrhea, and chlamydia) should be performed at least annually for all sexually active, HIV-positive persons. Women should be screened annually for cervical cancer precursor lesions by cervical Pap tests. More frequent STD screening might be appropriate depending on individual risk behaviors, the local epidemiology of STDs, and whether incident STDs are detected by screening or by the presence of symptoms. Recently identified HIV infection might not have been recently acquired; persons newly diagnosed with HIV might be at any stage of infection. Therefore, health-care providers should be alert for symptoms or signs that suggest advanced HIV infection (e.g., fever, weight loss, diarrhea, cough, shortness of breath, and oral candidiasis). The presence of any of these symptoms should prompt urgent referral to an infectious diseases provider. Similarly, providers should be alert for signs of psychological distress and be prepared to refer patients accordingly (see Counseling for Patients with HIV Infection and Referral to Support Services). # Counseling for Patients with HIV Infection and Referral to Support Services Those persons who test positive for HIV should receive prevention counseling before leaving the testing site. Such persons should receive or be referred for a medical evaluation and, if indicated, be provided with behavioral and psychological services as determined by a thorough psychosocial evaluation, which can also be used to identify high-risk behaviors. Providers who refer their HIV-positive patients to other professionals should establish means to ensure that these patients are linked successfully to such services, especially to on-going medical care. Providers should expect persons to be distressed when first informed of a positive HIV test result. Such persons face multiple major adaptive challenges, including coping with the reactions of others to a stigmatizing illness, developing and adopting strategies for maintaining physical and emotional health, initiating changes in behavior to prevent HIV transmission to others, and reducing the risk for acquiring additional STDs. Many persons will require assistance with making reproductive choices, gaining access to health services, and coping with changes in personal relationships. Therefore, behavioral and psychosocial services are an integral part of health care for HIV-infected persons. Patients testing positive for HIV have unique needs. Some patients require referral for specific behavioral interventions (e.g., a substance abuse program), mental health disorders (e.g., depression), or emotional distress. Others might require assistance with securing and maintaining employment and housing. Women should be counseled or appropriately referred regarding reproductive choices and contraceptive options, and patients with multiple psychosocial problems might be candidates for comprehensive risk-reduction counseling and services. The following are specific recommendations for HIV counseling and referral: • (11)(12)(13)(14)135,136). Involvement of nongovernment organizations and communitybased organizations might complement such efforts in the clinical setting. # Management of Sex Partners and Injection-Drug Partners Clinicians evaluating HIV-infected persons should determine whether any partners should be notified concerning possible exposure to HIV (77,137). In the context of HIV management, the term "partner" includes not only sex partners, but persons who share syringes or other injection equipment. Partner notification is an important component of disease management, because early diagnosis and treatment of HIV infection might reduce morbidity and provide the opportunity to encourage risk-reduction behaviors. Partner notification for HIV infection should be confidential. Specific guidance regarding spousal notification varies by jurisdiction. Detailed recommendations concerning identification, notification, diagnosis, and treatment of exposed partners are available in Recommendations for Partner Services Programs for HIV Infection, Syphilis, Gonorrhea, and Chlamydial Infections (137). Two complementary notification processes, patient referral and provider referral, can be used to identify partners. With patient referral, patients directly inform their partners of their exposure to HIV infection, whereas with provider referral, trained health department personnel locate partners on the basis of information provided by the patient. During the provider referral notification process, the confidentiality of patients is protected; their names are not revealed to partners who are notified. Many state and local health departments provide these services. The following are specific recommendations for implementing partner-notification procedures: • HIV-infected patients should be encouraged to notify their partners and to refer them for counseling and testing. If requested by the patient, health-care providers should assist in this process, either directly or by referral to health department partner-notification programs. • If patients are unwilling to notify their partners or if they cannot ensure that their partners will seek counseling, physicians or health department personnel should use confidential partner notification procedures. • Partners who have been reached and were exposed to genital secretions and/or blood of an HIV-infected partner though sex or injection-drug use within the preceding 72 hours should be offered postexposure prophylaxis with combination antiretrovirals (78). # Special Considerations Pregnancy All pregnant women in the United States should be tested for HIV infection as early during pregnancy as possible. A second test during the third trimester, preferably at <36 weeks' gestation, should be considered for all pregnant women and is recommended for women known to be at high risk for acquiring HIV, those who receive health care in jurisdictions with elevated incidence of HIV or AIDS among women, and women living in facilities in which prenatal screening identifies at least one HIV-infected pregnant women per 1,000 women screened (77). An RNA test should be used in conjunction with an HIV antibody test for women who have signs or symptoms consistent with acute HIV infection. The patient should first be informed that she will be tested for HIV as part of the panel of prenatal tests, unless she declines, or opts-out, of screening (77,86). For women who decline, providers should continue to strongly encourage testing and address concerns that pose obstacles to testing. Women who decline testing because they have had a previous negative HIV test should be informed about the importance of retesting during each pregnancy. Testing pregnant women is particularly important not only to maintain the health of the patient, but because interventions (i.e., antiretroviral and obstetrical) can reduce the risk for perinatal transmission of HIV. After a pregnant woman has been identified as being HIVinfected, she should be educated about the risk for perinatal infection. Evidence indicates that, in the absence of antiretroviral and other interventions, 15%-25% of infants born to HIV-infected mothers will become infected with HIV; such evidence also indicates that an additional 12%-14% of infants born to infected mothers who breastfeed into the second year of life will become infected (138,139). The risk for perinatal HIV transmission can be reduced to <2% through the use of antiretroviral regimens and obstetrical interventions (i.e., zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy) and by avoiding breastfeeding (138,140). Pregnant women who are HIVinfected should be counseled concerning their options (either on-site or by referral), given appropriate antenatal treatment, and advised not to breastfeed their infants. # HIV Infection Among Infants and Children Diagnosis of HIV infection in a pregnant woman indicates the need to consider whether the woman's other children might be infected. Infants and young children with HIV infection differ from adults and adolescents with respect to the diagnosis, clinical presentation, and management of HIV disease. For example, because maternal HIV antibody passes through the placenta, antibody tests for HIV are expected to be positive in the sera of both infected and uninfected infants born to seropositive mothers. A definitive determination of HIV infection for an infant aged <18 months is usually based on HIV nucleic acid testing (141). Management of infants, children, and adolescents who are known or suspected to be infected with HIV requires referral to physicians familiar with the manifestations and treatment of pediatric HIV infection (142,143). # Diseases Characterized by Genital, Anal, or Perianal Ulcers In the United States, most young, sexually active patients who have genital, anal, or perianal ulcers have either genital herpes or syphilis. The frequency of each condition differs by geographic area and population; however, genital herpes is the most prevalent of these diseases. More than one etiologic agent (e.g., herpes and syphilis) can be present in a genital, anal, or perianal ulcer. Less common infectious causes of genital, anal, or perianal ulcers include chancroid and donovanosis. HSV, syphilis, and chancroid have been associated with an increased risk for HIV transmission, and genital, anal, or perianal lesions might be associated with conditions that are not sexually transmitted (e.g., yeast, trauma, carcinoma, aphthae, fixed drug eruption, and psoriasis). A diagnosis based only on the patient's medical history and physical examination frequently is inaccurate. Therefore, all patients who have genital, anal, or perianal ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should also be performed. Specific tests for evaluation of genital, anal, or perianal ulcers include 1) syphilis serology and darkfield examination; 2) culture for HSV or PCR testing for HSV; and 3) serologic testing for type-specific HSV antibody. No FDA-cleared PCR test to diagnose either herpes or syphilis is available in the United States; however, such testing can be performed by clinical laboratories that have developed their own tests and have conducted a Clinical Laboratory Improvement Amendment (CLIA) verification study. Typespecific serology for HSV-2 might be helpful in identifying persons with genital herpes (see Genital Herpes, Type-Specific Serologic Tests). In addition, biopsy of genital, anal, or perianal ulcers can help identify the cause of ulcers that are unusual or that do not respond to initial therapy. HIV testing should be performed on all persons with genital, anal, or perianal ulcers who are not known to have HIV infection (see Diagnostic Considerations, sections on Syphilis, Chancroid, and Genital Herpes Simplex Virus). Health-care providers frequently must treat patients before test results are available, because early treatment decreases the possibility of ongoing transmission and because successful treatment of genital herpes depends on prompt initiation of therapy. The clinician should empirically treat for the diagnosis considered most likely on the basis of clinical presentation and epidemiologic circumstances (including travel history); even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis. # Chancroid The prevalence of chancroid has declined in the United States (93). When infection does occur, it is usually associated with sporadic outbreaks. Worldwide, chancroid appears to have declined as well, although infection might still occur in some regions of Africa and the Caribbean. Chancroid, as well as genital herpes and syphilis, is a risk factor in the transmission of HIV infection (144). A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is <80% (145). No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and have conducted a CLIA verification study. The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid (146). A probable diagnosis of chancroid, for both clinical and surveillance purposes, can be made if all of the following criteria are met: 1) the patient has one or more painful genital ulcers; 2) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; 3) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and 4) a test for HSV performed on the ulcer exudate is negative. # Treatment Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents transmission to others. In advanced cases, scarring can result, despite successful therapy. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Ceftriaxone 250 mg intramuscularly (IM) in a single dose OR Ciprofloxacin* 500 mg orally twice a day for 3 days* OR Erythromycin base 500 mg orally three times a day for 7 days * Ciprofloxacin is contraindicated for pregnant and lactating women. Azithromycin and ceftriaxone offer the advantage of singledose therapy. Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported. However, because cultures are not routinely performed, data are limited regarding the current prevalence of antimicrobial resistance. # other Management Considerations Men who are uncircumcised and patients with HIV infection do not respond as well to treatment as persons who are circumcised or HIV-negative. Patients should be tested for HIV infection at the time chancroid is diagnosed. If the initial test results were negative, a serologic test for syphilis and HIV infection should be performed 3 months after the diagnosis of chancroid. # Follow-Up Patients should be re-examined 3-7 days after initiation of therapy. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether 1) the diagnosis is correct, 2) the patient is coinfected with another STD, 3) the patient is infected with HIV, 4) the treatment was not used as instructed, or 5) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial. The time required for complete healing depends on the size of the ulcer; large ulcers might require >2 weeks. In addition, healing is slower for some uncircumcised men who have ulcers under the foreskin. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and might require needle aspiration or incision and drainage, despite otherwise successful therapy. Although needle aspiration of buboes is a simpler procedure, incision and drainage might be preferred because of reduced need for subsequent drainage procedures. # Management of Sex Partners Regardless of whether symptoms of the disease are present, sex partners of patients who have chancroid should be examined and treated if they had sexual contact with the patient during the 10 days preceding the patient's onset of symptoms. # Special Considerations # Pregnancy Ciprofloxacin is contraindicated during pregnancy and lactation. No adverse effects of chancroid on pregnancy outcome have been reported. # HIV Infection HIV-infected patients who have chancroid should be monitored closely because, as a group, they are more likely to experience treatment failure and to have ulcers that heal more slowly. HIV-infected patients might require repeated or longer courses of therapy than those recommended for HIV-negative patients, and treatment failures can occur with any regimen. Because data are limited concerning the therapeutic efficacy of the recommended ceftriaxone and azithromycin regimens in HIV-infected patients, these regimens should be used for such patients only if follow-up can be ensured. # Genital HSV Infections Genital herpes is a chronic, life-long viral infection. Two types of HSV have been identified as causing genital herpes: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and at least 50 million persons in the United States are infected with this type of genital herpes (147). However, an increasing proportion of anogenital herpetic infections in some populations has been attributed to HSV-1 infection. Most persons infected with HSV-2 have not been diagnosed with genital herpes. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. As a result, the majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Management of genital HSV should address the chronic nature of the disease and go beyond the treatment of acute episodes of genital ulcers. # Diagnosis of HSV Infection The clinical diagnosis of genital herpes is both nonsensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected persons. HSV-1 is causing an increasing proportion of first episodes of anogenital herpes in some populations (e.g., young women and MSM) and might now account for most of these infections (148,149). Recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for genital HSV-2 infection (150,151). A patient's prognosis and the type of counseling needed depends on the type of genital herpes (HSV-1 or HSV-2) causing the infection; therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing (152). Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for persons diagnosed with or at risk for STDs. # Virologic Tests Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions. The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and are increasingly used in many settings (153,154). PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS). Viral culture isolates should be typed to determine which type of HSV is causing the infection. Failure to detect HSV by culture or PCR does not indicate an absence of HSV infection, because viral shedding is intermittent. The use of cytologic detection of cellular changes of HSV infection is an insensitive and nonspecific method of diagnosis, both for genital lesions (i.e., Tzanck preparation) and for cervical Pap smears and therefore should not be relied upon. # Type-Specific Serologic Tests Both type-specific and nontype-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody (despite claims to the contrary) remain on the market (155); providers should specifically request serologic type-specific glycoprotein G (gG)-based assays when serology is performed for their patients (156)(157)(158). Both laboratory-based assays and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available. The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%-98%, and false-negative results might be more frequent at early stages of infection. The specificities of these assays are ≥96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Repeat or confirmatory testing might be indicated in some settings, especially if recent acquisition of genital herpes is suspected. IgM testing for HSV is not useful, because the IgM tests are not type-specific and might be positive during recurrent episodes of herpes (159). Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. In this instance, education and counseling appropriate for persons with genital herpes should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. Most persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital HSV-1 also can be asymptomatic (147)(148)(149). Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection, and regardless of site of infection, these persons remain at risk for acquiring HSV-2. Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV cultures; 2) a clinical diagnosis of genital herpes without laboratory confirmation; or 3) a partner with genital herpes. HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition. Screening for HSV-1 and HSV-2 in the general population is not indicated. # Management of Genital Herpes Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management. Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat first clinical and recurrent episodes, or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (160)(161)(162)(163)(164)(165)(166)(167)(168). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged. # First Clinical Episode of Genital Herpes Newly acquired genital herpes can cause a prolonged clinical illness with severe genital ulcerations and neurologic involvement. Even persons with first-episode herpes who have mild clinical manifestations initially can develop severe or pro-longed symptoms. Therefore, all patients with first episodes of genital herpes should receive antiviral therapy. # Recommended Regimens* Acyclovir 400 mg orally three times a day for 7-10 days OR Acyclovir 200 mg orally five times a day for 7-10 days OR Famciclovir 250 mg orally three times a day for 7-10 days OR Valacyclovir 1 g orally twice a day for 7-10 days Treatment can be extended if healing is incomplete after 10 days of therapy. # Established HSV-2 Infection Almost all persons with symptomatic first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions. Some persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Many persons might prefer suppressive therapy, which has the additional advantage of decreasing the risk for genital HSV-2 transmission to susceptible partners (169,170). # Suppressive Therapy for Recurrent Genital Herpes Suppressive therapy reduces the frequency of genital herpes recurrences by 70%-80% in patients who have frequent recurrences (166)(167)(168)(169); many persons receiving such therapy report having experienced no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year (171,172). Quality of life is improved in many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment. The frequency of recurrent genital herpes outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease might change. Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy with the patient. Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (170). Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes. Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes, but famciclovir appears somewhat less effective for suppression of viral shedding (163)(164)(165)(166)(167)173). Ease of administration and cost also are important considerations for prolonged treatment. # Recommended Regimens # Episodic Therapy for Recurrent Genital Herpes Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin. # Recommended Regimens # Severe Disease Intravenous (IV) acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis). The recommended regimen is acyclovir 5-10 mg/ kg IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. Acyclovir dose adjustment is recommended for impaired renal function. # Counseling Counseling of infected persons and their sex partners is critical to the management of genital herpes. The goals of counseling include 1) helping patients cope with the infection and 2) preventing sexual and perinatal transmission (174,175). Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashastd.org) and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling. Although the psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears minimal and transient (176), some HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled. The following recommendations apply to counseling of persons with genital HSV infection: • (177,178). # Management of Sex Partners The sex partners of patients who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection. # Special Considerations Allergy, Intolerance, and Adverse Reactions Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (179). # HIV Infection Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical. HSV shedding is increased in HIV-infected persons. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (180). Clinical manifestations of genital herpes might worsen during immune reconstitution after initiation of antiretroviral therapy. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive persons (181)(182)(183). The extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. HSV type-specific serologies can be offered to HIV-positive persons during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection. Acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of genital herpes. For severe HSV disease, initiating therapy with acyclovir 5-10 mg/kg IV every 8 hours might be necessary. # Recommended Regimens for Daily Suppressive Therapy in Persons with HIV If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing (184). Such persons should be managed in consultation with an HIV specialist, and alternate therapy should be administered. All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet, 40 mg/kg IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. Intravenous cidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days. Clinical management of antiviral resistance remains challenging among HIV-infected patients, and other preventative approaches might be necessary. However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy with outbreaks (185). # Genital Herpes in Pregnancy Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes (186). The risk for transmission to the neonate from an infected mother is high (30%-50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy (187). However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Because the risk for herpes is high in infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with an infectious disease specialist. Women without known genital herpes should be counseled to abstain from intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes. Some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy and that such testing should be offered to uninfected women whose sex partner has HSV infection. However, the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied. All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Although cesarean section does not completely eliminate the risk for HSV transmission to the infant, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to prevent neonatal HSV infection. The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been definitively established. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester (188) -findings that provide assurance to women who have had prenatal exposure to acyclovir. However, data regarding prenatal exposure to valacyclovir and famciclovir are too limited to provide useful information on pregnancy outcomes. Acyclovir can be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (189)(190)(191); the effect of antiviral therapy late in pregnancy on the incidence of neonatal herpes is not known. No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes. # neonatal Herpes Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious disease specialist. Surveillance cultures of mucosal surfaces to detect HSV infection might be considered before the development of clinical signs of neonatal herpes. In addition, administration of acyclovir might be considered for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants. All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes. # Granuloma Inguinale (Donovanosis) Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The disease occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa (192,193). Clinically, the disease is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudoboboes) might also occur. The lesions are highly vascular (i.e., beefy red appearance) and bleed easily on contact. The clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intraabdominal organs, bones, or the mouth. The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens. The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared molecular tests for the detection of K. granulomatis DNA exist, but such an assay might be useful when undertaken by laboratories that have conducted a CLIA verification study. # Treatment Several antimicrobial regimens have been effective, but only a limited number of controlled trials have been published (192). Treatment has been shown to halt progression of lesions, and healing typically proceeds inward from the ulcer margins; prolonged therapy is usually required to permit granulation and reepithelialization of the ulcers. Relapse can occur 6-18 months after apparently effective therapy. # Recommended Regimen Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed # Alternative Regimens Azithromycin 1 g orally once per week for at least 3 weeks and until all lesions have completely healed OR Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed OR Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed OR Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed The addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to these regimens can be considered if improvement is not evident within the first few days of therapy. # Follow-Up Patients should be followed clinically until signs and symptoms have resolved. # Management of Sex Partners Persons who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient's symptoms should be examined and offered therapy. However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established. # Special Considerations Pregnancy Pregnancy is a relative contraindication to the use of sulfonamides. Pregnant and lactating women should be treated with the erythromycin regimen, and consideration should be given to the addition of a parenteral aminoglycoside (e.g., gentamicin). Azithromycin might prove useful for treating granuloma inguinale during pregnancy, but published data are lacking. Doxycycline and ciprofloxacin are contraindicated in pregnant women. # HIV Infection Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who are HIV negative; however, the addition of a parenteral aminoglycoside (e.g., gentamicin) can also be considered. # Lymphogranuloma Venereum Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3 (194). The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis, including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus (195,196). LGV is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic, colorectal fistulas and strictures. Genital and colorectal LGV lesions can also develop secondary bacterial infection or can be coinfected with other sexually and nonsexually transmitted pathogens. Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers. C. trachomatis testing also should be conducted, if available. Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. NAATs for C. trachomatis are not FDA-cleared for testing rectal specimens, although some laboratories have performed the CLIA validation studies that are needed to provide results for clinical management. Additional molecular procedures (e.g., PCR-based genotyping) can be used to differentiate LGV from non-LGV C. trachomatis, but these are not widely available. Chlamydia serology (complement fixation titers >1:64) can support the diagnosis of LGV in the appropriate clinical context. Comparative data between types of serologic tests are lacking, and the diagnostic utility of serologic methods other than complement fixation and some microimmunofluorescence procedures has not been established. Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available. In the absence of specific LGV diagnostic testing, patients with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be treated for LGV as described in this report. # Treatment Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the infection can result in scarring. Buboes might require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/ femoral ulcerations. Doxycycline is the preferred treatment. # Recommended Regimen Doxycycline 100 mg orally twice a day for 21 days # Alternative Regimen Erythromycin base 500 mg orally four times a day for 21 days Although clinical data are lacking, azithromycin 1 g orally once weekly for 3 weeks is probably effective based on its chlamydial antimicrobial activity. Fluoroquinolone-based treatments might also be effective, but extended treatment intervals are likely required. # Follow-Up Patients should be followed clinically until signs and symptoms have resolved. # Management of Sex Partners Persons who have had sexual contact with a patient who has LGV within the 60 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a chlamydia regimen (azithromycin 1 gm orally single dose or doxycycline 100 mg orally twice a day for 7 days). # Special Considerations Pregnancy Pregnant and lactating women should be treated with erythromycin. Azithromycin might prove useful for treatment of LGV in pregnancy, but no published data are available regarding its safety and efficacy. Doxycycline is contraindicated in pregnant women. # HIV Infection Persons with both LGV and HIV infection should receive the same regimens as those who are HIV negative. Prolonged therapy might be required, and delay in resolution of symptoms might occur. # Syphilis Syphilis is a systemic disease caused by Treponema pallidum. On the basis of clinical findings, the disease has been divided into a series of overlapping stages, which are used to help guide treatment and follow-up. Persons who have syphilis might seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include, but are not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), neurologic infection (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities, which might occur through the natural history of untreated infection), or tertiary infection (i.e., cardiac or gummatous lesions). Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are either late latent syphilis or latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis might require a longer duration of therapy because organisms might be dividing more slowly; however, the validity of this concept has not been assessed. # Diagnostic Considerations Darkfield examinations and tests to detect T. pallidum in lesion exudate or tissue are the definitive methods for diagnosing early syphilis (197). Although no T. pallidum detection tests are commercially available, some laboratories provide locally developed PCR tests for the detection of T. pallidum. A presumptive diagnosis of syphilis is possible with the use of two types of serologic tests: 1) nontreponemal tests (e.g., Venereal Disease Research Laboratory [VDRL] and RPR) and 2) treponemal tests (e.g., fluorescent treponemal antibody absorbed [FTA-ABS] tests, the T. pallidum passive particle agglutination [TP-PA] assay, various EIAs, and chemiluminescence immunoassays). The use of only one type of serologic test is insufficient for diagnosis, because each type of test has limitations, including the possibility of false-positive test results in persons without syphilis. False-positive nontreponemal test results can be associated with various medical conditions unrelated to syphilis, including autoimmune conditions, older age, and injection-drug use (198,199); therefore, persons with a reactive nontreponemal test should receive a treponemal test to confirm the diagnosis of syphilis. Nontreponemal test antibody titers may correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained using the same serologic test. Sequential serologic tests in individual patients should be performed using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers frequently are slightly higher than VDRL titers. Nontreponemal test titers usually decline after treatment and might become nonreactive with time; however, in some persons, nontreponemal antibodies can persist for a long period of time -a response referred to as the "serofast reaction." Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%-25% of patients treated during the primary stage revert to being serologically nonreactive after 2-3 years (200). Treponemal test antibody titers should not be used to assess treatment response. Some clinical laboratories and blood banks have begun to screen samples using treponemal tests, typically by EIA or chemiluminescence immunoassays (201,202). This strategy will identify both persons with previous treatment for syphilis and persons with untreated or incompletely treated syphilis. The positive predictive value for syphilis associated with a treponemal screening test result might be lower among populations with a low prevalence of syphilis. Persons with a positive treponemal screening test should have a standard nontreponemal test with titer performed reflexively by the laboratory to guide patient management decisions. If the nontreponemal test is negative, then the laboratory should perform a different treponemal test (preferably one based on different antigens than the original test) to confirm the results of the initial test. If a second treponemal test is positive, persons with a history of previous treatment will require no further management unless sexual history suggests likelihood of re-exposure. Those without a history of treatment for syphilis should be offered treatment. Unless history or results of a physical examination suggest a recent infection, previously untreated persons should be treated for late latent syphilis. If the second treponemal test is negative, further evaluation or treatment is not indicated. For most HIV-infected persons, serologic tests are accurate and reliable for the diagnosis of syphilis and for following a patient's response to treatment. However, atypical syphilis serologic test results (i.e., unusually high, unusually low, or fluctuating titers) can occur in HIV-infected persons. When serologic tests do not correspond with clinical findings suggestive of early syphilis, use of other tests (e.g., biopsy and darkfield microscopy) should be considered. Clinical signs of neurosyphilis (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities) warrant further investigation and treatment for neurosyphilis. Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances. Cerebrospinal fluid (CSF) laboratory abnormalities are common in persons with early syphilis. The VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard serologic test for CSF. When reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis; however in early syphilis, it can be of unknown prognostic significance (203). Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, and a reactive CSF-VDRL with or without clinical manifestations. Among persons with HIV infection, the CSF leukocyte count usually is elevated (>5 white blood cell count [WBC]/mm 3 ); using a higher cutoff (>20 WBC/ mm 3 ) might improve the specificity of neurosyphilis diagnosis (204). The CSF-VDRL might be nonreactive even when neurosyphilis is present; therefore, additional evaluation using FTA-ABS testing on CSF can be considered. The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive; neurosyphilis is highly unlikely with a negative CSF FTA-ABS test (205). # Treatment Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by some forms of penicillin. Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis. Reports have indicated that practitioners have inadvertently prescribed combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) widely used in the United States. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the inappropriate combination therapy agent for treating syphilis (206). The effectiveness of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based not only on clinical trials and observational studies, but approximately 50 years of clinical experience. Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, fever, and other symptoms that usually occur within the first 24 hours after the initiation of any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis, presumably because bacterial burdens are higher during these stages. Antipyretics can be used to manage symptoms, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this should not prevent or delay therapy (see Syphilis During Pregnancy). # Management of Sex Partners Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present. Although such manifestations are uncommon after the first year of infection, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically and treated with a recommended regimen, according to the following recommendations: • Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively. • Persons who were exposed >90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain. • For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) can be assumed to have early syphilis. For the purpose of determining a treatment regimen, however, serologic titers should not be used to differentiate early from late latent syphilis (see Latent Syphilis, Treatment). • Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings. Sexual partners of infected patients should be considered at risk and provided treatment if they have had sexual contact with the patient within 3 months plus the duration of symptoms for patients diagnosed with primary syphilis, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for patients with early latent syphilis. # Primary and Secondary Syphilis Treatment Parenteral penicillin G has been used effectively for more than 50 years to achieve clinical resolution (i.e., the healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no comparative trials have been adequately conducted to guide the selection of an optimal penicillin regimen (i.e., the dose, duration, and preparation). Substantially fewer data are available for nonpenicillin regimens. Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis (primary, secondary, and early latent) do not enhance efficacy, regardless of HIV status. # Recommended Regimen for Adults # Recommended Regimen for Infants and Children Infants and children aged ≥1 month diagnosed with syphilis should have a CSF examination to detect asymptomatic neurosyphilis, and birth and maternal medical records should be reviewed to assess whether such children have congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (e.g., through consultation with child-protection services) (see Sexual Assault or Abuse of Children) and treated by using the following pediatric regimen. # Recommended Regimen for Infants and Children Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose # other Management Considerations All persons who have syphilis should be tested for HIV infection. In geographic areas in which the prevalence of HIV is high, persons who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative. Patients who have syphilis and symptoms or signs suggesting neurologic disease (e.g., meningitis and hearing loss) or ophthalmic disease (e.g., uveitis, iritis, neuroretinitis, and optic neuritis) should have an evaluation that includes CSF analysis, ocular slit-lamp ophthalmologic examination, and otologic examination. Treatment should be guided by the results of this evaluation. Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis (203). Therefore, in the absence of clinical neurologic findings, no evidence exists to support variation from the recommended treatment regimen for early syphilis. Symptomatic neurosyphilis develops in only a limited number of persons after treatment with the penicillin regimens recommended for primary and secondary syphilis. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present or treatment failure is documented, routine CSF analysis is not recommended for persons who have primary or secondary syphilis. # Follow-Up Treatment failure can occur with any regimen. However, assessing response to treatment frequently is difficult, and definitive criteria for cure or failure have not been established. In addition, nontreponemal test titers might decline more slowly for persons who previously have had syphilis (207). Clinical and serologic evaluation should be performed 6 months and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain. Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed. Although failure of nontreponemal test titers to decline fourfold within 6-12 months after therapy for primary or secondary syphilis might be indicative of treatment failure, clinical trial data have demonstrated that >15% of patients with early syphilis treated with the recommended therapy will not achieve the two dilution decline in nontreponemal titer used to define response at 1 year after treatment (208). Persons whose titers do not decline should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should receive additional clinical and serologic follow-up. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations. For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis). In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline 100 mg orally twice daily for 14 days (209,210) and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years. Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone (1 g daily either IM or IV for 10-14 days) is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined (211). Azithromycin as a single 2-g oral dose is effective for treating early syphilis (212)(213)(214). However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in several geographical areas in the United States (215)(216)(217). As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used in MSM or pregnant women. Close followup of persons receiving any alternative therapies is essential. Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Patients Who Have a History of Penicillin Allergy). # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Latent Syphilis Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis. Patients' conditions can be diagnosed as early latent syphilis if, during the year preceding the evaluation, they had 1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis. In addition, for persons whose only possible exposure occurred during the previous 12 months, reactive nontreponemal and treponemal tests are indicative of early latent syphilis. In the absence of these conditions, an asymptomatic person should be considered to have late latent syphilis or syphilis of unknown duration. Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, perianal area, perineum and vagina in women, and underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection. # Treatment Because latent syphilis is not transmitted sexually, the objective of treating patients with this stage of disease is to prevent complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens. The following regimens are recommended for penicillin nonallergic patients who have normal CSF examinations (if performed). # Recommended Regimens for Adults* Early Latent Syphilis Benzathine penicillin G 2.4 million units IM in a single dose # Late Latent Syphilis or Latent Syphilis of Unknown Duration Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals * Recommendations for treating syphilis in HIV-infected persons and pregnant women are discussed later in this report (see Syphilis among HIV-Infected Persons and Syphilis in Pregnancy). Available data demonstrate no enhanced efficacy of additional doses of penicillin G, amoxicillin, or other antibiotics in early syphilis, regardless of HIV status. Infants and children aged ≥1 month who have been diagnosed with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results. # Recommended Regimens for Children Early Latent Syphilis Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose # Late Latent Syphilis or Latent Syphilis of Unknown Duration Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units) # other Management Considerations Patients diagnosed with latent syphilis who demonstrate any of the following criteria should have a prompt CSF examination: • Neurologic (e.g., auditory disease, cranial nerve dysfunction, acute or chronic meningitis, stroke, acute or chronic altered mental status, and loss of vibration sense) or ophthalmic signs or symptoms (e.g., iritis and uveitis); • evidence of active tertiary syphilis (e.g., aortitis and gumma); or • serologic treatment failure. If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, the appropriate course of action is unclear. Pharmacologic considerations suggest that an interval of 10-14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections. Missed doses are not acceptable for pregnant patients receiving therapy for late latent syphilis. Pregnant women who miss any dose of therapy must repeat the full course of therapy. # Follow-Up Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. A CSF examination should be performed if 1) titers increase fourfold, 2) an initially high titer (≥1:32) fails to decline at least fourfold (i.e., two dilutions) within 12-24 months of therapy, or 3) signs or symptoms attributable to syphilis develop. In such circumstances, even if the CSF examination is negative, retreatment for latent syphilis should be initiated. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers might fail to decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment). The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), both for 28 days. These therapies should be used only in conjunction with close serologic and clinical follow-up. Based on biologic plausibility and pharmacologic properties, ceftriaxone might be effective for treating late latent syphilis or syphilis of unknown duration. However, the optimal dose and duration of ceftriaxone therapy have not been defined, and treatment decisions should be discussed in consultation with a specialist. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. The efficacy of these alternative regimens in HIVinfected persons has not been well studied. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Tertiary Syphilis Tertiary syphilis refers to gumma and cardiovascular syphilis but not to all neurosyphilis. Patients who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen. # MMWR December 17, 2010 # Recommended Regimen Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals other Management Considerations Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. These patients should be managed in consultation with an infectious disease specialist. # Follow-Up Limited information is available concerning clinical response and follow-up of patients who have tertiary syphilis. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Patients allergic to penicillin should be treated in consultation with an infectious disease specialist. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. neurosyphilis Treatment CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed. Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response. # Recommended Regimen Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days If compliance with therapy can be ensured, the following alternative regimen might be considered. # Alternative Regimen Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10-14 days The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy. # other Management Considerations Other considerations in the management of patients who have neurosyphilis are as follows: • All persons who have syphilis should be tested for HIV. • Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial. # Follow-Up If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important (219,220). The leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered. Limited data suggest that in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters (220). # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10-14 days can be used as an alternative treatment for patients with neurosyphilis (221,222). However, the possibility of cross-reactivity between ceftriaxone and penicillin exists. Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, desensitization in consultation with a specialist. # Pregnancy Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Syphilis During Pregnancy). # HIV Infection See Syphilis Among HIV-Infected Persons. # Syphilis Among HIV-Infected Persons Diagnostic Considerations Although they are uncommon, unusual serologic responses have been observed among HIV-infected persons who have syphilis. Most reports have involved serologic titers that were higher than expected, but false-negative serologic test results and delayed appearance of seroreactivity also have been reported (223). Regardless, both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for most patients who are coinfected with T. pallidum and HIV. When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons. # Treatment Compared with HIV-negative patients, HIV-positive patients who have early syphilis might be at increased risk for neurologic complications (224) and might have higher rates of serologic treatment failure with currently recommended regimens. The magnitude of these risks is not defined precisely, but is likely small. No treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-negative patients (208). Careful follow-up after therapy is essential. # Primary and Secondary Syphilis Among HIV-Infected Persons # Treatment Treatment of primary and secondary syphilis among HIVinfected persons is benzathine penicillin G, 2.4 million units IM in a single dose. Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis do not result in enhanced efficacy, regardless of HIV status (208). # Other Management Considerations Most HIV-infected persons respond appropriately to standard benzathine penicillin for primary and secondary syphilis. CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in HIV-infected persons, even in those without neurologic symptoms, although the clinical and prognostic significance of such CSF abnormalities with primary and secondary syphilis is unknown. Several studies have demonstrated that among persons infected with both HIV and syphilis, clinical and CSF abnormalities consistent with neurosyphilis are associated with a CD4 count of ≤350 cells/mL and/or an RPR titer of ≥1:32 (204,225,226); however, unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes. The use of antiretroviral therapy as per current guidelines might improve clinical outcomes in HIV-infected persons with syphilis (220,227,228). # Follow-Up HIV-infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. HIV-infected persons who meet the criteria for treatment failure (i.e., signs or symptoms that persist or recur or persons who have a sustained fourfold increase in nontreponemal test titer) should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment). CSF examination and retreatment also should be strongly considered for persons whose nontreponemal test titers do not decrease fourfold within 6-12 months of therapy. If CSF examination is normal, treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. HIV-infected, penicillin-allergic patients who have primary or secondary syphilis should be managed according to the recommendations for penicillin-allergic, HIVnegative patients. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). The use of alternatives to penicillin has not been well studied in HIV-infected patients. These therapies should be used only in conjunction with close serologic and clinical follow-up. # Latent Syphilis Among HIV-Infected Persons # Treatment HIV-infected persons with latent syphilis should be treated according to the stage-specific recommendations for HIVnegative persons. • Treatment of early latent syphilis among HIV-infected persons is benzathine penicillin G, 2.4 million units IM in a single dose. • Treatment of late latent syphilis or syphilis of unknown duration among HIV-infected persons is benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks. # Other Management Considerations All HIV-infected persons with syphilis and neurologic symptoms should undergo immediate CSF examination. Some studies have demonstrated that clinical and CSF abnormalities consistent with neurosyphilis are most likely in HIV-infected persons who have been diagnosed with syphilis and have a CD4 count of ≤350 cells/ml and/or an RPR titer of ≥1:32 (204,225,226); however unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes. # Follow-Up Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. If during 12-24 months the nontreponemal titer does not decline fourfold, CSF examination should be strongly considered and treatment administered accordingly. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. The efficacy of alternative nonpenicillin regimens in HIV-infected persons has not been well studied. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). These therapies should be used only in conjunction with close serologic and clinical follow-up. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective (229,230). However, the optimal dose and duration of ceftriaxone therapy have not been defined. # neurosyphilis Among HIV-Infected Persons # Treatment HIV-infected patients with neurosyphilis should be treated according to the recommendations for HIV-negative patients with neurosyphilis (see Neurosyphilis). # Follow Up If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to gauge response after therapy. Limited data suggest that changes in CSF parameters might occur more slowly in HIV-infected patients, especially those with more advanced immunosuppression (219,227). If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, retreatment should be considered. # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations Penicillin Allergy. HIV-infected, penicillin-allergic patients who have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis. Several small observational studies conducted in HIV-infected patients with neurosyphilis suggest that ceftriaxone 1-2 g IV daily for 10-14 days might be effective as an alternate agent (218,229,230). # Syphilis During Pregnancy All women should be screened serologically for syphilis early in pregnancy. Most states mandate screening at the first prenatal visit for all women (231); antepartum screening by nontreponemal antibody testing is typical, but in some settings, treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers. In populations in which use of prenatal care is not optimal, RPR test screening and treatment (if the RPR test is reactive) should be performed at the time that pregnancy is confirmed (232). For communities and populations in which the prevalence of syphilis is high and for patients at high risk, serologic testing should be performed twice during the third trimester (ideally at 28-32 weeks' gestation) and at delivery. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy. # Diagnostic Considerations Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined. Serofast low antibody titers might not require treatment; however, persistent higher titer antibody tests might indicate reinfection, and treatment might be required. # Treatment Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection (233). Evidence is insufficient to determine optimal, recommended penicillin regimens (234). # Recommended Regimen Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection. # other Management Considerations Some evidence suggests that additional therapy can be beneficial for pregnant women in some settings (e.g., a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis) (235). When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure (231); such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction (236). These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection. # Follow-Up Coordinated prenatal care and treatment are vital. Serologic titers should be repeated at 28-32 weeks' gestation and at delivery as recommended for the disease stage. Providers should ensure that the clinical and antibody responses are appropriate for the patient's stage of disease, although most women will deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer at delivery is fourfold higher than the pretreatment titer. Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high # Management of Sex Partners See General Principles, Management of Sex Partners. # Special Considerations # Penicillin Allergy For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Oral step-wise penicillin dose challenge or skin testing might be helpful in identifying women at risk for acute allergic reactions (see Management of Patients Who Have a History of Penicillin Allergy). Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin and azithromycin should not be used, because neither reliably cures maternal infection or treats an infected fetus (234). Data are insufficient to recommend ceftriaxone for treatment of maternal infection and prevention of congenital syphilis. # MMWR December 17, 2010 # HIV Infection Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIVinfected women should be evaluated for syphilis and receive treatment as recommended. Data are insufficient to recommend a specific regimen for HIV-infected pregnant women (see Syphilis Among HIV-Infected Patients). # Congenital Syphilis Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. In communities and populations in which the risk for congenital syphilis is high, serologic testing and a sexual history also should be obtained at 28 weeks' gestation and at delivery. Moreover, as part of the management of pregnant women who have syphilis, information concerning the treatment of sex partners should be obtained to assess the risk for reinfection. Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother's serum is preferred rather than testing of the infant's serum because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or the mother was infected late in pregnancy (see Diagnostic Considerations and Use of Serologic Tests). Screening can be performed using either a nontreponemal or treponemal test. If either screening test is positive, testing must be performed immediately using the other complimentary test (i.e., nontreponemal test followed by treponemal test or vice-versa). No infant or mother should leave the hospital unless maternal serologic status has been documented at least once during pregnancy; in communities and populations in which the risk for congenital syphilis is high, documentation should also occur at delivery. # Evaluation and Treatment of Infants During the First Month of Life The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus, which can complicate the interpretation of reactive serologic tests for syphilis in infants. Therefore, treatment decisions frequently must be made on the basis of 1) identification of syphilis in the mother; 2) adequacy of maternal treatment; 3) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and 4) comparison of maternal (at delivery) and infant nontreponemal serologic titers using the same test conducted preferably by the same laboratory. All infants born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on infant serum, because umbilical cord blood can become contaminated with maternal blood and yield a falsepositive result. Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or chemiluminescence assay) on a newborn's serum is not necessary. No commercially available immunoglobulin (IgM) test can be recommended. All infants born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (e.g., nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and pseudoparalysis of an extremity). Pathologic examination of the placenta or umbilical cord using specific fluorescent antitreponemal antibody staining is suggested. Darkfield microscopic examination of suspicious lesions or body fluids (e.g., nasal discharge) also should be performed. The following scenarios describe the evaluation and treatment of infants for congenital syphilis. # Scenario 1 Infants with proven or highly probable disease and 1. an abnormal physical examination that is consistent with congenital syphilis; 2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; ¶ or 3. a positive darkfield test of body fluid(s). # Recommended Evaluation • CSF analysis for VDRL, cell count, and protein** # Recommended Regimens Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant. # Scenario 2 Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother was not treated, inadequately treated, or has no documentation of having received treatment; 2. mother was treated with erythromycin or another nonpenicillin regimen; † † or 3. mother received treatment <4 weeks before delivery. # Recommended Evaluation • CSF analysis for VDRL, cell count, and protein • CBC, differential, and platelet count • Long-bone radiographs A complete evaluation is not necessary if 10 days of parenteral therapy is administered, although such evaluations might be useful. For instance, a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) can be performed to further support a diagnosis of congenital syphilis. If a single dose of benzathine penicillin G is used, then the infant must be fully evaluated (i.e., by CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and follow-up must be certain. If any part of the infant's evaluation is abnormal or not performed or if the CSF analysis is rendered uninterpretable because of contamination with blood, then a 10-day course of penicillin is required. § § # Recommended Regimens Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days OR Benzathine penicillin G 50,000 units/kg/dose IM in a single dose If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered. # Scenario 3 Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and 2. mother has no evidence of reinfection or relapse. # Recommended Evaluation No evaluation is required. # Recommended Regimen Benzathine penicillin G 50,000 units/kg/dose IM in a single dose* * Another approach involves not treating the infant, but rather providing close serologic follow-up in those whose mother's nontreponemal titers decreased fourfold after appropriate therapy for early syphilis or remained stable or low for late syphilis. # Scenario 4 Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the 1. mother's treatment was adequate before pregnancy and 2. mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4). # Recommended Evaluation No evaluation is required. # Recommended Regimen No treatment is required; however, benzathine penicillin G 50,000 units/kg as a single IM injection might be considered, particularly if follow-up is uncertain. † † A woman treated with a regimen other than those recommended in these guidelines for treatment should be considered untreated. § § If the infant's nontreponemal test is nonreactive and the provider determines that the mother's risk for untreated syphilis is low, treatment of the infant (single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis) without an evaluation can be considered. # Evaluation and Treatment of older Infants and Children Older infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children). Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection. # Recommended Evaluation • CSF analysis for VDRL, cell count, and protein • CBC, differential, and platelet count • Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, and auditory brain stem response) # Recommended Regimen Aqueous crystalline penicillin G 200,000-300,000 units/kg/day IV, administered as 50,000 units/kg every 4-6 hours for 10 days If the child has no clinical manifestations of disease, the CSF examination is normal, and the CSF VDRL test result is negative, treatment with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM can be considered. Any child who is suspected of having congenital syphilis or who has neurologic involvement should be treated with aqueous penicillin G. A single dose of benzathine penicillin G, 50,000 units/kg IM after the 10-day course of IV aqueous penicillin can be considered. This treatment also would be adequate for children who might have other treponemal infections. # Follow-Up All seroreactive infants (or infants whose mothers were seroreactive at delivery) should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2-3 months until the test becomes nonreactive or the titer has decreased fourfold. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months if the infant is not infected (i.e., if the reactive test result was caused by passive transfer of maternal IgG antibody) or was infected but adequately treated. The serologic response after therapy might be slower for infants treated after the neonatal period. If these titers are stable or increase after age 6-12 months, the child should be evaluated (e.g., given a CSF examination) and treated with a 10-day course of parenteral penicillin G. Treponemal tests should not be used to evaluate treatment response, because the results for an infected child can remain positive despite effective therapy. Passively transferred maternal treponemal antibodies can be present in an infant until age 15 months; therefore, a reactive treponemal test after age 18 months is diagnostic of congenital syphilis. If the nontreponemal test is nonreactive at this time, no further evaluation or treatment is necessary. If the nontreponemal test is reactive at age 18 months, the infant should be fully (re)evaluated and treated for congenital syphilis. Infants whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. A reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis. Follow-up of children treated for congenital syphilis after the newborn period should be conducted as recommended for neonates. # Special Considerations # Penicillin Allergy Infants and children who require treatment for syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized, if necessary, and then treated with penicillin (see Management of Patients With a History of Penicillin Allergy). Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone); if a nonpenicillin agent is used, close serologic and CSF follow-up are indicated. # Penicillin Shortage During periods when the availability of penicillin is compromised, the following is recommended (see http://www.cdc. gov/std/treatment/misc/penicillinG.htm). 1. For infants with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days). If aqueous or procaine penicillin G is not available, ceftriaxone (in doses appropriate for age and weight) can be considered with careful clinical and serologic follow-up. Ceftriaxone must be used with caution in infants with jaundice. For infants aged ≥30 days, use 75 mg/kg IV/IM a day in a single daily dose for 10-14 days; however, dose adjustment might be necessary based on current weight. For older infants, the dose should be 100 mg/kg a day in a single daily dose. Evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis. Therefore, ceftriaxone should be used in consultation with a specialist in the treatment of infants with congenital syphilis. Management may include a repeat CSF examination at age 6 months if the initial examination was abnormal. # HIV Infection Evidence is insufficient to determine whether infants who have congenital syphilis and whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants. # Management of Persons Who Have a History of Penicillin Allergy No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%-10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin (238,239), such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Readministration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity. Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin continue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE (238,239). These persons can then be treated safely with penicillin. Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions (238,239). Although these reagents are easily generated and have been available for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [i.e., the major determinant]) and penicillin G have been available commercially. These two tests identify an estimated 90%-97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%-10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant-positive patients, caution should be exercised when the full battery of skin-test reagents is not available (Box 2). Manufacturers are working to ensure better availability of the Pre-Pen skin test reagent as well as an accompanying minor determinant mixture. # Recommendations If the full battery of skin-test reagents is available, including both major and minor determinants (see Penicillin Allergy Skin Testing), patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test-positive patients should be desensitized before initiating treatment. If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. One approach suggests that persons with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another approach in those with negative skin-test results involves testdosing gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided. If the major determinant (Pre-Pen) is not available for skin testing, all patients with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In patients with reactions not likely to be IgE-mediated, outpatient-monitored test doses can be considered. # Penicillin Allergy Skin Testing Patients at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous or 2) are being treated with beta-adrenergic blocking agents, should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or fexafenadine during the preceding 24 hours, diphenhydramine HCl during the preceding 4 days, or hydroxyzine or phenathiazines during the preceding 3 weeks). # Procedures Dilute the antigens either 100-fold for preliminary testing (if the patient has had a life-threatening reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year). # Epicutaneous (Prick) Tests Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is ≥4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs. # Intradermal Test If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26-or 27-gauge needle on a syringe. The margins of the wheals induced by the injections should be marked with a ball point pen. An intradermal test is positive if the average wheal diameter 15 minutes after injection is >2 mm larger than the initial wheal size and also is >2 mm larger than the negative controls. Otherwise, the tests are negative. # Desensitization Patients who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1). This is a straightforward, relatively safe procedure that can be performed orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur. Desensitization usually can be completed in approximately 4-12 hours, after which time the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy. # Diseases Characterized by Urethritis and Cervicitis Urethritis Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are common. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis (240)(241)(242)(243). If clinic-based diagnostic tools (e.g., Gram-stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to health departments and a specific diagnosis might improve partner notification and treatment. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and hybridization tests require urethral swab specimens, whereas NAATs can be performed on urine specimens. Because of their Penicillin G should be freshly prepared or should come from a freshfrozen source. higher sensitivity, NAATs are preferred for the detection of C. trachomatis (197). # Etiology Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU), which is diagnosed when examination findings or microscopy indicate inflammation without GNID, is caused by C. trachomatis in 15%-40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men (244). Complications of NGU among males infected with C. trachomatis include epididymitis and Reiter's syndrome. Documentation of chlamydial infection is essential because of the need for partner referral for evaluation and treatment. In most cases of nonchlamydial NGU, no pathogen can be detected. M. genitalium, which appears to be sexually transmitted, is associated with both symptoms of urethritis and urethral inflammation and accounts for 15%-25% of NGU cases in the United States (240)(241)(242)(243). T. vaginalis, HSV, and adenovirus also can cause NGU, but data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent (244)(245)(246)(247). Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, genital lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (244). # Confirmed Urethritis Clinicians should attempt to obtain objective evidence of urethral inflammation. However, if clinic-based diagnostic tools (e.g., Gram-stain microscopy) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Urethritis can be documented on the basis of any of the following signs or laboratory tests: • Mucopurulent or purulent discharge on examination. • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis and is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing GNID. • Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high-power field. If none of these criteria are present, testing for N. gonorrhoeae and C. trachomatis using NAATs might identify additional infections (248). If the results demonstrate infection with either of these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment. If none of these criteria are present, empiric treatment of symptomatic males is recommended only for men at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated with drug regimens effective against gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated, if indicated. # nongonococcal Urethritis Diagnosis All patients who have confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Testing for chlamydia is strongly recommended because of the increased utility and availability of highly sensitive and specific testing methods (e.g., NAATs) and because a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in the exposed partner. # Treatment Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium respond better to azithromycin (249,250). Single-dose regimens have the advantage of improved compliance and directly observed treatment. To maximize compliance with recommended therapies, medications should be dispensed on-site in the clinic, and the first dose should be directly observed. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days To minimize transmission, men treated for NGU should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen, provided their symptoms have resolved. To minimize the risk for reinfection, men should be instructed to abstain from sexual intercourse until all of their sex partners are treated. Persons who have been diagnosed with a new STD should receive testing for other infections, including syphilis and HIV. # Follow-Up Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment. Providers should be alert to the possibility of chronic prostatitis/ chronic pelvic pain syndrome in male patients experiencing persistent pain (perineal, penile, or pelvic), discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months. Unless a patient's symptoms persist or therapeutic noncompliance or reinfection is suspected by the provider, a test-ofcure (i.e., repeat testing 3-4 weeks after completing therapy) is not recommended for persons with documented chlamydia or gonococcal infections who have received treatment with recommended or alterative regimens. However, because men with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment (251,252), repeat testing of all men diagnosed with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether patients believe that their sex partners were treated (251). # Partner Referral A specific diagnosis might facilitate partner referral. Therefore, testing for gonorrhea and chlamydia is encouraged. Because a substantial proportion of female partners of males with nonchlamydial NGU are infected with chlamydia, partner management is recommended for males with NGU regardless of whether a specific etiology is identified. All sex partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment with a drug regimen effective against chlamydia. Expedited partner treatment and patient referral are alternative approaches to treating partners (71). # Recurrent and Persistent Urethritis Objective signs of urethritis should be present before the initiation of antimicrobial therapy. In persons who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or recurrent urethritis can be retreated with the initial regimen if they did not comply with the treatment regimen or if they were reexposed to an untreated sex partner. Persistent urethritis after doxycycline treatment might be caused by doxycyclineresistant U. urealyticum or M. genitalium. T. vaginalis is also known to cause urethritis in men; a urethral swab, first void urine, or semen for culture or a NAAT (PCR or TMA) on a urethral swab or urine can be performed. If compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended while awaiting the results of the diagnostic tests. Studies involving a limited number of patients who experienced NGU treatment failures have demonstrated that Moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium (253,254). Men with a low probability of T. vaginalis (e.g., MSM) are unlikely to benefit from the addition of metronidazole or tinidazole. # Recommended Regimens Urologic examinations usually do not reveal a specific etiology for urethritis. A four-glass Meares-Stamey lower-urinarytract localization procedure (or four-glass test) might be helpful in localizing pathogens to the prostate (255). A substantial proportion of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. Estimates vary considerably depending on the source and sensitivity of the assay, but one study demonstrated that in 50% of men with this syndrome, ≥5 WBCs per high-power field were detected in expressed prostatic secretions (256). Referral to a urologist should be considered for men who experience pain for more than 3 months within a 6-month period. If men require treatment with a new antibiotic regimen for persistent urethritis and a sexually transmitted agent is the suspected cause, all partners in the past 60 days before the initial diagnosis and any interim partners should be referred for evaluation and appropriate treatment. # Special Considerations HIV Infection Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might facilitate HIV transmission. Patients who have NGU and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Cervicitis Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis or cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (257,258). Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in most clinical settings. Finally, although the presence of GNID on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is not a sensitive indicator, because it is observed in only 50% of women with this infection. # Etiology When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in most cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (e.g., women aged >30 years). Limited data indicate that infection with M. genitalium and BV and frequent douching might cause cervicitis (259)(260)(261)(262)(263). For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because most persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other factors (e.g., persistent abnormality of vaginal flora, douching [or exposure to other types of chemical irritants], or idiopathic inflammation in the zone of ectopy) might be involved. # Diagnosis Because cervicitis might be a sign of upper-genital-tract infection (endometritis), women who seek medical treatment for a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with the most sensitive and specific test available. Women with cervicitis also should be evaluated for the presence of BV and trichomoniasis, and if these organisms are detected, they should be treated. Because the sensitivity of microscopy to detect T. vaginalis is relatively low (approximately 50%), symptomatic women with cervicitis and negative microscopy for trichomonads should receive further testing (i.e., culture or other FDA-cleared method). Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (i.e., culture or serologic testing) for HSV-2 in this setting is unknown. Standardized diagnostic tests for M. genitalium are not commercially available. As discussed, NAAT should be used for diagnosing C. trachomatis and N. gonorrhoeae in women with cervicitis; this testing can be performed on either vaginal, cervical, or urine samples (197). A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (264,265). # Treatment Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided for those women at increased risk for this common STD (e.g., those aged ≤25 years, those with new or multiple sex partners, and those who engage in unprotected sex), especially if follow-up cannot be ensured and if a relatively insensitive diagnostic test is used in place of NAAT. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is >5% (those in younger age groups and those living in certain facilities). Trichomoniasis and BV should also be treated if detected. For women in whom any component of (or all) presumptive therapy is deferred, the results of sensitive tests for C. trachomatis and N. gonorrhoeae (e.g., NAATs) should determine the need for treatment subsequent to the initial evaluation. # Recommended Regimens for Presumptive Treatment* Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days * Consider concurrent treatment for gonococcal infection if prevalence of gonorrhea is high in the patient population under assessment. # Recurrent and Persistent Cervicitis Women with persistent cervicitis should be reevaluated for possible reexposure to an STD. If relapse and/or reinfection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined; in addition, the utility of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis remains unknown. Women who receive such therapy should return after treatment so that a determination can be made regarding whether cervicitis has resolved. Research is needed on the etiology of persistent cervicitis including the potential role of M. genitalium (266). In women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered. # Follow-Up Follow-up should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for re-evaluation because women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment. Therefore, repeat testing of all women with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267). # Management of Sex Partners Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the index patient; these partners should then be treated for the STDs for which the index patient received treatment. To avoid reinfection, patients and their sex partners should abstain from sexual intercourse until therapy is completed (i.e., 7 days after a single-dose regimen or after completion of a 7-day regimen). Expedited partner treatment and patient referral (see Partner Management) are alternative approaches to treating male partners of women that have chlamydia or gonococcal infections (68,69,71). # Special Considerations HIV Infection Patients who have cervicitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (268)(269)(270). # Chlamydial Infections Chlamydial Infections in Adolescents and Adults Chlamydial genital infection is the most frequently reported infectious disease in the United States, and prevalence is highest in persons aged ≤25 years (93). Several important sequelae can result from C. trachomatis infection in women, the most serious of which include PID, ectopic pregnancy, and infertility. Some women who have uncomplicated cervical infection already have subclinical upper-reproductive-tract infection upon diagnosis. Asymptomatic infection is common among both men and women. To detect chlamydial infections, health-care providers frequently rely on screening tests. Annual screening of all sexually active women aged ≤25 years is recommended, as is screening of older women with risk factors (e.g., those who have a new sex partner or multiple sex partners). In June 2007, USPSTF reviewed and updated their chlamydia screening guidance and found that the epidemiology of chlamydial infection in the United States had not changed since the last review (81,271). In issuing recommendations, USPSTF made the decision to alter the age groups used to demonstrate disease incidence (i.e., from persons aged ≤25 years to those aged ≤24 years). CDC has not changed its age cutoff, and thus continues to recommend annual chlamydia screening of sexually active women aged ≤25 years. Screening programs have been demonstrated to reduce both the prevalence of C. trachomatis infection and rates of PID in women (272,273). Although evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men because of several factors (including feasibility, efficacy, and cost-effectiveness) ( 94), the screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics). Among women, the primary focus of chlamydia screening efforts should be to detect chlamydia and prevent complications, whereas targeted chlamydia screening in men should only be considered when resources permit and do not hinder chlamydia screening efforts in women (274 275). An appropriate sexual risk assessment should be conducted for all persons and might indicate more frequent screening for some women or certain men (see MSM). # Diagnostic Considerations C. trachomatis urogenital infection in women can be diagnosed by testing urine or by collecting swab specimens from the endocervix or vagina. Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatis infections in persons that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. NAATs, cell culture, direct immunofluorescence, EIA, and nucleic acid hybridization tests are available for the detection of C. trachomatis on endocervical specimens and urethral swab specimens from men (197). NAATs are the most sensitive tests for these specimens and are FDA-cleared for use with urine. Some NAATs are cleared for use with vaginal swab specimens, which can be collected by a provider or self-collected by a patient. Self-collected vaginal swab specimens perform at least as well as with other approved specimens using NAATs (276,277), and women find this screening strategy highly acceptable. Rectal and oropharyngeal C. trachomatis infection in persons engaging in receptive anal or oral intercourse can be diagnosed by testing at the anatomic site of exposure. Most tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal or oropharyngeal swab specimens, and chlamydia culture is not widely available for this purpose. However, NAATs have demonstrated improved sensitivity and specificity compared with culture for the detection of C. trachomatis at rectal sites (278)(279)(280) and at oropharyngeal sites among men (278)(279)(280)(281). Some laboratories have met CLIA requirements and have validated NAAT testing on rectal swab specimens for C. trachomatis. Recent evidence suggests that the liquid-based cytology specimens collected for Pap smears might be acceptable specimens for NAAT testing, although test sensitivity using these specimens might be lower than those resulting from the use of cervical swab specimens (282); regardless, certain NAATs have been FDA-cleared for use on liquid-based cytology specimens. Persons who undergo testing and are diagnosed with chlamydia should be tested for other STDs. # Treatment Treating infected patients prevents sexual transmission of the disease, and treating all sex partners of those testing positive for chlamydia can prevent reinfection of the index patient and infection of other partners. Treating pregnant women usually prevents transmission of C. trachomatis to infants during birth. Chlamydia treatment should be provided promptly for all persons testing positive for infection; delays in receiving chlamydia treatment have been associated with complications (e.g., PID) in a limited proportion of chlamydia-infected subjects (283). Coinfection with C. trachomatis frequently occurs among patients who have gonococcal infection; therefore, presumptive treatment of such patients for chlamydia is appropriate (see Gonococcal Infection, Dual Therapy for Gonococcal and Chlamydial Infections). The following recommended treatment regimens and alternative regimens cure infection and usually relieve symptoms. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of genital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively (284). These studies were conducted primarily in populations in which follow-up was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT) was used for determining microbiological outcome. Azithromycin should always be available to treat patients for whom compliance with multiday dosing is uncertain. The clinical significance and transmissibility of C. trachomatis detected at oropharyngeal sites is unclear (285), and the efficacy of different antibiotic regimens in resolving oropharyngeal chlamydia remains unknown. In patients who have erratic health-care-seeking behavior, poor treatment compliance, or unpredictable follow-up, azithromycin might be more cost-effective in treating chlamydia because it enables the provision of a single-dose of directly observed therapy (284). Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that can lead to noncompliance. Levofloxacin and ofloxacin are effective treatment alternatives but are more expensive and offer no advantage in the dosage regimen. Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately. To maximize compliance with recommended therapies, medications for chlamydial infections should be dispensed on site, and the first dose should be directly observed. To minimize disease transmission to sex partners, persons treated for chlamydia should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen. To minimize the risk for reinfection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated. # Follow-Up Except in pregnant women, test-of-cure (i.e., repeat testing 3-4 weeks after completing therapy) is not advised for persons treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected. Moreover, the validity of chlamydial diagnostic testing at <3 weeks after completion of therapy (to identify patients who did not respond to therapy) has not been established. False-negative results might occur in the presence of persistent infections involving limited numbers of chlamydial organisms. In addition, NAAT conducted at <3 weeks after completion of therapy in persons who were treated successfully could yield false-positive results because of the continued presence of nonviable organisms (197). A high prevalence of C. trachomatis infection has been observed in women and men who were treated for chlamydial infection during the preceding several months (251,267,(286)(287)(288). Most post-treatment infections result from reinfection caused by failure of sex partners to receive treatment or the initiation of sexual activity with a new infected partner. Repeat infections confer an elevated risk for PID and other complications. Unlike the test-of-cure, which is not recommended, repeat C. trachomatis testing of recently infected women or men should be a priority for providers. Chlamydia-infected women and men should be retested approximately 3 months after treatment, regardless of whether they believe that their sex partners were treated (251,267). If retesting at 3 months is not possible, clinicians should retest whenever persons next present for medical care in the 12 months following initial treatment. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation, testing, and treatment if they had sexual contact with the patient during the 60 days preceding onset of the patient's symptoms or chlamydia diagnosis. Although the exposure intervals defined for the identification of at-risk sex partners are based on limited evaluation, the most recent sex partner should be evaluated and treated, even if the time of the last sexual contact was >60 days before symptom onset or diagnosis. Among heterosexual patients, if concerns exist that sex partners who are referred to evaluation and treatment will not seek these services (or if other management strategies are impractical or unsuccessful), patient delivery of antibiotic therapy to their partners can be considered (see Partner Management). Compared with standard partner referral, this approach, which involves delivering a prescription or the medication itself, has been associated with a trend toward a decrease in rates of persistent or recurrent chlamydia (68,69,71). Patients must also inform their partners of their infection and provide them with written materials about the importance of seeking evaluation for any symptoms suggestive of complications (e.g., testicular pain in men and pelvic or abdominal pain in women). Patient-delivered partner therapy is not routinely recommended for MSM because of a high risk for coexisting infections, especially undiagnosed HIV infection, in their partners. Patients should be instructed to abstain from sexual intercourse until they and their sex partners have completed treatment. Abstinence should be continued until 7 days after a single-dose regimen or after completion of a multiple-dose regimen. Timely treatment of sex partners is essential for decreasing the risk for reinfecting the index patient. # Special Considerations Pregnancy Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women. However, clinical experience and published studies suggest that azithromycin is safe and effective (289)(290)(291). Repeat testing to document chlamydial eradication (preferably by NAAT) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women to ensure therapeutic cure, considering the severe sequelae that might occur in mothers and neonates if the infection persists. Women aged <25 years and those at increased risk for chlamydia (i.e., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant (81). Pregnant women diagnosed with a chlamydial infection during the first trimester should not only receive a test to document chlamydial eradication, but be retested 3 months after treatment. # Recommended Regimens Azithromycin 1 g orally in a single dose OR Amoxicillin 500 mg orally three times a day for 7 days # Alternative Regimens Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin base 250 mg orally four times a day for 14 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 400 mg orally four times a day for 14 days The frequent gastrointestinal side effects associated with erythromycin can result in noncompliance with the alternative regimens. Although erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity, the lower dose 14-day erythromycin regimens can be considered if gastrointestinal tolerance is a concern. # HIV Infection Patients who have chlamydial infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Chlamydial Infections Among Infants Prenatal screening and treatment of pregnant women can prevent chlamydial infection among neonates. Pregnant women aged <25 years are at high risk for infection. C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. Although neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant, ocular prophylaxis with these agents does prevent gonococcal ophthalmia and therefore should be administered (see Ophthalmia Neonatorum Prophylaxis). Initial C. trachomatis perinatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, although infection might be asymptomatic in these locations. Instead, C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5-12 days after birth. C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1-3 months. Although C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, perinatal chlamydial infections (including ophthalmia and pneumonia) have occurred less frequently because of the institution of widespread prenatal screening and treatment of pregnant women. # ophthalmia neonatorum Caused by C. trachomatis A chlamydial etiology should be considered for all infants aged ≤30 days who have conjunctivitis, especially if the mother has a history of untreated chlamydia infection. # Diagnostic Considerations Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescence antibody [DFA] tests, EIA, and NAAT). Most nonculture tests are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations. Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a dacron-tipped swab or the swab specified by the manufacturer's test kit, and they must contain conjunctival cells, not exudate alone. Specific diagnosis of C. trachomatis infection confirms the need for treatment not only for the neonate, but also for the mother and her sex partner(s). Ocular specimens from infants being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae. # MMWR December 17, 2010 # Recommended Regimen Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days* , † * An association between oral erythromycin and infantile hypertrophic pyloric stenosis (IHIS) has been reported in infants aged <6 weeks who were treated with this drug. Infants treated with erythromycin should be followed for signs and symptoms of IHPS. † Data on use of other macrolides (e.g., azithromycin and clarithromycin) for the treatment of neonatal chlamydia infection are limited. The results of one study involving a limited number of patients suggest that a short course of azithromycin, 20 mg/kg/day orally, 1 dose daily for 3 days, might be effective (292). Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered. # Follow-Up Because the efficacy of erythromycin treatment is only approximately 80%, a second course of therapy might be required. Therefore, follow-up of infants is recommended to determine whether initial treatment was effective. The possibility of concomitant chlamydial pneumonia should be considered. # Management of Mothers and Their Sex Partners The mothers of infants who have chlamydial infection and the sex partners of these women should be evaluated and treated (see Chlamydial Infection in Adolescents and Adults). # Infant Pneumonia Caused by C. trachomatis Characteristic signs of chlamydial pneumonia in infants include 1) a repetitive staccato cough with tachypnea and 2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. In addition, peripheral eosinophilia (≥400 cells/ mm 3 ) occurs frequently. Wheezing is rare, and infants are typically afebrile. Because clinical presentations differ, initial treatment and diagnostic tests should include C. trachomatis for all infants aged 1-3 months who are suspected of having pneumonia (especially those whose mothers have untreated chlamydial infection). # Diagnostic Considerations Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, DFA, and NAAT) can be used, although nonculture tests of nasopharyngeal specimens have a lower sensitivity and specificity than nonculture tests of ocular specimens. DFA is the only FDA-cleared test for the detection of C. trachomatis from nasopharyngeal specimens. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis. Because test results for chlamydia often are not available in a timely manner, the decision to provide treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings. The results of tests for chlamydial infection assist in the management of an infant's illness and can help determine the need for treating the mother and her sex partner(s). # Recommended Regimen Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days # Follow-Up The effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%; a second course of therapy might be required. Follow-up of infants is recommended to determine whether the pneumonia has resolved, although some infants with chlamydial pneumonia continue to have abnormal pulmonary function tests later in childhood. # Management of Mothers and Their Sex Partners Mothers of infants who have chlamydia pneumonia and the sex partners of these women should be evaluated and treated according to the recommended treatment of adults for chlamydial infections (see Chlamydial Infection in Adolescents and Adults). # Infants Born to Mothers Who Have Chlamydial Infection Infants born to mothers who have untreated chlamydia are at high risk for infection; however, prophylatic antibiotic treatment is not indicated, and the efficacy of such treatment is unknown. Infants should be monitored to ensure appropriate treatment if symptoms develop. # Chlamydial Infections Among Children Sexual abuse must be considered a cause of chlamydial infection in preadolescent children, although perinatally transmitted C. trachomatis infection of the nasopharynx, urogenital tract, and rectum might persist for >1 year (see Sexual Assault or Abuse of Children). # Diagnostic Considerations Nonculture, nonamplified probe tests for chlamydia (EIA and DFA) should not be used because of the possibility of false-positive test results. With respiratory-tract specimens, false-positive results can occur because of cross-reaction of test reagents with C. pneumoniae; with genital and anal specimens, false-positive results might occur as a result of cross-reaction with fecal flora. # Recommended Regimen for Children Who Weigh <45 kg Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days # Recommended Regimen for Children Who Weigh ≥45 kg but Who Are Aged <8 Years Azithromycin 1 g orally in a single dose # Recommended Regimens for Children Aged ≥8 years # Follow-Up Follow-up cultures are necessary to ensure that treatment has been effective. # Gonococcal Infections Gonococcal Infections in Adolescents and Adults In the United States, an estimated 700,000 new N. gonorrhoeae infections occur each year (93,293). Gonorrhea is the second most commonly reported bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce symptoms that cause them to seek curative treatment soon enough to prevent serious sequelae, but treatment might not be soon enough to prevent transmission to others. Among women, gonococcal infections might not produce recognizable symptoms until complications (e.g., PID) have occurred. PID can result in tubal scarring that can lead to infertility or ectopic pregnancy. The prevalence of gonorrhea varies widely among communities and populations; health-care providers should consider local gonorrhea epidemiology when making screening decisions. Although widespread screening is not recommended because gonococcal infections among women are frequently asymptomatic, targeted screening of young women (i.e., those aged <25 years) at increased risk for infection is a primary component of gonorrhea control in the United States. For sexually active women, including those who are pregnant, USPSTF (82) recommends that clinicians provide gonorrhea screening only to those at increased risk for infection (e.g., women with previous gonorrhea infection, other STDs, new or multiple sex partners, and inconsistent condom use; those who engage in commercial sex work and drug use; women in certain demographic groups; and those living in communities with a high prevalence of disease). USPSTF does not recommend screening for gonorrhea in men and women who are at low risk for infection (82). # Diagnostic Considerations Because of its high specificity (>99%) and sensitivity (>95%), a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men. In addition, Gram stain of endocervical specimens, pharyngeal, or rectal specimens also are not sufficient to detect infection, and therefore are not recommended. Specific testing for N. gonorrhoeae is recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification. Specific diagnosis of infection with N. gonorrhoeae can be performed by testing endocervical, vaginal, urethral (men only), or urine specimens. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of genitourinary infection with N. gonorrhoeae (197). Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens. NAATs allow testing of the widest variety of specimen types including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women), and they are FDA-cleared for use. However, product inserts for each NAAT vendor must be carefully examined, because specimen types that are FDA-cleared for use vary by test. NAAT tests are not FDA-cleared for use in the rectum, pharynx, and conjunctiva; however, some public and private laboratories have established performance specifications for using NAAT with rectal and pharyngeal swab specimens, thereby allowing results to be used for clinical management. Laboratories that establish performance specifications for the use of NAATs with nongenital specimens must ensure that specificity is not compromised by cross-reaction with nongonococcal Neisseria species. The sensitivity of NAATs for the detection of N. gonorrhoeae in genital and nongenital anatomic sites is superior to culture but varies by NAAT type (197,(278)(279)(280)(281). Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing. All persons found to have who have gonorrhea also should be tested for other STDs, including chlamydia, syphilis, and HIV. # Dual Therapy for Gonococcal and Chlamydial Infections Patients infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the recommendation that patients treated for gonococcal infection also be treated routinely with a regimen that is effective against uncomplicated genital C. trachomatis infection (294). Because most gonococci in the United States are susceptible to doxycycline and azithromycin, routine cotreatment might also hinder the development of antimicrobial-resistant N. gonorrhoeae. Limited data suggest that dual treatment with azithromycin might enhance treatment efficacy for pharyngeal infection when using oral cephalosporins (295,296). # Antimicrobial-Resistant N. gonorrhoeae Gonorrhea treatment is complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobial therapies (297). Quinolone-resistant N. gonorrhoeae strains are now widely disseminated throughout the United States and the world (298). As of April 2007, quinolones are no longer recommended in the United States for the treatment of gonorrhea and associated conditions, such as PID (299). Consequently, only one class of antimicrobials, the cephalosporins, is recommended and available for the treatment of gonorrhea in the United States. The CDC website (http://www.cdc.gov/std/ gisp) and state health departments can provide the most current information. The proportion of isolates in CDC's Gonococcal Isolate Surveillance Project (GISP) demonstrating decreased susceptibility to ceftriaxone or cefixime has remained very low over time; during 1987-2008, only four isolates were found to have decreased susceptibility to ceftriaxone, and 48 isolates had decreased susceptibility to cefixime. In 2008, no isolates demonstrated decreased susceptibility to ceftriaxone; cefixime was not part of test panel during that year (93). Although only two cases of suspected treatment failure with ceftriaxone have been reported (300), approximately 50 patients are thought to have failed oral cephalosporin treatment (301)(302)(303)(304). Most of the treatment failures resulting from use of oral cephalosporins have been reported from Asian countries, although one possible case was reported in Hawaii in 2001 (305). To ensure appropriate antibiotic therapy, clinicians should ask patients testing positive for gonorrhea about recent travel to and sexual activity in these countries. Decreased susceptibility of N. gonorrhoeae to cephalosporins and other antimicrobials is expected to continue to spread; therefore, state and local surveillance for antimicrobial resistance is crucial for guiding local therapy recommendations (297). GISP, which samples approximately 3% of all U.S. men who have gonococcal infections, is a mainstay of surveillance. However, surveillance by clinicians also is critical. Clinicians who diagnose N. gonorrhoeae infection in a patient with suspected cephalosporin treatment failure should perform culture and susceptibility testing of relevant clinical specimens, consult a specialist for guidance in clinical management, and report the case to CDC through state and local public health authorities. Health departments should prioritize partner notification and contact tracing of patients with N. gonorrhoeae infection thought to be associated with cephalosporin treatment failure or associated with patients whose isolates demonstrate decreased susceptibility to cephalosporin. To maximize compliance with recommended therapies, medications for gonococcal infections should be dispensed on site. Ceftriaxone in a single injection of 250 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 99.2% of uncomplicated urogenital and anorectal and 98.9% of pharyngeal infections in published clinical trials (306,307). A 250-mg dose of ceftriaxone is now recommended over a 125-mg dose given the 1) increasingly wide geographic distribution of isolates demonstrating decreased susceptibility to cephalosporins in vitro, 2) reports of ceftriaxone treatment failures, 3) improved efficacy of ceftriaxone 250 mg in pharyngeal infection (which is often unrecognized), and 4) the utility of having a simple and consistent recommendation for treatment regardless of the anatomic site involved. # Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum # Recommended Regimens A 400-mg oral dose of cefixime does not provide as high, nor as sustained, a bactericidal level as that provided by the 250-mg dose of ceftriaxone. In published clinical trials, the 400-mg dose cured 97.5% of uncomplicated urogenital and anorectal (95% CI = 95.4%-99.8%) and 92.3% of pharyngeal gonococcal infections (95% CI = 74.9%-99.1%) (306,307). Although cefixime can be administered orally, this advantage is offset by the limited efficacy of cefixime (as well as other oral cephalosporins) for treating gonococcal infections of the pharynx. Providers should inquire about oral sexual exposure and if reported, treat these patients with ceftriaxone because of this drug's well documented efficacy in treating pharyngeal infection. Single-dose injectible cephalosporin regimens (other than ceftriaxone 250 mg IM) that are safe and highly effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg, administered IM), cefoxitin (2 g, administered IM with probenecid 1 g orally), and cefotaxime (500 mg, administered IM). None of the injectible cephalosporins offer any advantage over ceftriaxone for urogenital infection, and efficacy for pharyngeal infection is less certain (306,307). # Alternative Regimens Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimens, and they should not be used if pharyngeal infection is suspected. Some evidence suggests that cefpodoxime 400mg orally can be considered an alternative in the treatment of uncomplicated urogenital gonorrhea; this regimen meets the minimum efficacy criteria for alternative regimens for urogenital infection (demonstrated efficacy of ≥95% in clinical trials with lower 95% CI of >90%) (307). In one clinical trial, cefpodoxime 400 mg orally was found to have a urogenital and rectal cure rate of 96.6% (95% CI = 93.9%), but the efficacy of cefpodoxime 400 mg orally at the pharyngeal site was poor (70.3%, 95% CI = 53.0%) (Hall, unpublished data, 2010). Gonococcal strains with decreased susceptibility to oral cephalosporins have been reported in the United States (308). With a cure rate of 96.5% (95% CI = 93.6%-98.3%) for urogenital and rectal infection, cefpodoxime proxetil 200 mg orally meets the criteria for an alternative regimen; however, its use is not advised because of concerns about the pharmacodynamics of cefpodoxime using this dose. Efficacy in treating pharyngeal infection with cefpodoxime 200 mg is unsatisfactory (78.9%; 95% CI = 54.5%-94%), as with cefpodoxime at the 400-mg dose. Treatment with cefuroxime axetil 1 g orally meets the criteria for minimum efficacy as an alternative regimen for urogenital and rectal infection (95.9%; 95% CI = 94.3%-97.2%), but the pharmacodynamics of cefuroxime axetil 1 g orally are less favorable than those of cefpodoxime 400 mg, cefixime 400 mg, or ceftriaxone 125 mg (309). The efficacy of cefuroxime axetil 1 g orally in treating pharyngeal infection is poor (56.9%; 95% CI = 42.2%-70.7%). Spectinomycin, which is useful in persons who cannot tolerate cephalosporins, is expensive, must be injected, and is not available in the United States (updates available at: www. cdc.gov/std/treatment) (310). However, it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections. Spectinomycin has poor efficacy against pharyngeal infection (51.8%; 95% CI = 38.7%-64.9%) (306). Azithromycin 2 g orally is effective against uncomplicated gonococcal infection (99.2%; 95% CI = 97.3%-99.9%), but concerns over the ease with which N. gonorrhoeae can develop resistance to macrolides should restrict its use to limited circumstances. Although azithromycin 1 g meets alternative regimen criteria (97.6%; 95% CI = 95.7%-98.9%), it is not recommended because several studies have documented treatment failures, and concerns about possible rapid emergence of antimicrobial resistance with the 1-g dose of azithromycin are even greater than with the 2-g dose (311)(312)(313). N. gonorrhoeae in the United States is not adequately susceptible to penicillins, tetracyclines, and older macrolides (e.g., erythromycin) for these antimicrobials to be recommended. # Uncomplicated Gonococcal Infections of the Pharynx Most gonococcal infections of the pharynx are asymptomatic and can be relatively common in some populations (103,278,279,314). Gonococcal infections of the pharynx are more difficult to eradicate than infections at urogenital and anorectal sites (315). Few antimicrobial regimens, including those involving oral cephalosporins, can reliably cure >90% of gonococcal pharyngeal infections (306,307). Providers should ask their patients about oral sexual exposure; if reported, patients should be treated with a regimen with acceptable efficacy against pharyngeal infection. Chlamydial coinfection of the pharynx is unusual; however, because coinfection at genital sites sometimes occurs, treatment for both gonorrhea and chlamydia is recommended. # Recommended Regimens # Follow-Up Patients diagnosed with uncomplicated gonorrhea who are treated with any of the recommended or alternative regimens do not need a test-of-cure (i.e., repeat testing 3-4 weeks after completing therapy). Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Persistent urethritis, cervicitis, or proctitis also might be caused by C. trachomatis or other organisms. N. gonorrhoeae infection is prevalent among patients who have been diagnosed with and treated for gonorrhea in the preceding several months (64,251,252,267). Most infections result from reinfection rather than treatment failure, indicating a need for improved patient education and referral of sex partners. Clinicians should advise patients with gonorrhea to be retested 3 months after treatment. If patients do not seek medical care for retesting in 3 months, providers are encouraged to test these patients whenever they next seek medical care within the following 12 months, regardless of whether the patients believe that their sex partners were treated. Retesting is distinct from test-of-cure to detect therapeutic failure, which is not recommended. # Management of Sex Partners Effective clinical management of patients with treatable STDs requires treatment of the patients' recent sex partners to prevent reinfection and curtail further transmission. Patients should be instructed to refer their sex partners for evaluation and treatment. Sex partners of patients with N. gonorrhoeae infection whose last sexual contact with the patient was within 60 days before onset of symptoms or diagnosis of infection in the patient should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. For heterosexual patients with gonorrhea whose partners' treatment cannot be ensured or is unlikely, delivery of antibiotic therapy for gonorrhea (as well as for chlamydia) by the patients to their partners can be considered (see Partner Management). Use of this approach (68,71) should always be accompanied by efforts to educate partners about symptoms and to encourage partners to seek clinical evaluation. For male patients informing female partners, educational materials should include information about the importance of seeking medical evaluation for PID (especially if symptomatic). Possible undertreatment of PID in female partners and possible missed opportunities to diagnose other STDs are of concern and have not been evaluated in comparison with patient-delivered therapy and partner referral. This approach should not be considered a routine partner management strategy in MSM because of the high risk for coexisting undiagnosed STDs or HIV infection. # Special Considerations Allergy, Intolerance, and Adverse Reactions Reactions to first generation cephalosporins occur in approximately 5%-10% of persons with a history of penicillin allergy and occur less frequently with third-generation cephalosporins (239). In those persons with a history of penicillin allergy, the use of cephalosporins should be contraindicated only in those with a history of a severe reaction to penicillin (e.g., anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) (316). Because data are limited regarding alternative regimens for treating gonorrhea among persons who have severe cephalosporin allergy, providers treating such patients should consult infectious disease specialists. Azithromycin 2 g orally is effective against uncomplicated gonococcal infection, but because of concerns over emerging antimicrobial resistance to macrolides, its use should be limited. Cephalosporin treatment following desensitization is impractical in most clinical settings. # Pregnancy As with other patients, pregnant women infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin. Because spectinomycin is not available in the United States, azithromycin 2 g orally can be considered for women who cannot tolerate a cephalosporin. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. trachomatis infection during pregnancy (see Chlamydial Infections). # HIV Infection Patients who have gonococcal infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Suspected Cephalosporin Treatment Failure or Resistance Suspected treatment failure has been reported among persons receiving oral and injectable cephalosporins (300)(301)(302)(303)(304). Therefore, clinicians of patients with suspected treatment failure or persons infected with a strain found to demonstrate in vitro resistance should consult an infectious disease specialist, conduct culture and susceptibility testing of relevant clinical specimens, retreat with at least 250 mg of ceftriaxone IM or IV, ensure partner treatment, and report the situation to CDC through state and local public health authorities. # Gonococcal Conjunctivitis In the only published study of the treatment of gonococcal conjunctivitis among U.S. adults, all 12 study participants responded to a single 1-g IM injection of ceftriaxone (317). # Recommended Regimen Ceftriaxone 1 g IM in a single dose Consider lavage of the infected eye with saline solution once. Persons treated for gonococcal conjunctivitis should be treated presumptively for concurrent C. trachomatis infection. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infections, Management of Sex Partners). # Disseminated Gonococcal Infection (DGI) DGI frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation. No recent studies have been published on the treatment of DGI. # Treatment Hospitalization is recommended for initial therapy, especially for patients who might not comply with treatment, for those in whom diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Examination for clinical evidence of endocarditis and meningitis should be performed. Persons treated for DGI should be treated presumptively for concurrent C. trachomatis infection. All of the preceding regimens should be continued for 24-48 hours after improvement begins, at which time therapy can be switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. No treatment failures have been reported with the recommended regimens. # Recommended Regimen # Management of Sex Partners Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated gonococcal infections, patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners). # Gonococcal Meningitis and Endocarditis # Recommended Regimen Ceftriaxone 1-2 g IV every 12 hours Therapy for meningitis should be continued for 10-14 days; therapy for endocarditis should be continued for at least 4 weeks. Treatment of complicated DGI should be undertaken in consultation with an infectious disease specialist. # Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners). # Gonococcal Infections Among Infants Gonococcal infection among infants usually is caused by exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2-5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and reinfection at sites of fetal monitoring. # ophthalmia neonatorum Caused by N. gonorrhoeae Although N. gonorrhoeae causes ophthalmia neonatorum relatively infrequently in the United States, identifying and treating this infection is especially important because ophthalmia neonatorum can result in perforation of the globe of the eye and blindness. Infants at increased risk for gonococcal ophthalmia are those who do not receive ophthalmia prophylaxis and those whose mothers have had no prenatal care or whose mothers have a history of STDs or substance abuse. Gonococcal ophthalmia is strongly suspected when intracellular gram-negative diplococci are identified in conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures for N. gonorrhoeae are obtained. Appropriate chlamydial testing should be done simultaneously. Presumptive treatment for N. gonorrhoeae might be indicated for newborns who are at increased risk for gonococcal ophthalmia and who have increased WBCs (but not gonococci) in a Gram-stained smear of conjunctival exudate. In all cases of neonatal conjunctivitis, conjunctival exudates should be cultured for N. gonorrhoeae and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is vital because of the public health and social consequences of a diagnosis of gonorrhea. Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species, organisms that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory. # Recommended Regimen Ceftriaxone 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered. # other Management Considerations Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. trachomatis). Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely. # Follow-Up Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (e.g., sepsis, arthritis, and meningitis). One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis. # Management of Mothers and Their Sex Partners The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treating gonococcal infections in adults (see Gonococcal Infections in Adolescents and Adults). # DGI and Gonococcal Scalp Abscesses in newborns Sepsis, arthritis, and meningitis (or any combination of these conditions) are rare complications of neonatal gonococcal infection. Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate on chocolate agar. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum that are cultured on gonococcal selective medium are useful for identifying the primary site(s) of infection, especially if inflammation is present. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Diagnoses based on Gram-stained smears or presumptive identification of cultures should be confirmed with definitive tests on culture isolates. # Recommended Regimens Ceftriaxone 25-50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10-14 days, if meningitis is documented OR Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10-14 days, if meningitis is documented # Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection Infants born to mothers who have untreated gonorrhea are at high risk for infection. # Recommended Regimen in the Absence of Signs of Gonococcal Infection Ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg, in a single dose other Management Considerations Both mother and infant should be tested for chlamydial infection. # Follow-Up Follow-up examination is not required. # Management of Mothers and Their Sex Partners The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treatment of gonococcal infections in adults (see Gonococcal Infections). # Gonococcal Infections Among Children Sexual abuse is the most frequent cause of gonococcal infection in preadolescent children (see Sexual Assault or Abuse of Children). For preadolescent girls, vaginitis is the most common manifestation of this infection; gonococcalassociated PID after vaginal infection is likely less common in preadolescents than adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are common and frequently asymptomatic. # Diagnostic Considerations Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, culture remains the preferred method for diagnosis. Gram stains are inadequate for evaluating prepubertal children for gonorrhea and should not be used to diagnose or exlude gonorrhea. NAATs for the detection of N. gonorrhoeae can be used under certain circumstances (see Sexual Assault or Abuse of Children) # Recommended Regimen for Children Who Weigh >45 kg Treat with one of the regimens recommended for adults (see Gonococcal Infections) # Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Uncomplicated Gonococcal Vulvovaginitis, Cervicitis, Urethritis, Pharyngitis, or Proctitis Ceftriaxone 125 mg IM in a single dose # Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Bacteremia or Arthritis Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose daily for 7 days # Recommended Regimen for Children Who Weigh >45 kg and Who Have Bacteremia or Arthritis Ceftriaxone 50 mg/kg IM or IV in a single dose daily for 7 days # Follow-Up Follow-up cultures are unnecessary if ceftriaxone is used. # other Management Considerations Only parenteral cephalosporins (i.e., ceftriaxone) are recommended for use in children; cefotaxime is approved for gonococcal ophthalmia only. No data are available regarding the use of oral cefixime to treat gonococcal infections in children. All children found to have gonococcal infections should be evaluated for coinfection with syphilis and C. trachomatis. (For a discussion of concerns regarding sexual assault, see Sexual Assault or Abuse of Children.) # ophthalmia neonatorum Prophylaxis To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into the eyes of all newborn infants; this procedure is required by law in most states. All of the recommended prophylactic regimens in this section prevent gonococcal ophthalmia. However, the efficacy of these preparations in preventing chlamydial ophthalmia is less clear, and they do not eliminate nasopharyngeal colonization by C. trachomatis. The diagnosis and treatment of gonococcal and chlamydial infections in pregnant women is the best method for preventing neonatal gonococcal and chlamydial disease. Not all women, however, receive prenatal care, and therefore go untreated. Ocular prophylaxis is warranted for neonates, because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive. # Recommended Regimen Erythromycin (0.5%) ophthalmic ointment in each eye in a single application This preparation should be instilled into both eyes of every neonate as soon as possible after delivery. Ideally, ointment should be applied using single-use tubes or ampules rather than multiple-use tubes. If prophylaxis is delayed (i.e., not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis. All infants should be administered ocular prophylaxis, regardless of whether they are delivered vaginally or by cesarean section. Erythromycin is the only antibiotic ointment recommended for use in neonates. Silver nitrate and tetracycline ophthalmic ointment are no longer manufactured in the United States, bacitracin is not effective, and povidone iodine has not been studied adequately. If erythromycin ointment is not available, infants at risk for exposure to N. gonorrhoeae (especially those born to a mother with untreated gonococcal infection or who has received no prenatal care) can be administered ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg in a single dose. # Diseases Characterized by Vaginal Discharge Most women will have a vaginal infection, characterized by discharge, itching, or odor, during their lifetime. With the availability of complementary and alternative therapies and over-the-counter medications for candidiasis, many symptomatic women seek these products before or in addition to an evaluation by a medical provider. Obtaining a medical history alone has been shown to be insufficient for accurate diagnosis of vaginitis and can lead to the inappropriate administration of medication. Therefore, a careful history, examination, and laboratory testing to determine the etiology of vaginal complaints are warranted. Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (such as douching), and other medications should be elicited. The three diseases most frequently associated with vaginal discharge are BV (caused by the replacement of the vaginal flora by an overgrowth of anaerobic bacteria including Prevotella sp., Mobiluncus sp., G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes) trichomoniasis (caused by T. vaginalis), and candidiasis (usually caused by Candida albicans). Cervicitis also can sometimes cause a vaginal discharge. Although vulvovaginal candidiasis (VVC) usually is not transmitted sexually, it is included in this section because it is frequently diagnosed in women who have vaginal complaints or who are being evaluated for STDs. Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge. Clinical laboratory testing can identify the cause of vaginitis in most women and is discussed in detail in the sections of this report dedicated to each condition. In the clinician's office, the cause of vaginal symptoms might be determined by pH, a potassium hydroxide (KOH) test, and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (i.e., >4.5) is common with BV or trichomoniasis. Because pH testing is not highly specific, discharge should be further examined microscopically by first diluting one sample in one to two drops of 0.9% normal saline solution on one slide and a second sample in 10% KOH solution (samples that emit an amine odor immediately upon application of KOH suggest BV or trichomoniasis infection). Cover slips are then placed on the slides, and they are examined under a microscope at low and high power. The saline-solution specimen might yield motile T. vaginalis, or clue cells (i.e., epithelial cells with borders obscured by small bacteria), which are characteristic of BV, whereas the presence of WBCs without evidence of trichomonads or yeast in this solution is suggestive of cervicitis (see Cervicitis). The KOH specimen typically is used to identify the yeast or pseudohyphae of Candida species. However, the absence of trichomonads or pseudohyphae in KOH samples does not rule out these infections, because the sensitivity of microscropy is approximately 50% compared with NAAT (trichomoniasis) or culture (yeast). In settings where pH paper, KOH, and microscopy are not available, alternative commercially available point-of-care tests or clinical laboratory testing can be used to diagnose vaginitis. The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens after laboratory testing, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. # Bacterial Vaginosis BV is a polymicrobial clinical syndrome resulting from replacement of the normal hydrogen peroxide producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes. Some women experience transient vaginal microbial changes, whereas others experience them for a longer intervals of time. Among women presenting for care, BV is the most prevalent cause of vaginal discharge or malodor; however, in a nationally representative survey, most women with BV were asymptomatic (318). BV is associated with having multiple male or female partners, a new sex partner, douching, lack of condom use, and lack of vaginal lactobacilli; women who have never been sexually active can also be affected. The cause of the microbial alteration that characterizes BV is not fully understood, nor is whether BV results from acquisition of a sexually transmitted pathogen. Nonetheless, women with BV are at increased risk for the acquisition of some STDs (e.g., HIV, N. gonorrhoeae, C. trachomatis, and HSV-2), complications after gynecologic surgery, complications of pregnancy, and recurrence of BV. Treatment of male sex partners has not been beneficial in preventing the recurrence of BV. # Diagnostic Considerations BV can be diagnosed by the use of clinical criteria (i.e., Amsel's Diagnostic Criteria) (319) or Gram stain. A Gram stain (considered the gold standard laboratory method for diagnosing BV) is used to determine the relative concentration of lactobacilli (i.e., long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (i.e., G. vaginalis, Prevotella, Porphyromonas, and peptostreptococci), and curved Gramnegative rods (i.e., Mobiluncus) characteristic of BV. If a Gram stain is not available, clinical criteria can be used and require three of the following symptoms or signs: • homogeneous, thin, white discharge that smoothly coats the vaginal walls; • presence of clue cells on microscopic examination; • pH of vaginal fluid >4.5; or • a fishy odor of vaginal discharge before or after addition of 10% KOH (i.e., the whiff test). Detection of three of these criteria has been correlated with results by Gram stain (320). Other tests, including a DNA probebased test for high concentrations of G. vaginalis (Affirm VP III, Becton Dickinson, Sparks, Maryland), a prolineaminopeptidase test card (Pip Activity TestCard, Quidel, San Diego, California), and the OSOM BVBlue test have acceptable performance characteristics compared with Gram stain. Although a card test is available for the detection of elevated pH and trimethylamine, it has low sensitivity and specificity and therefore is not recommended. PCR also has been used in research settings for the detection of a variety of organisms associated with BV, but evaluation of its clinical utility is uncertain. Detection of one organism or group of organisms might be predictive of BV by Gram stain (321). However, additional evaluations are needed to confirm these associations. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. Cervical Pap tests have no clinical utility for the diagnosis of BV because of their low sensitivity. # Treatment Treatment is recommended for women with symptoms. The established benefits of therapy in nonpregnant women are to relieve vaginal symptoms and signs of infection. Other potential benefits to treatment include reduction in the risk for acquiring C. trachomatis or N. gonorrhoeae (322), HIV, and other viral STDs. # Recommended Regimens Metronidazole 500 mg orally twice a day for 7 days* OR Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days † * Consuming alcohol should be avoided during treatment and for 24 hours thereafter. † Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use (refer to clindamycin product labeling for additional information). Providers should consider patient preference, possible side-effects, drug interactions, and other coinfections when selecting a regimen. Women should be advised to refrain from intercourse or to use condoms consistently and correctly during the treatment regimen. Douching might increase the risk for relapse, and no data support the use of douching for treatment or relief of symptoms. # Alternative Regimens Tinidazole 2 g orally once daily for 2 days OR Tinidazole 1 g orally once daily for 5 days OR Clindamycin 300 mg orally twice daily for 7 days OR Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days Alternative regimens include several tinidazole regimens (323) or clindamycin (oral or intravaginal) (324). Additional regimens include metronidazole (750-mg extended release tablets once daily for 7 days), or a single dose of clindamycin intravaginal cream, although data on the performance of these alternative regimens are limited. Several studies have evaluated the clinical and microbiologic efficacy of using intravaginal lactobacillus formulations to treat BV and restore normal flora (325)(326)(327). Further research efforts to determine the role of these regimens in BV treatment and prevention are ongoing. # Follow-Up Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is common, women should be advised to return for evaluation if symptoms recur. Detection of certain BV-associated organisms have been associated with antimicrobial resistance and might determine risk for subsequent treatment failure (328)(329)(330)(331)(332)(333). Limited data are available regarding optimal management strategies for women with early treatment failure. Using a different treatment regimen might be an option in patients who have a recurrence; however, retreatment with the same topical regimen is another acceptable approach for treating recurrent BV during the early stages of infection (334). For women with multiple recurrences after completion of a recommended regimen, metronidazole gel twice weekly for 4-6 months has been shown to reduce recurrences, although this benefit might not persist when suppressive therapy is discontinued (335). Limited data suggest that oral nitroimidazole followed by intravaginal boric acid and suppressive metronidazole gel for those women in remission might be an option in women with recurrent BV (336). Monthly oral metronidazole administered with fluconazole has also been evaluated as suppressive therapy (337). # Management of Sex Partners The results of clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s). Therefore, routine treatment of sex partners is not recommended. # Special Considerations # Allergy or Intolerance to the Recommended Therapy Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole or tinidazole. Intravaginal metronidazole gel can be considered for women who do not tolerate systemic metronidazole. Intravaginal metronidazole should not be administered to women allergic to metronidazole. # Pregnancy Treatment is recommended for all pregnant women with symptoms. Although BV is associated with adverse pregnancy outcomes, including premature rupture of membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis, the only established benefit of therapy for BV in pregnant women is the reduction of symptoms and signs of vaginal infection. Additional potential benefits include reducing the risk for infectious complications associated with BV during pregnancy and reducing the risk for other infections (other STDs or HIV). Several trials have been undertaken to determine the efficacy of BV treatment among pregnant women. Two trials demonstrated that metronidazole was efficacious during pregnancy using the 250-mg regimen (338,339); however, metronidazole administered at 500 mg twice daily can be used. One trial involving a limited number of participants revealed that treatment with oral metronidazole 500 mg twice daily was equally effective as metronidazole gel, with cure rates of 70% using Amsel criteria to define cure (340), and a recent trial demonstrated a cure rate of 85% using Gram stain criteria after 4 weeks with oral clindamycin (341). Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns (342,343). Regardless of the antimicrobial agent used to treat pregnant women, oral therapy is preferred because of the possibility of subclinical upper-genital-tract infection. # Recommended Regimens for Pregnant Women Metronidazole 500 mg orally twice a day for 7 days OR Metronidazole 250 mg orally three times a day for 7 days OR Clindamycin 300 mg orally twice a day for 7 days Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i.e., those with a previous preterm birth) has been evaluated by several studies, which have yielded mixed results. Seven trials have evaluated treatment of pregnant women with asymptomatic BV at high risk for preterm delivery; one showed harm (344), two showed no benefit (345,346), and four demonstrated benefit (338,339,347,348). Therefore, evidence is insufficient to assess the impact of screening for BV in pregnant women at high risk for preterm delivery (85). Similarly, data are inconsistent regarding whether the treatment of asymptomatic pregnant women with BV who are at low risk for preterm delivery reduces adverse outcomes of pregnancy. Although USPSTF recommends against screening these women (85), one trial demonstrated a 40% reduction in spontaneous preterm birth among women using oral clindamycin during weeks 13-22 of gestation (348). Several additional trials have shown that intravaginal clindamycin given at an average gestation of later than 20 weeks did not reduce preterm birth, and in three of these trials, intravaginal clindamycin cream administered at 16-32 weeks' gestation was associated with an increase in adverse events (e.g., low birth weight and neonatal infections) in newborns (346,(349)(350)(351). Providers should be aware that intravaginal clindamycin cream might be associated with adverse outcomes if used in the latter half of pregnancy. # HIV Infection BV appears to recur with higher frequency in HIV-positive women (352). Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Trichomoniasis Trichomoniasis is caused by the protozoan T. vaginalis. Some men who are infected with T. vaginalis might not have symptoms; others have NGU. Some women have symptoms characterized by a diffuse, malodorous, yellow-green vaginal discharge with vulvar irritation. However, many women have minimal or no symptoms. Because of the high prevalence of trichomoniasis in clinical and nonclinical settings (64,92,353,354), testing for T. vaginalis should be performed in women seeking care for vaginal discharge. Screening for T. vaginalis in women can be considered in those at high risk for infection (i.e., women who have new or multiple partners, have a history of STDs, exchange sex for payment, and use injection drugs). Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only approximately 60%-70% and requires immediate evaluation of wet preparation slide for optimal results. FDA-cleared tests for trichomoniasis in women include OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic capillary flow dipstick technology, and the Affirm VP III (Becton Dickenson, San Jose, California), a nucleic acid probe test that evaluates for T. vaginalis, G. vaginalis, and C. albicans. Each of these tests, which are performed on vaginal secretions, have a sensitivity of >83% and a specificity of >97%. Both tests are considered point-of-care diagnostics. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, whereas results of the Affirm VP III are available within 45 minutes. Although these tests tend to be more sensitive than those requiring vaginal wet preparation, false positives might occur, especially in populations with a low prevalence of disease. Culture is another sensitive and highly specific commercially available method of diagnosis. Among women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions should be cultured for T. vaginalis. While the sensitivity of a Pap test for T. vaginalis diagnosis is poor, use of a liquid-based testing has demonstrated enhanced sensitivity; however, false-positive tests can occur, and confirmatory testing might be needed in some circumstances (355). An FDA-cleared PCR assay for detection of gonorrhea and chlamydial infection (Amplicor, manufactured by Roche Diagnostic Corp.) has been modified for T. vaginalis detection in vaginal or endocervical swabs and in urine from women and men; sensitivity ranges from 88%-97% and specificity from 98%-99% (356). APTIMA T. vaginalis Analyte Specific Reagents (ASR; manufactured by Gen-Probe, Inc.) also can detect T. vaginalis RNA by transcription-mediated amplification using the same instrumentation platforms available for the FDA-cleared APTIMA Combo2 assay for diagnosis of gonorrhea and chlamydial infection; published validation studies of T. vaginalis ASR found sensitivity ranging from 74%-98% and specificity of 87%-98% (357)(358)(359). Laboratories that use the Gen-Probe APTIMA Combo2 test for detection of N. gonorrhoeae and C. trachomatis can consider adding the T. vaginalis ASR to their testing armentarium, as long as the necessary CLIA verification studies have been conducted. In men, wet preparation is not a sensitive test, and no approved point-of-care tests are available. Culture testing of urethral swab, urine, or semen is one diagnostic option; however, NAATs (i.e., PCR or transcription-mediated amplification [TMA]) have superior sensitivity for T. vaginalis diagnosis in men (356,359). T. vaginalis has not been found to infect oral sites, and rectal prevalence appears low in MSM (360). Therefore, oral and rectal testing for T. vaginalis is not recommended. # Recommended Regimens Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose # Alternative Regimen Metronidazole 500 mg orally twice a day for 7 days* * Patients should be advised to avoid consuming alcohol during treatment with metronidazole or tinidazole. Abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole. The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these drugs, metronidazole and tinidazole are available in the United States and are cleared by the FDA for the treatment of trichomoniasis. In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90%-95%, and the recommended tinidazole regimen has resulted in cure rates of approximately 86%-100%. The appropriate treatment of sex partners might increase these reported rates. Randomized controlled trials comparing single 2-g doses of metronidazole and tinidazole suggest that tinidazole is equivalent or superior to metronidazole in achieving parasitologic cure and resolution of symptoms (361). Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission. Metronidazole gel is considerably less efficacious for the treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Topically applied antimicrobials (e.g., metronidazole gel) are unlikely to achieve therapeutic levels in the urethra or perivaginal glands; therefore, use of this gel is not recommended. Several other topically applied antimicrobials occasionally have been used for treatment of trichomoniasis; however, these preparations likely are no more effective than metronidazole gel. # Follow-Up Because of the high rate of reinfection among patients in whom trichomoniasis was diagnosed (17% were reinfected within 3 months in one study), rescreening for T. vaginalis at 3 months following initial infection can be considered for sexually active women with trichomoniasis; the benefit of this approach, however, has not been fully evaluated (64). No data support rescreening in men diagnosed with T. vaginalis. While most recurrent T. vaginalis infections are thought to result from having sex with an untreated partner (i.e., reinfection), some recurrent cases can be attributed to diminished susceptibility to metronidazole. Low-level metronidazole resistance has been identified in 2%-5% of cases of vaginal trichomoniasis (362,363), but high-level resistance only rarely occurs. Fortunately, infections caused by most of these organisms respond to tinidazole or higher doses of metronidazole. Tinidazole has a longer serum half-life and reaches higher levels in genitourinary tissues than metronidazole. In addition, many T. vaginalis isolates have lower minimal lethal concentrations (MLCs) to tinidazole than metronidazole. If treatment failure occurs with metronidazole 2-g single dose and reinfection is excluded, the patient can be treated with metronidazole 500 mg orally twice daily for 7 days. For patients failing this regimen, treatment with tinidazole or metronidazole at 2 g orally for 5 days should be considered. If these therapies are not effective, further management should be discussed with a specialist. The consultation should ideally include determination of the susceptibility of T. vaginalis to metronidazole and tinidazole. Consultation and T. vaginalis susceptibility testing is available from CDC (telephone: 404-718-4141; website: http://www.cdc.gov/std). # Management of Sex Partners Sex partners of patients with T. vaginalis should be treated. Patients should be instructed to abstain from sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner[s] are asymptomatic). Existing data suggest that patient-delivered partner therapy might have a role in partner management for trichomoniasis; however, no one partner management intervention has shown superiority over another in reducing reinfection rates (72,73). Although no data are available to guide treatment of the male partners of women with nitroimidazole treatment failure, on the basis of expert opinion, male partners should be evaluated and treated with either tinidazole in a single dose of 2 g orally or metronidazole twice a day at 500 mg orally for 7 days. # Special Considerations Allergy, Intolerance, and Adverse Reactions Metronidazole and tinidazole are both nitroimidazoles. Patients with an immediate-type allergy to a nitroimidazole can be managed by metronidazole desensitization in consultation with a specialist (364)(365)(366). Topical therapy with drugs other than nitroimidazoles can be attempted, but cure rates are low (<50%). # Pregnancy Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, particularly premature rupture of membranes, preterm delivery, and low birth weight. However, metronidazole treatment has not been shown to reduce perinatal morbidity. Although some trials suggest the possibility of increased prematurity or low birth weight after metronidazole treatment, limitations of the studies prevent definitive conclusions regarding risks for treatment (367,368). Treatment of T. vaginalis might relieve symptoms of vaginal discharge in pregnant women and might prevent respiratory or genital infection of the newborn and further sexual transmission. Clinicians should counsel patients regarding the potential risks and benefits of treatment and communicate the option of therapy deferral in asymptomatic pregnant women until after 37 weeks' gestation. All symptomatic pregnant women should not only be considered for treatment regardless of pregnancy stage, but be provided careful counseling regarding condom use and the continued risk of sexual transmission. Women can be treated with 2 g metronidazole in a single dose at any stage of pregnancy. Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants (342,343,369). The safety of tinidazole in pregnant women, however, has not been well evaluated. In lactating women who are administered metronidazole, withholding breastfeeding during treatment and for 12-24 hours after the last dose will reduce the exposure of the infant to metronidazole. For women treated with tinidazole, interruption of breastfeeding is recommended during treatment and for 3 days after the last dose. # HIV Infection There is increasing evidence for epidemiologic and biologic interaction between HIV and T. vaginalis (370)(371)(372)(373)(374)(375). T. vaginalis infection in HIV-infected women might enhance HIV transmission by increasing genital shedding of the virus (376,377), and treatment for T. vaginalis has been shown to reduce HIV shedding (376,377). For sexually active women who are HIV-positive, screening for trichomoniasis at entry into care with subsequent screening performed at least annually is recommended based on the reported prevalence of T. vaginalis, the effect of treatment at reducing vaginal HIV shedding, and the potential complications of upper-genital-tract infections among women who are left untreated (130,(370)(371)(372)(373)(374)(375). Rescreening 3 months after completion of therapy should be considered among HIV-positive women with trichomoniasis, a recommendation based on the high proportion of recurrent or persistent infection and the association between HIV and T. vaginalis infection (64,374,378). A recent randomized clinical trial involving women coinfected with trichomoniasis and HIV demonstrated that a single dose of metronidazole 2 gm orally was not as effective as 500 mg twice daily for 7 days (379). Therefore, a multi-dose treatment regimen for T. vaginalis can be considered in HIV-infected women. # Vulvovaginal Candidiasis VVC usually is caused by C. albicans, but occasionally is caused by other Candida sp. or yeasts. Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge. None of these symptoms is specific for VVC. An estimated 75% of women will have at least one episode of VVC, and 40%-45% will have two or more episodes within their lifetime. On the basis of clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (Box 3). Approximately 10%-20% of women will have complicated VVC that necessitates diagnostic and therapeutic considerations. # Uncomplicated VVC Diagnostic Considerations A diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritus, pain, swelling, and redness. Signs include vulvar edema, fissures, excoriations, or thick, curdy vaginal discharge. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either 1) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts, hyphae, or pseudohyphae or 2) a culture or other test yields a yeast species. Candida vaginitis is associated with a normal vaginal pH (<4.5), and therefore, pH testing is not a useful diagnostic tool. Use of 10% KOH in wet preparations improves the visualization of yeast and mycelia by disrupting cellular material that might obscure the yeast or pseudohyphae. Examination of a wet mount with KOH preparation should be performed for all women with symptoms or signs of VVC, and women with a positive result should receive treatment. For women with negative wet mounts who are symptomatic, vaginal cultures for Candida should be considered. If the wet mount is negative and Candida cultures cannot be done, empiric treatment can be considered for symptomatic women with any sign of VVC on examination. Identifying Candida by culture in the absence of symptoms or signs is not an indication for treatment, because approximately 10%-20% of women harbor Candida sp. and other yeasts in the vagina. VVC can occur concomitantly with STDs. Most healthy women with uncomplicated VVC have no identifiable precipitating factors. # Treatment Short-course topical formulations (i.e., single dose and regimens of 1-3 days) effectively treat uncomplicated VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures in 80%-90% of patients who complete therapy. The creams and suppositories in this regimen are oil-based and might weaken latex condoms and diaphragms. Patients and providers should refer to condom product labeling for further information. # Recommended Regimens Intravaginal preparations of butaconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC). Women whose condition has previously been diagnosed with VVC are not necessarily more capable of diagnosing themselves; therefore, any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should be evaluated with office-based testing. Unnecessary or inappropriate use of OTC preparations is common and can lead to a delay in the treatment of other vulvovaginitis etiologies, which can result in adverse clinical outcomes. # Follow-Up Patients should be instructed to return for follow-up visits only if symptoms persist or recur within 2 months of onset of the initial symptoms. # Management of Sex Partners VVC is not usually acquired through sexual intercourse; no data support the treatment of sex partners. A minority of male sex partners might have balanitis, which is characterized by erythematous areas on the glans of the penis in conjunction with pruritus or irritation. These men benefit from treatment with topical antifungal agents to relieve symptoms. # Special Considerations # Allergy, Intolerance, and Adverse Reactions Topical agents usually cause no systemic side effects, although local burning or irritation might occur. Oral agents occasionally cause nausea, abdominal pain, and headache. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Clinically important interactions can occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, rifampin, and warfarin. # Complicated VVC Recurrent Vulvovaginal Candidiasis (RVVC) RVVC, usually defined as four or more episodes of symptomatic VVC in 1 year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and most women with RVVC have no apparent predisposing or underlying conditions. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis and to identify unusual species (including nonalbicans species), particularly Candida glabrata. Although C. glabrata and other nonalbicans Candidia species are observed in 10%-20% of patients with RVVC, C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy. Conventional antimycotic therapies are not as effective against these species as they are against C. albicans. # Treatment Each individual episode of RVVC caused by C. albicans responds well to short-duration oral or topical azole therapy. However, to maintain clinical and mycologic control, some specialists recommend a longer duration of initial therapy (e.g., 7-14 days of topical therapy or a 100-mg, 150-mg, or 200-mg oral dose of fluconazole every third day for a total of 3 doses [day 1, 4, and 7]) to attempt mycologic remission before initiating a maintenance antifungal regimen. # Maintenance Regimens Oral fluconazole (i.e., 100-mg, 150-mg, or 200-mg dose) weekly for 6 months is the first line of treatment. If this regimen is not feasible, topical treatments used intermittently as a maintenance regimen can be considered. Suppressive maintenance antifungal therapies are effective in reducing RVVC. However, 30%-50% of women will have recurrent disease after maintenance therapy is discontinued. Routine treatment of sex partners is controversial. C. albicans azole resistance is rare in vaginal isolates, and susceptibility testing is usually not warranted for individual treatment guidance. # Severe VVC Severe vulvovaginitis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) is associated with lower clinical response rates in patients treated with short courses of topical or oral therapy. Either 7-14 days of topical azole or 150 mg of fluconazole in two sequential doses (second dose 72 hours after initial dose) is recommended. # nonalbicans VVC The optimal treatment of nonalbicans VVC remains unknown. Options include longer duration of therapy (7-14 # Uncomplicated VVC • (380). If symptoms recur, referral to a specialist is advised. # Special Considerations Compromised Host Women with underlying debilitating medical conditions (e.g., those with uncontrolled diabetes or those receiving corticosteroid treatment) do not respond as well to short-term therapies. Efforts to correct modifiable conditions should be made, and more prolonged (i.e., 7-14 days) conventional antimycotic treatment is necessary. # Pregnancy VVC frequently occurs during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women. # HIV Infection The incidence of VVC in HIV-infected women is unknown. Vaginal Candida colonization rates among HIV-infected women are higher than among those for seronegative women with similar demographic characteristics and high-risk behaviors, and the colonization rates correlate with increasing severity of immunosuppression. Symptomatic VVC is more frequent in seropositive women and similarly correlates with severity of immunodeficiency. In addition, among HIV-infected women, systemic azole exposure is associated with the isolation of nonalbicans Candida species from the vagina. On the basis of available data, therapy for VVC in HIVinfected women should not differ from that for seronegative women. Although long-term prophylactic therapy with fluconazole at a dose of 200 mg weekly has been effective in reducing C. albicans colonization and symptomatic VVC (381), this regimen is not recommended for routine primary prophylaxis in HIV-infected women in the absence of recurrent VVC (129). Given the frequency at which RVVC occurs in the immmunocompetent healthy population, the occurrence of RVVC should not be considered an indication for HIV testing among women previously testing HIV negative. Although VVC is associated with increased HIV seroconversion in HIVnegative women and increased HIV cervicovaginal levels in HIV-positive women, the effect of treatment for VVC on HIV acquisition and transmission remains unknown. # Pelvic Inflammatory Disease PID comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis (382). Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in many cases; however, microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) also have been associated with PID (383). In addition, cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium might be associated with some cases of PID (263,(384)(385)(386). All women who have acute PID should be tested for N. gonorrhoeae and C. trachomatis and should be screened for HIV infection. # Diagnostic Considerations Acute PID is difficult to diagnose because of the wide variation in the symptoms and signs. Many women with PID have subtle or mild symptoms. Delay in diagnosis and treatment probably contributes to inflammatory sequelae in the upper reproductive tract. Laparoscopy can be used to obtain a more accurate diagnosis of salpingitis and a more complete bacteriologic diagnosis. However, this diagnostic tool frequently is not readily available, and its use is not easy to justify when symptoms are mild or vague. Moreover, laparoscopy will not detect endometritis and might not detect subtle inflammation of the fallopian tubes. Consequently, a diagnosis of PID usually is based on clinical findings. The clinical diagnosis of acute PID is imprecise (387,388). Data indicate that a clinical diagnosis of symptomatic PID has a positive predictive value (PPV) for salpingitis of 65%-90% compared with laparoscopy. The PPV of a clinical diagnosis of acute PID depends on the epidemiologic characteristics of the population, with higher PPVs among sexually active young women (particularly adolescents), patients attending STD clinics, and those who live in other settings where the rates of gonorrhea or chlamydia are high. Regardlesss of PPV, however, in all settings, no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID. Combinations of diagnostic findings that improve either sensitivity (i.e., detect more women who have PID) or specificity (i.e., exclude more women who do not have PID) do so only at the expense of the other. For example, requiring two or more findings excludes more women who do not have PID but also reduces the number of women with PID who are identified. Many episodes of PID go unrecognized. Although some cases are asymptomatic, others are not diagnosed because the patient or the health-care provider fails to recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge). Because of the difficulty of diagnosis and the potential for damage to the reproductive health of women (even by apparently mild or subclinical PID), health-care providers should maintain a low threshold for the diagnosis of PID (382). The optimal treatment regimen and long-term outcome of early treatment of women with asymptomatic or subclinical PID are unknown. The following recommendations for diagnosing PID are intended to help health-care providers recognize when PID should be suspected and when they need to obtain additional information to increase diagnostic certainty. Diagnosis and management of other common causes of lower abdominal pain (e.g., ectopic pregnancy, acute appendicitis, and functional pain) are unlikely to be impaired by initiating empiric antimicrobial therapy for PID. Empiric treatment for PID should be initiated in sexually active young women and other women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than PID can be identified, and if one or more of the following minimum criteria are present on pelvic examination: • cervical motion tenderness or • uterine tenderness or • adnexal tenderness. The requirement that all three minimum criteria be present before the initiation of empiric treatment could result in insufficient sensitivity for the diagnosis of PID. The presence of signs of lower-genital-tract inflammation (predominance of leukocytes in vaginal secretions, cervical exudates, or cervical friability), in addition to one of the three minimum criteria, increases the specificity of the diagnosis. Upon deciding whether to initiate empiric treatment, clinicians should also consider the risk profile of the patient for STDs. More elaborate diagnostic evaluation frequently is needed because incorrect diagnosis and management of PID might cause unnecessary morbidity. One or more of the following additional criteria can be used to enhance the specificity of the minimum criteria and support a diagnosis of PID: • oral temperature >101° F (>38.3° C); • abnormal cervical or vaginal mucopurulent discharge; • presence of abundant numbers of WBC on saline microscopy of vaginal fluid; • elevated erythrocyte sedimentation rate; • elevated C-reactive protein; and • laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis. Most women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid (i.e., wet prep). If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of pain should be considered. A wet prep of vaginal fluid offers the ability to detect the presence of concomitant infections (e.g., BV and trichomoniasis). The most specific criteria for diagnosing PID include: • endometrial biopsy with histopathologic evidence of endometritis; • transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, or Doppler studies suggesting pelvic infection (e.g., tubal hyperemia); or • laparoscopic abnormalities consistent with PID. A diagnostic evaluation that includes some of these more extensive procedures might be warranted in some cases. Endometrial biopsy is warranted in women undergoing laparoscopy who do not have visual evidence of salpingitis, because endometritis is the only sign of PID for some women. # Treatment PID treatment regimens must provide empiric, broad spectrum coverage of likely pathogens. Several antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with short-term follow-up. However, only a limited number of investigations have assessed and compared these regimens with regard to elimination of infection in the endometrium and fallopian tubes or determined the incidence of long-term complications (e.g., tubal infertility and ectopic pregnancy) after antimicrobial regimens (389)(390)(391). All regimens used to treat PID should also be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper-reproductive-tract infection. The need to eradicate anaerobes from women who have PID has not been determined definitively. Anaerobic bacteria have been isolated from the upper-reproductive tract of women who have PID, and data from in vitro studies have revealed that some anaerobes (e.g., Bacteroides fragilis) can cause tubal and epithelial destruction. BV also is present in many women who have PID (383,391). Until treatment regimens that do not adequately cover these microbes have been demonstrated to prevent long-term sequelae (e.g., infertility and ectopic pregnancy) as successfully as the regimens that are effective against these microbes, the use of regimens with anaerobic activity should be considered. Treatment should be initiated as soon as the presumptive diagnosis has been made because prevention of long-term sequelae is dependent on early administration of appropriate antibiotics. When selecting a treatment regimen, health-care providers should consider availability, cost, patient acceptance, and antimicrobial susceptibility (392). In women with PID of mild or moderate clinical severity, outpatient therapy yields short-and long-term clinical outcomes similar to inpatient therapy. The decision of whether hospitalization is necessary should be based on the judgment of the provider and whether the patient meets any of the following suggested criteria: • surgical emergencies (e.g., appendicitis) cannot be excluded; • the patient is pregnant; • the patient does not respond clinically to oral antimicrobial therapy; • the patient is unable to follow or tolerate an outpatient oral regimen; • the patient has severe illness, nausea and vomiting, or high fever; or • the patient has a tubo-ovarian abscess. No evidence is available to suggest that adolescents benefit from hospitalization for treatment of PID. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women. Younger women with mild-to-moderate acute PID have similar outcomes with either outpatient or inpatient therapy, and clinical response to outpatient treatment is similar among younger and older women. # Parenteral Treatment For women with PID of mild or moderate severity, parenteral and oral therapies appear to have similar clinical efficacy. Many randomized trials have demonstrated the efficacy of both parenteral and oral regimens (390,391,393). Clinical experience should guide decisions regarding transition to oral therapy, which usually can be initiated within 24-48 hours of clinical improvement. In women with tubo-ovarian abscesses, at least 24 hours of direct inpatient observation is recommended. Because of the pain associated with intravenous infusion, doxycycline should be administered orally when possible. Oral and IV administration of doxycycline provide similar bioavailability. Parenteral therapy can be discontinued 24 hours after clinical improvement, but oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, clindamycin or metronidazole with doxycycline can be used for continued therapy rather than doxycycline alone because this regimen provides more effective anaerobic coverage. Limited data are available to support the use of other second-or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone), which also might be effective therapy for PID and could potentially replace cefotetan or cefoxitin. However, these cephalosporins are less active than cefotetan or cefoxitin against anaerobic bacteria. # Recommended Parenteral Regimen B Clindamycin 900 mg IV every 8 hours PLUS Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing (3-5 mg/kg) can be substituted. Although use of a single daily dose of gentamicin has not been evaluated for the treatment of PID, it is efficacious in analogous situations. Parenteral therapy can be discontinued 24 hours after clinical improvement; ongoing oral therapy should consist of doxycycline 100 mg orally twice a day, or clindamycin 450 mg orally four times a day to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, clindamycin should be continued rather than doxycycline, because clindamycin provides more effective anaerobic coverage. # Alternative Parenteral Regimens Limited data are available to support the use of other parenteral regimens. The following regimen has been investigated in at least one clinical trial and has broad-spectrum coverage (394). # Alternative Parenteral Regimens Ampicillin/Sulbactam 3 g IV every 6 hours PLUS Doxycycline 100 mg orally or IV every 12 hours Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. One trial demonstrated high short-term clinical cure rates with azithromycin, either as monotherapy for 1 week (500 mg IV for 1 or 2 doses followed by 250 mg orally for 5-6 days) or combined with a 12-day course of metronidazole (395). # oral Treatment Outpatient, oral therapy can be considered for women with mild-to-moderately severe acute PID, because the clinical outcomes among women treated with oral therapy are similar to those treated with parenteral therapy (390). The following regimens provide coverage against the frequent etiologic agents of PID. Patients who do not respond to oral therapy within 72 hours should be reevaluated to confirm the diagnosis and should be administered parenteral therapy on either an outpatient or inpatient basis. The optimal choice of a cephalosporin is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae. A single dose of cefoxitin is effective in obtaining short-term clinical response in women who have PID. However, the theoretical limitations in coverage of anaerobes by recommended cephalosporin antimicrobials might require the addition of metronidazole to the treatment regimen (393). Adding metronidazole also will effectively treat BV, which is frequently associated with PID. No data have been published regarding the use of oral cephalosporins for the treatment of PID. # Recommended Regimen # Alternative oral Regimens Although information regarding other outpatient regimens is limited, other regimens have undergone at least one clinical trial and have demonstrated broad spectrum coverage. In a single clinical trial, amoxicillin/clavulanic acid and doxycycline were effective together in obtaining short-term clinical response (394); however, gastrointestinal symptoms might limit compliance with this regimen. Azithromycin has demonstrated short-term effectiveness in one randomized trial (395), and in another study, it was effective when used combination with ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks (396). When considering alternative regimens, the addition of metronidazole should be considered because anaerobic organisms are suspected in the etiology of PID and metronidazole will also treat BV. As a result of the emergence of quinolone-resistant Neisseria gonorrhoeae, regimens that include a quinolone agent are no longer recommended for the treatment of PID. If parenteral cephalosporin therapy is not feasible, use of fluoroquinolones (levofloxacin 500 mg orally once daily or ofloxacin 400 mg twice daily for 14 days) with or without metronidazole (500 mg orally twice daily for 14 days) can be considered if the community prevalence and individual risk for gonorrhea are low. Diagnostic tests for gonorrhea must be performed before instituting therapy and the patient managed as follows if the test is positive. • If the culture for gonorrhea is positive, treatment should be based on results of antimicrobial susceptibility. • If the isolate is determined to be quinolone-resistant N. gonorrhoeae (QRNG) or if antimicrobial susceptibility cannot be assessed (e.g., if only NAAT testing is available), parenteral cephalosporin is recommended. However, if cephalosporin therapy is not feasible, the addition of azithromycin 2 g orally as a single dose to a quinolone-based PID regimen is recommended. # Follow-Up Patients should demonstrate substantial clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; and reduction in uterine, adnexal, and cervical motion tenderness) within 3 days after initiation of therapy. Patients who do not improve within this period usually require hospitalization, additional diagnostic tests, and surgical intervention. If no clinical improvement has occurred within 72 hours after outpatient oral or parenteral therapy, further assessment should be performed. Subsequent hospitalization and an assessment of the antimicrobial regimen and diagnostics (including the consideration of diagnostic laparoscopy for alternative diagnoses) are recommended in women without clinical improvement. Women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months of treatment. Repeat testing of all women who have been diagnosed with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267). All women diagnosed with acute PID should be offered HIV testing. # Management of Sex Partners Male sex partners of women with PID should be examined and treated if they had sexual contact with the patient during the 60 days preceding the patient's onset of symptoms. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. Evaluation and treatment are imperative because of the risk for reinfection of the patient and the strong likelihood of urethral gonococcal or chlamydial infection in the sex partner. Male partners of women who have PID caused by C. trachomatis and/or N. gonorrhoeae frequently are asymptomatic. Sex partners should be treated empirically with regimens effective against both of these infections, regardless of the etiology of PID or pathogens isolated from the infected woman. Even in clinical settings in which only women are treated, arrangements should be made to provide care or appropriate referral for male sex partners of women who have PID (see Partner Management). Expedited partner treatment and enhanced patient referral (see Partner Management) are alternative approaches to treating male partners of women who have chlamydia or gonococcal infections (68,69). # Prevention Screening and treating sexually active women for chlamydia reduces their risk for PID (272). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear (383,391). # Special Considerations Pregnancy Because of the high risk for maternal morbidity and preterm delivery, pregnant women who have suspected PID should be hospitalized and treated with parenteral antibiotics. # HIV Infection Differences in the clinical manifestations of PID between HIV-infected women and HIV-negative women have not been well delineated. In previous observational studies, HIV-infected women with PID were more likely to require surgical intervention; more comprehensive observational and controlled studies now have demonstrated that HIV-infected women with PID have similar symptoms when compared with uninfected controls (397)(398)(399), except they were more likely to have a tubo-ovarian abscess; both groups of women responded equally well to standard parenteral and oral antibiotic regimens. The microbiologic findings for HIV-positive and HIV-negative women were similar, except HIV-infected women had higher rates of concomitant M. hominis, candida, streptococcal, and HPV infections and HPV-related cytologic abnormalities. Regardlesss of these data, whether the management of immunodeficient HIV-infected women with PID requires more aggressive interventions (e.g., hospitalization or parenteral antimicrobial regimens) has not been determined. # Intrauterine Contraceptive Devices IUDs are popular contraceptive choices for women. Both levonorgestrel and copper-containing devices are marketed in the United States. The risk for PID associated with IUD use is primarily confined to the first 3 weeks after insertion and is uncommon thereafter (400,401). Given the popularity of IUDs, practitioners might encounter PID in IUD users. Evidence is insufficient to recommend that the removal of IUDs in women diagnosed with acute PID. However, caution should be exercised if the IUD remains in place, and close clinical follow-up is mandatory. The rate of treatment failure and recurrent PID in women continuing to use an IUD is unknown, and no data have been collected regarding treatment outcomes by type of IUD (e.g., copper or levonorgestrel). # Epididymitis Acute epididymitis is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis that lasts <6 weeks (402). Chronic epididymitis is characterized by a ≥6 week history of symptoms of discomfort and/or pain in the scrotum, testicle, or epididymis. In most cases of acute epididymitis, the testis is also involved in the process -a condition referred to as epididymo-orchitis. Chronic epididymitis has been subcategorized into inflammatory chronic epididymitis, obstructive chronic epididymitis, and chronic epididymalgia (403). Among sexually active men aged <35 years, acute epididymitis is most frequently caused by C. trachomatis or N. gonorrhoeae. Acute epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli and Pseudomonas spp.) also occurs among men who are the insertive partner during anal intercourse. Sexually transmitted acute epididymitis usually is accompanied by urethritis, which frequently is asymptomatic. In men aged >35 years, sexually transmitted epididymitis is uncommon, whereas bacteriuria secondary to obstructive urinary disease (e.g., benign prostatic hyperplasia) is more common. In this older population, nonsexually transmitted epididymitis is associated with urinary tract instrumentation or surgery, systemic disease, and immunosuppression. Chronic infectious epididymitis is most frequently seen in conditions associated with granulomatous reaction; Mycobacterium tuberculosis (TB) is the most common granulomatous disease affecting the epididymis. Up to 25% of patients can have bilateral disease, with ultrasound demonstrating an enlarged hyperemic epididymis with multiple cysts and calcifications. Tuberculous epididymitis should be suspected in all patients with a known history of or recent exposure to TB or in patients whose clinical status worsens despite appropriate antibiotic treatment. # Diagnostic Considerations Men who have acute epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present. Although the inflammation and swelling usually begin in the tail of the epididymis, they can spread to involve the rest of the epididymis and testicle. The spermatic cord is usually tender and swollen. Testicular torsion, a surgical emergency, should be considered in all cases, but it occurs more frequently among adolescents and in men without evidence of inflammation or infection. Emergency testing for torsion might be indicated when the onset of pain is sudden, pain is severe, or the test results available during the initial examination do not support a diagnosis of urethritis or urinary-tract infection. If the diagnosis is questionable, a urologist should be consulted immediately because testicular viability might be compromised. Radionuclide scanning of the scrotum is the most accurate radiologic method of diagnosis, but it is not routinely available. Although ultrasound is primarily used for ruling out torsion of the spermatic cord in cases of acute scrotum swelling, it will often demonstrate epididymal hyperemia and swelling in men with epididymitis. However, differentiation between testicular torsion and epididymitis must be made on the basis of clinical evaluation, because partial spermatic cord torsion can mimic epididymitis on scrotal ultrasound. Ultrasound provides minimal utility for men with a clinical presentation consistent with epididymitis; a negative ultrasound does not alter physician management of clinical epididymitis. Ultrasound, therefore, should be reserved for patients with scrotal pain who cannot be diagnosed accurately by physical examination, history, and objective laboratory findings. The evaluation of men for epididymitis should include one of the following: • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. Gram stain is the preferred rapid diagnostic test for evaluating urethritis because it is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing intracellular Gram-negative diplococci on urethral Gram stain. • Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high power field. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and nucleic acid hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine or urethral specimens. Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis. Depending on the risk, patients whose conditions are associated with acquiring an STD should receive testing for other STDs. # Treatment Empiric therapy is indicated before laboratory test results are available. The goals of treatment of acute epididymitis caused by C. trachomatis or N. gonorrhoeae are 1) microbiologic cure of infection, 2) improvement of signs and symptoms, 3) prevention of transmission to others, and 4) a decrease in potential complications (e.g., infertility or chronic pain). As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided. Because empiric therapy is often initiated before laboratory tests are available, all patients should receive ceftriaxone plus doxycycline for the initial therapy of epididymitis. Additional therapy can include a fluoroquinolone if acute epididymitis is not found to be caused by gonorrhea by NAAT or if the infection is most likely caused by enteric organisms. For men who are at risk for both sexually transmitted and enteric organisms (e.g., MSM who report insertive anal intercourse), ceftriaxone with a fluoroquinolone are recommended. # Recommended Regimens Ceftriaxone 250 mg IM in a single dose PLUS Doxycycline 100 mg orally twice a day for 10 days # For acute epididymitis most likely caused by enteric organisms Levofloxacin 500 mg orally once daily for 10 days OR Ofloxacin 300 mg orally twice a day for 10 days Although most patients can be treated on an out-patient basis, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess) or when patients are unable or unlikely to comply with an antimicrobial regimen. Because high fever is uncommon and indicates a complicated infection, these patients should be admitted for further evaluation. # Follow-Up Patients should be instructed to return to their health-care providers if their symptoms fail to improve within 48 hours of the initiation of treatment. Signs and symptoms of epididymitis that do not subside within 3 days requires re-evaluation of the diagnosis and therapy. Swelling and tenderness that persist after completion of antimicrobial therapy should be evaluated comprehensively. Differential diagnoses include tumor, abscess, infarction, testicular cancer, TB, and fungal epididymitis. # Management of Sex Partners Patients who have acute epididymitis that is confirmed or suspected to be caused by N. gonorrhoeae or C. trachomatis should be instructed to refer sex partners for evaluation and treatment if their contact with the index patient was within the 60 days preceding onset of their own symptoms. Patients should be instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (i.e., until therapy is completed and patient and partners no longer have symptoms). # Special Considerations HIV Infection Patients who have uncomplicated acute epididymitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Other etiologic agents have been implicated in acute epididymitis in HIV infection including CMV, salmonella, toxoplasmosis, Ureaplasma urealyticum, Corynebacterium sp., Mycoplasma sp., and Mima polymorpha. Fungi and mycobacteria are also more likely to cause acute epididymitis in immunosuppressed men than in immunocompetent men. # Human Papillomavirus (HPV) Infection More than 100 types of HPV exist, more than 40 of which can infect the genital area. Most HPV infections are asymptomatic, unrecognized, or subclinical. Oncogenic, or high-risk HPV types (e.g., HPV types 16 and 18), are the cause of cervical cancers. These HPV types are also associated with other anogenital cancers in men and women, including penile, vulvar, vaginal, and anal cancer, as well a subset of oropharyngeal cancers (404). Nononcogenic, or low-risk HPV types (e.g., HPV types 6 and 11), are the cause of genital warts and recurrent respiratory papillomatosis. Asymptomatic genital HPV infection is common and usually self-limited; it is estimated that more than 50% of sexually active persons become infected at least once in their lifetime (405). Persistent oncogenic HPV infection is the strongest risk factor for development of precancers and cancers. # HPV Tests HPV tests are available for women aged >30 years undergoing cervical cancer screening. These tests should not be used for men, for women <20 years of age, or as a general test for STDs. These HPV tests detect viral nucleic acid (i.e., DNA or RNA) or capsid protein. # Treatment Treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e, precancerous) lesions caused by infection. Subclinical genital HPV infection typically clears spontaneously, and therefore specific antiviral therapy is not recommended to eradicate HPV infection. In the absence of lesions, treatment is not recommended for subclinical genital HPV infection whether it is diagnosed by colposcopy, acetic acid application, or by laboratory tests for HPV DNA. Treatment also is not recommended for cervical intraepithelial neoplasia 1 (CIN1). # Prevention Two HPV vaccines are licensed in the United States: a bivalent vaccine (Cervarix) containing HPV types 16 and 18 and a quadrivalent vaccine (Gardasil) vaccine containing HPV types 6, 11, 16, and 18. Both vaccines offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18), and the quadrivalent HPV vaccine also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). Either vaccine can be administered to girls aged 11-12 years and can be administered to those as young as 9 years of age (15,16); girls and women ages 13-26 years who have not started or completed the vaccine series also should receive the vaccine. HPV vaccine is indicated for girls in this age group, because benefit is greatest if it is administered before the onset of sexual activity. The quadrivalent (Gardasil) HPV vaccine can also be used in males aged 9-26 years to prevent genital warts (17). Administering the vaccine to boys before the onset of sexual activity is optimal. Both HPV vaccines are administered as a 3-dose series of IM injections over a 6-month period, with the second and third doses given 1-2 and then 6 months after the first dose. Ideally, the same vaccine product should be used for the entire 3-dose series. HPV vaccine is available for eligible children and adolescents aged <19 years through the Vaccines for Children (VFC) program (available by calling CDC INFO [800- ). Women who have received HPV vaccine should continue routine cervical cancer screening because 30% of cervical cancers are caused by HPV types other than 16 or 18. In the United States, the vaccines are not licensed or recommended for use in women >26 years of age. No published data are available on the effectiveness, programmatic requirements, or cost-effectiveness of administering the HPV vaccine in STD clinic settings. # Genital Warts Of genital warts, 90% are caused by HPV 6 or 11. HPV types 6 or 11 are commonly found before, or at the time of, detection of genital warts (406). HPV types 16, 18, 31, 33, and 35 are found occasionally in visible genital warts (usually as coinfections with HPV 6 or 11) and can be associated with foci of high-grade intraepithelial neoplasia, particularly in persons who are infected with HIV infection. In addition to warts on genital areas, HPV types 6 and 11 have been associated with conjunctival, nasal, oral, and laryngeal warts. Genital warts are usually asymptomatic, but depending on the size and anatomic location, they can be painful or pruritic. Genital warts are usually flat, papular, or pedunculated growths on the genital mucosa. Genital warts occur commonly at certain anatomic sites, including around the introitus in women, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis. Genital warts can also occur at multiple sites in the anogenital epithelium or within the anogenital tract (e.g., cervix, vagina, urethra, perineum, perianal skin, and scrotum). Intra-anal warts are observed predominantly in persons who have had receptive anal intercourse, but they can also occur in men and women who do not have a history of anal sexual contact. Diagnosis of genital warts is usually clinical, made by visual inspection. Genital warts can be confirmed by biopsy, which might be indicated if 1) the diagnosis is uncertain; 2) the lesions do not respond to standard therapy; 3) the disease worsens during therapy; 4) the lesion is atypical; 5) the patient has comprised immunity; or 6) the warts are pigmented, indurated, fixed, bleeding, or ulcerated. Genital warts are usually asymptomatic, but depending on the size and anatomic location, they might be painful or pruritic. The use of HPV DNA testing for genital wart diagnosis is not recommended, because test results would not alter clinical management of the condition. The application of 3%-5% acetic acid, which causes skin color to turn white, has been used by some providers to detect HPV-infected genital mucosa. However, acetic acid application is not a specific test for HPV infection. Therefore, the routine use of this procedure for screening to detect mucosal changes attributed to HPV infection is not recommended. # Treatment The primary reason for treating genital warts is the amelioration of symptoms (including relieving cosmetic concerns) and ultimately, removal of the warts. In most patients, treatment can induce wart-free periods. If left untreated, visible genital warts can resolve on their own, remain unchanged, or increase in size or number. Available therapies for genital warts likely reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA resulting from treatment reduces future transmission remains unclear. No evidence indicates that the presence of genital warts or their treatment is associated with the development of cervical cancer. # Regimens Treatment of genital warts should be guided by the preference of the patient, available resources, and the experience of the health-care provider. No definitive evidence suggests that any of the available treatments are superior to any other, and no single treatment is ideal for all patients or all warts. The use of locally developed and monitored treatment algorithms has been associated with improved clinical outcomes and should be encouraged. Because of uncertainty regarding the effect of treatment on future transmission of HPV and the possibility of spontaneous resolution, an acceptable alternative for some persons is to forego treatment and wait for spontaneous resolution. Factors that influence selection of treatment include wart size, wart number, anatomic site of the wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience. Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy, which can consist of either a single treatment or complete course of treatment. In general, warts located on moist surfaces or in intertriginous areas respond best to topical treatment. The treatment modality should be changed if a patient has not improved substantially after a complete course of treatment or if side effects are severe. Most genital warts respond within 3 months of therapy. The response to treatment and any side effects should be evaluated throughout the course of therapy. Complications occur rarely when treatment is administered properly. Patients should be warned that persistent hypopigmentation or hyperpigmentation occurs commonly with ablative modalities and has also been described with immune modulating therapies (imiquimod). Depressed or hypertrophic scars are uncommon but can occur, especially if the patient has had insufficient time to heal between treatments. Rarely, treatment can result in disabling chronic pain syndromes (e.g., vulvodynia and hyperesthesia of the treatment site) or, in the case of anal warts, painful defecation or fistulas. A limited number of case reports of severe systemic effects resulting from treatment with podophyllin resin and interferon have been documented. Treatment regimens are classified into patient-applied and provider-applied modalities. Patient-applied modalities are preferred by some patients because they can be administered in the privacy of the patient's home. To ensure that patientapplied modalities are effective, patients must comply with the treatment regimen and must be capable of identifying and reaching all genital warts. Follow-up visits are not required for persons using patient-applied therapy. However, follow-up visits after several weeks of therapy enable providers to answer any questions patients might have about the use of the medication and any side effects they have experienced; follow-up visits also facilitate the assessment of a patient's response to treatment. Podofilox is an antimitotic drug that destroys warts, is relatively inexpensive, easy to use, safe, and self-applied. Podofilox solution should be applied with a cotton swab, or podofilox gel with a finger, to visible genital warts twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated, as necessary, for up to four cycles. The total wart area treated should not exceed 10 cm 2 , and the total volume of podofilox should be limited to 0.5 mL per day. If possible, the healthcare provider should apply the initial treatment to demonstrate the proper application technique and identify which warts should be treated. Mild to moderate pain or local irritation might develop after treatment. The safety of podofilox during pregnancy has not been established. # Recommended Regimens for External Genital Warts Imiquimod is a topically active immune enhancer that stimulates production of interferon and other cytokines. Imiquimod cream should be applied once daily at bedtime, three times a week for up to 16 weeks (407). The treatment area should be washed with soap and water 6-10 hours after the application. Local inflammatory reactions, including redness, irritation, induration, ulceration/erosions, and vesicles, are common with the use of imiquimod, and hypopigmentation has also been described (408). Imiquimod might weaken condoms and vaginal diaphragms. The safety of imiquimod during pregnancy has not been established. Sinecatechin ointment, a green-tea extract with an active product (catechins), should be applied three times daily (0.5cm strand of ointment to each wart) using a finger to ensure coverage with a thin layer of ointment until complete clearance of warts. This product should not be continued for longer than 16 weeks (409)(410)(411). The medication should not be washed off after use. Sexual (i.e., genital, anal, or oral) contact should be avoided while the ointment is on the skin. The most common side effects of sinecatechins 15% are erythema, pruritis/ burning, pain, ulceration, edema, induration, and vesicular rash. This medication may weaken condoms and diaphragms. No clinical data are available regarding the efficacy or safety of sinecatechins compared with other available anogenital wart treatment modalities. The medication is not recommended for HIV-infected persons, immunocompromised persons, or persons with clinical genital herpes because the safety and efficacy of therapy in these settings has not been established. The safety of sinecatechins during pregnancy also is unknown. Cryotherapy destroys warts by thermal-induced cytolysis. Health-care providers must be trained on the proper use of this therapy because over-and undertreatment can result in complications or low efficacy. Pain after application of the liquid nitrogen, followed by necrosis and sometimes blistering, is common. Local anesthesia (topical or injected) might facilitate therapy if warts are present in many areas or if the area of warts is large. Pedophyllin resin 10%-25% should be applied to each wart and allowed to air-dry before the treated area comes into contact with clothing; overapplication or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The treatment can be repeated weekly, if necessary. To avoid the possibility of complications associated with systemic absorption and toxicity, two guidelines should be followed: 1) application should be limited to <0.5 mL of podophyllin or an area of <10 cm 2 of warts per session and 2) the area to which treatment is administered should not contain any open lesions or wounds. The preparation should be thoroughly washed off 1-4 hours after application to reduce local irritation. The safety of podophyllin during pregnancy has not been established. Podophyllin resin preparations differ in the concentration of active components and contaminants. The shelf life and stability of podophyllin preparations are unknown. Both TCA and BCA are caustic agents that destroy warts by chemical coagulation of proteins. Although these preparations are widely used, they have not been investigated thoroughly. TCA solutions have a low viscosity comparable with that of water and can spread rapidly if applied excessively; therefore, they can damage adjacent tissues. A small amount should be applied only to the warts and allowed to dry before the patient sits or stands, at which time a white frosting develops. If pain is intense, the acid can be neutralized with soap or sodium bicarbonate. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate (i.e., baking soda), or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. Surgical therapy has the advantage of usually eliminating warts at a single visit. However, such therapy requires substantial clinical training, additional equipment, and a longer office visit. After local anesthesia is applied, the visible genital warts can be physically destroyed by electrocautery, in which case no additional hemostasis is required. Care must be taken to control the depth of electrocautery to prevent scarring. Alternatively, the warts can be removed either by tangential excision with a pair of fine scissors or a scalpel, by laser, or by curettage. Because most warts are exophytic, this procedure can be accomplished with a resulting wound that only extends into the upper dermis. Hemostasis can be achieved with an electrocautery unit or a chemical styptic (e.g., an aluminum chloride solution). Suturing is neither required nor indicated in most cases if surgical removal is performed properly. Surgical therapy is most beneficial for patients who have a large number or area of genital warts. Both carbon dioxide laser and surgery might be useful in the management of extensive warts or intraurethral warts, particularly for those persons who have not responded to other treatments. Because all available treatments have shortcomings, some clinics employ combination therapy (simultaneous use of two or more modalities on the same wart at the same time). Data are limited regarding the efficacy or risk of complications associated with use of such combinations. # Alternative Regimens Alternative regimens include treatment options that might be associated with more side effects and/or less data on efficacy. Alternative regimens include intralesional interferon, photodynamic therapy, and topical cidofovir. # Recommended Regimen for Cervical Warts For women who have exophytic cervical warts, a biopsy evaluation to exclude high-grade SIL must be performed before treatment is initiated. Management of exophytic cervical warts should include consultation with a specialist. # Recommended Regimens for Vaginal Warts Cryotherapy with liquid nitrogen. The use of a cryoprobe in the vagina is not recommended because of the risk for vaginal perforation and fistula formation. OR TCA or BCA 80%-90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. # Recommended Regimens for Urethral Meatus Warts Cryotherapy with liquid nitrogen OR Podophyllin 10%-25% in compound tincture of benzoin. The treatment area and adjacent normal skin must be dry before contact with podophyllin. This treatment can be repeated weekly, if necessary. The safety of podophyllin during pregnancy has not been established. Data are limited on the use of podofilox and imiquimod for treatment of distal meatal warts. # Recommended Regimens for Anal Warts Cryotherapy with liquid nitrogen OR TCA or BCA 80%-90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. # OR # Surgical removal Intra-anal warts should be managed in consultation with a specialist. Many persons with warts on the anal mucosa also have warts on the rectal mucosa, so persons with anal and/ or intra-anal warts might benefit from an inspection of the rectal mucosa by digital examination, standard anoscopy, or high-resolution anoscopy. # Counseling The following key counseling messages should be conveyed to all patients diagnosed with HPV infection: • Genital HPV infection is very common. Many types of HPV are passed on through genital contact, most often during vaginal and anal sexual contact. HPV can also be spread by oral sexual contact. • Most sexually active adults will get HPV at some point in their lives, though most will never know it because HPV infection usually has no signs or symptoms. • In most cases, HPV infection clears spontaneously, without causing any health problems. Nevertheless, some infections do progress to genital warts, precancers, and cancers. • The types of HPV that cause genital warts are different from the types that can cause anogenital cancers. • Within an ongoing sexual relationship, both partners are usually infected at the time one person is diagnosed with HPV infection, even though signs of infection might not be apparent. • A diagnosis of HPV in one sex partner is not indicative of sexual infidelity in the other partner. • Treatments are available for the conditions caused by HPV (e.g., genital warts), but not for the virus itself. • HPV does not affect a woman's fertility or ability to carry a pregnancy to term. • Correct and consistent male condom use might lower the chances of giving or getting genital HPV, but such use is not fully protective, because HPV can infect areas that are not covered by a condom. # • Sexually active persons can lower their chances of getting HPV by limiting their number of partners. However, HPV is common and often goes unrecognized; persons with only one lifetime sex partner can have the infection. For this reason, the only definitive method to avoid giving and getting HPV infection and genital warts is to abstain from sexual activity. • Tests for HPV are now available to help providers screen for cervical cancer in certain women. These tests are not useful for screening adolescent females for cervical cancer, nor are they useful for screening for other HPV-related cancers or genital warts in men or women. HPV tests should not be used to screen: -men; -partners of women with HPV; -adolescent females; or -for health conditions other than cervical cancer. • Two HPV vaccines are available, both of which offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18); the quadrivalent vaccine (Gardasil) also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). These vaccines are most effective when all doses are administered before sexual contact. Either vaccine is recommended for 11and 12-year-old girls and for females aged 13-26 years who did not receive or complete the vaccine series when they were younger. The quadrivalent HPV vaccine can be used in males aged 9-26 years to prevent genital warts. The following are specific counseling messages for those persons diagnosed with genital warts and their partners: • Genital warts are not life threatening. If left untreated, genital warts might go away, stay the same, or grow in size or number. Except in very rare and unusual cases, genital warts will not turn into cancer. • It is difficult to determine how or when a person became infected with HPV; genital warts can be transmitted to others even when no visible signs of warts are present, even after warts are treated. • It is not known how long a person remains contagious after warts are treated. It is also unclear whether informing subsequent sex partners about a past diagnosis of genital warts is beneficial to the health of those partners. • Genital warts commonly recur after treatment, especially in the first 3 months. • Women should get regular Pap tests as recommended, regardless of vaccination or genital wart history. Women with genital warts do not need to get Pap tests more often than recommended. • HPV testing is unnecessary in sexual partners of persons with genital warts. • If one sex partner has genital warts, both sex partners benefit from getting screened for other STDs. • Persons with genital warts should inform current sex partner(s) because the warts can be transmitted to other partners. In addition, they should refrain from sexual activity until the warts are gone or removed. • Correct and consistent male condom use can lower the chances of giving or getting genital warts, but such use is not fully protective because HPV can infect areas that are not covered by a condom. • The Gardasil vaccine, which has been approved for use in males and females aged 9-26 years, protects against the HPV types that cause 90% of genital warts (i.e., types 6 and 11). # Special Considerations Pregnancy Imiquimod, sinecatechins, podophyllin, and podofilox should not be used during pregnancy. Genital warts can proliferate and become friable during pregnancy. Although removal of warts during pregnancy can be considered, resolution might be incomplete or poor until pregnancy is complete. Rarely, HPV types 6 and 11 can cause respiratory papillomatosis in infants and children, although the route of transmission (i.e., transplacental, perinatal, or postnatal) is not completely understood. Whether cesarean section prevents respiratory papillomatosis in infants and children also is unclear (412); therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn. Cesarean delivery is indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding. Pregnant women with genital warts should be counseled concerning the low risk for warts on the larynx (recurrent respiratory papillomatosis) in their infants or children. # HIV Infection Persons who are HIV-infected are more likely to develop genital warts then persons who are not HIV-infected (413); moreover, lesions are more recalcitrant to treatment due to depressed cell-mediated immunity. No data suggest that treatment modalities for external genital warts should be different for HIV-infected persons. However, persons who are immunosuppressed because of HIV or other reasons might have larger or more numerous warts, might not respond as well as immunocompetent persons to therapy for genital warts, and might have more frequent recurrences after treatment (414)(415)(416). Squamous cell carcinomas arising in or resembling genital warts might occur more frequently among immunosuppressed persons, therefore requiring biopsy for confirmation of diagnosis for suspicious cases. Because of the increased incidence of anal cancer in HIVinfected MSM, screening for anal intraepithelial neoplasia by cytology can be considered (417). However, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic considerations that would support this screening approach. # Squamous Cell Carcinoma in Situ Persons in whom squamous cell carcinoma in situ of the genitalia is diagnosed should be referred to a specialist for treatment. Ablative modalities usually are effective, but careful follow-up is essential for patient management. # Cervical Cancer Screening for Women Who Attend STD Clinics or Have a History of STDs Women attending STD clinics for the treatment of genital infection with high-risk types of Human Papillomavirus (HR-HPV) might be at increased risk for cervical cancer; persistence of HR-HPV can cause cervical cancer and its precancerous lesions. One study demonstrated an HR-HPV prevalence of 27% among women receiving treatment in an STD clinic setting; prevalence was highest among persons aged 14-19 and decreased with increasing age (418). In an evaluation of women attending STD clinics, over half of women were at increased risk for cervical cancer as a result of HPV infection, cervical disease, or history of cervical disease compared with women without these characteristics (419). Cervical cytology (i.e., a Pap test) is an effective, low-cost screening test for preventing invasive cervical cancer. In a 2004 survey, 49% of all STD clinics in the United States reported providing cervical screening services, and 20% reported use of HPV DNA testing (419). Current guidelines from USPSTF and ACOG recommend that cervical screening begin at age 21 years (96,97). This recommendation is based on the low incidence of cervical cancer and limited utility of screening in younger women (98). ACS recommends that women start cervical screening with Pap tests after 3 years of initiating sexual activity but by no later than age 21 years (98). Recommended screening intervals (http://www. cdc.gov/cancer/cervical/pdf/guidelines.pdf ) should continue through 65 years according to USPSTF (http://www.ahrq. gov/clinic/uspstf/uspscerv.htm) or 70 years according to ACS (http://cancer.org/docroot/ped/content/ped_2_3x_acs_cancer detection_guidelines_36.asp). # Screening Recommendations STD clinics that provide routine cervical screening services should follow the available guidelines. However, to ensure the provision of adequate care, follow-up and referral sources must be in place. Cervical screening should be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests) and can include HR-HPV DNA tests in specific circumstances (420). For cythopathologic and HPV/DNA testing, STD clinics should use CLIA certified laboratories (421) and those that report cytopathology findings according to the following Bethesda 2001 terminology (422): atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and high-grade intraepithelial lesions (HSIL). The ASC category is subdivided into atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells-cannot exclude HSIL (ASC-H). During appointments in which a pelvic examination for STD screening is performed, the health-care provider should inquire about the result of the patient's most recent Pap test and discuss the following information with the patient: • # HPV Tests HPV tests are available for clinical use and are recommended for the triage of women aged ≥21 years who have abnormal Pap test results (ASC-US). Additionally, these tests can be used in conjunction with a Pap test (adjunct testing) for cervical cancer screening of women aged ≥30 years. These tests should not be used for women aged <20 years for screening or management of abnormal Pap tests or for STD screening. Current FDA-approved HPV tests detect viral nucleic acid (DNA). Several FDA-approved tests for high-risk HPV testing are available for use in the United States. The Hybrid Capture 2 High-Risk HPV DNA test (Qiagen, Gaithersburg, Maryland) and the Cervista HPV High-Risk test (Hologics, Beford, Massachusetts) detect any of 13-14 high-risk HPV types, whereas the Cervista HPV 16/18 test detects type-specific infection with HPV types 16 and 18. The Digene HC2 HPV DNA test (Qiagen, Gaithersburg, Maryland) detects any of 13 high-risk or five low-risk HPV types, although use of this test is not indicated in the STD clinic setting (i.e., only high-risk HPV DNA testing is necessary) (423). High-risk HPV DNA tests are recommended for the triage of women aged ≥21 years who have ASC-US cytology results. In addition, these tests are recommended for routine adjunctive testing (along with cervical cytology) used to screen women aged ≥30 years (424). HPV DNA testing (including HR HPV and HPV 16/18 tests) is not recommended for the following situations (425)(426)(427): • deciding whether to vaccinate for HPV; • conducting STD screening for HPV; • triaging LSIL; • testing adolescents aged <21 years; and • screening for primary cervical cancer as a stand-alone test (i.e., without a Pap test). Women might benefit from receiving printed information about the value of and indication for cervical cancer screening (i.e., Pap testing), and they should be provided a clinic visit report that states whether a Pap test was obtained during the clinic visit. When available, a copy of the Pap test result should be provided. Women with abnormal screening or diagnostic tests should be referred to clinic settings that employ providers who are experienced in managing these cases (see Follow-Up). Cervical screening programs should screen women who have received HPV vaccination in the same manner as unvaccinated women. # Follow-Up Among women aged ≥30 years with normal Pap tests and negative tests for HR-HPV, the screening interval can be increased to 3 years. At that time, routine testing with either a Pap test or a Pap and HR-HPV testing can resume (428). If the results of the Pap test are abnormal, follow-up care should be provided according to the ASCCP 2006 Consensus Guidelines for Management of Abnormal Cervical Cytology (429) (information regarding management and follow-up care is available at http://www.asccp.org). If resources in STD clinics do not allow for follow-up of women with abnormal results, protocols for referral for follow-up and case management should be in place. • or ASC-US usually need a referral to other local health-care providers or clinics for colposcopy and biopsy. Clinics and health-care providers who offer cervical screening services but cannot provide appropriate colposcopic follow-up of abnormal Pap tests should arrange referral to health-care facilities that will promptly evaluate and treat patients and report evaluation results to the referring clinic or health-care provider. Clinics and health-care providers should develop protocols that identify women who miss follow-up appointments so that these women can be located and scheduled for needed studies and management, and they should reevaluate these protocols routinely. Pap-test results, type and location of follow-up appointments, and results of follow-up appointment should be clearly documented in the clinic record. The establishment of colposcopy and biopsy services in local health departments, especially in circumstances in which referrals are difficult and follow-up is unlikely, should be considered if resources are available. # other Management Considerations The following additional considerations are associated with performing Pap tests: • The Pap test should not be considered a screening test for STDs. • All women receiving care in an STD-clinic setting should be considered for cervical cancer screening, regardless of sexual orientation (i.e., heterosexual women and those who identify themselves as lesbian or bisexual). # • If a woman is menstruating, a conventional cytology Pap test should be postponed, and the woman should be advised to have a Pap test at the earliest opportunity. • If specific infections other than HPV are identified, the patient might need to have a repeat Pap test after appropriate treatment for those infections. However, in most instances (even in the presence of some severe infections), Pap tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the Pap test after treatment is received. • When it is necessary to repeat the Pap test because the report was interpreted as unsatisfactory, the repeat test must be determined by the laboratory to be satisfactory and negative before screening can be resumed at regularly scheduled intervals. • The presence of a mucopurulent discharge should not delay the Pap test. The test can be performed after careful removal of the discharge with a saline-soaked cotton swab. • In the absence of other indications, women who have external genital warts do not need Pap tests more frequently than women who do not have warts. # Special Considerations Pregnancy Pregnant women should be screened at the same frequency as nonpregnant women; however, recommendations for management differ in this population (83,84,424). A swab and an Ayre's spatula can be used for obtaining Pap tests in pregnant women, but cytobrushes are not recommended. # HIV Infection Several studies have documented an increased prevalence of SIL in HIV-infected women (416,436). The following recommendations for Pap test screening among HIV-infected women are consistent with most of the guidelines published by the U.S. Department of Health and Human Services (HHS) (129) and are based partially on the opinions of professionals knowledgeable about the care and management of cervical cancer and HIV infection in women. HIV-positive women should be provided cervical cytology screening twice (every 6 months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter. HIV-positive women with ASC-H, LSIL, or HSIL on cytologic screening should undergo colposcopic evaluation. Recommendations for management of HIV-positive women with ASC-US vary. HHS recommends a more conservative management approach (i.e., immediate colposcopy), whereas ASCCP recommends that these women be managed like HIV-negative women with ASC-US (i.e., tested for HR HPV DNA) (424,429). # Adolescents Prevalence of HR HPV is high among adolescents aged <21 years (425). Infections in adolescent patients tend to clear rapidly, and lesions caused by these infections also have high rates of regression to normal. Therefore, ASCCP and ACOG recommend that adolescents with ASC-US or low-grade SIL be managed with repeat cytologic testing at 12 months and 24 months. Only those with HSIL at either follow-up visit or persistence of ASC-US or LSIL at 24 months should be referred for colposcopic evaluation. # Counseling Messages for Women Receiving Cervical Cancer Screening and HPV Testing When a woman receives abnormal cervical cytology test results, she might experience considerable anxiety, distress, fear, and confusion, which can serve as barriers to follow-up care. Furthermore, a positive HPV DNA test result might exacerbate these feelings and might also elicit partner concerns, worry about disclosure, and feelings of guilt, anger, and stigmatization. Health-care providers are the most trusted source of information about HPV and abnormal cervical cytology test results. Therefore, they have an important role to play in educating women about high-risk HPV and moderating the psychosocial impact of the diagnosis. STD clinic providers should offer patients counseling and information both verbally and in print when delivering HPV and Pap test results. Print materials are available at several websites (http://www.cdc.gov/std/hpv/common/; http://www. ashastd.org/hpv/hpv_publications.cfm). The manner in which this information is communicated to patients can influence the psychological effect of this diagnosis, as well as a woman's likelihood of following up with necessary testing or treatment. Providers should frame high-risk HPV in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Also, the provider should emphasize that HPV is often shared between partners and can lie dormant for many years; having HPV does not imply infidelity, nor should it necessarily raise concerns about a partner's health. In counseling women with high-risk HPV infections about partner management, messages should be tailored to the individual woman's circumstances. While no evidence supports either partner notification (PN) or clinical-evaluation referral for partners of patients with high-risk HPV, some women might benefit from having an informed discussion about their diagnosis with their partners. This type of communication can foster partner support and ensure the sharing of information that can inform decision-making (e.g., decisions regarding condom use). The following specific key messages should be communicated to patients receiving cervical screening: • The purpose of regular, lifelong cervical cancer screening is to identify cervical cancer precursors, which can be treated before progression to cervical cancer. • A positive high-risk HPV DNA test or an abnormal cervical cytology test is not indicative of cervical cancer. Appropriate follow-up is necessary to ensure that cervical abnormalities do not progress. Follow-up evaluation is essential to monitor cervical cytology. • A Pap test that reveals ASC-US indicates some abnormal areas on the cervix that may require close follow-up or treatment so that they do not progress. Additional testing might be required to confirm these results. It is essential that patients return for all follow-up appointments and recommended tests. Discussion concerning disclosure of a positive high-risk HPV test to sex partners might be appropriate and can include the following information: • HPV is very common. It can infect the genital areas of both men and women. It usually has no signs or symptoms. • Most sexually active persons get HPV at some time in their lives, though most will never know it. Even persons with only one lifetime sex partner can get HPV if their partner was infected. • While the immune system clears HPV infection most of the time, in some persons, HPV infection does not resolve. • No clinically validated test exists for men to determine if they have HPV infection. The most common manifestation of HPV infection in men is genital warts. High-risk HPV types seldom cause genital warts. • Partners who are in a long-term relationship tend to share HPV. Sexual partners of HPV-infected patients also likely have HPV, even though they might have no signs or symptoms of infection. • Detection of high-risk HPV infection in a woman does not mean that the woman or her partner is engaging in sexual activity outside of a relationship. HPV infection can be present for many years before it is detected, and no method can accurately confirm when HPV infection was acquired. Prevention measures for current and subsequent sex partners and risk reduction should be discussed. Providers should counsel women about condom use depending on their current circumstances. Consistent condom use by male partners of sexually active women can reduce the risk for cervical and vulvovaginal HPV infection (25), and condom use by couples in long-term partnerships might decrease the time required to clear HPV in the infected woman. Skin not covered by a condom remains vulnerable to HPV infection. HPV vaccines are available and recommended for girls and young women aged 9-26 years, even those who have been diagnosed with HPV infection. Male partners can be vaccinated with the quadrivalent vaccine (Gardasil) to prevent genital warts. # Vaccine-Preventable STDs Several STDs can be effectively prevented through preexposure vaccination with widely available vaccines, including HAV, HBV, and HPV. Vaccines for other STDs (e.g., HIV and HSV) are under development or are undergoing clinical trials. This guidance focuses largely on integrating the use of available vaccines into STD prevention and treatment activities. Every person being evaluated or treated for an STD should receive hepatitis B vaccination unless already vaccinated. In addition, some persons (e.g., MSM and IDUs) should receive hepatitis A vaccination. # Hepatitis A Hepatitis A, caused by infection with HAV, has an incubation period of approximately 28 days (range: 15-50 days). HAV replicates in the liver and is shed in high concentrations in feces from 2 weeks before to 1 week after the onset of clini-cal illness. HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease (CLD). However, 10%-15% of patients experience a relapse of symptoms during the 6 months after acute illness. Acute liver failure from hepatitis A is rare (overall case-fatality rate: 0.5%). The risk for symptomatic infection is directly related to age, with >80% of adults having symptoms compatible with acute viral hepatitis and most children having either asymptomatic or unrecognized infection. Antibody produced in response to HAV infection persists for life and confers protection against reinfection. HAV infection is primarily transmitted by the fecal-oral route, by either person-to-person contact or through consumption of contaminated food or water. Although viremia occurs early in infection and can persist for several weeks after onset of symptoms, bloodborne transmission of HAV is uncommon. HAV occasionally is detected in saliva in experimentally infected animals, but transmission by saliva has not been demonstrated. In the United States, almost half of all persons with hepatitis A report having no risk factor for the disease. Among adults with identified risk factors, most cases occur among international travelers, household or sexual contacts, nonhousehold contacts (e.g., those encountered through play and daycare), and IDUs (437). Because transmission of HAV during sexual activity probably results from fecal-oral contact, measures typically used to prevent the transmission of other STDs (e.g., use of condoms) do not prevent HAV transmission. In addition, efforts to promote good personal hygiene have not been successful in interrupting outbreaks of hepatitis A. Vaccination is the most effective means of preventing HAV transmission among persons at risk for infection (e.g., MSM, illegal drug users, and persons with CLD), many of whom might seek services in STD clinics. # Diagnosis The diagnosis of hepatitis A cannot be made on clinical grounds alone; serologic testing also is required. The presence of IgM antibody to HAV is diagnostic of acute HAV infection. A positive test for total anti-HAV indicates immunity to HAV infection but does not differentiate current from previous HAV infection. Although usually not sensitive enough to detect the low level of protective antibody after vaccination, anti-HAV tests also might be positive after hepatitis A vaccination. # Treatment Patients with acute hepatitis A usually require only supportive care, with no restrictions in diet or activity. Hospitalization might be necessary for patients who become dehydrated because of nausea and vomiting and is critical for patients with signs or symptoms of acute liver failure. Medications that might cause liver damage or are metabolized by the liver should be used with caution among persons with hepatitis A. # Prevention Two products are available for the prevention of HAV infection: hepatitis A vaccine (Table 2) and immune globulin (IG) for IM administration. Hepatitis A vaccines are prepared from formalin-inactivated, cell-culture-derived HAV and have been available in the United States since 1995, initially for persons aged ≥2 years. In 2005, the vaccines were approved by FDA for persons aged ≥12 months, and the vaccine is available for eligible children and adolescents aged <19 years through the VFC program (telephone: 800-232-4636). Administered IM in a 2-dose series at 0 and 6-12 months, these vaccines induce protective antibody levels in virtually all adults. By 1 month after the first dose, 94%-100% of adults have protective antibody levels; 100% of adults develop protective antibody after a second dose. In randomized controlled trials, the equivalent of 1 dose of hepatitis A vaccine administered before exposure has been 94%-100% effective in preventing clinical hepatitis A (2). Kinetic models of antibody decline indicate that protective levels of antibody persist for at least 20 years. IG is a sterile solution of concentrated immunoglobulins prepared from pooled human plasma processed by cold ethanol fractionation. In the United States, IG is produced only from plasma that has tested negative for hepatitis B surface antigen, antibodies to HIV and HCV, and HCV RNA. In addition, the process used to manufacture IG inactivates viruses (e.g., HBV, HCV, and HIV). When administered IM before or within 2 weeks after exposure to HAV, IG is >85% effective in preventing HAV infections. A combined hepatitis A and hepatitis B vaccine has been developed and licensed for use as a 3-dose series in adults aged ≥18 years (Table 3). When administered IM on a 0-, 1-, and 6-month schedule, the vaccine has equivalent immunogenicity to that of the monovalent vaccines. # Pre-exposure Vaccination Persons in the following groups who are likely to be treated in STD clinic settings should be offered hepatitis A vaccine: 1) all MSM; 2) illegal drug users (of both injection and noninjection drugs); and 3) persons with CLD, including persons with chronic HBV and HCV infection who have evidence of CLD. # Prevaccination Serologic Testing for Susceptibility Approximately one third of the U.S. population has serologic evidence of previous HAV infection, which increases with age and reaches 75% among persons aged >70 years. Screening for HAV infection might be cost-effective in populations where the prevalence of infection is likely to be high (e.g., persons aged >40 years and persons born in areas of high HAV endemicity). The potential cost-savings of testing should be weighed against the cost and the likelihood that testing will interfere with initiating vaccination. Vaccination of a person who is already immune is not harmful. # Postvaccination Serologic Testing Postvaccination serologic testing is not indicated because most persons respond to the vaccine. In addition, the commercially available serologic test is not sensitive enough to detect the low, but protective, levels of antibody produced by vaccination. # Postexposure Prophylaxis Persons who recently have been exposed to HAV and who previously have not received hepatitis A vaccine should be administered a single dose of single-antigen vaccine or IG (0.02 mL/kg) as soon as possible. Information about the relative efficacy of vaccine compared with IG postexposure is limited, and no data are available for persons aged >40 years or those with underlying medical conditions. Therefore, decisions to use vaccine or IG should take into account patient characteristics associated with more severe manifestations of hepatitis A, including older age and CLD. For healthy persons aged 12 months to 40 years, singleantigen hepatitis A vaccine at the age-appropriate dose is preferred over IG because of vaccine advantages, including long-term protection and ease of administration. For persons aged >40 years, IG is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group; vaccine can be used if IG cannot be obtained. The magnitude of the risk for HAV transmission from the exposure should be considered in decisions to use IG or vaccine. IG should be used for children aged <12 months, immunocompromised persons, persons who have had diagnosed CLD, and persons for whom vaccine is contraindicated. If IG is administered to persons for whom hepatitis A vaccine also is recommended, a dose of vaccine should be provided simultaneously with IG. The second vaccine dose should be administered according to the licensed schedule to complete the series. The efficacy of IG or vaccine when administered >2 weeks after exposure has not been established (438). # Special Considerations Limited data indicate that vaccination of persons with CLD and of persons with advanced HIV infection results in lower seroprotection rates and antibody concentrations (4). In HIV-infected persons, antibody response might be directly related to CD4+ levels. # Hepatitis B Hepatitis B is caused by infection with the hepatitis B virus (HBV). The incubation period from the time of exposure to onset of symptoms is 6 weeks to 6 months. The highest concentrations of HBV are found in blood, with lower concentrations found in other body fluids including wound exudates, semen, vaginal secretions, and saliva (439,440). HBV is more infectious and relatively more stable in the environment than other bloodborne pathogens like HCV and HIV. HBV infection can be self-limited or chronic. In adults, only approximately half of newly acquired HBV infections are symptomatic, and approximately 1% of reported cases result in acute liver failure and death. Risk for chronic infection is inversely related to age at acquisition; approximately 90% of infected infants and 30% of infected children aged <5 years become chronically infected, compared with 2%-6% of persons who become infected as adults. Among persons with chronic HBV infection, the risk for premature death from cirrhosis or hepatocellular carcinoma (HCC) is 15%-25%. HBV is efficiently transmitted by percutaneous or mucous membrane exposure to blood or body fluids that contain blood. The primary risk factors associated with infection among adolescents and adults are unprotected sex with an infected partner, unprotected sex with more than one partner, MSM, history of other STDs, and illegal injection-drug use. In addition, several studies have demonstrated the horizontal transmission of HBV, including through premastication, as a less common source of transmission (441,442). CDC's national strategy to eliminate transmission of HBV infection includes 1) prevention of perinatal infection through routine screening of all pregnant women for HBsAg and immunoprophylaxis of infants born to HBsAg-positive mothers or mothers whose HBsAg status is unknown, 2) routine infant vaccination, 3) vaccination of previously unvaccinated children and adolescents through age 18 years, and 4) vaccination of previously unvaccinated adults at increased risk for infection (3,4). High vaccination coverage rates, with subsequent declines in acute hepatitis B incidence, have been achieved among infants and adolescents (4,437,443). In contrast, vaccination coverage among most high-risk adult groups (e.g., persons with more than one sex partner in the previous 6 months, MSM, and IDUs) has remained low, and most new infections occur in these high-risk groups (3,108,(444)(445)(446). STD clinics and other settings that provide services to high-risk adults are ideal sites in which to provide hepatitis B vaccination to adults at risk for HBV infection. All unvaccinated adults seeking services in these settings should be assumed to be at risk for hepatitis B and should be offered hepatitis B vaccination. # Diagnosis Diagnosis of acute or chronic HBV infection requires serologic testing (Table 4). Because HBsAg is present in both acute and chronic infection, the presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is diagnostic of acute or recently acquired HBV infection. Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection. The presence of anti-HBc alone might indicate a false-positive result or acute, resolved, or chronic infection. # Treatment No specific therapy is available for persons with acute hepatitis B; treatment is supportive. Persons with chronic HBV infection should be referred for evaluation to a physician experienced in the management of CLD. Therapeutic agents cleared by FDA for treatment of chronic hepatitis B can achieve sustained suppression of HBV replication and remission of liver disease in some persons. In addition, patients with chronic hepatitis B might benefit from screening to detect HCC at an early stage. adults, Twinrix (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania), also is available. The recommended HBV dose varies by product and age of recipient (Table 3). When selecting a hepatitis B vaccination schedule, the health-care provider should consider the need to achieve completion of the vaccine series. Approved adolescent and adult schedules for both monovalent hepatitis B vaccine (i.e., Engerix-B and Recombivax HB) include the following: 0, 1, and 6 months; 0, 1, and 4 months; and 0, 2, and 4 months. A 4-dose schedule of Engerix-B at 0, 1, 2, and 12 months is licensed for all age groups. A 2-dose schedule of Recombivax HB adult formulation (10 µg) is licensed for adolescents aged 11-15 years. When scheduled to receive the second dose, adolescents aged >15 years should be switched to a 3-dose series, with doses two and three consisting of the pediatric formulation (5 µg) administered on an appropriate schedule. Twinrix can be administered to persons aged ≥18 years at risk for both HAV and HBV infections at 0, 1, and 6 months. Hepatitis B vaccine should be administered IM in the deltoid muscle and can be administered simultaneously with other vaccines. For adolescents and adults, the needle length should be 1-2 inches, depending on the recipient's weight (1 inch for females weighing <70 kg, 1.5 inches for males weighing <120 kg, and 2 inches for males and females weighing >120 kg and >100 kg, respectively). A 22-to 25-gauge needle is recommended. If the vaccine series is interrupted after the first or second dose of vaccine, the missed dose should be administered as soon as possible. The series does not need to be restarted after a missed dose. In adolescents and healthy adults aged <40 years, approximately 30%-55% acquire a protective antibody response (anti-HBs ≥10 mIU/mL) after the first vaccine dose, 75% after the second, and >90% after the third. Vaccineinduced immune memory has been demonstrated to persist for at least 15-20 years. Periodic testing to determine antibody levels after routine vaccination in immunocompetent persons is not necessary, and booster doses of vaccine are not currently recommended. Hepatitis B vaccination is generally well-tolerated by most recipients. Pain at the injection site and low-grade fever are reported by a minority of recipients. For children and adolescents, a causal association exists between receipt of hepatitis B vaccination and anaphylaxis: for each 1.1 million doses of vaccine administered, approximately one vaccinee will experience this type of reaction. No deaths have been reported in these patients (3,4,447). Vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of hepatitis B vaccine and in persons with a known anaphylactic reaction to any vaccine component. No evidence for a causal association has been demonstrated for other adverse events after administration of hepatitis B vaccine. # Pre-exposure Vaccination Hepatitis B vaccination is recommended for all unvaccinated adolescents, all unvaccinated adults at risk for HBV infection, and all adults seeking protection from HBV infection. For adults, acknowledgement of a specific risk factor is not a requirement for vaccination. Hepatitis B vaccine should be routinely offered to all unvaccinated persons attending STD clinics and to all unvaccinated persons seeking treatment for STDs in other settings. Other settings where all unvaccinated adults should be assumed to be at risk for hepatitis B and should receive hepatitis B vaccination include correctional facilities, facilities providing drug abuse treatment and prevention services, health-care settings serving MSM, and HIV testing and treatment facilities. All persons who receive clinical services in these settings should be offered hepatitis B vaccine unless they have a reliable vaccination history (i.e., a written, dated record of each dose of a complete series). In all settings, vaccination should be initiated even when completion of the vaccine series cannot be ensured. # Prevaccination Antibody Screening Prevaccination serologic testing for susceptibility might be considered to reduce the cost of vaccinating adult populations that have an expected high prevalence (20%-30%) of HBV infection (e.g., IDUs and MSM, especially those in older age groups). In addition, prevaccination testing for susceptibility is recommended for unvaccinated household, sexual, and needlesharing contacts of HBsAg-positive persons (108). Anti-HBc is the test of choice for prevaccination testing; persons who are anti-HBc-positive should be tested for HBsAg. If persons are determined to be HBsAg negative, no further action is required. If persons are determined to be HBsAg positive, the person should be referred for medical follow-up to include counseling and evaluation for antiviral treatment (see Management of HBsAg-Positive Persons). In addition, all household members, sex partners, and needle-sharing partners of HBsAg-positive persons should be vaccinated. Serologic testing should not be a barrier to vaccination of susceptible persons, especially in populations that are difficult to access. In most cases, the first vaccine dose should be administered immediately after collection of the blood sample for serologic testing. Vaccination of persons who are immune to HBV infection because of current or previous infection or vaccination does not increase the risk for adverse events. # Postvaccination Testing for Serologic Response Serologic testing for immunity is not necessary after routine vaccination of adolescents or adults. However, such testing is recommended for persons whose subsequent clinical management depends on knowledge of their immune status (e.g., health-care workers or public safety workers at high risk for continued percutaneous or mucosal exposure to blood or body fluids). In addition, postvaccination testing is recommended for 1) HIV-infected persons and other immunocompromised persons to determine the need for revaccination and the type of follow-up testing and 2) sex and needle-sharing partners of HBsAg-positive persons to determine the need for revaccination and for other methods to protect themselves from HBV infection. If indicated, testing should be performed 1-2 months after administration of the last dose of the vaccine series by using a method that allows determination of a protective level of anti-HBs (i.e., ≥10 mIU/mL). Persons determined to have anti-HBs levels of <10 mIU/mL after the primary vaccine series should be revaccinated with a 3-dose series and provided with anti-HBs testing 1-2 months after the third dose. Persons who do not respond to revaccination should be tested for HBsAg. If HBsAg positive, the person should receive appropriate management (see Management of HBsAg-Positive Persons); if HBsAg negative, the person should be considered susceptible to HBV infection and counseled concerning precautions to prevent HBV infection and the need for HBIG PEP for any known exposure (see Postexposure Prophylaxis). # Postexposure Prophylaxis Both passive-active PEP (the administration of HBIG and hepatitis B vaccine at separate sites) and active PEP (the administration of hepatitis B vaccination alone) have been demonstrated to be highly effective in preventing transmission after exposure to HBV (4). HBIG alone also has been demonstrated to be effective in preventing HBV transmission, but with the availability of hepatitis B vaccine, HBIG typically is used as an adjunct to vaccination. # Exposure to HBsAg-Positive Source Unvaccinated persons or persons known not to have responded to a complete hepatitis B vaccine series should receive both HBIG and hepatitis vaccine as soon as possible (preferably ≤24 hours) after a discrete, identifiable exposure to blood or body fluids that contain blood from an HBsAgpositive source (Table 5). Hepatitis B vaccine should be administered simultaneously with HBIG at a separate injection site, and the vaccine series should be completed by using the age-appropriate vaccine dose and schedule (Table 3). Exposed persons who are in the process of being vaccinated but who have not completed the vaccine series should receive the appropriate dose of HBIG (i.e., 0.06 mL/kg) and should complete the vaccine series. Exposed persons who are known to have responded to vaccination are considered protected; therefore, they need no additional doses of vaccine. Persons who have written documentation of a complete hepatitis B vaccine series who did not receive postvaccination testing should receive a single vaccine booster dose. Alternatively, these persons can be managed according to guidelines for management of persons with occupational exposure to blood or body fluids that contain blood (446). # Exposure to Source with Unknown HBsAg Status Unvaccinated persons who have a discrete, identifiable exposure to blood or body fluids containing blood from a source with unknown HBsAg status should receive the hepatitis B vaccine series, with the first dose initiated as soon as possible after exposure (preferably within 24 hours) and the series completed by using the age-appropriate dose and schedule. Exposed persons who are not fully vaccinated should complete the vaccine series. Exposed persons with written documentation of a complete hepatitis B vaccine series require no further treatment. # Special Considerations Pregnancy All pregnant women receiving STD services should be tested for HBsAg, regardless of whether they have been previously tested or vaccinated. All HBsAg-positive pregnant women should be reported to state and local perinatal hepatitis B prevention programs. HBsAg-negative pregnant women seeking STD treatment who have not been previously vaccinated should receive hepatitis B vaccination. Additional information regarding management of HBsAg-positive pregnant women and their infants is available at http://www. cdc.gov/mmwr/PDF/rr/rr5416.pdf. # HIV Infection HIV infection can impair the response to hepatitis B vaccination. HIV-infected persons should be tested for anti-HBs 1-2 months after the third vaccine dose (see Postvaccination Testing for Serologic Response). Modified dosing regimens, including a doubling of the standard antigen dose and administration of additional doses, might increase the response rate (130). # Management of HBsAg-Positive Persons This section provides recommendations for management of all HBsAg-positive persons. Additional recommendations for management of HBsAg-positive persons who are coinfected with HIV are available (130). • All persons with HBsAg-positive laboratory results should be reported to the state or local health department. † Immunoprophylaxis should be administered as soon as possible, preferably ≤24 hours. Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposures and 14 days for sexual exposures. The complete, 3-dose hepatitis B vaccine series should be administered. -refrain from donating blood, plasma, body organs, other tissue, or semen; and -refrain from sharing household articles (e.g., toothbrushes, razors, or personal injection equipment) that could become contaminated with blood. In addition, HBsAg-positive persons should refrain from premasticating food provided to susceptible persons. • To protect the liver from further harm, HBsAg-positive persons should be advised to: -avoid or limit alcohol consumption because of the effects of alcohol on the liver; -refrain from starting any new medicines, including OTC and herbal medicines, without checking with their health-care provider; and -obtain vaccination against hepatitis A if liver disease is determined to be present. When seeking medical or dental care, HBsAg-positive persons should be advised to inform their health-care providers of their HBsAg status so that they can be appropriately evaluated and managed. The following counseling messages should be considered for HBsAg-positive persons: • HBV is not usually spread by hugging, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact. • Persons should not be excluded from work, school, play, child care, or other settings because they are infected with HBV. • Involvement with a support group might help patients cope with chronic HBV infection. # Hepatitis C Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States; an estimated 3.2 million persons are chronically infected (449). Although HCV is not efficiently transmitted sexually, persons at risk for infection through injection-drug use might seek care in STD treatment facilities, HIV counseling and testing facilities, correctional facilities, drug treatment facilities, and other public health settings where STD and HIV prevention and control services are available. Persons newly infected with HCV typically are either asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1-3 weeks after exposure. The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8-9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure. Chronic HCV infection develops in 70%-85% of HCV-infected persons; 60%-70% of chronically infected persons develop evidence of active liver disease. Most infected persons remain unaware of their infection because they are not clinically ill. However, infected persons serve as a source of transmission to others and are at risk for CLD and other HCV-related chronic diseases for decades after infection. HCV is transmitted through parenteral exposures to contaminated blood, usually through use of injection drugs (sharing of needles or works) and to a lesser extent through exposures in health-care settings as a consequence of inadequate infection-control practices. Transmission rarely follows receipt of blood, tissues, and organs from HCV-infected donors who were not identified during routine screening activities, which have been mandated in the United States since 1992. Occupational and perinatal exposures, although less efficient, also can result in transmission of HCV. Sexual transmission of HCV had been considered to occur rarely. However, recent data indicate that sexual transmission of HCV can occur, especially among HIV-infected persons. CDC surveillance data demonstrate that 10% of persons with acute HCV infection report contact with a known HCV-infected sex partner as their only risk for infection (437). Specific studies of HCV transmission between heterosexual or homosexual couples have yielded mixed results, but generally have found low but increased rates of HCV infection in partners of persons with HCV infection compared with those whose partners are not HCV-infected (450)(451)(452)(453)(454)(455). Several studies have revealed that risk increases commensurate with increasing numbers of sex partners among heterosexual persons (450,451,(456)(457)(458) and MSM (459)(460)(461)(462), especially if those partners are coinfected with HIV (459)(460)(461)(462)(463)(464)(465). Apparent sexual transmission of HCV has recently been reported among HIV-infected MSM in multiple European cities (464,465) and New York City (466). Common practices associated with these clusters of infection include serosorting (i.e., HIV-infected men having sex with one another), group sex, and the use of cocaine and other nonintravenous drugs during sex. All persons with HIV infection should undergo serologic testing for HCV at initial evaluation (130,131). HIV-infected MSM can also acquire HCV after initial screening. Liver function tests should be serially monitored for abnormalities that could be caused by acute viral hepatitis or medication toxicity. HIV-infected persons with new and unexplained increases in ALT should be tested for acute HCV infection. To ensure the detection of acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Acute hepatitis C is a reportable condition in 49 states, and matching viral hepatitis and HIV surveillance registries can facilitate early detection of social networks of HCV transmission among HIV-infected MSM. Suspected clusters of acute infection should be reported to the appropriate public health authorities. Unprotected sexual contact between HIV-infected partners can facilitate spread of HCV, as the virus can be recovered from the semen of men coinfected with HIV (467). Specific prevention practices (e.g., barrier precautions that limit contact with body fluids during sexual contact with other MSM) should be discussed with patients. # Diagnosis and Treatment Anti-HCV testing is recommended for routine screening of asymptomatic persons based on their risk for infection or based on a recognized exposure (see Hepatitis C, Prevention). For such persons, testing for HCV infection should include the use of an FDA-cleared test for antibody to HCV (i.e., immunoassay, EIA, or enhanced chemiluminescence imunoassay and, if recommended, a supplemental antibody test) (468). Persons counseled and tested for HCV infection and determined to be anti-HCV positive should be evaluated (by referral or consultation, if appropriate) for the presence of active infection, presence or development of CLD, and possible treatment. Nucleic acid testing, including reverse transcriptase polymerase chain reaction (RT-PCR) to detect HCV RNA, is necessary to confirm the diagnosis of current HCV infection, and an elevated ALT level is biochemical evidence of CLD. Combination therapy with pegylated interferon and ribavirin is the treatment of choice for patients with chronic hepatitis C. Providers should consult with specialists knowledgeable about management of hepatitis C infection because these experts remain cognizant of the latest advances in the field of antiviral therapy for acute and chronic hepatitis C. # Prevention No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure. Reducing the burden of HCV infection and disease in the United States requires implementation of both primary and secondary prevention activities. Primary prevention reduces or eliminates HCV transmission, whereas secondary prevention activities are aimed at reducing CLD and other chronic diseases in HCV-infected persons by first identifying them and then providing medical management and antiviral therapy, if appropriate. Most scientific evidence demonstrates that although HCV can be transmitted sexually, such transmission happens rarely. Because incident HCV has not been demonstrated to occur in heterosexual partner-pairs followed over time (452)(453)(454), condom use might not be necessary in such circumstances. However, heterosexual and homosexual persons, especially those with concurrent HIV infection or with more than one partner, should protect themselves and their partners against transmission of HCV, HBV, HIV, and other pathogens by use of male latex condoms. Condom use is especially important for HIV-infected men, who might spread HCV to other men though unprotected sexual activity (464)(465)(466). Providers in STD clinics and other primary-care settings should identify those persons who should be offered HCV counseling and testing. In STD clinics and other settings that serve large numbers of persons at high risk for bloodborne infections (e.g., correctional settings), the major risk factor necessitating screening for HCV infection is past or current injection of illegal drugs. Because both HCV and HIV are transmitted through injection-drug use, about one fourth of all HIV patients are also coinfected with HCV. For this reason, all persons with HIV infection should be offered HCV counseling and testing. Other risk factors for which routine HCV testing is recommended include: • having had a blood transfusion or solid organ transplant before July 1992; • having received clotting factor concentrates produced before 1987; • having been on long-term dialysis; and • having signs and symptoms of liver disease (e.g., abnormal ALT). Persons who test negative for anti-HCV who had an exposure previously should be reassured that they are not infected. Those who test positive for anti-HCV (see Diagnosis and Treatment) should be provided information regarding how to protect their liver from further harm; for instance, HCVpositive persons should be advised to avoid drinking alcohol and taking any new medicines (including OTC and herbals) without checking with their clinician. To reduce the risk for transmission to others, HCV-positive persons should be advised to 1) not donate blood, body organs, other tissue, or semen; 2) not share any personal items that might have blood on them (e.g., toothbrushes and razors); and 3) cover cuts and sores on the skin to keep the virus from spreading by blood or secretions. HCV-positive persons with one long-term, steady sex partner do not need to change their sexual practices. They should discuss the low but present risk for transmission with their partner and discuss the need for counseling and testing. HCV-positive women do not need to avoid pregnancy or breastfeeding. HCV-positive persons should be evaluated (by referral or consultation, if appropriate) to detect active HCV infection and the presence of CLD. Evaluation should involve testing for liver function, additional assessment of the severity of liver disease, possible treatment, and the determination for the need of hepatitis A and B vaccination. Regardless of test results, persons who use or inject illegal drugs should be counseled to stop using and injecting drugs and to enter and complete substance abuse treatment (including relapse prevention). Persons who continue to inject drugs despite counseling should be encouraged to take the following steps to reduce personal and public health risks: • never reuse or share syringes, water, or drug preparation equipment; • # Postexposure Follow-Up No PEP has been demonstrated to be effective against HCV. Testing to determine whether HCV infection has developed is recommended for health-care workers after percutaneous or permucosal exposures to HCV-positive blood. Children born to HCV-positive women also should be tested for HCV. Prompt identification of acute infection is important, because outcomes are improved when treatment is initiated earlier in the course of illness. # Special Considerations Pregnancy Routine testing for HCV infection is not recommended for all pregnant women. Pregnant women with a known risk factor for HCV infection should be offered counseling and testing. Patients should be advised that approximately six of every 100 infants born to HCV-infected woman become infected; this infection occurs predominantly during or near delivery, and no treatment or delivery method-such as caesarian section-has been demonstrated to decrease this risk. The risk is increased, however, by the presence of maternal HCV viremia at delivery and also is greater (2-3 times) if the woman is coinfected with HIV. HCV has not been shown to be transmitted through breast milk, although HCV-positive mothers should consider abstaining from breastfeeding if their nipples are cracked or bleeding. Infants born to HCV-positive mothers should be tested for HCV infection and, if positive, evaluated for the presence of CLD. # HIV Infection Because of the high prevalence of HIV/HCV coinfection and because of critical clinical management issues for coinfected persons, all persons with HIV infection should undergo serologic testing for HCV. Providers should be aware of the likelihood that HIV-infected MSM will acquire HCV after initial screening. Liver function tests should be serially monitored, and those persons with new and unexplained increases in ALT should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Because a small percentage of coinfected persons fail to acquire HCV antibodies, HCV RNA should be tested in HIV-positive persons with unexplained liver disease who are anti-HCV negative. The course of liver disease is more rapid in HIV/HCV coinfected persons, and the risk for cirrhosis is nearly twice that of persons with HCV infection alone. Coinfected persons receiving HIV antiviral regimens are now being treated for HCV after their CD4+ cell counts increase, optimizing their immune response. # Proctitis, Proctocolitis, and Enteritis Sexually transmitted gastrointestinal syndromes include proctitis, proctocolitis, and enteritis. Evaluation for these syndromes should include appropriate diagnostic procedures (e.g., anoscopy or sigmoidoscopy, stool examination, and culture). Proctitis is inflammation of the rectum (i.e., the distal 10-12 cm) that can be associated with anorectal pain, tenesmus, or rectal discharge. N. gonorrhoeae, C. trachomatis (including LGV serovars), T. pallidum, and HSV are the most common sexually transmitted pathogens involved. In patients coinfected with HIV, herpes proctitis can be especially severe. Proctitis occurs predominantly among persons who participate in receptive anal intercourse. Proctocolitis is associated with symptoms of proctitis, diarrhea or abdominal cramps, and inflammation of the colonic mucosa extending to 12 cm above the anus. Fecal leukocytes might be detected on stool examination, depending on the pathogen. Pathogenic organisms include Campylobacter sp., Shigella sp., Entamoeba histolytica, and LGV serovars of C. trachomatis. CMV or other opportunistic agents can be involved in immunosuppressed HIV-infected patients. Proctocolitis can be acquired by the oral route or by oral-anal contact, depending on the pathogen. Enteritis usually results in diarrhea and abdominal cramping without signs of proctitis or proctocolitis; it occurs among persons whose sexual practices include oral-anal contact. In otherwise healthy persons, Giardia lamblia is most frequently implicated. When outbreaks of gastrointestinal illness occur among social or sexual networks of MSM, clinicians should consider sexual transmission as a mode of spread and provide counseling accordingly. Among HIV-infected patients, gastrointestinal illness can be caused by other infections that usually are not sexually transmitted, including CMV, Mycobacterium avium-intracellulare, Salmonella sp., Campylobacter sp., Shigella sp., Cryptosporidium, Microsporidium, and Isospora. Multiple stool examinations might be necessary to detect Giardia, and special stool preparations are required to diagnose cryptosporidiosis and microsporidiosis. In addition, enteritis can be directly caused by HIV infection. When laboratory diagnostic capabilities are available, treatment decisions should be based on the specific diagnosis. Diagnostic and treatment recommendations for all enteric infections are beyond the scope of these guidelines. # Treatment for Proctitis Acute proctitis of recent onset among persons who have recently practiced receptive anal intercourse is usually sexually acquired (469,470). Such patients should be examined by anoscopy and should be evaluated for infection with HSV, N. gonorrhoeae, C. trachomatis, and T. pallidum. If an anorectal exudate is detected on examination or if polymorphonuclear leukocytes are detected on a Gram-stained smear of anorectal secretions, the following therapy should be prescribed while awaiting additional laboratory tests. # Recommended Regimen Ceftriaxone 250 mg IM PLUS Doxycycline 100 mg orally twice a day for 7 days Patients with suspected or documented herpes proctitis should be managed in the same manner as those with genital herpes (see Genital HSV Infections). If painful perianal ulcers are present or mucosal ulcers are detected on anoscopy, presumptive therapy should include a regimen for genital herpes and LGV. Appropriate diagnostic testing for LGV should be conducted in accordance with state or federal guidelines, and doxycycline therapy should be administered 100 mg orally twice daily for 3 weeks. For MSM, treatment for LGV proctitis/proctocolitis with 3 weeks of doxycycline in those with anorectal chlamydia and either 1) proctitis (as detected by proctoscopic examination and the presence of >10 white-blood cells upon high-power field examination of an anorectal smear specimen) or 2) HIV infection can be considered. # Follow-Up Follow-up should be based on specific etiology and severity of clinical symptoms. Reinfection might be difficult to distinguish from treatment failure. # Management of Sex Partners Partners of persons with sexually transmitted enteric infections should be evaluated for any diseases diagnosed in the index patient. # Ectoparasitic Infections Pediculosis Pubis Persons who have pediculosis pubis (i.e., pubic lice) usually seek medical attention because of pruritus or because they notice lice or nits on their pubic hair. Pediculosis pubis is usually transmitted by sexual contact. Reported resistance to pediculicides has been increasing and is widespread (471)(472)(473). Malathion can be used when treatment failure is believed to have resulted from drug resistance. The odor and long duration of application for malathion make it a less attractive alternative than the recommended pediculcides. Ivermectin has been successfully used to treat lice, but it has only been evaluated in studies involving a limited number of participants. # Recommended Regimens # other Management Considerations The recommended regimens should not be applied to the eyes. Pediculosis of the eyelashes should be treated by applying occlusive ophthalmic ointment to the eyelid margins twice a day for 10 days. Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the heat cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is not necessary. Patients with pediculosis pubis should be evaluated for other STDs. # Follow-Up Patients should be evaluated after 1 week if symptoms persist. Retreatment might be necessary if lice are found or if eggs are observed at the hair-skin junction. Patients who do not respond to one of the recommended regimens should be retreated with an alternative regimen. # Management of Sex Partners Sex partners that have had sexual contact with the patient within the previous month should be treated. Patients should abstain from sexual contact with their sex partner(s) until patients and partners have been treated and reevaluated to rule out persistent disease. # Special Considerations # Pregnancy Pregnant and lactating women should be treated with either permethrin or pyrethrins with piperonyl butoxide; lindane and ivermectin are contraindicated in pregnancy and lactating women. # HIV Infection Patients who have pediculosis pubis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. # Scabies The predominant symptom of scabies is pruritus, but sensitization to Sarcoptes scabiei occurs before pruritus begins. The first time a person is infested with S. scabiei, sensitization can take several weeks to develop. However, pruritus might occur within 24 hours after a subsequent reinfestation. Scabies in adults frequently is sexually acquired, although scabies in children usually is not. # Recommended Regimens Permethrin cream (5%) applied to all areas of the body from the neck down and washed off after 8-14 hours OR Ivermectin 200 µg/kg orally, repeated in 2 weeks # Alternative Regimen Lindane (1%) 1 oz. of lotion (or 30 g of cream) applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours Lindane is not recommended as first-line therapy because of toxicity (471). It should only be used as an alternative if the patient cannot tolerate other therapies or if other therapies have failed. Lindane should not be used immediately after a bath or shower, and it should not be used by persons who have extensive dermatitis, women who are pregnant or lactating, or children aged <2 years. Lindane resistance has been reported in some areas of the world, including parts of the United States (474). Seizures have occurred when lindane was applied after a bath or used by patients who had extensive dermatitis. Aplastic anemia after lindane use also has been reported (471,474). Permethrin is effective and safe and less expensive than ivermectin (471,474). One study demonstrated increased mortality among elderly, debilitated persons who received ivermectin, but this observation has not been confirmed in subsequent studies (475). # other Management Considerations Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the hot cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is unnecessary. # Crusted Scabies Crusted scabies (i.e., Norwegian scabies) is an aggressive infestation that usually occurs in immunodeficient, debilitated, or malnourished persons (476). Patients who are receiving systemic or potent topical glucocorticoids, organ transplant recipients, mentally retarded or physically incapacitated persons, HIV-infected or human T-lymphotrophic virus-1-infected persons, and persons with various hematologic malignancies are at risk for developing crusted scabies. Crusted scabies is associated with greater transmissibility than scabies. No controlled therapeutic studies for crusted scabies have been conducted, and the appropriate treatment remains unclear. Substantial risk for treatment failure might exist with a single topical scabicide or with oral ivermectin treatment. Combined treatment with a topical scabicide and repeated treatment with oral ivermectin 200 µg/kg on days 1, 2, 8, 9, and 15 are suggested. Additional treatment on days 22 and 29 might be required for severe cases. Ivermectin should be combined with the application of either 5% topical benzyl benzoate or 5% topical permethrin (full body application to be repeated daily for 7 days then 2 times weekly until release from care or cure). Lindane should be avoided because of the risks for neurotoxicity associated with both heavy applications and denuded skin. Fingernails should be closely trimmed to reduce injury from excessive scratching. # Follow-Up Patients should be informed that the rash and pruritus of scabies might persist for up to 2 weeks after treatment. Symptoms or signs that persist for >2 weeks can be attributed to several factors. Treatment failure can be caused by resistance to medication, although faulty application of topical scabicides also can contribute to persistence -patients with crusted scabies might have poor penetration into thick scaly skin and harbor mites in these difficult-to-penetrate layers. Particular attention must be given to the fingernails of these patients. Reinfection from family members or fomites can occur in the absence of appropriate contact treatment and washing of bedding and clothing. Even when treatment is successful and reinfection is avoided, symptoms can persist or worsen as a result of allergic dermatitis. Finally, the presence of household mites can cause symptoms to persist as a result of cross reactivity between antigens. Retreatment can be considered after 1-2 weeks for patients who are still symptomatic or if live mites are present. Treatment with an alternative regimen is recommended for persons who do not respond to the recommended treatment. # Management of Sex Partners and Household Contacts Sexual contacts and those that have had close personal or household contact with the patient within the preceding month should be examined and treated. # Management of outbreaks in Communities, nursing Homes, and other Institutional Settings Scabies outbreaks frequently occur in nursing homes, hospitals, residential facilities, and other communities. Control of an epidemic can only be achieved by treatment of the entire population at risk. Ivermectin can be considered in this setting, especially if treatment with topical scabicides fails. Epidemics should be managed in consultation with an infectious disease specialist. # Special Considerations Infants, Young Children, and Pregnant or Lactating Women Infants, young children, and pregnant or lactating women should not be treated with lindane; however, they can be treated with permethrin. Ivermectin is not recommended for pregnant or lactating patients, and the safety of ivermectin in children who weigh <15 kg has not been determined. # HIV Infection Patients who have uncomplicated scabies and also are infected with HIV should receive the same treatment regimens as those who are HIV negative. HIV-infected patients and others who are immunosuppressed are at increased risk for crusted scabies, for which ivermectin has been reported to be effective in noncontrolled studies involving only a limited number of participants. HIV-infected patients with crusted scabies should be managed in consultation with an infectious disease specialist. # Sexual Assault and STDs # Adults and Adolescents The recommendations in this report are limited to the identification, prophylaxis, and treatment of STDs and conditions commonly identified in the management of such infections. The documentation of findings, collection of nonmicrobiologic specimens for forensic purposes, and management of potential pregnancy or physical and psychological trauma are beyond the scope of this report. Examinations of survivors of sexual assault should be conducted by an experienced clinician in a way that minimizes further trauma to the survivor. The decision to obtain genital or other specimens for STD diagnosis should be made on an individual basis. Care systems for survivors should be designed to ensure continuity (including timely review of test results), support adherence, and monitor for adverse reactions to any therapeutic or prophylactic regimens prescribed at initial examination. Laws in all 50 states strictly limit the evidentiary use of a survivor's previous sexual history, including evidence of previously acquired STDs, as part of an effort to undermine the credibility of the survivor's testimony. Evidentiary privilege against revealing any aspect of the examination or treatment also is enforced in most states. Although it rarely occurs, STD diagnoses might later be accessed, and the survivor and clinician might opt to defer testing for this reason. While collection of specimens at initial examination for laboratory STD diagnosis gives the survivor and clinician the option to defer empiric prophylactic antimicrobial treatment, compliance with follow up visits is traditionally poor (477,478). Among sexually active adults, the identification of an STD might represent an infection acquired prior to the assault, and therefore might be more important for the psychological and medical management of the patient than for legal purposes. Trichomoniasis, BV, gonorrhea, and chlamydial infection are the most frequently diagnosed infections among women who have been sexually assaulted. Such conditions are relatively prevalent, and the presence after an assault does not necessarily imply acquisition during the assault. However, a postassault examination presents an important opportunity to identify or prevent STDs. Chlamydial and gonococcal infections in women are of particular concern because of the possibility of ascending infection. In addition, HBV infection can be prevented by postexposure administration of hepatitis B vaccine. Reproductive-aged female survivors should be evaluated for pregnancy, if appropriate. # Evaluating Adults and Adolescents for Sexually Transmitted Diseases Initial Examination An initial examination might include the following procedures: • NAATs for C. trachomatis and N. gonorrhoeae. These tests are preferred for the diagnostic evaluation of sexual assault victims, regardless of the sites of penetration or attempted penetration (197). • Wet mount and culture or point-of-care testing of a vaginal-swab specimen for T. vaginalis infection. The wet mount also should be examined for evidence of BV and candidiasis, especially if vaginal discharge, malodor, or itching is evident. • A serum sample for immediate evaluation for HIV infection, hepatitis B, and syphilis. Decisions to perform these tests should be made on an individual basis. # Follow-Up Examinations After the initial postassault examination, follow-up examinations provide an opportunity to 1) detect new infections acquired during or after the assault; 2) complete hepatitis B vaccination, if indicated; 3) complete counseling and treatment for other STDs; and 4) monitor side effects and adherence to postexposure prophylactic medication, if prescribed. Examination for STDs can be repeated within 1-2 weeks of the assault. Because infectious agents acquired through assault might not have produced sufficient concentrations of organisms to result in positive test results at the initial examination, testing can be repeated during the follow-up visit, unless prophylactic treatment was provided. If treatment was provided, testing should be conducted only if the survivor reports having symptoms. If treatment was not provided, follow-up examination should be conducted within 1 week to ensure that results of positive tests can be discussed promptly with the survivor and that treatment is provided. Serologic tests for syphilis and HIV infection can be repeated 6 weeks, 3 months, and 6 months after the assault if initial test results were negative and infection in the assailant could not be ruled out (see Sexual Assault and STDs, Risk for Acquiring HIV Infection). # Prophylaxis Compliance with follow-up visits is poor among survivors of sexual assault (477,478). As a result, routine preventive therapy after a sexual assault should be encouraged. The following prophylactic regimen is suggested as preventive therapy: • Postexposure hepatitis B vaccination, without HBIG. This vaccine should be administered to sexual assault survivors at the time of the initial examination if they have not been previously vaccinated. Follow-up doses of vaccine should be administered 1-2 and 4-6 months after the first dose. For those requiring alternative treatments, refer to the specific sections in this report relevant to the specific agent. The efficacy of these regimens in preventing infections after sexual assault has not been evaluated. Clinicians should counsel patients regarding the possible benefits and toxicities associated with these treatment regimens; gastrointestinal side effects can occur with this combination. # other Management Considerations At the initial examination and, if indicated, at follow-up examinations, patients should be counseled regarding 1) symptoms of STDs and the need for immediate examination if symptoms occur and 2) abstinence from sexual intercourse until STD prophylactic treatment is completed. # Risk for Acquiring HIV Infection HIV seroconversion has occurred in persons whose only known risk factor was sexual assault or sexual abuse, but the frequency of this occurrence is probably low. In consensual sex, the risk for HIV transmission from vaginal intercourse is 0.1%-0.2% and for receptive rectal intercourse, 0.5%-3% (479). The risk for HIV transmission from oral sex is substantially lower. Specific circumstances of an assault (e.g., bleeding, which often accompanies trauma) might increase risk for HIV transmission in cases involving vaginal, anal, or oral penetration. Site of exposure to ejaculate, viral load in ejaculate, and the presence of an STD or genital lesions in the assailant or survivor also might increase the risk for HIV. Children might be at higher risk for transmission, because the sexual abuse of children is frequently associated with multiple episodes of assault and might result in mucosal trauma (see Sexual Assault or Abuse of Children). Postexposure therapy with zidovudine was associated with a reduced risk for acquiring HIV in a study of health-care workers who had percutaneous exposures to HIV-infected blood (480). On the basis of these results and the results of animal studies, PEP has been recommended for health-care workers who have occupational exposures to HIV (446). These findings have been extrapolated to other types of HIV exposure, including sexual assault (78). If HIV exposure has occurred, initiation of PEP as soon as possible after the exposure likely increases benefit. Although a definitive statement of benefit cannot be made regarding PEP after sexual assault, the possibility of HIV exposure from the assault should be assessed at the time of the postassault examination. The possible benefit of PEP in preventing HIV infection also should be discussed with the assault survivor if the assault poses a risk for HIV exposure. Several factors impact the medical recommendation for PEP and affect the assault survivor's acceptance of that recommendation, including 1) the likelihood of the assailant having HIV, 2) any exposure characteristics that might increase the risk for HIV transmission, 3) the time elapsed after the event, and 4) the potential benefits and risks associated with the PEP (78). Determination of the assailant's HIV status at the time of the assault examination usually in not possible. Therefore, the health-care provider should assess any available information concerning 1) characteristics and HIV risk behaviors of the assailant(s) (e.g., a man who has sex with other men and persons who use injection drugs or crack cocaine), 2) local epidemiology of HIV/AIDS, and 3) exposure characteristics of the assault. When an assailant's HIV status is unknown, factors that should be considered in determining whether an increased risk for HIV transmission exists include 1) whether vaginal or anal penetration occurred; 2) whether ejaculation occurred on mucous membranes; 3) whether multiple assailants were involved; 4) whether mucosal lesions are present in the assailant or survivor; and 5) any other characteristics of the assault, survivor, or assailant that might increase risk for HIV transmission. If PEP is offered, the following information should be discussed with the patient: 1) the unproven benefit and known toxicities of antiretrovirals; 2) the importance of close follow-up; 3) the benefit of adherence to recommended dosing; and 4) the necessity of early initiation of PEP to optimize potential benefits (i.e., as soon as possible after and up to 72 hours after the assault). Providers should emphasize that PEP appears to be well-tolerated in both adults and children and that severe adverse effects are rare (481)(482)(483). Clinical management of the survivor should be implemented according to the following guidelines (78). Specialist consultation on PEP regimens is recommended if HIV exposure during the assault was possible and if PEP is being considered. The sooner PEP is initiated after the exposure, the higher the likelihood that it will prevent HIV transmission if HIV exposure occurred; however, distress after an assault also might prevent the survivor from accurately weighing exposure risks and benefits of PEP and from making an informed decision to start such therapy. If use of PEP is judged to be warranted, the survivor should be offered a 3-5-day supply of PEP, and a follow-up visit should be scheduled several days later to allow for additional counseling. # Recommendations for Postexposure Assessment of Adolescent and Adult Survivors Within 72 Hours of Sexual Assault § § • Assess risk for HIV infection in the assailant. • Evaluate characteristics of the assault event that might increase risk for HIV transmission. • Consult with a specialist in HIV treatment, if PEP is being considered. • If the survivor appears to be at risk for HIV transmission from the assault, discuss antiretroviral prophylaxis, including toxicity and lack of proven benefit. • If the survivor chooses to start antiretroviral PEP (78), provide enough medication to last until the next return visit; reevaluate the survivor 3-7 days after initial assessment and assess tolerance of medications. • If PEP is started, perform CBC and serum chemistry at baseline (initiation of PEP should not be delayed, pending results). • Perform HIV antibody test at original assessment; repeat at 6 weeks, 3 months, and 6 months. # Sexual Assault or Abuse of Children Recommendations in this report are limited to the identification and treatment of STDs. Management of the psychosocial aspects of the sexual assault or abuse of children is beyond the scope of these recommendations. The identification of sexually transmissible agents in children beyond the neonatal period suggests sexual abuse. The significance of the identification of a sexually transmitted agent in such children as evidence of possible child sexual abuse varies by pathogen. Postnatally acquired gonorrhea; syphilis; and nontransfusion, nonperinatally acquired HIV are usually diagnostic of sexual abuse. Sexual abuse should be suspected when genital herpes is diagnosed. The investigation of sexual abuse among children who have an infection that could have been transmitted sexually should be conducted in compliance with recommendations by clinicians who have experience and training in all elements of the evaluation of child abuse, neglect, and assault. The social significance of an infection that might have been acquired sexually and the recommended action regarding reporting of suspected child sexual abuse varies by the specific organism, as do the recommendations regarding reporting of suspected child sexual abuse (Table 6). In all cases in which an STD has been diagnosed in a child, efforts should be made to detect evidence of sexual abuse, including conducting diagnostic testing for other commonly occurring STDs (484)(485)(486). The general rule that sexually transmissible infections beyond the neonatal period are evidence of sexual abuse has exceptions. For example, rectal or genital infection with C. trachomatis among young children might be the result of perinatally acquired infection and has, in some cases, persisted for as long as 2-3 years. Genital warts have been diagnosed in children who have been sexually abused, but also in children who have no other evidence of sexual abuse (487,488). BV has been diagnosed in children who have been abused, but its presence alone does not prove sexual abuse. In addition, most HBV infections in children result from household exposure to persons who have chronic HBV infection. The possibility of sexual abuse should be strongly considered if no conclusive explanation for nonsexual transmission of an STD can be identified. • A suspected assailant is known to have an STD or to be at high risk for STDs (e.g., has multiple sex partners or a history of STDs). • A sibling or another child or adult in the household or child's immediate environment has an STD. • The patient or parent requests testing. • Evidence of genital, oral, or anal penetration or ejaculation is present. If a child has symptoms, signs, or evidence of an infection that might be sexually transmitted, the child should be tested for other common STDs before the initiation of any treatment that could interfere with the diagnosis of those other STDs. Because of the legal and psychosocial consequences of a false-positive diagnosis, only tests with high specificities should be used. The potential benefit to the child of a reliable diagnosis of an STD justifies deferring presumptive treatment until specimens for highly specific tests are obtained by providers with experience in the evaluation of sexually abused and assaulted children. The scheduling of an examination should depend on the history of assault or abuse. If the initial exposure was recent, the infectious agents acquired through the exposure might not have produced sufficient concentrations of organisms to result in positive test results. A follow-up visit approximately 2 weeks after the most recent sexual exposure can include a repeat physical examination and collection of additional specimens. To allow sufficient time for antibodies to develop, another follow-up visit approximately 12 weeks after the most recent sexual exposure might be necessary to collect sera. A single examination might be sufficient if the child was abused for an extended period and if a substantial amount of time elapsed between the last suspected episode of abuse and the medical evaluation. The following recommendations for scheduling examinations serve as a general guide. The exact timing and nature of follow-up examinations should be determined on an individual basis and should be performed to minimize the possibility for psychological trauma and social stigma. Compliance with follow-up appointments might be improved when law enforcement personnel or child protective services are involved. # Initial and 2-Week Follow-Up Examinations During the initial examination and 2-week followup examination (if indicated), the following should be performed. • Visual inspection of the genital, perianal, and oral areas for genital discharge, odor, bleeding, irritation, warts, and ulcerative lesions. The clinical manifestations of some STDs are different in children than in adults. For example, typical vesicular lesions might not be present in the presence of HSV infection. Because this infection can be indicative of sexual abuse, specimens should be obtained from all vesicular or ulcerative genital or perianal lesions compatible with genital herpes and then sent for viral culture. • Specimen collection for N. gonorrhoeae culture from the pharynx and anus in boys and girls, the vagina in girls, and the urethra in boys. Cervical specimens are not recommended for prepubertal girls. For boys with a urethral discharge, a meatal specimen discharge is an adequate substitute for an intraurethral swab specimen. (197,486). Consultation with an expert is necessary before using NAATs in this context to minimize the possibility of cross-reaction with nongonococcal Neisseria species and other commensals (e.g., N. meningitidis, N. sicca, N. lactamica, N. cinerea, and Moraxella catarrhalis). NAATs can be used as an alternative to culture with vaginal specimens or urine from girls, whereas culture remains the preferred method for urethral specimens or urine from boys and for extragenital specimens (pharynx and rectum) from all children. All positive specimens should be retained for additional testing. HIV infection has been reported in children whose only known risk factor was sexual abuse. Serologic testing for HIV infection should be considered for abused children. The decision to test for HIV infection should be made on a case-bycase basis, depending on the likelihood of infection among assailant(s). Although data are insufficient concerning the efficacy and safety of PEP among both children and adults, treatment is well tolerated by infants and children (with and without HIV infection), and children have a minimal risk for serious adverse reactions because of the short period recommended for prohylaxis. (78,138). In considering whether to offer antiretroviral PEP, health-care providers should consider whether the child can be treated soon after the sexual exposure (i.e., within 72 hours), the likelihood that the assailant is infected with HIV, and the likelihood of high compliance with the prophylactic regimen. The potential benefit of treating a sexually abused child should be weighed against the risk for adverse reactions. If antiretroviral PEP is being considered, a provider specializing in evaluating or treating HIV-infected children should be consulted. # Recommendations for HIV-Related Postexposure Assessment of Children within 72 Hours of Sexual Assault • Review HIV/AIDS local epidemiology and assess risk for HIV infection in the assailant. • Evaluate circumstances of assault that might affect risk for HIV transmission. • Consult with a specialist in treating HIV-infected children if PEP is considered. • If the child appears to be at risk for HIV transmission from the assault, discuss PEP with the caregiver(s), including its toxicity and unknown efficacy. • If caregivers choose for the child to receive antiretroviral PEP (78,142,489), provide enough medication to last until the return visit at 3-7 days after the initial assessment, at which time the child should be reevaluated and tolerance of medication assessed; dosages should not exceed those for adults. • Perform HIV antibody test at original assessment, 6 weeks, 3 months, and 6 months. # Follow-Up Examination After Assault In circumstances in which transmission of syphilis, HIV, or hepatitis B is a concern but baseline tests are negative, an examination approximately 6 weeks, 3 months, and 6 months after the last suspected sexual exposure is recommended to allow time for antibodies to infectious agents to develop. In addition, results of HBsAg testing must be interpreted carefully, because HBV can be transmitted nonsexually. Decisions regarding which tests should be performed must be made on an individual basis. # Presumptive Treatment The risk of a child acquiring an STD as a result of sexual abuse or assault has not been well studied. Presumptive treatment for children who have been sexually assaulted or abused is not recommended because 1) the incidence of most STDs in children is low after abuse/assault, 2) prepubertal girls appear to be at lower risk for ascending infection than adolescent or adult women, and 3) regular follow-up of children usually can be ensured. However, some children or their parent(s) or guardian(s) might be concerned about the possibility of infection with an STD, even if the risk is perceived to be low by the health-care provider. Such concerns might be an appropriate indication for presumptive treatment in some settings and might be considered after all specimens for diagnostic tests relevant to the investigation have been collected. # Diagnostic Considerations # Prevention Two products have been approved for hepatitis B prevention: hepatitis B immune globulin (HBIG) and hepatitis B vaccine (3,4). HBIG provides temporary (i.e., 3-6 months) protection from HBV infection and is typically used as PEP either as an adjunct to hepatitis B vaccination in previously unvaccinated persons or alone in persons who have not responded to vaccination. HBIG is prepared from plasma known to contain high concentrations of anti-HBs. The recommended dose of HBIG is 0.06 mL/kg. Hepatitis B vaccine contains HBsAg produced in yeast by recombinant DNA technology and provides protection from HBV infection when used for both pre-exposure vaccination and PEP. The two available monovalent hepatitis B vaccines for use in adolescents and adults are Recombivax HB (Merck and Co., Inc., Whitehouse Station, New Jersey) and Engerix-B (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania). A combination vaccine (hepatitis A and hepatitis B) for use in * Combined hepatitis A and hepatitis B vaccine. This vaccine is recommended for persons aged ≥18 years who are at increased risk for both hepatitis B and hepatitis A virus infections. † Recombinant hepatitis B surface antigen protein dose, in micrograms. § Pediatric formulation administered on a 3-dose schedule; higher doses might be more immunogenic, but no specific recommendations have been made. ¶ Adult formulation administered on a 2-dose schedule. ** Dialysis formulation administered on a 3-dose schedule at 0, 1, and 6 months. † † Two 1.0-mL doses of the adult formulation administered at one site on a 4-dose schedule at 0, 1, 2, and 6 months. # Reporting All U.S. states and territories have laws that require the reporting of child abuse. Although the exact requirements differ by state, if a health-care provider has reasonable cause to suspect child abuse, a report must be made. Health-care providers should contact their state or local child-protection service agency regarding child-abuse reporting requirements in their states. # Evaluating Children for Sexually Transmitted Diseases Examinations of children for sexual assault or abuse should be conducted in a manner designed to minimize pain and trauma to the child. Collection of vaginal specimens in prepubertal children can be very uncomfortable and should be performed by an experienced clinician to avoid psychological and physical trauma to the child. The decision to obtain genital or other specimens from a child to conduct an STD evaluation must be made on an individual basis. The following situations place children at high-risk for STDs and constitute a strong indication for testing. • The child has or has had symptoms or signs of an STD or of an infection that can be sexually transmitted, even in the absence of suspicion of sexual abuse. Among the signs that are associated with a confirmed STD diagnosis are vaginal discharge or pain, genital itching or odor, urinary symptoms, and genital ulcers or lesions.	None	None
a9a2ea674f73082dd171b90b3708dac2024a53e1	cdc	None	# EXECUTIVE SUMMARY According to the World Health Organization (WHO), guidelines are "documents that contain recommendations about health interventions, whether they be clinical, public health, or policy recommendations." Recommendations provide information about what policy makers, health care providers, or patients should do. Recommendations imply choices between different interventions that have an impact on health and that have ramifications for the use of resources." The Centers for Disease Control and Prevention (CDC) is a leader in developing public health guidelines. Ideally, CDC guidelines are developed by a group of multidisciplinary stakeholders, based on evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. CDC guidelines should be clear, valid, transparent, reliable, accurate, and applicable. Although the term "recommendations" may be used more narrowly to identify specific actions and the term "guidelines" may more broadly refer to the umbrella under which multiple recommendations for action are provided, we use the terms guidelines and recommendations interchangeably in this document. Some guidelines are developed by federally-chartered advisory committees like the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC) and are subsequently accepted and issued by CDC. Other guidelines are developed under the initiative of CDC programs in collaboration with experts in the field. The most frequent CDC publication venue is the Morbidity and Mortality Weekly Report (MMWR), but other outlets mechanisms such as peerreviewed journals and agency publications are also used. Although CDC guidelines have garnered wide acceptance among stakeholders and partners, the rationale and development process is not always clear to the user. Because of the breadth of public health topics and audiences, adopting a single approach to developing guidelines at CDC poses a significant challenge. As a result of this challenge, we have refrained from recommending a single methodological approach for development and reporting of all CDC guidelines (although guidelines authors are encouraged to familiarize themselves with methods already used at CDC). Yet CDC guidelines should meet certain standards. This primer provides development and reporting standards to improve the transparency, validity, and reliability, of CDC guidelines and recommendations. Development standards include: - Identify the public health problem on a given topic, need for new or revised guidelines, and required resources for development - Involve knowledgeable, impartial, and representative participants in the process - Minimize and disclose competing interests among participants - Involve and consult affected organizations - Include a written charge to the development work group - Obtain the evidence preferably using systematic reviews - Use evidence-based frameworks and decision-making rules - Involve an explicit scientific quality and policy control process The above standards, along with reporting standards, are provided and covered in detail in Section 9. By following development and reporting standards, guidelines developers can improve the use of evidence, minimize bias, and enhance quality and consistency in reporting. Although occasionally some of these standards cannot be followed, most CDC guidelines will at least fulfill the intent of the standards. The reader should be able to understand the methods used to develop the guidelines, how the evidence was selected and assessed, and how the evidence led to the recommendations. Meeting these standards will also support CDC programs in developing guidelines that can be trusted by the public health community and the public. By improving the rigor and transparency of methods used to develop CDC's guidelines, criteria-based guideline clearinghouses will more readily adopt and publish CDC guidance, enhancing visibility and use. #CDC Guidelines and Recommendations Work Group July 2012 INTRODUCTION "Guidelines are documents that contain recommendations about health interventions whether they be clinical, public health, or policy recommendations." Recommendations provide information about what policy makers, health care providers, or patients should do. Recommendations imply choices between different interventions that have an impact on health and that have ramifications for the use of resources." The Centers for Disease Control and Prevention (CDC) is a leader in developing public health guidelines. Ideally, CDC guidelines are developed by a group of multidisciplinary stakeholders, are based on evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. CDC guidelines should be clear, valid, transparent, reliable, and applicable. # Purpose Guidelines developed at CDC cover a wide range of disciplines and needs. Guidelines may go from providing recommendations for interventions to increase physical activity to the treatment of pandemic influenza. Often, CDC guidelines address multiple stakeholders and provide recommendations for individuals, groups, and communities. Audiences may include health department staff, coordinating partner services, physicians looking for information on new treatments, labs looking for screening tests, and individuals looking for prevention programs and services. Recommendations in CDC guidelines may cover surveillance practices, program implementation, or even policy interventions. Nuances exist associated with the selection of a public health topic. For example, a particular public health topic selected for guideline development may require the use of federally-chartered advisory committees. The selection of a public health topic will affect the type and extent of the evidence of effectiveness. Or, addressing a public health topic may include policy-based interventions that could be socially or politically sensitive in nature. Diverse audiences and the nuances of public health topics pose challenges to recommending a common approach for developing and reporting guidelines. Content and format may vary with the needs of each group of users. Additionally, diverse audiences may have access to guidelines of other organizations containing recommendations that may be inconsistent with CDC recommendations. This diversity in audiences, topics, and communication formats poses particular challenges for ensuring the clarity and acceptance of CDC guidelines. Because of all these considerations, a standardized approach to guideline development is not recommended in this primer. Instead, the primer provides a series of critical elements and standards that can be used in CDC guideline development. # Audience This primer is for CDC staff, contract review teams, CDC federal advisory committees, and CDC partners and stakeholders. Guideline developers sponsored or co-sponsored by CDC will find the primer particularly useful, as will anyone involved in the clearance or publication of guidelines. Use of minimum standards in guideline development and reporting will improve guideline quality and facilitate the clearance and publication processes. # Scope Because of the difficulty in recommending a standardized approach for CDC guideline development, this primer is not a how-to manual. Instead, it covers elements common to the development of all guidelines, shows how standards can be integrated into the development process, and provides critical ways to improve CDC guidelines. This primer supplements the information outlined in CDC Guidelines: Improving the Quality (1996). 2. # GUIDELINES, POLICIES, AND OTHER CONSIDERATIONS Developing guidelines entails making many front-end decisions that, in the end, will save time and money. Early considerations about the need, evidence, and current methods for guideline development can assist developers in clarifying terms, concepts, and principles early on in the development process. We suggest guideline developers consider the following questions before beginning development of guidelines: - What are public health guidelines? - What are the differences between guidelines and policies? - Is there a need for new guidelines? - What type of evidence is available? - Who develops guidelines? Answers to these questions will guide decision-making at the onset of guideline development. This section will remind developers of organizations that can be sources of technical knowledge, methods, procedures, tool kits, and software. # Guidelines, Recommendations, and Guidance Although the term "recommendations" may be used more narrowly to identify specific actions and the term "guidelines" may be used more broadly to refer to the umbrella under which multiple recommendations are provided, we use the terms guidelines and recommendations interchangeably in this document. Typically, public health guidelines are developed by a group of multidisciplinary stakeholders, use evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. Guidelines should be clear, valid, transparent, reliable, and applicable. These terms are defined in Section 10. Although the term "guidance" is sometimes used to indicate a "less-direct type of advice," guidelines authors should be aware that the term "guidance document" is used by regulatory agencies for specific types of documents and that the Office of Management and Budget (OMB) has issued policies and procedures for developing guidance documents. Therefore, be aware that the use of the term "guidance" could lead to confusion with regulatory guidance documents, and consider using other terms. # Types of Guidelines Guidelines cover the full range of public health areas represented at CDC. Guidelines may be developed across the 10 essential public health services. For example, guidelines might be developed for monitoring health status, mobilizing community partnerships, selecting and implementing programs and policies, and evaluating health services. The target audience can be wide and varied, including, for example, clinicians, public health professionals, or policy makers. The evidence base for guidelines may be robust or sparse. Sometimes CDC must develop guidelines when evidence is lacking. In such cases, guidelines can be developed based on expert judgment and historical knowledge about the intervention in similar or different settings. Expert judgment may be based on experience and observations and on extrapolation of evidence from different settings or similar interventions. When guidelines on a specific topic are first developed, they may be called "initial" guidelines. Initial guidelines may be limited in scope. For example, a guideline might focus on recognition and initial assessment and less on differential diagnosis, management, or treatment issues after diagnosis. The guideline to recognize and assess early Alzheimer's disease produced by the Agency for Health Care Research and Quality (AHRQ) is an example of an initial guideline. "Comprehensive" or final guidelines (also called "full guidelines" by WHO) are broader in scope and are developed by a wide range of stakeholders, usually with participation from several agencies, academia, nongovernmental organizations, and communities. Such guidelines provide full consideration of a disease, condition, environmental emergency, or natural disaster. Comprehensive guidelines usually include many aspects related to the disease or condition including surveillance, detection, control, treatment, and prevention. An example of comprehensive guidelines is the Guidelines for Foodborne Disease Outbreak Response, published by the Council to Improve Foodborne Outbreak Response. "Interim" guidelines are those developed in response to emergencies or to rapid increases in cases of a disease or condition. These guidelines are labeled "interim" to clarify that such guidelines were developed using less thorough processes or were based on tentative or emerging data. WHO refers to such guidelines as "rapid" guidelines and their development period may vary between a few weeks and a couple of months. An example of an interim guideline is the CDC guideline for the use of face masks and respirators during an influenza pandemic. Initial and interim guidelines are often updated when new evidence is available. "Supplemental" guidelines update topics considered in previous guidelines or cover new topics. These guidelines-which may be initial, interim, or comprehensive-supplement previous guidelines with new or revised information. Examples of supplemental guidelines are the CDC updated guidelines for management of occupational exposures to HIV. # Guidelines and Policies Guidelines, unlike some types of policies, are not mandatory. In health care and public health, guidelines are not meant to enforce but rather to recommend programs or practices based on the best evidence available. Often, however, CDC and others' guidelines become "the standards of practice," unintentionally acquiring the force of policy. The adoption of a set of guidelines can affect an entire organization. Whatever the organization (for-profits, nonprofits, public health departments, or federal government agencies), guidelines provide information for decisionmaking. Implementation of guidelines might improve organization effectiveness and efficiency. Policies, on the other hand, are laws, regulations, procedures, administrative actions, incentives, disincentives (e.g. taxes, fines, fees, or other pecuniary or non-pecuniary penalties) or voluntary practices of government and other institutions. Many policies are enforceable and their implementation is frequently reflected in resource allocations. Policies also can be maps of actions that guide an organization or group in decision-making. Policies frequently address the impacts of decision-making on population health, the society, the economy, and the environment. Mandatory policies are similar to executive orders or decrees. Occasionally, policy making follows the issuing of guidelines. When this occurs, the policies function like road maps and are essential to implementing the guidelines. Increasingly, policies are being used as tools to improve public health efforts. Although guidelines typically support programmatic interventions or health practices, guidelines can also aid the use of policy to improve public health efforts (e.g., guidelines for policies on nutrition standards for food in schools; guidelines for policy on alcohol-impaired driving such as ignition interlocks, expanded use of sobriety checkpoints, and minimum drinking age). # Establishing the Need for New Guidelines Guideline developers should make sure that new guidelines are needed before guideline planning is started. Establishing the need for new guidelines entails assessing the public health need for systematic advice and identifying the existence of current or past guidelines on the same topic covering the same population and settings. This process also entails determining the existence of guidelines that need to be updated because of new research findings. The following questions may help guideline developers assess the need for new guidelines: - Are guidelines needed to sufficiently address the public health threat under consideration? - Why are guidelines needed now? - Are there new interventions that require new guidelines? - Have there been changes in the disease or pattern of the disease? - Have there been changes in the guideline audience? - Is there a new role for the CDC? - Is there sufficient new evidence available to develop the guidelines? - Are there current guidelines on the same topic published by other authorities that might be used instead? - If other guidelines exist, do they apply to the same target cohort, settings, and demographics? - Are there sufficient funding and resources available to support the planning, development, and dissemination of these guidelines? # Use of Evidence in Guidelines Guidelines should be developed using the best available evidence of effectiveness of preselected outcomes. "Evidence" is knowledge gained from scientific research that is interpreted in the context of public health practitioner experience, conditions of intervention implementation, and experience of the population targeted. When research evidence is available, systematic reviews can inform guideline development. Different types of research evidence exist for inclusion in systematic reviews including evidence from randomized controlled trials, observational studies (e.g., quasi-experimental and time-series studies), and qualitative studies. Keep in mind, however, that guidelines extend beyond systematic reviews in important ways. Although systematic reviews provide information about the scientific evidence behind an intervention ("this works"), guideline developers combine this information with expert judgment, information about harms and benefits, economic efficiency, and values and preferences to inform public health or clinical practice in guideline form ("this should be done"). The quality and strength of the evidence varies across areas of public health. Sometimes, practitioners in the field are needed to provide key pieces of information that can't be culled from the empirical literature. A practitioner perspective can be critical to understanding how interventions are carried out and which populations are targeted. # Organizations That Develop Guidelines Many organizations produce guidelines, develop databases of existing guidelines, or provide methods, tools, and training for developing guidelines. Some organizations, such as the AHRQ National Guidelines Clearinghouse, act as repositories of national guidelines. The clearinghouse has registered 2,373 clinical practice guidelines to date, produced by 285 organizations. Other organizations, like the Cochrane Collaboration and Campbell Collaboration, also act as repositories of their own accredited systematic reviews but also offer methods and electronic tools for conducting systematic reviews by independent groups in academia or government. The at the University of York (CRD) develop guidelines internally or under contract. The Canadian Medical Association provides a database of guidelines with a summary listing methods and development processes. In the United States, the U.S. Preventive Services Task Force (USPSTF) and The Community Preventive Services Task Force (CPSTF) develop recommendations under the umbrella authorities known as the Guide to Clinical Preventive Services (Clinical Guide) and Guide to Community Preventive Services (Community Guide), respectively. The Institute of Medicine (IOM) has published standards for developing clinical practice guidelines. CDC produces guidelines developed at the program level. Such guidelines are often developed in consultation with field experts and are typically published in the MMWR. CDC also works with advisory committees that develop guidelines like the ACIP and HICPAC. # GUIDELINE DEVELOPMENT PLANNING Guideline planning is critical to setting the stage for methods, processes, and procedures used during the development phase. Early planning will make the development process more fluid and the end product more transparent. Planning activities include: a) identifying the audience, b) identifying contributors and their roles, c) deciding on evidence and outcomes, d) developing the guideline logic framework, e) planning for guideline dissemination, implementation, and evaluation, and g) planning for guideline updates. # Identifying the Audience Public health guidelines often have diverse audiences (e.g., practitioners, policy makers, health care businesses, government agencies). Umbrella guidelines may try to balance information needs for these audiences. Audiences can be identified by addressing the following questions: - For whom are the guidelines or recommendations being developed? - To whom are the guidelines and recommendations being addressed? - To what extent are these guidelines going to assist them? Companion or support materials may further distill and interpret guideline content for specific audiences. For this reason, developers should distinguish between the actual guidelines and the support materials that will reference the guidelines. Supporting materials might include training materials, fact sheets, applications, pocket cards, algorithms, etc. Supporting materials differ from actual guidelines and require various development and dissemination methods. Developers therefore need to decide beforehand whether supporting materials will be part of the guideline development process or they will be developed after the primary guideline document is complete. # Identifying Contributors and Their Roles Major efforts to develop guidelines typically involve at least two distinct groups: a guideline steering committee (GSC) and a technical development group (TDG). Other groups might be needed, such as a dissemination group. Typically, the GSC will be comprised of CDC personnel. The function of the GSC is overseeing the guideline development process. GSC functions have been adapted from those proposed by NICE and might include: - Select members of the TDG (see below) - Draft standard operating procedures for the TDG - Define the goals and elements of the proposed guidelines - Approve the methods to synthesize the evidence and develop the recommendations - Determine the sources of evidence - Conduct a systematic search for evidence - Select and review the evidence - Summarize the evidence and specific outcomes - Assess the quality of the evidence - Present to the GSC the summary of the evidence - Provide the GSC with a preliminary assessment of the recommendations' strength - Provide the GSC with a preliminary draft of recommendations to the GSC - Draft the guidelines with members of the GSC - Discuss and incorporate suggestions from external reviewers - Write the final version of the guidelines If the guidelines are being developed with the help of other authorities and task forces, members of these groups might participate in the GSC and provide input during the development process. Stakeholders may also participate in the development of the guidelines through the GSC. Stakeholders are groups whose activities could be affected by implementation of the guidelines or who have legitimate reasons for providing input. Inclusion of stakeholders in developing guidelines will ensure that a) the right issues are identified and b) there is early buy-in and a better chance for early adoption of the guidelines. Inclusion of liaison groups will ensure that guidelines address the needs of the collaborating agencies and can increase adoption among communities, patients, and individuals in at-risk groups. Liaison groups may include representatives from affected populations, patients, or at-risk groups. Frequently, CDC collaborates with international organizations or Ministers of Health in developing joint guidelines and recommendations. For joint guideline documents, CDC developers should work with collaborators to encourage the use of evidence-based frameworks in developing guidelines. In developing a panel with outside members, whether they are stakeholders, liaisons, subject matter experts or members of international organizations, one might unknowingly construct a committee that is subject to the regulations of the Federal Advisory Committee Act (FACA). FACA regulations define how federal advisory committees legally operate and ensure that advice is objective and accessible to the public. FACA committees have fixed membership, organizational structure, and comprise members other than full-or part-time employees. FACA outlines requirements for developing a charter and membership, conducting public meetings, issuing statements, using federal register announcements, keeping minutes, and documenting decisions. CDC guideline developers are encouraged to review regulations pertinent to the development and use of federal advisory committees. # Protecting Scientific Integrity by Minimizing the Influence of Personal Interests Users of guidelines and recommendations need to feel confident that those participating in the development process were not unduly influenced by personal interests. Minimizing competing interests among members of steering committees and technical groups improves guideline acceptability, credibility, and scientific rigor. These interests might be financial, intellectual or professional. For example, competing financial interests might include research support, stock holdings, or employment at organizations affected by the guidelines. Intellectual and professional interests might include authorship of studies or provision of expert opinion publicly or in testimony related to the guidelines topic. Guidelines developers should assess whether participants' interests might influence their consideration of the scientific evidence or other factors that can influence the recommendations under consideration. CDC guideline developers should make every effort to either eliminate or manage financial, intellectual, or professional interests that compete with the goals of producing an evidence-based guideline. Developers should disclose in the guideline document the presence of financial, intellectual or professional interests. For example, a participant with a competing interest might be excluded from participating in the development of the final recommendation statement. The GSC might also choose to assign participants with competing interests a limited role, perhaps by excluding them from developing or approving recommendations. Participants should be chosen to balance interests in those cases where competing interests cannot be eliminated because it is desirable to have a range of opinions represented. For example, if a member of a systematic review team is the author of a study included in the review, the Cochrane Collaboration requires the inclusion of other team members who were not involved in the study in question. If employees of a pharmaceutical company or medical device manufacturer are members of a team conducting a review on a product produced by that company or manufacturer, extra effort should be made to make the review team multidisciplinary. The majority of the team members should have no employment or financial relationship to that particular company. Those with a direct financial interest in an intervention may consider abstaining from becoming members of the review team conducting a systematic review of that intervention. Special rules about conflicts of interest pertain to federal employees and "special government # Deciding on Evidence and Outcomes Core issues in determining the types of evidence to use in the development of recommendations hinges upon several considerations. Below are some considerations adapted from those suggested by NICE : - What is the most appropriate type of evidence to answer the question? - How can the most relevant evidence (published and unpublished) be identified? - How can the quality and applicability of evidence be assessed? - How can evidence from different kinds of research be synthesized? - How can quantitative and qualitative data be combined? Evidence-based approaches vary according to the sources used in gathering the evidence. There are many sources of evidence. The following is a listing of some of the most commonly used sources, combined or standing alone: - Systematic reviews of research studies - Meta-analyses of research studies - Econometric analyses - Decision analyses - Review of published systematic reviews - Review of published meta-analyses - Nonsystematic review of research studies # Expert judgments Once the TDG decides on approaches to obtain the evidence, it needs to identify the outcomes of interest. The identification of outcomes is topic specific. Outcomes can be prioritized, rated by the TDG, and presented to the GSC for review. Logic frameworks can be used to depict the links between the health problem and the interventions and between the interventions and outcomes of interest. # Developing the Logic Framework Logic frameworks (also known as conceptual or analytical frameworks) guide the assessment of an intervention's effectiveness for which guidelines are being developed. approach. Frameworks assist in addressing the following questions: - What interventions or professional practices are to be included in the guideline? - Which health outcomes (ultimate or intermediate) are expected effects of the intervention? - What types of evidence of effectiveness of the interventions are being considered? - How will the quality, quantity, and relevance of the evidence of effectiveness be assessed? - How will the strength of evidence of effectiveness and the strength of recommendation be related? - What assumptions about causal relationships of interventions and health outcomes will be accepted without direct scientific proof? - What form of exposition (narrative or graphic-flow chart, influence diagram, decision tree, or clinical algorithm) is most appropriate for describing the logic framework? The logic framework also helps guideline developers compose a persuasive supporting rationale for the interventions included in the guidelines. The logic framework links the interventions under consideration with the estimated effect, benefits, and harms. We recommend the inclusion of the logic framework in graphic format in the published version of the document. For examples of logic frameworks included in published recommendations, see the publications of the Community Guide. # Planning for Dissemination, Implementation, and Evaluation At this point in the development process, the GSC needs to decide whether the dissemination and translation of the guidelines will be done using "in-house" personnel or contractors. Those responsible for disseminating and translating the guidelines need to develop a plan that includes the following: - Target audiences - Venues (hard copies or electronic) - Peer-reviewed journals targeted - Professional organizations targeted - Development of focus groups (quantity, audiences, etc.) - Different formats according to audience needs - Activities and respective leads - Possible training needs - Timetable - Resource needs and costs - Use of plain language and audience-appropriate visuals that match the text - Need for translation of information into languages other than English If the GSC decides that electronic dissemination is the best option, the dissemination and translation group needs to determine the facilitators and barriers for the dissemination and identify the public's needs for evidence-based scientific information on the Internet. If the guidelines will be posted online, some organizations recommend developing online tools to evaluate the website. Implementation and impact evaluation of guidelines are not covered in detail in this primer. However, and because implementation and impact evaluation may influence the development of the guidelines, we encourage developers to consider during the planning phase the main issues that may arise after the release of the guidelines. A systematic review of the effectiveness of various interventions designed to assist in the implementation of research findings conducted by Bero et al in 1998 found that reminders alone or combined with audit and feedback, local consensus processes, and marketing and interactive training were best suited for consistently effective interventions. Audit and feedback alone, local leaders (such as practitioners), local consensus processes and patient-mediated interventions aimed at changing the behavior of health care providers were best suited for interventions of variable effectiveness. Educational materials and educational meetings were best suited for interventions with little or not effect. The use of specific strategies to implement research-based guidelines and recommendations seems to be necessary to ensure that practices change. The most successful are intensive efforts to alter practice. Bero et al contend the choice of intervention should be guided by the evidence on the effectiveness of dissemination and implementation strategies, the characteristics of the message, the recognition of external barriers to change, and the preparedness of practitioners to change. Another activity in the entire cycle of guideline planning, production, dissemination and implementation is the evaluation of impact. Impact evaluation methods are not explored in detail in this primer. However, like in the case of dissemination and implementation, developers need to keep in mind that the initial planning for impact evaluation may affect the development of the guidelines. Impact research in developing countries shows that several factors increase the impact of practice guidelines like involvement of the end-users in developing, launching, and introducing the guidelines; multiple training modalities; providing feedback to prescribers on their prescription practices in relation to guidelines; and effective monitoring and supervision. The main elements in evaluating the impact of guidelines and recommendations follow: - Assessing awareness - Assessing uptake - Assessing health impact - Assessing other impact (e.g., economic, social, environmental) # Planning for Updates We recommend the planning phase address dates and formats for updating the guidelines. As for dates, guideline developers may choose to indicate a specific time frame for retiring the guidelines─ either because new knowledge becomes available or technological advances render the existing guidelines obsolete. Guideline developers may also elect to indicate a time frame for updating the guidelines, either as a one-time event or periodically. As for format, guideline developers may choose to indicate that guidelines will be updated in their entirety or on specific sections. In that case, guideline developers may opt for publishing updates in summary and appendix form. Indicating retiring dates and publication formats for subsequent updated guidelines will make users prone to seeking updates and decrease the probability that practitioners will continue using out-of-date information or practices. # DEVELOPING GUIDELINES AND RECOMMENDATIONS Developing guidelines encompasses diverse processes and activities. This section mainly discusses processes for guidelines and recommendations based on evidence obtained from systematic reviews. The main processes involved in systematic reviews are 1) gathering the evidence, 2) abstracting and assessing the evidence, 3) summarizing findings, and 4) interpreting the evidence to develop the recommendations. Activities within each of the main classifications are included and explained below. If other sources of evidence are used, like expert judgment or surveillance data, the methods used to collect and assess the evidence need to be described in detail in the guideline document. Obtaining evidence in the absence of data is covered briefly in section 4.5. Descriptions of methods to gather information from other sources, including expert opinion, can be found in the literature. # Gathering the Evidence Once decisions are made on the type of evidence, sources for that evidence, and outcomes of interest, the next step of conducting a systematic review is gathering the evidence. The main activities included in gathering the evidence are 1) developing a search protocol and inclusion criteria, 2) conducting a literature search, and 3) selecting the relevant literature according to the pre-determined criteria. # Developing the Search Protocol Developing the search protocol involves determining where and how to look for evidence. The following are examples of sources of evidence: - Electronic and manual searches of published literature (peer or non-peer reviewed) - Electronic and manual searches of unpublished literature (e.g., reports, proceedings) - Searches of published or unpublished surveillance data Studies included in the search can be guided by the public health question of interest. Search protocols describe the selection of search terms (i.e., keywords), the sources and databases used for the search, the earliest date from which studies will be sought, and the inclusion criteria for those studies that will form the body of literature selected for screening. # Conducting the Literature Search The search is guided by the search protocol. The types of databases listed in the search protocol will depend greatly on the topic. Most searches, however, include readily available databases. The development of search terms and the locating of topic-specific databases can pose challenges, which can be mitigated by consulting those who are more experienced in the discipline. CDC's Library Services staff provides assistance when formulating and conducting literature searches. Different search platforms may yield different results, especially for recent data. For example, a search of OVID for search term "X" may yield a slightly different citation list than a search of PubMed for the same search term. The following databases, accessible via CDC's Library Services, are the most commonly used for systematic literature reviews: - PubMed - Medline (OVID) - Web of Knowledge - PsycINFO - Cochrane Library - Campbell Library - Embase - CINAHL - Education Resources Information Center (ERIC) - CAB Direct - EconLit If the body of evidence includes systematic reviews conducted by others, we recommend searching the following databases: AHRQ National Guidelines Clearinghouse, Cochrane Collaboration, Campbell Collaboration, CEBM, NICE, CRD, Clinical Guide, and Community Guide. # Selecting Relevant Literature The selection of relevant literature involves screening the search output according to the predetermined inclusion criteria. Those studies that meet the inclusion criteria are selected using a two-stage screening approach: - Titles and abstracts are screened independently by two reviewers - Full papers are screened independently by two reviewers Any difference of opinion should be resolved between the two reviewers or with the help of a third reviewer under the guidance of the technical lead. The selection process needs to be fully documented. Flow charts may be used to illustrate the inclusion and exclusion process. Software programs can be used to manage search results, but the use of software for this purpose should be explained in the final report. # Abstracting and Assessing the Evidence To ensure consistency, reduce bias, and improve validity and reliability, some organizations have developed standardized procedures to abstract and assess the evidence. Most of these tools are published online. For details on these instruments, consult the procedures of the Cochrane Collaboration and the Clinical Guide or the Community Guide. Evidence from new systematic reviews can be presented along with evidence from existing systematic reviews, meta-analyses, or review of meta-analyses. Developers need to keep in mind that the use of evidence from existing systematic reviews follows different criteria than the use of evidence from systematic reviews of single studies. For a critical assessment of existing systematic reviews, consult the CEMB. # Assessing Evidence Quality Evidence quality is defined as the extent to which one can be confident that an estimate of effect or association is real. Assessing evidence quality is important, as it is one of the factors that affect the strength of the recommendation. Methods chosen to assess evidence quality will likely be determined by the evidence-based approach selected for guideline development. These methods vary among guideline authorities like the ones developed by the Clinical Guide, Community Guide, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) authorities. Evidence quality assessment usually occurs in two phases: assessing individual study quality (often addressed in part by using study inclusion and exclusion criteria, as discussed in Section 4.1.1), and assessing the quality of the body of evidence. Determining the quality of the body of evidence may include assessing study designs and their limitations, as well as assessing internal validity, generalizability, consistency of results, effect size, confidence intervals, and applicability of the evidence to the target population and setting. For example, the Clinical Guide appraises evidence quality on the factors noted above and rates the overall certainty regarding the quality of the full body of evidence as high, moderate, or low. To illustrate, high-quality evidence generally includes consistent results from well-designed, wellconducted studies in representative primary care populations that assess the effects of the preventive service on health outcomes; the conclusion is therefore unlikely to be strongly affected by the results of future studies. In contrast, low-quality evidence signals that the evidence is insufficient to assess effects on health outcomes because of a limited number of studies, flaws in design, gaps in the chain of evidence, etc. The Clinical Guide uses evidence quality to estimate the expected magnitude of benefits, harms, and net benefits (benefits minus harms) that would result from widespread implementation of the preventive service. An indication of evidence certainty is provided within the recommendation statement. More detailed information on how the Clinical Guide rates evidence quality and develops recommendation statements can be found on its website. Similarly, the Community Guide rates the quality of individual studies based on potential threats to internal validity, such as description of the intervention implementation and potential for biases in sampling, measurement, analysis, recruitment, and interpretation of results. After individual study quality is assessed, the quality of the full body of evidence is characterized based on execution of the study designs, design suitability, number of studies, consistency of the results, and whether expert judgment was used or not. Final categories of evidence quality include "strong," "sufficient," "insufficient," or "based on expert opinion." Evidence quality directly relates to the Community Guide recommendation statements. For example, when the evidence is strong, the intervention is recommended based on strong evidence of effectiveness; when there is insufficient evidence, it is determined that available studies do not provide sufficient evidence to determine the effectiveness of the intervention. An alternate approach to rating evidence quality comes from the GRADE Working Group. This approach ranks evidence quality on several factors including study design, limitation of the studies in execution and analyses, consistency of results across studies, applicability of the evidence to the populations and settings proposed for the intervention, and precision in the estimate of effect. Study design is the first step for rating evidence quality. Studies are broadly classified into either randomized controlled trials (RCTs) or observational. Observational studies include time-series, cohort studies, case-control studies, case series, and case reports. Studies are given a numerical quality rating based on their design (e.g., a rating of "1" for RCTs, a rating of "3" for observational studies.) This numerical quality rating can be rated down based on risk of bias (i.e., study limitations that threaten internal validity), publication bias, imprecision, inconsistency, or indirectness. The quality rating can be rated up based on the effect size, doseresponse relationship, or if plausible confounders would have reduced a demonstrated effect. Based on a review of the evidence quality for all the studies, the full body of evidence is given a rating of either high (very confident that the true effect lies close to that of the estimate of the effect), moderate (moderate confidence in the effect estimate), low (limited confidence in the effect estimate), or very low (very little confidence in the effect estimate). A notable characteristic of the GRADE approach is the separation of the rating of evidence quality from the process by which the recommendation is determined. That is, evidence quality does not always equate with the strength of the recommendation. Although high-quality evidence usually leads to a strong recommendation, this is not always the case. On the other hand, low-quality evidence can sometimes lead to strong recommendations depending on factors such as values, preferences, and costs. For information on how evidence quality ratings inform recommendations, see Section 4.4. # Summarizing Findings The types of studies reviewed, methods used to summarize the evidence, and available statistics will determine the best ways for depicting the results. The summary of findings typically includes a narrative description of the findings along with tables or graphics depicting the outcomes of interest. Typically, findings from quantitative studies are presented in summary tables that describe the characteristics of included studies, sample sizes, measures of prevalence or health burden, effect sizes, and confidence intervals. Figures such as forest plots of effect size or risk of bias plots can be used to display the data. In addition to data that speaks to effectiveness of a particular public health strategy, developers should consider summarizing data on feasibility, economic efficiency, acceptability, risks, and unintended consequences in narrative or graphic form. Findings from qualitative studies that are included in the body of evidence should also be reported in text, table, or graphic form. Qualitative data might be reported within intervention studies and address questions related to the effectiveness of a public health intervention (e.g., to understand intervention feasibility and appropriateness; heterogeneity of findings; and values, preferences, and experiences of practitioners and intervention recipients). Qualitative data might also be collected directly by guideline developers through interviews with researchers or practitioners in the field. Also, qualitative data may be obtained among others from program evaluations, gray literature, opinion polls, and policy analyses. Systematic review authorities and academia have developed frameworks and tools for synthesizing qualitative data. Regardless of the methods used, or whether the data are coded from existing research studies or collected directly by guideline developers, the approach to summarizing the findings should be as transparent as possible. Formats may vary, as long as appropriate findings are summarized thoroughly in the guideline document. # Interpreting Evidence and Developing Recommendations Developing evidence-based recommendations involves inductive reasoning when it is derived from evidence, deductive reasoning when it is drawn from theory or methodological principles, and inferential reasoning when it involves moving from certainty to uncertainty about what would happen if the recommendation is implemented. Even in those instances when logic frameworks and systematic processes are followed, interpreting and translating evidence to recommendations can be surprisingly difficult. Developing recommendations is influenced by value judgments, policy considerations, and assumptions about a variety of factors, even after a careful review of the evidence. For example, a group that is concerned with feasibility considerations may come to a different set of recommendations than a group that is focused more narrowly on health outcomes, even if both groups are working from the same body of evidence. When considering the same body of evidence, a single specialty group may reach different conclusions than a multidisciplinary group in those cases where the specialty group is biased in favor of implementing interventions in which it has vested interest. Recommendations with higher validity may be produced using multidisciplinary groups where individual biases might be better balanced. The GRADE approach takes these factors into account when determining the direction and strength of recommendations. Recommendations are developed taking into account: 1) quality of the evidence (determined when assessing the results of the systematic review), 2) benefits vs. harms (by examining the health outcomes and legal and ethical considerations), 3) values and preferences of the target audience, and 4) resources (cost implications including feasibility and infrastructure requirements as well as cost-effectiveness analysis). By reviewing these four factors, the TDG determines the direction (i.e., for or against) and the strength (i.e., strong or weak/conditional) of the recommendation. It is important that factors used to develop the recommendation be explicitly recognized and reported. The usefulness of recommendations might be enhanced when they possess the following characteristics, adapted from those provided by NICE: - Are informed by the most appropriate and available evidence - Are set within a framework that acknowledges a range of social judgment - Take into account relevant theories of public health and behavioral change - Reflect the views and experiences of both those being advised to take action and the people who might be affected by that action - Are clear - Are practical Furthermore, developing guidelines includes considering all sources of evidence, including comments from committee discussions and expert judgment. It is important that the processes used for incorporating expert judgment be deliberately considered and be as explicit as possible. # Developing Guidelines with Limited Data On occasion, the rigorous research and findings needed for inclusion in the body of evidence are either lacking or limited. In such cases, guidelines may be based on indirect evidence, practitioner experience, and contextual knowledge. Guidelines based on empirical and contextual knowledge are likely more susceptible to bias and self-interest than guidelines based on direct research evidence. Therefore, the methods used to collect and assess information from experiential and contextual knowledge need to be made as explicit as possible. The complete lack of evidence on a public health intervention, action, or practice is rare. Most often, the information collected to assess public health burden (e.g., from surveillance data), the preferences of practitioners and communities (e.g., from expert opinion or solicitation of patient experience), and the context within which a public health practice is implemented (e.g., from case reports) may be accessed indirectly through the gray literature or drawn from expert opinion. Developers need to report on the nature and source of the evidence when that evidence was obtained from indirect sources. Developers also need to establish clear links between the indirect evidence and the public health problem addressed by the guidelines. Developers can use logic models to highlight how the pieces of evidence link to inform the recommendations. When this evidence is synthesized relying heavily on expert opinion, the best methods for identifying experts (or documents based on expert judgment) and developing consensus opinion statements need to be used and reported. Minimizing bias is essential when obtaining expert opinion and can be accomplished by selecting appropriate methods to gather and interpret the information (e.g., through structured consensus methods such as the Delphi method, nominal group process, or the Glaser method). # ECONOMIC CONSIDERATIONS The ways economic information is considered and incorporated in guidelines vary among guideline authorities. In the Community Guide for example, the CPSTF reviews the economic efficiency of interventions that it recommends based on strong or sufficient evidence of effectiveness. According to S. Chattopadhyay (personal communication, April 13, 2012), economic evidence is commonly incorporated in the rationale statement of the Task Force findings. However, for interventions that are particularly expensive to implement, such as using home visits to increase vaccination coverage for children or closing schools to control an influenza pandemic, the economic information is also noted in the recommendation statement of the Task Force's findings. When NICE develops recommendations, both clinical effectiveness and cost effectiveness are discussed. If there is strong evidence that one clinical strategy is both more effective and less costly, clearly this strategy is recommended for the target population. However, when one strategy is more effective but also more costly, then the magnitude of the cost-effectiveness measure is compared to the threshold used by NICE (see below). The GRADE approach considers cost as one of the factors to be considered in the development of the recommendations. One of the main concerns when considering economic information is that resources be chosen to obtain the greatest health improvement or, in other words, whether the intervention is efficient in economic terms. Economic efficiency influences the selection of an intervention, and this selection in turn affects the combination and quantity of resources used in implementing the intervention. Economic efficiency is informed by several economic measures. The most widely used in public health are measures such as cost-effectiveness, cost benefit, cost utility, and to a lesser extent, return on investment. The following considerations may be helpful when considering the magnitudes of economic measures for the development of recommendations: - The recommended level for the cost of an intervention depends on the available budget and on how much money managers are willing to spend in the intervention - The recommended level for cost-effectiveness ratios is set by convention and depends on what managers consider an affordable cost per outcome - The recommended level for cost-utility ratios varies among countries and organizations o The ratio used by NICE is £20,000 to £30,000 per quality adjusted life year (QALY). - The ratio used in the United States varies between $50,000 and $100,000 per QALY. - The amount recommended by WHO is 1 to 3 times the per capita gross domestic product (GDP). - In theory, a project is accepted if the net present value from a cost-benefit analysis is larger than 0 where the benefits are larger than the costs; however, in those cases where health interventions are not cost saving, managers must decide what level of cost per dollar of benefit is acceptable given current resources. - The recommended level for return on investment in financial terms is a positive return per unit of investment; that is, a positive ratio from dividing positive benefits by positive investments. A positive ratio is mathematically feasible by dividing negative benefits by negative investments. However, this is not conceptually feasible because there is no such thing as a "negative investment". By summarizing and interpreting economic studies, systematic reviews make economic information useful and accessible to guideline users. Economic data from systematic reviews facilitates the process of using limited resources in implementing interventions that contribute to making the greatest possible improvement in population health. For information on methods for conducting systematic reviews of economic evaluations, consult Carande-Kulis et al (2000) and the online methods section of the Community Guide. For standardized methods of economic evaluation and their application to public health, consult the online CDC course Economic Evaluation of Public Health Preparedness and Response Efforts. # WRITING THE GUIDELINES Guideline documents introduce recommendations to the public health community, describe the evidence supporting the recommendations and explain the process used to move from the evidence to the recommendations. In other words, when guidelines work groups start the writing process, a shift is needed from focusing on the scientific evidence to communicating the recommendations in a way that is most likely to influence practice. Additionally, the communication styles often used in scientific publications are not necessarily appropriate for guidelines documents. The authors of guidelines will need to carefully consider the needs of the target audience and adjust the format of the document and the communication strategy accordingly. The federal Plain Writing Act requires new or substantially revised documents for the public to be written in plain language. In general, a plain writing style that follows the federal language guidelines will make the information understandable for most readers, particularly for those who do not have technical knowledge of the subject matter. # Identifying the Level of Detail A major choice when developing the guidelines document is its level of detail. Although some guideline users may want a full and detailed description of the evidence synthesis process and background data, others may prefer a shorter format that focuses on the recommendations. A longer format can provide a wide range of information needed for multiple audiences (practitioners, policy makers, researchers, etc.) in a single document, but with the downside that user-specific information might be harder to find. Because the document may have multiple audiences, the authors might consider developing multiple versions instead of a single document for everyone. For example, full guidelines may be developed for publication in the MMWR, a reduced version for publication in a peerreviewed journal, a short synopsis for the practitioner, and a fact sheet for the public. A common approach is to publish a concise set of guidelines for practitioners, accompanied by a more comprehensive treatment of the science that can be published separately (or posted on the Web). Hybrid approaches, such as formats that combine a concise presentation of the guidelines along with a brief summary of the scientific evidence, can also be used. This combined approach makes important evidence available to those who want to dig a little deeper than just the bare-bones guidelines. # Describing the Audience The document needs to state: a) who will use the information, b) in what format, and c) how they will use it. Authors need to ensure that the communication style and technical levels are appropriate for the readers and that their needs are being met. Answering the following questions may ease the writing of the guidelines: - What population (age, gender, race and ethnicity, socioeconomic status) and setting (state or local health agency, community, home, workplace, hospital, ambulatory clinic) will the guidelines target? - Who are the guideline users (public, public health professional, advocate, or clinician)? - Whose knowledge, practices, behavior, or decisions will the guidelines attempt to address? - What health measurement, outcome, or condition (risk factor, prevalence, morbidity, mortality, quality of life, healthy, at-risk and asymptomatic, symptomatic, diseased) will the guidelines target for improvement? - What intervention, public health service, or provider practice will the guidelines target to implement or improve? The following questions may help the authors adjust the style and content to the target audience: - What kind of background information and evidence will the audience need? - What information will be needed to determine when the guidelines do and do not apply? - What information and resources will the readers need to implement the guidelines? - Will the audience be largely receptive to the guidelines, or will some readers be skeptical and need more rationale to support the recommendations? # Providing a Methods Section The methods section should provide readers with sufficient understanding of the processes leading to development of the guidelines, enabling them to judge the guidelines' quality, strengths, weaknesses, and limitations. Often, a methods section does not get much attention when guidelines documents are being developed. Sometimes a methods section is added as an afterthought, if at all. However, a well-crafted methods section establishes trust with the reader. Through the methods section, the reader gains an appreciation for the rigor and limitations of the guidelines development process. At a minimum, the methods section should state the following: - the evidence sources - what evidence was (and was not) considered - who participated in the synthesis - how evidence was summarized - how effect size of selected outcomes was reported - how evidence quality was assessed - how the evidence led to the recommendations - how the strength of the recommendations was assessed - how evidence gaps were treated More detail on each of these elements is provided below. # Describing the Evidence The methods section should briefly summarize the evidence domains considered and how the evidence was identified. The methods section should indicate the analytic framework and the specific review approach used to obtain the evidence. The method used to obtain the evidence should be described (e.g., systematic review) and justified. The search protocol, including search terms (e.g., keywords), sources used (e.g., databases, journals, repositories), and inclusion criteria (e.g., language, study type, human subjects inclusion, time frames, population) should be described. The criteria used to select the final evidence for developing the guidelines (e.g., study design, population, intervention, outcomes) should be detailed and justified. How evidence was coded and synthesized should be described (e.g., how data were extracted from studies; how data were synthesized, such as through use of effect measures; whether data were combined through meta-analysis; how heterogeneity in effects was explored). The method used to assess evidence quality should be described. # Describing Relevant Evidence That Was Not Considered Often, some evidence domains could be viewed as relevant but are not considered. For example, evidence may be excluded if it is not in English, not in the peer-reviewed literature, outside certain disciplines, etc. Excluded domains should be mentioned along with the rationale for why the evidence was not considered. Writers also might want to note topics that were not included (e.g., not addressing issues in pregnant women, in non-adults, a particular period for a birth cohort) and why these groups were not included. # Describing Partners Who Participated in the Guideline Development Process Guidelines are developed by people, and knowing who participated may be just as important to the reader as knowing what evidence was considered. Answering the "who" question is a crucial component of all methods sections and is especially important for guidelines that rely upon expert opinion. The document should indicate who participated, how they were selected, their expertise, and disciplines represented. The document should list the professional organizations from which participants were solicited. It should also state whether the work group was composed of or worked under one of CDC's official advisory committees. The document should specify the participants' roles (e.g., authors, advisors, reviewers) distinguishing between participants who approved the final recommendations and those who provided review or input. Finally, authors need to make sure the document specifies how competing interests (e.g., financial, intellectual, professional) among participants were identified, disclosed, and handled (e.g., through recusal from evidence synthesis, deciding on the final recommendation statements). # Describing How the Evidence Led to the Recommendations A good methods section describes how the evidence led to the recommendations. Frequently, this section is the most difficult to write. One challenge is that virtually all guidelines include some measure of expert opinion or judgment. Concisely explaining the rationale used by a panel of experts can be difficult, especially when the evidence base for the recommendation is sparse or a clear effect is not evident. But even for recommendations based on solid evidence, judgment calls will be made, which adds to the difficulty in developing a simple explanation for how the evidence led to the recommendation. The document should explain how the evidence was weighted, how evidence quality was judged, what evidence was considered more (or less) compelling, and how the strength of the evidence was determined. If information was obtained from expert opinion, the processes used (e.g., Delphi process, focus groups, questionnaires) should be described. The document also needs to include the processes used to reach agreement, such as informal consensus, formal consensus, or voting. Most guideline development efforts use a combination of processes. Those groups that have used formal evidence-based frameworks for developing guidelines will likely find it easier to describe the links between the evidence and the recommendations. However, even for guidelines that are largely based on expert opinion, the authors should avoid simply stating that experts reviewed the available materials and made recommendations. Invariably, some level of evidence and rationale exists even for guidelines based on expert opinion, and the authors should provide as much of the rationale as possible. Throughout the process, the authors should record major and possible subjective decisions made and the rationale and assumptions contributing to the decisions, as well as other alternatives considered. These records will enable the authors to accurately describe the suggested details in the methods section. Note that this point should be considered while the experts are still deliberating the recommendations because the rationale may be more difficult to reconstruct after the expert panel has been disbanded. If economic efficiency measures were presented as part of the evidence, the authors need to explain how any of this evidence was used. Most of the time, this evidence is not included in the decision criteria that translates the evidence into recommendations; instead, this evidence is presented as supplemental information. If this evidence was discussed before consensus on the recommendations was reached, the authors need to explain whether the evidence (or lack thereof) of economic efficiency influenced the recommendation. Economic efficiency is covered in detail in Section 5. # Describing How Evidence Gaps Were Treated It is rare for guidelines to lack even a few gaps in the evidence. Guidelines authors should be prepared to explain how these evidence gaps were addressed. Guidelines documents sometimes include statements that evidence gaps were bridged by expert opinion. Whenever possible, guidelines authors should explain what approaches were used by the experts to bridge the gaps, how incomplete evidence was treated, who made the judgment calls, and what assumptions were in play. For example, some guidelines panels may withhold recommendations when conclusive evidence is lacking, whereas others may follow a more precautionary approach and develop a recommendation even when evidence is scarce (unless there is evidence that the measures are harmful). Or, when evidence is lacking and as long as risks are minimal, guidelines panels may default to current established guidelines or practices. Regardless of the approach, the methods section should give readers sufficient information to understand the major gaps in evidence and to decide whether they agree with how these gaps were treated. The manner in which evidence gaps are treated can impede trust with the target audience. Glossing over evidence gaps may damage the credibility of the guidelines. # Writing Guidelines for Maximum Impact on Policy and Practice For guidelines to have maximum impact on policy and practice, the writing needs to be clear, Guidelines might be consulted more often if the recommendations are stated clearly and address WHO should do WHAT to WHOM, UNDER WHAT CIRCUMSTANCES, HOW, and WHY. Newly developed software is now becoming available to assist guidelines developers in crafting recommendation statements in this format. In addition, the Conference on Guideline Standardization has developed a checklist for reporting practice guidelines that can serve as a helpful resource. Of critical importance is clearly describing the methods used to synthesize and rate the quality of the evidence. Practitioners may be more likely to follow guidelines when the evidence base is strong and the recommendations are easy to understand. One international research study suggests that practitioners are more likely to change their decisions about practices when clear descriptions of evidence quality and strength of recommendations are provided, particularly through use of the GRADE approach. Practitioners also value discussion of factors that might affect the implementation of the recommended intervention or practice such as feasibility, reach, resource requirements, and acceptability. # EXTERNAL REVIEW AND VETTING OF CDC GUIDELINES Each release of a new CDC guideline might have a lasting impact on clinical and public health practice. Guidelines may be converted to policy, implying widespread implementation by a broad range of groups. Guidelines may be even converted into law, entailing subsequent regulatory enforcement. Because of the high profile CDC guidelines may acquire following their release, we recommend guidelines be vetted before publication. Vetting of CDC guidelines ensures that key stakeholders have the opportunity to review and provide critical input. Vetting not only assists in fostering transparency and credibility but also improves the clarity and understanding of the guidelines. Even though it may not be possible to incorporate all the feedback received, vetting of the guidelines has many benefits. Some benefits of vetting are: - Identifying overlooked issues (e.g., new evidence released outside of the literature search period) - Identifying possible post-guideline problems (e.g., feasibility considerations, misinterpretation by the target audiences) - Improving chances of buy-in and adoption - Providing a preview for guideline implementers to prepare to adopt new recommendations # Internal and External Vetting We recommend that CDC guidelines be vetted internally and externally. Vetting processes are defined by various factors such as scope (e.g., broad vs. narrow), level of controversy, number of stakeholders, and timeline (e.g., recommendations for urgency vs. routine revision of long-standing recommendations). Internal vetting is critical for guidelines that cross multiple programs. However, guidelines of narrow scope might not need to be vetted internally. Typically, the need for internal vetting should be determined by CDC's crossclearance policies. Questions about the need for cross-clearance should be directed to the program or the CIO Associate Director for Science (ADS). When cross-clearance is required, having involved the program or ADSs throughout the guideline development process will help ensure timely clearance. External vetting can occur in public meetings during a CDC advisory committee meeting, through informal reviews by key stakeholders, by community engagement forums when public interest in the guideline is expected to be significant, by formal request for comments (e.g., posting in Federal Register), or a combination of the above. Regardless of the format used, the vetting process must be carefully planned so adequate personnel and financial resources are available to handle the reviews. For example, following posting in the Federal Register, comments received will need to be compiled and reviewed. Responses should be prepared for each individual who provided comments (e.g., response matrix). The writing group will typically review the comments and craft responses. Having a record of responses will demonstrate that CDC considered each comment. This documentation is especially important when requests for follow-up occur through controlled correspondence or the Freedom of Information Act. Although the vetting process might vary slightly for different guidelines, each must have a process in place. Vetting is the critical step in the CDC guidelines development process that ensures transparency and credibility. Because of the importance and high impact of guidelines documents, authors should consult with their division or the CIO ADS on whether external peer review is warranted before final clearance. Peer review by external experts is common for guidelines documents as a way to get an independent assessment of the quality of the guidelines. The peer-review process may be limited to a review of the science of the guidelines or may include a review of all aspects of the document. If the review is limited to the science, then reviewers are chosen for their scientific expertise and are typically selected to be as independent of CDC as possible. For other types of review, inclusion of partners and potential users might be desirable, especially those chosen to represent a range of stakeholder positions. Reviews by stakeholders may be conducted within the scientific review process or separately. A specific type of external peer review is required for guidelines documents that are considered influential scientific information (ISI) or highly influential scientific assessments (HISA) as defined by the Final Information Quality Bulletin for Peer Review issued by OMB in 2004. This bulletin requires that specific information be reviewed by qualified experts before dissemination. As noted in the CDC clearance policy, "Clearance is not a forum for extensive peer review or for policy debate. Such discussions belong in the pre-clearance phase." Therefore, guidelines authors should ensure that guidelines documents have been appropriately reviewed for quality of execution and reporting and that policy issues have been resolved before submitting these documents for clearance. If guidelines documents have scientific or policy issues that overlap with other CIOs, those CIOs should be consulted early in the guidelines development process (and, should be part of the guidelines development team). # CLEARANCE OF CDC GUIDELINES AND RECOMMENDATIONS CDC sometimes develops guidelines jointly with other organizations. If a CDC staff member will be listed as a coauthor of a document, or if the document will include the CDC brand, the document requires clearance by CDC. For jointly developed documents, authors should discuss clearance requirements early in the process so external authors understand CDC clearance requirements and are aware that CDC will need to formally approve the final document. Also, CDC authors should ensure they understand review and clearance requirements that the collaborating organizations will impose. Additionally, CDC authors should consult with the division and CIO ADS and others in the clearance chain early in the development of guidelines documents to avoid surprises during the clearance process. Note that CDC clearance is required whenever CDC is listed as a coauthor on a guidelines document-even if CDC is not listed as a formal sponsor or if the person is in a group author listing. This CDC clearance requirement has two notable exceptions: - When a CDC author helps develop guidelines as an approved outside activity (conducted outside of working hours and without the use of CDC resources), the author may be listed without CDC affiliation - When CDC personnel are listed as contributors, reviewers, or consultants, although they are not listed as coauthors When these situations occur, include a disclaimer stating that these roles do not necessarily imply CDC agreement or endorsement of the guidelines or recommendations. In such cases formal CDC clearance is not necessary (although supervisory approval is needed). One additional clarification should be made on the use of disclaimers in guidelines documents. CDC authors are accustomed to using the standard disclaimer on journal publications required by OMB's Final Information Quality Bulletin for Peer Review. However, because CDC guidelines documents represent the official position of CDC, the OMB disclaimer should not be used on guidelines documents when they are sponsored by CDC or a CDC staff member is listed as a coauthor. Guidelines authors can consider whether other types of disclaimers are appropriate for the specific document (e.g., disclaimers noting that mention of specific products does not imply endorsement by CDC). # RECOMMENDED STANDARDS FOR CDC PUBLIC HEALTH # GUIDELINES There are advantages to using standardized approaches for guidelines development. A number of organizations have adopted uniform frameworks for guidelines they develop. However, the breadth of disciplines and topic areas at CDC makes it impractical to use a single, unified approach for CDC guidelines. Therefore, we are not recommending a single approach; instead, we have identified a set of recommended standards we recommend for CDC guidelines. Although these standards might not apply in special instances, most CDC guidelines can be developed using these principles. The guidelines development process should include the following: 1. Identify the public health problem on a given topic, need for new or revised guidelines, and required resources for development: Before developing CDC guidelines, the sponsoring program should identify the topic for the guidelines and assess the basis for developing new or revised guidelines. This assessment should include an evaluation of the public health need for the guidelines on the topic, the relationship to CDC's mission and priorities, a review of existing guidelines on the topic, pros and cons of developing the new guidelines (including implications if guidelines are not developed), estimated resources (personnel and budget), timeframe for developing the guidelines, and a list of partners or organizations that will be engaged. This assessment should be shared with senior leadership (e.g., CIO director) before starting development. 8. Involve an explicit scientific quality and policy control process: The guidelines development work groups should be provided with a description of how the guidelines will be finalized and cleared and how disagreements or inconsistencies will be resolved. Typically, guidelines development groups with external participants provide advice to CDC, and thus the role of CDC clearance and final CDC acceptance of the guidelines should be explained. The guidelines document should report on the following topics: 1. Guideline development process: Guidelines documents should clearly describe the process used to develop the guidelines. This description should include who participated in the process, how they participated, how decisions were made, who had final approval of the document, and potential competing interests among participants. 2. Evidence synthesis process: The guidelines document needs to describe the process used to synthesize the evidence; for example, through systematic literature review. If a systematic review was not feasible (e.g., because of resource allocations or time constraints) and only a narrative review is included, make sure the evidence-gathering process is as complete and methodical as possible and the report is clear about how the evidence was identified and evaluated. 3. The evidence base supporting the recommendations: The evidence base used to develop the guidelines should be described and summarized. A description of the methods used to evaluate the suitability of articles should be provided. Unpublished data sources should be described. If notable sources of evidence were not used, mention them and explain why they were not included in the body of evidence. 4. The quality of the evidence and strength of the recommendations: The document should describe the quality of the evidence, the method used to assess the quality of the evidence, how the evidence led to the recommendations, and the strength of the recommendations based on the effect size of selected outcomes and other factors (e.g., potential harms, values and preferences, economic efficiency). 5. Limitations and applicability of guidelines: Guidelines documents should explain significant limitations or caveats of the guidelines, including (when appropriate) situations where the guidelines may not apply. 6. Relationship to similar or overlapping guidelines: Guidelines should state how they are related to similar or overlapping guidelines. If a guidelines document updates or supersedes previous guidelines, this should be stated. # APPENDIX I -GLOSSARY Analytic framework -A process usually represented by a diagram that shows hypothesized links between an intervention and related intermediate or final health and non-health outcomes. Applicability -Whether the intervention process could be implemented in the local setting, no matter the outcome. Algorithm -A procedure consisting of a sequence of algebraic formulas and logical steps to calculate or determine a given task. Bias -Deviation of results or interferences from the truth. Body of evidence -The complete set of qualifying studies compiled using systematic or nonsystematic reviews. Case study -Method of study in which persons with the disease (or condition) of interest are compared with a suitable control group of persons without the disease. Comparison group -A group that was not exposed to a particular intervention; the control group, used to determine what would have happened if the intervention had not been carried -ut. Effect -The change in an outcome that results from an intervention. Effect size -The magnitude of the effect measured in a study of the intervention. Effectiveness -The degree to which an intervention achieves a desired outcome in practice. Efficiency -Carrying out production so as to obtain the maximum amount of output for any given set of inputs (technical efficiency) or choosing inputs so as to minimize cost of production (cost efficiency). Evidence-based − The use of scientific data to confirm that proposed interventions or practices are appropriate in light of their high probability of producing the best and most favorable outcome. External validity -The ability to generalize study results to populations and context beyond the particular ones included in the studies themselves (see applicability). Guideline steering committee − In-house group composed of CDC staff with the functions of overseeing each step of the guideline development process. Health outcome -The change in health that is hypothesized to result from the intervention (e.g., reduced morbidity or mortality or increased physical, mental, or psychological function). Impact -The association between an exposure and an outcome in a meaningful public health context. Measures of impact reflect the degree of exposure contributing to the frequency of disease in the population. Two measures of public health impact often used are the attributable proportion and efficacy or effectiveness. Intermediate outcome -One in a series of intermediate effects from an intervention potentially linked to a final health outcome. An intermediate outcome with a strong and established link to a final health outcome may serve as a recommendation outcome. Internal validity -A study trait indicating that the measured effect resulted from implementing the intervention. Intervention -A specific activity pursued by public health practitioners aimed at reducing disease risk, treating illness, ameliorating the consequences of disease and disability, or preventing a health problem. Meta-analysis -A systematic, quantitative method for combining information from multiple studies to derive a meaningful answer to a specific question. Other effects -Outcomes or effects other than anticipated as a possible result of the intervention; effects can be positive (beneficial) or negative (harmful). Policy -Laws, regulations, and formal and informal rules and understandings that are adopted on a collective basis to guide individual and collective behavior. Reliability -The degree of stability exhibited when a measurement is repeated under identical conditions; the degree to which the results obtained by a measurement procedure can be replicated. Systematic review -A process by which a body of literature is reviewed and assessed using systematic methods intended to reduce bias in the body of evidence. Transferability -Degree to which the results of a study or systematic review can be extrapolated to other circumstances, in particular to routine to public health or health care situations.	# EXECUTIVE SUMMARY According to the World Health Organization (WHO), guidelines are "documents that contain recommendations about health interventions, whether they be clinical, public health, or policy recommendations." Recommendations provide information about what policy makers, health care providers, or patients should do. Recommendations imply choices between different interventions that have an impact on health and that have ramifications for the use of resources." The Centers for Disease Control and Prevention (CDC) is a leader in developing public health guidelines. Ideally, CDC guidelines are developed by a group of multidisciplinary stakeholders, based on evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. CDC guidelines should be clear, valid, transparent, reliable, accurate, and applicable. Although the term "recommendations" may be used more narrowly to identify specific actions and the term "guidelines" may more broadly refer to the umbrella under which multiple recommendations for action are provided, we use the terms guidelines and recommendations interchangeably in this document. Some guidelines are developed by federally-chartered advisory committees like the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC) and are subsequently accepted and issued by CDC. Other guidelines are developed under the initiative of CDC programs in collaboration with experts in the field. The most frequent CDC publication venue is the Morbidity and Mortality Weekly Report (MMWR), but other outlets mechanisms such as peerreviewed journals and agency publications are also used. Although CDC guidelines have garnered wide acceptance among stakeholders and partners, the rationale and development process is not always clear to the user. Because of the breadth of public health topics and audiences, adopting a single approach to developing guidelines at CDC poses a significant challenge. As a result of this challenge, we have refrained from recommending a single methodological approach for development and reporting of all CDC guidelines (although guidelines authors are encouraged to familiarize themselves with methods already used at CDC). Yet CDC guidelines should meet certain standards. This primer provides development and reporting standards to improve the transparency, validity, and reliability, of CDC guidelines and recommendations. Development standards include: • Identify the public health problem on a given topic, need for new or revised guidelines, and required resources for development • Involve knowledgeable, impartial, and representative participants in the process • Minimize and disclose competing interests among participants • Involve and consult affected organizations • Include a written charge to the development work group • Obtain the evidence preferably using systematic reviews • Use evidence-based frameworks and decision-making rules • Involve an explicit scientific quality and policy control process The above standards, along with reporting standards, are provided and covered in detail in Section 9. By following development and reporting standards, guidelines developers can improve the use of evidence, minimize bias, and enhance quality and consistency in reporting. Although occasionally some of these standards cannot be followed, most CDC guidelines will at least fulfill the intent of the standards. The reader should be able to understand the methods used to develop the guidelines, how the evidence was selected and assessed, and how the evidence led to the recommendations. Meeting these standards will also support CDC programs in developing guidelines that can be trusted by the public health community and the public. By improving the rigor and transparency of methods used to develop CDC's guidelines, criteria-based guideline clearinghouses will more readily adopt and publish CDC guidance, enhancing visibility and use. # -CDC Guidelines and Recommendations Work Group July 2012 INTRODUCTION "Guidelines are documents that contain recommendations about health interventions whether they be clinical, public health, or policy recommendations." Recommendations provide information about what policy makers, health care providers, or patients should do. Recommendations imply choices between different interventions that have an impact on health and that have ramifications for the use of resources." [1] The Centers for Disease Control and Prevention (CDC) is a leader in developing public health guidelines. Ideally, CDC guidelines are developed by a group of multidisciplinary stakeholders, are based on evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. CDC guidelines should be clear, valid, transparent, reliable, and applicable. # Purpose Guidelines developed at CDC cover a wide range of disciplines and needs. Guidelines may go from providing recommendations for interventions to increase physical activity to the treatment of pandemic influenza. Often, CDC guidelines address multiple stakeholders and provide recommendations for individuals, groups, and communities. Audiences may include health department staff, coordinating partner services, physicians looking for information on new treatments, labs looking for screening tests, and individuals looking for prevention programs and services. Recommendations in CDC guidelines may cover surveillance practices, program implementation, or even policy interventions. Nuances exist associated with the selection of a public health topic. For example, a particular public health topic selected for guideline development may require the use of federally-chartered advisory committees. The selection of a public health topic will affect the type and extent of the evidence of effectiveness. Or, addressing a public health topic may include policy-based interventions that could be socially or politically sensitive in nature. Diverse audiences and the nuances of public health topics pose challenges to recommending a common approach for developing and reporting guidelines. Content and format may vary with the needs of each group of users. Additionally, diverse audiences may have access to guidelines of other organizations containing recommendations that may be inconsistent with CDC recommendations. This diversity in audiences, topics, and communication formats poses particular challenges for ensuring the clarity and acceptance of CDC guidelines. Because of all these considerations, a standardized approach to guideline development is not recommended in this primer. Instead, the primer provides a series of critical elements and standards that can be used in CDC guideline development. # Audience This primer is for CDC staff, contract review teams, CDC federal advisory committees, and CDC partners and stakeholders. Guideline developers sponsored or co-sponsored by CDC will find the primer particularly useful, as will anyone involved in the clearance or publication of guidelines. Use of minimum standards in guideline development and reporting will improve guideline quality and facilitate the clearance and publication processes. # Scope Because of the difficulty in recommending a standardized approach for CDC guideline development, this primer is not a how-to manual. Instead, it covers elements common to the development of all guidelines, shows how standards can be integrated into the development process, and provides critical ways to improve CDC guidelines. This primer supplements the information outlined in CDC Guidelines: Improving the Quality (1996). [2] 2. # GUIDELINES, POLICIES, AND OTHER CONSIDERATIONS Developing guidelines entails making many front-end decisions that, in the end, will save time and money. Early considerations about the need, evidence, and current methods for guideline development can assist developers in clarifying terms, concepts, and principles early on in the development process. We suggest guideline developers consider the following questions before beginning development of guidelines: • What are public health guidelines? • What are the differences between guidelines and policies? • Is there a need for new guidelines? • What type of evidence is available? • Who develops guidelines? Answers to these questions will guide decision-making at the onset of guideline development. This section will remind developers of organizations that can be sources of technical knowledge, methods, procedures, tool kits, and software. # Guidelines, Recommendations, and Guidance Although the term "recommendations" may be used more narrowly to identify specific actions and the term "guidelines" may be used more broadly to refer to the umbrella under which multiple recommendations are provided, we use the terms guidelines and recommendations interchangeably in this document. Typically, public health guidelines are developed by a group of multidisciplinary stakeholders, use evidence from systematic reviews and expert judgment, and include an assessment of benefits and harms. [3] Guidelines should be clear, valid, transparent, reliable, and applicable. These terms are defined in Section 10. Although the term "guidance" is sometimes used to indicate a "less-direct type of advice," guidelines authors should be aware that the term "guidance document" is used by regulatory agencies for specific types of documents and that the Office of Management and Budget (OMB) has issued policies and procedures for developing guidance documents. [4] Therefore, be aware that the use of the term "guidance" could lead to confusion with regulatory guidance documents, and consider using other terms. # Types of Guidelines Guidelines cover the full range of public health areas represented at CDC. Guidelines may be developed across the 10 essential public health services. [5] For example, guidelines might be developed for monitoring health status, mobilizing community partnerships, selecting and implementing programs and policies, and evaluating health services. The target audience can be wide and varied, including, for example, clinicians, public health professionals, or policy makers. The evidence base for guidelines may be robust or sparse. Sometimes CDC must develop guidelines when evidence is lacking. In such cases, guidelines can be developed based on expert judgment and historical knowledge about the intervention in similar or different settings. Expert judgment may be based on experience and observations and on extrapolation of evidence from different settings or similar interventions. When guidelines on a specific topic are first developed, they may be called "initial" guidelines. Initial guidelines may be limited in scope. For example, a guideline might focus on recognition and initial assessment and less on differential diagnosis, management, or treatment issues after diagnosis. The guideline to recognize and assess early Alzheimer's disease produced by the Agency for Health Care Research and Quality (AHRQ) is an example of an initial guideline. [6] "Comprehensive" or final guidelines (also called "full guidelines" by WHO) [1] are broader in scope and are developed by a wide range of stakeholders, usually with participation from several agencies, academia, nongovernmental organizations, and communities. Such guidelines provide full consideration of a disease, condition, environmental emergency, or natural disaster. Comprehensive guidelines usually include many aspects related to the disease or condition including surveillance, detection, control, treatment, and prevention. An example of comprehensive guidelines is the Guidelines for Foodborne Disease Outbreak Response, published by the Council to Improve Foodborne Outbreak Response. [7] "Interim" guidelines are those developed in response to emergencies or to rapid increases in cases of a disease or condition. These guidelines are labeled "interim" to clarify that such guidelines were developed using less thorough processes or were based on tentative or emerging data. WHO refers to such guidelines as "rapid" guidelines and their development period may vary between a few weeks and a couple of months. [1] An example of an interim guideline is the CDC guideline for the use of face masks and respirators during an influenza pandemic. [8] Initial and interim guidelines are often updated when new evidence is available. "Supplemental" guidelines update topics considered in previous guidelines or cover new topics. These guidelines-which may be initial, interim, or comprehensive-supplement previous guidelines with new or revised information. Examples of supplemental guidelines are the CDC updated guidelines for management of occupational exposures to HIV. [9] # Guidelines and Policies Guidelines, unlike some types of policies, are not mandatory. In health care and public health, guidelines are not meant to enforce but rather to recommend programs or practices based on the best evidence available. Often, however, CDC and others' guidelines become "the standards of practice," unintentionally acquiring the force of policy. The adoption of a set of guidelines can affect an entire organization. Whatever the organization (for-profits, nonprofits, public health departments, or federal government agencies), guidelines provide information for decisionmaking. Implementation of guidelines might improve organization effectiveness and efficiency. Policies, on the other hand, are laws, regulations, procedures, administrative actions, incentives, disincentives (e.g. taxes, fines, fees, or other pecuniary or non-pecuniary penalties) or voluntary practices of government and other institutions. Many policies are enforceable and their implementation is frequently reflected in resource allocations. Policies also can be maps of actions that guide an organization or group in decision-making. Policies frequently address the impacts of decision-making on population health, the society, the economy, and the environment. Mandatory policies are similar to executive orders or decrees. [10] Occasionally, policy making follows the issuing of guidelines. When this occurs, the policies function like road maps and are essential to implementing the guidelines. Increasingly, policies are being used as tools to improve public health efforts. Although guidelines typically support programmatic interventions or health practices, guidelines can also aid the use of policy to improve public health efforts (e.g., guidelines for policies on nutrition standards for food in schools; guidelines for policy on alcohol-impaired driving such as ignition interlocks, expanded use of sobriety checkpoints, and minimum drinking age). # Establishing the Need for New Guidelines Guideline developers should make sure that new guidelines are needed before guideline planning is started. Establishing the need for new guidelines entails assessing the public health need for systematic advice and identifying the existence of current or past guidelines on the same topic covering the same population and settings. This process also entails determining the existence of guidelines that need to be updated because of new research findings. The following questions may help guideline developers assess the need for new guidelines: • Are guidelines needed to sufficiently address the public health threat under consideration? • Why are guidelines needed now? • Are there new interventions that require new guidelines? • Have there been changes in the disease or pattern of the disease? • Have there been changes in the guideline audience? • Is there a new role for the CDC? • Is there sufficient new evidence available to develop the guidelines? • Are there current guidelines on the same topic published by other authorities that might be used instead? • If other guidelines exist, do they apply to the same target cohort, settings, and demographics? • Are there sufficient funding and resources available to support the planning, development, and dissemination of these guidelines? # Use of Evidence in Guidelines Guidelines should be developed using the best available evidence of effectiveness of preselected outcomes. "Evidence" is knowledge gained from scientific research that is interpreted in the context of public health practitioner experience, conditions of intervention implementation, and experience of the population targeted. [11,12] When research evidence is available, systematic reviews can inform guideline development. Different types of research evidence exist for inclusion in systematic reviews including evidence from randomized controlled trials, observational studies (e.g., quasi-experimental and time-series studies), and qualitative studies. Keep in mind, however, that guidelines extend beyond systematic reviews in important ways. Although systematic reviews provide information about the scientific evidence behind an intervention ("this works"), guideline developers combine this information with expert judgment, information about harms and benefits, economic efficiency, and values and preferences to inform public health or clinical practice in guideline form ("this should be done"). The quality and strength of the evidence varies across areas of public health. Sometimes, practitioners in the field are needed to provide key pieces of information that can't be culled from the empirical literature. A practitioner perspective can be critical to understanding how interventions are carried out and which populations are targeted. # Organizations That Develop Guidelines Many organizations produce guidelines, develop databases of existing guidelines, or provide methods, tools, and training for developing guidelines. Some organizations, such as the AHRQ National Guidelines Clearinghouse, act as repositories of national guidelines. The clearinghouse has registered 2,373 clinical practice guidelines to date, produced by 285 organizations. [13] Other organizations, like the Cochrane Collaboration and Campbell Collaboration, also act as repositories of their own accredited systematic reviews but also offer methods and electronic tools for conducting systematic reviews by independent groups in academia or government. [14,15] The at the University of York (CRD) develop guidelines internally or under contract. [17,18] The Canadian Medical Association provides a database of guidelines with a summary listing methods and development processes. [19] In the United States, the U.S. Preventive Services Task Force (USPSTF) and The Community Preventive Services Task Force (CPSTF) develop recommendations under the umbrella authorities known as the Guide to Clinical Preventive Services (Clinical Guide) and Guide to Community Preventive Services (Community Guide), respectively. [20,21] The Institute of Medicine (IOM) has published standards for developing clinical practice guidelines. [22] CDC produces guidelines developed at the program level. Such guidelines are often developed in consultation with field experts and are typically published in the MMWR. [23] CDC also works with advisory committees that develop guidelines like the ACIP and HICPAC. [24,25] # GUIDELINE DEVELOPMENT PLANNING Guideline planning is critical to setting the stage for methods, processes, and procedures used during the development phase. Early planning will make the development process more fluid and the end product more transparent. Planning activities include: a) identifying the audience, b) identifying contributors and their roles, c) deciding on evidence and outcomes, d) developing the guideline logic framework, e) planning for guideline dissemination, implementation, and evaluation, and g) planning for guideline updates. # Identifying the Audience Public health guidelines often have diverse audiences (e.g., practitioners, policy makers, health care businesses, government agencies). Umbrella guidelines may try to balance information needs for these audiences. Audiences can be identified by addressing the following questions: • For whom are the guidelines or recommendations being developed? • To whom are the guidelines and recommendations being addressed? • To what extent are these guidelines going to assist them? Companion or support materials may further distill and interpret guideline content for specific audiences. For this reason, developers should distinguish between the actual guidelines and the support materials that will reference the guidelines. Supporting materials might include training materials, fact sheets, applications, pocket cards, algorithms, etc. Supporting materials differ from actual guidelines and require various development and dissemination methods. Developers therefore need to decide beforehand whether supporting materials will be part of the guideline development process or they will be developed after the primary guideline document is complete. # Identifying Contributors and Their Roles Major efforts to develop guidelines typically involve at least two distinct groups: a guideline steering committee (GSC) and a technical development group (TDG). Other groups might be needed, such as a dissemination group. Typically, the GSC will be comprised of CDC personnel. The function of the GSC is overseeing the guideline development process. GSC functions have been adapted from those proposed by NICE and might include: [17] • Select members of the TDG (see below) • Draft standard operating procedures for the TDG • Define the goals and elements of the proposed guidelines • Approve the methods to synthesize the evidence and develop the recommendations • Determine the sources of evidence • • Conduct a systematic search for evidence • Select and review the evidence • Summarize the evidence and specific outcomes • Assess the quality of the evidence • Present to the GSC the summary of the evidence • Provide the GSC with a preliminary assessment of the recommendations' strength • Provide the GSC with a preliminary draft of recommendations to the GSC • Draft the guidelines with members of the GSC • Discuss and incorporate suggestions from external reviewers • Write the final version of the guidelines If the guidelines are being developed with the help of other authorities and task forces, members of these groups might participate in the GSC and provide input during the development process. Stakeholders may also participate in the development of the guidelines through the GSC. Stakeholders are groups whose activities could be affected by implementation of the guidelines or who have legitimate reasons for providing input. Inclusion of stakeholders in developing guidelines will ensure that a) the right issues are identified and b) there is early buy-in and a better chance for early adoption of the guidelines. Inclusion of liaison groups will ensure that guidelines address the needs of the collaborating agencies and can increase adoption among communities, patients, and individuals in at-risk groups. Liaison groups may include representatives from affected populations, patients, or at-risk groups. Frequently, CDC collaborates with international organizations or Ministers of Health in developing joint guidelines and recommendations. For joint guideline documents, CDC developers should work with collaborators to encourage the use of evidence-based frameworks in developing guidelines. In developing a panel with outside members, whether they are stakeholders, liaisons, subject matter experts or members of international organizations, one might unknowingly construct a committee that is subject to the regulations of the Federal Advisory Committee Act (FACA). FACA regulations define how federal advisory committees legally operate and ensure that advice is objective and accessible to the public. FACA committees have fixed membership, organizational structure, and comprise members other than full-or part-time employees. FACA outlines requirements for developing a charter and membership, conducting public meetings, issuing statements, using federal register announcements, keeping minutes, and documenting decisions. [26] CDC guideline developers are encouraged to review regulations pertinent to the development and use of federal advisory committees. [27] # Protecting Scientific Integrity by Minimizing the Influence of Personal Interests Users of guidelines and recommendations need to feel confident that those participating in the development process were not unduly influenced by personal interests. Minimizing competing interests among members of steering committees and technical groups improves guideline acceptability, credibility, and scientific rigor. These interests might be financial, intellectual or professional. [28] For example, competing financial interests might include research support, stock holdings, or employment at organizations affected by the guidelines. Intellectual and professional interests might include authorship of studies or provision of expert opinion publicly or in testimony related to the guidelines topic. Guidelines developers should assess whether participants' interests might influence their consideration of the scientific evidence or other factors that can influence the recommendations under consideration. CDC guideline developers should make every effort to either eliminate or manage financial, intellectual, or professional interests that compete with the goals of producing an evidence-based guideline. Developers should disclose in the guideline document the presence of financial, intellectual or professional interests. For example, a participant with a competing interest might be excluded from participating in the development of the final recommendation statement. The GSC might also choose to assign participants with competing interests a limited role, perhaps by excluding them from developing or approving recommendations. Participants should be chosen to balance interests in those cases where competing interests cannot be eliminated because it is desirable to have a range of opinions represented. For example, if a member of a systematic review team is the author of a study included in the review, the Cochrane Collaboration requires the inclusion of other team members who were not involved in the study in question. If employees of a pharmaceutical company or medical device manufacturer are members of a team conducting a review on a product produced by that company or manufacturer, extra effort should be made to make the review team multidisciplinary. The majority of the team members should have no employment or financial relationship to that particular company. Those with a direct financial interest in an intervention may consider abstaining from becoming members of the review team conducting a systematic review of that intervention. [14] Special rules about conflicts of interest pertain to federal employees and "special government # Deciding on Evidence and Outcomes Core issues in determining the types of evidence to use in the development of recommendations hinges upon several considerations. Below are some considerations adapted from those suggested by NICE [17]: • What is the most appropriate type of evidence to answer the question? • How can the most relevant evidence (published and unpublished) be identified? • How can the quality and applicability of evidence be assessed? • How can evidence from different kinds of research be synthesized? • How can quantitative and qualitative data be combined? Evidence-based approaches vary according to the sources used in gathering the evidence. There are many sources of evidence. The following is a listing of some of the most commonly used sources, combined or standing alone: • Systematic reviews of research studies • Meta-analyses of research studies • Econometric analyses • Decision analyses • Review of published systematic reviews • Review of published meta-analyses • Nonsystematic review of research studies # • Expert judgments Once the TDG decides on approaches to obtain the evidence, it needs to identify the outcomes of interest. The identification of outcomes is topic specific. Outcomes can be prioritized, rated by the TDG, and presented to the GSC for review. [3] Logic frameworks can be used to depict the links between the health problem and the interventions and between the interventions and outcomes of interest. # Developing the Logic Framework Logic frameworks (also known as conceptual or analytical frameworks) guide the assessment of an intervention's effectiveness for which guidelines are being developed. approach. [14] Frameworks assist in addressing the following questions: • What interventions or professional practices are to be included in the guideline? • Which health outcomes (ultimate or intermediate) are expected effects of the intervention? • What types of evidence of effectiveness of the interventions are being considered? • How will the quality, quantity, and relevance of the evidence of effectiveness be assessed? • How will the strength of evidence of effectiveness and the strength of recommendation be related? • What assumptions about causal relationships of interventions and health outcomes will be accepted without direct scientific proof? • What form of exposition (narrative or graphic-flow chart, influence diagram, decision tree, or clinical algorithm) is most appropriate for describing the logic framework? The logic framework also helps guideline developers compose a persuasive supporting rationale for the interventions included in the guidelines. The logic framework links the interventions under consideration with the estimated effect, benefits, and harms. We recommend the inclusion of the logic framework in graphic format in the published version of the document. For examples of logic frameworks included in published recommendations, see the publications of the Community Guide. [34,35] # Planning for Dissemination, Implementation, and Evaluation At this point in the development process, the GSC needs to decide whether the dissemination and translation of the guidelines will be done using "in-house" personnel or contractors. Those responsible for disseminating and translating the guidelines need to develop a plan that includes the following: • Target audiences • Venues (hard copies or electronic) • Peer-reviewed journals targeted • Professional organizations targeted • Development of focus groups (quantity, audiences, etc.) • Different formats according to audience needs • Activities and respective leads • Possible training needs • Timetable • Resource needs and costs • Use of plain language and audience-appropriate visuals that match the text • Need for translation of information into languages other than English If the GSC decides that electronic dissemination is the best option, the dissemination and translation group needs to determine the facilitators and barriers for the dissemination and identify the public's needs for evidence-based scientific information on the Internet. If the guidelines will be posted online, some organizations recommend developing online tools to evaluate the website. Implementation and impact evaluation of guidelines are not covered in detail in this primer. However, and because implementation and impact evaluation may influence the development of the guidelines, we encourage developers to consider during the planning phase the main issues that may arise after the release of the guidelines. A systematic review of the effectiveness of various interventions designed to assist in the implementation of research findings conducted by Bero et al in 1998 found that reminders alone or combined with audit and feedback, local consensus processes, and marketing and interactive training were best suited for consistently effective interventions. Audit and feedback alone, local leaders (such as practitioners), local consensus processes and patient-mediated interventions aimed at changing the behavior of health care providers were best suited for interventions of variable effectiveness. Educational materials and educational meetings were best suited for interventions with little or not effect. [36] The use of specific strategies to implement research-based guidelines and recommendations seems to be necessary to ensure that practices change. The most successful are intensive efforts to alter practice. Bero et al contend the choice of intervention should be guided by the evidence on the effectiveness of dissemination and implementation strategies, the characteristics of the message, the recognition of external barriers to change, and the preparedness of practitioners to change. [36] Another activity in the entire cycle of guideline planning, production, dissemination and implementation is the evaluation of impact. Impact evaluation methods are not explored in detail in this primer. However, like in the case of dissemination and implementation, developers need to keep in mind that the initial planning for impact evaluation may affect the development of the guidelines. Impact research in developing countries shows that several factors increase the impact of practice guidelines like involvement of the end-users in developing, launching, and introducing the guidelines; multiple training modalities; providing feedback to prescribers on their prescription practices in relation to guidelines; and effective monitoring and supervision. [37] The main elements in evaluating the impact of guidelines and recommendations follow: • Assessing awareness • Assessing uptake • Assessing health impact • Assessing other impact (e.g., economic, social, environmental) # Planning for Updates We recommend the planning phase address dates and formats for updating the guidelines. As for dates, guideline developers may choose to indicate a specific time frame for retiring the guidelines─ either because new knowledge becomes available or technological advances render the existing guidelines obsolete. Guideline developers may also elect to indicate a time frame for updating the guidelines, either as a one-time event or periodically. As for format, guideline developers may choose to indicate that guidelines will be updated in their entirety or on specific sections. In that case, guideline developers may opt for publishing updates in summary and appendix form. Indicating retiring dates and publication formats for subsequent updated guidelines will make users prone to seeking updates and decrease the probability that practitioners will continue using out-of-date information or practices. # DEVELOPING GUIDELINES AND RECOMMENDATIONS Developing guidelines encompasses diverse processes and activities. This section mainly discusses processes for guidelines and recommendations based on evidence obtained from systematic reviews. The main processes involved in systematic reviews are 1) gathering the evidence, 2) abstracting and assessing the evidence, 3) summarizing findings, and 4) interpreting the evidence to develop the recommendations. Activities within each of the main classifications are included and explained below. If other sources of evidence are used, like expert judgment or surveillance data, the methods used to collect and assess the evidence need to be described in detail in the guideline document. Obtaining evidence in the absence of data is covered briefly in section 4.5. Descriptions of methods to gather information from other sources, including expert opinion, can be found in the literature. [38,39] # Gathering the Evidence Once decisions are made on the type of evidence, sources for that evidence, and outcomes of interest, the next step of conducting a systematic review is gathering the evidence. The main activities included in gathering the evidence are 1) developing a search protocol and inclusion criteria, 2) conducting a literature search, and 3) selecting the relevant literature according to the pre-determined criteria. # Developing the Search Protocol Developing the search protocol involves determining where and how to look for evidence. The following are examples of sources of evidence: • Electronic and manual searches of published literature (peer or non-peer reviewed) • Electronic and manual searches of unpublished literature (e.g., reports, proceedings) • Searches of published or unpublished surveillance data Studies included in the search can be guided by the public health question of interest. Search protocols describe the selection of search terms (i.e., keywords), the sources and databases used for the search, the earliest date from which studies will be sought, and the inclusion criteria for those studies that will form the body of literature selected for screening. # Conducting the Literature Search The search is guided by the search protocol. The types of databases listed in the search protocol will depend greatly on the topic. Most searches, however, include readily available databases. The development of search terms and the locating of topic-specific databases can pose challenges, which can be mitigated by consulting those who are more experienced in the discipline. CDC's Library Services staff provides assistance when formulating and conducting literature searches. Different search platforms may yield different results, especially for recent data. For example, a search of OVID for search term "X" may yield a slightly different citation list than a search of PubMed for the same search term. The following databases, accessible via CDC's Library Services, are the most commonly used for systematic literature reviews: [40] • PubMed • Medline (OVID) • Web of Knowledge • PsycINFO • Cochrane Library • Campbell Library • Embase • CINAHL • Education Resources Information Center (ERIC) • CAB Direct • EconLit If the body of evidence includes systematic reviews conducted by others, we recommend searching the following databases: AHRQ National Guidelines Clearinghouse, Cochrane Collaboration, Campbell Collaboration, CEBM, NICE, CRD, Clinical Guide, and Community Guide. [13][14][15][16][17][18][19][20][21] # Selecting Relevant Literature The selection of relevant literature involves screening the search output according to the predetermined inclusion criteria. Those studies that meet the inclusion criteria are selected using a two-stage screening approach: • Titles and abstracts are screened independently by two reviewers • Full papers are screened independently by two reviewers Any difference of opinion should be resolved between the two reviewers or with the help of a third reviewer under the guidance of the technical lead. The selection process needs to be fully documented. Flow charts may be used to illustrate the inclusion and exclusion process. Software programs can be used to manage search results, but the use of software for this purpose should be explained in the final report. # Abstracting and Assessing the Evidence To ensure consistency, reduce bias, and improve validity and reliability, some organizations have developed standardized procedures to abstract and assess the evidence. Most of these tools are published online. For details on these instruments, consult the procedures of the Cochrane Collaboration [14] and the Clinical Guide or the Community Guide. [20,21] Evidence from new systematic reviews can be presented along with evidence from existing systematic reviews, meta-analyses, or review of meta-analyses. Developers need to keep in mind that the use of evidence from existing systematic reviews follows different criteria than the use of evidence from systematic reviews of single studies. For a critical assessment of existing systematic reviews, consult the CEMB. [16] # Assessing Evidence Quality Evidence quality is defined as the extent to which one can be confident that an estimate of effect or association is real. [16] Assessing evidence quality is important, as it is one of the factors that affect the strength of the recommendation. Methods chosen to assess evidence quality will likely be determined by the evidence-based approach selected for guideline development. These methods vary among guideline authorities like the ones developed by the Clinical Guide, Community Guide, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) authorities. [20,41,42] Evidence quality assessment usually occurs in two phases: assessing individual study quality (often addressed in part by using study inclusion and exclusion criteria, as discussed in Section 4.1.1), and assessing the quality of the body of evidence. Determining the quality of the body of evidence may include assessing study designs and their limitations, as well as assessing internal validity, generalizability, consistency of results, effect size, confidence intervals, and applicability of the evidence to the target population and setting. For example, the Clinical Guide appraises evidence quality on the factors noted above and rates the overall certainty regarding the quality of the full body of evidence as high, moderate, or low. To illustrate, high-quality evidence generally includes consistent results from well-designed, wellconducted studies in representative primary care populations that assess the effects of the preventive service on health outcomes; the conclusion is therefore unlikely to be strongly affected by the results of future studies. In contrast, low-quality evidence signals that the evidence is insufficient to assess effects on health outcomes because of a limited number of studies, flaws in design, gaps in the chain of evidence, etc. The Clinical Guide uses evidence quality to estimate the expected magnitude of benefits, harms, and net benefits (benefits minus harms) that would result from widespread implementation of the preventive service. An indication of evidence certainty is provided within the recommendation statement. More detailed information on how the Clinical Guide rates evidence quality and develops recommendation statements can be found on its website. [20] Similarly, the Community Guide rates the quality of individual studies based on potential threats to internal validity, such as description of the intervention implementation and potential for biases in sampling, measurement, analysis, recruitment, and interpretation of results. [41] After individual study quality is assessed, the quality of the full body of evidence is characterized based on execution of the study designs, design suitability, number of studies, consistency of the results, and whether expert judgment was used or not. Final categories of evidence quality include "strong," "sufficient," "insufficient," or "based on expert opinion." Evidence quality directly relates to the Community Guide recommendation statements. For example, when the evidence is strong, the intervention is recommended based on strong evidence of effectiveness; when there is insufficient evidence, it is determined that available studies do not provide sufficient evidence to determine the effectiveness of the intervention. An alternate approach to rating evidence quality comes from the GRADE Working Group. [42] This approach ranks evidence quality on several factors including study design, limitation of the studies in execution and analyses, consistency of results across studies, applicability of the evidence to the populations and settings proposed for the intervention, and precision in the estimate of effect. [43] Study design is the first step for rating evidence quality. Studies are broadly classified into either randomized controlled trials (RCTs) or observational. Observational studies include time-series, cohort studies, case-control studies, case series, and case reports. Studies are given a numerical quality rating based on their design (e.g., a rating of "1" for RCTs, a rating of "3" for observational studies.) This numerical quality rating can be rated down based on risk of bias (i.e., study limitations that threaten internal validity), publication bias, imprecision, inconsistency, or indirectness. The quality rating can be rated up based on the effect size, doseresponse relationship, or if plausible confounders would have reduced a demonstrated effect. Based on a review of the evidence quality for all the studies, the full body of evidence is given a rating of either high (very confident that the true effect lies close to that of the estimate of the effect), moderate (moderate confidence in the effect estimate), low (limited confidence in the effect estimate), or very low (very little confidence in the effect estimate). [44] A notable characteristic of the GRADE approach is the separation of the rating of evidence quality from the process by which the recommendation is determined. That is, evidence quality does not always equate with the strength of the recommendation. Although high-quality evidence usually leads to a strong recommendation, this is not always the case. On the other hand, low-quality evidence can sometimes lead to strong recommendations depending on factors such as values, preferences, and costs. For information on how evidence quality ratings inform recommendations, see Section 4.4. # Summarizing Findings The types of studies reviewed, methods used to summarize the evidence, and available statistics will determine the best ways for depicting the results. The summary of findings typically includes a narrative description of the findings along with tables or graphics depicting the outcomes of interest. Typically, findings from quantitative studies are presented in summary tables that describe the characteristics of included studies, sample sizes, measures of prevalence or health burden, effect sizes, and confidence intervals. Figures such as forest plots of effect size or risk of bias plots can be used to display the data. In addition to data that speaks to effectiveness of a particular public health strategy, developers should consider summarizing data on feasibility, economic efficiency, acceptability, risks, and unintended consequences in narrative or graphic form. Findings from qualitative studies that are included in the body of evidence should also be reported in text, table, or graphic form. Qualitative data might be reported within intervention studies and address questions related to the effectiveness of a public health intervention (e.g., to understand intervention feasibility and appropriateness; heterogeneity of findings; and values, preferences, and experiences of practitioners and intervention recipients). Qualitative data might also be collected directly by guideline developers through interviews with researchers or practitioners in the field. Also, qualitative data may be obtained among others from program evaluations, gray literature, opinion polls, and policy analyses. Systematic review authorities and academia have developed frameworks and tools for synthesizing qualitative data. [14] Regardless of the methods used, or whether the data are coded from existing research studies or collected directly by guideline developers, the approach to summarizing the findings should be as transparent as possible. Formats may vary, as long as appropriate findings are summarized thoroughly in the guideline document. [45,46] # Interpreting Evidence and Developing Recommendations Developing evidence-based recommendations involves inductive reasoning when it is derived from evidence, deductive reasoning when it is drawn from theory or methodological principles, and inferential reasoning when it involves moving from certainty to uncertainty about what would happen if the recommendation is implemented. [36] Even in those instances when logic frameworks and systematic processes are followed, interpreting and translating evidence to recommendations can be surprisingly difficult. Developing recommendations is influenced by value judgments, policy considerations, and assumptions about a variety of factors, even after a careful review of the evidence. For example, a group that is concerned with feasibility considerations may come to a different set of recommendations than a group that is focused more narrowly on health outcomes, even if both groups are working from the same body of evidence. When considering the same body of evidence, a single specialty group may reach different conclusions than a multidisciplinary group in those cases where the specialty group is biased in favor of implementing interventions in which it has vested interest. Recommendations with higher validity may be produced using multidisciplinary groups where individual biases might be better balanced. The GRADE approach takes these factors into account when determining the direction and strength of recommendations. Recommendations are developed taking into account: 1) quality of the evidence (determined when assessing the results of the systematic review), 2) benefits vs. harms (by examining the health outcomes and legal and ethical considerations), 3) values and preferences of the target audience, and 4) resources (cost implications including feasibility and infrastructure requirements as well as cost-effectiveness analysis). By reviewing these four factors, the TDG determines the direction (i.e., for or against) and the strength (i.e., strong or weak/conditional) of the recommendation. It is important that factors used to develop the recommendation be explicitly recognized and reported. The usefulness of recommendations might be enhanced when they possess the following characteristics, adapted from those provided by NICE: [17] • Are informed by the most appropriate and available evidence • Are set within a framework that acknowledges a range of social judgment • Take into account relevant theories of public health and behavioral change • Reflect the views and experiences of both those being advised to take action and the people who might be affected by that action • Are clear • Are practical Furthermore, developing guidelines includes considering all sources of evidence, including comments from committee discussions and expert judgment. It is important that the processes used for incorporating expert judgment be deliberately considered and be as explicit as possible. # Developing Guidelines with Limited Data On occasion, the rigorous research and findings needed for inclusion in the body of evidence are either lacking or limited. In such cases, guidelines may be based on indirect evidence, practitioner experience, and contextual knowledge. Guidelines based on empirical and contextual knowledge are likely more susceptible to bias and self-interest than guidelines based on direct research evidence. Therefore, the methods used to collect and assess information from experiential and contextual knowledge need to be made as explicit as possible. The complete lack of evidence on a public health intervention, action, or practice is rare. Most often, the information collected to assess public health burden (e.g., from surveillance data), the preferences of practitioners and communities (e.g., from expert opinion or solicitation of patient experience), and the context within which a public health practice is implemented (e.g., from case reports) may be accessed indirectly through the gray literature or drawn from expert opinion. Developers need to report on the nature and source of the evidence when that evidence was obtained from indirect sources. Developers also need to establish clear links between the indirect evidence and the public health problem addressed by the guidelines. Developers can use logic models to highlight how the pieces of evidence link to inform the recommendations. When this evidence is synthesized relying heavily on expert opinion, the best methods for identifying experts (or documents based on expert judgment) and developing consensus opinion statements need to be used and reported. Minimizing bias is essential when obtaining expert opinion and can be accomplished by selecting appropriate methods to gather and interpret the information (e.g., through structured consensus methods such as the Delphi method, nominal group process, or the Glaser method). [38,39] # ECONOMIC CONSIDERATIONS The ways economic information is considered and incorporated in guidelines vary among guideline authorities. In the Community Guide for example, the CPSTF reviews the economic efficiency of interventions that it recommends based on strong or sufficient evidence of effectiveness. According to S. Chattopadhyay (personal communication, April 13, 2012), economic evidence is commonly incorporated in the rationale statement of the Task Force findings. However, for interventions that are particularly expensive to implement, such as using home visits to increase vaccination coverage for children or closing schools to control an influenza pandemic, the economic information is also noted in the recommendation statement of the Task Force's findings. When NICE develops recommendations, both clinical effectiveness and cost effectiveness are discussed. If there is strong evidence that one clinical strategy is both more effective and less costly, clearly this strategy is recommended for the target population. However, when one strategy is more effective but also more costly, then the magnitude of the cost-effectiveness measure is compared to the threshold used by NICE (see below). [47] The GRADE approach considers cost as one of the factors to be considered in the development of the recommendations. [44] One of the main concerns when considering economic information is that resources be chosen to obtain the greatest health improvement or, in other words, whether the intervention is efficient in economic terms. Economic efficiency influences the selection of an intervention, and this selection in turn affects the combination and quantity of resources used in implementing the intervention. Economic efficiency is informed by several economic measures. The most widely used in public health are measures such as cost-effectiveness, cost benefit, cost utility, and to a lesser extent, return on investment. The following considerations may be helpful when considering the magnitudes of economic measures for the development of recommendations: • The recommended level for the cost of an intervention depends on the available budget and on how much money managers are willing to spend in the intervention • The recommended level for cost-effectiveness ratios is set by convention and depends on what managers consider an affordable cost per outcome • The recommended level for cost-utility ratios varies among countries and organizations o The ratio used by NICE is £20,000 to £30,000 per quality adjusted life year (QALY). o The ratio used in the United States varies between $50,000 and $100,000 per QALY. o The amount recommended by WHO is 1 to 3 times the per capita gross domestic product (GDP). • In theory, a project is accepted if the net present value from a cost-benefit analysis is larger than 0 where the benefits are larger than the costs; however, in those cases where health interventions are not cost saving, managers must decide what level of cost per dollar of benefit is acceptable given current resources. • The recommended level for return on investment in financial terms is a positive return per unit of investment; that is, a positive ratio from dividing positive benefits by positive investments. A positive ratio is mathematically feasible by dividing negative benefits by negative investments. However, this is not conceptually feasible because there is no such thing as a "negative investment". By summarizing and interpreting economic studies, systematic reviews make economic information useful and accessible to guideline users. Economic data from systematic reviews facilitates the process of using limited resources in implementing interventions that contribute to making the greatest possible improvement in population health. For information on methods for conducting systematic reviews of economic evaluations, consult Carande-Kulis et al (2000) and the online methods section of the Community Guide. [48,49] For standardized methods of economic evaluation and their application to public health, consult the online CDC course Economic Evaluation of Public Health Preparedness and Response Efforts. [50] # WRITING THE GUIDELINES Guideline documents introduce recommendations to the public health community, describe the evidence supporting the recommendations and explain the process used to move from the evidence to the recommendations. In other words, when guidelines work groups start the writing process, a shift is needed from focusing on the scientific evidence to communicating the recommendations in a way that is most likely to influence practice. Additionally, the communication styles often used in scientific publications are not necessarily appropriate for guidelines documents. The authors of guidelines will need to carefully consider the needs of the target audience and adjust the format of the document and the communication strategy accordingly. The federal Plain Writing Act requires new or substantially revised documents for the public to be written in plain language. In general, a plain writing style that follows the federal language guidelines will make the information understandable for most readers, particularly for those who do not have technical knowledge of the subject matter. [51] # Identifying the Level of Detail A major choice when developing the guidelines document is its level of detail. Although some guideline users may want a full and detailed description of the evidence synthesis process and background data, others may prefer a shorter format that focuses on the recommendations. A longer format can provide a wide range of information needed for multiple audiences (practitioners, policy makers, researchers, etc.) in a single document, but with the downside that user-specific information might be harder to find. Because the document may have multiple audiences, the authors might consider developing multiple versions instead of a single document for everyone. For example, full guidelines may be developed for publication in the MMWR, a reduced version for publication in a peerreviewed journal, a short synopsis for the practitioner, and a fact sheet for the public. A common approach is to publish a concise set of guidelines for practitioners, accompanied by a more comprehensive treatment of the science that can be published separately (or posted on the Web). Hybrid approaches, such as formats that combine a concise presentation of the guidelines along with a brief summary of the scientific evidence, can also be used. This combined approach makes important evidence available to those who want to dig a little deeper than just the bare-bones guidelines. # Describing the Audience The document needs to state: a) who will use the information, b) in what format, and c) how they will use it. Authors need to ensure that the communication style and technical levels are appropriate for the readers and that their needs are being met. Answering the following questions may ease the writing of the guidelines: • What population (age, gender, race and ethnicity, socioeconomic status) and setting (state or local health agency, community, home, workplace, hospital, ambulatory clinic) will the guidelines target? • Who are the guideline users (public, public health professional, advocate, or clinician)? • Whose knowledge, practices, behavior, or decisions will the guidelines attempt to address? • What health measurement, outcome, or condition (risk factor, prevalence, morbidity, mortality, quality of life, healthy, at-risk and asymptomatic, symptomatic, diseased) will the guidelines target for improvement? • What intervention, public health service, or provider practice will the guidelines target to implement or improve? The following questions may help the authors adjust the style and content to the target audience: • What kind of background information and evidence will the audience need? • What information will be needed to determine when the guidelines do and do not apply? • What information and resources will the readers need to implement the guidelines? • Will the audience be largely receptive to the guidelines, or will some readers be skeptical and need more rationale to support the recommendations? # Providing a Methods Section The methods section should provide readers with sufficient understanding of the processes leading to development of the guidelines, enabling them to judge the guidelines' quality, strengths, weaknesses, and limitations. Often, a methods section does not get much attention when guidelines documents are being developed. Sometimes a methods section is added as an afterthought, if at all. However, a well-crafted methods section establishes trust with the reader. Through the methods section, the reader gains an appreciation for the rigor and limitations of the guidelines development process. At a minimum, the methods section should state the following: • the evidence sources • what evidence was (and was not) considered • who participated in the synthesis • how evidence was summarized • how effect size of selected outcomes was reported • how evidence quality was assessed • how the evidence led to the recommendations • how the strength of the recommendations was assessed • how evidence gaps were treated More detail on each of these elements is provided below. # Describing the Evidence The methods section should briefly summarize the evidence domains considered and how the evidence was identified. The methods section should indicate the analytic framework and the specific review approach used to obtain the evidence. The method used to obtain the evidence should be described (e.g., systematic review) and justified. The search protocol, including search terms (e.g., keywords), sources used (e.g., databases, journals, repositories), and inclusion criteria (e.g., language, study type, human subjects inclusion, time frames, population) should be described. The criteria used to select the final evidence for developing the guidelines (e.g., study design, population, intervention, outcomes) should be detailed and justified. How evidence was coded and synthesized should be described (e.g., how data were extracted from studies; how data were synthesized, such as through use of effect measures; whether data were combined through meta-analysis; how heterogeneity in effects was explored). The method used to assess evidence quality should be described. # Describing Relevant Evidence That Was Not Considered Often, some evidence domains could be viewed as relevant but are not considered. For example, evidence may be excluded if it is not in English, not in the peer-reviewed literature, outside certain disciplines, etc. Excluded domains should be mentioned along with the rationale for why the evidence was not considered. Writers also might want to note topics that were not included (e.g., not addressing issues in pregnant women, in non-adults, a particular period for a birth cohort) and why these groups were not included. # Describing Partners Who Participated in the Guideline Development Process Guidelines are developed by people, and knowing who participated may be just as important to the reader as knowing what evidence was considered. Answering the "who" question is a crucial component of all methods sections and is especially important for guidelines that rely upon expert opinion. The document should indicate who participated, how they were selected, their expertise, and disciplines represented. The document should list the professional organizations from which participants were solicited. It should also state whether the work group was composed of or worked under one of CDC's official advisory committees. The document should specify the participants' roles (e.g., authors, advisors, reviewers) distinguishing between participants who approved the final recommendations and those who provided review or input. Finally, authors need to make sure the document specifies how competing interests (e.g., financial, intellectual, professional) among participants were identified, disclosed, and handled (e.g., through recusal from evidence synthesis, deciding on the final recommendation statements). # Describing How the Evidence Led to the Recommendations A good methods section describes how the evidence led to the recommendations. Frequently, this section is the most difficult to write. One challenge is that virtually all guidelines include some measure of expert opinion or judgment. Concisely explaining the rationale used by a panel of experts can be difficult, especially when the evidence base for the recommendation is sparse or a clear effect is not evident. But even for recommendations based on solid evidence, judgment calls will be made, which adds to the difficulty in developing a simple explanation for how the evidence led to the recommendation. The document should explain how the evidence was weighted, how evidence quality was judged, what evidence was considered more (or less) compelling, and how the strength of the evidence was determined. If information was obtained from expert opinion, the processes used (e.g., Delphi process, focus groups, questionnaires) should be described. The document also needs to include the processes used to reach agreement, such as informal consensus, formal consensus, or voting. Most guideline development efforts use a combination of processes. Those groups that have used formal evidence-based frameworks for developing guidelines will likely find it easier to describe the links between the evidence and the recommendations. However, even for guidelines that are largely based on expert opinion, the authors should avoid simply stating that experts reviewed the available materials and made recommendations. Invariably, some level of evidence and rationale exists even for guidelines based on expert opinion, and the authors should provide as much of the rationale as possible. Throughout the process, the authors should record major and possible subjective decisions made and the rationale and assumptions contributing to the decisions, as well as other alternatives considered. These records will enable the authors to accurately describe the suggested details in the methods section. Note that this point should be considered while the experts are still deliberating the recommendations because the rationale may be more difficult to reconstruct after the expert panel has been disbanded. If economic efficiency measures were presented as part of the evidence, the authors need to explain how any of this evidence was used. Most of the time, this evidence is not included in the decision criteria that translates the evidence into recommendations; instead, this evidence is presented as supplemental information. If this evidence was discussed before consensus on the recommendations was reached, the authors need to explain whether the evidence (or lack thereof) of economic efficiency influenced the recommendation. Economic efficiency is covered in detail in Section 5. # Describing How Evidence Gaps Were Treated It is rare for guidelines to lack even a few gaps in the evidence. Guidelines authors should be prepared to explain how these evidence gaps were addressed. Guidelines documents sometimes include statements that evidence gaps were bridged by expert opinion. Whenever possible, guidelines authors should explain what approaches were used by the experts to bridge the gaps, how incomplete evidence was treated, who made the judgment calls, and what assumptions were in play. For example, some guidelines panels may withhold recommendations when conclusive evidence is lacking, whereas others may follow a more precautionary approach and develop a recommendation even when evidence is scarce (unless there is evidence that the measures are harmful). Or, when evidence is lacking and as long as risks are minimal, guidelines panels may default to current established guidelines or practices. Regardless of the approach, the methods section should give readers sufficient information to understand the major gaps in evidence and to decide whether they agree with how these gaps were treated. The manner in which evidence gaps are treated can impede trust with the target audience. Glossing over evidence gaps may damage the credibility of the guidelines. # Writing Guidelines for Maximum Impact on Policy and Practice For guidelines to have maximum impact on policy and practice, the writing needs to be clear, Guidelines might be consulted more often if the recommendations are stated clearly and address WHO should do WHAT to WHOM, UNDER WHAT CIRCUMSTANCES, HOW, and WHY. Newly developed software is now becoming available to assist guidelines developers in crafting recommendation statements in this format. [52,53] In addition, the Conference on Guideline Standardization has developed a checklist for reporting practice guidelines that can serve as a helpful resource. [54] Of critical importance is clearly describing the methods used to synthesize and rate the quality of the evidence. Practitioners may be more likely to follow guidelines when the evidence base is strong and the recommendations are easy to understand. [55,56] One international research study suggests that practitioners are more likely to change their decisions about practices when clear descriptions of evidence quality and strength of recommendations are provided, particularly through use of the GRADE approach. [57] Practitioners also value discussion of factors that might affect the implementation of the recommended intervention or practice such as feasibility, reach, resource requirements, and acceptability. # EXTERNAL REVIEW AND VETTING OF CDC GUIDELINES Each release of a new CDC guideline might have a lasting impact on clinical and public health practice. Guidelines may be converted to policy, implying widespread implementation by a broad range of groups. Guidelines may be even converted into law, entailing subsequent regulatory enforcement. Because of the high profile CDC guidelines may acquire following their release, we recommend guidelines be vetted before publication. Vetting of CDC guidelines ensures that key stakeholders have the opportunity to review and provide critical input. Vetting not only assists in fostering transparency and credibility but also improves the clarity and understanding of the guidelines. Even though it may not be possible to incorporate all the feedback received, vetting of the guidelines has many benefits. Some benefits of vetting are: • Identifying overlooked issues (e.g., new evidence released outside of the literature search period) • Identifying possible post-guideline problems (e.g., feasibility considerations, misinterpretation by the target audiences) • Improving chances of buy-in and adoption • Providing a preview for guideline implementers to prepare to adopt new recommendations # Internal and External Vetting We recommend that CDC guidelines be vetted internally and externally. Vetting processes are defined by various factors such as scope (e.g., broad vs. narrow), level of controversy, number of stakeholders, and timeline (e.g., recommendations for urgency vs. routine revision of long-standing recommendations). Internal vetting is critical for guidelines that cross multiple programs. However, guidelines of narrow scope might not need to be vetted internally. Typically, the need for internal vetting should be determined by CDC's crossclearance policies. Questions about the need for cross-clearance should be directed to the program or the CIO Associate Director for Science (ADS). When cross-clearance is required, having involved the program or ADSs throughout the guideline development process will help ensure timely clearance. External vetting can occur in public meetings during a CDC advisory committee meeting, through informal reviews by key stakeholders, by community engagement forums when public interest in the guideline is expected to be significant, by formal request for comments (e.g., posting in Federal Register), or a combination of the above. [58] Regardless of the format used, the vetting process must be carefully planned so adequate personnel and financial resources are available to handle the reviews. For example, following posting in the Federal Register, comments received will need to be compiled and reviewed. Responses should be prepared for each individual who provided comments (e.g., response matrix). The writing group will typically review the comments and craft responses. Having a record of responses will demonstrate that CDC considered each comment. This documentation is especially important when requests for follow-up occur through controlled correspondence or the Freedom of Information Act. Although the vetting process might vary slightly for different guidelines, each must have a process in place. Vetting is the critical step in the CDC guidelines development process that ensures transparency and credibility. Because of the importance and high impact of guidelines documents, authors should consult with their division or the CIO ADS on whether external peer review is warranted before final clearance. Peer review by external experts is common for guidelines documents as a way to get an independent assessment of the quality of the guidelines. The peer-review process may be limited to a review of the science of the guidelines or may include a review of all aspects of the document. If the review is limited to the science, then reviewers are chosen for their scientific expertise and are typically selected to be as independent of CDC as possible. For other types of review, inclusion of partners and potential users might be desirable, especially those chosen to represent a range of stakeholder positions. Reviews by stakeholders may be conducted within the scientific review process or separately. A specific type of external peer review is required for guidelines documents that are considered influential scientific information (ISI) or highly influential scientific assessments (HISA) as defined by the Final Information Quality Bulletin for Peer Review issued by OMB in 2004. [59] This bulletin requires that specific information be reviewed by qualified experts before dissemination. As noted in the CDC clearance policy, "Clearance is not a forum for extensive peer review or for policy debate. Such discussions belong in the pre-clearance phase." Therefore, guidelines authors should ensure that guidelines documents have been appropriately reviewed for quality of execution and reporting and that policy issues have been resolved before submitting these documents for clearance. If guidelines documents have scientific or policy issues that overlap with other CIOs, those CIOs should be consulted early in the guidelines development process (and, should be part of the guidelines development team). # CLEARANCE OF CDC GUIDELINES AND RECOMMENDATIONS CDC sometimes develops guidelines jointly with other organizations. If a CDC staff member will be listed as a coauthor of a document, or if the document will include the CDC brand, the document requires clearance by CDC. For jointly developed documents, authors should discuss clearance requirements early in the process so external authors understand CDC clearance requirements and are aware that CDC will need to formally approve the final document. Also, CDC authors should ensure they understand review and clearance requirements that the collaborating organizations will impose. Additionally, CDC authors should consult with the division and CIO ADS and others in the clearance chain early in the development of guidelines documents to avoid surprises during the clearance process. Note that CDC clearance is required whenever CDC is listed as a coauthor on a guidelines document-even if CDC is not listed as a formal sponsor or if the person is in a group author listing. This CDC clearance requirement has two notable exceptions: • When a CDC author helps develop guidelines as an approved outside activity (conducted outside of working hours and without the use of CDC resources), the author may be listed without CDC affiliation • When CDC personnel are listed as contributors, reviewers, or consultants, although they are not listed as coauthors When these situations occur, include a disclaimer stating that these roles do not necessarily imply CDC agreement or endorsement of the guidelines or recommendations. In such cases formal CDC clearance is not necessary (although supervisory approval is needed). One additional clarification should be made on the use of disclaimers in guidelines documents. CDC authors are accustomed to using the standard disclaimer on journal publications required by OMB's Final Information Quality Bulletin for Peer Review. [59] However, because CDC guidelines documents represent the official position of CDC, the OMB disclaimer should not be used on guidelines documents when they are sponsored by CDC or a CDC staff member is listed as a coauthor. Guidelines authors can consider whether other types of disclaimers are appropriate for the specific document (e.g., disclaimers noting that mention of specific products does not imply endorsement by CDC). # RECOMMENDED STANDARDS FOR CDC PUBLIC HEALTH # GUIDELINES There are advantages to using standardized approaches for guidelines development. A number of organizations have adopted uniform frameworks for guidelines they develop. However, the breadth of disciplines and topic areas at CDC makes it impractical to use a single, unified approach for CDC guidelines. Therefore, we are not recommending a single approach; instead, we have identified a set of recommended standards we recommend for CDC guidelines. Although these standards might not apply in special instances, most CDC guidelines can be developed using these principles. The guidelines development process should include the following: 1. Identify the public health problem on a given topic, need for new or revised guidelines, and required resources for development: Before developing CDC guidelines, the sponsoring program should identify the topic for the guidelines and assess the basis for developing new or revised guidelines. This assessment should include an evaluation of the public health need for the guidelines on the topic, the relationship to CDC's mission and priorities, a review of existing guidelines on the topic, pros and cons of developing the new guidelines (including implications if guidelines are not developed), estimated resources (personnel and budget), timeframe for developing the guidelines, and a list of partners or organizations that will be engaged. This assessment should be shared with senior leadership (e.g., CIO director) before starting development. 8. Involve an explicit scientific quality and policy control process: The guidelines development work groups should be provided with a description of how the guidelines will be finalized and cleared and how disagreements or inconsistencies will be resolved. Typically, guidelines development groups with external participants provide advice to CDC, and thus the role of CDC clearance and final CDC acceptance of the guidelines should be explained. The guidelines document should report on the following topics: 1. Guideline development process: Guidelines documents should clearly describe the process used to develop the guidelines. This description should include who participated in the process, how they participated, how decisions were made, who had final approval of the document, and potential competing interests among participants. 2. Evidence synthesis process: The guidelines document needs to describe the process used to synthesize the evidence; for example, through systematic literature review. If a systematic review was not feasible (e.g., because of resource allocations or time constraints) and only a narrative review is included, make sure the evidence-gathering process is as complete and methodical as possible and the report is clear about how the evidence was identified and evaluated. 3. The evidence base supporting the recommendations: The evidence base used to develop the guidelines should be described and summarized. A description of the methods used to evaluate the suitability of articles should be provided. Unpublished data sources should be described. If notable sources of evidence were not used, mention them and explain why they were not included in the body of evidence. 4. The quality of the evidence and strength of the recommendations: The document should describe the quality of the evidence, the method used to assess the quality of the evidence, how the evidence led to the recommendations, and the strength of the recommendations based on the effect size of selected outcomes and other factors (e.g., potential harms, values and preferences, economic efficiency). 5. Limitations and applicability of guidelines: Guidelines documents should explain significant limitations or caveats of the guidelines, including (when appropriate) situations where the guidelines may not apply. 6. Relationship to similar or overlapping guidelines: Guidelines should state how they are related to similar or overlapping guidelines. If a guidelines document updates or supersedes previous guidelines, this should be stated. # APPENDIX I -GLOSSARY Analytic framework -A process usually represented by a diagram that shows hypothesized links between an intervention and related intermediate or final health and non-health outcomes. [21] Applicability -Whether the intervention process could be implemented in the local setting, no matter the outcome. [62] Algorithm -A procedure consisting of a sequence of algebraic formulas and logical steps to calculate or determine a given task. [63] Bias -Deviation of results or interferences from the truth. [64] Body of evidence -The complete set of qualifying studies compiled using systematic or nonsystematic reviews. [21] Case study -Method of study in which persons with the disease (or condition) of interest are compared with a suitable control group of persons without the disease. [65] Comparison group -A group that was not exposed to a particular intervention; the control group, used to determine what would have happened if the intervention had not been carried out. [21] Effect -The change in an outcome that results from an intervention. [21] Effect size -The magnitude of the effect measured in a study of the intervention. [21] Effectiveness -The degree to which an intervention achieves a desired outcome in practice. [21] Efficiency -Carrying out production so as to obtain the maximum amount of output for any given set of inputs (technical efficiency) or choosing inputs so as to minimize cost of production (cost efficiency). [66] Evidence-based − The use of scientific data to confirm that proposed interventions or practices are appropriate in light of their high probability of producing the best and most favorable outcome. [67] External validity -The ability to generalize study results to populations and context beyond the particular ones included in the studies themselves (see applicability). [21] Guideline steering committee − In-house group composed of CDC staff with the functions of overseeing each step of the guideline development process. Health outcome -The change in health that is hypothesized to result from the intervention (e.g., reduced morbidity or mortality or increased physical, mental, or psychological function). [21] Impact -The association between an exposure and an outcome in a meaningful public health context. Measures of impact reflect the degree of exposure contributing to the frequency of disease in the population. Two measures of public health impact often used are the attributable proportion and efficacy or effectiveness. [68] Intermediate outcome -One in a series of intermediate effects from an intervention potentially linked to a final health outcome. An intermediate outcome with a strong and established link to a final health outcome may serve as a recommendation outcome. [21] Internal validity -A study trait indicating that the measured effect resulted from implementing the intervention. [21] Intervention -A specific activity pursued by public health practitioners aimed at reducing disease risk, treating illness, ameliorating the consequences of disease and disability, or preventing a health problem. [63] Meta-analysis -A systematic, quantitative method for combining information from multiple studies to derive a meaningful answer to a specific question. [65] Other effects -Outcomes or effects other than anticipated as a possible result of the intervention; effects can be positive (beneficial) or negative (harmful). [21] Policy -Laws, regulations, and formal and informal rules and understandings that are adopted on a collective basis to guide individual and collective behavior. [65] Reliability -The degree of stability exhibited when a measurement is repeated under identical conditions; the degree to which the results obtained by a measurement procedure can be replicated. [65] Systematic review -A process by which a body of literature is reviewed and assessed using systematic methods intended to reduce bias in the body of evidence. [21] Transferability -Degree to which the results of a study or systematic review can be extrapolated to other circumstances, in particular to routine to public health or health care situations. [65]	None	None
5517b106da0213d9412877d5c34262296d201211	cdc	None	Health Laboratories (APHL) are writing to share information on the only available differentiation assay as well as interim solutions for HIV testing. The CDC and APHL continue to recommend that laboratories use a laboratory-based HIV antigen/antibody HIV screening immunoassay, followed, when reactive, by an HIV-1/HIV-2 antibody differentiation immunoassay. When the differentiation assay returns a negative or indeterminate result, perform an HIV-1 nucleic acid test (NAT). 1 In addition to being accurate, HIV testing should be expedited to reduce the time to antiretroviral treatment because infected persons have better health outcomes when they are treated earlier and treatment of infected persons reduces transmission of HIV to others. # Results provided by new HIV-1/HIV-2 antibody differentiation supplemental assay There is one FDA-approved HIV-1/HIV-2 antibody differentiation immunoassay for supplemental testing that continues to be manufactured (Geenius™ HIV 1/2 Supplemental Assay, Redmond, WA). Its package insert provides test result reporting language that should be followed. The test produces three results not generated by its predecessor: HIV-2 positive with HIV-1 cross reactivity, HIV-2 indeterminate, and HIV indeterminate. 2 - An HIV-2 positive with HIV-1 cross reactivity result should be considered HIV-2 positive. This result is distinct from HIV positive untypable (undifferentiated), which would indicate the possibility of dual infection with HIV-1 and HIV-2. Persons with either result should be referred to medical care. - Specimens with HIV-2 indeterminate results require additional testing. First, Geenius testing should be repeated with the same specimen. If the specimen tests HIVnegative on repeat this should be reported as the final result for the Geenius and testing with an HIV-1 NAT is indicated. If the specimen is repeatedly HIV-2 indeterminate, then according to the package insert, 3 testing should be repeated 2-4 - weeks later with a new specimen. However, data presented at the 2016 HIV Diagnostics Conference that became available after FDA approved the package insert indicate that some persons with repeatedly HIV-2 indeterminate results have acute HIV-1 infectiion. If a specimen repeatedly produces HIV-2 indeterminate results, an HIV-1 NAT should be conducted. If HIV-1 RNA is detected by NAT, this result indicates acute HIV-1 infection, and the person should be referred for immediate medical care. If the HIV-1 NAT result is negative, refer the specimen for testing with a different validated supplemental HIV-2 test (antibody test or NAT) or repeat testing in 2 to 4 weeks. Supplemental HIV-2 testing may be available through commercial laboratories, public health laboratories or CDC. - HIV indeterminate results should prompt the same testing sequence as described above for repeatedly HIV-2 indeterminate results. First, an HIV-1 NAT should be conducted. If HIV-1 RNA is detected by NAT, this result indicates acute HIV-1 infection, and the person should be referred for immediate medical care. If the HIV-1 NAT result is negative, refer the specimen for testing with a different validated supplemental HIV-2 test (antibody test or NAT) or repeat testing in 2 to 4 weeks. Supplemental HIV-2 testing may be available through commercial laboratories, public health laboratories or CDC. There may be circumstances under which a laboratory is unable to adopt the FDAapproved HIV-1/HIV-2 antibody differentiation immunoassay. In this situation, a laboratory has alternatives for that step in the algorithm, some of which could delay turnaround time for test results. - Send specimens to another laboratory that offers the FDA-approved supplemental HIV antibody differentiation assay. - Refer to CDC/APHL laboratory testing guidance section I, "Alternative Testing Sequences When Tests in the Recommended Algorithm Cannot be Used" . 1 - Validate another HIV test for use as a supplemental antibody test. A validated test is one for which an individual laboratory has demonstrated the ability to produce accurate results according to the standards of the Clinical Laboratory Improvement Amendments (CLIA) or other regulatory entities and can therefore be used to report clinical results for diagnosis and patient management. There will remain cases for which diagnostic tests and algorithms are not accurate. Biologic causes for false-positive and false-negative HIV test results have been reported. Preand post-analytic steps such as incorrect specimen type, specimen mix-up, mislabeling or data transcription errors can also lead to incorrect HIV test results. Inconsistent or conflicting test results should therefore be investigated with follow-up testing on a newly collected specimen. Thank you for your commitment to accurate laboratory testing for HIV. Please send any comments or questions to www.cdc.gov/info or 1-800-CDC-INFO.	# Health Laboratories (APHL) are writing to share information on the only available differentiation assay as well as interim solutions for HIV testing. The CDC and APHL continue to recommend that laboratories use a laboratory-based HIV antigen/antibody HIV screening immunoassay, followed, when reactive, by an HIV-1/HIV-2 antibody differentiation immunoassay. When the differentiation assay returns a negative or indeterminate result, perform an HIV-1 nucleic acid test (NAT). 1 In addition to being accurate, HIV testing should be expedited to reduce the time to antiretroviral treatment because infected persons have better health outcomes when they are treated earlier and treatment of infected persons reduces transmission of HIV to others. # Results provided by new HIV-1/HIV-2 antibody differentiation supplemental assay There is one FDA-approved HIV-1/HIV-2 antibody differentiation immunoassay for supplemental testing that continues to be manufactured (Geenius™ HIV 1/2 Supplemental Assay, Redmond, WA). Its package insert provides test result reporting language that should be followed. The test produces three results not generated by its predecessor: HIV-2 positive with HIV-1 cross reactivity, HIV-2 indeterminate, and HIV indeterminate. 2 • An HIV-2 positive with HIV-1 cross reactivity result should be considered HIV-2 positive. This result is distinct from HIV positive untypable (undifferentiated), which would indicate the possibility of dual infection with HIV-1 and HIV-2. Persons with either result should be referred to medical care. • Specimens with HIV-2 indeterminate results require additional testing. First, Geenius testing should be repeated with the same specimen. If the specimen tests HIVnegative on repeat this should be reported as the final result for the Geenius and testing with an HIV-1 NAT is indicated. If the specimen is repeatedly HIV-2 indeterminate, then according to the package insert, 3 testing should be repeated 2-4 • weeks later with a new specimen. However, data presented at the 2016 HIV Diagnostics Conference that became available after FDA approved the package insert indicate that some persons with repeatedly HIV-2 indeterminate results have acute HIV-1 infectiion. [4][5][6] If a specimen repeatedly produces HIV-2 indeterminate results, an HIV-1 NAT should be conducted. If HIV-1 RNA is detected by NAT, this result indicates acute HIV-1 infection, and the person should be referred for immediate medical care. If the HIV-1 NAT result is negative, refer the specimen for testing with a different validated supplemental HIV-2 test (antibody test or NAT) or repeat testing in 2 to 4 weeks. Supplemental HIV-2 testing may be available through commercial laboratories, public health laboratories or CDC. • HIV indeterminate results should prompt the same testing sequence as described above for repeatedly HIV-2 indeterminate results. First, an HIV-1 NAT should be conducted. If HIV-1 RNA is detected by NAT, this result indicates acute HIV-1 infection, and the person should be referred for immediate medical care. If the HIV-1 NAT result is negative, refer the specimen for testing with a different validated supplemental HIV-2 test (antibody test or NAT) or repeat testing in 2 to 4 weeks. Supplemental HIV-2 testing may be available through commercial laboratories, public health laboratories or CDC. There may be circumstances under which a laboratory is unable to adopt the FDAapproved HIV-1/HIV-2 antibody differentiation immunoassay. In this situation, a laboratory has alternatives for that step in the algorithm, some of which could delay turnaround time for test results. • Send specimens to another laboratory that offers the FDA-approved supplemental HIV antibody differentiation assay. • Refer to CDC/APHL laboratory testing guidance section I, "Alternative Testing Sequences When Tests in the Recommended Algorithm Cannot be Used" [pages 19-20]. 1 • Validate another HIV test for use as a supplemental antibody test. A validated test is one for which an individual laboratory has demonstrated the ability to produce accurate results according to the standards of the Clinical Laboratory Improvement Amendments (CLIA) or other regulatory entities and can therefore be used to report clinical results for diagnosis and patient management. There will remain cases for which diagnostic tests and algorithms are not accurate. Biologic causes for false-positive and false-negative HIV test results have been reported. Preand post-analytic steps such as incorrect specimen type, specimen mix-up, mislabeling or data transcription errors can also lead to incorrect HIV test results. Inconsistent or conflicting test results should therefore be investigated with follow-up testing on a newly collected specimen. Thank you for your commitment to accurate laboratory testing for HIV. Please send any comments or questions to www.cdc.gov/info or 1-800-CDC-INFO.	None	None
f0226eb221893996aa782a15db25187264c3095e	cdc	None	Key changes made to update the May 24, 2010, version o f the guidelines are summarized below. Throughout the revised guidelines, significant updates are highlighted and discussed. R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States i R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States iii Recom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health a n d Interventions to Reduce Perinatal HIV Transmission in the United States vii Public comments A 2-week public comment period follows release of the updated guidelines on the AIDSinfo Web site. The Panel reviews comments received to determine whether additional revisions to the guidelines are indicated. The public may also submit comments to the Panel at any time at# - This section and Table 3 include updates on recent results from international clinical trials, includ ing HPTN 046 in breastfeeding infants, which demonstrated that extending infant nevirapine pro phylaxis from 6 weeks to 6 months improved efficacy in reducing postnatal infections, and NICHD-HPTN 040/PACTG 1043 in formula-feeding infants, which demonstrated that when moth ers have not received antepartum antiretroviral (ARV) drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen. - Preconception Care and Table 4 # (Drug Interactions Between H orm onal Contraceptives and A n tiretroviral A gents) : - This section includes a new subsection on Reproductive Options for HIV Concordant and Serodiscordant Couples. The subsection includes discussion of HPTN 052 trial in discordant cou ples, which demonstrated that initiating antiretroviral therapy (ART) in infected individuals with CD4 cell counts from 350 to 550 cells/mm3 reduced the risk o f transmission to seronegative part ners. The subsection also includes discussion on trials of pre-exposure ARV prophylaxis. - The section includes a new Table (Table 4) on drug interactions between hormonal contracep tives and ARV drugs. - Table 5 on ARV drugs in pregnancy has been revised to include drug formulation and dosing in formation in addition to pregnancy-related pharmacokinetic and toxicity data and recommenda tions for use in pregnancy. Table 5 also includes the newly approved drug rilpivirine. - There is expanded discussion on treatment recommendations for adults and postpartum discon tinuation o f ARV drug regimens. - Tenofovir has moved from a nucleoside reverse transcriptase inhibitor (NRTI) for Use in Spe cial Considerations to an Alternative NRTI choice; it is the Preferred NRTI choice for women who are co-infected with HIV and hepatitis B virus. - Indinavir and nelfinavir have moved from Alternative protease inhibitor (PI) choices to PIs to Use in Special Circumstances. - HIV-Infected Pregnant W om en W ho H ave N ever R eceived Antiretroviral Drugs (Antiretroviral N aive): This section includes expanded discussion o f new data suggesting early and sustained control of HIV viral replication is associated with decreased transmission in women who have undetectable viral load at delivery-data which favors initiation o f ARV drugs as early in pregnancy as possible for all women. - HIV /H epatitis B C oinfection: The Panel now recommends combination ARV drug regimens in cluding anti-hepatitis B drugs for all HIV-infected pregnant women with hepatitis B virus (HBV) co infection: - All pregnant women with HIV/HBV coinfection should receive a combination ARV drug regi men, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue re verse transcriptase inhibitor (NtRTI) backbone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI). - A cute H IV Infection: This is a new section discussing diagnosis and management o f acute HIV-1 infection in pregnancy. - HIV-2 Infection and Pregnancy: This is a new section discussing diagnosis and management of HIV-2 infection in pregnancy. - Com bination Antiretroviral Drugs and Pregnancy O utcom e: Data from several new studies on preterm delivery and combination ARV drug regimens are reviewed in this section. The Panel notes the following: - Clinicians should be aware o f a possible small increased risk o f preterm birth in pregnant women receiving PI-based combination ARV regimens; however, given the clear benefits of such regimens for both the wom en's health and the prevention o f mother-to-child transmission, PIs should not be withheld for fear o f altering pregnancy outcome (A II). - Intrapartum Antiretroviral T herapy/Prophylaxis: Based on the results o f the NICHD-HPTN 040/P1043 clinical trial, the Panel's no longer recommends intrapartum single-dose nevirapine for HIV-infected women in labor who have not received antepartum drugs. In this circumstance, the Panel recommends the following: - Intravenous zidovudine is recommended for HIV-infected women in labor who have not re ceived antepartum ARV drugs, and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (A II). - Postpartum C are: This section includes expanded discussion o f considerations regarding stopping ARVs postpartum, including discussion o f results o f HPTN 052 and o f the importance o f counseling on safer sex practices and contraception during the postpartum period. - Infant Antiretroviral Prophylaxis and - The Panel now recommends that twice daily dosing can be used for the 6-week zidovudine prophylaxis regimen in full-term infants. - The recommended dose o f zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, begin ning as soon after birth as possible and preferably within 6-12 hours o f delivery. - The design and results o f the NICHD-HPTN 040/PACTG 1043 clinical trial in formula-fed in fants are discussed. The trial demonstrated that when mothers have not received antepartum ARV drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen. Based on these data, the Panel's recommenda tion is now: - Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, started as soon after birth as possible (AI). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses o f nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen o f zidovudine, nelfinavir and lamivudine. The 2drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States. (see General Considerations for Choice o f Infant Prophylaxis and Table 9) (A I). - Table 9 includes the dosing for the 2-drug regimen used in the NICHD-HPTN 040/PACTG 1043 trial. - A new subsection is included on management o f breastfeeding infants o f mothers first diag nosed with HIV infection during the postpartum period. , develops these guidelines. The guidelines provide health care providers with information for discussion with HIV-infected pregnant women to enable the patient/provider team to make informed decisions regarding the use o f ARV drugs during pregnancy and use o f scheduled cesarean delivery to reduce perinatal transmission o f HIV. The recommendations in the guidelines are accompanied by discussion o f various circumstances that commonly occur in clinical practice and the factors influencing treatment considerations. The Panel recognizes that strategies to pre vent perinatal transmission and concepts related to management o f HIV disease in pregnant women are rapidly evolving and will consider new evidence and adjust recommendations accordingly. The updated guidelines are available from the AID Sinfo Web site (). Health care providers considering the use o f ARV agents for HIV-infected women during pregnancy must take into account two separate but related issues: 1. antiretroviral treatment (ART) o f maternal HIV infection; and 2. ARV chemoprophylaxis to reduce the risk o f perinatal transmission o f HIV. The benefits o f ARV drugs for a pregnant woman must be weighed against the risks o f adverse events to the woman, fetus, and newborn. Combination drug regimens are considered the standard o f care both for treatment o f HIV infection and for prevention o f perinatal transmission o f HIV2, 6. After provider coun seling and discussion on ARV drug use during pregnancy, a pregnant w om an's informed choice on whether to take ARV drugs either for her treatment or for prevention o f mother-to-child transmission or to follow other medical recommendations intended to reduce perinatal transmission o f HIV should be re spected. Coercive and punitive policies are potentially counterproductive; they may undermine provider patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize fetal and neonatal well-being. The current guidelines have been structured to reflect the management o f an individual mother-child pair and are organized into a brief discussion o f preconception care followed by principles for management o f the woman and her infant during the antepartum, intrapartum, and postpartum periods. Although peri natal transmission of HIV occurs worldwide, these recommendations have been developed for use in the United States. Alternative strategies may be appropriate in other countries. Policies and practices in other countries regarding the use o f ARV drugs for reduction o f perinatal transmission o f HIV may differ from the recommendations in these guidelines and will depend on local considerations, including avail ability and cost o f ARV drugs, accessibility o f facilities for safe intravenous infusions during labor, and local recommendations regarding breastfeeding by HIV-infected women. # Guidelines Development Process # Topic Comment Goal of the guidelines Provide guidance to HIV care practitioners on the optimal use of antiretroviral (ARV) agents in pregnant women for treatment of HIV infection and for prevention of mother-to-child transmission of HIV in the United States. # Panel members The Panel is composed of approximately 30 voting members who have expertise in management of pregnant HIV-infected women (such as training in either obstetrics/gynecology or women's health) and interventions to prevent mother-to-child transmission (such as specialized training in pediatric HIV infection) as well as com munity representatives with knowledge of HIV infection in pregnant women and interventions to prevent mother-to-child transmission. The U.S. government representatives, appointed by their agencies, include at # Financial All members of the Panel submit a written financial disclosure annually reporting any association with man disclosures ufacturers of ARV drugs or diagnostics used for management of HIV infections. A list of the latest disclo sures is available on the AIDSinfo Web site (). # Users of the guidelines Providers of care to HIV-infected pregnant women and to HIV-exposed infants Funding source Office of AIDS Research (OAR), NIH # Evidence collection The recommendations in these guidelines are generally based on studies published in peer-reviewed jour nals. On some occasions, particularly when new information may affect patient safety, unpublished data presented at major conferences or prepared by the FDA and/or manufacturers as warnings to the public may be used as evidence to revise the guidelines. # Recommenda tion grading See Table 2 . # Method of synthesizing data Each section of the guidelines is assigned to a small group of Panel members with expertise in the area of in terest. The members synthesize the available data and propose recommendations to the entire Panel. The Panel discusses and votes on all proposals during monthly teleconferences. Proposals receiving endorsement from a consensus of members are included in the guidelines as official Panel recommendations. Other guidelines These guidelines focus on HIV-infected pregnant women and their infants. Other guidelines outline the use of antiretroviral therapy (ART) in nonpregnant HIV-infected adults and adolescents, HIV-infected children, and people who experience occupational or nonoccupational exposure to HIV. The guidelines described are also available on the AIDSinfo Web site (). Preconception management for non pregnant women of reproductive age is briefly discussed in this document. However, for more detailed dis cussion on issues of treatment of nonpregnant adults, the Working Group defers to the designated expertise offered by Panels that have developed those guidelines. # Update plan The Panel meets monthly by teleconference to review data that may warrant modification of the guidelines. Updates may be prompted by new drug approvals (or new indications, new dosing formulations, or changes in dosing frequency), new significant safety or efficacy data, or other information that may have a significant impact on the clinical care of patients. In the event of significant new data that may affect patient safety, the Panel may issue a warning announcement and accompanying recommendations on the AIDSinfo Web site until the guidelines can be updated with appropriate changes. Updated guidelines are available at the AIDSinfo Web site (). Recommendations in these guidelines are based on scientific evidence and expert opinion. Each recom mended statement is rated with a letter of A , B , or C that represents the strength o f the recommendation and with a numeral I , II, or III, according to the quality of evidence. # Basis for Recommendations Strength of Recommendation Quality of Evidence for Recommendation # Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmission of HIV (Updated September 14, 2011) Panel's Recommendations - Antiretroviral (ARV) drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepar tum viral load and providing infant pre-and post-exposure prophylaxis. Therefore, combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV (AI). Zidovudine and other ARV drugs can reduce perinatal transmission through a number o f mechanisms. Antenatal drug administration decreases maternal viral load in blood and genital secretions, which is a particularly important mechanism of action in women with high viral loads. Even among women with HIV RNA levels <1,000 copies/mL, however, ARV drugs have been shown to reduce the risk o f trans mission1. In addition, the level o f HIV RNA at delivery and receipt o f antenatal ARV drugs are inde pendently associated with risk o f transmission, suggesting that reduction in viral load is not solely responsible for the efficacy o f ARV prophylaxis2-3. Another mechanism o f protection is infant pre-exposure prophylaxis achieved by administering ARV drugs that cross the placenta from mothers to infants and produce adequate systemic drug levels in the infants. This mechanism o f protection likely is particularly important during passage through the birth canal, a time when infants receive intensive exposure to maternal genital-tract virus. Infant post-expo sure prophylaxis is achieved by administering drugs to infants after birth. This intervention provides protection from cell-free or cell-associated virus that may have entered the fetal/infant systemic circula tion through maternal-fetal transfusion associated with uterine contractions during labor or systemic dis semination o f virus swallowed during infant passage through the birth canal. The efficacy o f ARV drugs in reducing perinatal transmission likely is multifactorial, and each o f the mechanisms previously described may make a contribution. The importance o f the pre-and post-expo sure components of prophylaxis in reducing perinatal transmission is demonstrated by the efficacy o f in terventions that involve administration o f ARVs only during labor and/or to the newborns, discussed in the next section4-10. transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double blind, placebo-controlled trial. Lancet. # Lessons from International Clinical Trials of Short-Course Antiretroviral Regimens for Prevention of Perinatal Transmission of HIV (Updated September 14, 2011) Panel's Recommendations - All pregnant women who require therapy for their own health should receive a combination antepartum antiretroviral (ARV) drug regimen containing at least three drugs for treatment, which will also reduce the risk of perinatal transmis sion (AI). - Combination antepartum drug regimens are also recommended for prevention of perinatal transmission in women who do not yet require therapy for their own health (AII). - ARV prophylaxis is more effective when given for a longer than a shorter duration. Therefore, ARV drugs should be started as soon as possible in women who require treatment for their own health (AI), and without delay after the first trimester in women who do not require immediate initiation of therapy for their own health, although earlier initiation can be considered in these women as well (BIII) (see Recommendations for Use of Antiretroviral Drugs during Pregnancy). - In the absence of antepartum administration of ARV drugs, ARV drugs should be administered intrapartum in combina tion with infant ARV prophylaxis to reduce the risk of perinatal transmission (see Intrapartum Care) (AI); if antepartum and intrapartum ARV drugs are not received, infant ARV prophylaxis should be provided (see Infant Antiretroviral Pro phylaxis) (AI). - Adding single-dose intrapartum/newborn nevirapine to the standard antepartum combination ARV regimens used for prophylaxis or treatment in pregnant women in the United States is not recommended. This is because the drug does not appear to provide additional efficacy in reducing transmission and it may be associated with development of nevirapine resistance (AI). - Breastfeeding is not recommended for HIV-infected women in the United States-including those receiving combination antiretroviral therapy (ART)-because safe, affordable, and feasible alternatives are available (AII). A number o f simple regimens have been identified that are effective in reducing perinatal transmission in resource-limited countries (see Table 3) . Direct comparison o f results from trials o f these regimens are difficult because the studies involved diverse patient populations residing in different geographic loca tions, infected with various viral subtypes, and with different infant feeding practices. However, some general conclusions can be drawn from the results, which are relevant to understanding use o f ARV drugs for prevention o f perinatal transmission in both resource-limited and resource-rich countries. 30.6% at 15 months (30% efficacy). - MTCT was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy). - MTCT was 16.5% in ZDV arm vs. 26.1% in placebo arm at 3 months (37% efficacy). - MTCT was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy). # PETRA trial South Africa, Tanzania, and Uganda6 Breastfeeding and for mula feeding 12.3% in sdNVP arm vs. 9.3% in ZDV + 3TC arm at 8 weeks (difference not statistically significant, P = 0.11). Short-short arm stopped at interim analysis (10.5%). MTCT was 6.5% in long-long arm vs. 4.7% in long short arm and 8.6% in short-long arm at 6 months (no statistical dif ference). In utero transmission was significantly higher with short vs. long maternal therapy regimens (5.1% vs. 1.6%). 77% of women received dual-or triple-combination ARV regimens during pregnancy. Trial stopped early due to very low MTCT in both arms: 1.4% in sdNVP arm vs. 1.6% in placebo arm (53% of MTCT was in utero). ZDV-alone arm was stopped due to higher MTCT than the NVP-NVP arm (6.3% vs. 1.1%). In arms in which the mother received sdNVP MTCT rate did not differ significantly between the infant receiving or not receiving sdNVP (2.0% vs. 2.8%). MTCT was 6.5% (95% CI, 3.9%-9.1%) at 6 weeks; MTCT for histor ical control group receiving short ZDV (98% breastfed) was 12.8%. Formula feeding + ZDV (infant) 4 weeks + sdNVP infant only - Initial design: In formula-feeding arm, MTCT at 1 month was 2.4% in maternal and infant sdNVP arm and 8.3% in placebo arm (P = 0.05). In breastfeeding + infant ZDV arm, MTCT at 1 month was 8.4% in sdNVP arm and 4.1% in placebo arm (difference not statistically significant). - R e v is e d d e sig n : MTCT at 1 month was 4.3% in maternal + infant sdNVP arm and 3.7% in maternal placebo + infant sdNVP arm (no significant dif ference; no interaction with mode of infant feeding). - MTCT at 7 months was 9.1% in breastfeeding + ZDV arm and 5.6% in formula-feeding arm; mortality at 7 months was 4.9% in breastfeeding + ZDV arm vs. 9.3% in formula-feeding arm; HIV-free survival at 18 months was 15.6% breastfeeding + ZDV arm vs. 14.2% formula-feeding arm. -MTCT at 6 weeks was 5.3% in sdNVP arm vs. 2.5% in extended NVP arm (risk ratio 0.54, P = 0.009). -MTCT at 6 months was 9.0% in sdNVP arm vs. 6.9% in extended NVP arm (risk ratio 0.80, P = 0.16). - HIV-free survival significantly lower in extended NVP arm at both 6 weeks and 6 months of age. # PEPI-Malawi Trial Malawi19 Breastfeeding sdNVP + ZDV for 1 week (control) vs. two extended infant regimens (NVP or NVP/ZDV) for 14 weeks No AP ARV Oral IP: sdNVP (if mother presents in time) Infant sdNVP + ZDV for 1 week (control) vs. con trol + NVP for 14 weeks vs. control + NVP/ZDV for 14 weeks - Postnatal infection in infants unin fected at birth: -MTCT at age 6 weeks was 5.1% in control vs. 1.7% in extended NVP (67% efficacy) and 1.6% in ex tended NVP/ZDV arms (69% effi cacy). -MTCT at age 9 months was 10.6% in control vs. 5.2% in extended NVP (51% efficacy) and 6.4% in ex tended NVP/ZDV arms (40% effi cacy). - No significant difference in MTCT be tween the extended prophylaxis arms; however, more hematologic toxicity with NVP/ZDV. A rm 2: Maternal ZDV/3TC for 1 week (no further postnatal prophylaxis); infant sdNVP + ZDV for 1 week (no further postnatal prophy laxis) MITRA - MTCT at birth was 1.8% with mater nal triple-drug prophylaxis Arm 1 and 2.5% with ZDV/sdNVP Arm 2, not significantly different. In women with CD4 cell counts 350-500 cells/mm3, MTCT at birth was 1.7% in both arms. - MTCT at age 12 months was 5.4% with maternal triple-drug prophylaxis Arm 1 and 9.5% with ZDV/sdNVP (with no further postnatal prophy laxis after 1 week) Arm 2 (P = \|0.029). # Mma Bana Botswana24 Breastfeeding Maternal triple-drug prophylaxis (com pares 2 regimens) in women with CD4 cell counts >200 cells/mm3 A rm 1: ZDV/3TC/ABC # A rm 2: ZDV/3TC/LPV/r -MTCT at age 28 weeks was 5.7% in control Arm 1; 2.9% in maternal triple-drug prophylaxis Arm 2 (P = 0.009 vs. control); 1.7% in infant NVP Arm 3 (P <0.001 vs. control). - No significant difference between maternal triple-drug prophylaxis Arm 2 and infant NVP Arm 3 (P = 0.12). - In infants uninfected at age 6 weeks, the 6month infant HIV infection rate was 1.1% (0.3-1.8%) in the extended NVP Arm 1 and 2.4% (1.3-3.6%) in the placebo Arm 2 (P = 0.048). - At infant randomization at age 6 weeks, 29% of mothers in each arm were receiving a triple-ARV regimen for treatment of HIV. - For mothers receiving triple-ARV drugs at the time of randomization, in infants unin fected at age 6 weeks, the 6-month infant HIV infection rate was 0.2% and not statis tically different between extended NVP Arm 1 (0.5%) and placebo Arm 2 (0%). - For mothers with CD4 cell counts >350 cells/mm3 who were not receiving triple ARV drugs, in infants uninfected at age 6 weeks, the 6-month infant HIV infection rate was 0.7% (0-1.5%) in the extended NVP Arm 1 and 2.8% (1.3 -4.4%) in the placebo Arm 2 (P = 0.014). Efficacy has been demonstrated for a number o f short-course ARV regimens, including those with zi dovudine alone; zidovudine plus lamivudine; single-dose nevirapine; and single-dose nevirapine com bined with either short-course zidovudine or zidovudine/lamivudine2, 4-9, 13-15. In general, combination regimens are more effective than single-drug regimens in reducing perinatal transmission. In addition, administration of ARV drugs during the antepartum, intrapartum, and postpartum periods is superior in preventing perinatal transmission than administration o f ARV drugs only during the antepartum and in trapartum periods or intrapartum and postpartum periods6, 12, 28. Use o f ARV drugs to prevent transmis sion is highly effective, even among HIV-infected women with advanced disease24, 29. Almost all trials in resource-limited countries have included oral intrapartum prophylaxis, with varying durations o f maternal antenatal and/or infant (and sometimes maternal) postpartum prophylaxis. Perina tal transmission is reduced by regimens with antenatal components starting as late as 36 weeks' gestation and lacking an infant prophylaxis component2, 4-5. However, longer duration antenatal ARV prophylaxis (starting at 28 weeks' gestation) is more effective than shorter duration ARV prophylaxis (starting at 36 weeks' gestation), suggesting that a significant proportion o f in utero transmission occurs between 28 and 36 weeks' gestation9. Analyses from the European National Study o f HIV in Pregnancy and Child hood have shown that efficacy is increased with even longer duration antenatal ARV prophylaxis (start ing before 28 weeks' gestation), with each additional week o f a triple-drug regimen corresponding to a 10% reduction in risk o f transmission after adjustment for viral load, mode o f delivery, and sex o f the in fant30. More prolonged infant post-exposure prophylaxis does not appear to substitute for longer duration maternal ARV prophylaxis9. No trials have directly compared the efficacy o f zidovudine plus single-dose nevirapine with a triple drug ARV regimen for prevention o f in utero transmission in women with higher CD4 cell counts. In African women with CD4 cell counts ranging from 200 to 500 cells/mm3, the Kesho Bora trial compared a triple-ARV drug prophylaxis regimen with zidovudine plus single-dose nevirapine prophylaxis, both started at 28 weeks' gestation or later. The women in the triple-drug arm continued the drugs until breastfeeding ceased, while those in the zidovudine/single-dose nevirapine arm did not receive postnatal prophylaxis. Although the rate o f postnatal transmission was significantly lower in the triple-drug arm than in the zidovudine/single-dose nevirapine arm without postnatal prophylaxis, the rates o f transmis sion at birth were similar in women randomized to a triple-drug regimen (1.8%) and women randomized to antepartum zidovudine/single-dose nevirapine (2.5%); for women with CD4 cell counts from 350 to 500 cells/mm3, the rate o f infection at birth was 1.7% in each arm23. However, the study was not pow ered to address equivalence between regimens in preventing in utero infection in women with higher CD4 cell counts and the drugs in both arms were administered antepartum for only 6 weeks. Regimens that do not include maternal ARV prophylaxis during pregnancy have been evaluated because some women may lack antenatal care and present for prenatal care for the first time when they go into labor. Regimens that include only intrapartum and postpartum drug administration also have been shown to be effective in reducing perinatal transmission6-8. However, without continued infant post-exposure prophylaxis, intrapartum pre-exposure prophylaxis alone with nucleoside reverse transcriptase inhibitor (NRTI) drugs (zidovudine/lamivudine) is not effective in reducing transmission6. The SAINT trial demonstrated that the two proven effective intrapartum/postpartum regimens (zidovudine/lamivudine or single-dose intrapartum/newborn nevirapine) are similar in efficacy and safety8. In some situations, it may be impossible to administer maternal antepartum and intrapartum therapy and only infant prophylaxis may be an option. In the absence o f maternal therapy, the standard infant pro phylaxis regimen o f 6 weeks o f zidovudine was effective in reducing HIV transmission compared with no prophylaxis, based on epidemiologic data in resource-rich countries31. In a South African study o f in-fants born to mothers who did not receive antenatal or intrapartum ARV drug regimens, overall perinatal transmission rates were not significantly different for administration o f single-dose infant nevirapine given within 24 hours of delivery compared with 6 weeks o f infant zidovudine therapy15. However, a trial in Malawi in breastfeeding infants demonstrated that adding 1 week o f zidovudine therapy to infant single-dose nevirapine reduced the risk of transmission by 36% compared with infant single-dose nevi rapine alone13. To define the optimal infant prophylaxis regimen in the absence o f maternal antepartum ARV drug administration in a formula-fed population o f infants, the NICHD-HPTN 040/P1043 (NCT00099359) multicountry (Argentina, Brazil, South Africa, and the United States) clinical trial en rolled 1,735 formula-fed infants born to HIV-infected mothers who did not receive ARV drugs during the current pregnancy prior to labor (if women presented early enough, intravenous intrapartum zidovu dine was given). The study compared three infant ARV regimens: standard 6 weeks o f zidovudine alone versus 6 weeks of zidovudine plus three doses o f nevirapine given in the first week o f life (first dose birth to 48 hours; second dose 48 hours after first dose; third dose 96 hours after second dose) versus 6 weeks o f zidovudine plus lamivudine and nelfinavir given from birth through age 2 weeks. The study, presented at the 2011 Conference on Retroviruses and Opportunistic Infections, demonstrated that the combination regimens reduced the risk of intrapartum transmission by approximately 50% compared with infant prophylaxis with zidovudine alone (see Table 3). Based on these data, combination ARV pro phylaxis is now recommended in the United States for infants whose mothers have not received antena tal ARV drugs (see Infant Antiretroviral Prophylaxis). Several studies in formula-fed and breastfed populations in resource-limited countries have found that adding maternal/infant single-dose nevirapine to a maternal short-course zidovudine or zidovudine / lamivudine regimen increased efficacy compared with the short-course regimen alone11, 12, 16. Whether single-dose nevirapine provides any additional efficacy when combined with the standard recommended combination ARV prophylaxis regimens used in the United States was evaluated in PACTG 316, a clini cal trial conducted in the United States, Europe, Brazil, and the Bahamas. This study demonstrated that for nonbreastfeeding women in resource-rich countries, the addition o f single-dose nevirapine did not offer significant benefit in the setting o f combination ARV prophylaxis throughout pregnancy and very low viral load at the time o f delivery10. Thus, adding single-dose intrapartum nevirapine is generally not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis (see Intrapartum Care). Breastfeeding by HIV-infected women (including those receiving ARV drugs) is not recommended in the United States where replacement feeding is affordable, feasible, acceptable, sustainable, and safe and the risk of infant mortality due to diarrheal and respiratory infections is low. A number of studies have evalu ated the use of maternal or infant ARV prophylaxis during breastfeeding to reduce postnatal transmission (see Table 3). Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarily using daily infant nevirapine) during breastfeeding significantly decreases the risk of postnatal transmission in breast milk and that maternal triple-drug prophylaxis during breastfeeding likewise de creases postnatal infection18-25. Maternal prophylaxis with triple-drug regimens may be less effective than infant prophylaxis if first started in the postpartum period or late in pregnancy, likely because it takes sev eral weeks to months before full viral suppression in breast milk is achieved25, 32. Importantly, although sig nificantly lowering the risk of postnatal infection, neither infant nor maternal postpartum ARV prophylaxis completely eliminates the risk of HIV transmission through breast milk. Therefore, breastfeeding is not recommended for HIV-infected women in the United States (including those receiving combination ARV drug regimens). Finally, both infant nevirapine prophylaxis and maternal triple-drug prophylaxis during breastfeeding may be associated with development of ARV drug resistance in infants who become infected despite prophylaxis33-36. Three studies have found multiclass drug resistance in breastfeeding infants who Mother-to-child transmission has been observed across the entire range o f plasma HIV RNA levels, in cluding in women with undetectable viral loads1-3. In PACTG 076, an HIV RNA threshold below which there was no risk o f transmission was not identified; zidovudine was effective in reducing transmission regardless of maternal HIV RNA copy number4-5. HIV RNA levels correlate with risk o f transmission even in women treated with ARV agents6-9. Although the risk o f perinatal transmission in women with undetectable HIV RNA levels appears to be extremely low, transmission has been reported even among women with very low or undetectable levels o f mater nal HIV RNA10. Additionally, although HIV RNA may be an important risk factor for transmission, other factors also appear to play a role6, 9 11. Although there is a general correlation between viral loads in plasma and in the genital tract, discor dance also has been reported, particularly between HIV proviral load in blood and genital secretions, es pecially in the presence o f other genital tract infections12-15. Penetration o f ARV drugs into the female genital tract has been shown to vary between drugs16-17. If exposure to HIV in the maternal genital tract during delivery is a risk factor for perinatal transmission, plasma HIV RNA levels may not always be an accurate indicator o f risk. Long-term changes in one body compartment with ARV drugs may or may not be associated with comparable changes in other compartments. Additional studies are needed to deter mine the effect o f ARV drugs on genital tract viral load and the association between such effects and the risk o f perinatal transmission o f HIV. In the short-course zidovudine trial in Thailand, plasma and cervicovaginal HIV RNA levels were reduced by zidovudine prophylaxis, and each independently correlated with perinatal transmission18. Because transmission can occur even when HIV RNA copy numbers are low or undetectable, all HIV-in fected women should be counseled about and administered ARV drugs during pregnancy, regardless of their HIV RNA levels. References: - Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care (AIII). - Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintended preg nancy (AI). - During preconception counseling include information on safer sexual practices and elimination of use of alcohol and illicit drugs, and smoking, which are important for the health of all women as well as for fetal/infant health, should pregnancy occur (AII). - When evaluating HIV-infected women, include assessment of HIV disease status and need for antiretroviral therapy (ART) for their own health (AII). - Choose an ART regimen for HIV-infected women of childbearing age based on consideration of effectiveness for treat ment of maternal disease, teratogenic potential of the drugs in the regimen should pregnancy occur, and possible ad verse outcomes for mother and fetus (AII). The Centers for Disease Control and Prevention (CDC), the American College o f Obstetricians and Gy necologists, and other national organizations recommend offering all women o f childbearing age com prehensive family planning and the opportunity to receive preconception counseling and care as a component of routine primary medical care. The purpose o f preconception care is to improve the health o f each woman before conception by identifying risk factors for adverse maternal or fetal outcome, pro viding education and counseling targeted to the patient's individual needs, and treating or stabilizing medical conditions to optimize maternal and fetal outcomes1. Preconception care is not a single clinical visit but rather a process o f ongoing care and interventions integrated into primary care to address the needs o f women during the different stages o f reproductive life. Because more than h alf o f all pregnan cies in the United States are unintended2-5 it is important that comprehensive family planning and pre conception care be integrated into routine health visits. Providers should initiate and document a nonjudgmental conversation with all women o f reproductive age concerning their reproductive desires because women may be reluctant to bring this up themselves6. HIV care providers who routinely care for women of reproductive age play an important role in promoting preconception health and informed re productive decisions. The fundamental principles of preconception counseling and care are outlined in the CDC Preconception Care Work Group's Recommendations to Improve Preconception Health and Health Care. In addition to the general components of preconception counseling and care that are appropriate for all women of repro ductive age, HIV-infected women have specific needs that should be addressed7-8. Because many women infected with HIV are aware of their HIV status prior to pregnancy, issues that impact pregnancy may be addressed before conception during their routine medical care for HIV disease. In addition to those out lined by the CDC Preconception Care Work Group9 the following components of preconception counsel ing and care are specifically recommended for HIV-infected women. Health care providers should: a. Discuss reproductive options, actively assess women's pregnancy intentions on an ongoing basis throughout the course o f care and, when appropriate, make referrals to experts in HIV and wom en's health, including experts in reproductive endocrinology and infertility when necessary10. b. Offer all women effective and appropriate contraceptive methods to reduce the likelihood o f unin tended pregnancy. Providers should be aware o f potential interactions between ARV drugs and hor monal contraceptives that could lower contraceptive efficacy (see Table 4) . c. Counsel on safe sexual practices that prevent HIV transmission to sexual partners, protect women from acquiring sexually transmitted infections (STIs), and reduce the potential to acquire more viru lent or resistant strains o f HIV. d. Counsel on eliminating alcohol, illicit drug use, and cigarette smoking. e. Educate and counsel women about risk factors for perinatal transmission o f HIV, strategies to reduce those risks, potential effects of HIV or treatment on pregnancy course and outcomes, and the recom mendation that HIV-infected women in the United States not breastfeed because o f the risk o f trans mission o f HIV and the availability o f safe and sustainable infant feeding alternatives. f. When prescribing ART to women of childbearing age consider the regimen's effectiveness for treat ment o f HIV, an individual's hepatitis B disease status, the drugs' potential for teratogenicity should pregnancy occur, and possible adverse outcomes for mother and fetus11-13. g. Use the preconception period in women who are contemplating pregnancy to adjust ARV regimens to exclude efavirenz or other drugs with teratogenic potential. h. For women who are on ART for their own health and who want to get pregnant, make a primary treatment goal the attainment o f a stable, maximally suppressed maternal viral load prior to concep tion to decrease the risk o f mother-to-child transmission. i. Evaluate and appropriately manage therapy-associated side effects such as hyperglycemia, anemia, and hepatoxicity that may adversely impact maternal-fetal health outcomes. j. Evaluate the need for appropriate prophylaxis or treatment for opportunistic infections (OIs), includ ing safety, tolerability, and potential toxicity o f specific agents when used in pregnancy. k. Administer medical immunizations (e.g., influenza, pneumococcal, or hepatitis A and B vaccines) as indicated. l. Encourage sexual partners to receive HIV testing and, if infected, counseling and appropriate HIV care. Panel's Recommendations - For serodiscordant couples who want to conceive, expert consultation is recommended so that approaches can be tai lored to specific needs, which may vary from couple to couple (AIII). - Partners should be screened and treated for genital tract infections before attempting to conceive (AII). - For an HIV-infected female with an HIV-uninfected male partner, the safest conception option is artificial insemination, in cluding the option of self-insemination with her partner's sperm during the peri-ovulatory period (AIII). - For HIV-infected men with an HIV-uninfected female partner, the use of sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection should be considered if using donor sperm from an HIV-uninfected male for insemination is unacceptable (AII). - In a serodiscordant couple who wishes to conceive, initiation of antiretroviral therapy (ART) for the HIV-infected partner is recommended if the infected partner has a CD4 count 550 cells/mm3, initiation of ART could be considered (BIII). If therapy is initiated, maximal viral suppression is recommended before conception is attempted (AIII). - Data are insufficient at the current time to recommend peri-conception administration of antiretroviral (ARV) pre-expo sure prophylaxis for HIV-uninfected partners to reduce the risk of sexual transmission (AIII). For serodiscordant couples who want to conceive, expert consultation is recommended so that ap proaches can be tailored to specific needs, which may vary from couple to couple. Before attempting to conceive, both partners should be screened for genital tract infections. If any such infections are identified, they should be treated because genital tract inflammation is associated with genital tract shedding o f HIV1-2. Semen analysis is recommended for HIV-infected males before concep tion is attempted because HIV, and possibly ART, may be associated with a higher prevalence o f semen abnormalities such as low sperm count, low motility, higher rate o f abnormal forms, and low semen vol ume3-6. If such abnormalities are present, the uninfected female partner may be exposed unnecessarily and for prolonged periods to her partner's infectious genital fluids when the likelihood o f getting preg nant naturally is low or even nonexistent. Observational studies have demonstrated a decreased rate o f transmission o f HIV among heterosexual serodiscordant couples in which the HIV-infected partner is receiving ART compared with couples in which the HIV-infected partner is not receiving ART7-9. HPTN 052 is a randomized clinical trial de signed to evaluate whether immediate versus delayed initiation o f ART by HIV-infected individuals with CD4 counts of 350-550 cells/mm3 could prevent sexual transmission o f HIV among serodiscordant cou ples. Preliminary data from this study showed that earlier initiation o f ART led to a significant reduction in transmission o f HIV to the uninfected partner10. O f 28 cases o f HIV infection documented to be genet ically linked to the infected partner, 27 occurred among the 877 couples in which the HIV-infected part ner delayed initiation o f ART until the CD4 count fell below 250 cells/mm3, whereas only 1 case o f HIV infection occurred among the 886 couples with an HIV-infected partner who began immediate ART; 17 o f the 27 transmissions in the delayed therapy group occurred in individuals with CD4 counts >350 cells/mm3. These are the first data from a randomized trial to demonstrate that provision o f treatment to infected persons can reduce the risk o f transmission to their uninfected sexual partners11. Based on the results from HPTN 052, initiation o f ART would be recommended for the infected partner in a serodis cordant couple who has a CD4 count o f 550 cells/mm3, initation o f therapy could be considered, although the benefit of ART in reducing sexual transmission from individuals with higher CD4 counts has not been determined. Before conception is attempted, maximal viral suppression is recommended if an in fected individual is on ART for his/her own health or does not require therapy but opts to start ART to prevent sexual transmission. It is important to recognize that no single method (including treatment o f the infected partner) is fully protective against transmission o f HIV. Effective ART that decreases plasma viral load to undetectable levels is also associated with decrease in the concentration o f virus in genital secretions. However, dis cordance between plasma and genital viral loads has been reported, and individuals with an undetectable plasma viral load may have detectable genital tract virus12-13. Additionally, ARV drugs vary in their abil ity to penetrate the genital tract14. Thus, maximal viral suppression may not completely eliminate risk of heterosexual transmission. Reducing the risk of perinatal transmission is another potential rationale for starting ART prior to con ception in HIV-infected women who do not yet need treatment for their own health. Data suggest that early and sustained control of HIV viral replication may be associated with decreasing residual risk of perinatal transmission15-16, but that does not completely eliminate the risk o f perinatal transmission16. In addition, there are mixed reports on the possible effects o f combination ARV drug regimens on prematu rity and low birth weight, with some but not all data suggesting that such outcomes may be more fre quent in women on ARV drugs at conception17-18 (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants). The implications of initiating therapy prior to conception solely for prevention o f sexual and/or perinatal transmission should be discussed with the patient. These issues include willingness and ability to com mit to potential lifelong therapy, the potential risks versus benefits o f stopping or continuing the regimen after conception in the male or postpartum in the female, and the need for strict adherence to achieve maximal viral suppression. Consultation with an expert in HIV care is strongly recommended. For HIV-discordant couples in which the female is the HIV-infected partner, the safest form o f concep tion is artificial insemination, including the option to self-inseminate with the partner's sperm during the peri-ovulatory period. Condom use should be advised at all times. For HIV-discordant couples in which the male is the HIV-infected partner, the use o f sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection has been reported to be effective in avoiding seroconversion in uninfected women and off spring in several studies19-20. The National Perinatal HIV Hotline (1-888-448-8765) is a resource for a list o f institutions offering reproductive services for HIV-serodiscordant couples. More data are needed to demonstrate the complete efficacy of these techniques, and couples should be cautioned about the po tential risk of transmission o f HIV to the uninfected partner and to their offspring20. Discordant couples who do not have access to assisted reproduction services and who still wish to try to conceive after com prehensive counseling should be advised that timed, peri-ovulatory unprotected intercourse after the in fected partner has achieved maximal viral suppression (with use o f condoms at all other times) may reduce but not completely eliminate the risk o f sexual transmission20. Should the uninfected woman be come pregnant, she should be regularly counseled regarding consistent condom use to decrease her risk o f sexual transmission of HIV and the possible risk o f perinatal transmission (see Monitoring o f HIV Uninfected Pregnant Women with a Partner Known to be HIV Infected). Periconception pre-exposure prophylaxis may offer an additional option in the future to minimize risk of transmission of HIV within discordant couples. Pre-exposure prophylaxis is use o f ARV medications by an HIV-uninfected individual to maintain blood and genital drug levels sufficient to prevent acquisition o f HIV. An experimental 1% tenofovir gel used intravaginally both before and after sex reduced the inci dence o f HIV infection among women by up to 54% in a randomized, placebo-controlled trial conducted in South Africa21. This product is not available commercially, and additional trials are needed to confirm these findings. Five efficacy trials o f pre-exposure prophylaxis with oral ARV agents (primarily teno fovir alone) are currently under way22. In 1 study o f daily tenofovir/emtricitabine in HIV-seronegative men who have sex with men, there was a 44% reduction in the risk o f acquisition o f HIV compared with placebo23-24. However, the FEM-PrEP clinical trial, designed to study whether HIV-uninfected women at high risk o f being exposed to HIV can safely use a daily dose o f tenofovir/emtricitabine to prevent infec tion, was stopped early by its Data and Safety Monitoring Board (DSMB) because it was highly unlikely the study would be able to demonstrate the effectiveness o f tenofovir/emtricitabine in preventing HIV infection in the study population. The approximate rate o f new HIV infections among trial participants was 5 percent per year. A total o f 56 new HIV infections had occurred, with an equal number o f infec tions in participants assigned to tenofovir/emtricitabine and those assigned to a placebo pill25. Several studies evaluating the efficacy o f pre-exposure prophylaxis among heterosexual discordant cou ples are ongoing but data are not yet available. Currently data are insufficient to recommend periconception administration o f pre-exposure prophylaxis to uninfected partners to reduce the risk o f sexual transmission. In addition, the use o f pre-exposure prophylaxis during pregnancy and lactation for HIVuninfected women with HIV-infected partners has not been studied and cannot be recommended at this time. If pre-exposure prophylaxis is proven safe and efficacious in ongoing trials, this approach may offer an option for safer attempts at conception. However, it will be important to have outcome studies that examine adverse events, including risk o f congenital abnormalities. # M onitoring o f HIV-Uninfected Pregnant Women with Partners Known to B e H IV Infected Clinicians increasingly may be faced with the situation in which an HIV-uninfected woman presents dur ing pregnancy and relates that she has an HIV-infected partner. As is recommended for all pregnant women, the woman should be notified that HIV screening is recommended and that she will receive an HIV test as part of the routine panel of prenatal tests unless she declines. In addition, she should receive a second HIV test during the third trimester, preferably before 36 weeks of gestation, as is recommended for high-risk women. Furthermore, if the pregnant woman presents in labor without results of third-trimester testing, she should be screened with a rapid HIV test on the labor and delivery unit. If at any time during pregnancy the clinician suspects that a pregnant woman may be in the "window" period of seroconversion (i.e., has signs or symptoms consistent with acute HIV infection), then a plasma HIV RNA test should be used in conjunction with an HIV antibody test. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. All HIV-uninfected pregnant women with HIV-infected partners should always use condoms during sexual intercourse to prevent acquisition of HIV. Women should be counseled regarding the symp toms of acute retroviral syndrome (i.e., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, headache) and the importance of seeking medical care and testing if they experience such symptoms. - The known benefits and potential risks of ARV use during pregnancy should be discussed with all women (AIII). - ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIV RNA levels are above the threshold for resistance testing (e.g., >500 to 1,000 copies/mL) (see Antiretroviral Drug Resist ance and Resistance Testing in Pregnancy) (AI). When HIV is diagnosed late in pregnancy, ARV therapy or prophylaxis should be initiated pending results of resistance testing (BIII). - In counseling patients, the importance of adherence to the ARV regimen should be emphasized (AII). - Considerations regarding continuation of the ARV regimen for maternal therapeutic indications after delivery are the same as for nonpregnant individuals. The pros and cons of continuing versus discontinuing ARV drugs postpartum should be dis cussed with women so they can make educated decisions about postpartum ARV use before delivery (AIII). Such decisions should be made in consultation with the provider who will assume responsibility for the women's HIV care going forward after delivery. - Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is essential to ensure that infected women adhere to their ARV drug regimens (AIII). In addition to the standard antenatal assessments for all pregnant women, the initial evaluation o f an HIV-infected pregnant woman should include an assessment o f HIV disease status and recommendations for HIV-related medical care. This initial assessment should include the following: # W ith E FV or N VP (PI-naive or PI-ex p e rie n ced patients): LPV/r 500 mg/125 mg tablets BID (use a combination of two LPV/r 200 mg/50 mg tablets + one LPV/r 100 mg/25 mg tablet to make a total dose of LPV/r 500 mg/125 mg.) or LPV/r 533 mg/133 mg oral solution (6.5 mL) BID # Tablets: Take without regard to meals. # Oral solution: Take with food. # Not used in p reg nancy: # Tablets: Take with food. # C a p su le and oral solution: Take with food if possible, which may improve tolerability. # PI-experienced patients (o n ce -d a ily do sin g not reco m m end ed): - (FPV 700 mg + RTV 100 mg) BID W ith EFV: - (FPV 700 mg + RTV 100 mg) BID or - (FPV 1,400 mg + RTV 300 mg) once daily # Tablet: Take without regard to meals (if not boosted with RTV tablet). # S u sp en sio n : Take without food. # FP V with R T V tablet: Take with meals. # T P V taken with RTV tablets: Take with meals. # T P V taken with R TV ca p s u le s or solution: Take without regard to meals. ARV drugs for prevention o f perinatal transmission o f HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. In general, guidelines for the use o f ART for the benefit of maternal health during pregnancy are the same as for women who are not pregnant, with some modifications, based on concerns about specific drugs and limited experience dur ing pregnancy with newer drugs. ARV prophylaxis is recommended for all pregnant women with HIV infection who do not require therapy, regardless o f viral load (see HIV-Infected Pregnant Women Not on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f HIV). Decisions regarding initiation or modification of ARV drug regimens during pregnancy include considera tions regarding the benefits and risks of ARV drug use that are common to all HIV-infected adults in addi tion to considerations unique to pregnancy. In general, the ARV drug combinations now available are more convenient and better tolerated than regimens used previously, resulting in greater efficacy and improved adherence. During pregnancy maternal ARV toxicities must be considered, along with the potential impact of the ARV regimen on pregnancy outcome and on the fetuses and infants. Decisions about ARV drug regi mens are further complicated because only limited data exist on the long-term maternal consequences of use of the agents during pregnancy solely for prophylaxis of transmission. Similarly, only limited data are available on the long-term consequences to infants of in utero exposure to ARVs. The known benefits and known and unknown risks o f ARV drug use during pregnancy should be consid ered and discussed with women (see Special Considerations Regarding the Use o f Antiretroviral Drugs by HIV-infected Pregnant Women and their Infants). Results from preclinical and animal studies and available clinical information about use of the various agents during pregnancy also should be discussed (see Supplement: Safety and Toxicity o f Individual Antireroviral Agents in Pregnancy) . Potential risks of these drugs should be placed into perspective by reviewing the substantial benefits o f ARV drugs for maternal health and in reducing the risk of transmission of HIV to infants. Counseling of pregnant women about ARV use should be noncoercive, and providers should help women make informed deci sions regarding use o f ARV drugs. Discussions with women about initiation of ARV drug regimens should include information about: a. maternal risk of disease progression and the benefits and risks of initiation of therapy for maternal health; b. benefit o f combination ARV regimens for preventing perinatal transmission o f HIV50; c. potential adverse effects o f ARV drugs for mothers, fetuses, and infants, including potential interac tions with other medications the women may already be receiving; d. the limited long-term outcome data for both women who temporarily use ARV drugs during preg nancy for prophylaxis o f transmission and infants who are exposed to ARVs in utero; and e. the possibility of development o f ARV resistance, including the need for strict adherence to the pre scribed drug regimen to avoid it. Studies of zidovudine for the prevention o f perinatal transmission suggest that pre-exposure prophylaxis o f the infant from transplacental passage o f drug is an important component o f prevention. Thus, when selecting an ARV regimen for a pregnant woman, at least one nucleoside/nucleotide (NRTI) agent with high placental transfer should be included as a component o f the dual NRTI backbone (see Table 5)13, 18, In women with plasma HIV RNA above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting ARV drugs for maternal health or prophylaxis. When HIV is diagnosed late in pregnancy, however, ARV drugs should be initi ated pending results o f resistance testing (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Counseling should emphasize the importance o f adherence to the ARV drug regimen. Support services, mental health services, and drug abuse treatment may be required, depending on women's individual cir cumstances. Coordination o f services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is es sential to ensure that infected women adhere to their ARV drug regimens. Providers should work with women to develop long-range plans regarding continuity o f medical care and decisions about treatment for their own health after giving birth. Considerations regarding continua tion of the ARV regimen for maternal therapeutic indications are the same following delivery as for non pregnant individuals. The impact on short-and long-term maternal health is unknown for postpartum discontinuation o f combination ARV drug regimens used solely to prevent perinatal transmission. This is particularly important because women may have multiple pregnancies resulting in episodic receipt of ARV drugs. No increase in disease progression has been seen so far, however, in studies o f pregnant women with relatively high CD4 counts who stop combination ARV drug regimens after delivery53-55. The risks versus benefits o f stopping ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968). Current adult treatment guidelines strongly recommend ART for all individuals with CD4 cell counts <350 cells/mm3 based on randomized, controlled clinical trial data demonstrating a clear benefit in re duction o f mortality and morbidity. Pregnant women with CD4 counts <350 cells/mm3 should begin on combination ART as soon as possible during pregnancy and be counseled about the need to continue therapy after delivery and the importance o f adherence to the regimen. Based on observational cohort data, the adult treatment guidelines make a moderate-to-strong recom mendation for initiating lifelong ART in individuals with CD4 cell counts between 350 and 500 cells/mm3. Observational studies suggest a relative decrease in mortality (although the overall number of events was small) and possibly a decrease in complications such as cardiovascular events with initiation o f ART in this setting compared with waiting until CD4 cell counts drop below 350 cells/mm3 56-57. Preg nant women with CD4 cell counts between 350 and 500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission o f HIV and counseled about the cur rent treatment recommendations, the potential risks versus benefits o f stopping versus continuing the regimen after delivery, and the need for strict adherence if the regimen is continued postpartum. For individuals with CD4 counts >500 cells/mm3, the adult guidelines note that some experts would rec ommend initiating lifelong therapy, while other experts would view this as optional, given that data are inconclusive on the clinical benefit o f starting treatment at higher CD4 cell counts (>500 cells/mm3). So far, no increased risk of disease progression has been shown in studies o f pregnant women with rela tively high CD4 counts who stop ARV drugs after delivery53-55. The potential benefits o f early therapy must be weighed against possible drug toxicity, cost, and the risk o f development o f viral resistance with suboptimal adherence, which may be more likely during the postpartum period58. Pregnant women with CD4 cell counts >500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission. They should be assessed for their willingness and ability to commit to ongoing continuous therapy and counseled about the current treatment guidelines, the benefits and risks o f therapy, that data on the clinical benefit o f starting lifelong treatment at CD4 cell counts >500 cells/mm3 are inconclusive, and the importance o f adherence if the regimen is continued postpartum. In general, when drugs are discontinued postnatally, all drugs should be stopped simultaneously. How ever, as discussed later (see Stopping Antiretroviral Therapy during Pregnancy), in women receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, continuing the dual-NRTI back bone for a period of time after stopping the NNRTI is recommended to reduce the development of NNRTI resistance. An alternative strategy is to replace the NNRTI with a protease inhibitor (PI) drug while continuing the NRTI, then to discontinue all the drugs at the same time59. The optimal interval be tween stopping an NNRTI and stopping the other ARV drugs is unknown, but a minimum o f 7 days is recommended. Drug concentrations may be detectable for more than 3 weeks after efavirenz is stopped in patients receiving an efavirenz-based NNRTI regimen. Therefore, for patients receiving efavirenz, some experts recommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days. # The National Perinatal HIV Hotline (1-888-448-8765) The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected women and their infants. # Recommendations fo r Use o f Antiretroviral Drugs D uring Pregnancy The Panel recommends that choice o f ARV drug regimens for HIV-infected pregnant women be based on the same principles used to choose regimens for nonpregnant individuals, unless there are compelling pregnancy-specific maternal or fetal safety issues associated with specific drugs. The Panel reviews clin ical trial data published in peer-reviewed journals and data prepared by manufacturers for Food and Drug Administration (FDA) review related to treatment o f HIV-infected adult women, both pregnant and nonpregnant. The durability, tolerability, and simplicity o f a medication regimen is particularly impor tant for preserving future options for women who will be stopping medications after delivery and women who meet standard criteria for initiation o f ART per adult guidelines and will continue the regi men after pregnancy. Regimen selection should be individualized and the following factors should be considered: - comorbidities; - patient adherence potential; - convenience; - potential adverse maternal drug effects; - potential drug interactions with other medications; - results o f genotypic resistance testing; - pharmacokinetic (PK) changes in pregnancy; and - potential teratogenic effects and other adverse effects on fetuses or newborns. Information used by the Panel for recommending specific drugs or regimens for pregnant women in clude: - Data from randomized prospective clinical trials that demonstrate durable viral suppression as well as immunologic and clinical improvement; - Incidence rates and descriptions o f short-and long-term drug toxicity o f ARV regimens, with special attention to maternal toxicity and potential teratogenicity and fetal safety; - Specific knowledge about drug tolerability and simplified dosing regimens; - Known efficacy o f some drug regimens in reducing mother-to-child transmission o f HIV; - PK data during the prenatal period. (The physiologic changes o f pregnancy have the potential to alter drug PKs. ARV dosing during pregnancy should be based on PK data from studies in pregnant women. Physiologic changes are not fixed throughout pregnancy but, rather, reflect a continuum of change as pregnancy progresses, with return to baseline at various rates in the postpartum period.); and - Data from animal teratogenicity studies. Categories o f ARV regimens include: - Preferred: Drugs or drug combinations are designated as preferred for use in pregnant women when clinical trial data in adults have demonstrated optimal efficacy and durability with acceptable toxic ity and ease o f use; pregnancy-specific PK data are available to guide dosing; and no evidence o f ter atogenic effects or established association with teratogenic or clinically significant adverse outcomes for mothers, fetuses, or newborn are present. - Alternative: Drugs or drug combinations are designated as alternatives for initial therapy in pregnant women when clinical trial data in adults show efficacy but any one or more of the following conditions apply: experience in pregnancy is limited; data are lacking on teratogenic effects on the fetus; or the drug or regimen is associated with dosing, formulation, administration, or interaction issues. - Use in Special Circum stances: Drug or drug combinations in this category can be considered for use when intolerance or resistance prohibits use o f other drugs with fewer toxicity concerns or in women who have comorbidities or require concomitant medications that may limit drug choice, such as active tuberculosis requiring rifampin therapy. - Not Recom m ended: Drugs and drug combinations listed in this category are not recommended for therapy in pregnant women because o f inferior virologic response, potentially serious maternal or fetal safety concerns, or pharmacologic antagonism. - Insufficient D ata to Recom m end: The drugs and drug combinations in this category are approved for use in adults but lack pregnancy-specific PK or safety data, or such data are too limited to make a recommendation for use for pregnancy. A combination ARV regimen with at least three agents is recommended for use in pregnancy for either treatment or prophylaxis. Recommendations for choice o f ARV drug regimen during pregnancy must be individualized according to a pregnant woman's specific ARV history and the presence o f comorbidities. Some women may become pregnant and present for obstetrical care while receiving ART for their own health. In these cases, the choice o f active drugs with known safety data in pregnancy may be more lim ited. In general, women who are already on a fully suppressive regimen should continue their regimens. Use of efavirenz, however, should be avoided in the first trimester. Other HIV-infected women may not be receiving ART at the time they present for obstetrical care. Some women have never received ARV drugs, while others may have taken ARV drugs for treatment that was stopped or for prophylaxis to prevent perinatal transmission o f HIV in prior pregnancies or for pre-or post-exposure prophylaxis. Considerations for initiating therapy in pregnant women differ, depending upon whether ARV drugs are currently indicated for maternal health or solely for fetal protection. The following sections will provide detailed discussions o f recommendations based on maternal ARV history and whether there are maternal indications for therapy. For ARV-naive women, a combination regimen including two NRTIs and either an NNRTI or a PI (gen erally with low-dose ritonavir) would be preferred. Tenofovir is a preferred NRTI for nonpregnant women. Data from the Antiretroviral Pregnancy Registry on 1,092 pregnancies with first-trimester exposure to tenofovir have shown no increase in overall birth defects compared with the general population4. Animal studies, however, have shown decreased fetal growth and reduction in fetal bone porosity, and studies in infected children on chronic tenofovir-based therapy have shown bone demineralization in some children. Therefore, tenofovir would be considered an alternative NRTI during pregnancy for ARV-naive women. For pregnant women with chronic hepati tis B infection, however, tenofovir in combination with emtricitabine or lamivudine would be the pre ferred NRTI backbone o f a combination ARV regimen. The combination o f stavudine/didanosine should not be used in pregnant women because fatal cases o f lactic acidosis and hepatic failure have been re ported in women who received this combination throughout pregnancy. In addition to the two NRTIs, either an NNRTI or a PI would be preferred for combination regimens in ARV-naive pregnant women. Efavirenz, the preferred NNRTI for nonpregnant adults, is not recom mended for use in the first trimester because non-human primate data show risk o f anencephaly, micro ophthalmia, and cleft palate, and there are several concerning case reports o f neural tube defects and a single case o f anophthalmia with severe facial cleft in humans. Use o f efavirenz can be considered after the first trimester, based on clinical indication, but current data are limited in defining the safety o f this use. Nevirapine would be the preferred NNRTI for ARV-naive pregnant women with CD4 cell lympho cyte counts 250 cells/mm3 because o f an increased risk o f sympto matic and potentially fatal rash and hepatic toxicity (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants). Elevated transaminase levels at baseline also may increase the risk o f nevirapine toxicity66. Safety and PK data on etravirine and rilpivirine in pregnancy are insufficient to recommend use o f these NNRTI drugs in ARV-naive women. Lopinavir/ritonavir is the preferred PI regimen for ARV-naive pregnant women, based on efficacy stud ies in adults and experience with use in pregnancy (see Table 5 for dosing considerations). Alternative PIs include ritonavir-boosted atazanavir or saquinavir, although experience is more limited with these regimens in pregnancy. Nelfinavir can be considered in special circumstances when used solely for pro phylaxis o f perinatal transmission in ARV-naive women for whom therapy would not otherwise be indi cated and who cannot tolerate alternative agents. PK data and extensive clinical experience do exist for nelfinavir in pregnancy, but the rate o f viral response to nelfinavir-based regimens was lower than lopinavir/ritonavir or efavirenz-based regimens in clinical trials o f initial therapy in nonpregnant adults. Indinavir can also be considered in special circumstances for women in whom preferred or alternative drugs cannot be used. Indinavir may be associated with renal stones and has a higher pill burden than many other PI drugs. Data on use in pregnancy are too limited to recommend routine use o f darunavir, fosamprenavir, and tipranavir in pregnant women, although they can be considered for women who are intolerant o f other agents. Safety and PK data in pregnancy are insufficient to recommend use o f the entry inhibitors enfuvirtide and maraviroc and the integrase inhibitor raltegravir during pregnancy. Use o f these agents can be con sidered for women who have failed therapy with several other classes o f ARV drugs after consultation with HIV and obstetric specialists. Although data are insufficient to support or refute the teratogenic risk o f ARV drugs when administered during the first trimester, information to date does not support major teratogenic effects for the majority o f such agents. (For further data, see .) However, certain drugs are o f more concern than others-for example, efavirenz should be avoided during the first trimester o f pregnancy (see Supplement: Safety and Toxicity o f Individual Antiretroviral Drugs in Pregnancy). Table 5 provides recommendations for use o f specific ARV drugs in pregnancy and data on PKs and tox icity in pregnancy. Table 6 summarizes management recommendations for the mothers and infants in a variety o f clinical scenarios. # Clinical Scenario Recommendations Nonpregnant HIV-infected Initiate combination antiretroviral (ARV) drug therapy as per adult treatment guidelines. When women of childbearing po tential who have indications feasible, include one or more nucleoside reverse transcriptase inhibitors (NRTIs) with good placental passage as a component of the ARV regimen. for initiating antiretroviral therapy (ART) - Avoid drugs with teratogenic potential (e.g., efavirenz) in women who are trying to conceive or are not using adequate contraception. Exclude pregnancy and ensure access to effective (contraception before starting treatment with efavirenz. # HIV-infected women on com bination ARV drug therapy who become pregnant Women: - In general, in women who require treatment, ARV drugs should not be stopped during the first trimester or during pregnancy. - Continue current combination ART, if successfully suppressing viremia; however, avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the preg nancy. - Perform HIV ARV drug-resistance testing in women on therapy who have detectable viremia. - Continue combination ART regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally) and postpartum. - Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: - Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected pregnant women who are ARV naive and have indications for ART Women: - Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiating therapy if viral suppression is suboptimal. - Initiate combination ARV regimen. - Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy. - When feasible, include one or more NRTIs with good placental passage in the ARV regi men. - Use nevirapine as a component of the ARV regimen only in women who have CD4 counts 250 cells/mm3 only if the benefit clearly outweighs the risk. - In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester. - Continue the combination regimen during the intrapartum period (zidovudine given as con tinuous infusion3 during labor while other ARV agents are continued orally) and postpartum. - Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: - - Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiation of therapy if viral suppression is suboptimal. - Prescribe combination ARV drug prophylaxis (i.e., at least 3 drugs) to prevent perinatal transmission. - Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV. - Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy. - When feasible, use one or more NRTIs with good transplacental passage as a component of the ARV regimen. - Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity. - Continue ARV prophylaxis regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally). - Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant individuals (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half life, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), consider stopping NRTIs at least 7 days after stopping NNRTI. (See Stopping Antiretroviral Therapy Drugs Dur ing Pregnancy and Prevention of Antiretroviral Drug Resistance.) - Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: Start zidovudine as soon as possible after birth and administer for 6 weeks.1 # Clinical Scenario Recommendations HIV-infected pregnant women who are ARV experi enced but not currently re ceiving ARV drugs Women: - Obtain full ARV drug history, including prior resistance testing, and evaluate need for ART for maternal health. - Test for HIV ARV drug resistance before re-initiating ARV prophylaxis or therapy and retest after initiating combination ARV regimen if viral suppression is suboptimal. - Initiate a combination ARV regimen (e.g., at least 3 drugs), with regimen chosen based on results of resistance testing and history of prior therapy. - In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester. - Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV. - Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for the mother (e.g., combination stavudine/didanosine) throughout the pregnancy. - When feasible, include one or more NRTIs with good transplacental passage as a compo nent of the ARV regimen. - Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity. - Continue the combination regimen during intrapartum period (zidovudine given as continu ous infusiona during labor while other ARV agents are continued orally). - Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant adults (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half-life, such as NNRTIs, consider stopping NRTIs at least 7 days after stopping NNRTIs. (See Stopping Anti retroviral Therapy and Prevention of Antiretroviral Drug Resistance.) - Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: - Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected women who have received no ART before labor Women: Give zidovudine as continuous infusion1 during labor. Infants: Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is pre ferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9). - Evaluate need for initiation of maternal therapy postpartum. # Clinical Scenario Recommendations Infants born to HIV-infected women who have received no ART before or during labor Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9). - Evaluate need for initiation of maternal therapy postpartum. a Zidovudine continuous infusion: 2 mg/kg zidovudine intravenously over 1 hour, followed by continuous infusion of 1 mg/kg/hour until delivery. b Zidovudine dosing for infants >35 weeks' gestation at birth is 4 mg/kg/dose orally twice daily; for infants 30 weeks of gestation at birth or at 4 weeks of age if <30 weeks' gestation at birth. Centers for Disease Control and Prevention C. Guidelines for vaccinating pregnant women, Available at: preg guide.pdf. Atlanta, GA, 2007. 5) (AI). - For women who require immediate initiation of therapy for their own health, treatment should be started as soon as possible, including in the first trimester (AII). (Note that the use of efavirenz should be avoided during the first trimester.) - A three-drug combination ARV regimen for prophylaxis of perinatal transmission also is recommended for HIV-infected pregnant women who do not require treatment for their own health (AII). - Consideration can be given to delaying initiation of prophylaxis until after the first trimester (BIII) in women who are receiving ARV drugs solely for prevention of perinatal transmission, but earlier initiation of therapy may be more ef fective in reducing in utero transmission. - ARV regimens should include a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs with high levels of transplacental passage, if possible, to provide pre-exposure prophylaxis to the infant (AIII). If HIV RNA is above the threshold for resistance testing (i.e., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting the ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If HIV is diagnosed late in pregnancy, the ARV drug regimen should be initiated pending results of re sistance testing (BIII). - Nevirapine can be used as a component of the ARV drug regimen for pregnant women with CD4 cell counts 250 cells/mm3, however, nevirapine should be used only if the ben efit clearly outweighs the risk because the drug is associated with an increased risk of hepatic toxicity (AII). Pregnant women with HIV infection should receive standard clinical, immunologic, and virologie evalu ation. Decisions about the need for initiation of therapy should be based on the standard guidelines for nonpregnant adults1. # H IV-Infected Pregnant Women N ot on Antiretroviral Therapy and Who N eed Antiretroviral Treatment fo r Their Own Health Any HIV-infected pregnant woman who meets standard criteria for initiation o f ART as per ARV guide lines in nonpregnant adults should receive potent combination ART, generally consisting o f NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI), with continuation of therapy postpartum. Treatment should be started as soon as possible-including in the first trimesterfor women who require immediate initiation o f therapy for their own health because the potential benefit o f treatment for the mother outweighs potential risks to the fetus. The regimen generally should be cho sen from among those shown to be effective in nonpregnant adults, taking into account what is known about use o f the drugs during pregnancy and risk o f teratogenicity (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy)1. A review o f a large database o f nevirapine studies indicated that women with CD4 counts >250 cells/mm3 have an increased risk o f developing symptomatic, often rash-associated, nevirapine-related hepatotoxicity that can be severe, life threatening, and in some cases fatal2-3. A more recent study involv ing 820 women in Kenya, Zambia, and Thailand, however, did not find an association between CD4 count and development o f hepatotoxicity4. Rash and liver toxicity were associated with elevated baseline liver transaminases but not with CD4 count; all deaths from hepatic toxicity occurred in women with CD4 counts 250 cells/mm3, nevirapine should be used as a component o f a combination regimen only when the benefit clearly outweighs the risk. If nevirapine is used, frequent and careful monitoring o f transaminase levels is required, particularly dur ing the first 18 weeks o f treatment (see Nevirapine and Hepatic/Rash Toxicity). Transaminase levels should be checked in women who develop a rash while receiving nevirapine. Nevirapine should be stopped immediately in women who develop signs or symptoms o f hepatitis. # H IV-Infected Pregnant Women N ot on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f H IV HIV-infected pregnant women should be counseled regarding the benefits o f ARV drugs for prevention o f perinatal transmission even when initiation o f ART for maternal health is not recommended or is con sidered optional on the basis o f current guidelines for treatment o f nonpregnant persons1. Although such women are at low risk o f clinical disease progression if ARV treatment is delayed, use o f an ARV regi men that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission o f HIV and lessens the need for consideration o f elective cesarean delivery as an intervention to reduce risk o f transmission. The fetus is most susceptible to the potential teratogenic effects o f drugs during the first trimester and the risks o f ARV drug exposure during that period are not fully known. Therefore, women in the first trimester of pregnancy who do not require immediate initiation o f therapy for their own health may con sider delaying initiation o f ARV drugs until after 12 weeks o f gestation. This decision should be care fully considered by the health care provider and the woman. Their discussion should encompass an assessment of the wom an's health status, the benefits and risks to her o f delaying initiation o f ARV drugs for several weeks, the fact that most perinatal transmission o f HIV events occur late in pregnancy or during delivery, and the possibility that early control o f viral replication may be important in prevent ing the smaller proportion o f earlier in utero transmission. In a recent French study, lack o f early and sustained control o f maternal viral load appeared strongly associated with residual perinatal transmission o f HIV5. That study evaluated risk factors for perinatal transmission in women with HIV RNA <500 copies/mL at the time of delivery; overall HIV transmission was 0.5%. Women who transmitted were less likely to have received ARV drugs at the time o f conception than were nontransmitters and were less likely to have HIV RNA <500 copies/mL at 14, 28, and 32 weeks o f gestation. Among women starting ARV drugs during pregnancy, the gestational age at initiation o f therapy did not differ between groups (30 weeks), but viral load decreased earlier in the nontransmitters. These data suggest that early and sus tained control o f HIV viral replication is associated with decreasing residual risk o f transmission and favor initiating ARV drugs as early in pregnancy as possible for all women. ARV prophylaxis is recommended for all pregnant women with HIV infection, regardless o f viral load. Although rates o f perinatal transmission are low in women with undetectable or low HIV RNA levels, there is no threshold below which lack o f transmission can be assured6-8. The mechanism by which ARV drugs reduce perinatal HIV transmission is multifactorial. Although lowering maternal antenatal viral load is an important component o f prevention in women with higher viral load, ARV prophylaxis is ef fective even in women with low viral load9-13. Additional mechanisms o f protection include pre-exposure prophylaxis and post-exposure prophylaxis o f the infant. With pre-exposure prophylaxis, passage o f the ARV drug across the placenta results in presence o f drug levels sufficient for inhibition o f viral replica tion in the fetus, particularly during the birth process when there is intensive viral exposure. With post exposure prophylaxis, ARV drugs are administered to the infant after birth. Transplacental passage is excellent with zidovudine but may be variable with many other ARV drugs (Table 4). Therefore, when ever possible, combination ARV drug regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, stavudine, tenofovir, or abacavir (see Table 5)14-17. All pregnant women with HIV infection should be counseled about and offered combination ARV regi mens containing at least three drugs for prevention o f perinatal transmission o f HIV. In an analysis of perinatal transmission in 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overall mother-to-child transmission rate was 1.2%. A transmission rate o f 0.8% was seen in women on ARV drugs for at least the last 14 days o f pregnancy, regardless o f the type o f ARV regimen or mode o f delivery18. Transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with a planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women who received single-drug prophylaxis with zidovudine combined with a planned cesarean delivery (as recommended in the British HIV Association guidelines for women with HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health)19, not significantly dif ferent between groups. After adjustment for viral load, mode o f delivery, and sex o f the infant, longer duration o f use o f ARV drugs was associated with reduced transmission rates. A combination regimen including two NRTIs and either an NNRTI or a PI (the latter with or without lowdose ritonavir) would be the preferred prophylactic regimen for ARV-naive women receiving drugs solely for prevention of transmission, as discussed in Recommendations for Use of Antiretroviral Drugs during Pregnancy. A study in Botswana compared a PI-based triple-drug regimen to a triple-NRTI (zidovudine/lamivudine/abacavir) combination regimen for prevention of transmission in breastfeeding women with CD4 counts >200 cells/mm3 20. Both regimens had similar rates of viral suppression by deliv ery (96% receiving the PI regimen and 93% receiving the triple-NRTI regimen had HIV RNA <400 copies/mL) and perinatal transmission (0.4% and 1.4%, respectively, not significantly different). Thus, for women who plan to discontinue prophylaxis following delivery, a triple-NRTI regimen also can be consid ered. If using abacavir, testing for HLA-B5701, which identifies patients at risk of abacavir hypersensi tivity reactions21-22, should be performed and the results documented as negative before abacavir is started. Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk o f HIV transmis sion to the infant. Use o f zidovudine alone during pregnancy for prophylaxis o f perinatal transmission is not optimal, but it could be an option for women with low viral loads (i.e., HIV RNA <1,000 copies/mL) on no ARV drugs. Time-limited administration o f zidovudine during the second and third trimesters of pregnancy is less likely to induce the development o f resistance in women with low viral loads than in those with higher viral loads. This lower rate o f resistance is likely because o f the low level o f viral replication and the short duration o f exposure23-24. Following delivery, considerations regarding continuation o f the ARV regimen for treatment o f the mother are the same as for other nonpregnant adults (see General Principles for Use o f Antiretroviral Drugs during Pregnancy). # HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Treatment (Updated September 14, 2011) Panel's Recommendations - In general, pregnant women receiving and tolerating an antiretroviral therapy (ART) regimen that is currently effective in suppressing viral replication should continue on the regimen; however, the use of efavirenz should be avoided in the first trimester (AIII). - HIV antiretroviral (ARV) drug-resistance testing is recommended for pregnant women who have detectable viremia (e.g., >500-1,000 copies/mL) on therapy (see Failure of Viral Suppression) (AI). - Pregnant women receiving and tolerating nevirapine-containing regimens who are virologically suppressed should con tinue the regimen, regardless of CD4 count (AIII). In general, women who have been receiving antiretroviral treatment (ART) for their HIV infection should continue that treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of HIV transmission. Continuation of therapy, therefore, is recom mended when pregnancy is identified in HIV-infected women receiving ART. HIV-infected women receiving ART who present for care during the first trimester should be counseled re garding the benefits and potential risks of administration of ARVs during this period. Clinicians should re view the safety and risk/benefit profiles and reproductive considerations for the ARV agents used in the current HIV therapeutic regimen. The use of efavirenz should be avoided during the first trimester of preg nancy. If a first-trimester pregnancy is confirmed in a woman who is receiving efavirenz, an alternative ARV drug should be substituted when possible (see Monitoring of the Woman and Fetus during Pregnancy). Resistance testing should be performed in women who are on therapy but in whom viral replication is not fully suppressed. The results can be used to select a new regimen with a greater likelihood of suppressing viral replication to undetectable levels. It should be noted that resistance assays vary depending on the HIV RNA level required to detect resistance mutations. Some assays require HIV RNA levels of >500-1,000 copies/mL; other assays can be performed on patients with lower viral loads. Pregnant women for whom nevirapine-containing regimens are achieving viral suppression and who are tolerating therapy should continue that regimen, regardless of current CD4 count. Although hepatic toxic ity is a concern in women starting a nevirapine-containing regimen who have CD4 counts >250 cells/mm3, an increased risk of hepatic toxicity has not been seen in women receiving nevirapine-based therapy for whom the therapy has produced immune reconstitution. # HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications (Updated September 14, 2011) Panel's Recommendations - Obtain an accurate history of all prior antiretroviral (ARV) regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, tolerance to the medications, results of prior resistance testing, and any adher ence issues (AIII). - If HIV RNA is above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting an ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) # (AIII). In women who present late in pregnancy, therapy or prophylaxis should be initiated pending results of resistance test ing (BIII). - Choose and initiate a combination ARV drug regimen based on results of resistance testing and prior history of antiretro viral therapy (ART) while avoiding drugs with teratogenic potential (efavirenz in the first trimester of pregnancy) or with known adverse potential for the mother (AII). - Consult specialists in treatment of HIV infection about the choice of ART in women who previously received ARVs for their own health (AIII). - Perform repeat ARV drug-resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guide changes in ARV drugs in women do not achieve virologic suppression on their ARV regimens (see Monitoring of the Woman and Fetus During Pregnancy). During a previous pregnancy, HIV-infected women may have received ARV drugs solely for prevention of perinatal transmission. At any time in the past, they also may have discontinued ARVs given to them for treatment of their own disease. A small number of clinical trials or observational studies have generated information about how effective ART is in individuals who previously received ARV prophylaxis. The data are limited to outcomes with therapy containing nevirapine initiated after the use of peripartum sin gle-dose nevirapine1-5. Initial reports suggested a diminished virologic and clinical response to nevirapine-based ART if therapy was initiated within 6 months o f intrapartum single-dose nevirapine exposure1-3. Subsequent reports have confirmed that a shorter interval between intrapartum single-dose nevirapine exposure and therapy initiation is associated with decreased efficacy o f therapy and suggested that the diminished response may persist 12-24 months following exposure4-5. In addition, the subsequent failure o f non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART after single-dose nevirapine has been associated with lower CD4 count and higher HIV-RNA plasma concentration at the time o f single-dose nevirapine expo sure, and genotypic resistance to nevirapine. Adding other ARVs to single-dose nevirapine (e.g., use of an ARV "tail") decreases rates o f nevirapine resistance6-7 (see Antiretroviral Drug Resistance and Resist ance Testing in Pregnancy), but the effect on clinical response to the subsequent initiation o f NNRTIbased ART is unknown. There is concern that time-limited use o f ARV drugs during pregnancy for prophylaxis o f perinatal trans mission may lead to genotypic resistance and thus reduced efficacy o f the ARV drugs when used for treatment. Rates o f resistance appear to be low, based on standard genotyping, after prophylaxis for pre vention o f perinatal transmission with combination ARVs consisting o f zidovudine, lamivudine, and nevirapine8-9. However, particularly in women whose virus was inadequately suppressed during the pe riod o f prophylaxis, minority populations o f virus with resistance to nevirapine or lamivudine have been detected using sensitive allele-specific polymerase chain reaction (PCR) techniques9-11. Only limited data are available on the impact o f these resistance-conferring minority variants on prediction o f viro logic or clinical failure o f subsequent ART, and the PCR-based assays are not widely available. Both standard and sensitive genotyping techniques appear to show a low rate o f resistance to protease in hibitors (PIs) after pregnancy-limited use o f Pi-based combination ARV regimens for prophylaxis, but these results reflect assessments in only small numbers o f women11-12. However, to date, treatment fail ure has not been demonstrated with reinitiation o f combination ARV regimens (particularly those con taining the dual nucleoside reverse transcriptase inhibitor backbone o f zidovudine and lamivudine) following prophylactic use in pregnancy for prevention o f transmission, although controlled observations are lacking. Given the lack o f substantive data, it is reasonable to use results o f initial resistance testing, if available, to make preliminary decisions about ARV regimens in women whose only previous exposure to ARVs was during pregnancy for prophylaxis o f perinatal transmission. However, interpretation o f resistance testing following discontinuation o f ARV drugs can be complex because drug-resistance testing is most accurate if performed while an individual is taking the ARV regimen or within 4 weeks o f treatment dis continuation. In the absence o f selective drug pressure, resistant virus may revert to wild-type virus, and although detection o f drug-resistance mutations is informative for choosing a regimen, a negative find ing does not rule out the presence o f archived drug-resistant virus that could re-emerge once drugs are reinitiated. Therefore, when selecting a new regimen for use during the current pregnancy, all informa tion from the previous pregnancy-including regimens received, viral response, laboratory testing (in cluding HLA-B5701 results), and any tolerance or adherence issues-as well as the results of resistance testing should be taken into consideration. If the woman presents late in pregnancy, therapy or prophylaxis should be initiated pending results o f resistance testing. Careful monitoring o f virologic re sponse to the chosen ARV regimen is important. If the chosen regimen produces an insufficient viral response, decisions about switching regimens should be guided by repeat resistance testing and assessment o f medication adherence. These measures should be undertaken in consultation with an HIV treatment specialist. Some women who receive ART for their own health choose to discontinue the drugs for a variety o f rea sons, and the length of time between treatment termination and pregnancy may vary. In these cases, careful clinical and laboratory assessments are necessary before therapy is reinitiated during pregnancy. The evaluations should include a review o f a woman's prior history o f virologic response and medica tion toxicity as well as her adherence to therapy. The appropriate choice o f ARV regimen to be initiated during pregnancy will vary according to a woman's history o f ART; the indication for stopping therapy; the effect o f prior therapy on clinical, virologic, and immunologic status; and the results o f past and cur rent testing for resistance and for HLA-B5701. It may be possible, for example, to restart the same reg imen in women with a history o f prior ART associated with successful suppression o f viral load who then stopped all drugs simultaneously (or staggered discontinuation if NNRTI based) and who have no evidence of resistance. On the other hand, the selection o f an appropriate ARV regimen may be challeng ing even for health care providers experienced in HIV care in women with advanced HIV disease, a his tory o f extensive prior ART, or previous significant toxicity or nonadherence to ARV drugs. In such cases, restarting the prior regimen for a week or two before performing a resistance assay may yield more accurate results. In addition to obtaining genotypic resistance testing, it is strongly recommended that specialists in the treatment o f HIV infection be consulted early during the pregnancy about the choice o f suitable ART. Special Situations -HIV/Hepatitis B Virus Coinfection (Updated September 14, 2011) Panel's Recommendations - Screening for hepatitis B virus (HBV) infection is recommended for all pregnant women who have not been screened during the current pregnancy (AII). - The HBV vaccine series should be administered to pregnant women who screen negative for hepatitis B (i.e., hepatitis B surface antigen negative, hepatitis B core antibody negative, and hepatitis B surface antibody negative) (AII). - Pregnant women with chronic HBV infection should be screened for antibodies to hepatitis A virus (HAV), and those who screen negative should receive the HAV vaccine series (AII). - Interferon alfa and pegylated interferon alfa are not recommended during pregnancy (AIII). - The management of HIV/HBV coinfection in pregnancy is complex and consultation with an expert in HIV and HBV is strongly recommended (AIII). - All pregnant women with HIV/HBV coinfection should receive a combination antiretroviral (ARV) drug regimen, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue reverse transcriptase inhibitor (NtRTI) back bone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI). - If ARV drugs are discontinued postpartum in women with HIV/HBV coinfection, frequent monitoring of liver function tests for potential exacerbation of HBV infection is recommended, with prompt reinitiation of treatment for both HIV and HBV if a flare is suspected (BIII). - Pregnant women with HIV/HBV coinfection receiving ARV drugs should be counseled about the signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter (BIII). - Within 12 hours of birth, infants born to women with HBV infection should receive hepatitis B immune globulin (HBIG) and the first dose of the HBV vaccine series. The second and third doses of vaccine should be administered at ages 1 and 6 months, respectively (AI). All HIV-infected pregnant women should be screened for hepatitis A, B, and C. The management of HIV/HBVcoinfection in pregnancy is complex and consultation with an expert in HIV and HBV infection is strongly recommended. HIV-infected women who are found to have chronic HBV infection on the basis of persistent hepatitis B surface antigenemia for at least 6 months and who are hepatitis A immunoglobulin G (IgG) negative should receive the HAV vaccine series because of the added risk of acute hepatitis A in persons with chronic viral hepatitis. HIV-infected pregnant women who test negative for hepatitis B surface antibody and hepatitis B surface antigen should receive the HBV vaccine series. A positive test for hepatitis B core antibody alone can be a false-positive result, or it may signify past exposure with subsequent loss of hepatitis B surface antibody, or "occult" HBV infection, which can be confirmed by detection of HBV DNA3-4. The clinical significance of isolated hepatitis B core antibody is unknown5-6. Some experts recommend that HIV-infected persons with hepatitis B core antibody alone should be tested for HBV DNA before vaccination for HBV or before treat ment or prophylaxis with ARV drugs is initiated because of the risk of a paradoxical exacerbation of HBV and the occurrence of immune reconstitution inflammatory syndrome (IRIS)2. An ARV regimen that includes drugs active against both HIV and HBV is recommended for all individuals with HIV/HBV coinfection who require HBV treatment or who are starting ARV drugs, including pregnant women. Initiation of an ARV regimen that does not include anti-HBV drugs may be associated with reacti vation of HBV and development of IRIS; IRIS-related flare of HBV activity during pregnancy can occur even among women with relatively high CD4 cell counts at the time of ARV initiation. In addition, use of ARV drugs with anti-HBV activity during pregnancy lowers HBV viremia, potentially increasing the effi cacy of neonatal HBIG and hepatitis B vaccine in prevention of perinatal transmission of HBV. High mater nal HBV DNA levels are strongly correlated with perinatal HBV transmission and with failures of HBV passive-active immunoprophylaxis7-9. Several small studies suggest that lamivudine or telbivudine may re duce the risk of perinatal transmission of HBV if given during the third trimester to HBV-infected, HIVseronegative women with high HBV DNA viremia10-13. Although a high HBV viral load clearly is important, it is, however, not the only factor predisposing to failure of prophylaxis14. Because lamivudine, tenofovir, and emtricitabine have activity against both HIV and HBV, the recom mended dual-NRTI/NtRTI backbone for HIV/HBV-coinfected individuals, including pregnant women, is tenofovir/emtricitabine or tenofovir/lamivudine. Lamivudine has been extensively studied and is recom mended for use in pregnancy (Table 5). The Antiretroviral Pregnancy Registry includes reports on the out comes of 3,864 pregnancies that involved administration of lamivudine in the first trimester and there is no indication that the exposure was associated with an increased risk of birth defects15. Similarly, no increase in birth defects has been noted in 641 cases of first-trimester exposure to emtricitabine, which is an alterna tive NRTI for use in pregnancy (Table 5). Tenofovir is not teratogenic in animals, but reversible bone changes at high doses have been seen in multiple animal species. A total of 1,092 cases of first-trimester ex posure have been reported to the Antiretroviral Pregnancy Registry, with no increase in birth defects noted15. Although tenofovir is recommended as an alternative NtRTI during pregnancy for ARV-naive women, it is a preferred NtRTI in women with HIV/HBV coinfection (Table 5). Several other antivirals with activity against HBV, including entecavir, adefovir, and telbivudine, have had minimal evaluation in pregnancy. Entecavir is associated with skeletal anomalies in rats and rabbits but only at doses high enough to cause toxicity to the mother. No data are available on use of entecavir and ade fovir in human pregnancy. Telbivudine was given to 95 HBV-positive, HIV-negative women during the third trimester and was well tolerated13. Each of these anti-HBV drugs should be administered only in addi tion to a fully suppressive regimen for HIV. Because these other anti-HBV drugs also have weak activity against HIV, they may select for anti-HIV drug resistance in the absence of a fully suppressive ARV regi men as well as potential cross resistance to other ARV drugs. (Entecavir, for example, can select for the M184V mutation, which confers HIV resistance to lamivudine and emtricitabine.) These drugs should be used during pregnancy only if the preferred drugs are not appropriate in specific cases. Cases of exposure during pregnancy to any of the ARV drugs and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; ). Interferon alfa and pegylated interferon alfa are not recommended for use in pregnancy and should be used only if the potential benefits outweigh the potential risks. Although interferons are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents16. Following initiation of ARV drugs, an elevation in hepatic enzymes can occur in HIV/HBV-coinfected women-particularly those with low CD cell counts at the time of treatment initiation-as a result of an immune-mediated flare in HBV disease triggered by immune reconstitution with effective HIV therapy. HBV infection also can increase hepatotoxic risk of certain ARV drugs, specifically protease inhibitors (PIs) and nevirapine. Pregnant women with HIV/HBVcoinfection should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter. If hepatic toxicity occurs, it may be necessary to consider substituting a less hepatotoxic regimen or, if clinical symptoms or significant elevations of transaminases occur, drugs may need to be temporarily discontinued. Differentiating between a flare in HBV disease due to immune reconstitu tion and drug toxicity often can be difficult, and consultation with an expert in HIV and HBV coinfection is strongly recommended. Because tenofovir has potential to cause renal toxicity, kidney function also should be monitored regularly in women receiving this drug, based on toxicity seen in nonpregnant adults. Panel's Recommendations - Screening for hepatitis C virus (HCV) infection is recommended for all HIV-infected pregnant women who have not been screened during the current pregnancy (AIII). - Interferon alfa and pegylated interferon alfa are not recommended and ribavirin is contraindicated during pregnancy (AIII). - Recommendations for antiretroviral (ARV) drug use during pregnancy are the same for women who have chronic HCV as for those without HIV/HCV coinfection (BIII). - Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and then every 3 months thereafter (BIII). Tn a majority o f studies. the incidence o f HCV transmission from mother to infant increases if the mother is coinfected with HTV. with transmission rates between 10% and 20%7-10. These higher transmis sion rates are likely related to an increase in HCV viremia and/or other HTV-related impact on HCV dis ease activity11. Special Situations -HIV-2 Infection and Pregnancy (Updated September 14, 2011) Panel's Recommendations - HIV-2 infection should be suspected in pregnant women who are from-or have partners from-countries in which the disease is endemic, who are HIV antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot and an HIV-1 RNA viral load at or below the limit of detec tion (BII). - A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor (PI) currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have signifi cant clinical disease or CD4 counts <500 cells/mm3 (AIII). - Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred (AIII). Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative (BIII). - Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatment for their own health (i.e., CD4 counts >500 cells/mm3 and no significant clinical disease). Experts have recommended the following approaches: - A boosted PI-based regimen (two NRTIs plus lopinavir/ritonavir) for prophylaxis, with the drugs stopped postpartum (BIII); - Zidovudine prophylaxis alone during pregnancy and intrapartum (BIII). - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis (AIII). - All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen (BIII). - In the United States, breastfeeding is not recommended for infants of HIV-2-infected mothers (AIII). HIV-2 infection is endemic in Angola; Mozambique; West African countries including Cape Verde, Ivory Coast, Gambia, Guinea-Bissau, Mali, Mauritania, Nigeria, Sierra Leone, Benin, Burkina Faso, Ghana, Guinea, Liberia, Niger, Nigeria, Sao Tome, Senegal, and Togo; and in parts o f India1-3. It also oc curs in countries such as France and Portugal, which have large numbers o f immigrants from these re gions4. HIV-2 is rare in the United States. HIV-2 infection should be suspected in pregnant women who are from-or who have partners from-countries in which the disease is endemic, who are HIV-1 anti body positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeter minate results on HIV-1 Western blot and HIV-1 RNA viral loads at or below the limit o f detection5-6. This pattern o f HIV testing can also be seen in patients who have a false-positive HIV-1 test. The majority of commercially available HIV screening tests can detect both HIV-1 and HIV-2 but cannot distinguish between the two viruses. The only Food and Drug Administration (FDA)-approved antibody test that distinguishes between HIV-1 and HIV-2 is the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test. If HIV-2 is suspected, infection can be confirmed using a supplemental test such as an HIV-2 immunoblot or HIV-2-specific Western blot. HIV-2 immunoblots are available through commercial labs; however, none is FDA approved for HIV-2 diagnosis. HIV-2-specific Western blots can be requested through state health departments. HIV-2 viral load assays currently are not commercially available in the United States. The National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites that perform these tests. HIV-2 has a longer asymptomatic phase than HIV-1, with a slower progression to AIDS. The most com mon mode of HIV-2 transmission is through heterosexual sex. HIV-2 is less infectious than HIV-1, with a 5-fold lower rate o f sexual transmission and 20-to 30-fold lower rate o f vertical transmission3, 7-8. Sev eral studies confirm that rates o f mother-to-child transmission o f HIV-2 are low with and without inter ventions (0% -4%), which may be a result o f reduced plasma viral loads and less cervical viral shedding, compared with that seen in HIV-1-infected women9-12. HIV-2 also can be transmitted through breastfeed ing. HIV-2 infection does not protect against HIV-1 and dual infection, which carries the same prognosis as HIV-1 monoinfection, can occur. Few data exist on which to base treatment decisions or strategies for prevention o f mother-to-child trans mission in patients infected with HIV-2. NNRTIs and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis13-14. HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir having the most activity against the virus15. The integrase inhibitors raltegravir and elvitegravir also appear to be effective against HIV-23, 16-17. The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with two NRTIs and a boosted PI currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 counts <500 cells/mm318. Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred. Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative19-20. NNRTIs should not be used because they are not active against HIV-2. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen. For HIV-2-infected pregnant women with CD4 counts >500 cells/mm3 and no significant clinical dis ease, who do not require treatment for their own health, some experts would use a boosted PI-based reg imen for prophylaxis and stop the drugs postpartum. Other experts would consider zidovudine prophylaxis alone during pregnancy and intrapartum10. Because HIV-2 has a significantly lower risk of mother-to-child transmission than does HIV-1, single-drug prophylaxis with zidovudine alone can be considered for prevention o f mother-to-child transmission. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen20. The possible risks and benefits o f antiretroviral (ARV) prophylaxis should be discussed with the mother. Pregnant women who have HIV-1/HIV-2 coinfection should be treated according to the guidelines for HIV-1-monoinfected patients, making sure that the ARV regimen chosen is also appropriate for HIV-2. Other than the standard obstetrical indications, no data exist regarding the role o f elective cesarean de livery in women who are infected with HIV-2. The risk to the infant from breastfeeding is lower for HIV-2 than for HIV-1, but breastfeeding should be avoided in the United States and other resource-rich countries where safe infant formula is readily available10. Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologic assays at time points similar to those used for HIV-1 testing21. - Repeat HIV antibody testing in the third trimester is recommended for pregnant women with initial negative HIV antibody tests who are known to be at risk of HIV, are receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1,000 per year, are incarcerated, or reside in jurisdictions with elevated rates of HIV infection (see Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings) (AII). - All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) drug regimen as soon as possible to prevent mother-to-child transmission, with the goal of suppressing plasma HIV RNA to below de tectable levels (AI). - In women with acute HIV infection, baseline genotypic resistance testing should be performed simultaneously with initia tion of the ARV regimen, and the ARV regimen should be adjusted, if necessary, to optimize virologic response (AIII). An estimated 40%-90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms4, 6-10. Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses and individuals with the condition also can be asymptomatic. When acute retroviral syndrome is suspected, a plasma HIV RNA test typically is used in conjunction with an HIV antibody test to diagnose acute infection. A low-positive HIV RNA level (100,000 copies/mL)4, 10. In individuals infected with non-B HIV-1 subtypes, however, HIV RNA levels may be lower, even with acute infection, because those subtypes may not amplify as well as subtype B. In that sit uation, consultation with an HIV treatment specialist is recommended. Confirmatory serologic testing should be performed within 3 months on patients whose acute HIV infection is diagnosed with virologic testing but who are antibody negative or whose antibody levels cannot be determined. Acute HIV infection also can be detected by repeat HIV antibody testing later in pregnancy in women whose initial HIV antibody testing earlier in pregnancy was negative. A report from the Mother-Infant Rapid Intervention at Delivery (MIRIAD) study found that 6 (11%) o f 54 women whose HIV was iden tified with rapid HIV testing during labor had primary infection11. Repeat HIV testing in the third trimester is recommended for pregnant women known to be at risk o f HIV who receive care in facilities with an HIV incidence o f at least 1 case per 1,000 pregnant women per year, who are incarcerated, or who reside in jurisdictions with elevated HIV incidence (see Revised Recommendations for HIV Testing o f Adults, Adolescents, and Pregnant Women in Health-Care Settings) 12. Whether treatment o f acute or recent HIV infection results in long-term virologic, immunologic, or clini cal benefit is unknown, and in nonpregnant adults, therapy currently is considered optional13. In preg nant or breastfeeding women, however, acute or recent HIV infection is associated with a high risk of perinatal transmission o f HIV. All HIV-infected pregnant women with acute or recent infection should start a combination ARV regimen as soon as possible, with the goal o f preventing perinatal transmission by optimal suppression o f plasma HIV RNA below detectable levels. Data from the United States and Europe demonstrate that in 6% -16% o f patients, transmitted virus may be resistant to at least one ARV drug14-16. Therefore, baseline genotypic resistance testing should be performed to guide selection or ad justment of an optimal ARV drug regimen. If results o f resistance testing or the source virus's resistance pattern are known, that information should be used to guide selection o f the drug regimen, but initiation o f the ARV regimen should not be delayed. Because clinically significant resistance to PIs is less com mon than resistance to NNRTIs in ARV-naive persons, a PI-based ARV drug regimen generally should be initiated. Choice o f regimen should be based on recommendations for use o f ARV drugs in pregnancy (see Table 5). Following delivery, considerations regarding continuation o f the ARV regimen for treat ment are the same for the mother as for other nonpregnant individuals. When acute HIV infection is diagnosed during pregnancy, and particularly if it is documented in late preg nancy, cesarean delivery is more likely to be necessary because there may be insufficient time to fully sup press the patient's viral load. In nursing mothers in whom seroconversion is suspected, breastfeeding should be interrupted and it should not resume if infection is definitively confirmed (see Breastfeeding In fants of Mothers Diagnosed with HIV Infection in Infant Antiretroviral Prophylaxis). In such a situation, consultation with a pediatric HIV specialist regarding appropriate infant management is recommended. All women who are pregnant or breastfeeding should be counseled about prevention o f HIV acquisition. Several studies suggest that pregnancy may be a time o f increased risk o f transmission o f HIV17-19, even when controlling for sexual risk behaviors17. It is hypothesized that the heightened risk may be attributa ble to hormonal changes that affect the genital tract mucosa or immune responses17. Although no reliable data on HIV serodiscordance rates in the United States exist, data on women from sub-Saharan Africa show that women in serodiscordant relationships may be particularly vulnerable to acquisition o f HIV20. HIV testing o f the sexual partners o f pregnant women should be encouraged. The importance o f using condoms should be reinforced in pregnant women who may be at risk o f acquisition o f HIV, including those whose partners are HIV-infected. Special Situations -Stopping Antiretroviral Drugs during Pregnancy (Updated September 14, 2011) # Panel's Recommendations HIV-infected women receiving antiretroviral treatment (ART) who present for care during the first trimester should con tinue treatment during pregnancy (AII). Women who present in the first trimester on an efavirenz-containing regimen should continue on therapy without interruption but, when possible, an alternative antiretroviral (ARV) drug should be substituted for efavirenz (AIII). - If an ARV drug regimen is stopped acutely for severe or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses that preclude oral intake, all ARV drugs should be stopped and reinitiated at the same time (AIII). - If an ARV drug regimen is being stopped electively and the patient is receiving a non-nucleoside reverse transcriptase in hibitor (NNRTI) drug, consideration should be given to either: (1) stopping the NNRTI first and continuing the other ARV drugs for a period of time; or (2) switching from an NNRTI to a protease inhibitor (PI) before interruption and continuing the PI with the other ARV drugs for a period of time before electively stopping. The optimal interval between stopping an NNRTI and the other ARV drugs is unknown; at least 7 days is recommended. Given the potential for prolonged de tectable efavirenz concentrations for more than 3 weeks in patients receiving efavirenz-based therapy, some experts rec ommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days (CIII). - If nevirapine is stopped and more than 2 weeks have passed before restarting therapy, nevirapine should be restarted with the 2-week dose escalation period (AII). Discontinuation of ARV drug regimens during pregnancy may be indicated in some situations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive to antiemetics, acute illnesses or planned surgeries that preclude oral intake, lack of available medication, or at patients' request. HIV-infected women receiving ART who present for care during the first trimester o f pregnancy should continue treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of transmission of HIV. A recent analysis from a prospective cohort of 937 HIV-infected mother-child pairs found that interruption of ART during pregnancy, including interruption in the first and third trimesters, was independently associated with perinatal transmission. In the first trimester, the median time at interruption was 6 weeks' gestation and length of time without therapy was 8 weeks (interquartile range , 7-11 weeks); in the third trimester, the median time at interruption was 32 weeks and length of time without therapy was 6 weeks (IQR, 2-9 weeks). Although the perinatal trans mission rate for the entire cohort was only 1.3%, transmission occurred in 4.9% (95% confidence interval , 1.9%-13.2%, adjusted odds ratio 10.33, P = .005) with first-trimester interruption and 18.2% (95% CI, 4.5%-72.7%, AOR 46.96, P = .002) with third-trimester interruption1. Although the use of efavirenz should be avoided during the first trimester, therapy should not be interrupted in women taking the drug who present in the first trimester but, rather, an alternative ARV should be substituted, if possible. Continuation of all drugs during the intrapartum period generally is recommended. Women who are hav ing elective cesarean delivery can take oral medications before the procedure and restart drugs following surgery. Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at most the postpartum dose would be given a few hours late. When short-term drug interruption is indicated, in most cases, all ARV drugs should be stopped and rein troduced at the same time. This can be problematic with drugs that have a long half-life. However, in con-ditions such as serious or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses precluding oral intake, the clinician has no choice but to stop all ther apy at the same time. In the rare case in which a woman has limited oral intake but that does not meet food requirements for certain ARV agents, decisions about the ARV regimen administered during the intra partum period should be made on an individual basis and in consultation with an HIV treatment expert. NNRTI drugs such as nevirapine and efavirenz have very long half-lives and can be detected for 21 days or longer after discontinuation; efavirenz has a longer half-life than nevirapine2-6. Because other drugs in the ARV regimen have shorter half-lives and are cleared more rapidly, only detectable NNRTI drug levels persist, resulting in subtherapeutic drug levels that can increase the risk of selection of NNRTI-resistant mutations. In addition, certain genetic polymorphisms, which may be more common among racial/ethnic groups such as African Americans and Hispanics, may have potential to result in a slower rate of clear ance4, 6. To prevent prolonged exposure to a single drug, some experts recommend stopping the NNRTI first and continuing the other ARV drugs for a period of time3. However, the optimal interval between stopping an NNRTI and the other ARV drugs is unknown; detectable levels of NNRTIs may be present from less than 1 week to more than 3 weeks after discontinuation, with the longer duration primarily ob served with efavirenz6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an NNRTIto a PI-based regimen before interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of HIV RNA resuppression after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the dual-NRTIs7. The optimal duration for continuing either dual nucleosides or the substituted PI-based regimen after stop ping the NNRTI is unknown, but a minimum of 7 days is recommended based on studies to reduce resist ance following single-dose nevirapine8-9. A pharmacokinetic (PK) study of nevirapine elimination in African adults following cessation of steadystate nevirapine-containing regimens found that nevirapine concentrations were estimated to have fallen below 20 ng/mL in 3 of 19 (16%) and 14 of 19 (74%) subjects by 7 and 14 days, respectively, after the cessation of dosing10. Elimination half-life was 39 hours in these subjects, considerably shorter than that observed after peripartum exposure to single doses of nevirapine (average 55-60 hours), likely related to induction of nevirapine metabolism with chronic nevirapine exposure2, 11-12. Because efavirenz concentra tions have potential to be detectable for more than 3 weeks, some experts suggest that if efavirenz-based therapy is stopped, the dual NRTIs or PI may need to be continued for up to 30 days. Further research is needed to assess appropriate strategies for stopping NNRTI-containing combination regimens. Another consideration is reintroduction of nevirapine if it is temporarily stopped for some reason and sub sequently restarted. A 2-week, half-dose escalation currently is recommended in patients who are started on nevirapine. Dose escalation is necessary because nevirapine induces its own metabolism by inducing cytochrome P450 3A4 (CYP3A4) liver metabolic enzymes; thus, initial administration of the full thera peutic dose will result in elevated drug levels until metabolic enzyme induction has occurred. In cases where nevirapine has been discontinued for more than 2 weeks, another 2-week dose escalation is recom mended when it is reintroduced. Special Situations -Failure of Viral Suppression (Updated September 14, 2011) # Panel's Recommendations - If an ultrasensitive HIV RNA assay indicates failure of viral suppression to below detectable levels after an adequate pe riod of treatment: - Assess resistance and adherence (AII). - Consult an HIV treatment expert (AIII). - Scheduled cesarean delivery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time of delivery (AII). A three-pronged approach is indicated for management o f women on ARV regimens who have subopti mal suppression o f HIV RNA (i.e., detectable virus at any time during pregnancy using ultrasensitive as says). They should be: 1) evaluated for resistant virus (if plasma HIV RNA is >500-1,000 copies/mL); 2) assessed for adherence, incorrect dosing, or potential problems with absorption (e.g., with nausea/vomiting or lack o f attention to food requirements); and 3) consideration should be given to modifying the ARV regimen. Experts in the care of ARV-experienced adults should be consulted, partic ularly if a change in drug regimen is necessary. Hospitalization may be considered for directly observed drug administration, adherence education, and treatment o f comorbidities such as nausea and vomiting. HIV RNA levels should be assessed 2-4 weeks after an ARV drug regimen is initiated or changed to pro vide an initial assessment of effectiveness1. Baseline HIV RNA levels have been shown to affect the time to response in both pregnant and nonpregnant individuals2. Most patients with an adequate viral response at 24 weeks have had at least a one log10 copies/mL HIV RNA decrease within 1 -4 weeks after starting therapy1. Treatment-naive individuals should have HIV RNA <400 copies/mL after 24 weeks of treatment and <50 copies/mL after 48 weeks of treatment. Because maternal antenatal viral load correlates with risk o f perinatal transmission o f HIV, suppression o f HIV RNA to undetectable levels should be achieved as rapidly as possible. Scheduled cesarean deliv ery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time o f delivery (see Transmission and Mode o f Delivery) . Monitoring of the Woman and Fetus During Pregnancy (Updated September 14, 2011) # Panel's Recommendations - CD4 cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII). Monitoring of CD4 count may be performed every 6 months in patients on antiretroviral treatment (ART) for more than 2-3 years who are adherent to therapy, clinically stable, and have sustained viral suppression (BIII). - Plasma HIV RNA levels should be monitored at the initial visit (AI); 2-4 weeks after initiating (or changing) antiretroviral (ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery) (AIII). - Genotypic ARV drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500-1,000 copies/mL, whether they are ARV-naive or currently on therapy (AIII). Repeat testing is indicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII). - Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverse ef fects of the drugs a woman is receiving (AIII). - First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure (see Transmission and Mode of Delivery) (AII). - Given the limited data on the effect of combination ARV drugs on the fetus, most experts would recommend secondtrimester ultrasound to assess fetal anatomy for women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz (BIII). - In women on effective combination ARV regimens, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only after initiation of an effective combination ARV drug regimen and, if possible, when HIV RNA levels are unde tectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. In HIV-infected pregnant women CD4 cell count should be monitored at the initial visit and at least every 3 months during pregnancy, similar to recommendations in nonpregnant adults. Monitoring of CD4 counts may be performed every 6 months in patients on ART for more than 2-3 years who are adherent to ther apy, clinically stable, and have sustained viral suppression. Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2-4 weeks after initiating or changing ARV regimens, monthly until undetectable, and at least every 3 months thereafter. If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy. More frequent monitoring of viral load is recommended in pregnant versus nonpregnant individuals because of the urgency to lower viral load as rapidly as possible to reduce the risk of perinatal transmission. Therefore, there is a need to identify pregnant women in whom the decline in viral load is slower than expected. Adult ARV guidelines note that patients should have a decrease in plasma HIV RNA level by at least one log10 copies/mL within 1 month after initiation of potent therapy1. Viral suppression generally is achieved in 16-24 weeks in ARV-naive treatment-adherent individuals who do not harbor resistance mutations to the drugs they are receiving but, in rare cases, it may take longer. Viral load also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery). Because o f physiologic changes such as hemodilution that are associated with pregnancy, CD4 percent age may be more stable than absolute CD4 count during pregnancy2-5. Nevertheless, most clinicians still rely on absolute CD4 count to evaluate immune status during pregnancy because parameters for initiat ing therapy are based on those values. ARV drug-resistance testing should be performed in HIV-infected pregnant women before initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing (e.g., >500-1,000 copies/mL). Testing should also be performed in women with suboptimal viral suppression while receiv ing an ARV regimen or who have persistant viral rebound to detectable levels after prior viral suppres sion on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Drug-resistance testing in the setting o f virologic failure should be performed while patients are receiv ing ARV drugs or within 4 weeks after discontinuation o f drugs. Genotypic testing is preferable to phe notypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection of mixtures o f wild-type and resistant virus. Monitoring for potential complications of ARV drugs during pregnancy should be based on what is known about the adverse effects o f the drugs the woman is receiving. For example, routine hematologic monitoring is recommended for women receiving zidovudine-containing regimens. Liver function should be monitored in all women receiving ARV drugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors (PIs), and hepatic steatosis and lactic acidosis in pregnancy have been re lated to nucleoside reverse transcriptase inhibitor (NRTI) use. Women with CD4 counts >250 cells/mm3 are thought to be at particular risk o f developing symptomatic, rash-associated, nevirapine-associated hepatotoxicity within the first 18 weeks after initiation o f therapy. Data from a 2010 study, however, suggest that abnormal liver transaminase levels at baseline may be more predictive o f risk than CD4 cell count6. Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapy with nevirapine, and they should also be watched for clinical symptoms o f potential hepatotoxicity (see Nevirapine and Hepatic/Rash Toxicity). The drug can be used cautiously with careful monitoring in women with mildly abnormal liver function tests at the time of ARV drug initiation. First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide potential timing because such deliveries for prevention o f perinatal transmission of HIV should be performed at 38 weeks' gestation (see Transmission and Mode o f Delivery)7-8. In patients who are not seen until later in gestation, second-trimester ultrasound can be used for both anatomical scanning and determination of gestational age. Because less is known about the effect o f combination ARV drug regimens on the fetus during preg nancy, some experts consider more intensive fetal assessment for mothers receiving such therapy. Most experts would recommend second-trimester assessment o f fetal anatomy with ultrasound in women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz. Furthermore, in addition to standard clinical monitoring, some experts would also recommend ultrasound assessment o f fetal growth and well-being during the third trimester in woman who are re ceiving a combination drug regimen for which there is limited experience with use in pregnancy. The need for additional assessments such as non-stress testing should be determined based on ultrasound findings, any maternal comorbidities, and standard obstetrical indications. Although data are still somewhat limited, the risk o f transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective combination ARV drug regimens resulting in viral suppression. This is in contrast to the pre-combination drug regimen era, during which invasive procedures such as amniocentesis and chorionic villus sampling (CVS) were as sociated with a two-to fourfold increased risk o f perinatal transmission o f HIV9-11. In an evaluation of transmission rates o f HIV over time among women with or without amniocentesis, the transmission rate among women undergoing the procedure from 1984 to 1996 (pre-combination drug era) was 30% (3 of 10) compared with 16.2% (40 o f 247) in those who did not have amniocentesis12. In contrast, no trans missions were noted among 18 women undergoing amniocentesis between 1997 and 2000 who received suppressive combination ARV drug regimens12. In an Italian multicenter study that included deliveries between 1997 and 2003, 3.3% (2 o f 60) o f infants were HIV infected after early invasive diagnostic procedures (CVS, amniocentesis, or cordocentesis) during pregnancy, compared with 1.7% (12 o f 712) o f infants born to women without invasive proce dures (P = 0.30)13. No transmissions occurred among 45 women on combination ARV drug regimens during the procedure. One mother o f an infected infant had not been diagnosed as HIV infected at the time o f amniocentesis and was not receiving ARV prophylaxis; the newborn's virologic test at birth was negative. The mother o f a second infected infant had been receiving zidovudine prophylaxis for 3 weeks and had an HIV RNA level o f 10,000 copies/mL at the time o f the procedure; the preterm infant had a positive virologic test at birth. In 2 other single-center series, no transmissions occurred in 6 and 9 live born infants after amniocentesis in HIV-infected pregnant women on combination ARV drug regimens14" 15. In the largest series to date, no transmissions were seen among 81 women receiving effective combination ARV drug regimens at the time o f amniocentesis16. Thus, among 159 cases reported to date of amniocentesis or other invasive diagnostic procedures among women on effective combination ARV drug regimens, no transmissions have occurred, but a small in crease in risk cannot be ruled out. HIV-infected women who have indications for invasive testing in pregnancy, such as abnormal ultrasound or aneuploidy screening, should be counseled about the poten tial risk o f transmission o f HIV along with other risks o f the procedure and allowed to make an informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women and they recommend limiting invasive procedures to amniocentesis14, but existing data on trans mission risk associated with these procedures are limited. At a minimum, HIV-infected pregnant women should receive an effective combination ARV drug regimen prior to undergoing any invasive prenatal testing and ideally have an undetectable HIV RNA level at the time o f the procedure. In women with de tectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. These procedures should be done under continuous ultrasound guidance and, if possible, the placenta should be avoided. ARV drug recommendations for pregnant women infected with HIV have been based on the concept that drugs o f known benefit to women should not be withheld during pregnancy unless there are known ad verse effects on the mother, fetus, or infant and unless these adverse effects outweigh the benefits to the woman1. Pregnancy should not preclude the use o f optimal drug regimens. The decision to use any ARV drug during pregnancy should be made by the woman after discussing with her health care provider the known and potential benefits and risks to her and her fetus. Although clinical data on ARV drugs in pregnant women are more limited than in nonpregnant individu als, sufficient data exist on which to base recommendations related to drug choice for some o f the avail able ARV drugs. Physiologic changes that occur during pregnancy can affect the kinetics o f drug absorption, distribution, biotransformation, and elimination, thereby also affecting requirements for drug dosing and potentially altering the susceptibility o f the pregnant woman to drug toxicity1-2. During pregnancy, gastrointestinal transit time becomes prolonged; body water and fat increase throughout gestation and are accompanied by increases in cardiac output, ventilation, and liver and renal blood flow; plasma protein concentrations decrease; renal sodium reabsorption increases; and changes occur in metabolic enzyme pathways in the liver. Placental transport of drugs, compartmentalization o f drugs in the embryo/fetus and placenta, bio transformation o f drugs by the fetus and placenta, and elimination o f drugs by the fetus also can affect drug pharmacokinetics (PKs) in the pregnant woman. Currently available data on the PKs of antiretroviral (ARV) agents in pregnancy are summarized in Table 5. In general, the PKs of nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are similar in pregnant and nonpregnant women, although protease in hibitor (PI) PKs are more variable, particularly in later pregnancy. The current data suggest that in many women, exposure to lopinavir/ritonavir, atazanavir, and nelfinavir is decreased during the second and/or third trimester (see Table 5). The need for a dose adjustment depends on the PI, the treatment experience of a particular patient, and use (if any) of concomitant medications with potential for interaction3-10. Teratogenicity (Updated September 14, 2011) Panel's Recommendations - All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Reg istry (see details at ) (AIII). - Efavirenz should not be used in the first trimester and nonpregnant women receiving efavirenz should be counseled to avoid pregnancy (AIII). The potential harm to the fetus from maternal ingestion o f a specific drug depends not only on the drug itself but also on the dose ingested; the gestational age o f the fetus at exposure; the duration o f exposure; the interaction with other agents to which the fetus is exposed; and, to an unknown extent, the genetic makeup o f mother and fetus. Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotal ex perience, registry data, and clinical trials. Data are limited for antiretroviral (ARV) drugs, particularly when used in combination therapy. Drug choice should be individualized and must be based on discussion with the woman and available data from preclinical and clinical testing of the individual drugs. Preclinical data include results of in vitro and animal in vivo screening tests for carcinogenicity, clastogenicity/mutagenicity, and reproductive and teratogenic effects. However, the predictive value of such tests for adverse effects in humans is unknown. For example, of approximately 1,200 known animal teratogens, only about 30 are known to be teratogenic in humans1. Limited data exist regarding placental passage, long-term ani mal carcinogenicity, and animal teratogenicity for the Food and Drug Administration (FDA)-approved ARV drugs. Concerns have been raised about the risk of several ARV agents. In cynomolgus monkeys receiving efavirenz from gestational days 20-150 at a dose resulting in plasma concentrations comparable to systemic human exposure at therapeutic dosage, significant malformations were observed in 3 o f 20 infant monkeys2. The malformations included anencephaly and unilateral anophthalmia in 1, microphthalmia in another, and cleft palate in the third. In prospectively reported pregnancies with exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2011, birth defects were observed in 2.7% (17 o f 623) live births with first-trimester exposure; this proportion is not significantly different from that observed among U.S. births in the general popula tion (2.7%) as reported by the Registry3. Defects reported prospectively included 1 report of myelomeningocele and a separate report o f anophthalmia. The case o f anophthalmia included severe oblique facial clefts and amniotic banding that is known to be associated with anophthalmia3. In addi tion, 6 cases o f central nervous system (CNS) defects, including myelomeningocele, have been retro spectively detected in infants born to mothers receiving efavirenz during the first trimester2. A recent meta-analysis including data from 9 cohorts with prospective reporting on 1,132 first-trimester exposures did not find an increased risk o f overall birth defects among infants born to women on efavirenz during the first trimester compared with those on other ARV drugs during the first trimester (relative risk 0.87; 95% confidence interval , 0.61-1.24)4. One neural tube defect occurred among 1,256 live births. Two subsequent smaller studies had conflicting results. A cohort in West Africa found no visible anomalies among 147 infants born after first-trimester exposure to efavirenz, while an analysis o f the PACTG 219 database found a significantly increased risk o f birth defects among infants born to women after first-trimester exposure to efavirenz (5 o f 32; 15.6%), including 1 neural tube de fect also included in the retrospective Registry cases5-6. Although a causal relationship has not been established between these events and the use o f efavirenz, in light o f similar findings in primates, efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because o f the po tential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period o f fetal organogene sis. Women o f childbearing potential should undergo pregnancy testing prior to initiation o f efavirenz and should be counseled about the potential risk to the fetus and need to avoid pregnancy. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to be come pregnant or who are sexually active and not using effective contraception. Use after the first trimester can be considered if, after consideration o f other alternatives, it is the best choice for an indi vidual woman. If efavirenz is to be continued postpartum, adequate contraception must be ensured. Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in utero exposure to tenfovir at maternal doses resulting in levels approximately 25 times those used in humans, low birth weights and reductions in fetal bone porosity were seen. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Data from the Antiretroviral Pregnancy Registry show a birth defect incidence o f 2.4% in 1,092 women with first-trimester tenofovir exposure, similar to that in the general population3. However, because of the limited data on use in human pregnancy and concern re garding potential fetal bone effects and potential nephrotoxicity, tenofovir is recommended as an alterna tive rather than a preferred drug for use in pregnancy unless the pregnant woman has HIV/hepatitis B coinfection (see Table 5) . Health care providers who are caring for HIV-infected pregnant women and their newborns are strongly advised to report instances o f prenatal exposure to ARV drugs (either alone or in combination) to the An tiretroviral Pregnancy Registry. This registry is an epidemiologic project to collect observational, nonex perimental data regarding ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and as sist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The Anti retroviral Pregnancy Registry is a collaborative project o f pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners. The registry does not use patient names, and registry staff obtain birth outcome follow-up information from the reporting physician. Referrals should be directed to: # Panel's Recommendations - Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (Pl)-based combination antiretroviral (ARV) regimens; however, given the clear benefits of such regimens for both the women's health and the prevention of mother-to-child transmission, PIs should not be withheld for fear of alter ing pregnancy outcome (AII). Early data were conflicting as to whether receipt of combination ARV regimens during pregnancy is asso ciated with adverse pregnancy outcomes and, in particular, preterm delivery. The European Collaborative Study and the Swiss Mother + Child HIV Cohort Study investigated the effects of combination ARV regi mens in a population of 3,920 mother-child pairs. Adjusting for CD4 cell count and intravenous drug use, they found a roughly twofold increase in the odds of preterm delivery for infants exposed to combination regimens with or without PIs compared with no drugs; women receiving combination regimens that had been initiated before their pregnancy were twice as likely to deliver prematurely as those who started drugs during the third trimester1. However, Pi-based combination regimens were received by only 108 (3%) of the women studied; confounding by severity or indication may have biased the results (i.e., sicker women may have received PIs more often, but their advanced HIV infection may have actually caused the preterm births). Exposure to nucleoside reverse transcriptase inhibitor (NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with prematurity. An updated report from the European Collaborative Study, based on an adjusted analysis that included 2,279 mother-child pairs, found a 1.9-fold increased risk o f delivery at less than 37 weeks with combina tion ARV regimens started during pregnancy and a 2.1-fold increased risk with combination ARV regi mens started prepregnancy compared with mono-or dual-NRTI prophylaxis2. In this report, 767 women received combination ARV regimens during pregnancy, although the proportion receiving PIs was not specified. The risk o f delivery before 34 weeks' gestation was increased by 2.5-fold for those starting combination ARV regimens during pregnancy and 4.4-fold for those entering pregnancy on combination ARV regimens. In contrast, in an analysis o f 7 prospective clinical studies that included 2,123 HIV-infected pregnant women who delivered infants between 1990 and 1998 and had received antenatal ARV regimens and 1,143 women who did not receive antenatal ARV drugs, the use o f multiple ARV drugs compared with no drugs or treatment with one drug was not associated with increased rates o f preterm labor, low birth weight, low Apgar scores, or stillbirth3. Nor were any significant associations between adverse preg nancy outcome and use of ARV drugs by class or by category (including combination ARV regimens) found in an analysis from the Women and Infants Transmission Study (WITS), including 2,543 HIV-in fected women (some o f whom were included in the previous meta-analysis)4. More recent data have continued to be conflicting as to whether preterm delivery is increased with com bination ARV regimens. A prospective cohort study including 681 women from Brazil, Argentina, Mex ico, and the Bahamas did not find significant associations between use o f combination ARV regimens and preterm birth or low birth weight5. A single-center study from Miami including 1,337 women did find a 1.8-fold increased chance o f preterm birth among the 134 women in the cohort who received PIcontaining combination ARV regimens compared with other combination regimens, after adjustment for possible confounding variables6. However, women receiving Pi-containing combination ARV regimens uniformly were women with advanced disease or those who had failed other combination drug regi mens. The risk o f low birth weight and stillbirth were not increased in any drug regimen groups. A re cent meta-analysis o f 14 European and American clinical studies found no increase in risk o f preterm birth with either any ARV drug receipt compared with no drugs or combination ARV regimens including PIs compared with no drugs7. However, a significant but modest increased risk o f preterm birth (odds ratio 1.35; 95% confidence interval , 1.08-1.70) was found in women who received combina tion regimens with PIs compared with combination regimens without PIs. Other studies have detected small but significant increases (OR o f 1.2-1.5 in the largest studies) in preterm birth with PI-or non-PI-based combination ARV regimens as well8-11. Another variable that may confound these observational studies is the increased rate o f preterm birth if the combination ARV regi men is begun before conception compared with later during pregnancy, which itself may reflect con founding by severity or indication12. When data from the IMPAACT P1025 observational cohort were examined by multivariable analysis to correct for HIV disease stage, PI-based combination ARV regi mens were no more likely than non-PI-based combination ARV regimens to be associated with sponta neous preterm birth (OR 1.22; 95% CI, 0.70-2.12)13. A recent combined analysis o f three large studies-two from Europe and one from the United States-found heterogeneity in the association be tween combination ARV regimens and preterm birth, with significant increases in Europe but not the United States. However, increased rates o f preterm birth (adjusted OR 1.5) were found in all three cohorts when combination ARV regimens were compared with dual regimens. Additional factors found to be associated with preterm birth in all three cohorts included injection drug use and more ad vanced HIV disease14. A similar increase in preterm birth in women receiving combination ARV regi mens compared with dual regimens has been reported in the Swiss Mother and Child Cohort as well15. Clinicians should be aware o f a possible increased risk o f preterm birth with use o f combination ARV drug regimens; however, given the clear benefits for maternal health and reduction in perinatal transmis sion, these agents should not be withheld because o f the possibility o f increased risk o f preterm delivery. Until more information is known, HIV-infected pregnant women who are receiving combination regi mens for treatment of their HIV infection should continue their provider-recommended regimens. They should receive careful, regular monitoring for pregnancy complications and for potential toxicities. Nevirapine and Hepatic/Rash Toxicity (Updated September 14, 2011) # Panel's Recommendations - Nevirapine-based regimens should be initiated in women with CD4 counts >250 cells/mm3 only if the benefits clearly out weigh the risks because of the drug's potential for causing hepatic toxicity/hypersensitivity reaction (AII). - Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen well can continue on the therapy regardless of CD4 count (AII). # Increases in hepatic transaminase levels (alanine aminotransferase and aspartate aminotransferase ) associated with rash or systemic symptoms may be observed during the first 18 weeks of treatment with nevirapine. Signs and symptoms of systemic toxicity may be nonspecific and can include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, or hepatomegaly, with or without initially abnormal hepatic transaminases1. The development of severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more common in women than men and has been reported in pregnant women2-3. Other stud ies have found that hepatic adverse events with systemic symptoms (predominantly rash) were 3.2-fold more common in women than in men4-5. The degree of risk of rash and hepatic toxicity also appears to vary with CD4 cell count. In a summary analysis of data from 17 clinical trials of nevirapine therapy, women with CD4 cell counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 cell counts to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity4; a single-center study also found higher CD4 cell counts to be associated with increased risk of severe nevirapine-associ ated skin rash2. CD4 cell counts >250 cells/mm3 predicted rash illness, but not liver enzyme elevation, among pregnant and nonpregnant women initiating nevirapine-based combination antiretroviral (ARV) regimens in three U.S. university clinics6. Other international cohorts of nonpregnant women have experi enced hepatotoxicity and rash at similar rates as in U.S. studies, but not in association with CD4 cell counts >250 cells/mm3 7. In general, in controlled clinical trials, hepatic events, regardless of severity, have occurred in 4.0% (range 0%-11.0%) of patients who received nevirapine; severe or life-threatening rash has occurred in approximately 2% of patients receiving nevirapine8. Several early reports of death due to hepatic failure in HIV-infected pregnant women receiving nevirapine as part of a combination ARV regimen raised concerns that pregnant women might be at increased risk of hepatotoxicity from nevirapine compared with other ARV drugs9-10. Recent data challenge the notion that nevirapine is uniquely associated with increased hepatotoxicity during pregnancy11. In an analysis of two multicenter, prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (relative risk 4.7; 5% confidence interval , 3.4-6.5), but nevirapine use was not, regardless of pregnancy status11. Additional data from the same cohorts did not show any increased risk of hepatotoxicity in HIVinfected pregnant women receiving nevirapine-based combination ARV regimens versus non-nevirapinebased combination ARV regimens12. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women. Nevertheless, if nevirapine is used in pregnancy, health care providers should be aware of potential hepatotoxicity with or without rash and should conduct frequent and careful monitoring of clinical symptoms and hepatic transaminases (i.e., ALT and AST), particularly during the first 18 weeks of nevirapine use. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through Month 4, and every 1-3 months thereafter (see the He patotoxicity section of the table on Antiretroviral Therapy-Associated Common and/or Severe Adverse Ef fects in the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). In patients with pre-existing liver disease, monitoring should be performed more frequently when initiating nevirapine and monthly thereafter1. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop suggestive clinical symptoms accompanied by ele vation in serum transaminase levels (ALT and/or AST) or who have asymptomatic but severe transaminase elevations (i.e., more than five times the upper limit of normal) should stop nevirapine and not receive nevirapine again in the future. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission of HIV13. Women who enter pregnancy on nevirapine-containing regimens and are tolerating them well may continue therapy, regardless of CD4 cell count. Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity (Updated September 14, 2011) Panel's Recommendations - The combination of stavudine and didanosine should not be prescribed during pregnancy due to reports of lactic acidosis and maternal/neonatal mortality with prolonged use in pregnancy (AII). - Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to antiretroviral (ARV) drugs who present with severe clinical findings of unknown etiology, particularly neurologic findings (AII). - Long-term clinical follow-up is recommended for any child with in utero exposure to ARV drugs (AIII). Nucleoside reverse transcriptase inhibitor (NRTI) drugs are known to induce mitochondrial dysfunction because the drugs have varying affinity for mitochondrial gamma DNA polymerase. This affinity can in terfere with mitochondrial replication, resulting in mitochondrial DNA (mtDNA) depletion and dysfunc tion1. The relative potency of the NRTI drugs in inhibiting mitochondrial gamma DNA polymerase in vitro is highest for zalcitabine, followed by didanosine, stavudine, zidovudine, lamivudine, abacavir, and tenofovir2. In one study, didanosine and didanosine-containing regimens were associated with the great est degree o f mitochondrial suppression3. Toxicity related to mitochondrial dysfunction has been re ported to occur in infected patients receiving long-term treatment with NRTI drugs and generally has resolved with discontinuation o f the drug or drugs; a possible genetic susceptibility to these toxicities has been suggested1. These toxicities may be o f particular concern for pregnant women and infants with in utero exposure to NRTI drugs. # D uring Pregnancy Clinical disorders linked to mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancre atitis, hepatic steatosis, and lactic acidosis. Among these disorders, symptomatic lactic acidosis and hepatic steatosis may have a female preponderance4-5. These syndromes have similarities to rare but life-threaten ing syndromes that occur during pregnancy, most often during the third trimester: acute fatty liver and he molysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Data suggest that a disorder of mitochondrial fatty acid oxidation in the mother or her fetus during late pregnancy may play a role in the development of acute fatty liver of pregnancy and HELLP syndrome6-9 and possibly contribute to suscepti bility to ARV-associated mitochondrial toxicity. HELLP syndrome also can occur postpartum in women with severe preeclampsia10. In addition to low platelets and elevated liver enzymes, other laboratory find ings reported among HIV-infected pregnant women on ARV drugs include mitochondrial placental deple tion but without evidence of ultrastructual damage to placental cells. The clinical significance of reduced mtDNA in placentas exposed to ARV drugs remains unknown11. Lactic acidosis with microvacuolar hepatic steatosis is a toxicity related to NRTI drugs that is thought to be related to mitochondrial toxicity; it has been reported to occur in infected persons treated with NRTI drugs for longer than 6 months. In a report from the Food and Drug Administration (FDA) Spontaneous Adverse Event Program, typical initial symptoms included 1-6 weeks of nausea, vomiting, abdominal pain, dyspnea, and weakness12. Metabolic acidosis with elevated serum lactate levels and elevated hepatic enzymes was common. Patients described in that report were predominantly female and overweight. Al though the apparent incidence of this syndrome may increase with better clinical recognition, the actual in cidence may decrease as stavudine and didanosine are used less often in combination regimens. The frequency o f this syndrome in pregnant HIV-infected women receiving NRTI drugs is unknown. In 1999, Italian researchers reported a case o f severe lactic acidosis in an infected pregnant woman who was receiving stavudine/lamivudine at the time o f conception and throughout pregnancy and who expe rienced symptoms and fetal death at 38 weeks' gestation13. Bristol-Myers Squibb has reported three m a ternal deaths due to lactic acidosis, two with and one without accompanying pancreatitis, among women who were either pregnant or postpartum and whose antepartum regimen during pregnancy included stavudine and didanosine in combination with other ARV agents (either a protease inhibitor or nevi rapine)14-15. All women were receiving regimens containing these agents at the time o f conception and continued for the duration o f pregnancy; all presented late in gestation with symptomatic disease that progressed to death in the immediate postpartum period. Two cases were also associated with fetal death. Nonfatal cases o f lactic acidosis also have been reported in pregnant women receiving combina tion stavudine/didanosine16. It is unclear if pregnancy augments the incidence o f the lactic acidosis/hepatic steatosis syndrome that has been reported for nonpregnant persons receiving NRTI drugs. However, because pregnancy itself can mimic some of the early symptoms o f the lactic acidosis/hepatic steatosis syndrome or be associated with other disorders o f liver metabolism, these cases emphasize the need for physicians caring for HIVinfected pregnant women receiving NRTI drugs to be alert for early signs o f this syndrome. Additionally, because of the reports o f several cases o f maternal mortality secondary to lactic acidosis with prolonged use o f the combination o f stavudine and didanosine by HIV-infected pregnant women, clinicians should not prescribe this ARV combination during pregnancy. Combination stavudine/didanosine also is not recommended for nonpregnant adults. # In Utero Exposure It has been suggested that mitochondrial dysfunction might develop in infants with in utero exposure to NRTI drugs. Data from a French cohort of 1,754 uninfected infants born to HIV-infected women who received ARV drugs during pregnancy identified 8 infants with in utero or neonatal exposure to either zidovudine/lamivudine (4) or zidovudine alone (4) who developed indications o f mitochondrial dysfunc tion after the first few months o f life17. Two o f these infants (both exposed to zidovudine/lamivudine) contracted severe neurologic disease and died; 3 had mild-to-moderate symptoms; and 3 had no symp toms but had transient laboratory abnormalities. In a larger cohort o f 4,392 uninfected children (including the children in the previous study) followed within the French Pediatric Cohort or identified within a French National Register, the 18-month inci dence o f clinical symptoms o f mitochondrial dysfunction was 0.26% and 0.07% for mortality18. All chil dren had perinatal exposure to ARVs; risk was higher among infants exposed to combination ARV drugs (primarily zidovudine/lamivudine) than to zidovudine alone. The children presented with neurologic symptoms, often with abnormal magnetic resonance imaging and/or episodes o f significant hyperlactatemia, and deficits in mitochondrial respiratory chain complex enzyme function on biopsy o f muscle. The same group also has reported an increased risk o f simple febrile seizures in the first 18 months of life and persistently lower (but clinically insignificant) neutrophil, lymphocyte, and platelet counts in in fants with in utero exposure to NRTIs19-20. More recently, in continued follow-up o f the French Perinatal Cohort, researchers reported severe neurologic symptoms in the first 2 years o f life as a rare event (0.3% -0.5% )21. Other clinical studies from the United States and Europe generally have not duplicated the French re ports22-28. The Perinatal Safety Review Working Group performed a retrospective review o f deaths oc curring among children born to HIV-infected women and followed from 1986 to 1999 in 5 large, prospective U.S. perinatal cohorts. No deaths similar to those reported from France or with clinical find ings attributable to mitochondrial dysfunction were identified in a database o f more than 16,000 unin fected children born to HIV-infected women with and without exposure to ARV drugs23. However, most o f the infants with exposure to ARVs had been exposed to zidovudine alone and only a relatively small proportion (approximately 6%) had been exposed to zidovudine/lamivudine. The European Collaborative Study reviewed clinical symptoms in 2,414 uninfected children in their co hort with median follow-up o f 2.2 years (maximum, 16 years); 1,008 had perinatal exposure to ARVs25. No association was found between clinical manifestations suggestive o f mitochondrial abnormalities and perinatal exposure to ARVs. O f the 4 children with seizures in this cohort, none had perinatal exposure to ARVs. In a report from a long-term follow-up study in the United States (PACTG 219/219C), 20 chil dren with possible symptoms o f mitochondrial dysfunction were identified in a cohort o f 1,037 unin fected infants born to HIV-infected mothers27. Definitive diagnosis was not available because none of the children had biopsies for mitochondrial function. Three o f the 20 children had no exposure to ARV drugs. In the 17 remaining children, although overall exposure to NRTI drugs was not associated with symptoms, there was an association between symptoms and first exposure to zidovudine/lamivudine limited to the third trimester. Some small alterations in mtDNA and oxidative phosphorylation enzyme activities were found in stored specimens from these children, but the clinical significance o f these ob servations remains unknown29-30. Laboratory abnormalities without clinical symptoms have been reported in infants with perinatal expo sure to ARVs compared with unexposed infants in a number o f studies, most o f which are limited by small numbers o f subjects. In 1 study, mtDNA quantity was lower in cord and peripheral blood white cells at ages 1 and 2 years among 20 infants born to HIV-infected women compared with 30 infants born to uninfected women and was lowest among 10 HIV-exposed infants with zidovudine exposure com pared with 10 without zidovudine exposure31. In a subsequent study, mitochondrial changes were evalu ated in umbilical cord endothelial cells and cord blood from human infants and monkeys with in utero exposure to various NRTI-containing regimens32. Similar morphologic changes and mtDNA depletion were seen in the human and monkey infants. In the monkeys, mitochondrial damage demonstrated a gra dient, with greatest damage with stavudine/lamivudine > zidovudine/didanosine > zidovudine/lamivu dine > lamivudine. In a Canadian study of 73 ARV-exposed infants and 81 controls with blood samples during the first 8 months o f life, investigators found that in the first weeks o f life, blood mtDNA levels were higher and blood mitochondrial RNA levels were lower in the HIV-and ARV-exposed infants com pared with infants without HIV and ARV exposure33. One study reported that peripheral blood mononu clear cell (PBMC) mtDNA levels were lower at birth in HIV-exposed, ARV-exposed infants compared with non-HIV, non-ARV-exposed infants34. However, among the HIV-exposed infants, those with com bination ARV drug exposure in utero had higher mtDNA levels than those exposed only to zidovudine in utero. Umbilical cord mtDNA sequence variants were 3-fold higher among HIV-and zidovudine-ex posed infants compared with infants born to mothers without HIV infection35. Transient hyperlactatemia during the first few weeks o f life was reported among 17 HIV-exposed infants with perinatal exposure to ARVs; lactate levels returned to normal in all children and none developed symptoms o f mitochondrial dysfunction during follow-up36. Similarly, the French Perinatal Cohort Study has reported asymptomatic hyperlactatemia in one-third o f zidovudine-exposed newborns, which resolved following perinatal exposure to the drug21. Clinically asymptomatic hematologic findings have been reported by several investigators among uninfected infants with in utero exposure to ARV regimens in the United States and Europe37-39, and infants with exposure to triple-combination ARV regimens were found to be at increased risk o f lowered hemoglobin compared with those with perinatal exposure to zi dovudine or zidovudine/lamivudine40. The clinical significance o f these differences in mtDNA, lactate levels, and hematologic laboratory find ings is unclear, and further long-term studies are needed to validate the findings and assess the degree to which they affect growth and development o f infants exposed to ARV drugs. Thus, data are conflicting on whether mitochondrial dysfunction is associated with perinatal exposure to ARVs, and further studies are needed. Even if an association is more clearly demonstrated, the development o f severe or fatal mito chondrial disease appears to be extremely rare and should be balanced against the clear benefit o f ARV prophylaxis in reducing transmission o f a fatal infection by 70% or more25, 41-42. Development o f new di agnostic techniques, including use o f flow cytometry assays to screen for mitochondrial function, may lead to more accurate assessment o f mitochondrial toxicity43. Mitochondrial dysfunction should be con sidered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings o f unknown etiology, particularly neurologic findings. Current recommendations call for long-term clin ical follow-up for any child with in utero exposure to ARV drugs. Protease Inhibitor Therapy and Hyperglycemia (Updated September 14, 2011) Panel's Recommendations - HIV-infected women taking antiretroviral (ARV) drug regimens during pregnancy should undergo glucose screening with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation (AIII). Some experts would perform earlier glu cose screening in women receiving ongoing protease inhibitor (Pl)-based regimens initiated before pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance (BIII). Hyperglycemia, new-onset diabetes mellitus, exacerbation o f existing diabetes mellitus, and diabetic ke toacidosis have been reported in HIV-infected patients taking PIs1-4. In addition, pregnancy is itself a risk factor for hyperglycemia. To date, however, the majority have not shown an increased risk o f glucose in tolerance with Pi-based regimens during pregnancy. One small retrospective study that included 41 women receiving Pi-based combination ARV regimens found an increased risk o f glucose intolerance, but not gestational diabetes, among women on combination ARV regimens compared with zidovudine alone5, while two other retrospective studies did not find an increased risk o f glucose intolerance with Pis6-7. Secondary analyses o f two large cohorts did not find an association between the type o f ARV regi men and gestational diabetes, except for an association between initiation o f PIs before pregnancy or during the first trimester and gestational diabetes in the PACTG 316 cohort8-9. Finally, a prospective study including detailed evaluations for glucose intolerance and insulin resistance among HIV-infected pregnant women did not find differences between women on Pi-containing and non-PI-containing regi mens10. In both groups, however, the rate o f impaired glucose tolerance was high (38%), likely related to high body mass index and race/ethnicity among trial subjects. HIV-infected women receiving ARV regimens during pregnancy should receive standard glucose screen ing with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation. Some experts would perform earlier glucose screening in women with ongoing PI-based ARV regimens initiated before preg nancy (particularly in women o f minority race/ethnicity), similar to recommendations for women with high-risk factors for glucose intolerance, such as maternal obesity, advanced maternal age, and family history o f type II diabetes mellitus. # Antiretroviral Drug Resistance and Resistance Testing in Pregnancy (Updated September 14, 2011)_____________ # Indications for Antiretroviral Drug-Resistance Testing in HIV-Infected Pregnant Women Panel's Recommendations - HIV drug-resistance testing is recommended for: - All pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) not currently receiving antiretroviral (ARV) drugs, before starting treatment or prophylaxis (AIII). - All pregnant women receiving antenatal ARV drugs who have suboptimal viral suppression or persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII). - Empiric initiation of ARV drugs before results of resistance testing are available may be warranted, with adjustment as needed after the test results are available, for optimal prevention of perinatal transmission (BIII). Resistance testing is recommended for all ARV-naive pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) before initiating treatment or prophylaxis if prior resistance testing has not been done. For details regarding genotypic and phenotypic resistance testing see Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Ideally, resistance testing would have been done at a preconception visit to allow receipt o f results and to select an appropriate ARV drug regimen during pregnancy or before pregnancy if maternal therapy was indicated. Resistance testing should also be performed before initiation of therapy or prophylaxis in pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) who re ceived prophylaxis in previous pregnancies and are now restarting ARV drugs for prevention of perinatal transmission. No data currently are available to address the utility of resistance testing during pregnancy in women who do not require treatment for their own health or in women with multiple pregnancies who have received corresponding courses of ARV prophylaxis for prevention of mother-to-child transmission. The identification of baseline resistance mutations may allow selection of more effective and durable ARV regimens for women who need treatment and help ensure a wider range of future treatment options for women receiving ARV drugs solely for perinatal prophylaxis. There is no evidence, however, that baseline resistance testing in pregnancy is associated with a reduction in rates of perinatal transmission. Resistance testing should also be performed following initiation o f an ARV regimen during pregnancy or in HIV-infected pregnant women who are receiving antiretroviral therapy (ART) when they present for obstetrical care if there is suboptimal viral suppression or persistent viral load rebound to detectable lev els after prior viral suppression on the ARV regimen. In most settings, the results o f resistance testing guide selection o f the initial ARV regimen. In some situ ations in pregnant women, however, the clinician may choose to initiate empiric ARV drug regimen be fore resistance-testing results are available to optimize prevention o f perinatal transmission o f HIV Once resistance test results are obtained, the ARV drug regimen can be modified as needed. Most ex perts believe that for women in the third trimester, the benefits o f immediate initiation o f ARV drugs for prevention o f mother-to-child transmission, pending results o f resistance testing, outweigh the possible risk o f short-term use o f a regimen that could be suboptimal because o f pre-existing resistance. The development o f ARV drug resistance is one o f the major factors leading to therapeutic failure in HIV-infected individuals. In pregnancy, it is associated with specific concerns that differ from those seen in the nonpregnant population. Pre-existing resistance to a drug in an ARV prophylaxis regimen may di minish the regimen's efficacy in preventing perinatal transmission. The development o f resistance to drugs used during pregnancy for prophylaxis o f perinatal transmission may limit future maternal treat ment options or decrease the effectiveness o f prophylactic regimens in the current pregnancy or during future pregnancies. Infant treatment options also may be limited if maternal resistance is present or de velops and resistant virus is transmitted to the fetus. Several factors unique to pregnancy may increase the risk of development o f resistance. If drugs with significant differences in half-life (such as nevirapine or efavirenz combined with two nucleoside ana logue drugs) are included in the ARV regimen, simultaneous postpartum discontinuation o f all regimen components may result in persistent subtherapeutic drug levels and increase the risk o f development of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (see Stopping Antiretroviral Therapy during Pregnancy). Problems such as nausea and vomiting in early pregnancy may compromise adher ence and increase the risk o f resistance in women receiving ARV drugs. Pharmacokinetic (PK) changes during pregnancy, such as increased plasma volume and renal clearance, may lead to subtherapeutic drug levels, increasing the risk that resistance will develop. # Incidence o f Antiretroviral Resistance Em erging from the Use o f Perinatal Prophylac tic Regim ens The presence o f mutations conferring resistance to nucleoside analogue drugs appears to be correlated with more advanced maternal disease and longer duration o f prior or current exposure to these drugs1-4. The development o f zidovudine drug resistance when zidovudine is used alone appears uncommon in women with higher CD4 cell counts and lower viral loads5-6 but is more o f a concern in women with ad vanced disease and lower CD4 cell counts2. Development o f resistance associated with short-term use o f ARV agents for prevention o f mother-tochild transmission is most common with nevirapine, particularly single-dose nevirapine. Nevirapine has a low genetic barrier to resistance, with a single point mutation conferring resistance to nevirapine and to other first-generation NNRTI drugs. Furthermore, its long half-life, with blood levels detectable up to 21 days after a single dose in labor, increases selection pressure and the risk o f resistance7. Factors asso ciated with an increased risk o f resistance following single-dose nevirapine exposure include high base line viral load, low baseline CD4 cell count, viral subtype, and the number o f maternal doses. The rate of genotypic resistance after exposure to single-dose nevirapine has varied in studies, ranging from 15% to 75%8-18. Studies using more sensitive real-time polymerase chain reaction (PCR) techniques suggest that up to one-half o f resistance that develops is not detected by conventional sequence analysis16, 18-20. The prevalence o f resistance declines rapidly over time and the proportion o f resistant virus in those with de tectable virus 12 months after exposure is low. In a study o f virus from 67 South African women, using a sensitive allele-specific resistance assay, the K103N mutation was seen in 87% o f women at 6 weeks but in only 11% at 12 months after single-dose nevirapine exposure, with a median frequency o f the muta tion of 0.7% (range 0.5%-5.4%) in women with detectable resistance at 12 months20. In the PACTG 316 trial, the addition o f single-dose nevirapine following antepartum administration of other ARV regimens (primarily combination regimens because 77% o f women received antenatal combi nation ARV regimens still resulted in nevirapine resistance in 14 o f 95 (15%; 95% confidence interval , 8%-23%) women with detectable virus postpartum8. In this study, adding single-dose nevirapine # Significance o f Antiretroviral Drug Resistance in Pregnancy did not provide any additional efficacy in prevention o f mother-to-child transmission but was associated with development o f nevirapine resistance. Therefore, this approach is not recommended. A recent study examined the presence o f resistant mutations in HIV-1-infected women receiving combi nation ARV drug regimens that were stopped postpartum. All women evaluated received zidovudine and lamivudine, with 76% receiving nelfinavir and 8% receiving nevirapine. Rates o f M184V/I mutations postpartum were 65% and 29% in women receiving dual or triple prophylaxis, respectively. NNRTI re sistance was identified postpartum among 38% o f nevirapine recipients, whereas only 1% o f protease in hibitor (PI) recipients developed PI resistance21. # The Im pact o f Resistance on Pregnancy and the R isk o f Perinatal Transmission o f H IV Perinatal Transmission Perinatal transmission of resistant virus has been reported, but it appears to be unusual and there is little evidence that the presence o f resistance mutations increases the risk o f transmission when current rec ommendations for ARV management in pregnancy are followed. A substudy o f the Women and Infants Transmission Study (WITS) followed pregnant women receiving zidovudine alone for treatment o f HIV disease in the early 1990s. In this study, the detection o f zidovudine resistance conferred an increased risk o f transmission when analysis was adjusted for duration o f membrane rupture and total lymphocyte count2; however, women in this cohort had characteristics that would indicate a need for ART under the current Department o f Health and Human Services (HHS) recommendations for maternal health and for prevention o f perinatal transmission. When transmitting mothers had mixed viral populations o f wild type and virus with low-level zidovudine resistance, only wild-type virus was detected in the infant22, and other studies have suggested that drug-resistance mutations may diminish viral fitness23, possibly leading to a decrease in transmissibility. In another study, prevalence o f ARV drug resistance among HIV-infected newborns in New York State was examined. Eleven (12.1%) o f 91 infants born between 1989 and 1999 and 8 (19%) o f 42 infants born between 2001 and 2002 had mutations associated with decreased drug susceptibility. However, perinatal exposure to ARVs was not found to be a significant risk factor for the presence o f resistance during either time period24-25. Neither resistance to nevirapine that develops as a result of exposure to single-dose nevirapine nor exposure to single-dose nevirapine in a prior pregnancy has been shown to affect perinatal transmission rates26-27. # M aternal Response to Subsequent Treatment Regimens Because nevirapine resistance mutations can be detected postpartum in a significant proportion of women receiving single-dose intrapartum nevirapine prophylaxis, the response to subsequent NNRTI-based com bination therapy given for maternal health has been a concern12, 20, 26-29. A study performed in Zambia, Kenya, and Thailand found that prior exposure to single-dose nevirapine was associated with an increased risk of treatment failure in pregnant women receiving NNRTI-based ART, with the greatest risk being in women receiving ART within 12 months of previous nevirapine exposure30. The Optimal Combination Therapy After Nevirapine Exposure (OCTANE)/A5208 trial conducted in Africa compared nevirapine with lopinavir/ritonavir-based therapy in women requiring therapy who had prior exposure to single-dose nevirapine prophylaxis. The results suggest that prior exposure to single-dose nevirapine within 24 months of initiating therapy may be associated with a higher risk o f viral failure with nevirapine-based therapy compared with lopinavir/ritonavir-based therapy. In this study, significantly more women in the nevirapine arm (29, 24%) failed to achieve a subsequent undetectable viral load (25) or died (4) compared with women in the lopinavir/ritonavir arm (8, 7%; 7 virologic failures and 1 death; P <0.0005). Five of 13 (38%) women with documented nevirapine resistance at the start of therapy either had detectable virus or died. This study demonstrates that women with documented nevirapine resistance are most likely to bene fit from combination therapy that does not contain nevirapine (and because of cross resistance, efavirenz)29. Few data evaluate response to subsequent therapy in women who receive current combination drug regi mens for prophylaxis and discontinue the drugs postpartum. In theory, however, resistance should not occur if the regimen that was discontinued had fully suppressed viral replication. Issues relating to the discontinuation o f nevirapine-based combination therapy are discussed in Prevention o f Antiretroviral Drug Resistance. Management of Antiretroviral Drug Resistance during Pregnancy (Updated September 14, 2011) Panel's Recommendations - Women who have documented zidovudine resistance and are on regimens that do not include zidovudine for their own health should still receive intravenous zidovudine during labor whenever possible, along with their established antiretro viral (ARV) regimens (AII). - In women who are receiving a stavudine-containing regimen, the drug should be discontinued during labor while intra venous zidovudine is being administered (see Intrapartum Care) (AII). - The optimal prophylactic regimen for newborns of women with ARV resistance is unknown (see Infant Antiretroviral Pro phylaxis). Therefore, ARV prophylaxis for an infant born to a woman with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist, preferably before delivery (AIII). Ideally, ARV regimens used during pregnancy for treatment or prophylaxis should be chosen based upon the results o f ARV resistance testing. Although most transmission occurs intrapartum, 30% -35% of transmission may occur in utero1-3. The majority o f the latter infections are believed to occur later in pregnancy1 and they may be more likely in women with advanced HIV disease and/or high viral load2-3. Therefore, a delay in initiation o f an ARV drug regimen to await results o f resistance testing could result in in utero infection o f the infant, particularly in women at high risk o f transmission or who are late in pregnancy at the time the drugs are initiated. In such circumstances, as noted earlier, empiric initiation of the ARV drug regimen may be warranted, with modification o f the regimen once resistance testing re sults become available. For women who have documented zidovudine resistance and whose antepartum regimen does not in clude zidovudine, the drug still should be given intravenously during labor whenever possible (see Intra partum Care). Because stavudine may be antagonistic to zidovudine, it should be stopped during the intrapartum period and restarted after delivery (see Intrapartum Care). Other ARVs should be continued orally during labor to the extent possible. The optimal prophylactic regimen for newborns o f women with ARV drug-resistant virus is unknown. Therefore, ARV prophylaxis for infants born to women with known or suspected drug-resistant virus should be determined with a pediatric HIV specialist, preferably before delivery (see Infant Antiretroviral Prophylaxis) . The rationale for including zidovudine intrapartum when a woman is known to harbor virus with zi dovudine resistance is based on several factors. Data thus far have suggested that only wild-type virus appears to be transmitted to infants by mothers who have mixed populations o f wild-type virus and virus with low-level zidovudine resistance4. Other studies have suggested that drug-resistance mutations may dim inish viral fitness and possibly decrease transmissibility5. The efficacy o f the zidovudine prophylaxis appears to be based not only on a reduction in maternal HIV viral load but also on pre-and post-expo sure prophylaxis in the infant6-8. Zidovudine crosses the placenta readily and has one o f the highest maternal-to-cord blood ratios among the nucleoside analogue agents. In addition, zidovudine is metabolized to the active triphosphate within the placenta9-10, which may provide additional protection against trans mission. Metabolism to the active triphoshate, which is required for activity o f all nucleoside analogue agents, has not been observed within the placenta with other nucleoside analogues that have been evalu ated (didanosine and zalcitabine). Zidovudine penetrates the central nervous system (CNS) better than do other nucleoside analogues except stavudine, which has similar CNS penetration; this may help to eliminate a potential reservoir for transmitted HIV in the infant11-12. Thus, intrapartum intravenous ad ministration o f zidovudine currently is recommended even in the presence o f known resistance because o f the unique characteristics of the drug and its proven record in reducing perinatal transmission. Prevention of Antiretroviral Drug Resistance (Updated September 14, 2011) Panel's Recommendations - HIV-infected pregnant women should be given combination antiretroviral (ARV) drug regimens to maximally suppress viral replication; that is the most effective strategy for preventing development of resistance and minimizing risk of peri natal transmission (AII). - All pregnant women should be counseled about the importance of adherence to prescribed ARV medications to reduce the potential for development of resistance (AII). - Pregnant women who are receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination ARV therapy solely for prophylaxis of transmission that will be discontinued after delivery should receive nucleoside analogue agents for at least 7 days after the NNRTI is stopped to minimize risk of resistance (AI). An alternative strategy is to sub stitute a protease inhibitor (PI) for the NNRTI prior to the interruption and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for at least 7 days after stopping the NNRTI (CIII). The optimal interval between stopping an NNRTI and the other ARV drugs is not known (see Stopping Antiretroviral Therapy during Pregnancy and Postpartum Follow-Up of HIV-Infected Women). - Adding single-dose maternal/infant nevirapine to an ongoing combination ARV regimen given for treatment or prophy laxis does not increase efficacy in reducing perinatal transmission and may result in nevirapine drug resistance in the mother and/or infant; therefore single-dose maternal/infant nevirapine is not recommended in this situation (AI). The most effective way to prevent the development o f ARV drug resistance in pregnancy is to use and adhere to an effective combination o f ARV drugs to achieve maximal viral suppression. Several studies have shown that development o f nevirapine resistance is significantly decreased (but not eliminated) after exposure to single-dose intrapartum nevirapine (given alone or in combination with an tenatal ART) when zidovudine/lamivudine is given intrapartum and administered for 3-7 days postpar tum in women who have received single-dose nevirapine1-3. A variety o f other regimens (e.g., tenfovir/emtricitabine, zidovudine/didanosine) given for 7-30 days postpartum following maternal sin gle-dose nevirapine have also been shown to be very effective in reducing the development o f nevirap ine resistance4-6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual NRTIs for a period of time7. The optimal duration for continuation o f either dual nucleosides or the substituted PI-based regimen after stopping the NNRTI is unknown. NNRTI drugs have long half-lives, and drug levels can persist for up to 1-3 weeks after stopping the drug; efavirenz levels persist longer than nevirapine levels8-9. More research is needed on the optimal duration o f time and regimen to "cover" this period o f prolonged NNRTI exposure to prevent the emergence o f resistance after discon tinuation of NNRTI-based therapy. Many experts will stop the NNRTI drug and continue the other ARV drugs for at least 7 days, although other experts would recommend up to 30 days, particularly if an efavirenz-based regimen is being discontinued. Intrapartum Care (Updated September 14, 2011) # Intrapartum Antiretroviral Therapy/Prophylaxis Panel's Recommendations - Intrapartum intravenous zidovudine is recommended for all HIV-infected pregnant women, regardless of their antepar tum regimen, to reduce perinatal transmission of HIV (AI). - For women who are receiving a stavudine-containing antepartum regimen, stavudine should be discontinued during labor while intravenous zidovudine is being administered (AI). - Women who are receiving an antepartum combination antiretroviral (ARV) drug regimen should continue this regimen on schedule as much as possible during labor and before scheduled cesarean delivery (AIII). - Women receiving fixed-dose combination regimens that include zidovudine should receive intravenous zidovudine during labor while other oral ARV components are continued (AIII). - For women who have received antepartum ARV drugs but have suboptimal viral suppression near delivery (i.e., HIV RNA >1,000 copies/mL), scheduled cesarean delivery is recommended (see Mode of Delivery) (AI). The addition of single dose intrapartum/newborn nevirapine is not recommended (AI). - Women of unknown HIV status who present in labor should undergo rapid HIV antibody testing (AII). If the results are positive, a confirmatory HIV test should be done as soon as possible and maternal/infant ARV drugs should be initiated pending results of the confirmatory test (AII). If the confirmatory HIV test is positive, infant ARV drugs should be contin ued for 6 weeks (see Neonatal Postnatal Care) (AI); if the test is negative, the infant ARV drugs should be stopped. - Intravenous zidovudine is recommended for HIV-infected women in labor who have not received antepartum ARV drugs and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (AII). Table 8 shows dosing for zidovudine, given intravenously as a continuous infusion during labor and dur ing the neonatal period; Table 9 shows intrapartum and neonatal dosing for additional drugs to be con sidered in certain situations, as delineated below. # Women Who H ave R eceived Antepartum Antiretroviral Drugs # Use of Intravenous Zidovudine during Labor Results from PACTG 076 and subsequent epidemiologic studies have proven the efficacy o f the threepart zidovudine chemoprophylaxis regimen, alone or in combination with other ARV agents. The PACTG 076 zidovudine regimen includes a continuous intravenous infusion o f zidovudine during labor (initial loading dose o f 2 mg/kg intravenously over 1 hour, followed by continuous infusion o f 1 mg/kg/hour until delivery). Given results from this trial, intravenous zidovudine during the intrapartum period should be discussed with and recommended to all HIV-infected pregnant women. Administration o f intravenous zidovudine should begin 3 hours before scheduled cesarean delivery, according to stan dard dosing recommendations. Women receiving fixed-dose combination regimens that include zidovu dine, such as a zidovudine/lamivudine combination, should receive intravenous zidovudine during labor while other oral ARV components are continued. For example, in women who are receiving zidovudine/lamivudine during pregnancy, zidovudine should be given intravenously and lamivudine should be given orally during labor. If antenatal use o f zidovudine was precluded by known or suspected zidovudine resistance, intrapartum use o f the drug still should be recommended, except in woman with documented histories o f hypersensi-tivity. This intrapartum use o f the drug is recommended because o f the unique characteristics of zidovu dine and its proven record in reducing perinatal transmission, even in the presence o f maternal resistance to the drug (see Management o f Antiretroviral Drug Resistance during Pregnancy) . Because there is pharmacologic antagonism between zidovudine and stavudine, those drugs should not be coadministered during labor. Women who are receiving an antepartum stavudine-containing regimen should have the drug temporarily discontinued during labor while intravenous zidovudine is being administered, with other components o f the regimen continued orally. # Continuation o f Antenatal Antiretroviral Drugs during Labor Women who are receiving an antepartum combination ARV drug regimen should continue that regimen on schedule as much as possible during the intrapartum period to provide maximal virologic effect and to minimize the chance o f development o f drug resistance. When cesarean delivery is planned, oral med ications can be continued preoperatively with sips o f water. Medications requiring food ingestion for ab sorption can be taken with liquid dietary supplements, contingent on consultation with the attending anesthesiologist in the preoperative period. If the maternal ARV regimen must be interrupted temporar ily (e.g., for less than 24 hours) during the peripartum period, all drugs should be stopped and reinsti tuted simultaneously to minimize the chance that resistance will develop. # Women Who H ave R eceived Antepartum Antiretroviral D rugs B ut H ave Suboptimal Viral Suppression Near Delivery Women who have received combination ARV drug regimens may not achieve complete viral suppres sion by the time o f delivery because o f factors such as poor adherence, viral resistance, or late entry into care. Regardless of the reason, all women who have HIV RNA levels >1,000 copies/mL near the time of delivery should be offered a scheduled cesarean delivery at 38 weeks, which may significantly reduce the risk o f transmission (see Transmission and Mode o f Delivery). The addition o f single-dose nevirapine during labor has not been shown to reduce perinatal transmission o f HIV in this group of women. The PACTG 316 study, conducted in women in the United States, Eu rope, Brazil, and the Bahamas who were receiving ARV drugs during pregnancy (primarily combination therapy), showed that the addition o f single-dose nevirapine did not reduce the risk o f mother-to-child transmission of HIV, even in the setting o f maternal viremia. It was, however, associated with the devel opment o f nevirapine resistance in 15% of women with detectable HIV RNA levels postpartum1-2. Given the risk o f development o f resistance and the lack o f data to suggest added efficacy, addition o f single dose nevirapine is not recommended in women who have received combination antepartum ARV drugs. Use of additional medications for prophylaxis in infants may be warranted in special circumstances, such as in cases where maternal HIV RNA levels are high at or near the time o f delivery, especially if delivery is not a scheduled cesarean delivery (see Infant Antiretroviral Prophylaxis and Table 9) . How ever, no additional intrapartum interventions are indicated for the mothers. # Women Who H ave N ot R eceived Antepartum Antiretroviral Drugs # Women W ho Present in Labor W ithout Documentation of HIV Status All women with undocumented HIV status or without documentation o f HIV status at the time o f labor should be screened with rapid HIV testing unless they decline (opt-out screening). Rapid HIV testing is also recommended for women presenting in labor who tested negative for HIV in early pregnancy but are at increased risk o f HIV infection and were not retested in the third trimester3. Factors that may in crease risk of infection include diagnosis o f a sexually transmitted infection (STI), illicit drug use or ex change o f sex for money or drugs, multiple sexual partners during pregnancy, a sexual partner at risk of HIV infection, signs/symptoms o f acute HIV infection, or living in a region with an elevated incidence o f HIV in women o f childbearing age and not undergoing repeat HIV testing in the third trimester3. Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity serv ice and/or neonatal intensive care unit. Statutes and regulations regarding rapid testing vary from state to state; see for a review o f state HIV testing laws. Current information on rapid testing also should be available at all facilities with a maternity service and/or neonatal intensive care unit. Women with positive rapid HIV antibody tests should be presumed to be infected until standard HIV an tibody confirmatory testing clarifies their infection status. Along with confirmatory HIV antibody test ing, these women should receive appropriate assessments as soon as possible to determine their health status and make recommendations for whether antiretroviral therapy (ART) is needed based on that sta tus. Arrangements also should be made for establishing HIV care and providing ongoing psychosocial support after discharge. Intravenous zidovudine should be started immediately in all women with posi tive rapid HIV tests in labor to prevent perinatal transmission o f HIV, as discussed below. # Choice of Intrapartum/Postpartum Antiretroviral Regimen for Women without Antepartum Antiretroviral Therapy All HIV-infected women who have not received antepartum ARV drugs should have intravenous zidovu dine started immediately to prevent perinatal transmission o f HIV (see Table 8 for dosing information). Although intrapartum/neonatal ARV medications will not prevent perinatal transmission that occurs be fore labor, most transmission occurs near to or during labor and delivery. Pre-exposure prophylaxis for the fetus can be provided by giving mothers a drug that rapidly crosses the placenta, producing fetal sys temic ARV drug levels during intensive exposure to HIV in maternal genital secretions and in blood dur ing birth. In general, zidovudine and other nucleoside reverse transcriptase inhibitor (NRTI) drugs and non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs cross the placenta well, whereas protease inhibitors (PIs) do not (see Table 5). Epidemiologic data indicate that intravenous maternal intrapartum zidovudine followed by oral zidovu dine for 6 weeks for the infant significantly reduces transmission compared with no treatment4. In a New York State cohort study, transmission rates were 10% with intrapartum and neonatal zidovudine com pared with 27% without zidovudine, a 62% reduction in risk4. The PETRA study demonstrated that in trapartum prophylaxis alone, without an infant post-exposure prophylaxis component, is not effective in reducing perinatal transmission5. A large international trial (NICHD-HPTN 040/PACTG 1043) demonstrated that adding ARV agents to the neonatal portion o f the intrapartum/neonatal zidovudine regimen can further reduce mother-to-child transmission of HIV for mothers who have received no antepartum ARV drugs (see Infant Antiretroviral Prophylaxis). In this study, women who had not received antepartum ARV drugs received only intra venous zidovudine, whereas their infants received zidovudine in combination with other agents, achiev ing a 50% reduction in transmission. Therefore, no additional intrapartum drugs, including intrapartum maternal single-dose nevirapine, are indicated for the woman in this situation6. References: Transmission and Mode of Delivery (Updated September 14, 2011) Panel's Recommendations - Scheduled cesarean delivery at 38 weeks' gestation is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery, irrespective of administration of antepartum antiretroviral (ARV) drugs, and for women with un known HIV RNA levels near the time of delivery (AII). - Scheduled cesarean delivery is not routinely recommended for prevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levels <1,000 copies/mL near the time of delivery. Data are in sufficient to evaluate the potential benefit of cesarean delivery in this group, and given the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additional benefit in reducing transmis sion. This decision should be individualized based on discussion between the obstetrician and the mother (BII). - It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventing peri natal transmission. Management of women originally scheduled for cesarean delivery who present with ruptured mem branes or in labor must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current ARV regimen, and other clinical factors (BII). - Women should be informed of the risks associated with cesarean delivery; the risks to the woman should be balanced with potential benefits expected for the neonate (AIII). # Basis fo r Current Recommendations Scheduled cesarean delivery, defined as cesarean delivery performed before the onset o f labor and be fore rupture of membranes, is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery and for women with unknown HIV RNA levels1. This recommendation is based on findings from a multicenter, randomized clinical trial2 and from a large individual patient data meta-analysis3. These two studies were conducted at a time when the major ity of HIV-infected women received no ARV medications or zidovudine as a single drug and before the availability o f viral load information. Study results have since been extrapolated to make current recom mendations about the mode o f delivery in an era when combination ARV regimens during pregnancy are recommended and viral load information is readily available. In the randomized clinical trial, 1.8% of infants born to women randomized to undergo cesarean delivery were HIV infected compared with 10.5% of infants born to women randomized to vaginal delivery (P <0.001). When adjusted for ARV use in pregnancy (zidovudine alone), scheduled cesarean delivery lowered the risk of HIV transmission by 80%, although the results were no longer statistically significant (odds ratio 0.2, 95% confidence interval , 0-1.7). When the data were analyzed by the actual mode of deliv ery, rather than to which group women were allocated, there was still a protective effect of scheduled ce sarean delivery (adjusted OR 0.3; 95% CI, 0.1-0.8) but not with emergency cesarean delivery (AOR 1.0; 95% CI, 0.3-3.7)2. Results from a large meta-analysis of individual patient data from 15 prospective cohort studies also demonstrated the benefit of scheduled cesarean delivery with a 50% reduction in risk3. Primarily based on these data, the American College of Obstetricians and Gynecologists has recommended consideration of scheduled cesarean delivery for HIV-infected pregnant women since 19994. # HIV RNA Level o f 1,000 copies/mL as a Threshold for Recommendation of Scheduled Cesarean Delivery The original American College o f Obstetricians and Gynecologists committee opinion was updated in 2000 to include further refinements based on HIV RNA levels1. Currently, the American College o f Ob stetricians and Gynecologists1 recommends that women with HIV RNA >1,000 copies/mL be counseled regarding the potential benefits o f scheduled cesarean delivery. Initially, this threshold o f 1,000 copies/mL was based largely on data from the Women and Infants Transmission Study (WITS), a large prospective cohort study that reported no HIV transmission among 57 women with HIV RNA levels <1,000 copies/mL5. Since that time, newer studies have demonstrated that HIV transmission can occurr among infants born to women with low viral loads. In an analysis o f 957 women with plasma viral loads <1,000 copies/mL, cesarean delivery (scheduled or urgent) reduced the risk o f HIV transmission when adjusting for potential confounders including receipt o f maternal ARV medications, primarily zidovudine alone as prophylaxis (AOR 0.30; P = 0.022)6. Among infants born to 834 women with HIV RNA <1,000 copies/mL receiving ARV medications, 8 (1%) were HIV infected. In a more recent report from a comprehensive national surveillance system in the United Kingdom and Ireland, 3 (0.1%) o f 2,309 and 12 (1.2%) o f 1,023 infants born to women with HIV RNA o f <50 copies/mL and 50-999 copies/mL, respectively, were HIV infected7. The recent studies demonstrate that transmission can occur even at very low HIV RNA levels. However, given the low rate of transmission among this group, it is unclear whether scheduled cesarean delivery confers any additional benefit in reducing transmission. Although decisions about mode of delivery for women with HIV RNA levels <1,000 copies/mL should be individualized based on discussion between the obstetrician and the mother, scheduled cesarean delivery is not routinely recommended in this group. # Scheduled Cesarean Delivery in the Highly Active Antiretroviral Therapy Era In surveillance data from the United Kingdom and Ireland, pregnant women receiving combination ARV regimens (i.e., at least 3 drugs) had transmission rates o f about 1%, unadjusted for mode o f delivery7. Given the low transmission rates achievable with use of maternal combination ARV drug regimens, the benefit o f scheduled cesarean delivery is difficult to evaluate. Both the randomized clinical trial2 and meta-analysis3 documenting the benefits o f cesarean delivery included mostly women who were receiv ing either no ARVs or zidovudine only. However, other data partially address this issue. In a report from the European Collaborative Study that included data from 4,525 women, the overall trans mission rate among the subset of women on a combination ARV regimen was 11(1.2%) of 9188. Among the subset of 560 women with undetectable HIV RNA levels (<50 to <200 copies/mL, depending on site), scheduled cesarean delivery was associated with a significant reduction in perinatal transmission in uni variate analysis (OR 0.07; 95% CI, 0.02-0.31; P = 0.0004). However, after adjustment for ARV drug use (none vs. any), the effect was no longer significant (AOR 0.52; 95% CI, 0.14-2.03; P = 0.359). Similarly, data from a European surveillance study did not demonstrate a statistically significant difference in trans mission rates between scheduled cesarean delivery and planned vaginal delivery (AOR 1.24; 95% CI, 0.34-4.5) among women on combination ARV drug regimens7. The transmission rate among all women who received at least 14 days of ARV medications was 40 (0.8%) of 4,864, regardless of mode of delivery. Therefore, it is not clear whether there is any benefit from scheduled cesarean delivery among women who have been receiving combination ARV medications for several weeks. # Women Presenting Late in Pregnancy HIV-infected women who present in late pregnancy and are not receiving ARV drugs may not have HIV RNA results available before delivery. Without current therapy, HIV RNA levels are unlikely to be <1,000 copies/mL at baseline. Even if combination ARV medications were begun immediately, reduc tion in plasma HIV RNA to undetectable levels usually takes several weeks, depending on the kinetics of viral decay for the particular drug regimen9. In this instance, scheduled cesarean delivery is likely to pro vide additional benefit in reducing the risk o f perinatal transmission o f HIV for women, unless viral sup pression can be documented prior to 38 weeks. # Timing of Scheduled Cesarean Delivery In general, for women without HIV infection, American College of Obstetricians and Gynecologists rec ommends that scheduled cesarean delivery not be performed before 39 weeks' gestation because of the risk of iatrogenic prematurity10-11. However, in cases of cesarean delivery performed to prevent transmis sion of HIV, American College of Obstetricians and Gynecologists recommends scheduling cesarean de livery at 38 weeks' gestation in order to decrease the likelihood o f onset of labor or rupture of membranes before delivery1. Among all women undergoing repeat cesarean delivery, the risk of any neonatal adverse event-including neonatal death, respiratory complications, hypoglycemia, newborn sepsis, or admission to the neonatal intensive care unit-is 15.3% at 37 weeks, 11.0% at 38 weeks, and 8.0% at 39 weeks11. Gestational age should be determined by last menstrual period and ultrasonography because amniocentesis to document lung maturity should be avoided, when possible, in HIV-infected women. Among 1,194 infants born to HIV-infected mothers, 9 (1.6%) infants born vaginally had respiratory dis tress syndrome (RDS) compared with 18 (4.4%) of infants born by scheduled cesearean delivery (P <0.001). There was no statistically significant association between mode of delivery and infant RDS in an adjusted model that included infant gestational age and birth weight12. Clinicians should recognize that newborn complications may be increased in planned early term births <39 weeks' gestation. However, for HIV-infected women, the benefits of decreasing HIV transmission by planned delivery at 38 weeks are generally thought to outweigh the risks. When cesarean delivery is performed in HIV-infected women for an indication other than decreasing transmission of HIV, cesarean delivery should be scheduled at 38 weeks gestation based on accepted American College of Obstetricians and Gynecologists guidelines. # Risk of M aternal Complications Because maternal infectious morbidity is increased with cesarean delivery even among women without HIV infection, the administration of perioperative antimicrobial prophylaxis is recommended for all women undergoing cesarean delivery. Most studies have demonstrated that HIV-infected women have in creased rates of postoperative complications, mostly infectious, compared with HIV-uninfected women and that the risk of complications is related to the degree of immunosuppression13-18. Furthermore, a Cochrane review of six studies of HIV-infected women concluded that urgent cesarean delivery was asso ciated with the highest risk of postpartum morbidity, that scheduled cesarean delivery was intermediate in risk, and that vaginal delivery had the lowest risk of morbidity19. Complication rates in most studies2, 20-24 were within the range reported in populations of HIV-uninfected women with similar risk factors and were not of sufficient frequency or severity to outweigh the potential benefit of reduced transmission. Therefore, HIV-infected women should be counseled regarding the increased risks and potential benefits associated with cesarean delivery based on their HIV RNA levels and current ARV regimen. # Management o f Women W ho Present in Early Labor or With Ruptured Membranes Few data are available to address the question o f whether performing cesarean delivery after the onset of labor or membrane rupture may decrease the risk o f perinatal transmission o f HIV. Most studies have shown a similar risk o f transmission for cesarean delivery performed after labor and membrane rupture for obstetric indications and for vaginal delivery. In one study, the HIV transmission rate was similar in women undergoing emergency cesarean delivery and those delivering vaginally (1.6% vs. 1.9%, respectively)7. A meta-analysis o f women, most o f whom were on zidovudine as a single drug or receiving no ARV medications, demonstrated a 2% increased transmission risk for every additional hour o f ruptured membranes25. However, it is not clear how soon after the onset o f labor or the rupture o f membranes the benefit o f cesarean delivery is lost26. Therefore, the management o f women originally scheduled for ce sarean delivery who present with ruptured membranes or in labor must be individualized based on clini cal factors such as duration o f rupture, progress o f labor, plasma RNA level, and current ARV drug regimen status. When membrane rupture occurs before 37 weeks' gestation, decisions about delivery should be based on gestational age, HIV RNA level, current ARV regimen, and evidence o f acute infec tion such as chorioamnionitis; consultation with an expert is recommended. The ARV drug regimen should be continued and consideration given to initiating intravenous zidovudine if delivery appears im minent. No data exist to suggest that recommendations for administration o f steroids to accelerate fetal lung maturity should be altered among HIV-infected women. Table 7 provides a summary o f recommendations regarding mode o f delivery for different clinical sce narios. # Clinical Scenario Recommendations HIV-infected women presenting in late pregnancy (after about - Start ARV medications as per Table 6 . - Provide counseling on the likelihood that scheduled cesarean delivery will reduce the risk 36 weeks' gestation), known to of mother-to-child transmission, if viral suppression cannot be documented prior to 38 be HIV infected but not receiv ing antiretroviral (ARV) medica tions, and who have HIV RNA level and CD4 cell counts pend ing but unlikely to be available before delivery. weeks. Include information on the increased maternal risks of cesarean delivery, including increased rates of postoperative infection, anesthesia, and other surgical risks. - When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography. - Administer continuous intravenous zidovudine beginning 3 hours before scheduled ce sarean. - Continue other ARV medications on schedule, as much as possible, before and after surgery. - Use of prophylactic antibiotics at the time of cesarean delivery is recommended. HIV-infected women who began prenatal care early in the third trimester, are receiving combina tion ARV drug regimens, and have an initial virologic response but have HIV RNA levels that re main substantially >1,000 copies/mL at 36 weeks' gesta tion. - Continue the current combination ARV regimen because the drop in HIV RNA level is ap propriate. - Provide counseling on the timing of response to ARV medications and the likelihood that maternal HIV RNA levels may not fall below 1,000 copies/mL before delivery. Consider scheduled cesarean delivery if viral load suppression is not achieved by 38 weeks be cause of the potential additional benefit in preventing intrapartum transmission of HIV. In form patients about the increased maternal risks associated with cesarean delivery, including risks related to anesthesia and surgery and increased rates of postoperative in fection. - When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography. - When the delivery method selected is scheduled cesarean delivery, administer continuous intravenous zidovudine beginning 3 hours before scheduled cesarean. - Continue other ARV medications on schedule, as much as possible, before and after surgery. - Use of prophylactic antibiotics at the time of cesarean delivery is recommended. HIV-infected women on combi nation ARV drug regimens with undetectable HIV RNA levels at 36 weeks' gestation. - Provide counseling on the risk of perinatal transmission of HIV with a persistently unde tectable HIV RNA level, which is probably 1% or less, even with vaginal delivery. No evi dence currently exists to show that this risk can be lowered further by performing scheduled cesarean delivery. - Risk of complications is increased with cesarean delivery, compared with vaginal delivery, even in the HIV-uninfected population, and the risks must be balanced against the uncer tain benefits of cesarean delivery in women with undetectable viral load. HIV-infected women who have elected scheduled cesarean de livery but present after rupture of membranes at >37 weeks' gestation. - Start intravenous zidovudine immediately. - Individualize the decision regarding mode of delivery, based on clinical factors such as dura tion of rupture, anticipated progress of labor, plasma RNA level, and current ARV regimen. - When vaginal delivery is chosen, some clinicians may consider administration of oxy tocin, if clinically appropriate, in order to expedite delivery. Scalp electrodes and other in vasive monitoring and operative delivery should be avoided, if possible, unless there are clear obstetric indications. - When cesarean delivery is chosen, administration of the loading dose of intravenous zi dovudine ideally should be completed prior to the procedure. However, decisions regard ing timing of delivery should be individualized. Other Intrapartum Management Considerations (Updated September 14, 2011) # Panel's Recommendations - Generally avoid artificial rupture of membranes unless there are clear obstetric indications because of a potential in creased risk of transmission (BIII). - Routine use of fetal scalp electrodes for fetal monitoring should be avoided in the setting of maternal HIV infection unless there are clear obstetric indications (BIII). - Operative delivery with forceps or a vacuum extractor and/or episiotomy should be performed only if there are clear ob stetric indications (BIII). The antiretroviral drug (ARV) regimen a woman is receiving should be taken into consideration when treating excessive postpartum bleeding resulting from uterine atony: - In women who are receiving a cytochrome P (CYP) 3A4 enzyme inhibitor such as a protease inhibitor (PI), methergine should only be used if no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest ef fective dose for the shortest possible duration (BIII). - In women who are receiving a CYP3A4 enzyme inducer such as nevirapine or efavirenz, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect (BIII). If spontaneous rupture o f membranes occurs before or early during the course o f labor, interventions to decrease the interval to delivery, such as administration o f oxytocin, may be considered in women with out indications for cesarean delivery. Artificial rupture o f membranes should be avoided and used only for a clear obstetric indication in women with intact membranes and detectable viral load who present in labor and proceed to vaginal de livery. Data are limited on artificial rupture o f membranes in women with undetectable viral load and planned vaginal delivery. In general, the procedure should be performed only for clear obstetrical indica tions because o f the potential, albeit small, increased risk o f HIV transmission. Obstetric procedures that increase the risk o f fetal exposure to maternal blood, such as invasive fetal monitoring, have been implicated in increasing vertical transmission rates by some, but not all, investi gators, primarily in studies performed in the pre-combination antiretroviral therapy (ART) era1-4. Data are limited on routine use o f fetal scalp electrodes in labor in women receiving suppressive ARV regi mens and undetectable viral load; routine use o f fetal scalp electrodes for fetal monitoring should be avoided in the setting o f maternal HIV infection unless there are clear obstetric indications. Similarly, data are limited to the pre-combination ART era regarding the potential risk o f perinatal trans mission o f HIV associated with operative vaginal delivery with forceps or the vacuum extractor and/or use o f episiotomy2, 4. These procedures should be performed only if there are clear obstetric indications. Delayed cord clamping has been associated with improved iron status and benefits such as decreased risk o f intraventricular hemorrhage in preterm births to HIV-uninfected mothers5-7. Even though HIVspecific data on the practice are lacking, there is no reason to modify it in HIV-infected mothers. # Postpartum Hemorrhage, Antiretroviral Drugs, and M ethergine Use Oral or parenteral methergine or other ergot alkaloids are often used as first-line treatment for postpar tum hemorrhage resulting from uterine atony. However, methergine should not be coadministered with drugs that are potent CYP3A4 enzyme inhibitors, including PIs. Concomitant use o f ergotamines and PIs has been associated with exaggerated vasoconstrictive responses. When uterine atony results in ex cessive postpartum bleeding in women receiving PIs as a component o f an ARV regimen, methergine should be used in women with excessive postpartum bleeding who are receiving PIs as a component of ART only if alternative treatments such as prostaglandin F 2 alpha, misoprostol, or oxytocin are unavail able. If no alternative medications are available and the need for pharmacologic treatment outweighs the risks, methergine should be used in as low a dosage and for as short a period as possible. In contrast, ad ditional utertonic agents may be needed when other ARV drugs that are CYP3A4 inducers, such as nevi rapine and efavirenz, are used because o f the potential for decreased methergine levels and inadequate treatment effect. Postpartum Management (Updated September 14, 2011) Postpartum Follow-up of HIV-Infected Women # Panel's Recommendations - Contraceptive counseling should be included as a critical aspect of postpartum care (AIII). - Decisions about continuing antiretroviral (ARV) drugs after delivery should take into account current recommendations for initiation of antiretroviral therapy (ART), current and nadir CD4 cell counts and trajectory, HIV RNA levels, adherence issues, whether the woman has an HIV-uninfected sexual partner, and patient preference (AIII). - For women continuing ARV drugs postpartum, arrangements for new or continued supportive services should be made before hospital discharge because the immediate postpartum period poses unique challenges to adherence (AII). - Women with a positive rapid HIV antibody test during labor require comprehensive follow-up, including confirmation of HIV infection. If infection is confirmed, a full health assessment is warranted, including evaluation for associated medical conditions, counseling related to newly diagnosed HIV infection, and assessment of need for ART and opportunistic in fection (OI) prophylaxis (AII). The postpartum period provides an opportunity to review and optimize women's health care. Compre hensive care and support services are particularly important for women with HIV infection and their families, who often face multiple medical and social challenges. Components o f comprehensive care in clude the following medical and supportive care services as needed: - primary, gynecologic/obstetric, and HIV specialty care for the HIV-infected woman; - pediatric care for her infant; - family planning services; - mental health services; - substance abuse treatment; - support services; and - coordination of care through case management for the woman, her child(ren), and other family members. Support services should be tailored to individual women's needs and may include case management; child care; respite care; assistance with basic life needs, such as housing, food, and transportation; peer counseling; and legal and advocacy services. Ideally, this care should begin before pregnancy and con tinue throughout pregnancy and the postpartum period. During the postpartum period, maternal medical services must be coordinated between obstetric care providers and HIV specialists. It is especially critical to ensure continuity o f the antepartum ARV drug regimen when such treatment is required for a woman's health. The decision about whether to continue ARV drugs after delivery should be discussed with a woman and made before delivery. The postpartum period also is a critical time for addressing the issue of safer sex practices and contracep tion. Lack of breastfeeding is associated with earlier return of fertility; ovulation returns as early as 6 weeks postpartum, and even earlier in some women, putting them at risk of pregnancy shortly after deliv ery1. Interpregnancy intervals of less than 18 months have been associated with increased risk of poor peri natal and maternal outcomes in HIV-uninfected women2. Because of the stresses and demands of a new baby, women may be more receptive to use of effective contraception, yet simultaneously at higher risk of nonadherence to contraceptive use and thus unintended pregnancy3. This is an important concern in women who are on an efavirenz-containing regimen because of the potential risk of teratogencity. A "dual protection" strategy, such as use of condoms plus a second highly effective contraceptive, is ideal for women with HIV infection because it provides simultaneous protection against unintended pregnancy and HIV transmission or sexually transmitted disease (STD) acquisition or transmission4. Longer term, re versible contraceptive methods, such as injectables, implants, and intrauterine devices (IUDs) should be included as options. Drug interactions have been documented between oral contraceptives (OCs) and many ARV drugs (see Table 4 in Preconception Counseling). These interactions, however, do not necessarily rule out the use of hormonal contraceptives because there is no clear evidence of an effect on contraceptive or ARV efficacy or toxicity. OCs do significantly lower levels of amprenavir/fosamprenavir and, therefore, coadministra tion is not recommended; whether low-dose ritonavir boosting raises amprenavir levels sufficiently to allow coadministration is unknown. Depot medroxyprogesterone acetate (Depo-Provera, DMPA) pharma cokinetics (PKs) are not significantly affected by nevirapine, efavirenz, or nelfinavir, and levels of these drugs were not significantly altered by DMPA5. Adverse effects of DMPA are no different in HIV-infected women on ARV drugs than in HIV-uninfected women6. Other non-oral contraceptives, such as levonorgestrel implants, the combined contraceptive patch, the combined hormonal contraceptive vaginal ring, and the levonorgestrel IUD, are largely unstudied in combination with ARV drugs, but some data do exist on lopinavir/ritonavir interactions with the estrogen patch7. ARV drug interactions may be of less concern with contraceptive methods that exert primarily local activity and have minimal systemic absorp tion, but there is still a potential for interaction if metabolic or elimination pathways are shared5, 8. Perma nent sterilization is appropriate only for women who are certain they do not desire future childbearing. Women with nadir CD4 cell counts less than the currently recommended threshold for institution of ART9 and/or symptomatic HIV infection should be encouraged to continue their ARV regimens postpar tum without interruption. Decisions about whether to continue ARV drugs after delivery should be made in consultation with the HIV provider for women who began ARV drugs for prophylaxis o f transmission with nadir CD4 cell counts greater than that currently recommended for treatment. Factors to be taken into consideration should include current recommendations for initiation o f ART, current and nadir CD4 lymphocyte counts and trajectory, HIV RNA levels, adherence issues, partner HIV status, and patient preference. The risks versus benefits o f stopping combination ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968). Recent data from the HPTN 052 clinical trial showed that earlier initiation o f ARVs led to a significant reduction in sexual transmission o f HIV to uninfected partners in serodiscordant couples (see Preconcep tion Counseling) . HPTN 052 evaluated immediate versus delayed initiation o f ART to HIV-infected indi viduals with CD4 counts between 350 and 550 cells/mm3. Based on the results from that trial, continued administration o f ARV drugs may be recommended for prevention o f sexual transmission o f HIV for postpartum women who have CD4 cell counts between 350 and 550 cells/mm3 and have HIV-uninfected sexual partners, and it may be considered for those with CD4 cell counts greater than 550 cells/mm3 with HIV-uninfected sexual partners. It is important to counsel the woman that no single method (in cluding treatment o f the infected partner) is fully protective against HIV transmission and safer sexual practices should be continued. Concerns have been raised about adherence to ARV regimens during the postpartum period. Women should be counseled that postpartum physical and psychological changes and the stresses and demands o f caring for a new baby may make adherence more difficult and that additional support may be needed during this period10-12. Health care providers should be vigilant for signs o f depression and illicit drug or alcohol use that may require assessment and treatment and interfere with adherence. Poor adherence has been shown to be associated with virologic failure, development o f resistance, and decreased long-term effectiveness o f ART13-15. Simplification o f an ARV regimen (for example, to once-daily medications) can be considered. It may be preferable to temporarily interrupt ART in women who are unable to ad here to their regimens while they work with a provider on strategies to improve adherence. Efforts to maintain adequate adherence during the postpartum period may prolong the effectiveness o f therapy (see the section on Adherence in the Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). For women whose antepartum regimen included a non-nucleoside reverse transcriptase inhibitor (NNRTI) and who plan to stop ARV prophylaxis after delivery, consideration should be given to stopping the NNRTI and continuing the other ARV drugs for a period of time before stopping electively. The optimal interval be tween stopping an NNRTI and the other ARV drugs is unknown; a minimum of 7 days is recommended. Because efavirenz-based therapy has potential to result in prolonged, detectable NNRTI concentrations for more than 3 weeks, some experts recommend that patients receiving efavirenz continue their other ARV drugs or substitute a protease inhibitor (PI) for the NNRTI drug in combination with their other ARV drugs for up to 30 days after stopping efavirenz (see Stopping Antiretroviral Therapy during Pregnancy and Prevention of Antiretroviral Drug Resistance). Women whose antepartum regimen did not include an NNRTI and who plan to stop ARV prophylaxis after delivery should stop all ARV drugs at the same time. Doses of some PIs may be increased during pregnancy. For women continuing therapy, available data sug gest that standard doses can be used again, beginning immediately after delivery. Comprehensive medical assessment, counseling, and follow-up are required for women who test posi tive on rapid HIV antibody assay during labor or at delivery. To minimize the delay in definitive diagno sis, confirmatory HIV antibody testing should be performed as soon as possible after an initial positive rapid test16. Women who test positive on rapid HIV antibody assay should not breastfeed unless a confir matory HIV test is negative. Women with a new HIV diagnosis postpartum should receive the same thorough evaluation as other newly identified infected patients, including consideration o f ART and pro phylaxis for OIs, as indicated. Other children and partner(s) should be referred for HIV testing. Infants Born to Mothers with Unknown HIV Infection Status (Updated September 14, 2011) Panel's Recommendations - For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis (see Infant Antiretroviral Prophylaxis) if the rapid test is positive (AII). In the setting of a positive test, standard antibody con firmatory testing such as a Western blot also should be performed on mothers (or their infants) as soon as possible. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII). - If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) should be ob tained (AIII). - If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to a pediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combination anti retroviral therapy (ART) (AI). Rapid HIV antibody testing o f mothers and/or infants is recommended as soon as possible after birth when maternal HIV status is unknown and rapid HIV antibody testing was not performed during labor. If rapid testing is positive, infant ARV prophylaxis should be initiated immediately. Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity service and/or neonatal in tensive care or newborn nursery. A positive test result in mothers or infants should be presumed to indi cate maternal HIV infection until standard antibody confirmatory testing clarifies maternal status. A standard confirmatory test (e.g., Western blot) should be performed on mothers (or their infants) as soon as possible after the initial positive rapid test1. A positive HIV antibody test in an infant indicates mater nal but not necessarily infant HIV infection; diagnosis o f HIV infection in infants younger than age 18 months requires virologic testing. If the confirmatory test on a mother (or infant) is negative, ARV pro phylaxis can be discontinued. If the confirmatory test is positive, an HIV DNA PCR should be obtained urgently from the newborn. If the HIV DNA PCR is positive, ARV prophylaxis should be promptly dis continued and the infant should receive treatment for HIV infection with standard combination ART ac cording to established Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection developed by The Working Group on Antiretroviral Therapy and Medical Management o f HIV-Infected Children. Infant Antiretroviral Prophylaxis (Updated September 14, 2011; Erratum issued December 1 , 2011) Panel's Recommendations - The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (A I). - Zidovudine should be initiated as close to the time of birth as possible, preferably within 6-12 hours of delivery (A II). - The 6-week zidovudine prophylaxis regimen is recommended at gestational age-appropriate doses; zidovudine should be dosed differently for premature infants less than 35 weeks than for infants at least 35 weeks of age (see Zidovudine Dosing and Table 8) (A II). - In the United States, the use of antiretroviral (ARV) drugs other than zidovudine cannot be recommended in premature infants because of lack of dosing and safety data (B III) . - The use of intrapartum/neonatal zidovudine is recommended regardless of maternal history of zidovudine resistance (B III). - Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, begun as soon after birth as possible (A I). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen of zi dovudine, nelfinavir and lamivudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see General Considerations for Choice of Infant Prophylaxis and Table 9) (A I). - In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consulta tion with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on the potential risks and benefits of this approach (B III). - The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, in cluding infant care. # Zidovudine Dosing All HIV-exposed infants should receive postpartum ARV drugs to reduce perinatal transmission o f HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed in fants1-2. Table 8 shows zidovudine dosing intrapartum, which is a continuous intravenous infusion during labor, and neonatal dosing. Table 9 shows intrapartum and neonatal dosing for other drugs to be consid ered in certain situations as delineated below. The recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, beginning as soon after birth as possible and preferably within 6-12 hours o f delivery (Table 8) . Although the ACTG 076 study used a zidovudine regimen o f 2 mg/kg every 6 hours, data from many international studies support twice-daily oral infant dosing for prophylaxis3-12. Most o f these studies used a dose o f 4 mg/kg twice daily, adjusted for weight gain, but others have used a regimen based on birth weight for the entire 6-week treatment period13-14. The current World Health Organization (WHO) guidelines recommend a simplified zidovudine dosing regimen for the 6-week prophylaxis period consisting o f 10 mg given twice daily for infants weighing less than 2.5 kg at birth and 15 mg twice daily for infants weighing more than 2.5 kg at birth15. The ad vantages o f this simplified regimen are that it avoids the need for dosing calculations and involves ad ministration o f either 1.0 or 1.5 mL o f zidovudine syrup. The disadvantage is that, compared with mg-per-kg dosing, infants with birth weights greater than 3.75 kg will receive a smaller zidovudine dose and infants less than 3.75 kg will receive a larger zidovudine dose. The zidovudine dosing requirements differ for premature infants and term infants. Zidovudine is prima rily cleared through hepatic glucuronidation to an inactive metabolite; this metabolic pathway is imma ture in neonates, leading to prolonged zidovudine half-life and clearance compared with older infants. Clearance is further prolonged in premature infants because their hepatic metabolic function is even less mature than in term infants16-17. The recommended zidovudine dosage for infants less than 35 weeks' gestation is 2 mg/kg body weight per dose orally every 12 hours (or 1.5 mg/kg body weight intra venously per dose every 12 hours), increasing to 2 mg/kg body weight per dose every 8 hours at age 2 weeks for infants born at 30 weeks' gestation or more or at age 4 weeks in those born at less than 30 weeks' gestation. For infants born at more than 35 weeks' gestation or greater who are unable to tolerate oral zidovudine, the drug can be given intravenously at a dose o f 1.5 mg/kg body weight every 6 hours. In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regi men is recommended for infants born to mothers who have received antenatal combination ARV drug regimens18-20. This approach also can be considered in cases where adherence to or toxicity from the 6week zidovudine prophylaxis regimen is a concern. In an Irish observational study, a transmission rate o f 1.1% was observed in 916 infants who received 4 weeks o f zidovudine infant prophylaxis following antenatal maternal combination ARV prophylaxis. That is the standard regimen in Ireland and the trans mission rate was similar to that observed in the United States, where 6 weeks o f infant zidovudine pro phylaxis is standard20. A recent prospective, observational study reported that the 4-week zidovudine regimen allowed earlier recovery from anemia in otherwise healthy infants compared with the 6-week zidovudine regimen21. The optimal duration o f neonatal zidovudine chemoprophylaxis, however, has not been established in clinical trials, and in the United States, the standard 6-week infant zidovudine regi men is recommended unless there are concerns about adherence or toxicity. Consultation with an expert in pediatric HIV infection is advised if early discontinuation o f prophylaxis is considered. b ZDV dosing regimen is for infants >35 weeks' gestation. See Table 8 for recommended doses for premature infants. # General Considerations fo r Choice o f Infant Prophylaxis Infants born to mothers who have received standard antepartum and intrapartum ARV prophylaxis and have undetectable viral loads are at very low risk o f HIV transmission. However, the risk o f transmission is increased when maternal viral load at delivery is high or maternal antepartum and/or intrapartum pro phylaxis was not received. Most experts feel that the potential benefit o f combining zidovudine infant prophylaxis with additional ARV drugs may exceed the risk o f multiple drug exposure to infants born to: a. mothers who received antepartum and intrapartum ARV drugs but who had suboptimal viral suppres sion at delivery, particularly if delivery was vaginal; b. mothers who received only intrapartum ARV drugs; c. mothers who received no antepartum or intrapartum ARV drugs; and d. mothers with known ARV drug-resistant virus. In each o f these situations, there is a spectrum o f transmission risk that depends on a number o f maternal and infant factors, including maternal viral load, mode o f delivery, and gestational age at delivery. The risks and benefits o f infant exposure to ARV drugs in addition to zidovudine will differ depending on where the mother/child falls in the risk spectrum. For example, an infant delivered vaginally to a mother with an HIV RNA level >100,000 copies/mL at delivery has a higher risk o f acquiring HIV infection than an infant born by cesarean delivery to a mother with an HIV RNA level o f approximately 10,000 copies/mL at delivery. Thus, a generic recommendation cannot be made regarding use o f combination drug regimens for infant prophylaxis and each situation needs to be considered individually, balancing potential benefits (in terms of preventing perinatal transmission o f HIV) with risks (in terms o f toxicity to the infant). In addition, appropriate drug formulations and dosing regimens for neonates are incom pletely defined and data are minimal on the safety o f combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis and the Guidelines for the Use o f Anti retroviral Agents in Pediatric HIV Infection). Thus, decisions about use o f combination ARV prophy laxis in infants should be made in consultation with a pediatric HIV specialist before delivery and should be accompanied by a discussion with the mothers about potential risks and benefits o f this approach. Use of combination ARV prophylaxis for infants in high-risk situations is increasing. Despite widespread use of combination ARV prophylaxis, until recently there were no data evaluating the efficacy of these regimens versus zidovudine alone in the setting of high risk of mother-to-child transmis sion of HIV. Results from a Phase III randomized trial in 4 countries (including the United States) were presented at the 2011 Conference on Retroviruses and Opportunistic Infections (NICHD-HPTN 040/PACTG 1043)14. This study enrolled 1,746 infants born to HIV-infected women who did not receive any ARV drugs during pregnancy and, hence, were at high risk of infection. The study compared infant prophylaxis with the standard 6-week zidovudine regimen and 2 different combination regimens for pre vention of intrapartum transmission of HIV: 6 weeks of zidovudine plus 3 doses of nevirapine given dur ing the first week of life (first dose at birth-48 hours; second dose 48 hours after first dose; and third dose 96 hours after second dose) and 6 weeks of zidovudine plus 2 weeks of lamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower, compared with 6 weeks of zidovudine alone, in the 2and 3-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for zidovudine alone; P = 0.046 for each experi mental arm vs. zidovudine alone). The overall transmission rate of HIV (in utero + intrapartum) was also significantly lower in the 2-and 3-drug arms compared with zidovudine alone (7.1%, 7.4%, and 11.1%, re spectively, P = 0.035 for comparison of each experimental arm with zidovudine alone)14. Although trans mission rates with the two combination regimens were similar, neutropenia was significantly more common with the 3-drug regimen than with the 2-drug or zidovudine-alone regimen (27.5% vs. 15%, P <0.0001). In other studies, significantly higher rates of neutropenia and anemia have been reported with coadministration of zidovudine and lamivudine to infants24. The NICHD-HPTN 040/PACTG 1043 study provides proof o f principle that use o f a combination drug regimen for infants is more effective than zidovudine alone in the high-risk setting o f no maternal an tepartum administration o f ARV drugs. The two-drug regimen is less complex and had lower rates of toxicity than the three-drug regimen; additionally, nelfinavir powder is no longer commercially available in the United States, is not a preferred ARV drug for pediatric treatment, and drug levels in neonates are highly variable25. Therefore, the two-drug regimen is recommended for prophylaxis in infants born to mothers who have not received antepartum ARV drugs. Beyond the scenario studied in NICHD-HPTN 040/PACTG 1043, the choice o f ARV drug regimens for neonates is limited (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis) . Neonatal dosing information is not available for any o f the currently available boosted protease in hibitors (PIs). In addition, use of lopinavir/ritonavir in neonates has been associated with severe and sometimes fatal cardiac, renal, central nervous system (CNS), and metabolic toxicity26. Because o f the potential for toxicity, lopinavir/ritonavir should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days. # The National Perinatal HIV Hotline (1-888-448-8765) The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected pregnant women and their infants. # Recommendations fo r Infant Antiretroviral Prophylaxis in Specific Clinical Situations # Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with Effective Viral Suppression The risk o f HIV acquisition is small in infants born to women who received standard ARV prophylaxis regimens during pregnancy and labor and had undetectable viral loads at delivery or born by scheduled cesarean section to mothers with low viral loads at delivery. For example, in PACTG 316, the infection rate in infants born to women receiving antepartum PI-based therapy was 0.7% in 269 infants with HIV RNA levels o f less than 400 copies/mL at delivery2. Such infants should receive the 6-week zidovudine infant prophylaxis regimen. In that situation, combining zidovudine with additional ARV drugs to reduce transmission risk is not recommended because the benefit would be very limited. # Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs But Have Suboptimal Viral Suppression Near Delivery The risk o f perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs as well as women receiving ARVs27-29. Scheduled cesarean delivery is recommended for preven tion of perinatal transmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA >1,000 copies/mL) near the time o f delivery (see Intrapartum Care and Transmission and Mode o f Delivery). In PACTG 316, transmission occurred in 0% o f 17 infants when maternal HIV RNA levels at delivery were >10,000 copies/mL and delivery was by scheduled cesarean delivery2. However, not all women with detectable viremia near delivery will undergo cesarean delivery. The risk o f acquisition o f HIV will be higher in infants born to mothers with higher viral loads near delivery, par ticularly if delivery is vaginal. The gradient o f transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study (WITS), the risk o f transmission o f HIV was 30,000 copies/mL29. All infants should receive zidovudine for 6 weeks. No specific data address whether a more intensive combination infant prophylaxis regimen (two or three drugs) provides additional protection against transmission when maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery is significant. Elective cesarean section is recommended for pregnant women with HIV RNA levels >1,000 copies/mL near delivery. Extrapolation o f findings from the previously discussed NICHD-HPTN 040/PACTG 1043 study14 suggests that combination infant prophylaxis can be considered, de pending on assessment o f risk based on maternal viral load and mode o f delivery. That decision should be made in consultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on the potential risks and benefits o f this approach. # Infants Born to Mothers Who Received Only Intrapartum Antiretroviral Drugs All infants whose mothers have received only intrapartum ARV drugs should be given zidovudine for 6 weeks. This infant prophylaxis regimen is a critical component o f prevention when no maternal antepar tum ARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, without infant prophylaxis, is ineffective in reducing perinatal transmission3. A study in Thailand indi cated that longer infant prophylaxis with zidovudine (6 weeks vs. 3 days) is required for optimal efficacy when maternal antenatal exposure to zidovudine is <4 weeks30. Infant prophylaxis with zidovudine should be initiated as soon after delivery as possible. In the NICHD-HPTN 040/PACTG 043 trial previously discussed, 41% of women received zidovudine during labor. Admin istration of intrapartum zidovudine did not affect transmission rates. The results of this study support use of a two-drug regimen, involving 6 weeks of zidovudine plus three doses of nevirapine in the first week of life, because combination regimens were found to have increased efficacy in reducing intrapartum transmission compared with use of zidovudine alone and the three-drug regimen was associated with increased toxicity and nelfinavir powder is no longer commercially available in the United States14. # Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs Infants o f HIV-infected mothers who have received neither antepartum nor intrapartum ARV drugs should be started on ARV prophylaxis as soon after delivery as possible. Observational and Phase III ran domized studies suggest that prophylaxis provided to infants alone may be helpful in preventing trans mission o f HIV. Epidemiologic data from a New York State study indicated a decline in transmission when infants were given zidovudine for the first 6 weeks o f life compared with no prophylaxis31. Trans mission rates were 9% (95% confidence interval , 4.1%-17.5%) with zidovudine-alone prophylaxis in newborns (initiated within 48 hours after birth) versus 27% (95% CI, 21%-33%) with no zidovudine prophylaxis. For most infants in this study, prophylaxis was initiated within 12 hours o f birth32. The interval during which infant prophylaxis can be initiated and still be o f benefit is undefined. In the New York State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could be demonstrated. Data from animal studies indicate that the longer the delay in institution o f prophylaxis, the less likely that infection will be prevented. In most studies o f animals, ARV prophylaxis initiated 24 36 hours after exposure usually has been ineffective in preventing infection, although a delay in adminis tration has been associated with decreased viremia33-35. In the NICHD-HPTN 040/PACTG 1043 study, infant regimens were initiated within 48 hours o f life and usually within 12 hours o f life14. Initiation of infant prophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days, infection already would be established in most infants36. Initiating prophylaxis as soon after de livery as possible increases its potential efficacy and minimizes potential harm, such as development of resistant virus, if infection has occurred. # Infants Born to Mothers with Antiretroviral Drug-Resistant Virus The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus is un known. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery. Data from the WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viral populations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted37-38. Thus, the 6-week infant zidovudine prophylaxis (along with maternal intravenous intrapartum zidovu dine prophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations (TAMs) is identified. Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (re duced viral fitness) and transmissibility38. However, transmission from mother to child o f multidrug-re sistant virus has been reported39-41. For these newborns, use o f zidovudine in combination with other ARV drugs, selected on the basis of maternal virus resistance testing, can be considered. The efficacy o f this approach for prevention of transmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosing regimens for neonates are incompletely defined. Decisions regarding use o f additional drugs should be made in consultation with a pediatric HIV specialist and will depend on maternal history o f past and cur rent ARV drug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, and availability o f drug formulation and dosing information in the infant. ARV drugs with phar macokinetic (PK) and safety data in neonates sufficient to support their addition to zidovudine include lamivudine and nevirapine; although there are pharmacokinetic data in neonates for nelfinavir, nelfinavir powder for oral use is no longer commercially available in the United States. # Breastfeeding Infants of Mothers Diagnosed with HIV Infection Postpartum Breastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeed ing at the time of HIV diagnosis or suspected to be HIV infected. Pumping and temporarily discarding breast milk can be recommended to mothers who are suspected o f being HIV infected but whose infec tion is not yet confirmed and who want to continue to breastfeed. If HIV infection is ruled out, breast feeding can resume. The risk o f acquisition o f HIV associated with breastfeeding depends on multiple infant and maternal factors, including maternal viral load and CD4 cell count42. Infants o f women who develop acute HIV infection while breastfeeding are at greater risk o f becoming infected than are those o f women with chronic HIV infection43 because acute HIV infection is accompanied by a rapid increase in viral load and a corresponding decrease in CD4 cell count44. Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothers who breastfed their infants prior to HIV diagnosis have yet to be defined. Some experts would consider the use of post-exposure prophylaxis in infants for 4 -6 weeks after cessation o f breastfeeding. Post-exposure prophylaxis, however, is less likely to be effective in this circumstance compared with other nonoccupational exposures because the exposure to breast milk is likely to have occurred over a prolonged period rather than in a single exposure45. Several studies o f infants breastfed by women with chronic HIV infection have shown that daily infant nevirapine or nevirapine plus zidovudine can reduce the risk o f postnatal infection during breastfeeding8, 46-47. The NICHD-HPTN 040/PACTG 043 study demonstrated that combination ARV prophylaxis was more effective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who have not received antepartum ARV drugs14. However, whether the combination regimens in this trial are effective for preventing transmission after cessation o f breastfeeding in mothers with acute HIV infection is unknown. An alternative approach favored by some experts would be to offer a combination ARV regimen that would be effective for treatment o f HIV, should the infant become infected. If this route is chosen, cur rent recommendations for treatment should guide selection o f an appropriate combination ARV regimen (see Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection). Regardless o f whether post-exposure prophylaxis or "preemptive therapy" is chosen, the duration o f the intervention is un known. A 28-day course seems reasonable based on current recommendations for nonoccupational HIV exposure45. As in other situations, decisions regarding administration o f a prophylactic or preemptive treatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternal counseling on the potential risks and benefits o f this approach. Infants should be tested for HIV infection at baseline and 4 -6 weeks, 3 months, and 6 months after recogni tion of maternal infection to determine whether they are HIV infected. In infants younger than age 18 months, HIV DNA or RNA polymerase chain reaction (PCR) tests should be used for diagnosis. HIV DNA PCR is preferable for infants who are receiving combination ARV prophylaxis or preemptive treatment. HIV antibody assays can be used in infants older than age 18 months. Post-exposure ARV prophylaxis or preemptive treatment should be discontinued in infants who are found to be HIV infected while receiving one of these regimens. Resistance testing then should be performed and an appropriate combination therapy regimen initiated (see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection) . # Short-Term Antiretroviral D rug Safety and Choice fo r N eonatal Prophylaxis Infant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily o f transient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see Initial Postnatal Management). Data are limited on the toxicity to infants o f exposure to multiple ARV drugs. The latest information on neonatal dosing for ARV drugs can be found in the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Other than zidovudine, lamivudine is the nucleoside re verse transcriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies, neonatal exposure to combination zidovudine/lamivudine was generally limited to 1 week3, 14, 48. Six weeks o f infant zidovudine/lamivudine exposure also has been reported; these studies suggest that hematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had in utero exposure to maternal combination therapy. In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks of zidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a his torical cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neu tropenia in 18% o f infants exposed to zidovudine/lamivudine, with 2% o f infants requiring blood transfusion and 4% requiring treatment discontinuation for toxicity24. Similarly, in a Brazilian study of maternal antepartum and 6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxic ity was common, with anemia seen in 69% and neutropenia in 13% o f infants49. In a Phase I study of stavudine in pregnant women, infants received 6 weeks o f zidovudine/lamivudine and a single dose of stavudine at ages 1 and 6 weeks; 6 o f 14 (43%) infants experienced Grade 3 hematologic toxicity after birth (36% neutropenia and 7% anemia)50. Finally, in three Phase I studies o f PIs (saquinavir/ritonavir, indinavir, or nelfinavir) in pregnancy, a total o f 52 infants received 6 weeks o f zidovudine/lamivudine (in 26 infants, zidovudine/lamivudine was combined with nelfinavir); Grade 2 or higher hematologic toxicity was observed in 46% -62% o f infants51-53. In the NICHD-HPTN 040/PACTG 1043 study, signifi cantly higher rates o f Grade 3 or 4 neutropenia were seen with a three-drug regimen including zidovu dine and lamivudine than with zidovudine alone or a two-drug regimen with zidovudine and nevirapine (27.5% vs. 16% and 15%, respectively, P <0.0001)14. In contrast, Grade 3 or 4 anemia occurred in 23% -27% o f infants, with no differences between study arms14. Experience with other NRTI drugs for neonatal prophylaxis is more limited54-55. Hematologic and mito chondrial toxicity may be more common with exposure to multiple versus single NRTI drugs24, 56-59. Nevirapine is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) drug with a pediatric drug formulation and neonatal dosing information (see Guidelines for the Use of Antiretroviral Agents in Pedi atric HIV Infection) 60. In rare cases, chronic multiple-dose nevirapine has been associated with severe and potentially life-threatening rash and hepatic toxicity. These toxicities have not been observed in infants re ceiving single-dose nevirapine, the two-drug zidovudine regimen plus three doses of nevirapine in the first week of life in NICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophy laxis daily for 6 weeks to 6 months to prevent transmission of HIV via breast milk8, Dosing for premature infants is available for only zidovudine (see Table 8), making use o f other ARV drugs in this group more problematic. In preterm infants immature renal and hepatic metabolism in creases the risk o f overdosing and toxicity. Because zidovudine is the only ARV drug available in an in travenous formulation, the 6-week zidovudine prophylaxis regimen is recommended for preterm infants at gestational age-appropriate doses. Use o f ARV drugs other than zidovudine cannot be recommended in premature infants because data on dosing and safety are lacking. Initial Postnatal Management of the HIV-Exposed Neonate (Updated September 14, 2011) Panel's Recommendations - A complete blood count (CBC) and differential should be performed on newborns as a baseline evaluation (B III). - Decisions about the timing of subsequent monitoring of hematologic parameters in infants depend on baseline hemato logic values, gestational age at birth, clinical condition of the infants, the zidovudine dose being administered, receipt of concomitant medications, and maternal antepartum therapy (C III). - Some experts recommend more intensive monitoring of hematologic and serum chemistry and liver function assays at birth and when diagnostic HIV polymerase chain reaction (PCR) tests are obtained in infants exposed to combination antiretroviral (ARV) drug regimens in utero or during the neonatal period (C III). - If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether to continue infant ARV prophylaxis need to be individualized. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered (C III). - Routine measurement of serum lactate is not recommended. However, measurement can be considered if an infant de velops severe clinical symptoms of unknown etiology (particularly neurologic symptoms) (C III) . - Virologic tests are required to diagnose HIV infection in infants <18 months of age and should be performed within the first 14-21 days of life, at 1-2 months, and at 4 -6 months of age (A II). A CBC and differential should be performed on HIV-exposed newborns before initiation o f infant ARV drug prophylaxis. Decisions about the timing o f hematologic monitoring o f infants after birth depend on a number of factors, including baseline hematologic values, gestational age at birth, clinical condition of the infants, which ARV drugs are being administered, receipt o f concomitant medications, and maternal antepartum ARV drug regimen. Anemia is the primary complication seen in neonates given the standard 6-week postnatal zidovudine regimen. In PACTG 076, infants in the zidovudine group had lower hemo globin at birth than those in the placebo group, with the maximal difference (1 gm/dL) occurring at age 3 weeks1. The lowest mean value for hemoglobin (10 gm/dL) occurred at age 6 weeks in the zidovudine group. By age 12 weeks, hemoglobin values in both groups were similar. No significant differences in other laboratory parameters were observed between groups. Some experts recheck hematologic values in healthy infants receiving zidovudine prophylaxis only if symptoms are present. Hematologic safety data are limited on administration o f 4 mg/kg o f zidovudine twice daily in infants. When administering this dosing regimen, some experts recheck hemoglobin and neutrophil counts routinely after 4 weeks o f zidovudine prophylaxis and/or when diagnostic HIV PCR tests are obtained. In utero exposure to maternal combination ARV drug regimens may be associated with some increase in anemia and/or neutropenia compared with that seen in infants exposed to zidovudine alone2-5. In PACTG 316, where 77% o f mothers received antenatal combination therapy, significant Grade 3 or higher ane mia was noted in 13% and neutropenia in 12% o f infants, respectively. Depending on the combination regimen the mother has received, some experts advise more intensive laboratory monitoring, including serum chemistry and transaminases at birth plus a CBC at the time that diagnostic HIV PCR testing is done; monitoring o f bilirubin levels should be considered for infants exposed antenatally to atazanavir6. In addition, data are limited on infants receiving zidovudine in combination with other ARVs for pro phylaxis. However, higher rates o f hematologic toxicity have been observed in infants receiving zidovu dine/lamivudine combination prophylaxis compared with those receiving zidovudine alone or zidovudine plus nevirapine7. A recheck o f hemoglobin and neutrophil counts, therefore, is recommended for infants who receive combination zidovudine/lamivudine-containing ARV prophylaxis regimens 4 weeks after initiation of prophylaxis and/or at the time that diagnostic HIV PCR testing is done8. If hematologic abnormalities are found, decisions on whether to continue infant ARV prophylaxis need to be individualized. Considerations include the extent o f the abnormality, whether related symptoms are present, duration o f infant prophylaxis, risk o f HIV infection (as assessed by the m other's history of ARV prophylaxis, viral load near delivery, and mode o f delivery), and the availability o f alternative in terventions such as erythropoietin and transfusion. Consideration can be given to reducing the duration o f infant prophylaxis from 6 to 4 weeks, as is the case in many European centers. In a recent prospec tive, observational study, the 4-week regimen was found to allow earlier recovery from anemia in other wise healthy infants compared with the 6-week regimen9. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered. Hyperlactatemia has been reported in infants with in utero exposure to ARVs, but it appears to be tran sient and, in most cases, asymptomatic10-11. Routine measurement o f serum lactate is not recommended in asymptomatic neonates to assess for potential mitochondrial toxicity because the clinical relevance is unknown and the predictive value for toxicity appears poor10-11. Serum lactate measurement should be considered, however, for infants who develop severe clinical symptoms o f unknown etiology, particu larly neurologic symptoms. In infants with symptoms, if the levels are significantly abnormal (>5 mmol/L), ARV prophylaxis should be discontinued and an expert in pediatric HIV infection should be consulted regarding potential alternate prophylaxis. To prevent PCP, all infants born to women with HIV infection should begin trimethoprim-sulfamethoxa zole (TMP-SMX) prophylaxis at age 6 weeks, after completion o f the infant ARV prophylaxis regimen, unless there is adequate virologic test information to presumptively exclude HIV infection (see USPHS/IDSA Guidelines for the Prevention and Treatment o f Opportunistic Infections in HIV-Exposed and Infected Children)12. HIV infection in infants should be diagnosed using HIV DNA PCR or RNA virologic assays. Maternal HIV antibody crosses the placenta and will be detectable in all HIV-exposed infants up to age 18 months; therefore, standard antibody tests should not be used for HIV diagnosis in newborns. HIV viro logic testing should be performed within the first 14-21 days o f life, at 1-2 months, and at 4 -6 months o f age13. Some experts also perform a virologic test at birth, especially in women who have not had good virologic control during pregnancy or if adequate follow-up o f the infant may not be assured. A positive HIV virologic test should be confirmed as soon as possible with a second HIV virologic test on a differ ent specimen. Two positive HIV tests constitute a diagnosis o f HIV infection. Data do not indicate any delay in HIV diagnosis with HIV DNA PCR assays in infants who have received the zidovudine regi men1,14. However, the effect o f maternal or infant exposure to combination ARV drug regimens on the sensitivity o f infant virologic diagnostic testing-particularly using HIV RNA assays-is unknown. Therefore, although HIV RNA assays may be acceptable for diagnosis (particularly in older infants), HIV DNA PCR assays may be optimal for diagnosing infection in the neonatal period. Any newly diag nosed infant should undergo viral resistance testing by genotype and/or phenotype to assess for suscepti bility to combination ART. HIV may be presumptively excluded with two or more negative tests, one at age 14 days or older and the other at age 1 month or older. # Infant Feeding Practices and R isk o f H IV Transmission In the United States, where safe infant feeding alternatives are available and free for women in need, HIV-infected women should not breastfeed their infants. Maternal receipt o f combination ARV regimens is likely to reduce free virus in the breast milk, but the presence o f cell-associated virus (intracellular HIV DNA) remains unaffected and, therefore, may continue to pose a transmission risk15. Late HIV transmission events in infancy have recently been reported among three HIV-infected children suspected to have acquired HIV infection as a result o f consuming premasticated food given to them by their caregivers. Phylogenetic comparisons o f virus from cases and suspected sources and supporting clinical history and investigations identified the practice o f feeding premasticated foods to infants as a potential risk factor for HIV transmission. Health care providers should routinely inquire about this feed ing practice and instruct HIV-infected caregivers on safer feeding options16. Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants (Updated September 14, 2011) # Panel's Recommendations - Children with in utero/neonatal exposure to antiretroviral (ARV) drugs who develop significant organ system abnormali ties of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction (C III). - Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concerns regard ing the potential for carcinogenicity of nucleoside analogue ARV drugs (C III). Data remain insufficient to address the effect that exposure to zidovudine or other ARV agents in utero might have on long-term risk of neoplasia or organ system toxicities in children. Data from follow-up of PACTG 076 infants through age 6 years do not indicate any differences in immunologic, neurologic, and growth pa rameters between infants who were exposed to the zidovudine regimen and those who received placebo, and no malignancies have been seen1-3. As discussed earlier in NRTI Drugs and Mitochondrial Toxicity, data are conflicting regarding whether mitochondrial dysfunction is associated with perinatal exposure to ARVs. Mi tochondrial dysfunction should be considered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings of unknown etiology, particularly neurologic findings. Evaluation is ongoing o f early and late effects o f in utero exposure to ARVs, including the Pediatric HIV/AIDS Cohort Study (PHACS), Surveillance Monitoring o f Antiretroviral Toxicity Study, natural his tory studies, and HIV/AIDS surveillance conducted by state health departments and the Centers for Dis ease Control and Prevention (CDC). Because most o f the available follow-up data relate to in utero exposure to antenatal zidovudine alone and most pregnant women with HIV infection currently receive combination ARV drug regimens, it is critical that studies to evaluate potential adverse effects o f in utero drug exposure continue to be supported. Innovative methods are needed to provide follow-up o f infants with in utero exposure to ARV drugs. In formation regarding such exposure should be part o f ongoing permanent medical records for children, particularly those who are uninfected. Children with in utero exposure to ARVs who develop significant organ system abnormalities o f unknown etiology, particularly o f the nervous system or heart, should be evaluated for potential mitochondrial dysfunction4-6. Follow-up o f children with exposure to ARVs should continue into adulthood because o f the theoretical concerns regarding the potential for carcinogenicity of the nucleoside analogue ARV drugs. Long-term follow-up should include annual physical examinations o f all children exposed to ARV drugs. HIV surveillance databases from states that require HIV reporting provide an opportunity to collect popu lation-based information concerning in utero exposure to ARVs. To the extent permitted by federal law and regulations, data from these confidential registries can be compared with information from birth de fect and cancer registries to identify potential adverse outcomes. with abacavir during organogenesis at doses o f 1,000 mg/kg (about 35 times that o f human therapeu tic exposure based on area under the curve ). Toxicity to the developing embryo and fetus (in creased resorptions and decreased fetal body weight) occurred with abacavir administration o f 500 mg/kg/day to pregnant rodents. The offspring of female rats were treated with 500 mg/kg o f aba cavir, beginning at embryo implantation and ending at weaning. In these animals, an increased inci dence o f stillbirth and lower body weight was seen throughout life. However, in the rabbit, no evidence of drug-related developmental toxicity was observed and no increase in fetal malformations was observed at doses up to 700 mg/kg (about 8.5 times that o f human therapeutic exposure). In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to abacavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with abacavir. Among cases o f first trimester abacavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.0% (22 of 744 births; 95% confidence interval , 1.9%-4.5%) compared with 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1. - Placental and breast m ilk passage Abacavir crosses the placenta and is excreted into the breast milk o f lactating rats. - Hum an studies in pregnancy A Phase I study of abacavir in pregnant women indicates that the AUC drug concentration during preg nancy was similar to that at 6-12 weeks postpartum and in nonpregnant individuals2. Thus, no dose ad justment for abacavir is needed during pregnancy. Serious hypersensitivity reactions have been associated with abacavir therapy in nonpregnant adults and have rarely been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdomi nal pain. Abacavir should not be restarted following a hypersensitivity reaction because more severe symptoms will occur within hours and may include life-threatening hypotension and death. weight gains; however, the physical and functional development o f the offspring was not impaired and there were no major changes in the F2 generation. - Teratogenicity/developm ental toxicity No evidence o f teratogenicity or toxicity was observed with administration o f didanosine at 12 and 14 times human exposure, respectively, in pregnant rats and rabbits. Among cases o f first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence o f birth defects was 4.7% (19 o f 406 births; 95% CI, 2.8%-7.2%) compared with 2.7% in the U.S. population, based on CDC surveillance1. All defects were reviewed in detail by the Registry, and no pattern o f defects was discovered. The rate and types o f defects will continue to be closely monitored. # Placental and breast m ilk passage Placental transfer o f didanosine was limited in a Phase I/II safety and pharmacokinetic (PK) study2. This was confirmed in a study o f 100 HIV-infected pregnant women who were receiving NRTIs (generally as part of a two-or three-drug combination antiretroviral regimen). At the time of delivery, cord-to-maternal blood ratio for didanosine (n = 10) was 0.38 (range 0.0-2.0) and in 15 of 24 (62%) samples, cord blood concentrations for didanosine were below the limits o f detection3. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. It is not known if didanosine is excreted in human breast milk. - Hum an studies in pregnancy A Phase I study (PACTG 249) of didanosine was conducted in 14 HIV-infected pregnant women en rolled at gestational age 26-36 weeks and treated through 6 weeks postpartum2. The drug was well tolerated during pregnancy by the women and the fetuses. PK parameters after oral administration were not significantly affected by pregnancy, and dose modification from the usual adult dosage is not needed. Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents4-6; the FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in perinatal guidelines). These two drugs should be prescribed together to pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects. Chemother. Emtricitabine (Emtriva, FTC) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Emtricitabine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screen ing tests. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 26 times the human systemic exposure at a thera peutic dose o f 200 mg/day or in rats at doses up to 31 times the human systemic exposure at the ther apeutic dose. # Reproduction/fertility No effect o f emtricitabine on reproduction or fertility was observed with doses that produced sys temic drug exposures (as measured by AUC) approximately 60-fold higher in female mice and 140 fold higher in male mice than observed with human exposure at the recommended therapeutic dose. - Teratogenicity/developm ental toxicity Incidence o f fetal variations and malformations was not increased with emtricitabine dosing in mice that resulted in systemic drug exposure 60-fold higher than observed with human exposure at recom mended doses or in rabbits with dosing resulting in drug exposure 120-fold higher than human expo sure. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to emtric itabine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the preva lence o f birth defects was 2.7% (17 o f 641 births; 95% CI, 1.7%-4.8%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. - Placental and breast m ilk passage Emtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug concentration was 0.4 in mice and 0.5 in rabbits2. Emtricitabine has been shown to have good placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine daily during pregnancy, mean cord blood concentration was 300 ± 268 ng/mL and mean ratios o f cord blood/ma ternal emtricitabine concentrations were 1.17 ± 0.6 (n = 9)3. When 35 women were administered 400 mg o f emtricitabine in combination with tenofovir at delivery, median maternal and cord concentra tions were 1.02 (0.034-2.04) and 0.74 (0.0005-1.46) mg/L, respectively4. It is unknown if emtric itabine is excreted in human milk. - Hum an studies in pregnancy Emtricitabine PKs have been evaluated in 18 HIV-infected pregnant women receiving combination antiretroviral therapy (ART) including emtricitabine (200 mg once daily) at 30-36 weeks gestation and 6-12 weeks postpartum3. Emtricitabine exposure was modestly lower during the third trimester (8.6 p,gh/mL ) compared with the postpartum period (9.8 p,gh/mL ). Twothirds (12 o f 18) o f pregnant women versus 100% (14 o f 14) o f postpartum women met the AUC tar get (10th percentile in nonpregnant adults). Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration 52 ng/mL ) compared with the postpar tum period (86 ng/mL ). In another study o f 35 women who received 400 mg o f emtric itabine with tenofovir at delivery, median population AUC, maximum plasma concentration (Cmax), and Cmin were 14.3 p,gh/mL, 1,680 ng/mL, and 76 ng/mL, respectively4. Currently, data are insuffi cient to recommend a dosage adjustment during pregnancy. dine in humans have been monitored to detect at least a 1.5-fold increase in risk o f overall birth de fects and a 2-fold increase in the most commonly occurring birth defects, such as defects o f the car diovascular and genitourinary systems. No such increase in birth defects has been observed with lamivudine. Among cases o f first-trimester lamivudine exposure reported to the Antiretroviral Preg nancy Registry, the prevalence o f birth defects was 3.1% (118 o f 3,864 births, 95% CI, 2.5%-3.7%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. - Placental and breast m ilk passage Lamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternal concentrations2. Lamivudine is excreted into human breast milk. In a study in Kenya o f 67 HIV-in fected nursing mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, the median breast milk lamivudine concentration was 1,214 ng/mL and the median ratio o f lamivu dine concentration in breast milk to that in plasma was 2.563. In infants who received lamivudine only via breast milk, median plasma lamivudine concentration was 23 ng/mL (half-maximal in hibitory concentration o f wild-type HIV against lamivudine = 0.6-21 ng/mL). - Hum an studies in pregnancy A small Phase I study in South Africa evaluated the safety and PKs of lamivudine alone or in combina tion with zidovudine in 20 HIV-infected pregnant women; therapy was started at 38 weeks' gestation, continued through labor, and given to the infants for 1 week following birth2. The drug was well toler ated in the women at the recommended adult dose of 150 mg orally twice daily; PKs were similar to those observed in nonpregnant adults, and no PK interaction with zidovudine was observed. Intrapartum oral administration of combination zidovudine and lamivudine was well tolerated. Lamivudine was well tolerated in the neonates, but clearance was about 50% that o f older children, requiring a reduced dosing regimen (4 mg/kg/day in neonates compared with 8 mg/kg/day for infants older than 3 months). No data currently exist on the PKs o f lamivudine in infants 2 -6 weeks o f age, and the exact age at which lamivudine clearance begins to approximate that in older children is un known. carcinogenicity studies in mice and rats, stavudine was noncarcinogenic in doses producing expo sures 39 (mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels o f exposure (250 and 732 times human exposure at therapeutic doses), be nign and malignant liver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats. - Reproduction/fertility Stavudine has not been shown to have an effect on reproduction or fertility in rodents. A dose-related cytotoxic effect has been observed on preimplantation mouse embryos, with inhibition o f blastocyst formation at a concentration o f 100 pM and o f postblastocyst development at 10 pM 1. - Teratogenicity/developm ental toxicity studies No evidence o f teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, o f that seen at a clinical dosage o f 1 mg/kg/day. In rat fetuses, the inci dence o f a common skeletal variation-unossified or incomplete ossification o f sternebra-was in creased with 399 times human exposure, although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135 times human exposure. An increase in early rat neonatal mortality (birth-Day 4) occurred at 399 times human exposure, although survival o f neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to stavudine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with stavudine. Among cases o f first trimester stavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (19 o f 797 births; 95% CI, 1.4%-3.7%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance2. # Placental and breast m ilk passage Stavudine crosses the rat placenta in vivo and the human placenta ex vivo, resulting in a fetal/mater nal concentration o f approximately 0.50. In primates (pigtailed macaques), fetal/maternal plasma concentrations were approximately 0.803. Stavudine is excreted into the breast milk o f lactating rats. - Hum an studies in pregnancy A Phase I/II safety and PK study has been conducted o f combination stavudine and lamivudine in pregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, with stavudine PKs similar to those in nonpregnant adults4. Data from primate studies also indicated that pregnancy did not affect the PKs o f stavudine5. Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents6-8. The FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines). These drugs should be prescribed together for pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects. Tenofovir disoproxil fumarate (Viread, TDF) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Tenofovir is mutagenic in one o f two in vitro assays and has no evidence o f clastogenic activity. Long-term oral carcinogenicity studies o f tenofovir DF in mice and rats were carried out at 16 times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased at expo sures 16 times that observed in humans at therapeutic doses. In rats, the study was negative for car cinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. # Reproduction/fertility Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence o f impaired fertility or harm to the fetus due to tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days prior to mating and to female rats for 15 days prior to mating through Day 7 o f gestation. There was, however, an alter ation o f the estrous cycle in female rats administered 600 mg/kg/day. - Teratogenicity/developm ental toxicity Chronic exposure of fetal monkeys to tenofovir at a high dose of 30 mg/kg (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) from Days 20-150 of gestation did not re sult in gross structural abnormalities1. However, significantly lower fetal circulating insulin-like growth factor-1 (a primary regulator of linear growth) and higher insulin-like growth factor binding protein-3 levels were shown and were associated with overall body weights approximately 13% lower than un treated controls. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers were noted but were primarily limited to the treatment period and were reversible. Continued administration o f tenofovir at 30 mg/kg/day to infant monkeys resulted in significant growth restriction and severe bone toxicity in 2 o f 8 (25%) infants and effects on bone biomarkers and defective bone mineralization in all animals. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Abnormalities ranged from minimal decrease in bone mineral density and content (with oral dosing in rats and dogs that achieved drug exposures 6-10 times that achieved with therapeutic dosing in humans) to severe, pathologic osteomalacia (with subcutaneous dosing given to monkeys). Juvenile monkeys given chronic subcutaneous tenofovir at 30 mg/kg/day (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) developed osteomalacia, bone fractures, and marked hypophosphatemia. However, no clinical or radiologic bone toxicity was seen when juvenile monkeys received subcutaneous dosing o f 10 mg/kg/day (ex posure equivalent to 8 times the AUC achieved with therapeutic dosing in humans). Evidence of nephrotoxicity was observed in newborn and juvenile monkeys given tenofovir in doses resulting in exposures 12-50 times higher than the human dose, based on body surface area comparisons. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with tenofovir. Among cases o f first trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (26 o f 1,092 births, 95% CI, 1.6%-3.5%) compared with a 2.7% total preva lence in the U.S. population, based on CDC surveillance2. # Placental and breast m ilk passage Studies in rats have demonstrated that tenofovir is secreted in milk. Intravenous administration of teno fovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrat ing that tenofovir does cross the placenta3. In 3 studies of pregnant women on chronic dosing, the cord-to-maternal blood ratio ranged from 0.60 to 0.99, indicating high placental transfer4-6. In 2 studies of single-dose tenofovir (in some cases with emtricitabine) in labor that included 82 mother-infant pairs, the drugs were well tolerated and cord-to-maternal blood ratios were 0.61-0.677-9. Among women receiving a single 600-mg dose during labor, tenofovir was detectable in only 4 o f 25 (16%) breast milk samples during the first week after delivery, with a median concentration o f 13 (range 6-18) ng/mL9. In another study, 16 breast milk samples were obtained from 5 women who re ceived 600 mg o f tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir lev els in breast milk ranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oral dose o f tenofovir for neonates10. - H um an studies in pregnancy In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30-36 weeks' gestation and 6-12 weeks postpartum4. The percentage of women with tenofovir AUC exceeding the target o f 2 p,ghour/mL (the 10th percentile in nonpreg nant adults) was lower in the third trimester (74%, 14 o f 19 women) than postpartum (86%, 12 o f 14 women) (P = 0.02); however, trough levels were similar in the two groups. A recent case series found tenofovir to be well tolerated among 76 pregnant women, with only 2 stopping therapy, 1 for rash and the other for nausea. All 78 infants were healthy with no signs of toxicity, and all were HIV uninfected11. A follow-up study o f 20 o f the tenofovir-exposed infants and 20 controls found no differences between the groups in renal function, including cystatin C levels, through 2 years o f age12. A retrospective review o f 16 pregnancy outcomes among 15 heavily ARV experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants13. Zalcitabine (HIVID, ddC) is no longer available in the United States. Zidovudine (Retrovir, AZT, ZDV) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Zidovudine was shown to be mutagenic in two in vitro assays and clastogenic in one in vitro and two in vivo assays, but not cytogenic in a single-dose in vivo rat study. Long-term carcinogenicity studies have been performed with zidovudine in mice and rats1. In mice, seven late-appearing (>19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell pa pilloma occurred in the vagina o f an animal given an intermediate dose. No vaginal tumors were found at the lowest dose. In rats, two late-appearing (>20 months), nonmetastasizing vaginal squa mous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex in either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose o f 100 mg every 4 hours. How predictive the results o f rodent car cinogenicity studies may be for humans is unknown. Two transplacental carcinogenicity studies were conducted in mice2-3. In one study, zidovudine was ad ministered at doses of 20 mg/kg/day or 40 mg/kg/day from gestation Day 10 through parturition and lactation, with postnatal dosing continuing in offspring for 24 months3. The drug doses administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at rec ommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no in crease in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. In a second study, zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from Days 12-18 of gestation2. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. # Reproduction/fertility When administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, zidovudine had no effect on fertility, as judged by rates o f conception. Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-related cytotoxic effect on preimplantation mouse embryos can occur, with inhibition o f blastocyst and post blastocyst development at zidovudine concentrations similar to levels achieved with human thera peutic doses4. - Teratogenicity/developm ental toxicity Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evi denced by an increase in the incidence o f fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half o f the daily dose) in rats 66-226 times, and in rabbits 12-87 times, mean steady-state peak human plasma concentrations (after one-sixth o f the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose o f 3,000 mg/kg/day (very near the oral median lethal dose in rats o f 3,683 mg/kg) caused marked maternal toxicity and an increase in the in cidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence o f teratogenicity was seen in this experi ment at doses of 600 mg/kg/day or less. Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses that pro duced drug plasma concentrations 66-226 times (rats) and 12-87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No other develop mental anomalies were reported. In another developmental toxicity study, pregnant rats received zi dovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. How ever, there were no signs of teratogenicity at doses up to one-fifth the lethal dose. In humans, in the placebo-controlled perinatal trial PACTG 076, the incidence o f minor and major congenital abnormalities was similar between zidovudine and placebo groups and no specific pat terns of defects were seen5-6. A report from the Women and Infants Transmission Study (WITS), a cohort study enrolling women during pregnancy, described an association between first-trimester ex posure to zidovudine and a 10-fold increased risk o f hypospadias7. However, in the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to zidovudine have been moni tored to be able to detect at least a 1.5-fold increase in risk o f overall birth defects and a 2-fold in crease in defects in the more common classes, defects o f the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence o f birth defects was 3.3% (118 o f 3,620 births, 95% CI, 2.7% -3.9%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance8. # Placental and breast m ilk passage Zidovudine rapidly crosses the human placenta, achieving cord-to-maternal blood ratios o f about 0.80. Zidovudine is excreted into human breast milk. In one study in Kenya in 67 mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, zidovudine concentration in the breast milk o f mothers averaged 9 ng/mL and the ratio o f breast milk to maternal plasma zidovudine concentration averaged 44%9. No zidovudine was detectable in the plasma o f the nursing infants, who received zidovudine only via breast milk. # H um an studies in pregnancy Zidovudine is well tolerated in pregnancy at recommended adult doses and in the full-term neonate at 2 mg/kg body weight orally every 6 hours5, 10. Long-term data on the safety o f in utero drug expo sure in humans are not available for any ARV drug; however, short-term data on the safety o f zi dovudine are reassuring. In PACTG 076, no difference in disease progression was seen between women who received zidovudine and those who received placebo, based on follow-up through 4 years postpartum11. Additionally, no differences in immunologic, neurologic, or growth parameters were seen between infants with in utero zidovudine exposure and those who received placebo, based on nearly 6 years of follow up6, 12. Non-Nucleoside Reverse Transcriptase Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: - Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. - Genetic mutations and/or chromosomal damage can contribute to cancer formation. Five non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) currently are approved (delavirdine is no longer available in the United States). Nevirapine and efavirenz have been studied in human pregnancy. No adequate and well-controlled studies o f etravirine or rilpivirine use in pregnant women have been conducted. For information about potential interactions between NNRTIs and methergine, see Postpartum Hemor rhage. Antiretroviral Drugs, and Methergine Use in the perinatal guidelines. For more information regard ing nevirapine hepatic/rash toxicity. see Nevirapine and Hepatic/Rash Toxicity in the perinatal guidelines. Delavirdine (Rescriptor, DLV) is no longer available in the United States. Efavirenz (Sustiva, EFV) is classified as FDA pregnancy category D. # A nim al carcinogenicity studies Efavirenz was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies with efavirenz have been completed in mice and rats. A t systemic drug exposures approximately 1.7-fold higher than in humans receiving standard therapeutic doses. no increase in tumor incidence above background was observed in male mice. but in female mice. an increase above background was seen in hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas. No increase in tumor incidence above background was observed in male and female rats with systemic drug exposures lower than that in humans re ceiving therapeutic doses. # R eproduction/fertility anim al studies No effect o f efavirenz on reproduction or fertility in rodents has been seen. - Teratogenicity/developm ental toxicity An increase in fetal resorption was observed in rats at efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans at the recommended human dose (600 mg once daily). Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma con-centrations similar to and AUC values approximately half o f those achieved in humans administered efavirenz (600 mg once daily). Central nervous system (CNS) malformations were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20-150 at a dose o f 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure)1. The malformations included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in another fetus, and cleft palate in a third fetus. In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretrovi ral Pregnancy Registry through January 2011, birth defects were observed in 17 o f 623 live births with first-trimester exposure (2.7%, 95% confidence interval , 1.6%-4.3%). Although these data provide sufficient numbers of first-trimester exposures to rule out a 2-fold or greater increase in the risk o f overall birth defects, the low incidence o f neural tube defects in the general population means that a larger number o f exposures are still needed to be able to definitively rule out an increased risk of this specific defect. Prospective reports to the Antiretroviral Pregnancy Registry o f defects after first-trimester efavirenz exposure have documented 1 neural tube defect case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and 1 case o f bilateral facial clefts, anophthalmia, and amniotic band2. Among retrospective cases, there are 6 reports o f CNS de fects, including 3 cases o f meningomyelocele in infants born to mothers receiving efavirenz during the first trimester3. Although a causal relationship has not been established between these events and the use o f efavirenz, similar defects have been observed in preclinical studies o f the drug. # Placental and breast m ilk passage Efavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. In a study o f 13 women in Rwanda, efavirenz was given during the last trimester o f pregnancy and for 6 months after delivery4. Efavirenz concentra tions were measured in maternal plasma, breast milk, and infant plasma. Efavirenz passed into breast milk with a ratio o f 0.54 (mean breast milk to mean maternal plasma concentration) and 4.08 (mean skim milk to mean newborn plasma concentration). Mean infant plasma efavirenz concentrations were 13.1% o f maternal plasma levels. No data currently are available about efavirenz in neonates. - Hum an studies in pregnancy However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a significant increase in low-incidence birth defects (0.1-0.4% incidence o f neural tube defect in the general population). Efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period of fetal organogenesis. Women of childbearing age should undergo pregnancy testing prior to initiation of efavirenz and should be counseled about the potential risk to the fetus and the need to avoid pregnancy. Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may be associated with antiretroviral (ARV) drugs such as efavirenz. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contra ception. Barrier contraception should always be used in combination with other methods of contracep tion such as hormonal contraceptives and intrauterine devices. A study evaluating the interaction between efavirenz and depot medroxyprogesetrone (DMPA) in 17 women found no change in the phar macokinetic (PK) profile of either efavirenz or DMPA with concomitant use8. DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval. Limited PK data exist for efavirenz in pregnancy. In a study o f 25 pregnant women receiving efavirenz during the third trimester as part o f clinical care, efavirenz clearance was increased and C24h was decreased compared with postpartum. These differences are not o f sufficient magnitude to warrant dose adjustment during pregnancy9. Nevirapine (Viramune, NVP) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B . # A nim al carcinogenicity studies Nevirapine showed no evidence o f mutagenic or clastogenic activity in a battery o f in vitro and in vivo studies. Hepatocellular adenomas and carcinomas were increased at all doses in male mice and rats and at higher doses in female mice and rats. Systemic exposure at all doses studied was lower than systemic exposure in humans receiving therapeutic nevirapine doses. Given the lack o f genotoxic activity of nevirapine, the relevance to humans o f hepatocellular neoplasms in nevirapinetreated mice and rats is not known. # Reproduction/fertility Evidence o f impaired fertility was seen in female rats at nevirapine doses providing systemic expo sure comparable to human therapeutic exposure. - Teratogenicity/developm ental toxicity Teratogenic effects o f nevirapine have not been observed in reproductive studies with rats and rab bits at systemic exposures approximately equivalent to or 50% greater than the recommended human dose (based on AUC). In rats, however, a significant decrease in fetal weight occurred at doses pro ducing systemic concentrations approximately 50% higher than human therapeutic exposure. In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nevirapine in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth de fects. No such increase in birth defects has been observed with nevirapine. Among cases of first trimester nevirapine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.5% (25 of 987 births, 95% CI, 1.6%-3.7 %) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1. # Placental and breast m ilk passage Nevirapine crosses the placenta and achieves neonatal blood concentrations equivalent to that in the mother (cord-to-maternal blood ratio approximately 0.90)2. Nevirapine is excreted into human breast milk; the median concentration in 4 breast milk samples obtained from 3 women during the first week after delivery was approximately 76% (range 54%-104%) o f serum levels2. In 19 women re ceiving combination therapy with nevirapine, lamivudine, and zidovudine, breast milk nevirapine concentration was 6,795 ng/mL, which was 0.67 times that o f maternal serum3. Median nevirapine breast milk concentration was 4,564 ng/mL in a Kenyan study o f 67 HIV-infected nursing mothers receiving a combination o f zidovudine, lamivudine, and nevirapine3. The median nevirapine concen tration was 734 ng/mL in the infants, who received the drug only via breast milk. - Hum an studies in pregnancy # Short-Term Peripartum Prophylaxis: A Phase I study (PACTG 250) evaluated the safety and PKs o f nevirapine administered to infected pregnant women as a single 200-mg dose at the onset o f labor and as a single 2-mg/kg dose to in fants 48-72 hours o f age2. No adverse effects were seen in the women or the infants. The PK parameters o f intrapartum nevirapine were similar in pregnant women and in nonpregnant adults, but variability was increased during pregnancy, possibly as a result o f incomplete drug ab sorption associated with impaired gastrointestinal function during labor. Nevirapine elimination was prolonged in the infants. The regimen maintained serum concentrations associated with antiviral ac tivity in the infants for the first week o f life. The safety, toxicity, and PKs o f nevirapine were also studied in HIV-infected pregnant women begin ning chronic therapy late in the third trimester and their infants4. Initial-dose PK profiles in pregnant women were similar to those seen in nonpregnant adults. Serum nevirapine concentrations fell below the 100 ng/mL target concentration by Day 7 o f life in four o f eight infants, suggesting that nevirap ine elimination was accelerated in infants whose mother received chronic nevirapine administration compared with newborns whose mothers received only a single intrapartum dose. The HIVNET 012 study in Uganda compared nevirapine (200 mg orally to the mother at the onset of labor and 2 mg/kg to the neonate within 72 hours o f birth) with zidovudine (600 mg orally to the mother at the onset o f delivery and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily for the first 7 days o f life to the neonate). In this study, nevirapine lowered the risk o f transmis sion o f HIV by nearly 50% during the first 14-16 weeks o f life compared with zidovudine5. How ever, the women in this African trial were not receiving any other ARV drugs. In the United States, most infected women who know their HIV status during pregnancy receive combination ARV prophylaxis regimens, usually including zidovudine, as well as intravenous zi dovudine during delivery, with 6 weeks o f zidovudine given to their infants. A Phase III perinatal trial (PACTG 316) conducted in the United States, Europe, the Bahamas, and Brazil evaluated whether the HIVNET 012 single-dose nevirapine regimen in combination with standard combination prophylaxis regimens (at minimum the PACTG 076 zidovudine regimen; 77% o f women in the trial received combination ARV regimens) would provide additional benefits in reducing transmission. Transmission was not significantly different between those who received single-dose nevirapine (1.4%) and those who did not (1.6%)6. Nevirapine resistance can be induced by a single mutation. As a result o f its long half-life, the drug can be detected in plasma up to 3 weeks after administration o f a single intrapartum dose7. This pe riod o f persistent subtherapeutic drug levels exerts selective pressure that predisposes to the develop ment o f resistant strains o f HIV8. Nevirapine resistance mutations were detected at 6 weeks postpartum in 19% o f ARV-naive women in HIVNET 012 and 15% o f a subset o f women receiving additional ARV drugs during pregnancy in PACTG 316 who received single-dose nevirapine during labor9-10. In HIVNET 012, these mutations were no longer detectable in plasma virus in women at 13-18 months postpartum11. Evaluation at later time points was not done in PACTG 316. Single dose nevirapine appears to be as effective in preventing HIV transmission in subsequent pregnancies as when it is used for the first time12-13. Current data suggest that women starting NNRTI-based ther apy within 12-24 months o f single-dose nevirapine exposure have higher rates o f viral failure than those without single-dose nevirapine exposure and that use o f a protease inhibitor (PI)-based regi men (such as lopinavir/ritonavir) would be recommended in such situations14-16. Administration of postpartum ARVs to the mother can significantly reduce the frequency o f detection o f nevirapine-re sistant strains8, 17-22. # Longer Term Antenatal Combination Therapy: The PKs of nevirapine have been evaluated in pregnant women receiving nevirapine as part o f com bination ART during pregnancy. A study that determined nevirapine PKs in 26 women during preg nancy (7 second trimester, 19 third trimester) and again in the same women 4-12 weeks after delivery found that pregnancy did not alter nevirapine PK parameters23. In contrast, nevirapine clear ance was 20% greater, AUC was 28% lower, and maximum plasma concentration (Cmax) was 30% lower in 16 pregnant women compared with 13 nonpregnant women, based on nevirapine PK data from a therapeutic drug monitoring program that included 12-hour sampling24. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hep atitis, hepatic necrosis, and hepatic failure and severe, life-threatening hypersensitivity skin reactions, including Stevens-Johnson syndrome, have been reported in HIV-infected patients receiving nevirapine in combination with other drugs for treatment of HIV disease and in a small number of individuals re ceiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual exposure to HIV25. These toxicities have not been reported in women or infants receiving twodose nevirapine (the HIVNET 012 regimen) for prevention of perinatal transmission. The greatest risk of severe rash or hepatic events occurs during the first 6-18 weeks of therapy, although the risk of toxi city continues past this period and monitoring should continue at frequent intervals. Incidence o f severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more com mon in women than men and has been reported in pregnant women26-28. Other studies have found that hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in women than men29. Several studies suggest that the degree o f risk o f hepatic toxicity varies with CD4 cell count. In a summary analysis o f data from 17 clinical trials o f nevirapine therapy, women with CD4 counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 counts to experience symptomatic, often rash-associated, nevirapine-related hepatotoxicity29. Higher CD4 cell counts have also been associated with increased risk o f severe nevirapine-associated skin rash27. Rates o f hepatotoxicity and rash similar to those in U.S. studies have been seen in international co horts o f nonpregnant women but not in association with CD4 cell counts >250 cells/mm3 30. In gen eral, in controlled clinical trials, clinical hepatic events, regardless o f severity, occurred in 4.0% (range 2.5% -11.0%) o f patients who received nevirapine; however, the risk o f nevirapine-associated liver failure or hepatic mortality has been lower, in the range o f 0.04%-0.40%29, 31. Severe or lifethreatening rash occurs in approximately 2% o f patients receiving nevirapine31. Although deaths due to hepatic failure have been reported in HIV-infected pregnant women receiv ing nevirapine as part o f a combination ARV regimen, it is uncertain if pregnancy increases the risk of hepatotoxicity in women receiving nevirapine or other ARV drugs32. In an analysis o f 2 multicen ter prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (RR 4.7; 95% CI: 3.4-6.5), although nevirapine use was not, regardless o f pregnancy status33. Additional data from the same cohorts did not show any increased risk o f hepatotoxicity in HIV-infected pregnant women receiving nevirapine-based combination ART versus non-nevirapine-based combination ART34. In a cohort of 612 pregnant and nonpregnant women starting nevirapine-based therapy, CD4 cell count at initiation o f therapy but not liver enzyme elevation was a predictor o f rash; pregnancy was not an in dependent risk factor for the development o f toxicity35. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women. Women initiating nevirapine with CD4 cell counts >250 cells/mm3, including pregnant women re ceiving ARV drugs solely for prevention o f transmission, have an increased risk o f developing symp tomatic, often rash-associated, nevirapine-related hepatotoxicity, which can be severe, life-threatening and, in some cases fatal36. Therefore, nevirapine should be used as a component o f a combination regimen in this setting only if the benefit clearly outweighs the risk. Women with CD4 cell counts < 250/mm3 can receive nevirapine-based regimens, and women who become pregnant while taking nevirapine and who are tolerating their regimens well can continue therapy, regardless of CD4 cell count. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission o f HIV. Because pregnancy itself can mimic some o f the early symptoms o f hepatotoxicity, health care providers caring for women receiving nevirapine during pregnancy should be aware o f this potential complication. Frequent and careful monitoring o f clinical symptoms and hepatic transaminases (i.e., alanine aminotransferase and aspartate aminotransferase ) is necessary, particularly dur ing the first 18 weeks o f therapy. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through 4 months, and every 1-3 months thereafter (Adult Anti retroviral Guidelines); in patients with pre-existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter37. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop sugges tive clinical symptoms accompanied by elevation in serum transaminase levels (ALT and/or AST) or have asymptomatic but severe transaminase elevations should stop nevirapine and not receive the drug in the future. - Teratogenicity/developm ental toxicity No evidence o f embryonic or fetal toxicity or an effect on reproductive function was observed in rat and rabbit dams treated with rilpivirine during pregnancy and lactation at doses 15 and 70 times higher, respectively, than exposure in humans at the recommended dose o f 25 mg once daily. # Placental and breast m ilk passage No data exist on whether rilpivirine crosses the placenta or is excreted in breast milk in humans. Studies in lactating rats and their offspring indicate that rilpivirine is present in rat milk. - Hum an studies in pregnancy No adequate and well-controlled studies o f rilpivirine use in pregnant women have been conducted. Protease Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: - Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. - Genetic mutations and/or chromosomal damage can contribute to cancer formation. In in vitro and in vivo assays, atazanavir shows evidence o f clastogenicity but not mutagenicity. Twoyear carcinogenicity studies in mice and rats were conducted with atazanavir. In female mice, the in cidence of benign hepatocellular adenomas was increased at systemic exposures 2.8-2.9-fold higher than those in humans at the recommended therapeutic dose (300 mg/day atazanavir boosted with 100 mg/kg/day ritonavir). There were no increases in the incidence o f tumors in male mice at any dose. In rats, no significant positive trends in the incidence o f neoplasms occurred at systemic exposures up to 1.1-fold (males) or 3.9-fold (females) higher than those in humans at the recommended thera peutic dose. # Reproduction/fertility No effect o f atazanavir on reproduction or fertility in male and female rodents was seen at systemic drug exposures. The area under the curve (AUC) at this exposure level in rats was 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended thera peutic dose. - Teratogenicity/developm ental toxicity In animal reproduction studies, there was no evidence o f teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In developmental toxicity studies in rats, maternal dosing that resulted in maternal toxicity and produced systemic drug exposure 1.3 times the human exposure also resulted in weight loss or suppression o f weight gain in the offspring. However, offspring were unaffected at lower maternal doses that produced systemic drug exposure equivalent to that observed in humans at the recommended therapeutic dose. In a retrospective analysis from London o f atazanavir used in 31 women during 33 pregnancies (20 of whom were receiving atazanavir at conception), there were 2 miscarriages at 12 and 16 weeks, 26 infants born, and 5 women still pregnant1. No infant required phototherapy and no birth defects were seen; none of the infants was HIV infected. In the Antiretroviral Pregnancy Registry, sufficient num bers o f first-trimester exposure to atazanavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been ob served with atazanavir. The prevalence o f birth defects with first-trimester atazanavir exposure was 2.4% (12 o f 502 births, 95% confidence interval , 1.2%-4.1%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention (CDC) sur veillance2. Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition o f hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir. Studies have demonstrated that infants born to mothers who received atazanavir during pregnancy do not have pathologic or dangerous bilirubin elevations in the neonatal period1, 3-7. # Placental and breast m ilk passage In studies o f women receiving atazanavir/ritonavir-based combination therapy during pregnancy, the median cord blood atazanavir concentration was 13%-21% o f maternal serum levels at delivery3, 5-6. Atazanavir is excreted in the milk o f lactating rats. In a study o f three women, the median ratio of breast milk atazanavir concentration to that in plasma was 13%8. - Hum an studies in pregnancy Several studies have investigated the pharmacokinetics (PKs) o f atazanavir with ritonavir in preg nancy. In some o f these studies, virological results were also analyzed. Overall, most pregnant pa tients were able to achieve HIV RNA less than 50 copies/mL at time o f delivery9. In some studies, almost all pregnant patients achieved HIV RNA 100 ng/mL1. Three studies have evaluated full PK profiles o f atazanavir when administered daily as 300 mg with 100 mg ritonavir during pregnancy. In all of these studies, atazanavir AUC was lower during pregnancy than in his toric data from HIV-infected nonpregnant patients3, 5 10. In 1 o f the 3 studies, there was no difference between atazanavir AUC during pregnancy and postpartum, but AUC at both times was lower than in nonpregnant HIV-infected historic controls3. In the other 2 studies, atazanavir AUC was 25% lower during pregnancy than in the same patients postpartum5, 10. However, in both these studies (BMS AI424182 and IMPAACT P1026 atazanavir cohort), the postpartum AUC was elevated com pared with nonpregnant HIV-infected historic control patients. For example, in study AI424182, 34 women were treated with 300 mg atazanavir plus 100 mg ritonavir at 4-12 weeks postpartum and were observed to have a 34% increase in geometric AUC compared with the historic control o f HIVinfected, nonpregnant patients (62 pghr/mL vs. 46.1 pghr/mL respectively)6. Because o f the post partum elevation in AUC in this study, the atazanavir drug label recommends that postpartum patients should be closely monitored for adverse events during the first 2 months after delivery. Although use o f atazanavir with ritonavir combined with tenofovir and emtricitabine as a complete once-a-day dosing combination ARV regimen is becoming increasingly common in pregnancy, tenofovir reduces atazanavir exposure by 25% in nonpregnant adults11. This drug-drug interaction also is present during pregnancy, with a 25% reduction in atazanavir AUC in pregnant women also receiv ing tenofovir compared with the same women postpartum and a 50% reduction compared with post partum levels in women who did not receive tenofovir5. Use of an increased dose of atazanavir o f 400 mg with 100 mg ritonavir during pregnancy has been investigated in two studies10 5. In both studies pregnant women receiving the increased dose without tenofovir had an atazanavir AUC equivalent to that seen in historic nonpregnant HIV-infected con trols receiving standard-dose atazanavir without tenofovir. Pregnant women receiving the increased atazanavir dose with tenofovir had an AUC equivalent to that seen in nonpregnant HIV-infected pa tients receiving standard-dose atazanavir and tenofovir9. In the prescribing information for atazanavir6, the dose recommended for most pregnant women is 300 mg with 100 mg o f ritonavir. For additional details about dosing with interacting concomitant medications, please see Table 5 (Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharma cokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy) . Neonatal elevations in bilirubin have been reported in some-but not all-studies o f infants born to mothers receiving atazanavir during pregnancy3, 5 10. Phototherapy was needed to control hyperbiliru binemia in 5 o f 29 infants in 1 study7. In study AI424182, 6 o f 39 infants received phototherapy12. Decisions to use phototherapy to treat infants with hyperbilirubinemia frequently are subjective and guidelines for phototherapy of infants vary between countries, making it difficult, therefore, to com pare the severity o f hyperbilirubinemia between patients within a study and in different studies. Ele vated neonatal bilirubin is more likely in infants with uridine diphosphate glucuronosyltransferase 1 (UGT1A1) genotypes associated with decreased UGT function10. Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, dif ficult delivery, or sepsis has been reported in 3 o f 38 atazanavir-exposed infants with glucose sam ples collected in the first day o f life. All 3 hypoglycemic infants' glucose samples were adequately collected and processed in a timely fashion13. This finding o f infant hypoglycemia is similar to a prior report in which 2 (both nelfinavir) o f 14 infants exposed to PIs (nelfinavir, saquinavir, and indi navir) developed hypoglycemia in the first day o f life14. Fosamprenavir (Lexiva, FPV) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Fosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series o f in vitro and ani mal in vivo screening tests. Carcinogenicity studies o f fosamprenavir showed an increase in the inci dence o f hepatocellular adenomas and carcinomas at all doses tested in male mice and at the highest dose tested in female mice. In rats, the incidence o f hepatocellular adenomas and thyroid follicular cell adenomas in males (all doses tested) and in females (two highest doses tested) was also in creased. Repeat dose studies in rats produced effects consistent with enzyme activation, which pre disposes rats, but not humans, to thyroid neoplasms. In rats only there was an increase in interstitial cell hyperplasia at higher doses and an increase in uterine endometrial adenocarcinoma at the highest dose tested. The incidence o f endometrial findings was slightly increased over concurrent controls but was within background range for female rats. Thus the relevance o f the uterine endometrial ade nocarcinomas is uncertain. Exposures in the carcinogenicity studies were 0.3-to 0.7-fold (mice) and 0.7-to 1.4-fold (rats) those in humans given 1,400 mg twice daily o f fosamprenavir alone, and 0.2to 0.3-fold (mice) and 0.3-to 0.7-fold (rats) those in humans given 1,400 mg once daily o f fosampre navir plus 200 mg ritonavir once daily or 0.1-to 0.3-fold (mice) and 0.3-to 0.6-fold (rats) those in humans given 700 mg o f fosamprenavir plus 100 mg ritonavir twice daily. # R eproduction/fertility No impairment o f fertility or mating was seen in rats at doses providing 3-4 times the human expo sure to fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. At those doses, no affect was seen on the development or maturation o f sperm in rats. - Teratogenicity/developm ental toxicity Fosamprenavir was studied in rabbits at 0.8 and in rats at twice the exposure in humans to fosampre navir alone and at 0.3 (rabbits) and 0.7 (rats) times the exposure in humans to the combination of fosamprenavir and ritonavir. In rabbits administered fosamprenavir (alone or in combination) the in cidence of abortion was increased. In contrast, administration o f amprenavir at a lower dose in rab bits was associated with abortions and an increased incidence o f minor skeletal variations from deficient ossification of the femur, humerus, and trochlea. Fosamprenavir administered to pregnant rats (at twice human exposure) was associated with a reduction in pup survival and body weights in rats. F1 female rats had an increased time to successful mating, an increased length o f gestation, a re duced number o f uterine implantation sites per litter, and reduced gestational body weights com pared with controls. # Placental and breast m ilk passage It is unknown whether fosamprenavir crosses the placenta. Amprenavir is excreted in the milk o f lac-defects. No such increase in birth defects has been observed with indinavir. Among cases o f first trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.1% (6 o f 285 births, 95% CI, 0.8%-4.5%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. - Placental and breast m ilk passage Significant placental passage o f indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. In a Phase I study in pregnant women and their infants (PACTG 358, see below), transplacental passage o f indinavir was minimal2. In addition, in a study o f cord blood samples from 21 women treated with indinavir during pregnancy, the cord blood concentration o f indinavir was less than the assay limit o f detection in samples from all women3. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26 to 1.45); it is not known if indinavir is excreted in human milk. - Hum an studies in pregnancy The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A Phase I/II safety and PK study (PACTG 358) was conducted of indinavir (800 mg three times a day) in com bination with zidovudine and lamivudine in pregnant HIV-infected women and their infants2. The mean indinavir plasma AUC0-8hr at 30-32 weeks' gestation (n =11) was 74% (95% CI, 50%-86%) lower than that observed 6 weeks postpartum. The PKs of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in nonpregnant patients in another study. In an other study, two pregnant HIV-infected women receiving combination therapy including indinavir (800 mg three times a day) had significantly reduced AUC indinavir exposures in the third trimester com pared with postpartum evaluations (52% and 86%, respectively)4. Therefore, given the substantially lower antepartum exposures observed in these studies and the generally limited data in this patient population, use of indinavir as a sole PI is not recommended in HIV-infected pregnant patients. Lopinavir + Ritonavir (Kaletra, LPV/r) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery o f in vitro and in vivo assays. The lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the inci dence o f benign hepatocellular adenomas and an increase in the combined incidence o f hepatocellu lar adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure at the recommended therapeutic dose o f 400 mg/100 mg (based on AUC0-24hr measurement). Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence o f any other be nign or malignant neoplasm in mice or rats. - Reproduction/fertility Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and fe male rats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir o f the expo sures in humans at the recommended therapeutic dose. - Teratogenicity/developm ental toxicity No evidence exists of teratogenicity with administration o f lopinavir/ritonavir to pregnant rats or rabbits. In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence o f skeletal variations, and skeletal ossification delays) were observed. Drug exposure in the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In a peri-and postnatal study in rats, a decrease in survival o f pups between birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day or greater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxic dosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lopinavir/ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f over all birth defects. No such increase in birth defects has been observed with lopinavir/ritonavir. Among cases o f first-trimester lopinavir/ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.2% (16 o f 738 births, 95% CI, 1.2%-3.5%) compared with a total prevalence of 2.7% in the U.S. population, based on CDC surveillance1. # Placental and breast m ilk passage Lopinavir crosses the human placenta; in the P1026s PK study, the average ratio o f lopinavir concen tration in cord blood to maternal plasma at delivery was 0.20 ± 0.13. For ritonavir, data in humans indicate only minimal transplacental passage (see ritonavir). Lopinavir and ritonavir are secreted in the breast milk of lactating rats; it is not known if either drug is excreted in human milk. - Hum an studies in pregnancy The capsule formulation of lopinavir/ritonavir is no longer available; it has been replaced by a new tablet formulation o f lopinavir 200 mg/ritonavir 50 mg that is heat stable and does not have a food requirement. In nonpregnant adults, plasma concentrations o f lopinavir and ritonavir after administration o f two 200/50 mg lopinavir/ritonavir tablets are similar to those achieved with three 133/33 mg lopinavir/ri tonavir capsules given with food, although with less PK variability. In a study o f 51 pregnant women, plasma trough lopinavir levels during the third trimester were compared among 28 women receiving the capsule and 23 women receiving the tablet formulations at standard dosing. No statisti cal difference was found between the groups, with a mean lopinavir trough level o f 4.86 mg/L (cap sule) and 4.57 mg/L (tablets)2. However, the inter-individual variability was lower with the tablets than with the capsules. Five o f 28 women (17.8%) in the capsule group and 4 o f 23 women (17.4%) in the tablet group had trough levels less than the target (3 mg/L); 7 o f the 9 women had HIV RNA levels less than detection at the time of their sampling, and 2 with subtherapuetic levels (0.7 and 2.44 mg/L) had plasma RNA of 83 and 56 copies/mL, respectively, at the time o f their sampling. P1026s evaluated lopinavir PKs following standard dosing with the new lopinavir/ritonavir tablet formulation (2 tablets twice daily) until 30 weeks' gestation, followed by an increase to 3 tablets twice daily and return to standard dosing at postpartum hospital discharge. Median AUC was 72 p,gh/mL in 7 women receiving standard dosing during the second trimester, 97 p,gh/mL in 25 women receiving the increased dose during the third trimester, and 129 p,gh/mL in 19 women re ceiving standard dosing at 2 weeks postpartum. These data suggest that the higher lopinavir/ritonavir dose should be used in the third trimester; that it should be considered in the second trimester, partic ularly in women who are PI experienced; and that lopinavir/ritonavir can be reduced to standard dos ing shortly after delivery3. An alternative strategy for increasing lopinavir/ritonavir exposure during pregnancy is to add a pediatric lopinavir/ritonavir tablet (100/25 mg) to the standard dose o f 2 adult tablets (200/50 mg)4. Once-daily dosing o f lopinavir/ritonavir capsules or tablets is not recommended in pregnancy be cause no data exist to address whether drug levels are adequate with such administration. Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/vol ume) propylene glycol. Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation o f lopinavir (the active ingredient) as well as alcohol and propylene gly col. Preterm babies may be at increased risk o f health problems because they cannot metabolize propylene glycol; this could lead to accumulation and adverse events such as serious heart, kidney, or breathing problems. Postmarketing surveillance has identified 10 neonates (babies <4 weeks of age), 9 o f whom were born prematurely, who received lopinavir/ritonavir and experienced lifethreatening events5. Lopinavir/ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth, plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days has been attained. # A nim al carcinogenicity studies Nelfinvair was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baseline in male rats receiving nelfinavir dosages o f 300 mg/kg/day or higher (equal to a systemic exposure similar to that in humans at therapeutic doses) and female rats receiving 1,000 mg/kg/day (equal to a systemic exposure 3-fold higher than that in humans at therapeutic doses). # Reproduction/fertility No effect o f nelfinavir has been seen on reproductive performance, fertility, or embryo survival in rats at exposures comparable to human therapeutic exposure. Additional studies in rats indicated that exposure to nelfinavir in females from midpregnancy through lactation had no effect on the survival, growth, and development o f the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequent reproductive performance o f the offspring. - Teratogenicity/developm ental toxicity No evidence o f teratogenicity has been observed in pregnant rats at exposures comparable to human exposure and in rabbits with exposures significantly less than human exposure. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to nelfinavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with nelfinavir. Among cases o f first-trimester nelfinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.9% (46 o f 1,193 births, 95% CI, 2.8%-5.1%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. - Placental and breast m ilk transfer In a Phase I study in pregnant women and their infants (PACTG 353, see below), transplacental pas sage o f nelfinavir was minimal2. In addition, in a study o f cord blood samples from 38 women who were treated with nelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit o f detection in 24 (63%), and the cord blood concentration was low (median, 0.35 p,g/mL) in the remaining 14 women3. Nelfinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk. - Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 353) o f nelfinavir in combination with zidovudine and lamivudine was conducted in pregnant HIV-infected women and their infants2. In the first nine preg nant HIV-infected women enrolled in the study, nelfinavir administered at a dose o f 750 mg three times daily produced drug exposures that were variable and generally lower than those reported in nonpregnant adults with both twice-and three-times-daily dosing. Therefore, the study was modified to evaluate an increased dose o f nelfinavir given twice daily (1,250 mg twice daily), which resulted in adequate levels o f the drug in pregnancy. However, in another study o f women given 1,250 mg nelfinavir twice daily in the second and third trimesters, drug concentrations in the third trimester were lower than in the second trimester or in nonpregnant women4. In a PK study o f combination therapy including the new nelfinavir 625-mg tablet formulation (given as 1,250 mg twice daily) in 25 women at 30-36 weeks' gestation (and 12 at 6-12 weeks postpar tum), peak levels and AUC were lower in the third trimester than postpartum5. Only 16% (4 o f 25) of women during the third trimester and 8% (1 o f 12) women postpartum had trough values greater than the suggested minimum trough o f 800 ng/mL; however, viral load was <400 copies/mL in 96% of women in the third trimester and 86% postpartum. is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Ritonavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies in mice and rats have been completed. In male mice, a dose-dependent increase in adenomas of the liver and combined adenomas and carcinomas o f the liver was observed at levels o f 50, 100, or 200 mg/kg/day; based on AUC, exposure in male mice at the highest dose was approximately 0.3-fold that in male humans at the recommended therapeutic dose. No carcino genic effects were observed in female mice with exposures 0.6-fold that o f female humans at the rec ommended therapeutic dose. No carcinogenic effects were observed in rats at exposures up to 6% of recommended therapeutic human exposure. # Reproduction/fertility No effect o f ritonavir has been seen on reproductive performance or fertility in rats at drug exposures 40% (male) and 60% (female) o f that achieved with human therapeutic dosing; higher doses were not feasible because of hepatic toxicity in the rodents. - Teratogenicity/developm ental toxicity No ritonavir-related teratogenicity has been observed in rats or rabbits. Developmental toxicity, in cluding early resorptions, decreased body weight, ossification delays, and developmental variations such as wavy ribs and enlarged fontanelles, was observed in rats; however, these effects occurred only at maternally toxic dosages (exposure equivalent to 30% o f human therapeutic exposure). In ad dition, a slight increase in cryptorchidism was also noted in rats at exposures equivalent to 22% of the human therapeutic dose. In rabbits, developmental toxicity (resorptions, decreased litter size, and decreased fetal weight) was observed only at maternally toxic doses ( 1.8 times human therapeutic exposure based on body surface area). In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with ritonavir. Among cases o f first-trimester ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.4% (33 o f 1,401 births; 95% CI, 1.6%-3.3%) compared with a total prevalence o f 2.7% in the U.S. population, based on CDC surveillance1. - Placental and breast m ilk transfer Transplacental passage o f ritonavir has been observed in rats with fetal tissue to maternal serum ra tios >1.0 at 24 hours post-dose in mid-and late-gestation fetuses. In a human placental perfusion model, the clearance index o f ritonavir was very low, with little accumulation in the fetal compart ment and no accumulation in placental tissue2. In a Phase I study in pregnant women and their in fants (PACTG 354, see below), transplacental passage o f ritonavir was minimal3. Additionally, in a study o f cord blood samples from six women treated with ritonavir during pregnancy, the cord blood concentration was less than the assay limit o f detection in 83% and was only 0.38 p,g/mL in the re maining woman4. Ritonavir is excreted in the milk o f lactating rats; it is unknown if it is excreted in human milk. - Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 354) o f ritonavir (500 or 600 mg twice daily) in combina tion with zidovudine and lamivudine in pregnant HIV-infected women and their infants showed lower levels o f ritonavir during pregnancy than postpartum3. Ritonavir concentrations are also re duced during pregnancy versus postpartum when the drug is used at a low dose (100 mg) to boost the concentrations o f other PIs5-6. rabbit) o f those obtained in humans at the recommended clinical dose boosted with ritonavir. - Placental and breast m ilk transfer Placental transfer o f saquinavir in the rat and rabbit was minimal. In a Phase I study in pregnant women and their infants (PACTG 386, see below), transplacental passage o f saquinavir was mini m al1. In addition, in a study of cord blood samples from eight women treated with saquinavir during pregnancy, the cord blood concentration o f saquinavir was less than the assay limit o f detection in samples from all women2. Saquinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk. - Hum an studies in pregnancy Three studies have evaluated the PKs o f saquinavir-hard gel capsules combined with low-dose riton avir (saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily) in a total o f 19 preg nant women; trough levels were greater than the target in all but 1 woman3-4. In a small study o f 2 women who received saquinavir-hard gel capsules 1,200 mg/ritonavir 100 mg given once daily, trough levels were 285 and 684 ng/mL and the AUC0-24 were 28,010 and 16,790 ng hour/mL, greater than the target AUC o f 10,000 ng hour/mL5. Thus, the limited available data suggest that saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily should achieve adequate trough levels in HIV-infected pregnant women. Data are too limited to recommend once-daily dos ing at present. However, a recent analysis o f saquinavir-hard gel capsules administered once daily at 1,200 mg/100 mg ritonavir combined with various NRTIs during 46 pregnancies demonstrated saquinavir levels greater than the target minimum plasma concentration (Cmin) in 46 (93.4%) of pregnancy episodes and undetectable viral load at delivery in 88% o f episodes6. Target levels were achieved in the other 3 women with a dose o f 1,600 mg/100 mg. The drug was well tolerated. The PKs of the new 500-mg tablet formulation o f saquinavir boosted with ritonavir in a dose of saquinavir 1,000 mg/ritonavir 100 mg given twice daily were studied in 14 HIV-infected pregnant women at 33 weeks gestation and parameters were comparable to those observed in nonpregnant in dividuals; none o f the women had a subtherapeutic trough level7. One study o f a saquinavir/ritonavir-based combination ARV drug regimen in 42 women during preg nancy reported abnormal transaminase levels in 13 women (31%) within 2 -4 weeks o f treatment ini tiation, although the abnormalities were mild (toxicity Grade 1-2 in most, Grade 3 in 1 woman)8. ) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100, or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in com bination, or 10 mg/kg/day ritonavir. No drug-related findings were observed in male rats. At the highest dose o f tipranavir, an increased incidence o f benign follicular cell adenomas o f the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction. # R eproduction/fertility Tipranavir had no effect on fertility or early embryonic development in rats at exposure levels similar to human exposures at the recommended clinical dose (500/200 mg per day of tipranavir/ritonavir). - Teratogenicity/developm ental toxicity No teratogenicity was detected in studies o f pregnant rats and rabbits at exposure levels approxi mately 1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) was observed in rats exposed to 400 mg/kg/day or more o f tipranavir (~0.8-fold human ex posure). Fetal toxicity was not seen in rats and rabbits at levels o f 0.2-fold and 0.1-fold human expo sures. In rats, no adverse effects on developments were seen at levels o f 40 mg/kg/day (~0.2-fold human exposure), but at 400 mg/kg/day (~0.8-fold human exposure), growth inhibition in pups and maternal toxicity were seen. - Placental and breast m ilk transfer No animal studies o f placental or breast milk passage o f tipranavir have been reported. It is unknown if placental or breast milk passage o f tipranavir occurs in humans. - Hum an studies in pregnancy No studies of tipranavir have been completed in pregnant women or neonates. Tipranavir is one of the study drugs in the ongoing IMPAACT P1026: "Pharmacokinetic Study o f Anti-HIV Drugs Dur ing Pregnancy" . - Placental and breast m ilk passage Studies of radio-labeled enfuvirtide administered to lactating rats indicated radioactivity in the milk; however, it is not known if this reflected radio-labeled enfuvirtide or metabolites (e.g., amino acid and peptide fragments) o f enfuvirtide. It is not known if enfuvirtide crosses the human placenta or is excreted in human milk. A published case report o f two peripartum pregnant patients and their neonates and data from an ex vivo human placental cotyledon perfusion model suggest that enfuvir tide does not cross the placenta1-2. - Hum an studies in pregnancy Very limited data exist on the use o f enfuvirtide in pregnant women1, 3-4; no data exist in neonates. Maraviroc (Selzentry, MVC) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Maraviroc was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies found no increase in tumor incidence in mice (trans genic rasH2 mice) and rats at exposures up to 11-fold higher than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily). # R eproduction/fertility anim al studies Reproductive toxicity has been evaluated in rats. Maraviroc produced no adverse effects on fertility of male or female rats or sperm of male rats at exposures up to 20-fold higher than experienced with human therapeutic exposure at the recommended clinical dose (300 mg twice daily). - Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence o f harm to the fetus from maraviroc administered in doses up to 20-fold higher in rats and 5-fold higher in rabbits than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily). # Placental and breast m ilk passage It is unknown if maraviroc crosses the placenta in humans. In a study o f four macaques, a single oral dose o f either 60 mg/kg or 100 mg/kg was given 2 hours before cesarean delivery. Median maternal concentration at delivery was 974 ng/mL (range 86-2,830 ng/mL) and median infant concentration was 22 ng/mL (range 4-99 ng/mL) for a cord/matemal ratio o f .0231. Maternal levels were de tectable for 48 hours after a single dose, whereas infant levels were detectable for only 3.5 hours after birth. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. - Hum an studies in pregnancy No studies of maraviroc have been conducted in pregnant women or neonates. # A dditional concerns Although no increase in cancer has been observed with maraviroc, the drug has the potential to in crease risk because o f its mechanism o f action and possible effects on immune surveillance. Integrase Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: - Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. - Genetic mutations and/or chromosomal damage can contribute to cancer formation. One drug has been approved in this new class of antiretrovirals (ARVs) aimed at inhibiting integrase, the viral enzyme that catalyzes the two-step process of insertion of HIV DNA into the genome of the host cell. Integrase catalyzes a preparatory step that excises two nucleotides from one strand at both ends of the HIV DNA and a final "strand transfer" step that inserts the viral DNA into the exposed regions of cellular DNA. This second step in the integration process is targeted by the integrase inhibitor drug class. Integration is required for the stable maintenance of the viral genome as well as for efficient viral gene expression and replication. Integrase also affects retrotranscription and viral assembly. Host cells lack the integrase en zyme. Because HIV integrase represents a distinct therapeutic target, integrase inhibitors would be ex pected to maintain activity against HIV that is resistant to other classes of ARV drugs. Raltegravir (Isentress) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Raltegravir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f raltegravir are ongoing. # R eproduction/fertility anim al studies Raltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/ day (providing exposures 3-fold higher than the exposure at the recommended adult human dose). - Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal sur vival or fetal weights from raltegravir administered in doses producing systemic exposures approxi mately 3-to 4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended human daily dose). # Placental and breast m ilk passage Placental transfer o f raltegravir was demonstrated in both rats and rabbits. In rats given a maternal dose o f 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5-to 2.5-fold higher than in maternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drug concentrations in fetal plasma were approximately 2% o f the mean maternal plasma concentra tion at both 1 and 24 hours following a maternal dose o f 1,000 mg/kg/day. In a case report o f use in late pregnancy, the raltegravir cord blood-to-maternal blood ratio at delivery was 1.061. Raltegravir is secreted in the milk o f lactating rats, with mean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose o f 600 mg/kg/day. No effects in rat offspring were attrib utable to raltegravir exposure through breast milk. - Hum an studies in pregnancy Only limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PKs) were evaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability but did not appear to be consistently altered during the third trimester compared with postpartum and historical data in nonpregnant individuals; thus the standard dose appears appropri ate in pregnancy2. Raltegravir readily crossed the placenta; in 6 deliveries with evaluation, the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval , 0.09-2.26). In a separate report, 3 pregnant women with multiresistant HIV-1 were given raltegravir in late pregnancy to rap idly reduce maternal viral load3. Raltegravir concentrations within 3 hours o f delivery in the neonates o f 2 patients were approximately 7 and 9.5 times higher than in the m other's paired sample; in the third infant, maternal plasma was not available but neonatal concentration was still high 2.5 hours after delivery. However, no adverse reactions were observed in mothers or infants. Whether raltegravir is secreted in human milk is unknown. Some nelfinavir manufactured before 2008 may have contained low levels o f ethyl methane sul fonate (EMS), a process-related impurity. EMS is teratogenic, mutagenic, and carcinogenic in ani mals, although no data exist in humans and no increase in birth defects has been observed in the Antiretroviral Pregnancy Registry. All nelfinavir manufactured and released since March 31, 2008, meets the new final EMS limits established by the FDA for prescribing to all patient populations, in cluding pregnant women and pediatric patients. # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: - Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. - Genetic mutations and/or chromosomal damage can contribute to cancer formation. Six nucleoside analogue reverse transcriptase inhibitors (nucleoside NRTIs) and one nucleotide reverse transcriptase inhibitor (nucleotide NRTI) are currently approved (zalcitabine is no longer available in the United States). Data are available from clinical trials in human pregnancy for the nucleoside NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine, and the nucleotide NRTI tenofovir. The nucleoside analogue drugs require three intracellular phosphorylation steps to form the triphosphate nucleoside, which is the active drug moiety. Tenofovir, an acyclic nucleotide analogue drug, contains a monophosphate component attached to the adenine base, and hence requires only two phos phorylation steps to form the active moiety. For information regarding the nucleoside analogue drug class and potential mitochondrial toxicity in pregnancy and to the infant, see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines. Abacavir (Ziagen, ABC) is classified as Food and Drug Administration (FDA) pregnancy category C. # A nim al carcinogenicity studies Abacavir is mutagenic and clastogenic in some in vitro and in vivo assays. In long-term carcino genicity studies in mice and rats, malignant tumors o f the preputial gland o f males and the clitoral gland o f females were observed in both species, and malignant hepatic tumors and nonmalignant he patic and thyroid tumors were observed in female rats. The tumors were seen in rodents at doses that were 6-32 times that of human therapeutic exposure. # Reproduction/fertility No effect of abacavir on reproduction or fertility in male and female rodents has been seen at doses of up to 500 mg/kg/day (about 8 times that of human therapeutic exposure based on body surface area). # Teratogenicity/developm ental toxicity Abacavir is associated with developmental toxicity (decreased fetal body weight and reduced crownrump length) and increased incidence o f fetal anasarca and skeletal malformations in rats treated Didanosine (Videx, ddl) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Didanosine is both mutagenic and clastogenic in several in vitro and in vivo assays. Long-term ani mal carcinogenicity screening studies at human exposures o f 0.7-1.7 and 3 times, respectively, in mice and rats have been negative. # Reproduction/fertility At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid-and late lactation. These rats showed reduced food intake and body Lamivudine (Epivir, 3TC) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Lamivudine has weak mutagenic activity in one in vitro assay but no evidence o f in vivo genotoxicity in rats at 35-45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58 times human exposure have been negative in mice and rats, respectively. - Reproduction/fertility Lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47-70 times those in humans, revealed no evidence o f impaired fertility and no effect on the offsprings' sur vival, growth, and development up to the time o f weaning. # Teratogenicity/developm ental toxicity studies There is no evidence o f lamivudine-induced teratogenicity at 35 times human plasma levels in rats and rabbits. Early embryolethality was seen in rabbits at doses similar to human therapeutic expo sure but not in rats at 35 times the human exposure level. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lamivu-Etravirine (Intelence, ETR) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B . # A nim al carcinogenicity studies Etravirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies o f etravirine in rodents are ongoing. # Reproduction/fertility No effect on fertility and early embryonic development was observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to the recommended human dose (400 mg/day). # Teratogenicity/developm ental toxicity Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the rec ommended human dose o f 400 mg/day revealed no evidence o f fetal toxicity or altered development. Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1,000 mg/kg/day). In both species, no treatment-related embryo-fetal effects, including malformations, were observed. In addition, no treatment effects were observed in a sepa rate pre-and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic ex posures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day). # Placental and breast m ilk passage There are no data on whether etravirine crosses the placenta or is excreted in breast milk in humans. # Hum an studies in pregnancy No adequate and well-controlled studies of etravirine use in pregnant women have been conducted and very limited case report data are available on etravirine use in pregnancy. One small study described use of etravirine in combination with darunavir/ritonavir and other ARV drugs in four pregnant women; PK sampling was done to determine etravirine plasma concentration during the third trimester1. PK data from these women were similar to those in nonpregnant adults. Data on etravirine in postpartum cord blood and concurrent maternal plasma specimens were available for one patient with values of 112 ng/mL and 339 ng/mL (cord/maternal blood ratio 0.33). No maternal, fetal, or neonatal toxicity was reported; one infant was born with a small accessory auricle on the right ear with no other malformations; no birth defects were noted in the other children. Placental passage of etravirine was noted in another report of use of etravirine, darunavir/ritonavir, and enfuvirtide in a pregnant woman who gave birth to twins (cord blood levels 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2)2. In a separate report on two women receiving etravirine, darunavir/ritonavir, and raltegravir during pregnancy, no perinatal transmission of HIV or congenital abnormalities were observed. # Rilpivirine (Edurant) is classified as FDA pregnancy category B. - A nim al carcinogenicity studies Rilpivirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than expo sure in humans at the recommended dose o f 25 mg once daily. Hepatocellular neoplasms were ob served in both male and female mice at doses 21 times that o f human therapeutic exposure; the observed hepatocellular findings in mice may be rodent specific1. # R eproduction/fertility No effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400 mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose. Darunavir (Prezista, DRV) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Darunavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. A dose-related increase in the incidence o f hepatocellular adenomas and carcinomas was ob served in both male and female mice and rats as well as an increase in thyroid follicular cell adeno mas in male rats. The observed hepatocellular findings in rodents are considered to be o f limited relevance to humans. Repeated administration o f darunavir to rats caused hepatic microsomal en zyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4-and 0.7-fold (mice) and 0.7-and 1-fold (rats) o f those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily). # Reproduction/fertility No effects on fertility and early embryonic development were seen with darunavir in rats. - Teratogenicity/developm ental toxicity No embryotoxicity or teratogenicity was seen in mice, rats, or rabbits. Because o f limited bioavail ability of darunavir in animals and dosing limitation, the plasma exposures were approximately 50% (mice and rats) and 5% (rabbits) o f those obtained in humans. In the rat pre-and postnatal develop ment study, a reduction in pup weight gain was observed with darunavir alone or with ritonavir ex posure via breast milk during lactation. In juvenile rats, single doses o f darunavir (20 mg/kg-160 mg/kg at ages 5-11 days) or multiple doses o f darunavir (40 mg/kg-1,000 mg/kg at age 12 days) caused mortality. The deaths were associated with convulsions in some o f the animals. Within this age range, exposures in plasma, liver, and brain were dose and age dependent and were considerably greater than those observed in adult rats. tating rats; it is not known if it is excreted in human milk. - Hum an studies in pregnancy Very limited data exist on fosamprenavir in pregnant women. Fosamprenavir PKs have been re ported in 15 women during pregnancy and postpartum. Following standard dosing with fosampre navir 700 mg and ritonavir 100 mg, amprenavir AUC and 12-hour trough concentrations were somewhat lower during pregnancy and higher postpartum compared with historical data. Amprenavir exposure during pregnancy appeared to be adequate for patients without PI resistance mutations1. A pediatric liquid formulation o f fosamprenavir has been approved for children older than 2 years of age, but there is no dosing information for neonates. Indinavir (Crixivan, IDV) is classified as FDA pregnancy category C. # A nim al carcinogenicity studies Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivo assays. No increased inci dence o f any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid ade nomas were seen in male rats. # Reproduction/fertility No effect o f indinavir has been seen on reproductive performance, fertility, or embryo survival in rats. - Teratogenicity/developm ental toxicity There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater than therapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumer ary and cervical ribs was observed at doses comparable to those administered to humans. No treat ment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of mater nal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnant Rhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, in dinavir exacerbated the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. In Rhesus monkeys, fetal plasma drug levels were approximately 1%-2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposure to indinavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth Acquir Immune Defic Syndr. Jan 28 2011. Saquinavir (Invirase , SQV) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Saquinavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies found no indication o f carcinogenic activity in rats and mice adminis tered saquinavir for approximately 2 years at plasma exposures approximately 60% o f those ob tained in humans at the recommended therapeutic dose (rats) and at exposures equivalent to those in humans at the recommended therapeutic dose (mice). # Reproduction/fertility No effect o f saquinavir has been seen on reproductive performance, fertility, or embryo survival in rats. Because o f limited bioavailability o f saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% o f those obtained in humans at the recommended clinical dose boosted with ritonavir. - Teratogenicity/developm ental toxicity No evidence o f embryotoxicity or teratogenicity o f saquinavir has been found in rabbits or rats. Be cause o f limited bioavailability o f saquinavir in animals and/or dosing limitations, the plasma expo sures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using Entry Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: - Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. - Genetic mutations and/or chromosomal damage can contribute to cancer formation. Two drugs have been approved in this new class o f antiretrovirals (ARVs) aimed at inhibiting viral bind ing or fusion o f HIV to host target cells. Binding o f the viral envelope glycoprotein (gp)120 to the CD4 receptor induces conformational changes that enable gp120 to interact with a chemokine receptor such as CCR5 or CXCR4 on the host cell; binding o f gp120 to the coreceptor causes subsequent conforma tional changes in the viral transmembrane gp41, exposing the "fusion peptide" o f gp41, which inserts into the cell membrane. A helical region o f gp41, called HR1, then interacts with a similar helical region, HR2, on gp41, resulting in a "zipping" together o f the two helices and mediating the fusion o f cellular and viral membranes. Enfuvirtide, which requires subcutaneous administration, is a synthetic 36-aminoacid peptide derived from a naturally occurring m otif within the HR2 domain o f viral gp41, and the drug binds to the HR1 region, preventing the HR1-HR2 interaction and correct folding o f gp41 into its sec ondary structure, thereby inhibiting virus-cell fusion. Enfuvirtide was approved for use in combination with other ARV drugs to treat advanced HIV infection in adults and children 6 years o f age or older. Maraviroc interferes with viral entry at the chemokine coreceptor level; it is a CCR5 coreceptor antago nist approved for combination therapy for HIV infection in adults infected with CCR5-tropic virus. Enfuvirtide (Fuzeon, T-20) is classified as FDA pregnancy category B. # A nim al carcinogenicity studies Enfuvirtide was neither mutagenic or clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f enfuvirtide have not been conducted. # R eproduction/fertility anim al studies Reproductive toxicity has been evaluated in rats and rabbits. Enfuvirtide produced no adverse effects on fertility of male or female rats at doses up 30 mg/kg/day administered subcutaneously (1.6 times the maximum recommended adult human daily dose on an m2 body surface area basis). - Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence o f harm to the fetus from enfuvirtide administered in doses up to 27 times and 3.2 times, respectively, the adult human daily dose on an m 2 body surface area basis. Antiretroviral Pregnancy Registry (Updated September 14, 2011) The Antiretroviral Pregnancy Registry is an epidemiologic project to collect observational, nonexperi mental data on ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The registry is a collabo rative project o f the pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners. It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their newborns report cases o f prenatal exposure to ARV drugs (either alone or in combination) to the Antiretroviral Pregnancy Registry. The registry does not use patient names, and birth outcome fol low-up is obtained from the reporting physician by registry staff.	Key changes made to update the May 24, 2010, version o f the guidelines are summarized below. Throughout the revised guidelines, significant updates are highlighted and discussed. R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States i R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States iii Recom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health a n d Interventions to Reduce Perinatal HIV Transmission in the United States vii Public comments A 2-week public comment period follows release of the updated guidelines on the AIDSinfo Web site. The Panel reviews comments received to determine whether additional revisions to the guidelines are indicated. The public may also submit comments to the Panel at any time at# • This section and Table 3 include updates on recent results from international clinical trials, includ ing HPTN 046 in breastfeeding infants, which demonstrated that extending infant nevirapine pro phylaxis from 6 weeks to 6 months improved efficacy in reducing postnatal infections, and NICHD-HPTN 040/PACTG 1043 in formula-feeding infants, which demonstrated that when moth ers have not received antepartum antiretroviral (ARV) drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen. • Preconception Care and Table 4 # (Drug Interactions Between H orm onal Contraceptives and A n tiretroviral A gents) : • This section includes a new subsection on Reproductive Options for HIV Concordant and Serodiscordant Couples. The subsection includes discussion of HPTN 052 trial in discordant cou ples, which demonstrated that initiating antiretroviral therapy (ART) in infected individuals with CD4 cell counts from 350 to 550 cells/mm3 reduced the risk o f transmission to seronegative part ners. The subsection also includes discussion on trials of pre-exposure ARV prophylaxis. • The section includes a new Table (Table 4) on drug interactions between hormonal contracep tives and ARV drugs. • Table 5 on ARV drugs in pregnancy has been revised to include drug formulation and dosing in formation in addition to pregnancy-related pharmacokinetic and toxicity data and recommenda tions for use in pregnancy. Table 5 also includes the newly approved drug rilpivirine. • There is expanded discussion on treatment recommendations for adults and postpartum discon tinuation o f ARV drug regimens. • Tenofovir has moved from a nucleoside reverse transcriptase inhibitor (NRTI) for Use in Spe cial Considerations to an Alternative NRTI choice; it is the Preferred NRTI choice for women who are co-infected with HIV and hepatitis B virus. • Indinavir and nelfinavir have moved from Alternative protease inhibitor (PI) choices to PIs to Use in Special Circumstances. • HIV-Infected Pregnant W om en W ho H ave N ever R eceived Antiretroviral Drugs (Antiretroviral N aive): This section includes expanded discussion o f new data suggesting early and sustained control of HIV viral replication is associated with decreased transmission in women who have undetectable viral load at delivery-data which favors initiation o f ARV drugs as early in pregnancy as possible for all women. • HIV /H epatitis B C oinfection: The Panel now recommends combination ARV drug regimens in cluding anti-hepatitis B drugs for all HIV-infected pregnant women with hepatitis B virus (HBV) co infection: • All pregnant women with HIV/HBV coinfection should receive a combination ARV drug regi men, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue re verse transcriptase inhibitor (NtRTI) backbone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI). • A cute H IV Infection: This is a new section discussing diagnosis and management o f acute HIV-1 infection in pregnancy. • HIV-2 Infection and Pregnancy: This is a new section discussing diagnosis and management of HIV-2 infection in pregnancy. • Com bination Antiretroviral Drugs and Pregnancy O utcom e: Data from several new studies on preterm delivery and combination ARV drug regimens are reviewed in this section. The Panel notes the following: • Clinicians should be aware o f a possible small increased risk o f preterm birth in pregnant women receiving PI-based combination ARV regimens; however, given the clear benefits of such regimens for both the wom en's health and the prevention o f mother-to-child transmission, PIs should not be withheld for fear o f altering pregnancy outcome (A II). • Intrapartum Antiretroviral T herapy/Prophylaxis: Based on the results o f the NICHD-HPTN 040/P1043 clinical trial, the Panel's no longer recommends intrapartum single-dose nevirapine for HIV-infected women in labor who have not received antepartum drugs. In this circumstance, the Panel recommends the following: • Intravenous zidovudine is recommended for HIV-infected women in labor who have not re ceived antepartum ARV drugs, and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (A II). • Postpartum C are: This section includes expanded discussion o f considerations regarding stopping ARVs postpartum, including discussion o f results o f HPTN 052 and o f the importance o f counseling on safer sex practices and contraception during the postpartum period. • Infant Antiretroviral Prophylaxis and • The Panel now recommends that twice daily dosing can be used for the 6-week zidovudine prophylaxis regimen in full-term infants. • The recommended dose o f zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, begin ning as soon after birth as possible and preferably within 6-12 hours o f delivery. • The design and results o f the NICHD-HPTN 040/PACTG 1043 clinical trial in formula-fed in fants are discussed. The trial demonstrated that when mothers have not received antepartum ARV drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen. Based on these data, the Panel's recommenda tion is now: • Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, started as soon after birth as possible (AI). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses o f nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen o f zidovudine, nelfinavir and lamivudine. The 2drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States. (see General Considerations for Choice o f Infant Prophylaxis and Table 9) (A I). • Table 9 includes the dosing for the 2-drug regimen used in the NICHD-HPTN 040/PACTG 1043 trial. • A new subsection is included on management o f breastfeeding infants o f mothers first diag nosed with HIV infection during the postpartum period. , develops these guidelines. The guidelines provide health care providers with information for discussion with HIV-infected pregnant women to enable the patient/provider team to make informed decisions regarding the use o f ARV drugs during pregnancy and use o f scheduled cesarean delivery to reduce perinatal transmission o f HIV. The recommendations in the guidelines are accompanied by discussion o f various circumstances that commonly occur in clinical practice and the factors influencing treatment considerations. The Panel recognizes that strategies to pre vent perinatal transmission and concepts related to management o f HIV disease in pregnant women are rapidly evolving and will consider new evidence and adjust recommendations accordingly. The updated guidelines are available from the AID Sinfo Web site (http://aidsinfo.nih.gov). Health care providers considering the use o f ARV agents for HIV-infected women during pregnancy must take into account two separate but related issues: 1. antiretroviral treatment (ART) o f maternal HIV infection; and 2. ARV chemoprophylaxis to reduce the risk o f perinatal transmission o f HIV. The benefits o f ARV drugs for a pregnant woman must be weighed against the risks o f adverse events to the woman, fetus, and newborn. Combination drug regimens are considered the standard o f care both for treatment o f HIV infection and for prevention o f perinatal transmission o f HIV2, 6. After provider coun seling and discussion on ARV drug use during pregnancy, a pregnant w om an's informed choice on whether to take ARV drugs either for her treatment or for prevention o f mother-to-child transmission or to follow other medical recommendations intended to reduce perinatal transmission o f HIV should be re spected. Coercive and punitive policies are potentially counterproductive; they may undermine provider patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize fetal and neonatal well-being. The current guidelines have been structured to reflect the management o f an individual mother-child pair and are organized into a brief discussion o f preconception care followed by principles for management o f the woman and her infant during the antepartum, intrapartum, and postpartum periods. Although peri natal transmission of HIV occurs worldwide, these recommendations have been developed for use in the United States. Alternative strategies may be appropriate in other countries. Policies and practices in other countries regarding the use o f ARV drugs for reduction o f perinatal transmission o f HIV may differ from the recommendations in these guidelines and will depend on local considerations, including avail ability and cost o f ARV drugs, accessibility o f facilities for safe intravenous infusions during labor, and local recommendations regarding breastfeeding by HIV-infected women. # Guidelines Development Process # Topic Comment Goal of the guidelines Provide guidance to HIV care practitioners on the optimal use of antiretroviral (ARV) agents in pregnant women for treatment of HIV infection and for prevention of mother-to-child transmission of HIV in the United States. # Panel members The Panel is composed of approximately 30 voting members who have expertise in management of pregnant HIV-infected women (such as training in either obstetrics/gynecology or women's health) and interventions to prevent mother-to-child transmission (such as specialized training in pediatric HIV infection) as well as com munity representatives with knowledge of HIV infection in pregnant women and interventions to prevent mother-to-child transmission. The U.S. government representatives, appointed by their agencies, include at # Financial All members of the Panel submit a written financial disclosure annually reporting any association with man disclosures ufacturers of ARV drugs or diagnostics used for management of HIV infections. A list of the latest disclo sures is available on the AIDSinfo Web site (http://aidsinfo.nih.gov). # Users of the guidelines Providers of care to HIV-infected pregnant women and to HIV-exposed infants Funding source Office of AIDS Research (OAR), NIH # Evidence collection The recommendations in these guidelines are generally based on studies published in peer-reviewed jour nals. On some occasions, particularly when new information may affect patient safety, unpublished data presented at major conferences or prepared by the FDA and/or manufacturers as warnings to the public may be used as evidence to revise the guidelines. # Recommenda tion grading See Table 2 . # Method of synthesizing data Each section of the guidelines is assigned to a small group of Panel members with expertise in the area of in terest. The members synthesize the available data and propose recommendations to the entire Panel. The Panel discusses and votes on all proposals during monthly teleconferences. Proposals receiving endorsement from a consensus of members are included in the guidelines as official Panel recommendations. Other guidelines These guidelines focus on HIV-infected pregnant women and their infants. Other guidelines outline the use of antiretroviral therapy (ART) in nonpregnant HIV-infected adults and adolescents, HIV-infected children, and people who experience occupational or nonoccupational exposure to HIV. The guidelines described are also available on the AIDSinfo Web site (http://www.aidsinfo.nih.gov). Preconception management for non pregnant women of reproductive age is briefly discussed in this document. However, for more detailed dis cussion on issues of treatment of nonpregnant adults, the Working Group defers to the designated expertise offered by Panels that have developed those guidelines. # Update plan The Panel meets monthly by teleconference to review data that may warrant modification of the guidelines. Updates may be prompted by new drug approvals (or new indications, new dosing formulations, or changes in dosing frequency), new significant safety or efficacy data, or other information that may have a significant impact on the clinical care of patients. In the event of significant new data that may affect patient safety, the Panel may issue a warning announcement and accompanying recommendations on the AIDSinfo Web site until the guidelines can be updated with appropriate changes. Updated guidelines are available at the AIDSinfo Web site (http://www.aidsinfo.nih.gov). Recommendations in these guidelines are based on scientific evidence and expert opinion. Each recom mended statement is rated with a letter of A , B , or C that represents the strength o f the recommendation and with a numeral I , II, or III, according to the quality of evidence. # Basis for Recommendations Strength of Recommendation Quality of Evidence for Recommendation # Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmission of HIV (Updated September 14, 2011) Panel's Recommendations • Antiretroviral (ARV) drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepar tum viral load and providing infant pre-and post-exposure prophylaxis. Therefore, combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV (AI). Zidovudine and other ARV drugs can reduce perinatal transmission through a number o f mechanisms. Antenatal drug administration decreases maternal viral load in blood and genital secretions, which is a particularly important mechanism of action in women with high viral loads. Even among women with HIV RNA levels <1,000 copies/mL, however, ARV drugs have been shown to reduce the risk o f trans mission1. In addition, the level o f HIV RNA at delivery and receipt o f antenatal ARV drugs are inde pendently associated with risk o f transmission, suggesting that reduction in viral load is not solely responsible for the efficacy o f ARV prophylaxis2-3. Another mechanism o f protection is infant pre-exposure prophylaxis achieved by administering ARV drugs that cross the placenta from mothers to infants and produce adequate systemic drug levels in the infants. This mechanism o f protection likely is particularly important during passage through the birth canal, a time when infants receive intensive exposure to maternal genital-tract virus. Infant post-expo sure prophylaxis is achieved by administering drugs to infants after birth. This intervention provides protection from cell-free or cell-associated virus that may have entered the fetal/infant systemic circula tion through maternal-fetal transfusion associated with uterine contractions during labor or systemic dis semination o f virus swallowed during infant passage through the birth canal. The efficacy o f ARV drugs in reducing perinatal transmission likely is multifactorial, and each o f the mechanisms previously described may make a contribution. The importance o f the pre-and post-expo sure components of prophylaxis in reducing perinatal transmission is demonstrated by the efficacy o f in terventions that involve administration o f ARVs only during labor and/or to the newborns, discussed in the next section4-10. transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double blind, placebo-controlled trial. Lancet. 2002 # Lessons from International Clinical Trials of Short-Course Antiretroviral Regimens for Prevention of Perinatal Transmission of HIV (Updated September 14, 2011) Panel's Recommendations • All pregnant women who require therapy for their own health should receive a combination antepartum antiretroviral (ARV) drug regimen containing at least three drugs for treatment, which will also reduce the risk of perinatal transmis sion (AI). • Combination antepartum drug regimens are also recommended for prevention of perinatal transmission in women who do not yet require therapy for their own health (AII). • ARV prophylaxis is more effective when given for a longer than a shorter duration. Therefore, ARV drugs should be started as soon as possible in women who require treatment for their own health (AI), and without delay after the first trimester in women who do not require immediate initiation of therapy for their own health, although earlier initiation can be considered in these women as well (BIII) (see Recommendations for Use of Antiretroviral Drugs during Pregnancy). • In the absence of antepartum administration of ARV drugs, ARV drugs should be administered intrapartum in combina tion with infant ARV prophylaxis to reduce the risk of perinatal transmission (see Intrapartum Care) (AI); if antepartum and intrapartum ARV drugs are not received, infant ARV prophylaxis should be provided (see Infant Antiretroviral Pro phylaxis) (AI). • Adding single-dose intrapartum/newborn nevirapine to the standard antepartum combination ARV regimens used for prophylaxis or treatment in pregnant women in the United States is not recommended. This is because the drug does not appear to provide additional efficacy in reducing transmission and it may be associated with development of nevirapine resistance (AI). • Breastfeeding is not recommended for HIV-infected women in the United States-including those receiving combination antiretroviral therapy (ART)-because safe, affordable, and feasible alternatives are available (AII). A number o f simple regimens have been identified that are effective in reducing perinatal transmission in resource-limited countries (see Table 3) . Direct comparison o f results from trials o f these regimens are difficult because the studies involved diverse patient populations residing in different geographic loca tions, infected with various viral subtypes, and with different infant feeding practices. However, some general conclusions can be drawn from the results, which are relevant to understanding use o f ARV drugs for prevention o f perinatal transmission in both resource-limited and resource-rich countries. 30.6% at 15 months (30% efficacy). • MTCT was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy). • MTCT was 16.5% in ZDV arm vs. 26.1% in placebo arm at 3 months (37% efficacy). • MTCT was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy). # PETRA trial South Africa, Tanzania, and Uganda6 Breastfeeding and for mula feeding 12.3% in sdNVP arm vs. 9.3% in ZDV + 3TC arm at 8 weeks (difference not statistically significant, P = 0.11). > Short-short arm stopped at interim analysis (10.5%). MTCT was 6.5% in long-long arm vs. 4.7% in long short arm and 8.6% in short-long arm at 6 months (no statistical dif ference). In utero transmission was significantly higher with short vs. long maternal therapy regimens (5.1% vs. 1.6%). 77% of women received dual-or triple-combination ARV regimens during pregnancy. > Trial stopped early due to very low MTCT in both arms: 1.4% in sdNVP arm vs. 1.6% in placebo arm (53% of MTCT was in utero). > ZDV-alone arm was stopped due to higher MTCT than the NVP-NVP arm (6.3% vs. 1.1%). In arms in which the mother received sdNVP MTCT rate did not differ significantly between the infant receiving or not receiving sdNVP (2.0% vs. 2.8%). > MTCT was 6.5% (95% CI, 3.9%-9.1%) at 6 weeks; MTCT for histor ical control group receiving short ZDV (98% breastfed) was 12.8%. Formula feeding + ZDV (infant) 4 weeks + sdNVP infant only • Initial design: In formula-feeding arm, MTCT at 1 month was 2.4% in maternal and infant sdNVP arm and 8.3% in placebo arm (P = 0.05). In breastfeeding + infant ZDV arm, MTCT at 1 month was 8.4% in sdNVP arm and 4.1% in placebo arm (difference not statistically significant). • R e v is e d d e sig n : MTCT at 1 month was 4.3% in maternal + infant sdNVP arm and 3.7% in maternal placebo + infant sdNVP arm (no significant dif ference; no interaction with mode of infant feeding). • MTCT at 7 months was 9.1% in breastfeeding + ZDV arm and 5.6% in formula-feeding arm; mortality at 7 months was 4.9% in breastfeeding + ZDV arm vs. 9.3% in formula-feeding arm; HIV-free survival at 18 months was 15.6% breastfeeding + ZDV arm vs. 14.2% formula-feeding arm. -MTCT at 6 weeks was 5.3% in sdNVP arm vs. 2.5% in extended NVP arm (risk ratio 0.54, P = 0.009). -MTCT at 6 months was 9.0% in sdNVP arm vs. 6.9% in extended NVP arm (risk ratio 0.80, P = 0.16). • HIV-free survival significantly lower in extended NVP arm at both 6 weeks and 6 months of age. # PEPI-Malawi Trial Malawi19 Breastfeeding sdNVP + ZDV for 1 week (control) vs. two extended infant regimens (NVP or NVP/ZDV) for 14 weeks No AP ARV Oral IP: sdNVP (if mother presents in time) Infant sdNVP + ZDV for 1 week (control) vs. con trol + NVP for 14 weeks vs. control + NVP/ZDV for 14 weeks • Postnatal infection in infants unin fected at birth: -MTCT at age 6 weeks was 5.1% in control vs. 1.7% in extended NVP (67% efficacy) and 1.6% in ex tended NVP/ZDV arms (69% effi cacy). -MTCT at age 9 months was 10.6% in control vs. 5.2% in extended NVP (51% efficacy) and 6.4% in ex tended NVP/ZDV arms (40% effi cacy). • No significant difference in MTCT be tween the extended prophylaxis arms; however, more hematologic toxicity with NVP/ZDV. A rm 2: Maternal ZDV/3TC for 1 week (no further postnatal prophylaxis); infant sdNVP + ZDV for 1 week (no further postnatal prophy laxis) MITRA • MTCT at birth was 1.8% with mater nal triple-drug prophylaxis Arm 1 and 2.5% with ZDV/sdNVP Arm 2, not significantly different. In women with CD4 cell counts 350-500 cells/mm3, MTCT at birth was 1.7% in both arms. • MTCT at age 12 months was 5.4% with maternal triple-drug prophylaxis Arm 1 and 9.5% with ZDV/sdNVP (with no further postnatal prophy laxis after 1 week) Arm 2 (P = \|0.029). # Mma Bana Botswana24 Breastfeeding Maternal triple-drug prophylaxis (com pares 2 regimens) in women with CD4 cell counts >200 cells/mm3 A rm 1: ZDV/3TC/ABC # A rm 2: ZDV/3TC/LPV/r -MTCT at age 28 weeks was 5.7% in control Arm 1; 2.9% in maternal triple-drug prophylaxis Arm 2 (P = 0.009 vs. control); 1.7% in infant NVP Arm 3 (P <0.001 vs. control). • No significant difference between maternal triple-drug prophylaxis Arm 2 and infant NVP Arm 3 (P = 0.12). • In infants uninfected at age 6 weeks, the 6month infant HIV infection rate was 1.1% (0.3-1.8%) in the extended NVP Arm 1 and 2.4% (1.3-3.6%) in the placebo Arm 2 (P = 0.048). • At infant randomization at age 6 weeks, 29% of mothers in each arm were receiving a triple-ARV regimen for treatment of HIV. • For mothers receiving triple-ARV drugs at the time of randomization, in infants unin fected at age 6 weeks, the 6-month infant HIV infection rate was 0.2% and not statis tically different between extended NVP Arm 1 (0.5%) and placebo Arm 2 (0%). • For mothers with CD4 cell counts >350 cells/mm3 who were not receiving triple ARV drugs, in infants uninfected at age 6 weeks, the 6-month infant HIV infection rate was 0.7% (0-1.5%) in the extended NVP Arm 1 and 2.8% (1.3 -4.4%) in the placebo Arm 2 (P = 0.014). Efficacy has been demonstrated for a number o f short-course ARV regimens, including those with zi dovudine alone; zidovudine plus lamivudine; single-dose nevirapine; and single-dose nevirapine com bined with either short-course zidovudine or zidovudine/lamivudine2, 4-9, 13-15. In general, combination regimens are more effective than single-drug regimens in reducing perinatal transmission. In addition, administration of ARV drugs during the antepartum, intrapartum, and postpartum periods is superior in preventing perinatal transmission than administration o f ARV drugs only during the antepartum and in trapartum periods or intrapartum and postpartum periods6, 12, 28. Use o f ARV drugs to prevent transmis sion is highly effective, even among HIV-infected women with advanced disease24, 29. Almost all trials in resource-limited countries have included oral intrapartum prophylaxis, with varying durations o f maternal antenatal and/or infant (and sometimes maternal) postpartum prophylaxis. Perina tal transmission is reduced by regimens with antenatal components starting as late as 36 weeks' gestation and lacking an infant prophylaxis component2, 4-5. However, longer duration antenatal ARV prophylaxis (starting at 28 weeks' gestation) is more effective than shorter duration ARV prophylaxis (starting at 36 weeks' gestation), suggesting that a significant proportion o f in utero transmission occurs between 28 and 36 weeks' gestation9. Analyses from the European National Study o f HIV in Pregnancy and Child hood have shown that efficacy is increased with even longer duration antenatal ARV prophylaxis (start ing before 28 weeks' gestation), with each additional week o f a triple-drug regimen corresponding to a 10% reduction in risk o f transmission after adjustment for viral load, mode o f delivery, and sex o f the in fant30. More prolonged infant post-exposure prophylaxis does not appear to substitute for longer duration maternal ARV prophylaxis9. No trials have directly compared the efficacy o f zidovudine plus single-dose nevirapine with a triple drug ARV regimen for prevention o f in utero transmission in women with higher CD4 cell counts. In African women with CD4 cell counts ranging from 200 to 500 cells/mm3, the Kesho Bora trial compared a triple-ARV drug prophylaxis regimen with zidovudine plus single-dose nevirapine prophylaxis, both started at 28 weeks' gestation or later. The women in the triple-drug arm continued the drugs until breastfeeding ceased, while those in the zidovudine/single-dose nevirapine arm did not receive postnatal prophylaxis. Although the rate o f postnatal transmission was significantly lower in the triple-drug arm than in the zidovudine/single-dose nevirapine arm without postnatal prophylaxis, the rates o f transmis sion at birth were similar in women randomized to a triple-drug regimen (1.8%) and women randomized to antepartum zidovudine/single-dose nevirapine (2.5%); for women with CD4 cell counts from 350 to 500 cells/mm3, the rate o f infection at birth was 1.7% in each arm23. However, the study was not pow ered to address equivalence between regimens in preventing in utero infection in women with higher CD4 cell counts and the drugs in both arms were administered antepartum for only 6 weeks. Regimens that do not include maternal ARV prophylaxis during pregnancy have been evaluated because some women may lack antenatal care and present for prenatal care for the first time when they go into labor. Regimens that include only intrapartum and postpartum drug administration also have been shown to be effective in reducing perinatal transmission6-8. However, without continued infant post-exposure prophylaxis, intrapartum pre-exposure prophylaxis alone with nucleoside reverse transcriptase inhibitor (NRTI) drugs (zidovudine/lamivudine) is not effective in reducing transmission6. The SAINT trial demonstrated that the two proven effective intrapartum/postpartum regimens (zidovudine/lamivudine or single-dose intrapartum/newborn nevirapine) are similar in efficacy and safety8. In some situations, it may be impossible to administer maternal antepartum and intrapartum therapy and only infant prophylaxis may be an option. In the absence o f maternal therapy, the standard infant pro phylaxis regimen o f 6 weeks o f zidovudine was effective in reducing HIV transmission compared with no prophylaxis, based on epidemiologic data in resource-rich countries31. In a South African study o f in-fants born to mothers who did not receive antenatal or intrapartum ARV drug regimens, overall perinatal transmission rates were not significantly different for administration o f single-dose infant nevirapine given within 24 hours of delivery compared with 6 weeks o f infant zidovudine therapy15. However, a trial in Malawi in breastfeeding infants demonstrated that adding 1 week o f zidovudine therapy to infant single-dose nevirapine reduced the risk of transmission by 36% compared with infant single-dose nevi rapine alone13. To define the optimal infant prophylaxis regimen in the absence o f maternal antepartum ARV drug administration in a formula-fed population o f infants, the NICHD-HPTN 040/P1043 (NCT00099359) multicountry (Argentina, Brazil, South Africa, and the United States) clinical trial en rolled 1,735 formula-fed infants born to HIV-infected mothers who did not receive ARV drugs during the current pregnancy prior to labor (if women presented early enough, intravenous intrapartum zidovu dine was given). The study compared three infant ARV regimens: standard 6 weeks o f zidovudine alone versus 6 weeks of zidovudine plus three doses o f nevirapine given in the first week o f life (first dose birth to 48 hours; second dose 48 hours after first dose; third dose 96 hours after second dose) versus 6 weeks o f zidovudine plus lamivudine and nelfinavir given from birth through age 2 weeks. The study, presented at the 2011 Conference on Retroviruses and Opportunistic Infections, demonstrated that the combination regimens reduced the risk of intrapartum transmission by approximately 50% compared with infant prophylaxis with zidovudine alone (see Table 3). Based on these data, combination ARV pro phylaxis is now recommended in the United States for infants whose mothers have not received antena tal ARV drugs (see Infant Antiretroviral Prophylaxis). Several studies in formula-fed and breastfed populations in resource-limited countries have found that adding maternal/infant single-dose nevirapine to a maternal short-course zidovudine or zidovudine / lamivudine regimen increased efficacy compared with the short-course regimen alone11, 12, 16. Whether single-dose nevirapine provides any additional efficacy when combined with the standard recommended combination ARV prophylaxis regimens used in the United States was evaluated in PACTG 316, a clini cal trial conducted in the United States, Europe, Brazil, and the Bahamas. This study demonstrated that for nonbreastfeeding women in resource-rich countries, the addition o f single-dose nevirapine did not offer significant benefit in the setting o f combination ARV prophylaxis throughout pregnancy and very low viral load at the time o f delivery10. Thus, adding single-dose intrapartum nevirapine is generally not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis (see Intrapartum Care). Breastfeeding by HIV-infected women (including those receiving ARV drugs) is not recommended in the United States where replacement feeding is affordable, feasible, acceptable, sustainable, and safe and the risk of infant mortality due to diarrheal and respiratory infections is low. A number of studies have evalu ated the use of maternal or infant ARV prophylaxis during breastfeeding to reduce postnatal transmission (see Table 3). Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarily using daily infant nevirapine) during breastfeeding significantly decreases the risk of postnatal transmission in breast milk and that maternal triple-drug prophylaxis during breastfeeding likewise de creases postnatal infection18-25. Maternal prophylaxis with triple-drug regimens may be less effective than infant prophylaxis if first started in the postpartum period or late in pregnancy, likely because it takes sev eral weeks to months before full viral suppression in breast milk is achieved25, 32. Importantly, although sig nificantly lowering the risk of postnatal infection, neither infant nor maternal postpartum ARV prophylaxis completely eliminates the risk of HIV transmission through breast milk. Therefore, breastfeeding is not recommended for HIV-infected women in the United States (including those receiving combination ARV drug regimens). Finally, both infant nevirapine prophylaxis and maternal triple-drug prophylaxis during breastfeeding may be associated with development of ARV drug resistance in infants who become infected despite prophylaxis33-36. Three studies have found multiclass drug resistance in breastfeeding infants who Mother-to-child transmission has been observed across the entire range o f plasma HIV RNA levels, in cluding in women with undetectable viral loads1-3. In PACTG 076, an HIV RNA threshold below which there was no risk o f transmission was not identified; zidovudine was effective in reducing transmission regardless of maternal HIV RNA copy number4-5. HIV RNA levels correlate with risk o f transmission even in women treated with ARV agents6-9. Although the risk o f perinatal transmission in women with undetectable HIV RNA levels appears to be extremely low, transmission has been reported even among women with very low or undetectable levels o f mater nal HIV RNA10. Additionally, although HIV RNA may be an important risk factor for transmission, other factors also appear to play a role6, 9 11. Although there is a general correlation between viral loads in plasma and in the genital tract, discor dance also has been reported, particularly between HIV proviral load in blood and genital secretions, es pecially in the presence o f other genital tract infections12-15. Penetration o f ARV drugs into the female genital tract has been shown to vary between drugs16-17. If exposure to HIV in the maternal genital tract during delivery is a risk factor for perinatal transmission, plasma HIV RNA levels may not always be an accurate indicator o f risk. Long-term changes in one body compartment with ARV drugs may or may not be associated with comparable changes in other compartments. Additional studies are needed to deter mine the effect o f ARV drugs on genital tract viral load and the association between such effects and the risk o f perinatal transmission o f HIV. In the short-course zidovudine trial in Thailand, plasma and cervicovaginal HIV RNA levels were reduced by zidovudine prophylaxis, and each independently correlated with perinatal transmission18. Because transmission can occur even when HIV RNA copy numbers are low or undetectable, all HIV-in fected women should be counseled about and administered ARV drugs during pregnancy, regardless of their HIV RNA levels. References: • Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care (AIII). • Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintended preg nancy (AI). • During preconception counseling include information on safer sexual practices and elimination of use of alcohol and illicit drugs, and smoking, which are important for the health of all women as well as for fetal/infant health, should pregnancy occur (AII). • When evaluating HIV-infected women, include assessment of HIV disease status and need for antiretroviral therapy (ART) for their own health (AII). • Choose an ART regimen for HIV-infected women of childbearing age based on consideration of effectiveness for treat ment of maternal disease, teratogenic potential of the drugs in the regimen should pregnancy occur, and possible ad verse outcomes for mother and fetus (AII). The Centers for Disease Control and Prevention (CDC), the American College o f Obstetricians and Gy necologists, and other national organizations recommend offering all women o f childbearing age com prehensive family planning and the opportunity to receive preconception counseling and care as a component of routine primary medical care. The purpose o f preconception care is to improve the health o f each woman before conception by identifying risk factors for adverse maternal or fetal outcome, pro viding education and counseling targeted to the patient's individual needs, and treating or stabilizing medical conditions to optimize maternal and fetal outcomes1. Preconception care is not a single clinical visit but rather a process o f ongoing care and interventions integrated into primary care to address the needs o f women during the different stages o f reproductive life. Because more than h alf o f all pregnan cies in the United States are unintended2-5 it is important that comprehensive family planning and pre conception care be integrated into routine health visits. Providers should initiate and document a nonjudgmental conversation with all women o f reproductive age concerning their reproductive desires because women may be reluctant to bring this up themselves6. HIV care providers who routinely care for women of reproductive age play an important role in promoting preconception health and informed re productive decisions. The fundamental principles of preconception counseling and care are outlined in the CDC Preconception Care Work Group's Recommendations to Improve Preconception Health and Health Care. In addition to the general components of preconception counseling and care that are appropriate for all women of repro ductive age, HIV-infected women have specific needs that should be addressed7-8. Because many women infected with HIV are aware of their HIV status prior to pregnancy, issues that impact pregnancy may be addressed before conception during their routine medical care for HIV disease. In addition to those out lined by the CDC Preconception Care Work Group9 the following components of preconception counsel ing and care are specifically recommended for HIV-infected women. Health care providers should: a. Discuss reproductive options, actively assess women's pregnancy intentions on an ongoing basis throughout the course o f care and, when appropriate, make referrals to experts in HIV and wom en's health, including experts in reproductive endocrinology and infertility when necessary10. b. Offer all women effective and appropriate contraceptive methods to reduce the likelihood o f unin tended pregnancy. Providers should be aware o f potential interactions between ARV drugs and hor monal contraceptives that could lower contraceptive efficacy (see Table 4) . c. Counsel on safe sexual practices that prevent HIV transmission to sexual partners, protect women from acquiring sexually transmitted infections (STIs), and reduce the potential to acquire more viru lent or resistant strains o f HIV. d. Counsel on eliminating alcohol, illicit drug use, and cigarette smoking. e. Educate and counsel women about risk factors for perinatal transmission o f HIV, strategies to reduce those risks, potential effects of HIV or treatment on pregnancy course and outcomes, and the recom mendation that HIV-infected women in the United States not breastfeed because o f the risk o f trans mission o f HIV and the availability o f safe and sustainable infant feeding alternatives. f. When prescribing ART to women of childbearing age consider the regimen's effectiveness for treat ment o f HIV, an individual's hepatitis B disease status, the drugs' potential for teratogenicity should pregnancy occur, and possible adverse outcomes for mother and fetus11-13. g. Use the preconception period in women who are contemplating pregnancy to adjust ARV regimens to exclude efavirenz or other drugs with teratogenic potential. h. For women who are on ART for their own health and who want to get pregnant, make a primary treatment goal the attainment o f a stable, maximally suppressed maternal viral load prior to concep tion to decrease the risk o f mother-to-child transmission. i. Evaluate and appropriately manage therapy-associated side effects such as hyperglycemia, anemia, and hepatoxicity that may adversely impact maternal-fetal health outcomes. j. Evaluate the need for appropriate prophylaxis or treatment for opportunistic infections (OIs), includ ing safety, tolerability, and potential toxicity o f specific agents when used in pregnancy. k. Administer medical immunizations (e.g., influenza, pneumococcal, or hepatitis A and B vaccines) as indicated. l. Encourage sexual partners to receive HIV testing and, if infected, counseling and appropriate HIV care. Panel's Recommendations • For serodiscordant couples who want to conceive, expert consultation is recommended so that approaches can be tai lored to specific needs, which may vary from couple to couple (AIII). • Partners should be screened and treated for genital tract infections before attempting to conceive (AII). • For an HIV-infected female with an HIV-uninfected male partner, the safest conception option is artificial insemination, in cluding the option of self-insemination with her partner's sperm during the peri-ovulatory period (AIII). • For HIV-infected men with an HIV-uninfected female partner, the use of sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection should be considered if using donor sperm from an HIV-uninfected male for insemination is unacceptable (AII). • In a serodiscordant couple who wishes to conceive, initiation of antiretroviral therapy (ART) for the HIV-infected partner is recommended if the infected partner has a CD4 count <550 cells/mm3 (AI). For HIV-infected individuals with CD4 counts >550 cells/mm3, initiation of ART could be considered (BIII). If therapy is initiated, maximal viral suppression is recommended before conception is attempted (AIII). • Data are insufficient at the current time to recommend peri-conception administration of antiretroviral (ARV) pre-expo sure prophylaxis for HIV-uninfected partners to reduce the risk of sexual transmission (AIII). For serodiscordant couples who want to conceive, expert consultation is recommended so that ap proaches can be tailored to specific needs, which may vary from couple to couple. Before attempting to conceive, both partners should be screened for genital tract infections. If any such infections are identified, they should be treated because genital tract inflammation is associated with genital tract shedding o f HIV1-2. Semen analysis is recommended for HIV-infected males before concep tion is attempted because HIV, and possibly ART, may be associated with a higher prevalence o f semen abnormalities such as low sperm count, low motility, higher rate o f abnormal forms, and low semen vol ume3-6. If such abnormalities are present, the uninfected female partner may be exposed unnecessarily and for prolonged periods to her partner's infectious genital fluids when the likelihood o f getting preg nant naturally is low or even nonexistent. Observational studies have demonstrated a decreased rate o f transmission o f HIV among heterosexual serodiscordant couples in which the HIV-infected partner is receiving ART compared with couples in which the HIV-infected partner is not receiving ART7-9. HPTN 052 is a randomized clinical trial de signed to evaluate whether immediate versus delayed initiation o f ART by HIV-infected individuals with CD4 counts of 350-550 cells/mm3 could prevent sexual transmission o f HIV among serodiscordant cou ples. Preliminary data from this study showed that earlier initiation o f ART led to a significant reduction in transmission o f HIV to the uninfected partner10. O f 28 cases o f HIV infection documented to be genet ically linked to the infected partner, 27 occurred among the 877 couples in which the HIV-infected part ner delayed initiation o f ART until the CD4 count fell below 250 cells/mm3, whereas only 1 case o f HIV infection occurred among the 886 couples with an HIV-infected partner who began immediate ART; 17 o f the 27 transmissions in the delayed therapy group occurred in individuals with CD4 counts >350 cells/mm3. These are the first data from a randomized trial to demonstrate that provision o f treatment to infected persons can reduce the risk o f transmission to their uninfected sexual partners11. Based on the results from HPTN 052, initiation o f ART would be recommended for the infected partner in a serodis cordant couple who has a CD4 count o f <550 cells/mm3 if the couple wishes to conceive. For HIV-in fected individuals with CD4 counts >550 cells/mm3, initation o f therapy could be considered, although the benefit of ART in reducing sexual transmission from individuals with higher CD4 counts has not been determined. Before conception is attempted, maximal viral suppression is recommended if an in fected individual is on ART for his/her own health or does not require therapy but opts to start ART to prevent sexual transmission. It is important to recognize that no single method (including treatment o f the infected partner) is fully protective against transmission o f HIV. Effective ART that decreases plasma viral load to undetectable levels is also associated with decrease in the concentration o f virus in genital secretions. However, dis cordance between plasma and genital viral loads has been reported, and individuals with an undetectable plasma viral load may have detectable genital tract virus12-13. Additionally, ARV drugs vary in their abil ity to penetrate the genital tract14. Thus, maximal viral suppression may not completely eliminate risk of heterosexual transmission. Reducing the risk of perinatal transmission is another potential rationale for starting ART prior to con ception in HIV-infected women who do not yet need treatment for their own health. Data suggest that early and sustained control of HIV viral replication may be associated with decreasing residual risk of perinatal transmission15-16, but that does not completely eliminate the risk o f perinatal transmission16. In addition, there are mixed reports on the possible effects o f combination ARV drug regimens on prematu rity and low birth weight, with some but not all data suggesting that such outcomes may be more fre quent in women on ARV drugs at conception17-18 (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants). The implications of initiating therapy prior to conception solely for prevention o f sexual and/or perinatal transmission should be discussed with the patient. These issues include willingness and ability to com mit to potential lifelong therapy, the potential risks versus benefits o f stopping or continuing the regimen after conception in the male or postpartum in the female, and the need for strict adherence to achieve maximal viral suppression. Consultation with an expert in HIV care is strongly recommended. For HIV-discordant couples in which the female is the HIV-infected partner, the safest form o f concep tion is artificial insemination, including the option to self-inseminate with the partner's sperm during the peri-ovulatory period. Condom use should be advised at all times. For HIV-discordant couples in which the male is the HIV-infected partner, the use o f sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection has been reported to be effective in avoiding seroconversion in uninfected women and off spring in several studies19-20. The National Perinatal HIV Hotline (1-888-448-8765) is a resource for a list o f institutions offering reproductive services for HIV-serodiscordant couples. More data are needed to demonstrate the complete efficacy of these techniques, and couples should be cautioned about the po tential risk of transmission o f HIV to the uninfected partner and to their offspring20. Discordant couples who do not have access to assisted reproduction services and who still wish to try to conceive after com prehensive counseling should be advised that timed, peri-ovulatory unprotected intercourse after the in fected partner has achieved maximal viral suppression (with use o f condoms at all other times) may reduce but not completely eliminate the risk o f sexual transmission20. Should the uninfected woman be come pregnant, she should be regularly counseled regarding consistent condom use to decrease her risk o f sexual transmission of HIV and the possible risk o f perinatal transmission (see Monitoring o f HIV Uninfected Pregnant Women with a Partner Known to be HIV Infected). Periconception pre-exposure prophylaxis may offer an additional option in the future to minimize risk of transmission of HIV within discordant couples. Pre-exposure prophylaxis is use o f ARV medications by an HIV-uninfected individual to maintain blood and genital drug levels sufficient to prevent acquisition o f HIV. An experimental 1% tenofovir gel used intravaginally both before and after sex reduced the inci dence o f HIV infection among women by up to 54% in a randomized, placebo-controlled trial conducted in South Africa21. This product is not available commercially, and additional trials are needed to confirm these findings. Five efficacy trials o f pre-exposure prophylaxis with oral ARV agents (primarily teno fovir alone) are currently under way22. In 1 study o f daily tenofovir/emtricitabine in HIV-seronegative men who have sex with men, there was a 44% reduction in the risk o f acquisition o f HIV compared with placebo23-24. However, the FEM-PrEP clinical trial, designed to study whether HIV-uninfected women at high risk o f being exposed to HIV can safely use a daily dose o f tenofovir/emtricitabine to prevent infec tion, was stopped early by its Data and Safety Monitoring Board (DSMB) because it was highly unlikely the study would be able to demonstrate the effectiveness o f tenofovir/emtricitabine in preventing HIV infection in the study population. The approximate rate o f new HIV infections among trial participants was 5 percent per year. A total o f 56 new HIV infections had occurred, with an equal number o f infec tions in participants assigned to tenofovir/emtricitabine and those assigned to a placebo pill25. Several studies evaluating the efficacy o f pre-exposure prophylaxis among heterosexual discordant cou ples are ongoing but data are not yet available. Currently data are insufficient to recommend periconception administration o f pre-exposure prophylaxis to uninfected partners to reduce the risk o f sexual transmission. In addition, the use o f pre-exposure prophylaxis during pregnancy and lactation for HIVuninfected women with HIV-infected partners has not been studied and cannot be recommended at this time. If pre-exposure prophylaxis is proven safe and efficacious in ongoing trials, this approach may offer an option for safer attempts at conception. However, it will be important to have outcome studies that examine adverse events, including risk o f congenital abnormalities. # M onitoring o f HIV-Uninfected Pregnant Women with Partners Known to B e H IV Infected Clinicians increasingly may be faced with the situation in which an HIV-uninfected woman presents dur ing pregnancy and relates that she has an HIV-infected partner. As is recommended for all pregnant women, the woman should be notified that HIV screening is recommended and that she will receive an HIV test as part of the routine panel of prenatal tests unless she declines. In addition, she should receive a second HIV test during the third trimester, preferably before 36 weeks of gestation, as is recommended for high-risk women. Furthermore, if the pregnant woman presents in labor without results of third-trimester testing, she should be screened with a rapid HIV test on the labor and delivery unit. If at any time during pregnancy the clinician suspects that a pregnant woman may be in the "window" period of seroconversion (i.e., has signs or symptoms consistent with acute HIV infection), then a plasma HIV RNA test should be used in conjunction with an HIV antibody test. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. All HIV-uninfected pregnant women with HIV-infected partners should always use condoms during sexual intercourse to prevent acquisition of HIV. Women should be counseled regarding the symp toms of acute retroviral syndrome (i.e., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, headache) and the importance of seeking medical care and testing if they experience such symptoms. • The known benefits and potential risks of ARV use during pregnancy should be discussed with all women (AIII). • ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIV RNA levels are above the threshold for resistance testing (e.g., >500 to 1,000 copies/mL) (see Antiretroviral Drug Resist ance and Resistance Testing in Pregnancy) (AI). When HIV is diagnosed late in pregnancy, ARV therapy or prophylaxis should be initiated pending results of resistance testing (BIII). • In counseling patients, the importance of adherence to the ARV regimen should be emphasized (AII). • Considerations regarding continuation of the ARV regimen for maternal therapeutic indications after delivery are the same as for nonpregnant individuals. The pros and cons of continuing versus discontinuing ARV drugs postpartum should be dis cussed with women so they can make educated decisions about postpartum ARV use before delivery (AIII). Such decisions should be made in consultation with the provider who will assume responsibility for the women's HIV care going forward after delivery. • Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is essential to ensure that infected women adhere to their ARV drug regimens (AIII). In addition to the standard antenatal assessments for all pregnant women, the initial evaluation o f an HIV-infected pregnant woman should include an assessment o f HIV disease status and recommendations for HIV-related medical care. This initial assessment should include the following: # W ith E FV or N VP (PI-naive or PI-ex p e rie n ced patients): LPV/r 500 mg/125 mg tablets BID (use a combination of two LPV/r 200 mg/50 mg tablets + one LPV/r 100 mg/25 mg tablet to make a total dose of LPV/r 500 mg/125 mg.) or LPV/r 533 mg/133 mg oral solution (6.5 mL) BID # Tablets: Take without regard to meals. # Oral solution: Take with food. # Not used in p reg nancy: # Tablets: Take with food. # C a p su le and oral solution: Take with food if possible, which may improve tolerability. # PI-experienced patients (o n ce -d a ily do sin g not reco m m end ed): • (FPV 700 mg + RTV 100 mg) BID W ith EFV: • (FPV 700 mg + RTV 100 mg) BID or • (FPV 1,400 mg + RTV 300 mg) once daily # Tablet: Take without regard to meals (if not boosted with RTV tablet). # S u sp en sio n : Take without food. # FP V with R T V tablet: Take with meals. # T P V taken with RTV tablets: Take with meals. # T P V taken with R TV ca p s u le s or solution: Take without regard to meals. ARV drugs for prevention o f perinatal transmission o f HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. In general, guidelines for the use o f ART for the benefit of maternal health during pregnancy are the same as for women who are not pregnant, with some modifications, based on concerns about specific drugs and limited experience dur ing pregnancy with newer drugs. ARV prophylaxis is recommended for all pregnant women with HIV infection who do not require therapy, regardless o f viral load (see HIV-Infected Pregnant Women Not on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f HIV). Decisions regarding initiation or modification of ARV drug regimens during pregnancy include considera tions regarding the benefits and risks of ARV drug use that are common to all HIV-infected adults in addi tion to considerations unique to pregnancy. In general, the ARV drug combinations now available are more convenient and better tolerated than regimens used previously, resulting in greater efficacy and improved adherence. During pregnancy maternal ARV toxicities must be considered, along with the potential impact of the ARV regimen on pregnancy outcome and on the fetuses and infants. Decisions about ARV drug regi mens are further complicated because only limited data exist on the long-term maternal consequences of use of the agents during pregnancy solely for prophylaxis of transmission. Similarly, only limited data are available on the long-term consequences to infants of in utero exposure to ARVs. The known benefits and known and unknown risks o f ARV drug use during pregnancy should be consid ered and discussed with women (see Special Considerations Regarding the Use o f Antiretroviral Drugs by HIV-infected Pregnant Women and their Infants). Results from preclinical and animal studies and available clinical information about use of the various agents during pregnancy also should be discussed (see Supplement: Safety and Toxicity o f Individual Antireroviral Agents in Pregnancy) . Potential risks of these drugs should be placed into perspective by reviewing the substantial benefits o f ARV drugs for maternal health and in reducing the risk of transmission of HIV to infants. Counseling of pregnant women about ARV use should be noncoercive, and providers should help women make informed deci sions regarding use o f ARV drugs. Discussions with women about initiation of ARV drug regimens should include information about: a. maternal risk of disease progression and the benefits and risks of initiation of therapy for maternal health; b. benefit o f combination ARV regimens for preventing perinatal transmission o f HIV50; c. potential adverse effects o f ARV drugs for mothers, fetuses, and infants, including potential interac tions with other medications the women may already be receiving; d. the limited long-term outcome data for both women who temporarily use ARV drugs during preg nancy for prophylaxis o f transmission and infants who are exposed to ARVs in utero; and e. the possibility of development o f ARV resistance, including the need for strict adherence to the pre scribed drug regimen to avoid it. Studies of zidovudine for the prevention o f perinatal transmission suggest that pre-exposure prophylaxis o f the infant from transplacental passage o f drug is an important component o f prevention. Thus, when selecting an ARV regimen for a pregnant woman, at least one nucleoside/nucleotide (NRTI) agent with high placental transfer should be included as a component o f the dual NRTI backbone (see Table 5)13, 18, # 51-52 In women with plasma HIV RNA above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting ARV drugs for maternal health or prophylaxis. When HIV is diagnosed late in pregnancy, however, ARV drugs should be initi ated pending results o f resistance testing (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Counseling should emphasize the importance o f adherence to the ARV drug regimen. Support services, mental health services, and drug abuse treatment may be required, depending on women's individual cir cumstances. Coordination o f services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is es sential to ensure that infected women adhere to their ARV drug regimens. Providers should work with women to develop long-range plans regarding continuity o f medical care and decisions about treatment for their own health after giving birth. Considerations regarding continua tion of the ARV regimen for maternal therapeutic indications are the same following delivery as for non pregnant individuals. The impact on short-and long-term maternal health is unknown for postpartum discontinuation o f combination ARV drug regimens used solely to prevent perinatal transmission. This is particularly important because women may have multiple pregnancies resulting in episodic receipt of ARV drugs. No increase in disease progression has been seen so far, however, in studies o f pregnant women with relatively high CD4 counts who stop combination ARV drug regimens after delivery53-55. The risks versus benefits o f stopping ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968). Current adult treatment guidelines strongly recommend ART for all individuals with CD4 cell counts <350 cells/mm3 based on randomized, controlled clinical trial data demonstrating a clear benefit in re duction o f mortality and morbidity. Pregnant women with CD4 counts <350 cells/mm3 should begin on combination ART as soon as possible during pregnancy and be counseled about the need to continue therapy after delivery and the importance o f adherence to the regimen. Based on observational cohort data, the adult treatment guidelines make a moderate-to-strong recom mendation for initiating lifelong ART in individuals with CD4 cell counts between 350 and 500 cells/mm3. Observational studies suggest a relative decrease in mortality (although the overall number of events was small) and possibly a decrease in complications such as cardiovascular events with initiation o f ART in this setting compared with waiting until CD4 cell counts drop below 350 cells/mm3 56-57. Preg nant women with CD4 cell counts between 350 and 500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission o f HIV and counseled about the cur rent treatment recommendations, the potential risks versus benefits o f stopping versus continuing the regimen after delivery, and the need for strict adherence if the regimen is continued postpartum. For individuals with CD4 counts >500 cells/mm3, the adult guidelines note that some experts would rec ommend initiating lifelong therapy, while other experts would view this as optional, given that data are inconclusive on the clinical benefit o f starting treatment at higher CD4 cell counts (>500 cells/mm3). So far, no increased risk of disease progression has been shown in studies o f pregnant women with rela tively high CD4 counts who stop ARV drugs after delivery53-55. The potential benefits o f early therapy must be weighed against possible drug toxicity, cost, and the risk o f development o f viral resistance with suboptimal adherence, which may be more likely during the postpartum period58. Pregnant women with CD4 cell counts >500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission. They should be assessed for their willingness and ability to commit to ongoing continuous therapy and counseled about the current treatment guidelines, the benefits and risks o f therapy, that data on the clinical benefit o f starting lifelong treatment at CD4 cell counts >500 cells/mm3 are inconclusive, and the importance o f adherence if the regimen is continued postpartum. In general, when drugs are discontinued postnatally, all drugs should be stopped simultaneously. How ever, as discussed later (see Stopping Antiretroviral Therapy during Pregnancy), in women receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, continuing the dual-NRTI back bone for a period of time after stopping the NNRTI is recommended to reduce the development of NNRTI resistance. An alternative strategy is to replace the NNRTI with a protease inhibitor (PI) drug while continuing the NRTI, then to discontinue all the drugs at the same time59. The optimal interval be tween stopping an NNRTI and stopping the other ARV drugs is unknown, but a minimum o f 7 days is recommended. Drug concentrations may be detectable for more than 3 weeks after efavirenz is stopped in patients receiving an efavirenz-based NNRTI regimen. Therefore, for patients receiving efavirenz, some experts recommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days. # The National Perinatal HIV Hotline (1-888-448-8765) The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected women and their infants. # Recommendations fo r Use o f Antiretroviral Drugs D uring Pregnancy The Panel recommends that choice o f ARV drug regimens for HIV-infected pregnant women be based on the same principles used to choose regimens for nonpregnant individuals, unless there are compelling pregnancy-specific maternal or fetal safety issues associated with specific drugs. The Panel reviews clin ical trial data published in peer-reviewed journals and data prepared by manufacturers for Food and Drug Administration (FDA) review related to treatment o f HIV-infected adult women, both pregnant and nonpregnant. The durability, tolerability, and simplicity o f a medication regimen is particularly impor tant for preserving future options for women who will be stopping medications after delivery and women who meet standard criteria for initiation o f ART per adult guidelines and will continue the regi men after pregnancy. Regimen selection should be individualized and the following factors should be considered: • comorbidities; • patient adherence potential; • convenience; • potential adverse maternal drug effects; • potential drug interactions with other medications; • results o f genotypic resistance testing; • pharmacokinetic (PK) changes in pregnancy; and • potential teratogenic effects and other adverse effects on fetuses or newborns. Information used by the Panel for recommending specific drugs or regimens for pregnant women in clude: • Data from randomized prospective clinical trials that demonstrate durable viral suppression as well as immunologic and clinical improvement; • Incidence rates and descriptions o f short-and long-term drug toxicity o f ARV regimens, with special attention to maternal toxicity and potential teratogenicity and fetal safety; • Specific knowledge about drug tolerability and simplified dosing regimens; • Known efficacy o f some drug regimens in reducing mother-to-child transmission o f HIV; • PK data during the prenatal period. (The physiologic changes o f pregnancy have the potential to alter drug PKs. ARV dosing during pregnancy should be based on PK data from studies in pregnant women. Physiologic changes are not fixed throughout pregnancy but, rather, reflect a continuum of change as pregnancy progresses, with return to baseline at various rates in the postpartum period.); and • Data from animal teratogenicity studies. Categories o f ARV regimens include: • Preferred: Drugs or drug combinations are designated as preferred for use in pregnant women when clinical trial data in adults have demonstrated optimal efficacy and durability with acceptable toxic ity and ease o f use; pregnancy-specific PK data are available to guide dosing; and no evidence o f ter atogenic effects or established association with teratogenic or clinically significant adverse outcomes for mothers, fetuses, or newborn are present. • Alternative: Drugs or drug combinations are designated as alternatives for initial therapy in pregnant women when clinical trial data in adults show efficacy but any one or more of the following conditions apply: experience in pregnancy is limited; data are lacking on teratogenic effects on the fetus; or the drug or regimen is associated with dosing, formulation, administration, or interaction issues. • Use in Special Circum stances: Drug or drug combinations in this category can be considered for use when intolerance or resistance prohibits use o f other drugs with fewer toxicity concerns or in women who have comorbidities or require concomitant medications that may limit drug choice, such as active tuberculosis requiring rifampin therapy. • Not Recom m ended: Drugs and drug combinations listed in this category are not recommended for therapy in pregnant women because o f inferior virologic response, potentially serious maternal or fetal safety concerns, or pharmacologic antagonism. • Insufficient D ata to Recom m end: The drugs and drug combinations in this category are approved for use in adults but lack pregnancy-specific PK or safety data, or such data are too limited to make a recommendation for use for pregnancy. A combination ARV regimen with at least three agents is recommended for use in pregnancy for either treatment or prophylaxis. Recommendations for choice o f ARV drug regimen during pregnancy must be individualized according to a pregnant woman's specific ARV history and the presence o f comorbidities. Some women may become pregnant and present for obstetrical care while receiving ART for their own health. In these cases, the choice o f active drugs with known safety data in pregnancy may be more lim ited. In general, women who are already on a fully suppressive regimen should continue their regimens. Use of efavirenz, however, should be avoided in the first trimester. Other HIV-infected women may not be receiving ART at the time they present for obstetrical care. Some women have never received ARV drugs, while others may have taken ARV drugs for treatment that was stopped or for prophylaxis to prevent perinatal transmission o f HIV in prior pregnancies or for pre-or post-exposure prophylaxis. Considerations for initiating therapy in pregnant women differ, depending upon whether ARV drugs are currently indicated for maternal health or solely for fetal protection. The following sections will provide detailed discussions o f recommendations based on maternal ARV history and whether there are maternal indications for therapy. For ARV-naive women, a combination regimen including two NRTIs and either an NNRTI or a PI (gen erally with low-dose ritonavir) would be preferred. Tenofovir is a preferred NRTI for nonpregnant women. Data from the Antiretroviral Pregnancy Registry on 1,092 pregnancies with first-trimester exposure to tenofovir have shown no increase in overall birth defects compared with the general population4. Animal studies, however, have shown decreased fetal growth and reduction in fetal bone porosity, and studies in infected children on chronic tenofovir-based therapy have shown bone demineralization in some children. Therefore, tenofovir would be considered an alternative NRTI during pregnancy for ARV-naive women. For pregnant women with chronic hepati tis B infection, however, tenofovir in combination with emtricitabine or lamivudine would be the pre ferred NRTI backbone o f a combination ARV regimen. The combination o f stavudine/didanosine should not be used in pregnant women because fatal cases o f lactic acidosis and hepatic failure have been re ported in women who received this combination throughout pregnancy. In addition to the two NRTIs, either an NNRTI or a PI would be preferred for combination regimens in ARV-naive pregnant women. Efavirenz, the preferred NNRTI for nonpregnant adults, is not recom mended for use in the first trimester because non-human primate data show risk o f anencephaly, micro ophthalmia, and cleft palate, and there are several concerning case reports o f neural tube defects and a single case o f anophthalmia with severe facial cleft in humans. Use o f efavirenz can be considered after the first trimester, based on clinical indication, but current data are limited in defining the safety o f this use. Nevirapine would be the preferred NNRTI for ARV-naive pregnant women with CD4 cell lympho cyte counts <250 cells/mm3, and it can be continued in ARV-experienced women already receiving a nevirapine-based regimen, regardless o f CD4 cell count. In general, nevirapine should not be initiated in treatment-naive women with CD4 cell counts >250 cells/mm3 because o f an increased risk o f sympto matic and potentially fatal rash and hepatic toxicity (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants). Elevated transaminase levels at baseline also may increase the risk o f nevirapine toxicity66. Safety and PK data on etravirine and rilpivirine in pregnancy are insufficient to recommend use o f these NNRTI drugs in ARV-naive women. Lopinavir/ritonavir is the preferred PI regimen for ARV-naive pregnant women, based on efficacy stud ies in adults and experience with use in pregnancy (see Table 5 for dosing considerations). Alternative PIs include ritonavir-boosted atazanavir or saquinavir, although experience is more limited with these regimens in pregnancy. Nelfinavir can be considered in special circumstances when used solely for pro phylaxis o f perinatal transmission in ARV-naive women for whom therapy would not otherwise be indi cated and who cannot tolerate alternative agents. PK data and extensive clinical experience do exist for nelfinavir in pregnancy, but the rate o f viral response to nelfinavir-based regimens was lower than lopinavir/ritonavir or efavirenz-based regimens in clinical trials o f initial therapy in nonpregnant adults. Indinavir can also be considered in special circumstances for women in whom preferred or alternative drugs cannot be used. Indinavir may be associated with renal stones and has a higher pill burden than many other PI drugs. Data on use in pregnancy are too limited to recommend routine use o f darunavir, fosamprenavir, and tipranavir in pregnant women, although they can be considered for women who are intolerant o f other agents. Safety and PK data in pregnancy are insufficient to recommend use o f the entry inhibitors enfuvirtide and maraviroc and the integrase inhibitor raltegravir during pregnancy. Use o f these agents can be con sidered for women who have failed therapy with several other classes o f ARV drugs after consultation with HIV and obstetric specialists. Although data are insufficient to support or refute the teratogenic risk o f ARV drugs when administered during the first trimester, information to date does not support major teratogenic effects for the majority o f such agents. (For further data, see http://www.APRegistry.com.) However, certain drugs are o f more concern than others-for example, efavirenz should be avoided during the first trimester o f pregnancy (see Supplement: Safety and Toxicity o f Individual Antiretroviral Drugs in Pregnancy). Table 5 provides recommendations for use o f specific ARV drugs in pregnancy and data on PKs and tox icity in pregnancy. Table 6 summarizes management recommendations for the mothers and infants in a variety o f clinical scenarios. # Clinical Scenario Recommendations Nonpregnant HIV-infected Initiate combination antiretroviral (ARV) drug therapy as per adult treatment guidelines. When women of childbearing po tential who have indications feasible, include one or more nucleoside reverse transcriptase inhibitors (NRTIs) with good placental passage as a component of the ARV regimen. for initiating antiretroviral therapy (ART) • Avoid drugs with teratogenic potential (e.g., efavirenz) in women who are trying to conceive or are not using adequate contraception. Exclude pregnancy and ensure access to effective (contraception before starting treatment with efavirenz. # HIV-infected women on com bination ARV drug therapy who become pregnant Women: • In general, in women who require treatment, ARV drugs should not be stopped during the first trimester or during pregnancy. • Continue current combination ART, if successfully suppressing viremia; however, avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the preg nancy. • Perform HIV ARV drug-resistance testing in women on therapy who have detectable viremia. • Continue combination ART regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally) and postpartum. • Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: • Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected pregnant women who are ARV naive and have indications for ART Women: • Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiating therapy if viral suppression is suboptimal. • Initiate combination ARV regimen. • Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy. • When feasible, include one or more NRTIs with good placental passage in the ARV regi men. • Use nevirapine as a component of the ARV regimen only in women who have CD4 counts <250 cells/mm3. Because of the increased risk of severe hepatic toxicity, use nevirapine in women with CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk. • In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester. • Continue the combination regimen during the intrapartum period (zidovudine given as con tinuous infusion3 during labor while other ARV agents are continued orally) and postpartum. • Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: • • Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiation of therapy if viral suppression is suboptimal. • Prescribe combination ARV drug prophylaxis (i.e., at least 3 drugs) to prevent perinatal transmission. • Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV. • Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy. • When feasible, use one or more NRTIs with good transplacental passage as a component of the ARV regimen. • Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity. • Continue ARV prophylaxis regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally). • Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant individuals (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half life, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), consider stopping NRTIs at least 7 days after stopping NNRTI. (See Stopping Antiretroviral Therapy Drugs Dur ing Pregnancy and Prevention of Antiretroviral Drug Resistance.) • Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: ■ Start zidovudine as soon as possible after birth and administer for 6 weeks.1 # Clinical Scenario Recommendations HIV-infected pregnant women who are ARV experi enced but not currently re ceiving ARV drugs Women: • Obtain full ARV drug history, including prior resistance testing, and evaluate need for ART for maternal health. • Test for HIV ARV drug resistance before re-initiating ARV prophylaxis or therapy and retest after initiating combination ARV regimen if viral suppression is suboptimal. • Initiate a combination ARV regimen (e.g., at least 3 drugs), with regimen chosen based on results of resistance testing and history of prior therapy. • In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester. • Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV. • Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for the mother (e.g., combination stavudine/didanosine) throughout the pregnancy. • When feasible, include one or more NRTIs with good transplacental passage as a compo nent of the ARV regimen. • Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity. • Continue the combination regimen during intrapartum period (zidovudine given as continu ous infusiona during labor while other ARV agents are continued orally). • Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant adults (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half-life, such as NNRTIs, consider stopping NRTIs at least 7 days after stopping NNRTIs. (See Stopping Anti retroviral Therapy and Prevention of Antiretroviral Drug Resistance.) • Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infants: • Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected women who have received no ART before labor Women: Give zidovudine as continuous infusion1 during labor. Infants: Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is pre ferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9). • Evaluate need for initiation of maternal therapy postpartum. # Clinical Scenario Recommendations Infants born to HIV-infected women who have received no ART before or during labor Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9). • Evaluate need for initiation of maternal therapy postpartum. a Zidovudine continuous infusion: 2 mg/kg zidovudine intravenously over 1 hour, followed by continuous infusion of 1 mg/kg/hour until delivery. b Zidovudine dosing for infants >35 weeks' gestation at birth is 4 mg/kg/dose orally twice daily; for infants <35 weeks of gesta tion at birth is 1.5 mg/kg/dose intravenously or 2.0 mg/kg/dose orally, every 12 hours, advancing to every 8 hours at 2 weeks of age if >30 weeks of gestation at birth or at 4 weeks of age if <30 weeks' gestation at birth. # 2. Centers for Disease Control and Prevention C. Guidelines for vaccinating pregnant women, Available at: http://www.cdc.gov/vaccines/pubs/downloads/b preg guide.pdf. Atlanta, GA, 2007. 5) (AI). • For women who require immediate initiation of therapy for their own health, treatment should be started as soon as possible, including in the first trimester (AII). (Note that the use of efavirenz should be avoided during the first trimester.) • A three-drug combination ARV regimen for prophylaxis of perinatal transmission also is recommended for HIV-infected pregnant women who do not require treatment for their own health (AII). • Consideration can be given to delaying initiation of prophylaxis until after the first trimester (BIII) in women who are receiving ARV drugs solely for prevention of perinatal transmission, but earlier initiation of therapy may be more ef fective in reducing in utero transmission. • ARV regimens should include a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs with high levels of transplacental passage, if possible, to provide pre-exposure prophylaxis to the infant (AIII). # • If HIV RNA is above the threshold for resistance testing (i.e., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting the ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If HIV is diagnosed late in pregnancy, the ARV drug regimen should be initiated pending results of re sistance testing (BIII). • Nevirapine can be used as a component of the ARV drug regimen for pregnant women with CD4 cell counts <250 cells/mm3. In pregnant women with CD4 cell counts >250 cells/mm3, however, nevirapine should be used only if the ben efit clearly outweighs the risk because the drug is associated with an increased risk of hepatic toxicity (AII). Pregnant women with HIV infection should receive standard clinical, immunologic, and virologie evalu ation. Decisions about the need for initiation of therapy should be based on the standard guidelines for nonpregnant adults1. # H IV-Infected Pregnant Women N ot on Antiretroviral Therapy and Who N eed Antiretroviral Treatment fo r Their Own Health Any HIV-infected pregnant woman who meets standard criteria for initiation o f ART as per ARV guide lines in nonpregnant adults should receive potent combination ART, generally consisting o f NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI), with continuation of therapy postpartum. Treatment should be started as soon as possible-including in the first trimesterfor women who require immediate initiation o f therapy for their own health because the potential benefit o f treatment for the mother outweighs potential risks to the fetus. The regimen generally should be cho sen from among those shown to be effective in nonpregnant adults, taking into account what is known about use o f the drugs during pregnancy and risk o f teratogenicity (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy)1. A review o f a large database o f nevirapine studies indicated that women with CD4 counts >250 cells/mm3 have an increased risk o f developing symptomatic, often rash-associated, nevirapine-related hepatotoxicity that can be severe, life threatening, and in some cases fatal2-3. A more recent study involv ing 820 women in Kenya, Zambia, and Thailand, however, did not find an association between CD4 count and development o f hepatotoxicity4. Rash and liver toxicity were associated with elevated baseline liver transaminases but not with CD4 count; all deaths from hepatic toxicity occurred in women with CD4 counts <100 cells/mm3 at baseline. In women with CD4 counts >250 cells/mm3, nevirapine should be used as a component o f a combination regimen only when the benefit clearly outweighs the risk. If nevirapine is used, frequent and careful monitoring o f transaminase levels is required, particularly dur ing the first 18 weeks o f treatment (see Nevirapine and Hepatic/Rash Toxicity). Transaminase levels should be checked in women who develop a rash while receiving nevirapine. Nevirapine should be stopped immediately in women who develop signs or symptoms o f hepatitis. # H IV-Infected Pregnant Women N ot on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f H IV HIV-infected pregnant women should be counseled regarding the benefits o f ARV drugs for prevention o f perinatal transmission even when initiation o f ART for maternal health is not recommended or is con sidered optional on the basis o f current guidelines for treatment o f nonpregnant persons1. Although such women are at low risk o f clinical disease progression if ARV treatment is delayed, use o f an ARV regi men that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission o f HIV and lessens the need for consideration o f elective cesarean delivery as an intervention to reduce risk o f transmission. The fetus is most susceptible to the potential teratogenic effects o f drugs during the first trimester and the risks o f ARV drug exposure during that period are not fully known. Therefore, women in the first trimester of pregnancy who do not require immediate initiation o f therapy for their own health may con sider delaying initiation o f ARV drugs until after 12 weeks o f gestation. This decision should be care fully considered by the health care provider and the woman. Their discussion should encompass an assessment of the wom an's health status, the benefits and risks to her o f delaying initiation o f ARV drugs for several weeks, the fact that most perinatal transmission o f HIV events occur late in pregnancy or during delivery, and the possibility that early control o f viral replication may be important in prevent ing the smaller proportion o f earlier in utero transmission. In a recent French study, lack o f early and sustained control o f maternal viral load appeared strongly associated with residual perinatal transmission o f HIV5. That study evaluated risk factors for perinatal transmission in women with HIV RNA <500 copies/mL at the time of delivery; overall HIV transmission was 0.5%. Women who transmitted were less likely to have received ARV drugs at the time o f conception than were nontransmitters and were less likely to have HIV RNA <500 copies/mL at 14, 28, and 32 weeks o f gestation. Among women starting ARV drugs during pregnancy, the gestational age at initiation o f therapy did not differ between groups (30 weeks), but viral load decreased earlier in the nontransmitters. These data suggest that early and sus tained control o f HIV viral replication is associated with decreasing residual risk o f transmission and favor initiating ARV drugs as early in pregnancy as possible for all women. ARV prophylaxis is recommended for all pregnant women with HIV infection, regardless o f viral load. Although rates o f perinatal transmission are low in women with undetectable or low HIV RNA levels, there is no threshold below which lack o f transmission can be assured6-8. The mechanism by which ARV drugs reduce perinatal HIV transmission is multifactorial. Although lowering maternal antenatal viral load is an important component o f prevention in women with higher viral load, ARV prophylaxis is ef fective even in women with low viral load9-13. Additional mechanisms o f protection include pre-exposure prophylaxis and post-exposure prophylaxis o f the infant. With pre-exposure prophylaxis, passage o f the ARV drug across the placenta results in presence o f drug levels sufficient for inhibition o f viral replica tion in the fetus, particularly during the birth process when there is intensive viral exposure. With post exposure prophylaxis, ARV drugs are administered to the infant after birth. Transplacental passage is excellent with zidovudine but may be variable with many other ARV drugs (Table 4). Therefore, when ever possible, combination ARV drug regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, stavudine, tenofovir, or abacavir (see Table 5)14-17. All pregnant women with HIV infection should be counseled about and offered combination ARV regi mens containing at least three drugs for prevention o f perinatal transmission o f HIV. In an analysis of perinatal transmission in 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overall mother-to-child transmission rate was 1.2%. A transmission rate o f 0.8% was seen in women on ARV drugs for at least the last 14 days o f pregnancy, regardless o f the type o f ARV regimen or mode o f delivery18. Transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with a planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women who received single-drug prophylaxis with zidovudine combined with a planned cesarean delivery (as recommended in the British HIV Association guidelines for women with HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health)19, not significantly dif ferent between groups. After adjustment for viral load, mode o f delivery, and sex o f the infant, longer duration o f use o f ARV drugs was associated with reduced transmission rates. A combination regimen including two NRTIs and either an NNRTI or a PI (the latter with or without lowdose ritonavir) would be the preferred prophylactic regimen for ARV-naive women receiving drugs solely for prevention of transmission, as discussed in Recommendations for Use of Antiretroviral Drugs during Pregnancy. A study in Botswana compared a PI-based triple-drug regimen to a triple-NRTI (zidovudine/lamivudine/abacavir) combination regimen for prevention of transmission in breastfeeding women with CD4 counts >200 cells/mm3 20. Both regimens had similar rates of viral suppression by deliv ery (96% receiving the PI regimen and 93% receiving the triple-NRTI regimen had HIV RNA <400 copies/mL) and perinatal transmission (0.4% and 1.4%, respectively, not significantly different). Thus, for women who plan to discontinue prophylaxis following delivery, a triple-NRTI regimen also can be consid ered. If using abacavir, testing for HLA-B5701, which identifies patients at risk of abacavir hypersensi tivity reactions21-22, should be performed and the results documented as negative before abacavir is started. Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk o f HIV transmis sion to the infant. Use o f zidovudine alone during pregnancy for prophylaxis o f perinatal transmission is not optimal, but it could be an option for women with low viral loads (i.e., HIV RNA <1,000 copies/mL) on no ARV drugs. Time-limited administration o f zidovudine during the second and third trimesters of pregnancy is less likely to induce the development o f resistance in women with low viral loads than in those with higher viral loads. This lower rate o f resistance is likely because o f the low level o f viral replication and the short duration o f exposure23-24. Following delivery, considerations regarding continuation o f the ARV regimen for treatment o f the mother are the same as for other nonpregnant adults (see General Principles for Use o f Antiretroviral Drugs during Pregnancy). # HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Treatment (Updated September 14, 2011) Panel's Recommendations • In general, pregnant women receiving and tolerating an antiretroviral therapy (ART) regimen that is currently effective in suppressing viral replication should continue on the regimen; however, the use of efavirenz should be avoided in the first trimester (AIII). • HIV antiretroviral (ARV) drug-resistance testing is recommended for pregnant women who have detectable viremia (e.g., >500-1,000 copies/mL) on therapy (see Failure of Viral Suppression) (AI). • Pregnant women receiving and tolerating nevirapine-containing regimens who are virologically suppressed should con tinue the regimen, regardless of CD4 count (AIII). In general, women who have been receiving antiretroviral treatment (ART) for their HIV infection should continue that treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of HIV transmission. Continuation of therapy, therefore, is recom mended when pregnancy is identified in HIV-infected women receiving ART. HIV-infected women receiving ART who present for care during the first trimester should be counseled re garding the benefits and potential risks of administration of ARVs during this period. Clinicians should re view the safety and risk/benefit profiles and reproductive considerations for the ARV agents used in the current HIV therapeutic regimen. The use of efavirenz should be avoided during the first trimester of preg nancy. If a first-trimester pregnancy is confirmed in a woman who is receiving efavirenz, an alternative ARV drug should be substituted when possible (see Monitoring of the Woman and Fetus during Pregnancy). Resistance testing should be performed in women who are on therapy but in whom viral replication is not fully suppressed. The results can be used to select a new regimen with a greater likelihood of suppressing viral replication to undetectable levels. It should be noted that resistance assays vary depending on the HIV RNA level required to detect resistance mutations. Some assays require HIV RNA levels of >500-1,000 copies/mL; other assays can be performed on patients with lower viral loads. Pregnant women for whom nevirapine-containing regimens are achieving viral suppression and who are tolerating therapy should continue that regimen, regardless of current CD4 count. Although hepatic toxic ity is a concern in women starting a nevirapine-containing regimen who have CD4 counts >250 cells/mm3, an increased risk of hepatic toxicity has not been seen in women receiving nevirapine-based therapy for whom the therapy has produced immune reconstitution. # HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications (Updated September 14, 2011) Panel's Recommendations • Obtain an accurate history of all prior antiretroviral (ARV) regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, tolerance to the medications, results of prior resistance testing, and any adher ence issues (AIII). • If HIV RNA is above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting an ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) # (AIII). In women who present late in pregnancy, therapy or prophylaxis should be initiated pending results of resistance test ing (BIII). • Choose and initiate a combination ARV drug regimen based on results of resistance testing and prior history of antiretro viral therapy (ART) while avoiding drugs with teratogenic potential (efavirenz in the first trimester of pregnancy) or with known adverse potential for the mother (AII). • Consult specialists in treatment of HIV infection about the choice of ART in women who previously received ARVs for their own health (AIII). • Perform repeat ARV drug-resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guide changes in ARV drugs in women do not achieve virologic suppression on their ARV regimens (see Monitoring of the Woman and Fetus During Pregnancy). During a previous pregnancy, HIV-infected women may have received ARV drugs solely for prevention of perinatal transmission. At any time in the past, they also may have discontinued ARVs given to them for treatment of their own disease. A small number of clinical trials or observational studies have generated information about how effective ART is in individuals who previously received ARV prophylaxis. The data are limited to outcomes with therapy containing nevirapine initiated after the use of peripartum sin gle-dose nevirapine1-5. Initial reports suggested a diminished virologic and clinical response to nevirapine-based ART if therapy was initiated within 6 months o f intrapartum single-dose nevirapine exposure1-3. Subsequent reports have confirmed that a shorter interval between intrapartum single-dose nevirapine exposure and therapy initiation is associated with decreased efficacy o f therapy and suggested that the diminished response may persist 12-24 months following exposure4-5. In addition, the subsequent failure o f non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART after single-dose nevirapine has been associated with lower CD4 count and higher HIV-RNA plasma concentration at the time o f single-dose nevirapine expo sure, and genotypic resistance to nevirapine. Adding other ARVs to single-dose nevirapine (e.g., use of an ARV "tail") decreases rates o f nevirapine resistance6-7 (see Antiretroviral Drug Resistance and Resist ance Testing in Pregnancy), but the effect on clinical response to the subsequent initiation o f NNRTIbased ART is unknown. There is concern that time-limited use o f ARV drugs during pregnancy for prophylaxis o f perinatal trans mission may lead to genotypic resistance and thus reduced efficacy o f the ARV drugs when used for treatment. Rates o f resistance appear to be low, based on standard genotyping, after prophylaxis for pre vention o f perinatal transmission with combination ARVs consisting o f zidovudine, lamivudine, and nevirapine8-9. However, particularly in women whose virus was inadequately suppressed during the pe riod o f prophylaxis, minority populations o f virus with resistance to nevirapine or lamivudine have been detected using sensitive allele-specific polymerase chain reaction (PCR) techniques9-11. Only limited data are available on the impact o f these resistance-conferring minority variants on prediction o f viro logic or clinical failure o f subsequent ART, and the PCR-based assays are not widely available. Both standard and sensitive genotyping techniques appear to show a low rate o f resistance to protease in hibitors (PIs) after pregnancy-limited use o f Pi-based combination ARV regimens for prophylaxis, but these results reflect assessments in only small numbers o f women11-12. However, to date, treatment fail ure has not been demonstrated with reinitiation o f combination ARV regimens (particularly those con taining the dual nucleoside reverse transcriptase inhibitor [NRTI] backbone o f zidovudine and lamivudine) following prophylactic use in pregnancy for prevention o f transmission, although controlled observations are lacking. Given the lack o f substantive data, it is reasonable to use results o f initial resistance testing, if available, to make preliminary decisions about ARV regimens in women whose only previous exposure to ARVs was during pregnancy for prophylaxis o f perinatal transmission. However, interpretation o f resistance testing following discontinuation o f ARV drugs can be complex because drug-resistance testing is most accurate if performed while an individual is taking the ARV regimen or within 4 weeks o f treatment dis continuation. In the absence o f selective drug pressure, resistant virus may revert to wild-type virus, and although detection o f drug-resistance mutations is informative for choosing a regimen, a negative find ing does not rule out the presence o f archived drug-resistant virus that could re-emerge once drugs are reinitiated. Therefore, when selecting a new regimen for use during the current pregnancy, all informa tion from the previous pregnancy-including regimens received, viral response, laboratory testing (in cluding HLA-B5701 results), and any tolerance or adherence issues-as well as the results of resistance testing should be taken into consideration. If the woman presents late in pregnancy, therapy or prophylaxis should be initiated pending results o f resistance testing. Careful monitoring o f virologic re sponse to the chosen ARV regimen is important. If the chosen regimen produces an insufficient viral response, decisions about switching regimens should be guided by repeat resistance testing and assessment o f medication adherence. These measures should be undertaken in consultation with an HIV treatment specialist. Some women who receive ART for their own health choose to discontinue the drugs for a variety o f rea sons, and the length of time between treatment termination and pregnancy may vary. In these cases, careful clinical and laboratory assessments are necessary before therapy is reinitiated during pregnancy. The evaluations should include a review o f a woman's prior history o f virologic response and medica tion toxicity as well as her adherence to therapy. The appropriate choice o f ARV regimen to be initiated during pregnancy will vary according to a woman's history o f ART; the indication for stopping therapy; the effect o f prior therapy on clinical, virologic, and immunologic status; and the results o f past and cur rent testing for resistance and for HLA-B5701. It may be possible, for example, to restart the same reg imen in women with a history o f prior ART associated with successful suppression o f viral load who then stopped all drugs simultaneously (or staggered discontinuation if NNRTI based) and who have no evidence of resistance. On the other hand, the selection o f an appropriate ARV regimen may be challeng ing even for health care providers experienced in HIV care in women with advanced HIV disease, a his tory o f extensive prior ART, or previous significant toxicity or nonadherence to ARV drugs. In such cases, restarting the prior regimen for a week or two before performing a resistance assay may yield more accurate results. In addition to obtaining genotypic resistance testing, it is strongly recommended that specialists in the treatment o f HIV infection be consulted early during the pregnancy about the choice o f suitable ART. Special Situations -HIV/Hepatitis B Virus Coinfection (Updated September 14, 2011) Panel's Recommendations • Screening for hepatitis B virus (HBV) infection is recommended for all pregnant women who have not been screened during the current pregnancy (AII). • The HBV vaccine series should be administered to pregnant women who screen negative for hepatitis B (i.e., hepatitis B surface antigen negative, hepatitis B core antibody negative, and hepatitis B surface antibody negative) (AII). • Pregnant women with chronic HBV infection should be screened for antibodies to hepatitis A virus (HAV), and those who screen negative should receive the HAV vaccine series (AII). • Interferon alfa and pegylated interferon alfa are not recommended during pregnancy (AIII). • The management of HIV/HBV coinfection in pregnancy is complex and consultation with an expert in HIV and HBV is strongly recommended (AIII). • All pregnant women with HIV/HBV coinfection should receive a combination antiretroviral (ARV) drug regimen, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue reverse transcriptase inhibitor (NtRTI) back bone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI). • If ARV drugs are discontinued postpartum in women with HIV/HBV coinfection, frequent monitoring of liver function tests for potential exacerbation of HBV infection is recommended, with prompt reinitiation of treatment for both HIV and HBV if a flare is suspected (BIII). • Pregnant women with HIV/HBV coinfection receiving ARV drugs should be counseled about the signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter (BIII). • Within 12 hours of birth, infants born to women with HBV infection should receive hepatitis B immune globulin (HBIG) and the first dose of the HBV vaccine series. The second and third doses of vaccine should be administered at ages 1 and 6 months, respectively (AI). All HIV-infected pregnant women should be screened for hepatitis A, B, and C. The management of HIV/HBVcoinfection in pregnancy is complex and consultation with an expert in HIV and HBV infection is strongly recommended. HIV-infected women who are found to have chronic HBV infection on the basis of persistent hepatitis B surface antigenemia for at least 6 months and who are hepatitis A immunoglobulin G (IgG) negative should receive the HAV vaccine series because of the added risk of acute hepatitis A in persons with chronic viral hepatitis. HIV-infected pregnant women who test negative for hepatitis B surface antibody and hepatitis B surface antigen should receive the HBV vaccine series. A positive test for hepatitis B core antibody alone can be a false-positive result, or it may signify past exposure with subsequent loss of hepatitis B surface antibody, or "occult" HBV infection, which can be confirmed by detection of HBV DNA3-4. The clinical significance of isolated hepatitis B core antibody is unknown5-6. Some experts recommend that HIV-infected persons with hepatitis B core antibody alone should be tested for HBV DNA before vaccination for HBV or before treat ment or prophylaxis with ARV drugs is initiated because of the risk of a paradoxical exacerbation of HBV and the occurrence of immune reconstitution inflammatory syndrome (IRIS)2. An ARV regimen that includes drugs active against both HIV and HBV is recommended for all individuals with HIV/HBV coinfection who require HBV treatment or who are starting ARV drugs, including pregnant women. Initiation of an ARV regimen that does not include anti-HBV drugs may be associated with reacti vation of HBV and development of IRIS; IRIS-related flare of HBV activity during pregnancy can occur even among women with relatively high CD4 cell counts at the time of ARV initiation. In addition, use of ARV drugs with anti-HBV activity during pregnancy lowers HBV viremia, potentially increasing the effi cacy of neonatal HBIG and hepatitis B vaccine in prevention of perinatal transmission of HBV. High mater nal HBV DNA levels are strongly correlated with perinatal HBV transmission and with failures of HBV passive-active immunoprophylaxis7-9. Several small studies suggest that lamivudine or telbivudine may re duce the risk of perinatal transmission of HBV if given during the third trimester to HBV-infected, HIVseronegative women with high HBV DNA viremia10-13. Although a high HBV viral load clearly is important, it is, however, not the only factor predisposing to failure of prophylaxis14. Because lamivudine, tenofovir, and emtricitabine have activity against both HIV and HBV, the recom mended dual-NRTI/NtRTI backbone for HIV/HBV-coinfected individuals, including pregnant women, is tenofovir/emtricitabine or tenofovir/lamivudine. Lamivudine has been extensively studied and is recom mended for use in pregnancy (Table 5). The Antiretroviral Pregnancy Registry includes reports on the out comes of 3,864 pregnancies that involved administration of lamivudine in the first trimester and there is no indication that the exposure was associated with an increased risk of birth defects15. Similarly, no increase in birth defects has been noted in 641 cases of first-trimester exposure to emtricitabine, which is an alterna tive NRTI for use in pregnancy (Table 5). Tenofovir is not teratogenic in animals, but reversible bone changes at high doses have been seen in multiple animal species. A total of 1,092 cases of first-trimester ex posure have been reported to the Antiretroviral Pregnancy Registry, with no increase in birth defects noted15. Although tenofovir is recommended as an alternative NtRTI during pregnancy for ARV-naive women, it is a preferred NtRTI in women with HIV/HBV coinfection (Table 5). Several other antivirals with activity against HBV, including entecavir, adefovir, and telbivudine, have had minimal evaluation in pregnancy. Entecavir is associated with skeletal anomalies in rats and rabbits but only at doses high enough to cause toxicity to the mother. No data are available on use of entecavir and ade fovir in human pregnancy. Telbivudine was given to 95 HBV-positive, HIV-negative women during the third trimester and was well tolerated13. Each of these anti-HBV drugs should be administered only in addi tion to a fully suppressive regimen for HIV. Because these other anti-HBV drugs also have weak activity against HIV, they may select for anti-HIV drug resistance in the absence of a fully suppressive ARV regi men as well as potential cross resistance to other ARV drugs. (Entecavir, for example, can select for the M184V mutation, which confers HIV resistance to lamivudine and emtricitabine.) These drugs should be used during pregnancy only if the preferred drugs are not appropriate in specific cases. Cases of exposure during pregnancy to any of the ARV drugs and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com). Interferon alfa and pegylated interferon alfa are not recommended for use in pregnancy and should be used only if the potential benefits outweigh the potential risks. Although interferons are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents16. Following initiation of ARV drugs, an elevation in hepatic enzymes can occur in HIV/HBV-coinfected women-particularly those with low CD cell counts at the time of treatment initiation-as a result of an immune-mediated flare in HBV disease triggered by immune reconstitution with effective HIV therapy. HBV infection also can increase hepatotoxic risk of certain ARV drugs, specifically protease inhibitors (PIs) and nevirapine. Pregnant women with HIV/HBVcoinfection should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter. If hepatic toxicity occurs, it may be necessary to consider substituting a less hepatotoxic regimen or, if clinical symptoms or significant elevations of transaminases occur, drugs may need to be temporarily discontinued. Differentiating between a flare in HBV disease due to immune reconstitu tion and drug toxicity often can be difficult, and consultation with an expert in HIV and HBV coinfection is strongly recommended. Because tenofovir has potential to cause renal toxicity, kidney function also should be monitored regularly in women receiving this drug, based on toxicity seen in nonpregnant adults. Panel's Recommendations • Screening for hepatitis C virus (HCV) infection is recommended for all HIV-infected pregnant women who have not been screened during the current pregnancy (AIII). • Interferon alfa and pegylated interferon alfa are not recommended and ribavirin is contraindicated during pregnancy (AIII). • Recommendations for antiretroviral (ARV) drug use during pregnancy are the same for women who have chronic HCV as for those without HIV/HCV coinfection (BIII). • Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and then every 3 months thereafter (BIII). Tn a majority o f studies. the incidence o f HCV transmission from mother to infant increases if the mother is coinfected with HTV. with transmission rates between 10% and 20%7-10. These higher transmis sion rates are likely related to an increase in HCV viremia and/or other HTV-related impact on HCV dis ease activity11. Special Situations -HIV-2 Infection and Pregnancy (Updated September 14, 2011) Panel's Recommendations • HIV-2 infection should be suspected in pregnant women who are from-or have partners from-countries in which the disease is endemic, who are HIV antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot and an HIV-1 RNA viral load at or below the limit of detec tion (BII). • A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor (PI) currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have signifi cant clinical disease or CD4 counts <500 cells/mm3 (AIII). • Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred (AIII). Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative (BIII). • Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatment for their own health (i.e., CD4 counts >500 cells/mm3 and no significant clinical disease). Experts have recommended the following approaches: • A boosted PI-based regimen (two NRTIs plus lopinavir/ritonavir) for prophylaxis, with the drugs stopped postpartum (BIII); • Zidovudine prophylaxis alone during pregnancy and intrapartum (BIII). • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis (AIII). • All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen (BIII). • In the United States, breastfeeding is not recommended for infants of HIV-2-infected mothers (AIII). HIV-2 infection is endemic in Angola; Mozambique; West African countries including Cape Verde, Ivory Coast, Gambia, Guinea-Bissau, Mali, Mauritania, Nigeria, Sierra Leone, Benin, Burkina Faso, Ghana, Guinea, Liberia, Niger, Nigeria, Sao Tome, Senegal, and Togo; and in parts o f India1-3. It also oc curs in countries such as France and Portugal, which have large numbers o f immigrants from these re gions4. HIV-2 is rare in the United States. HIV-2 infection should be suspected in pregnant women who are from-or who have partners from-countries in which the disease is endemic, who are HIV-1 anti body positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeter minate results on HIV-1 Western blot and HIV-1 RNA viral loads at or below the limit o f detection5-6. This pattern o f HIV testing can also be seen in patients who have a false-positive HIV-1 test. The majority of commercially available HIV screening tests can detect both HIV-1 and HIV-2 but cannot distinguish between the two viruses. The only Food and Drug Administration (FDA)-approved antibody test that distinguishes between HIV-1 and HIV-2 is the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test. If HIV-2 is suspected, infection can be confirmed using a supplemental test such as an HIV-2 immunoblot or HIV-2-specific Western blot. HIV-2 immunoblots are available through commercial labs; however, none is FDA approved for HIV-2 diagnosis. HIV-2-specific Western blots can be requested through state health departments. HIV-2 viral load assays currently are not commercially available in the United States. The National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites that perform these tests. HIV-2 has a longer asymptomatic phase than HIV-1, with a slower progression to AIDS. The most com mon mode of HIV-2 transmission is through heterosexual sex. HIV-2 is less infectious than HIV-1, with a 5-fold lower rate o f sexual transmission and 20-to 30-fold lower rate o f vertical transmission3, 7-8. Sev eral studies confirm that rates o f mother-to-child transmission o f HIV-2 are low with and without inter ventions (0% -4%), which may be a result o f reduced plasma viral loads and less cervical viral shedding, compared with that seen in HIV-1-infected women9-12. HIV-2 also can be transmitted through breastfeed ing. HIV-2 infection does not protect against HIV-1 and dual infection, which carries the same prognosis as HIV-1 monoinfection, can occur. Few data exist on which to base treatment decisions or strategies for prevention o f mother-to-child trans mission in patients infected with HIV-2. NNRTIs and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis13-14. HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir having the most activity against the virus15. The integrase inhibitors raltegravir and elvitegravir also appear to be effective against HIV-23, 16-17. The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with two NRTIs and a boosted PI currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 counts <500 cells/mm318. Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred. Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative19-20. NNRTIs should not be used because they are not active against HIV-2. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen. For HIV-2-infected pregnant women with CD4 counts >500 cells/mm3 and no significant clinical dis ease, who do not require treatment for their own health, some experts would use a boosted PI-based reg imen for prophylaxis and stop the drugs postpartum. Other experts would consider zidovudine prophylaxis alone during pregnancy and intrapartum10. Because HIV-2 has a significantly lower risk of mother-to-child transmission than does HIV-1, single-drug prophylaxis with zidovudine alone can be considered for prevention o f mother-to-child transmission. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen20. The possible risks and benefits o f antiretroviral (ARV) prophylaxis should be discussed with the mother. Pregnant women who have HIV-1/HIV-2 coinfection should be treated according to the guidelines for HIV-1-monoinfected patients, making sure that the ARV regimen chosen is also appropriate for HIV-2. Other than the standard obstetrical indications, no data exist regarding the role o f elective cesarean de livery in women who are infected with HIV-2. The risk to the infant from breastfeeding is lower for HIV-2 than for HIV-1, but breastfeeding should be avoided in the United States and other resource-rich countries where safe infant formula is readily available10. Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologic assays at time points similar to those used for HIV-1 testing21. • Repeat HIV antibody testing in the third trimester is recommended for pregnant women with initial negative HIV antibody tests who are known to be at risk of HIV, are receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1,000 per year, are incarcerated, or reside in jurisdictions with elevated rates of HIV infection (see Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings) (AII). • All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) drug regimen as soon as possible to prevent mother-to-child transmission, with the goal of suppressing plasma HIV RNA to below de tectable levels (AI). • In women with acute HIV infection, baseline genotypic resistance testing should be performed simultaneously with initia tion of the ARV regimen, and the ARV regimen should be adjusted, if necessary, to optimize virologic response (AIII). An estimated 40%-90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms4, 6-10. Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses and individuals with the condition also can be asymptomatic. When acute retroviral syndrome is suspected, a plasma HIV RNA test typically is used in conjunction with an HIV antibody test to diagnose acute infection. A low-positive HIV RNA level (<10,000 copies/mL) may represent a false-positive test because values in acute infection generally are very high (>100,000 copies/mL)4, 10. In individuals infected with non-B HIV-1 subtypes, however, HIV RNA levels may be lower, even with acute infection, because those subtypes may not amplify as well as subtype B. In that sit uation, consultation with an HIV treatment specialist is recommended. Confirmatory serologic testing should be performed within 3 months on patients whose acute HIV infection is diagnosed with virologic testing but who are antibody negative or whose antibody levels cannot be determined. Acute HIV infection also can be detected by repeat HIV antibody testing later in pregnancy in women whose initial HIV antibody testing earlier in pregnancy was negative. A report from the Mother-Infant Rapid Intervention at Delivery (MIRIAD) study found that 6 (11%) o f 54 women whose HIV was iden tified with rapid HIV testing during labor had primary infection11. Repeat HIV testing in the third trimester is recommended for pregnant women known to be at risk o f HIV who receive care in facilities with an HIV incidence o f at least 1 case per 1,000 pregnant women per year, who are incarcerated, or who reside in jurisdictions with elevated HIV incidence (see Revised Recommendations for HIV Testing o f Adults, Adolescents, and Pregnant Women in Health-Care Settings) 12. Whether treatment o f acute or recent HIV infection results in long-term virologic, immunologic, or clini cal benefit is unknown, and in nonpregnant adults, therapy currently is considered optional13. In preg nant or breastfeeding women, however, acute or recent HIV infection is associated with a high risk of perinatal transmission o f HIV. All HIV-infected pregnant women with acute or recent infection should start a combination ARV regimen as soon as possible, with the goal o f preventing perinatal transmission by optimal suppression o f plasma HIV RNA below detectable levels. Data from the United States and Europe demonstrate that in 6% -16% o f patients, transmitted virus may be resistant to at least one ARV drug14-16. Therefore, baseline genotypic resistance testing should be performed to guide selection or ad justment of an optimal ARV drug regimen. If results o f resistance testing or the source virus's resistance pattern are known, that information should be used to guide selection o f the drug regimen, but initiation o f the ARV regimen should not be delayed. Because clinically significant resistance to PIs is less com mon than resistance to NNRTIs in ARV-naive persons, a PI-based ARV drug regimen generally should be initiated. Choice o f regimen should be based on recommendations for use o f ARV drugs in pregnancy (see Table 5). Following delivery, considerations regarding continuation o f the ARV regimen for treat ment are the same for the mother as for other nonpregnant individuals. When acute HIV infection is diagnosed during pregnancy, and particularly if it is documented in late preg nancy, cesarean delivery is more likely to be necessary because there may be insufficient time to fully sup press the patient's viral load. In nursing mothers in whom seroconversion is suspected, breastfeeding should be interrupted and it should not resume if infection is definitively confirmed (see Breastfeeding In fants of Mothers Diagnosed with HIV Infection in Infant Antiretroviral Prophylaxis). In such a situation, consultation with a pediatric HIV specialist regarding appropriate infant management is recommended. All women who are pregnant or breastfeeding should be counseled about prevention o f HIV acquisition. Several studies suggest that pregnancy may be a time o f increased risk o f transmission o f HIV17-19, even when controlling for sexual risk behaviors17. It is hypothesized that the heightened risk may be attributa ble to hormonal changes that affect the genital tract mucosa or immune responses17. Although no reliable data on HIV serodiscordance rates in the United States exist, data on women from sub-Saharan Africa show that women in serodiscordant relationships may be particularly vulnerable to acquisition o f HIV20. HIV testing o f the sexual partners o f pregnant women should be encouraged. The importance o f using condoms should be reinforced in pregnant women who may be at risk o f acquisition o f HIV, including those whose partners are HIV-infected. Special Situations -Stopping Antiretroviral Drugs during Pregnancy (Updated September 14, 2011) # Panel's Recommendations HIV-infected women receiving antiretroviral treatment (ART) who present for care during the first trimester should con tinue treatment during pregnancy (AII). Women who present in the first trimester on an efavirenz-containing regimen should continue on therapy without interruption but, when possible, an alternative antiretroviral (ARV) drug should be substituted for efavirenz (AIII). • If an ARV drug regimen is stopped acutely for severe or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses that preclude oral intake, all ARV drugs should be stopped and reinitiated at the same time (AIII). • If an ARV drug regimen is being stopped electively and the patient is receiving a non-nucleoside reverse transcriptase in hibitor (NNRTI) drug, consideration should be given to either: (1) stopping the NNRTI first and continuing the other ARV drugs for a period of time; or (2) switching from an NNRTI to a protease inhibitor (PI) before interruption and continuing the PI with the other ARV drugs for a period of time before electively stopping. The optimal interval between stopping an NNRTI and the other ARV drugs is unknown; at least 7 days is recommended. Given the potential for prolonged de tectable efavirenz concentrations for more than 3 weeks in patients receiving efavirenz-based therapy, some experts rec ommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days (CIII). • If nevirapine is stopped and more than 2 weeks have passed before restarting therapy, nevirapine should be restarted with the 2-week dose escalation period (AII). Discontinuation of ARV drug regimens during pregnancy may be indicated in some situations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive to antiemetics, acute illnesses or planned surgeries that preclude oral intake, lack of available medication, or at patients' request. HIV-infected women receiving ART who present for care during the first trimester o f pregnancy should continue treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of transmission of HIV. A recent analysis from a prospective cohort of 937 HIV-infected mother-child pairs found that interruption of ART during pregnancy, including interruption in the first and third trimesters, was independently associated with perinatal transmission. In the first trimester, the median time at interruption was 6 weeks' gestation and length of time without therapy was 8 weeks (interquartile range [IQR], 7-11 weeks); in the third trimester, the median time at interruption was 32 weeks and length of time without therapy was 6 weeks (IQR, 2-9 weeks). Although the perinatal trans mission rate for the entire cohort was only 1.3%, transmission occurred in 4.9% (95% confidence interval [CI], 1.9%-13.2%, adjusted odds ratio [AOR] 10.33, P = .005) with first-trimester interruption and 18.2% (95% CI, 4.5%-72.7%, AOR 46.96, P = .002) with third-trimester interruption1. Although the use of efavirenz should be avoided during the first trimester, therapy should not be interrupted in women taking the drug who present in the first trimester but, rather, an alternative ARV should be substituted, if possible. Continuation of all drugs during the intrapartum period generally is recommended. Women who are hav ing elective cesarean delivery can take oral medications before the procedure and restart drugs following surgery. Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at most the postpartum dose would be given a few hours late. When short-term drug interruption is indicated, in most cases, all ARV drugs should be stopped and rein troduced at the same time. This can be problematic with drugs that have a long half-life. However, in con-ditions such as serious or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses precluding oral intake, the clinician has no choice but to stop all ther apy at the same time. In the rare case in which a woman has limited oral intake but that does not meet food requirements for certain ARV agents, decisions about the ARV regimen administered during the intra partum period should be made on an individual basis and in consultation with an HIV treatment expert. NNRTI drugs such as nevirapine and efavirenz have very long half-lives and can be detected for 21 days or longer after discontinuation; efavirenz has a longer half-life than nevirapine2-6. Because other drugs in the ARV regimen have shorter half-lives and are cleared more rapidly, only detectable NNRTI drug levels persist, resulting in subtherapeutic drug levels that can increase the risk of selection of NNRTI-resistant mutations. In addition, certain genetic polymorphisms, which may be more common among racial/ethnic groups such as African Americans and Hispanics, may have potential to result in a slower rate of clear ance4, 6. To prevent prolonged exposure to a single drug, some experts recommend stopping the NNRTI first and continuing the other ARV drugs for a period of time3. However, the optimal interval between stopping an NNRTI and the other ARV drugs is unknown; detectable levels of NNRTIs may be present from less than 1 week to more than 3 weeks after discontinuation, with the longer duration primarily ob served with efavirenz6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an NNRTIto a PI-based regimen before interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of HIV RNA resuppression after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the dual-NRTIs7. The optimal duration for continuing either dual nucleosides or the substituted PI-based regimen after stop ping the NNRTI is unknown, but a minimum of 7 days is recommended based on studies to reduce resist ance following single-dose nevirapine8-9. A pharmacokinetic (PK) study of nevirapine elimination in African adults following cessation of steadystate nevirapine-containing regimens found that nevirapine concentrations were estimated to have fallen below 20 ng/mL in 3 of 19 (16%) and 14 of 19 (74%) subjects by 7 and 14 days, respectively, after the cessation of dosing10. Elimination half-life was 39 hours in these subjects, considerably shorter than that observed after peripartum exposure to single doses of nevirapine (average 55-60 hours), likely related to induction of nevirapine metabolism with chronic nevirapine exposure2, 11-12. Because efavirenz concentra tions have potential to be detectable for more than 3 weeks, some experts suggest that if efavirenz-based therapy is stopped, the dual NRTIs or PI may need to be continued for up to 30 days. Further research is needed to assess appropriate strategies for stopping NNRTI-containing combination regimens. Another consideration is reintroduction of nevirapine if it is temporarily stopped for some reason and sub sequently restarted. A 2-week, half-dose escalation currently is recommended in patients who are started on nevirapine. Dose escalation is necessary because nevirapine induces its own metabolism by inducing cytochrome P450 3A4 (CYP3A4) liver metabolic enzymes; thus, initial administration of the full thera peutic dose will result in elevated drug levels until metabolic enzyme induction has occurred. In cases where nevirapine has been discontinued for more than 2 weeks, another 2-week dose escalation is recom mended when it is reintroduced. Special Situations -Failure of Viral Suppression (Updated September 14, 2011) # Panel's Recommendations • If an ultrasensitive HIV RNA assay indicates failure of viral suppression to below detectable levels after an adequate pe riod of treatment: • Assess resistance and adherence (AII). • Consult an HIV treatment expert (AIII). • Scheduled cesarean delivery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time of delivery (AII). A three-pronged approach is indicated for management o f women on ARV regimens who have subopti mal suppression o f HIV RNA (i.e., detectable virus at any time during pregnancy using ultrasensitive as says). They should be: 1) evaluated for resistant virus (if plasma HIV RNA is >500-1,000 copies/mL); 2) assessed for adherence, incorrect dosing, or potential problems with absorption (e.g., with nausea/vomiting or lack o f attention to food requirements); and 3) consideration should be given to modifying the ARV regimen. Experts in the care of ARV-experienced adults should be consulted, partic ularly if a change in drug regimen is necessary. Hospitalization may be considered for directly observed drug administration, adherence education, and treatment o f comorbidities such as nausea and vomiting. HIV RNA levels should be assessed 2-4 weeks after an ARV drug regimen is initiated or changed to pro vide an initial assessment of effectiveness1. Baseline HIV RNA levels have been shown to affect the time to response in both pregnant and nonpregnant individuals2. Most patients with an adequate viral response at 24 weeks have had at least a one log10 copies/mL HIV RNA decrease within 1 -4 weeks after starting therapy1. Treatment-naive individuals should have HIV RNA <400 copies/mL after 24 weeks of treatment and <50 copies/mL after 48 weeks of treatment. Because maternal antenatal viral load correlates with risk o f perinatal transmission o f HIV, suppression o f HIV RNA to undetectable levels should be achieved as rapidly as possible. Scheduled cesarean deliv ery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time o f delivery (see Transmission and Mode o f Delivery) . Monitoring of the Woman and Fetus During Pregnancy (Updated September 14, 2011) # Panel's Recommendations • CD4 cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII). Monitoring of CD4 count may be performed every 6 months in patients on antiretroviral treatment (ART) for more than 2-3 years who are adherent to therapy, clinically stable, and have sustained viral suppression (BIII). • Plasma HIV RNA levels should be monitored at the initial visit (AI); 2-4 weeks after initiating (or changing) antiretroviral (ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery) (AIII). • Genotypic ARV drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500-1,000 copies/mL, whether they are ARV-naive or currently on therapy (AIII). Repeat testing is indicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII). • Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverse ef fects of the drugs a woman is receiving (AIII). • First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure (see Transmission and Mode of Delivery) (AII). • Given the limited data on the effect of combination ARV drugs on the fetus, most experts would recommend secondtrimester ultrasound to assess fetal anatomy for women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz (BIII). • In women on effective combination ARV regimens, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only after initiation of an effective combination ARV drug regimen and, if possible, when HIV RNA levels are unde tectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. In HIV-infected pregnant women CD4 cell count should be monitored at the initial visit and at least every 3 months during pregnancy, similar to recommendations in nonpregnant adults. Monitoring of CD4 counts may be performed every 6 months in patients on ART for more than 2-3 years who are adherent to ther apy, clinically stable, and have sustained viral suppression. Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2-4 weeks after initiating or changing ARV regimens, monthly until undetectable, and at least every 3 months thereafter. If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy. More frequent monitoring of viral load is recommended in pregnant versus nonpregnant individuals because of the urgency to lower viral load as rapidly as possible to reduce the risk of perinatal transmission. Therefore, there is a need to identify pregnant women in whom the decline in viral load is slower than expected. Adult ARV guidelines note that patients should have a decrease in plasma HIV RNA level by at least one log10 copies/mL within 1 month after initiation of potent therapy1. Viral suppression generally is achieved in 16-24 weeks in ARV-naive treatment-adherent individuals who do not harbor resistance mutations to the drugs they are receiving but, in rare cases, it may take longer. Viral load also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery). Because o f physiologic changes such as hemodilution that are associated with pregnancy, CD4 percent age may be more stable than absolute CD4 count during pregnancy2-5. Nevertheless, most clinicians still rely on absolute CD4 count to evaluate immune status during pregnancy because parameters for initiat ing therapy are based on those values. ARV drug-resistance testing should be performed in HIV-infected pregnant women before initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing (e.g., >500-1,000 copies/mL). Testing should also be performed in women with suboptimal viral suppression while receiv ing an ARV regimen or who have persistant viral rebound to detectable levels after prior viral suppres sion on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Drug-resistance testing in the setting o f virologic failure should be performed while patients are receiv ing ARV drugs or within 4 weeks after discontinuation o f drugs. Genotypic testing is preferable to phe notypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection of mixtures o f wild-type and resistant virus. Monitoring for potential complications of ARV drugs during pregnancy should be based on what is known about the adverse effects o f the drugs the woman is receiving. For example, routine hematologic monitoring is recommended for women receiving zidovudine-containing regimens. Liver function should be monitored in all women receiving ARV drugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors (PIs), and hepatic steatosis and lactic acidosis in pregnancy have been re lated to nucleoside reverse transcriptase inhibitor (NRTI) use. Women with CD4 counts >250 cells/mm3 are thought to be at particular risk o f developing symptomatic, rash-associated, nevirapine-associated hepatotoxicity within the first 18 weeks after initiation o f therapy. Data from a 2010 study, however, suggest that abnormal liver transaminase levels at baseline may be more predictive o f risk than CD4 cell count6. Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapy with nevirapine, and they should also be watched for clinical symptoms o f potential hepatotoxicity (see Nevirapine and Hepatic/Rash Toxicity). The drug can be used cautiously with careful monitoring in women with mildly abnormal liver function tests at the time of ARV drug initiation. First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide potential timing because such deliveries for prevention o f perinatal transmission of HIV should be performed at 38 weeks' gestation (see Transmission and Mode o f Delivery)7-8. In patients who are not seen until later in gestation, second-trimester ultrasound can be used for both anatomical scanning and determination of gestational age. Because less is known about the effect o f combination ARV drug regimens on the fetus during preg nancy, some experts consider more intensive fetal assessment for mothers receiving such therapy. Most experts would recommend second-trimester assessment o f fetal anatomy with ultrasound in women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz. Furthermore, in addition to standard clinical monitoring, some experts would also recommend ultrasound assessment o f fetal growth and well-being during the third trimester in woman who are re ceiving a combination drug regimen for which there is limited experience with use in pregnancy. The need for additional assessments such as non-stress testing should be determined based on ultrasound findings, any maternal comorbidities, and standard obstetrical indications. Although data are still somewhat limited, the risk o f transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective combination ARV drug regimens resulting in viral suppression. This is in contrast to the pre-combination drug regimen era, during which invasive procedures such as amniocentesis and chorionic villus sampling (CVS) were as sociated with a two-to fourfold increased risk o f perinatal transmission o f HIV9-11. In an evaluation of transmission rates o f HIV over time among women with or without amniocentesis, the transmission rate among women undergoing the procedure from 1984 to 1996 (pre-combination drug era) was 30% (3 of 10) compared with 16.2% (40 o f 247) in those who did not have amniocentesis12. In contrast, no trans missions were noted among 18 women undergoing amniocentesis between 1997 and 2000 who received suppressive combination ARV drug regimens12. In an Italian multicenter study that included deliveries between 1997 and 2003, 3.3% (2 o f 60) o f infants were HIV infected after early invasive diagnostic procedures (CVS, amniocentesis, or cordocentesis) during pregnancy, compared with 1.7% (12 o f 712) o f infants born to women without invasive proce dures (P = 0.30)13. No transmissions occurred among 45 women on combination ARV drug regimens during the procedure. One mother o f an infected infant had not been diagnosed as HIV infected at the time o f amniocentesis and was not receiving ARV prophylaxis; the newborn's virologic test at birth was negative. The mother o f a second infected infant had been receiving zidovudine prophylaxis for 3 weeks and had an HIV RNA level o f 10,000 copies/mL at the time o f the procedure; the preterm infant had a positive virologic test at birth. In 2 other single-center series, no transmissions occurred in 6 and 9 live born infants after amniocentesis in HIV-infected pregnant women on combination ARV drug regimens14" 15. In the largest series to date, no transmissions were seen among 81 women receiving effective combination ARV drug regimens at the time o f amniocentesis16. Thus, among 159 cases reported to date of amniocentesis or other invasive diagnostic procedures among women on effective combination ARV drug regimens, no transmissions have occurred, but a small in crease in risk cannot be ruled out. HIV-infected women who have indications for invasive testing in pregnancy, such as abnormal ultrasound or aneuploidy screening, should be counseled about the poten tial risk o f transmission o f HIV along with other risks o f the procedure and allowed to make an informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women and they recommend limiting invasive procedures to amniocentesis14, but existing data on trans mission risk associated with these procedures are limited. At a minimum, HIV-infected pregnant women should receive an effective combination ARV drug regimen prior to undergoing any invasive prenatal testing and ideally have an undetectable HIV RNA level at the time o f the procedure. In women with de tectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. These procedures should be done under continuous ultrasound guidance and, if possible, the placenta should be avoided. ARV drug recommendations for pregnant women infected with HIV have been based on the concept that drugs o f known benefit to women should not be withheld during pregnancy unless there are known ad verse effects on the mother, fetus, or infant and unless these adverse effects outweigh the benefits to the woman1. Pregnancy should not preclude the use o f optimal drug regimens. The decision to use any ARV drug during pregnancy should be made by the woman after discussing with her health care provider the known and potential benefits and risks to her and her fetus. Although clinical data on ARV drugs in pregnant women are more limited than in nonpregnant individu als, sufficient data exist on which to base recommendations related to drug choice for some o f the avail able ARV drugs. Physiologic changes that occur during pregnancy can affect the kinetics o f drug absorption, distribution, biotransformation, and elimination, thereby also affecting requirements for drug dosing and potentially altering the susceptibility o f the pregnant woman to drug toxicity1-2. During pregnancy, gastrointestinal transit time becomes prolonged; body water and fat increase throughout gestation and are accompanied by increases in cardiac output, ventilation, and liver and renal blood flow; plasma protein concentrations decrease; renal sodium reabsorption increases; and changes occur in metabolic enzyme pathways in the liver. Placental transport of drugs, compartmentalization o f drugs in the embryo/fetus and placenta, bio transformation o f drugs by the fetus and placenta, and elimination o f drugs by the fetus also can affect drug pharmacokinetics (PKs) in the pregnant woman. Currently available data on the PKs of antiretroviral (ARV) agents in pregnancy are summarized in Table 5. In general, the PKs of nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are similar in pregnant and nonpregnant women, although protease in hibitor (PI) PKs are more variable, particularly in later pregnancy. The current data suggest that in many women, exposure to lopinavir/ritonavir, atazanavir, and nelfinavir is decreased during the second and/or third trimester (see Table 5). The need for a dose adjustment depends on the PI, the treatment experience of a particular patient, and use (if any) of concomitant medications with potential for interaction3-10. Teratogenicity (Updated September 14, 2011) Panel's Recommendations • All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Reg istry (see details at http://www.APRegistry.com) (AIII). • Efavirenz should not be used in the first trimester and nonpregnant women receiving efavirenz should be counseled to avoid pregnancy (AIII). The potential harm to the fetus from maternal ingestion o f a specific drug depends not only on the drug itself but also on the dose ingested; the gestational age o f the fetus at exposure; the duration o f exposure; the interaction with other agents to which the fetus is exposed; and, to an unknown extent, the genetic makeup o f mother and fetus. Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotal ex perience, registry data, and clinical trials. Data are limited for antiretroviral (ARV) drugs, particularly when used in combination therapy. Drug choice should be individualized and must be based on discussion with the woman and available data from preclinical and clinical testing of the individual drugs. Preclinical data include results of in vitro and animal in vivo screening tests for carcinogenicity, clastogenicity/mutagenicity, and reproductive and teratogenic effects. However, the predictive value of such tests for adverse effects in humans is unknown. For example, of approximately 1,200 known animal teratogens, only about 30 are known to be teratogenic in humans1. Limited data exist regarding placental passage, long-term ani mal carcinogenicity, and animal teratogenicity for the Food and Drug Administration (FDA)-approved ARV drugs. Concerns have been raised about the risk of several ARV agents. In cynomolgus monkeys receiving efavirenz from gestational days 20-150 at a dose resulting in plasma concentrations comparable to systemic human exposure at therapeutic dosage, significant malformations were observed in 3 o f 20 infant monkeys2. The malformations included anencephaly and unilateral anophthalmia in 1, microphthalmia in another, and cleft palate in the third. In prospectively reported pregnancies with exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2011, birth defects were observed in 2.7% (17 o f 623) live births with first-trimester exposure; this proportion is not significantly different from that observed among U.S. births in the general popula tion (2.7%) as reported by the Registry3. Defects reported prospectively included 1 report of myelomeningocele and a separate report o f anophthalmia. The case o f anophthalmia included severe oblique facial clefts and amniotic banding that is known to be associated with anophthalmia3. In addi tion, 6 cases o f central nervous system (CNS) defects, including myelomeningocele, have been retro spectively detected in infants born to mothers receiving efavirenz during the first trimester2. A recent meta-analysis including data from 9 cohorts with prospective reporting on 1,132 first-trimester exposures did not find an increased risk o f overall birth defects among infants born to women on efavirenz during the first trimester compared with those on other ARV drugs during the first trimester (relative risk [RR] 0.87; 95% confidence interval [CI], 0.61-1.24)4. One neural tube defect occurred among 1,256 live births. Two subsequent smaller studies had conflicting results. A cohort in West Africa found no visible anomalies among 147 infants born after first-trimester exposure to efavirenz, while an analysis o f the PACTG 219 database found a significantly increased risk o f birth defects among infants born to women after first-trimester exposure to efavirenz (5 o f 32; 15.6%), including 1 neural tube de fect also included in the retrospective Registry cases5-6. Although a causal relationship has not been established between these events and the use o f efavirenz, in light o f similar findings in primates, efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because o f the po tential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period o f fetal organogene sis. Women o f childbearing potential should undergo pregnancy testing prior to initiation o f efavirenz and should be counseled about the potential risk to the fetus and need to avoid pregnancy. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to be come pregnant or who are sexually active and not using effective contraception. Use after the first trimester can be considered if, after consideration o f other alternatives, it is the best choice for an indi vidual woman. If efavirenz is to be continued postpartum, adequate contraception must be ensured. Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in utero exposure to tenfovir at maternal doses resulting in levels approximately 25 times those used in humans, low birth weights and reductions in fetal bone porosity were seen. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Data from the Antiretroviral Pregnancy Registry show a birth defect incidence o f 2.4% in 1,092 women with first-trimester tenofovir exposure, similar to that in the general population3. However, because of the limited data on use in human pregnancy and concern re garding potential fetal bone effects and potential nephrotoxicity, tenofovir is recommended as an alterna tive rather than a preferred drug for use in pregnancy unless the pregnant woman has HIV/hepatitis B coinfection (see Table 5) . Health care providers who are caring for HIV-infected pregnant women and their newborns are strongly advised to report instances o f prenatal exposure to ARV drugs (either alone or in combination) to the An tiretroviral Pregnancy Registry. This registry is an epidemiologic project to collect observational, nonex perimental data regarding ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and as sist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The Anti retroviral Pregnancy Registry is a collaborative project o f pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners. The registry does not use patient names, and registry staff obtain birth outcome follow-up information from the reporting physician. Referrals should be directed to: # Panel's Recommendations • Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (Pl)-based combination antiretroviral (ARV) regimens; however, given the clear benefits of such regimens for both the women's health and the prevention of mother-to-child transmission, PIs should not be withheld for fear of alter ing pregnancy outcome (AII). Early data were conflicting as to whether receipt of combination ARV regimens during pregnancy is asso ciated with adverse pregnancy outcomes and, in particular, preterm delivery. The European Collaborative Study and the Swiss Mother + Child HIV Cohort Study investigated the effects of combination ARV regi mens in a population of 3,920 mother-child pairs. Adjusting for CD4 cell count and intravenous drug use, they found a roughly twofold increase in the odds of preterm delivery for infants exposed to combination regimens with or without PIs compared with no drugs; women receiving combination regimens that had been initiated before their pregnancy were twice as likely to deliver prematurely as those who started drugs during the third trimester1. However, Pi-based combination regimens were received by only 108 (3%) of the women studied; confounding by severity or indication may have biased the results (i.e., sicker women may have received PIs more often, but their advanced HIV infection may have actually caused the preterm births). Exposure to nucleoside reverse transcriptase inhibitor (NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with prematurity. An updated report from the European Collaborative Study, based on an adjusted analysis that included 2,279 mother-child pairs, found a 1.9-fold increased risk o f delivery at less than 37 weeks with combina tion ARV regimens started during pregnancy and a 2.1-fold increased risk with combination ARV regi mens started prepregnancy compared with mono-or dual-NRTI prophylaxis2. In this report, 767 women received combination ARV regimens during pregnancy, although the proportion receiving PIs was not specified. The risk o f delivery before 34 weeks' gestation was increased by 2.5-fold for those starting combination ARV regimens during pregnancy and 4.4-fold for those entering pregnancy on combination ARV regimens. In contrast, in an analysis o f 7 prospective clinical studies that included 2,123 HIV-infected pregnant women who delivered infants between 1990 and 1998 and had received antenatal ARV regimens and 1,143 women who did not receive antenatal ARV drugs, the use o f multiple ARV drugs compared with no drugs or treatment with one drug was not associated with increased rates o f preterm labor, low birth weight, low Apgar scores, or stillbirth3. Nor were any significant associations between adverse preg nancy outcome and use of ARV drugs by class or by category (including combination ARV regimens) found in an analysis from the Women and Infants Transmission Study (WITS), including 2,543 HIV-in fected women (some o f whom were included in the previous meta-analysis)4. More recent data have continued to be conflicting as to whether preterm delivery is increased with com bination ARV regimens. A prospective cohort study including 681 women from Brazil, Argentina, Mex ico, and the Bahamas did not find significant associations between use o f combination ARV regimens and preterm birth or low birth weight5. A single-center study from Miami including 1,337 women did find a 1.8-fold increased chance o f preterm birth among the 134 women in the cohort who received PIcontaining combination ARV regimens compared with other combination regimens, after adjustment for possible confounding variables6. However, women receiving Pi-containing combination ARV regimens uniformly were women with advanced disease or those who had failed other combination drug regi mens. The risk o f low birth weight and stillbirth were not increased in any drug regimen groups. A re cent meta-analysis o f 14 European and American clinical studies found no increase in risk o f preterm birth with either any ARV drug receipt compared with no drugs or combination ARV regimens including PIs compared with no drugs7. However, a significant but modest increased risk o f preterm birth (odds ratio [OR] 1.35; 95% confidence interval [CI], 1.08-1.70) was found in women who received combina tion regimens with PIs compared with combination regimens without PIs. Other studies have detected small but significant increases (OR o f 1.2-1.5 in the largest studies) in preterm birth with PI-or non-PI-based combination ARV regimens as well8-11. Another variable that may confound these observational studies is the increased rate o f preterm birth if the combination ARV regi men is begun before conception compared with later during pregnancy, which itself may reflect con founding by severity or indication12. When data from the IMPAACT P1025 observational cohort were examined by multivariable analysis to correct for HIV disease stage, PI-based combination ARV regi mens were no more likely than non-PI-based combination ARV regimens to be associated with sponta neous preterm birth (OR 1.22; 95% CI, 0.70-2.12)13. A recent combined analysis o f three large studies-two from Europe and one from the United States-found heterogeneity in the association be tween combination ARV regimens and preterm birth, with significant increases in Europe but not the United States. However, increased rates o f preterm birth (adjusted OR [AOR] 1.5) were found in all three cohorts when combination ARV regimens were compared with dual regimens. Additional factors found to be associated with preterm birth in all three cohorts included injection drug use and more ad vanced HIV disease14. A similar increase in preterm birth in women receiving combination ARV regi mens compared with dual regimens has been reported in the Swiss Mother and Child Cohort as well15. Clinicians should be aware o f a possible increased risk o f preterm birth with use o f combination ARV drug regimens; however, given the clear benefits for maternal health and reduction in perinatal transmis sion, these agents should not be withheld because o f the possibility o f increased risk o f preterm delivery. Until more information is known, HIV-infected pregnant women who are receiving combination regi mens for treatment of their HIV infection should continue their provider-recommended regimens. They should receive careful, regular monitoring for pregnancy complications and for potential toxicities. Nevirapine and Hepatic/Rash Toxicity (Updated September 14, 2011) # Panel's Recommendations • Nevirapine-based regimens should be initiated in women with CD4 counts >250 cells/mm3 only if the benefits clearly out weigh the risks because of the drug's potential for causing hepatic toxicity/hypersensitivity reaction (AII). • Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen well can continue on the therapy regardless of CD4 count (AII). # Increases in hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ) associated with rash or systemic symptoms may be observed during the first 18 weeks of treatment with nevirapine. Signs and symptoms of systemic toxicity may be nonspecific and can include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, or hepatomegaly, with or without initially abnormal hepatic transaminases1. The development of severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more common in women than men and has been reported in pregnant women2-3. Other stud ies have found that hepatic adverse events with systemic symptoms (predominantly rash) were 3.2-fold more common in women than in men4-5. The degree of risk of rash and hepatic toxicity also appears to vary with CD4 cell count. In a summary analysis of data from 17 clinical trials of nevirapine therapy, women with CD4 cell counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 cell counts to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity4; a single-center study also found higher CD4 cell counts to be associated with increased risk of severe nevirapine-associ ated skin rash2. CD4 cell counts >250 cells/mm3 predicted rash illness, but not liver enzyme elevation, among pregnant and nonpregnant women initiating nevirapine-based combination antiretroviral (ARV) regimens in three U.S. university clinics6. Other international cohorts of nonpregnant women have experi enced hepatotoxicity and rash at similar rates as in U.S. studies, but not in association with CD4 cell counts >250 cells/mm3 7. In general, in controlled clinical trials, hepatic events, regardless of severity, have occurred in 4.0% (range 0%-11.0%) of patients who received nevirapine; severe or life-threatening rash has occurred in approximately 2% of patients receiving nevirapine8. Several early reports of death due to hepatic failure in HIV-infected pregnant women receiving nevirapine as part of a combination ARV regimen raised concerns that pregnant women might be at increased risk of hepatotoxicity from nevirapine compared with other ARV drugs9-10. Recent data challenge the notion that nevirapine is uniquely associated with increased hepatotoxicity during pregnancy11. In an analysis of two multicenter, prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (relative risk [RR] 4.7; 5% confidence interval [CI], 3.4-6.5), but nevirapine use was not, regardless of pregnancy status11. Additional data from the same cohorts did not show any increased risk of hepatotoxicity in HIVinfected pregnant women receiving nevirapine-based combination ARV regimens versus non-nevirapinebased combination ARV regimens12. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women. Nevertheless, if nevirapine is used in pregnancy, health care providers should be aware of potential hepatotoxicity with or without rash and should conduct frequent and careful monitoring of clinical symptoms and hepatic transaminases (i.e., ALT and AST), particularly during the first 18 weeks of nevirapine use. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through Month 4, and every 1-3 months thereafter (see the He patotoxicity section of the table on Antiretroviral Therapy-Associated Common and/or Severe Adverse Ef fects in the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). In patients with pre-existing liver disease, monitoring should be performed more frequently when initiating nevirapine and monthly thereafter1. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop suggestive clinical symptoms accompanied by ele vation in serum transaminase levels (ALT and/or AST) or who have asymptomatic but severe transaminase elevations (i.e., more than five times the upper limit of normal) should stop nevirapine and not receive nevirapine again in the future. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission of HIV13. Women who enter pregnancy on nevirapine-containing regimens and are tolerating them well may continue therapy, regardless of CD4 cell count. Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity (Updated September 14, 2011) Panel's Recommendations • The combination of stavudine and didanosine should not be prescribed during pregnancy due to reports of lactic acidosis and maternal/neonatal mortality with prolonged use in pregnancy (AII). • Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to antiretroviral (ARV) drugs who present with severe clinical findings of unknown etiology, particularly neurologic findings (AII). • Long-term clinical follow-up is recommended for any child with in utero exposure to ARV drugs (AIII). Nucleoside reverse transcriptase inhibitor (NRTI) drugs are known to induce mitochondrial dysfunction because the drugs have varying affinity for mitochondrial gamma DNA polymerase. This affinity can in terfere with mitochondrial replication, resulting in mitochondrial DNA (mtDNA) depletion and dysfunc tion1. The relative potency of the NRTI drugs in inhibiting mitochondrial gamma DNA polymerase in vitro is highest for zalcitabine, followed by didanosine, stavudine, zidovudine, lamivudine, abacavir, and tenofovir2. In one study, didanosine and didanosine-containing regimens were associated with the great est degree o f mitochondrial suppression3. Toxicity related to mitochondrial dysfunction has been re ported to occur in infected patients receiving long-term treatment with NRTI drugs and generally has resolved with discontinuation o f the drug or drugs; a possible genetic susceptibility to these toxicities has been suggested1. These toxicities may be o f particular concern for pregnant women and infants with in utero exposure to NRTI drugs. # D uring Pregnancy Clinical disorders linked to mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancre atitis, hepatic steatosis, and lactic acidosis. Among these disorders, symptomatic lactic acidosis and hepatic steatosis may have a female preponderance4-5. These syndromes have similarities to rare but life-threaten ing syndromes that occur during pregnancy, most often during the third trimester: acute fatty liver and he molysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Data suggest that a disorder of mitochondrial fatty acid oxidation in the mother or her fetus during late pregnancy may play a role in the development of acute fatty liver of pregnancy and HELLP syndrome6-9 and possibly contribute to suscepti bility to ARV-associated mitochondrial toxicity. HELLP syndrome also can occur postpartum in women with severe preeclampsia10. In addition to low platelets and elevated liver enzymes, other laboratory find ings reported among HIV-infected pregnant women on ARV drugs include mitochondrial placental deple tion but without evidence of ultrastructual damage to placental cells. The clinical significance of reduced mtDNA in placentas exposed to ARV drugs remains unknown11. Lactic acidosis with microvacuolar hepatic steatosis is a toxicity related to NRTI drugs that is thought to be related to mitochondrial toxicity; it has been reported to occur in infected persons treated with NRTI drugs for longer than 6 months. In a report from the Food and Drug Administration (FDA) Spontaneous Adverse Event Program, typical initial symptoms included 1-6 weeks of nausea, vomiting, abdominal pain, dyspnea, and weakness12. Metabolic acidosis with elevated serum lactate levels and elevated hepatic enzymes was common. Patients described in that report were predominantly female and overweight. Al though the apparent incidence of this syndrome may increase with better clinical recognition, the actual in cidence may decrease as stavudine and didanosine are used less often in combination regimens. The frequency o f this syndrome in pregnant HIV-infected women receiving NRTI drugs is unknown. In 1999, Italian researchers reported a case o f severe lactic acidosis in an infected pregnant woman who was receiving stavudine/lamivudine at the time o f conception and throughout pregnancy and who expe rienced symptoms and fetal death at 38 weeks' gestation13. Bristol-Myers Squibb has reported three m a ternal deaths due to lactic acidosis, two with and one without accompanying pancreatitis, among women who were either pregnant or postpartum and whose antepartum regimen during pregnancy included stavudine and didanosine in combination with other ARV agents (either a protease inhibitor [PI] or nevi rapine)14-15. All women were receiving regimens containing these agents at the time o f conception and continued for the duration o f pregnancy; all presented late in gestation with symptomatic disease that progressed to death in the immediate postpartum period. Two cases were also associated with fetal death. Nonfatal cases o f lactic acidosis also have been reported in pregnant women receiving combina tion stavudine/didanosine16. It is unclear if pregnancy augments the incidence o f the lactic acidosis/hepatic steatosis syndrome that has been reported for nonpregnant persons receiving NRTI drugs. However, because pregnancy itself can mimic some of the early symptoms o f the lactic acidosis/hepatic steatosis syndrome or be associated with other disorders o f liver metabolism, these cases emphasize the need for physicians caring for HIVinfected pregnant women receiving NRTI drugs to be alert for early signs o f this syndrome. Additionally, because of the reports o f several cases o f maternal mortality secondary to lactic acidosis with prolonged use o f the combination o f stavudine and didanosine by HIV-infected pregnant women, clinicians should not prescribe this ARV combination during pregnancy. Combination stavudine/didanosine also is not recommended for nonpregnant adults. # In Utero Exposure It has been suggested that mitochondrial dysfunction might develop in infants with in utero exposure to NRTI drugs. Data from a French cohort of 1,754 uninfected infants born to HIV-infected women who received ARV drugs during pregnancy identified 8 infants with in utero or neonatal exposure to either zidovudine/lamivudine (4) or zidovudine alone (4) who developed indications o f mitochondrial dysfunc tion after the first few months o f life17. Two o f these infants (both exposed to zidovudine/lamivudine) contracted severe neurologic disease and died; 3 had mild-to-moderate symptoms; and 3 had no symp toms but had transient laboratory abnormalities. In a larger cohort o f 4,392 uninfected children (including the children in the previous study) followed within the French Pediatric Cohort or identified within a French National Register, the 18-month inci dence o f clinical symptoms o f mitochondrial dysfunction was 0.26% and 0.07% for mortality18. All chil dren had perinatal exposure to ARVs; risk was higher among infants exposed to combination ARV drugs (primarily zidovudine/lamivudine) than to zidovudine alone. The children presented with neurologic symptoms, often with abnormal magnetic resonance imaging and/or episodes o f significant hyperlactatemia, and deficits in mitochondrial respiratory chain complex enzyme function on biopsy o f muscle. The same group also has reported an increased risk o f simple febrile seizures in the first 18 months of life and persistently lower (but clinically insignificant) neutrophil, lymphocyte, and platelet counts in in fants with in utero exposure to NRTIs19-20. More recently, in continued follow-up o f the French Perinatal Cohort, researchers reported severe neurologic symptoms in the first 2 years o f life as a rare event (0.3% -0.5% )21. Other clinical studies from the United States and Europe generally have not duplicated the French re ports22-28. The Perinatal Safety Review Working Group performed a retrospective review o f deaths oc curring among children born to HIV-infected women and followed from 1986 to 1999 in 5 large, prospective U.S. perinatal cohorts. No deaths similar to those reported from France or with clinical find ings attributable to mitochondrial dysfunction were identified in a database o f more than 16,000 unin fected children born to HIV-infected women with and without exposure to ARV drugs23. However, most o f the infants with exposure to ARVs had been exposed to zidovudine alone and only a relatively small proportion (approximately 6%) had been exposed to zidovudine/lamivudine. The European Collaborative Study reviewed clinical symptoms in 2,414 uninfected children in their co hort with median follow-up o f 2.2 years (maximum, 16 years); 1,008 had perinatal exposure to ARVs25. No association was found between clinical manifestations suggestive o f mitochondrial abnormalities and perinatal exposure to ARVs. O f the 4 children with seizures in this cohort, none had perinatal exposure to ARVs. In a report from a long-term follow-up study in the United States (PACTG 219/219C), 20 chil dren with possible symptoms o f mitochondrial dysfunction were identified in a cohort o f 1,037 unin fected infants born to HIV-infected mothers27. Definitive diagnosis was not available because none of the children had biopsies for mitochondrial function. Three o f the 20 children had no exposure to ARV drugs. In the 17 remaining children, although overall exposure to NRTI drugs was not associated with symptoms, there was an association between symptoms and first exposure to zidovudine/lamivudine limited to the third trimester. Some small alterations in mtDNA and oxidative phosphorylation enzyme activities were found in stored specimens from these children, but the clinical significance o f these ob servations remains unknown29-30. Laboratory abnormalities without clinical symptoms have been reported in infants with perinatal expo sure to ARVs compared with unexposed infants in a number o f studies, most o f which are limited by small numbers o f subjects. In 1 study, mtDNA quantity was lower in cord and peripheral blood white cells at ages 1 and 2 years among 20 infants born to HIV-infected women compared with 30 infants born to uninfected women and was lowest among 10 HIV-exposed infants with zidovudine exposure com pared with 10 without zidovudine exposure31. In a subsequent study, mitochondrial changes were evalu ated in umbilical cord endothelial cells and cord blood from human infants and monkeys with in utero exposure to various NRTI-containing regimens32. Similar morphologic changes and mtDNA depletion were seen in the human and monkey infants. In the monkeys, mitochondrial damage demonstrated a gra dient, with greatest damage with stavudine/lamivudine > zidovudine/didanosine > zidovudine/lamivu dine > lamivudine. In a Canadian study of 73 ARV-exposed infants and 81 controls with blood samples during the first 8 months o f life, investigators found that in the first weeks o f life, blood mtDNA levels were higher and blood mitochondrial RNA levels were lower in the HIV-and ARV-exposed infants com pared with infants without HIV and ARV exposure33. One study reported that peripheral blood mononu clear cell (PBMC) mtDNA levels were lower at birth in HIV-exposed, ARV-exposed infants compared with non-HIV, non-ARV-exposed infants34. However, among the HIV-exposed infants, those with com bination ARV drug exposure in utero had higher mtDNA levels than those exposed only to zidovudine in utero. Umbilical cord mtDNA sequence variants were 3-fold higher among HIV-and zidovudine-ex posed infants compared with infants born to mothers without HIV infection35. Transient hyperlactatemia during the first few weeks o f life was reported among 17 HIV-exposed infants with perinatal exposure to ARVs; lactate levels returned to normal in all children and none developed symptoms o f mitochondrial dysfunction during follow-up36. Similarly, the French Perinatal Cohort Study has reported asymptomatic hyperlactatemia in one-third o f zidovudine-exposed newborns, which resolved following perinatal exposure to the drug21. Clinically asymptomatic hematologic findings have been reported by several investigators among uninfected infants with in utero exposure to ARV regimens in the United States and Europe37-39, and infants with exposure to triple-combination ARV regimens were found to be at increased risk o f lowered hemoglobin compared with those with perinatal exposure to zi dovudine or zidovudine/lamivudine40. The clinical significance o f these differences in mtDNA, lactate levels, and hematologic laboratory find ings is unclear, and further long-term studies are needed to validate the findings and assess the degree to which they affect growth and development o f infants exposed to ARV drugs. Thus, data are conflicting on whether mitochondrial dysfunction is associated with perinatal exposure to ARVs, and further studies are needed. Even if an association is more clearly demonstrated, the development o f severe or fatal mito chondrial disease appears to be extremely rare and should be balanced against the clear benefit o f ARV prophylaxis in reducing transmission o f a fatal infection by 70% or more25, 41-42. Development o f new di agnostic techniques, including use o f flow cytometry assays to screen for mitochondrial function, may lead to more accurate assessment o f mitochondrial toxicity43. Mitochondrial dysfunction should be con sidered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings o f unknown etiology, particularly neurologic findings. Current recommendations call for long-term clin ical follow-up for any child with in utero exposure to ARV drugs. Protease Inhibitor Therapy and Hyperglycemia (Updated September 14, 2011) Panel's Recommendations • HIV-infected women taking antiretroviral (ARV) drug regimens during pregnancy should undergo glucose screening with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation (AIII). Some experts would perform earlier glu cose screening in women receiving ongoing protease inhibitor (Pl)-based regimens initiated before pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance (BIII). Hyperglycemia, new-onset diabetes mellitus, exacerbation o f existing diabetes mellitus, and diabetic ke toacidosis have been reported in HIV-infected patients taking PIs1-4. In addition, pregnancy is itself a risk factor for hyperglycemia. To date, however, the majority have not shown an increased risk o f glucose in tolerance with Pi-based regimens during pregnancy. One small retrospective study that included 41 women receiving Pi-based combination ARV regimens found an increased risk o f glucose intolerance, but not gestational diabetes, among women on combination ARV regimens compared with zidovudine alone5, while two other retrospective studies did not find an increased risk o f glucose intolerance with Pis6-7. Secondary analyses o f two large cohorts did not find an association between the type o f ARV regi men and gestational diabetes, except for an association between initiation o f PIs before pregnancy or during the first trimester and gestational diabetes in the PACTG 316 cohort8-9. Finally, a prospective study including detailed evaluations for glucose intolerance and insulin resistance among HIV-infected pregnant women did not find differences between women on Pi-containing and non-PI-containing regi mens10. In both groups, however, the rate o f impaired glucose tolerance was high (38%), likely related to high body mass index and race/ethnicity among trial subjects. HIV-infected women receiving ARV regimens during pregnancy should receive standard glucose screen ing with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation. Some experts would perform earlier glucose screening in women with ongoing PI-based ARV regimens initiated before preg nancy (particularly in women o f minority race/ethnicity), similar to recommendations for women with high-risk factors for glucose intolerance, such as maternal obesity, advanced maternal age, and family history o f type II diabetes mellitus. # Antiretroviral Drug Resistance and Resistance Testing in Pregnancy (Updated September 14, 2011)_____________ # Indications for Antiretroviral Drug-Resistance Testing in HIV-Infected Pregnant Women Panel's Recommendations • HIV drug-resistance testing is recommended for: • All pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) not currently receiving antiretroviral (ARV) drugs, before starting treatment or prophylaxis (AIII). • All pregnant women receiving antenatal ARV drugs who have suboptimal viral suppression or persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII). • Empiric initiation of ARV drugs before results of resistance testing are available may be warranted, with adjustment as needed after the test results are available, for optimal prevention of perinatal transmission (BIII). Resistance testing is recommended for all ARV-naive pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) before initiating treatment or prophylaxis if prior resistance testing has not been done. For details regarding genotypic and phenotypic resistance testing see Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Ideally, resistance testing would have been done at a preconception visit to allow receipt o f results and to select an appropriate ARV drug regimen during pregnancy or before pregnancy if maternal therapy was indicated. Resistance testing should also be performed before initiation of therapy or prophylaxis in pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) who re ceived prophylaxis in previous pregnancies and are now restarting ARV drugs for prevention of perinatal transmission. No data currently are available to address the utility of resistance testing during pregnancy in women who do not require treatment for their own health or in women with multiple pregnancies who have received corresponding courses of ARV prophylaxis for prevention of mother-to-child transmission. The identification of baseline resistance mutations may allow selection of more effective and durable ARV regimens for women who need treatment and help ensure a wider range of future treatment options for women receiving ARV drugs solely for perinatal prophylaxis. There is no evidence, however, that baseline resistance testing in pregnancy is associated with a reduction in rates of perinatal transmission. Resistance testing should also be performed following initiation o f an ARV regimen during pregnancy or in HIV-infected pregnant women who are receiving antiretroviral therapy (ART) when they present for obstetrical care if there is suboptimal viral suppression or persistent viral load rebound to detectable lev els after prior viral suppression on the ARV regimen. In most settings, the results o f resistance testing guide selection o f the initial ARV regimen. In some situ ations in pregnant women, however, the clinician may choose to initiate empiric ARV drug regimen be fore resistance-testing results are available to optimize prevention o f perinatal transmission o f HIV Once resistance test results are obtained, the ARV drug regimen can be modified as needed. Most ex perts believe that for women in the third trimester, the benefits o f immediate initiation o f ARV drugs for prevention o f mother-to-child transmission, pending results o f resistance testing, outweigh the possible risk o f short-term use o f a regimen that could be suboptimal because o f pre-existing resistance. The development o f ARV drug resistance is one o f the major factors leading to therapeutic failure in HIV-infected individuals. In pregnancy, it is associated with specific concerns that differ from those seen in the nonpregnant population. Pre-existing resistance to a drug in an ARV prophylaxis regimen may di minish the regimen's efficacy in preventing perinatal transmission. The development o f resistance to drugs used during pregnancy for prophylaxis o f perinatal transmission may limit future maternal treat ment options or decrease the effectiveness o f prophylactic regimens in the current pregnancy or during future pregnancies. Infant treatment options also may be limited if maternal resistance is present or de velops and resistant virus is transmitted to the fetus. Several factors unique to pregnancy may increase the risk of development o f resistance. If drugs with significant differences in half-life (such as nevirapine or efavirenz combined with two nucleoside ana logue drugs) are included in the ARV regimen, simultaneous postpartum discontinuation o f all regimen components may result in persistent subtherapeutic drug levels and increase the risk o f development of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (see Stopping Antiretroviral Therapy during Pregnancy). Problems such as nausea and vomiting in early pregnancy may compromise adher ence and increase the risk o f resistance in women receiving ARV drugs. Pharmacokinetic (PK) changes during pregnancy, such as increased plasma volume and renal clearance, may lead to subtherapeutic drug levels, increasing the risk that resistance will develop. # Incidence o f Antiretroviral Resistance Em erging from the Use o f Perinatal Prophylac tic Regim ens The presence o f mutations conferring resistance to nucleoside analogue drugs appears to be correlated with more advanced maternal disease and longer duration o f prior or current exposure to these drugs1-4. The development o f zidovudine drug resistance when zidovudine is used alone appears uncommon in women with higher CD4 cell counts and lower viral loads5-6 but is more o f a concern in women with ad vanced disease and lower CD4 cell counts2. Development o f resistance associated with short-term use o f ARV agents for prevention o f mother-tochild transmission is most common with nevirapine, particularly single-dose nevirapine. Nevirapine has a low genetic barrier to resistance, with a single point mutation conferring resistance to nevirapine and to other first-generation NNRTI drugs. Furthermore, its long half-life, with blood levels detectable up to 21 days after a single dose in labor, increases selection pressure and the risk o f resistance7. Factors asso ciated with an increased risk o f resistance following single-dose nevirapine exposure include high base line viral load, low baseline CD4 cell count, viral subtype, and the number o f maternal doses. The rate of genotypic resistance after exposure to single-dose nevirapine has varied in studies, ranging from 15% to 75%8-18. Studies using more sensitive real-time polymerase chain reaction (PCR) techniques suggest that up to one-half o f resistance that develops is not detected by conventional sequence analysis16, 18-20. The prevalence o f resistance declines rapidly over time and the proportion o f resistant virus in those with de tectable virus 12 months after exposure is low. In a study o f virus from 67 South African women, using a sensitive allele-specific resistance assay, the K103N mutation was seen in 87% o f women at 6 weeks but in only 11% at 12 months after single-dose nevirapine exposure, with a median frequency o f the muta tion of 0.7% (range 0.5%-5.4%) in women with detectable resistance at 12 months20. In the PACTG 316 trial, the addition o f single-dose nevirapine following antepartum administration of other ARV regimens (primarily combination regimens because 77% o f women received antenatal combi nation ARV regimens still resulted in nevirapine resistance in 14 o f 95 (15%; 95% confidence interval [CI], 8%-23%) women with detectable virus postpartum8. In this study, adding single-dose nevirapine # Significance o f Antiretroviral Drug Resistance in Pregnancy did not provide any additional efficacy in prevention o f mother-to-child transmission but was associated with development o f nevirapine resistance. Therefore, this approach is not recommended. A recent study examined the presence o f resistant mutations in HIV-1-infected women receiving combi nation ARV drug regimens that were stopped postpartum. All women evaluated received zidovudine and lamivudine, with 76% receiving nelfinavir and 8% receiving nevirapine. Rates o f M184V/I mutations postpartum were 65% and 29% in women receiving dual or triple prophylaxis, respectively. NNRTI re sistance was identified postpartum among 38% o f nevirapine recipients, whereas only 1% o f protease in hibitor (PI) recipients developed PI resistance21. # The Im pact o f Resistance on Pregnancy and the R isk o f Perinatal Transmission o f H IV Perinatal Transmission Perinatal transmission of resistant virus has been reported, but it appears to be unusual and there is little evidence that the presence o f resistance mutations increases the risk o f transmission when current rec ommendations for ARV management in pregnancy are followed. A substudy o f the Women and Infants Transmission Study (WITS) followed pregnant women receiving zidovudine alone for treatment o f HIV disease in the early 1990s. In this study, the detection o f zidovudine resistance conferred an increased risk o f transmission when analysis was adjusted for duration o f membrane rupture and total lymphocyte count2; however, women in this cohort had characteristics that would indicate a need for ART under the current Department o f Health and Human Services (HHS) recommendations for maternal health and for prevention o f perinatal transmission. When transmitting mothers had mixed viral populations o f wild type and virus with low-level zidovudine resistance, only wild-type virus was detected in the infant22, and other studies have suggested that drug-resistance mutations may diminish viral fitness23, possibly leading to a decrease in transmissibility. In another study, prevalence o f ARV drug resistance among HIV-infected newborns in New York State was examined. Eleven (12.1%) o f 91 infants born between 1989 and 1999 and 8 (19%) o f 42 infants born between 2001 and 2002 had mutations associated with decreased drug susceptibility. However, perinatal exposure to ARVs was not found to be a significant risk factor for the presence o f resistance during either time period24-25. Neither resistance to nevirapine that develops as a result of exposure to single-dose nevirapine nor exposure to single-dose nevirapine in a prior pregnancy has been shown to affect perinatal transmission rates26-27. # M aternal Response to Subsequent Treatment Regimens Because nevirapine resistance mutations can be detected postpartum in a significant proportion of women receiving single-dose intrapartum nevirapine prophylaxis, the response to subsequent NNRTI-based com bination therapy given for maternal health has been a concern12, 20, 26-29. A study performed in Zambia, Kenya, and Thailand found that prior exposure to single-dose nevirapine was associated with an increased risk of treatment failure in pregnant women receiving NNRTI-based ART, with the greatest risk being in women receiving ART within 12 months of previous nevirapine exposure30. The Optimal Combination Therapy After Nevirapine Exposure (OCTANE)/A5208 trial conducted in Africa compared nevirapine with lopinavir/ritonavir-based therapy in women requiring therapy who had prior exposure to single-dose nevirapine prophylaxis. The results suggest that prior exposure to single-dose nevirapine within 24 months of initiating therapy may be associated with a higher risk o f viral failure with nevirapine-based therapy compared with lopinavir/ritonavir-based therapy. In this study, significantly more women in the nevirapine arm (29, 24%) failed to achieve a subsequent undetectable viral load (25) or died (4) compared with women in the lopinavir/ritonavir arm (8, 7%; 7 virologic failures and 1 death; P <0.0005). Five of 13 (38%) women with documented nevirapine resistance at the start of therapy either had detectable virus or died. This study demonstrates that women with documented nevirapine resistance are most likely to bene fit from combination therapy that does not contain nevirapine (and because of cross resistance, efavirenz)29. Few data evaluate response to subsequent therapy in women who receive current combination drug regi mens for prophylaxis and discontinue the drugs postpartum. In theory, however, resistance should not occur if the regimen that was discontinued had fully suppressed viral replication. Issues relating to the discontinuation o f nevirapine-based combination therapy are discussed in Prevention o f Antiretroviral Drug Resistance. Management of Antiretroviral Drug Resistance during Pregnancy (Updated September 14, 2011) Panel's Recommendations • Women who have documented zidovudine resistance and are on regimens that do not include zidovudine for their own health should still receive intravenous zidovudine during labor whenever possible, along with their established antiretro viral (ARV) regimens (AII). • In women who are receiving a stavudine-containing regimen, the drug should be discontinued during labor while intra venous zidovudine is being administered (see Intrapartum Care) (AII). • The optimal prophylactic regimen for newborns of women with ARV resistance is unknown (see Infant Antiretroviral Pro phylaxis). Therefore, ARV prophylaxis for an infant born to a woman with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist, preferably before delivery (AIII). Ideally, ARV regimens used during pregnancy for treatment or prophylaxis should be chosen based upon the results o f ARV resistance testing. Although most transmission occurs intrapartum, 30% -35% of transmission may occur in utero1-3. The majority o f the latter infections are believed to occur later in pregnancy1 and they may be more likely in women with advanced HIV disease and/or high viral load2-3. Therefore, a delay in initiation o f an ARV drug regimen to await results o f resistance testing could result in in utero infection o f the infant, particularly in women at high risk o f transmission or who are late in pregnancy at the time the drugs are initiated. In such circumstances, as noted earlier, empiric initiation of the ARV drug regimen may be warranted, with modification o f the regimen once resistance testing re sults become available. For women who have documented zidovudine resistance and whose antepartum regimen does not in clude zidovudine, the drug still should be given intravenously during labor whenever possible (see Intra partum Care). Because stavudine may be antagonistic to zidovudine, it should be stopped during the intrapartum period and restarted after delivery (see Intrapartum Care). Other ARVs should be continued orally during labor to the extent possible. The optimal prophylactic regimen for newborns o f women with ARV drug-resistant virus is unknown. Therefore, ARV prophylaxis for infants born to women with known or suspected drug-resistant virus should be determined with a pediatric HIV specialist, preferably before delivery (see Infant Antiretroviral Prophylaxis) . The rationale for including zidovudine intrapartum when a woman is known to harbor virus with zi dovudine resistance is based on several factors. Data thus far have suggested that only wild-type virus appears to be transmitted to infants by mothers who have mixed populations o f wild-type virus and virus with low-level zidovudine resistance4. Other studies have suggested that drug-resistance mutations may dim inish viral fitness and possibly decrease transmissibility5. The efficacy o f the zidovudine prophylaxis appears to be based not only on a reduction in maternal HIV viral load but also on pre-and post-expo sure prophylaxis in the infant6-8. Zidovudine crosses the placenta readily and has one o f the highest maternal-to-cord blood ratios among the nucleoside analogue agents. In addition, zidovudine is metabolized to the active triphosphate within the placenta9-10, which may provide additional protection against trans mission. Metabolism to the active triphoshate, which is required for activity o f all nucleoside analogue agents, has not been observed within the placenta with other nucleoside analogues that have been evalu ated (didanosine and zalcitabine). Zidovudine penetrates the central nervous system (CNS) better than do other nucleoside analogues except stavudine, which has similar CNS penetration; this may help to eliminate a potential reservoir for transmitted HIV in the infant11-12. Thus, intrapartum intravenous ad ministration o f zidovudine currently is recommended even in the presence o f known resistance because o f the unique characteristics of the drug and its proven record in reducing perinatal transmission. Prevention of Antiretroviral Drug Resistance (Updated September 14, 2011) Panel's Recommendations • HIV-infected pregnant women should be given combination antiretroviral (ARV) drug regimens to maximally suppress viral replication; that is the most effective strategy for preventing development of resistance and minimizing risk of peri natal transmission (AII). • All pregnant women should be counseled about the importance of adherence to prescribed ARV medications to reduce the potential for development of resistance (AII). • Pregnant women who are receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination ARV therapy solely for prophylaxis of transmission that will be discontinued after delivery should receive nucleoside analogue agents for at least 7 days after the NNRTI is stopped to minimize risk of resistance (AI). An alternative strategy is to sub stitute a protease inhibitor (PI) for the NNRTI prior to the interruption and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for at least 7 days after stopping the NNRTI (CIII). The optimal interval between stopping an NNRTI and the other ARV drugs is not known (see Stopping Antiretroviral Therapy during Pregnancy and Postpartum Follow-Up of HIV-Infected Women). • Adding single-dose maternal/infant nevirapine to an ongoing combination ARV regimen given for treatment or prophy laxis does not increase efficacy in reducing perinatal transmission and may result in nevirapine drug resistance in the mother and/or infant; therefore single-dose maternal/infant nevirapine is not recommended in this situation (AI). The most effective way to prevent the development o f ARV drug resistance in pregnancy is to use and adhere to an effective combination o f ARV drugs to achieve maximal viral suppression. Several studies have shown that development o f nevirapine resistance is significantly decreased (but not eliminated) after exposure to single-dose intrapartum nevirapine (given alone or in combination with an tenatal ART) when zidovudine/lamivudine is given intrapartum and administered for 3-7 days postpar tum in women who have received single-dose nevirapine1-3. A variety o f other regimens (e.g., tenfovir/emtricitabine, zidovudine/didanosine) given for 7-30 days postpartum following maternal sin gle-dose nevirapine have also been shown to be very effective in reducing the development o f nevirap ine resistance4-6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual NRTIs for a period of time7. The optimal duration for continuation o f either dual nucleosides or the substituted PI-based regimen after stopping the NNRTI is unknown. NNRTI drugs have long half-lives, and drug levels can persist for up to 1-3 weeks after stopping the drug; efavirenz levels persist longer than nevirapine levels8-9. More research is needed on the optimal duration o f time and regimen to "cover" this period o f prolonged NNRTI exposure to prevent the emergence o f resistance after discon tinuation of NNRTI-based therapy. Many experts will stop the NNRTI drug and continue the other ARV drugs for at least 7 days, although other experts would recommend up to 30 days, particularly if an efavirenz-based regimen is being discontinued. Intrapartum Care (Updated September 14, 2011) # Intrapartum Antiretroviral Therapy/Prophylaxis Panel's Recommendations • Intrapartum intravenous zidovudine is recommended for all HIV-infected pregnant women, regardless of their antepar tum regimen, to reduce perinatal transmission of HIV (AI). • For women who are receiving a stavudine-containing antepartum regimen, stavudine should be discontinued during labor while intravenous zidovudine is being administered (AI). • Women who are receiving an antepartum combination antiretroviral (ARV) drug regimen should continue this regimen on schedule as much as possible during labor and before scheduled cesarean delivery (AIII). • Women receiving fixed-dose combination regimens that include zidovudine should receive intravenous zidovudine during labor while other oral ARV components are continued (AIII). • For women who have received antepartum ARV drugs but have suboptimal viral suppression near delivery (i.e., HIV RNA >1,000 copies/mL), scheduled cesarean delivery is recommended (see Mode of Delivery) (AI). The addition of single dose intrapartum/newborn nevirapine is not recommended (AI). • Women of unknown HIV status who present in labor should undergo rapid HIV antibody testing (AII). If the results are positive, a confirmatory HIV test should be done as soon as possible and maternal/infant ARV drugs should be initiated pending results of the confirmatory test (AII). If the confirmatory HIV test is positive, infant ARV drugs should be contin ued for 6 weeks (see Neonatal Postnatal Care) (AI); if the test is negative, the infant ARV drugs should be stopped. • Intravenous zidovudine is recommended for HIV-infected women in labor who have not received antepartum ARV drugs and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (AII). Table 8 shows dosing for zidovudine, given intravenously as a continuous infusion during labor and dur ing the neonatal period; Table 9 shows intrapartum and neonatal dosing for additional drugs to be con sidered in certain situations, as delineated below. # Women Who H ave R eceived Antepartum Antiretroviral Drugs # Use of Intravenous Zidovudine during Labor Results from PACTG 076 and subsequent epidemiologic studies have proven the efficacy o f the threepart zidovudine chemoprophylaxis regimen, alone or in combination with other ARV agents. The PACTG 076 zidovudine regimen includes a continuous intravenous infusion o f zidovudine during labor (initial loading dose o f 2 mg/kg intravenously over 1 hour, followed by continuous infusion o f 1 mg/kg/hour until delivery). Given results from this trial, intravenous zidovudine during the intrapartum period should be discussed with and recommended to all HIV-infected pregnant women. Administration o f intravenous zidovudine should begin 3 hours before scheduled cesarean delivery, according to stan dard dosing recommendations. Women receiving fixed-dose combination regimens that include zidovu dine, such as a zidovudine/lamivudine combination, should receive intravenous zidovudine during labor while other oral ARV components are continued. For example, in women who are receiving zidovudine/lamivudine during pregnancy, zidovudine should be given intravenously and lamivudine should be given orally during labor. If antenatal use o f zidovudine was precluded by known or suspected zidovudine resistance, intrapartum use o f the drug still should be recommended, except in woman with documented histories o f hypersensi-tivity. This intrapartum use o f the drug is recommended because o f the unique characteristics of zidovu dine and its proven record in reducing perinatal transmission, even in the presence o f maternal resistance to the drug (see Management o f Antiretroviral Drug Resistance during Pregnancy) . Because there is pharmacologic antagonism between zidovudine and stavudine, those drugs should not be coadministered during labor. Women who are receiving an antepartum stavudine-containing regimen should have the drug temporarily discontinued during labor while intravenous zidovudine is being administered, with other components o f the regimen continued orally. # Continuation o f Antenatal Antiretroviral Drugs during Labor Women who are receiving an antepartum combination ARV drug regimen should continue that regimen on schedule as much as possible during the intrapartum period to provide maximal virologic effect and to minimize the chance o f development o f drug resistance. When cesarean delivery is planned, oral med ications can be continued preoperatively with sips o f water. Medications requiring food ingestion for ab sorption can be taken with liquid dietary supplements, contingent on consultation with the attending anesthesiologist in the preoperative period. If the maternal ARV regimen must be interrupted temporar ily (e.g., for less than 24 hours) during the peripartum period, all drugs should be stopped and reinsti tuted simultaneously to minimize the chance that resistance will develop. # Women Who H ave R eceived Antepartum Antiretroviral D rugs B ut H ave Suboptimal Viral Suppression Near Delivery Women who have received combination ARV drug regimens may not achieve complete viral suppres sion by the time o f delivery because o f factors such as poor adherence, viral resistance, or late entry into care. Regardless of the reason, all women who have HIV RNA levels >1,000 copies/mL near the time of delivery should be offered a scheduled cesarean delivery at 38 weeks, which may significantly reduce the risk o f transmission (see Transmission and Mode o f Delivery). The addition o f single-dose nevirapine during labor has not been shown to reduce perinatal transmission o f HIV in this group of women. The PACTG 316 study, conducted in women in the United States, Eu rope, Brazil, and the Bahamas who were receiving ARV drugs during pregnancy (primarily combination therapy), showed that the addition o f single-dose nevirapine did not reduce the risk o f mother-to-child transmission of HIV, even in the setting o f maternal viremia. It was, however, associated with the devel opment o f nevirapine resistance in 15% of women with detectable HIV RNA levels postpartum1-2. Given the risk o f development o f resistance and the lack o f data to suggest added efficacy, addition o f single dose nevirapine is not recommended in women who have received combination antepartum ARV drugs. Use of additional medications for prophylaxis in infants may be warranted in special circumstances, such as in cases where maternal HIV RNA levels are high at or near the time o f delivery, especially if delivery is not a scheduled cesarean delivery (see Infant Antiretroviral Prophylaxis and Table 9) . How ever, no additional intrapartum interventions are indicated for the mothers. # Women Who H ave N ot R eceived Antepartum Antiretroviral Drugs # Women W ho Present in Labor W ithout Documentation of HIV Status All women with undocumented HIV status or without documentation o f HIV status at the time o f labor should be screened with rapid HIV testing unless they decline (opt-out screening). Rapid HIV testing is also recommended for women presenting in labor who tested negative for HIV in early pregnancy but are at increased risk o f HIV infection and were not retested in the third trimester3. Factors that may in crease risk of infection include diagnosis o f a sexually transmitted infection (STI), illicit drug use or ex change o f sex for money or drugs, multiple sexual partners during pregnancy, a sexual partner at risk of HIV infection, signs/symptoms o f acute HIV infection, or living in a region with an elevated incidence o f HIV in women o f childbearing age and not undergoing repeat HIV testing in the third trimester3. Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity serv ice and/or neonatal intensive care unit. Statutes and regulations regarding rapid testing vary from state to state; see http://www.nccc.ucsf.edu/consultation_library/state_hiv_testing_laws for a review o f state HIV testing laws. Current information on rapid testing also should be available at all facilities with a maternity service and/or neonatal intensive care unit. Women with positive rapid HIV antibody tests should be presumed to be infected until standard HIV an tibody confirmatory testing clarifies their infection status. Along with confirmatory HIV antibody test ing, these women should receive appropriate assessments as soon as possible to determine their health status and make recommendations for whether antiretroviral therapy (ART) is needed based on that sta tus. Arrangements also should be made for establishing HIV care and providing ongoing psychosocial support after discharge. Intravenous zidovudine should be started immediately in all women with posi tive rapid HIV tests in labor to prevent perinatal transmission o f HIV, as discussed below. # Choice of Intrapartum/Postpartum Antiretroviral Regimen for Women without Antepartum Antiretroviral Therapy All HIV-infected women who have not received antepartum ARV drugs should have intravenous zidovu dine started immediately to prevent perinatal transmission o f HIV (see Table 8 for dosing information). Although intrapartum/neonatal ARV medications will not prevent perinatal transmission that occurs be fore labor, most transmission occurs near to or during labor and delivery. Pre-exposure prophylaxis for the fetus can be provided by giving mothers a drug that rapidly crosses the placenta, producing fetal sys temic ARV drug levels during intensive exposure to HIV in maternal genital secretions and in blood dur ing birth. In general, zidovudine and other nucleoside reverse transcriptase inhibitor (NRTI) drugs and non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs cross the placenta well, whereas protease inhibitors (PIs) do not (see Table 5). Epidemiologic data indicate that intravenous maternal intrapartum zidovudine followed by oral zidovu dine for 6 weeks for the infant significantly reduces transmission compared with no treatment4. In a New York State cohort study, transmission rates were 10% with intrapartum and neonatal zidovudine com pared with 27% without zidovudine, a 62% reduction in risk4. The PETRA study demonstrated that in trapartum prophylaxis alone, without an infant post-exposure prophylaxis component, is not effective in reducing perinatal transmission5. A large international trial (NICHD-HPTN 040/PACTG 1043) demonstrated that adding ARV agents to the neonatal portion o f the intrapartum/neonatal zidovudine regimen can further reduce mother-to-child transmission of HIV for mothers who have received no antepartum ARV drugs (see Infant Antiretroviral Prophylaxis). In this study, women who had not received antepartum ARV drugs received only intra venous zidovudine, whereas their infants received zidovudine in combination with other agents, achiev ing a 50% reduction in transmission. Therefore, no additional intrapartum drugs, including intrapartum maternal single-dose nevirapine, are indicated for the woman in this situation6. References: Transmission and Mode of Delivery (Updated September 14, 2011) Panel's Recommendations • Scheduled cesarean delivery at 38 weeks' gestation is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery, irrespective of administration of antepartum antiretroviral (ARV) drugs, and for women with un known HIV RNA levels near the time of delivery (AII). • Scheduled cesarean delivery is not routinely recommended for prevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levels <1,000 copies/mL near the time of delivery. Data are in sufficient to evaluate the potential benefit of cesarean delivery in this group, and given the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additional benefit in reducing transmis sion. This decision should be individualized based on discussion between the obstetrician and the mother (BII). • It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventing peri natal transmission. Management of women originally scheduled for cesarean delivery who present with ruptured mem branes or in labor must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current ARV regimen, and other clinical factors (BII). • Women should be informed of the risks associated with cesarean delivery; the risks to the woman should be balanced with potential benefits expected for the neonate (AIII). # Basis fo r Current Recommendations Scheduled cesarean delivery, defined as cesarean delivery performed before the onset o f labor and be fore rupture of membranes, is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery and for women with unknown HIV RNA levels1. This recommendation is based on findings from a multicenter, randomized clinical trial2 and from a large individual patient data meta-analysis3. These two studies were conducted at a time when the major ity of HIV-infected women received no ARV medications or zidovudine as a single drug and before the availability o f viral load information. Study results have since been extrapolated to make current recom mendations about the mode o f delivery in an era when combination ARV regimens during pregnancy are recommended and viral load information is readily available. In the randomized clinical trial, 1.8% of infants born to women randomized to undergo cesarean delivery were HIV infected compared with 10.5% of infants born to women randomized to vaginal delivery (P <0.001). When adjusted for ARV use in pregnancy (zidovudine alone), scheduled cesarean delivery lowered the risk of HIV transmission by 80%, although the results were no longer statistically significant (odds ratio [OR] 0.2, 95% confidence interval [CI], 0-1.7). When the data were analyzed by the actual mode of deliv ery, rather than to which group women were allocated, there was still a protective effect of scheduled ce sarean delivery (adjusted OR [AOR] 0.3; 95% CI, 0.1-0.8) but not with emergency cesarean delivery (AOR 1.0; 95% CI, 0.3-3.7)2. Results from a large meta-analysis of individual patient data from 15 prospective cohort studies also demonstrated the benefit of scheduled cesarean delivery with a 50% reduction in risk3. Primarily based on these data, the American College of Obstetricians and Gynecologists has recommended consideration of scheduled cesarean delivery for HIV-infected pregnant women since 19994. # HIV RNA Level o f 1,000 copies/mL as a Threshold for Recommendation of Scheduled Cesarean Delivery The original American College o f Obstetricians and Gynecologists committee opinion was updated in 2000 to include further refinements based on HIV RNA levels1. Currently, the American College o f Ob stetricians and Gynecologists1 recommends that women with HIV RNA >1,000 copies/mL be counseled regarding the potential benefits o f scheduled cesarean delivery. Initially, this threshold o f 1,000 copies/mL was based largely on data from the Women and Infants Transmission Study (WITS), a large prospective cohort study that reported no HIV transmission among 57 women with HIV RNA levels <1,000 copies/mL5. Since that time, newer studies have demonstrated that HIV transmission can occurr among infants born to women with low viral loads. In an analysis o f 957 women with plasma viral loads <1,000 copies/mL, cesarean delivery (scheduled or urgent) reduced the risk o f HIV transmission when adjusting for potential confounders including receipt o f maternal ARV medications, primarily zidovudine alone as prophylaxis (AOR 0.30; P = 0.022)6. Among infants born to 834 women with HIV RNA <1,000 copies/mL receiving ARV medications, 8 (1%) were HIV infected. In a more recent report from a comprehensive national surveillance system in the United Kingdom and Ireland, 3 (0.1%) o f 2,309 and 12 (1.2%) o f 1,023 infants born to women with HIV RNA o f <50 copies/mL and 50-999 copies/mL, respectively, were HIV infected7. The recent studies demonstrate that transmission can occur even at very low HIV RNA levels. However, given the low rate of transmission among this group, it is unclear whether scheduled cesarean delivery confers any additional benefit in reducing transmission. Although decisions about mode of delivery for women with HIV RNA levels <1,000 copies/mL should be individualized based on discussion between the obstetrician and the mother, scheduled cesarean delivery is not routinely recommended in this group. # Scheduled Cesarean Delivery in the Highly Active Antiretroviral Therapy Era In surveillance data from the United Kingdom and Ireland, pregnant women receiving combination ARV regimens (i.e., at least 3 drugs) had transmission rates o f about 1%, unadjusted for mode o f delivery7. Given the low transmission rates achievable with use of maternal combination ARV drug regimens, the benefit o f scheduled cesarean delivery is difficult to evaluate. Both the randomized clinical trial2 and meta-analysis3 documenting the benefits o f cesarean delivery included mostly women who were receiv ing either no ARVs or zidovudine only. However, other data partially address this issue. In a report from the European Collaborative Study that included data from 4,525 women, the overall trans mission rate among the subset of women on a combination ARV regimen was 11(1.2%) of 9188. Among the subset of 560 women with undetectable HIV RNA levels (<50 to <200 copies/mL, depending on site), scheduled cesarean delivery was associated with a significant reduction in perinatal transmission in uni variate analysis (OR 0.07; 95% CI, 0.02-0.31; P = 0.0004). However, after adjustment for ARV drug use (none vs. any), the effect was no longer significant (AOR 0.52; 95% CI, 0.14-2.03; P = 0.359). Similarly, data from a European surveillance study did not demonstrate a statistically significant difference in trans mission rates between scheduled cesarean delivery and planned vaginal delivery (AOR 1.24; 95% CI, 0.34-4.5) among women on combination ARV drug regimens7. The transmission rate among all women who received at least 14 days of ARV medications was 40 (0.8%) of 4,864, regardless of mode of delivery. Therefore, it is not clear whether there is any benefit from scheduled cesarean delivery among women who have been receiving combination ARV medications for several weeks. # Women Presenting Late in Pregnancy HIV-infected women who present in late pregnancy and are not receiving ARV drugs may not have HIV RNA results available before delivery. Without current therapy, HIV RNA levels are unlikely to be <1,000 copies/mL at baseline. Even if combination ARV medications were begun immediately, reduc tion in plasma HIV RNA to undetectable levels usually takes several weeks, depending on the kinetics of viral decay for the particular drug regimen9. In this instance, scheduled cesarean delivery is likely to pro vide additional benefit in reducing the risk o f perinatal transmission o f HIV for women, unless viral sup pression can be documented prior to 38 weeks. # Timing of Scheduled Cesarean Delivery In general, for women without HIV infection, American College of Obstetricians and Gynecologists rec ommends that scheduled cesarean delivery not be performed before 39 weeks' gestation because of the risk of iatrogenic prematurity10-11. However, in cases of cesarean delivery performed to prevent transmis sion of HIV, American College of Obstetricians and Gynecologists recommends scheduling cesarean de livery at 38 weeks' gestation in order to decrease the likelihood o f onset of labor or rupture of membranes before delivery1. Among all women undergoing repeat cesarean delivery, the risk of any neonatal adverse event-including neonatal death, respiratory complications, hypoglycemia, newborn sepsis, or admission to the neonatal intensive care unit-is 15.3% at 37 weeks, 11.0% at 38 weeks, and 8.0% at 39 weeks11. Gestational age should be determined by last menstrual period and ultrasonography because amniocentesis to document lung maturity should be avoided, when possible, in HIV-infected women. Among 1,194 infants born to HIV-infected mothers, 9 (1.6%) infants born vaginally had respiratory dis tress syndrome (RDS) compared with 18 (4.4%) of infants born by scheduled cesearean delivery (P <0.001). There was no statistically significant association between mode of delivery and infant RDS in an adjusted model that included infant gestational age and birth weight12. Clinicians should recognize that newborn complications may be increased in planned early term births <39 weeks' gestation. However, for HIV-infected women, the benefits of decreasing HIV transmission by planned delivery at 38 weeks are generally thought to outweigh the risks. When cesarean delivery is performed in HIV-infected women for an indication other than decreasing transmission of HIV, cesarean delivery should be scheduled at 38 weeks gestation based on accepted American College of Obstetricians and Gynecologists guidelines. # Risk of M aternal Complications Because maternal infectious morbidity is increased with cesarean delivery even among women without HIV infection, the administration of perioperative antimicrobial prophylaxis is recommended for all women undergoing cesarean delivery. Most studies have demonstrated that HIV-infected women have in creased rates of postoperative complications, mostly infectious, compared with HIV-uninfected women and that the risk of complications is related to the degree of immunosuppression13-18. Furthermore, a Cochrane review of six studies of HIV-infected women concluded that urgent cesarean delivery was asso ciated with the highest risk of postpartum morbidity, that scheduled cesarean delivery was intermediate in risk, and that vaginal delivery had the lowest risk of morbidity19. Complication rates in most studies2, 20-24 were within the range reported in populations of HIV-uninfected women with similar risk factors and were not of sufficient frequency or severity to outweigh the potential benefit of reduced transmission. Therefore, HIV-infected women should be counseled regarding the increased risks and potential benefits associated with cesarean delivery based on their HIV RNA levels and current ARV regimen. # Management o f Women W ho Present in Early Labor or With Ruptured Membranes Few data are available to address the question o f whether performing cesarean delivery after the onset of labor or membrane rupture may decrease the risk o f perinatal transmission o f HIV. Most studies have shown a similar risk o f transmission for cesarean delivery performed after labor and membrane rupture for obstetric indications and for vaginal delivery. In one study, the HIV transmission rate was similar in women undergoing emergency cesarean delivery and those delivering vaginally (1.6% vs. 1.9%, respectively)7. A meta-analysis o f women, most o f whom were on zidovudine as a single drug or receiving no ARV medications, demonstrated a 2% increased transmission risk for every additional hour o f ruptured membranes25. However, it is not clear how soon after the onset o f labor or the rupture o f membranes the benefit o f cesarean delivery is lost26. Therefore, the management o f women originally scheduled for ce sarean delivery who present with ruptured membranes or in labor must be individualized based on clini cal factors such as duration o f rupture, progress o f labor, plasma RNA level, and current ARV drug regimen status. When membrane rupture occurs before 37 weeks' gestation, decisions about delivery should be based on gestational age, HIV RNA level, current ARV regimen, and evidence o f acute infec tion such as chorioamnionitis; consultation with an expert is recommended. The ARV drug regimen should be continued and consideration given to initiating intravenous zidovudine if delivery appears im minent. No data exist to suggest that recommendations for administration o f steroids to accelerate fetal lung maturity should be altered among HIV-infected women. Table 7 provides a summary o f recommendations regarding mode o f delivery for different clinical sce narios. # Clinical Scenario Recommendations HIV-infected women presenting in late pregnancy (after about • Start ARV medications as per Table 6 . • Provide counseling on the likelihood that scheduled cesarean delivery will reduce the risk 36 weeks' gestation), known to of mother-to-child transmission, if viral suppression cannot be documented prior to 38 be HIV infected but not receiv ing antiretroviral (ARV) medica tions, and who have HIV RNA level and CD4 cell counts pend ing but unlikely to be available before delivery. weeks. Include information on the increased maternal risks of cesarean delivery, including increased rates of postoperative infection, anesthesia, and other surgical risks. • When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography. • Administer continuous intravenous zidovudine beginning 3 hours before scheduled ce sarean. • Continue other ARV medications on schedule, as much as possible, before and after surgery. • Use of prophylactic antibiotics at the time of cesarean delivery is recommended. HIV-infected women who began prenatal care early in the third trimester, are receiving combina tion ARV drug regimens, and have an initial virologic response but have HIV RNA levels that re main substantially >1,000 copies/mL at 36 weeks' gesta tion. • Continue the current combination ARV regimen because the drop in HIV RNA level is ap propriate. • Provide counseling on the timing of response to ARV medications and the likelihood that maternal HIV RNA levels may not fall below 1,000 copies/mL before delivery. Consider scheduled cesarean delivery if viral load suppression is not achieved by 38 weeks be cause of the potential additional benefit in preventing intrapartum transmission of HIV. In form patients about the increased maternal risks associated with cesarean delivery, including risks related to anesthesia and surgery and increased rates of postoperative in fection. • When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography. • When the delivery method selected is scheduled cesarean delivery, administer continuous intravenous zidovudine beginning 3 hours before scheduled cesarean. • Continue other ARV medications on schedule, as much as possible, before and after surgery. • Use of prophylactic antibiotics at the time of cesarean delivery is recommended. HIV-infected women on combi nation ARV drug regimens with undetectable HIV RNA levels at 36 weeks' gestation. • Provide counseling on the risk of perinatal transmission of HIV with a persistently unde tectable HIV RNA level, which is probably 1% or less, even with vaginal delivery. No evi dence currently exists to show that this risk can be lowered further by performing scheduled cesarean delivery. • Risk of complications is increased with cesarean delivery, compared with vaginal delivery, even in the HIV-uninfected population, and the risks must be balanced against the uncer tain benefits of cesarean delivery in women with undetectable viral load. HIV-infected women who have elected scheduled cesarean de livery but present after rupture of membranes at >37 weeks' gestation. • Start intravenous zidovudine immediately. • Individualize the decision regarding mode of delivery, based on clinical factors such as dura tion of rupture, anticipated progress of labor, plasma RNA level, and current ARV regimen. • When vaginal delivery is chosen, some clinicians may consider administration of oxy tocin, if clinically appropriate, in order to expedite delivery. Scalp electrodes and other in vasive monitoring and operative delivery should be avoided, if possible, unless there are clear obstetric indications. • When cesarean delivery is chosen, administration of the loading dose of intravenous zi dovudine ideally should be completed prior to the procedure. However, decisions regard ing timing of delivery should be individualized. Other Intrapartum Management Considerations (Updated September 14, 2011) # Panel's Recommendations • Generally avoid artificial rupture of membranes unless there are clear obstetric indications because of a potential in creased risk of transmission (BIII). • Routine use of fetal scalp electrodes for fetal monitoring should be avoided in the setting of maternal HIV infection unless there are clear obstetric indications (BIII). • Operative delivery with forceps or a vacuum extractor and/or episiotomy should be performed only if there are clear ob stetric indications (BIII). • The antiretroviral drug (ARV) regimen a woman is receiving should be taken into consideration when treating excessive postpartum bleeding resulting from uterine atony: • In women who are receiving a cytochrome P (CYP) 3A4 enzyme inhibitor such as a protease inhibitor (PI), methergine should only be used if no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest ef fective dose for the shortest possible duration (BIII). • In women who are receiving a CYP3A4 enzyme inducer such as nevirapine or efavirenz, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect (BIII). If spontaneous rupture o f membranes occurs before or early during the course o f labor, interventions to decrease the interval to delivery, such as administration o f oxytocin, may be considered in women with out indications for cesarean delivery. Artificial rupture o f membranes should be avoided and used only for a clear obstetric indication in women with intact membranes and detectable viral load who present in labor and proceed to vaginal de livery. Data are limited on artificial rupture o f membranes in women with undetectable viral load and planned vaginal delivery. In general, the procedure should be performed only for clear obstetrical indica tions because o f the potential, albeit small, increased risk o f HIV transmission. Obstetric procedures that increase the risk o f fetal exposure to maternal blood, such as invasive fetal monitoring, have been implicated in increasing vertical transmission rates by some, but not all, investi gators, primarily in studies performed in the pre-combination antiretroviral therapy (ART) era1-4. Data are limited on routine use o f fetal scalp electrodes in labor in women receiving suppressive ARV regi mens and undetectable viral load; routine use o f fetal scalp electrodes for fetal monitoring should be avoided in the setting o f maternal HIV infection unless there are clear obstetric indications. Similarly, data are limited to the pre-combination ART era regarding the potential risk o f perinatal trans mission o f HIV associated with operative vaginal delivery with forceps or the vacuum extractor and/or use o f episiotomy2, 4. These procedures should be performed only if there are clear obstetric indications. Delayed cord clamping has been associated with improved iron status and benefits such as decreased risk o f intraventricular hemorrhage in preterm births to HIV-uninfected mothers5-7. Even though HIVspecific data on the practice are lacking, there is no reason to modify it in HIV-infected mothers. # Postpartum Hemorrhage, Antiretroviral Drugs, and M ethergine Use Oral or parenteral methergine or other ergot alkaloids are often used as first-line treatment for postpar tum hemorrhage resulting from uterine atony. However, methergine should not be coadministered with drugs that are potent CYP3A4 enzyme inhibitors, including PIs. Concomitant use o f ergotamines and PIs has been associated with exaggerated vasoconstrictive responses. When uterine atony results in ex cessive postpartum bleeding in women receiving PIs as a component o f an ARV regimen, methergine should be used in women with excessive postpartum bleeding who are receiving PIs as a component of ART only if alternative treatments such as prostaglandin F 2 alpha, misoprostol, or oxytocin are unavail able. If no alternative medications are available and the need for pharmacologic treatment outweighs the risks, methergine should be used in as low a dosage and for as short a period as possible. In contrast, ad ditional utertonic agents may be needed when other ARV drugs that are CYP3A4 inducers, such as nevi rapine and efavirenz, are used because o f the potential for decreased methergine levels and inadequate treatment effect. Postpartum Management (Updated September 14, 2011) Postpartum Follow-up of HIV-Infected Women # Panel's Recommendations • Contraceptive counseling should be included as a critical aspect of postpartum care (AIII). • Decisions about continuing antiretroviral (ARV) drugs after delivery should take into account current recommendations for initiation of antiretroviral therapy (ART), current and nadir CD4 cell counts and trajectory, HIV RNA levels, adherence issues, whether the woman has an HIV-uninfected sexual partner, and patient preference (AIII). • For women continuing ARV drugs postpartum, arrangements for new or continued supportive services should be made before hospital discharge because the immediate postpartum period poses unique challenges to adherence (AII). • Women with a positive rapid HIV antibody test during labor require comprehensive follow-up, including confirmation of HIV infection. If infection is confirmed, a full health assessment is warranted, including evaluation for associated medical conditions, counseling related to newly diagnosed HIV infection, and assessment of need for ART and opportunistic in fection (OI) prophylaxis (AII). The postpartum period provides an opportunity to review and optimize women's health care. Compre hensive care and support services are particularly important for women with HIV infection and their families, who often face multiple medical and social challenges. Components o f comprehensive care in clude the following medical and supportive care services as needed: • primary, gynecologic/obstetric, and HIV specialty care for the HIV-infected woman; • pediatric care for her infant; • family planning services; • mental health services; • substance abuse treatment; • support services; and • coordination of care through case management for the woman, her child(ren), and other family members. Support services should be tailored to individual women's needs and may include case management; child care; respite care; assistance with basic life needs, such as housing, food, and transportation; peer counseling; and legal and advocacy services. Ideally, this care should begin before pregnancy and con tinue throughout pregnancy and the postpartum period. During the postpartum period, maternal medical services must be coordinated between obstetric care providers and HIV specialists. It is especially critical to ensure continuity o f the antepartum ARV drug regimen when such treatment is required for a woman's health. The decision about whether to continue ARV drugs after delivery should be discussed with a woman and made before delivery. The postpartum period also is a critical time for addressing the issue of safer sex practices and contracep tion. Lack of breastfeeding is associated with earlier return of fertility; ovulation returns as early as 6 weeks postpartum, and even earlier in some women, putting them at risk of pregnancy shortly after deliv ery1. Interpregnancy intervals of less than 18 months have been associated with increased risk of poor peri natal and maternal outcomes in HIV-uninfected women2. Because of the stresses and demands of a new baby, women may be more receptive to use of effective contraception, yet simultaneously at higher risk of nonadherence to contraceptive use and thus unintended pregnancy3. This is an important concern in women who are on an efavirenz-containing regimen because of the potential risk of teratogencity. A "dual protection" strategy, such as use of condoms plus a second highly effective contraceptive, is ideal for women with HIV infection because it provides simultaneous protection against unintended pregnancy and HIV transmission or sexually transmitted disease (STD) acquisition or transmission4. Longer term, re versible contraceptive methods, such as injectables, implants, and intrauterine devices (IUDs) should be included as options. Drug interactions have been documented between oral contraceptives (OCs) and many ARV drugs (see Table 4 in Preconception Counseling). These interactions, however, do not necessarily rule out the use of hormonal contraceptives because there is no clear evidence of an effect on contraceptive or ARV efficacy or toxicity. OCs do significantly lower levels of amprenavir/fosamprenavir and, therefore, coadministra tion is not recommended; whether low-dose ritonavir boosting raises amprenavir levels sufficiently to allow coadministration is unknown. Depot medroxyprogesterone acetate (Depo-Provera, DMPA) pharma cokinetics (PKs) are not significantly affected by nevirapine, efavirenz, or nelfinavir, and levels of these drugs were not significantly altered by DMPA5. Adverse effects of DMPA are no different in HIV-infected women on ARV drugs than in HIV-uninfected women6. Other non-oral contraceptives, such as levonorgestrel implants, the combined contraceptive patch, the combined hormonal contraceptive vaginal ring, and the levonorgestrel IUD, are largely unstudied in combination with ARV drugs, but some data do exist on lopinavir/ritonavir interactions with the estrogen patch7. ARV drug interactions may be of less concern with contraceptive methods that exert primarily local activity and have minimal systemic absorp tion, but there is still a potential for interaction if metabolic or elimination pathways are shared5, 8. Perma nent sterilization is appropriate only for women who are certain they do not desire future childbearing. Women with nadir CD4 cell counts less than the currently recommended threshold for institution of ART9 and/or symptomatic HIV infection should be encouraged to continue their ARV regimens postpar tum without interruption. Decisions about whether to continue ARV drugs after delivery should be made in consultation with the HIV provider for women who began ARV drugs for prophylaxis o f transmission with nadir CD4 cell counts greater than that currently recommended for treatment. Factors to be taken into consideration should include current recommendations for initiation o f ART, current and nadir CD4 lymphocyte counts and trajectory, HIV RNA levels, adherence issues, partner HIV status, and patient preference. The risks versus benefits o f stopping combination ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968). Recent data from the HPTN 052 clinical trial showed that earlier initiation o f ARVs led to a significant reduction in sexual transmission o f HIV to uninfected partners in serodiscordant couples (see Preconcep tion Counseling) . HPTN 052 evaluated immediate versus delayed initiation o f ART to HIV-infected indi viduals with CD4 counts between 350 and 550 cells/mm3. Based on the results from that trial, continued administration o f ARV drugs may be recommended for prevention o f sexual transmission o f HIV for postpartum women who have CD4 cell counts between 350 and 550 cells/mm3 and have HIV-uninfected sexual partners, and it may be considered for those with CD4 cell counts greater than 550 cells/mm3 with HIV-uninfected sexual partners. It is important to counsel the woman that no single method (in cluding treatment o f the infected partner) is fully protective against HIV transmission and safer sexual practices should be continued. Concerns have been raised about adherence to ARV regimens during the postpartum period. Women should be counseled that postpartum physical and psychological changes and the stresses and demands o f caring for a new baby may make adherence more difficult and that additional support may be needed during this period10-12. Health care providers should be vigilant for signs o f depression and illicit drug or alcohol use that may require assessment and treatment and interfere with adherence. Poor adherence has been shown to be associated with virologic failure, development o f resistance, and decreased long-term effectiveness o f ART13-15. Simplification o f an ARV regimen (for example, to once-daily medications) can be considered. It may be preferable to temporarily interrupt ART in women who are unable to ad here to their regimens while they work with a provider on strategies to improve adherence. Efforts to maintain adequate adherence during the postpartum period may prolong the effectiveness o f therapy (see the section on Adherence in the Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). For women whose antepartum regimen included a non-nucleoside reverse transcriptase inhibitor (NNRTI) and who plan to stop ARV prophylaxis after delivery, consideration should be given to stopping the NNRTI and continuing the other ARV drugs for a period of time before stopping electively. The optimal interval be tween stopping an NNRTI and the other ARV drugs is unknown; a minimum of 7 days is recommended. Because efavirenz-based therapy has potential to result in prolonged, detectable NNRTI concentrations for more than 3 weeks, some experts recommend that patients receiving efavirenz continue their other ARV drugs or substitute a protease inhibitor (PI) for the NNRTI drug in combination with their other ARV drugs for up to 30 days after stopping efavirenz (see Stopping Antiretroviral Therapy during Pregnancy and Prevention of Antiretroviral Drug Resistance). Women whose antepartum regimen did not include an NNRTI and who plan to stop ARV prophylaxis after delivery should stop all ARV drugs at the same time. Doses of some PIs may be increased during pregnancy. For women continuing therapy, available data sug gest that standard doses can be used again, beginning immediately after delivery. Comprehensive medical assessment, counseling, and follow-up are required for women who test posi tive on rapid HIV antibody assay during labor or at delivery. To minimize the delay in definitive diagno sis, confirmatory HIV antibody testing should be performed as soon as possible after an initial positive rapid test16. Women who test positive on rapid HIV antibody assay should not breastfeed unless a confir matory HIV test is negative. Women with a new HIV diagnosis postpartum should receive the same thorough evaluation as other newly identified infected patients, including consideration o f ART and pro phylaxis for OIs, as indicated. Other children and partner(s) should be referred for HIV testing. Infants Born to Mothers with Unknown HIV Infection Status (Updated September 14, 2011) Panel's Recommendations • For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis (see Infant Antiretroviral Prophylaxis) if the rapid test is positive (AII). In the setting of a positive test, standard antibody con firmatory testing such as a Western blot also should be performed on mothers (or their infants) as soon as possible. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII). • If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) should be ob tained (AIII). • If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to a pediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combination anti retroviral therapy (ART) (AI). Rapid HIV antibody testing o f mothers and/or infants is recommended as soon as possible after birth when maternal HIV status is unknown and rapid HIV antibody testing was not performed during labor. If rapid testing is positive, infant ARV prophylaxis should be initiated immediately. Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity service and/or neonatal in tensive care or newborn nursery. A positive test result in mothers or infants should be presumed to indi cate maternal HIV infection until standard antibody confirmatory testing clarifies maternal status. A standard confirmatory test (e.g., Western blot) should be performed on mothers (or their infants) as soon as possible after the initial positive rapid test1. A positive HIV antibody test in an infant indicates mater nal but not necessarily infant HIV infection; diagnosis o f HIV infection in infants younger than age 18 months requires virologic testing. If the confirmatory test on a mother (or infant) is negative, ARV pro phylaxis can be discontinued. If the confirmatory test is positive, an HIV DNA PCR should be obtained urgently from the newborn. If the HIV DNA PCR is positive, ARV prophylaxis should be promptly dis continued and the infant should receive treatment for HIV infection with standard combination ART ac cording to established Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection developed by The Working Group on Antiretroviral Therapy and Medical Management o f HIV-Infected Children. Infant Antiretroviral Prophylaxis (Updated September 14, 2011; Erratum issued December 1 , 2011) Panel's Recommendations • The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (A I). • Zidovudine should be initiated as close to the time of birth as possible, preferably within 6-12 hours of delivery (A II). • The 6-week zidovudine prophylaxis regimen is recommended at gestational age-appropriate doses; zidovudine should be dosed differently for premature infants less than 35 weeks than for infants at least 35 weeks of age (see Zidovudine Dosing and Table 8) (A II). • In the United States, the use of antiretroviral (ARV) drugs other than zidovudine cannot be recommended in premature infants because of lack of dosing and safety data (B III) . • The use of intrapartum/neonatal zidovudine is recommended regardless of maternal history of zidovudine resistance (B III). • Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, begun as soon after birth as possible (A I). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen of zi dovudine, nelfinavir and lamivudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see General Considerations for Choice of Infant Prophylaxis and Table 9) (A I). • In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consulta tion with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on the potential risks and benefits of this approach (B III). • The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, in cluding infant care. # Zidovudine Dosing All HIV-exposed infants should receive postpartum ARV drugs to reduce perinatal transmission o f HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed in fants1-2. Table 8 shows zidovudine dosing intrapartum, which is a continuous intravenous infusion during labor, and neonatal dosing. Table 9 shows intrapartum and neonatal dosing for other drugs to be consid ered in certain situations as delineated below. The recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, beginning as soon after birth as possible and preferably within 6-12 hours o f delivery (Table 8) . Although the ACTG 076 study used a zidovudine regimen o f 2 mg/kg every 6 hours, data from many international studies support twice-daily oral infant dosing for prophylaxis3-12. Most o f these studies used a dose o f 4 mg/kg twice daily, adjusted for weight gain, but others have used a regimen based on birth weight for the entire 6-week treatment period13-14. The current World Health Organization (WHO) guidelines recommend a simplified zidovudine dosing regimen for the 6-week prophylaxis period consisting o f 10 mg given twice daily for infants weighing less than 2.5 kg at birth and 15 mg twice daily for infants weighing more than 2.5 kg at birth15. The ad vantages o f this simplified regimen are that it avoids the need for dosing calculations and involves ad ministration o f either 1.0 or 1.5 mL o f zidovudine syrup. The disadvantage is that, compared with mg-per-kg dosing, infants with birth weights greater than 3.75 kg will receive a smaller zidovudine dose and infants less than 3.75 kg will receive a larger zidovudine dose. The zidovudine dosing requirements differ for premature infants and term infants. Zidovudine is prima rily cleared through hepatic glucuronidation to an inactive metabolite; this metabolic pathway is imma ture in neonates, leading to prolonged zidovudine half-life and clearance compared with older infants. Clearance is further prolonged in premature infants because their hepatic metabolic function is even less mature than in term infants16-17. The recommended zidovudine dosage for infants less than 35 weeks' gestation is 2 mg/kg body weight per dose orally every 12 hours (or 1.5 mg/kg body weight intra venously per dose every 12 hours), increasing to 2 mg/kg body weight per dose every 8 hours at age 2 weeks for infants born at 30 weeks' gestation or more or at age 4 weeks in those born at less than 30 weeks' gestation. For infants born at more than 35 weeks' gestation or greater who are unable to tolerate oral zidovudine, the drug can be given intravenously at a dose o f 1.5 mg/kg body weight every 6 hours. In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regi men is recommended for infants born to mothers who have received antenatal combination ARV drug regimens18-20. This approach also can be considered in cases where adherence to or toxicity from the 6week zidovudine prophylaxis regimen is a concern. In an Irish observational study, a transmission rate o f 1.1% was observed in 916 infants who received 4 weeks o f zidovudine infant prophylaxis following antenatal maternal combination ARV prophylaxis. That is the standard regimen in Ireland and the trans mission rate was similar to that observed in the United States, where 6 weeks o f infant zidovudine pro phylaxis is standard20. A recent prospective, observational study reported that the 4-week zidovudine regimen allowed earlier recovery from anemia in otherwise healthy infants compared with the 6-week zidovudine regimen21. The optimal duration o f neonatal zidovudine chemoprophylaxis, however, has not been established in clinical trials, and in the United States, the standard 6-week infant zidovudine regi men is recommended unless there are concerns about adherence or toxicity. Consultation with an expert in pediatric HIV infection is advised if early discontinuation o f prophylaxis is considered. b ZDV dosing regimen is for infants >35 weeks' gestation. See Table 8 for recommended doses for premature infants. # General Considerations fo r Choice o f Infant Prophylaxis Infants born to mothers who have received standard antepartum and intrapartum ARV prophylaxis and have undetectable viral loads are at very low risk o f HIV transmission. However, the risk o f transmission is increased when maternal viral load at delivery is high or maternal antepartum and/or intrapartum pro phylaxis was not received. Most experts feel that the potential benefit o f combining zidovudine infant prophylaxis with additional ARV drugs may exceed the risk o f multiple drug exposure to infants born to: a. mothers who received antepartum and intrapartum ARV drugs but who had suboptimal viral suppres sion at delivery, particularly if delivery was vaginal; b. mothers who received only intrapartum ARV drugs; c. mothers who received no antepartum or intrapartum ARV drugs; and d. mothers with known ARV drug-resistant virus. In each o f these situations, there is a spectrum o f transmission risk that depends on a number o f maternal and infant factors, including maternal viral load, mode o f delivery, and gestational age at delivery. The risks and benefits o f infant exposure to ARV drugs in addition to zidovudine will differ depending on where the mother/child falls in the risk spectrum. For example, an infant delivered vaginally to a mother with an HIV RNA level >100,000 copies/mL at delivery has a higher risk o f acquiring HIV infection than an infant born by cesarean delivery to a mother with an HIV RNA level o f approximately 10,000 copies/mL at delivery. Thus, a generic recommendation cannot be made regarding use o f combination drug regimens for infant prophylaxis and each situation needs to be considered individually, balancing potential benefits (in terms of preventing perinatal transmission o f HIV) with risks (in terms o f toxicity to the infant). In addition, appropriate drug formulations and dosing regimens for neonates are incom pletely defined and data are minimal on the safety o f combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis and the Guidelines for the Use o f Anti retroviral Agents in Pediatric HIV Infection). Thus, decisions about use o f combination ARV prophy laxis in infants should be made in consultation with a pediatric HIV specialist before delivery and should be accompanied by a discussion with the mothers about potential risks and benefits o f this approach. Use of combination ARV prophylaxis for infants in high-risk situations is increasing. Despite widespread use of combination ARV prophylaxis, until recently there were no data evaluating the efficacy of these regimens versus zidovudine alone in the setting of high risk of mother-to-child transmis sion of HIV. Results from a Phase III randomized trial in 4 countries (including the United States) were presented at the 2011 Conference on Retroviruses and Opportunistic Infections (NICHD-HPTN 040/PACTG 1043)14. This study enrolled 1,746 infants born to HIV-infected women who did not receive any ARV drugs during pregnancy and, hence, were at high risk of infection. The study compared infant prophylaxis with the standard 6-week zidovudine regimen and 2 different combination regimens for pre vention of intrapartum transmission of HIV: 6 weeks of zidovudine plus 3 doses of nevirapine given dur ing the first week of life (first dose at birth-48 hours; second dose 48 hours after first dose; and third dose 96 hours after second dose) and 6 weeks of zidovudine plus 2 weeks of lamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower, compared with 6 weeks of zidovudine alone, in the 2and 3-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for zidovudine alone; P = 0.046 for each experi mental arm vs. zidovudine alone). The overall transmission rate of HIV (in utero + intrapartum) was also significantly lower in the 2-and 3-drug arms compared with zidovudine alone (7.1%, 7.4%, and 11.1%, re spectively, P = 0.035 for comparison of each experimental arm with zidovudine alone)14. Although trans mission rates with the two combination regimens were similar, neutropenia was significantly more common with the 3-drug regimen than with the 2-drug or zidovudine-alone regimen (27.5% vs. 15%, P <0.0001). In other studies, significantly higher rates of neutropenia and anemia have been reported with coadministration of zidovudine and lamivudine to infants24. The NICHD-HPTN 040/PACTG 1043 study provides proof o f principle that use o f a combination drug regimen for infants is more effective than zidovudine alone in the high-risk setting o f no maternal an tepartum administration o f ARV drugs. The two-drug regimen is less complex and had lower rates of toxicity than the three-drug regimen; additionally, nelfinavir powder is no longer commercially available in the United States, is not a preferred ARV drug for pediatric treatment, and drug levels in neonates are highly variable25. Therefore, the two-drug regimen is recommended for prophylaxis in infants born to mothers who have not received antepartum ARV drugs. Beyond the scenario studied in NICHD-HPTN 040/PACTG 1043, the choice o f ARV drug regimens for neonates is limited (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis) . Neonatal dosing information is not available for any o f the currently available boosted protease in hibitors (PIs). In addition, use of lopinavir/ritonavir in neonates has been associated with severe and sometimes fatal cardiac, renal, central nervous system (CNS), and metabolic toxicity26. Because o f the potential for toxicity, lopinavir/ritonavir should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days. # The National Perinatal HIV Hotline (1-888-448-8765) The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected pregnant women and their infants. # Recommendations fo r Infant Antiretroviral Prophylaxis in Specific Clinical Situations # Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with Effective Viral Suppression The risk o f HIV acquisition is small in infants born to women who received standard ARV prophylaxis regimens during pregnancy and labor and had undetectable viral loads at delivery or born by scheduled cesarean section to mothers with low viral loads at delivery. For example, in PACTG 316, the infection rate in infants born to women receiving antepartum PI-based therapy was 0.7% in 269 infants with HIV RNA levels o f less than 400 copies/mL at delivery2. Such infants should receive the 6-week zidovudine infant prophylaxis regimen. In that situation, combining zidovudine with additional ARV drugs to reduce transmission risk is not recommended because the benefit would be very limited. # Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs But Have Suboptimal Viral Suppression Near Delivery The risk o f perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs as well as women receiving ARVs27-29. Scheduled cesarean delivery is recommended for preven tion of perinatal transmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA >1,000 copies/mL) near the time o f delivery (see Intrapartum Care and Transmission and Mode o f Delivery). In PACTG 316, transmission occurred in 0% o f 17 infants when maternal HIV RNA levels at delivery were >10,000 copies/mL and delivery was by scheduled cesarean delivery2. However, not all women with detectable viremia near delivery will undergo cesarean delivery. The risk o f acquisition o f HIV will be higher in infants born to mothers with higher viral loads near delivery, par ticularly if delivery is vaginal. The gradient o f transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study (WITS), the risk o f transmission o f HIV was <1.8% in women who received triple-combination ARV prophylaxis and had HIV RNA levels <30,000 copies/mL at de livery; it increased to 4.8% in women with HIV RNA levels >30,000 copies/mL29. All infants should receive zidovudine for 6 weeks. No specific data address whether a more intensive combination infant prophylaxis regimen (two or three drugs) provides additional protection against transmission when maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery is significant. Elective cesarean section is recommended for pregnant women with HIV RNA levels >1,000 copies/mL near delivery. Extrapolation o f findings from the previously discussed NICHD-HPTN 040/PACTG 1043 study14 suggests that combination infant prophylaxis can be considered, de pending on assessment o f risk based on maternal viral load and mode o f delivery. That decision should be made in consultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on the potential risks and benefits o f this approach. # Infants Born to Mothers Who Received Only Intrapartum Antiretroviral Drugs All infants whose mothers have received only intrapartum ARV drugs should be given zidovudine for 6 weeks. This infant prophylaxis regimen is a critical component o f prevention when no maternal antepar tum ARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, without infant prophylaxis, is ineffective in reducing perinatal transmission3. A study in Thailand indi cated that longer infant prophylaxis with zidovudine (6 weeks vs. 3 days) is required for optimal efficacy when maternal antenatal exposure to zidovudine is <4 weeks30. Infant prophylaxis with zidovudine should be initiated as soon after delivery as possible. In the NICHD-HPTN 040/PACTG 043 trial previously discussed, 41% of women received zidovudine during labor. Admin istration of intrapartum zidovudine did not affect transmission rates. The results of this study support use of a two-drug regimen, involving 6 weeks of zidovudine plus three doses of nevirapine in the first week of life, because combination regimens were found to have increased efficacy in reducing intrapartum transmission compared with use of zidovudine alone and the three-drug regimen was associated with increased toxicity and nelfinavir powder is no longer commercially available in the United States14. # Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs Infants o f HIV-infected mothers who have received neither antepartum nor intrapartum ARV drugs should be started on ARV prophylaxis as soon after delivery as possible. Observational and Phase III ran domized studies suggest that prophylaxis provided to infants alone may be helpful in preventing trans mission o f HIV. Epidemiologic data from a New York State study indicated a decline in transmission when infants were given zidovudine for the first 6 weeks o f life compared with no prophylaxis31. Trans mission rates were 9% (95% confidence interval [CI], 4.1%-17.5%) with zidovudine-alone prophylaxis in newborns (initiated within 48 hours after birth) versus 27% (95% CI, 21%-33%) with no zidovudine prophylaxis. For most infants in this study, prophylaxis was initiated within 12 hours o f birth32. The interval during which infant prophylaxis can be initiated and still be o f benefit is undefined. In the New York State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could be demonstrated. Data from animal studies indicate that the longer the delay in institution o f prophylaxis, the less likely that infection will be prevented. In most studies o f animals, ARV prophylaxis initiated 24 36 hours after exposure usually has been ineffective in preventing infection, although a delay in adminis tration has been associated with decreased viremia33-35. In the NICHD-HPTN 040/PACTG 1043 study, infant regimens were initiated within 48 hours o f life and usually within 12 hours o f life14. Initiation of infant prophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days, infection already would be established in most infants36. Initiating prophylaxis as soon after de livery as possible increases its potential efficacy and minimizes potential harm, such as development of resistant virus, if infection has occurred. # Infants Born to Mothers with Antiretroviral Drug-Resistant Virus The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus is un known. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery. Data from the WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viral populations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted37-38. Thus, the 6-week infant zidovudine prophylaxis (along with maternal intravenous intrapartum zidovu dine prophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations (TAMs) is identified. Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (re duced viral fitness) and transmissibility38. However, transmission from mother to child o f multidrug-re sistant virus has been reported39-41. For these newborns, use o f zidovudine in combination with other ARV drugs, selected on the basis of maternal virus resistance testing, can be considered. The efficacy o f this approach for prevention of transmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosing regimens for neonates are incompletely defined. Decisions regarding use o f additional drugs should be made in consultation with a pediatric HIV specialist and will depend on maternal history o f past and cur rent ARV drug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, and availability o f drug formulation and dosing information in the infant. ARV drugs with phar macokinetic (PK) and safety data in neonates sufficient to support their addition to zidovudine include lamivudine and nevirapine; although there are pharmacokinetic data in neonates for nelfinavir, nelfinavir powder for oral use is no longer commercially available in the United States. # Breastfeeding Infants of Mothers Diagnosed with HIV Infection Postpartum Breastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeed ing at the time of HIV diagnosis or suspected to be HIV infected. Pumping and temporarily discarding breast milk can be recommended to mothers who are suspected o f being HIV infected but whose infec tion is not yet confirmed and who want to continue to breastfeed. If HIV infection is ruled out, breast feeding can resume. The risk o f acquisition o f HIV associated with breastfeeding depends on multiple infant and maternal factors, including maternal viral load and CD4 cell count42. Infants o f women who develop acute HIV infection while breastfeeding are at greater risk o f becoming infected than are those o f women with chronic HIV infection43 because acute HIV infection is accompanied by a rapid increase in viral load and a corresponding decrease in CD4 cell count44. Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothers who breastfed their infants prior to HIV diagnosis have yet to be defined. Some experts would consider the use of post-exposure prophylaxis in infants for 4 -6 weeks after cessation o f breastfeeding. Post-exposure prophylaxis, however, is less likely to be effective in this circumstance compared with other nonoccupational exposures because the exposure to breast milk is likely to have occurred over a prolonged period rather than in a single exposure45. Several studies o f infants breastfed by women with chronic HIV infection have shown that daily infant nevirapine or nevirapine plus zidovudine can reduce the risk o f postnatal infection during breastfeeding8, 46-47. The NICHD-HPTN 040/PACTG 043 study demonstrated that combination ARV prophylaxis was more effective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who have not received antepartum ARV drugs14. However, whether the combination regimens in this trial are effective for preventing transmission after cessation o f breastfeeding in mothers with acute HIV infection is unknown. An alternative approach favored by some experts would be to offer a combination ARV regimen that would be effective for treatment o f HIV, should the infant become infected. If this route is chosen, cur rent recommendations for treatment should guide selection o f an appropriate combination ARV regimen (see Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection). Regardless o f whether post-exposure prophylaxis or "preemptive therapy" is chosen, the duration o f the intervention is un known. A 28-day course seems reasonable based on current recommendations for nonoccupational HIV exposure45. As in other situations, decisions regarding administration o f a prophylactic or preemptive treatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternal counseling on the potential risks and benefits o f this approach. Infants should be tested for HIV infection at baseline and 4 -6 weeks, 3 months, and 6 months after recogni tion of maternal infection to determine whether they are HIV infected. In infants younger than age 18 months, HIV DNA or RNA polymerase chain reaction (PCR) tests should be used for diagnosis. HIV DNA PCR is preferable for infants who are receiving combination ARV prophylaxis or preemptive treatment. HIV antibody assays can be used in infants older than age 18 months. Post-exposure ARV prophylaxis or preemptive treatment should be discontinued in infants who are found to be HIV infected while receiving one of these regimens. Resistance testing then should be performed and an appropriate combination therapy regimen initiated (see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection) . # Short-Term Antiretroviral D rug Safety and Choice fo r N eonatal Prophylaxis Infant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily o f transient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see Initial Postnatal Management). Data are limited on the toxicity to infants o f exposure to multiple ARV drugs. The latest information on neonatal dosing for ARV drugs can be found in the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Other than zidovudine, lamivudine is the nucleoside re verse transcriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies, neonatal exposure to combination zidovudine/lamivudine was generally limited to 1 week3, 14, 48. Six weeks o f infant zidovudine/lamivudine exposure also has been reported; these studies suggest that hematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had in utero exposure to maternal combination therapy. In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks of zidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a his torical cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neu tropenia in 18% o f infants exposed to zidovudine/lamivudine, with 2% o f infants requiring blood transfusion and 4% requiring treatment discontinuation for toxicity24. Similarly, in a Brazilian study of maternal antepartum and 6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxic ity was common, with anemia seen in 69% and neutropenia in 13% o f infants49. In a Phase I study of stavudine in pregnant women, infants received 6 weeks o f zidovudine/lamivudine and a single dose of stavudine at ages 1 and 6 weeks; 6 o f 14 (43%) infants experienced Grade 3 hematologic toxicity after birth (36% neutropenia and 7% anemia)50. Finally, in three Phase I studies o f PIs (saquinavir/ritonavir, indinavir, or nelfinavir) in pregnancy, a total o f 52 infants received 6 weeks o f zidovudine/lamivudine (in 26 infants, zidovudine/lamivudine was combined with nelfinavir); Grade 2 or higher hematologic toxicity was observed in 46% -62% o f infants51-53. In the NICHD-HPTN 040/PACTG 1043 study, signifi cantly higher rates o f Grade 3 or 4 neutropenia were seen with a three-drug regimen including zidovu dine and lamivudine than with zidovudine alone or a two-drug regimen with zidovudine and nevirapine (27.5% vs. 16% and 15%, respectively, P <0.0001)14. In contrast, Grade 3 or 4 anemia occurred in 23% -27% o f infants, with no differences between study arms14. Experience with other NRTI drugs for neonatal prophylaxis is more limited54-55. Hematologic and mito chondrial toxicity may be more common with exposure to multiple versus single NRTI drugs24, 56-59. Nevirapine is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) drug with a pediatric drug formulation and neonatal dosing information (see Guidelines for the Use of Antiretroviral Agents in Pedi atric HIV Infection) 60. In rare cases, chronic multiple-dose nevirapine has been associated with severe and potentially life-threatening rash and hepatic toxicity. These toxicities have not been observed in infants re ceiving single-dose nevirapine, the two-drug zidovudine regimen plus three doses of nevirapine in the first week of life in NICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophy laxis daily for 6 weeks to 6 months to prevent transmission of HIV via breast milk8, Dosing for premature infants is available for only zidovudine (see Table 8), making use o f other ARV drugs in this group more problematic. In preterm infants immature renal and hepatic metabolism in creases the risk o f overdosing and toxicity. Because zidovudine is the only ARV drug available in an in travenous formulation, the 6-week zidovudine prophylaxis regimen is recommended for preterm infants at gestational age-appropriate doses. Use o f ARV drugs other than zidovudine cannot be recommended in premature infants because data on dosing and safety are lacking. Initial Postnatal Management of the HIV-Exposed Neonate (Updated September 14, 2011) Panel's Recommendations • A complete blood count (CBC) and differential should be performed on newborns as a baseline evaluation (B III). • Decisions about the timing of subsequent monitoring of hematologic parameters in infants depend on baseline hemato logic values, gestational age at birth, clinical condition of the infants, the zidovudine dose being administered, receipt of concomitant medications, and maternal antepartum therapy (C III). • Some experts recommend more intensive monitoring of hematologic and serum chemistry and liver function assays at birth and when diagnostic HIV polymerase chain reaction (PCR) tests are obtained in infants exposed to combination antiretroviral (ARV) drug regimens in utero or during the neonatal period (C III). • If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether to continue infant ARV prophylaxis need to be individualized. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered (C III). • Routine measurement of serum lactate is not recommended. However, measurement can be considered if an infant de velops severe clinical symptoms of unknown etiology (particularly neurologic symptoms) (C III) . • Virologic tests are required to diagnose HIV infection in infants <18 months of age and should be performed within the first 14-21 days of life, at 1-2 months, and at 4 -6 months of age (A II). A CBC and differential should be performed on HIV-exposed newborns before initiation o f infant ARV drug prophylaxis. Decisions about the timing o f hematologic monitoring o f infants after birth depend on a number of factors, including baseline hematologic values, gestational age at birth, clinical condition of the infants, which ARV drugs are being administered, receipt o f concomitant medications, and maternal antepartum ARV drug regimen. Anemia is the primary complication seen in neonates given the standard 6-week postnatal zidovudine regimen. In PACTG 076, infants in the zidovudine group had lower hemo globin at birth than those in the placebo group, with the maximal difference (1 gm/dL) occurring at age 3 weeks1. The lowest mean value for hemoglobin (10 gm/dL) occurred at age 6 weeks in the zidovudine group. By age 12 weeks, hemoglobin values in both groups were similar. No significant differences in other laboratory parameters were observed between groups. Some experts recheck hematologic values in healthy infants receiving zidovudine prophylaxis only if symptoms are present. Hematologic safety data are limited on administration o f 4 mg/kg o f zidovudine twice daily in infants. When administering this dosing regimen, some experts recheck hemoglobin and neutrophil counts routinely after 4 weeks o f zidovudine prophylaxis and/or when diagnostic HIV PCR tests are obtained. In utero exposure to maternal combination ARV drug regimens may be associated with some increase in anemia and/or neutropenia compared with that seen in infants exposed to zidovudine alone2-5. In PACTG 316, where 77% o f mothers received antenatal combination therapy, significant Grade 3 or higher ane mia was noted in 13% and neutropenia in 12% o f infants, respectively. Depending on the combination regimen the mother has received, some experts advise more intensive laboratory monitoring, including serum chemistry and transaminases at birth plus a CBC at the time that diagnostic HIV PCR testing is done; monitoring o f bilirubin levels should be considered for infants exposed antenatally to atazanavir6. In addition, data are limited on infants receiving zidovudine in combination with other ARVs for pro phylaxis. However, higher rates o f hematologic toxicity have been observed in infants receiving zidovu dine/lamivudine combination prophylaxis compared with those receiving zidovudine alone or zidovudine plus nevirapine7. A recheck o f hemoglobin and neutrophil counts, therefore, is recommended for infants who receive combination zidovudine/lamivudine-containing ARV prophylaxis regimens 4 weeks after initiation of prophylaxis and/or at the time that diagnostic HIV PCR testing is done8. If hematologic abnormalities are found, decisions on whether to continue infant ARV prophylaxis need to be individualized. Considerations include the extent o f the abnormality, whether related symptoms are present, duration o f infant prophylaxis, risk o f HIV infection (as assessed by the m other's history of ARV prophylaxis, viral load near delivery, and mode o f delivery), and the availability o f alternative in terventions such as erythropoietin and transfusion. Consideration can be given to reducing the duration o f infant prophylaxis from 6 to 4 weeks, as is the case in many European centers. In a recent prospec tive, observational study, the 4-week regimen was found to allow earlier recovery from anemia in other wise healthy infants compared with the 6-week regimen9. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered. Hyperlactatemia has been reported in infants with in utero exposure to ARVs, but it appears to be tran sient and, in most cases, asymptomatic10-11. Routine measurement o f serum lactate is not recommended in asymptomatic neonates to assess for potential mitochondrial toxicity because the clinical relevance is unknown and the predictive value for toxicity appears poor10-11. Serum lactate measurement should be considered, however, for infants who develop severe clinical symptoms o f unknown etiology, particu larly neurologic symptoms. In infants with symptoms, if the levels are significantly abnormal (>5 mmol/L), ARV prophylaxis should be discontinued and an expert in pediatric HIV infection should be consulted regarding potential alternate prophylaxis. To prevent PCP, all infants born to women with HIV infection should begin trimethoprim-sulfamethoxa zole (TMP-SMX) prophylaxis at age 6 weeks, after completion o f the infant ARV prophylaxis regimen, unless there is adequate virologic test information to presumptively exclude HIV infection (see USPHS/IDSA Guidelines for the Prevention and Treatment o f Opportunistic Infections in HIV-Exposed and Infected Children)12. HIV infection in infants should be diagnosed using HIV DNA PCR or RNA virologic assays. Maternal HIV antibody crosses the placenta and will be detectable in all HIV-exposed infants up to age 18 months; therefore, standard antibody tests should not be used for HIV diagnosis in newborns. HIV viro logic testing should be performed within the first 14-21 days o f life, at 1-2 months, and at 4 -6 months o f age13. Some experts also perform a virologic test at birth, especially in women who have not had good virologic control during pregnancy or if adequate follow-up o f the infant may not be assured. A positive HIV virologic test should be confirmed as soon as possible with a second HIV virologic test on a differ ent specimen. Two positive HIV tests constitute a diagnosis o f HIV infection. Data do not indicate any delay in HIV diagnosis with HIV DNA PCR assays in infants who have received the zidovudine regi men1,14. However, the effect o f maternal or infant exposure to combination ARV drug regimens on the sensitivity o f infant virologic diagnostic testing-particularly using HIV RNA assays-is unknown. Therefore, although HIV RNA assays may be acceptable for diagnosis (particularly in older infants), HIV DNA PCR assays may be optimal for diagnosing infection in the neonatal period. Any newly diag nosed infant should undergo viral resistance testing by genotype and/or phenotype to assess for suscepti bility to combination ART. HIV may be presumptively excluded with two or more negative tests, one at age 14 days or older and the other at age 1 month or older. # Infant Feeding Practices and R isk o f H IV Transmission In the United States, where safe infant feeding alternatives are available and free for women in need, HIV-infected women should not breastfeed their infants. Maternal receipt o f combination ARV regimens is likely to reduce free virus in the breast milk, but the presence o f cell-associated virus (intracellular HIV DNA) remains unaffected and, therefore, may continue to pose a transmission risk15. Late HIV transmission events in infancy have recently been reported among three HIV-infected children suspected to have acquired HIV infection as a result o f consuming premasticated food given to them by their caregivers. Phylogenetic comparisons o f virus from cases and suspected sources and supporting clinical history and investigations identified the practice o f feeding premasticated foods to infants as a potential risk factor for HIV transmission. Health care providers should routinely inquire about this feed ing practice and instruct HIV-infected caregivers on safer feeding options16. Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants (Updated September 14, 2011) # Panel's Recommendations • Children with in utero/neonatal exposure to antiretroviral (ARV) drugs who develop significant organ system abnormali ties of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction (C III). • Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concerns regard ing the potential for carcinogenicity of nucleoside analogue ARV drugs (C III). Data remain insufficient to address the effect that exposure to zidovudine or other ARV agents in utero might have on long-term risk of neoplasia or organ system toxicities in children. Data from follow-up of PACTG 076 infants through age 6 years do not indicate any differences in immunologic, neurologic, and growth pa rameters between infants who were exposed to the zidovudine regimen and those who received placebo, and no malignancies have been seen1-3. As discussed earlier in NRTI Drugs and Mitochondrial Toxicity, data are conflicting regarding whether mitochondrial dysfunction is associated with perinatal exposure to ARVs. Mi tochondrial dysfunction should be considered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings of unknown etiology, particularly neurologic findings. Evaluation is ongoing o f early and late effects o f in utero exposure to ARVs, including the Pediatric HIV/AIDS Cohort Study (PHACS), Surveillance Monitoring o f Antiretroviral Toxicity Study, natural his tory studies, and HIV/AIDS surveillance conducted by state health departments and the Centers for Dis ease Control and Prevention (CDC). Because most o f the available follow-up data relate to in utero exposure to antenatal zidovudine alone and most pregnant women with HIV infection currently receive combination ARV drug regimens, it is critical that studies to evaluate potential adverse effects o f in utero drug exposure continue to be supported. Innovative methods are needed to provide follow-up o f infants with in utero exposure to ARV drugs. In formation regarding such exposure should be part o f ongoing permanent medical records for children, particularly those who are uninfected. Children with in utero exposure to ARVs who develop significant organ system abnormalities o f unknown etiology, particularly o f the nervous system or heart, should be evaluated for potential mitochondrial dysfunction4-6. Follow-up o f children with exposure to ARVs should continue into adulthood because o f the theoretical concerns regarding the potential for carcinogenicity of the nucleoside analogue ARV drugs. Long-term follow-up should include annual physical examinations o f all children exposed to ARV drugs. HIV surveillance databases from states that require HIV reporting provide an opportunity to collect popu lation-based information concerning in utero exposure to ARVs. To the extent permitted by federal law and regulations, data from these confidential registries can be compared with information from birth de fect and cancer registries to identify potential adverse outcomes. with abacavir during organogenesis at doses o f 1,000 mg/kg (about 35 times that o f human therapeu tic exposure based on area under the curve [AUC]). Toxicity to the developing embryo and fetus (in creased resorptions and decreased fetal body weight) occurred with abacavir administration o f 500 mg/kg/day to pregnant rodents. The offspring of female rats were treated with 500 mg/kg o f aba cavir, beginning at embryo implantation and ending at weaning. In these animals, an increased inci dence o f stillbirth and lower body weight was seen throughout life. However, in the rabbit, no evidence of drug-related developmental toxicity was observed and no increase in fetal malformations was observed at doses up to 700 mg/kg (about 8.5 times that o f human therapeutic exposure). In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to abacavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with abacavir. Among cases o f first trimester abacavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.0% (22 of 744 births; 95% confidence interval [CI], 1.9%-4.5%) compared with 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1. • Placental and breast m ilk passage Abacavir crosses the placenta and is excreted into the breast milk o f lactating rats. • Hum an studies in pregnancy A Phase I study of abacavir in pregnant women indicates that the AUC drug concentration during preg nancy was similar to that at 6-12 weeks postpartum and in nonpregnant individuals2. Thus, no dose ad justment for abacavir is needed during pregnancy. Serious hypersensitivity reactions have been associated with abacavir therapy in nonpregnant adults and have rarely been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdomi nal pain. Abacavir should not be restarted following a hypersensitivity reaction because more severe symptoms will occur within hours and may include life-threatening hypotension and death. weight gains; however, the physical and functional development o f the offspring was not impaired and there were no major changes in the F2 generation. • Teratogenicity/developm ental toxicity No evidence o f teratogenicity or toxicity was observed with administration o f didanosine at 12 and 14 times human exposure, respectively, in pregnant rats and rabbits. Among cases o f first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence o f birth defects was 4.7% (19 o f 406 births; 95% CI, 2.8%-7.2%) compared with 2.7% in the U.S. population, based on CDC surveillance1. All defects were reviewed in detail by the Registry, and no pattern o f defects was discovered. The rate and types o f defects will continue to be closely monitored. # • Placental and breast m ilk passage Placental transfer o f didanosine was limited in a Phase I/II safety and pharmacokinetic (PK) study2. This was confirmed in a study o f 100 HIV-infected pregnant women who were receiving NRTIs (generally as part of a two-or three-drug combination antiretroviral [ARV] regimen). At the time of delivery, cord-to-maternal blood ratio for didanosine (n = 10) was 0.38 (range 0.0-2.0) and in 15 of 24 (62%) samples, cord blood concentrations for didanosine were below the limits o f detection3. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. It is not known if didanosine is excreted in human breast milk. • Hum an studies in pregnancy A Phase I study (PACTG 249) of didanosine was conducted in 14 HIV-infected pregnant women en rolled at gestational age 26-36 weeks and treated through 6 weeks postpartum2. The drug was well tolerated during pregnancy by the women and the fetuses. PK parameters after oral administration were not significantly affected by pregnancy, and dose modification from the usual adult dosage is not needed. Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents4-6; the FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in perinatal guidelines). These two drugs should be prescribed together to pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects. Chemother. Emtricitabine (Emtriva, FTC) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Emtricitabine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screen ing tests. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 26 times the human systemic exposure at a thera peutic dose o f 200 mg/day or in rats at doses up to 31 times the human systemic exposure at the ther apeutic dose. # • Reproduction/fertility No effect o f emtricitabine on reproduction or fertility was observed with doses that produced sys temic drug exposures (as measured by AUC) approximately 60-fold higher in female mice and 140 fold higher in male mice than observed with human exposure at the recommended therapeutic dose. • Teratogenicity/developm ental toxicity Incidence o f fetal variations and malformations was not increased with emtricitabine dosing in mice that resulted in systemic drug exposure 60-fold higher than observed with human exposure at recom mended doses or in rabbits with dosing resulting in drug exposure 120-fold higher than human expo sure. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to emtric itabine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the preva lence o f birth defects was 2.7% (17 o f 641 births; 95% CI, 1.7%-4.8%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. • Placental and breast m ilk passage Emtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug concentration was 0.4 in mice and 0.5 in rabbits2. Emtricitabine has been shown to have good placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine daily during pregnancy, mean cord blood concentration was 300 ± 268 ng/mL and mean ratios o f cord blood/ma ternal emtricitabine concentrations were 1.17 ± 0.6 (n = 9)3. When 35 women were administered 400 mg o f emtricitabine in combination with tenofovir at delivery, median maternal and cord concentra tions were 1.02 (0.034-2.04) and 0.74 (0.0005-1.46) mg/L, respectively4. It is unknown if emtric itabine is excreted in human milk. • Hum an studies in pregnancy Emtricitabine PKs have been evaluated in 18 HIV-infected pregnant women receiving combination antiretroviral therapy (ART) including emtricitabine (200 mg once daily) at 30-36 weeks gestation and 6-12 weeks postpartum3. Emtricitabine exposure was modestly lower during the third trimester (8.6 p,gh/mL [5.2-15.9]) compared with the postpartum period (9.8 p,gh/mL [7.4-30.3]). Twothirds (12 o f 18) o f pregnant women versus 100% (14 o f 14) o f postpartum women met the AUC tar get (10th percentile in nonpregnant adults). Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration [Cmm] 52 ng/mL ) compared with the postpar tum period (86 ng/mL [<10-306]). In another study o f 35 women who received 400 mg o f emtric itabine with tenofovir at delivery, median population AUC, maximum plasma concentration (Cmax), and Cmin were 14.3 p,gh/mL, 1,680 ng/mL, and 76 ng/mL, respectively4. Currently, data are insuffi cient to recommend a dosage adjustment during pregnancy. dine in humans have been monitored to detect at least a 1.5-fold increase in risk o f overall birth de fects and a 2-fold increase in the most commonly occurring birth defects, such as defects o f the car diovascular and genitourinary systems. No such increase in birth defects has been observed with lamivudine. Among cases o f first-trimester lamivudine exposure reported to the Antiretroviral Preg nancy Registry, the prevalence o f birth defects was 3.1% (118 o f 3,864 births, 95% CI, 2.5%-3.7%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. • Placental and breast m ilk passage Lamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternal concentrations2. Lamivudine is excreted into human breast milk. In a study in Kenya o f 67 HIV-in fected nursing mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, the median breast milk lamivudine concentration was 1,214 ng/mL and the median ratio o f lamivu dine concentration in breast milk to that in plasma was 2.563. In infants who received lamivudine only via breast milk, median plasma lamivudine concentration was 23 ng/mL (half-maximal in hibitory concentration [IC50] o f wild-type HIV against lamivudine = 0.6-21 ng/mL). • Hum an studies in pregnancy A small Phase I study in South Africa evaluated the safety and PKs of lamivudine alone or in combina tion with zidovudine in 20 HIV-infected pregnant women; therapy was started at 38 weeks' gestation, continued through labor, and given to the infants for 1 week following birth2. The drug was well toler ated in the women at the recommended adult dose of 150 mg orally twice daily; PKs were similar to those observed in nonpregnant adults, and no PK interaction with zidovudine was observed. Intrapartum oral administration of combination zidovudine and lamivudine was well tolerated. Lamivudine was well tolerated in the neonates, but clearance was about 50% that o f older children, requiring a reduced dosing regimen (4 mg/kg/day in neonates compared with 8 mg/kg/day for infants older than 3 months). No data currently exist on the PKs o f lamivudine in infants 2 -6 weeks o f age, and the exact age at which lamivudine clearance begins to approximate that in older children is un known. carcinogenicity studies in mice and rats, stavudine was noncarcinogenic in doses producing expo sures 39 (mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels o f exposure (250 [mice] and 732 [rats] times human exposure at therapeutic doses), be nign and malignant liver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats. • Reproduction/fertility Stavudine has not been shown to have an effect on reproduction or fertility in rodents. A dose-related cytotoxic effect has been observed on preimplantation mouse embryos, with inhibition o f blastocyst formation at a concentration o f 100 pM and o f postblastocyst development at 10 pM 1. • Teratogenicity/developm ental toxicity studies No evidence o f teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, o f that seen at a clinical dosage o f 1 mg/kg/day. In rat fetuses, the inci dence o f a common skeletal variation-unossified or incomplete ossification o f sternebra-was in creased with 399 times human exposure, although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135 times human exposure. An increase in early rat neonatal mortality (birth-Day 4) occurred at 399 times human exposure, although survival o f neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to stavudine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with stavudine. Among cases o f first trimester stavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (19 o f 797 births; 95% CI, 1.4%-3.7%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance2. # • Placental and breast m ilk passage Stavudine crosses the rat placenta in vivo and the human placenta ex vivo, resulting in a fetal/mater nal concentration o f approximately 0.50. In primates (pigtailed macaques), fetal/maternal plasma concentrations were approximately 0.803. Stavudine is excreted into the breast milk o f lactating rats. • Hum an studies in pregnancy A Phase I/II safety and PK study has been conducted o f combination stavudine and lamivudine in pregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, with stavudine PKs similar to those in nonpregnant adults4. Data from primate studies also indicated that pregnancy did not affect the PKs o f stavudine5. Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents6-8. The FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines). These drugs should be prescribed together for pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects. Tenofovir disoproxil fumarate (Viread, TDF) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Tenofovir is mutagenic in one o f two in vitro assays and has no evidence o f clastogenic activity. Long-term oral carcinogenicity studies o f tenofovir DF in mice and rats were carried out at 16 times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased at expo sures 16 times that observed in humans at therapeutic doses. In rats, the study was negative for car cinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. # • Reproduction/fertility Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence o f impaired fertility or harm to the fetus due to tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days prior to mating and to female rats for 15 days prior to mating through Day 7 o f gestation. There was, however, an alter ation o f the estrous cycle in female rats administered 600 mg/kg/day. • Teratogenicity/developm ental toxicity Chronic exposure of fetal monkeys to tenofovir at a high dose of 30 mg/kg (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) from Days 20-150 of gestation did not re sult in gross structural abnormalities1. However, significantly lower fetal circulating insulin-like growth factor-1 (a primary regulator of linear growth) and higher insulin-like growth factor binding protein-3 levels were shown and were associated with overall body weights approximately 13% lower than un treated controls. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers were noted but were primarily limited to the treatment period and were reversible. Continued administration o f tenofovir at 30 mg/kg/day to infant monkeys resulted in significant growth restriction and severe bone toxicity in 2 o f 8 (25%) infants and effects on bone biomarkers and defective bone mineralization in all animals. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Abnormalities ranged from minimal decrease in bone mineral density and content (with oral dosing in rats and dogs that achieved drug exposures 6-10 times that achieved with therapeutic dosing in humans) to severe, pathologic osteomalacia (with subcutaneous dosing given to monkeys). Juvenile monkeys given chronic subcutaneous tenofovir at 30 mg/kg/day (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) developed osteomalacia, bone fractures, and marked hypophosphatemia. However, no clinical or radiologic bone toxicity was seen when juvenile monkeys received subcutaneous dosing o f 10 mg/kg/day (ex posure equivalent to 8 times the AUC achieved with therapeutic dosing in humans). Evidence of nephrotoxicity was observed in newborn and juvenile monkeys given tenofovir in doses resulting in exposures 12-50 times higher than the human dose, based on body surface area comparisons. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with tenofovir. Among cases o f first trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (26 o f 1,092 births, 95% CI, 1.6%-3.5%) compared with a 2.7% total preva lence in the U.S. population, based on CDC surveillance2. # • Placental and breast m ilk passage Studies in rats have demonstrated that tenofovir is secreted in milk. Intravenous administration of teno fovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrat ing that tenofovir does cross the placenta3. In 3 studies of pregnant women on chronic dosing, the cord-to-maternal blood ratio ranged from 0.60 to 0.99, indicating high placental transfer4-6. In 2 studies of single-dose tenofovir (in some cases with emtricitabine) in labor that included 82 mother-infant pairs, the drugs were well tolerated and cord-to-maternal blood ratios were 0.61-0.677-9. Among women receiving a single 600-mg dose during labor, tenofovir was detectable in only 4 o f 25 (16%) breast milk samples during the first week after delivery, with a median concentration o f 13 (range 6-18) ng/mL9. In another study, 16 breast milk samples were obtained from 5 women who re ceived 600 mg o f tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir lev els in breast milk ranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oral dose o f tenofovir for neonates10. • H um an studies in pregnancy In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30-36 weeks' gestation and 6-12 weeks postpartum4. The percentage of women with tenofovir AUC exceeding the target o f 2 p,ghour/mL (the 10th percentile in nonpreg nant adults) was lower in the third trimester (74%, 14 o f 19 women) than postpartum (86%, 12 o f 14 women) (P = 0.02); however, trough levels were similar in the two groups. A recent case series found tenofovir to be well tolerated among 76 pregnant women, with only 2 stopping therapy, 1 for rash and the other for nausea. All 78 infants were healthy with no signs of toxicity, and all were HIV uninfected11. A follow-up study o f 20 o f the tenofovir-exposed infants and 20 controls found no differences between the groups in renal function, including cystatin C levels, through 2 years o f age12. A retrospective review o f 16 pregnancy outcomes among 15 heavily ARV experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants13. Zalcitabine (HIVID, ddC) is no longer available in the United States. Zidovudine (Retrovir, AZT, ZDV) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Zidovudine was shown to be mutagenic in two in vitro assays and clastogenic in one in vitro and two in vivo assays, but not cytogenic in a single-dose in vivo rat study. Long-term carcinogenicity studies have been performed with zidovudine in mice and rats1. In mice, seven late-appearing (>19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell pa pilloma occurred in the vagina o f an animal given an intermediate dose. No vaginal tumors were found at the lowest dose. In rats, two late-appearing (>20 months), nonmetastasizing vaginal squa mous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex in either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose o f 100 mg every 4 hours. How predictive the results o f rodent car cinogenicity studies may be for humans is unknown. Two transplacental carcinogenicity studies were conducted in mice2-3. In one study, zidovudine was ad ministered at doses of 20 mg/kg/day or 40 mg/kg/day from gestation Day 10 through parturition and lactation, with postnatal dosing continuing in offspring for 24 months3. The drug doses administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at rec ommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no in crease in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. In a second study, zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from Days 12-18 of gestation2. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. # • Reproduction/fertility When administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, zidovudine had no effect on fertility, as judged by rates o f conception. Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-related cytotoxic effect on preimplantation mouse embryos can occur, with inhibition o f blastocyst and post blastocyst development at zidovudine concentrations similar to levels achieved with human thera peutic doses4. • Teratogenicity/developm ental toxicity Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evi denced by an increase in the incidence o f fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half o f the daily dose) in rats 66-226 times, and in rabbits 12-87 times, mean steady-state peak human plasma concentrations (after one-sixth o f the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose o f 3,000 mg/kg/day (very near the oral median lethal dose in rats o f 3,683 mg/kg) caused marked maternal toxicity and an increase in the in cidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence o f teratogenicity was seen in this experi ment at doses of 600 mg/kg/day or less. Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses that pro duced drug plasma concentrations 66-226 times (rats) and 12-87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No other develop mental anomalies were reported. In another developmental toxicity study, pregnant rats received zi dovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. How ever, there were no signs of teratogenicity at doses up to one-fifth the lethal dose. In humans, in the placebo-controlled perinatal trial PACTG 076, the incidence o f minor and major congenital abnormalities was similar between zidovudine and placebo groups and no specific pat terns of defects were seen5-6. A report from the Women and Infants Transmission Study (WITS), a cohort study enrolling women during pregnancy, described an association between first-trimester ex posure to zidovudine and a 10-fold increased risk o f hypospadias7. However, in the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to zidovudine have been moni tored to be able to detect at least a 1.5-fold increase in risk o f overall birth defects and a 2-fold in crease in defects in the more common classes, defects o f the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence o f birth defects was 3.3% (118 o f 3,620 births, 95% CI, 2.7% -3.9%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance8. # • Placental and breast m ilk passage Zidovudine rapidly crosses the human placenta, achieving cord-to-maternal blood ratios o f about 0.80. Zidovudine is excreted into human breast milk. In one study in Kenya in 67 mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, zidovudine concentration in the breast milk o f mothers averaged 9 ng/mL and the ratio o f breast milk to maternal plasma zidovudine concentration averaged 44%9. No zidovudine was detectable in the plasma o f the nursing infants, who received zidovudine only via breast milk. # • H um an studies in pregnancy Zidovudine is well tolerated in pregnancy at recommended adult doses and in the full-term neonate at 2 mg/kg body weight orally every 6 hours5, 10. Long-term data on the safety o f in utero drug expo sure in humans are not available for any ARV drug; however, short-term data on the safety o f zi dovudine are reassuring. In PACTG 076, no difference in disease progression was seen between women who received zidovudine and those who received placebo, based on follow-up through 4 years postpartum11. Additionally, no differences in immunologic, neurologic, or growth parameters were seen between infants with in utero zidovudine exposure and those who received placebo, based on nearly 6 years of follow up6, 12. Non-Nucleoside Reverse Transcriptase Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: • Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. • Genetic mutations and/or chromosomal damage can contribute to cancer formation. Five non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) currently are approved (delavirdine is no longer available in the United States). Nevirapine and efavirenz have been studied in human pregnancy. No adequate and well-controlled studies o f etravirine or rilpivirine use in pregnant women have been conducted. For information about potential interactions between NNRTIs and methergine, see Postpartum Hemor rhage. Antiretroviral Drugs, and Methergine Use in the perinatal guidelines. For more information regard ing nevirapine hepatic/rash toxicity. see Nevirapine and Hepatic/Rash Toxicity in the perinatal guidelines. Delavirdine (Rescriptor, DLV) is no longer available in the United States. Efavirenz (Sustiva, EFV) is classified as FDA pregnancy category D. # • A nim al carcinogenicity studies Efavirenz was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies with efavirenz have been completed in mice and rats. A t systemic drug exposures approximately 1.7-fold higher than in humans receiving standard therapeutic doses. no increase in tumor incidence above background was observed in male mice. but in female mice. an increase above background was seen in hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas. No increase in tumor incidence above background was observed in male and female rats with systemic drug exposures lower than that in humans re ceiving therapeutic doses. # • R eproduction/fertility anim al studies No effect o f efavirenz on reproduction or fertility in rodents has been seen. • Teratogenicity/developm ental toxicity An increase in fetal resorption was observed in rats at efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans at the recommended human dose (600 mg once daily). Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma con-centrations similar to and AUC values approximately half o f those achieved in humans administered efavirenz (600 mg once daily). Central nervous system (CNS) malformations were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20-150 at a dose o f 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure)1. The malformations included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in another fetus, and cleft palate in a third fetus. In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretrovi ral Pregnancy Registry through January 2011, birth defects were observed in 17 o f 623 live births with first-trimester exposure (2.7%, 95% confidence interval [CI], 1.6%-4.3%). Although these data provide sufficient numbers of first-trimester exposures to rule out a 2-fold or greater increase in the risk o f overall birth defects, the low incidence o f neural tube defects in the general population means that a larger number o f exposures are still needed to be able to definitively rule out an increased risk of this specific defect. Prospective reports to the Antiretroviral Pregnancy Registry o f defects after first-trimester efavirenz exposure have documented 1 neural tube defect case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and 1 case o f bilateral facial clefts, anophthalmia, and amniotic band2. Among retrospective cases, there are 6 reports o f CNS de fects, including 3 cases o f meningomyelocele in infants born to mothers receiving efavirenz during the first trimester3. Although a causal relationship has not been established between these events and the use o f efavirenz, similar defects have been observed in preclinical studies o f the drug. # • Placental and breast m ilk passage Efavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. In a study o f 13 women in Rwanda, efavirenz was given during the last trimester o f pregnancy and for 6 months after delivery4. Efavirenz concentra tions were measured in maternal plasma, breast milk, and infant plasma. Efavirenz passed into breast milk with a ratio o f 0.54 (mean breast milk to mean maternal plasma concentration) and 4.08 (mean skim milk to mean newborn plasma concentration). Mean infant plasma efavirenz concentrations were 13.1% o f maternal plasma levels. No data currently are available about efavirenz in neonates. • Hum an studies in pregnancy However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a significant increase in low-incidence birth defects (0.1-0.4% incidence o f neural tube defect in the general population). Efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period of fetal organogenesis. Women of childbearing age should undergo pregnancy testing prior to initiation of efavirenz and should be counseled about the potential risk to the fetus and the need to avoid pregnancy. Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may be associated with antiretroviral (ARV) drugs such as efavirenz. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contra ception. Barrier contraception should always be used in combination with other methods of contracep tion such as hormonal contraceptives and intrauterine devices. A study evaluating the interaction between efavirenz and depot medroxyprogesetrone (DMPA) in 17 women found no change in the phar macokinetic (PK) profile of either efavirenz or DMPA with concomitant use8. DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval. Limited PK data exist for efavirenz in pregnancy. In a study o f 25 pregnant women receiving efavirenz during the third trimester as part o f clinical care, efavirenz clearance was increased and C24h was decreased compared with postpartum. These differences are not o f sufficient magnitude to warrant dose adjustment during pregnancy9. Nevirapine (Viramune, NVP) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B . # • A nim al carcinogenicity studies Nevirapine showed no evidence o f mutagenic or clastogenic activity in a battery o f in vitro and in vivo studies. Hepatocellular adenomas and carcinomas were increased at all doses in male mice and rats and at higher doses in female mice and rats. Systemic exposure at all doses studied was lower than systemic exposure in humans receiving therapeutic nevirapine doses. Given the lack o f genotoxic activity of nevirapine, the relevance to humans o f hepatocellular neoplasms in nevirapinetreated mice and rats is not known. # • Reproduction/fertility Evidence o f impaired fertility was seen in female rats at nevirapine doses providing systemic expo sure comparable to human therapeutic exposure. • Teratogenicity/developm ental toxicity Teratogenic effects o f nevirapine have not been observed in reproductive studies with rats and rab bits at systemic exposures approximately equivalent to or 50% greater than the recommended human dose (based on AUC). In rats, however, a significant decrease in fetal weight occurred at doses pro ducing systemic concentrations approximately 50% higher than human therapeutic exposure. In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nevirapine in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth de fects. No such increase in birth defects has been observed with nevirapine. Among cases of first trimester nevirapine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.5% (25 of 987 births, 95% CI, 1.6%-3.7 %) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1. # • Placental and breast m ilk passage Nevirapine crosses the placenta and achieves neonatal blood concentrations equivalent to that in the mother (cord-to-maternal blood ratio approximately 0.90)2. Nevirapine is excreted into human breast milk; the median concentration in 4 breast milk samples obtained from 3 women during the first week after delivery was approximately 76% (range 54%-104%) o f serum levels2. In 19 women re ceiving combination therapy with nevirapine, lamivudine, and zidovudine, breast milk nevirapine concentration was 6,795 ng/mL, which was 0.67 times that o f maternal serum3. Median nevirapine breast milk concentration was 4,564 ng/mL in a Kenyan study o f 67 HIV-infected nursing mothers receiving a combination o f zidovudine, lamivudine, and nevirapine3. The median nevirapine concen tration was 734 ng/mL in the infants, who received the drug only via breast milk. • Hum an studies in pregnancy # Short-Term Peripartum Prophylaxis: A Phase I study (PACTG 250) evaluated the safety and PKs o f nevirapine administered to infected pregnant women as a single 200-mg dose at the onset o f labor and as a single 2-mg/kg dose to in fants 48-72 hours o f age2. No adverse effects were seen in the women or the infants. The PK parameters o f intrapartum nevirapine were similar in pregnant women and in nonpregnant adults, but variability was increased during pregnancy, possibly as a result o f incomplete drug ab sorption associated with impaired gastrointestinal function during labor. Nevirapine elimination was prolonged in the infants. The regimen maintained serum concentrations associated with antiviral ac tivity in the infants for the first week o f life. The safety, toxicity, and PKs o f nevirapine were also studied in HIV-infected pregnant women begin ning chronic therapy late in the third trimester and their infants4. Initial-dose PK profiles in pregnant women were similar to those seen in nonpregnant adults. Serum nevirapine concentrations fell below the 100 ng/mL target concentration by Day 7 o f life in four o f eight infants, suggesting that nevirap ine elimination was accelerated in infants whose mother received chronic nevirapine administration compared with newborns whose mothers received only a single intrapartum dose. The HIVNET 012 study in Uganda compared nevirapine (200 mg orally to the mother at the onset of labor and 2 mg/kg to the neonate within 72 hours o f birth) with zidovudine (600 mg orally to the mother at the onset o f delivery and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily for the first 7 days o f life to the neonate). In this study, nevirapine lowered the risk o f transmis sion o f HIV by nearly 50% during the first 14-16 weeks o f life compared with zidovudine5. How ever, the women in this African trial were not receiving any other ARV drugs. In the United States, most infected women who know their HIV status during pregnancy receive combination ARV prophylaxis regimens, usually including zidovudine, as well as intravenous zi dovudine during delivery, with 6 weeks o f zidovudine given to their infants. A Phase III perinatal trial (PACTG 316) conducted in the United States, Europe, the Bahamas, and Brazil evaluated whether the HIVNET 012 single-dose nevirapine regimen in combination with standard combination prophylaxis regimens (at minimum the PACTG 076 zidovudine regimen; 77% o f women in the trial received combination ARV regimens) would provide additional benefits in reducing transmission. Transmission was not significantly different between those who received single-dose nevirapine (1.4%) and those who did not (1.6%)6. Nevirapine resistance can be induced by a single mutation. As a result o f its long half-life, the drug can be detected in plasma up to 3 weeks after administration o f a single intrapartum dose7. This pe riod o f persistent subtherapeutic drug levels exerts selective pressure that predisposes to the develop ment o f resistant strains o f HIV8. Nevirapine resistance mutations were detected at 6 weeks postpartum in 19% o f ARV-naive women in HIVNET 012 and 15% o f a subset o f women receiving additional ARV drugs during pregnancy in PACTG 316 who received single-dose nevirapine during labor9-10. In HIVNET 012, these mutations were no longer detectable in plasma virus in women at 13-18 months postpartum11. Evaluation at later time points was not done in PACTG 316. Single dose nevirapine appears to be as effective in preventing HIV transmission in subsequent pregnancies as when it is used for the first time12-13. Current data suggest that women starting NNRTI-based ther apy within 12-24 months o f single-dose nevirapine exposure have higher rates o f viral failure than those without single-dose nevirapine exposure and that use o f a protease inhibitor (PI)-based regi men (such as lopinavir/ritonavir) would be recommended in such situations14-16. Administration of postpartum ARVs to the mother can significantly reduce the frequency o f detection o f nevirapine-re sistant strains8, 17-22. # Longer Term Antenatal Combination Therapy: The PKs of nevirapine have been evaluated in pregnant women receiving nevirapine as part o f com bination ART during pregnancy. A study that determined nevirapine PKs in 26 women during preg nancy (7 second trimester, 19 third trimester) and again in the same women 4-12 weeks after delivery found that pregnancy did not alter nevirapine PK parameters23. In contrast, nevirapine clear ance was 20% greater, AUC was 28% lower, and maximum plasma concentration (Cmax) was 30% lower in 16 pregnant women compared with 13 nonpregnant women, based on nevirapine PK data from a therapeutic drug monitoring program that included 12-hour sampling24. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hep atitis, hepatic necrosis, and hepatic failure and severe, life-threatening hypersensitivity skin reactions, including Stevens-Johnson syndrome, have been reported in HIV-infected patients receiving nevirapine in combination with other drugs for treatment of HIV disease and in a small number of individuals re ceiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual exposure to HIV25. These toxicities have not been reported in women or infants receiving twodose nevirapine (the HIVNET 012 regimen) for prevention of perinatal transmission. The greatest risk of severe rash or hepatic events occurs during the first 6-18 weeks of therapy, although the risk of toxi city continues past this period and monitoring should continue at frequent intervals. Incidence o f severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more com mon in women than men and has been reported in pregnant women26-28. Other studies have found that hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in women than men29. Several studies suggest that the degree o f risk o f hepatic toxicity varies with CD4 cell count. In a summary analysis o f data from 17 clinical trials o f nevirapine therapy, women with CD4 counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 counts to experience symptomatic, often rash-associated, nevirapine-related hepatotoxicity29. Higher CD4 cell counts have also been associated with increased risk o f severe nevirapine-associated skin rash27. Rates o f hepatotoxicity and rash similar to those in U.S. studies have been seen in international co horts o f nonpregnant women but not in association with CD4 cell counts >250 cells/mm3 30. In gen eral, in controlled clinical trials, clinical hepatic events, regardless o f severity, occurred in 4.0% (range 2.5% -11.0%) o f patients who received nevirapine; however, the risk o f nevirapine-associated liver failure or hepatic mortality has been lower, in the range o f 0.04%-0.40%29, 31. Severe or lifethreatening rash occurs in approximately 2% o f patients receiving nevirapine31. Although deaths due to hepatic failure have been reported in HIV-infected pregnant women receiv ing nevirapine as part o f a combination ARV regimen, it is uncertain if pregnancy increases the risk of hepatotoxicity in women receiving nevirapine or other ARV drugs32. In an analysis o f 2 multicen ter prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (RR 4.7; 95% CI: 3.4-6.5), although nevirapine use was not, regardless o f pregnancy status33. Additional data from the same cohorts did not show any increased risk o f hepatotoxicity in HIV-infected pregnant women receiving nevirapine-based combination ART versus non-nevirapine-based combination ART34. In a cohort of 612 pregnant and nonpregnant women starting nevirapine-based therapy, CD4 cell count at initiation o f therapy but not liver enzyme elevation was a predictor o f rash; pregnancy was not an in dependent risk factor for the development o f toxicity35. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women. Women initiating nevirapine with CD4 cell counts >250 cells/mm3, including pregnant women re ceiving ARV drugs solely for prevention o f transmission, have an increased risk o f developing symp tomatic, often rash-associated, nevirapine-related hepatotoxicity, which can be severe, life-threatening and, in some cases fatal36. Therefore, nevirapine should be used as a component o f a combination regimen in this setting only if the benefit clearly outweighs the risk. Women with CD4 cell counts < 250/mm3 can receive nevirapine-based regimens, and women who become pregnant while taking nevirapine and who are tolerating their regimens well can continue therapy, regardless of CD4 cell count. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission o f HIV. Because pregnancy itself can mimic some o f the early symptoms o f hepatotoxicity, health care providers caring for women receiving nevirapine during pregnancy should be aware o f this potential complication. Frequent and careful monitoring o f clinical symptoms and hepatic transaminases (i.e., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) is necessary, particularly dur ing the first 18 weeks o f therapy. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through 4 months, and every 1-3 months thereafter (Adult Anti retroviral Guidelines); in patients with pre-existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter37. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop sugges tive clinical symptoms accompanied by elevation in serum transaminase levels (ALT and/or AST) or have asymptomatic but severe transaminase elevations should stop nevirapine and not receive the drug in the future. • Teratogenicity/developm ental toxicity No evidence o f embryonic or fetal toxicity or an effect on reproductive function was observed in rat and rabbit dams treated with rilpivirine during pregnancy and lactation at doses 15 and 70 times higher, respectively, than exposure in humans at the recommended dose o f 25 mg once daily. # • Placental and breast m ilk passage No data exist on whether rilpivirine crosses the placenta or is excreted in breast milk in humans. Studies in lactating rats and their offspring indicate that rilpivirine is present in rat milk. • Hum an studies in pregnancy No adequate and well-controlled studies o f rilpivirine use in pregnant women have been conducted. Protease Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: • Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. • Genetic mutations and/or chromosomal damage can contribute to cancer formation. In in vitro and in vivo assays, atazanavir shows evidence o f clastogenicity but not mutagenicity. Twoyear carcinogenicity studies in mice and rats were conducted with atazanavir. In female mice, the in cidence of benign hepatocellular adenomas was increased at systemic exposures 2.8-2.9-fold higher than those in humans at the recommended therapeutic dose (300 mg/day atazanavir boosted with 100 mg/kg/day ritonavir). There were no increases in the incidence o f tumors in male mice at any dose. In rats, no significant positive trends in the incidence o f neoplasms occurred at systemic exposures up to 1.1-fold (males) or 3.9-fold (females) higher than those in humans at the recommended thera peutic dose. # • Reproduction/fertility No effect o f atazanavir on reproduction or fertility in male and female rodents was seen at systemic drug exposures. The area under the curve (AUC) at this exposure level in rats was 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended thera peutic dose. • Teratogenicity/developm ental toxicity In animal reproduction studies, there was no evidence o f teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In developmental toxicity studies in rats, maternal dosing that resulted in maternal toxicity and produced systemic drug exposure 1.3 times the human exposure also resulted in weight loss or suppression o f weight gain in the offspring. However, offspring were unaffected at lower maternal doses that produced systemic drug exposure equivalent to that observed in humans at the recommended therapeutic dose. In a retrospective analysis from London o f atazanavir used in 31 women during 33 pregnancies (20 of whom were receiving atazanavir at conception), there were 2 miscarriages at 12 and 16 weeks, 26 infants born, and 5 women still pregnant1. No infant required phototherapy and no birth defects were seen; none of the infants was HIV infected. In the Antiretroviral Pregnancy Registry, sufficient num bers o f first-trimester exposure to atazanavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been ob served with atazanavir. The prevalence o f birth defects with first-trimester atazanavir exposure was 2.4% (12 o f 502 births, 95% confidence interval [CI], 1.2%-4.1%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention (CDC) sur veillance2. Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition o f hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir. Studies have demonstrated that infants born to mothers who received atazanavir during pregnancy do not have pathologic or dangerous bilirubin elevations in the neonatal period1, 3-7. # • Placental and breast m ilk passage In studies o f women receiving atazanavir/ritonavir-based combination therapy during pregnancy, the median cord blood atazanavir concentration was 13%-21% o f maternal serum levels at delivery3, 5-6. Atazanavir is excreted in the milk o f lactating rats. In a study o f three women, the median ratio of breast milk atazanavir concentration to that in plasma was 13%8. • Hum an studies in pregnancy Several studies have investigated the pharmacokinetics (PKs) o f atazanavir with ritonavir in preg nancy. In some o f these studies, virological results were also analyzed. Overall, most pregnant pa tients were able to achieve HIV RNA less than 50 copies/mL at time o f delivery9. In some studies, almost all pregnant patients achieved HIV RNA <50 copies/mL at time o f delivery4, 6-7. In a retro spective study reporting trough atazanavir concentrations in 19 pregnant women receiving atazanavir 300 mg and ritonavir 100 mg once daily at a median o f 30 weeks' gestation (14 in the third trimester), all but 2 women had a trough atazanavir concentration >100 ng/mL1. Three studies have evaluated full PK profiles o f atazanavir when administered daily as 300 mg with 100 mg ritonavir during pregnancy. In all of these studies, atazanavir AUC was lower during pregnancy than in his toric data from HIV-infected nonpregnant patients3, 5 10. In 1 o f the 3 studies, there was no difference between atazanavir AUC during pregnancy and postpartum, but AUC at both times was lower than in nonpregnant HIV-infected historic controls3. In the other 2 studies, atazanavir AUC was 25% lower during pregnancy than in the same patients postpartum5, 10. However, in both these studies (BMS AI424182 and IMPAACT P1026 atazanavir cohort), the postpartum AUC was elevated com pared with nonpregnant HIV-infected historic control patients. For example, in study AI424182, 34 women were treated with 300 mg atazanavir plus 100 mg ritonavir at 4-12 weeks postpartum and were observed to have a 34% increase in geometric AUC compared with the historic control o f HIVinfected, nonpregnant patients (62 pghr/mL vs. 46.1 pghr/mL respectively)6. Because o f the post partum elevation in AUC in this study, the atazanavir drug label recommends that postpartum patients should be closely monitored for adverse events during the first 2 months after delivery. Although use o f atazanavir with ritonavir combined with tenofovir and emtricitabine as a complete once-a-day dosing combination ARV regimen is becoming increasingly common in pregnancy, tenofovir reduces atazanavir exposure by 25% in nonpregnant adults11. This drug-drug interaction also is present during pregnancy, with a 25% reduction in atazanavir AUC in pregnant women also receiv ing tenofovir compared with the same women postpartum and a 50% reduction compared with post partum levels in women who did not receive tenofovir5. Use of an increased dose of atazanavir o f 400 mg with 100 mg ritonavir during pregnancy has been investigated in two studies10 5. In both studies pregnant women receiving the increased dose without tenofovir had an atazanavir AUC equivalent to that seen in historic nonpregnant HIV-infected con trols receiving standard-dose atazanavir without tenofovir. Pregnant women receiving the increased atazanavir dose with tenofovir had an AUC equivalent to that seen in nonpregnant HIV-infected pa tients receiving standard-dose atazanavir and tenofovir9. In the prescribing information for atazanavir6, the dose recommended for most pregnant women is 300 mg with 100 mg o f ritonavir. For additional details about dosing with interacting concomitant medications, please see Table 5 (Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharma cokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy) . Neonatal elevations in bilirubin have been reported in some-but not all-studies o f infants born to mothers receiving atazanavir during pregnancy3, 5 10. Phototherapy was needed to control hyperbiliru binemia in 5 o f 29 infants in 1 study7. In study AI424182, 6 o f 39 infants received phototherapy12. Decisions to use phototherapy to treat infants with hyperbilirubinemia frequently are subjective and guidelines for phototherapy of infants vary between countries, making it difficult, therefore, to com pare the severity o f hyperbilirubinemia between patients within a study and in different studies. Ele vated neonatal bilirubin is more likely in infants with uridine diphosphate glucuronosyltransferase 1 (UGT1A1) genotypes associated with decreased UGT function10. Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, dif ficult delivery, or sepsis has been reported in 3 o f 38 atazanavir-exposed infants with glucose sam ples collected in the first day o f life. All 3 hypoglycemic infants' glucose samples were adequately collected and processed in a timely fashion13. This finding o f infant hypoglycemia is similar to a prior report in which 2 (both nelfinavir) o f 14 infants exposed to PIs (nelfinavir, saquinavir, and indi navir) developed hypoglycemia in the first day o f life14. Fosamprenavir (Lexiva, FPV) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Fosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series o f in vitro and ani mal in vivo screening tests. Carcinogenicity studies o f fosamprenavir showed an increase in the inci dence o f hepatocellular adenomas and carcinomas at all doses tested in male mice and at the highest dose tested in female mice. In rats, the incidence o f hepatocellular adenomas and thyroid follicular cell adenomas in males (all doses tested) and in females (two highest doses tested) was also in creased. Repeat dose studies in rats produced effects consistent with enzyme activation, which pre disposes rats, but not humans, to thyroid neoplasms. In rats only there was an increase in interstitial cell hyperplasia at higher doses and an increase in uterine endometrial adenocarcinoma at the highest dose tested. The incidence o f endometrial findings was slightly increased over concurrent controls but was within background range for female rats. Thus the relevance o f the uterine endometrial ade nocarcinomas is uncertain. Exposures in the carcinogenicity studies were 0.3-to 0.7-fold (mice) and 0.7-to 1.4-fold (rats) those in humans given 1,400 mg twice daily o f fosamprenavir alone, and 0.2to 0.3-fold (mice) and 0.3-to 0.7-fold (rats) those in humans given 1,400 mg once daily o f fosampre navir plus 200 mg ritonavir once daily or 0.1-to 0.3-fold (mice) and 0.3-to 0.6-fold (rats) those in humans given 700 mg o f fosamprenavir plus 100 mg ritonavir twice daily. # • R eproduction/fertility No impairment o f fertility or mating was seen in rats at doses providing 3-4 times the human expo sure to fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. At those doses, no affect was seen on the development or maturation o f sperm in rats. • Teratogenicity/developm ental toxicity Fosamprenavir was studied in rabbits at 0.8 and in rats at twice the exposure in humans to fosampre navir alone and at 0.3 (rabbits) and 0.7 (rats) times the exposure in humans to the combination of fosamprenavir and ritonavir. In rabbits administered fosamprenavir (alone or in combination) the in cidence of abortion was increased. In contrast, administration o f amprenavir at a lower dose in rab bits was associated with abortions and an increased incidence o f minor skeletal variations from deficient ossification of the femur, humerus, and trochlea. Fosamprenavir administered to pregnant rats (at twice human exposure) was associated with a reduction in pup survival and body weights in rats. F1 female rats had an increased time to successful mating, an increased length o f gestation, a re duced number o f uterine implantation sites per litter, and reduced gestational body weights com pared with controls. # • Placental and breast m ilk passage It is unknown whether fosamprenavir crosses the placenta. Amprenavir is excreted in the milk o f lac-defects. No such increase in birth defects has been observed with indinavir. Among cases o f first trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.1% (6 o f 285 births, 95% CI, 0.8%-4.5%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. • Placental and breast m ilk passage Significant placental passage o f indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. In a Phase I study in pregnant women and their infants (PACTG 358, see below), transplacental passage o f indinavir was minimal2. In addition, in a study o f cord blood samples from 21 women treated with indinavir during pregnancy, the cord blood concentration o f indinavir was less than the assay limit o f detection in samples from all women3. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26 to 1.45); it is not known if indinavir is excreted in human milk. • Hum an studies in pregnancy The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A Phase I/II safety and PK study (PACTG 358) was conducted of indinavir (800 mg three times a day) in com bination with zidovudine and lamivudine in pregnant HIV-infected women and their infants2. The mean indinavir plasma AUC0-8hr at 30-32 weeks' gestation (n =11) was 74% (95% CI, 50%-86%) lower than that observed 6 weeks postpartum. The PKs of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in nonpregnant patients in another study. In an other study, two pregnant HIV-infected women receiving combination therapy including indinavir (800 mg three times a day) had significantly reduced AUC indinavir exposures in the third trimester com pared with postpartum evaluations (52% and 86%, respectively)4. Therefore, given the substantially lower antepartum exposures observed in these studies and the generally limited data in this patient population, use of indinavir as a sole PI is not recommended in HIV-infected pregnant patients. Lopinavir + Ritonavir (Kaletra, LPV/r) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery o f in vitro and in vivo assays. The lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the inci dence o f benign hepatocellular adenomas and an increase in the combined incidence o f hepatocellu lar adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure at the recommended therapeutic dose o f 400 mg/100 mg (based on AUC0-24hr measurement). Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence o f any other be nign or malignant neoplasm in mice or rats. • Reproduction/fertility Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and fe male rats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir o f the expo sures in humans at the recommended therapeutic dose. • Teratogenicity/developm ental toxicity No evidence exists of teratogenicity with administration o f lopinavir/ritonavir to pregnant rats or rabbits. In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence o f skeletal variations, and skeletal ossification delays) were observed. Drug exposure in the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In a peri-and postnatal study in rats, a decrease in survival o f pups between birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day or greater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxic dosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lopinavir/ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f over all birth defects. No such increase in birth defects has been observed with lopinavir/ritonavir. Among cases o f first-trimester lopinavir/ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.2% (16 o f 738 births, 95% CI, 1.2%-3.5%) compared with a total prevalence of 2.7% in the U.S. population, based on CDC surveillance1. # • Placental and breast m ilk passage Lopinavir crosses the human placenta; in the P1026s PK study, the average ratio o f lopinavir concen tration in cord blood to maternal plasma at delivery was 0.20 ± 0.13. For ritonavir, data in humans indicate only minimal transplacental passage (see ritonavir). Lopinavir and ritonavir are secreted in the breast milk of lactating rats; it is not known if either drug is excreted in human milk. • Hum an studies in pregnancy The capsule formulation of lopinavir/ritonavir is no longer available; it has been replaced by a new tablet formulation o f lopinavir 200 mg/ritonavir 50 mg that is heat stable and does not have a food requirement. In nonpregnant adults, plasma concentrations o f lopinavir and ritonavir after administration o f two 200/50 mg lopinavir/ritonavir tablets are similar to those achieved with three 133/33 mg lopinavir/ri tonavir capsules given with food, although with less PK variability. In a study o f 51 pregnant women, plasma trough lopinavir levels during the third trimester were compared among 28 women receiving the capsule and 23 women receiving the tablet formulations at standard dosing. No statisti cal difference was found between the groups, with a mean lopinavir trough level o f 4.86 mg/L (cap sule) and 4.57 mg/L (tablets)2. However, the inter-individual variability was lower with the tablets than with the capsules. Five o f 28 women (17.8%) in the capsule group and 4 o f 23 women (17.4%) in the tablet group had trough levels less than the target (3 mg/L); 7 o f the 9 women had HIV RNA levels less than detection at the time of their sampling, and 2 with subtherapuetic levels (0.7 and 2.44 mg/L) had plasma RNA of 83 and 56 copies/mL, respectively, at the time o f their sampling. P1026s evaluated lopinavir PKs following standard dosing with the new lopinavir/ritonavir tablet formulation (2 tablets twice daily) until 30 weeks' gestation, followed by an increase to 3 tablets twice daily and return to standard dosing at postpartum hospital discharge. Median AUC was 72 p,gh/mL in 7 women receiving standard dosing during the second trimester, 97 p,gh/mL in 25 women receiving the increased dose during the third trimester, and 129 p,gh/mL in 19 women re ceiving standard dosing at 2 weeks postpartum. These data suggest that the higher lopinavir/ritonavir dose should be used in the third trimester; that it should be considered in the second trimester, partic ularly in women who are PI experienced; and that lopinavir/ritonavir can be reduced to standard dos ing shortly after delivery3. An alternative strategy for increasing lopinavir/ritonavir exposure during pregnancy is to add a pediatric lopinavir/ritonavir tablet (100/25 mg) to the standard dose o f 2 adult tablets (200/50 mg)4. Once-daily dosing o f lopinavir/ritonavir capsules or tablets is not recommended in pregnancy be cause no data exist to address whether drug levels are adequate with such administration. Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/vol ume) propylene glycol. Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation o f lopinavir (the active ingredient) as well as alcohol and propylene gly col. Preterm babies may be at increased risk o f health problems because they cannot metabolize propylene glycol; this could lead to accumulation and adverse events such as serious heart, kidney, or breathing problems. Postmarketing surveillance has identified 10 neonates (babies <4 weeks of age), 9 o f whom were born prematurely, who received lopinavir/ritonavir and experienced lifethreatening events5. Lopinavir/ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth, plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days has been attained. # • A nim al carcinogenicity studies Nelfinvair was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baseline in male rats receiving nelfinavir dosages o f 300 mg/kg/day or higher (equal to a systemic exposure similar to that in humans at therapeutic doses) and female rats receiving 1,000 mg/kg/day (equal to a systemic exposure 3-fold higher than that in humans at therapeutic doses). # • Reproduction/fertility No effect o f nelfinavir has been seen on reproductive performance, fertility, or embryo survival in rats at exposures comparable to human therapeutic exposure. Additional studies in rats indicated that exposure to nelfinavir in females from midpregnancy through lactation had no effect on the survival, growth, and development o f the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequent reproductive performance o f the offspring. • Teratogenicity/developm ental toxicity No evidence o f teratogenicity has been observed in pregnant rats at exposures comparable to human exposure and in rabbits with exposures significantly less than human exposure. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to nelfinavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with nelfinavir. Among cases o f first-trimester nelfinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.9% (46 o f 1,193 births, 95% CI, 2.8%-5.1%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1. • Placental and breast m ilk transfer In a Phase I study in pregnant women and their infants (PACTG 353, see below), transplacental pas sage o f nelfinavir was minimal2. In addition, in a study o f cord blood samples from 38 women who were treated with nelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit o f detection in 24 (63%), and the cord blood concentration was low (median, 0.35 p,g/mL) in the remaining 14 women3. Nelfinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk. • Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 353) o f nelfinavir in combination with zidovudine and lamivudine was conducted in pregnant HIV-infected women and their infants2. In the first nine preg nant HIV-infected women enrolled in the study, nelfinavir administered at a dose o f 750 mg three times daily produced drug exposures that were variable and generally lower than those reported in nonpregnant adults with both twice-and three-times-daily dosing. Therefore, the study was modified to evaluate an increased dose o f nelfinavir given twice daily (1,250 mg twice daily), which resulted in adequate levels o f the drug in pregnancy. However, in another study o f women given 1,250 mg nelfinavir twice daily in the second and third trimesters, drug concentrations in the third trimester were lower than in the second trimester or in nonpregnant women4. In a PK study o f combination therapy including the new nelfinavir 625-mg tablet formulation (given as 1,250 mg twice daily) in 25 women at 30-36 weeks' gestation (and 12 at 6-12 weeks postpar tum), peak levels and AUC were lower in the third trimester than postpartum5. Only 16% (4 o f 25) of women during the third trimester and 8% (1 o f 12) women postpartum had trough values greater than the suggested minimum trough o f 800 ng/mL; however, viral load was <400 copies/mL in 96% of women in the third trimester and 86% postpartum. is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Ritonavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies in mice and rats have been completed. In male mice, a dose-dependent increase in adenomas of the liver and combined adenomas and carcinomas o f the liver was observed at levels o f 50, 100, or 200 mg/kg/day; based on AUC, exposure in male mice at the highest dose was approximately 0.3-fold that in male humans at the recommended therapeutic dose. No carcino genic effects were observed in female mice with exposures 0.6-fold that o f female humans at the rec ommended therapeutic dose. No carcinogenic effects were observed in rats at exposures up to 6% of recommended therapeutic human exposure. # • Reproduction/fertility No effect o f ritonavir has been seen on reproductive performance or fertility in rats at drug exposures 40% (male) and 60% (female) o f that achieved with human therapeutic dosing; higher doses were not feasible because of hepatic toxicity in the rodents. • Teratogenicity/developm ental toxicity No ritonavir-related teratogenicity has been observed in rats or rabbits. Developmental toxicity, in cluding early resorptions, decreased body weight, ossification delays, and developmental variations such as wavy ribs and enlarged fontanelles, was observed in rats; however, these effects occurred only at maternally toxic dosages (exposure equivalent to 30% o f human therapeutic exposure). In ad dition, a slight increase in cryptorchidism was also noted in rats at exposures equivalent to 22% of the human therapeutic dose. In rabbits, developmental toxicity (resorptions, decreased litter size, and decreased fetal weight) was observed only at maternally toxic doses ( 1.8 times human therapeutic exposure based on body surface area). In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with ritonavir. Among cases o f first-trimester ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.4% (33 o f 1,401 births; 95% CI, 1.6%-3.3%) compared with a total prevalence o f 2.7% in the U.S. population, based on CDC surveillance1. • Placental and breast m ilk transfer Transplacental passage o f ritonavir has been observed in rats with fetal tissue to maternal serum ra tios >1.0 at 24 hours post-dose in mid-and late-gestation fetuses. In a human placental perfusion model, the clearance index o f ritonavir was very low, with little accumulation in the fetal compart ment and no accumulation in placental tissue2. In a Phase I study in pregnant women and their in fants (PACTG 354, see below), transplacental passage o f ritonavir was minimal3. Additionally, in a study o f cord blood samples from six women treated with ritonavir during pregnancy, the cord blood concentration was less than the assay limit o f detection in 83% and was only 0.38 p,g/mL in the re maining woman4. Ritonavir is excreted in the milk o f lactating rats; it is unknown if it is excreted in human milk. • Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 354) o f ritonavir (500 or 600 mg twice daily) in combina tion with zidovudine and lamivudine in pregnant HIV-infected women and their infants showed lower levels o f ritonavir during pregnancy than postpartum3. Ritonavir concentrations are also re duced during pregnancy versus postpartum when the drug is used at a low dose (100 mg) to boost the concentrations o f other PIs5-6. rabbit) o f those obtained in humans at the recommended clinical dose boosted with ritonavir. • Placental and breast m ilk transfer Placental transfer o f saquinavir in the rat and rabbit was minimal. In a Phase I study in pregnant women and their infants (PACTG 386, see below), transplacental passage o f saquinavir was mini m al1. In addition, in a study of cord blood samples from eight women treated with saquinavir during pregnancy, the cord blood concentration o f saquinavir was less than the assay limit o f detection in samples from all women2. Saquinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk. • Hum an studies in pregnancy Three studies have evaluated the PKs o f saquinavir-hard gel capsules combined with low-dose riton avir (saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily) in a total o f 19 preg nant women; trough levels were greater than the target in all but 1 woman3-4. In a small study o f 2 women who received saquinavir-hard gel capsules 1,200 mg/ritonavir 100 mg given once daily, trough levels were 285 and 684 ng/mL and the AUC0-24 were 28,010 and 16,790 ng hour/mL, greater than the target AUC o f 10,000 ng hour/mL5. Thus, the limited available data suggest that saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily should achieve adequate trough levels in HIV-infected pregnant women. Data are too limited to recommend once-daily dos ing at present. However, a recent analysis o f saquinavir-hard gel capsules administered once daily at 1,200 mg/100 mg ritonavir combined with various NRTIs during 46 pregnancies demonstrated saquinavir levels greater than the target minimum plasma concentration (Cmin) in 46 (93.4%) of pregnancy episodes and undetectable viral load at delivery in 88% o f episodes6. Target levels were achieved in the other 3 women with a dose o f 1,600 mg/100 mg. The drug was well tolerated. The PKs of the new 500-mg tablet formulation o f saquinavir boosted with ritonavir in a dose of saquinavir 1,000 mg/ritonavir 100 mg given twice daily were studied in 14 HIV-infected pregnant women at 33 weeks gestation and parameters were comparable to those observed in nonpregnant in dividuals; none o f the women had a subtherapeutic trough level7. One study o f a saquinavir/ritonavir-based combination ARV drug regimen in 42 women during preg nancy reported abnormal transaminase levels in 13 women (31%) within 2 -4 weeks o f treatment ini tiation, although the abnormalities were mild (toxicity Grade 1-2 in most, Grade 3 in 1 woman)8. ) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100, or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in com bination, or 10 mg/kg/day ritonavir. No drug-related findings were observed in male rats. At the highest dose o f tipranavir, an increased incidence o f benign follicular cell adenomas o f the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction. # • R eproduction/fertility Tipranavir had no effect on fertility or early embryonic development in rats at exposure levels similar to human exposures at the recommended clinical dose (500/200 mg per day of tipranavir/ritonavir). • Teratogenicity/developm ental toxicity No teratogenicity was detected in studies o f pregnant rats and rabbits at exposure levels approxi mately 1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) was observed in rats exposed to 400 mg/kg/day or more o f tipranavir (~0.8-fold human ex posure). Fetal toxicity was not seen in rats and rabbits at levels o f 0.2-fold and 0.1-fold human expo sures. In rats, no adverse effects on developments were seen at levels o f 40 mg/kg/day (~0.2-fold human exposure), but at 400 mg/kg/day (~0.8-fold human exposure), growth inhibition in pups and maternal toxicity were seen. • Placental and breast m ilk transfer No animal studies o f placental or breast milk passage o f tipranavir have been reported. It is unknown if placental or breast milk passage o f tipranavir occurs in humans. • Hum an studies in pregnancy No studies of tipranavir have been completed in pregnant women or neonates. Tipranavir is one of the study drugs in the ongoing IMPAACT P1026: "Pharmacokinetic Study o f Anti-HIV Drugs Dur ing Pregnancy" . • Placental and breast m ilk passage Studies of radio-labeled enfuvirtide administered to lactating rats indicated radioactivity in the milk; however, it is not known if this reflected radio-labeled enfuvirtide or metabolites (e.g., amino acid and peptide fragments) o f enfuvirtide. It is not known if enfuvirtide crosses the human placenta or is excreted in human milk. A published case report o f two peripartum pregnant patients and their neonates and data from an ex vivo human placental cotyledon perfusion model suggest that enfuvir tide does not cross the placenta1-2. • Hum an studies in pregnancy Very limited data exist on the use o f enfuvirtide in pregnant women1, 3-4; no data exist in neonates. Maraviroc (Selzentry, MVC) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Maraviroc was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies found no increase in tumor incidence in mice (trans genic rasH2 mice) and rats at exposures up to 11-fold higher than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily). # • R eproduction/fertility anim al studies Reproductive toxicity has been evaluated in rats. Maraviroc produced no adverse effects on fertility of male or female rats or sperm of male rats at exposures up to 20-fold higher than experienced with human therapeutic exposure at the recommended clinical dose (300 mg twice daily). • Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence o f harm to the fetus from maraviroc administered in doses up to 20-fold higher in rats and 5-fold higher in rabbits than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily). # • Placental and breast m ilk passage It is unknown if maraviroc crosses the placenta in humans. In a study o f four macaques, a single oral dose o f either 60 mg/kg or 100 mg/kg was given 2 hours before cesarean delivery. Median maternal concentration at delivery was 974 ng/mL (range 86-2,830 ng/mL) and median infant concentration was 22 ng/mL (range 4-99 ng/mL) for a cord/matemal ratio o f .0231. Maternal levels were de tectable for 48 hours after a single dose, whereas infant levels were detectable for only 3.5 hours after birth. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. • Hum an studies in pregnancy No studies of maraviroc have been conducted in pregnant women or neonates. # • A dditional concerns Although no increase in cancer has been observed with maraviroc, the drug has the potential to in crease risk because o f its mechanism o f action and possible effects on immune surveillance. Integrase Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: • Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. • Genetic mutations and/or chromosomal damage can contribute to cancer formation. One drug has been approved in this new class of antiretrovirals (ARVs) aimed at inhibiting integrase, the viral enzyme that catalyzes the two-step process of insertion of HIV DNA into the genome of the host cell. Integrase catalyzes a preparatory step that excises two nucleotides from one strand at both ends of the HIV DNA and a final "strand transfer" step that inserts the viral DNA into the exposed regions of cellular DNA. This second step in the integration process is targeted by the integrase inhibitor drug class. Integration is required for the stable maintenance of the viral genome as well as for efficient viral gene expression and replication. Integrase also affects retrotranscription and viral assembly. Host cells lack the integrase en zyme. Because HIV integrase represents a distinct therapeutic target, integrase inhibitors would be ex pected to maintain activity against HIV that is resistant to other classes of ARV drugs. Raltegravir (Isentress) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Raltegravir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f raltegravir are ongoing. # • R eproduction/fertility anim al studies Raltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/ day (providing exposures 3-fold higher than the exposure at the recommended adult human dose). • Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal sur vival or fetal weights from raltegravir administered in doses producing systemic exposures approxi mately 3-to 4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended human daily dose). # • Placental and breast m ilk passage Placental transfer o f raltegravir was demonstrated in both rats and rabbits. In rats given a maternal dose o f 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5-to 2.5-fold higher than in maternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drug concentrations in fetal plasma were approximately 2% o f the mean maternal plasma concentra tion at both 1 and 24 hours following a maternal dose o f 1,000 mg/kg/day. In a case report o f use in late pregnancy, the raltegravir cord blood-to-maternal blood ratio at delivery was 1.061. Raltegravir is secreted in the milk o f lactating rats, with mean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose o f 600 mg/kg/day. No effects in rat offspring were attrib utable to raltegravir exposure through breast milk. • Hum an studies in pregnancy Only limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PKs) were evaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability but did not appear to be consistently altered during the third trimester compared with postpartum and historical data in nonpregnant individuals; thus the standard dose appears appropri ate in pregnancy2. Raltegravir readily crossed the placenta; in 6 deliveries with evaluation, the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval [CI], 0.09-2.26). In a separate report, 3 pregnant women with multiresistant HIV-1 were given raltegravir in late pregnancy to rap idly reduce maternal viral load3. Raltegravir concentrations within 3 hours o f delivery in the neonates o f 2 patients were approximately 7 and 9.5 times higher than in the m other's paired sample; in the third infant, maternal plasma was not available but neonatal concentration was still high 2.5 hours after delivery. However, no adverse reactions were observed in mothers or infants. Whether raltegravir is secreted in human milk is unknown. # Some nelfinavir manufactured before 2008 may have contained low levels o f ethyl methane sul fonate (EMS), a process-related impurity. EMS is teratogenic, mutagenic, and carcinogenic in ani mals, although no data exist in humans and no increase in birth defects has been observed in the Antiretroviral Pregnancy Registry. All nelfinavir manufactured and released since March 31, 2008, meets the new final EMS limits established by the FDA for prescribing to all patient populations, in cluding pregnant women and pediatric patients. # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: • Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. • Genetic mutations and/or chromosomal damage can contribute to cancer formation. Six nucleoside analogue reverse transcriptase inhibitors (nucleoside NRTIs) and one nucleotide reverse transcriptase inhibitor (nucleotide NRTI) are currently approved (zalcitabine is no longer available in the United States). Data are available from clinical trials in human pregnancy for the nucleoside NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine, and the nucleotide NRTI tenofovir. The nucleoside analogue drugs require three intracellular phosphorylation steps to form the triphosphate nucleoside, which is the active drug moiety. Tenofovir, an acyclic nucleotide analogue drug, contains a monophosphate component attached to the adenine base, and hence requires only two phos phorylation steps to form the active moiety. For information regarding the nucleoside analogue drug class and potential mitochondrial toxicity in pregnancy and to the infant, see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines. Abacavir (Ziagen, ABC) is classified as Food and Drug Administration (FDA) pregnancy category C. # • A nim al carcinogenicity studies Abacavir is mutagenic and clastogenic in some in vitro and in vivo assays. In long-term carcino genicity studies in mice and rats, malignant tumors o f the preputial gland o f males and the clitoral gland o f females were observed in both species, and malignant hepatic tumors and nonmalignant he patic and thyroid tumors were observed in female rats. The tumors were seen in rodents at doses that were 6-32 times that of human therapeutic exposure. # • Reproduction/fertility No effect of abacavir on reproduction or fertility in male and female rodents has been seen at doses of up to 500 mg/kg/day (about 8 times that of human therapeutic exposure based on body surface area). # • Teratogenicity/developm ental toxicity Abacavir is associated with developmental toxicity (decreased fetal body weight and reduced crownrump length) and increased incidence o f fetal anasarca and skeletal malformations in rats treated Didanosine (Videx, ddl) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Didanosine is both mutagenic and clastogenic in several in vitro and in vivo assays. Long-term ani mal carcinogenicity screening studies at human exposures o f 0.7-1.7 and 3 times, respectively, in mice and rats have been negative. # • Reproduction/fertility At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid-and late lactation. These rats showed reduced food intake and body Lamivudine (Epivir, 3TC) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Lamivudine has weak mutagenic activity in one in vitro assay but no evidence o f in vivo genotoxicity in rats at 35-45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58 times human exposure have been negative in mice and rats, respectively. • Reproduction/fertility Lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47-70 times those in humans, revealed no evidence o f impaired fertility and no effect on the offsprings' sur vival, growth, and development up to the time o f weaning. # • Teratogenicity/developm ental toxicity studies There is no evidence o f lamivudine-induced teratogenicity at 35 times human plasma levels in rats and rabbits. Early embryolethality was seen in rabbits at doses similar to human therapeutic expo sure but not in rats at 35 times the human exposure level. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lamivu-Etravirine (Intelence, ETR) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B . # • A nim al carcinogenicity studies Etravirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies o f etravirine in rodents are ongoing. # • Reproduction/fertility No effect on fertility and early embryonic development was observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to the recommended human dose (400 mg/day). # • Teratogenicity/developm ental toxicity Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the rec ommended human dose o f 400 mg/day revealed no evidence o f fetal toxicity or altered development. Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1,000 mg/kg/day). In both species, no treatment-related embryo-fetal effects, including malformations, were observed. In addition, no treatment effects were observed in a sepa rate pre-and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic ex posures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day). # • Placental and breast m ilk passage There are no data on whether etravirine crosses the placenta or is excreted in breast milk in humans. # • Hum an studies in pregnancy No adequate and well-controlled studies of etravirine use in pregnant women have been conducted and very limited case report data are available on etravirine use in pregnancy. One small study described use of etravirine in combination with darunavir/ritonavir and other ARV drugs in four pregnant women; PK sampling was done to determine etravirine plasma concentration during the third trimester1. PK data from these women were similar to those in nonpregnant adults. Data on etravirine in postpartum cord blood and concurrent maternal plasma specimens were available for one patient with values of 112 ng/mL and 339 ng/mL (cord/maternal blood ratio 0.33). No maternal, fetal, or neonatal toxicity was reported; one infant was born with a small accessory auricle on the right ear with no other malformations; no birth defects were noted in the other children. Placental passage of etravirine was noted in another report of use of etravirine, darunavir/ritonavir, and enfuvirtide in a pregnant woman who gave birth to twins (cord blood levels 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2)2. In a separate report on two women receiving etravirine, darunavir/ritonavir, and raltegravir during pregnancy, no perinatal transmission of HIV or congenital abnormalities were observed. # Rilpivirine (Edurant) is classified as FDA pregnancy category B. • A nim al carcinogenicity studies Rilpivirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than expo sure in humans at the recommended dose o f 25 mg once daily. Hepatocellular neoplasms were ob served in both male and female mice at doses 21 times that o f human therapeutic exposure; the observed hepatocellular findings in mice may be rodent specific1. # • R eproduction/fertility No effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400 mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose. Darunavir (Prezista, DRV) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Darunavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. A dose-related increase in the incidence o f hepatocellular adenomas and carcinomas was ob served in both male and female mice and rats as well as an increase in thyroid follicular cell adeno mas in male rats. The observed hepatocellular findings in rodents are considered to be o f limited relevance to humans. Repeated administration o f darunavir to rats caused hepatic microsomal en zyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4-and 0.7-fold (mice) and 0.7-and 1-fold (rats) o f those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily). # • Reproduction/fertility No effects on fertility and early embryonic development were seen with darunavir in rats. • Teratogenicity/developm ental toxicity No embryotoxicity or teratogenicity was seen in mice, rats, or rabbits. Because o f limited bioavail ability of darunavir in animals and dosing limitation, the plasma exposures were approximately 50% (mice and rats) and 5% (rabbits) o f those obtained in humans. In the rat pre-and postnatal develop ment study, a reduction in pup weight gain was observed with darunavir alone or with ritonavir ex posure via breast milk during lactation. In juvenile rats, single doses o f darunavir (20 mg/kg-160 mg/kg at ages 5-11 days) or multiple doses o f darunavir (40 mg/kg-1,000 mg/kg at age 12 days) caused mortality. The deaths were associated with convulsions in some o f the animals. Within this age range, exposures in plasma, liver, and brain were dose and age dependent and were considerably greater than those observed in adult rats. tating rats; it is not known if it is excreted in human milk. • Hum an studies in pregnancy Very limited data exist on fosamprenavir in pregnant women. Fosamprenavir PKs have been re ported in 15 women during pregnancy and postpartum. Following standard dosing with fosampre navir 700 mg and ritonavir 100 mg, amprenavir AUC and 12-hour trough concentrations were somewhat lower during pregnancy and higher postpartum compared with historical data. Amprenavir exposure during pregnancy appeared to be adequate for patients without PI resistance mutations1. A pediatric liquid formulation o f fosamprenavir has been approved for children older than 2 years of age, but there is no dosing information for neonates. Indinavir (Crixivan, IDV) is classified as FDA pregnancy category C. # • A nim al carcinogenicity studies Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivo assays. No increased inci dence o f any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid ade nomas were seen in male rats. # • Reproduction/fertility No effect o f indinavir has been seen on reproductive performance, fertility, or embryo survival in rats. • Teratogenicity/developm ental toxicity There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater than therapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumer ary and cervical ribs was observed at doses comparable to those administered to humans. No treat ment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of mater nal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnant Rhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, in dinavir exacerbated the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. In Rhesus monkeys, fetal plasma drug levels were approximately 1%-2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily. In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposure to indinavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth Acquir Immune Defic Syndr. Jan 28 2011. Saquinavir (Invirase [Hard-Gel Capsule], SQV) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Saquinavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies found no indication o f carcinogenic activity in rats and mice adminis tered saquinavir for approximately 2 years at plasma exposures approximately 60% o f those ob tained in humans at the recommended therapeutic dose (rats) and at exposures equivalent to those in humans at the recommended therapeutic dose (mice). # • Reproduction/fertility No effect o f saquinavir has been seen on reproductive performance, fertility, or embryo survival in rats. Because o f limited bioavailability o f saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% o f those obtained in humans at the recommended clinical dose boosted with ritonavir. • Teratogenicity/developm ental toxicity No evidence o f embryotoxicity or teratogenicity o f saquinavir has been found in rabbits or rats. Be cause o f limited bioavailability o f saquinavir in animals and/or dosing limitations, the plasma expo sures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using Entry Inhibitors (Updated September 14, 2011) # Glossary of Terms for Supplement Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes: • Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic. • Genetic mutations and/or chromosomal damage can contribute to cancer formation. Two drugs have been approved in this new class o f antiretrovirals (ARVs) aimed at inhibiting viral bind ing or fusion o f HIV to host target cells. Binding o f the viral envelope glycoprotein (gp)120 to the CD4 receptor induces conformational changes that enable gp120 to interact with a chemokine receptor such as CCR5 or CXCR4 on the host cell; binding o f gp120 to the coreceptor causes subsequent conforma tional changes in the viral transmembrane gp41, exposing the "fusion peptide" o f gp41, which inserts into the cell membrane. A helical region o f gp41, called HR1, then interacts with a similar helical region, HR2, on gp41, resulting in a "zipping" together o f the two helices and mediating the fusion o f cellular and viral membranes. Enfuvirtide, which requires subcutaneous administration, is a synthetic 36-aminoacid peptide derived from a naturally occurring m otif within the HR2 domain o f viral gp41, and the drug binds to the HR1 region, preventing the HR1-HR2 interaction and correct folding o f gp41 into its sec ondary structure, thereby inhibiting virus-cell fusion. Enfuvirtide was approved for use in combination with other ARV drugs to treat advanced HIV infection in adults and children 6 years o f age or older. Maraviroc interferes with viral entry at the chemokine coreceptor level; it is a CCR5 coreceptor antago nist approved for combination therapy for HIV infection in adults infected with CCR5-tropic virus. Enfuvirtide (Fuzeon, T-20) is classified as FDA pregnancy category B. # • A nim al carcinogenicity studies Enfuvirtide was neither mutagenic or clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f enfuvirtide have not been conducted. # • R eproduction/fertility anim al studies Reproductive toxicity has been evaluated in rats and rabbits. Enfuvirtide produced no adverse effects on fertility of male or female rats at doses up 30 mg/kg/day administered subcutaneously (1.6 times the maximum recommended adult human daily dose on an m2 body surface area basis). • Teratogenicity/developm ental toxicity anim al studies Studies in rats and rabbits revealed no evidence o f harm to the fetus from enfuvirtide administered in doses up to 27 times and 3.2 times, respectively, the adult human daily dose on an m 2 body surface area basis. Antiretroviral Pregnancy Registry (Updated September 14, 2011) The Antiretroviral Pregnancy Registry is an epidemiologic project to collect observational, nonexperi mental data on ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The registry is a collabo rative project o f the pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners. It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their newborns report cases o f prenatal exposure to ARV drugs (either alone or in combination) to the Antiretroviral Pregnancy Registry. The registry does not use patient names, and birth outcome fol low-up is obtained from the reporting physician by registry staff.	None	None
438de3b6ceb41a434bec0b99602b097440fca405	cdc	None	Widespread use of fluoride has been a major factor in the decline in the prevalence and severity of dental caries (i.e., tooth decay) in the United States and other economically developed countries. When used appropriately, fluoride is both safe and effective in preventing and controlling dental caries. All U.S. residents are likely exposed to some degree to fluoride, which is available from multiple sources. Both health-care professionals and the public have sought guidance on selecting the best way to provide and receive fluoride. During the late 1990s, CDC convened a work group to develop recommendations for using fluoride to prevent and control dental caries in the United States. This report includes these recommendations, as well as a) critical analysis of the scientific evidence regarding the efficacy and effectiveness of fluoride modalities in preventing and controlling dental caries, b) ordinal grading of the quality of the evidence, and c) assessment of the strength of each recommendation. Because frequent exposure to small amounts of fluoride each day will best reduce the risk for dental caries in all age groups, the work group recommends that all persons drink water with an optimal fluoride concentration and brush their teeth twice daily with fluoride toothpaste. For persons at high risk for dental caries, additional fluoride measures might be needed. Measured use of fluoride modalities is particularly appropriate during the time of anterior tooth enamel development (i.e., age <6 years). The recommendations in this report guide dental and other health-care providers, public health officials, policy makers, and the public in the use of fluoride to achieve maximum protection against dental caries while using resources efficiently and reducing the likelihood of enamel fluorosis. The recommendations address public health and professional practice, self-care, consumer product industries and health agencies, and further research. Adoption of these recommendations could further reduce dental caries in the United States and save public and private resources.# INTRODUCTION Dental caries (i.e., tooth decay) is an infectious, multifactorial disease afflicting most persons in industrialized countries and some developing countries (1 ). Fluoride reduces the incidence of dental caries and slows or reverses the progression of existing lesions (i.e., prevents cavities). Although pit and fissure sealants, meticulous oral hygiene, and appropriate dietary practices contribute to caries prevention and control, the most effective and widely used approaches have included fluoride use. Today, all U.S. residents are exposed to fluoride to some degree, and widespread use of fluoride has been a major factor in the decline in the prevalence and severity of dental caries in the United States and other economically developed countries (1 ). Although this decline is a major public health achievement, the burden of disease is still considerable in all age groups. Because many fluoride modalities are effective, inexpensive, readily available, and can be used in both private and public health settings, their use is likely to continue. Fluoride is the ionic form of the element fluorine, the 13th most abundant element in the earth's crust. Fluoride is negatively charged and combines with positive ions (e.g., calcium or sodium) to form stable compounds (e.g., calcium fluoride or sodium fluoride). Such fluorides are released into the environment naturally in both water and air. Fluoride compounds also are produced by some industrial processes that use the mineral apatite, a mixture of calcium phosphate compounds. In humans, fluoride is mainly associated with calcified tissues (i.e., bones and teeth) because of its high affinity for calcium. Fluoride's ability to inhibit or even reverse the initiation and progression of dental caries is well documented. The first use of adjusted fluoride in water for caries control began in 1945 and 1946 in the United States and Canada, when the fluoride concentration was adjusted in the drinking water supplying four communities (2)(3)(4)(5). The U.S. Public Health Service (PHS) developed recommendations in the 1940s and 1950s regarding fluoride concentrations in public water supplies. At that time, public health officials assumed that drinking water would be the major source of fluoride for most U.S. residents. The success of water fluoridation in preventing and controlling dental caries led to the development of fluoride-containing products, including toothpaste (i.e., dentifrice), mouthrinse, dietary supplements, and professionally applied or prescribed gel, foam, or varnish. In addition, processed beverages, which constitute an increasing proportion of the diets of many U.S. residents (6,7 ), and food can contain small amounts of fluoride, especially if they are processed with fluoridated water. Thus, U.S. residents have more sources of fluoride available now than 50 years ago. Much of the research on the efficacy and effectiveness of individual fluoride modalities in preventing and controlling dental caries was conducted before 1980, when dental caries was more common and more severe. Modalities were usually tested separately and with the assumption that the method would provide the main source of fluoride. Thus, various modes of fluoride use have evolved, each with its own recommended concentration, frequency of use, and dosage schedule. Health-care professionals and the public have sought guidance regarding selection of preventive modalities from among the available options. The United States does not have comprehensive recommendations for caries prevention and control through various combinations of fluoride modalities. Adoption of such recommendations could further reduce dental caries while saving public and private resources and reducing the prevalence of enamel fluorosis, a generally cosmetic developmental condition of tooth enamel. This report presents comprehensive recommendations on the use of fluoride to prevent and control dental caries in the United States. These recommendations were developed by a work group of 11 specialists in fluoride research or policy convened by CDC during the late 1990s and reviewed by an additional 23 specialists. Although the recommendations were developed specifically for the United States, aspects of this report could be relevant to other countries. The recommendations guide health-care providers and the public on efficient and appropriate use of fluoride modalities, direct attention to fluoride intake among children aged <6 years to decrease the risk for enamel fluorosis, and suggest areas for further research. This report focuses on critical analysis of the scientific evidence regarding the efficacy and effectiveness of each fluoride modality in preventing and controlling dental caries and on the use of multiple sources of fluoride. The safety of fluoride, which has been documented comprehensively by other scientific and public health organizations (e.g., PHS , National Research Council , World Health Organization , and Institute of Medicine ) is not addressed. # HOW FLUORIDE PREVENTS AND CONTROLS DENTAL CARIES Dental caries is an infectious, transmissible disease in which bacterial by-products (i.e., acids) dissolve the hard surfaces of teeth. Unchecked, the bacteria can penetrate the dissolved surface, attack the underlying dentin, and reach the soft pulp tissue. Dental caries can result in loss of tooth structure, pain, and tooth loss and can progress to acute systemic infection. Cariogenic bacteria (i.e., bacteria that cause dental caries) reside in dental plaque, a sticky organic matrix of bacteria, food debris, dead mucosal cells, and salivary components that adheres to tooth enamel. Plaque also contains minerals, primarily calcium and phosphorus, as well as proteins, polysaccharides, carbohydrates, and lipids. Cariogenic bacteria colonize on tooth surfaces and produce polysaccharides that enhance adherence of the plaque to enamel. Left undisturbed, plaque will grow and harbor increasing numbers of cariogenic bacteria. An initial step in the formation of a carious lesion takes place when cariogenic bacteria in dental plaque metabolize a substrate from the diet (e.g., sugars and other fermentable carbohydrates) and the acid produced as a metabolic by-product demineralizes (i.e., begins to dissolve) the adjacent enamel crystal surface (Figure 1). Demineralization involves the loss of calcium, phosphate, and carbonate. These minerals can be captured by surrounding plaque and be available for reuptake by the enamel surface. Fluoride, when present in the mouth, is also retained and concentrated in plaque. Fluoride works to control early dental caries in several ways. Fluoride concentrated in plaque and saliva inhibits the demineralization of sound enamel and enhances the remineralization (i.e., recovery) of demineralized enamel (12,13 ). As cariogenic bacteria metabolize carbohydrates and produce acid, fluoride is released from dental plaque in response to lowered pH at the tooth-plaque interface (14 ). The released fluoride and the fluoride present in saliva are then taken up, along with calcium and phosphate, by demineralized enamel to establish an improved enamel crystal structure. This improved structure is more acid resistant and contains more fluoride and less carbonate (12,(15)(16)(17)(18)(19) (Figure 1). Fluoride is more readily taken up by demineralized enamel than by sound enamel (20 ). Cycles of demineralization and remineralization continue throughout the lifetime of the tooth. Fluoride also inhibits dental caries by affecting the activity of cariogenic bacteria. As fluoride concentrates in dental plaque, it inhibits the process by which cariogenic bacteria metabolize carbohydrates to produce acid and affects bacterial production of adhesive polysaccharides (21 ). In laboratory studies, when a low concentration of fluoride is constantly present, one type of cariogenic bacteria, Streptococcus mutans, produces less acid (22)(23)(24)(25). Whether this reduced acid production reduces the cariogenicity of these bacteria in humans is unclear (26 ). Saliva is a major carrier of topical fluoride. The concentration of fluoride in ductal saliva, as it is secreted from salivary glands, is low -approximately 0.016 parts per million (ppm) in areas where drinking water is fluoridated and 0.006 ppm in nonfluoridated areas (27 ). This concentration of fluoride is not likely to affect cariogenic activity. However, drinking fluoridated water, brushing with fluoride toothpaste, or using other fluoride dental products can raise the concentration of fluoride in saliva present in the mouth 100to 1,000-fold. The concentration returns to previous levels within 1-2 hours but, during this time, saliva serves as an important source of fluoride for concentration in plaque and for tooth remineralization (28 ). Applying fluoride gel or other products containing a high concentration of fluoride to the teeth leaves a temporary layer of calcium fluoride-like material on the enamel surface. The fluoride in this material is released when the pH drops in the mouth in response to acid production and is available to remineralize enamel (29 ). In the earliest days of fluoride research, investigators hypothesized that fluoride affects enamel and inhibits dental caries only when incorporated into developing dental enamel (i.e., preeruptively, before the tooth erupts into the mouth) (30,31 ). Evidence supports this hypothesis (32)(33)(34), but distinguishing a true preeruptive effect after teeth erupt into a mouth where topical fluoride exposure occurs regularly is difficult. However, a high fluoride concentration in sound enamel cannot alone explain the marked reduction in dental caries that fluoride produces (35,36 ). The prevalence of dental caries in a population is not inversely related to the concentration of fluoride in enamel (37 ), and a higher concentration of enamel fluoride is not necessarily more efficacious in preventing dental caries (38 ). The laboratory and epidemiologic research that has led to the better understanding of how fluoride prevents dental caries indicates that fluoride's predominant effect is posteruptive and topical and that the effect depends on fluoride being in the right amount in the right place at the right time. Fluoride works primarily after teeth have erupted, especially when small amounts are maintained constantly in the mouth, specifically in dental plaque and saliva (37 ). Thus, adults also benefit from fluoride, rather than only children, as was previously assumed. # RISK FOR DENTAL CARIES The prevalence and severity of dental caries in the United States have decreased substantially during the preceding 3 decades (39 ). National surveys have reported that the prevalence of any dental caries among children aged 12-17 years declined from 90.4% in 1971-1974 to 67% in 1988-1991; severity (measured as the mean number of decayed, missing, or filled teeth) declined from 6.2 to 2.8 during this period (40)(41)(42)(43). These decreases in caries prevalence and severity have been uneven across the general population; the burden of disease now is concentrated among certain groups and persons. For example, 80% of the dental caries in permanent teeth of U.S. children aged 5-17 years occurs among 25% of those children (43 ). To develop and apply appropriate and effective caries prevention and control strategies, identification and assessment of groups and persons at high risk for developing new carious lesions is essential (44 ). Caries risk assessment is difficult because it attempts to account for the complex interaction of multiple factors. Although various methods for assessing risk exist, no single model predominates in this emerging science. Models that take multiple factors into account predict the risk more accurately, especially for groups rather than persons. However, for persons in a clinical setting, models do not improve on a dentist's perception of risk after examining a patient and considering the personal circumstances (45 ). Populations believed to be at increased risk for dental caries are those with low socioeconomic status (SES) or low levels of parental education, those who do not seek regular dental care, and those without dental insurance or access to dental services (45)(46)(47). Persons can be at high risk for dental caries even if they do not have these recognized factors. Individual factors that possibly increase risk include active dental caries; a history of high caries in older siblings or caregivers; root surfaces exposed by gingival recession; high levels of infection with cariogenic bacteria; impaired ability to maintain oral hygiene; malformed enamel or dentin; reduced salivary flow because of medications, radiation treatment, or disease; low salivary buffering capacity (i.e., decreased ability of saliva to neutralize acids); and the wearing of space maintainers, orthodontic appliances, or dental prostheses. Risk can increase if any of these factors are combined with dietary practices conducive to dental caries (i.e., frequent consumption of refined carbohydrates). Risk decreases with adequate exposure to fluoride (44,45 ). Risk for dental caries and caries experience- exists on a continuum, with each person at risk to some extent; 85% of U.S. adults have experienced tooth decay (48 ). Caries risk can vary over time -perhaps numerous times during a person's lifetime -as risk factors change. Because caries prediction is an inexact, developing science, risk is dichotomized as low and high in this report. If these two categories of risk were applied to the U.S. population, most persons would be classified as low risk at any given time. Children and adults who are at low risk for dental caries can maintain that status through frequent exposure to small amounts of fluoride (e.g., drinking fluoridated water and using fluoride toothpaste). Children and adults at high risk for dental caries might benefit from additional exposure to fluoride (e.g., mouthrinse, dietary supplements, and professionally applied products). All available information on risk factors should be considered before a group or person is identified as being at low or high risk for dental caries. However, when classification is uncertain, treating a person as high risk is prudent until further information or experience allows a more accurate assessment. This assumption For this report, the term "caries experience" is used to mean the sum of filled and unfilled cavities, along with any missing teeth resulting from tooth decay. # MMWR August 17, 2001 increases the immediate cost of caries prevention or treatment and might increase the risk for enamel fluorosis for children aged <6 years, but reduces the risk for dental caries for groups or persons misclassified as low risk. # RISK FOR ENAMEL FLUOROSIS The proper amount of fluoride helps prevent and control dental caries. Fluoride ingested during tooth development can also result in a range of visually detectable changes in enamel opacity (i.e., light refraction at or below the surface) because of hypomineralization. These changes have been broadly termed enamel fluorosis, certain extremes of which are cosmetically objectionable (49 ). (Many other developmental changes that affect the appearance of enamel are not related to fluoride .) Severe forms of this condition can occur only when young children ingest excess fluoride, from any source, during critical periods of tooth development. The occurrence of enamel fluorosis is reported to be most strongly associated with cumulative fluoride intake during enamel development, but the severity of the condition depends on the dose, duration, and timing of fluoride intake. The transition and early maturation stages of enamel development appear to be most susceptible to the effects of fluoride (51 ); these stages occur at varying times for different tooth types. For central incisors of the upper jaw, for example, the most sensitive period is estimated at age 15-24 months for boys and age 21-30 months for girls (51,52 ). Concerns regarding the risk for enamel fluorosis are limited to children aged 6 years are considered past the age that fluoride ingestion can cause cosmetically objectionable fluorosis because only certain posterior teeth are still at a susceptible stage of enamel development, and these will not be readily visible. In addition, the swallowing reflex has developed sufficiently by age 6 years for most children to be able to control inadvertent swallowing of fluoride toothpaste and mouthrinse. The very mild and mild forms of enamel fluorosis appear as chalklike, lacy markings across a tooth's enamel surface that are not readily apparent to the affected person or casual observer (53 ). In the moderate form, >50% of the enamel surface is opaque white. The rare, severe form manifests as pitted and brittle enamel. After eruption, teeth with moderate or severe fluorosis might develop areas of brown stain (54 ). In the severe form, the compromised enamel might break away, resulting in excessive wear of the teeth. Even in its severe form, enamel fluorosis is considered a cosmetic effect, not an adverse functional effect (8,11,55,56 ). Some persons choose to modify this condition with elective cosmetic treatment. The benefits of reduced dental caries and the risk for enamel fluorosis are linked. Early studies that examined the cause of "mottled enamel" (now called moderate to severe enamel fluorosis) led to the unexpected discovery that fluoride in community drinking water inhibits dental caries (57 ). Historically, a low prevalence of the milder forms of enamel fluorosis has been accepted as a reasonable and minor consequence balanced against the substantial protection from dental caries from drinking water con-taining an optimal concentration of fluoride, either naturally occurring or through adjustment (11,53 ). When enamel fluorosis was first systematically investigated during the 1930s and 1940s, its prevalence was 12%-15% for very mild and mild forms and zero for moderate and severe forms among children who lived in communities with drinking water that naturally contained 0.9-1.2 ppm fluoride (53 ). Although the prevalence of this condition in the United States has since increased (8,58,59 ), most fluorosis today is of the mildest form, which affects neither cosmetic appearance nor dental function. The increased prevalence in areas both with and without fluoridated community drinking water (8 ) indicates that, during the first 8 years of life (i.e., the window of time when this condition can develop), the total intake of fluoride from all sources has increased for some children. The 1986The -1987 National Survey of Dental Caries in U.S. School Children (the most recent national estimates of enamel fluorosis prevalence) indicated that the prevalence of any enamel fluorosis among children was 22%-23% (range: 26% of children aged 9 years to 19% of those aged 17 years) (60,61 ). Almost all cases reported in the survey were of the very mild or mild form, but some cases of the moderate (1.1%) and severe (0.3%) forms were observed. Cases of moderate and severe forms occurred even among children living in areas with low fluoride concentrations in the drinking water (61 ). Although this level of enamel fluorosis is not considered a public health problem (53 ), prudent public health practice should seek to minimize this condition, especially moderate to severe forms. In addition, changes in public perceptions of what is cosmetically acceptable could influence support for effective caries-prevention measures. Research into the causes of enamel fluorosis has focused on identifying risk factors (62)(63)(64)(65). Adherence to the recommendations in this report regarding appropriate use of fluoride for children aged <6 years will reduce the prevalence and severity of enamel fluorosis. # NATIONAL GUIDELINES FOR FLUORIDE USE PHS recommendations for fluoride use include an optimally adjusted concentration of fluoride in community drinking water to maximize caries prevention and limit enamel fluorosis. This concentration ranges from 0.7 ppm to 1.2 ppm depending on the average maximum daily air temperature of the area (66)(67)(68). In 1991, PHS also issued policy and research recommendations for fluoride use (8 ). The U.S. Environmental Protection Agency (EPA), which is responsible for the safety and quality of drinking water in the United States, sets a maximum allowable limit for fluoride in community drinking water at 4 ppm and a secondary limit (i.e., nonenforceable guideline) at 2 ppm (69,70 ). The U.S. Food and Drug Administration (FDA) is responsible for approving prescription and overthe-counter fluoride products marketed in the United States and for setting standards for labeling bottled water (71 ) and over-the-counter fluoride products (e.g., toothpaste and mouthrinse) (72 ). Nonfederal agencies also have published guidelines on fluoride use. The American Dental Association (ADA) reviews fluoride products for caries prevention through its voluntary Seal of Acceptance program; accepted products are listed in the ADA Guide to Dental Therapeutics (73 ). A dosage schedule for fluoride supplements for infants and children aged <16 years, which is scaled to the fluoride concentration in the community drinking water, has been jointly recommended by ADA, the American Academy of Pediatric Dentistry (AAPD), and the American Academy of Pediatrics (AAP) (Table 1) (44,74,75 ). In 1997, the Institute of Medicine published age-specific recommendations for total dietary intake of fluoride (Table 2). These recommendations list adequate intake to prevent dental caries and tolerable upper intake, defined as a level unlikely to pose risk for adverse effects in almost all persons. # FLUORIDE SOURCES AND THEIR EFFECTS Fluoridated community drinking water and fluoride toothpaste are the most common sources of fluoride in the United States and are largely responsible for the low risk for dental caries for most persons in this country. Persons at high risk for dental caries might require more frequent or more concentrated exposure to fluoride and might benefit from use of other fluoride modalities (e.g., mouthrinse, dietary supplements, and topical gel, foam, or varnish). The effects of each of these fluoride sources on dental caries and enamel fluorosis are described. # Fluoridated Drinking Water and Processed Beverages and Food Fluoridated drinking water contains a fluoride concentration effective for preventing dental caries; this concentration can occur naturally or be reached through water fluoridation, which is the controlled addition of fluoride to a public water supply. When fluoridated water is the main source of drinking water, a low concentration of fluoride is routinely introduced into the mouth. Some of this fluoride is taken up by dental plaque; some is transiently present in saliva, which serves as a reservoir for plaque fluoride; and some is loosely held on the enamel surfaces (76 ). Frequent consumption of fluoridated drinking water and beverages and food processed in fluoridated areas maintains the concentration of fluoride in the mouth. Estimates of fluoride intake among U.S. and Canadian adults have ranged from <1.0 mg fluoride per day in nonfluoridated areas to 1-3 mg fluoride per day in fluoridated areas (77)(78)(79)(80). The average daily dietary fluoride intake for both children and adults in fluoridated areas has remained relatively constant for several years (11 ). For children who live in optimally fluoridated areas, this average is approximately 0.05 mg/kg/day (range: 0.02-0.10); for children who live in nonfluoridated areas, the average is approximately half (11 ). In a survey of four U.S. cities with different fluoride concentrations in the drinking water (range: 0.37-1.04 ppm), children aged 2 years ingested 0.41-0.61 mg fluoride per day and infants aged 6 months ingested 0.21-0.54 mg fluoride per day (81,82 ). In the United States, water and processed beverages (e.g., soft drinks and fruit juices) can provide approximately 75% of a person's fluoride intake (83 ). Many processed beverages are prepared in locations where the drinking water is fluoridated. Foods and ingredients used in food processing vary in their fluoride content (11 ). As consumption of processed beverages by children increases, fluoride intake in communities without fluoridated water will increase whenever the water source for the processed beverage is fluoridated (84). In fluoridated areas, dietary fluoride intake has been stable because processed beverages have been substituted for tap water and for beverages prepared in the home using tap water (11 ). A study of Iowa infants estimated that the mean fluoride intake from water during different periods during the first 9 months of life, either consumed directly or added to infant formula or juice, was 0.29-0.38 mg per day, although estimated intake for some infants was as high as 1.73 mg per day (85 ). As foods are added to an infant's diet, replacing some of the formula prepared with fluoridated water, the amount of fluoride the infant receives typically decreases (86 ). The Iowa study also reported that infant formula and processed baby food contained variable amounts of fluoride. Since 1979, U.S. manufacturers of infant formula have voluntarily lowered the fluoride concentration of their products, both ready-to-feed and concentrates, to <0.3 ppm fluoride (87 ). # Drinking Water Community Water. During the 1940s, researchers determined that 1 ppm fluoride was the optimal concentration in community drinking water for climates similar to the Chicago area (88,89 ). This concentration would substantially reduce the prevalence of dental caries, while allowing an acceptably low prevalence (i.e., 10%-12%) of very mild and mild enamel fluorosis and no moderate or severe enamel fluorosis. Water fluoridation for caries control began in 1945 and 1946, when the fluoride concentration was adjusted in the drinking water supplying four communities in the United States and Canada (2)(3)(4)(5). This public health approach followed a long period of epidemiologic research into the effects of naturally occurring fluoride in drinking water (53,57,88,89 ). Current federal fluoridation guidelines, maintained by the PHS since 1962, state that community drinking water should contain 0.7-1.2 ppm fluoride, depending on the average maximum daily air temperature of the area. These temperature-related guidelines are based on epidemiologic studies conducted during the 1950s that led to the development of an algebraic formula for determining optimal fluoride concentrations (67,(90)(91)(92). This formula determined that a lower fluoride concentration was appropriate for communities in warmer climates because persons living in warmer climates drank more tap water. However, social and environmental changes since 1962 (e.g., increased use of air conditioning and more sedentary lifestyles) have reduced the likelihood that persons in warmer regions drink more tap water than persons in cooler regions (7 ). By 1992, fluoridated water was reaching 144 million persons in the United States (56% of the total population and 62% of those receiving municipal water supplies) (93 ). Approximately 10 million of these persons were receiving water containing naturally occurring fluoride at a concentration of >0.7 ppm. In 11 states and the District of Columbia, >90% of the population had such access, whereas 50% of their population (CDC, unpublished data, 2000) (Figure 2). # MMWR 11 Initial studies of community water fluoridation demonstrated that reductions in childhood dental caries attributable to fluoridation were approximately 50%-60% (94)(95)(96)(97). More recent estimates are lower -18%-40% (98,99 ). This decrease in attributable benefit is likely caused by the increasing use of fluoride from other sources, with the widespread use of fluoride toothpaste probably the most important. The diffusion or "halo" effect of beverages and food processed in fluoridated areas but consumed in nonfluoridated areas also indirectly spreads some benefit of fluoridated water to nonfluoridated communities. This effect lessens the differences in caries experience among communities (100 ). Quantifying the benefits of water fluoridation among adults is more complicated because adults are rarely surveyed, their fluoride histories are potentially more varied, and their tooth loss or restorations might be caused by dental problems other than caries (e.g., trauma or periodontal diseases). Nevertheless, adults are reported to receive caries-preventive benefits from community water fluoridation (99,(101)(102)(103). These benefits might be particularly advantageous for adults aged >50 years, many of whom are at increased risk for dental caries. Besides coronal caries, older adults typically experience gingival recession, which results in teeth with exposed root surfaces. Unlike the crowns of teeth, these root surfaces are not covered by enamel and are more susceptible to caries. Because tooth retention among older age groups has increased in recent decades in the United States (39 ), these groups' risk for caries will increase as the country's population ages. Older adults also frequently require multiple medications for chronic conditions, and many of these medications can reduce salivary output (104 ). Drinking water containing an optimal concentration of fluoride can mitigate the risk factors for caries among older adults. Studies have reported that the prevalence of root caries among adults is inversely related to fluoride concentration in the community drinking water (105)(106)(107). Water fluoridation also reduces the disparities in caries experience among poor and nonpoor children (108)(109)(110)(111). Caries experience is considerably higher among persons in low SES strata than among those in high SES strata (39,46,112 ). The reasons for this discrepancy are not well understood; perhaps persons in low SES strata have less knowledge of oral diseases, have less access to dental care, are less likely to follow recommended self-care practices, or are harder to reach through traditional approaches, including public health programs and private dental care (48 ). Thus, these persons might receive more benefit from fluoridated community water than persons from high SES strata. Regardless of SES, water fluoridation is the most effective and efficient strategy to reduce dental caries (112 ). Enamel fluorosis occurs among some persons in all communities, even in communities with a low natural concentration of fluoride. During 1930-1960, U.S. studies documented that, in areas with a natural or adjusted concentration of fluoride of approximately 1.0 ppm in the community drinking water, the permanent teeth of 7%-16% of children with lifetime residence in those areas exhibited very mild or mild forms of enamel fluorosis (53,113,114 ). Before 1945, when naturally fluoridated drinking water was virtually the only source of fluoride, the moderate and severe forms of this condition were not observed unless the natural fluoride concentration was >2 ppm (53 ). The likelihood of a child developing the mild forms of enamel fluorosis might be higher in a fluoridated area than in a nonfluoridated area, but prevalence might not change in every community (115,116 ). The most recent national study of this condition indicated that its prevalence had increased in both fluoridated and nonfluoridated areas since the 1940s, with the relative increase higher in nonfluoridated areas. In communities with drinking water containing 0.7-1.2 ppm fluoride, the prevalence was 1.3% for the moderate form of enamel fluorosis and zero for the severe form; thus, few cases of enamel fluorosis were likely to be of cosmetic consequence (8,61 ). Because combined fluoride intake from drinking water and processed beverages and food by children in fluoridated areas has reportedly remained stable since the 1940s, the increase in fluoride intake resulting in increased enamel fluorosis almost certainly stems from use of fluoride-containing dental products by children aged <6 years (11 ). Two studies reported that extended consumption of infant formula beyond age 10-12 months was a risk factor for enamel fluorosis, especially when formula concentrate was mixed with fluoridated water (62,63 ). These studies examined children who used pre-1979 formula (with higher fluoride concentrations). Whether fluoride intake from formula that exceeds the recommended amount during only the first 10-12 months of life contributes to the prevalence or severity of enamel fluorosis is unknown. Fluoride concentrations in drinking water should be maintained at optimal levels, both to achieve effective caries prevention and because changes in fluoride concentration as low as 0.2 ppm can result in a measurable change in the prevalence and severity of enamel fluorosis (52,117 ). Since the late 1970s, CDC has provided guidelines and recommendations for managers of fluoridated water supply systems at state and local levels to help them establish and maintain appropriate fluoride concentrations. CDC periodically updates these guidelines; the most recent revision was published in 1995 (68 ). School Water Systems. In some areas of the United States where fluoridating a community's drinking water was not feasible (e.g., rural areas), the alternative of fluoridating a school's public water supply system was promoted for many years. This method was used when a school had its own source of water and was not connected to a community water supply system (i.e., stand-alone systems). Because children are at school only part of each weekday, a fluoride concentration of 4.5 times the optimal concentration for a community in the same geographic area was recommended (118 ) to compensate for the more limited consumption of fluoridated water. At the peak of this practice in the early 1980s, a total of 13 states had initiated school water fluoridation in 470 schools serving 170,000 children (39 ). Since then, school water fluoridation has been phased out in several states; the current extent of this practice is not known. Studies of the effects of school water fluoridation in the United States reported that this practice reduced caries among schoolchildren by approximately 40% (118)(119)(120)(121)(122). A more recent study indicated that this effect might no longer be as pronounced (123 ). Several concerns regarding school water fluoridation exist. Operating and maintaining small fluoridation systems (i.e., those serving <500 persons) create practical and logistical difficulties (68 ). These difficulties have occasionally caused higher than recommended fluoride concentrations in the school drinking water, but no lasting effects among children have been observed (124)(125)(126). In schools that enroll preschoolers in day care programs, children aged <6 years might receive more than adequate fluoride. Bottled Water. Many persons drink bottled water, replacing tap water partially or completely as a source of drinking water. Water is classified as "bottled water" if it meets all applicable federal and state standards, is sealed in a sanitary container, and is sold for human consumption. Although some bottled waters marketed in the United States contain an optimal concentration of fluoride (approximately 1.0 ppm), most contain <0.3 ppm fluoride (127)(128)(129). Thus, a person substituting bottled water with a low fluoride concen- MMWR 13 tration for fluoridated community water might not receive the full benefits of community water fluoridation (130 ). For water bottled in the United States, current FDA regulations require that fluoride be listed on the label only if the bottler adds fluoride during processing; the concentration of fluoride is regulated but does not have to be stated on the label (Table 3). Few bottled water brands have labels listing the fluoride concentration. Determining Fluoride Concentration. Uneven geographic coverage of community water fluoridation throughout the United States, wide variations in natural fluoride concentrations found in drinking water, and almost nonexistent labeling of fluoride concentration in bottled water make knowing the concentration of fluoride in drinking water difficult for many persons. Persons in nonfluoridated areas can mistakenly believe their water contains an optimal concentration of fluoride. To obtain the fluoride concentration of community drinking water, a resident can contact the water supplier or a local public health authority, dentist, dental hygienist, physician, or other knowledgeable source. EPA requires that all community water supply systems provide each customer an annual report on the quality of water, including the fluoride concentration (131 ). Testing for private wells is available through local and state public health departments as well as some private laboratories. If the fluoride concentration is not listed on the label of bottled water, the bottler can be contacted directly to obtain this information. # Fluoride Toothpaste Fluoride is the only nonprescription toothpaste additive proven to prevent dental caries. When introduced into the mouth, fluoride in toothpaste is taken up directly by dental plaque (132)(133)(134) and demineralized enamel (135,136 ). Brushing with fluoride toothpaste also increases the fluoride concentration in saliva 100-to 1,000-fold; this concentration returns to baseline levels within 1-2 hours (137 ). Some of this salivary fluoride is taken up by dental plaque. The ambient fluoride concentration in saliva and plaque can increase during regular use of fluoride toothpaste (132,133 ). # MMWR August 17, 2001 By the 1990s, fluoride toothpaste accounted for >90% of the toothpaste market in the United States, Canada, and other developed countries (138 ). Because water fluoridation is not available in many countries, toothpaste might be the most important source of fluoride globally (1 ). Studies of 2-3 years duration have reported that fluoride toothpaste reduces caries experience among children by a median of 15%-30% (139)(140)(141)(142)(143)(144)(145)(146)(147)(148). This reduction is modest compared with the effect of water fluoridation, but water fluoridation studies usually measured lifetime -rather than a few years' -exposure. Regular lifetime use of fluoride toothpaste likely provides ongoing benefits that might approach those of fluoridated water. Combined use of fluoride toothpaste and fluoridated water offers protection above either used alone (99,149,150 ). Few studies evaluating the effectiveness of fluoride toothpaste, gel, rinse, and varnish among adult populations are available. Child populations have typically been used for studies on caries prevention because of perceived increased caries susceptibility and logistical reasons. However, teeth generally remain susceptible to caries throughout life, and topically applied fluorides could be effective in preventing caries in susceptible patients of any age (151,152 ). Most persons report brushing their teeth at least once per day (153,154 ), but more frequent use can offer additional protection (139,141,(155)(156)(157)(158). Brushing twice a day is a reasonable social norm that is both effective and convenient for most persons' daily routines, and this practice has become a basic recommendation for caries prevention. Whether increasing the number of daily brushings from two to three times a day results in lower dental caries experience is unclear. Because the amount and vigor of rinsing after toothbrushing affects fluoride concentration in the mouth and reportedly affects caries experience (157)(158)(159)(160), persons aged >6 years can retain more fluoride in the mouth by either rinsing briefly with a small amount of water or not at all. In the United States, the standard concentration of fluoride in fluoride toothpaste is 1,000-1,100 ppm. Toothpaste containing 1,500 ppm fluoride has been reported to be slightly more efficacious in reducing dental caries in U.S. and European studies (161)(162)(163)(164). Products with this fluoride concentration have been marketed in the United States, but are not available in all areas. These products might benefit persons aged >6 years at high risk for dental caries. Children who begin using fluoride toothpaste at age <2 years are at higher risk for enamel fluorosis than children who begin later or who do not use fluoride toothpaste at all (62,63,(165)(166)(167)(168)(169)(170). Because studies have not used the same criteria for age of initiation, amount of toothpaste used, or frequency of toothpaste use, the specific contribution of each factor to enamel fluorosis among this age group has not been established. Fluoride toothpaste contributes to the risk for enamel fluorosis because the swallowing reflex of children aged <6 years is not always well controlled, particularly among children aged <3 years (171,172 ). Children are also known to swallow toothpaste deliberately when they like its taste. A child-sized toothbrush covered with a full strip of toothpaste holds approximately 0.75-1.0 g of toothpaste, and each gram of fluoride toothpaste, as formulated in the United States, contains approximately 1.0 mg of fluoride. Children aged <6 years swallow a mean of 0.3 g of toothpaste per brushing (11 ) and can inadvertently swallow as much as 0.8 g (138,(173)(174)(175)(176). As a result, multiple brushings with fluoride toothpaste each day can result in ingestion of excess fluoride (177 ). For this reason, high-fluoride toothpaste (i.e., containing 1,500 ppm fluoride) is generally contraindicated for children aged <6 years. Use of a pea-sized amount (approximately 0.25 g) of fluoride toothpaste <2 times per day by children aged <6 years is reported to sharply reduce the importance of fluoride toothpaste as a risk factor for enamel fluorosis (65 ). Since 1991, manufacturers of fluoride toothpaste marketed in the United States have, as a requirement for obtaining the ADA Seal of Acceptance, placed instructions on the package label stating that children aged <6 years should use only this amount of toothpaste. Toothpaste labeling requirements mandated by FDA in 1996 (72 ) also direct parents of children aged <2 years to seek advice from a dentist or physician before introducing their child to fluoride toothpaste. The propensity of young children to swallow toothpaste has led to development of "child-strength" toothpaste with lower fluoride concentrations (176 ). Such a product would be a desirable alternative to currently available products for many young children. Clinical trials outside the United States have reported that toothpaste containing 250 ppm fluoride is less effective than toothpaste containing 1,000 ppm fluoride in preventing dental caries (178,179 ). However, toothpaste containing 500-550 ppm fluoride might be almost as efficacious as that containing 1,000 ppm fluoride (180 ). A British study reported that the prevalence of diffuse enamel opacities (an indicator of mild enamel fluorosis) in the upper anterior incisors was substantially lower among children who used toothpaste containing 550 ppm fluoride than among those who used toothpaste containing 1,050 ppm fluoride (181 ). Toothpaste containing 400 ppm fluoride has been available in Australia and New Zealand for approximately 20 years, but has not been tested in clinical trials, and no data are available to assess whether toothpaste at this concentration has reduced the prevalence of enamel fluorosis in those countries. A U.S. clinical trial of the efficacy of toothpaste with lower fluoride concentrations, required by FDA before approval for marketing and distribution, has not been conducted (182 ). # Fluoride Mouthrinse Fluoride mouthrinse is a concentrated solution intended for daily or weekly use. The fluoride from mouthrinse, like that from toothpaste, is retained in dental plaque and saliva to help prevent dental caries (183 ) Studies indicating that fluoride mouthrinse reduces caries experience among schoolchildren date mostly from the 1970s and early 1980s (184)(185)(186)(187)(188)(189)(190)(191). In one review, the average caries reduction in nonfluoridated communities attributable to fluoride mouthrinse was 31% (191 ). Two studies reported benefits of fluoride mouthrinse approximately 2.5 and 7 years after completion of school-based mouthrinsing programs (192,193 ), but a more recent study did not find such benefits 4 years after completion of a mouthrinsing program (194 ). The National Preventive Dentistry Demonstration Program (NPDDP), a large project conducted in 10 U.S. cities during 1976-1981 to compare the cost and effectiveness of combinations of caries-prevention procedures, reported that fluoride mouthrinse had little effect among schoolchildren, either among first-grade students with high and low caries experience (195 ) or among all second-and fifth-grade students (196 ). NPDDP documented only a limited reduction in dental caries attributable to fluoride mouthrinse, especially when children were also exposed to fluoridated water. Although no studies of enamel fluorosis associated with use of fluoride mouthrinse have been conducted, studies of the amount of fluoride swallowed by children aged 3-5 years using such rinses indicated that some young children might swallow substantial amounts (191 ). Use of fluoride mouthrinse by children aged >6 years does not place them at risk for cosmetically objectionable enamel fluorosis because they are generally past the age that fluoride ingestion might affect their teeth. # Dietary Fluoride Supplements Dietary fluoride supplements in the form of tablets, lozenges, or liquids (including fluoride-vitamin preparations) have been used throughout the world since the 1940s. Most supplements contain sodium fluoride as the active ingredient. Tablets and lozenges are manufactured with 1.0, 0.5, or 0.25 mg fluoride. To maximize the topical effect of fluoride, tablets and lozenges are intended to be chewed or sucked for 1-2 minutes before being swallowed. For infants, supplements are available as a liquid and used with a dropper. In 1986, an estimated 16% of U.S. children aged <2 years used fluoride supplements (197 ). All fluoride supplements must be prescribed by a dentist or physician. The prescription should be consistent with the 1994 dosage schedule developed by ADA, AAPD, and AAP (Table 1). Because fluoride supplements are intended to compensate for fluoride-deficient drinking water, the dosage schedule requires knowledge of the fluoride content of the child's primary drinking water; consideration should also be given to other sources of water (e.g., home, child care settings, school, or bottled water) and to other sources of fluoride (e.g., toothpaste or mouthrinse), which can complicate the prescribing decision. The evidence for using fluoride supplements to mitigate dental caries is mixed. Use of fluoride supplements by pregnant women does not benefit their offspring (198 ). Several studies have reported that fluoride supplements taken by infants and children before their teeth erupt reduce the prevalence and severity of caries in teeth (98,(199)(200)(201)(202)(203)(204)(205)(206)(207), but several other studies have not (19,(208)(209)(210)(211)(212). Among children aged 6-16 years, fluoride supplements taken after teeth erupt reduce caries experience (213)(214)(215). Fluoride supplements might be beneficial among adults who have limitations with toothbrushing, but this use requires further study. A few studies have reported no association between supplement use by children aged <6 years and enamel fluorosis (208,216 ), but most have reported a clear association (19,62,64,165,170,(199)(200)(201)209,210,212,(217)(218)(219)(220)(221)(222). In one study, the risk for this condition was high when supplements were used in fluoridated areas (odds ratio = 23.74; 95% confidence interval = 3.43-164.30) (62 ), a use inconsistent with the supplement schedule. Reports of the frequency of supplement use in fluoridated areas have ranged from 7% to 35% (223)(224)(225)(226)(227)(228). In response to the accumulated data on fluoride intake and the prevalence of enamel fluorosis, the supplement dosage schedule for children aged <6 years was markedly reduced in 1994 when ADA, AAPD, and AAP jointly established the current schedule (Table 1) (73 ). The risk for enamel fluorosis among children this age attributable to fluoride supplements could be lower, but not enough information is available yet to evaluate the effects of this change. When prescribing any pharmaceutical agent, dentists and physicians should attempt to maximize benefit and minimize harm (229 ). For infants and children aged <6 years, both a benefit of dental caries prevention and a risk for enamel fluorosis are possible. Although the primary (i.e., "baby") teeth of children aged 1-6 years would benefit from fluoride's posteruptive action, and some preeruptive benefit for developing permanent teeth could exist, fluoride supplements also could increase the risk for enamel fluorosis at this age (138,223 ). # Professionally Applied Fluoride Compounds In the United States, dentists and dental hygienists have been applying highconcentration fluoride compounds directly to patients' teeth for approximately 50 years. Application procedures were developed on the assumption that the fluoride would be incorporated into the crystalline structure of the dental enamel and develop a more acidresistant enamel. To maximize this reaction, a professional tooth cleaning was considered mandatory before the application. However, subsequent research has demonstrated that high-concentration fluoride compounds (e.g., those in gel or varnish) do not directly enter the enamel's crystalline structure (230 ). The compound forms a calcium fluoride-like material on the enamel's surface that releases fluoride for remineralization when the pH in the mouth drops. Thus, professional tooth cleaning solely to prepare the teeth for application of a fluoride compound is unnecessary; toothbrushing and flossing appear equally effective in improving the efficacy of highconcentration fluoride compounds (231 ). # Fluoride Gel and Foam Because an early study reported that fluoride uptake by dental enamel increased in an acidic environment (232 ), fluoride gel is often formulated to be highly acidic (pH of approximately 3.0). Products available in the United States include gel of acidulated phosphate fluoride (1.23% fluoride), gel or foam of sodium fluoride (0.9% fluoride), and self-applied (i.e., home use) gel of sodium fluoride (0.5% fluoride) or stannous fluoride (0.15% fluoride) (73 ). Clinical trials conducted during 1940-1970 demonstrated that professionally applied fluorides effectively reduce caries experience in children (233 ). In more recent studies, semiannual treatments reportedly caused an average decrease of 26% in caries experience in the permanent teeth of children residing in nonfluoridated areas (191,(234)(235)(236). The application time for the treatments was 4 minutes. In clinical practice, applying fluoride gel for 1 minute rather than 4 minutes is common, but the efficacy of this shorter application time has not been tested in human clinical trials. In addition, the optimal schedule for repeated application of fluoride gel has not been adequately studied to support definitive guidelines, and studies that have examined the efficacy of various gel application schedules in preventing and controlling dental caries have reported mixed results. On the basis of the available evidence, the usual recommended frequency is semiannual (151,237,238 ). Because these applications are relatively infrequent, generally at 3-to 12-month intervals, fluoride gel poses little risk for enamel fluorosis, even among patients aged <6 years. Proper application technique reduces the possibility that a patient will swallow the gel during application. # MMWR August 17, 2001 Fluoride Varnish High-concentration fluoride varnish is painted directly onto the teeth. Fluoride varnish is not intended to adhere permanently; this method holds a high concentration of fluoride in a small amount of material in close contact with the teeth for many hours. Fluoride varnish has practical advantages (e.g., ease of application, a nonoffensive taste, and use of smaller amounts of fluoride than required for gel applications). Such varnishes are available as sodium fluoride (2.26% fluoride) or difluorsilane (0.1% fluoride) preparations. Fluoride varnish has been widely used in Canada and Europe since the 1970s to prevent dental caries (152,239 ). FDA's Center for Devices and Radiological Health has cleared fluoride varnish as a medical device to be used as a cavity liner (i.e., to provide fluoride at the junction of filling material and tooth) and root desensitizer (i.e., to reduce sensitivity to temperature and touch that sometimes occurs on root surfaces exposed by receding gingiva) (240 ); FDA has not yet approved this product as an anticaries agent. Caries prevention is regarded as a drug claim, and companies would be required to submit appropriate clinical trial evidence for review before this product could be marketed as an anticaries agent. However, a prescribing practitioner can use fluoride varnish for caries prevention as an "off-label" use, based on professional judgement (241 ). Studies conducted in Canada (242 ) and Europe (243)(244)(245)(246) have reported that fluoride varnish is efficacious in preventing dental caries in children. Applied semiannually, this modality is as effective as professionally applied fluoride gel (247 ). Some researchers advocate application of fluoride varnish as many as four times per year to achieve maximum effect, but the evidence of benefits from more than two applications per year remains inconclusive (240,246,248 ). Other studies have reported that three applications in 1 week, once per year, might be more effective than the more conventional semiannual regimen (249,250 ). European studies have reported that fluoride varnish prevents decalcification (i.e., an early stage of dental caries) beneath orthodontic bands (251 ) and slows the progression of existing enamel lesions (252 ). Studies examining the effectiveness of varnish in controlling early childhood caries are being conducted in the United States. Research on fluoride varnish (e.g., optimal fluoride concentration, the most effective application protocols, and its efficacy relative to other fluoride modalities) is likely to continue in both Europe and North America. No published evidence indicates that professionally applied fluoride varnish is a risk factor for enamel fluorosis, even among children aged <6 years. Proper application technique reduces the possibility that a patient will swallow varnish during its application and limits the total amount of fluoride swallowed as the varnish wears off the teeth over several hours. # Fluoride Paste Fluoride-containing paste is routinely used during dental prophylaxis (i.e., cleaning). The abrasive paste, which contains 4,000-20,000 ppm fluoride, might restore the concentration of fluoride in the surface layer of enamel removed by polishing, but it is not an adequate substitute for fluoride gel or varnish in treating persons at high risk for dental caries (151 ). Fluoride paste is not accepted by FDA or ADA as an efficacious way to prevent dental caries. # Combinations of Fluoride Modalities Studies comparing various combinations of fluoride modalities have generally reported that their effectiveness in preventing dental caries is partially additive. That is, the percent reduction in the prevalence or severity of dental caries from a combination of modalities is higher than the percent reduction from each modality, but less than the sum of the percent reduction of the modalities combined. Attempts to use a formula to apply sequentially the percent reduction of an additional modality to the estimated remaining caries increment have overestimated the effect (151,253 ). For example, if the first modality reduces caries by 40% and the second modality reduces caries by 30%, then the calculation that caries will be reduced by a total of 58% (i.e., 40% plus 18% ) will likely be an overestimate. # QUALITY OF EVIDENCE FOR DENTAL CARIES PREVENTION AND CONTROL Members of the work group convened by CDC identified the published research in their areas of expertise and evaluated the quality of scientific evidence for each fluoride modality in preventing and controlling dental caries. Evidence was drawn from the most relevant English-language, peer-reviewed scientific publications regarding the current effectiveness of fluoride modalities. Additional references were suggested by reviewers. Members used their own methods for critically analyzing articles. A formal protocol for duplicate review was not followed, but members collectively agreed on the grade reflecting the quality of evidence regarding each fluoride modality. Criteria used to grade the quality of scientific evidence (i.e., ordinal grading) was adapted from the U.S. Preventive Services Task Force (Box 1) (254 ). Grades range from I to III. # BOX 1. Grading system used for determining the quality of evidence for a fluoride modality Grade Criteria I Evidence obtained from one or more properly conducted randomized clinical trials (i.e., one using concurrent controls, double-blind design, placebos, valid and reliable measurements, and well-controlled study protocols). # II-1 Evidence obtained from one or more controlled clinical trials without randomization (i.e., one using systematic subject selection, some type of concurrent controls, valid and reliable measurements, and wellcontrolled study protocols). # II-2 Evidence obtained from one or more well-designed cohort or case-control analytic studies, preferably from more than one center or research group. # II-3 Evidence obtained from cross-sectional comparisons between times and places; studies with historical controls; or dramatic results in uncontrolled experiments (e.g., the results of the introduction of penicillin treatment in the 1940s). # III Opinions of respected authorities on the basis of clinical experience, descriptive studies or case reports, or reports of expert committees. Source: US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Alexandria, VA: International Medical Publishing, 1996. # MMWR August 17, 2001 # Community Water Fluoridation Studies on the effectiveness of adjusting fluoride in community water to the optimal concentration cannot be designed as randomized clinical trials. Random allocation of study subjects is not possible when a community begins to fluoridate the water because all residents in a community have access to and are exposed to this source of fluoride. In addition, clinical studies cannot be conducted double-blind because both study subjects and researchers usually know whether a community's water has been fluoridated. Efforts to blind the examiners by moving study subjects to a neutral third site for clinical examinations, using radiographs of teeth without revealing where the subjects live, or including transient residents as study subjects have not fully resolved these inherent limitations. Early studies that led to the unexpected discovery that dental caries was less prevalent and severe among persons with mottled enamel (subsequently identified as a form of enamel fluorosis) were conducted before the caries-preventive effects of fluoride were known (255 ). In those studies, researchers did not have an a priori reason to suspect they would find either reduced or higher levels of dental caries experience in communities with low levels of mottled enamel. Researchers also had no reason to believe that patients selected where they lived according to their risk for dental caries. In that regard, these studies were randomized, and examiners were blinded. Despite the strengths of early studies of the efficacy of naturally occurring fluoride in community drinking water, the limitations of these studies make summarizing the quality of evidence on community water fluoridation as Grade I inappropriate (Table 1). The quality of evidence from studies on the effectiveness of adjusting fluoride concentration in community water to optimal levels is Grade II-1. Research limitations are counterbalanced by broadly similar results from numerous well-conducted field studies by other investigators that included thousands of persons throughout the world (256,257 ). # School Water Fluoridation Field trials on the effect of school water fluoridation were not blindly conducted and had no concurrent controls (118 ). Thus, the quality of evidence for this modality is Grade II-3. # Fluoride Toothpaste Studies that have demonstrated the efficacy of fluoride toothpaste in preventing and controlling dental caries include all of the essential features of well-conducted clinical trials. These include randomized groups, double-blind designs, placebo controls, and meticulous procedural protocols. Taken together, the trials on fluoride toothpaste provide solid evidence that fluoride is efficacious in controlling caries (144 ). The quality of evidence for toothpaste is Grade I. # Fluoride Mouthrinse Early studies of the efficacy of fluoride mouthrinse in reducing dental caries experience were randomized clinical trials (184,185 ) or studies that used historical control groups rather than concurrent control groups (186)(187)(188)(189). The quality of evidence for fluoride mouthrinse is Grade I. # MMWR 21 # Dietary Fluoride Supplements The only randomized controlled trial to assess fluoride supplements taken by pregnant women provides Grade I evidence of no benefit for their children. Many studies of the effectiveness of fluoride supplements in preventing dental caries among children aged <6 years have been flawed in design and conduct. Problems included self-selection into test and control groups, absence of concurrent controls, high attrition rates, and nonblinded examiners. Because of these flaws, the quality of evidence to support use of fluoride supplements by children aged <6 years is Grade II-3. The well-conducted randomized clinical trials on the effects of fluoride supplements on dental caries among children aged 6-16 years in programs conducted in schools provide Grade I evidence. # Fluoride Gel The quality of evidence for using fluoride gel to prevent and control dental caries in children is Grade I. However, data were gathered when dental caries was more prevalent and severe than today. Subjects in earlier studies were probably more representative of persons who now would be characterized as being at high risk for caries. # Fluoride Varnish The quality of evidence for the efficacy of high-concentration fluoride varnish in preventing and controlling dental caries in children is Grade I. Although the randomized controlled clinical studies that established Grade I evidence were conducted in Europe, U.S. results should be the same. # COST-EFFECTIVENESS OF FLUORIDE MODALITIES Documented effectiveness is the most basic requirement for providing a health-care service and an important prerequisite for preventive services (e.g., caries-preventive modalities). However, effectiveness alone is not a sufficient reason to initiate a service. Other factors, including cost, must be considered (254 ). A modality is more costeffective when deemed a less expensive way, from among competing alternatives, of meeting a stated objective (258 ). In public health planning, determination of the most cost-effective alternative for prevention is essential to using scarce resources efficiently. Dental-insurance carriers are also interested in cost-effectiveness so they can help purchasers use funds efficiently. Because half of dental expenditures are out of pocket (259 ), this topic interests patients and their dentists as well. Potential improvement to quality of life is also a consideration. The contribution of a healthy dentition to quality of life at any age has not been quantified, but is probably valued by most persons. Although solid data on the cost-effectiveness of fluoride modalities alone and in combination are needed, this information is scarce. In 1989, the Cost Effectiveness of Caries Prevention in Dental Public Health workshop, which was attended by health economists, epidemiologists, and dental public health professionals, attempted to assess the costeffectiveness of caries-preventive approaches available in the United States (260 ). All other things being equal, fluoride modalities are most cost-effective for persons at high risk for dental caries. Because persons at low risk develop little dental caries, limited benefit is gained by adding caries-preventive modalities to water fluoridation and fluoride toothpaste, even those demonstrated to be effective among populations at high risk. # MMWR August 17, 2001 Members of the CDC work group reached consensus regarding the populations for which each modality would be expected to have the necessary level of cost-effectiveness to warrant its use. # Community Water Fluoridation Health economists at the 1989 workshop on cost-effectiveness of caries prevention calculated that the average annual cost of water fluoridation in the United States was $0.51 per person (range: $0.12-$5.41) (260 ). In 1999 dollars,- this cost would be $0.72 per person (range: $0.17-$7.62). Factors reported to influence the per capita cost included - size of the community (the larger the population reached, the lower the per capita cost); - number of fluoride injection points in the water supply system; - amount and type of system feeder and monitoring equipment used; - amount and type of fluoride chemical used, its price, and its costs of transportation and storage; and - expertise of personnel at the water plant. When the effects of caries are repaired, the price of the restoration is based on the number of tooth surfaces affected. A tooth can have caries at >1 location (i.e., surface), so the number of surfaces saved is a more appropriate measure in calculating costeffectiveness than the number of teeth with caries. The 1989 workshop participants concluded that water fluoridation is one of the few public health measures that results in true cost savings (i.e., the measure saves more money than it costs to operate); in the United States, water fluoridation cost an estimated average of $3.35 per carious surface saved ($4.71 in 1999 dollars) (260 ). Even under the least favorable assumptions in 1989 (i.e., cities with populations <10,000, higher operating costs, and effectiveness projected at the low end of the range), the cost of a carious surface saved because of community water fluoridation ranged from $8 to $12 ($11-$17 in 1999 dollars) (260 ), which is still lower than the fee for a one-surface restoration ($54 in 1995 or $65 in 1999 dollars † ) (261 ). A Scottish study conducted in 1980 reported that community water fluoridation resulted in a 49% saving in dental treatment costs for children aged 4-5 years and a 54% saving for children aged 11-12 years (262 ). These savings were maintained even after the secular decline in the prevalence of dental caries was recognized (263 ). The effect of community water fluoridation on the costs of dental care for adults is less clear. This topic cannot be fully explored until the generations who grew up drinking optimally fluoridated water are older. # School Water Fluoridation Costs for school water fluoridation are similar to those of any public water supply system serving a small population (i.e., <1,000 persons). In 1988, the average annual cost of school water fluoridation was $4.52 per student per year (range: $0.81-$9.72) (264 ). In 1999 dollars,- this cost would be $6.37 per person (range: $1.14-$13.69). Use of this modality must be carefully weighed in the current environment of low caries prevalence, widespread use of fluoride toothpaste, and availability of other fluoride modalities that can be delivered in the school setting. # Fluoride Toothpaste Fluoride toothpaste is widely available, no more expensive than nonfluoride toothpaste, and periodically improved. Use of a pea-sized amount (0.25 g) twice per day requires approximately two tubes of toothpaste per year, for an estimated annual cost of $6-$12, depending on brand, tube size, and retail source (265 ). Persons who brush and use toothpaste regularly to maintain periodontal health and prevent stained teeth and halitosis (i.e., bad breath) incur no additional cost for the caries-preventive benefit of fluoride in toothpaste. Because of its multiple benefits, most persons consider fluoride toothpaste a highly cost-effective caries-preventive modality. # Fluoride Mouthrinse Public health programs of fluoride mouthrinsing have long been presumed to be costeffective, especially when teachers can supervise weekly rinsing in classrooms at no direct cost to the program. In other programs, volunteers or hourly workers provide supervision. Under these circumstances, administrators of fluoride mouthrinsing programs have claimed annual program costs of approximately $1 per child ($1.41 in 1999 dollars) (264 ). This figure likely is an underestimate because indirect costs are not included (196,266 ). Fluoride mouthrinsing is a reasonable procedure for groups and persons at high risk for dental caries, but its cost-effectiveness as a universal, populationwide strategy in the modern era of widespread fluoride exposure is questionable (267 ). # Dietary Fluoride Supplements Dietary fluoride supplements prescribed to persons cost an estimated $37 per year. Fluoride supplements in school programs have direct costs of approximately $2.50 per child ($3.52 in 1999 dollars*) for the tablet or lozenge (264 ); program administrative costs and considerations are similar to those in school mouthrinsing programs. # Professionally Applied Fluoride Compounds High-concentration fluoride gel and varnish are effective in preventing dental caries, but because application requires professional expertise, they are inherently more expensive than self-applied methods (e.g., drinking fluoridated water or brushing with fluoride toothpaste). For groups and persons at low risk for dental caries, professionally applied methods are unlikely to be cost-effective (268,269 ) (196 ). A Swedish study claimed that fluoride varnish was cost-effective, but few supporting data were presented (270 ). Varnish might be cost-effective in Scandinavian school dental services, in which dental professionals regularly examine and treat each student, but the cost-effectiveness of fluoride varnish in public health programs in the United States remains undocumented. Whether fluoride varnish or gel would be most efficiently used in clinical programs targeting groups at high risk for dental caries or should be reserved for individual patients at high risk is unclear. # Combinations of Fluoride Modalities Because the caries-preventive effects of a combination of fluoride modalities are only partially additive, estimates of the cost-effectiveness when adding a modality (e.g., fluoride mouthrinse for a group already drinking fluoridated water and using fluoride toothpaste) should take into account these smaller, incremental reductions in caries. This consideration is particularly relevant for groups and persons at low risk for caries (253 ). The scarcity of research on the cost-effectiveness of combinations limits the ability to draw more detailed conclusions. # RECOMMENDATIONS In developing the recommendations for specific fluoride modalities that address public health and clinical practice and self-care, the CDC work group considered the quality of evidence of each modality's effect on dental caries, its association with enamel fluorosis, and its cost-effectiveness. The strength of the recommendation for each fluoride modality was determined by the work group, which adapted a coding system used by the U.S. Preventive Services Task Force (Box 2). The work group considered these factors when determining the population for which each recommendation applies (Table 4 # BOX 2. Coding system used to classify recommendations for use of specific fluoride modalities to control dental caries # Code Criteria A Good evidence to support the use of the modality. # B Fair evidence to support the use of the modality. # C Lack of evidence to develop a specific recommendation (i.e., the modality has not been adequately tested) or mixed evidence (i.e., some studies support the use of the modality and some oppose it). # D Fair evidence to reject the use of the modality. # E Good evidence to reject the use of the modality. Source: US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Alexandria, VA: International Medical Publishing, 1996. # MMWR 25 group recognized that some recommendations can only be addressed by health-care industries or agencies and that additional research is required to resolve some questions regarding fluoride modalities. Before promoting a fluoride modality or combination of modalities, the dental-care or other health-care provider must consider a person's or group's risk for dental caries, current use of other fluoride sources, and potential for enamel fluorosis. Although these recommendations are based on assessments of caries risk as low or high, the healthcare provider might also differentiate among patients at high risk and provide more intensive interventions as needed. Also, a risk category can change over time; the type and frequency of preventive interventions should be adjusted accordingly. † Quality of evidence for targeting some modalities to persons at high risk is grade III (i.e., representing the opinion of respected authorities) and is based on considerations of costeffectiveness that were not included in the studies establishing efficacy or effectiveness. § Populations believed to be at increased risk for dental caries are those with low socioeconomic status or low levels of parental education, those who do not seek regular dental care, and those without dental insurance or access to dental services. Individual factors that possibly increase risk include active dental caries; a history of high caries experience in older siblings or caregivers; root surfaces exposed by gingival recession; high levels of infection with cariogenic bacteria; impaired ability to maintain oral hygiene; malformed enamel or dentin; reduced salivary flow because of medications, radiation treatment, or disease; low salivary buffering capacity (i.e., decreased ability of saliva to neutralize acids); and the wearing of space maintainers, orthodontic appliances, or dental prostheses. Risk can increase if any of these factors are combined with dietary practices conducive to dental caries (i.e., frequent consumption of refined carbohydrates). Risk decreases with adequate exposure to fluoride. ¶ No published studies confirm the effectiveness of fluoride supplements in controlling dental caries among persons aged >16 years. # MMWR August 17, 2001 Public Health and Clinical Practice # Continue and Extend Fluoridation of Community Drinking Water Community water fluoridation is a safe, effective, and inexpensive way to prevent dental caries. This modality benefits persons in all age groups and of all SES, including those difficult to reach through other public health programs and private dental care. Community water fluoridation also is the most cost-effective way to prevent tooth decay among populations living in areas with adequate community water supply systems. Continuation of community water fluoridation for these populations and its adoption in additional U.S. communities are the foundation for sound caries-prevention programs. In contrast, the appropriateness of fluoridating stand-alone water systems that supply individual schools is limited. Widespread use of fluoride toothpaste, availability of other fluoride modalities that can be delivered in the school setting, and the current environment of low caries prevalence limit the appropriateness of fluoridating school drinking water at 4.5 times the optimal concentration for community drinking water. Decisions to initiate or continue school fluoridation programs should be based on an assessment of present caries risk in the target school(s), alternative preventive modalities that might be available, and periodic evaluation of program effectiveness. # Counsel Parents and Caregivers Regarding Use of Fluoride Toothpaste by Young Children, Especially Those Aged <2 Years Fluoride toothpaste is a cost-effective way to reduce the prevalence of dental caries. However, for children aged <6 years, especially those aged <2 years, an increased risk for enamel fluorosis exists because of inadequately developed control of the swallowing reflex. Parents or caregivers should be counseled regarding self-care recommendations for toothpaste use for young children (i.e., limit the child's toothbrushing to <2 times a day, apply a pea-sized amount to the toothbrush, supervise toothbrushing, and encourage the child to spit out excess toothpaste). For children aged <2 years, the dentist or other health-care provider should consider the fluoride level in the community drinking water, other sources of fluoride, and factors likely to affect susceptibility to dental caries when weighing the risk and benefits of using fluoride toothpaste. # Target Mouthrinsing to Persons at High Risk Because fluoride mouthrinse has resulted in only limited reductions in caries experience among schoolchildren, especially as their exposure to other sources of fluoride has increased, its use should be targeted to groups and persons at high risk for caries (see Risk for Dental Caries). Children aged <6 years should not use fluoride mouthrinse without consultation with a dentist or other health-care provider because enamel fluorosis could occur if such mouthrinses are repeatedly swallowed. # Judiciously Prescribe Fluoride Supplements Fluoride supplements can be prescribed for children at high risk for dental caries and whose primary drinking water has a low fluoride concentration. For children aged <6 years, the dentist, physician, or other health-care provider should weigh the risk for caries without fluoride supplements, the caries prevention offered by supplements, and the potential for enamel fluorosis. Consideration of the child's other sources of fluoride, especially drinking water, is essential in determining this balance. Parents and caregivers should be informed of both the benefit of protection against dental caries and the possibility of enamel fluorosis. The prescription dosage of fluoride supplements should be consistent with the schedule established by ADA, AAPD, and AAP. Supplements can be prescribed for persons as appropriate or used in school-based programs. When practical, supplements should be prescribed as chewable tablets or lozenges to maximize the topical effects of fluoride. # Apply High-Concentration Fluoride Products to Persons at High Risk for Dental Caries High-concentration fluoride products can play an important role in preventing and controlling dental caries among groups and persons at high risk. Dentists and other health-care providers must consider the risk status and age of the patient to determine the appropriate intensity of treatment. Routine use of professionally applied fluoride gel or foam likely provides little benefit to persons not at high risk for dental caries, especially those who drink fluoridated water and brush daily with fluoride toothpaste. If FDA approves use of fluoride varnish to prevent and control dental caries, its indications for use will be similar to those of fluoride gel. Such varnishes have practical advantages for children aged <6 years at high risk. # Self-Care # Know the Fluoride Concentration in the Primary Source of Drinking Water All persons should know whether the fluoride concentration in their primary source of drinking water is below optimal, optimal, or above optimal. This knowledge is the basis for all individual and professional decisions regarding use of other fluoride modalities (e.g., mouthrinse or supplements). Parents and caregivers of children, especially children aged 2 ppm, children should use alternative sources of drinking water. Knowledge of the water's fluoride concentration is also key in public policy discussions regarding community water fluoridation. # Frequently Use Small Amounts of Fluoride All persons should receive frequent exposure to small amounts of fluoride, which minimizes dental caries by inhibiting demineralization of tooth enamel and facilitating tooth remineralization. This exposure can be readily accomplished by drinking water with an optimal fluoride concentration and brushing with a fluoride toothpaste twice daily. place no more than a pea-sized amount (0.25 g) of toothpaste on the toothbrush, brush the child's teeth (recommended particularly for preschool-aged children) or supervise the toothbrushing, and encourage the child to spit excess toothpaste into the sink to minimize the amount swallowed. Indiscriminate use can result in inadvertent swallowing of more fluoride than is recommended. # Supervise Use of Fluoride Toothpaste Among Children Aged <6 Years # Consider Additional Measures for Persons at High Risk for Dental Caries Persons at high risk for dental caries might require additional fluoride or other preventive measures to reduce development of caries. This additional fluoride can come from daily use of another fluoride product at home or from professionally applied, topical fluoride products. Other preventive measures might include dental sealants and targeted antimicrobial therapies. Parents and caregivers should not provide additional fluoride to children aged <6 years without consulting a dentist or other health-care provider regarding the associated benefits and potential for enamel fluorosis. Persons should seek professional advice regarding their risk status or that of their children. # Use an Alternative Source of Water for Children Aged 2 ppm Fluoride In some regions in the United States, community water supply systems and home wells contain a natural concentration of fluoride >2 ppm. At this concentration, children aged <8 years are at increased risk for developing enamel fluorosis, including the moderate and severe forms, and should have an alternative source of drinking water, preferably one containing fluoride at an optimal concentration. In areas where community water supply systems contain >2 ppm but <4 ppm fluoride, EPA requires that each household be notified annually of the desirability of using an alternative source of water for children aged <8 years. For families receiving water from home wells, testing is necessary to determine the natural fluoride concentration. # Consumer Product Industries and Health Agencies # Label the Fluoride Concentration of Bottled Water Producers of bottled water should label the fluoride concentration of their products. Such labeling will allow consumers to make informed decisions and dentists, dental hygienists, and other health-care professionals to appropriately advise patients regarding fluoride intake and use of fluoride products. # Promote Use of Small Amounts of Fluoride Toothpaste Among Children Aged <6 Years Labels and advertisements for fluoride toothpaste should promote use of a pea-sized amount (0.25 g) of toothpaste on a child-sized toothbrush for children aged <6 years. Efforts to educate parents and caregivers and to encourage supervised use of fluoride toothpaste among young children can reduce inadvertent swallowing of excess toothpaste. # MMWR 29 # Develop a Low-Fluoride Toothpaste for Children Aged <6 Years Manufacturers are encouraged to develop a dentifrice for children aged <6 years that is effective in preventing dental caries but alleviates the risk for enamel fluorosis. A "child-strength" toothpaste with a fluoride concentration lower than current products could reduce the risk for cosmetic concerns associated with inadvertent swallowing of toothpaste. # Collaborate to Educate Health-Care Professionals and the Public Professional health-care organizations, public health agencies, and suppliers of oralcare products should collaborate to educate health-care professionals and trainees and the public regarding the recommendations in this report. Broad collaborative efforts to educate health-care professionals and the public and to encourage behavior change can promote improved, coordinated use of fluoride modalities. # Further Research Continue Metabolic Studies of Fluoride Metabolic studies with animals and humans to determine the influence of environmental, physiological, and pathological conditions on the pharmacokinetics and effects of fluoride should continue. Research in these areas will enhance the knowledge base concerning fluoride use, thereby resulting in more effective and efficient use of fluoride. # Identify Biomarkers of Fluoride As an alternative to direct fluoride intake measurement, biomarkers (i.e., distinct biological indicators) should be identified to estimate a person's fluoride intake and the amount of fluoride in the body. Identification of such biomarkers could allow more efficient research. # Reevaluate the Method of Determining Optimal Fluoride Concentration of Community Drinking Water The current method of determining the optimal concentration of fluoride in community drinking water, which depends on the average maximum annual ambient air temperature, should be reevaluated because of the social and environmental changes that have occurred since it was adopted in 1962. Research into current consumption patterns of water, processed beverages, and processed foods is also needed. Such research will either validate the current method for determining optimal fluoride concentration in community drinking water or indicate improved methods. # Evaluate the Effect of Fluoride Mouthrinse, Fluoride Supplements, and Other Fluoride Modalities on Dental Caries Additional clinical trials are needed to evaluate the current effect of fluoride mouthrinse, supplements, and other modalities on dental caries both individually and in combination. Cohorts of particular interest are groups and persons at high risk for dental caries, including older adults (i.e., those aged >50 years). Such research, as well as studies to determine the effects of new fluoride modalities and various combinations among groups and persons at high risk, could lead to more effective and efficient use of these interventions. # MMWR August 17, 2001 # Study the Current Cost-Effectiveness of Fluoride Modalities The increasing availability of multiple fluoride modalities and the lower caries prevalence in the United States indicate a need for current cost-effectiveness studies of fluoride modalities, especially logical combinations of regimens in populations with different caries risks. Such research will allow both more efficient use of resources and a better understanding of the additive effects of combined modalities. # Conduct Descriptive and Analytic Epidemiologic Studies Descriptive and analytic epidemiologic studies should be conducted to determine the association between dental caries and fluoride exposure from several sources, as well as the current role of community water fluoridation in preventing coronal and root caries among adults. Studies should assess the effect of interruption or discontinuation of water fluoridation; the prevalence of fluorosis associated with different patterns of fluoride use and intake among various populations; and the relationship between objectively measured fluorosis and the aesthetic perceptions of persons, parents, and dentists and other health-care professionals. Studies are needed to refine methods of caries risk assessment. As appropriate, studies should use national, state, and local data. Research addressing these questions will improve understanding of the relationships between fluoride modalities and the benefits and unintended effects of their use. # Identify Effective Strategies to Promote Adoption of Recommendations for Using Fluoride Effective strategies should be identified to promote adherence by parents, caregivers, children, adults, and health-care providers to recommendations regarding fluoride use. Such research could result in more effective behavior change, more efficient use of resources, improved caries prevention, and less enamel fluorosis. # CONCLUSION When used appropriately, fluoride is a safe and effective agent that can be used to prevent and control dental caries. Fluoride has contributed profoundly to the improved dental health of persons in the United States and other countries. Fluoride is needed regularly throughout life to protect teeth against tooth decay. To ensure additional gains in oral health, water fluoridation should be extended to additional communities, and fluoride toothpaste should be used widely. Adoption of these and other recommendations in this report could lead to considerable savings in public and private resources without compromising fluoride's substantial benefit of improved dental health. # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 2.0 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.2 Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.6 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 MMWR August 17, 2001 # GOAL AND OBJECTIVES This MMWR provides recommendations regarding the use of fluoride to prevent and control dental caries in the United States. These recommendations were prepared by CDC staff members and a work group of specialists in fluoride research or policy. This goal of this report is to increase appropriate use of fluoride modalities in preventing and controlling dental caries through improved professional understanding and practice. Upon completion of this continuing educational activity, the reader should be able to a) list the factors used in the decision to prescribe fluoride supplements; b) describe the recommendations for counseling patients on the use of fluoride products in oral self-care practices, especially for children aged <6 years; c) list the sources for determining the current level of fluoride delivered by a community water system; d) identify the factors used to assess caries risk; e) explain how fluoride prevents dental caries; f) describe the recommendations for choosing the appropriate fluoride modalities for patients; and g) list the risk factors for enamel fluorosis. To receive continuing education credit, please answer all of the following questions. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	Widespread use of fluoride has been a major factor in the decline in the prevalence and severity of dental caries (i.e., tooth decay) in the United States and other economically developed countries. When used appropriately, fluoride is both safe and effective in preventing and controlling dental caries. All U.S. residents are likely exposed to some degree to fluoride, which is available from multiple sources. Both health-care professionals and the public have sought guidance on selecting the best way to provide and receive fluoride. During the late 1990s, CDC convened a work group to develop recommendations for using fluoride to prevent and control dental caries in the United States. This report includes these recommendations, as well as a) critical analysis of the scientific evidence regarding the efficacy and effectiveness of fluoride modalities in preventing and controlling dental caries, b) ordinal grading of the quality of the evidence, and c) assessment of the strength of each recommendation. Because frequent exposure to small amounts of fluoride each day will best reduce the risk for dental caries in all age groups, the work group recommends that all persons drink water with an optimal fluoride concentration and brush their teeth twice daily with fluoride toothpaste. For persons at high risk for dental caries, additional fluoride measures might be needed. Measured use of fluoride modalities is particularly appropriate during the time of anterior tooth enamel development (i.e., age <6 years). The recommendations in this report guide dental and other health-care providers, public health officials, policy makers, and the public in the use of fluoride to achieve maximum protection against dental caries while using resources efficiently and reducing the likelihood of enamel fluorosis. The recommendations address public health and professional practice, self-care, consumer product industries and health agencies, and further research. Adoption of these recommendations could further reduce dental caries in the United States and save public and private resources.# INTRODUCTION Dental caries (i.e., tooth decay) is an infectious, multifactorial disease afflicting most persons in industrialized countries and some developing countries (1 ). Fluoride reduces the incidence of dental caries and slows or reverses the progression of existing lesions (i.e., prevents cavities). Although pit and fissure sealants, meticulous oral hygiene, and appropriate dietary practices contribute to caries prevention and control, the most effective and widely used approaches have included fluoride use. Today, all U.S. residents are exposed to fluoride to some degree, and widespread use of fluoride has been a major factor in the decline in the prevalence and severity of dental caries in the United States and other economically developed countries (1 ). Although this decline is a major public health achievement, the burden of disease is still considerable in all age groups. Because many fluoride modalities are effective, inexpensive, readily available, and can be used in both private and public health settings, their use is likely to continue. Fluoride is the ionic form of the element fluorine, the 13th most abundant element in the earth's crust. Fluoride is negatively charged and combines with positive ions (e.g., calcium or sodium) to form stable compounds (e.g., calcium fluoride or sodium fluoride). Such fluorides are released into the environment naturally in both water and air. Fluoride compounds also are produced by some industrial processes that use the mineral apatite, a mixture of calcium phosphate compounds. In humans, fluoride is mainly associated with calcified tissues (i.e., bones and teeth) because of its high affinity for calcium. Fluoride's ability to inhibit or even reverse the initiation and progression of dental caries is well documented. The first use of adjusted fluoride in water for caries control began in 1945 and 1946 in the United States and Canada, when the fluoride concentration was adjusted in the drinking water supplying four communities (2)(3)(4)(5). The U.S. Public Health Service (PHS) developed recommendations in the 1940s and 1950s regarding fluoride concentrations in public water supplies. At that time, public health officials assumed that drinking water would be the major source of fluoride for most U.S. residents. The success of water fluoridation in preventing and controlling dental caries led to the development of fluoride-containing products, including toothpaste (i.e., dentifrice), mouthrinse, dietary supplements, and professionally applied or prescribed gel, foam, or varnish. In addition, processed beverages, which constitute an increasing proportion of the diets of many U.S. residents (6,7 ), and food can contain small amounts of fluoride, especially if they are processed with fluoridated water. Thus, U.S. residents have more sources of fluoride available now than 50 years ago. Much of the research on the efficacy and effectiveness of individual fluoride modalities in preventing and controlling dental caries was conducted before 1980, when dental caries was more common and more severe. Modalities were usually tested separately and with the assumption that the method would provide the main source of fluoride. Thus, various modes of fluoride use have evolved, each with its own recommended concentration, frequency of use, and dosage schedule. Health-care professionals and the public have sought guidance regarding selection of preventive modalities from among the available options. The United States does not have comprehensive recommendations for caries prevention and control through various combinations of fluoride modalities. Adoption of such recommendations could further reduce dental caries while saving public and private resources and reducing the prevalence of enamel fluorosis, a generally cosmetic developmental condition of tooth enamel. This report presents comprehensive recommendations on the use of fluoride to prevent and control dental caries in the United States. These recommendations were developed by a work group of 11 specialists in fluoride research or policy convened by CDC during the late 1990s and reviewed by an additional 23 specialists. Although the recommendations were developed specifically for the United States, aspects of this report could be relevant to other countries. The recommendations guide health-care providers and the public on efficient and appropriate use of fluoride modalities, direct attention to fluoride intake among children aged <6 years to decrease the risk for enamel fluorosis, and suggest areas for further research. This report focuses on critical analysis of the scientific evidence regarding the efficacy and effectiveness of each fluoride modality in preventing and controlling dental caries and on the use of multiple sources of fluoride. The safety of fluoride, which has been documented comprehensively by other scientific and public health organizations (e.g., PHS [8 ], National Research Council [9 ], World Health Organization [10 ], and Institute of Medicine [11 ]) is not addressed. # HOW FLUORIDE PREVENTS AND CONTROLS DENTAL CARIES Dental caries is an infectious, transmissible disease in which bacterial by-products (i.e., acids) dissolve the hard surfaces of teeth. Unchecked, the bacteria can penetrate the dissolved surface, attack the underlying dentin, and reach the soft pulp tissue. Dental caries can result in loss of tooth structure, pain, and tooth loss and can progress to acute systemic infection. Cariogenic bacteria (i.e., bacteria that cause dental caries) reside in dental plaque, a sticky organic matrix of bacteria, food debris, dead mucosal cells, and salivary components that adheres to tooth enamel. Plaque also contains minerals, primarily calcium and phosphorus, as well as proteins, polysaccharides, carbohydrates, and lipids. Cariogenic bacteria colonize on tooth surfaces and produce polysaccharides that enhance adherence of the plaque to enamel. Left undisturbed, plaque will grow and harbor increasing numbers of cariogenic bacteria. An initial step in the formation of a carious lesion takes place when cariogenic bacteria in dental plaque metabolize a substrate from the diet (e.g., sugars and other fermentable carbohydrates) and the acid produced as a metabolic by-product demineralizes (i.e., begins to dissolve) the adjacent enamel crystal surface (Figure 1). Demineralization involves the loss of calcium, phosphate, and carbonate. These minerals can be captured by surrounding plaque and be available for reuptake by the enamel surface. Fluoride, when present in the mouth, is also retained and concentrated in plaque. Fluoride works to control early dental caries in several ways. Fluoride concentrated in plaque and saliva inhibits the demineralization of sound enamel and enhances the remineralization (i.e., recovery) of demineralized enamel (12,13 ). As cariogenic bacteria metabolize carbohydrates and produce acid, fluoride is released from dental plaque in response to lowered pH at the tooth-plaque interface (14 ). The released fluoride and the fluoride present in saliva are then taken up, along with calcium and phosphate, by demineralized enamel to establish an improved enamel crystal structure. This improved structure is more acid resistant and contains more fluoride and less carbonate (12,(15)(16)(17)(18)(19) (Figure 1). Fluoride is more readily taken up by demineralized enamel than by sound enamel (20 ). Cycles of demineralization and remineralization continue throughout the lifetime of the tooth. Fluoride also inhibits dental caries by affecting the activity of cariogenic bacteria. As fluoride concentrates in dental plaque, it inhibits the process by which cariogenic bacteria metabolize carbohydrates to produce acid and affects bacterial production of adhesive polysaccharides (21 ). In laboratory studies, when a low concentration of fluoride is constantly present, one type of cariogenic bacteria, Streptococcus mutans, produces less acid (22)(23)(24)(25). Whether this reduced acid production reduces the cariogenicity of these bacteria in humans is unclear (26 ). Saliva is a major carrier of topical fluoride. The concentration of fluoride in ductal saliva, as it is secreted from salivary glands, is low -approximately 0.016 parts per million (ppm) in areas where drinking water is fluoridated and 0.006 ppm in nonfluoridated areas (27 ). This concentration of fluoride is not likely to affect cariogenic activity. However, drinking fluoridated water, brushing with fluoride toothpaste, or using other fluoride dental products can raise the concentration of fluoride in saliva present in the mouth 100to 1,000-fold. The concentration returns to previous levels within 1-2 hours but, during this time, saliva serves as an important source of fluoride for concentration in plaque and for tooth remineralization (28 ). Applying fluoride gel or other products containing a high concentration of fluoride to the teeth leaves a temporary layer of calcium fluoride-like material on the enamel surface. The fluoride in this material is released when the pH drops in the mouth in response to acid production and is available to remineralize enamel (29 ). In the earliest days of fluoride research, investigators hypothesized that fluoride affects enamel and inhibits dental caries only when incorporated into developing dental enamel (i.e., preeruptively, before the tooth erupts into the mouth) (30,31 ). Evidence supports this hypothesis (32)(33)(34), but distinguishing a true preeruptive effect after teeth erupt into a mouth where topical fluoride exposure occurs regularly is difficult. However, a high fluoride concentration in sound enamel cannot alone explain the marked reduction in dental caries that fluoride produces (35,36 ). The prevalence of dental caries in a population is not inversely related to the concentration of fluoride in enamel (37 ), and a higher concentration of enamel fluoride is not necessarily more efficacious in preventing dental caries (38 ). The laboratory and epidemiologic research that has led to the better understanding of how fluoride prevents dental caries indicates that fluoride's predominant effect is posteruptive and topical and that the effect depends on fluoride being in the right amount in the right place at the right time. Fluoride works primarily after teeth have erupted, especially when small amounts are maintained constantly in the mouth, specifically in dental plaque and saliva (37 ). Thus, adults also benefit from fluoride, rather than only children, as was previously assumed. # RISK FOR DENTAL CARIES The prevalence and severity of dental caries in the United States have decreased substantially during the preceding 3 decades (39 ). National surveys have reported that the prevalence of any dental caries among children aged 12-17 years declined from 90.4% in 1971-1974 to 67% in 1988-1991; severity (measured as the mean number of decayed, missing, or filled teeth) declined from 6.2 to 2.8 during this period (40)(41)(42)(43). These decreases in caries prevalence and severity have been uneven across the general population; the burden of disease now is concentrated among certain groups and persons. For example, 80% of the dental caries in permanent teeth of U.S. children aged 5-17 years occurs among 25% of those children (43 ). To develop and apply appropriate and effective caries prevention and control strategies, identification and assessment of groups and persons at high risk for developing new carious lesions is essential (44 ). Caries risk assessment is difficult because it attempts to account for the complex interaction of multiple factors. Although various methods for assessing risk exist, no single model predominates in this emerging science. Models that take multiple factors into account predict the risk more accurately, especially for groups rather than persons. However, for persons in a clinical setting, models do not improve on a dentist's perception of risk after examining a patient and considering the personal circumstances (45 ). Populations believed to be at increased risk for dental caries are those with low socioeconomic status (SES) or low levels of parental education, those who do not seek regular dental care, and those without dental insurance or access to dental services (45)(46)(47). Persons can be at high risk for dental caries even if they do not have these recognized factors. Individual factors that possibly increase risk include active dental caries; a history of high caries in older siblings or caregivers; root surfaces exposed by gingival recession; high levels of infection with cariogenic bacteria; impaired ability to maintain oral hygiene; malformed enamel or dentin; reduced salivary flow because of medications, radiation treatment, or disease; low salivary buffering capacity (i.e., decreased ability of saliva to neutralize acids); and the wearing of space maintainers, orthodontic appliances, or dental prostheses. Risk can increase if any of these factors are combined with dietary practices conducive to dental caries (i.e., frequent consumption of refined carbohydrates). Risk decreases with adequate exposure to fluoride (44,45 ). Risk for dental caries and caries experience* exists on a continuum, with each person at risk to some extent; 85% of U.S. adults have experienced tooth decay (48 ). Caries risk can vary over time -perhaps numerous times during a person's lifetime -as risk factors change. Because caries prediction is an inexact, developing science, risk is dichotomized as low and high in this report. If these two categories of risk were applied to the U.S. population, most persons would be classified as low risk at any given time. Children and adults who are at low risk for dental caries can maintain that status through frequent exposure to small amounts of fluoride (e.g., drinking fluoridated water and using fluoride toothpaste). Children and adults at high risk for dental caries might benefit from additional exposure to fluoride (e.g., mouthrinse, dietary supplements, and professionally applied products). All available information on risk factors should be considered before a group or person is identified as being at low or high risk for dental caries. However, when classification is uncertain, treating a person as high risk is prudent until further information or experience allows a more accurate assessment. This assumption For this report, the term "caries experience" is used to mean the sum of filled and unfilled cavities, along with any missing teeth resulting from tooth decay. # MMWR August 17, 2001 increases the immediate cost of caries prevention or treatment and might increase the risk for enamel fluorosis for children aged <6 years, but reduces the risk for dental caries for groups or persons misclassified as low risk. # RISK FOR ENAMEL FLUOROSIS The proper amount of fluoride helps prevent and control dental caries. Fluoride ingested during tooth development can also result in a range of visually detectable changes in enamel opacity (i.e., light refraction at or below the surface) because of hypomineralization. These changes have been broadly termed enamel fluorosis, certain extremes of which are cosmetically objectionable (49 ). (Many other developmental changes that affect the appearance of enamel are not related to fluoride [50 ].) Severe forms of this condition can occur only when young children ingest excess fluoride, from any source, during critical periods of tooth development. The occurrence of enamel fluorosis is reported to be most strongly associated with cumulative fluoride intake during enamel development, but the severity of the condition depends on the dose, duration, and timing of fluoride intake. The transition and early maturation stages of enamel development appear to be most susceptible to the effects of fluoride (51 ); these stages occur at varying times for different tooth types. For central incisors of the upper jaw, for example, the most sensitive period is estimated at age 15-24 months for boys and age 21-30 months for girls (51,52 ). Concerns regarding the risk for enamel fluorosis are limited to children aged <8 years; enamel is no longer susceptible once its preeruptive maturation is complete (11 ). Fluoride sources for children aged <8 years are drinking water, processed beverages and food, toothpaste, dietary supplements that include fluoride (tablets or drops), and other dental products. This report discusses the risk for enamel fluorosis among children aged <6 years. Children aged >6 years are considered past the age that fluoride ingestion can cause cosmetically objectionable fluorosis because only certain posterior teeth are still at a susceptible stage of enamel development, and these will not be readily visible. In addition, the swallowing reflex has developed sufficiently by age 6 years for most children to be able to control inadvertent swallowing of fluoride toothpaste and mouthrinse. The very mild and mild forms of enamel fluorosis appear as chalklike, lacy markings across a tooth's enamel surface that are not readily apparent to the affected person or casual observer (53 ). In the moderate form, >50% of the enamel surface is opaque white. The rare, severe form manifests as pitted and brittle enamel. After eruption, teeth with moderate or severe fluorosis might develop areas of brown stain (54 ). In the severe form, the compromised enamel might break away, resulting in excessive wear of the teeth. Even in its severe form, enamel fluorosis is considered a cosmetic effect, not an adverse functional effect (8,11,55,56 ). Some persons choose to modify this condition with elective cosmetic treatment. The benefits of reduced dental caries and the risk for enamel fluorosis are linked. Early studies that examined the cause of "mottled enamel" (now called moderate to severe enamel fluorosis) led to the unexpected discovery that fluoride in community drinking water inhibits dental caries (57 ). Historically, a low prevalence of the milder forms of enamel fluorosis has been accepted as a reasonable and minor consequence balanced against the substantial protection from dental caries from drinking water con-taining an optimal concentration of fluoride, either naturally occurring or through adjustment (11,53 ). When enamel fluorosis was first systematically investigated during the 1930s and 1940s, its prevalence was 12%-15% for very mild and mild forms and zero for moderate and severe forms among children who lived in communities with drinking water that naturally contained 0.9-1.2 ppm fluoride (53 ). Although the prevalence of this condition in the United States has since increased (8,58,59 ), most fluorosis today is of the mildest form, which affects neither cosmetic appearance nor dental function. The increased prevalence in areas both with and without fluoridated community drinking water (8 ) indicates that, during the first 8 years of life (i.e., the window of time when this condition can develop), the total intake of fluoride from all sources has increased for some children. The 1986The -1987 National Survey of Dental Caries in U.S. School Children (the most recent national estimates of enamel fluorosis prevalence) indicated that the prevalence of any enamel fluorosis among children was 22%-23% (range: 26% of children aged 9 years to 19% of those aged 17 years) (60,61 ). Almost all cases reported in the survey were of the very mild or mild form, but some cases of the moderate (1.1%) and severe (0.3%) forms were observed. Cases of moderate and severe forms occurred even among children living in areas with low fluoride concentrations in the drinking water (61 ). Although this level of enamel fluorosis is not considered a public health problem (53 ), prudent public health practice should seek to minimize this condition, especially moderate to severe forms. In addition, changes in public perceptions of what is cosmetically acceptable could influence support for effective caries-prevention measures. Research into the causes of enamel fluorosis has focused on identifying risk factors (62)(63)(64)(65). Adherence to the recommendations in this report regarding appropriate use of fluoride for children aged <6 years will reduce the prevalence and severity of enamel fluorosis. # NATIONAL GUIDELINES FOR FLUORIDE USE PHS recommendations for fluoride use include an optimally adjusted concentration of fluoride in community drinking water to maximize caries prevention and limit enamel fluorosis. This concentration ranges from 0.7 ppm to 1.2 ppm depending on the average maximum daily air temperature of the area (66)(67)(68). In 1991, PHS also issued policy and research recommendations for fluoride use (8 ). The U.S. Environmental Protection Agency (EPA), which is responsible for the safety and quality of drinking water in the United States, sets a maximum allowable limit for fluoride in community drinking water at 4 ppm and a secondary limit (i.e., nonenforceable guideline) at 2 ppm (69,70 ). The U.S. Food and Drug Administration (FDA) is responsible for approving prescription and overthe-counter fluoride products marketed in the United States and for setting standards for labeling bottled water (71 ) and over-the-counter fluoride products (e.g., toothpaste and mouthrinse) (72 ). Nonfederal agencies also have published guidelines on fluoride use. The American Dental Association (ADA) reviews fluoride products for caries prevention through its voluntary Seal of Acceptance program; accepted products are listed in the ADA Guide to Dental Therapeutics (73 ). A dosage schedule for fluoride supplements for infants and children aged <16 years, which is scaled to the fluoride concentration in the community drinking water, has been jointly recommended by ADA, the American Academy of Pediatric Dentistry (AAPD), and the American Academy of Pediatrics (AAP) (Table 1) (44,74,75 ). In 1997, the Institute of Medicine published age-specific recommendations for total dietary intake of fluoride (Table 2). These recommendations list adequate intake to prevent dental caries and tolerable upper intake, defined as a level unlikely to pose risk for adverse effects in almost all persons. # FLUORIDE SOURCES AND THEIR EFFECTS Fluoridated community drinking water and fluoride toothpaste are the most common sources of fluoride in the United States and are largely responsible for the low risk for dental caries for most persons in this country. Persons at high risk for dental caries might require more frequent or more concentrated exposure to fluoride and might benefit from use of other fluoride modalities (e.g., mouthrinse, dietary supplements, and topical gel, foam, or varnish). The effects of each of these fluoride sources on dental caries and enamel fluorosis are described. # Fluoridated Drinking Water and Processed Beverages and Food Fluoridated drinking water contains a fluoride concentration effective for preventing dental caries; this concentration can occur naturally or be reached through water fluoridation, which is the controlled addition of fluoride to a public water supply. When fluoridated water is the main source of drinking water, a low concentration of fluoride is routinely introduced into the mouth. Some of this fluoride is taken up by dental plaque; some is transiently present in saliva, which serves as a reservoir for plaque fluoride; and some is loosely held on the enamel surfaces (76 ). Frequent consumption of fluoridated drinking water and beverages and food processed in fluoridated areas maintains the concentration of fluoride in the mouth. Estimates of fluoride intake among U.S. and Canadian adults have ranged from <1.0 mg fluoride per day in nonfluoridated areas to 1-3 mg fluoride per day in fluoridated areas (77)(78)(79)(80). The average daily dietary fluoride intake for both children and adults in fluoridated areas has remained relatively constant for several years (11 ). For children who live in optimally fluoridated areas, this average is approximately 0.05 mg/kg/day (range: 0.02-0.10); for children who live in nonfluoridated areas, the average is approximately half (11 ). In a survey of four U.S. cities with different fluoride concentrations in the drinking water (range: 0.37-1.04 ppm), children aged 2 years ingested 0.41-0.61 mg fluoride per day and infants aged 6 months ingested 0.21-0.54 mg fluoride per day (81,82 ). In the United States, water and processed beverages (e.g., soft drinks and fruit juices) can provide approximately 75% of a person's fluoride intake (83 ). Many processed beverages are prepared in locations where the drinking water is fluoridated. Foods and ingredients used in food processing vary in their fluoride content (11 ). As consumption of processed beverages by children increases, fluoride intake in communities without fluoridated water will increase whenever the water source for the processed beverage is fluoridated (84). In fluoridated areas, dietary fluoride intake has been stable because processed beverages have been substituted for tap water and for beverages prepared in the home using tap water (11 ). A study of Iowa infants estimated that the mean fluoride intake from water during different periods during the first 9 months of life, either consumed directly or added to infant formula or juice, was 0.29-0.38 mg per day, although estimated intake for some infants was as high as 1.73 mg per day (85 ). As foods are added to an infant's diet, replacing some of the formula prepared with fluoridated water, the amount of fluoride the infant receives typically decreases (86 ). The Iowa study also reported that infant formula and processed baby food contained variable amounts of fluoride. Since 1979, U.S. manufacturers of infant formula have voluntarily lowered the fluoride concentration of their products, both ready-to-feed and concentrates, to <0.3 ppm fluoride (87 ). # Drinking Water Community Water. During the 1940s, researchers determined that 1 ppm fluoride was the optimal concentration in community drinking water for climates similar to the Chicago area (88,89 ). This concentration would substantially reduce the prevalence of dental caries, while allowing an acceptably low prevalence (i.e., 10%-12%) of very mild and mild enamel fluorosis and no moderate or severe enamel fluorosis. Water fluoridation for caries control began in 1945 and 1946, when the fluoride concentration was adjusted in the drinking water supplying four communities in the United States and Canada (2)(3)(4)(5). This public health approach followed a long period of epidemiologic research into the effects of naturally occurring fluoride in drinking water (53,57,88,89 ). Current federal fluoridation guidelines, maintained by the PHS since 1962, state that community drinking water should contain 0.7-1.2 ppm fluoride, depending on the average maximum daily air temperature of the area. These temperature-related guidelines are based on epidemiologic studies conducted during the 1950s that led to the development of an algebraic formula for determining optimal fluoride concentrations (67,(90)(91)(92). This formula determined that a lower fluoride concentration was appropriate for communities in warmer climates because persons living in warmer climates drank more tap water. However, social and environmental changes since 1962 (e.g., increased use of air conditioning and more sedentary lifestyles) have reduced the likelihood that persons in warmer regions drink more tap water than persons in cooler regions (7 ). By 1992, fluoridated water was reaching 144 million persons in the United States (56% of the total population and 62% of those receiving municipal water supplies) (93 ). Approximately 10 million of these persons were receiving water containing naturally occurring fluoride at a concentration of >0.7 ppm. In 11 states and the District of Columbia, >90% of the population had such access, whereas <5% received this benefit in two states. In 2000, a total of 38 states and the District of Columbia provided access to fluoridated public water supplies to >50% of their population (CDC, unpublished data, 2000) (Figure 2). # MMWR 11 Initial studies of community water fluoridation demonstrated that reductions in childhood dental caries attributable to fluoridation were approximately 50%-60% (94)(95)(96)(97). More recent estimates are lower -18%-40% (98,99 ). This decrease in attributable benefit is likely caused by the increasing use of fluoride from other sources, with the widespread use of fluoride toothpaste probably the most important. The diffusion or "halo" effect of beverages and food processed in fluoridated areas but consumed in nonfluoridated areas also indirectly spreads some benefit of fluoridated water to nonfluoridated communities. This effect lessens the differences in caries experience among communities (100 ). Quantifying the benefits of water fluoridation among adults is more complicated because adults are rarely surveyed, their fluoride histories are potentially more varied, and their tooth loss or restorations might be caused by dental problems other than caries (e.g., trauma or periodontal diseases). Nevertheless, adults are reported to receive caries-preventive benefits from community water fluoridation (99,(101)(102)(103). These benefits might be particularly advantageous for adults aged >50 years, many of whom are at increased risk for dental caries. Besides coronal caries, older adults typically experience gingival recession, which results in teeth with exposed root surfaces. Unlike the crowns of teeth, these root surfaces are not covered by enamel and are more susceptible to caries. Because tooth retention among older age groups has increased in recent decades in the United States (39 ), these groups' risk for caries will increase as the country's population ages. Older adults also frequently require multiple medications for chronic conditions, and many of these medications can reduce salivary output (104 ). Drinking water containing an optimal concentration of fluoride can mitigate the risk factors for caries among older adults. Studies have reported that the prevalence of root caries among adults is inversely related to fluoride concentration in the community drinking water (105)(106)(107). Water fluoridation also reduces the disparities in caries experience among poor and nonpoor children (108)(109)(110)(111). Caries experience is considerably higher among persons in low SES strata than among those in high SES strata (39,46,112 ). The reasons for this discrepancy are not well understood; perhaps persons in low SES strata have less knowledge of oral diseases, have less access to dental care, are less likely to follow recommended self-care practices, or are harder to reach through traditional approaches, including public health programs and private dental care (48 ). Thus, these persons might receive more benefit from fluoridated community water than persons from high SES strata. Regardless of SES, water fluoridation is the most effective and efficient strategy to reduce dental caries (112 ). Enamel fluorosis occurs among some persons in all communities, even in communities with a low natural concentration of fluoride. During 1930-1960, U.S. studies documented that, in areas with a natural or adjusted concentration of fluoride of approximately 1.0 ppm in the community drinking water, the permanent teeth of 7%-16% of children with lifetime residence in those areas exhibited very mild or mild forms of enamel fluorosis (53,113,114 ). Before 1945, when naturally fluoridated drinking water was virtually the only source of fluoride, the moderate and severe forms of this condition were not observed unless the natural fluoride concentration was >2 ppm (53 ). The likelihood of a child developing the mild forms of enamel fluorosis might be higher in a fluoridated area than in a nonfluoridated area, but prevalence might not change in every community (115,116 ). The most recent national study of this condition indicated that its prevalence had increased in both fluoridated and nonfluoridated areas since the 1940s, with the relative increase higher in nonfluoridated areas. In communities with drinking water containing 0.7-1.2 ppm fluoride, the prevalence was 1.3% for the moderate form of enamel fluorosis and zero for the severe form; thus, few cases of enamel fluorosis were likely to be of cosmetic consequence (8,61 ). Because combined fluoride intake from drinking water and processed beverages and food by children in fluoridated areas has reportedly remained stable since the 1940s, the increase in fluoride intake resulting in increased enamel fluorosis almost certainly stems from use of fluoride-containing dental products by children aged <6 years (11 ). Two studies reported that extended consumption of infant formula beyond age 10-12 months was a risk factor for enamel fluorosis, especially when formula concentrate was mixed with fluoridated water (62,63 ). These studies examined children who used pre-1979 formula (with higher fluoride concentrations). Whether fluoride intake from formula that exceeds the recommended amount during only the first 10-12 months of life contributes to the prevalence or severity of enamel fluorosis is unknown. Fluoride concentrations in drinking water should be maintained at optimal levels, both to achieve effective caries prevention and because changes in fluoride concentration as low as 0.2 ppm can result in a measurable change in the prevalence and severity of enamel fluorosis (52,117 ). Since the late 1970s, CDC has provided guidelines and recommendations for managers of fluoridated water supply systems at state and local levels to help them establish and maintain appropriate fluoride concentrations. CDC periodically updates these guidelines; the most recent revision was published in 1995 (68 ). School Water Systems. In some areas of the United States where fluoridating a community's drinking water was not feasible (e.g., rural areas), the alternative of fluoridating a school's public water supply system was promoted for many years. This method was used when a school had its own source of water and was not connected to a community water supply system (i.e., stand-alone systems). Because children are at school only part of each weekday, a fluoride concentration of 4.5 times the optimal concentration for a community in the same geographic area was recommended (118 ) to compensate for the more limited consumption of fluoridated water. At the peak of this practice in the early 1980s, a total of 13 states had initiated school water fluoridation in 470 schools serving 170,000 children (39 ). Since then, school water fluoridation has been phased out in several states; the current extent of this practice is not known. Studies of the effects of school water fluoridation in the United States reported that this practice reduced caries among schoolchildren by approximately 40% (118)(119)(120)(121)(122). A more recent study indicated that this effect might no longer be as pronounced (123 ). Several concerns regarding school water fluoridation exist. Operating and maintaining small fluoridation systems (i.e., those serving <500 persons) create practical and logistical difficulties (68 ). These difficulties have occasionally caused higher than recommended fluoride concentrations in the school drinking water, but no lasting effects among children have been observed (124)(125)(126). In schools that enroll preschoolers in day care programs, children aged <6 years might receive more than adequate fluoride. Bottled Water. Many persons drink bottled water, replacing tap water partially or completely as a source of drinking water. Water is classified as "bottled water" if it meets all applicable federal and state standards, is sealed in a sanitary container, and is sold for human consumption. Although some bottled waters marketed in the United States contain an optimal concentration of fluoride (approximately 1.0 ppm), most contain <0.3 ppm fluoride (127)(128)(129). Thus, a person substituting bottled water with a low fluoride concen- MMWR 13 tration for fluoridated community water might not receive the full benefits of community water fluoridation (130 ). For water bottled in the United States, current FDA regulations require that fluoride be listed on the label only if the bottler adds fluoride during processing; the concentration of fluoride is regulated but does not have to be stated on the label (Table 3). Few bottled water brands have labels listing the fluoride concentration. Determining Fluoride Concentration. Uneven geographic coverage of community water fluoridation throughout the United States, wide variations in natural fluoride concentrations found in drinking water, and almost nonexistent labeling of fluoride concentration in bottled water make knowing the concentration of fluoride in drinking water difficult for many persons. Persons in nonfluoridated areas can mistakenly believe their water contains an optimal concentration of fluoride. To obtain the fluoride concentration of community drinking water, a resident can contact the water supplier or a local public health authority, dentist, dental hygienist, physician, or other knowledgeable source. EPA requires that all community water supply systems provide each customer an annual report on the quality of water, including the fluoride concentration (131 ). Testing for private wells is available through local and state public health departments as well as some private laboratories. If the fluoride concentration is not listed on the label of bottled water, the bottler can be contacted directly to obtain this information. # Fluoride Toothpaste Fluoride is the only nonprescription toothpaste additive proven to prevent dental caries. When introduced into the mouth, fluoride in toothpaste is taken up directly by dental plaque (132)(133)(134) and demineralized enamel (135,136 ). Brushing with fluoride toothpaste also increases the fluoride concentration in saliva 100-to 1,000-fold; this concentration returns to baseline levels within 1-2 hours (137 ). Some of this salivary fluoride is taken up by dental plaque. The ambient fluoride concentration in saliva and plaque can increase during regular use of fluoride toothpaste (132,133 ). # MMWR August 17, 2001 By the 1990s, fluoride toothpaste accounted for >90% of the toothpaste market in the United States, Canada, and other developed countries (138 ). Because water fluoridation is not available in many countries, toothpaste might be the most important source of fluoride globally (1 ). Studies of 2-3 years duration have reported that fluoride toothpaste reduces caries experience among children by a median of 15%-30% (139)(140)(141)(142)(143)(144)(145)(146)(147)(148). This reduction is modest compared with the effect of water fluoridation, but water fluoridation studies usually measured lifetime -rather than a few years' -exposure. Regular lifetime use of fluoride toothpaste likely provides ongoing benefits that might approach those of fluoridated water. Combined use of fluoride toothpaste and fluoridated water offers protection above either used alone (99,149,150 ). Few studies evaluating the effectiveness of fluoride toothpaste, gel, rinse, and varnish among adult populations are available. Child populations have typically been used for studies on caries prevention because of perceived increased caries susceptibility and logistical reasons. However, teeth generally remain susceptible to caries throughout life, and topically applied fluorides could be effective in preventing caries in susceptible patients of any age (151,152 ). Most persons report brushing their teeth at least once per day (153,154 ), but more frequent use can offer additional protection (139,141,(155)(156)(157)(158). Brushing twice a day is a reasonable social norm that is both effective and convenient for most persons' daily routines, and this practice has become a basic recommendation for caries prevention. Whether increasing the number of daily brushings from two to three times a day results in lower dental caries experience is unclear. Because the amount and vigor of rinsing after toothbrushing affects fluoride concentration in the mouth and reportedly affects caries experience (157)(158)(159)(160), persons aged >6 years can retain more fluoride in the mouth by either rinsing briefly with a small amount of water or not at all. In the United States, the standard concentration of fluoride in fluoride toothpaste is 1,000-1,100 ppm. Toothpaste containing 1,500 ppm fluoride has been reported to be slightly more efficacious in reducing dental caries in U.S. and European studies (161)(162)(163)(164). Products with this fluoride concentration have been marketed in the United States, but are not available in all areas. These products might benefit persons aged >6 years at high risk for dental caries. Children who begin using fluoride toothpaste at age <2 years are at higher risk for enamel fluorosis than children who begin later or who do not use fluoride toothpaste at all (62,63,(165)(166)(167)(168)(169)(170). Because studies have not used the same criteria for age of initiation, amount of toothpaste used, or frequency of toothpaste use, the specific contribution of each factor to enamel fluorosis among this age group has not been established. Fluoride toothpaste contributes to the risk for enamel fluorosis because the swallowing reflex of children aged <6 years is not always well controlled, particularly among children aged <3 years (171,172 ). Children are also known to swallow toothpaste deliberately when they like its taste. A child-sized toothbrush covered with a full strip of toothpaste holds approximately 0.75-1.0 g of toothpaste, and each gram of fluoride toothpaste, as formulated in the United States, contains approximately 1.0 mg of fluoride. Children aged <6 years swallow a mean of 0.3 g of toothpaste per brushing (11 ) and can inadvertently swallow as much as 0.8 g (138,(173)(174)(175)(176). As a result, multiple brushings with fluoride toothpaste each day can result in ingestion of excess fluoride (177 ). For this reason, high-fluoride toothpaste (i.e., containing 1,500 ppm fluoride) is generally contraindicated for children aged <6 years. Use of a pea-sized amount (approximately 0.25 g) of fluoride toothpaste <2 times per day by children aged <6 years is reported to sharply reduce the importance of fluoride toothpaste as a risk factor for enamel fluorosis (65 ). Since 1991, manufacturers of fluoride toothpaste marketed in the United States have, as a requirement for obtaining the ADA Seal of Acceptance, placed instructions on the package label stating that children aged <6 years should use only this amount of toothpaste. Toothpaste labeling requirements mandated by FDA in 1996 (72 ) also direct parents of children aged <2 years to seek advice from a dentist or physician before introducing their child to fluoride toothpaste. The propensity of young children to swallow toothpaste has led to development of "child-strength" toothpaste with lower fluoride concentrations (176 ). Such a product would be a desirable alternative to currently available products for many young children. Clinical trials outside the United States have reported that toothpaste containing 250 ppm fluoride is less effective than toothpaste containing 1,000 ppm fluoride in preventing dental caries (178,179 ). However, toothpaste containing 500-550 ppm fluoride might be almost as efficacious as that containing 1,000 ppm fluoride (180 ). A British study reported that the prevalence of diffuse enamel opacities (an indicator of mild enamel fluorosis) in the upper anterior incisors was substantially lower among children who used toothpaste containing 550 ppm fluoride than among those who used toothpaste containing 1,050 ppm fluoride (181 ). Toothpaste containing 400 ppm fluoride has been available in Australia and New Zealand for approximately 20 years, but has not been tested in clinical trials, and no data are available to assess whether toothpaste at this concentration has reduced the prevalence of enamel fluorosis in those countries. A U.S. clinical trial of the efficacy of toothpaste with lower fluoride concentrations, required by FDA before approval for marketing and distribution, has not been conducted (182 ). # Fluoride Mouthrinse Fluoride mouthrinse is a concentrated solution intended for daily or weekly use. The fluoride from mouthrinse, like that from toothpaste, is retained in dental plaque and saliva to help prevent dental caries (183 ) Studies indicating that fluoride mouthrinse reduces caries experience among schoolchildren date mostly from the 1970s and early 1980s (184)(185)(186)(187)(188)(189)(190)(191). In one review, the average caries reduction in nonfluoridated communities attributable to fluoride mouthrinse was 31% (191 ). Two studies reported benefits of fluoride mouthrinse approximately 2.5 and 7 years after completion of school-based mouthrinsing programs (192,193 ), but a more recent study did not find such benefits 4 years after completion of a mouthrinsing program (194 ). The National Preventive Dentistry Demonstration Program (NPDDP), a large project conducted in 10 U.S. cities during 1976-1981 to compare the cost and effectiveness of combinations of caries-prevention procedures, reported that fluoride mouthrinse had little effect among schoolchildren, either among first-grade students with high and low caries experience (195 ) or among all second-and fifth-grade students (196 ). NPDDP documented only a limited reduction in dental caries attributable to fluoride mouthrinse, especially when children were also exposed to fluoridated water. Although no studies of enamel fluorosis associated with use of fluoride mouthrinse have been conducted, studies of the amount of fluoride swallowed by children aged 3-5 years using such rinses indicated that some young children might swallow substantial amounts (191 ). Use of fluoride mouthrinse by children aged >6 years does not place them at risk for cosmetically objectionable enamel fluorosis because they are generally past the age that fluoride ingestion might affect their teeth. # Dietary Fluoride Supplements Dietary fluoride supplements in the form of tablets, lozenges, or liquids (including fluoride-vitamin preparations) have been used throughout the world since the 1940s. Most supplements contain sodium fluoride as the active ingredient. Tablets and lozenges are manufactured with 1.0, 0.5, or 0.25 mg fluoride. To maximize the topical effect of fluoride, tablets and lozenges are intended to be chewed or sucked for 1-2 minutes before being swallowed. For infants, supplements are available as a liquid and used with a dropper. In 1986, an estimated 16% of U.S. children aged <2 years used fluoride supplements (197 ). All fluoride supplements must be prescribed by a dentist or physician. The prescription should be consistent with the 1994 dosage schedule developed by ADA, AAPD, and AAP (Table 1). Because fluoride supplements are intended to compensate for fluoride-deficient drinking water, the dosage schedule requires knowledge of the fluoride content of the child's primary drinking water; consideration should also be given to other sources of water (e.g., home, child care settings, school, or bottled water) and to other sources of fluoride (e.g., toothpaste or mouthrinse), which can complicate the prescribing decision. The evidence for using fluoride supplements to mitigate dental caries is mixed. Use of fluoride supplements by pregnant women does not benefit their offspring (198 ). Several studies have reported that fluoride supplements taken by infants and children before their teeth erupt reduce the prevalence and severity of caries in teeth (98,(199)(200)(201)(202)(203)(204)(205)(206)(207), but several other studies have not (19,(208)(209)(210)(211)(212). Among children aged 6-16 years, fluoride supplements taken after teeth erupt reduce caries experience (213)(214)(215). Fluoride supplements might be beneficial among adults who have limitations with toothbrushing, but this use requires further study. A few studies have reported no association between supplement use by children aged <6 years and enamel fluorosis (208,216 ), but most have reported a clear association (19,62,64,165,170,(199)(200)(201)209,210,212,(217)(218)(219)(220)(221)(222). In one study, the risk for this condition was high when supplements were used in fluoridated areas (odds ratio = 23.74; 95% confidence interval = 3.43-164.30) (62 ), a use inconsistent with the supplement schedule. Reports of the frequency of supplement use in fluoridated areas have ranged from 7% to 35% (223)(224)(225)(226)(227)(228). In response to the accumulated data on fluoride intake and the prevalence of enamel fluorosis, the supplement dosage schedule for children aged <6 years was markedly reduced in 1994 when ADA, AAPD, and AAP jointly established the current schedule (Table 1) (73 ). The risk for enamel fluorosis among children this age attributable to fluoride supplements could be lower, but not enough information is available yet to evaluate the effects of this change. When prescribing any pharmaceutical agent, dentists and physicians should attempt to maximize benefit and minimize harm (229 ). For infants and children aged <6 years, both a benefit of dental caries prevention and a risk for enamel fluorosis are possible. Although the primary (i.e., "baby") teeth of children aged 1-6 years would benefit from fluoride's posteruptive action, and some preeruptive benefit for developing permanent teeth could exist, fluoride supplements also could increase the risk for enamel fluorosis at this age (138,223 ). # Professionally Applied Fluoride Compounds In the United States, dentists and dental hygienists have been applying highconcentration fluoride compounds directly to patients' teeth for approximately 50 years. Application procedures were developed on the assumption that the fluoride would be incorporated into the crystalline structure of the dental enamel and develop a more acidresistant enamel. To maximize this reaction, a professional tooth cleaning was considered mandatory before the application. However, subsequent research has demonstrated that high-concentration fluoride compounds (e.g., those in gel or varnish) do not directly enter the enamel's crystalline structure (230 ). The compound forms a calcium fluoride-like material on the enamel's surface that releases fluoride for remineralization when the pH in the mouth drops. Thus, professional tooth cleaning solely to prepare the teeth for application of a fluoride compound is unnecessary; toothbrushing and flossing appear equally effective in improving the efficacy of highconcentration fluoride compounds (231 ). # Fluoride Gel and Foam Because an early study reported that fluoride uptake by dental enamel increased in an acidic environment (232 ), fluoride gel is often formulated to be highly acidic (pH of approximately 3.0). Products available in the United States include gel of acidulated phosphate fluoride (1.23% [12,300 ppm] fluoride), gel or foam of sodium fluoride (0.9% [9,040 ppm] fluoride), and self-applied (i.e., home use) gel of sodium fluoride (0.5% [5,000 ppm] fluoride) or stannous fluoride (0.15% [1,000 ppm] fluoride) (73 ). Clinical trials conducted during 1940-1970 demonstrated that professionally applied fluorides effectively reduce caries experience in children (233 ). In more recent studies, semiannual treatments reportedly caused an average decrease of 26% in caries experience in the permanent teeth of children residing in nonfluoridated areas (191,(234)(235)(236). The application time for the treatments was 4 minutes. In clinical practice, applying fluoride gel for 1 minute rather than 4 minutes is common, but the efficacy of this shorter application time has not been tested in human clinical trials. In addition, the optimal schedule for repeated application of fluoride gel has not been adequately studied to support definitive guidelines, and studies that have examined the efficacy of various gel application schedules in preventing and controlling dental caries have reported mixed results. On the basis of the available evidence, the usual recommended frequency is semiannual (151,237,238 ). Because these applications are relatively infrequent, generally at 3-to 12-month intervals, fluoride gel poses little risk for enamel fluorosis, even among patients aged <6 years. Proper application technique reduces the possibility that a patient will swallow the gel during application. # MMWR August 17, 2001 Fluoride Varnish High-concentration fluoride varnish is painted directly onto the teeth. Fluoride varnish is not intended to adhere permanently; this method holds a high concentration of fluoride in a small amount of material in close contact with the teeth for many hours. Fluoride varnish has practical advantages (e.g., ease of application, a nonoffensive taste, and use of smaller amounts of fluoride than required for gel applications). Such varnishes are available as sodium fluoride (2.26% [2,600 ppm] fluoride) or difluorsilane (0.1% [1,000 ppm] fluoride) preparations. Fluoride varnish has been widely used in Canada and Europe since the 1970s to prevent dental caries (152,239 ). FDA's Center for Devices and Radiological Health has cleared fluoride varnish as a medical device to be used as a cavity liner (i.e., to provide fluoride at the junction of filling material and tooth) and root desensitizer (i.e., to reduce sensitivity to temperature and touch that sometimes occurs on root surfaces exposed by receding gingiva) (240 ); FDA has not yet approved this product as an anticaries agent. Caries prevention is regarded as a drug claim, and companies would be required to submit appropriate clinical trial evidence for review before this product could be marketed as an anticaries agent. However, a prescribing practitioner can use fluoride varnish for caries prevention as an "off-label" use, based on professional judgement (241 ). Studies conducted in Canada (242 ) and Europe (243)(244)(245)(246) have reported that fluoride varnish is efficacious in preventing dental caries in children. Applied semiannually, this modality is as effective as professionally applied fluoride gel (247 ). Some researchers advocate application of fluoride varnish as many as four times per year to achieve maximum effect, but the evidence of benefits from more than two applications per year remains inconclusive (240,246,248 ). Other studies have reported that three applications in 1 week, once per year, might be more effective than the more conventional semiannual regimen (249,250 ). European studies have reported that fluoride varnish prevents decalcification (i.e., an early stage of dental caries) beneath orthodontic bands (251 ) and slows the progression of existing enamel lesions (252 ). Studies examining the effectiveness of varnish in controlling early childhood caries are being conducted in the United States. Research on fluoride varnish (e.g., optimal fluoride concentration, the most effective application protocols, and its efficacy relative to other fluoride modalities) is likely to continue in both Europe and North America. No published evidence indicates that professionally applied fluoride varnish is a risk factor for enamel fluorosis, even among children aged <6 years. Proper application technique reduces the possibility that a patient will swallow varnish during its application and limits the total amount of fluoride swallowed as the varnish wears off the teeth over several hours. # Fluoride Paste Fluoride-containing paste is routinely used during dental prophylaxis (i.e., cleaning). The abrasive paste, which contains 4,000-20,000 ppm fluoride, might restore the concentration of fluoride in the surface layer of enamel removed by polishing, but it is not an adequate substitute for fluoride gel or varnish in treating persons at high risk for dental caries (151 ). Fluoride paste is not accepted by FDA or ADA as an efficacious way to prevent dental caries. # Combinations of Fluoride Modalities Studies comparing various combinations of fluoride modalities have generally reported that their effectiveness in preventing dental caries is partially additive. That is, the percent reduction in the prevalence or severity of dental caries from a combination of modalities is higher than the percent reduction from each modality, but less than the sum of the percent reduction of the modalities combined. Attempts to use a formula to apply sequentially the percent reduction of an additional modality to the estimated remaining caries increment have overestimated the effect (151,253 ). For example, if the first modality reduces caries by 40% and the second modality reduces caries by 30%, then the calculation that caries will be reduced by a total of 58% (i.e., 40% plus 18% [30% of the 60% decay remaining after the first modality]) will likely be an overestimate. # QUALITY OF EVIDENCE FOR DENTAL CARIES PREVENTION AND CONTROL Members of the work group convened by CDC identified the published research in their areas of expertise and evaluated the quality of scientific evidence for each fluoride modality in preventing and controlling dental caries. Evidence was drawn from the most relevant English-language, peer-reviewed scientific publications regarding the current effectiveness of fluoride modalities. Additional references were suggested by reviewers. Members used their own methods for critically analyzing articles. A formal protocol for duplicate review was not followed, but members collectively agreed on the grade reflecting the quality of evidence regarding each fluoride modality. Criteria used to grade the quality of scientific evidence (i.e., ordinal grading) was adapted from the U.S. Preventive Services Task Force (Box 1) (254 ). Grades range from I to III. # BOX 1. Grading system used for determining the quality of evidence for a fluoride modality Grade Criteria I Evidence obtained from one or more properly conducted randomized clinical trials (i.e., one using concurrent controls, double-blind design, placebos, valid and reliable measurements, and well-controlled study protocols). # II-1 Evidence obtained from one or more controlled clinical trials without randomization (i.e., one using systematic subject selection, some type of concurrent controls, valid and reliable measurements, and wellcontrolled study protocols). # II-2 Evidence obtained from one or more well-designed cohort or case-control analytic studies, preferably from more than one center or research group. # II-3 Evidence obtained from cross-sectional comparisons between times and places; studies with historical controls; or dramatic results in uncontrolled experiments (e.g., the results of the introduction of penicillin treatment in the 1940s). # III Opinions of respected authorities on the basis of clinical experience, descriptive studies or case reports, or reports of expert committees. Source: US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Alexandria, VA: International Medical Publishing, 1996. # MMWR August 17, 2001 # Community Water Fluoridation Studies on the effectiveness of adjusting fluoride in community water to the optimal concentration cannot be designed as randomized clinical trials. Random allocation of study subjects is not possible when a community begins to fluoridate the water because all residents in a community have access to and are exposed to this source of fluoride. In addition, clinical studies cannot be conducted double-blind because both study subjects and researchers usually know whether a community's water has been fluoridated. Efforts to blind the examiners by moving study subjects to a neutral third site for clinical examinations, using radiographs of teeth without revealing where the subjects live, or including transient residents as study subjects have not fully resolved these inherent limitations. Early studies that led to the unexpected discovery that dental caries was less prevalent and severe among persons with mottled enamel (subsequently identified as a form of enamel fluorosis) were conducted before the caries-preventive effects of fluoride were known (255 ). In those studies, researchers did not have an a priori reason to suspect they would find either reduced or higher levels of dental caries experience in communities with low levels of mottled enamel. Researchers also had no reason to believe that patients selected where they lived according to their risk for dental caries. In that regard, these studies were randomized, and examiners were blinded. Despite the strengths of early studies of the efficacy of naturally occurring fluoride in community drinking water, the limitations of these studies make summarizing the quality of evidence on community water fluoridation as Grade I inappropriate (Table 1). The quality of evidence from studies on the effectiveness of adjusting fluoride concentration in community water to optimal levels is Grade II-1. Research limitations are counterbalanced by broadly similar results from numerous well-conducted field studies by other investigators that included thousands of persons throughout the world (256,257 ). # School Water Fluoridation Field trials on the effect of school water fluoridation were not blindly conducted and had no concurrent controls (118 ). Thus, the quality of evidence for this modality is Grade II-3. # Fluoride Toothpaste Studies that have demonstrated the efficacy of fluoride toothpaste in preventing and controlling dental caries include all of the essential features of well-conducted clinical trials. These include randomized groups, double-blind designs, placebo controls, and meticulous procedural protocols. Taken together, the trials on fluoride toothpaste provide solid evidence that fluoride is efficacious in controlling caries (144 ). The quality of evidence for toothpaste is Grade I. # Fluoride Mouthrinse Early studies of the efficacy of fluoride mouthrinse in reducing dental caries experience were randomized clinical trials (184,185 ) or studies that used historical control groups rather than concurrent control groups (186)(187)(188)(189). The quality of evidence for fluoride mouthrinse is Grade I. # MMWR 21 # Dietary Fluoride Supplements The only randomized controlled trial to assess fluoride supplements taken by pregnant women provides Grade I evidence of no benefit for their children. Many studies of the effectiveness of fluoride supplements in preventing dental caries among children aged <6 years have been flawed in design and conduct. Problems included self-selection into test and control groups, absence of concurrent controls, high attrition rates, and nonblinded examiners. Because of these flaws, the quality of evidence to support use of fluoride supplements by children aged <6 years is Grade II-3. The well-conducted randomized clinical trials on the effects of fluoride supplements on dental caries among children aged 6-16 years in programs conducted in schools provide Grade I evidence. # Fluoride Gel The quality of evidence for using fluoride gel to prevent and control dental caries in children is Grade I. However, data were gathered when dental caries was more prevalent and severe than today. Subjects in earlier studies were probably more representative of persons who now would be characterized as being at high risk for caries. # Fluoride Varnish The quality of evidence for the efficacy of high-concentration fluoride varnish in preventing and controlling dental caries in children is Grade I. Although the randomized controlled clinical studies that established Grade I evidence were conducted in Europe, U.S. results should be the same. # COST-EFFECTIVENESS OF FLUORIDE MODALITIES Documented effectiveness is the most basic requirement for providing a health-care service and an important prerequisite for preventive services (e.g., caries-preventive modalities). However, effectiveness alone is not a sufficient reason to initiate a service. Other factors, including cost, must be considered (254 ). A modality is more costeffective when deemed a less expensive way, from among competing alternatives, of meeting a stated objective (258 ). In public health planning, determination of the most cost-effective alternative for prevention is essential to using scarce resources efficiently. Dental-insurance carriers are also interested in cost-effectiveness so they can help purchasers use funds efficiently. Because half of dental expenditures are out of pocket (259 ), this topic interests patients and their dentists as well. Potential improvement to quality of life is also a consideration. The contribution of a healthy dentition to quality of life at any age has not been quantified, but is probably valued by most persons. Although solid data on the cost-effectiveness of fluoride modalities alone and in combination are needed, this information is scarce. In 1989, the Cost Effectiveness of Caries Prevention in Dental Public Health workshop, which was attended by health economists, epidemiologists, and dental public health professionals, attempted to assess the costeffectiveness of caries-preventive approaches available in the United States (260 ). All other things being equal, fluoride modalities are most cost-effective for persons at high risk for dental caries. Because persons at low risk develop little dental caries, limited benefit is gained by adding caries-preventive modalities to water fluoridation and fluoride toothpaste, even those demonstrated to be effective among populations at high risk. # MMWR August 17, 2001 Members of the CDC work group reached consensus regarding the populations for which each modality would be expected to have the necessary level of cost-effectiveness to warrant its use. # Community Water Fluoridation Health economists at the 1989 workshop on cost-effectiveness of caries prevention calculated that the average annual cost of water fluoridation in the United States was $0.51 per person (range: $0.12-$5.41) (260 ). In 1999 dollars, this cost would be $0.72 per person (range: $0.17-$7.62). Factors reported to influence the per capita cost included • size of the community (the larger the population reached, the lower the per capita cost); • number of fluoride injection points in the water supply system; • amount and type of system feeder and monitoring equipment used; • amount and type of fluoride chemical used, its price, and its costs of transportation and storage; and • expertise of personnel at the water plant. When the effects of caries are repaired, the price of the restoration is based on the number of tooth surfaces affected. A tooth can have caries at >1 location (i.e., surface), so the number of surfaces saved is a more appropriate measure in calculating costeffectiveness than the number of teeth with caries. The 1989 workshop participants concluded that water fluoridation is one of the few public health measures that results in true cost savings (i.e., the measure saves more money than it costs to operate); in the United States, water fluoridation cost an estimated average of $3.35 per carious surface saved ($4.71 in 1999 dollars) (260 ). Even under the least favorable assumptions in 1989 (i.e., cities with populations <10,000, higher operating costs, and effectiveness projected at the low end of the range), the cost of a carious surface saved because of community water fluoridation ranged from $8 to $12 ($11-$17 in 1999 dollars) (260 ), which is still lower than the fee for a one-surface restoration ($54 in 1995 or $65 in 1999 dollars † ) (261 ). A Scottish study conducted in 1980 reported that community water fluoridation resulted in a 49% saving in dental treatment costs for children aged 4-5 years and a 54% saving for children aged 11-12 years (262 ). These savings were maintained even after the secular decline in the prevalence of dental caries was recognized (263 ). The effect of community water fluoridation on the costs of dental care for adults is less clear. This topic cannot be fully explored until the generations who grew up drinking optimally fluoridated water are older. # School Water Fluoridation Costs for school water fluoridation are similar to those of any public water supply system serving a small population (i.e., <1,000 persons). In 1988, the average annual cost of school water fluoridation was $4.52 per student per year (range: $0.81-$9.72) (264 ). In 1999 dollars,* this cost would be $6.37 per person (range: $1.14-$13.69). Use of this modality must be carefully weighed in the current environment of low caries prevalence, widespread use of fluoride toothpaste, and availability of other fluoride modalities that can be delivered in the school setting. # Fluoride Toothpaste Fluoride toothpaste is widely available, no more expensive than nonfluoride toothpaste, and periodically improved. Use of a pea-sized amount (0.25 g) twice per day requires approximately two tubes of toothpaste per year, for an estimated annual cost of $6-$12, depending on brand, tube size, and retail source (265 ). Persons who brush and use toothpaste regularly to maintain periodontal health and prevent stained teeth and halitosis (i.e., bad breath) incur no additional cost for the caries-preventive benefit of fluoride in toothpaste. Because of its multiple benefits, most persons consider fluoride toothpaste a highly cost-effective caries-preventive modality. # Fluoride Mouthrinse Public health programs of fluoride mouthrinsing have long been presumed to be costeffective, especially when teachers can supervise weekly rinsing in classrooms at no direct cost to the program. In other programs, volunteers or hourly workers provide supervision. Under these circumstances, administrators of fluoride mouthrinsing programs have claimed annual program costs of approximately $1 per child ($1.41 in 1999 dollars) (264 ). This figure likely is an underestimate because indirect costs are not included (196,266 ). Fluoride mouthrinsing is a reasonable procedure for groups and persons at high risk for dental caries, but its cost-effectiveness as a universal, populationwide strategy in the modern era of widespread fluoride exposure is questionable (267 ). # Dietary Fluoride Supplements Dietary fluoride supplements prescribed to persons cost an estimated $37 per year. Fluoride supplements in school programs have direct costs of approximately $2.50 per child ($3.52 in 1999 dollars) for the tablet or lozenge (264 ); program administrative costs and considerations are similar to those in school mouthrinsing programs. # Professionally Applied Fluoride Compounds High-concentration fluoride gel and varnish are effective in preventing dental caries, but because application requires professional expertise, they are inherently more expensive than self-applied methods (e.g., drinking fluoridated water or brushing with fluoride toothpaste). For groups and persons at low risk for dental caries, professionally applied methods are unlikely to be cost-effective (268,269 ) (196 ). A Swedish study claimed that fluoride varnish was cost-effective, but few supporting data were presented (270 ). Varnish might be cost-effective in Scandinavian school dental services, in which dental professionals regularly examine and treat each student, but the cost-effectiveness of fluoride varnish in public health programs in the United States remains undocumented. Whether fluoride varnish or gel would be most efficiently used in clinical programs targeting groups at high risk for dental caries or should be reserved for individual patients at high risk is unclear. # Combinations of Fluoride Modalities Because the caries-preventive effects of a combination of fluoride modalities are only partially additive, estimates of the cost-effectiveness when adding a modality (e.g., fluoride mouthrinse for a group already drinking fluoridated water and using fluoride toothpaste) should take into account these smaller, incremental reductions in caries. This consideration is particularly relevant for groups and persons at low risk for caries (253 ). The scarcity of research on the cost-effectiveness of combinations limits the ability to draw more detailed conclusions. # RECOMMENDATIONS In developing the recommendations for specific fluoride modalities that address public health and clinical practice and self-care, the CDC work group considered the quality of evidence of each modality's effect on dental caries, its association with enamel fluorosis, and its cost-effectiveness. The strength of the recommendation for each fluoride modality was determined by the work group, which adapted a coding system used by the U.S. Preventive Services Task Force (Box 2). The work group considered these factors when determining the population for which each recommendation applies (Table 4 # BOX 2. Coding system used to classify recommendations for use of specific fluoride modalities to control dental caries # Code Criteria A Good evidence to support the use of the modality. # B Fair evidence to support the use of the modality. # C Lack of evidence to develop a specific recommendation (i.e., the modality has not been adequately tested) or mixed evidence (i.e., some studies support the use of the modality and some oppose it). # D Fair evidence to reject the use of the modality. # E Good evidence to reject the use of the modality. Source: US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Alexandria, VA: International Medical Publishing, 1996. # MMWR 25 group recognized that some recommendations can only be addressed by health-care industries or agencies and that additional research is required to resolve some questions regarding fluoride modalities. Before promoting a fluoride modality or combination of modalities, the dental-care or other health-care provider must consider a person's or group's risk for dental caries, current use of other fluoride sources, and potential for enamel fluorosis. Although these recommendations are based on assessments of caries risk as low or high, the healthcare provider might also differentiate among patients at high risk and provide more intensive interventions as needed. Also, a risk category can change over time; the type and frequency of preventive interventions should be adjusted accordingly. † Quality of evidence for targeting some modalities to persons at high risk is grade III (i.e., representing the opinion of respected authorities) and is based on considerations of costeffectiveness that were not included in the studies establishing efficacy or effectiveness. § Populations believed to be at increased risk for dental caries are those with low socioeconomic status or low levels of parental education, those who do not seek regular dental care, and those without dental insurance or access to dental services. Individual factors that possibly increase risk include active dental caries; a history of high caries experience in older siblings or caregivers; root surfaces exposed by gingival recession; high levels of infection with cariogenic bacteria; impaired ability to maintain oral hygiene; malformed enamel or dentin; reduced salivary flow because of medications, radiation treatment, or disease; low salivary buffering capacity (i.e., decreased ability of saliva to neutralize acids); and the wearing of space maintainers, orthodontic appliances, or dental prostheses. Risk can increase if any of these factors are combined with dietary practices conducive to dental caries (i.e., frequent consumption of refined carbohydrates). Risk decreases with adequate exposure to fluoride. ¶ No published studies confirm the effectiveness of fluoride supplements in controlling dental caries among persons aged >16 years. # MMWR August 17, 2001 Public Health and Clinical Practice # Continue and Extend Fluoridation of Community Drinking Water Community water fluoridation is a safe, effective, and inexpensive way to prevent dental caries. This modality benefits persons in all age groups and of all SES, including those difficult to reach through other public health programs and private dental care. Community water fluoridation also is the most cost-effective way to prevent tooth decay among populations living in areas with adequate community water supply systems. Continuation of community water fluoridation for these populations and its adoption in additional U.S. communities are the foundation for sound caries-prevention programs. In contrast, the appropriateness of fluoridating stand-alone water systems that supply individual schools is limited. Widespread use of fluoride toothpaste, availability of other fluoride modalities that can be delivered in the school setting, and the current environment of low caries prevalence limit the appropriateness of fluoridating school drinking water at 4.5 times the optimal concentration for community drinking water. Decisions to initiate or continue school fluoridation programs should be based on an assessment of present caries risk in the target school(s), alternative preventive modalities that might be available, and periodic evaluation of program effectiveness. # Counsel Parents and Caregivers Regarding Use of Fluoride Toothpaste by Young Children, Especially Those Aged <2 Years Fluoride toothpaste is a cost-effective way to reduce the prevalence of dental caries. However, for children aged <6 years, especially those aged <2 years, an increased risk for enamel fluorosis exists because of inadequately developed control of the swallowing reflex. Parents or caregivers should be counseled regarding self-care recommendations for toothpaste use for young children (i.e., limit the child's toothbrushing to <2 times a day, apply a pea-sized amount to the toothbrush, supervise toothbrushing, and encourage the child to spit out excess toothpaste). For children aged <2 years, the dentist or other health-care provider should consider the fluoride level in the community drinking water, other sources of fluoride, and factors likely to affect susceptibility to dental caries when weighing the risk and benefits of using fluoride toothpaste. # Target Mouthrinsing to Persons at High Risk Because fluoride mouthrinse has resulted in only limited reductions in caries experience among schoolchildren, especially as their exposure to other sources of fluoride has increased, its use should be targeted to groups and persons at high risk for caries (see Risk for Dental Caries). Children aged <6 years should not use fluoride mouthrinse without consultation with a dentist or other health-care provider because enamel fluorosis could occur if such mouthrinses are repeatedly swallowed. # Judiciously Prescribe Fluoride Supplements Fluoride supplements can be prescribed for children at high risk for dental caries and whose primary drinking water has a low fluoride concentration. For children aged <6 years, the dentist, physician, or other health-care provider should weigh the risk for caries without fluoride supplements, the caries prevention offered by supplements, and the potential for enamel fluorosis. Consideration of the child's other sources of fluoride, especially drinking water, is essential in determining this balance. Parents and caregivers should be informed of both the benefit of protection against dental caries and the possibility of enamel fluorosis. The prescription dosage of fluoride supplements should be consistent with the schedule established by ADA, AAPD, and AAP. Supplements can be prescribed for persons as appropriate or used in school-based programs. When practical, supplements should be prescribed as chewable tablets or lozenges to maximize the topical effects of fluoride. # Apply High-Concentration Fluoride Products to Persons at High Risk for Dental Caries High-concentration fluoride products can play an important role in preventing and controlling dental caries among groups and persons at high risk. Dentists and other health-care providers must consider the risk status and age of the patient to determine the appropriate intensity of treatment. Routine use of professionally applied fluoride gel or foam likely provides little benefit to persons not at high risk for dental caries, especially those who drink fluoridated water and brush daily with fluoride toothpaste. If FDA approves use of fluoride varnish to prevent and control dental caries, its indications for use will be similar to those of fluoride gel. Such varnishes have practical advantages for children aged <6 years at high risk. # Self-Care # Know the Fluoride Concentration in the Primary Source of Drinking Water All persons should know whether the fluoride concentration in their primary source of drinking water is below optimal, optimal, or above optimal. This knowledge is the basis for all individual and professional decisions regarding use of other fluoride modalities (e.g., mouthrinse or supplements). Parents and caregivers of children, especially children aged <6 years, must know the fluoride concentration in their child's drinking water when considering whether to alter the child's fluoride intake. For example, in nonfluoridated areas where the natural fluoride concentration is below optimal, fluoride supplements might be considered, whereas in areas where the natural fluoride concentration is >2 ppm, children should use alternative sources of drinking water. Knowledge of the water's fluoride concentration is also key in public policy discussions regarding community water fluoridation. # Frequently Use Small Amounts of Fluoride All persons should receive frequent exposure to small amounts of fluoride, which minimizes dental caries by inhibiting demineralization of tooth enamel and facilitating tooth remineralization. This exposure can be readily accomplished by drinking water with an optimal fluoride concentration and brushing with a fluoride toothpaste twice daily. place no more than a pea-sized amount (0.25 g) of toothpaste on the toothbrush, brush the child's teeth (recommended particularly for preschool-aged children) or supervise the toothbrushing, and encourage the child to spit excess toothpaste into the sink to minimize the amount swallowed. Indiscriminate use can result in inadvertent swallowing of more fluoride than is recommended. # Supervise Use of Fluoride Toothpaste Among Children Aged <6 Years # Consider Additional Measures for Persons at High Risk for Dental Caries Persons at high risk for dental caries might require additional fluoride or other preventive measures to reduce development of caries. This additional fluoride can come from daily use of another fluoride product at home or from professionally applied, topical fluoride products. Other preventive measures might include dental sealants and targeted antimicrobial therapies. Parents and caregivers should not provide additional fluoride to children aged <6 years without consulting a dentist or other health-care provider regarding the associated benefits and potential for enamel fluorosis. Persons should seek professional advice regarding their risk status or that of their children. # Use an Alternative Source of Water for Children Aged <8 Years Whose Primary Drinking Water Contains >2 ppm Fluoride In some regions in the United States, community water supply systems and home wells contain a natural concentration of fluoride >2 ppm. At this concentration, children aged <8 years are at increased risk for developing enamel fluorosis, including the moderate and severe forms, and should have an alternative source of drinking water, preferably one containing fluoride at an optimal concentration. In areas where community water supply systems contain >2 ppm but <4 ppm fluoride, EPA requires that each household be notified annually of the desirability of using an alternative source of water for children aged <8 years. For families receiving water from home wells, testing is necessary to determine the natural fluoride concentration. # Consumer Product Industries and Health Agencies # Label the Fluoride Concentration of Bottled Water Producers of bottled water should label the fluoride concentration of their products. Such labeling will allow consumers to make informed decisions and dentists, dental hygienists, and other health-care professionals to appropriately advise patients regarding fluoride intake and use of fluoride products. # Promote Use of Small Amounts of Fluoride Toothpaste Among Children Aged <6 Years Labels and advertisements for fluoride toothpaste should promote use of a pea-sized amount (0.25 g) of toothpaste on a child-sized toothbrush for children aged <6 years. Efforts to educate parents and caregivers and to encourage supervised use of fluoride toothpaste among young children can reduce inadvertent swallowing of excess toothpaste. # MMWR 29 # Develop a Low-Fluoride Toothpaste for Children Aged <6 Years Manufacturers are encouraged to develop a dentifrice for children aged <6 years that is effective in preventing dental caries but alleviates the risk for enamel fluorosis. A "child-strength" toothpaste with a fluoride concentration lower than current products could reduce the risk for cosmetic concerns associated with inadvertent swallowing of toothpaste. # Collaborate to Educate Health-Care Professionals and the Public Professional health-care organizations, public health agencies, and suppliers of oralcare products should collaborate to educate health-care professionals and trainees and the public regarding the recommendations in this report. Broad collaborative efforts to educate health-care professionals and the public and to encourage behavior change can promote improved, coordinated use of fluoride modalities. # Further Research Continue Metabolic Studies of Fluoride Metabolic studies with animals and humans to determine the influence of environmental, physiological, and pathological conditions on the pharmacokinetics and effects of fluoride should continue. Research in these areas will enhance the knowledge base concerning fluoride use, thereby resulting in more effective and efficient use of fluoride. # Identify Biomarkers of Fluoride As an alternative to direct fluoride intake measurement, biomarkers (i.e., distinct biological indicators) should be identified to estimate a person's fluoride intake and the amount of fluoride in the body. Identification of such biomarkers could allow more efficient research. # Reevaluate the Method of Determining Optimal Fluoride Concentration of Community Drinking Water The current method of determining the optimal concentration of fluoride in community drinking water, which depends on the average maximum annual ambient air temperature, should be reevaluated because of the social and environmental changes that have occurred since it was adopted in 1962. Research into current consumption patterns of water, processed beverages, and processed foods is also needed. Such research will either validate the current method for determining optimal fluoride concentration in community drinking water or indicate improved methods. # Evaluate the Effect of Fluoride Mouthrinse, Fluoride Supplements, and Other Fluoride Modalities on Dental Caries Additional clinical trials are needed to evaluate the current effect of fluoride mouthrinse, supplements, and other modalities on dental caries both individually and in combination. Cohorts of particular interest are groups and persons at high risk for dental caries, including older adults (i.e., those aged >50 years). Such research, as well as studies to determine the effects of new fluoride modalities and various combinations among groups and persons at high risk, could lead to more effective and efficient use of these interventions. # MMWR August 17, 2001 # Study the Current Cost-Effectiveness of Fluoride Modalities The increasing availability of multiple fluoride modalities and the lower caries prevalence in the United States indicate a need for current cost-effectiveness studies of fluoride modalities, especially logical combinations of regimens in populations with different caries risks. Such research will allow both more efficient use of resources and a better understanding of the additive effects of combined modalities. # Conduct Descriptive and Analytic Epidemiologic Studies Descriptive and analytic epidemiologic studies should be conducted to determine the association between dental caries and fluoride exposure from several sources, as well as the current role of community water fluoridation in preventing coronal and root caries among adults. Studies should assess the effect of interruption or discontinuation of water fluoridation; the prevalence of fluorosis associated with different patterns of fluoride use and intake among various populations; and the relationship between objectively measured fluorosis and the aesthetic perceptions of persons, parents, and dentists and other health-care professionals. Studies are needed to refine methods of caries risk assessment. As appropriate, studies should use national, state, and local data. Research addressing these questions will improve understanding of the relationships between fluoride modalities and the benefits and unintended effects of their use. # Identify Effective Strategies to Promote Adoption of Recommendations for Using Fluoride Effective strategies should be identified to promote adherence by parents, caregivers, children, adults, and health-care providers to recommendations regarding fluoride use. Such research could result in more effective behavior change, more efficient use of resources, improved caries prevention, and less enamel fluorosis. # CONCLUSION When used appropriately, fluoride is a safe and effective agent that can be used to prevent and control dental caries. Fluoride has contributed profoundly to the improved dental health of persons in the United States and other countries. Fluoride is needed regularly throughout life to protect teeth against tooth decay. To ensure additional gains in oral health, water fluoridation should be extended to additional communities, and fluoride toothpaste should be used widely. Adoption of these and other recommendations in this report could lead to considerable savings in public and private resources without compromising fluoride's substantial benefit of improved dental health. # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 2.0 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.2 Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.6 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 MMWR August 17, 2001 # GOAL AND OBJECTIVES This MMWR provides recommendations regarding the use of fluoride to prevent and control dental caries in the United States. These recommendations were prepared by CDC staff members and a work group of specialists in fluoride research or policy. This goal of this report is to increase appropriate use of fluoride modalities in preventing and controlling dental caries through improved professional understanding and practice. Upon completion of this continuing educational activity, the reader should be able to a) list the factors used in the decision to prescribe fluoride supplements; b) describe the recommendations for counseling patients on the use of fluoride products in oral self-care practices, especially for children aged <6 years; c) list the sources for determining the current level of fluoride delivered by a community water system; d) identify the factors used to assess caries risk; e) explain how fluoride prevents dental caries; f) describe the recommendations for choosing the appropriate fluoride modalities for patients; and g) list the risk factors for enamel fluorosis. To receive continuing education credit, please answer all of the following questions. # MMWR The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on	None	None
ef5472e8ea287380c81804c2cfa5b711cefae2a1	cdc	None	# Introduction Congenital syphilis causes fetal or perinatal death in 40% of the infants affected. The condition was well described in the 15th century and has long been recognized as a distinct syndrome in which the source is an infected adult. Several theories have been advanced to explain how the infection is transmitted, including transmission from a father infected with syphilis and transmission from an infant' s nursing an infected wet nurse. Transplacental transmission from an asymptomatic infected mother was first described in 1906. The availability of penicillin treatment for syphilis in pregnancy has not eradicated con genital syphilis. Since 1970, the incidence of congenital syphilis has closely reflected the incidence of primary and secondary syphilis in women. In 1986, more cases of congenital syphilis (365) were reported to the Division of Sexually Transmitted Diseases, Center for Prevention Services, CDC, than for any of the previous 15 years. That year almost one of every 10,000 live-born infants in the United States had congenital syphilis. The proportion of stillbirths caused by syphilis is unknown. In July 1987, CDC invited 10 consultants- to discuss the problem of congenital syphilis and to determine possible ways to solve the problem. This supplement to the Morbidity and Mortality Weekly Report (MMWR) presents guidelines that were developed from discussions with these consultants. Efforts were made to balance the ideal with the feasible, promoting a focused and coordinated source of guidance for health care providers. Although some aspects of the guidelines are based on limited data, the information provided here represents the best judgment of experts. # Surveillance Congenital syphilis surveillance should be conducted at the local, state, and national levels. The provisional case definition includes every infant (person <12 months of age) with one of the following: 1) a reactive nontreponemal serologic test for syphilis confirmed by a reactive treponemal test, 2) a positive darkfield microscopic examination on a non-oral mucous membrane, or 3) a positive fluorescent antibody examination for Treponema pallidum on any lesion. Physicians, clinics, and hospitals should report all cases that meet the provisional definition to the local public health authority. Laboratories should report indicative findings to the same authority. All areas that have five or more women with early infectious syphilis (infection of <1 year' s duration) per 100,000 population should establish an active surveillance system for congenital syphilis at key hospitals. At a minimum, hospitals in areas with a high incidence of syphilis or that serve patient populations known to be at increased risk for syphilis should perform routine serologic tests for syphilis (STS) using blood samples from the umbilical cord. All cases that are classified as "confirmed" or "compatible" or that require additional information to be classified should be reported to the state public health authority (see definitions of case classifications below). These initial reports identify problem areas and ensure appropriate follow-up at the state level. Later, a Congenital Syphilis Follow-up Form, CDC 73.126, should be completed and forwarded through the local and state public health authorities to the Division of Sexually Transmitted Diseases, CDC, for all infants (including stillborns) who have not been classified as "unlikely." Cases that cannot be classified with reasonable assurance (e.g., they are lost to follow-up) should also be described as fully as possible on the form CDC 73.126. The surveillance information documented on the form is used to determine why the particular case occurred and to identify trends. Completion of these forms enables investigators to measure the occurrence of congenital syphilis. All forms CDC 73.126 should be completed by the time an infant reaches 8 months of age, including forms for cases lost to follow-up. For surveillance purposes, stillbirths also should be evaluated for syphilis, and those with a diagnosis consistent with congenital syphilis should be documented on the form CDC 73.126 through local and state public health authorities in the same manner as live births. # Diagnostic Classifications of Congenital Syphilis Confirmed case - identification of T. pallidum by darkfield microscopy, fluorescent antibody, or other specific stains in specimens from lesions, autopsy material, placenta, or umbilical cord # OR - no symptoms in live-born infant whose mother, treated for syphilis during pregnancy, had a fourfold or greater fall in titer and the infant' s STS is also fourfold or lower than the maternal titer was at the time of treatment Two other aspects of surveillance for congenital syphilis warrant emphasis. First, a sensitive system is needed by which state and local sexually transmitted diseases (STD) control programs are made aware of reactive STS. The programs should evaluate and follow indi vidual reactive serologic test reports and should monitor the reporting patterns of laboratories and diagnosticians. Furthermore, a quality assurance system is needed to confirm that all medical laboratories performing tests for STD are complying with official reporting regula tions. Compliance should be checked by letter, telephone, or personal visit at least every 6 months. Second, state health departments should maintain a central registry of patients who receive treatment for syphilis. Each patient' s record should include specific information about the stage of disease, the type(s) and amount(s) of medication administered, the types and results of laboratory tests, and, if the patient is pregnant, the trimester during which she is treated. This information is essential for the proper medical management of pregnant women, their fetuses, and their infants. Strict confidentiality and data security procedures must be estab lished, periodically reviewed, and independently tested to ensure that registry information is neither misused nor unintentionally revealed to unauthorized persons. # 3, Control The control of early infectious syphilis is essential for the control of congenital syphilis. When the prevalence of infectious syphilis substantially increases among reproductive-age women, cases of congenital syphilis very likely will follow. Increased prevalence has been observed in several areas of the United States in recent years. To prevent future cases of congenital syphilis, STD control programs need to place more emphasis on early syphilis control, especially in areas with a high incidence. # D isease Intervention A ctivities for Early Infectious Syphilis The traditional "tools" of early syphilis control in the United States include an original - " Fourfold rise in titer," "fourfold fall in titer," and other similar phrases are used throughout this document. They refer to changes (up or down) in serum titers of at least two dilutions (two "tubes"), e.g., from 1:2 to 1:8 (and the reverse), or from 1:4 to 1:16 (and the reverse), or from 1:32 to 1:8 (and the reverse). interview of the patient to elicit information on sex partners, rapid notification of partners, selective reinterviews, and selected "clustering" around the patient and his/her examined sex partners to obtain information on other persons who may be at risk of infection. Recom mended techniques, methods, and procedures are discussed in the disease intervention courses sponsored by the Division of Sexually Transmitted Diseases. # Specific A ctivities for State and Local S T D C ontrol Program s for the Prevention o f Congenital Syphilis - Ensure that official public health statutes and/or regulations mandate STS on all pregnant women at the time of the initial prenatal visit and early in the third trimester. - Monitor public and private laboratories regularly to ensure the prompt and thorough reporting of reactive STS. - Assess the pregnancy status of women with diagnosed syphilis and of women who are the sex partners of men with diagnosed syphilis. - Ask early infectious syphilis patients or their unexamined sex partners who reside in neighborhoods with a high incidence of syphilis to identify women in the area who may be pregnant. Refer all identified women for serologic testing and prenatal care. - Inform every woman of reproductive age who is seen in an STD clinic (for any reason) about the need for prenatal care and STS in future pregnancies. - Encourage prenatal screening for syphilis wherever pregnant women are seen for health care, including women, infants, and children (WIC) programs, methadone maintenance clinics, detention facilities, and prenatal care facilities; whenever possible, review existing clinic protocols and suggest specific amendments to the clinic medical director. - Conduct selective serologic screening of women of childbearing age in groups with an increased risk of infection, e.g., women residing in neighborhoods that have a particularly high incidence of syphilis. - Deliver educational messages to the medical community about laboratory tests, diag nostic criteria, treatment, and follow-up of patients who are at risk of infection and who may be pregnant. - Develop and disseminate public service educational messages to women who share demographic characteristics with the women most often diagnosed with early syphilis. In many areas of the United States, these women are young, single, members of a minority group, and residents of a central city neighborhood. Brief, well-targeted radio announce ments in the language and vernacular of the audience may be particularly effective. # STD Program Priorities Although no published studies have evaluated the benefit-to-cost ratio in controlling early syphilis by using the traditional method (see section 3.1) versus less laborious and timeconsuming methods, the former has been a mainstay of most STD control programs in the United States for many years. The traditional syphilis-intervention process requires time, commitment, and human resources, and -like other public health strategies -it should be periodically assessed by state and local STD programs for its benefits and costs. In an era of increasing demands for public health resources, the relative effectiveness of the traditional process should be compared with that of less vigorous methods in areas of both high and low syphilis incidence. A thorough initial interview that includes obtaining information on the patient' s sex partners (names and addresses) usually takes at least 45 minutes. In areas with an increased incidence of syphilis, clinic procedures and flow patterns may need to be restructured to accommodate this essential time requirement. # O th er C o nsiderations The interrelationship of syphilis and human immunodeficiency virus (HIV) infection should be explored in areas with a high incidence of syphilis. HIV infection may influence the manifestation of syphilis or its response to therapy. The role, if any, of the genital ulcers of syphilis in increasing the risk of HIV transmission also needs study in U.S. population groups. State and local STD programs need to coordinate control resources for both syphilis and HIV, offer STS to all women requesting HIV tests, and perform periodic syphilis tests on all persons known to be HIV-antibody positive. # Prenatal Care Comprehensive prenatal care started early in pregnancy is essential in preventing con genital syphilis. Unfortunately, many obstacles make it difficult for women, particularly some poor and some minority women, to obtain needed care. These obstacles include financial barriers, the limited availability of health care providers who are willing to serve these populations, provider difficulty in communicating with patients who are poor or from different ethnic backgrounds, organizational arrangements that minimize accessibility and accept ability of treatment, poor coordination of services, and patients' inadequate understanding of the need for care. Any modifications of the present system that would reduce these obstacles would also improve the opportunities for women with syphilis to receive care. Additional specific strategies are needed to encourage the use of prenatal care by women who may be at increased risk of transmitting syphilis to their fetus, to ensure that these women are adequately screened, and to maintain follow-up. These strategies include targeted out reach efforts, coordination of activities among service providers, and special prenatal care components. # S T D C ontrol Program s STD control programs should institute special prenatal outreach programs for patients who are at risk for syphilis. All women of childbearing age who come to STD clinics should be asked the date of their last menstrual period. If they have not had a period in the previous 6 weeks, and if their periods are usually regular, they should be tested for pregnancy as soon as possible, preferably on site. If on-site pregnancy testing is not available, STD clinic personnel should make an appointment for the patient at a facility that can do the testing with minimum delay. An RPR card test should be performed routinely on all patients at STD clinics; the laboratory forms of pregnant patients should be "flagged" for priority processing. All pregnant patients, regardless of the results of the RPR, should be referred for prenatal care. If the RPR test is reactive, however, arrangements should be made immediately to institute appropriate treatment, sex partner referral, and prenatal care. State and local STD programs should arrange with prenatal care providers to treat women with reactive syphilis tests as medical emergencies. Such women should be given the highest priority for prenatal care, particularly at clinics with waiting lists. If the woman reports normal menses, or the pregnancy January 15, 1988 test is negative, she should be informed about the availability of family planning services and about the potential hazards to a fetus caused by STD, cigarette smoking, alcohol, and drugs. Patients with early infectious syphilis should be interviewed to identify their recent sexual partners. Women who are so identified should receive the highest priority for referral for treatment and, if pregnant, for enrollment in effective prenatal care. Patients with early infectious syphilis who live in high-incidence neighborhoods should also be asked to identify friends, associates, and family members who might be pregnant (see section 3.2). Outreach workers should contact these women, explain to them that syphilis is a potential problem in their community, offer them a test for syphilis, and assist them in enrolling in a prenatal care facility. Pregnant women with a reactive STS should receive the highest priority for treatment and prenatal care. STD program managers need to develop management systems that track and measure the outreach activities focused on pregnant patients and their prenatal care. # .2 D rug A ddiction Program s All women of childbearing age who come to clinics for drug addiction should also be asked the date of their last menstrual period, and the same procedures should be followed as those described for STD clinics, including on-site pregnancy testing. If the test is positive, an on-site RPR should be performed and referral made for prenatal care. Patients should also be informed about the availability of family planning services and potential fetal damage caused by STD, cigarette smoking, alcohol, and drugs. # .3 P regnancy Testing Sites All sites that provide pregnancy testing should be alerted to their responsibility for preventing congenital syphilis. If a woman has a positive pregnancy test, an RPR card test should be done immediately and on site. If the RPR is reactive, the same procedures should be followed as those described for STD clinics. Special attention should be paid to obtaining accurate addresses for use by the local STD intervention specialist. All sites that provide pregnancy testing should follow these procedures, including family planning clinics, school-based clinics, adolescent health clinics, hospital emergency rooms and outpatient clinics, and detention facilities. # Prenatal Care Sites Women must often wait several weeks for their first prenatal appointment because of overcrowded schedules and delays in determining Medicaid eligibility. Since a delay may reduce the likelihood of successful treatment if syphilis is identified, efforts should be made to test women early in pregnancy, possibly during a visit for laboratory tests. If syphilis is diagnosed, treatment and counseling should be started before the regularly scheduled prenatal care visit. # .5 C ontent o f Care Prenatal care providers are responsible for ensuring that their pregnant patients are tested for syphilis and for coordinating their activities with those of the local STD program so that infected women will receive treatment promptly. Recommended activities for prenatal care providers include: - Obtaining maternal blood for serologic testing at the first visit unless the results of a previous test during the current pregnancy are available. A second STS should be performed at the beginning of the third trimester (28 weeks). - Providing each patient with a card identifying what test was performed, the date it was done, the result, what treatment (if any) was given, and the clinic' s name and telephone number. - Maintaining a list, arranged by date of test and patient' s name, of the results of the STS. Entries should be maintained for 1 year after the pregnancy is terminated. Prenatal care providers are responsible for determining the serologic status of their patients. Providers either should obtain the specimen or should document that a nonreactive test was obtained earlier in the pregnancy. The patient-borne record of STS and reactive results will assist in this documentation. - Identifying specimens from pregnant women by clearly labeling the laboratory slips "prenatal." Reactive tests should be followed by the STD program as part of an ongoing surveillance activity (see section 2). - " Flagging" the charts of clients whose serologic tests are reactive. Charts should remain flagged until the patient returns to the clinic. If the patient does not return or respond to routine notification, the local health department should be informed and referral services requested. - Instructing pregnant patients who may not be involved in mutually monogamous rela tionships to insist that their sex partners use condoms during the full term of the pregnancy. - Providing monthly quantitative nontreponemal serologic tests for the remainder of the current pregnancy of women who have been treated for early syphilis. Women who show a fourfold rise in titer should be retreated. Treated women who do not show a fourfold decrease in titer within 3 months should be retreated. After delivery, follow-up should be conducted as outlined for nonpregnant patients. - Testing all patients for syphilis (RPR or VDRL) 1 month after they have completed treatment for any other STD diagnosed during pregnancy. # .6 M on ito rin g P erfo rm an ce The responsibility for monitoring the system of services for preventing congenital syphilis should rest with the state or local STD control program. Since personnel and priorities of the multiple programs involved in preventing congenital syphilis will change overtime, a tracking system to monitor performance and the changes in service delivery should be established and maintained. # Laboratory Tests The usefulness of laboratory tests in the diagnosis of syphilis depends upon the selection of appropriate standard tests, listed below. The quality of such tests depends upon the use of quality reagents by well-trained personnel. Laboratories and the staff performing laboratory tests should be under strict quality control procedures and should participate regularly in performance evaluation and quality assurance programs. # Laboratory Tests for Syphilis # Syphilis in Pregnancy # M aternal Serologies tP^inn If- h h°k ldbe Perf°rmed at the be9innin9 of prenatal care and at delivery. Intermediate P . e ©ginning of the third trimester (28 weeks) should also be routine for high-risk p a ions, eroreactive women must be evaluated promptly. This evaluation should include a is ory and physical examination, a quantitative nontreponemal test, and a confirmatory Despite possible false-positive results in nontreponemal and treponemal tests, expectant mothers should be treated if 1) they have a reactive STS and 2) a prompt and thorough evaluation of the cause of the seroreactivity cannot be ensured. Special tests that include deoxyribonucleic acid (DNA) and Reiter absorptions for the fluorescent treponemal antibody (FTA) test eliminate most of the false-positive results. These tests can be performed by the Sexually Transmitted Diseases Laboratory Program, Center for Infectious Diseases, CDC, upon request from a reference laboratory. Delay in the presumptive treatment of a seroreactive pregnant woman, however, should never be allowed to exceed 4 weeks. If a patient has a reactive nontreponemal test (e.g., VDRL), a nonreactive treponemal test (e.g., microhemagglutination assay for antibody to T. pallidum ), and no clinical or epidemiologic evidence of syphilis, no treatment is necessary. Both the quantitative non treponemal test and the confirmatory test should be repeated within 4 weeks. If clinical or serologic evidence of syphilis is found, or if the diagnosis of syphilis cannot be excluded with reasonable certainty, the patient should be treated as outlined below (section 6.2.3). In pregnancy, nontreponemal test titers tend to increase nonspecifically. This tendency causes difficulty in distinguishing between antibodies due to reinfection and antibodies remaining from an earlier treated infection. Patients who have been adequately treated for syphilis in the past and who have documen tation of their treatment need not be retreated unless clinical, serologic, or epidemiologic evidence of reinfection exists, e.g., darkfield-positive lesions, a sustained (for > 2 weeks) fourfold titer rise in a quantitative nontreponemal test, or a history of recent sexual exposure to a person with early infectious syphilis. # Treatm ent in P regnancy # Data Limitations In the past 20 years, no major clinical trials have involved the currently recommended treatments for syphilis in pregnant patients. Thus, public health personnel cannot determine whether a decrease in therapeutic efficacy has occurred with these treatment regimens. However, individual failures of treatment (i.e., the occurrence of congenital syphilis in an infant whose mother was treated) have been reported. Although denominator data would be neces sary for failure rates to be calculated, the reports nonetheless suggest the need to modify treatment strategies for pregnant women who have syphilis. For instance, the available data suggest that treatment with the currently recommended erythromycin regimen is associated with an unacceptably high failure rate. The treatment efficacy with any regimen varies with the stage of maternal infection and with the stage of pregnancy. Available data indicate that the rate of treatment failure may be significantly higher among women with secondary syphilis and among women treated in the last trimester of pregnancy. The physiologic variables associated with pregnancy or placental transfer mechanisms may be quantitatively more important during the last trimester of pregnancy, and the organism load may be higher during the secondary stage of syphilis. # Treatment of Choice for Syphilis in # Penicillin-Allergic Patients Penicillin may be given to pregnant women with syphilis even if they have a history of penicillin allergy provided 1) their skin-test reactions to the major and minor penicillin deter minants are negative or 2) their skin tests are positive but they are then desensitized to penicillin. Patients can be desensitized and then given standard dosages of this antibiotic. Penicillin desensitization can be accomplished by giving the patient gradually increasing oral- or intravenous penicillin doses over a period of 3-4 hours until full tolerance occurs. The intravenous desensitizing route has an advantage in that the penicillin can be stopped immediately if an allergic reaction develops; reactions, however, occur more frequently during intravenous desensitization. Desensitization should be done in consultation with an expert and only in facilities where emergency procedures are available, such as in a hospital. *One oral desensitizing regimen given to pregnant patients used penicillin V. The starting dose was 100 units and was increased every 15 minutes. The final cumulative dose was 1,296,700 units given over a period of 3-4 hours. These patients were hospitalized and an intravenous line was established, but no premedications were used. A contingency plan, which was not needed, was to repeat the last dose or abandon the procedure if a serious reaction developed (N Engl J Med 1985;312:1229-32). -r silver stains. Specimens from the placenta and umbilical cord should be microscopically examined for those infants born to mothers with reactive serologic results, when no histories are available, or when the placenta is hydropic. Additionally, all neonatal lesions should be examined for treponemes. Treponemes seen in lesion material or in autopsy or biopsy sections by silver stain or darkfield, although considered definitive, may be confused in endemic areas with the Borrelia of Lyme disease. Maternal nontreponemal serology may be used to differentiate Lyme disease from syphilis. The VDRL is uniformly nonreactive in Lyme disease. An effort should be made to diagnose congenital syphilis in a stillborn whenever clinical findings or a maternal history suggests the possibility of untreated syphilis. Direct and histologic microscopic examinations of placenta, organs, and umbilical cord, as well as radiographic examinations of long bones, are helpful in postmortem diagnosis. The MHA-TP test can be used on the blood of a stillborn; blood can be obtained by direct cardiac puncture. # Radiography All infants delivered of women with a reactive STS who were not treated before pregnancy or before 20 weeks' gestation should be fully evaluated. The evaluation should include an examination of the long bones for osteochondritis, osteitis, and periostitis. # Cerebrospinal Fluid Analysis Infants delivered of women with a reactive STS should have a cerebrospinal fluid (CSF) evaluation in any of the following circumstances: - the infant shows any signs compatible with congenital syphilis # OR - maternal therapy was inadequate, unknown, or it occurred late 20 weeks) in preg nancy OR - maternal therapy did not include penicillin OR - adequate follow-up cannot be ensured Other living infants with a diagnosis of confirmed or compatible (see definitions in section 2) congenital syphilis should have a CSF examination before treatment to provide a baseline for follow-up examination. Although the importance of the CSF examination is debated, a quan titative VDRL CSF test can be meaningful if it is done in conjunction with tests for elevated total protein and lymphocyte count. The RPR card test should not be used for CSF evaluation. Regardless of CSF results, however, all children with a diagnosis of confirmed or compatible congenital syphilis should be treated with a regimen effective for neurosyphilis. # N eo n atal Treatm ent Although no recent comprehensive and comparative data on the treatment of neonates are available, several case reports of apparent treatment failure in infants treated with benzathine penicillin have been published. Available data clearly identify an obligation to evaluate neo nates adequately to determine whether they have occult active infection. The most appropri ate approach to active infection requires the use of a 10-day regimen of crystalline or procaine penicillin rather than benzathine penicillin. All patients with neurosyphilis must be carefully monitored with periodic serologic testing, clinical evaluation at 6-month intervals, and repeat CSF examinations for at least 3 years. The possibility of reinfection should always be considered when patients with early syphilis are being retreated. A CSF examination should be performed before retreatment unless reinfection and a diagnosis of early syphilis can be established. Retreatment should be considered when: - clinical signs or symptoms of syphilis persist or recur # OR - a sustained fourfold increase occurs in the titer of a nontreponemal test # OR - an initially high-titer nontreponemal test fails to decrease fourfold within a year Patients should be retreated with the regimens recommended for syphilis of more than 1 year' s duration. Tetracycline is not recommended for pregnant women because of potential adverse effects on the fetus. Erythromycin treatment of syphilis during pregnancy is generally discouraged, should be considered only for patients who have documented evidence of penicillin allergy (skin test or anaphylaxis history) and who are not candidates for penicillin desensitization. Clinicians choosing erythromycin treatment have a weighty responsibility for close clinical follow-up of both the mother and fetus to assess the possibilities of treatment failure. # Maternal Treatment Follow-up - Pregnant women who have been treated for early syphilis should have monthly quan titative nontreponemal serologic tests for the remainder of their pregnancy. - Women who show a fourfold rise in titer should be retreated. - Treated women who do not show a fourfold decrease in titer in a 3-month period should be retreated. - After delivery, follow-up is the same as for nonpregnant patients. # Needed Studies Well-designed studies on the treatment of pregnant women who have syphilis are clearly needed. The more urgent topics include: - the transplacental pharmacokinetics of penicillin and other antibiotics; - treatment efficacy and a continuing analysis of treatment-failure cases with currently recommended regimens;°- a treatment regimen consisting of benzathine penicillin G followed by for cunhii'H j mpiCI In anc- Pr°b enecid, or high-dose amoxicillin/ampicillin and probenecid trimester dUnn9 pre9nancy' esPecial\|y for secondary syphilis encountered in the last S eneCidrfaS ,an. ac^unc- t0 current penicillin treatment regimens to augment their efficacy, particularly for secondary syphilis in late pregnancy; and - the role of infection with HIV in cases of prenatal syphilis treatment failure. # Syphilis in the Fetus and Neonate # Diagnostic Evaluation # Neonatal Serologic Tests for Syphilis Serum from the infant is preferred for both nontreponemal and confirmatory tests, since umbilical cord blood may produce false-positive results. After delivery and/or treatment, serial specimens are used to follow efficacy of treatment or degradation of transplacentally acquired maternal antibody. When laboratory methods become generally available for fetal/neonatal specific immune globulin (IgM) treponemal determinations, serum will be the specimen of choice. Carefully controlled field trials will need to be conducted to provide guidance for their use in clinical practice. # Microscopic Evaluation The placenta and the umbilical cord may serve as excellent sites for the collection o specimens that can be examined by darkfield microscopy, immunofluorescence, H & E stains, # Recommended Regimens for Symptomatic or Asymptomatic Infants Aqueous crystalline penicillin G 50,000 units/kg IM or IV daily in two divided doses for a minimum of 10 days OR Aqueous procaine penicillin G 50,000 units/kg IM daily for a minimum of 10 days. For asymptomatic infants whose mothers were treated adequately with a penicillin regimen during pregnancy, treatment is not necessary if follow-up can be ensured. For asymptomatic infants whose mothers were treated adequately with a penicillin regimen during pregnancy but whose follow-up cannot be ensured, many consultants recommend treatment with benzathine penicillin 50,000 units/kg IM in a single dose. Data on the efficacy of this regimen in congenital neurosyphilis are lacking; therefore, if neurosyphilis cannot be excluded, the 10-day regimens of aqueous crystalline penicillin or procaine penicillin are recommended. Only penicillin regimens are recommended for neonatal congenital syphilis. # N eonatal Follow-up In accordance with the guidelines of the American Academy of Pediatrics, follow-up for all infants should be incorporated into routine newborn care at 1,2,4,6, and 12 months. Serologic tests should be performed until they become nonreactive. Patients with persistent, stable, low titers should be considered candidates for retreatment. Treated infants should be similarly followed, with a CSF examination at 6-month intervals until the examination becomes non reactive. A reactive CSF VDRL at 6 months is an indication for retreatment. # Long-term Follow-up and Retreatment Penicillin dosages for congenital syphilis after the neonatal period remain the same as ose recommended for neonatal congenital syphilis. For larger children, the total amount of penicillin given should not exceed the dosage used in adult syphilis of more than 1 year' s duration. After the neonatal period, the dosage of tetracycline for congenital syphilis in patients who are allergic to penicillin should be individualized, but these dosages need not exceed those used in adult syphilis of more than 1 year' s duration. Tetracycline should not be given to children <8 years of age. A thorough developmental evaluation should be done during the third year of life (age 2) on all children treated in infancy who were symptomatic at birth or had active congenital infection. All patients with early syphilis or congenital syphilis should be encouraged to return for repeat quantitative nontreponemal tests at least 3,6, and 12 months after treatment. In these patients, quantitative nontreponemal test titers will decline to nonreactive or low titer reactive within a year following successful treatment with penicillin. Serologic test results decline more slowly in patients treated for disease of longer duration. Patients with syphilis of more than	# Introduction Congenital syphilis causes fetal or perinatal death in 40% of the infants affected. The condition was well described in the 15th century and has long been recognized as a distinct syndrome in which the source is an infected adult. Several theories have been advanced to explain how the infection is transmitted, including transmission from a father infected with syphilis and transmission from an infant' s nursing an infected wet nurse. Transplacental transmission from an asymptomatic infected mother was first described in 1906. The availability of penicillin treatment for syphilis in pregnancy has not eradicated con genital syphilis. Since 1970, the incidence of congenital syphilis has closely reflected the incidence of primary and secondary syphilis in women. In 1986, more cases of congenital syphilis (365) were reported to the Division of Sexually Transmitted Diseases, Center for Prevention Services, CDC, than for any of the previous 15 years. That year almost one of every 10,000 live-born infants in the United States had congenital syphilis. The proportion of stillbirths caused by syphilis is unknown. In July 1987, CDC invited 10 consultants* to discuss the problem of congenital syphilis and to determine possible ways to solve the problem. This supplement to the Morbidity and Mortality Weekly Report (MMWR) presents guidelines that were developed from discussions with these consultants. Efforts were made to balance the ideal with the feasible, promoting a focused and coordinated source of guidance for health care providers. Although some aspects of the guidelines are based on limited data, the information provided here represents the best judgment of experts. # Surveillance Congenital syphilis surveillance should be conducted at the local, state, and national levels. The provisional case definition includes every infant (person <12 months of age) with one of the following: 1) a reactive nontreponemal serologic test for syphilis confirmed by a reactive treponemal test, 2) a positive darkfield microscopic examination on a non-oral mucous membrane, or 3) a positive fluorescent antibody examination for Treponema pallidum on any lesion. Physicians, clinics, and hospitals should report all cases that meet the provisional definition to the local public health authority. Laboratories should report indicative findings to the same authority. All areas that have five or more women with early infectious syphilis (infection of <1 year' s duration) per 100,000 population should establish an active surveillance system for congenital syphilis at key hospitals. At a minimum, hospitals in areas with a high incidence of syphilis or that serve patient populations known to be at increased risk for syphilis should perform routine serologic tests for syphilis (STS) using blood samples from the umbilical cord. All cases that are classified as "confirmed" or "compatible" or that require additional information to be classified should be reported to the state public health authority (see definitions of case classifications below). These initial reports identify problem areas and ensure appropriate follow-up at the state level. Later, a Congenital Syphilis Follow-up Form, CDC 73.126, should be completed and forwarded through the local and state public health authorities to the Division of Sexually Transmitted Diseases, CDC, for all infants (including stillborns) who have not been classified as "unlikely." Cases that cannot be classified with reasonable assurance (e.g., they are lost to follow-up) should also be described as fully as possible on the form CDC 73.126. The surveillance information documented on the form is used to determine why the particular case occurred and to identify trends. Completion of these forms enables investigators to measure the occurrence of congenital syphilis. All forms CDC 73.126 should be completed by the time an infant reaches 8 months of age, including forms for cases lost to follow-up. For surveillance purposes, stillbirths also should be evaluated for syphilis, and those with a diagnosis consistent with congenital syphilis should be documented on the form CDC 73.126 through local and state public health authorities in the same manner as live births. # Diagnostic Classifications of Congenital Syphilis Confirmed case • identification of T. pallidum by darkfield microscopy, fluorescent antibody, or other specific stains in specimens from lesions, autopsy material, placenta, or umbilical cord # OR • no symptoms in live-born infant whose mother, treated for syphilis during pregnancy, had a fourfold or greater fall in titer and the infant' s STS is also fourfold or lower than the maternal titer was at the time of treatment Two other aspects of surveillance for congenital syphilis warrant emphasis. First, a sensitive system is needed by which state and local sexually transmitted diseases (STD) control programs are made aware of reactive STS. The programs should evaluate and follow indi vidual reactive serologic test reports and should monitor the reporting patterns of laboratories and diagnosticians. Furthermore, a quality assurance system is needed to confirm that all medical laboratories performing tests for STD are complying with official reporting regula tions. Compliance should be checked by letter, telephone, or personal visit at least every 6 months. Second, state health departments should maintain a central registry of patients who receive treatment for syphilis. Each patient' s record should include specific information about the stage of disease, the type(s) and amount(s) of medication administered, the types and results of laboratory tests, and, if the patient is pregnant, the trimester during which she is treated. This information is essential for the proper medical management of pregnant women, their fetuses, and their infants. Strict confidentiality and data security procedures must be estab lished, periodically reviewed, and independently tested to ensure that registry information is neither misused nor unintentionally revealed to unauthorized persons. # 3, Control The control of early infectious syphilis is essential for the control of congenital syphilis. When the prevalence of infectious syphilis substantially increases among reproductive-age women, cases of congenital syphilis very likely will follow. Increased prevalence has been observed in several areas of the United States in recent years. To prevent future cases of congenital syphilis, STD control programs need to place more emphasis on early syphilis control, especially in areas with a high incidence. # D isease Intervention A ctivities for Early Infectious Syphilis The traditional "tools" of early syphilis control in the United States include an original * " Fourfold rise in titer," "fourfold fall in titer," and other similar phrases are used throughout this document. They refer to changes (up or down) in serum titers of at least two dilutions (two "tubes"), e.g., from 1:2 to 1:8 (and the reverse), or from 1:4 to 1:16 (and the reverse), or from 1:32 to 1:8 (and the reverse). interview of the patient to elicit information on sex partners, rapid notification of partners, selective reinterviews, and selected "clustering" around the patient and his/her examined sex partners to obtain information on other persons who may be at risk of infection. Recom mended techniques, methods, and procedures are discussed in the disease intervention courses sponsored by the Division of Sexually Transmitted Diseases. # Specific A ctivities for State and Local S T D C ontrol Program s for the Prevention o f Congenital Syphilis • Ensure that official public health statutes and/or regulations mandate STS on all pregnant women at the time of the initial prenatal visit and early in the third trimester. • Monitor public and private laboratories regularly to ensure the prompt and thorough reporting of reactive STS. • Assess the pregnancy status of women with diagnosed syphilis and of women who are the sex partners of men with diagnosed syphilis. • Ask early infectious syphilis patients or their unexamined sex partners who reside in neighborhoods with a high incidence of syphilis to identify women in the area who may be pregnant. Refer all identified women for serologic testing and prenatal care. • Inform every woman of reproductive age who is seen in an STD clinic (for any reason) about the need for prenatal care and STS in future pregnancies. • Encourage prenatal screening for syphilis wherever pregnant women are seen for health care, including women, infants, and children (WIC) programs, methadone maintenance clinics, detention facilities, and prenatal care facilities; whenever possible, review existing clinic protocols and suggest specific amendments to the clinic medical director. • Conduct selective serologic screening of women of childbearing age in groups with an increased risk of infection, e.g., women residing in neighborhoods that have a particularly high incidence of syphilis. • Deliver educational messages to the medical community about laboratory tests, diag nostic criteria, treatment, and follow-up of patients who are at risk of infection and who may be pregnant. • Develop and disseminate public service educational messages to women who share demographic characteristics with the women most often diagnosed with early syphilis. In many areas of the United States, these women are young, single, members of a minority group, and residents of a central city neighborhood. Brief, well-targeted radio announce ments in the language and vernacular of the audience may be particularly effective. # STD Program Priorities Although no published studies have evaluated the benefit-to-cost ratio in controlling early syphilis by using the traditional method (see section 3.1) versus less laborious and timeconsuming methods, the former has been a mainstay of most STD control programs in the United States for many years. The traditional syphilis-intervention process requires time, commitment, and human resources, and -like other public health strategies -it should be periodically assessed by state and local STD programs for its benefits and costs. In an era of increasing demands for public health resources, the relative effectiveness of the traditional process should be compared with that of less vigorous methods in areas of both high and low syphilis incidence. A thorough initial interview that includes obtaining information on the patient' s sex partners (names and addresses) usually takes at least 45 minutes. In areas with an increased incidence of syphilis, clinic procedures and flow patterns may need to be restructured to accommodate this essential time requirement. # O th er C o nsiderations The interrelationship of syphilis and human immunodeficiency virus (HIV) infection should be explored in areas with a high incidence of syphilis. HIV infection may influence the manifestation of syphilis or its response to therapy. The role, if any, of the genital ulcers of syphilis in increasing the risk of HIV transmission also needs study in U.S. population groups. State and local STD programs need to coordinate control resources for both syphilis and HIV, offer STS to all women requesting HIV tests, and perform periodic syphilis tests on all persons known to be HIV-antibody positive. # Prenatal Care Comprehensive prenatal care started early in pregnancy is essential in preventing con genital syphilis. Unfortunately, many obstacles make it difficult for women, particularly some poor and some minority women, to obtain needed care. These obstacles include financial barriers, the limited availability of health care providers who are willing to serve these populations, provider difficulty in communicating with patients who are poor or from different ethnic backgrounds, organizational arrangements that minimize accessibility and accept ability of treatment, poor coordination of services, and patients' inadequate understanding of the need for care. Any modifications of the present system that would reduce these obstacles would also improve the opportunities for women with syphilis to receive care. Additional specific strategies are needed to encourage the use of prenatal care by women who may be at increased risk of transmitting syphilis to their fetus, to ensure that these women are adequately screened, and to maintain follow-up. These strategies include targeted out reach efforts, coordination of activities among service providers, and special prenatal care components. # S T D C ontrol Program s STD control programs should institute special prenatal outreach programs for patients who are at risk for syphilis. All women of childbearing age who come to STD clinics should be asked the date of their last menstrual period. If they have not had a period in the previous 6 weeks, and if their periods are usually regular, they should be tested for pregnancy as soon as possible, preferably on site. If on-site pregnancy testing is not available, STD clinic personnel should make an appointment for the patient at a facility that can do the testing with minimum delay. An RPR card test should be performed routinely on all patients at STD clinics; the laboratory forms of pregnant patients should be "flagged" for priority processing. All pregnant patients, regardless of the results of the RPR, should be referred for prenatal care. If the RPR test is reactive, however, arrangements should be made immediately to institute appropriate treatment, sex partner referral, and prenatal care. State and local STD programs should arrange with prenatal care providers to treat women with reactive syphilis tests as medical emergencies. Such women should be given the highest priority for prenatal care, particularly at clinics with waiting lists. If the woman reports normal menses, or the pregnancy January 15, 1988 test is negative, she should be informed about the availability of family planning services and about the potential hazards to a fetus caused by STD, cigarette smoking, alcohol, and drugs. Patients with early infectious syphilis should be interviewed to identify their recent sexual partners. Women who are so identified should receive the highest priority for referral for treatment and, if pregnant, for enrollment in effective prenatal care. Patients with early infectious syphilis who live in high-incidence neighborhoods should also be asked to identify friends, associates, and family members who might be pregnant (see section 3.2). Outreach workers should contact these women, explain to them that syphilis is a potential problem in their community, offer them a test for syphilis, and assist them in enrolling in a prenatal care facility. Pregnant women with a reactive STS should receive the highest priority for treatment and prenatal care. STD program managers need to develop management systems that track and measure the outreach activities focused on pregnant patients and their prenatal care. # .2 D rug A ddiction Program s All women of childbearing age who come to clinics for drug addiction should also be asked the date of their last menstrual period, and the same procedures should be followed as those described for STD clinics, including on-site pregnancy testing. If the test is positive, an on-site RPR should be performed and referral made for prenatal care. Patients should also be informed about the availability of family planning services and potential fetal damage caused by STD, cigarette smoking, alcohol, and drugs. # .3 P regnancy Testing Sites All sites that provide pregnancy testing should be alerted to their responsibility for preventing congenital syphilis. If a woman has a positive pregnancy test, an RPR card test should be done immediately and on site. If the RPR is reactive, the same procedures should be followed as those described for STD clinics. Special attention should be paid to obtaining accurate addresses for use by the local STD intervention specialist. All sites that provide pregnancy testing should follow these procedures, including family planning clinics, school-based clinics, adolescent health clinics, hospital emergency rooms and outpatient clinics, and detention facilities. # Prenatal Care Sites Women must often wait several weeks for their first prenatal appointment because of overcrowded schedules and delays in determining Medicaid eligibility. Since a delay may reduce the likelihood of successful treatment if syphilis is identified, efforts should be made to test women early in pregnancy, possibly during a visit for laboratory tests. If syphilis is diagnosed, treatment and counseling should be started before the regularly scheduled prenatal care visit. # .5 C ontent o f Care Prenatal care providers are responsible for ensuring that their pregnant patients are tested for syphilis and for coordinating their activities with those of the local STD program so that infected women will receive treatment promptly. Recommended activities for prenatal care providers include: • Obtaining maternal blood for serologic testing at the first visit unless the results of a previous test during the current pregnancy are available. A second STS should be performed at the beginning of the third trimester (28 weeks). • Providing each patient with a card identifying what test was performed, the date it was done, the result, what treatment (if any) was given, and the clinic' s name and telephone number. • Maintaining a list, arranged by date of test and patient' s name, of the results of the STS. Entries should be maintained for 1 year after the pregnancy is terminated. Prenatal care providers are responsible for determining the serologic status of their patients. Providers either should obtain the specimen or should document that a nonreactive test was obtained earlier in the pregnancy. The patient-borne record of STS and reactive results will assist in this documentation. • Identifying specimens from pregnant women by clearly labeling the laboratory slips "prenatal." Reactive tests should be followed by the STD program as part of an ongoing surveillance activity (see section 2). • " Flagging" the charts of clients whose serologic tests are reactive. Charts should remain flagged until the patient returns to the clinic. If the patient does not return or respond to routine notification, the local health department should be informed and referral services requested. • Instructing pregnant patients who may not be involved in mutually monogamous rela tionships to insist that their sex partners use condoms during the full term of the pregnancy. • Providing monthly quantitative nontreponemal serologic tests for the remainder of the current pregnancy of women who have been treated for early syphilis. Women who show a fourfold rise in titer should be retreated. Treated women who do not show a fourfold decrease in titer within 3 months should be retreated. After delivery, follow-up should be conducted as outlined for nonpregnant patients. • Testing all patients for syphilis (RPR or VDRL) 1 month after they have completed treatment for any other STD diagnosed during pregnancy. # .6 M on ito rin g P erfo rm an ce The responsibility for monitoring the system of services for preventing congenital syphilis should rest with the state or local STD control program. Since personnel and priorities of the multiple programs involved in preventing congenital syphilis will change overtime, a tracking system to monitor performance and the changes in service delivery should be established and maintained. # Laboratory Tests The usefulness of laboratory tests in the diagnosis of syphilis depends upon the selection of appropriate standard tests, listed below. The quality of such tests depends upon the use of quality reagents by well-trained personnel. Laboratories and the staff performing laboratory tests should be under strict quality control procedures and should participate regularly in performance evaluation and quality assurance programs. # Laboratory Tests for Syphilis # Syphilis in Pregnancy # M aternal Serologies tP^inn If* h h°k ldbe Perf°rmed at the be9innin9 of prenatal care and at delivery. Intermediate P . e ©ginning of the third trimester (28 weeks) should also be routine for high-risk p a ions, eroreactive women must be evaluated promptly. This evaluation should include a is ory and physical examination, a quantitative nontreponemal test, and a confirmatory Despite possible false-positive results in nontreponemal and treponemal tests, expectant mothers should be treated if 1) they have a reactive STS and 2) a prompt and thorough evaluation of the cause of the seroreactivity cannot be ensured. Special tests that include deoxyribonucleic acid (DNA) and Reiter absorptions for the fluorescent treponemal antibody (FTA) test eliminate most of the false-positive results. These tests can be performed by the Sexually Transmitted Diseases Laboratory Program, Center for Infectious Diseases, CDC, upon request from a reference laboratory. Delay in the presumptive treatment of a seroreactive pregnant woman, however, should never be allowed to exceed 4 weeks. If a patient has a reactive nontreponemal test (e.g., VDRL), a nonreactive treponemal test (e.g., microhemagglutination assay for antibody to T. pallidum [MHA-TP]), and no clinical or epidemiologic evidence of syphilis, no treatment is necessary. Both the quantitative non treponemal test and the confirmatory test should be repeated within 4 weeks. If clinical or serologic evidence of syphilis is found, or if the diagnosis of syphilis cannot be excluded with reasonable certainty, the patient should be treated as outlined below (section 6.2.3). In pregnancy, nontreponemal test titers tend to increase nonspecifically. This tendency causes difficulty in distinguishing between antibodies due to reinfection and antibodies remaining from an earlier treated infection. Patients who have been adequately treated for syphilis in the past and who have documen tation of their treatment need not be retreated unless clinical, serologic, or epidemiologic evidence of reinfection exists, e.g., darkfield-positive lesions, a sustained (for > 2 weeks) fourfold titer rise in a quantitative nontreponemal test, or a history of recent sexual exposure to a person with early infectious syphilis. # Treatm ent in P regnancy # Data Limitations In the past 20 years, no major clinical trials have involved the currently recommended treatments for syphilis in pregnant patients. Thus, public health personnel cannot determine whether a decrease in therapeutic efficacy has occurred with these treatment regimens. However, individual failures of treatment (i.e., the occurrence of congenital syphilis in an infant whose mother was treated) have been reported. Although denominator data would be neces sary for failure rates to be calculated, the reports nonetheless suggest the need to modify treatment strategies for pregnant women who have syphilis. For instance, the available data suggest that treatment with the currently recommended erythromycin regimen is associated with an unacceptably high failure rate. The treatment efficacy with any regimen varies with the stage of maternal infection and with the stage of pregnancy. Available data indicate that the rate of treatment failure may be significantly higher among women with secondary syphilis and among women treated in the last trimester of pregnancy. The physiologic variables associated with pregnancy or placental transfer mechanisms may be quantitatively more important during the last trimester of pregnancy, and the organism load may be higher during the secondary stage of syphilis. # Treatment of Choice for Syphilis in # Penicillin-Allergic Patients Penicillin may be given to pregnant women with syphilis even if they have a history of penicillin allergy provided 1) their skin-test reactions to the major and minor penicillin deter minants are negative or 2) their skin tests are positive but they are then desensitized to penicillin. Patients can be desensitized and then given standard dosages of this antibiotic. Penicillin desensitization can be accomplished by giving the patient gradually increasing oral* or intravenous penicillin doses over a period of 3-4 hours until full tolerance occurs. The intravenous desensitizing route has an advantage in that the penicillin can be stopped immediately if an allergic reaction develops; reactions, however, occur more frequently during intravenous desensitization. Desensitization should be done in consultation with an expert and only in facilities where emergency procedures are available, such as in a hospital. One oral desensitizing regimen given to pregnant patients used penicillin V. The starting dose was 100 units and was increased every 15 minutes. The final cumulative dose was 1,296,700 units given over a period of 3-4 hours. These patients were hospitalized and an intravenous line was established, but no premedications were used. A contingency plan, which was not needed, was to repeat the last dose or abandon the procedure if a serious reaction developed (N Engl J Med 1985;312:1229-32). or silver stains. Specimens from the placenta and umbilical cord should be microscopically examined for those infants born to mothers with reactive serologic results, when no histories are available, or when the placenta is hydropic. Additionally, all neonatal lesions should be examined for treponemes. Treponemes seen in lesion material or in autopsy or biopsy sections by silver stain or darkfield, although considered definitive, may be confused in endemic areas with the Borrelia of Lyme disease. Maternal nontreponemal serology may be used to differentiate Lyme disease from syphilis. The VDRL is uniformly nonreactive in Lyme disease. An effort should be made to diagnose congenital syphilis in a stillborn whenever clinical findings or a maternal history suggests the possibility of untreated syphilis. Direct and histologic microscopic examinations of placenta, organs, and umbilical cord, as well as radiographic examinations of long bones, are helpful in postmortem diagnosis. The MHA-TP test can be used on the blood of a stillborn; blood can be obtained by direct cardiac puncture. # Radiography All infants delivered of women with a reactive STS who were not treated before pregnancy or before 20 weeks' gestation should be fully evaluated. The evaluation should include an examination of the long bones for osteochondritis, osteitis, and periostitis. # Cerebrospinal Fluid Analysis Infants delivered of women with a reactive STS should have a cerebrospinal fluid (CSF) evaluation in any of the following circumstances: • the infant shows any signs compatible with congenital syphilis # OR • maternal therapy was inadequate, unknown, or it occurred late 20 weeks) in preg nancy OR • maternal therapy did not include penicillin OR • adequate follow-up cannot be ensured Other living infants with a diagnosis of confirmed or compatible (see definitions in section 2) congenital syphilis should have a CSF examination before treatment to provide a baseline for follow-up examination. Although the importance of the CSF examination is debated, a quan titative VDRL CSF test can be meaningful if it is done in conjunction with tests for elevated total protein and lymphocyte count. The RPR card test should not be used for CSF evaluation. Regardless of CSF results, however, all children with a diagnosis of confirmed or compatible congenital syphilis should be treated with a regimen effective for neurosyphilis. # N eo n atal Treatm ent Although no recent comprehensive and comparative data on the treatment of neonates are available, several case reports of apparent treatment failure in infants treated with benzathine penicillin have been published. Available data clearly identify an obligation to evaluate neo nates adequately to determine whether they have occult active infection. The most appropri ate approach to active infection requires the use of a 10-day regimen of crystalline or procaine penicillin rather than benzathine penicillin. All patients with neurosyphilis must be carefully monitored with periodic serologic testing, clinical evaluation at 6-month intervals, and repeat CSF examinations for at least 3 years. The possibility of reinfection should always be considered when patients with early syphilis are being retreated. A CSF examination should be performed before retreatment unless reinfection and a diagnosis of early syphilis can be established. Retreatment should be considered when: • clinical signs or symptoms of syphilis persist or recur # OR • a sustained fourfold increase occurs in the titer of a nontreponemal test # OR • an initially high-titer nontreponemal test fails to decrease fourfold within a year Patients should be retreated with the regimens recommended for syphilis of more than 1 year' s duration. # Tetracycline is not recommended for pregnant women because of potential adverse effects on the fetus. Erythromycin treatment of syphilis during pregnancy is generally discouraged, should be considered only for patients who have documented evidence of penicillin allergy (skin test or anaphylaxis history) and who are not candidates for penicillin desensitization. Clinicians choosing erythromycin treatment have a weighty responsibility for close clinical follow-up of both the mother and fetus to assess the possibilities of treatment failure. # Maternal Treatment Follow-up • Pregnant women who have been treated for early syphilis should have monthly quan titative nontreponemal serologic tests for the remainder of their pregnancy. • Women who show a fourfold rise in titer should be retreated. • Treated women who do not show a fourfold decrease in titer in a 3-month period should be retreated. • After delivery, follow-up is the same as for nonpregnant patients. # Needed Studies Well-designed studies on the treatment of pregnant women who have syphilis are clearly needed. The more urgent topics include: • the transplacental pharmacokinetics of penicillin and other antibiotics; • treatment efficacy and a continuing analysis of treatment-failure cases with currently recommended regimens;° a treatment regimen consisting of benzathine penicillin G followed by for cunhii'H j mpiCI In anc* Pr°b enecid, or high-dose amoxicillin/ampicillin and probenecid trimester dUnn9 pre9nancy' esPecial\|y for secondary syphilis encountered in the last S eneCidrfaS ,an. ac^unc* t0 current penicillin treatment regimens to augment their efficacy, particularly for secondary syphilis in late pregnancy; and • the role of infection with HIV in cases of prenatal syphilis treatment failure. # Syphilis in the Fetus and Neonate # Diagnostic Evaluation # Neonatal Serologic Tests for Syphilis Serum from the infant is preferred for both nontreponemal and confirmatory tests, since umbilical cord blood may produce false-positive results. After delivery and/or treatment, serial specimens are used to follow efficacy of treatment or degradation of transplacentally acquired maternal antibody. When laboratory methods become generally available for fetal/neonatal specific immune globulin (IgM) treponemal determinations, serum will be the specimen of choice. Carefully controlled field trials will need to be conducted to provide guidance for their use in clinical practice. # Microscopic Evaluation The placenta and the umbilical cord may serve as excellent sites for the collection o specimens that can be examined by darkfield microscopy, immunofluorescence, H & E stains, # Recommended Regimens for Symptomatic or Asymptomatic Infants Aqueous crystalline penicillin G 50,000 units/kg IM or IV daily in two divided doses for a minimum of 10 days OR Aqueous procaine penicillin G 50,000 units/kg IM daily for a minimum of 10 days. For asymptomatic infants whose mothers were treated adequately with a penicillin regimen during pregnancy, treatment is not necessary if follow-up can be ensured. For asymptomatic infants whose mothers were treated adequately with a penicillin regimen during pregnancy but whose follow-up cannot be ensured, many consultants recommend treatment with benzathine penicillin 50,000 units/kg IM in a single dose. Data on the efficacy of this regimen in congenital neurosyphilis are lacking; therefore, if neurosyphilis cannot be excluded, the 10-day regimens of aqueous crystalline penicillin or procaine penicillin are recommended. Only penicillin regimens are recommended for neonatal congenital syphilis. # N eonatal Follow-up In accordance with the guidelines of the American Academy of Pediatrics, follow-up for all infants should be incorporated into routine newborn care at 1,2,4,6, and 12 months. Serologic tests should be performed until they become nonreactive. Patients with persistent, stable, low titers should be considered candidates for retreatment. Treated infants should be similarly followed, with a CSF examination at 6-month intervals until the examination becomes non reactive. A reactive CSF VDRL at 6 months is an indication for retreatment. # Long-term Follow-up and Retreatment Penicillin dosages for congenital syphilis after the neonatal period remain the same as ose recommended for neonatal congenital syphilis. For larger children, the total amount of penicillin given should not exceed the dosage used in adult syphilis of more than 1 year' s duration. After the neonatal period, the dosage of tetracycline for congenital syphilis in patients who are allergic to penicillin should be individualized, but these dosages need not exceed those used in adult syphilis of more than 1 year' s duration. Tetracycline should not be given to children <8 years of age. A thorough developmental evaluation should be done during the third year of life (age 2) on all children treated in infancy who were symptomatic at birth or had active congenital infection. All patients with early syphilis or congenital syphilis should be encouraged to return for repeat quantitative nontreponemal tests at least 3,6, and 12 months after treatment. In these patients, quantitative nontreponemal test titers will decline to nonreactive or low titer reactive within a year following successful treatment with penicillin. Serologic test results decline more slowly in patients treated for disease of longer duration. Patients with syphilis of more than	None	None
4b76e69c678f96e604de03f6532257b62d0bb878	cdc	None	These revised recommendations on vaccinia (smallpox) vaccine update the previous recommendations (MMWR 1985;34:341-2) and include current information on its use among laboratory and health-care workers occupationally exposed to vaccinia, recombinant vaccinia viruses, and other orthopoxviruses that can infect humans. This report also contains revised recommendations on revaccination of high-risk workers and information on contraindications to vaccination.# INTRODUCTION Vaccinia (smallpox) vaccine is a highly effective immunizing agent that brought about the global eradication of smallpox. The last naturally occurring case of smallpox occurred in Somalia in 1977. In May 1980, the World Health Assembly certified that the world was free of naturally occurring smallpox (1). Because of vaccination programs and quarantine regulations, the risk of importation of smallpox into the United States was reduced by the 1960s. As a result, routine vaccinia vaccination was discontinued in 1971 (2). In 1976, the recommendation for routine vaccination of health-care workers was also discontinued (3). In 1982, the only active licensed producer of vaccinia vaccine in the United States discontinued production for general use, and in 1983, distribution to the civilian population was discontinued (4). For several years all military personnel continued to be routinely vaccinated. However, only selected groups of military personnel are currently vaccinated against smallpox. Since January 1982, smallpox vaccination has not been required for international travelers, and International Certificates of Vaccination no longer include smallpox vaccination (5). In 1980, the Immunization Practices Advisory Committee (ACIP) recommended the use of vaccinia vaccine to protect laboratory workers from possible infection while working with nonvariola orthopoxviruses (e.g., vaccinia and monkeypox) (6). In 1984, these recommendations were included in guidelines for biosafety in microbiological and biomedical laboratories (7). These guidelines expanded the recommendation to include persons working in animal-care areas where studies with orthopoxviruses were being conducted and recommended that these workers have documented evidence of satisfactory smallpox vaccination within the preceding 3 years. CDC has provided vaccinia vaccine for these laboratory workers since 1983 (8). Because studies of recombinant vaccinia virus vaccines have been advanced to the stage of clinical trials, health-care workers (e.g., physicians and nurses) may now be exposed to vaccinia and recombinant vaccinia viruses and should be considered for vaccinia vaccination. # VACCINIA VACCINE The vaccinia vaccine currently licensed in the United States is a lyophilized preparation of infectious vaccinia virus. - The vaccine was prepared from calf lymph with a seed virus derived from the New York City Board of Health (NYCBOH) strain of vaccinia; it has a concentration of 10 superscript 8 pockforming units (PFU) per milliliter. Vaccine is administered by using the multiple-puncture technique with a bifurcated needle. After percutaneous administration of a standard dose of vaccinia vaccine, >95% of primary vaccinees (i.e., persons receiving their first dose of vaccine) will develop neutralizing or hemagglutination inhibition antibody at a titer of greater than or equal to 1:10 (9). Neutralizing antibody titers of greater than or equal to 1:10 are found among 75% of persons for 10 years after receiving second doses and up to 30 years after receiving three doses of vaccine (10,11). The level of antibody that protects against smallpox (variola)infection is not known, but epidemiologic studies suggest that protection against smallpox persists a minimum of 5 years after revaccination (12). Also, the level of antibody required for protection against vaccinia infection is not known. However, when the response to revaccination is used as an indication of immunity, 30% of persons with titers <1:10 (13). # RECOMBINANT VACCINIA VIRUSES Vaccinia virus is the prototype of the genus Orthopoxvirus. It is a double-stranded DNA virus that has a broad host range under experimental conditions and is rarely isolated from animals outside the laboratory (14). There are many strains of vaccinia virus, which have different levels of virulence for humans and animals. For example, the Temple of Heaven and Copenhagen vaccinia strains are highly pathogenic in animals, whereas the NYCBOH strain, from which the Wyeth vaccine strain was derived, had relatively low pathogenicity (15). Vaccinia virus can be genetically engineered to contain and express foreign DNA without impairing the ability of the virus to replicate. Such foreign DNA can encode protein antigens that induce protection against one or more infectious agents. Recombinant vaccinia viruses have been engineered to express the immunizing antigens of herpesvirus, hepatitis B, rabies, influenza, human immunodeficiency viruses (HIV), and others (16)(17)(18)(19)(20)(21). Recombinant vaccinia viruses have been created from several strains of vaccinia virus. In the United States most recombinants have been made from either the NYCBOH strain or a mouse neuroadapted derivative, the WR strain. Some recombinants have been made from the Copenhagen and Lister vaccinia strains, which are more pathogenic in animals than the NYCBOH strain. Animal studies generally suggest that recombinants may be no more pathogenic than the parent strain of vaccinia virus. However, no consistently reliable laboratory marker or animal test predicts the attenuation of vaccinia virus or a particular recombinant for humans (22). Laboratory-acquired infections with vaccinia or recombinant viruses have been reported (23)(24)(25). However, since no surveillance system has been established to monitor laboratory workers, the risk of infection for persons who handle virus cultures or materials contaminated with these viruses is not known. With the initiation of human trials of recombinant vaccines, physicians, nurses, and other health-care personnel who provide clinical care to recipients of these vaccines could be exposed to both vaccinia and recombinant viruses. This exposure could occur from contact with dressings contaminated with the virus or through exposure to the vaccine. The risk of transmission of recombinant viruses to exposed health-care workers is unknown. To date, no reports of transmission to health-care personnel from vaccine recipients have been published. If appropriate infection-control precautions are observed, health-care workers are probably at less risk of infection than laboratory workers because of the smaller volume and lower titer of virus in clinical specimens compared with laboratory material (26,27). However, because of the potential for transmission of vaccinia or recombinant vaccinia viruses to such persons, the ACIP suggests that health-care personnel who have direct contact with contaminated dressings or other infectious material from volunteers in clinical studies be considered for vaccination. Laboratory and other health-care personnel who work with viral cultures or other infective materials should always observe appropriate biosafety guidelines and adhere to published infection control procedures (26)(27)(28). # VACCINE USAGE Vaccinia vaccine is recommended for laboratory workers who directly handle a) cultures or b) animals contaminated or infected with vaccinia, recombinant vaccinia viruses, or other orthopoxviruses that infect humans (e.g., monkeypox, cowpox). Other health-care workers (such as physicians and nurses) whose contact with these viruses is limited to contaminated materials (e.g., dressings) but who adhere to appropriate infection control measures are at lower risk of inadvertent infection than laboratory workers. However, because a theoretical risk of infection exists, vaccination may be considered for this group. Because of the low risk of infection, vaccination is not recommended for persons who do not directly handle virus cultures or materials or who do not work with animals contaminated or infected with these viruses. High seroconversion rates and infrequent adverse events (see Side Effects and Adverse Reactions) are two benefits of vaccination. Recipients are given controlled percutaneous doses (approximately 2.5X10 superscript 5 PFU ( 29)) of relatively low pathogenicity vaccinia. The resulting immunity should provide some degree of protection to recipients against infections resulting from uncontrolled, inadvertent inoculation by unusual routes (e.g., the eye) with a large dose of virus of higher or unknown pathogenicity. In addition, persons with preexisting immunity to vaccinia may be protected against seroconversion to the foreign antigen expressed by a recombinant virus (20). # Revaccination According to available data on the persistence of neutralizing antibody following vaccination, persons working with vaccinia, recombinant vaccinia viruses, or other nonvariola orthopoxviruses should be revaccinated every 10 years. # SIDE EFFECTS AND ADVERSE REACTIONS # Vaccine recipients A papule develops at the site of vaccination 2-5 days after percutaneous administration of vaccinia vaccine to a non-immune person (i.e., primary vaccination). The papule becomes vesicular, then pustular, and reaches its maximum size in 8-10 days. The pustule dries and forms a scab, which separates within 14-21 days after vaccination, leaving a typical scar. Primary vaccination can produce swelling and tenderness of regional lymph nodes, beginning 3-10 days after vaccination and persisting for 2-4 weeks after the skin lesion has healed. Maximum viral shedding occurs 4-14 days following vaccination, but vaccinia can be recovered from the site of vaccination until the scab separates from the skin (30,31). A fever is common after the vaccinia vaccination is administered. Up to 70% of children have 1 or more days of temperature of greater than or equal to 100 F from 4 to 14 days after primary vaccination (9), and 15%-20% have temperatures of greater than or equal to 102 F. After revaccination, 35% of children develop temperatures of greater than or equal to 100 F, and 5% have temperatures of greater than or equal to 102 F (13). Fever is less common in adults than children after vaccination or revaccination (31; CDC, unpublished data). Erythematous or urticarial rashes may occur approximately 10 days after primary vaccination. The vaccinee is usually afebrile, and the rash resolves spontaneously within 2 to 4 days. Rarely bullous erythema multiforme (Stevens-Johnson syndrome) occurs (32). Inadvertent inoculation at other sites is the most frequent complication of vaccinia vaccination, accounting for about half of all complications of primary vaccination and revaccination (Table_1). Inadvertent inoculation usually results from auto-inoculation of vaccine virus transferred from the site of vaccination. The most common sites involved are the face, eyelid, nose, mouth, genitalia, and rectum. Most lesions heal without specific therapy, but vaccinia immune globulin (VIG) may be useful for cases of ocular implantation (see Treatment of Complications of Vaccinia Vaccine). Generalized vaccinia among persons without underlying illnesses is characterized by a vesicular rash of varying extent. The rash is generally self limited and requires little or no therapy except among patients whose conditions appear to be toxic or who have serious underlying illnesses. More severe complications of vaccinia vaccination include eczema vaccinatum, progressive vaccinia, and postvaccinial encephalitis. These complications occur at least 10 times more often among primary vaccinees than among revaccinees and more frequently among infants than among older children and adults (33-35) (Table_1). Eczema vaccinatum is a localized or systemic dissemination of vaccinia virus among persons who have eczema or a history of eczema and other chronic or exfoliative skin conditions (e.g., atopic dermatitis). The illness is usually mild and self limited, but may be severe and occasionally fatal. The most serious cases among vaccine recipients occur among primary vaccinees and appear to be independent of the activity of the underlying eczema (36). Severe cases have also been observed after contact infection (see Contacts of vaccinees). Progressive vaccinia (vaccinia necrosum) is a severe, potentially fatal illness characterized by progressive necrosis in the area of vaccination, often with metastatic lesions. It occurs almost exclusively among persons with cellular immunodeficiency. The most serious complication is postvaccinial encephalitis. Most frequently it affects primary vaccinees <1 year of age. From 15% to 25% of affected vaccinees with this complication die, and 25% have permanent neurologic sequelae (32)(33)(34). Death is rare after vaccinia vaccination, with approximately 1 to 2 deaths per million primary vaccinations and 0.1 death per million revaccinations. Death is most often the result of postvaccinial encephalitis or progressive vaccinia. # Contacts of vaccinees Transmission of vaccinia may occur when a recently vaccinated person has contact with a susceptible person. In the CDC 10-state survey of complications of smallpox vaccination, the risk of transmission to contacts was 27 infections per million total vaccinations; 44% of these contact cases occurred among children less than or equal to 5 years of age (33). Since 1980, several occurrences of contact transmission of vaccinia from recently vaccinated military recruits have been reported, including six cases transmitted by a single vaccine recipient (37)(38)(39). Over 60% of contact transmission results in uncomplicated inadvertent inoculation. Approximately 30% of contact transmission results in eczema vaccinatum, which may be fatal (33). Eczema vaccinatum may be more severe among contacts than among vaccinated persons, possibly because of simultaneous multiple inoculations at several sites (34,40). Contact transmission rarely results in postvaccinial encephalitis or vaccinia necrosum. # PRECAUTIONS AND CONTRAINDICATIONS Before administering vaccinia vaccine, the physician should take a careful history to document the absence of contraindications to vaccination among both vaccinees and household contacts of vaccinees. Special efforts should be made to identify vaccinees and household contacts who have eczema, a history of eczema, or immunodeficiencies. Vaccinia vaccine should not be administered if these conditions are present among either recipients or household contacts. # History or presence of eczema Because of the increased risk of eczema vaccinatum, vaccinia vaccine should not be administered to persons with eczema or a past history of eczema or to those whose household contacts have eczema. Persons with other acute, chronic, or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, or varicella zoster) may also be at higher risk of eczema vaccinatum and should not be vaccinated until the condition resolves. # Pregnancy Vaccinia vaccine should not be administered to pregnant women. On rare occasions, almost always after primary vaccination, vaccinia virus has been reported to cause fetal infection (41). Fewer than 50 cases of fetal vaccinia are known, but cases have been observed as recently as 1978 (35,42). Fetal vaccinia usually results in stillbirth or death of the infant shortly after delivery. Vaccinia vaccine is not known to cause congenital malformations. # Altered immunocompetence Replication of vaccinia virus can be enhanced among persons with immune deficiency diseases and among those with immunosuppression (as occurs with leukemia, lymphoma, generalized malignancy, agammaglobulinemia, or therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids). Persons with such conditions or therapies or whose household contacts have such conditions should not be administered vaccinia vaccine. # Infection with human immunodeficiency virus (HIV) The risk of severe complications after vaccinia vaccination for persons infected with HIV is not known. At least one case of severe generalized vaccinia has been reported in an asymptomatic HIV-infected military recruit after the administration of multiple vaccines, including vaccinia (43). In addition, a recent report suggests that two HIV-infected persons may have died of a progressive vaccinia-like illness after treatment with inactivated autologous lymphocytes infected with a recombinant HIV-vaccinia virus (44). However, at present there is no evidence that smallpox vaccination accelerates the progression of HIV-related disease. Nevertheless, until additional information becomes available, it is prudent not to vaccinate persons who have HIV infection. # Allergies Vaccinia vaccine contains trace amounts of polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate. Persons who experience anaphylactic reactions (hives, swelling of the mouth and throat, difficulty breathing, hypotension, and shock) to any of these antibiotics should not be vaccinated. Vaccinia vaccine does not contain penicillin. # PREVENTION OF CONTACT TRANSMISSION OF VACCINIA Vaccinia virus may be cultured from the site of primary vaccination beginning at the time of development of a papule (2-5 days after vaccination) until the scab separates from the skin lesion (14-21 days after vaccination). During this time, care must be taken to prevent spread of the virus to another area of the body or to another person. The vaccination site should be covered at all times with a porous bandage until the scab has separated and the underlying skin has healed. An occlusive bandage should not be used. The vaccination site should be kept dry. When the vaccinee bathes, the site should be covered with an impermeable bandage. Vaccinated health-care workers may continue to have contact with patients, including those with immunodeficiencies, as long as the vaccination site is covered and good hand-washing technique is maintained. Semipermeable polyurethane dressings (e.g., Opsite (R)) are effective barriers to vaccinia and recombinant vaccinia viruses (21). However, exudate may accumulate beneath the dressing, and care must be taken to prevent viral contamination when the dressing is removed. In addition, accumulation of fluid beneath the dressing may increase the maceration of the vaccination site. Accumulation of exudate may be decreased by first covering the vaccination with dry gauze, then applying the dressing over the gauze. To date, experience with this type of containment dressing has been limited to research protocols, and further investigation is needed before it can be recommended for all vaccinia vaccine recipients. The most important measure to prevent inadvertent implantation and contact transmission from vaccinia vaccination is thorough hand washing after changing the bandage or after any other contact with the vaccination site. # TREATMENT OF COMPLICATIONS OF VACCINIA VACCINE The only product currently available for the treatment of complications of vaccinia vaccination is vaccinia immune globulin (VIG). VIG is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine. It is effective for the treatment of eczema vaccinatum and some cases of progressive vaccinia and may be useful in the treatment of ocular vaccinia resulting from inadvertent implantation. VIG is also recommended for severe generalized vaccinia if the patient has a toxic condition or a serious underlying disease. VIG is of no benefit in the treatment of postvaccinial encephalitis. The recommended dosage for treatment of complications is 0.6 mL/kg of body weight. VIG must be administered intramuscularly and should be administered as early as possible after the onset of symptoms. Because therapeutic doses of VIG may be large (e.g., 42 mL for a person weighing 70 kg), the product should be given in divided doses over a 24-to 36-hour period. Doses may be repeated, usually at intervals of 2-3 days, until recovery begins (e.g., no new lesions appear). CDC is the only source of VIG for civilians. # MISUSE OF VACCINIA VACCINE Vaccinia vaccine should never be used therapeutically for any reason. There is no evidence that it has any value in the treatment or prevention of recurrent herpes simplex infection, warts, or any disease other than those caused by human orthopoxviruses (45). Misuse of vaccinia vaccine to treat herpes infections has been associated with severe complications (46)(47). VACCINIA VACCINE AVAILABILITY CDC is the only source of vaccinia vaccine and VIG for civilians. CDC will provide vaccinia vaccine to protect laboratory and other health-care personnel whose occupations place them at risk of exposure to vaccinia and other closely related orthopoxviruses, including vaccinia recombinants. The vaccine should be administered under the supervision of a physician selected by the institution. Vaccine will be shipped to the responsible physician. Requests for vaccine and VIG, including the reason for the request, should be referred to: Health-care workers are requested to report complications of vaccinia vaccination to the Vaccine Adverse Event Reporting System (800-822-7967) or to their state or local health department. Drug # Table_1 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. ----------------------------------------------------------------------------------------------------- -----------------------------------------------------------------------------------------------------	These revised recommendations on vaccinia (smallpox) vaccine update the previous recommendations (MMWR 1985;34:341-2) and include current information on its use among laboratory and health-care workers occupationally exposed to vaccinia, recombinant vaccinia viruses, and other orthopoxviruses that can infect humans. This report also contains revised recommendations on revaccination of high-risk workers and information on contraindications to vaccination.# INTRODUCTION Vaccinia (smallpox) vaccine is a highly effective immunizing agent that brought about the global eradication of smallpox. The last naturally occurring case of smallpox occurred in Somalia in 1977. In May 1980, the World Health Assembly certified that the world was free of naturally occurring smallpox (1). Because of vaccination programs and quarantine regulations, the risk of importation of smallpox into the United States was reduced by the 1960s. As a result, routine vaccinia vaccination was discontinued in 1971 (2). In 1976, the recommendation for routine vaccination of health-care workers was also discontinued (3). In 1982, the only active licensed producer of vaccinia vaccine in the United States discontinued production for general use, and in 1983, distribution to the civilian population was discontinued (4). For several years all military personnel continued to be routinely vaccinated. However, only selected groups of military personnel are currently vaccinated against smallpox. Since January 1982, smallpox vaccination has not been required for international travelers, and International Certificates of Vaccination no longer include smallpox vaccination (5). In 1980, the Immunization Practices Advisory Committee (ACIP) recommended the use of vaccinia vaccine to protect laboratory workers from possible infection while working with nonvariola orthopoxviruses (e.g., vaccinia and monkeypox) (6). In 1984, these recommendations were included in guidelines for biosafety in microbiological and biomedical laboratories (7). These guidelines expanded the recommendation to include persons working in animal-care areas where studies with orthopoxviruses were being conducted and recommended that these workers have documented evidence of satisfactory smallpox vaccination within the preceding 3 years. CDC has provided vaccinia vaccine for these laboratory workers since 1983 (8). Because studies of recombinant vaccinia virus vaccines have been advanced to the stage of clinical trials, health-care workers (e.g., physicians and nurses) may now be exposed to vaccinia and recombinant vaccinia viruses and should be considered for vaccinia vaccination. # VACCINIA VACCINE The vaccinia vaccine currently licensed in the United States is a lyophilized preparation of infectious vaccinia virus. * The vaccine was prepared from calf lymph with a seed virus derived from the New York City Board of Health (NYCBOH) strain of vaccinia; it has a concentration of 10 superscript 8 pockforming units (PFU) per milliliter. Vaccine is administered by using the multiple-puncture technique with a bifurcated needle. After percutaneous administration of a standard dose of vaccinia vaccine, >95% of primary vaccinees (i.e., persons receiving their first dose of vaccine) will develop neutralizing or hemagglutination inhibition antibody at a titer of greater than or equal to 1:10 (9). Neutralizing antibody titers of greater than or equal to 1:10 are found among 75% of persons for 10 years after receiving second doses and up to 30 years after receiving three doses of vaccine (10,11). The level of antibody that protects against smallpox (variola)infection is not known, but epidemiologic studies suggest that protection against smallpox persists a minimum of 5 years after revaccination (12). Also, the level of antibody required for protection against vaccinia infection is not known. However, when the response to revaccination is used as an indication of immunity, <10% of persons with neutralizing titers of greater than or equal to 1:10 exhibit a primary-type response at revaccination, compared with>30% of persons with titers <1:10 (13). # RECOMBINANT VACCINIA VIRUSES Vaccinia virus is the prototype of the genus Orthopoxvirus. It is a double-stranded DNA virus that has a broad host range under experimental conditions and is rarely isolated from animals outside the laboratory (14). There are many strains of vaccinia virus, which have different levels of virulence for humans and animals. For example, the Temple of Heaven and Copenhagen vaccinia strains are highly pathogenic in animals, whereas the NYCBOH strain, from which the Wyeth vaccine strain was derived, had relatively low pathogenicity (15). Vaccinia virus can be genetically engineered to contain and express foreign DNA without impairing the ability of the virus to replicate. Such foreign DNA can encode protein antigens that induce protection against one or more infectious agents. Recombinant vaccinia viruses have been engineered to express the immunizing antigens of herpesvirus, hepatitis B, rabies, influenza, human immunodeficiency viruses (HIV), and others (16)(17)(18)(19)(20)(21). Recombinant vaccinia viruses have been created from several strains of vaccinia virus. In the United States most recombinants have been made from either the NYCBOH strain or a mouse neuroadapted derivative, the WR strain. Some recombinants have been made from the Copenhagen and Lister vaccinia strains, which are more pathogenic in animals than the NYCBOH strain. Animal studies generally suggest that recombinants may be no more pathogenic than the parent strain of vaccinia virus. However, no consistently reliable laboratory marker or animal test predicts the attenuation of vaccinia virus or a particular recombinant for humans (22). Laboratory-acquired infections with vaccinia or recombinant viruses have been reported (23)(24)(25). However, since no surveillance system has been established to monitor laboratory workers, the risk of infection for persons who handle virus cultures or materials contaminated with these viruses is not known. With the initiation of human trials of recombinant vaccines, physicians, nurses, and other health-care personnel who provide clinical care to recipients of these vaccines could be exposed to both vaccinia and recombinant viruses. This exposure could occur from contact with dressings contaminated with the virus or through exposure to the vaccine. The risk of transmission of recombinant viruses to exposed health-care workers is unknown. To date, no reports of transmission to health-care personnel from vaccine recipients have been published. If appropriate infection-control precautions are observed, health-care workers are probably at less risk of infection than laboratory workers because of the smaller volume and lower titer of virus in clinical specimens compared with laboratory material (26,27). However, because of the potential for transmission of vaccinia or recombinant vaccinia viruses to such persons, the ACIP suggests that health-care personnel who have direct contact with contaminated dressings or other infectious material from volunteers in clinical studies be considered for vaccination. Laboratory and other health-care personnel who work with viral cultures or other infective materials should always observe appropriate biosafety guidelines and adhere to published infection control procedures (26)(27)(28). # VACCINE USAGE Vaccinia vaccine is recommended for laboratory workers who directly handle a) cultures or b) animals contaminated or infected with vaccinia, recombinant vaccinia viruses, or other orthopoxviruses that infect humans (e.g., monkeypox, cowpox). Other health-care workers (such as physicians and nurses) whose contact with these viruses is limited to contaminated materials (e.g., dressings) but who adhere to appropriate infection control measures are at lower risk of inadvertent infection than laboratory workers. However, because a theoretical risk of infection exists, vaccination may be considered for this group. Because of the low risk of infection, vaccination is not recommended for persons who do not directly handle virus cultures or materials or who do not work with animals contaminated or infected with these viruses. High seroconversion rates and infrequent adverse events (see Side Effects and Adverse Reactions) are two benefits of vaccination. Recipients are given controlled percutaneous doses (approximately 2.5X10 superscript 5 PFU ( 29)) of relatively low pathogenicity vaccinia. The resulting immunity should provide some degree of protection to recipients against infections resulting from uncontrolled, inadvertent inoculation by unusual routes (e.g., the eye) with a large dose of virus of higher or unknown pathogenicity. In addition, persons with preexisting immunity to vaccinia may be protected against seroconversion to the foreign antigen expressed by a recombinant virus (20). # Revaccination According to available data on the persistence of neutralizing antibody following vaccination, persons working with vaccinia, recombinant vaccinia viruses, or other nonvariola orthopoxviruses should be revaccinated every 10 years. # SIDE EFFECTS AND ADVERSE REACTIONS # Vaccine recipients A papule develops at the site of vaccination 2-5 days after percutaneous administration of vaccinia vaccine to a non-immune person (i.e., primary vaccination). The papule becomes vesicular, then pustular, and reaches its maximum size in 8-10 days. The pustule dries and forms a scab, which separates within 14-21 days after vaccination, leaving a typical scar. Primary vaccination can produce swelling and tenderness of regional lymph nodes, beginning 3-10 days after vaccination and persisting for 2-4 weeks after the skin lesion has healed. Maximum viral shedding occurs 4-14 days following vaccination, but vaccinia can be recovered from the site of vaccination until the scab separates from the skin (30,31). A fever is common after the vaccinia vaccination is administered. Up to 70% of children have 1 or more days of temperature of greater than or equal to 100 F from 4 to 14 days after primary vaccination (9), and 15%-20% have temperatures of greater than or equal to 102 F. After revaccination, 35% of children develop temperatures of greater than or equal to 100 F, and 5% have temperatures of greater than or equal to 102 F (13). Fever is less common in adults than children after vaccination or revaccination (31; CDC, unpublished data). Erythematous or urticarial rashes may occur approximately 10 days after primary vaccination. The vaccinee is usually afebrile, and the rash resolves spontaneously within 2 to 4 days. Rarely bullous erythema multiforme (Stevens-Johnson syndrome) occurs (32). Inadvertent inoculation at other sites is the most frequent complication of vaccinia vaccination, accounting for about half of all complications of primary vaccination and revaccination (Table_1). Inadvertent inoculation usually results from auto-inoculation of vaccine virus transferred from the site of vaccination. The most common sites involved are the face, eyelid, nose, mouth, genitalia, and rectum. Most lesions heal without specific therapy, but vaccinia immune globulin (VIG) may be useful for cases of ocular implantation (see Treatment of Complications of Vaccinia Vaccine). Generalized vaccinia among persons without underlying illnesses is characterized by a vesicular rash of varying extent. The rash is generally self limited and requires little or no therapy except among patients whose conditions appear to be toxic or who have serious underlying illnesses. More severe complications of vaccinia vaccination include eczema vaccinatum, progressive vaccinia, and postvaccinial encephalitis. These complications occur at least 10 times more often among primary vaccinees than among revaccinees and more frequently among infants than among older children and adults (33-35) (Table_1). Eczema vaccinatum is a localized or systemic dissemination of vaccinia virus among persons who have eczema or a history of eczema and other chronic or exfoliative skin conditions (e.g., atopic dermatitis). The illness is usually mild and self limited, but may be severe and occasionally fatal. The most serious cases among vaccine recipients occur among primary vaccinees and appear to be independent of the activity of the underlying eczema (36). Severe cases have also been observed after contact infection (see Contacts of vaccinees). Progressive vaccinia (vaccinia necrosum) is a severe, potentially fatal illness characterized by progressive necrosis in the area of vaccination, often with metastatic lesions. It occurs almost exclusively among persons with cellular immunodeficiency. The most serious complication is postvaccinial encephalitis. Most frequently it affects primary vaccinees <1 year of age. From 15% to 25% of affected vaccinees with this complication die, and 25% have permanent neurologic sequelae (32)(33)(34). Death is rare after vaccinia vaccination, with approximately 1 to 2 deaths per million primary vaccinations and 0.1 death per million revaccinations. Death is most often the result of postvaccinial encephalitis or progressive vaccinia. # Contacts of vaccinees Transmission of vaccinia may occur when a recently vaccinated person has contact with a susceptible person. In the CDC 10-state survey of complications of smallpox vaccination, the risk of transmission to contacts was 27 infections per million total vaccinations; 44% of these contact cases occurred among children less than or equal to 5 years of age (33). Since 1980, several occurrences of contact transmission of vaccinia from recently vaccinated military recruits have been reported, including six cases transmitted by a single vaccine recipient (37)(38)(39). Over 60% of contact transmission results in uncomplicated inadvertent inoculation. Approximately 30% of contact transmission results in eczema vaccinatum, which may be fatal (33). Eczema vaccinatum may be more severe among contacts than among vaccinated persons, possibly because of simultaneous multiple inoculations at several sites (34,40). Contact transmission rarely results in postvaccinial encephalitis or vaccinia necrosum. # PRECAUTIONS AND CONTRAINDICATIONS Before administering vaccinia vaccine, the physician should take a careful history to document the absence of contraindications to vaccination among both vaccinees and household contacts of vaccinees. Special efforts should be made to identify vaccinees and household contacts who have eczema, a history of eczema, or immunodeficiencies. Vaccinia vaccine should not be administered if these conditions are present among either recipients or household contacts. # History or presence of eczema Because of the increased risk of eczema vaccinatum, vaccinia vaccine should not be administered to persons with eczema or a past history of eczema or to those whose household contacts have eczema. Persons with other acute, chronic, or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, or varicella zoster) may also be at higher risk of eczema vaccinatum and should not be vaccinated until the condition resolves. # Pregnancy Vaccinia vaccine should not be administered to pregnant women. On rare occasions, almost always after primary vaccination, vaccinia virus has been reported to cause fetal infection (41). Fewer than 50 cases of fetal vaccinia are known, but cases have been observed as recently as 1978 (35,42). Fetal vaccinia usually results in stillbirth or death of the infant shortly after delivery. Vaccinia vaccine is not known to cause congenital malformations. # Altered immunocompetence Replication of vaccinia virus can be enhanced among persons with immune deficiency diseases and among those with immunosuppression (as occurs with leukemia, lymphoma, generalized malignancy, agammaglobulinemia, or therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids). Persons with such conditions or therapies or whose household contacts have such conditions should not be administered vaccinia vaccine. # Infection with human immunodeficiency virus (HIV) The risk of severe complications after vaccinia vaccination for persons infected with HIV is not known. At least one case of severe generalized vaccinia has been reported in an asymptomatic HIV-infected military recruit after the administration of multiple vaccines, including vaccinia (43). In addition, a recent report suggests that two HIV-infected persons may have died of a progressive vaccinia-like illness after treatment with inactivated autologous lymphocytes infected with a recombinant HIV-vaccinia virus (44). However, at present there is no evidence that smallpox vaccination accelerates the progression of HIV-related disease. Nevertheless, until additional information becomes available, it is prudent not to vaccinate persons who have HIV infection. # Allergies Vaccinia vaccine contains trace amounts of polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate. Persons who experience anaphylactic reactions (hives, swelling of the mouth and throat, difficulty breathing, hypotension, and shock) to any of these antibiotics should not be vaccinated. Vaccinia vaccine does not contain penicillin. # PREVENTION OF CONTACT TRANSMISSION OF VACCINIA Vaccinia virus may be cultured from the site of primary vaccination beginning at the time of development of a papule (2-5 days after vaccination) until the scab separates from the skin lesion (14-21 days after vaccination). During this time, care must be taken to prevent spread of the virus to another area of the body or to another person. The vaccination site should be covered at all times with a porous bandage until the scab has separated and the underlying skin has healed. An occlusive bandage should not be used. The vaccination site should be kept dry. When the vaccinee bathes, the site should be covered with an impermeable bandage. Vaccinated health-care workers may continue to have contact with patients, including those with immunodeficiencies, as long as the vaccination site is covered and good hand-washing technique is maintained. Semipermeable polyurethane dressings (e.g., Opsite (R)) are effective barriers to vaccinia and recombinant vaccinia viruses (21). However, exudate may accumulate beneath the dressing, and care must be taken to prevent viral contamination when the dressing is removed. In addition, accumulation of fluid beneath the dressing may increase the maceration of the vaccination site. Accumulation of exudate may be decreased by first covering the vaccination with dry gauze, then applying the dressing over the gauze. To date, experience with this type of containment dressing has been limited to research protocols, and further investigation is needed before it can be recommended for all vaccinia vaccine recipients. The most important measure to prevent inadvertent implantation and contact transmission from vaccinia vaccination is thorough hand washing after changing the bandage or after any other contact with the vaccination site. # TREATMENT OF COMPLICATIONS OF VACCINIA VACCINE The only product currently available for the treatment of complications of vaccinia vaccination is vaccinia immune globulin (VIG). VIG is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine. It is effective for the treatment of eczema vaccinatum and some cases of progressive vaccinia and may be useful in the treatment of ocular vaccinia resulting from inadvertent implantation. VIG is also recommended for severe generalized vaccinia if the patient has a toxic condition or a serious underlying disease. VIG is of no benefit in the treatment of postvaccinial encephalitis. The recommended dosage for treatment of complications is 0.6 mL/kg of body weight. VIG must be administered intramuscularly and should be administered as early as possible after the onset of symptoms. Because therapeutic doses of VIG may be large (e.g., 42 mL for a person weighing 70 kg), the product should be given in divided doses over a 24-to 36-hour period. Doses may be repeated, usually at intervals of 2-3 days, until recovery begins (e.g., no new lesions appear). CDC is the only source of VIG for civilians. # MISUSE OF VACCINIA VACCINE Vaccinia vaccine should never be used therapeutically for any reason. There is no evidence that it has any value in the treatment or prevention of recurrent herpes simplex infection, warts, or any disease other than those caused by human orthopoxviruses (45). Misuse of vaccinia vaccine to treat herpes infections has been associated with severe complications (46)(47). VACCINIA VACCINE AVAILABILITY CDC is the only source of vaccinia vaccine and VIG for civilians. CDC will provide vaccinia vaccine to protect laboratory and other health-care personnel whose occupations place them at risk of exposure to vaccinia and other closely related orthopoxviruses, including vaccinia recombinants. The vaccine should be administered under the supervision of a physician selected by the institution. Vaccine will be shipped to the responsible physician. Requests for vaccine and VIG, including the reason for the request, should be referred to: Health-care workers are requested to report complications of vaccinia vaccination to the Vaccine Adverse Event Reporting System (800-822-7967) or to their state or local health department. Drug # Table_1 Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size. ----------------------------------------------------------------------------------------------------- -----------------------------------------------------------------------------------------------------	None	None
30dd9f08c9a0bc2dfa73cab8fb85aefa96f93970	cdc	None	Maryland, to develop recommendations for the use of zidovudine to reduce the risk for perinatal transmission of human immunodeficiency virus (HIV). The recent results of AIDS Clinical Trials Group Protocol 076, a controlled clinical trial sponsored by the National Institutes of Health in collaboration with the National Institute of Health and Medical Research and the National Agency of Research on AIDS in France, indicate that zidovudine administered to a selected group of HIV-infected women and their infants can reduce the risk for perinatal transmission of HIV by approximately twothirds. The implications of these results for use of zidovudine in HIV-infected pregnant women and neonates were discussed at the workshop. The following persons participated in the workshop and either served as the Executive Committee writing group that developed the recommendations or were members of the U.S. Public Health Service Task Force on the Use of Zidovudine to Reduce Perinatal HIV Transmission.# INTRODUCTION Worldwide, perinatal (i.e., mother-to-infant) transmission accounts for most human immunodeficiency virus (HIV) infections among children. In the United States, approximately 7,000 infants, 1,000-2,000 of whom are HIV infected, are born to HIVinfected women each year (2 ). In the United States, HIV is currently the seventh leading cause of death in children 1-4 years of age (3 ) and the fourth among women 25-44 years of age (4 ). The ideal approach to reducing perinatal transmission is to prevent HIV infection among women. However, despite ongoing efforts to provide education about HIV prevention, the incidence of infections among women of reproductive age in the United States is increasing in some areas (2 ). In the United States, where safe alternatives to breast milk are available, HIV-infected women are advised to refrain from breastfeeding to avoid postnatal transmission of HIV to their infants (5 ). However, refraining from breastfeeding will not prevent transmission occurring in utero or intrapartum, and strategies to reduce transmission during these periods are being evaluated. The recently reported interim results of the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Protocol 076, a clinical trial sponsored by the National Institutes of Health in collaboration with the National Institute of Health and Medical Research and the National Agency of Research on AIDS in France, indicate that zidovudine (ZDV) administered to a selected group of HIV-infected pregnant women and their infants can reduce the risk for perinatal HIV transmission by approximately two-thirds (1,6 ). This use of ZDV has the potential to substantially reduce the rate of perinatal transmission, which would reduce overall child mortality. However, the results of this study are directly applicable only to HIV-infected women with characteristics similar to those of the women who entered the study, and the long-term risks of ZDV used in this manner are not known. On June 6-7, 1994, the U.S. Public Health Service convened a workshop, "Use of ZDV to Prevent Perinatal HIV Transmission (ACTG Protocol 076): Workshop on Implications for Treatment, Counseling, and HIV Testing." The medical, scientific, public health, and legal communities and interested professional, community, and advocacy organizations were represented. The workshop addressed two issues related to the results of ACTG Protocol 076: a) treatment recommendations for the use of ZDV to reduce perinatal transmission of HIV and b) the implications of the trial results for HIV counseling and testing. This report summarizes the conclusions of the workshop with regard to the use of ZDV to reduce perinatal transmission, provides recommendations for treatment options for HIV-infected pregnant women and their newborns and medical monitoring for pregnant women and neonates receiving ZDV, and discusses issues related to long-term follow-up of women and their children who have received ZDV. # BACKGROUND Summary of Results of ACTG Protocol 076 On February 21, 1994, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development announced the interim results of a randomized, multicenter, double-blind, placebocontrolled clinical trial, ACTG Protocol 076. Eligible participants were HIV-infected pregnant women at 14-34 weeks of gestation who had received no antiretroviral therapy during their current pregnancy, had no clinical indications for antepartum antiretroviral therapy, and had CD4+ T-lymphocyte counts ≥200/µL at the time of entry into the study (Box 1). The study began in April 1991; as of December 20, 1993, the time of the interim analysis, 477 women had been enrolled and 421 infants born. The racial/ethnic distribution of the HIV-infected women enrolled in the trial was similar to that of the total population of HIV-infected women in the United States. Enrolled women were assigned randomly to receive a regimen of either ZDV or placebo. The ZDV regimen included oral ZDV initiated at 14-34 weeks of gestation and continued throughout the pregnancy, followed by intravenous ZDV during labor and oral administration of ZDV to the infant for 6 weeks after delivery (Box 2). The placebo regimen was administered identically. Blood specimens were obtained for HIV culture from all infants at birth and at 12, 24, and 78 weeks of age. A positive viral culture was considered indicative of HIV infection. Sera from the infants at 15 and 18 months of age also were tested for HIV antibody. The Kaplan-Meier method (7 ) was used to estimate the rate of perinatal transmission at 18 months of age among the 364 children whose HIV infection status was known on the basis of culture and who therefore were included in the interim analysis. The estimated transmission rate was 25.5% among the 184 children in the placebo group (95% confidence interval =18.4%-32.5%), compared with 8.3% among the 180 children in the ZDV group (95% CI=3.9%-12.8%). The difference in the estimated transmission rate between the two groups was statistically significant (p=0.00006). ZDV treatment did not appear to delay the diagnosis of HIV infection. Observed toxicity specifically attributable to ZDV was minimal among the women in this study. Adverse effects such as anemia, neutropenia, thrombocytopenia, and liver chemistry abnormalities were reported as frequently among women receiving placebo as among women receiving ZDV. Six women-three in each treatment group-discontinued therapy because of toxicity attributed to the study drug. The women were evaluated at 6 weeks and 6 months postpartum. A statistically significant increase in CD4+ T-lymphocyte count from baseline to 6 weeks postpartum was observed for women in both ZDV and placebo treatment groups; this increase was greater among women in the ZDV group. At 6 months postpartum, the CD4+ T-lymphocyte counts for both groups had decreased to similar levels. CD4+ T-lymphocyte counts decreased to <200/µL in only four women, including one receiving ZDV and three receiving placebo. No women died during the study. # BOX 2. Zidovudine regimen from AIDS Clinical Trials Group Protocol 076 - Oral administration of 100 mg of zidovudine (ZDV) five times daily, initiated at 14-34 weeks of gestation and continued throughout the pregnancy. - During labor, intravenous administration of ZDV in a 1-hour loading dose of 2 mg per kg of body weight, followed by a continuous infusion of 1 mg per kg of body weight per hour until delivery. - Oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg of body weight per dose every 6 hours) for the first 6 weeks of life, beginning 8-12 hours after birth. # BOX 1. Eligibility criteria for HIV-infected pregnant women participating in AIDS Clinical Trials Group Protocol 076 - Pregnancy at 14-34 weeks of gestation. - No antiretroviral therapy during the current pregnancy. - No clinical indications for antenatal antiretroviral therapy. - CD4+ T-lymphocyte count ≥200 cells/µL at the time of entry into the study. Serial sonographic evaluations for fetal growth and amniotic fluid volume as conducted in the study (at entry and every 4 weeks from 28 weeks of gestation until delivery) demonstrated no differences between pregnancies in women who had received placebo or ZDV. Birth parameters (gestational age; birth weight, length, and head circumference; and Apgar scores) were similar among infants born to women in either group. The median birth weight was 3,160 g (range: 1,040-5,267 g), and the median gestational age at birth was 39 weeks (range: 27-43 weeks). No statistically significant difference was observed between the ZDV and placebo groups in the number of infants with birth weight <2,500 g, who were small or large for gestational age, or who were born prematurely. The occurrence of major or minor congenital abnormalities was approximately equal between the two groups, and no pattern in the type of abnormalities was observed. The infants in the study tolerated the ZDV therapy well. The only adverse effect observed more frequently among infants in the ZDV treatment group was mild, transient anemia. Hemoglobin values for infants in the group receiving ZDV were lower than for the group receiving placebo, with a maximum mean difference of 1 gm/dL occurring at 3 weeks of age. The lowest mean hemoglobin value in infants receiving ZDV occurred at 6 weeks of age and resolved without therapy for anemia after the infants had completed the ZDV treatment. The hemoglobin values of infants receiving ZDV were similar to those of placebo recipients by 12 weeks of age. The incidence of neutropenia and serum chemistry abnormalities was similar between ZDV and placebo groups of infants, and no difference in the pattern of chemistry abnormalities was observed. Based on these interim findings, NIAID accepted the recommendation of its independent data and safety monitoring board to terminate enrollment into the trial and to offer ZDV to women in the placebo group who had not yet delivered and to their infants up to 6 weeks of age.- Follow-up of patients enrolled in the study is ongoing. # Limitations in Interpretation and Extrapolation of ACTG Protocol 076 Results This clinical trial demonstrated that the ACTG Protocol 076 ZDV regimen can substantially reduce perinatal HIV transmission. However, several important limitations should be noted. First, perinatal HIV transmission was still observed despite drug therapy. Second, the efficacy of this therapy is unknown for HIV-infected pregnant women who have advanced disease, who have received prior antiretroviral therapy, or who have ZDV-resistant virus strains. Third, although the ZDV regimen used in this trial was not associated with serious short-term adverse effects, such effects may be observed when this use of ZDV becomes more widespread. Fourth, the long-term risks for the child associated with exposure to ZDV in utero and early infancy have not been determined. Fifth, it is not known if use of ZDV during pregnancy will affect the drug's efficacy for the woman when it becomes clinically indicated for her own health. Further complicating the incorporation of this ZDV regimen into clinical practice is the fact that some HIV-infected women seek medical care late in pregnancy or when A summary of the study's findings is available from the AIDS Clinical Trials Information Service at 1(800)TRIALS-A (1874-2572). they are already in labor, when the full ZDV regimen used in ACTG Protocol 076 cannot be administered. Moreover, many pregnant women are not aware that they are HIV infected, are not tested before or during pregnancy, and remain undiagnosed. As a result, they do not receive information about therapy that could reduce the risk for HIV transmission to their infants. # Potential Long-Term Adverse Effects of ZDV Administered During Pregnancy The long-term effects of ZDV treatment during pregnancy solely to reduce perinatal transmission or of fetal and neonatal exposure to ZDV are not known. ZDV is a nucleoside analog that inhibits HIV replication by interfering with HIV RNA-dependent DNA polymerase. ZDV triphosphate also can inhibit human cellular DNA polymerases, but only at concentrations much higher than those required to inhibit HIV polymerase. However, gamma DNA polymerase, which is required for mitochondrial replication, may be inhibited by ZDV at concentrations nearer to those that can be achieved in vivo. Concerns related to the potential long-term toxicity of nucleoside analogs include potential mutagenic and carcinogenic effects, possible effects on tissues with high mitochondrial content (such as hepatic and cardiac tissue), possible teratogenicity, and possible effects on the reproductive system. ZDV has been shown to be a mutagen in vitro, and, in a mammalian in vitro cell transformation assay, ZDV was positive at concentrations of ≥0.5 µg/mL (8 ). Noninvasive squamous epithelial vaginal tumors were produced after 19-21 months of continuous dosing in 12% of mice administered a dosage equivalent to three times the estimated human exposure at the recommended therapeutic dosage. Similar findings were observed in 3% of rats that received 24 times the recommended therapeutic dosage. Carcinogenicity studies in rodents, however, may not be predictive of human experience. In humans, an increased incidence of non-Hodgkin's lymphoma has been reported in HIV-infected men receiving ZDV, but this increase probably reflects longer survival despite severe immunodeficiency rather than a direct effect of ZDV (9 ). The potential for carcinogenesis should be further assessed through continued follow-up of children who were exposed to ZDV in utero. Myopathy and cardiomyopathy have been associated with ZDV therapy. In an individual patient, the effects secondary to ZDV are often difficult to distinguish from those of HIV infection. A prospective study of HIV-infected children demonstrated no effect of ZDV therapy on cardiac function (10 ). Reproductivity/fertility studies in animals have demonstrated no adverse effects of ZDV on either the fertility of male or female rats or the reproductive capacity of their offspring (11 ). ZDV administered to mice early in gestation was associated with an embryotoxic effect and fetal resorptions; however, ZDV administered at or beyond midgestation had no detectable effect on the fetus (12,13 ). ZDV is assigned pregnancy category C status by the Food and Drug Administration (FDA).- Most studies of ZDV administered to pregnant animals have not demonstrated teratogenicity. In one study, pregnant rats were administered toxic doses of ZDV during organogenesis (i.e., equivalent to approximately 50 times the recommended daily clinical dose, based on relative body surface areas); developmental malformations and skeletal abnormalities were observed in 12% of fetuses (14 ). In humans, observational studies involving small numbers of subjects have demonstrated no apparent association of fetal malformations with antenatal ZDV use (15)(16)(17)(18)(19). In ACTG Protocol 076, the incidence of congenital malformations was similar for ZDV and placebo recipients. However, because ZDV was not administered until after 14 weeks of gestation in this study, the potential teratogenicity of ZDV administered during the first trimester cannot be assessed. Similarly, in a recent report from the Antiretroviral Pregnancy Registry maintained by the Wellcome Foundation and Hoffman LaRoche in conjunction with CDC, no increase in the risk of congenital abnormalities above that expected for all pregnancies was observed among infants born to 121 prospectively registered HIV-infected women who received ZDV during pregnancy, nor was there any unusual pattern of birth defects (20 ). Use of ZDV during pregnancy could be associated with the development of ZDV-resistant virus, which may lessen the drug's therapeutic benefit for the woman when it is needed for her own health. However, patients with early-stage HIV disease rarely develop ZDV-resistant strains before they have received 18-24 months of continuous therapy (21 ). After discontinuation of ZDV therapy, an increase in ZDVsusceptible isolates has been observed in some patients who had ZDV-resistant isolates while they were receiving ZDV, although resistance to ZDV has been reported to persist for more than a year after therapy was discontinued (22,23 ). Because the development of ZDV-resistant viral strains secondary to transient ZDV use during pregnancy is a theoretical concern, considerations for the woman's future health care should include the availability of alternative drugs for treatment of HIV infection. # GENERAL PRINCIPLES REGARDING TREATMENT RECOMMENDATIONS The following treatment recommendations have been formulated to provide a basis for discussion between the woman and her health-care provider about the use of ZDV to reduce perinatal transmission. HIV-infected women should be informed of the substantial benefit and short-term safety of ZDV administered during pregnancy and the neonatal period observed in ACTG Protocol 076. However, they also must be FDA pregnancy categories are: A, in which adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk during later trimesters); B, in which animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted; C, in which safety in human pregnancies has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, in which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; and X, in which studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. informed that the long-term risks of ZDV therapy to themselves and their children are unknown. A woman's decision to use ZDV to reduce the risk for HIV transmission to her infant should be based on a balance of the benefits and potential risks of the regimen to herself and to her child. Discussion of treatment options should be noncoercive, and the final decision to accept or reject ZDV treatment recommended for herself and her child is the right and responsibility of the woman. A decision not to accept treatment should not result in punitive action or denial of care, nor should ZDV be denied to a woman who decides to receive the regimen. Various circumstances that commonly occur in clinical practice are described and the factors influencing treatment considerations are highlighted in the following discussion (Box 3). All potential clinical situations cannot be enumerated, and, in many cases, definitive evidence upon which to base a recommendation is not currently available. Therefore, each pregnant woman and her health-care provider must consider the potential benefits, unknown long-term effects, and gaps in knowledge relating to her clinical situation. Furthermore, health-caregivers and institutions should provide culturally, linguistically, and educationally appropriate information and counseling to the HIV-infected woman so that she can make informed decisions. # CLINICAL SITUATIONS AND RECOMMENDATIONS FOR USE OF ZDV TO REDUCE PERINATAL TRANSMISSION Clinical Situation Meeting the Entry # Discussion: The results of ACTG Protocol 076 are directly applicable only to women who meet the entry criteria for the study (Table 1). The data from that study indicate that the complete ACTG Protocol 076 ZDV regimen will likely reduce the risk for perinatal transmission by about two-thirds. Because this study was randomized and placebo controlled, entry was restricted to women who had no clinical indications for ZDV use for their own health and who had CD4+ T-lymphocyte counts ≥200/µL. Prior ZDV use during the current pregnancy resulted in exclusion from the study. Few women (4%) had received ZDV before the current pregnancy, and most of that therapy was of limited duration. Women were not enrolled either before the 14th week or after the 34th week of gestation. The rationale for exclusion before 14 weeks of gestation was to preclude ZDV exposure during fetal organogenesis. The 34-week limit allowed most women to receive several weeks of ZDV before delivery to allow time for a decrease in maternal viral load (a presumed important determinant of transmission risk). Although ZDV was successful in reducing perinatal transmission, the study regimen did not completely prevent it. The possible reasons for transmission to these infected infants are being evaluated but have not yet been identified. Several case reports also have described perinatal transmission despite the initiation of ZDV therapy during pregnancy (24)(25)(26)(27). Although long-term toxicity to infants is unknown, this risk must be weighed against the decreased risk for transmission of an infection associated with substantial risk of death. Currently, there is no way to predict if an individual pregnancy will be associated with HIV transmission; therefore, each fetus must be considered to have an estimated 25% risk of a life-threatening infection. Because ZDV therapy reduced the rate of transmission by two-thirds (from 25.5% to 8.3%), any long-term toxicity related to ZDV would have to be severe (e.g., malignancy or profound developmental delay) and relatively common among ZDV-exposed infants to outweigh the substantial benefit. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider. # Clinical Situations Not Meeting the Study Entry Criteria Information about the benefit and short-term risks of ZDV therapy is applicable from this trial only for women who meet the entry criteria of the study. Recommendations about use of the ZDV regimen for women whose clinical conditions differ from the ACTG Protocol 076 eligibility criteria were derived from consensus interpretation of available scientific data. # II. Pregnant # Discussion: This patient population has clinical characteristics similar to those of women enrolled in ACTG Protocol 076; the major difference is gestational age at which ZDV therapy would begin. Therefore, the ZDV regimen for these women would differ from the ACTG Protocol 076 regimen only in duration of antenatal therapy. As much as 50%-70% of perinatal transmission may occur close to or during delivery (28 ). Therefore, the ACTG Protocol 076 ZDV regimen may have some benefit when initiated at >34 weeks of gestation, although the intervention is likely to decrease in effectiveness as the duration of antenatal ZDV administration is reduced. A study evaluating the effect of ZDV on quantitative p24 antigen levels indicates that maximal effect is observed after 8-16 weeks of therapy (29). A shorter duration of ZDV therapy may thus be associated with an effect on maternal viral load that is less than can be anticipated when ZDV is initiated before 34 weeks of gestation. Both potential risks and benefits for the woman and her infant may decrease the closer to delivery that the ZDV regimen is initiated. Further clinical trials should be designed to assess the efficacy of interventions that are initiated late in the third trimester for preventing perinatal transmission. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester. # III. Pregnant HIV-infected women with CD4+ T-lymphocyte counts 6 months) prior antiretroviral therapy. Discussion: Women in this group meet the current standard of care for ZDV treatment of HIV infection for their own benefit (30,31 ); therefore, administration of ZDV during pregnancy for these women provides direct benefit to them as well as potential benefit to their infants. The risk for HIV transmission to the infants of HIV-infected pregnant women with low CD4+ T-lymphocytes or percent of total lymphocytes ranges from 22% to 60% (32)(33)(34)(35)(36)(37)(38).Viral load has been shown to increase as CD4+ T-lymphocyte count decreases (39 ); thus, baseline viral loads can be expected to be high among the women in this group. Although viral replication and resultant capacity for mutations in this group are high, preexisting ZDV-resistant viral strains are unlikely to be present because these women have had little or no exposure to ZDV. Therefore, ZDV therapy can be expected to result in an acute reduction in maternal viral load analogous to that observed in women who have CD4+ T-lymphocyte counts ≥200/µL. Additionally, the mother's CD4+ T-lymphocyte count would not be expected to affect ZDV levels or toxicity in the infant after administration of ZDV during labor and the first 6 weeks of life. Hence, maternal CD4+ T-lymphocyte count should not affect the potential utility of neonatal levels of systemic ZDV for reducing intrapartum transmission. Although this population of pregnant women was not studied in ACTG Protocol 076, addition of the intrapartum and neonatal components of the ACTG Protocol 076 ZDV regimen to antenatal maternal therapy may reduce the risk for HIV transmission. However, the magnitude of the effect of ZDV on reducing the transmission rate in this group may not be the same as that demonstrated in ACTG Protocol 076 for women with CD4+ T-lymphocyte counts ≥200. Further clinical trials should assess the utility of interventions in this group of women. Because ZDV therapy is clinically indicated for these women for their own health, the additional risk of the remainder of the ACTG Protocol 076 regimen is the discomfort to the woman of another intravenous infusion during labor and the possible effects of the additional 6 weeks of ZDV exposure for the infant. # Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit (31 ). The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman. # IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy. # Discussion: Women who have received extensive prior ZDV therapy may be infected with viral strains with reduced susceptibility to ZDV. These resistant strains of HIV can be transmitted from mother to fetus; however, the frequency with which such transmission occurs is unknown. Resistant virus appears to emerge more quickly if therapy is initiated at later stages of HIV disease (21 ). The appearance of mutations associated with ZDV resistance follows a temporal pattern, and the level of in vitro resistance is proportional to the number of mutations in the reverse transcriptase-coding region of HIV (40 ). Phenotypically and genotypically diverse HIV populations can coexist in patients who are receiving ZDV therapy. In one study, ZDV-resistant strains appeared earlier during ZDV therapy in patients with advanced HIV disease than in patients whose ZDV therapy was initiated at an early stage of the disease. After 12 months of ZDV therapy, viral isolates from 89% of patients with late-stage disease and 31% of those with early-stage disease were resistant (21 ). However, isolates from only 33% of latestage patients demonstrate high-level resistance (defined as a 100-fold decrease in susceptibility ). Resistant virus also was more likely to be isolated from patients who had low CD4+ T-lymphocyte counts when therapy was initiated: 1-year estimated rates of resistance in patients with baseline CD4+ T-lymphocyte counts of >400, 100-400, and <100 cells/µL were 27%, 41%, and 89%, respectively. In patients with advanced disease, high-level resistance develops after 6-18 months of therapy. However, in patients with early-stage disease, highlevel resistance appears to be delayed until after 24 months of therapy (22 ). Therefore, ZDV-resistant strains are likely to be more common in women with advanced disease who have received prolonged therapy. ZDV-resistant viral strains also may be more common in persons receiving alternative antiretroviral agents because their disease progressed while they were receiving ZDV therapy. There is controversy regarding the association of clinical disease progression during ZDV therapy with the development of ZDV resistance and regarding whether resistance persists when therapy is changed to an alternative antiretroviral agent (41 ). Some studies involving small numbers of children have indicated that in vitro susceptibility to ZDV is correlated with clinical outcome, suggesting that ZDV-resistant isolates are associated with diminished efficacy of ZDV and more rapid clinical progression (42,43 ). However, at least one study indicated that disease progression may be associated more closely with the development of syncytia-inducing viral phenotype than with resistance to ZDV (44 ). Change to alternative antiretroviral therapy has been associated with reversal of ZDV resistance in some studies, but resistance has been reported to persist for considerable periods of time after discontinuation of ZDV (23,45 ). The prevalence of ZDV-resistant viral strains in women who are receiving alternative antiretroviral agents because of disease progression has not been defined. The capability of ZDV to reduce HIV transmission may be decreased for mothers in whom ZDV-resistant strains predominate, particularly if the strains have high-level resistance; however, this assumption is not yet supported by data. Further clinical trials to evaluate alternative approaches for such women are needed. # Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen on a case-bycase basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood that she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status. # V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor. # Discussion: Data from studies in humans are insufficient to evaluate the potential effectiveness of ZDV in this situation. Because the mother's exposure to ZDV would be brief, such therapy can be expected to have no effect on the level of maternal virus in blood or genital secretions. However, because of the intravenous loading dose and continuous infusion of ZDV during labor, the infant will be born with circulating levels of ZDV similar to those of infants whose mothers have received antenatal as well as intrapartum ZDV. ZDV may have some utility for this group of patients-regardless of whether the pregnancy is at term or preterm-because the presence of systemic levels of ZDV in the infant before or shortly after HIV exposure through contact with the mother's blood and genital secretions during delivery may help prevent intrapartum transmission. The intravenous route was chosen for drug dosing during labor in ACTG Protocol 076 because continuous intravenous infusion of drug after an initial loading dose results in predictable levels of ZDV in the mother. Under optimal circumstances, these maternal levels provide a substantial fetal blood level during birth, when the infant is presumed to be exposed extensively to HIV through contact with the mother's blood and genital secretions. Because gastric emptying is delayed during labor, the absorption of orally administered drugs is unpredictable (46 ). Therefore, oral administration of ZDV during labor might produce widely variable systemic levels in the mother and infant. Oral ZDV administered intrapartum cannot be assumed to be equivalent to the intravenous intrapartum ZDV component used in ACTG Protocol 076. Further studies are needed to characterize the pharmacokinetics of oral ZDV during labor. Intrapartum ZDV cannot prevent the substantial number of infections that occur before labor (26 ). Therefore, ZDV administered only during labor and to the newborn may not be effective. Because the mother would receive ZDV only during labor, her risk for developing resistant virus or ZDV toxicity would be minimal. The primary risk is that associated with an intravenous catheter. The risk to the infant would be limited to the potential toxicity associated with transfer of drug from the maternal intrapartum infusion and with 6 weeks of oral ZDV therapy, without in utero exposure to the drug. The effect of neonatal ZDV treatment in ameliorating disease progression in infected infants is unknown. Clinical trials should be designed to address the efficacy of antiretroviral therapy in this situation. # Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits. # VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy. # Discussion: Infants whose mothers have not received ZDV during late pregnancy and/or labor will not have circulating ZDV levels during birth, a period of presumed viral exposure. Data are insufficient to allow assessment of the potential efficacy of postexposure prophylaxis with ZDV in this situation. Studies of postexposure prophylaxis of retroviral infection with ZDV in animal models have yielded inconclusive results. Additionally, studies involving animal models should be interpreted with caution: many of these studies have involved nonhuman retroviruses that may have different pathogenic mechanisms from those of HIV, used methods of viral inoculation that are not relevant to perinatal transmission (e.g., intrathymic injection), and/or used a massive inoculum of virus (47 ). The limited data from animal studies indicate that if ZDV is to have any effect as postexposure prophylaxis, prompt administration (within hours) is important, and that even with early initiation of ZDV, such prophylaxis may not be protective. In a SCID-hu mouse model of HIV infection (an immune-deficient model reconstituted with human cells), a time-dependent suppression of HIV replication was observed with ZDV prophylaxis (48 ). When ZDV was administered within 2 hours of viral inoculation, viral replication was not detectable at 2 weeks after inoculation in all treated animals; when ZDV was administered 2-36 hours after inoculation, rates of viral detection at 2 weeks increased in proportion to increasing time since ZDV was administered; and when ZDV was administered 48 hours after inoculation, virus was detectable in all animals (48 ). Therefore, whether the effect of ZDV therapy is prevention or suppression of infection cannot be established. In several animal model systems, ZDV administration was observed only to suppress or ameliorate retroviral infection (49)(50)(51). # Infant Monitoring A complete blood count and differential should be performed at birth as a baseline evaluation. Repeat measurements of hemoglobin are recommended at 6 and 12 weeks of age. ZDV should be administered with caution to infants born with severe anemia (hemoglobin <8 gm/dL), and treatment of the anemia and intensive monitoring are warranted if the drug is administered. Previously published guidelines contain recommendations for diagnosing HIV infection in infants and for initiating PCP prophylaxis and antiretroviral therapy for those who are infected (53)(54)(55). The potential efficacy of ZDV therapy for HIV-infected children who require antiretroviral therapy and who received ZDV in utero and during early infancy has not been determined. A specialist in pediatric HIV infection may be consulted if therapy is necessary for infected children whose mothers received ZDV during pregnancy. Further research is needed to describe the response to therapy and progression of disease in such infants. # POTENTIAL LONG-TERM EFFECTS OF ZDV THERAPY FOR MOTHERS AND INFANTS AND RECOMMENDATIONS FOR FOLLOW-UP Discussion Observational data about the pregnancy outcomes of women who receive ZDV during pregnancy are being collected through the Antiretroviral Pregnancy Registry. The purpose of the registry is to provide surveillance for possible teratogenicity among infants born to women who received ZDV during pregnancy. Health-care providers can register such patients by calling the registry at (800 Concerns about the potential long-term adverse effects among women include development of ZDV-resistant virus when ZDV therapy is used intermittently to reduce perinatal transmission, particularly during more than one pregnancy, and the potential effect such resistance could have on disease progression for the woman. Although results of studies have demonstrated an association between emergence of ZDV resistance and total duration of ZDV exposure, none of the study designs has specifically addressed the effect of intermittent therapy on development of resistance. Continued follow-up of the women who participated in ACTG Protocol 076 and of their infants is planned. A protocol to provide prospective evaluation of the health of the women enrolled in ACTG Protocol 076 is being designed by the Women's Health Committee of the ACTG. This protocol will evaluate virologic, immunologic, and clinical parameters among participating women. Data are insufficient to address any effect that exposure to ZDV in utero might have on risk for neoplasia or organ system toxicities. ACTG Protocol 219 is an ongoing study designed to provide prospective evaluation for children who have been exposed through ACTG protocols to antiretroviral agents in utero or to HIV vaccines until they are 21 years of age. This protocol will provide intensive evaluation of multiple organ system functions, neuropsychologic testing, and quality of life. Information about the potential long-term effects of the complete or partial ACTG Protocol 076 ZDV regimen on women and children receiving the regimen outside a clinical trial protocol also may be provided from evaluation of federally funded and other prospective studies of HIVinfected women and their infants. # Recommendation: Additional efforts are required to characterize the long-term effects of the ACTG Protocol 076 ZDV regimen on women and children. The specific issues of viral resistance and disease progression should be addressed among women who receive ZDV during pregnancy solely to reduce perinatal HIV transmission. Monitoring for these HIV-infected women should include Pap smears and gynecologic examinations as recommended in previously published guidelines (56 ), as well as an assessment of the patient's future needs for family planning consultation and services. Long-term follow-up of both uninfected and infected infants born to mothers receiving ZDV during pregnancy is important. Assessment of organ system toxicities, neurodevelopment, pubertal development, reproductive capacity, and development of neoplasms should be emphasized. Special studies will need to be developed to address these specific concerns, and innovative methods and support systems should be designed to assist in follow-up of these women and their children. # CONCLUSION The decision by an HIV-infected pregnant woman to use ZDV to reduce the risk for perinatal transmission requires a complex balance of individual benefits and risks that is best accomplished through discussions with her health-care provider. Such discussions should be noncoercive, linguistically and culturally appropriate, and tailored to the patient's educational level. The recommendations in this report have been developed for use in the United States. Although perinatal transmission of HIV infection is an international problem, alternative strategies may be appropriate in other countries (57 ). The policy and practice in other countries may differ from these recommendations and depend on local considerations, such as availability of ZDV, access to facilities for intravenous infusion during labor, and alternative interventions that may be under evaluation. These recommendations have been developed in response to the urgent need to provide guidance to women and health-care providers in the United States about the use of ZDV to reduce the risk for perinatal HIV transmission and about the possible adverse outcomes of such ZDV treatment. They have been formulated on the basis of the available data from ACTG Protocol 076 and current information regarding factors associated with transmission. The information on which these recommendations are based is incomplete, and additional information is needed to optimize use of ZDV for this purpose. The decision to use the ACTG Protocol 076 regimen for preventing perinatal transmission of HIV requires weighing the benefits and potential risks to the HIV-infected woman and her child despite numerous uncertainties. Further research is a high priority and should include a) clarification of long-term risks of the ZDV regimen to the woman and/or her child, b) elucidation of the reasons for transmission despite use of the ZDV regimen, c) delineation of the relative efficacy of the various components of the ACTG Protocol 076 ZDV regimen for reducing transmission, d) evaluation of the efficacy of the regimen in women whose characteristics differ from those enrolled in ACTG Protocol 076, and e) evaluation of other interventions for preventing perinatal transmission. As further information becomes available, these recommendations may need to be modified. In addition, appropriate methods and materials should be developed for communicating treatment options, risks, and benefits to women and health-care providers so that they can make informed decisions about treatment. on a case-by-case basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status. V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor. # Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits. VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy. # Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is >24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant. # BOX 3. Summary: Clinical situations and recommendations for use of zidovudine to reduce perinatal HIV transmission (Continued) The material in this report was prepared for publication by: Lynne At least 13 reports have described the failure of prophylactic ZDV to prevent HIV infection in humans following exposure to HIV-infected blood, even though the drug was administered promptly after exposure (52 ). Although these anecdotal reports do not establish that ZDV therapy is ineffective as postexposure prophylaxis, its efficacy can be expected to be lower in this situation than with the full regimen. Further studies are needed to evaluate whether a therapy administered only during the neonatal period can effectively prevent perinatal transmission. # Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is >24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant. # RECOMMENDATIONS FOR MONITORING THE ZDV REGIMEN FOR MOTHERS AND INFANTS Women and their children should receive care together in a family-centered setting. Care should be coordinated between gynecologic, pediatric, internal medicine, infectious disease, and other health-care specialists to ensure that both mother and child receive appropriate medical follow-up. A comprehensive program of support services is necessary to ensure that both mother and child continue to receive health care. # Maternal Monitoring HIV-infected pregnant women should be monitored in accordance with previously published guidelines (31,53 ). Monitoring during pregnancy should include monthly assessment for ZDV-associated hematologic and liver chemistry abnormalities. Indications of toxicity that might require interrupting or stopping the dose of ZDV include a) hemoglobin <8 gm/dL, b) absolute neutrophil count <750 cells/µL, or c) AST (SGOT) or ALT (SGPT) greater than five times the upper limit of normal. CD4+ T-lymphocyte counts should be monitored to determine if prophylaxis for opportunistic infections, such as Pneumocystis carinii pneumonia (PCP), should be initiated. Pregnant HIV-infected women with CD4+ T-lymphocyte counts <200 cells/µL should receive appropriate PCP prophylaxis. If the CD4+ T-lymphocyte count is <600 cells/µL, the evaluation should be repeated each trimester. CD4+ T-lymphocyte counts should be measured at 6 weeks and 6 months postpartum to evaluate if antiretroviral therapy is indicated. # Fetal Monitoring Antepartum testing, including sonographic and nonstress testing and intrapartum fetal monitoring, should be performed only as clinically indicated, not specifically because the patient is being treated with ZDV during pregnancy. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider. # II. Pregnant HIV-infected women who are at >34 weeks of gestation, who have no history of extensive (>6 months) prior antiretroviral therapy, and who do not require ZDV for their own health. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester. # III. Pregnant HIV-infected women with CD4+ T- # Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit. The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman. # IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy. # Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen *These recommendations do not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. All material in the MMWR Series is in the public domain and may be used and reprinted without special permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1994-533-178/05020 Region IV	Maryland, to develop recommendations for the use of zidovudine to reduce the risk for perinatal transmission of human immunodeficiency virus (HIV). The recent results of AIDS Clinical Trials Group Protocol 076, a controlled clinical trial sponsored by the National Institutes of Health in collaboration with the National Institute of Health and Medical Research and the National Agency of Research on AIDS in France, indicate that zidovudine administered to a selected group of HIV-infected women and their infants can reduce the risk for perinatal transmission of HIV by approximately twothirds. The implications of these results for use of zidovudine in HIV-infected pregnant women and neonates were discussed at the workshop. The following persons participated in the workshop and either served as the Executive Committee writing group that developed the recommendations or were members of the U.S. Public Health Service Task Force on the Use of Zidovudine to Reduce Perinatal HIV Transmission.# INTRODUCTION Worldwide, perinatal (i.e., mother-to-infant) transmission accounts for most human immunodeficiency virus (HIV) infections among children. In the United States, approximately 7,000 infants, 1,000-2,000 of whom are HIV infected, are born to HIVinfected women each year (2 ). In the United States, HIV is currently the seventh leading cause of death in children 1-4 years of age (3 ) and the fourth among women 25-44 years of age (4 ). The ideal approach to reducing perinatal transmission is to prevent HIV infection among women. However, despite ongoing efforts to provide education about HIV prevention, the incidence of infections among women of reproductive age in the United States is increasing in some areas (2 ). In the United States, where safe alternatives to breast milk are available, HIV-infected women are advised to refrain from breastfeeding to avoid postnatal transmission of HIV to their infants (5 ). However, refraining from breastfeeding will not prevent transmission occurring in utero or intrapartum, and strategies to reduce transmission during these periods are being evaluated. The recently reported interim results of the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Protocol 076, a clinical trial sponsored by the National Institutes of Health in collaboration with the National Institute of Health and Medical Research and the National Agency of Research on AIDS in France, indicate that zidovudine (ZDV) administered to a selected group of HIV-infected pregnant women and their infants can reduce the risk for perinatal HIV transmission by approximately two-thirds (1,6 ). This use of ZDV has the potential to substantially reduce the rate of perinatal transmission, which would reduce overall child mortality. However, the results of this study are directly applicable only to HIV-infected women with characteristics similar to those of the women who entered the study, and the long-term risks of ZDV used in this manner are not known. On June 6-7, 1994, the U.S. Public Health Service convened a workshop, "Use of ZDV to Prevent Perinatal HIV Transmission (ACTG Protocol 076): Workshop on Implications for Treatment, Counseling, and HIV Testing." The medical, scientific, public health, and legal communities and interested professional, community, and advocacy organizations were represented. The workshop addressed two issues related to the results of ACTG Protocol 076: a) treatment recommendations for the use of ZDV to reduce perinatal transmission of HIV and b) the implications of the trial results for HIV counseling and testing. This report summarizes the conclusions of the workshop with regard to the use of ZDV to reduce perinatal transmission, provides recommendations for treatment options for HIV-infected pregnant women and their newborns and medical monitoring for pregnant women and neonates receiving ZDV, and discusses issues related to long-term follow-up of women and their children who have received ZDV. # BACKGROUND Summary of Results of ACTG Protocol 076 On February 21, 1994, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development announced the interim results of a randomized, multicenter, double-blind, placebocontrolled clinical trial, ACTG Protocol 076. Eligible participants were HIV-infected pregnant women at 14-34 weeks of gestation who had received no antiretroviral therapy during their current pregnancy, had no clinical indications for antepartum antiretroviral therapy, and had CD4+ T-lymphocyte counts ≥200/µL at the time of entry into the study (Box 1). The study began in April 1991; as of December 20, 1993, the time of the interim analysis, 477 women had been enrolled and 421 infants born. The racial/ethnic distribution of the HIV-infected women enrolled in the trial was similar to that of the total population of HIV-infected women in the United States. Enrolled women were assigned randomly to receive a regimen of either ZDV or placebo. The ZDV regimen included oral ZDV initiated at 14-34 weeks of gestation and continued throughout the pregnancy, followed by intravenous ZDV during labor and oral administration of ZDV to the infant for 6 weeks after delivery (Box 2). The placebo regimen was administered identically. Blood specimens were obtained for HIV culture from all infants at birth and at 12, 24, and 78 weeks of age. A positive viral culture was considered indicative of HIV infection. Sera from the infants at 15 and 18 months of age also were tested for HIV antibody. The Kaplan-Meier method (7 ) was used to estimate the rate of perinatal transmission at 18 months of age among the 364 children whose HIV infection status was known on the basis of culture and who therefore were included in the interim analysis. The estimated transmission rate was 25.5% among the 184 children in the placebo group (95% confidence interval [CI]=18.4%-32.5%), compared with 8.3% among the 180 children in the ZDV group (95% CI=3.9%-12.8%). The difference in the estimated transmission rate between the two groups was statistically significant (p=0.00006). ZDV treatment did not appear to delay the diagnosis of HIV infection. Observed toxicity specifically attributable to ZDV was minimal among the women in this study. Adverse effects such as anemia, neutropenia, thrombocytopenia, and liver chemistry abnormalities were reported as frequently among women receiving placebo as among women receiving ZDV. Six women-three in each treatment group-discontinued therapy because of toxicity attributed to the study drug. The women were evaluated at 6 weeks and 6 months postpartum. A statistically significant increase in CD4+ T-lymphocyte count from baseline to 6 weeks postpartum was observed for women in both ZDV and placebo treatment groups; this increase was greater among women in the ZDV group. At 6 months postpartum, the CD4+ T-lymphocyte counts for both groups had decreased to similar levels. CD4+ T-lymphocyte counts decreased to <200/µL in only four women, including one receiving ZDV and three receiving placebo. No women died during the study. # BOX 2. Zidovudine regimen from AIDS Clinical Trials Group Protocol 076 • Oral administration of 100 mg of zidovudine (ZDV) five times daily, initiated at 14-34 weeks of gestation and continued throughout the pregnancy. • During labor, intravenous administration of ZDV in a 1-hour loading dose of 2 mg per kg of body weight, followed by a continuous infusion of 1 mg per kg of body weight per hour until delivery. • Oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg of body weight per dose every 6 hours) for the first 6 weeks of life, beginning 8-12 hours after birth. # BOX 1. Eligibility criteria for HIV-infected pregnant women participating in AIDS Clinical Trials Group Protocol 076 • Pregnancy at 14-34 weeks of gestation. • No antiretroviral therapy during the current pregnancy. • No clinical indications for antenatal antiretroviral therapy. • CD4+ T-lymphocyte count ≥200 cells/µL at the time of entry into the study. Serial sonographic evaluations for fetal growth and amniotic fluid volume as conducted in the study (at entry and every 4 weeks from 28 weeks of gestation until delivery) demonstrated no differences between pregnancies in women who had received placebo or ZDV. Birth parameters (gestational age; birth weight, length, and head circumference; and Apgar scores) were similar among infants born to women in either group. The median birth weight was 3,160 g (range: 1,040-5,267 g), and the median gestational age at birth was 39 weeks (range: 27-43 weeks). No statistically significant difference was observed between the ZDV and placebo groups in the number of infants with birth weight <2,500 g, who were small or large for gestational age, or who were born prematurely. The occurrence of major or minor congenital abnormalities was approximately equal between the two groups, and no pattern in the type of abnormalities was observed. The infants in the study tolerated the ZDV therapy well. The only adverse effect observed more frequently among infants in the ZDV treatment group was mild, transient anemia. Hemoglobin values for infants in the group receiving ZDV were lower than for the group receiving placebo, with a maximum mean difference of 1 gm/dL occurring at 3 weeks of age. The lowest mean hemoglobin value in infants receiving ZDV occurred at 6 weeks of age and resolved without therapy for anemia after the infants had completed the ZDV treatment. The hemoglobin values of infants receiving ZDV were similar to those of placebo recipients by 12 weeks of age. The incidence of neutropenia and serum chemistry abnormalities was similar between ZDV and placebo groups of infants, and no difference in the pattern of chemistry abnormalities was observed. Based on these interim findings, NIAID accepted the recommendation of its independent data and safety monitoring board to terminate enrollment into the trial and to offer ZDV to women in the placebo group who had not yet delivered and to their infants up to 6 weeks of age.* Follow-up of patients enrolled in the study is ongoing. # Limitations in Interpretation and Extrapolation of ACTG Protocol 076 Results This clinical trial demonstrated that the ACTG Protocol 076 ZDV regimen can substantially reduce perinatal HIV transmission. However, several important limitations should be noted. First, perinatal HIV transmission was still observed despite drug therapy. Second, the efficacy of this therapy is unknown for HIV-infected pregnant women who have advanced disease, who have received prior antiretroviral therapy, or who have ZDV-resistant virus strains. Third, although the ZDV regimen used in this trial was not associated with serious short-term adverse effects, such effects may be observed when this use of ZDV becomes more widespread. Fourth, the long-term risks for the child associated with exposure to ZDV in utero and early infancy have not been determined. Fifth, it is not known if use of ZDV during pregnancy will affect the drug's efficacy for the woman when it becomes clinically indicated for her own health. Further complicating the incorporation of this ZDV regimen into clinical practice is the fact that some HIV-infected women seek medical care late in pregnancy or when A summary of the study's findings is available from the AIDS Clinical Trials Information Service at 1(800)TRIALS-A (1[800]874-2572). they are already in labor, when the full ZDV regimen used in ACTG Protocol 076 cannot be administered. Moreover, many pregnant women are not aware that they are HIV infected, are not tested before or during pregnancy, and remain undiagnosed. As a result, they do not receive information about therapy that could reduce the risk for HIV transmission to their infants. # Potential Long-Term Adverse Effects of ZDV Administered During Pregnancy The long-term effects of ZDV treatment during pregnancy solely to reduce perinatal transmission or of fetal and neonatal exposure to ZDV are not known. ZDV is a nucleoside analog that inhibits HIV replication by interfering with HIV RNA-dependent DNA polymerase. ZDV triphosphate also can inhibit human cellular DNA polymerases, but only at concentrations much higher than those required to inhibit HIV polymerase. However, gamma DNA polymerase, which is required for mitochondrial replication, may be inhibited by ZDV at concentrations nearer to those that can be achieved in vivo. Concerns related to the potential long-term toxicity of nucleoside analogs include potential mutagenic and carcinogenic effects, possible effects on tissues with high mitochondrial content (such as hepatic and cardiac tissue), possible teratogenicity, and possible effects on the reproductive system. ZDV has been shown to be a mutagen in vitro, and, in a mammalian in vitro cell transformation assay, ZDV was positive at concentrations of ≥0.5 µg/mL (8 ). Noninvasive squamous epithelial vaginal tumors were produced after 19-21 months of continuous dosing in 12% of mice administered a dosage equivalent to three times the estimated human exposure at the recommended therapeutic dosage. Similar findings were observed in 3% of rats that received 24 times the recommended therapeutic dosage. Carcinogenicity studies in rodents, however, may not be predictive of human experience. In humans, an increased incidence of non-Hodgkin's lymphoma has been reported in HIV-infected men receiving ZDV, but this increase probably reflects longer survival despite severe immunodeficiency rather than a direct effect of ZDV (9 ). The potential for carcinogenesis should be further assessed through continued follow-up of children who were exposed to ZDV in utero. Myopathy and cardiomyopathy have been associated with ZDV therapy. In an individual patient, the effects secondary to ZDV are often difficult to distinguish from those of HIV infection. A prospective study of HIV-infected children demonstrated no effect of ZDV therapy on cardiac function (10 ). Reproductivity/fertility studies in animals have demonstrated no adverse effects of ZDV on either the fertility of male or female rats or the reproductive capacity of their offspring (11 ). ZDV administered to mice early in gestation was associated with an embryotoxic effect and fetal resorptions; however, ZDV administered at or beyond midgestation had no detectable effect on the fetus (12,13 ). ZDV is assigned pregnancy category C status by the Food and Drug Administration (FDA). Most studies of ZDV administered to pregnant animals have not demonstrated teratogenicity. In one study, pregnant rats were administered toxic doses of ZDV during organogenesis (i.e., equivalent to approximately 50 times the recommended daily clinical dose, based on relative body surface areas); developmental malformations and skeletal abnormalities were observed in 12% of fetuses (14 ). In humans, observational studies involving small numbers of subjects have demonstrated no apparent association of fetal malformations with antenatal ZDV use (15)(16)(17)(18)(19). In ACTG Protocol 076, the incidence of congenital malformations was similar for ZDV and placebo recipients. However, because ZDV was not administered until after 14 weeks of gestation in this study, the potential teratogenicity of ZDV administered during the first trimester cannot be assessed. Similarly, in a recent report from the Antiretroviral Pregnancy Registry maintained by the Wellcome Foundation and Hoffman LaRoche in conjunction with CDC, no increase in the risk of congenital abnormalities above that expected for all pregnancies was observed among infants born to 121 prospectively registered HIV-infected women who received ZDV during pregnancy, nor was there any unusual pattern of birth defects (20 ). Use of ZDV during pregnancy could be associated with the development of ZDV-resistant virus, which may lessen the drug's therapeutic benefit for the woman when it is needed for her own health. However, patients with early-stage HIV disease rarely develop ZDV-resistant strains before they have received 18-24 months of continuous therapy (21 ). After discontinuation of ZDV therapy, an increase in ZDVsusceptible isolates has been observed in some patients who had ZDV-resistant isolates while they were receiving ZDV, although resistance to ZDV has been reported to persist for more than a year after therapy was discontinued (22,23 ). Because the development of ZDV-resistant viral strains secondary to transient ZDV use during pregnancy is a theoretical concern, considerations for the woman's future health care should include the availability of alternative drugs for treatment of HIV infection. # GENERAL PRINCIPLES REGARDING TREATMENT RECOMMENDATIONS The following treatment recommendations have been formulated to provide a basis for discussion between the woman and her health-care provider about the use of ZDV to reduce perinatal transmission. HIV-infected women should be informed of the substantial benefit and short-term safety of ZDV administered during pregnancy and the neonatal period observed in ACTG Protocol 076. However, they also must be FDA pregnancy categories are: A, in which adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk during later trimesters); B, in which animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted; C, in which safety in human pregnancies has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, in which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; and X, in which studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. informed that the long-term risks of ZDV therapy to themselves and their children are unknown. A woman's decision to use ZDV to reduce the risk for HIV transmission to her infant should be based on a balance of the benefits and potential risks of the regimen to herself and to her child. Discussion of treatment options should be noncoercive, and the final decision to accept or reject ZDV treatment recommended for herself and her child is the right and responsibility of the woman. A decision not to accept treatment should not result in punitive action or denial of care, nor should ZDV be denied to a woman who decides to receive the regimen. Various circumstances that commonly occur in clinical practice are described and the factors influencing treatment considerations are highlighted in the following discussion (Box 3). All potential clinical situations cannot be enumerated, and, in many cases, definitive evidence upon which to base a recommendation is not currently available. Therefore, each pregnant woman and her health-care provider must consider the potential benefits, unknown long-term effects, and gaps in knowledge relating to her clinical situation. Furthermore, health-caregivers and institutions should provide culturally, linguistically, and educationally appropriate information and counseling to the HIV-infected woman so that she can make informed decisions. # CLINICAL SITUATIONS AND RECOMMENDATIONS FOR USE OF ZDV TO REDUCE PERINATAL TRANSMISSION Clinical Situation Meeting the Entry # Discussion: The results of ACTG Protocol 076 are directly applicable only to women who meet the entry criteria for the study (Table 1). The data from that study indicate that the complete ACTG Protocol 076 ZDV regimen will likely reduce the risk for perinatal transmission by about two-thirds. Because this study was randomized and placebo controlled, entry was restricted to women who had no clinical indications for ZDV use for their own health and who had CD4+ T-lymphocyte counts ≥200/µL. Prior ZDV use during the current pregnancy resulted in exclusion from the study. Few women (4%) had received ZDV before the current pregnancy, and most of that therapy was of limited duration. Women were not enrolled either before the 14th week or after the 34th week of gestation. The rationale for exclusion before 14 weeks of gestation was to preclude ZDV exposure during fetal organogenesis. The 34-week limit allowed most women to receive several weeks of ZDV before delivery to allow time for a decrease in maternal viral load (a presumed important determinant of transmission risk). Although ZDV was successful in reducing perinatal transmission, the study regimen did not completely prevent it. The possible reasons for transmission to these infected infants are being evaluated but have not yet been identified. Several case reports also have described perinatal transmission despite the initiation of ZDV therapy during pregnancy (24)(25)(26)(27). Although long-term toxicity to infants is unknown, this risk must be weighed against the decreased risk for transmission of an infection associated with substantial risk of death. Currently, there is no way to predict if an individual pregnancy will be associated with HIV transmission; therefore, each fetus must be considered to have an estimated 25% risk of a life-threatening infection. Because ZDV therapy reduced the rate of transmission by two-thirds (from 25.5% to 8.3%), any long-term toxicity related to ZDV would have to be severe (e.g., malignancy or profound developmental delay) and relatively common among ZDV-exposed infants to outweigh the substantial benefit. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider. # Clinical Situations Not Meeting the Study Entry Criteria Information about the benefit and short-term risks of ZDV therapy is applicable from this trial only for women who meet the entry criteria of the study. Recommendations about use of the ZDV regimen for women whose clinical conditions differ from the ACTG Protocol 076 eligibility criteria were derived from consensus interpretation of available scientific data. # II. Pregnant # Discussion: This patient population has clinical characteristics similar to those of women enrolled in ACTG Protocol 076; the major difference is gestational age at which ZDV therapy would begin. Therefore, the ZDV regimen for these women would differ from the ACTG Protocol 076 regimen only in duration of antenatal therapy. As much as 50%-70% of perinatal transmission may occur close to or during delivery (28 ). Therefore, the ACTG Protocol 076 ZDV regimen may have some benefit when initiated at >34 weeks of gestation, although the intervention is likely to decrease in effectiveness as the duration of antenatal ZDV administration is reduced. A study evaluating the effect of ZDV on quantitative p24 antigen levels indicates that maximal effect is observed after 8-16 weeks of therapy (29). A shorter duration of ZDV therapy may thus be associated with an effect on maternal viral load that is less than can be anticipated when ZDV is initiated before 34 weeks of gestation. Both potential risks and benefits for the woman and her infant may decrease the closer to delivery that the ZDV regimen is initiated. Further clinical trials should be designed to assess the efficacy of interventions that are initiated late in the third trimester for preventing perinatal transmission. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester. # III. Pregnant HIV-infected women with CD4+ T-lymphocyte counts <200/µL who are at 14-34 weeks of gestation, who have no other clinical indications for ZDV, and who have no history of extensive (>6 months) prior antiretroviral therapy. Discussion: Women in this group meet the current standard of care for ZDV treatment of HIV infection for their own benefit (30,31 ); therefore, administration of ZDV during pregnancy for these women provides direct benefit to them as well as potential benefit to their infants. The risk for HIV transmission to the infants of HIV-infected pregnant women with low CD4+ T-lymphocytes or percent of total lymphocytes ranges from 22% to 60% (32)(33)(34)(35)(36)(37)(38).Viral load has been shown to increase as CD4+ T-lymphocyte count decreases (39 ); thus, baseline viral loads can be expected to be high among the women in this group. Although viral replication and resultant capacity for mutations in this group are high, preexisting ZDV-resistant viral strains are unlikely to be present because these women have had little or no exposure to ZDV. Therefore, ZDV therapy can be expected to result in an acute reduction in maternal viral load analogous to that observed in women who have CD4+ T-lymphocyte counts ≥200/µL. Additionally, the mother's CD4+ T-lymphocyte count would not be expected to affect ZDV levels or toxicity in the infant after administration of ZDV during labor and the first 6 weeks of life. Hence, maternal CD4+ T-lymphocyte count should not affect the potential utility of neonatal levels of systemic ZDV for reducing intrapartum transmission. Although this population of pregnant women was not studied in ACTG Protocol 076, addition of the intrapartum and neonatal components of the ACTG Protocol 076 ZDV regimen to antenatal maternal therapy may reduce the risk for HIV transmission. However, the magnitude of the effect of ZDV on reducing the transmission rate in this group may not be the same as that demonstrated in ACTG Protocol 076 for women with CD4+ T-lymphocyte counts ≥200. Further clinical trials should assess the utility of interventions in this group of women. Because ZDV therapy is clinically indicated for these women for their own health, the additional risk of the remainder of the ACTG Protocol 076 regimen is the discomfort to the woman of another intravenous infusion during labor and the possible effects of the additional 6 weeks of ZDV exposure for the infant. # Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit (31 ). The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman. # IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy. # Discussion: Women who have received extensive prior ZDV therapy may be infected with viral strains with reduced susceptibility to ZDV. These resistant strains of HIV can be transmitted from mother to fetus; however, the frequency with which such transmission occurs is unknown. Resistant virus appears to emerge more quickly if therapy is initiated at later stages of HIV disease (21 ). The appearance of mutations associated with ZDV resistance follows a temporal pattern, and the level of in vitro resistance is proportional to the number of mutations in the reverse transcriptase-coding region of HIV (40 ). Phenotypically and genotypically diverse HIV populations can coexist in patients who are receiving ZDV therapy. In one study, ZDV-resistant strains appeared earlier during ZDV therapy in patients with advanced HIV disease than in patients whose ZDV therapy was initiated at an early stage of the disease. After 12 months of ZDV therapy, viral isolates from 89% of patients with late-stage disease and 31% of those with early-stage disease were resistant (21 ). However, isolates from only 33% of latestage patients demonstrate high-level resistance (defined as a 100-fold decrease in susceptibility [41 ]). Resistant virus also was more likely to be isolated from patients who had low CD4+ T-lymphocyte counts when therapy was initiated: 1-year estimated rates of resistance in patients with baseline CD4+ T-lymphocyte counts of >400, 100-400, and <100 cells/µL were 27%, 41%, and 89%, respectively. In patients with advanced disease, high-level resistance develops after 6-18 months of therapy. However, in patients with early-stage disease, highlevel resistance appears to be delayed until after 24 months of therapy (22 ). Therefore, ZDV-resistant strains are likely to be more common in women with advanced disease who have received prolonged therapy. ZDV-resistant viral strains also may be more common in persons receiving alternative antiretroviral agents because their disease progressed while they were receiving ZDV therapy. There is controversy regarding the association of clinical disease progression during ZDV therapy with the development of ZDV resistance and regarding whether resistance persists when therapy is changed to an alternative antiretroviral agent (41 ). Some studies involving small numbers of children have indicated that in vitro susceptibility to ZDV is correlated with clinical outcome, suggesting that ZDV-resistant isolates are associated with diminished efficacy of ZDV and more rapid clinical progression (42,43 ). However, at least one study indicated that disease progression may be associated more closely with the development of syncytia-inducing viral phenotype than with resistance to ZDV (44 ). Change to alternative antiretroviral therapy has been associated with reversal of ZDV resistance in some studies, but resistance has been reported to persist for considerable periods of time after discontinuation of ZDV (23,45 ). The prevalence of ZDV-resistant viral strains in women who are receiving alternative antiretroviral agents because of disease progression has not been defined. The capability of ZDV to reduce HIV transmission may be decreased for mothers in whom ZDV-resistant strains predominate, particularly if the strains have high-level resistance; however, this assumption is not yet supported by data. Further clinical trials to evaluate alternative approaches for such women are needed. # Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen on a case-bycase basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood that she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status. # V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor. # Discussion: Data from studies in humans are insufficient to evaluate the potential effectiveness of ZDV in this situation. Because the mother's exposure to ZDV would be brief, such therapy can be expected to have no effect on the level of maternal virus in blood or genital secretions. However, because of the intravenous loading dose and continuous infusion of ZDV during labor, the infant will be born with circulating levels of ZDV similar to those of infants whose mothers have received antenatal as well as intrapartum ZDV. ZDV may have some utility for this group of patients-regardless of whether the pregnancy is at term or preterm-because the presence of systemic levels of ZDV in the infant before or shortly after HIV exposure through contact with the mother's blood and genital secretions during delivery may help prevent intrapartum transmission. The intravenous route was chosen for drug dosing during labor in ACTG Protocol 076 because continuous intravenous infusion of drug after an initial loading dose results in predictable levels of ZDV in the mother. Under optimal circumstances, these maternal levels provide a substantial fetal blood level during birth, when the infant is presumed to be exposed extensively to HIV through contact with the mother's blood and genital secretions. Because gastric emptying is delayed during labor, the absorption of orally administered drugs is unpredictable (46 ). Therefore, oral administration of ZDV during labor might produce widely variable systemic levels in the mother and infant. Oral ZDV administered intrapartum cannot be assumed to be equivalent to the intravenous intrapartum ZDV component used in ACTG Protocol 076. Further studies are needed to characterize the pharmacokinetics of oral ZDV during labor. Intrapartum ZDV cannot prevent the substantial number of infections that occur before labor (26 ). Therefore, ZDV administered only during labor and to the newborn may not be effective. Because the mother would receive ZDV only during labor, her risk for developing resistant virus or ZDV toxicity would be minimal. The primary risk is that associated with an intravenous catheter. The risk to the infant would be limited to the potential toxicity associated with transfer of drug from the maternal intrapartum infusion and with 6 weeks of oral ZDV therapy, without in utero exposure to the drug. The effect of neonatal ZDV treatment in ameliorating disease progression in infected infants is unknown. Clinical trials should be designed to address the efficacy of antiretroviral therapy in this situation. # Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits. # VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy. # Discussion: Infants whose mothers have not received ZDV during late pregnancy and/or labor will not have circulating ZDV levels during birth, a period of presumed viral exposure. Data are insufficient to allow assessment of the potential efficacy of postexposure prophylaxis with ZDV in this situation. Studies of postexposure prophylaxis of retroviral infection with ZDV in animal models have yielded inconclusive results. Additionally, studies involving animal models should be interpreted with caution: many of these studies have involved nonhuman retroviruses that may have different pathogenic mechanisms from those of HIV, used methods of viral inoculation that are not relevant to perinatal transmission (e.g., intrathymic injection), and/or used a massive inoculum of virus (47 ). The limited data from animal studies indicate that if ZDV is to have any effect as postexposure prophylaxis, prompt administration (within hours) is important, and that even with early initiation of ZDV, such prophylaxis may not be protective. In a SCID-hu mouse model of HIV infection (an immune-deficient model reconstituted with human cells), a time-dependent suppression of HIV replication was observed with ZDV prophylaxis (48 ). When ZDV was administered within 2 hours of viral inoculation, viral replication was not detectable at 2 weeks after inoculation in all treated animals; when ZDV was administered 2-36 hours after inoculation, rates of viral detection at 2 weeks increased in proportion to increasing time since ZDV was administered; and when ZDV was administered 48 hours after inoculation, virus was detectable in all animals (48 ). Therefore, whether the effect of ZDV therapy is prevention or suppression of infection cannot be established. In several animal model systems, ZDV administration was observed only to suppress or ameliorate retroviral infection (49)(50)(51). # Infant Monitoring A complete blood count and differential should be performed at birth as a baseline evaluation. Repeat measurements of hemoglobin are recommended at 6 and 12 weeks of age. ZDV should be administered with caution to infants born with severe anemia (hemoglobin <8 gm/dL), and treatment of the anemia and intensive monitoring are warranted if the drug is administered. Previously published guidelines contain recommendations for diagnosing HIV infection in infants and for initiating PCP prophylaxis and antiretroviral therapy for those who are infected (53)(54)(55). The potential efficacy of ZDV therapy for HIV-infected children who require antiretroviral therapy and who received ZDV in utero and during early infancy has not been determined. A specialist in pediatric HIV infection may be consulted if therapy is necessary for infected children whose mothers received ZDV during pregnancy. Further research is needed to describe the response to therapy and progression of disease in such infants. # POTENTIAL LONG-TERM EFFECTS OF ZDV THERAPY FOR MOTHERS AND INFANTS AND RECOMMENDATIONS FOR FOLLOW-UP Discussion Observational data about the pregnancy outcomes of women who receive ZDV during pregnancy are being collected through the Antiretroviral Pregnancy Registry. The purpose of the registry is to provide surveillance for possible teratogenicity among infants born to women who received ZDV during pregnancy. Health-care providers can register such patients by calling the registry at (800 Concerns about the potential long-term adverse effects among women include development of ZDV-resistant virus when ZDV therapy is used intermittently to reduce perinatal transmission, particularly during more than one pregnancy, and the potential effect such resistance could have on disease progression for the woman. Although results of studies have demonstrated an association between emergence of ZDV resistance and total duration of ZDV exposure, none of the study designs has specifically addressed the effect of intermittent therapy on development of resistance. ) Continued follow-up of the women who participated in ACTG Protocol 076 and of their infants is planned. A protocol to provide prospective evaluation of the health of the women enrolled in ACTG Protocol 076 is being designed by the Women's Health Committee of the ACTG. This protocol will evaluate virologic, immunologic, and clinical parameters among participating women. Data are insufficient to address any effect that exposure to ZDV in utero might have on risk for neoplasia or organ system toxicities. ACTG Protocol 219 is an ongoing study designed to provide prospective evaluation for children who have been exposed through ACTG protocols to antiretroviral agents in utero or to HIV vaccines until they are 21 years of age. This protocol will provide intensive evaluation of multiple organ system functions, neuropsychologic testing, and quality of life. Information about the potential long-term effects of the complete or partial ACTG Protocol 076 ZDV regimen on women and children receiving the regimen outside a clinical trial protocol also may be provided from evaluation of federally funded and other prospective studies of HIVinfected women and their infants. # Recommendation: Additional efforts are required to characterize the long-term effects of the ACTG Protocol 076 ZDV regimen on women and children. The specific issues of viral resistance and disease progression should be addressed among women who receive ZDV during pregnancy solely to reduce perinatal HIV transmission. Monitoring for these HIV-infected women should include Pap smears and gynecologic examinations as recommended in previously published guidelines (56 ), as well as an assessment of the patient's future needs for family planning consultation and services. Long-term follow-up of both uninfected and infected infants born to mothers receiving ZDV during pregnancy is important. Assessment of organ system toxicities, neurodevelopment, pubertal development, reproductive capacity, and development of neoplasms should be emphasized. Special studies will need to be developed to address these specific concerns, and innovative methods and support systems should be designed to assist in follow-up of these women and their children. # CONCLUSION The decision by an HIV-infected pregnant woman to use ZDV to reduce the risk for perinatal transmission requires a complex balance of individual benefits and risks that is best accomplished through discussions with her health-care provider. Such discussions should be noncoercive, linguistically and culturally appropriate, and tailored to the patient's educational level. The recommendations in this report have been developed for use in the United States. Although perinatal transmission of HIV infection is an international problem, alternative strategies may be appropriate in other countries (57 ). The policy and practice in other countries may differ from these recommendations and depend on local considerations, such as availability of ZDV, access to facilities for intravenous infusion during labor, and alternative interventions that may be under evaluation. These recommendations have been developed in response to the urgent need to provide guidance to women and health-care providers in the United States about the use of ZDV to reduce the risk for perinatal HIV transmission and about the possible adverse outcomes of such ZDV treatment. They have been formulated on the basis of the available data from ACTG Protocol 076 and current information regarding factors associated with transmission. The information on which these recommendations are based is incomplete, and additional information is needed to optimize use of ZDV for this purpose. The decision to use the ACTG Protocol 076 regimen for preventing perinatal transmission of HIV requires weighing the benefits and potential risks to the HIV-infected woman and her child despite numerous uncertainties. Further research is a high priority and should include a) clarification of long-term risks of the ZDV regimen to the woman and/or her child, b) elucidation of the reasons for transmission despite use of the ZDV regimen, c) delineation of the relative efficacy of the various components of the ACTG Protocol 076 ZDV regimen for reducing transmission, d) evaluation of the efficacy of the regimen in women whose characteristics differ from those enrolled in ACTG Protocol 076, and e) evaluation of other interventions for preventing perinatal transmission. As further information becomes available, these recommendations may need to be modified. In addition, appropriate methods and materials should be developed for communicating treatment options, risks, and benefits to women and health-care providers so that they can make informed decisions about treatment. on a case-by-case basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood she is infected with a ZDV-resistant HIV strain, and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The health-care provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status. V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor. # Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the health-care provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits. VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy. # Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is >24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant. # BOX 3. Summary: Clinical situations and recommendations for use of zidovudine to reduce perinatal HIV transmission (Continued) # The material in this report was prepared for publication by: Lynne # At least 13 reports have described the failure of prophylactic ZDV to prevent HIV infection in humans following exposure to HIV-infected blood, even though the drug was administered promptly after exposure (52 ). Although these anecdotal reports do not establish that ZDV therapy is ineffective as postexposure prophylaxis, its efficacy can be expected to be lower in this situation than with the full regimen. Further studies are needed to evaluate whether a therapy administered only during the neonatal period can effectively prevent perinatal transmission. # Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the health-care provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is >24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant. # RECOMMENDATIONS FOR MONITORING THE ZDV REGIMEN FOR MOTHERS AND INFANTS Women and their children should receive care together in a family-centered setting. Care should be coordinated between gynecologic, pediatric, internal medicine, infectious disease, and other health-care specialists to ensure that both mother and child receive appropriate medical follow-up. A comprehensive program of support services is necessary to ensure that both mother and child continue to receive health care. # Maternal Monitoring HIV-infected pregnant women should be monitored in accordance with previously published guidelines (31,53 ). Monitoring during pregnancy should include monthly assessment for ZDV-associated hematologic and liver chemistry abnormalities. Indications of toxicity that might require interrupting or stopping the dose of ZDV include a) hemoglobin <8 gm/dL, b) absolute neutrophil count <750 cells/µL, or c) AST (SGOT) or ALT (SGPT) greater than five times the upper limit of normal. CD4+ T-lymphocyte counts should be monitored to determine if prophylaxis for opportunistic infections, such as Pneumocystis carinii pneumonia (PCP), should be initiated. Pregnant HIV-infected women with CD4+ T-lymphocyte counts <200 cells/µL should receive appropriate PCP prophylaxis. If the CD4+ T-lymphocyte count is <600 cells/µL, the evaluation should be repeated each trimester. CD4+ T-lymphocyte counts should be measured at 6 weeks and 6 months postpartum to evaluate if antiretroviral therapy is indicated. # Fetal Monitoring Antepartum testing, including sonographic and nonstress testing and intrapartum fetal monitoring, should be performed only as clinically indicated, not specifically because the patient is being treated with ZDV during pregnancy. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her health-care provider. # II. Pregnant HIV-infected women who are at >34 weeks of gestation, who have no history of extensive (>6 months) prior antiretroviral therapy, and who do not require ZDV for their own health. # Recommendation: The health-care provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated late in the third trimester. # III. Pregnant HIV-infected women with CD4+ T- # Recommendation: The health-care provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit. The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman. # IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy. # Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the health-care provider should consider recommending the ACTG Protocol 076 regimen These recommendations do not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. All material in the MMWR Series is in the public domain and may be used and reprinted without special permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1994-533-178/05020 Region IV	None	None
3eb537a0fc6c347a99aa71d96ede214efae38b70	cdc	None	Vol. 47 / No. RR-4 MMWR iThese guidelines were developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children convened by the National Pediatric# INTRODUCTION In 1993, the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, composed of specialists caring for human immunodeficiency virus (HIV)-infected infants, children, and adolescents, was convened by the National Pediatric and Family HIV Resource Center (NPHRC). On the basis of available data and a consensus reflecting clinical experience, the Working Group concluded that antiretroviral therapy was indicated for any child with a definitive diagnosis of HIV infection who had evidence of substantial immunodeficiency (based on age-related CD4+ T-lymphocyte count thresholds) and/or who had HIV-associated symptoms. Zidovudine (ZDV) monotherapy was recommended as the standard of care for initiation of therapy. Routine antiretroviral therapy for infected children who were asymptomatic or had only minimal symptoms (e.g., isolated lymphadenopathy or hepatomegaly) and normal immune status was not recommended (1 ). Since the Working Group developed the 1993 recommendations, dramatic advances in laboratory and clinical research have been made. The rapidity and magnitude of HIV replication during all stages of infection are greater than previously believed and account for the emergence of drug-resistant viral variants when antiretroviral treatment does not maximally suppress replication (2,3 ). New assays that quantitate plasma HIV RNA copy number have become available, permitting a Information included in these guidelines may not represent Food and Drug Administration (FDA) approval or approved labeling for the particular product or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval. sensitive assessment of risk for disease progression and adequacy of antiretroviral therapy. A new class of antiretroviral drugs, protease inhibitors, has become available; these agents have reduced HIV viral load to levels that are undetectable and have reduced disease progression and mortality in many HIV-infected persons. Therefore, therapeutic strategies now focus on early institution of antiretroviral regimens capable of maximally suppressing viral replication to reduce the development of resistance and to preserve immunologic function. Additionally, the results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 have demonstrated that the risk for perinatal HIV transmission can be substantially diminished with the use of a regimen of ZDV administered during pregnancy, during labor, and to the newborn (4 ). These advances in HIV research have led to major changes in the treatment and monitoring of HIV infection in the United States. A summary of the basic principles underlying therapy of HIV-infected persons has been formulated by the National Institutes of Health (NIH) Panel to Define Principles of Therapy of HIV Infection (5 ). Treatment recommendations for infected adults and post-pubertal adolescents have been developed by the U.S. Department of Health and Human Services Panel of Clinical Practices for Treatment of HIV Infection (5 ). Although the pathogenesis of HIV infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, there are unique considerations needed for HIV-infected infants, children, and adolescents. Most HIV infections in children are acquired perinatally, and most perinatal transmission occurs during or near the time of birth, which raises the possibility of initiating treatment in an infected infant during the period of initial (e.g., primary) HIV infection (if sensitive diagnostic tests are used to define the infant's infection status early in life). Perinatal HIV infection occurs during the development of the infant's immune system; thus, both the clinical manifestations of HIV infection and the course of immunologic and virologic markers of infection differ from those for adults. Treatment of perinatally infected children will occur in the context of prior exposure to ZDV and other antiretroviral drugs used during pregnancy and the neonatal period, either for maternal treatment, to prevent perinatal transmission, or both (6,7 ). Additionally, drug pharmacokinetics change during the transition from the newborn period to adulthood, requiring specific evaluation of drug dosing and toxicity in infants and children. Finally, optimizing adherence to therapy in children and adoles-cents requires specific considerations. To update the 1993 antiretroviral treatment guidelines for children and to provide guidelines for antiretroviral treatment similar to those for HIV-infected adults (5 ), NPHRC, the Health Resources and Services Administration, and NIH reconvened the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, consisting of experts caring for HIV-infected children and adolescents, family members of HIV-infected children, and government agency representatives. The Working Group met in June 1996 and again in July 1997 to establish and finalize new guidelines for the treatment of HIV-infected infants, children, and adolescents. The treatment recommendations provided in this report are based on published and unpublished data regarding the treatment of HIV infection in adults and children and, when no definitive data were available, the clinical experience of the Working Group members. The Working Group intended the guidelines to be flexible and not to supplant the clinical judgement of experienced health-care providers. These guidelines will need to be modified as new information and clinical experience become available. # BACKGROUND Concepts Considered in the Formulation of Pediatric Treatment Guidelines The following concepts were considered in the formulation of these guidelines: - Identification of HIV-infected women before or during pregnancy is critical to providing optimal therapy for both infected women and their children and to preventing perinatal transmission. Therefore, prenatal HIV counseling and testing with consent should be the standard of care for all pregnant women in the United States (8)(9)(10). - Enrollment of pregnant HIV-infected women; their HIV-exposed newborns; and infected infants, children, and adolescents into clinical trials offers the best means of determining safe and effective therapies. - Pharmaceutical companies and the federal government should collaborate to ensure that drug formulations suitable for administration to infants and children are available at the time that new agents are being evaluated in adults. - Although some information regarding the efficacy of antiretroviral drugs for children can be extrapolated from clinical trials involving adults, concurrent clinical trials for children are needed to determine the impact of the drug on specific manifestations of HIV infection in children, including growth, development, and neurologic disease. However, the absence of clinical trials addressing pediatricspecific manifestations of HIV infection does not preclude the use of any approved antiretroviral drug in children. - All antiretroviral drugs approved for treatment of HIV infection may be used for children when indicated-irrespective of labeling notations. - Management of HIV infection in infants, children, and adolescents is rapidly evolving and becoming increasingly complex; therefore, wherever possible, management of HIV infection in children and adolescents should be directed by a specialist in the treatment of pediatric and adolescent HIV infection. If this is not possible, such experts should be consulted regularly. - Effective management of the complex and diverse needs of HIV-infected infants, children, adolescents, and their families requires a multidisciplinary team approach that includes physicians, nurses, social workers, psychologists, nutritionists, outreach workers, and pharmacists. In areas where enrollment in clinical trials is possible, enrolling the child in available trials should be discussed with the caregivers of the child. Information about clinical trials for HIV-infected adults and children can be obtained from the AIDS Clinical Trials Information Service, telephone (800) 874-2572 ( TRIALS-A). - Determination of HIV RNA copy number and CD4+ T-lymphocyte levels is essential for monitoring and modifying antiretroviral treatment in infected children and adolescents as well as adults; therefore, assays to measure these variables should be made available. - Health-care providers considering antiretroviral regimens for children and adolescents should consider certain factors influencing adherence to therapy, including a) availability and palatability of pediatric formulations; b) impact of the medication schedule on quality of life, including number of medications, frequency of administration, ability to co-administer with other prescribed medications, and need to take with or without food; c) ability of the child's caregiver or the adolescent to administer complex drug regimens and availability of resources that might be effective in facilitating adherence; and d) potential for drug interactions. - The choice of antiretroviral regimens should include consideration of factors associated with possible limitation of future treatment options, including the potential for the development of antiretroviral resistance. - Monitoring growth and development is essential for the care of HIV-infected children. Growth failure and neurodevelopmental deterioration may be specific manifestations of HIV infection in children. Nutritional-support therapy is an intervention that affects immune function, quality of life, and bioactivity of antiretroviral drugs. # Identification of Perinatal HIV Exposure Appropriate treatment of HIV-infected infants requires HIV-exposed infants to be identified as soon as possible, which can be best accomplished through the identification of HIV-infected women before or during pregnancy. Universal HIV counseling and voluntary HIV testing with consent are recommended as the standard of care for all pregnant women in the United States by the Public Health Service (PHS), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists and is endorsed by the Working Group (8)(9)(10). Early identification of HIV-infected women is crucial for the health of such women and for care of HIV-exposed and HIV-infected children. Knowledge of maternal HIV infection during the antenatal period enables a) HIV-infected women to receive appropriate antiretroviral therapy and prophylaxis against opportunistic infections for their own health; b) provision of antiretroviral chemoprophylaxis with ZDV during pregnancy, during labor, and to newborns to reduce the risk for HIV transmission from mother to child (4,6,7 ); c) counseling of infected women about the risks for HIV transmission through breast milk and advising against breastfeeding in the United States and other countries where safe alternatives to breast milk are available (11 ); d) initiation of prophylaxis against Pneumocystis carinii pneumonia (PCP) in all HIV-exposed infants beginning at age 4-6 weeks in accordance with PHS guidelines (12 ); and e) early diagnostic evaluation of HIV-exposed infants to permit early initiation of aggressive antiretroviral therapy in infected infants. If women are not tested for HIV during pregnancy, counseling and HIV testing should be recommended during the immediate postnatal period. For newborns in whom maternal serostatus was not determined during the prenatal or immediate postpartum period, HIV antibody should be tested for following counseling and consent of the mother. The HIV-exposure status of infants should be determined rapidly because the neonatal component of the recommended ZDV chemoprophylaxis regimen should begin as soon as possible after birth and because PCP prophylaxis should be initiated at age 4-6 weeks in all infants born to HIV-infected women. Those infants who have been abandoned, are in the custody of the state, or have positive toxicology screening tests should be considered at high risk for exposure to HIV, and mechanisms to facilitate rapid HIV screening of such infants should be developed. # Diagnosis of HIV Infection in Infants HIV infection can be definitively diagnosed in most infected infants by age 1 month and in virtually all infected infants by age 6 months by using viral diagnostic assays. A positive virologic test (i.e., detection of HIV by culture or DNA or RNA polymerase chain reaction ) indicates possible HIV infection and should be confirmed by a repeat virologic test on a second specimen as soon as possible after the results of the first test become available. Diagnostic testing should be performed before the infant is aged 48 hours, at age 1-2 months, and at age 3-6 months. Testing at age 14 days also may be advantageous for early detection of infection. HIV-exposed infants should be evaluated by or in consultation with a specialist in HIV infection in pediatric patients. HIV DNA PCR is the preferred virologic method for diagnosing HIV infection during infancy. A meta-analysis of published data from 271 infected children indicated that HIV DNA PCR was sensitive for the diagnosis of HIV infection during the neonatal period. Thirty-eight percent (90% confidence interval =29%-46%) of infected children had positive PCR tests by age 48 hours (13 ). No substantial change in sensitivity during the first week of life was observed, but sensitivity increased rapidly during the second week, with 93% of infected children (90% CI=76%-97%) testing positive by PCR by age 14 days. Assays that detect HIV RNA in plasma also may be useful for diagnosis of perinatal infection and may prove to be more sensitive than DNA PCR for early diagnosis of HIV infection in HIV-exposed infants (14 ). However, data are more limited regarding the sensitivity and specificity of HIV RNA assays compared with HIV DNA PCR for early diagnosis. HIV culture has a sensitivity similar to that of DNA PCR for the diagnosis of infection (15 ). However, HIV culture is more complex and expensive to perform than DNA PCR, and definitive results may not be available for 2-4 weeks. Although use of standard and immune-complex-dissociated p24 antigen tests are highly specific for HIV infection and have been used to diagnose infection in children, the sensitivity of these tests is less than the sensitivity of other HIV virologic tests. The use of p24 antigen testing alone is not recommended to exclude infection or for diagnosis of infection in infants aged <1 month because of a high frequency of false-positive assays during this time (16 ). Initial testing is recommended by age 48 hours because nearly 40% of infected infants can be identified at this time. Because of concerns regarding potential contamination with maternal blood, blood samples from the umbilical cord should not be used for diagnostic evaluations. Working definitions have been proposed for acquisition of HIV infection during the intrauterine and intrapartum periods. Infants who have a positive virologic test at or before age 48 hours are considered to have early (i.e., intrauterine) infection, whereas infants who have negative virologic tests during the first week of life and subsequent positive tests are considered to have late (i.e., intrapartum) infection (17 ). Some researchers have proposed that infants with early infection may have more rapid disease progression than those with late infection and therefore should receive a more aggressive therapeutic approach (18,19 ). However, recent data from prospective cohort studies have demonstrated that although early differences in HIV RNA levels have been present between infants with positive HIV culture within 48 hours of birth and those with a first positive culture after age 7 days, these differences were no longer statistically significant after age 2 months (20 ). HIV RNA copy number after the first month of life was more prognostic of rapid disease progression than the time at which HIV culture tests were positive (20 ). Repeat diagnostic testing also can be considered at age 14 days in infants with negative tests at birth, because the diagnostic sensitivity of virologic assays increases rapidly by age 2 weeks and early identification of infection would permit modification of antiretroviral therapy from the standard 6-week course of neonatal ZDV chemoprophylaxis to more aggressive combination antiretroviral therapy. Infants with initially negative virologic tests should be retested at age 1-2 months. With increasing use of ZDV to reduce perinatal transmission, most HIV-exposed neonates will receive 6 weeks of antiretroviral chemoprophylaxis. Although prophylactic antiretroviral therapy theoretically could affect the predictive value of HIV virologic testing in neonates, ZDV monotherapy did not delay the detection of HIV by culture in infants in PACTG protocol 076 and has not decreased the sensitivity and predictive values of many virologic assays (4,21 ). However, whether the current, more intensive combination antiretroviral regimens women may receive during pregnancy for treatment of their own HIV infection will affect diagnostic test sensitivity in their infants is unknown. HIV-exposed children who have had repeatedly negative virologic assays at birth and at age 1-2 months should be retested again at age 3-6 months. HIV infection is diagnosed by two positive HIV virologic tests performed on separate blood samples. HIV infection can be reasonably excluded among children with two or more negative virologic tests, two of which are performed at age ≥1 month, and one of those being performed at age ≥4 months (12 ). Two or more negative HIV immunoglobulin G (IgG) antibody tests performed at age >6 months with an interval of at least 1 month between the tests also can be used to reasonably exclude HIV infection among children with no clinical evidence of HIV infection. HIV infection can be definitively excluded if HIV IgG antibody is negative in the absence of hypogammaglobulinemia at age 18 months and if the child has both no clinical symptoms of HIV infection and negative HIV virologic assays. # Monitoring of Pediatric HIV Infection Immunologic Parameters in Children Clinicians interpreting CD4+ T-lymphocyte number for children must consider age as a variable. CD4+ T-lymphocyte count and percentage values in healthy infants who are not infected with HIV are considerably higher than those observed in uninfected adults and slowly decline to adult values by age 6 years (22,23 ). A pediatric clinical and immunologic staging system for HIV infection has been developed that includes age-related definitions of immune suppression (Tables 1 and 2) (24 ). Although the CD4+ absolute number that identifies a specific level of immune suppression changes with age, the CD4+ percentage that defines each immunologic category does not. Thus, a change in CD4+ percentage, not number, may be a better marker of identifying disease progression in children. In infected children and adults, the CD4+ cell count declines as HIV infection progresses, and patients with lower CD4+ cell counts have a poorer prognosis than patients with higher counts (Table 3). Because knowledge of immune status (i.e., CD4+ T-lymphocyte count and percentage) is essential when caring for HIV-infected infants and children, CD4+ T-lymphocyte values should be obtained as soon as possible after a child has a positive virologic test for HIV and every 3 months thereafter (25,26 ). Infected infants who have a thymic defect lymphocyte immunophenotypic profile (i.e., CD4+ count 850/mm 3 ) during the first 6 months of life have had more rapid HIV disease progression than infants who do not have this profile (27 ). The CD4+ T-lymphocyte count or percentage value is used in conjunction with other measurements to guide antiretroviral treatment decisions and primary prophylaxis for PCP after age 1 year. However, measurement of CD4+ cell values can be associated with considerable intrapatient variation. Even mild intercurrent illness or the receipt of vaccinations can produce a transient decrease in CD4+ cell number and percentage; thus, CD4+ values are best measured when patients are clinically stable. No modification in therapy should be made in response to a change in CD4+ cell values until the change has been substantiated by at least a second determination, with a minimum of 1 week between measurements. # Category N: Not Symptomatic Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A. # Category A: Mildly Symptomatic Children with two or more of the following conditions but none of the conditions listed in categories B and C: - Lymphadenopathy (≥0.5 cm at more than two sites; bilateral=one site) # HIV RNA in Children Viral burden in peripheral blood can be determined by using quantitative HIV RNA assays. During the period of primary infection in adults, HIV RNA copy number initially rises to high peak levels. Coincident with the body's humoral and cell-mediated immune response, RNA levels decline by as much as 2-3 log 10 copies to reach a stable lower level (i.e., the virologic set-point) approximately 6-12 months following acute infection, reflecting the balance between ongoing viral production and immune elimination (28,29 ). Several studies conducted among adults have indicated that infected persons with lower HIV copy number at the time of RNA stabilization have slower progression and improved survival compared with those with high HIV RNA set points (30,31 ). On the basis of such data, recommendations for the use of HIV RNA copy number in deciding to initiate and change antiretroviral therapy in infected adults have been developed (5 ). These recommendations also are applicable to infected adolescents, particularly those who have acquired HIV infection recently rather than through perinatal infection. These recommendations also are likely to be applicable to perinatally infected children aged >3 years. The HIV RNA pattern in perinatally infected infants differs from that in infected adults. High HIV RNA copy numbers persist in infected children for prolonged periods (32,33 ). In one prospective study, HIV RNA levels generally were low at birth (i.e., 100,000 copies/mL, ranging from undetectable to nearly 10 million copies/mL), and then decreased slowly; the mean HIV RNA level during the first year of life was 185,000 copies/mL (20 ). Additionally, in contrast to the adult pattern, after the first year of life, HIV RNA copy number slowly declines over the next few years of life (20,(34)(35)(36). This pattern probably reflects the lower efficiency of an immature but developing immune system in containing viral replication and possibly a greater number of HIV-susceptible cells. Recent data indicate that high HIV RNA levels (i.e., >299,000 copies/mL) in infants aged 100,000 copies/mL) in infants also have been associated with high risk for disease progression and mortality, particularly if CD4+ T-lymphocyte percentage is 1,700,000 copies/mL) (36 ). Among children aged ≥30 months at the time the study was initiated (mean age: 7.3 years), none of those with baseline RNA in the lowest quartile (e.g., undetectable to 15,000 copies/ mL) compared with 34% of those in the highest quartile (e.g., >150,000 copies/mL) had disease progression; children with RNA levels in the middle two quartiles (i.e., 15,000-50,000 and 50,001-150,000 copies/mL) had similar progression rates (13% and 16%, respectively). Data from children aged ≥30 months are similar to data from studies among infected adults, in which the risk for disease progression substantially increases when HIV RNA levels exceed 10,000-20,000 copies/mL (5 ). Despite data indicating that high RNA levels are associated with disease progression, the predictive value of specific HIV RNA levels for disease progression and death for an individual child is moderate (35 ). HIV RNA levels may be difficult to interpret during the first year of life because levels are high and there is marked overlap in levels between children who have and those who do not have rapid disease progression (32 ). Additional data indicate that CD4+ T-lymphocyte percentage and HIV RNA copy number at baseline and changes in these parameters over time assist in determining the mortality risk in infected children, and the use of the two markers together may more accurately define prognosis (35,36 ). Similar data and conclusions recently have been reported from several studies involving infected adults (37)(38)(39). # Methodologic Considerations in the Interpretation and Comparability of HIV RNA Assays Most of the published data regarding HIV RNA in children have been obtained using frozen, stored plasma and serum specimens. Some degradation of HIV RNA occurs with specimen storage and delay in specimen processing; thus, the published data on HIV RNA levels in infected children may not be directly comparable with data obtained from specimens that undergo immediate testing (e.g., specimens obtained for patient care). The HIV RNA assays used also differ by study. Therefore, direct extrapolation of the predictive value of HIV RNA levels reported in published studies to HIV RNA assays performed for clinical-care purposes may be problematic. Information from ongoing prospective studies will assist in the interpretation of HIV RNA levels among infected infants and children. The use of HIV RNA assays for clinical purposes requires specific considerations (40 ), which are discussed more completely elsewhere (5 ). Several different methods can be used for quantitating HIV RNA, each with different levels of sensitivity; although the results of the assays are correlated, the absolute HIV RNA copy number obtained from a single specimen tested by two different assays can differ by twofold (0.3 log 10 ) or more. For example, plasma RNA measured by the quantitative PCR assay (Amplicor HIV-1 Monitor ™ , manufactured by Roche Diagnostics Systems, Nutley, New Jersey) yields absolute values approximately twice (0.3 log 10 ) those obtained using a signal amplification, branched-chain DNA assay (Quantiplex ® , manufactured by Chiron Corporation, Emeryville, California) (5,41,42 ). Similarly, plasma RNA measured by the nucleic acid sequence-based amplification assay (NASBA ® , manufactured by Organon Technika, Durham, North Carolina) yields absolute values approximately twice those obtained using the Quantiplex ® assay but values relatively comparable with those obtained using the Amplicor HIV-1 Monitor ™ assay (41)(42)(43). Therefore, one HIV RNA assay method should be used consistently for monitoring each patient. Choice of HIV RNA assay, particularly for young children, may be influenced by the amount of blood required for the assay. The NASBA ® assay requires the least amount of blood (i.e., 100 µL of plasma), followed by the Amplicor HIV-1 Monitor ™ (i.e., 200 µL of plasma) and the Quantiplex ® assays (i.e., 1 mL of plasma). Biologic variation in HIV RNA levels within one person is well documented, and repeated measurement of HIV RNA levels in a clinically stable infected adult can vary by as much as threefold (0.5 log 10 ) in either direction over the course of a day or on different days (5,39,44 ). This biologic variation may be greater in infected infants and young children. In children with perinatally acquired HIV infection, RNA copy number slowly declines even without therapy during the first several years after birth, although it persists at higher levels than those observed in most infected adults (20,34,35 ). This decline is most rapid during the first 12-24 months after birth, with an average decline of approximately 0.6 log 10 per year; a slower decline continues until approximately age 4-5 years (average decline of 0.3 log 10 per year). This inherent biologic variability must be considered when interpreting changes in RNA copy number in children. Thus, only changes greater than fivefold (0.7 log 10 ) in infants aged <2 years and greater than threefold (0.5 log10) in children aged ≥2 years after repeated testing should be considered reflective of a biologically and clinically substantial change. To reduce the impact of assay variability in the clinical management of patients, two samples can be obtained at baseline and the average of the two values used for comparison with future tests. No alteration in therapy should be made as a result of a change in HIV copy number unless the change is confirmed by a second measurement. Because of the complexities of HIV RNA testing and the age-related changes in HIV RNA in children, interpretation of HIV RNA levels for clinical decisionmaking should be done by or in consultation with an expert in pediatric HIV infection. # Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents Adult guidelines for antiretroviral therapy are appropriate for post-pubertal adolescents because HIV-infected adolescents who were infected sexually or through injecting-drug use during adolescence follow a clinical course that is more similar to that of adults than to that of children (5 ). The immunopathogenesis and virologic course of HIV infection in adolescents is being defined. Most adolescents have been infected during their teenage years and are in an early stage of infection, making them ideal candidates for early intervention. A limited but increasing number of HIVinfected adolescents are long-term survivors of HIV infection acquired perinatally or through blood products as young children. Such adolescents may have a unique clinical course that differs from that of adolescents infected later in life (45 ). Because many adolescents with HIV infection are sexually active, issues associated with contraception and prevention of HIV transmission should be discussed between the health-care provider and the adolescent. Dosage for medications for HIV infection and opportunistic infections should be prescribed according to Tanner staging of puberty (46 ) and not on the basis of age (25 ). Adolescents in early puberty (i.e., Tanner Stage I and II) should be administered doses using pediatric schedules, whereas those in late puberty (i.e., Tanner Stage V) should follow adult dosing schedules. Youth who are in their growth spurt (i.e., in females, Tanner Stage III and in males, Tanner Stage IV) should be closely monitored for medication efficacy and toxicity when using adult or pediatric dosing guidelines. Puberty is a time of somatic growth and sex differentiation, with females developing more body fat and males more muscle mass. Although these physiologic changes theoretically could affect drug pharmacokinetics (especially for drugs with a narrow therapeutic index that are used in combination with protein-bound medicines or hepatic enzyme inducers or inhibitors), no clinically consequential impact has been noted with nucleoside analogue reverse transcriptase inhibitor (NRTI) antiretroviral drugs (47 ). Clinical experience with protease inhibitors and non-nucleoside reverse transcriptase inhibitor antiretroviral drugs is more limited. # Specific Issues of Adherence for HIV-Infected Children and Adolescents Lack of adherence to prescribed regimens and subtherapeutic levels of antiretroviral medications may enhance the development of drug resistance. Data indicate that the development of resistance to one of the available protease inhibitor antiretrovirals may reduce susceptibility to some or all of the other available protease inhibitor drugs, thus substantially reducing subsequent treatment options. Therefore, education of infected children and/or their caregivers regarding the importance of compliance with the prescribed drug regimen is necessary when therapy is initiated and should be reinforced during subsequent visits. Many strategies can be used to increase medication adherence, including intensive patient education over several visits before therapy is initiated, the use of cues and reminders for administering drugs, development of patient-focused treatment plans to accommodate specific patient needs, and mobilization of social and community support services. Adherence to drug regimens is especially problematic for children. Infants and young children are dependent on others for administration of medication; thus, assessment of the capacity for adherence to a complex multidrug regimen requires evaluation of the caregivers and their environments and the ability and willingness of the child to take the drug. Liquid formulations or formulations suitable for mixing with formula or food are necessary for administration of oral drugs to young children. Lack of palatability of such formulations can be problematic depending on the child's willingness and ability to accept and retain the medication. Absorption of some antiretroviral drugs can be affected by food, and attempting to time the administration of drugs around meals can be difficult for caregivers of young infants who require frequent feedings. Many other barriers to adherence to drug regimens exist for children and adolescents with HIV infection. For example, unwillingness of the caregivers to disclose their child's HIV infection status to others may create specific problems, including reluctance of caregivers to fill prescriptions in their home neighborhood, hiding or relabeling medications to maintain secrecy within the home, reduction of social support (a variable associated with diminished treatment adherence), and a tendency to eliminate midday doses when the parent is away from the home or the child is at school. A comprehensive assessment of adherence issues should be instituted for all children in whom antiretroviral treatment is considered; evaluations should include nursing, social, and behavioral assessments. Intensive follow-up is required particularly during the critical first few months after therapy is started; patients should be seen frequently to assess adherence, drug tolerance, and virologic response. Coordinated, comprehensive, family-centered systems of care often can address many of the daily problems facing families that may affect adherence to complex medical regimens. For some families, certain issues (e.g., a safe physical environment and adequate food and housing) may take priority over medication administration and need to be resolved. Case managers, mental-health counselors, peer educators, outreach workers, and other members of the multidisciplinary team often may be able to address specific barriers to adherence. HIV-infected adolescents have specific adherence problems. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with health-care systems. Many HIV-infected adolescents face challenges in adhering to medical regimens for reasons that include a) denial and fear of their HIV infection; b) misinformation; c) distrust of the medical establishment; d) fear and lack of belief in the effectiveness of medications; e) low self-esteem; f) unstructured and chaotic lifestyles; and g) lack of familial and social support. Treatment regimens for adolescents must balance the goal of prescribing a maximally potent antiretroviral regimen with realistic assessment of existing and potential support systems to facilitate adherence. Developmental issues make caring for adolescents unique. The adolescent's approach to illness is often different from that of adults. The concrete thought processes of adolescents make it difficult for them to take medications when they are asymptomatic, particularly if the medications have side effects. Adherence with complex regimens is particularly challenging at a time of life when adolescents do not want to be different from their peers. Further difficulties face adolescents who live with parents to whom they have not yet disclosed their HIV status and those who are homeless and have no place to store medicine. # TREATMENT RECOMMENDATIONS # Initiation of Antiretroviral Therapy General Considerations Antiretroviral therapy has provided substantial clinical benefit to HIV-infected children with immunologic or clinical symptoms of HIV infection. Studies have demonstrated substantial improvements in neurodevelopment, growth, and immunologic and/or virologic status with initiation of ZDV, didanosine (ddI), lamivudine (3TC), or stavudine monotherapy (48)(49)(50)(51)(52)(53). More recent pediatric trials of symptomatic children who have not previously received antiretrovirals have demonstrated that combination therapy with either ZDV and 3TC or ZDV and ddI is clinically, immunologically, and virologically superior to monotherapy with ddI or ZDV as initial therapy (36,54,55 ). A trial involving children who have previously received antiretrovirals has demonstrated that combination therapy that includes a protease inhibitor is virologically and immunologically superior to dual nucleoside combination therapy (56 ). Data from clinical trials that address the effectiveness of antiretroviral therapy in asymptomatic infants and children with normal immune function are not available. However, initiation of therapy early in the course of HIV infection, including during the period of primary infection in the neonate, is theoretically advantageous. Control of viral replication in perinatally infected infants is inadequate, as demonstrated by the high levels of HIV RNA that are observed during the first 1-2 years of life following perinatal infection. Initiation of aggressive antiretroviral therapy during this early period of viral replication could theoretically preserve immune function, diminish viral dissemination, lower the viral set point, and result in improved clinical outcome. In a preliminary study of early treatment of children, six HIV-infected infants aged 2-4 months were placed on a regimen of ZDV, ddI, and nevirapine; baseline HIV RNA levels were 40,000-1,500,000 copies per mL. Five of six infants had an early virologic response with a drop in RNA PCR to <10,000 copies/mL by day 14, and two of the infants maintained undetectable levels of HIV RNA through 168 days of therapy (57 ). These two children had persistently negative HIV cultures, undetectable RNA levels, and became HIV antibody negative, although HIV DNA PCR remained positive. Clinical trials are ongoing to assess the virologic, immunologic, and clinical response of young infants to early, aggressive antiretroviral therapy with three or four antiretroviral agents. The theoretical problems with early therapy include the potential for short-and long-term adverse effects-particularly for drugs being administered to infants aged <6 months, for whom information on pharmacokinetics, drug dosing, and safety is limited. These concerns are particularly relevant because life-long administration of therapy is likely to be necessary for HIV-infected infants. If viral replication is not suppressed, ongoing viral mutation is likely to result in the development of antiretroviral resistance, curtailing the duration of benefit that early therapy might confer and potentially limiting future treatment options. Therefore, intensive education of caregivers and patients about the importance of adherence to the prescribed treatment regimen should be provided before therapy is initiated so that a) potential problems and solutions can be identified and b) frequent follow-up can be provided to assess virologic response to therapy, drug tolerance, and adherence. # When to Initiate Therapy Antiretroviral therapy is recommended for HIV-infected children with clinical symptoms of HIV infection (i.e., those in clinical categories A, B, or C) (Table 2) or evidence of immune suppression (i.e., those in immune categories 2 or 3) (Table 1)-regardless of the age of the child or viral load (Table 7). Clinical trial data from both adults and children have demonstrated that antiretroviral therapy in symptomatic patients slows clinical and immunologic disease progression and reduces mortality (54,55,58 ). - Clinical symptoms associated with HIV infection (i.e., clinical categories A, B, or C ). - Evidence of immune suppression, indicated by CD4+ T-lymphocyte absolute number or percentage (i.e., immune category 2 or 3 ). - Age <12 months-regardless of clinical, immunologic, or virologic status. - For asymptomatic children aged ≥1 year with normal immune status, two options can be considered: -Preferred Approach Initiate therapy-regardless of age or symptom status. -Alternative Approach Defer treatment in situations in which the risk for clinical disease progression is low and other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding to initiate therapy include the following: -High or increasing HIV RNA copy number. # TABLE 7. Indications for initiation of antiretroviral therapy in children with human immunodeficiency virus (HIV) infection Ideally, antiretroviral therapy should be initiated in all HIV-infected infants aged <12 months as soon as a confirmed diagnosis is established-regardless of clinical or immunologic status or viral load. HIV-infected infants aged <12 months are considered at high risk for disease progression, and the predictive value of immunologic and virologic parameters to identify infants who will have rapid progression is less than that for older children. Identification of infection during the first few weeks of life permits clinicians to initiate antiretroviral therapy or intensify ongoing antiretroviral therapy used for chemoprophylaxis of perinatal transmission during the initial phases of primary infection. However, clinical trial data documenting therapeutic benefit from this approach are not available, and information on drug dosing in neonates is limited. Because resistance to antiretroviral drugs (particularly protease inhibitors) can develop rapidly when drug concentrations fall below therapeutic levels (either as a result of inadequate dosage or incomplete adherence), issues associated with adherence should be fully assessed and discussed with the HIV-infected infant's caregivers before the decision to initiate therapy is made. Two general approaches for initiating therapy in asymptomatic children aged ≥1 year were outlined by the Working Group. The first approach would be to initiate therapy in all HIV-infected children, regardless of age or symptom status. Such an approach would ensure a) treatment of infected children as early as possible in the course of disease and b) intervention before immunologic deterioration. Data from prospective cohort studies indicate that most HIV-infected infants will have clinical symptoms of infection by age 1 year (59,60 ). Most asymptomatic infected children aged >1 year also have CD4+ T-lymphocyte percentages of <25% (60 ), which is indicative of immunosuppression (Table 1) and warrants antiretroviral therapy. An alternative approach would be to defer treatment in asymptomatic children aged ≥1 year with normal immune status in situations in which the risk for clinical disease progression is low (e.g., low viral load) and when other factors (e.g., concern for adherence, safety, and persistence of antiretroviral response) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding when to initiate therapy include a) high or increasing HIV RNA levels, b) rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (i.e., immune category 2 ), or c) development of clinical symptoms. The level of HIV RNA considered indicative of increased risk for disease progression is not well defined for young children. Regardless of age, any child with HIV RNA levels of >100,000 copies/mL is at high risk for mortality (Table 4), and antiretroviral therapy should be initiated-regardless of clinical or immune status. HIV RNA levels in asymptomatic children aged ≥30 months that are the same as levels for which there are treatment recommendations for HIV-infected adults (e.g., >10,000-20,000 copies/mL) also may indicate the need to initiate treatment (Table 6). In addition, any child with HIV RNA levels that demonstrate a substantial increase (more than a 0.7 log 10 increase for children aged <2 years and more than a 0.5 log 10 increase for those aged ≥2 years) on repeated testing should be offered therapy-regardless of clinical or immunologic status or absolute level of viral load. These recommendations are based on limited data and may need revision as more information becomes available. Issues associated with adherence to treatment are especially important in considering whether and when to initiate therapy. Antiretroviral therapy is most effective in patients who have never received therapy and who therefore are less likely to have antiretroviral-resistant viral strains. Lack of adherence to prescribed regimens and subtherapeutic levels of antiretroviral medications, particularly protease inhibitors, may enhance the development of drug resistance. Participation by the caregivers and child in the decision-making process is crucial, especially in situations for which definitive data concerning efficacy are not available. # Choice of Initial Antiretroviral Therapy Combination therapy is recommended for all infants, children, and adolescents who are treated with antiretroviral agents (Table 8). When compared with monotherapy, combination therapy a) slows disease progression and improves survival, b) results in a greater and more sustained virologic response, and c) delays development of virus mutations resistant to the drugs being used. Monotherapy with the currently available antiretroviral drugs is no longer recommended to treat HIV infection. ZDV monotherapy is appropriate, however, when used in infants of indeterminate HIV status during the first 6 weeks of life to prevent perinatal HIV transmission. Infants who are identified as being HIV-infected while receiving ZDV chemoprophylaxis should be changed to a combination antiretroviral drug regimen. Aggressive antiretroviral therapy for primary perinatal infection with three drugs is recommended because it provides the best opportunity to preserve immune function and delay disease progression. The goal of antiretroviral therapy is to maximally suppress viral replication, preferably to undetectable levels. Based on clinical trials involving infected adults, the preferred regimen is combination therapy with two NRTIs and one protease inhibitor. Although these combinations have had limited evaluation in clinical trials involving children, they can reduce HIV RNA to undetectable levels in some children (61,62 ). An interim analysis from a clinical trial of children (i.e., PACTG protocol 338) has demonstrated that therapy with drug combinations that include a protease inhibitor is more effective than therapy with two NRTI antiretroviral drugs in reducing viral load to undetectable levels and increasing CD4+ T-lymphocyte number (56 ). New antiretroviral drugs and combinations are being studied in infected adults and children. Other drug combinations that demonstrate sustainable viral load suppression and acceptable toxicity and dosing profiles most likely will become available, which will increase treatment options for children in the future. Protease inhibitors with formulations appropriate for infants and children who cannot swallow pills include nelfinavir (Viracept ® , manufactured by Agouron Pharmaceuticals, Inc., La Jolla, California), available in a powder formulation that can be mixed with water or food, and ritonavir (Norvir ® , manufactured by Abbott Laboratories, North Chicago, Illinois), available in a liquid formulation. Optimal dosing of these drugs in children aged <2 years is not known but is being evaluated in clinical trials (See Appendix). Indinavir (Crixivan ® , manufactured by Merck and Company, Inc., West Point, Pennsylvania) and saquinavir (hard gel capsule, Invirase ™ , and soft gel capsule, Fortovase ™ , manufactured by Hoffman-LaRoche, Inc., Nutley, New Jersey) are not available in liquid formulations. Indinavir is recommended for consideration for children who can tolerate swallowing capsules. Optimal dosing of these drugs in infants and children is not known but is being evaluated in clinical trials (See # Preferred Regimen Evidence of clinical benefit and sustained suppression of HIV RNA in clinical trials in HIV-infected adults; clinical trials in HIV-infected children are ongoing. - One highly active protease inhibitor plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs) -Preferred protease inhibitor for infants and children who cannot swallow pills or capsules: nelfinavir or ritonavir. Alternative for children who can swallow pills or capsules: indinavir. -Recommended dual NRTI combinations: the most data on use in children are available for the combinations of zidovudine (ZDV) and dideoxyinosine (ddI) and for ZDV and lamivudine (3TC). More limited data are available for the combinations of stavudine (d4T) and ddI, d4T and 3TC, and ZDV and zalcitabine (ddC)* # Alternative Regimen Less likely to produce sustained HIV RNA suppression in infected adults; the combination of nevirapine, ZDV, and ddI produced substantial and sustained suppression of viral replication in two of six infants first treated at age <4 months. † # Nevirapine § and two NRTIs # Secondary Alternative Regimen Clinical benefit demonstrated in clinical trials involving infected adults and/or children, but initial viral suppression may not be sustained. # Two NRTIs # Not Recommended Evidence against use because of overlapping toxicity and/or because use may be virologically undesirable. - Any monotherapy ¶ - d4T and ZDV - ddC and ddI - ddC and d4T - ddC and 3TC ddC is not available in a liquid preparation commercially, although a liquid formulation is available through a compassionate use program of the manufacturer (Hoffman-LaRoche Inc., Nutley, New Jersey). ZDV and ddC is a less preferred choice for use in combination with a protease inhibitor. † Source: Luzuiraga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997;336:1343-9. § A liquid preparation of nevirapine is not available commercially, but is available through a compassionate use program of the manufacturer (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut). ¶ Except for ZDV chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is identified as HIV-infected while receiving ZDV prophylaxis, therapy should be changed to a combination antiretroviral drug regimen. # TABLE 8. Recommended antiretroviral regimens for initial therapy for human immunodeficiency virus (HIV) infection in children Appendix). The hard-gel capsule formulation of saquinavir (Invirase ™ ) has limited bioavailability and thus is not recommended for use with two NRTIs. Some studies have indicated substantial increases in saquinavir drug levels when co-administered with other protease inhibitors (e.g., ritonavir) or other drugs that inhibit the cytochrome P450 enzyme system. However, data regarding such combinations in children are not available. The soft-gel formulation of saquinavir (Fortovase ™ ) with enhanced bioavailability has been approved by the Food and Drug Administration (FDA) for treatment of HIV infection in adults; however, data regarding appropriate dosing of this formulation in pediatric patients are not available. Alternative regimens, although not ideal, may be considered for initial therapy in circumstances in which the caregiver has concerns regarding the feasibility of adherence to a complex drug regimen or when the patient and caregivers prefer an alternative regimen. Alternative regimens have been clinically beneficial in adult and pediatric patients, but these regimens may not suppress viral load to below detectable levels as consistently as does combination therapy with two NRTIs and a protease inhibitor. Such alternative regimens include combination regimens of two NRTIs with nevirapine substituted for the protease inhibitor or two NRTIs alone. However, drug regimens that do not result in sustained viral suppression may result in the development of viral resistance to the drugs being used. The initial antiretroviral regimen chosen for infected infants theoretically could be influenced by the antiretroviral regimen their mother may have received during pregnancy. However, data from PACTG protocol 076 indicate that ZDV resistance did not account for most infants who became infected despite maternal ZDV treatment (63 ), and data from PACTG protocol 185 indicate that duration of prior ZDV therapy in women with advanced HIV disease, many of whom received prolonged ZDV before pregnancy, was not associated with diminished ZDV efficacy for reduction of transmission (64 ). Data do not suggest that the antiretroviral regimen for infected infants should be chosen on the basis of maternal antiretroviral use. However, continuing to monitor the frequency of perinatal transmission of antiretroviral-resistant HIV isolates is crucial, because maternal therapy with multiple antiretroviral agents is becoming more common and the prevalence of resistant viral strains in the HIV-infected population may increase over time. # Issues Regarding Antiretroviral Dosing in Neonates Data regarding the appropriate dosing of antiretroviral drugs in neonates are limited; ZDV is the best studied antiretroviral drug in this age group. The recommended ZDV dosage for infants was derived from pharmacokinetics studies performed in fullterm infants (65 ). Because ZDV is primarily cleared through hepatic metabolism (i.e., glucuronidation), which is immature in neonates, the half-life and clearance of ZDV are prolonged in neonates compared with older infants, thus requiring adjustments in dosing (See Appendix). Premature infants have even greater immaturity in hepatic metabolic function than do full-term infants, and further prolongation in clearance has been documented in very premature infants (e.g., those born before 34 weeks' gestation) (66 ). Appropriate ZDV dosing for premature infants has not been defined but is being evaluated in a phase I clinical trial of premature infants born before 34 weeks' gestation (i.e., PACTG protocol 331) (See Appendix). The safety and pharmacokinetics of 3TC administered alone or in combination with ZDV in pregnant women and administered for 1 week to their newborns have been evaluated (67,68 ). Clearance was prolonged in these infants. On the basis of data from this study, the dose recommended for use in newborns is half the dose recommended in older children (See Appendix). No data are available regarding 3TC pharmacokinetics among infants aged 2-6 weeks, and the exact age at which 3TC clearance begins to approximate that in older children is not known. Nevirapine administration to HIV-infected pregnant women during labor and as a single dose to their newborns at age 2-3 days has been studied in a phase I trial (69 ). The half-life of nevirapine was prolonged in neonates compared with that in older children, indicating that some modification of nevirapine dosage is required for administration to neonates (See Appendix). Although phase I studies of several protease inhibitors (i.e., indinavir, ritonavir, nelfinavir, or saquinavir in combination with ZDV and 3TC) in pregnant infected women and their infants are ongoing in the United States, no data are available regarding drug dosage, safety, and tolerance of any of the protease inhibitors in neonates. # Changing Antiretroviral Therapy When to Change Antiretroviral Therapy The following three reasons warrant a change in antiretroviral therapy: a) failure of the current regimen with evidence of disease progression based on virologic, immunologic, or clinical parameters; b) toxicity or intolerance to the current regimen; and c) new data demonstrating that a drug or regimen is superior to the current regimen (Table 9). When therapy must be changed because of treatment failure or suboptimal response to treatment, clinicians should work with families to assess the possible contribution of adherence problems to the failure of the current regimen. Issues regarding adherence should be addressed to increase the likelihood of a successful outcome when initiating a new therapy. These issues are best addressed before therapy is instituted and need to be reinforced during therapy. Intensive family education, training in the administration of prescribed medications, and discussion of the importance of adherence to the drug regimen should be completed before initiation of new treatment. In addition, frequent patient visits and intensive follow-up during the initial months after a new antiretroviral regimen is started are needed to support and educate the family and to monitor adherence, tolerance, and virologic response to the new regimen. # Virologic Considerations for Changing Therapy Information is limited regarding HIV RNA response to antiretroviral therapy in infants and young children. However, the general virologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons. Because HIV RNA monitoring is critical for the management of infected children, Working Group members used the available data and clinical experience when definitive data were not available to make the following recommendations. These recommendations may require modification as new information becomes available. Ideally, antiretroviral therapy should maximally suppress viral replication to below levels capable of being detected with HIV RNA assays-which may not always be Virologic Considerations - Less than a minimally acceptable virologic response after 8-12 weeks of therapy. For children receiving antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a protease inhibitor, such a response is defined as a <10-fold (1.0 log10) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (i.e., dual NRTI combinations), an insufficient response is defined as a less than fivefold (0.7 log10) decrease in HIV RNA levels from baseline. - HIV RNA not suppressed to undetectable levels after 4-6 months of antiretroviral therapy. † - Repeated detection of HIV RNA in children who initially responded to antiretroviral therapy with undetectable levels. § - A reproducible increase in HIV RNA copy number among children who have had a substantial HIV RNA response but still have low levels of detectable HIV RNA. Such an increase would warrant change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (0.5 log 10 ) increase in copy number for children aged ≥2 years and a greater than fivefold (0.7 log 10 ) increase is observed for children aged <2 years. # Immunologic Considerations* - Change in immunologic classification (Table 1). ¶ - For children with CD4+ T-lymphocyte percentages of <15% (i.e., those in immune category 3), a persistent decline of five percentiles or more in CD4+ cell percentage (e.g., from 15% to 10%). - A rapid and substantial decrease in absolute CD4+ T-lymphocyte count (e.g., a >30% decline in <6 months). # Clinical Considerations - Progressive neurodevelopmental deterioration. - Growth failure defined as persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation. - Disease progression defined as advancement from one pediatric clinical category to another (e.g., from clinical category A to clinical category B). - At least two measurements (taken 1 week apart) should be performed before considering a change in therapy. † The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log10 decrease in HIV RNA copy number, even if RNA remains detectable at low levels. § More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (e.g., if when using an HIV RNA assay with a lower limit of detection of 1,000 copies/mL, there is a ≤0.7 log10 increase from undetectable to approximately 5,000 copies/mL in an infant aged <2 years). ¶ Minimal changes in CD4+ T-lymphocyte percentile that may result in change in immunologic category (e.g., from 26% to 24%, or 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ percentile within the same immunologic category (e.g., a drop from 35% to 25%). In patients with stable immunologic and virologic parameters, progression from one clinical category to another may not represent an indication to change therapy. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic considerations are important in deciding whether to change therapy. # TABLE 9. Considerations for changing antiretroviral therapy for human immunodeficiency virus (HIV)-infected children achievable in HIV-infected children. Perinatally infected children generally have high HIV RNA levels, and clinical benefit may be observed with decrements in HIV RNA levels that do not result in undetectable levels. However, failure to maximally suppress replication may be associated with increased probability of viral mutations and the emergence of drug resistance. Consideration of the implications of changing regimens and the choice of new drugs should include an acknowledgment of the potential for limiting the patient's future options for potent therapy. Consensus recommendations have been developed using plasma HIV RNA measurements to guide changes in antiretroviral therapy for HIV-infected adults (5 ). The recommendations for adults state that health-care providers should consider changing therapy if a) HIV RNA levels drop less than threefold (0.5 log 10 ) after 4 weeks of therapy and less than 10-fold (1.0 log 10 ) after 8 weeks of therapy or b) HIV RNA has not decreased to undetectable levels after 4-6 months of therapy. Because HIV RNA levels in infants who are perinatally infected are high compared with levels observed when therapy is initiated in most infected adults, the initial virologic response of infected infants and young children to initiation of antiretroviral therapy may take longer than observed in adults (i.e., 8-12 weeks). In addition, suppression of HIV RNA to undetectable levels may be achieved less often than has been reported for infected adults despite potent combination therapy with two NRTIs and a protease inhibitor. Therefore, virologic indications for changing therapy in infected children differ slightly from those recommended for infected adults. Adult guidelines should be followed for infected adolescents. Virologic response should be initially assessed 4 weeks after therapy is initiated. However, the time required to achieve maximal virologic response to therapy may vary depending on the specific baseline HIV RNA value at the time of starting therapy. If baseline HIV RNA levels are high (i.e., >1,000,000 copies/mL), virologic response may not be observed until 8-12 weeks after initiating antiretroviral therapy. However, if baseline HIV RNA levels are more similar to those observed in untreated infected adults (i.e., <100,000 copies/mL), initial response should be observed within 4 weeks following initiation of therapy. After a maximal virologic response is achieved, HIV RNA levels should be measured at least every 3 months to monitor continued response to therapy. At least two measurements (taken 1 week apart) should be performed before considering a change in therapy. The following situations may indicate a need for change in therapy in infected children: - Less than a minimally acceptable virologic response after 8-12 weeks of therapy. For children receiving antiretroviral therapy with two NRTIs and a protease inhibitor, such a response is defined as a <10-fold (1.0 log10) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (i.e., dual NRTI combinations), an insufficient response is defined as a less than fivefold (0.7 log10) decrease in HIV RNA levels from baseline. - HIV RNA not suppressed to undetectable levels after 4-6 months of antiretroviral therapy. However, although suppression of HIV RNA to undetectable levels and maintenance for prolonged periods is desirable, few data among children indicate that such suppression is always achievable. In addition, the number of alternative therapeutic regimens for children is limited. The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log10 fall in HIV RNA copy number, even if RNA remains detectable at low levels. - Repeated detection of HIV RNA in children who initially had had undetectable levels in response to antiretroviral therapy. The presence of repeatedly detectable RNA suggests the development of resistance or problems with adherence or drug bioavailability. More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (e.g., if using an HIV RNA assay with a lower limit of detection of 1,000 copies/mL, there is a ≤0.7 log 10 increase from undetectable to approximately 5,000 copies/mL in an infant aged <2 years). If adherence to therapy has been inconsistent, renewed efforts to educate the caregivers and patient and closer follow-up from members of a multidisciplinary care team may improve adherence. - A reproducible increase in HIV RNA copy number among children who have had a substantial HIV RNA response but still have low levels of detectable HIV RNA. Such an increase would warrant a change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (>0.5 log10) increase in copy number is observed in children aged ≥2 years. Because of the greater biologic variability in RNA in young children, a change in therapy is warranted when a greater than fivefold (>0.7 log10) increase is observed for children aged <2 years. # Immunologic Considerations for Changing Therapy CD4+ T-lymphocyte count and percentage are independent predictors of disease progression and mortality in HIV-infected children (35,36 ). The association of HIV RNA and CD4+ percentage with long-term mortality risk in HIV-infected children has been evaluated; for each absolute decline of five percentiles in CD4+ percentage at baseline or during follow-up, the mortality risk ratio increased by 1.3 (95% CI=1.2-1.5), independent of the child's HIV RNA level (35 ). For children with CD4+ percentages of <15% (i.e., those in immune category 3), prognosis also was correlated with the degree of depression of CD4+ percentage (i.e., life expectancy was less for children with CD4+ percentages of <5% compared with children with CD4+ percentages of 10%-14%) (Table 3). Before considering changing antiretroviral therapy because of a decline in CD4+ lymphocyte values, a minimum of one repeated measurement of CD4+ values should be obtained at least 1 week after the initial test. The following are immunologic indications that may warrant a change in antiretroviral therapy for HIV-infected children: - Change in immune classification (Table 1). However, minimal changes in CD4+ percentile that may result in a change in immune category (e.g., from 26% to 24% or from 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ percentile within the same immune category (e.g., a decrease from 35% to 25%). - For children with CD4+ percentages of <15% (i.e., those in immune category 3), a persistent decline of five percentiles or more in CD4+ cell percentage (e.g., from 15% to 10% or from 10% to 5%). - A rapid and substantial decrease in absolute CD4+ T-lymphocyte count (e.g., a >30% decline in <6 months). # Clinical Considerations for Changing Therapy The occurrence of certain clinical events while receiving antiretroviral therapy is evidence of HIV disease progression and/or a poor prognosis for infants and children. The following clinical criteria warrant consideration of a change in antiretroviral therapy: - Progressive neurodevelopmental deterioration (i.e., persistence or progression of deterioration documented on repeated testing as demonstrated by the presence of two or more of the following findings: impairment in brain growth, decline of cognitive function documented by psychometric testing, or clinical motor dysfunction). In such cases, the new treatment regimen optimally should include at least one antiretroviral drug with substantial central nervous system penetration (e.g., ZDV or nevirapine, which have cerebrospinal fluid/plasma ratios >0.5). - Growth failure (i.e., persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation). - Disease progression (i.e., advancement from one pediatric clinical category to another ). Prognosis is poorer as patients progress to more advanced clinical categories (59 ). However, in patients with stable immunologic and virologic parameters, progression from one clinical category to another (e.g., from clinical category A to category B) may not represent an indication to change therapy. For example, development of new opportunistic infections, particularly in patients who had severe immunosuppression at the time therapy was initiated, may not reflect a failure of antiretroviral therapy but persistence of immunologic dysfunction despite adequate antiviral response. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic parameters should be considered when deciding whether to change therapy. # Choice of a New Antiretroviral Regimen The choice of a new antiretroviral regimen is dictated by the indications that warranted the change in therapy and the limited available alternative antiretroviral agents. Although the efficacy of different combination antiretroviral regimens in children probably can be extrapolated from clinical trial data obtained for adults, data are limited regarding the pharmacokinetics, appropriate dosing, and short-and long-term safety of various combinations in infected children. New regimens should be chosen partly on the basis of the impact of the changes on future treatment options. The following principles should be followed when choosing a new antiretroviral regimen in children who have received prior treatment. - When therapy is changed because of toxicity or intolerance, agents with different toxicity and side-effect profiles should be chosen, when possible. Health-care providers should have comprehensive knowledge of the toxicity profile of each agent before selecting a new regimen. In the event of drug intolerance, change of a single drug in a multidrug regimen and, in certain circumstances, dose reduction are permissible options. However, antiretroviral drugs should only be reduced to the lower end of the therapeutic range for those antiretrovirals for which an effective dosing range is known, and adequacy of antiretroviral activity should be confirmed by the monitoring of HIV RNA levels. - When changing therapy because of treatment failure (Table 9), adherence to therapy should be assessed as a potential cause of failure. - If the patient is adherent to the prescribed drug regimen, assume the development of drug resistance and, if possible, change at least two drugs to new antiretroviral agents. Change in one drug or addition of a drug to a failing regimen is suboptimal. The new regimen should include at least three drugs, if possible. The potential for cross-resistance between antiretroviral drugs should be considered in choosing new drugs. - When considering changing to a new regimen, all other medications taken by the patient should be reviewed for possible drug interactions. - A change to a new regimen, especially one containing protease inhibitors, must include a discussion of treatment adherence issues between the caregivers of the infected child and the health-care provider. The health-care provider must recognize that certain medications are difficult to take in combination because of exacting and often conflicting requirements with respect to whether they can be taken with food and other antiretrovirals. - When changing therapy because of disease progression in a patient with advanced disease, the patient's quality of life must be considered. Detailed information regarding issues associated with specific drug choices for changing a failing regimen and potential cross-resistance between various antiretroviral drugs is available elsewhere (5 ). Because these issues are similar for all HIVinfected persons (regardless of age) they are not addressed specifically in this document. # MANAGING ADVERSE DRUG REACTIONS IN THE THERAPY OF PEDIATRIC HIV INFECTION The antiretroviral agents used and approved to treat HIV infection in children have all demonstrated individual and drug-class toxicities that limit the doses and combinations that can be used safely (70 ). The general principles of toxicity management are similar for adults and children. However, for many of the newer therapies (particularly the protease inhibitors), limited short-term and no long-term safety data or experience are available for infants, children, and adolescents. Thus, the amount of information on which to base guidelines for management of antiretroviral toxicities in children, especially when antiretroviral drugs are used in combination, is substantially more limited than that for adults. The data available from PACTG protocol 152 and PACTG protocol 300 indicate that some combinations of nucleoside analogues do not substantially increase the toxicity relative to monotherapy with those agents (54,55 ). The toxicities of antiretroviral drugs may occur at different frequencies in children and adults, and the implications of some of the toxicities substantially differ for children. The most obvious difference for children from the listing of toxicities in the adult guidelines is the increased indirect bilirubin associated with indinavir, which is labeled as inconsequential for adults. This toxicity could be of major consequence for newborn and young infants because severe hyperbilirubinemia is associated with kernicterus and would require specific monitoring and treatment should indinavir be administered to neonates. Additional examples of differences of potential toxicities between adults and children include the description of asymptomatic retinal depigmentation in children associated with ddI therapy and the relative lack of pancreatitis in children compared with adults receiving ddI therapy (See Appendix). Another treatment issue that affects children differently from adults concerns the feasibility of administering poorly palatable liquid antiretroviral formulations to children. Innovative techniques to increase palatability may be needed to enable tolerance of medications (e.g., various methods can be used to increase tolerance of ritonavir ). Indinavir is associated with hematuria and nephrolithiasis secondary to crystallization of the drug in the urine; adequate hydration (i.e., 48 oz of fluid daily) is recommended to reduce the incidence of this side effect. However, ensuring that voluntary fluid intake of this level is achieved may be more difficult in children than in adults. All efforts should be made to continue therapy in the presence of toxicities that are not life-threatening. Such efforts should include liberal use of adjunctive measures (e.g., granulocyte colony stimulating factor for treatment of neutropenia and erythropoietin and/or transfusions for treatment of anemia). If antiretroviral therapy must be discontinued for an extended period of time, to minimize the risk for developing drug resistance, all antiretroviral agents should be stopped simultaneously rather than continuing one or two agents alone because of potential increased viral replication. # CONCLUSION The Working Group has attempted to provide information specific to the use of antiretroviral drugs in infants, children, and adolescents while not duplicating the information available in antiretroviral recommendations for adults (5 ). Documents addressing recommendations for adults should be reviewed for basic information regarding disease pathogenesis and drug interactions. Although the general principles of therapy are the same for HIV-infected adults, adolescents, children, and infants, treatment of infection in pediatric patients requires an understanding of the unique aspects of HIV infection in children. Clinical trials of antiretroviral agents in HIVinfected children and the development of drug formulations appropriate for administration to children have often been delayed until after clinical trials in infected adults have been completed and/or the drug has been approved for use among infected adults. However, despite these delays, the paucity of pediatric-specific data cannot further deter the development of rational and reasonable pediatric treatment guidelines while studies in children are being undertaken. To maximize therapeutic options for HIV-infected pediatric patients throughout the course of their infection, drug formularies should facilitate the use of all FDA-approved antiretroviral agents as treatment options for children. Additionally, the conduct of clinical trials to define the pharmacokinetics, safety, and effectiveness in ameliorating the pediatric-specific manifestations of HIV infection of current and new antiretroviral agents is a priority; studies of new drugs should be conducted coincident with or soon after initial studies have been completed in adults. The Working Group will revise these guidelines as new data regarding antiretroviral therapy for infected infants, children, and adolescents become available. - Should not be administered in combination with zidovudine (poor antiretroviral effect). # Special instructions - Can be administered with food. - Need to decrease dose in patients with renal impairment. - For oral solution: shake well and keep refrigerated; solution stable for 30 days. # Zalcitabine (ddC), HIVID ® Preparations: Syrup: 0.1 mg/mL (investigational); Tablets: 0.375 and 0.75 mg Dosage Neonatal dose: Unknown. Pediatric usual dose: 0.01 mg per kg of body weight every 8 hours. Pediatric dosage range: 0.005 to 0.01 mg per kg of body weight every 8 hours. Adolescent/Adult dose: 0.75 mg three times a day. # Major toxicities Most frequent: Headache, gastrointestinal disturbances, and malaise. Unusual (more severe): Peripheral neuropathy, pancreatitis, hepatic toxicity, oral ulcers, esophageal ulcers, hematologic toxicity, and skin rashes. # Drug interactions - Cimetidine, amphotericin, foscarnet, and aminoglycosides may decrease renal clearance of ddC. - Antacids decrease absorption of ddC. - Concomitant use with ddI is not recommended because of the increased risk of peripheral neuropathy. - Intravenous pentamidine increases the risk for pancreatitis; do not use concurrently. # Special instructions - Administer on an empty stomach (1 hour before or 2 hours after a meal). - Decrease dosage in patients with impaired renal function. # Zidovudine (ZDV, AZT), RETROVIR ® Preparations: Syrup: 10 mg/mL; Capsules: 100 mg; Tablets: 300 mg; Concentrate for injection/for intravenous infusion: 10 mg/mL Dosage Dose for premature infants: (Standard neonatal dose may be excessive in premature infants.) Under study in Pediatric AIDS Clinical Trial Group protocol 331: 1.5 mg per kg of body weight every 12 hours from birth to 2 weeks of age; then increase to 2 mg per kg of body weight every 8 hours after 2 weeks of age. Neonatal dose: Oral: 2 mg per kg of body weight every 6 hours. Intravenous: 1. Adolescent/Adult dose: 200 mg three times a day or 300 mg twice daily. - Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. - Techniques to increase tolerance in children: a) mixing oral solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream; b) dulling the taste buds before administration by chewing ice, giving popsicles or spoonfuls of partially frozen orange or grape juice concentrates; c) coating the mouth by giving peanut butter to eat before the dose; or d) administration of strong-tasting foods such as maple syrup, cheese, or strong-flavored chewing gum immediately after dose. Adolescent/Adult dose: Hard gel capsules: 600 mg three times a day; Soft gel capsules: 1200 mg three times a day. # Major toxicities Most frequent: Diarrhea, abdominal discomfort, headache, nausea, paresthesias, and skin rash. Less common: Exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes. # Drug interactions - Saquinavir is metabolized by the cytochrome P450 3A4 (CYP 3A4) system in the liver, and there are numerous potential drug interactions.* - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - Saquinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Saquinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives, or sedative-hypnotics (e.g., midazolam or triazolam). - Saquinavir levels are significantly reduced with concurrent use of rifampin (decreases saquinavir levels by 80%), rifabutin (decreases saquinavir levels by 40%), and nevirapine (decreases saquinavir levels by 25%). - Saquinavir levels are decreased by carbamazepine, dexamethasone, phenobarbital, and phenytoin. - Saquinavir levels are increased by delvirdine and ketoconazole. - Saquinavir may increase levels of calcium channel blockers, clindamycin, dapsone, and quinidine. If used concurrently, patients should be closely monitored for toxicity. - Administration with other protease inhibitors: co-administration with indinavir, ritonavir, or nelfinavir increases concentration of saquinavir with little change in concentration of the other drug. # Special instructions - Administer within 2 hours of a full meal to increase absorption. - Concurrent administration of grapefruit juice increases saquinavir concentration. - Sun exposure can cause photosensitivity reactions, therefore sunscreen or protective clothing is recommended. # Appendix # CHARACTERISTICS OF AVAILABLE ANTIRETROVIRAL DRUGS Didanosine (dideoxyinosine) (ddI), VIDEX ® Preparations: Pediatric powder for oral solution (when reconstituted as solution containing antacid): 10 mg/mL; Chewable tablets with buffers: 25, 50, 100, and 150 mg; Buffered powder for oral solution: 100, 167, and 250 mg Dosage Neonatal dose (infants aged <90 days): 50 mg per m 2 of body surface area every 12 hours. Pediatric usual dose: In combination with other antiretrovirals: 90 mg per m 2 of body surface area every 12 hours. Pediatric dosage range: 90 to 150 mg per m 2 of body surface area every 12 hours. (Note: may need higher dose in patients with central nervous system disease.) Adolescent/Adult dose: Body weight ≥60 kg: 200 mg twice daily. Body weight <60 kg: 125 mg twice daily. # Major toxicities Most frequent: Diarrhea, abdominal pain, nausea, and vomiting. Unusual (more severe): Peripheral neuropathy (dose related), electrolyte abnormalities, and hyperuricemia. Uncommon: Pancreatitis (dose related, less common in children than adults), increased liver enzymes, and retinal depigmentation. # Drug interactions - Possible decrease in absorption of ketoconazole, itraconazole, and dapsone; administer at least 2 hours before or 2 hours after ddI. - Tetracycline and fluoroquinolone antibiotic absorption significantly decreased (chelation of drug by antacid in pediatric powder and tablets); administer 2 hours before or 2 hours after ddI. - Concomitant administration of ddI and delavirdine may decrease the absorption of these drugs; separate dosing by at least 2 hours. - Administration with protease inhibitors: indinavir should be administered at least 1 hour before or after ddI on an empty stomach. Ritonavir should be administered at least 2 hours before or after ddI. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. # Nucleoside Analogue Reverse Transcriptase Inhibitors- † # Special instructions - ddI formulation contains buffering agents or antacids. - Food decreases absorption; administer ddI on an empty stomach (1 hour before or 2 hours after a meal). Further evaluation in children regarding administration with meals is under study. - For oral solution: shake well and keep refrigerated; admixture is stable for 30 days. - When administering chewable tablets, at least two tablets should be administered to ensure adequate buffering capacity (e.g., if the child's dose is 50 mg, administer two 25-mg tablets and not one 50-mg tablet). # Lamivudine (3TC), EPIVIR ® Preparations: Solution: 10 mg/mL; Tablets: 150 mg # Dosage Neonatal dose (infants aged <30 days): 2 mg per kg of body weight twice daily. Pediatric dose: 4 mg per kg of body weight twice daily. Adolescent/Adult dose: Body weight ≥50 kg: 150 mg twice daily. Body weight <50 kg: 2 mg per kg body weight twice daily. # Major toxicities Most frequent: Headache, fatigue, nausea, diarrhea, skin rash, and abdominal pain. Unusual (more severe): Pancreatitis (primarily seen in children with advanced HIV infection receiving multiple other medications), peripheral neuropathy, decreased neutrophil count, and increased liver enzymes. # Drug interactions - Trimethoprim/sulfamethoxazole (TMP/SMX) increases 3TC blood levels (possibly competes for renal tubular secretion); unknown significance. - When used with zidovudine (ZDV) may prevent emergence of ZDV resistance, and for ZDV-resistant virus, revision to phenotypic ZDV sensitivity may be observed. # Special instructions - Can be administered with food. - For oral solution: store at room temperature. - Decrease dosage in patients with impaired renal function. # Stavudine (d4T), ZERIT ® Preparations # Major toxicities Most frequent: Hematologic toxicity, including granulocytopenia and anemia, and headache. Unusual: Myopathy, myositis, and liver toxicity. # Drug interactions - Increased toxicity may be observed with concomitant administration of the following drugs (therefore, more intensive toxicity monitoring may be warranted): ganciclovir, interferon-alpha, TMP/SMX, acyclovir, and other drugs that can be associated with bone marrow suppression. - The following drugs may increase ZDV concentration (and therefore potential toxicity): probenecid, atovaquone, methadone, valproic acid, and fluconazole. - Decreased renal clearance may be observed with co-administration of cimetidine (may be significant in patients with renal impairment). - ZDV metabolism may be increased with co-administration of rifampin and rifabutin (clinical significance unknown); clarithromycin may decrease concentrations of ZDV probably by interfering with absorption (preferably administer 4 hours apart). - Ribavirin decreases the intracellular phosphorylation of ZDV (conversion to active metabolite). - Phenytoin concentrations may increase or decrease. - Should not be administered in combination with d4T (poor antiretroviral effect). # Special instructions - Can be administered with food (although the manufacturer recommends administration 30 minutes before or 1 hour after a meal). - Decrease dosage in patients with severe renal impairment. - Substantial granulocytopenia or anemia may necessitate interruption of therapy until marrow recovery is observed; use of erythropoietin, filgrastim, or reduced ZDV dosage may be necessary in some patients. - Reduced dosage may be indicated in patients with substantial hepatic dysfunction. - Infuse intravenous loading dose or intermittent infusion dose over 1 hour. - For intravenous solution: dilute with 5% dextrose injection solution to concentration ≤4 mg/mL; refrigerated diluted solution is stable for 24 hours. - Some experts in pediatric HIV infection use a dose of 180 mg per m 2 of body surface area every 12 hours when using in drug combinations with other antiretroviral compounds, but data on this dosing in children is limited. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. § Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Delavirdine (DLV), RESCRIPTOR ® Preparations: Tablets: 100 mg # Dosage Neonatal dose: Unknown. Pediatric dose: Unknown. Adolescent/Adult dose: 400 mg three times a day. # Major toxicities Most frequent: Headache, fatigue, gastrointestinal complaints, and rash (may be severe). # Drug interactions - Metabolized in part by hepatic cytochrome P450 3A (CYP3A). There could potentially be multiple drug interactions. § - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - DLV decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. DLV is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); sedative-hypnotics (e.g., alprazolam, midazolam, or triazolam); calcium channel blockers (e.g., nifedipine); ergot alkaloid derivatives; amphetamines; cisapride; or warfarin. - DLV clearance is increased, resulting in substantially reduced concentrations of DLV, with concurrent use of rifabutin, rifampin, or anticonvulsants (e.g., phenytoin, carbamazepine, or phenobarbital). Concurrent use is not recommended. - Absorption of DLV is decreased if given with antacids or histamine 2 receptor antagonists. - Increased trough concentrations of DLV if given with ketoconazole or fluoxetine; increased levels of both drugs if DLV is given with clarithromycin. - DLV increases levels of dapsone and quinidine. - Administration with protease inhibitors: decreases metabolism of saquinavir and indinavir, resulting in a significant increase in saquinavir and indinavir concentrations and a slight decrease in DLV concentrations. # Special instructions - Can be administered with food. - Should be taken 1 hour before or 1 hour after ddI or antacids. - Tablets can be dissolved in water and the resulting dispersion taken promptly. # Non-nucleoside Reverse Transcriptase Inhibitors- † Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Nevirapine (NVP), VIRAMUNE ® Preparations: Suspension: 10 mg/mL (investigational); Tablets: 200 mg Dosage Neonatal dose (through age 3 months): Under study in Pediatric AIDS Clinical Trial Group protocol 356: 5 mg per kg of body weight once daily for 14 days, followed by 120 mg per m 2 of body surface area every 12 hours for 14 days, followed by 200 mg per m 2 of body surface area every 12 hours. Pediatric dose: 120 to 200 mg per m 2 of body surface area every 12 hours. Note: Initiate therapy with 120 mg per m 2 of body surface area administered once daily for 14 days. Increase to full dose administered every 12 hours if there are no rash or other untoward effects. Adolescent/Adult dose: 200 mg every 12 hours. Note: Initiate therapy at half dose for the first 14 days. Increase to full dose if there is no rash or other untoward effects. # Major toxicities Most frequent: Skin rash (some severe and life-threatening, including Stevens-Johnson syndrome), sedative effect, headache, diarrhea, and nausea. Unusual: Elevated liver enzymes and, rarely, hepatitis. # Drug interactions - Induces hepatic cytochrome P450 3A (CYP3A); autoinduction of metabolism occurs in 2-4 weeks with a 1.5-fold to twofold increase in clearance. There could potentially be multiple drug interactions. - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - Drugs having suspected interactions and should be used only with careful monitoring: rifampin and rifabutin; oral contraceptives (alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control); sedative-hypnotics (e.g., triazolam or midazolam); oral anticoagulants; digoxin; phenytoin; or theophylline. - Administration with protease inhibitors: indinavir and saquinavir concentrations are decreased significantly, and ritonavir concentration may be decreased. Whether increased doses of protease inhibitors are needed is unknown. # Special instructions - Can be administered with food. - May be administered concurrently with ddI. - NVP-associated skin rash usually occurs within the first 6 weeks of therapy. If rash occurs during the initial 14-day lead-in period, do not increase dose until rash resolves. NVP should be discontinued immediately in patients who develop severe rash or a rash accompanied by constitutional symptoms (i.e., fever, oral lesions, conjunctivitis, or blistering). - For investigational suspension: Must be shaken well; store at room temperature. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. § Data in children is limited, and doses may change as more information is obtained about the pharmacokinetics of these drugs in children. ¶ Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Indinavir, CRIXIVAN ® Preparations: Capsules: 200 and 400 mg Dosage Neonatal Dose: Unknown. Due to side effect of hyperbilirubinemia, should not be given to neonates until further information is available. Pediatric Dose: Under study in clinical trials: 500 mg per m 2 of body surface area every 8 hours. Adolescent/Adult dose: 800 mg every 8 hours. # Major toxicities Most frequent: Nausea, abdominal pain, headache, metallic taste, dizziness, and asymptomatic hyperbilirubinemia (10%). Unusual (more severe): Nephrolithiasis (4%) and exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, diabetes, and hemolytic anemia. # Drug interactions - Cytochrome P450 3A4 (CYP3A4) responsible for metabolism. There could potentially be multiple drug interactions. ¶ - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - Indinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Indinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives; or sedative-hypnotics (e.g., triazolam or midazolam). - Indinavir levels are significantly reduced with concurrent use of rifampin. Concurrent use is not recommended. - Rifabutin concentrations are increased, therefore a dose reduction of rifabutin to half the usual daily dose is recommended. - Ketoconazole and itraconazole cause an increase in indinavir concentrations (consider reducing adolescent/adult indinavir dose to 600 mg every 8 hours). - Co-administration of clarithromycin increases serum concentration of both drugs (dosing modification not needed). - Co-administration of nevirapine may decrease indinavir serum concentration. # Protease Inhibitors- † § Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. - Administration with other protease inhibitors: co-administration with nelfinavir increases concentration of both drugs; co-administration with saquinavir increases concentration of saquinavir. # Special instructions - Administer on an empty stomach 1 hour before or 2 hours after a meal (or can take with a light meal). - Adequate hydration required to minimize risk of nephrolithiasis (at least 48 oz of fluid daily in adult patients). - If co-administered with ddI, give at least 1 hour apart on an empty stomach. - Decrease dose in patients with hepatic insufficiency. - Capsules are sensitive to moisture and should be stored in original container with desiccant. # Nelfinavir, VIRACEPT ® Preparations: Powder for oral suspension: 50 mg per 1 level gram scoopful (200 mg per 1 level teaspoon); Tablets: 250 mg tablet # Dosage Neonatal dose: Under study in Pediatric AIDS Clinical Trial Group protocol 353: 10 mg per kg of body weight three times a day. (Note: no preliminary data available, investigational.) Pediatric dose: 20 to 30 mg per kg of body weight three times a day. Adolescent/Adult dose: 750 mg three times a day. # Major toxicities Most frequent: Diarrhea. Less common: Asthenia, abdominal pain, rash, and exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes. # Drug interactions - Nelfinavir is in part metabolized by cytochrome P450 3A4 (CYP3A4). There could potentially be multiple drug interactions.* - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - Nelfinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Nelfinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives; certain cardiac drugs (e.g., quinidine or amiodarone); or sedativehypnotics (e.g., triazolam or midazolam). - Nelfinavir levels are greatly reduced with concurrent use of rifampin. Concurrent use is not recommended. - Rifabutin causes less decline in nelfinavir concentrations; if co-administered with nelfinavir, rifabutin should be reduced to one half the usual dose. - Estradiol levels are reduced by nelfinavir, and alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control. - Co-administration with delavirdine (DLV) increases nelfinavir concentrations twofold and decreases DLV concentrations by 50%. There are no data on coadministration with nevirapine, but some experts use higher doses of nelfinavir if used in combination with nevirapine. - Administration with other protease inhibitors: co-administration with indinavir increases concentration of both drugs; co-administration with saquinavir increases concentration of saquinavir with little change in nelfinavir concentration; co-administration with ritonavir increases concentration of nelfinavir without change in ritonavir concentration. # Special instructions - Administer with meal or light snack. - If co-administered with ddI, nelfinavir should be administered 2 hours before or 1 hour after ddI. - For oral solution: powder may be mixed with water, milk, pudding, ice cream, or formula (for up to 6 hours). - Do not mix with any acidic food or juice because of resulting poor taste. - Do not add water to bottles of oral powder; a special scoop is provided with oral powder for measuring purposes. - Tablets readily dissolve in water and produce a dispersion that can be mixed with milk or chocolate milk; tablets also can be crushed and administered with pudding. # Ritonavir, NORVIR ® Preparations: Oral solution: 80 mg/mL; Capsules: 100 mg # Dosage Neonatal dose: Under study in Pediatric AIDS Clinical Trial Group protocol 354 (single dose pharmacokinetics). Pediatric usual dose: 400 mg per m 2 of body surface area every 12 hours. To minimize nausea/vomiting, initiate therapy starting at 250 mg per m 2 of body surface area every 12 hours and increase stepwise to full dose over 5 days as tolerated. Pediatric dosage range: 350 to 400 mg per m 2 of body surface area every 12 hours. Adolescent/Adult dose: 600 mg twice daily. To minimize nausea/vomiting, initiate therapy starting at 300 mg twice daily and increase stepwise to full dose over 5 days as tolerated. # Major toxicities Most frequent: Nausea, vomiting, diarrhea, headache, abdominal pain, and anorexia. Less common: Circumoral paresthesias and increase in liver enzymes. Rare: Spontaneous bleeding episodes in hemophiliacs, pancreatitis, increased levels of triglycerides and cholesterol, hyperglycemia, ketoacidosis, diabetes, and hepatitis. Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Drug interactions - Ritonavir is extensively metabolized by hepatic cytochrome P450 3A (CYP3A). There could potentially be multiple drug interactions. - Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. - Not recommended for concurrent use with analgesics (e.g., meperidine, piroxicam, or propoxyphene); antihistamines (e.g., astemizole or terfenadine); certain cardiac drugs (e.g., amiodarone, bepridil hydrochloride, encainide hydrochloride, flecainide acetate, propafenone, or quinidine); ergot alkaloid derivatives; cisapride; sedative-hypnotics (e.g., alprazolam, clorazepate, diazepam, estazolam, flurazepam hydrochloride, midazolam, triazolam, or zolpidem tartrate); certain psychotropic drugs (e.g., bupropion hydrochloride, clozapine, or pimozide); rifampin; or rifabutin. - Estradiol levels are reduced by ritonavir, and alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control. - Ritonavir increases metabolism of theophylline (levels should be monitored, and dose may need to be increased). - Ritonavir increases levels of clarithromycin (dose adjustment may be necessary in patients with impaired renal function); desipramine (dose adjustment may be necessary); and warfarin (monitoring of anticoagulant effect is necessary). - Ritonavir may increase or decrease digoxin levels (monitoring of levels is recommended). - Drugs that increase CYP3A activity can lead to increased clearance and therefore lower levels of ritonavir include carbamazepine, dexamethasone, phenobarbital, and phenytoin (anticonvulsant levels should be monitored because ritonavir can affect the metabolism of these drugs as well). - Administration with other protease inhibitors: co-administration with saquinavir and nelfinavir increases concentration of these drugs with little change in ritonavir concentration. # Special instructions - Administration with food increases absorption. - If ritonavir is prescribed with ddI, there should be 2 hours between taking each of the drugs. - Oral solution must be kept refrigerated and stored in original container; can be kept at room temperature if used within 30 days. - To minimize nausea, therapy should be initiated at a low dose and increased to full dose over 5 days as tolerated. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1998-633-228/67064 Region IV	Vol. 47 / No. RR-4 MMWR iThese guidelines were developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children convened by the National Pediatric# INTRODUCTION In 1993, the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, composed of specialists caring for human immunodeficiency virus (HIV)-infected infants, children, and adolescents, was convened by the National Pediatric and Family HIV Resource Center (NPHRC). On the basis of available data and a consensus reflecting clinical experience, the Working Group concluded that antiretroviral therapy was indicated for any child with a definitive diagnosis of HIV infection who had evidence of substantial immunodeficiency (based on age-related CD4+ T-lymphocyte count thresholds) and/or who had HIV-associated symptoms. Zidovudine (ZDV) monotherapy was recommended as the standard of care for initiation of therapy. Routine antiretroviral therapy for infected children who were asymptomatic or had only minimal symptoms (e.g., isolated lymphadenopathy or hepatomegaly) and normal immune status was not recommended (1 ). Since the Working Group developed the 1993 recommendations, dramatic advances in laboratory and clinical research have been made. The rapidity and magnitude of HIV replication during all stages of infection are greater than previously believed and account for the emergence of drug-resistant viral variants when antiretroviral treatment does not maximally suppress replication (2,3 ). New assays that quantitate plasma HIV RNA copy number have become available, permitting a Information included in these guidelines may not represent Food and Drug Administration (FDA) approval or approved labeling for the particular product or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval. sensitive assessment of risk for disease progression and adequacy of antiretroviral therapy. A new class of antiretroviral drugs, protease inhibitors, has become available; these agents have reduced HIV viral load to levels that are undetectable and have reduced disease progression and mortality in many HIV-infected persons. Therefore, therapeutic strategies now focus on early institution of antiretroviral regimens capable of maximally suppressing viral replication to reduce the development of resistance and to preserve immunologic function. Additionally, the results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 have demonstrated that the risk for perinatal HIV transmission can be substantially diminished with the use of a regimen of ZDV administered during pregnancy, during labor, and to the newborn (4 ). These advances in HIV research have led to major changes in the treatment and monitoring of HIV infection in the United States. A summary of the basic principles underlying therapy of HIV-infected persons has been formulated by the National Institutes of Health (NIH) Panel to Define Principles of Therapy of HIV Infection (5 ). Treatment recommendations for infected adults and post-pubertal adolescents have been developed by the U.S. Department of Health and Human Services Panel of Clinical Practices for Treatment of HIV Infection (5 ). Although the pathogenesis of HIV infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, there are unique considerations needed for HIV-infected infants, children, and adolescents. Most HIV infections in children are acquired perinatally, and most perinatal transmission occurs during or near the time of birth, which raises the possibility of initiating treatment in an infected infant during the period of initial (e.g., primary) HIV infection (if sensitive diagnostic tests are used to define the infant's infection status early in life). Perinatal HIV infection occurs during the development of the infant's immune system; thus, both the clinical manifestations of HIV infection and the course of immunologic and virologic markers of infection differ from those for adults. Treatment of perinatally infected children will occur in the context of prior exposure to ZDV and other antiretroviral drugs used during pregnancy and the neonatal period, either for maternal treatment, to prevent perinatal transmission, or both (6,7 ). Additionally, drug pharmacokinetics change during the transition from the newborn period to adulthood, requiring specific evaluation of drug dosing and toxicity in infants and children. Finally, optimizing adherence to therapy in children and adoles-cents requires specific considerations. To update the 1993 antiretroviral treatment guidelines for children and to provide guidelines for antiretroviral treatment similar to those for HIV-infected adults (5 ), NPHRC, the Health Resources and Services Administration, and NIH reconvened the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, consisting of experts caring for HIV-infected children and adolescents, family members of HIV-infected children, and government agency representatives. The Working Group met in June 1996 and again in July 1997 to establish and finalize new guidelines for the treatment of HIV-infected infants, children, and adolescents. The treatment recommendations provided in this report are based on published and unpublished data regarding the treatment of HIV infection in adults and children and, when no definitive data were available, the clinical experience of the Working Group members. The Working Group intended the guidelines to be flexible and not to supplant the clinical judgement of experienced health-care providers. These guidelines will need to be modified as new information and clinical experience become available. # BACKGROUND Concepts Considered in the Formulation of Pediatric Treatment Guidelines The following concepts were considered in the formulation of these guidelines: • Identification of HIV-infected women before or during pregnancy is critical to providing optimal therapy for both infected women and their children and to preventing perinatal transmission. Therefore, prenatal HIV counseling and testing with consent should be the standard of care for all pregnant women in the United States (8)(9)(10). • Enrollment of pregnant HIV-infected women; their HIV-exposed newborns; and infected infants, children, and adolescents into clinical trials offers the best means of determining safe and effective therapies. • Pharmaceutical companies and the federal government should collaborate to ensure that drug formulations suitable for administration to infants and children are available at the time that new agents are being evaluated in adults. • Although some information regarding the efficacy of antiretroviral drugs for children can be extrapolated from clinical trials involving adults, concurrent clinical trials for children are needed to determine the impact of the drug on specific manifestations of HIV infection in children, including growth, development, and neurologic disease. However, the absence of clinical trials addressing pediatricspecific manifestations of HIV infection does not preclude the use of any approved antiretroviral drug in children. • All antiretroviral drugs approved for treatment of HIV infection may be used for children when indicated-irrespective of labeling notations. • Management of HIV infection in infants, children, and adolescents is rapidly evolving and becoming increasingly complex; therefore, wherever possible, management of HIV infection in children and adolescents should be directed by a specialist in the treatment of pediatric and adolescent HIV infection. If this is not possible, such experts should be consulted regularly. • Effective management of the complex and diverse needs of HIV-infected infants, children, adolescents, and their families requires a multidisciplinary team approach that includes physicians, nurses, social workers, psychologists, nutritionists, outreach workers, and pharmacists. In areas where enrollment in clinical trials is possible, enrolling the child in available trials should be discussed with the caregivers of the child. Information about clinical trials for HIV-infected adults and children can be obtained from the AIDS Clinical Trials Information Service, telephone (800) 874-2572 ([800] TRIALS-A). • Determination of HIV RNA copy number and CD4+ T-lymphocyte levels is essential for monitoring and modifying antiretroviral treatment in infected children and adolescents as well as adults; therefore, assays to measure these variables should be made available. • Health-care providers considering antiretroviral regimens for children and adolescents should consider certain factors influencing adherence to therapy, including a) availability and palatability of pediatric formulations; b) impact of the medication schedule on quality of life, including number of medications, frequency of administration, ability to co-administer with other prescribed medications, and need to take with or without food; c) ability of the child's caregiver or the adolescent to administer complex drug regimens and availability of resources that might be effective in facilitating adherence; and d) potential for drug interactions. • The choice of antiretroviral regimens should include consideration of factors associated with possible limitation of future treatment options, including the potential for the development of antiretroviral resistance. • Monitoring growth and development is essential for the care of HIV-infected children. Growth failure and neurodevelopmental deterioration may be specific manifestations of HIV infection in children. Nutritional-support therapy is an intervention that affects immune function, quality of life, and bioactivity of antiretroviral drugs. # Identification of Perinatal HIV Exposure Appropriate treatment of HIV-infected infants requires HIV-exposed infants to be identified as soon as possible, which can be best accomplished through the identification of HIV-infected women before or during pregnancy. Universal HIV counseling and voluntary HIV testing with consent are recommended as the standard of care for all pregnant women in the United States by the Public Health Service (PHS), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists and is endorsed by the Working Group (8)(9)(10). Early identification of HIV-infected women is crucial for the health of such women and for care of HIV-exposed and HIV-infected children. Knowledge of maternal HIV infection during the antenatal period enables a) HIV-infected women to receive appropriate antiretroviral therapy and prophylaxis against opportunistic infections for their own health; b) provision of antiretroviral chemoprophylaxis with ZDV during pregnancy, during labor, and to newborns to reduce the risk for HIV transmission from mother to child (4,6,7 ); c) counseling of infected women about the risks for HIV transmission through breast milk and advising against breastfeeding in the United States and other countries where safe alternatives to breast milk are available (11 ); d) initiation of prophylaxis against Pneumocystis carinii pneumonia (PCP) in all HIV-exposed infants beginning at age 4-6 weeks in accordance with PHS guidelines (12 ); and e) early diagnostic evaluation of HIV-exposed infants to permit early initiation of aggressive antiretroviral therapy in infected infants. If women are not tested for HIV during pregnancy, counseling and HIV testing should be recommended during the immediate postnatal period. For newborns in whom maternal serostatus was not determined during the prenatal or immediate postpartum period, HIV antibody should be tested for following counseling and consent of the mother. The HIV-exposure status of infants should be determined rapidly because the neonatal component of the recommended ZDV chemoprophylaxis regimen should begin as soon as possible after birth and because PCP prophylaxis should be initiated at age 4-6 weeks in all infants born to HIV-infected women. Those infants who have been abandoned, are in the custody of the state, or have positive toxicology screening tests should be considered at high risk for exposure to HIV, and mechanisms to facilitate rapid HIV screening of such infants should be developed. # Diagnosis of HIV Infection in Infants HIV infection can be definitively diagnosed in most infected infants by age 1 month and in virtually all infected infants by age 6 months by using viral diagnostic assays. A positive virologic test (i.e., detection of HIV by culture or DNA or RNA polymerase chain reaction [PCR]) indicates possible HIV infection and should be confirmed by a repeat virologic test on a second specimen as soon as possible after the results of the first test become available. Diagnostic testing should be performed before the infant is aged 48 hours, at age 1-2 months, and at age 3-6 months. Testing at age 14 days also may be advantageous for early detection of infection. HIV-exposed infants should be evaluated by or in consultation with a specialist in HIV infection in pediatric patients. HIV DNA PCR is the preferred virologic method for diagnosing HIV infection during infancy. A meta-analysis of published data from 271 infected children indicated that HIV DNA PCR was sensitive for the diagnosis of HIV infection during the neonatal period. Thirty-eight percent (90% confidence interval [CI]=29%-46%) of infected children had positive PCR tests by age 48 hours (13 ). No substantial change in sensitivity during the first week of life was observed, but sensitivity increased rapidly during the second week, with 93% of infected children (90% CI=76%-97%) testing positive by PCR by age 14 days. Assays that detect HIV RNA in plasma also may be useful for diagnosis of perinatal infection and may prove to be more sensitive than DNA PCR for early diagnosis of HIV infection in HIV-exposed infants (14 ). However, data are more limited regarding the sensitivity and specificity of HIV RNA assays compared with HIV DNA PCR for early diagnosis. HIV culture has a sensitivity similar to that of DNA PCR for the diagnosis of infection (15 ). However, HIV culture is more complex and expensive to perform than DNA PCR, and definitive results may not be available for 2-4 weeks. Although use of standard and immune-complex-dissociated p24 antigen tests are highly specific for HIV infection and have been used to diagnose infection in children, the sensitivity of these tests is less than the sensitivity of other HIV virologic tests. The use of p24 antigen testing alone is not recommended to exclude infection or for diagnosis of infection in infants aged <1 month because of a high frequency of false-positive assays during this time (16 ). Initial testing is recommended by age 48 hours because nearly 40% of infected infants can be identified at this time. Because of concerns regarding potential contamination with maternal blood, blood samples from the umbilical cord should not be used for diagnostic evaluations. Working definitions have been proposed for acquisition of HIV infection during the intrauterine and intrapartum periods. Infants who have a positive virologic test at or before age 48 hours are considered to have early (i.e., intrauterine) infection, whereas infants who have negative virologic tests during the first week of life and subsequent positive tests are considered to have late (i.e., intrapartum) infection (17 ). Some researchers have proposed that infants with early infection may have more rapid disease progression than those with late infection and therefore should receive a more aggressive therapeutic approach (18,19 ). However, recent data from prospective cohort studies have demonstrated that although early differences in HIV RNA levels have been present between infants with positive HIV culture within 48 hours of birth and those with a first positive culture after age 7 days, these differences were no longer statistically significant after age 2 months (20 ). HIV RNA copy number after the first month of life was more prognostic of rapid disease progression than the time at which HIV culture tests were positive (20 ). Repeat diagnostic testing also can be considered at age 14 days in infants with negative tests at birth, because the diagnostic sensitivity of virologic assays increases rapidly by age 2 weeks and early identification of infection would permit modification of antiretroviral therapy from the standard 6-week course of neonatal ZDV chemoprophylaxis to more aggressive combination antiretroviral therapy. Infants with initially negative virologic tests should be retested at age 1-2 months. With increasing use of ZDV to reduce perinatal transmission, most HIV-exposed neonates will receive 6 weeks of antiretroviral chemoprophylaxis. Although prophylactic antiretroviral therapy theoretically could affect the predictive value of HIV virologic testing in neonates, ZDV monotherapy did not delay the detection of HIV by culture in infants in PACTG protocol 076 and has not decreased the sensitivity and predictive values of many virologic assays (4,21 ). However, whether the current, more intensive combination antiretroviral regimens women may receive during pregnancy for treatment of their own HIV infection will affect diagnostic test sensitivity in their infants is unknown. HIV-exposed children who have had repeatedly negative virologic assays at birth and at age 1-2 months should be retested again at age 3-6 months. HIV infection is diagnosed by two positive HIV virologic tests performed on separate blood samples. HIV infection can be reasonably excluded among children with two or more negative virologic tests, two of which are performed at age ≥1 month, and one of those being performed at age ≥4 months (12 ). Two or more negative HIV immunoglobulin G (IgG) antibody tests performed at age >6 months with an interval of at least 1 month between the tests also can be used to reasonably exclude HIV infection among children with no clinical evidence of HIV infection. HIV infection can be definitively excluded if HIV IgG antibody is negative in the absence of hypogammaglobulinemia at age 18 months and if the child has both no clinical symptoms of HIV infection and negative HIV virologic assays. # Monitoring of Pediatric HIV Infection Immunologic Parameters in Children Clinicians interpreting CD4+ T-lymphocyte number for children must consider age as a variable. CD4+ T-lymphocyte count and percentage values in healthy infants who are not infected with HIV are considerably higher than those observed in uninfected adults and slowly decline to adult values by age 6 years (22,23 ). A pediatric clinical and immunologic staging system for HIV infection has been developed that includes age-related definitions of immune suppression (Tables 1 and 2) (24 ). Although the CD4+ absolute number that identifies a specific level of immune suppression changes with age, the CD4+ percentage that defines each immunologic category does not. Thus, a change in CD4+ percentage, not number, may be a better marker of identifying disease progression in children. In infected children and adults, the CD4+ cell count declines as HIV infection progresses, and patients with lower CD4+ cell counts have a poorer prognosis than patients with higher counts (Table 3). Because knowledge of immune status (i.e., CD4+ T-lymphocyte count and percentage) is essential when caring for HIV-infected infants and children, CD4+ T-lymphocyte values should be obtained as soon as possible after a child has a positive virologic test for HIV and every 3 months thereafter (25,26 ). Infected infants who have a thymic defect lymphocyte immunophenotypic profile (i.e., CD4+ count <1,900/mm 3 and CD8+ count >850/mm 3 ) during the first 6 months of life have had more rapid HIV disease progression than infants who do not have this profile (27 ). The CD4+ T-lymphocyte count or percentage value is used in conjunction with other measurements to guide antiretroviral treatment decisions and primary prophylaxis for PCP after age 1 year. However, measurement of CD4+ cell values can be associated with considerable intrapatient variation. Even mild intercurrent illness or the receipt of vaccinations can produce a transient decrease in CD4+ cell number and percentage; thus, CD4+ values are best measured when patients are clinically stable. No modification in therapy should be made in response to a change in CD4+ cell values until the change has been substantiated by at least a second determination, with a minimum of 1 week between measurements. # Category N: Not Symptomatic Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A. # Category A: Mildly Symptomatic Children with two or more of the following conditions but none of the conditions listed in categories B and C: • Lymphadenopathy (≥0.5 cm at more than two sites; bilateral=one site) • # HIV RNA in Children Viral burden in peripheral blood can be determined by using quantitative HIV RNA assays. During the period of primary infection in adults, HIV RNA copy number initially rises to high peak levels. Coincident with the body's humoral and cell-mediated immune response, RNA levels decline by as much as 2-3 log 10 copies to reach a stable lower level (i.e., the virologic set-point) approximately 6-12 months following acute infection, reflecting the balance between ongoing viral production and immune elimination (28,29 ). Several studies conducted among adults have indicated that infected persons with lower HIV copy number at the time of RNA stabilization have slower progression and improved survival compared with those with high HIV RNA set points (30,31 ). On the basis of such data, recommendations for the use of HIV RNA copy number in deciding to initiate and change antiretroviral therapy in infected adults have been developed (5 ). These recommendations also are applicable to infected adolescents, particularly those who have acquired HIV infection recently rather than through perinatal infection. These recommendations also are likely to be applicable to perinatally infected children aged >3 years. The HIV RNA pattern in perinatally infected infants differs from that in infected adults. High HIV RNA copy numbers persist in infected children for prolonged periods (32,33 ). In one prospective study, HIV RNA levels generally were low at birth (i.e., <10,000 copies/mL), increased to high values by age 2 months (most infants had values >100,000 copies/mL, ranging from undetectable to nearly 10 million copies/mL), and then decreased slowly; the mean HIV RNA level during the first year of life was 185,000 copies/mL (20 ). Additionally, in contrast to the adult pattern, after the first year of life, HIV RNA copy number slowly declines over the next few years of life (20,(34)(35)(36). This pattern probably reflects the lower efficiency of an immature but developing immune system in containing viral replication and possibly a greater number of HIV-susceptible cells. Recent data indicate that high HIV RNA levels (i.e., >299,000 copies/mL) in infants aged <12 months may be correlated with disease progression and death; however, RNA levels in infants who have rapid disease progression and those who do not have overlapped considerably (20,33 ). High RNA levels (i.e., levels of >100,000 copies/mL) in infants also have been associated with high risk for disease progression and mortality, particularly if CD4+ T-lymphocyte percentage is <15% (Tables 4 and 5) (35 ). Similar findings have been reported in a preliminary analysis of data from PACTG protocol 152 correlating baseline virologic data with risk for disease progression or death during study follow-up (Table 6) (36 ). In this study, the relative risk for disease progression was reduced by 54% for each 1 log10 decrease in baseline HIV RNA level. Disease progression was documented in 11% of children aged <30 months at the time the study was initiated (mean age: 1.1 years) who had baseline RNA in the lowest quartile (e.g., from undetectable to 150,000 copies/mL) and in 52% of children with baseline RNA in the highest quartile (e.g., >1,700,000 copies/mL) (36 ). Among children aged ≥30 months at the time the study was initiated (mean age: 7.3 years), none of those with baseline RNA in the lowest quartile (e.g., undetectable to 15,000 copies/ mL) compared with 34% of those in the highest quartile (e.g., >150,000 copies/mL) had disease progression; children with RNA levels in the middle two quartiles (i.e., 15,000-50,000 and 50,001-150,000 copies/mL) had similar progression rates (13% and 16%, respectively). Data from children aged ≥30 months are similar to data from studies among infected adults, in which the risk for disease progression substantially increases when HIV RNA levels exceed 10,000-20,000 copies/mL (5 ). Despite data indicating that high RNA levels are associated with disease progression, the predictive value of specific HIV RNA levels for disease progression and death for an individual child is moderate (35 ). HIV RNA levels may be difficult to interpret during the first year of life because levels are high and there is marked overlap in levels between children who have and those who do not have rapid disease progression (32 ). Additional data indicate that CD4+ T-lymphocyte percentage and HIV RNA copy number at baseline and changes in these parameters over time assist in determining the mortality risk in infected children, and the use of the two markers together may more accurately define prognosis (35,36 ). Similar data and conclusions recently have been reported from several studies involving infected adults (37)(38)(39). # Methodologic Considerations in the Interpretation and Comparability of HIV RNA Assays Most of the published data regarding HIV RNA in children have been obtained using frozen, stored plasma and serum specimens. Some degradation of HIV RNA occurs with specimen storage and delay in specimen processing; thus, the published data on HIV RNA levels in infected children may not be directly comparable with data obtained from specimens that undergo immediate testing (e.g., specimens obtained for patient care). The HIV RNA assays used also differ by study. Therefore, direct extrapolation of the predictive value of HIV RNA levels reported in published studies to HIV RNA assays performed for clinical-care purposes may be problematic. Information from ongoing prospective studies will assist in the interpretation of HIV RNA levels among infected infants and children. The use of HIV RNA assays for clinical purposes requires specific considerations (40 ), which are discussed more completely elsewhere (5 ). Several different methods can be used for quantitating HIV RNA, each with different levels of sensitivity; although the results of the assays are correlated, the absolute HIV RNA copy number obtained from a single specimen tested by two different assays can differ by twofold (0.3 log 10 ) or more. For example, plasma RNA measured by the quantitative PCR assay (Amplicor HIV-1 Monitor ™ , manufactured by Roche Diagnostics Systems, Nutley, New Jersey) yields absolute values approximately twice (0.3 log 10 ) those obtained using a signal amplification, branched-chain DNA assay (Quantiplex ® , manufactured by Chiron Corporation, Emeryville, California) (5,41,42 ). Similarly, plasma RNA measured by the nucleic acid sequence-based amplification assay (NASBA ® , manufactured by Organon Technika, Durham, North Carolina) yields absolute values approximately twice those obtained using the Quantiplex ® assay but values relatively comparable with those obtained using the Amplicor HIV-1 Monitor ™ assay (41)(42)(43). Therefore, one HIV RNA assay method should be used consistently for monitoring each patient. Choice of HIV RNA assay, particularly for young children, may be influenced by the amount of blood required for the assay. The NASBA ® assay requires the least amount of blood (i.e., 100 µL of plasma), followed by the Amplicor HIV-1 Monitor ™ (i.e., 200 µL of plasma) and the Quantiplex ® assays (i.e., 1 mL of plasma). Biologic variation in HIV RNA levels within one person is well documented, and repeated measurement of HIV RNA levels in a clinically stable infected adult can vary by as much as threefold (0.5 log 10 ) in either direction over the course of a day or on different days (5,39,44 ). This biologic variation may be greater in infected infants and young children. In children with perinatally acquired HIV infection, RNA copy number slowly declines even without therapy during the first several years after birth, although it persists at higher levels than those observed in most infected adults (20,34,35 ). This decline is most rapid during the first 12-24 months after birth, with an average decline of approximately 0.6 log 10 per year; a slower decline continues until approximately age 4-5 years (average decline of 0.3 log 10 per year). This inherent biologic variability must be considered when interpreting changes in RNA copy number in children. Thus, only changes greater than fivefold (0.7 log 10 ) in infants aged <2 years and greater than threefold (0.5 log10) in children aged ≥2 years after repeated testing should be considered reflective of a biologically and clinically substantial change. To reduce the impact of assay variability in the clinical management of patients, two samples can be obtained at baseline and the average of the two values used for comparison with future tests. No alteration in therapy should be made as a result of a change in HIV copy number unless the change is confirmed by a second measurement. Because of the complexities of HIV RNA testing and the age-related changes in HIV RNA in children, interpretation of HIV RNA levels for clinical decisionmaking should be done by or in consultation with an expert in pediatric HIV infection. # Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents Adult guidelines for antiretroviral therapy are appropriate for post-pubertal adolescents because HIV-infected adolescents who were infected sexually or through injecting-drug use during adolescence follow a clinical course that is more similar to that of adults than to that of children (5 ). The immunopathogenesis and virologic course of HIV infection in adolescents is being defined. Most adolescents have been infected during their teenage years and are in an early stage of infection, making them ideal candidates for early intervention. A limited but increasing number of HIVinfected adolescents are long-term survivors of HIV infection acquired perinatally or through blood products as young children. Such adolescents may have a unique clinical course that differs from that of adolescents infected later in life (45 ). Because many adolescents with HIV infection are sexually active, issues associated with contraception and prevention of HIV transmission should be discussed between the health-care provider and the adolescent. Dosage for medications for HIV infection and opportunistic infections should be prescribed according to Tanner staging of puberty (46 ) and not on the basis of age (25 ). Adolescents in early puberty (i.e., Tanner Stage I and II) should be administered doses using pediatric schedules, whereas those in late puberty (i.e., Tanner Stage V) should follow adult dosing schedules. Youth who are in their growth spurt (i.e., in females, Tanner Stage III and in males, Tanner Stage IV) should be closely monitored for medication efficacy and toxicity when using adult or pediatric dosing guidelines. Puberty is a time of somatic growth and sex differentiation, with females developing more body fat and males more muscle mass. Although these physiologic changes theoretically could affect drug pharmacokinetics (especially for drugs with a narrow therapeutic index that are used in combination with protein-bound medicines or hepatic enzyme inducers or inhibitors), no clinically consequential impact has been noted with nucleoside analogue reverse transcriptase inhibitor (NRTI) antiretroviral drugs (47 ). Clinical experience with protease inhibitors and non-nucleoside reverse transcriptase inhibitor antiretroviral drugs is more limited. # Specific Issues of Adherence for HIV-Infected Children and Adolescents Lack of adherence to prescribed regimens and subtherapeutic levels of antiretroviral medications may enhance the development of drug resistance. Data indicate that the development of resistance to one of the available protease inhibitor antiretrovirals may reduce susceptibility to some or all of the other available protease inhibitor drugs, thus substantially reducing subsequent treatment options. Therefore, education of infected children and/or their caregivers regarding the importance of compliance with the prescribed drug regimen is necessary when therapy is initiated and should be reinforced during subsequent visits. Many strategies can be used to increase medication adherence, including intensive patient education over several visits before therapy is initiated, the use of cues and reminders for administering drugs, development of patient-focused treatment plans to accommodate specific patient needs, and mobilization of social and community support services. Adherence to drug regimens is especially problematic for children. Infants and young children are dependent on others for administration of medication; thus, assessment of the capacity for adherence to a complex multidrug regimen requires evaluation of the caregivers and their environments and the ability and willingness of the child to take the drug. Liquid formulations or formulations suitable for mixing with formula or food are necessary for administration of oral drugs to young children. Lack of palatability of such formulations can be problematic depending on the child's willingness and ability to accept and retain the medication. Absorption of some antiretroviral drugs can be affected by food, and attempting to time the administration of drugs around meals can be difficult for caregivers of young infants who require frequent feedings. Many other barriers to adherence to drug regimens exist for children and adolescents with HIV infection. For example, unwillingness of the caregivers to disclose their child's HIV infection status to others may create specific problems, including reluctance of caregivers to fill prescriptions in their home neighborhood, hiding or relabeling medications to maintain secrecy within the home, reduction of social support (a variable associated with diminished treatment adherence), and a tendency to eliminate midday doses when the parent is away from the home or the child is at school. A comprehensive assessment of adherence issues should be instituted for all children in whom antiretroviral treatment is considered; evaluations should include nursing, social, and behavioral assessments. Intensive follow-up is required particularly during the critical first few months after therapy is started; patients should be seen frequently to assess adherence, drug tolerance, and virologic response. Coordinated, comprehensive, family-centered systems of care often can address many of the daily problems facing families that may affect adherence to complex medical regimens. For some families, certain issues (e.g., a safe physical environment and adequate food and housing) may take priority over medication administration and need to be resolved. Case managers, mental-health counselors, peer educators, outreach workers, and other members of the multidisciplinary team often may be able to address specific barriers to adherence. HIV-infected adolescents have specific adherence problems. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with health-care systems. Many HIV-infected adolescents face challenges in adhering to medical regimens for reasons that include a) denial and fear of their HIV infection; b) misinformation; c) distrust of the medical establishment; d) fear and lack of belief in the effectiveness of medications; e) low self-esteem; f) unstructured and chaotic lifestyles; and g) lack of familial and social support. Treatment regimens for adolescents must balance the goal of prescribing a maximally potent antiretroviral regimen with realistic assessment of existing and potential support systems to facilitate adherence. Developmental issues make caring for adolescents unique. The adolescent's approach to illness is often different from that of adults. The concrete thought processes of adolescents make it difficult for them to take medications when they are asymptomatic, particularly if the medications have side effects. Adherence with complex regimens is particularly challenging at a time of life when adolescents do not want to be different from their peers. Further difficulties face adolescents who live with parents to whom they have not yet disclosed their HIV status and those who are homeless and have no place to store medicine. # TREATMENT RECOMMENDATIONS # Initiation of Antiretroviral Therapy General Considerations Antiretroviral therapy has provided substantial clinical benefit to HIV-infected children with immunologic or clinical symptoms of HIV infection. Studies have demonstrated substantial improvements in neurodevelopment, growth, and immunologic and/or virologic status with initiation of ZDV, didanosine (ddI), lamivudine (3TC), or stavudine monotherapy (48)(49)(50)(51)(52)(53). More recent pediatric trials of symptomatic children who have not previously received antiretrovirals have demonstrated that combination therapy with either ZDV and 3TC or ZDV and ddI is clinically, immunologically, and virologically superior to monotherapy with ddI or ZDV as initial therapy (36,54,55 ). A trial involving children who have previously received antiretrovirals has demonstrated that combination therapy that includes a protease inhibitor is virologically and immunologically superior to dual nucleoside combination therapy (56 ). Data from clinical trials that address the effectiveness of antiretroviral therapy in asymptomatic infants and children with normal immune function are not available. However, initiation of therapy early in the course of HIV infection, including during the period of primary infection in the neonate, is theoretically advantageous. Control of viral replication in perinatally infected infants is inadequate, as demonstrated by the high levels of HIV RNA that are observed during the first 1-2 years of life following perinatal infection. Initiation of aggressive antiretroviral therapy during this early period of viral replication could theoretically preserve immune function, diminish viral dissemination, lower the viral set point, and result in improved clinical outcome. In a preliminary study of early treatment of children, six HIV-infected infants aged 2-4 months were placed on a regimen of ZDV, ddI, and nevirapine; baseline HIV RNA levels were 40,000-1,500,000 copies per mL. Five of six infants had an early virologic response with a drop in RNA PCR to <10,000 copies/mL by day 14, and two of the infants maintained undetectable levels of HIV RNA through 168 days of therapy (57 ). These two children had persistently negative HIV cultures, undetectable RNA levels, and became HIV antibody negative, although HIV DNA PCR remained positive. Clinical trials are ongoing to assess the virologic, immunologic, and clinical response of young infants to early, aggressive antiretroviral therapy with three or four antiretroviral agents. The theoretical problems with early therapy include the potential for short-and long-term adverse effects-particularly for drugs being administered to infants aged <6 months, for whom information on pharmacokinetics, drug dosing, and safety is limited. These concerns are particularly relevant because life-long administration of therapy is likely to be necessary for HIV-infected infants. If viral replication is not suppressed, ongoing viral mutation is likely to result in the development of antiretroviral resistance, curtailing the duration of benefit that early therapy might confer and potentially limiting future treatment options. Therefore, intensive education of caregivers and patients about the importance of adherence to the prescribed treatment regimen should be provided before therapy is initiated so that a) potential problems and solutions can be identified and b) frequent follow-up can be provided to assess virologic response to therapy, drug tolerance, and adherence. # When to Initiate Therapy Antiretroviral therapy is recommended for HIV-infected children with clinical symptoms of HIV infection (i.e., those in clinical categories A, B, or C) (Table 2) or evidence of immune suppression (i.e., those in immune categories 2 or 3) (Table 1)-regardless of the age of the child or viral load (Table 7). Clinical trial data from both adults and children have demonstrated that antiretroviral therapy in symptomatic patients slows clinical and immunologic disease progression and reduces mortality (54,55,58 ). • Clinical symptoms associated with HIV infection (i.e., clinical categories A, B, or C [Table 2]). • Evidence of immune suppression, indicated by CD4+ T-lymphocyte absolute number or percentage (i.e., immune category 2 or 3 [Table 1]). • Age <12 months-regardless of clinical, immunologic, or virologic status. • For asymptomatic children aged ≥1 year with normal immune status, two options can be considered: -Preferred Approach Initiate therapy-regardless of age or symptom status. -Alternative Approach Defer treatment in situations in which the risk for clinical disease progression is low and other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding to initiate therapy include the following: -High or increasing HIV RNA copy number. # TABLE 7. Indications for initiation of antiretroviral therapy in children with human immunodeficiency virus (HIV) infection Ideally, antiretroviral therapy should be initiated in all HIV-infected infants aged <12 months as soon as a confirmed diagnosis is established-regardless of clinical or immunologic status or viral load. HIV-infected infants aged <12 months are considered at high risk for disease progression, and the predictive value of immunologic and virologic parameters to identify infants who will have rapid progression is less than that for older children. Identification of infection during the first few weeks of life permits clinicians to initiate antiretroviral therapy or intensify ongoing antiretroviral therapy used for chemoprophylaxis of perinatal transmission during the initial phases of primary infection. However, clinical trial data documenting therapeutic benefit from this approach are not available, and information on drug dosing in neonates is limited. Because resistance to antiretroviral drugs (particularly protease inhibitors) can develop rapidly when drug concentrations fall below therapeutic levels (either as a result of inadequate dosage or incomplete adherence), issues associated with adherence should be fully assessed and discussed with the HIV-infected infant's caregivers before the decision to initiate therapy is made. Two general approaches for initiating therapy in asymptomatic children aged ≥1 year were outlined by the Working Group. The first approach would be to initiate therapy in all HIV-infected children, regardless of age or symptom status. Such an approach would ensure a) treatment of infected children as early as possible in the course of disease and b) intervention before immunologic deterioration. Data from prospective cohort studies indicate that most HIV-infected infants will have clinical symptoms of infection by age 1 year (59,60 ). Most asymptomatic infected children aged >1 year also have CD4+ T-lymphocyte percentages of <25% (60 ), which is indicative of immunosuppression (Table 1) and warrants antiretroviral therapy. An alternative approach would be to defer treatment in asymptomatic children aged ≥1 year with normal immune status in situations in which the risk for clinical disease progression is low (e.g., low viral load) and when other factors (e.g., concern for adherence, safety, and persistence of antiretroviral response) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding when to initiate therapy include a) high or increasing HIV RNA levels, b) rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (i.e., immune category 2 [Table 1]), or c) development of clinical symptoms. The level of HIV RNA considered indicative of increased risk for disease progression is not well defined for young children. Regardless of age, any child with HIV RNA levels of >100,000 copies/mL is at high risk for mortality (Table 4), and antiretroviral therapy should be initiated-regardless of clinical or immune status. HIV RNA levels in asymptomatic children aged ≥30 months that are the same as levels for which there are treatment recommendations for HIV-infected adults (e.g., >10,000-20,000 copies/mL) also may indicate the need to initiate treatment (Table 6). In addition, any child with HIV RNA levels that demonstrate a substantial increase (more than a 0.7 log 10 [fivefold] increase for children aged <2 years and more than a 0.5 log 10 [threefold] increase for those aged ≥2 years) on repeated testing should be offered therapy-regardless of clinical or immunologic status or absolute level of viral load. These recommendations are based on limited data and may need revision as more information becomes available. Issues associated with adherence to treatment are especially important in considering whether and when to initiate therapy. Antiretroviral therapy is most effective in patients who have never received therapy and who therefore are less likely to have antiretroviral-resistant viral strains. Lack of adherence to prescribed regimens and subtherapeutic levels of antiretroviral medications, particularly protease inhibitors, may enhance the development of drug resistance. Participation by the caregivers and child in the decision-making process is crucial, especially in situations for which definitive data concerning efficacy are not available. # Choice of Initial Antiretroviral Therapy Combination therapy is recommended for all infants, children, and adolescents who are treated with antiretroviral agents (Table 8). When compared with monotherapy, combination therapy a) slows disease progression and improves survival, b) results in a greater and more sustained virologic response, and c) delays development of virus mutations resistant to the drugs being used. Monotherapy with the currently available antiretroviral drugs is no longer recommended to treat HIV infection. ZDV monotherapy is appropriate, however, when used in infants of indeterminate HIV status during the first 6 weeks of life to prevent perinatal HIV transmission. Infants who are identified as being HIV-infected while receiving ZDV chemoprophylaxis should be changed to a combination antiretroviral drug regimen. Aggressive antiretroviral therapy for primary perinatal infection with three drugs is recommended because it provides the best opportunity to preserve immune function and delay disease progression. The goal of antiretroviral therapy is to maximally suppress viral replication, preferably to undetectable levels. Based on clinical trials involving infected adults, the preferred regimen is combination therapy with two NRTIs and one protease inhibitor. Although these combinations have had limited evaluation in clinical trials involving children, they can reduce HIV RNA to undetectable levels in some children (61,62 ). An interim analysis from a clinical trial of children (i.e., PACTG protocol 338) has demonstrated that therapy with drug combinations that include a protease inhibitor is more effective than therapy with two NRTI antiretroviral drugs in reducing viral load to undetectable levels and increasing CD4+ T-lymphocyte number (56 ). New antiretroviral drugs and combinations are being studied in infected adults and children. Other drug combinations that demonstrate sustainable viral load suppression and acceptable toxicity and dosing profiles most likely will become available, which will increase treatment options for children in the future. Protease inhibitors with formulations appropriate for infants and children who cannot swallow pills include nelfinavir (Viracept ® , manufactured by Agouron Pharmaceuticals, Inc., La Jolla, California), available in a powder formulation that can be mixed with water or food, and ritonavir (Norvir ® , manufactured by Abbott Laboratories, North Chicago, Illinois), available in a liquid formulation. Optimal dosing of these drugs in children aged <2 years is not known but is being evaluated in clinical trials (See Appendix). Indinavir (Crixivan ® , manufactured by Merck and Company, Inc., West Point, Pennsylvania) and saquinavir (hard gel capsule, Invirase ™ , and soft gel capsule, Fortovase ™ , manufactured by Hoffman-LaRoche, Inc., Nutley, New Jersey) are not available in liquid formulations. Indinavir is recommended for consideration for children who can tolerate swallowing capsules. Optimal dosing of these drugs in infants and children is not known but is being evaluated in clinical trials (See # Preferred Regimen Evidence of clinical benefit and sustained suppression of HIV RNA in clinical trials in HIV-infected adults; clinical trials in HIV-infected children are ongoing. • One highly active protease inhibitor plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs) -Preferred protease inhibitor for infants and children who cannot swallow pills or capsules: nelfinavir or ritonavir. Alternative for children who can swallow pills or capsules: indinavir. -Recommended dual NRTI combinations: the most data on use in children are available for the combinations of zidovudine (ZDV) and dideoxyinosine (ddI) and for ZDV and lamivudine (3TC). More limited data are available for the combinations of stavudine (d4T) and ddI, d4T and 3TC, and ZDV and zalcitabine (ddC)* # Alternative Regimen Less likely to produce sustained HIV RNA suppression in infected adults; the combination of nevirapine, ZDV, and ddI produced substantial and sustained suppression of viral replication in two of six infants first treated at age <4 months. † # • Nevirapine § and two NRTIs # Secondary Alternative Regimen Clinical benefit demonstrated in clinical trials involving infected adults and/or children, but initial viral suppression may not be sustained. # • Two NRTIs # Not Recommended Evidence against use because of overlapping toxicity and/or because use may be virologically undesirable. • Any monotherapy ¶ • d4T and ZDV • ddC and ddI • ddC and d4T • ddC and 3TC ddC is not available in a liquid preparation commercially, although a liquid formulation is available through a compassionate use program of the manufacturer (Hoffman-LaRoche Inc., Nutley, New Jersey). ZDV and ddC is a less preferred choice for use in combination with a protease inhibitor. † Source: Luzuiraga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997;336:1343-9. § A liquid preparation of nevirapine is not available commercially, but is available through a compassionate use program of the manufacturer (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut). ¶ Except for ZDV chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is identified as HIV-infected while receiving ZDV prophylaxis, therapy should be changed to a combination antiretroviral drug regimen. # TABLE 8. Recommended antiretroviral regimens for initial therapy for human immunodeficiency virus (HIV) infection in children Appendix). The hard-gel capsule formulation of saquinavir (Invirase ™ ) has limited bioavailability and thus is not recommended for use with two NRTIs. Some studies have indicated substantial increases in saquinavir drug levels when co-administered with other protease inhibitors (e.g., ritonavir) or other drugs that inhibit the cytochrome P450 enzyme system. However, data regarding such combinations in children are not available. The soft-gel formulation of saquinavir (Fortovase ™ ) with enhanced bioavailability has been approved by the Food and Drug Administration (FDA) for treatment of HIV infection in adults; however, data regarding appropriate dosing of this formulation in pediatric patients are not available. Alternative regimens, although not ideal, may be considered for initial therapy in circumstances in which the caregiver has concerns regarding the feasibility of adherence to a complex drug regimen or when the patient and caregivers prefer an alternative regimen. Alternative regimens have been clinically beneficial in adult and pediatric patients, but these regimens may not suppress viral load to below detectable levels as consistently as does combination therapy with two NRTIs and a protease inhibitor. Such alternative regimens include combination regimens of two NRTIs with nevirapine substituted for the protease inhibitor or two NRTIs alone. However, drug regimens that do not result in sustained viral suppression may result in the development of viral resistance to the drugs being used. The initial antiretroviral regimen chosen for infected infants theoretically could be influenced by the antiretroviral regimen their mother may have received during pregnancy. However, data from PACTG protocol 076 indicate that ZDV resistance did not account for most infants who became infected despite maternal ZDV treatment (63 ), and data from PACTG protocol 185 indicate that duration of prior ZDV therapy in women with advanced HIV disease, many of whom received prolonged ZDV before pregnancy, was not associated with diminished ZDV efficacy for reduction of transmission (64 ). Data do not suggest that the antiretroviral regimen for infected infants should be chosen on the basis of maternal antiretroviral use. However, continuing to monitor the frequency of perinatal transmission of antiretroviral-resistant HIV isolates is crucial, because maternal therapy with multiple antiretroviral agents is becoming more common and the prevalence of resistant viral strains in the HIV-infected population may increase over time. # Issues Regarding Antiretroviral Dosing in Neonates Data regarding the appropriate dosing of antiretroviral drugs in neonates are limited; ZDV is the best studied antiretroviral drug in this age group. The recommended ZDV dosage for infants was derived from pharmacokinetics studies performed in fullterm infants (65 ). Because ZDV is primarily cleared through hepatic metabolism (i.e., glucuronidation), which is immature in neonates, the half-life and clearance of ZDV are prolonged in neonates compared with older infants, thus requiring adjustments in dosing (See Appendix). Premature infants have even greater immaturity in hepatic metabolic function than do full-term infants, and further prolongation in clearance has been documented in very premature infants (e.g., those born before 34 weeks' gestation) (66 ). Appropriate ZDV dosing for premature infants has not been defined but is being evaluated in a phase I clinical trial of premature infants born before 34 weeks' gestation (i.e., PACTG protocol 331) (See Appendix). The safety and pharmacokinetics of 3TC administered alone or in combination with ZDV in pregnant women and administered for 1 week to their newborns have been evaluated (67,68 ). Clearance was prolonged in these infants. On the basis of data from this study, the dose recommended for use in newborns is half the dose recommended in older children (See Appendix). No data are available regarding 3TC pharmacokinetics among infants aged 2-6 weeks, and the exact age at which 3TC clearance begins to approximate that in older children is not known. Nevirapine administration to HIV-infected pregnant women during labor and as a single dose to their newborns at age 2-3 days has been studied in a phase I trial (69 ). The half-life of nevirapine was prolonged in neonates compared with that in older children, indicating that some modification of nevirapine dosage is required for administration to neonates (See Appendix). Although phase I studies of several protease inhibitors (i.e., indinavir, ritonavir, nelfinavir, or saquinavir in combination with ZDV and 3TC) in pregnant infected women and their infants are ongoing in the United States, no data are available regarding drug dosage, safety, and tolerance of any of the protease inhibitors in neonates. # Changing Antiretroviral Therapy When to Change Antiretroviral Therapy The following three reasons warrant a change in antiretroviral therapy: a) failure of the current regimen with evidence of disease progression based on virologic, immunologic, or clinical parameters; b) toxicity or intolerance to the current regimen; and c) new data demonstrating that a drug or regimen is superior to the current regimen (Table 9). When therapy must be changed because of treatment failure or suboptimal response to treatment, clinicians should work with families to assess the possible contribution of adherence problems to the failure of the current regimen. Issues regarding adherence should be addressed to increase the likelihood of a successful outcome when initiating a new therapy. These issues are best addressed before therapy is instituted and need to be reinforced during therapy. Intensive family education, training in the administration of prescribed medications, and discussion of the importance of adherence to the drug regimen should be completed before initiation of new treatment. In addition, frequent patient visits and intensive follow-up during the initial months after a new antiretroviral regimen is started are needed to support and educate the family and to monitor adherence, tolerance, and virologic response to the new regimen. # Virologic Considerations for Changing Therapy Information is limited regarding HIV RNA response to antiretroviral therapy in infants and young children. However, the general virologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons. Because HIV RNA monitoring is critical for the management of infected children, Working Group members used the available data and clinical experience when definitive data were not available to make the following recommendations. These recommendations may require modification as new information becomes available. Ideally, antiretroviral therapy should maximally suppress viral replication to below levels capable of being detected with HIV RNA assays-which may not always be Virologic Considerations • Less than a minimally acceptable virologic response after 8-12 weeks of therapy. For children receiving antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a protease inhibitor, such a response is defined as a <10-fold (1.0 log10) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (i.e., dual NRTI combinations), an insufficient response is defined as a less than fivefold (0.7 log10) decrease in HIV RNA levels from baseline. • HIV RNA not suppressed to undetectable levels after 4-6 months of antiretroviral therapy. † • Repeated detection of HIV RNA in children who initially responded to antiretroviral therapy with undetectable levels. § • A reproducible increase in HIV RNA copy number among children who have had a substantial HIV RNA response but still have low levels of detectable HIV RNA. Such an increase would warrant change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (0.5 log 10 ) increase in copy number for children aged ≥2 years and a greater than fivefold (0.7 log 10 ) increase is observed for children aged <2 years. # Immunologic Considerations* • Change in immunologic classification (Table 1). ¶ • For children with CD4+ T-lymphocyte percentages of <15% (i.e., those in immune category 3), a persistent decline of five percentiles or more in CD4+ cell percentage (e.g., from 15% to 10%). • A rapid and substantial decrease in absolute CD4+ T-lymphocyte count (e.g., a >30% decline in <6 months). # Clinical Considerations • Progressive neurodevelopmental deterioration. • Growth failure defined as persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation. • Disease progression defined as advancement from one pediatric clinical category to another (e.g., from clinical category A to clinical category B).** * At least two measurements (taken 1 week apart) should be performed before considering a change in therapy. † The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log10 decrease in HIV RNA copy number, even if RNA remains detectable at low levels. § More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (e.g., if when using an HIV RNA assay with a lower limit of detection of 1,000 copies/mL, there is a ≤0.7 log10 increase from undetectable to approximately 5,000 copies/mL in an infant aged <2 years). ¶ Minimal changes in CD4+ T-lymphocyte percentile that may result in change in immunologic category (e.g., from 26% to 24%, or 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ percentile within the same immunologic category (e.g., a drop from 35% to 25%). ** In patients with stable immunologic and virologic parameters, progression from one clinical category to another may not represent an indication to change therapy. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic considerations are important in deciding whether to change therapy. # TABLE 9. Considerations for changing antiretroviral therapy for human immunodeficiency virus (HIV)-infected children achievable in HIV-infected children. Perinatally infected children generally have high HIV RNA levels, and clinical benefit may be observed with decrements in HIV RNA levels that do not result in undetectable levels. However, failure to maximally suppress replication may be associated with increased probability of viral mutations and the emergence of drug resistance. Consideration of the implications of changing regimens and the choice of new drugs should include an acknowledgment of the potential for limiting the patient's future options for potent therapy. Consensus recommendations have been developed using plasma HIV RNA measurements to guide changes in antiretroviral therapy for HIV-infected adults (5 ). The recommendations for adults state that health-care providers should consider changing therapy if a) HIV RNA levels drop less than threefold (0.5 log 10 ) after 4 weeks of therapy and less than 10-fold (1.0 log 10 ) after 8 weeks of therapy or b) HIV RNA has not decreased to undetectable levels after 4-6 months of therapy. Because HIV RNA levels in infants who are perinatally infected are high compared with levels observed when therapy is initiated in most infected adults, the initial virologic response of infected infants and young children to initiation of antiretroviral therapy may take longer than observed in adults (i.e., 8-12 weeks). In addition, suppression of HIV RNA to undetectable levels may be achieved less often than has been reported for infected adults despite potent combination therapy with two NRTIs and a protease inhibitor. Therefore, virologic indications for changing therapy in infected children differ slightly from those recommended for infected adults. Adult guidelines should be followed for infected adolescents. Virologic response should be initially assessed 4 weeks after therapy is initiated. However, the time required to achieve maximal virologic response to therapy may vary depending on the specific baseline HIV RNA value at the time of starting therapy. If baseline HIV RNA levels are high (i.e., >1,000,000 copies/mL), virologic response may not be observed until 8-12 weeks after initiating antiretroviral therapy. However, if baseline HIV RNA levels are more similar to those observed in untreated infected adults (i.e., <100,000 copies/mL), initial response should be observed within 4 weeks following initiation of therapy. After a maximal virologic response is achieved, HIV RNA levels should be measured at least every 3 months to monitor continued response to therapy. At least two measurements (taken 1 week apart) should be performed before considering a change in therapy. The following situations may indicate a need for change in therapy in infected children: • Less than a minimally acceptable virologic response after 8-12 weeks of therapy. For children receiving antiretroviral therapy with two NRTIs and a protease inhibitor, such a response is defined as a <10-fold (1.0 log10) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (i.e., dual NRTI combinations), an insufficient response is defined as a less than fivefold (0.7 log10) decrease in HIV RNA levels from baseline. • HIV RNA not suppressed to undetectable levels after 4-6 months of antiretroviral therapy. However, although suppression of HIV RNA to undetectable levels and maintenance for prolonged periods is desirable, few data among children indicate that such suppression is always achievable. In addition, the number of alternative therapeutic regimens for children is limited. The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log10 fall in HIV RNA copy number, even if RNA remains detectable at low levels. • Repeated detection of HIV RNA in children who initially had had undetectable levels in response to antiretroviral therapy. The presence of repeatedly detectable RNA suggests the development of resistance or problems with adherence or drug bioavailability. More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (e.g., if using an HIV RNA assay with a lower limit of detection of 1,000 copies/mL, there is a ≤0.7 log 10 increase from undetectable to approximately 5,000 copies/mL in an infant aged <2 years). If adherence to therapy has been inconsistent, renewed efforts to educate the caregivers and patient and closer follow-up from members of a multidisciplinary care team may improve adherence. • A reproducible increase in HIV RNA copy number among children who have had a substantial HIV RNA response but still have low levels of detectable HIV RNA. Such an increase would warrant a change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (>0.5 log10) increase in copy number is observed in children aged ≥2 years. Because of the greater biologic variability in RNA in young children, a change in therapy is warranted when a greater than fivefold (>0.7 log10) increase is observed for children aged <2 years. # Immunologic Considerations for Changing Therapy CD4+ T-lymphocyte count and percentage are independent predictors of disease progression and mortality in HIV-infected children (35,36 ). The association of HIV RNA and CD4+ percentage with long-term mortality risk in HIV-infected children has been evaluated; for each absolute decline of five percentiles in CD4+ percentage at baseline or during follow-up, the mortality risk ratio increased by 1.3 (95% CI=1.2-1.5), independent of the child's HIV RNA level (35 ). For children with CD4+ percentages of <15% (i.e., those in immune category 3), prognosis also was correlated with the degree of depression of CD4+ percentage (i.e., life expectancy was less for children with CD4+ percentages of <5% compared with children with CD4+ percentages of 10%-14%) (Table 3). Before considering changing antiretroviral therapy because of a decline in CD4+ lymphocyte values, a minimum of one repeated measurement of CD4+ values should be obtained at least 1 week after the initial test. The following are immunologic indications that may warrant a change in antiretroviral therapy for HIV-infected children: • Change in immune classification (Table 1). However, minimal changes in CD4+ percentile that may result in a change in immune category (e.g., from 26% to 24% or from 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ percentile within the same immune category (e.g., a decrease from 35% to 25%). • For children with CD4+ percentages of <15% (i.e., those in immune category 3), a persistent decline of five percentiles or more in CD4+ cell percentage (e.g., from 15% to 10% or from 10% to 5%). • A rapid and substantial decrease in absolute CD4+ T-lymphocyte count (e.g., a >30% decline in <6 months). # Clinical Considerations for Changing Therapy The occurrence of certain clinical events while receiving antiretroviral therapy is evidence of HIV disease progression and/or a poor prognosis for infants and children. The following clinical criteria warrant consideration of a change in antiretroviral therapy: • Progressive neurodevelopmental deterioration (i.e., persistence or progression of deterioration documented on repeated testing as demonstrated by the presence of two or more of the following findings: impairment in brain growth, decline of cognitive function documented by psychometric testing, or clinical motor dysfunction). In such cases, the new treatment regimen optimally should include at least one antiretroviral drug with substantial central nervous system penetration (e.g., ZDV or nevirapine, which have cerebrospinal fluid/plasma ratios >0.5). • Growth failure (i.e., persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation). • Disease progression (i.e., advancement from one pediatric clinical category to another [Table 2]). Prognosis is poorer as patients progress to more advanced clinical categories (59 ). However, in patients with stable immunologic and virologic parameters, progression from one clinical category to another (e.g., from clinical category A to category B) may not represent an indication to change therapy. For example, development of new opportunistic infections, particularly in patients who had severe immunosuppression at the time therapy was initiated, may not reflect a failure of antiretroviral therapy but persistence of immunologic dysfunction despite adequate antiviral response. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic parameters should be considered when deciding whether to change therapy. # Choice of a New Antiretroviral Regimen The choice of a new antiretroviral regimen is dictated by the indications that warranted the change in therapy and the limited available alternative antiretroviral agents. Although the efficacy of different combination antiretroviral regimens in children probably can be extrapolated from clinical trial data obtained for adults, data are limited regarding the pharmacokinetics, appropriate dosing, and short-and long-term safety of various combinations in infected children. New regimens should be chosen partly on the basis of the impact of the changes on future treatment options. The following principles should be followed when choosing a new antiretroviral regimen in children who have received prior treatment. • When therapy is changed because of toxicity or intolerance, agents with different toxicity and side-effect profiles should be chosen, when possible. Health-care providers should have comprehensive knowledge of the toxicity profile of each agent before selecting a new regimen. In the event of drug intolerance, change of a single drug in a multidrug regimen and, in certain circumstances, dose reduction are permissible options. However, antiretroviral drugs should only be reduced to the lower end of the therapeutic range for those antiretrovirals for which an effective dosing range is known, and adequacy of antiretroviral activity should be confirmed by the monitoring of HIV RNA levels. • When changing therapy because of treatment failure (Table 9), adherence to therapy should be assessed as a potential cause of failure. • If the patient is adherent to the prescribed drug regimen, assume the development of drug resistance and, if possible, change at least two drugs to new antiretroviral agents. Change in one drug or addition of a drug to a failing regimen is suboptimal. The new regimen should include at least three drugs, if possible. The potential for cross-resistance between antiretroviral drugs should be considered in choosing new drugs. • When considering changing to a new regimen, all other medications taken by the patient should be reviewed for possible drug interactions. • A change to a new regimen, especially one containing protease inhibitors, must include a discussion of treatment adherence issues between the caregivers of the infected child and the health-care provider. The health-care provider must recognize that certain medications are difficult to take in combination because of exacting and often conflicting requirements with respect to whether they can be taken with food and other antiretrovirals. • When changing therapy because of disease progression in a patient with advanced disease, the patient's quality of life must be considered. Detailed information regarding issues associated with specific drug choices for changing a failing regimen and potential cross-resistance between various antiretroviral drugs is available elsewhere (5 ). Because these issues are similar for all HIVinfected persons (regardless of age) they are not addressed specifically in this document. # MANAGING ADVERSE DRUG REACTIONS IN THE THERAPY OF PEDIATRIC HIV INFECTION The antiretroviral agents used and approved to treat HIV infection in children have all demonstrated individual and drug-class toxicities that limit the doses and combinations that can be used safely (70 ). The general principles of toxicity management are similar for adults and children. However, for many of the newer therapies (particularly the protease inhibitors), limited short-term and no long-term safety data or experience are available for infants, children, and adolescents. Thus, the amount of information on which to base guidelines for management of antiretroviral toxicities in children, especially when antiretroviral drugs are used in combination, is substantially more limited than that for adults. The data available from PACTG protocol 152 and PACTG protocol 300 indicate that some combinations of nucleoside analogues do not substantially increase the toxicity relative to monotherapy with those agents (54,55 ). The toxicities of antiretroviral drugs may occur at different frequencies in children and adults, and the implications of some of the toxicities substantially differ for children. The most obvious difference for children from the listing of toxicities in the adult guidelines is the increased indirect bilirubin associated with indinavir, which is labeled as inconsequential for adults. This toxicity could be of major consequence for newborn and young infants because severe hyperbilirubinemia is associated with kernicterus and would require specific monitoring and treatment should indinavir be administered to neonates. Additional examples of differences of potential toxicities between adults and children include the description of asymptomatic retinal depigmentation in children associated with ddI therapy and the relative lack of pancreatitis in children compared with adults receiving ddI therapy (See Appendix). Another treatment issue that affects children differently from adults concerns the feasibility of administering poorly palatable liquid antiretroviral formulations to children. Innovative techniques to increase palatability may be needed to enable tolerance of medications (e.g., various methods can be used to increase tolerance of ritonavir [See Appendix]). Indinavir is associated with hematuria and nephrolithiasis secondary to crystallization of the drug in the urine; adequate hydration (i.e., 48 oz of fluid daily) is recommended to reduce the incidence of this side effect. However, ensuring that voluntary fluid intake of this level is achieved may be more difficult in children than in adults. All efforts should be made to continue therapy in the presence of toxicities that are not life-threatening. Such efforts should include liberal use of adjunctive measures (e.g., granulocyte colony stimulating factor for treatment of neutropenia and erythropoietin and/or transfusions for treatment of anemia). If antiretroviral therapy must be discontinued for an extended period of time, to minimize the risk for developing drug resistance, all antiretroviral agents should be stopped simultaneously rather than continuing one or two agents alone because of potential increased viral replication. # CONCLUSION The Working Group has attempted to provide information specific to the use of antiretroviral drugs in infants, children, and adolescents while not duplicating the information available in antiretroviral recommendations for adults (5 ). Documents addressing recommendations for adults should be reviewed for basic information regarding disease pathogenesis and drug interactions. Although the general principles of therapy are the same for HIV-infected adults, adolescents, children, and infants, treatment of infection in pediatric patients requires an understanding of the unique aspects of HIV infection in children. Clinical trials of antiretroviral agents in HIVinfected children and the development of drug formulations appropriate for administration to children have often been delayed until after clinical trials in infected adults have been completed and/or the drug has been approved for use among infected adults. However, despite these delays, the paucity of pediatric-specific data cannot further deter the development of rational and reasonable pediatric treatment guidelines while studies in children are being undertaken. To maximize therapeutic options for HIV-infected pediatric patients throughout the course of their infection, drug formularies should facilitate the use of all FDA-approved antiretroviral agents as treatment options for children. Additionally, the conduct of clinical trials to define the pharmacokinetics, safety, and effectiveness in ameliorating the pediatric-specific manifestations of HIV infection of current and new antiretroviral agents is a priority; studies of new drugs should be conducted coincident with or soon after initial studies have been completed in adults. The Working Group will revise these guidelines as new data regarding antiretroviral therapy for infected infants, children, and adolescents become available. • Should not be administered in combination with zidovudine (poor antiretroviral effect). # Special instructions • Can be administered with food. • Need to decrease dose in patients with renal impairment. • For oral solution: shake well and keep refrigerated; solution stable for 30 days. # Zalcitabine (ddC), HIVID ® Preparations: Syrup: 0.1 mg/mL (investigational); Tablets: 0.375 and 0.75 mg Dosage Neonatal dose: Unknown. Pediatric usual dose: 0.01 mg per kg of body weight every 8 hours. Pediatric dosage range: 0.005 to 0.01 mg per kg of body weight every 8 hours. Adolescent/Adult dose: 0.75 mg three times a day. # Major toxicities Most frequent: Headache, gastrointestinal disturbances, and malaise. Unusual (more severe): Peripheral neuropathy, pancreatitis, hepatic toxicity, oral ulcers, esophageal ulcers, hematologic toxicity, and skin rashes. # Drug interactions • Cimetidine, amphotericin, foscarnet, and aminoglycosides may decrease renal clearance of ddC. • Antacids decrease absorption of ddC. • Concomitant use with ddI is not recommended because of the increased risk of peripheral neuropathy. • Intravenous pentamidine increases the risk for pancreatitis; do not use concurrently. # Special instructions • Administer on an empty stomach (1 hour before or 2 hours after a meal). • Decrease dosage in patients with impaired renal function. # Zidovudine (ZDV, AZT), RETROVIR ® Preparations: Syrup: 10 mg/mL; Capsules: 100 mg; Tablets: 300 mg; Concentrate for injection/for intravenous infusion: 10 mg/mL Dosage Dose for premature infants: (Standard neonatal dose may be excessive in premature infants.) Under study in Pediatric AIDS Clinical Trial Group protocol 331: 1.5 mg per kg of body weight every 12 hours from birth to 2 weeks of age; then increase to 2 mg per kg of body weight every 8 hours after 2 weeks of age. Neonatal dose: Oral: 2 mg per kg of body weight every 6 hours. Intravenous: 1. Adolescent/Adult dose: 200 mg three times a day or 300 mg twice daily. * Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. • Techniques to increase tolerance in children: a) mixing oral solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream; b) dulling the taste buds before administration by chewing ice, giving popsicles or spoonfuls of partially frozen orange or grape juice concentrates; c) coating the mouth by giving peanut butter to eat before the dose; or d) administration of strong-tasting foods such as maple syrup, cheese, or strong-flavored chewing gum immediately after dose. Adolescent/Adult dose: Hard gel capsules: 600 mg three times a day; Soft gel capsules: 1200 mg three times a day. # Major toxicities Most frequent: Diarrhea, abdominal discomfort, headache, nausea, paresthesias, and skin rash. Less common: Exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes. # Drug interactions • Saquinavir is metabolized by the cytochrome P450 3A4 (CYP 3A4) system in the liver, and there are numerous potential drug interactions.* • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • Saquinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Saquinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives, or sedative-hypnotics (e.g., midazolam or triazolam). • Saquinavir levels are significantly reduced with concurrent use of rifampin (decreases saquinavir levels by 80%), rifabutin (decreases saquinavir levels by 40%), and nevirapine (decreases saquinavir levels by 25%). • Saquinavir levels are decreased by carbamazepine, dexamethasone, phenobarbital, and phenytoin. • Saquinavir levels are increased by delvirdine and ketoconazole. • Saquinavir may increase levels of calcium channel blockers, clindamycin, dapsone, and quinidine. If used concurrently, patients should be closely monitored for toxicity. • Administration with other protease inhibitors: co-administration with indinavir, ritonavir, or nelfinavir increases concentration of saquinavir with little change in concentration of the other drug. # Special instructions • Administer within 2 hours of a full meal to increase absorption. • Concurrent administration of grapefruit juice increases saquinavir concentration. • Sun exposure can cause photosensitivity reactions, therefore sunscreen or protective clothing is recommended. # Appendix # CHARACTERISTICS OF AVAILABLE ANTIRETROVIRAL DRUGS Didanosine (dideoxyinosine) (ddI), VIDEX ® Preparations: Pediatric powder for oral solution (when reconstituted as solution containing antacid): 10 mg/mL; Chewable tablets with buffers: 25, 50, 100, and 150 mg; Buffered powder for oral solution: 100, 167, and 250 mg Dosage Neonatal dose (infants aged <90 days): 50 mg per m 2 of body surface area every 12 hours. Pediatric usual dose: In combination with other antiretrovirals: 90 mg per m 2 of body surface area every 12 hours. Pediatric dosage range: 90 to 150 mg per m 2 of body surface area every 12 hours. (Note: may need higher dose in patients with central nervous system disease.) Adolescent/Adult dose: Body weight ≥60 kg: 200 mg twice daily. Body weight <60 kg: 125 mg twice daily. # Major toxicities Most frequent: Diarrhea, abdominal pain, nausea, and vomiting. Unusual (more severe): Peripheral neuropathy (dose related), electrolyte abnormalities, and hyperuricemia. Uncommon: Pancreatitis (dose related, less common in children than adults), increased liver enzymes, and retinal depigmentation. # Drug interactions • Possible decrease in absorption of ketoconazole, itraconazole, and dapsone; administer at least 2 hours before or 2 hours after ddI. • Tetracycline and fluoroquinolone antibiotic absorption significantly decreased (chelation of drug by antacid in pediatric powder and tablets); administer 2 hours before or 2 hours after ddI. • Concomitant administration of ddI and delavirdine may decrease the absorption of these drugs; separate dosing by at least 2 hours. • Administration with protease inhibitors: indinavir should be administered at least 1 hour before or after ddI on an empty stomach. Ritonavir should be administered at least 2 hours before or after ddI. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. # Nucleoside Analogue Reverse Transcriptase Inhibitors † # Special instructions • ddI formulation contains buffering agents or antacids. • Food decreases absorption; administer ddI on an empty stomach (1 hour before or 2 hours after a meal). Further evaluation in children regarding administration with meals is under study. • For oral solution: shake well and keep refrigerated; admixture is stable for 30 days. • When administering chewable tablets, at least two tablets should be administered to ensure adequate buffering capacity (e.g., if the child's dose is 50 mg, administer two 25-mg tablets and not one 50-mg tablet). # Lamivudine (3TC), EPIVIR ® Preparations: Solution: 10 mg/mL; Tablets: 150 mg # Dosage Neonatal dose (infants aged <30 days): 2 mg per kg of body weight twice daily. Pediatric dose: 4 mg per kg of body weight twice daily. Adolescent/Adult dose: Body weight ≥50 kg: 150 mg twice daily. Body weight <50 kg: 2 mg per kg body weight twice daily. # Major toxicities Most frequent: Headache, fatigue, nausea, diarrhea, skin rash, and abdominal pain. Unusual (more severe): Pancreatitis (primarily seen in children with advanced HIV infection receiving multiple other medications), peripheral neuropathy, decreased neutrophil count, and increased liver enzymes. # Drug interactions • Trimethoprim/sulfamethoxazole (TMP/SMX) increases 3TC blood levels (possibly competes for renal tubular secretion); unknown significance. • When used with zidovudine (ZDV) may prevent emergence of ZDV resistance, and for ZDV-resistant virus, revision to phenotypic ZDV sensitivity may be observed. # Special instructions • Can be administered with food. • For oral solution: store at room temperature. • Decrease dosage in patients with impaired renal function. # Stavudine (d4T), ZERIT ® Preparations # Major toxicities Most frequent: Hematologic toxicity, including granulocytopenia and anemia, and headache. Unusual: Myopathy, myositis, and liver toxicity. # Drug interactions • Increased toxicity may be observed with concomitant administration of the following drugs (therefore, more intensive toxicity monitoring may be warranted): ganciclovir, interferon-alpha, TMP/SMX, acyclovir, and other drugs that can be associated with bone marrow suppression. • The following drugs may increase ZDV concentration (and therefore potential toxicity): probenecid, atovaquone, methadone, valproic acid, and fluconazole. • Decreased renal clearance may be observed with co-administration of cimetidine (may be significant in patients with renal impairment). • ZDV metabolism may be increased with co-administration of rifampin and rifabutin (clinical significance unknown); clarithromycin may decrease concentrations of ZDV probably by interfering with absorption (preferably administer 4 hours apart). • Ribavirin decreases the intracellular phosphorylation of ZDV (conversion to active metabolite). • Phenytoin concentrations may increase or decrease. • Should not be administered in combination with d4T (poor antiretroviral effect). # Special instructions • Can be administered with food (although the manufacturer recommends administration 30 minutes before or 1 hour after a meal). • Decrease dosage in patients with severe renal impairment. • Substantial granulocytopenia or anemia may necessitate interruption of therapy until marrow recovery is observed; use of erythropoietin, filgrastim, or reduced ZDV dosage may be necessary in some patients. • Reduced dosage may be indicated in patients with substantial hepatic dysfunction. • Infuse intravenous loading dose or intermittent infusion dose over 1 hour. • For intravenous solution: dilute with 5% dextrose injection solution to concentration ≤4 mg/mL; refrigerated diluted solution is stable for 24 hours. • Some experts in pediatric HIV infection use a dose of 180 mg per m 2 of body surface area every 12 hours when using in drug combinations with other antiretroviral compounds, but data on this dosing in children is limited. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. § Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Delavirdine (DLV), RESCRIPTOR ® Preparations: Tablets: 100 mg # Dosage Neonatal dose: Unknown. Pediatric dose: Unknown. Adolescent/Adult dose: 400 mg three times a day. # Major toxicities Most frequent: Headache, fatigue, gastrointestinal complaints, and rash (may be severe). # Drug interactions • Metabolized in part by hepatic cytochrome P450 3A (CYP3A). There could potentially be multiple drug interactions. § • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • DLV decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. DLV is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); sedative-hypnotics (e.g., alprazolam, midazolam, or triazolam); calcium channel blockers (e.g., nifedipine); ergot alkaloid derivatives; amphetamines; cisapride; or warfarin. • DLV clearance is increased, resulting in substantially reduced concentrations of DLV, with concurrent use of rifabutin, rifampin, or anticonvulsants (e.g., phenytoin, carbamazepine, or phenobarbital). Concurrent use is not recommended. • Absorption of DLV is decreased if given with antacids or histamine 2 receptor antagonists. • Increased trough concentrations of DLV if given with ketoconazole or fluoxetine; increased levels of both drugs if DLV is given with clarithromycin. • DLV increases levels of dapsone and quinidine. • Administration with protease inhibitors: decreases metabolism of saquinavir and indinavir, resulting in a significant increase in saquinavir and indinavir concentrations and a slight decrease in DLV concentrations. # Special instructions • Can be administered with food. • Should be taken 1 hour before or 1 hour after ddI or antacids. • Tablets can be dissolved in water and the resulting dispersion taken promptly. # Non-nucleoside Reverse Transcriptase Inhibitors † Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Nevirapine (NVP), VIRAMUNE ® Preparations: Suspension: 10 mg/mL (investigational); Tablets: 200 mg Dosage Neonatal dose (through age 3 months): Under study in Pediatric AIDS Clinical Trial Group protocol 356: 5 mg per kg of body weight once daily for 14 days, followed by 120 mg per m 2 of body surface area every 12 hours for 14 days, followed by 200 mg per m 2 of body surface area every 12 hours. Pediatric dose: 120 to 200 mg per m 2 of body surface area every 12 hours. Note: Initiate therapy with 120 mg per m 2 of body surface area administered once daily for 14 days. Increase to full dose administered every 12 hours if there are no rash or other untoward effects. Adolescent/Adult dose: 200 mg every 12 hours. Note: Initiate therapy at half dose for the first 14 days. Increase to full dose if there is no rash or other untoward effects. # Major toxicities Most frequent: Skin rash (some severe and life-threatening, including Stevens-Johnson syndrome), sedative effect, headache, diarrhea, and nausea. Unusual: Elevated liver enzymes and, rarely, hepatitis. # Drug interactions • Induces hepatic cytochrome P450 3A (CYP3A); autoinduction of metabolism occurs in 2-4 weeks with a 1.5-fold to twofold increase in clearance. There could potentially be multiple drug interactions. • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • Drugs having suspected interactions and should be used only with careful monitoring: rifampin and rifabutin; oral contraceptives (alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control); sedative-hypnotics (e.g., triazolam or midazolam); oral anticoagulants; digoxin; phenytoin; or theophylline. • Administration with protease inhibitors: indinavir and saquinavir concentrations are decreased significantly, and ritonavir concentration may be decreased. Whether increased doses of protease inhibitors are needed is unknown. # Special instructions • Can be administered with food. • May be administered concurrently with ddI. • NVP-associated skin rash usually occurs within the first 6 weeks of therapy. If rash occurs during the initial 14-day lead-in period, do not increase dose until rash resolves. NVP should be discontinued immediately in patients who develop severe rash or a rash accompanied by constitutional symptoms (i.e., fever, oral lesions, conjunctivitis, or blistering). • For investigational suspension: Must be shaken well; store at room temperature. Information in this appendix is not all inclusive. Complete and detailed prescribing and toxicity information on these drugs is available from the drug companies and should be reviewed by the health-care provider before prescribing these drugs. † Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules, whereas those in late puberty (Tanner Stage V) should be dosed using adult schedules. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. § Data in children is limited, and doses may change as more information is obtained about the pharmacokinetics of these drugs in children. ¶ Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Indinavir, CRIXIVAN ® Preparations: Capsules: 200 and 400 mg Dosage Neonatal Dose: Unknown. Due to side effect of hyperbilirubinemia, should not be given to neonates until further information is available. Pediatric Dose: Under study in clinical trials: 500 mg per m 2 of body surface area every 8 hours. Adolescent/Adult dose: 800 mg every 8 hours. # Major toxicities Most frequent: Nausea, abdominal pain, headache, metallic taste, dizziness, and asymptomatic hyperbilirubinemia (10%). Unusual (more severe): Nephrolithiasis (4%) and exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, diabetes, and hemolytic anemia. # Drug interactions • Cytochrome P450 3A4 (CYP3A4) responsible for metabolism. There could potentially be multiple drug interactions. ¶ • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • Indinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Indinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives; or sedative-hypnotics (e.g., triazolam or midazolam). • Indinavir levels are significantly reduced with concurrent use of rifampin. Concurrent use is not recommended. • Rifabutin concentrations are increased, therefore a dose reduction of rifabutin to half the usual daily dose is recommended. • Ketoconazole and itraconazole cause an increase in indinavir concentrations (consider reducing adolescent/adult indinavir dose to 600 mg every 8 hours). • Co-administration of clarithromycin increases serum concentration of both drugs (dosing modification not needed). • Co-administration of nevirapine may decrease indinavir serum concentration. # Protease Inhibitors † § Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. • Administration with other protease inhibitors: co-administration with nelfinavir increases concentration of both drugs; co-administration with saquinavir increases concentration of saquinavir. # Special instructions • Administer on an empty stomach 1 hour before or 2 hours after a meal (or can take with a light meal). • Adequate hydration required to minimize risk of nephrolithiasis (at least 48 oz of fluid daily in adult patients). • If co-administered with ddI, give at least 1 hour apart on an empty stomach. • Decrease dose in patients with hepatic insufficiency. • Capsules are sensitive to moisture and should be stored in original container with desiccant. # Nelfinavir, VIRACEPT ® Preparations: Powder for oral suspension: 50 mg per 1 level gram scoopful (200 mg per 1 level teaspoon); Tablets: 250 mg tablet # Dosage Neonatal dose: Under study in Pediatric AIDS Clinical Trial Group protocol 353: 10 mg per kg of body weight three times a day. (Note: no preliminary data available, investigational.) Pediatric dose: 20 to 30 mg per kg of body weight three times a day. Adolescent/Adult dose: 750 mg three times a day. # Major toxicities Most frequent: Diarrhea. Less common: Asthenia, abdominal pain, rash, and exacerbation of chronic liver disease. Rare: Spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes. # Drug interactions • Nelfinavir is in part metabolized by cytochrome P450 3A4 (CYP3A4). There could potentially be multiple drug interactions. • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • Nelfinavir decreases the metabolism of certain drugs, resulting in increased drug levels and potential toxicity. Nelfinavir is not recommended for concurrent use with antihistamines (e.g., astemizole or terfenadine); cisapride; ergot alkaloid derivatives; certain cardiac drugs (e.g., quinidine or amiodarone); or sedativehypnotics (e.g., triazolam or midazolam). • Nelfinavir levels are greatly reduced with concurrent use of rifampin. Concurrent use is not recommended. • Rifabutin causes less decline in nelfinavir concentrations; if co-administered with nelfinavir, rifabutin should be reduced to one half the usual dose. • Estradiol levels are reduced by nelfinavir, and alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control. • Co-administration with delavirdine (DLV) increases nelfinavir concentrations twofold and decreases DLV concentrations by 50%. There are no data on coadministration with nevirapine, but some experts use higher doses of nelfinavir if used in combination with nevirapine. • Administration with other protease inhibitors: co-administration with indinavir increases concentration of both drugs; co-administration with saquinavir increases concentration of saquinavir with little change in nelfinavir concentration; co-administration with ritonavir increases concentration of nelfinavir without change in ritonavir concentration. # Special instructions • Administer with meal or light snack. • If co-administered with ddI, nelfinavir should be administered 2 hours before or 1 hour after ddI. • For oral solution: powder may be mixed with water, milk, pudding, ice cream, or formula (for up to 6 hours). • Do not mix with any acidic food or juice because of resulting poor taste. • Do not add water to bottles of oral powder; a special scoop is provided with oral powder for measuring purposes. • Tablets readily dissolve in water and produce a dispersion that can be mixed with milk or chocolate milk; tablets also can be crushed and administered with pudding. # Ritonavir, NORVIR ® Preparations: Oral solution: 80 mg/mL; Capsules: 100 mg # Dosage Neonatal dose: Under study in Pediatric AIDS Clinical Trial Group protocol 354 (single dose pharmacokinetics). Pediatric usual dose: 400 mg per m 2 of body surface area every 12 hours. To minimize nausea/vomiting, initiate therapy starting at 250 mg per m 2 of body surface area every 12 hours and increase stepwise to full dose over 5 days as tolerated. Pediatric dosage range: 350 to 400 mg per m 2 of body surface area every 12 hours. Adolescent/Adult dose: 600 mg twice daily. To minimize nausea/vomiting, initiate therapy starting at 300 mg twice daily and increase stepwise to full dose over 5 days as tolerated. # Major toxicities Most frequent: Nausea, vomiting, diarrhea, headache, abdominal pain, and anorexia. Less common: Circumoral paresthesias and increase in liver enzymes. Rare: Spontaneous bleeding episodes in hemophiliacs, pancreatitis, increased levels of triglycerides and cholesterol, hyperglycemia, ketoacidosis, diabetes, and hepatitis. Drugs metabolized by the hepatic cytochrome P450 enzyme system have the potential for significant interactions with multiple drugs, some of which may be life-threatening. These interactions are outlined in detail in prescribing information available from the drug companies. These interactions will not be reiterated in this document, and the health-care provider should review those documents for detailed information. Before therapy with these drugs is initiated, the patient's medication profile should be carefully reviewed for potential drug interactions. # Drug interactions • Ritonavir is extensively metabolized by hepatic cytochrome P450 3A (CYP3A). There could potentially be multiple drug interactions. • Before administration, the patient's medication profile should be carefully reviewed for potential drug interactions. • Not recommended for concurrent use with analgesics (e.g., meperidine, piroxicam, or propoxyphene); antihistamines (e.g., astemizole or terfenadine); certain cardiac drugs (e.g., amiodarone, bepridil hydrochloride, encainide hydrochloride, flecainide acetate, propafenone, or quinidine); ergot alkaloid derivatives; cisapride; sedative-hypnotics (e.g., alprazolam, clorazepate, diazepam, estazolam, flurazepam hydrochloride, midazolam, triazolam, or zolpidem tartrate); certain psychotropic drugs (e.g., bupropion hydrochloride, clozapine, or pimozide); rifampin; or rifabutin. • Estradiol levels are reduced by ritonavir, and alternative or additional methods of birth control should be used if co-administering with hormonal methods of birth control. • Ritonavir increases metabolism of theophylline (levels should be monitored, and dose may need to be increased). • Ritonavir increases levels of clarithromycin (dose adjustment may be necessary in patients with impaired renal function); desipramine (dose adjustment may be necessary); and warfarin (monitoring of anticoagulant effect is necessary). • Ritonavir may increase or decrease digoxin levels (monitoring of levels is recommended). • Drugs that increase CYP3A activity can lead to increased clearance and therefore lower levels of ritonavir include carbamazepine, dexamethasone, phenobarbital, and phenytoin (anticonvulsant levels should be monitored because ritonavir can affect the metabolism of these drugs as well). • Administration with other protease inhibitors: co-administration with saquinavir and nelfinavir increases concentration of these drugs with little change in ritonavir concentration. # Special instructions • Administration with food increases absorption. • If ritonavir is prescribed with ddI, there should be 2 hours between taking each of the drugs. • Oral solution must be kept refrigerated and stored in original container; can be kept at room temperature if used within 30 days. • To minimize nausea, therapy should be initiated at a low dose and increased to full dose over 5 days as tolerated. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/ or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1998-633-228/67064 Region IV	None	None
9771ccf28f687262f317112f90ae1bb148ab2127	cdc	None	The document describes use of certain drugs and tests for some indications that do not reflect labeling approved by the U.S. Food and Drug Administration.# Contents Navigation tip: To advance to a specific topic, click its link below. In addition, this document contains hyperlinks to related topics in other sections of the document. To navigate to the related topic, click the hyperlink. To return from the topic back to the hyperlink location, press the ALT+left arrow keys on your keyboard. # Section 1. Introduction This Summary for Nonclinical Providers contains the subset of recommendations for nonclinical providers who work in community-based organizations or health departments operating outside health care facilities from the 2014 guideline, Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States, 2014. i The guideline includes new and longstanding federal guidance on biomedical, behavioral, and structural interventions that can decrease HIV transmission from persons with HIV by reducing their infectiousness and their risk of exposing others to HIV. The guideline updates and expands earlier federal guidance for clinical providers in the 2003 Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. ii The 2014 guideline and this Summary were developed by the Centers for Disease Control and Prevention, the Health Resources and Services Administration, the National Institutes of Health, the American Academy of HIV Medicine, the Association of Nurses in AIDS Care, the International Association of Providers of AIDS Care, the National Minority AIDS Council, and the Urban Coalition for HIV/AIDS Prevention Services. A Summary for Clinical Providers iii is directed to professionals who provide HIV prevention and care services in health care facilities. A Summary for Health Departments and HIV Planning Groups iv is directed to professionals who provide population-level services to communities affected by HIV. # Section 2. About the Summary # Who is this Summary for? This Summary is for nonclinical providers who provide individual-level services for persons with HIV in community-based organizations or health departments operating outside of health care facilities. These providers offer HIV testing, health education, riskreduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. # What does this Summary include?  Recommendations related to 11 domains of interventions that can decrease HIV transmission by reducing the infectiousness of persons with HIV or by reducing their risk of exposing others to HIV. In some cases, recommendations for nonclinical providers to offer an intervention were based on federal guidance for clinical providers, but the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers to offer these interventions.  Examples of practical strategies to support implementation of these recommendations  A list of links to federal guidance that supports these recommendations (Appendix A)  A link to an online Resource Library of practical materials to help implement these recommendations # How to use the Summary? Nonclinical providers can use this Summary - to  Learn how they and their organizations can promote HIV prevention with their clients with HIV  Select interventions that may be well-suited to their clients with HIV  Train staff on best practices in HIV prevention with persons with HIV # Additional information about the 2014 Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States The complete guideline is available at . It is directed to professionals who serve individuals or populations with HIV: clinical providers, nonclinical providers, and staff of health departments and HIV planning groups. It includes:  Executive summary The sequential box and table numbers in the complete guideline (which is directed to several different audiences) are not identical to the sequential box and table numbers in this Summary that only lists information for nonclinical providers). # Section 3. The Context of Prevention with Persons with HIV Background Individual, social, structural, ethical, legal, and policy issues shape the lives of persons with HIV and their ability to use HIV prevention and care services and adopt HIV prevention strategies. This section makes general recommendations about these contextual issues. Nonclinical providers working outside of health care facilities who understand these issues are better prepared to create a sense of shared responsibility and decision making with their clients with HIV. This may include  motivating clients with HIV to adopt prevention strategies and obtain essential services  endorsing the strategy of "treatment as prevention" to contribute to community well-being  communicating in a sensitive, respectful, and culturally competent manner # Encourage Communication that does not stigmatize or negatively judge persons with HIV or their gender identity, sexual orientation, sexual and drug-use behaviors, and medical or social characteristics Provision of information about rights and responsibilities of persons with HIV regarding confidentiality, privacy, protection from discrimination, and partner notification Planning by persons with HIV to notify exposed sex and drug-injection partners through partner notification assistance or self-disclosure that reflects an understanding of the benefits and risks of HIV disclosure in the jurisdiction Access to services and devices (e.g., condoms) that improve the knowledge, ability, and motivation of persons with HIV to improve their health, protect the health of partners, and reduce transmission of HIV Nonclinical providers working outside of health care facilities can play a crucial role in informing clients about the advantages of starting ART early, supporting adherence to long-term ART use, and providing information on other interventions that can reduce the risk of HIV transmission. Nonclinical providers can also inform clients with HIV about the availability of prophylactic medications for their HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition. Some recommendations for nonclinical providers to provide adherence information, education and support were based on federal guidance for clinical providers. However, the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers with appropriate training to offer these services. Other sections of this Summary address adherence to ART (Section 6); antiretroviral medication use by women using hormonal contraceptives and persons seeking conception (Section 10); use of ART and prophylaxis during pregnancy and the postpartum period (Section 11); and quality improvement and program evaluation (Section 13). # Recommendations Box 5. Recommendations-Antiretroviral Treatment for Care and Prevention # Initiating or resuming antiretroviral treatment (ART) Inform all persons with HIV about the following issues regarding antiretroviral treatment (ART) (i.e., treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication) (see Box 5-A): The health benefits of early initiation of ART, including - improving or maintaining health when compared with later initiation of ART - prolonging lifespan - reducing risk of HIV transmission to others a  The limitations of ART, including - the need for lifelong treatment - the need for high adherence - potential medication side effects - the use of ART substantially reduces, but may not eliminate, the risk of HIV transmission # The availability of HIV prophylaxis for uninfected partners when clinically indicated to reduce risk of HIV acquisition Inform all persons with HIV (and any of their HIV-uninfected partners referred for evaluation) about the following HIV prophylaxis issues b,c (see Box 5-B): The availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition # Section 6. Antiretroviral Treatment Adherence Background Sustained high adherence to antiretroviral therapy (ART) is essential to improve clinical outcomes and quality of life of clients with HIV and decrease their risk of HIV transmission. The success of ART depends on the extent to which a client takes ART according to the prescribed doses, dosing intervals, and other medication instructions. Nonclinical providers working outside of health facilities can help their clients achieve high ART adherence by collaborating with clinical providers on adherence support, such as counseling about the benefits of high adherence, training on medication reminder tools, and case management services. Some of the federal guidance that served as the basis for these recommendations for nonclinical providers was intended for health care providers. Based on opinions of the Project Workgroup and recent program experience, the writing group concluded that it would be beneficial and feasible for nonclinical providers to implement these recommendations. Other sections of this Summary address linkage and reengagement in HIV medical care (Section 4), initiating or resuming ART (Section 5); antiretroviral medication use by women using hormonal contraceptives and persons seeking conception (Section 10); use of ART and prophylaxis during pregnancy and the postpartum period (Section 11); and quality improvement and program evaluation (Section 13). # Box 6. Recommendations-Antiretroviral Treatment Adherence Participate in multidisciplinary teams with health educators, service linkage facilitators, community health workers, case managers, nurses, pharmacists, and physicians to assess and support adherence to antiretroviral treatment (ART) a,b Inform persons with HIV about the benefits of sustained high adherence, even if they are feeling well, and the risks of low adherence (e.g., illness, drug resistance, transmitting HIV to others) Provide adherence support tailored to each person's regimen and characteristics, according to provider role, authority, and setting (see Box 6-A) Provide or make referrals for services to address factors that may impair adherence (e.g., demographic, comorbidity, psychosocial, and structural issues) (see Nonclinical providers who work outside of health care facilities but are not health department employees can directly refer clients to health department partner services specialists who offer voluntary, confidential services. In some jurisdictions, these nonclinical providers who are trained and authorized by the health department to provide partner services can provide partner services in community-based HIV testing and prevention programs. Some recommendations for nonclinical providers to offer selected partner services were based on federal guidance for staff of health departments or clinical providers. However, the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers with appropriate training and authority to offer selected partner services, such as counseling persons with HIV about disclosure, collecting partner contact information, and offering HIV testing to partners. Other sections of this Summary address STD services for index patients and their partners (Section 9); use of nonoccupational postexposure prophylaxis (nPEP) and preexposure prophylaxis (PrEP) by HIV-uninfected partners (Section 5); and quality improvement and program evaluation (Section 13). - HIV testing if the partner is not known to be HIV-infected (followed by verification of test results) b # Recommendations - Risk-reduction services and devices (e.g., behavioral information, counseling, risk-reduction interventions, latex or polyurethane condoms) - Information about the availability of PrEP and nPEP for HIV-uninfected persons when clinically indicated to reduce the risk of HIV acquisition and referrals to clinical providers who offer prophylaxis  Linkage to - HIV care, treatment, and partner services if a preliminary or confirmatory HIV test is positive - Screening for STD and viral hepatitis if partner is asymptomatic, using tests recommended by CDC a - Presumptive STD treatment (while awaiting results of STD testing or clinical evaluation) if the partner was exposed to STD - Testing and clinical evaluation for STD and viral hepatitis if partner has relevant symptoms a - STD and viral hepatitis care and treatment if the partner is diagnosed with these conditions a - Other medical and social services that influence HIV transmission (e.g., substance use treatment, mental health services) Collect information about members of the partners' social network (including physical and virtual venues frequented), using CDC-recommended methods, if trained and authorized in this approach c Notes: a Viral hepatitis testing (and treatment of infected persons) has not been shown to influence HIV transmission but is included here because it is often offered in combination with HIV and STD testing for individual and public health benefits. b Partners who are unlikely to obtain prompt HIV testing in clinical settings should be linked to HIV testing at community-based organizations or home. c The first federal guidance in Appendix A, Section 8, describes CDC-recommended methods. # Section 9. Sexually Transmitted Disease (STD) Preventive Services Background Sexually transmitted diseases (STDs) are common in persons with HIV and many do not cause obvious symptoms or signs. Five STD may increase the risk of transmitting HIV: syphilis, gonorrhea, chlamydial infection, and HSV-2 in men and women and trichomoniasis in women. STD preventive services are an essential component of HIV prevention because the diagnosis of an STD is an objective marker of unprotected sexual activity that may result in HIV transmission; certain STDs may increase plasma HIV viral load and genital HIV shedding; and STD treatment may reduce STD-related morbidity and lower the risk of HIV transmission. Nonclinical providers working outside of health care facilities play a crucial role in STD preventive services. These include assessing risk factors for STD; providing sexual riskreduction information and interventions; and linking clients to STD screening, treatment, and partner services. Some nonclinical settings have the capacity to screen clients for gonorrhea and chlamydia (using client-collected specimens) or for syphilis (using blood drawn by onsite providers). Other sections of this Summary address confidentiality and reporting of HIV and STD information and the duty to warn partners of possible HIV exposure (Section 3); screening for sexual behavior, condom use, and STD symptoms and signs (Section 7); partner services for persons with HIV and their sex partners (Section 8); and quality improvement and program evaluation (Section 13). Notes: The first federal guidance in Appendix A, Section 9, indicates that type-specific serologic testing for herpes simplex virus type 2 (HSV-2) infection can be considered in persons with HIV with unknown herpes infection status. This section does not address screening for other conditions that may affect persons with HIV but have not been shown to facilitate HIV transmission to others, such as viral hepatitis and human papillomavirus infection. # Recommendations a Some nonclinical settings have the capacity to screen for gonorrhea and chlamydia (using client-collected urine, vaginal, rectal, and oropharyngeal specimens) or syphilis (using venous blood drawn by nonclinical provider); The first two federal guidance documents in Appendix A, Section 9, describe tests recommended by CDC. Commercially available NAATs for C. trachomatis and N. gonorrhoeae are not cleared by the U.S. Food and Drug Administration (FDA) for urine, vaginal, or rectal specimens collected in nonclinical settings. However, some laboratories have established performance specifications for testing specimens collected in nonclinical settings to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. The FDA has not cleared commercially available NAATs to test rectal specimens for gonorrhea and chlamydial infection or oropharyngeal specimens for gonorrhea. However, some laboratories have established performance specifications for testing these types of specimens to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. Screening for vaginal trichomoniasis is not performed in nonclinical settings. b The first federal guidance in Appendix A, Section 9, indicates CDC-recommended tests. # Section 10. Reproductive Health Care for Women and Men Background Reproductive health care involves several essential services for adolescents and adults with HIV who are of reproductive age and wish to prevent unplanned pregnancies or reduce the risk of sexual HIV transmission when attempting conception. Nonclinical providers working outside of health care facilities may provide important information, education, and referral for these services to individuals, HIV-concordant couples (in which both members are HIV-infected), or HIV-discordant couples (in which only one member is infected). For example, nonclinical providers can refer clients who want to prevent or delay pregnancy to contraceptive services and refer clients who want to conceive to health care providers who are familiar with special conception methods that reduce the risk of HIV transmission. Other sections in this Summary address methods-including use of ART-to prevent sexual or perinatal transmission of HIV during recognized pregnancies of HIV-infected women or HIV-uninfected women who have partners with HIV (Section 11); linkage to HIV medical care (Section 4), general aspects of use of ART by persons with HIV and antiretroviral prophylaxis by HIV-uninfected partners (Section 5); ART adherence (Section 6); methods to reduce sexual transmission of HIV (Section 7); services for sex partners of persons with HIV (Section 8); and quality improvement and program evaluation (Section 13). Persons who do not wish to conceive Provide education, reproductive health counseling, or make referral for contraceptive services as appropriate to provider role and setting to women and men who wish to prevent or delay future pregnancy # Recommendations # Provide services Assess pregnancy status of HIV-infected women and reproductive plans of women and men with HIV, with methods and frequency as appropriate to provider role and setting (e.g., self-reported pregnancy or referral for pregnancy testing) Offer periodic HIV testing to HIV-uninfected members of HIV-discordant couples, particularly those who are attempting conception or who report unprotected intercourse Note: Some topics may only be suited for nonclinical providers with appropriate skills and training. # Section 11. HIV Prevention Related to Pregnancy Background Pregnant women with HIV can transmit HIV to their fetuses and newborns if they do not use effective prevention strategies. The physiologic state of pregnancy can also increase the risk of sexual HIV transmission from HIV-infected pregnant women to uninfected male partners as well as from HIV-infected male partners to uninfected pregnant women. Nonclinical providers working outside of health care facilities can offer a variety of preventive services that can prevent HIV transmission from HIV-infected women with recognized pregnancies and can prevent HIV transmission to pregnant HIV-uninfected women who have HIV-infected sex or drug injection partners. These include providing information about methods to prevent HIV transmission during pregnancy, linking pregnant women with HIV to pregnancy care, and offering HIV testing to pregnant women and their partners. Other sections in this Summary address linking pregnant women to HIV medical care (Section 4); general aspects of antiretroviral treatment (ART) for persons with HIV and prophylaxis for HIV-uninfected partners (Section 5); general aspects of ART adherence (Section 6); behavioral risk-reduction interventions suited to HIV-infected partners of pregnant women (Section 7); notification of sex and drug-injection partners of pregnant women with HIV or of HIV-uninfected pregnant women (Section 8); screening pregnant women for sexually transmitted disease (STD) services (Section 9); contraception services and reproductive health counseling that can be offered after delivery (Section 10); and quality improvement and program evaluation (Section 13). Advise women to urge sex partners and drug-injection partners to get HIV testing and to use condoms to prevent HIV acquisition Provide education, counseling and/or referral for postpartum contraception services to all women who wish to prevent or delay future pregnancy, as appropriate to the setting Inform women and their partners that breastfeeding by HIV-infected women is not recommended in the United States and that formula feeding is recommended for the infants of these women # Recommendations # Specific prenatal services Promptly link women to HIV medical care, preferably to settings where providers have expertise in managing pregnancy in women with HIV Support adherence to antiretroviral treatment (ART) during the prenatal and postnatal periods for optimal maternal health and prevention of perinatal and sexual transmission Offer latex or polyurethane male and/or female condoms Offer women support, information, and assistance to notify their sex and druginjection partners about their HIV status Note: A woman with HIV must explicitly grant her provider permission to discuss her HIV infection status with her partners. Staff not trained in new encounter form reminder were least likely to provide information or referral for partner services Act Trained 100% of staff on new partner services procedures Revised reminder system to automatically print partner services information for all newly diagnosed clients before check out. Source: Adapted from the chapter on "Quality Improvement" in the second guidance document in Appendix A, Section 13.	The document describes use of certain drugs and tests for some indications that do not reflect labeling approved by the U.S. Food and Drug Administration.# Contents Navigation tip: To advance to a specific topic, click its link below. In addition, this document contains hyperlinks to related topics in other sections of the document. To navigate to the related topic, click the hyperlink. To return from the topic back to the hyperlink location, press the ALT+left arrow keys on your keyboard. # Section 1. Introduction This Summary for Nonclinical Providers contains the subset of recommendations for nonclinical providers who work in community-based organizations or health departments operating outside health care facilities from the 2014 guideline, Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States, 2014. i The guideline includes new and longstanding federal guidance on biomedical, behavioral, and structural interventions that can decrease HIV transmission from persons with HIV by reducing their infectiousness and their risk of exposing others to HIV. The guideline updates and expands earlier federal guidance for clinical providers in the 2003 Recommendations for Incorporating HIV Prevention into the Medical Care of Persons Living with HIV. ii The 2014 guideline and this Summary were developed by the Centers for Disease Control and Prevention, the Health Resources and Services Administration, the National Institutes of Health, the American Academy of HIV Medicine, the Association of Nurses in AIDS Care, the International Association of Providers of AIDS Care, the National Minority AIDS Council, and the Urban Coalition for HIV/AIDS Prevention Services. A Summary for Clinical Providers iii is directed to professionals who provide HIV prevention and care services in health care facilities. A Summary for Health Departments and HIV Planning Groups iv is directed to professionals who provide population-level services to communities affected by HIV. # Section 2. About the Summary # Who is this Summary for? This Summary is for nonclinical providers who provide individual-level services for persons with HIV in community-based organizations or health departments operating outside of health care facilities. These providers offer HIV testing, health education, riskreduction interventions, partner services, case management, or assistance with linkage or referral to medical and social services. These persons include HIV testing providers, peer and professional health educators, counselors, service linkage facilitators, partner services specialists, case managers, and social workers. # What does this Summary include?  Recommendations related to 11 domains of interventions that can decrease HIV transmission by reducing the infectiousness of persons with HIV or by reducing their risk of exposing others to HIV. In some cases, recommendations for nonclinical providers to offer an intervention [such as providing HIV prevention information] were based on federal guidance for clinical providers, but the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers to offer these interventions.  Examples of practical strategies to support implementation of these recommendations  A list of links to federal guidance that supports these recommendations (Appendix A)  A link to an online Resource Library of practical materials to help implement these recommendations # How to use the Summary? Nonclinical providers can use this Summary * to  Learn how they and their organizations can promote HIV prevention with their clients with HIV  Select interventions that may be well-suited to their clients with HIV  Train staff on best practices in HIV prevention with persons with HIV # Additional information about the 2014 Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States The complete guideline is available at http://stacks.cdc.gov/view/cdc/26062. It is directed to professionals who serve individuals or populations with HIV: clinical providers, nonclinical providers, and staff of health departments and HIV planning groups. It includes:  Executive summary The sequential box and table numbers in the complete guideline (which is directed to several different audiences) are not identical to the sequential box and table numbers in this Summary that only lists information for nonclinical providers). # Section 3. The Context of Prevention with Persons with HIV Background Individual, social, structural, ethical, legal, and policy issues shape the lives of persons with HIV and their ability to use HIV prevention and care services and adopt HIV prevention strategies. This section makes general recommendations about these contextual issues. Nonclinical providers working outside of health care facilities who understand these issues are better prepared to create a sense of shared responsibility and decision making with their clients with HIV. This may include  motivating clients with HIV to adopt prevention strategies and obtain essential services  endorsing the strategy of "treatment as prevention" to contribute to community well-being  communicating in a sensitive, respectful, and culturally competent manner # Encourage ■ Communication that does not stigmatize or negatively judge persons with HIV or their gender identity, sexual orientation, sexual and drug-use behaviors, and medical or social characteristics ■ Provision of information about rights and responsibilities of persons with HIV regarding confidentiality, privacy, protection from discrimination, and partner notification ■ Planning by persons with HIV to notify exposed sex and drug-injection partners through partner notification assistance or self-disclosure that reflects an understanding of the benefits and risks of HIV disclosure in the jurisdiction ■ Access to services and devices (e.g., condoms) that improve the knowledge, ability, and motivation of persons with HIV to improve their health, protect the health of partners, and reduce transmission of HIV Nonclinical providers working outside of health care facilities can play a crucial role in informing clients about the advantages of starting ART early, supporting adherence to long-term ART use, and providing information on other interventions that can reduce the risk of HIV transmission. Nonclinical providers can also inform clients with HIV about the availability of prophylactic medications for their HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition. Some recommendations for nonclinical providers to provide adherence information, education and support were based on federal guidance for clinical providers. However, the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers with appropriate training to offer these services. Other sections of this Summary address adherence to ART (Section 6); antiretroviral medication use by women using hormonal contraceptives and persons seeking conception (Section 10); use of ART and prophylaxis during pregnancy and the postpartum period (Section 11); and quality improvement and program evaluation (Section 13). # Recommendations Box 5. Recommendations-Antiretroviral Treatment for Care and Prevention # Initiating or resuming antiretroviral treatment (ART) ■ Inform all persons with HIV about the following issues regarding antiretroviral treatment (ART) (i.e., treatment with highly effective combinations of antiretroviral drugs to suppress HIV replication) (see Box 5-A):  The health benefits of early initiation of ART, including • improving or maintaining health when compared with later initiation of ART • prolonging lifespan • reducing risk of HIV transmission to others a  The limitations of ART, including • the need for lifelong treatment • the need for high adherence • potential medication side effects • the use of ART substantially reduces, but may not eliminate, the risk of HIV transmission # The availability of HIV prophylaxis for uninfected partners when clinically indicated to reduce risk of HIV acquisition ■ Inform all persons with HIV (and any of their HIV-uninfected partners referred for evaluation) about the following HIV prophylaxis issues b,c (see Box 5-B):  The availability of preexposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) for HIV-uninfected partners when clinically indicated to reduce their risk of HIV acquisition # Section 6. Antiretroviral Treatment Adherence Background Sustained high adherence to antiretroviral therapy (ART) is essential to improve clinical outcomes and quality of life of clients with HIV and decrease their risk of HIV transmission. The success of ART depends on the extent to which a client takes ART according to the prescribed doses, dosing intervals, and other medication instructions. Nonclinical providers working outside of health facilities can help their clients achieve high ART adherence by collaborating with clinical providers on adherence support, such as counseling about the benefits of high adherence, training on medication reminder tools, and case management services. Some of the federal guidance that served as the basis for these recommendations for nonclinical providers was intended for health care providers. Based on opinions of the Project Workgroup and recent program experience, the writing group concluded that it would be beneficial and feasible for nonclinical providers to implement these recommendations. Other sections of this Summary address linkage and reengagement in HIV medical care (Section 4), initiating or resuming ART (Section 5); antiretroviral medication use by women using hormonal contraceptives and persons seeking conception (Section 10); use of ART and prophylaxis during pregnancy and the postpartum period (Section 11); and quality improvement and program evaluation (Section 13). # Box 6. Recommendations-Antiretroviral Treatment Adherence ■ Participate in multidisciplinary teams with health educators, service linkage facilitators, community health workers, case managers, nurses, pharmacists, and physicians to assess and support adherence to antiretroviral treatment (ART) a,b ■ Inform persons with HIV about the benefits of sustained high adherence, even if they are feeling well, and the risks of low adherence (e.g., illness, drug resistance, transmitting HIV to others) ■ Provide adherence support tailored to each person's regimen and characteristics, according to provider role, authority, and setting (see Box 6-A) ■ Provide or make referrals for services to address factors that may impair adherence (e.g., demographic, comorbidity, psychosocial, and structural issues) (see Nonclinical providers who work outside of health care facilities but are not health department employees can directly refer clients to health department partner services specialists who offer voluntary, confidential services. In some jurisdictions, these nonclinical providers who are trained and authorized by the health department to provide partner services can provide partner services in community-based HIV testing and prevention programs. Some recommendations for nonclinical providers to offer selected partner services were based on federal guidance for staff of health departments or clinical providers. However, the federal workgroup of experts that developed the recommendations concluded that it would also be beneficial and feasible for nonclinical providers with appropriate training and authority to offer selected partner services, such as counseling persons with HIV about disclosure, collecting partner contact information, and offering HIV testing to partners. Other sections of this Summary address STD services for index patients and their partners (Section 9); use of nonoccupational postexposure prophylaxis (nPEP) and preexposure prophylaxis (PrEP) by HIV-uninfected partners (Section 5); and quality improvement and program evaluation (Section 13). • HIV testing if the partner is not known to be HIV-infected (followed by verification of test results) b # Recommendations • Risk-reduction services and devices (e.g., behavioral information, counseling, risk-reduction interventions, latex or polyurethane condoms) • Information about the availability of PrEP and nPEP for HIV-uninfected persons when clinically indicated to reduce the risk of HIV acquisition and referrals to clinical providers who offer prophylaxis  Linkage to • HIV care, treatment, and partner services if a preliminary or confirmatory HIV test is positive • Screening for STD and viral hepatitis if partner is asymptomatic, using tests recommended by CDC a • Presumptive STD treatment (while awaiting results of STD testing or clinical evaluation) if the partner was exposed to STD • Testing and clinical evaluation for STD and viral hepatitis if partner has relevant symptoms a • STD and viral hepatitis care and treatment if the partner is diagnosed with these conditions a • Other medical and social services that influence HIV transmission (e.g., substance use treatment, mental health services) ■ Collect information about members of the partners' social network (including physical and virtual venues frequented), using CDC-recommended methods, if trained and authorized in this approach c Notes: a Viral hepatitis testing (and treatment of infected persons) has not been shown to influence HIV transmission but is included here because it is often offered in combination with HIV and STD testing for individual and public health benefits. b Partners who are unlikely to obtain prompt HIV testing in clinical settings should be linked to HIV testing at community-based organizations or home. c The first federal guidance in Appendix A, Section 8, describes CDC-recommended methods. # Section 9. Sexually Transmitted Disease (STD) Preventive Services Background Sexually transmitted diseases (STDs) are common in persons with HIV and many do not cause obvious symptoms or signs. Five STD may increase the risk of transmitting HIV: syphilis, gonorrhea, chlamydial infection, and HSV-2 in men and women and trichomoniasis in women. STD preventive services are an essential component of HIV prevention because the diagnosis of an STD is an objective marker of unprotected sexual activity that may result in HIV transmission; certain STDs may increase plasma HIV viral load and genital HIV shedding; and STD treatment may reduce STD-related morbidity and lower the risk of HIV transmission. Nonclinical providers working outside of health care facilities play a crucial role in STD preventive services. These include assessing risk factors for STD; providing sexual riskreduction information and interventions; and linking clients to STD screening, treatment, and partner services. Some nonclinical settings have the capacity to screen clients for gonorrhea and chlamydia (using client-collected specimens) or for syphilis (using blood drawn by onsite providers). Other sections of this Summary address confidentiality and reporting of HIV and STD information and the duty to warn partners of possible HIV exposure (Section 3); screening for sexual behavior, condom use, and STD symptoms and signs (Section 7); partner services for persons with HIV and their sex partners (Section 8); and quality improvement and program evaluation (Section 13). Notes: The first federal guidance in Appendix A, Section 9, indicates that type-specific serologic testing for herpes simplex virus type 2 (HSV-2) infection can be considered in persons with HIV with unknown herpes infection status. This section does not address screening for other conditions that may affect persons with HIV but have not been shown to facilitate HIV transmission to others, such as viral hepatitis and human papillomavirus infection. # Recommendations a Some nonclinical settings have the capacity to screen for gonorrhea and chlamydia (using client-collected urine, vaginal, rectal, and oropharyngeal specimens) or syphilis (using venous blood drawn by nonclinical provider); The first two federal guidance documents in Appendix A, Section 9, describe tests recommended by CDC. Commercially available NAATs for C. trachomatis and N. gonorrhoeae are not cleared by the U.S. Food and Drug Administration (FDA) for urine, vaginal, or rectal specimens collected in nonclinical settings. However, some laboratories have established performance specifications for testing specimens collected in nonclinical settings to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. The FDA has not cleared commercially available NAATs to test rectal specimens for gonorrhea and chlamydial infection or oropharyngeal specimens for gonorrhea. However, some laboratories have established performance specifications for testing these types of specimens to meet requirements of the Clinical Laboratory Improvement Act for reporting test results for clinical management. Screening for vaginal trichomoniasis is not performed in nonclinical settings. b The first federal guidance in Appendix A, Section 9, indicates CDC-recommended tests. # Section 10. Reproductive Health Care for Women and Men Background Reproductive health care involves several essential services for adolescents and adults with HIV who are of reproductive age and wish to prevent unplanned pregnancies or reduce the risk of sexual HIV transmission when attempting conception. Nonclinical providers working outside of health care facilities may provide important information, education, and referral for these services to individuals, HIV-concordant couples (in which both members are HIV-infected), or HIV-discordant couples (in which only one member is infected). For example, nonclinical providers can refer clients who want to prevent or delay pregnancy to contraceptive services and refer clients who want to conceive to health care providers who are familiar with special conception methods that reduce the risk of HIV transmission. Other sections in this Summary address methods-including use of ART-to prevent sexual or perinatal transmission of HIV during recognized pregnancies of HIV-infected women or HIV-uninfected women who have partners with HIV (Section 11); linkage to HIV medical care (Section 4), general aspects of use of ART by persons with HIV and antiretroviral prophylaxis by HIV-uninfected partners (Section 5); ART adherence (Section 6); methods to reduce sexual transmission of HIV (Section 7); services for sex partners of persons with HIV (Section 8); and quality improvement and program evaluation (Section 13). Persons who do not wish to conceive ■ Provide education, reproductive health counseling, or make referral for contraceptive services as appropriate to provider role and setting to women and men who wish to prevent or delay future pregnancy # Recommendations # Provide services ■ Assess pregnancy status of HIV-infected women and reproductive plans of women and men with HIV, with methods and frequency as appropriate to provider role and setting (e.g., self-reported pregnancy or referral for pregnancy testing) ■ Offer periodic HIV testing to HIV-uninfected members of HIV-discordant couples, particularly those who are attempting conception or who report unprotected intercourse Note: Some topics may only be suited for nonclinical providers with appropriate skills and training. # Section 11. HIV Prevention Related to Pregnancy Background Pregnant women with HIV can transmit HIV to their fetuses and newborns if they do not use effective prevention strategies. The physiologic state of pregnancy can also increase the risk of sexual HIV transmission from HIV-infected pregnant women to uninfected male partners as well as from HIV-infected male partners to uninfected pregnant women. Nonclinical providers working outside of health care facilities can offer a variety of preventive services that can prevent HIV transmission from HIV-infected women with recognized pregnancies and can prevent HIV transmission to pregnant HIV-uninfected women who have HIV-infected sex or drug injection partners. These include providing information about methods to prevent HIV transmission during pregnancy, linking pregnant women with HIV to pregnancy care, and offering HIV testing to pregnant women and their partners. Other sections in this Summary address linking pregnant women to HIV medical care (Section 4); general aspects of antiretroviral treatment (ART) for persons with HIV and prophylaxis for HIV-uninfected partners (Section 5); general aspects of ART adherence (Section 6); behavioral risk-reduction interventions suited to HIV-infected partners of pregnant women (Section 7); notification of sex and drug-injection partners of pregnant women with HIV or of HIV-uninfected pregnant women (Section 8); screening pregnant women for sexually transmitted disease (STD) services (Section 9); contraception services and reproductive health counseling that can be offered after delivery (Section 10); and quality improvement and program evaluation (Section 13). ■ Advise women to urge sex partners and drug-injection partners to get HIV testing and to use condoms to prevent HIV acquisition ■ Provide education, counseling and/or referral for postpartum contraception services to all women who wish to prevent or delay future pregnancy, as appropriate to the setting ■ Inform women and their partners that breastfeeding by HIV-infected women is not recommended in the United States and that formula feeding is recommended for the infants of these women # Recommendations # Specific prenatal services ■ Promptly link women to HIV medical care, preferably to settings where providers have expertise in managing pregnancy in women with HIV ■ Support adherence to antiretroviral treatment (ART) during the prenatal and postnatal periods for optimal maternal health and prevention of perinatal and sexual transmission ■ Offer latex or polyurethane male and/or female condoms ■ Offer women support, information, and assistance to notify their sex and druginjection partners about their HIV status Note: A woman with HIV must explicitly grant her provider permission to discuss her HIV infection status with her partners. Staff not trained in new encounter form reminder were least likely to provide information or referral for partner services Act ■ Trained 100% of staff on new partner services procedures ■ Revised reminder system to automatically print partner services information for all newly diagnosed clients before check out. Source: Adapted from the chapter on "Quality Improvement" in the second guidance document in Appendix A, Section 13.	None	None
42b072e101ab6f552645692c330e397f47e0fb56	cdc	None	The Advisory Committee on Immunization Practices (ACIP) provides advice and guidance regarding effective control of vaccine-preventable diseases, including guidance for special populations that might warrant modification of routine recommendations (1). One such special population is pregnant and breastfeeding women. Formulation of recommendations for vaccination of pregnant and breastfeeding women is challenging because the available scientific evidence needed to guide decisions is limited. To promote use of a consistent process and uniform terminology, the ACIP Workgroup on Vaccines during Pregnancy and Breastfeeding was established in 2007 to develop guiding principles for drafting of ACIP recommendations for vaccination of pregnant and breastfeeding women. Workgroup members included ACIP members, members of professional medical organizations, experts in the field, and CDC consultants. During April 2007--March 2008, the workgroup reviewed existing policies on use of vaccines in pregnant and breastfeeding women. On the basis of this review, opinions of workgroup members, and feedback from partner organizations, the workgroup prepared the document Guiding Principles for Development of ACIP Recommendations for Vaccination during Pregnancy and Breastfeeding, which was approved by ACIP in March 2008. This document provides guidance to help standardize procedures for policy formulation and presentation of the rationale and recommendations for vaccination of pregnant and breastfeeding women. Topics in Guiding Principles include 1) guidance for structure of the background section, 2) guidance for structure and language of recommendations, 3) clarification of the definitions of precautions and contraindications in the context of pregnant and breastfeeding women, 4) suggestions for approaches to policy decision-making in the absence of adequate data, and 5) description of a consistent process to gather expert opinion. These principles will be applied to future ACIP vaccine statements and routine updates of existing statements in which vaccination of pregnant and breastfeeding women is considered. Guiding Principles is available at . References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication. All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version () and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices. Questions or messages regarding errors in formatting should be addressed to [email protected].	# The Advisory Committee on Immunization Practices (ACIP) provides advice and guidance regarding effective control of vaccine-preventable diseases, including guidance for special populations that might warrant modification of routine recommendations (1). One such special population is pregnant and breastfeeding women. Formulation of recommendations for vaccination of pregnant and breastfeeding women is challenging because the available scientific evidence needed to guide decisions is limited. To promote use of a consistent process and uniform terminology, the ACIP Workgroup on Vaccines during Pregnancy and Breastfeeding was established in 2007 to develop guiding principles for drafting of ACIP recommendations for vaccination of pregnant and breastfeeding women. Workgroup members included ACIP members, members of professional medical organizations, experts in the field, and CDC consultants. During April 2007--March 2008, the workgroup reviewed existing policies on use of vaccines in pregnant and breastfeeding women. On the basis of this review, opinions of workgroup members, and feedback from partner organizations, the workgroup prepared the document Guiding Principles for Development of ACIP Recommendations for Vaccination during Pregnancy and Breastfeeding, which was approved by ACIP in March 2008. This document provides guidance to help standardize procedures for policy formulation and presentation of the rationale and recommendations for vaccination of pregnant and breastfeeding women. Topics in Guiding Principles include 1) guidance for structure of the background section, 2) guidance for structure and language of recommendations, 3) clarification of the definitions of precautions and contraindications in the context of pregnant and breastfeeding women, 4) suggestions for approaches to policy decision-making in the absence of adequate data, and 5) description of a consistent process to gather expert opinion. These principles will be applied to future ACIP vaccine statements and routine updates of existing statements in which vaccination of pregnant and breastfeeding women is considered. Guiding Principles is available at http://www.cdc.gov/vaccines/recs/acip/downloads/preg-principles05-01-08.pdf. References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication. All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr) and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices. **Questions or messages regarding errors in formatting should be addressed to [email protected].	None	None
16f0c54cb7e1a2578a01cd988a025783ce857a39	cdc	None	A community should review these recommendations and develop its own response before the onset of a suicide cluster. The response to the crisis should involve all concerned sectors of the community and should be coordinated by: A. Coordinating Committee, which manages the day-to-day response to the crisis, and B. Host Agency, whose responsibilities would include "housing" the plan, monitoring the incidence of suicide, and calling meetings of the Coordi nating Committee when necessary.# If the response plan is to be implemented, the first step should be to contact and prepare those groups who will play key roles in the first days of the response. The response should be conducted in a manner that avoids glorification of the suicide victims and minimizes sensationalism. Persons who may be at high risk of suicide should be identified and have at least one screening interview with a trained counselor; these persons should be referred for further counseling or other services as needed. A timely flow of accurate, appropriate information should be provided to the media. Elements in the environment that might increase the likelihood of further suicides or suicide attempts should be identified and changed. Long-term issues suggested by the nature of the suicide cluster should be addressed. # INTRODUCTION Recent suicide clusters among teenagers and young adults have received national attention, and public concern about this issue is growing. Unfortunately, our under standing of the causes and means of preventing suicide clusters is far from complete. A suicide cluster may be defined as a group of suicides or suicide attempts, or both, that occur closer together in time and space than would normally be expected in a given community. A statistical analysis of national mortality data indicates that clusters of completed suicide occur predominantly among adolescents and young adults, and that such clusters account for approximately 1%-5% of all suicides in this age group (7). Suicide clusters are thought by many to occur through a process of "contagion," but this hypothesis has not yet been formally tested (2,3). Nevertheless, a great deal of anecdotal evidence suggests that, in any given suicide cluster, suicides occurring later in the cluster often appear to have been influenced by suicides occurring earlier in the cluster. Ecologic evidence also suggests that exposure of the general population to suicide through television may increase the risk of suicide for certain susceptible individuals (4,5), although this effect has not been found in all studies (5,7). The Centers for Disease Control (CDC) has assisted several state and local health departments in investigating and responding to apparent clusters of suicide and suicide attempts. These clusters created a crisis atmosphere in the communities in which they occurred and engendered intense concern on the part of parents, students, school officials, and others. In the midst of these clusters of suicides or suicide attempts, community leaders were faced with the simultaneous tasks of trying to prevent the cluster from expanding and trying to manage the crisis that already existed. Potential opportunities for prevention were often missed during the early stages of response as community leaders searched for information on how best to respond to suicide clusters. The recommendations contained in this report were developed to assist commu nity leaders in public health, mental health, education, and other fields to develop a community response plan for suicide clusters or for situations that might develop into suicide clusters. A workshop for developing these recommendations was jointly sponsored by the New Jersey State Department of Health and CDC on November 1987, in Newark, New Jersey.- Participants in that workshop included persons who had played key roles in community responses to nine different suicide clusters. They were from a variety of different sectors including education, medicine, local government, community mental health, local crisis centers, and state public health and mental health. Also participating in this workshop were representatives from the National Institute of Mental Health (NIMH), the Indian Health Service (IHS), the American Association of Suicidology (AAS), and the Association of State and Territorial Health Officials (ASTHO). These recommendations should not be considered explicit instructions to be followed by every community in the event of a suicide cluster. Rather, they are meant to provide community leaders with a conceptual framework for developing their own suicide-cluster-response plans, adapted to the particular needs, resources, and cultural characteristics of their communities. These recommendations will be revised periodically to reflect new knowledge in the field of suicide prevention and experience acquired in using this plan. Certain elements of the proposed plan for the prevention and containment of suicide clusters are quite different from those of crisis-response plans for other community emergencies. These differences are primarily attributable to the poten tially contagious nature of suicidal behavior and to the stigma and guilt often associated with suicide. Other elements of the proposed plan, however, are germane to crisis-response plans in general. Therefore, state and local health planners might consider whether the plan they develop from these recommendations should be integrated into existing guidelines for managing other emergencies or mental health crises. # I. A community should review these recommendations and develop its -wn response plan before the onset of a suicide cluster. Comment. When a suicide cluster is occurring in a com m unity-or when such a cluster seems about to occur-several steps in our recommended response plan should be taken right away. If such a timely reaction is to be possible, the response plan must necessarily already be developed, agreed upon, and understood by all the participants at the onset of the crisis. The recommended response requires a great deal of coordination among various sectors of the community. Such coordination is sometimes difficult to establish at the best of times and may be even more difficult to establish in the face of a crisis. In the early days of an evolving suicide cluster there has typically been a great deal of confusion. There is often a sense of urgency in the community that something needs to be done to prevent additional suicides, but there has usually been little initial coordination of effort in this regard. Moreover, community members often disagree about precisely what should be done to prevent a cluster from expanding. In almost every case, communities ultimately develop some sort of plan for responding to the crisis in a coordinated manner, but opportunities for prevention are often missed in the crucial first hours of the response. # II. The response to the crisis should involve all concerned sectors of the community and should be coordinated as follows: A. Individuals from concerned agencies-education, public health, mental health, local government, suicide crisis centers, and other appropriate agenciesshould be designated to serve on a coordinating committee, which would be responsible for deciding when the response plan should be implemented and coordinating its implementation. B. One agency should be designated as the "h ost" agency for the plan. The individual representing that agency would have the following responsibilities: 1. Call the initial meeting of the coordinating committee before any crisis occurs so that these recommendations can be incorporated into a plan that reflects the particular resources and needs of the community (see Section III, below). 2. Establish a notification mechanism by which the agency would be made aware of a potentially evolving suicide cluster (see Comment, below). 3. Convene the coordinating committee when it appears that a suicide cluster is occurring, or when it is suspected that a cluster may occur due to the influence of one or more recent suicides or other traumatic deaths (see Section IV, below). At this initial meeting, the members of the coordinating committee could decide whether to implement the community response plan and how extensive the response needs to be. 4. Maintain the suicide-cluster-response plan. The coordinating committee should meet periodically to assure that the plan remains operational. 5. Revise the community plan periodically to reflect new knowledge in the field of suicide prevention, the community's experiences in using the plan, and changes in the community itself. Comment. Every effort should be made to promote and implement the proposed plan as a community endeavor. During past suicide clusters, a single agency has often found itself "in the hot seat," that is, as the focal point of demands that something be done to contain the suicide cluster. No single agency, however, has the resources or expertise to adequately respond to an evolving suicide cluster. Moreover, the emergence of one agency as the sole focus for responding to an apparent suicide cluster has several unfortunate consequences. The agency and its representatives run the danger of becoming scapegoats for a community's fear and anger over the apparent cluster. Such a focus can potentially blind a community to other valuable M M W R August 19,1988 resources for responding to the crisis and to basic community problems that may have engendered the crisis. The concept of a "h ost" agency was developed because-even though the response will involve a variety of different agencies and community groups-one person must necessarily take responsibility for establishing a notification mechanism, maintaining the response plan, and calling meetings of the coordinating committee as outlined above. Which agency should serve as the host agency should be decided by each community. In past clusters, for example, a school district, a municipal government, a mental health association, and even a private, nonprofit mental health center have taken the lead in organizing their community's response. State or local public health or mental health agencies might also serve as host agencies for the plan. The role of host agency might also be rotated among the various agencies represented on the coordinating committee. The notification mechanism by which the host agency would be made aware of a potentially evolving suicide cluster would vary from community to community. In small communities, one death of a teenager by suicide might be unusual, and in ormation about the death would be quickly transmitted to a county-level host agency. In some large communities, however, there are many suicides each year 0un® Persons' Clearly, a more formal system would be needed in such a in "T J ? not,^. t^e ^ost agency when an unusual number of suicides had occurred in a particular high school or municipality. d^^n9,Wh0ther t0 'mP,ement the response plan is not an all-or-nothing what AYtont ,mPortant Unction of the coordinating committee is to decide to cluQtftmf e - H P an W/ 1 be ' mP,0mented. In situations in which it is feared that a miaht ho r. UI-*1 6 8 b e abc)V- t0 start' f°r example, the implementation of the plan rhcic th - C,UI f Subt e and limited, whereas in the event of a full-blown community crisis the implementation should be more extensive. # III. The relevant community resources should be identified. In addition to the agencies represented on the coordinating committee, the community should also seek to identify and enlist help from other community resources, including (but not limited to): a) hospitals and emergency departments b) emergency medical services c) local academic resources d) clergy e) parents groups (e.g., PTA) f) suicide crisis centers/hotlines g) survivor groups h) students i) police j) media k) representatives of education, public health, mental health, and local government, if not already represented on the coordinating committee Comment. The roles of each of the above groups should be defined as clearly as possible in the response plan before any crisis occurs. These roles should be agreed upon and reviewed by persons representing those groups. Most of those involved in the response will already know how to perform their particular duties. However, appropriate training for the staff of these groups should be provided as necessary (8 ). For example, if it is deemed desirable to conduct surveillance for suicide attempts through hospital emergency departments, officials at the state or local public health department might help design the system and train the emergency department staff. Other potential resources for training and counseling include state and local mental health agencies, mental health and other professional associations, and suicide crisis centers. It is particularly important that representatives of the local media be included in developing the plan. In at least one community faced with a suicide cluster, the media collaborated in preparing voluntary guidelines for reporting suicide clusters. Al though frequently perceived to be part of the problem, the media can be part of the solution. If representatives of the media are included in developing the plan, it is far more likely that their legitimate need for information can be satisfied without the sensationalism and confusion that has often been associated with suicide clusters. The following example representing a composite of several actual suicide clusters illustrates the need for inclusion of and cooperation among many community organizations. Suppose that two high school students from the same school commit suicide in separate incidents on a weekend during the regular school year. The coordinating committee decides that these two deaths may increase the risk of suicide or attempted suicide among other students. The responsibilities of some of the relevant community resources might be as follows: School officials might be responsible for announcing the deaths to the students in an appropriate manner (discussed below, Section VI). School counselors and teachers might assist in identifying any students whom they think are at high risk; students in the school might also help in this regard. The local mental health agency might provide counselors to work with troubled students, as well as supply training and support for the teachers. Emergency departments of community hospitals might set up a suicide-attempt surveillance system that would increase the sensitivity with which suicide attempters were identified and would ensure proper referral of the attempters for counseling. Hotlines might help identify potential suicide attempters, and police might assist in locating such persons when appropriate. Police may also help by identifying and maintaining contact with such high-risk persons as high school dropouts and those with a history of delinquency. Local government or public health authorities might help coordinate these various efforts, if so designated by the coordinating committee. # IV. The response plan should be implemented under either of the following two conditions: A. When a suicide cluster occurs in the community; that is, when suicides or attempted suicides occur closer together in space and time than is considered by members of the coordinating committee to be usual for their community; -OR -B. When one or more deaths from trauma occur in the community (especially among adolescents or young adults) which the members of the coordinating committee think may potentially influence others to attempt or complete suicide. Comment. It is difficult to define a "suicide cluster" explicitly. Clearly, both the number and the degree of "closeness" of cases of suicide in time and space that M MW R August 19, 1988 would constitute a suicide cluster vary depending on the size of the community and on its background incidence of suicide. But when a community considers that it is facing a cluster of suicides, it is essentially irrelevant whether the incident cases of suicide meet some predefined statistical test of significance. With the suddenly heightened awareness of and concern about suicide in such a community, steps should be taken to prevent further suicides that may be caused in part by the atmosphere, or "contagion," of the crisis. In several clusters of suicides or suicide attempts, the crisis situation was preceded by one or more traumatic deaths-intentional or unintentional-among the youth of the community. For example, in the 9 months preceding one cluster of four suicides and two suicide attempts among persons 15-24 years of age, there were four traumatic deaths among persons in the same age group and com m unity-tw o from unintentional injuries, one from suicide, and one of undetermined intentionality. One of the unintentional-injury deaths was caused by a fall from a cliff. Two of the persons who later committed suicide in the cluster had been close friends of this fall victim; one of the two had witnessed the fall. The hypothesis that a traumatic death can kindle a suicide cluster regardless of whether it is caused by intentional or unintentional injuries has not yet been tested. Nevertheless, the available anecdotal evidence suggests that some degree of imple mentation of the response plan be considered when a potentially influential traumatic death occurs in the community-especially if the person who dies is an adolescent or young adult. We should emphasize that the fear of a contagious effect of suicide is not the only reason to implement this plan. For example, suppose that in the wake of some local economic downturn a community noted an excess of suicide deaths among persons who had been laid off from work. This would be a suicide cluster, and it would be entirely appropriate for the coordinating committee to implement the response plan. It is irrelevant that the suicides are not apparently related to contagion from previous suicides but to a "common-source" problem, since there is an identified population (laid-off workers) potentially at a suddenly increased risk of suicide. Whether and when to implement the response plan should be determined by the coordinating committee. At this stage of our understanding of suicide clusters, we cannot specify that the response plan should be implemented only under a particular list of circumstances. Until further scientific investigation and experience with suicide clusters provides us with a more empirical basis for deciding when to implement the response plan, we must rely on prudent judgments by community leaders regarding the potential for further suicides in their communities. V. If the response plan is to be implemented, the first step should be to contact and prepare the various groups identified above. A. Immediately notify those who will play key roles in the crisis response of the deaths that prompted the implementation of the response plan (if they are not already aware of them). B. Review the respective responsibilities and tasks with each of these key players. C. Consider and prepare for the problems and stresses that these persons may encounter-burnout, feelings of guilt if new suicides occur, and the like-as they carry out their assigned tasks. Comment. Timely preparation of the groups involved is critical. In a past cluster that began with a scenario similar to that described in Section III above, the teachers and the students both heard about the suicide deaths at the same time over the school loudspeaker. The teachers were entirely unprepared to deal with the emotional response of the students and did not know what to say to them or where to refer those who were most upset. It would have been far preferable to have called a pre-school meeting with the teachers to outline the problem, discuss the appropriate roles of the teachers, and announce the various resources that were available (9). Support staff at the school -secretaries, bus drivers, janitors, nurses, and others-m ight also have been included at the meeting. Such preparation could have been of enormous help in several past suicide clusters. # VI. The crisis response should be conducted in a manner that avoids glorifying the suicide victims and minimizes sensationalism. A. Community spokespersons should present as accurate a picture as possible of the decedent(s) to students, parents, family, media, and others (see Section VIII, below). B. If there are suicides among persons of school age, the deaths should be announced (if necessary) in a manner that will provide maximal support for the students while minimizing the likelihood of hysteria. Comment. Community spokespersons should avoid glorifying decedents or sensa tionalizing their deaths in any way (5). To do so might increase the likelihood that someone who identifies with the decedents or who is having suicidal thoughts will also attempt suicide, so as to be similarly glorified or to receive similar positive attention. One community that had had several suicides among high school students installed a "memorial bench" on the school grounds, with the names of the suicide victims engraved on the bench. Although this gesture was undoubtedly intended to demonstrate sincere compassion, such a practice is potentially very dangerous. Spokespersons should also avoid vilifying the decedents in an effort to decrease the degree to which others might identify with them. In addition to being needlessly cruel to the families of the decedents, such an approach may only serve to make those who do identify with the decedents feel isolated and friendless. If the suicide victims are of school age, the deaths should be announced privately to those students who are most likely to be deeply affected by the tragedy-close friends, girl friends, boy friends, and the like. After the teachers are briefed (see Section V), the suicide deaths might be announced to the rest of the students either by individual teachers or over the school loudspeaker when all the students are in homeroom or some other similarly small, supervised groups. Funeral services should not be allowed to unnecessarily disrupt the regular school schedule. # VII. Persons who may be at high risk should be identified and have at least one screening interview with a trained counselor; these persons should be referred for further counseling or other services as needed. A. Active measures: 1. Identify relatives (siblings, parents, children) of the decedents and provide an opportunity for them to express their feelings and to discuss their own thoughts about suicide with a trained counselor. 2. Similarly, identify and provide counseling for boy friends/girl friends, close friends, and fellow employees who may be particularly affected by the deaths. a) Strategies to identify associates of the decedents or others who may be at increased risk of suicide might include: identifying the pall bearers at the funeral services of the decedent(s); checking with the funeral director regarding visitors who seemed particularly troubled at the services; keeping a list of hospital visitors of suicide attempters; and verifying the status of school absentees in the days following the suicide of a student. 3. In the case of suicides among school-age persons, enlist the aid of teachers and students in identifying any students whom they think may be at increased risk of suicide. 4. Identify and refer past and present suicide attempters for counseling if these persons were substantially exposed to suicide (see below), regardless of whether they were close friends of the decedents. a) "Substantially exposed" persons would include, for example, students in the same high school or workers at the same job location as the suicide victims. In past suicide clusters, such persons have committed or attempted suicide even though they did not personally know the victims who had committed suicide earlier in the cluster. 1. Consider establishing hotlines or walk-in suicide crisis centers-even tem porarily-if they do not already exist in the community; announce the availability of such hotlines/centers. 2. Provide counselors at a particular site (such as school, church, community center) and announce their availability for anyone troubled by the recent deaths. a) If suicides have occurred among school-age persons, provide counse lors in the schools if possible; announce their availability to the students. 3. Enlist the local media to publish sources of help-hotlines, walk-in centers, community meetings, and other similar sources. 4. Make counseling services available to persons involved in responding to the crisis as well. Comment. The recommendations for active measures to identify persons at high risk of suicide are based largely on scientific evidence that certain factors increase the risk of suicide. For example, mental illness (especially depressive illness) (10) and a history of past suicide attempts (11) are both strong risk factors for suicide. Certain sociologic factors such as unemployment (12), being widowed or divorced ( 13,14), other bereavement (15,16), and mobility (17), also appear to be important risk factors for suicide. The role of imitation or "contagion" is, as we noted above, less well-established than the risk factors listed above. Nevertheless, the anecdotal evidence from suicide clusters is quite compelling, and several of the specific suggestions made above regarding who should be considered for screening are based on such evidence. For example, in one high school-based cluster, two persons who committed suicide late in the cluster had been pall bearers at the funerals of suicide victims who had died earlier in the cluster. It is likely that persons who are exposed to one or more of the aforementioned risk factors-depression or recent loss, for exam ple-m ay be more susceptible to a contagious effect of suicide. # VIII. A timely flow of accurate, appropriate information should be provided to the media. A. Make certain that a single account of the situation is presented by appointing one person as information coordinator. This person's duties would include: 1. meeting frequently with designated media spokespersons (see Section Vlll-B, below) to share news and information, and to make certain that the spokespersons share a common understanding of the current situation 2. "directing traffic"-referring requests for particular types of information to selected media spokespersons or to others (e.g., academic resources) 3. maintaining a list of local and national resources for appropriate referral of media inquiries 4. scheduling and holding press conferences. B. Appoint a single media spokesperson from each of the relevant community sectors-public health, education, mental health, local government, and the like. 1. Each sector represented on the coordinating committee should have a spokesperson. This person is not necessarily the same representative who serves on the coordinating committee. 2. Spokespersons from additional agencies or public groups may be desig nated as appropriate. C. These spokespersons should provide frequent, timely access to the media and present a complete and honest picture of the pertinent events. When appropriate, regularly scheduled press conferences should be held. 1. Avoid "whitewashing" -that is, saying that everything is under control or giving other assurances that may later prove unwarranted. This practice would undermine the credibility of the community spokespersons. 2. Discuss the positive steps being taken, and try to get the media to help in the response by reporting where troubled persons can go for help. D. The precise nature of the methods used by decedent(s) in committing suicide should not be disclosed. For example, it is accurate to state that an individual committed suicide by carbon monoxide poisoning. But it is not necessary-and is potentially very dangerous-to explain that the decedent acquired a hose from a hardware store, that s/he hooked it up to the tail pipe of a car, and then sat in a car with its engine running in a closed garage at a particular address. Such revelations can only make imitative suicides more likely and are unnecessary to a presentation of the manner of death. E. Enlist the support of the community in referring all requests for information to these spokespersons. # M M W R August 19,1988 Comment. If some suicide clusters spread through "contagion," the vehicle for such contagion is information, perhaps sensationalized information, about the suicides that have occurred. The role of the media in causing or exacerbating a suicide cluster is controversial, but some investigators will no longer even discuss an evolving suicide cluster with media representatives for fear that newspaper or television accounts will lead to further suicides. Although a definitive understanding of this issue must be left to future research, it is prudent in the meantime to try to prevent needlessly sensationalized or distorted accounts of evolving suicide clusters. The media spokespersons should meet as a group and with the information coordinator regularly; under certain circumstances, they may need to check with each other several times a day. Gaining the cooperation of the community in referring requests to these spokespersons is a formidable task and will require early and ongoing efforts if it is to be accomplished. It may be helpful to assure community members that it is all right to say "n o " to media phone calls or requests for interviews. The cooperation of parents is especially essential in the context of a school-based suicide cluster. Interviews with students about the suicide of one or more of their peers can be very stressful. Parents who do not wish to have their children interviewed may be able to prevent such interviews by refusing to sign a release statement. A handout addressing how media requests should be handled might be prepared and distributed to parents, students, and other appropriate persons. Gaining the cooperation of media representatives in this regard is also a formidae task. In the midst of a crisis, the frequent presentation of accurate and credible in ormation is the best means of establishing such cooperation. It is preferable, owever, to develop a working relationship with local media representatives before a crisis occurs. # IX. Elements in the environment that might increase the likelihood of urther suicides or suicide attempts should be identified and changed. Comment. If a particular method or site was used in previous suicides or suicide attempts, modification efforts should be addressed to these methods or sites first. For example, if the decedent(s) jumped off a particular building, bridge, or cliff, barriers might be erected to prevent other such attempts. If the decedent(s) committed suicide by carbon monoxide poisoning in a particular garage, access to that garage should be limited or monitored or both. If the decedent(s) committed suicide with a firearm or by taking an overdose of drugs, then restricting immediate access to firearms or to potentially lethal quantities of prescription drugs should be considered. In the case of suicides committed in jail, belts and other articles that may be used to commit suicide by hanging should be removed, and vigilance over the jail cells should be increased. Some of these modifications can be accomplished directly through the efforts of the coordinating committee, while others (limiting access to drugs or firearms) can only be suggested by the committee for others to consider. Although immediate environmental modifications may be suggested by methods used in previous suicides, the modifications need not be limited only to those methods. If there is concern, for example, that the risk of suicide for particular adolescents may have been increased because of the influence of previous traumatic deaths, then common methods of suicide-firearm injury, carbon monoxide poison ing,overdose-should be made temporarily unavailable if possible. The coordinat ing committee should consider a variety of potentially relevant environmental factors in developing this element of the response strategy. X. Long-term issues suggested by the nature of the suicide cluster should be addressed. Comment. Common characteristics among the victims in a given suicide cluster may suggest that certain issues need to be addressed by the community. For example, if the decedent(s) in a particular suicide cluster tended to be adolescents or young adults who were outside the main stream of community life, efforts might be made to bring such persons back into the community. Or, if a large proportion of the suicide attempters or completers had not been suspected of having any problems, then a system should be developed (or the present system altered) so that troubled persons could receive help before they reached the stage of overt suicidal behavior. Communities should consider establishing a surveillance system for suicide attempts as well as completed suicides. Suicide-attempt surveillance systems are almost nonexistent; yet the benefits of such systems are potentially great. In the context of a suicide cluster, such a system would allow persons who have attempted suicide in the past to be identified. Such persons are known to be at high risk of further suicide attempts. It would also allow for ongoing identification of high-risk persons during and after the current crisis. Communities should consider establishing suicide-attempt surveillance systems in their local emergency departments or wher ever appropriate. This plan should be modified according to the community's experience with its operation. Parts of the plan that have worked well in a given setting should be stressed in the updated plan, and parts that were inapplicable or that did not work should be excluded. Finally, the Centers for Disease Control requests that communi ties that use the plan notify us of their experiences with the plan to allow appropriate updating of this document. Please write to: Chief, Intentional Injuries Section Mailstop F-36 Centers for Disease Control 1600 Clifton Road NE Atlanta, GA 30333	A community should review these recommendations and develop its own response before the onset of a suicide cluster. The response to the crisis should involve all concerned sectors of the community and should be coordinated by: A. Coordinating Committee, which manages the day-to-day response to the crisis, and B. Host Agency, whose responsibilities would include "housing" the plan, monitoring the incidence of suicide, and calling meetings of the Coordi nating Committee when necessary.# If the response plan is to be implemented, the first step should be to contact and prepare those groups who will play key roles in the first days of the response. The response should be conducted in a manner that avoids glorification of the suicide victims and minimizes sensationalism. Persons who may be at high risk of suicide should be identified and have at least one screening interview with a trained counselor; these persons should be referred for further counseling or other services as needed. A timely flow of accurate, appropriate information should be provided to the media. Elements in the environment that might increase the likelihood of further suicides or suicide attempts should be identified and changed. Long-term issues suggested by the nature of the suicide cluster should be addressed. # INTRODUCTION Recent suicide clusters among teenagers and young adults have received national attention, and public concern about this issue is growing. Unfortunately, our under standing of the causes and means of preventing suicide clusters is far from complete. A suicide cluster may be defined as a group of suicides or suicide attempts, or both, that occur closer together in time and space than would normally be expected in a given community. A statistical analysis of national mortality data indicates that clusters of completed suicide occur predominantly among adolescents and young adults, and that such clusters account for approximately 1%-5% of all suicides in this age group (7). Suicide clusters are thought by many to occur through a process of "contagion," but this hypothesis has not yet been formally tested (2,3). Nevertheless, a great deal of anecdotal evidence suggests that, in any given suicide cluster, suicides occurring later in the cluster often appear to have been influenced by suicides occurring earlier in the cluster. Ecologic evidence also suggests that exposure of the general population to suicide through television may increase the risk of suicide for certain susceptible individuals (4,5), although this effect has not been found in all studies (5,7). The Centers for Disease Control (CDC) has assisted several state and local health departments in investigating and responding to apparent clusters of suicide and suicide attempts. These clusters created a crisis atmosphere in the communities in which they occurred and engendered intense concern on the part of parents, students, school officials, and others. In the midst of these clusters of suicides or suicide attempts, community leaders were faced with the simultaneous tasks of trying to prevent the cluster from expanding and trying to manage the crisis that already existed. Potential opportunities for prevention were often missed during the early stages of response as community leaders searched for information on how best to respond to suicide clusters. The recommendations contained in this report were developed to assist commu nity leaders in public health, mental health, education, and other fields to develop a community response plan for suicide clusters or for situations that might develop into suicide clusters. A workshop for developing these recommendations was jointly sponsored by the New Jersey State Department of Health and CDC on November [16][17]1987, in Newark, New Jersey.* Participants in that workshop included persons who had played key roles in community responses to nine different suicide clusters. They were from a variety of different sectors including education, medicine, local government, community mental health, local crisis centers, and state public health and mental health. Also participating in this workshop were representatives from the National Institute of Mental Health (NIMH), the Indian Health Service (IHS), the American Association of Suicidology (AAS), and the Association of State and Territorial Health Officials (ASTHO). These recommendations should not be considered explicit instructions to be followed by every community in the event of a suicide cluster. Rather, they are meant to provide community leaders with a conceptual framework for developing their own suicide-cluster-response plans, adapted to the particular needs, resources, and cultural characteristics of their communities. These recommendations will be revised periodically to reflect new knowledge in the field of suicide prevention and experience acquired in using this plan. Certain elements of the proposed plan for the prevention and containment of suicide clusters are quite different from those of crisis-response plans for other community emergencies. These differences are primarily attributable to the poten tially contagious nature of suicidal behavior and to the stigma and guilt often associated with suicide. Other elements of the proposed plan, however, are germane to crisis-response plans in general. Therefore, state and local health planners might consider whether the plan they develop from these recommendations should be integrated into existing guidelines for managing other emergencies or mental health crises. # I. A community should review these recommendations and develop its own response plan before the onset of a suicide cluster. Comment. When a suicide cluster is occurring in a com m unity-or when such a cluster seems about to occur-several steps in our recommended response plan should be taken right away. If such a timely reaction is to be possible, the response plan must necessarily already be developed, agreed upon, and understood by all the participants at the onset of the crisis. The recommended response requires a great deal of coordination among various sectors of the community. Such coordination is sometimes difficult to establish at the best of times and may be even more difficult to establish in the face of a crisis. In the early days of an evolving suicide cluster there has typically been a great deal of confusion. There is often a sense of urgency in the community that something needs to be done to prevent additional suicides, but there has usually been little initial coordination of effort in this regard. Moreover, community members often disagree about precisely what should be done to prevent a cluster from expanding. In almost every case, communities ultimately develop some sort of plan for responding to the crisis in a coordinated manner, but opportunities for prevention are often missed in the crucial first hours of the response. # II. The response to the crisis should involve all concerned sectors of the community and should be coordinated as follows: A. Individuals from concerned agencies-education, public health, mental health, local government, suicide crisis centers, and other appropriate agenciesshould be designated to serve on a coordinating committee, which would be responsible for deciding when the response plan should be implemented and coordinating its implementation. B. One agency should be designated as the "h ost" agency for the plan. The individual representing that agency would have the following responsibilities: 1. Call the initial meeting of the coordinating committee before any crisis occurs so that these recommendations can be incorporated into a plan that reflects the particular resources and needs of the community (see Section III, below). 2. Establish a notification mechanism by which the agency would be made aware of a potentially evolving suicide cluster (see Comment, below). 3. Convene the coordinating committee when it appears that a suicide cluster is occurring, or when it is suspected that a cluster may occur due to the influence of one or more recent suicides or other traumatic deaths (see Section IV, below). At this initial meeting, the members of the coordinating committee could decide whether to implement the community response plan and how extensive the response needs to be. 4. Maintain the suicide-cluster-response plan. The coordinating committee should meet periodically to assure that the plan remains operational. 5. Revise the community plan periodically to reflect new knowledge in the field of suicide prevention, the community's experiences in using the plan, and changes in the community itself. Comment. Every effort should be made to promote and implement the proposed plan as a community endeavor. During past suicide clusters, a single agency has often found itself "in the hot seat," that is, as the focal point of demands that something be done to contain the suicide cluster. No single agency, however, has the resources or expertise to adequately respond to an evolving suicide cluster. Moreover, the emergence of one agency as the sole focus for responding to an apparent suicide cluster has several unfortunate consequences. The agency and its representatives run the danger of becoming scapegoats for a community's fear and anger over the apparent cluster. Such a focus can potentially blind a community to other valuable M M W R August 19,1988 resources for responding to the crisis and to basic community problems that may have engendered the crisis. The concept of a "h ost" agency was developed because-even though the response will involve a variety of different agencies and community groups-one person must necessarily take responsibility for establishing a notification mechanism, maintaining the response plan, and calling meetings of the coordinating committee as outlined above. Which agency should serve as the host agency should be decided by each community. In past clusters, for example, a school district, a municipal government, a mental health association, and even a private, nonprofit mental health center have taken the lead in organizing their community's response. State or local public health or mental health agencies might also serve as host agencies for the plan. The role of host agency might also be rotated among the various agencies represented on the coordinating committee. The notification mechanism by which the host agency would be made aware of a potentially evolving suicide cluster would vary from community to community. In small communities, one death of a teenager by suicide might be unusual, and in ormation about the death would be quickly transmitted to a county-level host agency. In some large communities, however, there are many suicides each year 0un® Persons' Clearly, a more formal system would be needed in such a in "T J ? not,^. t^e ^ost agency when an unusual number of suicides had occurred in a particular high school or municipality. d^^n9,Wh0ther t0 'mP,ement the response plan is not an all-or-nothing what AYtont ,mPortant Unction of the coordinating committee is to decide to cluQtftmf e • H P an W/ 1 be ' mP,0mented. In situations in which it is feared that a miaht ho r. UI-1 6 8 b e abc)V t0 start' f°r example, the implementation of the plan rhcic th • C,UI f Subt e and limited, whereas in the event of a full-blown community crisis the implementation should be more extensive. # III. The relevant community resources should be identified. In addition to the agencies represented on the coordinating committee, the community should also seek to identify and enlist help from other community resources, including (but not limited to): a) hospitals and emergency departments b) emergency medical services c) local academic resources d) clergy e) parents groups (e.g., PTA) f) suicide crisis centers/hotlines g) survivor groups h) students i) police j) media k) representatives of education, public health, mental health, and local government, if not already represented on the coordinating committee Comment. The roles of each of the above groups should be defined as clearly as possible in the response plan before any crisis occurs. These roles should be agreed upon and reviewed by persons representing those groups. Most of those involved in the response will already know how to perform their particular duties. However, appropriate training for the staff of these groups should be provided as necessary (8 ). For example, if it is deemed desirable to conduct surveillance for suicide attempts through hospital emergency departments, officials at the state or local public health department might help design the system and train the emergency department staff. Other potential resources for training and counseling include state and local mental health agencies, mental health and other professional associations, and suicide crisis centers. It is particularly important that representatives of the local media be included in developing the plan. In at least one community faced with a suicide cluster, the media collaborated in preparing voluntary guidelines for reporting suicide clusters. Al though frequently perceived to be part of the problem, the media can be part of the solution. If representatives of the media are included in developing the plan, it is far more likely that their legitimate need for information can be satisfied without the sensationalism and confusion that has often been associated with suicide clusters. The following example representing a composite of several actual suicide clusters illustrates the need for inclusion of and cooperation among many community organizations. Suppose that two high school students from the same school commit suicide in separate incidents on a weekend during the regular school year. The coordinating committee decides that these two deaths may increase the risk of suicide or attempted suicide among other students. The responsibilities of some of the relevant community resources might be as follows: School officials might be responsible for announcing the deaths to the students in an appropriate manner (discussed below, Section VI). School counselors and teachers might assist in identifying any students whom they think are at high risk; students in the school might also help in this regard. The local mental health agency might provide counselors to work with troubled students, as well as supply training and support for the teachers. Emergency departments of community hospitals might set up a suicide-attempt surveillance system that would increase the sensitivity with which suicide attempters were identified and would ensure proper referral of the attempters for counseling. Hotlines might help identify potential suicide attempters, and police might assist in locating such persons when appropriate. Police may also help by identifying and maintaining contact with such high-risk persons as high school dropouts and those with a history of delinquency. Local government or public health authorities might help coordinate these various efforts, if so designated by the coordinating committee. # IV. The response plan should be implemented under either of the following two conditions: A. When a suicide cluster occurs in the community; that is, when suicides or attempted suicides occur closer together in space and time than is considered by members of the coordinating committee to be usual for their community; -OR -B. When one or more deaths from trauma occur in the community (especially among adolescents or young adults) which the members of the coordinating committee think may potentially influence others to attempt or complete suicide. Comment. It is difficult to define a "suicide cluster" explicitly. Clearly, both the number and the degree of "closeness" of cases of suicide in time and space that M MW R August 19, 1988 would constitute a suicide cluster vary depending on the size of the community and on its background incidence of suicide. But when a community considers that it is facing a cluster of suicides, it is essentially irrelevant whether the incident cases of suicide meet some predefined statistical test of significance. With the suddenly heightened awareness of and concern about suicide in such a community, steps should be taken to prevent further suicides that may be caused in part by the atmosphere, or "contagion," of the crisis. In several clusters of suicides or suicide attempts, the crisis situation was preceded by one or more traumatic deaths-intentional or unintentional-among the youth of the community. For example, in the 9 months preceding one cluster of four suicides and two suicide attempts among persons 15-24 years of age, there were four traumatic deaths among persons in the same age group and com m unity-tw o from unintentional injuries, one from suicide, and one of undetermined intentionality. One of the unintentional-injury deaths was caused by a fall from a cliff. Two of the persons who later committed suicide in the cluster had been close friends of this fall victim; one of the two had witnessed the fall. The hypothesis that a traumatic death can kindle a suicide cluster regardless of whether it is caused by intentional or unintentional injuries has not yet been tested. Nevertheless, the available anecdotal evidence suggests that some degree of imple mentation of the response plan be considered when a potentially influential traumatic death occurs in the community-especially if the person who dies is an adolescent or young adult. We should emphasize that the fear of a contagious effect of suicide is not the only reason to implement this plan. For example, suppose that in the wake of some local economic downturn a community noted an excess of suicide deaths among persons who had been laid off from work. This would be a suicide cluster, and it would be entirely appropriate for the coordinating committee to implement the response plan. It is irrelevant that the suicides are not apparently related to contagion from previous suicides but to a "common-source" problem, since there is an identified population (laid-off workers) potentially at a suddenly increased risk of suicide. Whether and when to implement the response plan should be determined by the coordinating committee. At this stage of our understanding of suicide clusters, we cannot specify that the response plan should be implemented only under a particular list of circumstances. Until further scientific investigation and experience with suicide clusters provides us with a more empirical basis for deciding when to implement the response plan, we must rely on prudent judgments by community leaders regarding the potential for further suicides in their communities. V. If the response plan is to be implemented, the first step should be to contact and prepare the various groups identified above. A. Immediately notify those who will play key roles in the crisis response of the deaths that prompted the implementation of the response plan (if they are not already aware of them). B. Review the respective responsibilities and tasks with each of these key players. C. Consider and prepare for the problems and stresses that these persons may encounter-burnout, feelings of guilt if new suicides occur, and the like-as they carry out their assigned tasks. Comment. Timely preparation of the groups involved is critical. In a past cluster that began with a scenario similar to that described in Section III above, the teachers and the students both heard about the suicide deaths at the same time over the school loudspeaker. The teachers were entirely unprepared to deal with the emotional response of the students and did not know what to say to them or where to refer those who were most upset. It would have been far preferable to have called a pre-school meeting with the teachers to outline the problem, discuss the appropriate roles of the teachers, and announce the various resources that were available (9). Support staff at the school -secretaries, bus drivers, janitors, nurses, and others-m ight also have been included at the meeting. Such preparation could have been of enormous help in several past suicide clusters. # VI. The crisis response should be conducted in a manner that avoids glorifying the suicide victims and minimizes sensationalism. A. Community spokespersons should present as accurate a picture as possible of the decedent(s) to students, parents, family, media, and others (see Section VIII, below). B. If there are suicides among persons of school age, the deaths should be announced (if necessary) in a manner that will provide maximal support for the students while minimizing the likelihood of hysteria. Comment. Community spokespersons should avoid glorifying decedents or sensa tionalizing their deaths in any way (5). To do so might increase the likelihood that someone who identifies with the decedents or who is having suicidal thoughts will also attempt suicide, so as to be similarly glorified or to receive similar positive attention. One community that had had several suicides among high school students installed a "memorial bench" on the school grounds, with the names of the suicide victims engraved on the bench. Although this gesture was undoubtedly intended to demonstrate sincere compassion, such a practice is potentially very dangerous. Spokespersons should also avoid vilifying the decedents in an effort to decrease the degree to which others might identify with them. In addition to being needlessly cruel to the families of the decedents, such an approach may only serve to make those who do identify with the decedents feel isolated and friendless. If the suicide victims are of school age, the deaths should be announced privately to those students who are most likely to be deeply affected by the tragedy-close friends, girl friends, boy friends, and the like. After the teachers are briefed (see Section V), the suicide deaths might be announced to the rest of the students either by individual teachers or over the school loudspeaker when all the students are in homeroom or some other similarly small, supervised groups. Funeral services should not be allowed to unnecessarily disrupt the regular school schedule. # VII. Persons who may be at high risk should be identified and have at least one screening interview with a trained counselor; these persons should be referred for further counseling or other services as needed. A. Active measures: 1. Identify relatives (siblings, parents, children) of the decedents and provide an opportunity for them to express their feelings and to discuss their own thoughts about suicide with a trained counselor. 2. Similarly, identify and provide counseling for boy friends/girl friends, close friends, and fellow employees who may be particularly affected by the deaths. a) Strategies to identify associates of the decedents or others who may be at increased risk of suicide might include: identifying the pall bearers at the funeral services of the decedent(s); checking with the funeral director regarding visitors who seemed particularly troubled at the services; keeping a list of hospital visitors of suicide attempters; and verifying the status of school absentees in the days following the suicide of a student. 3. In the case of suicides among school-age persons, enlist the aid of teachers and students in identifying any students whom they think may be at increased risk of suicide. 4. Identify and refer past and present suicide attempters for counseling if these persons were substantially exposed to suicide (see below), regardless of whether they were close friends of the decedents. a) "Substantially exposed" persons would include, for example, students in the same high school or workers at the same job location as the suicide victims. In past suicide clusters, such persons have committed or attempted suicide even though they did not personally know the victims who had committed suicide earlier in the cluster. 1. Consider establishing hotlines or walk-in suicide crisis centers-even tem porarily-if they do not already exist in the community; announce the availability of such hotlines/centers. 2. Provide counselors at a particular site (such as school, church, community center) and announce their availability for anyone troubled by the recent deaths. a) If suicides have occurred among school-age persons, provide counse lors in the schools if possible; announce their availability to the students. 3. Enlist the local media to publish sources of help-hotlines, walk-in centers, community meetings, and other similar sources. 4. Make counseling services available to persons involved in responding to the crisis as well. Comment. The recommendations for active measures to identify persons at high risk of suicide are based largely on scientific evidence that certain factors increase the risk of suicide. For example, mental illness (especially depressive illness) (10) and a history of past suicide attempts (11) are both strong risk factors for suicide. Certain sociologic factors such as unemployment (12), being widowed or divorced ( 13,14), other bereavement (15,16), and mobility (17), also appear to be important risk factors for suicide. The role of imitation or "contagion" is, as we noted above, less well-established than the risk factors listed above. Nevertheless, the anecdotal evidence from suicide clusters is quite compelling, and several of the specific suggestions made above regarding who should be considered for screening are based on such evidence. For example, in one high school-based cluster, two persons who committed suicide late in the cluster had been pall bearers at the funerals of suicide victims who had died earlier in the cluster. It is likely that persons who are exposed to one or more of the aforementioned risk factors-depression or recent loss, for exam ple-m ay be more susceptible to a contagious effect of suicide. # VIII. A timely flow of accurate, appropriate information should be provided to the media. A. Make certain that a single account of the situation is presented by appointing one person as information coordinator. This person's duties would include: 1. meeting frequently with designated media spokespersons (see Section Vlll-B, below) to share news and information, and to make certain that the spokespersons share a common understanding of the current situation 2. "directing traffic"-referring requests for particular types of information to selected media spokespersons or to others (e.g., academic resources) 3. maintaining a list of local and national resources for appropriate referral of media inquiries 4. scheduling and holding press conferences. B. Appoint a single media spokesperson from each of the relevant community sectors-public health, education, mental health, local government, and the like. 1. Each sector represented on the coordinating committee should have a spokesperson. This person is not necessarily the same representative who serves on the coordinating committee. 2. Spokespersons from additional agencies or public groups may be desig nated as appropriate. C. These spokespersons should provide frequent, timely access to the media and present a complete and honest picture of the pertinent events. When appropriate, regularly scheduled press conferences should be held. 1. Avoid "whitewashing" -that is, saying that everything is under control or giving other assurances that may later prove unwarranted. This practice would undermine the credibility of the community spokespersons. 2. Discuss the positive steps being taken, and try to get the media to help in the response by reporting where troubled persons can go for help. D. The precise nature of the methods used by decedent(s) in committing suicide should not be disclosed. For example, it is accurate to state that an individual committed suicide by carbon monoxide poisoning. But it is not necessary-and is potentially very dangerous-to explain that the decedent acquired a hose from a hardware store, that s/he hooked it up to the tail pipe of a car, and then sat in a car with its engine running in a closed garage at a particular address. Such revelations can only make imitative suicides more likely and are unnecessary to a presentation of the manner of death. E. Enlist the support of the community in referring all requests for information to these spokespersons. # M M W R August 19,1988 Comment. If some suicide clusters spread through "contagion," the vehicle for such contagion is information, perhaps sensationalized information, about the suicides that have occurred. The role of the media in causing or exacerbating a suicide cluster is controversial, but some investigators will no longer even discuss an evolving suicide cluster with media representatives for fear that newspaper or television accounts will lead to further suicides. Although a definitive understanding of this issue must be left to future research, it is prudent in the meantime to try to prevent needlessly sensationalized or distorted accounts of evolving suicide clusters. The media spokespersons should meet as a group and with the information coordinator regularly; under certain circumstances, they may need to check with each other several times a day. Gaining the cooperation of the community in referring requests to these spokespersons is a formidable task and will require early and ongoing efforts if it is to be accomplished. It may be helpful to assure community members that it is all right to say "n o " to media phone calls or requests for interviews. The cooperation of parents is especially essential in the context of a school-based suicide cluster. Interviews with students about the suicide of one or more of their peers can be very stressful. Parents who do not wish to have their children interviewed may be able to prevent such interviews by refusing to sign a release statement. A handout addressing how media requests should be handled might be prepared and distributed to parents, students, and other appropriate persons. Gaining the cooperation of media representatives in this regard is also a formidae task. In the midst of a crisis, the frequent presentation of accurate and credible in ormation is the best means of establishing such cooperation. It is preferable, owever, to develop a working relationship with local media representatives before a crisis occurs. # IX. Elements in the environment that might increase the likelihood of urther suicides or suicide attempts should be identified and changed. Comment. If a particular method or site was used in previous suicides or suicide attempts, modification efforts should be addressed to these methods or sites first. For example, if the decedent(s) jumped off a particular building, bridge, or cliff, barriers might be erected to prevent other such attempts. If the decedent(s) committed suicide by carbon monoxide poisoning in a particular garage, access to that garage should be limited or monitored or both. If the decedent(s) committed suicide with a firearm or by taking an overdose of drugs, then restricting immediate access to firearms or to potentially lethal quantities of prescription drugs should be considered. In the case of suicides committed in jail, belts and other articles that may be used to commit suicide by hanging should be removed, and vigilance over the jail cells should be increased. Some of these modifications can be accomplished directly through the efforts of the coordinating committee, while others (limiting access to drugs or firearms) can only be suggested by the committee for others to consider. Although immediate environmental modifications may be suggested by methods used in previous suicides, the modifications need not be limited only to those methods. If there is concern, for example, that the risk of suicide for particular adolescents may have been increased because of the influence of previous traumatic deaths, then common methods of suicide-firearm injury, carbon monoxide poison ing,overdose-should be made temporarily unavailable if possible. The coordinat ing committee should consider a variety of potentially relevant environmental factors in developing this element of the response strategy. X. Long-term issues suggested by the nature of the suicide cluster should be addressed. Comment. Common characteristics among the victims in a given suicide cluster may suggest that certain issues need to be addressed by the community. For example, if the decedent(s) in a particular suicide cluster tended to be adolescents or young adults who were outside the main stream of community life, efforts might be made to bring such persons back into the community. Or, if a large proportion of the suicide attempters or completers had not been suspected of having any problems, then a system should be developed (or the present system altered) so that troubled persons could receive help before they reached the stage of overt suicidal behavior. Communities should consider establishing a surveillance system for suicide attempts as well as completed suicides. Suicide-attempt surveillance systems are almost nonexistent; yet the benefits of such systems are potentially great. In the context of a suicide cluster, such a system would allow persons who have attempted suicide in the past to be identified. Such persons are known to be at high risk of further suicide attempts. It would also allow for ongoing identification of high-risk persons during and after the current crisis. Communities should consider establishing suicide-attempt surveillance systems in their local emergency departments or wher ever appropriate. This plan should be modified according to the community's experience with its operation. Parts of the plan that have worked well in a given setting should be stressed in the updated plan, and parts that were inapplicable or that did not work should be excluded. Finally, the Centers for Disease Control requests that communi ties that use the plan notify us of their experiences with the plan to allow appropriate updating of this document. Please write to: Chief, Intentional Injuries Section Mailstop F-36 Centers for Disease Control 1600 Clifton Road NE Atlanta, GA 30333	None	None
a10a735dfe3281edf8a05defcf6eee34dae8f837	cdc	None	These revised recommendations of the Advisory Committee on Immunization Practices (ACIP) replace recommendations on poliomyelitis issued in 1982 and 1987, and present a new ACIP poliovirus vaccination policy that increases reliance on inactivated poliovirus vaccine (IPV). This change in policy is the most substantive since the introduction of oral poliovirus vaccine (OPV) in 1961. ACIP has determined that the risk-benefit ratio associated with the exclusive use of OPV for routine immunization has changed because of rapid progress in global polio eradication efforts. In particular, the relative benefits of OPV to the U.S. population have diminished because of the elimination of wild-virus-associated poliomyelitis in the Western Hemisphere and the reduced threat of poliovirus importation into the United States. The risk for vaccine-associated poliomyelitis caused by OPV is now judged less acceptable because of the diminished risk for wild-virus-associated disease (indigenous or imported). Consequently, ACIP recommends a transition policy that will increase use of IPV and decrease use of OPV during the next 3-5 years. The revised recommendations include three options for poliovirus vaccination, all of which meet acceptable standards of care: sequential vaccination with IPV followed by OPV, OPV alone, or IPV alone. For overall public health benefit, ACIP recommends a sequential vaccination schedule of two doses of IPV followed by two doses of OPV for routine childhood vaccination. Vaccination schedules that include OPV alone or IPV alone are also acceptable and are preferred in some situations (e.g., IPV alone is recommended for children who are immunosuppressed; OPV alone is preferred for children who begin the primary vaccination schedule after 6 months of age). Implementation of these recommendations should reduce the risk for vaccine-associated paralytic poliomyelitis and facilitate a transition to exclusive use of IPV following further progress in global polio eradication.# Poliomyelitis Prevention in the United States: Introduction of A Sequential Vaccination Schedule of Inactivated Poliovirus Vaccine Followed by Oral Poliovirus Vaccine INTRODUCTION Since the introduction of poliovirus vaccines in the 1950s and 1960s, poliomyelitis control has been achieved in the United States, the Americas, and elsewhere (1,2 ). In the United States, the last indigenously acquired cases of poliomyelitis caused by wild poliovirus were detected in 1979 (3 ). In 1985, the countries of the Americas established a goal of regional elimination of wild poliovirus by the year 1990 (4 ), and in 1988, the World Health Assembly adopted the goal of global poliomyelitis eradication by the year 2000 (5 ). In the Americas, the last case of poliomyelitis associated with isolation of wild poliovirus was detected in Peru in 1991 (6 ). The Western Hemisphere was certified to be free of indigenous wild poliovirus in 1994, an accomplishment achieved by the exclusive use of oral poliovirus vaccine (OPV) (7 ). The global poliomyelitis eradication initiative (PEI) has reduced the number of reported poliomyelitis cases worldwide by more than 80% since the mid-1980s, and worldwide eradication of the disease by the year 2000 appears feasible (8 ). The United States can remain free of poliomyelitis only by reducing or eliminating the risk for poliovirus importation. ACIP strongly reaffirms its support of the global PEI, which relies on OPV in countries where the disease remains endemic or has recently been endemic. ACIP urges that continuing and adequate support be made available to the PEI to achieve the goal of global eradication by the year 2000. Several factors have influenced the risk-benefit balance of the current immunization policy, including disease risk, risk for adverse vaccine reactions, and the cost of vaccines in the United States. Since 1980, an average of eight to nine cases of paralytic poliomyelitis associated with OPV has been reported annually in the United States. Vaccine-associated paralytic poliomyelitis (VAPP) has been the only indigenous form of the disease in the United States since 1979. Additional (unreported) cases of VAPP probably occur (9 ). The severity of these cases is similar to that of cases caused by wild virus. Although the risk for VAPP is low (approximately one case to 2.4 million doses distributed, or one case to 750,000 children receiving their first dose of OPV), CDC estimates that 30-40 cases of vaccine-associated paralysis would have occurred in the United States during 1997-2000 if the previously recommended poliovirus vaccination practices had not changed. Adoption of a sequential vaccination schedule of inactivated poliovirus vaccine (IPV) followed by OPV will likely prevent at least half of these cases of VAPP. ACIP has reevaluated the national poliomyelitis prevention policy because a) the global PEI has substantially reduced the risk for reintroduction of wild poliovirus to the United States and b) IPV provides high levels of individual protection without a concomitant risk for paralytic disease among vaccine recipients or persons with whom they have contact. After weighing the advantages and disadvantages of the various vaccines and schedules, ACIP concluded that three vaccination options offered essentially equal protection against poliomyelitis: a) sequential use of IPV and OPV, b) all OPV, and c) all IPV. ACIP considered the relevant scientific and programmatic issues and concluded that adoption of the sequential IPV-OPV vaccination schedule would yield the greatest overall public health benefit. This vaccination schedule includes doses of IPV administered at 2 and 4 months of age followed by doses of OPV administered at 12-18 months and 4-6 years of age. This strategy is intended to decrease the incidence of VAPP while maintaining high levels of population immunity to polioviruses to prevent poliomyelitis outbreaks should wild poliovirus be reintroduced to the United States. Nonetheless, the sequential vaccination schedule should be considered an interim recommendation. It is expected to remain in place 3-5 years until further progress toward global eradication is achieved. Such progress, along with the development and licensure of combination vaccines that reduce the need for multiple simultaneous vaccine injections, is expected to lead to adoption of an IPV-only vaccination schedule. Ultimately, when worldwide eradication of wild-type polioviruses is certified, all poliovirus vaccination can be discontinued. This statement summarizes the current recommendations for poliomyelitis prevention in the United States. It describes ACIP's rationale for selecting a sequential vaccination schedule of IPV followed by OPV as the preferred means to prevent both paralytic poliomyelitis caused by possible reintroduction of wild poliovirus and paralytic disease associated with OPV use. # CHARACTERISTICS OF POLIOMYELITIS Acute Poliomyelitis Poliomyelitis is a highly contagious infectious disease caused by poliovirus, an enterovirus. Most poliovirus infections are asymptomatic. Symptomatic cases are typically characterized by two phases-the first, a nonspecific febrile illness, is followed (in a small percentage of cases) by aseptic meningitis and/or paralytic disease. The ratio of cases of inapparent infection to paralytic disease ranges from 100:1 to 1,000:1. After poliovirus exposure, the virus replicates in the oropharynx and the intestinal tract. Viremia follows, and may result in infection of the central nervous system. Replication of poliovirus in motor neurons of the anterior horn and brain stem results in cell destruction and causes the typical clinical manifestations of paralytic poliomyelitis. Depending on the sites of paralysis, poliomyelitis can be classified as spinal, bulbar, or spino-bulbar disease. Progression to maximum paralysis is rapid (i.e., 2-4 days), is usually associated with fever and muscle pain, and rarely continues after the patient's temperature has returned to normal. Spinal paralysis is typically asymmetric, and more severe proximally than distally. Deep tendon reflexes are absent or diminished. Bulbar paralysis may compromise respiration and swallowing. Paralytic poliomyelitis is fatal in 2%-10% of cases. After the acute episode, many patients recover at least some muscle function and prognosis for recovery can usually be established within 6 months after onset of paralytic manifestations. # Post-Polio Syndrome After an interval of 30-40 years, 25%-40% of persons who contract paralytic poliomyelitis in childhood may experience muscle pain and exacerbation of existing weakness or develop new weakness or paralysis. This disease entity, which is referred to as post-polio syndrome, has been reported only in persons infected during the era of wild poliovirus circulation. Risk factors for post-polio syndrome include a) increasing length of time since acute poliovirus infection, b) presence of permanent residual impairment after recovery from the acute illness, and c) female sex (10 ). # Epidemiology Poliomyelitis, which occurs worldwide, is caused by three serotypes of poliovirus (i.e., types 1, 2, and 3). In countries where poliovirus is still endemic, paralytic disease is most often caused by poliovirus type 1, less frequently by poliovirus type 3, and least frequently by poliovirus type 2. The virus is transmitted from person to person primarily by direct fecal-oral contact. However, it also can be transmitted by indirect contact with infectious saliva or feces or by contaminated sewage or water. The first paralytic manifestations of poliomyelitis usually occur 7-21 days from the time of initial infection (range: 4-30 days). The period of communicability begins after the virus replicates -and is excreted in the oral secretions and feces-and ends with the termination of viral replication and excretion, usually 4-6 weeks after infection. After household exposure to wild poliovirus, >90% of susceptible contacts become infected. Infection by poliovirus results in lifelong immunity specific to the infecting viral serotype. Humans are the only reservoir for poliovirus. Long-term carrier states (i.e., excretion of virus by asymptomatic persons >6 months after infection) have been reported only in immunodeficient persons, among whom they are rare. Risk factors for paralytic disease include larger inocula of poliovirus, increasing age, pregnancy, strenuous exercise, tonsillectomy, and intramuscular injections administered while the patient is infected with poliovirus (11 ). # Poliomyelitis Eradication Following the widespread use of poliovirus vaccine in the mid-1950s, the incidence of poliomyelitis declined rapidly in many industrialized countries. In the United States, the number of cases of paralytic poliomyelitis reported each year declined from >20,000 cases in 1952 to <100 cases in the mid-1960s (3 ). In 1985, the member countries of the Pan American Health Organization adopted the goal of eliminating poliomyelitis from the Western Hemisphere by 1990 (4 ). The strategy to achieve this goal included a) increasing vaccination coverage, b) enhancing surveillance for suspected cases (i.e., surveillance for acute flaccid paralysis), and c) using supplemental immunization strategies (e.g., national immunization days , house-to-house vaccination, and containment activities) (12,13 ). Since 1991, when the last wild-virus-associated indigenous case was reported from Peru, no additional cases of poliomyelitis have been confirmed by isolation of wild virus despite intensive surveillance (6 ). In September 1994, an international commission certified the Western Hemisphere to be free of indigenous wild poliovirus. The commission based its judgment on detailed reports from national certification commissions that had been convened in every country in the region (8 ). In 1988, the World Health Assembly (the governing body of the World Health Organization ) adopted the goal of global eradication of poliomyelitis by the year 2000 (5 ). Substantial progress toward meeting this objective already has been achieved in many WHO regions (7,14,15 ) including East Asia (16)(17)(18), the Middle East (19 ), Southern and Eastern Africa, and Europe (7,(14)(15)(16)(17)(18)(19)(20)(21). By the end of 1996, almost all polio-endemic countries outside the African region of WHO had conducted NIDs, as had >50% of African countries. The PEI is supported by a coalition of international organizations that includes WHO, the United Nations Children's Fund (UNICEF), other bilateral and multilateral organizations, and Rotary International. # Secular Trends in Disease and Vaccination Coverage in the United States In the United States, poliovirus vaccines have eliminated poliomyelitis caused by wild poliovirus. The annual number of reported cases of paralytic disease declined from more than 20,000 in 1952 to an average of eight to nine cases annually during 1980-1991 (3,9 ). From 1980 through 1994, 133 cases of paralytic poliomyelitis were reported, including 125 cases of VAPP, six imported cases, and two indeterminate cases (CDC, unpublished data). Until worldwide poliomyelitis eradication is achieved, epidemics caused by importation of wild virus to the United States remain a possibility unless population immunity is maintained by vaccinating children early in their first year of life. In the United States, outbreaks of poliomyelitis occurred in 1970, 1972, and 1979 after wild poliovirus was introduced into susceptible populations that had low levels of vaccination coverage with OPV. Vaccination coverage among children in the United States is at the highest levels in history as a result of ongoing immunization initiatives. Assessments of the vaccination status of children entering kindergarten and first grade indicate that the percentage who had completed primary vaccination against poliomyelitis reached 95% in the 1980-81 school year and has since remained above that level. Serologic surveys indicate that >90% of school-age children, adolescents, and young adults have detectable antibody to poliovirus types 1 and 2, and >85% have antibody to type 3 (22,23 ). Data from seroprevalence surveys conducted in two innercity areas of the United States during 1990-1991 revealed that >80% of all children 12-47 months of age had antibodies to all three poliovirus serotypes. Of the children who had received at least three doses of OPV, 90% had antibody to all three serotypes (24 ). Vaccination levels among preschool-age children are lower than the levels at school entry, but have increased substantially in recent years. Data from the National Immunization Survey conducted from April 1994 through June 1995 indicated that, among children 19-35 months of age, vaccination coverage with at least three doses of OPV increased from 83% in 1994 to 88% in April-June, 1995 (25 ). Both laboratory surveillance for enteroviruses and poliomyelitis case surveillance suggest that endemic circulation of indigenous wild polioviruses ceased in the United States in the 1960s. In the 1970s, genotypic testing (e.g., molecular sequencing or oligonucleotide fingerprinting) of poliovirus isolates obtained from indigenous cases (both sporadically occurring and outbreak-associated) in the United States indicated that these viruses were imported (26 ). During the 1980s, five cases of poliomyelitis were classified as imported (9 ). The last imported case, reported in 1993, occurred in a child 2 years of age who was a resident of Nigeria; the child had been brought to New York for treatment of paralytic disease acquired in his home country. Laboratory investigations failed to isolate poliovirus in samples taken from this child. Recent experience in Canada illustrates the continuing potential for importation of wild poliovirus into the United States until global eradication is achieved. In 1993 and 1996, health officials in Canada isolated wild poliovirus in stool samples from residents of Alberta and Ontario. No cases of paralytic polio occurred as a result of these wild-virus importations. The strain isolated in 1993 was linked epidemiologically and by genomic sequencing to the 1992 poliomyelitis outbreak in the Netherlands (27 ). The isolate obtained in 1996 was from a child who had recently visited India (28 ). Inapparent infection with wild poliovirus no longer contributes to establishing or maintaining poliovirus immunity in the United States because these viruses no longer circulate in the population. Thus, universal vaccination of infants and children is the only means of establishing and maintaining population immunity against poliomyelitis. # Vaccine-Associated Paralytic Poliomyelitis Cases of VAPP were observed almost immediately after the introduction of live, attenuated poliovirus vaccines (29,30 ). During 1980-1994, 125 cases of VAPP were reported. Forty-nine cases of paralysis occurred among otherwise healthy vaccine recipients, 40 cases among healthy close contacts of vaccine recipients, and six cases among persons classified as community contacts (i.e., persons from whom vaccinerelated poliovirus was isolated although they had not been vaccinated recently or had direct contact with vaccine recipients). An additional 30 cases occurred in persons with abnormalities of the immune system who received OPV or who had direct contact with an OPV recipient (Table 1). The overall risk for VAPP is approximately one case in 2.4 million doses distributed. However, among immunocompetent persons, 82% of cases among vaccine recipients and 65% of cases among contacts occur following administration of the first dose. The most current estimate of the risk for VAPP is one case to 750,000 first doses of OPV distributed, essentially unchanged from previous estimates (Table 1) (3,9 ). Among persons who are not immunodeficient, the risk for VAPP associated with the first dose of OPV is sevenfold to 21-fold higher than the risk for subsequent doses (9 ). Immunodeficient persons, particularly those who have B-lymphocyte disorders that inhibit synthesis of immune globulins (i.e., agammaglobulinemia and hypogammaglobulinemia), are at greatest risk for VAPP (3,200-fold to 6,800-fold greater than the risk for immunocompetent OPV recipients) (31 ). # TABLE 1. Ratio of number of cases of vaccine-associated paralytic poliomyelitis (VAPP) to number of doses of trivalent OPV- distributed-United States, 1980-1994 # Case category # Ratio of number of cases to millions of doses of OPV- distributed and number of cases reported (N) 1980-1994 # All doses First doses Subsequent doses Live, oral poliovirus vaccine (attenuated). † Because the denominator is doses of OPV distributed, the calculated ratio is low. However, if the denominator is the number of immunodeficient infants born each year, the risk for VAPP in immunodeficient infants is 3,200-fold to 6,800-fold greater than in immunocompetent infants . # POLIOVIRUS VACCINES Oral Poliovirus Vaccine Trivalent OPV contains live attenuated strains of all three serotypes of poliovirus. The viruses are propagated in monkey kidney cell culture. Since it was licensed in the United States in 1963, OPV has been the nation's primary poliovirus vaccine. After complete primary vaccination with three doses of OPV, ≥95% of recipients develop long-lasting (probably life-long) immunity to all three poliovirus types. Approximately 50% of vaccine recipients develop antibody to all three serotypes after a single dose of OPV (32 ). OPV consistently induces immunity of the gastrointestinal tract that provides a substantial degree of resistance to reinfection with poliovirus. Administration of OPV interferes with subsequent infection by wild poliovirus, a property that is important in vaccination campaigns to control polio epidemics. Composition of OPV. One dose of OPV- (0.5 mL, administered orally from a single dose dispenser) contains a minimum of 10 6 TCID 50 (tissue culture infectious dose) Sabin strain of poliovirus type 1 (LSc 2ab), 10 5.1 TCID 50 Sabin strain of poliovirus type 2 (P712 Ch 2ab), and 10 5.8 TCID 50 Sabin strain of poliovirus type 3 (Leon 12a 1 b), balanced in a formulation of 10:1:3, respectively. The OPV manufactured in the United States contains approximately threefold to tenfold the minimum dose of virus necessary to meet these requirements consistently (33 ). Each dose of 0.5 mL also contains <25 µG each of streptomycin and neomycin. # Inactivated Poliovirus Vaccine Conventional IPV was introduced in the United States in 1955 and was used widely until OPV became available in the early 1960s. Thereafter, the use of IPV rapidly declined to a level of less than 2% of all poliovirus vaccine distributed annually in the United States. A method of producing a more potent IPV with greater antigenic content was developed in 1978 (34 ). The first of these more immunogenic vaccines was licensed in the United States in 1987. Results of studies from several countries have indicated that the enhanced-potency IPV is more immunogenic for both children and adults than previous formulations of IPV (35 ). A clinical trial of two preparations of enhanced-potency IPV was completed in the United States in 1984 (32 ). Among children who received three doses of one of the enhanced-potency IPVs at 2, 4, and 18 months of age, 99%-100% had developed serum antibodies to all three poliovirus types at 6 months of age-2 months after administration of the second dose. The percentage of children who had antibodies to all three serotypes of poliovirus did not increase or decrease during the 14-month period following the second dose, confirming that seroconversion had occurred in almost all the children. Furthermore, geometric mean antibody titers increased fivefold to tenfold after both the second and third doses. Data from subsequent studies have confirmed that 90%-100% of children develop protective antibody to all three types of poliovirus after administration of two doses of the currently available IPV; 99%-100% develop protective antibody after three doses (32,36,37 ). Results of studies showing long-term antibody persistence after three doses of enhanced-potency IPV are not yet available in the United States. However, data from one study indicated that antibody persisted throughout a 4-year follow-up period (38 ). In Sweden, studies of persons who received four doses of IPV (a vaccine with lower antigen content than the IPVs currently licensed in the United States) indicated that >90% of vaccinated persons had serum antibodies to poliovirus 25 years after administration of the fourth dose (39 ). Several European countries (e.g., Finland, Netherlands, and Sweden) have relied exclusively on enhanced-potency IPV for routine poliovirus vaccination to achieve elimination of poliomyelitis. More recently, most provinces of Canada have adopted vaccination schedules relying exclusively on IPV. Although persons vaccinated with IPV can subsequently be infected with and excrete either wild-type strains or vaccine-virus (attenuated) strains in their feces, considerable evidence from epidemiologic studies has demonstrated that vaccinating with IPV diminishes circulation of wild poliovirus in the community. In the poliomyelitis outbreak in the Netherlands during 1992-1993, immunity induced by IPV apparently prevented circulation of wild poliovirus in the general population (40 ). Composition of IPV. Two products are currently licensed in the United States: - IPOL™ : One dose (0.5 mL administered subcutaneously) consists of the sterile suspension of three types of poliovirus: Type 1 (Mahoney), type 2 (MEF-1), and type 3 (Saukett). The viruses are grown on Vero cells, a continuous line of monkey kidney cells, by the microcarrier method. After concentration, purification, and formaldehyde inactivation, each dose of vaccine contains 40 D antigen units of type 1, eight D antigen units of type 2, and 32 D antigen units of type 3. Each dose also contains 0.5% of 2-phenoxyethanol and up to 200 ppm of formaldehyde as preservatives, as well as trace amounts of neomycin, streptomycin, and polymyxin B used in vaccine production. - POLIOVAX™ : One dose (0.5 mL administered subcutaneously) consists of the sterile suspension of three types of poliovirus: Type 1 (Mahoney), type 2 (MEF-1), and type 3 (Saukett). The viruses are grown on human diploid (MRC-5) cell cultures, concentrated, purified, and formaldehyde inactivated. Each dose of vaccine contains 40 D antigen units of type 1, eight D antigen units of type 2, and 32 D antigen units of type 3, as well as 27 ppm formaldehyde, 0.5% 2-phenoxyethanol, 0.5% albumin (human), 20 ppm Tween 80™, and <1 ppm of bovine serum. Trace amounts of streptomycin and neomycin may be present as a result of the production process. # SEQUENTIAL USE OF IPV FOLLOWED BY OPV The sequential use of IPV and OPV has been proposed in the United States for more than a decade (41 ). In 1988, the Institute of Medicine reviewed poliomyelitis vaccination options for the United States and recommended adoption of a sequential schedule if a vaccine combining diphtheria and tetanus toxoids and pertussis vaccine and inactivated poliovirus vaccine (DTP-IPV) were licensed (42 ). A sequential schedule of three doses of IPV followed by three doses of OPV has been used in Denmark since 1968 (43 ). More recently, Hungary and Lithuania have adopted vaccination schedules that include at least one dose of IPV followed by OPV (44 ). In North America, one province in Canada (Prince Edward Island) has also used a sequential vaccination schedule for many years. # Immunogenicity Investigators have evaluated different sequential vaccination schedules that use one to three doses of IPV followed by one to three doses of OPV. Most have concluded that two doses of IPV are necessary to induce levels of poliovirus antibody protective against VAPP before the first dose of OPV is administered (32,36,37 ). In four of five studies, two doses of IPV induced development of protective antibodies to all three poliovirus serotypes in ≥90% of recipients (32,36,45,46 ). The fifth study indicated seroprevalence of antibodies to serotype 3 as low as 71% among recipients of an IPV produced in MRC-5 cells (POLIOVAX™ ) (37 ). In contrast, all studies using the IPV produced in Vero cells (the predominant IPV to be used in the United States) detected antibody to type 3 poliovirus among ≥94% of persons vaccinated. In each of four studies, investigators detected antibodies to poliovirus types 1 and 2 among >94% of persons who had received two doses of IPV followed by one dose of OPV; 81%-100% of these persons had antibody to type 3. The timing of the dose of OPV did not influence the prevalence of antibody to poliovirus (Table 2) (36,37,45,46 ). With the addition of a second dose of OPV, all studies report seroconversion rates ≥ 95% to all three serotypes (37,45 ). Both IPV and OPV induce immunity of the mucosa of the gastrointestinal tract, but the mucosal immunity induced by OPV is superior (47,48 ). Only one study has evaluated the improvement in this intestinal immunity when additional doses of OPV are administered after two doses of IPV. Among children who received three doses of IPV, the prevalence of viral shedding after administration of a challenge dose of OPV (i.e., a dose administered for purposes of measuring viral excretion) was 85%. In contrast, 66% of children who had received one previous dose of OPV and 25% of children who received two previous doses of OPV shed virus after the OPV challenge. No additional benefit was gained from a third dose (37 ). These data suggest that optimal gastrointestinal immunity is achieved after two doses of OPV in the sequential schedule. Both IPV and OPV are effective in reducing pharyngeal replication and subsequent transmission of poliovirus by the oral-oral route. # Safety of a Sequential Schedule The safety of sequential poliomyelitis vaccination schedules has been assessed among several hundred study participants (Table 2) and among infants residing in # VAPP A sequential vaccination schedule is expected to reduce VAPP by ≥50%. Circulating antibody against poliovirus induced by IPV is expected to reduce the already minimal risk for VAPP among immunocompetent recipients (among whom approximately three cases occur annually) nearly to zero (9 ). Further reduction in VAPP may result from decreases in the overall use of OPV in the United States. Decreased community exposure to excreted poliovirus derived from OPV is expected to reduce the number of community-acquired cases of VAPP (3 ). IPV-induced immunity of the pharyngeal mucosa and (to a lesser degree) of the intestinal mucosa may also reduce the number of contact cases by preventing oral-oral and fecal-oral transmission. Genetic sequencing studies suggest that reversion of Sabin poliovirus strains to potentially more neurovirulent phenotypes occurs commonly after OPV administration (49,50 ). Findings of two studies indicate that the use of a sequential vaccination schedule may not reduce the frequency of such reversions (51,52 ). However, findings from a third more systematic study designed to examine the issue of reversion suggest that, although administration of a dose of IPV before two or more doses of OPV may reduce shedding of type 3 virus (the most common cause of VAPP), the practice will not influence the shedding of types 1 or 2 or the extent of reversion (53 ). Thus, even if OPV is administered only to persons who have previously received one or more doses of IPV, reversion of vaccine poliovirus and excretion of revertant strains may still cause VAPP among susceptible contacts of OPV recipients. In the United States, an average of two cases of VAPP among immunodeficient persons is reported annually. The recommended sequential IPV-OPV vaccination schedule may also reduce the occurrence of such cases (3,9,31,54,55 ). Although the use of OPV is contraindicated in this group (54)(55)(56), the diagnosis of immunodeficiency is frequently not established by 2 months of age, when the infant is scheduled to receive the first dose of OPV under the previous ACIP recommendations (55 ). The new recommendations delay the administration of the first dose of OPV to 12-18 months of age. This change will allow an additional 10 months for diagnosis of any immunodeficiency disorder that would contraindicate administration of OPV. Some VAPP cases will likely occur despite the adoption of a sequential IPV-OPV vaccination schedule. Only the exclusive use of IPV or the discontinuation of all poliovirus vaccination efforts after achievement of global poliomyelitis eradication will completely eliminate VAPP. # Programmatic Issues Because no combination vaccine that includes IPV as a component is currently licensed in the United States, adoption of sequential IPV-OPV or all-IPV vaccination schedules will require additional injections at 2 and 4 months of age. In addition, acellular pertussis vaccine for use among infants has been licensed as DTaP rather than as a combined vaccine (e.g., DTaP-Haemophilus influenzae type b conjugate vaccine ) and is preferred for the pertussis vaccine series. DTP remains an acceptable alternative. Several licensed combination vaccines are available (e.g., DTP-HbCV, HbCV and hepatitis B combination vaccine ). Use of these vaccines during visits when IPV is administered will reduce the number of injections needed at a single visit. For each infant, health-care providers and parents must decide which of the following alternatives is preferable: a) additional injections, b) use of licensed combination vaccines, c) polio vaccination with OPV only, or d) additional clinic visits for administration of vaccines. Health-care providers should select a vaccination schedule for which the likelihood of compliance will be high, thereby promoting optimal protection against all vaccine-preventable childhood diseases. # RECOMMENDATIONS FOR POLIOVIRUS VACCINATION Routine Vaccination # Rationale for Choice of Vaccine Parents of children who are to be vaccinated should be informed of the poliovirus vaccines available, the three alternative vaccination schedules, and the basis for poliovirus vaccination recommendations. The benefits and risks of the vaccines as well as the advantages and disadvantages of the three vaccination options for individuals and for the community, should be discussed (Table 3). Vaccination schedules using IPV alone or OPV alone are both effective; both are acceptable options for preventing poliomyelitis. However, ACIP recommends the use of IPV followed by OPV for primary poliovirus vaccination of children in the United States because a) high levels of individual protection from two doses of IPV should reduce by 95% the number of VAPP cases that occurs among OPV recipients; b) sequential administration of IPV and OPV also may reduce VAPP among household and community contacts of OPV recipients because IPV provides some degree of intestinal and pharyngeal immunity; c) continued use of OPV induces intestinal immunity among vaccine recipients, thereby enhancing community resistance to transmission of wild virus (should it be reintroduced); d) fewer injections are required in the second year of life than would be required if only IPV were used, facilitating compliance with the overall childhood vaccination schedule; and e) stocking of both poliovirus vaccines by health-care providers enhances parental choice. Licensure of additional combination products will reduce the number of injections needed to administer the complete series of recommended childhood vaccinations. When the vaccination series is started after 6 months of age, OPV alone is preferred to enhance parent and provider compliance with the full childhood vaccination schedule. In this situation, the need to ensure administration of all recommended vaccines may require four or more simultaneous injections at each visit (see Accelerated Vaccination Schedule). OPV may be preferred if, during an initial visit, parents or providers decline the extra injections needed to administer all the recommended vaccines. OPV is preferred especially if there is concern that the child will not return on time for future vaccinations. OPV may also be preferred for children who are likely to travel to countries where polio is endemic. The superior gastrointestinal immunity conferred by OPV will reduce the risk that these children, should they be exposed during travel, might subsequently reintroduce wild poliovirus to the United States. IPV is the only poliovirus vaccine recommended for immunocompromised persons and their family contacts (see Immunocompromised Persons). In addition, an all-IPV vaccination schedule may be used when the number of injections is not a concern and is not likely to decrease parent or provider compliance with the childhood immunization schedule. Some parents or providers may prefer an all-IPV option to minimize the risk for VAPP. # Sequential Use of IPV and OPV For infants, children, and adolescents (i.e., persons <18 years of age), the primary sequential series of IPV and OPV consists of four doses. The primary series is administered at ages 2 months (IPV), 4 months (IPV), 12-18 months (OPV), and 4-6 years (OPV). For persons of any age, the first three doses should be separated by at least 4 weeks, although an interval of 6-8 weeks is preferred (see Accelerated Vaccination Schedule). Both IPV and OPV can be administered simultaneously with diphtheria and tetanus toxoids and whole-cell or acellular pertussis vaccine (DTP or DTaP), HbCV, hepatitis B vaccine, varicella vaccine, and measles-mumps-rubella (MMR) vaccine. # OPV Alone The primary series consists of three doses of vaccine. For infants, the primary series is usually integrated with the other vaccines routinely administered at 2, 4, and 6-18 months of age (Table 4). For routine vaccination, the minimum recommended interval between doses of OPV is 6-8 weeks. If the third dose of OPV is administered before the fourth birthday, a fourth dose of OPV should be provided before school entry (at 4-6 years of age). The fourth dose is not needed if the third dose is administered on or after the fourth birthday. OPV should not be used for the primary vaccination of persons ≥18 years of age (see Recommendations for Adults). # IPV Alone The primary series consists of three doses of vaccine. In infancy, these primary doses are integrated with the administration of other routinely administered vaccines. The first two doses are administered at 2 and 4 months of age; the third dose should be administered at 12-18 months of age with an interval of 6-12 months between the second and third doses (Table 4). Whereas the first and second doses of IPV are necessary to induce a primary immune response, the third dose of IPV ensures "boosting" of antibody titers to high levels. If accelerated protection is needed, the minimum interval between doses of IPV is 4 weeks, although the preferred interval between the second and third doses is 6 months (see Recommendations for Adults). All children who have received three doses of IPV before their fourth birthdays should receive a fourth dose before or at school entry. The fourth dose is not needed if the third dose is administered on or after the fourth birthday. # Interchangeability of Vaccines Completion of poliovirus vaccination with any of the three options (sequential IPV-OPV, OPV alone, or IPV alone) is preferred. However, if the vaccines are administered according to their licensed indications for minimum ages and intervals between doses, administration of four doses of IPV or OPV in any combination by 4-6 years of age is considered a complete poliovirus vaccination series. A minimum interval of 4 weeks should elapse if IPV is administered after OPV. # Options for Reducing the Number of Injections The number of injections needed to administer all recommended childhood vaccines to children 2 and 4 months of age (i.e., IPV, DTP or DTaP, HbCV, and hepatitis B) can be reduced to three (if IPV and HbCV combined with hepatitis B vaccine are administered) or two (if OPV and HbCV combined with hepatitis B vaccine are administered). For parents concerned about the number of injections, the following options to decrease the number of injections at the 2-and 4-month visits may be helpful: a) schedule the hepatitis B vaccine series at 0, 1, and 6 months of age (so that no doses of hepatitis B vaccine are needed during the 2-and 4-month visits); b) use licensed combination vaccines; c) schedule additional visits (if it can be ensured the child will be brought back for subsequent vaccinations at the recommended ages); and d) use OPV for the primary vaccination series. Development and licensure of additional combination products that contain the vaccine antigens recommended for children <1 year of age will make vaccination schedules that include IPV easier to implement. # Supplementary Vaccination at School Entry The poliovirus vaccination status of all children should be checked at school entry. The requirements for supplementary poliovirus vaccination depend on the type of vaccination schedule and the child's age and vaccination history. - Sequential IPV-OPV vaccination schedule. Children should receive a second dose of OPV to complete the four-dose sequential series, regardless of the age at which the series is initiated. Children who have previously received two doses of IPV followed by two doses of OPV do not require a supplementary dose at 4-6 years of age. - All-OPV vaccination schedule. Children who have previously received three doses of OPV should receive a fourth dose. However, if the third primary dose was administered on or after the fourth birthday, the fourth dose is not required - All-IPV vaccination schedule. Children who have previously received three doses of IPV should receive a fourth dose. However, if the third primary dose was administered on or after the fourth birthday, the fourth dose is not required. # Immunocompromised Persons IPV is the only poliovirus vaccine that should be administered to infants, adolescents, or adults if they have or are suspected to have a) an immunodeficiency disorder of any etiology (including infection with human immunodeficiency virus ), or if b) they are receiving immunosuppressive chemotherapy (e.g., cancer chemotherapy, or systemic steroid use). Because OPV virus can spread secondarily, OPV should not be administered to immunologically competent persons who live in a household with a person who has or is suspected to have any of these conditions; only IPV should be used. # Incompletely Vaccinated Children Children's poliovirus vaccination status should be reevaluated periodically. Those who are inadequately protected should complete the recommended vaccination series: - Sequential IPV-OPV vaccination schedule. The primary series of two doses of IPV followed by two doses of OPV is needed to ensure adequate humoral and intestinal immunity. Additional doses of vaccine are not needed if more than the recommended interval elapses between doses. - All-OPV vaccination schedule. The primary series of three doses of OPV is needed to ensure development of antibody to all three serotypes of poliovirus. Additional doses of vaccine are not needed if more than the recommended 6-8 weeks elapses between doses of OPV. - All-IPV vaccination schedule. Three doses of enhanced-potency IPV administered after 1987 are considered a complete primary series. As with OPV, no additional doses are needed if more time than recommended elapses between doses (e.g., >6-8 weeks between the first two doses or >6-12 months between the second and third doses). For IPV administered before 1988, four doses were required to complete a primary series (three doses administered at an interval of 4-8 weeks with a fourth dose 6-12 months after the third) (46,47 ). # Accelerated Vaccination Schedule For infants and children starting vaccination late (i.e., >6 months of age) or for whom accelerated protection against poliomyelitis is required, vaccination with OPV only is preferred (if not contraindicated). The minimum interval between doses of OPV under these circumstances is 4 weeks. A three-dose accelerated OPV series can be administered simultaneously with DTP or DTaP, HbCV, hepatitis B, MMR, and varicella vaccines. Limited data from the United States suggest that the rate of seroconversion among children vaccinated with three doses of OPV at 4-week intervals is similar to the rate among children who receive three doses of OPV at 8-week intervals (57 ). Children should be administered a supplemental dose of OPV at 4-6 years of age. For infants and children for whom IPV is indicated, the accelerated schedule permits administration of the first two doses of IPV with a minimum interval of 4 weeks. An interval of 6 months between the second and third doses is preferred because it will provide optimal immune response. As with OPV, these children should receive an additional dose of IPV at 4-6 years of age. For accelerated sequential IPV-OPV vaccination of infants and children, the first three doses (IPV, IPV, OPV) should be administered at 4-week intervals. The second dose of OPV should be administered at 4-6 years of age. Incompletely vaccinated children who are at increased risk for exposure to poliovirus should be administered the remaining required doses. If time is a limiting factor, incompletely vaccinated children should be administered at least a single dose of either vaccine (see Recommendations for Adults). # RECOMMENDATIONS FOR ADULTS Routine poliovirus vaccination of adults (generally persons ≥18 years of age) residing in the United States is not necessary. Most adults have a minimal risk for exposure to polioviruses in the United States and most are immune as a result of vaccination during childhood. Vaccination is recommended for certain adults who are at greater risk for exposure to polioviruses than the general population, including the following persons: - travelers to areas or countries where poliomyelitis is epidemic or endemic, - members of communities or specific population groups with disease caused by wild polioviruses, - laboratory workers who handle specimens that may contain polioviruses, - health-care workers who have close contact with patients who may be excreting wild polioviruses, - unvaccinated adults whose children will be receiving oral poliovirus vaccine. For unvaccinated adults, primary vaccination with IPV is recommended because the risk for vaccine-associated paralysis after administration of OPV is higher among adults than among children (29 ). Two doses of IPV should be administered at intervals of 4-8 weeks; a third dose should be administered 6-12 months after the second. If three doses of IPV cannot be administered within the recommended intervals before protection is needed, the following alternatives are recommended: - If ≥8 weeks are available before protection is needed, three doses of IPV should be administered at least 4 weeks apart. - If 4 weeks are available before protection is needed, two doses of IPV should be administered at least 4 weeks apart. - If <4 weeks are available before protection is needed, a single dose of OPV or IPV is recommended. The remaining doses of vaccine should be administered later, at the recommended intervals, if the person remains at increased risk. Adults who have had a primary series of OPV or IPV and who are at increased risk for exposure to poliovirus may receive another dose of either OPV or IPV. Persons who may be at increased risk include a) travelers to areas where poliomyelitis is endemic, b) certain laboratory personnel, and c) medical staff directly involved with the provision of care to patients who may be excreting poliovirus. These adults are not at increased risk for VAPP. The need for administration to adults of more than one supplementary dose of either IPV or OPV has not been established. Adults who have not been adequately vaccinated against poliomyelitis with OPV or IPV have a minimal risk for developing OPV-associated paralytic poliomyelitis when OPV is administered to children in their households. Since 1980, approximately onetwo cases of VAPP have occurred each year among adult household contacts of children who received OPV; during that time approximately 19 million doses of OPV were distributed yearly (see Adverse Reactions). Because of the overriding importance of ensuring prompt and complete immunization, sequential IPV-OPV vaccination of children should begin regardless of the poliovirus vaccine status of adult household contacts. If unvaccinated or inadequately vaccinated persons are known to reside in the child's household, IPV alone should be used to complete the child's vaccination, thereby reducing the already minimal risk for VAPP among adult household contacts. # PRECAUTIONS AND CONTRAINDICATIONS # Hypersensitivity or Anaphylactic Reactions to IPV, OPV, or the Antibiotics Contained in These Vaccines IPV should not be administered to persons who have experienced an anaphylactic reaction following a previous dose of IPV or an anaphylactic reaction to streptomycin, polymyxin B, or neomycin. OPV should not be administered to persons who have experienced an anaphylactic reaction to a previous dose of OPV. # Pregnancy Although no adverse effects of OPV or IPV have been documented among pregnant women or their fetuses, vaccination of pregnant women should be avoided. However, if a pregnant woman requires immediate protection against poliomyelitis, she may be administered OPV or IPV in accordance with the recommended schedules for adults. (See Recommendations for Adults.) # Immunodeficiency OPV should not be administered to persons who have immunodeficiency disorders (e.g., severe combined immunodeficiency syndrome, agammaglobulinemia, or hypogammaglobulinemia) because these persons are at substantially increased risk for VAPP. Similarly, OPV should not be administered to persons with altered immune states resulting from malignant disease (e.g., leukemia, lymphoma, or generalized malignancy), or to persons whose immune systems have been compromised (e.g., by therapy with corticosteroids, alkylating drugs, antimetabolites, or radiation or by HIV infection). OPV should not be used to vaccinate household contacts of immunodeficient patients; IPV is recommended. Many immunosuppressed persons are immune to polioviruses as a result of previous vaccination or exposure to wild-type virus at a time when they were immunologically competent. Although their risk for paralytic disease is thought to be less than that for persons with congenital or acquired immunodeficiency disorders, these persons should not receive OPV. Administration of IPV to immunodeficient persons is safe. Although a protective immune response in these persons cannot be assured, IPV may confer some protection. # Inadvertent Administration of OPV to Members of Households with Immunocompromised Persons If OPV is inadvertently administered to a household contact of an immunodeficient patient, the patient and the recipient of OPV should avoid close contact for approximately 4-6 weeks after vaccination. If this is not feasible, rigorous hygiene and hand washing after contact with feces (e.g., after diaper changing) and avoidance of contact with saliva (e.g., sharing food or utensils) may be an acceptable but probably a less effective alternative. Maximum excretion of vaccine virus occurs within 4 weeks after oral vaccination. # False Contraindications Breastfeeding does not interfere with successful immunization against poliomyelitis with IPV or OPV. A dose of IPV may be administered to a child who has diarrhea. A dose of OPV may be administered to a child who has mild diarrhea. Minor upper respiratory illnesses with or without fever, mild to moderate local reactions to a previous dose of vaccine, current antimicrobial therapy, and the convalescent phase of an acute illness are not contraindications for vaccination with IPV or OPV (58 ). # Regurgitation of OPV Infants may not completely swallow OPV. If, in the judgment of the person administering the vaccine, a substantial amount of vaccine is regurgitated or vomited soon after administration (i.e., within 5-10 minutes) another dose can be administered during the same visit. If this repeat dose is not retained, neither dose should be counted and the vaccine should be readministered during a later visit (58 ). # ADVERSE REACTIONS IPV No serious side effects of enhanced-potency IPV have been documented. Because IPV contains trace amounts of streptomycin, polymyxin B, and neomycin, hypersensitivity reactions may occur among persons sensitive to these antibiotics. # OPV In rare instances, administration of OPV has been associated with paralysis in healthy recipients and their contacts. No procedures are currently available for identifying persons (other than those with immunodeficiency) who are at risk for such adverse reactions. Although the risk for vaccine-associated paralysis is minimal, vaccinees (or their parents) and their susceptible, close, personal contacts should be informed of this risk (Table 1). Administration of OPV may very rarely cause paralytic poliomyelitis that results in death (3,31 ). # Guillain-Barré Syndrome The available evidence indicates that administration of OPV or IPV does not measurably increase the risk for Guillain-Barré syndrome (GBS). Preliminary findings from two studies in Finland led to a contrary conclusion in a review conducted by the Institute of Medicine (IOM) in 1993 (59,60 ). The investigators in Finland reported an apparent increase in the incidence of GBS that was temporally associated with a mass vaccination campaign during which OPV was administered to children and adults who had previously been vaccinated with IPV. After the IOM review was completed, however, these data were reanalyzed and an observational study was completed in the United States. Neither the reanalysis nor the newly completed study provided evidence of a causal relationship between OPV administration and GBS (61 ). The two most recent outbreaks of poliomyelitis reported in the United States affected members of religious groups who object to vaccination (i.e., outbreaks occurred in 1972 among Christian Scientists and in 1979 among members of an Amish community). Poliomyelitis should be suspected in any case of acute flaccid paralysis that affects an unvaccinated member of such a religious group. All such cases should be investigated promptly and followed up accordingly (see Surveillance). # Surveillance CDC conducts national surveillance for poliomyelitis in collaboration with state and local health departments. Suspected cases of poliomyelitis must be reported immediately to local or state health departments. CDC compiles and summarizes clinical, epidemiologic, and laboratory data concerning suspected cases. Three independent experts review the data and determine whether a suspected case meets the clinical case definition of paralytic poliomyelitis (i.e., a paralytic illness clinically and epidemiologically compatible with poliomyelitis in which a neurologic deficit is present 60 days after onset of symptoms ). On the basis of epidemiologic and laboratory criteria, CDC classifies confirmed cases of paralytic poliomyelitis as vaccine-associated or wild-type related and (based on OPV exposure data) as vaccine recipient or contact cases (9 ). For the recommended control measures to be undertaken in a timely manner, a preliminary assessment must ascertain as soon as possible whether a suspected case is likely vaccine-associated or caused by wild poliovirus (see Case Investigation and Laboratory Methods). # Laboratory Methods Specimens for virus isolation (e.g, stool, throat swab, and cerebrospinal fluid ) and serologic testing must be obtained in a timely fashion. The greatest yield for poliovirus is from stool culture, and timely collection of stool specimens increases the likelihood of case confirmation. At least two stool specimens and two throat swab specimens should be obtained from patients who are suspected to have poliomyelitis. Specimens should be obtained at least 24 hours apart as early in the course of illness as possible, ideally within 14 days of onset. Stool specimens collected ≥2 months after the onset of paralytic manifestations are unlikely to yield poliovirus. Throat swabs are less often positive than stool samples, and virus is rarely detected in CSF. In addition, an acute-phase serologic specimen should be obtained as early in the course of illness as possible, and a convalescent-phase specimen should be obtained at least 3 weeks later. The following tests should be performed on appropriate specimens collected from persons who have suspected cases of poliomyelitis: a) isolation of poliovirus in tissue culture; b) serotyping of a poliovirus isolate as type 1, 2, or 3; and c) intratypic differentiation using DNA/RNA probe hybridization or polymerase chain reaction to determine whether a poliovirus isolate is vaccine-related or wild-type. Acute-phase and convalescent-phase serum specimens should be tested for neutralizing antibody to each of the three poliovirus serotypes. A fourfold rise in antibody titer between appropriately timed acute-phase and convalescent-phase serum specimens is diagnostic for poliovirus infection. The recently revised standard protocol for poliovirus serology should be used (64 ). Commercial laboratories usually perform complement fixation and other tests. However, assays other than neutralization are difficult to interpret because of inadequate standardization and relative insensitivity. Laboratory experts at CDC are available for consultation and will test specimens from patients who have suspected poliomyelitis (i.e., patients with acute paralytic manifestations); telephone (404) 639-2749. # RECOMMENDED SURVEILLANCE, RESEARCH, AND EDUCATION ACTIVITIES Several programmatic activities in disease surveillance, research, and education should be implemented in conjunction with the new poliovirus vaccination schedule. The recommended activities are: a) Enhance surveillance for paralytic poliomyelitis to facilitate early detection and control of outbreaks caused by imported wild virus and to evaluate the impact of the revised vaccination schedule on incidence of VAPP. b) Conduct expanded surveillance of potential adverse effects of IPV as the vaccine is administered to more children and adults. c) Assess the possible influence of the revised vaccination schedule on childhood vaccine coverage (particularly in populations in which coverage is suboptimal); continue development of vaccine registries. d) Expand surveillance of other vaccine-preventable childhood diseases as a means of detecting possible effects of the revised polio vaccination schedule (particularly the required additional injections) on coverage with all vaccines recommended for infants and children. e) Develop and evaluate materials to educate parents and health-care providers about poliovirus vaccines and vaccination schedules. f) Evaluate parent and provider acceptance of the additional injections required by the revised vaccination schedule at 2 and 4 months of age. g) Accelerate development of combination vaccines. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read subscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1997-532-228/47051 Region IV # Reporting of Adverse Events Following Vaccination The National Childhood Vaccine Injury Act of 1986 requires health-care providers to report serious adverse events following poliovirus vaccination (62 ). The events that must be reported are detailed in the Reportable Events Table within this Act, and include paralytic poliomyelitis and any acute complications or sequelae of paralytic poliomyelitis. Adverse reactions should be reported to the Vaccine Adverse Events Reporting System (VAERS). VAERS reporting forms and information are available 24 hours a day by calling (800) 822-7967. # Vaccine Injury Compensation Program The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, provides a mechanism through which compensation can be paid on behalf of a person who died or was injured as a result of receiving vaccine. A Vaccine Injury Table in the Act lists the vaccines covered by the program and the injuries, disabilities, illnesses, and conditions (including death) for which compensation may be paid. Development or onset of vaccine-associated paralytic poliomyelitis in an OPV recipient (within 30 days), or in a person in contact with an OPV vaccinee (not specified), or in an immunodeficient person (within 6 months) are potentially compensable under this law. Additional information is available (63 ).* # INVESTIGATION AND REPORTING OF SUSPECTED POLIOMYELITIS CASES # Case Investigation Each suspected case of poliomyelitis should prompt an immediate epidemiologic investigation. If evidence suggests the transmission of wild poliovirus, an active search for other cases that may initially have been misdiagnosed (e.g., as GBS, polyneuritis, or transverse myelitis) should be conducted. Control measures (including an OPV vaccination campaign designed to contain further transmission) should be instituted immediately. If evidence suggests vaccine-related poliovirus, no vaccination plan need be developed, because no outbreaks associated with live, attenuated vaccine-related poliovirus strains have been documented. Within an epidemic area, OPV should be provided for all immunocompetent persons, regardless of previous OPV vaccination status (	These revised recommendations of the Advisory Committee on Immunization Practices (ACIP) replace recommendations on poliomyelitis issued in 1982 and 1987, and present a new ACIP poliovirus vaccination policy that increases reliance on inactivated poliovirus vaccine (IPV). This change in policy is the most substantive since the introduction of oral poliovirus vaccine (OPV) in 1961. ACIP has determined that the risk-benefit ratio associated with the exclusive use of OPV for routine immunization has changed because of rapid progress in global polio eradication efforts. In particular, the relative benefits of OPV to the U.S. population have diminished because of the elimination of wild-virus-associated poliomyelitis in the Western Hemisphere and the reduced threat of poliovirus importation into the United States. The risk for vaccine-associated poliomyelitis caused by OPV is now judged less acceptable because of the diminished risk for wild-virus-associated disease (indigenous or imported). Consequently, ACIP recommends a transition policy that will increase use of IPV and decrease use of OPV during the next 3-5 years. The revised recommendations include three options for poliovirus vaccination, all of which meet acceptable standards of care: sequential vaccination with IPV followed by OPV, OPV alone, or IPV alone. For overall public health benefit, ACIP recommends a sequential vaccination schedule of two doses of IPV followed by two doses of OPV for routine childhood vaccination. Vaccination schedules that include OPV alone or IPV alone are also acceptable and are preferred in some situations (e.g., IPV alone is recommended for children who are immunosuppressed; OPV alone is preferred for children who begin the primary vaccination schedule after 6 months of age). Implementation of these recommendations should reduce the risk for vaccine-associated paralytic poliomyelitis and facilitate a transition to exclusive use of IPV following further progress in global polio eradication.# Poliomyelitis Prevention in the United States: Introduction of A Sequential Vaccination Schedule of Inactivated Poliovirus Vaccine Followed by Oral Poliovirus Vaccine INTRODUCTION Since the introduction of poliovirus vaccines in the 1950s and 1960s, poliomyelitis control has been achieved in the United States, the Americas, and elsewhere (1,2 ). In the United States, the last indigenously acquired cases of poliomyelitis caused by wild poliovirus were detected in 1979 (3 ). In 1985, the countries of the Americas established a goal of regional elimination of wild poliovirus by the year 1990 (4 ), and in 1988, the World Health Assembly adopted the goal of global poliomyelitis eradication by the year 2000 (5 ). In the Americas, the last case of poliomyelitis associated with isolation of wild poliovirus was detected in Peru in 1991 (6 ). The Western Hemisphere was certified to be free of indigenous wild poliovirus in 1994, an accomplishment achieved by the exclusive use of oral poliovirus vaccine (OPV) (7 ). The global poliomyelitis eradication initiative (PEI) has reduced the number of reported poliomyelitis cases worldwide by more than 80% since the mid-1980s, and worldwide eradication of the disease by the year 2000 appears feasible (8 ). The United States can remain free of poliomyelitis only by reducing or eliminating the risk for poliovirus importation. ACIP strongly reaffirms its support of the global PEI, which relies on OPV in countries where the disease remains endemic or has recently been endemic. ACIP urges that continuing and adequate support be made available to the PEI to achieve the goal of global eradication by the year 2000. Several factors have influenced the risk-benefit balance of the current immunization policy, including disease risk, risk for adverse vaccine reactions, and the cost of vaccines in the United States. Since 1980, an average of eight to nine cases of paralytic poliomyelitis associated with OPV has been reported annually in the United States. Vaccine-associated paralytic poliomyelitis (VAPP) has been the only indigenous form of the disease in the United States since 1979. Additional (unreported) cases of VAPP probably occur (9 ). The severity of these cases is similar to that of cases caused by wild virus. Although the risk for VAPP is low (approximately one case to 2.4 million doses distributed, or one case to 750,000 children receiving their first dose of OPV), CDC estimates that 30-40 cases of vaccine-associated paralysis would have occurred in the United States during 1997-2000 if the previously recommended poliovirus vaccination practices had not changed. Adoption of a sequential vaccination schedule of inactivated poliovirus vaccine (IPV) followed by OPV will likely prevent at least half of these cases of VAPP. ACIP has reevaluated the national poliomyelitis prevention policy because a) the global PEI has substantially reduced the risk for reintroduction of wild poliovirus to the United States and b) IPV provides high levels of individual protection without a concomitant risk for paralytic disease among vaccine recipients or persons with whom they have contact. After weighing the advantages and disadvantages of the various vaccines and schedules, ACIP concluded that three vaccination options offered essentially equal protection against poliomyelitis: a) sequential use of IPV and OPV, b) all OPV, and c) all IPV. ACIP considered the relevant scientific and programmatic issues and concluded that adoption of the sequential IPV-OPV vaccination schedule would yield the greatest overall public health benefit. This vaccination schedule includes doses of IPV administered at 2 and 4 months of age followed by doses of OPV administered at 12-18 months and 4-6 years of age. This strategy is intended to decrease the incidence of VAPP while maintaining high levels of population immunity to polioviruses to prevent poliomyelitis outbreaks should wild poliovirus be reintroduced to the United States. Nonetheless, the sequential vaccination schedule should be considered an interim recommendation. It is expected to remain in place 3-5 years until further progress toward global eradication is achieved. Such progress, along with the development and licensure of combination vaccines that reduce the need for multiple simultaneous vaccine injections, is expected to lead to adoption of an IPV-only vaccination schedule. Ultimately, when worldwide eradication of wild-type polioviruses is certified, all poliovirus vaccination can be discontinued. This statement summarizes the current recommendations for poliomyelitis prevention in the United States. It describes ACIP's rationale for selecting a sequential vaccination schedule of IPV followed by OPV as the preferred means to prevent both paralytic poliomyelitis caused by possible reintroduction of wild poliovirus and paralytic disease associated with OPV use. # CHARACTERISTICS OF POLIOMYELITIS Acute Poliomyelitis Poliomyelitis is a highly contagious infectious disease caused by poliovirus, an enterovirus. Most poliovirus infections are asymptomatic. Symptomatic cases are typically characterized by two phases-the first, a nonspecific febrile illness, is followed (in a small percentage of cases) by aseptic meningitis and/or paralytic disease. The ratio of cases of inapparent infection to paralytic disease ranges from 100:1 to 1,000:1. After poliovirus exposure, the virus replicates in the oropharynx and the intestinal tract. Viremia follows, and may result in infection of the central nervous system. Replication of poliovirus in motor neurons of the anterior horn and brain stem results in cell destruction and causes the typical clinical manifestations of paralytic poliomyelitis. Depending on the sites of paralysis, poliomyelitis can be classified as spinal, bulbar, or spino-bulbar disease. Progression to maximum paralysis is rapid (i.e., 2-4 days), is usually associated with fever and muscle pain, and rarely continues after the patient's temperature has returned to normal. Spinal paralysis is typically asymmetric, and more severe proximally than distally. Deep tendon reflexes are absent or diminished. Bulbar paralysis may compromise respiration and swallowing. Paralytic poliomyelitis is fatal in 2%-10% of cases. After the acute episode, many patients recover at least some muscle function and prognosis for recovery can usually be established within 6 months after onset of paralytic manifestations. # Post-Polio Syndrome After an interval of 30-40 years, 25%-40% of persons who contract paralytic poliomyelitis in childhood may experience muscle pain and exacerbation of existing weakness or develop new weakness or paralysis. This disease entity, which is referred to as post-polio syndrome, has been reported only in persons infected during the era of wild poliovirus circulation. Risk factors for post-polio syndrome include a) increasing length of time since acute poliovirus infection, b) presence of permanent residual impairment after recovery from the acute illness, and c) female sex (10 ). # Epidemiology Poliomyelitis, which occurs worldwide, is caused by three serotypes of poliovirus (i.e., types 1, 2, and 3). In countries where poliovirus is still endemic, paralytic disease is most often caused by poliovirus type 1, less frequently by poliovirus type 3, and least frequently by poliovirus type 2. The virus is transmitted from person to person primarily by direct fecal-oral contact. However, it also can be transmitted by indirect contact with infectious saliva or feces or by contaminated sewage or water. The first paralytic manifestations of poliomyelitis usually occur 7-21 days from the time of initial infection (range: 4-30 days). The period of communicability begins after the virus replicates -and is excreted in the oral secretions and feces-and ends with the termination of viral replication and excretion, usually 4-6 weeks after infection. After household exposure to wild poliovirus, >90% of susceptible contacts become infected. Infection by poliovirus results in lifelong immunity specific to the infecting viral serotype. Humans are the only reservoir for poliovirus. Long-term carrier states (i.e., excretion of virus by asymptomatic persons >6 months after infection) have been reported only in immunodeficient persons, among whom they are rare. Risk factors for paralytic disease include larger inocula of poliovirus, increasing age, pregnancy, strenuous exercise, tonsillectomy, and intramuscular injections administered while the patient is infected with poliovirus (11 ). # Poliomyelitis Eradication Following the widespread use of poliovirus vaccine in the mid-1950s, the incidence of poliomyelitis declined rapidly in many industrialized countries. In the United States, the number of cases of paralytic poliomyelitis reported each year declined from >20,000 cases in 1952 to <100 cases in the mid-1960s (3 ). In 1985, the member countries of the Pan American Health Organization adopted the goal of eliminating poliomyelitis from the Western Hemisphere by 1990 (4 ). The strategy to achieve this goal included a) increasing vaccination coverage, b) enhancing surveillance for suspected cases (i.e., surveillance for acute flaccid paralysis), and c) using supplemental immunization strategies (e.g., national immunization days [NIDs], house-to-house vaccination, and containment activities) (12,13 ). Since 1991, when the last wild-virus-associated indigenous case was reported from Peru, no additional cases of poliomyelitis have been confirmed by isolation of wild virus despite intensive surveillance (6 ). In September 1994, an international commission certified the Western Hemisphere to be free of indigenous wild poliovirus. The commission based its judgment on detailed reports from national certification commissions that had been convened in every country in the region (8 ). In 1988, the World Health Assembly (the governing body of the World Health Organization [WHO]) adopted the goal of global eradication of poliomyelitis by the year 2000 (5 ). Substantial progress toward meeting this objective already has been achieved in many WHO regions (7,14,15 ) including East Asia (16)(17)(18), the Middle East (19 ), Southern and Eastern Africa, and Europe (7,(14)(15)(16)(17)(18)(19)(20)(21). By the end of 1996, almost all polio-endemic countries outside the African region of WHO had conducted NIDs, as had >50% of African countries. The PEI is supported by a coalition of international organizations that includes WHO, the United Nations Children's Fund (UNICEF), other bilateral and multilateral organizations, and Rotary International. # Secular Trends in Disease and Vaccination Coverage in the United States In the United States, poliovirus vaccines have eliminated poliomyelitis caused by wild poliovirus. The annual number of reported cases of paralytic disease declined from more than 20,000 in 1952 to an average of eight to nine cases annually during 1980-1991 (3,9 ). From 1980 through 1994, 133 cases of paralytic poliomyelitis were reported, including 125 cases of VAPP, six imported cases, and two indeterminate cases (CDC, unpublished data). Until worldwide poliomyelitis eradication is achieved, epidemics caused by importation of wild virus to the United States remain a possibility unless population immunity is maintained by vaccinating children early in their first year of life. In the United States, outbreaks of poliomyelitis occurred in 1970, 1972, and 1979 after wild poliovirus was introduced into susceptible populations that had low levels of vaccination coverage with OPV. Vaccination coverage among children in the United States is at the highest levels in history as a result of ongoing immunization initiatives. Assessments of the vaccination status of children entering kindergarten and first grade indicate that the percentage who had completed primary vaccination against poliomyelitis reached 95% in the 1980-81 school year and has since remained above that level. Serologic surveys indicate that >90% of school-age children, adolescents, and young adults have detectable antibody to poliovirus types 1 and 2, and >85% have antibody to type 3 (22,23 ). Data from seroprevalence surveys conducted in two innercity areas of the United States during 1990-1991 revealed that >80% of all children 12-47 months of age had antibodies to all three poliovirus serotypes. Of the children who had received at least three doses of OPV, 90% had antibody to all three serotypes (24 ). Vaccination levels among preschool-age children are lower than the levels at school entry, but have increased substantially in recent years. Data from the National Immunization Survey conducted from April 1994 through June 1995 indicated that, among children 19-35 months of age, vaccination coverage with at least three doses of OPV increased from 83% in 1994 to 88% in April-June, 1995 (25 ). Both laboratory surveillance for enteroviruses and poliomyelitis case surveillance suggest that endemic circulation of indigenous wild polioviruses ceased in the United States in the 1960s. In the 1970s, genotypic testing (e.g., molecular sequencing or oligonucleotide fingerprinting) of poliovirus isolates obtained from indigenous cases (both sporadically occurring and outbreak-associated) in the United States indicated that these viruses were imported (26 ). During the 1980s, five cases of poliomyelitis were classified as imported (9 ). The last imported case, reported in 1993, occurred in a child 2 years of age who was a resident of Nigeria; the child had been brought to New York for treatment of paralytic disease acquired in his home country. Laboratory investigations failed to isolate poliovirus in samples taken from this child. Recent experience in Canada illustrates the continuing potential for importation of wild poliovirus into the United States until global eradication is achieved. In 1993 and 1996, health officials in Canada isolated wild poliovirus in stool samples from residents of Alberta and Ontario. No cases of paralytic polio occurred as a result of these wild-virus importations. The strain isolated in 1993 was linked epidemiologically and by genomic sequencing to the 1992 poliomyelitis outbreak in the Netherlands (27 ). The isolate obtained in 1996 was from a child who had recently visited India (28 ). Inapparent infection with wild poliovirus no longer contributes to establishing or maintaining poliovirus immunity in the United States because these viruses no longer circulate in the population. Thus, universal vaccination of infants and children is the only means of establishing and maintaining population immunity against poliomyelitis. # Vaccine-Associated Paralytic Poliomyelitis Cases of VAPP were observed almost immediately after the introduction of live, attenuated poliovirus vaccines (29,30 ). During 1980-1994, 125 cases of VAPP were reported. Forty-nine cases of paralysis occurred among otherwise healthy vaccine recipients, 40 cases among healthy close contacts of vaccine recipients, and six cases among persons classified as community contacts (i.e., persons from whom vaccinerelated poliovirus was isolated although they had not been vaccinated recently or had direct contact with vaccine recipients). An additional 30 cases occurred in persons with abnormalities of the immune system who received OPV or who had direct contact with an OPV recipient (Table 1). The overall risk for VAPP is approximately one case in 2.4 million doses distributed. However, among immunocompetent persons, 82% of cases among vaccine recipients and 65% of cases among contacts occur following administration of the first dose. The most current estimate of the risk for VAPP is one case to 750,000 first doses of OPV distributed, essentially unchanged from previous estimates (Table 1) (3,9 ). Among persons who are not immunodeficient, the risk for VAPP associated with the first dose of OPV is sevenfold to 21-fold higher than the risk for subsequent doses (9 ). Immunodeficient persons, particularly those who have B-lymphocyte disorders that inhibit synthesis of immune globulins (i.e., agammaglobulinemia and hypogammaglobulinemia), are at greatest risk for VAPP (3,200-fold to 6,800-fold greater than the risk for immunocompetent OPV recipients) (31 ). # TABLE 1. Ratio of number of cases of vaccine-associated paralytic poliomyelitis (VAPP) to number of doses of trivalent OPV* distributed-United States, 1980-1994 # Case category # Ratio of number of cases to millions of doses of OPV* distributed and number of cases reported (N) 1980-1994 # All doses First doses Subsequent doses Live, oral poliovirus vaccine (attenuated). † Because the denominator is doses of OPV distributed, the calculated ratio is low. However, if the denominator is the number of immunodeficient infants born each year, the risk for VAPP in immunodeficient infants is 3,200-fold to 6,800-fold greater than in immunocompetent infants [31]. # POLIOVIRUS VACCINES Oral Poliovirus Vaccine Trivalent OPV contains live attenuated strains of all three serotypes of poliovirus. The viruses are propagated in monkey kidney cell culture. Since it was licensed in the United States in 1963, OPV has been the nation's primary poliovirus vaccine. After complete primary vaccination with three doses of OPV, ≥95% of recipients develop long-lasting (probably life-long) immunity to all three poliovirus types. Approximately 50% of vaccine recipients develop antibody to all three serotypes after a single dose of OPV (32 ). OPV consistently induces immunity of the gastrointestinal tract that provides a substantial degree of resistance to reinfection with poliovirus. Administration of OPV interferes with subsequent infection by wild poliovirus, a property that is important in vaccination campaigns to control polio epidemics. Composition of OPV. One dose of OPV (0.5 mL, administered orally from a single dose dispenser) contains a minimum of 10 6 TCID 50 (tissue culture infectious dose) Sabin strain of poliovirus type 1 (LSc 2ab), 10 5.1 TCID 50 Sabin strain of poliovirus type 2 (P712 Ch 2ab), and 10 5.8 TCID 50 Sabin strain of poliovirus type 3 (Leon 12a 1 b), balanced in a formulation of 10:1:3, respectively. The OPV manufactured in the United States contains approximately threefold to tenfold the minimum dose of virus necessary to meet these requirements consistently (33 ). Each dose of 0.5 mL also contains <25 µG each of streptomycin and neomycin. # Inactivated Poliovirus Vaccine Conventional IPV was introduced in the United States in 1955 and was used widely until OPV became available in the early 1960s. Thereafter, the use of IPV rapidly declined to a level of less than 2% of all poliovirus vaccine distributed annually in the United States. A method of producing a more potent IPV with greater antigenic content was developed in 1978 (34 ). The first of these more immunogenic vaccines was licensed in the United States in 1987. Results of studies from several countries have indicated that the enhanced-potency IPV is more immunogenic for both children and adults than previous formulations of IPV (35 ). A clinical trial of two preparations of enhanced-potency IPV was completed in the United States in 1984 (32 ). Among children who received three doses of one of the enhanced-potency IPVs at 2, 4, and 18 months of age, 99%-100% had developed serum antibodies to all three poliovirus types at 6 months of age-2 months after administration of the second dose. The percentage of children who had antibodies to all three serotypes of poliovirus did not increase or decrease during the 14-month period following the second dose, confirming that seroconversion had occurred in almost all the children. Furthermore, geometric mean antibody titers increased fivefold to tenfold after both the second and third doses. Data from subsequent studies have confirmed that 90%-100% of children develop protective antibody to all three types of poliovirus after administration of two doses of the currently available IPV; 99%-100% develop protective antibody after three doses (32,36,37 ). Results of studies showing long-term antibody persistence after three doses of enhanced-potency IPV are not yet available in the United States. However, data from one study indicated that antibody persisted throughout a 4-year follow-up period (38 ). In Sweden, studies of persons who received four doses of IPV (a vaccine with lower antigen content than the IPVs currently licensed in the United States) indicated that >90% of vaccinated persons had serum antibodies to poliovirus 25 years after administration of the fourth dose (39 ). Several European countries (e.g., Finland, Netherlands, and Sweden) have relied exclusively on enhanced-potency IPV for routine poliovirus vaccination to achieve elimination of poliomyelitis. More recently, most provinces of Canada have adopted vaccination schedules relying exclusively on IPV. Although persons vaccinated with IPV can subsequently be infected with and excrete either wild-type strains or vaccine-virus (attenuated) strains in their feces, considerable evidence from epidemiologic studies has demonstrated that vaccinating with IPV diminishes circulation of wild poliovirus in the community. In the poliomyelitis outbreak in the Netherlands during 1992-1993, immunity induced by IPV apparently prevented circulation of wild poliovirus in the general population (40 ). Composition of IPV. Two products are currently licensed in the United States: • IPOL™ : One dose (0.5 mL administered subcutaneously) consists of the sterile suspension of three types of poliovirus: Type 1 (Mahoney), type 2 (MEF-1), and type 3 (Saukett). The viruses are grown on Vero cells, a continuous line of monkey kidney cells, by the microcarrier method. After concentration, purification, and formaldehyde inactivation, each dose of vaccine contains 40 D antigen units of type 1, eight D antigen units of type 2, and 32 D antigen units of type 3. Each dose also contains 0.5% of 2-phenoxyethanol and up to 200 ppm of formaldehyde as preservatives, as well as trace amounts of neomycin, streptomycin, and polymyxin B used in vaccine production. • POLIOVAX™ : One dose (0.5 mL administered subcutaneously) consists of the sterile suspension of three types of poliovirus: Type 1 (Mahoney), type 2 (MEF-1), and type 3 (Saukett). The viruses are grown on human diploid (MRC-5) cell cultures, concentrated, purified, and formaldehyde inactivated. Each dose of vaccine contains 40 D antigen units of type 1, eight D antigen units of type 2, and 32 D antigen units of type 3, as well as 27 ppm formaldehyde, 0.5% 2-phenoxyethanol, 0.5% albumin (human), 20 ppm Tween 80™, and <1 ppm of bovine serum. Trace amounts of streptomycin and neomycin may be present as a result of the production process. # SEQUENTIAL USE OF IPV FOLLOWED BY OPV The sequential use of IPV and OPV has been proposed in the United States for more than a decade (41 ). In 1988, the Institute of Medicine reviewed poliomyelitis vaccination options for the United States and recommended adoption of a sequential schedule if a vaccine combining diphtheria and tetanus toxoids and pertussis vaccine and inactivated poliovirus vaccine (DTP-IPV) were licensed (42 ). A sequential schedule of three doses of IPV followed by three doses of OPV has been used in Denmark since 1968 (43 ). More recently, Hungary and Lithuania have adopted vaccination schedules that include at least one dose of IPV followed by OPV (44 ). In North America, one province in Canada (Prince Edward Island) has also used a sequential vaccination schedule for many years. # Immunogenicity Investigators have evaluated different sequential vaccination schedules that use one to three doses of IPV followed by one to three doses of OPV. Most have concluded that two doses of IPV are necessary to induce levels of poliovirus antibody protective against VAPP before the first dose of OPV is administered (32,36,37 ). In four of five studies, two doses of IPV induced development of protective antibodies to all three poliovirus serotypes in ≥90% of recipients (32,36,45,46 ). The fifth study indicated seroprevalence of antibodies to serotype 3 as low as 71% among recipients of an IPV produced in MRC-5 cells (POLIOVAX™ ) (37 ). In contrast, all studies using the IPV produced in Vero cells (the predominant IPV to be used in the United States) detected antibody to type 3 poliovirus among ≥94% of persons vaccinated. In each of four studies, investigators detected antibodies to poliovirus types 1 and 2 among >94% of persons who had received two doses of IPV followed by one dose of OPV; 81%-100% of these persons had antibody to type 3. The timing of the dose of OPV did not influence the prevalence of antibody to poliovirus (Table 2) (36,37,45,46 ). With the addition of a second dose of OPV, all studies report seroconversion rates ≥ 95% to all three serotypes (37,45 ). Both IPV and OPV induce immunity of the mucosa of the gastrointestinal tract, but the mucosal immunity induced by OPV is superior (47,48 ). Only one study has evaluated the improvement in this intestinal immunity when additional doses of OPV are administered after two doses of IPV. Among children who received three doses of IPV, the prevalence of viral shedding after administration of a challenge dose of OPV (i.e., a dose administered for purposes of measuring viral excretion) was 85%. In contrast, 66% of children who had received one previous dose of OPV and 25% of children who received two previous doses of OPV shed virus after the OPV challenge. No additional benefit was gained from a third dose (37 ). These data suggest that optimal gastrointestinal immunity is achieved after two doses of OPV in the sequential schedule. Both IPV and OPV are effective in reducing pharyngeal replication and subsequent transmission of poliovirus by the oral-oral route. # Safety of a Sequential Schedule The safety of sequential poliomyelitis vaccination schedules has been assessed among several hundred study participants (Table 2) and among infants residing in # VAPP A sequential vaccination schedule is expected to reduce VAPP by ≥50%. Circulating antibody against poliovirus induced by IPV is expected to reduce the already minimal risk for VAPP among immunocompetent recipients (among whom approximately three cases occur annually) nearly to zero (9 ). Further reduction in VAPP may result from decreases in the overall use of OPV in the United States. Decreased community exposure to excreted poliovirus derived from OPV is expected to reduce the number of community-acquired cases of VAPP (3 ). IPV-induced immunity of the pharyngeal mucosa and (to a lesser degree) of the intestinal mucosa may also reduce the number of contact cases by preventing oral-oral and fecal-oral transmission. Genetic sequencing studies suggest that reversion of Sabin poliovirus strains to potentially more neurovirulent phenotypes occurs commonly after OPV administration (49,50 ). Findings of two studies indicate that the use of a sequential vaccination schedule may not reduce the frequency of such reversions (51,52 ). However, findings from a third more systematic study designed to examine the issue of reversion suggest that, although administration of a dose of IPV before two or more doses of OPV may reduce shedding of type 3 virus (the most common cause of VAPP), the practice will not influence the shedding of types 1 or 2 or the extent of reversion (53 ). Thus, even if OPV is administered only to persons who have previously received one or more doses of IPV, reversion of vaccine poliovirus and excretion of revertant strains may still cause VAPP among susceptible contacts of OPV recipients. In the United States, an average of two cases of VAPP among immunodeficient persons is reported annually. The recommended sequential IPV-OPV vaccination schedule may also reduce the occurrence of such cases (3,9,31,54,55 ). Although the use of OPV is contraindicated in this group (54)(55)(56), the diagnosis of immunodeficiency is frequently not established by 2 months of age, when the infant is scheduled to receive the first dose of OPV under the previous ACIP recommendations (55 ). The new recommendations delay the administration of the first dose of OPV to 12-18 months of age. This change will allow an additional 10 months for diagnosis of any immunodeficiency disorder that would contraindicate administration of OPV. Some VAPP cases will likely occur despite the adoption of a sequential IPV-OPV vaccination schedule. Only the exclusive use of IPV or the discontinuation of all poliovirus vaccination efforts after achievement of global poliomyelitis eradication will completely eliminate VAPP. # Programmatic Issues Because no combination vaccine that includes IPV as a component is currently licensed in the United States, adoption of sequential IPV-OPV or all-IPV vaccination schedules will require additional injections at 2 and 4 months of age. In addition, acellular pertussis vaccine for use among infants has been licensed as DTaP rather than as a combined vaccine (e.g., DTaP-Haemophilus influenzae type b conjugate vaccine [HbCV]) and is preferred for the pertussis vaccine series. DTP remains an acceptable alternative. Several licensed combination vaccines are available (e.g., DTP-HbCV, HbCV and hepatitis B combination vaccine [COMVAX™ , Merck Co.]). Use of these vaccines during visits when IPV is administered will reduce the number of injections needed at a single visit. For each infant, health-care providers and parents must decide which of the following alternatives is preferable: a) additional injections, b) use of licensed combination vaccines, c) polio vaccination with OPV only, or d) additional clinic visits for administration of vaccines. Health-care providers should select a vaccination schedule for which the likelihood of compliance will be high, thereby promoting optimal protection against all vaccine-preventable childhood diseases. # RECOMMENDATIONS FOR POLIOVIRUS VACCINATION Routine Vaccination # Rationale for Choice of Vaccine Parents of children who are to be vaccinated should be informed of the poliovirus vaccines available, the three alternative vaccination schedules, and the basis for poliovirus vaccination recommendations. The benefits and risks of the vaccines as well as the advantages and disadvantages of the three vaccination options for individuals and for the community, should be discussed (Table 3). Vaccination schedules using IPV alone or OPV alone are both effective; both are acceptable options for preventing poliomyelitis. However, ACIP recommends the use of IPV followed by OPV for primary poliovirus vaccination of children in the United States because a) high levels of individual protection from two doses of IPV should reduce by 95% the number of VAPP cases that occurs among OPV recipients; b) sequential administration of IPV and OPV also may reduce VAPP among household and community contacts of OPV recipients because IPV provides some degree of intestinal and pharyngeal immunity; c) continued use of OPV induces intestinal immunity among vaccine recipients, thereby enhancing community resistance to transmission of wild virus (should it be reintroduced); d) fewer injections are required in the second year of life than would be required if only IPV were used, facilitating compliance with the overall childhood vaccination schedule; and e) stocking of both poliovirus vaccines by health-care providers enhances parental choice. Licensure of additional combination products will reduce the number of injections needed to administer the complete series of recommended childhood vaccinations. When the vaccination series is started after 6 months of age, OPV alone is preferred to enhance parent and provider compliance with the full childhood vaccination schedule. In this situation, the need to ensure administration of all recommended vaccines may require four or more simultaneous injections at each visit (see Accelerated Vaccination Schedule). OPV may be preferred if, during an initial visit, parents or providers decline the extra injections needed to administer all the recommended vaccines. OPV is preferred especially if there is concern that the child will not return on time for future vaccinations. OPV may also be preferred for children who are likely to travel to countries where polio is endemic. The superior gastrointestinal immunity conferred by OPV will reduce the risk that these children, should they be exposed during travel, might subsequently reintroduce wild poliovirus to the United States. IPV is the only poliovirus vaccine recommended for immunocompromised persons and their family contacts (see Immunocompromised Persons). In addition, an all-IPV vaccination schedule may be used when the number of injections is not a concern and is not likely to decrease parent or provider compliance with the childhood immunization schedule. Some parents or providers may prefer an all-IPV option to minimize the risk for VAPP. # Sequential Use of IPV and OPV For infants, children, and adolescents (i.e., persons <18 years of age), the primary sequential series of IPV and OPV consists of four doses. The primary series is administered at ages 2 months (IPV), 4 months (IPV), 12-18 months (OPV), and 4-6 years (OPV). For persons of any age, the first three doses should be separated by at least 4 weeks, although an interval of 6-8 weeks is preferred (see Accelerated Vaccination Schedule). Both IPV and OPV can be administered simultaneously with diphtheria and tetanus toxoids and whole-cell or acellular pertussis vaccine (DTP or DTaP), HbCV, hepatitis B vaccine, varicella vaccine, and measles-mumps-rubella (MMR) vaccine. # OPV Alone The primary series consists of three doses of vaccine. For infants, the primary series is usually integrated with the other vaccines routinely administered at 2, 4, and 6-18 months of age (Table 4). For routine vaccination, the minimum recommended interval between doses of OPV is 6-8 weeks. If the third dose of OPV is administered before the fourth birthday, a fourth dose of OPV should be provided before school entry (at 4-6 years of age). The fourth dose is not needed if the third dose is administered on or after the fourth birthday. OPV should not be used for the primary vaccination of persons ≥18 years of age (see Recommendations for Adults). # IPV Alone The primary series consists of three doses of vaccine. In infancy, these primary doses are integrated with the administration of other routinely administered vaccines. The first two doses are administered at 2 and 4 months of age; the third dose should be administered at 12-18 months of age with an interval of 6-12 months between the second and third doses (Table 4). Whereas the first and second doses of IPV are necessary to induce a primary immune response, the third dose of IPV ensures "boosting" of antibody titers to high levels. If accelerated protection is needed, the minimum interval between doses of IPV is 4 weeks, although the preferred interval between the second and third doses is 6 months (see Recommendations for Adults). All children who have received three doses of IPV before their fourth birthdays should receive a fourth dose before or at school entry. The fourth dose is not needed if the third dose is administered on or after the fourth birthday. # Interchangeability of Vaccines Completion of poliovirus vaccination with any of the three options (sequential IPV-OPV, OPV alone, or IPV alone) is preferred. However, if the vaccines are administered according to their licensed indications for minimum ages and intervals between doses, administration of four doses of IPV or OPV in any combination by 4-6 years of age is considered a complete poliovirus vaccination series. A minimum interval of 4 weeks should elapse if IPV is administered after OPV. # Options for Reducing the Number of Injections The number of injections needed to administer all recommended childhood vaccines to children 2 and 4 months of age (i.e., IPV, DTP or DTaP, HbCV, and hepatitis B) can be reduced to three (if IPV and HbCV combined with hepatitis B vaccine are administered) or two (if OPV and HbCV combined with hepatitis B vaccine are administered). For parents concerned about the number of injections, the following options to decrease the number of injections at the 2-and 4-month visits may be helpful: a) schedule the hepatitis B vaccine series at 0, 1, and 6 months of age (so that no doses of hepatitis B vaccine are needed during the 2-and 4-month visits); b) use licensed combination vaccines; c) schedule additional visits (if it can be ensured the child will be brought back for subsequent vaccinations at the recommended ages); and d) use OPV for the primary vaccination series. Development and licensure of additional combination products that contain the vaccine antigens recommended for children <1 year of age will make vaccination schedules that include IPV easier to implement. # Supplementary Vaccination at School Entry The poliovirus vaccination status of all children should be checked at school entry. The requirements for supplementary poliovirus vaccination depend on the type of vaccination schedule and the child's age and vaccination history. • Sequential IPV-OPV vaccination schedule. Children should receive a second dose of OPV to complete the four-dose sequential series, regardless of the age at which the series is initiated. Children who have previously received two doses of IPV followed by two doses of OPV do not require a supplementary dose at 4-6 years of age. • All-OPV vaccination schedule. Children who have previously received three doses of OPV should receive a fourth dose. However, if the third primary dose was administered on or after the fourth birthday, the fourth dose is not required • All-IPV vaccination schedule. Children who have previously received three doses of IPV should receive a fourth dose. However, if the third primary dose was administered on or after the fourth birthday, the fourth dose is not required. # Immunocompromised Persons IPV is the only poliovirus vaccine that should be administered to infants, adolescents, or adults if they have or are suspected to have a) an immunodeficiency disorder of any etiology (including infection with human immunodeficiency virus [HIV]), or if b) they are receiving immunosuppressive chemotherapy (e.g., cancer chemotherapy, or systemic steroid use). Because OPV virus can spread secondarily, OPV should not be administered to immunologically competent persons who live in a household with a person who has or is suspected to have any of these conditions; only IPV should be used. # Incompletely Vaccinated Children Children's poliovirus vaccination status should be reevaluated periodically. Those who are inadequately protected should complete the recommended vaccination series: • Sequential IPV-OPV vaccination schedule. The primary series of two doses of IPV followed by two doses of OPV is needed to ensure adequate humoral and intestinal immunity. Additional doses of vaccine are not needed if more than the recommended interval elapses between doses. • All-OPV vaccination schedule. The primary series of three doses of OPV is needed to ensure development of antibody to all three serotypes of poliovirus. Additional doses of vaccine are not needed if more than the recommended 6-8 weeks elapses between doses of OPV. • All-IPV vaccination schedule. Three doses of enhanced-potency IPV administered after 1987 are considered a complete primary series. As with OPV, no additional doses are needed if more time than recommended elapses between doses (e.g., >6-8 weeks between the first two doses or >6-12 months between the second and third doses). For IPV administered before 1988, four doses were required to complete a primary series (three doses administered at an interval of 4-8 weeks with a fourth dose 6-12 months after the third) (46,47 ). # Accelerated Vaccination Schedule For infants and children starting vaccination late (i.e., >6 months of age) or for whom accelerated protection against poliomyelitis is required, vaccination with OPV only is preferred (if not contraindicated). The minimum interval between doses of OPV under these circumstances is 4 weeks. A three-dose accelerated OPV series can be administered simultaneously with DTP or DTaP, HbCV, hepatitis B, MMR, and varicella vaccines. Limited data from the United States suggest that the rate of seroconversion among children vaccinated with three doses of OPV at 4-week intervals is similar to the rate among children who receive three doses of OPV at 8-week intervals (57 ). Children should be administered a supplemental dose of OPV at 4-6 years of age. For infants and children for whom IPV is indicated, the accelerated schedule permits administration of the first two doses of IPV with a minimum interval of 4 weeks. An interval of 6 months between the second and third doses is preferred because it will provide optimal immune response. As with OPV, these children should receive an additional dose of IPV at 4-6 years of age. For accelerated sequential IPV-OPV vaccination of infants and children, the first three doses (IPV, IPV, OPV) should be administered at 4-week intervals. The second dose of OPV should be administered at 4-6 years of age. Incompletely vaccinated children who are at increased risk for exposure to poliovirus should be administered the remaining required doses. If time is a limiting factor, incompletely vaccinated children should be administered at least a single dose of either vaccine (see Recommendations for Adults). # RECOMMENDATIONS FOR ADULTS Routine poliovirus vaccination of adults (generally persons ≥18 years of age) residing in the United States is not necessary. Most adults have a minimal risk for exposure to polioviruses in the United States and most are immune as a result of vaccination during childhood. Vaccination is recommended for certain adults who are at greater risk for exposure to polioviruses than the general population, including the following persons: • travelers to areas or countries where poliomyelitis is epidemic or endemic, • members of communities or specific population groups with disease caused by wild polioviruses, • laboratory workers who handle specimens that may contain polioviruses, • health-care workers who have close contact with patients who may be excreting wild polioviruses, • unvaccinated adults whose children will be receiving oral poliovirus vaccine. For unvaccinated adults, primary vaccination with IPV is recommended because the risk for vaccine-associated paralysis after administration of OPV is higher among adults than among children (29 ). Two doses of IPV should be administered at intervals of 4-8 weeks; a third dose should be administered 6-12 months after the second. If three doses of IPV cannot be administered within the recommended intervals before protection is needed, the following alternatives are recommended: • If ≥8 weeks are available before protection is needed, three doses of IPV should be administered at least 4 weeks apart. • If <8 but >4 weeks are available before protection is needed, two doses of IPV should be administered at least 4 weeks apart. • If <4 weeks are available before protection is needed, a single dose of OPV or IPV is recommended. The remaining doses of vaccine should be administered later, at the recommended intervals, if the person remains at increased risk. Adults who have had a primary series of OPV or IPV and who are at increased risk for exposure to poliovirus may receive another dose of either OPV or IPV. Persons who may be at increased risk include a) travelers to areas where poliomyelitis is endemic, b) certain laboratory personnel, and c) medical staff directly involved with the provision of care to patients who may be excreting poliovirus. These adults are not at increased risk for VAPP. The need for administration to adults of more than one supplementary dose of either IPV or OPV has not been established. Adults who have not been adequately vaccinated against poliomyelitis with OPV or IPV have a minimal risk for developing OPV-associated paralytic poliomyelitis when OPV is administered to children in their households. Since 1980, approximately onetwo cases of VAPP have occurred each year among adult household contacts of children who received OPV; during that time approximately 19 million doses of OPV were distributed yearly (see Adverse Reactions). Because of the overriding importance of ensuring prompt and complete immunization, sequential IPV-OPV vaccination of children should begin regardless of the poliovirus vaccine status of adult household contacts. If unvaccinated or inadequately vaccinated persons are known to reside in the child's household, IPV alone should be used to complete the child's vaccination, thereby reducing the already minimal risk for VAPP among adult household contacts. # PRECAUTIONS AND CONTRAINDICATIONS # Hypersensitivity or Anaphylactic Reactions to IPV, OPV, or the Antibiotics Contained in These Vaccines IPV should not be administered to persons who have experienced an anaphylactic reaction following a previous dose of IPV or an anaphylactic reaction to streptomycin, polymyxin B, or neomycin. OPV should not be administered to persons who have experienced an anaphylactic reaction to a previous dose of OPV. # Pregnancy Although no adverse effects of OPV or IPV have been documented among pregnant women or their fetuses, vaccination of pregnant women should be avoided. However, if a pregnant woman requires immediate protection against poliomyelitis, she may be administered OPV or IPV in accordance with the recommended schedules for adults. (See Recommendations for Adults.) # Immunodeficiency OPV should not be administered to persons who have immunodeficiency disorders (e.g., severe combined immunodeficiency syndrome, agammaglobulinemia, or hypogammaglobulinemia) because these persons are at substantially increased risk for VAPP. Similarly, OPV should not be administered to persons with altered immune states resulting from malignant disease (e.g., leukemia, lymphoma, or generalized malignancy), or to persons whose immune systems have been compromised (e.g., by therapy with corticosteroids, alkylating drugs, antimetabolites, or radiation or by HIV infection). OPV should not be used to vaccinate household contacts of immunodeficient patients; IPV is recommended. Many immunosuppressed persons are immune to polioviruses as a result of previous vaccination or exposure to wild-type virus at a time when they were immunologically competent. Although their risk for paralytic disease is thought to be less than that for persons with congenital or acquired immunodeficiency disorders, these persons should not receive OPV. Administration of IPV to immunodeficient persons is safe. Although a protective immune response in these persons cannot be assured, IPV may confer some protection. # Inadvertent Administration of OPV to Members of Households with Immunocompromised Persons If OPV is inadvertently administered to a household contact of an immunodeficient patient, the patient and the recipient of OPV should avoid close contact for approximately 4-6 weeks after vaccination. If this is not feasible, rigorous hygiene and hand washing after contact with feces (e.g., after diaper changing) and avoidance of contact with saliva (e.g., sharing food or utensils) may be an acceptable but probably a less effective alternative. Maximum excretion of vaccine virus occurs within 4 weeks after oral vaccination. # False Contraindications Breastfeeding does not interfere with successful immunization against poliomyelitis with IPV or OPV. A dose of IPV may be administered to a child who has diarrhea. A dose of OPV may be administered to a child who has mild diarrhea. Minor upper respiratory illnesses with or without fever, mild to moderate local reactions to a previous dose of vaccine, current antimicrobial therapy, and the convalescent phase of an acute illness are not contraindications for vaccination with IPV or OPV (58 ). # Regurgitation of OPV Infants may not completely swallow OPV. If, in the judgment of the person administering the vaccine, a substantial amount of vaccine is regurgitated or vomited soon after administration (i.e., within 5-10 minutes) another dose can be administered during the same visit. If this repeat dose is not retained, neither dose should be counted and the vaccine should be readministered during a later visit (58 ). # ADVERSE REACTIONS IPV No serious side effects of enhanced-potency IPV have been documented. Because IPV contains trace amounts of streptomycin, polymyxin B, and neomycin, hypersensitivity reactions may occur among persons sensitive to these antibiotics. # OPV In rare instances, administration of OPV has been associated with paralysis in healthy recipients and their contacts. No procedures are currently available for identifying persons (other than those with immunodeficiency) who are at risk for such adverse reactions. Although the risk for vaccine-associated paralysis is minimal, vaccinees (or their parents) and their susceptible, close, personal contacts should be informed of this risk (Table 1). Administration of OPV may very rarely cause paralytic poliomyelitis that results in death (3,31 ). # Guillain-Barré Syndrome The available evidence indicates that administration of OPV or IPV does not measurably increase the risk for Guillain-Barré syndrome (GBS). Preliminary findings from two studies in Finland led to a contrary conclusion in a review conducted by the Institute of Medicine (IOM) in 1993 (59,60 ). The investigators in Finland reported an apparent increase in the incidence of GBS that was temporally associated with a mass vaccination campaign during which OPV was administered to children and adults who had previously been vaccinated with IPV. After the IOM review was completed, however, these data were reanalyzed and an observational study was completed in the United States. Neither the reanalysis nor the newly completed study provided evidence of a causal relationship between OPV administration and GBS (61 ). The two most recent outbreaks of poliomyelitis reported in the United States affected members of religious groups who object to vaccination (i.e., outbreaks occurred in 1972 among Christian Scientists and in 1979 among members of an Amish community). Poliomyelitis should be suspected in any case of acute flaccid paralysis that affects an unvaccinated member of such a religious group. All such cases should be investigated promptly and followed up accordingly (see Surveillance). # Surveillance CDC conducts national surveillance for poliomyelitis in collaboration with state and local health departments. Suspected cases of poliomyelitis must be reported immediately to local or state health departments. CDC compiles and summarizes clinical, epidemiologic, and laboratory data concerning suspected cases. Three independent experts review the data and determine whether a suspected case meets the clinical case definition of paralytic poliomyelitis (i.e., a paralytic illness clinically and epidemiologically compatible with poliomyelitis in which a neurologic deficit is present 60 days after onset of symptoms [unless death has occurred or follow-up status is unknown]). On the basis of epidemiologic and laboratory criteria, CDC classifies confirmed cases of paralytic poliomyelitis as vaccine-associated or wild-type related and (based on OPV exposure data) as vaccine recipient or contact cases (9 ). For the recommended control measures to be undertaken in a timely manner, a preliminary assessment must ascertain as soon as possible whether a suspected case is likely vaccine-associated or caused by wild poliovirus (see Case Investigation and Laboratory Methods). # Laboratory Methods Specimens for virus isolation (e.g, stool, throat swab, and cerebrospinal fluid [CSF]) and serologic testing must be obtained in a timely fashion. The greatest yield for poliovirus is from stool culture, and timely collection of stool specimens increases the likelihood of case confirmation. At least two stool specimens and two throat swab specimens should be obtained from patients who are suspected to have poliomyelitis. Specimens should be obtained at least 24 hours apart as early in the course of illness as possible, ideally within 14 days of onset. Stool specimens collected ≥2 months after the onset of paralytic manifestations are unlikely to yield poliovirus. Throat swabs are less often positive than stool samples, and virus is rarely detected in CSF. In addition, an acute-phase serologic specimen should be obtained as early in the course of illness as possible, and a convalescent-phase specimen should be obtained at least 3 weeks later. The following tests should be performed on appropriate specimens collected from persons who have suspected cases of poliomyelitis: a) isolation of poliovirus in tissue culture; b) serotyping of a poliovirus isolate as type 1, 2, or 3; and c) intratypic differentiation using DNA/RNA probe hybridization or polymerase chain reaction to determine whether a poliovirus isolate is vaccine-related or wild-type. Acute-phase and convalescent-phase serum specimens should be tested for neutralizing antibody to each of the three poliovirus serotypes. A fourfold rise in antibody titer between appropriately timed acute-phase and convalescent-phase serum specimens is diagnostic for poliovirus infection. The recently revised standard protocol for poliovirus serology should be used (64 ). Commercial laboratories usually perform complement fixation and other tests. However, assays other than neutralization are difficult to interpret because of inadequate standardization and relative insensitivity. Laboratory experts at CDC are available for consultation and will test specimens from patients who have suspected poliomyelitis (i.e., patients with acute paralytic manifestations); telephone (404) 639-2749. # RECOMMENDED SURVEILLANCE, RESEARCH, AND EDUCATION ACTIVITIES Several programmatic activities in disease surveillance, research, and education should be implemented in conjunction with the new poliovirus vaccination schedule. The recommended activities are: a) Enhance surveillance for paralytic poliomyelitis to facilitate early detection and control of outbreaks caused by imported wild virus and to evaluate the impact of the revised vaccination schedule on incidence of VAPP. b) Conduct expanded surveillance of potential adverse effects of IPV as the vaccine is administered to more children and adults. c) Assess the possible influence of the revised vaccination schedule on childhood vaccine coverage (particularly in populations in which coverage is suboptimal); continue development of vaccine registries. d) Expand surveillance of other vaccine-preventable childhood diseases as a means of detecting possible effects of the revised polio vaccination schedule (particularly the required additional injections) on coverage with all vaccines recommended for infants and children. e) Develop and evaluate materials to educate parents and health-care providers about poliovirus vaccines and vaccination schedules. f) Evaluate parent and provider acceptance of the additional injections required by the revised vaccination schedule at 2 and 4 months of age. g) Accelerate development of combination vaccines. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to [email protected]. The body content should read subscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/ or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1997-532-228/47051 Region IV # Reporting of Adverse Events Following Vaccination The National Childhood Vaccine Injury Act of 1986 requires health-care providers to report serious adverse events following poliovirus vaccination (62 ). The events that must be reported are detailed in the Reportable Events Table within this Act, and include paralytic poliomyelitis and any acute complications or sequelae of paralytic poliomyelitis. Adverse reactions should be reported to the Vaccine Adverse Events Reporting System (VAERS). VAERS reporting forms and information are available 24 hours a day by calling (800) 822-7967. # Vaccine Injury Compensation Program The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, provides a mechanism through which compensation can be paid on behalf of a person who died or was injured as a result of receiving vaccine. A Vaccine Injury Table in the Act lists the vaccines covered by the program and the injuries, disabilities, illnesses, and conditions (including death) for which compensation may be paid. Development or onset of vaccine-associated paralytic poliomyelitis in an OPV recipient (within 30 days), or in a person in contact with an OPV vaccinee (not specified), or in an immunodeficient person (within 6 months) are potentially compensable under this law. Additional information is available (63 ). # INVESTIGATION AND REPORTING OF SUSPECTED POLIOMYELITIS CASES # Case Investigation Each suspected case of poliomyelitis should prompt an immediate epidemiologic investigation. If evidence suggests the transmission of wild poliovirus, an active search for other cases that may initially have been misdiagnosed (e.g., as GBS, polyneuritis, or transverse myelitis) should be conducted. Control measures (including an OPV vaccination campaign designed to contain further transmission) should be instituted immediately. If evidence suggests vaccine-related poliovirus, no vaccination plan need be developed, because no outbreaks associated with live, attenuated vaccine-related poliovirus strains have been documented. Within an epidemic area, OPV should be provided for all immunocompetent persons, regardless of previous OPV vaccination status (	None	None
6445a921bf4b9452cec2de5418a08cfb2a9cde9b	cdc	None	Tick ID Tick ID Maps Lyme Disease Babesiosis Anaplasmosis Tularemia Other Tickborne Diseases Rocky Mountain Spotted Fever Ehrlichiosis Tick Bites/ Prevention BLACKLEGGED TICK Ixodes scapularis Where found: Widely distributed in the northeastern and upper midwestern United States. Transmits: Lyme disease, anaplasmosis, babesiosis, and Powassan disease. Comments: The greatest risk of being bitten exists in the spring, summer, and fall. However, adults may be out searching for a host any time winter temperatures are above freezing. Stages most likely to bite humans are nymphs and adult females. 3 2 LONE STAR TICK Amblyomma americanum Where found: Widely distributed in the southeastern and eastern United States. Transmits: Ehrlichia chaffeensis and Ehrlichia ewingii (which cause human ehrlichiosis), tularemia, and STARI. Comments: A very aggressive tick that bites humans. The adult female is distinguished by a white dot or "lone star" on her back. Lone star tick saliva can be irritating; redness and discomfort at a bite site does not necessarily indicate an infection. The nymph and adult females most frequently bite humans and transmit disease.Where found: Widely distributed east of the Rocky Mountains. Also occurs in limited areas on the Pacific Coast. Transmits: Tularemia and Rocky Mountain spotted fever. Comments: The highest risk of being bitten occurs during spring and summer. Dog ticks are sometimes called wood ticks. Adult females are most likely to bite humans. Engorged female Ixodes scapularis tick. Color may vary. NOTE: Illustrations are not to scale. Tick ID Tick ID Maps Lyme Disease Babesiosis Anaplasmosis Tularemia Other Tickborne Diseases Rocky Mountain Spotted Fever Ehrlichiosis Tick Bites/ Prevention BROWN DOG TICK Rhipicephalus sanguineus Where found: Worldwide. Transmits: Rocky Mountain spotted fever (in the southwestern U.S. and along the U.S.-Mexico border). Comments: Dogs are the primary host for the brown dog tick in each of its life stages, but the tick may also bite humans or other mammals.# Comments: Adult ticks feed primarily on large mammals. Larvae and nymphs feed on small rodents. Adult ticks are primarily associated with pathogen transmission to humans. - Cough - Rash (rare cases) 9 8 The Signs and Symptoms list presents symptoms commonly seen with anaplasmosis. However, it is important to note that few people will develop all symptoms and the number and combination of symptoms varies greatly from person to person. # LABS Confirmation of the diagnosis is based on laboratory testing, but antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation. # GENERAL LABORATORY FINDINGS LABORATORY CONFIRMATION Typically Observed During the First Week of Clinical Disease: Antibodies to A. phagocytophilum are detectable 7-10 - days after illness onset. The gold-standard serologic Mild anemia - test looks for a four-fold change in antibody titers using Thrombocytopenia - immunofluorescence assay (IFA) on paired samples. The first Leukopenia (characterized by relative and absolute sample should be taken within the first week of illness and lymphopenia and a left shift) - the second should be taken 2 to 4 weeks later. Mild to moderate elevations in hepatic transaminases may occur in some patients. - Demonstration of a four-fold change in IgG-specific antibody - Visualization of morulae in the cytoplasm of granulocytes titer by immunofluorescence assay (IFA) test in paired serum during examination of blood smears is highly suggestive of samples; or a diagnosis; however, blood smear examination is insensitive - Detection of DNA by PCR of whole blood. This method is and should never be relied upon solely to rule anaplasmosis in most sensitive within the first week of illness; sensitivity may or out. decrease after administration of antibiotics. NOTE: IgM antibodies are less specific than IgG antibodies and are more likely to generate false positives. IgM results alone should not be used for laboratory diagnosis. # NOTE: Consider the possibility of coinfection with Babesia microti and/or Borrelia burgdorferi. # NOTE: Antibody titers are frequently negative in the first 7-10 days of illness, thus serologic tests may be falsely negative during this time period. Anaplasmosis Anaplasmosis, ehrlichiosis, and Rocky Mountain spotted fever are treated in the same manner with doxycycline. Clinical suspicion of any of these diseases is sufficient to begin treatment. Delay in treatment may result in severe illness and even death. The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status, or allergies. Consult an infectious disease specialist in cases of documented pregnancy or life-threatening allergies to doxycycline. AGENT Anaplasma phagocytophilum TREATMENT # WHERE FOUND Ehrlichiosis is most frequently reported from the southeastern and south-central U.S., from the eastern seaboard extending westward to Texas. The areas from which cases are reported correspond with the known geographic distribution of the lone star tick (Amblyomma americanum), which is associated with transmission of both E. chaffeensis and E. ewingii. Three states (Oklahoma, Missouri, Arkansas) account for 35% of all reported E. chaffeensis infections. In 2009, a new Ehrlichia species, provisionally called Ehrlichia muris-like (EML) was identified among patients in the upper Midwest. Since that time more than 67 cases have been identified. At this time, the tick responsible for transmitting EML is unknown and clinical presentations have not been differentiated from that of other Ehrlichia species. Ehrlichiosis and anaplasmosis have a similar clinical presentation, but they are transmitted by two different species of ticks and generally occur in different regions of the U.S. The Signs and Symptoms list presents symptoms commonly seen with ehrlichiosis. However, it is important to note that few people will develop all symptoms and the number and combination of symptoms varies greatly from person to person. # LABS Confirmation of the diagnosis is based on laboratory testing, but antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation. # GENERAL LABORATORY FINDINGS LABORATORY CONFIRMATION # LABORATORY DIAGNOSIS - Demonstration of diagnostic IgM or IgG antibodies in serum. A two-tier testing protocol is recommended-EIA or IFA should be performed first; if positive or equivocal it is followed by a Western blot. - Isolation of organism from a clinical specimen. - In suspected Lyme meningitis, testing for intrathecal IgM or IgG antibodies may be helpful. # NOTES ON SEROLOGIC TESTS FOR LYME DISEASE - Serologic tests are insensitive during the first few weeks of infection. During this stage, patients with an EM rash may be diagnosed clinically. While not necessary, acute and convalescent titers may be helpful in some cases. - In persons with illness > 1 month, only IgG testing should be performed (not IgM). A positive IgM test alone is not sufficient to diagnose current disease. - Due to antibody persistence, single positive serologic test results cannot distinguish between active and past infection. - Serologic tests cannot be used to measure treatment response. - Enzyme immunoassay (EIA) and immunofluorescence assay (IFA) tests have low specificity and may yield false-positive results. They may cross-react with antibodies to commensal or pathogenic spirochetes, some viral infections (e.g., varicella, Epstein-Barr virus), or certain autoimmune diseases (e.g., lupus). # NOTE: Lyme Disease AGENT Borrelia burgdorferi TREATMENT # Tick Bites/ Prevention The erythema migrans (EM) rash occurs in 70-80% of patients with Lyme disease. EM rashes expand slowly over a few days after which they may develop a "bull's-eye" appearance consisting of a red ring with central clearing. However, EM may take alternate forms-solid lesions, blue-purple hues, and crusted or blistering lesions have all been documented. The rash is not painful or pruritic, but it may be warm to the touch. If early localized Lyme disease is not treated, patients may develop multiple secondary circular rashes as spirochetes disseminate throughout the body. Classic EM-Circular red rash with central clearing that slowly expands - Typically appears 2-5 days after the onset of fever - Small, flat, pink, non-itchy spots (macules) initially appear on the wrists, forearms, and ankles then spread to the trunk and sometimes palms and soles. - Rash may not develop until late in the disease process, after treatment should have already begun. Approximately 10% of RMSF patients never develop a rash at all. - Consider RMSF if other signs and symptoms support a diagnosis, even if a rash is not present. # Petechial Rash - Red to purple spots (petechiae) are usually not seen until day 6 or later after onset of symptoms. - Petechial rash is considered a sign of progression to severe disease. Every attempt should be made to begin treatment before petechiae develop. # GENERAL LABORATORY FINDINGS - Thrombocytopenia - Mildly elevated hepatic transaminase levels - Hyponatremia # LABORATORY CONFIRMATION Antibodies to R. rickettsii are detectable 7-10 days after illness onset. The gold-standard serologic test looks for a four-fold change in antibody titers using immunofluorescence assay (IFA) on paired samples. The first sample should be taken within the first week of illness and the second should be taken 2 to 4 weeks later. - Demonstration of a four-fold change in IgG-specific antibody titer by immunofluorescence assay (IFA) test in paired serum samples; or - Detection of DNA in a skin biopsy of rash by polymerase chain reaction (PCR) assay (generally unreliable for acute blood samples). - Immunohistochemical (IHC) staining of organism from skin or tissue biopsy NOTE: IgM antibodies are less specific than IgG antibodies and are more likely to generate false positives. IgM results alone should not be used for laboratory diagnosis. NOTE: Antibody titers are frequently negative in the first 7-10 days of illness, thus serologic tests may be falsely negative during this time period. # Rocky Mountain Spotted Fever AGENT Rickettsia rickettsii TREATMENT # Tick Bites/ Prevention Anaplasmosis, ehrlichiosis, and Rocky Mountain spotted fever are treated in the same manner with doxycycline. † Clinical suspicion of any of these diseases is sufficient to begin treatment. Delay in treatment may result in severe illness and even death. The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status, or allergies. Consult an infectious disease specialist in cases of pregnancy or documented life-threatening allergies to doxycycline. # WHERE FOUND In the U.S., naturally occurring tularemia infections have been reported from all states except Hawaii. Ticks that transmit tularemia to humans include the dog tick (Dermacentor variabilis), the wood tick (Dermacentor andersoni), and the lone star tick (Amblyomma americanum). Other transmission routes include inhalation and direct inoculation. # INCUBATION PERIOD: SIGNS AND SYMPTOMS 3-5 days (range 1-21 # Tick Bites/ Prevention The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status or allergies. Consult an infectious disease specialist for the most current treatment guidelines or for individual patient treatment decisions. # Tickborne Diseases Abroad Activities that increase risk for tick exposure worldwide include (but are not limited to): outdoor recreation such as camping, hiking, fishing, or bicycling; military training; outdoor occupations such as forestry; and collecting mushrooms, berries, or flowers in forested or agricultural areas. # DISEASE & ETIOLOGIC AGENT(S) GEOGRAPHIC LOCATION AND ADDITIONAL RISK FACTORS # Lyme Disease Borrelia afzelii, Borrelia garinii, B. burgdorferi sensu stricto # Eastern and central Europe, northern Asia # Tick-Borne Encephalitis Tick-borne encephalitis virus Temperate regions of Europe and northern Asia. May also be acquired by ingestion of unpasteurized dairy products from infected goats, sheep, or cows. Spotted Fever Group Rickettsioses (includes tick typhuses) R. akari, R. parkeri, R. africae, R. japonica, R. felis, etc. All continents except Antarctica. R. africae infection has been reported as a cause of fever in travelers returning from South Africa. # Crimean-Congo Hemorrhagic Fever CCHF virus Asia, Africa, and Europe. May also be acquired by contact with infected blood or saliva or inhalation of infected aerosols. # Omsk Hemorrhagic Fever Omsk hemorrhagic fever virus Southwestern Russia. May also be acquired by direct contact with infected muskrats. # Kyasanur Forest Disease Kyasanur forest disease virus Southern India, Saudi Arabia (aka Alkhurma disease in Saudi Arabia). Typically associated with exposure while harvesting forest products. NOTE: Anaplasmosis, babesiosis, ehrlichiosis, tularemia, TBRF, and Powassan disease can also be acquired internationally. Please see disease-specific references for more information on worldwide distribution. # Tick Bites/Prevention # Tick Bites/ Prevention Ticks are generally found near the ground, in brushy or wooded areas. They can't jump or fly. Instead, they climb tall grasses or shrubs and wait for a potential host to brush against them. When this happens, they climb onto the host and seek a site for attachment. # PREVENTION 1. Wear repellent containing at least 20% DEET or permethrin-treated clothing. Additional repellent options are available. For more information, see /. 2. Treat dogs and cats for ticks as recommended by a veterinarian. 3. Check for ticks daily, especially under the arms, in and around the ears, inside the belly button, behind the knees, between the legs, around the waist, and on the hairline and scalp. 4. Shower soon after being outdoors. 5. For tips on "tick-safe" landscaping, see www.cdc.gov/lyme/prev/in_the_yard.html. # TICK REMOVAL 6. Use fine-tipped tweezers to grasp the tick as close to the skin's surface as possible. You may use specialized tick removal tools, if you already have them. The key is to remove the tick as soon as possible. Avoid folklore remedies such as using nail polish, petroleum jelly, or heat to make the tick detach from the skin. 7. Pull upward with steady, even pressure. Don't twist or jerk the tick; this can cause the mouth-parts to break off and remain in the skin. If this happens, remove the mouth-parts with clean tweezers. If you are unable to remove the mouth parts easily, leave them alone and let the skin heal. 8. After removing the tick, thoroughly clean the bite area and your hands with rubbing alcohol, an iodine scrub, or soap and water. Antibiotic treatment following a tick bite is not recommended as a means to prevent anaplasmosis, babesiosis, ehrlichiosis, or Rocky Mountain spotted fever. There is no evidence this practice is effective, and it may simply delay onset of disease. Instead, persons who experience a tick bite should be alert for symptoms suggestive of tickborne illness and consult a physician if fever, rash, or other symptoms of concern develop. Tularemia prophylaxis is recommended only in cases of laboratory exposure to infectious materials: - Doxycycline (100 mg orally BID X 14 days) is generally recommended for prophylaxis in adults. - Ciprofloxacin (500 mg orally BID) is not FDA-approved for prophylaxis of tularemia but has demonstrated efficacy in various studies, and may be an alternative for patients unable to take doxycycline.	Tick ID Tick ID Maps Lyme Disease Babesiosis Anaplasmosis Tularemia Other Tickborne Diseases Rocky Mountain Spotted Fever Ehrlichiosis Tick Bites/ Prevention BLACKLEGGED TICK Ixodes scapularis Where found: Widely distributed in the northeastern and upper midwestern United States. Transmits: Lyme disease, anaplasmosis, babesiosis, and Powassan disease. Comments: The greatest risk of being bitten exists in the spring, summer, and fall. However, adults may be out searching for a host any time winter temperatures are above freezing. Stages most likely to bite humans are nymphs and adult females. 3 2 LONE STAR TICK Amblyomma americanum Where found: Widely distributed in the southeastern and eastern United States. Transmits: Ehrlichia chaffeensis and Ehrlichia ewingii (which cause human ehrlichiosis), tularemia, and STARI. Comments: A very aggressive tick that bites humans. The adult female is distinguished by a white dot or "lone star" on her back. Lone star tick saliva can be irritating; redness and discomfort at a bite site does not necessarily indicate an infection. The nymph and adult females most frequently bite humans and transmit disease.Where found: Widely distributed east of the Rocky Mountains. Also occurs in limited areas on the Pacific Coast. Transmits: Tularemia and Rocky Mountain spotted fever. Comments: The highest risk of being bitten occurs during spring and summer. Dog ticks are sometimes called wood ticks. Adult females are most likely to bite humans. Engorged female Ixodes scapularis tick. Color may vary. NOTE: Illustrations are not to scale. Tick ID Tick ID Maps Lyme Disease Babesiosis Anaplasmosis Tularemia Other Tickborne Diseases Rocky Mountain Spotted Fever Ehrlichiosis Tick Bites/ Prevention BROWN DOG TICK Rhipicephalus sanguineus Where found: Worldwide. Transmits: Rocky Mountain spotted fever (in the southwestern U.S. and along the U.S.-Mexico border). Comments: Dogs are the primary host for the brown dog tick in each of its life stages, but the tick may also bite humans or other mammals.# Comments: Adult ticks feed primarily on large mammals. Larvae and nymphs feed on small rodents. Adult ticks are primarily associated with pathogen transmission to humans. • Cough • Rash (rare cases) 9 8 The Signs and Symptoms list presents symptoms commonly seen with anaplasmosis. However, it is important to note that few people will develop all symptoms and the number and combination of symptoms varies greatly from person to person. # LABS Confirmation of the diagnosis is based on laboratory testing, but antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation. # GENERAL LABORATORY FINDINGS LABORATORY CONFIRMATION Typically Observed During the First Week of Clinical Disease: Antibodies to A. phagocytophilum are detectable 7-10 • days after illness onset. The gold-standard serologic Mild anemia • test looks for a four-fold change in antibody titers using Thrombocytopenia • immunofluorescence assay (IFA) on paired samples. The first Leukopenia (characterized by relative and absolute sample should be taken within the first week of illness and lymphopenia and a left shift) • the second should be taken 2 to 4 weeks later. Mild to moderate elevations in hepatic transaminases may occur in some patients. • Demonstration of a four-fold change in IgG-specific antibody • Visualization of morulae in the cytoplasm of granulocytes titer by immunofluorescence assay (IFA) test in paired serum during examination of blood smears is highly suggestive of samples; or a diagnosis; however, blood smear examination is insensitive • Detection of DNA by PCR of whole blood. This method is and should never be relied upon solely to rule anaplasmosis in most sensitive within the first week of illness; sensitivity may or out. decrease after administration of antibiotics. NOTE: IgM antibodies are less specific than IgG antibodies and are more likely to generate false positives. IgM results alone should not be used for laboratory diagnosis. # NOTE: Consider the possibility of coinfection with Babesia microti and/or Borrelia burgdorferi. # NOTE: Antibody titers are frequently negative in the first 7-10 days of illness, thus serologic tests may be falsely negative during this time period. Anaplasmosis Anaplasmosis, ehrlichiosis, and Rocky Mountain spotted fever are treated in the same manner with doxycycline. Clinical suspicion of any of these diseases is sufficient to begin treatment. Delay in treatment may result in severe illness and even death. The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status, or allergies. Consult an infectious disease specialist in cases of documented pregnancy or life-threatening allergies to doxycycline. AGENT Anaplasma phagocytophilum TREATMENT # WHERE FOUND Ehrlichiosis is most frequently reported from the southeastern and south-central U.S., from the eastern seaboard extending westward to Texas. The areas from which cases are reported correspond with the known geographic distribution of the lone star tick (Amblyomma americanum), which is associated with transmission of both E. chaffeensis and E. ewingii. Three states (Oklahoma, Missouri, Arkansas) account for 35% of all reported E. chaffeensis infections. In 2009, a new Ehrlichia species, provisionally called Ehrlichia muris-like (EML) was identified among patients in the upper Midwest. Since that time more than 67 cases have been identified. At this time, the tick responsible for transmitting EML is unknown and clinical presentations have not been differentiated from that of other Ehrlichia species. Ehrlichiosis and anaplasmosis have a similar clinical presentation, but they are transmitted by two different species of ticks and generally occur in different regions of the U.S. The Signs and Symptoms list presents symptoms commonly seen with ehrlichiosis. However, it is important to note that few people will develop all symptoms and the number and combination of symptoms varies greatly from person to person. # LABS Confirmation of the diagnosis is based on laboratory testing, but antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation. # GENERAL LABORATORY FINDINGS LABORATORY CONFIRMATION # LABORATORY DIAGNOSIS • Demonstration of diagnostic IgM or IgG antibodies in serum. A two-tier testing protocol is recommended-EIA or IFA should be performed first; if positive or equivocal it is followed by a Western blot. • Isolation of organism from a clinical specimen. • In suspected Lyme meningitis, testing for intrathecal IgM or IgG antibodies may be helpful. # NOTES ON SEROLOGIC TESTS FOR LYME DISEASE • Serologic tests are insensitive during the first few weeks of infection. During this stage, patients with an EM rash may be diagnosed clinically. While not necessary, acute and convalescent titers may be helpful in some cases. • In persons with illness > 1 month, only IgG testing should be performed (not IgM). A positive IgM test alone is not sufficient to diagnose current disease. • Due to antibody persistence, single positive serologic test results cannot distinguish between active and past infection. • Serologic tests cannot be used to measure treatment response. • Enzyme immunoassay (EIA) and immunofluorescence assay (IFA) tests have low specificity and may yield false-positive results. They may cross-react with antibodies to commensal or pathogenic spirochetes, some viral infections (e.g., varicella, Epstein-Barr virus), or certain autoimmune diseases (e.g., lupus). # NOTE: Lyme Disease AGENT Borrelia burgdorferi TREATMENT # Tick Bites/ Prevention The erythema migrans (EM) rash occurs in 70-80% of patients with Lyme disease. EM rashes expand slowly over a few days after which they may develop a "bull's-eye" appearance consisting of a red ring with central clearing. However, EM may take alternate forms-solid lesions, blue-purple hues, and crusted or blistering lesions have all been documented. The rash is not painful or pruritic, but it may be warm to the touch. If early localized Lyme disease is not treated, patients may develop multiple secondary circular rashes as spirochetes disseminate throughout the body. Classic EM-Circular red rash with central clearing that slowly expands • Typically appears 2-5 days after the onset of fever • Small, flat, pink, non-itchy spots (macules) initially appear on the wrists, forearms, and ankles then spread to the trunk and sometimes palms and soles. • Rash may not develop until late in the disease process, after treatment should have already begun. Approximately 10% of RMSF patients never develop a rash at all. • Consider RMSF if other signs and symptoms support a diagnosis, even if a rash is not present. # Petechial Rash • Red to purple spots (petechiae) are usually not seen until day 6 or later after onset of symptoms. • Petechial rash is considered a sign of progression to severe disease. Every attempt should be made to begin treatment before petechiae develop. # GENERAL LABORATORY FINDINGS • Thrombocytopenia • Mildly elevated hepatic transaminase levels • Hyponatremia # LABORATORY CONFIRMATION Antibodies to R. rickettsii are detectable 7-10 days after illness onset. The gold-standard serologic test looks for a four-fold change in antibody titers using immunofluorescence assay (IFA) on paired samples. The first sample should be taken within the first week of illness and the second should be taken 2 to 4 weeks later. • Demonstration of a four-fold change in IgG-specific antibody titer by immunofluorescence assay (IFA) test in paired serum samples; or • Detection of DNA in a skin biopsy of rash by polymerase chain reaction (PCR) assay (generally unreliable for acute blood samples). • Immunohistochemical (IHC) staining of organism from skin or tissue biopsy NOTE: IgM antibodies are less specific than IgG antibodies and are more likely to generate false positives. IgM results alone should not be used for laboratory diagnosis. NOTE: Antibody titers are frequently negative in the first 7-10 days of illness, thus serologic tests may be falsely negative during this time period. # Rocky Mountain Spotted Fever AGENT Rickettsia rickettsii TREATMENT # Tick Bites/ Prevention Anaplasmosis, ehrlichiosis, and Rocky Mountain spotted fever are treated in the same manner with doxycycline. † Clinical suspicion of any of these diseases is sufficient to begin treatment. Delay in treatment may result in severe illness and even death. The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status, or allergies. Consult an infectious disease specialist in cases of pregnancy or documented life-threatening allergies to doxycycline. # WHERE FOUND In the U.S., naturally occurring tularemia infections have been reported from all states except Hawaii. Ticks that transmit tularemia to humans include the dog tick (Dermacentor variabilis), the wood tick (Dermacentor andersoni), and the lone star tick (Amblyomma americanum). Other transmission routes include inhalation and direct inoculation. # INCUBATION PERIOD: SIGNS AND SYMPTOMS 3-5 days (range 1-21 # Tick Bites/ Prevention The regimens listed below are guidelines only and may need to be adjusted depending on a patient's age, medical history, underlying health conditions, pregnancy status or allergies. Consult an infectious disease specialist for the most current treatment guidelines or for individual patient treatment decisions. # Tickborne Diseases Abroad Activities that increase risk for tick exposure worldwide include (but are not limited to): outdoor recreation such as camping, hiking, fishing, or bicycling; military training; outdoor occupations such as forestry; and collecting mushrooms, berries, or flowers in forested or agricultural areas. # DISEASE & ETIOLOGIC AGENT(S) GEOGRAPHIC LOCATION AND ADDITIONAL RISK FACTORS # Lyme Disease Borrelia afzelii, Borrelia garinii, B. burgdorferi sensu stricto # Eastern and central Europe, northern Asia # Tick-Borne Encephalitis Tick-borne encephalitis virus Temperate regions of Europe and northern Asia. May also be acquired by ingestion of unpasteurized dairy products from infected goats, sheep, or cows. Spotted Fever Group Rickettsioses (includes tick typhuses) R. akari, R. parkeri, R. africae, R. japonica, R. felis, etc. All continents except Antarctica. R. africae infection has been reported as a cause of fever in travelers returning from South Africa. # Crimean-Congo Hemorrhagic Fever CCHF virus Asia, Africa, and Europe. May also be acquired by contact with infected blood or saliva or inhalation of infected aerosols. # Omsk Hemorrhagic Fever Omsk hemorrhagic fever virus Southwestern Russia. May also be acquired by direct contact with infected muskrats. # Kyasanur Forest Disease Kyasanur forest disease virus Southern India, Saudi Arabia (aka Alkhurma disease in Saudi Arabia). Typically associated with exposure while harvesting forest products. NOTE: Anaplasmosis, babesiosis, ehrlichiosis, tularemia, TBRF, and Powassan disease can also be acquired internationally. Please see disease-specific references for more information on worldwide distribution. # Tick Bites/Prevention # Tick Bites/ Prevention Ticks are generally found near the ground, in brushy or wooded areas. They can't jump or fly. Instead, they climb tall grasses or shrubs and wait for a potential host to brush against them. When this happens, they climb onto the host and seek a site for attachment. # PREVENTION 1. Wear repellent containing at least 20% DEET or permethrin-treated clothing. Additional repellent options are available. For more information, see http://cfpub.epa.gov/oppref/insect/. 2. Treat dogs and cats for ticks as recommended by a veterinarian. 3. Check for ticks daily, especially under the arms, in and around the ears, inside the belly button, behind the knees, between the legs, around the waist, and on the hairline and scalp. 4. Shower soon after being outdoors. 5. For tips on "tick-safe" landscaping, see www.cdc.gov/lyme/prev/in_the_yard.html. # TICK REMOVAL 6. Use fine-tipped tweezers to grasp the tick as close to the skin's surface as possible. You may use specialized tick removal tools, if you already have them. The key is to remove the tick as soon as possible. Avoid folklore remedies such as using nail polish, petroleum jelly, or heat to make the tick detach from the skin. 7. Pull upward with steady, even pressure. Don't twist or jerk the tick; this can cause the mouth-parts to break off and remain in the skin. If this happens, remove the mouth-parts with clean tweezers. If you are unable to remove the mouth parts easily, leave them alone and let the skin heal. 8. After removing the tick, thoroughly clean the bite area and your hands with rubbing alcohol, an iodine scrub, or soap and water. Antibiotic treatment following a tick bite is not recommended as a means to prevent anaplasmosis, babesiosis, ehrlichiosis, or Rocky Mountain spotted fever. There is no evidence this practice is effective, and it may simply delay onset of disease. Instead, persons who experience a tick bite should be alert for symptoms suggestive of tickborne illness and consult a physician if fever, rash, or other symptoms of concern develop. Tularemia prophylaxis is recommended only in cases of laboratory exposure to infectious materials: • Doxycycline (100 mg orally BID X 14 days) is generally recommended for prophylaxis in adults. • Ciprofloxacin (500 mg orally BID) is not FDA-approved for prophylaxis of tularemia but has demonstrated efficacy in various studies, and may be an alternative for patients unable to take doxycycline.	None	None
9c18995bd919c68ce488b98f203cdfa399dcfa53	cdc	None	This document will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling. CDC does not accept commercial support. Front cover photos, left to right: intrauterine device, oral contraceptive pills, diaphragm, syringe for injectable contraceptives, male condom, transdermal contraceptive patch, etonogestrel implant, vaginal ring.# Introduction Unintended pregnancy rates remain high in the United States; approximately 50% of all pregnancies are unintended, with higher proportions among adolescent and young women, women who are racial/ethnic minorities, and women with lower levels of education and income (1). Unintended pregnancies increase the risk for poor maternal and infant outcomes (2) and in 2002, resulted in $5 billion in direct medical costs in the United States (3). Approximately half of unintended pregnancies are among women who were not using contraception at the time they became pregnant; the other half are among women who became pregnant despite reported use of contraception (4). Therefore, strategies to prevent unintended pregnancy include assisting women at risk for unintended pregnancy and their partners with choosing appropriate contraceptive methods and helping women use methods correctly and consistently to prevent pregnancy. In 2010, CDC first adapted global guidance from the World Health Organization (WHO) to help health-care providers counsel women, men, and couples about contraceptive method choice. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC), focuses on who can safely use specific methods of contraception and provides recommendations for the safety of contraceptive methods for women with various medical conditions (e.g., hypertension and diabetes) and characteristics (e.g., age, parity, and smoking status) (Appendix A) (5). The recommendations in this new guide, U.S. Selected Practice Recommendations for Contraceptive Use, 2013 (U.S. SPR), focuses on how contraceptive methods can be used and provides recommendations on optimal use of contraceptive methods for persons of all ages, including adolescents. During the past 15 years, CDC has contributed to the development and updating of the WHO global family planning guidance. CDC has supported WHO by coordinating the identification, critical appraisal, and synthesis of the scientific evidence on which the WHO guidance is based. In 2002, WHO published the first edition of the Selected Practice Recommendations for Contraceptive Use (WHO SPR), which presented evidence-based global guidance on how to use contraceptive methods safely and effectively once they are deemed to be medically appropriate. Since then, WHO has regularly updated its guidance on the basis of new evidence, and the document is now in its second edition (6), with an additional update in 2008 (7). The WHO global guidance is not intended for use directly by health-care providers; rather, WHO intends for the guidance to be used by local or national policy makers, family planning program managers, and the scientific community as a reference when they develop family planning guidance at the country or program level (6). For example, the United Kingdom adapted WHO SPR and in 2002 published the U.K. Selected Practice Recommendations for Contraceptive Use for use by U.K. health-care providers (8). CDC initiated a formal adaptation process to create U.S. SPR, using both the second edition of WHO SPR (6) and the 2008 update (7) as the basis for the U.S. version. Although much of the guidance is the same as the WHO guidance, the recommendations are specific to U.S. family planning practice. In addition, guidance on contraceptive methods not available in the United States has been removed, and four new topics for guidance have been added (the effectiveness of female sterilization, extended use of combined hormonal methods and bleeding problems, starting regular contraception after use of emergency contraception, and determining when contraception is no longer needed). This document contains recommendations for health-care providers for the safe and effective use of contraceptive methods and addresses provision of contraceptive methods and management of side effects and other problems with contraceptive method use. Although the term woman is used throughout this report, these recommendations refer to all females of reproductive age, including adolescents. Adolescents are identified throughout this document as a special population that might benefit from more frequent follow-up. These recommendations are meant to serve as a source of clinical guidance for health-care providers; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients; persons should seek advice from their health-care providers when considering family planning options. # Methods CDC initiated a process to adapt WHO SPR for the United States. This adaptation process included four steps: 1) determining the scope of and process for the adaptation, including an October 2010 meeting in which individual feedback was solicited from a small group of partners and experts; 2) preparing the systematic reviews of the evidence during October 2010-September 2011 to be used for the adaptation, including peer review; 3) convening a larger meeting of experts in October 2011 to examine the evidence and receive input on the recommendations; and 4) finalizing recommendations by CDC. During October 21-22, 2010, CDC convened a meeting of 10 partners and U.S. family planning experts in Atlanta, Georgia, to discuss the scope of and process for a U.S. adaptation of WHO SPR. A list of participants is provided at the end of this report. CDC identified the specific WHO recommendations that might benefit from modification for the United States. Criteria used to modify the WHO recommendations included the availability of new scientific evidence or the context in which family planning services are provided in the United States. CDC also identified several WHO recommendations that needed additional specificity to be useful for U.S. health-care providers, as well as the need for additional recommendations not currently included in WHO SPR. In addition, the meeting members discussed removing recommendations that provide information about contraceptive methods that are not available in the United States. Representatives from CDC and WHO conducted systematic reviews of the scientific evidence for each of the WHO recommendations being considered for adaptation and for each new topic being considered for addition to the guidance. The purpose of these systematic reviews was to identify evidence related to the common clinical challenges associated with the recommendations. When no direct evidence was available, indirect evidence and theoretical issues were considered. Standard guidelines were followed for reporting systematic reviews (9,10), and strength and quality of the evidence were graded using the system of the U.S. Preventive Services Task Force (11). Each complete systematic review was peer reviewed by two or three experts before its use in the adaptation process. Peer reviewers, who were identified from the list of persons scheduled to participate in the October 2011 meeting, were asked to comment on the search strategy, list of articles included in the reviews, and the summary of findings. The systematic reviews were finalized and provided to participants before the October 2011 meeting and were published in May 2013 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). During October 4-7, 2011, CDC convened a meeting in Atlanta, Georgia, of 36 experts who were invited to assist in guideline development and provide their perspective on the scientific evidence presented and the discussions on potential recommendations that followed. The group included obstetrician/ gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with research and clinical practice expertise in contraceptive safety, effectiveness, and management. All participants received all of the systematic reviews before the meeting. During the meeting, the evidence from the systematic review for each topic was presented, and participants discussed the evidence and the translation of the scientific evidence into recommendations that would meet the needs of U.S. healthcare providers. In particular, participants discussed whether and how the U.S. context might be different from the global context and whether these differences suggested any need for modifications to the global guidance. CDC gathered the input from the experts during the meeting and finalized the recommendations in this report. The document was peer reviewed by meeting participants, who were asked to comment on specific issues that were raised during the meeting. Feedback also was received from an external review panel, composed of health-care providers who had not participated in the adaptation meetings. These providers were asked to provide comments on the accuracy, feasibility, and clarity of the recommendations, as well as to provide other comments. Areas of research that need additional investigation also were considered during the meeting (31). # How To Use This Document The recommendations in this report are intended to help health-care providers address issues related to use of contraceptives, such as how to help a woman initiate use of a contraceptive method, which examinations and tests are needed before initiating use of a contraceptive method, what regular follow-up is needed, and how to address problems that often arise during use, including missed pills and side effects such as unscheduled bleeding. Each recommendation addresses what a woman or health-care provider can do in specific situations. For situations in which certain groups of women might be medically ineligible to follow the recommendations, comments and reference to U.S. MEC are provided (5). The full U.S. MEC recommendations and the evidence supporting those recommendations were published in 2010 (5). The information in this document is organized by contraceptive method, and the methods generally are presented in order of effectiveness, from highest to lowest. However, the recommendations are not intended to provide guidance on every aspect of provision and management of contraceptive method use. Instead, they use the best available evidence to address specific issues regarding common, yet sometimes complex, clinical issues. Each contraceptive method section generally includes information about initiation of the method, regular follow-up, and management of problems with use (e.g., usage errors and side effects). Each section first provides the recommendation and then includes a comments and evidence section, which includes comments about the recommendations and a brief summary of the scientific evidence on which the recommendation is based. Recommendations in this document are provided for permanent methods of contraception, such as vasectomy and female sterilization, as well as for reversible methods of contraception, including the copper-containing intrauterine device (Cu-IUD); levonorgestrel-releasing IUD (LNG-IUD); the etonogestrel implant; progestin-only injectables; progestinonly pills (POPs); combined hormonal contraceptive methods that contain both estrogen and a progestin, including combined oral contraceptives (COCs), a transdermal contraceptive patch, and a vaginal contraceptive ring; and the standard days method (SDM). Recommendations also are provided for emergency use of the Cu-IUD and emergency contraceptive pills (ECPs). For each contraceptive method, recommendations are provided on the timing for initiation of the method and indications for when and for how long additional contraception, or a back-up method, is needed. Many of these recommendations include guidance that a woman can start a contraceptive method at any time during her menstrual cycle if it is reasonably certain that the woman is not pregnant. Guidance for health-care providers on how to be reasonably certain that a woman is not pregnant is provided. For each contraceptive method, recommendations include the examinations and tests needed before initiation of the method. These recommendations apply to persons who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Most women need no or very few examinations or tests before initiating a contraceptive method. The following classification system was developed by WHO and adopted by CDC to categorize the applicability of the various examinations or tests before initiation of contraceptive methods (6): Class A: These tests and examinations are essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: These tests and examinations contribute substantially to safe and effective use, although implementation can be considered within the public health context, service context, or both. The risk for not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: These tests and examinations do not contribute substantially to safe and effective use of the contraceptive method. These classifications focus on the relation of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Systematic reviews were conducted for several different types of examinations and tests to assess whether a screening test was associated with safe use of contraceptive methods. Because no single convention exists for screening panels for certain diseases, including diabetes, lipid disorders, and liver diseases, the search strategies included broad terms for the tests and diseases of interest. Summary charts and clinical algorithms that summarize the guidance for the various contraceptive methods have been developed for many of the recommendations, including when to start using specific contraceptive methods (Appendix B), examinations and tests needed before initiating the various contraceptive methods (Appendix C), routine follow-up after initiating contraception (Appendix D), management of bleeding irregularities (Appendix E), and management of IUDs when users are found to have pelvic inflammatory disease (PID) (Appendix F). These summaries might be helpful to health-care providers when managing family planning patients. Additional tools are available on the U.S. SPR website (. gov/reproductivehealth/UnintendedPregnancy/USSPR.htm). # Summary of Changes from WHO SPR Much of the guidance in U.S. SPR is the same or very similar to the WHO SPR guidance. U.S. SPR includes new guidance on the use of the combined contraceptive patch and vaginal ring, as well as recommendations for four new topics: - how to start regular contraception after taking ECPs - management of bleeding irregularities among women using extended or continuous combined hormonal contraceptives (including pills, the patch, and the ring) - when a woman can rely on female sterilization for contraception - when a woman can stop using contraceptives and not be at risk for unintended pregnancy Adaptations to the WHO SPR recommendations include 1) changes to the length of the grace period for depot medroxyprogesterone acetate (DMPA) reinjection, 2) differences in some of the examinations and tests recommended before contraceptive method initiation, 3) differences in some of the recommendations for management of bleeding irregularities because of new data and drug availability in the United States, and 4) a modified missed pill algorithm to respond to concerns of the CDC expert group and other reviewers that simplified algorithms are preferable. # Contraceptive Method Choice Many elements need to be considered individually by a woman, man, or couple when choosing the most appropriate contraceptive method. Some of these elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. Contraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Table 1). Both consistent and correct use can vary greatly with characteristics such as age, income, desire to prevent or delay pregnancy, and culture. Methods that depend on consistent and correct use by clients have a wide range of effectiveness between typical and perfect users. IUDs and implants are considered long-acting, reversible contraception (LARC); these methods are highly effective because they do not depend on regular compliance from the user. LARC methods are appropriate for most women, including adolescents and nulliparous women. All women should be counseled about the full range and effectiveness of contraceptive options for which they are medically eligible so that they can identify the optimal method (Figure 1). In choosing a method of contraception, the risk for human immunodeficiency virus (HIV) infection and other sexually transmitted diseases (STDs) also should be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STDs and HIV. Consistent and correct use of the male latex condom reduces the risk for HIV infection and other STDs, including chlamydial infection, gonorrhea, and trichomoniasis (32). On the basis of a limited number of clinical studies, when a male condom cannot be used properly to prevent infection, a female condom should be considered (32). All patients, regardless of contraceptive choice, should be counseled about the use of condoms and the risk for STDs, including HIV infection (32). Additional information about prevention and treatment of STDs is available from the CDC Sexually Transmitted Diseases Treatment Guidelines (32). # Maintaining Updated Guidance As with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. Working with WHO, CDC uses the continuous identification of research evidence (CIRE) system to ensure that WHO and CDC guidance is based on the best available evidence and that a mechanism is in place to update guidance when new evidence becomes available (33). CDC will continue to work with WHO to identify and assess all new relevant evidence and determine whether changes in the recommendations are warranted. In most cases, U.S. SPR will follow any updates in the WHO guidance, which typically occurs every 3-4 years (or sooner if warranted by new data). In addition, CDC will review any interim WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations that are not included in the WHO guidance and will completely review U.S. SPR every 3-4 years. Updates to the guidance can be found on the U.S. SPR website (/ UnintendedPregnancy/USSPR.htm). # How To Be Reasonably Certain that a Woman Is Not Pregnant In most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman who is about to start using a contraceptive method. Several criteria for assessing pregnancy risk are listed in the recommendation that follows. These criteria are highly accurate (i.e., a negative predictive value of 99%-100%) in ruling out pregnancy among women who are not pregnant (34)(35)(36)(37). Therefore, CDC recommends that health-care providers use these criteria to assess pregnancy - Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Estimates of the probability of pregnancy during the first year of typical use for spermicides and the diaphragm are taken from the 1995 National Survey of Family Growth (NSFG) corrected for underreporting of abortion; estimates for fertility awareness-based methods, withdrawal, the male condom, the pill and Depo-Provera are taken from the 1995 and 2002 NSFG corrected for underreporting of abortion. † Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. § Among couples attempting to avoid pregnancy, the percentage who continues to use a method for 1 year. ¶ The percentage becoming pregnant in the second and third columns are based on data from populations where contraception is not used and from women who cease using contraception to become pregnant. Among such populations, approximately 89% become pregnant within 1 year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within 1 year among women not relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. † † The ovulation and two day methods are based on evaluation of cervical mucus. The standard days method avoids intercourse on cycle days 8-19. The symptothermal method is a double-check method based on evaluation of cervical mucus to determine the first fertile day and evaluation of cervical mucus and temperature to determine the last fertile day. § § Without spermicides. * With spermicidal cream or jelly. † † † This is a highly effective, temporary method of contraception. However, to maintain in effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches age 6 months. status in a woman who is about to start using contraceptives (Box 1). If a woman meets one of these criteria (and therefore the health-care provider can be reasonably certain that she is not pregnant), a urine pregnancy test might be considered in addition to these criteria (based on clinical judgment), bearing in mind the limitations of the accuracy of pregnancy testing. If a woman does not meet any of these criteria, then the health-care provider cannot be reasonably certain that she is not pregnant, even with a negative pregnancy test. Routine pregnancy testing for every woman is not necessary. On the basis of clinical judgment, health-care providers might consider the addition of a urine pregnancy test; however, they should be aware of the limitations, including accuracy of the test relative to the time of last sexual intercourse, recent delivery, or spontaneous or induced abortion. Routine pregnancy testing for every woman is not necessary. If a woman has had recent (i.e., within the last 5 days) unprotected sexual intercourse, consider offering emergency contraception (either a Cu-IUD or ECPs), if pregnancy is not desired. Comments and Evidence Summary. The criteria for determining whether a woman is pregnant depend on the assurance that she has not ovulated within a certain amount of time after her last menses, spontaneous or induced abortion, or delivery. Among menstruating women, the timing of ovulation can vary widely. During an average 28-day cycle, ovulation generally occurs during days 9-20 (38). In addition, the likelihood of ovulation is low from days 1-7 of the menstrual cycle (39). After a spontaneous or an induced abortion, ovulation can occur within 2-3 weeks and has been found to occur as early as 8-13 days after the end of the pregnancy. Therefore, the likelihood of ovulation is low ≤7 days after an abortion (40)(41)(42). A recent systematic review reported that the mean day of first ovulation among postpartum nonlactating women occurred 45-94 days after delivery (43). In one study, the earliest ovulation was reported at 25 days after delivery. Among women who are within 6 months postpartum, are fully or nearly fully breastfeeding, and are amenorrheic, the risk for pregnancy is <2% (44). Although pregnancy tests often are performed before initiating contraception, the accuracy of qualitative urine pregnancy tests varies depending on the timing of the test relative to missed menses, recent sexual intercourse, or recent pregnancy. The sensitivity of a pregnancy test is defined as the concentration of human chorionic gonadotropin (hCG) at which 95% of tests are positive. Most qualitative pregnancy tests approved by the U.S. Food and Drug Administration (FDA) report a sensitivity of 20-25 mIU/mL in urine (45)(46)(47)(48) However, pregnancy detection rates can vary widely because of differences in test sensitivity and the timing of testing relative to missed menses (47,49). Some studies have shown that an additional 11 days past the day of expected menses are needed to detect 100% of pregnancies using qualitative tests (46). In addition, pregnancy tests cannot detect a pregnancy resulting from recent sexual intercourse. Qualitative tests also might have positive results for several weeks after termination of pregnancy because hCG can be present for several weeks after delivery or abortion (spontaneous or induced) (50)(51)(52). For contraceptive methods other than IUDs, the benefits of starting to use a contraceptive method likely exceed any risk, even in situations in which the health-care provider is uncertain whether the woman is pregnant. Therefore, the health-care provider can consider having patients start using contraceptive methods other than IUDs at any time, with a follow-up pregnancy test in 2-4 weeks. The risks of not starting to use contraception should be weighed against the risks of initiating contraception use in a woman who might be already pregnant. Most studies have shown no increased risk for adverse outcomes, including congenital anomalies or neonatal or infant death, among infants exposed in utero to COCs (53)(54)(55). Studies also have shown no increased risk for neonatal or infant death or developmental abnormalities among infants exposed in utero to DMPA (54,56,57). In contrast, for women who want to begin using an IUD (Cu-IUD or LNG-IUD), in situations in which the healthcare provider is uncertain whether the woman is pregnant, the woman should be provided with another contraceptive method to use until the health-care provider is reasonably certain that she is not pregnant and can insert the IUD. Pregnancies among women with IUDs are at higher risk for complications such as spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis (58). A systematic review identified four analyses of data from three diagnostic accuracy studies that evaluated the performance of the criteria listed above through use of a pregnancy checklist compared with a urine pregnancy test conducted concurrently (12). The performance of the checklist to diagnose or exclude pregnancy varied, with sensitivity of 55%-100% and specificity of 39%-89%. The negative predictive value was consistent across studies at 99%-100%; the pregnancy checklist correctly ruled out women who were not pregnant. One of the studies assessed the added usefulness of signs and symptoms of pregnancy and found that these criteria did not substantially improve the performance of the pregnancy checklist, although the number of women with signs and symptoms was small (34) (Level of evidence: Diagnostic accuracy studies, fair, direct). # Intrauterine Contraception Three IUDs are available in the United States, the Cu-IUD and two LNG-IUDs (containing a total of either 13.5 mg or 52 mg levonorgestrel). Fewer than 1 woman out of 100 becomes pregnant in the first year of using IUDs (with typical use) (59). IUDs are long acting, are reversible, and can be # BOX 1. How To Be Reasonably Certain that a Woman Is Not Pregnant A health-care provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria: - is ≤7 days after the start of normal menses - has not had sexual intercourse since the start of last normal menses - has been correctly and consistently using a reliable method of contraception - is ≤7 days after spontaneous or induced abortion - is within 4 weeks postpartum - is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority of feeds are breastfeeds),- amenorrheic, and <6 months postpartum used by women of all ages, including adolescents, and both by parous and nulliparous women. IUDs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Cu-IUDs Timing - The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). - The Cu-IUD also can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. If the day of ovulation can be estimated, the Cu-IUD also can be inserted >5 days after sexual intercourse as long as insertion does not occur >5 days after ovulation. # Need for Back-Up Contraception - No additional contraceptive protection is needed after Cu-IUD insertion. # Special Considerations Amenorrhea (Not Postpartum) - Timing: The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: No additional contraceptive protection is needed. # Postpartum (Including After Cesarean Section) - Timing: The Cu-IUD can be inserted at any time postpartum, including immediately postpartum (U.S. MEC 1 or 2) (Box 2), if it is reasonably certain that the woman is not pregnant (Box 1). The Cu-IUD should not be inserted in a woman with puerperal sepsis (U.S. MEC 4). - Need for back-up contraception: No additional contraceptive protection is needed. # Postabortion (Spontaneous or Induced) - Timing: The Cu-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first trimester abortion and U.S. MEC 2 for second trimester abortion). The Cu-IUD should not be inserted immediately after septic abortion (U.S. MEC 4). - Need for back-up contraception: No additional contraceptive protection is needed. # Switching from Another Contraceptive Method - Timing: The Cu-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: No additional contraceptive protection is needed. Comments and Evidence Summary. In situations in which the health-care provider is not reasonably certain that the woman is not pregnant, the woman should be provided with another contraceptive method to use until the health-care provider can be reasonably certain that she is not pregnant and can insert the Cu-IUD. A systematic review identified eight studies that suggested that timing of Cu-IUD insertion in relation to the menstrual cycle in nonpostpartum women had little effect on long-term outcomes (rates of continuation, removal, expulsion, or pregnancy) or on short-term outcomes (pain at insertion, bleeding at insertion, or immediate expulsion) (13) (Level of evidence: II-2, fair, direct). # Initiation of LNG-IUDs # Timing of LNG-IUD Insertion - The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception - If the LNG-IUD is inserted within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. - If the LNG-IUD is inserted >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) - Timing: The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Including After Cesarean Section) # Postabortion (Spontaneous or Induced) - Timing: The LNG-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first-trimester abortion and U.S. MEC 2 for secondtrimester abortion). The LNG-IUD should not be inserted immediately after a septic abortion (U.S. MEC 4). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the IUD is placed at the time of a surgical abortion. # Switching from Another Contraceptive Method - Timing: The LNG-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: If it has been >7 days since menstrual bleeding began, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from a Cu-IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health-care provider can consider providing ECPs at the time of LNG-IUD insertion. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the woman should be provided with another contraceptive method to use until the health-care provider can be reasonably certain that she is not pregnant and can insert the LNG-IUD. If a woman needs to use additional contraceptive protection when switching to an LNG-IUD from another contraceptive method, consider continuing her previous method for 7 days after LNG-IUD insertion. No direct evidence was found regarding the effects of inserting LNG-IUDs on different days of the cycle on short-or longterm outcomes (13). # Examinations and Tests Needed Before Initiation of a Cu-IUD or an LNG-IUD Among healthy women, few examinations or tests are needed before initiation of an IUD (Table 2). Bimanual examination and cervical inspection are necessary before IUD insertion. A baseline weight and BMI measurement might be useful for monitoring IUD users over time. If a woman has not been screened for STDs according to STD screening guidelines, screening can be performed at the time of insertion. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use IUDs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of IUDs. However, measuring weight and calculating BMI (weight / height 2 ) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Bimanual examination and cervical inspection are necessary before IUD insertion to assess uterine size and position and to detect any cervical or uterine abnormalities that might indicate infection or otherwise prevent IUD insertion (61,62). STDs: Women should be routinely screened for chlamydial infection and gonorrhea according to national screening guidelines. The CDC Sexually Transmitted Diseases Treatment Guidelines provide information on screening eligibility, timing, and frequency of screening and on screening for persons with risk factors (32). If STD screening guidelines have been followed, most women do not need additional STD screening at the time of IUD insertion. If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3) (5). For these women, IUD insertion should be delayed until appropriate testing and treatment occur. A systematic review did not identify any evidence regarding women who were screened versus not screened for STDs before IUD insertion (14). Although women with STDs at the time of IUD insertion have a higher risk for PID, the overall rate of PID among all IUD users is low (63,64). Hemoglobin: Women with iron-deficiency anemia can use the LNG-IUD (U.S. MEC 1) (5); therefore, screening for anemia is not necessary for safe initiation of the LNG-IUD. Women with iron-deficiency anemia generally can use the Cu-IUD (U.S. MEC 2). Measurement of hemoglobin before initiation of Cu-IUDs is not necessary because of the minimal change in hemoglobin among women with and without anemia using Cu-IUDs. A systematic review identified four studies that provided direct evidence for changes in hemoglobin among women with anemia who received Cu-IUDs (30). Evidence from one randomized trial (65) and one prospective cohort study (66) showed no significant changes in hemoglobin among Cu-IUD users with anemia, whereas two prospective cohort studies (67,68) showed a statistically significant decrease in hemoglobin levels during 12 months of follow-up; however, the magnitude of the decrease was small and most likely not clinically significant. The systematic review also identified 21 studies that provided indirect evidence by examining changes in hemoglobin among healthy women receiving Cu-IUDs (69-89), which generally showed no clinically significant changes in hemoglobin levels with up to 5 years of follow-up (Level of evidence: I to II-2, fair, direct). Liver enzymes: Women with liver disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for liver disease is not necessary for the safe initiation of the Cu-IUD. Although women with certain liver diseases generally should not use the LNG-IUD (U.S. MEC 3) (5), screening for liver disease before initiation of the LNG-IUD is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptive use (14). The prevalence of liver disorders among women of reproductive age is low. In 2008, among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited, and no evidence exists for the LNG-IUD. Clinical breast examination: Women with breast disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for breast disease is not necessary for the safe initiation of the Cu-IUD. Although women with current breast cancer should not use the LNG-IUD (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before inserting an IUD is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Cervical cytology: Although women with cervical cancer should not undergo IUD insertion (U.S. MEC 4) (5), screening asymptomatic women with cervical cytology before IUD insertion is not necessary because of the high rates of cervical screening, low incidence of cervical cancer in the United States, and high likelihood that a woman with cervical cancer already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with cervical cytology before initiation of IUDs (14). Cervical cancer is rare in the United States, with an incidence rate of 8.1 per 100,000 women per year during 2004-2008 (95). The incidence and mortality rates from cervical cancer have declined dramatically in the United States, largely because of cervical cytology screening (96). Overall screening rates for cervical cancer in the United States are high; among women aged 22-30 years, approximately 87% reported having cervical cytology screening within the last 3 years (97). HIV screening: Although women with acquired immunodeficiency syndrome (AIDS) who are not clinically well should generally not undergo IUD insertion (U.S. MEC 3) (5), HIV screening is not necessary before IUD insertion because of the high likelihood that a woman in the United States with such an advanced stage of disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened for HIV infection before IUD insertion (14). Limited evidence suggests that IUDs are not associated with disease progression, increased infection, or other adverse health effects among women with HIV infection (98). Other screening: Women with hypertension, diabetes, hyperlipidemia, or thrombogenic mutations can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, screening for these conditions is not necessary for the safe initiation of IUDs. # Provision of Prophylactic Antibiotics at the Time of IUD Insertion - Prophylactic antibiotics are generally not recommended for Cu-IUD or LNG-IUD insertion. Comments and Evidence Summary. Theoretically, IUD insertion could induce bacterial spread and lead to complications such as PID or infective endocarditis. A metaanalysis was conducted of randomized controlled trials examining antibiotic prophylaxis versus placebo or no treatment for IUD insertion (99). Use of prophylaxis reduced the frequency of unscheduled return visits but did not significantly reduce the incidence of PID or premature IUD discontinuation. Although the risk for PID was higher within the first 20 days after insertion, the incidence of PID was low among all women who had IUDs inserted (63). In addition, the American Heart Association recommends that the use of prophylactic antibiotics solely to prevent infective endocarditis is not needed for genitourinary procedures (100). Studies have not demonstrated a conclusive link between genitourinary procedures and infective endocarditis or a preventive benefit of prophylactic antibiotics during such procedures (100). # Routine Follow-Up After IUD Insertion These recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, persons with certain medical conditions or characteristics, and persons with multiple medical conditions. - Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. - At other routine visits, health-care providers who see IUD users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the IUD for safe and effective continued use on the basis of U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider performing an examination to check for the presence of the IUD strings. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Evidence from a systematic review about the effect of a specific follow-up visit schedule on IUD continuation is very limited and of poor quality. The evidence did not suggest that greater frequency of visits or earlier timing of the first follow-up visit after insertion improves continuation of use ( 16) (Level of evidence: II-2, poor, direct). Evidence from four studies from a systematic review on the incidence of PID among IUD initiators, or IUD removal as a result of PID, suggested that the incidence of PID did not differ between women using Cu-IUDs and those using DMPA, COCs, or LNG-IUDs (17) (Level of evidence: I to II-2, good, indirect). Evidence on the timing of PID after IUD insertion is mixed. Although the rate of PID was generally low, the largest study suggested that the rate of PID was significantly higher in the first 20 days after insertion (63) (Level of evidence: I to II-3, good to poor, indirect). # Bleeding Irregularities with Cu-IUD Use - Before Cu-IUD insertion, provide counseling about potential changes in bleeding patterns during Cu-IUD use. Unscheduled spotting or light bleeding, as well as heavy or prolonged bleeding, is common during the first 3-6 months of Cu-IUD use, is generally not harmful, and decreases with continued Cu-IUD use. - If clinically indicated, consider an underlying gynecological problem, such as Cu-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids), especially in women who have already been using the Cu-IUD for a few months or longer and who have developed a new onset of heavy or prolonged bleeding. If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecological problem is not found and the woman requests treatment, the following treatment option can be considered during days of bleeding: -Nonsteroidal antiinflammatory drugs (NSAIDs) for short-term treatment (5-7 days) - If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the Cu-IUD, information about common side effects such as unscheduled spotting or light bleeding or heavy or prolonged menstrual bleeding, especially during the first 3-6 months of use, should be discussed (70). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other contraceptives (i.e., DMPA) (101,102). Evidence is limited on specific drugs, doses, and durations of use for effective treatments for bleeding irregularities with Cu-IUD use; therefore, although this document includes general recommendations for treatments to consider, evidence for specific regimens is lacking. A systematic review identified 11 articles that examined various therapeutic treatments for heavy menstrual bleeding, prolonged menstrual bleeding, or both among women using Cu-IUDs (18). Nine studies examined the use of various oral NSAIDs for the treatment of heavy or prolonged menstrual bleeding among Cu-IUD users and compared them to either a placebo or a baseline cycle. Three of these trials examined the use of indomethacin (103)(104)(105), another three examined mefenamic acid (106-108), and another three examined flufenamic acid (103,104,109). Other NSAIDs used in the reported trials included alclofenac (103,104), suprofen (110), and diclofenac sodium (111). All but one NSAID study (107) demonstrated statistically significant or notable reductions in mean total menstrual blood loss with NSAID use. One study among 19 Cu-IUD users with heavy bleeding suggested that treatment with oral tranexamic acid can significantly reduce mean blood loss during treatment compared with placebo (111). Data regarding the overall safety of tranexamic acid are limited; an FDA warning states that tranexamic acid is contraindicated in women with active thromboembolic disease or with a history or intrinsic risk for thrombosis or thromboembolism (112,113). Treatment with aspirin demonstrated no statistically significant change in mean blood loss among women whose pretreatment menstrual blood loss was >80 mL or 60-80 mL; treatment resulted in a significant increase among women whose pretreatment menstrual blood loss was <60 mL (114). One study examined the use of a synthetic form of vasopressin, intranasal desmopressin (300 µg/day), for the first 5 days of menses for three treatment cycles and found a significant reduction in mean blood loss compared with baseline (106) (Level of evidence: I to II-3, poor to fair, direct). Only one small study examined treatment of spotting with three separate NSAIDs and did not observe improvements in spotting in any of the groups (103) (Level of evidence: I, poor, direct). # Bleeding Irregularities (Including Amenorrhea) with LNG-IUD Use - Before LNG-IUD insertion, provide counseling about potential changes in bleeding patterns during LNG-IUD use. Unscheduled spotting or light bleeding is expected during the first 3-6 months of LNG-IUD use, is generally not harmful, and decreases with continued LNG-IUD use. Over time, bleeding generally decreases with LNG-IUD use, and many women experience only light menstrual bleeding or amenorrhea. Heavy or prolonged bleeding, either unscheduled or menstrual, is uncommon during LNG-IUD use. # Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding) - If clinically indicated, consider an underlying gynecological problem, such as LNG-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Amenorrhea - Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired Comments and Evidence Summary. During contraceptive counseling and before insertion of the LNG-IUD, information about common side effects such as unscheduled spotting or light bleeding, especially during the first 3-6 months of use, should be discussed. Approximately half of LNG-IUD users are likely to experience amenorrhea or oligomenorrhea by 2 years of use (115). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). No direct evidence was found regarding therapeutic treatments for bleeding irregularities during LNG-IUD use. # Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have PID - Treat the PID according to the CDC Sexually Transmitted Diseases Treatment Guidelines (32). - Provide comprehensive management for STDs, including counseling about condom use. - The IUD does not need to be removed immediately if the woman needs ongoing contraception. - Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of the IUD. - If the woman wants to discontinue use, remove the IUD sometime after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. - If the IUD is removed, consider ECPs if appropriate. Counsel the woman on alternative contraceptive methods, and offer another method if it is desired. - A summary of IUD management in women with PID is provided (Appendix F). Comments and Evidence Summary. Treatment outcomes do not generally differ between women with PID who retain the IUD and those who have the IUD removed; however, appropriate antibiotic treatment and close clinical follow-up are necessary. A systematic review identified four studies that included women using copper or nonhormonal IUDs who developed PID and compared outcomes between women who had the IUD removed or did not (19). One randomized trial showed that women with IUDs removed had longer hospitalizations than those who did not, although no differences in PID recurrences or subsequent pregnancies were observed (116). Another randomized trial showed no differences in laboratory findings among women who removed the IUD compared with those who did not (117). One prospective cohort study showed no differences in clinical or laboratory findings during hospitalization; however, the IUD removal group had longer hospitalizations (118). One randomized trial showed that the rate of recovery for most clinical signs and symptoms was higher among women who had the IUD removed than among women who did not (119). No evidence was found regarding women using LNG-IUDs (Level of evidence: I to II-2, fair, direct). # Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Be Pregnant - Evaluate for possible ectopic pregnancy. - Advise the woman that she has an increased risk for spontaneous abortion (including septic abortion that might be life threatening) and of preterm delivery if the IUD is left in place. The removal of the IUD reduces these risks but might not decrease the risk to the baseline level of a pregnancy without an IUD. -If she does not want to continue the pregnancy, counsel her about options. -If she wants continue the pregnancy, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. # IUD Strings Are Visible or Can Be Retrieved Safely from the Cervical Canal - Advise the woman that the IUD should be removed as soon as possible. -If the IUD is to be removed, remove it by pulling on the strings gently. -Advise the woman that she should return promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. - If she chooses to keep the IUD, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. # IUD Strings Are Not Visible and Cannot Be Retrieved Safely - If ultrasonography is available, consider performing or referring for ultrasound examination to determine the location of the IUD. If the IUD cannot be located, it might have been expelled or have perforated the uterine wall. - If ultrasonography is not possible or the IUD is determined by ultrasound to be inside the uterus, advise the woman to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. Comments and Evidence Summary. Removing the IUD improves the pregnancy outcome if the IUD strings are visible or the device can be retrieved safely from the cervical canal. Risks for spontaneous abortion, preterm delivery, and infection are substantial if the IUD is left in place. Theoretically, the fetus might be affected by hormonal exposure from an LNG-IUD; however, whether this exposure increases the risk for fetal abnormalities is unknown. A systematic review identified nine studies suggesting that women who did not remove their IUDs during pregnancy were at greater risk for adverse pregnancy outcomes (including spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis) compared with women who had their IUDs removed or who did not have an IUD (58). Cu-IUD removal decreased risks but not to the baseline risk for pregnancies without an IUD. One case series examined LNG-IUDs. When they were not removed, eight in 10 pregnancies ended in spontaneous abortions (Level of evidence: II-2, fair, direct). # Implants The etonogestrel implant, a single rod with 68 mg of etonogestrel, is available in the United States. Fewer than 1 woman out of 100 become pregnant in the first year of use of the etonogestrel implant with typical use (59). The implant is long acting, is reversible, and can be used by women of all ages, including adolescents. The implant does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Implants Timing - The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception - If the implant is inserted within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If the implant is inserted >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) - Timing: The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) # Postabortion (Spontaneous or Induced) - Timing: The implant can be inserted within the first 7 days, including immediately after the abortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the implant is placed at the time of a surgical abortion. # Switching from Another Contraceptive Method - Timing: The implant can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days after insertion. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the woman to retain the IUD for at least 7 days after the implant is inserted and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting the implant likely exceed any risk; therefore, starting the implant should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to an implant from another contraceptive method, consider continuing her previous method for 7 days after implant insertion. No direct evidence was found regarding the effects of starting the etonogestrel implant at different times of the cycle. # Examinations and Tests Needed Before Implant Insertion Among healthy women, no examinations or tests are needed before initiation of an implant, although a baseline weight and BMI measurement might be useful for monitoring implant users over time (Table 3). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. # Comments and Evidence Summary. Weight (BMI): Obese women can use implants (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of implants. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: A pelvic examination is not necessary before initiation of implants because it would not facilitate detection of conditions for which implant use would be unsafe. Women with current breast cancer should not use implants (U.S. MEC 4); women with certain liver diseases generally should not use implants (U.S. MEC 3) (5). However, none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed. No evidence was found regarding implants (Level of evidence: II-2 fair, direct). Liver enzymes: Although women with certain liver diseases generally should not use implants (U.S. MEC 3) (5), screening for liver disease before initiation of implants is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008, the percentage of adults aged 18-44 years with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for implants. Clinical breast examination: Although women with current breast cancer should not use implants (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating an implant is not necessary because of the low prevalence of breast cancer among women of reproductive age (15-49 years). A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with hypertension, diabetes, hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) implants ( 5); therefore, screening for these conditions is not necessary for the safe initiation of implants. # Routine Follow-Up After Implant Insertion These recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. - Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. - At other routine visits, health-care providers seeing implant users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the implant for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. A systematic review did not identify any evidence regarding whether a routine follow-up visit after initiating an implant improves correct or continued use (16). # Bleeding Irregularities (Including Amenorrhea) During Implant Use - Before implant insertion, provide counseling about potential changes in bleeding patterns during implant use. Unscheduled spotting or light bleeding is common with implant use, and some women experience amenorrhea. These bleeding changes are generally not harmful and might or might not decrease with continued implant use. Heavy or prolonged bleeding, unscheduled or menstrual, is uncommon during implant use. Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding) - If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) - If irregular bleeding persists and the woman finds it unacceptable, counsel her on alternative methods, and offer another method if it is desired. # Amenorrhea - Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the implant, information about common side effects, such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use should be discussed. A pooled analysis of data from 11 clinical trials indicate that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (121). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). A systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily LNG contraceptive implants (122)(123)(124)(125)(126). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (124,125). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (126,127). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (126). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (128). Evidence also suggests that estrogen (129)(130)(131), daily COCs (129), levonorgestrel pills (130), tamoxifen (132), or tranexamic acid (133) can reduce the number of bleeding or spotting days during treatment among levonorgestrel implant users. In one small study, vitamin E was found to significantly reduce the mean number of bleeding days after the first treatment cycle; however, another larger study reported no significant differences in length of bleeding and spotting episodes with vitamin E treatment (134,135). Use of aspirin did not result in a significant difference in median length of bleeding or bleeding and spotting episodes after treatment (134). One study among implant users reported a reduction in number of bleeding days after initiating ibuprofen; however, another trial did not demonstrate any significant differences in the number of spotting and bleeding episodes with ibuprofen compared with placebo (123,130). # Injectables Progestin-only injectable contraceptives (DMPA, 150 mg intramuscularly or 104 mg subcutaneously) are available in the United States; the only difference between these two formulations is the route of administration. Approximately 6 out of 100 women will become pregnant in the first year of use of DMPA with typical use (59). DMPA is reversible and can be used by women of all ages, including adolescents. DMPA does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Injectables Timing - The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception - If DMPA is started within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. - If DMPA is started >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) - Timing: The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) # Postpartum (Not Breastfeeding) - Timing: The first DMPA injection can be given at any time, including immediately postpartum (U.S. MEC 1) if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: A woman who is ≥21 days postpartum and has not experienced return of her menstrual cycle needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. If her menstrual cycles have returned and it has been >7 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postabortion (Spontaneous or Induced) - Timing: The first DMPA injection can be given within the first 7 days, including immediately postabortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the injection is given at the time of a surgical abortion. # Switching from Another Contraceptive Method - Timing: The first DMPA injection can be given immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: If it has been >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after the injection and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting DMPA likely exceed any risk; therefore, starting DMPA should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to DMPA from another contraceptive method, consider continuing her previous method for 7 days after DMPA injection. A systematic review identified eight articles examining DMPA initiation on different days of the menstrual cycle (20). Evidence from two studies with small samples indicated that DMPA injections given up to day 7 of the menstrual cycle inhibited ovulation; when DMPA was administered after day 7, ovulation occurred in some women. Cervical mucus was of poor quality (i.e., not favorable for sperm penetration) in 90% of women within 24 hours of the injection (Level of evidence: II-2, fair) (136)(137)(138). Studies found that use of another contraceptive method until DMPA could be initiated (bridging option) did not help women initiate DMPA and was associated with more unintended pregnancies than immediate receipt of DMPA (139-143) (Level of evidence: I to II-3, fair to poor, indirect). # Examinations and Tests Needed Before Initiation of an Injectable Among healthy women, no examinations or tests are needed before initiation of DMPA, although a baseline weight and BMI measurement might be useful for monitoring DMPA users over time (Table 4). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for obesity is not necessary for the safe initiation of DMPA. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. (See guidance on follow-up for DMPA users for evidence on weight gain with DMPA use.) Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of DMPA because it does not facilitate detection of conditions for which DMPA would be unsafe. Although women with current breast cancer should not use DMPA (U.S. MEC 4), and women with severe hypertension, heart disease, vascular disease, migraine headaches with aura, or certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2, fair, direct). Blood pressure: Women with hypertension generally can use DMPA (U.S. MEC 2), with the exception of women with severe hypertension or vascular disease, who generally should not use DMPA (U.S. MEC 3) (5). Screening for hypertension before initiation of DMPA is not necessary because of the low prevalence of undiagnosed severe hypertension and the high likelihood that women with these conditions already would have had them diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a blood pressure measurement before initiation of progestin-only contraceptives (21). The prevalence of undiagnosed hypertension among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, the percentage with diagnosed hypertension was 7.8%, and the percentage with undiagnosed hypertension was 1.9% (144). Glucose: Although women with complicated diabetes generally should not use DMPA (U.S. MEC 3) (5), screening for diabetes before initiation of DMPA is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes would already have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (14). The prevalence of diabetes among women of reproductive age is low. During 1999-2008 among women aged 20-44 years - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. in the United States, the percentage with diagnosed diabetes was 3% and the percentage with undiagnosed diabetes was 0.5% (144). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (145)(146)(147)(148)(149)(150)(151). Liver enzymes: Although women with certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), screening for liver disease before initiation of DMPA is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for DMPA. Clinical breast examination: Although women with current breast cancer should not use DMPA (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating DMPA is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for these conditions is not necessary for the safe initiation of DMPA. # Routine Follow-Up After Injectable Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. - Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time for reinjection. No routine follow-up visit is required. - At other routine visits, health-care providers seeing injectable users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the injectable for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Although no evidence exists regarding whether a routine follow-up visit after initiating DMPA improves correct or continued use, monitoring weight or BMI change over time is important for DMPA users. A systematic review identified a limited body of evidence that examined whether weight gain in the few months after DMPA initiation predicted future weight gain (17). Two studies found significant differences in weight gain or BMI at follow-up periods ranging from 12 to 36 months between early weight gainers (i.e., those who gained >5% of their baseline body weight within 6 months after initiation) and those who were not early weight gainers (152,153). The differences between groups were more pronounced at 18, 24, and 36 months than at 12 months. One study found that most adolescent DMPA users who had gained >5% of their baseline weight by 3 months gained even more weight by 12 months (154) (Level of evidence: II-2, fair, to II-3, fair, direct). # Timing of Repeat Injections Reinjection Interval - Provide repeat DMPA injections every 3 months (13 weeks). # Special Considerations Early Injection - The repeat DMPA injection can be given early when necessary. # Late Injection - The repeat DMPA injection can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection. - If the woman is >2 weeks late (>15 weeks from the last injection) for a repeat DMPA injection, she can have the injection if it is reasonably certain that she is not pregnant (Box 1). She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. She might consider the use of emergency contraception if appropriate. Comments and Evidence Summary. There are no time limits on early injections; injections can be given when necessary (e.g., when a woman cannot return at the routine interval). WHO has extended the time that a woman can have a late reinjection (i.e., grace period) for DMPA use from 2 weeks to 4 weeks on the basis of data from one study showing low pregnancy rates through 4 weeks; however, the CDC expert group did not consider the data to be generalizable to the United States because a large proportion of women in the study were breastfeeding. Therefore, U.S. SPR recommends a grace period of 2 weeks. A systematic review identified 12 studies evaluating time to pregnancy or ovulation after the last injection of DMPA (155). Although pregnancy rates were low during the 2-week interval following the reinjection date and for 4 weeks following the reinjection date, data were sparse and one study included a large proportion of breastfeeding women (156)(157)(158). Studies also indicated a wide variation in time to ovulation after the last DMPA injection, with the majority ranging from 15 to 49 weeks from the last injection (159-167) (Level of evidence: II-2, fair, direct). # Bleeding Irregularities (Including Amenorrhea) During Injectable Use - Before DMPA initiation, provide counseling about potential changes in bleeding patterns during DMPA use. Amenorrhea and unscheduled spotting or light bleeding is common with DMPA use, and heavy or prolonged bleeding can occur with DMPA use. These bleeding irregularities are generally not harmful and might decrease with continued DMPA use. # Unscheduled Spotting or Light Bleeding - If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment option during days of bleeding can be considered: -NSAIDs for short-term treatment (5-7 days) - If unscheduled spotting or light bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Heavy or Prolonged Bleeding - If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (such as fibroids or polyps). If an underlying gynecologic problem is identified, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) - If heavy or prolonged bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Amenorrhea - Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiation of DMPA, information about common side effects such as irregular bleeding should be discussed. Unscheduled bleeding or spotting is common with DMPA use (168). Additionally, amenorrhea is common after ≥1 years of continuous use (168,169). These bleeding irregularities are generally not harmful. Enhanced counseling among DMPA users detailing expected bleeding patterns and reassurance that these irregularities generally are not harmful has been shown to reduce DMPA discontinuation in clinical trials (101,102). A systematic review, as well as two additional studies, examined the treatment of bleeding irregularities during DMPA use (122,170,171). Two small studies found significant cessation of bleeding within 7 days of starting treatment among women taking valdecoxib for 5 days or mefenamic acid for 5 days compared with placebo (172,173). Treatment with ethinyl estradiol was found to stop bleeding better than placebo during the treatment period, although rates of discontinuation were high, and safety outcomes were not examined (174). In one small study among DMPA users who had been experiencing amenorrhea for 2 months, treatment with COCs was found to alleviate amenorrhea better than placebo (175). No studies examined the effects of aspirin on bleeding irregularities among DMPA users. # Combined Hormonal Contraceptives Combined hormonal contraceptives contain both estrogen and a progestin and include 1) COCs (various formulations), 2) a transdermal contraceptive patch (which releases 150 µg of norelgestromin and 20 µg ethinyl estradiol daily), and 3) a vaginal contraceptive ring (which releases 120 µg etonogestrel and 15 µg ethinyl estradiol daily). Approximately 9 out of 100 women become pregnant in the first year of use with combined hormonal contraceptives with typical use (59). These methods are reversible and can be used by women of all ages. Combined hormonal contraceptives are generally used for 21-24 consecutive days, followed by 4-7 hormone-free days (either no use or placebo pills). These methods are sometimes used for an extended period with infrequent or no hormonefree days. Combined hormonal contraceptives do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Combined Hormonal Contraceptives Timing - Combined hormonal contraceptives can be initiated at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception - If combined hormonal contraceptives are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If combined hormonal contraceptives are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) - Timing: Combined hormonal contraceptives can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) - Timing: Combined hormonal contraceptives can be started when the woman is medically eligible to use the method (176) and if it is reasonably certain that she is not pregnant. (Box 1). # Postabortion (Spontaneous or Induced) - Timing: Combined hormonal contraceptives can be started within the first 7 days after first or second trimester abortion, including immediately postabortion (U.S. MEC 1). - Need for back-up contraception: She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless combined hormonal contraceptives are started at the time of a surgical abortion. # Switching from Another Contraceptive Method - Timing: Combined hormonal contraceptives can be started immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after combined hormonal contraceptives are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting combined hormonal contraceptives likely exceed any risk; therefore, starting combined hormonal contraceptives should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to combined hormonal contraceptives from another contraceptive method, consider continuing her previous method for 7 days after starting combined hormonal contraceptives. A systematic review of 18 studies examined the effects of starting combined hormonal contraceptives on different days of the menstrual cycle (22). Overall, the evidence suggested that pregnancy rates did not differ by the timing of combined hormonal contraceptive initiation (143,177-179) (Level of evidence: I to II-3, fair, indirect). The more follicular activity that occurred before starting COCs, the more likely ovulation was to occur; however, no ovulations occurred when COCs were started at a follicle diameter of 10 mm (mean cycle day 7.6) or when the ring was started at 13 mm (median cycle day 11) (180-189) (Level of evidence: I to II-3, fair, indirect). Bleeding patterns and other side effects did not vary with the timing of combined hormonal contraceptive initiation (177,178,(190)(191)(192)(193)(194) (Level of evidence: I to II-2, good to poor, direct). Although continuation rates of combined hormonal contraceptives were initially improved by the "quick start" approach (i.e., starting on the day of the visit), the advantage disappeared over time (178,179,(190)(191)(192)(193)(194)(195) (Level of evidence: I to II-2, good to poor, direct). # Examinations and Tests Needed Before Initiation of Combined Hormonal Contraceptives Among healthy women, few examinations or tests are needed before initiation of combined hormonal contraceptives (Table 5). Blood pressure should be measured before initiation of combined hormonal contraceptives. Baseline weight and BMI measurements might be useful for monitoring combined hormonal contraceptive users over time. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Blood pressure: Women who have more severe hypertension (systolic pressure of ≥160 mm Hg or diastolic pressure of ≥100 mm Hg) or vascular disease should not use combined hormonal contraceptives (U.S. MEC 4), and women who have less severe hypertension (systolic pressure of 140-159 mm Hg or diastolic pressure of 90-99 mm Hg) or adequately controlled hypertension generally should not use combined hormonal contraceptives (U.S. MEC 3) (5). Therefore, blood pressure should be measured before initiating combined hormonal contraceptives. If access to health care is limited, blood pressure measurements may be obtained in nonclinical settings, such as pharmacies or fire stations, and reported by the woman to her provider. Evidence suggests that cardiovascular outcomes are worse among women who did not have their blood pressure measured before initiating COCs. A systematic review identified six articles from three studies that reported cardiovascular outcomes among women who had blood pressure measurements and women who did not have blood pressure measurements before initiating COCs (21). Three case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for acute myocardial infarction than women who did have blood pressure measurements (196)(197)(198). Two case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for ischemic stroke than women who did have blood pressure measurements (199,200). One case-control study showed no difference in the risk for hemorrhagic stroke among women who initiated COCs regardless of whether their blood pressure was measured (201). Studies that examined hormonal contraceptive methods other than COCs were not identified (Level of evidence: II-2, fair, direct). # Weight (BMI): Obese women generally can use combined hormonal contraceptives (U.S. MEC 2) (5); therefore, screening for obesity is not necessary for the safe initiation of combined hormonal contraceptives. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of combined hormonal contraceptives because it does not facilitate detection of conditions for which hormonal contraceptives would be unsafe. Women with certain conditions such as current breast cancer, severe hypertension or vascular disease, heart disease, migraine headaches with aura, and certain liver diseases, as well as women aged ≥35 years who smoke ≥15 cigarettes per day, should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5); however, none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were found (Level of evidence: II-2 fair, direct). Glucose: Although women with complicated diabetes should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives, depending on the severity of the condition (5), screening for diabetes before initiation of hormonal contraceptives is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (14). The prevalence of diabetes among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, the percentage with diagnosed diabetes was 3% and the percentage with undiagnosed diabetes was 0.5% (144). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (145)(146)(147)(148)(149)(150)(151). Lipids: Although some women with hyperlipidemias generally should not use combined hormonal contraceptives (U.S. MEC 2/3, depending on the type and severity of the hyperlipidemia and presence of other cardiovascular risk factors) (5), screening for hyperlipidemia before initiation of - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. § Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. hormonal contraceptives is not necessary because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (14). The prevalence of hyperlipidemia among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, approximately 10% had hypercholesterolemia, defined as total cholesterol ≥ 240 mg/dL or currently taking lipid-lowering medications, and the prevalence of undiagnosed hypercholesterolemia was approximately 2% (144). Studies have shown mixed results about the effects of hormonal methods on lipid levels, and the clinical significance of these changes is unclear (202)(203)(204). In addition, women with abnormal lipid levels at baseline were not found to have increased risk for adverse changes to their lipid profile when using hormonal methods (202). Liver enzymes: Although women with certain liver diseases should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5), screening for liver disease before initiation of combined hormonal contraceptives is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited; no evidence exists for other types of combined hormonal contraceptives. Thrombogenic mutations: Women with thrombogenic mutations should not use combined hormonal contraceptives (U.S. MEC 4) (5) because of the increased risk for venous thromboembolism (205). However, studies have shown that universal screening for thrombogenic mutations before initiating COCs is not cost-effective because of the rarity of the conditions and the high cost of screening (206)(207)(208). Clinical breast examination: Although women with current breast cancer should not use combined hormonal contraceptives (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating combined hormonal contraceptives is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with anemia, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) combined hormonal contraceptives (5); therefore, screening for these conditions is not necessary for the safe initiation of combined hormonal contraceptives. # Number of Pill Packs that Should Be Provided at Initial and Return Visits - At the initial and return visits, provide or prescribe up to a 1-year supply of COCs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. - A woman should be able to obtain COCs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy. A systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (23). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (209)(210)(211). However, one study found that there was no difference in continuation when patients were provided one and then three packs versus four packs all at once (212). In addition to continuation, a greater number of pills packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (i.e., 13 packs versus three packs) also was associated with increased pill wastage in one study (210) (Level of evidence: I to II-2, fair, direct). # Routine Follow-Up After Combined Hormonal Contraceptive Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. - Advise a woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. - At other routine visits, health-care providers seeing combined hormonal contraceptive users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of combined hormonal contraceptives for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Assess blood pressure. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence exists regarding whether a routine follow-up visit after initiating combined hormonal contraceptives improves correct or continued use. Monitoring blood pressure is important for combined hormonal contraceptive users. Health-care providers might consider recommending women obtain blood pressure measurements in nonclinical settings (e.g., pharmacy or fire station). A systematic review identified five studies that examined the incidence of hypertension among women who began using a COC versus those who started a nonhormonal method of contraception or a placebo (17). Few women developed hypertension after initiating COCs, and studies examining increases in blood pressure after COC initiation found mixed results. No studies were identified that examined changes in blood pressure among patch or vaginal ring users (Level of evidence: I, fair, to II-2, fair, indirect). # Late or Missed Doses and Side Effects from Combined Hormonal Contraceptive Use For the following recommendations, a dose is considered late when <24 hours have elapsed since the dose should have been taken. A dose is considered missed if ≥24 hours have elapsed since the dose should have been taken. For example, if a COC pill was supposed to have been taken on Monday at 9:00 a.m. and is taken at 11:00 a.m., the pill is late; however, by Tuesday morning at 11:00 a.m., Monday's 9:00 a.m. pill has been missed and Tuesday's 9:00 a.m. pill is late. For COCs, the recommendations only apply to late or missed hormonally active pills and not to placebo pills. Recommendations are provided for late or missed pills (Figure 2), the patch (Figure 3), and the ring (Figure 4). Comments and Evidence Summary. Inconsistent or incorrect use of combined hormonal contraceptives is a major cause of combined hormonal contraceptive failure. Extending the hormone-free interval is considered to be a particularly risky time to miss combined hormonal contraceptives. Seven days of continuous combined hormonal contraceptive use is deemed necessary to reliably prevent ovulation. The recommendations reflect a balance between simplicity and precision of science. Women who frequently miss COCs or experience other usage errors with combined hormonal patch or combined vaginal ring should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). A systematic review identified 36 studies that examined measures of contraceptive effectiveness of combined hormonal contraceptives during cycles with extended hormone-free intervals, shortened hormone-free intervals, or deliberate nonadherence on days not adjacent to the hormone-free interval (24). Most of the studies examined COCs (188,, two examined the combined hormonal patch (234,241), and six examined the combined vaginal ring (185,(242)(243)(244)(245)(246). No direct evidence on the effect of missed pills on the risk for pregnancy was found. Studies of women deliberately extending the hormone-free interval up to 14 days found wide variability in the amount of follicular development and occurrence of ovulation (216,219,221,222,224,225,(227)(228)(229)(230); in general, the risk for ovulation was low, and among women who did ovulate, cycles were usually abnormal. In studies of women who deliberately missed pills on various days during the cycle not adjacent to the hormone-free interval, ovulation occurred infrequently (214,(220)(221)(222)230,231,233,234). Studies comparing 7-day hormone-free intervals with shorter hormone-free intervals found lower rates of pregnancy (213,217,226,232) and significantly greater suppression of ovulation (215,225,(236)(237)(238)240) among women with shorter intervals in all but one study (235), which found no difference. Two studies that compared 30-µg ethinyl estradiol pills with 20-µg ethinyl estradiol pills showed more follicular activity when 20-µg ethinyl estradiol pills were missed (216,219). In studies examining the combined vaginal ring, three studies found that nondeliberate extension of the hormone-free interval for 24 to <48 hours from the scheduled period did not increase the risk for pregnancy (242,243,245); one study found that ring insertion after a deliberately extended hormone-free interval that allowed a 13-mm follicle to develop interrupted ovarian function and further follicular growth (185); and one study found that inhibition of ovulation was maintained after deliberately forgetting to remove the ring for up to 2 weeks after normal ring use (246). In studies examining the combined hormonal patch, one study found that missing 1-3 consecutive days before patch replacement (either wearing one patch 3 days longer before replacement or going 3 days without a patch before replacing the next patch) on days not adjacent to the patch-free interval resulted in little follicular activity and low risk for ovulation (234), and one pharmacokinetic study found that serum levels of ethinyl estradiol and progestin norelgestromin remained within reference ranges after extending patch wear for 3 days (241). No studies were found on extending the patch-free interval. In studies that provide indirect evidence on the effects of missed combined hormonal contraception on surrogate measures of pregnancy, how differences in surrogate measures correspond to pregnancy risk is unclear (Level of evidence: I, good, indirect to II-3, poor, direct). # Vomiting or Severe Diarrhea While Using COCs Certain steps should be taken by women who experience vomiting or severe diarrhea while using COCs (Figure 5). Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of COCs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence that addresses vomiting or severe diarrhea while using COCs, these recommendations are based on the recommendations # FIGURE 2. Recommended actions after late or missed combined oral contraceptives If one hormonal pill is late: (<24 hours since a pill should have been taken) If one hormonal pill has been missed: (24 to <48 hours since a pill should have been taken) If two or more consecutive hormonal pills have been missed: (≥48 hours since a pill should have been taken) - Take the late or missed pill as soon as possible. - Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day). - No additional contraceptive protection is needed. - Emergency contraception is not usually needed but can be considered if hormonal pills were missed earlier in the cycle or in the last week of the previous cycle. - Take the most recent missed pill as soon as possible. (Any other missed pills should be discarded.) - Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day). - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days. for missed COCs. No evidence was found on the effects of vomiting or diarrhea on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality. # Unscheduled Bleeding with Extended or Continuous Use of Combined Hormonal Contraceptives - Before initiation of combined hormonal contraceptives, provide counseling about potential changes in bleeding patterns during extended or continuous combined hormonal contraceptive use. (Extended contraceptive use is defined as a planned hormone-free interval after at least two contiguous cycles. Continuous contraceptive use is defined as uninterrupted use of hormonal contraception without a hormone-free interval .) - Unscheduled spotting or bleeding is common during the first 3-6 months of extended or continuous combined hormonal contraceptive use. It is generally not harmful and decreases with continued combined hormonal contraceptive use. - If clinically indicated, consider an underlying gynecological problem, such as inconsistent use, interactions with other medications, cigarette smoking, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecological problem is not found and the woman wants treatment, the following treatment option can be considered: -Advise the woman to discontinue combined hormonal contraceptive use (i.e., a hormone-free interval) for 3-4 consecutive days; a hormone-free interval is not recommended during the first 21 days of using the continuous or extended combined hormonal contraceptive method. A hormone-free interval also is not recommended more than once per month because contraceptive effectiveness might be reduced. - If unscheduled spotting or bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiating extended or continuous - If detachment takes place but the woman is unsure when the detachment occurred, consider the patch to have been detached for ≥48 hours since a patch should have been applied or reattached. combined hormonal contraceptives, information about common side effects such as unscheduled spotting or bleeding, especially during the first 3-6 months of use, should be discussed (248). These bleeding irregularities are generally not harmful and usually improve with persistent use of the hormonal method. To avoid unscheduled spotting or bleeding, counseling should emphasize the importance of correct use and timing; for users of contraceptive pills, emphasize consistent pill use. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with DMPA (101,102). A systematic review identified three studies with small study populations that addressed treatments for unscheduled bleeding among women using extended or continuous combined hormonal contraceptives (25). In two separate randomized clinical trials in which women were taking either contraceptive pills or using the contraceptive ring continuously for 168 days, women assigned to a hormone-free interval of 3 or 4 days reported improved bleeding. Although they noted an initial increase in flow, this was followed by an abrupt decrease 7-8 days later with eventual cessation of flow 11-12 days later. These findings were compared with women who continued to use their method without a hormone-free interval, in which a greater proportion reported either treatment failure or fewer days of amenorrhea (249,250). In another randomized trial of 66 women with unscheduled bleeding among women using 84 days of hormonally active contraceptive pills, oral doxycycline (100 mg twice daily) initiated the first day of bleeding and taken for 5 days did not result in any improvement in bleeding compared with placebo (251) (Level of evidence: I, fair, direct). # Progestin-Only Pills POPs contain only a progestin and no estrogen and are available in the United States. Approximately 9 out of 100 women become pregnant in the first year of use with POPs with typical use (59). POPs are reversible and can be used by women of all ages. POPs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # FIGURE 4. Recommended actions after delayed insertion or reinsertion with combined vaginal ring Delayed insertion of a new ring or delayed reinsertion- of a current ring for <48 hours since a ring should have been inserted Delayed insertion of a new ring or delayed reinsertion- for ≥48 hours since a ring should have been inserted - Insert ring as soon as possible. - Keep the ring in until the scheduled ring removal day. - No additional contraceptive protection is needed. - Emergency contraception is not usually needed but can be considered if delayed insertion or reinsertion occurred earlier in the cycle or in the last week of the previous cycle. - Insert ring as soon as possible. - Keep the ring in until the scheduled ring removal day. - Use back-up contraception (e.g., condoms) -r avoid sexual intercourse until a ring has been worn for 7 consecutive days. - If removal takes place but the woman is unsure of how long the ring has been removed, consider the ring to have been removed for ≥48 hours since a ring should have been inserted or reinserted. # Initiation of POPs Timing - POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception - If POPs are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If POPs are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Special Considerations Amenorrhea (Not Postpartum) - Timing: POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postpartum (Breastfeeding) - returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postpartum (Not Breastfeeding) - Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 1), if it is reasonably certain that the woman is not pregnant (Box 1). - Need for back-up contraception: Women who are ≥21 days postpartum and whose menstrual cycles have not returned need to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. If her menstrual cycles have returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postabortion (Spontaneous or Induced) - Timing: POPs can be started within the first 7 days, including immediately postabortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days unless POPs are started at the time of a surgical abortion. # Switching from Another Contraceptive Method - Timing: POPs can be started immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 2 days after POPs are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 2 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting POPs likely exceed any risk; therefore, starting POPs should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. Unlike COCs, POPs inhibit ovulation in about half of cycles, although the rates vary widely by individual (252). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (252). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use has been deemed necessary to achieve the contraceptive effects on cervical mucus (252). If a woman needs to use additional contraceptive protection when switching to POPs from another contraceptive method, consider continuing her previous method for 2 days after starting POPs. No direct evidence was found regarding the effects of starting POPs at different times of the cycle. # Examinations and Tests Needed Before Initiation of POPs Among healthy women, no examinations or tests are needed before initiation of POPs, although a baseline weight and BMI measurement might be useful for monitoring POP users over time (Table 6). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use POPs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of POPs. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of POPs because it does not facilitate detection of conditions for which POPs would be unsafe. Women with current breast cancer should not use POPs (U.S. MEC 4), and women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5); however, neither of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2 fair, direct). Liver enzymes: Although women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5), screening for liver disease before initiation of POPs is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among U.S. adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94). Clinical breast examination: Although women with current breast cancer should not use POPs (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating POPs is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women ages 20-49 was approximately 72 per 100,000 women (95). Other screening: Women with hypertension, diabetes, hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) POPs (5); therefore, screening for these conditions is not necessary for the safe initiation of POPs. # Number of Pill Packs that Should Be Provided at Initial and Return Visits - At the initial and return visits, provide or prescribe up to a 1-year supply of POPs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. - A woman should be able to obtain POPs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy. A systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (23). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (209)(210)(211). However, one study found that there was no difference in continuation when patients were provided one and then three packs versus four packs all at once (212). In addition to continuation, a greater number of pill packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (13 packs versus three packs) also was associated with increased pill wastage in one study (210) (Level of evidence: I to II-2, fair, direct). # Routine Follow-Up After POP Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. - Advise a woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. - At other routine visits, health-care providers seeing POP users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of POPs for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence was found regarding whether a routine follow-up visit after initiating POPs improves correct or continued use. # Missed POPs For the following recommendations, a dose is considered missed if it has been >3 hours since it should have been taken. - Take one pill as soon as possible. - Continue taking pills daily, one each day, at the same time each day, even if it means taking two pills on the same day. - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until pills have been taken correctly, on time, for 2 consecutive days. - Emergency contraception should be considered if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Inconsistent or incorrect use of oral contraceptive pills is a major reason for oral contraceptive failure. Unlike COCs, POPs inhibit ovulation in about half of cycles, although this rate varies widely by individual (252). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (252). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use was deemed necessary to achieve the contraceptive effects on cervical mucus (252). Women who frequently miss POPs should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). No evidence was found regarding the effects of missed POPs available in the United States on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality. # Vomiting or Severe Diarrhea (for any Reason or Duration) that Occurs Within 3 Hours After Taking a Pill - Take another pill as soon as possible (if possible, despite discomfort). - Continue taking pills daily, one each day, at the same time each day. - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until 2 days after vomiting or diarrhea has resolved. - Emergency contraception should be considered if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of POPs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence to address this question, these recommendations are based on the recommendations for missed POPs. No evidence was found regarding the effects of vomiting or diarrhea on measures of contraceptive effectiveness, including pregnancy, follicular development, hormone levels, or cervical mucus quality. # Standard Days Method SDM is a method based on fertility awareness; users must avoid unprotected sexual intercourse on days 8-19 of the menstrual cycle (253). Approximately 5 out of 100 women become pregnant in the first year of use with perfect (i.e., correct and consistent) use of SDM (253); effectiveness based on typical use is not available for this method but is expected to be lower than that for perfect use. SDM is reversible and can be used by women of all ages. SDM does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Use of SDM Among Women with Various Menstrual Cycle Durations Menstrual Cycles of 26-32 Days - These women may use the method. - Provide a barrier method of contraception for protection on days 8-19 if she wants one. - If she has unprotected sexual intercourse during days 8-19, consider the use of emergency contraception if appropriate. # Two or More Menstrual Cycles of 32 Days Within Any 1 Year of SDM Use - Advise the woman that the method might not be appropriate for her because of a higher risk for pregnancy. Help her consider another method. Comments and Evidence Summary. The probability of pregnancy is increased when the menstrual cycle is outside the range of 26-32 days, even if unprotected sexual intercourse is avoided on days 8-19. A study of 7,600 menstrual cycles, including information on cycle length and signs of ovulation, concluded that the theoretical effectiveness of SDM is greatest for women with cycles of 26-32 days, that the method is still effective for women who occasionally have a cycle outside this range, and that it is less effective for women who consistently have cycles outside this range. Information from daily hormonal measurements shows that the timing of the 6-day fertile window varies greatly, even among women with regular cycles (39,254,255). # Emergency Contraception Emergency contraception consists of methods that can be used by women after sexual intercourse to prevent pregnancy. Emergency contraception methods have varying ranges of effectiveness depending on the method and timing of administration. Four options are available in the United States: the Cu-IUD and three types of ECPs. # Types of Emergency Contraception Intrauterine Device - Cu-IUD # ECPs - Ulipristal acetate (UPA) in a single dose (30 mg) - Levonorgestrel in a single dose (1.5 mg) or as a split dose (1 dose of 0.75 mg of levonorgestrel followed by a second dose of 0.75 mg of levonorgestrel 12 hours later) - Combined estrogen and progestin in 2 doses (Yuzpe regimen: 1 dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel followed by a second dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel 12 hours later) # Initiation of Emergency Contraception Timing # Cu-IUD - The Cu-IUD can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. - In addition, when the day of ovulation can be estimated, the Cu-IUD can be inserted beyond 5 days after sexual intercourse, as long as insertion does not occur >5 days after ovulation. # ECPs - ECPs should be taken as soon as possible within 5 days of unprotected sexual intercourse. Comments and Evidence Summary. Cu-IUDs are highly effective as emergency contraception (256) and can be continued as regular contraception. UPA and levonorgestrel ECPs have similar effectiveness when taken within 3 days after unprotected sexual intercourse; however, UPA has been shown to be more effective than the levonorgestrel formulation 3-5 days after unprotected sexual intercourse (257). The combined estrogen and progestin regimen is less effective than UPA or levonorgestrel and also is associated with more frequent occurrence of side effects (nausea and vomiting) (258). The levonorgestrel formulation might be less effective than UPA among obese women (257). Two studies of UPA use found consistent decreases in pregnancy rates when administered within 120 hours of unprotected sexual intercourse (257,259). Five studies found that the levonorgestrel and combined regimens decreased risk for pregnancy through the fifth day after unprotected sexual intercourse; however, rates of pregnancy were slightly higher when ECPs were taken after 3 days (260)(261)(262)(263)(264). A meta-analysis of levonorgestrel ECPs found that pregnancy rates were low when administered within 4 days after unprotected sexual intercourse but increased at 4-5 days (265) (Level of evidence: I to II-2, good to poor, direct). # Advance Provision of ECPs - An advance supply of ECPs may be provided so that ECPs will be available when needed and can be taken as soon as possible after unprotected sexual intercourse. Comments and Evidence Summary. A systematic review identified 17 studies that reported on safety or effectiveness of advance ECPs in adult or adolescent women (26). Any use of ECPs was two to seven times greater among women who received an advance supply of ECPs. However, a summary estimate (relative risk = 0.97; 95% confidence interval = 0.77-1.22) of five randomized controlled trials did not indicate a significant reduction in unintended pregnancies at 12 months with advance provision of ECPs. In the majority of studies among adults or adolescents, patterns of regular contraceptive use, pregnancy rates, and incidence of STDs did not vary between those who received advance ECPs and those who did not. Although available evidence supports the safety of advance provision of ECPs, effectiveness of advance provision of ECPs in reducing pregnancy rates at the population level has not been demonstrated (Level of evidence: I to II-3, good to poor, direct). # Initiation of Regular Contraception After ECPs UPA - Any regular contraceptive method can be started immediately after the use of UPA. - The woman needs to abstain from sexual intercourse or use barrier contraception for 14 days or until her next menses, whichever comes first. - Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. # Levonorgestrel and Combined Estrogen and Progestin ECPs - Any regular contraceptive method can be started immediately after the use of levonorgestrel or combined estrogen and progestin ECPs. - The woman needs to abstain from sexual intercourse or use barrier contraception for 7 days. - Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. Comments and Evidence Summary. Data on when a woman can start regular contraception after ECPs are limited to expert opinion and product labeling (27). Theoretically, the effectiveness of systemic hormonal contraception might be decreased when administered concurrently or in close succession because of the antiprogestin properties of UPA (266,267); these theoretical concerns do not exist for combined estrogen and progestin or levonorgestrel formulations of ECPs. The resumption or initiation of regular hormonal contraception after ECP use involves consideration of the risk for pregnancy if ECPs fail and the risks for unintended pregnancy if contraception initiation is delayed until the subsequent menstrual cycle. If a woman is planning to initiate contraception after the next menstrual period after ECP use, the cycle in which ECPs are used might be shortened, prolonged, or involve unscheduled bleeding. # Prevention and Management of Nausea and Vomiting with ECP Use # Nausea and Vomiting - Levonorgestrel and UPA ECPs cause less nausea and vomiting than combined estrogen and progestin ECPs. - Routine use of antiemetics before taking ECPs is not recommended. Pretreatment with antiemetics may be considered depending on availability and clinical judgment. # Vomiting Within 3 Hours of Taking ECPs - Another dose of ECP should be taken as soon as possible. Use of an antiemetic should be considered. Comments and Evidence Summary. Many women do not experience nausea or vomiting when taking ECPs, and predicting which women will experience nausea or vomiting is difficult. Although routine use of antiemetics before taking ECPs is not recommended, antiemetics are effective in some women and can be offered when appropriate. Health-care providers who are deciding whether to offer antiemetics to women taking ECPs should consider the following: 1) women taking combined estrogen and progestin ECPs are more likely to experience nausea and vomiting than those who take levonorgestrel or UPA ECPs; 2) evidence indicates that antiemetics reduce the occurrence of nausea and vomiting in women taking combined estrogen and progestin ECPs; and 3) women who take antiemetics might experience other side effects from the antiemetics. A systematic review examined incidence of nausea and vomiting with different ECP regimens and effectiveness of antinausea drugs in reducing nausea and vomiting with ECP use (28). The levonorgestrel regimen was associated with significantly less nausea than a nonstandard dose of UPA (50 mg) and the standard combined estrogen and progestin regimen (268)(269)(270). Use of the split-dose levonorgestrel showed no differences in nausea and vomiting compared with the single-dose levonorgestrel (260,261,263,271) (Level of evidence: I, good-fair, indirect). Two trials of antinausea drugs, meclizine and metoclopramide, taken before combined estrogen and progestin ECPs, reduced the severity of nausea (272,273). Significantly less vomiting occurred with meclizine but not metoclopramide (Level of evidence: I, good-fair, direct). No direct evidence was found regarding the effects of vomiting after taking ECPs. # Female Sterilization Laparoscopic, abdominal, and hysteroscopic methods of female sterilization are available in the United States, and some of these procedures can be performed in an outpatient procedure or office setting. Fewer than 1 out of 100 women become pregnant in the first year after female sterilization (59). Because these methods are intended to be irreversible, all women should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception. Female sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # When Hysteroscopic Sterilization Is Reliable for Contraception - Before a woman can rely on hysteroscopic sterilization for contraception, a hysterosalpingogram (HSG) must be performed 3 months after the sterilization procedure to confirm bilateral tubal occlusion. - The woman should be advised that she needs to abstain from sexual intercourse or use additional contraceptive protection until she has confirmed bilateral tubal occlusion. # When Laparoscopic and Abdominal Approches Are Reliable for Contraception - A woman can rely on sterilization for contraception immediately after laparoscopic and abdominal approaches. No additional contraceptive protection is needed. Comments and Evidence Summary. HSG confirmation is necessary to confirm bilateral tubal occlusion after hysteroscopic sterilization. The inserts for the hysteroscopic sterilization system available in the United States are placed bilaterally into the fallopian tubes and require 3 months for adequate fibrosis and scarring leading to bilateral tubal occlusion. After hysteroscopic sterilization, advise the woman to correctly and consistently use an effective method of contraception while awaiting confirmation. If compliance with another method might be a problem, a woman and her health-care provider may consider DMPA injection at the time of sterilization to ensure adequate contraception for 3 months. Unlike laparoscopic and abdominal sterilizations, pregnancy risk beyond 7 years of follow-up has not been studied among women who received hysteroscopic sterilization. Pregnancy risk with at least 10 years of follow-up has been studied among women who received laparoscopic and abdominal sterilizations (274,275). Although these methods are highly effective, pregnancies can occur many years after the procedure, and the risk for pregnancy is higher among younger women (274,276). A systematic review was conducted to identify studies that reported whether pregnancies occurred after hysteroscopic sterilization (29). Twenty-four studies were identified that reported whether pregnancies occurred after hysteroscopic sterilization and found that very few pregnancies occurred among women with confirmed bilateral tubal occlusion; however, few studies include long-term follow-up, and none with follow-up for >7 years. Among women who had successful bilateral placement, most pregnancies that occurred after hysteroscopic sterilization were in women who did not have confirmed bilateral tubal occlusion at 3 months, either because of lack of follow up or misinterpretation of HSG results (277)(278)(279). Some pregnancies occurred within 3 months of placement, including among women who were already pregnant at the time of the procedure, women who did not use alternative contraception, or women who had failures of alternative contraception (277,278,(280)(281)(282)(283). Although these studies generally demonstrated high rates of bilateral placement, some pregnancies occurred as a result of lack of bilateral placement identified on later imaging (277,278,280,281,283,284). Most pregnancies occurred after deviations from FDA directions, which include placement in the early follicular phase of the menstrual cycle, imaging at 3 months to document proper placement, and use of effective alternative contraception until documented occlusion (Level of evidence: II-3, fair, direct). # Male Sterilization Male sterilization, or vasectomy, is one of the few contraceptive methods available to men and can be performed in an outpatient procedure or office setting. Fewer than 1 woman out of 100 becomes pregnant in the first year after her male partner undergoes sterilization (59). Because male sterilization is intended to be irreversible, all men should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception for women. Male sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # When Vasectomy Is Reliable for Contraception - A semen analysis should be performed 8-16 weeks after a vasectomy to ensure the procedure was successful. - The man should be advised that he should use additional contraceptive protection or abstain from sexual intercourse until he has confirmation of vasectomy success by postvasectomy semen analysis. # Other Postprocedure Recommendations - The man should refrain from ejaculation for approximately 1 week after the vasectomy to allow for healing of surgical sites and, after certain methods of vasectomy, occlusion of the vas. Comments and Evidence Summary. The Vasectomy Guideline Panel of the American Urological Association performed a systematic review of key issues concerning the practice of vasectomy (285). All English-language publications on vasectomy published during 1949-2011 were reviewed. For more information, see the American Urological Association Vasectomy Guidelines (available at / education/vasectomy.cfm). Motile sperm disappear within a few weeks after vasectomy (286)(287)(288)(289). The time to azoospermia varies widely in different studies; however, by 12 weeks after the vasectomy, 80% of men have azoospermia, and almost all others have rare nonmotile sperm (defined as ≤100,000 nonmotile sperm per milliliter) (285). The number of ejaculations after vasectomy is not a reliable indicator of when azoospermia or rare nonmotile sperm will be achieved (285). Once azoospermia or rare nonmotile sperm has been achieved, patients can rely on the vasectomy for contraception, although not with 100% certainty. The risk for pregnancy after a man has achieved postvasectomy azoospermia is approximately one in 2,000 (290)(291)(292)(293)(294). A median of 78% (range 33%-100%) of men return for a single postvasectomy semen analysis (285). In the largest cohorts that appear typical of North American vasectomy practice, approximately two thirds of men (55%-71%) return for at least one postvasectomy semen analysis (291,(295)(296)(297)(298)(299). Assigning men an appointment after their vasectomy might improve compliance with follow-up (300). # When Women Can Stop Using Contraceptives - Contraceptive protection is still needed for women aged >44 years if the woman wants to avoid pregnancy. Comments and Evidence Summary. The age at which a woman is no longer at risk for pregnancy is not known. Although uncommon, spontaneous pregnancies occur among women aged >44 years. Both the American College of Obstetricians and Gynecologists and the North American Menopause Society recommend that women continue contraceptive use until menopause or age 50-55 years (301,302). The median age of menopause is approximately 51 years in North America (301) but can vary from ages 40 to 60 years (303). The median age of definitive loss of natural fertility is 41 years but can range up to age 51 years (304,305). No reliable laboratory tests are available to confirm definitive loss of fertility in a woman. The assessment of follicle-stimulating hormone levels to determine when a woman is no longer fertile might not be accurate (301). Health-care providers should consider the risks for becoming pregnant in a woman of advanced reproductive age, as well as any risks of continuing contraception until menopause. Pregnancies among women of advanced reproductive age are at higher risk for maternal complications, such as hemorrhage, venous thromboembolism, and death, and fetal complications, such as spontaneous abortion, stillbirth, and congenital anomalies (306)(307)(308). Risks associated with continuing contraception, in particular risks for acute cardiovascular events (venous thromboembolism, myocardial infarction, or stroke) or breast cancer, also are important to consider. U.S. MEC states that on the basis of age alone, women aged >45 years can use POPs, implants, the LNG-IUD, or the Cu-IUD (U.S. MEC 1) (5). Women aged >45 years generally can use combined hormonal contraceptives and DMPA (U.S. MEC 2) (5). However, women in this age group might have chronic conditions or other risk factors that might render use of hormonal contraceptive methods unsafe; U.S. MEC might be helpful in guiding the safe use of contraceptives in these women. The incidence of venous thromboembolism was higher among oral contraceptive users aged ≥45 years compared with younger oral contraceptive users in two studies (309)(310)(311); however, an interaction between hormonal contraception and increased age compared with baseline risk was not demonstrated (309,310) or was not examined (311). The relative risk for myocardial infarction was higher among all oral contraceptive users than in nonusers, although a trend of increased relative risk with increasing age was not demonstrated (312,313). No studies were found regarding the risk for stroke in COC users aged ≥45 years (Level of evidence: II-2, good to poor, direct). A pooled analysis by the Collaborative Group on Hormonal Factors and Breast Cancer in 1996 (314) found small increased relative risks for breast cancer among women aged ≥45 years whose last use of combined hormonal contraceptives was <5 years previously and for those whose last use was 5-9 years previously. Seven more recent studies suggested small but nonsignificant increased relative risks for breast carcinoma in situ or breast cancer among women who had used oral contraceptives or DMPA when they were aged ≥40 years compared with those who had never used either method (315-321) (Level of evidence: II-2, fair, direct). # Conclusion Women, men, and couples have increasing numbers of safe and effective choices for contraceptive methods, including LARC methods such as IUDs and implants, to reduce the risk for unintended pregnancy. However, with these expanded options comes the need for evidence-based guidance to help health-care providers offer quality family planning care to their patients, including choosing the most appropriate contraceptive method for individual circumstances and using that method correctly, consistently, and continuously to maximize effectiveness. Removing unnecessary barriers can help patients access and successfully use contraceptive methods. Several medical barriers to initiating and continuing contraceptive methods might exist, such as unnecessary screening examinations and tests before starting the method (e.g., a pelvic examination before initiation of COCs), inability to receive the contraceptive on the same day as the visit (e.g., waiting for test results that might not be needed or waiting until the woman's next menstrual period to start use), and difficulty obtaining continued contraceptive supplies (e.g., restrictions on number of pill packs dispensed at one time). Removing unnecessary steps, such as providing prophylactic antibiotics at the time of IUD insertion or requiring unnecessary follow-up procedures, also can help patients access and successfully use contraception. Most women can start most contraceptive methods at any time, and few examinations or tests, if any, are needed before starting a contraceptive method. Routine follow-up for most women includes assessment of her satisfaction with the contraceptive method, concerns about method use, and changes in health status or medications that could affect medical eligibility for continued use of the method. Because changes in bleeding patterns are one of the major reasons for discontinuation of contraception, recommendations are provided for the management of bleeding irregularities with various contraceptive methods. In addition, because women and health-care providers can be confused about the procedures for missed pills and dosing errors with the contraceptive patch and ring, the instructions are streamlined for easier use. ECPs and emergency use of the Cu-IUD are important options for women, and recommendations on using these methods, as well as starting regular contraception after use of emergency contraception, are provided. Male and female sterilization are highly effective methods of contraception for men, women, and couples who have completed childbearing; for men undergoing vasectomy and women undergoing a hysteroscopic sterilization procedure, additional contraceptive protection is needed until the success of the procedure can be confirmed. CDC is committed to working with partners at the federal, national, and local levels to disseminate, implement, and evaluate the recommendations in U.S. SPR so that the information reaches health-care providers. Strategies for dissemination and implementation include collaborating with other federal agencies and professional and service organizations to widely distribute the recommendations through presentations, electronic distribution, newsletters, and other publications; development of provider tools and job aids to assist providers in implementing the new recommendations; and training activities for students, as well as for continuing education. CDC will conduct a survey of family planning health-care providers before and after release of this report to assess attitudes and practices related to contraceptive use. Results from this survey will assist CDC in evaluating the impact of these recommendations on the provision of contraceptives in the United States. Finally, CDC will continually monitor new scientific evidence and will update these recommendations as warranted by new evidence. Updates to the recommendations, as well as provider tools and other resources, are available on the CDC U.S. SPR website (http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USSPR.htm). (ii) without prolonged immobilization - In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § A bimanual examination (not cervical inspection) is needed for diaphragm fitting. ¶ Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD Treatment Guidelines (available at ). If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3). For these women, IUD insertion should be delayed until appropriate testing and treatment occurs. # I The examinations or tests noted apply to women who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC), might be useful in such circumstances (5). The following classification was considered useful in differentiating the applicability of the various examinations or tests: Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. # Appendix C Examinations and Tests Needed Before Initiation of Contraceptive Methods Class C: does not contribute substantially to safe and effective use of the contraceptive method. These classifications focus on the relationship of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. No examinations or tests are needed before initiating condoms or spermicides. A bimanual examination is necessary for diaphragm fitting. A bimanual examination and cervical inspection are needed for cervical cap fitting. # General follow-up Advise women to return at any time to discuss side effects or other problems or if they want to change the method. Advise women using IUDs, implants, or injectables when the IUD or implant needs to be removed or when a reinjection is needed. No routine follow-up visit is required. X X X X X # Other routine visits Assess the woman's satisfaction with her current method and whether she has any concerns about method use. X X X X X Assess any changes in health status, including medications, that would change the method's appropriateness for safe and effective continued use based on U.S. MEC (i.e., category 3 and 4 conditions and characteristics) (Box 2). X X X X X Consider performing an examination to check for the presence of IUD strings. # X ---- Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. # Appendix D Routine Follow-Up After Contraceptive Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. # Appendix A Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 Updated June 2012. This summary sheet only contains a subset of the recommendations from the US MEC. For complete guidance, see: / reproductivehealth/unintendedpregnancy/USMEC.htm. Most contraceptive methods do not protect against sexually transmitted infections (STIs). Consistent and correct use of the male latex condom reduces the risk of STIs and HIV. # Key: 1. No restriction (method can be used) 2. Advantages generally outweigh theoretical or proven risks 3. Theoretical or proven risks usually outweigh the advantages 4. Unacceptable health risk (method not to be used) # Condition Sub-condition Antimicrobial therapy a) Broad spectrum antibiotics ) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. † Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD Treatment Guidelines (available at ). If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3) (Box 2). For these women, IUD insertion should be delayed until appropriate testing and treatment occurs. # Appendix B When To Start Using Specific Contraceptive Methods # Appendix E Management of Women with Bleeding Irregularities While Using Contraception If bleeding persists, or if the woman requests it, medical treatment can be considered.* # Cu-IUD users For unscheduled spotting or light bleeding or for heavy or prolonged bleeding: - NSAIDs (5-7 days of treatment) # Appendix F Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have Pelvic Inflammatory Disease - Treat PID.- - Counsel about condom use. - IUD does not need to be removed. Woman wants to continue IUD. Woman wants to discontinue IUD. # Clinical improvement No clinical improvement - Offer another contraceptive method. - Offer emergency contraception. Continue IUD. Reassess in 24-48 hours. Remove IUD after beginning antibiotics. - Continue antibiotics. - Consider removal of IUD. - Offer another contraceptive method. - Offer emergency contraception. Abbreviations: Cu-IUD = copper-containing IUD; IUD = intrauterine device; LNG-IUD = levonorgestrel-releasing IUD; PID = pelvic inflammatory disease. - Treat according to CDC's STD Treatment Guidelines (available at ).	This document will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling. CDC does not accept commercial support. Front cover photos, left to right: intrauterine device, oral contraceptive pills, diaphragm, syringe for injectable contraceptives, male condom, transdermal contraceptive patch, etonogestrel implant, vaginal ring.# Introduction Unintended pregnancy rates remain high in the United States; approximately 50% of all pregnancies are unintended, with higher proportions among adolescent and young women, women who are racial/ethnic minorities, and women with lower levels of education and income (1). Unintended pregnancies increase the risk for poor maternal and infant outcomes (2) and in 2002, resulted in $5 billion in direct medical costs in the United States (3). Approximately half of unintended pregnancies are among women who were not using contraception at the time they became pregnant; the other half are among women who became pregnant despite reported use of contraception (4). Therefore, strategies to prevent unintended pregnancy include assisting women at risk for unintended pregnancy and their partners with choosing appropriate contraceptive methods and helping women use methods correctly and consistently to prevent pregnancy. In 2010, CDC first adapted global guidance from the World Health Organization (WHO) to help health-care providers counsel women, men, and couples about contraceptive method choice. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC), focuses on who can safely use specific methods of contraception and provides recommendations for the safety of contraceptive methods for women with various medical conditions (e.g., hypertension and diabetes) and characteristics (e.g., age, parity, and smoking status) (Appendix A) (5). The recommendations in this new guide, U.S. Selected Practice Recommendations for Contraceptive Use, 2013 (U.S. SPR), focuses on how contraceptive methods can be used and provides recommendations on optimal use of contraceptive methods for persons of all ages, including adolescents. During the past 15 years, CDC has contributed to the development and updating of the WHO global family planning guidance. CDC has supported WHO by coordinating the identification, critical appraisal, and synthesis of the scientific evidence on which the WHO guidance is based. In 2002, WHO published the first edition of the Selected Practice Recommendations for Contraceptive Use (WHO SPR), which presented evidence-based global guidance on how to use contraceptive methods safely and effectively once they are deemed to be medically appropriate. Since then, WHO has regularly updated its guidance on the basis of new evidence, and the document is now in its second edition (6), with an additional update in 2008 (7). The WHO global guidance is not intended for use directly by health-care providers; rather, WHO intends for the guidance to be used by local or national policy makers, family planning program managers, and the scientific community as a reference when they develop family planning guidance at the country or program level (6). For example, the United Kingdom adapted WHO SPR and in 2002 published the U.K. Selected Practice Recommendations for Contraceptive Use for use by U.K. health-care providers (8). CDC initiated a formal adaptation process to create U.S. SPR, using both the second edition of WHO SPR (6) and the 2008 update (7) as the basis for the U.S. version. Although much of the guidance is the same as the WHO guidance, the recommendations are specific to U.S. family planning practice. In addition, guidance on contraceptive methods not available in the United States has been removed, and four new topics for guidance have been added (the effectiveness of female sterilization, extended use of combined hormonal methods and bleeding problems, starting regular contraception after use of emergency contraception, and determining when contraception is no longer needed). This document contains recommendations for health-care providers for the safe and effective use of contraceptive methods and addresses provision of contraceptive methods and management of side effects and other problems with contraceptive method use. Although the term woman is used throughout this report, these recommendations refer to all females of reproductive age, including adolescents. Adolescents are identified throughout this document as a special population that might benefit from more frequent follow-up. These recommendations are meant to serve as a source of clinical guidance for health-care providers; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients; persons should seek advice from their health-care providers when considering family planning options. # Methods CDC initiated a process to adapt WHO SPR for the United States. This adaptation process included four steps: 1) determining the scope of and process for the adaptation, including an October 2010 meeting in which individual feedback was solicited from a small group of partners and experts; 2) preparing the systematic reviews of the evidence during October 2010-September 2011 to be used for the adaptation, including peer review; 3) convening a larger meeting of experts in October 2011 to examine the evidence and receive input on the recommendations; and 4) finalizing recommendations by CDC. During October 21-22, 2010, CDC convened a meeting of 10 partners and U.S. family planning experts in Atlanta, Georgia, to discuss the scope of and process for a U.S. adaptation of WHO SPR. A list of participants is provided at the end of this report. CDC identified the specific WHO recommendations that might benefit from modification for the United States. Criteria used to modify the WHO recommendations included the availability of new scientific evidence or the context in which family planning services are provided in the United States. CDC also identified several WHO recommendations that needed additional specificity to be useful for U.S. health-care providers, as well as the need for additional recommendations not currently included in WHO SPR. In addition, the meeting members discussed removing recommendations that provide information about contraceptive methods that are not available in the United States. Representatives from CDC and WHO conducted systematic reviews of the scientific evidence for each of the WHO recommendations being considered for adaptation and for each new topic being considered for addition to the guidance. The purpose of these systematic reviews was to identify evidence related to the common clinical challenges associated with the recommendations. When no direct evidence was available, indirect evidence and theoretical issues were considered. Standard guidelines were followed for reporting systematic reviews (9,10), and strength and quality of the evidence were graded using the system of the U.S. Preventive Services Task Force (11). Each complete systematic review was peer reviewed by two or three experts before its use in the adaptation process. Peer reviewers, who were identified from the list of persons scheduled to participate in the October 2011 meeting, were asked to comment on the search strategy, list of articles included in the reviews, and the summary of findings. The systematic reviews were finalized and provided to participants before the October 2011 meeting and were published in May 2013 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). During October 4-7, 2011, CDC convened a meeting in Atlanta, Georgia, of 36 experts who were invited to assist in guideline development and provide their perspective on the scientific evidence presented and the discussions on potential recommendations that followed. The group included obstetrician/ gynecologists, pediatricians, family physicians, nurse-midwives, nurse practitioners, epidemiologists, and others with research and clinical practice expertise in contraceptive safety, effectiveness, and management. All participants received all of the systematic reviews before the meeting. During the meeting, the evidence from the systematic review for each topic was presented, and participants discussed the evidence and the translation of the scientific evidence into recommendations that would meet the needs of U.S. healthcare providers. In particular, participants discussed whether and how the U.S. context might be different from the global context and whether these differences suggested any need for modifications to the global guidance. CDC gathered the input from the experts during the meeting and finalized the recommendations in this report. The document was peer reviewed by meeting participants, who were asked to comment on specific issues that were raised during the meeting. Feedback also was received from an external review panel, composed of health-care providers who had not participated in the adaptation meetings. These providers were asked to provide comments on the accuracy, feasibility, and clarity of the recommendations, as well as to provide other comments. Areas of research that need additional investigation also were considered during the meeting (31). # How To Use This Document The recommendations in this report are intended to help health-care providers address issues related to use of contraceptives, such as how to help a woman initiate use of a contraceptive method, which examinations and tests are needed before initiating use of a contraceptive method, what regular follow-up is needed, and how to address problems that often arise during use, including missed pills and side effects such as unscheduled bleeding. Each recommendation addresses what a woman or health-care provider can do in specific situations. For situations in which certain groups of women might be medically ineligible to follow the recommendations, comments and reference to U.S. MEC are provided (5). The full U.S. MEC recommendations and the evidence supporting those recommendations were published in 2010 (5). The information in this document is organized by contraceptive method, and the methods generally are presented in order of effectiveness, from highest to lowest. However, the recommendations are not intended to provide guidance on every aspect of provision and management of contraceptive method use. Instead, they use the best available evidence to address specific issues regarding common, yet sometimes complex, clinical issues. Each contraceptive method section generally includes information about initiation of the method, regular follow-up, and management of problems with use (e.g., usage errors and side effects). Each section first provides the recommendation and then includes a comments and evidence section, which includes comments about the recommendations and a brief summary of the scientific evidence on which the recommendation is based. Recommendations in this document are provided for permanent methods of contraception, such as vasectomy and female sterilization, as well as for reversible methods of contraception, including the copper-containing intrauterine device (Cu-IUD); levonorgestrel-releasing IUD (LNG-IUD); the etonogestrel implant; progestin-only injectables; progestinonly pills (POPs); combined hormonal contraceptive methods that contain both estrogen and a progestin, including combined oral contraceptives (COCs), a transdermal contraceptive patch, and a vaginal contraceptive ring; and the standard days method (SDM). Recommendations also are provided for emergency use of the Cu-IUD and emergency contraceptive pills (ECPs). For each contraceptive method, recommendations are provided on the timing for initiation of the method and indications for when and for how long additional contraception, or a back-up method, is needed. Many of these recommendations include guidance that a woman can start a contraceptive method at any time during her menstrual cycle if it is reasonably certain that the woman is not pregnant. Guidance for health-care providers on how to be reasonably certain that a woman is not pregnant is provided. For each contraceptive method, recommendations include the examinations and tests needed before initiation of the method. These recommendations apply to persons who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Most women need no or very few examinations or tests before initiating a contraceptive method. The following classification system was developed by WHO and adopted by CDC to categorize the applicability of the various examinations or tests before initiation of contraceptive methods (6): Class A: These tests and examinations are essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: These tests and examinations contribute substantially to safe and effective use, although implementation can be considered within the public health context, service context, or both. The risk for not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: These tests and examinations do not contribute substantially to safe and effective use of the contraceptive method. These classifications focus on the relation of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Systematic reviews were conducted for several different types of examinations and tests to assess whether a screening test was associated with safe use of contraceptive methods. Because no single convention exists for screening panels for certain diseases, including diabetes, lipid disorders, and liver diseases, the search strategies included broad terms for the tests and diseases of interest. Summary charts and clinical algorithms that summarize the guidance for the various contraceptive methods have been developed for many of the recommendations, including when to start using specific contraceptive methods (Appendix B), examinations and tests needed before initiating the various contraceptive methods (Appendix C), routine follow-up after initiating contraception (Appendix D), management of bleeding irregularities (Appendix E), and management of IUDs when users are found to have pelvic inflammatory disease (PID) (Appendix F). These summaries might be helpful to health-care providers when managing family planning patients. Additional tools are available on the U.S. SPR website (http://www.cdc. gov/reproductivehealth/UnintendedPregnancy/USSPR.htm). # Summary of Changes from WHO SPR Much of the guidance in U.S. SPR is the same or very similar to the WHO SPR guidance. U.S. SPR includes new guidance on the use of the combined contraceptive patch and vaginal ring, as well as recommendations for four new topics: • how to start regular contraception after taking ECPs • management of bleeding irregularities among women using extended or continuous combined hormonal contraceptives (including pills, the patch, and the ring) • when a woman can rely on female sterilization for contraception • when a woman can stop using contraceptives and not be at risk for unintended pregnancy Adaptations to the WHO SPR recommendations include 1) changes to the length of the grace period for depot medroxyprogesterone acetate (DMPA) reinjection, 2) differences in some of the examinations and tests recommended before contraceptive method initiation, 3) differences in some of the recommendations for management of bleeding irregularities because of new data and drug availability in the United States, and 4) a modified missed pill algorithm to respond to concerns of the CDC expert group and other reviewers that simplified algorithms are preferable. # Contraceptive Method Choice Many elements need to be considered individually by a woman, man, or couple when choosing the most appropriate contraceptive method. Some of these elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. Contraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Table 1). Both consistent and correct use can vary greatly with characteristics such as age, income, desire to prevent or delay pregnancy, and culture. Methods that depend on consistent and correct use by clients have a wide range of effectiveness between typical and perfect users. IUDs and implants are considered long-acting, reversible contraception (LARC); these methods are highly effective because they do not depend on regular compliance from the user. LARC methods are appropriate for most women, including adolescents and nulliparous women. All women should be counseled about the full range and effectiveness of contraceptive options for which they are medically eligible so that they can identify the optimal method (Figure 1). In choosing a method of contraception, the risk for human immunodeficiency virus (HIV) infection and other sexually transmitted diseases (STDs) also should be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STDs and HIV. Consistent and correct use of the male latex condom reduces the risk for HIV infection and other STDs, including chlamydial infection, gonorrhea, and trichomoniasis (32). On the basis of a limited number of clinical studies, when a male condom cannot be used properly to prevent infection, a female condom should be considered (32). All patients, regardless of contraceptive choice, should be counseled about the use of condoms and the risk for STDs, including HIV infection (32). Additional information about prevention and treatment of STDs is available from the CDC Sexually Transmitted Diseases Treatment Guidelines (32). # Maintaining Updated Guidance As with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. Working with WHO, CDC uses the continuous identification of research evidence (CIRE) system to ensure that WHO and CDC guidance is based on the best available evidence and that a mechanism is in place to update guidance when new evidence becomes available (33). CDC will continue to work with WHO to identify and assess all new relevant evidence and determine whether changes in the recommendations are warranted. In most cases, U.S. SPR will follow any updates in the WHO guidance, which typically occurs every 3-4 years (or sooner if warranted by new data). In addition, CDC will review any interim WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations that are not included in the WHO guidance and will completely review U.S. SPR every 3-4 years. Updates to the guidance can be found on the U.S. SPR website (http://www.cdc.gov/reproductivehealth/ UnintendedPregnancy/USSPR.htm). # How To Be Reasonably Certain that a Woman Is Not Pregnant In most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman who is about to start using a contraceptive method. Several criteria for assessing pregnancy risk are listed in the recommendation that follows. These criteria are highly accurate (i.e., a negative predictive value of 99%-100%) in ruling out pregnancy among women who are not pregnant (34)(35)(36)(37). Therefore, CDC recommends that health-care providers use these criteria to assess pregnancy * Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Estimates of the probability of pregnancy during the first year of typical use for spermicides and the diaphragm are taken from the 1995 National Survey of Family Growth (NSFG) corrected for underreporting of abortion; estimates for fertility awareness-based methods, withdrawal, the male condom, the pill and Depo-Provera are taken from the 1995 and 2002 NSFG corrected for underreporting of abortion. † Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. § Among couples attempting to avoid pregnancy, the percentage who continues to use a method for 1 year. ¶ The percentage becoming pregnant in the second and third columns are based on data from populations where contraception is not used and from women who cease using contraception to become pregnant. Among such populations, approximately 89% become pregnant within 1 year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within 1 year among women not relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. † † The ovulation and two day methods are based on evaluation of cervical mucus. The standard days method avoids intercourse on cycle days 8-19. The symptothermal method is a double-check method based on evaluation of cervical mucus to determine the first fertile day and evaluation of cervical mucus and temperature to determine the last fertile day. § § Without spermicides. * With spermicidal cream or jelly. † † † This is a highly effective, temporary method of contraception. However, to maintain in effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches age 6 months. status in a woman who is about to start using contraceptives (Box 1). If a woman meets one of these criteria (and therefore the health-care provider can be reasonably certain that she is not pregnant), a urine pregnancy test might be considered in addition to these criteria (based on clinical judgment), bearing in mind the limitations of the accuracy of pregnancy testing. If a woman does not meet any of these criteria, then the health-care provider cannot be reasonably certain that she is not pregnant, even with a negative pregnancy test. Routine pregnancy testing for every woman is not necessary. On the basis of clinical judgment, health-care providers might consider the addition of a urine pregnancy test; however, they should be aware of the limitations, including accuracy of the test relative to the time of last sexual intercourse, recent delivery, or spontaneous or induced abortion. Routine pregnancy testing for every woman is not necessary. If a woman has had recent (i.e., within the last 5 days) unprotected sexual intercourse, consider offering emergency contraception (either a Cu-IUD or ECPs), if pregnancy is not desired. Comments and Evidence Summary. The criteria for determining whether a woman is pregnant depend on the assurance that she has not ovulated within a certain amount of time after her last menses, spontaneous or induced abortion, or delivery. Among menstruating women, the timing of ovulation can vary widely. During an average 28-day cycle, ovulation generally occurs during days 9-20 (38). In addition, the likelihood of ovulation is low from days 1-7 of the menstrual cycle (39). After a spontaneous or an induced abortion, ovulation can occur within 2-3 weeks and has been found to occur as early as 8-13 days after the end of the pregnancy. Therefore, the likelihood of ovulation is low ≤7 days after an abortion (40)(41)(42). A recent systematic review reported that the mean day of first ovulation among postpartum nonlactating women occurred 45-94 days after delivery (43). In one study, the earliest ovulation was reported at 25 days after delivery. Among women who are within 6 months postpartum, are fully or nearly fully breastfeeding, and are amenorrheic, the risk for pregnancy is <2% (44). Although pregnancy tests often are performed before initiating contraception, the accuracy of qualitative urine pregnancy tests varies depending on the timing of the test relative to missed menses, recent sexual intercourse, or recent pregnancy. The sensitivity of a pregnancy test is defined as the concentration of human chorionic gonadotropin (hCG) at which 95% of tests are positive. Most qualitative pregnancy tests approved by the U.S. Food and Drug Administration (FDA) report a sensitivity of 20-25 mIU/mL in urine (45)(46)(47)(48) However, pregnancy detection rates can vary widely because of differences in test sensitivity and the timing of testing relative to missed menses (47,49). Some studies have shown that an additional 11 days past the day of expected menses are needed to detect 100% of pregnancies using qualitative tests (46). In addition, pregnancy tests cannot detect a pregnancy resulting from recent sexual intercourse. Qualitative tests also might have positive results for several weeks after termination of pregnancy because hCG can be present for several weeks after delivery or abortion (spontaneous or induced) (50)(51)(52). For contraceptive methods other than IUDs, the benefits of starting to use a contraceptive method likely exceed any risk, even in situations in which the health-care provider is uncertain whether the woman is pregnant. Therefore, the health-care provider can consider having patients start using contraceptive methods other than IUDs at any time, with a follow-up pregnancy test in 2-4 weeks. The risks of not starting to use contraception should be weighed against the risks of initiating contraception use in a woman who might be already pregnant. Most studies have shown no increased risk for adverse outcomes, including congenital anomalies or neonatal or infant death, among infants exposed in utero to COCs (53)(54)(55). Studies also have shown no increased risk for neonatal or infant death or developmental abnormalities among infants exposed in utero to DMPA (54,56,57). In contrast, for women who want to begin using an IUD (Cu-IUD or LNG-IUD), in situations in which the healthcare provider is uncertain whether the woman is pregnant, the woman should be provided with another contraceptive method to use until the health-care provider is reasonably certain that she is not pregnant and can insert the IUD. Pregnancies among women with IUDs are at higher risk for complications such as spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis (58). A systematic review identified four analyses of data from three diagnostic accuracy studies that evaluated the performance of the criteria listed above through use of a pregnancy checklist compared with a urine pregnancy test conducted concurrently (12). The performance of the checklist to diagnose or exclude pregnancy varied, with sensitivity of 55%-100% and specificity of 39%-89%. The negative predictive value was consistent across studies at 99%-100%; the pregnancy checklist correctly ruled out women who were not pregnant. One of the studies assessed the added usefulness of signs and symptoms of pregnancy and found that these criteria did not substantially improve the performance of the pregnancy checklist, although the number of women with signs and symptoms was small (34) (Level of evidence: Diagnostic accuracy studies, fair, direct). # Intrauterine Contraception Three IUDs are available in the United States, the Cu-IUD and two LNG-IUDs (containing a total of either 13.5 mg or 52 mg levonorgestrel). Fewer than 1 woman out of 100 becomes pregnant in the first year of using IUDs (with typical use) (59). IUDs are long acting, are reversible, and can be # BOX 1. How To Be Reasonably Certain that a Woman Is Not Pregnant A health-care provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria: • is ≤7 days after the start of normal menses • has not had sexual intercourse since the start of last normal menses • has been correctly and consistently using a reliable method of contraception • is ≤7 days after spontaneous or induced abortion • is within 4 weeks postpartum • is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority [≥85%] of feeds are breastfeeds),* amenorrheic, and <6 months postpartum used by women of all ages, including adolescents, and both by parous and nulliparous women. IUDs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Cu-IUDs Timing • The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). • The Cu-IUD also can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. If the day of ovulation can be estimated, the Cu-IUD also can be inserted >5 days after sexual intercourse as long as insertion does not occur >5 days after ovulation. # Need for Back-Up Contraception • No additional contraceptive protection is needed after Cu-IUD insertion. # Special Considerations Amenorrhea (Not Postpartum) • Timing: The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: No additional contraceptive protection is needed. # Postpartum (Including After Cesarean Section) • Timing: The Cu-IUD can be inserted at any time postpartum, including immediately postpartum (U.S. MEC 1 or 2) (Box 2), if it is reasonably certain that the woman is not pregnant (Box 1). The Cu-IUD should not be inserted in a woman with puerperal sepsis (U.S. MEC 4). • Need for back-up contraception: No additional contraceptive protection is needed. # Postabortion (Spontaneous or Induced) • Timing: The Cu-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first trimester abortion and U.S. MEC 2 for second trimester abortion). The Cu-IUD should not be inserted immediately after septic abortion (U.S. MEC 4). • Need for back-up contraception: No additional contraceptive protection is needed. # Switching from Another Contraceptive Method • Timing: The Cu-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: No additional contraceptive protection is needed. Comments and Evidence Summary. In situations in which the health-care provider is not reasonably certain that the woman is not pregnant, the woman should be provided with another contraceptive method to use until the health-care provider can be reasonably certain that she is not pregnant and can insert the Cu-IUD. A systematic review identified eight studies that suggested that timing of Cu-IUD insertion in relation to the menstrual cycle in nonpostpartum women had little effect on long-term outcomes (rates of continuation, removal, expulsion, or pregnancy) or on short-term outcomes (pain at insertion, bleeding at insertion, or immediate expulsion) (13) (Level of evidence: II-2, fair, direct). # Initiation of LNG-IUDs # Timing of LNG-IUD Insertion • The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception • If the LNG-IUD is inserted within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. • If the LNG-IUD is inserted >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) • Timing: The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Including After Cesarean Section) • # Postabortion (Spontaneous or Induced) • Timing: The LNG-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first-trimester abortion and U.S. MEC 2 for secondtrimester abortion). The LNG-IUD should not be inserted immediately after a septic abortion (U.S. MEC 4). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the IUD is placed at the time of a surgical abortion. # Switching from Another Contraceptive Method • Timing: The LNG-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: If it has been >7 days since menstrual bleeding began, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from a Cu-IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health-care provider can consider providing ECPs at the time of LNG-IUD insertion. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the woman should be provided with another contraceptive method to use until the health-care provider can be reasonably certain that she is not pregnant and can insert the LNG-IUD. If a woman needs to use additional contraceptive protection when switching to an LNG-IUD from another contraceptive method, consider continuing her previous method for 7 days after LNG-IUD insertion. No direct evidence was found regarding the effects of inserting LNG-IUDs on different days of the cycle on short-or longterm outcomes (13). # Examinations and Tests Needed Before Initiation of a Cu-IUD or an LNG-IUD Among healthy women, few examinations or tests are needed before initiation of an IUD (Table 2). Bimanual examination and cervical inspection are necessary before IUD insertion. A baseline weight and BMI measurement might be useful for monitoring IUD users over time. If a woman has not been screened for STDs according to STD screening guidelines, screening can be performed at the time of insertion. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use IUDs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of IUDs. However, measuring weight and calculating BMI (weight [kg] / height [m] 2 ) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Bimanual examination and cervical inspection are necessary before IUD insertion to assess uterine size and position and to detect any cervical or uterine abnormalities that might indicate infection or otherwise prevent IUD insertion (61,62). STDs: Women should be routinely screened for chlamydial infection and gonorrhea according to national screening guidelines. The CDC Sexually Transmitted Diseases Treatment Guidelines provide information on screening eligibility, timing, and frequency of screening and on screening for persons with risk factors (32). If STD screening guidelines have been followed, most women do not need additional STD screening at the time of IUD insertion. If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3) (5). For these women, IUD insertion should be delayed until appropriate testing and treatment occur. A systematic review did not identify any evidence regarding women who were screened versus not screened for STDs before IUD insertion (14). Although women with STDs at the time of IUD insertion have a higher risk for PID, the overall rate of PID among all IUD users is low (63,64). Hemoglobin: Women with iron-deficiency anemia can use the LNG-IUD (U.S. MEC 1) (5); therefore, screening for anemia is not necessary for safe initiation of the LNG-IUD. Women with iron-deficiency anemia generally can use the Cu-IUD (U.S. MEC 2). Measurement of hemoglobin before initiation of Cu-IUDs is not necessary because of the minimal change in hemoglobin among women with and without anemia using Cu-IUDs. A systematic review identified four studies that provided direct evidence for changes in hemoglobin among women with anemia who received Cu-IUDs (30). Evidence from one randomized trial (65) and one prospective cohort study (66) showed no significant changes in hemoglobin among Cu-IUD users with anemia, whereas two prospective cohort studies (67,68) showed a statistically significant decrease in hemoglobin levels during 12 months of follow-up; however, the magnitude of the decrease was small and most likely not clinically significant. The systematic review also identified 21 studies that provided indirect evidence by examining changes in hemoglobin among healthy women receiving Cu-IUDs (69-89), which generally showed no clinically significant changes in hemoglobin levels with up to 5 years of follow-up (Level of evidence: I to II-2, fair, direct). Liver enzymes: Women with liver disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for liver disease is not necessary for the safe initiation of the Cu-IUD. Although women with certain liver diseases generally should not use the LNG-IUD (U.S. MEC 3) (5), screening for liver disease before initiation of the LNG-IUD is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptive use (14). The prevalence of liver disorders among women of reproductive age is low. In 2008, among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited, and no evidence exists for the LNG-IUD. Clinical breast examination: Women with breast disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for breast disease is not necessary for the safe initiation of the Cu-IUD. Although women with current breast cancer should not use the LNG-IUD (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before inserting an IUD is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Cervical cytology: Although women with cervical cancer should not undergo IUD insertion (U.S. MEC 4) (5), screening asymptomatic women with cervical cytology before IUD insertion is not necessary because of the high rates of cervical screening, low incidence of cervical cancer in the United States, and high likelihood that a woman with cervical cancer already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with cervical cytology before initiation of IUDs (14). Cervical cancer is rare in the United States, with an incidence rate of 8.1 per 100,000 women per year during 2004-2008 (95). The incidence and mortality rates from cervical cancer have declined dramatically in the United States, largely because of cervical cytology screening (96). Overall screening rates for cervical cancer in the United States are high; among women aged 22-30 years, approximately 87% reported having cervical cytology screening within the last 3 years (97). HIV screening: Although women with acquired immunodeficiency syndrome (AIDS) who are not clinically well should generally not undergo IUD insertion (U.S. MEC 3) (5), HIV screening is not necessary before IUD insertion because of the high likelihood that a woman in the United States with such an advanced stage of disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened for HIV infection before IUD insertion (14). Limited evidence suggests that IUDs are not associated with disease progression, increased infection, or other adverse health effects among women with HIV infection (98). Other screening: Women with hypertension, diabetes, hyperlipidemia, or thrombogenic mutations can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, screening for these conditions is not necessary for the safe initiation of IUDs. # Provision of Prophylactic Antibiotics at the Time of IUD Insertion • Prophylactic antibiotics are generally not recommended for Cu-IUD or LNG-IUD insertion. Comments and Evidence Summary. Theoretically, IUD insertion could induce bacterial spread and lead to complications such as PID or infective endocarditis. A metaanalysis was conducted of randomized controlled trials examining antibiotic prophylaxis versus placebo or no treatment for IUD insertion (99). Use of prophylaxis reduced the frequency of unscheduled return visits but did not significantly reduce the incidence of PID or premature IUD discontinuation. Although the risk for PID was higher within the first 20 days after insertion, the incidence of PID was low among all women who had IUDs inserted (63). In addition, the American Heart Association recommends that the use of prophylactic antibiotics solely to prevent infective endocarditis is not needed for genitourinary procedures (100). Studies have not demonstrated a conclusive link between genitourinary procedures and infective endocarditis or a preventive benefit of prophylactic antibiotics during such procedures (100). # Routine Follow-Up After IUD Insertion These recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, persons with certain medical conditions or characteristics, and persons with multiple medical conditions. • Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. • At other routine visits, health-care providers who see IUD users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the IUD for safe and effective continued use on the basis of U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider performing an examination to check for the presence of the IUD strings. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Evidence from a systematic review about the effect of a specific follow-up visit schedule on IUD continuation is very limited and of poor quality. The evidence did not suggest that greater frequency of visits or earlier timing of the first follow-up visit after insertion improves continuation of use ( 16) (Level of evidence: II-2, poor, direct). Evidence from four studies from a systematic review on the incidence of PID among IUD initiators, or IUD removal as a result of PID, suggested that the incidence of PID did not differ between women using Cu-IUDs and those using DMPA, COCs, or LNG-IUDs (17) (Level of evidence: I to II-2, good, indirect). Evidence on the timing of PID after IUD insertion is mixed. Although the rate of PID was generally low, the largest study suggested that the rate of PID was significantly higher in the first 20 days after insertion (63) (Level of evidence: I to II-3, good to poor, indirect). # Bleeding Irregularities with Cu-IUD Use • Before Cu-IUD insertion, provide counseling about potential changes in bleeding patterns during Cu-IUD use. Unscheduled spotting or light bleeding, as well as heavy or prolonged bleeding, is common during the first 3-6 months of Cu-IUD use, is generally not harmful, and decreases with continued Cu-IUD use. • If clinically indicated, consider an underlying gynecological problem, such as Cu-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids), especially in women who have already been using the Cu-IUD for a few months or longer and who have developed a new onset of heavy or prolonged bleeding. If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecological problem is not found and the woman requests treatment, the following treatment option can be considered during days of bleeding: -Nonsteroidal antiinflammatory drugs (NSAIDs) for short-term treatment (5-7 days) • If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the Cu-IUD, information about common side effects such as unscheduled spotting or light bleeding or heavy or prolonged menstrual bleeding, especially during the first 3-6 months of use, should be discussed (70). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other contraceptives (i.e., DMPA) (101,102). Evidence is limited on specific drugs, doses, and durations of use for effective treatments for bleeding irregularities with Cu-IUD use; therefore, although this document includes general recommendations for treatments to consider, evidence for specific regimens is lacking. A systematic review identified 11 articles that examined various therapeutic treatments for heavy menstrual bleeding, prolonged menstrual bleeding, or both among women using Cu-IUDs (18). Nine studies examined the use of various oral NSAIDs for the treatment of heavy or prolonged menstrual bleeding among Cu-IUD users and compared them to either a placebo or a baseline cycle. Three of these trials examined the use of indomethacin (103)(104)(105), another three examined mefenamic acid (106-108), and another three examined flufenamic acid (103,104,109). Other NSAIDs used in the reported trials included alclofenac (103,104), suprofen (110), and diclofenac sodium (111). All but one NSAID study (107) demonstrated statistically significant or notable reductions in mean total menstrual blood loss with NSAID use. One study among 19 Cu-IUD users with heavy bleeding suggested that treatment with oral tranexamic acid can significantly reduce mean blood loss during treatment compared with placebo (111). Data regarding the overall safety of tranexamic acid are limited; an FDA warning states that tranexamic acid is contraindicated in women with active thromboembolic disease or with a history or intrinsic risk for thrombosis or thromboembolism (112,113). Treatment with aspirin demonstrated no statistically significant change in mean blood loss among women whose pretreatment menstrual blood loss was >80 mL or 60-80 mL; treatment resulted in a significant increase among women whose pretreatment menstrual blood loss was <60 mL (114). One study examined the use of a synthetic form of vasopressin, intranasal desmopressin (300 µg/day), for the first 5 days of menses for three treatment cycles and found a significant reduction in mean blood loss compared with baseline (106) (Level of evidence: I to II-3, poor to fair, direct). Only one small study examined treatment of spotting with three separate NSAIDs and did not observe improvements in spotting in any of the groups (103) (Level of evidence: I, poor, direct). # Bleeding Irregularities (Including Amenorrhea) with LNG-IUD Use • Before LNG-IUD insertion, provide counseling about potential changes in bleeding patterns during LNG-IUD use. Unscheduled spotting or light bleeding is expected during the first 3-6 months of LNG-IUD use, is generally not harmful, and decreases with continued LNG-IUD use. Over time, bleeding generally decreases with LNG-IUD use, and many women experience only light menstrual bleeding or amenorrhea. Heavy or prolonged bleeding, either unscheduled or menstrual, is uncommon during LNG-IUD use. # Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding) • If clinically indicated, consider an underlying gynecological problem, such as LNG-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Amenorrhea • Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired Comments and Evidence Summary. During contraceptive counseling and before insertion of the LNG-IUD, information about common side effects such as unscheduled spotting or light bleeding, especially during the first 3-6 months of use, should be discussed. Approximately half of LNG-IUD users are likely to experience amenorrhea or oligomenorrhea by 2 years of use (115). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). No direct evidence was found regarding therapeutic treatments for bleeding irregularities during LNG-IUD use. # Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have PID • Treat the PID according to the CDC Sexually Transmitted Diseases Treatment Guidelines (32). • Provide comprehensive management for STDs, including counseling about condom use. • The IUD does not need to be removed immediately if the woman needs ongoing contraception. • Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of the IUD. • If the woman wants to discontinue use, remove the IUD sometime after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. • If the IUD is removed, consider ECPs if appropriate. Counsel the woman on alternative contraceptive methods, and offer another method if it is desired. • A summary of IUD management in women with PID is provided (Appendix F). Comments and Evidence Summary. Treatment outcomes do not generally differ between women with PID who retain the IUD and those who have the IUD removed; however, appropriate antibiotic treatment and close clinical follow-up are necessary. A systematic review identified four studies that included women using copper or nonhormonal IUDs who developed PID and compared outcomes between women who had the IUD removed or did not (19). One randomized trial showed that women with IUDs removed had longer hospitalizations than those who did not, although no differences in PID recurrences or subsequent pregnancies were observed (116). Another randomized trial showed no differences in laboratory findings among women who removed the IUD compared with those who did not (117). One prospective cohort study showed no differences in clinical or laboratory findings during hospitalization; however, the IUD removal group had longer hospitalizations (118). One randomized trial showed that the rate of recovery for most clinical signs and symptoms was higher among women who had the IUD removed than among women who did not (119). No evidence was found regarding women using LNG-IUDs (Level of evidence: I to II-2, fair, direct). # Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Be Pregnant • Evaluate for possible ectopic pregnancy. • Advise the woman that she has an increased risk for spontaneous abortion (including septic abortion that might be life threatening) and of preterm delivery if the IUD is left in place. The removal of the IUD reduces these risks but might not decrease the risk to the baseline level of a pregnancy without an IUD. -If she does not want to continue the pregnancy, counsel her about options. -If she wants continue the pregnancy, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. # IUD Strings Are Visible or Can Be Retrieved Safely from the Cervical Canal • Advise the woman that the IUD should be removed as soon as possible. -If the IUD is to be removed, remove it by pulling on the strings gently. -Advise the woman that she should return promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. • If she chooses to keep the IUD, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. # IUD Strings Are Not Visible and Cannot Be Retrieved Safely • If ultrasonography is available, consider performing or referring for ultrasound examination to determine the location of the IUD. If the IUD cannot be located, it might have been expelled or have perforated the uterine wall. • If ultrasonography is not possible or the IUD is determined by ultrasound to be inside the uterus, advise the woman to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. Comments and Evidence Summary. Removing the IUD improves the pregnancy outcome if the IUD strings are visible or the device can be retrieved safely from the cervical canal. Risks for spontaneous abortion, preterm delivery, and infection are substantial if the IUD is left in place. Theoretically, the fetus might be affected by hormonal exposure from an LNG-IUD; however, whether this exposure increases the risk for fetal abnormalities is unknown. A systematic review identified nine studies suggesting that women who did not remove their IUDs during pregnancy were at greater risk for adverse pregnancy outcomes (including spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis) compared with women who had their IUDs removed or who did not have an IUD (58). Cu-IUD removal decreased risks but not to the baseline risk for pregnancies without an IUD. One case series examined LNG-IUDs. When they were not removed, eight in 10 pregnancies ended in spontaneous abortions (Level of evidence: II-2, fair, direct). # Implants The etonogestrel implant, a single rod with 68 mg of etonogestrel, is available in the United States. Fewer than 1 woman out of 100 become pregnant in the first year of use of the etonogestrel implant with typical use (59). The implant is long acting, is reversible, and can be used by women of all ages, including adolescents. The implant does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Implants Timing • The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception • If the implant is inserted within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If the implant is inserted >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) • Timing: The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) • # Postabortion (Spontaneous or Induced) • Timing: The implant can be inserted within the first 7 days, including immediately after the abortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the implant is placed at the time of a surgical abortion. # Switching from Another Contraceptive Method • Timing: The implant can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days after insertion. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the woman to retain the IUD for at least 7 days after the implant is inserted and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting the implant likely exceed any risk; therefore, starting the implant should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to an implant from another contraceptive method, consider continuing her previous method for 7 days after implant insertion. No direct evidence was found regarding the effects of starting the etonogestrel implant at different times of the cycle. # Examinations and Tests Needed Before Implant Insertion Among healthy women, no examinations or tests are needed before initiation of an implant, although a baseline weight and BMI measurement might be useful for monitoring implant users over time (Table 3). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. # Comments and Evidence Summary. Weight (BMI): Obese women can use implants (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of implants. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: A pelvic examination is not necessary before initiation of implants because it would not facilitate detection of conditions for which implant use would be unsafe. Women with current breast cancer should not use implants (U.S. MEC 4); women with certain liver diseases generally should not use implants (U.S. MEC 3) (5). However, none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed. No evidence was found regarding implants (Level of evidence: II-2 fair, direct). Liver enzymes: Although women with certain liver diseases generally should not use implants (U.S. MEC 3) (5), screening for liver disease before initiation of implants is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008, the percentage of adults aged 18-44 years with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for implants. Clinical breast examination: Although women with current breast cancer should not use implants (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating an implant is not necessary because of the low prevalence of breast cancer among women of reproductive age (15-49 years). A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with hypertension, diabetes, hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) implants ( 5); therefore, screening for these conditions is not necessary for the safe initiation of implants. # Routine Follow-Up After Implant Insertion These recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. • Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. • At other routine visits, health-care providers seeing implant users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the implant for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. A systematic review did not identify any evidence regarding whether a routine follow-up visit after initiating an implant improves correct or continued use (16). # Bleeding Irregularities (Including Amenorrhea) During Implant Use • Before implant insertion, provide counseling about potential changes in bleeding patterns during implant use. Unscheduled spotting or light bleeding is common with implant use, and some women experience amenorrhea. These bleeding changes are generally not harmful and might or might not decrease with continued implant use. Heavy or prolonged bleeding, unscheduled or menstrual, is uncommon during implant use. Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding) • If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) • If irregular bleeding persists and the woman finds it unacceptable, counsel her on alternative methods, and offer another method if it is desired. # Amenorrhea • Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the implant, information about common side effects, such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use should be discussed. A pooled analysis of data from 11 clinical trials indicate that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (121). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (101,102). A systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily LNG contraceptive implants (122)(123)(124)(125)(126). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (124,125). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (126,127). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (126). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (128). Evidence also suggests that estrogen (129)(130)(131), daily COCs (129), levonorgestrel pills (130), tamoxifen (132), or tranexamic acid (133) can reduce the number of bleeding or spotting days during treatment among levonorgestrel implant users. In one small study, vitamin E was found to significantly reduce the mean number of bleeding days after the first treatment cycle; however, another larger study reported no significant differences in length of bleeding and spotting episodes with vitamin E treatment (134,135). Use of aspirin did not result in a significant difference in median length of bleeding or bleeding and spotting episodes after treatment (134). One study among implant users reported a reduction in number of bleeding days after initiating ibuprofen; however, another trial did not demonstrate any significant differences in the number of spotting and bleeding episodes with ibuprofen compared with placebo (123,130). # Injectables Progestin-only injectable contraceptives (DMPA, 150 mg intramuscularly or 104 mg subcutaneously) are available in the United States; the only difference between these two formulations is the route of administration. Approximately 6 out of 100 women will become pregnant in the first year of use of DMPA with typical use (59). DMPA is reversible and can be used by women of all ages, including adolescents. DMPA does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Injectables Timing • The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception • If DMPA is started within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. • If DMPA is started >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) • Timing: The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) • # Postpartum (Not Breastfeeding) • Timing: The first DMPA injection can be given at any time, including immediately postpartum (U.S. MEC 1) if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: A woman who is ≥21 days postpartum and has not experienced return of her menstrual cycle needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. If her menstrual cycles have returned and it has been >7 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postabortion (Spontaneous or Induced) • Timing: The first DMPA injection can be given within the first 7 days, including immediately postabortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the injection is given at the time of a surgical abortion. # Switching from Another Contraceptive Method • Timing: The first DMPA injection can be given immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: If it has been >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after the injection and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting DMPA likely exceed any risk; therefore, starting DMPA should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to DMPA from another contraceptive method, consider continuing her previous method for 7 days after DMPA injection. A systematic review identified eight articles examining DMPA initiation on different days of the menstrual cycle (20). Evidence from two studies with small samples indicated that DMPA injections given up to day 7 of the menstrual cycle inhibited ovulation; when DMPA was administered after day 7, ovulation occurred in some women. Cervical mucus was of poor quality (i.e., not favorable for sperm penetration) in 90% of women within 24 hours of the injection (Level of evidence: II-2, fair) (136)(137)(138). Studies found that use of another contraceptive method until DMPA could be initiated (bridging option) did not help women initiate DMPA and was associated with more unintended pregnancies than immediate receipt of DMPA (139-143) (Level of evidence: I to II-3, fair to poor, indirect). # Examinations and Tests Needed Before Initiation of an Injectable Among healthy women, no examinations or tests are needed before initiation of DMPA, although a baseline weight and BMI measurement might be useful for monitoring DMPA users over time (Table 4). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for obesity is not necessary for the safe initiation of DMPA. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. (See guidance on follow-up for DMPA users for evidence on weight gain with DMPA use.) Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of DMPA because it does not facilitate detection of conditions for which DMPA would be unsafe. Although women with current breast cancer should not use DMPA (U.S. MEC 4), and women with severe hypertension, heart disease, vascular disease, migraine headaches with aura, or certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2, fair, direct). Blood pressure: Women with hypertension generally can use DMPA (U.S. MEC 2), with the exception of women with severe hypertension or vascular disease, who generally should not use DMPA (U.S. MEC 3) (5). Screening for hypertension before initiation of DMPA is not necessary because of the low prevalence of undiagnosed severe hypertension and the high likelihood that women with these conditions already would have had them diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a blood pressure measurement before initiation of progestin-only contraceptives (21). The prevalence of undiagnosed hypertension among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, the percentage with diagnosed hypertension was 7.8%, and the percentage with undiagnosed hypertension was 1.9% (144). Glucose: Although women with complicated diabetes generally should not use DMPA (U.S. MEC 3) (5), screening for diabetes before initiation of DMPA is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes would already have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (14). The prevalence of diabetes among women of reproductive age is low. During 1999-2008 among women aged 20-44 years * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. in the United States, the percentage with diagnosed diabetes was 3% and the percentage with undiagnosed diabetes was 0.5% (144). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (145)(146)(147)(148)(149)(150)(151). Liver enzymes: Although women with certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), screening for liver disease before initiation of DMPA is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for DMPA. Clinical breast examination: Although women with current breast cancer should not use DMPA (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating DMPA is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for these conditions is not necessary for the safe initiation of DMPA. # Routine Follow-Up After Injectable Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. • Advise a woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time for reinjection. No routine follow-up visit is required. • At other routine visits, health-care providers seeing injectable users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the injectable for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Although no evidence exists regarding whether a routine follow-up visit after initiating DMPA improves correct or continued use, monitoring weight or BMI change over time is important for DMPA users. A systematic review identified a limited body of evidence that examined whether weight gain in the few months after DMPA initiation predicted future weight gain (17). Two studies found significant differences in weight gain or BMI at follow-up periods ranging from 12 to 36 months between early weight gainers (i.e., those who gained >5% of their baseline body weight within 6 months after initiation) and those who were not early weight gainers (152,153). The differences between groups were more pronounced at 18, 24, and 36 months than at 12 months. One study found that most adolescent DMPA users who had gained >5% of their baseline weight by 3 months gained even more weight by 12 months (154) (Level of evidence: II-2, fair, to II-3, fair, direct). # Timing of Repeat Injections Reinjection Interval • Provide repeat DMPA injections every 3 months (13 weeks). # Special Considerations Early Injection • The repeat DMPA injection can be given early when necessary. # Late Injection • The repeat DMPA injection can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection. • If the woman is >2 weeks late (>15 weeks from the last injection) for a repeat DMPA injection, she can have the injection if it is reasonably certain that she is not pregnant (Box 1). She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. She might consider the use of emergency contraception if appropriate. Comments and Evidence Summary. There are no time limits on early injections; injections can be given when necessary (e.g., when a woman cannot return at the routine interval). WHO has extended the time that a woman can have a late reinjection (i.e., grace period) for DMPA use from 2 weeks to 4 weeks on the basis of data from one study showing low pregnancy rates through 4 weeks; however, the CDC expert group did not consider the data to be generalizable to the United States because a large proportion of women in the study were breastfeeding. Therefore, U.S. SPR recommends a grace period of 2 weeks. A systematic review identified 12 studies evaluating time to pregnancy or ovulation after the last injection of DMPA (155). Although pregnancy rates were low during the 2-week interval following the reinjection date and for 4 weeks following the reinjection date, data were sparse and one study included a large proportion of breastfeeding women (156)(157)(158). Studies also indicated a wide variation in time to ovulation after the last DMPA injection, with the majority ranging from 15 to 49 weeks from the last injection (159-167) (Level of evidence: II-2, fair, direct). # Bleeding Irregularities (Including Amenorrhea) During Injectable Use • Before DMPA initiation, provide counseling about potential changes in bleeding patterns during DMPA use. Amenorrhea and unscheduled spotting or light bleeding is common with DMPA use, and heavy or prolonged bleeding can occur with DMPA use. These bleeding irregularities are generally not harmful and might decrease with continued DMPA use. # Unscheduled Spotting or Light Bleeding • If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment option during days of bleeding can be considered: -NSAIDs for short-term treatment (5-7 days) • If unscheduled spotting or light bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Heavy or Prolonged Bleeding • If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (such as fibroids or polyps). If an underlying gynecologic problem is identified, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) • If heavy or prolonged bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. # Amenorrhea • Amenorrhea does not require any medical treatment. Provide reassurance. -If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiation of DMPA, information about common side effects such as irregular bleeding should be discussed. Unscheduled bleeding or spotting is common with DMPA use (168). Additionally, amenorrhea is common after ≥1 years of continuous use (168,169). These bleeding irregularities are generally not harmful. Enhanced counseling among DMPA users detailing expected bleeding patterns and reassurance that these irregularities generally are not harmful has been shown to reduce DMPA discontinuation in clinical trials (101,102). A systematic review, as well as two additional studies, examined the treatment of bleeding irregularities during DMPA use (122,170,171). Two small studies found significant cessation of bleeding within 7 days of starting treatment among women taking valdecoxib for 5 days or mefenamic acid for 5 days compared with placebo (172,173). Treatment with ethinyl estradiol was found to stop bleeding better than placebo during the treatment period, although rates of discontinuation were high, and safety outcomes were not examined (174). In one small study among DMPA users who had been experiencing amenorrhea for 2 months, treatment with COCs was found to alleviate amenorrhea better than placebo (175). No studies examined the effects of aspirin on bleeding irregularities among DMPA users. # Combined Hormonal Contraceptives Combined hormonal contraceptives contain both estrogen and a progestin and include 1) COCs (various formulations), 2) a transdermal contraceptive patch (which releases 150 µg of norelgestromin and 20 µg ethinyl estradiol daily), and 3) a vaginal contraceptive ring (which releases 120 µg etonogestrel and 15 µg ethinyl estradiol daily). Approximately 9 out of 100 women become pregnant in the first year of use with combined hormonal contraceptives with typical use (59). These methods are reversible and can be used by women of all ages. Combined hormonal contraceptives are generally used for 21-24 consecutive days, followed by 4-7 hormone-free days (either no use or placebo pills). These methods are sometimes used for an extended period with infrequent or no hormonefree days. Combined hormonal contraceptives do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Initiation of Combined Hormonal Contraceptives Timing • Combined hormonal contraceptives can be initiated at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception • If combined hormonal contraceptives are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If combined hormonal contraceptives are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Special Considerations Amenorrhea (Not Postpartum) • Timing: Combined hormonal contraceptives can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. # Postpartum (Breastfeeding) • Timing: Combined hormonal contraceptives can be started when the woman is medically eligible to use the method (176) and if it is reasonably certain that she is not pregnant. (Box 1). # Postabortion (Spontaneous or Induced) • Timing: Combined hormonal contraceptives can be started within the first 7 days after first or second trimester abortion, including immediately postabortion (U.S. MEC 1). • Need for back-up contraception: She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless combined hormonal contraceptives are started at the time of a surgical abortion. # Switching from Another Contraceptive Method • Timing: Combined hormonal contraceptives can be started immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after combined hormonal contraceptives are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting combined hormonal contraceptives likely exceed any risk; therefore, starting combined hormonal contraceptives should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to combined hormonal contraceptives from another contraceptive method, consider continuing her previous method for 7 days after starting combined hormonal contraceptives. A systematic review of 18 studies examined the effects of starting combined hormonal contraceptives on different days of the menstrual cycle (22). Overall, the evidence suggested that pregnancy rates did not differ by the timing of combined hormonal contraceptive initiation (143,177-179) (Level of evidence: I to II-3, fair, indirect). The more follicular activity that occurred before starting COCs, the more likely ovulation was to occur; however, no ovulations occurred when COCs were started at a follicle diameter of 10 mm (mean cycle day 7.6) or when the ring was started at 13 mm (median cycle day 11) (180-189) (Level of evidence: I to II-3, fair, indirect). Bleeding patterns and other side effects did not vary with the timing of combined hormonal contraceptive initiation (177,178,(190)(191)(192)(193)(194) (Level of evidence: I to II-2, good to poor, direct). Although continuation rates of combined hormonal contraceptives were initially improved by the "quick start" approach (i.e., starting on the day of the visit), the advantage disappeared over time (178,179,(190)(191)(192)(193)(194)(195) (Level of evidence: I to II-2, good to poor, direct). # Examinations and Tests Needed Before Initiation of Combined Hormonal Contraceptives Among healthy women, few examinations or tests are needed before initiation of combined hormonal contraceptives (Table 5). Blood pressure should be measured before initiation of combined hormonal contraceptives. Baseline weight and BMI measurements might be useful for monitoring combined hormonal contraceptive users over time. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Blood pressure: Women who have more severe hypertension (systolic pressure of ≥160 mm Hg or diastolic pressure of ≥100 mm Hg) or vascular disease should not use combined hormonal contraceptives (U.S. MEC 4), and women who have less severe hypertension (systolic pressure of 140-159 mm Hg or diastolic pressure of 90-99 mm Hg) or adequately controlled hypertension generally should not use combined hormonal contraceptives (U.S. MEC 3) (5). Therefore, blood pressure should be measured before initiating combined hormonal contraceptives. If access to health care is limited, blood pressure measurements may be obtained in nonclinical settings, such as pharmacies or fire stations, and reported by the woman to her provider. Evidence suggests that cardiovascular outcomes are worse among women who did not have their blood pressure measured before initiating COCs. A systematic review identified six articles from three studies that reported cardiovascular outcomes among women who had blood pressure measurements and women who did not have blood pressure measurements before initiating COCs (21). Three case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for acute myocardial infarction than women who did have blood pressure measurements (196)(197)(198). Two case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for ischemic stroke than women who did have blood pressure measurements (199,200). One case-control study showed no difference in the risk for hemorrhagic stroke among women who initiated COCs regardless of whether their blood pressure was measured (201). Studies that examined hormonal contraceptive methods other than COCs were not identified (Level of evidence: II-2, fair, direct). # Weight (BMI): Obese women generally can use combined hormonal contraceptives (U.S. MEC 2) (5); therefore, screening for obesity is not necessary for the safe initiation of combined hormonal contraceptives. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of combined hormonal contraceptives because it does not facilitate detection of conditions for which hormonal contraceptives would be unsafe. Women with certain conditions such as current breast cancer, severe hypertension or vascular disease, heart disease, migraine headaches with aura, and certain liver diseases, as well as women aged ≥35 years who smoke ≥15 cigarettes per day, should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5); however, none of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were found (Level of evidence: II-2 fair, direct). Glucose: Although women with complicated diabetes should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives, depending on the severity of the condition (5), screening for diabetes before initiation of hormonal contraceptives is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (14). The prevalence of diabetes among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, the percentage with diagnosed diabetes was 3% and the percentage with undiagnosed diabetes was 0.5% (144). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (145)(146)(147)(148)(149)(150)(151). Lipids: Although some women with hyperlipidemias generally should not use combined hormonal contraceptives (U.S. MEC 2/3, depending on the type and severity of the hyperlipidemia and presence of other cardiovascular risk factors) (5), screening for hyperlipidemia before initiation of * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. § Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. hormonal contraceptives is not necessary because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (14). The prevalence of hyperlipidemia among women of reproductive age is low. During 1999-2008 among women aged 20-44 years in the United States, approximately 10% had hypercholesterolemia, defined as total cholesterol ≥ 240 mg/dL or currently taking lipid-lowering medications, and the prevalence of undiagnosed hypercholesterolemia was approximately 2% (144). Studies have shown mixed results about the effects of hormonal methods on lipid levels, and the clinical significance of these changes is unclear (202)(203)(204). In addition, women with abnormal lipid levels at baseline were not found to have increased risk for adverse changes to their lipid profile when using hormonal methods (202). Liver enzymes: Although women with certain liver diseases should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5), screening for liver disease before initiation of combined hormonal contraceptives is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited; no evidence exists for other types of combined hormonal contraceptives. Thrombogenic mutations: Women with thrombogenic mutations should not use combined hormonal contraceptives (U.S. MEC 4) (5) because of the increased risk for venous thromboembolism (205). However, studies have shown that universal screening for thrombogenic mutations before initiating COCs is not cost-effective because of the rarity of the conditions and the high cost of screening (206)(207)(208). Clinical breast examination: Although women with current breast cancer should not use combined hormonal contraceptives (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating combined hormonal contraceptives is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women aged 20-49 years was approximately 72 per 100,000 women (95). Other screening: Women with anemia, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) combined hormonal contraceptives (5); therefore, screening for these conditions is not necessary for the safe initiation of combined hormonal contraceptives. # Number of Pill Packs that Should Be Provided at Initial and Return Visits • At the initial and return visits, provide or prescribe up to a 1-year supply of COCs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. • A woman should be able to obtain COCs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy. A systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (23). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (209)(210)(211). However, one study found that there was no difference in continuation when patients were provided one and then three packs versus four packs all at once (212). In addition to continuation, a greater number of pills packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (i.e., 13 packs versus three packs) also was associated with increased pill wastage in one study (210) (Level of evidence: I to II-2, fair, direct). # Routine Follow-Up After Combined Hormonal Contraceptive Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. • Advise a woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. • At other routine visits, health-care providers seeing combined hormonal contraceptive users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of combined hormonal contraceptives for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Assess blood pressure. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence exists regarding whether a routine follow-up visit after initiating combined hormonal contraceptives improves correct or continued use. Monitoring blood pressure is important for combined hormonal contraceptive users. Health-care providers might consider recommending women obtain blood pressure measurements in nonclinical settings (e.g., pharmacy or fire station). A systematic review identified five studies that examined the incidence of hypertension among women who began using a COC versus those who started a nonhormonal method of contraception or a placebo (17). Few women developed hypertension after initiating COCs, and studies examining increases in blood pressure after COC initiation found mixed results. No studies were identified that examined changes in blood pressure among patch or vaginal ring users (Level of evidence: I, fair, to II-2, fair, indirect). # Late or Missed Doses and Side Effects from Combined Hormonal Contraceptive Use For the following recommendations, a dose is considered late when <24 hours have elapsed since the dose should have been taken. A dose is considered missed if ≥24 hours have elapsed since the dose should have been taken. For example, if a COC pill was supposed to have been taken on Monday at 9:00 a.m. and is taken at 11:00 a.m., the pill is late; however, by Tuesday morning at 11:00 a.m., Monday's 9:00 a.m. pill has been missed and Tuesday's 9:00 a.m. pill is late. For COCs, the recommendations only apply to late or missed hormonally active pills and not to placebo pills. Recommendations are provided for late or missed pills (Figure 2), the patch (Figure 3), and the ring (Figure 4). Comments and Evidence Summary. Inconsistent or incorrect use of combined hormonal contraceptives is a major cause of combined hormonal contraceptive failure. Extending the hormone-free interval is considered to be a particularly risky time to miss combined hormonal contraceptives. Seven days of continuous combined hormonal contraceptive use is deemed necessary to reliably prevent ovulation. The recommendations reflect a balance between simplicity and precision of science. Women who frequently miss COCs or experience other usage errors with combined hormonal patch or combined vaginal ring should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). A systematic review identified 36 studies that examined measures of contraceptive effectiveness of combined hormonal contraceptives during cycles with extended hormone-free intervals, shortened hormone-free intervals, or deliberate nonadherence on days not adjacent to the hormone-free interval (24). Most of the studies examined COCs (188,, two examined the combined hormonal patch (234,241), and six examined the combined vaginal ring (185,(242)(243)(244)(245)(246). No direct evidence on the effect of missed pills on the risk for pregnancy was found. Studies of women deliberately extending the hormone-free interval up to 14 days found wide variability in the amount of follicular development and occurrence of ovulation (216,219,221,222,224,225,(227)(228)(229)(230); in general, the risk for ovulation was low, and among women who did ovulate, cycles were usually abnormal. In studies of women who deliberately missed pills on various days during the cycle not adjacent to the hormone-free interval, ovulation occurred infrequently (214,(220)(221)(222)230,231,233,234). Studies comparing 7-day hormone-free intervals with shorter hormone-free intervals found lower rates of pregnancy (213,217,226,232) and significantly greater suppression of ovulation (215,225,(236)(237)(238)240) among women with shorter intervals in all but one study (235), which found no difference. Two studies that compared 30-µg ethinyl estradiol pills with 20-µg ethinyl estradiol pills showed more follicular activity when 20-µg ethinyl estradiol pills were missed (216,219). In studies examining the combined vaginal ring, three studies found that nondeliberate extension of the hormone-free interval for 24 to <48 hours from the scheduled period did not increase the risk for pregnancy (242,243,245); one study found that ring insertion after a deliberately extended hormone-free interval that allowed a 13-mm follicle to develop interrupted ovarian function and further follicular growth (185); and one study found that inhibition of ovulation was maintained after deliberately forgetting to remove the ring for up to 2 weeks after normal ring use (246). In studies examining the combined hormonal patch, one study found that missing 1-3 consecutive days before patch replacement (either wearing one patch 3 days longer before replacement or going 3 days without a patch before replacing the next patch) on days not adjacent to the patch-free interval resulted in little follicular activity and low risk for ovulation (234), and one pharmacokinetic study found that serum levels of ethinyl estradiol and progestin norelgestromin remained within reference ranges after extending patch wear for 3 days (241). No studies were found on extending the patch-free interval. In studies that provide indirect evidence on the effects of missed combined hormonal contraception on surrogate measures of pregnancy, how differences in surrogate measures correspond to pregnancy risk is unclear (Level of evidence: I, good, indirect to II-3, poor, direct). # Vomiting or Severe Diarrhea While Using COCs Certain steps should be taken by women who experience vomiting or severe diarrhea while using COCs (Figure 5). Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of COCs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence that addresses vomiting or severe diarrhea while using COCs, these recommendations are based on the recommendations # FIGURE 2. Recommended actions after late or missed combined oral contraceptives If one hormonal pill is late: (<24 hours since a pill should have been taken) If one hormonal pill has been missed: (24 to <48 hours since a pill should have been taken) If two or more consecutive hormonal pills have been missed: (≥48 hours since a pill should have been taken) • Take the late or missed pill as soon as possible. • Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day). • No additional contraceptive protection is needed. • Emergency contraception is not usually needed but can be considered if hormonal pills were missed earlier in the cycle or in the last week of the previous cycle. • Take the most recent missed pill as soon as possible. (Any other missed pills should be discarded.) • Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day). • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days. for missed COCs. No evidence was found on the effects of vomiting or diarrhea on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality. • # Unscheduled Bleeding with Extended or Continuous Use of Combined Hormonal Contraceptives • Before initiation of combined hormonal contraceptives, provide counseling about potential changes in bleeding patterns during extended or continuous combined hormonal contraceptive use. (Extended contraceptive use is defined as a planned hormone-free interval after at least two contiguous cycles. Continuous contraceptive use is defined as uninterrupted use of hormonal contraception without a hormone-free interval [247].) • Unscheduled spotting or bleeding is common during the first 3-6 months of extended or continuous combined hormonal contraceptive use. It is generally not harmful and decreases with continued combined hormonal contraceptive use. • If clinically indicated, consider an underlying gynecological problem, such as inconsistent use, interactions with other medications, cigarette smoking, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecological problem is not found and the woman wants treatment, the following treatment option can be considered: -Advise the woman to discontinue combined hormonal contraceptive use (i.e., a hormone-free interval) for 3-4 consecutive days; a hormone-free interval is not recommended during the first 21 days of using the continuous or extended combined hormonal contraceptive method. A hormone-free interval also is not recommended more than once per month because contraceptive effectiveness might be reduced. • If unscheduled spotting or bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiating extended or continuous * If detachment takes place but the woman is unsure when the detachment occurred, consider the patch to have been detached for ≥48 hours since a patch should have been applied or reattached. combined hormonal contraceptives, information about common side effects such as unscheduled spotting or bleeding, especially during the first 3-6 months of use, should be discussed (248). These bleeding irregularities are generally not harmful and usually improve with persistent use of the hormonal method. To avoid unscheduled spotting or bleeding, counseling should emphasize the importance of correct use and timing; for users of contraceptive pills, emphasize consistent pill use. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with DMPA (101,102). A systematic review identified three studies with small study populations that addressed treatments for unscheduled bleeding among women using extended or continuous combined hormonal contraceptives (25). In two separate randomized clinical trials in which women were taking either contraceptive pills or using the contraceptive ring continuously for 168 days, women assigned to a hormone-free interval of 3 or 4 days reported improved bleeding. Although they noted an initial increase in flow, this was followed by an abrupt decrease 7-8 days later with eventual cessation of flow 11-12 days later. These findings were compared with women who continued to use their method without a hormone-free interval, in which a greater proportion reported either treatment failure or fewer days of amenorrhea (249,250). In another randomized trial of 66 women with unscheduled bleeding among women using 84 days of hormonally active contraceptive pills, oral doxycycline (100 mg twice daily) initiated the first day of bleeding and taken for 5 days did not result in any improvement in bleeding compared with placebo (251) (Level of evidence: I, fair, direct). # Progestin-Only Pills POPs contain only a progestin and no estrogen and are available in the United States. Approximately 9 out of 100 women become pregnant in the first year of use with POPs with typical use (59). POPs are reversible and can be used by women of all ages. POPs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # FIGURE 4. Recommended actions after delayed insertion or reinsertion with combined vaginal ring Delayed insertion of a new ring or delayed reinsertion* of a current ring for <48 hours since a ring should have been inserted Delayed insertion of a new ring or delayed reinsertion* for ≥48 hours since a ring should have been inserted • Insert ring as soon as possible. • Keep the ring in until the scheduled ring removal day. • No additional contraceptive protection is needed. • Emergency contraception is not usually needed but can be considered if delayed insertion or reinsertion occurred earlier in the cycle or in the last week of the previous cycle. • Insert ring as soon as possible. • Keep the ring in until the scheduled ring removal day. • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until a ring has been worn for 7 consecutive days. * If removal takes place but the woman is unsure of how long the ring has been removed, consider the ring to have been removed for ≥48 hours since a ring should have been inserted or reinserted. # Initiation of POPs Timing • POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). # Need for Back-Up Contraception • If POPs are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If POPs are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Special Considerations Amenorrhea (Not Postpartum) • Timing: POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postpartum (Breastfeeding) • returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postpartum (Not Breastfeeding) • Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 1), if it is reasonably certain that the woman is not pregnant (Box 1). • Need for back-up contraception: Women who are ≥21 days postpartum and whose menstrual cycles have not returned need to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. If her menstrual cycles have returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. # Postabortion (Spontaneous or Induced) • Timing: POPs can be started within the first 7 days, including immediately postabortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days unless POPs are started at the time of a surgical abortion. # Switching from Another Contraceptive Method • Timing: POPs can be started immediately if it is reasonably certain that the woman is not pregnant (Box 1). Waiting for her next menstrual period is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A healthcare provider may consider any of the following options: -Advise the women to retain the IUD for at least 2 days after POPs are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 2 days before removing the IUD and switching to the new method. -Advise the woman to use ECPs at the time of IUD removal. Comments and Evidence Summary. In situations in which the health-care provider is uncertain whether the woman might be pregnant, the benefits of starting POPs likely exceed any risk; therefore, starting POPs should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. Unlike COCs, POPs inhibit ovulation in about half of cycles, although the rates vary widely by individual (252). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (252). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use has been deemed necessary to achieve the contraceptive effects on cervical mucus (252). If a woman needs to use additional contraceptive protection when switching to POPs from another contraceptive method, consider continuing her previous method for 2 days after starting POPs. No direct evidence was found regarding the effects of starting POPs at different times of the cycle. # Examinations and Tests Needed Before Initiation of POPs Among healthy women, no examinations or tests are needed before initiation of POPs, although a baseline weight and BMI measurement might be useful for monitoring POP users over time (Table 6). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Comments and Evidence Summary. Weight (BMI): Obese women can use POPs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of POPs. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of POPs because it does not facilitate detection of conditions for which POPs would be unsafe. Women with current breast cancer should not use POPs (U.S. MEC 4), and women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5); however, neither of these conditions are likely to be detected by pelvic examination (120). A systematic review identified two case-control studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (15). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2 fair, direct). Liver enzymes: Although women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5), screening for liver disease before initiation of POPs is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (14). The prevalence of liver disorders among women of reproductive age is low. In 2008 among U.S. adults aged 18-44 years, the percentage with liver disease (not further specified) was 1.0% (90). In 2009, the incidence of acute hepatitis A, B, or C among women was <1 per 100,000 population (91). During 1998-2007, the incidence of liver carcinoma among women was approximately 3 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94). Clinical breast examination: Although women with current breast cancer should not use POPs (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating POPs is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (15). The incidence of breast cancer among women of reproductive age in the United States is low. In 2009, the incidence of breast cancer among women ages 20-49 was approximately 72 per 100,000 women (95). Other screening: Women with hypertension, diabetes, hyperlipidemia, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) POPs (5); therefore, screening for these conditions is not necessary for the safe initiation of POPs. # Number of Pill Packs that Should Be Provided at Initial and Return Visits • At the initial and return visits, provide or prescribe up to a 1-year supply of POPs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. • A woman should be able to obtain POPs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy. A systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (23). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (209)(210)(211). However, one study found that there was no difference in continuation when patients were provided one and then three packs versus four packs all at once (212). In addition to continuation, a greater number of pill packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (13 packs versus three packs) also was associated with increased pill wastage in one study (210) (Level of evidence: I to II-2, fair, direct). # Routine Follow-Up After POP Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. • Advise a woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. • At other routine visits, health-care providers seeing POP users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of POPs for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence was found regarding whether a routine follow-up visit after initiating POPs improves correct or continued use. # Missed POPs For the following recommendations, a dose is considered missed if it has been >3 hours since it should have been taken. • Take one pill as soon as possible. • Continue taking pills daily, one each day, at the same time each day, even if it means taking two pills on the same day. • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until pills have been taken correctly, on time, for 2 consecutive days. • Emergency contraception should be considered if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Inconsistent or incorrect use of oral contraceptive pills is a major reason for oral contraceptive failure. Unlike COCs, POPs inhibit ovulation in about half of cycles, although this rate varies widely by individual (252). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (252). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use was deemed necessary to achieve the contraceptive effects on cervical mucus (252). Women who frequently miss POPs should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). No evidence was found regarding the effects of missed POPs available in the United States on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality. # Vomiting or Severe Diarrhea (for any Reason or Duration) that Occurs Within 3 Hours After Taking a Pill • Take another pill as soon as possible (if possible, despite discomfort). • Continue taking pills daily, one each day, at the same time each day. • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until 2 days after vomiting or diarrhea has resolved. • Emergency contraception should be considered if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of POPs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence to address this question, these recommendations are based on the recommendations for missed POPs. No evidence was found regarding the effects of vomiting or diarrhea on measures of contraceptive effectiveness, including pregnancy, follicular development, hormone levels, or cervical mucus quality. # Standard Days Method SDM is a method based on fertility awareness; users must avoid unprotected sexual intercourse on days 8-19 of the menstrual cycle (253). Approximately 5 out of 100 women become pregnant in the first year of use with perfect (i.e., correct and consistent) use of SDM (253); effectiveness based on typical use is not available for this method but is expected to be lower than that for perfect use. SDM is reversible and can be used by women of all ages. SDM does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # Use of SDM Among Women with Various Menstrual Cycle Durations Menstrual Cycles of 26-32 Days • These women may use the method. • Provide a barrier method of contraception for protection on days 8-19 if she wants one. • If she has unprotected sexual intercourse during days 8-19, consider the use of emergency contraception if appropriate. # Two or More Menstrual Cycles of <26 or >32 Days Within Any 1 Year of SDM Use • Advise the woman that the method might not be appropriate for her because of a higher risk for pregnancy. Help her consider another method. Comments and Evidence Summary. The probability of pregnancy is increased when the menstrual cycle is outside the range of 26-32 days, even if unprotected sexual intercourse is avoided on days 8-19. A study of 7,600 menstrual cycles, including information on cycle length and signs of ovulation, concluded that the theoretical effectiveness of SDM is greatest for women with cycles of 26-32 days, that the method is still effective for women who occasionally have a cycle outside this range, and that it is less effective for women who consistently have cycles outside this range. Information from daily hormonal measurements shows that the timing of the 6-day fertile window varies greatly, even among women with regular cycles (39,254,255). # Emergency Contraception Emergency contraception consists of methods that can be used by women after sexual intercourse to prevent pregnancy. Emergency contraception methods have varying ranges of effectiveness depending on the method and timing of administration. Four options are available in the United States: the Cu-IUD and three types of ECPs. # Types of Emergency Contraception Intrauterine Device • Cu-IUD # ECPs • Ulipristal acetate (UPA) in a single dose (30 mg) • Levonorgestrel in a single dose (1.5 mg) or as a split dose (1 dose of 0.75 mg of levonorgestrel followed by a second dose of 0.75 mg of levonorgestrel 12 hours later) • Combined estrogen and progestin in 2 doses (Yuzpe regimen: 1 dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel followed by a second dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel 12 hours later) # Initiation of Emergency Contraception Timing # Cu-IUD • The Cu-IUD can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. • In addition, when the day of ovulation can be estimated, the Cu-IUD can be inserted beyond 5 days after sexual intercourse, as long as insertion does not occur >5 days after ovulation. # ECPs • ECPs should be taken as soon as possible within 5 days of unprotected sexual intercourse. Comments and Evidence Summary. Cu-IUDs are highly effective as emergency contraception (256) and can be continued as regular contraception. UPA and levonorgestrel ECPs have similar effectiveness when taken within 3 days after unprotected sexual intercourse; however, UPA has been shown to be more effective than the levonorgestrel formulation 3-5 days after unprotected sexual intercourse (257). The combined estrogen and progestin regimen is less effective than UPA or levonorgestrel and also is associated with more frequent occurrence of side effects (nausea and vomiting) (258). The levonorgestrel formulation might be less effective than UPA among obese women (257). Two studies of UPA use found consistent decreases in pregnancy rates when administered within 120 hours of unprotected sexual intercourse (257,259). Five studies found that the levonorgestrel and combined regimens decreased risk for pregnancy through the fifth day after unprotected sexual intercourse; however, rates of pregnancy were slightly higher when ECPs were taken after 3 days (260)(261)(262)(263)(264). A meta-analysis of levonorgestrel ECPs found that pregnancy rates were low when administered within 4 days after unprotected sexual intercourse but increased at 4-5 days (265) (Level of evidence: I to II-2, good to poor, direct). # Advance Provision of ECPs • An advance supply of ECPs may be provided so that ECPs will be available when needed and can be taken as soon as possible after unprotected sexual intercourse. Comments and Evidence Summary. A systematic review identified 17 studies that reported on safety or effectiveness of advance ECPs in adult or adolescent women (26). Any use of ECPs was two to seven times greater among women who received an advance supply of ECPs. However, a summary estimate (relative risk = 0.97; 95% confidence interval = 0.77-1.22) of five randomized controlled trials did not indicate a significant reduction in unintended pregnancies at 12 months with advance provision of ECPs. In the majority of studies among adults or adolescents, patterns of regular contraceptive use, pregnancy rates, and incidence of STDs did not vary between those who received advance ECPs and those who did not. Although available evidence supports the safety of advance provision of ECPs, effectiveness of advance provision of ECPs in reducing pregnancy rates at the population level has not been demonstrated (Level of evidence: I to II-3, good to poor, direct). # Initiation of Regular Contraception After ECPs UPA • Any regular contraceptive method can be started immediately after the use of UPA. • The woman needs to abstain from sexual intercourse or use barrier contraception for 14 days or until her next menses, whichever comes first. • Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. # Levonorgestrel and Combined Estrogen and Progestin ECPs • Any regular contraceptive method can be started immediately after the use of levonorgestrel or combined estrogen and progestin ECPs. • The woman needs to abstain from sexual intercourse or use barrier contraception for 7 days. • Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. Comments and Evidence Summary. Data on when a woman can start regular contraception after ECPs are limited to expert opinion and product labeling (27). Theoretically, the effectiveness of systemic hormonal contraception might be decreased when administered concurrently or in close succession because of the antiprogestin properties of UPA (266,267); these theoretical concerns do not exist for combined estrogen and progestin or levonorgestrel formulations of ECPs. The resumption or initiation of regular hormonal contraception after ECP use involves consideration of the risk for pregnancy if ECPs fail and the risks for unintended pregnancy if contraception initiation is delayed until the subsequent menstrual cycle. If a woman is planning to initiate contraception after the next menstrual period after ECP use, the cycle in which ECPs are used might be shortened, prolonged, or involve unscheduled bleeding. # Prevention and Management of Nausea and Vomiting with ECP Use # Nausea and Vomiting • Levonorgestrel and UPA ECPs cause less nausea and vomiting than combined estrogen and progestin ECPs. • Routine use of antiemetics before taking ECPs is not recommended. Pretreatment with antiemetics may be considered depending on availability and clinical judgment. # Vomiting Within 3 Hours of Taking ECPs • Another dose of ECP should be taken as soon as possible. Use of an antiemetic should be considered. Comments and Evidence Summary. Many women do not experience nausea or vomiting when taking ECPs, and predicting which women will experience nausea or vomiting is difficult. Although routine use of antiemetics before taking ECPs is not recommended, antiemetics are effective in some women and can be offered when appropriate. Health-care providers who are deciding whether to offer antiemetics to women taking ECPs should consider the following: 1) women taking combined estrogen and progestin ECPs are more likely to experience nausea and vomiting than those who take levonorgestrel or UPA ECPs; 2) evidence indicates that antiemetics reduce the occurrence of nausea and vomiting in women taking combined estrogen and progestin ECPs; and 3) women who take antiemetics might experience other side effects from the antiemetics. A systematic review examined incidence of nausea and vomiting with different ECP regimens and effectiveness of antinausea drugs in reducing nausea and vomiting with ECP use (28). The levonorgestrel regimen was associated with significantly less nausea than a nonstandard dose of UPA (50 mg) and the standard combined estrogen and progestin regimen (268)(269)(270). Use of the split-dose levonorgestrel showed no differences in nausea and vomiting compared with the single-dose levonorgestrel (260,261,263,271) (Level of evidence: I, good-fair, indirect). Two trials of antinausea drugs, meclizine and metoclopramide, taken before combined estrogen and progestin ECPs, reduced the severity of nausea (272,273). Significantly less vomiting occurred with meclizine but not metoclopramide (Level of evidence: I, good-fair, direct). No direct evidence was found regarding the effects of vomiting after taking ECPs. # Female Sterilization Laparoscopic, abdominal, and hysteroscopic methods of female sterilization are available in the United States, and some of these procedures can be performed in an outpatient procedure or office setting. Fewer than 1 out of 100 women become pregnant in the first year after female sterilization (59). Because these methods are intended to be irreversible, all women should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception. Female sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # When Hysteroscopic Sterilization Is Reliable for Contraception • Before a woman can rely on hysteroscopic sterilization for contraception, a hysterosalpingogram (HSG) must be performed 3 months after the sterilization procedure to confirm bilateral tubal occlusion. • The woman should be advised that she needs to abstain from sexual intercourse or use additional contraceptive protection until she has confirmed bilateral tubal occlusion. # When Laparoscopic and Abdominal Approches Are Reliable for Contraception • A woman can rely on sterilization for contraception immediately after laparoscopic and abdominal approaches. No additional contraceptive protection is needed. Comments and Evidence Summary. HSG confirmation is necessary to confirm bilateral tubal occlusion after hysteroscopic sterilization. The inserts for the hysteroscopic sterilization system available in the United States are placed bilaterally into the fallopian tubes and require 3 months for adequate fibrosis and scarring leading to bilateral tubal occlusion. After hysteroscopic sterilization, advise the woman to correctly and consistently use an effective method of contraception while awaiting confirmation. If compliance with another method might be a problem, a woman and her health-care provider may consider DMPA injection at the time of sterilization to ensure adequate contraception for 3 months. Unlike laparoscopic and abdominal sterilizations, pregnancy risk beyond 7 years of follow-up has not been studied among women who received hysteroscopic sterilization. Pregnancy risk with at least 10 years of follow-up has been studied among women who received laparoscopic and abdominal sterilizations (274,275). Although these methods are highly effective, pregnancies can occur many years after the procedure, and the risk for pregnancy is higher among younger women (274,276). A systematic review was conducted to identify studies that reported whether pregnancies occurred after hysteroscopic sterilization (29). Twenty-four studies were identified that reported whether pregnancies occurred after hysteroscopic sterilization and found that very few pregnancies occurred among women with confirmed bilateral tubal occlusion; however, few studies include long-term follow-up, and none with follow-up for >7 years. Among women who had successful bilateral placement, most pregnancies that occurred after hysteroscopic sterilization were in women who did not have confirmed bilateral tubal occlusion at 3 months, either because of lack of follow up or misinterpretation of HSG results (277)(278)(279). Some pregnancies occurred within 3 months of placement, including among women who were already pregnant at the time of the procedure, women who did not use alternative contraception, or women who had failures of alternative contraception (277,278,(280)(281)(282)(283). Although these studies generally demonstrated high rates of bilateral placement, some pregnancies occurred as a result of lack of bilateral placement identified on later imaging (277,278,280,281,283,284). Most pregnancies occurred after deviations from FDA directions, which include placement in the early follicular phase of the menstrual cycle, imaging at 3 months to document proper placement, and use of effective alternative contraception until documented occlusion (Level of evidence: II-3, fair, direct). # Male Sterilization Male sterilization, or vasectomy, is one of the few contraceptive methods available to men and can be performed in an outpatient procedure or office setting. Fewer than 1 woman out of 100 becomes pregnant in the first year after her male partner undergoes sterilization (59). Because male sterilization is intended to be irreversible, all men should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception for women. Male sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV. # When Vasectomy Is Reliable for Contraception • A semen analysis should be performed 8-16 weeks after a vasectomy to ensure the procedure was successful. • The man should be advised that he should use additional contraceptive protection or abstain from sexual intercourse until he has confirmation of vasectomy success by postvasectomy semen analysis. # Other Postprocedure Recommendations • The man should refrain from ejaculation for approximately 1 week after the vasectomy to allow for healing of surgical sites and, after certain methods of vasectomy, occlusion of the vas. Comments and Evidence Summary. The Vasectomy Guideline Panel of the American Urological Association performed a systematic review of key issues concerning the practice of vasectomy (285). All English-language publications on vasectomy published during 1949-2011 were reviewed. For more information, see the American Urological Association Vasectomy Guidelines (available at http://www.auanet.org/ education/vasectomy.cfm). Motile sperm disappear within a few weeks after vasectomy (286)(287)(288)(289). The time to azoospermia varies widely in different studies; however, by 12 weeks after the vasectomy, 80% of men have azoospermia, and almost all others have rare nonmotile sperm (defined as ≤100,000 nonmotile sperm per milliliter) (285). The number of ejaculations after vasectomy is not a reliable indicator of when azoospermia or rare nonmotile sperm will be achieved (285). Once azoospermia or rare nonmotile sperm has been achieved, patients can rely on the vasectomy for contraception, although not with 100% certainty. The risk for pregnancy after a man has achieved postvasectomy azoospermia is approximately one in 2,000 (290)(291)(292)(293)(294). A median of 78% (range 33%-100%) of men return for a single postvasectomy semen analysis (285). In the largest cohorts that appear typical of North American vasectomy practice, approximately two thirds of men (55%-71%) return for at least one postvasectomy semen analysis (291,(295)(296)(297)(298)(299). Assigning men an appointment after their vasectomy might improve compliance with follow-up (300). # When Women Can Stop Using Contraceptives • Contraceptive protection is still needed for women aged >44 years if the woman wants to avoid pregnancy. Comments and Evidence Summary. The age at which a woman is no longer at risk for pregnancy is not known. Although uncommon, spontaneous pregnancies occur among women aged >44 years. Both the American College of Obstetricians and Gynecologists and the North American Menopause Society recommend that women continue contraceptive use until menopause or age 50-55 years (301,302). The median age of menopause is approximately 51 years in North America (301) but can vary from ages 40 to 60 years (303). The median age of definitive loss of natural fertility is 41 years but can range up to age 51 years (304,305). No reliable laboratory tests are available to confirm definitive loss of fertility in a woman. The assessment of follicle-stimulating hormone levels to determine when a woman is no longer fertile might not be accurate (301). Health-care providers should consider the risks for becoming pregnant in a woman of advanced reproductive age, as well as any risks of continuing contraception until menopause. Pregnancies among women of advanced reproductive age are at higher risk for maternal complications, such as hemorrhage, venous thromboembolism, and death, and fetal complications, such as spontaneous abortion, stillbirth, and congenital anomalies (306)(307)(308). Risks associated with continuing contraception, in particular risks for acute cardiovascular events (venous thromboembolism, myocardial infarction, or stroke) or breast cancer, also are important to consider. U.S. MEC states that on the basis of age alone, women aged >45 years can use POPs, implants, the LNG-IUD, or the Cu-IUD (U.S. MEC 1) (5). Women aged >45 years generally can use combined hormonal contraceptives and DMPA (U.S. MEC 2) (5). However, women in this age group might have chronic conditions or other risk factors that might render use of hormonal contraceptive methods unsafe; U.S. MEC might be helpful in guiding the safe use of contraceptives in these women. The incidence of venous thromboembolism was higher among oral contraceptive users aged ≥45 years compared with younger oral contraceptive users in two studies (309)(310)(311); however, an interaction between hormonal contraception and increased age compared with baseline risk was not demonstrated (309,310) or was not examined (311). The relative risk for myocardial infarction was higher among all oral contraceptive users than in nonusers, although a trend of increased relative risk with increasing age was not demonstrated (312,313). No studies were found regarding the risk for stroke in COC users aged ≥45 years (Level of evidence: II-2, good to poor, direct). A pooled analysis by the Collaborative Group on Hormonal Factors and Breast Cancer in 1996 (314) found small increased relative risks for breast cancer among women aged ≥45 years whose last use of combined hormonal contraceptives was <5 years previously and for those whose last use was 5-9 years previously. Seven more recent studies suggested small but nonsignificant increased relative risks for breast carcinoma in situ or breast cancer among women who had used oral contraceptives or DMPA when they were aged ≥40 years compared with those who had never used either method (315-321) (Level of evidence: II-2, fair, direct). # Conclusion Women, men, and couples have increasing numbers of safe and effective choices for contraceptive methods, including LARC methods such as IUDs and implants, to reduce the risk for unintended pregnancy. However, with these expanded options comes the need for evidence-based guidance to help health-care providers offer quality family planning care to their patients, including choosing the most appropriate contraceptive method for individual circumstances and using that method correctly, consistently, and continuously to maximize effectiveness. Removing unnecessary barriers can help patients access and successfully use contraceptive methods. Several medical barriers to initiating and continuing contraceptive methods might exist, such as unnecessary screening examinations and tests before starting the method (e.g., a pelvic examination before initiation of COCs), inability to receive the contraceptive on the same day as the visit (e.g., waiting for test results that might not be needed or waiting until the woman's next menstrual period to start use), and difficulty obtaining continued contraceptive supplies (e.g., restrictions on number of pill packs dispensed at one time). Removing unnecessary steps, such as providing prophylactic antibiotics at the time of IUD insertion or requiring unnecessary follow-up procedures, also can help patients access and successfully use contraception. Most women can start most contraceptive methods at any time, and few examinations or tests, if any, are needed before starting a contraceptive method. Routine follow-up for most women includes assessment of her satisfaction with the contraceptive method, concerns about method use, and changes in health status or medications that could affect medical eligibility for continued use of the method. Because changes in bleeding patterns are one of the major reasons for discontinuation of contraception, recommendations are provided for the management of bleeding irregularities with various contraceptive methods. In addition, because women and health-care providers can be confused about the procedures for missed pills and dosing errors with the contraceptive patch and ring, the instructions are streamlined for easier use. ECPs and emergency use of the Cu-IUD are important options for women, and recommendations on using these methods, as well as starting regular contraception after use of emergency contraception, are provided. Male and female sterilization are highly effective methods of contraception for men, women, and couples who have completed childbearing; for men undergoing vasectomy and women undergoing a hysteroscopic sterilization procedure, additional contraceptive protection is needed until the success of the procedure can be confirmed. CDC is committed to working with partners at the federal, national, and local levels to disseminate, implement, and evaluate the recommendations in U.S. SPR so that the information reaches health-care providers. Strategies for dissemination and implementation include collaborating with other federal agencies and professional and service organizations to widely distribute the recommendations through presentations, electronic distribution, newsletters, and other publications; development of provider tools and job aids to assist providers in implementing the new recommendations; and training activities for students, as well as for continuing education. CDC will conduct a survey of family planning health-care providers before and after release of this report to assess attitudes and practices related to contraceptive use. Results from this survey will assist CDC in evaluating the impact of these recommendations on the provision of contraceptives in the United States. Finally, CDC will continually monitor new scientific evidence and will update these recommendations as warranted by new evidence. Updates to the recommendations, as well as provider tools and other resources, are available on the CDC U.S. SPR website (http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USSPR.htm). (ii) without prolonged immobilization * In cases in which access to health care might be limited, the blood pressure measurement can be obtained by the woman in a nonclinical setting (e.g., pharmacy or fire station) and self-reported to the provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 2). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § A bimanual examination (not cervical inspection) is needed for diaphragm fitting. ¶ Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD Treatment Guidelines (available at http://www.cdc.gov/std/treatment). If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3). For these women, IUD insertion should be delayed until appropriate testing and treatment occurs. # I The examinations or tests noted apply to women who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC), might be useful in such circumstances (5). The following classification was considered useful in differentiating the applicability of the various examinations or tests: Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. # Appendix C Examinations and Tests Needed Before Initiation of Contraceptive Methods Class C: does not contribute substantially to safe and effective use of the contraceptive method. These classifications focus on the relationship of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. No examinations or tests are needed before initiating condoms or spermicides. A bimanual examination is necessary for diaphragm fitting. A bimanual examination and cervical inspection are needed for cervical cap fitting. # General follow-up Advise women to return at any time to discuss side effects or other problems or if they want to change the method. Advise women using IUDs, implants, or injectables when the IUD or implant needs to be removed or when a reinjection is needed. No routine follow-up visit is required. X X X X X # Other routine visits Assess the woman's satisfaction with her current method and whether she has any concerns about method use. X X X X X Assess any changes in health status, including medications, that would change the method's appropriateness for safe and effective continued use based on U.S. MEC (i.e., category 3 and 4 conditions and characteristics) (Box 2). X X X X X Consider performing an examination to check for the presence of IUD strings. # X ---- Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. # Appendix D Routine Follow-Up After Contraceptive Initiation These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations that might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions. # Appendix A Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 Updated June 2012. This summary sheet only contains a subset of the recommendations from the US MEC. For complete guidance, see: http://www.cdc.gov/ reproductivehealth/unintendedpregnancy/USMEC.htm. Most contraceptive methods do not protect against sexually transmitted infections (STIs). Consistent and correct use of the male latex condom reduces the risk of STIs and HIV. # Key: 1. No restriction (method can be used) 2. Advantages generally outweigh theoretical or proven risks 3. Theoretical or proven risks usually outweigh the advantages 4. Unacceptable health risk (method not to be used) # Condition Sub-condition Antimicrobial therapy a) Broad spectrum antibiotics ) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. † Most women do not require additional STD screening at the time of IUD insertion if they have already been screened according to CDC's STD Treatment Guidelines (available at http://www.cdc.gov/std/treatment). If a woman has not been screened according to guidelines, screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with purulent cervicitis or current chlamydial infection or gonorrhea should not undergo IUD insertion (U.S. MEC 4). Women who have a very high individual likelihood of STD exposure (e.g., those with a currently infected partner) generally should not undergo IUD insertion (U.S. MEC 3) (Box 2). For these women, IUD insertion should be delayed until appropriate testing and treatment occurs. # Appendix B When To Start Using Specific Contraceptive Methods # Appendix E Management of Women with Bleeding Irregularities While Using Contraception If bleeding persists, or if the woman requests it, medical treatment can be considered.* # Cu-IUD users For unscheduled spotting or light bleeding or for heavy or prolonged bleeding: • NSAIDs (5-7 days of treatment) # Appendix F Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have Pelvic Inflammatory Disease • Treat PID.* • Counsel about condom use. • IUD does not need to be removed. Woman wants to continue IUD. Woman wants to discontinue IUD. # Clinical improvement No clinical improvement • Offer another contraceptive method. • Offer emergency contraception. Continue IUD. Reassess in 24-48 hours. Remove IUD after beginning antibiotics. • Continue antibiotics. • Consider removal of IUD. • Offer another contraceptive method. • Offer emergency contraception. Abbreviations: Cu-IUD = copper-containing IUD; IUD = intrauterine device; LNG-IUD = levonorgestrel-releasing IUD; PID = pelvic inflammatory disease. * Treat according to CDC's STD Treatment Guidelines (available at http://www.cdc.gov/std/treatment).	None	None
d99648eb7a8d5a900235d5a3861c86bf1e583a8d	cdc	None	All shipping and storage containers for lithium chromate, lithium bichromate, sodium chromate, sodium bichromate, potassium chromate, potassium bichromate, rubidium chromate, rubidium bichromate, cesium chromate, cesium bichromate, and ammonium chromate, the hydrates of these compounds, high purity aqueous solutions of these compounds, and dry mixtures containing only these materials shall bear the same label except that "Inhalation may cause cancer" shall be deleted and "Extreme Health Hazard" shall be replaced by "Moderate Health Hazard". (c) Because of the flammable characteristics of ammonium bichromate (dichromate), shipping and storage containers for dry forms of this compound shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances: AMMONIUM BICHROMATE DANGER! HIGHLY FLAMMABLE MODERATE HEALTH HAZARD MAY CAUSE IRRITATION, RASH, OR EXTERNAL ULCERS. Keep away from heat, sparks, and open flame. Keep container closed. Avoid contact with skin and eyes. Avoid breathing dust or solution spray. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Call a physician. Flush skin with water. Wash clothing before reuse.Combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply.# I. RECOMMENDATIONS FOR A CHROMIUM(VI) STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chromium(VI), ie, hexavalent chromium or Cr(VI), in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and safety of workers for up to a 10-hour workday, 40-hour workweek over a working lifetime. Compliance with all sections of the standard should prevent all noncarcinogenic adverse effects of exposure to chromium(VI) In the workplace air and through skin exposure and should reduce materially the risk of lung cancer from occupational exposure to carcinogenic chromium(VI). The standard is measurable by techniques that are valid, reproducible, and available. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. For the purpose of this standard, "chromium(VI)" is defined as the chromium In all materials in the +6 (hexavalent) state. There are 2 recommended standards for chromium(VI). One addresses occupational exposure to a group of noncarcinogenic, but otherwise hazardous, materials, while the other pertains to occupations and workplaces where there is exposure to other chromium(VI) materials associated with an increased incidence of lung cancer. On the basis of the chemical analysis of airborne chromium(VI) materials, there is no practical means of distinguishing between these 2 groups of chromium(VI) materials. Until the airborne chromium(VI) in a particular workplace is demonstrated by the employer to be of the type considered to be noncarcinogenic, all airborne chromium(VI) shall be considered to comprise carcinogenic materials. Based . on current evidence, "noncarcinogenic chromium(VI)" is the chromium(VI) in monochromates and bichromates (dichromates) of hydrogen, lithium, sodium, potassium, rubidium, cesium, and ammonium, and chromium(VI) oxide (chromic acid anhydride). "Carcinogenic chromium(VI)" comprises any and all chromium(VI) materials not included in the noncarcinogenic group above. "Occupational exposure to carcinogenic chromium(VI)" is defined as exposure to airborne chromium(VI) at concentrations greater than one-half of the workplace environmental limit for carcinogenic chromium(VI). "Occupational exposure to noncarcinogenic chromium(VI)" is defined as exposure to airborne chromium(VI) at concentrations greater than one-half of the workplace environmental limit for noncarcinogenic chromium(VI). Exposure to chromium(VI) at concentrations less than one-half of the workplace environmental limit will not require adherence to the following sections, except for 3(a,b,c,d), 4a, 5, 6(b,c,e,f), and 7. Procedures for sampling and analysis of chromium(VI) in air shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. # Section 2 -Medical Medical surveillance shall be made available as outlined below for all workers with occupational exposure to carcinogenic or noncarcinogenic chromium(VI), including maintenance personnel periodically exposed during routine maintenance or emergency repair operations. (a) Preplacement and annual medical examinations shall include: (1) A comprehensive or interim work history. A detailed medical history Including information on conditions Indicating the Inadvisability of further exposure to chromium(VI), eg, potential skin or pulmonary sensitization, a skin or mucous membrane condition that may be exacerbated by chromium(VI), smoking habits, and history of liver or kidney disease. (3) Examination of the skin for evidence of dermatitis or chrome ulcers, and of the membranes of the upper respiratory tract for irritation, bleeding, ulcerations, or perforations. (4) An evaluation of the worker's ability to use negative or positive pressure respirators. (5) Urinalysis. (b) For workers with occupational exposure to carcinogenic chromium(VI), preplacement and annual medical examinations shall include 14" X 17" chest X-rays. Other tests, including sputum cytology and liver function studies, shall be considered by the responsible physician. (c) For workers with occupational exposure to noncarcinogenic chromium(VI) and not to carcinogenic chromium(VI), preplacement medical examinations shall include 14" x 17" chest X-rays. Thereafter, X-ray examinations shall be offered at 5-year intervals and annually after age 40. Other tests, such as liver function studies, may be considered by the responsible physician. (d) Medical examinations shall be made available to all workers with signs or symptoms of skin or upper respiratory tract irritation likely to have been the result of exposure to chromium(VI). (e) If clinical evidence of adverse effects due to chromium(VI) is developed from these medical examinations, the worker shall be kept under a physician's care until the worker has completely recovered or maximal improvement has occurred. (f) Initial annual examinations for presently employed workers shall be offered within 6 months of the promulgation of a standard incorporating these recommendations. (g) The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, and of the employer shall have access to all medical records. Physicians designated and authorized by any employee or former employee shall have access to that worker's medical records. (h) Medical records shall be maintained for all employees with occupational exposure to carcinogenic or noncarcinogenic chromium(VI) and for maintenance personnel with periodic exposure. Preplacement X-rays and X-rays for the 5 years preceding termination of employment and all medical records with pertinent supporting documents shall be retained at least 30 years after the individual's employment is terminated. All storage containers of chromic acid, or chromium(VI) oxide (chromic acid anhydride) shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances. # CHROMIUM TRIOXIDE (CHROMIC ACID) DANGER! POWERFUL OXIDIZER CONTACT WITH OTHER MATERIAL MAY CAUSE FIRE MAY CAUSE DELAYED BURNS OR EXTERNAL ULCERS Keep container closed. Do not get in eyes, on skin, on clothing. Do not breathe dust or mist from solutions. In case of contact, immediately flush skin or eyes with plenty of water for at least 15 minutes. For eyes, get medical attention immediately. Wash clothing before reuse. Use fresh clothing daily. Take showers after work, using plenty of soap. # (e) In areas where there Is occupational exposure to carcinogenic chromium(VI), the following warning sign shall be posted in readily visible locations, particularly at the entrances to the area. # WARNING CANCER-SUSPECT AGENT USED IN THIS AREA UNAUTHORIZED PERSONS KEEP OUT The sign shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All The sign shall be posted in readily visible locations, particularly at the entrances to the area. The sign shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All illiterate workers shall receive such training. (1) Coveralls or other full-body protective clothing shall be worn in areas where there is occupational exposure to chromium(VI). Protective clothing shall be changed at least daily at the end of the shift and more frequently if it should become grossly contaminated. (2) Impervious gloves, aprons, and footwear shall be worn at operations where solutions of chromium(VI) may contact the skin. Protective gloves shall be worn at operations where dry compounds of chromium(VI) are handled and may contact the skin. (3) Eye protection shall be provided by the employer and used by the employees where eye contact with chromium(VI) is likely. Selection, use, and maintenance of eye protective equipment shall be in accordance with the provisions of the American National Standard Practice for Occupational and Educational Eye and Face Protection, ANSI Z87. . Unless eye protection is afforded by a respirator hood or facepiece, protective goggles or a face shield shall be worn at operations where there is danger of contact of the eye with dry or wet compounds of chromium(VI) because of spills, splashes, or excessive dust or mists in the air. The employer shall ensure that all personal protective devices are inspected regularly and maintained in clean and satisfactory working condition. (5) Work clothing shall not be taken home by employees. The employer shall provide for maintenance and laundering of protective clothing. The employer shall ensure that precautions necessary to protect laundry personnel are taken when soiled protective clothing is laundered. (b) Respiratory Protection from Carcinogenic Chromium(VI) Engineering controls shall be used wherever feasible to maintain airborne carcinogenic and noncarcinogenic chromium(VI) concentrations below those recommended in Section 1 above. Compliance with the permissible exposure limits by the use of respirators is only allowed when airborne chromium(VI) concentrations are in excess of the workplace environmental limit because required engineering controls are being installed or tested, when nonroutine maintenance or repair is being accomplished, or during emergencies. When a respirator is thus permitted, it shall be selected and used in accordance with the following requirements: (1) For the purpose of determining the type of respirator to be used, the employer shall measure the airborne concentration of chromium(VI) in the workplace initially and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the airborne concentration of chromium(VI); this requirement does not apply when carcinogenic chromium(VI) is present. The employer shall ensure that no worker is overexposed to chromium(VI) because of improper respirator selection, fit, use, or maintenance. The employer shall provide respirators in accordance with Table 1-1, or Table 1-2 when appropriate, and shall ensure that the employee uses the respirator provided. (5) Respirators described in Tables 1-1 and 1-2 shall be those approved under the provisions of 29 CFR 1910.134 and 30 CFR 11. The employer shall ensure that respirators are adequately cleaned, and that employees are instructed on the use of respirators assigned to them and on how to test for leakage. Where an emergency may develop which could result in employee injury from chromium(VI), the employer shall provide an escape device as listed in Table 1-1, or in Table 1-2 where appropriate. Instruction shall Include, as a minimum, all information in Appendix III which is applicable to the specific chromium(VI) product or material to which there is exposure. This information shall be posted in the work area and kept on file, readily accessible to the worker at all places of employment where chromium(VI) is involved in unit processes and operations. Evacuation or Escape (no concen tration limit) Half-mask respirator with replaceable high efficiency filter(s) or Type C supplied-air respirator, demand type (negative pressure), with half-mask facepiece Full facepiece respirator with replaceable high efficiency filter(s) or Type C supplied-air respirator, demand type (negative pressure), with full facepiece or Self-contained breathing apparatus in demand mode (negative pressure), with full facepiece Powered air-purifying (positive pressure) respirator with high efficiency filter(s) Self-contained breathing apparatus with positive pressure in full facepiece or Combination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply Self-contained breathing apparatus with positive pressure in full facepiece or Combination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure) or Gas mask, Type N, with high efficiency filter, and mouthpiece respirator with high efficiency filter(s) Note: A high efficiency filter is defined as a filter having an efficiency of at least 99.97% against 0.3 jum DOP(Dioctyl Phthalate) A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, proper maintenance procedures, and cleanup methods, and that they know how to use respiratory protective equipment and protective clothing correctly. (2) Clean protective clothing shall be put on before each work shift. (3) If, during the shift, the clothing becomes wetted with a solution, slurry, or paste of a chromium(VI) material, or grossly contaminated with a dry form of such material, it shall be removed promptly and placed in a special container for garments for decontamination or disposal. The employee shall wash the contaminated skin area thoroughly with soap and a copious amount of water. A complete shower is preferred after anything but limited, minor contact. Then, clean protective clothing shall be put on before resuming work. When working directly with chromium(VI) oxide, with unsealed containers of chromium(VI) oxide, or with chromium(VI) oxide in other than fully enclosed operations, protective devices and clothing shall be removed and the arms, hands, and face thoroughly washed after working with chromium(VI) oxide, and at 30-minute intervals when working with chromium(VI) oxide for extended periods of time. (4) Minor areas of skin (principally the hands) contaminated by contact with chromium(VI) shall be washed immediately and thoroughly with an abundance of water. Water shall be easily accessible in the work areas from low-pressure, free-running hose lines or showers. (5) If chromium(VI) comes into contact with the eyes, the eyes should be flushed with a large volume of low-pressure flowing water for at least 15 minutes. Medical attention shall be obtained without delay but not at the expense of thoroughly flushing the eyes. (c) Procedures for emergencies, including firefighting, shall be established to meet foreseeable events. Necessary emergency equipment, including appropriate respiratory protective devices, shall be kept in readily accessible locations. Only self-contained breathing apparatus with positive pressure in the faceplece shall be used in firefighting. Appropriate respirators shall be available for use during evacuation. (d) Special supervision and care shall be exercised to ensure that the exposures of repair and maintenance personnel to chromium(VI) shall be within the limits prescribed by this standard. (e) Prompt cleaning of spills of chromium(VI) No dry sweeping shall be performed. Wet methods or dry vacuuming shall be used as appropriate. (2) Wet spills and flushing of wet or dry spills shall be channeled for appropriate treatment or collection for disposal. They shall not be channeled directly into the sanitary sewer system. (f) General requirements (1) Good practices of housekeeping shall be observed to prevent or minimize contamination of areas and equipment and to prevent build-up of such contamination. (2) Good personal hygiene practices shall be encouraged. (3) Equipment shall be kept in good repair and free of leaks. (4) Containers of dry chromium(VI) shall be kept covered insofar as is practical. Section 7 -Sanitation (a) Washing Facilities Emergency showers and eye-flushing fountains with adequate pressure of cool water shall be provided and be quickly accessible in areas where there is potential of skin or eye contact with chromium(VI). This equipment shall be frequently inspected and maintained in good working condition. Showers and washbasins shall be provided in the employees' locker areas. Employees exposed to chromium(VI) shall wash before eating or smoking during the work shift. (b) Food Facilities Food storage, preparation, and eating shall be prohibited in areas where chromium(VI) is handled, processed, or stored. Eating facilities provided for employees shall be located in nonexposure areas. Washing facilities should be accessible nearby. (c) Employees shall not smoke in areas where chromium(VI) is handled, processed, or stored. Appendix II; if samples can be demonstrated to contain only noncarcinogenic chromium(VI), other methods of chemical analysis equivalent to the method in Appendix II may be used. Records of these surveys, including the basis for concluding that there is no occupational exposure to chromium(VI) shall be maintained until a new survey is conducted. In workplaces where chromium(VI) is handled or processed, surveys shall be repeated annually and when any process change indicates a need for réévaluation. Requirements set forth below apply to areas in which there is occupational exposure to chromium(VI). Employers shall maintain records of workplace environmental exposures to chromium(VI) based upon the following sampling, analytical, and recording schedules: (a) In all monitoring, samples representative of the exposure in the breathing zone of employees shall be collected by personal samplers. (b) An adequate number of samples shall be taken in order to permit construction of TWA exposures for every operation or process. Except as otherwise determined by a professional industrial hygienist, the minimum number of representative TWA determinations for an operation or process shall be based on the number of workers exposed as provided in (c) The first determination of the workers' exposures to airborne chromium(VI) shall be completed within 6 months after the promulgation of a standard incorporating these recommendations. (d) A réévaluation of the exposures of workers to airborne chropium(VI) shall be made within 30 days after installation of a new process or process changes. (e) Samples of airborne chromium(VI) shall be collected and analyzed at least every 2 months for those work areas with occupational exposure to carcinogenic chromium(VI) and at least every 3 months if the airborne chromium(VI) is noncarcinogenic. (f) A réévaluation of the worker's exposures to airborne chromium(VI) shall be repeated at 1-week intervals when the airborne concentration has been found to exceed the recommended workplace environmental limit. In such cases, suitable controls shall be instituted and monitoring shall continue at 1-week intervals until 3 consecutive surveys indicate the adequacy of controls. (g) Records of all sampling and analysis of airborne chromium(VI) and of medical examinations shall be maintained for at least 30 Silica is also found in the ore in varying amounts. According to Bourne and Yee the approximate analysis of chromite ores from Rhodesia and Transvaal is 48% chromium(III) oxide, 18% iron(III) oxide, 15% aluminum oxide, 3% silicon dioxide, and 12% magnesium oxide. In the United States, the 3 most common methods of producing chromium(VI) compounds are the high-lime, the low-lime, and the lime-free processes. Each of these processes involves the roasting of chromite ore with soda ash and various amounts of lime with subsequent treatment to form sodium chromate. Other chromium(VI) compounds may be formed by a change of pH and the addition of other compounds. Solutions of chromium(VI) compounds thus formed may then be crystallized, purified, packaged, and sold. Chromium(VI) has been found in glue, cement, detergents, and other materials, including chromite ore. [ the fingers and on the glans penis. The finger lesion was in an area where there had been either a wound or an abrasion of the cuticle. Cumin described the effects of habitual application of bichromate solution to the skin as an eruption of papulae which become pustular and, upon prolonged exposure, develop deep sloughs under the pustules. The sloughs were described as peculiarly penetrating to the extent of producing in one instance a complete perforation of the muscular substance of the hand. Ducatel in 1753 noted that ulceration of the skin could occur from the action of potassium bichromate. He also described a worker who accidentally drank some of it and vomited violently until his death 5 hours later. Delpech and Hillairet in 1869 described the manufacture of potassium chromate and bichromate in Argenteuil, France, and the effects on workers which resulted from exposure to those chromium(VI) materials. In the process described, chromite ore was either roasted with potassium nitrate, thus producing potassium chromate, or with potassium sulfate and calcium carbonate, followed by treatment with sulfuric acid, to produce potassium bichromate. Seven cases were described in which all workers had perforated nasal septa and 3 also had skin ulcers. Their exposures were to both acidic and alkaline chromiun(VI) salts but not to chromic acid anhydride. In 1884 Mackenzie described the toxic effects of potassium bichromate. He was told by a workman, who had been engaged in the factory for 15 years, that destruction of the nasal septum sometimes took place after 24^-48 hours of exposure to bichromate. It is likely that exposures were massive in the plant for at that time hand-rabbled reverberatory furnaces were used with little or no forced ventilation or good work practices. DaCosta et al in 1916 described in detail 19 of 44 cases of chrome ulcers in tanners and dyers. The most common sites of ulcers were the folds of the dorsal surface of the fingers over the knuckles, with other cases on palms, forearms, backs of hands, interdigital folds, sides of fingers, edges of finger nails, wrists, knees, and on other parts of the body, notably 1 near the groin and another on the foreskin of the penis. It was noted that the ulcerated area had been kept wet with chromate solution in practically all cases. Aside from describing the etiology of the ulcerations, the authors suggested preventive measures including various impervious coverings for the hands and wrists and a preventive ointment of lanolin and petrolatum; therapy consisted of soaking in hot lead water (diluted lead subacetate) and carbonate of soda. In 1925, Parkhurst reported 3 cases of chrome dermatitis in workers in contact with blueprints that were fixed in a solution of potassium dichromate. One case was a 19-year-old woman who had been engaged in the production of blueprints for 6 weeks. The appearance of the lesion was that of crowded vesicles of pinpoint size on a diffusely erythematous and edematous background on the hands, wrists, and forearms. She showed a positive patch test with a 0.5% solution of potassium dichromate. The eruption subsided a few days after discontinuation of exposure. Frequent rinsing of hands with a solution of sodium bisulfite and then with water was suggested as a preventive measure to reduce hexavalent chromium to trivalent chromium. The other 2 cases treated by another physician were apparently similar. He prescribed treatment with a 1% solution of aluminum acetate, Lassar's paste, and calamine lotion. Bloomfield and Blum in 1928 published a study of workers engaged in a chromium plating operation. Workers were exposed primarily to an acidic mist of chromium(VI), which the authors called chromic acid, emanating from plating tanks. Of the 23 workers examined in the operation, 20 had perforated or ulcerated nasal septa, inflamed mucosa, nosebleed, and cutaneous ulcers ("chrome holes"). In the same year, 12 cases of ulceration and signs of irritation of the respiratory tract from solutions of "chromic acid" were reported by Blair. The workers suffered from coryza, sneezing, watery discharge from the eyes and nose, itching and burning of the nose, ulceration of the nasal mucosa, perforation of the nasal septum (chrome holes), and ulcerative lesions of the hands and fingers (chrome ulcers). In 1930 the Inspectorate of Factories in London issued a report which dealt with the examination of 223 persons engaged in chromium-plating and an unspecified number of people engaged in anodic oxidation. Of the 223 chromium-plating workers, 95 (42.6%) had dermatitis, skin ulcers, or scars from old skin ulcers; 116 (52%) had perforated or ulcerated nasal septa or "devitalization of the mucous membrane." Times from onset of exposure to appearance of symptoms were as short as 2 weeks for ulceration of the nasal mucous membrane and 6-48 months for perforation of the nasal septum. Smith in 1931 described a man who, upon admission to hospital, had ulceration of the skin of both hands, difficulty in breathing, and tenderness of muscles of extremities. Prior to hospitalization he was engaged in washing zinc plates with a solution of ammonium bichromate. Smith observed erythema of the forearms and hands, desquamation on areas of fingers and palms, vesicular lesions, and shallow ulcers on both hands and forearms. In addition, she noted 2 similar lesions on the abdomen. The diagnosis was chronic chrome poisoning with dermatitis venenata, acute nephritis, asthma, and acute myositis of the upper and lower extremities. The patient was patch-and intradermally-tested with solutions of ammonium bichromate followed by evidence of sensitization. Pfeil in 1935 reported 2 cases of pulmonary carcinoma in men who worked in the chrome x industry in Germany. In 1911, a foreman in a large chromium manufacturing plant in Germany complaining about coughing and expectoration was examined by Pfeil. The man's sputum had a reddish tinge. Costal pleurisy set in accompanied by a bloody exudate. The patient also suffered fractured ribs and was diagnosed as having a lung tumor. Post mortem examination confirmed his diagnosis of primary pulmonary carcinoma with metastases. In the next year, Pfeil treated a second patient for exudative costal pleurisy. This patient, who worked in the same chrome plant as the first, was found to have pulmonary carcinoma upon his death. The foreman was involved in a secondary process where he was apparently exposed to residues from quinone production which probably contained a complex mixture of chromium(III) and chromium(VI). The second man was said to work in the chrome industry but no further description was given. Five more men died from lung cancer in this same chrome plant before 1935. Of the cases of lung cancer and gastrointestinal cancer studied by Teleky, some occurred among chrome workers. Teleky concluded from this that chromium is a lung carcinogen and might be a gastrointestinal carcinogen, but the data he presented do not support more than a suggestion of the relationships. In later years, many additional deaths from lung cancer occurred in the German chromate industry, but it was not until 1948 that an excessive incidence of lung cancer was reported among workers in the United States chromate industry. # Effects on Humans In a review, Mertz summarized the occurrence of chromium in nature and its function in biologic systems. Later, Glinsmann and Mertz studied the relationship between chromium(III) and glucose tolerance in humans by the oral administration of aqueous solutions of chromium(III) chloride. Six subjects with maturity onset diabetes (where the impairment in glucose tolerance did not appear to be related to a simple insulin deficiency but rather insulin effectiveness appeared to be reduced) were given 0.06-1 mg chromium(III) 3 times/day with meals for periods of 15-120 days. During this time, oral glucose tolerances were determined. Three of the 6 had improved tolerances while on chromium(III), compared to control periods. In 10 nondiabetic subjects with normal oral glucose tolerance, administration of 0.15-1 mg chromium(III)/day for 21 days resulted in no detectable alterations. The authors interpreted these results to suggest that chromium is required for optimum glucose use in man. Several studies have reported and reviewed concentrations of chromium in various biologic tissues and fluids. However, any interpretation of the amounts of chromium found in biologic samples should be accompanied by a close scrutiny of the analytical chemical methods employed. As new, more sensitive, and precise methods have been developed and used, authors have reported lower estimates of the quantities of chromium in certain biologic materials. The National Academy of # Sciences-National Research Council Committee on Biologic Effects of Atmospheric Pollutants reported a wide range of concentrations of chromium occurring in biologic samples from both unexposed and occupationally exposed populations. For this reason, it would be very difficult to interpret biologic concentrations of chromium as a measure of the absorption of chromium. Mancuso reported that men exposed to airborne water-soluble chromium compounds excreted more chromium in the urine than those exposed to water-insoluble ones. He also noted elevated concentrations of chromium in the blood and urine for several years after exposure to chromiumcontaining materials. However, because of the wide disparity of "normal" and "exposed" blood and urine concentrations reported in the literature, any such correlations between exposure and biologic concentrations of chromium must be Interpreted with caution. were observed in half the workers in the brilliant-chrome industries. Duration of exposure was unstated, but it was mentioned that the harmful effects were noted in less than a year, and that few workers remained many years in the industry. Individual safety equipment was lacking in 26.6% of the plants; this may have been responsible for the high incidence of cutaneous ulcers. Zvaifler and Gresh published separate reports of an anodizing plant study. Zvaifler noted that there was a distinct difference in the physiologic effects of chromium(VI) mists from plating tanks and the mists from anodizing tanks but he presented no data to support his conclusion. He mentioned that the chromium(VI) poisonings which resulted from exposure to mists emanated from anodizing tanks containing "5% chromic acid" generally involved ulceration of the nasal mucosa and skin rashes but rarely perforation of the septum. Gresh [ The investigation revealed that personal protective equipment was not worn and employees frequently wiped their faces and picked their noses with unwashed fingers or while wearing gloves. The authors thus concluded, probably correctly, that poor work practices were responsible to some degree for the nasal involvement. Determinations of pulmonary involvement were not reported in the study. In another study by NIOSH of a different chromium plating plant, a maximum airborne chromium(VI) concentration of 3 Mg/cu m was found. In this operation, the plating solution contained approximately 210 g chromium(VI) oxide/liter. No ulcerated nasal mucosae or perforated nasal septa were found, although half of the 32 employees had varying degrees of mucosal irritation. This incidence of mucosal irritation was not thought to be significant by the investigators because the survey was carried out at the peak of the 1972-73 influenza epidemic. Fifteen workers had been employed 8 years or more, 7 between 4 and 8 years, 4 between 1 and 4 years, and 6 less than 1 year. Although he did not report airborne concentrations of chromium(VI), Meyers in 1950 observed 2 patients who had inhaled chromic acid mists, for only a few hours one day. One man developed a cough, severe frontal headaches, pulmonary congestion and edema, dyspnea, and persisting sub8temal pain. The other developed hoarseness and a cough productive of green mucoid sputum. Five months after exposure, the X-ray examination showed some emphysematous changes and a small pleural effusion. Pascale et al in 1952 reported 5 persons with hepatic injury apparently due to exposure to chromic acid mist from plating baths. One who had been employed 5 years at a chromium plating factory was hospitalized with jaundice and was found to be excreting significant amounts of chromium. Her lungs and cardiovascular system were normal. A liver biopsy showed microscopic changes resembling those found in toxic hepatitis. To Investigate the possibility that the liver damage was of occupational origin, 8 fellow workers were screened for urinary chromium excretion. Four of these were found to be excreting significant amounts and were examined in more detail. In 3 workers who had been exposed to chromic acid mists for 1 to A years, liver biopsies and a series of 12 hepatic tests showed mild to moderate abnormalities. No liver biopsy was taken from the fifth worker, who had been removed from further exposure because of nasal ulceration after 6 months at the plating bath. Only 1 of his liver function tests indicated a borderline abnormality. The urinary excretion of chromium (2.8 and 2.9 mg/24 hours) by the 2 workers employed 4 years was greater than the excretion (1.48 mg/24 hours) by the worker employed 5 years who suffered the greatest liver damage. The lowest urinary chromium excretion (0.184 mg/24 hours) was measured in the fifth worker, the individual with least exposure. All 5 exhibited some signs of damage to the nasal mucosa. This plus the concentrations of urinary chromium suggests that exposures to chromium(VI) were significant, but no environmental data were reported. Several authors have dealt with exposures to chromium(VI) materials, exclusive of chromic acid anhydride and aqueous solutions thereof (known as "chromic acid"). In the chromate-producing industry in the United States, only a small part of which produced chromic acid anhydride, the principal exposures to chromium(VI) were probably to sodium chromate and bichromate. To a lesser degree, exposure to potassium chromate and bichromate was also present. In 1884 Mackenzie described the toxic effects of potassium bichromate. He related having been told by a workman, who had been engaged in the factory for 15 years, that destruction of the nasal septum sometimes took place after 24-48 hours of exposure. From his own experience, Mackenzie observed that this destruction was preceded by general congestion of the mucous membrane, nosebleed, and coryza. The turbinates, nasal pharynx, and lower pharynx were also ulcerated. What he described as the lower respiratory tract (probably the lower part of the upper respiratory tract) was generally found to be highly inflamed and swollen. Accompanying the catarrhal symptoms, there were sometimes intense headache, inflammation and perforation of the tympanic membranes and subsequent otorrhea. At that time hand-rabbled reverberatory furnaces were used and since there was little or no forced ventilation or good work practices, it is probable that exposure levels were high. Much later, in 1948, Machle and Gregorius described the incidence of nasal irritation and septal perforation in a chromateproducing plant that manufactured sodium chromate and bichromate. The incidence of nasal septal perforation was 43.5% in 354 employees. Airborne chromate concentrations were determined to range from 10 to 2,800 jug/cu m at the time of the study, but the plant has been in operation for at least 17 years. Some employees had probably worked in the plant when reverberatory furnaces were used, a notorious source of high exposure. In the early fifties, an epidemiologic study as reported by Bourne and Yee and by Mancuso The incidence of these signs, as was the incidence of ear disorders such as discharge, impaired hearing, and tinnitus, was more than twice that found in nonchromate-worker control groups. Liver enlargement was noted in 14 chromate workers. Those with enlarged livers were at least 15 years older and had worked an average of 4 years longer in the chromate industry than those without enlarged livers, but the number in the group was too small to allow a statistical comparison with a group not exposed to chromate. Those with cutaneous ulcers or scars of ulcers numbered 451. Most of the active ulcers had occurred within the 6 months prior to the study. Lung cancers were also found in this group and will be discussed later. Urinalysis revealed white and red blood cells and casts with greater frequency than is usually observed in the average industrial population. Casts in urine were found in a greater percentage of workers who had worked 10 years or more than in those who had worked less than 10 years. Frequency of white blood cells in urine of chromate workers showed an increase with years of exposure. The number of red blood cells in urine did not change appreciably with years of chromate exposure. As a result of dental examinations of 561 workers, incidences of keratosis of the lips, gingiva, and palate; yellow-stained teeth and tongue; and periodontitis were greater than twice the incidences in a control population of 124. The observed signs of excessive exposure to chromium(VI)-nasal mucosal irritation and ulceration and to a lesser extent nasal septal perforation-were likely, in the acute or subacute nature of the lesions, to be closely related to airborne chromium(VI) at the average concentration measured at the time of the study-68 ng/cu m. There is reason to suspect that liver and kidney damage occurred, based on observations of enlarged livers and casts in urine, as a result of long-term exposure to chromium(VI) , but the results were not conclusive. Numerous cases of allergic dermatitis with varying degrees of eczema have been reported. 21,25,61,62, Parkhurst in 1925 reported the case of a woman employed in blueprint production using a process where a 1% potassium dichromate solution was used as a fixative. He rubbed a 0.5% potassium dichromate solution on the right thigh of the woman and soon there was a local sensation of itching and burning. Twelve hdurs later, the patient developed a follicular erythematopapular dermatitis where the solution had been applied. A similar application was made to the left thigh with resulting itching and burning. However, the application of an aqueous saturated solution of bisulfite prevented the development of a dermatitis in this area. In 1931, Smith observed a case of chrome poisoning with manifes tations of sensitization in a man employed in a photographic printing firm, where his duties involved handling and washing sheets of zinc treated with a solution of ammonium dichromate, and occasionally preparing the solution. The man developed a mild erythema 24 hours following a patch test with 1% ammonium dichromate solution on a 1-sq cm area of normal skin on his forearm. After 3 days the erythematous area had doubled in size and had developed vesicles. Eight days later, an intradermal injection of 0.1 cc of a 0.5% aqueous solution of ammonium bichromate was given in the right forearm. Within an hour the patient developed a generalized pruritus with soreness at the site of the injection. Within 6 hours he had (1) a slight erythema at the site of a previously negative patch test, (2) an erythematous area 5 cm x 3 cm with tenderness at the injection site, (3) a localized patch of maculopapules on the area in which the patch test had been 9 days earlier, (4) a vesicular erythematous dermatitis covering the entire hands and lower parts of the forearms, (5) generalized mild erythema with a few urticarial wheals on the buttocks, and (6) a recurrence of the diaphoresis and sibilant rales he had had some 15 days earlier, upon admission to the hospital. The man recovered after his exposure to chromium(VI) ceased. Three control subjects were similarly injected and showed no reaction. Hall in 1944 reported 132 dermatitis cases in aircraft workers who had contact with a primer consisting of a suspension of zinc chromate powder and magnesium silicate in a xylene solution of certain resins, including a phenol-formaldehyde resin. Apparently, the mean duration of employment was 7 months (range: 1 week-9 years) for those who had dermatitis from the primer and who were allergic to zinc chromate pigment. A series of patch tests showed 90 of the workers (68%) were sensitive to the zinc chromate pigment only. (The zinc chromate pigment was apparently a mixture of zinc chromate and calcium carbonate.) In 1949, Pirila and Kilpio reported 45 cases of allergic contact dermatitis observed in the Helsinki area from 1945-48. Forty-one reacted positively to patch-testing with a 0.5% aqueous solution of potassium dichromate (pH 4.15). The breakdown of cases by occupation was as follows: bookworkers, 11; cement and lime workers, 10; radio factory workers using a photostatic procedure, 7; metal factory workers, 4; painters and polishers, 4; fur workers, 3; others, 6. In 1952, Gngebrigtsen reported 8 cases of cement eczema among 300-400 Norwegian workers exposed "more or less directly" to cement dust that contained 0.002-0.020% water-soluble chromium(VI) described only as He did not react to distilled water. The control subjects did not react to any of these 3 chromium(VI) solutions. In 1960, Calnan showed that British cement contained from nondetectable amounts to 12 ppm chromium(VI), expressed as potassium bichromate. He concluded that cement dermatitis was primary irritant dermatitis complicated by a secondary contact sensitivity to "hexavalent chromate" Winston and Walsh reported that 6 out of 200 employees were incapacitated by chromate dermatitis in a diesel locomotive repair shop. One of the 6 cases was described; the dermatitis consisted of patchy, pruritic, erythematous, slightly scaly lesions extending from the dorsum of the hands over both forearms to the elbows. All were exposed to an alkaline diesel locomotive radiator fluid which was prepared from sodium dichromate, soda ash, disodium phosphate, and sodium silicate. One and one-half pounds of this powdered mixture, which contained 66% sodium dichromate, was dissolved in 2 gallons of water in an open pail. This solution (approximately 6% sodium dichromate) was poured into the radiator and diluted with about 210 gallons of water, giving a solution of about 0.08% sodium dichromate. All of the men gave positive reactions to 0.25% sodium dichromate (pH 4.25) patch tests and to samples of the radiator fluid (pH 10). Walsh in a summary report on chromate hazards in industry described results of some patch tests: 2% "chromic acid" applied for 24 hours on superficial skin abrasions produced a crusted lesion in 3 weeks; 0.5% sodium dichromate, reapplied daily for 3 days, produced a crusted lesion in 3 weeks; 0.5% potassium chromate, applied for 8 hours/day for 3 days, produced lesions in 3 days; 0.05% sodium dichromate, 0.005% sodium dichromate, and pure zinc chromate also produced lesions in 3 days after being in contact with the skin for 8 hours/day for 3 days. Lead chromate did not produce a reaction after the same exposure period. A 10% solution of chromium(III) nitrate produced redness after the solution was reapplied daily for 3 days. Edmundson patch-tested 56 men who had chrome ulcers with 0.5% potassium bichromate for 24 hours. Only 2 yielded positive reactions and they were said to have a history of chrome dermatitis. He interpreted his results to indicate that when chrome produces ulcers it does not sensitize workers. Morris in 1955 reported 2 cases of sensitization to chrome glue prepared at least in part from scraps of chrome tanned leather. Both patients gave positive reactions to the otherwise undescribed chromebearing parent material to which they were exposed, and both were allergic to chrome-dyed leather shoes. From the nature of the tanning process it seems probable that the substance causing the sensitivity was chromium(III). One of these patients reacted positively to a 0.1% solution of sodium bichromate. McCord et al described in detail the lithography process, as it existed in 1930, which used an extremely acidic solution of chromium(VI). Twenty-five lithographers and 12 tanning workers who had been exposed to chromium, but showed no signs of dermatitis, were selected for study. Each reactions. This report was apparently the first to note that injury from chromium(VI) could occur without previous skin trauma or disease. Levin et al, from similar studies conducted in the late 1950's, confirmed that chromium(VI) was the primary causative agent in lithographer's dermatitis. However, they found that trauma and the use of various other chemicals associated with lithography such as fat solvents and primary irritants made workers' skin more prone to irritation by the chromium(VI)-bearing materials. In 1961, Fregert described the manufacture of matches and demonstrated that match heads which contained chromium(VI) could partially dissolve when held in moist fingers and could cause an allergic eczematous contact dermatitis. The source of chromlum(VI) was probably an ingredient of the manufacture since potassium dichromate is usually added both to the igniting composition and to the striking composition. The author was, however, unable to find chromium(VI) in the striking composition, probably because it had been reduced to chromium(III). Although this study was done in Sweden, he attalyzed matches from 21 countries and found concentrations as high as 1.7% water-leachable chromium(VI) expressed as potassium dichromate in unburnt matches and 1-10% of the original chromium(VI) concentration in the burnt matches. He stated that every patient in a group of 33 who had chromate eczema reacted positively to either unburnt or burnt match heads. In 1963 2 separate studies of dermatitis resulting from chromium(VI) used in the automobile industry were published. Engel and Calnan investigated an outbreak of dermatitis in the British automobile industry among workers who were engaged in the wet sanding of primer paint containing zinc chromate. Almost all (91%) of them had positive reactions to a 0.5% solution of potassium dichromate (pH 4.15); however, a few did not react until the solution was made alkaline (pH 10.3) Newhouse found dermatitis in automobile assemblers from handling a chromate dip used as an antirust agent on bolts, nuts, screws, and washers. About one-quarter of these responded positively to potassium dichromate patch-testing. Fregert and Ovrum in 1963 reported a case of a welder who contracted a facial dermatitis after inhalation of and contact with welding fumes from either arc welding or oxygas welding. Subsequent investigation demonstrated that the chromium in certain welding rods could be oxidized to chromium(VI) and that chromium(VI) was dispersed into the air in the vicinity of the weld. The authors patch-tested 5 people who were hypersensitive to chromate with an aqueous solution of collected welding fumes calculated to be 0.1% chromium(VI) (as potassium dichromate). All gave positive reactions. The authors elicited no response from 10 subjects not hypersensitive to chromate. Their analyses of various commercial welding rods showed chromium contents up to 18%. A year later, Shelley reported a similar case. A crane operator provided a history of chronic eczematous eruptions of both hands. Twentyeight compounds were patch-tested and the only positive reaction was to an aqueous 0.25% solution of potassium dichromate (pH 4.28). Two and one-half months later, the man walked by an acetylene-welding operation where the fumes were strong and experienced appreciable inhalation of the fumes. On the next day he reported a rapidly developing vesicular flare on his hands. The dermatitis subsided after he avoided further contact with chromiumcontaining objects and welding fumes. Jaeger and Pelloni in France demonstrated that workers with Goldman and Karotkin in 1935 reported a case of acute exposure involving a 25-year-old woman who had swallowed an aqueous solution containing a heaping teaspoonful of potassium dichromate crystals. Shortly thereafter she had a paroxysm of vomiting. Two days later she was hospitalized. At this time she had severe nephritis and severe hepatitis, an erythematous skin eruption, and a "positive" chromium test in urine. The skin rash began to fade 13 days after the initial reaction and disappeared after 5 more days; she recovered from hepatitis and nephritis in 3 months. Major reported the development of severe nephritis in a patient the day after chromium(VI) oxide was applied to a wound as a cauterant; the man died 19 days later. Vigliani and Zurlo studied over a 3-year period approximately 150 workers in a plant producing alkali chromates; during this time the airborne chromium(VI) concentration range was 57-78 ng/cu m. Ulceration of the nasal septum, inflammation of the conjunctiva and laryngeal mucosa, and chronic asthmatic bronchitis were the most commonly seen disturbances, but their frequency was not mentioned. One case of nasal septal cancer and 1 of lung cancer were also observed. No data regarding sampling locations, sampling techniques, or analytical methods were presented. Unequivocal evidence relating a specific chromium(VI) compound to the development of lung cancer in humans has not been developed. There is, however, epidemiologic evidence in workers and experimental evidence in animals that suggests carcinogenic properties of some chromium(VI)-containing materials. This evidence is discussed in the following 2 sections. # Epidemiologic Studies The first extensive epidemiologic studies involving exposure to chromium(VI)-containing materials and the risk of lung cancer were performed in Germany by Lehmann. He found only 2 cancer cases and dismissed them as nonoccupatlonal in nature but the reasons for this conclusion seem to be faulty in view of current knowledge. Lehmann gave no information on the extent of exposure to chromium(VI). Later German reports, reviewed by Baetjer One of the studies referred to by Baetjer is of particular interest. Because the authors apparently determined that the pancreas was the primary site adenocarcinoma, and as there have been no other reports of chromium(VI) causing cancer of the pancreas, it seems improbable that chromium(VI) was the causative agent. In addition to the cancer cases in the cohort, 1 man developed an adenocarcinoma of the prostate after an unmentioned exposure period and another, a 33-year-old man, was diagnosed as having an adenoid cystic carcinoma of the inferior nasal turbinate after working in the plant for 3 months. The plants in which these men worked were not designated. In light of the short, less than 3-year, period of employment of the worker who developed prostate cancer and the lack of any other report linking exposure to chromium(VI) and prostate cancer, it is unlikely that chromium(VI) was responsible. Because the worker who developed a carcinoma of the nasal turbinate was exposed for only 3 months, an extremely potent carcinogen must have been present. Other reports do not suggest that chromium(VI) is capable of producing cancer in such a short time. The authors calculated the risk of getting lung cancer for each worker separately for each calendar year of the observation period. This was accomplished by using the age-specific incidence rates of cancer supplied to them by the Cancer Registry of Norway. The total risk for the population of workers was then obtained by adding the risks for each worker for each year of the observation period. The expected number of cases of cancer obtained by this method was then compared to the observed number in the group. The expected number of lung cancer cases in the cohort was calculated to be 0.079 for the total period of observation. Since 3 cases were found, the observed/expected ratio was 38. The total number of manyears at risk of the cohort was 244. There were several shortcomings in the Machle and Gregorius study. The authors differentiated exposure to 2 categories of chromium compounds, ie, soluble and insoluble, but did not differentiate between chromium(III) and chromium(VI). Chromium(III) and chromium(VI) materials leachable by water were classified as the soluble group. The insoluble group of compounds included all those not leached by the repeated treatment with water. This group probably included primarily chromite ore, based on the degrees of water-solubillty of the compounds which were probably present. Thus, although the authors did not determine chromium (III) and chromium(VI) directly, it appears that "insoluble" compounds were predominately chromium(III) and "soluble" compounds were predominately chromium(VI). Chromium(VI) of only slight water solubility was not determined in this study, but based on the analytical procedure used part of it was likely found in the soluble group and part in the insoluble group. The pH's of airborne samples were 6.7-9.4, indicating that most samples included both chromates and dichromates. All samples germane to the chromate-plant study were apparently taken by air filtration using the apparatus mentioned by Bourne and Streett. Collection efficiencies for chromium(VI) oxide as a mist using this apparatus were determined at 0.07 mg/cu m, 0.14 mg/cu m, and 0.22 mg/cu m to be 93.6%, 98.3%, and 92.5%, respectively, for 15-minute samples at a flow rate of 28.3 liters/min. Collection efficiencies for dust were determined at 4.62 mg/cu m and 25 mg/cu m to be 99.0% and 99.9%, respectively. Mists used in the collection efficiency test were generated using an apparatus, described by Silverman and Ege, which nebulized into the air stream an aqueous solution of chromium(VI) oxide (25%) and sulfuric acid (0.125%). The dusts were generated in the same equipment except that the nebulizer was replaced with a vibrating vessel into which dust was introduced. The size distribution of the particles in the mist in the chromate plant was: 15.87% less than 1.5 pm, 50% less than 3.8 jum, and 84.13% less than 9.8 /an. In the dust the distribution was 15.87% less than 0.8 fm, 50% less than 1.7 /xm, and 84.13% less than 3.7 im. Mancuso and Hueper investigated the incidence of cancer in this chromate plant. Using the results of analyses of air samples for soluble and insoluble chromium, they calculated the possible exposures of 7 men who died from lung cancer between 1938 and 1950. Although none of the 7 were working in the plant when the sampling and analysis were performed, the calculated TWA exposures could have had some relationship to their actual exposures. The years of first exposure in the chrome plant for the 7 were 1931-41. Changes in the concentrations of chromium in airborne dusts and mists could have occurred during the years of exposure of these men to decrease the relevance of determinations of TWA exposures made at the time of this study. The scope of such changes is very difficult to evaluate. The airborne concentrations of chromium leachable by water determined by Mancuso and Hueper to which the 7 were exposed were 0.01-0.15 mg/cu m (Table XI-5). These concentrations were apparently calculated timeweighted average concentrations taking into account the various jobs the men accomplished during the average day. The men were also exposed to chromium not leachable by water, in addition, at airborne concentrations of 0.1-0,58 mg/cu m. Because of the lack of specificity in the analytical method used , the airborne concentration of the only slightly watersoluble chromium(VI) is inestimable. In another paper, Mancuso reported the incidences of other effects found in the epidemiologic study. Although the various groups were defined by total chrome exposure and ratio of insoluble to soluble chrome, the actual maximum ranges of concentrations of chromium, either leachable or not leachable by water, have been calculated from their data and appear in In 1959 Baetjer et al reported the determination of chromium in the lungs of 16 decedents who had been employed in old chromate plants. Eleven of the men who had been employed for 2-42 years had lung cancer; 5 of the men employed 1.5-19 years did not. The results of analyses by the method presented in an appendix to their report were both highly variable and inconclusive, that is, there was no significant correlation between the presence of lung cancer and chromium in lung tissue. The US Public Health Service published in 1953 a report of an extensive study of the health of 897 workers in the chromate-producing industry. Morbidity and mortality data were based upon paid death claims and cases of sickness and nonindustrial injuries disabling for 8 calendar days or longer among the members of the sick benefit plans of the plants. From 1940 to 1948, there were 28.9 times as many deaths from respiratory cancer among males in the study as would have been expected on the basis of the average death rate for the United States for the period 1940-48 inclusive, excluding violent, accidental deaths. Medical examinations were performed on about 96% (897 males) of the total work force of the 6 study plants. Ten workers were considered to have bronchogenic carcinoma, a rate for chromate workers of more than 50 times the rate for the general population. Three of these men were known to have had lung cancer prior to the survey. These 10 men, who averaged 54.5 years of age, had a mean duration of exposure of 22.8 years (Table XI- 7). This represents a very high lung cancer incidence. Five hundred nine (56.7%) had perforation of the nasal septum. The incidence of perforation of the nasal septum was stated to have no relation to either years of exposure or to the incidence of lung cancer. Studies relating exposure to chromium compounds and incidence of dental caries indicated a low degree of correlation, but there was an increased incidence of gingivitis and periodontitis. X-ray examinations showed no significant fibrosis, but bilateral hilar enlargements were noted. There was no significant correlation between duration of exposure and heart disease. Other positive correlations mentioned were an increased frequency of white blood cells and casts in the urine and a decreased sedimentation rate of erythrocytes, all of which were related to years of exposure. Blacks appeared to be more severely affected, in general, than whites, perhaps due to a greater exposure among blacks. This study also involved an extensive sampling program in which over 1,800 samples of air contaminants, settled dust, and process material were collected and analyzed. The report stated that the dry-end processes, ie, milling, roasting, and leaching, generated dusts containing principally lime, chromite ore, soda ash, roast residue, and sodium chromate. Sodium dichromate and sodium sulfate were usually associated with the wet-end operations of neutralizing, treating, and concentrating. In 1952, Brinton et al published a study of the morbidity and mortality in the chromate workers of another study. They demonstrated a greater rate of sickness and nonindustrial injury in chromate workers as compared to a large industrial group. This difference was due to the 10fold increase in the incidence of cancer in chromate workers, largely because of respiratory cancer, which was increased 14-fold for whites and 80-fold for nonwhites. In 1966 Taylor reported a study Chromium(VI) concentrations were less than 1 up to 25 mg/cu m. The author observed either diffuse thickening or rupture of alveolar walls and proliferation of cellular elements along the blood vessels and bronchi. Desquamation of the bronchial epithelium was also found. No tumors were found, but the maximum exposure was only 8 months. In 1930, Hunter and Roberts injected subcutaneously Macacus rhesus monkeys with various amounts of an aqueous 2% solution of potassium bichromate. One monkey given 36.3 cc of the solution (0.02 g/kg) and another given 10 cc were dead 12 hours later. Evidence of acute lesionswas present in the kidneys of both animals. Four other monkeys were given repeated, 1-5 cc doses of the solution at 3-to 7-week intervals. In 2 of these, acute lesions were also found in the kidneys. The other 2 animals lived longer, for about 160 days, and sustained chronic renal damage; in 1, practically all the original epithelium of both proximal and distal convoluted tubules was destroyed. The authors further remarked that the regeneration of tubular epithelium was of distinctly atypical morphology and that the tissue was apparently resistant to further injury by bichromate. In 1940 Shimkin and Leiter reported the intravenous injection of various materials into tumor-susceptible strain A mice. Single, 5-mg injections of chromite ore did not result in an increased incidence of In another series, 12.5 mg of calcium chromate in gelatin capsules was implanted intramuscularly and intrapleurally in rats. After 7 months, of the 6 rats with intramuscular implants, 2 developed tumors; of the 6 rats with intrapleural implants, 3 developed tumors. The latter experiment, despite its lack of a control group, appears to verify that the chromium(VI) compounds and not the sheep fat were the causative agents for the tumors observed. Payne fractionated and analyzed the residue from the first leaching of roasted chromite ore, and tested the material in animals. This In a further study, Hueper and Payne gave rats monthly intrapleural and intramuscular injections of sodium dichromate in gelatin. Each injection consisted of 2 mg of sodium dichromate dissolved in 0.05 ml of a 10% gelatin solution. A total of 16 injections were given. Survivors were sacrificed at the end of a 24-month observation period. Various tumors were seen. Of the 20 male and 19 female rats in each series receiving intrapleural injections, 3 developed malignant tumors, 1 of which was at the site of injection. Rats receiving intramuscular injections developed 4 benign and 2 malignant tumors, none at the site of injection. The 4 tumors which were not at the injection sites were of a type found in a similar incidence in control animals. Four benign and 12 malignant tumors, none at the site of injection, were observed in the control group. Because of the greater incidence of malignant tumors in control animals, it is impossible to conclude that sodium dichromate was responsible for any malignancies. In another experiment, In 1968 and 1969 Laskin et al reported a study of selected chromium compounds in a cholesterol carrier using a new intrabronchial implantation technique. The pellets used were in the form of a cylindrical matrix of stainless steel mesh and about 1 mm in diameter and 5 mm in length. They were implanted in the bronchus and held in place by a trochar fitted with spring-wire hooks and introduced through a tracheotomy. One of 100 rats implanted with process residue developed a squamous cell carcinoma at the site after 594 days. No other compounds produced tumors at the site of implantation, although among the 100 rats in each group hepatocell carcinomas were observed in 1 rat given process residue, in 1 rat given chromium(III) chromate, and in 2 rats given chromium(VI) oxide. Five of 24 control rats developed squamous metaplasia and, in addition, 1 developed a sarcoma. Of the tumors seen, all were invasive and some had metastasized. In all experimental groups except the 1 exposed to chromium(VI) oxide, there was evidence of atypical squamous metaplasia of the bronchus. Since these studies implicated calcium chromate as a lung carcinogen, inhalation studies using this compound were begun. Early rangefinding studies with calcium chromate resulted in rapid and significant mortality at both 10 and 20 mg/cu m (2.7 and 5.4 mg chromium(VI)/cu m, respectively) in both rats and hamsters. Results reported in 1972 suggested a carcinogenic action in rats and possibly in hamsters after chronic exposure to calcium chromate aerosols at 2.0 mg/cu tn (0.67 mg chromium(VI)/cu m ) . After 589 exposures over 891 days, 4 carcinomas were observed. Of the original 100 rats, 1 keratinizing squamous cell carcinoma of the lung, 1 laryngeal squamous cell carcinoma with invasion of perineural spaces and adjoining cartilaginous rings, and 1 malignant peritruncal tumor of undetermined type and origin were observed. One squamous cell carcinoma of the larynx was found among the original 100 hamsters. In addition, a number of mucosal changes were noted. In rats, 2 animals showed laryngeal hyperplasia and 3 showed laryngeal squamous metaplasia. Effects in hamsters were more marked with 8 animals showing laryngeal hyperplasia. Eight additional animals showed squamous metaplasia of which 5 were atypical with downgrowth. Another hamster, dying at 611 days, showed a squamous papilloma in the larynx with hyperplasia and hyperkeratosis. Nettesheim et al exposed 136 female mice and 136 male mice, all germ-free derived and specific-pathogen-free C57BL/6, to 1 jun diameter calcium chromate aerosol at a concentration of 13 mg/cu m. He also exposed 545 mice of the same type to PR8 influenza virus prior to the calcium chromate exposure. Two control groups of the same size and composition breathing filtered air were used and only 1 was infected with the virus. In all, 21 pulmonary adenomas were obaerved in the 2 exposed groups and only 5 in the uninfected controls. No tumors were found in the infected controls. No bronchogenic tumors were found. The authors determined that there was a significantly larger (P<0.0077) incidence of lung tumors in mice exposed to calcium chromate, compared to controls. Prior exposure to 100 roentgens of whole-body X-radiation in another series of mice did not affect tumor incidence, but prior PR8 influenza infection appeared to reduce the incidence of tumors from calcium chromate. The authors also gave 15 weekly intratracheal injections of calcium chromate to 2 groups of hamsters. Hamsters in 1 group received 0.5 mg/week, the hamsters in the other group received 0.1 mg/week. The lesions produced were similar to those observed in the mice, but scarring of the lung parenchyma was more widespread and adenomatosis was regularly observed. Hamsters also had frank bullous emphysema and extensive goblet cell hyperplasia in all parts of the tracheobronchial tree. In a study by Zekeev et al in 1973, the blastomogenic and toxic effects of chromium(III) oxide, ammonium bichromate, sodium bichromate, chromium ores, and dolomite were observed in rats. Some rats were preliminarily treated with "non-carcinogenic" doses of 3,4-benzpyrene. Positive control groups received 3-methylcholanthrene. Lungs of all rats either dying during the study or killed at its termination were examined both macroscopically and microscopically. Apart from those in the lung, tumors were similar both in type and number in all groups. The bronchial tumors found and microscopically confirmed are given in Table III and discoloration of the teeth. Although it is apparent that any chromium(VI) materials may cause the less severe effects if they are present in aqueous solution in sufficient concentrations, the specific materials which were responsible for lung cancer have not been identified. To some extent the toxicities of chromium(VI) materials vary with their solubilities, but denotation of compounds on the basis of solubility alone has not been sufficiently precise to suggest a dichotomy of toxic effects, where high incidences of ulceration and perforation occurred, there were 37 employees. Twelve of the 21 workers employed 1 year or less and 15 of the 16 workers employed more than 1 year had ulceration and crusting of septal mucosa, avascular scarified areas of septal mucosa without erosion or ulceration, or perforation of the nasal septum. In the plant in Finland, the incidence of signs and symptoms of chromium(VI) poisoning is impossible to establish because insufficient information was provided. However, it is apparent that most persons with signs and symptoms had been employed for 1-5 years, during which time the working conditions were less hygienic than those in effect at the time of the study. The third plant with 32 employees provided great contrast with the other 2. In this plant no ulceration or perforation occurred, despite the fact that the workers had been employed for a much longer period of time-15 were employed 8 years or more; 7, between 4 and 8 years; 4, between 1 and 4 years; and only 6, less than 1 year. to "chromic acid" and resulting skin ulceration, the lack of skin ulceration in the third contrasting study suggests that good work practices were used in this plant. The criteria document on exposure to chromic acid concluded that, in the presence of good work practices, an environmental limit of 50 In 1884, Mackenzie reported that ulceration of the nasal mucosal membrane followed by nasal septal perforation usually occurred after an exposure to bichromate of only a few days. Corrosion of both the nose and throat was also common and was occasionally accompanied by inflammation and perforation of the ear drums. No estimates of the degree of exposure required to produce these disorders were presented, but at that time the manufacturing processes were undoubtedly accompanied by an extremely dusty environment. In a survey of the chromate-producing industry in 1948, Machle and Gregorius Fregert found positive reactions to water-soluble hexavalent chromium in patients with chromate eczema. Morris reported positive reactions to chrome-containing glue and chrome-dyed leather shoes. Calnan concluded that cement dermatitis was primary irritant dermatitis complicated by a secondary contact sensitivity to "hexavalent chromate" . Engebrigtsen confirmed that workers with cement eczema reacted positively to patch tests with aqueous 0.5% solutions of potassium bichromate. Jaeger and Pelloni found that 94% of those with cement eczema gave positive patch test results with aqueous 0.5% solutions of potassium bichromate. McCord et al found that few workers who developed chrome ulcers were sensitized to an aqueous solution of 0.5% potassium bichromate. Pirila and Kilpio reported that some workers who had been exposed to materials likely to contain chromium compounds-bookworkers, cement and lime workers, persons working with fish glue, metal factory workers, painters and polishers, and fur workers-were allergic to aqueous 0.5% solutions of potassium dichromate. Denton et al reported on a man who reacted strongly to an aqueous 0.005% solution of potassium dichromate. Winston and Walsh reported on a man who had a patchy, pruritic, erythematous dermatitis from working with a chromate-silicate-phosphate mixture (pH 10); the man had positive reactions to 0.25% sodium dichromate and to the above mixture. Levin et al reported that lithographers developed an allergy to chromium(VI) which was elucidated by patch tests with various chromium(VI) materials including an aqueous 1% solution of potassium dichromate and other nondescript solutions. Engel and Calnan found a group of workers who wet-sanded zinc chromate primer paint and who reacted positively to aqueous 0.5% solutions of potassium dichromate, and a group who did not react to an aqueous 0.5% solution of potassium dichromate until it was made alkaline (pH 10.3). Newhouse found that 24% of the automobile assemblers studied yielded positive reactions to aqueous 0.5% solutions of potassium dichromate. The chromate dip used on bolts, nuts, and washers as an antirust agent was ascertained to have been responsible for the dermatitis. Fregert and Ovrum found that welders exposed to aerosols of chromium(VI) developed hypersensitivity which was confirmed by patch testing with aqueous 0.1% solutions of chromium(VI) as potassium dichromate derived from welding fumes. Shelley reported a similar sensitivity to welding fumes; a man with chronic, eczematous eruptions had positive reactions to aqueous 0.25% solutions of potassium dichromate. Loewenthal observed a green-tattooed bricklayer with eczema who yielded positive reactions to aqueous 0.1% and 2% solutions of potassium dichromate. Cairns and Calnan described a green-tattooed cement worker with eczema who reacted to aqueous 0.1% and 0.5% solutions of potassium dichromate and to an aqueous 2% solution of cobalt chloride. Walsh ascertained that aqueous 0.5% sodium dichromate, 0.5% potassium chromate, 0.05% sodium dichromate, and 0.005% sodium dichromate solutions produced lesions on abraded skin. Perone et al found that among 95 construction workers who worked regularly with cement, 1 reacted to an aqueous 0.25% solution of potassium dichromate and 1 other man reacted to an aqueous extract of cement containing 450 ppb (450 ng/g) hexavalent chromium but not to the 0.25% solution of potassium dichromate. Improvements were also made in other plants. At the time of the study in 1949 the range of exposures for the 7 who died from lung cancer was estimated from employment histories, job classifications, and 1949-50 environmental chromium concentrations. The range of exposures was calculated to be 10-150 fxg/cn m and the mean was 50 jig/cu m , ( Eight cancers were found in a group of 100 rats when pellets of calcium chromate in a cholesterol carrier were implanted intrabronchially. Six of these were squamous cell carcinomas and were found in animals dying after 386-671 days. One animal dying after 474 days had metastases to the kidney. Two adenocarcinomas produced by calcium chromate were observed at 366 and 609 days. Both of these demonstrated mucus production. These rats showed atypical squamous metaplasia of the bronchus. Calcium chromate produced cancers in 10 of 35 rats at the sites of intramuscular injections. In addition, it produced cancers in 28 of 35 rats at the sites of intrapleural administration. Inhalation of calcium chromate produced in rats 1 keratinizing squamous cell carcinoma, 1 laryngeal squamous cell carcinoma with invasion of perineural spaces and adjoining cartilagenous rings, and 1 malignant peritruncal tumor of undetermined type and origin. At the same concentration of airborne calcium chromate, 1 hamster developed a squamous cell carcinoma of the larynx which was invading and destroying the cartilage. In terms of chromium(VI), this calcium chromate concentration was 670 ¡ig/cu m. Animals received 589 exposures at this concentration over 891 days. In view of these findings, the investigators examined the larynges. Two rats showed laryngeal hyperplasia and 3 showed laryngeal squamous metaplasia. Effects in hamsters were more marked with 8 animals showing laryngeal hyperplasia. An additional 8 animals showed squamous metaplasia of which 5 were "atypical with downgrowth." Another hamster, dying after 611 days, showed a squamous papilloma in the larynx with hyperplasia and hyperkeratosis. One study used calcium chromate with a solubility in water of 1,200-1,400 ppm ground in a ball mill after the solubility was determined. Approximately 136 C57BL/6 mice of each sex were exposed to 13 mg calcium chromate/cu m for 5 hours/day, 5 days/week for their lifetimes. Six males in the exposed group developed lung tumors; 3 of the unexposed had lung tumors. Eight females in the exposed group had lung tumors; 2 in the control group had lung tumors. The lung tumors in the calcium chromate-exposed animals were generally not different from those in the control. All tumors were pulmonary adenomas or adenocarcinomas. This material has been referred to as chromic chromate in some instances. In a study by Payne, sintered calcium chromate was mixed with sheep fat and implanted into muscle tissue of the thighs of 52 mice. At the end of 14 months, a total of 9 implantation-site sarcomas were found. While the animal data leave much to be desired, there is sufficient information to support the conclusion that c h r o m i u m ( V I ) compounds are implicated in the production of cancer, regardless of the mode of administration. From the information available, it appears that a chromium(VI) mate rial generated by the alkaline roasting of chromite ore, has carcinogenic characteristics when inhaled. IV. ENVIRONMENTAL DATA Sampling and Chemical Analysis Air sampling for chromium compounds has been performed by a variety of methods suitable for particulate sampling and poses no significant prob lems. Samples have been collected using electrostatic precipitators, It Is probable that chromium in other oxidation states will accompany chromium(VI) In the air; hence, analytical methods are required which differentiate between chromium(VI) and the other forms. Most published methods relying on Instrumental analysis are in reality total chromium methods, and will differentiate chromium(VI) from chromium(III) only if certain separation steps are included in the procedure. One separation procedure, the method for determining chromium(VI) recommended in the NIOSH criteria document for occupational exposure to chromic acid, relies on the complexation of chromium(VI) with ammonium pyrrolidine dithiocarbamate (APDC), followed by extraction with methylisobutyl ketone polarography, spark source mass spectrometry, and X-ray fluorescence. It is also feasible, after forming chromium acetylacetonates or trifluoroacetylacetonates, to determine chromium by means of the very sensitive and selective gas chromatographic procedures. Beyerman published a comprehensive review of the analytical methods for minute amounts of chromium. He critically compared the many methods with regard to their sensitivities, specificities, accuracies, and precisions. In addition he examined certain processes which are common to many methods such as the digestion of biologic samples in various strong acids. He specifically noted that consistently low results occurred when digestions were performed with perchloric acid due to the formation of chromyl chloride which was emitted as a gas. He further studied many common analytical reagents and showed that some of them were significantly contaminated with chromium, which could lead to erroneous results and high blank values. Errors due to the adsorption by the walls of glassware used were also appreciable, and other errors inherent in common analytical procedures were described. A particularly thorough study of extraction of chromium compounds with organic solvents was made, and various means of separating chromium(VI) by extraction were described. The analytical methods considered by Beyerman Included those based on colorimetric measurements, emission spectrography, flame photometry, X-ray emission spectrography, activation analysis, and 2 electrometric methodspolarography and biamperometry. Most Instrumental procedures are generally not specific for chromium(VI) and are not suitable for such analyses unless, as stated above, prior separations are made. In the NIOSH method recommended in the criteria document for occupational exposure to chromic acid for example, atomic absorption spectrophotometrlc analysis is performed after extraction of chromium(VI) from the chromium(III). There are means of performing an analysis in such a manner that only chromium(VI) is determined, and several such methods are based on the fact that chromlum(VI) reacts with iodide to form iodine that may thereafter be determined by a variety of standard iodometrlc procedures. Such methods are not truly specific for chromium(VI) for they may be subject to interference by other oxidants or reductants. The reagents hematoxylin and s-dlphenylcarbazlde 131,133, have been used for chromium(VI) analyses, and the latter reagent in particular is widely favored for analysis of chromium(VI) in air. s-Diphenylcarbazide forms a colored complex with chromium(VI), but not with other chromium compounds, and the stability of the color formed contributes to the sensitivity of the method. Several materials, notably iron, copper, nickel, and vanadium, may interfere with the analysis , but relatively large amounts are tolerated without significant effect. In addition, certain other compounds such as cyanides, organic matter, and reducing agents may also interfere. The effect of reducing substances, if present, must be taken into account in any method for determining chromium(VI), since they tend to decrease the actual airborne concentration of chromium(VI). In many sampling situations, however, the presence of significant quantities of such interferences may be ruled out and it is probable that in all but exceptional circumstances the method may be considered specific for chromium(VI) and subject to a minimum of interferences. As noted previously, Abell and Carlberg have demonstrated that reduction of chromium(VI) by the organic matter of the filter does not occur if polyvinyl chloride filters are used, and it is likely, though not proved, that certain other types of filtration media would also be suitable. Subsequent experience with, and the development of, refinements to the s-diphenylcarbazide method by NIOSH demonstrates the superiority of this method. NIOSH now recommends this as well for chromic acid instead of the method in the chromic acid criteria document because the sdiphenylcarbazide method has shown at least indirectly the ability of many hygienists to obtain excellent results with it. In addition, the sdiphenylcarbazide method is simpler to use than the method in the chromic acid criteria document and requires the purchase and use of less expensive, more commonplace analytical instrumentation. For many years, test papers have been commercially available which rely on the reaction of chromium(VI) with a paper impregnated with sdiphenylcarbazide reagent. Such papers, at best, give only an approximate indication of the concentration of chromium(VI) if present in a mist and cannot be expected to reliably indicate the presence of dry particulate matter containing chromium(VI). There has been great interest in the determination of chromium in biologic materials, both for nutrition studies and in relation to occupa tional exposure to chromium compounds. Dif ferential analysis for chromium(VI) in biologic samples is not easy, and most analyses reflect the total chromium intake. Many of the analytical difficulties encountered in chromium analyses are particularly troublesome in biologic samples where the extremely low concentrations of the element and the difficulties of ensuring complete oxidation of the chromium may cause substantial analytical errors. It is perhaps for these reasons that biologic monitoring of chromium, as discussed in Chapter III, is of relatively little value in assessing exposure to chromium(VI) in the occupational environment. # Control of Exposure In many operations in the production and use of chromium(VI), exposures can be eliminated or kept within safe limits by use of closed system operations for reactors, conveyors, and holding or storage containers. In such systems care must be exercised to ensure tight and reliable seals and joints, access ports, covers, and other such places. Failure of such seals can result in dust or spray emission into the atmosphere of the workroom. When possible, such closed systems should be maintained under negative gage pressure. Even with closed systems, there will be unloading, charging, transferring, discharging, packaging, and transporting operations which afford various opportunities for contact with chromium(VI) and for the emission of dust and mist containing chromium(VI). Emission of airborne chromium(VI) can be controlled at the source by suitably designed exhaust ventilation. In employing exhaust ventilation for such control, certain recommended practices, and design and operating fundamentals should be followed. Sources of emission should be as fully enclosed by hoods as possible. The exhaust air should be passed through air cleaners of suitable efficiency to reduce the chromium(VI) concentration to acceptable levels before discharge into the community air. Atmospheric exposure to and other contact with chromium(VI) can and should be reduced or controlled by isolating the process or emission source from employees. Location of an operation in an isolated area can also limit the number of employees who will be exposed in that operation. Such operations must be amenable to remote or automated control or to only intermittent attention by an operator. In effect, the worker can be Isolated from the process by providing a clean area (clean room) in which the atmosphere is maintained essentially free of chromium(VI) and other significant contaminants. This may be accomplished by supplying air from an uncontaminated area or by filtering ambient air through high-efficiency filters. A clean area may be established as the control room for remote control operations or as an area to which operators may retreat for such periods as their presence may not be required at the process equipment. Ventilation and Isolation of the processes will reduce the probability of excessive contact with chromium(VI). For protection of eyes and skin, however, these measures may not be adequate for some operations. For those operations where contact of the chemicals with the eyes or skin may occur, whether by the nature of the work or by accidental splashes, sprays or spills, proper protective equipment, work clothing, and good work practices are required to control the exposure (see Chapter VI). The operations for which it is most difficult to control exposures are those of the maintenance and repair workers. The duties of these employees require that they enter or otherwise come into close contact with equipment or areas which may be grossly contaminated with chromium(VI). The TLV documentation stated "A review of the present status of the suitability of the TLV between TLV subcommittee members and industrial-hygiene representatives of the chromate industry 10 years after improved controls had been in operation revealed that (1) the TLV for chromic acid mist was satisfactory; (2) it contained a safety factor of 3 or 4; and (3) the limit was probably satisfactory for the pre vention of lung cancer, as no new cases had appeared during the 10-year period; but (4) that the 10-year period was probably too short to be certain of its validity in this respect." Data in support of these points were not presented and discussed. In the 1973 edition of the Threshold Limit Values a change was proposed in the chromium TLV's. The TLV for chromic acid and chromates remained 0.1 mg/cu m as chromic acid anhydride. The TLV for "Chromium, sol. chromic, chromous salts as Cr" remained 0.5 mg/cu m, but the category "chromium... metal and insoluble salts", which had been 1.0 mg/cu m, was marked for intended changes in order to be included as a group of substances in industrial use that have proved carcinogenic in man, or have induced cancer in animals under appropriate experimental conditions. The group was labeled "Chromates, certain insoluble forms" with a TLV of 100 Mg/cu m. This group of certain insoluble chromates probably included calcium and zinc chromates and sintered chromium(VI) oxide (called chromic chromate) and others. The group was discussed in the 1971 TLV documentation under "Chromic Acid and Chromates" for which the TLV was 0.1 mg/cu m, but in 1973 these materials were apparently removed from that group and placed under "chromium...metal and insoluble salts." It was not mentioned, however whether this intended TLV, 100 ng/cu m, was in terms of chromium, chromium(VI) oxide, or as chromates. Thus, the intended change to 100 jug/cu m may have been an increase, no change, or a decrease in the TLV for these materials. Nonetheless, the intent was apparently to denote "Chromates, certain insoluble forms" as "Human carcinogens." # I In 1974 the situation was clarified, in that the TLV for "chromic acid and chromates" was 0.1 mg/cu m as chromium(VI) oxide and that the TLV's of "Chromates, certain insoluble forms, (Pb, Zn, and chromatechromite ore...)" were 0.1 mg/cu m as chromium and these materials were noted as human carcinogens. It should be noted that the 1974 TLV for these compounds represented an increase in the TLV over the 1972 TLV. The present (1975) federal standard for chromic acid and chromates is a ceiling concentration of 1 mg/10 cu m, ie, 100 ng/cu m, (29 CFR 1910.1000) based on the American National Standard Z37. 7-1971. In 1963 the Threshold Limits Committee recommended a limit of 0.1 mg chromium(VI) oxide/cu m for tertiary butyl chromate, an ester of tertiary butyl alcohol and chromic acid, which was unchanged in the 1974 TLV's. As support for this recommendation, they cited the study by Roubal and Krivucova in the 1971 documentation. Roubal and Krivucova 68,83] pulmonary congestion and edema, epigastric pain, erosion and discoloration of the teeth, and perforated eardrums have been reported on occasions, but again it seems reasonable that sufficient contact with any chromium(VI) material could cause these effects. In addition to causing these effects, some chromium(VI) compounds have been found to be associated with an increased incidence of lung cancer. 95,180] Delpech and Hillalret in 1869 described the effects of potassium chromate and bichromate on workers in the French chromate industry. Workers suffered respiratory ailments from the first day of their employment. One assigned the task of washing "simple chromates", began to suffer from nasal membrane injury, headache, and shortness of breath several days after he started this job. Another worker, involved in calcining and bichromate extraction also had shortness of breath. No environmental data were reported but exposures were probably high because of the then prevailing poor hygiene around reverberatory furnaces. In the chromate-producing Industry in the United States, only a small part of which produced chromic acid anhydride, the principal exposures to chromium(VI) were evidently to sodium chromate and bichromate because these were and are the principal intermediate and product of the alkaline roasting operation. To a lesser degree, there was also exposure to potassium chromate and bichromate. In 1884 Mackenzie related having been told by a workman that destruction of the nasal septum sometimes took place after 24-48 hours of exposure. This destruction was associated with general congestion of the mucous membrane, nosebleed, coryza, ulceration of the turbinates, nasal pharynx, and lower pharynx, and inflammation of the lower respiratory tract. Intense headache, Inflammation and perforation of the tympanic membranes, and subsequent otorrhea also occurred. Exposures in this plant were probably very high, based on remarks about the history of the operation. In 1948, Machle and Gregorius reported the incidence of nasal septal perforation in a sodium chromate-sodlum bichromate-producing plant to be 43.5% in 354 employees. Airborne chromate concentrations were 10-2,800 Mg/cu m at the time of the study. The plant had been In operation for at least 17 years; thus, some employees had probably worked in the plant when reverberatory furnaces were used, a notorious source of exposure. This study provided evidence that exposure to sodium bichromate and chromic acid anhydride does not produce lung cancer. During the 17year period plant D2 had been in operation, no deaths from lung cancer occurred. By contrast, In plant Dl, which used alkaline roasting of chromite ore to manufacture sodium chromate, there were 5 deaths from lung cancer in the same period. As discussed in the section on Epidemiologic Studies, exposure to the intermediate in alkaline roasting has been associated with an Increased incidence of lung cancer. In the early 1950's, an epidemiologic study was carried out in a single chrome plant in Ohio which produced sodium chromate and bichromate but no chromium(VI) oxide. In this study, the overall incidences of nasal septum perforations, chronic chemical rhinitis, and chronic chemical pharyngitis were significantly greater than those of the control group. The chromium(VI) concentration was as great as 0.5 mg/cu m. However, the incidences of these disorders in the groups of workers exposed at less than Results of analysis of airborne chromium showed cross-contamination of work areas in that airborne chromite ore and water-soluble chromium(VI) as well as acid-soluble, water-insoluble chromium, were found in nearly all areas of the plants; the acid-soluble, water-insoluble chromium was analyzed by direct colorimetry. Of the 897 workers examined, 57% had perforation of the nasal septum, 11% had a severely red throat, 8% had edema of the uvula and 50% had cutaneous ulcers or scars. The Incidence of severely reddened throat and edema of the uvula was greater than twice that of control groups. Data on cutaneous effects in the control group were not given. There was also an Increased incidence of lung cancer in these chromate workers. A more recent study has Indicated poor work practices (eg, nose-picking) to be the likely causes of nasal ulcers and perforations. It seems evident that ulcers on the skin and hands (and other exposed skin areas) are also from local contact, thus the result of poor work practices. Although Mancuso and the US Public Health Service report did not make observations on this point, it seems likely that the high incidence of nasal and cutaneous ulcers and sequelae in their studies was also largely, conceivably entirely, due to such work habits. However, a contributory role of airborne chromlum(VI) in the development of nasal ulcers and septal perforations and the major role in the development of primary nasal irritation must be considered. Liver enlargement was noted In about 2% of the chromate workers. Those with enlarged livers were at least 15 years older and had worked an average of 4 years longer in the chromate industry than those without enlarged livers. The frequency with which white and red blood cells and casts were found in the urine was usually greater than that in the average industrial population, suggesting kidney damage. The nonneoplastlc signs of exposure to chromium(VI)-nasal mucosal irritation and ulceration and, to a lesser extent, nasal septal perforation-were likely to be closely related to airborne chromium(VI) at the average concentration measured at the time of the study, ie, 68 jug/cu m. There was some evidence that liver and kidney damage occurred as a result of long-term exposure to chromium(VI). Results were more conclusive relative to kidney damage in controlled experiments with monkeys, which sustained kidney damage after subcutaneous Injections of sodium bichromate. Absorption of large amounts of chromium(VI) has, on a few occasions, resulted in hepatic injury; it has also produced severe nephritis. Because there have been several instances in which kidney damage has apparently been the result of chromium(VI) absorption, routine urinalysis should be performed where there is occupational exposure to chromium(VI). Hepatic injury has also been reported as the result of chromium(VI) absorption; for this reason, it is recommended that in routine medical examinations the responsible physician should consider appropriate liver studies. From these studies of the effects of exposure to sodium or potassium chromate or bichromate, two contain information useful in deriving an exposure-effect relationship. The work of Mancuso be modified and expanded to include these salts in addition to "chromic acid anhydride and aqueous solutions thereof" would be addressing a group of compounds of uniform toxicity. In the light of the study by Machle and Gregorius which showed an elevated incidence of lung cancer only in that part of the operation involving lime roasting, it seems clear that the lung cancer found in the US Public Health Service study occurred in that part of the population involved in lime roasting. This is supported by some observations of the authors, in that, of those workers with lung cancer whose work history was sufficiently described, most had worked at or near the lime mills or kilns. It is also supported by Laskln et al and written information supplied by Levy in 1975 which indicated that the highest incidence of lung cancer was found in animals treated with calcium chromate. The information from Levy indicated no lung cancers were produced in animals treated with sodium chromate or bichromate. When the toxicities of chromium(VI) compounds are examined, it becomes apparent that several have demonstrated carcinogenic activity. 95,107,117,118,120,161,180] Nearly all the implications of carcinogenicity have arisen from studies of the worker population of the chromate-bichromate producing industry and from animal studies using the intermediates produced in that industry. Some Implications have arisen from the pigment-producing industry and from animal studies using pigments and chemically analogous chromium(VI) compounds. Other Industries and processes are suspect despite the absence of appropriate studies because they use or produce materials chemically similar to the Intermediates in the chromatebichromate industry or chromium(VI) pigments. The only industry which has been extensively studied 95,161,180] has been the chromate-bichromate producing industry in the United States. However, even studies of this industry have provided only small amounts of information. Thus, the relationship between airborne concentrations of certain chromium(VI) compounds and the incidence of cancer is uncertain. Machle and Gregorius published the first report of a high incidence of lung cancer among workers in the US chromate Plant £, studied by Machle and Gregorius, was later examined extensively by another team of investigators. 95,161,180] This plant produced sodium chromate and sodium bichromate through alkaline roasting of chromite ore, but no chromium(VI) oxide. In 1 study, Mancuso and Hueper the time between their periods of employment and the analysis of airborne chromium(VI), it is unlikely that the calculated TWA exposures adequately reflected the actual exposure to chromium(VI) the men had while working. In addition, airborne chromium(III) and chromium(VI) were present in all areas of this plant making it impossible to associate the high incidence of lung cancer with exposure to a particular chromium compound. In As in the above study the large number of variables in this study precludes the derivation of a dose-response relationship. In 1975, Watanabe and Fukuchl reported preliminary results of a recent survey of a Japanese chromate-produclng plant. The survey showed that in 136 workers who had been employed for at least 9 years there were 10 cases of lung cancer. The number of deaths from lung cancer was 21.2 times as high as the expected number of deaths. In the plants studied by Gross and Kolsch which produced lead chromate pigments and zinc chromate pigments from chromium(VI), a high incidence of lung cancer was also reported. Unfortunately, no information was provided on airborne concentrations of chromlum(VI) materials in these plants. Langard and Norseth found the incidence of lung cancer in a plant producing both lead chromate and zinc chromate pigments to be 38 times the expected Incidence. In a cohort of 24 workers, the 3 who developed lung cancer were exposed for 6, 7. In animal studies, inhalation of calcium chromate was found to produce 1 keratinizing squamous cell carcinoma, 1 laryngeal squamous cell # VI. WORK PRACTICES In the production and use of chromium(VI) materials, work practices must be designed to minimize or to prevent the inhalation of such materials and their contact with skin and eyes. Good work practices are a primary means of controlling certain exposures and will often supplement other control measures. Enclosure of materials, processes, and operations is completely effective as a control only when the integrity of the system is maintained. Such systems should be inspected frequently for leaks and any leaks found should be promptly repaired. Special attention should be given to the condition of seals and joints, access ports, and other such places. Similarly, points of wear or damage should be inspected regularly. Gloves, aprons, goggles, face shields, and other personal protective devices must be maintained in good hygienic and uncontaminated condition. They should be cleaned or replaced frequently and on a regular schedule. Employees should keep such equipment In suitable, designated containers or places when the equipment is not in use. Workers may reduce the potential exposures significantly by retiring to clean areas when their presence at the operation point is not necessary. A clean area may simply be a room or a space where sustained environmental levels are such that it can be considered as being without occupational exposure to chromium(VI). A clean area can be deliberately established by means of ventilation which provides either filtered air or air from an uncontaminated source in a manner and amount which maintains the environ mental level of chromium(VI) at a nonexposure level. In areas and at operation sites where the use of respiratory protection is required, the employee shall wear the designated type of respirator and observe the practices of the respiratory protective devices program. The necessity of cleanliness and maintenance of respirators should be emphasized. Practices which lead to the contamination of the interior of the facepiece should be prohibited. # Precision and Accuracy Ten filters spiked with 1.0 ng of chromium(VI) (a 0.01-ml droplet of 100 ppm chromium(VI) standard solution was placed on each filter and allowed to dry) gave recoveries of 93% with a relative standard deviation of 3.2% when analyzed within 1 hour of deposition; after 1 week, the average recovery dropped to 50%. Twenty-two filters, each loaded with about 5 n g of chromium(VI) in a chromic acid mist generator, gave results with a relative standard deviation of 4.3%. No corroborative tests have been performed on this method. Apparatus 22-mm round, matched cuvettes. Filtering apparatus. Spectrophotometer set to operate at 540 nm. # Reagents Water: Unless otherwise designated, all water used is double distilled or deionized. Half-normal sulfuric acid solution: Add 13.9 ml of concentrated sulfuric acid to some water in a 1-liter volumetric flask and dilute to mark. The exact concentration is not critical but it is suggested that the same solution be used for a complete test-samples, blanks, and standards. After thorough mixing, it is convenient to transfer part of the solution to a small plastic wash bottle. (3) With each batch of samples, 1 filter labeled as a blank should be submitted. This filter should be subjected to exactly the same handling as the samples except that no air is drawn through it. The samples should be shipped in a suitable container, designed to prevent damage in transit. (c) Analysis of samples (1) Pipet 15 ml of water into each cuvette to be used. Put a piece of tape on the cuvette so that its bottom edge matches the meniscus. Rinse the cuvetteB. (2) Blank filters are folded and placed directly into cuvettes. Sample filters are folded and placed in large test tubes. (3) Six or 7 ml of 0.5 K sulfuric acid is added to each tube and the tube is shaken to assure that all surfaces of the filter are washed. The filters are removed from the tubes with small forceps with careful washing of all surfaces with an additional 1 or 2 ml of 0.5 N sulfuric acid. The washed filters are discarded. The method is extremely simple, very selective for chromium(VI), and sensitive. The samples, when collected on PVC filters, are very stable. The recovery after 2 weeks is essentially the same as for the first day. Filters kept for 9 weeks gave an average recovery that was 79% of the first day's results. However, samples made by spiking PVC filters are not very stable and give poor recoveries. Spiked filters are therefore not recommended for standards. # X. APPENDIX III -MATERIAL SAFETY DATA SHEET The following items of Information which are applicable to a specific product or material shall be provided in the appropriate block of the Material Safety Data Sheet (MSDS). The product designation is Inserted in the block in the upper left Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, mild irritation and possibly some blistering. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. Respirators shall be specified as to type and NIOSH or US Bureau of Mines approval class, ie, "Supplied air," "Organic vapor canister," "Suitable for dusts not more toxic than lead," etc. Protective equipment must be specified as to type and materials of construction. # reliability, itaalyses by the method recommended in the chromic acid criteria document, which uses atomic absorption spectrophotometry, have been subsequently found by NIOSH to be much more time consuming than those using the s-diphenylcarbazide colorimetric method; thus, it appears that routine analysis would be simplified by a recommendation that the sdiphenylcarbazide colorimetric method be used for the determination of all chromium(VI) compounds, whether or not carcinogenic. Therefore, the recommended analytical chemical method is that described in Appendix II and it uses the spectrophotometric determination of a colored complex of chromium(VI) and s-diphenylcarbazide. Because of the carcinogenicity of some chromium(VI) materials and the lack of evidence suggesting a safe workplace environmental limit, it seems appropriate to recommend that no detectable amounts of these substances be allowed in workplace air with a specified method of sampling and chemical analysis. The recommended analytical method (v.s.) will reliably detect 0.5 jug chromium(VI). The lower detection limit is approximately 0.05 jig chromium(VI) by this method but detection and determination are not reliable at this limit because of (1) variations in the background concentrations of airborne and reagent substances that interfere with the determination of chromium(VI) at this trace level and (2) the Inherent unreliability of the calibration curve generated by determinations of known amounts of chromium below, at, and slightly above the detection limit. Because of this unreliability at this limit of detection and the resultant questions about the validity of compliance actions at airborne chromium(VI) Some part of the total, usually between 10,000 and 20,000 tons was added directly to steel. The balance was used to make ferroalloys and Cr metal. A small quantity, usually between 5,000 and 10,000 tons, was used in direct furnace repairs; the balance was used in making brick and other refractory products. Derived from reference 185 The projection includes allowance for losses during use of the ferroalloys in metallurgical processing and an additional 10% loss for processing chromite into ferroalloys. The average assay of ore for metallurgical uses is 50% Cr203; the average assay of ore for refractory use is 35% Cr203 and no processing loss is assumed; average assay of ore for chemicals and facing sand uses is 45% Cr203. Derived from reference 185	All shipping and storage containers for lithium chromate, lithium bichromate, sodium chromate, sodium bichromate, potassium chromate, potassium bichromate, rubidium chromate, rubidium bichromate, cesium chromate, cesium bichromate, and ammonium chromate, the hydrates of these compounds, high purity aqueous solutions of these compounds, and dry mixtures containing only these materials shall bear the same label except that "Inhalation may cause cancer" shall be deleted and "Extreme Health Hazard" shall be replaced by "Moderate Health Hazard". (c) Because of the flammable characteristics of ammonium bichromate (dichromate), shipping and storage containers for dry forms of this compound shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances: AMMONIUM BICHROMATE DANGER! HIGHLY FLAMMABLE MODERATE HEALTH HAZARD MAY CAUSE IRRITATION, RASH, OR EXTERNAL ULCERS. Keep away from heat, sparks, and open flame. Keep container closed. Avoid contact with skin and eyes. Avoid breathing dust or solution spray. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Call a physician. Flush skin with water. Wash clothing before reuse.Combination supplied air respirator, pressure-demand type, with auxiliary self-contained air supply.# I. RECOMMENDATIONS FOR A CHROMIUM(VI) STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chromium(VI), ie, hexavalent chromium or Cr(VI), in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and safety of workers for up to a 10-hour workday, 40-hour workweek over a working lifetime. Compliance with all sections of the standard should prevent all noncarcinogenic adverse effects of exposure to chromium(VI) In the workplace air and through skin exposure and should reduce materially the risk of lung cancer from occupational exposure to carcinogenic chromium(VI). The standard is measurable by techniques that are valid, reproducible, and available. Sufficient technology exists to permit compliance with the recommended standard. The standard will be subject to review and revision as necessary. For the purpose of this standard, "chromium(VI)" is defined as the chromium In all materials in the +6 (hexavalent) state. There are 2 recommended standards for chromium(VI). One addresses occupational exposure to a group of noncarcinogenic, but otherwise hazardous, materials, while the other pertains to occupations and workplaces where there is exposure to other chromium(VI) materials associated with an increased incidence of lung cancer. On the basis of the chemical analysis of airborne chromium(VI) materials, there is no practical means of distinguishing between these 2 groups of chromium(VI) materials. Until the airborne chromium(VI) in a particular workplace is demonstrated by the employer to be of the type considered to be noncarcinogenic, all airborne chromium(VI) shall be considered to comprise carcinogenic materials. Based . on current evidence, "noncarcinogenic chromium(VI)" is the chromium(VI) in monochromates and bichromates (dichromates) of hydrogen, lithium, sodium, potassium, rubidium, cesium, and ammonium, and chromium(VI) oxide (chromic acid anhydride). "Carcinogenic chromium(VI)" comprises any and all chromium(VI) materials not included in the noncarcinogenic group above. "Occupational exposure to carcinogenic chromium(VI)" is defined as exposure to airborne chromium(VI) at concentrations greater than one-half of the workplace environmental limit for carcinogenic chromium(VI). "Occupational exposure to noncarcinogenic chromium(VI)" is defined as exposure to airborne chromium(VI) at concentrations greater than one-half of the workplace environmental limit for noncarcinogenic chromium(VI). Exposure to chromium(VI) at concentrations less than one-half of the workplace environmental limit will not require adherence to the following sections, except for 3(a,b,c,d), 4a, 5, 6(b,c,e,f), and 7. Procedures for sampling and analysis of chromium(VI) in air shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. # Section 2 -Medical Medical surveillance shall be made available as outlined below for all workers with occupational exposure to carcinogenic or noncarcinogenic chromium(VI), including maintenance personnel periodically exposed during routine maintenance or emergency repair operations. (a) Preplacement and annual medical examinations shall include: (1) A comprehensive or interim work history. (2) A detailed medical history Including information on conditions Indicating the Inadvisability of further exposure to chromium(VI), eg, potential skin or pulmonary sensitization, a skin or mucous membrane condition that may be exacerbated by chromium(VI), smoking habits, and history of liver or kidney disease. (3) Examination of the skin for evidence of dermatitis or chrome ulcers, and of the membranes of the upper respiratory tract for irritation, bleeding, ulcerations, or perforations. (4) An evaluation of the worker's ability to use negative or positive pressure respirators. (5) Urinalysis. (b) For workers with occupational exposure to carcinogenic chromium(VI), preplacement and annual medical examinations shall include 14" X 17" chest X-rays. Other tests, including sputum cytology and liver function studies, shall be considered by the responsible physician. (c) For workers with occupational exposure to noncarcinogenic chromium(VI) and not to carcinogenic chromium(VI), preplacement medical examinations shall include 14" x 17" chest X-rays. Thereafter, X-ray examinations shall be offered at 5-year intervals and annually after age 40. Other tests, such as liver function studies, may be considered by the responsible physician. (d) Medical examinations shall be made available to all workers with signs or symptoms of skin or upper respiratory tract irritation likely to have been the result of exposure to chromium(VI). (e) If clinical evidence of adverse effects due to chromium(VI) is developed from these medical examinations, the worker shall be kept under a physician's care until the worker has completely recovered or maximal improvement has occurred. (f) Initial annual examinations for presently employed workers shall be offered within 6 months of the promulgation of a standard incorporating these recommendations. (g) The medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, and of the employer shall have access to all medical records. Physicians designated and authorized by any employee or former employee shall have access to that worker's medical records. (h) Medical records shall be maintained for all employees with occupational exposure to carcinogenic or noncarcinogenic chromium(VI) and for maintenance personnel with periodic exposure. Preplacement X-rays and X-rays for the 5 years preceding termination of employment and all medical records with pertinent supporting documents shall be retained at least 30 years after the individual's employment is terminated. All storage containers of chromic acid, or chromium(VI) oxide (chromic acid anhydride) shall bear the following label in addition to, or in combination with, labels required by other statutes, regulations, or ordinances. # CHROMIUM TRIOXIDE (CHROMIC ACID) DANGER! POWERFUL OXIDIZER CONTACT WITH OTHER MATERIAL MAY CAUSE FIRE MAY CAUSE DELAYED BURNS OR EXTERNAL ULCERS Keep container closed. Do not get in eyes, on skin, on clothing. Do not breathe dust or mist from solutions. In case of contact, immediately flush skin or eyes with plenty of water for at least 15 minutes. For eyes, get medical attention immediately. Wash clothing before reuse. Use fresh clothing daily. Take showers after work, using plenty of soap. # (e) In areas where there Is occupational exposure to carcinogenic chromium(VI), the following warning sign shall be posted in readily visible locations, particularly at the entrances to the area. # WARNING CANCER-SUSPECT AGENT USED IN THIS AREA UNAUTHORIZED PERSONS KEEP OUT The sign shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All The sign shall be posted in readily visible locations, particularly at the entrances to the area. The sign shall be printed both in English and in the predominant language of non-English-speaking workers, if any, unless they are otherwise trained and informed of the hazardous areas. All illiterate workers shall receive such training. (1) Coveralls or other full-body protective clothing shall be worn in areas where there is occupational exposure to chromium(VI). Protective clothing shall be changed at least daily at the end of the shift and more frequently if it should become grossly contaminated. (2) Impervious gloves, aprons, and footwear shall be worn at operations where solutions of chromium(VI) may contact the skin. Protective gloves shall be worn at operations where dry compounds of chromium(VI) are handled and may contact the skin. (3) Eye protection shall be provided by the employer and used by the employees where eye contact with chromium(VI) is likely. Selection, use, and maintenance of eye protective equipment shall be in accordance with the provisions of the American National Standard Practice for Occupational and Educational Eye and Face Protection, ANSI Z87. . Unless eye protection is afforded by a respirator hood or facepiece, protective goggles or a face shield shall be worn at operations where there is danger of contact of the eye with dry or wet compounds of chromium(VI) because of spills, splashes, or excessive dust or mists in the air. The employer shall ensure that all personal protective devices are inspected regularly and maintained in clean and satisfactory working condition. (5) Work clothing shall not be taken home by employees. The employer shall provide for maintenance and laundering of protective clothing. The employer shall ensure that precautions necessary to protect laundry personnel are taken when soiled protective clothing is laundered. (b) Respiratory Protection from Carcinogenic Chromium(VI) Engineering controls shall be used wherever feasible to maintain airborne carcinogenic and noncarcinogenic chromium(VI) concentrations below those recommended in Section 1 above. Compliance with the permissible exposure limits by the use of respirators is only allowed when airborne chromium(VI) concentrations are in excess of the workplace environmental limit because required engineering controls are being installed or tested, when nonroutine maintenance or repair is being accomplished, or during emergencies. When a respirator is thus permitted, it shall be selected and used in accordance with the following requirements: (1) For the purpose of determining the type of respirator to be used, the employer shall measure the airborne concentration of chromium(VI) in the workplace initially and thereafter whenever process, worksite, climate, or control changes occur which are likely to increase the airborne concentration of chromium(VI); this requirement does not apply when carcinogenic chromium(VI) is present. (2) The employer shall ensure that no worker is overexposed to chromium(VI) because of improper respirator selection, fit, use, or maintenance. ( The employer shall provide respirators in accordance with Table 1-1, or Table 1-2 when appropriate, and shall ensure that the employee uses the respirator provided. (5) Respirators described in Tables 1-1 and 1-2 shall be those approved under the provisions of 29 CFR 1910.134 and 30 CFR 11. The employer shall ensure that respirators are adequately cleaned, and that employees are instructed on the use of respirators assigned to them and on how to test for leakage. Where an emergency may develop which could result in employee injury from chromium(VI), the employer shall provide an escape device as listed in Table 1-1, or in Table 1-2 where appropriate. Instruction shall Include, as a minimum, all information in Appendix III which is applicable to the specific chromium(VI) product or material to which there is exposure. This information shall be posted in the work area and kept on file, readily accessible to the worker at all places of employment where chromium(VI) is involved in unit processes and operations. Evacuation or Escape (no concen tration limit) Half-mask respirator with replaceable high efficiency filter(s) or Type C supplied-air respirator, demand type (negative pressure), with half-mask facepiece Full facepiece respirator with replaceable high efficiency filter(s) or Type C supplied-air respirator, demand type (negative pressure), with full facepiece or Self-contained breathing apparatus in demand mode (negative pressure), with full facepiece Powered air-purifying (positive pressure) respirator with high efficiency filter(s) Self-contained breathing apparatus with positive pressure in full facepiece or Combination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply Self-contained breathing apparatus with positive pressure in full facepiece or Combination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure) or Gas mask, Type N, with high efficiency filter, and mouthpiece respirator with high efficiency filter(s) Note: A high efficiency filter is defined as a filter having an efficiency of at least 99.97% against 0.3 jum DOP(Dioctyl Phthalate) A continuing educational program shall be instituted to ensure that all workers have current knowledge of job hazards, proper maintenance procedures, and cleanup methods, and that they know how to use respiratory protective equipment and protective clothing correctly. (2) Clean protective clothing shall be put on before each work shift. (3) If, during the shift, the clothing becomes wetted with a solution, slurry, or paste of a chromium(VI) material, or grossly contaminated with a dry form of such material, it shall be removed promptly and placed in a special container for garments for decontamination or disposal. The employee shall wash the contaminated skin area thoroughly with soap and a copious amount of water. A complete shower is preferred after anything but limited, minor contact. Then, clean protective clothing shall be put on before resuming work. When working directly with chromium(VI) oxide, with unsealed containers of chromium(VI) oxide, or with chromium(VI) oxide in other than fully enclosed operations, protective devices and clothing shall be removed and the arms, hands, and face thoroughly washed after working with chromium(VI) oxide, and at 30-minute intervals when working with chromium(VI) oxide for extended periods of time. (4) Minor areas of skin (principally the hands) contaminated by contact with chromium(VI) shall be washed immediately and thoroughly with an abundance of water. Water shall be easily accessible in the work areas from low-pressure, free-running hose lines or showers. (5) If chromium(VI) comes into contact with the eyes, the eyes should be flushed with a large volume of low-pressure flowing water for at least 15 minutes. Medical attention shall be obtained without delay but not at the expense of thoroughly flushing the eyes. (c) Procedures for emergencies, including firefighting, shall be established to meet foreseeable events. Necessary emergency equipment, including appropriate respiratory protective devices, shall be kept in readily accessible locations. Only self-contained breathing apparatus with positive pressure in the faceplece shall be used in firefighting. Appropriate respirators shall be available for use during evacuation. (d) Special supervision and care shall be exercised to ensure that ■ the exposures of repair and maintenance personnel to chromium(VI) shall be within the limits prescribed by this standard. (e) Prompt cleaning of spills of chromium(VI) No dry sweeping shall be performed. Wet methods or dry vacuuming shall be used as appropriate. (2) Wet spills and flushing of wet or dry spills shall be channeled for appropriate treatment or collection for disposal. They shall not be channeled directly into the sanitary sewer system. (f) General requirements (1) Good practices of housekeeping shall be observed to prevent or minimize contamination of areas and equipment and to prevent build-up of such contamination. (2) Good personal hygiene practices shall be encouraged. (3) Equipment shall be kept in good repair and free of leaks. (4) Containers of dry chromium(VI) shall be kept covered insofar as is practical. Section 7 -Sanitation (a) Washing Facilities Emergency showers and eye-flushing fountains with adequate pressure of cool water shall be provided and be quickly accessible in areas where there is potential of skin or eye contact with chromium(VI). This equipment shall be frequently inspected and maintained in good working condition. Showers and washbasins shall be provided in the employees' locker areas. Employees exposed to chromium(VI) shall wash before eating or smoking during the work shift. (b) Food Facilities Food storage, preparation, and eating shall be prohibited in areas where chromium(VI) is handled, processed, or stored. Eating facilities provided for employees shall be located in nonexposure areas. Washing facilities should be accessible nearby. (c) Employees shall not smoke in areas where chromium(VI) is handled, processed, or stored. Appendix II; if samples can be demonstrated to contain only noncarcinogenic chromium(VI), other methods of chemical analysis equivalent to the method in Appendix II may be used. Records of these surveys, including the basis for concluding that there is no occupational exposure to chromium(VI) shall be maintained until a new survey is conducted. In workplaces where chromium(VI) is handled or processed, surveys shall be repeated annually and when any process change indicates a need for réévaluation. Requirements set forth below apply to areas in which there is occupational exposure to chromium(VI). Employers shall maintain records of workplace environmental exposures to chromium(VI) based upon the following sampling, analytical, and recording schedules: (a) In all monitoring, samples representative of the exposure in the breathing zone of employees shall be collected by personal samplers. (b) An adequate number of samples shall be taken in order to permit construction of TWA exposures for every operation or process. Except as otherwise determined by a professional industrial hygienist, the minimum number of representative TWA determinations for an operation or process shall be based on the number of workers exposed as provided in (c) The first determination of the workers' exposures to airborne chromium(VI) shall be completed within 6 months after the promulgation of a standard incorporating these recommendations. (d) A réévaluation of the exposures of workers to airborne chropium(VI) shall be made within 30 days after installation of a new process or process changes. (e) Samples of airborne chromium(VI) shall be collected and analyzed at least every 2 months for those work areas with occupational exposure to carcinogenic chromium(VI) and at least every 3 months if the airborne chromium(VI) is noncarcinogenic. (f) A réévaluation of the worker's exposures to airborne chromium(VI) shall be repeated at 1-week intervals when the airborne concentration has been found to exceed the recommended workplace environmental limit. In such cases, suitable controls shall be instituted and monitoring shall continue at 1-week intervals until 3 consecutive surveys indicate the adequacy of controls. (g) Records of all sampling and analysis of airborne chromium(VI) and of medical examinations shall be maintained for at least 30 [2] Silica is also found in the ore in varying amounts. [2] According to Bourne and Yee [3] the approximate analysis of chromite ores from Rhodesia and Transvaal is 48% chromium(III) oxide, 18% iron(III) oxide, 15% aluminum oxide, 3% silicon dioxide, and 12% magnesium oxide. In the United States, the 3 most common methods of producing chromium(VI) compounds are the high-lime, the low-lime, and the lime-free processes. [4,5] Each of these processes involves the roasting of chromite ore with soda ash and various amounts of lime with subsequent treatment to form sodium chromate. Other chromium(VI) compounds may be formed by a change of pH and the addition of other compounds. Solutions of chromium(VI) compounds thus formed may then be crystallized, purified, packaged, and sold. [7] Chromium(VI) has been found in glue, [8] cement, [9][10][11] detergents, [12] and other materials, including chromite ore. [ the fingers and on the glans penis. The finger lesion was in an area where there had been either a wound or an abrasion of the cuticle. Cumin described the effects of habitual application of bichromate solution to the skin as an eruption of papulae which become pustular and, upon prolonged exposure, develop deep sloughs under the pustules. The sloughs were described as peculiarly penetrating to the extent of producing in one instance a complete perforation of the muscular substance of the hand. Ducatel [17] in 1753 noted that ulceration of the skin could occur from the action of potassium bichromate. He also described a worker who accidentally drank some of it and vomited violently until his death 5 hours later. Delpech and Hillairet in 1869 [18] described the manufacture of potassium chromate and bichromate in Argenteuil, France, and the effects on workers which resulted from exposure to those chromium(VI) materials. In the process described, chromite ore was either roasted with potassium nitrate, thus producing potassium chromate, or with potassium sulfate and calcium carbonate, followed by treatment with sulfuric acid, to produce potassium bichromate. Seven cases were described in which all workers had perforated nasal septa and 3 also had skin ulcers. Their exposures were to both acidic and alkaline chromiun(VI) salts but not to chromic acid anhydride. In 1884 Mackenzie described [19] the toxic effects of potassium bichromate. He was told by a workman, who had been engaged in the factory for 15 years, that destruction of the nasal septum sometimes took place after 24^-48 hours of exposure to bichromate. It is likely that exposures were massive in the plant for at that time hand-rabbled reverberatory furnaces were used [6] with little or no forced ventilation or good work practices. DaCosta et al [20] in 1916 described in detail 19 of 44 cases of chrome ulcers in tanners and dyers. The most common sites of ulcers were the folds of the dorsal surface of the fingers over the knuckles, with other cases on palms, forearms, backs of hands, interdigital folds, sides of fingers, edges of finger nails, wrists, knees, and on other parts of the body, notably 1 near the groin and another on the foreskin of the penis. It was noted that the ulcerated area had been kept wet with chromate solution in practically all cases. Aside from describing the etiology of the ulcerations, the authors suggested preventive measures including various impervious coverings for the hands and wrists and a preventive ointment of lanolin and petrolatum; therapy consisted of soaking in hot lead water (diluted lead subacetate) and carbonate of soda. In 1925, Parkhurst [21] reported 3 cases of chrome dermatitis in workers in contact with blueprints that were fixed in a solution of potassium dichromate. One case was a 19-year-old woman who had been engaged in the production of blueprints for 6 weeks. The appearance of the lesion was that of crowded vesicles of pinpoint size on a diffusely erythematous and edematous background on the hands, wrists, and forearms. She showed a positive patch test with a 0.5% solution of potassium dichromate. The eruption subsided a few days after discontinuation of exposure. Frequent rinsing of hands with a solution of sodium bisulfite and then with water was suggested as a preventive measure to reduce hexavalent chromium to trivalent chromium. The other 2 cases treated by another physician were apparently similar. He prescribed treatment with a 1% solution of aluminum acetate, Lassar's paste, and calamine lotion. Bloomfield and Blum [22] in 1928 published a study of workers engaged in a chromium plating operation. Workers were exposed primarily to an acidic mist of chromium(VI), which the authors called chromic acid, emanating from plating tanks. Of the 23 workers examined in the operation, 20 had perforated or ulcerated nasal septa, inflamed mucosa, nosebleed, and cutaneous ulcers ("chrome holes"). In the same year, 12 cases of ulceration and signs of irritation of the respiratory tract from solutions of "chromic acid" were reported by Blair. [23] The workers suffered from coryza, sneezing, watery discharge from the eyes and nose, itching and burning of the nose, ulceration of the nasal mucosa, perforation of the nasal septum (chrome holes), and ulcerative lesions of the hands and fingers (chrome ulcers). In 1930 the Inspectorate of Factories in London issued a report [24] which dealt with the examination of 223 persons engaged in chromium-plating and an unspecified number of people engaged in anodic oxidation. Of the 223 chromium-plating workers, 95 (42.6%) had dermatitis, skin ulcers, or scars from old skin ulcers; 116 (52%) had perforated or ulcerated nasal septa or "devitalization of the mucous membrane." Times from onset of exposure to appearance of symptoms were as short as 2 weeks for ulceration of the nasal mucous membrane and 6-48 months for perforation of the nasal septum. Smith [25] in 1931 described a man who, upon admission to hospital, had ulceration of the skin of both hands, difficulty in breathing, and tenderness of muscles of extremities. Prior to hospitalization he was engaged in washing zinc plates with a solution of ammonium bichromate. Smith observed erythema of the forearms and hands, desquamation on areas of fingers and palms, vesicular lesions, and shallow ulcers on both hands and forearms. In addition, she noted 2 similar lesions on the abdomen. The diagnosis was chronic chrome poisoning with dermatitis venenata, acute nephritis, asthma, and acute myositis of the upper and lower extremities. The patient was patch-and intradermally-tested with solutions of ammonium bichromate followed by evidence of sensitization. Pfeil [26] in 1935 reported 2 cases of pulmonary carcinoma in men who worked in the chrome x industry in Germany. In 1911, a foreman in a large chromium manufacturing plant in Germany complaining about coughing and expectoration was examined by Pfeil. [26] The man's sputum had a reddish tinge. Costal pleurisy set in accompanied by a bloody exudate. The patient also suffered fractured ribs and was diagnosed as having a lung tumor. Post mortem examination confirmed his diagnosis of primary pulmonary carcinoma with metastases. In the next year, Pfeil treated a second patient for exudative costal pleurisy. This patient, who worked in the same chrome plant as the first, was found to have pulmonary carcinoma upon his death. The foreman was involved in a secondary process where he was apparently exposed to residues from quinone production which probably contained a complex mixture of chromium(III) and chromium(VI). The second man was said to work in the chrome industry but no further description was given. Five more men died from lung cancer in this same chrome plant before 1935. Of the cases of lung cancer and gastrointestinal cancer studied by Teleky, [27] some occurred among chrome workers. Teleky concluded from this that chromium is a lung carcinogen and might be a gastrointestinal carcinogen, but the data he presented do not support more than a suggestion of the relationships. In later years, many additional deaths from lung cancer occurred in the German chromate industry, [27][28][29][30][31][32] but it was not until 1948 [33] that an excessive incidence of lung cancer was reported among workers in the United States chromate industry. # Effects on Humans In a review, Mertz [34] summarized the occurrence of chromium in nature and its function in biologic systems. Later, Glinsmann and Mertz [35] studied the relationship between chromium(III) and glucose tolerance in humans by the oral administration of aqueous solutions of chromium(III) chloride. Six subjects with maturity onset diabetes (where the impairment in glucose tolerance did not appear to be related to a simple insulin deficiency but rather insulin effectiveness appeared to be reduced) were given 0.06-1 mg chromium(III) 3 times/day with meals for periods of 15-120 days. During this time, oral glucose tolerances were determined. Three of the 6 had improved tolerances while on chromium(III), compared to control periods. In 10 nondiabetic subjects with normal oral glucose tolerance, administration of 0.15-1 mg chromium(III)/day for 21 days resulted in no detectable alterations. The authors interpreted these results to suggest that chromium is required for optimum glucose use in man. Several studies have reported and reviewed concentrations of chromium in various biologic tissues and fluids. [5, [36][37][38][39][40][41][42] However, any interpretation of the amounts of chromium found in biologic samples should be accompanied by a close scrutiny of the analytical chemical methods employed. As new, more sensitive, and precise methods have been developed and used, authors have reported lower estimates of the quantities of chromium in certain biologic materials. [38,43] The National Academy of # Sciences-National Research Council Committee on Biologic Effects of Atmospheric Pollutants [44] reported a wide range of concentrations of chromium occurring in biologic samples from both unexposed and occupationally exposed populations. For this reason, it would be very difficult to interpret biologic concentrations of chromium as a measure of the absorption of chromium. Mancuso [41] reported that men exposed to airborne water-soluble chromium compounds excreted more chromium in the urine than those exposed to water-insoluble ones. He also noted elevated concentrations of chromium in the blood and urine for several years after exposure to chromiumcontaining materials. However, because of the wide disparity of "normal" and "exposed" blood and urine concentrations reported in the literature, any such correlations between exposure and biologic concentrations of chromium must be Interpreted with caution. were observed in half the workers in the brilliant-chrome industries. Duration of exposure was unstated, but it was mentioned that the harmful effects were noted in less than a year, and that few workers remained many years in the industry. Individual safety equipment was lacking in 26.6% of the plants; this may have been responsible for the high incidence of cutaneous ulcers. Zvaifler [63] and Gresh [64] published separate reports of an anodizing plant study. Zvaifler [63] noted that there was a distinct difference in the physiologic effects of chromium(VI) mists from plating tanks and the mists from anodizing tanks but he presented no data to support his conclusion. He mentioned that the chromium(VI) poisonings which resulted from exposure to mists emanated from anodizing tanks containing "5% chromic acid" generally involved ulceration of the nasal mucosa and skin rashes but rarely perforation of the septum. Gresh [ The investigation revealed that personal protective equipment was not worn and employees frequently wiped their faces and picked their noses with unwashed fingers or while wearing gloves. The authors thus concluded, probably correctly, that poor work practices were responsible to some degree for the nasal involvement. Determinations of pulmonary involvement were not reported in the study. In another study by NIOSH [65] of a different chromium plating plant, a maximum airborne chromium(VI) concentration of 3 Mg/cu m was found. In this operation, the plating solution contained approximately 210 g chromium(VI) oxide/liter. No ulcerated nasal mucosae or perforated nasal septa were found, although half of the 32 employees had varying degrees of mucosal irritation. This incidence of mucosal irritation was not thought to be significant by the investigators because the survey was carried out at the peak of the 1972-73 influenza epidemic. Fifteen workers had been employed 8 years or more, 7 between 4 and 8 years, 4 between 1 and 4 years, and 6 less than 1 year. Although he did not report airborne concentrations of chromium(VI), Meyers [67] in 1950 observed 2 patients who had inhaled chromic acid mists, for only a few hours one day. One man developed a cough, severe frontal headaches, pulmonary congestion and edema, dyspnea, and persisting sub8temal pain. The other developed hoarseness and a cough productive of green mucoid sputum. Five months after exposure, the X-ray examination showed some emphysematous changes and a small pleural effusion. Pascale et al [68] in 1952 reported 5 persons with hepatic injury apparently due to exposure to chromic acid mist from plating baths. One who had been employed 5 years at a chromium plating factory was hospitalized with jaundice and was found to be excreting significant amounts of chromium. Her lungs and cardiovascular system were normal. A liver biopsy showed microscopic changes resembling those found in toxic hepatitis. To Investigate the possibility that the liver damage was of occupational origin, 8 fellow workers were screened for urinary chromium excretion. Four of these were found to be excreting significant amounts and were examined in more detail. In 3 workers who had been exposed to chromic acid mists for 1 to A years, liver biopsies and a series of 12 hepatic tests showed mild to moderate abnormalities. No liver biopsy was taken from the fifth worker, who had been removed from further exposure because of nasal ulceration after 6 months at the plating bath. Only 1 of his liver function tests indicated a borderline abnormality. The urinary excretion of chromium (2.8 and 2.9 mg/24 hours) by the 2 workers employed 4 years was greater than the excretion (1.48 mg/24 hours) by the worker employed 5 years who suffered the greatest liver damage. The lowest urinary chromium excretion (0.184 mg/24 hours) was measured in the fifth worker, the individual with least exposure. All 5 exhibited some signs of damage to the nasal mucosa. This plus the concentrations of urinary chromium suggests that exposures to chromium(VI) were significant, but no environmental data were reported. Several authors [5,18,19,33,41,62] have dealt with exposures to chromium(VI) materials, exclusive of chromic acid anhydride and aqueous solutions thereof (known as "chromic acid"). In the chromate-producing industry in the United States, only a small part of which produced chromic acid anhydride, the principal exposures to chromium(VI) were probably to sodium chromate and bichromate. To a lesser degree, exposure to potassium chromate and bichromate was also present. In 1884 Mackenzie [19] described the toxic effects of potassium bichromate. He related having been told by a workman, who had been engaged in the factory for 15 years, that destruction of the nasal septum sometimes took place after 24-48 hours of exposure. From his own experience, Mackenzie observed that this destruction was preceded by general congestion of the mucous membrane, nosebleed, and coryza. The turbinates, nasal pharynx, and lower pharynx were also ulcerated. What he described as the lower respiratory tract (probably the lower part of the upper respiratory tract) was generally found to be highly inflamed and swollen. Accompanying the catarrhal symptoms, there were sometimes intense headache, inflammation and perforation of the tympanic membranes and subsequent otorrhea. At that time hand-rabbled reverberatory furnaces were used [6] and since there was little or no forced ventilation or good work practices, it is probable that exposure levels were high. Much later, in 1948, Machle and Gregorius [33] described the incidence of nasal irritation and septal perforation in a chromateproducing plant that manufactured sodium chromate and bichromate. The incidence of nasal septal perforation was 43.5% in 354 employees. Airborne chromate concentrations were determined to range from 10 to 2,800 jug/cu m at the time of the study, but the plant has been in operation for at least 17 years. Some employees had probably worked in the plant when reverberatory furnaces were used, a notorious source of high exposure. In the early fifties, an epidemiologic study as reported by Bourne and Yee [3] and by Mancuso [41] The incidence of these signs, as was the incidence of ear disorders such as discharge, impaired hearing, and tinnitus, was more than twice that found in nonchromate-worker control groups. Liver enlargement was noted in 14 chromate workers. Those with enlarged livers were at least 15 years older and had worked an average of 4 years longer in the chromate industry than those without enlarged livers, but the number in the group was too small to allow a statistical comparison with a group not exposed to chromate. Those with cutaneous ulcers or scars of ulcers numbered 451. Most of the active ulcers had occurred within the 6 months prior to the study. Lung cancers were also found in this group and will be discussed later. Urinalysis revealed white and red blood cells and casts with greater frequency than is usually observed in the average industrial population. Casts in urine were found in a greater percentage of workers who had worked 10 years or more than in those who had worked less than 10 years. Frequency of white blood cells in urine of chromate workers showed an increase with years of exposure. The number of red blood cells in urine did not change appreciably with years of chromate exposure. As a result of dental examinations of 561 workers, incidences of keratosis of the lips, gingiva, and palate; yellow-stained teeth and tongue; and periodontitis were greater than twice the incidences in a control population of 124. The observed signs of excessive exposure to chromium(VI)-nasal mucosal irritation and ulceration and to a lesser extent nasal septal perforation-were likely, in the acute or subacute nature of the lesions, to be closely related to airborne chromium(VI) at the average concentration measured at the time of the study-68 ng/cu m. There is reason to suspect that liver and kidney damage occurred, based on observations of enlarged livers and casts in urine, as a result of long-term exposure to chromium(VI) , but the results were not conclusive. Numerous cases of allergic dermatitis with varying degrees of eczema have been reported. [7][8][9][10][11]21,25,61,62,[69][70][71][72][73][74][75][76][77][78][79][80][81] Parkhurst [21] in 1925 reported the case of a woman employed in blueprint production using a process where a 1% potassium dichromate solution was used as a fixative. He rubbed a 0.5% potassium dichromate solution on the right thigh of the woman and soon there was a local sensation of itching and burning. Twelve hdurs later, the patient developed a follicular erythematopapular dermatitis where the solution had been applied. A similar application was made to the left thigh with resulting itching and burning. However, the application of an aqueous saturated solution of bisulfite prevented the development of a dermatitis in this area. In 1931, Smith [25] observed a case of chrome poisoning with manifes tations of sensitization in a man employed in a photographic printing firm, where his duties involved handling and washing sheets of zinc treated with a solution of ammonium dichromate, and occasionally preparing the solution. The man developed a mild erythema 24 hours following a patch test with 1% ammonium dichromate solution on a 1-sq cm area of normal skin on his forearm. After 3 days the erythematous area had doubled in size and had developed vesicles. Eight days later, an intradermal injection of 0.1 cc of a 0.5% aqueous solution of ammonium bichromate was given in the right forearm. Within an hour the patient developed a generalized pruritus with soreness at the site of the injection. Within 6 hours he had (1) a slight erythema at the site of a previously negative patch test, (2) an erythematous area 5 cm x 3 cm with tenderness at the injection site, (3) a localized patch of maculopapules on the area in which the patch test had been 9 days earlier, (4) a vesicular erythematous dermatitis covering the entire hands and lower parts of the forearms, (5) generalized mild erythema with a few urticarial wheals on the buttocks, and (6) a recurrence of the diaphoresis and sibilant rales he had had some 15 days earlier, upon admission to the hospital. The man recovered after his exposure to chromium(VI) ceased. Three control subjects were similarly injected and showed no reaction. Hall [70] in 1944 reported 132 dermatitis cases in aircraft workers who had contact with a primer consisting of a suspension of zinc chromate powder and magnesium silicate in a xylene solution of certain resins, including a phenol-formaldehyde resin. Apparently, the mean duration of employment was 7 months (range: 1 week-9 years) for those who had dermatitis from the primer and who were allergic to zinc chromate pigment. A series of patch tests showed 90 of the workers (68%) were sensitive to the zinc chromate pigment only. (The zinc chromate pigment was apparently a mixture of zinc chromate and calcium carbonate.) In 1949, Pirila and Kilpio [71] reported 45 cases of allergic contact dermatitis observed in the Helsinki area from 1945-48. Forty-one reacted positively to patch-testing with a 0.5% aqueous solution of potassium dichromate (pH 4.15). The breakdown of cases by occupation was as follows: bookworkers, 11; cement and lime workers, 10; radio factory workers using a photostatic procedure, 7; metal factory workers, 4; painters and polishers, 4; fur workers, 3; others, 6. In 1952, Gngebrigtsen [10] reported 8 cases of cement eczema among 300-400 Norwegian workers exposed "more or less directly" to cement dust that contained 0.002-0.020% water-soluble chromium(VI) described only as He did not react to distilled water. The control subjects did not react to any of these 3 chromium(VI) solutions. In 1960, Calnan [9] showed that British cement contained from nondetectable amounts to 12 ppm chromium(VI), expressed as potassium bichromate. He concluded that cement dermatitis was primary irritant dermatitis complicated by a secondary contact sensitivity to "hexavalent chromate" [chromium(VI)]. Winston and Walsh [73] reported that 6 out of 200 employees were incapacitated by chromate dermatitis in a diesel locomotive repair shop. One of the 6 cases was described; the dermatitis consisted of patchy, pruritic, erythematous, slightly scaly lesions extending from the dorsum of the hands over both forearms to the elbows. All were exposed to an alkaline diesel locomotive radiator fluid which was prepared from sodium dichromate, soda ash, disodium phosphate, and sodium silicate. One and one-half pounds of this powdered mixture, which contained 66% sodium dichromate, was dissolved in 2 gallons of water in an open pail. This solution (approximately 6% sodium dichromate) was poured into the radiator and diluted with about 210 gallons of water, giving a solution of about 0.08% sodium dichromate. All of the men gave positive reactions to 0.25% sodium dichromate (pH 4.25) patch tests and to samples of the radiator fluid (pH 10). Walsh [62] in a summary report on chromate hazards in industry described results of some patch tests: 2% "chromic acid" applied for 24 hours on superficial skin abrasions produced a crusted lesion in 3 weeks; 0.5% sodium dichromate, reapplied daily for 3 days, produced a crusted lesion in 3 weeks; 0.5% potassium chromate, applied for 8 hours/day for 3 days, produced lesions in 3 days; 0.05% sodium dichromate, 0.005% sodium dichromate, and pure zinc chromate also produced lesions in 3 days after being in contact with the skin for 8 hours/day for 3 days. Lead chromate did not produce a reaction after the same exposure period. A 10% solution of chromium(III) nitrate produced redness after the solution was reapplied daily for 3 days. Edmundson [61] patch-tested 56 men who had chrome ulcers with 0.5% potassium bichromate for 24 hours. Only 2 yielded positive reactions and they were said to have a history of chrome dermatitis. He interpreted his results to indicate that when chrome produces ulcers it does not sensitize workers. Morris [8] in 1955 reported 2 cases of sensitization to chrome glue prepared at least in part from scraps of chrome tanned leather. Both patients gave positive reactions to the otherwise undescribed chromebearing parent material to which they were exposed, and both were allergic to chrome-dyed leather shoes. From the nature of the tanning process it seems probable that the substance causing the sensitivity was chromium(III). One of these patients reacted positively to a 0.1% solution of sodium bichromate. McCord et al [7] described in detail the lithography process, as it existed in 1930, which used an extremely acidic solution of chromium(VI). Twenty-five lithographers and 12 tanning workers who had been exposed to chromium, but showed no signs of dermatitis, were selected for study. Each reactions. This report was apparently the first to note that injury from chromium(VI) could occur without previous skin trauma or disease. Levin et al, [74] from similar studies conducted in the late 1950's, confirmed that chromium(VI) was the primary causative agent in lithographer's dermatitis. However, they found that trauma and the use of various other chemicals associated with lithography such as fat solvents and primary irritants made workers' skin more prone to irritation by the chromium(VI)-bearing materials. In 1961, Fregert [69] described the manufacture of matches and demonstrated that match heads which contained chromium(VI) could partially dissolve when held in moist fingers and could cause an allergic eczematous contact dermatitis. The source of chromlum(VI) was probably an ingredient of the manufacture since potassium dichromate is usually added both to the igniting composition and to the striking composition. The author was, however, unable to find chromium(VI) in the striking composition, probably because it had been reduced to chromium(III). Although this study was done in Sweden, he attalyzed matches from 21 countries and found concentrations as high as 1.7% water-leachable chromium(VI) expressed as potassium dichromate in unburnt matches and 1-10% of the original chromium(VI) concentration in the burnt matches. He stated that every patient in a group of 33 who had chromate eczema reacted positively to either unburnt or burnt match heads. In 1963 2 separate studies [75,76] of dermatitis resulting from chromium(VI) used in the automobile industry were published. Engel and Calnan [75] investigated an outbreak of dermatitis in the British automobile industry among workers who were engaged in the wet sanding of primer paint containing zinc chromate. Almost all (91%) of them had positive reactions to a 0.5% solution of potassium dichromate (pH 4.15); however, a few did not react until the solution was made alkaline (pH 10.3) Newhouse [76] found dermatitis in automobile assemblers from handling a chromate dip used as an antirust agent on bolts, nuts, screws, and washers. About one-quarter of these responded positively to potassium dichromate patch-testing. Fregert and Ovrum [77] in 1963 reported a case of a welder who contracted a facial dermatitis after inhalation of and contact with welding fumes from either arc welding or oxygas welding. Subsequent investigation demonstrated that the chromium in certain welding rods could be oxidized to chromium(VI) and that chromium(VI) was dispersed into the air in the vicinity of the weld. The authors patch-tested 5 people who were hypersensitive to chromate with an aqueous solution of collected welding fumes calculated to be 0.1% chromium(VI) (as potassium dichromate). All gave positive reactions. The authors elicited no response from 10 subjects not hypersensitive to chromate. Their analyses of various commercial welding rods showed chromium contents up to 18%. A year later, Shelley [78] reported a similar case. A crane operator provided a history of chronic eczematous eruptions of both hands. Twentyeight compounds were patch-tested and the only positive reaction was to an aqueous 0.25% solution of potassium dichromate (pH 4.28). Two and one-half months later, the man walked by an acetylene-welding operation where the fumes were strong and experienced appreciable inhalation of the fumes. On the next day he reported a rapidly developing vesicular flare on his hands. The dermatitis subsided after he avoided further contact with chromiumcontaining objects and welding fumes. Jaeger and Pelloni [11] in France demonstrated that workers with Goldman and Karotkin [83] in 1935 reported a case of acute exposure involving a ■25-year-old woman who had swallowed an aqueous solution containing a heaping teaspoonful of potassium dichromate crystals. Shortly thereafter she had a paroxysm of vomiting. Two days later she was hospitalized. At this time she had severe nephritis and severe hepatitis, an erythematous skin eruption, and a "positive" chromium test in urine. The skin rash began to fade 13 days after the initial reaction and disappeared after 5 more days; she recovered from hepatitis and nephritis in 3 months. Major [84] reported the development of severe nephritis in a patient the day after chromium(VI) oxide was applied to a wound as a cauterant; the man died 19 days later. Vigliani and Zurlo [85] studied over a 3-year period approximately 150 workers in a plant producing alkali chromates; during this time the airborne chromium(VI) concentration range was 57-78 ng/cu m. Ulceration of the nasal septum, inflammation of the conjunctiva and laryngeal mucosa, and chronic asthmatic bronchitis were the most commonly seen disturbances, but their frequency was not mentioned. One case of nasal septal cancer and 1 of lung cancer were also observed. No data regarding sampling locations, sampling techniques, or analytical methods were presented. Unequivocal evidence relating a specific chromium(VI) compound to the development of lung cancer in humans has not been developed. There is, however, epidemiologic evidence in workers and experimental evidence in animals that suggests carcinogenic properties of some chromium(VI)-containing materials. This evidence is discussed in the following 2 sections. # Epidemiologic Studies The first extensive epidemiologic studies involving exposure to chromium(VI)-containing materials and the risk of lung cancer were performed in Germany by Lehmann. [86] He found only 2 cancer cases and dismissed them as nonoccupatlonal in nature but the reasons for this conclusion seem to be faulty in view of current knowledge. Lehmann gave no information on the extent of exposure to chromium(VI). Later German reports, reviewed by Baetjer [87] One of the studies referred to by Baetjer is of particular interest. Because the authors apparently determined that the pancreas was the primary site adenocarcinoma, and as there have been no other reports of chromium(VI) causing cancer of the pancreas, it seems improbable that chromium(VI) was the causative agent. In addition to the cancer cases in the cohort, 1 man developed an adenocarcinoma of the prostate after an unmentioned exposure period and another, a 33-year-old man, was diagnosed as having an adenoid cystic carcinoma of the inferior nasal turbinate after working in the plant for 3 months. The plants in which these men worked were not designated. In light of the short, less than 3-year, period of employment of the worker who developed prostate cancer and the lack of any other report linking exposure to chromium(VI) and prostate cancer, it is unlikely that chromium(VI) was responsible. Because the worker who developed a carcinoma of the nasal turbinate was exposed for only 3 months, an extremely potent carcinogen must have been present. Other reports [87,88] do not suggest that chromium(VI) is capable of producing cancer in such a short time. The authors calculated the risk of getting lung cancer for each worker separately for each calendar year of the observation period. This was accomplished by using the age-specific incidence rates of cancer supplied to them by the Cancer Registry of Norway. The total risk for the population of workers was then obtained by adding the risks for each worker for each year of the observation period. The expected number of cases of cancer obtained by this method was then compared to the observed number in the group. The expected number of lung cancer cases in the cohort was calculated to be 0.079 for the total period of observation. Since 3 cases were found, the observed/expected ratio was 38. The total number of manyears at risk of the cohort was 244. There were several shortcomings in the Machle and Gregorius study. The authors differentiated exposure to 2 categories of chromium compounds, ie, soluble and insoluble, but did not differentiate between chromium(III) and chromium(VI). Chromium(III) and chromium(VI) materials leachable by water were classified as the soluble group. [92] The insoluble group of compounds included all those not leached by the repeated treatment with water. This group probably included primarily chromite ore, based on the degrees of water-solubillty of the compounds which were probably present. Thus, although the authors did not determine chromium (III) and chromium(VI) directly, it appears that "insoluble" compounds were predominately chromium(III) and "soluble" compounds were predominately chromium(VI). Chromium(VI) of only slight water solubility was not determined in this study, but based on the analytical procedure used [92] part of it was likely found in the soluble group and part in the insoluble group. The pH's of airborne samples were 6.7-9.4, indicating that most samples included both chromates and dichromates. All samples germane to the chromate-plant study were apparently taken by air filtration using the apparatus mentioned by Bourne and Streett. [93] Collection efficiencies for chromium(VI) oxide as a mist using this apparatus were determined at 0.07 mg/cu m, 0.14 mg/cu m, and 0.22 mg/cu m to be 93.6%, 98.3%, and 92.5%, respectively, for 15-minute samples at a flow rate of 28.3 liters/min. Collection efficiencies for dust were determined at 4.62 mg/cu m and 25 mg/cu m to be 99.0% and 99.9%, respectively. Mists used in the collection efficiency test were generated using an apparatus, described by Silverman and Ege, [96] which nebulized into the air stream an aqueous solution of chromium(VI) oxide (25%) and sulfuric acid (0.125%). The dusts were generated in the same equipment except that the nebulizer was replaced with a vibrating vessel into which dust was introduced. The size distribution of the particles in the mist in the chromate plant was: 15.87% less than 1.5 pm, 50% less than 3.8 jum, and 84.13% less than 9.8 /an. In the dust the distribution was 15.87% less than 0.8 fm, 50% less than 1.7 /xm, and 84.13% less than 3.7 im. Mancuso and Hueper [90] investigated the incidence of cancer in this chromate plant. Using the results of analyses of air samples for soluble and insoluble chromium, they calculated the possible exposures of 7 men who died from lung cancer between 1938 and 1950. Although none of the 7 were working in the plant when the sampling and analysis were performed, the calculated TWA exposures could have had some relationship to their actual exposures. The years of first exposure in the chrome plant for the 7 were 1931-41. Changes in the concentrations of chromium in airborne dusts and mists could have occurred during the years of exposure of these men to decrease the relevance of determinations of TWA exposures made at the time of this study. The scope of such changes is very difficult to evaluate. The airborne concentrations of chromium leachable by water determined by Mancuso and Hueper [90] to which the 7 were exposed were 0.01-0.15 mg/cu m (Table XI-5). These concentrations were apparently calculated timeweighted average concentrations taking into account the various jobs the men accomplished during the average day. The men were also exposed to chromium not leachable by water, in addition, at airborne concentrations of 0.1-0,58 mg/cu m. Because of the lack of specificity in the analytical method used [92], the airborne concentration of the only slightly watersoluble chromium(VI) is inestimable. In another paper, Mancuso [41] reported the incidences of other effects found in the epidemiologic study. Although the various groups were defined by total chrome exposure and ratio of insoluble to soluble chrome, the actual maximum ranges of concentrations of chromium, either leachable or not leachable by water, have been calculated from their data and appear in In 1959 Baetjer et al [97] reported the determination of chromium in the lungs of 16 decedents who had been employed in old chromate plants. Eleven of the men who had been employed for 2-42 years had lung cancer; 5 of the men employed 1.5-19 years did not. The results of analyses by the method presented in an appendix to their report [97] were both highly variable and inconclusive, that is, there was no significant correlation between the presence of lung cancer and chromium in lung tissue. The US Public Health Service published in 1953 a report [5] of an extensive study of the health of 897 workers in the chromate-producing industry. Morbidity and mortality data were based upon paid death claims and cases of sickness and nonindustrial injuries disabling for 8 calendar days or longer among the members of the sick benefit plans of the plants. From 1940 to 1948, there were 28.9 times as many deaths from respiratory cancer among males in the study as would have been expected on the basis of the average death rate for the United States for the period 1940-48 inclusive, excluding violent, accidental deaths. Medical examinations were performed on about 96% (897 males) of the total work force of the 6 study plants. Ten workers were considered to have bronchogenic carcinoma, a rate for chromate workers of more than 50 times the rate for the general population. Three of these men were known to have had lung cancer prior to the survey. These 10 men, who averaged 54.5 years of age, had a mean duration of exposure of 22.8 years (Table XI- 7). This represents a very high lung cancer incidence. Five hundred nine (56.7%) had perforation of the nasal septum. The incidence of perforation of the nasal septum was stated to have no relation to either years of exposure or to the incidence of lung cancer. Studies relating exposure to chromium compounds and incidence of dental caries indicated a low degree of correlation, but there was an increased incidence of gingivitis and periodontitis. X-ray examinations showed no significant fibrosis, but bilateral hilar enlargements were noted. There was no significant correlation between duration of exposure and heart disease. Other positive correlations mentioned were an increased frequency of white blood cells and casts in the urine and a decreased sedimentation rate of erythrocytes, all of which were related to years of exposure. Blacks appeared to be more severely affected, in general, than whites, perhaps due to a greater exposure among blacks. This study also involved an extensive sampling program in which over 1,800 samples of air contaminants, settled dust, and process material were collected and analyzed. The report stated that the dry-end processes, ie, milling, roasting, and leaching, generated dusts containing principally lime, chromite ore, soda ash, roast residue, and sodium chromate. Sodium dichromate and sodium sulfate were usually associated with the wet-end operations of neutralizing, treating, and concentrating. In 1952, Brinton et al [98] published a study of the morbidity and mortality in the chromate workers of another study. [5] They demonstrated a greater rate of sickness and nonindustrial injury in chromate workers as compared to a large industrial group. This difference was due to the 10fold increase in the incidence of cancer in chromate workers, largely because of respiratory cancer, which was increased 14-fold for whites and 80-fold for nonwhites. In 1966 Taylor reported a study [99] Chromium(VI) concentrations were less than 1 up to 25 mg/cu m. The author observed either diffuse thickening or rupture of alveolar walls and proliferation of cellular elements along the blood vessels and bronchi. Desquamation of the bronchial epithelium was also found. No tumors were found, but the maximum exposure was only 8 months. In 1930, Hunter and Roberts [105] injected subcutaneously Macacus rhesus monkeys with various amounts of an aqueous 2% solution of potassium bichromate. One monkey given 36.3 cc of the solution (0.02 g/kg) and another given 10 cc were dead 12 hours later. Evidence of acute lesionswas present in the kidneys of both animals. Four other monkeys were given repeated, 1-5 cc doses of the solution at 3-to 7-week intervals. In 2 of these, acute lesions were also found in the kidneys. The other 2 animals lived longer, for about 160 days, and sustained chronic renal damage; in 1, practically all the original epithelium of both proximal and distal convoluted tubules was destroyed. The authors further remarked that the regeneration of tubular epithelium was of distinctly atypical morphology and that the tissue was apparently resistant to further injury by bichromate. In 1940 Shimkin and Leiter [106] reported the intravenous injection of various materials into tumor-susceptible strain A mice. Single, 5-mg injections of chromite ore did not result in an increased incidence of In another series, 12.5 mg of calcium chromate in gelatin capsules was implanted intramuscularly and intrapleurally in rats. After 7 months, of the 6 rats with intramuscular implants, 2 developed tumors; of the 6 rats with intrapleural implants, 3 developed tumors. The latter experiment, despite its lack of a control group, appears to verify that the chromium(VI) compounds and not the sheep fat were the causative agents for the tumors observed. Payne [110] fractionated and analyzed the residue from the first leaching of roasted chromite ore, and tested the material in animals. This In a further study, Hueper and Payne [111] gave rats monthly intrapleural and intramuscular injections of sodium dichromate in gelatin. Each injection consisted of 2 mg of sodium dichromate dissolved in 0.05 ml of a 10% gelatin solution. A total of 16 injections were given. Survivors were sacrificed at the end of a 24-month observation period. Various tumors were seen. Of the 20 male and 19 female rats in each series receiving intrapleural injections, 3 developed malignant tumors, 1 of which was at the site of injection. Rats receiving intramuscular injections developed 4 benign and 2 malignant tumors, none at the site of injection. The 4 tumors which were not at the injection sites were of a type found in a similar incidence in control animals. Four benign and 12 malignant tumors, none at the site of injection, were observed in the control group. Because of the greater incidence of malignant tumors in control animals, it is impossible to conclude that sodium dichromate was responsible for any malignancies. In another experiment, [111] In 1968 and 1969 Laskin et al [13] reported a study of selected chromium compounds in a cholesterol carrier using a new intrabronchial implantation technique. The pellets used were in the form of a cylindrical matrix of stainless steel mesh and about 1 mm in diameter and 5 mm in length. They were implanted in the bronchus and held in place by a trochar fitted with spring-wire hooks and introduced through a tracheotomy. One of 100 rats implanted with process residue developed a squamous cell carcinoma at the site after 594 days. No other compounds produced tumors at the site of implantation, although among the 100 rats in each group hepatocell carcinomas were observed in 1 rat given process residue, in 1 rat given chromium(III) chromate, and in 2 rats given chromium(VI) oxide. Five of 24 control rats developed squamous metaplasia and, in addition, 1 developed a sarcoma. Of the tumors seen, all were invasive and some had metastasized. In all experimental groups except the 1 exposed to chromium(VI) oxide, there was evidence of atypical squamous metaplasia of the bronchus. Since these studies implicated calcium chromate as a lung carcinogen, inhalation studies using this compound were begun. [118] Early rangefinding studies [119] with calcium chromate resulted in rapid and significant mortality at both 10 and 20 mg/cu m (2.7 and 5.4 mg chromium(VI)/cu m, respectively) in both rats and hamsters. Results [118] reported in 1972 suggested a carcinogenic action in rats and possibly in hamsters after chronic exposure to calcium chromate aerosols at 2.0 mg/cu tn (0.67 mg chromium(VI)/cu m ) . After 589 exposures over 891 days, 4 carcinomas were observed. Of the original 100 rats, 1 keratinizing squamous cell carcinoma of the lung, 1 laryngeal squamous cell carcinoma with invasion of perineural spaces and adjoining cartilaginous rings, and 1 malignant peritruncal tumor of undetermined type and origin were observed. One squamous cell carcinoma of the larynx was found among the original 100 hamsters. In addition, a number of mucosal changes were noted. [118] In rats, 2 animals showed laryngeal hyperplasia and 3 showed laryngeal squamous metaplasia. Effects in hamsters were more marked with 8 animals showing laryngeal hyperplasia. Eight additional animals showed squamous metaplasia of which 5 were atypical with downgrowth. Another hamster, dying at 611 days, showed a squamous papilloma in the larynx with hyperplasia and hyperkeratosis. [118] Nettesheim et al [120] exposed 136 female mice and 136 male mice, all germ-free derived and specific-pathogen-free C57BL/6, to 1 jun diameter calcium chromate aerosol at a concentration of 13 mg/cu m. He also exposed 545 mice of the same type to PR8 influenza virus prior to the calcium chromate exposure. Two control groups of the same size and composition breathing filtered air were used and only 1 was infected with the virus. In all, 21 pulmonary adenomas were obaerved in the 2 exposed groups and only 5 in the uninfected controls. No tumors were found in the infected controls. No bronchogenic tumors were found. The authors determined that there was a significantly larger (P<0.0077) incidence of lung tumors in mice exposed to calcium chromate, compared to controls. Prior exposure to 100 roentgens of whole-body X-radiation in another series of mice did not affect tumor incidence, but prior PR8 influenza infection appeared to reduce the incidence of tumors from calcium chromate. The authors [120] also gave 15 weekly intratracheal injections of calcium chromate to 2 groups of hamsters. Hamsters in 1 group received 0.5 mg/week, the hamsters in the other group received 0.1 mg/week. The lesions produced were similar to those observed in the mice, but scarring of the lung parenchyma was more widespread and adenomatosis was regularly observed. Hamsters also had frank bullous emphysema and extensive goblet cell hyperplasia in all parts of the tracheobronchial tree. In a study by Zekeev et al [121] in 1973, the blastomogenic and toxic effects of chromium(III) oxide, ammonium bichromate, sodium bichromate, chromium ores, and dolomite were observed in rats. Some rats were preliminarily treated with "non-carcinogenic" doses of 3,4-benzpyrene. Positive control groups received 3-methylcholanthrene. Lungs of all rats either dying during the study or killed at its termination were examined both macroscopically and microscopically. Apart from those in the lung, tumors were similar both in type and number in all groups. The bronchial tumors found and microscopically confirmed are given in Table III [19] and discoloration of the teeth. [5] Although it is apparent that any chromium(VI) materials may cause the less severe effects if they are present in aqueous solution in sufficient concentrations, the specific materials which were responsible for lung cancer have not been identified. To some extent the toxicities of chromium(VI) materials vary with their solubilities, but denotation of compounds on the basis of solubility alone has not been sufficiently precise to suggest a dichotomy of toxic effects, where high incidences of ulceration and perforation occurred, there were 37 employees. Twelve of the 21 workers employed 1 year or less and 15 of the 16 workers employed more than 1 year had ulceration and crusting of septal mucosa, avascular scarified areas of septal mucosa without erosion or ulceration, or perforation of the nasal septum. In the plant in Finland, [60] the incidence of signs and symptoms of chromium(VI) poisoning is impossible to establish because insufficient information was provided. However, it is apparent that most persons with signs and symptoms had been employed for 1-5 years, during which time the working conditions were less hygienic than those in effect at the time of the study. The third plant [65] with 32 employees provided great contrast with the other 2. [57, 58,60] In this plant [65] no ulceration or perforation occurred, despite the fact that the workers had been employed for a much longer period of time-15 were employed 8 years or more; 7, between 4 and 8 years; 4, between 1 and 4 years; and only 6, less than 1 year. to "chromic acid" and resulting skin ulceration, the lack of skin ulceration in the third contrasting study [65] suggests that good work practices were used in this plant. The criteria document [122] on exposure to chromic acid concluded that, in the presence of good work practices, an environmental limit of 50 In 1884, Mackenzie [19] reported that ulceration of the nasal mucosal membrane followed by nasal septal perforation usually occurred after an exposure to bichromate of only a few days. Corrosion of both the nose and throat was also common and was occasionally accompanied by inflammation and perforation of the ear drums. No estimates of the degree of exposure required to produce these disorders were presented, but at that time the manufacturing processes were undoubtedly accompanied by an extremely dusty environment. In a survey of the chromate-producing industry in 1948, Machle and Gregorius [33] Fregert [69] found positive reactions to water-soluble hexavalent chromium in patients with chromate eczema. Morris [8] reported positive reactions to chrome-containing glue and chrome-dyed leather shoes. Calnan [9] concluded that cement dermatitis was primary irritant dermatitis complicated by a secondary contact sensitivity to "hexavalent chromate" [presumably chromium(VI)]. Engebrigtsen [10] confirmed that workers with cement eczema reacted positively to patch tests with aqueous 0.5% solutions of potassium bichromate. Jaeger and Pelloni [11] found that 94% of those with cement eczema gave positive patch test results with aqueous 0.5% solutions of potassium bichromate. McCord et al [7] [61] found that few workers who developed chrome ulcers were sensitized to an aqueous solution of 0.5% potassium bichromate. Pirila and Kilpio [71] reported that some workers who had been exposed to materials likely to contain chromium compounds-bookworkers, cement and lime workers, persons working with fish glue, metal factory workers, painters and polishers, and fur workers-were allergic to aqueous 0.5% solutions of potassium dichromate. Denton et al [72] reported on a man who reacted strongly to an aqueous 0.005% solution of potassium dichromate. Winston and Walsh [73] reported on a man who had a patchy, pruritic, erythematous dermatitis from working with a chromate-silicate-phosphate mixture (pH 10); the man had positive reactions to 0.25% sodium dichromate and to the above mixture. Levin et al [74] reported that lithographers developed an allergy to chromium(VI) which was elucidated by patch tests with various chromium(VI) materials including an aqueous 1% solution of potassium dichromate and other nondescript solutions. Engel and Calnan [75] found a group of workers who wet-sanded zinc chromate primer paint and who reacted positively to aqueous 0.5% solutions of potassium dichromate, and a group who did not react to an aqueous 0.5% solution of potassium dichromate until it was made alkaline (pH 10.3). Newhouse [76] found that 24% of the automobile assemblers studied yielded positive reactions to aqueous 0.5% solutions of potassium dichromate. The chromate dip used on bolts, nuts, and washers as an antirust agent was ascertained to have been responsible for the dermatitis. Fregert and Ovrum [77] found that welders exposed to aerosols of chromium(VI) developed hypersensitivity which was confirmed by patch testing with aqueous 0.1% solutions of chromium(VI) as potassium dichromate derived from welding fumes. Shelley [78] reported a similar sensitivity to welding fumes; a man with chronic, eczematous eruptions had positive reactions to aqueous 0.25% solutions of potassium dichromate. Loewenthal [79] observed a green-tattooed bricklayer with eczema who yielded positive reactions to aqueous 0.1% and 2% solutions of potassium dichromate. Cairns and Calnan [80] described a green-tattooed cement worker with eczema who reacted to aqueous 0.1% and 0.5% solutions of potassium dichromate and to an aqueous 2% solution of cobalt chloride. Walsh [62] ascertained that aqueous 0.5% sodium dichromate, 0.5% potassium chromate, 0.05% sodium dichromate, and 0.005% sodium dichromate solutions produced lesions on abraded skin. Perone et al [81] found that among 95 construction workers who worked regularly with cement, 1 reacted to an aqueous 0.25% solution of potassium dichromate and 1 other man reacted to an aqueous extract of cement containing 450 ppb (450 ng/g) hexavalent chromium but not to the 0.25% solution of potassium dichromate. Improvements were also made in other plants. [123] At the time of the study in 1949 [3,41,90] the range of exposures for the 7 who died from lung cancer was estimated from employment histories, job classifications, and 1949-50 environmental chromium concentrations. The range of exposures was calculated to be 10-150 fxg/cn m and the mean was 50 jig/cu m , ( [Ill] Eight cancers were found in a group of 100 rats when pellets of calcium chromate in a cholesterol carrier were implanted intrabronchially. Six of these were squamous cell carcinomas and were found in animals dying after 386-671 days. One animal dying after 474 days had metastases to the kidney. Two adenocarcinomas produced by calcium chromate were observed at 366 and 609 days. Both of these demonstrated mucus production. These rats showed atypical squamous metaplasia of the bronchus. [117] Calcium chromate produced cancers in 10 of 35 rats at the sites of intramuscular injections. [116] In addition, it produced cancers in 28 of 35 rats at the sites of intrapleural administration. [116] Inhalation of calcium chromate produced in rats 1 keratinizing squamous cell carcinoma, 1 laryngeal squamous cell carcinoma with invasion of perineural spaces and adjoining cartilagenous rings, and 1 malignant peritruncal tumor of undetermined type and origin. At the same concentration of airborne calcium chromate, 1 hamster developed a squamous cell carcinoma of the larynx which was invading and destroying the cartilage. In terms of chromium(VI), this calcium chromate concentration was 670 ¡ig/cu m. Animals received 589 exposures at this concentration over 891 days. In view of these findings, the investigators examined the larynges. Two rats showed laryngeal hyperplasia and 3 showed laryngeal squamous metaplasia. Effects in hamsters were more marked with 8 animals showing laryngeal hyperplasia. An additional 8 animals showed squamous metaplasia of which 5 were "atypical with downgrowth." Another hamster, dying after 611 days, showed a squamous papilloma in the larynx with hyperplasia and hyperkeratosis. [118] One study [120] used calcium chromate with a solubility in water of 1,200-1,400 ppm ground in a ball mill after the solubility was determined. Approximately 136 C57BL/6 mice of each sex were exposed to 13 mg calcium chromate/cu m for 5 hours/day, 5 days/week for their lifetimes. Six males in the exposed group developed lung tumors; 3 of the unexposed had lung tumors. Eight females in the exposed group had lung tumors; 2 in the control group had lung tumors. The lung tumors in the calcium chromate-exposed animals were generally not different from those in the control. All tumors were pulmonary adenomas or adenocarcinomas. This material has been referred to as chromic chromate in some instances. [116,108] In a study by Payne, [109] sintered calcium chromate was mixed with sheep fat and implanted into muscle tissue of the thighs of 52 mice. At the end of 14 months, a total of 9 implantation-site sarcomas were found. While the animal data leave much to be desired, there is sufficient information to support the conclusion that c h r o m i u m ( V I ) compounds are implicated in the production of cancer, regardless of the mode of administration. From the information available, it appears that a chromium(VI) mate rial generated by the alkaline roasting of chromite ore, has carcinogenic characteristics when inhaled. [88,89] IV. ENVIRONMENTAL DATA Sampling and Chemical Analysis Air sampling for chromium compounds has been performed by a variety of methods suitable for particulate sampling and poses no significant prob lems. Samples have been collected using electrostatic precipitators, It Is probable that chromium in other oxidation states will accompany chromium(VI) In the air; hence, analytical methods are required which differentiate between chromium(VI) and the other forms. Most published methods relying on Instrumental analysis are in reality total chromium methods, and will differentiate chromium(VI) from chromium(III) only if certain separation steps are included in the procedure. One separation procedure, the method for determining chromium(VI) recommended in the NIOSH criteria document for occupational exposure to chromic acid, [122,135] relies on the complexation of chromium(VI) with ammonium pyrrolidine dithiocarbamate (APDC), followed by extraction with methylisobutyl ketone polarography, [92,130] spark source mass spectrometry, [148] and X-ray fluorescence. [149] It is also feasible, after forming chromium acetylacetonates or trifluoroacetylacetonates, to determine chromium by means of the very sensitive and selective gas chromatographic procedures. [ [150][151][152][153] Beyerman [154,155] published a comprehensive review of the analytical methods for minute amounts of chromium. He critically compared the many methods with regard to their sensitivities, specificities, accuracies, and precisions. In addition he examined certain processes which are common to many methods such as the digestion of biologic samples in various strong acids. He specifically noted that consistently low results occurred when digestions were performed with perchloric acid due to the formation of chromyl chloride which was emitted as a gas. He further studied many common analytical reagents and showed that some of them were significantly contaminated with chromium, which could lead to erroneous results and high blank values. Errors due to the adsorption by the walls of glassware used were also appreciable, and other errors inherent in common analytical procedures were described. A particularly thorough study of extraction of chromium compounds with organic solvents was made, and various means of separating chromium(VI) by extraction were described. The analytical methods considered by Beyerman Included those based on colorimetric measurements, emission spectrography, flame photometry, X-ray emission spectrography, activation analysis, and 2 electrometric methodspolarography and biamperometry. Most Instrumental procedures are generally not specific for chromium(VI) and are not suitable for such analyses unless, as stated above, prior separations are made. In the NIOSH method recommended in the criteria document for occupational exposure to chromic acid [122] for example, atomic absorption spectrophotometrlc analysis is performed after extraction of chromium(VI) from the chromium(III). There are means of performing an analysis in such a manner that only chromium(VI) is determined, and several such methods are based on the fact that chromlum(VI) reacts with iodide to form iodine that may thereafter be determined by a variety of standard iodometrlc procedures. [86,126,128] Such methods are not truly specific for chromium(VI) for they may be subject to interference by other oxidants or reductants. The reagents hematoxylin [86,128] and s-dlphenylcarbazlde [5,[126][127][128]131,133,[156][157][158] have been used for chromium(VI) analyses, and the latter reagent in particular is widely favored for analysis of chromium(VI) in air. s-Diphenylcarbazide forms a colored complex with chromium(VI), but not with other chromium compounds, and the stability of the color formed contributes to the sensitivity of the method. Several materials, notably iron, copper, nickel, and vanadium, may interfere with the analysis [156], but relatively large amounts are tolerated without significant effect. In addition, certain other compounds such as cyanides, organic matter, and reducing agents may also interfere. The effect of reducing substances, if present, must be taken into account in any method for determining chromium(VI), since they tend to decrease the actual airborne concentration of chromium(VI). In many sampling situations, however, the presence of significant quantities of such interferences may be ruled out and it is probable that in all but exceptional circumstances the method may be considered specific for chromium(VI) and subject to a minimum of interferences. As noted previously, Abell and Carlberg [66] have demonstrated that reduction of chromium(VI) by the organic matter of the filter does not occur if polyvinyl chloride filters are used, and it is likely, though not proved, that certain other types of filtration media would also be suitable. Subsequent experience with, and the development of, refinements to the s-diphenylcarbazide method by NIOSH demonstrates the superiority of this method. NIOSH now recommends this as well for chromic acid instead of the method in the chromic acid criteria document [122] because the sdiphenylcarbazide method has shown at least indirectly the ability of many hygienists to obtain excellent results with it. In addition, the sdiphenylcarbazide method is simpler to use than the method in the chromic acid criteria document [122] and requires the purchase and use of less expensive, more commonplace analytical instrumentation. For many years, test papers have been commercially available which rely on the reaction of chromium(VI) with a paper impregnated with sdiphenylcarbazide reagent. [96] Such papers, at best, give only an approximate indication of the concentration of chromium(VI) if present in a mist and cannot be expected to reliably indicate the presence of dry particulate matter containing chromium(VI). There has been great interest in the determination of chromium in biologic materials, both for nutrition studies and in relation to occupa tional exposure to chromium compounds. [137,138,142,147,151,[159][160][161][162] Dif ferential analysis for chromium(VI) in biologic samples is not easy, and most analyses reflect the total chromium intake. Many of the analytical difficulties encountered in chromium analyses are particularly troublesome in biologic samples where the extremely low concentrations of the element and the difficulties of ensuring complete oxidation of the chromium may cause substantial analytical errors. It is perhaps for these reasons that biologic monitoring of chromium, as discussed in Chapter III, is of relatively little value in assessing exposure to chromium(VI) in the occupational environment. # Control of Exposure In many operations in the production and use of chromium(VI), exposures can be eliminated or kept within safe limits by use of closed system operations for reactors, conveyors, and holding or storage containers. [3,91,123] In such systems care must be exercised to ensure tight and reliable seals and joints, access ports, covers, and other such places. Failure of such seals can result in dust or spray emission into the atmosphere of the workroom. [123] When possible, such closed systems should be maintained under negative gage pressure. Even with closed systems, there will be unloading, charging, transferring, discharging, packaging, and transporting operations which afford various opportunities for contact with chromium(VI) and for the emission of dust and mist containing chromium(VI). Emission of airborne chromium(VI) can be controlled at the source by suitably designed exhaust ventilation. In employing exhaust ventilation for such control, certain recommended practices, [163] and design and operating fundamentals [164] should be followed. Sources of emission should be as fully enclosed by hoods as possible. The exhaust air should be passed through air cleaners of suitable efficiency to reduce the chromium(VI) concentration to acceptable levels before discharge into the community air. Atmospheric exposure to and other contact with chromium(VI) can and should be reduced or controlled by isolating the process or emission source from employees. Location of an operation in an isolated area can also limit the number of employees who will be exposed in that operation. Such operations must be amenable to remote or automated control or to only intermittent attention by an operator. In effect, the worker can be Isolated from the process by providing a clean area (clean room) in which the atmosphere is maintained essentially free of chromium(VI) and other significant contaminants. This may be accomplished by supplying air from an uncontaminated area or by filtering ambient air through high-efficiency filters. A clean area may be established as the control room for remote control operations or as an area to which operators may retreat for such periods as their presence may not be required at the process equipment. Ventilation and Isolation of the processes will reduce the probability of excessive contact with chromium(VI). For protection of eyes and skin, however, these measures may not be adequate for some operations. For those operations where contact of the chemicals with the eyes or skin may occur, whether by the nature of the work or by accidental splashes, sprays or spills, proper protective equipment, work clothing, and good work practices are required to control the exposure (see Chapter VI). The operations for which it is most difficult to control exposures are those of the maintenance and repair workers. The duties of these employees require that they enter or otherwise come into close contact with equipment or areas which may be grossly contaminated with chromium(VI). The TLV documentation stated "A review of the present status of the suitability of the TLV between TLV subcommittee members and industrial-hygiene representatives of the chromate industry 10 years after improved controls had been in operation revealed that (1) the TLV for chromic acid mist was satisfactory; (2) it contained a safety factor of 3 or 4; and (3) the limit was probably satisfactory for the pre vention of lung cancer, as no new cases had appeared during the 10-year period; but (4) that the 10-year period was probably too short to be certain of its validity in this respect." [170] Data in support of these points were not presented and discussed. In the 1973 edition of the Threshold Limit Values [173] a change was proposed in the chromium TLV's. The TLV for chromic acid and chromates remained 0.1 mg/cu m as chromic acid anhydride. The TLV for "Chromium, sol. chromic, chromous salts as Cr" remained 0.5 mg/cu m, but the category "chromium... metal and insoluble salts", which had been 1.0 mg/cu m, [170] was marked for intended changes in order to be included as a group of substances in industrial use that have proved carcinogenic in man, or have induced cancer in animals under appropriate experimental conditions. The group was labeled "Chromates, certain insoluble forms" with a TLV of 100 Mg/cu m. This group of certain insoluble chromates probably included calcium and zinc chromates and sintered chromium(VI) oxide (called chromic chromate) and others. The group was discussed in the 1971 TLV documentation [170] under "Chromic Acid and Chromates" for which the TLV was 0.1 mg/cu m, but in 1973 these materials were apparently removed from that group and placed under "chromium...metal and insoluble salts." It was not mentioned, however whether this intended TLV, 100 ng/cu m, was in terms of chromium, chromium(VI) oxide, or as chromates. Thus, the intended change to 100 jug/cu m may have been an increase, no change, or a decrease in the TLV for these materials. Nonetheless, the intent was apparently to denote "Chromates, certain insoluble forms" as "Human carcinogens." # I In 1974 the situation was clarified, [174] in that the TLV for "chromic acid and chromates" was 0.1 mg/cu m as chromium(VI) oxide and that the TLV's of "Chromates, certain insoluble forms, (Pb, Zn, and chromatechromite ore...)" were 0.1 mg/cu m as chromium and these materials were noted as human carcinogens. It should be noted that the 1974 TLV for these compounds represented an increase in the TLV over the 1972 TLV. The present (1975) federal standard for chromic acid and chromates is a ceiling concentration of 1 mg/10 cu m, ie, 100 ng/cu m, (29 CFR 1910.1000) based on the American National Standard Z37. 7-1971. [166] In 1963 [175] the Threshold Limits Committee recommended a limit of 0.1 mg chromium(VI) oxide/cu m for tertiary butyl chromate, an ester of tertiary butyl alcohol and chromic acid, which was unchanged in the 1974 TLV's. [174] As support for this recommendation, they cited the study by Roubal and Krivucova [176] in the 1971 documentation. [170] Roubal and Krivucova [176] 68,83] pulmonary congestion and edema, [67] epigastric pain, [59] erosion and discoloration of the teeth, [5,56] and perforated eardrums [19] have been reported on occasions, but again it seems reasonable that sufficient contact with any chromium(VI) material could cause these effects. In addition to causing these effects, some chromium(VI) compounds have been found to be associated with an increased incidence of lung cancer. [3,5,33,41,[88][89][90][91][92][93]95,180] Delpech and Hillalret in 1869 [18] described the effects of potassium chromate and bichromate on workers in the French chromate industry. Workers suffered respiratory ailments from the first day of their employment. One assigned the task of washing "simple chromates", began to suffer from nasal membrane injury, headache, and shortness of breath several days after he started this job. Another worker, involved in calcining and bichromate extraction also had shortness of breath. No environmental data were reported but exposures were probably high because of the then prevailing poor hygiene around reverberatory furnaces. In the chromate-producing Industry in the United States, only a small part of which produced chromic acid anhydride, the principal exposures to chromium(VI) were evidently to sodium chromate and bichromate because these were and are the principal intermediate and product of the alkaline roasting operation. To a lesser degree, there was also exposure to potassium chromate and bichromate. In 1884 Mackenzie [19] related having been told by a workman that destruction of the nasal septum sometimes took place after 24-48 hours of exposure. This destruction was associated with general congestion of the mucous membrane, nosebleed, coryza, ulceration of the turbinates, nasal pharynx, and lower pharynx, and inflammation of the lower respiratory tract. Intense headache, Inflammation and perforation of the tympanic membranes, and subsequent otorrhea also occurred. Exposures in this plant were probably very high, based on remarks about the history of the operation. [6] In 1948, Machle and Gregorius [33] reported the incidence of nasal septal perforation in a sodium chromate-sodlum bichromate-producing plant to be 43.5% in 354 employees. Airborne chromate concentrations were 10-2,800 Mg/cu m at the time of the study. The plant had been In operation for at least 17 years; thus, some employees had probably worked in the plant when reverberatory furnaces were used, a notorious source of exposure. This study provided evidence that exposure to sodium bichromate and chromic acid anhydride does not produce lung cancer. During the 17year period plant D2 had been in operation, no deaths from lung cancer occurred. By contrast, In plant Dl, which used alkaline roasting of chromite ore to manufacture sodium chromate, there were 5 deaths from lung cancer in the same period. As discussed in the section on Epidemiologic Studies, exposure to the intermediate in alkaline roasting has been associated with an Increased incidence of lung cancer. In the early 1950's, an epidemiologic study [3,41] was carried out in a single chrome plant in Ohio which produced sodium chromate and bichromate but no chromium(VI) oxide. In this study, the overall incidences of nasal septum perforations, chronic chemical rhinitis, and chronic chemical pharyngitis were significantly greater than those of the control group. The chromium(VI) concentration was as great as 0.5 mg/cu m. However, the incidences of these disorders in the groups of workers exposed at less than Results of analysis of airborne chromium showed cross-contamination of work areas in that airborne chromite ore and water-soluble chromium(VI) as well as acid-soluble, water-insoluble chromium, were found in nearly all areas of the plants; the acid-soluble, water-insoluble chromium was analyzed by direct colorimetry. Of the 897 workers examined, 57% had perforation of the nasal septum, 11% had a severely red throat, 8% had edema of the uvula and 50% had cutaneous ulcers or scars. The Incidence of severely reddened throat and edema of the uvula was greater than twice that of control groups. Data on cutaneous effects in the control group were not given. There was also an Increased incidence of lung cancer in these chromate workers. A more recent study [57,58] has Indicated poor work practices (eg, nose-picking) to be the likely causes of nasal ulcers and perforations. It seems evident that ulcers on the skin and hands (and other exposed skin areas) are also from local contact, thus the result of poor work practices. Although Mancuso [41] and the US Public Health Service report [5] did not make observations on this point, it seems likely that the high incidence of nasal and cutaneous ulcers and sequelae in their studies was also largely, conceivably entirely, due to such work habits. However, a contributory role of airborne chromlum(VI) in the development of nasal ulcers and septal perforations and the major role in the development of primary nasal irritation must be considered. Liver enlargement was noted In about 2% of the chromate workers. Those with enlarged livers were at least 15 years older and had worked an average of 4 years longer in the chromate industry than those without enlarged livers. The frequency with which white and red blood cells and casts were found in the urine was usually greater than that in the average industrial population, suggesting kidney damage. The nonneoplastlc signs of exposure to chromium(VI)-nasal mucosal irritation and ulceration and, to a lesser extent, nasal septal perforation-were likely to be closely related to airborne chromium(VI) at the average concentration measured at the time of the study, ie, 68 jug/cu m. There was some evidence that liver and kidney damage occurred as a result of long-term exposure to chromium(VI). Results were more conclusive relative to kidney damage in controlled experiments with monkeys, which sustained [105] kidney damage after subcutaneous Injections of sodium bichromate. Absorption of large amounts of chromium(VI) has, on a few occasions, [68,83] resulted in hepatic injury; it has also produced severe nephritis. [83,84] Because there have been several instances [5,83,84,105] in which kidney damage has apparently been the result of chromium(VI) absorption, routine urinalysis should be performed where there is occupational exposure to chromium(VI). Hepatic injury [5, 68,83] has also been reported [5,68,83] as the result of chromium(VI) absorption; for this reason, it is recommended that in routine medical examinations the responsible physician should consider appropriate liver studies. From these studies of the effects of exposure to sodium or potassium chromate or bichromate, two [5,41] contain information useful in deriving an exposure-effect relationship. The work of Mancuso [41] [122] be modified and expanded to include these salts in addition to "chromic acid anhydride and aqueous solutions thereof" would be addressing a group of compounds of uniform toxicity. In the light of the study by Machle and Gregorius [33] which showed an elevated incidence of lung cancer only in that part of the operation involving lime roasting, it seems clear that the lung cancer found in the US Public Health Service study [5] occurred in that part of the population involved in lime roasting. This is supported by some observations of the authors, [5] in that, of those workers with lung cancer whose work history was sufficiently described, most had worked at or near the lime mills or kilns. It is also supported by Laskln et al [118] and written information supplied by Levy in 1975 which indicated that the highest incidence of lung cancer was found in animals treated with calcium chromate. The information from Levy indicated no lung cancers were produced in animals treated with sodium chromate or bichromate. When the toxicities of chromium(VI) compounds are examined, it becomes apparent that several have demonstrated carcinogenic activity. [3,5,33,A 1, [88][89][90][91][92][93]95,107,117,118,120,161,180] Nearly all the implications of carcinogenicity have arisen from studies of the worker population of the chromate-bichromate producing industry and from animal studies using the intermediates produced in that industry. Some Implications have arisen from the pigment-producing industry [88,89] and from animal studies [116, LS Levy, written communication, March 1975] using pigments and chemically analogous chromium(VI) compounds. Other Industries and processes are suspect despite the absence of appropriate studies because they use or produce materials chemically similar to the Intermediates in the chromatebichromate industry or chromium(VI) pigments. [124,181] The only industry which has been extensively studied [5,33,41,[90][91][92][93]95,161,180] has been the chromate-bichromate producing industry in the United States. However, even studies of this industry have provided only small amounts of information. Thus, the relationship between airborne concentrations of certain chromium(VI) compounds and the incidence of cancer is uncertain. Machle and Gregorius [33] published the first report of a high incidence of lung cancer among workers in the US chromate Plant £, studied by Machle and Gregorius, [33] was later examined extensively by another team of investigators. [3,41,[90][91][92][93]95,161,180] This plant produced sodium chromate and sodium bichromate through alkaline roasting of chromite ore, but no chromium(VI) oxide. In 1 study, Mancuso and Hueper [90] the time between their periods of employment and the analysis of airborne chromium(VI), it is unlikely that the calculated TWA exposures adequately reflected the actual exposure to chromium(VI) the men had while working. In addition, airborne chromium(III) and chromium(VI) were present in all areas of this plant making it impossible to associate the high incidence of lung cancer with exposure to a particular chromium compound. In As in the above study [90] the large number of variables in this study [5] precludes the derivation of a dose-response relationship. In 1975, Watanabe and Fukuchl reported preliminary results [182] of a recent survey of a Japanese chromate-produclng plant. The survey showed that in 136 workers who had been employed for at least 9 years there were 10 cases of lung cancer. The number of deaths from lung cancer was 21.2 times as high as the expected number of deaths. In the plants studied by Gross and Kolsch [88] which produced lead chromate pigments and zinc chromate pigments from chromium(VI), a high incidence of lung cancer was also reported. Unfortunately, no information was provided on airborne concentrations of chromlum(VI) materials in these plants. Langard and Norseth [89] found the incidence of lung cancer in a plant producing both lead chromate and zinc chromate pigments to be 38 times the expected Incidence. In a cohort of 24 workers, the 3 who developed lung cancer were exposed for 6, 7. In animal studies, inhalation of calcium chromate was found [118] to produce 1 keratinizing squamous cell carcinoma, 1 laryngeal squamous cell # VI. WORK PRACTICES In the production and use of chromium(VI) materials, work practices must be designed to minimize or to prevent the inhalation of such materials and their contact with skin and eyes. Good work practices are a primary means of controlling certain exposures and will often supplement other control measures. Enclosure of materials, processes, and operations is completely effective as a control only when the integrity of the system is maintained. Such systems should be inspected frequently for leaks and any leaks found should be promptly repaired. Special attention should be given to the condition of seals and joints, access ports, and other such places. [123] Similarly, points of wear or damage should be inspected regularly. Gloves, aprons, goggles, face shields, and other personal protective devices must be maintained in good hygienic and uncontaminated condition. They should be cleaned or replaced frequently and on a regular schedule. Employees should keep such equipment In suitable, designated containers or places when the equipment is not in use. Workers may reduce the potential exposures significantly by retiring to clean areas when their presence at the operation point is not necessary. A clean area may simply be a room or a space where sustained environmental levels are such that it can be considered as being without occupational exposure to chromium(VI). A clean area can be deliberately established by means of ventilation which provides either filtered air or air from an uncontaminated source in a manner and amount which maintains the environ mental level of chromium(VI) at a nonexposure level. In areas and at operation sites where the use of respiratory protection is required, the employee shall wear the designated type of respirator and observe the practices of the respiratory protective devices program. The necessity of cleanliness and maintenance of respirators should be emphasized. Practices which lead to the contamination of the interior of the facepiece should be prohibited. # Precision and Accuracy Ten filters spiked with 1.0 ng of chromium(VI) (a 0.01-ml droplet of 100 ppm chromium(VI) standard solution was placed on each filter and allowed to dry) gave recoveries of 93% with a relative standard deviation of 3.2% when analyzed within 1 hour of deposition; after 1 week, the average recovery dropped to 50%. Twenty-two filters, each loaded with about 5 n g of chromium(VI) in a chromic acid mist generator, gave results with a relative standard deviation of 4.3%. No corroborative tests have been performed on this method. Apparatus 22-mm round, matched cuvettes. Filtering apparatus. Spectrophotometer set to operate at 540 nm. # Reagents Water: Unless otherwise designated, all water used is double distilled or deionized. Half-normal sulfuric acid solution: Add 13.9 ml of concentrated sulfuric acid to some water in a 1-liter volumetric flask and dilute to mark. The exact concentration is not critical but it is suggested that the same solution be used for a complete test-samples, blanks, and standards. After thorough mixing, it is convenient to transfer part of the solution to a small plastic wash bottle. (3) With each batch of samples, 1 filter labeled as a blank should be submitted. This filter should be subjected to exactly the same handling as the samples except that no air is drawn through it. (4) The samples should be shipped in a suitable container, designed to prevent damage in transit. (c) Analysis of samples (1) Pipet 15 ml of water into each cuvette to be used. Put a piece of tape on the cuvette so that its bottom edge matches the meniscus. Rinse the cuvetteB. (2) Blank filters are folded and placed directly into cuvettes. Sample filters are folded and placed in large test tubes. (3) Six or 7 ml of 0.5 K sulfuric acid is added to each tube and the tube is shaken to assure that all surfaces of the filter are washed. The filters are removed from the tubes with small forceps with careful washing of all surfaces with an additional 1 or 2 ml of 0.5 N sulfuric acid. The washed filters are discarded. The method is extremely simple, very selective for chromium(VI), and sensitive. The samples, when collected on PVC filters, are very stable. The recovery after 2 weeks is essentially the same as for the first day. Filters kept for 9 weeks gave an average recovery that was 79% of the first day's results. However, samples made by spiking PVC filters are not very stable and give poor recoveries. Spiked filters are therefore not recommended for standards. # X. APPENDIX III -MATERIAL SAFETY DATA SHEET The following items of Information which are applicable to a specific product or material shall be provided in the appropriate block of the Material Safety Data Sheet (MSDS). The product designation is Inserted in the block in the upper left Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets. The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved. Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, mild irritation and possibly some blistering. Eye Contact-some pain and mild transient irritation; no corneal scarring. "Emergency and First Aid Procedures" should be written in lay language and should primarily represent first aid treatment that could be provided by paramedical personnel or individuals trained in first aid. Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. Respirators shall be specified as to type and NIOSH or US Bureau of Mines approval class, ie, "Supplied air," "Organic vapor canister," "Suitable for dusts not more toxic than lead," etc. Protective equipment must be specified as to type and materials of construction. # reliability, itaalyses by the method recommended in the chromic acid criteria document, which uses atomic absorption spectrophotometry, have been subsequently found by NIOSH to be much more time consuming than those using the s-diphenylcarbazide colorimetric method; thus, it appears that routine analysis would be simplified by a recommendation that the sdiphenylcarbazide colorimetric method be used for the determination of all chromium(VI) compounds, whether or not carcinogenic. Therefore, the recommended analytical chemical method is that described in Appendix II and it uses the spectrophotometric determination of a colored complex of chromium(VI) and s-diphenylcarbazide. Because of the carcinogenicity of some chromium(VI) materials and the lack of evidence suggesting a safe workplace environmental limit, it seems appropriate to recommend that no detectable amounts of these substances be allowed in workplace air with a specified method of sampling and chemical analysis. The recommended analytical method (v.s.) will reliably detect 0.5 jug chromium(VI). The lower detection limit is approximately 0.05 jig chromium(VI) by this method but detection and determination are not reliable at this limit because of (1) variations in the background concentrations of airborne and reagent substances that interfere with the determination of chromium(VI) at this trace level and (2) the Inherent unreliability of the calibration curve generated by determinations of known amounts of chromium below, at, and slightly above the detection limit. Because of this unreliability at this limit of detection and the resultant questions about the validity of compliance actions at airborne chromium(VI) Some part of the total, usually between 10,000 and 20,000 tons was added directly to steel. The balance was used to make ferroalloys and Cr metal. ** A small quantity, usually between 5,000 and 10,000 tons, was used in direct furnace repairs; the balance was used in making brick and other refractory products. Derived from reference 185 The projection includes allowance for losses during use of the ferroalloys in metallurgical processing and an additional 10% loss for processing chromite into ferroalloys. The average assay of ore for metallurgical uses is 50% Cr203; the average assay of ore for refractory use is 35% Cr203 and no processing loss is assumed; average assay of ore for chemicals and facing sand uses is 45% Cr203. Derived from reference 185	None	None
c74fc13b17b03cafd4e3cdb2e58375ebe3f712f0	cdc	None	Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure levels that are safe for various periods of employment, including but not limited to the exposures at which no employee will suffer diminished health, functional capacity, or life expectancy because of his or her work experience. Criteria documents contain a critical review of the scientific and technical information about the prevalence of hazards, the existence of safety and health risks, and the adequacy of control methods. By means of criteria documents, NIOSH communicates these recommended standards to regulatory agencies, including the Occupational Safety and Health Administration, health professionals in academic institutions, industry, organized labor, public interest groups, and others in the occupational safety and health community. This criteria document is derived from the NIOSH evaluation of critical health effects studies of occupational exposure to diacetyl and 2,3-pentanedione. It provides recommendations for controlling workplace exposures including recommended exposure limits derived by using current quantitative risk assessment methodology on human and animal health effects data.# Using cross-sectional pulmonary function data from diacetyl-exposed employees, NIOSH conducted assessments to determine the exposure-response relationship and to identify risk of pulmonary function decrease at various levels of diacetyl exposure. NIOSH found that a relationship exists between diacetyl exposures and lower pulmonary function. Utilizing this analysis, NIOSH recommends keeping exposure to diacetyl below a concentration of 5 parts per billion as a time-weighted average during a 40-hour work week. To further protect against effects of short-term exposures, NIOSH recommends a short-term exposure limit for diacetyl of 25 parts per billion for a 15-minute time period. In many operations, 2,3-pentanedione is being used to substitute for diacetyl. Published toxicological studies indicate that 2,3-pentanedione exposure can cause damage similar to that caused by diacetyl in laboratory studies. Therefore, NIOSH recommends keeping occupational exposure to 2,3-pentanedione below a level comparable to the level recommended for diacetyl. However, the recommended sampling and analytical method can only reliably quantify it to 9.3 parts per billion in an 8-hour sample. NIOSH also recommends a short-term exposure limit for 2,3-pentanedione of 31 parts per billion during a 15-minute period. Engineering and work practices are available to control diacetyl and 2,3-pentanedione exposures below the recommended exposure limits. A hierarchy of controls including elimination, substitution, engineering controls, administrative controls, and the use of personal protective equipment should be followed to control workplace exposures. # Executive Summary Diacetyl and its substitute, 2,3-pentanedione, are widely used flavoring compounds. There have been extensive reports of serious respiratory disease and decreased lung function in employees exposed to diacetyl. The NIOSH objective in establishing recommended exposure limits (RELs) for diacetyl and 2,3-pentanedione is to reduce the risk of respiratory impairment (decreased lung function) and the severe irreversible lung disease obliterative bronchiolitis associated with occupational exposure to these compounds. In this disease the smallest airways in the lungs, the bronchioles, become scarred and constricted, blocking the movement of air. In addition, maintaining exposures below the RELs will help prevent other adverse health effects including but not limited to irritation of the skin, eyes, and respiratory tract in exposed employees. The recommendation to limit exposure to diacetyl and 2,3-pentanedione is based upon data from human and animal studies and the quantitative risk assessment; however, additional considerations include sampling and analytical feasibility and the achievability of engineering controls. Diacetyl is used extensively in the food flavoring and production industries, and occupational exposure to this substance has been associated with severe respiratory impairment and the disease obliterative bronchiolitis. 2,3-Pentanedione, which has been used as a substitute for diacetyl, is also of concern because of structural similarities with diacetyl and because animal studies show similar toxicity for the respiratory tract [Hubbs et al. 2012;. The first observation of obliterative bronchiolitis in a food production employee may have occurred in 1985 in a facility where diacetyl was listed among ingredients used in making flavorings for the baking industry . The link between exposure to diacetyl and lower pulmonary function was confirmed in the early 2000s, and research further showed that diacetyl exposure leads to a decrease in pulmonary function . Occupational exposures to diacetyl have been assessed in a variety of food production and flavoring facilities Martyny et al. 2008;NIOSH 2003aNIOSH , b, 2004aNIOSH , b, 2006NIOSH , 2007NIOSH , 2008aNIOSH , b, 2009NIOSH , 2011. Another compound, acetoin, was present along with diacetyl in many of the workplaces where obliterative bronchiolitis occurred in employees who made or used diacetyl ; . However, current data indicate that acetoin is considerably less hazardous than diacetyl and it does not have the reactive α-dicarbonyl group, which has been implicated in the toxicity of diacetyl and 2,3-pentanedione . Mean diacetyl air concentrations measured at the first microwave popcorn facility where obliterative bronchiolitis was reported were highest in the mixing room (57.2 parts per million ), followed by the packaging area (2.8 ppm) . Mean personal diacetyl air concentrations at five other microwave popcorn plants were lower: 0.023 to 1.16 ppm in the mixing room and 0.35 to 1.33 ppm in the packaging rooms/areas ]. Mean full-shift diacetyl air concentrations measured vi Occupational Exposure to Diacetyl and 2,3-Pentanedione at flavor manufacturing facilities ranged from 0.07 ppm to 2.73 ppm Martyny et al. 2008;NIOSH 2003aNIOSH , b, 2004aNIOSH , b, 2006NIOSH , 2007NIOSH , 2008aNIOSH , b, 2009NIOSH , 2011. In addition to cases consistent with obliterative bronchiolitis in flavoring manufacturing, diacetyl manufacturing, and microwave popcorn production, case reports have surfaced in other industries in which flavorings are introduced. In cookie manufacturing with artificial butter flavoring in Brazil, four cases of bronchiolitis were described in young men, aged 24 to 27 years, who had worked between 1 and 3 years handling flavorings in preparation of cookie dough . In a coffee production plant, two cases have biopsy confirmation of obliterative bronchiolitis among employees with artificial flavorings exposure in the production of roasted coffee beans and ground coffee . In 2012, NIOSH conducted a health hazard evaluation (HHE) involving 75 current employees (88% participation) . Excluding the five sentinel former employees (all never-smokers under age 42), standardized morbidity ratios were elevated 1.6-fold for shortness of breath and 2.7-fold for obstructive spirometric abnormalities. Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetylexposed employees presented in Chapter 3 have provided substantial evidence of a causal relationship between diacetyl exposure and development of this disease. These findings in conjunction with laboratory experiments providing biological plausibility, meet the standard criteria used to determine causation: that an exposure is the likely cause of specific health effects . NIOSH has reviewed the literature on diacetyl toxicology and exposures in the workplace and subsequently conducted a quantitative risk assessment. The quantitative risk assessment used to derive the REL was based solely on human (employee) data, but the results were informed and corroborated by animal risk assessments. On the basis of a quantitative risk assessment of data collected in a series of NIOSH health hazard investigations (full description in Chapter 5), NIOSH has concluded that employee exposure to diacetyl is associated with a reduction in lung function. Specifically, a statistically significant exposure-associated reduction in the forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ratio and percent predicted FEV 1 (ppFEV 1 ) and an exposure-associated estimated incidence of symptomatic obstructive lung disease were observed. NIOSH quantified these exposureresponse relationships and determined the exposure levels that correspond to a variety of risks (Chapter 5, Table 5.35). Lifetime risks in the range of 1:1,000 corresponded to working lifetime diacetyl exposure of approximately 5 parts per billion (ppb). Once the risks were characterized, NIOSH examined the analytical methods (OSHA Methods 1012 and 1016) and available engineering controls and determined that they supported establishing a REL at that level. It should be noted that diacetyl and 2,3-pentanedione are found in cigarette smoke and some flavored e-cigarettes . As extensively discussed in Chapter 3, increased prevalence of airway obstruction and decreased FEV 1 can be identified in smokers who are exposed to diacetyl in comparison to prevalence in smokers in the U.S. population. Most importantly, because diacetyl causes obstructive lung disease and because smoking causes obstructive lung disease, the presence of diacetyl in cigarette smoke in no way diminishes the need to control diacetyl exposures in employees. NIOSH concludes that the toxicological responses to diacetyl observed in animal studies support the conclusions of the epidemiologically-based risk assessment for diacetyl. Further, the animal-based Occupational Exposure to Diacetyl and 2,3-Pentanedione vii risk assessment presented in Chapter 6 corroborates the epidemiologic assessment by demonstrating a causal link between diacetyl exposure and respiratory health effects and by showing a clear doseresponse relationship in exposed animals as was observed in employees exposed to diacetyl in the epidemiologic assessment. On this basis, NIOSH recommends a REL of 5 ppb for diacetyl as a time-weighted average (TWA) for up to 8 hours/day during a 40-hour workweek. NIOSH has determined that employees exposed to diacetyl at this level for 8 hours a day, 40 hours a week for a 45-year working lifetime should have no more than a 1/1,000 excess risk of lung function falling below the lower limit of normal due to diacetyl exposure. To ensure that employee exposures are routinely below the REL for diacetyl, NIOSH also recommends using an action level (AL) of 2.6 ppb with the exposure monitoring program to ensure that all control efforts (engineering controls, medical surveillance, and work practices) are in place and working properly. When exposures exceed the AL, employers should take corrective action (determine the source of exposure, identify methods for controlling exposure) to ensure that exposures are maintained below the REL. NIOSH has concluded that the use of an AL in conjunction with periodic monitoring of employee exposures (described in Chapter 10) is helpful to protect employees. NIOSH is also recommending a short-term exposure limit (STEL) for diacetyl of 25 ppb for a 15-minute time period. The establishment of a STEL is based on the concern that peak exposures may have greater toxicity than the same total dose spread out over a longer period of time. 2,3-Pentanedione is used in many operations; it is structurally similar to diacetyl because it is a 5-carbon alpha diketone, whereas diacetyl is a 4-carbon alpha diketone. Published toxicology studies indicate that 2,3-pentanedione exposure can cause damage to the lining of airways similar to that caused by diacetyl in laboratory studies [Hubbs et al. 2012;. Therefore, NIOSH recommends controlling occupational exposure to 2,3-pentanedione to a level comparable to that recommended for diacetyl. However, analytical limitations allow 2,3-pentanedione to be reliably measured only above 9.3 ppb. This recommended exposure limit is slightly higher than the recommended exposure limit for diacetyl. NIOSH recommends keeping exposure to 2,3-pentanedione below 9.3 ppb in an 8-hour average during a 40-hour work week. NIOSH has estimated that employees exposed to 2,3-pentanedione at this concentration should have a similar risk of decreased pulmonary function as employees exposed to diacetyl. NIOSH also recommends a short-term exposure limit for 2,3-pentanedione of 31 ppb during a 15-minute period. Research into various flavoring industries has led to the development of engineering controls that may help reduce employee exposure to diacetyl, 2,3-pentanedione, and other chemicals. Chapter 8 describes engineering controls for the industries where diacetyl is handled or used within products. Table 8.2 in Chapter 8 provides a summary of NIOSH-evaluated engineering control efficiencies for the mixing of food flavorings. NIOSH acknowledges that the frequent use of personal protective equipment (PPE), including respirators, may be required for some employees who handle diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products. The frequent use of PPE may be required during job tasks for which (1) routinely high airborne concentrations of diacetyl or 2,3-pentanedione (e.g., pouring, mixing, packaging) exist, (2) the airborne concentration of diacetyl or 2,3-pentanedione is unknown or unpredictable, and ( 3) job tasks are associated with highly variable airborne concentrations because of environmental conditions or the manner in which the job task is performed. In all work environments viii Occupational Exposure to Diacetyl and 2,3-Pentanedione where diacetyl, 2,3-pentanedione, diacetyl-containing flavorings, or flavored products are found control of exposure through engineering controls should be the highest priority. NIOSH recommends that employers develop and implement comprehensive occupational safety and health programs to protect employees with potential exposure to diacetyl, 2,3-pentanedione, and other potentially hazardous flavoring compounds. This program should include periodic exposure and medical evaluation and monitoring exposure controls and appropriate employee training on potential health effects, respiratory protection, and use of controls. Employers should (1) determine employee exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds used in the workplace; (2) evaluate the effectiveness of work practice and engineering controls; and (3) facilitate the selection of appropriate personal protective equipment. Because diacetyl and 2,3-pentanedione are found in cigarette smoke and e-cigarettes, NIOSH also recommends that all employers make tobacco cessation programs available to employees and have workplaces that are free of tobacco smoking and vaping with flavored nicotine delivery systems . All permanent, temporary, and contract employees who work in or enter areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds or products that contain these compounds are used or produced should be included in the medical monitoring program. Employees who work in or enter these areas for a total of 40 or more hours per year should be included in the medical monitoring program. Because of the potentially rapid progression and grave consequences of flavoring-related lung disease, it is important that the medical monitoring program director be able to quickly evaluate clinical data and make medical judgments about appropriate diagnostic and therapeutic measures, including medical removal. For this reason, the medical monitoring program director should be a licensed physician with training and experience in identifying and preventing occupational lung disease. The medical program that includes the following: good quality spirometry testing for pulmonary function medical evaluation for employees found with abnormal spirometry removal from exposure pending medical evaluation analysis of group medical surveillance and longitudinal spirometry data to assess workrelated risk factors on the basis of job, task, area, and other exposure indices The purpose of this epidemiologic surveillance is to assist monitoring physicians in assessing the likelihood of work-related causes of abnormalities and to prioritize interventions, if needed. Identifying excessive declines in spirometry, even if absolute spirometric values remain within the normal range, offers the best opportunity to intervene before progression to symptomatic impairment and to prevent the development of clinically significant occupational lung disease. The rapid onset and progression of diacetyl-related lung disease requires more frequent medical monitoring evaluations be done than with slowly progressive occupational lung diseases, such as silicosis and coal employees pneumoconiosis. While the focus of this document is on diacetyl and 2,3-pentanedione, NIOSH has concern regarding other volatile and reactive flavorings potentially capable of producing similar toxic effects. Therefore, NIOSH recommends that such exposures be carefully considered and controlled in consultation with workplace safety professionals and the recommendations contained within this criteria document. 1 Introduction # Purpose This document presents the criteria and components of a recommended standard necessary to reduce or eliminate significant risk of health impairment from exposure to diacetyl and 2,3-pentanedione and prevent flavorings-related lung disease. This document was developed in accordance with the Occupational Safety and Health Act of 1970 . This Act charges NIOSH with recommending occupational safety and health standards and developing criteria for toxic materials. These criteria are to describe exposures that are safe for various periods of employment, including but not limited to the exposures at which no employee will suffer diminished health, functional capacity, or life expectancy as a result of his or her work experience. The purpose of the criteria document is to evaluate the scientific literature concerning potential health effects, toxicology, risk assessment, engineering controls, work practices, personal protective equipment, and recommendations pertaining to diacetyl and 2,3-pentanedione. The criteria document provides a basis for the REL for diacetyl and 2,3-pentanedione, although compliance with this recommended standard is not the sole objective. The intended outcome of the document is to reduce occupational exposures to diacetyl and 2,3-pentanedione and thereby prevent flavorings-related lung disease through hazard guidance implementation. In their entirety, the RELs and the guidance are intended to help employers develop a more healthful work environment. The RELs and guidance will also provide useful information to help employees actively participate in their own protection. # Scope This criteria document contains a review of relevant scientific information related to diacetyl and 2,3-pentanedione, and provides the rationale and criteria for establishing appropriate risk management recommendations. The basis for developing a criteria document on diacetyl and 2,3-pentanedione is described in this chapter. Chapter 2 provides an overview of studies conducted to characterize occupational exposure to diacetyl and 2,3-pentanedione. Chapter 3 describes the health effects observed in employees exposed to diacetyl and other flavoring compounds. Chapter 4 describes toxicology research from diacetyl and 2,3-pentanedione, while Chapters 5 and 6 describe the assessment of risk based on available human and animal data. Chapter 7 provides the basis for the RELs for diacetyl and 2,3-pentanedione. Chapter 8 describes procedures for informing employees about the safety of diacetyl and diacetyl substitutes as well as engineering interventions that could significantly reduce exposures when appropriately applied and fully operational. Also included in Chapter 8 are recommendations for establishing globally harmonized system for classification and labelling (GHS) classifications for diacetyl and 2,3-pentanedione based on the revised OSHA hazard communication standard. Additionally, recommendations for an effective respiratory protection program are provided. Chapter 9 provides medical surveillance guidelines for the ongoing evaluation of the health status of employees. Chapter 10 describes the components of an effective exposure monitoring program and work practices that when implemented correctly, can reduce occupational exposures. Finally, Chapter 11 presents key research needs. This document results from a review of all relevant literature on diacetyl and 2,3-pentanedione, and describes selected studies which characterize exposures and discusses techniques shown to be effective in reducing those exposures. Published literature through October 2016 was used and extracted from databases including but not limited to PubMed, NIOSHTIC-2, Web of Knowledge, Toxline, and Chem Abstracts. The literature search was developed to identify critical scientific data relevant to workplace safety and health including physical and chemical properties, human health effects, laboratory testing, chemical toxicokinetics, toxicity, engineering controls, personal protective equipment and function, risk management, and modeling systems that are relevant to diacetyl and 2,3-pentanedione. The literature was searched using specific terminology for each scientific discipline. Evaluated data sources included peer reviewed journal articles, government publications, and peer reviewed data sources, high caliber professional practice manuals (i.e., ACGIH 2012 andFEMA 2012) and high-quality information submitted to government dockets. In a few instances personal communications are cited where authors were contacted for additional clarification. The information that was identified in the comprehensive literature search was evaluated with considerations that included if the studies were peer-reviewed, if the data were generated with standardized protocols, if the exposure conditions were described in detail, confounders and existing information in peer reviewed journals. Specific studies pertaining to workplace exposure assessment, human health effects, and toxicology were specifically identified and are described in Chapters 2, 3, and 4 respectively. # Background Diacetyl is one of the main components in butter flavoring that imparts a buttery taste, and it has been identified as a prominent volatile organic compound (VOC) in air samples from microwave popcorn plants and flavoring manufacturing plants Ashley et al. 2008;Kanwal 2003;Kanwal and Martin 2003;Martyny et al. 2008;NIOSH 2004a;Parmet and Von Essen 2002]. Diacetyl is used as a natural and artificial flavoring ingredient and aroma carrier in bakery products, dairy products, snack foods, and more. It is mainly used as a butter flavoring but is also used in the flavor formulation of a number of other flavors, including but not limited to strawberry, caramel, hazelnut, and butterscotch. It is also present as a natural byproduct in some fermented food products such as beer and roasted food products such as coffee. Occupational exposures in the flavoring and food production industries have been associated with respiratory disease, including obliterative bronchiolitis, an uncommon lung disease often characterized by fixed airways obstruction. Obliterative bronchiolitis refers to disease processes that show some degree of inflammation, narrowing, or obliteration of small airways (bronchioles) in the lung and is discussed in more detail in Chapter 3, specifically section 3.1.1. Although a causative relationship between diacetyl and respiratory disease has been observed, diacetyl may not be the only flavoring compound related to health impairment. Other flavoring ingredients such 1 . Introduction as acetaldehyde, butyric acid, and acetoin, have been present in workforces with adverse health effects . In addition, new diacetyl substitutes with little or no toxicological information related to occupational safety and health are being used in production. Day et al. observed the flavoring compound 2,3-pentanedione in food production facilities. This compound has been used as a diacetyl substitute in many flavor manufacturing facilities because it has a related chemical structure and similar flavor properties to diacetyl. Published reports on the toxicity of 2,3-pentanedione from experimental inhalation studies with rats indicate that exposure causes airway epithelial damage similar to that produced by diacetyl [Hubbs et al. 2012;. No state or national registries are available to identify potential cases of obliterative bronchiolitis among employees. In 1985, two employees with fixed obstructive lung disease suggestive of obliterative bronchiolitis were observed in a facility where flavorings with diacetyl were made for the baking industry NIOSH 1986]. Catastrophic fixed airways disease suggestive of obliterative bronchiolitis was observed in these two former mixing employees who were young nonsmokers with job tasks that involved blending corn starch and flour with various flavorings. Two additional employees who formerly had mixing responsibilities also had otherwise unexplained obstruction, whereas two current mixers were unaffected. A review of common ingredients listed diacetyl among other flavoring compounds. In the microwave popcorn industry, the first occurrences of obliterative bronchiolitis were observed in the year 2000 when eight employees formerly employed in a microwave popcorn facility were diagnosed with the disease . The observation of this case series led to the identification of another case of obliterative bronchiolitis in a separate facility . Since then, numerous cases of obliterative bronchiolitis have been observed in the microwave popcorn industry CDC 2002;Ezrailson 2002;NIOSH 2003NIOSH , 2004aNIOSH , b, 2006Parmet 2002;Schachter 2002]. In addition, a retrospective epidemiologic study found cases of obliterative bronchiolitis in employees who were employed in a diacetyl manufacturing plant with exposures to diacetyl, acetoin, acetic acid, and acetaldehyde . In 2004 and 2006, two cases of obliterative bronchiolitis among employees who made food flavorings were reported to the California Department of Public Health (CDPH). An industry-wide public health investigation performed by CDPH, the California Occupational Safety and Health Administration (Cal/OSHA), and NIOSH initially found an additional five employees with severe, fixed obstructive lung disease . Outreach to the industry regarding the diacetyl hazard, including Cal/OSHA consultation site visits, prompted quick implementation of exposure controls and medical surveillance programs. A longer-term effort was focused on companies' installation of effective engineering controls and further assessment of medical surveillance findings over time by CDPH and NIOSH. A crosssectional analysis of medical surveillance data from 16 companies confirmed the risk of lung disease among employees at companies using diacetyl . In 2010, California issued the first occupational standard for diacetyl . Employees within the flavoring production industry have complex exposures in terms of the physical form of the agents (vapors, mists, and airborne dusts) and the number of different chemicals used. Although thousands of flavoring compounds are in use, few have occupational exposure limits. The Flavor and Extract Manufacturers Association (FEMA) reports that of the more than 1,000 flavoring compounds considered to be potential respiratory irritants or hazards, only 46 have established OSHA permissible exposure limits (PELs) . Given the lack of occupational exposure limits for most flavoring compounds, assessing workplace exposures and developing exposure control guidance are critical to help reduce the risk of flavorings-related lung disease. In 2010, California promulgated a regulation for occupational exposure to food flavorings containing diacetyl that requires installation of exposure controls to reduce exposures to the lowest feasible levels. In 2012, the American Conference of Governmental Industrial Hygienists (ACGIH) published a threshold limit value® of 0.010 ppm 8-hour TWA with a STEL of 0.020 ppm for diacetyl . In 2014, the European Commission published the Recommendation from the Scientific Committee on Occupational Exposure Limits of 0.02 ppm 8-hour TWA with a STEL of 0.10 ppm for diacetyl . # Chemical and Physical Properties The compound diacetyl has Chemical Abstract Service (CAS) number 431-03-8 and has several synonyms including 2,3-butanedione (International Union of Pure and Applied Chemistry nomenclature), 2,3-butadione, 2,3-diketobutane, biacetyl, dimethyl diketone, and dimethylglyoxal. The compound 2,3-pentanedione has CAS number 600- and is also referred to by the name acetyl propionyl. Both diacetyl and 2,3-pentanedione are alpha diketones or vicinal diketones (also referred to less specifically as alpha dicarbonyls), which means that their molecular structures contain two carbonyl functional groups that are adjacent to one another, and the carbon molecules attached to the oxygen molecules are also attached to only carbon molecules. A listing of physical and chemical properties of diacetyl and 2,3-pentanedione and their molecular structures is presented in Table 1-1. The odor threshold of diacetyl and 2,3-pentanedione has been reported by many studies . It is not uncommon for odor threshold values reported in the literature to range over four orders of magnitude for the same chemical . Odor threshold variability can result from the source of data, the characteristics of human olfactory response, and the differences in experimental methodology . The following criteria were used to analyze the diacetyl and 2,3-pentandione odor threshold literature: (1) only primary odor threshold sources that were found in the literature and that were written in English were used; (2) only sources that clearly indicated the type of threshold being measured as a detection or recognition threshold were used; (3) sources that used a panel of at least five judges to account for the range of olfactory sensitivity in the population were used; and ( 4) sources that presented the different concentrations of odor samples in a way that eliminated olfactory fatigue were used. The geometric mean of the selected values was reported in Diacetyl can be synthesized chemically from four starting materials: (1) from methyl ethyl ketone, either by converting it into an isonitroso compound and then hydrolyzing with hydrochloric acid or by partial oxidation of methyl ethyl ketone over a copper or vanadium oxide catalyst (odor measurement of diacetyl vapor-air mixtures). Note: geometric mean of two literature reported threshold values with a geometric standard deviation of 5.33 ppb. 0.84 ppb (odor measurement of diacetyl vapor in the headspace above aqueous solutions, diacetyl concentrations in solution converted to air concentrations using Henry's Law constant). Note: geometric mean of three literature reported threshold values with a geometric standard deviation of 1.44 ppb. 1.2 ppb (recognition threshold) Note: not a geometric mean because obtained from a single source. 15 ppb (odor measurement of 2,3-pentanedione vapor-air mixtures). Note: compared to 1.4 ppb for diacetyl obtained from the same reference. ¶ 9.4 ppb (odor measurement of 2,3-pentanedione vapor in the headspace above aqueous solutions, 2,3-pentanedione concentration in solution converted to an air concentration using Henry's Law constant). Note: compared to 0.70 ppb for diacetyl obtained from the same reference. ¶ National Toxicology Program 2007]; (2) from 2,3-butanediol, by oxidative dehydrogenation of 2,3-butanediol over a copper or silver catalyst ; (3) from acetoin (obtained by electrochemical oxidation of methyl ethyl ketone), by reacting acetoin with molecular oxygen in the presence of a copper oxide catalyst ; or, ( 4) from 1-hydroxyacetone (obtained by dehydrogenation of 1,2-propanediol), by the acid-catalyzed condensation of 1-hydroxyacetone with formaldehyde . Diacetyl is also a byproduct of fermentation. Natural diacetyl is used in the form of starter distillate, a concentrated flavor distillate, which may contain different concentrations of diacetyl depending on production conditions . The compound 2,3-pentanedione is also naturally produced by fermentation and is recovered from dairy waste to be used as a flavoring ingredient . The chemical synthesis of 2,3-pentanedione is achieved in the following ways: (1) the condensation of lactic acid and an alkali metal lactate ; (2) the acid-catalyzed condensation of 1-hydroxyacetone with paraldehyde ; or (3) the oxidation of 2-pentanone with excess sodium nitrite and diluted hydrochloric acid in the presence of hydroxylamine hydrochloride . # Production Uses and Applications The flavor manufacturing industry commonly uses diacetyl and 2,3-pentanedione during flavor formulation production. Flavor formulations are then sold to downstream users for the production of flavored food products. Flavored food production is the process of manufacturing food and beverage products that contain added flavor formulations or flavorings to enhance or modify the taste of the product. Examples of flavored food products include bakery products such as cake mixes, flour and margarines, dairy products such as cheese and yogurt, snack foods such as soft spreads and crackers, beverages such as soft drinks, in addition to candy, ice cream, frozen foods, and many other food and beverage products. The addition of concentrated flavorings including diacetyl is a cost effective way to impart the desired properties to manufactured food items. In flavor formulations, diacetyl and 2,3-pentanedione are typically found as components in liquid solutions but can also be added to powders in dry mixtures to create a solid particulate formulation. Many volatile compounds are also encapsulated in an amorphous carbohydrate, producing more stable products with more manageable properties. Encapsulated powder flavorings are often created with a spray dryer, which converts a slurry mixture into a powder in which the flavorings are surrounded by the powder instead of simply coating the powder. When the encapsulated powder comes into contact with moisture, the flavor is released quickly and completely . The percentage of diacetyl or 2,3-pentanedione in a particular flavor formulation varies widely depending upon the product and its use. In past years, microwave popcorn contained the highest proportion of diacetyl ranging from 1% to 25% diacetyl . The diacetyl content in flavor formulations has declined rapidly as many manufacturers have reduced or substituted diacetyl with other flavoring compounds with similar characteristics, such as 2,3-pentanedione. Most confectionary flavors contain up to 1% diacetyl while marshmallow production uses up to 5% . Starter distillate, produced by fermenting milk with starter cultures, contains diacetyl in the range of 1% to 5% and is often used as a flavor enhancer in the dairy industry. Diacetyl is the major flavor component of starter distillate, constituting as much as 80% to 90% of the mixture's organic flavor compounds . A NIOSH health hazard evaluation (HHE) at a modified dairy production company found concentrations of airborne diacetyl ranging up to 2.14 parts per million on a full-shift TWA basis . Diacetyl is also used as a chemical modifier of arginine residues in proteins in studying glycation (the nonenzymatic browning of foods or the nonenzymatic binding of sugar and protein molecules in the body) . Other uses for diacetyl include reactant/starting material in chemical or biochemical reactions, analytical reagent, antimicrobial/preservative, electron stabilizing compound and modifier of radiation response for chemical and biological systems, and photoinitiator/photosensitizer in polymerizations . # Potential for Exposures It is difficult to quantify the number of employees directly involved with flavor manufacturing and more specifically having exposure to diacetyl or diacetyl substitutes in the United States. According to the Environmental Protection Agency (EPA) Non-Confidential Inventory Updating Report, diacetyl had an aggregate production volume between 10,000 and 500,000 pounds in [EPA 2002. The North American Industry Classification System (NAICS) category 311, the most relevant category, indicates nearly 1.5 million employees are employed in food manufacturing. Bureau of Labor Statistics and Department of Commerce data provide a breakdown of a portion of that number into categories shown in Table 1-2. According to the FEMA, whose members account for approximately 95% of all flavors produced in the United States, a total of 6,520 employees work directly in flavor manufacturing or related laboratory activities in membership companies . Initial research concerning occupational exposure to diacetyl has focused on employees who directly produce flavorings or use them in the microwave popcorn industry. However, the employment figures for the food production industry suggest that some other employees have potential exposure to diacetyl and other food flavorings. For example, respiratory issues have been anecdotally reported for cheese production (Wisconsin), yogurt production (Ohio), and potato chip manufacturing . Employers in the food manufacturing sector are generally small business owners with 89% and 2,3-Pentanedione 9 1 . Introduction of establishments employing fewer than 100 employees and nearly 53% of establishments employing fewer than 10 employees . Industries that comprise food manufacturing can be found in every state in the United States; however, concentrations of specific industries are found in general geographic locations. For example, in 2004, 33% of the cheese manufacturing employees employed in the United States were in Wisconsin, and 20% of employees employed in the fruit and vegetable preservation industry were in California . There is increasing likelihood that various substances will be used as substitutes for diacetyl or 2,3-pentanedione. The potential for both employees' exposure and disease from exposure to these substitutes still remains largely unstudied. ACGIH . 2012 TLVs® and BEIs®: threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists Signature Publications. AIHA . Odor thresholds for chemicals with established occupational health standards. Dupraz C, Brosseau L, Guy H, May M, Reed L, eds. Fairfax, VA: American Industrial Hygiene Association. Akpinar-Elci M, Travis WD, Lynch DA, . Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 24 (2):298-302. Alleman T, Darcey DJ . Case report: bronchiolitis obliterans organizing pneumonia in a spice process technician. J Occup Environ Med 44 (3):215-216. Aquila W, Botzem J, Brunner M, Fuchs H, Krause W, Pandl K, Schäfer-Lüderssen U . Process for the preparation of α-diketones from ketols or ketals from ketols. US Patent 6316676, filed February 28, 2001, and issued November 13, 2001. Ashley K, McKernan LT, Burroughs E, Deddens J, Pendergrass S, Streicher RP . Analytical performance criteria. Field evaluation of diacetyl sampling and analytical methods. J Occup Environ Hyg 5 (11): D111-116. Betterton E . The partitioning of ketones between the gas and aqueous phases. Atmos Environ 25A:1473-1477. BLS (Bureau of Labor Statistics) . Food manufacturing. . Date accessed: October 2007. BLS (Bureau of Labor Statistics) . National Employment Matrix, 2008-18, for NAICS 3113, 3115, 3118, and 3119. . htm. Date accessed: December 2010. Burdock GA . Encyclopedia of food and color additives. Boca Raton, FL: CRC Press, p. 2115. Buttery RG, Ling LC, Stern DJ . Studies on popcorn aroma and flavor volatiles. J Agr Food Chem 45( 3):837-843. California Code of Regulations. Title 8, §5197. CDC (Centers for Disease Control and Prevention) . Fixed obstructive lung disease in workers at a microwave popcorn factory- Missouri, 2000:345-347. CDC (Centers for Disease Control and Prevention) . Fixed obstructive lung disease among workers in the flavor-manufacturing industry -California, 2004:389-393. Chem Service Inc. . Material safety data sheet, 2,3-pentanedione, O-818. Day G, LeBouf R, Grote A, Pendergrass S, Cummings K, . Identification and measurement of diacetyl substitutes in dry bakery mix production. J Occup Environ Hyg 8 (2):93-103. EPA . Non-confidential inventory updating report. . Date accessed: March 2011. EU . Recommendation from the Scientific Committee on Occupational Exposure Limits for diacetyl. SCOEL/SUM/149. Ezrailson EG . Bronchiolitis in popcorn-factory workers. N Engl J Med 347 (24):1980-1982; author reply 1980-1982; discussion 1980-1982. FDA (Food and Drug Administration) . Code of Federal Regulations, Title 21, Volume 3, Part 184, Direct food substances affirmed as generally recognized Occupational Exposure to Diacetyl and 2,3-Pentanedione as safe, 21 CFR184.1278, diacetyl. U.S. Government Printing Office. FEMA . Respiratory health and safety in the flavor manufacturing workplace. In: The flavor and extract manufacturers association of the United States. Washington, DC: p. 28. Fischer Scientific . Material safety data sheet, 2,3-Butanedione, 99%. / msds/03275.htm. Date accessed: November 2009. Hall G, Andersson J . Volatile fat oxidation products. I. Determination of odour thresholds and odour intensity functions by dynamic olfactometry. Lebensmittel-Wissenschaft+ Technologie= Food science+ technology. OSHA . Chemical sampling information, 2,3 pentanedione. / chemicalsampling/data/CH_260240.html. Date accessed: September 2014. Parmet AJ . Bronchiolitis in popcorn-factory workers. N Engl J Med 347 (24):1980-1982; author reply 1980-1982; discussion 1980-1982. Parmet AJ, Von Essen S . Rapidly progressive, fixed airway obstructive disease in popcorn workers: a new occupational pulmonary illness? J Occup Environ Med 44 (3):216-218. Pouchert CJ, ed. . The Aldrich library of FT-IR spectra. Edition I, Volume I. Milwaukee, WI: Aldrich Chemical Co. Saraiva MA, Borges CM, Florencio MH . Nonenzymatic model glycation reactions: a comprehensive study of the reactivity of a modified arginine with aldehydic and diketonic dicarbonyl compounds by electrospray mass spectrometry. J Mass Spectrom 41 (6): . Occupational Exposure to Diacetyl and 2,3-Pentanedione Schachter EN . Popcorn worker's lung. N Engl J Med 347 (5):360-361. Sega GM, Lewis MJ, Woskow MH . Evaluation of beer flavor compounds. Proceedings of the annual meeting of the ASBC 25:156-164. Sigma Aldrich . Material safety data sheet, No. B85037, 2,3-butanedione. . com/MSDS/MSDS/DisplayMSDSPage.do?country=US &language=en&productNumber=D3634&brand=SIGM A&PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Fsigma%2Fd3634 %3Flang%3Den. Date accessed: December 2009. Snider JR, Dawson GA . Tropospheric light alcohols, carbonyls, and acetonitrile: concentrations in Southwestern United States and Henry Law data. J Geophysical Res: Atmos 90(ND2):3797-3805. Strekowski RS, George C . Measurement of Henry's Law Constants for acetone, 2-butanone, 2,3-butanedione, and isobutyraldehyde using a horizontal flow reactor. J Chem Eng Data 50 (3):804-810. Ubbink J, Schoonman A . Flavor delivery systems. In: Kirk RE, Othmer DF, eds. Kirk-Othmer encyclopedia of chemical technology. 4th ed. Cary, NC: John Wiley and Sons, Inc., pp. 527-563. United States Census Bureau, United States Department of Commerce . Spice and Extract Manufacturing. 2002 Economic Census. Manufacturing Industry Series. Volume: EC02-311942(RV). van Rooy FG, Rooyackers JM, Prokop M, Houba R, Smit LA, Heederik DJ . Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 176( 5):498-504. # Assessing Occupational Exposure in Employees # Introduction Measurement of diacetyl and 2,3-pentanedione exposure is helpful in preventing flavoringsrelated lung disease, even with complex flavorings formulations. Exposures to diacetyl and 2,3-pentanedione can be monitored using personal and area (environmental) air samples because the predominant route of exposure is inhalation. Results from air sampling can be compared with established criteria such as the NIOSH RELs. Measuring employees' exposures to diacetyl or 2,3-pentanedione may help identify processes, locations, or tasks with exposures of concern; guide corrective actions such as engineering controls; identify improved work practices; and select appropriate respiratory protection. This chapter discusses (1) available sampling and analytical techniques for monitoring diacetyl and 2,3-pentanedione vapor in the workplace; (2) techniques for measuring diacetyl and 2,3-pentanedione in airborne dust and bulk materials; (3) real-time techniques for measuring relevant airborne analytes and other flavoring compounds; and (4) results of some occupational exposure assessments by NIOSH and others of facilities that use diacetyl and 2,3-pentanedione. Many work environments have mixed exposures, with multiple chemical agents present. Although the primary focus of this criteria document is diacetyl and 2,3-pentanedione, other compounds can also be of concern. Depending upon the processes employed in a workplace, sampling should be conducted for agents of concern to maintain safe work environments. Common sampling and analytical methods to determine concentrations of diacetyl and 2,3-pentanedione are presented in Appendices A-E. # Time-integrated Air Sampling and Analytical Methods for Diacetyl and 2,3-Pentanedione Vapor Personal breathing zone sampling is the preferred approach for estimating employee exposure. For personal sampling, an employee wears the air sampling equipment, and the inlet to the collection medium is positioned within the employee's breathing zone. Area sampling is performed for several purposes such as to evaluate exposure characteristics associated with an area or process, and to determine the efficiency of control systems. While the same sampling equipment may be used in some cases for both personal and area sampling, area sampling is stationary, in contrast to personal sampling, which allows for mobility by accompanying the employee throughout the sampling period. # OSHA Methods 1012 and 1013 In response to the need for longer sampling time periods with a lower limit of detection or reliable quantitation limit, the Occupational Safety and Health Administration (OSHA) validated two sampling and analytical methods, OSHA Method 1012 and OSHA Method 1013. These methods can be used for the simultaneous determination of diacetyl and acetoin. As of the publication of this document, these are the recommended methods for diacetyl. OSHA Methods 1012 and 1013 use two 600 milligram (mg) sorbent tubes containing specially cleaned and dried silica gel (SKC Inc.,Eighty Four,PA, in series and air is sampled at a flow rate of 50 milliliters per minute (mL/min) for up to 180 minutes for determination of TWA concentrations, and a flow rate of 200 mL/min for 15 minutes for short-term concentration measurements. An opaque sampling tube protective cover should be used in conjunction with the sampler to prevent the glass sampling tube from breaking and to protect the sample from light, which can decompose diacetyl and acetoin. After sampling, the tubes should be separated, capped, and protected from light with aluminum foil or other opaque material. There is no requirement that samples be kept cold during shipping or storage. OSHA Method 1013 has a reliable quantitation limit of 12 ppb (0.041 mg/m 3 ) diacetyl for a 9-liter sample, and samples are analyzed by gas chromatography using a flame ionization detector (GC-FID). OSHA Method 1012 has a nearly 10 times lower RQL of 1.3 ppb (4.57 micrograms per meter cubed ) diacetyl for a 9-liter sample, which is achieved by derivatizing diacetyl with 2 milligram per milliliter (mg/mL) O- (2,3,4,5,6-pentafluorobenzyl) hydroxylamine hydrochloride in the extraction solution and analyzing by gas chromatography using an electron capture detector (GC-ECD). An advantage of OSHA Method 1013 is that sample preparation can be performed in one hour, whereas the derivatization step of OSHA Method 1012 requires 36 hours. After samples have been extracted and analyzed using OSHA Method 1013, if needed (e.g., if sample concentration is not detectable), they can be derivatized and analyzed using OSHA Method 1012 to benefit from its lower detection capability. # OSHA Method 1016 OSHA Method 1016 can be used to measure 2,3-pentanedione concentrations. OSHA Method 1016 uses the same sampling media, sample collection procedure and analytical procedure as OSHA method 1013. However, OSHA Method 1016 allows for the simultaneous analysis of 2,3-pentanedione, diacetyl, and acetoin by using a different analytical column to optimize the analytical separation of these compounds. In addition, OSHA Method 1016 requires samples to be shipped cold. If diacetyl and/or acetoin are not anticipated to be present, OSHA Method 1016 can be used to sample for an additional 20 minutes, or 200 minutes, at 50 mL/min to determine TWA concentrations of 2,3-pentanedione . For a 10-liter sample, the RQL of 2,3-pentanedione is 9.3 ppb (38 µg/m 3 ). # OSHA Method PV2118 Superseded by OSHA Methods 1012 and 1013, OSHA Method PV2118 was developed as an air sampling method for diacetyl that uses two 150/75 mg silica gel sorbent tubes in series at a recommended flow rate of 50 mL/min for one hour. In response to the limited capacity of this sampler in humid environments, a modified version of OSHA Method PV2118 was used by some practitioners in the field. The modified method uses larger 400/200 mg sorbent tubes packed with specially cleaned silica gel allowing for greater sample capacity without breakthrough of diacetyl. Sample analysis remained unchanged. # NIOSH Method 2557 While no longer recommended for use, NIOSH developed NIOSH Method 2557[NIOSH 1994 for measuring diacetyl vapor in air. It called for the collection of samples onto a 150/75 mg carbon molecular sieve sorbent tube (Cat. No. 226-121, SKC Inc., Eighty Four, PA) at a flow rate between 10 and 200 mL/min for a sample volume between 1 and 10 liters. The method specifies that samples be stored cold and analyzed within 7 days of sampling. Until 2007, NIOSH Method 2557 was the predominant air sampling and analytical method for diacetyl used in the field, but it is no longer recommended for use . field and chamber investigations indicated that NIOSH Method 2557 was adversely affected by humidity, resulting in an underestimation of true diacetyl concentrations. To aid in the evaluation of sampling and analytical methods for diacetyl, a field comparison study between new and existing sampling collection methods was conducted . Side-by-side field samples were collected in flavor manufacturing facilities and analyzed according to NIOSH Method 2557, OSHA Method PV2118, and a modified version of OSHA Method PV2118. The results of this field work confirmed the tendency of NIOSH Method 2557 to underestimate the true concentration of diacetyl as humidity increases. However, no mathematical correlation was found in this data set which would produce an adjustment factor to allow for correction of results. As a result, NIOSH researchers collaborated with scientists at the OSHA Salt Lake Technical Center laboratory to study the effects of humidity on measured diacetyl air concentrations using NIOSH Method 2557. This laboratory has chamber facilities for the generation of known diacetyl air concentrations with the ability to control both temperature and relative humidity (RH). Controlled test atmospheres of diacetyl were generated and sampled through an array of sampling tubes at calibrated flow rates. Test atmospheres were controlled for diacetyl concentration, temperature, and relative humidity. Results indicated that diacetyl recoveries for NIOSH Method 2557 were affected by absolute humidity (AH), storage time of sample tube prior to extraction, and diacetyl air concentration. The study resulted in the development of a mathematical procedure to adjust diacetyl concentrations previously measured using NIOSH Method 2557. The procedure is presented in Appendix F and is also published elsewhere ]. # Other Air Sampling Method(s) in Development Because of current interest in occupational exposure to flavoring compounds, new methods continue to be developed for their measurement. At this time, however, none of these methods are validated. A method is being developed by NIOSH to measure alpha-dicarbonyl compounds (such as diacetyl and 2,3-pentanedione) in air via derivatization with 1,2-phenylenediamine. This compound is known to react with alpha-dicarbonyl compounds to form stable quinoxaline derivatives . In this method, air is sampled through a sorbent tube containing silica gel coated with 1,2-phenylenediamine at 0.1% by weight. Samples are extracted in the lab and extraction solutions analyzed by gas chromatographynitrogen/phosphorus detection (GC-NPD). A potential advantage of this method is greater sampling volume and sampling time without the breakthrough that would be experienced if sampling for an extended time with uncoated silica gel tubes. Experiments to date indicate no breakthrough of diacetyl, 2,3-pentanedione, or 2,3-hexanedione from the sampling tubes after passing 144 liters of air at 80% RH. This enables sampling for 8 hours without changing out sampling tubes. Another advantage is the high sensitivity of NPD detection, which will enable measurement of alpha-dicarbonyl compounds below the proposed REL for diacetyl of 5 ppb. A new method for collecting air samples using evacuated canisters has been evaluated for several VOCs . The 450-milliliter canisters, which can be equipped with either instantaneous grab sampling attachments or restricted-flow controllers (for task-based or full-shift sampling), are suitable for collection of area and personal samples. The air samples are analyzed for VOCs using a preconcentrator/gas chromatography-mass spectrometry (GC-MS) system. At present, this canister method is in the process of being validated with three additional compounds, diacetyl, 2,3-pentanedione and 2,3-hexanedione, and is being reviewed for incorporation into the NIOSH Manual of Analytical Methods. A method for priority flavoring compounds is being investigated that utilizes a novel sampler-the helium diffusion sampler (HDS) . The HDS collects a whole air sample for either short-term or full-shift sampling. The advantages of HDS are that no air sampling pump is required, there is no concern about breakthrough of the sample components, and there is minimal sample handling in the laboratory. A portion of the collected air sample is analyzed by a preconcentrator/GC-MS in the selected ion monitoring mode. Although HDS will not support limits of detection achieved by TD-GC-MS because of the relatively small air volume sampled (~20 mL), it may have adequate sensitivity to measure diacetyl at the proposed REL. # NIOSH Method 2549 -Qualitative Determination of Volatile Organic Compounds To sample for diacetyl, 2,3-pentanedione, as well as a wide range of other flavoring VOCs, thermal desorption sorbent tubes can provide a high degree of sensitivity. This is because desorption of compounds from thermal desorption tubes does not involve dilution into an extraction solvent. Instead, compounds are thermally desorbed from the sampling tubes in a thermal desorption system. This technique is primarily used for qualitative screening purposes because of the ability of thermal desorption tubes to capture a diverse range of VOCs, but specific compounds can be quantified if corresponding standards are analyzed along with the samples. The thermal desorption tube is usually a stainless steel tube configured and filled with a single sorbent bed or multiple beds of various sorbents including carbonaceous materials, carbon molecular sieves, and/or porous polymers. The sorbents can be heated to high temperatures without breakdown or the generation of artifacts, so thermal desorption tubes can be cleaned and reused multiple times. The tubes are analyzed with a thermal desorber-GC-MS (TD-GC-MS) . # Sampling for Diacetyl and 2,3-Pentanedione in Airborne Dust and in Bulk Materials Although diacetyl and 2,3-pentanedione are normally found in liquid form, they can also be encapsulated in or coated on a powder substrate. Air sampling for dust that may be generated during handling of powdered flavorings can be achieved by active sampling methods. During the sample collection, however, some of the diacetyl and 2,3-pentanedione may volatilize, i.e., release from the dust particles and enter the vapor phase due to contact with moisture. In addition, environments in which dust is generated may also contain vapors of the flavoring compounds. Sorbent tubes used for the collection of vapor-phase diacetyl or 2,3-pentanedione cannot be used to adequately sample for dust at the low flow rates required by the tubes . As a result, modifications to the sampling methods are necessary to assess exposure to both vapor and dust. # Size-Selective Air Sampling for Dust Measurement of airborne dust particles according to their size (e.g. inhalable, thoracic, and respirable) can help to understand where they may deposit in the respiratory tract. Several types of sampling devices are available (e.g., inhalable dust samplers, impactors, cyclones, and sampling cassettes) to provide measurements of different size fractions of airborne dust. In most cases, dust is collected onto a filter, and the filter can be analyzed via gravimetric means to provide the mass of the dust. Filters should be hydrophobic in nature (e.g., polyvinyl chloride) in order to minimize collection of moisture. After being measured gravimetrically, filters can be analyzed for diacetyl and other compounds by the procedure described in section 2.3.2. Validated methods such as NIOSH Method 0500 for total dust and NIOSH Method 0600 for respirable dust are available for the collection and gravimetric analysis of airborne dust. # Sampling for Diacetyl and 2,3-Pentanedione in Airborne Dust A sampling and analytical method is being developed by NIOSH for the quantitative measurement of diacetyl, 2,3-pentanedione, and potentially other flavoring compounds in dust. A sampling cassette with a filter is used to collect airborne dust. The filter is then extracted in water and the aqueous solution is heated to promote the transfer of volatile components to the headspace above the solution. The headspace is sampled using a solid-phase microextraction (SPME) fiber. Headspace SPME involves an equilibrium process in which the volatile analytes establish equilibria between the sample solution, the headspace above the solution, and the polymer-coated fused silica fiber. The mechanism by which the analytes are extracted from the headspace is based on absorption of the analytes onto the fiber. The fiber is inserted directly into a GC-MS. The analytes are extraced from the fiber in the hot injection port and concentrated onto an analytical column. Because the entire sample collected on the fiber is introduced into the GC-MS instrument, as opposed to an aliquot of the sample for methods in which a solvent extract is used, lower detection limits can be achieved. This same procedure can be used to measure diacetyl, 2,3-pentanedione, and potentially other flavoring compounds in samples of bulk powders. # Bulk Liquids and Solids # Sample collection Although the review of safety data sheets or other available product documentation may be helpful to identify flavor compounds and potential exposures, they are not always comprehensive or specific. Collection and analysis of bulk flavoring materials can be useful to identify and quantify chemical ingredients and guide exposure assessment strategies. Prior to collecting bulk samples, it is important to consider the physical state of the materials to be sampled (liquids, pastes, or powders), the need to sample opened or unopened containers, the sampling locations, the number of samples to collect, and the amount of sample to collect (often determined by requirements of the laboratory analysis). Bulk samples should be representative; in other words, they should be derived from a variety of sampling locations and obtained from multiple batches to capture any variability in the bulk materials used. When sampling, it is important to collect and transport the sample in a manner that does not contaminate or cross-contaminate the bulk materials. Only clean or unused sample containers that are compatible with the bulk materials sampled should be used. In general, glass containers are ideal because they will not react with most chemicals, but polyethylene or polypropylene containers may also be appropriate. A typical container is a 20-mL glass scintillation vial with a polytetrafluoroethylene (PTFE)-lined screw cap. Each container should be clearly labeled with information about the bulk sample including material sampled, company and product number, site of sampling, date of sampling, sample tracking number and any hazards or precautions to be taken when handling the bulk sample. After sampling, consideration should be given to preserve the integrity of the bulk samples during storage and shipping. For example, care should be taken to keep samples cold and protected from light if necessary. In addition, bulk materials should not be shipped together with air samples. Established Department of Transportation (DOT) and International Air and Transport Association (IATA) shipping regulations of hazardous materials and dangerous goods should be followed if hazardous materials are to be shipped. Materials that are considered hazardous for the purpose of transportation under the DOT regulations are listed in the hazardous materials table in Title 49 of the Code of Federal Regulations (CFR), Section 172.101 ; materials that are considered dangerous goods for the purpose of shipping by air under IATA regulations are listed in the list of dangerous goods in IATA dangerous goods regulations, section 4.2 . The DOT and IATA regulations guide the classification/identification and packaging of hazardous materials and the marking and labeling of shipping containers containing hazardous materials. If the materials to be shipped are known to be hazardous but the specific names of the materials are not found on either the DOT hazardous materials table or the IATA list of dangerous goods, then the materials must be classified into a hazard class according to section 3 of the IATA dangerous goods regulations handbook, and a proper shipping name must be assigned according to section 4 of the IATA dangerous goods regulations handbook. A person must be trained in DOT and IATA regulations and certified in order to mark a shipment as hazardous. If it is unknown whether the materials to be shipped are hazardous or not, then a person who is trained in DOT and IATA regulations should be consulted. # Measurement of diacetyl or 2,3-pentanedione content of bulk powders The analytical procedure being developed for airborne dust samples described in section 2.3.2 will also be used for analysis of bulk powder samples. # Real-time Techniques for Diacetyl and Other Flavoring Compounds Several analytical methods provide real-time or near real-time measurements of volatile compounds in air such as diacetyl and 2,3-pentanedione. These methods have the unique advantage of providing continuous exposure information over very short averaging periods that can be viewed as it is being generated during sampling or later if the instrument has data-logging capabilities. The abundance of measurement information provides valuable insight into variations in concentrations throughout the sampling period as well as the short-term concentration peaks that can possibly be associated with their sources. While real-time monitoring instruments generally lack sufficient sensitivity and specificity for monitoring REL levels of diacetyl and 2,3-pentanedione, they can be useful for screening, identifying appropriate work practices, and to find leaks and "hotspots." This information can be very useful in the development of exposure controls. # Photoionization Detectors Photoionization detectors (PIDs) can be used to monitor VOC air concentrations in industrial work environments, including flavoring manufacturing facilities, and have become favored instruments for on-site monitoring because of ease of operation, reliability, versatility, cost, and response to a wide variety of substances. PID instruments measure the relative concentration of VOCs by passing the molecules of those compounds past an ultraviolet lamp that emits radiation over a narrow wavelength range in the ultraviolet region of the electromagnetic spectrum. Photons of ultraviolet radiation will form a molecular ion by removing an electron from orbit around that molecule, allowing for electronic detection of that ion, hence the name. The energy of the radiation emitted by the lamp is inversely proportional to its wavelength, and common PID lamps produce energy in the range from approximately 8 to 12 electron volts (eV). The amount of work required to form a molecular ion by removing an electron from orbit, a property known as ionization potential, varies by compound but for many hydrocarbons is in the range from 7 to 11 eV. Because nitrogen, oxygen, and many of the minor components of air (i.e., water vapor, carbon monoxide, carbon dioxide, argon) have ionization potentials significantly higher than 12 eV, they are not ionized by the photons emitted from a PID. This property allows for the continuous monitoring of air to obtain an estimate of total hydrocarbon concentration. PIDs respond to a broad range of VOCs and do not provide concentrations specific to any particular compound. They are often calibrated for isobutylene and can commonly detect total VOC concentrations from 1 to 2,000 ppm. Modern PIDs can be programmed to measure the concentration of VOCs at fixed time intervals and store these data for subsequent download to a computer. # Infrared Analyzers The absorption of infrared (IR) radiation, while more commonly used as a qualitative tool, can also be used to quantify many substances by determination of response relative to known concentrations of that substance. Absorption of electromagnetic radiation in the IR region of the spectrum will produce transitions among vibrational and rotational states of the molecules absorbing that rotation. This absorption can only occur at wavelengths exactly matching the vibrational frequency of a chemical bond, and by selecting the proper analytical wavelength it is possible to obtain reasonable specificity in the compound being quantified. Diacetyl can be detected and measured by using an IR gas analyzer such as the Thermo Electron MIRAN® "SapphIRe" (Thermo Fisher Scientific Inc., Waltham, MA), which is a portable directreading instrument that has the advantage of displaying real-time concentrations. The SapphIRe is a single beam IR spectrophotometer with a pathlength of 0.5 or 12.5 meters. It has a sample cell volume of 2.23 liters and a built-in pump that runs at approximately 14 liters per minute. Single sample analyses are updated every 0.5 seconds. The detector is available with preloaded factory calibrations for over 100 gases, but because diacetyl is not in this standard library it should be set up for this application by the factory. The concentration range that can be measured is dependent on the compound in question. The high and low settings for the pathlength extend this range considerably. The predecessor model, the Foxboro/Wilks MIRAN 1A, has adjustable wavelength and pathlength controls and can be calibrated for gases or vapors using the closed loop system available. Many MIRAN 1A models are still in use in the field. The best wavelength for measuring diacetyl is about 9 micrometers. Neither water nor carbon dioxide should interfere significantly at that wavelength. The minimum detectable concentration should be less than 0.5 ppm at the highest pathlength. Fourier transform infrared gas analyzer (FTIR) spectroscopy can be used to analyze a sample of gaseous molecules for both chemical composition and for the concentration of individual chemical constituents. In this analysis, chemical functional groups absorb IR radiation at specific, unique frequencies producing a characteristic spectrum of absorbed versus transmitted radiation. From this spectrum, identification and quantitation of the gas is possible. FTIR analysis can produce real-time quantitation of flavoring compounds in air providing chemical specific full-shift, partial-shift, and peak concentration measures although interferences can pose analytical difficulties in quantifying specific flavoring compounds in complex environments with multiple organic chemicals present. # Photoacoustic Spectroscopy (Infrared Absorbance) Techniques Because the absorption of infrared radiation produces transitions among vibrational states of molecules, the application of rapid pulses of IR photons at the proper wavelength can be used to produce pressure variations in the air surrounding the molecules absorbing that radiation. Those pressure variations can be detected as sound waves, the amplitude of which is proportional to the concentration of the analyte of interest. Using IR radiation and measuring this resultant amplitude to quantify an analyte is the technique of photoacoustic spectroscopy. Diacetyl has been measured using the Innova photoacoustic infrared gas analyzers, which are direct-reading instruments that have the advantage of displaying real-time concentrations. Both personal and area concentrations were measured during tasks involving exposure to diacetyl in liquid and powder form and then 8-hour TWA exposures were calculated. The powder exposures only measured vapor released and did not include diacetyl adsorbed on the powder . Current available models of the photoacoustic analyzer are the 1314 and 1412, available from California Analytical Instruments, Inc., Orange, CA. The measurement system is based on photoacoustic infrared detection and provides the capability of measuring virtually any gas that absorbs in the infrared spectrum. Gas selectivity is achieved through the use of optical filters that provide both a means of detecting the gas of interest and compensating for interfering gases and water. Specifications on the unit indicate a dynamic range of 4 orders of magnitude and a repeatability of 1% of the measured value. The analyzer displays updated concentrations approximately every 30 seconds. The analyzer can be calibrated using diacetyl standards and can analyze diacetyl concentrations from the parts per billion range to hundreds or thousands of parts per million. # Industrial Hygiene Surveys and Exposure Assessments Several investigations have been completed by NIOSH and others within the flavoring and food production industries. Exposure conditions vary widely, depending upon site-specific parameters and the processes employed. Many diacetyl samples have been collected to evaluate occupational exposures in the workplace and are described below. When pertinent data on absolute humidity and time to sample extraction were available, measurements obtained using NIOSH Method 2557 were subsequently corrected for the method's tendency to underestimate ]. An overview of diacetyl samples collected during multiple investigations is presented in Table 2-1. # NIOSH Microwave Popcorn Production Exposure Assessments NIOSH conducted health hazard evaluations at six microwave popcorn plants from 2000 to 2003 . In these facilities diacetyl-containing butter flavorings (liquids, pastes, or powders) were mixed with heated soybean oil in large heated mixing tanks. Salt and coloring were added to the flavoring mixture which was transferred to packaging lines and combined with kernel popcorn in microwaveable bags. Diacetyl concentrations were measured with NIOSH Method 2557 in multiple production locations using personal and area samples. In the plants, 29 area and 17 personal samples were collected in mixing areas, and 67 area and 65 personal samples were collected in packaging areas. Humidity-corrected mean diacetyl air concentrations ranged from 0.63 to 57.2 ppm for area samples and from 0.035 to 1.33 ppm for personal samples in the mixing areas. In the packaging areas, mean concentrations ranged from 0.019 to 3.0 ppm for area samples and from 0.023 to 1.16 ppm for personal samples. In general, diacetyl concentrations were higher in the mixing rooms when the diacetyl-containing butter flavorings were heated. In 2010, a microwave popcorn company asked NIOSH to evaluate chemical constituents in eight liquid butter flavorings because their supplier did not identify chemical substitutes they were using in place of diacetyl . Quantitative GC-MS analysis showed acetoin in five samples, 2,3-pentanedione in four, and 2,3-hexanedione in one, all at concentrations of 0.5% or less by weight, except for one acetoin sample at 2%. The more sensitive semiquantitative headspace analysis with thermal detection tubes found diacetyl and acetoin in all samples, 2,3-pentanedione in five, 2,3-hexanedione in one, and 2,3-heptanedione in one. # Other Microwave Popcorn Production Exposure Assessments White et al. conducted a comprehensive, repeated exposure monitoring campaign at four microwave popcorn plants. A total of 639 full shift diacetyl samples were collected during the day and night shifts in multiple production areas including all employees who worked in the slurry (mixing) room. In that study 49% of 639 samples were below their limit of detection with the maximum measurement of 11.72 ppm after correction for humidity . Overall, exposures were higher for mixers compared to non-mixers and were consistent with diacetyl concentrations observed during previous NIOSH investigations. Diacetyl exposures declined substantially for mixers after the installation of engineering controls. # NIOSH Flavoring Manufacturing Exposure Assessments In 1985, NIOSH conducted a health hazard evaluation at a plant in Indiana that produced flavorings for the baking industry . Case histories showed severe fixed obstructive lung disease among employees in a mixing room. Data from previous air monitoring indicated a high dust concentration in the personal breathing zone of an employee during a mixing operation. Diacetyl was on a list of ingredients commonly used at this facility but airborne measurements of diacetyl or other flavoring compounds were not made. Although the investigators were unable to identify specific etiology at that time, they concluded that employees' disease was most likely caused by some agent in the mixing room at the plant. NIOSH personnel conducted evaluations at three California flavoring manufacturing facilities where they measured exposures to diacetyl and other related compounds , the mean full-shift concentration of diacetyl in the liquid production room was 0.26 ppm, while in the powder production room it was 0.07 ppm. For personal samples that were collected with NIOSH Method 2557 and not corrected for humidity and time to extraction, the mean concentrations in liquid production and powder production rooms were 0.10 ppm and 0.05 ppm. This work also indicated high variability in concentrations of volatile organic compounds (as measured with a PID) and dust (as measured with personal dust monitors) with time. A health hazard evaluation was conducted at a facility in Wisconsin that manufactured flavorings, modified dairy products, and bacterial additives. One of the flavoring products made at this plant was liquid starter distillate, a product of distillation of fermented milk stock, which contains about 4.5% diacetyl. Starter distillate and liquid diacetyl were used to make a variety of powdered (via spray drying processes) and liquid flavorings. NIOSH staff obtained 21 personal and 29 area air samples using modified OSHA Method PV2118 for diacetyl throughout the facility. They found the highest full-shift TWA concentrations in the starter distillate room (geometric mean of 1.78 ppm for personal and 1.06 ppm for area samples), followed by the spray dry room (0.756 and 1.07 ppm) and the flavors room (0.329 and 0.171 ppm). In the spray dry room, FTIR realtime measurements indicated peak diacetyl concentrations up to 90 ppm in the employee's breathing zone while dumping diacetyl from buckets to mixing tanks and while pumping diacetyl from a barrel into buckets. A peak exposure of about 18 ppm was measured in the breathing zone of an employee in the same room while cleaning a barrel with a water hose. Company air sampling data were obtained during a health hazard evaluation at an Indiana flavorings plant that used many ingredients, including diacetyl and starter distillate, in the batch production of a variety of liquid and powdered flavorings . Using NIOSH Method 2557 prior to the HHE request to measure diacetyl, they collected 22 samples. The geometric mean full-shift TWA diacetyl concentration in spray drying operations was 0.123 ppm for personal samples and 0.169 ppm for area samples, while in the other production areas, mean concentrations up to 0.762 ppm and 0.375 ppm were measured for personal and area samples, respectively. Because of the problems with NIOSH Method 2557, these results were likely underestimations of the true concentrations. No data on humidity or time from collection to analysis was available, so no correction could be estimated. Subsequent measurements (45 personal and 71 area samples) by the company, after some control intervention, were collected using validated OSHA sampling Methods PV2118 and 1012 for diacetyl. In the spray drying operations, the geometric mean for full-shift diacetyl personal samples was 0.182 ppm, and for area samples it was 0.167 ppm. The highest mean concentration in the other production areas was 1.900 ppm for personal samples (liquid compounding area) and 0.076 ppm for area samples (coffee and tea area). Another health hazard evaluation was performed at a flavorings plant in Kentucky that produced flavors, colors, and food and beverage ingredients used in the manufacture of consumer products . Diacetyl was not found in use during the NIOSH air sampling survey. Using evacuated canisters, diacetyl and 2,3-hexanedione were not detected in any of the instantaneous or 3-hour area air samples taken in several parts of the plant. 2,3-Pentanedione was detected in two area air samples taken in the liquid samples room. The detection limits ranged from 1.4 to 2.9 ppb for diacetyl, 1.5 to 3.2 ppb for 2,3-pentanedione, and 1.7 to 3.6 ppb for 2,3-hexanedione. Of the two air samples that detected 2,3-pentanedione in the room, one was an instantaneous sample taken near a trash can for disposal of used pipettes while making a flavoring recipe and resulted in a level of 47 ppb. The other sample that detected 26 ppb 2,3-pentanedione was collected for 187 minutes in the center of the room. During the sampling period, several employees were preparing recipes, which included fruit and cheese flavors. # Other Flavoring Manufacturing Exposure Assessments In a study evaluating diacetyl exposures in 16 flavor manufacturing facilities, Martyny et al. measured levels of that compound from the limit of detection (0.01 to 0.18 ppm depending on sample duration) to as high as 60 ppm. Using a protocol designed to obtain measurements during worst-case exposures by collecting samples only during processes in which diacetyl was being used, 181 personal and area samples were collected generally for 1 to 3 hours. Samples for diacetyl were collected and analyzed using NIOSH Method 2557[NIOSH 1994 ppb), as were two of the three also sampled with the more sensitive draft NIOSH method using 1,2-phenylenediame-treated silica gel tubes (0.5 ppb limit of detection) -the detectable concentration was 0.9 ppb while using smoke flavoring. Of six area samples collected alongside cleaning operations with evacuated canisters for 2,3-pentanedione (1.2 to 2.9 ppb limits of detection) and 2,3-hexanedione (1.5 to 3.6 ppb limits of detection), one measured 2,3-pentanedione at 6.2 ppb and 2,3-hexanedione at 9.0 ppb during a nearly 3-hour cleaning procedure of cooking equipment containing strawberry cream cheese remnants while no cream cheese was being made in the room. The snack food production plant applied powdered seasonings onto potato, corn, and tortilla chips after they were fried. Headspace analyses of bulk samples of seasonings found trace amounts of diacetyl, but no other alpha-diketone compounds, in four of the seven samples: barbeque, honey barbeque, cheddar sour cream, and chili cheese. Diacetyl, 2,3-pentanedione, and 2,3-hexanedione were not detected in the five 15-to 180-minute personal breathing zone evacuated canister air samples from processing line operators during nacho cheese tortilla chip production. The detection limits ranged from 2.8 to 6.0 ppb for diacetyl, 3.4 to 7.2 ppb for 2,3-pentanedione, and 3.2 to 6.8 ppb for 2,3-hexanedione. Although diacetyl was detected in three area samples collected instantaneously near the seasoning hopper, it was not quantifiable. Because it was found between the detectable level of 1.3 ppb and the quantifiable level of 4.3 ppb, the reported concentrations of 1.4 to 1.7 ppb are considered estimates. The area samples did not detect 2,3-pentanedione or 2,3-hexanedione (detection limits of 1.5 and 1.6 ppb, respectively). The coffee production plant produced flavored and unflavored whole bean and ground coffee. Full-shift area air samples collected for diacetyl with OSHA Method 1012 and for 2,3-pentanedione with OSHA Method 1016 had highest mean concentrations by location in the grinding/packaging room (103 ppb diacetyl, 63 ppb 2,3-pentanedione), flavoring room (90 ppb diacetyl, 151 ppb 2,3-pentanedione), and the production offices (62 ppb diacetyl, 32 ppb 2,3-pentanedione), which were located within the larger grinding/packaging room. These were followed by mean concentrations in the roasting room (20 ppb diacetyl, 6 ppb 2,3-pentanedione), green bean and finished goods warehouses (11 ppb diacetyl, <3 ppb 2,3-pentanedione), quality control room (8 ppb diacetyl, <3 ppb 2,3-pentanedione), maintenance shop (7 ppb diacetyl, <3 ppb 2,3-pentanedione), and the nonproduction offices (4 ppb diacetyl, <3 ppb 2,3-pentanedione). The flavoring room was under negative pressure with respect to the adjacent grinding/packaging room where unflavored roasted coffee was processed. Personal sample mean concentrations by location in the coffee plant were highest for employees working in the grinding/packaging room (93 ppb diacetyl, 53 ppb 2,3-pentanedione), flavoring room (80 ppb diacetyl, 122 ppb 2,3-pentanedione), production offices (81 ppb diacetyl, 22 ppb 2,3-pentanedione), all over (59 ppb diacetyl, 39 ppb 2,3-pentanedione), and housekeeping (54 ppb diacetyl, 18 ppb 2,3-pentanedione). These were followed by those in the roasting room (26 ppb diacetyl, 7 ppb 2,3-pentanedione), quality control room (24 ppb diacetyl, 11 ppb 2,3-pentanedione), warehouse (8 ppb diacetyl, <3 ppb 2,3-pentanedione), and nonproduction offices (7 ppb diacetyl, <3 ppb 2,3-pentanedione). The mean area concentrations on the grinding/packaging and flavoring room mezzanines, where roasted whole and ground bean storage hoppers were located, were higher than those measured on the main production levels of the rooms. A 15-minute short-term air sample collected at the open hatch of a grinding/packaging room mezzanine hopper holding unflavored ground coffee above an active packaging line measured concentrations of 14,300 ppb diacetyl and 13,800 ppb 2,3-pentanedione. The location of the sample was representative of the proximity of employees' faces as they frequently and momentarily monitored coffee levels in the hoppers throughout their shift. NIOSH also conducted a small industrywide study at some flavored food production facilities where diacetyl and other food flavorings were added to various food products. Seventy-four personal and 105 area samples were collected for diacetyl using OSHA Method 1013. With one exception where local exhaust ventilation was documented in some locations, no engineering controls were noted in any facility. Of the 179 total samples, 12 had detectable levels of diacetyl (LOD 0.5 -1.0 ug/sample). The eight area samples ranged from 0.03 to 3.1 ppm, with three samples above 1 ppm (1.1, 2.1 and 3.1 ppm). The four personal samples ranged from 0.06 to 0.6 ppm . # OSHA Site Visits Related to Diacetyl and Flavorings that Contain Diacetyl Between January 2008 and January 2010, an OSHA contractor measured diacetyl exposure to employees in a series of 12 industrial hygiene surveys at various facilities that use (11 facilities) or manufacture (1 facility) formulated flavorings, including flavorings that contain diacetyl [Eastern Research Group 2008a, b, c, d, 2009a, b, c, d, e, 2010a. In the first two surveys, conducted in January 2008, diacetyl was measured using OSHA Method PV2118. In the subsequent 10 surveys, OSHA Methods 1012 and 1013 were used. At all facilities, visual observation was made of engineering controls in place at the various operations evaluated. The measured range of diacetyl concentrations are presented in At the time of most of these field investigations, which preceded the California diacetyl regulation implemented in December 2010, little 2,3-pentanedione was being used for artificial butter flavoring. When food manufacturers began to request that diacetyl percentage be less than 1% of flavoring constituents, flavor manufacturers sometimes did not inform their clients of the substitution of 2,3-pentanedione and other diacetyl substitutes . Accordingly, populations with 2,3-pentanedione exposure without previous diacetyl exposure are difficult to identify. Thus, illness attributable to 2,3-pentanedione alone has not been studied. # Obstructive Lung Disease Consistent with Obliterative Bronchiolitis The most significant health consideration for flavoring-exposed employees is the development of exertional dyspnea or findings consistent with obliterative bronchiolitis (also often called constrictive bronchiolitis, see discussion of terminology). Most textbooks characterize obliterative bronchiolitis as a rare disease with airways obstruction, defined by a decreased FEV 1 and a decreased FEV 1 to FVC ratio on spirometry testing. The magnitude of decline in FEV 1 determines the severity of the disorder. However, three recent case series of biopsy-confirmed obliterative bronchiolitis document that many cases have normal spirometry and, when abnormal, the spirometric pattern can be restrictive, obstructive, or mixed restrictive and obstructive in nature . Because of the historical assumption that obliterative bronchiolitis is an obstructive disease, the early NIOSH investigations focused on obstructive abnormalities. Airways obstruction can occur in diseases such as smoking-related COPD (including emphysema and chronic bronchitis) and in asthma. In emphysema, the airways obstruction is usually FOOD PRODUCTION All three employees in a popcorn popping business developed symptoms of airways disease during their tenure; all were lifetime nonsmokers. One of the employees had significant reversible airways obstruction with some clinical evidence suggesting possible bronchiolitis obliterans in addition to asthma. FOOD PRODUCTION At a plant using a newly reformulated flavoring that included 2,3-pentanedione, no obstruction was identified in the 22 employees tested. Participants had higher than expected rates of shortness of breath, physician-diagnosed asthma, and a restrictive pattern on spirometry (four cases ranging from mild to moderately severe), compared to U.S. adults. Some participants reported symptoms with a workrelated pattern. # NIOSH F Three cross-sectional surveys, FOOD PREPARATION Studies of employees at three sites found higher prevalences of spirometric restriction, wheeze, dyspnea on exertion, nasal and eye irritation, and nasal allergies when compared to national rates. Cooks were 3-4 times more likely to report work-related respiratory symptoms. Fixed airways obstruction identified in two employees did not appear to be work-related. # NIOSH D Cross-sectional survey, FLAVORING MANUFACTURING This study of 34 employees found that bacterial products employees had higher prevalences of work-related eye symptoms and posthire skin problems than flavoring employees; both groups reported lower respiratory symptoms related to the substances they handled at work. One employee was identified with fixed airways obstruction and two employees with restriction on spirometry. NIOSH 2009a], clinical bronchiolitis obliterans , bronchiolitis obliterans syndrome , and flavoring-related bronchiolitis obliterans . Of the few surgical lung biopsies that have been performed in affected employees, some have been interpreted as showing evidence of "constrictive bronchiolitis" or "obliterative bronchiolitis" . The term fixed obstructive lung disease is the least specific of the terms. The term popcorn worker's lung refers to the population of employees in which the disease was first identified. The term flavorings-related lung disease refers to the full spectrum of lung diseases that may be related to flavorings exposure and is not necessarily limited to obstructive conditions. The terms flavoring-related bronchiolitis obliterans, constrictive bronchiolitis, and obliterative bronchiolitis refer to pathologic findings of inflammation and fibrosis primarily involving the bronchioles, leading to irreversible airflow limitation. Terminology is complicated by the fact that, historically, researchers have applied the term "bronchiolitis obliterans" to different distinct disorders that involve the bronchioles . The terms clinical bronchiolitis obliterans and bronchiolitis obliterans syndrome refer to those who are thought to suffer from this pathologic condition based on clinical findings, but have not undergone lung biopsy for pathological confirmation. Additional discussion regarding diagnostic terminology in relation to the different recognized forms of bronchiolitis is included in section 3.1.1. # Bronchiolar Disease and Terminology Bronchiolitis obliterans refers to disease processes that show some degree of inflammation, narrowing, or obliteration of small airways (bronchioles) in the lung . Historically, bronchiolitis obliterans has been classified into two groups: proliferative bronchiolitis obliterans and constrictive bronchiolitis obliterans . The disorder known as bronchiolitis obliterans organizing pneumonia (BOOP) is included in the proliferative group. BOOP is characterized pathologically by intraluminal polyps in the respiratory bronchioles, alveolar ducts, and alveolar spaces accompanied by organizing pneumonia in the more distal parenchyma. Clinically it is usually associated with diffuse alveolar opacities on chest x-ray and computed tomography scan; pulmonary function testing may show a restrictive defect . BOOP was first described in 1985. Prior to this, many cases that matched the description for BOOP were classified as idiopathic bronchiolitis obliterans . The American Thoracic Society and the European Respiratory Society have recommended the use of the term cryptogenic organizing pneumonitis (COP) instead of BOOP to avoid confusion with the disease constrictive bronchiolitis obliterans . While proliferative bronchiolitis can be idiopathic (e.g., COP), known associations include collagen vascular diseases (e.g., systemic lupus erythematosus), acute infections (e.g., influenza, mycoplasma), organ transplantation, and aspiration pneumonitis. Proliferative bronchiolitis is generally responsive to corticosteroid medications and is usually reversible . Obliterative bronchiolitis (also referred to as constrictive bronchiolitis obliterans , constrictive bronchiolitis , and bronchiolitis obliterans ) is a rare disorder characterized by alterations in the walls of respiratory and membranous bronchioles that cause concentric narrowing or complete obliteration of the airway lumen, without involvement of the distal lung parenchyma by inflammation or organizing pneumonia . In affected individuals, pulmonary function tests usually show airways obstruction and hyperinflation , but biopsy-confirmed cases may have normal or restrictive spirometry . Chest x-rays may be normal or show hyperinflation, peripheral attenuation of the vascular markings, and nodular or reticular opacities . The predominant finding of obliterative bronchiolitis on high-resolution computed tomography (HRCT) scan is heterogeneity of lung density due to mosaic perfusion and air trapping . Other findings of bronchiolitis on HRCT scan include centrilobular thickening, bronchial wall thickening, bronchiolar dilatation, and the tree-in-bud pattern. Cylindrical bronchiectasis is frequently associated with obliterative bronchiolitis; scans with both inspiratory and expiratory views are helpful because expiratory views are important in assessing air trapping . Identification of the obliterative bronchiolitis lesion on lung biopsy may be difficult because of its patchy distribution , often requiring step-sectioning and special staining to identify airway walls . The diagnosis is a multidisciplinary one involving a team with clinical, radiologic, and histopathologic expertise; HRCT evidence often replaces the need for surgical lung biopsy . In comparison to proliferative bronchiolitis, obliterative bronchiolitis is generally unresponsive to corticosteroid medications and often progresses to more severe disease , although progression after exposure cessation is not characteristic of flavoring-related disease consistent with obliterative bronchiolitis ]. As mentioned previously and discussed in detail in the next section (3.1.2), the medical evaluations of employees who have developed lung disease during exposure to diacetyl and other flavoring compounds have generally revealed findings consistent with obliterative bronchiolitis. Because of concerns for patient welfare and the invasive nature and imperfect sensitivity of lung biopsy for diagnosing obliterative bronchiolitis, most patients have been diagnosed based upon clinical findings. Despite the small number of lung biopsies conducted, findings consistent with obliterative bronchiolitis have been identified in multiple flavorings-exposed patients NIOSH 2007a]. Patients exposed to sulfur mustard gas are another patient population where obliterative bronchiolitis has been diagnosed in a small subfraction of the patients while other patients are diagnosed using contemporary clinical criteria, including HRCT scans . Other known causes of obliterative bronchiolitis include uncontrolled inhalation exposures to ammonia, chlorine, phosgene, nitrogen dioxide and sulfur dioxide, collagen vascular diseases (especially rheumatoid arthritis), infections, and organ transplantation (bone marrow, heart-lung, lung) . Because of the difficulty of identifying the lesions of obliterative bronchiolitis on lung biopsy, and because the disease occurs commonly after heart-lung and lung transplants, in 1993 a committee sponsored by the International Society for Heart and Lung Transplantation proposed a clinical description for the disease termed bronchiolitis obliterans syndrome. The syndrome refers to graft deterioration secondary to persistent airflow obstruction as defined by pulmonary function changes with or without histolopathologic confirmation. Probable risk factors for BOS include acute graft rejection and cytomegalovirus pneumonitis . The term BOS has also been used in cases of obliterative bronchiolitis resulting from chemical injury and diagnosed using clinical criteria with or without biopsy Ghanei et al. 2004a; . Because the terminology used in the peerreviewed literature of flavorings-exposed employees has included several different accepted and frequently interchanged diagnostic terms, and indeed may have been influenced by the peer-review process itself, this criteria document sometimes provides the terms used in the cited papers and includes the criteria used in the patient evaluations. All eight cases that had HRCT scans showed marked bronchial wall thickening and mosaic attenuation with air trapping; five cases also showed mild cylindrical bronchiectasis. In two of three cases that underwent lung biopsy, the reviewing pathologist reported findings that supported or were consistent with a diagnosis of bronchiolitis obliterans ]. These nine employees had developed a dry persistent cough, shortness of breath on exertion, and wheezing after a median of 1.5 years of employment. At the time of symptom onset, five of the employees had been working in the room where butter flavorings, salt, and colorings were combined with heated soybean oil. The other four employees had been working in the adjacent room where the oil and flavoring mixture was combined with kernel popcorn in microwavable bags (packaging area). None of these employees were initially diagnosed by their personal physicians as having obliterative bronchiolitis. Initial diagnoses received by these employees included pneumonia, asthma, emphysema, bronchitis, COPD, hay fever, and sinusitis. Five of the employees had minimal smoking history. All nine employees had been prescribed oral corticosteroids, but none had improvement in lung function. Five of the employees had been placed on lung transplant waiting lists by their personal physicians ]. # Index plant lung function testing The NIOSH medical survey at the index microwave popcorn plant (Facility G) in November 2000 included lung function testing with spirometry and DL CO , chest x-rays, and a questionnaire NIOSH 2006]. NIOSH compared the prevalences of respiratory symptoms, self-reported physiciandiagnosed asthma and chronic bronchitis, and airways obstruction on spirometry to data from the Third National Health and Nutrition Examination Survey (NHANES III) . Of 135 current employees, 117 (87%) completed the questionnaire, and 97 (83%) of the survey participants worked in the microwave popcorn production areas of the plant. The remaining 20 survey participants worked in areas where butter flavorings were not used such as plain kernel popcorn packaging, offices, warehouse, and outside receiving. The prevalences of respiratory and systemic symptoms, mucous membrane irritation, and skin irritation were higher among employees in microwave popcorn production areas than in other areas. Among all survey participants, the prevalences of chronic cough and shortness of breath when hurrying on level ground or walking up a slight hill were 2.6 times higher than expected; the prevalence of wheezing was three times higher than expected. The prevalences of self-reported physician-diagnosed asthma and chronic bronchitis were 1.8 and 2.1 times higher than expected, respectively. Of the 116 employees who underwent spirometry, 21 had airways obstruction, 3.3 times higher than expected. Airways obstruction in nonsmokers was 10.8 times higher than expected, and only two employees with airways obstruction had a significant response to administered bronchodilator. Five of six employees in the quality control (QC) laboratory had airways obstruction; these employees popped up to 100 bags of microwave popcorn in microwave ovens per employee per 8-hour work shift. Of the 115 survey participants who had an x-ray, 111 had no abnormalities, two had evidence of emphysema, one had saber-sheath tracheal narrowing attributable to COPD or tracheal stenosis, and one had focal upper-zone scarring and atelectasis at the left lung base. DL CO was normal in 96 of 103 employees tested, including all but one of those with airways obstruction. # Index plant environmental survey In addition to the cross-sectional medical survey, NIOSH conducted a detailed environmental survey at the index microwave popcorn plant (Facility G) in November 2000 NIOSH 2006]. The predominant VOC in the air of the plant was the butter flavoring compound diacetyl. All measurements above detectable limits (except where noted otherwise below) were subsequently corrected for underestimation inherent to NIOSH Method 2557 related to absolute humidity and days to extraction . The relative humidity and temperature measurements used for correction were available from in-facility area-specific and shift-specific measurements during all sampling, and sample-specific days to extraction were supplied by the laboratory. The mixing room had the highest mean air concentration of diacetyl (57.2 ppm); the next highest mean air concentration of diacetyl was in the packaging area for machine operators (2.8 ppm). The mean air concentration of diacetyl in the QC laboratory was 0.8 ppm, and for maintenance it was 0.9 ppm. The much higher prevalence of airways obstruction in QC employees, despite much lower average air concentrations of diacetyl, may reflect an enhanced risk of peak flavoring exposures when microwaved bags of popcorn product were opened; peak exposures were also likely present in maintenance employees and mixers. Mean diacetyl air concentrations in other plant areas were less than 0.15 ppm. . # Findings of index plant follow-up surveys NIOSH conducted seven follow-up medical and eight follow-up environmental surveys at the index microwave popcorn plant (Facility G) from 2001 to 2003 NIOSH 2006]. These surveys were conducted to follow employee symptoms and lung function over time as exposures decreased with the implementation of engineering controls. NIOSH recommended a respiratory protection program for mixing room employees to minimize their exposures while engineering controls were being implemented; this program was initiated at the time of the November 2000 NIOSH survey. Starting in February 2001, the company began implementing several engineering controls to decrease air concentrations of flavoring compounds in the mixing room, the main source of air contaminants in the plant. An exhaust fan was installed in an outer wall of the mixing room to move contaminated air from this room to the outdoors and to maintain this room under negative air pressure relative to the rest of the plant. An air lock was installed at the entrance to the mixing room to further isolate the room from the rest of the plant. Local exhaust ventilation of the air space (headspace) above the contents of the heated flavoring tanks and the mixing tank in which flavorings are mixed into heated soybean oil was accomplished via ducts connecting the tank lids to the wall exhaust fan. A pump was installed to facilitate closed transfer of heated butter flavorings into the mixing tank. In 2002, the company constructed and began using a new mixing room that was more isolated from the packaging area than the original mixing room. In the packaging area, additional general dilution ventilation was implemented in 2001 along with local exhaust ventilation for seven heated holding tanks located on a mezzanine above the packaging lines that contained soybean oil and butter flavoring mixtures transferred via pipes from the mixing room. . In their analyses of data from the eight NIOSH medical surveys at Facility G from November 2000 to August 2003, NIOSH compared health outcomes in microwave popcorn production employees hired after the implementation of exposure controls to health outcomes in employees who had been working at the plant prior to the implementation of controls . For these analyses, investigators classified employees according to their hire date as follows: "Group 1" consisted of employees who were already working at the plant at the time of the November 2000 survey (i.e., before exposure controls were implemented), and "Group 2" consisted of employees who started work at the plant after the November 2000 survey (i.e., after exposure controls were implemented and exposures had declined). Because of a high turnover rate among employees hired after the November 2000 survey, participation in more than one medical survey was much higher in Group 1 ( 100 Group 2 employees who participated in more than one survey worked in the packaging area. Therefore, for all Group 2 packaging area employees who participated in more than one survey, investigators compared symptoms and lung function on their first survey to their last survey results. In Group 1, the only statistically significant change in symptom prevalence over time was a decline in reported eye, nose, or throat irritation. There were no statistically significant changes in the prevalence of airways obstruction or in mean percent predicted FEV 1 . Based on data from employees' first surveys, packaging area employees in Group 2 had lower prevalences of respiratory symptoms and airways obstruction on spirometry, and mean percent predicted FEV 1 was significantly higher compared to packaging area employees in Group 1. All these differences were statistically significant except for usual cough. There were no statistically significant changes in the prevalences of symptoms, airways obstruction, or mean percent predicted FEV 1 from first to last survey in Group 2 packaging area employees . Of interest is that 47% of all employees with abnormal spirometry tested by NIOSH (in Groups 1 and 2) were asymptomatic. NIOSH conducted a mortality study on Facility G employees based on Social Security Administration vital status determination as of November 30, . These plants and the index plant (Facility G) were similar with regard to some production and exposure characteristics; however, there were some important differences as well ]. The similarities in production and exposure characteristics at the six microwave popcorn plants evaluated by NIOSH were as follows: (1) At each plant, one to three employees per work shift (i.e., mixers) measured butter flavorings (liquids, pastes, and powders) in open containers such as 5-gallon buckets and poured the flavoring into heated soybean oil in large (e.g., 500-gallon) heated mixing tanks, most of which had loose-fitting lids. (2) Most mixers did not use respirators. Only one mixer at one plant reported consistent use of a respirator with organic vapor cartridges during mixing tasks. (3) Mixers added salt and coloring to the oil and flavoring mixture, which was then transferred by pipes to nearby packaging lines to be combined with kernel popcorn in microwaveable bags. (4) Employees on the packaging lines operated the packaging machines and facilitated the placement of the finished product into cartons and boxes. In most plants, QC employees popped product in microwave ovens that were usually located in a separate QC laboratory. Other employees were located in warehouse and office areas. In separate areas of some plants, employees also packaged plain kernel popcorn in plastic bags without oil or flavorings. The six microwave popcorn plants differed in size as follows: (1) Two small plants (Facilities J and O) had fewer than 15 employees, one or two mixing tanks, and one packaging line. (2) One medium-sized plant (Facility N) had approximately 50 employees, one mixing tank, three holding tanks for heated oil and butter flavoring mixtures, and three packaging lines. (3) The three largest plants (Facilities G, K, and L) had more than 100 employees, five or more tanks, and seven or more packaging lines. In some plants, flavoring-mixing activities and tanks were in a separate room adjacent to the packaging area. In other plants, some or all tanks of heated oil and flavoring were adjacent to or were inadequately isolated from the packaging lines ]. In addition to the employees with findings consistent with bronchiolitis obliterans at the index microwave popcorn plant, employees with fixed airways obstruction and air trapping on HRCT scans consistent with obliterative bronchiolitis were identified at four of the other five microwave popcorn plants where NIOSH conducted HHEs ]. Including the index plant, the three largest plants and one of the small plants had affected mixers NIOSH 2003bNIOSH , 2004a. Like the index plant, the medium-sized plant had affected packaging area employees. At both of these plants, packaging area employees worked near tanks of heated oil and butter flavorings . The biopsies of three of the six employees who underwent lung biopsy at the medium-sized plant were reported by the reviewing pathologists as having findings consistent with bronchiolitis obliterans NIOSH 2003a]. Compared to mean diacetyl air concentrations measured at the index microwave popcorn plant, mean corrected diacetyl air concentrations at the other five microwave popcorn plants were lower: 0.02 to 0.83 ppm in the packaging areas and 0.63 to 1.54 ppm in the mixing rooms/areas ]. NIOSH conducted analyses of aggregated data from the medical surveys conducted at the six microwave popcorn plants ]. Only the data from the first survey at the index microwave popcorn plant were aggregated with the data from the surveys at the other plants. Compared to employees who had never worked as mixers, employees who had at least one day of experience mixing butter flavorings into heated soybean oil had statistically significant (P 0.05 for all other comparisons). Of 27 packaging area employees with airways obstruction at plants where tanks were adjacent to or inadequately isolated from the packaging lines, 21 of 23 who were administered a bronchodilator had fixed airways obstruction. After excluding index plant data from the analyses, packaging area employees in plants where tanks were adjacent to or inadequately isolated from the packaging lines still had higher prevalences of airways obstruction (11.5% vs 5.5%; not statistically significant) and wheezing (25% vs 10.7%, P = 0.01) compared to packaging area employees at plants where tanks were isolated. The prevalences of other respiratory symptoms were similar in both groups. The findings across the six plants suggested that those employee groups with peak exposures, sometimes with relatively low average exposures, had higher prevalences of chest symptoms or pulmonary function abnormalities than those employees without intermittent high exposures ]. # Results of private surveys A large food company hired private consultants to conduct medical and environmental surveys at the company's four microwave popcorn plants . To assess for evidence of rapid lung function decline, the investigators identified employees with a progressive increase or decrease in FEV 1 of greater than 8% or 330 mL over 12 months among employees who participated in all three spirometry tests . They found no association between current diacetyl exposure (less than 0.05 ppm or greater than/ equal to 0.05 ppm) and a short-term persistent increase or decrease in FEV 1 , adjusted for pack-years of smoking and body mass index. Of 39 mixers with mixing experience before the implementation of mandatory PAPR use, five had airways obstruction. Three of the five had bronchodilator administered, and all three had a bronchodilator response. Three of the five had HRCT scans; two of the scans showed air trapping on the expiratory view. The investigators concluded that, "The contribution of exposure to butter flavouring with diacetyl to these clinical findings is uncertain." Three mixers who began mixing after the implementation of mandatory PAPR use were found to have airways obstruction. Preplacement spirometry was not available for these individuals. One of the three employees had pre-existing asthma, and the other two had long smoking histories (24 and 63 pack-years, respectively). The investigators concluded that the airways obstruction in these three individuals was likely due to asthma and smoking but could not rule out the possibility that short-term exposure to diacetyl contributed to the airways obstruction when respirators had not been used 100% of the time. Analyses of 6 years of spirometric follow-up of these four plant cohorts are pending. Management had required employees to wear respirators when weighing or adding the flavors or base ingredients to the mixers. However, employees did not always wear respirators during clean-up activities where exposure to powdered flavors was possible. NIOSH concluded that it was probable that some agent in the mixing room produced severe fixed obstructive lung disease in two employees. They did not identify a specific etiologic agent, but suspected an airborne agent because the lung was the only affected organ and because air sampling by the Indiana Division of Labor had revealed high dust exposures. The Indiana Division of Labor collected 20-minute air samples that showed dust air concentrations of 20 mg/m 3 in an employee's breathing zone and 2.5 mg/m 3 inside the hood of an employee's supplied-air respirator. NIOSH analyzed bulk ingredient samples for levels of proteolytic enzymes and endotoxin. They did not identify proteolytic activity in any of the samples; endotoxin levels were "below levels seen in other workplaces where endotoxin has been associated with large decrements in FEV 1 " . Air sampling for specific flavoring compounds was not conducted. A cluster of cases consistent with obliterative bronchiolitis among production employees at a flavoring manufacturing company was reported by Dr. James Lockey at the 2002 American Thoracic Society International Conference . After identification of an index case of biopsy-documented bronchiolitis obliterans at this plant, a survey of the workforce identified an additional four employees with clinical findings consistent with obliterative bronchiolitis. All five employees with these findings had normal spirometry tests at the start of employment. These employees went on to develop moderate to severe fixed airways obstruction. For 4 to 5 years after cessation of exposure to flavoring compounds, the affected employees had no further declines in their lung function. . This prevalence was similar to that expected in comparison to national data from NHANES III . However, the distribution by severity of obstruction was highly skewed, with six mild cases, seven moderate, one severe, and the remaining four very severe. The prevalence of severe and very severe obstruction combined was 2.7 times higher than expected overall (95% CI 1.2-6.4) and 15 times higher than expected in employees less than 40 years old (95% CI 5. 1-44.1). Sixteen obstructed cases worked in four companies using ≥ 800 pounds of diacetyl annually compared to two obstructed cases in companies using less diacetyl (prevalence of 5.3% versus 1.2%), for an odds ratio (OR) of 4.5 (95% . The prevalence of obstruction in employees currently doing any production task was 4.5% compared to 2.0% in production support employees (laboratory technicians/scientists, quality control technicians, maintenance/repair employees, warehouse employees, and truck drivers) and 2.3% in office employees. Of the 18 employees with obstruction, 14 currently worked in production, two worked in production support (one had just moved from production because of dyspnea), one with previous production experience currently worked in the office, and one could not be classified. Tenure was statistically significantly higher in employees with moderate or worse obstruction than in employees with mild obstruction (1.5 versus 9.0 years; P = 0.02). Half of the 18 employees with obstruction reported no chest symptoms (five of six employees with mild obstruction and four of seven with moderate obstruction). Of the 13 with documented postbronchodilator spirometry, 12 had fixed obstruction (including all four with severe or very severe obstruction). Of the 12 of 18 with obstruction who had medical evaluation results submitted to the California Department of Public Health, eight were diagnosed by their physicians to have either bronchiolitis obliterans (one biopsy-confirmed) or fixed obstruction related to flavorings; all eight had moderate to very severe disease . Some of the cases included in this analysis of California flavoring employee surveillance data were presented above in the descriptions of two NIOSH HHEs at California flavoring plants (Facilities B and C). # Lung disease in diacetyl production employees Lung disease consistent with obliterative bronchiolitis was reported among employees of a plant in the Netherlands that produced diacetyl . # Other food production case reports In addition to cases consistent with obliterative bronchiolitis in flavoring manufacture, diacetyl manufacture, and microwave popcorn production, case reports have surfaced in other food production industries in which flavorings are introduced into food products. In cookie manufacture with artificial butter flavoring in Brazil, four cases of bronchiolitis were described in young men, aged 24 to 27 years, who had worked between 1 and 3 years handling flavorings in preparation of cookie dough . NIOSH summarizes the evidence concerning spirometric restriction in flavoring-exposed employees in this section. . Of 15 cases of chronic dyspnea and cough following sulfur mustard exposure 20 years previously, 13 had normal spirometry, one had restriction, and one had obstruction; all had pathologic evidence of bronchiolar disease. The cases with biopsy-documented constrictive bronchiolitis all had normal spirometry, and the two with the abnormal spirometry had chronic cellular bronchiolitis . Of 19 cases of biopsy-documented obliterative bronchiolitis, six had normal spirometry (although 2 had isolated gas trapping), 11 had obstruction, one had restriction, and one had a mixed pattern . This last case series originated from a clinical referral center without common exposures. These pathologic case series suggest two conclusions. First, abnormal spirometry is insensitive to pathologic obliterative bronchiolitis that results in symptoms warranting clinical evaluation. Second, the finding of restriction in populations with cases of fixed airways obstruction consistent with obliterative bronchiolitis is likely to be part of the spectrum of obliterative bronchiolitis, although the differential diagnosis in individual employees requires investigation. # Index Plant Findings Regarding Restriction Among the former employees who developed findings consistent with obliterative bronchiolitis while working at the index microwave popcorn plant (Facility G), lung function tests in one employee showed a reduced total lung capacity and reduced residual volume in addition to airways obstruction. These reduced lung volumes indicate that this employee had restrictive lung disease as well as airways obstruction . This former employee also had a low carbon monoxide diffusing capacity and was unusual among the former employee cases in having some reversibility after ceasing employment at the microwave popcorn ]. In the first cross-sectional survey of the index plant (Facility G), 10 of 116 employees had isolated abnormal FVC, of whom 7 had low total lung capacity; 11 employees had isolated airways obstruction. An additional 10 employees had both low FVC and airways obstruction, for a total of 21 of 116 employees having any restrictive spirometric pattern. None of those with any restriction had radiologic interstitial abnormalities. When the prevalence of any restrictive abnormality was examined by cumulative exposure quartile (using exposure estimates corrected for humidity and time to extraction), a trend for exposure response relationship was evident: From lowest to highest exposure quartile, the prevalence of any restriction was 10.7%, 13.3%, 20.7%, and 24.1% (P = 0.08). During follow up of these plant employees, one employee with rapidly falling pulmonary functions in a restrictive pattern underwent open lung biopsy. The pathology report documented caseating lung granulomas around airways, but grossly normal areas of lung were not sampled for examination of possible obliterative bronchiolitis. Cultures and stains for microorganisms did not yield an infectious etiology, and the physician concluded 3-2). In the three large microwave popcorn plants (Facilities G, K, and L), the restrictive proportion of abnormal spirometry ranged from 32.3% to 53.8%. These proportions are similar to those cited in two case series of biopsy-documented constrictive bronchiolitis, which were 50% in the case of U.S. soldiers in Iraq and Afghanistan and Iranians following sulfur mustard exposure, in which the pathology included proliferative bronchiolitis . In the three large microwave popcorn plants, the proportion of mixed restrictive and obstructive spirometry in those with abnormal spirometry was similar to the proportion with pure obstructive and pure restrictive abnormalities. In the consecutive clinical case series , the much lower proportion of restrictive abnormalities may be explained by the prevailing understanding a decade ago that obliterative bronchiolitis is an obstructive disease. # NIOSH Findings of Restrictive Spirometry at Flavoring Manufacturing Plants As in the microwave popcorn investigations, flavoring manufacturing workforces with cases consistent with obliterative bronchiolitis have also had employees with restrictive spirometry, with proportions of restriction among those with abnormal spirometry ranging from 28.6% to 88.2% (Table 3- 2). NIOSH found an unusually high prevalence of a restrictive spirometric pattern among production employees at a flavoring manufacturing plant (Facility I) in Indiana . Among the 106 employees with interpretable spirometry test results obtained by the company, 30 (28%) had a restrictive pattern (22 with a mild abnormality, six with a moderate abnormality, one with a moderately severe abnormality, and one with a severe abnormality). In addition, three employees had obstructive abnormalities, and one had a very severe mixed abnormality. Combining all spirometric abnormalities with those with only excessive decline in FEV 1 in the subset of employees with serial abnormalities, 39 (37%) employees had abnormal findings. In comparison to the U.S. general population, the employee prevalence of restrictive spirometric abnormalities was 3.8 times higher than expected, after adjustment for race, ethnicity, sex, age, smoking status, and body mass index. NIOSH later detected an error in abstraction of smoking information from company spirometry reports and corrected this comparison to 3.7 . NIOSH also found evidence of rapid lung function decline in this workforce (section 3.3) with a 7.0-fold risk of excessive decline in the subgroup of production employees with higher potential for flavorings exposure (later corrected to 5.8) . Average declines in percent predicted FEV 1 and FVC for the employees with four annual measurements were in a pattern consistent with the evolution of restrictive lung disease. As in other flavoring plants, chemical exposures were diverse, although diacetyl was used nearly daily. Personal samples of diacetyl obtained by the company using NIOSH Method 2557 (uncorrected for absolute humidity and days to extraction) ranged to 0.76 ppm and area measurements to 10.2 ppm. Company samples in 2008-2009 using OSHA methods (not requiring correction) ranged to 1.9 ppm for personal and 2.9 ppm for area samples. A company-sponsored re-analysis of Facility I spirometry data reported finding that no flavoring compounds, including diacetyl, had produced an increased risk of abnormal spirometric findings or longitudinal changes in spirometry . The study confirmed an excess risk of abnormal restrictive spirometry reported by NIOSH investigators with a similar prevalence ratio of in comparison to the general population reflected in NHANES III. The authors offered the inadequacy of the NHANES III study population as a comparison group, despite adjusting for age, sex, and body mass index, because the national data were largely drawn from urban centers, and the authors alleged that the flavoring employees in a large city in Indiana were largely agrarian. As an alternative comparison group, the authors described the employee group with lower potential for flavoring exposure as an internal control group with no or minimal exposure, also referring to them as an administrative group. However, all employees in the medical surveillance program were in production areas, and company data documented measurable diacetyl in all production areas, including worrisome measurements in packaging which was classified in the NIOSH health hazard evaluation as having lower potential for exposure. Thus, the similar distribution of abnormal restrictive spirometry across the production workforce, without regard to higher and lower potential for flavoring exposure, remained unexplained and cannot be attributed to misclassification of lung disease by spirometry, variable quality spirometry, or body habitus, also mentioned by the authors. The most likely explanation for the 3.3-3.7 increased odds for restrictive disease in the Facility I workforce is that risk for workrelated abnormality existed across both groups of production area employees in comparison to the national predicted estimate. The Ronk et al. study conclusion that none of the flavoring compounds caused workrelated spirometric abnormalities hinges on absence of association of pulmonary function abnormalities or decrements in employees with tenure in higher potential for flavoring exposure areas. The authors explain the difference in findings between their "negative" study and the NIOSH findings of work-related spirometric abnormalities by a NIOSH methodologic flaw in not taking account of correlated measures of serial lung functions. However, the authors misrepresent NIOSH analyses in which the outcome variables were the slopes of spirometric changes, expressed as mL/ year, based on linear regression as a smoothing function. NIOSH also used categorical outcomes of excessive spirometric decline. Neither of these NIOSH outcomes reflected correlated serial data. In addressing serial (correlated) spirometry measures, Ronk et al. used generalized estimating equation modeling, which is a reasonable approach. However, the authors chose an exchangeable correlation structure, which assumes that the variation between any two measures is equal; this assumption would not appear appropriate for pulmonary function test measures at varying intervals. Measures taken at a 6-month interval would likely be more correlated than measures at several-year intervals, as occurred in the Facility I spirometry data set. The generalized estimating equation models assume that cumulative tenure is linearly related to the change in spirometry measures, which may not be the case in a short-latency health effect as has occurred in flavoring-exposed employees. The Ronk et al. paper omits report of average changes in FEV 1 and FVC per year in their model without workplace covariates, which might have indicated unusually high average decrements per year. NIOSH had found that the average FVC decline in the employee population was 108 mL/year, about 3.5-fold the expected decline of approximately 30 mL/year. Ronk et al. separately modeled tenure in work areas with higher potential for exposure and tenure in liquid compounding with the apparent assumption that the remainder of the plant population had zero tenure (exposure), which is simply false. In particular, the liquid compounding tenure model ignores tenure in other higher potential for exposure jobs, which would clearly result in no associations with their work parameters. In contrast, the simpler NIOSH analyses of decline in lung function by areas with higher and lower potential for flavoring exposure demonstrated that both average declines and excessive decline differed between the two groups of production employees in statistically significant ways. These simple methods were not affected by correlated measurements. # Rapid Lung Function Decline Indirect and direct evidence shows that employees exposed to flavoring-related compounds can experience excessive lung function decline, whether within the normal range of spirometry or in those with either restrictive or obstructive spirometric abnormalities. Indirect evidence comes from reviews of medical records and work histories of flavoring-exposed employees who developed obliterative bronchiolitis. In a case series summarizing the eight affected former employees and one additional current employee at the index microwave popcorn plant (Facility G), the median length of employment prior to symptom onset was 1.5 years; the median duration of employment was 2 years . At a company that manufactured flavors for the baking industry (Facility A), two flavoring production employees developed respiratory symptoms and severe fixed airways obstruction within 7 months of starting work at the plant . Although these employees did not have baseline spirometry tests before they began working with flavorings, it is unlikely that their lung function was already significantly decreased when they started work. Production jobs such as preparing the oil and flavoring mixture for microwave popcorn production and mixing liquid and powder flavor ingredients in flavoring manufacture often require the employee to lift 50-to 100-pound containers. It is unlikely that employees could have performed such tasks if their lung function was already severely compromised when they started work. Some affected employees stopped working when they could no longer do the job because of severe shortness of breath on exertion, while others were relocated to less strenuous jobs . Direct evidence that employees exposed to flavoring-related compounds can experience rapid lung function decline comes from exposed employees who have had serial spirometry tests. Normal average FEV 1 decline is about 30 mL/year, and percent predicted FEV 1 does not usually change in the absence of disease because the predicted value is age corrected . Three of the affected former employees from the index microwave popcorn plant (Facility G) had declines in their FEV 1 percent of predicted of approximately 20% to 30% over approximately 2 years ]. NIOSH evaluated data from the eight NIOSH medical surveys at the index microwave popcorn plant for evidence of rapid lung function decline . The investigators chose as the criterion for rapid decline a decrease in FEV 1 of 300 mL and/or 10% from an employee's initial (baseline) spirometry test to the employee's last spirometry test. This criterion was similar to a threshold developed based on a study of coal miners evaluated over time with spirometry of high technical quality in which the researchers concluded that "when healthy working males perform spirometry according to American Thoracic Society standards, a yearly decline in FEV 1 greater than 8% or 330 mL should not be considered normal…" . The sensitive criterion used by the investigators, who did not annualize declines, was chosen because of the potential severity of the irreversible health outcome and the high technical quality of the pulmonary function tests, which allows for a sensitive cutpoint. For their analysis of the data from the surveys at the index microwave popcorn plant, investigators excluded survey participants with fewer than three interpretable spirometry tests because interpretation of change over time based on only two tests is less reliable . Of the 88 survey participants who participated in three or more NIOSH medical surveys at the index microwave popcorn plant (Facility G) and had started working there prior to the implementation of exposure controls ("Group 1"), 19 (22%) had FEV 1 declines of greater than 300 mL and/or 10% from their first to their last spirometry test. Four of these 19 employees had worked at some point in the mixing room, including one employee who experienced a 1,300-mL decline from the first test in November 2000 to the next test 5 months later; the next spirometry test 4 months after the second test showed an additional decline in FEV 1 of 600 mL, resulting in the employee leaving employment. This employee's FEV 1 continued to fall after leaving employment, with a total fall of 2,800 mL over 2.75 years, representing a decline from 96% of predicted FEV 1 to 39% of predicted FEV 1 . In comparison to survey participants who began working at the plant before the company started implementing exposure controls, only 3 (7%) of 41 survey participants with three or more spirometry tests who were hired after the company began implementing controls ("Group 2") had FEV 1 declines of greater than 300 mL and/or 10% from their first to their last spirometry test . Of the 27 Group 1 employees who participated in all eight medical surveys, mean annualized decline in FEV 1 in the first year of follow-up was 144 mL per year. Annualized decline in the second year of follow-up fell to 40 mL per year as exposures were controlled, and the annualized decline fell to 22 mL per year in the third year of follow-up, a rate of decline consistent with normal agingrelated lung function decline . . In contrast, in a microwave popcorn manufacturing cohort studied over 12 months, no relationship was demonstrated between current exposure level (dichotomized at 0.05 ppm) and an abnormal decrease in FEV 1 (found in 7% of employees using a criterion of a greater than 320 mL or 8% decline over one year), adjusted for pack-years of smoking and body mass index . As indicated in the studies above, different approaches have been used by investigators over time to define excessive or rapid decline in FEV 1 . These include percentage decline with various criteria, absolute decline with various criteria, normative population-based criteria for longitudinal limits of decline over various time intervals, and spirometry quality-adjusted criteria, all of which are discussed in Chapter 9, section 9.5. # Asthma At the index microwave popcorn plant and at one of the other five microwave popcorn plants that NIOSH evaluated (Facilities G and L), the prevalence of self-reported physiciandiagnosed asthma was approximately two times higher than expected [NIOSH 2004b[NIOSH , 2006. This suggests the possibility that some employees exposed to diacetyl and other flavoring compounds may be at increased risk for asthma (reversible airways obstruction) while others might be at risk for obliterative bronchiolitis (fixed airways obstruction). However, few of the survey participants with airways obstruction at these two plants who were administered a bronchodilator medication had a significant response (i.e., their airways obstruction was fixed); therefore, it is possible that some of these individuals had a different lung disease and that asthma may have been a misdiagnosis. Some employees at microwave popcorn plants and flavoring plants who were initially diagnosed with asthma were ultimately found to have fixed airways obstruction and other findings consistent with obliterative bronchiolitis ; . It is possible that individuals with pre-existing asthma may experience an exacerbation of their asthma due to the irritant properties of diacetyl or similar vapors. Many asthmatics react nonspecifically with bronchospasm to strong odors. Diacetyl has been reported to be a sensitizer in a rodent local lymph node assay, and other diketones, including 2,3-pentanedione, 2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione, have similar potency as sensitizers # Dermatologic Effects Of the former employees who developed findings consistent with obliterative bronchiolitis while working at the index microwave popcorn plant (Facility G), one employee also developed a severe skin rash # Discussion Medical evaluations of employees who have developed progressive shortness of breath while working at several microwave popcorn plants and flavoring plants have shown findings consistent with the severe irreversible lung disease obliterative bronchiolitis. Some affected employees have experienced extremely rapid declines in lung function, with severe airways obstruction occurring within several months of the start of exposure to flavoring compounds NIOSH 1986]. Whether restrictive lung disease is part of the spectrum of obliterative bronchiolitis in flavoring-exposed employees remains incompletely evaluated, although restrictive spirometry has been a common finding; in one plant, excessive FEV 1 declines in a restrictive pattern appear to be associated with potential for flavorings exposure. Employees as young as 22 years old have been affected by obstructive disease. Some affected employees have been placed on lung transplant waiting lists by their physicians because of the severity of their disease , and some flavoring-exposed employees have received lung transplants. The findings from investigations and studies conducted at multiple plants have revealed a link between exposure to diacetyl and risk for severe occupational lung disease. These findings meet the criteria that are often used to determine if the results of multiple studies indicate that an exposure is the likely cause of specific health effects . The first of these criteria is temporality: the exposure precedes disease development. Evidence of this comes from the many instances where initially asymptomatic diacetyl-exposed employees developed progressive shortness of breath within months of starting work and then were found to have severe fixed airways obstruction NIOSH 1986;. Additionally, NIOSH documented rapid falls in lung function in exposed employees with initially normal spirometry at three plants . California public health surveillance showed that excessive FEV 1 decline occurred in employees in flavor manufacturing plants that participated in a preventive program attempting to lower flavoring exposures . Temporality requires the exposure to precede disease development, and the inverse is that new disease cases should decline in a population with cessation of exposure, an evaluation by intervention or "experiment". Follow-up medical and environmental surveys at the index microwave popcorn plant (Facility G) revealed evidence of decreased lung disease risk with control of exposures. In employees hired before exposures were controlled, the prevalences of respiratory symptoms and airways obstruction and mean percent predicted FEV 1 did not change significantly over time (consistent with an irreversible disease). However, employees hired after exposures were controlled had lower prevalences of respiratory symptoms and airways obstruction and higher mean percent predicted FEV 1 on their first medical survey than employees hired before exposures were controlled, and these findings did not change significantly over time NIOSH 2006]. Additionally, among 27 employees who participated in all eight NIOSH medical surveys from 2000 to 2003, annualized declines in FEV 1 improved from 144 mL per year to 40 mL per year to 22 mL per year, the last being consistent with normal aging-related lung function decline . Similarly, the former employee index cases with clinical bronchiolitis obliterans had stable FEV 1 within about 2 years of exposure cessation ]. Another criterion is strength of the association: the magnitude of the apparent health risk due to the exposure. In analyses of data from the initial NIOSH medical survey at the index microwave popcorn plant (Facility G), the prevalence of airways obstruction among nonsmoking current employees was approximately 11 times higher than expected in comparison to national data from NHANES III. It was approximately three times higher than expected in older smokers . In analyses of California flavoring employee surveillance data, the prevalence of severe airways obstruction was approximately three times higher than expected among all employees compared to national data. The prevalence in employees less than 40 years old was 15 times higher than expected . The criterion of replication of findings (and strength of the association) between diacetyl exposure and development of severe occupational lung disease is apparent in the number of plants where employees have been affected and the number of production employees in these plants. The six microwave popcorn plants NIOSH evaluated represent a large segment of the microwave popcorn industry in the United States. Employees who developed findings consistent with obliterative bronchiolitis at these plants prepared the mixture of butter flavorings and soybean oil ("mixers") or worked nearby in the packaging area. Four of the six microwave popcorn plants NIOSH evaluated had affected mixers ]. Each of these plants had one to three mixers per work shift at the time of the NIOSH HHEs. The occurrence of multiple cases of severe airways obstruction in such a small job category (approximately 20 mixers across the six plants) is far greater than expected when compared to the U.S. population prevalence of severe airways obstruction from NHANES III data (0.1%, or 1 in 1,000, in individuals less than 50 years old, including smokers and never-smokers) . A similar magnitude of risk exists in some flavoring companies. At least six flavoring production employees developed findings consistent with obliterative bronchiolitis at three flavoring plants (Facilities A, B, and C) where NIOSH conducted medical surveys. There were approximately 30 production employees across these three plants at the time of the NIOSH HHEs [NIOSH 1986[NIOSH , 2007a[NIOSH , 2008. Consistency is also supported by the occurrence of lung disease consistent with obliterative bronchiolitis in diacetyl-exposed employees in at least eight flavoring manufacturing plants, a diacetyl production plant, a cookie manufacturing plant, and a coffee production plant CDC 2007;Kim et al. 2010;NIOSH 1986NIOSH , 2007aNIOSH , 2008; . Private consultants who conducted medical and environmental surveys at four microwave popcorn plants owned by one large food company also found in their data analyses that a history of working as a mixer and higher cumulative exposure to diacetyl were associated with decreased lung function . Additional criteria to support a causal link between diacetyl exposure and severe lung disease include biologic plausibility, doseresponse relationship, and consideration of alternate explanations. Biologic plausibility is supported by experimental studies of diacetyl toxicity summarized in Chapter 4. NIOSH found evidence of a dose-response relationship (i.e., worse lung disease or more employees affected with higher diacetyl exposure) in analyses of medical survey data from the index microwave popcorn plant (Facility G) and in analyses of aggregated data from medical surveys at the index plant and five additional microwave popcorn plants. The analyses of data from the initial survey at the index plant showed an increasing prevalence of abnormal spirometry with increasing quartiles of estimated cumulative diacetyl exposure . Analyses of aggregated data from surveys at the six microwave popcorn plants showed higher prevalences of respiratory symptoms and worse lung function in mixers with more than 12 months experience and in packaging area employees at plants where heated tanks of oil and flavorings were not adequately isolated, compared to less exposed comparison groups ]. Additional evidence of a dose-response relationship was found in analyses of California flavoring employee surveillance data. An analysis of obstruction by amount of plant diacetyl use showed that there were 16 employees with obstruction in four companies that used more than 800 pounds of diacetyl annually compared to two employees with obstruction in companies that used less diacetyl (prevalence of 5.3% versus 1.2%), for an OR of 4.5 (95% CI 1.03-19.9) . In diacetyl-exposed employees with severe fixed airways obstruction and other findings of obliterative bronchiolitis, a consideration of alternate explanations should take into account the fact that while obstructive lung diseases such as asthma and smoking-related emphysema are common in the general population, severe airways obstruction is rare, especially in young individuals. Asthma is characterized by episodes of reversible airways obstructionsome individuals with severe or inadequately treated asthma can develop fixed airways obstruction. However, asthma does not appear to be a possible explanation for cases of severe lung disease among diacetyl-exposed employees for the following reasons: (1) Most affected employees denied having any pre-existing lung disease or symptoms at the start of exposure. (2) Once shortness of breath developed, it did not improve when employees were away from the workplace as would be expected in employees with occupational asthma (either new onset asthma or exacerbation of pre-existing asthma). ( 3) Employees' illnesses did not improve when they took medications for asthma such as bronchodilators and corticosteroids. (4) Most employees did not have a significant response to administration of bronchodilators in any of their spirometry tests (i.e., airways obstruction was fixed). While some diacetyl-exposed employees who developed severe lung disease were smokers, the natural history of smoking-related disease and the results of medical evaluations of affected employees make it unlikely that the cases of severe fixed airways obstruction among diacetyl-exposed employees are smoking-related. Compared to the normal decline in lung function that occurs with aging (FEV 1 declines approximately 30 mL/year), in a subset of smokers lung function declines more rapidly (FEV 1 declines on average approximately 45-70 mL/year). An estimated 10%-15% of all smokers develop clinically important airflow obstruction . Smokers who experience rapid lung function decline will typically start to become short of breath once their FEV 1 falls below 60% of predicted; this usually occurs around age 50. Severe airways obstruction (e.g., FEV 1 less than 40% predicted) typically does not occur before 55-60 years of age . Several diacetyl-exposed employees developed severe fixed airways obstruction while still in their 20s and 30s. Any smoking history among these affected employees (as well as in affected employees younger than 50) would not explain their severe fixed airways obstruction. Additional evidence against smoking as a cause of severe lung disease in these employees is the fact that most employees' DL CO measurements were normal. In airways obstruction due to smoking-related emphysema, DL CO is reduced. Obliterative bronchiolitis is known to occur as a result of a variety of infections, exposures, or nonpulmonary diseases. Examples include overexposure to highly irritating gases or vapors such as chlorine, ammonia, and nitrogen oxides or in association with connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis, or in organ transplant recipients. The diacetyl-exposed employees who developed severe fixed airways obstruction did not have histories or medical evaluation findings to suggest that they had developed obliterative bronchiolitis from another exposure or medical condition. Airways obstruction can also occur due to diseases that affect other airways besides the bronchioles such as bronchiectasis or upper airway lesions . However, individuals with airways obstruction from such other causes typically have characteristic history, physical exam, and medical test findings that usually serve to reveal the nature of the illness (e.g., copious sputum in someone with bronchiectasis or evidence of upper airway obstruction on spirometry). Such findings were not apparent in diacetyl-exposed employees who developed severe fixed airways obstruction. Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetylexposed employees have provided substantial evidence of a causal relationship between diacetyl exposure and development of this disease. Exposure preceded disease development, and lung disease risk decreased with control of exposures. Analyses of data from workplace medical and environmental surveys revealed a strong, consistent association of the disease with diacetyl manufacture, use of diacetyl in flavoring production, and use of diacetyl-containing butter flavorings in microwave popcorn production. The investigations have also shown evidence of a dose-response effect, and animal and other laboratory studies have provided evidence of biologic plausibility. Medical evaluations of affected employees did not identify alternative explanations for their illness besides their workplace exposure to diacetyl and other flavoring compounds. Accordingly, the criteria for interpreting epidemiologic associations as causal have all been met by the body of investigation presented in this criteria document for a recommended standard. Alleman T, Darcey DJ . Case report: bronchiolitis obliterans organizing pneumonia in a spice process technician. J Occup Environ Med 44( 3):215-216. Anderson SE, Franko J, Wells JR, Lukomska E, Meade BJ . Evaluation of the hypersensitivity potential of alternative butter flavorings. Food Chem Toxicol 62C:373-381. # ATS, ERS (American Thoracic Society, European Respiratory Society) . American Thoracic Society/ European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 165( 2 CDC . Fixed obstructive lung disease in workers at a microwave popcorn factory-Missouri, 2000-2002. MMWR 51( 16):345-347. CDC . Fixed obstructive lung disease among workers in the flavor-manufacturing industry- California, 2004:389-393. CDC . Obliterative bronchiolitis in workers in a coffee-processing facility-Texas, 2008-2012. MMWR 62( 16):305-307. Rowell M, Kehe K, Balszuweit F, Thiermann H . The chronic effects of sulfur mustard exposure. Toxicology 263( 1):9-11. Ryu JH, Scanlon PD . Obstructive lung diseases: COPD, asthma, and many imitators. Mayo Clin Proc 76( 11):1144-1153. Sahakian N, Kullman G, Lynch D, Kreiss K . Asthma arising in flavoring-exposed food production workers. Int J Occup Med Environ Health 21( 2):173-177. Schachter EN . Popcorn worker's lung. N Engl J Med 347( 5):360-361. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN . Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 2( 5 Chemical and physical properties of diacetyl and 2,3-pentanedione are presented in section 1.4. As mentioned there, diacetyl is an α-dicarbonyl. Endogenous α-dicarbonyl compounds are among the reactive carbonyl species implicated in the formation of advanced glycation end products . Like other α-dicarbonyl compounds, diacetyl is reactive, with a tendency to cause protein cross-links . The reactivity of the α-dicarbonyl compounds is enhanced by electron attracting groups and decreased by electron donors ]. Thus, diacetyl is a reactive compound, but its alkyl components are electron donors that may somewhat decrease the reactivity of the adjacent carbonyl groups . Diacetyl and related α-dicarbonyl compounds can inactivate proteins, principally through reactions with the amino acid, arginine . The related α-dicarbonyl flavoring, 2,3-pentanedione, has been reported to be even more reactive with arginine groups than diacetyl . Recently, in vitro studies indicate that diacetyl can cause β-amyloid aggregates and covalently modify β-amyloid at 5th arginine (Arg 5 ), although the in vivo relevance of this finding remains to be investigated . Thus, existing studies indicate that diacetyl is a reactive compound that can modify proteins and suggest that diacetyl-associated protein modification may occur in vivo. # Diacetyl and 2,3-Pentanedione in Food Diacetyl and 2,3-pentanedione have a long history as components of food, suggesting that exposures can occur in diverse workplaces. They occur as natural products in many foods . Diacetyl imparts the flavor and aroma of butter to many common foods and drinks including butter, cheese, yogurt, beer, and wine . Diacetyl in food plays an important role in food preference . While less extensively studied in foods than diacetyl, 2,3-pentanedione is a common flavoring in margarine and vegetable spreads . Roasted coffee also contains appreciable amounts of diacetyl . Because diacetyl is not a component of green coffee beans, it appears to be a product of the roasting process . Bacteria and yeast produce diacetyl during fermentation . It can be produced by metabolism of an acetaldehyde-thiamine pyrophosphate complex in the presence of acetyl-coenzyme A . Microbes can also produce diacetyl from pyruvate in the presence of acetyl-coenzyme A . Microbial culture conditions, such as pH, can influence the relative amount of diacetyl produced during fermentation . In addition, the steam distillate of several bacterial cultures grown on skim milk is known as "starter distillate" and is also considered a flavoring . Major components of some starter distillate samples include diacetyl and acetic acid . A recent study demonstrated that diacetyl remains a frequent component of commercial starter distillate samples, and diacetyl concentrations exceeded 20 mg/g in one sample . Starter distillate can also contain 2,3-pentanedione as well as butyric acid, which inhibits the metabolism of diacetyl and 2,3-pentanedione . Thus, diacetyl and 2,3-penanedione can occur naturally in food, may be added to food as flavorings, may be produced during the roasting process, and can be anticipated components when starter distillate is added as a flavoring. # Metabolism in Mammalian Cells In the rat and hamster liver, diacetyl is metabolized principally by reduction to acetoin in an enzymatic reaction catalyzed by dicarbonyl/Lxylulose reductase (DCXR), the enzyme is also known as diacetyl reductase, with either nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as coenzymes . Acetoin can be further reduced to 2,3-butanediol in an NADH-dependent manner . This diacetyl reductase activity is higher in the liver than in the kidney, and kidney activity is higher than in the brain. However, after oral administration of diacetyl, the levels of acetoin are much higher in the brain than in the kidney or liver. 2,3-Butanediol accumulates in liver, kidney, and brain after the administration of diacetyl, acetoin, or 2,3-butanediol. Oral administration of acetoin and, to a lesser extent, 2,3-butanediol, in rats also causes diacetyl accumulation in the liver and brain . However, liver homogenates do not produce significant diacetyl from acetoin or 2, 3-butanediol . Thus, the metabolic interconversion of the 4-carbon compounds, acetoin, diacetyl, and 2,3-butanediol occurs in mammalian systems in vivo and in vitro but the full spectrum of metabolic pathways remains incompletely investigated. As mentioned above, in mammalian cells, the predominant metabolic pathway for diacetyl is catalyzed by DCXR, a tetrameric protein that is comprised of four subunits, each 244 amino acids long . In addition to the reductive metabolism of diacetyl, DCXR catalyzes the metabolism of several other dicarbonyl compounds, including 2,3-pentanedione, 2,3-hexanedione, 2,3-heptanedione, and 3,4-hexanedione . In addition, DCXR catalyzes the reductive metabolism of a number of monosaccharides, including L-xylulose, and plays a role in the glucuronic acid/uronate cycle of glucose metabolism as well as the metabolism of carbonyl compounds . Inhibitors of DCXR are well described and include n-butyric acid, 2-furoic acid, benzoic acid, and nicotinic acid . At least one of these DCXR inhibitors, n-butyric acid, is well absorbed in the nose, and its presence in vapor mixtures causes small but significant decreases in diacetyl absorption in the nasal mucosa and, thereby, leaves more diacetyl in the vapor stream of the nasal airways for delivery to the lung . Occupational Exposure to Diacetyl and 2,3-Pentanedione 81 4 . Toxicology of Diacetyl and 2,3-Pentanedione Very weak tracheal contractions with threshold at 1 mM, relaxation at exposures above 3 mM. Diacetyl effect on response to intraluminal (mucosal) methacholine: 4-hour perfusion with 3 mM diacetyl increased methacholine reactivity 10 times; 10 mM diacetyl completely inhibited the methacholine response. Depolarization of transepithelial potential difference at 3 and 10 mM. Decrease in transepithelial potential difference at 10 mM. Gloede et al. F344 rats Respiratory uptake of diacetyl in F344 rats was used to validate a model of respiratory tract uptake of diacetyl At a given inhaled diacetyl dose, the predicted dose to the bronchiolar epithelium of a lightly exercising employee is predicted to be more than 40 times the dose to the bronchiole of a rat. Describes a low affinity, high capacity and a high affinity, low capacity pathway for diacetyl metabolism in the rat respiratory epithelium. The high affinity pathway is inhibited by sodium benzoate, indicating that it is DCXR. Male and female Wistar-Han rats and B6C3F1 mice 2,3-Pentanedione 0, 50, 100 or 200 ppm 6 hr/day, 5 days/week, Up to 12 exposures In rats, 12-day 2,3-pentanedione exposure cause necrosis of respiratory epithelium and atrophy of olfactory neuroepithelium in the nose; intramural and intraluminal fibrosis of intrapulmonary airways. In rats, 5 or 10 days of inhaling 200 ppm 2,3-pentanedione increased bronchoalveolar lavage fluid concentrations of monocyte chemotactic protein-1, monocyte chemotactic protein-3, C-reactive protein, fibroblast growth factor-9, and fibrinogen. In mice, 12-day 2,3-pentanedione exposure caused necrosis of nasal turbinates, suppurative exudate and atrophy of olfactory neuroepithelium in the nose; inflammation in intrapulmonary airways with necrosis, ulceration and regeneration at 200 ppm exposure. Morris and Hubbs Male Sprague-Dawley rats Diacetyl 100 or 300 ppm in airstream flows of 100-400 mL/min A hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) was used to extrapolate diacetyl and butyric acid uptake in rat airways epithelium to human airways epithelium. The CFD-PBPK suggests that nasal injury in rats can predict a risk to deep lung tissue in humans. Diacetyl damages airway epithelium when it reaches a critical concentration in the target cells; the CFD-PBPK indicates that more diacetyl will be absorbed in the nose of rats than in humans. Butyric acid is shown to shift diacetyl absorption from the nose and trachea into deeper lung tissue. In the rat kidney, DCXR is localized in the distal tubules and collecting ducts and colocalizes with carboxylmethyllysine, an advanced glycation end product . In the mouse kidney, DCXR is localized to the brush border of the proximal renal tubules . In the human prostate epithelial cells and in normal human skin, DCXR is associated with the cell membrane . In human skin, DCXR is located near the adhesion molecules, e-cadherin and β-catenin . Similarly, in the vascular endothelium in the dermis, DCXR localizes near intercellular junctions, suggesting a potential role for DCXR in cell adhesion . In addition, DCXR activity is present in the respiratory mucosa of the rat, with the highest activity in the olfactory epithelium . DCXR knockout mice are not well characterized phenotypically but are reported to be fertile . People without DCXR excrete pentose in their urine but are otherwise believed to be healthy, indicating that DCXR and the major diacetyl metabolic pathway are not essential for life . Importantly, the metabolism of diacetyl is not exclusively by DCXR. For example, aldo-keto reductase 1C15 is a newly-described aldoketo reductase expressed in rat lung that can metabolize α-diketones . Recently, a low affinity, high capacity and a high affinity, low capacity pathway for diacetyl metabolism have been described in the respiratory tract of the rat . The high affinity pathway was inhibited by sodium benzoate indicating that it is DCXR. The low affinity pathway is not believed to play a major role at diacetyl concentrations associated with most occupational exposures. # In Vivo and in Vitro Toxicology Studies Diacetyl and 2,3-pentanedione may be consumed in food, the vapors may be inhaled, and direct skin contact is possible. In vivo studies have modeled these routes of human exposure. # In Vivo Toxicology of Orally Administered Diacetyl Subchronic (90-day) gavage administration of 540 mg diacetyl/kg/day caused multiple changes in exposed rats, including decreased body weight, increased water consumption, increased adrenal weight, increased relative kidney and liver weights (in females absolute kidney and liver weights were also increased), decreased blood hemoglobin concentration and gastric ulceration . No adverse effects were noted at the next highest dose level, which was 90 mg/kg/day. On a mg/ kg basis, the 90 mg/kg/level was estimated to be roughly 500-fold greater than the estimated human maximum daily intake of diacetyl from foods consumed at that time, with 50 ppm diacetyl being the highest estimated concentration in any food . # Effects of Topically Applied Diacetyl and 2,3-Pentanedione in Vivo Sensitization following topical application of diacetyl is predicted on the basis of results of a murine local lymph node assay . On the basis of the results of the local lymph node assay and immune cell phenotyping, it is suggested that diacetyl and 2,3-pentanedione function as T-cell mediated chemical sensitizers . Cutaneous sensitization by diacetyl and 2,3-pentanedione may be initiated through haptenation with proteins containing the amino acids lysine and arginine . Diacetyl is corrosive to the cornea of the eye using the Draise test ]. # Toxicology of Inhaled Diacetyl in Vivo In rats, acute exposures to diacetyl or diacetylcontaining butter flavoring vapors cause necrosis in the epithelial lining of nasal and pulmonary airways. Rats inhaling vapors of butter flavoring that contained diacetyl developed multifocal necrotizing bronchitis one day after a 6-hour exposure. The mainstem bronchus was the most affected intrapulmonary airway. However, nasal airways were more affected than intrapulmonary airways. Necrosuppurative rhinitis was seen in rats inhaling butter flavoring vapors at concentrations of butter flavoring that did not cause damage in intrapulmonary airways . As a single agent acute exposure in rats, a 6-hour diacetyl inhalation exposure caused epithelial necrosis and inflammation in bronchi at concentrations of > 294.6 ppm and caused epithelial necrosis and inflammation in the trachea and larynx at concentrations of ≥224 ppm ]. The airway epithelial damage in rats inhaling 356 ppm was remarkable, with an average pathology score of 9.5 on a 10-point scale in the nasopharyngeal duct and larynx, while damage in the tracheal epithelium averaged 8.7 on a 10-point scale. In a pattern reminiscent of airway damage from butter flavoring vapors, diacetyl causes greater damage to nasal airways than to intrapulmonary airways . The data from the National Toxicology Program 90-day inhalation study are available online and was used for the NIOSH animal-based risk assessment (see Chapter 6). Airway damage in mice one day after diacetyl inhalation was found to correlate with markers of increased protein turnover, implicating protein damage in the etiology of diacetylinduced airway damage . Eighteen hours after a 6-hour exposure to inhaled diacetyl (100, 200, 300, or 360 ppm), in anesthetized rats 360 ppm elevated slightly lung resistance and dynamic compliance . Subsequent inhalation of methacholine aerosol (0.3-10 mg/mL) revealed that airway reactivity was decreased after exposure to diacetyl at 360 ppm. It had been predicted, based on extensive epithelial damage noted after diacetyl inhalation, that reactivity to inhaled methacholine would be increased. Eighteen hours after a 6-hour exposure to inhaled 2,3-pentanedione (120, 240, 300, or 360 ppm), in anesthetized rats basal lung resistance (R L ) and dynamic lung compliance (C dyn ) were not affected. Following inhalation of 346 ppm diacetyl by rats, foci in the trachea that demonstrate epithelial denudation also appear to have loss of sensory nerves, as reflected in a decreased density of PGP9.5-immunoreactive nerve fibers. However, in the epithelium adjacent to denuded foci, increased numbers of nerve fibers contain immunoreactive substance P, a neuropeptide important in neurogenic airway inflammation. In addition, the number of substance P immunoreactive neurons increase in the ganglia supplying the trachea in a dose-dependent manner in exposed rats. These findings suggest that diacetyl-induced airway epithelial damage may be accompanied by changes in the sensory nerves . In mice, inhaling diacetyl at concentrations of 200 or 400 ppm for 6 hours/day for up to 5 days causes respiratory tract changes similar to those seen in rats inhaling diacetyl or butter flavoring vapors . At both 200 and 400 ppm, diacetyl caused necrotizing rhinitis in mice that was most prominent in the front portion of the nose. At 400, but not at 200 ppm, the olfactory epithelium demonstrated vacuolar degeneration and apoptosis. Necrotizing laryngitis was consistently observed in all mice inhaling 400 ppm diacetyl, while only one mouse inhaling 200 ppm diacetyl had comparable necrotizing laryngitis, but erosive laryngitis was present in 9 of 10 mice inhaling the 200 ppm concentration. Exposing mice to diacetyl for only 1 hour/day at 100, 200, or 400 ppm diacetyl, 5 days per week, for 2 to 4 weeks rather than 6 hours/day for the same number of days eliminated epithelial necrosis in mice inhaling 200 ppm diacetyl and decreased the severity of epithelial necrosis in mice inhaling 400 ppm diacetyl. Lymphocytic inflammation was seen around the bronchi in some mice inhaling 100 ppm and in all mice inhaling 200 or 400 ppm diacetyl . Exposing mice to diacetyl for 15 minutes per day at 1,200 ppm diacetyl, 5 days/week for 2 weeks also caused lymphocytic infiltrates around bronchi, and lymphocytic infiltrates extended deeper into the lung, reaching the level of the preterminal bronchioles ]. Subchronic, 12-week, diacetyl inhalation for 6 hours/day, 5 days/week caused significant histopathologic changes in mice at all concentrations studied. Peribronchial lymphocytic infiltrates were seen at terminal sacrifice at 12 weeks in all subchronically-exposed mice inhaling 100 ppm diacetyl and in some mice inhaling 25 or 50 ppm diacetyl. In mice inhaling 100 ppm diacetyl, bronchial epithelial changes included denudation, attenuation, and hyperplasia . Chronic active nasal inflammation was seen in all mice inhaling 50 or 100 ppm and in four of five mice inhaling 25 ppm diacetyl for 12 weeks, an exposure that also caused minimal to mild lymphocytic bronchitis in two of five mice. This suggests that the no observable adverse effect level in mice for subchronic inhalation may be less than 25 ppm diacetyl. Butyric acid caused a small but significant reduction in nasal uptake of diacetyl in the rat nose, and, thereby, increased the diacetyl exposure to the lung due to a reduced "scrubbing" effect . Oropharyngeal aspiration permits exposures that bypass the rodent nose and, hence, scrubbing at that site . A single aspiration exposure to 400 mg/kg diacetyl produced a fibrohistiocytic response at the bronchioloalveolar junction of mice after 4 days. While oropharyngeal aspiration of diacetyl delivers a high bolus dose of diacetyl, the unusual fibrohistiocytic response could suggest that the smallest airways may be particularly susceptible to diacetyl-induced epithelial injury and fibrosis . A subsequent study demonstrates development of obliterative bronchiolitis in rats after intratracheal instillation of diacetyl . In this model, diacetyl-induced obliterative bronchiolitis was associated with abnormal repair of the injured bronchiolar epithelium. The reports of the induction of obliterative bronchiolitis and obliterative bronchiolitis-like changes in the deep lung of laboratory animals following aspiration of diacetyl are important because no prior animal model of obliterative bronchiolitis existed, and it is a technique that bypasses the rodent nose, which CFD-PBK models have demonstrated to absorb more diacetyl than will be absorbed in the upper airways of employees (section 4.2.6). However, as noted in the study, the very large single dose used in these studies may have limitations for the use of single exposure intratracheal instillations for risk assessment purposes . A study demonstrated bronchial fibrosis in rats inhaling 150 or 200 ppm diacetyl for 2 weeks ]. Pulmonary function changes have been investigated in mice after acute or subchronic diacetyl exposure. In mice, acute 2-hour diacetyl inhalation at concentrations from 191 to 1154 ppm caused a decrease in respiratory rate and an increase in the "time of break" between inhalation and exhalation, an indicator of sensory irritation . In addition, acute diacetyl inhalation in mice caused decreases in tidal volume and mid-expiratory flow rate. Mice previously exposed to high diacetyl concentrations were less sensitive to the sensory irritation effects of a diacetyl challenge exposure, while mice previously exposed to low diacetyl concentrations were more sensitive to a diacetyl challenge exposure. Extrapolation of the mouse dose-response relationship to humans suggested no sensory irritation to warn employees during acute diacetyl exposures at concentrations less than 20 ppm . As mentioned earlier, a recent study suggests that acute diacetyl inhalation exposures can actually increase the number of substance P-positive neurons in the jugular ganglia and the number of nerve fibers containing substance P in the epithelium adjacent to sites of epithelial damage, but decreases the sensory innervation at the actual sites of greatest epithelial damage . As a group, these studies suggest dysregulation of airway sensory innervation and responses. Additional studies support the potential for diacetyl to alter pulmonary function in exposed rodents. Mice inhaling 100 ppm diacetyl for 12 weeks had concentration-dependent decreases in respiratory rate and minute volume after 3 and 6 weeks of exposure; mice inhaling 50 ppm diacetyl had decreased respiratory rates after 6 weeks exposure, but pulmonary function improved with time with continued exposure at these concentrations ]. However, after 18 weeks of exposure, respiratory rates in mice inhaling 25 ppm diacetyl were significantly lower than in controls ]. The effects of diacetyl inhalation may not be limited to the respiratory tract. Inhaling 2,500 ppm diacetyl for 45 minutes increased 2-deoxyglucose uptake in foci in the posterior portion of the rat brain olfactory bulb . While this finding has generally been interpreted as being related to olfaction , the potential exists for toxicity to olfactory neurons that radiate into the olfactory bulb. Phagocytosis of olfactory nerve material and increases in Tnfα mRNA were recently demonstrated in the olfactory bulb of mice one day after a 6-hr diacetyl inhalation exposure. By immunofluorescence, the multifunctional scaffolding protein sequestosome-1 accumulated in the olfactory bulb of these mice and often congregated in the microglial cells that contained phagocytized olfactory neuronal material . Although powdered butter flavoring can produce fewer vapors than liquid butter flavorings, the powders have a major respirable component . If powdered butter flavorings are substituted for liquid butter flavorings, diacetyl and 2,3-pentanedione vapor concentrations may well be below exposure limits. In particular, encapsulated flavoring powders are designed to contain diacetyl or 2,3-pentanedione vapors. However, inhalable particulates can be deposited in the nose, the conducting airways, and deep lung. No peer reviewed studies have investigated the potential for encapsulated flavorings to release diacetyl and/or 2,3-pentanedione directly to the target cells lining airways. However, a recent study indicates that more than a quarter of particulates in flavoring powders are less than 10 μm in diameter. Therefore, powders have the potential to reach the intrapulmonary airways . # In Vitro Toxicology of Diacetyl and 2,3-Pentanedione Diacetyl is mutagenic in the Salmonella typhimurium tester strains TA100 and TA104 . However, diacetyl also reacts with mutagenic heterocyclic amines and suppresses the mutagenicity of heterocyclic amines in Salmonella typhimurium tester strain TA98. Diacetyl also enhances chromosome loss by proprionitrile in Saccharomyces cerevisiae. Recently, diacetyl in the presence of human S9 demonstrated a high degree of mutagenicity in a mouse lymphoma mutation assay . Consistent with these findings, recent in vitro studies of direct interactions between diacetyl and single-stranded oligonucleotides under acellular conditions indicate that diacetyl can form adducts with 2-deoxyguanosine . Additional studies on the genotoxicity of diacetyl have been reviewed in the background documents available online as part of the National Toxicology Program . In isolated mitochondria, diacetyl closes the mitochondrial permeability transition pore and renders it insensitive to Ca 2+ . This effect of diacetyl occurs at concentrations that could occur in tissues of diacetyl-exposed individuals, with half-maximal inhibition of the mitochondrial transition reported to be at a diacetyl concentration of 1 mM . This concentration has been shown to have pharmacological activity in airways and has been modeled to be achieved in the airway wall after inhalation (see below). The effect of diacetyl on the mitochondrial permeability transition pore appears to be caused by arginine modification (see above) . In addition, diacetyl can be metabolized by pig heart mitochondrial pyruvate kinase to form acetate and acetyl-CoA with a K m value of 0.46 mM. Diacetyl is also a competitive inhibitor of pyruvate metabolism by pyruvate dehydrogenase with a K i of 0.43 mM . The isolated, perfused trachea system employing tracheas from unexposed guinea pigs has been used to investigate the effects of diacetyl in vitro ]. In this model, the direct, potentially toxic effects of the agent on epithelium may be examined. Agents such as diacetyl may be applied to the epithelium (mucosal surface) or separately to the smooth muscle (serosal surface) of the trachea while measuring contractile or relaxant responses of the airway smooth muscle. An advantage of this model is that the effects of the diketone do not involve an inflammatory response, inasmuch as the trachea has been removed from the animal and there is no source for the recruitment of inflammatory cells into the wall of the airway. In unstimulated tracheas, diacetyl or 2,3-pentanedione applied to the mucosal surface in concentrations 1 mM and higher dissolved in a physiological salt solution elicited small contractions; in concentrations higher than 3 mM (i.e., 10 and 30 mM), contractions to diacetyl and 2,3-pentanedione were followed by relaxations. The relaxation responses were larger than the contractile responses. Exploring these phenomena further, adding the flavorings to the mucosa of tracheas that were first contracted with methacholine, a bronchoconstrictor agonist, resulted in full relaxation of the smooth muscle over the same range of diacetyl concentrations. These findings indicate that diacetyl is a weak contractile agent when applied to the epithelial surface, but that it is capable of eliciting strong relaxant responses. Thus, a diversity of responses in the airway that depend on the diacetyl concentration is produced. Investigation of inhaled diacetyl effects (60, 100, 200, 300, and 360 ppm) and inhaled 2,3-pentanedione effects (120, 240, 320, and 360 ppm) on reactivity of tracheas removed from exposed rats and studied in the isolated, perfused trachea model showed that reactivity to methacholine applied to the mucosal surface was increased slightly after inhalation of 300 and 360 ppm diacetyl and 320 and 360 ppm 2,3-pentanedione. Based on epithelial damage in airways after exposure to diacetyl, a larger increase in airway reactivity had been anticipated . Diacetyl inhalation elicits substantial histopathologic changes to airway epithelium, including denudation and necrosis (section 4.2.3). Commonly, damage to respiratory epithelium leads to airway hyperreactivity. For example, after ozone inhalation, airway reactivity of guinea pigs to inhaled methacholine is increased; likewise, reactivity to methacholine applied to the mucosa of isolated, perfused trachea is also increased . Incubation of perfused trachea with diacetyl dissolved in a physiological salt solution and applied to the mucosal surface led to no effect (1 mM diacetyl), an approximately 10-fold increase in reactivity to methacholine (3 mM), or full suppression of contraction to methacholine (10 mM) ]. The effects of diacetyl in isolated airways from naïve animals does not involve the airway epithelium . Damage to the epithelium after diacetyl inhalation suggests that epithelial ion transport and electrical resistance could be affected by the diketone. In rat tracheal segments investigated in vitro with Ussing chambers, diacetyl dissolved in physiological salt solution at 3 mM decreased transepithelial potential difference (V t , mV), indicative of a decrease in electrogenic ion transport and/or an effect on paracellular ion transport involving tight junctions, whereas 10 mM diacetyl reduced V t further and decreased transepithelial resistance (R t , Ωcm 2 ). R t is an index of tight junction permeability. Thus, ion transport and epithelial integrity are affected directly by diacetyl. The diacetyl concentrations observed to affect tracheal diameter and elicit bioelectric responses, i.e., 1 to 3 mM, are within the range estimated to occur in the rat tracheal mucosa after diacetyl inhalation. Using a CFD-PBK model, Morris and Hubbs calculated that inhalation levels of 100, 200, and 300 ppm diacetyl could yield concentrations in the mucosa of 1.1 to 1.2, 2.3 to 2.5, and 3.7 to 3.8 mM diacetyl, respectively. This suggests that some or all of the observed in vitro effects may occur in the airways during vapor inhalation. The mechanism(s) of the effects of diacetyl on trachea in vitro are not known at present. However, a related structure, 2,3-butanedione monixime, has been reported to inhibit contraction of smooth muscle, perhaps as a result of inhibiting phosphorylation of myosin light chains . Bioelectric responses of neurons also have been reported to be inhibited by 2,3-butanedione monixime . 2,3-Pentanedione is not mutagenic in Salmonella typhimurium strains TA98, TA100, TA102, or TA104 . A recent study demonstrates that in vitro diacetyl exposure increases shedding of the epidermal growth factor ligand, amphiregulin. These findings are further supported by evidence that amphiregulin transcripts and protein are also increased in an in vivo model of obliterative bronchiolitis induced by repeated intratracheal instillation of diacetyl . Amphiregulin has previously been reported to play a role in pulmonary fibrosis, although the nature of that role is not fully understood . # Toxicology of Inhaled Diacetyl Substitutes Diacetyl is the compound largely responsible for the flavor of butter in butter . However, exposures in workplaces that make or use butter flavoring and emissions from heated butter flavoring involve multiple volatile compounds . Among the potential replacements for diacetyl, starter mix contains high concentrations of diacetyl . Another chemical that adds the flavor of butter to food is acetoin, and it was present along with diacetyl in many of the workplaces where obliterative bronchiolitis occurred in employees who make or use diacetyl ; . Acetoin is structurally very similar to diacetyl but an α-hydroxyketone in acetoin replaces the reactive α-diketone implicated in the toxicity of diacetyl and 2,3-pentanedione . In a National Toxicology Program (NTP) 90-day study on acetoin, the chosen maximum exposure level (generally representing the maximum tolerated dose) was 800 ppm, whereas in the NTP 90-day diacetyl study the maximum exposure level was 100 ppm (Chapter 6). In 90-day inhalation exposures, diacetyl produced statistically significant respiratory tract lesions from exposures as low as 25 ppm, in both rats and mice (Chapter 6). Statistically significant histopathology changes in the 25 ppm diacetyl exposures were nasal respiratory epithelial metaplasia (in both male and female rats), nasal olfactory epithelial degeneration in female rats; nasal respiratory epithelial necrosis (in male and female mice) plus chronic inflammation and respiratory epithelial hyperplasia of the larynx in female mice (Chapter 6). In addition acetoin (150 ppm), after inhalation for 6 hours by rats, had no effect on reactivity to inhaled methacholine while inhaled acetic acid (27 ppm for 6 hours), another component of flavoring mixture, increased airway reactivity to methacholine . Thus, current data, while limited, indicate that acetoin is considerably less hazardous than diacetyl. 2,3-Pentanedione is structurally very similar to diacetyl because it is a 5-carbon α-diketone, and diacetyl is a 4-carbon α-diketone. Eighteen hours after a 6-hour inhalation exposure to 2,3-pentanedione (120, 240, 320, and 360 ppm), R L and C dyn in anesthetized rats were unaffected . Subsequently, airway reactivity to inhaled methacholine aerosol was decreased after inhalation of 120, 240, and 320 ppm 2,3-pentanedione. 2,3-Pentanedione affected methacholine reactivity more than diacetyl. Airway hyperreactivity to methacholine had been anticipated, in view of the epithelium damage caused by the flavoring. Following inhalation exposure of rats to these same concentrations of 2,3-pentanedione and perfusion of the trachea in vitro, reactivity to mucosally-applied methacholine was increased by 240, 320, and 360 ppm 2,3-pentanedione . The magnitude of this effect surpassed that caused by diacetyl inhalation. Morphologic data suggest that 2,3-pentanedione can cause airway epithelial damage similar to the damage caused by diacetyl . Rats repeatedly inhaling 2,3-pentanedione at concentrations ≥ 150 ppm for up to 2 weeks develop fibrosis of intrapulmonary airways, a morphologic change similar to obliterative bronchiolitis in humans . Recently, more than 3500 genes were found to be upregulated in RNA isolated from the fibrotic bronchi of 2,3-pentanedione exposed rats . Some of the up-regulated genes were ones previously implicated in fibrosis, including transforming growth factor-β2, interleukin-1α, interleukin-18, interleukin-33, and fibronectin. In addition, at high exposure concentrations, messenger RNA changes were noted in the brain of rats after acute 2,3-pentanedione inhalation . # Diacetyl and 2,3-Pentanedione in Cigarette Smoke A recent study suggests that mainstream tobacco smoke collected by a smoking machine contained significant amounts of diacetyl that varied with the smoking parameters set by different organizations. 2006;Polzin et al. 2007]. Other recent studies have identified diacetyl and 2,3-pentanedione in electronic cigarette liquids and aerosols . In one study, after derivatization with 1,2phenylenediamine, quantification by GC-NPD, and confirmation by GC-MS, 301-433 µg diacetyl/cigarette was measured in the total mainstream smoke withdrawn from each burning cigarette from 15 different commercial reference cigarettes . However, that study did not use a smoking machine to simulate actual smoking behavior, so that the amount of diacetyl observed may not be representative of the amount produced under realistic smoking conditions. In another study, using GC/MS and a smoking machine with ISO parameters, a range of 12.7-145 µg diacetyl/cigarette was measured from 41 different types of cigarettes . Thus, several studies suggest that significant diacetyl is present in mainstream cigarette smoke, although the concentrations vary . Finally, electronic cigarette liquids often contain diacetyl and 2,3-pentanedione . The Pierce et al. 1975]. Assuming that all of the air an employee inhales contains the concentration of diacetyl measured in the workplace, it is critical to recognize that the mainstream smoke of a smoker is not the only source of air; they are also breathing air with much lower diacetyl concentrations. Assuming that the other air breathed by smokers does not contain diacetyl, the workplace equivalent exposure concentration for a smoker during the smoking time period is roughly 190-to 560fold lower than the concentration measured in the mainstream cigarette smoke using the ISO parameters of one 0.035 L puff/min (6.75/0.035 is 193 and 19.5/.035 is 557). Using the ISO parameters, this would be an average equivalent of a workplace concentration of 0.45 to 1.3 ppm for diacetyl and 58 to 170 ppb for 2,3-pentanedione during the smoking process. If the smoking machine parameters of 9.3 minutes/cigarette are used to calculate the duration of exposure, a smoker who smokes one pack of 20 cigarettes/ day spends 186 minutes a day smoking, but the employee is working for 8 hours. Therefore, the 8-hour time-weighted average equivalent concentration for the smoker is 2.6-fold lower to reflect the time period they are not exposed, which would be 170 to 500 ppb for diacetyl and 22 to 65 ppb for 2,3-pentanedione, depending upon exercise level. Calculations of workplace equivalent exposures are similar using total mass of diacetyl and 2,3-pentanedione reported by Pierce et al. , these concentrations of diacetyl would be predicted to decrease FEV 1 in some individuals if inhaled for a working lifetime (see Chapter 5). Indeed, many smokers do demonstrate significant decreases in FEV 1 . Additionally, cigarette smoking is a major risk factor for chronic obstructive pulmonary disease, and a decrease in FEV 1 is a characteristic feature of this disease. In addition, bronchiolar fibrosis is part of the airway remodeling response that characterizes chronic obstructive pulmonary disease . Decreases in FEV 1 and fibrosis of bronchioles are features that also characterize obliterative bronchiolitis . However, smokers with chronic obstructive pulmonary disease have additional morphologic changes in their lungs, including emphysema, that are not seen in obliterative bronchiolitis . While it has been hypothesized that the failure to diagnose diacetyl-induced obliterative bronchiolitis as a cigarette smoker-associated disease suggests that diacetyl does not cause obliterative bronchiolitis in exposed employees , the data when corrected for the actual corresponding occupational exposure concentrations may instead suggest the hypothesis that diacetyl and related reactive carbonyl compounds in cigarettes could potentially contribute to chronic obstructive pulmonary disease. Because chronic obstructive pulmonary disease is a leading cause of morbidity and mortality , the role of diacetyl and other reactive carbonyl compounds in cigarette smoke in contributing to chronic obstructive pulmonary disease is a worthy topic for future studies. As extensively discussed in Chapter 3, airway obstruction and decreased FEV 1 can, nevertheless, be identified in smokers who are exposed to diacetyl. Most importantly, because diacetyl causes obstructive lung disease and because smoking causes obstructive lung disease, the presence of diacetyl in cigarette smoke does not diminish the need to control diacetyl exposures in employees. In fact, it highlights the greater risks occurring in employees who are exposed to diacetyl in the workplace and who also smoke. # Relevance of Diacetyl Animal Studies to Humans Four converging lines of evidence support the relevance of diacetyl inhalation studies in rats and mice to humans. First, diacetyl inhalation causes damage to respiratory epithelium in rats and mice. This finding is important because injury to the respiratory epithelium of the deep lung is the accepted cause for obliterative bronchiolitis. Second, dosimetry calculations indicate that diacetyl concentration in respiratory epithelium of the human deep lung under working conditions may be much higher than diacetyl concentrations in laboratory animals. Third, another organic compound, sulfur mustard, implicated in causing obliterative bronchiolitis in humans, produces a similar pattern of predominantly nasal injury in rats exposed by nose-only inhalation . Fourth, repeated inhalation exposure to 2,3-pentanedione causes fibrosis of intrapulmonary airways ]. Each of these findings supports the conclusion that with appropriate dosimetry studies, damage to the respiratory epithelium of the upper airways of rodents should be considered when evaluating risk for humans. Animal exposure studies have revealed that the upper airways of rodents are sensitive to flavoring-induced toxicity, whereas the lower airways of humans are most affected by these agents. Importantly, diacetyl exposures in rodents caused extensive damage to the respiratory epithelium lining the nose and the trachea ]. The cell types that are injured in the nose and trachea in rodents are very similar to the respiratory epithelium lining the airways of the deep lung of humans that are involved pathophysiologically in the development of obliterative bronchiolitis . In addition, the bronchi were damaged at high concentrations in acute exposures and at lower concentrations in subchronic exposures in mice. Thus, inhalation toxicology studies showed that diacetyl could damage respiratory epithelium, providing biological plausibility for its etiologic role in obliterative bronchiolitis. Indeed, at the time of the first inhalation toxicology studies of diacetyl, no accepted cause of obliterative bronchiolitis in humans had been demonstrated to cause obliterative bronchiolitis in rodents. Recently, repeated inhalation exposures to 2,3-pentanedione have been shown to cause fibrosis of intrapulmonary airways in rats, demonstrating a pathologic change in the rodent model that is very similar to obliterative bronchiolitis in humans . Interpretation of the species difference in the anatomic location of diacetyl-induced damage to respiratory epithelium may be explained by species differences in respiratory tract anatomy, breathing patterns, and diacetyl dosimetry. Rodents are obligate nasal breathers while humans are oronasal breathers. Inhaled air may bypass the human nose, particularly during exertion . In addition, the rodent nasal passageways and the rodent trachea are much narrower than the corresponding human nasal passageways and trachea. Small airway diameter increases the percentage of the airstream that is in contact with the mucous layer, increases resistance, and thereby increases mucosal absorption of watersoluble vapors . Thus, the dimensions of the rodent nose predict much greater absorption of diacetyl vapors in the rodent than in the human nose. However, the surface area of the airways within the human lung is 100 times greater than the surface area of airways in the rat lung . These anatomic differences predict that, at a given exposure concentration, the mucosa in the rodent nose receives a much higher diacetyl dose than does the human nose and that the human lung receives a much higher dose than the rodent lung. To investigate these dosimetry predictions, a CFD-PBPK model of diacetyl uptake was developed . The CFD-PBPK model also predicted greater intrapulmonary diacetyl concentrations in the lung of humans than in rats at a given exposure concentration, especially during mouth breathing . Under resting conditions at an exposure concentration of 100 ppm, the rat nose and trachea are predicted to remove 39% of the inhaled diacetyl, while the trachea of a mouth breathing human would remove 4% of the inhaled diacetyl. This same study suggests the potential importance of nasal lesions in rats for predicting pulmonary toxicity in humans . Because the respiratory epithelium of the terminal bronchiole of humans is believed to be the target tissue for the development of obliterative bronchiolitis , and because diacetyl doses reaching the respiratory epithelium in the nose of rodents can be similar to diacetyl doses reaching the respiratory epithelium of the deep lung in humans, it may be appropriate to consider toxicity to the respiratory epithelium lining the nose of rodents in evaluating the risk of diacetyl to mouthbreathing employees. In addition, butyric acid, which is a component of some butter flavorings, caused a small but statistically significant reduction in nasal uptake of diacetyl in the rat nose, and thereby increased the diacetyl exposure to the lung due to a reduced "scrubbing effect" . A subsequent CFD-PBK model indicates that with low levels of exercise that could occur in the workplace, diacetyl dose to the bronchiolar epithelium of humans may be more than 40-fold greater than the dose received by the bronchiolar epithelium of experimentally exposed rodents . Damage to the nose of rodents has recently been described for another agent implicated in causing obliterative bronchiolitis in humans, sulfur mustard , a chemical warfare agent. Obliterative bronchiolitis is considered a major cause of progressive respiratory disease in survivors of sulfur mustard exposure . Noseonly inhalation exposures of F344 rats to sulfur mustard caused severe mucosal damage in the rat nose but the changes in the lung were absent or minimal . When the nose was bypassed using intubation with tubing lined by Teflon®, sulfur mustard did indeed cause necrosis of the epithelium lining the proximal airways . This suggests that sulfur mustard, an accepted cause of obliterative bronchiolitis in humans, causes a similar pattern of injury to the pattern observed with diacetyl at different levels of the respiratory tract of rodents. Thus, predominantly nasal injury has been seen in rodent inhalation studies with organic agents implicated in causing obliterative bronchiolitis. # Conclusions Inhalation toxicity studies in rats and mice, and in vitro studies in guinea pig tracheal preparations, indicate that diacetyl-containing butter flavoring vapors can damage airway epithelium and cause inflammation in the respiratory tract after acute or subchronic exposure. In addition, in vivo local lymph node assays indicate that diacetyl is a sensitizer, and in vitro studies indicate that diacetyl is mutagenic. Diacetyl can react with arginine residues causing structural changes in proteins that influence the function of the altered proteins. These functional changes in proteins include changes in enzyme activity and the mitochondrial permeability pore. Pharmacologic studies in vitro indicate that diacetyl can alter ion transport and reduce epithelial integrity. CFD-PBPK modeling indicates that diacetyl concentrations in the deep airways of humans may be higher than those in laboratory rodents, explaining the tendency for diacetyl-induced airway damage to be more anterior in the respiratory tract of rodents than in humans. Most recently, studies of the related α-diketone, 2,3-pentanedione, suggest that the airway toxicity of diacetyl may be shared with other structurally related, α-diketones, and that inhalation of either diacetyl and 2,3-pentanedione can cause airway fibrosis in rats. This page intentionally left blank. # References Aeschbacher HU, Wolleb U, Loliger J, Spadone JC, Liardon R . Contribution of coffee aroma constituents to the mutagenicity of coffee. Food Chem Toxicol 27( 4 Colley J, Gaunt IF, Lansdown AB, Grasso P, Gangolli SD . Acute and short-term toxicity of diacetyl in rats. Food Cosmet Toxicol 7( 6):571-580. Conolly RB, Kimbell JS, Janszen D, Schlosser PM, Kalisak D, Preston J, Miller FJ . Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset. Toxicol Sci 82( 1 Eriksson O, Fontaine E, Bernardi P . Chemical modification of arginines by 2,3-butanedione and phenylglyoxal causes closure of the mitochondrial permeability transition pore. J Biol Chem 273( 20 Larsen ST, Alarie Y, Hammer M, Nielsen GD . Acute airway effects of diacetyl in mice. Inhal Toxicol 21( 13 Majcher MA, Klensporf-Pawlik D, Dziadas M, Jelen HH . Identification of aroma active compounds of cereal coffee brew and its roasted ingredients. J Agric Food Chem 61( 11):2648-2654. Morris JB, Hubbs AF . Inhalation dosimetry of diacetyl and butyric acid, two components of butter flavoring vapors. Toxicol Sci 108( 1 the diacetyl exposure response, standard risk assessment procedures can be applied. # Environmental Assessment and Exposure Estimation For workplace environmental assessments, the HHE surveys generally collected full-shift personal breathing zone and area diacetyl air samples using NIOSH Method 2557. This sampling identified a number of air contaminants in addition to diacetyl and acetoin (Table 5-2), including acetaldehyde. Problems in diacetyl sample determination with NIOSH Method 2557 related to humidity at the time of sampling and the elapsed time to sample extraction were subsequently uncovered. NIOSH researchers worked extensively to understand this problem and derive an appropriate correction for estimating diacetyl levels . This correction, based on absolute humidity and time to extraction, was applied to the diacetyl exposure levels above the limit of detection (LOD) as measured in the selected HHEs. For other chemical exposures in microwave popcorn production determined using NIOSH Method 2557, such as acetoin, no humidity/extraction correction was needed. For laboratory diacetyl determinations below the LOD, the sample value was set equal to LOD/2. For determinations above the LOD following an outbreak of eye irritation. NIOSHmeasured diacetyl exposure levels for key process locations showed considerable variation across the four selected HHE sites with higher levels at Company G and Company N (Table 5-3 chronic disease investigations . However, for the first industrial hygiene survey (November 2000), only area samples were collected. For this survey, personal-sample equivalents to the area samples were estimated using area and personal sampling data from surveys 2 and 3 for the higher-exposed jobs, and using other procedures for samples with the lower values (Appendix H, Table H. Unique exposure time periods were developed for each of the eight exposure categories to reflect impact of the exposure control changes implemented at the plant from November 2000 to July 2003. Within the time periods for each JEM exposure category, exposures were assumed to be constant. Exposure estimates in the JEM were assigned to employees based on their history of jobs performed, job duration, and the calendar time period. For work history prior to the first industrial hygiene survey, exposure estimates from the first time period were used. For some employees such as those in the mixers exposure category, the measured personal diacetyl exposure was adjusted for the use of respirators in selected exposure periods (Appendix H). Problems in the retrospective exposure assessment for diacetyl include ( 1) uncertainty over when diacetyl was introduced and on the extent of its use as a flavoring component over time (and therefore on employee exposure levels), ( 2) variation in diacetyl content across different product lines over time, ( 3) the relative presence of diacetyl as a vapor vs. mist, adsorbed to powders or encapsulated, and ( 4) seasonal variation in the role of natural ventilation. Cumulative exposure and other exposure metrics were calculated starting at the dates when diacetyl was estimated to have first been used in regular production at the four plants: Company K (July 1, 1988), Company L (January 1, 1994), Company G (July 1, 1986), and Company N (July 1, 1986). These dates are uncertain, particularly for Company N. # Work History The employees studied were current employees at time of survey except at Company G where some former employees were also examined. All results presented are for current employees except at Company G where, due to repeated pulmonary testing over months or years, initially current employees could become former employees at a subsequent survey. Participation was voluntary and generally quite high among current employees (66%-91%) ( successive periods in specific department and job title assignments with corresponding beginning and ending dates. Gaps in employment were treated as unexposed and not included in duration-of-exposure measures. # Outcomes Reported symptoms and PFT results defined the HHE outcomes. A medical questionnaire was administered that included standard ATS items on respiratory health ] as well as dermal symptoms, allergies, detailed smoking history, and questions on other exposures and protective equipment used. Sustained-symptom onset dates were also collected. Spirometry testing was performed following ATS guidelines ]. The predicted and lower limit of normal (LLofN) values for FEV 1 , FVC and FEV 1 /FVC were calculated using prediction equations produced from NHANES III [Hankinson et al. 1999 The most appropriate measure of past diacetyl exposure for predicting health consequences is not known and hence was determined by assessment of the statistical fit of models using different exposure terms. Cumulative exposure (time summation of concentration, cum(DA)) was the starting choice for exposure metric, but dose-rate effects were examined by calculating the time summation of the square root or square of diacetyl concentration corresponding respectively to diminishing and increasing marginal responses to increasing exposure intensity (dose-rate effects) as follows: cum(DA) = Σ i (DA), cum(DA 0.5 ) = Σ i (DA 0.5 ) , and cum(DA 2.0 ) = Σ i (DA 2.0 ) where the summation was over calendar days. Transformed cumulative exposures as the square root, square, or logarithm were evaluated as were duration of exposure and average exposure concentration (cumulative exposure/ duration of exposure). Peak exposures were not available from full-shift (8-hour) TWA concentrations although selected jobs had been analyzed using a real-time method (FTIR) to assess time-variability. To make full use of the serial spirometry determinations at Company G, a longitudinal analysis of ppFEV 1 was performed in which exposure metrics were calculated from time of first diacetyl exposure up to the time of each successive spirometry determination. This analysis included employees with two or more spirometry results. All employees were active at their first survey but could have left employment prior to a subsequent survey. These models were fit using PROC MIXED in SAS 9.2 with random effects permitted for individual employee's intercepts and exposure responses. A second set of metrics was calculated with exposure cumulation starting at the time of an employee's first survey and used in a subsidiary longitudinal analysis along with the full cumulative exposure metric. This analysis permitted a test of homogeneity, i.e., ( 1) for exposure effects before and after the first survey and ( 2) for possible survivor bias. Pooled analyses were conducted for two plant populations (Company K, L) with similar reported average exposures and estimated exposure responses. A plant effect was introduced to allow for systematic differences between the two sites, and there was a test of heterogeneity in the exposure effects. # Models of the Incidence of Pulmonary Obstruction For analyses of onset of discrete adverse effect outcomes, conducted for the Company G population (n=361), three case-definitions of pulmonary impairment were applied: ( -6 ) and (p=4×10 -7 ) performing considerably better than exposure duration alone, and with average exposure to diacetyl and Cum(DA 2.0 ) performing less well than duration (Table 5-5). The estimate for the exposure-response with Cum(DA) was a 0.50 reduction in ppFEV 1 for each ppm-year of cumulative exposure (Tables 5-5, 5-6). (After 1 year at 1 ppm an employee's ppFEV 1 , starting at 100, would be predicted to be 99.5.) For FEV 1 /FVC the percent reduction with 1 ppm-yr DA was 0.16. Seventy-nine percent of the cross-sectional study population (n=286) had duration of employment of < 4 yr and 49% had less than 6 months, reflecting a high workforce turnover rate. Models restricted to < 4 yr duration produced considerably larger effect estimates; for ppFEV 1 : −1.07 (vs. −0.50) and for FEV 1 / FVC: −0.87 (vs. −0.16) (Table 5-5). With < 4 yr, the metric was a less strong predictor than Cum(DA). In the models with the better predicting exposure metrics, gender and ethnicity (possible indicators of differential healthy employee selection) were unimportant predictors. Ever-smoking was associated with an increase in ppFEV 1 but cumulative smoking, in pack-years, predicted a decline in ppFEV 1 (implying that, initially, smokers may be healthier than nonsmokers); both effects were statistically significant (Table 5-6). Regression models based on the first Company G spirometry determination rather than the last yielded similar estimates of diacetyl effects (data not shown). The metric cumulative square root of diacetyl concentration was a slightly stronger predictor of spirometry changes than simple cumulative exposure (Table 5-6), implying that if there is any dose-rate effect it is The best-predicting exposure metric depended on the HHE population analyzed (Tables 5-7, 5.8). In predicting FEV 1 /FVC the R-square values were consistently larger compared with the ppFEV 1 regressions but the exposure effects were sometimes less significant. For Company G, Avg(DA) and were the better predictors of FEV 1 /FVC; for Company K, Cum(DA) was best while for Company L, Avg(DA), and Cum(DA 2.0 ) were all equivalent better predictors. For ppFEV 1 , model fit at Company K was strongest for (Cum(DA)) 2.0 , however, Cum(DA) provided a similar fit. For Company L, Avg(DA) was the strongest predictor of ppFEV 1 . In the pooled analysis of the Company K and Company L plants, the differences in exposure response (heterogeneity) between the plants for ppFEV 1 and FEV 1 /FVC were highly significant for the better predicting metrics Cum(DA) and (Cum(DA) 2 (Tables 5-9, 5-10). The pooled regression estimate for the Cum(DA) metric corresponded to a decline in ppFEV 1 of 4.22 per ppm-yr of cumulative exposure (Table 5-9), almost an order of magnitude higher than the Company G estimated decline in ppFEV 1 of 0.50 per ppm-yr of cumulative exposure (Table 5-6) but with very different estimates for the individual plants. For plant K, the estimated fall in ppFEV 1 per ppm-yr was 7.83 while for Plant L the decrease in ppFEV 1 was 2.70 (= −7.83+5.13) per ppm-yr. At these two plants, many of the environmental samples collected were below the limit of detection for diacetyl, and the HHE environmental assessments were cross-sectional and not necessarily reflective of exposures prior to the survey date. This may explain the divergence in optimum exposure metrics compared with the Company G results. For example, if jobs with the highest exposures had been given priority for control interventions, then the subsequently measured levels would underestimate most of the jobs previously having the highest levels. Therefore, an exposure metric like Cum(DA 2.0 ), which gives greater weight to high values, might better predict spirometry changes than Cum(DA), as was observed at Company K for ppFEV 1 and FEV 1 /FVC, and at Company L for FEV 1 /FVC (Table 5- 5). Because of the inconsistencies between them and less certain exposure histories, the results for Company K and Company L were not the final basis for the NIOSH risk assessment for diacetyl which, instead, relied on the Company G findings. By far the highest exposures at Company G were among mixers (Table 5-3) raising the possibility that the observed losses in pulmonary function could be limited to that group. To examine this question, the basic multiple regression models (Table 5-6) were applied to the population at Plant G from which all employees who were ever mixers had been excluded. The result was slightly stronger estimates of the DA effect both for (1) the linear cumulative exposure term (β=0.61 vs. 0.50 for full population; R 2 =0.182 vs. 0.169, resp.) and ( 2) the square root of cumulative exposure (β=3.02 vs. 2.75 for full population; R 2 =0.182 vs. 0.173, respectively) (results not shown). Another concern was the possibility of a diacetyl-smoking interaction, with smoking possibly enhancing the harmful effect of diacetyl. Models for ppFEV 1 and FEV 1 / FVC including interaction terms (products of the diacetyl exposure metrics with the ever-smoking and pack-yrs terms) yielded statistically significant protective effects of ever-smoking on the linear and square root cumulative diacetyl exposures and small, mostly insignificant, additive interactions for the pack-years × diacetyl metric terms (P = 0.04 -0.25 depending on exposure metric and outcome; data not shown). In the absence of the smoking interaction terms, the diacetyl effects in non-smokers are somewhat underestimated and overestimated in smokers. Acetoin is another exposure in the popcorn flavoring environment (typically present with diacetyl in flavoring additive packages), and its presence was strongly associated with diacetyl (corr = 0.85) at Plant G, but it is not subject to the humidity degradation problem in air sampling. In response to concerns that the corrected historical exposure measurements for diacetyl were inaccurate, NIOSH repeated models of exposure-response relationships using acetoin measures. Applying to acetoin the procedure used for constructing the exposure matrix for diacetyl resulted in estimated acetoin concentrations over employees' work histories. Multiple linear regressions predicting percent of predicted FEV 1 based on acetoin exposure metrics produced the same pattern of results as observed with diacetyl and with almost identical model fit. For the metric square root of cumulative exposure, the R 2 observed was 0.1743 and 0.1737, respectively, for acetoin and diacetyl; the t-statistics for the exposure terms were 5.09 and 5.06 respectively. In microwave production jobs at Plant G, the mean DA concentration over all sampling surveys, combining both area and personal samples, was 3.4 ppm compared with 0.28 ppm for acetoin determinations from the same air samples. Because there is little support for acetoin itself playing a major role other than as surrogate for diacetyl in pulmonary toxicity, and because acetoin was present at much lower concentrations, this result supports the validity of the diacetyl exposure assessment and subsequent findings, but also implies that the diacetyl effects are being underestimated as a result of misclassification, otherwise the diacetyl effects would produce a stronger model fit than acetoin. 5-7, 5-8); the effects remain statistically significant. Differences in the effects of employees' exposures accruing from their initial evaluation (their first survey) until the current survey, compared to all exposures prior to the current survey, using either the metric Cum(DA) or , were small and not statistically significant (P > 0.7) (Table 5 -11, models 3 and 4). This supports the conclusion that bias arising from cases preferentially leaving employment prior to the first survey is not different from that following the first survey when exposures were declining, suggesting that the bias in estimating the decline in ppFEV 1 is not large. # Incidence of Pulmonary Impairment at Company G # Evidence of Variable Susceptibility to Diacetyl Effects When the joint distribution of cases by exposure duration and cumulative exposure was examined (case definition 1; all jobs had exposures > 0.0), the pattern suggested the possible presence of a low-risk survivor population or variable susceptibility. For example, there were five cases in the cell with lowest duration and lowest exposure and another five cases in a different cell with comparable person-years of observation (89 years) in the highest exposure category and 2 to 4 years duration (Tables 5-16, 5-17). Thus similar rates were observed despite the greater than tenfold difference in cumulative exposure. Of the 36 cases, 22 occurred in the first 4 years of exposed employment, which encompassed about 80% of the study population. The rapid onset of this disease has been reported CDC 2007;Israel et al. 2009;NIOSH 2006NIOSH , 2008. Examination of onset graphically (data not shown) also suggested that many cases arose after relatively short employment duration. A similar pattern was exhibited in the 46 cases (defn 1) identified among former employees (no longer employed at the time of their first survey) (data not shown). The predicted baseline incidence (from the model with diacetyl exposure set = 0) in the same array ( with a term of the form 2 ×exp(−0.69 × Duration), i.e., halflife of 1 year and squared average exposure, produced a significant fit (LRT=7.97, 2df, p=.0186; Table 5-24, model 3) with the two exposure terms being considerably stronger predictors than in models with either one alone (Table 5-24, models 1-3). Of the choices examined for parameters in the shortduration risk term, the best fit occurred with a halflife of 2.0 years and squared average exposure (LRT=9.52, 2df, p=.0086; Table 5-24, model 4; Table 5 -25). In this model, the estimated rate ratio for 1.0 pack-year of smoking (with no diacetyl exposure) relative to a very low baseline rate was 17.7 and, for 1.0 ppm-yr of diacetyl exposure in the "low-risk" group (with duration >4 years and no smoking), the rate ratio was 12.3; the initial high risk (at start of exposure, zero duration, and no smoking) rate ratio at 1 ppm diacetyl was 69.8. A similar result was obtained with case definitions 1 and 2 (data not shown) although, for case definition 1, the exposure parameter estimates were not statistically significant. The relative fit of various incidence-rate model specifications (case definition 3) indicates that, for a single metric, the average prior exposure metric fits best, but considerable improvement comes with an added duration term (Table 5-26, models 1-3 vs. . The best fit was for (a) square root of cumulative exposure with duration term (loglinear relative rate model 5), and for (b) cumulative exposure and the term for a high-risk subpopulation (linear relative rate model 10). # Interpretation of Modeling Results Multiple linear regression models of continuous spirometry outcomes at Company G reveal that both cum(DA) and are the preferred predictors of FEV 1 decline based on model fit. Average exposure was the weakest predictor of ppFEV 1 . Subsidiary analyses indicate that (1) a dose-rate effect, if present, is small and negative (i.e., effects are not limited to high exposures); (2) bias arising from possible removal of earlier cases was probably small, and ( 3) the bias introduced by the correction procedure addressing degradation of diacetyl air samples is also small although possibly resulting in underestimation of the diacetyl effect. Evidence for non uniform susceptibility includes the somewhat superior prediction by compared to Cum(DA) which may be a reflection of a reduced response in the population at longer durations of exposure. In the modeling of incidence, fewer cases met the third case definition than the first or second (19 vs. 36, 27) due to the requirement that both ppFEV 1 and FEV 1 /FVC be less than their LLofN. This was consistent with some restriction as was observed in regression models of FVC (data not shown). Using the third case definition, the estimated baseline rate is very small (Table 5-24, models 3, 4); baseline annual rate = 0.007% per year (365.25× exp(−15.48)=0.00007), indicating that virtually all cases were attributable to either diacetyl exposure or smoking. The strong association with the term representing short duration of exposure supports the conjecture that the population with "normal" susceptibility was declining by about half with each 2 years of exposure duration. Although average diacetyl exposure by itself is a strong predictor of incidence, as with prediction of FEV 1 /FVC, this appears to be an artifact of changing population susceptibility and has little biological plausibility as a risk factor itself. The existence of a changing population composition with respect to susceptibility poses a challenge for predicting excess cases over a 45-year working lifetime because the composition of the population with respect to the factor(s) conveying risk is unknown and workforce turnover continually introduces a higher-risk segment into employment. (more typical employment durations and implying a larger workforce ever exposed). The nominal standard for acceptable risk used was one per thousand excess risk of impairment, a standard choice used in OSHA regulation for chronic diseases. # Benchmark Dose # Methods For continuously distributed respiratory endpoints such as FEV 1 , the benchmark dose approach permits estimation of excess prevalence of impairment as a function of prior exposure history . On the basis of regression models and population data on the distribution of FEV 1 from NHANES III , the proportions of the workforce predicted to be impaired after working at specified exposure levels can be calculated. Unlike animal-based studies where exposures are in discrete levels, the analyses here utilized continuously distributed exposure metrics and a linear statistical model which made unnecessary the point-of-departure procedure commonly used in benchmark dose calculations. This method, however, does require specification of what degree of deficit constitutes impairment and the maximum increase in impairment prevalence that is considered acceptable, which are policy choices. The exposure resulting in a maximum allowable increase in impairment over some time period is called the benchmark dose (BMD). # Risk assessment with percent predicted FEV 1 and FEV 1 /FVC With the conventional benchmark dose procedure, the excess prevalence of an adverse condition is calculated using an exposureresponse relationship derived from modeling. With the linear regression result for percent predicted FEV 1 and Cum(DA) (coef.=−0.50, Table 5-6), the excess prevalence after 2.5, 10, or 45 years of exposure for falling below (1) 60% of predicted, or (2) the 5th percentile of normal, was calculated as a function of exposure level (Table 5 -27). Given these two pulmonary impairments, a 1/1000 excess prevalence after 45 years was found for diacetyl exposures (BMDs, central tendency estimates) of about 0.04, and 0.007 ppm diacetyl, respectively. Using the exposure metric, , which better predicts ppFEV 1 in the full population, substantially lower BMDs result (data not shown); 1/1000 excess risk for impairment at the 5th percentile after 45 years occurs with a diacetyl exposure concentration of less than 0.0001 ppm vs. 0.007 with the Cum(DA) metric (Table 5-27). These lower BMDs result from the increasing (negative) slope of the exposure response with diminishing exposure metric. Although better captures the risk of initially employed employees, extrapolation to decreasing durations with this nonlinear metric could introduce considerable error. For this reason NIOSH chose Cum(DA) over as the basis for risk assessment using the BMD procedure. In addition, to address the same issue for early exposures, the BMD was also calculated based on results from the < 4 yr population (Table 5-28) but also for a 45 yr. working lifetime. The resulting excess prevalence estimates were about double those based on the full population. For impairment defined in relation to LLofN as opposed to some fixed threshold such as the 5th percentile of ppFEV 1 , the BMD procedure is less direct because LLofN is specific to age, height, gender and race. The distribution of various functions of FEV 1 and LLofN, such as FEV 1 /LLofN or (FEV 1 -LLofN)/(ppFEV 1 -LLofN) are not readily specifiable. An alternate approach was taken: in the NHANES population , the cumulative exposure (Cum(DA)) that would reduce an individual's FEV 1 to their LLofN was calculated using the exposure-response estimates from the preferred regression models of ppFEV 1 (coef.=-0.50, -1.07 (< 4 yr); Table 5-6). The prevalence of individuals predicted to be below their LLofN was then calculated in the NHANES III population as a function of exposure over 2.5, 10 or 45 years. This "empirical" BMD procedure (using the empirical, nonparametric distribution of the NHANES population) yielded BMDs for both FEV 1 and FEV 1 /FVC for the full population and for < 4 yr (Table 5 -29). For FEV 1 below the LLofN (FEV 1 ) the BMD values were similar to those calculated the traditional way for ppFEV 1 in relation to impairment at the 5th percentile of normal; the excess prevalence after 45 years at 0.01 ppm diacetyl was 2.5/1000 and 1.5/1000, respectively (Tables 5-27, . BMDs for FEV 1 /FVC below the LLofN (FEV 1 / FVC) were comparable to those for FEV 1 (Table 5 -29). In the pooled Company K and Company L population, where reported exposures were lower than at Company G, the estimated 1/1000 BMDs for 45 yr were much lower: for FEV 1 , 0.0005 ppm and FEV 1 /FVC, 0.0004 ppm (Table 5 -30). Using the less satisfactory, average exposure, Avg(DA), as the predicting metric in the Company G population, the excess prevalence was estimated to be considerably lower (Table 5-31), and of course, did not depend on Baseline prevalence for < 60% of predicated = 0.0053, for <5th percentile = 0.0498 duration of work. The 1/1000 BMD for FEV 1 , was correspondingly higher: 0.05 ppm diacetyl. # Excess Lifetime Risk for Pulmonary Impairment # Methods Using the life-table approach as implemented in the Biological Effects of Ionizing Radiation IV report together with the observed exposure-response relationship from models of incidence rate, one can estimate the excess numbers of cases of diacetyl-associated impairment that would occur as a result of lifetime exposures at various concentrations. This method assumes irreversibility and removes incident cases from the population at risk with increasing age along with deaths arising from the usual causes in the general population. Although typical applications of the excess lifetime risk calculation are for deaths arising from chronic diseases, the method can be applied to incidence of an irreversible condition provided a baseline incidence rate for the condition is known and an estimate of the exposure-related incidence rate ratio is available. In this analysis, Poisson regression Rodriguez et al. 1994] and five others predicted mortality using current FEV 1 . Three studies provide estimates of rate ratios (RRs) that can be applied to a life-table analysis of excess lifetime risk . The estimates range from 1.010 to 1.019 per percent decline in FEV 1 in men, and from 1.01 to 1.025 in women. Assuming a RR of 1.015 per percent decline in FEV 1 , and using the exposure response for FEV 1 from the full population and from the < 4 yr group, a life-table analysis produced estimates of excess lifetime risk (Table 5-33) that were comparable (fortuitously) to those based on the incidence of pulmonary impairment, e.g., FEV 1 falling below LLofN (Table 5-32). These estimates of excess mortality are the result of a generic effect of declining FEV 1 on mortality not specific to obliterative was protective). Alternate formulations such as for dose-rate, comparing exposure effects preand post-first survey, comparing prediction based on diacetyl vs. acetoin, a surrogate for diacetyl, all supported the final choices utilized in the risk assessment. On the question of exposure uncertainties prior to the NIOSH surveys, particularly the date when widespread diacetyl exposures commenced at Company G, analyses specifying different years for the start of exposures suggested that the optimum starting year was about 1994 instead of 1986, but this assumption had only a small impact on the estimated exposure response because most employees surveyed were hired after 1994. In constructing the exposure matrix for the plants studied, the decision was made not to apply the humidity correction for air samples below the LOD. To determine if this choice affected the analytical results, analyses were repeated having applied the correction to all air samples. The resulting difference in parameter estimate for the model of percent predicted FEV 1 with the cumulative exposure term was very small: −0.500 vs. −0.499. For the metric, square root of cumulative exposure, the parameter estimate is slightly larger when samples < LOD are corrected: −2.77 (uncorrected) vs. −2.82 (corrected). For the models of FEV 1 /FVC there was no change. Therefore there was no impact on risk estimates which were based on these parameter estimates. Several alternate explanations were considered for the apparent variability in susceptibility: (1) The proportion of Hispanic employees was higher among the short duration cases: Hispanics also comprised a higher proportion among recent hires and the cross-sectional surveys tended to reflect more recent employees due to high turnover. (2) Bias from candidate cases lacking styptom onset: using the date of their first qualifying spirometry would tend to increase rather than decrease the estimate of duration of exposure until onset and thus would not account for the short-duration cases. (3) Recall bias on symptom onset: employees with fast onset probably estimated symptom onset in relation to hire date, which is generally precisely known, not in relation to survey date. For example, an employee with 3 years employment probably would recall that symptoms began after about 6 months on the job, not 2.5 years ago. (4) Jobs with peak exposures would favor an early onset: this would happen only if the cumulative exposure metric was underestimating the relevant exposure. This could occur with a positive dose-rate effect, but what was observed was, if anything, a negative dose-rate effect (Table 5-5) where summing the square root of air concentrations over time was a much better predictor than summing the square of concentrations. Serious exposure misclassification could cause a pattern indistinguishable from variable susceptibility; employees whose exposures were substantially underestimated would appear to respond more strongly (faster) with adverse health effects and conversely for employees whose exposures are overestimated. However, the "high risk" cases were not largely associated with specific job groups such as mixers or quality control; many came from the general production line, and excluding mixers did not reduce affect estimates. Undoubtedly misclassification was present but a systematic discrepancy in risk by a factor of 10, as observed between the short and long duration groups and others arising from misclassification is implausible. In summary, these sensitivity analyses substantiated the parameters, variables, and assumptions used in the final risk assessment and provide confidence in the risk estimates. # Discussion The NIOSH HHE investigations in popcorn manufacturing were not specifically designed for quantitative risk assessment and have limitations in terms of unknown selection of study subjects and limited historical exposure information. Nonetheless, these observations of diacetyl-exposed employees have proved useful for risk assessment. The likelihood that the Company G population represents a survivor cohort together with the relatively high participation rate implies that underestimation of effects has probably resulted. Further underestimation has resulted from exclusion of asymptomatic cases in the analyses of incidence. Acting against bias from selection of a surviving population and missing cases is the possibility that participants may have included a more than representative proportion of cases. However, the high participation rate (~80%) limits this potential participation bias. The exposure metric, average exposure, which is simply the cumulative exposure divided by duration of exposure (employment duration since start of diacetyl use) was a strong predictor of pulmonary impairment in some analyses. It is implausible that average exposure, in a homogeneous population, would predict impairment without consideration of duration. Rather, a more credible explanation for the association of impairment with average exposure is the changing composition of the population over time since exposures began. The more responsive individuals leaving the population sooner than others would diminish the apparent importance of cumulative exposure. Thus average exposure might predict impairment, but it could be very population-specific depending on duration of observation and how the particular plant population changed over time, and would not be a generalizable exposure response. For this reason average exposure was not utilized in the risk assessment procedures. Appropriate in the risk assessment and development of the REL for diacetyl is consideration that the health effects should be viewed in the complementary contexts of an individual employee's risk of impairment which is the clinician's measure of impact, and the risk incurred by the population of employees with diacetyl exposure. The American Thoracic Society, in a statement on the effects of air pollution, concluded that shifts in the respiratory health of a population, resulting from some exposure, that diminish individual reserve function, are adverse "even in the absence of the immediate occurrence of frank illness" . In the clinical context, if an employee's FEV 1 /FVC is less than 0.7 (or FEV 1 less than or equal to 80%), that would be considered mild COPD . Similarly, if diacetyl exposure decreases the mean pulmonary function of the exposed population by some small increment, this too could be considered an adverse event . The health significance of small spirometry changes, such as a 1% decline in FEV 1 after 2 years of exposure at 1 ppm diacetyl, depends partly on whether such changes are early indications of lung pathology that eventually would manifest as obliterative bronchiolitis. In studies of obliterative bronchiolitis arising from lung transplantation, unrelenting irreversible FEV 1 decrements are observed that ultimately lead to the diagnosis of obliterative bronchiolitis and fatal disease . However, incomplete knowledge concerning the natural history of obliterative bronchiolitis development with diacetyl exposure is a limitation in the present risk assessment. Not only is risk for mortality increased, as estimated in this risk assessment, quality of life is degraded and risk is increased for cardiovascular disease and progressive respiratory disease . The decrease in FEV 1 predicted after working for 10 years in diacetyl exposures of 0.2 ppm (about 1% loss) is comparable to changes observed in children, a more vulnerable population, exposed to levels of air pollution that lead to clinical impairment in later life . Variation in susceptibility poses issues for risk assessment. If less-susceptible individuals are remaining in employment longer, the estimated exposure response for long durations when applied to a hypothetical population of 1,000 employees employed 45 years, will generate excess risk values that understate the true risk of a workforce that turns over more often. All of the risk assessment procedures used here assume some degree of low-dose linearity, with effects diminishing proportionally with decreasing exposure levels that are held constant over 10 or 45 years. Model linearity was observed particularly after limiting the population to < 4 yr duration. Moreover a significant fraction of career-average exposures fell below 0.01 ppm (17% of employees) a factor of only 2.0 higher than the proposed REL. Thus low-dose extrapolation was limited. Below 0.01 ppm, there can be some significant departure from linearity although diversity in response would tend to favor linearity to lower levels . # Conclusion Excess prevalence (BMD) and lifetime risk estimates variously derived for 45 years of diacetyl exposure were similar, based on Company G analyses (Table 5-34). Impairment has been defined here as pulmonary function falling below the lower limit of normal. The BMD estimates for excess prevalence of FEV 1 impairment are within a factor of 2.0 of the life- Dose-response data for diacetyl toxicity in laboratory animals are available, and there are limited but useful animal data on the toxicity of 2,3-pentanedione. Although the NIOSH REL for diacetyl is based on the analysis of human data described in Chapter 5, NIOSH has assessed the animal data for diacetyl to determine whether they are consistent with the human data. For 2,3-pentanedione, NIOSH has conducted a comparative potency analysis, comparing the toxicity of inhaled 2,3-pentanedione to that of diacetyl. These quantitative risk assessments are described below. NIOSH interpretation of the findings and implications for occupational exposure recommendations for diacetyl are described below and in Chapter 7. Laboratory animal studies designed to evaluate the effects of exposure to butter flavoring vapor or of diacetyl alone have demonstrated a relationship between exposure and respiratory effects. In rats exposed by inhalation to butter flavoring vapor for 6 hours (diacetyl concentrations ranged from 203 to 352 ppm), rhinitis (at the lowest exposure concentration) and bronchitis (at the higher two exposure concentrations) were observed one day after exposure . In a follow-up study rats were exposed by inhalation to diacetyl (intermittently or continuously for up to 6 hours), which resulted in various adverse respiratory effects including epithelial necrosis and inflammation in the nose, larynx, trachea, and bronchi ]. The nasal region was observed to be the most sensitive. reported similar adverse respiratory effects in mice exposed by inhalation to diacetyl for up to 12 weeks. Adverse nasal and lung effects were observed with the latter found in the bronchial, peribronchial, and peribronchiolar regions. The NTP has issued findings from a 90-day inhalation study of diacetyl in both mice and rats . Adverse effects were observed in the nose, larynx, trachea, and bronchi in mice and rats. Because the 2011 NTP study had the longest exposure durations among all experimental animal studies, included two species, and used more animals per dose group than the study, it was used in the doseresponse analysis to BMDs, the lower bound on the BMDs (BMDLs), and corresponding human equivalent concentrations (HECs), as discussed below. # 2,3-Pentanedione Histopathological data from repeatedexposure inhalation toxicology studies with 2,3-pentanedione were first published in 2012, but are limited to 2-week exposures using small numbers of animals . Although these data are limited, it is possible to compare the toxicity produced by 2,3-pentanedione to that produced by diacetyl under similar conditions, and thus estimate the potency of 2,3-pentanedione relative to diacetyl. Therefore, the limited toxicological data for 2,3-pentanedione are not used directly to establish a REL for 2,3-pentanedione, but only to develop an estimate of the toxic potency of 2,3-pentanedione relative to that of diacetyl. Like diacetyl, 2,3-pentanedione is a reactive alpha-dicarbonyl compound that can damage protein . Recently, bronchial fibrosis has been documented in rats inhaling either 2,3-pentanedione or diacetyl for 2 weeks ]. # Methods # Data # Diacetyl The response data that were analyzed were obtained from the experimental study reported by the NTP . Male and female Wistar-Han rats and male and female B6C3F 1 hybrid mice were exposed to diacetyl vapors at concentrations of 6.25, 12.5, 25, 60, and 100 ppm, 6 hours per day, 5 days per week, for 13 weeks. The microscopic evaluations of tissues from the larynx, lung, nose, and trachea described whether or not one or more lesions were detected, the types of lesions that were detected, and the assignment of a numeric score describing the lesion's severity on an ordinal scale (1-minimal, 2-mild, 3-moderate, 4-marked) for each type that was detected. Descriptions of the types of lesions observed among rats and mice that were considered for this analysis are given in Tables 6-1 and 6-2, respectively. # 2,3-Pentanedione The results of a 2-week inhalation study of 2,3-pentanedione toxicity were reported by Morgan et al. . Individual animal data 2010). These data describe the pathological responses of male and female Wistar-Han rats and B6C3F1 mice exposed to 2,3-pentanedione by inhalation for 6 hours per day, 5 days per week, for 2 weeks plus 2 days. The exposure concentrations were 0 ppm, 50 ppm, 100 ppm, and 200 ppm, with six animals per dose group; nasal, tracheal, and pulmonary endpoints were assessed. The tissue and pathological endpoints that could be modeled successfully for both 2,3-pentanedione and diacetyl (for comparative purposes) are listed in Table 6-3. In addition to the 13-week NTP bioassay data described above for diacetyl, the 2,3-pentanedione data were also compared to data for diacetyl from . These data describe the pathological responses of male C57Bl/6 mice exposed to diacetyl by inhalation for 6 hours per day, 5 days per week, for either 6 or 12 weeks. The exposure concentrations were 0 ppm, 25 ppm, 50 ppm, and 100 ppm, with five animals per dose group. Nasal, tracheal, and pulmonary endpoints similar to those examined in the 2,3-pentanedione study were assessed. In addition to the data in the publication, tables of individual Includes lesions classified as "Squamous Epithelium, Hyperplasia, Atypical" ‡ Includes lesions classified as "Bronchus, Epithelium, Hyperplasia, Atypical" § One male classified as having a minimal "Bronchus, Epithelium, Degeneration" lesion was pooled with 10 other males having a regenerative response. ¶ One male and two females classified as having a "Respiratory Epithelium, Degeneration" lesion were pooled with 20 other males, and 20 other females having the regenerative response. # Analytical approach An empirical approach based on parametric regression modeling of the ordinal response data was adopted to maximize the information available for analysis from the limited numbers of rodents - in order to assess the potency of diacetyl to increase risk and to assess the relative potency of the two chemicals. # Benchmark concentration analysis for rats exposed to diacetyl The assessment of the potency of diacetyl to increase risk employed the benchmark dose approach that was originally proposed for risk assessment of non-cancer responses by Crump . development over the past three decades, and it has become an accepted approach for risk assessment . Benchmark concentration (BMC) estimates for the pathological endpoints listed in Table 6-1 (for rats) were based on modeling of the exposure concentrations and the associated pathology. In order to avoid the loss of information inherent in dichotomizing ordinal response data, a categorical regression procedure for ordinal data was used to estimate benchmark concentrations. Categorical regression has been previously used in the analysis of toxicological data with multiple levels of severity . The severity scores ‡ for each tissue and type of lesion were assumed to be samples from a multinomial distribution following a complementary § cumulative logistic model fitted separately for each species and sex as follows: where Y ci denotes the corresponding severity score of the i th rodent exposed to concentration, conc c , j Є element of {observed severity scores excluding zero} for the corresponding tissue and type of lesion, Pr( Y ci ≥j)denotes the expected proportion of response score Y ci greater than or equal to j , each α j is an unknown real-valued parameter with α j' j, and β is an unknown real-valued parameter describing the slope of the effect of concentration on the logit scale. ‡ When no evidence of the lesion being modeled was detected a severity score of zero (0) was assigned. § The term complementary discerns this model from an equivalent cumulative logistic model of Pr(Y ci ≥j) . lower one-sided 95% confidence limit (BMCL) were estimated. # Benchmark concentration analysis for mice exposed to diacetyl Benchmark concentration estimates for the pathological endpoints listed in Table 6-2 (for mice) were developed as described above for the rat data; however, an analysis of the residual errors of the fitted models provided substantial evidence against the model for the data on mice (Figure 6-1). These residuals have mean equal to zero asymptotically if the linear-in-concentration model is correct. However, the distribution of the residuals of Figure 6-1 is shifted above zero at 50 ppm corresponding to underprediction and the distribution is shifted below zero corresponding to overprediction at 100 ppm. Figure 6-1 provides support for making a modification of the dose-response model in a manner that allows for a reduction of the rate of increase of the response at high doses. Because mice are able to substantially alter their breathing rates in a dose-dependent manner when exposed the model of the data for mice was modified to include a quadratic dose term to allow it to more closely fit the data in the high-dose region of the dose-response relationship; this term was parameterized to represent a directly proportional relationship of the change in breathing rate with concentration relative to the breathing rate of the controls. The resulting estimate for male mice exposed to diacetyl was compared with corresponding ventilation measurements provided by Dr. Daniel Morgan, NIEHS (personal communication to Randall Smith, NIOSH, June 5, 2014). In addition, two parameters allowing for adjustment of the intercepts of each sex and a third parameter allowing for adjustment of the effect of exposure were added to the model to account for the varying durations of these studies. This model was further extended to incorporate the comparative potency analysis of 2,3-pentanedione relative to diacetyl and incorporated an allowance for the responses of each mouse to be correlated by including random effects. It is described below in section 6.2.2.7. # Extrapolation of rodent benchmark concentrations to humans Extrapolation of rodent BMCs to humans was based on a PBPK/CFD model for diacetyl Morris and Hubbs 2009]. The Gloede et al. extension of the Morris and Hubbs model predicts tissue concentrations of diacetyl for mucosal surfaces in the nose, trachea, bronchi, and bronchioles of rats and humans exposed to 1 ppm diacetyl. Nose-breathing and mouth-breathing humans are considered, as well as the effects of light exercise as might be expected to occur in the workplace. The Gloede et al. model assumes mouth breathing during light exercise conditions. For extrapolation purposes, an 8-hour work day was considered to consist of 2.5 hours of sedentary exposure and 5.5 hours of light exercise, as described by the International Commission on Radiological Protection (ICRP) human respiratory tract model . The ICRP model assumes 20 breaths per minute and a tidal volume of 1,250 mL for light exercise and 12 breaths per minute and a tidal volume of 625 mL for sedentary sitting, for a total inhalation volume of 9.6 m 3 in an 8-hour work day. Therefore, to extrapolate from rodents to humans, the BMC estimates described above were adjusted by a weighted average of the rat:human ratios of the predicted tissue concentrations for a particular anatomical region, under sedentary and light exercise conditions. The Gloede et al. estimates incorporating tissue metabolism (V max for the rat, and K cat for humans) were used, because local metabolism is predicted to impact significantly on the local tissue concentration (Table 3). For example, the predicted tissue diacetyl concentration for the proximal tracheal mucosa of a rat exposed to 1 ppm diacetyl is 0.33 µM, while the predicted tissue concentration for the same anatomical region is 1.4 µM in a sedentary nose-breathing human and 2.5 µM in a mouth-breathing exercising human. The rat BMCs based on pathological changes to this anatomical region were divided by a factor of (1.4 µM - 2.5 hours + 2.5 µM - 5.5 hours)/(0.33 µM - 6 hours), or 8.71. The factor of 6 hours in the denominator adjusts for the 6-hour/day duration of the experimental exposures, as compared to the 8-hour workday assumed for occupational exposures. Gloede et al. did not report tissue concentration estimates for the larynx; BMC extrapolation for this region was based on the tissue concentrations estimated for the proximal trachea. Gloede et al. reported tissue concentrations for both mainstem and small bronchi, and BMC extrapolation for bronchial endpoints were based on the mean of the rat:human ratios of tissue concentrations for mainstem bronchi and small bronchi. Rat to human scaling for the alveoli was based on the estimated fractional penetration of diacetyl through the bronchioles in the Gloede et al. PBPK model, provided by Dr. John Morris, University of Connecticut (personal communication to Dr. David A. Dankovic, NIOSH, November 8, 2012). The rat:human extrapolation factors used are shown in Table 6-4. # Extrapolation of BMCs and BMCLs from the mouse to the rat Because no PBPK model for diacetyl exposures in the mouse is currently available, the rat PBPK model was extended to the mouse using the EPA reference concentration (RfC) methodology . In the RfC methodology, the deposition and uptake of volatile chemicals are estimated from a combination of chemical characteristics (i.e., reactivity and solubility) and the physiological characteristics of the relevant species (i.e., minute ventilation and the surface area of the relevant portion of the respiratory tract). Diacetyl is classified as a "category 1" gas in the RfC methodology because of its high water solubility. Category 1 gases are not expected to reach the pulmonary region in high concentration, but rather to be deposited primarily in the upper respiratory tract and the tracheobronchial region. This is consistent with the behavior of diacetyl in the Gloede et al. PBPK model, so that the classification of diacetyl as a category 1 gas appears to be appropriate. Interspecies dosimetric adjustments via the RfC methodology are based on an estimate of the regional gas dose ratio (RGDR). The RGDR estimates the ratio of gas deposition with a given respiratory tract region in the two species being compared. For the ET region, the RGDR is calculated , eqn. 4-18, as: where: V E = minute volume (mL/min = cm 3 /min) SA = surface area (cm 2 ) ET = a subscript denoting the extrathoracic region A, B = subscripts denoting experimental animal and target species, respectively For the TB region, the RGDR is calculated , eqn. 4-22, as: where: V E = minute volume (mL/min = cm 3 /min) SA = surface area (cm 2 ) TB = a subscript denoting the tracheobronchial region ET = a subscript denoting the extrathoracic region A, B = subscripts denoting experimental animal and target species, respectively Table 3, except as noted below for alveoli. ‡ Mouse-to-human scaling assuming mouse is 2.4 times as sensitive as the rat for nasal effects and 3.2 times as sensitive for tracheobronchial effects, based on the regional gas dose ratio (see section 6.2.2.4) § "Average bronchi" = arithmetic mean of values for mainstem and small bronchi ¶ Rat to human scaling for the alveoli was based on the estimated fractional penetration of diacetyl through the bronchioles in the Gloede et al. PBPK model. The values assumed for V E and SA, and the resulting RGDR values for mouse-to-rat extrapolation, are shown in Table 6-5. The rat V E value is based on data from Gloede et al. , and the mouse V E was taken from . The SA values are from EPA . The RGDR is used to adjust a point of departure (POD), i.e., a BMC or BMCL in the laboratory species to an equivalent concentration in the target species as follows: POD BEC = POD A - RGDR where: POD BEC = POD equivalent concentration in the target species; POD A = POD in the experimental species; and RGDR = Species A-to-species B regional gas dose ratio for the appropriate region of the respiratory tract. Although the RGDR is typically used to develop human equivalent concentrations from experimental animal data, in this case it is used to develop a rat equivalent concentration for a point of departure estimated from experimental data in the mouse. The Gloede et al. PBPK model is then used to extrapolate from the rat equivalent concentration to a human equivalent concentration. Mouse-to-rat regional gas dose ratio for the upper respiratory tract ¶ Mouse-to-rat regional gas dose ratio for the tracheobronchial region This conclusion is based on the analysis of Allen , who concluded that the 6-and 12-week mouse experiments had response rates that could be modeled together (i.e., the duration of the experiment could be ignored) for all the lesions analyzed; there did not appear to be a progression toward higher rates of response or more severe responses when the exposure level remained the same but the duration of exposure was increased from 6 to 12 weeks. However, because of the small number of animals used in this study, the power to detect differences between the 6-week and 12-week experiments is limited. As a consequence of the limited duration of the experimental studies and the limited ability to detect differences between the responses at 6 and 12 weeks, the possibility of increased toxicity with lifetime exposure cannot be entirely ruled out. This possibility was addressed through the application of an uncertainty factor (UF) -discussed below -rather than a dosimetric adjustment. # Application of uncertainty factors The HECs are estimates of frankly toxic exposure levels, and must be adjusted by the application of UFs to allow for uncertainty in animal-to-human extrapolation, interindividual variability, and less than lifetime exposure. In general, these UFs are assumed to be 10-fold for animal-to-human extrapolation and another 10-fold for interindividual variability. The animal-to-human extrapolation can be subdivided into a factor of 4 for pharmacokinetics and a factor of 2.5 for interspecies variability in susceptibility . In this case, the interspecies pharmacokinetic factor is replaced by the use of the Gloede et al. pharmacokinetic model, leaving an interspecies UF of 2.5. The UF for interindividual variability can be subdivided into two factors of √10, or 3.2, one for interindividual variability in pharmacokinetics and the other for interindividual variability in susceptibility . Because the toxicity of diacetyl occurs at the point of contact with respiratory tract mucosa there is relatively little opportunity for interindividual variability in pharmacokinetics, and so the first subfactor is not applied. However, interindividual variability in susceptibility to toxicity cannot be ruled out; therefore, a factor of 3.2 is applied. In addition, a factor of 3 is applied for conversion from subchronic to chronic exposure. When the three factors (3.2fold for interindividual variability, 2.5-fold for interspecies variability, and 3-fold for subchronic to chronic) are multiplied, the resulting total UF is 24. # Joint analysis of the data on mice from the diacetyl and 2,3-pentanedione bioassays To avoid the loss of information inherent in dichotomizing ordinal data the severity scores of each type of lesion observed among nasal and lung tissues were modeled as having been sampled from conditional multinomial distributions given the unobserved random effects associated with each mouse described by the following family of complementary cumulative logistic models: = α sjr(t) + u bskci + ω s τ bskci +f bskcti β sjr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ skt , γ s )} - conc bskci , where α sjr(t) + u skci + ω s τ bskci describes effects in the absence of exposure, f bskcti β sjr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ skt , γ s )} - conc bskci describes effects of exposure and b indexes the bioassay study s indexes sex, k = 0 ←→ 2,3-pentanedione exposure and k = 1 ←→ diacetyl exposure, bkc identifies the exposure group and conc bkc is the corresponding exposure concentration, i = 1, ..., n bskc indicates each of the mice within the exposure group identified by bskc and conc bskci denotes the corresponding exposure concentration, r(t) identifies the response lesion, r nested within tissue, t, (lung or nasal), Y bskcr(t)i is the response variable that is integer-valued based on the assigned severity score and it ranges over {0,1,2,3} for all response lesions ‡ ‡ except necrosis of the respiratory epithelium of the nose where the range was {0,1,2}, Pr(Y bskcir(t) ≥ j) represents the expected proportion having response severity score greater than or equal to j for j Є {1, ..., max (Y bskcr(t)i )}, α sjt(r) denotes the intercept parameters for lesion r(t) which are subject to constraints α s2t(r) −α s1t(r) =∆α s2 <0 and α s3t(r) −α s2t(r) =∆α s3 <0 thus ensuring § § α s3t(r) <α s2t(r) <α s1t(r) , u bskci ~N(0, σ 2 su ) is a normally distributed random effect associated with the i th mouse of bskc; likelihood ratio tests of null values of the variance ‡ ‡ When no evidence of the lesion being modeled was detected a severity score of zero (0) was assigned. § § Hence, the requirement that r(Y kcit(r) ≥ 3) < Pr(Y kcit(r) ≥ 2) < Pr(Y kcit(r) ≥ 1) is satisfied for the controls. at low doses for {r(t)}; the hypothesis, 0 sr(t) = 0 s , was tested and subject to being incorporated into the model, and φ skt allows for an adjustment for a quadratic effect of concentration that may be attributed to directly proportional changes in respiratory ventilation with concentration where φ skt is the constant of proportionality in units of controls' ventilation; thus φ skt describes the change relative to controls. The hypothesis, φ sk,lung = φ sk,nose = φ sk , was tested and subject to being incorporated into the model. f bskcti is one of a pair of lognormally distributed random effects (one effect per tissue indicated by t) of the i th mouse of exposure group bskc acting multiplicatively on the effect of dose. Thus, an allowance for multiplicative variations from mouse to mouse by tissuespecific positive factors acting on the magnitudes of the slope parameters was incorporated. Each f bskcti was modeled as having unit expectation and variance (e σ 2 st −1); thus, the variance of log (f bskcti ) = σ 2 st , t = 1, 2 for the lung and nose, respectively, together with an associated covariance parameter σ s12 . The hypothesis that lognormal random effects are independent was examined by testing σ s12 = 0 and was subject to being incorporated. Furthermore, the hypothesis that only one lognormal random effect for each mouse was necessary, i.e., f bskc1i = f bskc2i was tested and subject to being incorporated. Model development proceeded by sequentially fitting a series of nested models of increasing complexity with all random effects omitted. This was advantageous for obtaining initial estimates of the fixed effects parameters for fitting a corresponding model that included random effects. Models were fitted by the method of maximum likelihood; the likelihoods of models containing unobserved random effects were obtained by integrating out these effects using adaptive Gaussian quadrature as described by Pinheiro and Bates . Likelihood ratio tests were performed to test hypotheses about model parameters and associated P values were based on the chi-square approximation to −2log (LR). Evidence against incorporating the previously described restrictions on model parameters was deemed significant if the P value of the corresponding test was less than 0.05 for selecting the model on which to base the estimation of relative potency parameters and benchmark concentrations. The model selected for estimation of relative potencies and BMCs contained three lognormal random effects parameters and 53 fixed-effects parameters; it had the following form: st ) = 0 for lognormal random effects of nasal responses of female mice was replaced by nullifying this parameter, The adequacy of a single lognormal random effect was rejected, Independence of the lognormal random effects for lung and nasal tissues of male mice was assumed. = α sjr(t) +ω s τ bskci +f bskcti β sr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ sk , γ)}conc bskci where m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ sk , γ) = i.e., The model was coded and fitted using the NLMixed procedure of SAS TM 9.3. At least two lines of evidence provided support that the algorithm for fitting the model converged to a solution for the parameters that was a unique optimum as follows: (1) The Hessian matrix of the fit was positive definite † † † and (2) exploration of the likelihood surface in a neighborhood of the solution via examination of likelihood profiles supported its optimality in all cases that were examined. Hence, this evidence supports the identifiability of the parameters of the model with these data suggesting that the model is not overparameterized. The fit of the model was assessed by calculating grouped ‡ ‡ ‡ Pearson residuals conditional on the † † † NLMixed minimizes -log(L) and it provides a warning if its criteria for a positive definite Hessian is not satisfied; no such warning was given. ‡ ‡ ‡ The term "grouped" is to clarify that they are based on summing the observed and fitted expectations and variances over the mice within each treatment group defined by each unique combination of b x k x s x c. empirical Bayes estimates of the random effects for each tissue-response as follows: where the fitted expectations and variances of each mouse were based on the associated binomial distribution of a factoring of the conditional multinomial likelihood into its conditionally independent binomial components corresponding to the "outcomes" (Y≥1 \| f ) , (Y≥2\|Y≥1,f ), and (Y≥3\|Y≥2,f ). Furthermore, a saturated fixed-effects model with random effects omitted was compared to the selected model by examination of twice the difference of log(Likelihood) values relative to the difference in the number of parameters. Finally, an ad hoc procedure was applied wherein binomial deviance residuals corresponding to factoring the multinomial likelihood of the corresponding 53 parameter model (with random effects omitted) into a product of conditional binomial terms were used to estimate a factor for adjusting the width of the confidence intervals analogous to an adjustment for overdispersion because the model-based confidence intervals may be too narrow if the model is incorrect. Twosided 95% confidence limits with and without adjustment were calculated from application of a normal approximation to the natural logarithms of the relative potencies and the BMCs associated with a 10% benchmark response for additional risk. § § § § § § i.e., Pr(Y skcr(t) ≥ j \| conc=BMC jskr(t) , f skcti = 1)−Pr(Y skcr(t) ≥ j \| conc = 0, f skcti = 1) = 0.10. # Benchmark concentration analysis using quantal models To explore the impact of the categorical regression procedure described above on the BMC estimates for diacetyl, the data for the pathological endpoints listed in Table 6-1 (for rats) and Table 6-2 (for mice) were also dichotomized, and alternative benchmark concentration estimates were developed using quantal modeling and model averaging. Any response of minimal or greater severity was treated as a positive response, and the model averaging procedure was based on fitting the multistage, Weibull, and log-probit models, as described by Wheeler and Bailer . Only datasets with two or more partial response groups were modeled. The benchmark response rate was set at 10%, and the resulting BMC and BMCL estimates are shown in Table 6-9. Only models with an average-model P value of 0.05 or greater were considered to fit the data adequately. # Results # Diacetyl BMC and BMCL estimates based on diacetyl toxicity in rats and mice were developed as described in sections 6.2.2.1 and 6.2.2.7, respectively. Not all of the pathological endpoints listed in Tables 6-1 and 6 Although evidence of systematic departures of the residuals was not apparent, 13 of the residuals indicated deviations from the fit of the joint model of diacetyl and 2,3-pentanedione by more than three standard errors (not shown). Although less than one such residual deviation would be expected for normally distributed residuals the observation of 13 such deviations seems suggestive that extraneous variations may be present and motivated our having increased the widths of model-based confidence limits by the application of an overdispersion factor of 1.61 for adjusting the model-based standard errors. Overall, the BMCs range from 16.8-68 ppm diacetyl, and the BMCLs range from 10-49.9 ppm diacetyl. After interspecies pharmacokinetic adjustments based on the Gloede et al. model, the human-equivalent BMCL values (BMCL_HECs) range from 1.4-95.8 ppm diacetyl, and the BMCL candidate REL values (after the application of uncertainty factors) range from 0.06-4.0 ppm diacetyl. # Sensitivity analysis As a sensitivity analysis, alternative BMC and BMCL values were also derived for the NTP diacetyl study by dichotomizing the data, fitting quantal models, and model averaging, as described in section 6. Another assumption made in this risk assessment is that toxicity observed in mice can be scaled to rats using the EPA RfC methodology to estimate a mouse-to-rate respiratory dose ratio, or RGDR. It was assumed that this extrapolation is best performed on the basis of measured values of respiratory ventilation, as opposed to estimating respiratory ventilation on the basis of body weight. As detailed above in section 6.2.2.4, use of the measured respiratory ventilation rates leads to RGDRs of 2.4 for upper-respiratory toxicity and 3.2 for lower respiratory toxicity. The impact of the decision to use measured respiratory rates in the RGDR calculation was evaluated by a comparison to the RGDRs which would be obtained using the default RfC methodology, based on body weights, and described in EPA . Using the EPA default methodology, in which the respiratory ventilation rate is estimated from the animal biody weight, results in RGDRs of 1.15 for upper respiratory tract effects and 1.5 for lower respiratory tract effects. Therefore the mouse-to-rat scaling factor would be approximately halved, and as shown in Table 6-9 the lowest candidate REL value would be reduced to 0.03 ppm, based on chronic bronchial inflammation in the female mouse lung. A key assumption made in this risk assessment is that the Gloede et al. PBPK model is the most appropriate method for extrapolating from rats to humans. A possible alternative would be to use the EPA RfC methodology to estimate animal-to-human scaling factors, based on the RGDR. Measured respiratory ventilation values are available for mice and rats, as used in section 6.2.2.4, and the human occupational respiration rate can be assumed to be 20 L/min. Using these values and the EPA procedures for category 1 gases, the estimated RGDRs for rat-to-human extrapolation are 0.18, 1.9, and 2.1 for the upper respiratory tract, the tracheobronchial region, and the pulmonary tract, respectively. Corresponding values for mouse-to-human extrapolation are 0.43, 5.9, and 6.9 for the upper respiratory tract, the tracheobronchial region, and the pulmonary tract, respectively. These RGDRs would replace the Gloede et al. PBPK model for extrapolating from rats to humans, and would result in candidate RELs ranging from 0.15-16.1 ppm for BMCs, and from 0.10-14.3 ppm for BMCLs. The lowest candidate REL derived using the RGDR method would be 0.10 ppm, as opposed to 0.06 ppm using the Gloede et al. model. The endpoints yielding the lowest alternative candidate REL values from the sensitivity analysis are shown in Table 6-9, along with the lowest of the candidate RELs from the main analysis, for comparison. Alternative analysis using respiratory ventilation rates based on body weight, rather than measured values. ¶ Alternative analysis using EPA RfC methodology rather than the Gloede et al. PBPK model. The animal-to-human PK factor shown here is the RGDR for the rat nose, which in EPA methodology is applied to the BMC/BMCL as a multiplicative factor. This is unlike the PBPK-derived PK factors above, which are applied as divisors for the BMC/BMCL values. # 2,3-Pentanedione The ventilation coefficient of 2,3-pentanedione among male mice was −0.312 ± 0.0139 and among females it was −0.182 ± 0.0530. The relative potency estimates (diacetyl/2,3-pentanedione) are shown in Table 6-10, below, and range from 0.81-7.3, depending on sex and the specific endpoint evaluated. A relative potency of 1.00 indicates that the two compounds have equal toxic potency for the endpoints examined; a relative potency less than 1.00 indicates that 2,3-pentanedione is more toxic than diacetyl, while a relative potency greater than 1.00 indicates that 2,3-pentanedione is less toxic than diacetyl. Model-based 95% confidence limits range from 0.55-14, and the overdispersionadjusted confidence limits range from 0.44-21. These estimates suggest that the potency of diacetyl was significantly greater than that of 2,3-pentanedione among female mice for these responses. However, one source of contribution to these estimates among females is that their fitted ventilation coefficient of diacetyl exposure was 2.9-fold of the coefficient fitted for 2,3-pentanedione exposure; thus, the observed responses were associated with substantially less diacetyl having been inhaled thereby increasing its fitted potency relative to 2,3-pentanedione. In contrast the corresponding value among males was 1.2. Furthermore, all seven estimates among females depended on the modeling assumption that the exposure duration parameter was identical to that of males and results of profiling the likelihood (not shown) illustrated that this dependence was unidimensional, i.e., the seven relative potency estimates for the females varied in unison with the duration parameter, whereas this was not the case for the seven parameter estimates of the males. Hence, the interpretation of the relative potency estimates among females warrants a substantially larger degree Estimate of φ s,PD ± Model-based standard error per 100 ppm of caution. Although the majority of the relative potency estimates among male mice are greater than 1.0, suggesting that 2,3-pentanedione may be somewhat less toxic than diacetyl, two of the seven relative potency estimates (for olfactory epithelial atrophy and respiratory epithelial degeneration in the nasal tissues of male mice) are less than 1.0. In addition to these endpoints, the overdispersion-adjusted lower confidence limit estimates of relative potency for necrosis of the nasal respiratory epithelium, chronic bronchial inflammation and bronchial epithelial regeneration are also less than 1.0. Hence, these results suggest that equal or greater toxic potency for 2,3-pentanedione relative to diacetyl cannot be ruled out on the basis of currently available data. 6.4 Discussion 6.4.1 Diacetyl # Modeling issues in BMC estimation for diacetyl Categorical regression modeling for diacetyl BMC estimation was initially conducted as described in section 6.2.2.1 for rat and mouse data. However, it was noted that the mouse models showed systematic overprediction of the observed response at the highest exposure concentrations. Mice are well known to exhibit reduced respiration when exposed to respiratory irritants , including diacetyl . Reduced respiratory rate and reduced minute volume have been observed in male mice exposed to diacetyl ]. Speculatively, reduced respiration at high exposure concentrations may contribute to the attenuation of response noted in the high exposure groups, relative to a model where the effects of exposure are proportional to concentration. A strategy was therefore employed of modifying the model structure by including a quadratic dose term parameterized to represent directly proportional changes of ventilation with concentration in modeling the mouse data, which allowed sufficient model flexibility to accommodate the attenuation of response seen in the high-dose mouse data. The resulting coefficients of ventilation for nasal and lung tissues within each sex and exposure chemical were homogeneous and subsequently pooled. Furthermore, the coefficients of male mice for each chemical were similar and the diacetyl coefficient was consistent with the observations of minute volume by . However, the coefficients of the two chemicals for the females were substantially dissimilar. The seven tissue responses of each mouse were jointly analyzed because they were governed by the same ventilation coefficient. To account for correlations among the responses, random effects were included in the model thereby utilizing all of the data for the estimation of parameters common to all responses. However, the increased complexity of the model in combination with the small sample sizes and discrete responses presented challenges for assessing its fit. Residuals were calculated conditional on estimates of the random effects but interpretations of these residuals based on their having an approximately normal distribution appeared to be problematic because a systematic relationship between their skewness and concentration was apparent. However, our interpretation of these residuals as providing evidence of deviations exceeding modelbased predictions is prudent and motivated the increase of the widths of the confidence intervals. However, these modifications were not necessary in modeling the rat data, and were not included in the models developed for BMC estimation with the rat data. In the current analysis, BMC estimates for diacetyl, based on categorical regression modeling, range from 16.8-68 ppm diacetyl, and the BMCL estimates range from 10-49.9 ppm diacetyl (Tables 6-6, 6-7, and 6-8). For comparison, alternative BMC estimates based on a quantal modeling range from 14.6-78 ppm, and quantal model BMCL estimates range from 2.4-57.9 ppm. Although the central BMC estimates were similar for the quantal and categorical modeling approaches, some of the quantal model BMCL estimates are several-fold lower than any obtained using categorical modeling. It is possible that this result may be due to the inclusion of additional information -response severity, as well as incidence -in the categorical regression modeling approach, leading to narrower confidence limits in comparison to the quantal modeling results. Additional sensitivity analyses explored the sensitivity of the toxicologically-based risk assessment for diacetyl to basing the mouse-to-rat extrapolation on allometrically-scaled respiration rates rather than measured values, and to basing the animal-to-human extrapolation on RfC methodology rather than the Gloede et al. PBPK model. As described in section 6.3.1.1, varying these assumptions would have relatively modest effects on the toxicologicallybased REL estimate for diacetyl. As shown in Table 6-9, the lowest candidate REL values from the various sensitivity analyses are all within a factor of ±2 of the candidate REL values from the main analysis, suggesting that the value of the toxicologically-based candidate REL is not strongly dependent on these assumptions. # Comparison with other toxicologically-based risk assessments The numerical values of BMD estimates for diacetyl are not all directly comparable, even when based on a common response rate of 10%, because of variations in the dose units used (ppm concentration versus regional penetration versus tissue concentration). The occupational exposure limits (OELs) developed by the various authors are directly comparable, but depend in part on assumptions regarding uncertainty factors, which may vary between studies. In contrast, the HEC estimates derived in this analysis can be directly compared to the HEC estimates that have been developed in prior risk assessments. Earlier toxicologically-based risk assessments of diacetyl have been based on the 6-week and 12-week mouse study of , rather than the more extensive subchronic study conducted by the NTP . Because the NTP subchronic study included data from both mice and rats and included both more dose levels and more animals per dose group than the study, the NTP diacetyl study was chosen as the basis for risk assessment in this document. However, comparison of the current risk assessment findings to the results of the earlier risk assessments is instructive. The HECs derived in prior diacetyl risk assessments are summarized in Table 6-11. The BMC 10 HEC estimates in the current study span a range of 1.8-143.7 ppm, compared to the range of 4.5-61 ppm reported in prior diacetyl risk assessments. The BMCL 10 HEC estimates in the current study span a range of 1.4-95.9 ppm, compared to the range of 1.3-10 ppm reported in prior diacetyl risk assessments. The wider range of HEC estimates in the current study, as compared to prior analyses, is partially due to the application of animal-tohuman dosimetry estimates from the Gloede et al. PBPK/CFD model, which was published subsequent to the prior risk assessments and was, obviously, not available to prior risk assessors. In addition, the current study has the benefit of a more extensive toxicological data base for diacetyl because of publication of the NTP subchronic inhalation study, and therefore includes data from more pathological endpoints than the prior analyses did. Maier et al. conducted a risk assessment for diacetyl for the purpose of deriving an OEL. This risk assessment was based on the mouse pilot study data of , using BMD methodology. The authors concluded that the most sensitive endpoint in the mouse prepared under OSHA contract number DOLQ059622303 ( 2009) Task Order 50. These reports served as the basis for the toxicologically-based diacetyl risk assessment in the draft NIOSH criteria document for diacetyl in 2011 but have been supplanted in the current document by an analysis of more recent data. A summary of the risk assessment extracted from these reports is included here, for comparison to the current toxicologically-based quantitative risk assessment. The quantitative risk assessment was based on an analysis of adverse respiratory effects in mice exposed to diacetyl by inhalation for up to 12 weeks . Adverse nasal and lung effects were observed with the latter found in the peribronchial, bronchial, and peribronchiolar regions. The study was used to derive BMDs, BMDLs, and corresponding HECs, as discussed below. The responses analyzed were those most relevant to longer-term exposures, i.e., those from the subchronic portion of the study that included constant exposures of 25, 50, and 100 ppm for 6 hours/day, 5 days/week, for either 6 or 12 weeks. The 6-and 12-week data were pooled for the final analysis, based on a likelihood ratio test that indicated that the 6-and 12-week results were not significantly different. A variety of dosimetric adjustments were considered in extrapolating the results from mice to humans. The most significant of these adjustments was the choice of dose metrics, either "regional penetration" (based on the percentage of diacetyl reaching a given portion of the respiratory tract), or "tissue concentration" (based on the Morris and Hubbs PBPK model). Because the choice of dose metrics has a significant impact on the HEC, and it is not clear which dose metric is preferable, HECs derived using both dose metrics are reported in Table 6-11. An assessment completed by Toxicology Excellence for Risk Assessment (TERA) also utilized the dose-response data of , and estimated HECs based on BMDLs for 10% risk, comparable to those estimated in the current analysis. TERA excluded the nasal lesions from consideration prior to their analysis, stating that the evidence of upper respiratory symptoms in humans exposed to diacetyl was inconsistent and that those symptoms lacked reliable concentrationresponse information. In contrast, the current assessment assumes that the dose-response relationship in a test species, rather than the lesion site, is the best criterion for choosing which endpoints to model for quantitative risk estimation. Thus, the current analysis assumes that site concordance is not a requirement because once the dose has been adequately adjusted (and ideally, once toxicodynamic considerations have been carefully considered), a valid dose-response relationship at any respiratory tract site/lesion in a test species is a reasonable basis for characterizing human risk. Additionally, exact site concordance across species would not be expected after exposure to diacetyl because of the differences in deposition of the chemical within the respiratory tracts of rodents and humans, as indicated by the PBPK model of Gloede et al. . The Gloede et al. model indicates that a much higher percentage of inhaled diacetyl reaches the bronchial and bronchiolar regions in humans than in rodents which provides a basis for the findings that diacetyl toxicity is observed primarily in the upper respiratory tract of rodents and the lower respiratory tract of humans. TERA estimated HECs using the EPA default methods modified by the PBPK/CFD model predictions of Morris and Hubbs . However, rather than using the relationships between the default and CFDmodel-predicted scrubbing factors to define a mouse-specific estimate of airway scrubbing of diacetyl, they assumed that mice were exactly like the CFD-modeled rats (i.e., used the CFD model predictions for the rats as if they were equally relevant to mice). The TERA risk assessment did not consider light exercise conditions, as may occur in the workplace, as these were not incorporated into the PBPK/CFD modeling of Morris and Hubbs . Moreover, for the effective dose (regional penetration) measure calculated by TERA, the default mouse ventilation rates were used. As discussed above in regard to the Allen risk assessment, the experimentally measured ventilation rates for the study were substantially greater than the EPA default values (by a factor of 3 to 5), and this would have a major impact on the HEC estimates (TERA's estimates would be about 3 to 5 times greater, because the major effect of changing the ventilation rate is on the effective dose measure, V E /SA, rather than the scrubbing). TERA's analysis resulted in estimates of HECs that were 9 and 2 ppm, corresponding to the estimated BMD( 10) and BMDL( 10), respectively, from their dose-response analysis of the peribronchial inflammation endpoint from . The TERA assessment suggested that a composite uncertainty factor of 10 should be used to adjust those HECs downward to an OEL. That factor of 10 was the product of a factor of 3 for interspecies differences and another factor of 3 for human variability . These factors of 3 are well-accepted uncertainty factors commonly used by EPA and others in risk assessment. Their recommended OEL was therefore 0.2 ppm (as an 8-hour TWA). # 2,3-Pentanedione Toxic potency estimation for 2,3-pentanedione is constrained by both the limited numbers of animals that have been tested and the differing exposure durations used in the diacetyl and 2,3-pentanedione studies. The currently available histopathological data for repeated exposures to 2,3-pentanedione are limited to a single study involving exposures of 2 weeks + 2 days (totaling 12 exposures per animal), in both rats and mice. The rat data and female mouse data for diacetyl are limited to a single 13-week study , so that no data on the relationship of toxicity to duration of exposure are available for the rat or the female mouse. For male mice, limited data are available from the 6-and 12-week exposures reported by . Although no mouse studies are available that closely approximate the 2 week + 2 day exposure protocol used in the 2,3-pentanedione study, the 6-, 12-, and 13-week diacetyl data on male mice were used to estimate an adjustment to predict what the toxicity of diacetyl would have been in a study of the same duration as the 2,3-pentanedione study. Although a small increase of toxicity with exposure duration was fitted it was retained in the model even though it was not significant in order to account for it as a source of variation in obtaining the standard errors of the seven relative potency estimates † † † † of each sex. The resulting relative potency estimates suggest that 2,3-pentanedione may have equal or greater toxic potency than diacetyl for five of the seven responses of male mice from † † † † For those readers acquainted with the concept of Stein estimation for adjusting a set of three or more estimates an application of a criterion of Bock to the covariance matrix of each set did not support making them. 6-10 superficially suggest that 2,3-pentanedione is or seems to be less toxic than diacetyl to female mice, these estimates are sensitively dependent on the assumption that the parameter for exposure duration is identical to that of males. Furthermore, there is a complete lack of information from these studies for assessing this assumption and profiling the likelihood indicated that the relative potency estimates of the female mice were substantially sensitive to this parameter whereas this did not hold for the estimates of the males. Hence, it would be prudent to refrain from concluding that 2,3-pentanedione is less toxic than diacetyl to female mice on the basis of the estimates of Table 6-10. Recent data support the conclusion that 2,3-pentanedione should be used cautiously in the workplace and exposures to 2,3-pentanedione should be minimized. Rats (but not mice) develop intramural and intraluminal airway fibrosis following exposure to either diacetyl or 2,3-pentanedione ]. This lesion shares many features with obliterative bronchiolitis of humans, the condition that originally brought medical attention to employees exposed to diacetyl. A 2-week inhalation exposure of 150 or 200 ppm to either diacetyl or 2,3-pentanedione could produce bronchial fibrosis in rats ]. This finding suggests that 2,3-pentanedione causes airway fibrosis comparable to diacetyl at equal exposure concentrations. Because no chronic or subchronic studies of 2,3-pentanedione are currently available and the number of rats in the 2-week exposure is low, it is not possible to quantitatively assess the toxicity of 2,3-pentanedione relative to diacetyl for producing airway fibrosis. However, these data do suggest that it would be prudent to treat 2,3-pentanedione as at least equally toxic as diacetyl until additional toxicological data become available on the toxic potency of 2,3-pentanedione. # Conclusions Pathological lesions produced by inhalation exposure to diacetyl and 2,3-pentanedione have been assessed using categorical regression techniques and benchmark dose estimation. For diacetyl a CFD/PBPK model is available for both rats and humans that allows rodent BMC and BMCL estimates to be extrapolated directly to human exposures. The results of this exercise indicate that the most sensitive endpoint in terms of estimated human toxicity is that associated with eosinophilic inflammation in the male rat lung. The HEC associated with this endpoint is 1.8 ppm, with a 95% lower-bound estimate of 1.4 ppm (Table 6-6). Application of a 24-fold uncertainty factor to the lower-bound HEC leads to a candidate REL of 0.06 ppm, or 60 ppb diacetyl. The estimated human toxicity based on chronic bronchial inflammation in the female mouse lung is very similar to the ratbased estimate (Table 6- 8), and also leads to a candidate REL of 0.06 ppm or 60 ppb. If human data on the toxicity of diacetyl were not available, these estimates could serve as the bases for REL development for diacetyl. Because human data do exist and are sufficient for derivation of an REL, the toxicologically-based candidate RELs should be viewed as complementary to the epidemiologically-based REL. Because the toxicologically-based REL is within an order of magnitude of the epidemiologically-based REL it supports the epidemiologically-based REL. Morris JB, Hubbs AF . Inhalation dosimetry of diacetyl and butyric acid, two components of butter flavoring vapors. Toxicol Sci 108( 1 Wheeler MW, Bailer AJ . Properties of model-averaged BMDLs: a study of model averaging in dichotomous response risk estimation. Risk Anal 27(3):659-670. WHO . Environmental Health Criteria 170. Assessing human health risks of chemicals: Derivation of guidance values for health-based exposure limits. International Programme on Chemical Safety, Geneva, Switzerland. 7 Basis of the Recommended Standards for Diacetyl and 2,3-Pentanedione In the Occupational Safety and Health Act of 1970 (Public Law 91-96), Congress mandated that NIOSH develop and recommend criteria for identifying and controlling workplace hazards that may result in occupational illness or injury. In fulfilling this mandate, NIOSH has reviewed the relevant human and/or animal data to assess the health effects of diacetyl and 2,3-pentanedione; assessed the risks of occupational exposure; characterized anticipated employee exposures; and developed recommended criteria for exposure limits, exposure monitoring, engineering and work practice controls, and medical monitoring. The basis for the RELs is described in this chapter. The primary objective of the recommendations for diacetyl is to reduce loss of lung function associated with diacetyl exposure because diacetyl (and potentially related diones) has been shown to cause potentially fatal obliterative bronchiolitis in employees. The NIOSH REL for 2,3-pentanedione would be identical to that for diacetyl but is slightly higher based upon the limitations of the analytical method. # Health Effect Studies of Employees Exposed to Diacetyl As detailed in Chapter 3, medical evaluations showed that employees exposed to diacetyl developed progressive shortness of breath while working at several microwave popcorn plants and flavoring plants, findings consistent with the severe irreversible lung disease obliterative bronchiolitis. Obliterative bronchiolitis, sometimes characterized by spirometric abnormality, has been described in employees in the microwave popcorn and flavor-manufacturing industries . Some affected employees have experienced extremely rapid declines in lung function, with severe airways obstruction in some cases occurring within several months of the start of exposure to flavoring compounds NIOSH 1986]. Employees as young as 22 years old have been affected. Some affected employees have been placed on lung transplant waiting lists by their physicians because of the severity of their disease ]. The findings from investigations and studies conducted at multiple plants presented in Chapter 3 have established a link between exposure to diacetyl and risk for severe occupational lung disease. These findings meet the standard criteria used to determine causation: that an exposure is the likely cause of specific health effects . Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetyl-exposed employees have provided clear evidence of a causal relationship between diacetyl exposure and development of this disease. # Toxicological Studies of Diacetyl In rats, acute exposures to diacetyl or diacetylcontaining butter flavoring vapors cause necrosis in the epithelial lining of nasal and pulmonary airways. Rats inhaling vapors of butter flavoring that contained diacetyl developed multifocal necrotizing bronchitis one day after a 6-hour exposure. The mainstem bronchus was the most affected intrapulmonary airway. However, nasal airways were more affected than intrapulmonary airways. Necrosuppurative rhinitis was seen in rats inhaling butter flavoring vapors at concentrations that did not cause damage in intrapulmonary airways . As a single agent acute exposure in rats, diacetyl caused epithelial necrosis and inflammation in bronchi at concentrations of >290 ppm and caused epithelial necrosis and inflammation in the trachea and larynx at concentrations of ≥220 ppm . In a pattern similar to that of airway damage from diacetyl-containing butter flavoring vapors, diacetyl causes greater damage to nasal airways than to intrapulmonary airways in rats ]. In mice, inhaling diacetyl at concentrations of 200 or 400 ppm for 6 hours/day for up to 5 days caused respiratory tract changes similar to those seen in rats inhaling diacetyl or diacetylcontaining butter flavoring vapors . Subchronic diacetyl inhalation caused significant histopathological changes in mice at all concentrations studied. Peribronchial lymphocytic infiltrates were seen at terminal sacrifice at 12 weeks in all subchronically exposed mice inhaling 100 ppm diacetyl and in some mice inhaling 25 or 50 ppm diacetyl. Using a CFD-PBPK model, the rodent pathologic changes, though at higher regions in the respiratory tract, were consistent with the human bronchiolar pathology once differential nasal scrubbing, size of airway, and target organ doses were accounted for Morris and Hubbs 2009]. In rats in which nasal scrubbing was bypassed by administering a single dose of 125 mg/kg diacetyl via intratracheal instillation, histopathological alterations # Objectives The NIOSH objective in establishing RELs for diacetyl and 2,3-pentanedione is to reduce the risk of respiratory impairment (decreased lung function) and the severe irreversible lung disease obliterative bronchiolitis associated with occupational exposure to these compounds. In addition, maintaining exposures below the RELs will help prevent other adverse health effects including but not limited to irritation of the skin, eyes, and respiratory tract in exposed employees. The recommendation to limit exposure to diacetyl and 2,3-pentanedione is based upon data from human and animal studies and the quantitative risk assessment, however, additional considerations included sampling and analytical feasibility and the achievability of engineering controls. A variety of risk estimates were evaluated and presented in Chapter 5. NIOSH has historically targeted excess risks predicted to be in the range of approximately 1 per 1,000 in establishing RELs (see Chapter 5, Tables 5-34 NIOSH is also recommending a STEL for diacetyl of 25 ppb for a 15-minute time period. The establishment of a short-term exposure limit is based on the concern that peak exposures may have greater toxicity than the same total dose spread out over a longer period of time. Some limited evidence of this type of dose-rate effect is available in animal studies ]. On the basis of general industrial hygiene principles, the STEL, which is five times the REL, would serve to reduce peak exposures and tend to reduce overall employee exposures to diacetyl. The selection of a STEL that is five times the REL is based upon past precautionary practice . In the absence of a STEL in workplaces complying with the NIOSH REL for diacetyl of 5 ppb TWA, employees could theoretically be exposed to 2,400 ppb diacetyl for 1 minute or 480 ppb for 5 minutes in an 8-hour day with no additional exposure the remaining part of their 8-hour shift. The STEL for diacetyl of 25 ppb would limit those exposures to a possible peak of 375 ppb for 1 minute and 75 ppb for 5 minutes and should prevent acute irritation from brief high exposures. 7.5.2 Recommended Exposure Limit for 2,3-Pentanedione 2,3-Pentanedione, which has been used as a substitute for diacetyl, is also of concern because of structural similarities with diacetyl and because animal studies show similar toxicity for the respiratory tract . Morphologic data suggest that 2,3-pentanedione can cause airway epithelial damage similar to the damage caused by diacetyl . Rats repeatedly inhaling 2,3-pentanedione at concentrations ≥ 150 ppm for up to 2 weeks develop fibrosis of intrapulmonary airways, a morphologic change similar to obliterative bronchiolitis in humans . Recently, more than 3500 genes were found to be upregulated in RNA isolated from the fibrotic bronchi of 2,3-pentanedione exposed rats . Some of the up-regulated genes were ones previously implicated in fibrosis, including transforming growth factor-β2, interleukin-1α, interleukin-18, interleukin-33, and fibronectin. In addition, at high exposure concentrations, messenger RNA changes were noted in the brain of rats after acute 2,3-pentanedione inhalation . The toxic potency of the two materials appears to be comparable in mice exposed by inhalation (see Chapter 6, section 2 for a full discussion). Given the structural similarity between diacetyl and 2,3-pentanedione and the evidence published, NIOSH would prefer to recommend an identical REL for diacetyl and 2,3-pentanedione. However, OSHA Method 1016, the validated analytical method available for 2,3-pentanedione, can only reliably quantify 2,3-pentanedione at concentrations 9.3 ppb and above. Therefore the NIOSH REL for 2,3-pentanedione, while informed by the toxicological potential, is based upon the limitations of the analytical method and is established at 9.3 ppb. This REL for 2,3-pentanedione will result in a residual risk of lung disease similar to diacetyl, but may be higher. It does not imply that 2,3-pentanedione is safer than diacetyl. Because the REL is established at the reliable quantitation level, no AL is established for 2,3-pentanedione. Because of their structural similarity, concerns for short-term exposures to 2,3-pentanedione also apply. Accordingly, a STEL for 2,3-pentanedione is established at 31 ppb (i.e., the lowest concentrations the method can sample accurately during a 15-minute time period). The NIOSH REL for 2,3-pentanedione of 9.3 ppb and STEL of 31 ppb would limit exposures to a possible peak of 465 ppb for 1 minute and 93 ppb for 5 minutes. Because of the concern for potential dose-rate effects, NIOSH recommends STELs for diacetyl and 2,3-pentanedione to reduce peak exposures to employees. Maintaining diacetyl and 2,3-pentanedione concentrations at or below the RELs and STELs requires the implementation of a comprehensive safety and health program that includes engineering controls, exposure monitoring, routine medical surveillance, and employee training in good work practices. Specific recommendations for these components can be found in Chapters 2, 8, 9, and 10 of this document. # Rationale for the Recommended Exposure Limit The recommendation to limit occupational exposures to diacetyl to an 8-hour TWA of 5 ppb is based on data from human quantitative risk assessment with additional rationale provided by animal toxicological studies. From the human studies, 5 ppb represents a reasonable summary of estimates from several concordant approaches to risk assessment. Although smoking affects the excess lifetime risk estimates, a full treatment for the purpose of developing separate REL recommendations on smoking status would require including interactions between smoking and diacetyl exposure histories for which NIOSH believes there is insufficient historical information and statistical power to implement. Furthermore, there is no precedent for developing standards that are specific to smoking status. NIOSH also recommends an AL of 2.6 ppb to help protect employees from exposure to diacetyl above the 5 ppb REL and a STEL of 25 ppb to limit peak exposures and protect against dose-rate effects. Engineering controls and work practices are available to control diacetyl exposures below the REL (and the AL) in workplaces. OSHA Method 1012 is a validated analytical method that can be used to effectively measure employee exposures to diacetyl. Establishing the recommended exposure limits for diacetyl is consistent with the mission of NIOSH mandated in the Occupational Safety and Health Act of 1970. # Controlling Diacetyl and 2,3-Pentanedione Exposures in the Workplace In general, many industries have implemented engineering controls to reduce exposure and risk of disease among their employees. Many of the processes where diacetyl and 2,3-pentanedione are manufactured, handled, or used are similar to other industries and may allow for common approaches to reducing employee exposure. These processes include blending, mixing, and handling of flavoring compounds in liquid and powder form. A 3-year study of a microwave popcorn production facility showed that the use of exposure controls can dramatically reduce diacetyl concentrations in mixing rooms and for all production employees . As a result of the implementation of exposure controls, average combined personal and area diacetyl air concentrations declined an order of magnitude in the mixing room (from 57.2 ppm to 2.88 ppm) while concentrations in the quality control laboratory (from 0.82 ppm to < LOD) and packaging area (from 2.76 ppm to < LOD for machine operators) declined to below detectable limits. These interventions included providing general room exhaust ventilation to the mixing room and local exhaust ventilation for the heated flavoring and mixing tanks. Closed transfer processes were implemented through the installation of a pump to transfer heated butter flavorings from the holding tanks to oil/flavor mixing tanks. The building of an enclosure for all oil/flavor holding tanks and installing local exhaust ventilation on all tanks further reduced exposures to employees in the packaging area of this plant. In the final survey conducted following the implementation of all engineering and process controls, personal diacetyl exposures for all employees/job categories in the plant were below detectable limits with the exception of mixers which ranged from below the LOD to 12.6 ppm. The design concepts required for working with hazardous materials include specification of general ventilation, local exhaust ventilation, maintenance, cleaning and disposal, personal protective equipment, exposure monitoring, and medical surveillance . Bag emptying, bag filling, charging tanks, benchtop weighing and handling, and drum filling and emptying are a few of the production processes of concern. Other more specialized processes (for example, candy panning, a process in which candy pieces in a rotating drum are sprayed with chocolate or other flavoring compounds; coffee roasting; commercial fry-cooking) may also result in employee exposure. Special attention should be given to manual handling of flavoring compounds, particularly in heated processes, and when spraying flavoring compounds. Research on food industry practices has led to the development of engineering controls that may help reduce employee exposure to diacetyl, 2,3-pentanedione, and other chemicals. Chapter 8 describes engineering controls for the industries where diacetyl is handled or used within products. Table 8-2 in Chapter 8 provides a summary of NIOSH evaluated engineering control efficiencies for the mixing of food flavorings. Although many job categories can be effectively controlled to levels below the REL, tasks associated with transfer of diacetyl may continue to pose risk to the employees even following the implementation of controls. For example, mixers may continue to be exposed at levels above the REL when handling butter flavorings and from tank emissions. However, these exposures can be reduced through the implementation of closed transfer systems and local exhaust ventilation approaches discussed in Chapter 8. NIOSH acknowledges that the frequent use of personal protective equipment, including respirators, may be required for some employees who handle diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products. The frequent use of PPE may be required during job tasks for which (1) airborne concentrations of diacetyl or 2,3-pentanedione (e.g., pouring, mixing, packaging) above the REL exist, ( 2) the airborne concentration of diacetyl or 2,3-pentanedione is unknown or unpredictable, and ( 3) job tasks are associated with highly variable airborne concentrations because of environmental conditions or the manner in which the job is performed. In all work environments where diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products are found, control of exposure through engineering controls should be the highest priority. # Hazards Associated with Diacetyl Substitutes Much has been made of the possible removal/ substitution of diacetyl and 2,3-pentanedione from the flavor manufacturing or food production industries. A health benefit from substitution can only be realized if the substitute is safer than diacetyl or 2,3-pentanedione. However, the current knowledge on toxicity of available substitutes is limited; few if any have OELs, and therefore exposure to substitutes should be controlled. There is reason to think that, like diacetyl, other alpha-dicarbonyl compounds would have a tendency to cause protein cross-links . The reactivity of the alpha-dicarbonyl compounds is enhanced by electron-attracting groups and decreased by electron donors . Alpha-dicarbonyl compounds can inactivate proteins, principally through reactions with the amino acid, arginine . The related alphadicarbonyl flavoring, 2,3-pentanedione, has been reported to be even more reactive with arginine groups than diacetyl . While the focus of this document is on diacetyl and 2,3-pentanedione, NIOSH has concern about other flavoring substitutes with structures similar to diacetyl or moieties that are biologically active and capable of producing similar toxic effects as diacetyl. Therefore, NIOSH recommends that such exposures also be considered and controlled to concentrations as low as possible, taking into account potential additive effects of flavoring compounds. The guidance recommendations presented in Chapter 8 regarding control of exposures are applicable not only to diacetyl and 2,3-pentanedione, but also to their substitutes and other flavorings and flavoring compounds used in this industry. The control of exposures is discussed in detail in Chapter 8, but several LEV systems described have been shown to be particularly effective in controlling diacetyl and would be expected to work well for similar compounds. Ventilated backdraft workstations used for small batch mixing have been evaluated in two field studies conducted in flavoring production plants. The field studies showed reductions in exposure of 90%-97% when performing mixing tasks using these stations . Also, the use of controls to reduce employee exposure during pouring and mixing of ingredients in a commercial mixer has been evaluated in a flavoring production plant . The use of LEV at the mixing tank helps to maintain the vessel at a negative pressure and contain evaporative emissions. NIOSH evaluated the impact of a ventilated tank lid on the exposure of an employee during the mixing of a food flavoring . # Summary The following points summarize the relevant information used as the basis for the NIOSH recommendation for limiting occupational exposure to diacetyl and 2,3-pentanedione: The idea behind this hierarchy is that the control methods at the top of the list are potentially more effective, protective, and economical (in the long run) than those at the bottom. Following the hierarchy normally leads to the implementation of inherently safer systems where the risk of illness or injury has been substantially reduced. The first item in the hierarchy is elimination/ substitution. The intention of eliminating a flavoring or other chemical in the workplace is to remove the exposure by removing the source. Similarly, the goal of substitution is to substitute a flavoring or chemical with another of lower toxicity. The removal of diacetyl and 2,3-pentanedione from the flavor manufacturing or flavoring industries would be practical only with the substitution of an alternative butter flavor chemical, which is currently being done in some situations. However, the current knowledge on toxicity of available substitutes is limited, and exposure to substitutes may also need to be controlled. Therefore, elimination and substitution may not provide a feasible control and are not discussed in detail. The recommendations that follow are applicable not only to diacetyl and 2,3-pentanedione, but also to other flavorings and flavoring compounds used in this industry. Engineering controls, as discussed below, are mechanical techniques for removing contaminants from the workplace. For instance, local exhaust ventilation can be used to capture and remove emissions from a hazardous or nuisance source. A major advantage of this type of system is that, when properly designed, it requires minimal user effort or training. The use of respirators, a form of PPE, is discussed because this control, while not favored, is in common use in some facilities. As the discussion demonstrates, considerable effort is required in the proper selection and use of respiratory protection in the workplace. Finally, the protection of skin, eyes, and face is also discussed. # Engineering Controls Currently, there is no model or standard guidance for engineering controls for flavoring and food production processes. If it is not possible to eliminate toxic compounds from the workplace or replace them with less toxic substances, then the use of engineering controls and work practices to minimize exposures is the next level of controls for the necessary reduction of exposure. # General Considerations A properly designed supply air ventilation system can provide plant ventilation, building pressurization, and exhaust air replacement. When LEV is installed in production areas, it is important to consider the need for replacement air. In general, it is necessary to balance the amount of exhausted air with a nearly equal amount of supply air. Without replacement air, uncontrolled drafts will exist at doors, windows, and other openings; doors become difficult to open because of the high pressure difference; and exhaust fan performance may degrade. Good supply air design consists of ducted supply with air discharge registers about 10 feet above floor level . Controls need to be fitted to individual processes by each plant and cannot be a "onesize-fits-all" approach. Controls need to be evaluated after installation. Evaluations should be completed to quantify exposures after controls have been implemented to ensure that target goals have been achieved. It is important to confirm that the LEV system is operating as designed by periodically measuring exhaust airflows. A standard measurement, hood static pressure, provides important information on the hood performance, because any change in airflow results in a change in hood static pressure. For hoods designed to prevent exposures to hazardous airborne contaminants, the ACGIH Operation and Maintenance Manual recommends the installation of a fixed hood static pressure gauge . In addition to routine monitoring of the hood static pressure, additional system checks should be completed periodically to ensure adequate system performance, including smoke tube testing, hood slot/face velocity measurements, and duct velocity measurements using an anemometer. These system evaluation tasks should become part of a routine preventive maintenance schedule to check system performance. It is important to note that the collection and release of air contaminants may be regulated; companies should contact agencies responsible for local air pollution control to ensure compliance with emissions requirements when implementing new or revised engineering controls. To minimize exposure and reduce the risk of flavoring-related lung disease, a few standard precautions should be followed in areas where flavoring-related exposures may occur: Isolate rooms where flavorings or flavoring compounds are handled from the rest of the plant with walls, doors, or other barriers. Maintain flavoring mixing rooms and other areas where flavorings are handled under negative air pressure relative to the rest of the plant. Check status with airflow indication equipment such as a smoke tube. Install hood static pressure gauges (manometers) near hoods to provide a way to verify proper hood performance. Check pressure frequently to ensure that the system is operating properly compared to baseline. Check hood face velocities and capture velocities frequently to ensure that system is performing as designed. Ensure that employees are properly trained on the use of the controls if using proximity switches for fan activation. Consider installing a control "on/ off " light to indicate the status of the exhaust fan. Place hoods away from doors, windows, air supply registers, and aisles when possible to reduce the impact of cross drafts. Provide supply air to production rooms to replace most of the exhausted air. Direct exhaust air discharge stacks away from air intakes, doors, and windows. Inspect hoods and enclosures for signs of damage or leaks (rust/corrosion, open access doors, etc.) and obstructions (paper, gloves, rags, etc.). Where possible, use screens to prevent foreign objects from being pulled into the system through openings (slots, hood faces, etc.). # Primary Production Processes and Controls The food and flavoring production industries have several primary processes that may result in increased potential for employee exposure to diacetyl, 2,3-pentanedione and other flavoring compounds. These may be grouped, from an exposure standpoint, into a few general categories including production operations, packaging operations, cleaning, and maintenance operations . Employees in each of these job categories may potentially be exposed to flavoring compounds, including diacetyl and 2,3-pentanedione. Table 8-1 displays a list of job categories and work activities associated with these manufacturing processes. For each activity, the section of this document that discusses relevant exposure control and the figure(s) at the end of this chapter that shows relevant LEV systems are indicated. Other job categories may potentially be exposed to flavoring compounds. These include supervisory personnel, laboratory and quality controls personnel, and cleaning and maintenance personnel. When these personnel are in production areas, they should comply with recommended control procedures and wear appropriate PPE posted for that specific area. Additional considerations may be necessary for the maintenance job category, specifically for intermittent tasks such as filter change out. Many different industries have implemented engineering controls to reduce exposure and risk of disease among their employees. Many of the processes used in the flavoring and food manufacturing industries are similar to those of other industries and may allow for common approaches to reducing employee exposure. These processes include blending, mixing, and handling of flavoring compounds in liquid and powder form. The design concepts required for working with hazardous materials include specification of general ventilation, LEV, maintenance, cleaning and disposal, PPE, exposure monitoring, and medical surveillance . Bag emptying, bag filling, charging tanks, benchtop weighing and handling, and drum filling and emptying are a few of the production processes of concern. Other more specialized processes (for example, candy panning, a process in which candy pieces in a rotating drum are sprayed with chocolate or other flavoring compounds) may also result in employee exposure. Special attention should be given to manual handling of flavoring compounds, particularly in heated processes, and when spraying flavoring compounds. Research into various food industries has led to the development of potential engineering controls to help reduce employee exposure to diacetyl, 2,3-pentanedione and other chemicals. The following sections describe the primary production processes used in the food and flavoring industries and discuss engineering controls that can be used to minimize employee exposure to diacetyl, 2,3-pentanedione and other potential airborne hazards. # Benchtop weighing and handling Small-scale weighing and handling of ingredients are common tasks used in flavoring production, bakeries, dairy production, and snack food manufacturing. The tasks of weighing out dry and wet food ingredients can lead to employee exposure primarily through the scooping, pouring, and dumping of these materials. Studies in bakeries have shown that the employees exposed to dusts, commonly from flour, are those who perform mixing and weighing tasks . In addition, a recent survey at a commercial bakery showed that mixer operators were exposed to diacetyl when they measured and added an artificial butter flavor to a dough mixer . Because weighing and pouring are often performed on a benchtop workstation, the addition of slotted backdraft ventilation for both the bench and the weighing area is recommended. This approach can also be applied to larger-scale operations. The application of engineering controls to reduce employee exposure to chemicals during mixing and weighing has been evaluated in flavoring production. In flavoring production facilities, compounders measure and pour flavoring compounds on a bench and then transfer these mixtures to open tanks for liquid flavoring production or to blenders used for powdered flavoring production. The use of ventilated backdraft workstations, adapted from welding bench designs available in the ACGIH Industrial Ventilation Design Manual (Figure 8-1) has been evaluated by NIOSH in two field studies conducted in flavoring production plants . Ventilated back-draft workstations used for small batch mixing have been evaluated in two field studies conducted in flavoring production plants (Figure 8-2). These stations were designed to maintain an air velocity of 100-150 feet per minute (fpm) at the face of the enclosure. The field studies showed reductions in exposure of 90%-97% when performing mixing tasks using these stations . The key design parameters are to enclose as much of the activity as possible and to use properly sized exhaust slots to maintain a uniform air velocity across the face of the station. Other groups have also produced designs that may be amenable to the control of exposure during benchtop mixing and weighing activities. The HSE has developed a series of control approaches based on common processes in a variety of industries. One approach is similar to the one evaluated by NIOSH in flavoring facilities and recommends a control velocity of 100-200 fpm (0.5-1 meters per second ) at the face of the workstation when working with flour improvers (Figure 8-3) . The selection of proper control velocity should be made on the basis of the material being used (powder versus liquid), plant conditions (background drafts), and momentum of contaminant source (pouring versus spraying or vigorous mixing). The use of baffles on the side and top of these workstations to better enclose the process provides improved control and minimizes the deleterious effects of cross drafts on contaminant control. Plastic curtains can provide reasonable enclosure while allowing improved access to the bench area. The proper positioning of these workstations away from doors, windows, air supply registers, and aisle ways will also help to reduce the impact of cross drafts. # Laboratory chemical hoods Laboratory personnel will typically perform benchtop weighing and handling of flavorings in a chemical fume hood. A properly designed and maintained chemical fume hood can offer significant employee protection if used properly. There are many different hood designs, but the most common categories are the conventional or constant-flow hood, the bypass hood, and the variable air volume constant-velocity hood. The constant-flow hood is the oldest and simplest chemical hood design. The exhaust fan induces a constant volumetric airflow moving through the sash opening. For this hood design, the face velocity is lowest when the sash is wide open; when the sash is lowered the face velocity increases. The bypass hood maintains a constant hood face velocity and incorporates a bypass grille above the sash opening. When the sash is wide open it blocks the bypass grille, allowing all of the air to flow through the hood opening. As the sash is lowered, it uncovers increasingly greater amounts of the bypass grille, allowing increasing amounts of air to flow through this alternative path. If it is designed and operated properly, the amount of air flowing through the bypass grille is just sufficient to maintain a constant face velocity. Typically, however, this constant velocity can be maintained over a certain part of the sash's total range. The constant-velocity hood uses a control system to detect the sash position, face velocity and system pressure, and change the fan motor speed or other mechanism, such as mechanical dampers, to increase the airflow when the sash is raised and decrease it when the sash is lowered, thus maintaining a constant face velocity. All chemical hoods have certain common design elements, including an exhaust fan to move air through the hood, a moving sash, exhaust slots, and a horizontal work surface (Figure 8-4). The sash can be designed to move in either a vertical or a horizontal direction. A crucial performance element for any chemical hood is the face velocity, defined as the average air velocity at the face of the hood at the sash opening. Maintaining a constant, minimum face velocity provides confidence that operations and hazardous agents within the hood will be contained. The current consensus of the literature is that the average face velocity for a laboratory chemical hood should be in the range of 80-120 fpm . The flow control system on a constant-velocity hood should be adjusted to give a face velocity in this range. Each chemical hood should be clearly marked with the proper hood sash location that will give the desired face velocity; depending on the hood design, this could be a single location or a range of locations. Containment verification using tracer gases to provide quantitative data and smoke testing to visualize airflow patterns is recommended when the hood is installed, when substantial changes are made to the ventilation system, and periodically as part of a preventive maintenance program. In addition to the face velocity, it is important that the airflow be distributed evenly across the hood face. ANSI/AIHA Z9. 5 recommends that variations of velocity across the hood face should be within ±20% of the average face velocity; however, some laboratories select a stricter standard of ±10%. # Charging/filling tanks and mixers The addition of solid and liquid ingredients into tanks and other mixing vessels can cause exposure to dusts and vapors due to the displacement of air in the vessel. Medical and environmental surveys conducted in the microwave popcorn manufacturing industry have shown that employees who mixed butter flavorings into heated soybean oil had the highest exposures to diacetyl and the highest risk of developing severe irreversible lung disease ]. These employees measured out artificial butter flavoring in open containers and poured the flavoring into heated mixing tanks filled with oil. Real-time monitoring of a mixer at one plant measured a diacetyl peak of more than 80 ppm over several minutes as he poured flavorings into the mixing tank . NIOSH investigations at a plant where many exposed employees developed severe lung disease also showed that the implementation of LEV for heated tanks of oil and flavorings and general dilution ventilation for production areas reduced diacetyl concentrations. As a result of the implementation of exposure controls, average personal diacetyl air concentrations declined in the mixing room, from 57.2 ppm to 2.88 ppm . Exposures to diacetyl were also recorded at a plant that produced flavorings and other products in employees who added flavors to mixing and spray dryer feed tanks while the tanks were being filled. One employee who was adding diacetyl-containing starter distillate and starch to a spray dryer slurry feed tank was exposed to elevated levels of volatile organic compounds including diacetyl for a sustained period of time . In addition, elevated concentrations of volatile contaminants were measured as an employee poured diacetylcontaining starter distillate from a collection vessel into a bulk container. The use of controls to reduce employee exposure during pouring and mixing of ingredients in a commercial mixer has been evaluated in a flavoring production plant . The implementation of LEV at the mixing tank helps to maintain the vessel at a negative pressure and contain evaporative emissions. NIOSH evaluated the impact of a ventilated tank lid on the exposure of an employee during the mixing of a food flavoring (Figure 8 -5) . The use of the ventilated tank lid resulted in a reduction of approximately 76% compared to the same operation without the ventilated tank lid. However, most of the exposure during the evaluated mixing process was attributed to tasks performed outside of the hood. Ventilated tank lids have also been recommended by the HSE to contain vapors during the mixing of liquids with other liquids or solids . A NIOSH laboratory study of different mixing tank hood designs for a 4 foot diameter tank showed that capture efficiencies above 90% were possible for all hoods and configurations at an exhaust flow rate of 200 cubic feet per minute (cfm) with a crossdraft of 100 fpm or less . Another approach evaluated by NIOSH at a flavoring manufacturing facility was the use of a ventilated mixing booth. This booth allows a large portable mixing tank to be rolled inside so that chemical vapors emitted during pouring and mixing of flavoring compounds in the tank are captured and exhausted (Figure 8-6). However, the booth provides some flexibility and can also be used for other production tasks such as large pouring and product packaging activities. The use of slots across the booth plenum helps evenly distribute the flow across the height and width of the booth. A field study showed hood capture efficiencies of greater than 95% based on tracer gas tests . An important design consideration is to make the booth deep enough to fully contain the process. Other approaches to controlling exposure during filling of mixing vessels and tanks include the use of a simple exhaust hood near the opening of fixed tanks. This approach is highlighted in the HSE Control Approach 210, titled "Charging Reactors and Mixers from a Sack or Keg" (Figure 8-7) . This design calls for the use of a local exhaust hood near the tank opening with an inward velocity of at least 200 fpm. Another design provided by the HSE and ACGIH for mixers and tanks includes the use of rim exhausts placed around the edge of the mixer/tank. These designs take the shape of an annular slotted hood, which pulls air away from employees as they add ingredients or operate the mixer (Figure 8 # Bag dumping/emptying Manual handling of solid powders is a process used in many industries, including food and flavoring production. The opening and dumping of bags of powdered ingredients is commonly performed by employees in the production of flavorings, dairy products, snack foods, and in baked goods. Typically, an employee cuts open bags of material (e.g., 50-pound bags) and dumps the ingredients into a hopper, and then stacks or disposes of the empty bags. In powdered flavoring production, these hoppers are commonly outfitted onto blenders used to load the base starch ingredient for dry flavor blends. In snack food production, they may be used to load spices and flavors for application to the product via open drum coaters just before packaging. These open-ended devices typically are used to coat larger, more irregularly shaped materials such as cereal flakes or expanded snacks. Coatings may be applied as a slurry or as a dry mix following spray application of oil or lecithin. The drums rotate as the flavoring is being applied to allow for even coverage of the snacks. This process can cause employee exposure to the powdered flavoring; a case of bronchiolitis obliterans organizing pneumonia was reported in a spice process technician whose primary responsibility was to manually dump spices from bags into a slurry for application to potato chips . Technology used to control dusts during bag dumping has been in place for many years. The standard control-a ventilated bag dump station-consists of a hopper outfitted with an exhaust ventilation system to pull dusts away from employees as they open and dump bags of powdery materials. The designs for these devices are available from several sources of industrial ventilation guidance. The HSE has developed a control approach for a ventilated station for emptying bags of solid materials. The control includes the specification of a face velocity of 200 fpm (1.0 m/s) and includes a waste bag collection chute (Figure 8-9) . Research into the effectiveness of these types of devices has shown that they can effectively reduce employee exposure to dust and vapors. A review of commercially available units showed that their use controlled dust levels to 1-2 mg/m 3 . However, dust contamination on the surface of the bag and handling or disposal of bags caused increased employee exposure. An integral pass through to a bag disposal chute or compactor will help reduce dust exposure resulting from bag handling. Further studies in mineral processing plants showed that the use of an overhead air supply also significantly decreased employee exposure . The ACGIH Ventilation Manual also has two designs that are applicable to the control of powder materials during bag dumping. Design plate VS-15-20, Toxic Material Bag Opening, is similar in design to the HSE station described above but recommends a slightly higher control velocity of 250 fpm at the face of the station opening. # Bag filling The process by which bags are filled with products is typically done by flavor manufacturers and other producers of powder materials. Powder flavorings are typically mixed with industrial blenders or produced by a spray drying process. For the blending process, a powdered starch or other carbohydrate is combined with a liquid or paste flavoring agent. When the blending is completed, the powder product may be discharged into a bulk tote or packaged into smaller containers. In the spray drying process, a mixture of liquid and powder ingredients (slurry) is sprayed within a large sealed tank. Heat within the tank dries the slurry droplets, leaving a powder as the Occupational Exposure to Diacetyl and 2,3-Pentanedione 191 finished product. This powder is then collected and packaged in product containers. Studies conducted at flavoring production facilities have shown that intermittent peak exposures to dust and flavoring volatile ingredients occur when powder products are being packaged following blending or spray drying . This design guidance recommends an air velocity of 200 fpm (1.0 m/s) into the enclosure. The ACGIH Industrial Ventilation Manual, Design plate VS-15-02, Bag Filling, is similar in design to the HSE exhaust hood but specifies an overall hood exhaust flow of 400-500 cfm for nontoxic dust or 1,000-1,500 cfm for toxic dust with a maximum inward air velocity of 500 fpm . In addition to ventilation solutions, other dust control approaches have been used in a variety of industries and should be applicable for food and flavoring production. For example, an inflatable seal can be used to create a dust tight seal on the discharge outlet of an industrial blender (Figure 8 -13). The outlet spout can be fitted with an inflatable seal that prevents dust from escaping during the bag filling process. The seal inflates during the product transfer from the blender to the packaging bag (providing the seal) and deflates once the transfer is completed to allow removal of the packaging bag. These systems are available on many commercially available bulk bag filling systems . Another system that can be used is the continuous liner system. Polypropylene liners are often used when products are discharged from the industrial blenders into the final product container. In this operation, a sleeve of polypropylene liners is stowed around the circumference of the discharge outlet. The first liner, the bottom having been sealed, is pulled down into the overpack (usually a 5-gallon bucket or a cardboard box). Product is discharged into the liner through a butterfly valve on the blender outlet. Once full, the top of the first liner sleeve is closed with tape or a fastener, or it is heat sealed and cut. The product is sealed within the poly-lined container, and a new sealed poly-liner is pulled down to start discharge into the next container. This continuous process seals off the primary leak paths for dust during unloading of an industrial blender or other equipment. These systems are commonly used in the pharmaceutical industry and may provide effective alternatives to traditional local exhaust ventilation control systems for food and flavoring production. # Summary of Capture Efficiencies of Control Approaches Producing flavorings and flavored foods involves a variety of steps. These processes require the handling and manipulation of flavorings and flavoring compounds, which have been shown to be a point of exposure for employees. Table 8-2 shows the capture efficiencies of those controls which have been evaluated by NIOSH in the laboratory or in flavoring manufacturing plants and discussed in this chapter. These controls have shown to be effective at reducing potential employee exposure by 90% or greater across the wide range of processes and tasks commonly seen in flavoring and flavored food production. However, for some tasks, this may not be enough to reach the exposure control goals. When implementing engineering controls, it 192 Occupational Exposure to Diacetyl and 2,3-Pentanedione is important to use a tiered approach, which includes reducing the emissions at the source through containment, process modifications, or local exhaust ventilation as well as using facility provisions such as pressurization schemes. These approaches should be used in conjunction with those described below including administrative controls and the use of personal protective equipment. # Administrative Controls Work practices, an administrative control, are procedures followed by employers and employees to control hazards in the workplace. The emission of the volatile components in each flavoring mixture can be minimized by preventing spillage. To the extent possible, containers used to mix and store flavoring compounds should be covered when not in use. This practice will minimize the evaporation of chemicals into the workplace air and minimize likelihood of inadvertent spills. Manual handling of chemicals also provides a potentially significant source of employee exposures and emissions. Use of closed transfer processes, where feasible, significantly reduces exposure. Also, slow careful pouring/handling of chemicals can reduce splashing, spillage, and exposure during this activity . Reduction in spills and elimination of leakage from vessels aid in reducing the overall emission of chemicals into the workplace and lower employee exposure. # Good Housekeeping Practices An organized, clean workplace enables faster and easier production, improves quality assurance, and reduces the potential for slips, trips, and falls. It is important to maintain good general housekeeping practices so that leaks, spills, and other process integrity problems are readily detected and corrected. # Reduced Process Temperatures for Priority Flavoring Compounds To minimize volatilization, the temperature of diacetyl, 2,3-pentanedione, and other flavoring compounds in heated tanks should be maintained as low as production processes will allow, even when closed systems are used. Employers should make sure that: All temperature-related equipment such as thermometers and automatic shutoff mechanisms are regularly checked to ensure that they are in good working order. Tank thermometers and thermostats are calibrated at least monthly or as recommended by the manufacturer. Employees take periodic manual temperature readings with a stem thermometer inserted just below the surface of the heated agents or with an infrared thermometer. # Cleaning Practices for Equipment and Tools Where possible, cold water should be used to clean out tanks and blenders to reduce the volatilization of chemicals into plant air. Employees who are involved in cleaning or are working nearby should use appropriate PPE including respiratory protection, eye, and skin protection. # Limit Access to Priority Flavoring Compounds Employers should structure work tasks to minimize the amount of time employees spend near priority chemicals and production processes that involve these chemicals. Employers should limit access to areas where diacetyl, 2,3-pentanedione, or other flavoring compounds are used to only those employees who are essential to the process or operation. These areas should be clearly marked with signage. # Informing Employees about the Hazard # Safety and health programs Employers should establish a comprehensive safety and health program for all employees who are performing any activity, such as manufacturing, using, handling, or disposing of diacetyl or 2,3-pentanedione, that involves exposure to these compounds or mixtures that include these compounds. This program should include training on workplace hazards, monitoring of airborne diacetyl and 2,3-pentanedione levels, and medical surveillance of employees exposed to these compounds or mixtures that include these compounds. All containers of food flavorings fall under the labeling requirements of the OSHA hazard communication standard (HCS) unless they are covered under the Federal Food, Drug and Cosmetic Act or the Virus-Serum-Toxin Act of 1913 . Employee training should include information outlined in the OSHA HCS in the section titled "Employee Information and Training" . This includes information about diacetyl and 2,3-pentanedione and mixtures containing these compounds to which employees are exposed, explanation of safety National Toxicology Program 2011]. Several case studies, public health investigations, and a cohort mortality follow-up study link exposure to flavorings containing diacetyl to fixed airway obstruction Cavalcanti et al. 2012;CDC 2002CDC , 2007CDC , 2013Halldin et al. 2013]. Precautionary statements for the health and physical hazard classifications presented can be found in Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200. † Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200 provides several precedence rules regarding the application of pictograms and signal words as well as rules for combining or omitting hazard and precautionary statements. These precedence rules save space on the label and improve readability. ‡ NIOSH recommends that these GHS classifications should appear on product labels and SDSs when found in mixtures below the specific cut-off values/concentration limits that are provided in the hazard communication standard [29 CFR 1910[29 CFR .1200. See section 8.3.7.3 below for further information. [29 CFR 1910[29 CFR .1200. *Precautionary statements for the health and physical hazard classifications presented can be found in Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200. † Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200 provides several precedence rules regarding the application of pictograms and signal words as well as rules for combining or omitting hazard and precautionary statements. These precedence rules save space on the label and improve readability. ‡ NIOSH recommends that these GHS classifications should appear on product labels and SDSs when found in mixtures below the specific cut-off values/concentration limits that are provided in the hazard communication standard [29 CFR 1910[29 CFR .1200. See section 8.3.7.3 below for further information. physical hazard criteria presented in Appendix B of the hazard communication standard on the basis of the previous version of the HCS, but that guidance does not address some of the requirements in the revised HCS based on GHS. The GHS classification for acute inhalation toxicity, category 2 for diacetyl is based upon rat acute inhalation studies of diacetyl and 2,3-pentanedione . In the diacetyl study, the histopathology changes seen in rats exposed for 6 hours to a time-weighted average of 294.6 to 365 ppm diacetyl would be predicted to cause death if the animals had been observed for a longer time period. In exposures conducted in this concentration range, the severity scores in the airway epithelium of trachea, larynx, and multiple sections of nose had an average score of 7.5 to 9.5 on a scale of 1 to 10 (with 10 being most severe). Damage to airway epithelium is the accepted underlying cause for obliterative bronchiolitis in man, which causes human morbidity and mortality . The importance of extrapulmonary airway injury in the rodents to human risk assessment is discussed in the toxicology section. In the 2,3-pentanedione inhalation study in rats, clinical observations documented that no clinical signs were present immediately after the 6 hour inhalation exposures to 318 or 354 ppm but respiratory signs were present in more than half of the rats at 18 hours post-exposure, when the rats were sacrificed . While both of these inhalation studies were not intended to produce lethality, contemporary laboratory animal studies frequently use early indicators of impending mortality rather than actual mortality for studies of lethality . The presence of extensive respiratory epithelial damage in 100% of the rats at exposures of approximately 294.6 ppm or greater for 6 hours in both of these studies and timedependent progressive respiratory clinical signs are considered a humane endpoint for use in place of mortality. In this case, expert scientific judgment needs to be used to determine the LC50 because of the humane considerations. Because all rats had high pathology scores after inhaling 294.6 ppm or higher, NIOSH concludes that the LC50 based on a 4-hour exposure would be 441 ppm (the 4-hr equivalent of 294.6 ppm) or less. After inhaling 100 to 120 ppm diacetyl for 6 hours, histopathology changes were limited to the first nasal section and single exposures at this concentration did not suggest potential acute lethality. Similarly, after inhaling 111 ppm 2,3-pentanedione for 6 hours, rats did not have clinical signs and significant histopathology changes were limited to the first two nasal sections. This equates to a GHS acute inhalation toxicity category 2 classification (>100 and <500 ppm) for both diacetyl and 2,3-pentanedione. # Classifying mixtures containing diacetyl and 2,3-pentanedione The HCS indicates that mixtures that contain compounds that require classification and labeling can be evaluated under a set of bridging principles if no toxicological data are available for the mixture itself. These bridging principles can be applied when there is "sufficient data on both the individual ingredients and similarly tested mixtures to adequately characterize the hazards of the mixture" [29 8-3 and 8-4), the specific cut-off values/ concentration limits specified by the HCS are ≥1%. Exceptions include the hazard category for "serious eye damage/eye irritation" (≥3%) and for "flammable liquids," for which the HCS does not have a cut-off value/concentration limit. If these mixtures contain classified compounds below the specified HCS cut-off values/concentration limits, classification and labeling of those mixtures are not usually required. However, the standard indicates that "while the adopted cut-off values/concentration limits adequately identify the hazard for most mixtures, there may be some that contain hazardous ingredients at lower concentrations than the specified cut-off values/concentration limits that still pose an identifiable hazard [29 CFR 1910[29 CFR .1200. As explained below, this is an important consideration for mixtures containing diacetyl and 2,3-pentanedione. FEMA has also recommended that this same warning should be used for containers of neat substances such as diacetyl and 2,3-pentanedione as well as other "high priority" substances listed in the FEMA guidance document. Additionally, FEMA has recommended that all containers of compounded flavors (liquid and dry or powdered) or natural flavoring complexes that contain diacetyl, 2,3-pentanedione or other flavoring substances in concentrations of >1.0% should be labeled with the above warning . It is of note that the use of the word "warning" in the FEMA text is inconsistent with the specific criteria for its use and application as a signal word in the HCS. NIOSH recommends removal of the word "warning" when using the FEMA text (see section 8.3.7.4 for details) # Labeling and posting To communicate hazard information effectively to employees, employers should: Post appropriate labeling on all flavoring product containers according to the HCS requirements [29 CFR 1910[29 CFR .1200. In this document, NIOSH is providing the recommended label elements, including signal word, hazard statements, and pictograms, that should be included for labeling of diacetyl and 2,3-pentanedione on SDSs and labels for shipping containers [see . The precautionary statements that are also required can be found in Appendix C to the HCS [29 CFR 1910[29 CFR .1200 removing them, any limitations on their use, and their maintenance. Procedures for regularly evaluating the effectiveness of the program. If an air-purifying respirator with cartridge/ canister for the protection against gases and vapors does not have an end-of-service-life indicator, then the employer is required to implement a cartridge/canister change schedule based on objective information that will ensure that the cartridges/canisters are changed before the end of their service life, according to the OSHA respiratory protection standard which was revised in 1998. The revised OSHA respiratory protection standard removed the previous method of determining the end of a cartridge's service life by using warning properties such as odor and irritation. A cartridge's useful service life is how long it provides adequate protection from the harmful chemicals in the air which are identified in the respirator approval. A change schedule to establish the time period for replacing respirator cartridges and canisters is the part of the written respirator program that is used to determine how often cartridges should be replaced. Data and information relied upon to establish the schedule should be included in the respirator program. The use of warning properties such as odor and irritation cannot be used as the sole basis for determining change schedules. However, respirator users should be trained to understand that they should leave the area if abnormal odor or irritation is experienced. The respirator should be checked to see if the odor or irritation is evidence that respirator cartridges need to be replaced or the respirator facepiece needs adjustment for better face seal fit. The following table indicates which types of respirators are recommended for use against diacetyl and 2,3-pentanedione and the maximum use concentrations for diacetyl and 2,3-pentanedione, calculated using the OSHA-assigned protection factors for each type of respirator listed [29 CFR 1910.134 (d) # Dermal, Eye, and Face Protection Diacetyl can cause skin and eye irritation. Chemical resistant gloves or sleeves or other appropriate protection for exposed skin should be used when handling liquid, paste, or powdered flavoring compounds containing diacetyl that could cause dermal injury . It is important to select the most appropriate chemical resistant glove for the application and to determine how long it can be worn, and whether it can be reused. Procedures should be implemented to ensure that the gloves are replaced before breakthrough occurs. NIOSH recommends that before purchasing gloves or other protective clothing, the employer should refer to the SDS from the manufacturer of the diacetyl and 2,3-pentanedione being used, and /or request documentation from the glove or protective clothing manufacturer that the gloves meet the appropriate test standard(s) for the hazard(s) anticipated, and to request any glove and protective clothing breakthrough time data against diacetyl and 2,3-pentanedione that may be available from these sources. Tight-fitting SCBA = Self-contained breathing apparatus - Maximum use concentrations will be lower than shown when those concentrations are equal to or exceed immediately dangerous to life and health levels. † The employer should have evidence provided by the respirator manufacturer that testing of these respirators demonstrates performance at a level of protection of 1,000 or greater to receive an assigned protection factor (APF) of 1,000. Absent such evidence, these respirators receive an APF of 25. Diacetyl and 2,3 . The ANSI standard was revised in 2010 . The current edition also includes respirators that cover the eyes and face as approvable under the standard. # Occupational Exposure to Goggles for chemical splash should be used for eye protection for employees with potential exposures to diacetyl, 2,3-pentanedione, or food flavorings containing these compounds who are not also required to wear a respirator with a full facepiece, hood, or helmet. Face shields can also be used in conjunction with goggles to shield the wearer's face, or portions thereof, in addition to the eyes for protection from liquid splash. Face shields should be worn only in conjunction with spectacles and goggles, as required by ANSI Z87. 1-20101- [ANSI 2010. A face shield with a polyethylene terephthalate visor should provide good chemical resistance against diacetyl, 2,3-pentanedione, or food flavorings containing these compounds. Gloves and protective clothing such as aprons made from butyl rubber, Teflon™, or Tychem™ are effective in reducing skin contact with ketones to prevent skin irritation . Diacetyl and 2,3-pentanedione are diketones and certain food flavorings containing either may contain other ketones or diketones. Glove suppliers should be contacted to ensure that appropriate glove materials are selected for the specific chemicals involved . An analysis should be performed on each operation involving diacetyl, 2,3-pentanedione, or other food flavoring compounds to assess the potential exposures and to establish specific guidance about when to use skin, eye, and face protection. CDC (Centers for Disease Control and Prevention) . Fixed obstructive lung disease among workers in the flavor-manufacturing industry -California, 2004. CDC . # Medical Monitoring Medical monitoring of employees, sometimes called medical screening, involves periodic medical follow up for early detection of workrelated disease. The intended benefit of early detection is to identify disease in early stages when steps can still be taken to prevent progression from pre-clinical to clinical disease or from milder to more symptomatic disease. This approach is called secondary prevention because it attempts to ameliorate or at least halt the progression of health effects that have already occurred. Evidence of early disease identified through medical monitoring serves as a sentinel event or warning that other employees might be at risk for the same exposures and outcomes. This warning should stimulate efforts to evaluate the workplace to identify possible risk factors for exposures that can be controlled. Systematic evaluation and use of medical monitoring data obtained from individual employees to better protect a population of employees is an important component of the overall medical surveillance program. This approach contributes to the goal of primary prevention, to prevent disease from developing in other employees. # Medical Surveillance The systematic analysis of aggregated results over time constitutes medical (epidemiologic) surveillance of trends in symptoms or functional changes that can be assessed in relationship to jobs, tasks, and exposures . For medical monitoring to serve surveillance purposes, a formal process should be in place to assure that data from a screened employee population is evaluated in aggregate at regular intervals. Epidemiologic analysis of medical # Medical Monitoring Program Director The medical monitoring program director should be a licensed physician with training and experience in identifying and preventing occupational lung disease. This is because flavoring-related lung disease can progress rapidly and have grave consequences, so it is important to assure that the medical monitoring program director can quickly evaluate clinical data and make medical judgments about appropriate diagnostic and therapeutic measures, including medical removal. This individual (hereafter referred to as "the medical monitoring program director") should ensure that the monitoring program collects high quality data, including relevant questionnaire data and high quality spirometry tests that adhere to ATS/ERS technical guidelines for spirometry , or the most recent equivalent guidelines. The medical monitoring program director should also ensure that medical monitoring data is appropriately evaluated for surveillance purposes, including evaluation of aggregated results to identify risk factors and opportunities to better prevent flavoring-related lung disease. The employer should ensure that the medical monitoring program director is familiar with the natural history of flavoring-related lung disease and is knowledgeable about operating a spirometry program that maintains high test accuracy, precision and validity. The employer should provide the following to the medical monitoring program director: A copy of the NIOSH Alert, "Preventing Lung Disease in Workers Who Use or Make Flavorings" ; A copy of this criteria document; A description of work areas, job categories, and work tasks; A description of any personal protective equipment to be used by employees; and Results of any environmental sampling related to potential flavorings exposures. # Employees to Include in the Medical Monitoring Program All permanent, temporary, and contract employees who work in or enter areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds or products that contain these compounds are used or produced should be included in the medical monitoring program. Employees who work in or enter these areas for a total of 40 or more hours per year should be included in the medical monitoring program. In addition to production employees, employees who are periodically exposed such as supervisors, warehouse employees, laboratory employees, quality assurance/control employees, shipping and receiving employees, maintenance employees, janitorial employees, and office employees should also be included in the program, as employees with lung function abnormalities were identified in nonproduction jobs during several NIOSH HHE investigations . Employees with past experience in such jobs or performing such duties should be included in the monitoring program for one year and longer if abnormalities are present . To achieve the intent of primary and secondary prevention, employers have an interest in attaining a high rate of employee participation in regular medical monitoring. Voluntary participation should be encouraged at a time and place convenient to employees and should be provided at no cost to employees. # Medical Monitoring Program Elements The medical monitoring evaluation should include a questionnaire to obtain health and exposure information and spirometry to assess lung function. The questionnaire data from all employees in a medical monitoring program should be entered into a database along with spirometry results for use in epidemiologic analyses for medical surveillance. These analyses may reveal associations between health outcomes and exposure variables such as work tasks and practices that can be addressed to decrease lung disease risk (see section 9.9). # Questionnaire The purpose of the questionnaire is to obtain standardized information on demographics, work history, exposures, personal risk factors such as smoking and health history. The medical monitoring program director can use information from the questionnaire when assessing the employee at each evaluation. Because employees with biopsy-documented obliterative bronchiolitis may have normal spirometry, chest symptoms such as exertional shortness of breath merit attention as suggestive of an occupational lung condition requiring employee education and follow up. Similarly, persons with abnormal spirometry, despite absent chest symptoms, may have occupational lung disease requiring attention. Work history questions should allow employees to correctly indicate the specific job titles they have held at their current employer. For each job title, the questionnaire should collect information on specific work tasks and practices that may affect the employee's exposure to diacetyl and similar flavoring compounds. For example, for an employee whose job requires direct handling of diacetyl-containing flavorings, specific questions might address how often a particular task is performed, the amounts of flavorings used, whether open or closed containers of flavorings are used, and whether respiratory protection is used, including the type of respirator used and when it is worn. To help the medical monitoring program director develop appropriate questions on jobs and exposures, the employer should provide the medical monitoring program director with the specific job titles of potentially exposed employees, a description of the work tasks for each job that may be associated with potential for exposure to diacetyl and similar flavoring compounds, and the types of personal protective equipment (e.g., respirators) and other measures that employees have available to them to minimize exposures in each job. A visit to the plant by the medical monitoring program director to view the production process may provide additional useful information for questionnaire development. The questionnaire should contain questions on the presence or absence of respiratory symptoms such as shortness of breath on exertion, cough, and wheezing; respiratory illnesses such as asthma, emphysema, chronic bronchitis, and COPD; and the dates of diagnosis. Additional questions might inquire about work-related nasal, ocular, and dermal symptoms. The American Thoracic Society Respiratory Symptom Questionnaire While respiratory symptom information is important in the assessment of employees exposed to diacetyl and similar flavoring compounds or products that contain these compounds, the medical monitoring program director should not conclude that an employee's exposures are below harmful levels solely by the absence of respiratory symptoms. Employees may not experience respiratory symptoms early in the course of excessive lung function decline. NIOSH medical surveys of flavoring-exposed employees have identified airways obstruction and excessive declines in lung function in employees who did not report respiratory symptoms. Similarly, about half of the employees with airways obstruction found in surveillance of California flavoring manufacturing employees had no chest symptoms . Absence of symptoms does not negate the need for clinical differential diagnosis and evaluation of employees with spirometric abnormalities. The medical monitoring program director should counsel employees identified as having pre-existing lung disease on their initial evaluation regarding the potential risks of working in areas where they may be exposed to diacetyl and other flavoring compounds. The medical monitoring program director should also explain that it may be hard to determine the relative contributions of work exposures vs. pre-existing lung disease to any future abnormal lung function declines. Such employees should also be referred to their personal physician for additional evaluation and recommendations regarding potential exposure to these substances. # Spirometry Every employee in the medical monitoring program should have a spirometry test at each evaluation irrespective of respiratory symptom status. Evaluation of lung function over time is the most important component of medical monitoring for identifying possible workrelated lung disease in employees exposed to diacetyl and similar flavoring compounds (see section 9.6). High quality spirometry tests are necessary to allow the medical monitoring program director to correctly interpret the results and make appropriate recommendations to the employee and the employer. Accurate spirometry measurements depend on four key elements: (1) a trained technician who can obtain valid test results, ( 2) a reliable and accurate spirometer, ( 3) an approved testing protocol, and ( 4) a spirometry quality assurance program directed by a laboratory supervisor or the medical monitoring program director. # Spirometer specifications Spirometry testing equipment should meet the ATS/ERS guidance for standardization of spirometry or most recent equivalent , specifications for spirometer accuracy and precision, and real-time display size and content. Written verification from a third party testing laboratory (not the manufacturer or distributor) that the model of spirometer being used has successfully passed its validation checks as required by the most current ATS/ ERS protocol should be requested from the spirometer manufacturer. # Spirometry testing protocol and reporting information Administration of spirometry tests should follow the ATS/ERS guidance for standardization of spirometry or most recent equivalent Testing Procedures 1. Spirometer calibration checks should be performed using a currently calibrated (per manufacturer recommendations) 3-liter syringe on each day of testing . A copy of the spirometer calibration report should be maintained in either electronic or hard copy form. 2. Spirometry should be performed in the same documented position (either sitting or standing) during the baseline and all subsequent tests. 3. A minimum of three forced exhalation maneuvers producing "acceptable curves" on the spirometry report should be characterized by the following: Lack of hesitation (back-extrapolation volume should be less than 5% of FVC or 150 mL, whichever is larger) No cough in the first second of the maneuver No evidence of airflow cessation, variable effort, leak, obstructed mouthpiece, positive or negative zero flow error(s), or extra breath(s) Acceptable end-of-test criteria (≤ 25 mL increase in volume for 1 second or a maneuver longer than 15 seconds) 4. Less than 150 mL difference between the two highest FVC measurements and the two highest FEV 1 measurements is the goal. # Spirometry Predicted Values If spirometry software allows a choice of predicted values, NHANES III or the most recent equivalent should be used as they are based on a large sample of the U.S. population. Because predicted values are not available from NHANES III for Asian people born in the United States, these predicted values may be estimated by multiplying the NHANES III Caucasian predicted values for FEV 1 and FVC by 0.88 . In the future, it will be preferable to use Asian-specific equations for predicted values, such as from NHANES Plus data, when they are available. If spirometry software does not include lower limits of normal values, the spirometry reference value calculator at / spirometry/RefCalculator.html can be used to calculate lower limits of normal for NHANES III reference values. ]. These guidelines outline the criteria to follow to ensure overall test results are valid (Figure 9-1). The technician should be able to view real-time testing displays as specified in the most recent ATS/ERS spirometry standardization. On-site back-up of the results should include spirometry test reports and retention of all spirometry test results in printed or electronic format. Spirometry test reports for the employee's health record should contain, at a minimum, the employee's age, height, sex, race, and weight; numerical values and volume-time and flow-volume spirograms for at least the three best valid expiratory maneuvers; normal reference value set used; employee position during testing (standing or sitting); dates of test and last calibration check; ambient temperature and barometric pressure (volume spirometers); and the technician's unique identification number or initials. The name, postal mailing and contact e-mail addresses, and telephone and fax numbers of the facility completing the spirometry test results and forms should also be recorded. Townsend 2011]. When suboptimal quality tests with potential for improvement are identified, the reviewing physician or other appropriate healthcare professional should provide feedback to the appropriate technician(s) along with specific suggestions for improvement. Some studies have found evidence that providing regular feedback to technicians improves test quality and decreases variability. In two studies where extensive feedback was provided to technicians on the quality of their tests, the investigators found lower measures of variability for their test measurements than in other studies where extensive feedback to technicians was not provided . In these studies, the technicians received immediate feedback from the spirometry device on the acceptability of a forced exhalation maneuver and on the overall quality of the test. The investigators also provided ongoing review of the quality of their tests and gave feedback to the technicians; additional technician training was provided as needed. Test quality in these studies was graded using an A, B, C, D, F scale. In a study of a workplace spirometry testing program, use of a new spirometer that provided technicians with feedback during the test led to increases in the mean FEV 1 and mean FVC of the study group, compared to use of an older spirometer without feedback capability . With poor quality tests, some employees' results that are truly normal may be considered abnormal, and employers may incur costs for lost work time in follow-up testing and clinical evaluation. In addition, employees may suffer needless worry, risks of unnecessary medical tests, and may be subject to workplace discrimination or even job loss. An example of an incorrect interpretation due to a poor quality test is the finding of a restrictive abnormality because the test subject did not exhale long enough during the maneuver; this results in a falsely low FVC. High quality spirometry tests are also necessary for comparison of spirometry results over time, an important consideration for flavoring-exposed employees. Low quality spirometry has greater variability in test results; over time, decreased precision may cause the medical monitoring program director to incorrectly identify whether an employee has had an excessive decline in lung function from one test to the next. In reviewing the quality of spirometry tests performed for employers by private healthcare providers, NIOSH has identified instances where the quality of most tests was poor and thus not useful for assessing lung function changes over time Kreiss et al. 2012;NIOSH 2004bNIOSH , 2006]. High quality spirometry minimizes the variability in the results caused by technical aspects (i.e., how the test was conducted) so that changes in spirometry measurements over time reflect true changes in lung function more accurately. In California public health surveillance, only one of 13 commercial providers of surveillance spirometry for flavoring employees who reported results to the California Department of Public Health met a minimum quality criterion of 80% of test sessions with FEV 1 of good quality . Employers of flavoring-exposed employees should be aware of the characteristics of high quality spirometry programs so they can evaluate the quality of spirometry services offered by medical providers, monitor performance, and take corrective actions if necessary. OSHA and NIOSH have published an information sheet on spirometry for employers . # Frequency of Medical Monitoring Evaluations Newly hired employees and current employees should have baseline evaluations before they are allowed to work in or enter areas as previously described where they may be exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds. Employees in the medical monitoring program should be evaluated with a questionnaire and spirometry every 6 months due to the potentially rapid development of flavoring-related lung disease . If an employee exposed to diacetyl or similar flavoring compounds is identified as likely having lung disease from this exposure, then all employees who perform similar job tasks or have a similar or greater potential for exposure should be evaluated every 3 months. # Reporting Medical Monitoring Results The medical monitoring program director or designee should review and interpret questionnaire and spirometry results, including assessing spirometry quality. During an employee's scheduled visit for a medical monitoring program evaluation, the medical monitoring program director or designee should inquire about the employee's knowledge of the potential risk from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds and of how to minimize the risk. The medical monitoring program director or designee should educate employees as needed , and encourage employees to report any new persistent respiratory symptoms to their supervisor or the monitoring physician. At the end of each evaluation visit or as soon as possible thereafter, the medical monitoring program director should provide the employee with a written report describing the following items: The results of any medical tests performed on the employee The medical monitoring program director's opinion regarding any abnormalities detected during the evaluation and recommendations for further evaluation and treatment Whether or not the employee has any detected medical condition which would place the employee at increased risk to health from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds Recommendations, if necessary, for reducing the employee's exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds Any recommended limitation upon the employee's use of personal protective equipment. The medical monitoring program director should inform the employer in writing of the following: Any recommendations for limiting the employee's workplace exposures (e.g., reducing exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds by removal, or limitations of the employee's duties or activities) or on the employee's use of personal protective equipment A statement that the physician has informed the employee of the results of the medical examination and any medical conditions that require further evaluation or treatment. The specific condition, issue, or concern resulting in recommendations for limiting the employee's exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds or on the employee's use of personal protective equipment should not be specified in the write-up to the employer without the employee's consent. Also, any aspect of the employee's medical history that has no bearing on whether the employee should continue to work in areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds are used should not be revealed to the employer. A copy of the medical monitoring program director's written opinion provided to the employer should also be provided to the employee. # Early Identification of Affected Employees Early recognition of employees with lung disease due to exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds is essential to prevent rapid progression to severe irreversible disease. Identifying affected employees will also stimulate prevention efforts so that risk to other employees is minimized. The most effective means for identifying affected employees early is careful evaluation of results of serial spirometry tests of employees in the medical monitoring program. Symptom reports alone are not a reliable indicator of early disease, as many employees with early disease will be asymptomatic. However, symptom reports of exertional shortness of breath can reflect pathologic obliterative bronchiolitis even when spirometry remains normal . At each evaluation of an employee in the medical monitoring program, the medical monitoring program director should compare the results of the current spirometry test to the baseline (pre-exposure) test, or to the test with the highest values if post-hire spirometry values were higher than at baseline. The most important finding that may indicate development of lung disease from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds is an abnormal decline in the FEV 1 . An employee's longitudinal test results may reveal an abnormal decline in FEV 1 compared to baseline even when each individual test value is found to be normal because it is above the LLofN calculated from the reference population . While such test results might not meet the criteria for an abnormality such as airways obstruction or spirometric restriction, an abnormal decline in FEV 1 may indicate early disease in this case and should be further evaluated. Additionally, any new abnormality on spirometry compared to baseline should prompt further evaluation. Flavoring-exposed employees with obstructive abnormalities (FEV 1 /FVC ratio and FEV 1 less than the LLofN) need additional medical tests to assess whether they have obliterative bronchiolitis. Employees with restrictive abnormalities (FVC less than LLofN and normal FEV 1 /FVC ratio) also need additional medical tests to differentiate between nonlung causes and lung causes of spirometric restriction, including obliterative bronchiolitis . The criteria for an abnormal excessive decline in the FEV 1 depend on the quality of the spirometry tests performed as part of the medical monitoring program and the time period of follow-up . ATS/ERS and ACOEM have stated that a decline in FEV 1 over one year should exceed 15% before being considered clinically meaningful Townsend 2011]. By this criterion, someone with a baseline FEV 1 of 4 liters would 234 Occupational Exposure to Diacetyl and 2,3-Pentanedione have to experience a decline of at least 600 mL for the results to be considered abnormal. Because lung disease caused by flavorings can progress rapidly, it is useful to identify those potentially at risk before so much lung function is lost NIOSH 2006NIOSH , 2007. Some studies indicate that when ATS/ ERS criteria for spirometry quality are followed and high standards of quality are achieved, a threshold less than 15% can indicate an abnormally rapid decline in FEV 1 in a year. In a study that used data from a spirometry surveillance program for coal miners, Wang and Petsonk found that the 5th percentile for FEV 1 declines over 6 months in all employees studied was 320 mL (7.8%). In stable employees (those employees whose FEV 1 slope over 5 years was less than 90 mL/year), it was 300 mL (7.1%). In healthy employees (those employees without symptoms or methacholine responsiveness over 5 years), it was 280 mL (6.5%). The quality of spirometry data in this study reflected a withinperson variation of 3% that is rarely achievable. Within-person variation of 6% is typical for spirometry programs, and an assumption of that level of variability was used by ATS to develop its recommendation for using 15% loss of FEV 1 as a threshold . In another study that used data with a withinperson variation of 4% from a spirometry surveillance program for thousands of employees at a large chemical company, Wang et al. found that the 5th percentile values for FEV 1 decline for testing at one-year intervals were 380 mL (10.4%) in men and 280 mL (10.6%) in women. These studies suggest that in a medical monitoring program that follows ATS/ERS criteria and achieves high quality spirometry, an FEV 1 decline of 10% or higher in one year or less can be considered abnormal and used as a threshold for further medical evaluation of the employee. ACOEM now accepts this 10% criterion after allowing for expected average annual loss due to aging in high risk settings when the relationship between longitudinal results and endpoint disease is clear, as in flavoring-exposed employees . Lower quality spirometry programs have the disadvantage of only being able to detect larger declines in FEV 1 as abnormal. NIOSH has developed a computer program, SPIROLA, to help spirometry programs measure their within-person variation in FEV 1 as a measure of the precision of spirometry obtained by the spirometry providers (an indication of spirometry quality across the providers' programs). SPIROLA also provides a longitudinal limit of decline (LLD) for each individual tested, a threshold for determining abnormal loss of FEV 1 that is adjusted for the quality of the provider's spirometry program . The LLD allows the spirometry provider to determine if an individual's serial spirometry results suggest an excessive decline in lung function and allows higher quality programs to identify smaller changes in lung function as abnormal (. cdc.gov/niosh/topics/spirometry/spirola-software.html). The advantage of using relative lower LLD and 5th percentile approaches over the 15% criterion in flavorings-exposed microwave popcorn employees has been demonstrated . # Continuity of Medical Monitoring Employers may change medical providers of medical monitoring services. Employers should ensure that prior medical monitoring program directors transfer medical monitoring records, including spirometry tests and questionnaires, to new medical monitoring program directors. If necessary to gain access, employers or new providers should ask employees to sign releases allowing new providers to obtain previous medical monitoring and surveillance records from previous provider(s). Occupational Exposure to Diacetyl and 2,3-Pentanedione 235 The first step in evaluating an employee whose medical monitoring spirometry test shows either an excessive decline in FEV 1 (even if individual test results are still above the LLofN) or a new abnormality (e.g., obstructive, restrictive, or mixed spirometric abnormality) compared to baseline is to repeat the test within one month to confirm the change. If the repeat spirometry test confirms an excessive decline in FEV 1 or other abnormality, the employee should be referred for more extensive pulmonary function tests (PFTs) (described below). The medical monitoring program director may request these and other necessary tests or refer the employee to a pulmonary medicine physician at no cost to the employee. # Other Pulmonary Function Tests The referred employee should receive complete PFTs that include spirometry with an assessment of bronchodilator response, DLCO, and static lung volumes. Most employees who have developed lung disease while being exposed to diacetyl and similar flavoring compounds have not had a response to bronchodilator Kim et al. 2010]. In other words, they had fixed airways obstruction with an FEV 1 and/or FVC increase less than 12% and 200 mL after bronchodilator) . DL CO in affected employees with airways obstruction has usually been normal, although some individuals with advanced disease have had a low DL CO . Lung volume measurements have shown a normal or elevated total lung capacity (TLC) and an increased residual volume, consistent with air trapping ]. Individuals with moderate to severe airways obstruction may have a mixed obstructive/ restrictive (reduced FEV 1 , FEV 1 /FVC ratio, and FVC) pattern of spirometry because air trapping decreases the FVC. The actual underlying physiology can be clarified by determining lung volumes. # High-resolution Computerized Tomography Employees found to have fixed airways obstruction or other abnormalities on complete PFTs should have additional evaluation with a highresolution computerized tomography (HRCT) scan of the chest with inspiratory and expiratory views. Heterogeneous air trapping during expiration has been the most common finding in flavoring-exposed employees with fixed airways obstruction. Other common findings include cylindrical bronchiectasis, bronchial wall thickening, and a mosaic pattern of attenuation. Centrilobular nodules may also be seen . Patchy ground glass opacities have been observed less commonly. These findings may not be present despite obliterative bronchiolitis documented by biopsy . HRCTs have not been systematically performed in flavoring-exposed employees with restrictive pulmonary function abnormalities or with excessive FEV 1 declines within the normal range of FEV 1 . Specialist consideration of the diagnostic utility of this test is suggested. # Lung Biopsy It is not routinely necessary to obtain a lung biopsy to diagnose obliterative bronchiolitis in employees exposed to diacetyl or 2,3-pentanedione when spirometry and HRCT results are consistent with the diagnosis. While some physicians might desire biopsy confirmation, it is important to recognize that the patchy nature of obliterative bronchiolitis and lack of familiarity of some pathologists with the techniques necessary to identify bronchiolar lesions may prevent identification of the disease on biopsy. HRCT has become the method of choice for assessing 236 Occupational Exposure to Diacetyl and 2,3-Pentanedione bronchiolar morphology, often replacing surgical lung biopsy . Physicians caring for another population at high risk for obliterative bronchiolitis, lung transplant patients, use a similar noninvasive approach. Obliterative bronchiolitis commonly occurs after patients receive a lung transplant. Because this disease is difficult to identify on biopsy, the International Society for Heart and Lung Transplantation developed a clinical description for the disease termed bronchiolitis obliterans syndrome. The syndrome refers to graft deterioration secondary to persistent airflow obstruction as defined by pulmonary function changes with or without biopsy confirmation . The term bronchiolitis obliterans syndrome has also been applied to flavoring-exposed employees without surgical lung biopsies ; , but may lead to confusion because flavoring-related obliterative bronchiolitis differs in natural history from post-transplant bronchiolitis obliterans syndrome, which is relentlessly progressive. There are some situations, described in the next section, where lung biopsy is appropriate for diagnosis. To obtain adequate tissue for diagnosis, a thoracoscopic or open lung biopsy should be obtained. Obtaining wedge biopsies from multiple lobes is recommended, as this approach increases the diagnostic yield . Transbronchial lung biopsies are not useful for evaluating clinical obliterative bronchiolitis in employees exposed to diacetyl, 2,3-pentanedione, or similar compounds. # Determining Diagnosis Responsible for Lung Disease Determination of the diagnosis responsible for lung disease in an employee exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds should take into account the changes identified in medical monitoring spirometry tests, the results of complete PFTs and of HRCT scans of the chest, the course of the employee's illness over time, and medical, work, and personal risk factor history. In an exposed employee with evidence of clinical obliterative bronchiolitis on PFTs or HRCT scans and no other identifiable cause for the disease, biopsy is not necessary. The noninvasive clinical findings alone are sufficient to conclude that an exposed employee likely has clinical obliterative bronchiolitis and should no longer be exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds. When clinically apparent lung disease occurs in several employees at a particular plant, the need for biopsy confirmation in each employee is usually unnecessary. When HRCT is normal in dyspneic employees, particularly if the PFTs are restrictive or normal, lung biopsy has a role. Some medical surveys of flavoring-exposed employees have revealed an increased prevalence of an isolated restrictive pattern on spirometry (i.e., without concurrent airways obstruction), but static lung volume measurements of TLC and biopsies have not been available in these studies to confirm restrictive lung disease , many pulmonary and occupational medicine specialists are not aware of the range of spirometric findings in this disease and may be reluctant to diagnose obliterative bronchiolitis in patients with spirometric restriction or normal spirometry without pathologic confirmation. Employees who develop restrictive abnormalities or who have excessive parallel FEV 1 and FVC declines should have assessment of lung volumes, diffusing capacity, and HRCT to differentiate between restrictive lung disease and other causes of restrictive spirometric patterns. Further evaluation of restrictive lung disease for a specific diagnosis should be pursued as clinically appropriate and may require biopsy. Case reports of pathologic findings in dyspneic flavoring-exposed employees with restrictive or normal spirometry will be of interest in further guidance for clinicians responsible for the lung health of such employees. The evaluating physician should exclude alternative causes of respiratory disease such as work-related asthma (new onset asthma or exacerbation of pre-existing asthma). An employee with no past asthma history who experiences post-hire recurrent respiratory symptoms and has airways obstruction responsive to bronchodilator on PFTs (reversible airways obstruction) may have new onset asthma due to workplace exposures. If an employee with asthma symptoms does not have changes over time on medical monitoring spirometry, a methacholine or mannitol challenge test may be necessary to determine if the employee has airways hyperresponsiveness as occurs in asthma. Worsening symptoms in an employee with pre-existing asthma may be due to exposure to diacetyl, similar flavoring compounds, or other agents in the workplace ]. An important consideration for diacetyl-exposed employees with worsening pre-existing asthma or new onset reversible airways obstruction is that this may actually reflect early disease that may ultimately progress to clinical obliterative bronchiolitis. An employee at a California flavoring plant who had stable pre-existing asthma (no symptoms at time of hire) developed progressive shortness of breath and was found to have severe fixed airways obstruction on PFTs; a lung biopsy showed evidence of bronchiolitis obliterans . Employees with worsening pre-existing asthma or new onset reversible airways obstruction should be evaluated with an HRCT scan of the chest to determine if findings consistent with clinical obliterative bronchiolitis are present. However, because HRCT abnormalities may be insensitive in detecting early or mild disease, such asthmatic employees require careful and frequent follow-up . An employee exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds who has normal pre-exposure spirometry and subsequently develops fixed airways obstruction and has evidence of air trapping on complete PFTs or on HRCT scan, or has an excessive decline in FEV 1 and whose pulmonary function does not improve after exposure cessation, likely has clinical obliterative bronchiolitis due to this exposure. In exposed employees who smoke, fixed airways obstruction should not be attributed to smoking if there is no evidence of emphysema on medical tests. Clinically significant emphysema occurs in a subset of smokers after many years of smoking; it is uncommon in smokers less than 50 years old . In middle-aged and older smoking employees, work history, clinical course, and medical tests are important in attempting to differentiate between smoking-related COPD and flavoring-related obstruction. Smoking explains about 80% of COPD in the United States, with about 15% attributable to work exposures. Smoking diacetyl-exposed employees appear to have lower excess risk of obstruction than never-smoking flavoringexposed employees . Occupational Exposure to Diacetyl and 2,3-Pentanedione # Response to Identification of Workrelated Lung Disease Employees with abnormalities identified on medical monitoring spirometry should be counseled about the risks of further exposure and that removal from exposure is prudent because of the irreversibility of the disease, short latency, and often rapid progression. Employees who receive a diagnosis of flavoringrelated lung disease or who have findings on medical evaluation that indicate likely clinical obliterative bronchiolitis or other lung disease due to workplace exposures should be placed on work restrictions to prevent any further exposure to flavoring compounds or other substances in the workplace that may cause their lung disease to worsen. Personal protective equipment is the least effective means for controlling employee exposures. The proper use of personal protective equipment requires a high level of employer and employee involvement and commitment to be effective. The use of respiratory protection is not equivalent to removal from exposures because employees may still be exposed due to incomplete compliance, selection of an inappropriate respirator, or respirator malfunction . If possible, employers should offer affected employees the opportunity to transfer to available jobs in work areas that have minimal or nonexistent exposures. Such employees should retain seniority, wages, and benefits. Employers of an employee with confirmed or likely flavorings-related lung disease should arrange for an industrial hygiene evaluation of the plant areas where the employee had been assigned. The evaluation may identify aspects of the production process or work practices where control strategies can be implemented to minimize exposures. This may prevent additional employees from developing work-related lung disease. Medical monitoring evaluations of employees in these areas should increase in frequency from every 6 months to every 3 months, with a return to 6-month intervals after factors that may have led to excessive exposure have been corrected and 12 months have passed during which no additional employees with likely flavoring-related lung disease are identified (see section 9.4). When informed, employers should record all flavoring-related lung disease cases in the OSHA Form 300 Logs of Work-Related Injuries and Illnesses. # Medical Surveillance Analyses A workplace assessment conducted after identification of a sentinel case of work-related lung disease may reveal sources of uncontrolled exposures from particular aspects of production processes and work practices that can be improved to prevent other employees from becoming affected. However, this approach may not identify all such risk factors for hazardous exposure in a given workplace. Additional risk factors may be identified through a medical monitoring and surveillance program, which includes the use of epidemiologic techniques for analyses of aggregated data obtained from evaluations of all employees in a medical monitoring program. Such analyses show trends and distributions of health outcomes by exposure variables such as work area, job category, and work task. In some instances, the results of such analyses may provide early evidence of risk factors that can be addressed before employees develop significant lung disease. Because production processes and work practices in manufacturing plants that use diacetyl or similar flavoring compounds or products that contain these compounds vary from plant to plant, medical surveillance may also allow identification of risk factors unique to a particular plant. For these reasons, systematic evaluation of medical monitoring data is an important component of medical monitoring and surveillance programs for employees exposed to diacetyl or similar flavoring compounds. If the medical monitoring program director is not able to conduct such analyses, the employer or medical monitoring program director should arrange for consultants with expertise in epidemiology to undertake this task. Two examples below show how medical surveillance can help to identify lung disease risk factors in the workplace. Example 1. At the plant where microwave popcorn employees were first identified as being at risk for severe fixed airways obstruction consistent with clinical obliterative bronchiolitis from exposure to butter flavoring vapors (index facility G), four known affected former employees had worked in the mixing room as mixers of oil and butter flavorings, and four other affected former employees had worked on the packaging lines near the mixing room. A medical survey of current employees showed that the prevalence of airways obstruction on NIOSH spirometry tests was 3.3 times higher than expected in comparison to U.S. population data, a finding that was consistent with the known disease in former employees. The environmental assessment showed that air concentrations of the butter flavoring compound diacetyl were highest in the mixing room. The next highest exposures were in the packaging line area because of contamination from the mixing room, which was not isolated from the rest of the plant. Diacetyl air concentrations in other parts of the plant were lower. Analyses of the medical and environmental data showed a dose-response relationship between abnormal spirometry and quartiles of estimated cumulative exposure to diacetyl NIOSH 2006]. Additional analyses of the medical survey data revealed an unexpected finding: Among current employees, the highest prevalence of airways obstruction was found in QC laboratory employees, five of six (83%) of whom had airways obstruction . These employees popped approximately 100 bags of microwave popcorn in microwave ovens per 8-hour shift. The mean time-weighted average diacetyl air concentration in the QC laboratory was 0.8 ppm compared to approximately 57.2 ppm in the mixing room and 2.8 ppm for machine operators in the packaging line area. QC laboratory employees may be at risk for lung disease because they experience intermittent peak exposures to vapors of diacetyl from microwave popcorn bags during and after popping in microwave ovens; mixers experience similar intermittent peaks when they add butter flavorings to tanks of heated oil . Another possible explanation is that the much higher temperatures that occur in microwave popping (compared with the temperatures in heated tanks of oil and butter flavorings) increase the volatilization of other chemicals. QC laboratory employees' exposures may be substantially different from those of other production employees; diacetyl air concentrations alone may not be a satisfactory predictor of risk for these employees. Because of this evidence of risk to QC laboratory employees, NIOSH recommended implementing exposure controls in the QC laboratory in addition to the mixing room and packaging line area NIOSH 2006]. In evaluations at five other microwave popcorn plants, NIOSH found evidence of affected mixers in four plants and evidence of affected packaging line employees in one plant . No other plant had an elevated prevalence of airways obstruction in QC employees. Fewer bags of microwave popcorn were popped per employee per day in those plants, and the mean time-weighted average diacetyl air concentrations in the QC laboratories were lower than at index facility G. Occupational Exposure to Diacetyl and 2,3-Pentanedione Example 2. At a microwave popcorn plant where a young mixing room employee developed moderately severe fixed airways obstruction and other findings consistent with clinical obliterative bronchiolitis, management had put a mandatory respirator use policy for mixing room employees in place soon after the company first started production. In addition to using respirators, the company had also ventilated and isolated the mixing room from the rest of the plant and had local exhaust ventilation for tanks of heated oil and butter flavorings. Butter flavorings were handled in open containers as they were at other microwave popcorn plants. The respirators used were full facepiece respirators with organic vapor cartridges and particulate filters. Included in the questionnaire that NIOSH administered to current employees during a medical survey at the plant were questions about respirator use for the following work tasks: (1) weighing or handling open containers of flavorings, ( 2) pouring flavorings into tanks in the mixing room, (3) pouring other ingredients into tanks in the mixing room, ( 4) checking the levels in the tanks, and ( 5) other duties in the mixing room. Thirteen current employees reported ever having worked as a mixer; six had abnormal lung function on NIOSH spirometry tests. The reported percentages of time these employees used respirators during these activities ranged from 0% to 100%. The median reported percentage of time was 20% for all activities, except for those where other ingredients (not flavorings) were poured into tanks in the mixing room where the median was 50% . These results showed that employees were not fully compliant with management's respirator use policy; management was able to address this problem through employee education and enforcement of the policy. Had the company become aware of this problem earlier by regularly collecting and evaluating information on respirator use during medical monitoring evaluations, it could have increased compliance with respirator use and thus minimized some employees' exposures to butter flavoring compounds. (Before 2001 when NIOSH informed microwave popcorn companies of the risk of severe lung disease to employees exposed to butter flavorings, the company had been unaware of the respiratory toxicity potential of diacetyl. The company had implemented a mandatory respirator use policy for mixing room employees many years earlier to prevent severe eye irritation that employees had experienced when handling certain flavorings.) Thus, analysis of population data generated by medical monitoring and surveillance programs plays an important role in primary prevention by helping employers of flavoring-exposed employees to recognize and take steps to characterize and correct hazardous conditions. Recognition can require epidemiologic evaluation of medical monitoring, population, and environmental data. It is therefore important for employers to ensure that this applied epidemiology is provided as part of the medical monitoring and surveillance program. Employers should develop and implement comprehensive occupational safety and health programs to prevent occupational injuries, illnesses, and deaths. To be successful, safety and health programs should be developed and implemented as part of an employer's management system, with strong management commitment, employee involvement, and occupational safety and health expertise. A safety and health program designed to protect employees from the adverse effects of exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds should include mechanisms to identify all risk factors for exposure to flavoring substances. Just as medical monitoring is part of an overall occupational safety and health program, so is exposure monitoring. Exposure monitoring should be conducted whenever there is workplace exposure to diacetyl or 2,3-pentanedione. # Exposure Monitoring Program Goals A workplace exposure monitoring program should have clear, stated goals . Site-specific exposure assessment strategies should be developed to accomplish each of these goals: (1) to determine employee exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds used in the workplace; (2) # Exposure Monitoring Program Elements Proper measurement of contaminants in the environment involves a variety of program elements. The sampling and analytical methods referred to in this chapter include an outline of tested and validated procedures that produce statistically reliable data when used in the manner prescribed. Several of the more significant elements of a monitoring program are described below . Where possible, a written sampling strategy or protocol should be developed prior to sampling; this protocol should guide all aspects of the sampling process. The protocol should contain a description of ( 1) the objectives of sampling, (2) what to sample, ( 3) whom and where to sample, ( 4) how to sample, ( 5) when to 246Occupational Exposure to Diacetyl and 2,3-Pentanedione sample, ( 6) how long to sample, ( 7) how many samples to collect, and ( 8) how to handle, store, and ship samples . A walk-through survey or preliminary worksite visit is often useful in developing the sampling strategy and knowledge of the data-keeping system to be used to store and retrieve subsequent information can also have an effect. The sampling strategy should be developed to facilitate data analysis and interpretation for the specific exposure assessment goal. # Objectives of Sampling Sampling as part of an exposure monitoring program for diacetyl, 2,3-pentanedione, and other flavoring substances has several objectives. Often, this sampling is part of a comprehensive assessment to identify and quantify exposure hazards throughout a designated plant or work area to protect employees' health. The frequency of monitoring will depend on the purpose and rationale of the sampling campaign. Specific sampling objectives can include: (1) Characterizing (qualitatively or quantitatively) the flavoring compounds present in workplace air or in bulk materials (2) Ensuring compliance with existing OELs (3) Assessing the effectiveness of engineering controls, work practices, PPE, training, or other methods used for exposure control (4) Identifying areas, tasks, or jobs with higher exposures that require additional exposure control (5) Evaluating exposures related to production process changes and from changes in products made or materials used (6) Evaluating specific high risk job categories to ensure that exposures do not exceed exposure standards or guidelines (7) Measuring exposures of employees who report symptoms or illnesses Sampling can also be used to assess any fugitive emissions from plant processes into the surrounding community. Exposure monitoring should be conducted by qualified professionals. The sampling strategy should provide an opportunity to determine each employee's exposure, either by direct measure using personal breathing zone samples or through reasonable estimates based on the sampling of similar work tasks or jobs. Sampling strategies that group employees according to exposure zones, uniform job titles, or functional job categories have been used in some industries to reduce the number of required samples while increasing the confidence that all employees at similar risk will be identified . Area sampling may also be useful in exposure monitoring for determining sources of airborne contaminants and assessing the effectiveness of engineering controls. When sampling to determine whether employee exposures are below an OEL, a compliance sampling strategy, and/or a "focused strategy," that targets employees perceived to have the highest exposure concentrations may be more useful than random sampling. A focused strategy is most efficient for identifying exposures above the OEL if maximum-risk employees and time periods are accurately identified. Focused sampling may help identify short-duration tasks involving high airborne concentrations that could result in elevated exposures over a full work shift and also tasks that result in exposures over the STEL. # What to Sample (Specific Agents and Physical States) Because flavorings can consist of many chemicals in addition to diacetyl and 2,3-pentanedione, deciding what to sample often requires preliminary knowledge of the specific flavoring compounds being produced or used, or that are present in flavorings or other food ingredients used in the workplace, and the known exposure hazards posed by each. Information on possible food and flavoring compounds present in workplace air can be obtained from reviews of product ingredient lists, flavor or food recipes, SDSs, and other information provided by the employer or flavor manufacturer . In the flavor manufacturing industry, the recipe for each flavoring indicates the chemicals, solvents, and other ingredients used in the formulation. In the food manufacturing industry, this information may be available directly from the company or from SDSs for all flavorings and other ingredients used, although some flavoring SDSs do not list all potentially hazardous chemicals that may be present. Additional information may be needed from the flavoring manufacturers. Often, qualitative characterization may be useful prior to quantitative measurement to better guide the selection of substances to measure in the workplace. A review of any past exposure assessment reports from the target workplace or similar workplaces, may also be helpful in selecting which agents to sample. In either case, a list of substances to which employees will potentially be exposed should be developed to help determine which of those compounds are the most critical to sample . In instances where a company has stopped using diacetyl and 2,3-pentanedione in a flavor or food product, this list should include the butter flavor substances substituted for diacetyl or 2,3-pentanedione. Determining which chemicals to sample and measure should be based upon the chemical, physical, and toxicological properties as well as the chemical quantities in use. For example, industry reference materials may provide helpful information on which flavoring compounds to use or avoid . Other databases that might prove helpful may include but are not limited to National Library of Medicine (Hazardous Substances to represent the exposures of those groups . Area sampling may be useful for determining sources of airborne contaminants and identifying the worst-case chemical concentrations in various locations or processes. Selection of which employees or work locations should be sampled can help to characterize (confirm or refute) suspected areas of potential concern. # How to Sample A variety of methods are available to sample for diacetyl, 2,3-pentanedione, or other food and flavoring substances. These include ( 1) gas and vapor air methods, ( 2) methods to sample particulates in air, ( 3) direct reading and real-time methods for gases/vapors and for particulates, ( 4) evacuated container sampling methods, ( 5) particle size distribution methods, ( 6) bulk air methods, and ( 7) bulk material methods. Selecting appropriate sampling and analytical methods and using professionally accepted techniques maximize the validity of measurements of flavoring compounds in the work environment. While the state of the art in measuring diacetyl and 2,3-pentanedione continues to evolve, the methods with the most veracity at the time of publication of this document are OSHA Methods 1012 and 1013 for diacetyl and OSHA Method 1016 for 2,3-pentanedione. Some sampling and analytical methods for diacetyl, 2,3-pentanedione, and other flavoring compounds published by NIOSH at http:// www.cdc.gov/niosh/nmam/ and by OSHA at . html are described in detail in Chapter 2 of this document and are presented in Appendices A-E. These methods include recommendations on sampling media, flow rate, duration, storage, shipment, sampling and analytical equipment, and procedures. A typical protocol for measuring diacetyl and 2,3-pentanedione is presented in Appendix I. To minimize the likelihood of inaccurate results, sampling equipment should be maintained in reliable working order through proper care and maintenance. All equipment should be regularly inspected and cleaned; sampling pumps should be calibrated before and after each use. Because differences in pressure drop across the sampler affect flow rate, each sampling pump should be precalibrated and postcalibrated with the specific type of sampling media used for sampling. Careful record keeping in the field is also important. A detailed description of the work tasks conducted and the processes and materials involved is essential. Pertinent information such as sampling location, job category or task, air temperature, relative humidity, and possible interfering compounds in air should be documented. To avoid confusion in the laboratory, samples should be carefully labeled and accompanied by accurate paperwork. The exact sampling duration should be known to accurately calculate the sampled volume. Determining the sampling duration from the recorded start and stop times assumes that the pump functions consistently over the entire sampling period. Occasional spot checks to verify proper sampler operation should be made throughout the sampling period. Personnel performing field sampling should not overlook quality assurance procedures. The field sampling parameters, such as calibration checks and accurate timing, often affect precision and accuracy of the final result more than the measurement's parameters. Field personnel should devote time to learning the sampling and analytical methods and sampling equipment operation procedures prior to arriving at the sampling site. These methods usually specify the sampling media to be used, the correct flow rate and sample volume, as well as special precautions of sample handling, shipping, and possible interferences. Because many modern analytical techniques are extremely sensitive, care should be taken to avoid contaminating field samples. Samples should not be stored or shipped with bulk materials that might spill or otherwise contaminate the field samples. The glassware or other containers used in sampling and shipping should be cleaned as recommended in the analytical method. For many sampling methods, the analytical laboratory requires submission of a specific number of blank samples with each set of samples to be analyzed; this number of samples is specific to the method. Blanks are used to mitigate the potential for unrecognized contamination due to media or sample handling . The two types of sample blanks are field blanks and media blanks. Field blanks are unopened new samplers or media taken to the sampling site and handled in every way like the actual samples, except that no air is drawn through them. Media blanks are simply unopened new samplers or media that are submitted to the laboratory with the samples (these blanks are not usually taken to the field). Additional blind field blanks, labeled as field samples, should be sent along with the field samples as a further check on the analysis. Another occasionally used quality control practice is to include spiked samples-samples with known amounts of flavoring substance addedalong with the other field samples sent to the laboratory for analysis. These spiked samples are often prepared by a separate laboratory and then included with the other field samples sent to the analytical laboratory. They are labeled as field samples so that the analytical laboratory is blinded to their identity as spiked samples. The variety of types of direct-reading methods available for monitoring specific gases and vapors, as well as general contaminant concentration, is large and expanding. Detector tubes (short-term and long-term), also referred to as colorimetric indicator tubes, are widely used sampling devices for obtaining immediate, quantitative measures of gas or vapor concentrations in air. Also, aerosol monitors, integrating passive monitors for certain gases, and portable instrumentation for gas chromatography or infrared spectroscopy, are becoming more commonly used for measuring exposures to flavoring compounds . Many direct-reading instruments now used for personal or area measurements have evolved from laboratory or process control instruments. These types of monitoring techniques have significant advantages, although to date none of these methods has been validated for monitoring diacetyl, 2,3-pentanedione, or other flavoring compounds in the work environment. # When to Sample Because of the considerable variation in exposure during the production of food or flavoring products, individuals conducting air sampling should coordinate with plant management to ensure that sampling is conducted when food or flavoring products of particular interest are being manufactured. Sampling several products or production runs may be necessary to better characterize exposures. Additionally, some products may be produced infrequently, and production schedules may change rapidly, so the timing of sampling can be challenging. Exposure monitoring should be conducted whenever changes in production processes, controls, work practices, or other conditions indicate a potential change in exposure conditions. In order to determine compliance with STEL criteria, sampling should be done during tasks that are considered likely to produce the highest short-term exposures. A series of sequential or overlapping samples can be taken for 15-minute intervals to determine the maximum exposures. # How Long to Sample In general, TWA exposures should be determined by collecting samples over a full work shift, for comparison with OELs and other toxicological data. Information on allowable sampling duration is given in validated sampling and analytical methods; depending on the method, in some instances it is necessary to collect multiple shorter-term samples to obtain an integrated full work-shift sample. Work shifts that exceed 8 hours require extended sampling duration. When the potential for exposure to diacetyl, 2,3-pentanedione, or flavoring compounds is sporadic throughout a work shift, shortterm or task-based sampling may be needed to replace or supplement full-shift sampling. Short-term samples for diacetyl and 2,3-pentanedione can be collected for 15 minutes in duration. Data from these short-term measurements and other task-based sampling can provide valuable perspective on task-based exposures and on the effectiveness of various control techniques. They can also be used to evaluate exposures relative to a short-term exposure limit such as the STEL values recommended for diacetyl and 2,3-pentanedione. # How Many Samples to Collect The numbers of samples to collect is important in that it relates to the confidence that can be placed in the exposure estimate. The number of samples needed for an accurate and reliable exposure assessment depends on the purpose of the sampling, the number of processes, work tasks or jobs to be evaluated, the variability inherent in the measured contaminant concentrations, sampling and analytical variability, and other factors. In most instances, time and budget constraints are major factors determining sample size. Statistical methods are available for calculating the minimum sample size needed to characterize a maximum risk employee exposure subgroup or to achieve a set degree of statistical confidence in the representativeness of an exposure measurement . Recently, exposure control banding and Bayesian decision analysis have been used to help support exposure assessment decisions with limited sample numbers . As stated above, a monitoring strategy should assess the effectiveness of various methods used to control airborne flavoring substance concentrations and to identify areas or tasks that are associated with higher exposures to flavoring substances. A common technique for evaluating the effectiveness of controls is to compare the outcome of environmental measurements made prior to the installation of those controls with measurements made following that installation. A control technique can be judged, for example, to be 50% efficient if the post-installation contaminant concentration is half of the pre-installation concentration. The TWA and STEL measurements of exposure to flavoring substances, made with the collection of personal breathing zone air samples, can be used to assess employees' exposures relative to an OEL. As discussed in the section of this document describing the development of the RELs, an 8-hour TWA measurement in excess of 5 ppb diacetyl or 9.3 ppb 2,3-pentanedione indicates that the employee in question was at a greater risk of developing occupationally induced illness. A 15-minute short-term exposure in excess of 25 ppb diacetyl or 31 ppb 2,3-pentanedione during task based personal sampling would be interpreted similarly. If monitoring indicates that exposures have increased over past measurements, or exposures exceed the selected OELs, a thorough investigation of controls to identify problems and guide remedial actions is needed. Regular routine monitoring (e.g., yearly) will help ensure the continued effectiveness of controls. Employers should monitor employees in such a fashion that he has a high degree of confidence that a very high percentage of actual daily exposures are below the REL. In statistical terms, the employer should try to attain 95% confidence that no more than 5% of employee days are over the REL. # Notification of Employees Employers should establish procedures for the timely notification of employees of their environmental monitoring results or results that represent their work group, any identified exposure hazards, and any subsequent actions taken based on this monitoring to reduce their exposures. Employees should be informed about any products or processes that may generate high concentrations of diacetyl, 2,3-pentanedione, or other flavoring compounds and any PPE and changes in work practices needed in response. Employers should ensure that employees understand this information and their role in helping to maintain a healthful workplace. Information should be conveyed in English and other languages as needed to ensure that all employees receive and comprehend this information. # Research Needs In this chapter, knowledge gaps pertaining to diacetyl, 2,3-pentanedione and flavoringinduced lung disease are identified. General areas of need include environmental research to better measure and control exposures to flavoring substances, clinical and field studies on the epidemiology of flavoring-induced diseases, research related to personal protective equipment, and toxicological studies concerning the etiology of flavoring-related diseases. # Chromatography Team Industrial Hygiene Chemistry Division OSHA Salt Lake Technical Center The purpose of this evaluation was to develop a sampling procedure for diacetyl that gave a better storage stability than did the NIOSH Method 2557, which used SKC Anasorb CMS as the sampling medial .The NIOSH method requires that the samples be refrigerated immediately after sampling, and the analysis be performed within 7 days. A more stable sampling media was desired for OSHA samples. The following media were tested at SLTC but all gave poor storage stability: coconut shell charcoal Lot 2000, 4-tert-butylcatechol coated charcoal, XAD-7, and OVS-7. Silica gel tubes (150mg/75 mg) were tried next and had an average storage recovery of 94.9% for samples stored at room temperature for 14 days. A sampling train of two silica gel tubes in series was necessary because a significant amount of the diacetyl was found on the smaller, backup section of the first tube in the retention study. A second tube in series insures that all of the sample will be collected on the sampling train . The desorbing solvent of 95:5 ethyl alcohol:water with 0.25 µL/mL p-cymene internal standard gave an average recovery of 99.1 % over the concentration range of 26.5 to 529 µg of diacetyl. 1.1.2 Toxic Effects.2 (This section is for information only and should not be taken as the basis of OSHA policy.) In 2002, the CDC published a report in the Morbidity and Mortality Weekly Report (MMWR) on employee exposures at a microwave popcorn factory in Missouri. A group of former employees had developed fi xed airways obstructive lung disease. All eight had a respiratory illness that resembled a rare lung disease called bronchiolitis obliterans. Some of the cases had such severe illness they were candidates for lung transplants. The main volatile organic chemical (VOC) found in the workplace atmospheres was diacetyl, which was used in a mixture of heated soybean oil, salt and flavorings to impart a butter flavoring to the popcorn. During NIOSH 's investigation of the facility, diacetyl was chosen as a marker compound for voe exposure. The MMWR publication reported that the geometric mean air concentration of diacetyl was 18 ppm in the room where the mixing tank was located, 1.3 ppm in the packaging area, and 0.02 in other areas of the plant. Of the eight former employees with severe respiratory illness, four were mi xers and four worked in packaging. The report concluded that "workers exposed to flavorings at microwave popcorn factories are at risk for developing fi xed obstructive lung disease." The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equal descending increments of analyte, such that the highest sampler loading was 3.7 µg diacetyl. This is the amount spiked on a sampler that would produce a peak approximately 3 times the response for a sample blank. These spiked samplers were analyzed with the recommended analytical parameters, and the data obtained used to calculate the required parameters (standard error of estimate and slope) for the calculation of the DLOP. The slope was 13.89 and the SEE was 41.82. The RQL is considered the lower limit for precise quantitative measurements. RQL is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to 125% of the analyte is recovered. The DLOP and RQL were 0.902 µg and 3.01 µg respectively Below is chromatogram of the RQL level. # .a All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. 2.1 Apparatus 2.1.1 Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. 2.1.2 Silica gel tubes: glass tube with both ends flame sealed, 70 mm x 6-mm i.d. containing 2 sections of 20/40 mesh silica gel separated by a 2-mm portion of urethane foam. The adsorbing section contains 150 mg of silica gel, the backup section 75 mg. A 3-mm portion of urethane foam is placed between the outlet end of the tube and the backup section. A plug of silane-treated glass wool is placed in front of the front section tubes or equivalent was used in this evaluation. # Reagents None required . # Technique 2.3.1 Immediately before sampling, break off the ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use tube holders to minimize the hazard of broken glass. All tubes should be from the same lot. 2.3.2 Connect two tubes in series to the sampling pump with flexible tubing. The smaller sections of the silica gel tubes should be positioned nearer the sampling pump. The tube closer to the pump is used as a backup. A minimum amount of tubing is used to connect the two sampling tubes together. Position the sampling pump, tube holder and tubing so they do not impede work performance or safety. Draw the air to be sampled directly into the inlet of the tube holder. The air being sampled is not to be passed through any hose or tubing before entering the sampling tube. 2.3.4 After sampling for the appropriate time, remove the adsorbent tube and seal it with plastic end caps. Seal each sample end-to-end with an OSHA-21 form as soon as possible. 2.3.5 Submit at least one blank sample with each set of samples. Handle the blank sample in the same manner as the other samples except draw no air through it. 2.3.6 Record sample air volumes (liters), sampling time (minutes) and sampling rate (ml/min) for each sample, along with any potential interferences on the OSHA-91A form. 2.3.7 Submit the samples to the laboratory for analysis as soon as possible after sampling. If delay is unavoidable, store the samples at refrigerator temperature. Ship any bulk samples separate from the air samples. # .4 Extraction efficiency The extraction efficiency was determined by liquid-spiking silica gel tubes with diacetyl at 0.1 to 2 times the target concentration. These samples were stored overnight at ambient temperature and then extracted for 30 minutes with occasional shaking and analyzed. The mean extraction efficiency over the studied range was 99.1 %. The wet extraction efficiency was determined at the target concentration by liquid spiking the analyte on the front, larger, section of the first silica gel tube of the sampling train of two silica gel tubes in series, and drawing 3 L humid air (absolute humidity of 15.9 mg/L of water, about 80% relative humidity at 22.2oq through them. The mean recovery for the wet samples was 100.2 % Based on the data collected in this evaluation, 3-l air samples should be collected at a sampling rate of 0.05 l/min for 60 minutes. 2.8 Interferences (sampling) 2.8.1 There are no known compounds that will severely interfere with the collection of diacetyl. 2.8.2 Suspected interferences should be reported to the laboratory with submitted samples. # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan. Avoid skin contact and inhalation of all chemicals and review all appropriate MSDSs. # Apparatus 3.1.1 A gas chromatograph equipped with an FID. For this evaluation, an Agilent 6890 Plus gas Chromatograph equipped with a 7683 Automatic Sampler was used. 3.1.2 A GC column capable of separating diacetyl from the desorption solvent, internal standard and any potential interferences. A 60-m x 0.32-mm i.d. capillary DBWAX with a 0.5-µm df (J&W Scientific) was used in the evaluation. 3.1.3 An electronic integrator or some other suitable means of measuring peak areas. A Waters Millennium 32 Data System was used in this evaluation. 3.1.4 Amber glass vials with poly(tetrafluoroethylene)-lined caps. For this evaluation 2-ml vials were used. 3.1.5 A dispenser capable of delivering 1.0 ml of desorbing solvent to prepare standards and samples. If a dispenser is not available, a 1.0-ml volumetric pipet may be used. 3.1.7 Volumetric flasks -10-ml and other convenient sizes for preparing standards. 3.2.4 The extraction solvent was 0.25 µl/ml p-cymene in ethyl alcohol:water (95:5). 3.2.5 GC grade nitrogen, air, and hydrogen. 3.3 Standard preparation 3.3.1 Prepare working analytical standards by injecting micro liter amounts of diacetyl into volumetric flasks containing the extraction solvent. An analytical standard at a concentration of 0.530 mg/ml (5.3 µL/10 ml) is equivalent to 50 ppm based on a 3-l air volume. Stock standards were stored in amber vials at refrigerated temperature for stability. 3.3.2 Bracket sample concentrations with working standard concentrations. If sample concentrations are higher than the concentration range of prepared standards, prepare and analyze additional standards, at least as high a concentration as the highest sample, to ascertain the linearity of response, or dilute the sample with extracting solvent to obtain a concentration within the existing standard range. The range of standards used in this study was from 0.00132 to 0.60 mg/ml analyze additional standards, at least as high a concentration as the highest sample, to ascertain the linearity of response, or dilute the sample with extracting solvent to obtain a concentration within the existing standard range. The range of standards used in this study was from 0.00132 to 0.60 mg/ml. 3.4 Sample preparation 3.4.1 Remove the plastic end caps from the sample tubes and carefully transfer both adsorbent sections from front tube and each section of backup tube to separate labeled 2-ml amber glass vials. Discard the glass tube and glass wool plug. 3.4.2 Add 1.0 ml of extraction solvent to each vial using the same dispenser as used for preparation of standards. 3.4.3 Immediately seal the vials with poly(tetrafluoroethylene)-lined caps. 3.4.4 Place vials on shaker and agitate for 60 minutes. (Y = 696 x -336) maa 3.6.1 Any compound that produces a GC response and has a similar retention time as the analyte is a potential interference. If any potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate an interference from the analyte. 3.6.2 When necessary, the identity or purity of an analyte peak may be confirmed by mass spectrometry or by another analytical procedure. The mass spectrum in # Calculations The amount of analyte per sampler is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for extraction efficiency. This total amount is then corrected by subtracting the total amount (if any) found on the blank. The air concentration is calculated using the following formulas. To obtain adequate sensitivity for this method, it was necessary to derivatize the acetoin and diacetyl. 2, was the first derivatizing agent tried, but DNPH can react with both ketone and a-hydroxy ketones 6, and while it initially formed unique derivatives of acetoin and diacetyl by reacting with the first ketone group, it eventually reacted also with the alcohol group on acetoin and the second ketone group on diacetyl, forming the same derivative. In EPA Method 556. 1 0-pentafluorobenzyl hydroxy_lamine hydrochloride (PFBHA) was used to derivatize ketone and aldehyde groups. 7 Unique derivatives of acetoin and diacetyl are formed by reacting them with PFBHA. The first ketone group on diacetyl reacts within four hours with PFBHA, but the second ketone group takes 36 hours to reach completion. Acetoin reacts within 3 hours. In this method, samples are extracted and derivatized in an extraction solution containing PFBHA. This is accomplished by first rotating the samples for 60 min and then allowing the samples to stand at room temperature for an additional 36 hours for the derivatization reaction to reach completion. This method is designed for low air concentrations of acetoin, diacetyl, and potential interferences. If high exposures are anticipated, use OSHA Method 1013 8 or increase 6 Smith, M., March, J.;March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.;John Wiley & Sons Inc.: New York, 2001, p 1193. EPA Method 556.1 Determination of Carbonyl Compounds in Drinking Water by Fast Gas Chromatography, 1999 NIOSH Health Hazard Evaluations (HHE) of microwave popcorn manufacturing plants found fixed airway obstruction, in some cases, consistent with bronchiolitis obliterans in some employees. 9 Acetoin, diacetyl, acetic acid, acetaldehyde, and 2-nonanone were amongst the chemicals found by NIOSH in several popcorn manufacturing plants. 10 Diacetyl was found to be present in all workplaces where the bronchiolitis obliterans was observed, and acetoin was found in some of the workplaces. Animal toxicology studies were performed by NIOSH with diacetyl, or butter flavorings containing diacetyl. Respiratory tract damage, including necrosis of the nasal and tracheal epithelium, and death were reported in rodents exposed to diacetyl, and butter flavorings containing diacetyl, at an air concentration of approximately 200 ppm of diacetyl for 6 hours. Mice exposed to 200 and 400 ppm diacetyl via inhalation for 6 hours per day over 5 days had the following health effects: death, acute necrotizing rhinitis, and erosive or necrotizing laryngitis. Mice exposed to 200 and 400 milligrams per kilogram (mg/kg) diacetyl via oropharyngeal aspiration for 6 hours per day over 5 days had bronchiolar fibrosis and death. Rats exposed to butter flavoring vapors containing 300 ppm diacetyl for 6 hours had epithelial injury in the nasal passages and pulmonary airways. ; 2,3-butanolone; 2-butanone, 3-hydoxy-; 2-butanol-3-one; dimethylketol; y-hydroxy-{3-oxobutane; 3-hydroxybutan-2-one; 3-hydroxy-2-butanone; 1-hydroxyethyl methyl ketone; methyl acetyl carbinol A624 513-86-0 (monomer); 23147-57-1 (dimer/ 3 148 Acetyl Methyl Carbinol Dimer, 2008. Department of Health and Human Services, National Institutes of Health, National Center for Biotechnology Information. http:llpubchem.ncbi.nlm.nih.govlsummarylsummary.cgi?cid= 90884&1oc=ec_rcs (accessed 311712008). 24 Material Safety Data Sheet: Acetoin, 2008. The Good Scents Company Web site. lmsds/md102388.html (accessed 311712008 # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # 1 Apparatus Samples are collected with two tubes in series. The tubes consist of 110-cm x 7-mm o.d. glass sampling tubes packed with one section (600 mg) of specially cleaned and dried silica gel. From the front to back, the sampler consists of a silane-treated glass wool plug, glass fiber filter, 600 mg specially cleaned silica gel, and a second silane-treated glass wool plug. The silica gel should be cleaned and dried as described in Appendix A of OSHA Method 1013. 31 The tubes used in this evaluation were labeled front and back tube. The front tube is connected to the back tube with a piece of tubing to form the sampling train. For this evaluation commercially prepared sampling tubes containing the specially dried silica gel were purchased from SKC, Inc. (Catalog no. 226-183, lot no. CPM112907-001). Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. Use aluminum foil, opaque tape, or a tube holder, such as SKC, , to protect samples from light. # Reagents None required # Technique Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking the tube. Use tube holders to minimize the hazard of broken glass and to protect tubes from light exposure during sampling. All tubes should be from the same lot. A sampling train is created by attaching two tubes in series with a small section of tubing so that the front opening of the back tube is close to the back opening of the front tube. The front of each tube contains glass wool followed by a glass fiber filter, and the back of the tube contains only the glass wool. ) diacetyl with an average relative humidity (RH) of 80% at 23 °C. The samples were collected at 0.05 Umin. The 5% breakthrough air volumes were determined to be 12.1 L for diacetyl and greater than 24 L for acetoin. There was no acetoin or diacetyl on the back-up tube when a 15 min sample was taken at 0.2 Umin. The 5% breakthrough air volumes for a flow rate of 0.2 Umin were determined to be 11.98 L for diacetyl and greater than 13 L for acetoin. Extraction efficiency (Section 4. 8) It is the responsibility of each analytical laboratory to determine the extraction efficiency of the analyte from the media because the adsorbent material, internal standard, reagents and laboratory techniques may be different than those listed in this evaluation and influence the results. The mean extraction efficiencies from dry silica gel over the range of RQL to 2 times the target concentration were: 102.0% (0.022 to 3.28 µg/sample) for acetoin and 97.6% (0.01 to 3.16 µg/sample) for diacetyl. The extraction efficiency was not affected by the presence of water. Extracted samples remain stable for at least 24 h. Recommended sampling time and sampling rate Sample with dried silica gel tubes for up to 180 min at 0.05 Umin (9 L) to collect TWA (long term) samples, and for 15 min at 0.2 Umin (3 L) to collect short-term samples. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limits for dried silica gel tubes for a 15 min sample taken at 0.2 Umin are 0.0044 ppm (0.016 mg/m 3 ) for acetoin and 0.0042 ppm (0.015 mglm Interferences, sampling (Section 4.9) Retention efficiency The mean retention efficiency was 96. 7% for acetoin and 96. 9% for diacetyl when dried silica gel tubes containing 0.819 µg of acetoin and 0.808 µg of diacetyl were allowed to sample 6. 75 L of contaminant-free air having an average relative humidity of 80% at 23 °C. (Section 4.9) # Low humidity The ability of dried silica gel tubes to collect the analytes from a relatively dry atmosphere was determined by sampling an atmosphere containing two times the target concentration and at an average relative humidity of 20% RH at 23 °C. The mean recoveries (% of theoretical) were 98. 7% for acetoin and 98.5% for diacetyl. (Section 4.9) # Low concentration The ability of dried silica gel tubes to collect the analytes at low concentrations was tested by sampling an atmosphere at 0. 1 times the target concentration with at an average relative humidity of 80% RH at 23 °C. The mean recoveries (% of theoretical) were 99.0% for acetoin and 98.4% for diacetyl. (Section 4.9) Sampling interference The ability of dried silica gel tubes to collect the analyte when other potential interferences are present was tested under two separate series of tests. The first test was an atmosphere similar to ones found at some popcorn manufacturing plants consisting of acetoin and diacetyl at the target concentration with an interference mixture of acetaldehyde, acetic acid, and methyl ethyl ketone at an average humidity of 80% at 23 °C. All three of these interferences can react with PFBHA. The concentrations of the analytes in this test atmosphere were: 0.051 ppm (0.184 mglm The concentrations of these interferences are much higher than would normally be expected in a food or flavoring manufacturing workplace. The PFBHA extraction solution needed to be modified to 18 mg/mL PFBHA (72. 1 µmoles/mL) to insure that there was enough PFBHA to derivatize all the analytes. These interferences and acetoin react fully within 4 hours of extraction, but the diacetyl requires 36 hours to fully react. These three test atmospheres each contained the one of the followinq concentrations of interference: 190 ppm (350 mg/m 3 ) acetaldehyde, 9.49 ppm (23.3 mglm) acetic acid, or 190 ppm (560 mglm 3 ) methyl ethyl ketone. These three compounds were chosen because they can collect onto the dried silica gel tubes and can react with the PFBHA. For each test, three sampling trains had contaminated air (air containing the analytes and an interference) drawn through them at 0.05 Umin for 180 min for each test. All of the samples were immediately analyzed. The average recoveries (% of theoretical) with 190 ppm acetaldehyde were 97.8% for acetoin and 95.5% for diacetyl. The average recoveries (% of theoretical) with 9.49 ppm acetic acid were 97.3% for acetoin and 32 Burright, D.;Chan, Y.;Elskamp, C.;Rose, M. Evaluation Guidelines For Air Sampling Methods Utilizing Chromatographic Analysis, 1999. U.S. Department of Labor, Occupational Safety and Health Administration Web site. .govldtslsltclmethodslchromguidelindex.html (accessed 311512008). 11 of 34 T-1012-FV-01-0811-M 98. 2% for diacetyl. The average recoveries (% of theoretical) with 200 ppm methyl ethyl ketone were 98.4% for acetoin and 97. 6% for diacetyl. These interferences were not a sampling interference, but under normal sample analysis, these levels of interferences would be analytical interferences. (Section 4. 9) Light Acetoin and diacetyl are light-sensitive. The interference of light during sampling was tested using three foil-wrapped sampling trains and three uncovered sampling trains. An atmosphere containing twice the target concentration at an average relative humidity of 78% at 23 °C was sampled for 180 min at 0. 05 Umin, and the samples were extracted that day. The average recovery for acetoin of the foil-wrapped samplers was 98.5% and the uncovered samplers had an average recovery of 93. 9%. The average recovery for diacetyl of the foil-wrapped samplers was 98.9% and the uncovered samplers had an average recovery of 94.3%. An additional three sampling trains were collected at the same time, and were protected from the light by aluminum foil. After collection, these samplers had the foil removed and were placed on the counter at ambient temperature under room light. These samples were analyzed 24 h after sampling during which they were exposed to the room light for 14 of the 24 h. The average recoveries were 81.3% for acetoin and 80.0% for diacetyl. Light is a significant interference; therefore, both tubes in the sampling train need to be covered by aluminum foil or opaque tape during and after sampling. (Section 4.9) Powder form The powder form of acetoin and diacetyl tested consisted of starch coated with acetoin and diacetyl. Three tests were performed on this powder. The first consisted of a sampling train of a pre-weighed PVC filter in a conical cassette in series with two dried silica gel tubes. The two dried silica gel tubes were used to collect any vapors of acetoin and diacetyl which would strip off from the powder. Known amounts of the powder were placed onto the PVC filter, and 9 L of air at an average relative humidity of 78% at 22 °C were pulled through the sampling trains at 0.05 Umin. The recovery of acetoin and diacetyl on the pre-weighed PVC filters was 0% to 1.9% for acetoin and 0% to 2.3% for diacetyl. The recovery on the dried silica gel tubes was 96.6% for acetoin and 97.8% for diacetyl. The acetoin and diacetyl recoveries were calculated from the percentages obtained from analysis of the powder and the amounts of powder weighed out. The second and third tests consisted of a sampling train of two dried silica gel tubes in series, with the powder spiked on the front glass wool of the front tube. The two tests had 9 L of air drawn through the sampling trains at 0.05 Umin, the first test used air at an average relative humidity of 20% at 22 °C, and the other test used air at an average relative humidity of 78% at 22 °C. At 20% RH most of the acetoin and diacetyl were found on the front glass wool and glass fiber filter, but at 78% RH most of the acetoin and diacetyl were found on the dried silica gel beds. These tubes can collect particulates, but cannot be used as a particulate sampler at 0.05 Umin. (Section 4.9) # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan . Avoid skin contact and inhalation of all chemicals and review all MSDSs before beginning this analytical procedure. # 1 Apparatus Gas chromatograph equipped with an electron capture detector. An Agilent Model 6890 GC equipped with a Chemstation, an automatic sample injector, and a µ-electron capture detector (µECO) was used in this evaluation. 33 Occupational Exposure to Hazardous Chemicals in Laboratories. Code of Federal Regulations, Part 1910.1450, Title 29, 2003. and the data obtained were used to determine the required parameters (slope and standard error of estimate) for the calculation of the DLAP. For acetoin, the slope and standard error of estimate, respectively, were 3818 and 219. For diacetyl, the slope and standard error of estimate, respectively, were 9595 and 366. .l!l § 0 (.) "' @ <( # Vi' .l!l § 0 (.) "' @ Ten samplers were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a sample blank. These spiked samplers and the sample blank were analyzed with the recommended analytical parameters, and the data obtained used to calculate the required parameters (slope and standard error of estimate) for the calculation of the DLOP. For acetoin, the slope and standard error of estimate, respectively, were 46. 9 and 227. For diacetyl,the The standard error of estimate was determined from the linear regression of data points from standards over a range that covers 0.25 to 2 times the TWA target concentration. Calibration curves were constructed and shown in Section 3. 5. 2 from the three injections each of five standards. The standard errors of estimates were 0.019 µg for acetoin and 0.052 µg for diacetyl. Storage samples for acetoin and diacetyl were prepared using dried silica gel tubes from controlled test atmospheres using the recommended sampling conditions. The concentrations were 0.051 ppm (0.184 mg!m 3 ) acetoin and 0.050 ppm (0.180 mg/m 3 ) diacetyl at an average relative humidity of 80% at 23 °C. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Recoveries are not corrected for extraction efficiency. Storage studies were also performed using tubes packed with 4001200 mg sections of dried silica gel, at an average relative humidity of 22% RH at 23 °C to determine the effects of low humidity on storage and on migration. The concentrations were 0.051 ppm (0.184 mg/m 3) acetoin and 0. 050 ppm (0. 180 mg/m 3 ) diacetyl. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 22% RH ambient and refrigerated storage samples showed no migration for acetoin or diacetyl. Recoveries are not corrected for extraction efficiency. At the beginning of this method, the SKC 226-183 tubes were available as a 4001200 mg tube. Migration studies showed that it would be necessary to use two tubes in series, so subsequent tubes were packed as a single 600 mg tube. A 600 mg section makes it easier for the analyst to prepare the samples for extraction. Migration occurs when the analyte equilibrates between the two sections of the tube after collection. There is more migration with higher humidities, due to the higher amounts of water collected. Using 4001200 mg dried silica gel tubes, at 80% RH acetoin showed no migration but the diacetyl refrigerated samples at day 18 showed a 4. 5% migration and ambient showed 15. 2% migration. Based on these results, a single 4001200 mg dried silica gel tube should not be used for sampling. A capability of collection at higher flow rates with a 15 minute short term sample was tested for breakthrough. A test atmosphere was dynamically generated with an average relative humidity of 79% at 23 °C at concentrations of 0.101 ppm (0.365 µglm 3) acetoin and 0.101 ppm (0.355 mg/m 3 ) diacetyl. A sampling train consisting of two dried silica gel tubes (4001200 mg) in series was used to test the capacity. Three sampling trains at each flow rate of 0.1 Umin or 0.2 Umin were tested. There was no acetoin or diacetyl on the second tube of any of the sampling trains. Since the short term sampling may be a time of higher exposure, two higher concentrations were also tested. The first was 0.541 ppm (1.95 ) diacetyl at an average relative humidity of 79% at 23 °C. In all of these tests there was no acetoin or diacetyl on the back-up tube of the sampling train. # 8 Extraction efficiency and stability of extracted samples The extraction efficiency is dependent on the extraction solvent as well as the internal standard. The extraction solvent used for this evaluation consisted of 95:5 ethyl alcohol:water with 2 mg/mL PFBHA and 20 µg/mL 4-bromobenzyl bromide. Other extraction solvents or internal standards may be used provided that the new extraction solution or internal standard is tested. The new extraction solvent or internal standard should be tested as described below. # Extraction efficiency The extraction efficiencies of acetoin and diacetyl were determined by liquid-spiking four dried silica gel tubes, at each concentration level, with the analyte from the RQL to 2 times the target concentration. These samples were stored overnight at ambient temperature and then analyzed. The samples need to be extracted on a rotator for 1 hour, and then allowed to set at room temperature for 36 hours. Do not use a shaker as recoveries will be much lower (Table 4.8.3). The mean extraction efficiency over the working range from the RQL to 2 times the target concentration is 102.0% for acetoin and 97.6% for diacetyl. The extraction efficiency for the wet samplers and samplers extracted on the shaker were not included in the overall mean because it would bias the results. The test of wet samplers was performed to determine if the amount of water that would collect under high humidity conditions at the recommended air volume would affect the extraction efficiency. Wet samplers were prepared by sampling humid air having an average relative humidity of about 80% at 23 °C for 180 minutes at 0. 05 Umin and then liquid-spiking the sampler with the analyte. The dried silica gel tube (600 mg) collects 140 mg water at 78% RH and 23 °C when sampled for 9 L. # Stability of extracted samples The stability of extracted samples was investigated by reanalyzing the target concentration samples 24 h after initial analysis. After the original analysis was performed, two autosampler vials were recapped with new septa while the remaining two retained their punctured septa. The samples were reanalyzed with fresh standards. The average percent change was +O. 7% for acetoin and +1.6% for diacetyl when samples were resealed with new septa and -1.1% for acetoin and +0.3% for diacetyl when samples retained their punctured septa. Each septum was punctured 5 times for each analysis. The test was performed at room temperature. # of 34 T-1012-FV-01-0811-M atmosphere containing twice the target concentration at an average humidity of 78% at 23 °C was sampled for 180 min at 0. 05 Umin, and the samples were extracted that day. An additional three sampling trains were collected at the same time, and were protected from the light by aluminum foil. After collection, these samplers had the foil removed and were placed on the counter at ambient temperature under room light. These samples were analyzed 24 h after sampling during which they were exposed to the room light for 14 of the 24 h, and the recoveries were 80. 7%, 84. 7%, and 78.5% for acetoin and 79.3%, 82.4%, and 78.4% for diacetyl. # Powder form The powder form of acetoin and diacetyl tested consisted of starch coated with acetoin and diacetyl. Three tests were performed on this powder. The first consisted of a sampling train of a pre-weighed (tared) PVC filter in a conical cassette in series with two dried silica gel tubes. Two dried silica gel tubes were used to collect any vapors of acetoin and diacetyl which would be stripped off of the powder. Known amounts of the powder were placed onto the PVC filter, and 9 L of air at an average relative humidity of 78% RH and 22 °C were pulled through the sampling trains at 0. 05 Umin. The recovery of acetoin and diacetyl on the pre-weighed PVC filters was 0% to 1.9% for acetoin and 0% to 2.3% for diacetyl, with larger amounts found on the PVC filters that were spiked with larger amounts of powder. Most of the acetoin and diacetyl was stripped from the starch and collected on the dried silica gel tubes. The average recovery found on the dried silica gel tubes was 96. 6% for acetoin and 97. 8% for diacetyl (Table 4.9.4). The acetoin and diacetyl theoretical weights were calculated from the percentages obtained from analysis of the powder and the amounts of the powder weighed out. The second and third tests consisted of a sampling train of two dried silica gel tubes in series, with the powder spiked on the front glass wool of the front tube. The two tests had 9 L air drawn through the sampling trains at 0.05 Umin, the first test used air at an average relative humidity of 20% at 22 °C, and the other test used air at an average relative humidity of 78% at 22 °C. At 20% RH most of the acetoin and diacetyl were found on the front glass wool and glass fiber filter, but at 78% RH most of the acetoin and diacetyl were found on the dried silica gel beds. The sampling trains with 78% RH air drawn through them had the highest amounts of acetoin and diacetyl on the glass wool and filter on the tube spiked with the highest amount of powder, which may be due to the size of the clump of powder weighed out (Table 4. 9. 5 and 4.9.6). Material Safety Data Sheet: Diacetyl, Chemwatch, Victoria, Australia (accesed 311712008). Sheet: 2,3-Butanedione, https:llfscimage.fishersci.comlmsds/03275.htm (accessed 311712008). Material Safety Data Sheet: 2,3-Butanedione, http:llwww.chemservice.com/msds/msds_detail.asp?catnum=0-816 (accessed 311712008). # Material Safety Data # 31of34 T-1012-FV-01-0811-M # . General Discussion For assistance with accessibility problems in using figures and illustrations presented in this method, please contact the Salt Lake Technical Center (SL TC) at (801) 233-4900. This procedure was designed and tested for internal use by OSHA personnel. Mention of any company name or commercial product does not constitute endorsement by OSHA. This procedure, Method 1013, was streamlined for monitoring low ppm levels, and Method 1012 6 was optimized for ppb levels. Both methods use two 600 mg silica gel sorbent tubes in series. Both methods have a recommended sampling time of 3 hours (9 L) and both use the same solvent for sample extraction. However, in Method 1012, acetoin and diacetyl are derivatized using 0-pentafluorobenzyl hydroxylamine hydrochloride. This derivatization results in a reliable quantitation limit approximately 10 times less than Method 1013. The disadvantage of derivatizing acetoin and diacetyl is that the derivatization step requires 36 hours; whereas, with this method sample preparation can be performed in 1 hour. Also, samples extracted and analyzed according to this procedure can then be derivatized and analyzed using Method 1012, if needed. The silica gel used in the sampler for this method, and for Method 1012, has been specially cleaned and dried as described in Appendix A. It was found that sampler capacity for diacetyl was not based on analyte concentration but limited by the amount of water remaining on the silica gel after cleanup and on the amount of water collected during sampling. In other words, the silica gel tube acts as a chromatography column and water elutes the collected diacetyl. By removing as much water as possible from the silica gel prior to sampling, the sampling volume for diacetyl can be increased because the time required to saturate the silica gel during sampling increases. Diacetyl was also found to gradually migrate within the sampling tube during storage resulting in the need to use a second tube in series during sampling in order to detect breakthrough. Acetoin has no capacity or migration issues on silica gel at the recommended sampling volume. The powder and liquid formulated forms of acetoin and diacetyl may contain oily compounds and other base materials such as maltodrextin. These materials could affect the extraction of acetoin and diacetyl from the silica gel. The sampler contains a front glass wool plug followed by a glass fiber filter that serves only to trap any of these materials before they enter the silica gel bed. Retention studies using a powder containing acetoin and diacetyl showed the acetoin and diacetyl can be stripped off the powder and collected on the silica gel. These studies demonstrate that the glass fiber filter is not an efficient collector for diacetyl and acetoin, and will not normally be analyzed (see OSHA Method 1012 7 , Section 4.9). Toxic effects (This section is for information only and should not be taken as the basis of OSHA policy.) Exposure to acetoin may result in skin, eyes, nose and throat irritation. Exposure to diacetyl "liquid or vapors can cause irritation to the skin, eyes, nose, and throat". "Animals exposed to diacetyl experienced damage to the nose and upper airways, including severe damage to cells lining the respiratory tract" and "NIOSH has reported that employees exposed to butter flavorings containing diacetyl are at risk of developing occupational lung diseases". 9 Diacetyl, and to some extent acetoin, may be responsible for the occurrence of a rare and potentially fatal lung disease, bronchiolitis obliterans, among workers in microwave popcorn manufacturing plants and flavor manufacturing plants. 10 Symptoms of bronchiolitis obliterans include cough, shortness of breath with exertion, and spirometry test results showing fixed airways obstruction. # Workplace exposure Acetoin has a somewhat creamy taste and a woody yogurt odor. It is used as an ingredient in yogurt, butter, milk and strawberry flavors. It occurs naturally in foods such as wines, chesses, fruits and vegetables. 14 Occupational exposures can occur by inhalation or skin contact in locations where it is produced, used as a food additive, or used to produce flavorings or aromas. Diacetyl has a strong butter odor in dilute form and a chlorine-quinone odor when concentrated. It is used as an ingredient to produce a butter flavor in many foods and beverages. It occurs naturally in alcoholic and nonalcoholic beverages, dairy products, fruits, plants, vegetables, meats, and natural aromas. 15 Like acetoin, occupational exposures to diacetyl can occur by inhalation or skin contact in locations where it is produced, used as a food additive, or used to produce flavorings or aromas. Recently, occupational exposure to butter flavorings in the production of microwave popcorn and in other industries has received much publicity. NIOSH has identified acetoin and diacetyl as useful indicator compounds that can be used to represent exposure to butter flavorings. Areas of special concern include flavor production rooms, areas where mixing/blending operations occur, packing/packaging operations, areas where flavors are handled openly, rooms where mixing tanks are located, quality control laboratories, and maintenance and cleaning operations. # Reproducibility Six samples collected from a controlled test atmosphere were submitted for analysis by the OSHA Salt Lake Technical Center. The samples were analyzed according to a draft copy of this procedure after 20 days of storage at refrigerated temperature. No individual sample result deviated from its theoretical value by more than the precision reported in Section 1 .2.5. (Section 4.6) # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # Apparatus Sampler: glass tube with both ends flame sealed, 110-mm x 7-mm i.d., containing a glass fiber filter and 1 section of 20140 mesh silica gel. From front to back, the sampling tube consists of a silane-treated glass wool plug, a glass fiber filter to collect particulate, 600 mg of silica gel and a second plug of silane-treated glass wool. The silica gel should be cleaned and dried as described in Appendix A. Sampling tubes are available for purchase through SKC, . Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. Use aluminum foil or a tube cover, such as SKC, Inc Tube Cover D (cat. no. 224-290), to protect samples from light. # Reagents None required # Technique Immediately before sampling, break the ends off of two flame-sealed glass tubes to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use a tube holder to minimize the hazard of broken glass and to protect samplers from light exposure during sampling. All tubes should be from the same lot. Connect the two silica gel sampling tubes in series, using the least amount of flexible tubing as possible between the sampling tubes, and then connect to a sampling pump with flexible tubing. The filter in the silica gel tubes should be positioned away from the sampling pump. The tube closer to the pump is used as a backup. Use a tube cover or wrap sampling tubes in aluminum foil to insure that both sampling tubes are protected from light exposure. Place the sampling tubes in a vertical position with the inlet in the breathing zone and position the sampling pump and tubing so they do not impede work performance or safety. Draw air directly into the inlet of the sampler. The air being sampled should not pass through any hose or tubing before entering the sampler. After sampling for the appropriate time, disconnect the tubes from the pump tubing and seal each tube with plastic end caps. Separately wrap each tube in aluminum foil and seal end-to end with a Form OSHA-21. Submit at least one blank sample with each set of samples. Handle the blank sample in the same manner as the other samples except draw no air through it. Record sample air volume (L), sampling time (min) and sampling rate (L/min) for each sample, along with any potential interferences on the Form OSHA-91A. Submit the samples to the laboratory for analysis as soon as possible after sampling. If a delay is unavoidable, store the samples in a refrigerator. Ship any bulk samples separate from the air samples. Sampler capacity (Section 4.7) The sampling capacity of the front tube was tested by sampling a dynamically generated test atmosphere of acetoin ( 3.58 mg/m 3 or 0.99 ppm) and diacetyl (3.55 mg/m 3 or 1.01 ppm) with an average relative humidity of 40% at 34 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of approximately 0.05 L/min for 270 min. The 5% breakthrough sampling time was determined to be 248 min for diacetyl. No breakthrough was observed for acetoin. (Note: In order to volatilize acetoin the test atmosphere generation conditions were modified slightly for this method evaluation as described in the second paragraph of Section 4.11.) Extraction efficiency (Section 4.8) It is the responsibility of each analytical laboratory to determine the extraction efficiency because the adsorbent material, reagents and laboratory techniques may be different than those listed in this evaluation and influence the results. The mean extraction efficiency for acetoin from dry silica gel over the range of RQL to 2 times the target concentration (0.33 to 31.0 µg per sample) was 92.9%. The extraction efficiency was not affected by the presence of water. The mean extraction efficiency for diacetyl from dry silica gel over the range of RQL to 2 times the target concentration (0.38 to 29.9 µg per sample) was 99.6%. The extraction efficiency was not affected by the presence of water. Extracted samples remain stable for at least 72 hr. Recommended sampling time and sampling rate Sample for up to 180 min at 0.05 L/min (9 L) to collect TWA (long-term) samples. Sample for up to 15 min at 0.2 L/min (3 L) to collect short-term samples. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limit is 0.032 ppm (0.12 mg/m 3 ) for acetoin and 0.035 ppm (0.12 mg/m 3 ) for diacetyl when 3 Lare collected. Interferences, sampling (Section 4.9) # Retention efficiency The retention efficiency for all samples was 100.6% of theoretical for acetoin and 96.6% for diacetyl, when samplers containing approximately 8.3 µg of acetoin and 8.1 µg of diacetyl were allowed to sample 6.75 L of contaminant-free air having an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 L/min. # Low humidity The collection efficiency for all samples was 100.7% of theoretical for acetoin and 101.5% for diacetyl, when the samplers were used to sample a test atmosphere containing two times the target concentration having an average relative humidity of 8% at 33 °C (absolute humidity of 2.82 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. # Low concentration The collection efficiency for all samples was 91.8% of theoretical for acetoin and 95.6% for diacetyl, when the samplers were used to sample a test atmosphere containing approximately 0.1 times the target concentration having an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. The collection efficiency for all samples when taking short term samples was 106% of theoretical for acetoin and 90.6% for diacetyl, when the samplers were used to sample a test atmosphere containing approximately 0.1 times the target concentration having an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Samples were collected at a sampling rate of0.2 Umin for 15 min. # Sampling interference The collection efficiency for all samples was 95.5% of theoretical for acetoin and 101.8% for diacetyl, when the sampler was used to sample a test atmosphere containing approximately one times the target concentration of acetoin and diacetyl and 2.59 mg/m 3 of 2-nonanone and 1.88 mg/m 3 of 2,3-pentanedione. The test atmosphere had an average relative humidity of 38% at 34 °C (absolute humidity of 14.1 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 181 min. Sampler exposure to light, particularly sunlight, during sampling will result in degradation of both acetoin and diacetyl. The recovery for all samples was 67 .0% of theoretical for acetoin and 6.43% for diacetyl, when the sampler was used to sample a test atmosphere containing approximately one times the target concentration of acetoin and diacetyl and then exposed to 3 h of direct sunlight (samples were covered during sampling). The test atmosphere had an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. See Section 4.9 for data on other light tests performed. # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan . Avoid skin contact and inhalation of all chemicals and review all appropriate MSDSs. # Apparatus A gas chromatograph equipped with an FID. For this evaluation an Agilent Technologies 6890 Plus Gas Chromatograph equipped with a 7683 Automatic Sampler and an Agilent tapered, deactivated, split, low pressure drop liner with glass wool (catalog no. 5183-4647). A GC column capable of separating acetoin and diacetyl from the desorption solvent, internal standard and any potential interferences. A Restek 60-m x 0.32-mm i.d. Rix-Volatiles (1.5-µm df) capillary column was used in this evaluation. Bracket sample concentrations with standard concentrations. If upon analysis, sample concentrations fall outside the range of prepared standards, prepare and analyze additional standards to confirm instrument response, or dilute high samples with extraction solvent and reanalyze the diluted samples. # Sample preparation Remove the plastic end caps from the front sample tube and carefully transfer the silica gel to a 4-ml amber glass vial. The sampling tube and the back of the glass fiber filter should be carefully inspected to insure that all the silica gel is transferred into the 4-ml vial. Remove the plastic end caps from the backup tube and carefully transfer the silica gel to a second 4-ml amber glass vial. If the industrial hygienist requests analysis of the front glass fiber filter, which is not normally analyzed, place the front glass wool plug and filter from the front tube into a third 4-ml vial. If analysis of filter is not requested then discard the front glass wool plug and filter. Discard the glass tubes and back glass wool plugs and back glass fiber filter. Add 2.0 ml of extraction solution to each vial and immediately seal with PTFE-lined caps. Note: The use of an extraction solution or internal standard other than that specified in Section 3.2 should not be used unless a full extraction efficiency study is performed using both dry and wet media as described in Section 4.8. Place the 4-ml vials on a mechanical rotator and rotate at approximately 40 rpm for 60 min. Transfer the extraction solution in each 4-ml vial to a 2-ml amber glass autosampler vial and seal with a PTFE-lined cap. Analyze samples for acetoin and diacetyl as described in Section 3.5. # Calibration An internal standard calibration method is used. A calibration curve can be constructed by plotting !STD-corrected response of standard injections versus micrograms of analyte per sample. Bracket the samples with freshly prepared analytical standards over the range of concentrations. The Guidelines define analytical parameters, specify required laboratory tests, statistical calculations and acceptance criteria. Detection limit of the analytical procedure (DLAP) The DLAP is measured as mass of analyte introduced onto the chromatographic column. Ten analytical standards were prepared with equally descending increments with the highest standard containing 1.1 O µg/sample acetoin and 1 .05 µg/sample diacetyl. This is the concentration that would produce a peak approximately 10 times the response of a calibration blank. These standards, and the calibration blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 spit), and the data obtained were used to determine the required parameters (standard error of estimate and slope) for the calculation of the DLAP. For acetoin values of 5171 and 30 were obtained for the slope and standard error of estimate respectively. The DLAP for acetoin was calculated to be 0.017 ng acetoin. For diacetyl values of 4325 and 47 were obtained for the slope and standard error of estimate respectively. The DLAP for diacetyl was calculated to be 0.033 ng diacetyl. Detection limit of the overall procedure (DLOP) and reliable quantitation limit (RQL) The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equally descending increments of acetoin and diacetyl, such that the highest sampler loading was equivalent to 1.10 µg of acetoin per sample and 0.96 µg of diacetyl per sample. This is the amount spiked on a sampler that would produce a peak approximately 10 times the response of a calibration blank. These spiked samplers, and the sample blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 spit), and the data obtained were used to determine the required parameters (slope and standard error of estimate) for the calculation of the DLOP. For acetoin values of 1029 and 36 were obtained for the slope and standard error of estimate respectively. The DLOP was calculated to be 0.10 µg acetoin per sample (0.0031 ppm or 0.011 mg/m 3 for a TWA sample). For diacetyl values of 1241 and 46 were obtained for the slope and standard error of estimate respectively. The DLOP was calculated to be 0.11 µg diacetyl per sample (0.0034 ppm or 0.012 mg/m 3 for a TWA sample). The RQL is considered the lower limit for precise quantitative measurements. It is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to The standard error of estimate was determined from the linear regression of data points from standards over a range that covers approximately 0.25 to 2 times the target concentration. Calibration curves for acetoin and diacetyl were constructed and are shown in Section 3.5.2 from the three injections of five standards. The standard error of estimate is 0.42 µg/sample for acetoin and 0.82 µg/sample for diacetyl. The precision at the 95% confidence level is obtained by multiplying the standard error of estimate by 1.96 (the z-statistic from the standard normal distribution at the 95% confidence level). In Section 4.5, 95% confidence intervals are drawn about their respective regression lines in the storage graph figures. For acetoin the precision of the overall procedure of ±11.2% was obtained from the standard error of estimate of 5.73% in Figure 4.5.1. For diacetyl the precision of the overall procedure of ±10.1 % was obtained from the standard error of estimate of 5.15% in Figure 4.5.3. The precision includes an additional 5% for sampling error. Storage samples for acetoin and diacetyl were prepared by collecting samples from a controlled test atmosphere using the recommended sampling conditions. The concentration of acetoin and diacetyl were at the target concentration with an average relative humidity of 41 % at 34 °C (absolute humidity of 15.2 mg/L H 2 0). Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the samples were stored at reduced temperature (3 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 21 °C). At 3-4 day intervals, three samples were selected from each of the two storage sets and analyzed. Sample results were not corrected for extraction efficiency. # Reproducibility Six samples were prepared by collecting them from a controlled test atmosphere similar to that which was used in the collection of the storage samples. The samples were submitted to the OSHA Salt Lake Technical Center for analysis along with a draft copy of this method. The samples were analyzed after being stored for 20 days at refrigerated temperature (about 3 °C). Sample results were corrected for extraction efficiency. No sample result for acetoin and diacetyl had a deviation greater than the precision of the overall procedure determined in Section 4.4. The sampling capacity of the front tube was tested by sampling from a dynamically generated test atmosphere at 2 times the target concentration of acetoin (3.58 mg/m 3 or 0.99 ppm) and diacetyl (3.55 mg/m 3 or 1.01 ppm) with an average relative humidity of 40% at 34 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min. Backup tubes were placed in-line behind the front tube and were changed regularly after the initial collection of 225 min. Breakthrough for diacetyl was observed after sampling 12.4 L. No breakthrough was observed for acetoin even after sampling for 265 min. The recommended sampling time is 3 h. The extraction efficiency is dependent on the extraction solvent as well as the internal standard. Other extraction solvents or internal standards may be used provided that the new extraction solution or internal standard is tested. The new extraction solvent or internal standard should be tested as described below. # Extraction efficiency The extraction efficiency of acetion and diacetyl was determined by liquid spiking four samplers, at each concentration level, with the analytes from the RQL to 2 times the target concentrations. These samples were stored overnight at ambient temperature and then analyzed. The mean extraction efficiency over the working range of the RQL to 2 times the target concentration is 92.9% for acetoin. The extraction efficiency for the wet samplers was not included in the overall mean because it would bias the results. The mean extraction efficiency over the working range of the RQL to 2 times the target concentration is 99.6% for diacetyl. The extraction efficiency for the wet samplers was not included in the overall mean because it would bias the results. # Stability of extracted samples The stability of extracted samples was investigated by reanalyzing the target concentration samples 24 h and 72 h after initial analysis. After each analysis was performed, two vials were recapped with new septa while the remaining two retained their punctured septa. The samples were reanalyzed with fresh standards. Samples were stored at ambient temperature and each septum was punctured 4 times for each analysis. Interferences (sampling) Retention The ability of the sampler to retain acetoin and diacetyl was tested by sampling from a dynamically generated test atmosphere of acetoin (3.67 -----------------then all six samplers were analyzed. The mean of the samples in the second set had retained 100.6% for acetoin and 96.6% for diacetyl of the mean collected by the first three samples. # Low humidity The ability of the sampler to collect acetoin and diacetyl from a relatively dry atmosphere was tested by sampling from a dynamically generated test atmosphere of acetoin ( 4.06 mg/m 3 or 1.13 ppm) and diacetyl (4.03 mg/m 3 or 1 .14 ppm) with an average relative humidity of 8% at 33 °C (absolute humidity of 2.82 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 180 min. All of the samples were immediately analyzed. The samplers collected 103.0%, 96.9% and 102.2% of theoretical for acetoin and 96.7%, 106.6% and 101.2% of theoretical for diacetyl. # Low concentration The ability of the sampler to collect acetoin and diacetyl at low concentrations was tested by sampling from a dynamically generated test atmosphere of 0.1 times the target concentration of acetion (0.185 mg/m 3 or 0.0515 ppm) and diacetyl (0.175 mg/m 3 or 0.0497 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 180 min. All of the samples were immediately analyzed. The samplers collected 93.9%, 91.5% and 89.9% of theoretical for acetoin and 92.8%, 97.4% and 96. 7% of theoretical for diacetyl. The ability of the sampler to collect acetoin and diacetyl at low concentrations when taking short term samples was tested by sampling from a dynamically generated test atmosphere of 0.1 times the target concentration of acetion (0.185 mg/m 3 or 0.0514 ppm) and diacetyl (0.175 mg/m 3 or 0.0497 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.2 L/min for 15 min. All of the samples were immediately analyzed. The samplers collected 103.8%, 104.1 % and 110.0% of theoretical for acetoin and 88.1 %, 89.2% and 94.4% of theoretical for diacetyl. # Interferences The ability of the sampler to collect acetoin and diacetyl was tested when other potential interferences are present by sampling an atmosphere containing 1.63 mg/m 3 (0.45 ppm) of acetoin, 1.56 mg/m 3 (0.44 ppm) of diacetyl, 2.59 mg/m 3 (0.44 ppm) of 2-nonanone and 1.88 mg/m 3 (0.44 ppm) of 2,3-pentanedione with an average relative humidity of 38% at 34 °C (absolute humidity of 14.1 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 181 min. All of the samples were immediately analyzed. The samplers collected 93.2%, 96.5% and 96.8% of theoretical for acetoin and 100.6%, 100.6% and 104.1% of theoretical for diacetyl. Selection of 2-nonanone as a potential interference was based on its common use in butter flavorings used in microwave popcorn manufacturing facilities 29 . 2,3-Pentanedione was selected because it has been suggested as a possible replacement for diacetyl. (Note: The GC retention time of 2-nonanone was 14.4 min and 7.4 min for 2,3pentanedione. For this test the GC column temperature program was slightly changed to Initial 60 °C, hold 4 min; ramp at 15 °C/min to 225 °C, hold 0 min; ramp at 60 °C/min to 250 °C, hold 4 min to allow for the elution of 2-nonanone.) # Light The possibility of light degradation was tested for both acetoin and diacetyl on the sampling medium and in the extraction solution. For the sample medium test 12 samples were collected by sampling from a dynamically generated test atmosphere of acetoin (1.92 mg/m 3 or 0.53 ppm) and diacetyl (1.87 mg/m 3 or 0.53 ppm) with an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min for 3 hours. Nine of not covered and three of the sampling, none during sampling covered samples were -----------------------immediately analyzed after sampling. Three of the covered samples were placed under a fluorescent lamp for 24 h and the reaming three were placed outside in direct sunlight for three hours before analyzing. The samples covered during sampling and immediately analyzed after sampling had mean recoveries of 94.4% of theoretical for acetoin and 96.6% for diacetyl. The samples not covered during sampling and immediately analyzed after sampling had mean recoveries of 94.1 % of theoretical for acetoin and 96.2% for diacetyl. The samples covered during sampling and then exposed to fluorescent light for 24 h before analysis had mean recoveries of 88.7% of theoretical for acetoin and 86.8% for diacetyl. The samples covered during sampling and then exposed to sunlight for 3 h before analysis had mean recoveries of 67.0% of theoretical for acetoin and 6.43% for diacetyl. This data clearly indicates that the sampler should be protected from exposure to light. To test the possibility of light degradation on extracted samples nine analytical standards at the target concentration were prepared. Six of the standards were placed in 2-ml amber glass vials and three were placed in 2-ml clear glass vials. Three of the amber vials, along with the clear glass vials were stored on the autosampler tray during the entire test while the other three amber vials were stored in the refrigerator when not being analyzed. All nine standards were analyzed eight times over a 10 day period with none of the septa being replaced during the test. With the exception of diacetyl in clear vials, acetoin and diacetyl did not degrade. This data clearly indicates that extracted samples should be protected from exposure to light. This data also indicates that acetoin and diacetyl are stable in the extraction solution for up to 9 days as long as they are stored in amber vials. The internal standard, 3-pentanone, was stable for up to 9 days in both the clear and ambient vials. # Diacetyl migration within sampling tubes In the majority of solid sorbent sampling tubes used by (3.17 mg/m 3 or 0.90 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min for 3 hours. Three samples were analyzed on the day of generation and the other twelve were stored in a closed drawer at ambient temperature (about 21 °C). At 3-4 day intervals, three additional samples were analyzed. After 14 days up to 13.0% of diacetyl was found to have migrated from the front to the back section of the modified sampling tube. Acetoin did not migrate within the sampling tube. Generation of test atmospheres A test atmosphere generator, as diagramed in Figure 4.11, was set up in a walk-in hood. House air was dried and then humidified and regulated using a Miller Nelson Model 401 Flow Temperature-Humidity Control System. A measured flow (typically 10 µL per min) of an acetoin and diacetyl water solution was pumped through a 0.53-mm uncoated fused silica capillary tube into the inlet manifold, using a Series D ISCO Syringe Pump with Controller, and mixed with dilution air (typically 100 liters per min) coming from the Miller Nelson Control System. The inlet manifold was heated by wrapping it in heat tape, regulated with a variable autotransformer, in order to insure vaporization of acetoin. The acetoin and diacetyl gas mixture then flowed continuously into the mixing chamber (76-cm x 15-cm) and then into the sampling chamber (56-cm x 9.5-cm). Samples were collected through sampling ports on the sampling chamber. Temperature and humidity were measured near the exit of the sampling chamber using an Omega Digital Thermo hygrometer model RH411. When necessary, the identity or purity of an analyte peak can be confirmed by GC-mass spectrometry or by another analytical procedure. The mass spectra in Figure 4.12.1 and 4.12.2 are taken from the NIST spectral library. # General Discussion For assistance with accessibility problems in using figures and illustrations presented in this method, please contact Salt Lake Technical Center (SL TC) at (801) 233-4900. These procedures were designed and tested for internal use by OSHA personnel. Mention of any company name or commercial product does not constitute endorsement by OSHA. 1.1 Background # History OSHA is concerned about workplace exposure to 2,3-pentanedione because it is a butter flavoring agent that is sometimes substituted for diacetyl. 1 2,3-Pentanedione is chemically similar to diacetyl and may have similar toxicological properties. 2 This work was performed because OSHA has no sampling and analytical method for 2,3pentanedione and none was found in a literature review. One of the main objectives of this work was to enable OSHA CSHOs to monitor workplace exposure to diacetyl, acetoin and 2,3-pentanedione simultaneously on the same sample. Because of the similarities of the chemicals, it was decided to validate existing sampling and analytical methodology specified in OSHA Method 1013 3 for 2,3pentanedione. That method requires sampling with two commercially available silica gel tubes connected in series. This method specifies a different GC column than specified in Method 1013 in order to optimize the analytical separation. The reliable quatitation limits for acetoin and diacetyl cited in OSHA Method 1013 were confirmed with the GC column used in this validation. 1.1.2 Toxic effects (This section is for information only and should not be taken as the basis of OSHA policy.) 2,3-Pentanedione is moderately toxic by ingestion, a skin irritant, and can cause eye and respiratory tract irritation. 4 The oral LD 50 in rats is 3000 mg/kg. The skin irritation test in rabbits showed moderate irritation for an exposure of 500 mg/24h. Studies exposing rats to 118, 241, 318, or 354 ppm 2,3-pentanedione for 6 hours showed epithelial changes in the airways which increased with increasing air concentrations with necrosuppurative tracheitis in the rats exposed to 354 ppm. 5 This epithelial cell damage was found to progress post-exposure in rats sacrificed a day later. These epithelial changes included degeneration, apoptosis, necrosis, and neutrophilic inflammation. 1.1.3 Workplace exposure 2,3-Pentanedione is a natural flavorant and odorant that is also synthesized for use in odor and flavor manufacturing. 6 It is used to give products a buttery, nutty, cheesy, fruity, toasted, chocolate, or caramel taste. It also gives products a buttery, fruity, and caramel odor. There can be as much as 58 ppm in food flavorings, and up to 0.08% in fragrances. 2,3-Pentanedione is used as a solvent for cellulose acetate, paints, inks, lacquers, as a starting material for dyes, pesticides and pharmaceuticals, and as a photoinitializer for photo-reactive dyes. # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # Apparatus Samples are collected with 110-cm x 7-mm o.d. glass sampling tubes packed with a single section (600 mg) of specially cleaned and dried silica gel. The section is held in place with glass wool and with a glass fiber filter in the front and glass wool at the back. A sampling train is prepared by placing two tubes in series. For this validation, commercially prepared sampling tubes were purchased from SKC, Inc. The two tubes are identical, but SKC labels the tubes as "Part A" which is the front tube and as "Part B" which is the back tube (Catalog no. 226-183, lot no. 6148). Use an opaque tube holder, such as SKC, to cover the sampling train during sampling. If the tube holder is not opaque, wrap the sampler with aluminum foil. Light can decompose collected 2,3-pentanedione. Samples are collected using a personal sampling pump calibrated to within ±5% of the recommended flow rate with the sampling device in-line. # Reagents None required # Technique Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use sampling tube holders to minimize the hazard to the worker from the broken ends of the tubes and to minimize the potential of glass shards entering the foodstuffs. All tubes should be from the same lot. A sampling train is prepared by attaching a Part A tube in front of and in series with a Part B tube, with both glass fiber filters facing forward. The Part B tube in the sampling train is used as a back-up and is positioned nearest the sampling pump. Attach the tube holder (with the adsorbent tube sampling train) to the sampling pump so that the sampling train is in an approximately vertical position with the inlet facing down in the worker's breathing zone during sampling. Position the sampling pump, tube holder and tubing so they do not impede work performance or safety. Draw the air to be sampled directly into the inlet of the tube holder. The air being sampled is not to be passed through any hose or tubing before entering the sampling tube. Sample for up to 200 min at 50 ml/min (10 L) to collect TWA (long-term) samples. If acetoin and/or diacetyl are anticipated to be present, sample for up to 180 min at 50 ml/min (9 L) to collect TWA (long-term) samples. The extraction solvent used for this validation consisted of 0.007 µL/ml 3-pentanone in 95% v/v ethyl alcohol/water. The 3-pentanone was added to the ethyl alcohol as an internal standard (ISTD). # Standard preparation (Note: Store all standards in amber glass bottles and vials) Prepare concentrated stock standards in water at 1.021 mg/ml (1 .021 µg/µl) by injecting 11 µl of neat 2,3-pentanedione into water in a 10-ml volumetric flask and diluting to the mark. This stock standard will remain stable for two weeks if stored in an amber bottle in the refrigerator. When using refrigerated stock standards, be sure to allow the standards to warm to room temperature and then shake them vigorously before use. Prepare analytical standards by injecting microliter amounts of concentrated stock standards into 2-ml volumetric flasks containing about 1.75 ml of extraction solvent and then diluting with extraction solvent over a concentration range of 0.1 to 20 µg/ml (0.2 to 40 µg/2 ml). For example: a target concentration standard of 20.4 µg/sample was prepared by injecting 20 µl of the stock standard into a 2-ml flask containing about 1.75 ml of extraction solvent and then diluting to the mark with extraction solvent (10.2 µg/ml or 0.5 ppm based on a 2-ml extraction volume per sample and 10 lair volumes). Bracket sample concentrations with standard concentrations. If upon analysis, sample concentrations fall outside the range of prepared standards, prepare and analyze additional standards to confirm instrument response, or dilute high samples with extraction solvent and reanalyze the diluted samples. # Sample preparation (Note: prepare all samples in amber glass vials) Remove the plastic end caps from the front sample tube and carefully transfer the silica gel to a labeled 4-ml amber glass vial. The sampling tube and the back of the glass fiber filter should be carefully inspected to ensure that all the silica gel is transferred into the 4-ml vial. Remove the plastic end caps from the backup tube and carefully transfer the silica gel to a second labeled 4-ml amber glass vial. If the industrial hygienist requests analysis of the front glass fiber filter, which is not normally analyzed, place the front glass wool plug and filter from the front tube into a third 4-ml vial. If analysis of filter is not requested then discard the front glass wool plug and filter. Discard the glass tubes and back glass wool plugs and back glass fiber filter. Add 2.0 ml of extraction solvent to each vial and immediately seal the vials with PTFE-lined caps. Immediately place the vials on a rotator for 60 min. Transfer the sample into autosampler vials for analysis. (Key: 1) ethyl alcohol; 2) 2,3pentanedione; and 3) 3-pentanone.) 3.6 Interferences (analytical) 3.6.1 Any compound that produces a GC response and has a similar retention time as the analyte or internal standard is a potential interference. If potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate interferences from the analyte. 3.6.2 When necessary, the identity of an analyte peak can be confirmed with additional analytical data or procedures (Section 4.10). # Calculations The amount of analyte per sample is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for extraction efficiency. The second tube is analyzed primarily to determine the extent of sampler saturation. If any analyte is found on the back tube, it is added to the amount on the front tube. If more than 20% of the total amount is found on the back tube, report that the sampler may have been saturated on the Form OSHA-91 B. This total amount is then corrected by subtracting the total amount (if any) found on the blank. The air concentration is calculated using the following formulas. Detection limit of the analytical procedure (DLAP) The DLAP is measured as mass of analyte introduced into the chromatographic column. Ten analytical standards were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a reagent blank at or near the retention time of the analyte. The standards and the reagent blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 split). The data obtained were used to determine the required parameters (standard error of estimate and slope) for the calculation of the DLAP. The slope and standard error of estimate, respectively, were 6.62 and 62.2. The DLAP was calculated to be 28 pg. 4.2 Detection limit of the overall procedure (DLOP) and reliable quantitation limit (RQL) The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a sample blank at or near the retention time of the analyte. The RQL is considered the lower limit for precise quantitative measurements. It is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to 125% of the analyte is recovered. The RQL for 2,3-pentanedione is 0.38 µg per sample (9.3 ppb or 38 µg/m 3 for a TWA sample). Recovery at this concentration is 97.9%. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limit for the recommended sampler is 31 ppb (127 µg/m 3 ) when 3 Lis sampled. # Precision of the analytical method The precision of the analytical method was measured as the mass equivalent to the standard error of estimate determined from the linear regression of data points from standards over a range that covers 0.1 to 2 times the TWA target concentration for the sampler. A calibration curve was constructed and shown in Section 3.5.2 from the three injections each of five standards. The standard error of estimate was 0.49 µg. Storage samples for 2,3-pentanedione were prepared by sampling a dynamically generated controlled test atmosphere using the recommended sampling parameters. The concentration of 2,3-pentanedione in the test atmosphere was 0.501 ppm ( 2.05 mg/m 3) and the relative humidity was 80% at 23 °C. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Sample results are not corrected for extraction efficiency. Results for the ambient storage test decreased by more than 10% which is a significant uncorrectable bias that must be avoided, therefore, samples should be stored in a refrigerator until analyzed, and analysis should be completed within two weeks of sampling. Recovery is determined from the regression line and the maximum change allowed by OSHA methods development guidelines is ±10%. # Precision (overall procedure) The precision of the overall procedure at the 95% confidence level is obtained by multiplying the standard error of estimate by 1.96 (the z-statistic from the standard normal distribution at the 95% confidence level). Ninety-five percent confidence intervals are drawn about the regression lines in the storage stability figures shown in Section 4.4. Two dried silica gel tubes in series The precision at the 95% confidence for the refrigerated temperature (4 °C) 17-day storage test was± 10.1 %. It contains an additional 5% for sampling pump error. # Recovery The recovery of 2,3-pentanedione from samples used in a 17-day storage test remained above 91 .3% when samples were stored at 4 °C. # Reproducibility Six samples were prepared by sampling a dynamically generated controlled test atmosphere similar to that used in the collection of the storage samples. The concentrations of 2,3pentanedione in the test atmosphere was 0.501 ppm (2.05 mg/m 3 ) at 78% relative humidity and 23 °C. The samples were submitted to the OSHA Salt Lake Technical Center for analysis. The samples were analyzed after being stored at 4 °C for 4 days. Sample results were corrected for extraction efficiency. No sample result had a deviation greater than the precision of the overall procedure determined in Section 4.4. The sampling capacity of the front tube of the recommended air sampler (two dried silica gel tubes in series) was tested by sampling a dynamically generated controlled test atmosphere containing 2,3-pentanedione at two times the target concentration (1.01 ppm or 4.10 mg/m 3 ) and 80% relative humidity at 23 °C. The samples were collected at 50 ml/min. The second tube in the sampling train was changed at 3 h then at 0.25 h intervals for the rest of the sampling. The presence of analyte on the second tube was defined as breakthrough. The percentage of the amount found on the second tube in relation to the concentration of the test atmosphere was defined as % breakthrough. The % breakthrough was plotted versus the air volume sampled to determine breakthrough air volumes. Breakthrough is considered to have occurred when the effluent from the active sampler contains a concentration of analyte that is 5% of the upstream concentration. The 5% breakthrough air volume for 2,3-pentanedione was 12.5 L. The recommended air volume is 80% of the breakthrough air volume which is 10 L (200 min sampled at 50 ml/min). 12of17 # Extraction efficiency and stability of extracted samples The extraction efficiency is affected by the extraction solvent, the internal standard, the sampling medium, and the technique used to extract the samples. Other reagents and techniques than described in this method can be used provided they are tested as specified in the guidelines. # Extraction efficiency The extraction efficiency of 2,3-pentanedione was determined by liquid-spiking four front sampling tubes of the recommended air sampler at each concentration level. These samples were stored overnight at ambient temperature and then analyzed. The overall mean extraction efficiency over the working range of 0.1 to 2 times the target concentration was 97.6%. The presence of water had no significant effect on extraction efficiency. The extraction efficiencies for the RQL and for the wet samplers are not included in the overall mean. Wet media were prepared by sampling humid air (78% RH at 23 °C) for 200 min at 50 ml/min. The data obtained are shown in Table 4.8.1. sampled at 50 ml/min for 150 min and then all six samplers were analyzed. The data obtained are shown in Tables 4.9.1. The effect of low humidity was tested by sampling a dynamically generated controlled test atmosphere containing two times the target concentration (1 ppm or 4.1 mg/m 3 ) of 2,3pentanedione at 20% relative humidity and 23 °C. The test atmosphere was sampled with three of the recommended samplers at 50 ml/min for 200 min. All of the samples were immediately analyzed. Sample results were 98.8%, 99.1%, and 97.4% of theoretical. # Low concentration The effect of low concentration was tested by sampling a dynamically generated controlled test atmosphere containing 0.1 times the target concentration (0.05 ppm or 0.205 mg/m 3 ) of 2,3pentanedione at 80% relative humidity and 23 °C. The test atmosphere was sampled with three of the recommended samplers at 0.05 ml/min for 200 min. All of the samples were immediately analyzed. Sample results were 98.7%, 97.0%, and 95.8% of theoretical. # Chemical interference The ability of the recommended sampler to collect 2,3-pentanedione was tested when other potential interferences are present by sampling an atmosphere containing 0.5 ppm (2.05 mg/m 3 ) 2,3-pentanedione at 80% relative humidity and 23 °C and two interferences whose concentrations were 0.51 ppm (1.82 mg/m 3 ) acetoin, and 0.51 ppm (1.78 mg/m 3 ) diacetyl. The test atmosphere was sampled with three of the recommended samplers at 50 ml/min for 200 min. All of the samples were immediately analyzed. Sample results for 2,3-pentanedione were 97.1 %, 96.3%, and 95.5% of theoretical. 2,3pentanedione at an average humidity of 80% at 23°C was sampled for 200 minutes at 50 ml/min. The three foil-wrapped and three unwrapped samples were analyzed immediately and the average recovery for the foil wrapped was 98.2% and the un-wrapped sampler average recovery was 96.6%. Three of the foil-wrapped samplers had the foil removed after sampling and were exposed to fluorescent room lights for 24 h before analysis and had an average recovery of 90.3%. The last three foil wrapped samplers had the foil removed and were exposed to 3 h of sunlight before analysis 15of17 and had an average recovery of 42.4%. This data clearly indicates that the sampler should be protected from exposure to light. To test the possibility of light degradation on extracted samples nine analytical standards at the target concentration were prepared. Six of the standards were placed in 2-ml amber glass vials and three were placed in 2-ml clear glass vials. Three of the amber vials, along with the clear glass vials were stored on the autosampler tray during the entire test while the other three amber vials were stored in the refrigerator when not being analyzed. All nine standards were analyzed eight times over a 10 day period with none of the septa being replaced during the test. The standards in clear vials degraded significantly, but standards in amber vials did not degrade. This data clearly indicates that extracted samples should be protected from exposure to light. The internal standard, 3-pentanone was stable for up to 9 days in both the clear and ambient vials. The data obtained is shown in Table 4.9.3. 4.11. The test atmosphere generation and temperature, and volume of the dilution sampling apparatus. air were regulated by use of a Miller Nelson Flow-Temperature-Humidity controller. The test atmosphere passed into a glass mixing chamber (76-cm x 30-cm) from the vapor generator, and then into a glass exposure chamber (76-cm x 20-cm). Active samplers were attached to glass ports extending from the exposure chamber. The humidity and temperature were measured at the exit of the exposure chamber with an Omega Digital Thermo-hygrometer. The theoretical concentrations were calculated from the ISCO pump flow rate, the concentration of the 2,3-pentanedione solution, and the air flow volumes. The theoretical concentrations were used throughout this validation. 1. Sampler: Thermal sampling tube, %" s.s. tube, multi-bed sorbents capable of trapping organic compounds in the C 3 -C 16 range. Exact sampler configuration depends on thermal desorber system used. See Figure 1 for example. 2. Personal sampling pump, 0.01 to 0.05 L/min, with flexible tubing. 3. Shipping containers for thermal desorber sampling tubes. 4. Instrumentation: thermal desorption system, focusing capability, desorption temperature appropriate to sorbents in tube (-300 °C), and interfaced directly to a GC-MS system. 5. Gas chromatograph with injector fitted with 1/4" column adapter, 1/4" Swagelok nuts and Teflon ferrules (or equivalent). 6. Syringes: 1-µL, 10-µL (liquid); 100-µL, 500-µL (gas tight) 7. Volumetric Flasks, 10-ml. 8. Gas bulb, 2 L SPECIAL PRECAUTIONS:Some solvents are flammable and should be handled with caution in a fume hood. Precautions should be taken to avoid inhalation of the vapors from solvents as well. Skin contact should be avoided. # SAMPLING: NOTE: Prior to field use, clean all thermal desorption tubes thoroughly by heating at or above the intended tube desorption temperature for 1-2 hours with carrier gas flowing at a rate of at least 50 ml/min. Always store tubes with long-term storage caps attached, or in containers that prevent contamination. Identify each tube uniquely with a permanent number on either the tube or tube container. Under no circumstances should tape or labels be applied directly to the thermal desorption tubes. 1. Calibrate each personal sampling pump with a representative sampler in line. 2. Remove the caps of the sampler immediately before sampling. Attach sampler to personal sampling pump with flexible tubing. NOTE: With a multi-bed sorbent tube, it is extremely important to sample in the correct direction, from least to maximum strength sorbent. 3. For general screening, sample at 0.01 to 0.05 L/min for a maximum sample volume of 6 L. Replace caps immediately after sampling. Keep field blanks capped at all times. Tubes can act as diffusive samplers if left uncapped in a contaminated environment. 4. Collect a "humidity test" sample to determine if the thermal adsorption tubes have a high water background. NOTE: At higher sample volumes, additional analyte and water (from humidity) may be collected on the sampling tube. At sufficiently high levels of analyte or water in the sample, the mass spectrometer may malfunction during analysis resulting in loss of data for a given sample. 5. Collect a "control" sample. For indoor air samples this could be either an outside sample at the same location or an indoor sample taken in a non-complaint area. 6. Ship in sample storage containers at ambient temperature. Store at -10 °C. # SAMPLE PREPARATION: 7. Allow samples to equilibrate to room temperature prior to analysis. Remove each sampler from is storage container. Preparation of spiked samples Spiked tubes can be prepared from either liquid or gas bulb standards. Liquid standards: Prepare stock solutions by adding known amounts of analytes to 10-ml volumetric flasks containing high purity solvent (carbon disulfide, methanol, toluene). Solvents are chosen based on solubility for the analytes of interest and ability to be separated from the analytes when chromatographed. Highly volatile compounds should be dissolved in a less volatile solvent. For most compounds, carbon disulfide is a good general purpose solvent, although this will interfere with early eluting compounds. # Gas bulb standards: Inject known amounts of organic analytes of interest into a gas bulb of known volume filled with clean air . Prior to closing the bulb, place a magnetic stirrer and several glass beads are placed in the bulb to assist in agitation after introduction of the analytes. After injection of all of the analytes of interest into the bulb, warm the bulb to 50 °C and place it on a magnetic stirring plate and stir for several minutes to ensure complete vaporization of the analytes. After the bulb has been stirred and cooled to room temperature, remove aliquots from the bulb with a gas syringe and inject into a sample tube as described below. Tube spiking Fit a GC injector with a%" column adapter. Maintain the injector at 120 °C to assist in vaporization of the injected sample. Attach cleaned thermal desorption tubes to injector with%" Swagelok nuts and Teflon ferrules, and adjust helium flow though the injector to 50 ml/min. Attach the sampling tube so that flow direction is the same as for sampling. Take an aliquot of standard solution (gas standards 100 to 500 µL; liquid standards, 0.1 to 2 µL) and inject into the GC injector. Allow to equilibrate for 10 minutes. Remove tube and analyze by thermal desorption using the same conditions as for field samples. lnstrumentation:Actual media, instrumentation, and conditions used for general screening of unknown environments are as follows: Perkin-Elmer ATD 400 (automated thermal desorption system) interfaced directly to a Hewlett-Packard 5980 gas chromatograph/HP5970 mass selective detector and data system. # INTRODUCTION D iacetyl (2,, a dike tone chemical used to impart a buttery taste in many flavoring mixtures, has been associated with severe respiratory disease in several different occupational settings, including microwave popcorn manufacturing, flavoring production, and diacetyl manufacturing_Cl-3 l Laboratory animal studies have documented that diacetyl alone has toxic properties that are similar to the effects of exposure to diacetyl-containing artifi cial butter flavoring mixtures.C 4 - 5 l The Occupational Safety and Health Administration (OSHA) is in the process ofrulemaking on occupational exposure to diacetyl. National Institute for Occupational Safety and Health (NIOSH) researchers developed and published an analytical method, NIOSH Method 2557, to measure airborne diacetyl in the workplace.C 6 -7 l This method specifies air sample collection through carbon molecular sieve (CMS) sorbent tubes, followed by extraction with acetone/methanol (99: 1) and analysis by gas chromatography with flame ionization detection (GC/FID) within 7 days of sampling. Subsequent to the use of this sampling method in several workplace investigations, NIOSH researchers found that the method appeared to progressively 8 Nine each of the 0.5 and 25 ppm samples and 18 of the 5.0 ppm samples were used in both humidity and storage stability analyses. # Sampling Test Conditions Samples were collected between January 2008 and De cember 2009 during four 1-week periods and one 2-week period of tests. We collected a total of 964 CMS tube sam ples during 80 tests, with relative humidity (RH) levels rang ing from 16 to 92% and temperatures of 22.4 to 33.8°C giving absolute humidity (AH) levels ranging from 3.5 to 22.5 mg H 2 0/L air and with diacetyl concentrations ranging from 0.23 to 25.7 ppm. Samples were collected over 2, 4, or 8 hr to test for differences in diacetyl recovery due to sampling duration or because of limit of detection (LOD) concerns during tests at low diacetyl concentrations. Sam ples were collected using sampling flow rates of 50 or 150 cc/min to investigate any effect on diacetyl recovery associ ated with differences in sampling flow rate. The test atmo sphere conditions and sample numbers are summarized in Table I. Over the five visits, we collected 134 silica gel samples at a flow rate of 50 cc/min during 43 of the 2-hr tests. These samples were collected with an AH range of 3.57 to 22.50 mg H 2 0/L air and diacetyl concentrations from 0.56 to 25.7 ppm. # Sample Storage Stability Tests In total, storage stability of diacetyl both in the sampling tubes (in-tube) and after extraction from the tubes was in vestigated using 214 samples (Table I). In the first set of experimental conditions, six sets of triplicate samples were collected at 50 cc/min from a 5.7 ppm diacetyl test atmosphere at each of three AH levels: 3.97, 8.59, and 18.67 mg H 2 0/L air (RH= 17, 36, and 78%, respectively, at 25.7°C). Samples were sent overnight on ice to the analytical laboratory, where they were extracted and analyzed according to NIOSH Method 2557 for diacetyl 1, 4, 7, 10, 13, and 16 days post-sampling. All samples were stored in a refrigerator until the scheduled day of extraction. After analysis of the first set of samples on Day 1 post sampling, the remaining liquid portion (without sorbent mate rial) of each sample was split into two new vials and one stored at room temperature and the other refrigerated. These samples underwent further stability testing via re-analysis 1, 2, 5, and 11 days post-extraction. New septum caps were placed on each vial after each analysis, and freshly prepared standards were used for each re-analysis. To investigate diacetyl concentration effect on storage stability, during the final week of tests, six sets of triplicate samples each were collected from 0.57, 5.6, and 25.0 ppm diacetyl test atmospheres at each of three mean AH levels: 3.6, 8.5, and 18.5 mg H 2 0/L air. The samples were extracted and analyzed 1,4,7,10,16, and 35 days post sampling. When splitting the samples for the extract storage stability tests, equal portions of the sorbent material were placed into the two vials with the liquid to better simulate treatment of field samples as directed in Method 2557. Re analysis of these samples was completed on Days 2, 5, 13, and 34 post-extraction. # RESULTS 0 f 964 CMS samples collected, 717 were used in humidity effect analyses (extraction Day 1 after sampling), 214 were used in sample storage stability analyses (36 of these were used in both analyses), 42 samples from 1 day of tests were excluded due to excessive analytical laboratory variability (the mean coefficient of variation for that day's tests was 73% as compared with a range of 3% to 23% for other days), 13 were excluded due to greater than 5% changes in sampling flow rate during the tests, 3 were excluded due to errors during sampling, 1 had missing data from the analytical laboratory, 1 outlier (greater than 300% recovery) was excluded, and 9 samples collected at low concentration and high humidity were excluded because of nondetectable diacetyl. Of the 134 silica gel samples, 121 that had matching CMS sample groups during 39 tests were used in the comparison analyses. # Effects of Sampling Port Position, Sampling Duration, and Sampling Flow Rate During the first week of tests, homogeneous mixing of di acetyl in the exposure chamber was investigated, and analysis of variance indicated no significant effects of sampling port position on diacetyl recovery. An analysis of variance model using data from the first three laboratory visits (n = 448) with percent diacetyl recovery as the outcome variable and AH, test atmosphere diacetyl concentration, target sampling flow rate, and sampling duration as the predictor variables indicated a significant (p = 0.0042) effect of sampling flow rate, with percent diacetyl recovery being higher for the 150 cc/min sampling flow rate than for 50 cc/min. The magnitude of the effect was not large; the adjusted means (least squares means) for 150 cc/min and 50 cc/min were 44.9 and 40.3% diacetyl recovery, respectively. In this model there was no significant effect for sampling duration (p = 0.89), with adjusted means of 42. 3, 41.8, and 43. 7% diacetyl recovery for sampling durations of 2, 4, and 8 hr, respectively. # Absolute Humidity Effect-Model for Data from Samples Extracted on Day 1 After Sampling We investigated the effect of temperature on diacetyl recov ery by plotting percent diacetyl recovered against either RH (Figure 2a) in% or AH (Figure 2b) in mg H 2 0/L air using data from samples collected from a target diacetyl concentration of 5 ppm at target temperatures of 25°C and 32°C. We calculated AH from RH and temperature (Tc) using Eq. 1, which we derived from a National Weather Service approximation for humidity calculations in surface observations.01l As seen in Figure 2, the substantial difference in diacetyl recovery for the two temperatures was removed when humidity was expressed as AH. Thereafter, we modeled the percent recovered diacetyl in terms of AH. Using the JMP model library of nonlinear functions, we visually determined that the 4-parameter logistic function was suitable to describe the sigmoidal relationship of percent re covered diacetyl with humidity, for samples extracted on Day 1 after sampling. The 4-parameter logistic model has parameters 81, 82, 83, and 84, each of which has graphical meaning. The parameter 8 1 represents the horizontal asymptote on the right hand side of the graph where humidity is at the highest level; 8 2 represents the horizontal asymptote on the left-hand side of the graph where humidity is at the lowest level; 8 3 is the "slope" or the shape parameter; and 8 4 is the humidity at which 50% of the maximal response is observed. The general equation in terms of the 4-parameter logistic model is: 82-81 y = 81 + -------- 1 + exp In our models, percent recovered diacetyl was the Y vari able, and humidity was the X variable. We fitted separate 4-parameter logistic models to the data for each of the target test atmosphere diacetyl concentrations (0.2, 0.5, 5.0, and 20 ppm). We had too few levels of AH for the 1.0 ppm test atmosphere diacetyl concentration to adequately fit the 4-parameter logistic model. Figure 3 shows the separate 4-parameter logistic models for percent recovered diacetyl vs. AH as fitted through the overall test data (for both sampling flow rates combined). Using information from these models, we created one non linear model for the data overall; this model took into ac count differences in the 4-parameter values for the individual logistic models. We found that 8 1 was well approximated (R 2 = 0.99) by a linear function of target concentration Co We entered this form of the equation (Eq. 3) into the nonlin ear fitting platform for a fit through all the data (including the data for a test atmosphere diacetyl concentration of 1.0 ppm). We repeated the fit through the data stratified by sampling flow rate. The final values for the parameters (b 0 , m 1 , 8 2 , 8 3 , and 8 4 ) both overall and for the two sampling flow rates are given in Table II (the table also contains parameter values for the effect of in-tube storage as described below). The R 2 (amount of total variability in the data accounted for by the model) for the overall model was 0.91. The R 2 for the 150 cc/min model was 0.93, and the R 2 for the 50 cc/min model was 0.90. Figure 4 shows how Eq. 3 describes the pattern of diacetyl recoveries for a range of concentrations both overall and for the two sampling flow rates and illustrates that the effect of sampling flow rate was not large. Equation 3predicts that at a concentration of approximately 56 ppm, the diacetyl recovery would be approximately 100% at all AH values (this was similar for the overall model and the 50 and 150 cc/min models). At diacetyl concentrations above these values, the model predicts diacetyl recoveries of higher than 100% across the range of AH values, which does not represent a real-life solution. Predicted diacetyl recoveries from Eq. 3 for very low diacetyl concentrations do not have the same problem since, mathematically, in the limit as the diacetyl concentration goes to zero, the recoveries range from approximately 100% to approximately 7% as AH goes from low to high. # OSHA Silica Gel Sample Results Diacetyl concentrations from the 121 silica gel samples taken at a number of AH conditions were quite similar to the calculated test atmosphere concentrations (Figure 5a) and were not affected by AH. Using the model (Eq. 3) we calcu lated the corrected diacetyl concentrations from the matched NIOSH Method 2557 CMS samples, and as shown in Figure 5b, we found a strong linear relationship with the silica gel results. # Model for Effect of In-Tube Storage Plots of extract storage and in-tube storage stabilities are shown in Figure 6. Samples stored as extracts, either with or without sorbent material, under refrigerated conditions were stable, having less than 2 % loss at each of the three All levels overnearly 40 days of storage (1.4% at 7 days and 1.7% at 38 days). Under ambient conditions, the loss was 2.9% at 7 days and 11.0% at 38 days. In contrast, plots of diacetyl recovered by number of days of in-tube storage (i.e., days from sampling to extraction) indicated decreased recovery over time, with the changes over time showing dependence on both AH and diacetyl concentration. For a given diacetyl concentration, diacetyl losses over time were greater with increasing AH. For a given AH, diacetyl losses over time were greater with decreasing concentration. To model in-tube storage effects, we used first-order decay functions to estimate decay constants for the 12 combinations of diacetyl concentrations and AH. We normalized the diacetyl recovery data by dividing the diacetyl recovery data by the mean for recovery on Day 1 after sampling and included (t-1) in the first-order decay functions (see below). The first-order decay model is given by: Y =(starting amount) exp , where starting amount = 1 for normalized data, t = days from sampling to extraction, and k is the decay constant. We substituted functions of AH and diacetyl concentration for the decay constants (k). This was accomplished in two steps. In Step 1, we fitted quadratic functions to the k values for the three target diacetyl concentration (0.5 ppm, 5 ppm, and 25 ppm) curves of k vs. AH. In Step 2, we substituted three parameter first-order decay functions for the coefficients for the intercept, the AH term and the AH 2 term of the quadratic function based on the diacetyl concentrations. This gave esti mates for the nine coefficients (q, r, s, u, v, w, x, y, and z) in the model (as shown below). In a final step, the values of the nine parameters were used as starting values to get a fit of this nonlinear model through the full set of in-tube storage data. The R 2 for this model was 0.90. The coefficients are given in Table II. The form of the nonlinear model for the effect of in-tube storage was: Normalized recovery= g(Co, AH, t) = exp where The full model can be conceptualized in two steps. First, the AH, the recovered diacetyl concentration (c), and the number of days from sampling to extraction (t) are used to predict the recovered diacetyl concentration on Day 1 of extraction after sampling. Second, this predicted diacetyl value and AH is used to predict the corrected concentration. The full model for the percent of diacetyl recovered is: lOOc Percent recovered diacetyl = --= h(C 0 , AH)g(C 0 , AH, t) Co ( 5) Full Model + h(Co)AH + f3(Co)AH 2 )(t -l)] where his given by Eq. 3 and g is given by Eq. 4. Since, in practice, the values of c, AH, and tare known, and the value of Co is the predicted corrected diacetyl concentra tion, we solved Eq. 5 for C 0 . Using Eqs. 3 and 4, Eq. 5 can be rewritten as: AH, t) where Since this is a nonlinear equation for C 0 , it is necessary to use an iterative procedure to find C 0 . Initially, Eq. 6 is solved for Co using the quadratic formula with the dependence of g on Co ignored: b 2 + 4 a Ceca, ~H, t)) aC6 + bCo -( c ) = 0 (6) g(Co, Co= _ _ _ _ _ _ 2_a _ _ _ _ _ -b+ (7) (Note: The other solution for Eq. 6 using the quadratic formula yields a nonphysical negative value for Co since a > 0 and b > 0.) c In Eqs. 6 and 7 the value of ( ) is the estimate g(Co, AH, t) for the diacetyl concentration corrected for days to extraction after sampling. To solve Eq. 7, an iterative procedure is used with the i value cgl used to calculate the Ci+ 1) value cg+ 1 l b2 + 4a ( 0 c ) g(C 0 ' , AH, t) cg+1) = ------------ 2a -b+(8) It is necessary to start the procedure with an initial Co (i.e., c6 1 \ We found the procedure robust to the choice of starting value and suggest the use of c (the recovered concentration reported by the laboratory). The sequence of solutions is then calculated until two consecutive values for Co are identical to a chosen number of decimal places (convergence). We tested the model for regions of convergence using theoretical recovered concentrations ( c) from 0.001to70 ppm, AH from 2 to 25 mg H 2 0/L air, and days to extraction from 1 to 36. We found that convergence occurred for all concentrations above 1.0 ppm. For lower concentrations, convergence occurred whenever AH was less than 14.5 mg H 2 0/L air and days to extraction were fewer than 9. The region of convergence improved from a concentration of0.001 to 1.0 ppm. At 1.0 ppm, convergence occurred whenever AH was less than 21 mg H 2 0 IL air and days to extraction were fewer than 17. As discussed above, for values of Co > 56 ppm, the Day 1 model does not yield real-life solutions. For these values, only the model for effect of days to extraction should be applied and we predict the concentration of diacetyl for Day 1 of extraction after sampling. If the converged value as calculated above is> 56 ppm, use it as the starting value c6 1 l in an iterative procedure using the equation: cCi+l) - c 0 - (Cl ) g C 0 ', AH, t(9) The sequence of solutions is then calculated until two consecutive values for Co are identical to a chosen number of decimal places. Figure 7 is a flow diagram of the correc tion procedure as described above. When corrected diacetyl concentrations fall between 0.23 and 25.7 ppm, which were the lowest and highest diacetyl test atmosphere concentrations requires laboratory-reported concentrations of diacetyl in ppm (samples collected and analyzed using NIOSH Method 2557), temperature and RH (to calculate AH) conditions at the time of sampling, and the number of days from sample collection to sample extraction for analysis. We give overall parameter values for the full model, as well as for sampling flow rates of 50 and 150 cc/min (Table II). Since the effect of sampling flow rate was not large, investigators have the option of using the overall parameter values, especially if their historical data were collected at sampling flow rates other than 50 and 150 cc/min. A strength of this work was the use of a controlled test atmosphere to simulate historical field survey conditions where airborne diacetyl was sampled together with humid air. By using two target temperatures with similar ranges of RH, we were able to show that both temperature and RH had an effect on diacetyl recovery and that using AH (mg H 2 0/L air) was the key variable to connect the correlation between temperature and concentration. This finding extends the work ofMcKernan and colleagues, CS) who were unable to separate the effect of temperature and RH in their field-based work. By running tests with several different test atmosphere diacetyl concentrations over a wide range from 0.23 to 25.7 ppm, we were able to observe differences in diacetyl recovery related to theoretical diacetyl concentration. We found a large difference in diacetyl recovery between the test atmosphere diacetyl concentration of about 25 ppm and all the lower concentrations, especially at the higher AH values. The final correction equation predicts that humidity would no longer have an effect on diacetyl recovery at approximately 56 ppm, but we have no empirical data to test this prediction. Corrected diacetyl concentrations that lie outside our test atmosphere range represent extrapo lations of the models, and we have less confidence in these concentrations. We do not suggest the use of the correction procedure with historical concentration data below the limit of detection (LOD), for which concentration may have been estimated (e.g., using LOD/2 or LOD/,J2°). It is not possible to know if the workplace diacetyl concentration was indeed below the LOD or if the losses due to humidity and days from sampling to extraction in the laboratory caused the sample value to be below the LOD. We did find some regions of AH and days from sampling to extraction for recovered concentra tions of 1.0 ppm or less where the full model does not con verge; however, such conditions should not occur often in the field. Our storage stability test findings were contrary to the NIOSH Method 2557 specification of good stability for 7 days from sampling to analysis. (7) This may have been due to the fact that storage stability tests completed during method development used spiked sampling tubes without using hu mid air rather than our actively sampled tubes using a test atmosphere. As our results showed, early extraction mini mized further sample loss, especially when the samples were refrigerated in accordance with the method, which means that delays in analysis after extraction should not cause ap-preciable loss. A limitation of our work is that we did not collect in-tube storage data for all the tests to determine the effect of AH on sample recovery, but we did collect data for three target test atmosphere diacetyl concentrations and three target AH values. Thus, we estimated the effect of AH and the effect of in-tube storage on different data sets and combined the two models mathematically to create the final model. Our correction equations accounted for about 90% of the variability in the experimental data by taking into account the effects of AH, test atmosphere diacetyl concentration, sampling flow rate, and days of in-tube storage. The variability seen in the data at any combination of AH and diacetyl concen tration values has a number of sources, including variability in keeping test atmosphere conditions constant, variability in sampling flow rates during the tests, sampling duration differences (although not found significant), and analytical laboratory variability. Our test atmosphere experiments used no flavoring chem icals besides diacetyl. In field situations, diacetyl may occur together with other chemicals in the air. Any effect of these mixtures on the diacetyl recovery using NIOSH Method 2557 might not be accounted for with our correction procedure. Comparison between corrected diacetyl concentrations and the results from side-by-side samples taken with OSHA meth ods indicated a high correlation, which increases our con fidence in the applicability of the correction method. Despite the limitations, the correction procedure enables more accurate quantitative risk assessment now under way for regulatory guidance on occupational exposure to diacetyl. Representative exposures in the flavoring manufacturing industry are difficult to assess because of short-duration batch production methods in which hour-to-hour and day-to-day variations in diacetyl exposures is expected in workplaces where scores of different kinds of flavorings are manufactured. Hence, relative stabil ity of diacetyl exposures in microwave popcorn production facilities offers the advantage of less potential for exposure misclassification. However, without appropriate correction, the systematic underestimation of true diacetyl exposures in the 2000-2006 historical data would lead to overestimation of health risk associated with diacetyl exposure. Accordingly, use of our correction procedure to recalculate the historical exposure estimates from microwave popcorn production facilities previ ously studied by NIOSH and others will contribute to ongoing efforts to understand the health risk associated with occu pational exposure to diacetyl. Our experimental work may also motivate further research exploring the mechanism by which analyte recovery from CMS sorbent may be affected by sampling site humidity for a variety of analytes. # CONCLUSIONS W e have developed a mathematical procedure that al lows measurements from historical diacetyl samples collected and analyzed using NIOSH Method 2557, which may be biased low, to be adjusted for a more accurate exposure assessment. In addition to the historical laboratory-reported diacetyl concentrations, this correction procedure requires data on AH (determined from temperature and RH measurements) during sampling and on the number of days between sample collection and laboratory extraction of the sampling tubes. NIOSH Method 2557 should not be used to measure airborne diacetyl in future studies. # Overview To estimate worker exposures for risk assessment, we developed a job exposure matrix (JEM) containing estimates of the average 8-hour, time-weighted average (TWA) exposure levels for diacetyl vapor in parts per million parts air (ppm). This JEM includes estimates for eight major job categories with selected time periods specific for each job category to reflect changes in processes and engineering controls over time. The exposure levels presented in the JEM are based on diacetyl air sampling data collected during nine industrial hygiene surveys conducted by NIOSH industrial hygienists between November 2000 and July 2003 at a microwave popcorn plant in Missouri NIOSH 2006]. Details of the JEM construction are described below. # Industrial Hygiene Surveys A total of nine industrial hygiene surveys were conducted over a period of 4 years from 2000 to 2003. The sampling was typically conducted during the day shift, because this shift presented the opportunity to sample all job categories. However, samples were also collected from second and third shifts, but not routinely. The dates for these industrial hygiene surveys are presented in Table A4.l. Personal breathing zone (PBZ) and area diacetyl samples were collected during these surveys using NIOSH Method 2557. These measurements were subsequently adjusted to account for interferences due to humidity and sample storage . During all surveys except the first, full-shift PBZ samples were collected from workers performing typical tasks representative of each of the major job categories. In addition, concurrent full-shift area samples were taken throughout the plant from locations where workers would typically spend their time. The PBZ sample measurements were used to develop the exposure estimates for the eight job categories in the JEM. In some instances where personal diacetyl samples were not collected, for example during the first survey, area samples were used to obtain estimates of personal equivalent diacetyl exposures. # Creation of Job Categories and Estimation of Arithmetic Means For the purpose of developing exposure estimates for the JEM, plant job titles were aggregated into eight job categories based primarily on work and environmental similarities with respect to potential for diacetyl exposures . These eight categories are listed in Table A4.2 along with the jobs that comprise each category. Arithmetic means (AM) using PBZ samples were calculated for the cells in the JEM as the AMs are the preferred measure of central tendency for estimating cumulative exposure in chronic disease investigations . Few PBZ measurements were collected for most job categories in each of the nine surveys (range: n= 1-6) except for the job category of Microwave line (range n= . Moreover, a large fraction of the PBZ measurements were below the limit of detection (LOD) for most job categories (>50%) especially during surveys 6-9, except for the job categories of microwave packaging line, quality control and microwave mixing. Thus because of the small sample size and large fractions of LOD data, a simple substitution method ofreplacing LOD measurements with a value ofLOD/2 was used . The calculation of the arithmetic mean exposures by the different time periods is described in detail in the next section on "Creation of Exposure Periods." As noted earlier, PBZ diacetyl samples were not collected during survey 1 and had to be estimated from personal and area samples collected during subsequent surveys (i.e. surveys 2-9). A hierarchical approach was used to estimate the PBZ exposures for survey 1 depending on the job category and the availability and fraction of personal or area measurements below the LOD. To start with, for jobs categories with sufficient personal and area samples in surveys 2-9, a prediction model was used to estimate personal exposures from area exposure measurements (e.g. microwave mixers, microwave line, quality control). For job categories with small sample size and/or large fraction of measurements below the LOD for surveys 2-9, the arithmetic mean of the area samples from survey 1 was assigned to personal estimates for survey 1, assuming a ratio of 1 for personal to area measurements (e.g., warehouse, outside/office, polyethylene line). For jobs with no area measurements in survey 1 (e.g., bag print) or the area measurements were not representative of personal measurements (maintenance), exposure estimates from similar jobs in survey 1 were assigned. The detailed approach to calculate personal-equivalent diacetyl exposure for each job category for the first survey is described in Table A4.3. # 4 Creation of Exposure Periods After estimating the personal-equivalent exposures for survey 1, arithmetic means were calculated for the different time periods. Unique exposure time periods were developed for each of the eight job categories to reflect impact of the exposure control changes implemented at the plant between November 2000 to July 2003. Table A4.4 lists these exposure control changes according to the time of implementation. These exposure time periods varied by job categories since some control changes would have a greater impact on some job categories than others. In addition, the fraction of LOD samples for job categories during the different surveys also impacted the creation of time periods. Surveys for which a large fraction of the measurements for a job category were below the LOD were combined into one time period. For example, for warehouse, 50%-100% of personal measurements were below the LOD for surveys 3-9, hence these surveys were combined into one time period. For the selection of time periods for the job categories, the LOD patterns were consistent with the implementation of controls. The detailed approach used to create the time periods for each job category is described in Table A4.5. Thus a JEM was created consisting of 8 job categories and 2-5 time periods spanning the time duration from November 2000 to July 2003. # 5 Adjustment for Respirator Use The JEM created as described above was based on samples collected from workers breathing zone and did not account for respirator use by workers. However, during survey 4 and onward, workers in microwave mixing were using respirators and the JEM estimates were adjusted in the appropriate time periods to reflect the PPE use. Thus for the mixers during time periods 3 and 4, we adjusted the measured personal diacetyl exposure for the use of respirators. During these time periods, mixers used respiratory protection while in the mixing room and these respirators included either a P APR or air-line respirator with a loose fitting hood; both types of respirators have an applied protection factor (APF) of 25 . We assumed, based on survey observations and questionnaire responses, that mixers spent, on average, about 4 hours per shift in the mixing room in respiratory protection. Because respirators were required in the mixing room by plant management, we assumed that mixers wore respirators at all times while in the mixing room and did not wear these respirators when outside the mixing room and in the microwave packaging room. During these time periods, the mixers' desk was located in the microwave packaging room near packing line 1 so we further assumed that, when not in respirators in the mixing room, mixers would be in the microwave packaging area and receive diacetyl exposures consistent with those personal exposures measured in microwave packaging. The mixer personal samples were taken outside of the respirator and would reflect both mixing and packaging exposure components. Accordingly, to adjust mixer exposures to diacetyl for the use of respirator, we ( 1) determined the mixing room exposure component from the combined mixing and packing line diacetyl concentration as reflected in the personal sample (back calculated) and ( 2) applied a protection factor of 25 to the mixing room component of the mixers exposure. To determine the mixing room (A) personal diacetyl exposure from the combined mixing and packaging (C) concentration measured by personal sampling we applied the following equation: C = (4A(mixing) + 4B(packaging))/8; solving for A gives, A= 2C -B Where A= the mixing room personal exposure component in ppm, B =the packaging room personal exposure component in ppm, and C = the measured mixer personal exposure in ppm reflecting both mixing room and packaging room components. To correct the mixers exposure for the use of respiratory protection, we used the following equation: CR= 1h (A/25 + B) where CR= respirator adjusted mixer diacetyl exposure in ppm, A= personal mixer diacetyl exposure in the mixing room in ppm and B = personal diacetyl exposure in the microwave packaging area in ppm. This adjusted diacetyl concentration in ppm was applied to mixers for time periods 3 and 4 to adjust for the use of respiratory protection by mixers while in the mixing room. Calculate ratio of the survey 3 diacetyl mean for personal samples to the average of survey 3 diacetyl mean from personal samples for polyethylene, mixer, and microwave packaging line job categories. Apply this ratio to the average of the same three groups from survey 1 after they have been converted to personal equivalent exposures. 3Outside Processing I Office Use the mean of the area sample diacetyl concentrations from survey 1. Polyethylene Line Use the mean of the area sample diacetyl concentrations from survey 1. Microwave Mixing Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to determine personal equivalent diacetyl exposures. 6 Microwave Packaging Line Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to estimate personal equivalent exposures. Bag Print Use the average of the personal equivalent diacetyl exposures for survey 1 from the microwave packaging line and warehouse job categories. (Note: there were no bag print area diacetyl samples for survey 1) 8 Quality Control Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to determine personal equivalent diacetyl exposures. Microwave ovens moved into popping room in quality control lab 14 -18, 2003) Time 3 (Surveys 4 -7 sampling results): Reflects the control changes including the installation of an outside supply air intake system providing clean, tempered air into the warehouse, the completion of LEV ventilation on mezzanine flavor holding tanks and the air-lock installation on the mixing room. All these microwave mixing and production control changes would impact maintenance workers since they would work in these production areas. Also, maintenance exposures during this time period were still primarily above the LOD. Time 4 (Surveys 8 & 9 sampling results): Reflects the control changes including first use of enclosure of the mezzanine tanks. Additionally, maintenance exposures during this time period were largely below detectable limits. Outside Processing I Office Workers: Time I (Surveys I -9 sampling results): Reflects low, predominantly non-detectable exposures for workers who were outside (outside processing) or normally away from microwave mixing and production operations. Polyethylene Line: Time I (Surveys I & 2 sampling results): Reflects polyethylene line worker exposures before major control changes in the microwave production area that could impact polyethylene line workers; although exposures in this category were low by comparison to microwave production lines, there were some detectable diacetyl exposures in personal and area samples for polyethylene line workers during this time period so a separate time period was used. While the polyethylene lines were located away from the microwave production area, there was some potential for exposure in this work group prior to control changes. Reflects the first use of the new mixing room and the addition of new mixing room exhaust fans. This period also reflects enclosure of the mezzanine area reducing microwave production exposures outside the mixing room below quantifiable or detectable levels. Bag Printing: Time 1 (Survey 1 & 2 sampling results): Reflects exposures before major control changes that would impact bag printing exposures due to close proximity to the microwave production lines. Also, when the bag printing operations were shut down, bag print workers would often work on the microwave production lines. Time 2 (Survey 3 sampling results): Reflects the first control changes implemented in the microwave mixing room including the addition of exhaust ventilation, closed transfer of liquid flavorings, and flavor tank ventilation. These control changes would impact bag printing exposures since the bag print lines were located in the warehouse just outside a large open doorway into microwave production; additionally, when the bag printing operations were shut down, bag print workers would often work on the microwave production lines. Time 3 (Surveys 4 -7 sampling results): Reflects several control changes including the installation of an outside supply air intake system providing clean, tempered air into the warehouse and subsequently for microwave production area exhaust fans. This period also reflects completion of LEV ventilation on mezzanine flavor holding tanks and air-lock installation isolating the mixing room from packaging areas. Time (Surveys 8 & 9 sampling results): Reflects the first use of the new mixing room and the addition of new mixing room exhaust fans. This period also reflects enclosure of the mezzanine area reducing microwave production exposures outside the mixing room below quantifiable or detectable levels. Time 2 (Survey 3 sampling results): Reflects the first control changes implemented in the microwave mixing room including the addition of exhaust ventilation, closed transfer of liquid flavorings, and flavor tank ventilation. These changes would impact quality control exposures since the quality control room opened into the microwave production area. Also, the quality control room was generally under negative pressure relative to the microwave production room at this time. Time 3 (Surveys 4 -6 sampling results): Reflects installation of an exhaust fan and fresh air intake in the quality control lab. It also reflects several changes that would impact quality control worker exposures through reduction of diacetyl concentrations in the microwave mixing and production areas including the installation of an outside supply air intake system providing clean, tempered air into the warehouse and subsequently for microwave production area exhaust fans; installation of a mixing room air-lock; and ventilation of mezzanine flavor holding tanks. Time 4 (Surveys 7 & 8 sampling results): Reflects the enclosure of the microwave ovens in the quality control lab. Time 5 (Survey 9 sampling results): Reflects the relocation of all microwave ovens into a separate, ventilated room. This step reduced quality control exposures below detectable levels. Other control changes to the microwave production area during this period reduced microwave production exposures below detectable levels further impacting quality control exposures. Typical protocol for collecting air samples for diacetyl and 2, 3-pentanedione. While the elements of a well-designed exposure monitoring program are discussed in Chapter 10, the details of a typical sampling protocol for determination of airborne concentrations of diacetyl and 2, 3-pentanedione vapor are described here. This protocol, which is based on OSHA pentanedione. It consists of two silica gel tubes connected in series using the least amount as possible flexible tubing. Each tube contains a single 600-mg section of specially cleaned and dried silica gel with a glass-wool plug and a glass fiber filter at front of the tube before the silica gel, and another glass wool plug at the end of the tube. This method is selected because it has greater sensitivity than OSHA Method 1013. Method 1012 requires the use of an ethanol solution containing a derivatizing reagent to extract and chemically derivative diacetyl in the samples. # Preparation Before entering the work area all members of the sampling team should be made aware of any requirements for safety equipment such as hair nets, respirators, or safety shoes, and possess all necessary equipment and training, including respirator certification if needed. Procedures and schedules should be coordinated with the analytical laboratory to assure compatibility of procedures and availability of personnel to process samples in a timely manner. All sampling equipment and supplies should be prepared in advance. Equipment may include battery powered personal sampling pumps capable of operating in the appropriate flow rate range and pressure drop, chargers for those pumps, sample holders of a size compatible with the sampling media, and flexible tubing to connect pumps and sample holders. In this protocol diacetyl and 2, 3-pentanedione vapor samples are collected with two silica gel sorbent tubes in series (SKC Inc.,Eighty Four,PA,. The front tube is connected to the back tube with a piece of tubing to form the sampling train. If the sample holders are not opaque, these sorbent tubes should be wrapped in foil or opaque tape during and after sampling to prevent 2 exposure to light. Each sampling tube should be marked with a unique identification number, either before or after sampling. This information is entered in the field data sheet along with the corresponding pump ID, calibrated flow rate, and other information. A useful convention is to mark each of the two tubes of a sample with the same initial identifier, then add an "f' for the front tube and an "r" for the rear tube. Sampling trains should be assembled and calibrated with sampling media in line, and this sampling media should not be used for any other purpose. Nominal sampling rates for this method are 0.05 Lpm for 180-minute TWA samples and 0.2 Lpm for 15-minute STEL samples. Calibrated flow rate for each pump should be recorded on a field data sheet with an identification code for that pump. A supply of belts, clips, tape, and miscellaneous tools should be available to attach the sampling trains to workers to minimize interference or safety concerns with their jobs. # Collection To collect samples for the full work shift, the sampling team should be prepared to place sampling trains on the workers as they begin their shifts. Workers and locations to be evaluated should have been previously identified from knowledge of the tasks to be performed and the compounds to be used. A common practice in selecting sampling locations is to choose tasks anticipated to produce the greatest level of exposure to diacetyl or 2, 3-pentanedione and to sample the workers conducting those tasks or collect area samples in those areas. This allows for the greatest likelihood of obtaining samples above the limit of detection for the analytical method, and assumes that if exposure is controlled so that the highest exposures are within allowable limits then all exposures are within those limits. Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Attach the tube holder to the worker so that the adsorbent tube is in an approximately vertical position with the inlet in the breathing zone. Position the sampling pump, tube holder, and tubing so they do not impede work performance or safety. As each sampling train is placed and started, the start time should be noted on the field data sheet for that pump, along with the name or other identifier of the person wearing that pump, job title or a description of tasks, and location within the work facility. Sampling site temperature, relative humidity, barometric pressure, and any other relevant observations should be recorded on field data sheets throughout the duration of sampling. Members of the sampling team should rotate among the sampling locations during the collection of samples. They should occasionally check all sampling devices, observe workers tasks, and note observations on the field data sheet. The use of personal protective equipment and other safety and health controls, ventilation, and all other salient observations should also be noted. Attempt to determine through observation and discussions if workers are engaging in "normal operations." OSHA states a reliable quantitation limit of 1.3 ppb ( 4.57 ug/m 3 ) for diacetyl and 9.3 ppb (38 µg/m 3 ) for 2, 3-pentanedione with a 180-minute sample duration and a flow rate of 0.05 lpm (or 15 minutes at 0.2 lpm). If the shift being sampled is 8 hours long, three samples approaching 180 minutes would be acceptable to obtain a TWA analyte concentration. These samples should be able to quantify diacetyl and 2, 3-pentanedione at the REL of 5 ppb) TWA or 25 ppb) STEL without exceeding the breakthrough capacity of the sorbent media. # Sampling Surveys Employers shall conduct exposure monitoring surveys to ensure that worker exposures (measured by full-shift samples) do not exceed the REL, either on a time weighted or short term basis. Because adverse respiratory health effects may occur at the REL, it is desirable to achieve lower concentrations whenever possible. When workers are potentially exposed to airborne flavoring compounds, employers shall conduct exposure monitoring surveys as follows: - Collect representative personal samples over the entire work shift . - Perform periodic sampling at least annually and whenever any major process change takes place or whenever another reason exists to suspect that exposure concentrations may have changed. - Collect all routine personal samples in the breathing zones of the workers. - If workers are exposed to concentrations above the REL, perform more frequent exposure monitoring as engineering changes are implemented and until at least two consecutive samples indicate that exposures no longer exceed the REL . - Notify all workers of monitoring results and of any actions taken to reduce their exposures. - When developing an exposure sampling strategy, consider variations in work and production schedules as well as the inherent variability in most area sampling . # Focused sampling When sampling to determine whether worker exposures to diacetyl or 2, 3-pentanedione are below the REL, a focused sampling strategy may be more practical than a random sampling approach. A focused sampling strategy targets workers perceived to be exposed to the highest concentrations of a hazardous substance . This strategy is most efficient for identifying exposures above the REL if maximum-risk workers and time periods are accurately identified. Short tasks involving high concentrations of airborne vapors could result in elevated exposure over full work shifts. # Area sampling Area sampling may be useful in exposure monitoring to determine sources of airborne diacetyl or 2, 3-pentanedione, and to assess the effectiveness of engineering controls. # Post-collection After sampling for the appropriate time, remove the sampling train, record stop time, and remove equipment to an uncontaminated area where you can separate the tubes, and seal each tube with plastic end caps. Although tubes were protected from light during sampling, it is also necessary to wrap each tube in aluminum foil or opaque tape making sure that the sample identification number is observable. Samples should be shipped cold (preferable via an overnight carrier) to the accredited analytical laboratory using a "six-pack" cooler and frozen ice packs (Blue Ice) or similar means to refrigerate samples. Submit blank samples as discussed with the laboratory with each set of samples. Handle the blank samples in the same manner as the other samples except draw no air through them. Measure the air flow rate through each sampling train (using surrogate sampling media in line, not the actual sample), record this post-sampling flow rate. Determine total sampling time (minutes), mean sampling flow rate, and sample volumes (liters). Place sampling pumps on charge for reuse in required. Submit the samples to the laboratory for analysis as soon as possible after sampling. As a precaution, store the samples at refrigerator temperature if a delay in shipment is unavoidable. Ship any bulk samples separate from the air samples.	Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure levels that are safe for various periods of employment, including but not limited to the exposures at which no employee will suffer diminished health, functional capacity, or life expectancy because of his or her work experience. Criteria documents contain a critical review of the scientific and technical information about the prevalence of hazards, the existence of safety and health risks, and the adequacy of control methods. By means of criteria documents, NIOSH communicates these recommended standards to regulatory agencies, including the Occupational Safety and Health Administration, health professionals in academic institutions, industry, organized labor, public interest groups, and others in the occupational safety and health community. This criteria document is derived from the NIOSH evaluation of critical health effects studies of occupational exposure to diacetyl and 2,3-pentanedione. It provides recommendations for controlling workplace exposures including recommended exposure limits derived by using current quantitative risk assessment methodology on human and animal health effects data.# Using cross-sectional pulmonary function data from diacetyl-exposed employees, NIOSH conducted assessments to determine the exposure-response relationship and to identify risk of pulmonary function decrease at various levels of diacetyl exposure. NIOSH found that a relationship exists between diacetyl exposures and lower pulmonary function. Utilizing this analysis, NIOSH recommends keeping exposure to diacetyl below a concentration of 5 parts per billion as a time-weighted average during a 40-hour work week. To further protect against effects of short-term exposures, NIOSH recommends a short-term exposure limit for diacetyl of 25 parts per billion for a 15-minute time period. In many operations, 2,3-pentanedione is being used to substitute for diacetyl. Published toxicological studies indicate that 2,3-pentanedione exposure can cause damage similar to that caused by diacetyl in laboratory studies. Therefore, NIOSH recommends keeping occupational exposure to 2,3-pentanedione below a level comparable to the level recommended for diacetyl. However, the recommended sampling and analytical method can only reliably quantify it to 9.3 parts per billion in an 8-hour sample. NIOSH also recommends a short-term exposure limit for 2,3-pentanedione of 31 parts per billion during a 15-minute period. Engineering and work practices are available to control diacetyl and 2,3-pentanedione exposures below the recommended exposure limits. A hierarchy of controls including elimination, substitution, engineering controls, administrative controls, and the use of personal protective equipment should be followed to control workplace exposures. # Executive Summary Diacetyl and its substitute, 2,3-pentanedione, are widely used flavoring compounds. There have been extensive reports of serious respiratory disease and decreased lung function in employees exposed to diacetyl. The NIOSH objective in establishing recommended exposure limits (RELs) for diacetyl and 2,3-pentanedione is to reduce the risk of respiratory impairment (decreased lung function) and the severe irreversible lung disease obliterative bronchiolitis associated with occupational exposure to these compounds. In this disease the smallest airways in the lungs, the bronchioles, become scarred and constricted, blocking the movement of air. In addition, maintaining exposures below the RELs will help prevent other adverse health effects including but not limited to irritation of the skin, eyes, and respiratory tract in exposed employees. The recommendation to limit exposure to diacetyl and 2,3-pentanedione is based upon data from human and animal studies and the quantitative risk assessment; however, additional considerations include sampling and analytical feasibility and the achievability of engineering controls. Diacetyl is used extensively in the food flavoring and production industries, and occupational exposure to this substance has been associated with severe respiratory impairment and the disease obliterative bronchiolitis. 2,3-Pentanedione, which has been used as a substitute for diacetyl, is also of concern because of structural similarities with diacetyl and because animal studies show similar toxicity for the respiratory tract [Hubbs et al. 2012;. The first observation of obliterative bronchiolitis in a food production employee may have occurred in 1985 in a facility where diacetyl was listed among ingredients used in making flavorings for the baking industry [NIOSH 1985]. The link between exposure to diacetyl and lower pulmonary function was confirmed in the early 2000s, and research further showed that diacetyl exposure leads to a decrease in pulmonary function . Occupational exposures to diacetyl have been assessed in a variety of food production and flavoring facilities Martyny et al. 2008;NIOSH 2003aNIOSH , b, 2004aNIOSH , b, 2006NIOSH , 2007NIOSH , 2008aNIOSH , b, 2009NIOSH , 2011. Another compound, acetoin, was present along with diacetyl in many of the workplaces where obliterative bronchiolitis occurred in employees who made or used diacetyl ; . However, current data indicate that acetoin is considerably less hazardous than diacetyl and it does not have the reactive α-dicarbonyl group, which has been implicated in the toxicity of diacetyl and 2,3-pentanedione [Hubbs et al. 2016;National Toxicology Program 2015;Zaccone et al. 2013]. Mean diacetyl air concentrations measured at the first microwave popcorn facility where obliterative bronchiolitis was reported were highest in the mixing room (57.2 parts per million [ppm]), followed by the packaging area (2.8 ppm) . Mean personal diacetyl air concentrations at five other microwave popcorn plants were lower: 0.023 to 1.16 ppm in the mixing room and 0.35 to 1.33 ppm in the packaging rooms/areas ]. Mean full-shift diacetyl air concentrations measured vi Occupational Exposure to Diacetyl and 2,3-Pentanedione at flavor manufacturing facilities ranged from 0.07 ppm to 2.73 ppm Martyny et al. 2008;NIOSH 2003aNIOSH , b, 2004aNIOSH , b, 2006NIOSH , 2007NIOSH , 2008aNIOSH , b, 2009NIOSH , 2011. In addition to cases consistent with obliterative bronchiolitis in flavoring manufacturing, diacetyl manufacturing, and microwave popcorn production, case reports have surfaced in other industries in which flavorings are introduced. In cookie manufacturing with artificial butter flavoring in Brazil, four cases of bronchiolitis were described in young men, aged 24 to 27 years, who had worked between 1 and 3 years handling flavorings in preparation of cookie dough [Cavalcanti et al. 2012]. In a coffee production plant, two cases have biopsy confirmation of obliterative bronchiolitis among employees with artificial flavorings exposure in the production of roasted coffee beans and ground coffee [ CDC 2013]. In 2012, NIOSH conducted a health hazard evaluation (HHE) involving 75 current employees (88% participation) [Bailey et al. 2015]. Excluding the five sentinel former employees (all never-smokers under age 42), standardized morbidity ratios were elevated 1.6-fold for shortness of breath and 2.7-fold for obstructive spirometric abnormalities. Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetylexposed employees presented in Chapter 3 have provided substantial evidence of a causal relationship between diacetyl exposure and development of this disease. These findings in conjunction with laboratory experiments providing biological plausibility, meet the standard criteria used to determine causation: that an exposure is the likely cause of specific health effects [Gordis 1996;Hill 1965]. NIOSH has reviewed the literature on diacetyl toxicology and exposures in the workplace and subsequently conducted a quantitative risk assessment. The quantitative risk assessment used to derive the REL was based solely on human (employee) data, but the results were informed and corroborated by animal risk assessments. On the basis of a quantitative risk assessment of data collected in a series of NIOSH health hazard investigations (full description in Chapter 5), NIOSH has concluded that employee exposure to diacetyl is associated with a reduction in lung function. Specifically, a statistically significant exposure-associated reduction in the forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ratio and percent predicted FEV 1 (ppFEV 1 ) and an exposure-associated estimated incidence of symptomatic obstructive lung disease were observed. NIOSH quantified these exposureresponse relationships and determined the exposure levels that correspond to a variety of risks (Chapter 5, Table 5.35). Lifetime risks in the range of 1:1,000 corresponded to working lifetime diacetyl exposure of approximately 5 parts per billion (ppb). Once the risks were characterized, NIOSH examined the analytical methods (OSHA Methods 1012 and 1016) and available engineering controls and determined that they supported establishing a REL at that level. It should be noted that diacetyl and 2,3-pentanedione are found in cigarette smoke [Fujioka and Shibamoto 2006;Pierce et al. 2014;Polzin et al. 2007] and some flavored e-cigarettes [Allen et al. 2016;Farsalinos et al. 2015]. As extensively discussed in Chapter 3, increased prevalence of airway obstruction and decreased FEV 1 can be identified in smokers who are exposed to diacetyl in comparison to prevalence in smokers in the U.S. population. Most importantly, because diacetyl causes obstructive lung disease and because smoking causes obstructive lung disease, the presence of diacetyl in cigarette smoke in no way diminishes the need to control diacetyl exposures in employees. NIOSH concludes that the toxicological responses to diacetyl observed in animal studies support the conclusions of the epidemiologically-based risk assessment for diacetyl. Further, the animal-based Occupational Exposure to Diacetyl and 2,3-Pentanedione vii risk assessment presented in Chapter 6 corroborates the epidemiologic assessment by demonstrating a causal link between diacetyl exposure and respiratory health effects and by showing a clear doseresponse relationship in exposed animals as was observed in employees exposed to diacetyl in the epidemiologic assessment. On this basis, NIOSH recommends a REL of 5 ppb for diacetyl as a time-weighted average (TWA) for up to 8 hours/day during a 40-hour workweek. NIOSH has determined that employees exposed to diacetyl at this level for 8 hours a day, 40 hours a week for a 45-year working lifetime should have no more than a 1/1,000 excess risk of lung function falling below the lower limit of normal due to diacetyl exposure. To ensure that employee exposures are routinely below the REL for diacetyl, NIOSH also recommends using an action level (AL) of 2.6 ppb with the exposure monitoring program to ensure that all control efforts (engineering controls, medical surveillance, and work practices) are in place and working properly. When exposures exceed the AL, employers should take corrective action (determine the source of exposure, identify methods for controlling exposure) to ensure that exposures are maintained below the REL. NIOSH has concluded that the use of an AL in conjunction with periodic monitoring of employee exposures (described in Chapter 10) is helpful to protect employees. NIOSH is also recommending a short-term exposure limit (STEL) for diacetyl of 25 ppb for a 15-minute time period. The establishment of a STEL is based on the concern that peak exposures may have greater toxicity than the same total dose spread out over a longer period of time. 2,3-Pentanedione is used in many operations; it is structurally similar to diacetyl because it is a 5-carbon alpha diketone, whereas diacetyl is a 4-carbon alpha diketone. Published toxicology studies indicate that 2,3-pentanedione exposure can cause damage to the lining of airways similar to that caused by diacetyl in laboratory studies [Hubbs et al. 2012;. Therefore, NIOSH recommends controlling occupational exposure to 2,3-pentanedione to a level comparable to that recommended for diacetyl. However, analytical limitations allow 2,3-pentanedione to be reliably measured only above 9.3 ppb. This recommended exposure limit is slightly higher than the recommended exposure limit for diacetyl. NIOSH recommends keeping exposure to 2,3-pentanedione below 9.3 ppb in an 8-hour average during a 40-hour work week. NIOSH has estimated that employees exposed to 2,3-pentanedione at this concentration should have a similar risk of decreased pulmonary function as employees exposed to diacetyl. NIOSH also recommends a short-term exposure limit for 2,3-pentanedione of 31 ppb during a 15-minute period. Research into various flavoring industries has led to the development of engineering controls that may help reduce employee exposure to diacetyl, 2,3-pentanedione, and other chemicals. Chapter 8 describes engineering controls for the industries where diacetyl is handled or used within products. Table 8.2 in Chapter 8 provides a summary of NIOSH-evaluated engineering control efficiencies for the mixing of food flavorings. NIOSH acknowledges that the frequent use of personal protective equipment (PPE), including respirators, may be required for some employees who handle diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products. The frequent use of PPE may be required during job tasks for which (1) routinely high airborne concentrations of diacetyl or 2,3-pentanedione (e.g., pouring, mixing, packaging) exist, (2) the airborne concentration of diacetyl or 2,3-pentanedione is unknown or unpredictable, and ( 3) job tasks are associated with highly variable airborne concentrations because of environmental conditions or the manner in which the job task is performed. In all work environments viii Occupational Exposure to Diacetyl and 2,3-Pentanedione where diacetyl, 2,3-pentanedione, diacetyl-containing flavorings, or flavored products are found control of exposure through engineering controls should be the highest priority. NIOSH recommends that employers develop and implement comprehensive occupational safety and health programs to protect employees with potential exposure to diacetyl, 2,3-pentanedione, and other potentially hazardous flavoring compounds. This program should include periodic exposure and medical evaluation and monitoring exposure controls and appropriate employee training on potential health effects, respiratory protection, and use of controls. Employers should (1) determine employee exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds used in the workplace; (2) evaluate the effectiveness of work practice and engineering controls; and (3) facilitate the selection of appropriate personal protective equipment. Because diacetyl and 2,3-pentanedione are found in cigarette smoke [Fujioka and Shibamoto 2006;Pierce et al. 2014;Polzin et al. 2007] and e-cigarettes, NIOSH also recommends that all employers make tobacco cessation programs available to employees and have workplaces that are free of tobacco smoking and vaping with flavored nicotine delivery systems [NIOSH 2015]. All permanent, temporary, and contract employees who work in or enter areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds or products that contain these compounds are used or produced should be included in the medical monitoring program. Employees who work in or enter these areas for a total of 40 or more hours per year should be included in the medical monitoring program. Because of the potentially rapid progression and grave consequences of flavoring-related lung disease, it is important that the medical monitoring program director be able to quickly evaluate clinical data and make medical judgments about appropriate diagnostic and therapeutic measures, including medical removal. For this reason, the medical monitoring program director should be a licensed physician with training and experience in identifying and preventing occupational lung disease. The medical program that includes the following: ■ good quality spirometry testing for pulmonary function ■ medical evaluation for employees found with abnormal spirometry ■ removal from exposure pending medical evaluation ■ analysis of group medical surveillance and longitudinal spirometry data to assess workrelated risk factors on the basis of job, task, area, and other exposure indices The purpose of this epidemiologic surveillance is to assist monitoring physicians in assessing the likelihood of work-related causes of abnormalities and to prioritize interventions, if needed. Identifying excessive declines in spirometry, even if absolute spirometric values remain within the normal range, offers the best opportunity to intervene before progression to symptomatic impairment and to prevent the development of clinically significant occupational lung disease. The rapid onset and progression of diacetyl-related lung disease requires more frequent medical monitoring evaluations be done than with slowly progressive occupational lung diseases, such as silicosis and coal employees pneumoconiosis. While the focus of this document is on diacetyl and 2,3-pentanedione, NIOSH has concern regarding other volatile and reactive flavorings potentially capable of producing similar toxic effects. Therefore, NIOSH recommends that such exposures be carefully considered and controlled in consultation with workplace safety professionals and the recommendations contained within this criteria document. 1 Introduction # Purpose This document presents the criteria and components of a recommended standard necessary to reduce or eliminate significant risk of health impairment from exposure to diacetyl and 2,3-pentanedione and prevent flavorings-related lung disease. This document was developed in accordance with the Occupational Safety and Health Act of 1970 [29 U.S.C. 669(a)(3); 29 U.S.C. 671(c) (1)]. This Act charges NIOSH with recommending occupational safety and health standards and developing criteria for toxic materials. These criteria are to describe exposures that are safe for various periods of employment, including but not limited to the exposures at which no employee will suffer diminished health, functional capacity, or life expectancy as a result of his or her work experience. The purpose of the criteria document is to evaluate the scientific literature concerning potential health effects, toxicology, risk assessment, engineering controls, work practices, personal protective equipment, and recommendations pertaining to diacetyl and 2,3-pentanedione. The criteria document provides a basis for the REL for diacetyl and 2,3-pentanedione, although compliance with this recommended standard is not the sole objective. The intended outcome of the document is to reduce occupational exposures to diacetyl and 2,3-pentanedione and thereby prevent flavorings-related lung disease through hazard guidance implementation. In their entirety, the RELs and the guidance are intended to help employers develop a more healthful work environment. The RELs and guidance will also provide useful information to help employees actively participate in their own protection. # Scope This criteria document contains a review of relevant scientific information related to diacetyl and 2,3-pentanedione, and provides the rationale and criteria for establishing appropriate risk management recommendations. The basis for developing a criteria document on diacetyl and 2,3-pentanedione is described in this chapter. Chapter 2 provides an overview of studies conducted to characterize occupational exposure to diacetyl and 2,3-pentanedione. Chapter 3 describes the health effects observed in employees exposed to diacetyl and other flavoring compounds. Chapter 4 describes toxicology research from diacetyl and 2,3-pentanedione, while Chapters 5 and 6 describe the assessment of risk based on available human and animal data. Chapter 7 provides the basis for the RELs for diacetyl and 2,3-pentanedione. Chapter 8 describes procedures for informing employees about the safety of diacetyl and diacetyl substitutes as well as engineering interventions that could significantly reduce exposures when appropriately applied and fully operational. Also included in Chapter 8 are recommendations for establishing globally harmonized system for classification and labelling (GHS) classifications for diacetyl and 2,3-pentanedione based on the revised OSHA hazard communication standard. Additionally, recommendations for an effective respiratory protection program are provided. Chapter 9 provides medical surveillance guidelines for the ongoing evaluation of the health status of employees. Chapter 10 describes the components of an effective exposure monitoring program and work practices that when implemented correctly, can reduce occupational exposures. Finally, Chapter 11 presents key research needs. This document results from a review of all relevant literature on diacetyl and 2,3-pentanedione, and describes selected studies which characterize exposures and discusses techniques shown to be effective in reducing those exposures. Published literature through October 2016 was used and extracted from databases including but not limited to PubMed, NIOSHTIC-2, Web of Knowledge, Toxline, and Chem Abstracts. The literature search was developed to identify critical scientific data relevant to workplace safety and health including physical and chemical properties, human health effects, laboratory testing, chemical toxicokinetics, toxicity, engineering controls, personal protective equipment and function, risk management, and modeling systems that are relevant to diacetyl and 2,3-pentanedione. The literature was searched using specific terminology for each scientific discipline. Evaluated data sources included peer reviewed journal articles, government publications, and peer reviewed data sources, high caliber professional practice manuals (i.e., ACGIH 2012 andFEMA 2012) and high-quality information submitted to government dockets. In a few instances personal communications are cited where authors were contacted for additional clarification. The information that was identified in the comprehensive literature search was evaluated with considerations that included if the studies were peer-reviewed, if the data were generated with standardized protocols, if the exposure conditions were described in detail, confounders and existing information in peer reviewed journals. Specific studies pertaining to workplace exposure assessment, human health effects, and toxicology were specifically identified and are described in Chapters 2, 3, and 4 respectively. # Background Diacetyl is one of the main components in butter flavoring that imparts a buttery taste, and it has been identified as a prominent volatile organic compound (VOC) in air samples from microwave popcorn plants and flavoring manufacturing plants Ashley et al. 2008;Kanwal 2003;Kanwal and Martin 2003;Martyny et al. 2008;NIOSH 2004a;Parmet and Von Essen 2002]. Diacetyl is used as a natural and artificial flavoring ingredient and aroma carrier in bakery products, dairy products, snack foods, and more. It is mainly used as a butter flavoring but is also used in the flavor formulation of a number of other flavors, including but not limited to strawberry, caramel, hazelnut, and butterscotch. It is also present as a natural byproduct in some fermented food products such as beer and roasted food products such as coffee. Occupational exposures in the flavoring and food production industries have been associated with respiratory disease, including obliterative bronchiolitis, an uncommon lung disease often characterized by fixed airways obstruction. Obliterative bronchiolitis refers to disease processes that show some degree of inflammation, narrowing, or obliteration of small airways (bronchioles) in the lung and is discussed in more detail in Chapter 3, specifically section 3.1.1. Although a causative relationship between diacetyl and respiratory disease has been observed, diacetyl may not be the only flavoring compound related to health impairment. Other flavoring ingredients such 1 . Introduction as acetaldehyde, butyric acid, and acetoin, have been present in workforces with adverse health effects [Lockey et al. 1998; ]. In addition, new diacetyl substitutes with little or no toxicological information related to occupational safety and health are being used in production. Day et al. [2011] observed the flavoring compound 2,3-pentanedione in food production facilities. This compound has been used as a diacetyl substitute in many flavor manufacturing facilities because it has a related chemical structure and similar flavor properties to diacetyl. Published reports on the toxicity of 2,3-pentanedione from experimental inhalation studies with rats indicate that exposure causes airway epithelial damage similar to that produced by diacetyl [Hubbs et al. 2012;. No state or national registries are available to identify potential cases of obliterative bronchiolitis among employees. In 1985, two employees with fixed obstructive lung disease suggestive of obliterative bronchiolitis were observed in a facility where flavorings with diacetyl were made for the baking industry NIOSH 1986]. Catastrophic fixed airways disease suggestive of obliterative bronchiolitis was observed in these two former mixing employees who were young nonsmokers with job tasks that involved blending corn starch and flour with various flavorings. Two additional employees who formerly had mixing responsibilities also had otherwise unexplained obstruction, whereas two current mixers were unaffected. A review of common ingredients listed diacetyl among other flavoring compounds. In the microwave popcorn industry, the first occurrences of obliterative bronchiolitis were observed in the year 2000 when eight employees formerly employed in a microwave popcorn facility were diagnosed with the disease . The observation of this case series led to the identification of another case of obliterative bronchiolitis in a separate facility [ Parmet 2002]. Since then, numerous cases of obliterative bronchiolitis have been observed in the microwave popcorn industry CDC 2002;Ezrailson 2002;NIOSH 2003NIOSH , 2004aNIOSH , b, 2006Parmet 2002;Schachter 2002]. In addition, a retrospective epidemiologic study found cases of obliterative bronchiolitis in employees who were employed in a diacetyl manufacturing plant with exposures to diacetyl, acetoin, acetic acid, and acetaldehyde . In 2004 and 2006, two cases of obliterative bronchiolitis among employees who made food flavorings were reported to the California Department of Public Health (CDPH). An industry-wide public health investigation performed by CDPH, the California Occupational Safety and Health Administration (Cal/OSHA), and NIOSH initially found an additional five employees with severe, fixed obstructive lung disease [CDC 2007]. Outreach to the industry regarding the diacetyl hazard, including Cal/OSHA consultation site visits, prompted quick implementation of exposure controls and medical surveillance programs. A longer-term effort was focused on companies' installation of effective engineering controls and further assessment of medical surveillance findings over time by CDPH and NIOSH. A crosssectional analysis of medical surveillance data from 16 companies confirmed the risk of lung disease among employees at companies using diacetyl [Kim et al. 2010]. In 2010, California issued the first occupational standard for diacetyl [California Code of Regulations. Title 8,§5197]. Employees within the flavoring production industry have complex exposures in terms of the physical form of the agents (vapors, mists, and airborne dusts) and the number of different chemicals used. Although thousands of flavoring compounds are in use, few have occupational exposure limits. The Flavor and Extract Manufacturers Association (FEMA) reports that of the more than 1,000 flavoring compounds considered to be potential respiratory irritants or hazards, only 46 have established OSHA permissible exposure limits (PELs) [FEMA 2012]. Given the lack of occupational exposure limits for most flavoring compounds, assessing workplace exposures and developing exposure control guidance are critical to help reduce the risk of flavorings-related lung disease. In 2010, California promulgated a regulation for occupational exposure to food flavorings containing diacetyl that requires installation of exposure controls to reduce exposures to the lowest feasible levels. In 2012, the American Conference of Governmental Industrial Hygienists (ACGIH) published a threshold limit value® of 0.010 ppm 8-hour TWA with a STEL of 0.020 ppm for diacetyl [ACGIH 2012]. In 2014, the European Commission published the Recommendation from the Scientific Committee on Occupational Exposure Limits of 0.02 ppm 8-hour TWA with a STEL of 0.10 ppm for diacetyl [EU 2014]. # Chemical and Physical Properties The compound diacetyl has Chemical Abstract Service (CAS) number 431-03-8 and has several synonyms including 2,3-butanedione (International Union of Pure and Applied Chemistry nomenclature), 2,3-butadione, 2,3-diketobutane, biacetyl, dimethyl diketone, and dimethylglyoxal. The compound 2,3-pentanedione has CAS number 600- and is also referred to by the name acetyl propionyl. Both diacetyl and 2,3-pentanedione are alpha diketones or vicinal diketones (also referred to less specifically as alpha dicarbonyls), which means that their molecular structures contain two carbonyl functional groups that are adjacent to one another, and the carbon molecules attached to the oxygen molecules are also attached to only carbon molecules. A listing of physical and chemical properties of diacetyl and 2,3-pentanedione and their molecular structures is presented in Table 1-1. The odor threshold of diacetyl and 2,3-pentanedione has been reported by many studies [Buttery et al. 1997;Hall and Andersson 1983;Leksrisompong et al. 2010;Nagata and Takeuchi 1990;Sega et al. 1967]. It is not uncommon for odor threshold values reported in the literature to range over four orders of magnitude for the same chemical [AIHA 1989]. Odor threshold variability can result from the source of data, the characteristics of human olfactory response, and the differences in experimental methodology [AIHA 1989]. The following criteria were used to analyze the diacetyl and 2,3-pentandione odor threshold literature: (1) only primary odor threshold sources that were found in the literature and that were written in English were used; (2) only sources that clearly indicated the type of threshold being measured as a detection or recognition threshold were used; (3) sources that used a panel of at least five judges to account for the range of olfactory sensitivity in the population were used; and ( 4) sources that presented the different concentrations of odor samples in a way that eliminated olfactory fatigue were used. The geometric mean of the selected values was reported in Diacetyl can be synthesized chemically from four starting materials: (1) from methyl ethyl ketone, either by converting it into an isonitroso compound and then hydrolyzing with hydrochloric acid or by partial oxidation of methyl ethyl ketone over a copper or vanadium oxide catalyst [Aquila et al. 2001;6 Occupational Exposure to Diacetyl and 2,3-Pentanedione Odor detection threshold 0.27 ppb [Hall and Andersson 1983;Nagata and Takeuchi 1990] (odor measurement of diacetyl vapor-air mixtures). Note: geometric mean of two literature reported threshold values with a geometric standard deviation of 5.33 ppb. 0.84 ppb [Buttery et al. 1997;Leksrisompong et al. 2010;Sega et al. 1967] (odor measurement of diacetyl vapor in the headspace above aqueous solutions, diacetyl concentrations in solution converted to air concentrations using Henry's Law constant). Note: geometric mean of three literature reported threshold values with a geometric standard deviation of 1.44 ppb. 1.2 ppb [Lawless et al. 1994] (recognition threshold) Note: not a geometric mean because obtained from a single source. 15 ppb [Hall and Andersson 1983] (odor measurement of 2,3-pentanedione vapor-air mixtures). Note: compared to 1.4 ppb for diacetyl obtained from the same reference. ¶ 9.4 ppb [Buttery et al. 1997] (odor measurement of 2,3-pentanedione vapor in the headspace above aqueous solutions, 2,3-pentanedione concentration in solution converted to an air concentration using Henry's Law constant). Note: compared to 0.70 ppb for diacetyl obtained from the same reference. ¶ National Toxicology Program 2007]; (2) from 2,3-butanediol, by oxidative dehydrogenation of 2,3-butanediol over a copper or silver catalyst [National Toxicology Program 2007]; (3) from acetoin (obtained by electrochemical oxidation of methyl ethyl ketone), by reacting acetoin with molecular oxygen in the presence of a copper oxide catalyst [Aquila et al. 2001]; or, ( 4) from 1-hydroxyacetone (obtained by dehydrogenation of 1,2-propanediol), by the acid-catalyzed condensation of 1-hydroxyacetone with formaldehyde [National Toxicology Program 2007]. Diacetyl is also a byproduct of fermentation. Natural diacetyl is used in the form of starter distillate, a concentrated flavor distillate, which may contain different concentrations of diacetyl depending on production conditions [Burdock 1997]. The compound 2,3-pentanedione is also naturally produced by fermentation and is recovered from dairy waste to be used as a flavoring ingredient [Miller et al. 1998]. The chemical synthesis of 2,3-pentanedione is achieved in the following ways: (1) the condensation of lactic acid and an alkali metal lactate [Miller et al. 1998]; (2) the acid-catalyzed condensation of 1-hydroxyacetone with paraldehyde [Lambrecht et al. 2004]; or (3) the oxidation of 2-pentanone with excess sodium nitrite and diluted hydrochloric acid in the presence of hydroxylamine hydrochloride [Burdock 1997]. # Production Uses and Applications The flavor manufacturing industry commonly uses diacetyl and 2,3-pentanedione during flavor formulation production. Flavor formulations are then sold to downstream users for the production of flavored food products. Flavored food production is the process of manufacturing food and beverage products that contain added flavor formulations or flavorings to enhance or modify the taste of the product. Examples of flavored food products include bakery products such as cake mixes, flour and margarines, dairy products such as cheese and yogurt, snack foods such as soft spreads and crackers, beverages such as soft drinks, in addition to candy, ice cream, frozen foods, and many other food and beverage products. The addition of concentrated flavorings including diacetyl is a cost effective way to impart the desired properties to manufactured food items. In flavor formulations, diacetyl and 2,3-pentanedione are typically found as components in liquid solutions but can also be added to powders in dry mixtures to create a solid particulate formulation. Many volatile compounds are also encapsulated in an amorphous carbohydrate, producing more stable products with more manageable properties. Encapsulated powder flavorings are often created with a spray dryer, which converts a slurry mixture into a powder in which the flavorings are surrounded by the powder instead of simply coating the powder. When the encapsulated powder comes into contact with moisture, the flavor is released quickly and completely [Ubbink and Schoonman 2002]. The percentage of diacetyl or 2,3-pentanedione in a particular flavor formulation varies widely depending upon the product and its use. In past years, microwave popcorn contained the highest proportion of diacetyl ranging from 1% to 25% diacetyl [ Hallagan 2007]. The diacetyl content in flavor formulations has declined rapidly as many manufacturers have reduced or substituted diacetyl with other flavoring compounds with similar characteristics, such as 2,3-pentanedione. Most confectionary flavors contain up to 1% diacetyl while marshmallow production uses up to 5% [ Hallagan 2007]. Starter distillate, produced by fermenting milk with starter cultures, contains diacetyl in the range of 1% to 5% and is often used as a flavor enhancer in the dairy industry. Diacetyl is the major flavor component of starter distillate, constituting as much as 80% to 90% of the mixture's organic flavor compounds [FDA 2009]. A NIOSH health hazard evaluation (HHE) at a modified dairy production company found concentrations of airborne diacetyl ranging up to 2.14 parts per million on a full-shift TWA basis [NIOSH 2009]. Diacetyl is also used as a chemical modifier of arginine residues in proteins in studying glycation (the nonenzymatic browning of foods or the nonenzymatic binding of sugar and protein molecules in the body) [Saraiva et al. 2006]. Other uses for diacetyl include reactant/starting material in chemical or biochemical reactions, analytical reagent, antimicrobial/preservative, electron stabilizing compound and modifier of radiation response for chemical and biological systems, and photoinitiator/photosensitizer in polymerizations [National Toxicology Program 1994]. # Potential for Exposures It is difficult to quantify the number of employees directly involved with flavor manufacturing and more specifically having exposure to diacetyl or diacetyl substitutes in the United States. According to the Environmental Protection Agency (EPA) Non-Confidential Inventory Updating Report, diacetyl had an aggregate production volume between 10,000 and 500,000 pounds in [EPA 2002. The North American Industry Classification System (NAICS) category 311, the most relevant category, indicates nearly 1.5 million employees are employed in food manufacturing. Bureau of Labor Statistics and Department of Commerce data provide a breakdown of a portion of that number into categories shown in Table 1-2. According to the FEMA, whose members account for approximately 95% of all flavors produced in the United States, a total of 6,520 employees work directly in flavor manufacturing or related laboratory activities in membership companies [ Hallagan 2010]. Initial research concerning occupational exposure to diacetyl has focused on employees who directly produce flavorings or use them in the microwave popcorn industry. However, the employment figures for the food production industry suggest that some other employees have potential exposure to diacetyl and other food flavorings. For example, respiratory issues have been anecdotally reported for cheese production (Wisconsin), yogurt production (Ohio), and potato chip manufacturing [Alleman and Darcey 2002]. Employers in the food manufacturing sector are generally small business owners with 89% and 2,3-Pentanedione 9 1 . Introduction of establishments employing fewer than 100 employees and nearly 53% of establishments employing fewer than 10 employees [United States Census Bureau 2004]. Industries that comprise food manufacturing can be found in every state in the United States; however, concentrations of specific industries are found in general geographic locations. For example, in 2004, 33% of the cheese manufacturing employees employed in the United States were in Wisconsin, and 20% of employees employed in the fruit and vegetable preservation industry were in California [ BLS 2007]. There is increasing likelihood that various substances will be used as substitutes for diacetyl or 2,3-pentanedione. The potential for both employees' exposure and disease from exposure to these substitutes still remains largely unstudied. 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Proceedings of the annual meeting of the ASBC 25:156-164. Sigma Aldrich [2010]. Material safety data sheet, No. B85037, 2,3-butanedione. http://www.sigmaaldrich. com/MSDS/MSDS/DisplayMSDSPage.do?country=US &language=en&productNumber=D3634&brand=SIGM A&PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Fsigma%2Fd3634 %3Flang%3Den. Date accessed: December 2009. Snider JR, Dawson GA [1985]. Tropospheric light alcohols, carbonyls, and acetonitrile: concentrations in Southwestern United States and Henry Law data. J Geophysical Res: Atmos 90(ND2):3797-3805. Strekowski RS, George C [2005]. Measurement of Henry's Law Constants for acetone, 2-butanone, 2,3-butanedione, and isobutyraldehyde using a horizontal flow reactor. J Chem Eng Data 50 (3):804-810. Ubbink J, Schoonman A [2002]. Flavor delivery systems. In: Kirk RE, Othmer DF, eds. Kirk-Othmer encyclopedia of chemical technology. 4th ed. Cary, NC: John Wiley and Sons, Inc., pp. 527-563. United States Census Bureau, United States Department of Commerce [2004]. Spice and Extract Manufacturing. 2002 Economic Census. Manufacturing Industry Series. Volume: EC02-311942(RV). van Rooy FG, Rooyackers JM, Prokop M, Houba R, Smit LA, Heederik DJ [2007]. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 176( 5):498-504. # Assessing Occupational Exposure in Employees # Introduction Measurement of diacetyl and 2,3-pentanedione exposure is helpful in preventing flavoringsrelated lung disease, even with complex flavorings formulations. Exposures to diacetyl and 2,3-pentanedione can be monitored using personal and area (environmental) air samples because the predominant route of exposure is inhalation. Results from air sampling can be compared with established criteria such as the NIOSH RELs. Measuring employees' exposures to diacetyl or 2,3-pentanedione may help identify processes, locations, or tasks with exposures of concern; guide corrective actions such as engineering controls; identify improved work practices; and select appropriate respiratory protection. This chapter discusses (1) available sampling and analytical techniques for monitoring diacetyl and 2,3-pentanedione vapor in the workplace; (2) techniques for measuring diacetyl and 2,3-pentanedione in airborne dust and bulk materials; (3) real-time techniques for measuring relevant airborne analytes and other flavoring compounds; and (4) results of some occupational exposure assessments by NIOSH and others of facilities that use diacetyl and 2,3-pentanedione. Many work environments have mixed exposures, with multiple chemical agents present. Although the primary focus of this criteria document is diacetyl and 2,3-pentanedione, other compounds can also be of concern. Depending upon the processes employed in a workplace, sampling should be conducted for agents of concern to maintain safe work environments. Common sampling and analytical methods to determine concentrations of diacetyl and 2,3-pentanedione are presented in Appendices A-E. # Time-integrated Air Sampling and Analytical Methods for Diacetyl and 2,3-Pentanedione Vapor Personal breathing zone sampling is the preferred approach for estimating employee exposure. For personal sampling, an employee wears the air sampling equipment, and the inlet to the collection medium is positioned within the employee's breathing zone. Area sampling is performed for several purposes such as to evaluate exposure characteristics associated with an area or process, and to determine the efficiency of control systems. While the same sampling equipment may be used in some cases for both personal and area sampling, area sampling is stationary, in contrast to personal sampling, which allows for mobility by accompanying the employee throughout the sampling period. # OSHA Methods 1012 and 1013 In response to the need for longer sampling time periods with a lower limit of detection or reliable quantitation limit, the Occupational Safety and Health Administration (OSHA) validated two sampling and analytical methods, OSHA Method 1012 and OSHA Method 1013[OSHA 2008a. OSHA Method 1013 is for monitoring low ppm levels, while OSHA Method 1012 is for monitoring ppb levels [OSHA 2008b]. These methods can be used for the simultaneous determination of diacetyl and acetoin. As of the publication of this document, these are the recommended methods for diacetyl. OSHA Methods 1012 and 1013 use two 600 milligram (mg) sorbent tubes containing specially cleaned and dried silica gel (SKC Inc.,Eighty Four,PA, in series and air is sampled at a flow rate of 50 milliliters per minute (mL/min) for up to 180 minutes for determination of TWA concentrations, and a flow rate of 200 mL/min for 15 minutes for short-term concentration measurements. An opaque sampling tube protective cover should be used in conjunction with the sampler to prevent the glass sampling tube from breaking and to protect the sample from light, which can decompose diacetyl and acetoin. After sampling, the tubes should be separated, capped, and protected from light with aluminum foil or other opaque material. There is no requirement that samples be kept cold during shipping or storage. OSHA Method 1013 has a reliable quantitation limit of 12 ppb (0.041 mg/m 3 ) diacetyl for a 9-liter sample, and samples are analyzed by gas chromatography using a flame ionization detector (GC-FID). OSHA Method 1012 has a nearly 10 times lower RQL of 1.3 ppb (4.57 micrograms per meter cubed [µg/m 3 ]) diacetyl for a 9-liter sample, which is achieved by derivatizing diacetyl with 2 milligram per milliliter (mg/mL) O- (2,3,4,5,6-pentafluorobenzyl) hydroxylamine hydrochloride in the extraction solution and analyzing by gas chromatography using an electron capture detector (GC-ECD). An advantage of OSHA Method 1013 is that sample preparation can be performed in one hour, whereas the derivatization step of OSHA Method 1012 requires 36 hours. After samples have been extracted and analyzed using OSHA Method 1013, if needed (e.g., if sample concentration is not detectable), they can be derivatized and analyzed using OSHA Method 1012 to benefit from its lower detection capability. # OSHA Method 1016 OSHA Method 1016[OSHA 2010] can be used to measure 2,3-pentanedione concentrations. OSHA Method 1016 uses the same sampling media, sample collection procedure and analytical procedure as OSHA method 1013. However, OSHA Method 1016 allows for the simultaneous analysis of 2,3-pentanedione, diacetyl, and acetoin by using a different analytical column to optimize the analytical separation of these compounds. In addition, OSHA Method 1016 requires samples to be shipped cold. If diacetyl and/or acetoin are not anticipated to be present, OSHA Method 1016 can be used to sample for an additional 20 minutes, or 200 minutes, at 50 mL/min to determine TWA concentrations of 2,3-pentanedione [ OSHA 2010]. For a 10-liter sample, the RQL of 2,3-pentanedione is 9.3 ppb (38 µg/m 3 ). # OSHA Method PV2118 Superseded by OSHA Methods 1012 and 1013, OSHA Method PV2118 [OSHA 2003] was developed as an air sampling method for diacetyl that uses two 150/75 mg silica gel sorbent tubes in series at a recommended flow rate of 50 mL/min for one hour. In response to the limited capacity of this sampler in humid environments, a modified version of OSHA Method PV2118 was used by some practitioners in the field. The modified method uses larger 400/200 mg sorbent tubes packed with specially cleaned silica gel allowing for greater sample capacity without breakthrough of diacetyl. Sample analysis remained unchanged. # NIOSH Method 2557 While no longer recommended for use, NIOSH developed NIOSH Method 2557[NIOSH 1994 for measuring diacetyl vapor in air. It called for the collection of samples onto a 150/75 mg carbon molecular sieve sorbent tube (Cat. No. 226-121, SKC Inc., Eighty Four, PA) at a flow rate between 10 and 200 mL/min for a sample volume between 1 and 10 liters. The method specifies that samples be stored cold and analyzed within 7 days of sampling. Until 2007, NIOSH Method 2557 was the predominant air sampling and analytical method for diacetyl used in the field, but it is no longer recommended for use [Ashley et al. 2008]. field and chamber investigations indicated that NIOSH Method 2557 was adversely affected by humidity, resulting in an underestimation of true diacetyl concentrations. To aid in the evaluation of sampling and analytical methods for diacetyl, a field comparison study between new and existing sampling collection methods was conducted [Ashley et al. 2008]. Side-by-side field samples were collected in flavor manufacturing facilities and analyzed according to NIOSH Method 2557, OSHA Method PV2118, and a modified version of OSHA Method PV2118. The results of this field work confirmed the tendency of NIOSH Method 2557 to underestimate the true concentration of diacetyl as humidity increases. However, no mathematical correlation was found in this data set which would produce an adjustment factor to allow for correction of results. As a result, NIOSH researchers collaborated with scientists at the OSHA Salt Lake Technical Center laboratory to study the effects of humidity on measured diacetyl air concentrations using NIOSH Method 2557. This laboratory has chamber facilities for the generation of known diacetyl air concentrations with the ability to control both temperature and relative humidity (RH). Controlled test atmospheres of diacetyl were generated and sampled through an array of sampling tubes at calibrated flow rates. Test atmospheres were controlled for diacetyl concentration, temperature, and relative humidity. Results indicated that diacetyl recoveries for NIOSH Method 2557 were affected by absolute humidity (AH), storage time of sample tube prior to extraction, and diacetyl air concentration. The study resulted in the development of a mathematical procedure to adjust diacetyl concentrations previously measured using NIOSH Method 2557. The procedure is presented in Appendix F and is also published elsewhere ]. # Other Air Sampling Method(s) in Development Because of current interest in occupational exposure to flavoring compounds, new methods continue to be developed for their measurement. At this time, however, none of these methods are validated. A method is being developed by NIOSH to measure alpha-dicarbonyl compounds (such as diacetyl and 2,3-pentanedione) in air via derivatization with 1,2-phenylenediamine. This compound is known to react with alpha-dicarbonyl compounds to form stable quinoxaline derivatives [Rodrigues et al. 1999]. In this method, air is sampled through a sorbent tube containing silica gel coated with 1,2-phenylenediamine at 0.1% by weight. Samples are extracted in the lab and extraction solutions analyzed by gas chromatographynitrogen/phosphorus detection (GC-NPD). A potential advantage of this method is greater sampling volume and sampling time without the breakthrough that would be experienced if sampling for an extended time with uncoated silica gel tubes. Experiments to date indicate no breakthrough of diacetyl, 2,3-pentanedione, or 2,3-hexanedione from the sampling tubes after passing 144 liters of air at 80% RH. This enables sampling for 8 hours without changing out sampling tubes. Another advantage is the high sensitivity of NPD detection, which will enable measurement of alpha-dicarbonyl compounds below the proposed REL for diacetyl of 5 ppb. A new method for collecting air samples using evacuated canisters has been evaluated for several VOCs [LeBouf et al. 2012]. The 450-milliliter canisters, which can be equipped with either instantaneous grab sampling attachments or restricted-flow controllers (for task-based or full-shift sampling), are suitable for collection of area and personal samples. The air samples are analyzed for VOCs using a preconcentrator/gas chromatography-mass spectrometry (GC-MS) system. At present, this canister method is in the process of being validated with three additional compounds, diacetyl, 2,3-pentanedione and 2,3-hexanedione, and is being reviewed for incorporation into the NIOSH Manual of Analytical Methods. A method for priority flavoring compounds is being investigated that utilizes a novel sampler-the helium diffusion sampler (HDS) [Entech Instruments Incorporated 2011]. The HDS collects a whole air sample for either short-term or full-shift sampling. The advantages of HDS are that no air sampling pump is required, there is no concern about breakthrough of the sample components, and there is minimal sample handling in the laboratory. A portion of the collected air sample is analyzed by a preconcentrator/GC-MS in the selected ion monitoring mode. Although HDS will not support limits of detection achieved by TD-GC-MS because of the relatively small air volume sampled (~20 mL), it may have adequate sensitivity to measure diacetyl at the proposed REL. # NIOSH Method 2549 -Qualitative Determination of Volatile Organic Compounds To sample for diacetyl, 2,3-pentanedione, as well as a wide range of other flavoring VOCs, thermal desorption sorbent tubes can provide a high degree of sensitivity. This is because desorption of compounds from thermal desorption tubes does not involve dilution into an extraction solvent. Instead, compounds are thermally desorbed from the sampling tubes in a thermal desorption system. This technique is primarily used for qualitative screening purposes because of the ability of thermal desorption tubes to capture a diverse range of VOCs, but specific compounds can be quantified if corresponding standards are analyzed along with the samples. The thermal desorption tube is usually a stainless steel tube configured and filled with a single sorbent bed or multiple beds of various sorbents including carbonaceous materials, carbon molecular sieves, and/or porous polymers. The sorbents can be heated to high temperatures without breakdown or the generation of artifacts, so thermal desorption tubes can be cleaned and reused multiple times. The tubes are analyzed with a thermal desorber-GC-MS (TD-GC-MS) [ NIOSH 1994]. # Sampling for Diacetyl and 2,3-Pentanedione in Airborne Dust and in Bulk Materials Although diacetyl and 2,3-pentanedione are normally found in liquid form, they can also be encapsulated in or coated on a powder substrate. Air sampling for dust that may be generated during handling of powdered flavorings can be achieved by active sampling methods. During the sample collection, however, some of the diacetyl and 2,3-pentanedione may volatilize, i.e., release from the dust particles and enter the vapor phase due to contact with moisture. In addition, environments in which dust is generated may also contain vapors of the flavoring compounds. Sorbent tubes used for the collection of vapor-phase diacetyl or 2,3-pentanedione cannot be used to adequately sample for dust at the low flow rates required by the tubes [OSHA 2008a]. As a result, modifications to the sampling methods are necessary to assess exposure to both vapor and dust. # Size-Selective Air Sampling for Dust Measurement of airborne dust particles according to their size (e.g. inhalable, thoracic, and respirable) can help to understand where they may deposit in the respiratory tract. Several types of sampling devices are available (e.g., inhalable dust samplers, impactors, cyclones, and sampling cassettes) to provide measurements of different size fractions of airborne dust. In most cases, dust is collected onto a filter, and the filter can be analyzed via gravimetric means to provide the mass of the dust. Filters should be hydrophobic in nature (e.g., polyvinyl chloride) in order to minimize collection of moisture. After being measured gravimetrically, filters can be analyzed for diacetyl and other compounds by the procedure described in section 2.3.2. Validated methods such as NIOSH Method 0500 for total dust and NIOSH Method 0600 for respirable dust [NIOSH 1994] are available for the collection and gravimetric analysis of airborne dust. # Sampling for Diacetyl and 2,3-Pentanedione in Airborne Dust A sampling and analytical method is being developed by NIOSH for the quantitative measurement of diacetyl, 2,3-pentanedione, and potentially other flavoring compounds in dust. A sampling cassette with a filter is used to collect airborne dust. The filter is then extracted in water and the aqueous solution is heated to promote the transfer of volatile components to the headspace above the solution. The headspace is sampled using a solid-phase microextraction (SPME) fiber. Headspace SPME involves an equilibrium process in which the volatile analytes establish equilibria between the sample solution, the headspace above the solution, and the polymer-coated fused silica fiber. The mechanism by which the analytes are extracted from the headspace is based on absorption of the analytes onto the fiber. The fiber is inserted directly into a GC-MS. The analytes are extraced from the fiber in the hot injection port and concentrated onto an analytical column. Because the entire sample collected on the fiber is introduced into the GC-MS instrument, as opposed to an aliquot of the sample for methods in which a solvent extract is used, lower detection limits can be achieved. This same procedure can be used to measure diacetyl, 2,3-pentanedione, and potentially other flavoring compounds in samples of bulk powders. # Bulk Liquids and Solids # Sample collection Although the review of safety data sheets or other available product documentation may be helpful to identify flavor compounds and potential exposures, they are not always comprehensive or specific. Collection and analysis of bulk flavoring materials can be useful to identify and quantify chemical ingredients and guide exposure assessment strategies. Prior to collecting bulk samples, it is important to consider the physical state of the materials to be sampled (liquids, pastes, or powders), the need to sample opened or unopened containers, the sampling locations, the number of samples to collect, and the amount of sample to collect (often determined by requirements of the laboratory analysis). Bulk samples should be representative; in other words, they should be derived from a variety of sampling locations and obtained from multiple batches to capture any variability in the bulk materials used. When sampling, it is important to collect and transport the sample in a manner that does not contaminate or cross-contaminate the bulk materials. Only clean or unused sample containers that are compatible with the bulk materials sampled should be used. In general, glass containers are ideal because they will not react with most chemicals, but polyethylene or polypropylene containers may also be appropriate. A typical container is a 20-mL glass scintillation vial with a polytetrafluoroethylene (PTFE)-lined screw cap. Each container should be clearly labeled with information about the bulk sample including material sampled, company and product number, site of sampling, date of sampling, sample tracking number and any hazards or precautions to be taken when handling the bulk sample. After sampling, consideration should be given to preserve the integrity of the bulk samples during storage and shipping. For example, care should be taken to keep samples cold and protected from light if necessary. In addition, bulk materials should not be shipped together with air samples. Established Department of Transportation (DOT) and International Air and Transport Association (IATA) shipping regulations of hazardous materials and dangerous goods should be followed if hazardous materials are to be shipped. Materials that are considered hazardous for the purpose of transportation under the DOT regulations are listed in the hazardous materials table in Title 49 of the Code of Federal Regulations (CFR), Section 172.101 [49 CFR 172.101]; materials that are considered dangerous goods for the purpose of shipping by air under IATA regulations are listed in the list of dangerous goods in IATA dangerous goods regulations, section 4.2 [IATA 2012]. The DOT and IATA regulations guide the classification/identification and packaging of hazardous materials and the marking and labeling of shipping containers containing hazardous materials. If the materials to be shipped are known to be hazardous but the specific names of the materials are not found on either the DOT hazardous materials table or the IATA list of dangerous goods, then the materials must be classified into a hazard class according to section 3 of the IATA dangerous goods regulations handbook, and a proper shipping name must be assigned according to section 4 of the IATA dangerous goods regulations handbook. A person must be trained in DOT and IATA regulations and certified in order to mark a shipment as hazardous. If it is unknown whether the materials to be shipped are hazardous or not, then a person who is trained in DOT and IATA regulations should be consulted. # Measurement of diacetyl or 2,3-pentanedione content of bulk powders The analytical procedure being developed for airborne dust samples described in section 2.3.2 will also be used for analysis of bulk powder samples. # Real-time Techniques for Diacetyl and Other Flavoring Compounds Several analytical methods provide real-time or near real-time measurements of volatile compounds in air such as diacetyl and 2,3-pentanedione. These methods have the unique advantage of providing continuous exposure information over very short averaging periods that can be viewed as it is being generated during sampling or later if the instrument has data-logging capabilities. The abundance of measurement information provides valuable insight into variations in concentrations throughout the sampling period as well as the short-term concentration peaks that can possibly be associated with their sources. While real-time monitoring instruments generally lack sufficient sensitivity and specificity for monitoring REL levels of diacetyl and 2,3-pentanedione, they can be useful for screening, identifying appropriate work practices, and to find leaks and "hotspots." This information can be very useful in the development of exposure controls. # Photoionization Detectors Photoionization detectors (PIDs) can be used to monitor VOC air concentrations in industrial work environments, including flavoring manufacturing facilities, and have become favored instruments for on-site monitoring because of ease of operation, reliability, versatility, cost, and response to a wide variety of substances. PID instruments measure the relative concentration of VOCs by passing the molecules of those compounds past an ultraviolet lamp that emits radiation over a narrow wavelength range in the ultraviolet region of the electromagnetic spectrum. Photons of ultraviolet radiation will form a molecular ion by removing an electron from orbit around that molecule, allowing for electronic detection of that ion, hence the name. The energy of the radiation emitted by the lamp is inversely proportional to its wavelength, and common PID lamps produce energy in the range from approximately 8 to 12 electron volts (eV). The amount of work required to form a molecular ion by removing an electron from orbit, a property known as ionization potential, varies by compound but for many hydrocarbons is in the range from 7 to 11 eV. Because nitrogen, oxygen, and many of the minor components of air (i.e., water vapor, carbon monoxide, carbon dioxide, argon) have ionization potentials significantly higher than 12 eV, they are not ionized by the photons emitted from a PID. This property allows for the continuous monitoring of air to obtain an estimate of total hydrocarbon concentration. PIDs respond to a broad range of VOCs and do not provide concentrations specific to any particular compound. They are often calibrated for isobutylene and can commonly detect total VOC concentrations from 1 to 2,000 ppm. Modern PIDs can be programmed to measure the concentration of VOCs at fixed time intervals and store these data for subsequent download to a computer. # Infrared Analyzers The absorption of infrared (IR) radiation, while more commonly used as a qualitative tool, can also be used to quantify many substances by determination of response relative to known concentrations of that substance. Absorption of electromagnetic radiation in the IR region of the spectrum will produce transitions among vibrational and rotational states of the molecules absorbing that rotation. This absorption can only occur at wavelengths exactly matching the vibrational frequency of a chemical bond, and by selecting the proper analytical wavelength it is possible to obtain reasonable specificity in the compound being quantified. Diacetyl can be detected and measured by using an IR gas analyzer such as the Thermo Electron MIRAN® "SapphIRe" (Thermo Fisher Scientific Inc., Waltham, MA), which is a portable directreading instrument that has the advantage of displaying real-time concentrations. The SapphIRe is a single beam IR spectrophotometer with a pathlength of 0.5 or 12.5 meters. It has a sample cell volume of 2.23 liters and a built-in pump that runs at approximately 14 liters per minute. Single sample analyses are updated every 0.5 seconds. The detector is available with preloaded factory calibrations for over 100 gases, but because diacetyl is not in this standard library it should be set up for this application by the factory. The concentration range that can be measured is dependent on the compound in question. The high and low settings for the pathlength extend this range considerably. The predecessor model, the Foxboro/Wilks MIRAN 1A, has adjustable wavelength and pathlength controls and can be calibrated for gases or vapors using the closed loop system available. Many MIRAN 1A models are still in use in the field. The best wavelength for measuring diacetyl is about 9 micrometers. Neither water nor carbon dioxide should interfere significantly at that wavelength. The minimum detectable concentration should be less than 0.5 ppm at the highest pathlength. Fourier transform infrared gas analyzer (FTIR) spectroscopy can be used to analyze a sample of gaseous molecules for both chemical composition and for the concentration of individual chemical constituents. In this analysis, chemical functional groups absorb IR radiation at specific, unique frequencies producing a characteristic spectrum of absorbed versus transmitted radiation. From this spectrum, identification and quantitation of the gas is possible. FTIR analysis can produce real-time quantitation of flavoring compounds in air providing chemical specific full-shift, partial-shift, and peak concentration measures although interferences can pose analytical difficulties in quantifying specific flavoring compounds in complex environments with multiple organic chemicals present. # Photoacoustic Spectroscopy (Infrared Absorbance) Techniques Because the absorption of infrared radiation produces transitions among vibrational states of molecules, the application of rapid pulses of IR photons at the proper wavelength can be used to produce pressure variations in the air surrounding the molecules absorbing that radiation. Those pressure variations can be detected as sound waves, the amplitude of which is proportional to the concentration of the analyte of interest. Using IR radiation and measuring this resultant amplitude to quantify an analyte is the technique of photoacoustic spectroscopy. Diacetyl has been measured using the Innova photoacoustic infrared gas analyzers, which are direct-reading instruments that have the advantage of displaying real-time concentrations. Both personal and area concentrations were measured during tasks involving exposure to diacetyl in liquid and powder form and then 8-hour TWA exposures were calculated. The powder exposures only measured vapor released and did not include diacetyl adsorbed on the powder [Martyny et al. 2008]. Current available models of the photoacoustic analyzer are the 1314 and 1412, available from California Analytical Instruments, Inc., Orange, CA. The measurement system is based on photoacoustic infrared detection and provides the capability of measuring virtually any gas that absorbs in the infrared spectrum. Gas selectivity is achieved through the use of optical filters that provide both a means of detecting the gas of interest and compensating for interfering gases and water. Specifications on the unit indicate a dynamic range of 4 orders of magnitude and a repeatability of 1% of the measured value. The analyzer displays updated concentrations approximately every 30 seconds. The analyzer can be calibrated using diacetyl standards and can analyze diacetyl concentrations from the parts per billion range to hundreds or thousands of parts per million. # Industrial Hygiene Surveys and Exposure Assessments Several investigations have been completed by NIOSH and others within the flavoring and food production industries. Exposure conditions vary widely, depending upon site-specific parameters and the processes employed. Many diacetyl samples have been collected to evaluate occupational exposures in the workplace and are described below. When pertinent data on absolute humidity and time to sample extraction were available, measurements obtained using NIOSH Method 2557 were subsequently corrected for the method's tendency to underestimate ]. An overview of diacetyl samples collected during multiple investigations is presented in Table 2-1. # NIOSH Microwave Popcorn Production Exposure Assessments NIOSH conducted health hazard evaluations at six microwave popcorn plants from 2000 to 2003 . In these facilities diacetyl-containing butter flavorings (liquids, pastes, or powders) were mixed with heated soybean oil in large heated mixing tanks. Salt and coloring were added to the flavoring mixture which was transferred to packaging lines and combined with kernel popcorn in microwaveable bags. Diacetyl concentrations were measured with NIOSH Method 2557 in multiple production locations using personal and area samples. In the plants, 29 area and 17 personal samples were collected in mixing areas, and 67 area and 65 personal samples were collected in packaging areas. Humidity-corrected mean diacetyl air concentrations ranged from 0.63 to 57.2 ppm for area samples and from 0.035 to 1.33 ppm for personal samples in the mixing areas. In the packaging areas, mean concentrations ranged from 0.019 to 3.0 ppm for area samples and from 0.023 to 1.16 ppm for personal samples. In general, diacetyl concentrations were higher in the mixing rooms when the diacetyl-containing butter flavorings were heated. In 2010, a microwave popcorn company asked NIOSH to evaluate chemical constituents in eight liquid butter flavorings because their supplier did not identify chemical substitutes they were using in place of diacetyl [Boylstein 2012]. Quantitative GC-MS analysis showed acetoin in five samples, 2,3-pentanedione in four, and 2,3-hexanedione in one, all at concentrations of 0.5% or less by weight, except for one acetoin sample at 2%. The more sensitive semiquantitative headspace analysis with thermal detection tubes found diacetyl and acetoin in all samples, 2,3-pentanedione in five, 2,3-hexanedione in one, and 2,3-heptanedione in one. # Other Microwave Popcorn Production Exposure Assessments White et al. [2010] conducted a comprehensive, repeated exposure monitoring campaign at four microwave popcorn plants. A total of 639 full shift diacetyl samples were collected during the day and night shifts in multiple production areas including all employees who worked in the slurry (mixing) room. In that study 49% of 639 samples were below their limit of detection with the maximum measurement of 11.72 ppm after correction for humidity [White et al. 2010]. Overall, exposures were higher for mixers compared to non-mixers and were consistent with diacetyl concentrations observed during previous NIOSH investigations. Diacetyl exposures declined substantially for mixers after the installation of engineering controls. # NIOSH Flavoring Manufacturing Exposure Assessments In 1985, NIOSH conducted a health hazard evaluation at a plant in Indiana that produced flavorings for the baking industry [NIOSH 1986]. Case histories showed severe fixed obstructive lung disease among employees in a mixing room. Data from previous air monitoring indicated a high dust concentration in the personal breathing zone of an employee during a mixing operation. Diacetyl was on a list of ingredients commonly used at this facility but airborne measurements of diacetyl or other flavoring compounds were not made. Although the investigators were unable to identify specific etiology at that time, they concluded that employees' disease was most likely caused by some agent in the mixing room at the plant. NIOSH personnel conducted evaluations at three California flavoring manufacturing facilities where they measured exposures to diacetyl and other related compounds [NIOSH 2007a[NIOSH , 2008a. The objectives of these surveys included identifying common work tasks, plant processes, and procedures, as well as characterizing potential occupational exposures within the flavoring industry. Most of the data collected were from the liquid and powder production areas, with some information also coming from spray drying, preproduction, quality assurance, administration, and research and development locations. 2008a], the mean full-shift concentration of diacetyl in the liquid production room was 0.26 ppm, while in the powder production room it was 0.07 ppm. For personal samples that were collected with NIOSH Method 2557 and not corrected for humidity and time to extraction, the mean concentrations in liquid production and powder production rooms were 0.10 ppm and 0.05 ppm. This work also indicated high variability in concentrations of volatile organic compounds (as measured with a PID) and dust (as measured with personal dust monitors) with time. A health hazard evaluation was conducted at a facility in Wisconsin [NIOSH 2009c] that manufactured flavorings, modified dairy products, and bacterial additives. One of the flavoring products made at this plant was liquid starter distillate, a product of distillation of fermented milk stock, which contains about 4.5% diacetyl. Starter distillate and liquid diacetyl were used to make a variety of powdered (via spray drying processes) and liquid flavorings. NIOSH staff obtained 21 personal and 29 area air samples using modified OSHA Method PV2118 for diacetyl throughout the facility. They found the highest full-shift TWA concentrations in the starter distillate room (geometric mean of 1.78 ppm for personal and 1.06 ppm for area samples), followed by the spray dry room (0.756 and 1.07 ppm) and the flavors room (0.329 and 0.171 ppm). In the spray dry room, FTIR realtime measurements indicated peak diacetyl concentrations up to 90 ppm in the employee's breathing zone while dumping diacetyl from buckets to mixing tanks and while pumping diacetyl from a barrel into buckets. A peak exposure of about 18 ppm was measured in the breathing zone of an employee in the same room while cleaning a barrel with a water hose. Company air sampling data were obtained during a health hazard evaluation at an Indiana flavorings plant that used many ingredients, including diacetyl and starter distillate, in the batch production of a variety of liquid and powdered flavorings [NIOSH 2011]. Using NIOSH Method 2557 prior to the HHE request to measure diacetyl, they collected 22 samples. The geometric mean full-shift TWA diacetyl concentration in spray drying operations was 0.123 ppm for personal samples and 0.169 ppm for area samples, while in the other production areas, mean concentrations up to 0.762 ppm and 0.375 ppm were measured for personal and area samples, respectively. Because of the problems with NIOSH Method 2557, these results were likely underestimations of the true concentrations. No data on humidity or time from collection to analysis was available, so no correction could be estimated. Subsequent measurements (45 personal and 71 area samples) by the company, after some control intervention, were collected using validated OSHA sampling Methods PV2118 and 1012 for diacetyl. In the spray drying operations, the geometric mean for full-shift diacetyl personal samples was 0.182 ppm, and for area samples it was 0.167 ppm. The highest mean concentration in the other production areas was 1.900 ppm for personal samples (liquid compounding area) and 0.076 ppm for area samples (coffee and tea area). Another health hazard evaluation was performed at a flavorings plant in Kentucky that produced flavors, colors, and food and beverage ingredients used in the manufacture of consumer products [NIOSH 2013a]. Diacetyl was not found in use during the NIOSH air sampling survey. Using evacuated canisters, diacetyl and 2,3-hexanedione were not detected in any of the instantaneous or 3-hour area air samples taken in several parts of the plant. 2,3-Pentanedione was detected in two area air samples taken in the liquid samples room. The detection limits ranged from 1.4 to 2.9 ppb for diacetyl, 1.5 to 3.2 ppb for 2,3-pentanedione, and 1.7 to 3.6 ppb for 2,3-hexanedione. Of the two air samples that detected 2,3-pentanedione in the room, one was an instantaneous sample taken near a trash can for disposal of used pipettes while making a flavoring recipe and resulted in a level of 47 ppb. The other sample that detected 26 ppb 2,3-pentanedione was collected for 187 minutes in the center of the room. During the sampling period, several employees were preparing recipes, which included fruit and cheese flavors. # Other Flavoring Manufacturing Exposure Assessments In a study evaluating diacetyl exposures in 16 flavor manufacturing facilities, Martyny et al. [ Martyny et al. 2008] measured levels of that compound from the limit of detection (0.01 to 0.18 ppm depending on sample duration) to as high as 60 ppm. Using a protocol designed to obtain measurements during worst-case exposures by collecting samples only during processes in which diacetyl was being used, 181 personal and area samples were collected generally for 1 to 3 hours. Samples for diacetyl were collected and analyzed using NIOSH Method 2557[NIOSH 1994 ppb), as were two of the three also sampled with the more sensitive draft NIOSH method using 1,2-phenylenediame-treated silica gel tubes (0.5 ppb limit of detection) -the detectable concentration was 0.9 ppb while using smoke flavoring. Of six area samples collected alongside cleaning operations with evacuated canisters for 2,3-pentanedione (1.2 to 2.9 ppb limits of detection) and 2,3-hexanedione (1.5 to 3.6 ppb limits of detection), one measured 2,3-pentanedione at 6.2 ppb and 2,3-hexanedione at 9.0 ppb during a nearly 3-hour cleaning procedure of cooking equipment containing strawberry cream cheese remnants while no cream cheese was being made in the room. The snack food production plant applied powdered seasonings onto potato, corn, and tortilla chips after they were fried. Headspace analyses of bulk samples of seasonings found trace amounts of diacetyl, but no other alpha-diketone compounds, in four of the seven samples: barbeque, honey barbeque, cheddar sour cream, and chili cheese. Diacetyl, 2,3-pentanedione, and 2,3-hexanedione were not detected in the five 15-to 180-minute personal breathing zone evacuated canister air samples from processing line operators during nacho cheese tortilla chip production. The detection limits ranged from 2.8 to 6.0 ppb for diacetyl, 3.4 to 7.2 ppb for 2,3-pentanedione, and 3.2 to 6.8 ppb for 2,3-hexanedione. Although diacetyl was detected in three area samples collected instantaneously near the seasoning hopper, it was not quantifiable. Because it was found between the detectable level of 1.3 ppb and the quantifiable level of 4.3 ppb, the reported concentrations of 1.4 to 1.7 ppb are considered estimates. The area samples did not detect 2,3-pentanedione or 2,3-hexanedione (detection limits of 1.5 and 1.6 ppb, respectively). The coffee production plant produced flavored and unflavored whole bean and ground coffee. Full-shift area air samples collected for diacetyl with OSHA Method 1012 and for 2,3-pentanedione with OSHA Method 1016 had highest mean concentrations by location in the grinding/packaging room (103 ppb diacetyl, 63 ppb 2,3-pentanedione), flavoring room (90 ppb diacetyl, 151 ppb 2,3-pentanedione), and the production offices (62 ppb diacetyl, 32 ppb 2,3-pentanedione), which were located within the larger grinding/packaging room. These were followed by mean concentrations in the roasting room (20 ppb diacetyl, 6 ppb 2,3-pentanedione), green bean and finished goods warehouses (11 ppb diacetyl, <3 ppb 2,3-pentanedione), quality control room (8 ppb diacetyl, <3 ppb 2,3-pentanedione), maintenance shop (7 ppb diacetyl, <3 ppb 2,3-pentanedione), and the nonproduction offices (4 ppb diacetyl, <3 ppb 2,3-pentanedione). The flavoring room was under negative pressure with respect to the adjacent grinding/packaging room where unflavored roasted coffee was processed. Personal sample mean concentrations by location in the coffee plant were highest for employees working in the grinding/packaging room (93 ppb diacetyl, 53 ppb 2,3-pentanedione), flavoring room (80 ppb diacetyl, 122 ppb 2,3-pentanedione), production offices (81 ppb diacetyl, 22 ppb 2,3-pentanedione), all over (59 ppb diacetyl, 39 ppb 2,3-pentanedione), and housekeeping (54 ppb diacetyl, 18 ppb 2,3-pentanedione). These were followed by those in the roasting room (26 ppb diacetyl, 7 ppb 2,3-pentanedione), quality control room (24 ppb diacetyl, 11 ppb 2,3-pentanedione), warehouse (8 ppb diacetyl, <3 ppb 2,3-pentanedione), and nonproduction offices (7 ppb diacetyl, <3 ppb 2,3-pentanedione). The mean area concentrations on the grinding/packaging and flavoring room mezzanines, where roasted whole and ground bean storage hoppers were located, were higher than those measured on the main production levels of the rooms. A 15-minute short-term air sample collected at the open hatch of a grinding/packaging room mezzanine hopper holding unflavored ground coffee above an active packaging line measured concentrations of 14,300 ppb diacetyl and 13,800 ppb 2,3-pentanedione. The location of the sample was representative of the proximity of employees' faces as they frequently and momentarily monitored coffee levels in the hoppers throughout their shift. NIOSH also conducted a small industrywide study at some flavored food production facilities where diacetyl and other food flavorings were added to various food products. Seventy-four personal and 105 area samples were collected for diacetyl using OSHA Method 1013. With one exception where local exhaust ventilation was documented in some locations, no engineering controls were noted in any facility. Of the 179 total samples, 12 had detectable levels of diacetyl (LOD 0.5 -1.0 ug/sample). The eight area samples ranged from 0.03 to 3.1 ppm, with three samples above 1 ppm (1.1, 2.1 and 3.1 ppm). The four personal samples ranged from 0.06 to 0.6 ppm [Curwin et al. 2015]. # OSHA Site Visits Related to Diacetyl and Flavorings that Contain Diacetyl Between January 2008 and January 2010, an OSHA contractor measured diacetyl exposure to employees in a series of 12 industrial hygiene surveys at various facilities that use (11 facilities) or manufacture (1 facility) formulated flavorings, including flavorings that contain diacetyl [Eastern Research Group 2008a, b, c, d, 2009a, b, c, d, e, 2010a. In the first two surveys, conducted in January 2008, diacetyl was measured using OSHA Method PV2118. In the subsequent 10 surveys, OSHA Methods 1012 and 1013 were used. At all facilities, visual observation was made of engineering controls in place at the various operations evaluated. The measured range of diacetyl concentrations are presented in At the time of most of these field investigations, which preceded the California diacetyl regulation implemented in December 2010, little 2,3-pentanedione was being used for artificial butter flavoring. When food manufacturers began to request that diacetyl percentage be less than 1% of flavoring constituents, flavor manufacturers sometimes did not inform their clients of the substitution of 2,3-pentanedione and other diacetyl substitutes [Boylstein 2012;Day et al. 2011;NIOSH 2009b]. Accordingly, populations with 2,3-pentanedione exposure without previous diacetyl exposure are difficult to identify. Thus, illness attributable to 2,3-pentanedione alone has not been studied. # Obstructive Lung Disease Consistent with Obliterative Bronchiolitis The most significant health consideration for flavoring-exposed employees is the development of exertional dyspnea or findings consistent with obliterative bronchiolitis (also often called constrictive bronchiolitis, see discussion of terminology). Most textbooks characterize obliterative bronchiolitis as a rare disease with airways obstruction, defined by a decreased FEV 1 and a decreased FEV 1 to FVC ratio on spirometry testing. The magnitude of decline in FEV 1 determines the severity of the disorder. However, three recent case series of biopsy-confirmed obliterative bronchiolitis document that many cases have normal spirometry and, when abnormal, the spirometric pattern can be restrictive, obstructive, or mixed restrictive and obstructive in nature [Ghanei et al. 2008;King et al. 2011;Markopoulou et al. 2002]. Because of the historical assumption that obliterative bronchiolitis is an obstructive disease, the early NIOSH investigations focused on obstructive abnormalities. Airways obstruction can occur in diseases such as smoking-related COPD (including emphysema and chronic bronchitis) and in asthma. In emphysema, the airways obstruction is usually FOOD PRODUCTION All three employees in a popcorn popping business developed symptoms of airways disease during their tenure; all were lifetime nonsmokers. One of the employees had significant reversible airways obstruction with some clinical evidence suggesting possible bronchiolitis obliterans in addition to asthma. FOOD PRODUCTION At a plant using a newly reformulated flavoring that included 2,3-pentanedione, no obstruction was identified in the 22 employees tested. Participants had higher than expected rates of shortness of breath, physician-diagnosed asthma, and a restrictive pattern on spirometry (four cases ranging from mild to moderately severe), compared to U.S. adults. Some participants reported symptoms with a workrelated pattern. # NIOSH [2009c] F Three cross-sectional surveys, FOOD PREPARATION Studies of employees at three sites found higher prevalences of spirometric restriction, wheeze, dyspnea on exertion, nasal and eye irritation, and nasal allergies when compared to national rates. Cooks were 3-4 times more likely to report work-related respiratory symptoms. Fixed airways obstruction identified in two employees did not appear to be work-related. # NIOSH [2009d] D Cross-sectional survey, FLAVORING MANUFACTURING This study of 34 employees found that bacterial products employees had higher prevalences of work-related eye symptoms and posthire skin problems than flavoring employees; both groups reported lower respiratory symptoms related to the substances they handled at work. One employee was identified with fixed airways obstruction and two employees with restriction on spirometry. NIOSH 2009a], clinical bronchiolitis obliterans , bronchiolitis obliterans syndrome , and flavoring-related bronchiolitis obliterans [ Kreiss 2007]. Of the few surgical lung biopsies that have been performed in affected employees, some have been interpreted as showing evidence of "constrictive bronchiolitis" or "obliterative bronchiolitis" . The term fixed obstructive lung disease is the least specific of the terms. The term popcorn worker's lung refers to the population of employees in which the disease was first identified. The term flavorings-related lung disease refers to the full spectrum of lung diseases that may be related to flavorings exposure and is not necessarily limited to obstructive conditions. The terms flavoring-related bronchiolitis obliterans, constrictive bronchiolitis, and obliterative bronchiolitis refer to pathologic findings of inflammation and fibrosis primarily involving the bronchioles, leading to irreversible airflow limitation. Terminology is complicated by the fact that, historically, researchers have applied the term "bronchiolitis obliterans" to different distinct disorders that involve the bronchioles [King 2003;King and Kinder 2008]. The terms clinical bronchiolitis obliterans and bronchiolitis obliterans syndrome refer to those who are thought to suffer from this pathologic condition based on clinical findings, but have not undergone lung biopsy for pathological confirmation. Additional discussion regarding diagnostic terminology in relation to the different recognized forms of bronchiolitis is included in section 3.1.1. # Bronchiolar Disease and Terminology Bronchiolitis obliterans refers to disease processes that show some degree of inflammation, narrowing, or obliteration of small airways (bronchioles) in the lung [King 2003;King and Kinder 2008]. Historically, bronchiolitis obliterans has been classified into two groups: proliferative bronchiolitis obliterans and constrictive bronchiolitis obliterans [King 2003;King and Kinder 2008]. The disorder known as bronchiolitis obliterans organizing pneumonia (BOOP) is included in the proliferative group. BOOP is characterized pathologically by intraluminal polyps in the respiratory bronchioles, alveolar ducts, and alveolar spaces accompanied by organizing pneumonia in the more distal parenchyma. Clinically it is usually associated with diffuse alveolar opacities on chest x-ray and computed tomography scan; pulmonary function testing may show a restrictive defect [King 2003;King and Kinder 2008]. BOOP was first described in 1985. Prior to this, many cases that matched the description for BOOP were classified as idiopathic bronchiolitis obliterans [King 2003;King and Kinder 2008]. The American Thoracic Society and the European Respiratory Society have recommended the use of the term cryptogenic organizing pneumonitis (COP) instead of BOOP to avoid confusion with the disease constrictive bronchiolitis obliterans [ATS and ERS 2002]. While proliferative bronchiolitis can be idiopathic (e.g., COP), known associations include collagen vascular diseases (e.g., systemic lupus erythematosus), acute infections (e.g., influenza, mycoplasma), organ transplantation, and aspiration pneumonitis. Proliferative bronchiolitis is generally responsive to corticosteroid medications and is usually reversible [King and Kinder 2008]. Obliterative bronchiolitis (also referred to as constrictive bronchiolitis obliterans [ATS and ERS 2002], constrictive bronchiolitis [Schlesinger et al. 1998;Visscher and Myers 2006], and bronchiolitis obliterans [King 2003;King and Kinder 2008]) is a rare disorder characterized by alterations in the walls of respiratory and membranous bronchioles that cause concentric narrowing or complete obliteration of the airway lumen, without involvement of the distal lung parenchyma by inflammation or organizing pneumonia [King 2003;King and Kinder 2008]. In affected individuals, pulmonary function tests usually show airways obstruction and hyperinflation [King and Kinder 2008], but biopsy-confirmed cases may have normal or restrictive spirometry [Ghanei et al. 2008;King et al. 2011;Markopoulou et al. 2002]. Chest x-rays may be normal or show hyperinflation, peripheral attenuation of the vascular markings, and nodular or reticular opacities [King 2003]. The predominant finding of obliterative bronchiolitis on high-resolution computed tomography (HRCT) scan is heterogeneity of lung density due to mosaic perfusion and air trapping [King 2003;King and Kinder 2008]. Other findings of bronchiolitis on HRCT scan include centrilobular thickening, bronchial wall thickening, bronchiolar dilatation, and the tree-in-bud pattern. Cylindrical bronchiectasis is frequently associated with obliterative bronchiolitis; scans with both inspiratory and expiratory views are helpful because expiratory views are important in assessing air trapping [King 2003]. Identification of the obliterative bronchiolitis lesion on lung biopsy may be difficult because of its patchy distribution [Estenne et al. 2002;Schlesinger et al. 1998;Visscher and Myers 2006], often requiring step-sectioning and special staining to identify airway walls [King 2003;King and Kinder 2008]. The diagnosis is a multidisciplinary one involving a team with clinical, radiologic, and histopathologic expertise; HRCT evidence often replaces the need for surgical lung biopsy [King and Kinder 2008]. In comparison to proliferative bronchiolitis, obliterative bronchiolitis is generally unresponsive to corticosteroid medications and often progresses to more severe disease [King and Kinder 2008], although progression after exposure cessation is not characteristic of flavoring-related disease consistent with obliterative bronchiolitis ]. As mentioned previously and discussed in detail in the next section (3.1.2), the medical evaluations of employees who have developed lung disease during exposure to diacetyl and other flavoring compounds have generally revealed findings consistent with obliterative bronchiolitis. Because of concerns for patient welfare and the invasive nature and imperfect sensitivity of lung biopsy for diagnosing obliterative bronchiolitis, most patients have been diagnosed based upon clinical findings. Despite the small number of lung biopsies conducted, findings consistent with obliterative bronchiolitis have been identified in multiple flavorings-exposed patients NIOSH 2007a]. Patients exposed to sulfur mustard gas are another patient population where obliterative bronchiolitis has been diagnosed in a small subfraction of the patients while other patients are diagnosed using contemporary clinical criteria, including HRCT scans [Ghanei et al. 2004a;Ghanei et al. 2004b;Ghanei et al. 2008;Rowell et al. 2009]. Other known causes of obliterative bronchiolitis include uncontrolled inhalation exposures to ammonia, chlorine, phosgene, nitrogen dioxide and sulfur dioxide, collagen vascular diseases (especially rheumatoid arthritis), infections, and organ transplantation (bone marrow, heart-lung, lung) [King and Kinder 2008]. Because of the difficulty of identifying the lesions of obliterative bronchiolitis on lung biopsy, and because the disease occurs commonly after heart-lung and lung transplants, in 1993 a committee sponsored by the International Society for Heart and Lung Transplantation proposed a clinical description for the disease termed bronchiolitis obliterans syndrome. The syndrome refers to graft deterioration secondary to persistent airflow obstruction as defined by pulmonary function changes with or without histolopathologic confirmation. Probable risk factors for BOS include acute graft rejection and cytomegalovirus pneumonitis [Estenne et al. 2002]. The term BOS has also been used in cases of obliterative bronchiolitis resulting from chemical injury and diagnosed using clinical criteria with or without biopsy Ghanei et al. 2004a; . Because the terminology used in the peerreviewed literature of flavorings-exposed employees has included several different accepted and frequently interchanged diagnostic terms, and indeed may have been influenced by the peer-review process itself, this criteria document sometimes provides the terms used in the cited papers and includes the criteria used in the patient evaluations. All eight cases that had HRCT scans showed marked bronchial wall thickening and mosaic attenuation with air trapping; five cases also showed mild cylindrical bronchiectasis. In two of three cases that underwent lung biopsy, the reviewing pathologist reported findings that supported or were consistent with a diagnosis of bronchiolitis obliterans ]. These nine employees had developed a dry persistent cough, shortness of breath on exertion, and wheezing after a median of 1.5 years of employment. At the time of symptom onset, five of the employees had been working in the room where butter flavorings, salt, and colorings were combined with heated soybean oil. The other four employees had been working in the adjacent room where the oil and flavoring mixture was combined with kernel popcorn in microwavable bags (packaging area). None of these employees were initially diagnosed by their personal physicians as having obliterative bronchiolitis. Initial diagnoses received by these employees included pneumonia, asthma, emphysema, bronchitis, COPD, hay fever, and sinusitis. Five of the employees had minimal smoking history. All nine employees had been prescribed oral corticosteroids, but none had improvement in lung function. Five of the employees had been placed on lung transplant waiting lists by their personal physicians ]. # Index plant lung function testing The NIOSH medical survey at the index microwave popcorn plant (Facility G) in November 2000 included lung function testing with spirometry and DL CO , chest x-rays, and a questionnaire NIOSH 2006]. NIOSH compared the prevalences of respiratory symptoms, self-reported physiciandiagnosed asthma and chronic bronchitis, and airways obstruction on spirometry to data from the Third National Health and Nutrition Examination Survey (NHANES III) [CDC 1996]. Of 135 current employees, 117 (87%) completed the questionnaire, and 97 (83%) of the survey participants worked in the microwave popcorn production areas of the plant. The remaining 20 survey participants worked in areas where butter flavorings were not used such as plain kernel popcorn packaging, offices, warehouse, and outside receiving. The prevalences of respiratory and systemic symptoms, mucous membrane irritation, and skin irritation were higher among employees in microwave popcorn production areas than in other areas. Among all survey participants, the prevalences of chronic cough and shortness of breath when hurrying on level ground or walking up a slight hill were 2.6 times higher than expected; the prevalence of wheezing was three times higher than expected. The prevalences of self-reported physician-diagnosed asthma and chronic bronchitis were 1.8 and 2.1 times higher than expected, respectively. Of the 116 employees who underwent spirometry, 21 had airways obstruction, 3.3 times higher than expected. Airways obstruction in nonsmokers was 10.8 times higher than expected, and only two employees with airways obstruction had a significant response to administered bronchodilator. Five of six employees in the quality control (QC) laboratory had airways obstruction; these employees popped up to 100 bags of microwave popcorn in microwave ovens per employee per 8-hour work shift. Of the 115 survey participants who had an x-ray, 111 had no abnormalities, two had evidence of emphysema, one had saber-sheath tracheal narrowing attributable to COPD or tracheal stenosis, and one had focal upper-zone scarring and atelectasis at the left lung base. DL CO was normal in 96 of 103 employees tested, including all but one of those with airways obstruction. # Index plant environmental survey In addition to the cross-sectional medical survey, NIOSH conducted a detailed environmental survey at the index microwave popcorn plant (Facility G) in November 2000 NIOSH 2006]. The predominant VOC in the air of the plant was the butter flavoring compound diacetyl. All measurements above detectable limits (except where noted otherwise below) were subsequently corrected for underestimation inherent to NIOSH Method 2557 related to absolute humidity and days to extraction . The relative humidity and temperature measurements used for correction were available from in-facility area-specific and shift-specific measurements during all sampling, and sample-specific days to extraction were supplied by the laboratory. The mixing room had the highest mean air concentration of diacetyl (57.2 ppm); the next highest mean air concentration of diacetyl was in the packaging area for machine operators (2.8 ppm). The mean air concentration of diacetyl in the QC laboratory was 0.8 ppm, and for maintenance it was 0.9 ppm. The much higher prevalence of airways obstruction in QC employees, despite much lower average air concentrations of diacetyl, may reflect an enhanced risk of peak flavoring exposures when microwaved bags of popcorn product were opened; peak exposures were also likely present in maintenance employees and mixers. Mean diacetyl air concentrations in other plant areas were less than 0.15 ppm. . # Findings of index plant follow-up surveys NIOSH conducted seven follow-up medical and eight follow-up environmental surveys at the index microwave popcorn plant (Facility G) from 2001 to 2003 NIOSH 2006]. These surveys were conducted to follow employee symptoms and lung function over time as exposures decreased with the implementation of engineering controls. NIOSH recommended a respiratory protection program for mixing room employees to minimize their exposures while engineering controls were being implemented; this program was initiated at the time of the November 2000 NIOSH survey. Starting in February 2001, the company began implementing several engineering controls to decrease air concentrations of flavoring compounds in the mixing room, the main source of air contaminants in the plant. An exhaust fan was installed in an outer wall of the mixing room to move contaminated air from this room to the outdoors and to maintain this room under negative air pressure relative to the rest of the plant. An air lock was installed at the entrance to the mixing room to further isolate the room from the rest of the plant. Local exhaust ventilation of the air space (headspace) above the contents of the heated flavoring tanks and the mixing tank in which flavorings are mixed into heated soybean oil was accomplished via ducts connecting the tank lids to the wall exhaust fan. A pump was installed to facilitate closed transfer of heated butter flavorings into the mixing tank. In 2002, the company constructed and began using a new mixing room that was more isolated from the packaging area than the original mixing room. In the packaging area, additional general dilution ventilation was implemented in 2001 along with local exhaust ventilation for seven heated holding tanks located on a mezzanine above the packaging lines that contained soybean oil and butter flavoring mixtures transferred via pipes from the mixing room. . In their analyses of data from the eight NIOSH medical surveys at Facility G from November 2000 to August 2003, NIOSH compared health outcomes in microwave popcorn production employees hired after the implementation of exposure controls to health outcomes in employees who had been working at the plant prior to the implementation of controls . For these analyses, investigators classified employees according to their hire date as follows: "Group 1" consisted of employees who were already working at the plant at the time of the November 2000 survey (i.e., before exposure controls were implemented), and "Group 2" consisted of employees who started work at the plant after the November 2000 survey (i.e., after exposure controls were implemented and exposures had declined). Because of a high turnover rate among employees hired after the November 2000 survey, participation in more than one medical survey was much higher in Group 1 ( 100 Group 2 employees who participated in more than one survey worked in the packaging area. Therefore, for all Group 2 packaging area employees who participated in more than one survey, investigators compared symptoms and lung function on their first survey to their last survey results. In Group 1, the only statistically significant change in symptom prevalence over time was a decline in reported eye, nose, or throat irritation. There were no statistically significant changes in the prevalence of airways obstruction or in mean percent predicted FEV 1 . Based on data from employees' first surveys, packaging area employees in Group 2 had lower prevalences of respiratory symptoms and airways obstruction on spirometry, and mean percent predicted FEV 1 was significantly higher compared to packaging area employees in Group 1. All these differences were statistically significant except for usual cough. There were no statistically significant changes in the prevalences of symptoms, airways obstruction, or mean percent predicted FEV 1 from first to last survey in Group 2 packaging area employees . Of interest is that 47% of all employees with abnormal spirometry tested by NIOSH (in Groups 1 and 2) were asymptomatic. NIOSH conducted a mortality study on Facility G employees based on Social Security Administration vital status determination as of November 30, [Halldin et al. 2013 There is no specific ICD-10 code for obliterative bronchiolitis, so it is likely that death from the condition would be coded using a COPD classification code. Consistent with this, the specific code J44 "other COPD" was assigned as a multiple cause of death for the four decedents (0.98 expected; SMR = 4.10, 95% CI 1.12-10.49). Three of the four COPD-coded deaths occurred among former employees and employees employed before the company began to implement interventions to reduce diacetyl exposure (Group 1 above). 2003a, b, c, 2004a, b]. These plants and the index plant (Facility G) were similar with regard to some production and exposure characteristics; however, there were some important differences as well ]. The similarities in production and exposure characteristics at the six microwave popcorn plants evaluated by NIOSH were as follows: (1) At each plant, one to three employees per work shift (i.e., mixers) measured butter flavorings (liquids, pastes, and powders) in open containers such as 5-gallon buckets and poured the flavoring into heated soybean oil in large (e.g., 500-gallon) heated mixing tanks, most of which had loose-fitting lids. (2) Most mixers did not use respirators. Only one mixer at one plant reported consistent use of a respirator with organic vapor cartridges during mixing tasks. (3) Mixers added salt and coloring to the oil and flavoring mixture, which was then transferred by pipes to nearby packaging lines to be combined with kernel popcorn in microwaveable bags. (4) Employees on the packaging lines operated the packaging machines and facilitated the placement of the finished product into cartons and boxes. In most plants, QC employees popped product in microwave ovens that were usually located in a separate QC laboratory. Other employees were located in warehouse and office areas. In separate areas of some plants, employees also packaged plain kernel popcorn in plastic bags without oil or flavorings. The six microwave popcorn plants differed in size as follows: (1) Two small plants (Facilities J and O) had fewer than 15 employees, one or two mixing tanks, and one packaging line. (2) One medium-sized plant (Facility N) had approximately 50 employees, one mixing tank, three holding tanks for heated oil and butter flavoring mixtures, and three packaging lines. (3) The three largest plants (Facilities G, K, and L) had more than 100 employees, five or more tanks, and seven or more packaging lines. In some plants, flavoring-mixing activities and tanks were in a separate room adjacent to the packaging area. In other plants, some or all tanks of heated oil and flavoring were adjacent to or were inadequately isolated from the packaging lines ]. In addition to the employees with findings consistent with bronchiolitis obliterans at the index microwave popcorn plant, employees with fixed airways obstruction and air trapping on HRCT scans consistent with obliterative bronchiolitis were identified at four of the other five microwave popcorn plants where NIOSH conducted HHEs ]. Including the index plant, the three largest plants and one of the small plants had affected mixers NIOSH 2003bNIOSH , 2004a. Like the index plant, the medium-sized plant had affected packaging area employees. At both of these plants, packaging area employees worked near tanks of heated oil and butter flavorings [NIOSH 2003a[NIOSH , 2006]. The biopsies of three of the six employees who underwent lung biopsy at the medium-sized plant were reported by the reviewing pathologists as having findings consistent with bronchiolitis obliterans NIOSH 2003a]. Compared to mean diacetyl air concentrations measured at the index microwave popcorn plant, mean corrected diacetyl air concentrations at the other five microwave popcorn plants were lower: 0.02 to 0.83 ppm in the packaging areas and 0.63 to 1.54 ppm in the mixing rooms/areas ]. NIOSH conducted analyses of aggregated data from the medical surveys conducted at the six microwave popcorn plants ]. Only the data from the first survey at the index microwave popcorn plant were aggregated with the data from the surveys at the other plants. Compared to employees who had never worked as mixers, employees who had at least one day of experience mixing butter flavorings into heated soybean oil had statistically significant (P < 0.05) higher prevalences of respiratory symptoms and a statistically significant lower mean percent predicted FEV 1 . Compared to mixers with 12 months or less experience, mixers with more than 12 months experience had higher prevalences of respiratory symptoms (shortness of breath was statistically significant) and airways obstruction on spirometry. Mean percent predicted FEV 1 was 82% in mixers with more than 12 months experience compared to 95% in mixers with 12 months or less experience (P = 0.004). The same pattern of higher prevalences of respiratory symptoms and worse lung function in ever mixers (who had ever worked at least one day mixing flavorings in oil) and in mixers with more than 12 months experience was still evident after index plant data were excluded from the analyses ]. Compared to packaging area employees at plants where tanks of heated oil and butter flavorings were isolated from the packaging lines, packaging area employees at plants where tanks were adjacent to or inadequately isolated from the packaging lines had higher prevalences of respiratory symptoms and airways obstruction on spirometry and lower mean percent predicted FEV 1 (29% vs. 10% for wheezing, P = 0.001; 14% vs. 5% for airways obstruction, P = 0.06; P > 0.05 for all other comparisons). Of 27 packaging area employees with airways obstruction at plants where tanks were adjacent to or inadequately isolated from the packaging lines, 21 of 23 who were administered a bronchodilator had fixed airways obstruction. After excluding index plant data from the analyses, packaging area employees in plants where tanks were adjacent to or inadequately isolated from the packaging lines still had higher prevalences of airways obstruction (11.5% vs 5.5%; not statistically significant) and wheezing (25% vs 10.7%, P = 0.01) compared to packaging area employees at plants where tanks were isolated. The prevalences of other respiratory symptoms were similar in both groups. The findings across the six plants suggested that those employee groups with peak exposures, sometimes with relatively low average exposures, had higher prevalences of chest symptoms or pulmonary function abnormalities than those employees without intermittent high exposures ]. # Results of private surveys A large food company hired private consultants to conduct medical and environmental surveys at the company's four microwave popcorn plants [Lockey et al. 2009;White et al. 2010]. To assess for evidence of rapid lung function decline, the investigators identified employees with a progressive increase or decrease in FEV 1 of greater than 8% or 330 mL over 12 months among employees who participated in all three spirometry tests [Lockey et al. 2009]. They found no association between current diacetyl exposure (less than 0.05 ppm or greater than/ equal to 0.05 ppm) and a short-term persistent increase or decrease in FEV 1 , adjusted for pack-years of smoking and body mass index. Of 39 mixers with mixing experience before the implementation of mandatory PAPR use, five had airways obstruction. Three of the five had bronchodilator administered, and all three had a bronchodilator response. Three of the five had HRCT scans; two of the scans showed air trapping on the expiratory view. The investigators concluded that, "The contribution of exposure to butter flavouring with diacetyl to these clinical findings is uncertain." Three mixers who began mixing after the implementation of mandatory PAPR use were found to have airways obstruction. Preplacement spirometry was not available for these individuals. One of the three employees had pre-existing asthma, and the other two had long smoking histories (24 and 63 pack-years, respectively). The investigators concluded that the airways obstruction in these three individuals was likely due to asthma and smoking but could not rule out the possibility that short-term exposure to diacetyl contributed to the airways obstruction when respirators had not been used 100% of the time. Analyses of 6 years of spirometric follow-up of these four plant cohorts are pending. Management had required employees to wear respirators when weighing or adding the flavors or base ingredients to the mixers. However, employees did not always wear respirators during clean-up activities where exposure to powdered flavors was possible. NIOSH concluded that it was probable that some agent in the mixing room produced severe fixed obstructive lung disease in two employees. They did not identify a specific etiologic agent, but suspected an airborne agent because the lung was the only affected organ and because air sampling by the Indiana Division of Labor had revealed high dust exposures. The Indiana Division of Labor collected 20-minute air samples that showed dust air concentrations of 20 mg/m 3 in an employee's breathing zone and 2.5 mg/m 3 inside the hood of an employee's supplied-air respirator. NIOSH analyzed bulk ingredient samples for levels of proteolytic enzymes and endotoxin. They did not identify proteolytic activity in any of the samples; endotoxin levels were "below levels seen in other workplaces where endotoxin has been associated with large decrements in FEV 1 " [NIOSH 1986]. Air sampling for specific flavoring compounds was not conducted. A cluster of cases consistent with obliterative bronchiolitis among production employees at a flavoring manufacturing company was reported by Dr. James Lockey at the 2002 American Thoracic Society International Conference [Lockey et al. 2009]. After identification of an index case of biopsy-documented bronchiolitis obliterans at this plant, a survey of the workforce identified an additional four employees with clinical findings consistent with obliterative bronchiolitis. All five employees with these findings had normal spirometry tests at the start of employment. These employees went on to develop moderate to severe fixed airways obstruction. For 4 to 5 years after cessation of exposure to flavoring compounds, the affected employees had no further declines in their lung function. [Kim et al. 2010]. This prevalence was similar to that expected in comparison to national data from NHANES III [CDC 1996]. However, the distribution by severity of obstruction was highly skewed, with six mild cases, seven moderate, one severe, and the remaining four very severe. The prevalence of severe and very severe obstruction combined was 2.7 times higher than expected overall (95% CI 1.2-6.4) and 15 times higher than expected in employees less than 40 years old (95% CI 5. 1-44.1). Sixteen obstructed cases worked in four companies using ≥ 800 pounds of diacetyl annually compared to two obstructed cases in companies using less diacetyl (prevalence of 5.3% versus 1.2%), for an odds ratio (OR) of 4.5 (95% . The prevalence of obstruction in employees currently doing any production task was 4.5% compared to 2.0% in production support employees (laboratory technicians/scientists, quality control technicians, maintenance/repair employees, warehouse employees, and truck drivers) and 2.3% in office employees. Of the 18 employees with obstruction, 14 currently worked in production, two worked in production support (one had just moved from production because of dyspnea), one with previous production experience currently worked in the office, and one could not be classified. Tenure was statistically significantly higher in employees with moderate or worse obstruction than in employees with mild obstruction (1.5 versus 9.0 years; P = 0.02). Half of the 18 employees with obstruction reported no chest symptoms (five of six employees with mild obstruction and four of seven with moderate obstruction). Of the 13 with documented postbronchodilator spirometry, 12 had fixed obstruction (including all four with severe or very severe obstruction). Of the 12 of 18 with obstruction who had medical evaluation results submitted to the California Department of Public Health, eight were diagnosed by their physicians to have either bronchiolitis obliterans (one biopsy-confirmed) or fixed obstruction related to flavorings; all eight had moderate to very severe disease [Kim et al. 2010]. Some of the cases included in this analysis of California flavoring employee surveillance data were presented above in the descriptions of two NIOSH HHEs at California flavoring plants (Facilities B and C). # Lung disease in diacetyl production employees Lung disease consistent with obliterative bronchiolitis was reported among employees of a plant in the Netherlands that produced diacetyl [ [NIOSH 2003b[NIOSH , 2004a. Real-time measurements at one of these plants showed that a mixer's diacetyl exposures increased up to 80 ppm to 120 ppm when he added liquid butter flavorings to a mixing tank [NIOSH 2004a]. # Other food production case reports In addition to cases consistent with obliterative bronchiolitis in flavoring manufacture, diacetyl manufacture, and microwave popcorn production, case reports have surfaced in other food production industries in which flavorings are introduced into food products. In cookie manufacture with artificial butter flavoring in Brazil, four cases of bronchiolitis were described in young men, aged 24 to 27 years, who had worked between 1 and 3 years handling flavorings in preparation of cookie dough [Cavalcanti et al. 2012] [Ghanei et al. 2008;King et al. 2011;Markopoulou et al. 2002]. NIOSH summarizes the evidence concerning spirometric restriction in flavoring-exposed employees in this section. [King et al. 2011]. Of 15 cases of chronic dyspnea and cough following sulfur mustard exposure 20 years previously, 13 had normal spirometry, one had restriction, and one had obstruction; all had pathologic evidence of bronchiolar disease. The cases with biopsy-documented constrictive bronchiolitis all had normal spirometry, and the two with the abnormal spirometry had chronic cellular bronchiolitis [Ghanei et al. 2008]. Of 19 cases of biopsy-documented obliterative bronchiolitis, six had normal spirometry (although 2 had isolated gas trapping), 11 had obstruction, one had restriction, and one had a mixed pattern [Markopoulou et al. 2002]. This last case series originated from a clinical referral center without common exposures. These pathologic case series suggest two conclusions. First, abnormal spirometry is insensitive to pathologic obliterative bronchiolitis that results in symptoms warranting clinical evaluation. Second, the finding of restriction in populations with cases of fixed airways obstruction consistent with obliterative bronchiolitis is likely to be part of the spectrum of obliterative bronchiolitis, although the differential diagnosis in individual employees requires investigation. # Index Plant Findings Regarding Restriction Among the former employees who developed findings consistent with obliterative bronchiolitis while working at the index microwave popcorn plant (Facility G), lung function tests in one employee showed a reduced total lung capacity and reduced residual volume in addition to airways obstruction. These reduced lung volumes indicate that this employee had restrictive lung disease as well as airways obstruction . This former employee also had a low carbon monoxide diffusing capacity and was unusual among the former employee cases in having some reversibility after ceasing employment at the microwave popcorn ]. In the first cross-sectional survey of the index plant (Facility G), 10 of 116 employees had isolated abnormal FVC, of whom 7 had low total lung capacity; 11 employees had isolated airways obstruction. An additional 10 employees had both low FVC and airways obstruction, for a total of 21 of 116 employees having any restrictive spirometric pattern. None of those with any restriction had radiologic interstitial abnormalities. When the prevalence of any restrictive abnormality was examined by cumulative exposure quartile (using exposure estimates corrected for humidity and time to extraction), a trend for exposure response relationship was evident: From lowest to highest exposure quartile, the prevalence of any restriction was 10.7%, 13.3%, 20.7%, and 24.1% (P = 0.08). During follow up of these plant employees, one employee with rapidly falling pulmonary functions in a restrictive pattern underwent open lung biopsy. The pathology report documented caseating lung granulomas around airways, but grossly normal areas of lung were not sampled for examination of possible obliterative bronchiolitis. Cultures and stains for microorganisms did not yield an infectious etiology, and the physician concluded 3-2). In the three large microwave popcorn plants (Facilities G, K, and L), the restrictive proportion of abnormal spirometry ranged from 32.3% to 53.8%. These proportions are similar to those cited in two case series of biopsy-documented constrictive bronchiolitis, which were 50% in the case of U.S. soldiers in Iraq and Afghanistan [King et al. 2011] and Iranians following sulfur mustard exposure, in which the pathology included proliferative bronchiolitis [Ghanei et al. 2008]. In the three large microwave popcorn plants, the proportion of mixed restrictive and obstructive spirometry in those with abnormal spirometry was similar to the proportion with pure obstructive and pure restrictive abnormalities. In the consecutive clinical case series [Markopoulou et al. 2002], the much lower proportion of restrictive abnormalities may be explained by the prevailing understanding a decade ago that obliterative bronchiolitis is an obstructive disease. # NIOSH Findings of Restrictive Spirometry at Flavoring Manufacturing Plants As in the microwave popcorn investigations, flavoring manufacturing workforces with cases consistent with obliterative bronchiolitis have also had employees with restrictive spirometry, with proportions of restriction among those with abnormal spirometry ranging from 28.6% to 88.2% (Table 3- 2). NIOSH found an unusually high prevalence of a restrictive spirometric pattern among production employees at a flavoring manufacturing plant (Facility I) in Indiana [NIOSH 2011]. Among the 106 employees with interpretable spirometry test results obtained by the company, 30 (28%) had a restrictive pattern (22 with a mild abnormality, six with a moderate abnormality, one with a moderately severe abnormality, and one with a severe abnormality). In addition, three employees had obstructive abnormalities, and one had a very severe mixed abnormality. Combining all spirometric abnormalities with those with only excessive decline in FEV 1 in the subset of employees with serial abnormalities, 39 (37%) employees had abnormal findings. In comparison to the U.S. general population, the employee prevalence of restrictive spirometric abnormalities was 3.8 times higher than expected, after adjustment for race, ethnicity, sex, age, smoking status, and body mass index. NIOSH later detected an error in abstraction of smoking information from company spirometry reports and corrected this comparison to 3.7 [Kreiss 2014]. NIOSH also found evidence of rapid lung function decline in this workforce (section 3.3) with a 7.0-fold risk of excessive decline in the subgroup of production employees with higher potential for flavorings exposure (later corrected to 5.8) [Kreiss 2014]. Average declines in percent predicted FEV 1 and FVC for the employees with four annual measurements were in a pattern consistent with the evolution of restrictive lung disease. As in other flavoring plants, chemical exposures were diverse, although diacetyl was used nearly daily. Personal samples of diacetyl obtained by the company using NIOSH Method 2557 (uncorrected for absolute humidity and days to extraction) ranged to 0.76 ppm and area measurements to 10.2 ppm. Company samples in 2008-2009 using OSHA methods (not requiring correction) ranged to 1.9 ppm for personal and 2.9 ppm for area samples. A company-sponsored re-analysis of Facility I spirometry data reported finding that no flavoring compounds, including diacetyl, had produced an increased risk of abnormal spirometric findings or longitudinal changes in spirometry [Ronk et al. 2013]. The study confirmed an excess risk of abnormal restrictive spirometry reported by NIOSH investigators with a similar prevalence ratio of in comparison to the general population reflected in NHANES III. The authors offered the inadequacy of the NHANES III study population as a comparison group, despite adjusting for age, sex, and body mass index, because the national data were largely drawn from urban centers, and the authors alleged that the flavoring employees in a large city in Indiana were largely agrarian. As an alternative comparison group, the authors described the employee group with lower potential for flavoring exposure as an internal control group with no or minimal exposure, also referring to them as an administrative group. However, all employees in the medical surveillance program were in production areas, and company data documented measurable diacetyl in all production areas, including worrisome measurements in packaging which was classified in the NIOSH health hazard evaluation as having lower potential for exposure. Thus, the similar distribution of abnormal restrictive spirometry across the production workforce, without regard to higher and lower potential for flavoring exposure, remained unexplained and cannot be attributed to misclassification of lung disease by spirometry, variable quality spirometry, or body habitus, also mentioned by the authors. The most likely explanation for the 3.3-3.7 increased odds for restrictive disease in the Facility I workforce is that risk for workrelated abnormality existed across both groups of production area employees in comparison to the national predicted estimate. The Ronk et al. [2013] study conclusion that none of the flavoring compounds caused workrelated spirometric abnormalities hinges on absence of association of pulmonary function abnormalities or decrements in employees with tenure in higher potential for flavoring exposure areas. The authors explain the difference in findings between their "negative" study and the NIOSH findings of work-related spirometric abnormalities by a NIOSH methodologic flaw in not taking account of correlated measures of serial lung functions. However, the authors misrepresent NIOSH analyses in which the outcome variables were the slopes of spirometric changes, expressed as mL/ year, based on linear regression as a smoothing function. NIOSH also used categorical outcomes of excessive spirometric decline. Neither of these NIOSH outcomes reflected correlated serial data. In addressing serial (correlated) spirometry measures, Ronk et al. [2013] used generalized estimating equation modeling, which is a reasonable approach. However, the authors chose an exchangeable correlation structure, which assumes that the variation between any two measures is equal; this assumption would not appear appropriate for pulmonary function test measures at varying intervals. Measures taken at a 6-month interval would likely be more correlated than measures at several-year intervals, as occurred in the Facility I spirometry data set. The generalized estimating equation models assume that cumulative tenure is linearly related to the change in spirometry measures, which may not be the case in a short-latency health effect as has occurred in flavoring-exposed employees. The Ronk et al. [2013] paper omits report of average changes in FEV 1 and FVC per year in their model without workplace covariates, which might have indicated unusually high average decrements per year. NIOSH had found that the average FVC decline in the employee population was 108 mL/year, about 3.5-fold the expected decline of approximately 30 mL/year. Ronk et al. [2013] separately modeled tenure in work areas with higher potential for exposure and tenure in liquid compounding with the apparent assumption that the remainder of the plant population had zero tenure (exposure), which is simply false. In particular, the liquid compounding tenure model ignores tenure in other higher potential for exposure jobs, which would clearly result in no associations with their work parameters. In contrast, the simpler NIOSH analyses of decline in lung function by areas with higher and lower potential for flavoring exposure demonstrated that both average declines and excessive decline differed between the two groups of production employees in statistically significant ways. These simple methods were not affected by correlated measurements. # Rapid Lung Function Decline Indirect and direct evidence shows that employees exposed to flavoring-related compounds can experience excessive lung function decline, whether within the normal range of spirometry or in those with either restrictive or obstructive spirometric abnormalities. Indirect evidence comes from reviews of medical records and work histories of flavoring-exposed employees who developed obliterative bronchiolitis. In a case series summarizing the eight affected former employees and one additional current employee at the index microwave popcorn plant (Facility G), the median length of employment prior to symptom onset was 1.5 years; the median duration of employment was 2 years . At a company that manufactured flavors for the baking industry (Facility A), two flavoring production employees developed respiratory symptoms and severe fixed airways obstruction within 7 months of starting work at the plant [NIOSH 1986]. Although these employees did not have baseline spirometry tests before they began working with flavorings, it is unlikely that their lung function was already significantly decreased when they started work. Production jobs such as preparing the oil and flavoring mixture for microwave popcorn production and mixing liquid and powder flavor ingredients in flavoring manufacture often require the employee to lift 50-to 100-pound containers. It is unlikely that employees could have performed such tasks if their lung function was already severely compromised when they started work. Some affected employees stopped working when they could no longer do the job because of severe shortness of breath on exertion, while others were relocated to less strenuous jobs [NIOSH 1986[NIOSH , 2007a[NIOSH , 2008. Severe airways obstruction as seen in obliterative bronchiolitis is rare in the general population. Data from NHANES III show that, among individuals less than 50 years old (including both smokers and never-smokers), the prevalence of obstruction with an FEV 1 less than 40% of predicted is 0.1% (1 in 1,000 people) [CDC 1996]. Direct evidence that employees exposed to flavoring-related compounds can experience rapid lung function decline comes from exposed employees who have had serial spirometry tests. Normal average FEV 1 decline is about 30 mL/year, and percent predicted FEV 1 does not usually change in the absence of disease because the predicted value is age corrected [Redlich et al. 2014]. Three of the affected former employees from the index microwave popcorn plant (Facility G) had declines in their FEV 1 percent of predicted of approximately 20% to 30% over approximately 2 years ]. NIOSH evaluated data from the eight NIOSH medical surveys at the index microwave popcorn plant for evidence of rapid lung function decline . The investigators chose as the criterion for rapid decline a decrease in FEV 1 of 300 mL and/or 10% from an employee's initial (baseline) spirometry test to the employee's last spirometry test. This criterion was similar to a threshold developed based on a study of coal miners evaluated over time with spirometry of high technical quality in which the researchers concluded that "when healthy working males perform spirometry according to American Thoracic Society standards, a yearly decline in FEV 1 greater than 8% or 330 mL should not be considered normal…" [Wang and Petsonk 2004]. The sensitive criterion used by the investigators, who did not annualize declines, was chosen because of the potential severity of the irreversible health outcome and the high technical quality of the pulmonary function tests, which allows for a sensitive cutpoint. For their analysis of the data from the surveys at the index microwave popcorn plant, investigators excluded survey participants with fewer than three interpretable spirometry tests because interpretation of change over time based on only two tests is less reliable . Of the 88 survey participants who participated in three or more NIOSH medical surveys at the index microwave popcorn plant (Facility G) and had started working there prior to the implementation of exposure controls ("Group 1"), 19 (22%) had FEV 1 declines of greater than 300 mL and/or 10% from their first to their last spirometry test. Four of these 19 employees had worked at some point in the mixing room, including one employee who experienced a 1,300-mL decline from the first test in November 2000 to the next test 5 months later; the next spirometry test 4 months after the second test showed an additional decline in FEV 1 of 600 mL, resulting in the employee leaving employment. This employee's FEV 1 continued to fall after leaving employment, with a total fall of 2,800 mL over 2.75 years, representing a decline from 96% of predicted FEV 1 to 39% of predicted FEV 1 . In comparison to survey participants who began working at the plant before the company started implementing exposure controls, only 3 (7%) of 41 survey participants with three or more spirometry tests who were hired after the company began implementing controls ("Group 2") had FEV 1 declines of greater than 300 mL and/or 10% from their first to their last spirometry test . Of the 27 Group 1 employees who participated in all eight medical surveys, mean annualized decline in FEV 1 in the first year of follow-up was 144 mL per year. Annualized decline in the second year of follow-up fell to 40 mL per year as exposures were controlled, and the annualized decline fell to 22 mL per year in the third year of follow-up, a rate of decline consistent with normal agingrelated lung function decline [ Kreiss 2007]. . In contrast, in a microwave popcorn manufacturing cohort studied over 12 months, no relationship was demonstrated between current exposure level (dichotomized at 0.05 ppm) and an abnormal decrease in FEV 1 (found in 7% of employees using a criterion of a greater than 320 mL or 8% decline over one year), adjusted for pack-years of smoking and body mass index [Lockey et al. 2009]. As indicated in the studies above, different approaches have been used by investigators over time to define excessive or rapid decline in FEV 1 . These include percentage decline with various criteria, absolute decline with various criteria, normative population-based criteria for longitudinal limits of decline over various time intervals, and spirometry quality-adjusted criteria, all of which are discussed in Chapter 9, section 9.5. # Asthma At the index microwave popcorn plant and at one of the other five microwave popcorn plants that NIOSH evaluated (Facilities G and L), the prevalence of self-reported physiciandiagnosed asthma was approximately two times higher than expected [NIOSH 2004b[NIOSH , 2006. This suggests the possibility that some employees exposed to diacetyl and other flavoring compounds may be at increased risk for asthma (reversible airways obstruction) while others might be at risk for obliterative bronchiolitis (fixed airways obstruction). However, few of the survey participants with airways obstruction at these two plants who were administered a bronchodilator medication had a significant response (i.e., their airways obstruction was fixed); therefore, it is possible that some of these individuals had a different lung disease and that asthma may have been a misdiagnosis. Some employees at microwave popcorn plants and flavoring plants who were initially diagnosed with asthma were ultimately found to have fixed airways obstruction and other findings consistent with obliterative bronchiolitis ; . It is possible that individuals with pre-existing asthma may experience an exacerbation of their asthma due to the irritant properties of diacetyl or similar vapors. Many asthmatics react nonspecifically with bronchospasm to strong odors. Diacetyl has been reported to be a sensitizer in a rodent local lymph node assay, and other diketones, including 2,3-pentanedione, 2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione, have similar potency as sensitizers [Anderson et al. 2013] # Dermatologic Effects Of the former employees who developed findings consistent with obliterative bronchiolitis while working at the index microwave popcorn plant (Facility G), one employee also developed a severe skin rash # Discussion Medical evaluations of employees who have developed progressive shortness of breath while working at several microwave popcorn plants and flavoring plants have shown findings consistent with the severe irreversible lung disease obliterative bronchiolitis. Some affected employees have experienced extremely rapid declines in lung function, with severe airways obstruction occurring within several months of the start of exposure to flavoring compounds NIOSH 1986]. Whether restrictive lung disease is part of the spectrum of obliterative bronchiolitis in flavoring-exposed employees remains incompletely evaluated, although restrictive spirometry has been a common finding; in one plant, excessive FEV 1 declines in a restrictive pattern appear to be associated with potential for flavorings exposure. Employees as young as 22 years old have been affected by obstructive disease. Some affected employees have been placed on lung transplant waiting lists by their physicians because of the severity of their disease , and some flavoring-exposed employees have received lung transplants. The findings from investigations and studies conducted at multiple plants have revealed a link between exposure to diacetyl and risk for severe occupational lung disease. These findings meet the criteria that are often used to determine if the results of multiple studies indicate that an exposure is the likely cause of specific health effects [Gordis 1996;Hill 1965]. The first of these criteria is temporality: the exposure precedes disease development. Evidence of this comes from the many instances where initially asymptomatic diacetyl-exposed employees developed progressive shortness of breath within months of starting work and then were found to have severe fixed airways obstruction NIOSH 1986;. Additionally, NIOSH documented rapid falls in lung function in exposed employees with initially normal spirometry at three plants [NIOSH 2006[NIOSH , 2008[NIOSH , 2011. Lockey et al. reported at the 2002 American Thoracic Society International Conference that five flavoring employees who developed moderate or severe fixed airways obstruction had normal spirometry at the start of employment [Lockey et al. 2009]. California public health surveillance showed that excessive FEV 1 decline occurred in employees in flavor manufacturing plants that participated in a preventive program attempting to lower flavoring exposures [Kreiss et al. 2012]. Temporality requires the exposure to precede disease development, and the inverse is that new disease cases should decline in a population with cessation of exposure, an evaluation by intervention or "experiment". Follow-up medical and environmental surveys at the index microwave popcorn plant (Facility G) revealed evidence of decreased lung disease risk with control of exposures. In employees hired before exposures were controlled, the prevalences of respiratory symptoms and airways obstruction and mean percent predicted FEV 1 did not change significantly over time (consistent with an irreversible disease). However, employees hired after exposures were controlled had lower prevalences of respiratory symptoms and airways obstruction and higher mean percent predicted FEV 1 on their first medical survey than employees hired before exposures were controlled, and these findings did not change significantly over time NIOSH 2006]. Additionally, among 27 employees who participated in all eight NIOSH medical surveys from 2000 to 2003, annualized declines in FEV 1 improved from 144 mL per year to 40 mL per year to 22 mL per year, the last being consistent with normal aging-related lung function decline [ Kreiss 2007]. Similarly, the former employee index cases with clinical bronchiolitis obliterans had stable FEV 1 within about 2 years of exposure cessation ]. Another criterion is strength of the association: the magnitude of the apparent health risk due to the exposure. In analyses of data from the initial NIOSH medical survey at the index microwave popcorn plant (Facility G), the prevalence of airways obstruction among nonsmoking current employees was approximately 11 times higher than expected in comparison to national data from NHANES III. It was approximately three times higher than expected in older smokers . In analyses of California flavoring employee surveillance data, the prevalence of severe airways obstruction was approximately three times higher than expected among all employees compared to national data. The prevalence in employees less than 40 years old was 15 times higher than expected [Kim et al. 2010]. The criterion of replication of findings (and strength of the association) between diacetyl exposure and development of severe occupational lung disease is apparent in the number of plants where employees have been affected and the number of production employees in these plants. The six microwave popcorn plants NIOSH evaluated represent a large segment of the microwave popcorn industry in the United States. Employees who developed findings consistent with obliterative bronchiolitis at these plants prepared the mixture of butter flavorings and soybean oil ("mixers") or worked nearby in the packaging area. Four of the six microwave popcorn plants NIOSH evaluated had affected mixers ]. Each of these plants had one to three mixers per work shift at the time of the NIOSH HHEs. The occurrence of multiple cases of severe airways obstruction in such a small job category (approximately 20 mixers across the six plants) is far greater than expected when compared to the U.S. population prevalence of severe airways obstruction from NHANES III data (0.1%, or 1 in 1,000, in individuals less than 50 years old, including smokers and never-smokers) [CDC 1996]. A similar magnitude of risk exists in some flavoring companies. At least six flavoring production employees developed findings consistent with obliterative bronchiolitis at three flavoring plants (Facilities A, B, and C) where NIOSH conducted medical surveys. There were approximately 30 production employees across these three plants at the time of the NIOSH HHEs [NIOSH 1986[NIOSH , 2007a[NIOSH , 2008. Consistency is also supported by the occurrence of lung disease consistent with obliterative bronchiolitis in diacetyl-exposed employees in at least eight flavoring manufacturing plants, a diacetyl production plant, a cookie manufacturing plant, and a coffee production plant CDC 2007;Kim et al. 2010;NIOSH 1986NIOSH , 2007aNIOSH , 2008; . Private consultants who conducted medical and environmental surveys at four microwave popcorn plants owned by one large food company also found in their data analyses that a history of working as a mixer and higher cumulative exposure to diacetyl were associated with decreased lung function [Lockey et al. 2009]. Additional criteria to support a causal link between diacetyl exposure and severe lung disease include biologic plausibility, doseresponse relationship, and consideration of alternate explanations. Biologic plausibility is supported by experimental studies of diacetyl toxicity summarized in Chapter 4. NIOSH found evidence of a dose-response relationship (i.e., worse lung disease or more employees affected with higher diacetyl exposure) in analyses of medical survey data from the index microwave popcorn plant (Facility G) and in analyses of aggregated data from medical surveys at the index plant and five additional microwave popcorn plants. The analyses of data from the initial survey at the index plant showed an increasing prevalence of abnormal spirometry with increasing quartiles of estimated cumulative diacetyl exposure . Analyses of aggregated data from surveys at the six microwave popcorn plants showed higher prevalences of respiratory symptoms and worse lung function in mixers with more than 12 months experience and in packaging area employees at plants where heated tanks of oil and flavorings were not adequately isolated, compared to less exposed comparison groups ]. Additional evidence of a dose-response relationship was found in analyses of California flavoring employee surveillance data. An analysis of obstruction by amount of plant diacetyl use showed that there were 16 employees with obstruction in four companies that used more than 800 pounds of diacetyl annually compared to two employees with obstruction in companies that used less diacetyl (prevalence of 5.3% versus 1.2%), for an OR of 4.5 (95% CI 1.03-19.9) [Kim et al. 2010]. In diacetyl-exposed employees with severe fixed airways obstruction and other findings of obliterative bronchiolitis, a consideration of alternate explanations should take into account the fact that while obstructive lung diseases such as asthma and smoking-related emphysema are common in the general population, severe airways obstruction is rare, especially in young individuals. Asthma is characterized by episodes of reversible airways obstructionsome individuals with severe or inadequately treated asthma can develop fixed airways obstruction. However, asthma does not appear to be a possible explanation for cases of severe lung disease among diacetyl-exposed employees for the following reasons: (1) Most affected employees denied having any pre-existing lung disease or symptoms at the start of exposure. (2) Once shortness of breath developed, it did not improve when employees were away from the workplace as would be expected in employees with occupational asthma (either new onset asthma or exacerbation of pre-existing asthma). ( 3) Employees' illnesses did not improve when they took medications for asthma such as bronchodilators and corticosteroids. (4) Most employees did not have a significant response to administration of bronchodilators in any of their spirometry tests (i.e., airways obstruction was fixed). While some diacetyl-exposed employees who developed severe lung disease were smokers, the natural history of smoking-related disease and the results of medical evaluations of affected employees make it unlikely that the cases of severe fixed airways obstruction among diacetyl-exposed employees are smoking-related. Compared to the normal decline in lung function that occurs with aging (FEV 1 declines approximately 30 mL/year), in a subset of smokers lung function declines more rapidly (FEV 1 declines on average approximately 45-70 mL/year). An estimated 10%-15% of all smokers develop clinically important airflow obstruction [Ryu and Scanlon 2001]. Smokers who experience rapid lung function decline will typically start to become short of breath once their FEV 1 falls below 60% of predicted; this usually occurs around age 50. Severe airways obstruction (e.g., FEV 1 less than 40% predicted) typically does not occur before 55-60 years of age [Wise 2008]. Several diacetyl-exposed employees developed severe fixed airways obstruction while still in their 20s and 30s. Any smoking history among these affected employees (as well as in affected employees younger than 50) would not explain their severe fixed airways obstruction. Additional evidence against smoking as a cause of severe lung disease in these employees is the fact that most employees' DL CO measurements were normal. In airways obstruction due to smoking-related emphysema, DL CO is reduced. Obliterative bronchiolitis is known to occur as a result of a variety of infections, exposures, or nonpulmonary diseases. Examples include overexposure to highly irritating gases or vapors such as chlorine, ammonia, and nitrogen oxides or in association with connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis, or in organ transplant recipients. The diacetyl-exposed employees who developed severe fixed airways obstruction did not have histories or medical evaluation findings to suggest that they had developed obliterative bronchiolitis from another exposure or medical condition. Airways obstruction can also occur due to diseases that affect other airways besides the bronchioles such as bronchiectasis or upper airway lesions [Ryu and Scanlon 2001]. However, individuals with airways obstruction from such other causes typically have characteristic history, physical exam, and medical test findings that usually serve to reveal the nature of the illness (e.g., copious sputum in someone with bronchiectasis or evidence of upper airway obstruction on spirometry). Such findings were not apparent in diacetyl-exposed employees who developed severe fixed airways obstruction. Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetylexposed employees have provided substantial evidence of a causal relationship between diacetyl exposure and development of this disease. Exposure preceded disease development, and lung disease risk decreased with control of exposures. Analyses of data from workplace medical and environmental surveys revealed a strong, consistent association of the disease with diacetyl manufacture, use of diacetyl in flavoring production, and use of diacetyl-containing butter flavorings in microwave popcorn production. The investigations have also shown evidence of a dose-response effect, and animal and other laboratory studies have provided evidence of biologic plausibility. Medical evaluations of affected employees did not identify alternative explanations for their illness besides their workplace exposure to diacetyl and other flavoring compounds. Accordingly, the criteria for interpreting epidemiologic associations as causal have all been met by the body of investigation presented in this criteria document for a recommended standard. Alleman T, Darcey DJ [2002]. Case report: bronchiolitis obliterans organizing pneumonia in a spice process technician. J Occup Environ Med 44( 3):215-216. Anderson SE, Franko J, Wells JR, Lukomska E, Meade BJ [2013]. Evaluation of the hypersensitivity potential of alternative butter flavorings. Food Chem Toxicol 62C:373-381. # ATS, ERS (American Thoracic Society, European Respiratory Society) [2002]. American Thoracic Society/ European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 165( 2 CDC [2002]. Fixed obstructive lung disease in workers at a microwave popcorn factory-Missouri, 2000-2002. MMWR 51( 16):345-347. CDC [2007]. Fixed obstructive lung disease among workers in the flavor-manufacturing industry- California, 2004:389-393. CDC [2013]. Obliterative bronchiolitis in workers in a coffee-processing facility-Texas, 2008-2012. MMWR 62( 16):305-307. Rowell M, Kehe K, Balszuweit F, Thiermann H [2009]. The chronic effects of sulfur mustard exposure. Toxicology 263( 1):9-11. Ryu JH, Scanlon PD [2001]. Obstructive lung diseases: COPD, asthma, and many imitators. Mayo Clin Proc 76( 11):1144-1153. Sahakian N, Kullman G, Lynch D, Kreiss K [2008]. Asthma arising in flavoring-exposed food production workers. Int J Occup Med Environ Health 21( 2):173-177. Schachter EN [2002]. Popcorn worker's lung. N Engl J Med 347( 5):360-361. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN [1998]. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 2( 5 Chemical and physical properties of diacetyl and 2,3-pentanedione are presented in section 1.4. As mentioned there, diacetyl is an α-dicarbonyl. Endogenous α-dicarbonyl compounds are among the reactive carbonyl species implicated in the formation of advanced glycation end products [Nakagawa et al. 2002a;Wondrak et al. 2002]. Like other α-dicarbonyl compounds, diacetyl is reactive, with a tendency to cause protein cross-links . The reactivity of the α-dicarbonyl compounds is enhanced by electron attracting groups and decreased by electron donors ]. Thus, diacetyl is a reactive compound, but its alkyl components are electron donors that may somewhat decrease the reactivity of the adjacent carbonyl groups . Diacetyl and related α-dicarbonyl compounds can inactivate proteins, principally through reactions with the amino acid, arginine [Epperly and Dekker 1989;Mathews et al. 2010;Saraiva et al. 2006]. The related α-dicarbonyl flavoring, 2,3-pentanedione, has been reported to be even more reactive with arginine groups than diacetyl [Epperly and Dekker 1989]. Recently, in vitro studies indicate that diacetyl can cause β-amyloid aggregates and covalently modify β-amyloid at 5th arginine (Arg 5 ), although the in vivo relevance of this finding remains to be investigated [More et al. 2012b]. Thus, existing studies indicate that diacetyl is a reactive compound that can modify proteins and suggest that diacetyl-associated protein modification may occur in vivo. # Diacetyl and 2,3-Pentanedione in Food Diacetyl and 2,3-pentanedione have a long history as components of food, suggesting that exposures can occur in diverse workplaces. They occur as natural products in many foods [Jiang et al. 2013;Majcher and Jelen 2005;Majcher et al. 2013;Rincon-Delgadillo et al. 2012;Santos et al. 2013]. Diacetyl imparts the flavor and aroma of butter to many common foods and drinks including butter, cheese, yogurt, beer, and wine [Jang et al. 2013;Rincon-Delgadillo et al. 2012]. Diacetyl in food plays an important role in food preference [Liggett et al. 2008]. While less extensively studied in foods than diacetyl, 2,3-pentanedione is a common flavoring in margarine and vegetable spreads [Rincon-Delgadillo et al. 2012]. Roasted coffee also contains appreciable amounts of diacetyl [CDC 2013;Daglia et al. 2007a;Daglia et al. 2007b]. Because diacetyl is not a component of green coffee beans, it appears to be a product of the roasting process [Daglia et al. 2007a]. Bacteria and yeast produce diacetyl during fermentation [Chuang and Collins 1968]. It can be produced by metabolism of an acetaldehyde-thiamine pyrophosphate complex in the presence of acetyl-coenzyme A [Speckman and Collins 1968]. Microbes can also produce diacetyl from pyruvate in the presence of acetyl-coenzyme A [Chuang and Collins 1968]. Microbial culture conditions, such as pH, can influence the relative amount of diacetyl produced during fermentation [Garcia-Quintans et al. 2008;St-Gelais et al. 2009]. In addition, the steam distillate of several bacterial cultures grown on skim milk is known as "starter distillate" and is also considered a flavoring [FASEB 1980;FDA 1983]. Major components of some starter distillate samples include diacetyl and acetic acid [FASEB 1980;Rincon-Delgadillo et al. 2012]. A recent study demonstrated that diacetyl remains a frequent component of commercial starter distillate samples, and diacetyl concentrations exceeded 20 mg/g in one sample [Rincon-Delgadillo et al. 2012]. Starter distillate can also contain 2,3-pentanedione as well as butyric acid, which inhibits the metabolism of diacetyl and 2,3-pentanedione [Morris and Hubbs 2009;Nakagawa et al. 2002a;Rincon-Delgadillo et al. 2012]. Thus, diacetyl and 2,3-penanedione can occur naturally in food, may be added to food as flavorings, may be produced during the roasting process, and can be anticipated components when starter distillate is added as a flavoring. # Metabolism in Mammalian Cells In the rat and hamster liver, diacetyl is metabolized principally by reduction to acetoin in an enzymatic reaction catalyzed by dicarbonyl/Lxylulose reductase (DCXR), the enzyme is also known as diacetyl reductase, with either nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as coenzymes [Nakagawa et al. 2002a;Otsuka et al. 1996;Sawada et al. 1985]. Acetoin can be further reduced to 2,3-butanediol in an NADH-dependent manner [Otsuka et al. 1996]. This diacetyl reductase activity is higher in the liver than in the kidney, and kidney activity is higher than in the brain. However, after oral administration of diacetyl, the levels of acetoin are much higher in the brain than in the kidney or liver. 2,3-Butanediol accumulates in liver, kidney, and brain after the administration of diacetyl, acetoin, or 2,3-butanediol. Oral administration of acetoin and, to a lesser extent, 2,3-butanediol, in rats also causes diacetyl accumulation in the liver and brain [Otsuka et al. 1996]. However, liver homogenates do not produce significant diacetyl from acetoin or 2, 3-butanediol [Otsuka et al. 1996]. Thus, the metabolic interconversion of the 4-carbon compounds, acetoin, diacetyl, and 2,3-butanediol occurs in mammalian systems in vivo and in vitro but the full spectrum of metabolic pathways remains incompletely investigated. As mentioned above, in mammalian cells, the predominant metabolic pathway for diacetyl is catalyzed by DCXR, a tetrameric protein that is comprised of four subunits, each 244 amino acids long [El-Kabbani et al. 2005;Ishikura et al. 2001;Nakagawa et al. 2002a;Sawada et al. 1985]. In addition to the reductive metabolism of diacetyl, DCXR catalyzes the metabolism of several other dicarbonyl compounds, including 2,3-pentanedione, 2,3-hexanedione, 2,3-heptanedione, and 3,4-hexanedione [Nakagawa et al. 2002a]. In addition, DCXR catalyzes the reductive metabolism of a number of monosaccharides, including L-xylulose, and plays a role in the glucuronic acid/uronate cycle of glucose metabolism as well as the metabolism of carbonyl compounds [Carbone et al. 2005;El-Kabbani et al. 2005;Nakagawa et al. 2002a]. Inhibitors of DCXR are well described and include n-butyric acid, 2-furoic acid, benzoic acid, and nicotinic acid [Carbone et al. 2005;Nakagawa et al. 2002a]. At least one of these DCXR inhibitors, n-butyric acid, is well absorbed in the nose, and its presence in vapor mixtures causes small but significant decreases in diacetyl absorption in the nasal mucosa and, thereby, leaves more diacetyl in the vapor stream of the nasal airways for delivery to the lung [Morris and Hubbs 2009]. Occupational Exposure to Diacetyl and 2,3-Pentanedione 81 4 . Toxicology of Diacetyl and 2,3-Pentanedione Very weak tracheal contractions with threshold at 1 mM, relaxation at exposures above 3 mM. Diacetyl effect on response to intraluminal (mucosal) methacholine: 4-hour perfusion with 3 mM diacetyl increased methacholine reactivity 10 times; 10 mM diacetyl completely inhibited the methacholine response. Depolarization of transepithelial potential difference at 3 and 10 mM. Decrease in transepithelial potential difference at 10 mM. Gloede et al. [2011] F344 rats Respiratory uptake of diacetyl in F344 rats was used to validate a model of respiratory tract uptake of diacetyl At a given inhaled diacetyl dose, the predicted dose to the bronchiolar epithelium of a lightly exercising employee is predicted to be more than 40 times the dose to the bronchiole of a rat. Describes a low affinity, high capacity and a high affinity, low capacity pathway for diacetyl metabolism in the rat respiratory epithelium. The high affinity pathway is inhibited by sodium benzoate, indicating that it is DCXR. [ and 2,3 Oropharyngeal aspiration of diacetyl 0, 100, 200, or 400 mg/kg, single dose 4 days post-aspiration Foci of fibrohistiocytic proliferation with little or no inflammation present at the junction of the terminal bronchioles and alveolar ducts (400 mg/kg) Morgan et al. [2012] Male and female Wistar-Han rats and B6C3F1 mice 2,3-Pentanedione 0, 50, 100 or 200 ppm 6 hr/day, 5 days/week, Up to 12 exposures In rats, 12-day 2,3-pentanedione exposure cause necrosis of respiratory epithelium and atrophy of olfactory neuroepithelium in the nose; intramural and intraluminal fibrosis of intrapulmonary airways. In rats, 5 or 10 days of inhaling 200 ppm 2,3-pentanedione increased bronchoalveolar lavage fluid concentrations of monocyte chemotactic protein-1, monocyte chemotactic protein-3, C-reactive protein, fibroblast growth factor-9, and fibrinogen. In mice, 12-day 2,3-pentanedione exposure caused necrosis of nasal turbinates, suppurative exudate and atrophy of olfactory neuroepithelium in the nose; inflammation in intrapulmonary airways with necrosis, ulceration and regeneration at 200 ppm exposure. Morris and Hubbs [2009] Male Sprague-Dawley rats Diacetyl 100 or 300 ppm in airstream flows of 100-400 mL/min A hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) was used to extrapolate diacetyl and butyric acid uptake in rat airways epithelium to human airways epithelium. The CFD-PBPK suggests that nasal injury in rats can predict a risk to deep lung tissue in humans. Diacetyl damages airway epithelium when it reaches a critical concentration in the target cells; the CFD-PBPK indicates that more diacetyl will be absorbed in the nose of rats than in humans. Butyric acid is shown to shift diacetyl absorption from the nose and trachea into deeper lung tissue. In the rat kidney, DCXR is localized in the distal tubules and collecting ducts and colocalizes with carboxylmethyllysine, an advanced glycation end product [Nakagawa et al. 2002a]. In the mouse kidney, DCXR is localized to the brush border of the proximal renal tubules [Nakagawa et al. 2002a]. In the human prostate epithelial cells and in normal human skin, DCXR is associated with the cell membrane [Cho-Vega et al. 2007a, b;Cho-Vega et al. 2007b]. In human skin, DCXR is located near the adhesion molecules, e-cadherin and β-catenin [Cho-Vega et al. 2007b]. Similarly, in the vascular endothelium in the dermis, DCXR localizes near intercellular junctions, suggesting a potential role for DCXR in cell adhesion [Cho-Vega et al. 2007b]. In addition, DCXR activity is present in the respiratory mucosa of the rat, with the highest activity in the olfactory epithelium [Morris and Hubbs 2009]. DCXR knockout mice are not well characterized phenotypically but are reported to be fertile [Nakagawa et al. 2002b]. People without DCXR excrete pentose in their urine but are otherwise believed to be healthy, indicating that DCXR and the major diacetyl metabolic pathway are not essential for life [Flynn 1955;Lane and Jenkins 1985]. Importantly, the metabolism of diacetyl is not exclusively by DCXR. For example, aldo-keto reductase 1C15 is a newly-described aldoketo reductase expressed in rat lung that can metabolize α-diketones [Endo et al. 2007]. Recently, a low affinity, high capacity and a high affinity, low capacity pathway for diacetyl metabolism have been described in the respiratory tract of the rat . The high affinity pathway was inhibited by sodium benzoate indicating that it is DCXR. The low affinity pathway is not believed to play a major role at diacetyl concentrations associated with most occupational exposures. # In Vivo and in Vitro Toxicology Studies Diacetyl and 2,3-pentanedione may be consumed in food, the vapors may be inhaled, and direct skin contact is possible. In vivo studies have modeled these routes of human exposure. # In Vivo Toxicology of Orally Administered Diacetyl Subchronic (90-day) gavage administration of 540 mg diacetyl/kg/day caused multiple changes in exposed rats, including decreased body weight, increased water consumption, increased adrenal weight, increased relative kidney and liver weights (in females absolute kidney and liver weights were also increased), decreased blood hemoglobin concentration and gastric ulceration [Colley et al. 1969]. No adverse effects were noted at the next highest dose level, which was 90 mg/kg/day. On a mg/ kg basis, the 90 mg/kg/level was estimated to be roughly 500-fold greater than the estimated human maximum daily intake of diacetyl from foods consumed at that time, with 50 ppm diacetyl being the highest estimated concentration in any food [Colley et al. 1969]. # Effects of Topically Applied Diacetyl and 2,3-Pentanedione in Vivo Sensitization following topical application of diacetyl is predicted on the basis of results of a murine local lymph node assay [Anderson et al. 2013;Anderson et al. 2007;]. On the basis of the results of the local lymph node assay and immune cell phenotyping, it is suggested that diacetyl and 2,3-pentanedione function as T-cell mediated chemical sensitizers [Anderson et al. 2013]. Cutaneous sensitization by diacetyl and 2,3-pentanedione may be initiated through haptenation with proteins containing the amino acids lysine and arginine . Diacetyl is corrosive to the cornea of the eye using the Draise test ]. # Toxicology of Inhaled Diacetyl in Vivo In rats, acute exposures to diacetyl or diacetylcontaining butter flavoring vapors cause necrosis in the epithelial lining of nasal and pulmonary airways. Rats inhaling vapors of butter flavoring that contained diacetyl developed multifocal necrotizing bronchitis one day after a 6-hour exposure. The mainstem bronchus was the most affected intrapulmonary airway. However, nasal airways were more affected than intrapulmonary airways. Necrosuppurative rhinitis was seen in rats inhaling butter flavoring vapors at concentrations of butter flavoring that did not cause damage in intrapulmonary airways [Hubbs et al. 2002]. As a single agent acute exposure in rats, a 6-hour diacetyl inhalation exposure caused epithelial necrosis and inflammation in bronchi at concentrations of > 294.6 ppm and caused epithelial necrosis and inflammation in the trachea and larynx at concentrations of ≥224 ppm ]. The airway epithelial damage in rats inhaling 356 ppm was remarkable, with an average pathology score of 9.5 on a 10-point scale in the nasopharyngeal duct and larynx, while damage in the tracheal epithelium averaged 8.7 on a 10-point scale. In a pattern reminiscent of airway damage from butter flavoring vapors, diacetyl causes greater damage to nasal airways than to intrapulmonary airways . The data from the National Toxicology Program 90-day inhalation study are available online and was used for the NIOSH animal-based risk assessment (see Chapter 6). Airway damage in mice one day after diacetyl inhalation was found to correlate with markers of increased protein turnover, implicating protein damage in the etiology of diacetylinduced airway damage [Hubbs et al. 2016]. Eighteen hours after a 6-hour exposure to inhaled diacetyl (100, 200, 300, or 360 ppm), in anesthetized rats 360 ppm elevated slightly lung resistance and dynamic compliance [Zaccone et al. 2013]. Subsequent inhalation of methacholine aerosol (0.3-10 mg/mL) revealed that airway reactivity was decreased after exposure to diacetyl at 360 ppm. It had been predicted, based on extensive epithelial damage noted after diacetyl inhalation, that reactivity to inhaled methacholine would be increased. Eighteen hours after a 6-hour exposure to inhaled 2,3-pentanedione (120, 240, 300, or 360 ppm), in anesthetized rats basal lung resistance (R L ) and dynamic lung compliance (C dyn ) were not affected. Following inhalation of 346 ppm diacetyl by rats, foci in the trachea that demonstrate epithelial denudation also appear to have loss of sensory nerves, as reflected in a decreased density of PGP9.5-immunoreactive nerve fibers. However, in the epithelium adjacent to denuded foci, increased numbers of nerve fibers contain immunoreactive substance P, a neuropeptide important in neurogenic airway inflammation. In addition, the number of substance P immunoreactive neurons increase in the ganglia supplying the trachea in a dose-dependent manner in exposed rats. These findings suggest that diacetyl-induced airway epithelial damage may be accompanied by changes in the sensory nerves [Goravanahally et al. 2014]. In mice, inhaling diacetyl at concentrations of 200 or 400 ppm for 6 hours/day for up to 5 days causes respiratory tract changes similar to those seen in rats inhaling diacetyl or butter flavoring vapors . At both 200 and 400 ppm, diacetyl caused necrotizing rhinitis in mice that was most prominent in the front portion of the nose. At 400, but not at 200 ppm, the olfactory epithelium demonstrated vacuolar degeneration and apoptosis. Necrotizing laryngitis was consistently observed in all mice inhaling 400 ppm diacetyl, while only one mouse inhaling 200 ppm diacetyl had comparable necrotizing laryngitis, but erosive laryngitis was present in 9 of 10 mice inhaling the 200 ppm concentration. Exposing mice to diacetyl for only 1 hour/day at 100, 200, or 400 ppm diacetyl, 5 days per week, for 2 to 4 weeks rather than 6 hours/day for the same number of days eliminated epithelial necrosis in mice inhaling 200 ppm diacetyl and decreased the severity of epithelial necrosis in mice inhaling 400 ppm diacetyl. Lymphocytic inflammation was seen around the bronchi in some mice inhaling 100 ppm and in all mice inhaling 200 or 400 ppm diacetyl . Exposing mice to diacetyl for 15 minutes per day at 1,200 ppm diacetyl, 5 days/week for 2 weeks also caused lymphocytic infiltrates around bronchi, and lymphocytic infiltrates extended deeper into the lung, reaching the level of the preterminal bronchioles ]. Subchronic, 12-week, diacetyl inhalation for 6 hours/day, 5 days/week caused significant histopathologic changes in mice at all concentrations studied. Peribronchial lymphocytic infiltrates were seen at terminal sacrifice at 12 weeks in all subchronically-exposed mice inhaling 100 ppm diacetyl and in some mice inhaling 25 or 50 ppm diacetyl. In mice inhaling 100 ppm diacetyl, bronchial epithelial changes included denudation, attenuation, and hyperplasia . Chronic active nasal inflammation was seen in all mice inhaling 50 or 100 ppm and in four of five mice inhaling 25 ppm diacetyl for 12 weeks, an exposure that also caused minimal to mild lymphocytic bronchitis in two of five mice. This suggests that the no observable adverse effect level in mice for subchronic inhalation may be less than 25 ppm diacetyl. Butyric acid caused a small but significant reduction in nasal uptake of diacetyl in the rat nose, and, thereby, increased the diacetyl exposure to the lung due to a reduced "scrubbing" effect [Morris and Hubbs 2009]. Oropharyngeal aspiration permits exposures that bypass the rodent nose and, hence, scrubbing at that site [Foster et al. 2001;Rao et al. 2003]. A single aspiration exposure to 400 mg/kg diacetyl produced a fibrohistiocytic response at the bronchioloalveolar junction of mice after 4 days. While oropharyngeal aspiration of diacetyl delivers a high bolus dose of diacetyl, the unusual fibrohistiocytic response could suggest that the smallest airways may be particularly susceptible to diacetyl-induced epithelial injury and fibrosis . A subsequent study demonstrates development of obliterative bronchiolitis in rats after intratracheal instillation of diacetyl [Palmer et al. 2011]. In this model, diacetyl-induced obliterative bronchiolitis was associated with abnormal repair of the injured bronchiolar epithelium. The reports of the induction of obliterative bronchiolitis and obliterative bronchiolitis-like changes in the deep lung of laboratory animals following aspiration of diacetyl are important because no prior animal model of obliterative bronchiolitis existed, and it is a technique that bypasses the rodent nose, which CFD-PBK models have demonstrated to absorb more diacetyl than will be absorbed in the upper airways of employees (section 4.2.6). However, as noted in the study, the very large single dose used in these studies may have limitations for the use of single exposure intratracheal instillations for risk assessment purposes [Palmer et al. 2011]. A study demonstrated bronchial fibrosis in rats inhaling 150 or 200 ppm diacetyl for 2 weeks ]. Pulmonary function changes have been investigated in mice after acute or subchronic diacetyl exposure. In mice, acute 2-hour diacetyl inhalation at concentrations from 191 to 1154 ppm caused a decrease in respiratory rate and an increase in the "time of break" between inhalation and exhalation, an indicator of sensory irritation [Larsen et al. 2009]. In addition, acute diacetyl inhalation in mice caused decreases in tidal volume and mid-expiratory flow rate. Mice previously exposed to high diacetyl concentrations were less sensitive to the sensory irritation effects of a diacetyl challenge exposure, while mice previously exposed to low diacetyl concentrations were more sensitive to a diacetyl challenge exposure. Extrapolation of the mouse dose-response relationship to humans suggested no sensory irritation to warn employees during acute diacetyl exposures at concentrations less than 20 ppm [Larsen et al. 2009]. As mentioned earlier, a recent study suggests that acute diacetyl inhalation exposures can actually increase the number of substance P-positive neurons in the jugular ganglia and the number of nerve fibers containing substance P in the epithelium adjacent to sites of epithelial damage, but decreases the sensory innervation at the actual sites of greatest epithelial damage [Goravanahally et al. 2014]. As a group, these studies suggest dysregulation of airway sensory innervation and responses. Additional studies support the potential for diacetyl to alter pulmonary function in exposed rodents. Mice inhaling 100 ppm diacetyl for 12 weeks had concentration-dependent decreases in respiratory rate and minute volume after 3 and 6 weeks of exposure; mice inhaling 50 ppm diacetyl had decreased respiratory rates after 6 weeks exposure, but pulmonary function improved with time with continued exposure at these concentrations ]. However, after 18 weeks of exposure, respiratory rates in mice inhaling 25 ppm diacetyl were significantly lower than in controls ]. The effects of diacetyl inhalation may not be limited to the respiratory tract. Inhaling 2,500 ppm diacetyl for 45 minutes increased 2-deoxyglucose uptake in foci in the posterior portion of the rat brain olfactory bulb [Johnson et al. 2007]. While this finding has generally been interpreted as being related to olfaction [Johnson et al. 2007], the potential exists for toxicity to olfactory neurons that radiate into the olfactory bulb. Phagocytosis of olfactory nerve material and increases in Tnfα mRNA were recently demonstrated in the olfactory bulb of mice one day after a 6-hr diacetyl inhalation exposure. By immunofluorescence, the multifunctional scaffolding protein sequestosome-1 accumulated in the olfactory bulb of these mice and often congregated in the microglial cells that contained phagocytized olfactory neuronal material [Hubbs et al. 2016]. Although powdered butter flavoring can produce fewer vapors than liquid butter flavorings, the powders have a major respirable component [Boylstein et al. 2006;Rigler and Longo 2010]. If powdered butter flavorings are substituted for liquid butter flavorings, diacetyl and 2,3-pentanedione vapor concentrations may well be below exposure limits. In particular, encapsulated flavoring powders are designed to contain diacetyl or 2,3-pentanedione vapors. However, inhalable particulates can be deposited in the nose, the conducting airways, and deep lung. No peer reviewed studies have investigated the potential for encapsulated flavorings to release diacetyl and/or 2,3-pentanedione directly to the target cells lining airways. However, a recent study indicates that more than a quarter of particulates in flavoring powders are less than 10 μm in diameter. Therefore, powders have the potential to reach the intrapulmonary airways [Rigler and Longo 2010]. # In Vitro Toxicology of Diacetyl and 2,3-Pentanedione Diacetyl is mutagenic in the Salmonella typhimurium tester strains TA100 and TA104 [Kim et al. 1987;Marnett et al. 1985]. However, diacetyl also reacts with mutagenic heterocyclic amines and suppresses the mutagenicity of heterocyclic amines in Salmonella typhimurium tester strain TA98. Diacetyl also enhances chromosome loss by proprionitrile in Saccharomyces cerevisiae. Recently, diacetyl in the presence of human S9 demonstrated a high degree of mutagenicity in a mouse lymphoma mutation assay [Whittaker et al. 2008]. Consistent with these findings, recent in vitro studies of direct interactions between diacetyl and single-stranded oligonucleotides under acellular conditions indicate that diacetyl can form adducts with 2-deoxyguanosine [More et al. 2012a]. Additional studies on the genotoxicity of diacetyl have been reviewed in the background documents available online as part of the National Toxicology Program [National Toxicology Program 2007]. In isolated mitochondria, diacetyl closes the mitochondrial permeability transition pore and renders it insensitive to Ca 2+ [Eriksson et al. 1998]. This effect of diacetyl occurs at concentrations that could occur in tissues of diacetyl-exposed individuals, with half-maximal inhibition of the mitochondrial transition reported to be at a diacetyl concentration of 1 mM [Eriksson et al. 1998]. This concentration has been shown to have pharmacological activity in airways and has been modeled to be achieved in the airway wall after inhalation (see below). The effect of diacetyl on the mitochondrial permeability transition pore appears to be caused by arginine modification (see above) [Eriksson et al. 1998]. In addition, diacetyl can be metabolized by pig heart mitochondrial pyruvate kinase to form acetate and acetyl-CoA with a K m value of 0.46 mM. Diacetyl is also a competitive inhibitor of pyruvate metabolism by pyruvate dehydrogenase with a K i of 0.43 mM [Sumegi et al. 1982]. The isolated, perfused trachea system employing tracheas from unexposed guinea pigs has been used to investigate the effects of diacetyl in vitro ]. In this model, the direct, potentially toxic effects of the agent on epithelium may be examined. Agents such as diacetyl may be applied to the epithelium (mucosal surface) or separately to the smooth muscle (serosal surface) of the trachea while measuring contractile or relaxant responses of the airway smooth muscle. An advantage of this model is that the effects of the diketone do not involve an inflammatory response, inasmuch as the trachea has been removed from the animal and there is no source for the recruitment of inflammatory cells into the wall of the airway. In unstimulated tracheas, diacetyl or 2,3-pentanedione applied to the mucosal surface in concentrations 1 mM and higher dissolved in a physiological salt solution elicited small contractions; in concentrations higher than 3 mM (i.e., 10 and 30 mM), contractions to diacetyl and 2,3-pentanedione were followed by relaxations. The relaxation responses were larger than the contractile responses. Exploring these phenomena further, adding the flavorings to the mucosa of tracheas that were first contracted with methacholine, a bronchoconstrictor agonist, resulted in full relaxation of the smooth muscle over the same range of diacetyl concentrations. These findings indicate that diacetyl is a weak contractile agent when applied to the epithelial surface, but that it is capable of eliciting strong relaxant responses. Thus, a diversity of responses in the airway that depend on the diacetyl concentration is produced. Investigation of inhaled diacetyl effects (60, 100, 200, 300, and 360 ppm) and inhaled 2,3-pentanedione effects (120, 240, 320, and 360 ppm) on reactivity of tracheas removed from exposed rats and studied in the isolated, perfused trachea model showed that reactivity to methacholine applied to the mucosal surface was increased slightly after inhalation of 300 and 360 ppm diacetyl and 320 and 360 ppm 2,3-pentanedione. Based on epithelial damage in airways after exposure to diacetyl, a larger increase in airway reactivity had been anticipated [Zaccone et al. 2013]. Diacetyl inhalation elicits substantial histopathologic changes to airway epithelium, including denudation and necrosis (section 4.2.3). Commonly, damage to respiratory epithelium leads to airway hyperreactivity. For example, after ozone inhalation, airway reactivity of guinea pigs to inhaled methacholine is increased; likewise, reactivity to methacholine applied to the mucosa of isolated, perfused trachea is also increased [Fedan et al. 2000]. Incubation of perfused trachea with diacetyl dissolved in a physiological salt solution and applied to the mucosal surface led to no effect (1 mM diacetyl), an approximately 10-fold increase in reactivity to methacholine (3 mM), or full suppression of contraction to methacholine (10 mM) ]. The effects of diacetyl in isolated airways from naïve animals does not involve the airway epithelium [Zaccone et al. 2013]. Damage to the epithelium after diacetyl inhalation suggests that epithelial ion transport and electrical resistance could be affected by the diketone. In rat tracheal segments investigated in vitro with Ussing chambers, diacetyl dissolved in physiological salt solution at 3 mM decreased transepithelial potential difference (V t , mV), indicative of a decrease in electrogenic ion transport and/or an effect on paracellular ion transport involving tight junctions, whereas 10 mM diacetyl reduced V t further and decreased transepithelial resistance (R t , Ωcm 2 ). R t is an index of tight junction permeability. Thus, ion transport and epithelial integrity are affected directly by diacetyl. The diacetyl concentrations observed to affect tracheal diameter and elicit bioelectric responses, i.e., 1 to 3 mM, are within the range estimated to occur in the rat tracheal mucosa after diacetyl inhalation. Using a CFD-PBK model, Morris and Hubbs [Morris and Hubbs 2009] calculated that inhalation levels of 100, 200, and 300 ppm diacetyl could yield concentrations in the mucosa of 1.1 to 1.2, 2.3 to 2.5, and 3.7 to 3.8 mM diacetyl, respectively. This suggests that some or all of the observed in vitro effects may occur in the airways during vapor inhalation. The mechanism(s) of the effects of diacetyl on trachea in vitro are not known at present. However, a related structure, 2,3-butanedione monixime, has been reported to inhibit contraction of smooth muscle, perhaps as a result of inhibiting phosphorylation of myosin light chains [Lizarraga et al. 1998;Siegman et al. 1994;Stowe et al. 1997;Waurick et al. 1999]. Bioelectric responses of neurons also have been reported to be inhibited by 2,3-butanedione monixime [Lizarraga et al. 1998]. 2,3-Pentanedione is not mutagenic in Salmonella typhimurium strains TA98, TA100, TA102, or TA104 [Aeschbacher et al. 1989;Marnett et al. 1985]. A recent study demonstrates that in vitro diacetyl exposure increases shedding of the epidermal growth factor ligand, amphiregulin. These findings are further supported by evidence that amphiregulin transcripts and protein are also increased in an in vivo model of obliterative bronchiolitis induced by repeated intratracheal instillation of diacetyl [Kelly et al. 2014]. Amphiregulin has previously been reported to play a role in pulmonary fibrosis, although the nature of that role is not fully understood [Zhou et al. 2012]. # Toxicology of Inhaled Diacetyl Substitutes Diacetyl is the compound largely responsible for the flavor of butter in butter [FASEB 1980;FDA 1983]. However, exposures in workplaces that make or use butter flavoring and emissions from heated butter flavoring involve multiple volatile compounds [Boylstein et al. 2006;]. Among the potential replacements for diacetyl, starter mix contains high concentrations of diacetyl [FASEB 1980;FDA 1983]. Another chemical that adds the flavor of butter to food is acetoin, and it was present along with diacetyl in many of the workplaces where obliterative bronchiolitis occurred in employees who make or use diacetyl ; . Acetoin is structurally very similar to diacetyl but an α-hydroxyketone in acetoin replaces the reactive α-diketone implicated in the toxicity of diacetyl and 2,3-pentanedione [Hubbs et al. 2012]. In a National Toxicology Program (NTP) 90-day study on acetoin, the chosen maximum exposure level (generally representing the maximum tolerated dose) was 800 ppm, whereas in the NTP 90-day diacetyl study the maximum exposure level was 100 ppm (Chapter 6). In 90-day inhalation exposures, diacetyl produced statistically significant respiratory tract lesions from exposures as low as 25 ppm, in both rats and mice (Chapter 6). Statistically significant histopathology changes in the 25 ppm diacetyl exposures were nasal respiratory epithelial metaplasia (in both male and female rats), nasal olfactory epithelial degeneration in female rats; nasal respiratory epithelial necrosis (in male and female mice) plus chronic inflammation and respiratory epithelial hyperplasia of the larynx in female mice (Chapter 6). In addition acetoin (150 ppm), after inhalation for 6 hours by rats, had no effect on reactivity to inhaled methacholine while inhaled acetic acid (27 ppm for 6 hours), another component of flavoring mixture, increased airway reactivity to methacholine [Zaccone et al. 2013]. Thus, current data, while limited, indicate that acetoin is considerably less hazardous than diacetyl. 2,3-Pentanedione is structurally very similar to diacetyl because it is a 5-carbon α-diketone, and diacetyl is a 4-carbon α-diketone. Eighteen hours after a 6-hour inhalation exposure to 2,3-pentanedione (120, 240, 320, and 360 ppm), R L and C dyn in anesthetized rats were unaffected [Zaccone et al. 2013]. Subsequently, airway reactivity to inhaled methacholine aerosol was decreased after inhalation of 120, 240, and 320 ppm 2,3-pentanedione. 2,3-Pentanedione affected methacholine reactivity more than diacetyl. Airway hyperreactivity to methacholine had been anticipated, in view of the epithelium damage caused by the flavoring. Following inhalation exposure of rats to these same concentrations of 2,3-pentanedione and perfusion of the trachea in vitro, reactivity to mucosally-applied methacholine was increased by 240, 320, and 360 ppm 2,3-pentanedione [Zaccone et al. 2013]. The magnitude of this effect surpassed that caused by diacetyl inhalation. Morphologic data suggest that 2,3-pentanedione can cause airway epithelial damage similar to the damage caused by diacetyl [Hubbs et al. 2012;]. Rats repeatedly inhaling 2,3-pentanedione at concentrations ≥ 150 ppm for up to 2 weeks develop fibrosis of intrapulmonary airways, a morphologic change similar to obliterative bronchiolitis in humans . Recently, more than 3500 genes were found to be upregulated in RNA isolated from the fibrotic bronchi of 2,3-pentanedione exposed rats [Morgan et al. 2015]. Some of the up-regulated genes were ones previously implicated in fibrosis, including transforming growth factor-β2, interleukin-1α, interleukin-18, interleukin-33, and fibronectin. In addition, at high exposure concentrations, messenger RNA changes were noted in the brain of rats after acute 2,3-pentanedione inhalation [Hubbs et al. 2012]. # Diacetyl and 2,3-Pentanedione in Cigarette Smoke A recent study suggests that mainstream tobacco smoke collected by a smoking machine contained significant amounts of diacetyl that varied with the smoking parameters set by different organizations. 2006;Polzin et al. 2007]. Other recent studies have identified diacetyl and 2,3-pentanedione in electronic cigarette liquids and aerosols [Allen et al. 2016;Farsalinos et al. 2015]. In one study, after derivatization with 1,2phenylenediamine, quantification by GC-NPD, and confirmation by GC-MS, 301-433 µg diacetyl/cigarette was measured in the total mainstream smoke withdrawn from each burning cigarette from 15 different commercial reference cigarettes [Fujioka and Shibamoto 2006]. However, that study did not use a smoking machine to simulate actual smoking behavior, so that the amount of diacetyl observed may not be representative of the amount produced under realistic smoking conditions. In another study, using GC/MS and a smoking machine with ISO parameters, a range of 12.7-145 µg diacetyl/cigarette was measured from 41 different types of cigarettes [Polzin et al. 2007]. Thus, several studies suggest that significant diacetyl is present in mainstream cigarette smoke, although the concentrations vary [Fujioka and Shibamoto 2006;Pierce et al. 2014;Polzin et al. 2007]. Finally, electronic cigarette liquids often contain diacetyl and 2,3-pentanedione [Allen et al. 2016;Farsalinos et al. 2015]. The Pierce et al. [2014] 1975]. Assuming that all of the air an employee inhales contains the concentration of diacetyl measured in the workplace, it is critical to recognize that the mainstream smoke of a smoker is not the only source of air; they are also breathing air with much lower diacetyl concentrations. Assuming that the other air breathed by smokers does not contain diacetyl, the workplace equivalent exposure concentration for a smoker during the smoking time period is roughly 190-to 560fold lower than the concentration measured in the mainstream cigarette smoke using the ISO parameters of one 0.035 L puff/min (6.75/0.035 is 193 and 19.5/.035 is 557). Using the ISO parameters, this would be an average equivalent of a workplace concentration of 0.45 to 1.3 ppm for diacetyl and 58 to 170 ppb for 2,3-pentanedione during the smoking process. If the smoking machine parameters of 9.3 minutes/cigarette are used to calculate the duration of exposure, a smoker who smokes one pack of 20 cigarettes/ day spends 186 minutes a day smoking, but the employee is working for 8 hours. Therefore, the 8-hour time-weighted average equivalent concentration for the smoker is 2.6-fold lower to reflect the time period they are not exposed, which would be 170 to 500 ppb for diacetyl and 22 to 65 ppb for 2,3-pentanedione, depending upon exercise level. Calculations of workplace equivalent exposures are similar using total mass of diacetyl and 2,3-pentanedione reported by Pierce et al. [ Although it is important to recognize that breathing patterns differ between cigarette smokers or electronic cigarette users ("vapers") and employees, which may affect the pharmacokinetics of inhaled diacetyl and 2,3-pentanedione [Hubbs et al. 2015], these concentrations of diacetyl would be predicted to decrease FEV 1 in some individuals if inhaled for a working lifetime (see Chapter 5). Indeed, many smokers do demonstrate significant decreases in FEV 1 [Barnes 2004;Fletcher and Peto 1977;Wright et al. 1987;Xu et al. 1994]. Additionally, cigarette smoking is a major risk factor for chronic obstructive pulmonary disease, and a decrease in FEV 1 is a characteristic feature of this disease. In addition, bronchiolar fibrosis is part of the airway remodeling response that characterizes chronic obstructive pulmonary disease [Kim et al. 2008;Sohal et al. 2013]. Decreases in FEV 1 and fibrosis of bronchioles are features that also characterize obliterative bronchiolitis [Schlesinger et al. 1998]. However, smokers with chronic obstructive pulmonary disease have additional morphologic changes in their lungs, including emphysema, that are not seen in obliterative bronchiolitis [Snider 2003]. While it has been hypothesized that the failure to diagnose diacetyl-induced obliterative bronchiolitis as a cigarette smoker-associated disease suggests that diacetyl does not cause obliterative bronchiolitis in exposed employees [Pierce et al. 2014], the data when corrected for the actual corresponding occupational exposure concentrations may instead suggest the hypothesis that diacetyl and related reactive carbonyl compounds in cigarettes could potentially contribute to chronic obstructive pulmonary disease. Because chronic obstructive pulmonary disease is a leading cause of morbidity and mortality [Halbert et al. 2006;Lopez et al. 2006], the role of diacetyl and other reactive carbonyl compounds in cigarette smoke in contributing to chronic obstructive pulmonary disease is a worthy topic for future studies. As extensively discussed in Chapter 3, airway obstruction and decreased FEV 1 can, nevertheless, be identified in smokers who are exposed to diacetyl. Most importantly, because diacetyl causes obstructive lung disease and because smoking causes obstructive lung disease, the presence of diacetyl in cigarette smoke does not diminish the need to control diacetyl exposures in employees. In fact, it highlights the greater risks occurring in employees who are exposed to diacetyl in the workplace and who also smoke. # Relevance of Diacetyl Animal Studies to Humans Four converging lines of evidence support the relevance of diacetyl inhalation studies in rats and mice to humans. First, diacetyl inhalation causes damage to respiratory epithelium in rats and mice. This finding is important because injury to the respiratory epithelium of the deep lung is the accepted cause for obliterative bronchiolitis. Second, dosimetry calculations indicate that diacetyl concentration in respiratory epithelium of the human deep lung under working conditions may be much higher than diacetyl concentrations in laboratory animals. Third, another organic compound, sulfur mustard, implicated in causing obliterative bronchiolitis in humans, produces a similar pattern of predominantly nasal injury in rats exposed by nose-only inhalation [Weber et al. 2010]. Fourth, repeated inhalation exposure to 2,3-pentanedione causes fibrosis of intrapulmonary airways ]. Each of these findings supports the conclusion that with appropriate dosimetry studies, damage to the respiratory epithelium of the upper airways of rodents should be considered when evaluating risk for humans. Animal exposure studies have revealed that the upper airways of rodents are sensitive to flavoring-induced toxicity, whereas the lower airways of humans are most affected by these agents. Importantly, diacetyl exposures in rodents caused extensive damage to the respiratory epithelium lining the nose and the trachea ]. The cell types that are injured in the nose and trachea in rodents are very similar to the respiratory epithelium lining the airways of the deep lung of humans that are involved pathophysiologically in the development of obliterative bronchiolitis [Borthwick et al. 2009;King 1989]. In addition, the bronchi were damaged at high concentrations in acute exposures and at lower concentrations in subchronic exposures in mice. Thus, inhalation toxicology studies showed that diacetyl could damage respiratory epithelium, providing biological plausibility for its etiologic role in obliterative bronchiolitis. Indeed, at the time of the first inhalation toxicology studies of diacetyl, no accepted cause of obliterative bronchiolitis in humans had been demonstrated to cause obliterative bronchiolitis in rodents. Recently, repeated inhalation exposures to 2,3-pentanedione have been shown to cause fibrosis of intrapulmonary airways in rats, demonstrating a pathologic change in the rodent model that is very similar to obliterative bronchiolitis in humans . Interpretation of the species difference in the anatomic location of diacetyl-induced damage to respiratory epithelium may be explained by species differences in respiratory tract anatomy, breathing patterns, and diacetyl dosimetry. Rodents are obligate nasal breathers while humans are oronasal breathers. Inhaled air may bypass the human nose, particularly during exertion [Conolly et al. 2004]. In addition, the rodent nasal passageways and the rodent trachea are much narrower than the corresponding human nasal passageways and trachea. Small airway diameter increases the percentage of the airstream that is in contact with the mucous layer, increases resistance, and thereby increases mucosal absorption of watersoluble vapors [Frederick et al. 1998;Morris 1997]. Thus, the dimensions of the rodent nose predict much greater absorption of diacetyl vapors in the rodent than in the human nose. However, the surface area of the airways within the human lung is 100 times greater than the surface area of airways in the rat lung [Mercer et al. 1994]. These anatomic differences predict that, at a given exposure concentration, the mucosa in the rodent nose receives a much higher diacetyl dose than does the human nose and that the human lung receives a much higher dose than the rodent lung. To investigate these dosimetry predictions, a CFD-PBPK model of diacetyl uptake was developed [Morris and Hubbs 2009]. The CFD-PBPK model also predicted greater intrapulmonary diacetyl concentrations in the lung of humans than in rats at a given exposure concentration, especially during mouth breathing [Morris and Hubbs 2009]. Under resting conditions at an exposure concentration of 100 ppm, the rat nose and trachea are predicted to remove 39% of the inhaled diacetyl, while the trachea of a mouth breathing human would remove 4% of the inhaled diacetyl. This same study suggests the potential importance of nasal lesions in rats for predicting pulmonary toxicity in humans [Morris and Hubbs 2009]. Because the respiratory epithelium of the terminal bronchiole of humans is believed to be the target tissue for the development of obliterative bronchiolitis [King 1989], and because diacetyl doses reaching the respiratory epithelium in the nose of rodents can be similar to diacetyl doses reaching the respiratory epithelium of the deep lung in humans, it may be appropriate to consider toxicity to the respiratory epithelium lining the nose of rodents in evaluating the risk of diacetyl to mouthbreathing employees. In addition, butyric acid, which is a component of some butter flavorings, caused a small but statistically significant reduction in nasal uptake of diacetyl in the rat nose, and thereby increased the diacetyl exposure to the lung due to a reduced "scrubbing effect" [Morris and Hubbs 2009]. A subsequent CFD-PBK model indicates that with low levels of exercise that could occur in the workplace, diacetyl dose to the bronchiolar epithelium of humans may be more than 40-fold greater than the dose received by the bronchiolar epithelium of experimentally exposed rodents . Damage to the nose of rodents has recently been described for another agent implicated in causing obliterative bronchiolitis in humans, sulfur mustard [bis (2-chloroethyl) sulfide], a chemical warfare agent. Obliterative bronchiolitis is considered a major cause of progressive respiratory disease in survivors of sulfur mustard exposure [Ghanei 2004a,b,c;Ghanei et al. 2008;Rowell et al. 2009]. Noseonly inhalation exposures of F344 rats to sulfur mustard caused severe mucosal damage in the rat nose but the changes in the lung were absent or minimal [Weber et al. 2010]. When the nose was bypassed using intubation with tubing lined by Teflon®, sulfur mustard did indeed cause necrosis of the epithelium lining the proximal airways [Weber et al. 2010]. This suggests that sulfur mustard, an accepted cause of obliterative bronchiolitis in humans, causes a similar pattern of injury to the pattern observed with diacetyl at different levels of the respiratory tract of rodents. Thus, predominantly nasal injury has been seen in rodent inhalation studies with organic agents implicated in causing obliterative bronchiolitis. # Conclusions Inhalation toxicity studies in rats and mice, and in vitro studies in guinea pig tracheal preparations, indicate that diacetyl-containing butter flavoring vapors can damage airway epithelium and cause inflammation in the respiratory tract after acute or subchronic exposure. In addition, in vivo local lymph node assays indicate that diacetyl is a sensitizer, and in vitro studies indicate that diacetyl is mutagenic. Diacetyl can react with arginine residues causing structural changes in proteins that influence the function of the altered proteins. These functional changes in proteins include changes in enzyme activity and the mitochondrial permeability pore. Pharmacologic studies in vitro indicate that diacetyl can alter ion transport and reduce epithelial integrity. CFD-PBPK modeling indicates that diacetyl concentrations in the deep airways of humans may be higher than those in laboratory rodents, explaining the tendency for diacetyl-induced airway damage to be more anterior in the respiratory tract of rodents than in humans. Most recently, studies of the related α-diketone, 2,3-pentanedione, suggest that the airway toxicity of diacetyl may be shared with other structurally related, α-diketones, and that inhalation of either diacetyl and 2,3-pentanedione can cause airway fibrosis in rats. This page intentionally left blank. # References Aeschbacher HU, Wolleb U, Loliger J, Spadone JC, Liardon R [1989]. Contribution of coffee aroma constituents to the mutagenicity of coffee. Food Chem Toxicol 27( 4 Colley J, Gaunt IF, Lansdown AB, Grasso P, Gangolli SD [1969]. Acute and short-term toxicity of diacetyl in rats. Food Cosmet Toxicol 7( 6):571-580. Conolly RB, Kimbell JS, Janszen D, Schlosser PM, Kalisak D, Preston J, Miller FJ [2004]. Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset. Toxicol Sci 82( 1 Eriksson O, Fontaine E, Bernardi P [1998]. Chemical modification of arginines by 2,3-butanedione and phenylglyoxal causes closure of the mitochondrial permeability transition pore. J Biol Chem 273( 20 Larsen ST, Alarie Y, Hammer M, Nielsen GD [2009]. Acute airway effects of diacetyl in mice. Inhal Toxicol 21( 13 Majcher MA, Klensporf-Pawlik D, Dziadas M, Jelen HH [2013]. Identification of aroma active compounds of cereal coffee brew and its roasted ingredients. J Agric Food Chem 61( 11):2648-2654. Morris JB, Hubbs AF [2009]. Inhalation dosimetry of diacetyl and butyric acid, two components of butter flavoring vapors. Toxicol Sci 108( 1 the diacetyl exposure response, standard risk assessment procedures can be applied. # Environmental Assessment and Exposure Estimation For workplace environmental assessments, the HHE surveys generally collected full-shift personal breathing zone and area diacetyl air samples using NIOSH Method 2557. This sampling identified a number of air contaminants in addition to diacetyl and acetoin (Table 5-2), including acetaldehyde. Problems in diacetyl sample determination with NIOSH Method 2557 related to humidity at the time of sampling and the elapsed time to sample extraction were subsequently uncovered. NIOSH researchers worked extensively to understand this problem and derive an appropriate correction for estimating diacetyl levels . This correction, based on absolute humidity and time to extraction, was applied to the diacetyl exposure levels above the limit of detection (LOD) as measured in the selected HHEs. For other chemical exposures in microwave popcorn production determined using NIOSH Method 2557, such as acetoin, no humidity/extraction correction was needed. For laboratory diacetyl determinations below the LOD, the sample value was set equal to LOD/2. For determinations above the LOD following an outbreak of eye irritation. NIOSHmeasured diacetyl exposure levels for key process locations showed considerable variation across the four selected HHE sites with higher levels at Company G and Company N (Table 5-3 chronic disease investigations [Smith 1992]. However, for the first industrial hygiene survey (November 2000), only area samples were collected. For this survey, personal-sample equivalents to the area samples were estimated using area and personal sampling data from surveys 2 and 3 for the higher-exposed jobs, and using other procedures for samples with the lower values (Appendix H, Table H. # 3). Unique exposure time periods were developed for each of the eight exposure categories to reflect impact of the exposure control changes implemented at the plant from November 2000 to July 2003. Within the time periods for each JEM exposure category, exposures were assumed to be constant. Exposure estimates in the JEM were assigned to employees based on their history of jobs performed, job duration, and the calendar time period. For work history prior to the first industrial hygiene survey, exposure estimates from the first time period were used. For some employees such as those in the mixers exposure category, the measured personal diacetyl exposure was adjusted for the use of respirators in selected exposure periods (Appendix H). Problems in the retrospective exposure assessment for diacetyl include ( 1) uncertainty over when diacetyl was introduced and on the extent of its use as a flavoring component over time (and therefore on employee exposure levels), ( 2) variation in diacetyl content across different product lines over time, ( 3) the relative presence of diacetyl as a vapor vs. mist, adsorbed to powders or encapsulated, and ( 4) seasonal variation in the role of natural ventilation. Cumulative exposure and other exposure metrics were calculated starting at the dates when diacetyl was estimated to have first been used in regular production at the four plants: Company K (July 1, 1988), Company L (January 1, 1994), Company G (July 1, 1986), and Company N (July 1, 1986). These dates are uncertain, particularly for Company N. # Work History The employees studied were current employees at time of survey except at Company G where some former employees were also examined. All results presented are for current employees except at Company G where, due to repeated pulmonary testing over months or years, initially current employees could become former employees at a subsequent survey. Participation was voluntary and generally quite high among current employees (66%-91%) ( successive periods in specific department and job title assignments with corresponding beginning and ending dates. Gaps in employment were treated as unexposed and not included in duration-of-exposure measures. # Outcomes Reported symptoms and PFT results defined the HHE outcomes. A medical questionnaire was administered that included standard ATS items on respiratory health ] as well as dermal symptoms, allergies, detailed smoking history, and questions on other exposures and protective equipment used. Sustained-symptom onset dates were also collected. Spirometry testing was performed following ATS guidelines ]. The predicted and lower limit of normal (LLofN) values for FEV 1 , FVC and FEV 1 /FVC were calculated using prediction equations produced from NHANES III [Hankinson et al. 1999 The most appropriate measure of past diacetyl exposure for predicting health consequences is not known and hence was determined by assessment of the statistical fit of models using different exposure terms. Cumulative exposure (time summation of concentration, cum(DA)) was the starting choice for exposure metric, but dose-rate effects were examined by calculating the time summation of the square root or square of diacetyl concentration corresponding respectively to diminishing and increasing marginal responses to increasing exposure intensity (dose-rate effects) as follows: cum(DA) = Σ i (DA), cum(DA 0.5 ) = Σ i (DA 0.5 ) , and cum(DA 2.0 ) = Σ i (DA 2.0 ) where the summation was over calendar days. Transformed cumulative exposures as the square root, square, or logarithm were evaluated as were duration of exposure and average exposure concentration (cumulative exposure/ duration of exposure). Peak exposures were not available from full-shift (8-hour) TWA concentrations although selected jobs had been analyzed using a real-time method (FTIR) to assess time-variability. To make full use of the serial spirometry determinations at Company G, a longitudinal analysis of ppFEV 1 was performed in which exposure metrics were calculated from time of first diacetyl exposure up to the time of each successive spirometry determination. This analysis included employees with two or more spirometry results. All employees were active at their first survey but could have left employment prior to a subsequent survey. These models were fit using PROC MIXED in SAS 9.2 [SAS Institute Inc. 2008] with random effects permitted for individual employee's intercepts and exposure responses. A second set of metrics was calculated with exposure cumulation starting at the time of an employee's first survey and used in a subsidiary longitudinal analysis along with the full cumulative exposure metric. This analysis permitted a test of homogeneity, i.e., ( 1) for exposure effects before and after the first survey and ( 2) for possible survivor bias. Pooled analyses were conducted for two plant populations (Company K, L) with similar reported average exposures and estimated exposure responses. A plant effect was introduced to allow for systematic differences between the two sites, and there was a test of heterogeneity in the exposure effects. # Models of the Incidence of Pulmonary Obstruction For analyses of onset of discrete adverse effect outcomes, conducted for the Company G population (n=361), three case-definitions of pulmonary impairment were applied: ( -6 ) and (p=4×10 -7 ) performing considerably better than exposure duration alone, and with average exposure to diacetyl [Avg(DA)] and Cum(DA 2.0 ) performing less well than duration (Table 5-5). The estimate for the exposure-response with Cum(DA) was a 0.50 reduction in ppFEV 1 for each ppm-year of cumulative exposure (Tables 5-5, 5-6). (After 1 year at 1 ppm an employee's ppFEV 1 , starting at 100, would be predicted to be 99.5.) For FEV 1 /FVC the percent reduction with 1 ppm-yr DA was 0.16. Seventy-nine percent of the cross-sectional study population (n=286) had duration of employment of < 4 yr and 49% had less than 6 months, reflecting a high workforce turnover rate. Models restricted to < 4 yr duration produced considerably larger effect estimates; for ppFEV 1 : −1.07 (vs. −0.50) and for FEV 1 / FVC: −0.87 (vs. −0.16) (Table 5-5). With < 4 yr, the metric was a less strong predictor than Cum(DA). In the models with the better predicting exposure metrics, gender and ethnicity (possible indicators of differential healthy employee selection) were unimportant predictors. Ever-smoking was associated with an increase in ppFEV 1 but cumulative smoking, in pack-years, predicted a decline in ppFEV 1 (implying that, initially, smokers may be healthier than nonsmokers); both effects were statistically significant (Table 5-6). Regression models based on the first Company G spirometry determination rather than the last yielded similar estimates of diacetyl effects (data not shown). The metric cumulative square root of diacetyl concentration was a slightly stronger predictor of spirometry changes than simple cumulative exposure (Table 5-6), implying that if there is any dose-rate effect it is The best-predicting exposure metric depended on the HHE population analyzed (Tables 5-7, 5.8). In predicting FEV 1 /FVC the R-square values were consistently larger compared with the ppFEV 1 regressions but the exposure effects were sometimes less significant. For Company G, Avg(DA) and were the better predictors of FEV 1 /FVC; for Company K, Cum(DA) was best while for Company L, Avg(DA), and Cum(DA 2.0 ) were all equivalent better predictors. For ppFEV 1 , model fit at Company K was strongest for (Cum(DA)) 2.0 , however, Cum(DA) provided a similar fit. For Company L, Avg(DA) was the strongest predictor of ppFEV 1 . In the pooled analysis of the Company K and Company L plants, the differences in exposure response (heterogeneity) between the plants for ppFEV 1 and FEV 1 /FVC were highly significant for the better predicting metrics Cum(DA) and (Cum(DA) 2 (Tables 5-9, 5-10). The pooled regression estimate for the Cum(DA) metric corresponded to a decline in ppFEV 1 of 4.22 per ppm-yr of cumulative exposure (Table 5-9), almost an order of magnitude higher than the Company G estimated decline in ppFEV 1 of 0.50 per ppm-yr of cumulative exposure (Table 5-6) but with very different estimates for the individual plants. For plant K, the estimated fall in ppFEV 1 per ppm-yr was 7.83 while for Plant L the decrease in ppFEV 1 was 2.70 (= −7.83+5.13) per ppm-yr. At these two plants, many of the environmental samples collected were below the limit of detection for diacetyl, and the HHE environmental assessments were cross-sectional and not necessarily reflective of exposures prior to the survey date. This may explain the divergence in optimum exposure metrics compared with the Company G results. For example, if jobs with the highest exposures had been given priority for control interventions, then the subsequently measured levels would underestimate most of the jobs previously having the highest levels. Therefore, an exposure metric like Cum(DA 2.0 ), which gives greater weight to high values, might better predict spirometry changes than Cum(DA), as was observed at Company K for ppFEV 1 and FEV 1 /FVC, and at Company L for FEV 1 /FVC (Table 5- 5). Because of the inconsistencies between them and less certain exposure histories, the results for Company K and Company L were not the final basis for the NIOSH risk assessment for diacetyl which, instead, relied on the Company G findings. By far the highest exposures at Company G were among mixers (Table 5-3) raising the possibility that the observed losses in pulmonary function could be limited to that group. To examine this question, the basic multiple regression models (Table 5-6) were applied to the population at Plant G from which all employees who were ever mixers had been excluded. The result was slightly stronger estimates of the DA effect both for (1) the linear cumulative exposure term (β=0.61 vs. 0.50 for full population; R 2 =0.182 vs. 0.169, resp.) and ( 2) the square root of cumulative exposure (β=3.02 vs. 2.75 for full population; R 2 =0.182 vs. 0.173, respectively) (results not shown). Another concern was the possibility of a diacetyl-smoking interaction, with smoking possibly enhancing the harmful effect of diacetyl. Models for ppFEV 1 and FEV 1 / FVC including interaction terms (products of the diacetyl exposure metrics with the ever-smoking and pack-yrs terms) yielded statistically significant protective effects of ever-smoking on the linear and square root cumulative diacetyl exposures and small, mostly insignificant, additive interactions for the pack-years × diacetyl metric terms (P = 0.04 -0.25 depending on exposure metric and outcome; data not shown). In the absence of the smoking interaction terms, the diacetyl effects in non-smokers are somewhat underestimated and overestimated in smokers. Acetoin is another exposure in the popcorn flavoring environment (typically present with diacetyl in flavoring additive packages), and its presence was strongly associated with diacetyl (corr = 0.85) at Plant G, but it is not subject to the humidity degradation problem in air sampling. In response to concerns that the corrected historical exposure measurements for diacetyl were inaccurate, NIOSH repeated models of exposure-response relationships using acetoin measures. Applying to acetoin the procedure used for constructing the exposure matrix for diacetyl resulted in estimated acetoin concentrations over employees' work histories. Multiple linear regressions predicting percent of predicted FEV 1 based on acetoin exposure metrics produced the same pattern of results as observed with diacetyl and with almost identical model fit. For the metric square root of cumulative exposure, the R 2 observed was 0.1743 and 0.1737, respectively, for acetoin and diacetyl; the t-statistics for the exposure terms were 5.09 and 5.06 respectively. In microwave production jobs at Plant G, the mean DA concentration over all sampling surveys, combining both area and personal samples, was 3.4 ppm compared with 0.28 ppm for acetoin determinations from the same air samples. Because there is little support for acetoin itself playing a major role other than as surrogate for diacetyl in pulmonary toxicity, and because acetoin was present at much lower concentrations, this result supports the validity of the diacetyl exposure assessment and subsequent findings, but also implies that the diacetyl effects are being underestimated as a result of misclassification, otherwise the diacetyl effects would produce a stronger model fit than acetoin. 5-7, 5-8); the effects remain statistically significant. Differences in the effects of employees' exposures accruing from their initial evaluation (their first survey) until the current survey, compared to all exposures prior to the current survey, using either the metric Cum(DA) or , were small and not statistically significant (P > 0.7) (Table 5 -11, models 3 and 4). This supports the conclusion that bias arising from cases preferentially leaving employment prior to the first survey is not different from that following the first survey when exposures were declining, suggesting that the bias in estimating the decline in ppFEV 1 is not large. # Incidence of Pulmonary Impairment at Company G # Evidence of Variable Susceptibility to Diacetyl Effects When the joint distribution of cases by exposure duration and cumulative exposure was examined (case definition 1; all jobs had exposures > 0.0), the pattern suggested the possible presence of a low-risk survivor population or variable susceptibility. For example, there were five cases in the cell with lowest duration and lowest exposure and another five cases in a different cell with comparable person-years of observation (89 years) in the highest exposure category and 2 to 4 years duration (Tables 5-16, 5-17). Thus similar rates were observed despite the greater than tenfold difference in cumulative exposure. Of the 36 cases, 22 occurred in the first 4 years of exposed employment, which encompassed about 80% of the study population. The rapid onset of this disease has been reported CDC 2007;Israel et al. 2009;NIOSH 2006NIOSH , 2008. Examination of onset graphically (data not shown) also suggested that many cases arose after relatively short employment duration. A similar pattern was exhibited in the 46 cases (defn 1) identified among former employees (no longer employed at the time of their first survey) (data not shown). The predicted baseline incidence (from the model with diacetyl exposure set = 0) in the same array ( with a term of the form [Avg(DA)] 2 ×exp(−0.69 × Duration), i.e., halflife of 1 year and squared average exposure, produced a significant fit (LRT=7.97, 2df, p=.0186; Table 5-24, model 3) with the two exposure terms being considerably stronger predictors than in models with either one alone (Table 5-24, models 1-3). Of the choices examined for parameters in the shortduration risk term, the best fit occurred with a halflife of 2.0 years and squared average exposure (LRT=9.52, 2df, p=.0086; Table 5-24, model 4; Table 5 -25). In this model, the estimated rate ratio for 1.0 pack-year of smoking (with no diacetyl exposure) relative to a very low baseline rate was 17.7 and, for 1.0 ppm-yr of diacetyl exposure in the "low-risk" group (with duration >4 years and no smoking), the rate ratio was 12.3; the initial high risk (at start of exposure, zero duration, and no smoking) rate ratio at 1 ppm diacetyl was 69.8. A similar result was obtained with case definitions 1 and 2 (data not shown) although, for case definition 1, the exposure parameter estimates were not statistically significant. The relative fit of various incidence-rate model specifications (case definition 3) indicates that, for a single metric, the average prior exposure metric fits best, but considerable improvement comes with an added duration term (Table 5-26, models 1-3 vs. [4][5][6]. The best fit was for (a) square root of cumulative exposure with duration term (loglinear relative rate model 5), and for (b) cumulative exposure and the term for a high-risk subpopulation (linear relative rate model 10). # Interpretation of Modeling Results Multiple linear regression models of continuous spirometry outcomes at Company G reveal that both cum(DA) and are the preferred predictors of FEV 1 decline based on model fit. Average exposure was the weakest predictor of ppFEV 1 . Subsidiary analyses indicate that (1) a dose-rate effect, if present, is small and negative (i.e., effects are not limited to high exposures); (2) bias arising from possible removal of earlier cases was probably small, and ( 3) the bias introduced by the correction procedure addressing degradation of diacetyl air samples is also small although possibly resulting in underestimation of the diacetyl effect. Evidence for non uniform susceptibility includes the somewhat superior prediction by compared to Cum(DA) which may be a reflection of a reduced response in the population at longer durations of exposure. In the modeling of incidence, fewer cases met the third case definition than the first or second (19 vs. 36, 27) due to the requirement that both ppFEV 1 and FEV 1 /FVC be less than their LLofN. This was consistent with some restriction as was observed in regression models of FVC (data not shown). Using the third case definition, the estimated baseline rate is very small (Table 5-24, models 3, 4); baseline annual rate = 0.007% per year (365.25× exp(−15.48)=0.00007), indicating that virtually all cases were attributable to either diacetyl exposure or smoking. The strong association with the term representing short duration of exposure supports the conjecture that the population with "normal" susceptibility was declining by about half with each 2 years of exposure duration. Although average diacetyl exposure by itself is a strong predictor of incidence, as with prediction of FEV 1 /FVC, this appears to be an artifact of changing population susceptibility and has little biological plausibility as a risk factor itself. The existence of a changing population composition with respect to susceptibility poses a challenge for predicting excess cases over a 45-year working lifetime because the composition of the population with respect to the factor(s) conveying risk is unknown and workforce turnover continually introduces a higher-risk segment into employment. (more typical employment durations and implying a larger workforce ever exposed). The nominal standard for acceptable risk used was one per thousand excess risk of impairment, a standard choice used in OSHA regulation for chronic diseases. # Benchmark Dose # Methods For continuously distributed respiratory endpoints such as FEV 1 , the benchmark dose approach permits estimation of excess prevalence of impairment as a function of prior exposure history [Bailer et al. 1997;Clewell et al. 2003;Crump 1995;Park et al. 2006]. On the basis of regression models and population data on the distribution of FEV 1 from NHANES III [CDC and NCHS 2011], the proportions of the workforce predicted to be impaired after working at specified exposure levels can be calculated. Unlike animal-based studies where exposures are in discrete levels, the analyses here utilized continuously distributed exposure metrics and a linear statistical model which made unnecessary the point-of-departure procedure commonly used in benchmark dose calculations. This method, however, does require specification of what degree of deficit constitutes impairment and the maximum increase in impairment prevalence that is considered acceptable, which are policy choices. The exposure resulting in a maximum allowable increase in impairment over some time period is called the benchmark dose (BMD). # Risk assessment with percent predicted FEV 1 and FEV 1 /FVC With the conventional benchmark dose procedure, the excess prevalence of an adverse condition is calculated using an exposureresponse relationship derived from modeling. With the linear regression result for percent predicted FEV 1 and Cum(DA) (coef.=−0.50, Table 5-6), the excess prevalence after 2.5, 10, or 45 years of exposure for falling below (1) 60% of predicted, or (2) the 5th percentile of normal, was calculated as a function of exposure level (Table 5 -27). Given these two pulmonary impairments, a 1/1000 excess prevalence after 45 years was found for diacetyl exposures (BMDs, central tendency estimates) of about 0.04, and 0.007 ppm diacetyl, respectively. Using the exposure metric, , which better predicts ppFEV 1 in the full population, substantially lower BMDs result (data not shown); 1/1000 excess risk for impairment at the 5th percentile after 45 years occurs with a diacetyl exposure concentration of less than 0.0001 ppm vs. 0.007 with the Cum(DA) metric (Table 5-27). These lower BMDs result from the increasing (negative) slope of the exposure response with diminishing exposure metric. Although better captures the risk of initially employed employees, extrapolation to decreasing durations with this nonlinear metric could introduce considerable error. For this reason NIOSH chose Cum(DA) over as the basis for risk assessment using the BMD procedure. In addition, to address the same issue for early exposures, the BMD was also calculated based on results from the < 4 yr population (Table 5-28) but also for a 45 yr. working lifetime. The resulting excess prevalence estimates were about double those based on the full population. For impairment defined in relation to LLofN as opposed to some fixed threshold such as the 5th percentile of ppFEV 1 , the BMD procedure is less direct because LLofN is specific to age, height, gender and race. The distribution of various functions of FEV 1 and LLofN, such as FEV 1 /LLofN or (FEV 1 -LLofN)/(ppFEV 1 -LLofN) are not readily specifiable. An alternate approach was taken: in the NHANES population [CDC and NCHS 2011], the cumulative exposure (Cum(DA)) that would reduce an individual's FEV 1 to their LLofN was calculated using the exposure-response estimates from the preferred regression models of ppFEV 1 (coef.=-0.50, -1.07 (< 4 yr); Table 5-6). The prevalence of individuals predicted to be below their LLofN was then calculated in the NHANES III population as a function of exposure over 2.5, 10 or 45 years. This "empirical" BMD procedure (using the empirical, nonparametric distribution of the NHANES population) yielded BMDs for both FEV 1 and FEV 1 /FVC for the full population and for < 4 yr (Table 5 -29). For FEV 1 below the LLofN (FEV 1 ) the BMD values were similar to those calculated the traditional way for ppFEV 1 in relation to impairment at the 5th percentile of normal; the excess prevalence after 45 years at 0.01 ppm diacetyl was 2.5/1000 and 1.5/1000, respectively (Tables 5-27, . BMDs for FEV 1 /FVC below the LLofN (FEV 1 / FVC) were comparable to those for FEV 1 (Table 5 -29). In the pooled Company K and Company L population, where reported exposures were lower than at Company G, the estimated 1/1000 BMDs for 45 yr were much lower: for FEV 1 , 0.0005 ppm and FEV 1 /FVC, 0.0004 ppm (Table 5 -30). Using the less satisfactory, average exposure, Avg(DA), as the predicting metric in the Company G population, the excess prevalence was estimated to be considerably lower (Table 5-31), and of course, did not depend on Baseline prevalence for < 60% of predicated = 0.0053, for <5th percentile = 0.0498 duration of work. The 1/1000 BMD for FEV 1 , was correspondingly higher: 0.05 ppm diacetyl. # Excess Lifetime Risk for Pulmonary Impairment # Methods Using the life-table approach as implemented in the Biological Effects of Ionizing Radiation IV report [Committee on the Biological Effects of Ionizing Radiation 1988] together with the observed exposure-response relationship from models of incidence rate, one can estimate the excess numbers of cases of diacetyl-associated impairment that would occur as a result of lifetime exposures at various concentrations. This method assumes irreversibility and removes incident cases from the population at risk with increasing age along with deaths arising from the usual causes in the general population. Although typical applications of the excess lifetime risk calculation are for deaths arising from chronic diseases, the method can be applied to incidence of an irreversible condition provided a baseline incidence rate for the condition is known and an estimate of the exposure-related incidence rate ratio is available. In this analysis, Poisson regression Rodriguez et al. 1994] and five others predicted mortality using current FEV 1 [Bang et al. 1993;Hole et al. 1996;Ryan et al. 1999;Sabia et al. 2010;Schunemann et al. 2000;Sin et al. 2005]. Three studies provide estimates of rate ratios (RRs) that can be applied to a life-table analysis of excess lifetime risk [Bang et al. 1993;Ryan et al. 1999;Schunemann et al. 2000]. The estimates range from 1.010 to 1.019 per percent decline in FEV 1 in men, and from 1.01 to 1.025 in women. Assuming a RR of 1.015 per percent decline in FEV 1 , and using the exposure response for FEV 1 from the full population and from the < 4 yr group, a life-table analysis produced estimates of excess lifetime risk (Table 5-33) that were comparable (fortuitously) to those based on the incidence of pulmonary impairment, e.g., FEV 1 falling below LLofN (Table 5-32). These estimates of excess mortality are the result of a generic effect of declining FEV 1 on mortality not specific to obliterative was protective). Alternate formulations such as for dose-rate, comparing exposure effects preand post-first survey, comparing prediction based on diacetyl vs. acetoin, a surrogate for diacetyl, all supported the final choices utilized in the risk assessment. On the question of exposure uncertainties prior to the NIOSH surveys, particularly the date when widespread diacetyl exposures commenced at Company G, analyses specifying different years for the start of exposures suggested that the optimum starting year was about 1994 instead of 1986, but this assumption had only a small impact on the estimated exposure response because most employees surveyed were hired after 1994. In constructing the exposure matrix for the plants studied, the decision was made not to apply the humidity correction for air samples below the LOD. To determine if this choice affected the analytical results, analyses were repeated having applied the correction to all air samples. The resulting difference in parameter estimate for the model of percent predicted FEV 1 with the cumulative exposure term was very small: −0.500 vs. −0.499. For the metric, square root of cumulative exposure, the parameter estimate is slightly larger when samples < LOD are corrected: −2.77 (uncorrected) vs. −2.82 (corrected). For the models of FEV 1 /FVC there was no change. Therefore there was no impact on risk estimates which were based on these parameter estimates. Several alternate explanations were considered for the apparent variability in susceptibility: (1) The proportion of Hispanic employees was higher among the short duration cases: Hispanics also comprised a higher proportion among recent hires and the cross-sectional surveys tended to reflect more recent employees due to high turnover. (2) Bias from candidate cases lacking styptom onset: using the date of their first qualifying spirometry would tend to increase rather than decrease the estimate of duration of exposure until onset and thus would not account for the short-duration cases. (3) Recall bias on symptom onset: employees with fast onset probably estimated symptom onset in relation to hire date, which is generally precisely known, not in relation to survey date. For example, an employee with 3 years employment probably would recall that symptoms began after about 6 months on the job, not 2.5 years ago. (4) Jobs with peak exposures would favor an early onset: this would happen only if the cumulative exposure metric was underestimating the relevant exposure. This could occur with a positive dose-rate effect, but what was observed was, if anything, a negative dose-rate effect (Table 5-5) where summing the square root of air concentrations over time was a much better predictor than summing the square of concentrations. Serious exposure misclassification could cause a pattern indistinguishable from variable susceptibility; employees whose exposures were substantially underestimated would appear to respond more strongly (faster) with adverse health effects and conversely for employees whose exposures are overestimated. However, the "high risk" cases were not largely associated with specific job groups such as mixers or quality control; many came from the general production line, and excluding mixers did not reduce affect estimates. Undoubtedly misclassification was present but a systematic discrepancy in risk by a factor of 10, as observed between the short and long duration groups and others arising from misclassification is implausible. In summary, these sensitivity analyses substantiated the parameters, variables, and assumptions used in the final risk assessment and provide confidence in the risk estimates. # Discussion The NIOSH HHE investigations in popcorn manufacturing were not specifically designed for quantitative risk assessment and have limitations in terms of unknown selection of study subjects and limited historical exposure information. Nonetheless, these observations of diacetyl-exposed employees have proved useful for risk assessment. The likelihood that the Company G population represents a survivor cohort together with the relatively high participation rate implies that underestimation of effects has probably resulted. Further underestimation has resulted from exclusion of asymptomatic cases in the analyses of incidence. Acting against bias from selection of a surviving population and missing cases is the possibility that participants may have included a more than representative proportion of cases. However, the high participation rate (~80%) limits this potential participation bias. The exposure metric, average exposure, which is simply the cumulative exposure divided by duration of exposure (employment duration since start of diacetyl use) was a strong predictor of pulmonary impairment in some analyses. It is implausible that average exposure, in a homogeneous population, would predict impairment without consideration of duration. Rather, a more credible explanation for the association of impairment with average exposure is the changing composition of the population over time since exposures began. The more responsive individuals leaving the population sooner than others would diminish the apparent importance of cumulative exposure. Thus average exposure might predict impairment, but it could be very population-specific depending on duration of observation and how the particular plant population changed over time, and would not be a generalizable exposure response. For this reason average exposure was not utilized in the risk assessment procedures. Appropriate in the risk assessment and development of the REL for diacetyl is consideration that the health effects should be viewed in the complementary contexts of an individual employee's risk of impairment which is the clinician's measure of impact, and the risk incurred by the population of employees with diacetyl exposure. The American Thoracic Society, in a statement on the effects of air pollution, concluded that shifts in the respiratory health of a population, resulting from some exposure, that diminish individual reserve function, are adverse "even in the absence of the immediate occurrence of frank illness" [ATS 2000]. In the clinical context, if an employee's FEV 1 /FVC is less than 0.7 (or FEV 1 less than or equal to 80%), that would be considered mild COPD [ GOLD 2011]. Similarly, if diacetyl exposure decreases the mean pulmonary function of the exposed population by some small increment, this too could be considered an adverse event [ATS 2000]. The health significance of small spirometry changes, such as a 1% decline in FEV 1 after 2 years of exposure at 1 ppm diacetyl, depends partly on whether such changes are early indications of lung pathology that eventually would manifest as obliterative bronchiolitis. In studies of obliterative bronchiolitis arising from lung transplantation, unrelenting irreversible FEV 1 decrements are observed that ultimately lead to the diagnosis of obliterative bronchiolitis and fatal disease [Heng et al. 1998]. However, incomplete knowledge concerning the natural history of obliterative bronchiolitis development with diacetyl exposure is a limitation in the present risk assessment. Not only is risk for mortality increased, as estimated in this risk assessment, quality of life is degraded [Ferrer et al. 2002] and risk is increased for cardiovascular disease and progressive respiratory disease [Cullen et al. 1983;Ebi-Kryston et al. 1989;Knuiman et al. 1999;Kuller et al. 1989;Schroeder et al. 2003;Wise 2006]. The decrease in FEV 1 predicted after working for 10 years in diacetyl exposures of 0.2 ppm (about 1% loss) is comparable to changes observed in children, a more vulnerable population, exposed to levels of air pollution that lead to clinical impairment in later life [Gauderman et al. 2004]. Variation in susceptibility poses issues for risk assessment. If less-susceptible individuals are remaining in employment longer, the estimated exposure response for long durations when applied to a hypothetical population of 1,000 employees employed 45 years, will generate excess risk values that understate the true risk of a workforce that turns over more often. All of the risk assessment procedures used here assume some degree of low-dose linearity, with effects diminishing proportionally with decreasing exposure levels that are held constant over 10 or 45 years. Model linearity was observed particularly after limiting the population to < 4 yr duration. Moreover a significant fraction of career-average exposures fell below 0.01 ppm (17% of employees) a factor of only 2.0 higher than the proposed REL. Thus low-dose extrapolation was limited. Below 0.01 ppm, there can be some significant departure from linearity although diversity in response would tend to favor linearity to lower levels [Clewell and Crump 2005;National Research Council 2009]. # Conclusion Excess prevalence (BMD) and lifetime risk estimates variously derived for 45 years of diacetyl exposure were similar, based on Company G analyses (Table 5-34). Impairment has been defined here as pulmonary function falling below the lower limit of normal. The BMD estimates for excess prevalence of FEV 1 impairment are within a factor of 2.0 of the life- Dose-response data for diacetyl toxicity in laboratory animals are available, and there are limited but useful animal data on the toxicity of 2,3-pentanedione. Although the NIOSH REL for diacetyl is based on the analysis of human data described in Chapter 5, NIOSH has assessed the animal data for diacetyl to determine whether they are consistent with the human data. For 2,3-pentanedione, NIOSH has conducted a comparative potency analysis, comparing the toxicity of inhaled 2,3-pentanedione to that of diacetyl. These quantitative risk assessments are described below. NIOSH interpretation of the findings and implications for occupational exposure recommendations for diacetyl are described below and in Chapter 7. Laboratory animal studies designed to evaluate the effects of exposure to butter flavoring vapor or of diacetyl alone have demonstrated a relationship between exposure and respiratory effects. In rats exposed by inhalation to butter flavoring vapor for 6 hours (diacetyl concentrations ranged from 203 to 352 ppm), rhinitis (at the lowest exposure concentration) and bronchitis (at the higher two exposure concentrations) were observed one day after exposure [Hubbs et al. 2002]. In a follow-up study rats were exposed by inhalation to diacetyl (intermittently or continuously for up to 6 hours), which resulted in various adverse respiratory effects including epithelial necrosis and inflammation in the nose, larynx, trachea, and bronchi ]. The nasal region was observed to be the most sensitive. reported similar adverse respiratory effects in mice exposed by inhalation to diacetyl for up to 12 weeks. Adverse nasal and lung effects were observed with the latter found in the bronchial, peribronchial, and peribronchiolar regions. The NTP has issued findings from a 90-day inhalation study of diacetyl in both mice and rats [National Toxicology Program 2011]. Adverse effects were observed in the nose, larynx, trachea, and bronchi in mice and rats. Because the 2011 NTP study had the longest exposure durations among all experimental animal studies, included two species, and used more animals per dose group than the study, it was used in the doseresponse analysis to BMDs, the lower bound on the BMDs (BMDLs), and corresponding human equivalent concentrations (HECs), as discussed below. # 2,3-Pentanedione Histopathological data from repeatedexposure inhalation toxicology studies with 2,3-pentanedione were first published in 2012, but are limited to 2-week exposures using small numbers of animals . Although these data are limited, it is possible to compare the toxicity produced by 2,3-pentanedione to that produced by diacetyl under similar conditions, and thus estimate the potency of 2,3-pentanedione relative to diacetyl. Therefore, the limited toxicological data for 2,3-pentanedione are not used directly to establish a REL for 2,3-pentanedione, but only to develop an estimate of the toxic potency of 2,3-pentanedione relative to that of diacetyl. Like diacetyl, 2,3-pentanedione is a reactive alpha-dicarbonyl compound that can damage protein [Epperly and Dekker 1989;. In acute inhalation studies, 2,3-pentanedione has respiratory epithelial toxicity comparable to diacetyl [Hubbs et al. 2012]. Recently, bronchial fibrosis has been documented in rats inhaling either 2,3-pentanedione or diacetyl for 2 weeks ]. # Methods # Data # Diacetyl The response data that were analyzed were obtained from the experimental study reported by the NTP [2011]. Male and female Wistar-Han rats and male and female B6C3F 1 hybrid mice were exposed to diacetyl vapors at concentrations of 6.25, 12.5, 25, 60, and 100 ppm, 6 hours per day, 5 days per week, for 13 weeks. The microscopic evaluations of tissues from the larynx, lung, nose, and trachea described whether or not one or more lesions were detected, the types of lesions that were detected, and the assignment of a numeric score describing the lesion's severity on an ordinal scale (1-minimal, 2-mild, 3-moderate, 4-marked) for each type that was detected. Descriptions of the types of lesions observed among rats and mice that were considered for this analysis are given in Tables 6-1 and 6-2, respectively. # 2,3-Pentanedione The results of a 2-week inhalation study of 2,3-pentanedione toxicity were reported by Morgan et al. [2012]. Individual animal data 2010). These data describe the pathological responses of male and female Wistar-Han rats and B6C3F1 mice exposed to 2,3-pentanedione by inhalation for 6 hours per day, 5 days per week, for 2 weeks plus 2 days. The exposure concentrations were 0 ppm, 50 ppm, 100 ppm, and 200 ppm, with six animals per dose group; nasal, tracheal, and pulmonary endpoints were assessed. The tissue and pathological endpoints that could be modeled successfully for both 2,3-pentanedione and diacetyl (for comparative purposes) are listed in Table 6-3. In addition to the 13-week NTP bioassay data described above for diacetyl, the 2,3-pentanedione data were also compared to data for diacetyl from . These data describe the pathological responses of male C57Bl/6 mice exposed to diacetyl by inhalation for 6 hours per day, 5 days per week, for either 6 or 12 weeks. The exposure concentrations were 0 ppm, 25 ppm, 50 ppm, and 100 ppm, with five animals per dose group. Nasal, tracheal, and pulmonary endpoints similar to those examined in the 2,3-pentanedione study were assessed. In addition to the data in the publication, tables of individual Includes lesions classified as "Squamous Epithelium, Hyperplasia, Atypical" ‡ Includes lesions classified as "Bronchus, Epithelium, Hyperplasia, Atypical" § One male classified as having a minimal "Bronchus, Epithelium, Degeneration" lesion was pooled with 10 other males having a regenerative response. ¶ One male and two females classified as having a "Respiratory Epithelium, Degeneration" lesion were pooled with 20 other males, and 20 other females having the regenerative response. # Analytical approach An empirical approach based on parametric regression modeling of the ordinal response data was adopted to maximize the information available for analysis from the limited numbers of rodents * in order to assess the potency of diacetyl to increase risk and to assess the relative potency of the two chemicals. # Benchmark concentration analysis for rats exposed to diacetyl The assessment of the potency of diacetyl to increase risk employed the benchmark dose approach that was originally proposed for risk assessment of non-cancer responses by Crump [1984]. development over the past three decades, and it has become an accepted approach for risk assessment [ EPA 2012]. Benchmark concentration (BMC) estimates for the pathological endpoints listed in Table 6-1 (for rats) were based on modeling of the exposure concentrations and the associated pathology. In order to avoid the loss of information inherent in dichotomizing ordinal response data, a categorical regression procedure for ordinal data was used to estimate benchmark concentrations. Categorical regression has been previously used in the analysis of toxicological data with multiple levels of severity [Guth et al. 1997;Haber et al. 2001]. The severity scores ‡ for each tissue and type of lesion were assumed to be samples from a multinomial distribution following a complementary § cumulative logistic model fitted separately for each species and sex as follows: where Y ci denotes the corresponding severity score of the i th rodent exposed to concentration, conc c , j Є element of {observed severity scores excluding zero} for the corresponding tissue and type of lesion, Pr( Y ci ≥j)denotes the expected proportion of response score Y ci greater than or equal to j , each α j is an unknown real-valued parameter with α j' < α j for j'> j, and β is an unknown real-valued parameter describing the slope of the effect of concentration on the logit scale. ‡ When no evidence of the lesion being modeled was detected a severity score of zero (0) was assigned. § The term complementary discerns this model from an equivalent cumulative logistic model of Pr(Y ci ≥j) . lower one-sided 95% confidence limit (BMCL) were estimated. # Benchmark concentration analysis for mice exposed to diacetyl Benchmark concentration estimates for the pathological endpoints listed in Table 6-2 (for mice) were developed as described above for the rat data; however, an analysis of the residual errors of the fitted models provided substantial evidence against the model for the data on mice (Figure 6-1). These residuals have mean equal to zero asymptotically if the linear-in-concentration model is correct. However, the distribution of the residuals of Figure 6-1 is shifted above zero at 50 ppm corresponding to underprediction and the distribution is shifted below zero corresponding to overprediction at 100 ppm. Figure 6-1 provides support for making a modification of the dose-response model in a manner that allows for a reduction of the rate of increase of the response at high doses. Because mice are able to substantially alter their breathing rates in a dose-dependent manner when exposed [Larsen et al. 2009;] the model of the data for mice was modified to include a quadratic dose term to allow it to more closely fit the data in the high-dose region of the dose-response relationship; this term was parameterized to represent a directly proportional relationship of the change in breathing rate with concentration relative to the breathing rate of the controls. The resulting estimate for male mice exposed to diacetyl was compared with corresponding ventilation measurements provided by Dr. Daniel Morgan, NIEHS (personal communication to Randall Smith, NIOSH, June 5, 2014). In addition, two parameters allowing for adjustment of the intercepts of each sex and a third parameter allowing for adjustment of the effect of exposure were added to the model to account for the varying durations of these studies. This model was further extended to incorporate the comparative potency analysis of 2,3-pentanedione relative to diacetyl and incorporated an allowance for the responses of each mouse to be correlated by including random effects. It is described below in section 6.2.2.7. # Extrapolation of rodent benchmark concentrations to humans Extrapolation of rodent BMCs to humans was based on a PBPK/CFD model for diacetyl Morris and Hubbs 2009]. The Gloede et al. [2011] extension of the Morris and Hubbs [2009] model predicts tissue concentrations of diacetyl for mucosal surfaces in the nose, trachea, bronchi, and bronchioles of rats and humans exposed to 1 ppm diacetyl. Nose-breathing and mouth-breathing humans are considered, as well as the effects of light exercise as might be expected to occur in the workplace. The Gloede et al. [2011] model assumes mouth breathing during light exercise conditions. For extrapolation purposes, an 8-hour work day was considered to consist of 2.5 hours of sedentary exposure and 5.5 hours of light exercise, as described by the International Commission on Radiological Protection (ICRP) human respiratory tract model [ ICRP 1994]. The ICRP model assumes 20 breaths per minute and a tidal volume of 1,250 mL for light exercise and 12 breaths per minute and a tidal volume of 625 mL for sedentary sitting, for a total inhalation volume of 9.6 m 3 in an 8-hour work day. Therefore, to extrapolate from rodents to humans, the BMC estimates described above were adjusted by a weighted average of the rat:human ratios of the predicted tissue concentrations for a particular anatomical region, under sedentary and light exercise conditions. The Gloede et al. [2011] estimates incorporating tissue metabolism (V max for the rat, and K cat for humans) were used, because local metabolism is predicted to impact significantly on the local tissue concentration (Table 3). For example, the predicted tissue diacetyl concentration for the proximal tracheal mucosa of a rat exposed to 1 ppm diacetyl is 0.33 µM, while the predicted tissue concentration for the same anatomical region is 1.4 µM in a sedentary nose-breathing human and 2.5 µM in a mouth-breathing exercising human. The rat BMCs based on pathological changes to this anatomical region were divided by a factor of (1.4 µM * 2.5 hours + 2.5 µM * 5.5 hours)/(0.33 µM * 6 hours), or 8.71. The factor of 6 hours in the denominator adjusts for the 6-hour/day duration of the experimental exposures, as compared to the 8-hour workday assumed for occupational exposures. Gloede et al. [2011] did not report tissue concentration estimates for the larynx; BMC extrapolation for this region was based on the tissue concentrations estimated for the proximal trachea. Gloede et al. [2011] reported tissue concentrations for both mainstem and small bronchi, and BMC extrapolation for bronchial endpoints were based on the mean of the rat:human ratios of tissue concentrations for mainstem bronchi and small bronchi. Rat to human scaling for the alveoli was based on the estimated fractional penetration of diacetyl through the bronchioles in the Gloede et al. PBPK model, provided by Dr. John Morris, University of Connecticut (personal communication to Dr. David A. Dankovic, NIOSH, November 8, 2012). The rat:human extrapolation factors used are shown in Table 6-4. # Extrapolation of BMCs and BMCLs from the mouse to the rat Because no PBPK model for diacetyl exposures in the mouse is currently available, the rat PBPK model was extended to the mouse using the EPA reference concentration (RfC) methodology [ EPA 1994]. In the RfC methodology, the deposition and uptake of volatile chemicals are estimated from a combination of chemical characteristics (i.e., reactivity and solubility) and the physiological characteristics of the relevant species (i.e., minute ventilation and the surface area of the relevant portion of the respiratory tract). Diacetyl is classified as a "category 1" gas in the RfC methodology because of its high water solubility. Category 1 gases are not expected to reach the pulmonary region in high concentration, but rather to be deposited primarily in the upper respiratory tract and the tracheobronchial region. This is consistent with the behavior of diacetyl in the Gloede et al. PBPK model, so that the classification of diacetyl as a category 1 gas appears to be appropriate. Interspecies dosimetric adjustments via the RfC methodology are based on an estimate of the regional gas dose ratio (RGDR). The RGDR estimates the ratio of gas deposition with a given respiratory tract region in the two species being compared. For the ET region, the RGDR is calculated [EPA 1994], eqn. 4-18, as: where: V E = minute volume (mL/min = cm 3 /min) SA = surface area (cm 2 ) ET = a subscript denoting the extrathoracic region A, B = subscripts denoting experimental animal and target species, respectively For the TB region, the RGDR is calculated [ EPA 1994], eqn. 4-22, as: where: V E = minute volume (mL/min = cm 3 /min) SA = surface area (cm 2 ) TB = a subscript denoting the tracheobronchial region ET = a subscript denoting the extrathoracic region A, B = subscripts denoting experimental animal and target species, respectively Table 3, except as noted below for alveoli. ‡ Mouse-to-human scaling assuming mouse is 2.4 times as sensitive as the rat for nasal effects and 3.2 times as sensitive for tracheobronchial effects, based on the regional gas dose ratio (see section 6.2.2.4) § "Average bronchi" = arithmetic mean of values for mainstem and small bronchi ¶ Rat to human scaling for the alveoli was based on the estimated fractional penetration of diacetyl through the bronchioles in the Gloede et al. PBPK model. The values assumed for V E and SA, and the resulting RGDR values for mouse-to-rat extrapolation, are shown in Table 6-5. The rat V E value is based on data from Gloede et al. [2011], and the mouse V E was taken from . The SA values are from EPA [1994]. The RGDR is used to adjust a point of departure (POD), i.e., a BMC or BMCL in the laboratory species to an equivalent concentration in the target species as follows: POD BEC = POD A * RGDR where: POD BEC = POD equivalent concentration in the target species; POD A = POD in the experimental species; and RGDR = Species A-to-species B regional gas dose ratio for the appropriate region of the respiratory tract. Although the RGDR is typically used to develop human equivalent concentrations from experimental animal data, in this case it is used to develop a rat equivalent concentration for a point of departure estimated from experimental data in the mouse. The Gloede et al. [2011] PBPK model is then used to extrapolate from the rat equivalent concentration to a human equivalent concentration. Mouse-to-rat regional gas dose ratio for the upper respiratory tract ¶ Mouse-to-rat regional gas dose ratio for the tracheobronchial region This conclusion is based on the analysis of Allen [2009a], who concluded that the 6-and 12-week mouse experiments had response rates that could be modeled together (i.e., the duration of the experiment could be ignored) for all the lesions analyzed; there did not appear to be a progression toward higher rates of response or more severe responses when the exposure level remained the same but the duration of exposure was increased from 6 to 12 weeks. However, because of the small number of animals used in this study, the power to detect differences between the 6-week and 12-week experiments is limited. As a consequence of the limited duration of the experimental studies and the limited ability to detect differences between the responses at 6 and 12 weeks, the possibility of increased toxicity with lifetime exposure cannot be entirely ruled out. This possibility was addressed through the application of an uncertainty factor (UF) -discussed below -rather than a dosimetric adjustment. # Application of uncertainty factors The HECs are estimates of frankly toxic exposure levels, and must be adjusted by the application of UFs to allow for uncertainty in animal-to-human extrapolation, interindividual variability, and less than lifetime exposure. In general, these UFs are assumed to be 10-fold for animal-to-human extrapolation and another 10-fold for interindividual variability. The animal-to-human extrapolation can be subdivided into a factor of 4 for pharmacokinetics and a factor of 2.5 for interspecies variability in susceptibility [ WHO 1994]. In this case, the interspecies pharmacokinetic factor is replaced by the use of the Gloede et al. [2011] pharmacokinetic model, leaving an interspecies UF of 2.5. The UF for interindividual variability can be subdivided into two factors of √10, or 3.2, one for interindividual variability in pharmacokinetics and the other for interindividual variability in susceptibility [ WHO 1994]. Because the toxicity of diacetyl occurs at the point of contact with respiratory tract mucosa there is relatively little opportunity for interindividual variability in pharmacokinetics, and so the first subfactor is not applied. However, interindividual variability in susceptibility to toxicity cannot be ruled out; therefore, a factor of 3.2 is applied. In addition, a factor of 3 is applied for conversion from subchronic to chronic exposure. When the three factors (3.2fold for interindividual variability, 2.5-fold for interspecies variability, and 3-fold for subchronic to chronic) are multiplied, the resulting total UF is 24. # Joint analysis of the data on mice from the diacetyl and 2,3-pentanedione bioassays To avoid the loss of information inherent in dichotomizing ordinal data the severity scores of each type of lesion observed among nasal and lung tissues were modeled as having been sampled from conditional multinomial distributions given the unobserved random effects associated with each mouse described by the following family of complementary cumulative logistic models: = α sjr(t) + u bskci + ω s •τ bskci +f bskcti β sjr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ skt , γ s )} • conc bskci , where α sjr(t) + u skci + ω s •τ bskci describes effects in the absence of exposure, f bskcti β sjr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ skt , γ s )} • conc bskci describes effects of exposure and b indexes the bioassay study s indexes sex, k = 0 ←→ 2,3-pentanedione exposure and k = 1 ←→ diacetyl exposure, bkc identifies the exposure group and conc bkc is the corresponding exposure concentration, i = 1, ..., n bskc indicates each of the mice within the exposure group identified by bskc and conc bskci denotes the corresponding exposure concentration, r(t) identifies the response lesion, r nested within tissue, t, (lung or nasal), Y bskcr(t)i is the response variable that is integer-valued based on the assigned severity score and it ranges over {0,1,2,3} for all response lesions ‡ ‡ except necrosis of the respiratory epithelium of the nose where the range was {0,1,2}, Pr(Y bskcir(t) ≥ j) represents the expected proportion having response severity score greater than or equal to j for j Є {1, ..., max (Y bskcr(t)i )}, α sjt(r) denotes the intercept parameters for lesion r(t) which are subject to constraints α s2t(r) −α s1t(r) =∆α s2 <0 and α s3t(r) −α s2t(r) =∆α s3 <0 thus ensuring § § α s3t(r) <α s2t(r) <α s1t(r) , u bskci ~N(0, σ 2 su ) is a normally distributed random effect associated with the i th mouse of bskc; likelihood ratio tests of null values of the variance ‡ ‡ When no evidence of the lesion being modeled was detected a severity score of zero (0) was assigned. § § Hence, the requirement that r(Y kcit(r) ≥ 3) < Pr(Y kcit(r) ≥ 2) < Pr(Y kcit(r) ≥ 1) is satisfied for the controls. at low doses for {r(t)}; the hypothesis, 0 sr(t) = 0 s , was tested and subject to being incorporated into the model, and φ skt allows for an adjustment for a quadratic effect of concentration that may be attributed to directly proportional changes in respiratory ventilation with concentration where φ skt is the constant of proportionality in units of controls' ventilation; thus φ skt describes the change relative to controls. The hypothesis, φ sk,lung = φ sk,nose = φ sk , was tested and subject to being incorporated into the model. f bskcti is one of a pair of lognormally distributed random effects (one effect per tissue indicated by t) of the i th mouse of exposure group bskc acting multiplicatively on the effect of dose. Thus, an allowance for multiplicative variations from mouse to mouse by tissuespecific positive factors acting on the magnitudes of the slope parameters was incorporated. Each f bskcti was modeled as having unit expectation and variance (e σ 2 st −1); thus, the variance of log (f bskcti ) = σ 2 st , t = 1, 2 for the lung and nose, respectively, together with an associated covariance parameter σ s12 . The hypothesis that lognormal random effects are independent was examined by testing σ s12 = 0 and was subject to being incorporated. Furthermore, the hypothesis that only one lognormal random effect for each mouse was necessary, i.e., f bskc1i = f bskc2i was tested and subject to being incorporated. Model development proceeded by sequentially fitting a series of nested models of increasing complexity with all random effects omitted. This was advantageous for obtaining initial estimates of the fixed effects parameters for fitting a corresponding model that included random effects. Models were fitted by the method of maximum likelihood; the likelihoods of models containing unobserved random effects were obtained by integrating out these effects using adaptive Gaussian quadrature as described by Pinheiro and Bates [1995]. Likelihood ratio tests were performed to test hypotheses about model parameters and associated P values were based on the chi-square approximation to −2log (LR). Evidence against incorporating the previously described restrictions on model parameters was deemed significant if the P value of the corresponding test was less than 0.05 for selecting the model on which to base the estimation of relative potency parameters and benchmark concentrations. The model selected for estimation of relative potencies and BMCs contained three lognormal random effects parameters and 53 fixed-effects parameters; it had the following form: st ) = 0 for lognormal random effects of nasal responses of female mice was replaced by nullifying this parameter, The adequacy of a single lognormal random effect was rejected, Independence of the lognormal random effects for lung and nasal tissues of male mice [implied by acceptance of σ s12 = 0 ] was assumed. = α sjr(t) +ω s •τ bskci +f bskcti β sr(t) {m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ sk , γ)}•conc bskci where m(s, k, conc bskci , t, τ bskci ; θ sr(t) , φ sk , γ) =[1+γ•τ skci ] [1+I(k=1)•(θ sr(t) −1) +φ sk • conc kci ] i.e., The model was coded and fitted using the NLMixed procedure of SAS TM 9.3. At least two lines of evidence provided support that the algorithm for fitting the model converged to a solution for the parameters that was a unique optimum as follows: (1) The Hessian matrix of the fit was positive definite † † † and (2) exploration of the likelihood surface in a neighborhood of the solution via examination of likelihood profiles supported its optimality in all cases that were examined. Hence, this evidence supports the identifiability of the parameters of the model with these data suggesting that the model is not overparameterized. The fit of the model was assessed by calculating grouped ‡ ‡ ‡ Pearson residuals conditional on the † † † NLMixed minimizes -log(L) and it provides a warning if its criteria for a positive definite Hessian is not satisfied; no such warning was given. ‡ ‡ ‡ The term "grouped" is to clarify that they are based on summing the observed and fitted expectations and variances over the mice within each treatment group defined by each unique combination of b x k x s x c. empirical Bayes estimates of the random effects for each tissue-response as follows: where the fitted expectations and variances of each mouse were based on the associated binomial distribution of a factoring of the conditional multinomial likelihood into its conditionally independent binomial components corresponding to the "outcomes" (Y≥1 \| f ) , (Y≥2\|Y≥1,f ), and (Y≥3\|Y≥2,f ). Furthermore, a saturated fixed-effects model with random effects omitted was compared to the selected model by examination of twice the difference of log(Likelihood) values relative to the difference in the number of parameters. Finally, an ad hoc procedure was applied wherein binomial deviance residuals corresponding to factoring the multinomial likelihood of the corresponding 53 parameter model (with random effects omitted) into a product of conditional binomial terms were used to estimate a factor for adjusting the width of the confidence intervals analogous to an adjustment for overdispersion because the model-based confidence intervals may be too narrow if the model is incorrect. Twosided 95% confidence limits with and without adjustment were calculated from application of a normal approximation to the natural logarithms of the relative potencies and the BMCs associated with a 10% benchmark response for additional risk. § § § § § § i.e., Pr(Y skcr(t) ≥ j \| conc=BMC jskr(t) , f skcti = 1)−Pr(Y skcr(t) ≥ j \| conc = 0, f skcti = 1) = 0.10. # Benchmark concentration analysis using quantal models To explore the impact of the categorical regression procedure described above on the BMC estimates for diacetyl, the data for the pathological endpoints listed in Table 6-1 (for rats) and Table 6-2 (for mice) were also dichotomized, and alternative benchmark concentration estimates were developed using quantal modeling and model averaging. Any response of minimal or greater severity was treated as a positive response, and the model averaging procedure was based on fitting the multistage, Weibull, and log-probit models, as described by Wheeler and Bailer [2007]. Only datasets with two or more partial response groups were modeled. The benchmark response rate was set at 10%, and the resulting BMC and BMCL estimates are shown in Table 6-9. Only models with an average-model P value of 0.05 or greater were considered to fit the data adequately. # Results # Diacetyl BMC and BMCL estimates based on diacetyl toxicity in rats and mice were developed as described in sections 6.2.2.1 and 6.2.2.7, respectively. Not all of the pathological endpoints listed in Tables 6-1 and 6 Although evidence of systematic departures of the residuals was not apparent, 13 of the residuals indicated deviations from the fit of the joint model of diacetyl and 2,3-pentanedione by more than three standard errors (not shown). Although less than one such residual deviation would be expected for normally distributed residuals the observation of 13 such deviations seems suggestive that extraneous variations may be present and motivated our having increased the widths of model-based confidence limits by the application of an overdispersion factor of 1.61 for adjusting the model-based standard errors. Overall, the BMCs range from 16.8-68 ppm diacetyl, and the BMCLs range from 10-49.9 ppm diacetyl. After interspecies pharmacokinetic adjustments based on the Gloede et al. [2011] model, the human-equivalent BMCL values (BMCL_HECs) range from 1.4-95.8 ppm diacetyl, and the BMCL candidate REL values (after the application of uncertainty factors) range from 0.06-4.0 ppm diacetyl. # Sensitivity analysis As a sensitivity analysis, alternative BMC and BMCL values were also derived for the NTP [2011] diacetyl study by dichotomizing the data, fitting quantal models, and model averaging, as described in section 6. Another assumption made in this risk assessment is that toxicity observed in mice can be scaled to rats using the EPA [1994] RfC methodology to estimate a mouse-to-rate respiratory dose ratio, or RGDR. It was assumed that this extrapolation is best performed on the basis of measured values of respiratory ventilation, as opposed to estimating respiratory ventilation on the basis of body weight. As detailed above in section 6.2.2.4, use of the measured respiratory ventilation rates leads to RGDRs of 2.4 for upper-respiratory toxicity and 3.2 for lower respiratory toxicity. The impact of the decision to use measured respiratory rates in the RGDR calculation was evaluated by a comparison to the RGDRs which would be obtained using the default RfC methodology, based on body weights, and described in EPA [1994]. Using the EPA [1994] default methodology, in which the respiratory ventilation rate is estimated from the animal biody weight, results in RGDRs of 1.15 for upper respiratory tract effects and 1.5 for lower respiratory tract effects. Therefore the mouse-to-rat scaling factor would be approximately halved, and as shown in Table 6-9 the lowest candidate REL value would be reduced to 0.03 ppm, based on chronic bronchial inflammation in the female mouse lung. A key assumption made in this risk assessment is that the Gloede et al. [2011] PBPK model is the most appropriate method for extrapolating from rats to humans. A possible alternative would be to use the EPA [1994] RfC methodology to estimate animal-to-human scaling factors, based on the RGDR. Measured respiratory ventilation values are available for mice and rats, as used in section 6.2.2.4, and the human occupational respiration rate can be assumed to be 20 L/min. Using these values and the EPA [1994] procedures for category 1 gases, the estimated RGDRs for rat-to-human extrapolation are 0.18, 1.9, and 2.1 for the upper respiratory tract, the tracheobronchial region, and the pulmonary tract, respectively. Corresponding values for mouse-to-human extrapolation are 0.43, 5.9, and 6.9 for the upper respiratory tract, the tracheobronchial region, and the pulmonary tract, respectively. These RGDRs would replace the Gloede et al. PBPK model for extrapolating from rats to humans, and would result in candidate RELs ranging from 0.15-16.1 ppm for BMCs, and from 0.10-14.3 ppm for BMCLs. The lowest candidate REL derived using the RGDR method would be 0.10 ppm, as opposed to 0.06 ppm using the Gloede et al. [2011] model. The endpoints yielding the lowest alternative candidate REL values from the sensitivity analysis are shown in Table 6-9, along with the lowest of the candidate RELs from the main analysis, for comparison. Alternative analysis using respiratory ventilation rates based on body weight, rather than measured values. ¶ Alternative analysis using EPA [1994] RfC methodology rather than the Gloede et al. [2011] PBPK model. # The animal-to-human PK factor shown here is the RGDR for the rat nose, which in EPA methodology is applied to the BMC/BMCL as a multiplicative factor. This is unlike the PBPK-derived PK factors above, which are applied as divisors for the BMC/BMCL values. # 2,3-Pentanedione The ventilation coefficient of 2,3-pentanedione among male mice was −0.312 ± 0.0139 and among females it was −0.182 ± 0.0530. The relative potency estimates (diacetyl/2,3-pentanedione) are shown in Table 6-10, below, and range from 0.81-7.3, depending on sex and the specific endpoint evaluated. A relative potency of 1.00 indicates that the two compounds have equal toxic potency for the endpoints examined; a relative potency less than 1.00 indicates that 2,3-pentanedione is more toxic than diacetyl, while a relative potency greater than 1.00 indicates that 2,3-pentanedione is less toxic than diacetyl. Model-based 95% confidence limits range from 0.55-14, and the overdispersionadjusted confidence limits range from 0.44-21. These estimates suggest that the potency of diacetyl was significantly greater than that of 2,3-pentanedione among female mice for these responses. However, one source of contribution to these estimates among females is that their fitted ventilation coefficient of diacetyl exposure was 2.9-fold of the coefficient fitted for 2,3-pentanedione exposure; thus, the observed responses were associated with substantially less diacetyl having been inhaled thereby increasing its fitted potency relative to 2,3-pentanedione. In contrast the corresponding value among males was 1.2. Furthermore, all seven estimates among females depended on the modeling assumption that the exposure duration parameter was identical to that of males and results of profiling the likelihood (not shown) illustrated that this dependence was unidimensional, i.e., the seven relative potency estimates for the females varied in unison with the duration parameter, whereas this was not the case for the seven parameter estimates of the males. Hence, the interpretation of the relative potency estimates among females warrants a substantially larger degree ** Estimate of φ s,PD ± Model-based standard error per 100 ppm of caution. Although the majority of the relative potency estimates among male mice are greater than 1.0, suggesting that 2,3-pentanedione may be somewhat less toxic than diacetyl, two of the seven relative potency estimates (for olfactory epithelial atrophy and respiratory epithelial degeneration in the nasal tissues of male mice) are less than 1.0. In addition to these endpoints, the overdispersion-adjusted lower confidence limit estimates of relative potency for necrosis of the nasal respiratory epithelium, chronic bronchial inflammation and bronchial epithelial regeneration are also less than 1.0. Hence, these results suggest that equal or greater toxic potency for 2,3-pentanedione relative to diacetyl cannot be ruled out on the basis of currently available data. 6.4 Discussion 6.4.1 Diacetyl # Modeling issues in BMC estimation for diacetyl Categorical regression modeling for diacetyl BMC estimation was initially conducted as described in section 6.2.2.1 for rat and mouse data. However, it was noted that the mouse models showed systematic overprediction of the observed response at the highest exposure concentrations. Mice are well known to exhibit reduced respiration when exposed to respiratory irritants [Alarie and Stokinger 1973], including diacetyl [Larsen et al. 2009]. Reduced respiratory rate and reduced minute volume have been observed in male mice exposed to diacetyl ]. Speculatively, reduced respiration at high exposure concentrations may contribute to the attenuation of response noted in the high exposure groups, relative to a model where the effects of exposure are proportional to concentration. A strategy was therefore employed of modifying the model structure by including a quadratic dose term parameterized to represent directly proportional changes of ventilation with concentration in modeling the mouse data, which allowed sufficient model flexibility to accommodate the attenuation of response seen in the high-dose mouse data. The resulting coefficients of ventilation for nasal and lung tissues within each sex and exposure chemical were homogeneous and subsequently pooled. Furthermore, the coefficients of male mice for each chemical were similar and the diacetyl coefficient was consistent with the observations of minute volume by . However, the coefficients of the two chemicals for the females were substantially dissimilar. The seven tissue responses of each mouse were jointly analyzed because they were governed by the same ventilation coefficient. To account for correlations among the responses, random effects were included in the model thereby utilizing all of the data for the estimation of parameters common to all responses. However, the increased complexity of the model in combination with the small sample sizes and discrete responses presented challenges for assessing its fit. Residuals were calculated conditional on estimates of the random effects but interpretations of these residuals based on their having an approximately normal distribution appeared to be problematic because a systematic relationship between their skewness and concentration was apparent. However, our interpretation of these residuals as providing evidence of deviations exceeding modelbased predictions is prudent and motivated the increase of the widths of the confidence intervals. However, these modifications were not necessary in modeling the rat data, and were not included in the models developed for BMC estimation with the rat data. In the current analysis, BMC estimates for diacetyl, based on categorical regression modeling, range from 16.8-68 ppm diacetyl, and the BMCL estimates range from 10-49.9 ppm diacetyl (Tables 6-6, 6-7, and 6-8). For comparison, alternative BMC estimates based on a quantal modeling range from 14.6-78 ppm, and quantal model BMCL estimates range from 2.4-57.9 ppm. Although the central BMC estimates were similar for the quantal and categorical modeling approaches, some of the quantal model BMCL estimates are several-fold lower than any obtained using categorical modeling. It is possible that this result may be due to the inclusion of additional information -response severity, as well as incidence -in the categorical regression modeling approach, leading to narrower confidence limits in comparison to the quantal modeling results. Additional sensitivity analyses explored the sensitivity of the toxicologically-based risk assessment for diacetyl to basing the mouse-to-rat extrapolation on allometrically-scaled respiration rates rather than measured values, and to basing the animal-to-human extrapolation on RfC methodology [EPA 1994] rather than the Gloede et al. [2011] PBPK model. As described in section 6.3.1.1, varying these assumptions would have relatively modest effects on the toxicologicallybased REL estimate for diacetyl. As shown in Table 6-9, the lowest candidate REL values from the various sensitivity analyses are all within a factor of ±2 of the candidate REL values from the main analysis, suggesting that the value of the toxicologically-based candidate REL is not strongly dependent on these assumptions. # Comparison with other toxicologically-based risk assessments The numerical values of BMD estimates for diacetyl are not all directly comparable, even when based on a common response rate of 10%, because of variations in the dose units used (ppm concentration versus regional penetration versus tissue concentration). The occupational exposure limits (OELs) developed by the various authors are directly comparable, but depend in part on assumptions regarding uncertainty factors, which may vary between studies. In contrast, the HEC estimates derived in this analysis can be directly compared to the HEC estimates that have been developed in prior risk assessments. Earlier toxicologically-based risk assessments of diacetyl [Allen 2009;Maier 2010] have been based on the 6-week and 12-week mouse study of , rather than the more extensive subchronic study conducted by the NTP [2011]. Because the NTP [2011] subchronic study included data from both mice and rats and included both more dose levels and more animals per dose group than the study, the NTP [2011] diacetyl study was chosen as the basis for risk assessment in this document. However, comparison of the current risk assessment findings to the results of the earlier risk assessments is instructive. The HECs derived in prior diacetyl risk assessments are summarized in Table 6-11. The BMC 10 HEC estimates in the current study span a range of 1.8-143.7 ppm, compared to the range of 4.5-61 ppm reported in prior diacetyl risk assessments. The BMCL 10 HEC estimates in the current study span a range of 1.4-95.9 ppm, compared to the range of 1.3-10 ppm reported in prior diacetyl risk assessments. The wider range of HEC estimates in the current study, as compared to prior analyses, is partially due to the application of animal-tohuman dosimetry estimates from the Gloede et al. [2011] PBPK/CFD model, which was published subsequent to the prior risk assessments and was, obviously, not available to prior risk assessors. In addition, the current study has the benefit of a more extensive toxicological data base for diacetyl because of publication of the NTP [2011] subchronic inhalation study, and therefore includes data from more pathological endpoints than the prior analyses did. Maier et al. [2010] conducted a risk assessment for diacetyl for the purpose of deriving an OEL. This risk assessment was based on the mouse pilot study data of , using BMD methodology. The authors concluded that the most sensitive endpoint in the mouse [Allen 2009b] prepared under OSHA contract number DOLQ059622303 ( 2009) Task Order 50. These reports served as the basis for the toxicologically-based diacetyl risk assessment in the draft NIOSH criteria document for diacetyl in 2011 but have been supplanted in the current document by an analysis of more recent data. A summary of the risk assessment extracted from these reports is included here, for comparison to the current toxicologically-based quantitative risk assessment. The [Allen 2009a] quantitative risk assessment was based on an analysis of adverse respiratory effects in mice exposed to diacetyl by inhalation for up to 12 weeks . Adverse nasal and lung effects were observed with the latter found in the peribronchial, bronchial, and peribronchiolar regions. The study was used to derive BMDs, BMDLs, and corresponding HECs, as discussed below. The responses analyzed were those most relevant to longer-term exposures, i.e., those from the subchronic portion of the study that included constant exposures of 25, 50, and 100 ppm for 6 hours/day, 5 days/week, for either 6 or 12 weeks. The 6-and 12-week data were pooled for the final analysis, based on a likelihood ratio test that indicated that the 6-and 12-week results were not significantly different. A variety of dosimetric adjustments were considered in extrapolating the results from mice to humans. The most significant of these adjustments was the choice of dose metrics, either "regional penetration" (based on the percentage of diacetyl reaching a given portion of the respiratory tract), or "tissue concentration" (based on the Morris and Hubbs [2009] PBPK model). Because the choice of dose metrics has a significant impact on the HEC, and it is not clear which dose metric is preferable, HECs derived using both dose metrics are reported in Table 6-11. An assessment completed by Toxicology Excellence for Risk Assessment (TERA) [IDFA 2008] also utilized the dose-response data of , and estimated HECs based on BMDLs for 10% risk, comparable to those estimated in the current analysis. TERA excluded the nasal lesions from consideration prior to their analysis, stating that the evidence of upper respiratory symptoms in humans exposed to diacetyl was inconsistent and that those symptoms lacked reliable concentrationresponse information. In contrast, the current assessment assumes that the dose-response relationship in a test species, rather than the lesion site, is the best criterion for choosing which endpoints to model for quantitative risk estimation. Thus, the current analysis assumes that site concordance is not a requirement because once the dose has been adequately adjusted (and ideally, once toxicodynamic considerations have been carefully considered), a valid dose-response relationship at any respiratory tract site/lesion in a test species is a reasonable basis for characterizing human risk. Additionally, exact site concordance across species would not be expected after exposure to diacetyl because of the differences in deposition of the chemical within the respiratory tracts of rodents and humans, as indicated by the PBPK model of Gloede et al. [2011]. The Gloede et al. [2011] model indicates that a much higher percentage of inhaled diacetyl reaches the bronchial and bronchiolar regions in humans than in rodents which provides a basis for the findings that diacetyl toxicity is observed primarily in the upper respiratory tract of rodents and the lower respiratory tract of humans. TERA [IDFA 2008] estimated HECs using the EPA default methods [EPA 1994] modified by the PBPK/CFD model predictions of Morris and Hubbs [2009]. However, rather than using the relationships between the default and CFDmodel-predicted scrubbing factors to define a mouse-specific estimate of airway scrubbing of diacetyl, they assumed that mice were exactly like the CFD-modeled rats (i.e., used the CFD model predictions for the rats as if they were equally relevant to mice). The TERA [IDFA 2008] risk assessment did not consider light exercise conditions, as may occur in the workplace, as these were not incorporated into the PBPK/CFD modeling of Morris and Hubbs [2009]. Moreover, for the effective dose (regional penetration) measure calculated by TERA, the default mouse ventilation rates were used. As discussed above in regard to the Allen [2009a] risk assessment, the experimentally measured ventilation rates for the study were substantially greater than the EPA default values (by a factor of 3 to 5), and this would have a major impact on the HEC estimates (TERA's estimates would be about 3 to 5 times greater, because the major effect of changing the ventilation rate is on the effective dose measure, V E /SA, rather than the scrubbing). TERA's analysis resulted in estimates of HECs that were 9 and 2 ppm, corresponding to the estimated BMD( 10) and BMDL( 10), respectively, from their dose-response analysis of the peribronchial inflammation endpoint from . The TERA assessment suggested that a composite uncertainty factor of 10 should be used to adjust those HECs downward to an OEL. That factor of 10 was the product of a factor of 3 for interspecies differences and another factor of 3 for human variability [IDFA 2008]. These factors of 3 are well-accepted uncertainty factors commonly used by EPA and others in risk assessment. Their recommended OEL was therefore 0.2 ppm (as an 8-hour TWA). # 2,3-Pentanedione Toxic potency estimation for 2,3-pentanedione is constrained by both the limited numbers of animals that have been tested and the differing exposure durations used in the diacetyl and 2,3-pentanedione studies. The currently available histopathological data for repeated exposures to 2,3-pentanedione are limited to a single study involving exposures of 2 weeks + 2 days (totaling 12 exposures per animal), in both rats and mice. The rat data and female mouse data for diacetyl are limited to a single 13-week study [National Toxicology Program 2011], so that no data on the relationship of toxicity to duration of exposure are available for the rat or the female mouse. For male mice, limited data are available from the 6-and 12-week exposures reported by . Although no mouse studies are available that closely approximate the 2 week + 2 day exposure protocol used in the 2,3-pentanedione study, the 6-, 12-, and 13-week diacetyl data on male mice were used to estimate an adjustment to predict what the toxicity of diacetyl would have been in a study of the same duration as the 2,3-pentanedione study. Although a small increase of toxicity with exposure duration was fitted it was retained in the model even though it was not significant in order to account for it as a source of variation in obtaining the standard errors of the seven relative potency estimates † † † † of each sex. The resulting relative potency estimates suggest that 2,3-pentanedione may have equal or greater toxic potency than diacetyl for five of the seven responses of male mice from † † † † For those readers acquainted with the concept of Stein estimation for adjusting a set of three or more estimates an application of a criterion of Bock [1975] to the covariance matrix of each set did not support making them. 6-10 superficially suggest that 2,3-pentanedione is or seems to be less toxic than diacetyl to female mice, these estimates are sensitively dependent on the assumption that the parameter for exposure duration is identical to that of males. Furthermore, there is a complete lack of information from these studies for assessing this assumption and profiling the likelihood indicated that the relative potency estimates of the female mice were substantially sensitive to this parameter whereas this did not hold for the estimates of the males. Hence, it would be prudent to refrain from concluding that 2,3-pentanedione is less toxic than diacetyl to female mice on the basis of the estimates of Table 6-10. Recent data support the conclusion that 2,3-pentanedione should be used cautiously in the workplace and exposures to 2,3-pentanedione should be minimized. Rats (but not mice) develop intramural and intraluminal airway fibrosis following exposure to either diacetyl or 2,3-pentanedione ]. This lesion shares many features with obliterative bronchiolitis of humans, the condition that originally brought medical attention to employees exposed to diacetyl. A 2-week inhalation exposure of 150 or 200 ppm to either diacetyl or 2,3-pentanedione could produce bronchial fibrosis in rats ]. This finding suggests that 2,3-pentanedione causes airway fibrosis comparable to diacetyl at equal exposure concentrations. Because no chronic or subchronic studies of 2,3-pentanedione are currently available and the number of rats in the 2-week exposure is low, it is not possible to quantitatively assess the toxicity of 2,3-pentanedione relative to diacetyl for producing airway fibrosis. However, these data do suggest that it would be prudent to treat 2,3-pentanedione as at least equally toxic as diacetyl until additional toxicological data become available on the toxic potency of 2,3-pentanedione. # Conclusions Pathological lesions produced by inhalation exposure to diacetyl and 2,3-pentanedione have been assessed using categorical regression techniques and benchmark dose estimation. For diacetyl a CFD/PBPK model is available for both rats and humans that allows rodent BMC and BMCL estimates to be extrapolated directly to human exposures. The results of this exercise indicate that the most sensitive endpoint in terms of estimated human toxicity is that associated with eosinophilic inflammation in the male rat lung. The HEC associated with this endpoint is 1.8 ppm, with a 95% lower-bound estimate of 1.4 ppm (Table 6-6). Application of a 24-fold uncertainty factor to the lower-bound HEC leads to a candidate REL of 0.06 ppm, or 60 ppb diacetyl. The estimated human toxicity based on chronic bronchial inflammation in the female mouse lung is very similar to the ratbased estimate (Table 6- 8), and also leads to a candidate REL of 0.06 ppm or 60 ppb. If human data on the toxicity of diacetyl were not available, these estimates could serve as the bases for REL development for diacetyl. Because human data do exist and are sufficient for derivation of an REL, the toxicologically-based candidate RELs should be viewed as complementary to the epidemiologically-based REL. Because the toxicologically-based REL is within an order of magnitude of the epidemiologically-based REL it supports the epidemiologically-based REL. Morris JB, Hubbs AF [2009]. Inhalation dosimetry of diacetyl and butyric acid, two components of butter flavoring vapors. Toxicol Sci 108( 1 Wheeler MW, Bailer AJ [2007]. Properties of model-averaged BMDLs: a study of model averaging in dichotomous response risk estimation. Risk Anal 27(3):659-670. WHO [1994]. Environmental Health Criteria 170. Assessing human health risks of chemicals: Derivation of guidance values for health-based exposure limits. International Programme on Chemical Safety, Geneva, Switzerland. 7 Basis of the Recommended Standards for Diacetyl and 2,3-Pentanedione In the Occupational Safety and Health Act of 1970 (Public Law 91-96), Congress mandated that NIOSH develop and recommend criteria for identifying and controlling workplace hazards that may result in occupational illness or injury. In fulfilling this mandate, NIOSH has reviewed the relevant human and/or animal data to assess the health effects of diacetyl and 2,3-pentanedione; assessed the risks of occupational exposure; characterized anticipated employee exposures; and developed recommended criteria for exposure limits, exposure monitoring, engineering and work practice controls, and medical monitoring. The basis for the RELs is described in this chapter. The primary objective of the recommendations for diacetyl is to reduce loss of lung function associated with diacetyl exposure because diacetyl (and potentially related diones) has been shown to cause potentially fatal obliterative bronchiolitis in employees. The NIOSH REL for 2,3-pentanedione would be identical to that for diacetyl but is slightly higher based upon the limitations of the analytical method. # Health Effect Studies of Employees Exposed to Diacetyl As detailed in Chapter 3, medical evaluations showed that employees exposed to diacetyl developed progressive shortness of breath while working at several microwave popcorn plants and flavoring plants, findings consistent with the severe irreversible lung disease obliterative bronchiolitis. Obliterative bronchiolitis, sometimes characterized by spirometric abnormality, has been described in employees in the microwave popcorn and flavor-manufacturing industries [CDC 2002[CDC , 2007]. Some affected employees have experienced extremely rapid declines in lung function, with severe airways obstruction in some cases occurring within several months of the start of exposure to flavoring compounds NIOSH 1986]. Employees as young as 22 years old have been affected. Some affected employees have been placed on lung transplant waiting lists by their physicians because of the severity of their disease ]. The findings from investigations and studies conducted at multiple plants presented in Chapter 3 have established a link between exposure to diacetyl and risk for severe occupational lung disease. These findings meet the standard criteria used to determine causation: that an exposure is the likely cause of specific health effects [Gordis 1996;Hill 1965]. Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetyl-exposed employees have provided clear evidence of a causal relationship between diacetyl exposure and development of this disease. # Toxicological Studies of Diacetyl In rats, acute exposures to diacetyl or diacetylcontaining butter flavoring vapors cause necrosis in the epithelial lining of nasal and pulmonary airways. Rats inhaling vapors of butter flavoring that contained diacetyl developed multifocal necrotizing bronchitis one day after a 6-hour exposure. The mainstem bronchus was the most affected intrapulmonary airway. However, nasal airways were more affected than intrapulmonary airways. Necrosuppurative rhinitis was seen in rats inhaling butter flavoring vapors at concentrations that did not cause damage in intrapulmonary airways [Hubbs et al. 2002]. As a single agent acute exposure in rats, diacetyl caused epithelial necrosis and inflammation in bronchi at concentrations of >290 ppm and caused epithelial necrosis and inflammation in the trachea and larynx at concentrations of ≥220 ppm . In a pattern similar to that of airway damage from diacetyl-containing butter flavoring vapors, diacetyl causes greater damage to nasal airways than to intrapulmonary airways in rats ]. In mice, inhaling diacetyl at concentrations of 200 or 400 ppm for 6 hours/day for up to 5 days caused respiratory tract changes similar to those seen in rats inhaling diacetyl or diacetylcontaining butter flavoring vapors . Subchronic diacetyl inhalation caused significant histopathological changes in mice at all concentrations studied. Peribronchial lymphocytic infiltrates were seen at terminal sacrifice at 12 weeks in all subchronically exposed mice inhaling 100 ppm diacetyl and in some mice inhaling 25 or 50 ppm diacetyl. Using a CFD-PBPK model, the rodent pathologic changes, though at higher regions in the respiratory tract, were consistent with the human bronchiolar pathology once differential nasal scrubbing, size of airway, and target organ doses were accounted for Morris and Hubbs 2009]. In rats in which nasal scrubbing was bypassed by administering a single dose of 125 mg/kg diacetyl via intratracheal instillation, histopathological alterations # Objectives The NIOSH objective in establishing RELs for diacetyl and 2,3-pentanedione is to reduce the risk of respiratory impairment (decreased lung function) and the severe irreversible lung disease obliterative bronchiolitis associated with occupational exposure to these compounds. In addition, maintaining exposures below the RELs will help prevent other adverse health effects including but not limited to irritation of the skin, eyes, and respiratory tract in exposed employees. The recommendation to limit exposure to diacetyl and 2,3-pentanedione is based upon data from human and animal studies and the quantitative risk assessment, however, additional considerations included sampling and analytical feasibility and the achievability of engineering controls. A variety of risk estimates were evaluated and presented in Chapter 5. NIOSH has historically targeted excess risks predicted to be in the range of approximately 1 per 1,000 in establishing RELs (see Chapter 5, Tables 5-34 NIOSH is also recommending a STEL for diacetyl of 25 ppb for a 15-minute time period. The establishment of a short-term exposure limit is based on the concern that peak exposures may have greater toxicity than the same total dose spread out over a longer period of time. Some limited evidence of this type of dose-rate effect is available in animal studies ]. On the basis of general industrial hygiene principles, the STEL, which is five times the REL, would serve to reduce peak exposures and tend to reduce overall employee exposures to diacetyl. The selection of a STEL that is five times the REL is based upon past precautionary practice [Federal Register 1997]. In the absence of a STEL in workplaces complying with the NIOSH REL for diacetyl of 5 ppb TWA, employees could theoretically be exposed to 2,400 ppb diacetyl for 1 minute or 480 ppb for 5 minutes in an 8-hour day with no additional exposure the remaining part of their 8-hour shift. The STEL for diacetyl of 25 ppb would limit those exposures to a possible peak of 375 ppb for 1 minute and 75 ppb for 5 minutes and should prevent acute irritation from brief high exposures. 7.5.2 Recommended Exposure Limit for 2,3-Pentanedione 2,3-Pentanedione, which has been used as a substitute for diacetyl, is also of concern because of structural similarities with diacetyl and because animal studies show similar toxicity for the respiratory tract [Hubbs et al. 2012;]. Morphologic data suggest that 2,3-pentanedione can cause airway epithelial damage similar to the damage caused by diacetyl [Hubbs et al. 2012;]. Rats repeatedly inhaling 2,3-pentanedione at concentrations ≥ 150 ppm for up to 2 weeks develop fibrosis of intrapulmonary airways, a morphologic change similar to obliterative bronchiolitis in humans . Recently, more than 3500 genes were found to be upregulated in RNA isolated from the fibrotic bronchi of 2,3-pentanedione exposed rats [Morgan et al. 2015]. Some of the up-regulated genes were ones previously implicated in fibrosis, including transforming growth factor-β2, interleukin-1α, interleukin-18, interleukin-33, and fibronectin. In addition, at high exposure concentrations, messenger RNA changes were noted in the brain of rats after acute 2,3-pentanedione inhalation [Hubbs et al. 2012]. The toxic potency of the two materials appears to be comparable in mice exposed by inhalation (see Chapter 6, section 2 for a full discussion). Given the structural similarity between diacetyl and 2,3-pentanedione and the evidence published, NIOSH would prefer to recommend an identical REL for diacetyl and 2,3-pentanedione. However, OSHA Method 1016, the validated analytical method available for 2,3-pentanedione, can only reliably quantify 2,3-pentanedione at concentrations 9.3 ppb and above. Therefore the NIOSH REL for 2,3-pentanedione, while informed by the toxicological potential, is based upon the limitations of the analytical method and is established at 9.3 ppb. This REL for 2,3-pentanedione will result in a residual risk of lung disease similar to diacetyl, but may be higher. It does not imply that 2,3-pentanedione is safer than diacetyl. Because the REL is established at the reliable quantitation level, no AL is established for 2,3-pentanedione. Because of their structural similarity, concerns for short-term exposures to 2,3-pentanedione also apply. Accordingly, a STEL for 2,3-pentanedione is established at 31 ppb (i.e., the lowest concentrations the method can sample accurately during a 15-minute time period). The NIOSH REL for 2,3-pentanedione of 9.3 ppb and STEL of 31 ppb would limit exposures to a possible peak of 465 ppb for 1 minute and 93 ppb for 5 minutes. Because of the concern for potential dose-rate effects, NIOSH recommends STELs for diacetyl and 2,3-pentanedione to reduce peak exposures to employees. Maintaining diacetyl and 2,3-pentanedione concentrations at or below the RELs and STELs requires the implementation of a comprehensive safety and health program that includes engineering controls, exposure monitoring, routine medical surveillance, and employee training in good work practices. Specific recommendations for these components can be found in Chapters 2, 8, 9, and 10 of this document. # Rationale for the Recommended Exposure Limit The recommendation to limit occupational exposures to diacetyl to an 8-hour TWA of 5 ppb is based on data from human quantitative risk assessment with additional rationale provided by animal toxicological studies. From the human studies, 5 ppb represents a reasonable summary of estimates from several concordant approaches to risk assessment. Although smoking affects the excess lifetime risk estimates, a full treatment for the purpose of developing separate REL recommendations on smoking status would require including interactions between smoking and diacetyl exposure histories for which NIOSH believes there is insufficient historical information and statistical power to implement. Furthermore, there is no precedent for developing standards that are specific to smoking status. NIOSH also recommends an AL of 2.6 ppb to help protect employees from exposure to diacetyl above the 5 ppb REL and a STEL of 25 ppb to limit peak exposures and protect against dose-rate effects. Engineering controls and work practices are available to control diacetyl exposures below the REL (and the AL) in workplaces. OSHA Method 1012 is a validated analytical method that can be used to effectively measure employee exposures to diacetyl. Establishing the recommended exposure limits for diacetyl is consistent with the mission of NIOSH mandated in the Occupational Safety and Health Act of 1970. # Controlling Diacetyl and 2,3-Pentanedione Exposures in the Workplace In general, many industries have implemented engineering controls to reduce exposure and risk of disease among their employees. Many of the processes where diacetyl and 2,3-pentanedione are manufactured, handled, or used are similar to other industries and may allow for common approaches to reducing employee exposure. These processes include blending, mixing, and handling of flavoring compounds in liquid and powder form. A 3-year study of a microwave popcorn production facility showed that the use of exposure controls can dramatically reduce diacetyl concentrations in mixing rooms and for all production employees . As a result of the implementation of exposure controls, average combined personal and area diacetyl air concentrations declined an order of magnitude in the mixing room (from 57.2 ppm to 2.88 ppm) while concentrations in the quality control laboratory (from 0.82 ppm to < LOD) and packaging area (from 2.76 ppm to < LOD for machine operators) declined to below detectable limits. These interventions included providing general room exhaust ventilation to the mixing room and local exhaust ventilation for the heated flavoring and mixing tanks. Closed transfer processes were implemented through the installation of a pump to transfer heated butter flavorings from the holding tanks to oil/flavor mixing tanks. The building of an enclosure for all oil/flavor holding tanks and installing local exhaust ventilation on all tanks further reduced exposures to employees in the packaging area of this plant. In the final survey conducted following the implementation of all engineering and process controls, personal diacetyl exposures for all employees/job categories in the plant were below detectable limits with the exception of mixers which ranged from below the LOD to 12.6 ppm. The design concepts required for working with hazardous materials include specification of general ventilation, local exhaust ventilation, maintenance, cleaning and disposal, personal protective equipment, exposure monitoring, and medical surveillance [Naumann et al. 1996]. Bag emptying, bag filling, charging tanks, benchtop weighing and handling, and drum filling and emptying are a few of the production processes of concern. Other more specialized processes (for example, candy panning, a process in which candy pieces in a rotating drum are sprayed with chocolate or other flavoring compounds; coffee roasting; commercial fry-cooking) may also result in employee exposure. Special attention should be given to manual handling of flavoring compounds, particularly in heated processes, and when spraying flavoring compounds. Research on food industry practices has led to the development of engineering controls that may help reduce employee exposure to diacetyl, 2,3-pentanedione, and other chemicals. Chapter 8 describes engineering controls for the industries where diacetyl is handled or used within products. Table 8-2 in Chapter 8 provides a summary of NIOSH evaluated engineering control efficiencies for the mixing of food flavorings. Although many job categories can be effectively controlled to levels below the REL, tasks associated with transfer of diacetyl may continue to pose risk to the employees even following the implementation of controls. For example, mixers may continue to be exposed at levels above the REL when handling butter flavorings and from tank emissions. However, these exposures can be reduced through the implementation of closed transfer systems and local exhaust ventilation approaches discussed in Chapter 8. NIOSH acknowledges that the frequent use of personal protective equipment, including respirators, may be required for some employees who handle diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products. The frequent use of PPE may be required during job tasks for which (1) airborne concentrations of diacetyl or 2,3-pentanedione (e.g., pouring, mixing, packaging) above the REL exist, ( 2) the airborne concentration of diacetyl or 2,3-pentanedione is unknown or unpredictable, and ( 3) job tasks are associated with highly variable airborne concentrations because of environmental conditions or the manner in which the job is performed. In all work environments where diacetyl, 2,3-pentanedione, diacetyl-containing flavorings or flavored products are found, control of exposure through engineering controls should be the highest priority. # Hazards Associated with Diacetyl Substitutes Much has been made of the possible removal/ substitution of diacetyl and 2,3-pentanedione from the flavor manufacturing or food production industries. A health benefit from substitution can only be realized if the substitute is safer than diacetyl or 2,3-pentanedione. However, the current knowledge on toxicity of available substitutes is limited; few if any have OELs, and therefore exposure to substitutes should be controlled. There is reason to think that, like diacetyl, other alpha-dicarbonyl compounds would have a tendency to cause protein cross-links . The reactivity of the alpha-dicarbonyl compounds is enhanced by electron-attracting groups and decreased by electron donors . Alpha-dicarbonyl compounds can inactivate proteins, principally through reactions with the amino acid, arginine [Epperly and Dekker 1989;Saraiva et al. 2006]. The related alphadicarbonyl flavoring, 2,3-pentanedione, has been reported to be even more reactive with arginine groups than diacetyl [Epperly and Dekker 1989]. While the focus of this document is on diacetyl and 2,3-pentanedione, NIOSH has concern about other flavoring substitutes with structures similar to diacetyl or moieties that are biologically active and capable of producing similar toxic effects as diacetyl. Therefore, NIOSH recommends that such exposures also be considered and controlled to concentrations as low as possible, taking into account potential additive effects of flavoring compounds. The guidance recommendations presented in Chapter 8 regarding control of exposures are applicable not only to diacetyl and 2,3-pentanedione, but also to their substitutes and other flavorings and flavoring compounds used in this industry. The control of exposures is discussed in detail in Chapter 8, but several LEV systems described have been shown to be particularly effective in controlling diacetyl and would be expected to work well for similar compounds. Ventilated backdraft workstations used for small batch mixing have been evaluated in two field studies conducted in flavoring production plants. The field studies showed reductions in exposure of 90%-97% when performing mixing tasks using these stations [NIOSH 2008a]. Also, the use of controls to reduce employee exposure during pouring and mixing of ingredients in a commercial mixer has been evaluated in a flavoring production plant [NIOSH 2008b]. The use of LEV at the mixing tank helps to maintain the vessel at a negative pressure and contain evaporative emissions. NIOSH evaluated the impact of a ventilated tank lid on the exposure of an employee during the mixing of a food flavoring [NIOSH 2008b]. # Summary The following points summarize the relevant information used as the basis for the NIOSH recommendation for limiting occupational exposure to diacetyl and 2,3-pentanedione: The idea behind this hierarchy is that the control methods at the top of the list are potentially more effective, protective, and economical (in the long run) than those at the bottom. Following the hierarchy normally leads to the implementation of inherently safer systems where the risk of illness or injury has been substantially reduced. The first item in the hierarchy is elimination/ substitution. The intention of eliminating a flavoring or other chemical in the workplace is to remove the exposure by removing the source. Similarly, the goal of substitution is to substitute a flavoring or chemical with another of lower toxicity. The removal of diacetyl and 2,3-pentanedione from the flavor manufacturing or flavoring industries would be practical only with the substitution of an alternative butter flavor chemical, which is currently being done in some situations. However, the current knowledge on toxicity of available substitutes is limited, and exposure to substitutes may also need to be controlled. Therefore, elimination and substitution may not provide a feasible control and are not discussed in detail. The recommendations that follow are applicable not only to diacetyl and 2,3-pentanedione, but also to other flavorings and flavoring compounds used in this industry. Engineering controls, as discussed below, are mechanical techniques for removing contaminants from the workplace. For instance, local exhaust ventilation can be used to capture and remove emissions from a hazardous or nuisance source. A major advantage of this type of system is that, when properly designed, it requires minimal user effort or training. The use of respirators, a form of PPE, is discussed because this control, while not favored, is in common use in some facilities. As the discussion demonstrates, considerable effort is required in the proper selection and use of respiratory protection in the workplace. Finally, the protection of skin, eyes, and face is also discussed. # Engineering Controls Currently, there is no model or standard guidance for engineering controls for flavoring and food production processes. If it is not possible to eliminate toxic compounds from the workplace or replace them with less toxic substances, then the use of engineering controls and work practices to minimize exposures is the next level of controls for the necessary reduction of exposure. # General Considerations A properly designed supply air ventilation system can provide plant ventilation, building pressurization, and exhaust air replacement. When LEV is installed in production areas, it is important to consider the need for replacement air. In general, it is necessary to balance the amount of exhausted air with a nearly equal amount of supply air. Without replacement air, uncontrolled drafts will exist at doors, windows, and other openings; doors become difficult to open because of the high pressure difference; and exhaust fan performance may degrade. Good supply air design consists of ducted supply with air discharge registers about 10 feet above floor level [ ACGIH 2013]. Controls need to be fitted to individual processes by each plant and cannot be a "onesize-fits-all" approach. Controls need to be evaluated after installation. Evaluations should be completed to quantify exposures after controls have been implemented to ensure that target goals have been achieved. It is important to confirm that the LEV system is operating as designed by periodically measuring exhaust airflows. A standard measurement, hood static pressure, provides important information on the hood performance, because any change in airflow results in a change in hood static pressure. For hoods designed to prevent exposures to hazardous airborne contaminants, the ACGIH Operation and Maintenance Manual recommends the installation of a fixed hood static pressure gauge [ ACGIH 2007]. In addition to routine monitoring of the hood static pressure, additional system checks should be completed periodically to ensure adequate system performance, including smoke tube testing, hood slot/face velocity measurements, and duct velocity measurements using an anemometer. These system evaluation tasks should become part of a routine preventive maintenance schedule to check system performance. It is important to note that the collection and release of air contaminants may be regulated; companies should contact agencies responsible for local air pollution control to ensure compliance with emissions requirements when implementing new or revised engineering controls. To minimize exposure and reduce the risk of flavoring-related lung disease, a few standard precautions should be followed in areas where flavoring-related exposures may occur: ■ Isolate rooms where flavorings or flavoring compounds are handled from the rest of the plant with walls, doors, or other barriers. ■ Maintain flavoring mixing rooms and other areas where flavorings are handled under negative air pressure relative to the rest of the plant. Check status with airflow indication equipment such as a smoke tube. ■ Install hood static pressure gauges (manometers) near hoods to provide a way to verify proper hood performance. Check pressure frequently to ensure that the system is operating properly compared to baseline. Check hood face velocities and capture velocities frequently to ensure that system is performing as designed. ■ Ensure that employees are properly trained on the use of the controls if using proximity switches for fan activation. Consider installing a control "on/ off " light to indicate the status of the exhaust fan. ■ Place hoods away from doors, windows, air supply registers, and aisles when possible to reduce the impact of cross drafts. ■ Provide supply air to production rooms to replace most of the exhausted air. ■ Direct exhaust air discharge stacks away from air intakes, doors, and windows. ■ Inspect hoods and enclosures for signs of damage or leaks (rust/corrosion, open access doors, etc.) and obstructions (paper, gloves, rags, etc.). Where possible, use screens to prevent foreign objects from being pulled into the system through openings (slots, hood faces, etc.). # Primary Production Processes and Controls The food and flavoring production industries have several primary processes that may result in increased potential for employee exposure to diacetyl, 2,3-pentanedione and other flavoring compounds. These may be grouped, from an exposure standpoint, into a few general categories including production operations, packaging operations, cleaning, and maintenance operations [Eastern Research Group 2008b]. Employees in each of these job categories may potentially be exposed to flavoring compounds, including diacetyl and 2,3-pentanedione. Table 8-1 displays a list of job categories and work activities associated with these manufacturing processes. For each activity, the section of this document that discusses relevant exposure control and the figure(s) at the end of this chapter that shows relevant LEV systems are indicated. Other job categories may potentially be exposed to flavoring compounds. These include supervisory personnel, laboratory and quality controls personnel, and cleaning and maintenance personnel. When these personnel are in production areas, they should comply with recommended control procedures and wear appropriate PPE posted for that specific area. Additional considerations may be necessary for the maintenance job category, specifically for intermittent tasks such as filter change out. Many different industries have implemented engineering controls to reduce exposure and risk of disease among their employees. Many of the processes used in the flavoring and food manufacturing industries are similar to those of other industries and may allow for common approaches to reducing employee exposure. These processes include blending, mixing, and handling of flavoring compounds in liquid and powder form. The design concepts required for working with hazardous materials include specification of general ventilation, LEV, maintenance, cleaning and disposal, PPE, exposure monitoring, and medical surveillance [Naumann et al. 1996]. Bag emptying, bag filling, charging tanks, benchtop weighing and handling, and drum filling and emptying are a few of the production processes of concern. Other more specialized processes (for example, candy panning, a process in which candy pieces in a rotating drum are sprayed with chocolate or other flavoring compounds) may also result in employee exposure. Special attention should be given to manual handling of flavoring compounds, particularly in heated processes, and when spraying flavoring compounds. Research into various food industries has led to the development of potential engineering controls to help reduce employee exposure to diacetyl, 2,3-pentanedione and other chemicals. The following sections describe the primary production processes used in the food and flavoring industries and discuss engineering controls that can be used to minimize employee exposure to diacetyl, 2,3-pentanedione and other potential airborne hazards. # Benchtop weighing and handling Small-scale weighing and handling of ingredients are common tasks used in flavoring production, bakeries, dairy production, and snack food manufacturing. The tasks of weighing out dry and wet food ingredients can lead to employee exposure primarily through the scooping, pouring, and dumping of these materials. Studies in bakeries have shown that the employees exposed to dusts, commonly from flour, are those who perform mixing and weighing tasks [Elms et al. 2003]. In addition, a recent survey at a commercial bakery showed that mixer operators were exposed to diacetyl when they measured and added an artificial butter flavor to a dough mixer [Eastern Research Group 2008a]. Because weighing and pouring are often performed on a benchtop workstation, the addition of slotted backdraft ventilation for both the bench and the weighing area is recommended. This approach can also be applied to larger-scale operations. The application of engineering controls to reduce employee exposure to chemicals during mixing and weighing has been evaluated in flavoring production. In flavoring production facilities, compounders measure and pour flavoring compounds on a bench and then transfer these mixtures to open tanks for liquid flavoring production or to blenders used for powdered flavoring production. The use of ventilated backdraft workstations, adapted from welding bench designs available in the ACGIH Industrial Ventilation Design Manual (Figure 8-1) has been evaluated by NIOSH in two field studies conducted in flavoring production plants [ ACGIH 2013]. Ventilated back-draft workstations used for small batch mixing have been evaluated in two field studies conducted in flavoring production plants (Figure 8-2). These stations were designed to maintain an air velocity of 100-150 feet per minute (fpm) at the face of the enclosure. The field studies showed reductions in exposure of 90%-97% when performing mixing tasks using these stations [NIOSH 2008c, d]. The key design parameters are to enclose as much of the activity as possible and to use properly sized exhaust slots to maintain a uniform air velocity across the face of the station. Other groups have also produced designs that may be amenable to the control of exposure during benchtop mixing and weighing activities. The HSE has developed a series of control approaches based on common processes in a variety of industries. One approach is similar to the one evaluated by NIOSH in flavoring facilities and recommends a control velocity of 100-200 fpm (0.5-1 meters per second [m/s]) at the face of the workstation when working with flour improvers (Figure 8-3) [Health and Safety Executive 2003i]. The selection of proper control velocity should be made on the basis of the material being used (powder versus liquid), plant conditions (background drafts), and momentum of contaminant source (pouring versus spraying or vigorous mixing). The use of baffles on the side and top of these workstations to better enclose the process provides improved control and minimizes the deleterious effects of cross drafts on contaminant control. Plastic curtains can provide reasonable enclosure while allowing improved access to the bench area. The proper positioning of these workstations away from doors, windows, air supply registers, and aisle ways will also help to reduce the impact of cross drafts. # Laboratory chemical hoods Laboratory personnel will typically perform benchtop weighing and handling of flavorings in a chemical fume hood. A properly designed and maintained chemical fume hood can offer significant employee protection if used properly. There are many different hood designs, but the most common categories are the conventional or constant-flow hood, the bypass hood, and the variable air volume constant-velocity hood. The constant-flow hood is the oldest and simplest chemical hood design. The exhaust fan induces a constant volumetric airflow moving through the sash opening. For this hood design, the face velocity is lowest when the sash is wide open; when the sash is lowered the face velocity increases. The bypass hood maintains a constant hood face velocity and incorporates a bypass grille above the sash opening. When the sash is wide open it blocks the bypass grille, allowing all of the air to flow through the hood opening. As the sash is lowered, it uncovers increasingly greater amounts of the bypass grille, allowing increasing amounts of air to flow through this alternative path. If it is designed and operated properly, the amount of air flowing through the bypass grille is just sufficient to maintain a constant face velocity. Typically, however, this constant velocity can be maintained over a certain part of the sash's total range. The constant-velocity hood uses a control system to detect the sash position, face velocity and system pressure, and change the fan motor speed or other mechanism, such as mechanical dampers, to increase the airflow when the sash is raised and decrease it when the sash is lowered, thus maintaining a constant face velocity. All chemical hoods have certain common design elements, including an exhaust fan to move air through the hood, a moving sash, exhaust slots, and a horizontal work surface (Figure 8-4). The sash can be designed to move in either a vertical or a horizontal direction. A crucial performance element for any chemical hood is the face velocity, defined as the average air velocity at the face of the hood at the sash opening. Maintaining a constant, minimum face velocity provides confidence that operations and hazardous agents within the hood will be contained. The current consensus of the literature is that the average face velocity for a laboratory chemical hood should be in the range of 80-120 fpm [Burgess et al. 2004]. The flow control system on a constant-velocity hood should be adjusted to give a face velocity in this range. Each chemical hood should be clearly marked with the proper hood sash location that will give the desired face velocity; depending on the hood design, this could be a single location or a range of locations. Containment verification using tracer gases to provide quantitative data and smoke testing to visualize airflow patterns is recommended when the hood is installed, when substantial changes are made to the ventilation system, and periodically as part of a preventive maintenance program. In addition to the face velocity, it is important that the airflow be distributed evenly across the hood face. ANSI/AIHA Z9. 5 [2003] recommends that variations of velocity across the hood face should be within ±20% of the average face velocity; however, some laboratories select a stricter standard of ±10%. # Charging/filling tanks and mixers The addition of solid and liquid ingredients into tanks and other mixing vessels can cause exposure to dusts and vapors due to the displacement of air in the vessel. Medical and environmental surveys conducted in the microwave popcorn manufacturing industry have shown that employees who mixed butter flavorings into heated soybean oil had the highest exposures to diacetyl and the highest risk of developing severe irreversible lung disease ]. These employees measured out artificial butter flavoring in open containers and poured the flavoring into heated mixing tanks filled with oil. Real-time monitoring of a mixer at one plant measured a diacetyl peak of more than 80 ppm over several minutes as he poured flavorings into the mixing tank . NIOSH investigations at a plant where many exposed employees developed severe lung disease also showed that the implementation of LEV for heated tanks of oil and flavorings and general dilution ventilation for production areas reduced diacetyl concentrations. As a result of the implementation of exposure controls, average personal diacetyl air concentrations declined in the mixing room, from 57.2 ppm to 2.88 ppm . Exposures to diacetyl were also recorded at a plant that produced flavorings and other products in employees who added flavors to mixing and spray dryer feed tanks while the tanks were being filled. One employee who was adding diacetyl-containing starter distillate and starch to a spray dryer slurry feed tank was exposed to elevated levels of volatile organic compounds including diacetyl for a sustained period of time [NIOSH 2009]. In addition, elevated concentrations of volatile contaminants were measured as an employee poured diacetylcontaining starter distillate from a collection vessel into a bulk container. The use of controls to reduce employee exposure during pouring and mixing of ingredients in a commercial mixer has been evaluated in a flavoring production plant [NIOSH 2008d]. The implementation of LEV at the mixing tank helps to maintain the vessel at a negative pressure and contain evaporative emissions. NIOSH evaluated the impact of a ventilated tank lid on the exposure of an employee during the mixing of a food flavoring (Figure 8 -5) [NIOSH 2008d]. The use of the ventilated tank lid resulted in a reduction of approximately 76% compared to the same operation without the ventilated tank lid. However, most of the exposure during the evaluated mixing process was attributed to tasks performed outside of the hood. Ventilated tank lids have also been recommended by the HSE to contain vapors during the mixing of liquids with other liquids or solids [Health and Safety Executive 2003e]. A NIOSH laboratory study of different mixing tank hood designs for a 4 foot diameter tank showed that capture efficiencies above 90% were possible for all hoods and configurations at an exhaust flow rate of 200 cubic feet per minute (cfm) with a crossdraft of 100 fpm or less [Hirst et al. 2014]. Another approach evaluated by NIOSH at a flavoring manufacturing facility was the use of a ventilated mixing booth. This booth allows a large portable mixing tank to be rolled inside so that chemical vapors emitted during pouring and mixing of flavoring compounds in the tank are captured and exhausted (Figure 8-6). However, the booth provides some flexibility and can also be used for other production tasks such as large pouring and product packaging activities. The use of slots across the booth plenum helps evenly distribute the flow across the height and width of the booth. A field study showed hood capture efficiencies of greater than 95% based on tracer gas tests [Dunn et al. 2008]. An important design consideration is to make the booth deep enough to fully contain the process. Other approaches to controlling exposure during filling of mixing vessels and tanks include the use of a simple exhaust hood near the opening of fixed tanks. This approach is highlighted in the HSE Control Approach 210, titled "Charging Reactors and Mixers from a Sack or Keg" (Figure 8-7) [Health and Safety Executive 2003a]. This design calls for the use of a local exhaust hood near the tank opening with an inward velocity of at least 200 fpm. Another design provided by the HSE and ACGIH for mixers and tanks includes the use of rim exhausts placed around the edge of the mixer/tank. These designs take the shape of an annular slotted hood, which pulls air away from employees as they add ingredients or operate the mixer (Figure 8 # Bag dumping/emptying Manual handling of solid powders is a process used in many industries, including food and flavoring production. The opening and dumping of bags of powdered ingredients is commonly performed by employees in the production of flavorings, dairy products, snack foods, and in baked goods. Typically, an employee cuts open bags of material (e.g., 50-pound bags) and dumps the ingredients into a hopper, and then stacks or disposes of the empty bags. In powdered flavoring production, these hoppers are commonly outfitted onto blenders used to load the base starch ingredient for dry flavor blends. In snack food production, they may be used to load spices and flavors for application to the product via open drum coaters just before packaging. These open-ended devices typically are used to coat larger, more irregularly shaped materials such as cereal flakes or expanded snacks. Coatings may be applied as a slurry or as a dry mix following spray application of oil or lecithin. The drums rotate as the flavoring is being applied to allow for even coverage of the snacks. This process can cause employee exposure to the powdered flavoring; a case of bronchiolitis obliterans organizing pneumonia was reported in a spice process technician whose primary responsibility was to manually dump spices from bags into a slurry for application to potato chips [Alleman and Darcey 2002]. Technology used to control dusts during bag dumping has been in place for many years. The standard control-a ventilated bag dump station-consists of a hopper outfitted with an exhaust ventilation system to pull dusts away from employees as they open and dump bags of powdery materials. The designs for these devices are available from several sources of industrial ventilation guidance. The HSE has developed a control approach for a ventilated station for emptying bags of solid materials. The control includes the specification of a face velocity of 200 fpm (1.0 m/s) and includes a waste bag collection chute (Figure 8-9) [Health and Safety Executive 2003g]. Research into the effectiveness of these types of devices has shown that they can effectively reduce employee exposure to dust and vapors. A review of commercially available units showed that their use controlled dust levels to 1-2 mg/m 3 [Heitbrink and McKinnery 1986]. However, dust contamination on the surface of the bag and handling or disposal of bags caused increased employee exposure. An integral pass through to a bag disposal chute or compactor will help reduce dust exposure resulting from bag handling. Further studies in mineral processing plants showed that the use of an overhead air supply also significantly decreased employee exposure [Cecala et al. 1988]. The ACGIH Ventilation Manual also has two designs that are applicable to the control of powder materials during bag dumping. Design plate VS-15-20, Toxic Material Bag Opening, is similar in design to the HSE station described above but recommends a slightly higher control velocity of 250 fpm at the face of the station opening. # Bag filling The process by which bags are filled with products is typically done by flavor manufacturers and other producers of powder materials. Powder flavorings are typically mixed with industrial blenders or produced by a spray drying process. For the blending process, a powdered starch or other carbohydrate is combined with a liquid or paste flavoring agent. When the blending is completed, the powder product may be discharged into a bulk tote or packaged into smaller containers. In the spray drying process, a mixture of liquid and powder ingredients (slurry) is sprayed within a large sealed tank. Heat within the tank dries the slurry droplets, leaving a powder as the Occupational Exposure to Diacetyl and 2,3-Pentanedione 191 finished product. This powder is then collected and packaged in product containers. Studies conducted at flavoring production facilities have shown that intermittent peak exposures to dust and flavoring volatile ingredients occur when powder products are being packaged following blending or spray drying [NIOSH 2007[NIOSH , 2008a[NIOSH , b, 2009. The use of a ventilated collar-type hood around the discharge point can help minimize employee exposure to dust and vapors. The HSE has developed a control approach for an exhaust hood for the filling of bags with solid materials. The control includes the specification of a ventilated enclosure around the powder discharge outlet and has applicability to the filling of smaller product bags as well as intermediate bulk containers (Figure 8-12) [Health and Safety Executive 2003d, h]. This design guidance recommends an air velocity of 200 fpm (1.0 m/s) into the enclosure. The ACGIH Industrial Ventilation Manual, Design plate VS-15-02, Bag Filling, is similar in design to the HSE exhaust hood but specifies an overall hood exhaust flow of 400-500 cfm for nontoxic dust or 1,000-1,500 cfm for toxic dust with a maximum inward air velocity of 500 fpm [ ACGIH 2013]. In addition to ventilation solutions, other dust control approaches have been used in a variety of industries and should be applicable for food and flavoring production. For example, an inflatable seal can be used to create a dust tight seal on the discharge outlet of an industrial blender (Figure 8 -13). The outlet spout can be fitted with an inflatable seal that prevents dust from escaping during the bag filling process. The seal inflates during the product transfer from the blender to the packaging bag (providing the seal) and deflates once the transfer is completed to allow removal of the packaging bag. These systems are available on many commercially available bulk bag filling systems [Hirst et al. 2002]. Another system that can be used is the continuous liner system. Polypropylene liners are often used when products are discharged from the industrial blenders into the final product container. In this operation, a sleeve of polypropylene liners is stowed around the circumference of the discharge outlet. The first liner, the bottom having been sealed, is pulled down into the overpack (usually a 5-gallon bucket or a cardboard box). Product is discharged into the liner through a butterfly valve on the blender outlet. Once full, the top of the first liner sleeve is closed with tape or a fastener, or it is heat sealed and cut. The product is sealed within the poly-lined container, and a new sealed poly-liner is pulled down to start discharge into the next container. This continuous process seals off the primary leak paths for dust during unloading of an industrial blender or other equipment. These systems are commonly used in the pharmaceutical industry and may provide effective alternatives to traditional local exhaust ventilation control systems for food and flavoring production. # Summary of Capture Efficiencies of Control Approaches Producing flavorings and flavored foods involves a variety of steps. These processes require the handling and manipulation of flavorings and flavoring compounds, which have been shown to be a point of exposure for employees. Table 8-2 shows the capture efficiencies of those controls which have been evaluated by NIOSH in the laboratory or in flavoring manufacturing plants and discussed in this chapter. These controls have shown to be effective at reducing potential employee exposure by 90% or greater across the wide range of processes and tasks commonly seen in flavoring and flavored food production. However, for some tasks, this may not be enough to reach the exposure control goals. When implementing engineering controls, it 192 Occupational Exposure to Diacetyl and 2,3-Pentanedione is important to use a tiered approach, which includes reducing the emissions at the source through containment, process modifications, or local exhaust ventilation as well as using facility provisions such as pressurization schemes. These approaches should be used in conjunction with those described below including administrative controls and the use of personal protective equipment. # Administrative Controls Work practices, an administrative control, are procedures followed by employers and employees to control hazards in the workplace. The emission of the volatile components in each flavoring mixture can be minimized by preventing spillage. To the extent possible, containers used to mix and store flavoring compounds should be covered when not in use. This practice will minimize the evaporation of chemicals into the workplace air and minimize likelihood of inadvertent spills. Manual handling of chemicals also provides a potentially significant source of employee exposures and emissions. Use of closed transfer processes, where feasible, significantly reduces exposure. Also, slow careful pouring/handling of chemicals can reduce splashing, spillage, and exposure during this activity [Boylstein et al. 2006]. Reduction in spills and elimination of leakage from vessels aid in reducing the overall emission of chemicals into the workplace and lower employee exposure. # Good Housekeeping Practices An organized, clean workplace enables faster and easier production, improves quality assurance, and reduces the potential for slips, trips, and falls. It is important to maintain good general housekeeping practices so that leaks, spills, and other process integrity problems are readily detected and corrected. # Reduced Process Temperatures for Priority Flavoring Compounds To minimize volatilization, the temperature of diacetyl, 2,3-pentanedione, and other flavoring compounds in heated tanks should be maintained as low as production processes will allow, even when closed systems are used. Employers should make sure that: ■ All temperature-related equipment such as thermometers and automatic shutoff mechanisms are regularly checked to ensure that they are in good working order. ■ Tank thermometers and thermostats are calibrated at least monthly or as recommended by the manufacturer. ■ Employees take periodic manual temperature readings with a stem thermometer inserted just below the surface of the heated agents or with an infrared thermometer. # Cleaning Practices for Equipment and Tools Where possible, cold water should be used to clean out tanks and blenders to reduce the volatilization of chemicals into plant air. Employees who are involved in cleaning or are working nearby should use appropriate PPE including respiratory protection, eye, and skin protection. # Limit Access to Priority Flavoring Compounds Employers should structure work tasks to minimize the amount of time employees spend near priority chemicals and production processes that involve these chemicals. Employers should limit access to areas where diacetyl, 2,3-pentanedione, or other flavoring compounds are used to only those employees who are essential to the process or operation. These areas should be clearly marked with signage. # Informing Employees about the Hazard # Safety and health programs Employers should establish a comprehensive safety and health program for all employees who are performing any activity, such as manufacturing, using, handling, or disposing of diacetyl or 2,3-pentanedione, that involves exposure to these compounds or mixtures that include these compounds. This program should include training on workplace hazards, monitoring of airborne diacetyl and 2,3-pentanedione levels, and medical surveillance of employees exposed to these compounds or mixtures that include these compounds. All containers of food flavorings fall under the labeling requirements of the OSHA hazard communication standard (HCS) unless they are covered under the Federal Food, Drug and Cosmetic Act or the Virus-Serum-Toxin Act of 1913 [29 CFR 1910[29 CFR .1200]. Employee training should include information outlined in the OSHA HCS in the section titled "Employee Information and Training" [29 CFR 1910[29 CFR .1200]. This includes information about diacetyl and 2,3-pentanedione and mixtures containing these compounds to which employees are exposed, explanation of safety National Toxicology Program 2011]. Several case studies, public health investigations, and a cohort mortality follow-up study link exposure to flavorings containing diacetyl to fixed airway obstruction Cavalcanti et al. 2012;CDC 2002CDC , 2007CDC , 2013Halldin et al. 2013]. Precautionary statements for the health and physical hazard classifications presented can be found in Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200. † Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200 provides several precedence rules regarding the application of pictograms and signal words as well as rules for combining or omitting hazard and precautionary statements. These precedence rules save space on the label and improve readability. ‡ NIOSH recommends that these GHS classifications should appear on product labels and SDSs when found in mixtures below the specific cut-off values/concentration limits that are provided in the hazard communication standard [29 CFR 1910[29 CFR .1200. See section 8.3.7.3 below for further information. [29 CFR 1910[29 CFR .1200. Precautionary statements for the health and physical hazard classifications presented can be found in Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200. † Appendix C of the hazard communication standard [29 CFR 1910[29 CFR .1200 provides several precedence rules regarding the application of pictograms and signal words as well as rules for combining or omitting hazard and precautionary statements. These precedence rules save space on the label and improve readability. ‡ NIOSH recommends that these GHS classifications should appear on product labels and SDSs when found in mixtures below the specific cut-off values/concentration limits that are provided in the hazard communication standard [29 CFR 1910[29 CFR .1200. See section 8.3.7.3 below for further information. physical hazard criteria presented in Appendix B of the hazard communication standard [29 CFR 1910[29 CFR .1200. These classifications are based on the data from employee investigations (Chapter 3) and from experimental toxicology studies (Chapter 4). OSHA has provided guidance on hazard communication for diacetyl and food flavorings that contain diacetyl [OSHA 2013] on the basis of the previous version of the HCS, but that guidance does not address some of the requirements in the revised HCS based on GHS. The GHS classification for acute inhalation toxicity, category 2 for diacetyl is based upon rat acute inhalation studies of diacetyl and 2,3-pentanedione [Hubbs et al. 2012;]. In the diacetyl study, the histopathology changes seen in rats exposed for 6 hours to a time-weighted average of 294.6 to 365 ppm diacetyl would be predicted to cause death if the animals had been observed for a longer time period. In exposures conducted in this concentration range, the severity scores in the airway epithelium of trachea, larynx, and multiple sections of nose had an average score of 7.5 to 9.5 on a scale of 1 to 10 (with 10 being most severe). Damage to airway epithelium is the accepted underlying cause for obliterative bronchiolitis in man, which causes human morbidity and mortality [King 1989]. The importance of extrapulmonary airway injury in the rodents to human risk assessment is discussed in the toxicology section. In the 2,3-pentanedione inhalation study in rats, clinical observations documented that no clinical signs were present immediately after the 6 hour inhalation exposures to 318 or 354 ppm but respiratory signs were present in more than half of the rats at 18 hours post-exposure, when the rats were sacrificed [Hubbs et al. 2012]. While both of these inhalation studies were not intended to produce lethality, contemporary laboratory animal studies frequently use early indicators of impending mortality rather than actual mortality for studies of lethality [Stokes 2002]. The presence of extensive respiratory epithelial damage in 100% of the rats at exposures of approximately 294.6 ppm or greater for 6 hours in both of these studies and timedependent progressive respiratory clinical signs are considered a humane endpoint for use in place of mortality. In this case, expert scientific judgment needs to be used to determine the LC50 because of the humane considerations. Because all rats had high pathology scores after inhaling 294.6 ppm or higher, NIOSH concludes that the LC50 based on a 4-hour exposure would be 441 ppm (the 4-hr equivalent of 294.6 ppm) or less. After inhaling 100 to 120 ppm diacetyl for 6 hours, histopathology changes were limited to the first nasal section and single exposures at this concentration did not suggest potential acute lethality. Similarly, after inhaling 111 ppm 2,3-pentanedione for 6 hours, rats did not have clinical signs and significant histopathology changes were limited to the first two nasal sections. This equates to a GHS acute inhalation toxicity category 2 classification (>100 and <500 ppm) for both diacetyl and 2,3-pentanedione. # Classifying mixtures containing diacetyl and 2,3-pentanedione The HCS indicates that mixtures that contain compounds that require classification and labeling can be evaluated under a set of bridging principles if no toxicological data are available for the mixture itself. These bridging principles can be applied when there is "sufficient data on both the individual ingredients and similarly tested mixtures to adequately characterize the hazards of the mixture" [29 8-3 and 8-4), the specific cut-off values/ concentration limits specified by the HCS are ≥1%. Exceptions include the hazard category for "serious eye damage/eye irritation" (≥3%) and for "flammable liquids," for which the HCS does not have a cut-off value/concentration limit. If these mixtures contain classified compounds below the specified HCS cut-off values/concentration limits, classification and labeling of those mixtures are not usually required. However, the standard indicates that "while the adopted cut-off values/concentration limits adequately identify the hazard for most mixtures, there may be some that contain hazardous ingredients at lower concentrations than the specified cut-off values/concentration limits that still pose an identifiable hazard [29 CFR 1910[29 CFR .1200. As explained below, this is an important consideration for mixtures containing diacetyl and 2,3-pentanedione. FEMA has also recommended that this same warning should be used for containers of neat substances such as diacetyl and 2,3-pentanedione as well as other "high priority" substances listed in the FEMA guidance document. Additionally, FEMA has recommended that all containers of compounded flavors (liquid and dry or powdered) or natural flavoring complexes that contain diacetyl, 2,3-pentanedione or other flavoring substances in concentrations of >1.0% should be labeled with the above warning [FEMA 2012]. It is of note that the use of the word "warning" in the FEMA text is inconsistent with the specific criteria for its use and application as a signal word in the HCS. NIOSH recommends removal of the word "warning" when using the FEMA text (see section 8.3.7.4 for details) # Labeling and posting To communicate hazard information effectively to employees, employers should: ■ Post appropriate labeling on all flavoring product containers according to the HCS requirements [29 CFR 1910[29 CFR .1200. In this document, NIOSH is providing the recommended label elements, including signal word, hazard statements, and pictograms, that should be included for labeling of diacetyl and 2,3-pentanedione on SDSs and labels for shipping containers [see . The precautionary statements that are also required can be found in Appendix C to the HCS [29 CFR 1910[29 CFR .1200 removing them, any limitations on their use, and their maintenance. ■ Procedures for regularly evaluating the effectiveness of the program. If an air-purifying respirator with cartridge/ canister for the protection against gases and vapors does not have an end-of-service-life indicator, then the employer is required to implement a cartridge/canister change schedule based on objective information that will ensure that the cartridges/canisters are changed before the end of their service life, according to the OSHA respiratory protection standard which was revised in 1998. The revised OSHA respiratory protection standard removed the previous method of determining the end of a cartridge's service life by using warning properties such as odor and irritation. A cartridge's useful service life is how long it provides adequate protection from the harmful chemicals in the air which are identified in the respirator approval. A change schedule to establish the time period for replacing respirator cartridges and canisters is the part of the written respirator program that is used to determine how often cartridges should be replaced. Data and information relied upon to establish the schedule should be included in the respirator program. The use of warning properties such as odor and irritation cannot be used as the sole basis for determining change schedules. However, respirator users should be trained to understand that they should leave the area if abnormal odor or irritation is experienced. The respirator should be checked to see if the odor or irritation is evidence that respirator cartridges need to be replaced or the respirator facepiece needs adjustment for better face seal fit. The following table indicates which types of respirators are recommended for use against diacetyl and 2,3-pentanedione and the maximum use concentrations for diacetyl and 2,3-pentanedione, calculated using the OSHA-assigned protection factors for each type of respirator listed [29 CFR 1910.134 (d) # Dermal, Eye, and Face Protection Diacetyl can cause skin and eye irritation. Chemical resistant gloves or sleeves or other appropriate protection for exposed skin should be used when handling liquid, paste, or powdered flavoring compounds containing diacetyl that could cause dermal injury [29 CFR 1910.138]. It is important to select the most appropriate chemical resistant glove for the application and to determine how long it can be worn, and whether it can be reused. Procedures should be implemented to ensure that the gloves are replaced before breakthrough occurs. NIOSH recommends that before purchasing gloves or other protective clothing, the employer should refer to the SDS from the manufacturer of the diacetyl and 2,3-pentanedione being used, and /or request documentation from the glove or protective clothing manufacturer that the gloves meet the appropriate test standard(s) for the hazard(s) anticipated, and to request any glove and protective clothing breakthrough time data against diacetyl and 2,3-pentanedione that may be available from these sources. Tight-fitting SCBA = Self-contained breathing apparatus Maximum use concentrations will be lower than shown when those concentrations are equal to or exceed immediately dangerous to life and health levels. † The employer should have evidence provided by the respirator manufacturer that testing of these respirators demonstrates performance at a level of protection of 1,000 or greater to receive an assigned protection factor (APF) of 1,000. Absent such evidence, these respirators receive an APF of 25. Diacetyl and 2,3 [29 CFR 1910.133]. The ANSI standard was revised in 2010 [ANSI 2010]. The current edition also includes respirators that cover the eyes and face as approvable under the standard. # Occupational Exposure to Goggles for chemical splash should be used for eye protection for employees with potential exposures to diacetyl, 2,3-pentanedione, or food flavorings containing these compounds who are not also required to wear a respirator with a full facepiece, hood, or helmet. Face shields can also be used in conjunction with goggles to shield the wearer's face, or portions thereof, in addition to the eyes for protection from liquid splash. Face shields should be worn only in conjunction with spectacles and goggles, as required by ANSI Z87. 1-20101- [ANSI 2010. A face shield with a polyethylene terephthalate visor should provide good chemical resistance against diacetyl, 2,3-pentanedione, or food flavorings containing these compounds. Gloves and protective clothing such as aprons made from butyl rubber, Teflon™, or Tychem™ are effective in reducing skin contact with ketones to prevent skin irritation [ OSHA 2013]. Diacetyl and 2,3-pentanedione are diketones and certain food flavorings containing either may contain other ketones or diketones. Glove suppliers should be contacted to ensure that appropriate glove materials are selected for the specific chemicals involved [ OSHA 2002]. An analysis should be performed on each operation involving diacetyl, 2,3-pentanedione, or other food flavoring compounds to assess the potential exposures and to establish specific guidance about when to use skin, eye, and face protection. CDC (Centers for Disease Control and Prevention) [2007]. Fixed obstructive lung disease among workers in the flavor-manufacturing industry -California, 2004. CDC [2013]. # Medical Monitoring Medical monitoring of employees, sometimes called medical screening, involves periodic medical follow up for early detection of workrelated disease. The intended benefit of early detection is to identify disease in early stages when steps can still be taken to prevent progression from pre-clinical to clinical disease or from milder to more symptomatic disease. This approach is called secondary prevention because it attempts to ameliorate or at least halt the progression of health effects that have already occurred. Evidence of early disease identified through medical monitoring serves as a sentinel event or warning that other employees might be at risk for the same exposures and outcomes. This warning should stimulate efforts to evaluate the workplace to identify possible risk factors for exposures that can be controlled. Systematic evaluation and use of medical monitoring data obtained from individual employees to better protect a population of employees is an important component of the overall medical surveillance program. This approach contributes to the goal of primary prevention, to prevent disease from developing in other employees. # Medical Surveillance The systematic analysis of aggregated results over time constitutes medical (epidemiologic) surveillance of trends in symptoms or functional changes that can be assessed in relationship to jobs, tasks, and exposures [Silverstein 1990]. For medical monitoring to serve surveillance purposes, a formal process should be in place to assure that data from a screened employee population is evaluated in aggregate at regular intervals. Epidemiologic analysis of medical # Medical Monitoring Program Director The medical monitoring program director should be a licensed physician with training and experience in identifying and preventing occupational lung disease. This is because flavoring-related lung disease can progress rapidly and have grave consequences, so it is important to assure that the medical monitoring program director can quickly evaluate clinical data and make medical judgments about appropriate diagnostic and therapeutic measures, including medical removal. This individual (hereafter referred to as "the medical monitoring program director") should ensure that the monitoring program collects high quality data, including relevant questionnaire data and high quality spirometry tests that adhere to ATS/ERS technical guidelines for spirometry , or the most recent equivalent guidelines. The medical monitoring program director should also ensure that medical monitoring data is appropriately evaluated for surveillance purposes, including evaluation of aggregated results to identify risk factors and opportunities to better prevent flavoring-related lung disease. The employer should ensure that the medical monitoring program director is familiar with the natural history of flavoring-related lung disease and is knowledgeable about operating a spirometry program that maintains high test accuracy, precision and validity. The employer should provide the following to the medical monitoring program director: ■ A copy of the NIOSH Alert, "Preventing Lung Disease in Workers Who Use or Make Flavorings" [NIOSH 2003]; ■ A copy of this criteria document; ■ A description of work areas, job categories, and work tasks; ■ A description of any personal protective equipment to be used by employees; and ■ Results of any environmental sampling related to potential flavorings exposures. # Employees to Include in the Medical Monitoring Program All permanent, temporary, and contract employees who work in or enter areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds or products that contain these compounds are used or produced should be included in the medical monitoring program. Employees who work in or enter these areas for a total of 40 or more hours per year should be included in the medical monitoring program. In addition to production employees, employees who are periodically exposed such as supervisors, warehouse employees, laboratory employees, quality assurance/control employees, shipping and receiving employees, maintenance employees, janitorial employees, and office employees should also be included in the program, as employees with lung function abnormalities were identified in nonproduction jobs during several NIOSH HHE investigations . Employees with past experience in such jobs or performing such duties should be included in the monitoring program for one year and longer if abnormalities are present [California Department of Public Health 2012]. To achieve the intent of primary and secondary prevention, employers have an interest in attaining a high rate of employee participation in regular medical monitoring. Voluntary participation should be encouraged at a time and place convenient to employees and should be provided at no cost to employees. # Medical Monitoring Program Elements The medical monitoring evaluation should include a questionnaire to obtain health and exposure information and spirometry to assess lung function. The questionnaire data from all employees in a medical monitoring program should be entered into a database along with spirometry results for use in epidemiologic analyses for medical surveillance. These analyses may reveal associations between health outcomes and exposure variables such as work tasks and practices that can be addressed to decrease lung disease risk (see section 9.9). # Questionnaire The purpose of the questionnaire is to obtain standardized information on demographics, work history, exposures, personal risk factors such as smoking and health history. The medical monitoring program director can use information from the questionnaire when assessing the employee at each evaluation. Because employees with biopsy-documented obliterative bronchiolitis may have normal spirometry, chest symptoms such as exertional shortness of breath merit attention as suggestive of an occupational lung condition requiring employee education and follow up. Similarly, persons with abnormal spirometry, despite absent chest symptoms, may have occupational lung disease requiring attention. Work history questions should allow employees to correctly indicate the specific job titles they have held at their current employer. For each job title, the questionnaire should collect information on specific work tasks and practices that may affect the employee's exposure to diacetyl and similar flavoring compounds. For example, for an employee whose job requires direct handling of diacetyl-containing flavorings, specific questions might address how often a particular task is performed, the amounts of flavorings used, whether open or closed containers of flavorings are used, and whether respiratory protection is used, including the type of respirator used and when it is worn. To help the medical monitoring program director develop appropriate questions on jobs and exposures, the employer should provide the medical monitoring program director with the specific job titles of potentially exposed employees, a description of the work tasks for each job that may be associated with potential for exposure to diacetyl and similar flavoring compounds, and the types of personal protective equipment (e.g., respirators) and other measures that employees have available to them to minimize exposures in each job. A visit to the plant by the medical monitoring program director to view the production process may provide additional useful information for questionnaire development. The questionnaire should contain questions on the presence or absence of respiratory symptoms such as shortness of breath on exertion, cough, and wheezing; respiratory illnesses such as asthma, emphysema, chronic bronchitis, and COPD; and the dates of diagnosis. Additional questions might inquire about work-related nasal, ocular, and dermal symptoms. The American Thoracic Society Respiratory Symptom Questionnaire While respiratory symptom information is important in the assessment of employees exposed to diacetyl and similar flavoring compounds or products that contain these compounds, the medical monitoring program director should not conclude that an employee's exposures are below harmful levels solely by the absence of respiratory symptoms. Employees may not experience respiratory symptoms early in the course of excessive lung function decline. NIOSH medical surveys of flavoring-exposed employees have identified airways obstruction and excessive declines in lung function [NIOSH 2008] in employees who did not report respiratory symptoms. Similarly, about half of the employees with airways obstruction found in surveillance of California flavoring manufacturing employees had no chest symptoms [Kim et al. 2010]. Absence of symptoms does not negate the need for clinical differential diagnosis and evaluation of employees with spirometric abnormalities. The medical monitoring program director should counsel employees identified as having pre-existing lung disease on their initial evaluation regarding the potential risks of working in areas where they may be exposed to diacetyl and other flavoring compounds. The medical monitoring program director should also explain that it may be hard to determine the relative contributions of work exposures vs. pre-existing lung disease to any future abnormal lung function declines. Such employees should also be referred to their personal physician for additional evaluation and recommendations regarding potential exposure to these substances. # Spirometry Every employee in the medical monitoring program should have a spirometry test at each evaluation irrespective of respiratory symptom status. Evaluation of lung function over time is the most important component of medical monitoring for identifying possible workrelated lung disease in employees exposed to diacetyl and similar flavoring compounds (see section 9.6). High quality spirometry tests are necessary to allow the medical monitoring program director to correctly interpret the results and make appropriate recommendations to the employee and the employer. Accurate spirometry measurements depend on four key elements: (1) a trained technician who can obtain valid test results, ( 2) a reliable and accurate spirometer, ( 3) an approved testing protocol, and ( 4) a spirometry quality assurance program directed by a laboratory supervisor or the medical monitoring program director. # Spirometer specifications Spirometry testing equipment should meet the ATS/ERS guidance for standardization of spirometry or most recent equivalent , specifications for spirometer accuracy and precision, and real-time display size and content. Written verification from a third party testing laboratory (not the manufacturer or distributor) that the model of spirometer being used has successfully passed its validation checks as required by the most current ATS/ ERS protocol should be requested from the spirometer manufacturer. # Spirometry testing protocol and reporting information Administration of spirometry tests should follow the ATS/ERS guidance for standardization of spirometry or most recent equivalent Testing Procedures 1. Spirometer calibration checks should be performed using a currently calibrated (per manufacturer recommendations) 3-liter syringe on each day of testing . A copy of the spirometer calibration report should be maintained in either electronic or hard copy form. 2. Spirometry should be performed in the same documented position (either sitting or standing) during the baseline and all subsequent tests. 3. A minimum of three forced exhalation maneuvers producing "acceptable curves" on the spirometry report should be characterized by the following: ■ Lack of hesitation (back-extrapolation volume should be less than 5% of FVC or 150 mL, whichever is larger) ■ No cough in the first second of the maneuver ■ No evidence of airflow cessation, variable effort, leak, obstructed mouthpiece, positive or negative zero flow error(s), or extra breath(s) ■ Acceptable end-of-test criteria (≤ 25 mL increase in volume for 1 second or a maneuver longer than 15 seconds) 4. Less than 150 mL difference between the two highest FVC measurements and the two highest FEV 1 measurements is the goal. # Spirometry Predicted Values If spirometry software allows a choice of predicted values, NHANES III or the most recent equivalent should be used [Hankinson et al. 1999] as they are based on a large sample of the U.S. population. Because predicted values are not available from NHANES III for Asian people born in the United States, these predicted values may be estimated by multiplying the NHANES III Caucasian predicted values for FEV 1 and FVC by 0.88 [Hankinson et al. 2010;Redlich et al. 2014]. In the future, it will be preferable to use Asian-specific equations for predicted values, such as from NHANES Plus data, when they are available. If spirometry software does not include lower limits of normal values, the spirometry reference value calculator at http://www.cdc.gov/niosh/topics/ spirometry/RefCalculator.html can be used to calculate lower limits of normal for NHANES III reference values. ]. These guidelines outline the criteria to follow to ensure overall test results are valid (Figure 9-1). The technician should be able to view real-time testing displays as specified in the most recent ATS/ERS spirometry standardization. On-site back-up of the results should include spirometry test reports and retention of all spirometry test results in printed or electronic format. Spirometry test reports for the employee's health record should contain, at a minimum, the employee's age, height, sex, race, and weight; numerical values and volume-time and flow-volume spirograms for at least the three best valid expiratory maneuvers; normal reference value set used; employee position during testing (standing or sitting); dates of test and last calibration check; ambient temperature and barometric pressure (volume spirometers); and the technician's unique identification number or initials. The name, postal mailing and contact e-mail addresses, and telephone and fax numbers of the facility completing the spirometry test results and forms should also be recorded. Townsend 2011]. When suboptimal quality tests with potential for improvement are identified, the reviewing physician or other appropriate healthcare professional should provide feedback to the appropriate technician(s) along with specific suggestions for improvement. Some studies have found evidence that providing regular feedback to technicians improves test quality and decreases variability. In two studies where extensive feedback was provided to technicians on the quality of their tests, the investigators found lower measures of variability for their test measurements than in other studies where extensive feedback to technicians was not provided [Enright et al. 1991;Malmstrom et al. 2002]. In these studies, the technicians received immediate feedback from the spirometry device on the acceptability of a forced exhalation maneuver and on the overall quality of the test. The investigators also provided ongoing review of the quality of their tests and gave feedback to the technicians; additional technician training was provided as needed. Test quality in these studies was graded using an A, B, C, D, F scale. In a study of a workplace spirometry testing program, use of a new spirometer that provided technicians with feedback during the test led to increases in the mean FEV 1 and mean FVC of the study group, compared to use of an older spirometer without feedback capability [Banks et al. 1996]. With poor quality tests, some employees' results that are truly normal may be considered abnormal, and employers may incur costs for lost work time in follow-up testing and clinical evaluation. In addition, employees may suffer needless worry, risks of unnecessary medical tests, and may be subject to workplace discrimination or even job loss. An example of an incorrect interpretation due to a poor quality test is the finding of a restrictive abnormality because the test subject did not exhale long enough during the maneuver; this results in a falsely low FVC. High quality spirometry tests are also necessary for comparison of spirometry results over time, an important consideration for flavoring-exposed employees. Low quality spirometry has greater variability in test results; over time, decreased precision may cause the medical monitoring program director to incorrectly identify whether an employee has had an excessive decline in lung function from one test to the next. In reviewing the quality of spirometry tests performed for employers by private healthcare providers, NIOSH has identified instances where the quality of most tests was poor and thus not useful for assessing lung function changes over time Kreiss et al. 2012;NIOSH 2004bNIOSH , 2006]. High quality spirometry minimizes the variability in the results caused by technical aspects (i.e., how the test was conducted) so that changes in spirometry measurements over time reflect true changes in lung function more accurately. In California public health surveillance, only one of 13 commercial providers of surveillance spirometry for flavoring employees who reported results to the California Department of Public Health met a minimum quality criterion of 80% of test sessions with FEV 1 of good quality [Kreiss et al. 2012]. Employers of flavoring-exposed employees should be aware of the characteristics of high quality spirometry programs so they can evaluate the quality of spirometry services offered by medical providers, monitor performance, and take corrective actions if necessary. OSHA and NIOSH have published an information sheet on spirometry for employers [NIOSH 2011b]. # Frequency of Medical Monitoring Evaluations Newly hired employees and current employees should have baseline evaluations before they are allowed to work in or enter areas as previously described where they may be exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds. Employees in the medical monitoring program should be evaluated with a questionnaire and spirometry every 6 months due to the potentially rapid development of flavoring-related lung disease [Redlich et al. 2014]. If an employee exposed to diacetyl or similar flavoring compounds is identified as likely having lung disease from this exposure, then all employees who perform similar job tasks or have a similar or greater potential for exposure should be evaluated every 3 months. # Reporting Medical Monitoring Results The medical monitoring program director or designee should review and interpret questionnaire and spirometry results, including assessing spirometry quality. During an employee's scheduled visit for a medical monitoring program evaluation, the medical monitoring program director or designee should inquire about the employee's knowledge of the potential risk from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds and of how to minimize the risk. The medical monitoring program director or designee should educate employees as needed [California Department of Public Health 2012], and encourage employees to report any new persistent respiratory symptoms to their supervisor or the monitoring physician. At the end of each evaluation visit or as soon as possible thereafter, the medical monitoring program director should provide the employee with a written report describing the following items: ■ The results of any medical tests performed on the employee ■ The medical monitoring program director's opinion regarding any abnormalities detected during the evaluation and recommendations for further evaluation and treatment ■ Whether or not the employee has any detected medical condition which would place the employee at increased risk to health from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds ■ Recommendations, if necessary, for reducing the employee's exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds ■ Any recommended limitation upon the employee's use of personal protective equipment. The medical monitoring program director should inform the employer in writing of the following: ■ Any recommendations for limiting the employee's workplace exposures (e.g., reducing exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds by removal, or limitations of the employee's duties or activities) or on the employee's use of personal protective equipment ■ A statement that the physician has informed the employee of the results of the medical examination and any medical conditions that require further evaluation or treatment. The specific condition, issue, or concern resulting in recommendations for limiting the employee's exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds or on the employee's use of personal protective equipment should not be specified in the write-up to the employer without the employee's consent. Also, any aspect of the employee's medical history that has no bearing on whether the employee should continue to work in areas where diacetyl, 2,3-pentanedione, or similar flavoring compounds are used should not be revealed to the employer. A copy of the medical monitoring program director's written opinion provided to the employer should also be provided to the employee. # Early Identification of Affected Employees Early recognition of employees with lung disease due to exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds is essential to prevent rapid progression to severe irreversible disease. Identifying affected employees will also stimulate prevention efforts so that risk to other employees is minimized. The most effective means for identifying affected employees early is careful evaluation of results of serial spirometry tests of employees in the medical monitoring program. Symptom reports alone are not a reliable indicator of early disease, as many employees with early disease will be asymptomatic. However, symptom reports of exertional shortness of breath can reflect pathologic obliterative bronchiolitis even when spirometry remains normal [ Kreiss 2013]. At each evaluation of an employee in the medical monitoring program, the medical monitoring program director should compare the results of the current spirometry test to the baseline (pre-exposure) test, or to the test with the highest values if post-hire spirometry values were higher than at baseline. The most important finding that may indicate development of lung disease from exposure to diacetyl, 2,3-pentanedione, or similar flavoring compounds is an abnormal decline in the FEV 1 . An employee's longitudinal test results may reveal an abnormal decline in FEV 1 compared to baseline even when each individual test value is found to be normal because it is above the LLofN calculated from the reference population [Townsend et al 2011;Kreiss et al. 2012;Redlich et al. 2014]. While such test results might not meet the criteria for an abnormality such as airways obstruction or spirometric restriction, an abnormal decline in FEV 1 may indicate early disease in this case and should be further evaluated. Additionally, any new abnormality on spirometry compared to baseline should prompt further evaluation. Flavoring-exposed employees with obstructive abnormalities (FEV 1 /FVC ratio and FEV 1 less than the LLofN) need additional medical tests to assess whether they have obliterative bronchiolitis. Employees with restrictive abnormalities (FVC less than LLofN and normal FEV 1 /FVC ratio) also need additional medical tests to differentiate between nonlung causes and lung causes of spirometric restriction, including obliterative bronchiolitis [Ghanei et al. 2008;King et al. 2011;Markopoulou et al. 2002]. The criteria for an abnormal excessive decline in the FEV 1 depend on the quality of the spirometry tests performed as part of the medical monitoring program and the time period of follow-up [Redlich et al. 2014]. ATS/ERS and ACOEM have stated that a decline in FEV 1 over one year should exceed 15% before being considered clinically meaningful Townsend 2011]. By this criterion, someone with a baseline FEV 1 of 4 liters would 234 Occupational Exposure to Diacetyl and 2,3-Pentanedione have to experience a decline of at least 600 mL for the results to be considered abnormal. Because lung disease caused by flavorings can progress rapidly, it is useful to identify those potentially at risk before so much lung function is lost NIOSH 2006NIOSH , 2007. Some studies indicate that when ATS/ ERS criteria for spirometry quality are followed and high standards of quality are achieved, a threshold less than 15% can indicate an abnormally rapid decline in FEV 1 in a year. In a study that used data from a spirometry surveillance program for coal miners, Wang and Petsonk [2004] found that the 5th percentile for FEV 1 declines over 6 months in all employees studied was 320 mL (7.8%). In stable employees (those employees whose FEV 1 slope over 5 years was less than 90 mL/year), it was 300 mL (7.1%). In healthy employees (those employees without symptoms or methacholine responsiveness over 5 years), it was 280 mL (6.5%). The quality of spirometry data in this study reflected a withinperson variation of 3% that is rarely achievable. Within-person variation of 6% is typical for spirometry programs, and an assumption of that level of variability was used by ATS to develop its recommendation for using 15% loss of FEV 1 as a threshold [Redlich et al. 2014]. In another study that used data with a withinperson variation of 4% from a spirometry surveillance program for thousands of employees at a large chemical company, Wang et al. [2006] found that the 5th percentile values for FEV 1 decline for testing at one-year intervals were 380 mL (10.4%) in men and 280 mL (10.6%) in women. These studies suggest that in a medical monitoring program that follows ATS/ERS criteria and achieves high quality spirometry, an FEV 1 decline of 10% or higher in one year or less can be considered abnormal and used as a threshold for further medical evaluation of the employee. ACOEM now accepts this 10% criterion after allowing for expected average annual loss due to aging in high risk settings when the relationship between longitudinal results and endpoint disease is clear, as in flavoring-exposed employees [Townsend 2011]. Lower quality spirometry programs have the disadvantage of only being able to detect larger declines in FEV 1 as abnormal. NIOSH has developed a computer program, SPIROLA, to help spirometry programs measure their within-person variation in FEV 1 as a measure of the precision of spirometry obtained by the spirometry providers (an indication of spirometry quality across the providers' programs). SPIROLA also provides a longitudinal limit of decline (LLD) for each individual tested, a threshold for determining abnormal loss of FEV 1 that is adjusted for the quality of the provider's spirometry program [NIOSH 2010]. The LLD allows the spirometry provider to determine if an individual's serial spirometry results suggest an excessive decline in lung function and allows higher quality programs to identify smaller changes in lung function as abnormal (http://www. cdc.gov/niosh/topics/spirometry/spirola-software.html). The advantage of using relative lower LLD and 5th percentile approaches over the 15% criterion in flavorings-exposed microwave popcorn employees has been demonstrated [Chaisson et al. 2010]. # Continuity of Medical Monitoring Employers may change medical providers of medical monitoring services. Employers should ensure that prior medical monitoring program directors transfer medical monitoring records, including spirometry tests and questionnaires, to new medical monitoring program directors. If necessary to gain access, employers or new providers should ask employees to sign releases allowing new providers to obtain previous medical monitoring and surveillance records from previous provider(s). Occupational Exposure to Diacetyl and 2,3-Pentanedione 235 The first step in evaluating an employee whose medical monitoring spirometry test shows either an excessive decline in FEV 1 (even if individual test results are still above the LLofN) or a new abnormality (e.g., obstructive, restrictive, or mixed spirometric abnormality) compared to baseline is to repeat the test within one month to confirm the change. If the repeat spirometry test confirms an excessive decline in FEV 1 or other abnormality, the employee should be referred for more extensive pulmonary function tests (PFTs) (described below). The medical monitoring program director may request these and other necessary tests or refer the employee to a pulmonary medicine physician at no cost to the employee. # Other Pulmonary Function Tests The referred employee should receive complete PFTs that include spirometry with an assessment of bronchodilator response, DLCO, and static lung volumes. Most employees who have developed lung disease while being exposed to diacetyl and similar flavoring compounds have not had a response to bronchodilator Kim et al. 2010]. In other words, they had fixed airways obstruction with an FEV 1 and/or FVC increase less than 12% and 200 mL after bronchodilator) . DL CO in affected employees with airways obstruction has usually been normal, although some individuals with advanced disease have had a low DL CO . Lung volume measurements have shown a normal or elevated total lung capacity (TLC) and an increased residual volume, consistent with air trapping ]. Individuals with moderate to severe airways obstruction may have a mixed obstructive/ restrictive (reduced FEV 1 , FEV 1 /FVC ratio, and FVC) pattern of spirometry because air trapping decreases the FVC. The actual underlying physiology can be clarified by determining lung volumes. # High-resolution Computerized Tomography Employees found to have fixed airways obstruction or other abnormalities on complete PFTs should have additional evaluation with a highresolution computerized tomography (HRCT) scan of the chest with inspiratory and expiratory views. Heterogeneous air trapping during expiration has been the most common finding in flavoring-exposed employees with fixed airways obstruction. Other common findings include cylindrical bronchiectasis, bronchial wall thickening, and a mosaic pattern of attenuation. Centrilobular nodules may also be seen [Cox et al. 2014]. Patchy ground glass opacities have been observed less commonly. These findings may not be present despite obliterative bronchiolitis documented by biopsy [King et al. 2011]. HRCTs have not been systematically performed in flavoring-exposed employees with restrictive pulmonary function abnormalities or with excessive FEV 1 declines within the normal range of FEV 1 . Specialist consideration of the diagnostic utility of this test is suggested. # Lung Biopsy It is not routinely necessary to obtain a lung biopsy to diagnose obliterative bronchiolitis in employees exposed to diacetyl or 2,3-pentanedione when spirometry and HRCT results are consistent with the diagnosis. While some physicians might desire biopsy confirmation, it is important to recognize that the patchy nature of obliterative bronchiolitis and lack of familiarity of some pathologists with the techniques necessary to identify bronchiolar lesions may prevent identification of the disease on biopsy. HRCT has become the method of choice for assessing 236 Occupational Exposure to Diacetyl and 2,3-Pentanedione bronchiolar morphology, often replacing surgical lung biopsy [King and Kinder 2008]. Physicians caring for another population at high risk for obliterative bronchiolitis, lung transplant patients, use a similar noninvasive approach. Obliterative bronchiolitis commonly occurs after patients receive a lung transplant. Because this disease is difficult to identify on biopsy, the International Society for Heart and Lung Transplantation developed a clinical description for the disease termed bronchiolitis obliterans syndrome. The syndrome refers to graft deterioration secondary to persistent airflow obstruction as defined by pulmonary function changes with or without biopsy confirmation [Estenne et al. 2002]. The term bronchiolitis obliterans syndrome has also been applied to flavoring-exposed employees without surgical lung biopsies ; , but may lead to confusion because flavoring-related obliterative bronchiolitis differs in natural history from post-transplant bronchiolitis obliterans syndrome, which is relentlessly progressive. There are some situations, described in the next section, where lung biopsy is appropriate for diagnosis. To obtain adequate tissue for diagnosis, a thoracoscopic or open lung biopsy should be obtained. Obtaining wedge biopsies from multiple lobes is recommended, as this approach increases the diagnostic yield [Devakonda et al. 2010]. Transbronchial lung biopsies are not useful for evaluating clinical obliterative bronchiolitis in employees exposed to diacetyl, 2,3-pentanedione, or similar compounds. # Determining Diagnosis Responsible for Lung Disease Determination of the diagnosis responsible for lung disease in an employee exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds should take into account the changes identified in medical monitoring spirometry tests, the results of complete PFTs and of HRCT scans of the chest, the course of the employee's illness over time, and medical, work, and personal risk factor history. In an exposed employee with evidence of clinical obliterative bronchiolitis on PFTs or HRCT scans and no other identifiable cause for the disease, biopsy is not necessary. The noninvasive clinical findings alone are sufficient to conclude that an exposed employee likely has clinical obliterative bronchiolitis and should no longer be exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds. When clinically apparent lung disease occurs in several employees at a particular plant, the need for biopsy confirmation in each employee is usually unnecessary. When HRCT is normal in dyspneic employees, particularly if the PFTs are restrictive or normal, lung biopsy has a role. Some medical surveys of flavoring-exposed employees have revealed an increased prevalence of an isolated restrictive pattern on spirometry (i.e., without concurrent airways obstruction), but static lung volume measurements of TLC and biopsies have not been available in these studies to confirm restrictive lung disease [Kreiss 2012;NIOSH 2009NIOSH , 2011c. The evidence for restrictive and normal pulmonary functions in obliterative bronchiolitis is in patients exposed to other lung hazards, such as sulfur mustard gas and in U.S. soldiers serving in Iraq and Afghanistan, some of whom had sulfur dioxide exposure. Despite evidence from three biopsy-confirmed case series of obliterative bronchiolitis [Ghanei et al. 2008;King et al. 2011;Markopoulou et al. 2002], many pulmonary and occupational medicine specialists are not aware of the range of spirometric findings in this disease and may be reluctant to diagnose obliterative bronchiolitis in patients with spirometric restriction or normal spirometry without pathologic confirmation. Employees who develop restrictive abnormalities or who have excessive parallel FEV 1 and FVC declines should have assessment of lung volumes, diffusing capacity, and HRCT to differentiate between restrictive lung disease and other causes of restrictive spirometric patterns. Further evaluation of restrictive lung disease for a specific diagnosis should be pursued as clinically appropriate and may require biopsy. Case reports of pathologic findings in dyspneic flavoring-exposed employees with restrictive or normal spirometry will be of interest in further guidance for clinicians responsible for the lung health of such employees. The evaluating physician should exclude alternative causes of respiratory disease such as work-related asthma (new onset asthma or exacerbation of pre-existing asthma). An employee with no past asthma history who experiences post-hire recurrent respiratory symptoms and has airways obstruction responsive to bronchodilator on PFTs (reversible airways obstruction) may have new onset asthma due to workplace exposures. If an employee with asthma symptoms does not have changes over time on medical monitoring spirometry, a methacholine or mannitol challenge test may be necessary to determine if the employee has airways hyperresponsiveness as occurs in asthma. Worsening symptoms in an employee with pre-existing asthma may be due to exposure to diacetyl, similar flavoring compounds, or other agents in the workplace ]. An important consideration for diacetyl-exposed employees with worsening pre-existing asthma or new onset reversible airways obstruction is that this may actually reflect early disease that may ultimately progress to clinical obliterative bronchiolitis. An employee at a California flavoring plant who had stable pre-existing asthma (no symptoms at time of hire) developed progressive shortness of breath and was found to have severe fixed airways obstruction on PFTs; a lung biopsy showed evidence of bronchiolitis obliterans [NIOSH 2007]. Employees with worsening pre-existing asthma or new onset reversible airways obstruction should be evaluated with an HRCT scan of the chest to determine if findings consistent with clinical obliterative bronchiolitis are present. However, because HRCT abnormalities may be insensitive in detecting early or mild disease, such asthmatic employees require careful and frequent follow-up [King et al. 2011]. An employee exposed to diacetyl, 2,3-pentanedione, or similar flavoring compounds who has normal pre-exposure spirometry and subsequently develops fixed airways obstruction and has evidence of air trapping on complete PFTs or on HRCT scan, or has an excessive decline in FEV 1 and whose pulmonary function does not improve after exposure cessation, likely has clinical obliterative bronchiolitis due to this exposure. In exposed employees who smoke, fixed airways obstruction should not be attributed to smoking if there is no evidence of emphysema on medical tests. Clinically significant emphysema occurs in a subset of smokers after many years of smoking; it is uncommon in smokers less than 50 years old [Wise 2008]. In middle-aged and older smoking employees, work history, clinical course, and medical tests are important in attempting to differentiate between smoking-related COPD and flavoring-related obstruction. Smoking explains about 80% of COPD in the United States, with about 15% attributable to work exposures. Smoking diacetyl-exposed employees appear to have lower excess risk of obstruction than never-smoking flavoringexposed employees . # 238 Occupational Exposure to Diacetyl and 2,3-Pentanedione # Response to Identification of Workrelated Lung Disease Employees with abnormalities identified on medical monitoring spirometry should be counseled about the risks of further exposure and that removal from exposure is prudent because of the irreversibility of the disease, short latency, and often rapid progression. Employees who receive a diagnosis of flavoringrelated lung disease or who have findings on medical evaluation that indicate likely clinical obliterative bronchiolitis or other lung disease due to workplace exposures should be placed on work restrictions to prevent any further exposure to flavoring compounds or other substances in the workplace that may cause their lung disease to worsen. Personal protective equipment is the least effective means for controlling employee exposures. The proper use of personal protective equipment requires a high level of employer and employee involvement and commitment to be effective. The use of respiratory protection is not equivalent to removal from exposures because employees may still be exposed due to incomplete compliance, selection of an inappropriate respirator, or respirator malfunction [California Department of Public Health 2012]. If possible, employers should offer affected employees the opportunity to transfer to available jobs in work areas that have minimal or nonexistent exposures. Such employees should retain seniority, wages, and benefits. Employers of an employee with confirmed or likely flavorings-related lung disease should arrange for an industrial hygiene evaluation of the plant areas where the employee had been assigned. The evaluation may identify aspects of the production process or work practices where control strategies can be implemented to minimize exposures. This may prevent additional employees from developing work-related lung disease. Medical monitoring evaluations of employees in these areas should increase in frequency from every 6 months to every 3 months, with a return to 6-month intervals after factors that may have led to excessive exposure have been corrected and 12 months have passed during which no additional employees with likely flavoring-related lung disease are identified (see section 9.4). When informed, employers should record all flavoring-related lung disease cases in the OSHA Form 300 Logs of Work-Related Injuries and Illnesses. # Medical Surveillance Analyses A workplace assessment conducted after identification of a sentinel case of work-related lung disease may reveal sources of uncontrolled exposures from particular aspects of production processes and work practices that can be improved to prevent other employees from becoming affected. However, this approach may not identify all such risk factors for hazardous exposure in a given workplace. Additional risk factors may be identified through a medical monitoring and surveillance program, which includes the use of epidemiologic techniques for analyses of aggregated data obtained from evaluations of all employees in a medical monitoring program. Such analyses show trends and distributions of health outcomes by exposure variables such as work area, job category, and work task. In some instances, the results of such analyses may provide early evidence of risk factors that can be addressed before employees develop significant lung disease. Because production processes and work practices in manufacturing plants that use diacetyl or similar flavoring compounds or products that contain these compounds vary from plant to plant, medical surveillance may also allow identification of risk factors unique to a particular plant. For these reasons, systematic evaluation of medical monitoring data is an important component of medical monitoring and surveillance programs for employees exposed to diacetyl or similar flavoring compounds. If the medical monitoring program director is not able to conduct such analyses, the employer or medical monitoring program director should arrange for consultants with expertise in epidemiology to undertake this task. Two examples below show how medical surveillance can help to identify lung disease risk factors in the workplace. Example 1. At the plant where microwave popcorn employees were first identified as being at risk for severe fixed airways obstruction consistent with clinical obliterative bronchiolitis from exposure to butter flavoring vapors (index facility G), four known affected former employees had worked in the mixing room as mixers of oil and butter flavorings, and four other affected former employees had worked on the packaging lines near the mixing room. A medical survey of current employees showed that the prevalence of airways obstruction on NIOSH spirometry tests was 3.3 times higher than expected in comparison to U.S. population data, a finding that was consistent with the known disease in former employees. The environmental assessment showed that air concentrations of the butter flavoring compound diacetyl were highest in the mixing room. The next highest exposures were in the packaging line area because of contamination from the mixing room, which was not isolated from the rest of the plant. Diacetyl air concentrations in other parts of the plant were lower. Analyses of the medical and environmental data showed a dose-response relationship between abnormal spirometry and quartiles of estimated cumulative exposure to diacetyl NIOSH 2006]. Additional analyses of the medical survey data revealed an unexpected finding: Among current employees, the highest prevalence of airways obstruction was found in QC laboratory employees, five of six (83%) of whom had airways obstruction . These employees popped approximately 100 bags of microwave popcorn in microwave ovens per 8-hour shift. The mean time-weighted average diacetyl air concentration in the QC laboratory was 0.8 ppm compared to approximately 57.2 ppm in the mixing room and 2.8 ppm for machine operators in the packaging line area. QC laboratory employees may be at risk for lung disease because they experience intermittent peak exposures to vapors of diacetyl from microwave popcorn bags during and after popping in microwave ovens; mixers experience similar intermittent peaks when they add butter flavorings to tanks of heated oil [NIOSH 2003]. Another possible explanation is that the much higher temperatures that occur in microwave popping (compared with the temperatures in heated tanks of oil and butter flavorings) increase the volatilization of other chemicals. QC laboratory employees' exposures may be substantially different from those of other production employees; diacetyl air concentrations alone may not be a satisfactory predictor of risk for these employees. Because of this evidence of risk to QC laboratory employees, NIOSH recommended implementing exposure controls in the QC laboratory in addition to the mixing room and packaging line area NIOSH 2006]. In evaluations at five other microwave popcorn plants, NIOSH found evidence of affected mixers in four plants and evidence of affected packaging line employees in one plant . No other plant had an elevated prevalence of airways obstruction in QC employees. Fewer bags of microwave popcorn were popped per employee per day in those plants, and the mean time-weighted average diacetyl air concentrations in the QC laboratories were lower than at index facility G. # 240 Occupational Exposure to Diacetyl and 2,3-Pentanedione Example 2. At a microwave popcorn plant where a young mixing room employee developed moderately severe fixed airways obstruction and other findings consistent with clinical obliterative bronchiolitis, management had put a mandatory respirator use policy for mixing room employees in place soon after the company first started production. In addition to using respirators, the company had also ventilated and isolated the mixing room from the rest of the plant and had local exhaust ventilation for tanks of heated oil and butter flavorings. Butter flavorings were handled in open containers as they were at other microwave popcorn plants. The respirators used were full facepiece respirators with organic vapor cartridges and particulate filters. Included in the questionnaire that NIOSH administered to current employees during a medical survey at the plant were questions about respirator use for the following work tasks: (1) weighing or handling open containers of flavorings, ( 2) pouring flavorings into tanks in the mixing room, (3) pouring other ingredients into tanks in the mixing room, ( 4) checking the levels in the tanks, and ( 5) other duties in the mixing room. Thirteen current employees reported ever having worked as a mixer; six had abnormal lung function on NIOSH spirometry tests. The reported percentages of time these employees used respirators during these activities ranged from 0% to 100%. The median reported percentage of time was 20% for all activities, except for those where other ingredients (not flavorings) were poured into tanks in the mixing room where the median was 50% [NIOSH 2004a]. These results showed that employees were not fully compliant with management's respirator use policy; management was able to address this problem through employee education and enforcement of the policy. Had the company become aware of this problem earlier by regularly collecting and evaluating information on respirator use during medical monitoring evaluations, it could have increased compliance with respirator use and thus minimized some employees' exposures to butter flavoring compounds. (Before 2001 when NIOSH informed microwave popcorn companies of the risk of severe lung disease to employees exposed to butter flavorings, the company had been unaware of the respiratory toxicity potential of diacetyl. The company had implemented a mandatory respirator use policy for mixing room employees many years earlier to prevent severe eye irritation that employees had experienced when handling certain flavorings.) Thus, analysis of population data generated by medical monitoring and surveillance programs plays an important role in primary prevention by helping employers of flavoring-exposed employees to recognize and take steps to characterize and correct hazardous conditions. Recognition can require epidemiologic evaluation of medical monitoring, population, and environmental data. It is therefore important for employers to ensure that this applied epidemiology is provided as part of the medical monitoring and surveillance program. Employers should develop and implement comprehensive occupational safety and health programs to prevent occupational injuries, illnesses, and deaths. To be successful, safety and health programs should be developed and implemented as part of an employer's management system, with strong management commitment, employee involvement, and occupational safety and health expertise. A safety and health program designed to protect employees from the adverse effects of exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds should include mechanisms to identify all risk factors for exposure to flavoring substances. Just as medical monitoring is part of an overall occupational safety and health program, so is exposure monitoring. Exposure monitoring should be conducted whenever there is workplace exposure to diacetyl or 2,3-pentanedione. # Exposure Monitoring Program Goals A workplace exposure monitoring program should have clear, stated goals [Mulhausen and Damiano 1998]. Site-specific exposure assessment strategies should be developed to accomplish each of these goals: (1) to determine employee exposure to diacetyl, 2,3-pentanedione, and other flavoring compounds used in the workplace; (2) # Exposure Monitoring Program Elements Proper measurement of contaminants in the environment involves a variety of program elements. The sampling and analytical methods referred to in this chapter include an outline of tested and validated procedures that produce statistically reliable data when used in the manner prescribed. Several of the more significant elements of a monitoring program are described below [Gross and Pechter 2002;Milz et al. 2003;Soule 2000]. Where possible, a written sampling strategy or protocol should be developed prior to sampling; this protocol should guide all aspects of the sampling process. The protocol should contain a description of ( 1) the objectives of sampling, (2) what to sample, ( 3) whom and where to sample, ( 4) how to sample, ( 5) when to 246Occupational Exposure to Diacetyl and 2,3-Pentanedione sample, ( 6) how long to sample, ( 7) how many samples to collect, and ( 8) how to handle, store, and ship samples [Gross and Pechter 2002;Milz et al. 2003;Soule 2000]. A walk-through survey or preliminary worksite visit is often useful in developing the sampling strategy [Jennison et al. 1996] and knowledge of the data-keeping system to be used to store and retrieve subsequent information can also have an effect. The sampling strategy should be developed to facilitate data analysis and interpretation for the specific exposure assessment goal. # Objectives of Sampling Sampling as part of an exposure monitoring program for diacetyl, 2,3-pentanedione, and other flavoring substances has several objectives. Often, this sampling is part of a comprehensive assessment to identify and quantify exposure hazards throughout a designated plant or work area to protect employees' health. The frequency of monitoring will depend on the purpose and rationale of the sampling campaign. Specific sampling objectives can include: (1) Characterizing (qualitatively or quantitatively) the flavoring compounds present in workplace air or in bulk materials (2) Ensuring compliance with existing OELs (3) Assessing the effectiveness of engineering controls, work practices, PPE, training, or other methods used for exposure control (4) Identifying areas, tasks, or jobs with higher exposures that require additional exposure control (5) Evaluating exposures related to production process changes and from changes in products made or materials used (6) Evaluating specific high risk job categories to ensure that exposures do not exceed exposure standards or guidelines (7) Measuring exposures of employees who report symptoms or illnesses Sampling can also be used to assess any fugitive emissions from plant processes into the surrounding community. Exposure monitoring should be conducted by qualified professionals. The sampling strategy should provide an opportunity to determine each employee's exposure, either by direct measure using personal breathing zone samples or through reasonable estimates based on the sampling of similar work tasks or jobs. Sampling strategies that group employees according to exposure zones, uniform job titles, or functional job categories have been used in some industries to reduce the number of required samples while increasing the confidence that all employees at similar risk will be identified [Mulhausen and Damiano 1998]. Area sampling may also be useful in exposure monitoring for determining sources of airborne contaminants and assessing the effectiveness of engineering controls. When sampling to determine whether employee exposures are below an OEL, a compliance sampling strategy, and/or a "focused strategy," that targets employees perceived to have the highest exposure concentrations may be more useful than random sampling. A focused strategy is most efficient for identifying exposures above the OEL if maximum-risk employees and time periods are accurately identified. Focused sampling may help identify short-duration tasks involving high airborne concentrations that could result in elevated exposures over a full work shift and also tasks that result in exposures over the STEL. # What to Sample (Specific Agents and Physical States) Because flavorings can consist of many chemicals in addition to diacetyl and 2,3-pentanedione, deciding what to sample often requires preliminary knowledge of the specific flavoring compounds being produced or used, or that are present in flavorings or other food ingredients used in the workplace, and the known exposure hazards posed by each. Information on possible food and flavoring compounds present in workplace air can be obtained from reviews of product ingredient lists, flavor or food recipes, SDSs, and other information provided by the employer or flavor manufacturer [Gross and Pechter 2002]. In the flavor manufacturing industry, the recipe for each flavoring indicates the chemicals, solvents, and other ingredients used in the formulation. In the food manufacturing industry, this information may be available directly from the company or from SDSs for all flavorings and other ingredients used, although some flavoring SDSs do not list all potentially hazardous chemicals that may be present. Additional information may be needed from the flavoring manufacturers. Often, qualitative characterization may be useful prior to quantitative measurement to better guide the selection of substances to measure in the workplace. A review of any past exposure assessment reports from the target workplace or similar workplaces, may also be helpful in selecting which agents to sample. In either case, a list of substances to which employees will potentially be exposed should be developed to help determine which of those compounds are the most critical to sample [Mulhausen and Damiano 1998]. In instances where a company has stopped using diacetyl and 2,3-pentanedione in a flavor or food product, this list should include the butter flavor substances substituted for diacetyl or 2,3-pentanedione. Determining which chemicals to sample and measure should be based upon the chemical, physical, and toxicological properties as well as the chemical quantities in use. For example, industry reference materials may provide helpful information on which flavoring compounds to use or avoid [FEMA 2012]. Other databases that might prove helpful may include but are not limited to National Library of Medicine (Hazardous Substances to represent the exposures of those groups [Mulhausen and Damiano 1998;NIOSH 1977]. Area sampling may be useful for determining sources of airborne contaminants and identifying the worst-case chemical concentrations in various locations or processes. Selection of which employees or work locations should be sampled can help to characterize (confirm or refute) suspected areas of potential concern. # How to Sample A variety of methods are available to sample for diacetyl, 2,3-pentanedione, or other food and flavoring substances. These include ( 1) gas and vapor air methods, ( 2) methods to sample particulates in air, ( 3) direct reading and real-time methods for gases/vapors and for particulates, ( 4) evacuated container sampling methods, ( 5) particle size distribution methods, ( 6) bulk air methods, and ( 7) bulk material methods. Selecting appropriate sampling and analytical methods and using professionally accepted techniques maximize the validity of measurements of flavoring compounds in the work environment. While the state of the art in measuring diacetyl and 2,3-pentanedione continues to evolve, the methods with the most veracity at the time of publication of this document are OSHA Methods 1012 and 1013 for diacetyl and OSHA Method 1016 for 2,3-pentanedione. Some sampling and analytical methods for diacetyl, 2,3-pentanedione, and other flavoring compounds published by NIOSH at http:// www.cdc.gov/niosh/nmam/ and by OSHA at http://www.osha.gov/dts/sltc/methods/index. html are described in detail in Chapter 2 of this document and are presented in Appendices A-E. These methods include recommendations on sampling media, flow rate, duration, storage, shipment, sampling and analytical equipment, and procedures. A typical protocol for measuring diacetyl and 2,3-pentanedione is presented in Appendix I. To minimize the likelihood of inaccurate results, sampling equipment should be maintained in reliable working order through proper care and maintenance. All equipment should be regularly inspected and cleaned; sampling pumps should be calibrated before and after each use. Because differences in pressure drop across the sampler affect flow rate, each sampling pump should be precalibrated and postcalibrated with the specific type of sampling media used for sampling. Careful record keeping in the field is also important. A detailed description of the work tasks conducted and the processes and materials involved is essential. Pertinent information such as sampling location, job category or task, air temperature, relative humidity, and possible interfering compounds in air should be documented. To avoid confusion in the laboratory, samples should be carefully labeled and accompanied by accurate paperwork. The exact sampling duration should be known to accurately calculate the sampled volume. Determining the sampling duration from the recorded start and stop times assumes that the pump functions consistently over the entire sampling period. Occasional spot checks to verify proper sampler operation should be made throughout the sampling period. Personnel performing field sampling should not overlook quality assurance procedures. The field sampling parameters, such as calibration checks and accurate timing, often affect precision and accuracy of the final result more than the measurement's parameters. Field personnel should devote time to learning the sampling and analytical methods and sampling equipment operation procedures prior to arriving at the sampling site. These methods usually specify the sampling media to be used, the correct flow rate and sample volume, as well as special precautions of sample handling, shipping, and possible interferences. Because many modern analytical techniques are extremely sensitive, care should be taken to avoid contaminating field samples. Samples should not be stored or shipped with bulk materials that might spill or otherwise contaminate the field samples. The glassware or other containers used in sampling and shipping should be cleaned as recommended in the analytical method. For many sampling methods, the analytical laboratory requires submission of a specific number of blank samples with each set of samples to be analyzed; this number of samples is specific to the method. Blanks are used to mitigate the potential for unrecognized contamination due to media or sample handling [ NIOSH 1994]. The two types of sample blanks are field blanks and media blanks. Field blanks are unopened new samplers or media taken to the sampling site and handled in every way like the actual samples, except that no air is drawn through them. Media blanks are simply unopened new samplers or media that are submitted to the laboratory with the samples (these blanks are not usually taken to the field). Additional blind field blanks, labeled as field samples, should be sent along with the field samples as a further check on the analysis. Another occasionally used quality control practice is to include spiked samples-samples with known amounts of flavoring substance addedalong with the other field samples sent to the laboratory for analysis. These spiked samples are often prepared by a separate laboratory and then included with the other field samples sent to the analytical laboratory. They are labeled as field samples so that the analytical laboratory is blinded to their identity as spiked samples. The variety of types of direct-reading methods available for monitoring specific gases and vapors, as well as general contaminant concentration, is large and expanding. Detector tubes (short-term and long-term), also referred to as colorimetric indicator tubes, are widely used sampling devices for obtaining immediate, quantitative measures of gas or vapor concentrations in air. Also, aerosol monitors, integrating passive monitors for certain gases, and portable instrumentation for gas chromatography or infrared spectroscopy, are becoming more commonly used for measuring exposures to flavoring compounds [ACGIH 2001;Soule 2000]. Many direct-reading instruments now used for personal or area measurements have evolved from laboratory or process control instruments. These types of monitoring techniques have significant advantages, although to date none of these methods has been validated for monitoring diacetyl, 2,3-pentanedione, or other flavoring compounds in the work environment. # When to Sample Because of the considerable variation in exposure during the production of food or flavoring products, individuals conducting air sampling should coordinate with plant management to ensure that sampling is conducted when food or flavoring products of particular interest are being manufactured. Sampling several products or production runs may be necessary to better characterize exposures. Additionally, some products may be produced infrequently, and production schedules may change rapidly, so the timing of sampling can be challenging. Exposure monitoring should be conducted whenever changes in production processes, controls, work practices, or other conditions indicate a potential change in exposure conditions. In order to determine compliance with STEL criteria, sampling should be done during tasks that are considered likely to produce the highest short-term exposures. A series of sequential or overlapping samples can be taken for 15-minute intervals to determine the maximum exposures. # How Long to Sample In general, TWA exposures should be determined by collecting samples over a full work shift, for comparison with OELs and other toxicological data. Information on allowable sampling duration is given in validated sampling and analytical methods; depending on the method, in some instances it is necessary to collect multiple shorter-term samples to obtain an integrated full work-shift sample. Work shifts that exceed 8 hours require extended sampling duration. When the potential for exposure to diacetyl, 2,3-pentanedione, or flavoring compounds is sporadic throughout a work shift, shortterm or task-based sampling may be needed to replace or supplement full-shift sampling. Short-term samples for diacetyl and 2,3-pentanedione can be collected for 15 minutes in duration. Data from these short-term measurements and other task-based sampling can provide valuable perspective on task-based exposures and on the effectiveness of various control techniques. They can also be used to evaluate exposures relative to a short-term exposure limit [Milz et al. 2003] such as the STEL values recommended for diacetyl and 2,3-pentanedione. # How Many Samples to Collect The numbers of samples to collect is important in that it relates to the confidence that can be placed in the exposure estimate. The number of samples needed for an accurate and reliable exposure assessment depends on the purpose of the sampling, the number of processes, work tasks or jobs to be evaluated, the variability inherent in the measured contaminant concentrations, sampling and analytical variability, and other factors. In most instances, time and budget constraints are major factors determining sample size. Statistical methods are available for calculating the minimum sample size needed to characterize a maximum risk employee exposure subgroup or to achieve a set degree of statistical confidence in the representativeness of an exposure measurement [NIOSH 1977[NIOSH , 1994Snedecor and Cochran 1967;Soule 2000]. Recently, exposure control banding and Bayesian decision analysis have been used to help support exposure assessment decisions with limited sample numbers [Hewett et al. 2006]. As stated above, a monitoring strategy should assess the effectiveness of various methods used to control airborne flavoring substance concentrations and to identify areas or tasks that are associated with higher exposures to flavoring substances. A common technique for evaluating the effectiveness of controls is to compare the outcome of environmental measurements made prior to the installation of those controls with measurements made following that installation. A control technique can be judged, for example, to be 50% efficient if the post-installation contaminant concentration is half of the pre-installation concentration. The TWA and STEL measurements of exposure to flavoring substances, made with the collection of personal breathing zone air samples, can be used to assess employees' exposures relative to an OEL. As discussed in the section of this document describing the development of the RELs, an 8-hour TWA measurement in excess of 5 ppb diacetyl or 9.3 ppb 2,3-pentanedione indicates that the employee in question was at a greater risk of developing occupationally induced illness. A 15-minute short-term exposure in excess of 25 ppb diacetyl or 31 ppb 2,3-pentanedione during task based personal sampling would be interpreted similarly. If monitoring indicates that exposures have increased over past measurements, or exposures exceed the selected OELs, a thorough investigation of controls to identify problems and guide remedial actions is needed. Regular routine monitoring (e.g., yearly) will help ensure the continued effectiveness of controls. Employers should monitor employees in such a fashion that he has a high degree of confidence that a very high percentage of actual daily exposures are below the REL. In statistical terms, the employer should try to attain 95% confidence that no more than 5% of employee days are over the REL. # Notification of Employees Employers should establish procedures for the timely notification of employees of their environmental monitoring results or results that represent their work group, any identified exposure hazards, and any subsequent actions taken based on this monitoring to reduce their exposures. Employees should be informed about any products or processes that may generate high concentrations of diacetyl, 2,3-pentanedione, or other flavoring compounds and any PPE and changes in work practices needed in response. Employers should ensure that employees understand this information and their role in helping to maintain a healthful workplace. Information should be conveyed in English and other languages as needed to ensure that all employees receive and comprehend this information. # Research Needs In this chapter, knowledge gaps pertaining to diacetyl, 2,3-pentanedione and flavoringinduced lung disease are identified. General areas of need include environmental research to better measure and control exposures to flavoring substances, clinical and field studies on the epidemiology of flavoring-induced diseases, research related to personal protective equipment, and toxicological studies concerning the etiology of flavoring-related diseases. # Chromatography Team Industrial Hygiene Chemistry Division OSHA Salt Lake Technical Center The purpose of this evaluation was to develop a sampling procedure for diacetyl that gave a better storage stability than did the NIOSH Method 2557, which used SKC Anasorb CMS as the sampling medial .The NIOSH method requires that the samples be refrigerated immediately after sampling, and the analysis be performed within 7 days. A more stable sampling media was desired for OSHA samples. The following media were tested at SLTC but all gave poor storage stability: coconut shell charcoal Lot 2000, 4-tert-butylcatechol coated charcoal, XAD-7, and OVS-7. Silica gel tubes (150mg/75 mg) were tried next and had an average storage recovery of 94.9% for samples stored at room temperature for 14 days. A sampling train of two silica gel tubes in series was necessary because a significant amount of the diacetyl was found on the smaller, backup section of the first tube in the retention study. A second tube in series insures that all of the sample will be collected on the sampling train . The desorbing solvent of 95:5 ethyl alcohol:water with 0.25 µL/mL p-cymene internal standard gave an average recovery of 99.1 % over the concentration range of 26.5 to 529 µg of diacetyl. 1.1.2 Toxic Effects.2 (This section is for information only and should not be taken as the basis of OSHA policy.) In 2002, the CDC published a report in the Morbidity and Mortality Weekly Report (MMWR) on employee exposures at a microwave popcorn factory in Missouri. A group of former employees had developed fi xed airways obstructive lung disease. All eight had a respiratory illness that resembled a rare lung disease called bronchiolitis obliterans. Some of the cases had such severe illness they were candidates for lung transplants. The main volatile organic chemical (VOC) found in the workplace atmospheres was diacetyl, which was used in a mixture of heated soybean oil, salt and flavorings to impart a butter flavoring to the popcorn. During NIOSH 's investigation of the facility, diacetyl was chosen as a marker compound for voe exposure. The MMWR publication reported that the geometric mean air concentration of diacetyl was 18 ppm in the room where the mixing tank was located, 1.3 ppm in the packaging area, and 0.02 in other areas of the plant. Of the eight former employees with severe respiratory illness, four were mi xers and four worked in packaging. The report concluded that "workers exposed to flavorings at microwave popcorn factories are at risk for developing fi xed obstructive lung disease." The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equal descending increments of analyte, such that the highest sampler loading was 3.7 µg diacetyl. This is the amount spiked on a sampler that would produce a peak approximately 3 times the response for a sample blank. These spiked samplers were analyzed with the recommended analytical parameters, and the data obtained used to calculate the required parameters (standard error of estimate and slope) for the calculation of the DLOP. The slope was 13.89 and the SEE was 41.82. The RQL is considered the lower limit for precise quantitative measurements. RQL is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to 125% of the analyte is recovered. The DLOP and RQL were 0.902 µg and 3.01 µg respectively Below is chromatogram of the RQL level. # .a All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. 2.1 Apparatus 2.1.1 Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. 2.1.2 Silica gel tubes: glass tube with both ends flame sealed, 70 mm x 6-mm i.d. containing 2 sections of 20/40 mesh silica gel separated by a 2-mm portion of urethane foam. The adsorbing section contains 150 mg of silica gel, the backup section 75 mg. A 3-mm portion of urethane foam is placed between the outlet end of the tube and the backup section. A plug of silane-treated glass wool is placed in front of the front section tubes or equivalent was used in this evaluation. # Reagents None required . # Technique 2.3.1 Immediately before sampling, break off the ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use tube holders to minimize the hazard of broken glass. All tubes should be from the same lot. 2.3.2 Connect two tubes in series to the sampling pump with flexible tubing. The smaller sections of the silica gel tubes should be positioned nearer the sampling pump. The tube closer to the pump is used as a backup. A minimum amount of tubing is used to connect the two sampling tubes together. Position the sampling pump, tube holder and tubing so they do not impede work performance or safety. # 2.3.3 Draw the air to be sampled directly into the inlet of the tube holder. The air being sampled is not to be passed through any hose or tubing before entering the sampling tube. 2.3.4 After sampling for the appropriate time, remove the adsorbent tube and seal it with plastic end caps. Seal each sample end-to-end with an OSHA-21 form as soon as possible. 2.3.5 Submit at least one blank sample with each set of samples. Handle the blank sample in the same manner as the other samples except draw no air through it. 2.3.6 Record sample air volumes (liters), sampling time (minutes) and sampling rate (ml/min) for each sample, along with any potential interferences on the OSHA-91A form. 2.3.7 Submit the samples to the laboratory for analysis as soon as possible after sampling. If delay is unavoidable, store the samples at refrigerator temperature. Ship any bulk samples separate from the air samples. # .4 Extraction efficiency The extraction efficiency was determined by liquid-spiking silica gel tubes with diacetyl at 0.1 to 2 times the target concentration. These samples were stored overnight at ambient temperature and then extracted for 30 minutes with occasional shaking and analyzed. The mean extraction efficiency over the studied range was 99.1 %. The wet extraction efficiency was determined at the target concentration by liquid spiking the analyte on the front, larger, section of the first silica gel tube of the sampling train of two silica gel tubes in series, and drawing 3 L humid air (absolute humidity of 15.9 mg/L of water, about 80% relative humidity at 22.2oq through them. The mean recovery for the wet samples was 100.2 % Based on the data collected in this evaluation, 3-l air samples should be collected at a sampling rate of 0.05 l/min for 60 minutes. 2.8 Interferences (sampling) 2.8.1 There are no known compounds that will severely interfere with the collection of diacetyl. 2.8.2 Suspected interferences should be reported to the laboratory with submitted samples. # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan. Avoid skin contact and inhalation of all chemicals and review all appropriate MSDSs. # Apparatus 3.1.1 A gas chromatograph equipped with an FID. For this evaluation, an Agilent 6890 Plus gas Chromatograph equipped with a 7683 Automatic Sampler was used. 3.1.2 A GC column capable of separating diacetyl from the desorption solvent, internal standard and any potential interferences. A 60-m x 0.32-mm i.d. capillary DBWAX with a 0.5-µm df (J&W Scientific) was used in the evaluation. 3.1.3 An electronic integrator or some other suitable means of measuring peak areas. A Waters Millennium 32 Data System was used in this evaluation. 3.1.4 Amber glass vials with poly(tetrafluoroethylene)-lined caps. For this evaluation 2-ml vials were used. 3.1.5 A dispenser capable of delivering 1.0 ml of desorbing solvent to prepare standards and samples. If a dispenser is not available, a 1.0-ml volumetric pipet may be used. 3.1.7 Volumetric flasks -10-ml and other convenient sizes for preparing standards. 3.2.4 The extraction solvent was 0.25 µl/ml p-cymene in ethyl alcohol:water (95:5). 3.2.5 GC grade nitrogen, air, and hydrogen. 3.3 Standard preparation 3.3.1 Prepare working analytical standards by injecting micro liter amounts of diacetyl into volumetric flasks containing the extraction solvent. An analytical standard at a concentration of 0.530 mg/ml (5.3 µL/10 ml) is equivalent to 50 ppm based on a 3-l air volume. Stock standards were stored in amber vials at refrigerated temperature for stability. 3.3.2 Bracket sample concentrations with working standard concentrations. If sample concentrations are higher than the concentration range of prepared standards, prepare and analyze additional standards, at least as high a concentration as the highest sample, to ascertain the linearity of response, or dilute the sample with extracting solvent to obtain a concentration within the existing standard range. The range of standards used in this study was from 0.00132 to 0.60 mg/ml analyze additional standards, at least as high a concentration as the highest sample, to ascertain the linearity of response, or dilute the sample with extracting solvent to obtain a concentration within the existing standard range. The range of standards used in this study was from 0.00132 to 0.60 mg/ml. 3.4 Sample preparation 3.4.1 Remove the plastic end caps from the sample tubes and carefully transfer both adsorbent sections from front tube and each section of backup tube to separate labeled 2-ml amber glass vials. Discard the glass tube and glass wool plug. 3.4.2 Add 1.0 ml of extraction solvent to each vial using the same dispenser as used for preparation of standards. 3.4.3 Immediately seal the vials with poly(tetrafluoroethylene)-lined caps. 3.4.4 Place vials on shaker and agitate for 60 minutes. (Y = 696 x -336) maa 3.6.1 Any compound that produces a GC response and has a similar retention time as the analyte is a potential interference. If any potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate an interference from the analyte. 3.6.2 When necessary, the identity or purity of an analyte peak may be confirmed by mass spectrometry or by another analytical procedure. The mass spectrum in # Calculations The amount of analyte per sampler is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for extraction efficiency. This total amount is then corrected by subtracting the total amount (if any) found on the blank. The air concentration is calculated using the following formulas. To obtain adequate sensitivity for this method, it was necessary to derivatize the acetoin and diacetyl. 2, was the first derivatizing agent tried, but DNPH can react with both ketone and a-hydroxy ketones 6, and while it initially formed unique derivatives of acetoin and diacetyl by reacting with the first ketone group, it eventually reacted also with the alcohol group on acetoin and the second ketone group on diacetyl, forming the same derivative. In EPA Method 556. 1 0-pentafluorobenzyl hydroxy_lamine hydrochloride (PFBHA) was used to derivatize ketone and aldehyde groups. 7 Unique derivatives of acetoin and diacetyl are formed by reacting them with PFBHA. The first ketone group on diacetyl reacts within four hours with PFBHA, but the second ketone group takes 36 hours to reach completion. Acetoin reacts within 3 hours. In this method, samples are extracted and derivatized in an extraction solution containing PFBHA. This is accomplished by first rotating the samples for 60 min and then allowing the samples to stand at room temperature for an additional 36 hours for the derivatization reaction to reach completion. This method is designed for low air concentrations of acetoin, diacetyl, and potential interferences. If high exposures are anticipated, use OSHA Method 1013 8 or increase 6 Smith, M., March, J.;March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.;John Wiley & Sons Inc.: New York, 2001, p 1193. EPA Method 556.1 Determination of Carbonyl Compounds in Drinking Water by Fast Gas Chromatography, 1999 NIOSH Health Hazard Evaluations (HHE) of microwave popcorn manufacturing plants found fixed airway obstruction, in some cases, consistent with bronchiolitis obliterans in some employees. 9 Acetoin, diacetyl, acetic acid, acetaldehyde, and 2-nonanone were amongst the chemicals found by NIOSH in several popcorn manufacturing plants. 10 Diacetyl was found to be present in all workplaces where the bronchiolitis obliterans was observed, and acetoin was found in some of the workplaces. Animal toxicology studies were performed by NIOSH with diacetyl, or butter flavorings containing diacetyl. Respiratory tract damage, including necrosis of the nasal and tracheal epithelium, and death were reported in rodents exposed to diacetyl, and butter flavorings containing diacetyl, at an air concentration of approximately 200 ppm of diacetyl for 6 hours. Mice exposed to 200 and 400 ppm diacetyl via inhalation for 6 hours per day over 5 days had the following health effects: death, acute necrotizing rhinitis, and erosive or necrotizing laryngitis. Mice exposed to 200 and 400 milligrams per kilogram (mg/kg) diacetyl via oropharyngeal aspiration for 6 hours per day over 5 days had bronchiolar fibrosis and death. Rats exposed to butter flavoring vapors containing 300 ppm diacetyl for 6 hours had epithelial injury in the nasal passages and pulmonary airways. ; 2,3-butanolone; 2-butanone, 3-hydoxy-; 2-butanol-3-one; dimethylketol; y-hydroxy-{3-oxobutane; 3-hydroxybutan-2-one; 3-hydroxy-2-butanone; 1-hydroxyethyl methyl ketone; methyl acetyl carbinol A624 513-86-0 (monomer); 23147-57-1 (dimer/ 3 148 Acetyl Methyl Carbinol Dimer, 2008. Department of Health and Human Services, National Institutes of Health, National Center for Biotechnology Information. http:llpubchem.ncbi.nlm.nih.govlsummarylsummary.cgi?cid= 90884&1oc=ec_rcs (accessed 311712008). 24 Material Safety Data Sheet: Acetoin, 2008. The Good Scents Company Web site. http://www.thegoodscentscompany.com lmsds/md102388.html (accessed 311712008 # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # 1 Apparatus Samples are collected with two tubes in series. The tubes consist of 110-cm x 7-mm o.d. glass sampling tubes packed with one section (600 mg) of specially cleaned and dried silica gel. From the front to back, the sampler consists of a silane-treated glass wool plug, glass fiber filter, 600 mg specially cleaned silica gel, and a second silane-treated glass wool plug. The silica gel should be cleaned and dried as described in Appendix A of OSHA Method 1013. 31 The tubes used in this evaluation were labeled front and back tube. The front tube is connected to the back tube with a piece of tubing to form the sampling train. For this evaluation commercially prepared sampling tubes containing the specially dried silica gel were purchased from SKC, Inc. (Catalog no. 226-183, lot no. CPM112907-001). Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. Use aluminum foil, opaque tape, or a tube holder, such as SKC, , to protect samples from light. # Reagents None required # Technique Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking the tube. Use tube holders to minimize the hazard of broken glass and to protect tubes from light exposure during sampling. All tubes should be from the same lot. A sampling train is created by attaching two tubes in series with a small section of tubing so that the front opening of the back tube is close to the back opening of the front tube. The front of each tube contains glass wool followed by a glass fiber filter, and the back of the tube contains only the glass wool. ) diacetyl with an average relative humidity (RH) of 80% at 23 °C. The samples were collected at 0.05 Umin. The 5% breakthrough air volumes were determined to be 12.1 L for diacetyl and greater than 24 L for acetoin. There was no acetoin or diacetyl on the back-up tube when a 15 min sample was taken at 0.2 Umin. The 5% breakthrough air volumes for a flow rate of 0.2 Umin were determined to be 11.98 L for diacetyl and greater than 13 L for acetoin. # 5 Extraction efficiency (Section 4. 8) It is the responsibility of each analytical laboratory to determine the extraction efficiency of the analyte from the media because the adsorbent material, internal standard, reagents and laboratory techniques may be different than those listed in this evaluation and influence the results. The mean extraction efficiencies from dry silica gel over the range of RQL to 2 times the target concentration were: 102.0% (0.022 to 3.28 µg/sample) for acetoin and 97.6% (0.01 to 3.16 µg/sample) for diacetyl. The extraction efficiency was not affected by the presence of water. Extracted samples remain stable for at least 24 h. # 6 Recommended sampling time and sampling rate Sample with dried silica gel tubes for up to 180 min at 0.05 Umin (9 L) to collect TWA (long term) samples, and for 15 min at 0.2 Umin (3 L) to collect short-term samples. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limits for dried silica gel tubes for a 15 min sample taken at 0.2 Umin are 0.0044 ppm (0.016 mg/m 3 ) for acetoin and 0.0042 ppm (0.015 mglm Interferences, sampling (Section 4.9) Retention efficiency The mean retention efficiency was 96. 7% for acetoin and 96. 9% for diacetyl when dried silica gel tubes containing 0.819 µg of acetoin and 0.808 µg of diacetyl were allowed to sample 6. 75 L of contaminant-free air having an average relative humidity of 80% at 23 °C. (Section 4.9) # Low humidity The ability of dried silica gel tubes to collect the analytes from a relatively dry atmosphere was determined by sampling an atmosphere containing two times the target concentration and at an average relative humidity of 20% RH at 23 °C. The mean recoveries (% of theoretical) were 98. 7% for acetoin and 98.5% for diacetyl. (Section 4.9) # Low concentration The ability of dried silica gel tubes to collect the analytes at low concentrations was tested by sampling an atmosphere at 0. 1 times the target concentration with at an average relative humidity of 80% RH at 23 °C. The mean recoveries (% of theoretical) were 99.0% for acetoin and 98.4% for diacetyl. (Section 4.9) Sampling interference The ability of dried silica gel tubes to collect the analyte when other potential interferences are present was tested under two separate series of tests. The first test was an atmosphere similar to ones found at some popcorn manufacturing plants consisting of acetoin and diacetyl at the target concentration with an interference mixture of acetaldehyde, acetic acid, and methyl ethyl ketone at an average humidity of 80% at 23 °C. All three of these interferences can react with PFBHA. The concentrations of the analytes in this test atmosphere were: 0.051 ppm (0.184 mglm The concentrations of these interferences are much higher than would normally be expected in a food or flavoring manufacturing workplace. The PFBHA extraction solution needed to be modified to 18 mg/mL PFBHA (72. 1 µmoles/mL) to insure that there was enough PFBHA to derivatize all the analytes. These interferences and acetoin react fully within 4 hours of extraction, but the diacetyl requires 36 hours to fully react. These three test atmospheres each contained the one of the followinq concentrations of interference: 190 ppm (350 mg/m 3 ) acetaldehyde, 9.49 ppm (23.3 mglm) acetic acid, or 190 ppm (560 mglm 3 ) methyl ethyl ketone. These three compounds were chosen because they can collect onto the dried silica gel tubes and can react with the PFBHA. For each test, three sampling trains had contaminated air (air containing the analytes and an interference) drawn through them at 0.05 Umin for 180 min for each test. All of the samples were immediately analyzed. The average recoveries (% of theoretical) with 190 ppm acetaldehyde were 97.8% for acetoin and 95.5% for diacetyl. The average recoveries (% of theoretical) with 9.49 ppm acetic acid were 97.3% for acetoin and 32 Burright, D.;Chan, Y.;Elskamp, C.;Rose, M. Evaluation Guidelines For Air Sampling Methods Utilizing Chromatographic Analysis, 1999. U.S. Department of Labor, Occupational Safety and Health Administration Web site. http://www.osha .govldtslsltclmethodslchromguidelindex.html (accessed 311512008). 11 of 34 T-1012-FV-01-0811-M 98. 2% for diacetyl. The average recoveries (% of theoretical) with 200 ppm methyl ethyl ketone were 98.4% for acetoin and 97. 6% for diacetyl. These interferences were not a sampling interference, but under normal sample analysis, these levels of interferences would be analytical interferences. (Section 4. 9) Light Acetoin and diacetyl are light-sensitive. The interference of light during sampling was tested using three foil-wrapped sampling trains and three uncovered sampling trains. An atmosphere containing twice the target concentration at an average relative humidity of 78% at 23 °C was sampled for 180 min at 0. 05 Umin, and the samples were extracted that day. The average recovery for acetoin of the foil-wrapped samplers was 98.5% and the uncovered samplers had an average recovery of 93. 9%. The average recovery for diacetyl of the foil-wrapped samplers was 98.9% and the uncovered samplers had an average recovery of 94.3%. An additional three sampling trains were collected at the same time, and were protected from the light by aluminum foil. After collection, these samplers had the foil removed and were placed on the counter at ambient temperature under room light. These samples were analyzed 24 h after sampling during which they were exposed to the room light for 14 of the 24 h. The average recoveries were 81.3% for acetoin and 80.0% for diacetyl. Light is a significant interference; therefore, both tubes in the sampling train need to be covered by aluminum foil or opaque tape during and after sampling. (Section 4.9) Powder form The powder form of acetoin and diacetyl tested consisted of starch coated with acetoin and diacetyl. Three tests were performed on this powder. The first consisted of a sampling train of a pre-weighed PVC filter in a conical cassette in series with two dried silica gel tubes. The two dried silica gel tubes were used to collect any vapors of acetoin and diacetyl which would strip off from the powder. Known amounts of the powder were placed onto the PVC filter, and 9 L of air at an average relative humidity of 78% at 22 °C were pulled through the sampling trains at 0.05 Umin. The recovery of acetoin and diacetyl on the pre-weighed PVC filters was 0% to 1.9% for acetoin and 0% to 2.3% for diacetyl. The recovery on the dried silica gel tubes was 96.6% for acetoin and 97.8% for diacetyl. The acetoin and diacetyl recoveries were calculated from the percentages obtained from analysis of the powder and the amounts of powder weighed out. The second and third tests consisted of a sampling train of two dried silica gel tubes in series, with the powder spiked on the front glass wool of the front tube. The two tests had 9 L of air drawn through the sampling trains at 0.05 Umin, the first test used air at an average relative humidity of 20% at 22 °C, and the other test used air at an average relative humidity of 78% at 22 °C. At 20% RH most of the acetoin and diacetyl were found on the front glass wool and glass fiber filter, but at 78% RH most of the acetoin and diacetyl were found on the dried silica gel beds. These tubes can collect particulates, but cannot be used as a particulate sampler at 0.05 Umin. (Section 4.9) # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan # 33 . Avoid skin contact and inhalation of all chemicals and review all MSDSs before beginning this analytical procedure. # 1 Apparatus Gas chromatograph equipped with an electron capture detector. An Agilent Model 6890 GC equipped with a Chemstation, an automatic sample injector, and a µ-electron capture detector (µECO) was used in this evaluation. 33 Occupational Exposure to Hazardous Chemicals in Laboratories. Code of Federal Regulations, Part 1910.1450, Title 29, 2003. and the data obtained were used to determine the required parameters (slope and standard error of estimate) for the calculation of the DLAP. For acetoin, the slope and standard error of estimate, respectively, were 3818 and 219. For diacetyl, the slope and standard error of estimate, respectively, were 9595 and 366. # 2' .l!l § 0 (.) "' @ <( # Vi' :;;. # 2' .l!l § 0 (.) "' @ Ten samplers were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a sample blank. These spiked samplers and the sample blank were analyzed with the recommended analytical parameters, and the data obtained used to calculate the required parameters (slope and standard error of estimate) for the calculation of the DLOP. For acetoin, the slope and standard error of estimate, respectively, were 46. 9 and 227. For diacetyl,the # 4.4 The standard error of estimate was determined from the linear regression of data points from standards over a range that covers 0.25 to 2 times the TWA target concentration. Calibration curves were constructed and shown in Section 3. 5. 2 from the three injections each of five standards. The standard errors of estimates were 0.019 µg for acetoin and 0.052 µg for diacetyl. Storage samples for acetoin and diacetyl were prepared using dried silica gel tubes from controlled test atmospheres using the recommended sampling conditions. The concentrations were 0.051 ppm (0.184 mg!m 3 ) acetoin and 0.050 ppm (0.180 mg/m 3 ) diacetyl at an average relative humidity of 80% at 23 °C. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Recoveries are not corrected for extraction efficiency. Storage studies were also performed using tubes packed with 4001200 mg sections of dried silica gel, at an average relative humidity of 22% RH at 23 °C to determine the effects of low humidity on storage and on migration. The concentrations were 0.051 ppm (0.184 mg/m 3) acetoin and 0. 050 ppm (0. 180 mg/m 3 ) diacetyl. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 22% RH ambient and refrigerated storage samples showed no migration for acetoin or diacetyl. Recoveries are not corrected for extraction efficiency. At the beginning of this method, the SKC 226-183 tubes were available as a 4001200 mg tube. Migration studies showed that it would be necessary to use two tubes in series, so subsequent tubes were packed as a single 600 mg tube. A 600 mg section makes it easier for the analyst to prepare the samples for extraction. Migration occurs when the analyte equilibrates between the two sections of the tube after collection. There is more migration with higher humidities, due to the higher amounts of water collected. Using 4001200 mg dried silica gel tubes, at 80% RH acetoin showed no migration but the diacetyl refrigerated samples at day 18 showed a 4. 5% migration and ambient showed 15. 2% migration. Based on these results, a single 4001200 mg dried silica gel tube should not be used for sampling. A capability of collection at higher flow rates with a 15 minute short term sample was tested for breakthrough. A test atmosphere was dynamically generated with an average relative humidity of 79% at 23 °C at concentrations of 0.101 ppm (0.365 µglm 3) acetoin and 0.101 ppm (0.355 mg/m 3 ) diacetyl. A sampling train consisting of two dried silica gel tubes (4001200 mg) in series was used to test the capacity. Three sampling trains at each flow rate of 0.1 Umin or 0.2 Umin were tested. There was no acetoin or diacetyl on the second tube of any of the sampling trains. Since the short term sampling may be a time of higher exposure, two higher concentrations were also tested. The first was 0.541 ppm (1.95 ) diacetyl at an average relative humidity of 79% at 23 °C. In all of these tests there was no acetoin or diacetyl on the back-up tube of the sampling train. # 8 Extraction efficiency and stability of extracted samples The extraction efficiency is dependent on the extraction solvent as well as the internal standard. The extraction solvent used for this evaluation consisted of 95:5 ethyl alcohol:water with 2 mg/mL PFBHA and 20 µg/mL 4-bromobenzyl bromide. Other extraction solvents or internal standards may be used provided that the new extraction solution or internal standard is tested. The new extraction solvent or internal standard should be tested as described below. # Extraction efficiency The extraction efficiencies of acetoin and diacetyl were determined by liquid-spiking four dried silica gel tubes, at each concentration level, with the analyte from the RQL to 2 times the target concentration. These samples were stored overnight at ambient temperature and then analyzed. The samples need to be extracted on a rotator for 1 hour, and then allowed to set at room temperature for 36 hours. Do not use a shaker as recoveries will be much lower (Table 4.8.3). The mean extraction efficiency over the working range from the RQL to 2 times the target concentration is 102.0% for acetoin and 97.6% for diacetyl. The extraction efficiency for the wet samplers and samplers extracted on the shaker were not included in the overall mean because it would bias the results. The test of wet samplers was performed to determine if the amount of water that would collect under high humidity conditions at the recommended air volume would affect the extraction efficiency. Wet samplers were prepared by sampling humid air having an average relative humidity of about 80% at 23 °C for 180 minutes at 0. 05 Umin and then liquid-spiking the sampler with the analyte. The dried silica gel tube (600 mg) collects 140 mg water at 78% RH and 23 °C when sampled for 9 L. # Stability of extracted samples The stability of extracted samples was investigated by reanalyzing the target concentration samples 24 h after initial analysis. After the original analysis was performed, two autosampler vials were recapped with new septa while the remaining two retained their punctured septa. The samples were reanalyzed with fresh standards. The average percent change was +O. 7% for acetoin and +1.6% for diacetyl when samples were resealed with new septa and -1.1% for acetoin and +0.3% for diacetyl when samples retained their punctured septa. Each septum was punctured 5 times for each analysis. The test was performed at room temperature. # of 34 T-1012-FV-01-0811-M atmosphere containing twice the target concentration at an average humidity of 78% at 23 °C was sampled for 180 min at 0. 05 Umin, and the samples were extracted that day. An additional three sampling trains were collected at the same time, and were protected from the light by aluminum foil. After collection, these samplers had the foil removed and were placed on the counter at ambient temperature under room light. These samples were analyzed 24 h after sampling during which they were exposed to the room light for 14 of the 24 h, and the recoveries were 80. 7%, 84. 7%, and 78.5% for acetoin and 79.3%, 82.4%, and 78.4% for diacetyl. # Powder form The powder form of acetoin and diacetyl tested consisted of starch coated with acetoin and diacetyl. Three tests were performed on this powder. The first consisted of a sampling train of a pre-weighed (tared) PVC filter in a conical cassette in series with two dried silica gel tubes. Two dried silica gel tubes were used to collect any vapors of acetoin and diacetyl which would be stripped off of the powder. Known amounts of the powder were placed onto the PVC filter, and 9 L of air at an average relative humidity of 78% RH and 22 °C were pulled through the sampling trains at 0. 05 Umin. The recovery of acetoin and diacetyl on the pre-weighed PVC filters was 0% to 1.9% for acetoin and 0% to 2.3% for diacetyl, with larger amounts found on the PVC filters that were spiked with larger amounts of powder. Most of the acetoin and diacetyl was stripped from the starch and collected on the dried silica gel tubes. The average recovery found on the dried silica gel tubes was 96. 6% for acetoin and 97. 8% for diacetyl (Table 4.9.4). The acetoin and diacetyl theoretical weights were calculated from the percentages obtained from analysis of the powder and the amounts of the powder weighed out. The second and third tests consisted of a sampling train of two dried silica gel tubes in series, with the powder spiked on the front glass wool of the front tube. The two tests had 9 L air drawn through the sampling trains at 0.05 Umin, the first test used air at an average relative humidity of 20% at 22 °C, and the other test used air at an average relative humidity of 78% at 22 °C. At 20% RH most of the acetoin and diacetyl were found on the front glass wool and glass fiber filter, but at 78% RH most of the acetoin and diacetyl were found on the dried silica gel beds. The sampling trains with 78% RH air drawn through them had the highest amounts of acetoin and diacetyl on the glass wool and filter on the tube spiked with the highest amount of powder, which may be due to the size of the clump of powder weighed out (Table 4. 9. 5 and 4.9.6). Material Safety Data Sheet: Diacetyl, Chemwatch, Victoria, Australia (accesed 311712008). Sheet: 2,3-Butanedione, https:llfscimage.fishersci.comlmsds/03275.htm (accessed 311712008). Material Safety Data Sheet: 2,3-Butanedione, http:llwww.chemservice.com/msds/msds_detail.asp?catnum=0-816 (accessed 311712008). # Material Safety Data # 31of34 T-1012-FV-01-0811-M # . General Discussion For assistance with accessibility problems in using figures and illustrations presented in this method, please contact the Salt Lake Technical Center (SL TC) at (801) 233-4900. This procedure was designed and tested for internal use by OSHA personnel. Mention of any company name or commercial product does not constitute endorsement by OSHA. This procedure, Method 1013, was streamlined for monitoring low ppm levels, and Method 1012 6 was optimized for ppb levels. Both methods use two 600 mg silica gel sorbent tubes in series. Both methods have a recommended sampling time of 3 hours (9 L) and both use the same solvent for sample extraction. However, in Method 1012, acetoin and diacetyl are derivatized using 0-pentafluorobenzyl hydroxylamine hydrochloride. This derivatization results in a reliable quantitation limit approximately 10 times less than Method 1013. The disadvantage of derivatizing acetoin and diacetyl is that the derivatization step requires 36 hours; whereas, with this method sample preparation can be performed in 1 hour. Also, samples extracted and analyzed according to this procedure can then be derivatized and analyzed using Method 1012, if needed. The silica gel used in the sampler for this method, and for Method 1012, has been specially cleaned and dried as described in Appendix A. It was found that sampler capacity for diacetyl was not based on analyte concentration but limited by the amount of water remaining on the silica gel after cleanup and on the amount of water collected during sampling. In other words, the silica gel tube acts as a chromatography column and water elutes the collected diacetyl. By removing as much water as possible from the silica gel prior to sampling, the sampling volume for diacetyl can be increased because the time required to saturate the silica gel during sampling increases. Diacetyl was also found to gradually migrate within the sampling tube during storage resulting in the need to use a second tube in series during sampling in order to detect breakthrough. Acetoin has no capacity or migration issues on silica gel at the recommended sampling volume. The powder and liquid formulated forms of acetoin and diacetyl may contain oily compounds and other base materials such as maltodrextin. These materials could affect the extraction of acetoin and diacetyl from the silica gel. The sampler contains a front glass wool plug followed by a glass fiber filter that serves only to trap any of these materials before they enter the silica gel bed. Retention studies using a powder containing acetoin and diacetyl showed the acetoin and diacetyl can be stripped off the powder and collected on the silica gel. These studies demonstrate that the glass fiber filter is not an efficient collector for diacetyl and acetoin, and will not normally be analyzed (see OSHA Method 1012 7 , Section 4.9). # 1.1.2 Toxic effects (This section is for information only and should not be taken as the basis of OSHA policy.) Exposure to acetoin may result in skin, eyes, nose and throat irritation. Exposure to diacetyl "liquid or vapors can cause irritation to the skin, eyes, nose, and throat". "Animals exposed to diacetyl experienced damage to the nose and upper airways, including severe damage to cells lining the respiratory tract" and "NIOSH has reported that employees exposed to butter flavorings containing diacetyl are at risk of developing occupational lung diseases". 9 Diacetyl, and to some extent acetoin, may be responsible for the occurrence of a rare and potentially fatal lung disease, bronchiolitis obliterans, among workers in microwave popcorn manufacturing plants and flavor manufacturing plants. 10 Symptoms of bronchiolitis obliterans include cough, shortness of breath with exertion, and spirometry test results showing fixed airways obstruction. # Workplace exposure Acetoin has a somewhat creamy taste and a woody yogurt odor. It is used as an ingredient in yogurt, butter, milk and strawberry flavors. It occurs naturally in foods such as wines, chesses, fruits and vegetables. 14 Occupational exposures can occur by inhalation or skin contact in locations where it is produced, used as a food additive, or used to produce flavorings or aromas. Diacetyl has a strong butter odor in dilute form and a chlorine-quinone odor when concentrated. It is used as an ingredient to produce a butter flavor in many foods and beverages. It occurs naturally in alcoholic and nonalcoholic beverages, dairy products, fruits, plants, vegetables, meats, and natural aromas. 15 Like acetoin, occupational exposures to diacetyl can occur by inhalation or skin contact in locations where it is produced, used as a food additive, or used to produce flavorings or aromas. Recently, occupational exposure to butter flavorings in the production of microwave popcorn and in other industries has received much publicity. NIOSH has identified acetoin and diacetyl as useful indicator compounds that can be used to represent exposure to butter flavorings. # 16 Areas of special concern include flavor production rooms, areas where mixing/blending operations occur, packing/packaging operations, areas where flavors are handled openly, rooms where mixing tanks are located, quality control laboratories, and maintenance and cleaning operations. # Reproducibility Six samples collected from a controlled test atmosphere were submitted for analysis by the OSHA Salt Lake Technical Center. The samples were analyzed according to a draft copy of this procedure after 20 days of storage at refrigerated temperature. No individual sample result deviated from its theoretical value by more than the precision reported in Section 1 .2.5. (Section 4.6) # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # Apparatus Sampler: glass tube with both ends flame sealed, 110-mm x 7-mm i.d., containing a glass fiber filter and 1 section of 20140 mesh silica gel. From front to back, the sampling tube consists of a silane-treated glass wool plug, a glass fiber filter to collect particulate, 600 mg of silica gel and a second plug of silane-treated glass wool. The silica gel should be cleaned and dried as described in Appendix A. Sampling tubes are available for purchase through SKC, . Samples are collected using a personal sampling pump calibrated, with the sampling device attached, to within ±5% of the recommended flow rate. Use aluminum foil or a tube cover, such as SKC, Inc Tube Cover D (cat. no. 224-290), to protect samples from light. # Reagents None required # Technique Immediately before sampling, break the ends off of two flame-sealed glass tubes to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use a tube holder to minimize the hazard of broken glass and to protect samplers from light exposure during sampling. All tubes should be from the same lot. Connect the two silica gel sampling tubes in series, using the least amount of flexible tubing as possible between the sampling tubes, and then connect to a sampling pump with flexible tubing. The filter in the silica gel tubes should be positioned away from the sampling pump. The tube closer to the pump is used as a backup. Use a tube cover or wrap sampling tubes in aluminum foil to insure that both sampling tubes are protected from light exposure. Place the sampling tubes in a vertical position with the inlet in the breathing zone and position the sampling pump and tubing so they do not impede work performance or safety. Draw air directly into the inlet of the sampler. The air being sampled should not pass through any hose or tubing before entering the sampler. After sampling for the appropriate time, disconnect the tubes from the pump tubing and seal each tube with plastic end caps. Separately wrap each tube in aluminum foil and seal end-to end with a Form OSHA-21. Submit at least one blank sample with each set of samples. Handle the blank sample in the same manner as the other samples except draw no air through it. Record sample air volume (L), sampling time (min) and sampling rate (L/min) for each sample, along with any potential interferences on the Form OSHA-91A. Submit the samples to the laboratory for analysis as soon as possible after sampling. If a delay is unavoidable, store the samples in a refrigerator. Ship any bulk samples separate from the air samples. # 2.4 Sampler capacity (Section 4.7) The sampling capacity of the front tube was tested by sampling a dynamically generated test atmosphere of acetoin ( 3.58 mg/m 3 or 0.99 ppm) and diacetyl (3.55 mg/m 3 or 1.01 ppm) with an average relative humidity of 40% at 34 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of approximately 0.05 L/min for 270 min. The 5% breakthrough sampling time was determined to be 248 min for diacetyl. No breakthrough was observed for acetoin. (Note: In order to volatilize acetoin the test atmosphere generation conditions were modified slightly for this method evaluation as described in the second paragraph of Section 4.11.) # 2.5 Extraction efficiency (Section 4.8) It is the responsibility of each analytical laboratory to determine the extraction efficiency because the adsorbent material, reagents and laboratory techniques may be different than those listed in this evaluation and influence the results. The mean extraction efficiency for acetoin from dry silica gel over the range of RQL to 2 times the target concentration (0.33 to 31.0 µg per sample) was 92.9%. The extraction efficiency was not affected by the presence of water. The mean extraction efficiency for diacetyl from dry silica gel over the range of RQL to 2 times the target concentration (0.38 to 29.9 µg per sample) was 99.6%. The extraction efficiency was not affected by the presence of water. Extracted samples remain stable for at least 72 hr. # 2.6 Recommended sampling time and sampling rate Sample for up to 180 min at 0.05 L/min (9 L) to collect TWA (long-term) samples. Sample for up to 15 min at 0.2 L/min (3 L) to collect short-term samples. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limit is 0.032 ppm (0.12 mg/m 3 ) for acetoin and 0.035 ppm (0.12 mg/m 3 ) for diacetyl when 3 Lare collected. # 2.7 Interferences, sampling (Section 4.9) # Retention efficiency The retention efficiency for all samples was 100.6% of theoretical for acetoin and 96.6% for diacetyl, when samplers containing approximately 8.3 µg of acetoin and 8.1 µg of diacetyl were allowed to sample 6.75 L of contaminant-free air having an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 L/min. # Low humidity The collection efficiency for all samples was 100.7% of theoretical for acetoin and 101.5% for diacetyl, when the samplers were used to sample a test atmosphere containing two times the target concentration having an average relative humidity of 8% at 33 °C (absolute humidity of 2.82 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. # Low concentration The collection efficiency for all samples was 91.8% of theoretical for acetoin and 95.6% for diacetyl, when the samplers were used to sample a test atmosphere containing approximately 0.1 times the target concentration having an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. The collection efficiency for all samples when taking short term samples was 106% of theoretical for acetoin and 90.6% for diacetyl, when the samplers were used to sample a test atmosphere containing approximately 0.1 times the target concentration having an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Samples were collected at a sampling rate of0.2 Umin for 15 min. # Sampling interference The collection efficiency for all samples was 95.5% of theoretical for acetoin and 101.8% for diacetyl, when the sampler was used to sample a test atmosphere containing approximately one times the target concentration of acetoin and diacetyl and 2.59 mg/m 3 of 2-nonanone and 1.88 mg/m 3 of 2,3-pentanedione. The test atmosphere had an average relative humidity of 38% at 34 °C (absolute humidity of 14.1 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 181 min. Sampler exposure to light, particularly sunlight, during sampling will result in degradation of both acetoin and diacetyl. The recovery for all samples was 67 .0% of theoretical for acetoin and 6.43% for diacetyl, when the sampler was used to sample a test atmosphere containing approximately one times the target concentration of acetoin and diacetyl and then exposed to 3 h of direct sunlight (samples were covered during sampling). The test atmosphere had an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). Samples were collected at a sampling rate of 0.05 Umin for 180 min. See Section 4.9 for data on other light tests performed. # Analytical Procedure Adhere to the rules set down in your Chemical Hygiene Plan # 26 . Avoid skin contact and inhalation of all chemicals and review all appropriate MSDSs. # Apparatus A gas chromatograph equipped with an FID. For this evaluation an Agilent Technologies 6890 Plus Gas Chromatograph equipped with a 7683 Automatic Sampler and an Agilent tapered, deactivated, split, low pressure drop liner with glass wool (catalog no. 5183-4647). A GC column capable of separating acetoin and diacetyl from the desorption solvent, internal standard and any potential interferences. A Restek 60-m x 0.32-mm i.d. Rix-Volatiles (1.5-µm df) capillary column was used in this evaluation. Bracket sample concentrations with standard concentrations. If upon analysis, sample concentrations fall outside the range of prepared standards, prepare and analyze additional standards to confirm instrument response, or dilute high samples with extraction solvent and reanalyze the diluted samples. # Sample preparation Remove the plastic end caps from the front sample tube and carefully transfer the silica gel to a 4-ml amber glass vial. The sampling tube and the back of the glass fiber filter should be carefully inspected to insure that all the silica gel is transferred into the 4-ml vial. Remove the plastic end caps from the backup tube and carefully transfer the silica gel to a second 4-ml amber glass vial. If the industrial hygienist requests analysis of the front glass fiber filter, which is not normally analyzed, place the front glass wool plug and filter from the front tube into a third 4-ml vial. If analysis of filter is not requested then discard the front glass wool plug and filter. Discard the glass tubes and back glass wool plugs and back glass fiber filter. Add 2.0 ml of extraction solution to each vial and immediately seal with PTFE-lined caps. Note: The use of an extraction solution or internal standard other than that specified in Section 3.2 should not be used unless a full extraction efficiency study is performed using both dry and wet media as described in Section 4.8. Place the 4-ml vials on a mechanical rotator and rotate at approximately 40 rpm for 60 min. Transfer the extraction solution in each 4-ml vial to a 2-ml amber glass autosampler vial and seal with a PTFE-lined cap. Analyze samples for acetoin and diacetyl as described in Section 3.5. # Calibration An internal standard calibration method is used. A calibration curve can be constructed by plotting !STD-corrected response of standard injections versus micrograms of analyte per sample. Bracket the samples with freshly prepared analytical standards over the range of concentrations. The Guidelines define analytical parameters, specify required laboratory tests, statistical calculations and acceptance criteria. # 4.1 Detection limit of the analytical procedure (DLAP) The DLAP is measured as mass of analyte introduced onto the chromatographic column. Ten analytical standards were prepared with equally descending increments with the highest standard containing 1.1 O µg/sample acetoin and 1 .05 µg/sample diacetyl. This is the concentration that would produce a peak approximately 10 times the response of a calibration blank. These standards, and the calibration blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 spit), and the data obtained were used to determine the required parameters (standard error of estimate and slope) for the calculation of the DLAP. For acetoin values of 5171 and 30 were obtained for the slope and standard error of estimate respectively. The DLAP for acetoin was calculated to be 0.017 ng acetoin. For diacetyl values of 4325 and 47 were obtained for the slope and standard error of estimate respectively. The DLAP for diacetyl was calculated to be 0.033 ng diacetyl. Detection limit of the overall procedure (DLOP) and reliable quantitation limit (RQL) The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equally descending increments of acetoin and diacetyl, such that the highest sampler loading was equivalent to 1.10 µg of acetoin per sample and 0.96 µg of diacetyl per sample. This is the amount spiked on a sampler that would produce a peak approximately 10 times the response of a calibration blank. These spiked samplers, and the sample blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 spit), and the data obtained were used to determine the required parameters (slope and standard error of estimate) for the calculation of the DLOP. For acetoin values of 1029 and 36 were obtained for the slope and standard error of estimate respectively. The DLOP was calculated to be 0.10 µg acetoin per sample (0.0031 ppm or 0.011 mg/m 3 for a TWA sample). For diacetyl values of 1241 and 46 were obtained for the slope and standard error of estimate respectively. The DLOP was calculated to be 0.11 µg diacetyl per sample (0.0034 ppm or 0.012 mg/m 3 for a TWA sample). The RQL is considered the lower limit for precise quantitative measurements. It is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to # 5.5 The standard error of estimate was determined from the linear regression of data points from standards over a range that covers approximately 0.25 to 2 times the target concentration. Calibration curves for acetoin and diacetyl were constructed and are shown in Section 3.5.2 from the three injections of five standards. The standard error of estimate is 0.42 µg/sample for acetoin and 0.82 µg/sample for diacetyl. The precision at the 95% confidence level is obtained by multiplying the standard error of estimate by 1.96 (the z-statistic from the standard normal distribution at the 95% confidence level). In Section 4.5, 95% confidence intervals are drawn about their respective regression lines in the storage graph figures. For acetoin the precision of the overall procedure of ±11.2% was obtained from the standard error of estimate of 5.73% in Figure 4.5.1. For diacetyl the precision of the overall procedure of ±10.1 % was obtained from the standard error of estimate of 5.15% in Figure 4.5.3. The precision includes an additional 5% for sampling error. Storage samples for acetoin and diacetyl were prepared by collecting samples from a controlled test atmosphere using the recommended sampling conditions. The concentration of acetoin and diacetyl were at the target concentration with an average relative humidity of 41 % at 34 °C (absolute humidity of 15.2 mg/L H 2 0). Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the samples were stored at reduced temperature (3 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 21 °C). At 3-4 day intervals, three samples were selected from each of the two storage sets and analyzed. Sample results were not corrected for extraction efficiency. # Reproducibility Six samples were prepared by collecting them from a controlled test atmosphere similar to that which was used in the collection of the storage samples. The samples were submitted to the OSHA Salt Lake Technical Center for analysis along with a draft copy of this method. The samples were analyzed after being stored for 20 days at refrigerated temperature (about 3 °C). Sample results were corrected for extraction efficiency. No sample result for acetoin and diacetyl had a deviation greater than the precision of the overall procedure determined in Section 4.4. # 3 The sampling capacity of the front tube was tested by sampling from a dynamically generated test atmosphere at 2 times the target concentration of acetoin (3.58 mg/m 3 or 0.99 ppm) and diacetyl (3.55 mg/m 3 or 1.01 ppm) with an average relative humidity of 40% at 34 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min. Backup tubes were placed in-line behind the front tube and were changed regularly after the initial collection of 225 min. Breakthrough for diacetyl was observed after sampling 12.4 L. No breakthrough was observed for acetoin even after sampling for 265 min. The recommended sampling time is 3 h. The extraction efficiency is dependent on the extraction solvent as well as the internal standard. Other extraction solvents or internal standards may be used provided that the new extraction solution or internal standard is tested. The new extraction solvent or internal standard should be tested as described below. # Extraction efficiency The extraction efficiency of acetion and diacetyl was determined by liquid spiking four samplers, at each concentration level, with the analytes from the RQL to 2 times the target concentrations. These samples were stored overnight at ambient temperature and then analyzed. The mean extraction efficiency over the working range of the RQL to 2 times the target concentration is 92.9% for acetoin. The extraction efficiency for the wet samplers was not included in the overall mean because it would bias the results. The mean extraction efficiency over the working range of the RQL to 2 times the target concentration is 99.6% for diacetyl. The extraction efficiency for the wet samplers was not included in the overall mean because it would bias the results. # Stability of extracted samples The stability of extracted samples was investigated by reanalyzing the target concentration samples 24 h and 72 h after initial analysis. After each analysis was performed, two vials were recapped with new septa while the remaining two retained their punctured septa. The samples were reanalyzed with fresh standards. Samples were stored at ambient temperature and each septum was punctured 4 times for each analysis. # 4.9 Interferences (sampling) Retention The ability of the sampler to retain acetoin and diacetyl was tested by sampling from a dynamically generated test atmosphere of acetoin (3.67 -----------------then all six samplers were analyzed. The mean of the samples in the second set had retained 100.6% for acetoin and 96.6% for diacetyl of the mean collected by the first three samples. # Low humidity The ability of the sampler to collect acetoin and diacetyl from a relatively dry atmosphere was tested by sampling from a dynamically generated test atmosphere of acetoin ( 4.06 mg/m 3 or 1.13 ppm) and diacetyl (4.03 mg/m 3 or 1 .14 ppm) with an average relative humidity of 8% at 33 °C (absolute humidity of 2.82 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 180 min. All of the samples were immediately analyzed. The samplers collected 103.0%, 96.9% and 102.2% of theoretical for acetoin and 96.7%, 106.6% and 101.2% of theoretical for diacetyl. # Low concentration The ability of the sampler to collect acetoin and diacetyl at low concentrations was tested by sampling from a dynamically generated test atmosphere of 0.1 times the target concentration of acetion (0.185 mg/m 3 or 0.0515 ppm) and diacetyl (0.175 mg/m 3 or 0.0497 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 180 min. All of the samples were immediately analyzed. The samplers collected 93.9%, 91.5% and 89.9% of theoretical for acetoin and 92.8%, 97.4% and 96. 7% of theoretical for diacetyl. The ability of the sampler to collect acetoin and diacetyl at low concentrations when taking short term samples was tested by sampling from a dynamically generated test atmosphere of 0.1 times the target concentration of acetion (0.185 mg/m 3 or 0.0514 ppm) and diacetyl (0.175 mg/m 3 or 0.0497 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.2 L/min for 15 min. All of the samples were immediately analyzed. The samplers collected 103.8%, 104.1 % and 110.0% of theoretical for acetoin and 88.1 %, 89.2% and 94.4% of theoretical for diacetyl. # Interferences The ability of the sampler to collect acetoin and diacetyl was tested when other potential interferences are present by sampling an atmosphere containing 1.63 mg/m 3 (0.45 ppm) of acetoin, 1.56 mg/m 3 (0.44 ppm) of diacetyl, 2.59 mg/m 3 (0.44 ppm) of 2-nonanone and 1.88 mg/m 3 (0.44 ppm) of 2,3-pentanedione with an average relative humidity of 38% at 34 °C (absolute humidity of 14.1 mg/L H 2 0). Three samplers had contaminated air drawn through them at 0.05 L/min for 181 min. All of the samples were immediately analyzed. The samplers collected 93.2%, 96.5% and 96.8% of theoretical for acetoin and 100.6%, 100.6% and 104.1% of theoretical for diacetyl. Selection of 2-nonanone as a potential interference was based on its common use in butter flavorings used in microwave popcorn manufacturing facilities 29 . 2,3-Pentanedione was selected because it has been suggested as a possible replacement for diacetyl. (Note: The GC retention time of 2-nonanone was 14.4 min and 7.4 min for 2,3pentanedione. For this test the GC column temperature program was slightly changed to Initial 60 °C, hold 4 min; ramp at 15 °C/min to 225 °C, hold 0 min; ramp at 60 °C/min to 250 °C, hold 4 min to allow for the elution of 2-nonanone.) # Light The possibility of light degradation was tested for both acetoin and diacetyl on the sampling medium and in the extraction solution. For the sample medium test 12 samples were collected by sampling from a dynamically generated test atmosphere of acetoin (1.92 mg/m 3 or 0.53 ppm) and diacetyl (1.87 mg/m 3 or 0.53 ppm) with an average relative humidity of 40% at 35 °C (absolute humidity of 15.6 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min for 3 hours. Nine of not covered and three of the sampling, none during sampling covered samples were -----------------------immediately analyzed after sampling. Three of the covered samples were placed under a fluorescent lamp for 24 h and the reaming three were placed outside in direct sunlight for three hours before analyzing. The samples covered during sampling and immediately analyzed after sampling had mean recoveries of 94.4% of theoretical for acetoin and 96.6% for diacetyl. The samples not covered during sampling and immediately analyzed after sampling had mean recoveries of 94.1 % of theoretical for acetoin and 96.2% for diacetyl. The samples covered during sampling and then exposed to fluorescent light for 24 h before analysis had mean recoveries of 88.7% of theoretical for acetoin and 86.8% for diacetyl. The samples covered during sampling and then exposed to sunlight for 3 h before analysis had mean recoveries of 67.0% of theoretical for acetoin and 6.43% for diacetyl. This data clearly indicates that the sampler should be protected from exposure to light. To test the possibility of light degradation on extracted samples nine analytical standards at the target concentration were prepared. Six of the standards were placed in 2-ml amber glass vials and three were placed in 2-ml clear glass vials. Three of the amber vials, along with the clear glass vials were stored on the autosampler tray during the entire test while the other three amber vials were stored in the refrigerator when not being analyzed. All nine standards were analyzed eight times over a 10 day period with none of the septa being replaced during the test. With the exception of diacetyl in clear vials, acetoin and diacetyl did not degrade. This data clearly indicates that extracted samples should be protected from exposure to light. This data also indicates that acetoin and diacetyl are stable in the extraction solution for up to 9 days as long as they are stored in amber vials. The internal standard, 3-pentanone, was stable for up to 9 days in both the clear and ambient vials. # Diacetyl migration within sampling tubes In the majority of solid sorbent sampling tubes used by (3.17 mg/m 3 or 0.90 ppm) with an average relative humidity of 42% at 33 °C (absolute humidity of 14.8 mg/L H 2 0). The samples were collected at a sampling rate of 0.05 L/min for 3 hours. Three samples were analyzed on the day of generation and the other twelve were stored in a closed drawer at ambient temperature (about 21 °C). At 3-4 day intervals, three additional samples were analyzed. After 14 days up to 13.0% of diacetyl was found to have migrated from the front to the back section of the modified sampling tube. Acetoin did not migrate within the sampling tube. # 4.11 Generation of test atmospheres A test atmosphere generator, as diagramed in Figure 4.11, was set up in a walk-in hood. House air was dried and then humidified and regulated using a Miller Nelson Model 401 Flow Temperature-Humidity Control System. A measured flow (typically 10 µL per min) of an acetoin and diacetyl water solution was pumped through a 0.53-mm uncoated fused silica capillary tube into the inlet manifold, using a Series D ISCO Syringe Pump with Controller, and mixed with dilution air (typically 100 liters per min) coming from the Miller Nelson Control System. The inlet manifold was heated by wrapping it in heat tape, regulated with a variable autotransformer, in order to insure vaporization of acetoin. The acetoin and diacetyl gas mixture then flowed continuously into the mixing chamber (76-cm x 15-cm) and then into the sampling chamber (56-cm x 9.5-cm). Samples were collected through sampling ports on the sampling chamber. Temperature and humidity were measured near the exit of the sampling chamber using an Omega Digital Thermo hygrometer model RH411. When necessary, the identity or purity of an analyte peak can be confirmed by GC-mass spectrometry or by another analytical procedure. The mass spectra in Figure 4.12.1 and 4.12.2 are taken from the NIST spectral library. # General Discussion For assistance with accessibility problems in using figures and illustrations presented in this method, please contact Salt Lake Technical Center (SL TC) at (801) 233-4900. These procedures were designed and tested for internal use by OSHA personnel. Mention of any company name or commercial product does not constitute endorsement by OSHA. 1.1 Background # History OSHA is concerned about workplace exposure to 2,3-pentanedione because it is a butter flavoring agent that is sometimes substituted for diacetyl. 1 2,3-Pentanedione is chemically similar to diacetyl and may have similar toxicological properties. 2 This work was performed because OSHA has no sampling and analytical method for 2,3pentanedione and none was found in a literature review. One of the main objectives of this work was to enable OSHA CSHOs to monitor workplace exposure to diacetyl, acetoin and 2,3-pentanedione simultaneously on the same sample. Because of the similarities of the chemicals, it was decided to validate existing sampling and analytical methodology specified in OSHA Method 1013 3 for 2,3pentanedione. That method requires sampling with two commercially available silica gel tubes connected in series. This method specifies a different GC column than specified in Method 1013 in order to optimize the analytical separation. The reliable quatitation limits for acetoin and diacetyl cited in OSHA Method 1013 were confirmed with the GC column used in this validation. 1.1.2 Toxic effects (This section is for information only and should not be taken as the basis of OSHA policy.) 2,3-Pentanedione is moderately toxic by ingestion, a skin irritant, and can cause eye and respiratory tract irritation. 4 The oral LD 50 in rats is 3000 mg/kg. The skin irritation test in rabbits showed moderate irritation for an exposure of 500 mg/24h. Studies exposing rats to 118, 241, 318, or 354 ppm 2,3-pentanedione for 6 hours showed epithelial changes in the airways which increased with increasing air concentrations with necrosuppurative tracheitis in the rats exposed to 354 ppm. 5 This epithelial cell damage was found to progress post-exposure in rats sacrificed a day later. These epithelial changes included degeneration, apoptosis, necrosis, and neutrophilic inflammation. 1.1.3 Workplace exposure 2,3-Pentanedione is a natural flavorant and odorant that is also synthesized for use in odor and flavor manufacturing. 6 It is used to give products a buttery, nutty, cheesy, fruity, toasted, chocolate, or caramel taste. It also gives products a buttery, fruity, and caramel odor. There can be as much as 58 ppm in food flavorings, and up to 0.08% in fragrances. 2,3-Pentanedione is used as a solvent for cellulose acetate, paints, inks, lacquers, as a starting material for dyes, pesticides and pharmaceuticals, and as a photoinitializer for photo-reactive dyes. # Sampling Procedure All safety practices that apply to the work area being sampled should be followed. The sampling equipment should be attached to the worker in such a manner that it will not interfere with work performance or safety. # Apparatus Samples are collected with 110-cm x 7-mm o.d. glass sampling tubes packed with a single section (600 mg) of specially cleaned and dried silica gel. The section is held in place with glass wool and with a glass fiber filter in the front and glass wool at the back. A sampling train is prepared by placing two tubes in series. For this validation, commercially prepared sampling tubes were purchased from SKC, Inc. The two tubes are identical, but SKC labels the tubes as "Part A" which is the front tube and as "Part B" which is the back tube (Catalog no. 226-183, lot no. 6148). Use an opaque tube holder, such as SKC, to cover the sampling train during sampling. If the tube holder is not opaque, wrap the sampler with aluminum foil. Light can decompose collected 2,3-pentanedione. Samples are collected using a personal sampling pump calibrated to within ±5% of the recommended flow rate with the sampling device in-line. # Reagents None required # Technique Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Wear eye protection when breaking ends. Use sampling tube holders to minimize the hazard to the worker from the broken ends of the tubes and to minimize the potential of glass shards entering the foodstuffs. All tubes should be from the same lot. A sampling train is prepared by attaching a Part A tube in front of and in series with a Part B tube, with both glass fiber filters facing forward. The Part B tube in the sampling train is used as a back-up and is positioned nearest the sampling pump. Attach the tube holder (with the adsorbent tube sampling train) to the sampling pump so that the sampling train is in an approximately vertical position with the inlet facing down in the worker's breathing zone during sampling. Position the sampling pump, tube holder and tubing so they do not impede work performance or safety. Draw the air to be sampled directly into the inlet of the tube holder. The air being sampled is not to be passed through any hose or tubing before entering the sampling tube. Sample for up to 200 min at 50 ml/min (10 L) to collect TWA (long-term) samples. If acetoin and/or diacetyl are anticipated to be present, sample for up to 180 min at 50 ml/min (9 L) to collect TWA (long-term) samples. The extraction solvent used for this validation consisted of 0.007 µL/ml 3-pentanone in 95% v/v ethyl alcohol/water. The 3-pentanone was added to the ethyl alcohol as an internal standard (ISTD). # Standard preparation (Note: Store all standards in amber glass bottles and vials) Prepare concentrated stock standards in water at 1.021 mg/ml (1 .021 µg/µl) by injecting 11 µl of neat 2,3-pentanedione into water in a 10-ml volumetric flask and diluting to the mark. This stock standard will remain stable for two weeks if stored in an amber bottle in the refrigerator. When using refrigerated stock standards, be sure to allow the standards to warm to room temperature and then shake them vigorously before use. Prepare analytical standards by injecting microliter amounts of concentrated stock standards into 2-ml volumetric flasks containing about 1.75 ml of extraction solvent and then diluting with extraction solvent over a concentration range of 0.1 to 20 µg/ml (0.2 to 40 µg/2 ml). For example: a target concentration standard of 20.4 µg/sample was prepared by injecting 20 µl of the stock standard into a 2-ml flask containing about 1.75 ml of extraction solvent and then diluting to the mark with extraction solvent (10.2 µg/ml or 0.5 ppm based on a 2-ml extraction volume per sample and 10 lair volumes). Bracket sample concentrations with standard concentrations. If upon analysis, sample concentrations fall outside the range of prepared standards, prepare and analyze additional standards to confirm instrument response, or dilute high samples with extraction solvent and reanalyze the diluted samples. # Sample preparation (Note: prepare all samples in amber glass vials) Remove the plastic end caps from the front sample tube and carefully transfer the silica gel to a labeled 4-ml amber glass vial. The sampling tube and the back of the glass fiber filter should be carefully inspected to ensure that all the silica gel is transferred into the 4-ml vial. Remove the plastic end caps from the backup tube and carefully transfer the silica gel to a second labeled 4-ml amber glass vial. If the industrial hygienist requests analysis of the front glass fiber filter, which is not normally analyzed, place the front glass wool plug and filter from the front tube into a third 4-ml vial. If analysis of filter is not requested then discard the front glass wool plug and filter. Discard the glass tubes and back glass wool plugs and back glass fiber filter. Add 2.0 ml of extraction solvent to each vial and immediately seal the vials with PTFE-lined caps. Immediately place the vials on a rotator for 60 min. Transfer the sample into autosampler vials for analysis. (Key: 1) ethyl alcohol; 2) 2,3pentanedione; and 3) 3-pentanone.) 3.6 Interferences (analytical) 3.6.1 Any compound that produces a GC response and has a similar retention time as the analyte or internal standard is a potential interference. If potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate interferences from the analyte. 3.6.2 When necessary, the identity of an analyte peak can be confirmed with additional analytical data or procedures (Section 4.10). # Calculations The amount of analyte per sample is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for extraction efficiency. The second tube is analyzed primarily to determine the extent of sampler saturation. If any analyte is found on the back tube, it is added to the amount on the front tube. If more than 20% of the total amount is found on the back tube, report that the sampler may have been saturated on the Form OSHA-91 B. This total amount is then corrected by subtracting the total amount (if any) found on the blank. The air concentration is calculated using the following formulas. # 4.1 Detection limit of the analytical procedure (DLAP) The DLAP is measured as mass of analyte introduced into the chromatographic column. Ten analytical standards were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a reagent blank at or near the retention time of the analyte. The standards and the reagent blank were analyzed with the recommended analytical parameters (1-µL injection with a 2:1 split). The data obtained were used to determine the required parameters (standard error of estimate and slope) for the calculation of the DLAP. The slope and standard error of estimate, respectively, were 6.62 and 62.2. The DLAP was calculated to be 28 pg. 4.2 Detection limit of the overall procedure (DLOP) and reliable quantitation limit (RQL) The DLOP is measured as mass per sample and expressed as equivalent air concentrations, based on the recommended sampling parameters. Ten samplers were spiked with equally descending increments of analyte. The highest amount is the amount spiked on the sampler that would produce a peak approximately 10 times the response of a sample blank at or near the retention time of the analyte. The RQL is considered the lower limit for precise quantitative measurements. It is determined from the regression line parameters obtained for the calculation of the DLOP, providing 75% to 125% of the analyte is recovered. The RQL for 2,3-pentanedione is 0.38 µg per sample (9.3 ppb or 38 µg/m 3 for a TWA sample). Recovery at this concentration is 97.9%. When short-term samples are collected, the air concentration equivalent to the reliable quantitation limit becomes larger. For example, the reliable quantitation limit for the recommended sampler is 31 ppb (127 µg/m 3 ) when 3 Lis sampled. # Precision of the analytical method The precision of the analytical method was measured as the mass equivalent to the standard error of estimate determined from the linear regression of data points from standards over a range that covers 0.1 to 2 times the TWA target concentration for the sampler. A calibration curve was constructed and shown in Section 3.5.2 from the three injections each of five standards. The standard error of estimate was 0.49 µg. Storage samples for 2,3-pentanedione were prepared by sampling a dynamically generated controlled test atmosphere using the recommended sampling parameters. The concentration of 2,3-pentanedione in the test atmosphere was 0.501 ppm ( 2.05 mg/m 3) and the relative humidity was 80% at 23 °C. Thirty-three storage samples were prepared. Three samples were analyzed on the day of generation. Fifteen of the tubes were stored at reduced temperature (4 °C) and the other fifteen were stored in a closed drawer at ambient temperature (about 23 °C). At 3 to 4-day intervals, three samples were selected from each of the two storage sets and analyzed. Sample results are not corrected for extraction efficiency. Results for the ambient storage test decreased by more than 10% which is a significant uncorrectable bias that must be avoided, therefore, samples should be stored in a refrigerator until analyzed, and analysis should be completed within two weeks of sampling. Recovery is determined from the regression line and the maximum change allowed by OSHA methods development guidelines is ±10%. # Precision (overall procedure) The precision of the overall procedure at the 95% confidence level is obtained by multiplying the standard error of estimate by 1.96 (the z-statistic from the standard normal distribution at the 95% confidence level). Ninety-five percent confidence intervals are drawn about the regression lines in the storage stability figures shown in Section 4.4. # 4.5.1 Two dried silica gel tubes in series The precision at the 95% confidence for the refrigerated temperature (4 °C) 17-day storage test was± 10.1 %. It contains an additional 5% for sampling pump error. # Recovery The recovery of 2,3-pentanedione from samples used in a 17-day storage test remained above 91 .3% when samples were stored at 4 °C. # Reproducibility Six samples were prepared by sampling a dynamically generated controlled test atmosphere similar to that used in the collection of the storage samples. The concentrations of 2,3pentanedione in the test atmosphere was 0.501 ppm (2.05 mg/m 3 ) at 78% relative humidity and 23 °C. The samples were submitted to the OSHA Salt Lake Technical Center for analysis. The samples were analyzed after being stored at 4 °C for 4 days. Sample results were corrected for extraction efficiency. No sample result had a deviation greater than the precision of the overall procedure determined in Section 4.4. The sampling capacity of the front tube of the recommended air sampler (two dried silica gel tubes in series) was tested by sampling a dynamically generated controlled test atmosphere containing 2,3-pentanedione at two times the target concentration (1.01 ppm or 4.10 mg/m 3 ) and 80% relative humidity at 23 °C. The samples were collected at 50 ml/min. The second tube in the sampling train was changed at 3 h then at 0.25 h intervals for the rest of the sampling. The presence of analyte on the second tube was defined as breakthrough. The percentage of the amount found on the second tube in relation to the concentration of the test atmosphere was defined as % breakthrough. The % breakthrough was plotted versus the air volume sampled to determine breakthrough air volumes. Breakthrough is considered to have occurred when the effluent from the active sampler contains a concentration of analyte that is 5% of the upstream concentration. The 5% breakthrough air volume for 2,3-pentanedione was 12.5 L. The recommended air volume is 80% of the breakthrough air volume which is 10 L (200 min sampled at 50 ml/min). 12of17 # Extraction efficiency and stability of extracted samples The extraction efficiency is affected by the extraction solvent, the internal standard, the sampling medium, and the technique used to extract the samples. Other reagents and techniques than described in this method can be used provided they are tested as specified in the guidelines. # 15 # Extraction efficiency The extraction efficiency of 2,3-pentanedione was determined by liquid-spiking four front sampling tubes of the recommended air sampler at each concentration level. These samples were stored overnight at ambient temperature and then analyzed. The overall mean extraction efficiency over the working range of 0.1 to 2 times the target concentration was 97.6%. The presence of water had no significant effect on extraction efficiency. The extraction efficiencies for the RQL and for the wet samplers are not included in the overall mean. Wet media were prepared by sampling humid air (78% RH at 23 °C) for 200 min at 50 ml/min. The data obtained are shown in Table 4.8.1. sampled at 50 ml/min for 150 min and then all six samplers were analyzed. The data obtained are shown in Tables 4.9.1. The effect of low humidity was tested by sampling a dynamically generated controlled test atmosphere containing two times the target concentration (1 ppm or 4.1 mg/m 3 ) of 2,3pentanedione at 20% relative humidity and 23 °C. The test atmosphere was sampled with three of the recommended samplers at 50 ml/min for 200 min. All of the samples were immediately analyzed. Sample results were 98.8%, 99.1%, and 97.4% of theoretical. # Low concentration The effect of low concentration was tested by sampling a dynamically generated controlled test atmosphere containing 0.1 times the target concentration (0.05 ppm or 0.205 mg/m 3 ) of 2,3pentanedione at 80% relative humidity and 23 °C. The test atmosphere was sampled with three of the recommended samplers at 0.05 ml/min for 200 min. All of the samples were immediately analyzed. Sample results were 98.7%, 97.0%, and 95.8% of theoretical. # Chemical interference The ability of the recommended sampler to collect 2,3-pentanedione was tested when other potential interferences are present by sampling an atmosphere containing 0.5 ppm (2.05 mg/m 3 ) 2,3-pentanedione at 80% relative humidity and 23 °C and two interferences whose concentrations were 0.51 ppm (1.82 mg/m 3 ) acetoin, and 0.51 ppm (1.78 mg/m 3 ) diacetyl. The test atmosphere was sampled with three of the recommended samplers at 50 ml/min for 200 min. All of the samples were immediately analyzed. Sample results for 2,3-pentanedione were 97.1 %, 96.3%, and 95.5% of theoretical. 2,3pentanedione at an average humidity of 80% at 23°C was sampled for 200 minutes at 50 ml/min. The three foil-wrapped and three unwrapped samples were analyzed immediately and the average recovery for the foil wrapped was 98.2% and the un-wrapped sampler average recovery was 96.6%. Three of the foil-wrapped samplers had the foil removed after sampling and were exposed to fluorescent room lights for 24 h before analysis and had an average recovery of 90.3%. The last three foil wrapped samplers had the foil removed and were exposed to 3 h of sunlight before analysis 15of17 and had an average recovery of 42.4%. This data clearly indicates that the sampler should be protected from exposure to light. To test the possibility of light degradation on extracted samples nine analytical standards at the target concentration were prepared. Six of the standards were placed in 2-ml amber glass vials and three were placed in 2-ml clear glass vials. Three of the amber vials, along with the clear glass vials were stored on the autosampler tray during the entire test while the other three amber vials were stored in the refrigerator when not being analyzed. All nine standards were analyzed eight times over a 10 day period with none of the septa being replaced during the test. The standards in clear vials degraded significantly, but standards in amber vials did not degrade. This data clearly indicates that extracted samples should be protected from exposure to light. The internal standard, 3-pentanone was stable for up to 9 days in both the clear and ambient vials. The data obtained is shown in Table 4.9.3. 4.11. The test atmosphere generation and temperature, and volume of the dilution sampling apparatus. air were regulated by use of a Miller Nelson Flow-Temperature-Humidity controller. The test atmosphere passed into a glass mixing chamber (76-cm x 30-cm) from the vapor generator, and then into a glass exposure chamber (76-cm x 20-cm). Active samplers were attached to glass ports extending from the exposure chamber. The humidity and temperature were measured at the exit of the exposure chamber with an Omega Digital Thermo-hygrometer. The theoretical concentrations were calculated from the ISCO pump flow rate, the concentration of the 2,3-pentanedione solution, and the air flow volumes. The theoretical concentrations were used throughout this validation. 1. Sampler: Thermal sampling tube, %" s.s. tube, multi-bed sorbents capable of trapping organic compounds in the C 3 -C 16 range. Exact sampler configuration depends on thermal desorber system used. See Figure 1 for example. 2. Personal sampling pump, 0.01 to 0.05 L/min, with flexible tubing. 3. Shipping containers for thermal desorber sampling tubes. 4. Instrumentation: thermal desorption system, focusing capability, desorption temperature appropriate to sorbents in tube (-300 °C), and interfaced directly to a GC-MS system. 5. Gas chromatograph with injector fitted with 1/4" column adapter, 1/4" Swagelok nuts and Teflon ferrules (or equivalent). 6. Syringes: 1-µL, 10-µL (liquid); 100-µL, 500-µL (gas tight) 7. Volumetric Flasks, 10-ml. 8. Gas bulb, 2 L SPECIAL PRECAUTIONS:Some solvents are flammable and should be handled with caution in a fume hood. Precautions should be taken to avoid inhalation of the vapors from solvents as well. Skin contact should be avoided. # SAMPLING: NOTE: Prior to field use, clean all thermal desorption tubes thoroughly by heating at or above the intended tube desorption temperature for 1-2 hours with carrier gas flowing at a rate of at least 50 ml/min. Always store tubes with long-term storage caps attached, or in containers that prevent contamination. Identify each tube uniquely with a permanent number on either the tube or tube container. Under no circumstances should tape or labels be applied directly to the thermal desorption tubes. 1. Calibrate each personal sampling pump with a representative sampler in line. 2. Remove the caps of the sampler immediately before sampling. Attach sampler to personal sampling pump with flexible tubing. NOTE: With a multi-bed sorbent tube, it is extremely important to sample in the correct direction, from least to maximum strength sorbent. 3. For general screening, sample at 0.01 to 0.05 L/min for a maximum sample volume of 6 L. Replace caps immediately after sampling. Keep field blanks capped at all times. Tubes can act as diffusive samplers if left uncapped in a contaminated environment. 4. Collect a "humidity test" sample to determine if the thermal adsorption tubes have a high water background. NOTE: At higher sample volumes, additional analyte and water (from humidity) may be collected on the sampling tube. At sufficiently high levels of analyte or water in the sample, the mass spectrometer may malfunction during analysis resulting in loss of data for a given sample. 5. Collect a "control" sample. For indoor air samples this could be either an outside sample at the same location or an indoor sample taken in a non-complaint area. 6. Ship in sample storage containers at ambient temperature. Store at -10 °C. # SAMPLE PREPARATION: 7. Allow samples to equilibrate to room temperature prior to analysis. Remove each sampler from is storage container. Preparation of spiked samples Spiked tubes can be prepared from either liquid or gas bulb standards. Liquid standards: Prepare stock solutions by adding known amounts of analytes to 10-ml volumetric flasks containing high purity solvent (carbon disulfide, methanol, toluene). Solvents are chosen based on solubility for the analytes of interest and ability to be separated from the analytes when chromatographed. Highly volatile compounds should be dissolved in a less volatile solvent. For most compounds, carbon disulfide is a good general purpose solvent, although this will interfere with early eluting compounds. # Gas bulb standards: Inject known amounts of organic analytes of interest into a gas bulb of known volume filled with clean air [4]. Prior to closing the bulb, place a magnetic stirrer and several glass beads are placed in the bulb to assist in agitation after introduction of the analytes. After injection of all of the analytes of interest into the bulb, warm the bulb to 50 °C and place it on a magnetic stirring plate and stir for several minutes to ensure complete vaporization of the analytes. After the bulb has been stirred and cooled to room temperature, remove aliquots from the bulb with a gas syringe and inject into a sample tube as described below. Tube spiking Fit a GC injector with a%" column adapter. Maintain the injector at 120 °C to assist in vaporization of the injected sample. Attach cleaned thermal desorption tubes to injector with%" Swagelok nuts and Teflon ferrules, and adjust helium flow though the injector to 50 ml/min. Attach the sampling tube so that flow direction is the same as for sampling. Take an aliquot of standard solution (gas standards 100 to 500 µL; liquid standards, 0.1 to 2 µL) and inject into the GC injector. Allow to equilibrate for 10 minutes. Remove tube and analyze by thermal desorption using the same conditions as for field samples. lnstrumentation:Actual media, instrumentation, and conditions used for general screening of unknown environments are as follows: Perkin-Elmer ATD 400 (automated thermal desorption system) interfaced directly to a Hewlett-Packard 5980 gas chromatograph/HP5970 mass selective detector and data system. # INTRODUCTION D iacetyl (2,, a dike tone chemical used to impart a buttery taste in many flavoring mixtures, has been associated with severe respiratory disease in several different occupational settings, including microwave popcorn manufacturing, flavoring production, and diacetyl manufacturing_Cl-3 l Laboratory animal studies have documented that diacetyl alone has toxic properties that are similar to the effects of exposure to diacetyl-containing artifi cial butter flavoring mixtures.C 4 • 5 l The Occupational Safety and Health Administration (OSHA) is in the process ofrulemaking on occupational exposure to diacetyl. National Institute for Occupational Safety and Health (NIOSH) researchers developed and published an analytical method, NIOSH Method 2557, to measure airborne diacetyl in the workplace.C 6 -7 l This method specifies air sample collection through carbon molecular sieve (CMS) sorbent tubes, followed by extraction with acetone/methanol (99: 1) and analysis by gas chromatography with flame ionization detection (GC/FID) within 7 days of sampling. Subsequent to the use of this sampling method in several workplace investigations, NIOSH researchers found that the method appeared to progressively 8 Nine each of the 0.5 and 25 ppm samples and 18 of the 5.0 ppm samples were used in both humidity and storage stability analyses. # Sampling Test Conditions Samples were collected between January 2008 and De cember 2009 during four 1-week periods and one 2-week period of tests. We collected a total of 964 CMS tube sam ples during 80 tests, with relative humidity (RH) levels rang ing from 16 to 92% and temperatures of 22.4 to 33.8°C giving absolute humidity (AH) levels ranging from 3.5 to 22.5 mg H 2 0/L air and with diacetyl concentrations ranging from 0.23 to 25.7 ppm. Samples were collected over 2, 4, or 8 hr to test for differences in diacetyl recovery due to sampling duration or because of limit of detection (LOD) concerns during tests at low diacetyl concentrations. Sam ples were collected using sampling flow rates of 50 or 150 cc/min to investigate any effect on diacetyl recovery associ ated with differences in sampling flow rate. The test atmo sphere conditions and sample numbers are summarized in Table I. Over the five visits, we collected 134 silica gel samples at a flow rate of 50 cc/min during 43 of the 2-hr tests. These samples were collected with an AH range of 3.57 to 22.50 mg H 2 0/L air and diacetyl concentrations from 0.56 to 25.7 ppm. # Sample Storage Stability Tests In total, storage stability of diacetyl both in the sampling tubes (in-tube) and after extraction from the tubes was in vestigated using 214 samples (Table I). In the first set of experimental conditions, six sets of triplicate samples were collected at 50 cc/min from a 5.7 ppm diacetyl test atmosphere at each of three AH levels: 3.97, 8.59, and 18.67 mg H 2 0/L air (RH= 17, 36, and 78%, respectively, at 25.7°C). Samples were sent overnight on ice to the analytical laboratory, where they were extracted and analyzed according to NIOSH Method 2557 for diacetyl 1, 4, 7, 10, 13, and 16 days post-sampling. All samples were stored in a refrigerator until the scheduled day of extraction. After analysis of the first set of samples on Day 1 post sampling, the remaining liquid portion (without sorbent mate rial) of each sample was split into two new vials and one stored at room temperature and the other refrigerated. These samples underwent further stability testing via re-analysis 1, 2, 5, and 11 days post-extraction. New septum caps were placed on each vial after each analysis, and freshly prepared standards were used for each re-analysis. To investigate diacetyl concentration effect on storage stability, during the final week of tests, six sets of triplicate samples each were collected from 0.57, 5.6, and 25.0 ppm diacetyl test atmospheres at each of three mean AH levels: 3.6, 8.5, and 18.5 mg H 2 0/L air. The samples were extracted and analyzed 1,4,7,10,16, and 35 days post sampling. When splitting the samples for the extract storage stability tests, equal portions of the sorbent material were placed into the two vials with the liquid to better simulate treatment of field samples as directed in Method 2557. Re analysis of these samples was completed on Days 2, 5, 13, and 34 post-extraction. # RESULTS 0 f 964 CMS samples collected, 717 were used in humidity effect analyses (extraction Day 1 after sampling), 214 were used in sample storage stability analyses (36 of these were used in both analyses), 42 samples from 1 day of tests were excluded due to excessive analytical laboratory variability (the mean coefficient of variation for that day's tests was 73% as compared with a range of 3% to 23% for other days), 13 were excluded due to greater than 5% changes in sampling flow rate during the tests, 3 were excluded due to errors during sampling, 1 had missing data from the analytical laboratory, 1 outlier (greater than 300% recovery) was excluded, and 9 samples collected at low concentration and high humidity were excluded because of nondetectable diacetyl. Of the 134 silica gel samples, 121 that had matching CMS sample groups during 39 tests were used in the comparison analyses. # Effects of Sampling Port Position, Sampling Duration, and Sampling Flow Rate During the first week of tests, homogeneous mixing of di acetyl in the exposure chamber was investigated, and analysis of variance indicated no significant effects of sampling port position on diacetyl recovery. An analysis of variance model using data from the first three laboratory visits (n = 448) with percent diacetyl recovery as the outcome variable and AH, test atmosphere diacetyl concentration, target sampling flow rate, and sampling duration as the predictor variables indicated a significant (p = 0.0042) effect of sampling flow rate, with percent diacetyl recovery being higher for the 150 cc/min sampling flow rate than for 50 cc/min. The magnitude of the effect was not large; the adjusted means (least squares means) for 150 cc/min and 50 cc/min were 44.9 and 40.3% diacetyl recovery, respectively. In this model there was no significant effect for sampling duration (p = 0.89), with adjusted means of 42. 3, 41.8, and 43. 7% diacetyl recovery for sampling durations of 2, 4, and 8 hr, respectively. # Absolute Humidity Effect-Model for Data from Samples Extracted on Day 1 After Sampling We investigated the effect of temperature on diacetyl recov ery by plotting percent diacetyl recovered against either RH (Figure 2a) in% or AH (Figure 2b) in mg H 2 0/L air using data from samples collected from a target diacetyl concentration of 5 ppm at target temperatures of 25°C and 32°C. We calculated AH from RH and temperature (Tc) using Eq. 1, which we derived from a National Weather Service approximation for humidity calculations in surface observations.01l As seen in Figure 2, the substantial difference in diacetyl recovery for the two temperatures was removed when humidity was expressed as AH. Thereafter, we modeled the percent recovered diacetyl in terms of AH. Using the JMP model library of nonlinear functions, we visually determined that the 4-parameter logistic function was suitable to describe the sigmoidal relationship of percent re covered diacetyl with humidity, for samples extracted on Day 1 after sampling. The 4-parameter logistic model has parameters 81, 82, 83, and 84, each of which has graphical meaning. The parameter 8 1 represents the horizontal asymptote on the right hand side of the graph where humidity is at the highest level; 8 2 represents the horizontal asymptote on the left-hand side of the graph where humidity is at the lowest level; 8 3 is the "slope" or the shape parameter; and 8 4 is the humidity at which 50% of the maximal response is observed. The general equation in terms of the 4-parameter logistic model is: 82-81 y = 81 + -------- 1 + exp[8 3 (X -84)](2) In our models, percent recovered diacetyl was the Y vari able, and humidity was the X variable. We fitted separate 4-parameter logistic models to the data for each of the target test atmosphere diacetyl concentrations (0.2, 0.5, 5.0, and 20 ppm). We had too few levels of AH for the 1.0 ppm test atmosphere diacetyl concentration to adequately fit the 4-parameter logistic model. Figure 3 shows the separate 4-parameter logistic models for percent recovered diacetyl vs. AH as fitted through the overall test data (for both sampling flow rates combined). Using information from these models, we created one non linear model for the data overall; this model took into ac count differences in the 4-parameter values for the individual logistic models. We found that 8 1 was well approximated (R 2 = 0.99) by a linear function of target concentration Co We entered this form of the equation (Eq. 3) into the nonlin ear fitting platform for a fit through all the data (including the data for a test atmosphere diacetyl concentration of 1.0 ppm). We repeated the fit through the data stratified by sampling flow rate. The final values for the parameters (b 0 , m 1 , 8 2 , 8 3 , and 8 4 ) both overall and for the two sampling flow rates are given in Table II (the table also contains parameter values for the effect of in-tube storage as described below). The R 2 (amount of total variability in the data accounted for by the model) for the overall model was 0.91. The R 2 for the 150 cc/min model was 0.93, and the R 2 for the 50 cc/min model was 0.90. Figure 4 shows how Eq. 3 describes the pattern of diacetyl recoveries for a range of concentrations both overall and for the two sampling flow rates and illustrates that the effect of sampling flow rate was not large. Equation 3predicts that at a concentration of approximately 56 ppm, the diacetyl recovery would be approximately 100% at all AH values (this was similar for the overall model and the 50 and 150 cc/min models). At diacetyl concentrations above these values, the model predicts diacetyl recoveries of higher than 100% across the range of AH values, which does not represent a real-life solution. Predicted diacetyl recoveries from Eq. 3 for very low diacetyl concentrations do not have the same problem since, mathematically, in the limit as the diacetyl concentration goes to zero, the recoveries range from approximately 100% to approximately 7% as AH goes from low to high. # OSHA Silica Gel Sample Results Diacetyl concentrations from the 121 silica gel samples taken at a number of AH conditions were quite similar to the calculated test atmosphere concentrations (Figure 5a) and were not affected by AH. Using the model (Eq. 3) we calcu lated the corrected diacetyl concentrations from the matched NIOSH Method 2557 CMS samples, and as shown in Figure 5b, we found a strong linear relationship with the silica gel results. # Model for Effect of In-Tube Storage Plots of extract storage and in-tube storage stabilities are shown in Figure 6. Samples stored as extracts, either with or without sorbent material, under refrigerated conditions were stable, having less than 2 % loss at each of the three All levels overnearly 40 days of storage (1.4% at 7 days and 1.7% at 38 days). Under ambient conditions, the loss was 2.9% at 7 days and 11.0% at 38 days. In contrast, plots of diacetyl recovered by number of days of in-tube storage (i.e., days from sampling to extraction) indicated decreased recovery over time, with the changes over time showing dependence on both AH and diacetyl concentration. For a given diacetyl concentration, diacetyl losses over time were greater with increasing AH. For a given AH, diacetyl losses over time were greater with decreasing concentration. To model in-tube storage effects, we used first-order decay functions to estimate decay constants for the 12 combinations of diacetyl concentrations and AH. We normalized the diacetyl recovery data by dividing the diacetyl recovery data by the mean for recovery on Day 1 after sampling and included (t-1) in the first-order decay functions (see below). The first-order decay model is given by: Y =(starting amount) exp [-k(t-1)], where starting amount = 1 for normalized data, t = days from sampling to extraction, and k is the decay constant. We substituted functions of AH and diacetyl concentration for the decay constants (k). This was accomplished in two steps. In Step 1, we fitted quadratic functions to the k values for the three target diacetyl concentration (0.5 ppm, 5 ppm, and 25 ppm) curves of k vs. AH. In Step 2, we substituted three parameter first-order decay functions for the coefficients for the intercept, the AH term and the AH 2 term of the quadratic function based on the diacetyl concentrations. This gave esti mates for the nine coefficients (q, r, s, u, v, w, x, y, and z) in the model (as shown below). In a final step, the values of the nine parameters were used as starting values to get a fit of this nonlinear model through the full set of in-tube storage data. The R 2 for this model was 0.90. The coefficients are given in Table II. The form of the nonlinear model for the effect of in-tube storage was: Normalized recovery= g(Co, AH, t) = exp where The full model can be conceptualized in two steps. First, the AH, the recovered diacetyl concentration (c), and the number of days from sampling to extraction (t) are used to predict the recovered diacetyl concentration on Day 1 of extraction after sampling. Second, this predicted diacetyl value and AH is used to predict the corrected concentration. The full model for the percent of diacetyl recovered is: lOOc Percent recovered diacetyl = --= h(C 0 , AH)g(C 0 , AH, t) Co ( 5) Full Model + h(Co)AH + f3(Co)AH 2 )(t -l)] where his given by Eq. 3 and g is given by Eq. 4. Since, in practice, the values of c, AH, and tare known, and the value of Co is the predicted corrected diacetyl concentra tion, we solved Eq. 5 for C 0 . Using Eqs. 3 and 4, Eq. 5 can be rewritten as: AH, t) where Since this is a nonlinear equation for C 0 , it is necessary to use an iterative procedure to find C 0 . Initially, Eq. 6 is solved for Co using the quadratic formula with the dependence of g on Co ignored: b 2 + 4 a Ceca, ~H, t)) aC6 + bCo -( c ) = 0 (6) g(Co, Co= _ _ _ _ _ _ 2_a _ _ _ _ _ -b+ (7) (Note: The other solution for Eq. 6 using the quadratic formula yields a nonphysical negative value for Co since a > 0 and b > 0.) c In Eqs. 6 and 7 the value of ( ) is the estimate g(Co, AH, t) for the diacetyl concentration corrected for days to extraction after sampling. To solve Eq. 7, an iterative procedure is used with the i value cgl used to calculate the Ci+ 1) value cg+ 1 l b2 + 4a ( 0 c ) g(C 0 ' , AH, t) cg+1) = ------------ 2a -b+(8) It is necessary to start the procedure with an initial Co (i.e., c6 1 \ We found the procedure robust to the choice of starting value and suggest the use of c (the recovered concentration reported by the laboratory). The sequence of solutions is then calculated until two consecutive values for Co are identical to a chosen number of decimal places (convergence). We tested the model for regions of convergence using theoretical recovered concentrations ( c) from 0.001to70 ppm, AH from 2 to 25 mg H 2 0/L air, and days to extraction from 1 to 36. We found that convergence occurred for all concentrations above 1.0 ppm. For lower concentrations, convergence occurred whenever AH was less than 14.5 mg H 2 0/L air and days to extraction were fewer than 9. The region of convergence improved from a concentration of0.001 to 1.0 ppm. At 1.0 ppm, convergence occurred whenever AH was less than 21 mg H 2 0 IL air and days to extraction were fewer than 17. As discussed above, for values of Co > 56 ppm, the Day 1 model does not yield real-life solutions. For these values, only the model for effect of days to extraction should be applied and we predict the concentration of diacetyl for Day 1 of extraction after sampling. If the converged value as calculated above is> 56 ppm, use it as the starting value c6 1 l in an iterative procedure using the equation: cCi+l) - c 0 - (Cl ) g C 0 ', AH, t(9) The sequence of solutions is then calculated until two consecutive values for Co are identical to a chosen number of decimal places. Figure 7 is a flow diagram of the correc tion procedure as described above. When corrected diacetyl concentrations fall between 0.23 and 25.7 ppm, which were the lowest and highest diacetyl test atmosphere concentrations requires laboratory-reported concentrations of diacetyl in ppm (samples collected and analyzed using NIOSH Method 2557), temperature and RH (to calculate AH) conditions at the time of sampling, and the number of days from sample collection to sample extraction for analysis. We give overall parameter values for the full model, as well as for sampling flow rates of 50 and 150 cc/min (Table II). Since the effect of sampling flow rate was not large, investigators have the option of using the overall parameter values, especially if their historical data were collected at sampling flow rates other than 50 and 150 cc/min. A strength of this work was the use of a controlled test atmosphere to simulate historical field survey conditions where airborne diacetyl was sampled together with humid air. By using two target temperatures with similar ranges of RH, we were able to show that both temperature and RH had an effect on diacetyl recovery and that using AH (mg H 2 0/L air) was the key variable to connect the correlation between temperature and concentration. This finding extends the work ofMcKernan and colleagues, CS) who were unable to separate the effect of temperature and RH in their field-based work. By running tests with several different test atmosphere diacetyl concentrations over a wide range from 0.23 to 25.7 ppm, we were able to observe differences in diacetyl recovery related to theoretical diacetyl concentration. We found a large difference in diacetyl recovery between the test atmosphere diacetyl concentration of about 25 ppm and all the lower concentrations, especially at the higher AH values. The final correction equation predicts that humidity would no longer have an effect on diacetyl recovery at approximately 56 ppm, but we have no empirical data to test this prediction. Corrected diacetyl concentrations that lie outside our test atmosphere range represent extrapo lations of the models, and we have less confidence in these concentrations. We do not suggest the use of the correction procedure with historical concentration data below the limit of detection (LOD), for which concentration may have been estimated (e.g., using LOD/2 or LOD/,J2°). It is not possible to know if the workplace diacetyl concentration was indeed below the LOD or if the losses due to humidity and days from sampling to extraction in the laboratory caused the sample value to be below the LOD. We did find some regions of AH and days from sampling to extraction for recovered concentra tions of 1.0 ppm or less where the full model does not con verge; however, such conditions should not occur often in the field. Our storage stability test findings were contrary to the NIOSH Method 2557 specification of good stability for 7 days from sampling to analysis. (7) This may have been due to the fact that storage stability tests completed during method development used spiked sampling tubes without using hu mid air rather than our actively sampled tubes using a test atmosphere. As our results showed, early extraction mini mized further sample loss, especially when the samples were refrigerated in accordance with the method, which means that delays in analysis after extraction should not cause ap-preciable loss. A limitation of our work is that we did not collect in-tube storage data for all the tests to determine the effect of AH on sample recovery, but we did collect data for three target test atmosphere diacetyl concentrations and three target AH values. Thus, we estimated the effect of AH and the effect of in-tube storage on different data sets and combined the two models mathematically to create the final model. Our correction equations accounted for about 90% of the variability in the experimental data by taking into account the effects of AH, test atmosphere diacetyl concentration, sampling flow rate, and days of in-tube storage. The variability seen in the data at any combination of AH and diacetyl concen tration values has a number of sources, including variability in keeping test atmosphere conditions constant, variability in sampling flow rates during the tests, sampling duration differences (although not found significant), and analytical laboratory variability. Our test atmosphere experiments used no flavoring chem icals besides diacetyl. In field situations, diacetyl may occur together with other chemicals in the air. Any effect of these mixtures on the diacetyl recovery using NIOSH Method 2557 might not be accounted for with our correction procedure. Comparison between corrected diacetyl concentrations and the results from side-by-side samples taken with OSHA meth ods indicated a high correlation, which increases our con fidence in the applicability of the correction method. Despite the limitations, the correction procedure enables more accurate quantitative risk assessment now under way for regulatory guidance on occupational exposure to diacetyl. Representative exposures in the flavoring manufacturing industry are difficult to assess because of short-duration batch production methods in which hour-to-hour and day-to-day variations in diacetyl exposures is expected in workplaces where scores of different kinds of flavorings are manufactured. Hence, relative stabil ity of diacetyl exposures in microwave popcorn production facilities offers the advantage of less potential for exposure misclassification. However, without appropriate correction, the systematic underestimation of true diacetyl exposures in the 2000-2006 historical data would lead to overestimation of health risk associated with diacetyl exposure. Accordingly, use of our correction procedure to recalculate the historical exposure estimates from microwave popcorn production facilities previ ously studied by NIOSH and others will contribute to ongoing efforts to understand the health risk associated with occu pational exposure to diacetyl. Our experimental work may also motivate further research exploring the mechanism by which analyte recovery from CMS sorbent may be affected by sampling site humidity for a variety of analytes. # CONCLUSIONS W e have developed a mathematical procedure that al lows measurements from historical diacetyl samples collected and analyzed using NIOSH Method 2557, which may be biased low, to be adjusted for a more accurate exposure assessment. In addition to the historical laboratory-reported diacetyl concentrations, this correction procedure requires data on AH (determined from temperature and RH measurements) during sampling and on the number of days between sample collection and laboratory extraction of the sampling tubes. NIOSH Method 2557 should not be used to measure airborne diacetyl in future studies. # Overview To estimate worker exposures for risk assessment, we developed a job exposure matrix (JEM) containing estimates of the average 8-hour, time-weighted average (TWA) exposure levels for diacetyl vapor in parts per million parts air (ppm). This JEM includes estimates for eight major job categories with selected time periods specific for each job category to reflect changes in processes and engineering controls over time. The exposure levels presented in the JEM are based on diacetyl air sampling data collected during nine industrial hygiene surveys conducted by NIOSH industrial hygienists between November 2000 and July 2003 at a microwave popcorn plant in Missouri NIOSH 2006]. Details of the JEM construction are described below. # Industrial Hygiene Surveys A total of nine industrial hygiene surveys were conducted over a period of 4 years from 2000 to 2003. The sampling was typically conducted during the day shift, because this shift presented the opportunity to sample all job categories. However, samples were also collected from second and third shifts, but not routinely. The dates for these industrial hygiene surveys are presented in Table A4.l. Personal breathing zone (PBZ) and area diacetyl samples were collected during these surveys using NIOSH Method 2557. These measurements were subsequently adjusted to account for interferences due to humidity and sample storage . During all surveys except the first, full-shift PBZ samples were collected from workers performing typical tasks representative of each of the major job categories. In addition, concurrent full-shift area samples were taken throughout the plant from locations where workers would typically spend their time. The PBZ sample measurements were used to develop the exposure estimates for the eight job categories in the JEM. In some instances where personal diacetyl samples were not collected, for example during the first survey, area samples were used to obtain estimates of personal equivalent diacetyl exposures. # Creation of Job Categories and Estimation of Arithmetic Means For the purpose of developing exposure estimates for the JEM, plant job titles were aggregated into eight job categories based primarily on work and environmental similarities with respect to potential for diacetyl exposures [Com and Esmen 1979]. These eight categories are listed in Table A4.2 along with the jobs that comprise each category. Arithmetic means (AM) using PBZ samples were calculated for the cells in the JEM as the AMs are the preferred measure of central tendency for estimating cumulative exposure in chronic disease investigations [Smith 1992]. Few PBZ measurements were collected for most job categories in each of the nine surveys (range: n= 1-6) except for the job category of Microwave line (range n= [11][12][13][14][15][16][17][18]. Moreover, a large fraction of the PBZ measurements were below the limit of detection (LOD) for most job categories (>50%) especially during surveys 6-9, except for the job categories of microwave packaging line, quality control and microwave mixing. Thus because of the small sample size and large fractions of LOD data, a simple substitution method ofreplacing LOD measurements with a value ofLOD/2 was used [Ganser and Hewett 2010]. The calculation of the arithmetic mean exposures by the different time periods is described in detail in the next section on "Creation of Exposure Periods." As noted earlier, PBZ diacetyl samples were not collected during survey 1 and had to be estimated from personal and area samples collected during subsequent surveys (i.e. surveys 2-9). A hierarchical approach was used to estimate the PBZ exposures for survey 1 depending on the job category and the availability and fraction of personal or area measurements below the LOD. To start with, for jobs categories with sufficient personal and area samples in surveys 2-9, a prediction model was used to estimate personal exposures from area exposure measurements (e.g. microwave mixers, microwave line, quality control). For job categories with small sample size and/or large fraction of measurements below the LOD for surveys 2-9, the arithmetic mean of the area samples from survey 1 was assigned to personal estimates for survey 1, assuming a ratio of 1 for personal to area measurements (e.g., warehouse, outside/office, polyethylene line). For jobs with no area measurements in survey 1 (e.g., bag print) or the area measurements were not representative of personal measurements (maintenance), exposure estimates from similar jobs in survey 1 were assigned. The detailed approach to calculate personal-equivalent diacetyl exposure for each job category for the first survey is described in Table A4.3. # 4 Creation of Exposure Periods After estimating the personal-equivalent exposures for survey 1, arithmetic means were calculated for the different time periods. Unique exposure time periods were developed for each of the eight job categories to reflect impact of the exposure control changes implemented at the plant between November 2000 to July 2003. Table A4.4 lists these exposure control changes according to the time of implementation. These exposure time periods varied by job categories since some control changes would have a greater impact on some job categories than others. In addition, the fraction of LOD samples for job categories during the different surveys also impacted the creation of time periods. Surveys for which a large fraction of the measurements for a job category were below the LOD were combined into one time period. For example, for warehouse, 50%-100% of personal measurements were below the LOD for surveys 3-9, hence these surveys were combined into one time period. For the selection of time periods for the job categories, the LOD patterns were consistent with the implementation of controls. The detailed approach used to create the time periods for each job category is described in Table A4.5. Thus a JEM was created consisting of 8 job categories and 2-5 time periods spanning the time duration from November 2000 to July 2003. # 5 Adjustment for Respirator Use The JEM created as described above was based on samples collected from workers breathing zone and did not account for respirator use by workers. However, during survey 4 and onward, workers in microwave mixing were using respirators and the JEM estimates were adjusted in the appropriate time periods to reflect the PPE use. Thus for the mixers during time periods 3 and 4, we adjusted the measured personal diacetyl exposure for the use of respirators. During these time periods, mixers used respiratory protection while in the mixing room and these respirators included either a P APR or air-line respirator with a loose fitting hood; both types of respirators have an applied protection factor (APF) of 25 [NIOSH 2004]. We assumed, based on survey observations and questionnaire responses, that mixers spent, on average, about 4 hours per shift in the mixing room in respiratory protection. Because respirators were required in the mixing room by plant management, we assumed that mixers wore respirators at all times while in the mixing room and did not wear these respirators when outside the mixing room and in the microwave packaging room. During these time periods, the mixers' desk was located in the microwave packaging room near packing line 1 so we further assumed that, when not in respirators in the mixing room, mixers would be in the microwave packaging area and receive diacetyl exposures consistent with those personal exposures measured in microwave packaging. The mixer personal samples were taken outside of the respirator and would reflect both mixing and packaging exposure components. Accordingly, to adjust mixer exposures to diacetyl for the use of respirator, we ( 1) determined the mixing room exposure component from the combined mixing and packing line diacetyl concentration as reflected in the personal sample (back calculated) and ( 2) applied a protection factor of 25 to the mixing room component of the mixers exposure. To determine the mixing room (A) personal diacetyl exposure from the combined mixing and packaging (C) concentration measured by personal sampling we applied the following equation: C = (4A(mixing) + 4B(packaging))/8; solving for A gives, A= 2C -B Where A= the mixing room personal exposure component in ppm, B =the packaging room personal exposure component in ppm, and C = the measured mixer personal exposure in ppm reflecting both mixing room and packaging room components. To correct the mixers exposure for the use of respiratory protection, we used the following equation: CR= 1h (A/25 + B) where CR= respirator adjusted mixer diacetyl exposure in ppm, A= personal mixer diacetyl exposure in the mixing room in ppm and B = personal diacetyl exposure in the microwave packaging area in ppm. This adjusted diacetyl concentration in ppm was applied to mixers for time periods 3 and 4 to adjust for the use of respiratory protection by mixers while in the mixing room. Calculate ratio of the survey 3 diacetyl mean for personal samples to the average of survey 3 diacetyl mean from personal samples for polyethylene, mixer, and microwave packaging line job categories. Apply this ratio to the average of the same three groups from survey 1 after they have been converted to personal equivalent exposures. 3Outside Processing I Office Use the mean of the area sample diacetyl concentrations from survey 1. 4 Polyethylene Line Use the mean of the area sample diacetyl concentrations from survey 1. 5 Microwave Mixing Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to determine personal equivalent diacetyl exposures. 6 Microwave Packaging Line Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to estimate personal equivalent exposures. # 7 Bag Print Use the average of the personal equivalent diacetyl exposures for survey 1 from the microwave packaging line and warehouse job categories. (Note: there were no bag print area diacetyl samples for survey 1) 8 Quality Control Model personal to area diacetyl concentrations from surveys 2-9 and apply model to survey 1 area samples to determine personal equivalent diacetyl exposures. Microwave ovens moved into popping room in quality control lab 14 -18, 2003) Time 3 (Surveys 4 -7 sampling results): Reflects the control changes including the installation of an outside supply air intake system providing clean, tempered air into the warehouse, the completion of LEV ventilation on mezzanine flavor holding tanks and the air-lock installation on the mixing room. All these microwave mixing and production control changes would impact maintenance workers since they would work in these production areas. Also, maintenance exposures during this time period were still primarily above the LOD. Time 4 (Surveys 8 & 9 sampling results): Reflects the control changes including first use of enclosure of the mezzanine tanks. Additionally, maintenance exposures during this time period were largely below detectable limits. Outside Processing I Office Workers: Time I (Surveys I -9 sampling results): Reflects low, predominantly non-detectable exposures for workers who were outside (outside processing) or normally away from microwave mixing and production operations. Polyethylene Line: Time I (Surveys I & 2 sampling results): Reflects polyethylene line worker exposures before major control changes in the microwave production area that could impact polyethylene line workers; although exposures in this category were low by comparison to microwave production lines, there were some detectable diacetyl exposures in personal and area samples for polyethylene line workers during this time period so a separate time period was used. While the polyethylene lines were located away from the microwave production area, there was some potential for exposure in this work group prior to control changes. Reflects the first use of the new mixing room and the addition of new mixing room exhaust fans. This period also reflects enclosure of the mezzanine area reducing microwave production exposures outside the mixing room below quantifiable or detectable levels. 7 Bag Printing: Time 1 (Survey 1 & 2 sampling results): Reflects exposures before major control changes that would impact bag printing exposures due to close proximity to the microwave production lines. Also, when the bag printing operations were shut down, bag print workers would often work on the microwave production lines. Time 2 (Survey 3 sampling results): Reflects the first control changes implemented in the microwave mixing room including the addition of exhaust ventilation, closed transfer of liquid flavorings, and flavor tank ventilation. These control changes would impact bag printing exposures since the bag print lines were located in the warehouse just outside a large open doorway into microwave production; additionally, when the bag printing operations were shut down, bag print workers would often work on the microwave production lines. Time 3 (Surveys 4 -7 sampling results): Reflects several control changes including the installation of an outside supply air intake system providing clean, tempered air into the warehouse and subsequently for microwave production area exhaust fans. This period also reflects completion of LEV ventilation on mezzanine flavor holding tanks and air-lock installation isolating the mixing room from packaging areas. Time (Surveys 8 & 9 sampling results): Reflects the first use of the new mixing room and the addition of new mixing room exhaust fans. This period also reflects enclosure of the mezzanine area reducing microwave production exposures outside the mixing room below quantifiable or detectable levels. Time 2 (Survey 3 sampling results): Reflects the first control changes implemented in the microwave mixing room including the addition of exhaust ventilation, closed transfer of liquid flavorings, and flavor tank ventilation. These changes would impact quality control exposures since the quality control room opened into the microwave production area. Also, the quality control room was generally under negative pressure relative to the microwave production room at this time. Time 3 (Surveys 4 -6 sampling results): Reflects installation of an exhaust fan and fresh air intake in the quality control lab. It also reflects several changes that would impact quality control worker exposures through reduction of diacetyl concentrations in the microwave mixing and production areas including the installation of an outside supply air intake system providing clean, tempered air into the warehouse and subsequently for microwave production area exhaust fans; installation of a mixing room air-lock; and ventilation of mezzanine flavor holding tanks. Time 4 (Surveys 7 & 8 sampling results): Reflects the enclosure of the microwave ovens in the quality control lab. Time 5 (Survey 9 sampling results): Reflects the relocation of all microwave ovens into a separate, ventilated room. This step reduced quality control exposures below detectable levels. Other control changes to the microwave production area during this period reduced microwave production exposures below detectable levels further impacting quality control exposures. Typical protocol for collecting air samples for diacetyl and 2, 3-pentanedione. While the elements of a well-designed exposure monitoring program are discussed in Chapter 10, the details of a typical sampling protocol for determination of airborne concentrations of diacetyl and 2, 3-pentanedione vapor are described here. This protocol, which is based on OSHA pentanedione. It consists of two silica gel tubes connected in series using the least amount as possible flexible tubing. Each tube contains a single 600-mg section of specially cleaned and dried silica gel with a glass-wool plug and a glass fiber filter at front of the tube before the silica gel, and another glass wool plug at the end of the tube. This method is selected because it has greater sensitivity than OSHA Method 1013. Method 1012 requires the use of an ethanol solution containing a derivatizing reagent to extract and chemically derivative diacetyl in the samples. # Preparation Before entering the work area all members of the sampling team should be made aware of any requirements for safety equipment such as hair nets, respirators, or safety shoes, and possess all necessary equipment and training, including respirator certification if needed. Procedures and schedules should be coordinated with the analytical laboratory to assure compatibility of procedures and availability of personnel to process samples in a timely manner. All sampling equipment and supplies should be prepared in advance. Equipment may include battery powered personal sampling pumps capable of operating in the appropriate flow rate range and pressure drop, chargers for those pumps, sample holders of a size compatible with the sampling media, and flexible tubing to connect pumps and sample holders. In this protocol diacetyl and 2, 3-pentanedione vapor samples are collected with two silica gel sorbent tubes in series (SKC Inc.,Eighty Four,PA,. The front tube is connected to the back tube with a piece of tubing to form the sampling train. If the sample holders are not opaque, these sorbent tubes should be wrapped in foil or opaque tape during and after sampling to prevent 2 exposure to light. Each sampling tube should be marked with a unique identification number, either before or after sampling. This information is entered in the field data sheet along with the corresponding pump ID, calibrated flow rate, and other information. A useful convention is to mark each of the two tubes of a sample with the same initial identifier, then add an "f' for the front tube and an "r" for the rear tube. Sampling trains should be assembled and calibrated with sampling media in line, and this sampling media should not be used for any other purpose. Nominal sampling rates for this method are 0.05 Lpm for 180-minute TWA samples and 0.2 Lpm for 15-minute STEL samples. Calibrated flow rate for each pump should be recorded on a field data sheet with an identification code for that pump. A supply of belts, clips, tape, and miscellaneous tools should be available to attach the sampling trains to workers to minimize interference or safety concerns with their jobs. # Collection To collect samples for the full work shift, the sampling team should be prepared to place sampling trains on the workers as they begin their shifts. Workers and locations to be evaluated should have been previously identified from knowledge of the tasks to be performed and the compounds to be used. A common practice in selecting sampling locations is to choose tasks anticipated to produce the greatest level of exposure to diacetyl or 2, 3-pentanedione and to sample the workers conducting those tasks or collect area samples in those areas. This allows for the greatest likelihood of obtaining samples above the limit of detection for the analytical method, and assumes that if exposure is controlled so that the highest exposures are within allowable limits then all exposures are within those limits. Immediately before sampling, break off both ends of the flame-sealed tube to provide an opening approximately half the internal diameter of the tube. Attach the tube holder to the worker so that the adsorbent tube is in an approximately vertical position with the inlet in the breathing zone. Position the sampling pump, tube holder, and tubing so they do not impede work performance or safety. As each sampling train is placed and started, the start time should be noted on the field data sheet for that pump, along with the name or other identifier of the person wearing that pump, job title or a description of tasks, and location within the work facility. Sampling site temperature, relative humidity, barometric pressure, and any other relevant observations should be recorded on field data sheets throughout the duration of sampling. Members of the sampling team should rotate among the sampling locations during the collection of samples. They should occasionally check all sampling devices, observe workers tasks, and note observations on the field data sheet. The use of personal protective equipment and other safety and health controls, ventilation, and all other salient observations should also be noted. Attempt to determine through observation and discussions if workers are engaging in "normal operations." OSHA states a reliable quantitation limit of 1.3 ppb ( 4.57 ug/m 3 ) for diacetyl and 9.3 ppb (38 µg/m 3 ) for 2, 3-pentanedione with a 180-minute sample duration and a flow rate of 0.05 lpm (or 15 minutes at 0.2 lpm). If the shift being sampled is 8 hours long, three samples approaching 180 minutes would be acceptable to obtain a TWA analyte concentration. These samples should be able to quantify diacetyl and 2, 3-pentanedione at the REL of 5 ppb) TWA or 25 ppb) STEL without exceeding the breakthrough capacity of the sorbent media. # Sampling Surveys Employers shall conduct exposure monitoring surveys to ensure that worker exposures (measured by full-shift samples) do not exceed the REL, either on a time weighted or short term basis. Because adverse respiratory health effects may occur at the REL, it is desirable to achieve lower concentrations whenever possible. When workers are potentially exposed to airborne flavoring compounds, employers shall conduct exposure monitoring surveys as follows: • Collect representative personal samples over the entire work shift [NIOSH 1977]. • Perform periodic sampling at least annually and whenever any major process change takes place or whenever another reason exists to suspect that exposure concentrations may have changed. • Collect all routine personal samples in the breathing zones of the workers. • If workers are exposed to concentrations above the REL, perform more frequent exposure monitoring as engineering changes are implemented and until at least two consecutive samples indicate that exposures no longer exceed the REL [NIOSH 1977]. • Notify all workers of monitoring results and of any actions taken to reduce their exposures. • When developing an exposure sampling strategy, consider variations in work and production schedules as well as the inherent variability in most area sampling [NIOSH 1995]. # Focused sampling When sampling to determine whether worker exposures to diacetyl or 2, 3-pentanedione are below the REL, a focused sampling strategy may be more practical than a random sampling approach. A focused sampling strategy targets workers perceived to be exposed to the highest concentrations of a hazardous substance [Leidel and Busch 1994]. This strategy is most efficient for identifying exposures above the REL if maximum-risk workers and time periods are accurately identified. Short tasks involving high concentrations of airborne vapors could result in elevated exposure over full work shifts. # Area sampling Area sampling may be useful in exposure monitoring to determine sources of airborne diacetyl or 2, 3-pentanedione, and to assess the effectiveness of engineering controls. # Post-collection After sampling for the appropriate time, remove the sampling train, record stop time, and remove equipment to an uncontaminated area where you can separate the tubes, and seal each tube with plastic end caps. Although tubes were protected from light during sampling, it is also necessary to wrap each tube in aluminum foil or opaque tape making sure that the sample identification number is observable. Samples should be shipped cold (preferable via an overnight carrier) to the accredited analytical laboratory using a "six-pack" cooler and frozen ice packs (Blue Ice) or similar means to refrigerate samples. Submit blank samples as discussed with the laboratory with each set of samples. Handle the blank samples in the same manner as the other samples except draw no air through them. Measure the air flow rate through each sampling train (using surrogate sampling media in line, not the actual sample), record this post-sampling flow rate. Determine total sampling time (minutes), mean sampling flow rate, and sample volumes (liters). Place sampling pumps on charge for reuse in required. Submit the samples to the laboratory for analysis as soon as possible after sampling. As a precaution, store the samples at refrigerator temperature if a delay in shipment is unavoidable. Ship any bulk samples separate from the air samples. # Acknowledgments The following document was authored by a multidisciplinary team from six NIOSH divisions. The lead division was the Education and Information Division, Paul Schulte, PhD, Director, Lauralynn Taylor McKernan, ScD, CIH (Manager/Author), and R. Todd Niemeier, MS, CIH (Co-manager/Author). This page intentionally left blank. Occupational Exposure to Diacetyl and 2,3-Pentanedione htdocs/Chem_Background/ExSumPdf/431-03-8.pdf. Date accessed: December 2010. National Toxicology Program [2007]. Chemical information review document for artificial butter flavoring and constituents: diacetyl and acetoin . http://ntp.niehs.nih.gov/ ntp/htdocs/Chem_Background/ExSumPdf/Artificial_ butter_flavoring.pdf. Date accessed: NIOSH [1986] NIOSH [2010]. Spirometry in the occupational setting: Spirometry Longitudinal Data Analysis (SPIROLA) software. Atlanta, GA: Centers for Disease Control and Prevention, National Institute for Occupational Safety # Samples are collected by drawing a known volume of air through two silica gel sampling tubes connected in series. Samples are extracted with ethyl alcohol: water (95:5) and analyzed by GC using a flame ionization detector (FID). Recommended sampling time and sampling rate: 60 min at 0.05 L/min (3 L) Reliable quantitation limit: 0.28 ppm (1.00 mg/m3) Special requirements: Samples are collected on two silica gel tubes in series. The second tube is used as a backup for the first tube. Samples should be protected from the light after sampling. # Status of method: Partially evaluated method. This method has been subjected to established evaluation procedures of the Method Development Team and is presented for information and trial use. Samples are collected by drawing workplace air through two tubes containing specially cleaned and dried silica gel connected in series. Samples are extracted and derivatized with a solution of 95:5 ethyl a/cohol:water containing 2 mg/mL of 0- (2, 3, 4, 5, 6-pentafluorobenzyl) hydroxy/amine hydrochloride (PFBHA) and analyzed by gas chromatography using an electron capture detector (GC-ECD). 180 min at 0.05 Umin (9. and 2,3-Pentanedione 268 1 # . General Discussion For assistance with accessibility problems in using figures and illustrations presented in this method, please contact Salt Lake Technical Center (SL TC) at (801) 233-4900. This procedure was designed and tested for internal use by OSHA personnel. Mention of any company name or commercial product does not constitute endorsement by OSHA. 1.1 Background 1. 1. 1 History On September 24, 2007 OSHA issued a Hazard Communication Guidance for Diacetyl and Food Flavorings Containing Diacetyl 1 in which diacetyl was identified as an indicator compound for hazardous exposures found at plants packaging microwave popcorn. This was based on Health Hazard Evaluations performed by NIOSH which found the occurrence of severe lung disease in some employees at microwave popcorn packaging plants and flavorings manufacturing facilities. In three NIOSH Health Hazard Evaluation reports, acetoin and diacetyl are listed as major constituents of butter flavoring and they were used as indicators of exposure to butter flavoring vapors. 2 ' 3 ' 4 OSHA has a partially validated method for diacetyl, PV2118, which recommends the use of two standard sized silica gel tubes in series to collect diacetyl at 0. 05 Umin for 1 hour. 5 There were three reasons a new method was needed: 1) the reliable quantitation limit of PV2118 is 0.28 ppm which is higher than the target concentration of 0.05 ppm for this method; 2) a new medium was needed to enable the industrial hygienist to sample for a longer sampling time and take fewer samples; and 3) to allow acetoin and diacetyl to be sampled and analyzed together. The new medium used in this method is a tube packed with specially cleaned and dried silica gel (600 mg) with a glass wool plug and a glass fiber filter in front of the dried silica gel bed (this medium is referred to as dried silica gel in this method). It was necessary to specially dry the silica gel to obtain a higher capacity because of the amount of water already present on the silica gel in the currently commercially available tubes. The dried silica gel tube can be used to sample diacetyl for up to 1.5 times longer than the currently available silica gel tube. There was not a capacity problem with acetoin. The powder and liquid formulated forms of acetoin and diacetyl may contain oily compounds and other base materials such as maltodrextin. These materials could affect the extraction of acetoin and diacetyl from the silica gel. The glass fiber filter in the tube serves only to trap these materials before they enter the silica gel bed. Retention studies using a powder containing acetoin and diacetyl showed that the acetoin and diacetyl can be stripped off the powder and collected on the silica gel, especially when sampling high humidity air. (Section 4.9) Hazard Communication Guidance for Diacetyl and Food Flavorings Containing Diacetyl, 2007. U.S. Department of Labor, Occupational Safety and Health Administration Web site. http:llwww.osha.gov/dsglguidanceldiacetyl-guidance.html (accessed 311712008). 2 HETA 2001-0474-2943American Pop Corn Company, 2004. Centers for Disease Control and Prevention, The National Institute for Occupational Safety and Health Web site. http:llwww.cdc.gov/nioshlhhelreports/pdfs/2001-047 4-2943). 3 HETA 2002-0408-2915Agrilink Foods Popcorn Plant, 2003. Centers for Disease Control and Prevention, The National Institute for Occupational Safety and Health Web site. http:llwww.cdc.gov/nioshlhhelreports/pdfs/2002-0408-2915. HETA 2003-0112-2949ConAgra Snack Foods, 2004. Centers for Disease Control and Prevention, The National Institute for Occupational Safety and Health Web site. http:llwww.cdc.gov/nioshlhhelreports/pdfs/2003-0112-2949). Shah, Y. C. OSHA Diacetyl ( OSHA Method PV2118), 2003. Appendix B -OSHA 1012 (Acetoin and Diacetyl) Occupational Exposure to Diacetyl and 2,3-Pentanedione # 1.3 Workplace exposure Workers are exposed to acetoin and diacetyl in various manufacturing processes. Acetoin and diacetyl are natural flavorings that are also synthesized for use in odor and flavor manufacturing. 12 ' 13 Acetoin and diacetyl are found in tobacco smoke, vapors from garbage, vapors from liquid and solid animal wastes, exhaust emissions from petroleum based fuels, vapors from moldy buildings, charcoal production, vapors from latex-polyurethane backed carpet, and as chemical reagents and in chemical reactions. 14 Diacetyl is also used as an anti-microbial preservative, modifier of radiation responses for chemical and biological systems, and as a photoinitializer in polymerization of plastics. 11 Hazard Communication Guidance for Diacetyl and Food Flavorings Containing Diacetyl, 2007. U.S. Department of Labor, Occupational Safety and Health Administration Web site. http:llwww.osha.gov/dsglguidanceldiacetyl-guidance.html (accessed 311712008). 12 Fenarolli's Handbook of Flavor Ingredients, 5th ed.;Burdock, G.A.;CRC Press;Boca Raton, FL, 2005, p 11. 13 Fenarolli's Handbook of Flavor Ingredients, 5th ed.;Burdock, G.A.;CRC Press;Boca Raton, FL, 2005, p 411. 14 Chemical Information Review Document for Artificial Butter Flavoring and Constituents Diacetyl (GAS No. 431-03-8) and Acetoin (GAS No. 513-86-0), 2007. Department of Health and Human Services, National Toxicology Program Web site. http:llntp.niehs.nih.govlntplhtdocs!Chem_Background!ExSumpdfl Artificial_butter_flavoring.pdf (accessed 311712008). 15 HETA 2000-0401-2991Gilster-Mary Lee Corporation, 2000 Diacetyl is used as a fragrance and flavor ingredient to give products a buttery or creamy odor and flavor. 18 Diacetyl annual use in food and flavor manufacturing in 2004 was 153,500 pounds. The FDA maximum allowable concentration for diacetyl in beverages is 5 ppm,and in food is 50 ppm. Diacetyl naturally occurs in butter,milk products,yogurt,grains,meat,wines,beer,oils of pine,oil of angelica,oils of lavender and other flowers,many flowers,raspberries,strawberries,citrus,ligonberry,guava,cabbage,peas,tomato,vinegar,cheeses,chicken,beef,mutton,pork,cognac,whiskies,tea,and coffee. Diacetyl is used in manufacturing as a flavoring in alcoholic beverages, baked goods, cheese, chewing gum, fats and oils, frozen dairy products, gelatins and puddings, gravies, hard candy, soft candy, imitation dairy, meat products, milk products, nonalcoholic beverages, and snack foods. 1. 1.4 Physical properties and other descriptive information Acetoin is found as the liquid monomer and the solid dimer. The pure monomer forms the dimer at room temperature. The monomer can be formed from the dimer by heating, distilling, or by dissolving in water or other solvents. HETA 2001-0474-2943American Pop Corn Company, 2001Burdock, G.A.;CRC Press;Boca Raton, FL, 2005, p 11. Fenarolli's Handbook of Flavor Ingredients, 5th ed.;Burdock, G.A.;CRC Press;Boca Raton, FL, 2005, p 411. Budavari, S., Ed;The Merck Index, 13th ed.;Merck & Co. Inc.: Whitehouse Station, NJ, 2001;p 68. Material Safety Data Sheet: Acetoin, Chemwatch, Victoria, Australia (accesed 3117108 diacetyf5,26,21,2a synonyms: biacetyl; 2,3-butanedione; 2,3-butadione; 2,3-diketobutane; dimethyldiketone; dimethylglyoxal; glyoxal, dimethyl Index, 13th ed.;Budavari, S., Ed.;Merck & Co. Inc.: Whitehouse Station, NJ, 2001;p 522. Material Safety Data Sheet: Diacetyl, Chemwatch, Victoria, Australia (accessed 311712008). Material Safety Data Sheet: 2, 3-Butanedione, 2007. Fisher Scientific Web site. https:llfscimage.fishersci.comlmsds/03275.htm (accessed 311712008). Material Safety Data Sheet: 2,3-Butanedione, 2007. Chem Service Inc Web site. http:llwww.chemservice.com/msds/ msds_detail.asp?catnum=0-816 (accessed 311712008 Micro-analytical balance capable of weighing at least 0. 001 mg. An Ohaus Galaxy 160D was used in this evaluation. Rotator. A Fisher Rota Rack was used to extract the samples. # 2 Reagents Acetoin, , reagent grade or better. Acetoin used in this evaluation was 99+% (lot no. 05025DH) purchased from Sigma-Aldrich (Milwaukee, WI). Diacetyl, , reagent grade or better. Diacetyl used in this evaluation was 97% (lot no. 10815TD) purchased from Sigma-Aldrich (Milwaukee, WI). Ethyl alcohol, 95% vlv (190 proof) A.C.S. Spectrophotometric grade. Ethyl alcohol used in this evaluation was 95% (lot no. 80513970) purchased from Acros (Morris Plains, NJ). 0- (2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride, (PFBHA), reagent grade or better. PFBHA used in this evaluation was 99+% (lot no. 1242759 54706063) purchased from Fluka, a subsidiary of Sigma-Aldrich (Milwaukee, WI). , reagent grade or better. 4-Bromobenzylbromide used in this evaluation was 98% (lot no. A0251708) purchased from Acros (Morris Plains, NJ). DI water, 18 Mo-cm. A Barnstead NanoPure Diamond system was used to purify the water for this evaluation. The PFBHA extraction solution used for this evaluation consisted of 20 µg/mL 4-bromobenzylbromide in the 95:5 ethyl alcohol:water with 2 mg/mL PFBHA. The 4-bromobenzylbromide was added to 95:5 ethyl alcohol:water as an internal standard. Other internal standards can be used provided they are fully tested. Store this solution in a tightly sealed container in a refrigerator that does not contain solutions of aldehydes, acids, or ketones. This solution can absorb formaldehyde, other aldehydes, ketones, and acids out of the air. These compounds will react with the PFBHA, decreasing the amount available to react with acetoin or diacetyl. This solution can be stored in the refrigerator for 1 week. 13 # Standard preparation Prepare stock solution of acetoin and diacetyl in water. Acetoin is usually sold as the dimer, which will disassociate in water to the monomer as the solid dimer dissolves. This stock solution will remain stable for four weeks if stored in an amber bottle in the refrigerator. # 34 Freshly prepare analytical standards from the stock solutions for each analysis. These analytical standards are prepared for each of the analytes by injection of micro/iter amounts of a stock solution into 2-mL volumetric flasks and diluting with the PFBHA extraction solution over a concentration range of 0.02 to 6 µg/sample. For example: a target concentration standard of 1. 60 µg/sample acetoin and 1. 56 µg/sample diacetyl was prepared by injecting 16 µL of a stock solution containing 0.10 µg/mL acetoin and 0.10 µUmL (0.0975 µg/mL) diacetyl in water into a 2-mL volumetric flask containing about 1. 75 mL of PFBHA extraction solution and then diluting to the mark with PFBHA extraction solution (this is equivalent to 0.80 µg/mL acetoin or 0.049 ppm based on a 2-mL extraction and 9 L air volume, and 0. 78 µg/mL diacetyl or 0. 049 ppm based on a 2-mL extraction and 9 Lair volume). Standards must be allowed to react with the PFBHA at room temperature for 36 hours. # Bracket sample concentrations with standard concentrations. If upon analysis, sample concentrations fall outside the range of prepared standards, prepare and analyze additional standards to confirm instrument response, or dilute high samples with PFBHA extraction solution and reanalyze the diluted samples. # Sample preparation Remove the plastic end caps from the sample tube and carefully transfer the section of the adsorbent from each tube into separate 4-mL amber vials. Normally the front glass wool plug and glass fiber filter are discarded. If the industrial hygienist requests the analysis, the front glass wool plug and the glass fiber filter should be placed into a separate 4-mL amber vial. Discard the glass tubes and back glass wool plugs. Add 2. 0 mL of PFBHA extraction solution to each vial and immediately seal the vials with PTFE-lined caps. Place the samples on a mechanical rotator and rotate at approximately 40 rpm for 60 min. Do not use a shaker to extract samples, as the recoveries will be lower. Allow the samples to stand at room temperature for an additional 36 hours for the derivatization reaction to reach completion. Transfer each solution from the 4-mL vial to a labeled amber 2-mL glass autosampler vial and seal with a PTFE-lined cap. If more sensitivity is desired for samples prepared by OSHA Method 1013 # 35 , they can be derivatized by the PFBHA solution and analyzed by GC-ECD. The samples in OSHA 1013 are extracted with 2 mL 95:5 ethyl alcohol:water. The samples can be derivatized by the following procedure: add 0.5-mL of sample and 0.5-mL of PFBHA extraction solution into a labeled 2-mL vial, and react for 36 hours, and then analyze by GC-ECD following the analytical conditions in this method. Standards prepared by OSHA Method 1013 are derivatized following the same procedure. The RQL will be a factor of 2 higher due to this dilution of the samples. and 2,3-Pentanedione 3. 6 Interferences (analytical) Any compound that produces a GC-ECD response and has a similar retention time as the analyte is a potential interference. If any potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate an interference from the analyte. # 7 Calculations The amount of analyte per sampler is obtained from the appropriate calibration curve in terms of micrograms of analyte per sample, uncorrected for extraction efficiency. The front amount found is then corrected by subtracting the total amount (if any) found on the front blank. The back amount found is then corrected by subtracting the total amount (if any) found on the back blank. The amount found on the back dried silica gel tube is added to the front tube for the total loading on each sample. The back-up tube is analyzed separately to determine the extent of analyte saturation to determine if breakthrough occurred. Even though the analytes are analyzed as the PFBHA derivatives and the calibration and results are as the amount of analyte. The air concentration is calculated using the following formulas. General background information about the determination of detection limits and precision of the overall procedure is found in the "Evaluation Guidelines for Air Sampling Methods Utilizing Chromatography Analysis". 36 The Guidelines define analytical parameters, specify required laboratory tests, statistical calculations, and acceptance criteria. # 1 Detection limit of the analytical procedure (DLAP) The DLAP is measured as the mass of analyte introduced onto the chromatographic column. Ten analytical standards were prepared with equally descending increments with the highest standard containing 97.9 ng/mL acetoin, and for diacetyl the highest standard was 95.5 ng/mL. and 2,3-Pentanedione 290 4.7 # Sampler capacity The sampling capacity of the front tube of two dried silica gel tubes in series was tested by sampling from a dynamically generated test atmosphere with an average relative humidity of 81% at 23°C at concentrations of 0.101 ppm (0.365 mg/m 3 ) acetoin, and 0.101 ppm (0.355 mg/m 3) diacetyl. The second tube in the sampling train was changed at 1 h intervals for the first 3 hours then at 0. 5 hour intervals for the rest of the sampling. The dried silica gel tube sampling trains were used to sample at approximately 0.05 Umin (each air volume listed below uses that specific tube's flow rate). The presence of analyte on the second tube was defined as breakthrough. The percentage of the amount found on the second tube of the total concentration is the % breakthrough. The % breakthrough was plotted versus the air volume sampled to determine the 5% breakthrough air volumes. The 5% breakthrough air volume for diacetyl was 12. 1 L. The recommended air volume is 80% of the breakthrough air volume which is 9. 68 L. Acetoin had no breakthrough after samples were collected for up to 8 hours. and 2,3 # -Pentanedione # Low concentration The ability of dried silica gel tubes to collect the analytes from a low concentration atmosphere was tested by using a test atmosphere at 0. 1 times the target concentration having an average relative humidity of 80% at 23 °C. The test atmosphere was dynamically generated at 0.0051 ppm (0.0184 mglm 3) acetoin and 0.0051 ppm (0.0180 mglm 3) diacetyl. Three samplers had contaminated air drawn through them at 0. 05 Umin for 180 min. All of the samples were immediately analyzed. The recoveries (% of theoretical) for acetoin were: 99.8%, 99.9%, and 97.2%, and fordiacetyl were: 97.3%, 98.1%, and 99.8%. # Sampling interference The ability of dried silica gel tubes to collect the analytes from an atmosphere containing interferences was tested under two different sets of conditions. The first set of conditions was a test atmosphere of 0.051 ppm (0.0184 mglm 3 ) acetoin and 0.051 ppm (0.0180 mglm 3 ) diacetyl and an interference mixture of 1.01 ppm (1.82 methyl ethyl ketone at an average humidity of 80% at 23 °C. These lower concentrations were chosen for two reasons: they are similar to some of the concentrations found in plants manufacturing microwave popcorn, and all of these compounds will be derivatized by the PFBHA; therefore, there would be enough PFBHA in solution to derivatize all of the analytes that were collected (8.01 µmole/mL PFBHA). The recoveries (% of theoretical) of acetoin and diacetyl were: 95.4%, 98. 5%, and 99. 7% for acetoin and 95.8%, 98.9%, and 99.8% for diacetyl. There was no analyte on the backup tube of the two dried silica gel tubes in series for any of the tests. # The second series of tests was with acetoin and diacetyl at the target concentration and each of the interferences listed above individually at their PEL concentration following the guidelines in SL TC "Evaluation Guidelines for Air Sampling Methods Utilizing Chromatographic Analysis" 38 • The concentrations of these interferences are much higher than would normally be expected in a food or flavoring manufacturing workplace. These three compounds were chosen as interferences because they collect on the dried silica gel tubes and react with the PFBHA. The extraction solution needed to be modified to 18 mg/mL PFBHA (72. 1 µmoles/mL) to insure that there was enough PFBHA in solution to derivatize all the analytes. These three atmospheres each contained acetoin and diacetr,1 with one of the following concentrations of the interference mixture in it: 194 ppm (350 mg/m) acetaldehyde, 9.49 # Generation oftest atmospheres The test atmosphere of acetoin and diacetyl was generated from a water solution. The following apparatus was placed in a walk-in hood. The acetoin and diacetyl vapors were generated by pumping the solution, using the lsco pump, through a short length of 0. 53-mm uncoated fused silica capillary tubing into a vapor generator where it was heated and evaporated into the dilution air stream (Figure 4. 11 ). The vapor generator consisted of a 15-cm length of 5-cm diameter glass tubing with a side port for introduction of the capillary tubing. The test atmosphere generation and sampling apparatus. . 2 Limit defining parameters 1.2.1 Detection limit of the analytical procedure The detection limit of the analytical procedure is 0.017 ng for acetoin and 0.033 ng for diacetyl. These are the amount of analytes that will give a detector response that is significantly different from the response of a calibration blank. (Section 4.1) 1.2.2 Detection limit of the overall procedure The detection limit of the overall procedure for acetoin is 0.10 µg per sample (0.0031 ppm or 0.011 mg/m 3 ) and 0.11 µg per sample for diacetyl (0.0034 ppm or 0.012 mg/m 3). These are the amounts spiked onto the sampler that will give a detector response that is significantly different from the response of a sampler blank. (Section 4.2) # Reliable quantitation limit The reliable quantitation limit for acetoin is 0.35 µg per sample (0.011 ppm or 0.039 mg/m 3 for a TWA sample) and 0.37 µg per sample for diacetyl (0.012 ppm or 0.041 mg/m 3 for a TWA sample). These are the amounts spiked onto the sampler that will give a detector response that is considered the lower limit for precise quantitative measurements. (Section 4.2) # Instrument calibration The standard error of estimate is 0.42 µg for acetoin over the range of 3.73 µg to 31.0 µg. The standard error of estimate is 0.82 µg for diacetyl over the range of 3.58 µg to 29.9 µg. These ranges correspond to approximately 0.25 to 2 times the target concentration. (Section 4.3) # Precision The precision of the overall procedure at the 95% confidence level for the ambient temperature 18-day storage test (at the target concentration) is ±11.2% for acetoin and ±10.1 % for diacetyl. These include an additional 5% for sampling pump variability. (Section 4.4) # Recovery The recovery from samples used in a 18-day storage test remained above 88.5% for acetoin and 102. 7% for diacetyl when the samples were stored at ambient temperature. (Section 4.5) A dispenser capable of delivering 2.0 ml of desorbing solvent to prepare standards and samples. If a dispenser is not available, a 2.0-ml volumetric pipet can be used. Amber glass vials with PTFE-lined caps. For this evaluation 2 and 4-ml vials were used. Calibrated 10-µl and 25-µl syringes for preparing standards. Water purifier. A Barnstead NANOpure Diamond system was used to produce 18.0 Mn-cm DI water in this evaluation. Water bath. A Precision Scientific (5 -100 °C range) water bath was used in this evaluation. A mechanical rotator. A Fisher Roto-Rack was used in this evaluation. Class A 1-l volumetric flasks. Class A 1-ml and 5-ml volumetric pipets. The extraction solvent used for this evaluation consisted of 0.007 µL/ml 3-pentanone in 95% v/v ethyl alcohol. The 3-pentanone was added to the ethyl alcohol as an internal standard (ISTD). # Standard preparation Prepare a concentrated stock standard of acetoin and diacetyl in 18.0 Mn-cm DI water and store in an amber vial or bottle. (Note: Acetoin is usually obtained as the solid dimmer and will convert back to the monomer when dissolved in water.) Acetoin will slowly dissolve in water, however, this process can be accelerated by placing the solution in a 60 °C water bath for 10 min. Refrigerate the stock standard when not in use and remake once a month. Prepare working analytical standards by injecting micro liter amounts of the concentrated stock standard into amber 4-ml vials containing 2 ml of the extraction solvent delivered by the same dispenser used to extract samples. For example, to prepare a target level standard (16.25 µg/sample acetoin and 15.86 µg/sample diacetyl) , inject 13 µl of a stock standard containing 1 .25 µg/µl acetoin and 1.22 µg/µl diacetyl into 2-ml of extraction solvent. Transfer working standards to 2-ml amber glass autosampler vials. Interferences (analytical) 3.6.1 Any compound that produces an FID response and has a similar retention time as the analytes or internal standard is a potential interference. If any potential interferences were reported, they should be considered before samples are extracted. Generally, chromatographic conditions can be altered to separate an interference from the analyte. 3.6.2 When necessary, the identity of an analyte peak may be confirmed with additional analytical data (Section 4.12). # Calculations The amount of analyte per sampler is obtained from the appropriate calibration curve in terms of micrograms per sample, uncorrected for extraction efficiency. The back tube is analyzed primarily to determine the extent of sampler saturation. If any analyte is found on the back tube, it is added to the amount on the front tube. This total amount is then corrected by subtracting the total amount (if any) found on the blank. The air concentration is calculated using the following formulas. General background information about the determination of detection limits and prec1s1on of the overall procedure is found in the "Evaluation Guidelines for Air Sampling Methods Utilizing and 2,3-Pentanedione 322 The average percent change for acetoin samples after 24 h was +0.5% for samples that were resealed with new septa and +0.5% for those that retained their punctured septa. The test was performed at room temperature (about 21 °C). The average percent change for acetoin samples after 72 h was -1.8% for samples that were resealed with new septa and -0.9% for those that retained their punctured septa. The average percent change for diacetyl after 24 h was +0.4% for samples that were resealed with new septa and -1.4% for those that retained their punctured septa. The test was performed at room temperature (about 21 °C). The average percent change for diacetyl samples after 72 h was +1.0% for samples that were resealed with new septa and -0.8% for those that retained their punctured septa. . # Total micrograms per sample of analyte is Below are instructions on how the silica gel is prepared for the sampling tubes used in this evaluation. # A.1 .1 Apparatus Tube furnace and quartz process tube. A Lindberg model 55035 tube furnace and 1-inch diameter quartz process tube were used in this evaluation. Nitrogen gas. # A.1 .2 Silica Gel Washed 20/40 mesh silica gel with 30 angstrom pore size (washed silica gel can be purchased from SKC, Inc.). A description of a washing procedure for silica gel can be found in the appendix of NIOSH 7903 30 . # A.1 .3 Preparation of silica gel Insert a quartz wool plug in a 1-inch diameter quartz process tube, followed by 50 g of washed silica gel and a second quartz wool plug to hold the silica gel in place. Place the process tube in a tube furnace and set the temperature to 180 °C. Continually purge the process tube with nitrogen at a rate of about 0.5 L/min. Allow the silica gel to dry in the tube furnace for 4 hours. After 4 hours allow the process tube to cool while continuing to purge the tube with nitrogen. Once the silica gel is cool, remove one of the quartz wool plugs, and transfer silica gel into an airtight container. Record sample air volumes (L), sampling time (min), and sampling rate (ml/min) for each sample, along with any potential interferences on the Form OSHA-91A. Submit the samples to the laboratory for analysis as soon as possible after sampling, preferably by overnight or express shipping. If delay is unavoidable, store the samples in a refrigerator. Ship samples cold to laboratory, such as shipping with frozen plastic ice packs in a cooler. Ship any bulk samples separate from the air samples. # Analytical Procedure Adhere to the rules set down in your laboratory's Chemical Hygiene Plan 13 (for instance OSHA SL TC adheres to: "The OSHA SL TC Chemical Hygiene Plan"). Avoid skin contact and inhalation of all chemicals and review all MSDSs before beginning this analytical procedure. Follow all applicable quality assurance practices established in your internal quality system (for instance OSHA SL TC follows: "The OSHA SL TC Quality Assurance Manual"). # Apparatus Gas chromatograph equipped with an FID. An Agilent 6890 GC System equipped with a Chemstation, an automatic sample injector, and an Agilent tapered, deactivated, split, low pressure drop injection port liner with glass wool (catalog no. 5183-4647) was used in this validation. A GC column capable of separating 2,3-pentanedione from the extraction solvent, potential interferences, and internal standard. A DB-1 60-m x 0.32-mm i.d. (5-µm df) capillary column was used in this validation. An electronic integrator or other suitable means of measuring GC detector response. A Waters Empower 2 Data System was used in this validation. Amber glass vials with PTFE-lined caps. Two and 4-ml vials were used in this validation. A dispenser capable of delivering 2.0 ml of extraction solvent to prepare standards and samples. If a dispenser is not available, 2.0-ml volumetric pipettes can be used. Class A volumetric flasks -10-ml and other convenient sizes for preparing standards. Calibrated syringe -25-µL and other convenient sizes for preparing standards. Rotator. A Fisher Roto Rack was used to extract the samples in this validation. # Reagents DI water, 18.0 MQ-cm. A Barnstead NanoPure Diamond system was used to purify the water in this validation. Ethyl Alcohol, . The ethyl alcohol:water solution used in this validation was 95% v/v (190 proof) A.C.S. spectrophotometric grade (lot no. 80513920) purchased from Acros Organics (Morris Plains, NJ). Do not use absolute alcohol or denatured alcohol in this method. # Stability of extracted samples The stability of extracted samples was examined by reanalyzing the target concentration samples 24, 48, and 72 h after the initial analysis. After the original analysis was performed two vials were recapped with new septa which were replaced after each analysis. The remaining two vials retained their punctured septa throughout this test. All samples were allowed to stand in the autosampler tray at 22 °C. The samples were reanalyzed with freshly prepared standards. Diff is the difference between the initial analysis and the subsequent analysis. Each septum was punctured 5 times for each analysis. The data obtained are shown in Table 4.8.2. The tested sampling interferences had no significant effect on the ability of the recommended sampler to collect or retain 2,3-pentanedione when the samples were protected from exposure to light. # Retention Retention was tested by sampling a dynamically generated controlled test atmosphere containing two times the target concentration (1 ppm or 4.1 mg!m3) of 2,3-pentanedione at 80% relative humidity and 23 °C. The test atmosphere was sampled with the recommended sampler at 50 ml/min for 50 min. After 50 min sampling was discontinued and the samplers were separated into two sets of 3 samplers each. 1 ). The sampling has been conducted using multi-bed thermal desorption tubes. The analysis procedure has been able to identify a wide range of organic compounds, based on operator expertise and library searching. INTERFERENCES: Compounds which coelute on the chromatographic column may present an interference in the identification of each compound. By appropriate use of background subtraction, the mass spectrometrist may be able to obtain more representative spectra of each compound and provide a tentative identity (See Table 1 ). OTHER METl-DDS: Other methods have been published for the determination of specific compounds in air by thermal desorption/gas chromatography [1][2][3]. One of the primary differences in these methods is the sorbents used in the thermal desorption tubes. The method has been used for a number of field screening evaluations to detect volatile organic compounds. Estimate of the limit of detection for the method is based on the analysis of spiked samples for a number of different types of organic compounds. For the compounds studied, reliable mass spectra were collected at a level of 100 ng per compound or less. In situations where high levels of humidity may be present on the sample, some of the polar volatile compounds may not be efficiently collected on the internal trap of the thermal desorber. In these situations, purging of the samples with 3 L of helium at 100 ml/min removed the excess water and did not appreciably affect the recovery of the analytes on the sample. Multi-bed sorbent tubes: Other sorbent combinations and instrumentation/conditions shown to be equivalent may be substituted for those listed below. In particular, if the compounds of interest are known, specifc sorbents and conditions can be chosen that work best for that particular compound(s). The tubes that have been used in NIOSH studies with the Perkin Elmer ATD system are %" stainless steel tubes, and are shown in the diagram below: We studied the effect of humidity on measured diacetyl air concentrations using NIOSH Method 2557 with the aim of developing a means for mathematically correcting previously obtained measurements of airborne diacetyl. In addition, we investigated sample storage stability over time because we were aware that some previously obtained field samples had been analyzed beyond the method's specified 7-day maximum storage duration. # METHODS # Protocol The initial objective of our experiments was to determine if sampling site humidity affects diacetyl recovery in air samples and, if so, to develop a mathematical procedure to correct existing diacetyl air sampling data from previous workplace studies for those effects. NIOSH and OSHA investigators conducted a total of 6 weeks of tests during five visits by NIOSH investigators to the OSHA Salt Lake Technical Center (SLTC) laboratory. During the first week of tests, we started to investigate the effect of humidity and sampling flow rate, as well as the homogeneity of diacetyl mixing in the dynamically generated controlled test atmosphere. During the second and third weeks, we investigated effects of temperature, sampling duration, sampling flow rate, and test atmosphere diacetyl concentration on diacetyl recovery. Based on results of the first 3 weeks of tests, during the following 2-week test period, we ran tests to further evaluate the effect of test atmosphere diacetyl concentration. In addi tion, during that 2-week test period we studied sample storage stability using a single test atmosphere diacetyl concentration. Based on the sample storage stability results, we further eval uated the test atmosphere diacetyl concentration effect during a final week of tests. Since we found an effect of sample storage duration on diacetyl recovery, which was dependent on both humidity and test atmosphere diacetyl concentration, the primary objective was extended to include this effect in the mathematical correction procedure. During each of the five visits, we also collected a number of samples using OSHA Method PV2118 (OSHA 1013CIO) was used once it became available) to compare with test atmosphere diacetyl concentration. # Test Atmosphere Generation Test atmospheres of diacetyl were generated at the OSHA SLTC laboratory by pumping an aqueous diacetyl solution (approximately 1 to 100% diacetyl depending on target con centration), using a syringe pump (Series D; Teledyne Isco Inc., Lincoln, Neb.), through a short length of 0.53 mm di ameter uncoated fused silica capillary tubing into a vapor generator where it was heated and evaporated into a dilution airstream (Figure 1). The vapor generator, a 20 cm length of 3 cm diameter glass tubing with a side port for introduc tion of the capillary tubing, was wrapped with heating tape to evaporate the solution. Humidity, temperature, and vol ume of the dilution stream of air were regulated by use of a flow-temperature-humidity control system (Model HCS-401; Miller-Nelson Instruments Inc., Pleasanton, Calif.). The diacetyl-laden air passed from the vapor generator into a glass mixing chamber (76 cm length x 15 cm diameter) and then into a glass exposure chamber (76 cm length x 8 cm diameter). Eighteen evenly spaced glass tube sampling ports extended from the exposure chamber: nine from the bottom and nine from a side. The temperature and relative humidity were measured at the exit of the exposure chamber with a digital thermo-hygrometer (Model RH-411; Omega Engineer ing, Inc., Stamford, Conn.). The test atmosphere generation apparatus was located in a walk-in hood. Theoretical test atmosphere concentrations of diacetyl were derived using mass flow calculations. These calculations used syringe pump flow rate, chamber airflow rate, and diacetyl concentration in the aqueous solution. # Sampling Procedure CMS sorbent tubes (Anasorb CMS 226-121; SKC, Eighty Four, Pa.) and pairs (in series) of SKC Model 226-183 silica gel sorbent tubes were attached to the sampling ports, and the test atmosphere was pulled via vacuum through the sorbent tubes with sampling flow rate controlled by adjustable orifices. For each test, flow through each sorbent tube was pre-and post calibrated with a flowmeter (Model 4100; TSI, Inc., Shoreview, Minn.). After sampling, the sorbent tubes were immediately capped, wrapped in foil, and placed on ice packs in a cooler along with blank sorbent tubes. The coolers were shipped nightly via express mail to a NIOSH-contracted analytical laboratory, where the sorbent tubes were extracted on arrival on Day 1 after sampling (or later, as directed for a few sets of CMS tubes used for storage stability experiments) and analyzed by GC/FID. used in our experiments, we consider the corrections to be within the interpolated range and have the most confidence in these values. Figure 8 shows diacetyl concentrations predicted by our models for a number of different conditions. We chose three laboratory-reported diacetyl concentrations (c) of 0.02, 1.0, and 20 ppm over a wide range of AH and days from sampling to extraction (t) that should represent possible field conditions. We see that both changes in AH and t substantially affect the value of the corrected concentration. In Figure 8a, we indicate a point where nonconvergence begins for c = 0.02 ppm and AH= 19 on the 14 days from sampling to extraction curve. In Figure 8c, we indicate a region where Co > 56, which is only corrected for days from sampling to extraction. # DISCUSSION F rom experimental test atmosphere work, we have created a procedure that allows historical diacetyl concentration data from analysis of samples using NIOSH Method 2557 to be corrected to more accurately estimate historical workplace airborne diacetyl concentrations. This correction procedure provides a means for applying these diacetyl concentration es timates in planned quantitative risk assessment relating health effects observed among workers to their diacetyl exposure. In addition, it will allow for a better understanding of historical workplace concentrations of diacetyl that will give insight for exposure control strategies. Use of this correction procedure The mean diacetyl vapor concentrations estimated for the three plants with a single NIOSH survey are shown in Tables A3.1 -A3.3. For the fourth plant, Company G, time-dependent exposure levels were estimated in the NIOSH-OSHA JEM collaboration (Table A3.4). All Method 2557 measurements were corrected for temperature, humidity, and days to extraction. Temperature control installed on one flavoring tank Tempered, outside supply air intake system completed, providing August 7, 2001 replacement air for microwave popcorn production areas Follow-up Survey (September 4 -8, 2001) September 11, 2001 Exhaust fan installed in quality control lab September 18, 2001 Fresh air intake installed in quality control lab September [21][22][23][24][25][26][27][28][29][30]2001 Completion of local exhaust ventilation for all mezzanine oil tanks November 2,2001 Flavoring transfer pump installed for 5-gallon containers November 2, 2001 Air lock installed outside of mixing room Follow-up Survey (November 6 -8, 2001) Follow-up Survey (March 18 -21, 2002 Started use of supplied-air respirators for mixers in mixing room and mezzanine (air-purifying respirators with organic vapor cartridges and	None	None
6493e14358071bbd4b18ec9e74e61c479dab216f	cdc	None	Association o f State and Territorial Health Officials (ASTHO) conducted a survey o f state health department personnel regarding programs, policies, and public health systems that stress the prevention and control o f the use o f tobacco. This survey provided detailed data associated with state tobacco-use control programs and their essential components (e.g.f budgets, planning, coalitions, surveillance systems, smoking cessation pro grams, educational activities, legislative actions, and health department poli cies). States vary widely in the strength and coverage o f their programs for preventing and controlling tobacco use. The ASTHO survey data may be used to help plan and evaluate state health department programs as part o f an effort to prevent chronic diseases related to tobacco use. Outcomes o f state activities may be evaluated through surveys such as CDC's Behavioral Risk Factor Surveillance System (BRFSS) and the Current Population Survey (CPS) o f the Bureau o f the Census. Future surveys o f state activities for controlling the use o f tobacco may be included in the evaluation o f the upcoming# INTRODUCTION The Association of State and Territorial Health Officials (ASTHO) conducted a survey in October 1989 to assess progress among the states in the public health practice of preventing and controlling tobacco use. The survey was also conducted to provide states with incentives to create and implement efforts to control tobacco use. The survey covered several components of effective state programs that address such efforts among targeted populations. Additional sources either supplemented or validated state information on tobacco-use control data collected through the ASTHO survey. In the fall of 1989, ASTHO established a network of health professionals responsible for communication between the federal government and state health departments on issues related to tobacco-use prevention and control. As the identi fiable contacts for information transfer on tobacco-related matters, these persons served as respondents to the ASTHO survey. # METHODS The survey's 10 major sections are 1) background information on tobacco and tobacco control; 2) adult tobacco-use surveillance; 3) adolescent tobacco-use surveillance; 4) reporting and analysis of data on the impact of tobacco-related disease; 5) regulatory activities; 6) coalitions against tobacco use; 7) special populations; 8) community information on education activities; 9) economic incen tives, deterrents; and 10) educational institutions. ASTHO contacts solicited the help of state departments of education to answer questions about tobacco-use control activities in educational institutions (public and private schools). This section of the survey assessed the ability of each state to measure progress toward smoke-free schools and the extent to which educational institutions addressed antitobacco education. Central data sources were used to supplement the survey results for the following areas of this report: legislative activities; taxation; and number of schools, districts, and enrolled students. Sources used to supplement information on legislative issues included State Legislated Actions on Tobacco Issues of the Tobacco-Free America Project (7) and Major Local Smoking Ordinances in the United States, National Institutes of Health (2). The Tobacco Institute also provided state-specific data on taxation (3). For information related to schools and school districts, the 1990 World Almanac was used to supplement information supplied by the states (4). Finally, previously tabulated data were reviewed and updated by the ASTHO network in December 1990. # Data Collection and Analysis ASTHO sent the questionnaires to all 50 states and the District of Columbia. For the purpose of this report, the District of Columbia is considered a state when summary data are presented. In some cases, supplemental information was obtained by tele phone. Responses were tabulated and analyzed using True Epistat and dBase IV (5,6). # RESULTS The response rates were 100% for both the main section and educational sections. # Background Information on Tobacco and Tobacco-Use Control As of October 1990, 12 states had developed a specific freestanding plan for preventing and controlling tobacco use (Table 1). In 22 states, the plan is a part of another plan for controlling chronic disease. Most of these plans address areas related to high-risk populations, health care, smoking cessation issues, worksite policies, and other areas in preventing tobacco use. The 12 freestanding plans were all published after 1980, and most after 1985 (7). Excluding California, the average state budget devoted to tobacco-related health activities was $70,917. The state funds ranged from no funds (27 states) to $151 million in California, where a portion of the state cigarette excise tax is earmarked for health activities ( 8 ) (Table 2). In addition to California, six other states had earmarked a portion of the excise cigarette tax for public health activities. Additional funds, including grants, cooperative agreements, and in-kind services, averaged $54,230 per state (including California). The sixteen states growing tobacco (Figure 1) produced a combined total of $2,381,000,000 in tobacco agricultural revenue in 1989 (Table 3), representing 1.5% of the total U.S. agricultural farm receipts (9 ). The percentage of state agricultural farm receipts generated by tobacco growing ranged from 0.2% (Missouri and Wisconsin) to 21.8% (Kentucky). # Surveillance of Adult Tobacco Use CDC's BRFSS is a telephone-based system that collects yearly data on tobacco use and other health-related behaviors among adults 18 years of age and older. In 1990, 46 states participated in the BRFSS (70). Twenty-one states collected data on adult smoking prevalence from non-BRFSS sources (Table 4). Twenty of these states collected data on adult special target populations (blacks, Hispanics, Asians/Pacific Islanders, American Indians, persons with low socioeconomic status, and women of reproductive age ). In addition to the BRFFS, state-specific data on tobacco use among adults 16 years of age and older are available from two Current Population Surveys (CPS) that were performed by the U.S. Bureau of the Census in 1985 and 1989 (7 7,72). The 1985 CPS provided state-specific estimates of both smoking prevalence and smokeless-tobacco use. The 1989 survey provided information only on smoking prevalence. # Surveillance of Youth Tobacco Use No national system exists for monitoring state-specific tobacco use by adoles cents. However, CDC has developed a standard survey (the Youth Risk Behavior Survey ) to collect comparable school-based data from the states ( 13). By the completion of the survey in January 1990, three states had participated in the YRBS; 19 additional states had participated by the end of 1990end of . From 1986end of -1990 states reported collecting data on tobacco use among adolescents from sources other than the YRBS (Table 5). The respondents were asked follow-up questions to determine if these surveys covered the basic question topics from the YRBS. The surveys examined such specific areas as tobacco experimentation, current tobacco use, age of initiation of tobacco use, and smokeless tobacco use. Twenty-six states had informa tion on experimentation with tobacco-use, 32 states collected data on prevalence of tobacco use, 19 states had information on age of initiation of tobacco use, and 25 states had information on smokeless tobacco use. # Tobacco-Related Disease Impact Data-Reporting and Analysis All 51 state health departments used a software package developed by the Minnesota Department of Health, the Smoking-Attributable Mortality, Morbidity, and Economic Costs (SAMMEC), to obtain data on smoking-attributable deaths and economic costs (74). In five states, a record of the decedent's smoking history was required on death certificates (Table 6). Four states reported data on smoking-attributable hospital discharges, and eight states have information on smoking-attributable state-funded medical care costs. In 33 states, maternal smoking history was recorded on birth certificates. # Regulatory Activities # Smoking in Public Places In 1989, 45 states had laws restricting smoking in public places (Table 7); in 38 of these states, the restrictions also applied to public-sector workplaces. In 17 states, these restrictions extended to private-sector workplaces (7). The Surgeon General's 1989 report on smoking and health defined extensive regulations as those that restricted smoking in the private-sector workplace (Figure 2)(75). Local smoking ordinances in cities and counties encompassed a wide range of public settings, including restaurants, elevators, hotels, libraries, museums, retail stores, schools, public transit, and other enclosed public places. In all, 490 local ordinances restricted or prohibited smoking in public places (Table 8). # Health Department Tobacco-Use Policies With the exception of North Carolina and Virginia, all state health departments had a written policy on smoking in state health department buildings in 1989 (Table 9). Twenty-four (47%) of these states completely banned smoking in state health department facilities; 31 states (61%) permit the sale of tobacco products in health department buildings. # Restrictions on Minors' Access to Tobacco Products As of October 1990,46 states prohibited the sale of tobacco products to underaged persons (Table 10). The minimum age for purchasing tobacco varied from 16 years of age (Kentucky, Virginia) to 19 years of age (Alabama, Alaska, Utah); the most common minimum age is 18 years of age (37 states) (Table 10) (7,76). Nine states restricted the placement of vending machines that contain tobacco products (Table 10); one state (Colorado) banned the sale of smokeless tobacco in vending machines, and another (Utah) banned the sale of all tobacco products in vending machines. Twenty-two states required a state-issued retail tobacco license for vendors selling tobacco products (Table 11). The fees for these retail licenses ranged from $0 to $250 (average: $33). # Restrictions on Tobacco Advertising Two states (Massachusetts and Utah) have policies that restrict advertising of tobacco products on state property or property under the state's jurisdiction. Local policies in six states (Arizona, California, Colorado, Hawaii, Massachusetts, and Nebraska) restrict advertising of tobacco products on local government property, such as buses, transit stations, or sports facilities. # Tobacco-Control Coalitions As of October 1990, 50 states had tobacco-related working groups or coalitions of individuals or agencies concerned with preventing and controlling tobacco use (Table 12) (77). The coalition members represent the health professions, the general community, groups concerned with legislation and policy, and educational groups (Table 13). Eighty-two percent of these state coalitions carried out public education and information activities, 72% addressed legislative efforts, 48% educated profes sionals, 44% worked on developing a plan for tobacco-use control, and 26% carried out research and evaluation (Table 14). The average funding for coalitions in reporting states (excluding California) is $5,536 (Table 12). # Special Populations Special populations targeted for intensive tobacco-use prevention and control efforts by the U.S. Department of Health and Human Services include adolescents, women of reproductive age (15-44 years old), Asians/Pacific Islanders, American Indians, Hispanics, and blacks (18). Forty states have programs (in addition to the BRFSS) that include education and information for some or all of these groups (Table 15). Thirty-three states had cessation programs, and 26 states collected behavorial data on these high-risk populations. # Community Information/Education # Public Information Activities Twenty-two state health departments produced public service announcements designed to prevent tobacco use (Table 16). Forty-five states used public service announcements produced by federal agencies (such as the Office on Smoking and Health and the National Cancer Institute). Thirty-two states initiated public informa tion campaigns in their states within the last 2 years. These campaigns used various forms of media (billboards, radio, television, etc.) (Table 17). # Smoking Cessation Programs Thirty-five states offered smoking cessation programs to state health employees, and 26 states offered such programs to members of the community (Table 18). # Economic Incentives and Deterrents Colorado, Kansas, and Washington were the only states that had health benefits packages with differential rates for smokers and nonsmokers for state government employees (Table 19). Fourteen states reported having third-party payers of medical care that offered differential rates to consumers, and seven states had third-party payers of medical care that offered reimbursement for treatment of tobacco addic tion. These data may be an underestimate, however, because some large national insurers sold policies in many states, (e.g., Blue Cross and Blue Shield Company of Southwestern Virginia) ( 19). State tobacco excise taxes ranged from 2 cents per pack in North Carolina to 41 cents per pack in Texas (Table 2) (3). The average state excise tax collected per pack was 23 cents. The lowest tax rates were primarily in the tobacco-producing states. # Educational Institutions Thirty-nine states had state laws that restricted tobacco use in schools (Table 20). Twenty-seven states banned smoking for students; only eight states banned smoking for both students and staff. In 16 states, the state department of education reported having formal policies on tobaco use in schools. Information in was based on states that provided data for those specific questions related to tobacco-use prevention and educational institutions. Only two states, Ohio and Nevada, provided information on private primary and secondary schools. There are 15,323 school districts in the United States (Table 21) ( 4). Among the 25 states reporting information on policies in school districts, 2,311 (30.8%) of the school districts in these states banned smoking for both students and staff. Among the states with information on smoking policies in public primary schools, 4,468 (33.9%) of these schools banned smoking for both students and staff (Table 22). Among the reporting states, 21,097 (96.2%) schools completely banned smoking for students (i.e., students could not smoke on school grounds). Within the 26 states that provided data on tobacco-use education, 18,588 of 21,129 (87.9%) public primary schools taught tobacco-use prevention. Among the states reporting information on smoking policies in public secondary schools, 1,368 (21.2%) of 6,459 schools completely banned smoking for both students and staff, and 7,481 (83.1%) completely banned smoking for students (Table 23). For the 23 states that provided information on tobacco-use education, 7,623 of the 9,456 public secondary schools (80.6%) taught tobacco-use prevention. Among 12 states that provided information, approximately 2.8 million (48.5%) public primary and secondary students attended smoke-free schools (Table 24). # DISCUSSION The 1989 ASTHO survey provides data on the activity of all 51 states regarding the prevention and control of tobacco use. States varied greatly in their approaches to the control of tobacco use. Some states had extensive surveillance systems and pro grams in place, whereas others had only limited programs and funding. Data from the 1989 ASTHO survey and subsequent surveys may be linked to state-specific data on smoking prevalence, cigarette consumption, and smoking cessation. These statespecific data (from CDC's BRFSS and the Bureau of the Census' CPS) may be used to assess the outcome of recent state activities in preventing and controlling tobacco use. A national guide that may direct state progress in these and other areas of concern is Healthy People 2000: National Health Promotion and Disease Prevention Objectives, which lists 16 tobacco-related objectives for the year 2000 (18). (The Appendix section of this issue reprints those 16 objectives.) Little information about programs and policies to prevent tobacco use among young persons is available either to the ASTHO tobacco-control network or to state departments of education. Fewer than half of the states reported any information related to the education portion of the survey. Consequently, selective reporting from certain states may overstate the percentage of smoke-free schools. In addition, those states that reported 100% prevalence of tobacco-use education assumed, but did not verify, total compliance to state requirements. Efforts to collect these data are important in assessing the overall public health approach to preventing and control ling tobacco use. Because the 1989-90 ASTHO survey provided baseline information on broad activities to prevent and control tobacco use, subsequent surveys may be useful in assessing states' progress. To conduct such assessments, state-specific objectives should be established, and a system for measuring states' progress in these objectives should be implemented. The evaluation could initially be applied to the different control activities covered by the survey (such as education, coalitions, and surveillance). An overall measure for each component for controlling and preventing tobacco use should then be developed. The Rocky Mountain Tobacco-Free Challenge has included an evaluation of state activities on tobacco-use control (20). Initiated in 1988, this program is a regional effort among eight states to reduce tobacco use and chronic diseases (21). The ASTHO survey is an important baseline for monitoring tobacco-use control programs at the state and local levels. Future surveys may provide data that can be used to measure the effects of planned intervention programs, such as the National Cancer Institute's ASSIST, which will begin in 1993 (20). These surveys may also provide means to measure progress toward the year 2000 health objectives for the nation (18). Tobacco-related objectives, outlined in Healthy People 2000: National Health Promotion and Disease Prevention Objectives, provide a national guide for assessing progress in preventing and controlling tobacco use. The following is reprinted from Healthy People 2000 (18). The Year 2000 Objectives for the Nation call for the following tobacco-related objectives: 3.1 Reduce coronary heart disease deaths to no more than 100 per 100,000 people. 3.2 Slow the rise in lung cancer deaths to achieve a rate of no more than 42 per 100,000 people. 3.3 Slow the rise in deaths from chronic obstructive pulmonary disease to achieve a rate of no more than 25 per 100,000 people. 3.4 Reduce cigarette smoking to a prevalence of no more than 15 percent among people aged 20 and older. 3.5 Reduce the initiation of cigarette smoking by children and youth so that no more than 15 percent have become regular cigarette smokers by age 20. 3.6 Increase to at least 50 percent the proportion of cigarette smokers aged 18 and older who stopped smoking cigarettes for at least one day during the preceding year. 3.7 Increase smoking cessation during pregnancy so that at least 60 percent of women who are cigarette smokers at the time they become pregnant quit smoking early in pregnancy and maintain abstinence for the remainder of their pregnancy. 3.8 Reduce to no more than 20 percent the proportion of children aged 6 and younger who are regularly exposed to tobacco smoke at home. 3.9 Reduce smokeless tobacco use by males aged 12 through 24 to a prevalence of no more than 4 percent. 3.10 Establish tobacco-free environments and include tobacco use prevention in the curricula of all elementary, middle, and secondary schools, preferably as part of quality school health education. 3.11 Increase to at least 75 percent the proportion of worksites with a formal smoking policy that prohibits or severely restricts smoking at the workplace. 3.12 Enact in 50 States comprehensive laws on clean indoor air that prohibit or strictly lim it smoking in the workplace and enclosed public places (including health care facilities, schools, and public transportation). 3.13 Enact and enforce in 50 States laws prohibiting the sale and distribution of tobacco products to youth younger than age 19. 3.14 Increase to 50 the number of States with plans to reduce tobacco use, especially among youth. 3.15 Eliminate or severely restrict all forms of tobacco product advertising and promotion to which youth younger than age 18 are likely to be exposed. 3.16 Increase to at least 75 percent the proportion of primary care and oral health care providers who routinely advise cessation and provide assistance and followup for all of their tobacco-using patients.	Association o f State and Territorial Health Officials (ASTHO) conducted a survey o f state health department personnel regarding programs, policies, and public health systems that stress the prevention and control o f the use o f tobacco. This survey provided detailed data associated with state tobacco-use control programs and their essential components (e.g.f budgets, planning, coalitions, surveillance systems, smoking cessation pro grams, educational activities, legislative actions, and health department poli cies). States vary widely in the strength and coverage o f their programs for preventing and controlling tobacco use. The ASTHO survey data may be used to help plan and evaluate state health department programs as part o f an effort to prevent chronic diseases related to tobacco use. Outcomes o f state activities may be evaluated through surveys such as CDC's Behavioral Risk Factor Surveillance System (BRFSS) and the Current Population Survey (CPS) o f the Bureau o f the Census. Future surveys o f state activities for controlling the use o f tobacco may be included in the evaluation o f the upcoming# INTRODUCTION The Association of State and Territorial Health Officials (ASTHO) conducted a survey in October 1989 to assess progress among the states in the public health practice of preventing and controlling tobacco use. The survey was also conducted to provide states with incentives to create and implement efforts to control tobacco use. The survey covered several components of effective state programs that address such efforts among targeted populations. Additional sources either supplemented or validated state information on tobacco-use control data collected through the ASTHO survey. In the fall of 1989, ASTHO established a network of health professionals responsible for communication between the federal government and state health departments on issues related to tobacco-use prevention and control. As the identi fiable contacts for information transfer on tobacco-related matters, these persons served as respondents to the ASTHO survey. # METHODS The survey's 10 major sections are 1) background information on tobacco and tobacco control; 2) adult tobacco-use surveillance; 3) adolescent tobacco-use surveillance; 4) reporting and analysis of data on the impact of tobacco-related disease; 5) regulatory activities; 6) coalitions against tobacco use; 7) special populations; 8) community information on education activities; 9) economic incen tives, deterrents; and 10) educational institutions. ASTHO contacts solicited the help of state departments of education to answer questions about tobacco-use control activities in educational institutions (public and private schools). This section of the survey assessed the ability of each state to measure progress toward smoke-free schools and the extent to which educational institutions addressed antitobacco education. Central data sources were used to supplement the survey results for the following areas of this report: legislative activities; taxation; and number of schools, districts, and enrolled students. Sources used to supplement information on legislative issues included State Legislated Actions on Tobacco Issues of the Tobacco-Free America Project (7) and Major Local Smoking Ordinances in the United States, National Institutes of Health (2). The Tobacco Institute also provided state-specific data on taxation (3). For information related to schools and school districts, the 1990 World Almanac was used to supplement information supplied by the states (4). Finally, previously tabulated data were reviewed and updated by the ASTHO network in December 1990. # Data Collection and Analysis ASTHO sent the questionnaires to all 50 states and the District of Columbia. For the purpose of this report, the District of Columbia is considered a state when summary data are presented. In some cases, supplemental information was obtained by tele phone. Responses were tabulated and analyzed using True Epistat and dBase IV (5,6). # RESULTS The response rates were 100% for both the main section and educational sections. # Background Information on Tobacco and Tobacco-Use Control As of October 1990, 12 states had developed a specific freestanding plan for preventing and controlling tobacco use (Table 1). In 22 states, the plan is a part of another plan for controlling chronic disease. Most of these plans address areas related to high-risk populations, health care, smoking cessation issues, worksite policies, and other areas in preventing tobacco use. The 12 freestanding plans were all published after 1980, and most after 1985 (7). Excluding California, the average state budget devoted to tobacco-related health activities was $70,917. The state funds ranged from no funds (27 states) to $151 million in California, where a portion of the state cigarette excise tax is earmarked for health activities ( 8 ) (Table 2). In addition to California, six other states had earmarked a portion of the excise cigarette tax for public health activities. Additional funds, including grants, cooperative agreements, and in-kind services, averaged $54,230 per state (including California). The sixteen states growing tobacco (Figure 1) produced a combined total of $2,381,000,000 in tobacco agricultural revenue in 1989 (Table 3), representing 1.5% of the total U.S. agricultural farm receipts (9 ). The percentage of state agricultural farm receipts generated by tobacco growing ranged from 0.2% (Missouri and Wisconsin) to 21.8% (Kentucky). # Surveillance of Adult Tobacco Use CDC's BRFSS is a telephone-based system that collects yearly data on tobacco use and other health-related behaviors among adults 18 years of age and older. In 1990, 46 states participated in the BRFSS (70). Twenty-one states collected data on adult smoking prevalence from non-BRFSS sources (Table 4). Twenty of these states collected data on adult special target populations (blacks, Hispanics, Asians/Pacific Islanders, American Indians, persons with low socioeconomic status, and women of reproductive age [15-44 years old]). In addition to the BRFFS, state-specific data on tobacco use among adults 16 years of age and older are available from two Current Population Surveys (CPS) that were performed by the U.S. Bureau of the Census in 1985 and 1989 (7 7,72). The 1985 CPS provided state-specific estimates of both smoking prevalence and smokeless-tobacco use. The 1989 survey provided information only on smoking prevalence. # Surveillance of Youth Tobacco Use No national system exists for monitoring state-specific tobacco use by adoles cents. However, CDC has developed a standard survey (the Youth Risk Behavior Survey [YRBS]) to collect comparable school-based data from the states ( 13). By the completion of the survey in January 1990, three states had participated in the YRBS; 19 additional states had participated by the end of 1990end of . From 1986end of -1990 states reported collecting data on tobacco use among adolescents from sources other than the YRBS (Table 5). The respondents were asked follow-up questions to determine if these surveys covered the basic question topics from the YRBS. The surveys examined such specific areas as tobacco experimentation, current tobacco use, age of initiation of tobacco use, and smokeless tobacco use. Twenty-six states had informa tion on experimentation with tobacco-use, 32 states collected data on prevalence of tobacco use, 19 states had information on age of initiation of tobacco use, and 25 states had information on smokeless tobacco use. # Tobacco-Related Disease Impact Data-Reporting and Analysis All 51 state health departments used a software package developed by the Minnesota Department of Health, the Smoking-Attributable Mortality, Morbidity, and Economic Costs (SAMMEC), to obtain data on smoking-attributable deaths and economic costs (74). In five states, a record of the decedent's smoking history was required on death certificates (Table 6). Four states reported data on smoking-attributable hospital discharges, and eight states have information on smoking-attributable state-funded medical care costs. In 33 states, maternal smoking history was recorded on birth certificates. # Regulatory Activities # Smoking in Public Places In 1989, 45 states had laws restricting smoking in public places (Table 7); in 38 of these states, the restrictions also applied to public-sector workplaces. In 17 states, these restrictions extended to private-sector workplaces (7). The Surgeon General's 1989 report on smoking and health defined extensive regulations as those that restricted smoking in the private-sector workplace (Figure 2)(75). Local smoking ordinances in cities and counties encompassed a wide range of public settings, including restaurants, elevators, hotels, libraries, museums, retail stores, schools, public transit, and other enclosed public places. In all, 490 local ordinances restricted or prohibited smoking in public places (Table 8). # Health Department Tobacco-Use Policies With the exception of North Carolina and Virginia, all state health departments had a written policy on smoking in state health department buildings in 1989 (Table 9). Twenty-four (47%) of these states completely banned smoking in state health department facilities; 31 states (61%) permit the sale of tobacco products in health department buildings. # Restrictions on Minors' Access to Tobacco Products As of October 1990,46 states prohibited the sale of tobacco products to underaged persons (Table 10). The minimum age for purchasing tobacco varied from 16 years of age (Kentucky, Virginia) to 19 years of age (Alabama, Alaska, Utah); the most common minimum age is 18 years of age (37 states) (Table 10) (7,76). Nine states restricted the placement of vending machines that contain tobacco products (Table 10); one state (Colorado) banned the sale of smokeless tobacco in vending machines, and another (Utah) banned the sale of all tobacco products in vending machines. Twenty-two states required a state-issued retail tobacco license for vendors selling tobacco products (Table 11). The fees for these retail licenses ranged from $0 to $250 (average: $33). # Restrictions on Tobacco Advertising Two states (Massachusetts and Utah) have policies that restrict advertising of tobacco products on state property or property under the state's jurisdiction. Local policies in six states (Arizona, California, Colorado, Hawaii, Massachusetts, and Nebraska) restrict advertising of tobacco products on local government property, such as buses, transit stations, or sports facilities. # Tobacco-Control Coalitions As of October 1990, 50 states had tobacco-related working groups or coalitions of individuals or agencies concerned with preventing and controlling tobacco use (Table 12) (77). The coalition members represent the health professions, the general community, groups concerned with legislation and policy, and educational groups (Table 13). Eighty-two percent of these state coalitions carried out public education and information activities, 72% addressed legislative efforts, 48% educated profes sionals, 44% worked on developing a plan for tobacco-use control, and 26% carried out research and evaluation (Table 14). The average funding for coalitions in reporting states (excluding California) is $5,536 (Table 12). # Special Populations Special populations targeted for intensive tobacco-use prevention and control efforts by the U.S. Department of Health and Human Services include adolescents, women of reproductive age (15-44 years old), Asians/Pacific Islanders, American Indians, Hispanics, and blacks (18). Forty states have programs (in addition to the BRFSS) that include education and information for some or all of these groups (Table 15). Thirty-three states had cessation programs, and 26 states collected behavorial data on these high-risk populations. # Community Information/Education # Public Information Activities Twenty-two state health departments produced public service announcements designed to prevent tobacco use (Table 16). Forty-five states used public service announcements produced by federal agencies (such as the Office on Smoking and Health and the National Cancer Institute). Thirty-two states initiated public informa tion campaigns in their states within the last 2 years. These campaigns used various forms of media (billboards, radio, television, etc.) (Table 17). # Smoking Cessation Programs Thirty-five states offered smoking cessation programs to state health employees, and 26 states offered such programs to members of the community (Table 18). # Economic Incentives and Deterrents Colorado, Kansas, and Washington were the only states that had health benefits packages with differential rates for smokers and nonsmokers for state government employees (Table 19). Fourteen states reported having third-party payers of medical care that offered differential rates to consumers, and seven states had third-party payers of medical care that offered reimbursement for treatment of tobacco addic tion. These data may be an underestimate, however, because some large national insurers sold policies in many states, (e.g., Blue Cross and Blue Shield Company of Southwestern Virginia) ( 19). State tobacco excise taxes ranged from 2 cents per pack in North Carolina to 41 cents per pack in Texas (Table 2) (3). The average state excise tax collected per pack was 23 cents. The lowest tax rates were primarily in the tobacco-producing states. # Educational Institutions Thirty-nine states had state laws that restricted tobacco use in schools (Table 20). Twenty-seven states banned smoking for students; only eight states banned smoking for both students and staff. In 16 states, the state department of education reported having formal policies on tobaco use in schools. Information in was based on states that provided data for those specific questions related to tobacco-use prevention and educational institutions. Only two states, Ohio and Nevada, provided information on private primary and secondary schools. There are 15,323 school districts in the United States (Table 21) ( 4). Among the 25 states reporting information on policies in school districts, 2,311 (30.8%) of the school districts in these states banned smoking for both students and staff. Among the states with information on smoking policies in public primary schools, 4,468 (33.9%) of these schools banned smoking for both students and staff (Table 22). Among the reporting states, 21,097 (96.2%) schools completely banned smoking for students (i.e., students could not smoke on school grounds). Within the 26 states that provided data on tobacco-use education, 18,588 of 21,129 (87.9%) public primary schools taught tobacco-use prevention. Among the states reporting information on smoking policies in public secondary schools, 1,368 (21.2%) of 6,459 schools completely banned smoking for both students and staff, and 7,481 (83.1%) completely banned smoking for students (Table 23). For the 23 states that provided information on tobacco-use education, 7,623 of the 9,456 public secondary schools (80.6%) taught tobacco-use prevention. Among 12 states that provided information, approximately 2.8 million (48.5%) public primary and secondary students attended smoke-free schools (Table 24). # DISCUSSION The 1989 ASTHO survey provides data on the activity of all 51 states regarding the prevention and control of tobacco use. States varied greatly in their approaches to the control of tobacco use. Some states had extensive surveillance systems and pro grams in place, whereas others had only limited programs and funding. Data from the 1989 ASTHO survey and subsequent surveys may be linked to state-specific data on smoking prevalence, cigarette consumption, and smoking cessation. These statespecific data (from CDC's BRFSS and the Bureau of the Census' CPS) may be used to assess the outcome of recent state activities in preventing and controlling tobacco use. A national guide that may direct state progress in these and other areas of concern is Healthy People 2000: National Health Promotion and Disease Prevention Objectives, which lists 16 tobacco-related objectives for the year 2000 (18). (The Appendix section of this issue reprints those 16 objectives.) Little information about programs and policies to prevent tobacco use among young persons is available either to the ASTHO tobacco-control network or to state departments of education. Fewer than half of the states reported any information related to the education portion of the survey. Consequently, selective reporting from certain states may overstate the percentage of smoke-free schools. In addition, those states that reported 100% prevalence of tobacco-use education assumed, but did not verify, total compliance to state requirements. Efforts to collect these data are important in assessing the overall public health approach to preventing and control ling tobacco use. Because the 1989-90 ASTHO survey provided baseline information on broad activities to prevent and control tobacco use, subsequent surveys may be useful in assessing states' progress. To conduct such assessments, state-specific objectives should be established, and a system for measuring states' progress in these objectives should be implemented. The evaluation could initially be applied to the different control activities covered by the survey (such as education, coalitions, and surveillance). An overall measure for each component for controlling and preventing tobacco use should then be developed. The Rocky Mountain Tobacco-Free Challenge has included an evaluation of state activities on tobacco-use control (20). Initiated in 1988, this program is a regional effort among eight states to reduce tobacco use and chronic diseases (21). The ASTHO survey is an important baseline for monitoring tobacco-use control programs at the state and local levels. Future surveys may provide data that can be used to measure the effects of planned intervention programs, such as the National Cancer Institute's ASSIST, which will begin in 1993 (20). These surveys may also provide means to measure progress toward the year 2000 health objectives for the nation (18). Tobacco-related objectives, outlined in Healthy People 2000: National Health Promotion and Disease Prevention Objectives, provide a national guide for assessing progress in preventing and controlling tobacco use. The following is reprinted from Healthy People 2000 (18). The Year 2000 Objectives for the Nation call for the following tobacco-related objectives: 3.1 Reduce coronary heart disease deaths to no more than 100 per 100,000 people. 3.2 Slow the rise in lung cancer deaths to achieve a rate of no more than 42 per 100,000 people. 3.3 Slow the rise in deaths from chronic obstructive pulmonary disease to achieve a rate of no more than 25 per 100,000 people. 3.4 Reduce cigarette smoking to a prevalence of no more than 15 percent among people aged 20 and older. 3.5 Reduce the initiation of cigarette smoking by children and youth so that no more than 15 percent have become regular cigarette smokers by age 20. 3.6 Increase to at least 50 percent the proportion of cigarette smokers aged 18 and older who stopped smoking cigarettes for at least one day during the preceding year. 3.7 Increase smoking cessation during pregnancy so that at least 60 percent of women who are cigarette smokers at the time they become pregnant quit smoking early in pregnancy and maintain abstinence for the remainder of their pregnancy. 3.8 Reduce to no more than 20 percent the proportion of children aged 6 and younger who are regularly exposed to tobacco smoke at home. 3.9 Reduce smokeless tobacco use by males aged 12 through 24 to a prevalence of no more than 4 percent. 3.10 Establish tobacco-free environments and include tobacco use prevention in the curricula of all elementary, middle, and secondary schools, preferably as part of quality school health education. 3.11 Increase to at least 75 percent the proportion of worksites with a formal smoking policy that prohibits or severely restricts smoking at the workplace. 3.12 Enact in 50 States comprehensive laws on clean indoor air that prohibit or strictly lim it smoking in the workplace and enclosed public places (including health care facilities, schools, and public transportation). 3.13 Enact and enforce in 50 States laws prohibiting the sale and distribution of tobacco products to youth younger than age 19. 3.14 Increase to 50 the number of States with plans to reduce tobacco use, especially among youth. 3.15 Eliminate or severely restrict all forms of tobacco product advertising and promotion to which youth younger than age 18 are likely to be exposed. 3.16 Increase to at least 75 percent the proportion of primary care and oral health care providers who routinely advise cessation and provide assistance and followup for all of their tobacco-using patients. # ----------------------------------------------------------------	None	None
0b220e1f811164e338bc8fd3c48a006e0b25820c	cdc	None	In February 2000, a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (Prevnar,™ marketed by Wyeth Lederle Vaccines) was licensed for use among infants and young children. CDC's Advisory Committee on Immunization Practices (ACIP) recommends that the vaccine be used for all children aged 2-23 months and for children aged 24-59 months who are at increased risk for pneumococcal disease (e.g., children with sickle cell disease, human immunodeficiency virus infection, and other immunocompromising or chronic medical conditions). ACIP also recommends that the vaccine be considered for all other children aged 24-59 months, with priority given to a) children aged 24-35 months, b) children who are of Alaska Native, American Indian, and African-American descent, and c) children who attend group day care centers. This report includes ACIP's recommended vaccination schedule for infants at ages 2, 4, 6, and 12-15 months. This report also includes a pneumococcal vaccination schedule for infants and young children who are beginning their vaccination series at an older age and for those who missed doses. In addition, this report updates earlier recommendations for use of 23-valent pneumococcal polysaccharide vaccine among children aged ³2 years. Among children aged 24-59 months for whom polysaccharide vaccine is already recommended, ACIP recommends vaccination with the new conjugate vaccine followed, ³2 months later, by 23-valent polysaccharide vaccine. Conjugate vaccine has not been studied sufficiently among older children or adults to make recommendations for its use among persons aged ³5 years. Persons aged ³5 years who are at increased risk for serious pneumococcal disease should continue to receive 23-valent polysaccharide vaccine in accordance with previous ACIP recommendations. - Defined in that study as any setting outside the home where a child regularly spends ³4 hours/week with ³2 unrelated children under adult supervision.# INTRODUCTION Streptococcus pneumoniae (pneumococcus) remains a leading cause of serious illness among young children worldwide and is the most frequent cause of pneumonia, bacteremia, sinusitis, and acute otitis media (AOM). In the United States, S. pneumoniae causes approximately 17,000 cases/year of invasive disease among children aged <5 years, including 700 cases of meningitis and 200 deaths (CDC's Active Bacterial Core Surveillance [ CDC's Advisory Committee on Immunization Practices (ACIP) previously recommended 23-valent pneumococcal polysaccharide vaccines for use among children aged ³2 years who have high rates of disease, including those with sickle cell disease (SCD), chronic underlying diseases, human immunodeficiency virus (HIV) infection, or others who are immunocompromised. The new 7-valent pneumococcal conjugate vaccine (PCV7;- Prevnar,™ licensed in February 2000 and marketed by Wyeth Lederle Vaccines) should be a key addition to existing pneumococcal disease prevention measures. Although the previously licensed 23-valent pneumococcal polysaccharide vaccines (PPV23; PNU-IMUNE ® 23 marketed by Wyeth-Ayerst Laboratories and Pneumovax ® 23 by Merck and Company) are effective in preventing invasive pneumococcal disease among older children and adults, these vaccines do not protect children aged <2 years, the age group with the highest rate of disease (1)(2)(3). Furthermore, PPV23 does not decrease nasopharyngeal carriage, a substantial source of transmission of pneumococci (4 ). In contrast, conjugate vaccine decreases colonization, and PCV7 prevents pneumococcal disease among children aged £2 years (5)(6)(7). This report provides ACIP's recommendations for pneumococcal vaccination of children aged <5 years. # BACKGROUND Incidence of Invasive Disease Among Children The highest rates of invasive pneumococcal disease (e.g., bacteremia, meningitis, or other infection of a normally sterile site) occur among young children, especially those aged <2 years. In 1998, estimated incidence in the United States of invasive pneumococcal infections among children aged <12 months and 12-23 months were 165 and 203 cases/100,000 population, respectively, with peak incidence occurring among children aged 6-11 months (235/100,000). In contrast, incidence among persons of all ages and among persons aged ³65 years were 24 and 61/100,000, respectively (Figure 1) (8 ). In the United States, the most common manifestation of invasive pneumococcal disease among young children is bacteremia without a known site of infection, which accounts for approximately 70% of invasive pneumococcal cases among children aged ; accessed September 15, 2000). # Occurrence of Noninvasive Syndromes S. pneumoniae also contributes substantially to noninvasive respiratory infections and is the most common bacterial cause of community-acquired pneumonia, AOM, and sinusitis among young children (10)(11)(12)(13)(14)(15)(16). In two prospective studies of communityacquired pneumonia among young children, 17%-28% of cases were diagnosed as pneumococcal (10,11 ). However, these and other studies probably underestimate the actual proportion of pneumococcal pneumonia cases as a result of low sensitivity of routine diagnostic testing. Studies using diagnostic tympanocentesis among children with AOM have found S. pneumoniae in 28%-55% of all middle ear aspirates (12)(13)(14)(15). Otitis media is the most frequent reason for pediatric office visits in the United States, resulting in >15 million visits/year (17)(18)(19). By age 12 months, 62% of children have had at least one episode of AOM; peak incidence of AOM occurs during ages 6 months-1year (20 ). Although serious complications are rare, economic costs of otitis media are estimated at >$3.5 billion/year in the United States (21 ). During 1996, approximately 500,000 tympanostomy tubes were placed in children's ears in the United States (22 ). AOM is also the leading reason for prescribing antibiotics during childhood, and use of antibiotics for treatment of AOM and sinusitis contributes substantially to increased antimicrobial resistance (23)(24)(25). # Children at Increased Risk for Pneumococcal Infections Racial and Ethnic Populations In the United States, higher rates of invasive pneumococcal disease occur among African-Americans, Alaska Natives, and specific American Indian populations, compared with whites (Table 1) (26)(27)(28)(29)(30)(31)(32). Incidence of pneumococcal bacteremia and meningitis among Alaska Native children aged <5 years ranges from 598 cases/100,000 population among children aged 6-11 months to 56 cases/100,000 population for children aged 36-47 months, which is approximately four times that of similarly aged non-Alaska Native/ non-American Indian children (30 ). The highest rates for any ethnic group in the United States are found among Navajo and Apache populations living on reservations in the southwestern United States. Incidence among children aged 1-2 years in these populations is 557-2,396/100,000 (31,32 ). Among children aged <5 years, incidence of invasive pneumococcal disease among African-American children in the United States is 2-3 times higher than the rate among white children of the same age (8,27,29,33 ). In a casecontrol study of risk factors for invasive disease among young children, the association of race with disease risk was not statistically significant in an analysis that controlled for socioeconomic status (34 ). However, other studies have reported persistence of increased risk when controlling for income (27,33,(35)(36)(37). Reasons for increased rates of disease among Alaska Natives, American Indians, and African-Americans are unclear but probably multifactorial. # Children with Functional or Anatomic Asplenia Other children at high risk for invasive pneumococcal disease include patients with SCD, other sickle hemoglobinopathies (e.g., hemoglobin S-C disease or S-ß-thalassemia), and those who are otherwise functionally or anatomically asplenic (38)(39)(40). Although rates of pneumococcal infection among children with hemoglobin S-C disease are lower than rates among persons with SCD, rates are higher than among healthy children (41,42 ). Rates of overall bacterial sepsis in other hemoglobinopathies (e.g., S-ßthalassemia) have not been calculated but are estimated to be intermediate between those for hemoglobin S-C and hemoglobin SS diseases (40 ). High risk for pneumococcal infections among persons with SCD is thought to be caused by the combination of low levels of circulating antibodies, splenic dysfunction, and complement deficiency, resulting in decreased clearance of encapsulated bacteria from the bloodstream (43,44 ). The protective effect of pneumococcal polysaccharide vaccine among SCD patients, initially reported in a study published in 1977, has not been reproduced consistently by subsequent prospective or case-control studies (45)(46)(47)(48)(49). Although use of prophylactic penicillin has reduced the risk for pneumococcal disease, children aged <5 years with SCD still have increased rates of invasive disease (range: 1,230-1,500/100,000 population), probably reflecting noncompliance with and failure of penicillin prophylaxis combined with suboptimal protection by pneumococcal polysaccharide vaccine (38,39,47,49 ). # HIV-Infected Children Children infected with HIV have a markedly increased risk for pneumococcal infection compared with those who are not HIV-infected (50,51 ). In two prospective cohort studies, HIV-infected children had rates of invasive pneumococcal disease that were 2.8 and 12.6 times the rate among HIV-negative control subjects for children aged <5 and <3 years, respectively (52,53 ). Incidence of invasive pneumococcal disease is 6.1 cases/ 100 patient-years among HIV-infected children through age 7 years (54 ). # Children in Day Care Out-of-home day care increases the risk for invasive pneumococcal disease and AOM among children (34,55,56 ). In a study of risk factors for invasive pneumococcal disease among children in the United States, attendance at a group day care center- during the preceding 3 months was associated with an approximately 2.3-fold increase in invasive disease among children aged 12-23 months, and 3.2-fold increased risk among children aged 24-59 months (34 ). Moreover, in a recent population-based case-control study, nonelderly adults (i.e., persons aged 18-64 years) who lived in a household that included children who attended day care were at greater risk for acquiring invasive pneumococcal infections than adults who did not (multivariate odds ratio = 3.0) (57 ). In studies of otitis media resulting from all causes, risk for AOM was higher among children who attended day care outside the home compared with family day care (58,59 ), and risk for middle ear effusions increased with exposure to larger numbers of children in day care settings (60 ). Younger age when starting day care also increases risk for experiencing recurrent AOM (59 ). Day care attendance is also a risk factor for other acute upper respiratory tract infections among children aged <5 years (61 ). # Antimicrobial Resistance Treatment of pneumococcal disease among young children is complicated by emergence of pneumococcal strains resistant to penicillin and other antibiotics (12,62 ). Among a national sample of invasive pneumococcal isolates, resistance to penicillin (i.e., minimum inhibitory concentration ³ 2.0 µg/ml) has increased substantially during the past decade, from 1.3% in 1992 to 13.6% in 1997 (62,63 ). In certain areas of the United States, approximately 35% of invasive isolates are penicillin-nonsusceptible (i.e., intermediate susceptibility or resistant ) (63 ). In one nasopharyngeal carriage study among children in a rural Kentucky community, 59% of children attending day care centers carried penicillin-nonsusceptible S. pneumoniae (64 ). Risk factors associated with infection with penicillin-resistant pneumococci include younger age, attendance at a day care center, higher socioeconomic status, recent (i.e., £3 months) antibiotic use, and recurrent AOM (26,34,65,66 ). Recent day care attendance and recent antibiotic treatment are associated independently with invasive disease as a result of penicillin-resistant pneumococci (34 ). Penicillin resistance has been associated with treatment failures in AOM and meningitis (12,(67)(68)(69); these failures could be because of difficulty in achieving high antimicrobial concentrations in middle ear fluid and cerebrospinal fluid (CSF) (70 ). Additional research is needed to determine the association between penicillin resistance and treatment failure in pneumococcal pneumonia or bacteremia among children (12,(71)(72)(73). # Pneumococcal Serotypes The capsule of the Streptococcus pneumoniae bacterium consists of polysaccharides and constitutes a major virulence factor for the bacterium (74 ). Antibodies directed against the capsular polysaccharide protect against infection; type-specific antibodies bind capsular antigens; and opsonization facilitates phagocytosis (75 ). Knowledge of the distribution of pneumococcal serotypes causing disease is fundamental to evaluating the potential impact of a pneumococcal vaccine. Currently, 90 serotypes of S. pneumoniae have been identified on the basis of antigenic differences in their capsular polysaccharides (76 ). The majority of serotypes cause serious disease, yet a relatively limited number of serotypes cause the majority of invasive pneumococcal infections. The 10 most common serotypes are estimated to account for approximately 62% of invasive disease worldwide; however, ranking and serotype prevalence differ by age group and country (77 ). In the United States, the seven most common serotypes isolated from the blood or CSF of children aged <6 years (i.e., 14, 6B, 19F, 18C, 23F, 4, and 9V) account for 80% of infections and are the serotypes in the licensed PCV7 (Figure 2). These same seven serotypes, by comparison, account for only 50% of isolates among persons aged ³6 years in the United States (78,79 ). Distribution of serotype coverage also differs among Alaska Natives and American Indians in the United States; the proportion of vaccine serotypes causing invasive pneumococcal disease among children aged <5 years is less among Alaska Natives and American Indians than among non-Alaska Natives/ non-American Indians (30,31 ). Types 1 and 5 account for only a limited percentage of invasive isolates in the United States, but are more common in Western Europe and in certain developing countries (77,80,81 seven PCV7 serotypes accounted for 71% of infections among children aged <24 months (82 ). Among 414 S. pneumoniae isolates obtained from middle ear fluid cultures among children with AOM in Finland, 250 (60%) were caused by serotypes contained in PCV7 (83 ). Antimicrobial resistance is detected most frequently among serotypes included in PCV7. According to 1998 surveillance data from eight states, the PCV7 serotypes accounted for 80% of 312 penicillin-nonsusceptible isolates (MIC ³ 0.1 µg/ml) collected from normally sterile sites among children aged <6 years (ABCs/EIP Network, unpublished data, 1999). A similar serotype distribution of penicillin-nonsusceptible isolates was identified during a study of nasopharyngeal carriage among 216 children aged <6 years in Memphis, Tennessee; 78% of resistant isolates were of the same seven serotypes (65 ). # PNEUMOCOCCAL CONJUGATE VACCINE # Advantages of Pneumococcal Conjugate Vaccine: Immunologic Theory Bacterial polysaccharides, including those present on the pneumococcal capsule, are T-independent antigens. T-independent antigens stimulate mature B-lymphocytes but not T-lymphocytes. This type of antigen induces an immune system response that is neither long-lasting nor characterized by an anamnestic (i.e., booster) response upon subsequent challenge with native polysaccharides (84,85 ). Polysaccharide vaccines fail to elicit a protective immune system response among infants and very young children because these children respond poorly to T-independent antigens. Although antibody response to T-dependent antigens is present soon after birth, immune system responses to T-independent antigens develop during the first years of life. Certain serotypes that cause the majority of pneumococcal disease among children (i.e., 6A, 14, 19F, and 23F) remain poorly immunogenic until approximately age 5 years (86 ). Conjugation of polysaccharides to proteins changes the nature of the antipolysaccharide response from T-independent to T-dependent. This antigen complex stimulates a T-helper-cell response, leading to a substantial primary response among infants and a strong booster response at reexposure (84 ). Success of Hib conjugate vaccine in reducing by 95% incidence of invasive Hib disease among young children after the vaccine's introduction for use among infants in 1990 is one example of the potential efficacy of bacterial polysaccharide-protein conjugate vaccines. Declines in Hib disease occurred among children aged <1 year before the vaccine was licensed for use among this age group (87 ). This herd-immunity effect was consistent with later observations that Hib conjugate vaccine interrupts transmission by reducing acquisition of carriage. Pneumococcal conjugate vaccines, in contrast with polysaccharides, has been reported to reduce carriage and might lead to population effects beyond direct protection. # Vaccine Composition The 7-valent pneumococcal conjugate vaccine (Prevnar) includes seven purified capsular polysaccharides of S. pneumoniae, each coupled with a nontoxic variant of diphtheria toxin, CRM197 (CRM, cross-reactive material). The vaccine contains approximately 2 µg each of capsular polysaccharide from serotypes 4, 9V, 14, 19F, and 23F, and oligosaccharide from 18C, 4 µg of serotype 6B, 20 µg of the carrier protein CRM197, and 0.125 mg of aluminum/0.5-ml dose as an aluminum phosphate adjuvant. Prevnar contains no thimerosal or other preservative. Serotypes included in PCV7 and potentially cross-reactive serotypes (i.e., 6A, 9A, 9L, 18B, and 18F) accounted for 86% of bacteremia, 83% of meningitis, and 65% of AOM among children aged <6 years occurring in the United States during the period 1978-1994 (79 ). # Immunogenicity Polysaccharide-protein conjugate vaccine induces type-specific antibodies that bind to polysaccharide on the surface of bacteria and enhance opsonization, phagocytosis, and killing of pneumococci. The amount of antibody required to prevent either pneumococcal carriage or disease is unknown. Additionally, quantitative measurement of total antibody concentration, as measured in the majority of pneumococcal antibody assays, might not correlate with the level of functional immune system response. Functional measurements (e.g., opsonophagocytic activity) might be more appropriate than serum antibody concentrations for evaluating clinically relevant responses to pneumococcal vaccination (88 ). Although specific levels of antibody or opsonophagocytic activity that correlate with protection against pneumococcal disease remain unknown, presence of type-specific antibody to capsular polysaccharide is associated with protection among adults. Studies of Hib conjugate vaccine have reported that levels of anticapsular antibody ³0.15 µg/ml are protective against subsequent Hib infection; thus, researchers have hypothesized that this minimum level might also be protective against pneumococcal disease (89)(90)(91). Through measurement of total antibody concentrations, researchers have demonstrated that pneumococcal conjugate vaccines using several protein carriers are more immunogenic than PPV23 among young children (92)(93)(94)(95)(96)(97)(98). # Immunogenicity Studies Among Healthy Infants and Children In one study, 212 healthy infants were randomized to receive either PCV7 or an investigational meningococcal conjugate vaccine at ages 2, 4, 6, and 12-15 months. Vaccination with PCV7 resulted in substantial increases in serum antibody concentrations to all seven serotypes compared with baseline concentrations. After three doses of PCV7, from 92% (serotypes 6B and 23F) to 100% (serotype 4) of children had ³0.15 µg/ml of type-specific antibody, and from 51% (serotype 9V) to 90% (serotype 19F) achieved a level of ³1.0 µg/ml against the vaccine serotypes. The fourth dose resulted in an anamnestic response to each of the seven serotypes (95 ). # Children with SCD In a study of children and young adults with SCD, children aged ³2 years received either PPV23 only (n = 12) or PCV7 (two doses, 8 weeks apart) followed by PPV23 8 weeks later (n = 11) (93 ). When measured 3-6 weeks after administration of PPV23, serum antibody geometric mean concentrations (GMCs) were higher among the PCV7 plus PPV23 group than among the PPV23-only group for all of the PCV7 serotypes, reaching statistical significance for serotypes 14 and 19F. Serum antibody GMCs were similar between the two groups for serotypes 1 and 15B, two serotypes contained in PPV23 but not in PCV7, demonstrating that PCV7 did not interfere with the immune system response to PPV23. After administration of PPV23, 4 of 11 subjects in the PCV7 plus PPV23 group and 2 of 11 in the PPV23-only group reported fever. Rates and severity of local reactions to PPV23 did not differ between the two groups. In a study of 34 infants aged 2.0 µg/ml 1 month after the third dose for all seven vaccine serotypes (97,99 ). Among 27 study participants who remained in the study and who were vaccinated with PPV23 at age 24 months, a substantial booster response (GMC > 9.0 µg/ml) occurred after administration of PPV23 for all serotypes in the PCV7 vaccine. Both serum opsonic activity and total IgG antibodies were measured for two serotypes (i.e., 6B and 14), and both tests demonstrated substantial increases after the PPV23 booster. # HIV-Infected Children Data are limited regarding use of PCV7 among HIV-infected children. However, in two studies using 5-valent formulations of greater antigen content (i.e., 10 µg each of serotypes 6B, 14, 18C, 19F, and 23F oligosaccharides) and the same carrier protein, conjugate vaccine was demonstrated to be immunogenic among HIV-infected children (94,100 ). In a study among 60 children aged ³2 years, 5-valent pneumococcal conjugate vaccine was more immunogenic for all five serotypes than was PPV23 among both HIV-infected (n = 30) and HIV-uninfected (n = 30) children. Among HIV-infected children, 60% demonstrated a ³4-fold rise in IgG level after one dose of conjugate vaccine, compared with 31% after one dose of PPV23 (P < 0.05) (94 ). Prevaccination CDC HIV classification and CD4 counts of the HIV-infected children were similar among the conjugate vaccine and PPV23 groups. In a second study using the same conjugate vaccine among younger children, antibody response to three doses of 5-valent pneumococcal conjugate vaccine was compared between 18 HIV-infected children aged £2 years and 33 children without HIV infection (100 ). The vaccine was found to be immunogenic among both groups. Antibody levels achieved by the HIV-infected infants and toddlers were higher than those reported after one dose of 5-valent pneumococcal conjugate vaccine in the study of children aged ³2 years discussed previously (94 ). In both studies, no substantial difference in frequency of local or systemic reactions was reported among children who received the conjugate vaccine compared with control groups. # Alaska Natives and American Indians Researchers have studied the immunogenicity of a pneumococcal conjugate vaccine using a different carrier protein among Alaska Native, American Indian, and non-Alaska Native/non-American Indian infants aged <2 years (101 ). A 7-valent pneumococcal vaccine consisting of serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F linked with the outer membrane protein complex of Neisseria meningitidis was administered to Alaska Native, American Indian (i.e., Apache and Navajo), and non-Alaska Native/non-American Indian infants aged 2, 4, and 6 months, with a booster dose at age 15 months. Response after three primary doses of vaccine was similar among all three groups of infants, except for serotypes 14 and 23F. However, 1 month after the booster dose, serotype-specific GMCs increased to all seven serotypes among the three groups of infants when compared with the pneumococcal IgG GMCs before the booster dose. Although a different conjugatecarrier protein was used, this study indicated that PCV7 immunogenicity among Alaska Natives and American Indians will likely be similar to immune system response among - Routine vaccinations included diphtheria toxoid-tetanus toxoid-pertussis vaccine; Haemophilus influenzae type b conjugate; hepatitis B; oral and inactivated poliovirus; measles-mumps-rubella; and varicella. non-Alaska Natives/non-American Indians. Prevnar is under evaluation in an efficacy study among American Indians, and study results are pending. # Efficacy Data from a trial using PCV7 provide evidence of the vaccine's efficacy against invasive pneumococcal disease, as well as its effectiveness against clinical pneumonia and AOM among healthy children aged <2 years. The results are summarized in the following section. Other clinical efficacy trials using 7-, 9-and 11-valent pneumococcal conjugate vaccines are currently being conducted or are planned in the United States, South Africa, and certain other countries. Outcomes to be measured in these studies include protective efficacy against overall mortality, pneumonia, invasive disease, AOM, and nasopharyngeal carriage of pneumococci. # Efficacy Trials In a prospective double-blind study among patients of a health maintenance organization in northern California, a total of 37,830 healthy children (i.e., without immune system disorders or serious chronic disease) were randomly assigned to receive either PCV7 or a control (meningococcal C conjugate) vaccine. Vaccinations were administered at ages 2, 4, 6, and 12-15 months. Routine, licensed vaccines- were administered concurrently according to schedule. Initially, diphtheria toxoid-tetanus toxoid whole-cell pertussis (DTwP) vaccine was included among the childhood vaccinations; however, during the study, use of acellular pertussis vaccine became routine. As of March 2000, >50% of study participants had been followed for ³36 months (7 ). Invasive pneumococcal disease was defined as an acute illness consistent with pneumococcal disease in a child from whom S. pneumoniae was cultured from a normally sterile site (e.g., blood or CSF). Cases were identified through active surveillance. At the time of the primary efficacy analysis in August 1998, PCV7 was 100% efficacious against vaccine serotypes among children who were either fully vaccinated (i.e., completed the three-dose primary series) or partially vaccinated (i.e., received ³1 doses) (95% confidence interval = 80.5%-100% and 85.4%-100%, respectively). Additional cases have been identified since completion of the primary analysis. When all cases of invasive disease were evaluated during follow-up analysis in April 1999, PCV7 was 97.4% (95% CI = 82.7%-99.9%) and 93.9% (95% CI = 79.6%-98.5%) efficacious against vaccine serotypes among children who were fully or partially vaccinated, respectively (Table 2). Statistically significant serotype-specific protection also was reported for four of the seven vaccine serotypes (i.e., 19F, 14, 18C, and 23F). The study's ability to evaluate efficacy for the remaining three serotypes was limited because too few cases were caused by these serotypes in either treatment group (7 ). No evidence existed of an increase in invasive disease caused by nonvaccine serotypes. To examine effectiveness of PCV7 in preventing pneumonia of any etiology among the study population as a secondary outcome, investigators reviewed hospital, outpatient, and emergency room records of the children in the study. Monitored outcomes included clinical diagnoses of pneumonia, clinical pneumonia with abnormal chest X-rays, and clinical pneumonia with consolidation of ³2.5-cm found on chest X-rays. Among children who received ³1 doses of study vaccine (intent-to-treat analysis), use of PCV7 resulted in 11.4% (95% CI = 1.3%-20.5%) fewer episodes of clinical pneumonia, regardless of X-ray or culture result. Cases of clinical pneumonia accompanied by an X-ray with any evidence of an infiltrate were reduced by 33.0% (95% CI = 7.3%-51.5%). Among children who had clinically diagnosed pneumonia and X-ray evidence of an area of consolidation of ³2.5 cm as read by both a pediatrician and a radiologist, efficacy of PCV7 was 73.1% (95% CI = 3.0%-88.3%) (102 ). Effectiveness of PCV7 in preventing health-care visits for AOM from all causes, including risk for first AOM episode, frequent AOM episodes, and tympanostomy tube placement, was assessed as a secondary outcome in the Northern California Kaiser Permanente efficacy trial. Episodes of physician-diagnosed AOM among the study population were identified retrospectively through computerized databases of clinic and emergency room encounters. To exclude return visits related to one episode of AOM, a case of AOM was defined as a visit for otitis media, with no visits for otitis media made during the previous 21 days, or if the visit had occurred during the previous 21-42 days, the appointment had been made <3 days in advance. Frequent AOM was defined as ³3 episodes within 6 months or ³4 episodes within 1 year. A substantial reduction in episodes of AOM was found. Vaccine impact was greatest for frequent otitis and tympanostomy tube placement (Table 3) (7 ). Compared with children who received control vaccine, children who received PCV7 had 6.4% (95% CI = 3.9%-8.7%) fewer episodes of AOM, 9.1% (95% CI = 4.1%-13.8%) fewer episodes of frequent AOM (defined as ³3 episodes in 6 months or ³4 in 1 year), and they underwent 20.3% (95% CI = 3.6%-34.1%) fewer tympanostomy tube placements (Table 3). Among a subset of study children with spontaneously ruptured tympanic membranes, S. pneumoniae was cultured from the draining ears of 6 children vaccinated with PCV7 and 17 children who received the control vaccine (vaccine efficacy was 65% for AOM caused by vaccine-serotype pneumococci ). The ability of PCV7 to protect children against AOM was also evaluated in an efficacy trial conducted in Finland (103 ). Children (N = 1,662) were randomized to receive either PCV7 or hepatitis B (control) vaccine at ages 2, 4, 6, and 12 months. Outcomes measured included AOM with concurrent myringotomy to establish bacterial diagnosis. Investigators reported 2,596 AOM episodes during the follow-up period in perprotocol analysis. Of these, 357 episodes were caused by vaccine-serotype pneumococci. A total of 107 episodes occurred among the PCV7 group, and 250 among the control group, for an estimated efficacy of 57% (95% CI = 44%-67%) against culture-confirmed AOM caused by vaccine serotypes. The estimated percent efficacy was lower for outcomes that included nonvaccine pneumococcal serotypes or other pathogens causing AOM. For prevention of AOM caused by pneumococci of any serotype, efficacy was estimated to be 34% (95% CI = 21%-45%), and efficacy against AOM irrespective of etiology was 6% (95% CI = -4%-16%) (83 ). Further analysis revealed an efficacy against vaccine-related serotypes (i.e., 6A, 9N, 18B, 19A, and 23A) of 51% (95% CI = 27%-67%). An increase of 33% in the rate of AOM episodes caused by nonvaccine serotypes occurred among the group who received PCV7 compared with the control group. However, in spite of the increase in disease caused by nonvaccine serotypes, the net effect regarding pneumococcal AOM was a reduction of 34%. # Effect on Antimicrobial Use Prevention of pneumococcal infections among young children after widespread use of PCV7 might result in decreased use of antibiotics, as reported in the Northern California Kaiser Permanente vaccine efficacy trial where a 5.3% reduction was reported among the group of children who received PCV7 (104 ). A reduction in antibiotic use might slow or reverse the trend of increasing prevalence of antimicrobial resistance among pneumococci. # Other Studies of Vaccine Impact Hib conjugate vaccines reduce acquisition of nasopharyngeal carriage of the bacterium among infants and children, an effect that is thought to contribute to the success of Hib vaccination programs by providing herd immunity (105 ). A 40% and 50% reduction of vaccine-serotype S. pneumoniae carriage has been reported in studies of a 9-valent CRM197 pneumococcal conjugate vaccine conducted in Israel and South Africa, respectively (5,6 ). In both studies, vaccination resulted in a reduction in nasopharyngeal carriage of vaccine-type pneumococci and a simultaneous increase in detection of carriage of pneumococci of nonvaccine serotypes. Whether this represents true replacement or unmasking of serotypes that were also colonizing the nasopharynx is unknown. Additional information regarding the impact of PCV7 on nasopharyngeal carriage is expected from a future efficacy trial among Navajo and Apache populations. In a double-blind, randomized study of a 9-valent pneumococcal conjugate vaccine containing the CRM197 carrier among healthy toddlers attending day care centers in Israel, conjugate vaccine or control (meningococcal C conjugate) vaccine was administered to children in two age groups, 12-17 months (two doses) and 18-35 months (one dose). Primary outcomes were carriage rates of vaccine serotype-and penicillin-resistant pneumococci. After 21 months of follow-up, carriage rates of vaccine-serotype pneumococci were substantially lower among toddlers who were vaccinated with 9-valent pneumococcal conjugate vaccine compared with the control group. For both vaccineserotype and penicillin-resistant S. pneumoniae, differences in carriage persisted for children aged <36 months and those ³36 months, although the difference was greatest for children aged <36 months. The study also reported herd immunity within families; siblings of 9-valent pneumococcal conjugate vaccine recipients were substantially less likely to carry antibiotic-resistant pneumococci compared with siblings of controlvaccine recipients (106 ). # Duration of Protection Duration of protection after vaccination with PCV7 is unknown. However, immunologic memory does occur. Among infants aged £20 months who received primary vaccination with two or three doses of PCV7, administration of PPV23 £18 months later resulted in a booster response. A similar response was elicited among children aged 2-3 years when administered PPV23 £20 months after a bivalent (i.e., 6A plus 23F) CRM197 conjugate vaccine (92,96 ). Additional studies of PCV7 with longer follow-up periods are needed. Evaluation of duration of protection will be critical for older children at high risk for disease (e.g., those with SCD or HIV infection). # Cost-Benefit Analysis Costs and benefits of a routine PCV7 program for healthy U.S. infants and children were evaluated in a study using current estimates of pneumococcal disease burden (i.e., meningitis, bacteremia, pneumonia, and AOM episodes), clinical outcomes, vaccine efficacy, and health-care costs (107 ). Sources of clinical outcomes and costs included published and unpublished data, expert consensus, and computerized databases from Kaiser Permanente of Northern California. For each annual U.S. birth cohort, routine PCV7 vaccination is estimated to prevent approximately 12,000 (78% of potential) cases of pneumococcal meningitis and bacteremia; 53,000 (69% of potential) pneumococcal pneumonia cases; and >1 million (8% of potential) episodes of clinically diagnosed otitis media. Vaccination of healthy infants would result in net savings to society if vaccine costs were £$46/dose. Net savings to health insurers would result if the vaccine costs were £$18/dose. A program in which one dose of vaccine was administered to children aged 24-59 months to bring them up-to-date with their vaccinations would result in societal cost savings at a vaccine price of £$80 for children aged 24-35 months and £$50 for those aged 48-59 months. From the health-care-payer perspective, savings would result if vaccine costs were £$40 and £$20 when administered to children aged 24-35 months and 48-59 months, respectively. Results of this study demonstrate that costeffectiveness of vaccination of infants and toddlers is most influenced by vaccine price, - Initially all children in the study received the whole-cell pertussis vaccine and oral poliovirus vaccine; however, after changes in vaccine recommendations midway through the study, participants began receiving the diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine and the inactivated poliovirus vaccine. especially among children aged ³24 months. In a recent reanalysis of cost-effectiveness of PCV7 using additional and updated information (including newly available safety data, national costs, and rates of tympanostomy tube placement), the same investigators found that break-even costs for vaccination of infants from societal and health-carepayer perspective were $40 and $17, respectively (108 ). # Vaccine Safety # Safety of Administration of PCV7 Series Among Infants Rates and types of adverse events associated with PCV7 administered at ages 2, 4, 6, and 12-15 months are acceptable when compared with the demonstrated benefits of vaccination. In the Northern California Kaiser Permanente efficacy trial, rates of adverse events were compared between children who received PCV7 and those who received the control vaccine (investigational group C meningococcal conjugate). Routine childhood vaccines were administered concurrently with PCV7 and control vaccines.- To assess vaccine safety, information regarding local and systemic reactions was collected at 48-72 hours and 14 days after each dose. Using telephone interviews, investigators collected adverse-event histories for two subsets of the study population -initially a group receiving DTwP (N = 6,000) and later a group receiving diphtheria toxoid-tetanus toxoid acellular pertussis (DTaP) vaccine (N = 1,500). Frequency of uncommon events requiring medical attention after vaccination was evaluated for the entire study cohort and included emergency room and outpatient clinic visits occurring £30 days and hospitalizations occurring £60 days after receiving the study vaccines. PCV7 vaccination resulted in less frequent local reactions than DTwP vaccine, but more frequent local reactions than DTaP vaccine and the control vaccine. Except for erythema, no pattern of increasing local reactogenicity with subsequent doses of PCV7 was reported (Table 4). Fever ³100.4 F (³38 C) £48 hours after vaccination was more common among children who received PCV7 concomitantly with DTaP vaccine and other recommended vaccines than among those who received the control vaccine. This difference was statistically significant after each dose of vaccine in the primary series but not the fourth dose (Table 5). Rates of fever >102.2 F (>39 C) were substantially greater among those who received PCV7 after dose two of the primary series (i.e., 2.5% versus 0.8%). Febrile seizures after vaccination were slightly more common in the PCV7 group; however, the majority of events occurred when whole-cell pertussis vaccine was administered concurrently with PCV7. Using hospitalizations, emergency room visits, and data from all other sources, seizures occurring £3 days after vaccination were reported for four children who received control vaccine and eight who received PCV7. Of the eight PCV7 recipients who had a seizure, seven had received concurrent DTwP vaccine. Two children who were vaccinated with concurrent DTaP vaccine had a seizure £3 days after therefore, this column represents the fourth dose of a pertussis vaccine, but not necessarily a fourth dose of DTaP. § P < 0.05 when PCV7 site is compared with DTaP site using the sign test. vaccination, one in each of the PCV7 and control-vaccine groups (109 ). The seizure rate £3 days after vaccination with PCV7 and concurrent vaccinations was approximately 1/ 7,000 doses, below historic rates after whole-cell pertussis vaccinations (109,110 ). As of April 20, 1999, a total of 32 children who were originally enrolled in the study had died (109 ); however, none of the deaths were reported by investigators to be related to the vaccine. A total of 12 cases of sudden infant death syndrome (SIDS) were observed among the study cohort £1 year after vaccination, 4 among the PCV7 group (0.2 cases/1,000 children) and 8 among the control group (0.4 cases/1,000 children). These rates are less than expected historically; 0.5 cases/1,000 children were observed in California in 1996 and 1997. One death attributable to SIDS occurred within the first week of vaccination in a child who received PCV7 concurrently with other vaccines. In an age-and season-adjusted analysis based on California SIDS data, 1.06 cases would have been expected £1 week after vaccination (7 ). # Safety of Administration of PCV7 Among Older Children Safety data are available from four immunogenicity studies of PCV7 among older infants and children (109 ). Approximately 900 doses of PCV7 were administered to 560 children aged 7 months-9 years following the recommended schedule for vaccination administration for children who are beyond the age of the infant schedule. Comparisons across the studies demonstrate that, generally, frequency of local reactions was higher among older children than among children vaccinated at age <1 year. Frequency of fever of ³100.4 F (³38 C) after one dose of PCV7 ranged from 6.8% to 36.7%. No distinct, age-related patterns of systemic reactions was evident. Fussiness was the most commonly observed systemic reaction (Tables 6,7). # Safety of Administration of PCV7 After PPV23 Minimal safety data are available regarding the sequence of PPV23 followed by PCV7. However, in one published study of children and young adults with SCD, 16 of the study participants had already received one dose of PPV23 3-15 years previously (persons who had received PPV23 within the previous 2 years were excluded). Of these 16 SCD patients, 9 who had received two doses of PCV7 followed by one dose of PPV23 8 weeks later were compared with 7 who had received one dose of PPV23. No severe reactions were reported; local reactions were similar between the two groups (93 ). # Safety of Administration of PPV23 After PCV7 Five studies have been completed in which 152 infants, children, or young adults received ³1 doses of 2-, 5-, or 7-valent pneumococcal conjugate vaccine conjugated to CRM197 followed by a dose of PPV23. Populations studied included healthy infants and children (92,96 ), HIV-infected children and young adults (94 ), and infants and children with SCD (93,99 ). PPV23 was administered 6 weeks-20 months after pneumococcal conjugate vaccine. Adverse events were described in three of the five studies. No serious adverse events were identified after the dose of PPV23. No increase in adverse events was reported among HIV-infected persons who received 5-valent pneumococcal conjugate vaccine followed by PPV23 as compared with those who received PPV23 alone (94 ). Among children with SCD who received either PCV7 followed by PPV23 or PPV23 alone, fever occurred among 4 of 11 and 2 of 11 children, respectively. Local reactions did not differ between the two groups (93 ). # PPV23 Revaccination No published studies have been designed specifically to examine adverse events among children who were administered a second dose of PPV23 after an earlier dose of PPV23. However, in the previously described study (93 ) in which young children and adults with SCD were vaccinated with either PCV7 and PPV23 consecutively or PPV23 alone, 16 of 23 enrolled patients had been vaccinated with one dose of PPV23 3-15 years earlier. All patients were randomized to receive either one dose of PPV23 or two doses of PCV7 followed by a booster dose of PPV23 8 weeks later. No severe reactions were reported after the second dose of PPV23. # Vaccine Administration PCV7 is administered intramuscularly as a 0.5-ml dose. PCV7 is licensed for use among infants aged ³6 weeks. PCV7 can be administered at the same time as other routine childhood vaccinations in a separate syringe at a separate injection site. In clinical studies of PCV7, when routine childhood vaccinations were administered simultaneously with PCV7 vaccine but at different sites, suppression of Hib response occurred after the fourth dose. However, >97% of children achieved antibody titers ³1 µg/ml. Additionally, a limited decrease in antibody response to poliovirus Type 1 occurred; however, clinical significance of these decreased responses is uncertain (109,111 ). Conjugate vaccines containing diphtheria toxoid or protein as carriers (e.g., CRM197) should not be considered immunizing agents against diphtheria. Thus, no change in the vaccination schedule for DTaP vaccine is currently recommended. Simultaneous administration of PCV7 with other vaccines at the 2-, 4-, and 6-month visits might necessitate five injections at each visit. Physicians might consider potential approaches to decreasing the number of simultaneous injections that are needed. One approach is to administer the first two doses of hepatitis B vaccine at birth and age 1 month. Alternatively, a Hibhepatitis B combination product is available for use at ages 2, 4, and 12-15 months. An - VAERS forms can be obtained by calling (800) 822-7967, and additional information is available at (accessed July 31, 2000). † A Strong evidence, including results of efficacy studies, supports vaccine use. B Moderate evidence, including immunogenicity data but not efficacy data, supports vaccine use. C No efficacy or immunogenicity studies are available regarding this population, but protection is anticipated on the basis of such studies among other groups; vaccination is supported by respected authorities. -ption to decrease the number of simultaneous injections when the fourth dose is administered would be to divide needed injections between visits at ages 12 months and 15 or 18 months. Combination vaccine products currently being evaluated by manufacturers might further decrease the need for multiple injections. # Precautions and Contraindications Vaccination with PCV7 is contraindicated among persons known to have a hypersensitivity to any component of the vaccine. Health-care providers can choose to delay vaccination of children with moderate or severe illness until the child has recovered, although minor illnesses (e.g., mild upper-respiratory infection with or without low-grade fever) are not contraindications to vaccination. Any adverse event suspected to be associated with PCV7 vaccination should be reported to the Vaccine Adverse Events Reporting System (VAERS).- Concurrent administration of PCV7 and PPV23 is not recommended because safety and efficacy of concurrent vaccination has not been studied. # RECOMMENDATIONS FOR USE OF PCV7 # Children for Whom PCV7 Is Recommended Children Aged £23 Months All children aged £23 months should be vaccinated with PCV7 (Table 8). Infant vaccination provides the earliest possible protection, and children aged £23 months have the highest rates of pneumococcal infection. PCV7 is safe and highly efficacious in preventing invasive disease, and it is effective in preventing a portion of AOM cases and pneumonia among healthy infants and young children (Strength of evidence: children aged 2-6 months, A; † children aged 7-23 months, B) (Table 9). Vaccination Schedule. Infants receiving their first dose at age £6 months should receive three doses of PCV7 at intervals of approximately 2 months, followed by a fourth dose at age 12-15 months (Table 10). Newborns should begin the schedule at age 2 months, although PCV7 can be administered as young as age 6 weeks. Prematurely born infants (i.e., <37 weeks gestation) should receive PCV7 at the recommended chronologic age concurrent with other routine vaccinations. For infants with prolonged nursery stays, initiation of vaccination should begin during discharge planning. Children aged ³7 months not previously vaccinated should also be vaccinated according to the recommended schedule (Table 10). The proposed vaccination schedule is the same for all children aged £23 months, regardless of the presence of underlying medical conditions (e.g., children with HIV infection, SCD or other asplenia, chronic disease, or who are otherwise immunocompromised). Interruption of the vaccination schedule does not require reinstitution of the entire series or the addition of extra doses (Table 11). # Children Aged 24-59 Months Who Are at High Risk for Pneumococcal Infection Children aged 24-59 months should receive PCV7 vaccination if they are at high risk for pneumococcal infection caused by an underlying medical condition (Table 8). This recommendation applies to the following groups: - children with SCD and other sickle cell hemoglobinopathies, including hemoglobin SS, hemoglobin S-C, or hemoglobin S-ß-thalassemia, or children who are functionally or anatomically asplenic; - children with HIV infection; - children who have chronic disease, including chronic cardiac and pulmonary disease (excluding asthma), diabetes mellitus, or CSF leak; and Vaccination Schedule. For children aged 24-59 months with underlying medical conditions (Table 8), ACIP recommends two doses of PCV7, administered 2 months apart, followed by one dose of PPV23 administered ³2 months after the second dose of PCV7 (Tables 10,12). The recommendation for two PCV7 doses is based on results of an immunogenicity study conducted among SCD patients. That study reported that a nonstatistically significant antibody response to serotype 6B after one dose of PCV7 increased statistically significantly after a second dose of PCV7 (93 ). Serotype 6B is one of the most common pneumococcal serotypes colonizing or causing invasive disease among SCD patients and healthy children (47,(112)(113)(114). 8). Penicillin prophylaxis should be continued for children with SCD to age ³5 years, regardless of vaccination with PCV7. Protective efficacy of PCV7 for children with SCD has not been studied, and the vaccine does not protect against all serotypes causing disease. However, penicillin prophylaxis substantially reduces the risk for invasive pneumococcal infections among SCD patients (112 ). # Other Children Who Might Benefit from Vaccination with PCV7 ACIP recommends that health-care providers consider PCV7 vaccination for all other children aged 24-59 months, with priority given to the following populations: - children aged 24-35 months; - children of Alaska Native or American Indian descent; - children of African-American descent; - children who attend group day care centers;- This recommendation is made on the basis of the moderate risk for pneumococcal disease, including antibiotic-resistant infections, among these populations and on potential cost-benefit. Data regarding efficacy and immunogenicity of PCV7 are limited for these specific risk and age groups. However, the vaccine is safe and immunogenic among all healthy children aged 24-59 months. Also, immunogenicity data are available regarding use of another pneumococcal conjugate vaccine among Apache, Navajo, and Alaska Native children (101 ), and efficacy data for children aged £23 months probably are relevant for healthy children aged 24-59 months (Strength of Evidence: B). PPV23 is licensed for use among children aged ³2 years who are at high risk for pneumococcal infections (e.g., those with SCD or HIV infection). However, the conjugate vaccine has advantages over PPV23, which include induction of immune system memory (possibly resulting in longer duration of protection), reduction in carriage, probable higher efficacy against serotypes causing most invasive disease, and probable effectiveness against noninvasive syndromes (e.g., nonbacteremic pneumonia and AOM). If pneumococcal vaccine is to be used among healthy children aged 24-59 months, ACIP recommends that PCV7 be used. Vaccination Schedules. ACIP recommends that one dose of PCV7 be considered for Alaska Native and American Indian children aged 24-59 months. Previously, ACIP recommended PPV23 for Alaska Natives and certain American Indian populations aged ³2 years (1 ). However, use of PCV7 among these children offers multiple potential advantages over PPV23 as previously discussed. In contrast, PPV23 offers potentially broader serotype coverage. Recent studies demonstrate that only 68% and 57% of invasive infections among Alaska Natives and American Indians in the U.S. Southwest aged 24-59 months, respectively, were caused by serotypes included in the 7-valent conjugate vaccine, lower proportions than among non-Alaska Native/non-American Indian populations (115,116 ). Therefore, vaccination program personnel and other healthcare providers might consider whether Alaska Native and American Indian children aged 24-59 months would benefit by the additional coverage provided by the 23-valent polysaccharide vaccine. Data are limited regarding safety and immunogenicity of PPV23 after PCV7. If additional serotype coverage is desired by parents and health-care providers, PPV23 should be administered ³2 months after PCV7 (Strength of evidence: C). A community-randomized trial to evaluate the efficacy of PCV7 among Navajo and Apache children in preventing pneumococcal disease is underway. Future recommendations for use of PCV7 among Alaska Native and American Indian populations might be modified on the basis of that trial. ACIP recommends that physicians consider administering one dose of PCV7 to their African-American pediatric patients aged 24-59 months because of their increased risk for pneumococcal infection. The proportion of invasive pneumococcal disease among African-American children that is caused by PCV7 serotypes does not differ from whites in the United States, and rates of invasive disease decline with age (ABCs/EIP Network, unpublished data, 2000). Therefore, no additional vaccination with PPV23 is recommended (Strength of evidence: B). Additionally, because of increased risk for invasive pneumococcal disease, colonization with antibiotic-resistant pneumococcal strains, and AOM, health-care providers should consider administering one dose of PCV7 to previously unvaccinated children aged 24-59 months who attend group day care centers. # Children Aged ³5 Years and Adults Who Are At High Risk for Pneumococcal Infection Data are limited regarding efficacy of PCV7 among children aged ³5 years and adults. However, limited studies report that a) 5-valent pneumococcal conjugate vaccine is immunogenic among HIV-infected children aged 2-9 years (94 ); b) PCV7 is immunogenic among children aged 2-13 years with recurrent respiratory infections (117 ); and c) PCV7 is immunogenic among older children and adults aged 4-30 years with SCD (93 ). Administering PCV7 to older children with high-risk conditions is not contraindicated. Studies among healthy adults aged ³50 years (118 ) and among HIV-infected adults aged 18-65 years (119 ) did not demonstrate substantially greater ELISA antibody concentrations after administration of 5-valent pneumococcal conjugate vaccine compared with PPV23. Also, the proportion of invasive pneumococcal isolates covered by PCV7 is only 50%-60% among older children and adults, in contrast with 80%-90% coverage by PPV23 among this older group. Therefore, current data do not support a recommendation to replace PPV23 with PCV7 among older children and adults. # Recommendations for Use of PCV7 Among Children Previously Vaccinated with PPV23 Children aged 24-59 months who are at high risk for pneumococcal disease and who have already received PPV23 (i.e., children with SCD, HIV infection, or who have other immunocompromising illnesses or chronic diseases) could benefit from the immunologic priming and T-cell-dependent immune system response induced by PCV7. Thus, among children in these groups at high risk, sequential use of the two pneumococcal vaccines can provide additional protection. Health-care providers should vaccinate children aged 24-59 months at high risk who have not previously received PCV7 but who have already received PPV23 with two doses of PCV7 administered ³2 months apart. Vaccination with PCV7 should be initiated ³2 months after vaccination with PPV23. Providers should be aware that minimal safety data are available regarding this vaccine sequence. # Recommendations for Use of PPV23 Among Children Previously Vaccinated with PCV7 # Administration of PCV7 Followed by PPV23 Among Children at High Risk for Pneumococcal Disease Children who have completed the PCV7 vaccination series before age 2 years and who are among risk groups for which PPV23 is already recommended should receive one dose of PPV23 at age 2 years (³2 months after the last dose of PCV7). These groups at high risk include children with SCD, children with functional or anatomic asplenia, children who are HIV-infected, and children who have immunocompromising or chronic diseases (1 ) (Table 8). Although data regarding safety of PPV23 administered after PCV7 are limited, the opportunity to provide additional serotype coverage among these children at very high risk justifies use of the vaccines sequentially. For children of Alaska Native or American Indian descent, addition of PPV23 after PCV7 can be considered. # Revaccination with PPV23 Immunocompromised children or children with SCD or functional or anatomic asplenia should be revaccinated with PPV23 as previously recommended (1 ) (Table 12). If the child is aged £10 years, one revaccination should be considered 3-5 years after the previous dose of PPV23 (1,120 ). Data are limited regarding adverse events related to a second dose of PPV23 administered after PCV7. Health-care providers should not administer a second dose of PPV23 any earlier than 3 years after the initial dose of PPV23. # AREAS FOR FUTURE RESEARCH With recent licensure and introduction of PCV7, close monitoring of disease trends and long-term vaccine safety will be high priorities for public health organizations and health-care providers. Postlicensure surveillance will be necessary to a) detect potential changes in serotype distribution, including any increase in disease caused by serotypes not contained in PCV7; b) follow trends in antimicrobial resistance and antibiotic use; c) detect potential herd immunity induced by widespread use of PCV7; and d) track vaccine-related health events. # MMWR October 6, 2000 Areas where research is ongoing or necessary to determine the most effective use of PCV7 include the following: - Optimal vaccination schedule for older children at high risk. Further studies are needed to identify optimal vaccination schedules for PCV7 and PPV23 among children aged ³2 years who are at high risk for infection, including children with SCD, HIV infection, and other chronic diseases or immunocompromising conditions, particularly children who have received a bone marrow transplant. Research is critical regarding optimal scheduling of vaccination with PCV7 among children who have already received PPV23 and revaccination with PPV23 after vaccination with PCV7. - Combined vaccines including PCV7 and other routine vaccines for infants. Reducing the number of required separate injections would improve the infant vaccination schedule. Additional research is needed to evaluate safety and immunogenicity of PCV7 when administered in combination with other antigens. - Studies of safety, immunogenicity, and efficacy among adults at high risk for pneumococcal infection. Additional studies are needed to evaluate potential use of PCV7 among adults at increased risk for pneumococcal infection. Benefits and risks involved with using a 7-, 9-, 11-, or 15-valent pneumococcal conjugate vaccine in place of or in addition to PPV23 warrant further investigation. Rationale for additional study of a combined or sequential regimen includes potential benefits of conjugate pneumococcal vaccines (e.g., induction of immunologic memory with increased duration of protection, reduction of nasopharyngeal carriage of pneumococci, and potential impact on nonbacteremic pneumonia) along with the benefit of broader serotype coverage provided by PPV23. - Duration of protection. For persons of all age groups, duration of protection after vaccination with PCV7 is unknown. Investigation of potential need for revaccination with PCV7 or PPV23 after primary vaccination is warranted. - Identifying and defining immune system correlates of protection. Type-specific antibody concentration necessary to confer protection against pneumococcal infection is unknown. Researchers are attempting to determine and standardize the level of antibody, as measured by ELISA, that provides serotype-specific protection against pneumococcal disease. Functional tests of induced immune system response (e.g., opsonophagocytosis) are also being evaluated. A determination of immunologic markers that best correlate with clinical protection is needed. Validated immune system correlates of protection will accelerate evaluation and licensure of new vaccines against pneumococcal infection. - Alternative pneumococcal vaccines. Research is ongoing regarding development of alternative pneumococcal vaccines. Investigators are evaluating possible roles of conserved pneumococcal proteins (e.g., pneumolysin, surface protein A, or surface adhesion A) as antigens that have potential to provide broad protection against disease caused by all pneumococcal serotypes (121 ). Use of other peptides or pneumococcal proteins as carriers in conjugate vaccines is also being studied. Additionally, alternative routes of delivery including intranasally and orally administered vaccines are under investigation (122,123 ). October 6, 2000 / Vol. 49 / No. RR-9 # Recommendations and Reports # Continuing Education Activity Sponsored by CDC # Preventing Pneumococcal Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices (ACIP) EXPIRATION -OCTOBER 6, 2003 You must complete and return the response form electronically or by mail by October 6, 2003, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1. 5 # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.5 hours in category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.6 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 # MMWR October 6, 2000 # Goals and Objectives This MMWR provides guidance for preventing pneumococcal disease among infants and young children in the United States. These recommendations were developed by the Advisory Committee on Immunization Practices (ACIP). The goals of this report are to provide ACIP's recommendations regarding the 7-valent pneumococcal polysaccharide-protein conjugate vaccine and to update previous ACIP recommendations regarding use of 23valent pneumococcal polysaccharide vaccine among children. Upon completion of this educational activity, the reader should be able to a) describe the burden of pneumococcal disease among infants and young children in the United States; b) describe the characteristics of the newly licensed 7-valent pneumococcal conjugate vaccine; c) identify groups of infants and children for whom the 7-valent pneumococcal polysaccharide-protein conjugate vaccine is recommended; d) recognize contraindications to the administration of pneumococcal conjugate vaccine; and e) identify children for whom vaccination with 23-valent pneumococcal polysaccharide is appropriate.	In February 2000, a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (Prevnar,™ marketed by Wyeth Lederle Vaccines) was licensed for use among infants and young children. CDC's Advisory Committee on Immunization Practices (ACIP) recommends that the vaccine be used for all children aged 2-23 months and for children aged 24-59 months who are at increased risk for pneumococcal disease (e.g., children with sickle cell disease, human immunodeficiency virus infection, and other immunocompromising or chronic medical conditions). ACIP also recommends that the vaccine be considered for all other children aged 24-59 months, with priority given to a) children aged 24-35 months, b) children who are of Alaska Native, American Indian, and African-American descent, and c) children who attend group day care centers. This report includes ACIP's recommended vaccination schedule for infants at ages 2, 4, 6, and 12-15 months. This report also includes a pneumococcal vaccination schedule for infants and young children who are beginning their vaccination series at an older age and for those who missed doses. In addition, this report updates earlier recommendations for use of 23-valent pneumococcal polysaccharide vaccine among children aged ³2 years. Among children aged 24-59 months for whom polysaccharide vaccine is already recommended, ACIP recommends vaccination with the new conjugate vaccine followed, ³2 months later, by 23-valent polysaccharide vaccine. Conjugate vaccine has not been studied sufficiently among older children or adults to make recommendations for its use among persons aged ³5 years. Persons aged ³5 years who are at increased risk for serious pneumococcal disease should continue to receive 23-valent polysaccharide vaccine in accordance with previous ACIP recommendations. * Defined in that study as any setting outside the home where a child regularly spends ³4 hours/week with ³2 unrelated children under adult supervision.# INTRODUCTION Streptococcus pneumoniae (pneumococcus) remains a leading cause of serious illness among young children worldwide and is the most frequent cause of pneumonia, bacteremia, sinusitis, and acute otitis media (AOM). In the United States, S. pneumoniae causes approximately 17,000 cases/year of invasive disease among children aged <5 years, including 700 cases of meningitis and 200 deaths (CDC's Active Bacterial Core Surveillance [ CDC's Advisory Committee on Immunization Practices (ACIP) previously recommended 23-valent pneumococcal polysaccharide vaccines for use among children aged ³2 years who have high rates of disease, including those with sickle cell disease (SCD), chronic underlying diseases, human immunodeficiency virus (HIV) infection, or others who are immunocompromised. The new 7-valent pneumococcal conjugate vaccine (PCV7;* Prevnar,™ licensed in February 2000 and marketed by Wyeth Lederle Vaccines) should be a key addition to existing pneumococcal disease prevention measures. Although the previously licensed 23-valent pneumococcal polysaccharide vaccines (PPV23; PNU-IMUNE ® 23 marketed by Wyeth-Ayerst Laboratories and Pneumovax ® 23 by Merck and Company) are effective in preventing invasive pneumococcal disease among older children and adults, these vaccines do not protect children aged <2 years, the age group with the highest rate of disease (1)(2)(3). Furthermore, PPV23 does not decrease nasopharyngeal carriage, a substantial source of transmission of pneumococci (4 ). In contrast, conjugate vaccine decreases colonization, and PCV7 prevents pneumococcal disease among children aged £2 years (5)(6)(7). This report provides ACIP's recommendations for pneumococcal vaccination of children aged <5 years. # BACKGROUND Incidence of Invasive Disease Among Children The highest rates of invasive pneumococcal disease (e.g., bacteremia, meningitis, or other infection of a normally sterile site) occur among young children, especially those aged <2 years. In 1998, estimated incidence in the United States of invasive pneumococcal infections among children aged <12 months and 12-23 months were 165 and 203 cases/100,000 population, respectively, with peak incidence occurring among children aged 6-11 months (235/100,000). In contrast, incidence among persons of all ages and among persons aged ³65 years were 24 and 61/100,000, respectively (Figure 1) (8 ). In the United States, the most common manifestation of invasive pneumococcal disease among young children is bacteremia without a known site of infection, which accounts for approximately 70% of invasive pneumococcal cases among children aged <2 years. Only 12%-16% of patients with invasive pneumococcal disease among this age group have pneumonia (ABCs/EIP Network, unpublished data, 2000). With the success of conjugate vaccines in preventing invasive Haemophilus influenzae type b (Hib) disease, S. pneumoniae has become the leading cause of bacterial meningitis in the United States. Children aged <1 year have the highest incidence of pneumococcal meningitis, which is approximately 10/100,000 population (9 ). * Abbreviations used in this report are those used by ACIP during development of vaccination recommendations; they are similar to those already published by the American Academy of Pediatrics (Source: American Academy of Pediatrics. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine [Prevnar], pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000:106:362-6). A new standardized nomenclature system is in development as part of CDC's Vaccine Identification Standards Initiative (available at <http://www.cdc.gov/ nip/visi/prototypes/vaxabbrev.htm>; accessed September 15, 2000). # Occurrence of Noninvasive Syndromes S. pneumoniae also contributes substantially to noninvasive respiratory infections and is the most common bacterial cause of community-acquired pneumonia, AOM, and sinusitis among young children (10)(11)(12)(13)(14)(15)(16). In two prospective studies of communityacquired pneumonia among young children, 17%-28% of cases were diagnosed as pneumococcal (10,11 ). However, these and other studies probably underestimate the actual proportion of pneumococcal pneumonia cases as a result of low sensitivity of routine diagnostic testing. Studies using diagnostic tympanocentesis among children with AOM have found S. pneumoniae in 28%-55% of all middle ear aspirates (12)(13)(14)(15). Otitis media is the most frequent reason for pediatric office visits in the United States, resulting in >15 million visits/year (17)(18)(19). By age 12 months, 62% of children have had at least one episode of AOM; peak incidence of AOM occurs during ages 6 months-1year (20 ). Although serious complications are rare, economic costs of otitis media are estimated at >$3.5 billion/year in the United States (21 ). During 1996, approximately 500,000 tympanostomy tubes were placed in children's ears in the United States (22 ). AOM is also the leading reason for prescribing antibiotics during childhood, and use of antibiotics for treatment of AOM and sinusitis contributes substantially to increased antimicrobial resistance (23)(24)(25). # Children at Increased Risk for Pneumococcal Infections Racial and Ethnic Populations In the United States, higher rates of invasive pneumococcal disease occur among African-Americans, Alaska Natives, and specific American Indian populations, compared with whites (Table 1) (26)(27)(28)(29)(30)(31)(32). Incidence of pneumococcal bacteremia and meningitis among Alaska Native children aged <5 years ranges from 598 cases/100,000 population among children aged 6-11 months to 56 cases/100,000 population for children aged 36-47 months, which is approximately four times that of similarly aged non-Alaska Native/ non-American Indian children (30 ). The highest rates for any ethnic group in the United States are found among Navajo and Apache populations living on reservations in the southwestern United States. Incidence among children aged 1-2 years in these populations is 557-2,396/100,000 (31,32 ). Among children aged <5 years, incidence of invasive pneumococcal disease among African-American children in the United States is 2-3 times higher than the rate among white children of the same age (8,27,29,33 ). In a casecontrol study of risk factors for invasive disease among young children, the association of race with disease risk was not statistically significant in an analysis that controlled for socioeconomic status (34 ). However, other studies have reported persistence of increased risk when controlling for income (27,33,(35)(36)(37). Reasons for increased rates of disease among Alaska Natives, American Indians, and African-Americans are unclear but probably multifactorial. # Children with Functional or Anatomic Asplenia Other children at high risk for invasive pneumococcal disease include patients with SCD, other sickle hemoglobinopathies (e.g., hemoglobin S-C disease or S-ß-thalassemia), and those who are otherwise functionally or anatomically asplenic (38)(39)(40). Although rates of pneumococcal infection among children with hemoglobin S-C disease are lower than rates among persons with SCD, rates are higher than among healthy children (41,42 ). Rates of overall bacterial sepsis in other hemoglobinopathies (e.g., S-ßthalassemia) have not been calculated but are estimated to be intermediate between those for hemoglobin S-C and hemoglobin SS diseases (40 ). High risk for pneumococcal infections among persons with SCD is thought to be caused by the combination of low levels of circulating antibodies, splenic dysfunction, and complement deficiency, resulting in decreased clearance of encapsulated bacteria from the bloodstream (43,44 ). The protective effect of pneumococcal polysaccharide vaccine among SCD patients, initially reported in a study published in 1977, has not been reproduced consistently by subsequent prospective or case-control studies (45)(46)(47)(48)(49). Although use of prophylactic penicillin has reduced the risk for pneumococcal disease, children aged <5 years with SCD still have increased rates of invasive disease (range: 1,230-1,500/100,000 population), probably reflecting noncompliance with and failure of penicillin prophylaxis combined with suboptimal protection by pneumococcal polysaccharide vaccine (38,39,47,49 ). # HIV-Infected Children Children infected with HIV have a markedly increased risk for pneumococcal infection compared with those who are not HIV-infected (50,51 ). In two prospective cohort studies, HIV-infected children had rates of invasive pneumococcal disease that were 2.8 and 12.6 times the rate among HIV-negative control subjects for children aged <5 and <3 years, respectively (52,53 ). Incidence of invasive pneumococcal disease is 6.1 cases/ 100 patient-years among HIV-infected children through age 7 years (54 ). # Children in Day Care Out-of-home day care increases the risk for invasive pneumococcal disease and AOM among children (34,55,56 ). In a study of risk factors for invasive pneumococcal disease among children in the United States, attendance at a group day care center* during the preceding 3 months was associated with an approximately 2.3-fold increase in invasive disease among children aged 12-23 months, and 3.2-fold increased risk among children aged 24-59 months (34 ). Moreover, in a recent population-based case-control study, nonelderly adults (i.e., persons aged 18-64 years) who lived in a household that included children who attended day care were at greater risk for acquiring invasive pneumococcal infections than adults who did not (multivariate odds ratio [OR] = 3.0) (57 ). In studies of otitis media resulting from all causes, risk for AOM was higher among children who attended day care outside the home compared with family day care (58,59 ), and risk for middle ear effusions increased with exposure to larger numbers of children in day care settings (60 ). Younger age when starting day care also increases risk for experiencing recurrent AOM (59 ). Day care attendance is also a risk factor for other acute upper respiratory tract infections among children aged <5 years (61 ). # Antimicrobial Resistance Treatment of pneumococcal disease among young children is complicated by emergence of pneumococcal strains resistant to penicillin and other antibiotics (12,62 ). Among a national sample of invasive pneumococcal isolates, resistance to penicillin (i.e., minimum inhibitory concentration [MIC] ³ 2.0 µg/ml) has increased substantially during the past decade, from 1.3% in 1992 to 13.6% in 1997 (62,63 ). In certain areas of the United States, approximately 35% of invasive isolates are penicillin-nonsusceptible (i.e., intermediate susceptibility [MIC = 0.12-1.0 µg/ml] or resistant [MIC ³ 2.0 µg/ml]) (63 ). In one nasopharyngeal carriage study among children in a rural Kentucky community, 59% of children attending day care centers carried penicillin-nonsusceptible S. pneumoniae (64 ). Risk factors associated with infection with penicillin-resistant pneumococci include younger age, attendance at a day care center, higher socioeconomic status, recent (i.e., £3 months) antibiotic use, and recurrent AOM (26,34,65,66 ). Recent day care attendance and recent antibiotic treatment are associated independently with invasive disease as a result of penicillin-resistant pneumococci (34 ). Penicillin resistance has been associated with treatment failures in AOM and meningitis (12,(67)(68)(69); these failures could be because of difficulty in achieving high antimicrobial concentrations in middle ear fluid and cerebrospinal fluid (CSF) (70 ). Additional research is needed to determine the association between penicillin resistance and treatment failure in pneumococcal pneumonia or bacteremia among children (12,(71)(72)(73). # Pneumococcal Serotypes The capsule of the Streptococcus pneumoniae bacterium consists of polysaccharides and constitutes a major virulence factor for the bacterium (74 ). Antibodies directed against the capsular polysaccharide protect against infection; type-specific antibodies bind capsular antigens; and opsonization facilitates phagocytosis (75 ). Knowledge of the distribution of pneumococcal serotypes causing disease is fundamental to evaluating the potential impact of a pneumococcal vaccine. Currently, 90 serotypes of S. pneumoniae have been identified on the basis of antigenic differences in their capsular polysaccharides (76 ). The majority of serotypes cause serious disease, yet a relatively limited number of serotypes cause the majority of invasive pneumococcal infections. The 10 most common serotypes are estimated to account for approximately 62% of invasive disease worldwide; however, ranking and serotype prevalence differ by age group and country (77 ). In the United States, the seven most common serotypes isolated from the blood or CSF of children aged <6 years (i.e., 14, 6B, 19F, 18C, 23F, 4, and 9V) account for 80% of infections and are the serotypes in the licensed PCV7 (Figure 2). These same seven serotypes, by comparison, account for only 50% of isolates among persons aged ³6 years in the United States (78,79 ). Distribution of serotype coverage also differs among Alaska Natives and American Indians in the United States; the proportion of vaccine serotypes causing invasive pneumococcal disease among children aged <5 years is less among Alaska Natives and American Indians than among non-Alaska Natives/ non-American Indians (30,31 ). Types 1 and 5 account for only a limited percentage of invasive isolates in the United States, but are more common in Western Europe and in certain developing countries (77,80,81 seven PCV7 serotypes accounted for 71% of infections among children aged <24 months (82 ). Among 414 S. pneumoniae isolates obtained from middle ear fluid cultures among children with AOM in Finland, 250 (60%) were caused by serotypes contained in PCV7 (83 ). Antimicrobial resistance is detected most frequently among serotypes included in PCV7. According to 1998 surveillance data from eight states, the PCV7 serotypes accounted for 80% of 312 penicillin-nonsusceptible isolates (MIC ³ 0.1 µg/ml) collected from normally sterile sites among children aged <6 years (ABCs/EIP Network, unpublished data, 1999). A similar serotype distribution of penicillin-nonsusceptible isolates was identified during a study of nasopharyngeal carriage among 216 children aged <6 years in Memphis, Tennessee; 78% of resistant isolates were of the same seven serotypes (65 ). # PNEUMOCOCCAL CONJUGATE VACCINE # Advantages of Pneumococcal Conjugate Vaccine: Immunologic Theory Bacterial polysaccharides, including those present on the pneumococcal capsule, are T-independent antigens. T-independent antigens stimulate mature B-lymphocytes but not T-lymphocytes. This type of antigen induces an immune system response that is neither long-lasting nor characterized by an anamnestic (i.e., booster) response upon subsequent challenge with native polysaccharides (84,85 ). Polysaccharide vaccines fail to elicit a protective immune system response among infants and very young children because these children respond poorly to T-independent antigens. Although antibody response to T-dependent antigens is present soon after birth, immune system responses to T-independent antigens develop during the first years of life. Certain serotypes that cause the majority of pneumococcal disease among children (i.e., 6A, 14, 19F, and 23F) remain poorly immunogenic until approximately age 5 years (86 ). Conjugation of polysaccharides to proteins changes the nature of the antipolysaccharide response from T-independent to T-dependent. This antigen complex stimulates a T-helper-cell response, leading to a substantial primary response among infants and a strong booster response at reexposure (84 ). Success of Hib conjugate vaccine in reducing by 95% incidence of invasive Hib disease among young children after the vaccine's introduction for use among infants in 1990 is one example of the potential efficacy of bacterial polysaccharide-protein conjugate vaccines. Declines in Hib disease occurred among children aged <1 year before the vaccine was licensed for use among this age group (87 ). This herd-immunity effect was consistent with later observations that Hib conjugate vaccine interrupts transmission by reducing acquisition of carriage. Pneumococcal conjugate vaccines, in contrast with polysaccharides, has been reported to reduce carriage and might lead to population effects beyond direct protection. # Vaccine Composition The 7-valent pneumococcal conjugate vaccine (Prevnar) includes seven purified capsular polysaccharides of S. pneumoniae, each coupled with a nontoxic variant of diphtheria toxin, CRM197 (CRM, cross-reactive material). The vaccine contains approximately 2 µg each of capsular polysaccharide from serotypes 4, 9V, 14, 19F, and 23F, and oligosaccharide from 18C, 4 µg of serotype 6B, 20 µg of the carrier protein CRM197, and 0.125 mg of aluminum/0.5-ml dose as an aluminum phosphate adjuvant. Prevnar contains no thimerosal or other preservative. Serotypes included in PCV7 and potentially cross-reactive serotypes (i.e., 6A, 9A, 9L, 18B, and 18F) accounted for 86% of bacteremia, 83% of meningitis, and 65% of AOM among children aged <6 years occurring in the United States during the period 1978-1994 (79 ). # Immunogenicity Polysaccharide-protein conjugate vaccine induces type-specific antibodies that bind to polysaccharide on the surface of bacteria and enhance opsonization, phagocytosis, and killing of pneumococci. The amount of antibody required to prevent either pneumococcal carriage or disease is unknown. Additionally, quantitative measurement of total antibody concentration, as measured in the majority of pneumococcal antibody assays, might not correlate with the level of functional immune system response. Functional measurements (e.g., opsonophagocytic activity) might be more appropriate than serum antibody concentrations for evaluating clinically relevant responses to pneumococcal vaccination (88 ). Although specific levels of antibody or opsonophagocytic activity that correlate with protection against pneumococcal disease remain unknown, presence of type-specific antibody to capsular polysaccharide is associated with protection among adults. Studies of Hib conjugate vaccine have reported that levels of anticapsular antibody ³0.15 µg/ml are protective against subsequent Hib infection; thus, researchers have hypothesized that this minimum level might also be protective against pneumococcal disease (89)(90)(91). Through measurement of total antibody concentrations, researchers have demonstrated that pneumococcal conjugate vaccines using several protein carriers are more immunogenic than PPV23 among young children (92)(93)(94)(95)(96)(97)(98). # Immunogenicity Studies Among Healthy Infants and Children In one study, 212 healthy infants were randomized to receive either PCV7 or an investigational meningococcal conjugate vaccine at ages 2, 4, 6, and 12-15 months. Vaccination with PCV7 resulted in substantial increases in serum antibody concentrations to all seven serotypes compared with baseline concentrations. After three doses of PCV7, from 92% (serotypes 6B and 23F) to 100% (serotype 4) of children had ³0.15 µg/ml of type-specific antibody, and from 51% (serotype 9V) to 90% (serotype 19F) achieved a level of ³1.0 µg/ml against the vaccine serotypes. The fourth dose resulted in an anamnestic response to each of the seven serotypes (95 ). # Children with SCD In a study of children and young adults with SCD, children aged ³2 years received either PPV23 only (n = 12) or PCV7 (two doses, 8 weeks apart) followed by PPV23 8 weeks later (n = 11) (93 ). When measured 3-6 weeks after administration of PPV23, serum antibody geometric mean concentrations (GMCs) were higher among the PCV7 plus PPV23 group than among the PPV23-only group for all of the PCV7 serotypes, reaching statistical significance for serotypes 14 and 19F. Serum antibody GMCs were similar between the two groups for serotypes 1 and 15B, two serotypes contained in PPV23 but not in PCV7, demonstrating that PCV7 did not interfere with the immune system response to PPV23. After administration of PPV23, 4 of 11 subjects in the PCV7 plus PPV23 group and 2 of 11 in the PPV23-only group reported fever. Rates and severity of local reactions to PPV23 did not differ between the two groups. In a study of 34 infants aged <24 months with SCD who were vaccinated with PCV7 at ages 2, 4, and 6 months, GMCs of type-specific immunoglobulin G (IgG) antibodies measured by enzyme-linked immunoabsorbent assay (ELISA) increased from <0.1 µg/ml at baseline to >2.0 µg/ml 1 month after the third dose for all seven vaccine serotypes (97,99 ). Among 27 study participants who remained in the study and who were vaccinated with PPV23 at age 24 months, a substantial booster response (GMC > 9.0 µg/ml) occurred after administration of PPV23 for all serotypes in the PCV7 vaccine. Both serum opsonic activity and total IgG antibodies were measured for two serotypes (i.e., 6B and 14), and both tests demonstrated substantial increases after the PPV23 booster. # HIV-Infected Children Data are limited regarding use of PCV7 among HIV-infected children. However, in two studies using 5-valent formulations of greater antigen content (i.e., 10 µg each of serotypes 6B, 14, 18C, 19F, and 23F oligosaccharides) and the same carrier protein, conjugate vaccine was demonstrated to be immunogenic among HIV-infected children (94,100 ). In a study among 60 children aged ³2 years, 5-valent pneumococcal conjugate vaccine was more immunogenic for all five serotypes than was PPV23 among both HIV-infected (n = 30) and HIV-uninfected (n = 30) children. Among HIV-infected children, 60% demonstrated a ³4-fold rise in IgG level after one dose of conjugate vaccine, compared with 31% after one dose of PPV23 (P < 0.05) (94 ). Prevaccination CDC HIV classification and CD4 counts of the HIV-infected children were similar among the conjugate vaccine and PPV23 groups. In a second study using the same conjugate vaccine among younger children, antibody response to three doses of 5-valent pneumococcal conjugate vaccine was compared between 18 HIV-infected children aged £2 years and 33 children without HIV infection (100 ). The vaccine was found to be immunogenic among both groups. Antibody levels achieved by the HIV-infected infants and toddlers were higher than those reported after one dose of 5-valent pneumococcal conjugate vaccine in the study of children aged ³2 years discussed previously (94 ). In both studies, no substantial difference in frequency of local or systemic reactions was reported among children who received the conjugate vaccine compared with control groups. # Alaska Natives and American Indians Researchers have studied the immunogenicity of a pneumococcal conjugate vaccine using a different carrier protein among Alaska Native, American Indian, and non-Alaska Native/non-American Indian infants aged <2 years (101 ). A 7-valent pneumococcal vaccine consisting of serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F linked with the outer membrane protein complex of Neisseria meningitidis was administered to Alaska Native, American Indian (i.e., Apache and Navajo), and non-Alaska Native/non-American Indian infants aged 2, 4, and 6 months, with a booster dose at age 15 months. Response after three primary doses of vaccine was similar among all three groups of infants, except for serotypes 14 and 23F. However, 1 month after the booster dose, serotype-specific GMCs increased to all seven serotypes among the three groups of infants when compared with the pneumococcal IgG GMCs before the booster dose. Although a different conjugatecarrier protein was used, this study indicated that PCV7 immunogenicity among Alaska Natives and American Indians will likely be similar to immune system response among * Routine vaccinations included diphtheria toxoid-tetanus toxoid-pertussis vaccine; Haemophilus influenzae type b conjugate; hepatitis B; oral and inactivated poliovirus; measles-mumps-rubella; and varicella. non-Alaska Natives/non-American Indians. Prevnar is under evaluation in an efficacy study among American Indians, and study results are pending. # Efficacy Data from a trial using PCV7 provide evidence of the vaccine's efficacy against invasive pneumococcal disease, as well as its effectiveness against clinical pneumonia and AOM among healthy children aged <2 years. The results are summarized in the following section. Other clinical efficacy trials using 7-, 9-and 11-valent pneumococcal conjugate vaccines are currently being conducted or are planned in the United States, South Africa, and certain other countries. Outcomes to be measured in these studies include protective efficacy against overall mortality, pneumonia, invasive disease, AOM, and nasopharyngeal carriage of pneumococci. # Efficacy Trials In a prospective double-blind study among patients of a health maintenance organization in northern California, a total of 37,830 healthy children (i.e., without immune system disorders or serious chronic disease) were randomly assigned to receive either PCV7 or a control (meningococcal C conjugate) vaccine. Vaccinations were administered at ages 2, 4, 6, and 12-15 months. Routine, licensed vaccines* were administered concurrently according to schedule. Initially, diphtheria toxoid-tetanus toxoid whole-cell pertussis (DTwP) vaccine was included among the childhood vaccinations; however, during the study, use of acellular pertussis vaccine became routine. As of March 2000, >50% of study participants had been followed for ³36 months (7 ). Invasive pneumococcal disease was defined as an acute illness consistent with pneumococcal disease in a child from whom S. pneumoniae was cultured from a normally sterile site (e.g., blood or CSF). Cases were identified through active surveillance. At the time of the primary efficacy analysis in August 1998, PCV7 was 100% efficacious against vaccine serotypes among children who were either fully vaccinated (i.e., completed the three-dose primary series) or partially vaccinated (i.e., received ³1 doses) (95% confidence interval [CI] = 80.5%-100% and 85.4%-100%, respectively). Additional cases have been identified since completion of the primary analysis. When all cases of invasive disease were evaluated during follow-up analysis in April 1999, PCV7 was 97.4% (95% CI = 82.7%-99.9%) and 93.9% (95% CI = 79.6%-98.5%) efficacious against vaccine serotypes among children who were fully or partially vaccinated, respectively (Table 2). Statistically significant serotype-specific protection also was reported for four of the seven vaccine serotypes (i.e., 19F, 14, 18C, and 23F). The study's ability to evaluate efficacy for the remaining three serotypes was limited because too few cases were caused by these serotypes in either treatment group (7 ). No evidence existed of an increase in invasive disease caused by nonvaccine serotypes. To examine effectiveness of PCV7 in preventing pneumonia of any etiology among the study population as a secondary outcome, investigators reviewed hospital, outpatient, and emergency room records of the children in the study. Monitored outcomes included clinical diagnoses of pneumonia, clinical pneumonia with abnormal chest X-rays, and clinical pneumonia with consolidation of ³2.5-cm found on chest X-rays. Among children who received ³1 doses of study vaccine (intent-to-treat analysis), use of PCV7 resulted in 11.4% (95% CI = 1.3%-20.5%) fewer episodes of clinical pneumonia, regardless of X-ray or culture result. Cases of clinical pneumonia accompanied by an X-ray with any evidence of an infiltrate were reduced by 33.0% (95% CI = 7.3%-51.5%). Among children who had clinically diagnosed pneumonia and X-ray evidence of an area of consolidation of ³2.5 cm as read by both a pediatrician and a radiologist, efficacy of PCV7 was 73.1% (95% CI = 3.0%-88.3%) (102 ). Effectiveness of PCV7 in preventing health-care visits for AOM from all causes, including risk for first AOM episode, frequent AOM episodes, and tympanostomy tube placement, was assessed as a secondary outcome in the Northern California Kaiser Permanente efficacy trial. Episodes of physician-diagnosed AOM among the study population were identified retrospectively through computerized databases of clinic and emergency room encounters. To exclude return visits related to one episode of AOM, a case of AOM was defined as a visit for otitis media, with no visits for otitis media made during the previous 21 days, or if the visit had occurred during the previous 21-42 days, the appointment had been made <3 days in advance. Frequent AOM was defined as ³3 episodes within 6 months or ³4 episodes within 1 year. A substantial reduction in episodes of AOM was found. Vaccine impact was greatest for frequent otitis and tympanostomy tube placement (Table 3) (7 ). Compared with children who received control vaccine, children who received PCV7 had 6.4% (95% CI = 3.9%-8.7%) fewer episodes of AOM, 9.1% (95% CI = 4.1%-13.8%) fewer episodes of frequent AOM (defined as ³3 episodes in 6 months or ³4 in 1 year), and they underwent 20.3% (95% CI = 3.6%-34.1%) fewer tympanostomy tube placements (Table 3). Among a subset of study children with spontaneously ruptured tympanic membranes, S. pneumoniae was cultured from the draining ears of 6 children vaccinated with PCV7 and 17 children who received the control vaccine (vaccine efficacy was 65% for AOM caused by vaccine-serotype pneumococci [P = 0.035]). The ability of PCV7 to protect children against AOM was also evaluated in an efficacy trial conducted in Finland (103 ). Children (N = 1,662) were randomized to receive either PCV7 or hepatitis B (control) vaccine at ages 2, 4, 6, and 12 months. Outcomes measured included AOM with concurrent myringotomy to establish bacterial diagnosis. Investigators reported 2,596 AOM episodes during the follow-up period in perprotocol analysis. Of these, 357 episodes were caused by vaccine-serotype pneumococci. A total of 107 episodes occurred among the PCV7 group, and 250 among the control group, for an estimated efficacy of 57% (95% CI = 44%-67%) against culture-confirmed AOM caused by vaccine serotypes. The estimated percent efficacy was lower for outcomes that included nonvaccine pneumococcal serotypes or other pathogens causing AOM. For prevention of AOM caused by pneumococci of any serotype, efficacy was estimated to be 34% (95% CI = 21%-45%), and efficacy against AOM irrespective of etiology was 6% (95% CI = -4%-16%) (83 ). Further analysis revealed an efficacy against vaccine-related serotypes (i.e., 6A, 9N, 18B, 19A, and 23A) of 51% (95% CI = 27%-67%). An increase of 33% in the rate of AOM episodes caused by nonvaccine serotypes occurred among the group who received PCV7 compared with the control group. However, in spite of the increase in disease caused by nonvaccine serotypes, the net effect regarding pneumococcal AOM was a reduction of 34%. # Effect on Antimicrobial Use Prevention of pneumococcal infections among young children after widespread use of PCV7 might result in decreased use of antibiotics, as reported in the Northern California Kaiser Permanente vaccine efficacy trial where a 5.3% reduction was reported among the group of children who received PCV7 (104 ). A reduction in antibiotic use might slow or reverse the trend of increasing prevalence of antimicrobial resistance among pneumococci. # Other Studies of Vaccine Impact Hib conjugate vaccines reduce acquisition of nasopharyngeal carriage of the bacterium among infants and children, an effect that is thought to contribute to the success of Hib vaccination programs by providing herd immunity (105 ). A 40% and 50% reduction of vaccine-serotype S. pneumoniae carriage has been reported in studies of a 9-valent CRM197 pneumococcal conjugate vaccine conducted in Israel and South Africa, respectively (5,6 ). In both studies, vaccination resulted in a reduction in nasopharyngeal carriage of vaccine-type pneumococci and a simultaneous increase in detection of carriage of pneumococci of nonvaccine serotypes. Whether this represents true replacement or unmasking of serotypes that were also colonizing the nasopharynx is unknown. Additional information regarding the impact of PCV7 on nasopharyngeal carriage is expected from a future efficacy trial among Navajo and Apache populations. In a double-blind, randomized study of a 9-valent pneumococcal conjugate vaccine containing the CRM197 carrier among healthy toddlers attending day care centers in Israel, conjugate vaccine or control (meningococcal C conjugate) vaccine was administered to children in two age groups, 12-17 months (two doses) and 18-35 months (one dose). Primary outcomes were carriage rates of vaccine serotype-and penicillin-resistant pneumococci. After 21 months of follow-up, carriage rates of vaccine-serotype pneumococci were substantially lower among toddlers who were vaccinated with 9-valent pneumococcal conjugate vaccine compared with the control group. For both vaccineserotype and penicillin-resistant S. pneumoniae, differences in carriage persisted for children aged <36 months and those ³36 months, although the difference was greatest for children aged <36 months. The study also reported herd immunity within families; siblings of 9-valent pneumococcal conjugate vaccine recipients were substantially less likely to carry antibiotic-resistant pneumococci compared with siblings of controlvaccine recipients (106 ). # Duration of Protection Duration of protection after vaccination with PCV7 is unknown. However, immunologic memory does occur. Among infants aged £20 months who received primary vaccination with two or three doses of PCV7, administration of PPV23 £18 months later resulted in a booster response. A similar response was elicited among children aged 2-3 years when administered PPV23 £20 months after a bivalent (i.e., 6A plus 23F) CRM197 conjugate vaccine (92,96 ). Additional studies of PCV7 with longer follow-up periods are needed. Evaluation of duration of protection will be critical for older children at high risk for disease (e.g., those with SCD or HIV infection). # Cost-Benefit Analysis Costs and benefits of a routine PCV7 program for healthy U.S. infants and children were evaluated in a study using current estimates of pneumococcal disease burden (i.e., meningitis, bacteremia, pneumonia, and AOM episodes), clinical outcomes, vaccine efficacy, and health-care costs (107 ). Sources of clinical outcomes and costs included published and unpublished data, expert consensus, and computerized databases from Kaiser Permanente of Northern California. For each annual U.S. birth cohort, routine PCV7 vaccination is estimated to prevent approximately 12,000 (78% of potential) cases of pneumococcal meningitis and bacteremia; 53,000 (69% of potential) pneumococcal pneumonia cases; and >1 million (8% of potential) episodes of clinically diagnosed otitis media. Vaccination of healthy infants would result in net savings to society if vaccine costs were £$46/dose. Net savings to health insurers would result if the vaccine costs were £$18/dose. A program in which one dose of vaccine was administered to children aged 24-59 months to bring them up-to-date with their vaccinations would result in societal cost savings at a vaccine price of £$80 for children aged 24-35 months and £$50 for those aged 48-59 months. From the health-care-payer perspective, savings would result if vaccine costs were £$40 and £$20 when administered to children aged 24-35 months and 48-59 months, respectively. Results of this study demonstrate that costeffectiveness of vaccination of infants and toddlers is most influenced by vaccine price, * Initially all children in the study received the whole-cell pertussis vaccine and oral poliovirus vaccine; however, after changes in vaccine recommendations midway through the study, participants began receiving the diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine and the inactivated poliovirus vaccine. especially among children aged ³24 months. In a recent reanalysis of cost-effectiveness of PCV7 using additional and updated information (including newly available safety data, national costs, and rates of tympanostomy tube placement), the same investigators found that break-even costs for vaccination of infants from societal and health-carepayer perspective were $40 and $17, respectively (108 ). # Vaccine Safety # Safety of Administration of PCV7 Series Among Infants Rates and types of adverse events associated with PCV7 administered at ages 2, 4, 6, and 12-15 months are acceptable when compared with the demonstrated benefits of vaccination. In the Northern California Kaiser Permanente efficacy trial, rates of adverse events were compared between children who received PCV7 and those who received the control vaccine (investigational group C meningococcal conjugate). Routine childhood vaccines were administered concurrently with PCV7 and control vaccines.* To assess vaccine safety, information regarding local and systemic reactions was collected at 48-72 hours and 14 days after each dose. Using telephone interviews, investigators collected adverse-event histories for two subsets of the study population -initially a group receiving DTwP (N = 6,000) and later a group receiving diphtheria toxoid-tetanus toxoid acellular pertussis (DTaP) vaccine (N = 1,500). Frequency of uncommon events requiring medical attention after vaccination was evaluated for the entire study cohort and included emergency room and outpatient clinic visits occurring £30 days and hospitalizations occurring £60 days after receiving the study vaccines. PCV7 vaccination resulted in less frequent local reactions than DTwP vaccine, but more frequent local reactions than DTaP vaccine and the control vaccine. Except for erythema, no pattern of increasing local reactogenicity with subsequent doses of PCV7 was reported (Table 4). Fever ³100.4 F (³38 C) £48 hours after vaccination was more common among children who received PCV7 concomitantly with DTaP vaccine and other recommended vaccines than among those who received the control vaccine. This difference was statistically significant after each dose of vaccine in the primary series but not the fourth dose (Table 5). Rates of fever >102.2 F (>39 C) were substantially greater among those who received PCV7 after dose two of the primary series (i.e., 2.5% versus 0.8%). Febrile seizures after vaccination were slightly more common in the PCV7 group; however, the majority of events occurred when whole-cell pertussis vaccine was administered concurrently with PCV7. Using hospitalizations, emergency room visits, and data from all other sources, seizures occurring £3 days after vaccination were reported for four children who received control vaccine and eight who received PCV7. Of the eight PCV7 recipients who had a seizure, seven had received concurrent DTwP vaccine. Two children who were vaccinated with concurrent DTaP vaccine had a seizure £3 days after therefore, this column represents the fourth dose of a pertussis vaccine, but not necessarily a fourth dose of DTaP. § P < 0.05 when PCV7 site is compared with DTaP site using the sign test. vaccination, one in each of the PCV7 and control-vaccine groups (109 ). The seizure rate £3 days after vaccination with PCV7 and concurrent vaccinations was approximately 1/ 7,000 doses, below historic rates after whole-cell pertussis vaccinations (109,110 ). As of April 20, 1999, a total of 32 children who were originally enrolled in the study had died (109 ); however, none of the deaths were reported by investigators to be related to the vaccine. A total of 12 cases of sudden infant death syndrome (SIDS) were observed among the study cohort £1 year after vaccination, 4 among the PCV7 group (0.2 cases/1,000 children) and 8 among the control group (0.4 cases/1,000 children). These rates are less than expected historically; 0.5 cases/1,000 children were observed in California in 1996 and 1997. One death attributable to SIDS occurred within the first week of vaccination in a child who received PCV7 concurrently with other vaccines. In an age-and season-adjusted analysis based on California SIDS data, 1.06 cases would have been expected £1 week after vaccination (7 ). # Safety of Administration of PCV7 Among Older Children Safety data are available from four immunogenicity studies of PCV7 among older infants and children (109 ). Approximately 900 doses of PCV7 were administered to 560 children aged 7 months-9 years following the recommended schedule for vaccination administration for children who are beyond the age of the infant schedule. Comparisons across the studies demonstrate that, generally, frequency of local reactions was higher among older children than among children vaccinated at age <1 year. Frequency of fever of ³100.4 F (³38 C) after one dose of PCV7 ranged from 6.8% to 36.7%. No distinct, age-related patterns of systemic reactions was evident. Fussiness was the most commonly observed systemic reaction (Tables 6,7). # Safety of Administration of PCV7 After PPV23 Minimal safety data are available regarding the sequence of PPV23 followed by PCV7. However, in one published study of children and young adults with SCD, 16 of the study participants had already received one dose of PPV23 3-15 years previously (persons who had received PPV23 within the previous 2 years were excluded). Of these 16 SCD patients, 9 who had received two doses of PCV7 followed by one dose of PPV23 8 weeks later were compared with 7 who had received one dose of PPV23. No severe reactions were reported; local reactions were similar between the two groups (93 ). # Safety of Administration of PPV23 After PCV7 Five studies have been completed in which 152 infants, children, or young adults received ³1 doses of 2-, 5-, or 7-valent pneumococcal conjugate vaccine conjugated to CRM197 followed by a dose of PPV23. Populations studied included healthy infants and children (92,96 ), HIV-infected children and young adults (94 ), and infants and children with SCD (93,99 ). PPV23 was administered 6 weeks-20 months after pneumococcal conjugate vaccine. Adverse events were described in three of the five studies. No serious adverse events were identified after the dose of PPV23. No increase in adverse events was reported among HIV-infected persons who received 5-valent pneumococcal conjugate vaccine followed by PPV23 as compared with those who received PPV23 alone (94 ). Among children with SCD who received either PCV7 followed by PPV23 or PPV23 alone, fever occurred among 4 of 11 and 2 of 11 children, respectively. Local reactions did not differ between the two groups (93 ). # PPV23 Revaccination No published studies have been designed specifically to examine adverse events among children who were administered a second dose of PPV23 after an earlier dose of PPV23. However, in the previously described study (93 ) in which young children and adults with SCD were vaccinated with either PCV7 and PPV23 consecutively or PPV23 alone, 16 of 23 enrolled patients had been vaccinated with one dose of PPV23 3-15 years earlier. All patients were randomized to receive either one dose of PPV23 or two doses of PCV7 followed by a booster dose of PPV23 8 weeks later. No severe reactions were reported after the second dose of PPV23. # Vaccine Administration PCV7 is administered intramuscularly as a 0.5-ml dose. PCV7 is licensed for use among infants aged ³6 weeks. PCV7 can be administered at the same time as other routine childhood vaccinations in a separate syringe at a separate injection site. In clinical studies of PCV7, when routine childhood vaccinations were administered simultaneously with PCV7 vaccine but at different sites, suppression of Hib response occurred after the fourth dose. However, >97% of children achieved antibody titers ³1 µg/ml. Additionally, a limited decrease in antibody response to poliovirus Type 1 occurred; however, clinical significance of these decreased responses is uncertain (109,111 ). Conjugate vaccines containing diphtheria toxoid or protein as carriers (e.g., CRM197) should not be considered immunizing agents against diphtheria. Thus, no change in the vaccination schedule for DTaP vaccine is currently recommended. Simultaneous administration of PCV7 with other vaccines at the 2-, 4-, and 6-month visits might necessitate five injections at each visit. Physicians might consider potential approaches to decreasing the number of simultaneous injections that are needed. One approach is to administer the first two doses of hepatitis B vaccine at birth and age 1 month. Alternatively, a Hibhepatitis B combination product is available for use at ages 2, 4, and 12-15 months. An * VAERS forms can be obtained by calling (800) 822-7967, and additional information is available at <http://www.vaers.org> (accessed July 31, 2000). † A Strong evidence, including results of efficacy studies, supports vaccine use. B Moderate evidence, including immunogenicity data but not efficacy data, supports vaccine use. C No efficacy or immunogenicity studies are available regarding this population, but protection is anticipated on the basis of such studies among other groups; vaccination is supported by respected authorities. option to decrease the number of simultaneous injections when the fourth dose is administered would be to divide needed injections between visits at ages 12 months and 15 or 18 months. Combination vaccine products currently being evaluated by manufacturers might further decrease the need for multiple injections. # Precautions and Contraindications Vaccination with PCV7 is contraindicated among persons known to have a hypersensitivity to any component of the vaccine. Health-care providers can choose to delay vaccination of children with moderate or severe illness until the child has recovered, although minor illnesses (e.g., mild upper-respiratory infection with or without low-grade fever) are not contraindications to vaccination. Any adverse event suspected to be associated with PCV7 vaccination should be reported to the Vaccine Adverse Events Reporting System (VAERS).* Concurrent administration of PCV7 and PPV23 is not recommended because safety and efficacy of concurrent vaccination has not been studied. # RECOMMENDATIONS FOR USE OF PCV7 # Children for Whom PCV7 Is Recommended Children Aged £23 Months All children aged £23 months should be vaccinated with PCV7 (Table 8). Infant vaccination provides the earliest possible protection, and children aged £23 months have the highest rates of pneumococcal infection. PCV7 is safe and highly efficacious in preventing invasive disease, and it is effective in preventing a portion of AOM cases and pneumonia among healthy infants and young children (Strength of evidence: children aged 2-6 months, A; † children aged 7-23 months, B) (Table 9). Vaccination Schedule. Infants receiving their first dose at age £6 months should receive three doses of PCV7 at intervals of approximately 2 months, followed by a fourth dose at age 12-15 months (Table 10). Newborns should begin the schedule at age 2 months, although PCV7 can be administered as young as age 6 weeks. Prematurely born infants (i.e., <37 weeks gestation) should receive PCV7 at the recommended chronologic age concurrent with other routine vaccinations. For infants with prolonged nursery stays, initiation of vaccination should begin during discharge planning. Children aged ³7 months not previously vaccinated should also be vaccinated according to the recommended schedule (Table 10). The proposed vaccination schedule is the same for all children aged £23 months, regardless of the presence of underlying medical conditions (e.g., children with HIV infection, SCD or other asplenia, chronic disease, or who are otherwise immunocompromised). Interruption of the vaccination schedule does not require reinstitution of the entire series or the addition of extra doses (Table 11). # Children Aged 24-59 Months Who Are at High Risk for Pneumococcal Infection Children aged 24-59 months should receive PCV7 vaccination if they are at high risk for pneumococcal infection caused by an underlying medical condition (Table 8). This recommendation applies to the following groups: • children with SCD and other sickle cell hemoglobinopathies, including hemoglobin SS, hemoglobin S-C, or hemoglobin S-ß-thalassemia, or children who are functionally or anatomically asplenic; • children with HIV infection; • children who have chronic disease, including chronic cardiac and pulmonary disease (excluding asthma), diabetes mellitus, or CSF leak; and Vaccination Schedule. For children aged 24-59 months with underlying medical conditions (Table 8), ACIP recommends two doses of PCV7, administered 2 months apart, followed by one dose of PPV23 administered ³2 months after the second dose of PCV7 (Tables 10,12). The recommendation for two PCV7 doses is based on results of an immunogenicity study conducted among SCD patients. That study reported that a nonstatistically significant antibody response to serotype 6B after one dose of PCV7 increased statistically significantly after a second dose of PCV7 (93 ). Serotype 6B is one of the most common pneumococcal serotypes colonizing or causing invasive disease among SCD patients and healthy children (47,(112)(113)(114). 8). Penicillin prophylaxis should be continued for children with SCD to age ³5 years, regardless of vaccination with PCV7. Protective efficacy of PCV7 for children with SCD has not been studied, and the vaccine does not protect against all serotypes causing disease. However, penicillin prophylaxis substantially reduces the risk for invasive pneumococcal infections among SCD patients (112 ). # Other Children Who Might Benefit from Vaccination with PCV7 ACIP recommends that health-care providers consider PCV7 vaccination for all other children aged 24-59 months, with priority given to the following populations: • children aged 24-35 months; • children of Alaska Native or American Indian descent; • children of African-American descent; • children who attend group day care centers;* This recommendation is made on the basis of the moderate risk for pneumococcal disease, including antibiotic-resistant infections, among these populations and on potential cost-benefit. Data regarding efficacy and immunogenicity of PCV7 are limited for these specific risk and age groups. However, the vaccine is safe and immunogenic among all healthy children aged 24-59 months. Also, immunogenicity data are available regarding use of another pneumococcal conjugate vaccine among Apache, Navajo, and Alaska Native children (101 ), and efficacy data for children aged £23 months probably are relevant for healthy children aged 24-59 months (Strength of Evidence: B). PPV23 is licensed for use among children aged ³2 years who are at high risk for pneumococcal infections (e.g., those with SCD or HIV infection). However, the conjugate vaccine has advantages over PPV23, which include induction of immune system memory (possibly resulting in longer duration of protection), reduction in carriage, probable higher efficacy against serotypes causing most invasive disease, and probable effectiveness against noninvasive syndromes (e.g., nonbacteremic pneumonia and AOM). If pneumococcal vaccine is to be used among healthy children aged 24-59 months, ACIP recommends that PCV7 be used. Vaccination Schedules. ACIP recommends that one dose of PCV7 be considered for Alaska Native and American Indian children aged 24-59 months. Previously, ACIP recommended PPV23 for Alaska Natives and certain American Indian populations aged ³2 years (1 ). However, use of PCV7 among these children offers multiple potential advantages over PPV23 as previously discussed. In contrast, PPV23 offers potentially broader serotype coverage. Recent studies demonstrate that only 68% and 57% of invasive infections among Alaska Natives and American Indians in the U.S. Southwest aged 24-59 months, respectively, were caused by serotypes included in the 7-valent conjugate vaccine, lower proportions than among non-Alaska Native/non-American Indian populations (115,116 ). Therefore, vaccination program personnel and other healthcare providers might consider whether Alaska Native and American Indian children aged 24-59 months would benefit by the additional coverage provided by the 23-valent polysaccharide vaccine. Data are limited regarding safety and immunogenicity of PPV23 after PCV7. If additional serotype coverage is desired by parents and health-care providers, PPV23 should be administered ³2 months after PCV7 (Strength of evidence: C). A community-randomized trial to evaluate the efficacy of PCV7 among Navajo and Apache children in preventing pneumococcal disease is underway. Future recommendations for use of PCV7 among Alaska Native and American Indian populations might be modified on the basis of that trial. ACIP recommends that physicians consider administering one dose of PCV7 to their African-American pediatric patients aged 24-59 months because of their increased risk for pneumococcal infection. The proportion of invasive pneumococcal disease among African-American children that is caused by PCV7 serotypes does not differ from whites in the United States, and rates of invasive disease decline with age (ABCs/EIP Network, unpublished data, 2000). Therefore, no additional vaccination with PPV23 is recommended (Strength of evidence: B). Additionally, because of increased risk for invasive pneumococcal disease, colonization with antibiotic-resistant pneumococcal strains, and AOM, health-care providers should consider administering one dose of PCV7 to previously unvaccinated children aged 24-59 months who attend group day care centers. # Children Aged ³5 Years and Adults Who Are At High Risk for Pneumococcal Infection Data are limited regarding efficacy of PCV7 among children aged ³5 years and adults. However, limited studies report that a) 5-valent pneumococcal conjugate vaccine is immunogenic among HIV-infected children aged 2-9 years (94 ); b) PCV7 is immunogenic among children aged 2-13 years with recurrent respiratory infections (117 ); and c) PCV7 is immunogenic among older children and adults aged 4-30 years with SCD (93 ). Administering PCV7 to older children with high-risk conditions is not contraindicated. Studies among healthy adults aged ³50 years (118 ) and among HIV-infected adults aged 18-65 years (119 ) did not demonstrate substantially greater ELISA antibody concentrations after administration of 5-valent pneumococcal conjugate vaccine compared with PPV23. Also, the proportion of invasive pneumococcal isolates covered by PCV7 is only 50%-60% among older children and adults, in contrast with 80%-90% coverage by PPV23 among this older group. Therefore, current data do not support a recommendation to replace PPV23 with PCV7 among older children and adults. # Recommendations for Use of PCV7 Among Children Previously Vaccinated with PPV23 Children aged 24-59 months who are at high risk for pneumococcal disease and who have already received PPV23 (i.e., children with SCD, HIV infection, or who have other immunocompromising illnesses or chronic diseases) could benefit from the immunologic priming and T-cell-dependent immune system response induced by PCV7. Thus, among children in these groups at high risk, sequential use of the two pneumococcal vaccines can provide additional protection. Health-care providers should vaccinate children aged 24-59 months at high risk who have not previously received PCV7 but who have already received PPV23 with two doses of PCV7 administered ³2 months apart. Vaccination with PCV7 should be initiated ³2 months after vaccination with PPV23. Providers should be aware that minimal safety data are available regarding this vaccine sequence. # Recommendations for Use of PPV23 Among Children Previously Vaccinated with PCV7 # Administration of PCV7 Followed by PPV23 Among Children at High Risk for Pneumococcal Disease Children who have completed the PCV7 vaccination series before age 2 years and who are among risk groups for which PPV23 is already recommended should receive one dose of PPV23 at age 2 years (³2 months after the last dose of PCV7). These groups at high risk include children with SCD, children with functional or anatomic asplenia, children who are HIV-infected, and children who have immunocompromising or chronic diseases (1 ) (Table 8). Although data regarding safety of PPV23 administered after PCV7 are limited, the opportunity to provide additional serotype coverage among these children at very high risk justifies use of the vaccines sequentially. For children of Alaska Native or American Indian descent, addition of PPV23 after PCV7 can be considered. # Revaccination with PPV23 Immunocompromised children or children with SCD or functional or anatomic asplenia should be revaccinated with PPV23 as previously recommended (1 ) (Table 12). If the child is aged £10 years, one revaccination should be considered 3-5 years after the previous dose of PPV23 (1,120 ). Data are limited regarding adverse events related to a second dose of PPV23 administered after PCV7. Health-care providers should not administer a second dose of PPV23 any earlier than 3 years after the initial dose of PPV23. # AREAS FOR FUTURE RESEARCH With recent licensure and introduction of PCV7, close monitoring of disease trends and long-term vaccine safety will be high priorities for public health organizations and health-care providers. Postlicensure surveillance will be necessary to a) detect potential changes in serotype distribution, including any increase in disease caused by serotypes not contained in PCV7; b) follow trends in antimicrobial resistance and antibiotic use; c) detect potential herd immunity induced by widespread use of PCV7; and d) track vaccine-related health events. # MMWR October 6, 2000 Areas where research is ongoing or necessary to determine the most effective use of PCV7 include the following: • Optimal vaccination schedule for older children at high risk. Further studies are needed to identify optimal vaccination schedules for PCV7 and PPV23 among children aged ³2 years who are at high risk for infection, including children with SCD, HIV infection, and other chronic diseases or immunocompromising conditions, particularly children who have received a bone marrow transplant. Research is critical regarding optimal scheduling of vaccination with PCV7 among children who have already received PPV23 and revaccination with PPV23 after vaccination with PCV7. • Combined vaccines including PCV7 and other routine vaccines for infants. Reducing the number of required separate injections would improve the infant vaccination schedule. Additional research is needed to evaluate safety and immunogenicity of PCV7 when administered in combination with other antigens. • Studies of safety, immunogenicity, and efficacy among adults at high risk for pneumococcal infection. Additional studies are needed to evaluate potential use of PCV7 among adults at increased risk for pneumococcal infection. Benefits and risks involved with using a 7-, 9-, 11-, or 15-valent pneumococcal conjugate vaccine in place of or in addition to PPV23 warrant further investigation. Rationale for additional study of a combined or sequential regimen includes potential benefits of conjugate pneumococcal vaccines (e.g., induction of immunologic memory with increased duration of protection, reduction of nasopharyngeal carriage of pneumococci, and potential impact on nonbacteremic pneumonia) along with the benefit of broader serotype coverage provided by PPV23. • Duration of protection. For persons of all age groups, duration of protection after vaccination with PCV7 is unknown. Investigation of potential need for revaccination with PCV7 or PPV23 after primary vaccination is warranted. • Identifying and defining immune system correlates of protection. Type-specific antibody concentration necessary to confer protection against pneumococcal infection is unknown. Researchers are attempting to determine and standardize the level of antibody, as measured by ELISA, that provides serotype-specific protection against pneumococcal disease. Functional tests of induced immune system response (e.g., opsonophagocytosis) are also being evaluated. A determination of immunologic markers that best correlate with clinical protection is needed. Validated immune system correlates of protection will accelerate evaluation and licensure of new vaccines against pneumococcal infection. • Alternative pneumococcal vaccines. Research is ongoing regarding development of alternative pneumococcal vaccines. Investigators are evaluating possible roles of conserved pneumococcal proteins (e.g., pneumolysin, surface protein A, or surface adhesion A) as antigens that have potential to provide broad protection against disease caused by all pneumococcal serotypes (121 ). Use of other peptides or pneumococcal proteins as carriers in conjugate vaccines is also being studied. Additionally, alternative routes of delivery including intranasally and orally administered vaccines are under investigation (122,123 ). # October 6, 2000 / Vol. 49 / No. RR-9 # Recommendations and Reports # Continuing Education Activity Sponsored by CDC # Preventing Pneumococcal Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices (ACIP) EXPIRATION -OCTOBER 6, 2003 You must complete and return the response form electronically or by mail by October 6, 2003, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1. 5 # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.5 hours in category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.1 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 1.6 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 # MMWR October 6, 2000 # Goals and Objectives This MMWR provides guidance for preventing pneumococcal disease among infants and young children in the United States. These recommendations were developed by the Advisory Committee on Immunization Practices (ACIP). The goals of this report are to provide ACIP's recommendations regarding the 7-valent pneumococcal polysaccharide-protein conjugate vaccine and to update previous ACIP recommendations regarding use of 23valent pneumococcal polysaccharide vaccine among children. Upon completion of this educational activity, the reader should be able to a) describe the burden of pneumococcal disease among infants and young children in the United States; b) describe the characteristics of the newly licensed 7-valent pneumococcal conjugate vaccine; c) identify groups of infants and children for whom the 7-valent pneumococcal polysaccharide-protein conjugate vaccine is recommended; d) recognize contraindications to the administration of pneumococcal conjugate vaccine; and e) identify children for whom vaccination with 23-valent pneumococcal polysaccharide is appropriate.	None	None
a3a54942cf4c7ed6b15118f701d9abfdbc5e97e5	cdc	None	When a novel influenza A virus with pandemic potential emerges, nonpharmaceutical interventions (NPIs) often are the most readily available interventions to help slow transmission of the virus in communities, which is especially important before a pandemic vaccine becomes widely available. NPIs, also known as community mitigation measures, are actions that persons and communities can take to help slow the spread of respiratory virus infections, including seasonal and pandemic influenza viruses. These guidelines replace the 2007 Interim Pre-pandemic Planning Guidance: Community Strategy for Pandemic Influenza Mitigation in the United States -Early, Targeted, Layered Use of Nonpharmaceutical Interventions (/ cdc/11425). Several elements remain unchanged from the 2007 guidance, which described recommended NPIs and the supporting rationale and key concepts for the use of these interventions during influenza pandemics. NPIs can be phased in, or layered, on the basis of pandemic severity and local transmission patterns over time. Categories of NPIs include personal protective measures for everyday use (e.g., voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene); personal protective measures reserved for influenza pandemics (e.g., voluntary home quarantine of exposed household members and use of face masks in community settings when ill); community measures aimed at increasing social distancing (e.g., school closures and dismissals, social distancing in workplaces, and postponing or cancelling mass gatherings); and environmental measures (e.g., routine cleaning of frequently touched surfaces). Several new elements have been incorporated into the 2017 guidelines. First, to support updated recommendations on the use of NPIs, the latest scientific evidence available since the influenza A (H1N1)pdm09 pandemic has been added. Second, a summary of lessons learned from the 2009 H1N1 pandemic response is presented to underscore the importance of broad and flexible prepandemic planning. Third, a new section on community engagement has been included to highlight that the timely and effective use of NPIs depends on community acceptance and active participation. Fourth, to provide new or updated pandemic assessment and planning tools, the novel influenza virus pandemic intervals tool, the Influenza Risk Assessment Tool, the Pandemic Severity Assessment Framework, and a set of prepandemic planning scenarios are described. Finally, to facilitate implementation of the updated guidelines and to assist states and localities with prepandemic planning and decision-making, this report links to six supplemental prepandemic NPI planning guides for different community settings that are available online ().# CONTENTS # Disclosure of Relationship CDC, our planners, or content experts, and their spouses/ partners wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. Content will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling CDC did not accept commercial support for this continuing education activity. # Introduction Nonpharmaceutical interventions (NPIs) are strategies for disease, injury, and exposure control (/ phpr/capabilities/DSLR_capabilities_July.pdf ). They include actions that persons and communities can take to help slow the spread of respiratory viruses (e.g., seasonal and pandemic influenza viruses). These actions include personal protective measures for everyday use (e.g., staying home when ill, covering coughs and sneezes, and washing hands often) and communitywide measures reserved for pandemics and aimed at reducing opportunities for exposure (e.g., coordinated closures and dismissals of child care facilities and schools and cancelling mass gatherings). When a novel influenza A virus with pandemic potential emerges, NPIs can be used in conjunction with available pharmaceutical interventions (antiviral medications) to help slow its transmission in communities, especially when a vaccine is not yet widely available. Given current vaccine technology, a pandemic vaccine might not be available for up to 6 months ( ForConsumers/ConsumerUpdates/ucm336267.htm). NPIs can be used before a pandemic is declared in areas where a novel influenza A virus is detected and during a pandemic. These 2017 guidelines provide evidence-based recommendations on the use of NPIs in mitigating the effects of pandemic influenza. These guidelines update and expand the 2007 strategy (/ cdc/11425).* # Purpose The purpose of these guidelines is to help state, tribal, local, and territorial health departments with prepandemic planning and decision-making by providing updated recommendations on the use of NPIs. These recommendations have incorporated lessons learned from the federal, state, and local responses to the influenza A (H1N1)pdm09 virus pandemic (hereafter referred to as the 2009 H1N1 pandemic) and findings from research. Communities, families and individuals, employers, and schools can create plans that use these interventions to help slow the spread of a pandemic and prevent disease and death. Specific goals for implementing NPIs early in a pandemic include slowing acceleration of the number of cases in a community, reducing the peak number of cases during the pandemic and related health care demands on hospitals and infrastructure, and decreasing overall cases and health effects (Figure 1). When a pandemic begins, public health authorities need to decide on an appropriate set of NPIs for implementation and to reiterate the importance of personal protective measures for everyday use (e.g., voluntary home isolation of ill persons , respiratory etiquette, and hand hygiene) and environmental cleaning measures (e.g., routine cleaning of frequently touched surfaces), which are recommended at all times for prevention of respiratory illnesses (Table 1). Personal protective measures reserved for pandemics (e.g., voluntary home quarantine of exposed household members and use of face masks by ill persons) also might be recommended (Table 1). A more difficult decision is how and when to implement community-level NPIs that might be warranted but are more disruptive (e.g., temporary school closures and dismissals, social distancing in workplaces and the community, and cancellation of mass gatherings) (Table 1). These decisions are made by state and local officials on the basis of conditions in the applicable jurisdictions, with guidance from CDC (according to pandemic severity and potential efficacy) and governing authorities (1). Prepandemic planning, along with community engagement, is an essential component of these decisions (Table 2). The decision regarding whether and when to recommend additional NPIs is another component (Table 3). State and local public health departments might use certain influenza surveillance indicators to help decide when to consider implementing NPIs such as school closures and dismissals and other social distancing measures in schools, workplaces, and public settings during an influenza pandemic. The choice of influenza surveillance indicators might differ among states and localities, depending on the availability and capacity of their public health resources. Examples of possible influenza surveillance indicators include additional patient visits to health care providers for influenza-like illness (ILI) and increased geographic spread of influenza within a state. Indicators for school closures and dismissals might include increased school absenteeism rates or the earliest laboratoryconfirmed influenza cases among students, teachers, or staff members. Indicators that might help confirm that NPI implementation should continue include increased influenzaassociated hospitalizations or increases in adult or pediatric deaths attributed to influenza. Additional information about NPI prepandemic planning is available (supplementary Chapter 1 ). # Background An influenza pandemic occurs when a novel virus emerges for which the majority of the population has little or no immunity. Influenza pandemics are facilitated by sustained human-tohuman transmission, and the infection spreads worldwide over a relatively short period (2). The first influenza pandemic of the 21st century began in 2009, 2 years after the 2007 strategy for prepandemic planning was published. Lessons learned during the response to the 2009 H1N1 pandemic underscored the importance of a flexible approach to the use of NPIs, particularly during the early stages of a pandemic, and led to the development of new tools for assessing pandemic severity and prepandemic planning (Box 1). # Lessons Learned from the 2009 H1N1 Pandemic Response The 2009 H1N1 pandemic was a reminder to be prepared for the unpredictable nature of pandemics. Knowing in advance which subtype of pandemic virus will emerge is impossible, as is where and when it will emerge, how quickly the virus will spread, how severe the illness will be, and who will be the most affected. Because of this unpredictability, prepandemic planning must be broad and flexible. The 2007 strategy for prepandemic planning was developed with the assumption that the next influenza pandemic would be severe, like the 1957 pandemic, which was characterized by high transmissibility and medium clinical severity. When the 2007 strategy was developed, the primary concern was that a pandemic virus might evolve from the highly pathogenic avian influenza A (H5N1) virus, a virus that reemerged in Asia in 2003 in domestic poultry and spread to Africa, the Middle East, and Europe among poultry, with sporadic zoonotic transmission (37). Moreover, CDC thought that this virus would most likely emerge overseas, providing the United States with time to prepare for a domestic response, including making use of prepandemic H5N1 vaccine in CDC's Strategic National Stockpile. Instead, the 2009 pandemic influenza A virus turned out to be a novel H1N1 virus that appears to have emerged in southern Mexico and was first identified in two persons in California (13). Although the 2009 H1N1 pandemic in the United States was moderate in terms of overall morbidity and mortality among the U.S. general population, severe outcomes from H1N1pdm09 virus infection were more common among children, young adults, and specific groups at risk for serious complications (e.g., pregnant women) than among older adults (Box 1). Although the emergence of the H1N1pdm09 virus prompted development of pandemic vaccines, a pandemic vaccine was not available until October 2009, 6 months after the initial report that identified the pandemic virus. In addition, another 2 months were required (December 2009) for sufficient stocks to be manufactured, distributed, and available to vaccinate several population groups, including school-aged children and persons living with or caring for infants aged <6 months, as recommended by the Advisory Committee on Immunization Practices (ACIP). † Even though work is ongoing to accelerate † In July 2009, ACIP recommended vaccination of several population groups, including children aged 6 months through 18 years because cases of H1N1 influenza had occurred in children who were in close contact with each other in school and child care settings (). # BOX 1. Lessons learned from the 2009 H1N1 pandemic response The 2009 H1N1 pandemic demonstrated the unpredictable nature of influenza viruses and showed that prepandemic planning must be broad and flexible. Lessons learned during the 2009 H1N1 pandemic response from the United States and other affected countries follow. # H1N1 and children The epidemiology of pandemic influenza might be different from the epidemiology of seasonal influenza; therefore, different populations might be disproportionately affected. - An estimated 43-89 million people in the United States were infected with H1N1pdm09 virus during April 2009-April 2010, and approximately 12,000 people died (3). - Severe outcomes of influenza include complications that require hospitalization and can be fatal (e.g., pneumonia or bronchitis). Severe outcomes from H1N1pdm09 virus infection were most common among children, young adults, and specific groups at high risk for complications (e.g., pregnant women) rather than in adults aged ≥65 years, the group most at risk from seasonal influenza (4)(5)(6)(7). Over the course of the pandemic, an estimated 86,000 children were hospitalized in the United States, which is 2-3 times the number admitted during a typical influenza season (5). The number of deaths among children also was more than twice as high as during a regular influenza season. - On August 28, 2009, the Advisory Committee on Immunization Practices recommended that children be placed higher on the priority list for receiving the monovalent H1N1 vaccine, which became available in October 2009 (8). - Children at risk for severe outcomes from the H1N1pdm09 virus (and from any influenza virus) included those with underlying health conditions such as asthma, diabetes, obesity, or heart, lung, or neurologic diseases. Approximately 60% of hospitalized children had one or more of these conditions, compared with 80% of hospitalized adults (5). Infants born to mothers infected with the H1N1pdm09 virus also might have been at risk, as suggested by U.S. and Canadian studies which found that infants whose mothers received the H1N1 vaccine were less likely to be small for their gestational age or delivered preterm (9,10). # Public health tools to assess pandemic severity and guide NPI selection The 2007 Pandemic Severity Index had limited usefulness because attack rates and case-fatality ratios were difficult to measure and imprecise early in the pandemic. - The earliest available data on attack rates and casefatality ratios suggested that the 2009 H1N1 pandemic virus was highly transmissible and caused severe outcomes. However, the cases being reported overestimated severity because they were primarily derived from mortality data. On the basis of this initial information and continued reports of cases of disease with severe outcomes in Mexico, including deaths among previously healthy young adults (11), CDC recommended that communities with laboratory-confirmed cases of H1N1pdm09 virus consider closing child care facilities and schools, depending on the extent and severity of illness (12). CDC also recommended other NPIs described in the 2007 strategy, including voluntary home isolation for ill persons (i.e., staying home when ill) and voluntary home quarantine for exposed household members (i.e., staying home when a household member is ill). - Within 12 days of recognition of the emerging pandemic, the national influenza surveillance system generated sufficient data for a refined assessment. -From April 23, 2009, when H1N1pdm09 virus was detected in California ( 13 # NPIs and influenza transmission Well-established methods to prevent seasonal influenza transmission, such as hand hygiene promotion, also were effective in pandemic influenza settings to prevent the spread of H1N1pdm09 virus in some communities. - Hand hygiene. A randomized trial, conducted over 12 weeks in 60 elementary schools in Cairo, Egypt, during the 2009 H1N1 pandemic, demonstrated a 47% reduction in confirmed cases of influenza after twice-daily hand washing and health hygiene instruction in comparison with a control group that did not receive health hygiene instruction or have access to soap and hand-drying materials (16). This study demonstrated the effects of hand washing on laboratory-confirmed influenza in a population of persons that typically have little or no access to soap or hand-drying materials and among whom frequent hand washing is not standard. (20,22). In the United States, schools in Georgia that shortened school days had less absenteeism due to severe respiratory illness (23). Additional assessments are needed to determine the value of combining voluntary home quarantine with antiviral chemoprophylaxis. - Although the 2007 strategy suggested that communities consider combining voluntary home quarantine with prophylactic use of antiviral medications, assuming a feasible means of distribution, HHS did not adopt antiviral chemoprophylaxis as its official policy because of concerns about insufficient supplies and drug resistance. - During the 2009 H1N1 pandemic, antiviral chemoprophylaxis of exposed persons contained the spread of the disease, along with the implementation of social distancing measures, in a few small, welldefined settings, including a summer camp (24) and a BOX 1. (Continued) Lessons learned from the 2009 H1N1 pandemic response cruise ship (25). Moreover, an observational cohort study of 259 households in the United Kingdom found that administration of antiviral medications to 285 confirmed patients and their 761 close contacts was very effective (92%) in preventing household transmission (26). - Although limited, the H1N1pdm09 experience suggests that antiviral chemoprophylaxis might be recommended in the future in some settings as an adjunct to selfquarantine, assuming that additional antiviral medications are on the market, providing more treatment choices and making the emergence of drug resistance less of a concern. However, this recommendation would require much greater quantities of antiviral medications, even if no new products are developed, to ensure sufficient supplies. # Mobilizing the public Most members of the public complied with public health recommendations regarding hand hygiene and social distancing. - The Harvard Opinion Research Program conducted 13 polls on the response of the U.S. public during the 2009-2010 pandemic, including the response of the general public, pregnant women, new mothers, parents, and businesses. These randomized telephone polls found the following: -A total of 59% of 1,067 Americans reported washing their hands or using hand sanitizer more frequently during the 2009 H1N1 pandemic (27). A total of 25% avoided places where numerous people tend to gather, such as sporting events, malls, or public transportation. -Most (85%) of 514 pregnant women washed or sanitized their hands more frequently to reduce the chance of infection with H1N1pdm09 virus (27). A total of 68% reported taking steps to avoid proximity to someone who had influenza-like symptoms, and 31% avoided mass gathering places. Most (91%) of 526 new mothers also washed or sanitized their hands more frequently, and 81% took steps to avoid being near someone who had influenza-like symptoms. School-related NPIs, including school closures and dismissals, were acceptable and feasible. - According to a Harvard Opinion Research Program poll of 523 parents from 39 U.S. states whose child care center or school closed temporarily in response to the 2009 H1N1 pandemic, 90% of parents agreed with the dismissal decision, and 85% believed the dismissal reduced influenza transmission (27,28). -A total of 75% of parents who responded stated that the dismissal was not a problem, and 3% stated it was a major problem. Approximately 20% of parents reported that an adult in the household missed work because of the dismissal, and 19% had a child who missed a free or reduced-cost lunch. Of these, 2% and <1%, respectively, said missing work and missing lunch were major problems. -Most of the 523 parents polled believed that at least one of the following factors was a major reason the institution had closed: 1) to keep children apart and reduce the chance they would infect each other (81%), 2) because the school decided cleaning the building and surfaces that children touch was important for reducing the spread of the illness (73%), and 3) because the school or child care center could not operate effectively when numerous students were absent (58%). - A study conducted through an online survey of school principals showed that implementing NPIs in public schools in New York City, New York, was feasible during the 2009 H1N1 pandemic (29). Schools successfully implemented respiratory etiquette education, handhygiene measures, and environmental measures and isolated ill students. Another online survey found that the majority of public schools in Georgia also were able to successfully implement both personal and community NPIs recommended by CDC (23). Public health practitioners should be prepared to explain that the initial pandemic guidance might change if a pandemic is more or less severe than initially assessed. - Within 12 days of recognizing the emerging pandemic on April 23, 2009, CDC updated its initial guidance on NPIs (issued on May 1, 2009) on May 5, 2009, on the basis of more complete and robust data that suggested that the majority of U.S. cases were less severe than those reported from Mexico. - Certain public health departments reported difficulties in communicating the updated guidance on school closures to their communities, especially communities that were planning to implement school closures or had already done so (30,31). - The H1N1pdm09 experience with school closures suggests the need to coordinate and harmonize school closure policies across jurisdictions and to proactively communicate and explain any jurisdictional differences. Public engagement, community preparedness, and trust in government action are important for successful NPI implementation during a pandemic. - Practical obstacles to NPI implementation that required community-level solutions included 1) ill persons going to work because they lacked unpaid leave (32), 2) lack of clarity about decision-making authority to close schools for public health reasons in some jurisdictions (30,33), and 3) lack of access to clean water, soap, or hand sanitizer in some workplaces. the pace of development, distribution, and administration of a vaccine during future pandemics, this experience reaffirmed the importance of the use of NPIs in the early stages of a pandemic before a well-matched vaccine is widely available (i.e., vaccines produced using a virus that is very similar to the circulating virus). Another lesson learned about NPI implementation during the 2009 H1N1 pandemic was that rapidly changing guidance can create confusion and difficulties during implementation (Box 1) (30,31). Nevertheless, field studies found that schoolrelated NPIs, including school closures recommended to mitigate the impact of the 2009 H1N1 pandemic during spring 2009, were considered acceptable and feasible for most parents and caregivers, even when parents had to miss work and in the absence of free or reduced-cost school lunches for students (28,(38)(39)(40)(41). Other interventions that reduced the spread of H1N1pdm09 virus in some communities included hand hygiene (42), regularly scheduled school summer breaks (19), and social distancing measures, such as cancelling mass gatherings and closing public places (22). # Community Engagement The 2009 H1N1 pandemic underscored that effective prepandemic planning requires the involvement of public health and local leaders, employers, organizations, and stakeholders and is essential to ensure timely and effective use of NPIs to limit disease spread during a pandemic (Box 2). Effective use of NPIs depends on the acceptance and participation of individual persons who implement personal protective measures and of communities that implement communitywide measures such as temporary school closures (/ capabilities/DSLR_capabilities_July.pdf ). The 2007 guidance took into account the results of a 2006 opinion poll conducted with a representative national sample of 1,697 adults aged ≥18 years. The results indicated that when faced with an outbreak of pandemic influenza, the majority of persons in the United States would be willing to make major changes in their lives and cooperate with public health recommendations on the use of NPIs (). Findings were # BOX 2. Principles of community engagement # Planning Before initiating a community engagement effort, consider the following: 1. Be clear about the purpose or goals of the engagement effort and the relevant populations and communities. 2. Become knowledgeable about the community's culture, economic conditions, social networks, political and power structures, norms and values, demographic trends, history, and experience with efforts by outside groups to engage it in various programs. Learn about the community's perceptions of those initiating the engagement activities. # Initiation For engagement to occur, the following steps are necessary: 3. Go to the community, establish relationships, build trust, work with the formal and informal leaders, and seek commitment from community organizations and leaders to create processes for mobilizing the community. 4. Remember and accept that collective selfdetermination is the responsibility and right of all people in a community. No external entity should assume the ability to bestow on a community the power to act in its own self-interest. # Implementation For engagement to succeed, consider the following: 5. Partnering with the community is necessary to create change and improve health. 6. All aspects of community engagement must recognize and respect the diversity of the community. Awareness of the various cultures of a community and other factors affecting diversity must be paramount in planning, designing, and implementing approaches to engaging a community. 7. Community engagement can only be sustained by identifying and mobilizing community assets and strengths and by developing the community's capacity and resources to make decisions and take action. 8. Organizations that would like to involve a community and those seeking to effect change must be prepared to release control of actions or interventions to the community and be flexible enough to meet changing needs. 9. Community collaboration requires long-term commitment by the engaging organizations and its partners. For example, in 2006, 85% of the respondents said that they and all members of their household would stay home for 7-10 days if another household member were ill with pandemic influenza. The H1N1 opinion polls also identified barriers to implementation of NPIs among persons and communities (e.g., the ability to stay home when ill, job security, and income protection) (. hsph.harvard.edu/horp/project-on-the-public-response-to-h1n1). States and localities could establish local planning councils or hold public engagement meetings that address these and other issues related to public health preparedness, pandemic education, and planning. States and local communities also can draw on planning guidance provided in the CDC Public Health Preparedness Capabilities: National Standards for State and Local Planning, which lists NPIs as one of 15 capabilities (. gov/phpr/capabilities/DSLR_capabilities_July.pdf). Additional information about pandemic influenza and NPI community engagement is available (supplementary Chapter 1 . cdc.gov/view/cdc/44313). # New Tools for Prepandemic Planning and Pandemic Assessment Novel Influenza Virus Pandemic Intervals In 2014, CDC updated its 2008 guidance on pandemic intervals to include six intervals that describe influenza pandemic progression in a way that supports flexible prepandemic preparedness and response. The intervals include 1) investigation of novel influenza cases, 2) recognition of potential for ongoing transmission, 3) initiation, 4) acceleration, 5) deceleration of the pandemic wave, and 6) preparation for a future pandemic wave (43). These intervals can be used during prepandemic planning and can serve as a platform for public health decision-making and actions during the beginning of a potential influenza pandemic. Each interval is associated with particular response activities, including implementation of select NPIs during the initiation and acceleration intervals and coordinated discontinuation of select community-level NPIs reserved for pandemics during the deceleration interval (Figure 2) (Table 4). Although the six-interval framework describes the sequence of pandemic disease evolution over time, the framework does not characterize the transmissibility of the virus or the clinical severity of the outbreak. Therefore, CDC has developed additional tools for pandemic planning and response, including the Influenza Risk Assessment Tool (supplementary Chapter 2 / cdc/44313); / tools/risk-assessment.htm) and the Pandemic Severity Assessment Framework (PSAF). Additional information about the pandemic intervals is available (supplementary Chapter 2 ). # Pandemic Severity Assessment Framework An influenza pandemic can range from mild to extremely severe in terms of clinical severity and transmission rate. When a pandemic emerges, public health authorities should assess its projected impact and recommend rapid action to reduce virus transmission, protect populations at high risk for complications, and minimize societal disruption. As observed during the 2009 H1N1 pandemic response, attack rates and case-fatality ratios can be difficult to measure early in a pandemic because of variations in care-seeking behavior and testing practices; not everyone seeks care for their illness, and not everyone is tested and receives a diagnosis of pandemic influenza. As a result, severe cases might be more likely to be reported, resulting in an overestimate of the casehospitalization or case-fatality ratio. Tools for prepandemic planning have been updated and augmented based on that experience, and the Pandemic Severity Index in the 2007 guidance has been replaced with PSAF. PSAF uses multiple clinical and epidemiologic indicators to provide a more comprehensive assessment of the transmissibility and clinical severity of an emerging pandemic. Whereas the Pandemic Severity Index was based on the assumption that a future pandemic would cause an illness rate of 30% in the U.S. population and relied on an assessment of casefatality ratios to determine severity of an evolving pandemic, PSAF incorporates multiple measures of clinical severity (e.g., case-fatality ratios, case-hospitalization ratios, and deaths-hospitalizations ratios) and viral transmissibility (e.g., secondary household attack rates, school attack rates, workplace attack rates, community attack rates, or all of these, as well as rates of emergency department and outpatient visits for ILI) (44). When a pandemic begins, in the United States or anywhere in the world, CDC makes an initial assessment of viral transmissibility and clinical severity on the basis of these multiple PSAF measures (Table 5) (44). On the basis of the initial assessment, CDC recommends that affected U.S. jurisdictions respond (and other jurisdictions prepare to respond). Although data are limited during the initial 3-4 weeks after the emergence of a pandemic virus, these early data are compiled into a broad, preliminary assessment. CDC uses PSAF scores of viral transmissibility and clinical severity to place the pandemic within one of four assessment quadrants (Figure 3). Depending on the surveillance capacity in the location where the novel virus emerges and first spreads, 4-8 weeks or longer might be required to accrue sufficient data for a refined assessment of an evolving pandemic. Once data are available, the refined assessment is used to more precisely characterize the clinical severity and transmissibility of the pandemic virus (Figure 4) (Table 6). These initial and refined assessments of pandemic severity are used, in coordination with state and local public health partners, to guide the use of NPI measures. Additional information about PSAF is available (supplementary Chapter 2 / view/cdc/44313). # Methods # Guidelines Development Process This 2017 update consists of three separate documents: this report and two supplementary documents (/ view/cdc/44313 and ). This report provides a brief introduction to pandemic influenza and NPIs; describes the 2007 strategy and the purpose of the updates, particularly after the 2009 H1N1 pandemic; outlines the methods used to develop this update and describe the evidence considered for NPI use during an influenza pandemic; presents CDC's NPI recommendations; and discusses key areas for further NPI research. The two supplementary documents contain more specific and detailed information about pandemic influenza and NPIs. One document (Technical Report 1 / cdc/44313) is divided into chapters and provides an introduction to and overview of NPIs, a description of the new tools developed for pandemic influenza planning and assessment, and a toolbox describing the NPI evidence base, implementation issues, and research gaps. The second document (Technical Report 2 https:// stacks.cdc.gov/view/cdc/44314) consists of several appendices that provide a glossary of terms, a detailed description of the methods used for developing the NPI recommendations, a comprehensive summary table of the NPI body of evidence, and a list of tools and resources for pandemic influenza planning and preparedness. This 2017 update was developed through collaboration involving input from several sources, including peer-reviewed scientific literature, current research, CDC subject-matter experts, and external stakeholders (e.g., federal agencies, public health officials, and business and education partners). Development of these updated guidelines involved participation by multiple CDC groups (e.g., the Community Mitigation Guidelines Work Group and the coordination, abstraction, and consultation teams), as well as a group of external stakeholders who reviewed a document, summarizing the overall direction and key principles and concepts of the guidelines. Input from the work group members, subject-matter experts, and stakeholders was considered and incorporated during the creation of the 2017 planning guidelines. The guidelines were developed during October 2011-October 2016 (Table 7). The complete list of contributors and their roles in the process are available (supplementary Appendix 2 / view/cdc/44314). # FIGURE 2. Preparedness and response framework for novel influenza A virus pandemics, with CDC intervals and World Health Organization phases # Use of NPIs During Influenza Pandemics Ten years ago, when the 2007 strategy was being developed, the evidence for the use of NPIs during influenza pandemics was limited, consisting primarily of historical analyses and contemporary observations rather than controlled scientific studies (45,46). These analyses and observations were supplemented by modeling studies that used historical data to evaluate NPI use in U.S. cities during the 1918 pandemic (47,48) or that simulated pandemic scenarios as they might occur in the future (49)(50)(51). The simulations, like the historical analyses, generally supported the effectiveness of early, targeted, and phased-in (layered) use of multiple NPIs § in preventing spread of disease, especially when used § The pandemic mitigation framework proposed in the 2007 strategy was based on the early, targeted, and layered use of multiple NPIs. NPIs should be initiated early in a pandemic before local epidemics grow exponentially, be targeted toward those at the nexus of transmission (in affected areas where the novel virus circulates), and be layered together to reduce community transmission as much as possible. A list of NPIs that are recommended at all times and those that are reserved for pandemics is provided (Table 1). in combination with antiviral medications (46,49). This conclusion seemed plausible, confirming the presumption that individual, partially effective NPIs act in complementary ways to decrease various factors that facilitate the spread of influenza under different circumstances and settings (52). However, the NPI modeling studies had substantial limitations, including lack of data supporting assumptions about the effectiveness of individual NPIs, economic and social costs of NPIs, and likely rates of compliance (46,49,53). In 2016, the evidence supporting the effectiveness of NPIs, both when used alone and in combination, was more substantial and included controlled studies evaluating different NPIs. New modeling studies based on data collected during the 2009 H1N1 pandemic response also became available. This update is based on approximately 191 journal articles written in English and published from 1990 through September 2016 that focused on personal protective measures in general; school closure effectiveness and unintended consequences; school absenteeism; spread of disease in child care facilities, colleges, and universities; impact of mass gatherings; and role and impact of NPIs in non-health care workplace settings. These articles were reviewed, abstracted, and synthesized. To assess the strength of the evidence, a five-step NPI rating scheme process was developed by adapting and applying the approach of the Guide to Community Preventive Services (The Community Guide) (). Additional information about the NPI rating scheme process is available (supplementary Appendices 3 and 4 / view/cdc/44314). The selected articles were organized into three groups: 1) personal NPIs (personal protective measures for everyday use and personal protective measures reserved for influenza pandemics); 2) community NPIs (social distancing measures and school closures and dismissals); and 3) environmental NPIs (surface cleaning measures) (Table 8). Key steps included selecting the relevant literature, abstracting and synthesizing the evidence, and assessing the evidence quality (both individual study quality and quality of the body of evidence). A recommendation was formulated based on the evidence of effectiveness for each NPI. The strength of NPI recommendations took into consideration the effectiveness of the intervention, the ease of implementation (including unwanted consequences), and the importance of the intervention as a public health strategy. Additional information about the NPI evidence base is available (supplementary Chapter 3 / cdc/44313 and supplementary Appendix 5 . cdc.gov/view/cdc/44314). # Recommendations on the Use of Personal, Community, and Environmental NPIs NPIs routinely recommended for prevention of respiratory virus transmission, such as seasonal influenza, include personal protective measures for everyday use (i.e., voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene) and environmental surface cleaning measures (i.e., routine cleaning of frequently touched surfaces and objects). During an influenza pandemic, these NPIs are recommended regardless of the pandemic severity level. Additional personal and community NPIs also might be recommended. Personal protective measures reserved for pandemics include voluntary home quarantine of exposed household members and use of face masks in community settings when ill. Community NPIs might include temporary closures or dismissals of child care facilities and schools with students in grades kindergarten through 12 (K-12), as well as other social distancing measures that increase the physical space between people (e.g., workplace measures such as replacing in-person meetings with teleconferences or modifying, postponing, or cancelling mass gatherings) (Figure 5) (Table 1). Local decisions about NPI selection and timing involve consideration of overall pandemic severity and local conditions (1) and require flexibility and possible modifications as the pandemic progresses and new information becomes available. Updated recommendations on the use of NPIs to help slow the spread and decrease the impact of an influenza pandemic are provided, as is information on the rationale for using each NPI as part of a comprehensive public health strategy for pandemic response and the appropriate settings and use for each NPI according to the severity of the pandemic (Table 9). ¶ The recommendations that follow are considered an update to the existing recommendations in the 2007 guidance because the same set of NPIs has been maintained and recommended for use early in a pandemic. However, the difference between the guidance issued in 2007 and in 2017 is the clear delineation of NPIs into two categories: 1) NPIs recommended at all times and 2) NPIs recommended for use only during pandemics (based on the level of pandemic severity and local conditions). The 2017 update also provides additional evidence to support the NPI recommendations. ¶ Influenza pandemics can range from mild to extreme in terms of rates of viral transmission and clinical severity, as described in the four prepandemic planning scenarios developed by CDC. A very severe or extreme pandemic, such as the 1918 pandemic, is characterized by high to very high transmissibility and clinical severity. A severe pandemic, such as the pandemics of 1957 and 1968, is characterized by high transmissibility and low to medium clinical severity. A mild or moderate pandemic, such as the 2009 pandemic, is characterized by low to medium transmissibility and clinical severity. # Personal NPIs NPIs that can be implemented by individual persons include the following: - Personal protective measures for everyday use: These include voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene. # Personal protective measures reserved for pandemics: These include voluntary home quarantine of exposed household members and use of face masks in community settings when ill. # Personal Protective Measures for Everyday Use Personal protective measures are preventive actions that can be used daily to slow the spread of respiratory viruses (https:// www.cdc.gov/nonpharmaceutical-interventions/personal/ index.html; supplementary Chapter 3 / view/cdc/44313). These measures include the following: - Voluntary home isolation (i.e., staying home when ill or self-isolation): Persons with influenza stay home for at least 24 hours after a fever or signs of a fever (chills, sweating, and feeling warm or flushed) are gone (. htm), except to obtain medical care or other necessities. † † To ensure that the fever is gone, patients' temperature should be measured in the absence of medication that lowers fever (e.g., acetaminophen or ibuprofen). In addition to fever, common influenza symptoms include cough or chest discomfort, muscle or body aches, headache, and fatigue. Rationale for use as a public health strategy. Most persons infected with an influenza virus might become infectious 1 day before the onset of symptoms and remain infectious up to 5-7 days after becoming ill (54,55). However, studies found that infants and immunocompromised persons might shed influenza viruses for prolonged periods (up to 21 days and a mean of 19 days, respectively) (56,57). The effectiveness of personal protective measures depends on their ability to interrupt virus transmission from one person to another. Voluntary home isolation, which is a form of patient isolation, prevents an ill person from infecting other people outside of their household. § § Respiratory etiquette reduces the dispersion of droplets contaminated with influenza virus being propelled through the air by coughing or sneezing. Hand hygiene reduces the transmission of influenza viruses that occurs when one person touches another (e.g., with a contaminated hand). Contamination also can occur through self-inoculation via fomite transmission (indirect contact transmission) when persons touch a contaminated surface and then touch their nose with a contaminated hand. A study conducted in households in Bangkok, Thailand, found that increased handwashing reduced surface contamination with influenza virus, which lowered the potential for self-inoculation via fomite transmission (58). Additional studies found that influenza viruses can remain viable on the human hand for roughly 3-5 minutes (59) and that influenza viruses can remain on fingers for 30 minutes after contamination (60). - Colors transition from light to dark as the estimated number of deaths increases. Transmissibility: measured on a scale of 1-5 and includes school, workplace, and community attack rates, secondary household attack rates, school and/or workplace absenteeism rates, and rates of emergency department and outpatient visits for influenza-like illness. Clinical severity: measured on a scale of 1-7 and includes case-fatality ratios, case-hospitalization ratios, and deaths-hospitalizations ratios. # Settings and use. Voluntary home isolation involves persons remaining at home when ill with influenza. Respiratory etiquette and hand hygiene are recommended in homes and in all other community settings, including schools and workplaces. All three personal protective measures are considered everyday preventive actions that should be implemented year-round but that are especially important during annual influenza seasons and influenza pandemics (Table 10). Use of these personal protective measures might result in some secondary (unintended or unwanted) consequences (e.g., concerns about job security for ill persons who lack paid sick leave or skin irritations due to frequent hand washing). # CDC recommendations Voluntary home isolation: CDC recommends voluntary home isolation of ill persons (staying home when ill) year-round and especially during annual influenza seasons and influenza pandemics. Respiratory etiquette and hand hygiene: CDC recommends respiratory etiquette and hand hygiene in all community settings, including homes, child care facilities, schools, workplaces, and other places where people gather, year-round and especially during annual influenza seasons and influenza pandemics. Voluntary home quarantine of non-ill household members of persons with influenza (also called self-quarantine or household quarantine) helps prevent disease spread from households to schools, workplaces, and other households because those household members have been exposed to the influenza virus. Exposed household members of symptomatic persons (with confirmed or probable pandemic influenza) should stay home for up to 3 days (the estimated incubation period for seasonal influenza) (61) starting from their initial contact with the ill person. If they then become ill, they should practice voluntary home isolation (i.e., they should remain at home until recovered as discussed previously; / index.html). For certain exposed household members (e.g., those at high risk for influenza complications or with severe immune deficiencies), guidelines should be consulted regarding the prophylactic use of antiviral medications (. gov/flu/professionals/antivirals/index.htm). Rationale for use as a public health strategy. Voluntary home quarantine might help slow a pandemic by reducing community transmission from households with a person who has influenza because the exposed household members are at increased risk for infection. Furthermore, certain infected (but not yet symptomatic) household members could begin shedding influenza virus at least a day before exhibiting symptoms and could infect friends, neighbors, and others in the community (e.g., at school or work) before becoming symptomatic. Therefore, all members of a household with a symptomatic person (with confirmed or probable pandemic influenza) might be asked to stay home for a specified period of time (up to 3 days) to assess for early signs and symptoms of pandemic influenza virus infection. If other household members become ill during this period, then the time for voluntary home quarantine might need to be extended for another incubation period. The evidence for voluntary home quarantine, particularly when used in combination with other NPIs, includes a systematic literature review, historical analyses of the 1918 pandemic, and mathematical modeling studies (supplementary Chapter 3 and supplementary Appendix 5 / cdc/44314). Settings and use. Voluntary home quarantine of exposed household members might be recommended during severe, very severe, or extreme influenza pandemics (Table 10) to help reduce the chance of transmitting the virus to others outside of the household. Advance planning is needed to minimize potential secondary consequences for persons who have special cultural, economic, legal, mental, physical, or social status needs (e.g., older adults who depend on necessary community-based services such as home-delivered meals and transportation to health care services). Other secondary consequences might include missed work and loss of income for persons whose employers do not have paid sick leave policies that include home quarantine during pandemics. # CDC recommendations Voluntary home quarantine: CDC might recommend voluntary home quarantine of exposed household members as a personal protective measure during severe, very severe, or extreme influenza pandemics in combination with other personal protective measures such as respiratory etiquette and hand hygiene. If a member of the household is symptomatic with confirmed or probable pandemic influenza, then all members of the household should stay home for up to 3 days (the estimated incubation period for seasonal influenza), ¶ ¶ starting from their initial contact with the ill person, to monitor for influenza symptoms. # Use of Face Masks in Community Settings Face masks (disposable surgical, medical, or dental procedure masks) are widely used by health care workers to prevent respiratory infections both in health care workers and patients. They also might be worn by ill persons during severe, very severe, or extreme pandemics to prevent spread of influenza to household members and others in the community. However, little evidence supports the use of face masks by well persons in community settings, although some trials conducted during the 2009 H1N1 pandemic found that early combined use of face masks and other NPIs (such as hand hygiene) might be effective (supplementary Chapter 3 / view/cdc/44313). Rationale for use as a public health strategy. Face masks provide a physical barrier that prevents the transmission of influenza viruses from an ill person to a well person by blocking large-particle respiratory droplets propelled by coughing or sneezing. Face mask use by well persons is not routinely needed in most situations to prevent acquiring the influenza virus. However, use of face masks by well persons ¶ ¶ If the incubation period for the next pandemic were shorter or longer than 3 days, CDC would amend the recommendation accordingly. might be beneficial in certain situations (e.g., when persons at high risk for influenza complications cannot avoid crowded settings or parents are caring for ill children at home). Face mask use by well persons also might reduce self-inoculation (e.g., touching the nose with the hand after touching a contaminated surface). Settings and use. Disposable surgical, medical, and dental procedure masks are used widely in health care settings to prevent exposure to respiratory infections. Face masks have few secondary consequences (e.g., discomfort or difficulty breathing) when worn properly and consistently, and face masks sized for children are available. (Additional information about face masks is available at . fda.gov/medicaldevices/productsandmedicalprocedures/ generalhospitaldevicesandsupplies/personalprotectiveequipment/ ucm055977.htm and / respirators-vs-surgicalmasks-factsheet.html.) # FIGURE 5. Phased addition of nonpharmaceutical interventions to prevent the spread of pandemic influenza in communities # CDC recommendations Use of face masks by ill persons: CDC might recommend the use of face masks by ill persons as a source control measure during severe, very severe, or extreme influenza pandemics when crowded community settings cannot be avoided (e.g., when adults and children with influenza symptoms seek medical attention) or when ill persons are in close contact with others (e.g., when symptomatic persons share common spaces with other household members or symptomatic postpartum women care for and nurse their infants). Some evidence indicates that face mask use by ill persons might protect others from infection. Use of face masks by well persons: CDC does not routinely recommend the use of face masks by well persons in the home or other community settings as a means of avoiding infection during influenza pandemics except under special, high-risk circumstances (/ professionals/infectioncontrol/maskguidance.htm). For example, during a severe pandemic, pregnant women and other persons at high risk for influenza complications might use face masks if unable to avoid crowded settings, especially if no pandemic vaccine is available. In addition, persons caring for ill family members at home (e.g., a parent of a child exhibiting influenza symptoms) might use face masks to avoid infection when in close contact with a patient, just as health care personnel wear masks in health care settings. # Community NPIs NPIs that can be implemented by communities include the following: - School closures and dismissals: These include temporary closures and dismissals of child care facilities, K-12 schools, and institutions of higher education. - Social distancing measures: These include measures for schools, workplaces, and mass gatherings. # School Closures and Dismissals In the event of a pandemic, state and local public health authorities play an important role in protecting the school community and should establish and maintain partnerships with district and school leaders, school emergency operations planning teams, and local municipality leaders (e.g., mayors). Public health authorities are a credible source of information, have multiple (often free) resources available for information awareness campaigns, and provide guidance for increasing school response measures. Depending on the severity of the pandemic, these measures might range from everyday preventive actions to preemptive, coordinated school closures and dismissals. A school closure means closing a school and sending all the students and staff members home, whereas during a school dismissal, a school might stay open for staff members while the children stay home. Preemptive school dismissals can be used to disrupt transmission of influenza before many students and staff members become ill. Coordinated dismissals refer to the simultaneous or sequential closing of schools in a jurisdiction. Thus, preemptive, coordinated school closures and dismissals can be used early during an influenza pandemic to prevent virus transmission in schools and surrounding communities by reducing close contact among the following groups (supplementary Chapter 3 https:// stacks.cdc.gov/view/cdc/44313): - Children in child care centers and preschools - School-aged children and teens in K-12 schools - Young adults in institutions of higher education During a dismissal, the school facilities are kept open, which allows teachers to develop and deliver lessons and materials, thus maintaining continuity of teaching and learning, and allows other staff members to continue to provide services and help with additional response efforts. School closures and dismissals might be coupled with social distancing measures (e.g., cancelling sporting events and other mass gatherings) to reduce out-ofschool social contact among children when schools are closed. Rationale for use as a public health strategy. Preventing the spread of disease in educational settings among children and young adults reduces the risk for infection for these age groups and slows virus transmission in the community. Components of the strategy might include preemptive, coordinated school closures and dismissals implemented during the earliest stages of a pandemic, before many students and staff members become ill. Preemptive, coordinated dismissals can be implemented by the following facilities for the following reasons: - Child care facilities and K-12 schools -Children have higher influenza attack rates than adults (62) and are infectious for a longer period than adults (63,64). -Influenza transmission is common in schools and contributes to school absenteeism and parental absenteeism from work (65,66). -The presence of school-aged children in a household is a risk factor for influenza virus infection in families (62,65,67). -Social contact and mixing patterns among school-aged children differ substantially depending on the grade and school level, during various periods of the school day, between weekdays and weekends, and between regular school terms and holiday breaks (68)(69)(70)(71). Physical floor plans and intergrade activities (e.g., cafeteria size and lunch breaks) also can affect in-school social mixing (68). -Schoolchildren can introduce the influenza virus into a community, leading to increased rates of illness among their household or community contacts (72-74). - Institutions of higher education -Influenza outbreaks on college and university campuses typically have high attack rates (44%-73%) (75-78) and cause substantial morbidity (79,80). For example, during the 2009 H1N1 pandemic, influenza spread rapidly through a university campus within 2 weeks (81); on another residential campus, one infected freshman initiated an outbreak that resulted in 226 laboratory-confirmed cases. Freshmen were the main facilitators of the spread of the H1N1pdm09 virus because of their higher number and frequency of social contacts (82). -Influenza is more prevalent among residential students at boarding schools and colleges than among nonresidential students (78,83). -ILIs are common among college and university students and are associated with increased health care use, decreased health status, and impaired school performance (84). Implementation of preemptive, coordinated school closures and dismissals during an evolving influenza pandemic might have one or more of the following three public health objectives: Additional information on the use of preemptive, coordinated school closures and dismissals of different durations is available (supplementary Chapter 3 ). - Objective 1: To gain time for an initial assessment of transmissibility and clinical severity of the pandemic virus in the very early stage of its circulation in humans (closures for up to 2 weeks) - Objective 2: To slow down the spread of the pandemic virus in areas that are beginning to experience local outbreaks and thereby allow time for the local health care system to prepare additional resources for responding to increased demand for health care services (closures up to 6 weeks) - Objective 3: To allow time for pandemic vaccine production and distribution (closures up to 6 months) Two other types of school closures and dismissals might be implemented during a pandemic for public health or institutional reasons. These interventions do not slow disease spread in the community; therefore, they are not considered NPIs. They include the following: - Selective school closures and dismissals: These might be implemented by schools that serve students at high risk for complications from infection with influenza, † † † especially when transmission rates are high. For example, a school that serves children with certain medical conditions or pregnant teens might decide to close while other schools in the area remain open. In addition, some communities or early childhood programs might consider closing child care facilities to help decrease the spread of influenza among children aged <5 years. Selective dismissals are intended to protect persons at high risk for influenza rather than to help reduce virus transmission within the community. - Reactive school closures and dismissals: These might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. For example, a child care center might close because it is unable to operate under these conditions. Reactive dismissals, which might occur during outbreaks of seasonal influenza (85) and during pandemics (15), are unlikely to affect virus transmission because they typically take place after considerable, if not widespread, transmission has already occurred in the community. For example, a 4-day reactive closure in a western Kentucky school district did † † † Persons at high risk for influenza-related complications include children aged <5 years (and especially aged <2 years), adults aged ≥65 years, pregnant women, residents of nursing homes and other long-term care facilities, and American Indians/Alaska Natives. Those at high risk also include persons with asthma, neurological and neurodevelopmental conditions, chronic lung disease, and heart disease; disorders of the blood, endocrine system, kidney, or liver; metabolic disorders; and weakened immune systems from disease or medication. Two other groups at higher risk are persons aged <19 years who receive long-term aspirin therapy and those with extreme obesity (https:// www.cdc.gov/flu/about/disease/high_risk.htm). not reduce ILI transmission in the rural community (86). Similarly, closing 559 Michigan schools at least once during the fall wave (i.e., second wave) of the 2009 H1N1 pandemic had little effect on community levels of ILI (87). For more information about preparing for influenza and the different types of dismissals, see CDC websites regarding 1) child care facilities (/ toolkit/pdf/childcare_toolkit.pdf ), 2) K-12 schools (https:// www.cdc.gov/h1n1flu/schools/toolkit/pdf/schoolflutoolkit.pdf), and 3) institutions of higher education (/ h1n1flu/institutions/toolkit/pdf/IHE_toolkit.pdf ). Settings and use. Preemptive, coordinated school closures and dismissals might be implemented at child care facilities, K-12 schools, and institutions of higher education. They are most likely to be implemented when an influenza pandemic is severe, very severe, or extreme (Table 10). Secondary consequences include missed work and loss of income for parents who stay home from work to care for their children and missed opportunities to vaccinate school-aged children rapidly unless other mechanisms are considered. # CDC recommendations School closures and dismissals: CDC might recommend the use of preemptive, coordinated school closures and dismissals during severe, very severe, or extreme influenza pandemics. This recommendation is in accord with the conclusions of the U.S. Community Preventive Services Task Force (), which makes the following recommendations: - The task force recommends preemptive, coordinated school dismissals during a severe influenza pandemic. - The task force found insufficient evidence to recommend for or against preemptive, coordinated school dismissals during a mild or moderate influenza pandemic. In these instances, jurisdictions should make decisions that balance local benefits and potential harms. # Social Distancing Measures for Schools, Workplaces, and Mass Gatherings Social distancing measures can reduce virus transmission by decreasing the frequency and duration of social contact among persons of all ages. These measures are common-sense approaches to limiting face-to-face contact, which reduces person-to-person transmission. Rationale for use as a public health strategy. Social distancing measures that reduce opportunities for person-toperson virus transmission can help delay the spread and slow the exponential growth of a pandemic. The optimal strategy is to implement these measures simultaneously in places where persons gather. Although direct evidence is limited for the effectiveness of these measures, components of the strategy might include reducing social contacts at the following places: - Schools: Children have higher influenza attack rates than adults, and influenza transmission is common in schools. (93). An infected traveler attending a mass gathering might introduce influenza to a previously unaffected area, and a person who becomes infected at the event can further spread the infection after returning home (89,90,92,(94)(95)(96). Even when a circulating virus has a relatively low basic reproductive rate (R 0 ), intensely crowded settings might lead to high secondary attack rates (92). For example, during the 2013 Hajj (Islamic pilgrimage to Mecca) in Saudi Arabia, influenza A/H1N1 virus was found in only two Indonesians on arrival but spread to 25 persons from Africa, Central Asia, and Southeast Asia after the Hajj because of the extremely crowded conditions when performing rituals (97). Multiple social distancing measures can be implemented simultaneously. Although there is limited empirical evidence supporting the effectiveness of implementing any individual measure alone (other than school closures and dismissals), the evidence for implementing multiple social distancing measures in combination with other NPIs includes systematic literature reviews, historical analyses of the 1918 pandemic, and mathematical modeling studies (supplementary Chapter 3 and supplementary Appendix 5 ). Settings and use. Social distancing measures can be implemented in a range of community settings, including educational facilities, workplaces, and public places where people gather (e.g., parks, religious institutions, theaters, and sports arenas). The choice of social distancing measure depends on the severity of the pandemic (Table 10 # CDC recommendations Social distancing measures: Even though the evidence base for the effectiveness of some of these measures is limited, CDC might recommend the simultaneous use of multiple social distancing measures to help reduce the spread of influenza in community settings (e.g., schools, workplaces, and mass gatherings) during severe, very severe, or extreme influenza pandemics while minimizing the secondary consequences of the measures. Social distancing measures include the following: - Increasing the distance to at least 3 feet (98) between persons when possible might reduce person-to person transmission. This applies to apparently healthy persons without symptoms. In the event of a very severe or extreme pandemic, this recommended minimal distance between people might be increased. - Persons in community settings who show symptoms consistent with influenza and who might be infected with (probable) pandemic influenza should be separated from well persons as soon as practical, be sent home, and practice voluntary home isolation. # Environmental NPIs: Environmental Surface Cleaning Measures Environmental surface cleaning measures can help eliminate influenza viruses from frequently touched surfaces and objects, including tables, door knobs, toys, desks, and computer keyboards. These measures involve cleaning surfaces with detergent-based cleaners or disinfectants that have been registered with the Environmental Protection Agency. ¶ ¶ ¶ Rationale for use as a public health strategy. Although the percentage of influenza cases involving contact transmission (i.e., hand transfer of virus from contaminated objects to the eyes, nose, or mouth) is unknown, this mode of transmission is a recognized route of virus spread (99). The routine use of cleaning measures that eliminate viruses from contaminated surfaces might reduce the spread of influenza viruses (supplementary Chapter 3 ). ¶ ¶ ¶ Antimicrobial products registered for use against H1N1 influenza and other influenza A viruses on hard surfaces (/ oppad001/web/pdf/influenza-a-product-list.pdf ). The rationale for and key concepts regarding the use of NPIs during influenza pandemics first presented in the 2007 guidance remain unchanged. Because production of a pandemic vaccine can take up to 6 months and antiviral medications might be prioritized for treatment, NPIs are likely to be the only prevention tools available early in a pandemic. Therefore, they are critical to slowing the spread of the pandemic influenza virus while a pandemic vaccine is under development. Like the 2007 strategy, this 2017 update affirms the importance of prepandemic planning and preparedness for use of NPIs during a pandemic response and recommends the early, targeted, and simultaneous implementation of multiple NPIs to decrease influenza virus transmission. Although community-level NPIs can help slow virus transmission, as supported by historical information (100), empirical observations (101), and mathematical modeling (102), these measures are likely to cause unwanted consequences by introducing new norms for social behavior (e.g., adopting precautionary health-protective behaviors such as limiting face-to-face contact with family and friends, only shopping for essential items, avoiding places where people congregate, or not using public transportation) (103), interrupting routine societal functions, and entailing additional costs. If an evolving influenza pandemic is characterized by high clinical severity, the benefits of deploying NPIs, including those with greater potential for secondary consequences, are likely to outweigh potential harms. The more difficult decision is determining how and when to implement the community-level NPIs that are more disruptive to society (e.g., temporary K-12 school closures) during pandemics of moderate severity. In each locality, the goal should be to implement NPIs early enough and long enough to maximize effectiveness while minimizing economic and social costs to ensure that NPIs are commensurate to the pandemic severity. # New Elements Added in 2017 New elements in this report, in addition to the evidencebased NPI recommendations, include a summary of key lessons learned from the 2009 H1N1 pandemic response (Box 1), information on community engagement and preparedness (supplementary Chapter 1 / cdc/44313), and information on new or updated pandemic assessment tools (supplementary Chapter 2 . gov/view/cdc/44313), which include the novel influenza virus pandemic intervals tool, the Influenza Risk Assessment Tool, and PSAF. As described in the following sections, this report also presents two additional planning tools designed to assist states and localities in ensuring pandemic preparedness. # Prepandemic Planning Scenarios for NPI Implementation According to Pandemic Severity During the initial stages of a pandemic, CDC will use the PSAF tool to prepare an initial assessment of pandemic severity that provides early guidance on use of NPIs to help slow the transmission of the novel virus. To facilitate the use of the initial assessment information by state and local health departments, CDC has provided a set of four prepandemic planning scenarios. Each scenario aligns with one of the four assessment quadrants (Figure 3) and provides information on past influenza pandemics for comparison (Table 9). These planning scenarios are designed to facilitate state and local prepandemic planning for NPI implementation according to pandemic severity (as classified by PSAF) (Figure 6) (Tables 9 and 10). After sufficient epidemiologic data are accrued and the refined assessment of pandemic severity becomes available, CDC will issue updated pandemic NPI guidance, which will be tailored more precisely to the specific pandemic. Additional information about the planning scenarios and phasing of NPIs is available (supplementary Chapter 2 https:// stacks.cdc.gov/view/cdc/44313). # Supplemental Prepandemic NPI Planning Guides The 2007 report included supplemental prepandemic NPI planning guides for individuals and families; child care programs, K-12 schools, and institutions of higher education; community-and faith-based organizations; and businesses and other workplaces. These guides have been updated, and two new guides have been developed for public health communicators and event planners that address NPI communications and modification, postponement, or cancellation of mass gatherings. These guides are intended to help operationalize the 2017 update and provide specific information that can assist different groups in their prepandemic planning and decision-making (https:// www.cdc.gov/nonpharmaceutical-interventions). # Future Research Although progress has been made since 2009 toward building the evidence base for use of NPIs to slow the spread of pandemic influenza, additional research is needed. For personal NPIs, areas for additional research include evaluating the effects of increased frequency and quality of hand washing on influenza virus transmission, determining the role of infected persons who are not symptomatic in the transmission of influenza viruses in households, and assessing the effectiveness, acceptability, and feasibility of recommending face mask use by well persons in community settings as a means of avoiding infection during a pandemic. For community NPIs, one topic for additional study involves gathering empirical data on social mixing patterns in schools and community settings. These data can be used to create high-fidelity, high-resolution mathematical models of virus transmission in these settings to facilitate data-driven evaluations of different social distancing measures. Another area of research for community NPIs involves assessing the potential secondary consequences (e.g., missed work) of select community-level measures (e.g., school closures) for families, communities, and society to assess the economic effects of these measures. For environmental NPIs, additional research is needed to better understand surface contamination (e.g., which types of surfaces are more likely to be contaminated with influenza viruses) and identify situations in which surface cleaning should be emphasized (e.g., in households with confirmed influenza cases versus in healthy households). Additional information about NPI research gaps is available (supplementary Chapter 3 ). # Conclusion The 2009 H1N1 pandemic provided an opportunity to test, in practice, the key concepts of NPIs in mitigating the impact of an influenza pandemic, just 2 years after the publication of the 2007 guidance. As the experience from 2009 has shown, NPIs can be a critical component of pandemic influenza mitigation. Although well-matched pandemic vaccines remain the main tool in reducing the risk of acquiring infection and in controlling the spread of a pandemic virus, vaccines might not be widely available for up to 6 months after the emergence of a pandemic influenza virus, given current vaccine production technology. Furthermore, as during the 2009 H1N1 pandemic, antiviral medications might be prioritized for treatment but not used for widespread chemoprophylaxis because of concerns about antiviral resistance and limited stockpiles of antiviral medications. Therefore, NPIs might be the only prevention tools readily available for persons and communities to help slow transmission of an influenza virus during the initial stages of a pandemic. However, individual NPIs might be only partially effective in limiting community transmission when implemented alone. Thus, the most efficient implementation involves early, targeted, and layered use of multiple NPIs (). In addition, some community-level NPIs that potentially have the greatest epidemiologic effects on pandemic influenza virus transmission in communities, most notably school closures and dismissals, also are most likely to be associated with secondary (unwanted) consequences (104). Hence, prepandemic planning, including engaging communities in planning activities well ahead of the next pandemic, is critical to enable appropriate local decisionmaking during the early stages of a pandemic. After the 2009 H1N1 pandemic, evidence on the effectiveness and feasibility of NPIs expanded substantially. A summary of the evidence in this 2017 update includes 2009 H1N1-related research (supplementary Appendix 5 / cdc/44314). However, knowledge gaps remain and should be addressed by future research. Further updates of these guidelines will be developed and issued when significant new information and evidence emerges about the effectiveness and feasibility of NPIs in mitigating the impact of pandemic influenza. This interval is indicated by the identification of an animal case of influenza A subtype with potential implications for human health or identification of a human case of novel influenza A anywhere in the world. # Recognition: # Recognition of potential for ongoing transmission This interval is indicated by an increasing number of cases or clusters of novel influenza A in humans and by virus characteristics indicating potential for ongoing human-to-human transmission anywhere in the world. # Initiation: Initiation of the pandemic wave This interval is indicated by confirmation of cases of novel influenza A in humans and demonstration of efficient and sustained human-to-human transmission anywhere in the world. # Acceleration: Acceleration of the pandemic wave This interval is indicated by an increasing rate of novel influenza A cases identified nationally, indicating establishment in the country. # Deceleration: Deceleration of the pandemic wave This interval is indicated by decreasing rates of novel influenza A infection. # Preparation: Preparation for a future pandemic wave This interval is indicated by sporadic cases of novel influenza A infection and surveillance rates returning to baseline. # CDC Community Mitigation Guidelines Work Group Alexandra # Conflict of Interest The CDC contributors wish to disclose that they have no financial or competing interests or other relationships that would unfairly influence these CDC guidelines and recommendations. Voluntary home quarantine of exposed household members (staying home for up to 3 days † when a household member is ill) Reserved for pandemics Use of face masks in community settings when ill Community School closures and dismissals § Temporary, preemptive, coordinated dismissals of child care facilities and schools for grades K-12 ¶ Reserved for pandemics # Social distancing measures (examples) Dividing classes into smaller groups and creating opportunities for distance learning (e.g., via the internet or local television or radio stations) # Reserved for pandemics Telecommuting and remote-meeting options in workplaces Mass gathering modifications, postponements, or cancellations Environmental Environmental surface cleaning measures Routine cleaning of frequently touched surfaces and objects in homes, child care facilities, schools, and workplaces Recommended at all times Abbreviation: NPI = nonpharmaceutical intervention. - Personal, community, and environmental NPIs should be 1) initiated early in a pandemic before local epidemics begin to grow exponentially, 2) targeted toward the nexus of transmission (in affected areas where the novel virus circulates), and 3) layered together to reduce community transmission to the greatest extent possible. † If the incubation period for the next pandemic influenza virus is longer or shorter than 3 days, CDC will amend the recommendation. § A school closure involves closing a school and sending all the students and staff members home. A school dismissal could involve a school staying open for staff members while the students stay home. ¶ Preemptive, coordinated dismissals might be implemented early during a pandemic to decrease the spread of influenza before many students and staff members become ill. Selective dismissals might be implemented by schools that serve students at high risk for complications from infection with influenza. Reactive dismissals might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. Selective and reactive dismissals do not help slow disease transmission in the community. -Educational issues (e.g., missed educational opportunities or loss of free or subsidized school meals because of school dismissals) -Financial issues (e.g., workers who cannot afford to stay home when they are ill or to care for an ill family member because they do not have paid sick leave) -Legal issues (e.g., local jurisdictions that do not have the legal authority to close schools or cancel mass gatherings for public health reasons) -Workplace issues (e.g., access to clean water, soap, or hand sanitizer and flexible workplace policies or arrangements) # Development of the recommendations The approach used by the Guide to Community Preventive Services (The Community Guide) was adapted and applied to develop the NPI recommendations in the updated planning guidelines. # Planning guides To help operationalize the updated guidelines, six community mitigation prepandemic planning guides have been developed for key populations and decision-makers in community settings. During September-October 2015, before submission for CDC clearance, the National Public Health Information Coalition facilitated discussion of the planning guides by representatives of the public health, education, and business communities. The guides are part of a set of practical, user-friendly, and plain-language companion implementation materials. # Updating the guidelines The 2017 guidelines will be updated when new information warrants their modification. Abbreviation: NPI = nonpharmaceutical intervention. Abbreviation: NPI = nonpharmaceutical intervention. - Personal, community, and environmental NPIs should be 1) initiated early in a pandemic before local epidemics begin to grow exponentially, 2) targeted toward the nexus of transmission (in affected areas where the novel virus circulates), and 3) layered together to reduce community transmission to the greatest extent possible. † During a very severe or extreme pandemic (similar to the 1918 pandemic), CDC is likely to take an aggressive stance and recommend certain additional NPIs. § Recommended NPIs are the same for seasonal influenza. ¶ Preemptive, coordinated dismissals might be implemented early during a pandemic to decrease the spread of influenza before many students and staff members become ill. Selective dismissals might be implemented by schools that serve students at high risk for complications from infection with influenza. Reactive dismissals might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. Selective and reactive dismissals do not help slow disease transmission in the community. Social distancing measures that reduce face-to-face contact in schools might include dividing classes into smaller groups of students who are spaced further apart from each other within the classroom. † † Social distancing measures that reduce face-to-face contact in workplaces might include offering telework and remote meeting options. Flexible sick leave policies should be implemented to encourage workers to stay home if needed. § § In all scenarios, mass gathering attendance during local outbreaks should be discouraged for persons at high risk for severe influenza-related complications.	When a novel influenza A virus with pandemic potential emerges, nonpharmaceutical interventions (NPIs) often are the most readily available interventions to help slow transmission of the virus in communities, which is especially important before a pandemic vaccine becomes widely available. NPIs, also known as community mitigation measures, are actions that persons and communities can take to help slow the spread of respiratory virus infections, including seasonal and pandemic influenza viruses. These guidelines replace the 2007 Interim Pre-pandemic Planning Guidance: Community Strategy for Pandemic Influenza Mitigation in the United States -Early, Targeted, Layered Use of Nonpharmaceutical Interventions (https://stacks.cdc.gov/view/ cdc/11425). Several elements remain unchanged from the 2007 guidance, which described recommended NPIs and the supporting rationale and key concepts for the use of these interventions during influenza pandemics. NPIs can be phased in, or layered, on the basis of pandemic severity and local transmission patterns over time. Categories of NPIs include personal protective measures for everyday use (e.g., voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene); personal protective measures reserved for influenza pandemics (e.g., voluntary home quarantine of exposed household members and use of face masks in community settings when ill); community measures aimed at increasing social distancing (e.g., school closures and dismissals, social distancing in workplaces, and postponing or cancelling mass gatherings); and environmental measures (e.g., routine cleaning of frequently touched surfaces). Several new elements have been incorporated into the 2017 guidelines. First, to support updated recommendations on the use of NPIs, the latest scientific evidence available since the influenza A (H1N1)pdm09 pandemic has been added. Second, a summary of lessons learned from the 2009 H1N1 pandemic response is presented to underscore the importance of broad and flexible prepandemic planning. Third, a new section on community engagement has been included to highlight that the timely and effective use of NPIs depends on community acceptance and active participation. Fourth, to provide new or updated pandemic assessment and planning tools, the novel influenza virus pandemic intervals tool, the Influenza Risk Assessment Tool, the Pandemic Severity Assessment Framework, and a set of prepandemic planning scenarios are described. Finally, to facilitate implementation of the updated guidelines and to assist states and localities with prepandemic planning and decision-making, this report links to six supplemental prepandemic NPI planning guides for different community settings that are available online (https://www.cdc.gov/nonpharmaceutical-interventions).# CONTENTS # Disclosure of Relationship CDC, our planners, or content experts, and their spouses/ partners wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. Content will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling CDC did not accept commercial support for this continuing education activity. # Introduction Nonpharmaceutical interventions (NPIs) are strategies for disease, injury, and exposure control (https://www.cdc.gov/ phpr/capabilities/DSLR_capabilities_July.pdf ). They include actions that persons and communities can take to help slow the spread of respiratory viruses (e.g., seasonal and pandemic influenza viruses). These actions include personal protective measures for everyday use (e.g., staying home when ill, covering coughs and sneezes, and washing hands often) and communitywide measures reserved for pandemics and aimed at reducing opportunities for exposure (e.g., coordinated closures and dismissals of child care facilities and schools and cancelling mass gatherings). When a novel influenza A virus with pandemic potential emerges, NPIs can be used in conjunction with available pharmaceutical interventions (antiviral medications) to help slow its transmission in communities, especially when a vaccine is not yet widely available. Given current vaccine technology, a pandemic vaccine might not be available for up to 6 months (https://www.fda.gov/%20 ForConsumers/ConsumerUpdates/ucm336267.htm). NPIs can be used before a pandemic is declared in areas where a novel influenza A virus is detected and during a pandemic. These 2017 guidelines provide evidence-based recommendations on the use of NPIs in mitigating the effects of pandemic influenza. These guidelines update and expand the 2007 strategy (https://stacks.cdc.gov/view/ cdc/11425).* # Purpose The purpose of these guidelines is to help state, tribal, local, and territorial health departments with prepandemic planning and decision-making by providing updated recommendations on the use of NPIs. These recommendations have incorporated lessons learned from the federal, state, and local responses to the influenza A (H1N1)pdm09 virus pandemic (hereafter referred to as the 2009 H1N1 pandemic) and findings from research. Communities, families and individuals, employers, and schools can create plans that use these interventions to help slow the spread of a pandemic and prevent disease and death. Specific goals for implementing NPIs early in a pandemic include slowing acceleration of the number of cases in a community, reducing the peak number of cases during the pandemic and related health care demands on hospitals and infrastructure, and decreasing overall cases and health effects (Figure 1). When a pandemic begins, public health authorities need to decide on an appropriate set of NPIs for implementation and to reiterate the importance of personal protective measures for everyday use (e.g., voluntary home isolation of ill persons [staying home when ill], respiratory etiquette, and hand hygiene) and environmental cleaning measures (e.g., routine cleaning of frequently touched surfaces), which are recommended at all times for prevention of respiratory illnesses (Table 1). Personal protective measures reserved for pandemics (e.g., voluntary home quarantine of exposed household members [staying home when a household member is ill] and use of face masks by ill persons) also might be recommended (Table 1). A more difficult decision is how and when to implement community-level NPIs that might be warranted but are more disruptive (e.g., temporary school closures and dismissals, social distancing in workplaces and the community, and cancellation of mass gatherings) (Table 1). These decisions are made by state and local officials on the basis of conditions in the applicable jurisdictions, with guidance from CDC (according to pandemic severity and potential efficacy) and governing authorities (1). Prepandemic planning, along with community engagement, is an essential component of these decisions (Table 2). The decision regarding whether and when to recommend additional NPIs is another component (Table 3). State and local public health departments might use certain influenza surveillance indicators to help decide when to consider implementing NPIs such as school closures and dismissals and other social distancing measures in schools, workplaces, and public settings during an influenza pandemic. The choice of influenza surveillance indicators might differ among states and localities, depending on the availability and capacity of their public health resources. Examples of possible influenza surveillance indicators include additional patient visits to health care providers for influenza-like illness (ILI) and increased geographic spread of influenza within a state. Indicators for school closures and dismissals might include increased school absenteeism rates or the earliest laboratoryconfirmed influenza cases among students, teachers, or staff members. Indicators that might help confirm that NPI implementation should continue include increased influenzaassociated hospitalizations or increases in adult or pediatric deaths attributed to influenza. Additional information about NPI prepandemic planning is available (supplementary Chapter 1 https://stacks.cdc.gov/view/cdc/44313). # Background An influenza pandemic occurs when a novel virus emerges for which the majority of the population has little or no immunity. Influenza pandemics are facilitated by sustained human-tohuman transmission, and the infection spreads worldwide over a relatively short period (2). The first influenza pandemic of the 21st century began in 2009, 2 years after the 2007 strategy for prepandemic planning was published. Lessons learned during the response to the 2009 H1N1 pandemic underscored the importance of a flexible approach to the use of NPIs, particularly during the early stages of a pandemic, and led to the development of new tools for assessing pandemic severity and prepandemic planning (Box 1). # Lessons Learned from the 2009 H1N1 Pandemic Response The 2009 H1N1 pandemic was a reminder to be prepared for the unpredictable nature of pandemics. Knowing in advance which subtype of pandemic virus will emerge is impossible, as is where and when it will emerge, how quickly the virus will spread, how severe the illness will be, and who will be the most affected. Because of this unpredictability, prepandemic planning must be broad and flexible. The 2007 strategy for prepandemic planning was developed with the assumption that the next influenza pandemic would be severe, like the 1957 pandemic, which was characterized by high transmissibility and medium clinical severity. When the 2007 strategy was developed, the primary concern was that a pandemic virus might evolve from the highly pathogenic avian influenza A (H5N1) virus, a virus that reemerged in Asia in 2003 in domestic poultry and spread to Africa, the Middle East, and Europe among poultry, with sporadic zoonotic transmission (37). Moreover, CDC thought that this virus would most likely emerge overseas, providing the United States with time to prepare for a domestic response, including making use of prepandemic H5N1 vaccine in CDC's Strategic National Stockpile. Instead, the 2009 pandemic influenza A virus turned out to be a novel H1N1 virus that appears to have emerged in southern Mexico and was first identified in two persons in California (13). Although the 2009 H1N1 pandemic in the United States was moderate in terms of overall morbidity and mortality among the U.S. general population, severe outcomes from H1N1pdm09 virus infection were more common among children, young adults, and specific groups at risk for serious complications (e.g., pregnant women) than among older adults (Box 1). Although the emergence of the H1N1pdm09 virus prompted development of pandemic vaccines, a pandemic vaccine was not available until October 2009, 6 months after the initial report that identified the pandemic virus. In addition, another 2 months were required (December 2009) for sufficient stocks to be manufactured, distributed, and available to vaccinate several population groups, including school-aged children and persons living with or caring for infants aged <6 months, as recommended by the Advisory Committee on Immunization Practices (ACIP). † Even though work is ongoing to accelerate † In July 2009, ACIP recommended vaccination of several population groups, including children aged 6 months through 18 years because cases of H1N1 influenza had occurred in children who were in close contact with each other in school and child care settings (https://www.cdc.gov/h1n1flu/vaccination/acip.htm). # BOX 1. Lessons learned from the 2009 H1N1 pandemic response The 2009 H1N1 pandemic demonstrated the unpredictable nature of influenza viruses and showed that prepandemic planning must be broad and flexible. Lessons learned during the 2009 H1N1 pandemic response from the United States and other affected countries follow. # H1N1 and children The epidemiology of pandemic influenza might be different from the epidemiology of seasonal influenza; therefore, different populations might be disproportionately affected. • An estimated 43-89 million people in the United States were infected with H1N1pdm09 virus during April 2009-April 2010, and approximately 12,000 people died (3). • Severe outcomes of influenza include complications that require hospitalization and can be fatal (e.g., pneumonia or bronchitis). Severe outcomes from H1N1pdm09 virus infection were most common among children, young adults, and specific groups at high risk for complications (e.g., pregnant women) rather than in adults aged ≥65 years, the group most at risk from seasonal influenza (4)(5)(6)(7). Over the course of the pandemic, an estimated 86,000 children were hospitalized in the United States, which is 2-3 times the number admitted during a typical influenza season (5). The number of deaths among children also was more than twice as high as during a regular influenza season. • On August 28, 2009, the Advisory Committee on Immunization Practices recommended that children be placed higher on the priority list for receiving the monovalent H1N1 vaccine, which became available in October 2009 (8). • Children at risk for severe outcomes from the H1N1pdm09 virus (and from any influenza virus) included those with underlying health conditions such as asthma, diabetes, obesity, or heart, lung, or neurologic diseases. Approximately 60% of hospitalized children had one or more of these conditions, compared with 80% of hospitalized adults (5). Infants born to mothers infected with the H1N1pdm09 virus also might have been at risk, as suggested by U.S. and Canadian studies which found that infants whose mothers received the H1N1 vaccine were less likely to be small for their gestational age or delivered preterm (9,10). # Public health tools to assess pandemic severity and guide NPI selection The 2007 Pandemic Severity Index had limited usefulness because attack rates and case-fatality ratios were difficult to measure and imprecise early in the pandemic. • The earliest available data on attack rates and casefatality ratios suggested that the 2009 H1N1 pandemic virus was highly transmissible and caused severe outcomes. However, the cases being reported overestimated severity because they were primarily derived from mortality data. On the basis of this initial information and continued reports of cases of disease with severe outcomes in Mexico, including deaths among previously healthy young adults (11), CDC recommended that communities with laboratory-confirmed cases of H1N1pdm09 virus consider closing child care facilities and schools, depending on the extent and severity of illness (12). CDC also recommended other NPIs described in the 2007 strategy, including voluntary home isolation for ill persons (i.e., staying home when ill) and voluntary home quarantine for exposed household members (i.e., staying home when a household member is ill). • Within 12 days of recognition of the emerging pandemic, the national influenza surveillance system generated sufficient data for a refined assessment. -From April 23, 2009, when H1N1pdm09 virus was detected in California ( 13 # NPIs and influenza transmission Well-established methods to prevent seasonal influenza transmission, such as hand hygiene promotion, also were effective in pandemic influenza settings to prevent the spread of H1N1pdm09 virus in some communities. • Hand hygiene. A randomized trial, conducted over 12 weeks in 60 elementary schools in Cairo, Egypt, during the 2009 H1N1 pandemic, demonstrated a 47% reduction in confirmed cases of influenza after twice-daily hand washing and health hygiene instruction in comparison with a control group that did not receive health hygiene instruction or have access to soap and hand-drying materials (16). This study demonstrated the effects of hand washing on laboratory-confirmed influenza in a population of persons that typically have little or no access to soap or hand-drying materials and among whom frequent hand washing is not standard. (20,22). In the United States, schools in Georgia that shortened school days had less absenteeism due to severe respiratory illness (23). Additional assessments are needed to determine the value of combining voluntary home quarantine with antiviral chemoprophylaxis. • Although the 2007 strategy suggested that communities consider combining voluntary home quarantine with prophylactic use of antiviral medications, assuming a feasible means of distribution, HHS did not adopt antiviral chemoprophylaxis as its official policy because of concerns about insufficient supplies and drug resistance. • During the 2009 H1N1 pandemic, antiviral chemoprophylaxis of exposed persons contained the spread of the disease, along with the implementation of social distancing measures, in a few small, welldefined settings, including a summer camp (24) and a BOX 1. (Continued) Lessons learned from the 2009 H1N1 pandemic response cruise ship (25). Moreover, an observational cohort study of 259 households in the United Kingdom found that administration of antiviral medications to 285 confirmed patients and their 761 close contacts was very effective (92%) in preventing household transmission (26). • Although limited, the H1N1pdm09 experience suggests that antiviral chemoprophylaxis might be recommended in the future in some settings as an adjunct to selfquarantine, assuming that additional antiviral medications are on the market, providing more treatment choices and making the emergence of drug resistance less of a concern. However, this recommendation would require much greater quantities of antiviral medications, even if no new products are developed, to ensure sufficient supplies. # Mobilizing the public Most members of the public complied with public health recommendations regarding hand hygiene and social distancing. • The Harvard Opinion Research Program conducted 13 polls on the response of the U.S. public during the 2009-2010 pandemic, including the response of the general public, pregnant women, new mothers, parents, and businesses. These randomized telephone polls found the following: -A total of 59% of 1,067 Americans reported washing their hands or using hand sanitizer more frequently during the 2009 H1N1 pandemic (27). A total of 25% avoided places where numerous people tend to gather, such as sporting events, malls, or public transportation. -Most (85%) of 514 pregnant women washed or sanitized their hands more frequently to reduce the chance of infection with H1N1pdm09 virus (27). A total of 68% reported taking steps to avoid proximity to someone who had influenza-like symptoms, and 31% avoided mass gathering places. Most (91%) of 526 new mothers also washed or sanitized their hands more frequently, and 81% took steps to avoid being near someone who had influenza-like symptoms. School-related NPIs, including school closures and dismissals, were acceptable and feasible. • According to a Harvard Opinion Research Program poll of 523 parents from 39 U.S. states whose child care center or school closed temporarily in response to the 2009 H1N1 pandemic, 90% of parents agreed with the dismissal decision, and 85% believed the dismissal reduced influenza transmission (27,28). -A total of 75% of parents who responded stated that the dismissal was not a problem, and 3% stated it was a major problem. Approximately 20% of parents reported that an adult in the household missed work because of the dismissal, and 19% had a child who missed a free or reduced-cost lunch. Of these, 2% and <1%, respectively, said missing work and missing lunch were major problems. -Most of the 523 parents polled believed that at least one of the following factors was a major reason the institution had closed: 1) to keep children apart and reduce the chance they would infect each other (81%), 2) because the school decided cleaning the building and surfaces that children touch was important for reducing the spread of the illness (73%), and 3) because the school or child care center could not operate effectively when numerous students were absent (58%). • A study conducted through an online survey of school principals showed that implementing NPIs in public schools in New York City, New York, was feasible during the 2009 H1N1 pandemic (29). Schools successfully implemented respiratory etiquette education, handhygiene measures, and environmental measures and isolated ill students. Another online survey found that the majority of public schools in Georgia also were able to successfully implement both personal and community NPIs recommended by CDC (23). Public health practitioners should be prepared to explain that the initial pandemic guidance might change if a pandemic is more or less severe than initially assessed. • Within 12 days of recognizing the emerging pandemic on April 23, 2009, CDC updated its initial guidance on NPIs (issued on May 1, 2009) on May 5, 2009, on the basis of more complete and robust data that suggested that the majority of U.S. cases were less severe than those reported from Mexico. • Certain public health departments reported difficulties in communicating the updated guidance on school closures to their communities, especially communities that were planning to implement school closures or had already done so (30,31). • The H1N1pdm09 experience with school closures suggests the need to coordinate and harmonize school closure policies across jurisdictions and to proactively communicate and explain any jurisdictional differences. Public engagement, community preparedness, and trust in government action are important for successful NPI implementation during a pandemic. • Practical obstacles to NPI implementation that required community-level solutions included 1) ill persons going to work because they lacked unpaid leave (32), 2) lack of clarity about decision-making authority to close schools for public health reasons in some jurisdictions (30,33), and 3) lack of access to clean water, soap, or hand sanitizer in some workplaces. the pace of development, distribution, and administration of a vaccine during future pandemics, this experience reaffirmed the importance of the use of NPIs in the early stages of a pandemic before a well-matched vaccine is widely available (i.e., vaccines produced using a virus that is very similar to the circulating virus). Another lesson learned about NPI implementation during the 2009 H1N1 pandemic was that rapidly changing guidance can create confusion and difficulties during implementation (Box 1) (30,31). Nevertheless, field studies found that schoolrelated NPIs, including school closures recommended to mitigate the impact of the 2009 H1N1 pandemic during spring 2009, were considered acceptable and feasible for most parents and caregivers, even when parents had to miss work and in the absence of free or reduced-cost school lunches for students (28,(38)(39)(40)(41). Other interventions that reduced the spread of H1N1pdm09 virus in some communities included hand hygiene (42), regularly scheduled school summer breaks (19), and social distancing measures, such as cancelling mass gatherings and closing public places (22). # Community Engagement The 2009 H1N1 pandemic underscored that effective prepandemic planning requires the involvement of public health and local leaders, employers, organizations, and stakeholders and is essential to ensure timely and effective use of NPIs to limit disease spread during a pandemic (Box 2). Effective use of NPIs depends on the acceptance and participation of individual persons who implement personal protective measures and of communities that implement communitywide measures such as temporary school closures (https://www.cdc.gov/phpr/ capabilities/DSLR_capabilities_July.pdf ). The 2007 guidance took into account the results of a 2006 opinion poll conducted with a representative national sample of 1,697 adults aged ≥18 years. The results indicated that when faced with an outbreak of pandemic influenza, the majority of persons in the United States would be willing to make major changes in their lives and cooperate with public health recommendations on the use of NPIs (http://archive.sph.harvard.edu/pressreleases/2006-releases/press10262006.html). Findings were # BOX 2. Principles of community engagement # Planning Before initiating a community engagement effort, consider the following: 1. Be clear about the purpose or goals of the engagement effort and the relevant populations and communities. 2. Become knowledgeable about the community's culture, economic conditions, social networks, political and power structures, norms and values, demographic trends, history, and experience with efforts by outside groups to engage it in various programs. Learn about the community's perceptions of those initiating the engagement activities. # Initiation For engagement to occur, the following steps are necessary: 3. Go to the community, establish relationships, build trust, work with the formal and informal leaders, and seek commitment from community organizations and leaders to create processes for mobilizing the community. 4. Remember and accept that collective selfdetermination is the responsibility and right of all people in a community. No external entity should assume the ability to bestow on a community the power to act in its own self-interest. # Implementation For engagement to succeed, consider the following: 5. Partnering with the community is necessary to create change and improve health. 6. All aspects of community engagement must recognize and respect the diversity of the community. Awareness of the various cultures of a community and other factors affecting diversity must be paramount in planning, designing, and implementing approaches to engaging a community. 7. Community engagement can only be sustained by identifying and mobilizing community assets and strengths and by developing the community's capacity and resources to make decisions and take action. 8. Organizations that would like to involve a community and those seeking to effect change must be prepared to release control of actions or interventions to the community and be flexible enough to meet changing needs. 9. Community collaboration requires long-term commitment by the engaging organizations and its partners. For example, in 2006, 85% of the respondents said that they and all members of their household would stay home for 7-10 days if another household member were ill with pandemic influenza. The H1N1 opinion polls also identified barriers to implementation of NPIs among persons and communities (e.g., the ability to stay home when ill, job security, and income protection) (https://www. hsph.harvard.edu/horp/project-on-the-public-response-to-h1n1). States and localities could establish local planning councils or hold public engagement meetings that address these and other issues related to public health preparedness, pandemic education, and planning. States and local communities also can draw on planning guidance provided in the CDC Public Health Preparedness Capabilities: National Standards for State and Local Planning, which lists NPIs as one of 15 capabilities (https://www.cdc. gov/phpr/capabilities/DSLR_capabilities_July.pdf). Additional information about pandemic influenza and NPI community engagement is available (supplementary Chapter 1 https://stacks. cdc.gov/view/cdc/44313). # New Tools for Prepandemic Planning and Pandemic Assessment Novel Influenza Virus Pandemic Intervals In 2014, CDC updated its 2008 guidance on pandemic intervals to include six intervals that describe influenza pandemic progression in a way that supports flexible prepandemic preparedness and response. The intervals include 1) investigation of novel influenza cases, 2) recognition of potential for ongoing transmission, 3) initiation, 4) acceleration, 5) deceleration of the pandemic wave, and 6) preparation for a future pandemic wave (43). These intervals can be used during prepandemic planning and can serve as a platform for public health decision-making and actions during the beginning of a potential influenza pandemic. Each interval is associated with particular response activities, including implementation of select NPIs during the initiation and acceleration intervals and coordinated discontinuation of select community-level NPIs reserved for pandemics during the deceleration interval (Figure 2) (Table 4). Although the six-interval framework describes the sequence of pandemic disease evolution over time, the framework does not characterize the transmissibility of the virus or the clinical severity of the outbreak. Therefore, CDC has developed additional tools for pandemic planning and response, including the Influenza Risk Assessment Tool (supplementary Chapter 2 https://stacks.cdc.gov/view/ cdc/44313); https://www.cdc.gov/flu/pandemic-resources/ tools/risk-assessment.htm) and the Pandemic Severity Assessment Framework (PSAF). Additional information about the pandemic intervals is available (supplementary Chapter 2 https://stacks.cdc.gov/view/cdc/44313). # Pandemic Severity Assessment Framework An influenza pandemic can range from mild to extremely severe in terms of clinical severity and transmission rate. When a pandemic emerges, public health authorities should assess its projected impact and recommend rapid action to reduce virus transmission, protect populations at high risk for complications, and minimize societal disruption. As observed during the 2009 H1N1 pandemic response, attack rates and case-fatality ratios can be difficult to measure early in a pandemic because of variations in care-seeking behavior and testing practices; not everyone seeks care for their illness, and not everyone is tested and receives a diagnosis of pandemic influenza. As a result, severe cases might be more likely to be reported, resulting in an overestimate of the casehospitalization or case-fatality ratio. Tools for prepandemic planning have been updated and augmented based on that experience, and the Pandemic Severity Index in the 2007 guidance has been replaced with PSAF. PSAF uses multiple clinical and epidemiologic indicators to provide a more comprehensive assessment of the transmissibility and clinical severity of an emerging pandemic. Whereas the Pandemic Severity Index was based on the assumption that a future pandemic would cause an illness rate of 30% in the U.S. population and relied on an assessment of casefatality ratios to determine severity of an evolving pandemic, PSAF incorporates multiple measures of clinical severity (e.g., case-fatality ratios, case-hospitalization ratios, and deaths-hospitalizations ratios) and viral transmissibility (e.g., secondary household attack rates, school attack rates, workplace attack rates, community attack rates, or all of these, as well as rates of emergency department and outpatient visits for ILI) (44). When a pandemic begins, in the United States or anywhere in the world, CDC makes an initial assessment of viral transmissibility and clinical severity on the basis of these multiple PSAF measures (Table 5) (44). On the basis of the initial assessment, CDC recommends that affected U.S. jurisdictions respond (and other jurisdictions prepare to respond). Although data are limited during the initial 3-4 weeks after the emergence of a pandemic virus, these early data are compiled into a broad, preliminary assessment. CDC uses PSAF scores of viral transmissibility and clinical severity to place the pandemic within one of four assessment quadrants (Figure 3). Depending on the surveillance capacity in the location where the novel virus emerges and first spreads, 4-8 weeks or longer might be required to accrue sufficient data for a refined assessment of an evolving pandemic. Once data are available, the refined assessment is used to more precisely characterize the clinical severity and transmissibility of the pandemic virus (Figure 4) (Table 6). These initial and refined assessments of pandemic severity are used, in coordination with state and local public health partners, to guide the use of NPI measures. Additional information about PSAF is available (supplementary Chapter 2 https://stacks.cdc.gov/ view/cdc/44313). # Methods # Guidelines Development Process This 2017 update consists of three separate documents: this report and two supplementary documents (https://stacks.cdc.gov/ view/cdc/44313 and https://stacks.cdc.gov/view/cdc/44314). This report provides a brief introduction to pandemic influenza and NPIs; describes the 2007 strategy and the purpose of the updates, particularly after the 2009 H1N1 pandemic; outlines the methods used to develop this update and describe the evidence considered for NPI use during an influenza pandemic; presents CDC's NPI recommendations; and discusses key areas for further NPI research. The two supplementary documents contain more specific and detailed information about pandemic influenza and NPIs. One document (Technical Report 1 https://stacks.cdc.gov/view/ cdc/44313) is divided into chapters and provides an introduction to and overview of NPIs, a description of the new tools developed for pandemic influenza planning and assessment, and a toolbox describing the NPI evidence base, implementation issues, and research gaps. The second document (Technical Report 2 https:// stacks.cdc.gov/view/cdc/44314) consists of several appendices that provide a glossary of terms, a detailed description of the methods used for developing the NPI recommendations, a comprehensive summary table of the NPI body of evidence, and a list of tools and resources for pandemic influenza planning and preparedness. This 2017 update was developed through collaboration involving input from several sources, including peer-reviewed scientific literature, current research, CDC subject-matter experts, and external stakeholders (e.g., federal agencies, public health officials, and business and education partners). Development of these updated guidelines involved participation by multiple CDC groups (e.g., the Community Mitigation Guidelines Work Group and the coordination, abstraction, and consultation teams), as well as a group of external stakeholders who reviewed a document, summarizing the overall direction and key principles and concepts of the guidelines. Input from the work group members, subject-matter experts, and stakeholders was considered and incorporated during the creation of the 2017 planning guidelines. The guidelines were developed during October 2011-October 2016 (Table 7). The complete list of contributors and their roles in the process are available (supplementary Appendix 2 https://stacks.cdc.gov/ view/cdc/44314). # FIGURE 2. Preparedness and response framework for novel influenza A virus pandemics, with CDC intervals and World Health Organization phases # Use of NPIs During Influenza Pandemics Ten years ago, when the 2007 strategy was being developed, the evidence for the use of NPIs during influenza pandemics was limited, consisting primarily of historical analyses and contemporary observations rather than controlled scientific studies (45,46). These analyses and observations were supplemented by modeling studies that used historical data to evaluate NPI use in U.S. cities during the 1918 pandemic (47,48) or that simulated pandemic scenarios as they might occur in the future (49)(50)(51). The simulations, like the historical analyses, generally supported the effectiveness of early, targeted, and phased-in (layered) use of multiple NPIs § in preventing spread of disease, especially when used § The pandemic mitigation framework proposed in the 2007 strategy was based on the early, targeted, and layered use of multiple NPIs. NPIs should be initiated early in a pandemic before local epidemics grow exponentially, be targeted toward those at the nexus of transmission (in affected areas where the novel virus circulates), and be layered together to reduce community transmission as much as possible. A list of NPIs that are recommended at all times and those that are reserved for pandemics is provided (Table 1). in combination with antiviral medications (46,49). This conclusion seemed plausible, confirming the presumption that individual, partially effective NPIs act in complementary ways to decrease various factors that facilitate the spread of influenza under different circumstances and settings (52). However, the NPI modeling studies had substantial limitations, including lack of data supporting assumptions about the effectiveness of individual NPIs, economic and social costs of NPIs, and likely rates of compliance (46,49,53). In 2016, the evidence supporting the effectiveness of NPIs, both when used alone and in combination, was more substantial and included controlled studies evaluating different NPIs. New modeling studies based on data collected during the 2009 H1N1 pandemic response also became available. This update is based on approximately 191 journal articles written in English and published from 1990 through September 2016 that focused on personal protective measures in general; school closure effectiveness and unintended consequences; school absenteeism; spread of disease in child care facilities, colleges, and universities; impact of mass gatherings; and role and impact of NPIs in non-health care workplace settings. These articles were reviewed, abstracted, and synthesized. To assess the strength of the evidence, a five-step NPI rating scheme process was developed by adapting and applying the approach of the Guide to Community Preventive Services (The Community Guide) (https://www.thecommunityguide.org). Additional information about the NPI rating scheme process is available (supplementary Appendices 3 and 4 https://stacks.cdc.gov/ view/cdc/44314). The selected articles were organized into three groups: 1) personal NPIs (personal protective measures for everyday use and personal protective measures reserved for influenza pandemics); 2) community NPIs (social distancing measures and school closures and dismissals); and 3) environmental NPIs (surface cleaning measures) (Table 8). Key steps included selecting the relevant literature, abstracting and synthesizing the evidence, and assessing the evidence quality (both individual study quality and quality of the body of evidence). A recommendation was formulated based on the evidence of effectiveness for each NPI. The strength of NPI recommendations took into consideration the effectiveness of the intervention, the ease of implementation (including unwanted consequences), and the importance of the intervention as a public health strategy. Additional information about the NPI evidence base is available (supplementary Chapter 3 https://stacks.cdc.gov/view/ cdc/44313 and supplementary Appendix 5 https://stacks. cdc.gov/view/cdc/44314). # Recommendations on the Use of Personal, Community, and Environmental NPIs NPIs routinely recommended for prevention of respiratory virus transmission, such as seasonal influenza, include personal protective measures for everyday use (i.e., voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene) and environmental surface cleaning measures (i.e., routine cleaning of frequently touched surfaces and objects). During an influenza pandemic, these NPIs are recommended regardless of the pandemic severity level. Additional personal and community NPIs also might be recommended. Personal protective measures reserved for pandemics include voluntary home quarantine of exposed household members and use of face masks in community settings when ill. Community NPIs might include temporary closures or dismissals of child care facilities and schools with students in grades kindergarten through 12 (K-12), as well as other social distancing measures that increase the physical space between people (e.g., workplace measures such as replacing in-person meetings with teleconferences or modifying, postponing, or cancelling mass gatherings) (Figure 5) (Table 1). Local decisions about NPI selection and timing involve consideration of overall pandemic severity and local conditions (1) and require flexibility and possible modifications as the pandemic progresses and new information becomes available. Updated recommendations on the use of NPIs to help slow the spread and decrease the impact of an influenza pandemic are provided, as is information on the rationale for using each NPI as part of a comprehensive public health strategy for pandemic response and the appropriate settings and use for each NPI according to the severity of the pandemic (Table 9). ¶ The recommendations that follow are considered an update to the existing recommendations in the 2007 guidance because the same set of NPIs has been maintained and recommended for use early in a pandemic. However, the difference between the guidance issued in 2007 and in 2017 is the clear delineation of NPIs into two categories: 1) NPIs recommended at all times and 2) NPIs recommended for use only during pandemics (based on the level of pandemic severity and local conditions). The 2017 update also provides additional evidence to support the NPI recommendations. ¶ Influenza pandemics can range from mild to extreme in terms of rates of viral transmission and clinical severity, as described in the four prepandemic planning scenarios developed by CDC. A very severe or extreme pandemic, such as the 1918 pandemic, is characterized by high to very high transmissibility and clinical severity. A severe pandemic, such as the pandemics of 1957 and 1968, is characterized by high transmissibility and low to medium clinical severity. A mild or moderate pandemic, such as the 2009 pandemic, is characterized by low to medium transmissibility and clinical severity. # Personal NPIs NPIs that can be implemented by individual persons include the following: • Personal protective measures for everyday use: These include voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene. # • Personal protective measures reserved for pandemics: These include voluntary home quarantine of exposed household members and use of face masks in community settings when ill. # Personal Protective Measures for Everyday Use Personal protective measures are preventive actions that can be used daily to slow the spread of respiratory viruses (https:// www.cdc.gov/nonpharmaceutical-interventions/personal/ index.html; supplementary Chapter 3 https://stacks.cdc.gov/ view/cdc/44313). These measures include the following: • Voluntary home isolation (i.e., staying home when ill or self-isolation): Persons with influenza stay home for at least 24 hours after a fever or signs of a fever (chills, sweating, and feeling warm or flushed)** are gone (https://www.cdc.gov/flu/protect/preventing. htm), except to obtain medical care or other necessities. † † To ensure that the fever is gone, patients' temperature should be measured in the absence of medication that lowers fever (e.g., acetaminophen or ibuprofen). In addition to fever, common influenza symptoms include cough or chest discomfort, muscle or body aches, headache, and fatigue. Rationale for use as a public health strategy. Most persons infected with an influenza virus might become infectious 1 day before the onset of symptoms and remain infectious up to 5-7 days after becoming ill (54,55). However, studies found that infants and immunocompromised persons might shed influenza viruses for prolonged periods (up to 21 days and a mean of 19 days, respectively) (56,57). The effectiveness of personal protective measures depends on their ability to interrupt virus transmission from one person to another. Voluntary home isolation, which is a form of patient isolation, prevents an ill person from infecting other people outside of their household. § § Respiratory etiquette reduces the dispersion of droplets contaminated with influenza virus being propelled through the air by coughing or sneezing. Hand hygiene reduces the transmission of influenza viruses that occurs when one person touches another (e.g., with a contaminated hand). Contamination also can occur through self-inoculation via fomite transmission (indirect contact transmission) when persons touch a contaminated surface and then touch their nose with a contaminated hand. A study conducted in households in Bangkok, Thailand, found that increased handwashing reduced surface contamination with influenza virus, which lowered the potential for self-inoculation via fomite transmission (58). Additional studies found that influenza viruses can remain viable on the human hand for roughly 3-5 minutes (59) and that influenza viruses can remain on fingers for 30 minutes after contamination (60). * Colors transition from light to dark as the estimated number of deaths increases. Transmissibility: measured on a scale of 1-5 and includes school, workplace, and community attack rates, secondary household attack rates, school and/or workplace absenteeism rates, and rates of emergency department and outpatient visits for influenza-like illness. Clinical severity: measured on a scale of 1-7 and includes case-fatality ratios, case-hospitalization ratios, and deaths-hospitalizations ratios. # Settings and use. Voluntary home isolation involves persons remaining at home when ill with influenza. Respiratory etiquette and hand hygiene are recommended in homes and in all other community settings, including schools and workplaces. All three personal protective measures are considered everyday preventive actions that should be implemented year-round but that are especially important during annual influenza seasons and influenza pandemics (Table 10). Use of these personal protective measures might result in some secondary (unintended or unwanted) consequences (e.g., concerns about job security for ill persons who lack paid sick leave or skin irritations due to frequent hand washing). # CDC recommendations Voluntary home isolation: CDC recommends voluntary home isolation of ill persons (staying home when ill) year-round and especially during annual influenza seasons and influenza pandemics. Respiratory etiquette and hand hygiene: CDC recommends respiratory etiquette and hand hygiene in all community settings, including homes, child care facilities, schools, workplaces, and other places where people gather, year-round and especially during annual influenza seasons and influenza pandemics. Voluntary home quarantine of non-ill household members of persons with influenza (also called self-quarantine or household quarantine) helps prevent disease spread from households to schools, workplaces, and other households because those household members have been exposed to the influenza virus. Exposed household members of symptomatic persons (with confirmed or probable pandemic influenza) should stay home for up to 3 days (the estimated incubation period for seasonal influenza) (61) starting from their initial contact with the ill person. If they then become ill, they should practice voluntary home isolation (i.e., they should remain at home until recovered as discussed previously; https://www.cdc.gov/quarantine/ index.html). For certain exposed household members (e.g., those at high risk for influenza complications or with severe immune deficiencies), guidelines should be consulted regarding the prophylactic use of antiviral medications (https://www.cdc. gov/flu/professionals/antivirals/index.htm). Rationale for use as a public health strategy. Voluntary home quarantine might help slow a pandemic by reducing community transmission from households with a person who has influenza because the exposed household members are at increased risk for infection. Furthermore, certain infected (but not yet symptomatic) household members could begin shedding influenza virus at least a day before exhibiting symptoms and could infect friends, neighbors, and others in the community (e.g., at school or work) before becoming symptomatic. Therefore, all members of a household with a symptomatic person (with confirmed or probable pandemic influenza) might be asked to stay home for a specified period of time (up to 3 days) to assess for early signs and symptoms of pandemic influenza virus infection. If other household members become ill during this period, then the time for voluntary home quarantine might need to be extended for another incubation period. The evidence for voluntary home quarantine, particularly when used in combination with other NPIs, includes a systematic literature review, historical analyses of the 1918 pandemic, and mathematical modeling studies (supplementary Chapter 3 https://stacks.cdc.gov/view/cdc/44313 and supplementary Appendix 5 https://stacks.cdc.gov/view/ cdc/44314). Settings and use. Voluntary home quarantine of exposed household members might be recommended during severe, very severe, or extreme influenza pandemics (Table 10) to help reduce the chance of transmitting the virus to others outside of the household. Advance planning is needed to minimize potential secondary consequences for persons who have special cultural, economic, legal, mental, physical, or social status needs (e.g., older adults who depend on necessary community-based services such as home-delivered meals and transportation to health care services). Other secondary consequences might include missed work and loss of income for persons whose employers do not have paid sick leave policies that include home quarantine during pandemics. # CDC recommendations Voluntary home quarantine: CDC might recommend voluntary home quarantine of exposed household members as a personal protective measure during severe, very severe, or extreme influenza pandemics in combination with other personal protective measures such as respiratory etiquette and hand hygiene. If a member of the household is symptomatic with confirmed or probable pandemic influenza, then all members of the household should stay home for up to 3 days (the estimated incubation period for seasonal influenza), ¶ ¶ starting from their initial contact with the ill person, to monitor for influenza symptoms. # Use of Face Masks in Community Settings Face masks (disposable surgical, medical, or dental procedure masks) are widely used by health care workers to prevent respiratory infections both in health care workers and patients. They also might be worn by ill persons during severe, very severe, or extreme pandemics to prevent spread of influenza to household members and others in the community. However, little evidence supports the use of face masks by well persons in community settings, although some trials conducted during the 2009 H1N1 pandemic found that early combined use of face masks and other NPIs (such as hand hygiene) might be effective (supplementary Chapter 3 https://stacks.cdc.gov/ view/cdc/44313). Rationale for use as a public health strategy. Face masks provide a physical barrier that prevents the transmission of influenza viruses from an ill person to a well person by blocking large-particle respiratory droplets propelled by coughing or sneezing. Face mask use by well persons is not routinely needed in most situations to prevent acquiring the influenza virus. However, use of face masks by well persons ¶ ¶ If the incubation period for the next pandemic were shorter or longer than 3 days, CDC would amend the recommendation accordingly. might be beneficial in certain situations (e.g., when persons at high risk for influenza complications cannot avoid crowded settings or parents are caring for ill children at home). Face mask use by well persons also might reduce self-inoculation (e.g., touching the nose with the hand after touching a contaminated surface). Settings and use. Disposable surgical, medical, and dental procedure masks are used widely in health care settings to prevent exposure to respiratory infections. Face masks have few secondary consequences (e.g., discomfort or difficulty breathing) when worn properly and consistently, and face masks sized for children are available. (Additional information about face masks is available at https://www. fda.gov/medicaldevices/productsandmedicalprocedures/ generalhospitaldevicesandsupplies/personalprotectiveequipment/ ucm055977.htm and https://www.osha.gov/Publications/ respirators-vs-surgicalmasks-factsheet.html.) # FIGURE 5. Phased addition of nonpharmaceutical interventions to prevent the spread of pandemic influenza in communities # CDC recommendations Use of face masks by ill persons: CDC might recommend the use of face masks by ill persons as a source control measure during severe, very severe, or extreme influenza pandemics when crowded community settings cannot be avoided (e.g., when adults and children with influenza symptoms seek medical attention) or when ill persons are in close contact with others (e.g., when symptomatic persons share common spaces with other household members or symptomatic postpartum women care for and nurse their infants). Some evidence indicates that face mask use by ill persons might protect others from infection. Use of face masks by well persons: CDC does not routinely recommend the use of face masks by well persons in the home or other community settings as a means of avoiding infection during influenza pandemics except under special, high-risk circumstances (https://www.cdc.gov/flu/ professionals/infectioncontrol/maskguidance.htm). For example, during a severe pandemic, pregnant women and other persons at high risk for influenza complications might use face masks if unable to avoid crowded settings, especially if no pandemic vaccine is available. In addition, persons caring for ill family members at home (e.g., a parent of a child exhibiting influenza symptoms) might use face masks to avoid infection when in close contact with a patient, just as health care personnel wear masks in health care settings. # Community NPIs NPIs that can be implemented by communities include the following: • School closures and dismissals: These include temporary closures and dismissals of child care facilities, K-12 schools, and institutions of higher education. • Social distancing measures: These include measures for schools, workplaces, and mass gatherings. # School Closures and Dismissals In the event of a pandemic, state and local public health authorities play an important role in protecting the school community and should establish and maintain partnerships with district and school leaders, school emergency operations planning teams, and local municipality leaders (e.g., mayors). Public health authorities are a credible source of information, have multiple (often free) resources available for information awareness campaigns, and provide guidance for increasing school response measures. Depending on the severity of the pandemic, these measures might range from everyday preventive actions to preemptive, coordinated school closures and dismissals. A school closure means closing a school and sending all the students and staff members home, whereas during a school dismissal, a school might stay open for staff members while the children stay home. Preemptive school dismissals can be used to disrupt transmission of influenza before many students and staff members become ill. Coordinated dismissals refer to the simultaneous or sequential closing of schools in a jurisdiction. Thus, preemptive, coordinated school closures and dismissals can be used early during an influenza pandemic to prevent virus transmission in schools and surrounding communities by reducing close contact among the following groups (supplementary Chapter 3 https:// stacks.cdc.gov/view/cdc/44313): • Children in child care centers and preschools • School-aged children and teens in K-12 schools • Young adults in institutions of higher education During a dismissal, the school facilities are kept open, which allows teachers to develop and deliver lessons and materials, thus maintaining continuity of teaching and learning, and allows other staff members to continue to provide services and help with additional response efforts. School closures and dismissals might be coupled with social distancing measures (e.g., cancelling sporting events and other mass gatherings) to reduce out-ofschool social contact among children when schools are closed. Rationale for use as a public health strategy. Preventing the spread of disease in educational settings among children and young adults reduces the risk for infection for these age groups and slows virus transmission in the community. Components of the strategy might include preemptive, coordinated school closures and dismissals implemented during the earliest stages of a pandemic, before many students and staff members become ill. Preemptive, coordinated dismissals can be implemented by the following facilities for the following reasons: • Child care facilities and K-12 schools -Children have higher influenza attack rates than adults (62) and are infectious for a longer period than adults (63,64). -Influenza transmission is common in schools and contributes to school absenteeism and parental absenteeism from work (65,66). -The presence of school-aged children in a household is a risk factor for influenza virus infection in families (62,65,67). -Social contact and mixing patterns among school-aged children differ substantially depending on the grade and school level, during various periods of the school day, between weekdays and weekends, and between regular school terms and holiday breaks (68)(69)(70)(71). Physical floor plans and intergrade activities (e.g., cafeteria size and lunch breaks) also can affect in-school social mixing (68). -Schoolchildren can introduce the influenza virus into a community, leading to increased rates of illness among their household or community contacts (72-74). • Institutions of higher education -Influenza outbreaks on college and university campuses typically have high attack rates (44%-73%) (75-78) and cause substantial morbidity (79,80). For example, during the 2009 H1N1 pandemic, influenza spread rapidly through a university campus within 2 weeks (81); on another residential campus, one infected freshman initiated an outbreak that resulted in 226 laboratory-confirmed cases. Freshmen were the main facilitators of the spread of the H1N1pdm09 virus because of their higher number and frequency of social contacts (82). -Influenza is more prevalent among residential students at boarding schools and colleges than among nonresidential students (78,83). -ILIs are common among college and university students and are associated with increased health care use, decreased health status, and impaired school performance (84). Implementation of preemptive, coordinated school closures and dismissals during an evolving influenza pandemic might have one or more of the following three public health objectives*: * Additional information on the use of preemptive, coordinated school closures and dismissals of different durations is available (supplementary Chapter 3 https://stacks.cdc.gov/view/cdc/44313). • Objective 1: To gain time for an initial assessment of transmissibility and clinical severity of the pandemic virus in the very early stage of its circulation in humans (closures for up to 2 weeks) • Objective 2: To slow down the spread of the pandemic virus in areas that are beginning to experience local outbreaks and thereby allow time for the local health care system to prepare additional resources for responding to increased demand for health care services (closures up to 6 weeks) • Objective 3: To allow time for pandemic vaccine production and distribution (closures up to 6 months) Two other types of school closures and dismissals might be implemented during a pandemic for public health or institutional reasons. These interventions do not slow disease spread in the community; therefore, they are not considered NPIs. They include the following: • Selective school closures and dismissals: These might be implemented by schools that serve students at high risk for complications from infection with influenza, † † † especially when transmission rates are high. For example, a school that serves children with certain medical conditions or pregnant teens might decide to close while other schools in the area remain open. In addition, some communities or early childhood programs might consider closing child care facilities to help decrease the spread of influenza among children aged <5 years. Selective dismissals are intended to protect persons at high risk for influenza rather than to help reduce virus transmission within the community. • Reactive school closures and dismissals: These might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. For example, a child care center might close because it is unable to operate under these conditions. Reactive dismissals, which might occur during outbreaks of seasonal influenza (85) and during pandemics (15), are unlikely to affect virus transmission because they typically take place after considerable, if not widespread, transmission has already occurred in the community. For example, a 4-day reactive closure in a western Kentucky school district did † † † Persons at high risk for influenza-related complications include children aged <5 years (and especially aged <2 years), adults aged ≥65 years, pregnant women, residents of nursing homes and other long-term care facilities, and American Indians/Alaska Natives. Those at high risk also include persons with asthma, neurological and neurodevelopmental conditions, chronic lung disease, and heart disease; disorders of the blood, endocrine system, kidney, or liver; metabolic disorders; and weakened immune systems from disease or medication. Two other groups at higher risk are persons aged <19 years who receive long-term aspirin therapy and those with extreme obesity (https:// www.cdc.gov/flu/about/disease/high_risk.htm). not reduce ILI transmission in the rural community (86). Similarly, closing 559 Michigan schools at least once during the fall wave (i.e., second wave) of the 2009 H1N1 pandemic had little effect on community levels of ILI (87). For more information about preparing for influenza and the different types of dismissals, see CDC websites regarding 1) child care facilities (https://www.cdc.gov/h1n1flu/childcare/ toolkit/pdf/childcare_toolkit.pdf ), 2) K-12 schools (https:// www.cdc.gov/h1n1flu/schools/toolkit/pdf/schoolflutoolkit.pdf), and 3) institutions of higher education (https://www.cdc.gov/ h1n1flu/institutions/toolkit/pdf/IHE_toolkit.pdf ). Settings and use. Preemptive, coordinated school closures and dismissals might be implemented at child care facilities, K-12 schools, and institutions of higher education. They are most likely to be implemented when an influenza pandemic is severe, very severe, or extreme (Table 10). Secondary consequences include missed work and loss of income for parents who stay home from work to care for their children and missed opportunities to vaccinate school-aged children rapidly unless other mechanisms are considered. # CDC recommendations School closures and dismissals: CDC might recommend the use of preemptive, coordinated school closures and dismissals during severe, very severe, or extreme influenza pandemics. This recommendation is in accord with the conclusions of the U.S. Community Preventive Services Task Force (https://www.thecommunityguide.org/findings/emergencypreparedness-and-response-school-dismissals-reduce-transmissionpandemic-influenza), which makes the following recommendations: • The task force recommends preemptive, coordinated school dismissals during a severe influenza pandemic. • The task force found insufficient evidence to recommend for or against preemptive, coordinated school dismissals during a mild or moderate influenza pandemic. In these instances, jurisdictions should make decisions that balance local benefits and potential harms. # Social Distancing Measures for Schools, Workplaces, and Mass Gatherings Social distancing measures can reduce virus transmission by decreasing the frequency and duration of social contact among persons of all ages. These measures are common-sense approaches to limiting face-to-face contact, which reduces person-to-person transmission. Rationale for use as a public health strategy. Social distancing measures that reduce opportunities for person-toperson virus transmission can help delay the spread and slow the exponential growth of a pandemic. The optimal strategy is to implement these measures simultaneously in places where persons gather. Although direct evidence is limited for the effectiveness of these measures, components of the strategy might include reducing social contacts at the following places: • Schools: Children have higher influenza attack rates than adults, and influenza transmission is common in schools. (93). An infected traveler attending a mass gathering might introduce influenza to a previously unaffected area, and a person who becomes infected at the event can further spread the infection after returning home (89,90,92,(94)(95)(96). Even when a circulating virus has a relatively low basic reproductive rate (R 0 ), intensely crowded settings might lead to high secondary attack rates (92). For example, during the 2013 Hajj (Islamic pilgrimage to Mecca) in Saudi Arabia, influenza A/H1N1 virus was found in only two Indonesians on arrival but spread to 25 persons from Africa, Central Asia, and Southeast Asia after the Hajj because of the extremely crowded conditions when performing rituals (97). Multiple social distancing measures can be implemented simultaneously. Although there is limited empirical evidence supporting the effectiveness of implementing any individual measure alone (other than school closures and dismissals), the evidence for implementing multiple social distancing measures in combination with other NPIs includes systematic literature reviews, historical analyses of the 1918 pandemic, and mathematical modeling studies (supplementary Chapter 3 https://stacks.cdc.gov/view/cdc/44313 and supplementary Appendix 5 https://stacks.cdc.gov/view/cdc/44314). Settings and use. Social distancing measures can be implemented in a range of community settings, including educational facilities, workplaces, and public places where people gather (e.g., parks, religious institutions, theaters, and sports arenas). The choice of social distancing measure depends on the severity of the pandemic (Table 10 # CDC recommendations Social distancing measures: Even though the evidence base for the effectiveness of some of these measures is limited, CDC might recommend the simultaneous use of multiple social distancing measures to help reduce the spread of influenza in community settings (e.g., schools, workplaces, and mass gatherings) during severe, very severe, or extreme influenza pandemics while minimizing the secondary consequences of the measures. Social distancing measures include the following: • Increasing the distance to at least 3 feet (98) between persons when possible might reduce person-to person transmission. This applies to apparently healthy persons without symptoms. In the event of a very severe or extreme pandemic, this recommended minimal distance between people might be increased. • Persons in community settings who show symptoms consistent with influenza and who might be infected with (probable) pandemic influenza should be separated from well persons as soon as practical, be sent home, and practice voluntary home isolation. # Environmental NPIs: Environmental Surface Cleaning Measures Environmental surface cleaning measures can help eliminate influenza viruses from frequently touched surfaces and objects, including tables, door knobs, toys, desks, and computer keyboards. These measures involve cleaning surfaces with detergent-based cleaners or disinfectants that have been registered with the Environmental Protection Agency. ¶ ¶ ¶ Rationale for use as a public health strategy. Although the percentage of influenza cases involving contact transmission (i.e., hand transfer of virus from contaminated objects to the eyes, nose, or mouth) is unknown, this mode of transmission is a recognized route of virus spread (99). The routine use of cleaning measures that eliminate viruses from contaminated surfaces might reduce the spread of influenza viruses (supplementary Chapter 3 https://stacks.cdc.gov/view/cdc/44313). ¶ ¶ ¶ Antimicrobial products registered for use against H1N1 influenza and other influenza A viruses on hard surfaces (https://archive.epa.gov/pesticides/ oppad001/web/pdf/influenza-a-product-list.pdf ). The rationale for and key concepts regarding the use of NPIs during influenza pandemics first presented in the 2007 guidance remain unchanged. Because production of a pandemic vaccine can take up to 6 months and antiviral medications might be prioritized for treatment, NPIs are likely to be the only prevention tools available early in a pandemic. Therefore, they are critical to slowing the spread of the pandemic influenza virus while a pandemic vaccine is under development. Like the 2007 strategy, this 2017 update affirms the importance of prepandemic planning and preparedness for use of NPIs during a pandemic response and recommends the early, targeted, and simultaneous implementation of multiple NPIs to decrease influenza virus transmission. Although community-level NPIs can help slow virus transmission, as supported by historical information (100), empirical observations (101), and mathematical modeling (102), these measures are likely to cause unwanted consequences by introducing new norms for social behavior (e.g., adopting precautionary health-protective behaviors such as limiting face-to-face contact with family and friends, only shopping for essential items, avoiding places where people congregate, or not using public transportation) (103), interrupting routine societal functions, and entailing additional costs. If an evolving influenza pandemic is characterized by high clinical severity, the benefits of deploying NPIs, including those with greater potential for secondary consequences, are likely to outweigh potential harms. The more difficult decision is determining how and when to implement the community-level NPIs that are more disruptive to society (e.g., temporary K-12 school closures) during pandemics of moderate severity. In each locality, the goal should be to implement NPIs early enough and long enough to maximize effectiveness while minimizing economic and social costs to ensure that NPIs are commensurate to the pandemic severity. # New Elements Added in 2017 New elements in this report, in addition to the evidencebased NPI recommendations, include a summary of key lessons learned from the 2009 H1N1 pandemic response (Box 1), information on community engagement and preparedness (supplementary Chapter 1 https://stacks.cdc.gov/view/ cdc/44313), and information on new or updated pandemic assessment tools (supplementary Chapter 2 https://stacks.cdc. gov/view/cdc/44313), which include the novel influenza virus pandemic intervals tool, the Influenza Risk Assessment Tool, and PSAF. As described in the following sections, this report also presents two additional planning tools designed to assist states and localities in ensuring pandemic preparedness. # Prepandemic Planning Scenarios for NPI Implementation According to Pandemic Severity During the initial stages of a pandemic, CDC will use the PSAF tool to prepare an initial assessment of pandemic severity that provides early guidance on use of NPIs to help slow the transmission of the novel virus. To facilitate the use of the initial assessment information by state and local health departments, CDC has provided a set of four prepandemic planning scenarios. Each scenario aligns with one of the four assessment quadrants (Figure 3) and provides information on past influenza pandemics for comparison (Table 9). These planning scenarios are designed to facilitate state and local prepandemic planning for NPI implementation according to pandemic severity (as classified by PSAF) (Figure 6) (Tables 9 and 10). After sufficient epidemiologic data are accrued and the refined assessment of pandemic severity becomes available, CDC will issue updated pandemic NPI guidance, which will be tailored more precisely to the specific pandemic. Additional information about the planning scenarios and phasing of NPIs is available (supplementary Chapter 2 https:// stacks.cdc.gov/view/cdc/44313). # Supplemental Prepandemic NPI Planning Guides The 2007 report included supplemental prepandemic NPI planning guides for individuals and families; child care programs, K-12 schools, and institutions of higher education; community-and faith-based organizations; and businesses and other workplaces. These guides have been updated, and two new guides have been developed for public health communicators and event planners that address NPI communications and modification, postponement, or cancellation of mass gatherings. These guides are intended to help operationalize the 2017 update and provide specific information that can assist different groups in their prepandemic planning and decision-making (https:// www.cdc.gov/nonpharmaceutical-interventions). # Future Research Although progress has been made since 2009 toward building the evidence base for use of NPIs to slow the spread of pandemic influenza, additional research is needed. For personal NPIs, areas for additional research include evaluating the effects of increased frequency and quality of hand washing on influenza virus transmission, determining the role of infected persons who are not symptomatic in the transmission of influenza viruses in households, and assessing the effectiveness, acceptability, and feasibility of recommending face mask use by well persons in community settings as a means of avoiding infection during a pandemic. For community NPIs, one topic for additional study involves gathering empirical data on social mixing patterns in schools and community settings. These data can be used to create high-fidelity, high-resolution mathematical models of virus transmission in these settings to facilitate data-driven evaluations of different social distancing measures. Another area of research for community NPIs involves assessing the potential secondary consequences (e.g., missed work) of select community-level measures (e.g., school closures) for families, communities, and society to assess the economic effects of these measures. For environmental NPIs, additional research is needed to better understand surface contamination (e.g., which types of surfaces are more likely to be contaminated with influenza viruses) and identify situations in which surface cleaning should be emphasized (e.g., in households with confirmed influenza cases versus in healthy households). Additional information about NPI research gaps is available (supplementary Chapter 3 https://stacks.cdc.gov/view/cdc/44313). # Conclusion The 2009 H1N1 pandemic provided an opportunity to test, in practice, the key concepts of NPIs in mitigating the impact of an influenza pandemic, just 2 years after the publication of the 2007 guidance. As the experience from 2009 has shown, NPIs can be a critical component of pandemic influenza mitigation. Although well-matched pandemic vaccines remain the main tool in reducing the risk of acquiring infection and in controlling the spread of a pandemic virus, vaccines might not be widely available for up to 6 months after the emergence of a pandemic influenza virus, given current vaccine production technology. Furthermore, as during the 2009 H1N1 pandemic, antiviral medications might be prioritized for treatment but not used for widespread chemoprophylaxis because of concerns about antiviral resistance and limited stockpiles of antiviral medications. Therefore, NPIs might be the only prevention tools readily available for persons and communities to help slow transmission of an influenza virus during the initial stages of a pandemic. However, individual NPIs might be only partially effective in limiting community transmission when implemented alone. Thus, the most efficient implementation involves early, targeted, and layered use of multiple NPIs (https://www.cdc.gov/flu/pandemic-resources/planningpreparedness/community-mitigation.html). In addition, some community-level NPIs that potentially have the greatest epidemiologic effects on pandemic influenza virus transmission in communities, most notably school closures and dismissals, also are most likely to be associated with secondary (unwanted) consequences (104). Hence, prepandemic planning, including engaging communities in planning activities well ahead of the next pandemic, is critical to enable appropriate local decisionmaking during the early stages of a pandemic. After the 2009 H1N1 pandemic, evidence on the effectiveness and feasibility of NPIs expanded substantially. A summary of the evidence in this 2017 update includes 2009 H1N1-related research (supplementary Appendix 5 https://stacks.cdc.gov/view/ cdc/44314). However, knowledge gaps remain and should be addressed by future research. Further updates of these guidelines will be developed and issued when significant new information and evidence emerges about the effectiveness and feasibility of NPIs in mitigating the impact of pandemic influenza. This interval is indicated by the identification of an animal case of influenza A subtype with potential implications for human health or identification of a human case of novel influenza A anywhere in the world. # Recognition: # Recognition of potential for ongoing transmission This interval is indicated by an increasing number of cases or clusters of novel influenza A in humans and by virus characteristics indicating potential for ongoing human-to-human transmission anywhere in the world. # Initiation: Initiation of the pandemic wave This interval is indicated by confirmation of cases of novel influenza A in humans and demonstration of efficient and sustained human-to-human transmission anywhere in the world. # Acceleration: Acceleration of the pandemic wave This interval is indicated by an increasing rate of novel influenza A cases identified nationally, indicating establishment in the country. # Deceleration: Deceleration of the pandemic wave This interval is indicated by decreasing rates of novel influenza A infection. # Preparation: Preparation for a future pandemic wave This interval is indicated by sporadic cases of novel influenza A infection and surveillance rates returning to baseline. # CDC Community Mitigation Guidelines Work Group Alexandra # Conflict of Interest The CDC contributors wish to disclose that they have no financial or competing interests or other relationships that would unfairly influence these CDC guidelines and recommendations. Voluntary home quarantine of exposed household members (staying home for up to 3 days † when a household member is ill) Reserved for pandemics Use of face masks in community settings when ill Community School closures and dismissals § Temporary, preemptive, coordinated dismissals of child care facilities and schools for grades K-12 ¶ Reserved for pandemics # Social distancing measures (examples) Dividing classes into smaller groups and creating opportunities for distance learning (e.g., via the internet or local television or radio stations) # Reserved for pandemics Telecommuting and remote-meeting options in workplaces Mass gathering modifications, postponements, or cancellations Environmental Environmental surface cleaning measures Routine cleaning of frequently touched surfaces and objects in homes, child care facilities, schools, and workplaces Recommended at all times Abbreviation: NPI = nonpharmaceutical intervention. * Personal, community, and environmental NPIs should be 1) initiated early in a pandemic before local epidemics begin to grow exponentially, 2) targeted toward the nexus of transmission (in affected areas where the novel virus circulates), and 3) layered together to reduce community transmission to the greatest extent possible. † If the incubation period for the next pandemic influenza virus is longer or shorter than 3 days, CDC will amend the recommendation. § A school closure involves closing a school and sending all the students and staff members home. A school dismissal could involve a school staying open for staff members while the students stay home. ¶ Preemptive, coordinated dismissals might be implemented early during a pandemic to decrease the spread of influenza before many students and staff members become ill. Selective dismissals might be implemented by schools that serve students at high risk for complications from infection with influenza. Reactive dismissals might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. Selective and reactive dismissals do not help slow disease transmission in the community. -Educational issues (e.g., missed educational opportunities or loss of free or subsidized school meals because of school dismissals) -Financial issues (e.g., workers who cannot afford to stay home when they are ill or to care for an ill family member because they do not have paid sick leave) -Legal issues (e.g., local jurisdictions that do not have the legal authority to close schools or cancel mass gatherings for public health reasons) -Workplace issues (e.g., access to clean water, soap, or hand sanitizer and flexible workplace policies or arrangements) # Development of the recommendations The approach used by the Guide to Community Preventive Services (The Community Guide) was adapted and applied to develop the NPI recommendations in the updated planning guidelines. # Planning guides To help operationalize the updated guidelines, six community mitigation prepandemic planning guides have been developed for key populations and decision-makers in community settings. During September-October 2015, before submission for CDC clearance, the National Public Health Information Coalition facilitated discussion of the planning guides by representatives of the public health, education, and business communities. The guides are part of a set of practical, user-friendly, and plain-language companion implementation materials. # Updating the guidelines The 2017 guidelines will be updated when new information warrants their modification. Abbreviation: NPI = nonpharmaceutical intervention. Abbreviation: NPI = nonpharmaceutical intervention. * Personal, community, and environmental NPIs should be 1) initiated early in a pandemic before local epidemics begin to grow exponentially, 2) targeted toward the nexus of transmission (in affected areas where the novel virus circulates), and 3) layered together to reduce community transmission to the greatest extent possible. † During a very severe or extreme pandemic (similar to the 1918 pandemic), CDC is likely to take an aggressive stance and recommend certain additional NPIs. § Recommended NPIs are the same for seasonal influenza. ¶ Preemptive, coordinated dismissals might be implemented early during a pandemic to decrease the spread of influenza before many students and staff members become ill. Selective dismissals might be implemented by schools that serve students at high risk for complications from infection with influenza. Reactive dismissals might be implemented when many students and staff members are ill and not attending school or when many students and staff members are arriving at school ill and being sent home. Selective and reactive dismissals do not help slow disease transmission in the community. ** Social distancing measures that reduce face-to-face contact in schools might include dividing classes into smaller groups of students who are spaced further apart from each other within the classroom. † † Social distancing measures that reduce face-to-face contact in workplaces might include offering telework and remote meeting options. Flexible sick leave policies should be implemented to encourage workers to stay home if needed. § § In all scenarios, mass gathering attendance during local outbreaks should be discouraged for persons at high risk for severe influenza-related complications.	None	None

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